PMID- 26475809 TI - Change in endothelial vascular reactivity and acute brain dysfunction during critical illness. PMID- 26475810 TI - Randomized controlled pilot study: does intraoperative clonidine reduce the incidence of post-hospitalization negative behaviour changes in children who are distressed during induction of general anaesthesia? PMID- 26475811 TI - Preoperative ward. PMID- 26475812 TI - Long-term outcome in kidney recipients from donors treated with hydroxyethylstarch 130/0.4 and hydroxyethylstarch 200/0.6. PMID- 26475813 TI - The Totaltrack: an initial evaluation. PMID- 26475814 TI - Memory and consciousness intertwingled. PMID- 26475815 TI - Enhanced recovery from surgery in the U.K.: an audit of the enhanced recovery partnership programme 2009-2012. PMID- 26475816 TI - Recommendations for perioperative oxygenation. PMID- 26475817 TI - A lowest oxygen level acceptable (LOLA) standard should apply to all ages. PMID- 26475818 TI - Reply: To PMID 25498579. PMID- 26475825 TI - Effects of Ethacrynic Acid Addition to Diet on Fitness and Development in the Psocid Liposcelis bostrychophila Badonnel. AB - Fertility life table provides a comprehensive description of arthropod population dynamics by the estimation of parameters about arthropod population growth potential. It can also clarify the sublethal effects of chemicals on insects. Ethacrynic acid (EA), an inhibitor of glutathione S-transferases, is a diuretic compound that has been confirmed to modulate drug resistance in organisms. In this study, the effects of EA on growth and development of Liposcelis bostrychophila Badonnel were investigated in the laboratory to explore the potential possibilities of EA as an active agent to manage insecticide-resistant psocids. The treatment of psocids was obtained by feeding on the routine diet containing 3% EA for three successive generations, and psocids on routine diet served as control. The results indicated that EA possessed some negative effects on the life-table parameters of the psocid in F1 and F2 generations. The addition of EA to diet stunted psocids growth by lengthening development time and increasing mortality with a greater effect in the F2 generation. In the third generation of psocids on EA diet, it seemed there was a return to normal. Psocid fitness was influenced by addition of EA to standard diet. Using rm values, the fitness for EA diet in F1, F2, and F3 compared with the counterpart of routine diet was calculated as 0.80, 0.74, and 0.87, respectively. PMID- 26475826 TI - Alightment of Spotted Wing Drosophila (Diptera: Drosophilidae) on Odorless Disks Varying in Color. AB - Methods for trapping spotted wing drosophila, Drosophila suzukii (Matsmura) (Diptera: Drosophilidae), have not yet been optimized for detecting this devastating pest of soft-skinned fruits. Here, we report outcomes of choice and no-choice laboratory bioassays quantifying the rates of spotted wing drosophila alightment on 5-cm-diameter sticky disks of various colors, but no fruit odors. Red, purple, and black disks captured the most spotted wing drosophila when presented against a white background. Male and female spotted wing drosophila responded identically in these tests. Significantly more D. suzukii were captured on the red and yellow disks than those presenting the corresponding grayscale for that color, proving that D. suzukii perceives colors and not just the level of target brightness. Fluorescent red is the best candidate for trap color, while clear and white are the least desirable. However, when the background was switched to black, all nonfluorescent colors were equally acceptable to spotted wing drosophila, suggesting that background must be specified when reporting spotted wing drosophila color preference. Additional spotted wing drosophila research is justified on the effects of target color against natural backgrounds. PMID- 26475828 TI - Health survey of 167 pet rabbits (Oryctolagus cuniculus) in Finland. AB - Only a limited amount of information is available about health status of pet rabbits. The aim of this study was to obtain data about the health status of pet rabbits considered healthy by the owners in Finland. Physical examination and lateral abdominal and lateral skull radiography were performed on 167 pet rabbits of which 118 (70.7 per cent) had abnormal findings in at least one examination. The most common findings were acquired dental disease (n=67, 40.1 per cent), vertebral column deformities and degenerative lesions (n=52, 31.1 per cent), skin disorders (n=28, 16.8 per cent) and eye disorders (n=12, 7.2 per cent). Vertebral column angulating deformities were significantly more common in dwarf lop rabbits (P<=0.001). The prevalence of health disorders was significantly higher in rabbits over three years of age of which 51 (82.3 per cent) had findings in at least one examination (P<0.05). Rabbits as prey animals hide their illness, which cause difficulties to owners to recognise health problems. Because of the high prevalence of clinical and radiological findings in apparently healthy pet rabbits, regular physical examinations are advised, especially for animals over three years old. PMID- 26475829 TI - A time-varying effect model for studying gender differences in health behavior. AB - This study proposes a time-varying effect model that can be used to characterize gender-specific trajectories of health behaviors and conduct hypothesis testing for gender differences. The motivating examples demonstrate that the proposed model is applicable to not only multi-wave longitudinal studies but also short term studies that involve intensive data collection. The simulation study shows that the accuracy of estimation of trajectory functions improves as the sample size and the number of time points increase. In terms of the performance of the hypothesis testing, the type I error rates are close to their corresponding significance levels under all combinations of sample size and number of time points. Furthermore, the power increases as the alternative hypothesis deviates more from the null hypothesis, and the rate of this increasing trend is higher when the sample size and the number of time points are larger. PMID- 26475830 TI - Fast clustering using adaptive density peak detection. AB - Common limitations of clustering methods include the slow algorithm convergence, the instability of the pre-specification on a number of intrinsic parameters, and the lack of robustness to outliers. A recent clustering approach proposed a fast search algorithm of cluster centers based on their local densities. However, the selection of the key intrinsic parameters in the algorithm was not systematically investigated. It is relatively difficult to estimate the "optimal" parameters since the original definition of the local density in the algorithm is based on a truncated counting measure. In this paper, we propose a clustering procedure with adaptive density peak detection, where the local density is estimated through the nonparametric multivariate kernel estimation. The model parameter is then able to be calculated from the equations with statistical theoretical justification. We also develop an automatic cluster centroid selection method through maximizing an average silhouette index. The advantage and flexibility of the proposed method are demonstrated through simulation studies and the analysis of a few benchmark gene expression data sets. The method only needs to perform in one single step without any iteration and thus is fast and has a great potential to apply on big data analysis. A user-friendly R package ADPclust is developed for public use. PMID- 26475831 TI - Activities of the peptidyl transferase center of ribosomes lacking protein L27. AB - The ribosome is the molecular machine responsible for protein synthesis in all living organisms. Its catalytic core, the peptidyl transferase center (PTC), is built of rRNA, although several proteins reach close to the inner rRNA shell. In the Escherichia coli ribosome, the flexible N-terminal tail of the ribosomal protein L27 contacts the A- and P-site tRNA. Based on computer simulations of the PTC and on previous biochemical evidence, the N-terminal alpha-amino group of L27 was suggested to take part in the peptidyl-transfer reaction. However, the contribution of this group to catalysis has not been tested experimentally. Here we investigate the role of L27 in peptide-bond formation using fast kinetics approaches. We show that the rate of peptide-bond formation at physiological pH, both with aminoacyl-tRNA or with the substrate analog puromycin, is independent of the presence of L27; furthermore, translation of natural mRNAs is only marginally affected in the absence of L27. The pH dependence of the puromycin reaction is unaltered in the absence of L27, indicating that the N-terminal alpha amine is not the ionizing group taking part in catalysis. Likewise, L27 is not required for the peptidyl-tRNA hydrolysis during termination. Thus, apart from the known effect on subunit association, which most likely explains the phenotype of the deletion strains, L27 does not appear to be a key player in the core mechanism of peptide-bond formation on the ribosome. PMID- 26475833 TI - Improving vessel healing with fully bioresorbable drug-eluting stents: more than a pipe dream? PMID- 26475834 TI - Family or SNPs: what counts for hereditary risk of coronary artery disease? PMID- 26475835 TI - Open-Source Approach May Speed Drug Discovery. AB - In an effort to speed early-stage drug discovery, a Toronto, Canada-based research group has developed and made freely available a new drug prototype that shows promise in targeting a protein involved in breast cancer and leukemia. PMID- 26475837 TI - Online Corrigendum. PMID- 26475836 TI - Dr. Dr. h.c. Chris Galanos. PMID- 26475838 TI - Diagnosis of Pediatric Foreign Body Ingestion: Clinical Presentation, Physical Examination, and Radiologic Findings. AB - OBJECTIVES: (1) To describe clinical and radiologic findings in patients with esophageal foreign bodies. (2) To examine the sensitivity and specificity of history, physical examination, and radiologic studies in children with suspected foreign body ingestion. METHODS: A retrospective cohort study was performed evaluating all children who underwent esophagoscopy for suspected foreign body ingestion at our institution from 2006 to 2013. RESULTS: Five hundred forty-three patients were included (54% male). Average age was 4.7 years (SD = 4.1 years). Foreign bodies were identified on esophagoscopy in 497 cases (92%). Ingestion was witnessed in 23% of cases. Most common presenting symptoms were choking/gagging (49%), vomiting (47%), and dysphagia/odynophagia (42%). Most patients with foreign bodies had a normal exam (76%). Most foreign bodies were radiopaque (83%). In 59% of patients with normal chest radiographs, a foreign body was present. Sensitivity and specificity of 1 or more findings on history, physical examination, and imaging were 99% and 0%, 21% and 76%, and 83% and 100%, respectively. CONCLUSIONS: Most patients with esophageal foreign bodies are symptomatic. Although many patients will have a normal physical examination, an abnormal exam should increase suspicion for a foreign body. Most esophageal foreign bodies are radiopaque, but a normal chest radiograph cannot rule out a foreign body. PMID- 26475839 TI - Do the Autism Spectrum Quotient (AQ) and Autism Spectrum Quotient Short Form (AQ S) Primarily Reflect General ASD Traits or Specific ASD Traits? A Bi-Factor Analysis. AB - In the current study, we fit confirmatory bi-factor models to the items of the Autism Spectrum Quotient (AQ) and Autism Spectrum Quotient Short Form (AQ-S) in order to assess the extents to which the items of each reflect general versus specific factors. The models were fit in a combined sample of individuals with and without a clinical diagnosis of autism spectrum disorders. Results indicated that, with the exception of the Attention to Details factor in the AQ and the Numbers/Patterns factors in the AQ-S, items primarily reflected a general factor. This suggests that when attempting to estimate an association between a specific symptom measured by the AQ or AQ-S and some criterion, associations will be confounded by the general factor. To resolve this, we recommend using a bi-factor measurement model or factor scores from a bi-factor measurement whenever hypotheses about specific symptoms are being assessed. PMID- 26475840 TI - Peritoneal Dialysis Catheter Increases Leukocyte Recruitment in the Mouse Parietal Peritoneum Microcirculation and Causes Fibrosis. AB - ? BACKGROUND: The objective of this study was to examine the effects of a conventional dialysis solution and peritoneal catheter on leukocyte-endothelial cell interactions in the microcirculation of the parietal peritoneum in a subacute peritoneal dialysis (PD) mouse model. ? METHODS: An intraperitoneal (IP) catheter with a subcutaneous injection port was implanted into mice and, after a 2-week healing period, the animals were injected daily for 6 weeks with a 2.5% dextrose solution. Intravital microscopy (IVM) of the parietal peritoneum microcirculation was performed 4 hours after the last injection of the dialysis solution. Leukocyte-endothelial cell interactions were quantified and compared with catheterized controls without dialysis treatment and naive mice. ? RESULTS: The number of rolling and extravascular leukocytes along with peritoneal fibrosis and neovascularization were significantly increased in the catheterized animals compared with naive mice but did not significantly differ between the 2 groups of catheterized animals with sham injections or dialysis solution treatment. ? CONCLUSION: The peritoneal catheter implant increased leukocyte rolling and extravasation, peritoneal fibrosis and vascularization in the parietal peritoneum independently from the dialysis solution treatment. PMID- 26475841 TI - Nonalcoholic Fatty Liver Disease (NAFLD)-A New Cardiovascular Risk Factor in Peritoneal Dialysis Patients. AB - ? BACKGROUND: Recent investigations indicated that nonalcoholic fatty liver disease (NAFLD), a hepatic component of metabolic syndrome (MS), is associated with an increased risk of cardiovascular disease (CVD). Accordingly, we were interested in exploring the frequency of NAFLD in peritoneal dialysis (PD) patients and analyzing factors in PD patients associated with NAFLD occurrence. In addition, we were interested in investigating whether NAFLD is associated with higher CVD risk in our PD patients. ? METHODS: In the present cross-sectional study, we analyzed 58 PD patients. The controlled attenuation parameter (CAP) was used to detect and quantify liver steatosis with the help of transient elastography (TE) (FibroScan, Echosense SA, Paris, France). A carotid ultrasound was performed in all patients to measure carotid intimae media thickness (IMT) and plaque as surrogate measures of increased CVD risk, and we investigated their association with NAFLD. ? RESULTS: Nonalcoholic fatty liver disease was present in 74.1% of PD patients. Peritoneal dialysis/nonalcoholic fatty liver disease patients had statistically greater daily (136.5 +/- 62.6 vs 93.6 +/- 36.1; p = 0.02) and monthly (4,095.3 +/- 1,877.7 vs 2,806.6 +/- 1,083.2; p = 0.02) glucose load in comparison to the non-NAFLD/PD patients. In the next step, we were interested in analyzing what demographic and clinical characteristics in our PD patients are associated with a higher NAFLD occurrence. Presence of diabetes mellitus (DM), arterial hypertension (AH), dyslipidemia, body mass index > 25 kg/m(2), and daily glucose load > 100 g were associated with NAFLD occurrence. Peritoneal dialysis patients with NAFLD showed more carotid atherosclerosis than PD patients without NAFLD. In addition, CAP values (as indicator of liver steatosis) showed strong positive association with IMT (r = 0.801; p < 0.0001). Nonalcoholic fatty liver disease was a strong predictor of carotid atherosclerosis in PD patients. ? CONCLUSION: Nonalcoholic fatty liver disease is highly prevalent in PD patients. Peritoneal dialysis patients with NAFLD are at high risk of atherosclerosis. Assessment of NAFLD in PD patients may be helpful for CVD risk stratification. PMID- 26475842 TI - Analysis of Hospitalization after Peritoneal Dialysis Catheter Implantation. AB - ? BACKGROUND: Implantation of the peritoneal dialysis catheter (PDC), usually an elective procedure, may necessitate unexpected hospitalization and even transfer to intensive care due to the multiple comorbidities and inherent instability of the end-stage renal disease patient. Information on hospitalization after PDC implantation is limited and details about the reason for hospitalization are lacking. ? METHODS: We performed a cohort study in consecutive patients who underwent PDC implantation at a single institution from September 2007 to September 2013. Clinical characteristics of enrolled patients, technique of the implantation procedure, and all-cause unexpected hospitalization and morbidity within 14 days after implantation were analyzed. ? RESULTS: Excluding the patients with pre-arranged admission, a total of 246 patients receiving 252 PDC implantations during the 6 years were studied. After 39 procedures (15.5%), patients had an unexpected hospital stay or re-admission due to operative complications (33.3%), worsening of disease (35.9%), or a single-night hospital stay for observation (30.8%). Compared with discharged patients, the patients with unexpected hospitalization were older (p = 0.001), experienced higher rates of previous episodes of heart failure (p = 0.006) and heart disease (p < 0.001), had more use of general anesthesia (GA) (p = 0.046), underwent more added procedures during the implantation (p = 0.02), and had more episodes of flow obstruction and peritonitis after implantation (p = 0.012 and p < 0.001, respectively). Using a multivariable logistic regression, we showed that age, cardiac morbidity, use of general anesthesia, PDC flow problems and peritonitis after implantation were independent predictors of all-cause unexpected hospitalization. ? CONCLUSIONS: For the first time, our study analyzed the predictors of unplanned hospitalization after PDC implantation and identified the salient risk factors. Increased focus to identify patients at greatest risk for hospitalization, evaluation of processes of care, and implementation of preventive strategies may be helpful to reduce unplanned hospitalization after catheter insertion. PMID- 26475843 TI - Spatial Analysis of Case-Mix and Dialysis Modality Associations. AB - ? BACKGROUND: Health-care systems must attempt to provide appropriate, high quality, and economically sustainable care that meets the needs and choices of patients with end-stage renal disease (ESRD). France offers 9 different modalities of dialysis, each characterized by dialysis technique, the extent of professional assistance, and the treatment site. The aim of this study was 1) to describe the various dialysis modalities in France and the patient characteristics associated with each of them, and 2) to analyze their regional patterns to identify possible unexpected associations between case-mixes and dialysis modalities. ? METHODS: The clinical characteristics of the 37,421 adult patients treated by dialysis were described according to their treatment modality. Agglomerative hierarchical cluster analysis was used to aggregate the regions into clusters according to their use of these modalities and the characteristics of their patients. ? RESULT: The gradient of patient characteristics was similar from home hemodialyis (HD) to in-center HD and from non-assisted automated peritoneal dialysis (APD) to assisted continuous ambulatory peritoneal dialysis (CAPD). Analyzing their spatial distribution, we found differences in the patient case-mix on dialysis across regions but also differences in the health-care provided for them. The classification of the regions into 6 different clusters allowed us to detect some unexpected associations between case-mixes and treatment modalities. ? CONCLUSIONS: The 9 modalities of treatment available make it theoretically possible to adapt treatment to patients' clinical characteristics and abilities. However, although we found an overall appropriate association of dialysis modalities to the case mix, major inter-region heterogeneity and the low rate of peritoneal dialysis (PD) and home HD suggest that factors besides patients' clinical conditions impact the choice of dialysis modality. The French organization should now be evaluated in terms of patients' quality of life, satisfaction, survival, and global efficiency. PMID- 26475844 TI - Effects of Ginger on Serum Lipids and Lipoproteins in Peritoneal Dialysis Patients: A Randomized Controlled Trial. AB - ? BACKGROUND: In peritoneal dialysis (PD) patients, one of the major risk factors for cardiovascular disease is lipid abnormalities. This study was designed to investigate the effects of ginger supplementation on serum lipids and lipoproteins in PD patients. ? METHODS: In this randomized, double-blind, placebo controlled trial, 36 PD patients were randomly assigned to either the ginger or the placebo group. The patients in the ginger group received 1,000 mg ginger daily for 10 weeks, while the placebo group received corresponding placebos. At baseline and at the end of week 10, 7 mL of blood were obtained from each patient after a 12- to 14-hour fast, and serum concentrations of triglyceride, total cholesterol, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and lipoprotein (a) [Lp (a)] were measured. ? RESULTS: Serum triglyceride concentration decreased significantly up to 15% in the ginger group at the end of week 10 compared with baseline (p < 0.01), and the reduction was significant in comparison with the placebo group (p < 0.05). There were no significant differences between the 2 groups in mean changes of serum total cholesterol, LDL-C, HDL-C, and Lp (a). ? CONCLUSION: This study indicates that daily administration of 1,000 mg ginger reduces serum triglyceride concentration, which is a risk factor for cardiovascular disease, in PD patients. PMID- 26475845 TI - Hydration Status of Patients Dialyzed with Biocompatible Peritoneal Dialysis Fluids. AB - ? BACKGROUND: Biocompatible fluids for peritoneal dialysis (PD) have been introduced to improve dialysis and patient outcome in end-stage renal disease. However, their impact on hydration status (HS), residual renal function (RRF), and dialysis adequacy has been a matter of debate. The aim of the study was to evaluate the influence of a biocompatible dialysis fluid on the HS of prevalent PD patients. ? METHODS: The study population consisted of 18 prevalent PD subjects, treated with standard dialysis fluids. At baseline, 9 patients were switched to a biocompatible solution, low in glucose degradation products (GDPs) (Balance; Fresenius Medical Care, Bad Homburg, Germany). Hydration status was assessed through clinical evaluation, laboratory parameters, echocardiography, and bioimpedance spectroscopy over a 24-month observation period. ? RESULTS: During the study period, urine volume decreased similarly in both groups. At the end of the evaluation, there were also no differences in clinical (body weight, edema, blood pressure), laboratory (N-terminal pro-brain natriuretic peptide, NTproBNP), or echocardiography determinants of HS. However, dialysis ultrafiltration decreased in the low-GDP group and, at the end of the study, equaled 929 +/- 404 mL, compared with 1,317 +/- 363 mL in the standard-fluid subjects (p = 0.06). Hydration status assessed by bioimpedance spectroscopy was +3.64 +/- 2.08 L in the low-GDP patients and +1.47 +/- 1.61 L in the controls (p = 0.03). ? CONCLUSIONS: The use of a low-GDP biocompatible dialysis fluid was associated with a tendency to overhydration, probably due to diminished ultrafiltration in prevalent PD patients. PMID- 26475846 TI - The Association of Individual and Regional Socioeconomic Status on Initial Peritonitis and Outcomes in Peritoneal Dialysis Patients: A Propensity Score Matched Cohort Study. AB - ? BACKGROUND: Research indicates that the socioeconomic status (SES) of individuals and the area where they live are related to initial peritonitis and outcomes in peritoneal dialysis (PD). We conducted a retrospective, multi-center cohort study in China to examine these associations. ? METHODS: Data on 2,171 PD patients were collected from 7 centers, including baseline demographic, socioeconomic, and laboratory data. We explored the potential risk factors for initial peritonitis and outcomes using univariate Cox regression and unadjusted binary logistic regression. Then, we used propensity score matching to balance statistically significant risk factors for initial peritonitis and outcomes, and Kaplan-Meier survival analysis to compare differences in peritonitis-free rates between different groups of participants after matching. ? RESULTS: A total of 563 (25.9%) initial episodes of peritonitis occurred during the study period. The Kaplan-Meier peritonitis-free rate curve showed high-income patients had a significantly lower risk than low-income patients (p = 0.007) after matching for age, hemoglobin, albumin, and regional SES and PD center. The risk of treatment failure was significantly lower in the high-income than the low-income group after matching for the organism causing peritonitis and PD center: odds ratio (OR) = 0.27 (0.09 - 0.80, p = 0.018). Regional SES and education were not associated with initial peritonitis and outcomes. ? CONCLUSIONS: Our study demonstrates low individual income is a risk factor for the initial onset of peritonitis and treatment failure after initial peritonitis. PMID- 26475847 TI - Association of Body Mass Index With Mortality in Peritoneal Dialysis Patients: A Systematic Review and Meta-Analysis. AB - ? BACKGROUND: Although higher body mass index (BMI) is associated with better outcomes in hemodialysis patients, the relationship in peritoneal dialysis (PD) patients is less clear. We aimed to synthesize the results from all large and high-quality studies to examine whether underweight, overweight, or obesity is associated with any significantly different risk of death in peritoneal dialysis patients. ? METHODS: We searched MEDLINE, EMBASE, Web of Science, CINAHL, and Cochrane CENTRAL, and screened 7,123 retrieved studies for inclusion. Two investigators independently selected the studies using predefined criteria and assessed each study's quality using the Newcastle-Ottawa Quality Assessment Scale. We meta-analyzed the results of the largest studies with no overlap in their data sources. ? RESULTS: We included 9 studies (n = 156,562) in the systematic review and 4 studies in the meta-analyses. When examined without stratifying studies by follow-up duration, the results of the studies were inconsistent. Hence, we pooled the study results stratified based upon their follow-up durations, as suggested by a large study, and observed that being underweight was associated with higher 1-year mortality but had no significant association with 2- and 3- to 5-year mortalities. In contrast, being overweight or obese was associated with lower 1-year mortality but it had no significant association with 2-, and 3- to 5-year mortalities. ? CONCLUSION: Over the short term, being underweight was associated with higher mortality and being overweight or obese was associated with lower mortality. The associations of body mass with mortality were not significant over the long-term. PMID- 26475848 TI - Biocompatible Dialysis Solutions Preserve Peritoneal Mesothelial Cell and Vessel Wall Integrity. A Case-Control Study on Human Biopsies. AB - ? INTRODUCTION: Chronic exposure to conventional peritoneal dialysis (PD) solutions has been related to peritoneal function alterations in PD patients, and associated with mesothelial cell loss, submesothelial fibrosis, vasculopathy, and angiogenesis. In vitro and ex vivo analyses, as well as studies with animal models, have demonstrated that biocompatible PD solutions attenuate these morphological alterations. Our aim was to confirm the morphological benefits of biocompatible solutions in PD patients. ? METHODS: We analyzed biopsies from 23 patients treated with biocompatible solutions (study group, SG), and compared them with a control group (n = 23) treated with conventional solutions (CG), matched for time on PD. ? RESULTS: A total of 56.5% of SG patients showed total or partial preservation of mesothelial cells monolayer, in contrast with 26.1% of patients in CG (p = 0.036). Peritoneal fibrosis was not significantly less frequent in SG patients (47.8% SG vs 69.6% CG; p = 0.13). In patients without previous peritonitis, a significantly lower prevalence of fibrosis was present in SG patients (41.7% SG vs 77.8% CG; p = 0.04). Hyalinizing vasculopathy (HV) was significantly lower in SG (4.3% SG vs 30.4% CG; p = 0.02). Cytokeratin-positive fibroblast-like cells were detected in 10 patients (22%), but the prevalence was not significantly lower in SG. In the univariate regression analysis, the use of biocompatible solutions was associated with mesothelial monolayer integrity (p = 0.04) and an absence of vasculopathy (p = 0.04). ? CONCLUSION: The present study demonstrates in vivo in human biopsies that biocompatible solutions are better tolerated by the peritoneum in the medium and long term than conventional solutions. PMID- 26475849 TI - Can Free Water Transport Be Used as a Clinical Parameter for Peritoneal Fibrosis in Long-Term PD Patients? AB - Sodium sieving in peritoneal dialysis (PD) occurs in a situation with high osmotically-driven ultrafiltration rates. This dilutional phenomenon is caused by free water transport through the water channel aquaporin-1. It has recently been described that encapsulating peritoneal fibrosis is associated with impaired free water transport, despite normal expression of aquaporin-1. In this review, it will be argued that free water transport can be used for assessment of fibrotic peritoneal alterations, due to the water-binding capacity of collagen. Finally, the consequences for clinical practice will be discussed. PMID- 26475850 TI - Comparative evaluation of in vivo biocompatibility and biodegradability of regenerated silk scaffolds reinforced with/without natural silk fibers. AB - Nowadays, exceptional advantages of silk fibroin over synthetic and natural polymers have impelled the scientists to application of this biomaterial for tissue engineering purposes. Recently, we showed that embedding natural degummed silk fibers in regenerated Bombyx mori silk-based scaffold significantly increases the mechanical stiffness, while the porosity of the scaffolds remains the same. In the present study, we evaluated degradation rate, biocompatibility and regenerative properties of the regenerated 2% and 4% wt silk-based composite scaffolds with or without embedded natural degummed silk fibers within 90 days in both athymic nude and wild-type C57BL/6 mice through subcutaneous implantation. In all scaffolds, a suitable interconnected porous structure for cell penetration was seen under scanning electron microscopy. Compressive tests revealed a functional relationship between fiber reinforcement and compressive modulus. In addition, the fiber/fibroin composite scaffolds support cell attachment and proliferation. On days 30 to 90 after subcutaneous implantation, the retrieved tissues were examined via gross morphology, histopathology, immunofluorescence staining and reverse transcription-polymerase chain reaction as shown in Figure 1. Results showed that embedding the silk fibers within the matrix enhances the biodegradability of the matrix resulting in replacement of the composite scaffolds with the fresh connective tissue. Fortification of the composites with degummed fibers not only regulates the degradation profile but also increases the mechanical performance of the scaffolds. This report also confirmed that pore size and structure play an important role in the degradation rate. In conclusion, the findings of the present study narrate key role of additional surface area in improving in vitro and in vivo biological properties of the scaffolds and suggest the potential ability of these fabricated composite scaffolds for connective tissue regeneration. spjba;30/6/793/FIG10885328215601925F1fig1 0885328215601925Figure 1.Illustrative summary of the main methods and findings.RS: regenerated silk; RSF: regenerated fibroin/ silk fiber composite scaffolds; H&E: Hematoxylin and eosin; COX-1: Cyclooxygenase. PMID- 26475851 TI - Biotin-conjugated fusogenic liposomes for high-quality cell purification. AB - Purification of defined cell populations from mixed primary cell sources is essential for many biomedical and biotechnological applications but often very difficult to accomplish due to missing specific surface markers. In this study, we developed a new approach for efficient cell population separation based on the specific membrane fusion characteristics of distinct cell types upon treatment with fusogenic liposomes. When such liposomes are conjugated with biotin, specific cell populations can be efficiently surface functionalized by biotin after liposomal treatment while other populations remain unlabeled. Due to the high affinity of biotin for avidin-like proteins, biotin functionalized cells are ideal targets for conjugation of e.g. avidin tagged magnetic beads, fluorophores or antibodies with bioanalytical relevance. Here, based on the differential biotinylation of distinct cell populations high quality separation of cardiac fibroblasts from myocytes, and cerebromicrovascular endothelial cells from fibroblasts was successfully established. PMID- 26475852 TI - Potential in two types of collagen scaffolds for urological tissue engineering applications - Are there differences in growth behaviour of juvenile and adult vesical cells? AB - The aging society has a deep impact on patient care in urology. The number of patients in need of partial or whole bladder wall replacement is increasing simultaneously with the number of cancer incidents. Therefore, urological research requires a model of bladder wall replacement in adult and elderly people. Two types of porcine collagen I/III scaffolds were used in vitro for comparison of cell growth of two different pig breeds at different growth stages. Scaffolds were characterised with scanning electron and laser scanning microscopy. Urothelial and detrusor smooth muscle cells were isolated from 15 adult Gottingen minipigs and 15 juvenile German Landrace pigs. Growth behaviour was examined in cell culture and seeded onto the collagen scaffolds via immunohistochemistry, two-photon laser scanning microscopy and a viability assay. The collagen scaffolds showed different structured surfaces which are appropriate for seeding of the two different cell types. Moisturisation of the scaffolds resulted in a change of the structure. Cell growth of German Landrace urothelial cells and smooth muscle cells was significantly higher than cell growth of the Gottingen minipig cells. Seeding of scaffolds with both cell types from both pig races was possible which could be shown by immunohistochemistry and two-photon laser scanning microscopy. Growth behaviour on the scaffolds was significantly increased for the German Landrace compared to Gottingen minipig. Nevertheless, seeding with the adult Gottingen minipig cells resulted in a closed layer on the surface and urothelial cells and smooth muscle cells showed increasing growth until day 14. The results show that these collagen scaffolds are adequate for the seeding with vesical cells. Moreover, they seem appropriate for the use as an in vitro model for the adult or elderly as the cells of the adult Gottingen minipig too, show good growth behaviour. PMID- 26475854 TI - Insights into Ubiquitination from the Unique Clamp-like Binding of the RING E3 AO7 to the E2 UbcH5B. AB - RING proteins constitute the largest class of E3 ubiquitin ligases. Unlike most RINGs, AO7 (RNF25) binds the E2 ubiquitin-conjugating enzyme, UbcH5B (UBE2D2), with strikingly high affinity. We have defined, by co-crystallization, the distinctive means by which AO7 binds UbcH5B. AO7 contains a structurally unique UbcH5B binding region (U5BR) that is connected by an 11-amino acid linker to its RING domain, forming a clamp surrounding the E2. The U5BR interacts extensively with a region of UbcH5B that is distinct from both the active site and the RING interacting region, referred to as the backside of the E2. An apparent paradox is that the high-affinity binding of the AO7 clamp to UbcH5B, which is dependent on the U5BR, decreases the rate of ubiquitination. We establish that this is a consequence of blocking the stimulatory, non-covalent, binding of ubiquitin to the backside of UbcH5B. Interestingly, when non-covalent backside ubiquitin binding cannot occur, the AO7 clamp now enhances the rate of ubiquitination. The high-affinity binding of the AO7 clamp to UbcH5B has also allowed for the co crystallization of previously described and functionally important RING mutants at the RING-E2 interface. We show that mutations having marked effects on function only minimally affect the intermolecular interactions between the AO7 RING and UbcH5B, establishing a high degree of complexity in activation through the RING-E2 interface. PMID- 26475855 TI - Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis. AB - The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1(-/-)) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-kappaB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4(-/-) mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. PMID- 26475856 TI - The N-terminal Region of the Ubiquitin Regulatory X (UBX) Domain-containing Protein 1 (UBXD1) Modulates Interdomain Communication within the Valosin containing Protein p97. AB - Valosin-containing protein/p97 is an ATP-driven protein segregase that cooperates with distinct protein cofactors to control various aspects of cellular homeostasis. Mutations at the interface between the regulatory N-domain and the first of two ATPase domains (D1 and D2) deregulate the ATPase activity and cause a multisystem degenerative disorder, inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia/amyotrophic lateral sclerosis. Intriguingly, the mutations affect only a subset of p97-mediated pathways correlating with unbalanced cofactor interactions and most prominently compromised binding of the ubiquitin regulatory X domain-containing protein 1 (UBXD1) cofactor during endolysosomal sorting of caveolin-1. However, how the mutations impinge on the p97-cofactor interplay is unclear so far. In cell-based endosomal localization studies, we identified a critical role of the N-terminal region of UBXD1 (UBXD1-N). Biophysical studies using NMR and CD spectroscopy revealed that UBXD1-N can be classified as intrinsically disordered. NMR titration experiments confirmed a valosin-containing protein/p97 interaction motif and identified a second binding site at helices 1 and 2 of UBXD1-N as binding interfaces for p97. In reverse titration experiments, we identified two distant epitopes on the p97 N-domain that include disease-associated residues and an additional interaction between UBXD1-N and the D1D2 barrel of p97 that was confirmed by fluorescence anisotropy. Functionally, binding of UBXD1-N to p97 led to a reduction of ATPase activity and partial protection from proteolysis. These findings indicate that UBXD1-N intercalates into the p97-ND1 interface, thereby modulating interdomain communication of p97 domains and its activity with relevance for disease pathogenesis. We propose that the polyvalent binding mode characterized for UBXD1-N is a more general principle that defines a subset of p97 cofactors. PMID- 26475857 TI - P2Y1 Receptor Activation of the TRPV4 Ion Channel Enhances Purinergic Signaling in Satellite Glial Cells. AB - Transient receptor potential (TRP) ion channels of peripheral sensory pathways are important mediators of pain, itch, and neurogenic inflammation. They are expressed by primary sensory neurons and by glial cells in the central nervous system, but their expression and function in satellite glial cells (SGCs) of sensory ganglia have not been explored. SGCs tightly ensheath neurons of sensory ganglia and can regulate neuronal excitability in pain and inflammatory states. Using a modified dissociation protocol, we isolated neurons with attached SGCs from dorsal root ganglia of mice. SGCs, which were identified by expression of immunoreactive Kir4.1 and glutamine synthetase, were closely associated with neurons, identified using the pan-neuronal marker NeuN. A subpopulation of SGCs expressed immunoreactive TRP vanilloid 4 (TRPV4) and responded to the TRPV4 selective agonist GSK1016790A by an influx of Ca(2+) ions. SGCs did not express functional TRPV1, TRPV3, or TRP ankyrin 1 channels. Responses to GSK1016790A were abolished by the TRPV4 antagonist HC067047 and were absent in SGCs from Trpv4(-/ ) mice. The P2Y1-selective agonist 2-methylthio-ADP increased [Ca(2+)]i in SGCs, and responses were prevented by the P2Y1-selective antagonist MRS2500. P2Y1 receptor-mediated responses were enhanced in TRPV4-expressing SGCs and HEK293 cells, suggesting that P2Y1 couples to and activates TRPV4. PKC inhibitors prevented P2Y1 receptor activation of TRPV4. Our results provide the first evidence for expression of TRPV4 in SGCs and demonstrate that TRPV4 is a purinergic receptor-operated channel in SGCs of sensory ganglia. PMID- 26475858 TI - Genetic Screen Reveals Link between the Maternal Effect Sterile Gene mes-1 and Pseudomonas aeruginosa-induced Neurodegeneration in Caenorhabditis elegans. AB - Increasing evidence indicates that immune responses to microbial infections may contribute to neurodegenerative diseases. Here, we show that Pseudomonas aeruginosa infection of Caenorhabditis elegans causes a number of neural changes that are hallmarks of neurodegeneration. Using an unbiased genetic screen to identify genes involved in the control of P. aeruginosa-induced neurodegeneration, we identified mes-1, which encodes a receptor tyrosine kinase like protein that is required for unequal cell divisions in the early embryonic germ line. We showed that sterile but not fertile mes-1 animals were resistant to neurodegeneration induced by P. aeruginosa infection. Similar results were observed using animals carrying a mutation in the maternal effect gene pgl-1, which is required for postembryonic germ line development, and the germ line deficient strains glp-1 and glp-4. Additional studies indicated that the FOXO transcription factor DAF-16 is required for resistance to P. aeruginosa-induced neurodegeneration in germ line-deficient strains. Thus, our results demonstrate that P. aeruginosa infection results in neurodegeneration phenotypes in C. elegans that are controlled by the germ line in a cell-nonautonomous manner. PMID- 26475859 TI - Molecular Determinants of Substrate Specificity in Sodium-coupled Glutamate Transporters. AB - Crystal structures of the archaeal homologue GltPh have provided important insights into the molecular mechanism of transport of the excitatory neurotransmitter glutamate. Whereas mammalian glutamate transporters can translocate both glutamate and aspartate, GltPh is only one capable of aspartate transport. Most of the amino acid residues that surround the aspartate substrate in the binding pocket of GltPh are highly conserved. However, in the brain transporters, Thr-352 and Met-362 of the reentrant hairpin loop 2 are replaced by the smaller Ala and Thr, respectively. Therefore, we have studied the effects of T352A and M362T on binding and transport of aspartate and glutamate by GltPh. Substrate-dependent intrinsic fluorescence changes were monitored in transporter constructs containing the L130W mutation. GltPh-L130W/T352A exhibited an ~15-fold higher apparent affinity for l-glutamate than the wild type transporter, and the M362T mutation resulted in an increased affinity of ~40-fold. An even larger increase of the apparent affinity for l-glutamate, around 130-fold higher than that of wild type, was observed with the T352A/M362T double mutant. Radioactive uptake experiments show that GltPh-T352A not only transports aspartate but also l glutamate. Remarkably, GltPh-M362T exhibited l-aspartate but not l-glutamate transport. The double mutant retained the ability to transport l-glutamate, but its kinetic parameters were very similar to those of GltPh-T352A alone. The differential impact of mutation on binding and transport of glutamate suggests that hairpin loop 2 not only plays a role in the selection of the substrate but also in its translocation. PMID- 26475860 TI - The Catalytic Efficiency of Lipin 1beta Increases by Physically Interacting with the Proto-oncoprotein c-Fos. AB - Phosphatidic acid (PA) is a central precursor for membrane phospholipid biosynthesis. The lipin family is a magnesium-dependent type I PA phosphatase involved in de novo synthesis of neutral lipids and phospholipids. The regulation of lipin activity may govern the pathways by which these lipids are synthesized and control the cellular levels of important signaling lipids. Moreover, the proto-oncoprotein c-Fos has an emerging role in glycerolipid synthesis regulation; by interacting with key synthesizing enzymes it is able to increase overall phospho- and glycolipid synthesis. We studied the lipin 1beta enzyme activity in a cell-free system using PA/Triton X-100 mixed micelles as substrate, analyzing it in the presence/absence of c-Fos. We found that lipin 1beta kcat value increases around 40% in the presence of c-Fos, with no change in the lipin 1beta affinity for the PA/Triton X-100 mixed micelles. We also probed a physical interaction between both proteins. Although the c-Fos domain involved in lipin activation is its basic domain, the interaction domain is mapped to the N terminal c-Fos. In conclusion, we provide evidence for a novel positive regulator of lipin 1beta PA phosphatase activity that is not achieved via altering its subcellular localization or affinity for membranes but rather through directly increasing its catalytic efficiency. PMID- 26475861 TI - Early Growth Response 1 (Egr-1) Regulates N-Methyl-d-aspartate Receptor (NMDAR) dependent Transcription of PSD-95 and alpha-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor (AMPAR) Trafficking in Hippocampal Primary Neurons. AB - The N-methyl-d-aspartate receptor (NMDAR) controls synaptic plasticity and memory function and is one of the major inducers of transcription factor Egr-1 in the hippocampus. However, how Egr-1 mediates the NMDAR signal in neurons has remained unclear. Here, we show that the hippocampus of mice lacking Egr-1 displays electrophysiology properties and ultrastructure that are similar to mice overexpressing PSD-95, a major scaffolding protein of postsynaptic density involved in synapse formation, synaptic plasticity, and synaptic targeting of AMPA receptors (AMPARs), which mediate the vast majority of excitatory transmission in the CNS. We demonstrate that Egr-1 is a transcription repressor of the PSD-95 gene and is recruited to the PSD-95 promoter in response to NMDAR activation. Knockdown of Egr-1 in rat hippocampal primary neurons blocks NMDAR induced PSD-95 down-regulation and AMPAR endocytosis. Likewise, overexpression of Egr-1 in rat hippocampal primary neurons causes reduction in PSD-95 protein level and promotes AMPAR endocytosis. Our data indicate that Egr-1 is involved in NMDAR mediated PSD-95 down-regulation and AMPAR endocytosis, a process important in the expression of long term depression. PMID- 26475862 TI - Tumor Suppressor Lzap Suppresses Wnt/beta-Catenin Signaling to Promote Zebrafish Embryonic Ventral Cell Fates via the Suppression of Inhibitory Phosphorylation of Glycogen Synthase Kinase 3. AB - Wnt/beta-catenin signaling controls various cell fates in metazoan development, and its dysregulation is often associated with cancer formation. However, regulations of this signaling pathway are not completely understood. Here, we report that Lzap, a tumor suppressor, controls nuclear translocation of beta catenin. In zebrafish embryos disruption of lzap increases the expression of chordin (chd), which encodes a bone morphogenetic protein (BMP) antagonist that is localized in prospective dorsal cells and promotes dorsal fates. Consistently, lzap-deficient embryos with attenuated BMP signaling are dorsalized, which can be rescued by overexpression of zebrafish lzap or bmp2b or human LZAP. The expansion of chd expression in embryos lacking lzap is due to the accumulation of nuclear beta-catenin in ventral cells, in which beta-catenin is usually degraded. Furthermore, the activity of GSK3, a master regulator of beta-catenin degradation, is suppressed in lzap-deficient embryos via inhibitory phosphorylation. Finally, we also report that a similar regulatory axis is also likely to be present in a human tongue carcinoma cell line, SAS. Our results reveal that Lzap is a novel regulator of GSK3 for the maintenance of ventral cell properties and may prevent carcinogenesis via the regulation of beta-catenin degradation. PMID- 26475863 TI - Assembly and Molecular Architecture of the Phosphoinositide 3-Kinase p85alpha Homodimer. AB - Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that are activated by growth factor and G-protein-coupled receptors and propagate intracellular signals for growth, survival, proliferation, and metabolism. p85alpha, a modular protein consisting of five domains, binds and inhibits the enzymatic activity of class IA PI3K catalytic subunits. Here, we describe the structural states of the p85alpha dimer, based on data from in vivo and in vitro solution characterization. Our in vitro assembly and structural analyses have been enabled by the creation of cysteine-free p85alpha that is functionally equivalent to native p85alpha. Analytical ultracentrifugation studies showed that p85alpha undergoes rapidly reversible monomer-dimer assembly that is highly exothermic in nature. In addition to the documented SH3-PR1 dimerization interaction, we identified a second intermolecular interaction mediated by cSH2 domains at the C-terminal end of the polypeptide. We have demonstrated in vivo concentration-dependent dimerization of p85alpha using fluorescence fluctuation spectroscopy. Finally, we have defined solution conditions under which the protein is predominantly monomeric or dimeric, providing the basis for small angle x-ray scattering and chemical cross-linking structural analysis of the discrete dimer. These experimental data have been used for the integrative structure determination of the p85alpha dimer. Our study provides new insight into the structure and assembly of the p85alpha homodimer and suggests that this protein is a highly dynamic molecule whose conformational flexibility allows it to transiently associate with multiple binding proteins. PMID- 26475864 TI - Matrix Metalloproteinase 10 Degradomics in Keratinocytes and Epidermal Tissue Identifies Bioactive Substrates With Pleiotropic Functions. AB - Matrix metalloproteinases (MMPs) are important players in skin homeostasis, wound repair, and in the pathogenesis of skin cancer. It is now well established that most of their functions are related to processing of bioactive proteins rather than components of the extracellular matrix (ECM). MMP10 is highly expressed in keratinocytes at the wound edge and at the invasive front of tumors, but hardly any non-ECM substrates have been identified and its function in tissue repair and carcinogenesis is unclear. To better understand the role of MMP10 in the epidermis, we employed multiplexed iTRAQ-based Terminal Amine Isotopic Labeling of Substrates (TAILS) and monitored MMP10-dependent proteolysis over time in secretomes from keratinocytes. Time-resolved abundance clustering of neo-N termini classified MMP10-dependent cleavage events by efficiency and refined the MMP10 cleavage site specificity by revealing a so far unknown preference for glutamate in the P1 position. Moreover, we identified and validated the integrin alpha 6 subunit, cysteine-rich angiogenic inducer 61 and dermokine as novel direct MMP10 substrates and provide evidence for MMP10-dependent but indirect processing of phosphatidylethanolamine-binding protein 1. Finally, we sampled the epidermal proteome and degradome in unprecedented depth and confirmed MMP10 dependent processing of dermokine in vivo by TAILS analysis of epidermis from transgenic mice that overexpress a constitutively active mutant of MMP10 in basal keratinocytes. The newly identified substrates are involved in cell adhesion, migration, proliferation, and/or differentiation, indicating a contribution of MMP10 to local modulation of these processes during wound healing and cancer development. Data are available via ProteomeXchange with identifier PXD002474. PMID- 26475865 TI - CYP76C1 (Cytochrome P450)-Mediated Linalool Metabolism and the Formation of Volatile and Soluble Linalool Oxides in Arabidopsis Flowers: A Strategy for Defense against Floral Antagonists. AB - The acyclic monoterpene alcohol linalool is one of the most frequently encountered volatile compounds in floral scents. Various linalool oxides are usually emitted along with linalool, some of which are cyclic, such as the furanoid lilac compounds. Recent work has revealed the coexistence of two flower expressed linalool synthases that produce the (S)- or (R)-linalool enantiomers and the involvement of two P450 enzymes in the linalool oxidation in the flowers of Arabidopsis thaliana. Partially redundant enzymes may also contribute to floral linalool metabolism. Here, we provide evidence that CYP76C1 is a multifunctional enzyme that catalyzes a cascade of oxidation reactions and is the major linalool metabolizing oxygenase in Arabidopsis flowers. Based on the activity of the recombinant enzyme and mutant analyses, we demonstrate its prominent role in the formation of most of the linalool oxides identified in vivo, both as volatiles and soluble conjugated compounds, including 8-hydroxy, 8 oxo, and 8-COOH-linalool, as well as lilac aldehydes and alcohols. Analysis of insect behavior on CYP76C1 mutants and in response to linalool and its oxygenated derivatives demonstrates that CYP76C1-dependent modulation of linalool emission and production of linalool oxides contribute to reduced floral attraction and favor protection against visitors and pests. PMID- 26475866 TI - Cyclin-Dependent Kinase Regulation of Diurnal Transcription in Chlamydomonas. AB - We analyzed global transcriptome changes during synchronized cell division in the green alga Chlamydomonas reinhardtii. The Chlamydomonas cell cycle consists of a long G1 phase, followed by an S/M phase with multiple rapid, alternating rounds of DNA replication and segregation. We found that the S/M period is associated with strong induction of ~2300 genes, many with conserved roles in DNA replication or cell division. Other genes, including many involved in photosynthesis, are reciprocally downregulated in S/M, suggesting a gene expression split correlating with the temporal separation between G1 and S/M. The Chlamydomonas cell cycle is synchronized by light-dark cycles, so in principle, these transcriptional changes could be directly responsive to light or to metabolic cues. Alternatively, cell-cycle-periodic transcription may be directly regulated by cyclin-dependent kinases. To distinguish between these possibilities, we analyzed transcriptional profiles of mutants in the kinases CDKA and CDKB, as well as other mutants with distinct cell cycle blocks. Initial cell-cycle-periodic expression changes are largely CDK independent, but later regulation (induction and repression) is under differential control by CDKA and CDKB. Deviation from the wild-type transcriptional program in diverse cell cycle mutants will be an informative phenotype for further characterization of the Chlamydomonas cell cycle. PMID- 26475867 TI - Phytol from Degradation of Chlorophyll Feeds Biosynthesis of Tocopherols. PMID- 26475868 TI - Encephalitis in Australian children: contemporary trends in hospitalisation. AB - OBJECTIVE: The clinical epidemiology of childhood encephalitis in Australia is inadequately understood. We aimed to describe recent trends in childhood encephalitis-related hospitalisation. STUDY DESIGN: We identified encephalitis related hospital admissions (2000-2012) in national datasets among children <=14 years using ICD encephalitis codes. We calculated hospitalisation rates and analysed trends by year, age, gender, location, indigenous status and aetiology. RESULTS: Rates of childhood encephalitis hospitalisations significantly declined over an 11-year period (2000-2012; average hospitalisation rate 3.2/100 000). Varicella encephalitis hospitalisations decreased significantly, associated with high levels of varicella vaccine coverage since 2006. Acute disseminated encephalomyelitis (ADEM) was the most common 'specified' cause of encephalitis hospitalisation (15%-17%), and its rate has significantly increased. The highest hospitalisation rates occurred in the <1 year age group (5.8/100 000) and varied by location (highest in Northern Territory). The majority (58.9%) of hospitalised encephalitis had no cause identified; this proportion was highest in the <1 year age group (77%). The most common specified infectious causes included: herpes simplex virus, enterovirus, bacterial meningoencephalitis and varicella. When aggregated, the proportion of childhood encephalitis coded as viral was 21.2%. CONCLUSION: Hospitalisation of childhood encephalitis has slightly decreased in Australia. High rates of childhood immunisation have been associated with a reduction of varicella-associated encephalitis in Australian children. ADEM, an immune-mediated encephalitis, is the most common recognised cause of encephalitis in children. Young children (<1 year) have the highest admission rates. The high proportion of 'unspecified' encephalitis deaths and hospitalisations is an ongoing challenge. PMID- 26475869 TI - Plasticity beyond cancer cells and the "immunosuppressive switch". AB - Tumor initiation, growth, and metastatic progression are complex processes that, in order to be successful, require extraordinary cellular plasticity. Accordingly, tumor cell plasticity and how it affects disease progression have been studied extensively. However, as our understanding of the tumor microenvironment deepens, we are confronted with the notion that functional plasticity in the context of cancer is not limited to tumor cells alone but is also commonly seen in normal stromal cells of the microenvironment, and specifically in immune cells. Here, we review the functional plasticity these cells exhibit in the context of cancer, highlighting the role of circulating and tumor-associated neutrophils. We further discuss how this plasticity supports or limits tumor progression, inducing an "immunosuppressive switch" to promote further tumor growth and development. PMID- 26475870 TI - Tetracycline antibiotics impair mitochondrial function and its experimental use confounds research. AB - Tetracyclines, a class of antibiotics that target bacterial translation, are commonly used in research for inducible gene expression using Tet-ON/Tet-OFF systems. However, such tetracycline-inducible systems carry a risk. Given that mitochondria have a "bacterial" ancestry, these antibiotics also target mitochondrial translation and impair mitochondrial function. Indeed, treatment with doxycycline-a tetracycline derivative-disturbs mitochondrial proteostasis and metabolic activity, and induces widespread gene-expression changes. Together, this affects physiology in well-established model systems ranging from cultured cells to simple organisms and to mice and plants. These changes are observed with doxycycline doses that are widely used to regulate gene expression. In light of these findings, and bearing in mind the conserved role of mitochondria in metabolism and whole organism homeostasis, we caution against the use of tetracyclines in experimental approaches. The use of newly developed tetracycline based systems that are more sensitive could be an alternative; however, even if no overt mitochondrial toxicity is detected, widespread changes in gene expression may sensitize cells to the intended tetracycline-controlled loss or gain of function, thereby introducing a "two-hit model." This is highly relevant for cancer research, as mitochondrial metabolism holds a central position in the reallocation of nutrients for biomass production known as the Warburg effect. PMID- 26475871 TI - Pituitary apoplexy presenting with bilateral oculomotor nerve palsy. PMID- 26475873 TI - Pseudoangiomatous stromal hyperplasia causing massive breast enlargement. AB - Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a benign mesenchymal proliferative process, initially described by Vuitch et al. We report an unusual case of a 46-year-old woman who presented with a 6-week history of bilateral massive, asymmetrical, painful enlargement of her breasts, without a history of trauma. On clinical examination, both breasts were markedly enlarged and oedematous, but there were no discrete palpable masses. Preoperative image guided core biopsies and surgery showed PASH. PASH is increasingly recognised as an incidental finding on image-guided core biopsy performed for screen detected lesions. There are a few reported cases of PASH presenting as rapid breast enlargement. In our case, the patient presented with painful, asymmetrical, massive breast enlargement. Awareness needs to be raised of this entity as a differential diagnosis in massive, painful breast enlargement. PMID- 26475872 TI - Differential serotonergic innervation of the amygdala in bonobos and chimpanzees. AB - Humans' closest living relatives are bonobos (Pan paniscus) and chimpanzees (Pan troglodytes), yet these great ape species differ considerably from each other in terms of social behavior. Bonobos are more tolerant of conspecifics in competitive contexts and often use sexual behavior to mediate social interactions. Chimpanzees more frequently employ aggression during conflicts and actively patrol territories between communities. Regulation of emotional responses is facilitated by the amygdala, which also modulates social decision making, memory and attention. Amygdala responsiveness is further regulated by the neurotransmitter serotonin. We hypothesized that the amygdala of bonobos and chimpanzees would differ in its neuroanatomical organization and serotonergic innervation. We measured volumes of regions and the length density of serotonin transporter-containing axons in the whole amygdala and its lateral, basal, accessory basal and central nuclei. Results showed that accessory basal nucleus volume was larger in chimpanzees than in bonobos. Of particular note, the amygdala of bonobos had more than twice the density of serotonergic axons than chimpanzees, with the most pronounced differences in the basal and central nuclei. These findings suggest that variation in serotonergic innervation of the amygdala may contribute to mediating the remarkable differences in social behavior exhibited by bonobos and chimpanzees. PMID- 26475874 TI - Acute bilateral useless hand syndrome: a rare presenting manifestation of vitamin B12 deficiency. AB - We report a case of bilateral useless hand syndrome, a rare presenting manifestation of vitamin B12 deficiency. A 38-year-old man, a strict vegetarian and a teacher by occupation, presented with acute onset clumsiness of both hands while performing fine movements. Detailed history-taking, examination of the patient and relevant investigations (complete blood count, serum vitamin B12 and MRI of the cervical spinal cord) were carried out. Laboratory analysis was suggestive of vitamin B12 deficiency and MRI demonstrated a lesion involving the posterior columns of the cervical cord. The patient was diagnosed as a case of non-compressive cervical myelopathy predominantly involving the posterior column due to vitamin B12 deficiency. Acute bilateral useless hand syndrome can be a rare presenting feature of vitamin B12 deficiency. PMID- 26475875 TI - Type B aortic dissection triggered by heart transplantation in a patient with Marfan syndrome. AB - Heart transplantation in patients with Marfan syndrome is challenging and raises concerns with regards to the haemodynamic and immunosuppressive-induced effects on the inherently fragile aorta. Most aortic events following transplantation reported so far in the literature occurred in patients with pre-existent distal aortic dissection. We report a case of successful orthotopic heart transplantation in a patient with Marfan syndrome that was complicated by late onset type B dissection in pre-existing mild and stable distal aortic dilation. Serial aortic imaging revealed progressive growth at the level of the descending thoracic aorta. An open thoracoabdominal aortic repair procedure was successfully performed 6 months after the transplantation. PMID- 26475876 TI - Geographical tongue induced by axitinib. PMID- 26475877 TI - Candida albicans osteomyelitis as a cause of chest pain and visual loss. AB - Candida albicans osteomyelitis is a rare disease that occurs in immunocompromised individuals, sometimes with a late diagnosis related to the mismatch between symptoms and candidemia. This case refers to a 36-year-old male patient with a history of oesophageal surgery for achalasia with multiple subsequent surgeries and hospitalisation in the intensive care unit for oesophageal fistula complication. Four months after discharge, the patient was admitted to the infectious diseases department with pain in the 10th-12th left ribs, swelling of the 4th-6th costal cartilage and decreased visual acuity. An MRI study showed thickening and diffuse enhancement, with no defined borders in the cartilage and ribs, compatible with infection. After performing a CT-guided bone biopsy, isolated C. albicans sensitive to antifungal agents was detected. The patient started therapy with liposomal amphotericin B and maintenance fluconazole for 6 months and showed clinical and radiological improvement within this time. PMID- 26475878 TI - Deep brain stimulation complicated by bilateral large cystic cavitation around the leads in a patient with Parkinson's disease. AB - Deep brain stimulation (DBS) is an approved and effective therapy for patients suffering from advanced Parkinson's disease (PD). Several clinical trials have indicated significant motor function improvement in patients undergoing subthalamic nucleus stimulation. This therapy is, rarely, associated with complications, mostly related to infections, seizures or stimulation-induced side effects. We report a case of a 71-year-old man with a 10-year history of PD who underwent bilateral placement of subthalamic nucleus DBS. As a complication, the patient showed subjective postoperative cognitive decline, and subsequent MRI showed peri-lead oedema, which progressed to large cystic cavitation around the leads without indication of infection. The patient received steroid therapy and the cavitations regressed without surgical intervention. PMID- 26475879 TI - Pause-dependent paroxysmal phase-4 atrioventricular block. PMID- 26475880 TI - A paradoxical decline: intracranial lesions in two HIV-positive patients recovering from cryptococcal meningitis. AB - Cryptococcal immune reconstitution inflammatory syndrome (C-IRIS) is an increasingly important manifestation among patients with HIV/AIDS, especially as the use of antiretroviral therapy (ART) is expanding worldwide. Cryptococcus and associated C-IRIS are common causes of meningitis. While intracranial lesions are common in HIV/AIDS, they are rarely due to cryptococcosis or C-IRIS. We describe two cases of paradoxical C-IRIS associated with the development of intracranial cryptococcomas in HIV/AIDS. Both patients had an initial episode of cryptococcal meningitis treated with antifungal therapy. At the time, they had initiated or modified ART with subsequent evidence of immune reconstitution. Two months later, they developed aseptic meningitis with intracranial lesions. After exhaustive work ups, both patients were diagnosed with paradoxical C-IRIS and biopsy confirmed intracranial cryptococcomas. We review the important clinical, diagnostic and therapeutic features of cryptococcomas associated with C-IRIS in HIV/AIDS. PMID- 26475881 TI - Sinus venosus atrial septal defect presenting with brain abscesses in a 77-year old immunocompetent patient. AB - We present a case of 77-year-old immunocompetent patient who initially presented with vertigo, nausea and vomiting, with symptoms later progressing to headaches and increased lethargy. Brain MRI revealed ring-enhancing lesions typical of abscesses in the right cerebellum. Transoesophageal echocardiogram (TEE) was performed to look for the source of his abscesses, and uncovered a sinus venosus type atrial septal defect. Cardiac CT was carried out; the patient was found to have a sinus venosus atrial septal defect with partial anomalous pulmonary venous return. Moreover, dental examination showed multiple dental caries with poor oral hygiene. The patient was started on intravenous empiric antibiotics and steroids. Subsequent brain imaging showed almost complete resolution of the abscesses. The patient's symptoms started to improve, and he was eventually sent to an intensive rehabilitation centre with future plans to surgically correct his congenital heart disease to prevent further complications. PMID- 26475882 TI - A well known and important adverse effect of phenytoin in a neurosurgical patient. AB - Gum hypertrophy is a well-known and important adverse effect of phenytoin therapy in a neurosurgical patient. We present an interesting case of a 21-year-old man who, following head injury after a road traffic accident, developed status epilepticus diagnosed with gum hypertrophy in the jaws, with ongoing antiepileptics. He was managed conservatively as per hospital protocol. PMID- 26475883 TI - Late quadriceps tendon rupture at the donor site following cruciate ligament reconstruction using central quadriceps tendon graft. AB - Central quadriceps tendon (CQT) graft has been successfully used as a viable autograft option in cruciate ligament reconstruction of the knee. The prime emphasis in the majority of the literature is given to surgical details of quadriceps graft harvesting and outcome of cruciate ligament reconstruction. There is less discussion about donor site morbidity in CQT graft, and it is less frequent as compared to that in bone patellar tendon bone graft. We report an extremely unusual case of late quadriceps tendon rupture at the donor site following anterior cruciate ligament reconstruction using CQT graft. PMID- 26475884 TI - The ointment is mightier than the scalpel. PMID- 26475885 TI - Obstruction and perforation of the small bowel caused by inadvertent ingestion of a blister pill pack in an elderly patient. AB - Perforation of the small bowel due to foreign body ingestion is a rare instance that occurs in less than 1% of all ingestions. Although rare, ingestion of blister pill packaging is becoming more recognised as a causative agent for intestinal perforation, but is very rarely reported to cause intestinal obstruction. This is a report of a 66-year-old woman who presented with intestinal obstruction and underwent laparotomy, revealing small bowel perforation by a piece of blister pill pack foil. The patient was incognisant of the ingestion. PMID- 26475887 TI - Students' aptitude rewarded. PMID- 26475886 TI - Insurer to go ahead with preferred referral network. PMID- 26475888 TI - BVA supports veterinary charities. PMID- 26475889 TI - New TB rules for non-bovine animals in Scotland. PMID- 26475890 TI - Defra seeks a dialogue on animal import controls. PMID- 26475891 TI - Annual charity challenge 'the best so far'. PMID- 26475892 TI - Cooperating on animal disease and zoonosis research. PMID- 26475893 TI - Tackling illegal pet imports. AB - Nigel Gibbens, the UK's Chief Veterinary Officer, outlines what Defra is doing to address abuse of the EU pet travel scheme. PMID- 26475894 TI - Enterprise awards presented. PMID- 26475895 TI - Pine marten project gets underway. PMID- 26475896 TI - Sheep - and sun - in Scotland. AB - Sue Tongue reports from the Sheep Veterinary Society's autumn meeting, held on the Island of Mull from September 28 to 30. PMID- 26475898 TI - Clostridium perfringens infections - a diagnostic challenge. PMID- 26475899 TI - Benazepril in dogs with asymptomatic mitral valve disease. AB - BestBETs for Vets are generated by the Centre for Evidence-based Veterinary Medicine at the University of Nottingham to help answer specific questions and assist in clinical decision making. Although evidence is often limited, they aim to find, present and draw conclusions from the best available evidence, using a standardised framework. A more detailed description of how BestBETs for Vets are produced was published in Veterinary Record earlier this year (VR, April 4, 2015, vol 176, pp 354-356). PMID- 26475900 TI - Plasma derived colostrum and life expectancy in calves. AB - BestBETs for Vets are generated by the Centre for Evidence-based Veterinary Medicine at the University of Nottingham to help answer specific questions and assist in clinical decision making. Although evidence is often limited, they aim to find, present and draw conclusions from the best available evidence, using a standardised framework. A more detailed description of how BestBETs for Vets are produced was published in Veterinary Record earlier this year (VR, April 4, 2015, vol 176, pp 354-356). PMID- 26475901 TI - Shortage of experienced vets. PMID- 26475902 TI - Shortage of experienced vets. PMID- 26475903 TI - What is cure? PMID- 26475904 TI - What is cure? PMID- 26475905 TI - Developing the RCVS fellowship. PMID- 26475906 TI - Evidence-based veterinary medicine. PMID- 26475907 TI - Ear gel to treat otitis externa in dogs. PMID- 26475908 TI - Liver supplement for dogs and cats. PMID- 26475909 TI - Injectable anaesthetic back in stock. PMID- 26475911 TI - Diagnosing swine influenza. PMID- 26475912 TI - Screening for thyroid disorders. PMID- 26475913 TI - PCV-2 vaccine licensed for pregnant and lactating sows. PMID- 26475914 TI - Treating bacterial infections. PMID- 26475915 TI - Giving your heart to pathology. AB - Jim KIaassen recently joined Axiom Veterinary Laboratories as a clinical pathologist. During his career, Dr Klaassen has worked in small animal practice, lectured in clinical pathology, undertaken preclinical research and held senior roles in commercial veterinary laboratories in the USA, including as chief medical officer of Antech Diagnostics. PMID- 26475916 TI - Diary of a (new) parliamentary intern. AB - Anthony Ridge is the new parliamentary intern to Lord Trees. Here, he reflects on his new job and discovering his place in the veterinary profession. Anthony will be sharing his experiences with Vet Record Careers. PMID- 26475917 TI - Photo Quiz: Thigh Abscess in a Morbidly Obese Diabetic Patient. PMID- 26475920 TI - The impact of childhood residential mobility on mental health outcomes in adolescence and early adulthood: a record linkage study. AB - BACKGROUND: Understanding the causes of poor mental health in early childhood and adolescence is important as this can be a significant determinant of mental well being in later years. One potential and relatively unexplored factor is residential mobility in formative years. Previous studies have been relatively small and potentially limited due to methodological issues. The main aim of this study was to investigate the relationship between early residential instability and poor mental health among adolescents and young adults in Northern Ireland. METHODS: A Census-based record linkage study of 28% of children aged 0-8 years in 2001 in Northern Ireland (n=49,762) was conducted, with six monthly address change assessments from health registration data and self-reported mental health status from the 2011 Census. Logistic regression models were built adjusting for socioeconomic status (SES), household composition and marital dissolution. RESULTS: There was a graded relationship between the number of address changes and mental ill-health (adjusted OR 3.67, 95% CIs 2.11 to 6.39 for 5 or more moves). This relationship was not modified by SES or household composition. Marital dissolution was associated with poor mental health but did not modify the relationship between address change and mental health (p=0.206). There was some indication that movement after the age of five was associated with an increased likelihood of poor mental health. CONCLUSIONS: This large study clearly confirms the close relationship between address change in early years and later poor mental health. Residential mobility may be a useful marker for children at risk of poorer mental health in adolescence and early adulthood. PMID- 26475921 TI - How stakeholder participation can contribute to systematic reviews of complex interventions. AB - Although patient and public involvement in research is a requirement for research funding in many countries, the knowledge base for how to effectively involve people-and evidence of the effectiveness of involvement-is weak. This article describes how methods used in participatory health research were used to involve patients, clients, providers and community health workers across all stages of a realist review. Sustained involvement enabled better identification of the components of the complex intervention of community-based peer support. It also challenged assumptions of how peer support is constructed, leading the review team to question whether the process of designing and implementing interventions has more influence on effectiveness than previously recognised in empirical studies. We conclude with a discussion on when sustained involvement should be used, and the challenges of incorporating it into the traditional researcher-led approach to systematic reviews. PMID- 26475922 TI - Cotton Square Morphology Offers New Insights into Host Plant Resistance to Cotton Fleahopper (Hemiptera: Miridae) in Upland Cotton. AB - Cotton fleahopper, Pseudatomoscelis seriatus (Reuter) (Hemiptera: Miridae), is a piercing-sucking pest of cotton (Gossypium hirsutum L.) that feeds preferentially on developing flower buds, called squares. Heavy infestations cause yield reductions that result from abscission of squares damaged by the cotton fleahopper feeding. Antixenosis, or nonpreference, has been reported as a mechanism of host plant resistance in cotton to cotton fleahopper. Square structure, particularly the placement of the reproductive tissues, and stylet penetration were investigated as factors that influence resistance to cotton fleahopper in cotton lines derived from crosses with Pilose, a cultigen of upland cotton resistant to cotton fleahopper, and backcrossed with high-yielding, susceptible lines. Ovary depth varied among the lines tested and was found to be a heritable trait that affected the ability of a fleahopper's feeding stylets to penetrate the reproductive tissues in the square and might influence preference. Behavioral assays suggested antixenosis as a mechanism of host plant resistance, and the trait conferring antixenosis was found to be heritable. Results suggest ovary depth plays a role in conferring resistance to cotton fleahopper and is an exploitable trait in resistance breeding. PMID- 26475923 TI - An update on cell surface proteins containing extensin-motifs. AB - In recent years it has become clear that there are several molecular links that interconnect the plant cell surface continuum, which is highly important in many biological processes such as plant growth, development, and interaction with the environment. The plant cell surface continuum can be defined as the space that contains and interlinks the cell wall, plasma membrane and cytoskeleton compartments. In this review, we provide an updated view of cell surface proteins that include modular domains with an extensin (EXT)-motif followed by a cytoplasmic kinase-like domain, known as PERKs (for proline-rich extensin-like receptor kinases); with an EXT-motif and an actin binding domain, known as formins; and with extracellular hybrid-EXTs. We focus our attention on the EXT motifs with the short sequence Ser-Pro(3-5), which is found in several different protein contexts within the same extracellular space, highlighting a putative conserved structural and functional role. A closer understanding of the dynamic regulation of plant cell surface continuum and its relationship with the downstream signalling cascade is a crucial forthcoming challenge. PMID- 26475924 TI - A Central Role for HLA-DR3 in Anti-Smith Antibody Responses and Glomerulonephritis in a Transgenic Mouse Model of Spontaneous Lupus. AB - MHC, especially HLA-DR3 and HLA-DR2, is one of the most important genetic susceptibility regions for systemic lupus erythematosus. Human studies to understand the role of specific HLA alleles in disease pathogenesis have been hampered by the presence of strong linkage disequilibrium in this region. To overcome this, we produced transgenic mice expressing HLA-DR3 (DRbeta1*0301) and devoid of endogenous class II (both I-A and I-E genes, AE(0)) on a lupus-prone NZM2328 background (NZM2328.DR3(+)AE(0)). Both NZM2328 and NZM2328.DR3(+)AE(0) mice developed anti-dsDNA and glomerulonephritis, but anti-dsDNA titers were higher in the latter. Although kidney histological scores were similar in NZM2328 and NZM2328.DR3(+)AE(0) mice (7.2 +/- 4.3 and 8.6 +/- 5.7, respectively, p = 0.48), the onset of severe proteinuria occurred earlier in NZM2328.DR3(+)AE(0) mice compared with NZM2328 mice (median, 5 and 9 mo respectively, p < 0.001). Periarterial lymphoid aggregates, classic wire loop lesions, and occasional crescents were seen only in kidneys from NZM2328.DR3(+)AE(0) mice. Interestingly, NZM2328.DR3(+)AE(0) mice, but not NZM2328 mice, spontaneously developed anti Smith (Sm) Abs. The anti-Sm Abs were seen in NZM2328.DR3(+)AE(0) mice that were completely devoid of endogenous class II (AE(-/) (-)) but not in mice homozygous (AE(+/+)) or heterozygous (AE(+/-)) for endogenous MHC class II. It appears that only HLA-DR3 molecules can preferentially select SmD-reactive CD4(+) T cells for generation of the spontaneous anti-Sm immune response. Thus, our mouse model unravels a critical role for HLA-DR3 in generating an autoimmune response to SmD and lupus nephritis in the NZM2328 background. PMID- 26475925 TI - Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion Induced Acute Lung Injury. AB - Diverse clinical factors, including intestinal ischemia, contribute to acute lung injury (ALI), which has up to a 40% mortality rate. During the development of lung injury an immune response is elicited that exacerbates the lung insult. Neutrophils have been well studied in mediating the pulmonary insults through an assortment of mechanisms, such as release of granule contents and production of proinflammatory cytokines due to the overactivation of complement and cytokines. In this study, we found that enhanced endoplasmic reticulum (ER) stress was observed in infiltrated neutrophils in the early stage of an ALI mice model. In neutrophils, complement 5a (C5a) inspires strong ER stress through inositol requiring kinase 1a and, to a less extent, the protein kinase R-like ER kinase signaling pathway. The granule release induced by C5a was ER stress mediated. Knowkdown of X-box-binding protein 1, a downstream signaling molecule of inositol requiring kinase 1a, impaired granule release, based on myeloperoxidase production. Further analysis revealed that C5a induced ER stress by binding to C5a receptor in neutrophils. Using xbp(f/f) MRP8-cre mice in which X-box-binding protein 1 is deficient specifically in neutrophils and ER stress is deprived, we confirmed that ER stress in neutrophils was required for granule release in vivo and led to ALI, whereas dampening ER stress in neutrophils substantially alleviated ALI. Taken together, our results demonstrated that C5a receptor mediated ER stress induced granule release in neutrophils, contributing to the development of ALI. This novel mechanism suggests a new potential therapeutic target in autophagy regulation for ALI. PMID- 26475926 TI - TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased Central Nervous System Demyelinating Autoimmune Disease. AB - TNF-alpha antagonists provide benefit to patients with inflammatory autoimmune disorders such as Crohn's disease, rheumatoid arthritis, and ankylosing spondylitis. However, TNF antagonism unexplainably exacerbates CNS autoimmunity, including multiple sclerosis and neuromyelitis optica. The underlying mechanisms remain enigmatic. We demonstrate that TNFR2 deficiency results in female-biased spontaneous autoimmune CNS demyelination in myelin oligodendrocyte glycoprotein specific 2D2 TCR transgenic mice. Disease in TNFR2(-/-) 2D2 mice was associated with CNS infiltration of T and B cells as well as increased production of myelin oligodendrocyte glycoprotein-specific IL-17, IFN-gamma, and IgG2b. Attenuated disease in TNF(-/-) 2D2 mice relative to TNFR2(-/-) 2D2 mice identified distinctive roles for TNFR1 and TNFR2. Oral antibiotic treatment eliminated spontaneous autoimmunity in TNFR2(-/-) 2D2 mice to suggest role for gut microbiota. Illumina sequencing of fecal 16S rRNA identified a distinct microbiota profile in male TNFR2(-/-) 2D2 that was associated with disease protection. Akkermansia muciniphila, Sutterella sp., Oscillospira sp., Bacteroides acidifaciens, and Anaeroplasma sp. were selectively more abundant in male TNFR2(-/-) 2D2 mice. In contrast, Bacteroides sp., Bacteroides uniformis, and Parabacteroides sp. were more abundant in affected female TNFR2(-/-) 2D2 mice, suggesting a role in disease causation. Overall, TNFR2 blockade appears to disrupt commensal bacteria-host immune symbiosis to reveal autoimmune demyelination in genetically susceptible mice. Under this paradigm, microbes likely contribute to an individual's response to anti-TNF therapy. This model provides a foundation for host immune-microbiota-directed measures for the prevention and treatment of CNS-demyelinating autoimmune disorders. PMID- 26475927 TI - A Complement-Optimized EGFR Antibody Improves Cytotoxic Functions of Polymorphonuclear Cells against Tumor Cells. AB - Complement-dependent cytotoxicity (CDC) has been suggested to be an important mechanism of action of tumor-targeting Abs. However, single unmodified epidermal growth factor receptor (EGFR)-targeting IgG1 Abs fail to trigger efficient CDC. For the current study, we generated a CDC-optimized variant of the EGFR Ab matuzumab (H425 wt) by introducing amino acid substitutions K326A/E333A (H425 mt). This Ab was then used to elucidate the impact of complement activation on the capacity of effector cells such as mononuclear cells (MNC) and polymorphonuclear cells (PMN) to exert Ab-dependent cell-mediated cytotoxicity (ADCC). H425 mt, but not H425 wt, significantly induced complement deposition, release of anaphylatoxins, and CDC against distinct tumor cell lines, whereas no differences in ADCC by MNC or PMN were detected. Notably, stronger cytotoxicity was induced by H425 mt than by H425 wt in whole blood assays and in experiments in which MNC or PMN were combined with serum. Although MNC-ADCC was not affected by C5 cleavage, the cytotoxic activity of PMN in the presence of serum strongly depended on C5 cleavage, pointing to a direct interaction between complement and PMN. Strong cell surface expression of C5a receptors was detected on PMN, whereas NK cells completely lacked expression. Stimulation of PMN with C5a led to upregulation of activated complement receptor 3, resulting in enhanced complement receptor 3-dependent PMN-ADCC against tumor cells. In conclusion, complement optimized EGFR Abs may constitute a promising strategy to improve tumor cell killing by enhancing the interaction between humoral and cellular effector functions in Ab-based tumor therapy. PMID- 26475928 TI - Responsiveness of Developing T Cells to IL-7 Signals Is Sustained by miR-17~92. AB - miRNAs regulate a large variety of developmental processes including development of the immune system. T cell development is tightly controlled through the interplay of transcriptional programs and cytokine-mediated signals. However, the role of individual miRNAs in this process remains largely elusive. In this study, we demonstrated that hematopoietic cell-specific loss of miR-17~92, a cluster of six miRNAs implicated in B and T lineage leukemogenesis, resulted in profound defects in T cell development both at the level of prethymic T cell progenitors as well as intrathymically. We identified reduced surface expression of IL-7R and concomitant limited responsiveness to IL-7 signals as a common mechanism resulting in reduced cell survival of common lymphoid progenitors and thymocytes at the double-negative to double-positive transition. In conclusion, we identified miR-17~92 as a critical modulator of multiple stages of T cell development. PMID- 26475929 TI - Sensor Function for Butyrophilin 3A1 in Prenyl Pyrophosphate Stimulation of Human Vgamma2Vdelta2 T Cells. AB - Vgamma2Vdelta2 T cells play important roles in human immunity to pathogens and in cancer immunotherapy by responding to isoprenoid metabolites, such as (E)-4 hydroxy-3-methyl-but-2-enyl pyrophosphate and isopentenyl pyrophosphate. The Ig superfamily protein butyrophilin (BTN)3A1 was shown to be required for prenyl pyrophosphate stimulation. We proposed that the intracellular B30.2 domain of BTN3A1 binds prenyl pyrophosphates, resulting in a change in the extracellular BTN3A1 dimer that is detected by Vgamma2Vdelta2 TCRs. Such B30.2 binding was demonstrated recently. However, other investigators reported that the extracellular BTN3A1 IgV domain binds prenyl pyrophosphates, leading to the proposal that the Vgamma2Vdelta2 TCR recognizes the complex. To distinguish between these mechanisms, we mutagenized residues in the two binding sites and tested the mutant BTN3A1 proteins for their ability to mediate prenyl pyrophosphate stimulation of Vgamma2Vdelta2 T cells to proliferate and secrete TNF-alpha. Mutagenesis of residues in the IgV site had no effect on Vgamma2Vdelta2 T cell proliferation or secretion of TNF-alpha. In contrast, mutagenesis of residues within the basic pocket and surrounding V regions of the B30.2 domain abrogated prenyl pyrophosphate-induced proliferation. Mutations of residues making hydrogen bonds to the pyrophosphate moiety also abrogated TNF alpha secretion, as did mutation of aromatic residues making contact with the alkenyl chain. Some mutations further from the B30.2 binding site also diminished stimulation, suggesting that the B30.2 domain may interact with a second protein. These findings support intracellular sensing of prenyl pyrophosphates by BTN3A1 rather than extracellular presentation. PMID- 26475930 TI - Vaccination With Heterologous HIV-1 Envelope Sequences and Heterologous Adenovirus Vectors Increases T-Cell Responses to Conserved Regions: HVTN 083. AB - BACKGROUND: Increasing the breadth of human immunodeficiency virus type 1 (HIV-1) vaccine-elicited immune responses or targeting conserved regions may improve coverage of circulating strains. HIV Vaccine Trials Network 083 tested whether cellular immune responses with these features are induced by prime-boost strategies, using heterologous vectors, heterologous inserts, or a combination of both. METHODS: A total of 180 participants were randomly assigned to receive combinations of adenovirus vectors (Ad5 or Ad35) and HIV-1 envelope (Env) gene inserts (clade A or B) in a prime-boost regimen. RESULTS: T-cell responses to heterologous and homologous insert regimens targeted a similar number of epitopes (ratio of means, 1.0; 95% confidence interval [CI], .6-1.6; P = .91), but heterologous insert regimens induced significantly more epitopes that were shared between EnvA and EnvB than homologous insert regimens (ratio of means, 2.7; 95% CI, 1.2-5.7; P = .01). Participants in the heterologous versus homologous insert groups had T-cell responses that targeted epitopes with greater evolutionary conservation (mean entropy [+/-SD], 0.32 +/- 0.1 bits; P = .003), and epitopes recognized by responders provided higher coverage (49%; P = .035). Heterologous vector regimens had higher numbers of total, EnvA, and EnvB epitopes than homologous vector regimens (P = .02, .044, and .045, respectively). CONCLUSIONS: These data demonstrate that vaccination with heterologous insert prime boosting increased T-cell responses to shared epitopes, while heterologous vector prime boosting increased the number of T-cell epitopes recognized. CLINICAL TRIALS REGISTRATION: NCT01095224. PMID- 26475932 TI - HCV-infected cells and differentiation increase monocyte immunoregulatory galectin-9 production. AB - The lectin galectin-9 may help establish and maintain chronic hepatitis C virus infection. Galectin-9 is elevated in the liver and sera of hepatitis C virus patients, induces apoptosis of hepatitis C virus-specific T cells, and increases inhibitory regulatory T cells. Kupffer cells stain strongly for galectin-9 protein in hepatitis C virus patients. In the current study, we determined stimuli that induce galectin-9 production by monocytes and macrophages in hepatitis C virus infection. With the use of real-time PCR and flow cytometry, we analyzed galectin-9 mRNA and protein from human monocytes cocultured with hepatitis C virus-infected cells or noninfectious hepatitis C virus subgenomic replicon cells. We focused on finding the stimuli for galectin-9 production. Additionally, we measured galectin-9 during monocyte-to-macrophage maturation. Finally, we examined galectin-9 in peripheral monocytes from hepatitis C virus patients using flow cytometry. Galectin-9 mRNA increased 8-fold when primary monocytes were exposed to hepatitis C virus--infected cells. Maximum induction required proximity or contact and did not require IFN-gamma or hepatitis C virus virions. Coculture of monocytes with subgenomic replicon cells increased galectin 9 5-fold, and purified exosomes from infected cells stimulated galectin-9 production. Stimulation of monocyte TLR3, -7, and -8 increased galectin-9 production. Differentiation of monocytes to macrophages increased galectin-9, and nonclassic monocytes from hepatitis C virus patients had the highest levels of galectin-9. Hepatitis C virus-infected cells stimulated monocytes to produce galectin-9 in close proximity, possibly, in part, as a result of exosomes and endosomal TLRs. Differentiation of monocytes to macrophages increased galectin-9. Nonclassic monocytes from hepatitis C virus patients express the highest galectin 9 levels, suggesting they may contribute to elevated galectin-9 and adaptive immune inhibition in hepatitis C virus infection. PMID- 26475931 TI - Herpes Simplex Virus Type-2 Cervicovaginal Shedding Among Women Living With HIV-1 and Receiving Antiretroviral Therapy in Burkina Faso: An 8-Year Longitudinal Study. AB - BACKGROUND: The impact of antiretroviral therapy (ART) on herpes simplex virus type-2 (HSV-2) replication is unclear. The aim of this study was to assess factors associated with cervicovaginal HSV-2 DNA shedding and genital ulcer disease (GUD) in a cohort of women living with human immunodeficiency virus type 1 (HIV-1) in Burkina Faso. METHODS: Participants were screened for cervicovaginal HSV-2 DNA, GUD, cervicovaginal and systemic HIV-1 RNA, and reproductive tract infections every 3-6 months over 8 years. Associations with HSV-2 shedding and quantity were examined using random-effects logistic and linear regression, respectively. RESULTS: Of the 236 women with data on HSV-2 shedding, 151 took ART during the study period. Cervicovaginal HSV-2 DNA was detected in 42% of women (99 of 236) in 8.2% of visits (151 of 1848). ART was associated with a reduction in the odds of HSV-2 shedding, which declined for each year of ART use (odds ratio [OR], 0.74; 95% confidence interval [CI], .59-.92). In the multivariable model, the impact of ART was primarily associated with suppression of systemic HIV-1 RNA (adjusted OR, 0.32; 95% CI, .15-.67). A reduction in the odds of GUD was also observed during ART, mainly in those with HIV-1 suppression (adjusted OR, 0.53; 95% CI, .25-1.11). CONCLUSIONS: ART is strongly associated with a decrease in cervicovaginal HSV-2 shedding, and the impact was sustained over several years. PMID- 26475933 TI - Prevalence of Myofascial Trigger Points in Spinal Disorders: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To retrieve, appraise, and synthesize the results of studies on the prevalence of active and latent myofascial trigger points (MTrPs) in subjects with spinal pain disorders. DATA SOURCES: The databases PubMed, Embase, and CINAHL were searched, with no date or language restrictions. Search terms included controlled and free-text terms for spinal disorders and MTrPs. Further searches were conducted in Google Scholar and by contacting 3 experts in the field. Citation tracking of eligible studies was performed. STUDY SELECTION: Two reviewers independently selected observational studies assessing the prevalence of active and/or latent MTrPs in at least 1 group of adults with a spinal disorder. Twelve studies met the eligibility criteria. DATA EXTRACTION: Methodologic quality was assessed by 2 reviewers independently using a modified version of the Downs and Black checklist. Two reviewers also used a customized form to extract studies and subjects' characteristics and the proportions of subjects with active and/or latent MTrPs in each muscle assessed. DATA SYNTHESIS: A meta-analysis was performed when there was sufficient clinical homogeneity in at least 2 studies for the same spinal disorder. The Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the body of evidence in each meta-analysis. A qualitative description of the results of single studies was provided. Low-quality evidence underpinned pooled estimates of MTrPs in the upper-body muscles of subjects with chronic neck pain. The point prevalence of MTrPs in different muscles of other disorders (eg, whiplash associated disorders, nonspecific low back pain) was extracted from single studies with low methodologic quality and small samples. Active MTrPs were found to be present in all assessed muscles of subjects diagnosed with different spinal pain disorders. Latent MTrPs were not consistently more prevalent in subjects with a spinal disorder than in healthy controls. CONCLUSIONS: The MTrPs point prevalence estimates in this review should be viewed with caution because future studies with large samples and high methodologic quality are likely to change them substantially. PMID- 26475934 TI - Rhizosphere microbiome metagenomics of gray mangroves (Avicennia marina) in the Red Sea. AB - Mangroves are unique, and endangered, coastal ecosystems that play a vital role in the tropical and subtropical environments. A comprehensive description of the microbial communities in these ecosystems is currently lacking, and additional studies are required to have a complete understanding of the functioning and resilience of mangroves worldwide. In this work, we carried out a metagenomic study by comparing the microbial community of mangrove sediment with the rhizosphere microbiome of Avicennia marina, in northern Red Sea mangroves, along the coast of Saudi Arabia. Our results revealed that rhizosphere samples presented similar profiles at the taxonomic and functional levels and differentiated from the microbiome of bulk soil controls. Overall, samples showed predominance by Proteobacteria, Bacteroidetes and Firmicutes, with high abundance of sulfate reducers and methanogens, although specific groups were selectively enriched in the rhizosphere. Functional analysis showed significant enrichment in 'metabolism of aromatic compounds', 'mobile genetic elements', 'potassium metabolism' and 'pathways that utilize osmolytes' in the rhizosphere microbiomes. To our knowledge, this is the first metagenomic study on the microbiome of mangroves in the Red Sea, and the first application of unbiased 454 pyrosequencing to study the rhizosphere microbiome associated with A. marina. Our results provide the first insights into the range of functions and microbial diversity in the rhizosphere and soil sediments of gray mangrove (A. marina) in the Red Sea. PMID- 26475935 TI - V-GAP: Viral genome assembly pipeline. AB - Next-generation sequencing technologies have allowed the rapid determination of the complete genomes of many organisms. Although shotgun sequences from large genome organisms are still difficult to reconstruct perfect contigs each of which represents a full chromosome, those from small genomes have been assembled successfully into a very small number of contigs. In this study, we show that shotgun reads from phage genomes can be reconstructed into a single contig by controlling the number of read sequences used in de novo assembly. We have developed a pipeline to assemble small viral genomes with good reliability using a resampling method from shotgun data. This pipeline, named V-GAP (Viral Genome Assembly Pipeline), will contribute to the rapid genome typing of viruses, which are highly divergent, and thus will meet the increasing need for viral genome comparisons in metagenomic studies. PMID- 26475936 TI - Bacterial community structures of deep-sea water investigated by molecular biological techniques. AB - The aim of the present study was to investigate the bacterial community structures of deep-sea water (DSW) and surface seawater (SSW) samples in Japan by molecular biological techniques. DGGE analyses and pyrosequencing analysis revealed that bacterial community structures of DSW were diverse and differed from those of SSW. This is the first report on the horizontal variation of bacterial community structures of DSW throughout Japan. In addition, pyrosequencing analysis revealed that the number of phyla in DSW was larger than that in SSW, and specific phyla, such as Firmicutes and Planctomycetes, were characterized by a higher proportion of the bacterial community structure in DSW than in SSW. Taken together, these results indicate that a variety of bacteria that are specifically adapted to the DSW environments can be expected to be found in DSW, and DSW would thus be a potential resource for novel or unique microorganisms and compounds. PMID- 26475937 TI - Influences of diurnal sampling bias on fixed-point monitoring of plankton biodiversity determined using a massively parallel sequencing-based technique. AB - In this study, we investigated the influence of diurnal sampling bias on the community structure of plankton by comparing the biodiversity among seawater samples (n=9) obtained every 3h for 24h by using massively parallel sequencing (MPS)-based plankton monitoring at a fixed point conducted at Himedo seaport in Yatsushiro Sea, Japan. The number of raw operational taxonomy units (OTUs) and OTUs after re-sampling was 507-658 (558 +/- 104, mean +/- standard deviation) and 448-544 (467 +/- 81), respectively, indicating high plankton biodiversity at the sampling location. The relative abundance of the top 20 OTUs in the samples from Himedo seaport was 48.8-67.7% (58.0 +/- 5.8%), and the highest-ranked OTU was Pseudo-nitzschia species (Bacillariophyta) with a relative abundance of 17.3 39.2%, followed by Oithona sp. 1 and Oithona sp. 2 (Arthropoda). During seawater sampling, the semidiurnal tidal current having an amplitude of 0.3ms(-1) was dominant, and the westward residual current driven by the northeasterly wind was continuously observed during the 24-h monitoring. Therefore, the relative abundance of plankton species apparently fluctuated among the samples, but no significant difference was noted according to G-test (p>0.05). Significant differences were observed between the samples obtained from a different locality (Kusuura in Yatsushiro Sea) and at different dates, suggesting that the influence of diurnal sampling bias on plankton diversity, determined using the MPS-based survey, was not significant and acceptable. PMID- 26475938 TI - Characterization of avian pathogenic Escherichia coli isolated in eastern China. AB - In order to investigate the biological characteristics of avian pathogenic Escherichia coli (APEC) isolated in eastern China, a total of 243 isolates were isolated from diseased poultry on different farms during the period from 2007 to 2014. These isolates were characterized for serogroups (polymerase chain reaction and agglutination), the presence of virulence-associated genes (fimC, iss, ompA, fyuA, stx2f, iroC, iucD, hlyE, tsh, cvaC, irp2, and papC) and class I integrons (polymerase chain reaction), drug susceptibilities (disk diffusion method) and the biofilm-forming abilities (semi-quantitative method). The results showed that the most predominant serogroups were O78 (87 isolates, 35.8%) and O2 (35 isolates, 14.4%). Gene profiling found that fimC and ompA were frequently distributed among the isolates and that 77.4% of the isolates were positive for class 1 integrons. Overall, isolates displayed resistance to tetracycline (97.5%), nalidixic acid (82.3%), ampicillin (81.1%), sulphafurazole (80.7%), streptomycin (79.0%), trimethoprim (78.2%) and cotrimoxazole (78.2%). Multiple drug resistance was exhibited in 80.3% of the isolates, and the presence of class 1 integrons is associated with multidrug resistance. Finally, 151 isolates had the ability to form biofilms in vitro, and drug resistance seemed relative to biofilm-forming abilities. PMID- 26475939 TI - Speciation of two gobioid species, Pterogobius elapoides and Pterogobius zonoleucus revealed by multi-locus nuclear and mitochondrial DNA analyses. AB - To understand how geographical differentiation of gobioid fish species led to speciation, two populations of the Pacific Ocean and the Sea of Japan for each of the two gobioid species, Pterogobius elapoides and Pterogobius zonoleucus, were studied in both morphological and molecular features. Analyzing mitochondrial genes, Akihito et al. (2008) suggested that P. zonoleucus does not form a monophyletic clade relative to P. elapoides, indicating that "Sea of Japan P. zonoleucus" and P. elapoides form a clade excluding "Pacific P. zonoleucus" as an outgroup. Because morphological classification clearly distinguish these two species and a gene tree may differ from a population tree, we examined three nuclear genes, S7RP, RAG1, and TBR1, in this work, in order to determine whether nuclear and mitochondrial trees are concordant, thus shedding light on the evolutionary history of this group of fishes. Importantly, nuclear trees were based on exactly the same individuals that were used for the previously published mtDNA trees. The tree based on RAG1 exon sequences suggested a closer relationship of P. elapoides with "Sea of Japan P. zonoleucus", which was in agreement with the mitochondrial tree. In contrast, S7RP and TBR1 introns recovered a monophyletic P. zonoleucus. If the mitochondrial tree represents the population tree in which P. elapoides evolved from "Sea of Japan P. zonoleucus", the population size of P. elapoides is expected to be smaller than that of "Sea of Japan P. zonoleucus". This is because a smaller population of the new species is usually differentiated from a larger population of the ancestral species when the speciation occurred. However, we found no evidence of such a small population size during the evolution of P. elapoides. Therefore, we conclude that the monophyletic P. zonoleucus as suggested by S7RP and TBR1 most likely represents the population tree, which is consistent with the morphological classification. In this case, it is possible that the incongruent mitochondrial and RAG1 trees are either due to incomplete lineage sorting of ancestral polymorphisms or to introgression by hybridization. Because of a smaller effective population size of mitochondria compared with nuclear genes, the introgression might be a more likely scenario in explaining the incongruent mitochondrial tree than the incomplete lineage sorting. Because of smaller effective population size of "Sea of Japan P. zonoleucus" than that of P. elapoides, the direction of the introgression was likely to be from the latter to the former. This evolutionary work of the two gobioid species highlights the need of analyzing multiple gene trees for both nuclear and mitochondrial genes as well as scrutinization of morphological characteristics to obtain a population tree representing the organismal evolutionary history. PMID- 26475940 TI - Modern Guidelines for Bowel Preparation and Antimicrobial Prophylaxis for Open and Laparoscopic Urologic Surgery. AB - Mechanical bowel preparation (MBP) and antibiotics (oral and/or intravenous) have historically been used to decrease infectious complications in surgeries that involve manipulation of bowel or potential risk of injury. The use of MBP has recently been challenged in the colorectal surgery literature, thus inspiring similar critical evaluation of our practices in urology. This review gives a brief overview of the history of mechanical and oral antibiotic bowel preparation, as well as the evolution of the practice trends in colorectal surgery and urology. We also examine contemporary guidelines in skin preparation as well as antimicrobial prophylaxis before surgery. PMID- 26475941 TI - Update on Antibiotic Prophylaxis for Genitourinary Procedures in Patients with Artificial Joint Replacement and Artificial Heart Valves. AB - Infection of artificial joint replacements and heart valves is an uncommon but serious complication encountered anytime after the implantation of these prostheses. It is known that bacteremia can lead to infection of a prosthetic device. However, there is no strong evidence to correlate urologic procedures with the development of periprosthetic joint infection or prosthetic valve endocarditis. Therefore, antibiotic prophylaxis for the prevention of endocarditis is not recommended in patients undergoing urologic procedures. However, guidelines regarding prophylaxis to prevent infection of an artificial joint in the setting of a genitourinary procedure are more varied. PMID- 26475942 TI - Preprostate Biopsy Rectal Culture and Postbiopsy Sepsis. AB - Transrectal ultrasound-guided biopsy of the prostate (TRUSP) remains the primary procedure for the accurate histologic diagnosis of prostate cancer. Fluoroquinolones (FQs) are still recommended as the agents of choice for antimicrobial prophylaxis for TRUSP despite the alarming increasing incidence of FQ-resistant organisms among men undergoing TRUSP. This article reviews the current TRUSP antimicrobial prophylaxis guidelines, antimicrobial resistance and its implications for these guidelines, the incidence of post-TRUSP infectious complications including urosepsis, the seminal data supporting pre-TRUSP rectal swab (RS), RS technique and protocol, and the current available literature surrounding the efficacy of RS in reducing post-TRUSP infectious complications. PMID- 26475943 TI - Treatment of the Infected Stone. AB - Infected kidney stones refer to stones that form because of urinary tract infections with urease-producing bacteria, secondarily infected stones of any composition, or stones obstructing the urinary tract leading to pyelonephritis. The mainstay of treatment of infection stones is complete stone removal. Kidney stones that obstruct the urinary tract and cause obstructive pyelonephritis are also frequently referred to as infected stones. Obstructive pyelonephritis is a urologic emergency as it can result in sepsis and even death. Infection stones and obstructive stones causing pyelonephritis are different disease processes, and their workup and management are described separately. PMID- 26475944 TI - Treatment of Fungal Urinary Tract Infection. AB - Funguria, and particularly candiduria, is an increasingly common problem encountered by the practicing urologist and is associated with high-acuity care, indwelling catheters, diabetes mellitus, antibiotic and steroid use, and urinary tract disease. In most cases, candiduria is asymptomatic and follows a benign clinical course with antifungal therapy only required in symptomatic or high-risk cases, because spontaneous resolution is common in patients with asymptomatic colonization. Rarely, invasive infections can occur (such as fungus balls or renal abscesses) and may require percutaneous and endoscopic interventions. This article highlights the workup and treatment of funguria and its related urologic manifestations. PMID- 26475945 TI - Current Concepts in Infections Associated with Penile Prostheses and Artificial Sphincters. AB - Implantation of penile prostheses and artificial urinary sphincters have gained widespread acceptance for the treatment of refractory erectile dysfunction and incontinence, respectively. In the past 3 decades, improved device design and an increased understanding of the pathophysiology of device infections have contributed to a decrease in infection rates. However, understanding the concepts related to infection prevention and management remains critical. In this article, the authors review and discuss these concepts and provide outlines for the practicing urologists for both infection prevention and treatment. PMID- 26475946 TI - Epidemiology and Management of Emerging Drug-Resistant Gram-Negative Bacteria: Extended-Spectrum beta-Lactamases and Beyond. AB - Worldwide prevalence of antimicrobial resistance is rapidly increasing, primarily a result of antibiotic misuse in the medical community. Resistant infections involving the urinary tract are typically caused by gram-negative bacteria. When treating these infections, clinicians have few effective antimicrobials to choose from and many are associated with significant adverse effects. There are now situations when clinicians are tasked with managing infections from pan-resistant organisms; thus, it is of paramount importance that spread of resistance be controlled. This review discusses common gram-negative resistance classes, highlighting the mechanisms of resistance, risk factors, type of infections, treatment, and outcomes associated with each class. PMID- 26475947 TI - Sexually Transmitted Infections. AB - Sexually transmitted infections (STIs) remain a significant burden on public health in the United States. Primary prevention counseling with early diagnosis and treatment remain the best methods to decrease the incidence of STIs. Through significant public heath interventions, the incidence of gonorrhea, Chlamydia, and trichomoniasis is decreasing; however, the incidence of primary and secondary syphilis is increasing. Human papilloma virus remains the most common STI, but new vaccinations have the possibility of having a significant impact on this virus's disease potential. This review discusses the most common STIs in the United States, focusing on clinical presentation, diagnosis, and treatment. PMID- 26475948 TI - Work-up of Pediatric Urinary Tract Infection. AB - Pediatric urinary tract infection (UTI) costs the health care system more than $180 million annually, and accounts for more than 1.5 million clinician visits per year. Accurate and timely diagnosis of these infections is important for determining appropriate treatment and preventing long-term complications such as renal scarring, hypertension, and end-stage renal disease. After the first 12 months, girls are more likely to be diagnosed with a UTI. About half of boys with UTI are diagnosed within the first 12 months of life. Diagnosis of UTI is made based on history and examination findings and confirmed by urine testing. PMID- 26475949 TI - Urinary Tract Infection and Neurogenic Bladder. AB - Urinary tract infections (UTIs) are frequent, recurrent, and lifelong for patients with neurogenic bladder and present challenges in diagnosis and treatment. Patients often present without classic symptoms of UTI but with abdominal or back pain, increased spasticity, and urinary incontinence. Failure to recognize and treat infections can quickly lead to life-threatening autonomic dysreflexia or sepsis, whereas overtreatment contributes to antibiotic resistance, thus limiting future treatment options. Multiple prevention methods are used but evidence-based practices are few. Prevention and treatment of symptomatic UTI requires a multimodal approach that focuses on bladder management as well as accurate diagnosis and appropriate antibiotic treatment. PMID- 26475950 TI - Asymptomatic Bacteriuria in Noncatheterized Adults. AB - Asymptomatic bacteriuria (ASB) is a common finding and frequently detected in premenopausal nonpregnant women, institutionalized patients, patients with diabetes mellitus, and the ambulatory elderly population. Despite clear recommendations regarding diagnosis and management of ASB in these populations from the Infectious Diseases Society of America (IDSA), there remains an alarming rate of antimicrobial overuse. This article reviews definitions of ASB, epidemiology of ASB, literature surrounding ASB in diabetic patients, risk factors of ASB, microbiologic data regarding bacterial virulence, use of ASB strains for treatment of symptomatic urinary tract infection, and approaches to addressing translational barriers to implementing IDSA recommendations regarding diagnosis and management of ASB. PMID- 26475951 TI - Urinary Tract Infection and Bacteriuria in Pregnancy. AB - Bacteriuria during pregnancy may be classified as asymptomatic bacteriuria, infections of the lower urinary tract (cystitis), or infections of the upper urinary tract (pyelonephritis). Lower tract bacteriuria is associated with an increased risk of developing pyelonephritis in pregnancy, which is itself associated with adverse maternal and fetal outcomes. Pregnant women should be screened for the presence of bacteriuria early in pregnancy. All bacteriuria in pregnancy should be treated, and antimicrobial choice in pregnancy should reflect safety for both the mother and the fetus. After treatment of bacteriuria, patients should be followed closely due to risk of recurrent bacteriuria. PMID- 26475952 TI - Bacteruria and Urinary Tract Infections in the Elderly. AB - Both urinary tract infection (UTI) and asymptomatic bacteriuria (ASB) are common problems among elderly adults and represent a significant health care burden. Despite their frequency, differentiating between ASB and true UTI remains controversial among health care providers. Several challenges exist in the evaluation of urinary symptoms in the elderly patient. Symptoms of UTI are variable; problems are encountered in the collection, testing, and interpretation of urine specimens; and results of urinalysis are often misinterpreted and mishandled. Multiple studies have shown no morbidity or mortality benefit to antibiotic therapy in either community or long-term care facility residents with ASB. PMID- 26475953 TI - Contemporary Antibiotic Management for Urologic Procedures and Infections. PMID- 26475954 TI - Contemporary Antibiotic Management for Urologic Procedures and Infections. PMID- 26475955 TI - Watching what's coming near increases tactile sensitivity: An experimental investigation. AB - During medical examinations, doctors regularly investigate a patient's somatosensory system by approaching the patient with a medical device (e.g. Von Frey hairs, algometer) or with their hands. It is assumed that the obtained results reflect the true capacities of the somatosensory system. However, evidence from crossmodal spatial research suggests that sensory experiences in one modality (e.g. touch) can be influenced by concurrent information from other modalities (e.g. vision), especially near the body (i.e. in peripersonal space). Hence, we hypothesized that seeing someone approaching your body could alter tactile sensitivity in that body-part. In the In Vivo Approaching Object (IVAO) paradigm, participants detected and localized threshold-level vibrotactile stimuli administered on the left of right hand (=tactile targets). In Experiment 1, this was always preceded by the experimenter approaching the same (congruent trials) or the other (incongruent trials) hand with a pen (=visual cue). In Experiment 2, a condition was added in which a point further away from the hands (also left vs. right) was approached. Response Accuracy was calculated for congruent and incongruent trials (Experiment 1 & 2) and compared between the close and far condition (Experiment 2). As expected, Response Accuracy was higher in congruent trials compared to incongruent trials, but only near the body. As a result, evidence was found for a crossmodal interaction effect between visual and tactile information in peripersonal space. These results suggest that somatosensory evaluations-both medical or research-based-may be biased by viewing an object approaching the body. PMID- 26475956 TI - Immune reactivity in rats selected for the enhancement or elimination of aggressiveness towards humans. AB - This study analyzes immune reactivity in two lines of rats selected for the enhancement or elimination of aggressiveness toward humans. Compared to nonaggressive line, aggressive rats showed increased blood ratio of CD4(+) and CD8(+)T lymphocytes, monocyte chemoattractant protein (MCP)-1 level both before and after immunization with sheep red blood cells (SRBC), enhanced IgM-immune response, as well as decreased level of interleukin (IL)-1alpha before immunization. However, antigen administration produced IL-1alpha increase in aggressive rats and its decrease in nonaggressive rats compared to non-immunized rats of the same lines. In addition, line-dependent alterations of T lymphocyte distribution in response to immune activation have been found only in the spleen. It is suggested that genetic differences in aggressive behavior may contribute to differences in immune function. PMID- 26475957 TI - Optimize Your Electronic Medical Record to Increase Value: Reducing Laboratory Overutilization. AB - PURPOSE: The purpose of this study is to decrease overutilization of laboratory testing by eliminating a feature of the electronic ordering system that allowed providers to order laboratory tests to occur daily without review. METHODS: We collected rates of utilization of a group of commonly ordered laboratory tests (number of tests per patient per day) throughout the entire hospital from June 10, 2013 through June 10, 2015. Our intervention, which eliminated the ability to order daily recurring tests, was implemented on June 11, 2014. We compared pre- and postintervention rates in order to assess the impact and surveyed providers about their experience with the intervention. RESULTS: We examined 1,296,742 laboratory tests performed on 92,799 unique patients over 434,059 patient days. Before the intervention, the target tests were ordered using this daily recurring mechanism 33% of the time. After the intervention we observed an 8.5% (P <.001) to 20.9% (P <.001) reduction in tests per patient per day. The reduction in rate for some of the target tests persisted during the study period, but not for the 2 most commonly ordered tests. We estimated an approximate reduction in hospital costs of $300,000 due to the intervention. CONCLUSION: A simple modification to the order entry system significantly and immediately altered provider practices throughout a large tertiary care academic center. This strategy is replicable by the many hospitals that use the same electronic health record system, and possibly, by users of other systems. Future areas of study include evaluating the additive effects of education and real-time decision support. PMID- 26475958 TI - Your Kidneys May Outlive You. PMID- 26475959 TI - Germline BRCA1/2 testing practices in ovarian cancer: Current state and opportunities for new directions. AB - PURPOSE: Given the implications for clinical care and prevention in identifying a BRCA1/2 mutation, the objective of this study was to determine current BRCA1/2 testing practices in ovarian cancer and to identify future directions. METHODS: Two parallel complementary web-based surveys were sent by email to representatives of Gynecologic Cancer InterGroup (GCIG) and to referral centers in countries with and without GCIG membership. Questions posed addressed indications of BRCA1/2 testing for ovarian cancer; the implication of genetic counseling; and prevention strategies employed. RESULTS: Among the GCIG, 22 collaborative groups from 19 countries answered the survey. For the complementary survey, 22 referral centers replied. Findings show criteria to offer germline BRCA1/2 testing are mixed; 55% of GCIG members based testing decisions on histology and, among all respondents the main testing criterion remains family history. Typically, genetic counseling is scheduled prior to the genetic testing; however, if negative, results may not be communicated by the genetic counselor. Time between testing and communicating results varies widely between the groups. Lastly, recommendations to relatives regarding risk reduction surgery are inconsistent. CONCLUSION: Our study highlights the need for collaborative efforts to devise international guidelines around BRCA1/2 testing in ovarian cancer to ensure consistent BRCA1/2 screening practices are adopted. Clinical practice is evolving rapidly and as BRCA1/2 testing is expected to become more widespread, new approaches are required. Coordinating BRCA1/2 testing practices is crucial in terms of care for the patient diagnosed with ovarian cancer but also towards cancer prevention for affected family members. PMID- 26475960 TI - The performance of Dynamic Spectral Imaging colposcopy depends on indication for referrals. AB - OBJECTIVE. A previous study has shown that Dynamic Spectral Imaging (DSI) colposcopy increases the sensitivity of the colposcopic examination in women referred with abnormal cytology. In this study we have reanalyzed the performance of DSI and conventional colposcopy for new referral conditions and for low-grade cytology referrals versus high-grade cytology referrals. METHOD. Data from a previous validation trial was used to assess the performance of DSI in different cytology groups:Women referred with BMD (borderline and mild dyskaryosis) cytology and women referred with NBMD cytology either hrHPV positive or negative were separately analyzed. Furthermore, we tried to assess the clinical performance by appropriate filtering of patients to replicate two different referral strategies. RESULTS. The sensitivity of DSI and conventional colposcopy to detect CIN2+ lesions in women referred with BMD cytology is 82% and 44% respectively (p= 0.001) and in the NBMD group 77% and 64% respectively (p= 0.24). If the two techniques are combined the sensitivity is 85%.When the conditions of new screening strategies are applied DSI colposcopy has a higher sensitivity to detect CIN2+ than conventional colposcopy. Findings are similar when CIN3+ is used as a threshold. CONCLUSION. We found that in most cases DSI colposcopy has a higher sensitivity than conventional colposcopy, even when referral criteria are changed. Unlike conventional colposcopy, the sensitivity of colposcopy with DSI in low-grade cytology referrals was found similar to the sensitivity in high grade cytology referrals. This suggests that a baseline colposcopy sensitivity may be possible with the adjunctive use of the DSI map, irrespective of referral cytology. PMID- 26475961 TI - Secondary debulking surgery for isolated para-aortic nodal recurrence in endometrial cancer requiring partial resection of the inferior vena cava. AB - OBJECTIVE: We report the details of a surgical technique for the cytoreduction of metastatic para-aortic lymph nodes with involvement of the inferior vena cava (IVC) requiring partial resection and repair of the IVC. METHODS: A 52-year-old woman presented with endometrial cancer and isolated nodal recurrence involving the IVC. A vascular clamp was applied to the segment of the IVC that the metastatic lymph nodes had involved, and an en bloc resection of the para-aortic lymph nodes with the involved segment of the IVC was performed. RESULTS AND CONCLUSION: In this case, a partial resection of the IVC was performed to enable a complete cytoreduction without encroaching on the tumor planes. No intraoperative or postoperative complications, including vascular complications, occurred. This surgical procedure can be adopted for the management of metastatic para-aortic lymph nodes in selected patients. PMID- 26475962 TI - Expanding roles of superoxide dismutases in cell regulation and cancer. AB - Reactive oxygen species (ROS) have important roles in normal physiology and diseases, particularly cancer. Under normal physiological conditions, they participate in redox reactions and serve as second messengers for regulatory functions. Owing to aberrant metabolism, cancer cells accumulate excessive ROS, thus requiring a robustly active antioxidant system to prevent cellular damage. Superoxide dismutases (SODs) are enzymes that catalyze the removal of superoxide free radicals. There are three distinct members of this metalloenzyme family in mammals: SOD1 (Cu/ZnSOD), SOD2 (MnSOD) and SOD3 (ecSOD). SODs are increasingly recognized for their regulatory functions in growth, metabolism and oxidative stress responses, which are also crucial for cancer development and survival. Growing evidence shows that SODs are also potentially useful anticancer drug targets. This review will focus on recent research of SODs in cellular regulation, with emphasis on their roles in cancer biology and therapy. PMID- 26475963 TI - Detecting and quantifying parasite-induced host mortality from intensity data: method comparisons and limitations. AB - Parasites can significantly impact animal populations by changing host behaviour, reproduction and survival. Detecting and quantifying these impacts is critical for understanding disease dynamics and managing wild animal populations. However, for wild hosts infected with macroparasites, it is notoriously difficult to quantify the fatal parasite load and number of animals that have died due to disease. When ethical or logistical constraints prohibit experimental determination of these values, examination of parasite intensity and distribution data may offer an alternative solution. In this study we introduce a novel method for using intensity data to detect and quantify parasite-induced mortality in wildlife populations. We use simulations to show that this method is more reliable than previously proposed methods while providing quantitative estimates of parasite-induced mortality from empirical data that are consistent with previously published qualitative estimates. However this method, and all techniques that estimate parasite-induced mortality from intensity data alone, have several important assumptions that must be scrutinised before applying those to real-world data. Given that these assumptions are met, our method is a new exploratory tool that can help inform more rigorous studies of parasite-induced host mortality. PMID- 26475964 TI - Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction. AB - AIM: Chalcones are naturally occurring compounds with recognized anticancer activity. It was recently shown that the O-prenyl derivative (2) of 2'-hydroxy 3,4,4',5,6'-pentamethoxychalcone (1) had a remarkably increased cytotoxicity against human tumour cells compared to its precursor. With this study, we aimed to investigate the molecular mechanism underlying the improved tumour cytotoxicity of prenylchalcone 2. MAIN METHODS: The impact of chalcones 1 and 2 on p53-MDM2 interaction was investigated using yeast growth-inhibitory and p53 transactivation assays. Their tumour growth-inhibitory effects were assessed on human colon adenocarcinoma HCT116 cell lines with wild-type p53 and its p53-null derivative, followed by analysis of cell cycle and apoptosis. In tumour cells, the activation of a mitochondrial pathway was checked by analysis of reactive oxygen species generation, Bax mitochondrial translocation and cytochrome c release. Additionally, the up-regulation of p53 transcriptional activity was investigated through Western blot analysis of p53 target expression levels, and the disruption of the p53-MDM2 interaction was confirmed by co immunoprecipitation. KEY FINDINGS: The potent cell tumour growth-inhibitory activity of prenylchalcone 2 was associated with the activation of a p53 pathway involving cell cycle arrest and a mitochondria-dependent apoptosis. Furthermore, a correlation between the distinct cytotoxicity of chalcones 1 and 2 and their ability to disrupt the p53-MDM2 interaction was established. SIGNIFICANCE: This work shows that prenylation is a determinant factor for the enhancement of chalcones tumour cytotoxicity by improving their ability to disrupt the p53-MDM2 interaction. Prenylchalcone 2 represents a starting basis for the design of new p53-MDM2 interaction inhibitors with improved antitumor properties. PMID- 26475965 TI - Propofol-enhanced autophagy increases motility and angiogenic capacity of cultured human umbilical vascular endothelial cells. AB - AIMS: Propofol (PPF), an intravenous anesthetic agent, is previously reported to attenuate oxidative stress- and inflammation-induced endothelial cell dysfunction. This study investigated its effect on endothelial cell biology. MAIN METHODS: Cultured human umbilical vein endothelial cells (HUVECs) were treated with PPF and subject to measurements for nitric oxide (NO) production, autophagy flux, signal transduction, migration, and in vitro angiogenesis. KEY FINDINGS: Non-cytotoxic PPF treatment was found to significantly upregulate inducible nitric oxide synthase (NOS2) but downregulate constitutive NOS3 expression. It also potentiated LPS-induced ICAM-1 overexpression and NO overproduction. Mechanistically, the PPF-activated signal transduction in PI3K/Akt, ERK1/2, p38 MAPK, and JNK pathways were involved in the PPF-driven NO overproduction. PPF exhibited a stimulatory effect on autophagy flux by increasing expression of autophagy markers including mTOR, Beclin-1, Atg5, and LC3I/II, as well as a late endosomal indicator, Rab7. However, PPF appeared to antagonize the Rab7 upregulation by LPS. Functionally, PPF enhanced in vitro migratory and angiogenic capacities of HUVECs, but this enhancement was drastically abrogated by the presence of autophagy inhibitors, indicating a pro-angiogenic contribution of PPF enhanced autophagy in cultured HUVECs. SIGNIFICANCE: Our findings support the notion that PPF enhances motility and angiogenic capacity of cultured HUVECs through an autophagy-involved regulatory mechanism. PMID- 26475966 TI - Gallic acid reduces the effect of LPS on apoptosis and inhibits the formation of neutrophil extracellular traps. AB - Apoptosis and NETosis of neutrophils are two major mechanisms of programmed cell death that differ in their morphological characteristics and effects on the immune system. Apoptosis can be delayed by the presence of pathogens or chemical components such as lipopolysaccharide (LPS). Neutrophils have other antimicrobial strategy, called neutrophil extracellular traps (NETs), which contributes to the elimination and control of the pathogen. NETosis is induced by infection, inflammation or trauma and represents an innate immune activation mechanism. The objective of this study was to evaluate the effect of gallic acid (GA) in the modulation of apoptosis and NETs release. The results show that GA decreased the anti-apoptotic effect of LPS, blocked the induction of NETs and prevented the formation of free radicals induced by LPS. These findings demonstrate that the GA is a novel therapeutic agent for decreasing the exacerbated response of the body against an infectious agent. PMID- 26475967 TI - Neochamaejasmin B increases the bioavailability of chamaechromone coexisting in Stellera chamaejasme L. via inhibition of MRP2 and BCRP. AB - Chamaechromone and neochamaejasmin B (NCB) are the most abundant components in the dried roots of the toxic perennial herb Stellera chamaejasme L. and have pharmacological activities. The objective of this study was to investigate the transport mechanism of these two components in vivo and in vitro. The transport and cellular accumulation studies in Madin-Darby canine kidney (MDCK) cells overexpressing human multidrug resistance protein 2 (MRP2) or P-gp and LLC-PK1 cells overexpressing human breast cancer resistance protein (BCRP) were performed. The results showed that chamaechromone was a good substrate of MRP2 and BCRP but not a substrate of P-gp. NCB was found to be a MRP2 inhibitor in transfected cells and significantly enhanced the cellular accumulation of chamaechromone in MDCK cells overexpressing MRP2. Similar results were obtained in LLC-PK1-BCRP cells. In addition, the influence of NCB on the bioavailability of chamaechromone following their co-administration was also determined in rats. The results showed that the area under the plasma concentration-time curve and maximal plasma concentration of chamaechromone in rats were increased by 48.9% and 81.9%, respectively. The mechanism of improving the oral bioavailability of chamaechromone was attributable to the inhibition of the BCRP and MRP2-mediated efflux of chamaechromone by NCB. PMID- 26475968 TI - Rethinking the paradigm for the development of inhaled drugs. AB - Nebulized treatment is an important delivery option for the young, elderly, and those with severe chronic respiratory disease, but there is a lack of new nebulized drug products being produced for these patients, leading to the potential for under-treatment. This communication describes a new drug development paradigm as a timely solution to this issue. Often, drug development is initiated with nebulizers in the early stages, to provide cheaper and faster drug development, and then switched to inhaler devices in later clinical trials to address the majority of patients. However, the waste of resource on parallel development of the inhaler can be large due to the high early attrition rate of new drug development. The new paradigm uses the nebulizer to continue drug development through to market, and initiates inhaler development after completion of the riskier early phase studies. New drug safety and efficacy can be assessed faster and more efficiently by using a nebulized formulation rather than developing an inhaler. The results of calculations of expected net present value showed that the new paradigm produced higher expected net present values than the conventional model over a range of economic scenarios. This new paradigm could therefore provide improved returns on investments, as well as more modern drugs in nebulized form for those patients unable to use inhalers. PMID- 26475969 TI - Improvement of mechanical properties of pellet containing tablets by thermal treatment. AB - Batches of partially spray-dried lactose tablets with three different initial tensile strength (~20N, ~35N, ~50N) were made. Changes along a 24h long thermal treatment at 100 degrees C in tensile strength, friability, individual mass, water content, disintegration time, average free volume and wetting properties were evaluated. Caffeine containing gastroresistant pellets were gained by drug layering and filmcoating of inert microcrystalline cellulose pellet cores in fluid bed equipment. Shape, size, mechanical properties, drug content and dissolution profile of the coated pellets were determined. Batches of pellet containing tablets with three different pellet-filler ratios were compressed where partially spray-dried lactose was used as a filler-binder material.Characteristics of pellet containing tablets were evaluated before and after a 24h long thermal treatment at 100 degrees C. Results shown that the poor initial mechanical properties (friability, tensile strength) were improved by thermal exposure while there were no remarkable alterations in drug release profiles. PMID- 26475970 TI - Design and evaluation of surface and adjuvant modified PLGA microspheres for uptake by dendritic cells to improve vaccine responses. AB - Designing strategies for targeting antigens to dendritic cells is a major goal in vaccinology. Here, PLGA (poly lactic-co-glycolic acid) microspheres and with several surface modifications that affect to their uptake by human blood primary dendritic cells and monocytes have been evaluated. Higher uptake was found by all the cell types when cationic microspheres (PLGA modified with polyethylene imine) were used. These cationic particles were in vivo evaluated in mice. In addition, MPLA(1) or poly(I:C)(2) and alpha-GalCer(3) were also encapsulated to address their adjuvant effect. All the microspheres were able to produce humoral immune responses, albeit they were higher for cationic microspheres. Moreover, surface charge seemed to have a role on biasing the immune response; cationic microspheres induced higher IFN-gamma levels, indicative of Th1 activation, while unmodified ones mainly triggered IL4 and IL17A release, showing Th2 activation. Thus, we have shown here the potential and versatility of these MS, which may be tailored to needs. PMID- 26475971 TI - Absorption of ipratropium and l-carnitine into the pulmonary circulation of the ex-vivo rat lung is driven by passive processes rather than active uptake by OCT/OCTN transporters. AB - The organic cation transporters OCT and OCTN have been reported to play a significant role in the cellular uptake of substrates within in vitro lung cells. However, no studies to date have investigated the effect of these transporters upon transepithelial absorption of substrates into the pulmonary circulation. We investigated the contribution of OCT and OCTN transporters to total pulmonary absorption of l-carnitine and the anti-muscarinic drug, ipratropium, across an intact isolated perfused rat lung (IPRL). The results obtained from the IPRL were contrasted with active transport in vitro using three human pulmonary cell lines and primary rat alveolar epithelial cells. Ex-vivo studies showed that OCT/OCTN transporters do not play a role in the overall pulmonary absorption of l carnitine or ipratropium, as evidenced by the effect of chemical inhibition of these transporters upon pulmonary absorption. In contrast, in vitro studies showed that OCT/OCTN transporters play a significant role in cellular accumulation of substrates with preferential uptake of ipratropium by OCTs, and of l-carnitine uptake by OCTNs. The results show that in vitro uptake studies cannot be predictive of airway to blood absorption in vivo. Nevertheless, localised submucosal pulmonary concentrations of inhaled drugs and their pulmonary pharmacodynamic profiles may be influenced by OCT/OCTN transport activity. PMID- 26475972 TI - Inaugural Survey on Practice Patterns of Orbital Floor Fractures for American Oral and Maxillofacial Surgeons. AB - PURPOSE: In recent years, several studies have reported on practitioners' preferences for the treatment of orbital floor fractures, showing widely varying practice patterns. The purpose of the present study was to identify the practice patterns among oral and maxillofacial surgeons involved in the management of orbital floor fractures in the United States and compare them with the available published data. MATERIALS AND METHODS: An anonymous survey was created and electronically mailed to surgeons. We also reviewed the published data on orbital floor fractures using a PubMed and MEDLINE search. The responses to the survey were analyzed using descriptive statistics. RESULTS: The factors that had the greatest influence on the surgeon's decision to operate were a defect size > 2 cm2, enophthalmos, entrapment, and persistent diplopia. The most common surgical approach reported was a preseptal transconjunctival approach (32.0%), followed by the subciliary (27.9%) and postseptal transconjunctival (26.2%) approaches. The most commonly reported implant for orbital reconstruction was titanium (65.4%), followed by Medpor (43.7%) and composite Medpor and titanium (26.4%). The review of the published data showed a consensus among many of the operative indications mentioned, including a large defect size, enophthalmos, clinical entrapment, and persistent diplopia. CONCLUSIONS: Oral and maxillofacial surgeons in the United States have a wide range of practice habits in the management of orbital floor fractures. Although the quality of the available evidence is poor, it supports a consistent approach to the management of orbital floor fractures in terms of the indications and surgical approach. The choice of reconstructive material and timing of repair remain more controversial. A clear need exists for improvement in the available data to help guide and set standards of care for the specialties managing orbital floor fractures. PMID- 26475973 TI - Orbital Exenteration to Manage Infiltrative Sinonasal, Orbital Adnexal, and Cutaneous Malignancies Provides Acceptable Survival Outcomes: An Institutional Review, Literature Review, and Meta-Analysis. AB - PURPOSE: Orbital exenteration (OE) is an aggressive operative undertaking that results in a disfiguring and dysfunctional outcome for patients. The purpose of our study was to determine the survival outcome for patients who underwent OE for malignant disease that had invaded the orbit. MATERIALS AND METHODS: We conducted an ambispective cohort study based on a review of the records of 31 consecutive patients who had undergone OE within John Hunter Hospital. The study period was 2006 to 2013. The predictor variables were the demographic, tumor site, and clinicopathologic characteristics that might influence survival. The secondary outcome variable was survival. Descriptive statistics were calculated for the categorical and continuous variables. Kaplan-Meier estimates of the survival distribution were plotted. We also performed a review of published studies and a meta-analysis to investigate the nature of OE performed by various surgical disciplines. RESULTS: Of the 31 patients included in the present study, 24 were men and 7 were women. The mean age was 65 years. Of the 31 cases, 15 were squamous cell carcinoma, 8 were basal cell carcinoma, and 8 were a mixture of other pathologic types. The time to median (50%) survival for all patients was 78.4 months. The 1-year survival rate was 93.4% and the 5-year survival rate was 54.1%. Although not statistically significant, notable differences were found in the interval to death with respect to the identification of perineural invasion, lymphovascular invasion, and histopathologic features. The review of published studies suggested a difference in the histologic features and location of the disorder treated, the extent of OE undertaken, and the method of reconstruction between the ophthalmology and nonophthalmology surgical disciplines. CONCLUSIONS: Although OE results in significant disfigurement and dysfunction, it does provide good survival outcomes, given the extent of disease at presentation, evident in our group of patients. Continuation of the study, with greater numbers of patients, will serve to increase the statistical power of our observations. PMID- 26475974 TI - Narrowing the critical region for overgrowth within 13q14.2-q14.3 microdeletions. AB - Large chromosomal deletions from 13q13.3 to 13q21.3 have previously been associated with overgrowth. We present two patients with deletions at 13q14.2q14.3 who have macrocephaly, tall stature relative to their parents, cardiac phenotypes, and intellectual disability. This report narrows the critical region for tall stature, macrocephaly, and possibly cardiac disease. PMID- 26475976 TI - Learning context modulates the processing of expectancy violations. AB - The detection of unexpected or unfavorable events is crucial for successful behavioral adaptation. There is a family of ERP components, the so-called error negativities, that has been associated with these detection processes. In the current study, we explored the functional characteristics of one of these components, the N2b which reflects the detection of unexpected events in a stream of stimuli in our environment, in more detail. In a sequence learning task, we found that the same type of deviant event elicited an N2b only when it conveyed information about the to-be-learned sequence, but not when it was rendered learning-irrelevant by means of task instruction. This supports the view that deviant events generate an error negativity in a similar way as committed errors and negative feedback. It also demonstrates that error monitoring processes are very flexible and can be tailored to the specific demands of the task at hand, i.e., expectancy violations only activate the error system when the detected mismatch is classified as relevant for the specific goals in the current learning context. Additionally, a P3 to all deviant types was found reflecting a higher order form of performance monitoring associated with evaluation of task-relevant events and updating of working memory contents. PMID- 26475975 TI - New approaches for direct conversion of patient fibroblasts into neural cells. AB - Recent landmark studies have demonstrated the production of disease-relevant human cell types by two different methods; differentiation of stem cells using external morphogens or lineage conversion using genetic factors. Directed differentiation changes embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) into a desired cell type by providing developmental cues in an in vitro environment. Direct reprogramming is achieved by the introduction of exogenous lineage specific transcription factors to convert any somatic cell type into another, thereby bypassing an intermediate pluripotent stage. A variety of somatic cell types such as blood, keratinocytes and fibroblasts can be used to derive iPSC cells. However, the process is time consuming,laborious, expensive and gives rise to cells with reported epigenetic heterogeneity even amongst different iPSC lines from same patient which could propagate phenotypic variability. A major concern with the use of pluripotent cells as starting material for cell replacement therapy is their incomplete differentiation and their propensity to form tumors following transplantation. In comparison, transcription factor mediated reprogramming offers a direct route to target cell types. This could allow for rapid comparison of large cohorts of patient and control samples at a given time for disease modeling. Additionally, transcription factors that drive maturation may yield more functionally mature cells than directed differentiation. Several studies have demonstrated the feasibility of generating of cell types such as cardiomyocytes, hepatocytes, and neurons from fibroblasts. Here, we will discuss recent advances and key challenges regarding direct reprogramming of somatic cell types into diverse neural cells. This article is part of a Special Issue entitled SI: Exploiting human neurons. PMID- 26475977 TI - Epigenetic modifications in human fragile X pluripotent stem cells; Implications in fragile X syndrome modeling. AB - Patients with fragile X syndrome (FXS) exhibit moderate to severe intellectual disabilities. In addition, one-third of FXS patients show characteristics of autism spectrum disorder. FXS is caused by a trinucleotide repeat expansion, which leads to silencing of the fragile X mental retardation (FMR1) gene. The absence of the FMR1 gene product, FMRP, is the reason for the disease symptoms. It has been suggested that repeat instability and transcription of the FMR1 gene occur during early embryonic development, while after cell differentiation repeats become stable and the FMR1 gene is silent. Epigenetic marks, such as DNA methylation, are associated with gene silencing and repeat stability at the FMR1 locus. However, the mechanisms leading to gene silencing and repeat expansion are still ambiguous, because studies at the human genomic locus were limited until now. The FXS pluripotent stem cells, recently derived from FXS adult cells and FXS blastocysts, are new useful tools to examine these mechanisms at the human endogenous FMR1 locus. This review summarizes the epigenetic features and experimental studies of FXS human embryonic and FXS induced pluripotent stem cells, generated so far. This article is part of a Special Issue entitled SI: Exploiting human neurons. PMID- 26475978 TI - Fisetin alleviates early brain injury following experimental subarachnoid hemorrhage in rats possibly by suppressing TLR 4/NF-kappaB signaling pathway. AB - Early brain injury (EBI) determines the unfavorable outcomes after subarachnoid hemorrhage (SAH). Fisetin, a natural flavonoid, has anti-inflammatory and neuroprotection properties in several brain injury models, but the role of fisetin on EBI following SAH remains unknown. Our study aimed to explore the effects of fisetin on EBI after SAH in rats. Adult male Sprague-Dawley rats were randomly divided into the sham and SAH groups, fisetin (25mg/kg or 50mg/kg) or equal volume of vehicle was given at 30min after SAH. Neurological scores and brain edema were assayed. The protein expression of toll-like receptor 4 (TLR 4), p65, ZO-1 and bcl-2 was examined by Western blot. TLR 4 and p65 were also assessed by immunohistochemistry (IHC). Enzyme-linked immunosorbent assay (ELISA) was performed to detect the production of pro-inflammatory cytokines. Terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL) was perform to assess neural cell apoptosis. High-dose (50mg/kg) fisetin significantly improved neurological function and reduced brain edema at both 24h and 72h after SAH. Remarkable reductions of TLR 4 expression and nuclear factor kappaB (NF-kappaB) translocation to nucleus were detected after fisetin treatment. In addition, fisetin significantly reduced the productions of pro inflammatory cytokines, decreased neural cell apoptosis and increased the protein expression of ZO-1 and bcl-2. Our data provides the evidence for the first time that fisetin plays a protective role in EBI following SAH possibly by suppressing TLR 4/NF-kappaB mediated inflammatory pathway. PMID- 26475979 TI - Berberine protects against light-induced photoreceptor degeneration in the mouse retina. AB - Oxidative stress and inflammation play key roles in the light damage (LD) model of photoreceptor degeneration, as well as in age-related macular degeneration (AMD). We sought to investigate whether Berberine (BBR), an antioxidant herb extract, would protect the retina against light-induced degeneration. To accomplish this, Balb/c mice were treated with BBR or PBS via gavage for 7 days, and then were placed in constant cool white light-emitting diode (LED) light (10,000 lux) for 4 h. Retinal function and degeneration were evaluated by histology, electroretinography (ERG) and optical coherence tomography (OCT) at 7d after LD. Additionally, mRNA levels of cell-type specific, antioxidant, and inflammatory genes were compared 7d after LD. Photoreceptor DNA fragmentation was assessed via the terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay. LD resulted in substantial photoreceptor-specific cell death. Histological analysis using plastic sections showed dosing with BBR preserved photoreceptors. The ERG analysis demonstrated functional protection by BBR in rod b, -a, and cone-b waves. In OCT images, mice receiving PBS showed severe thinning and disorganization of the photoreceptor layer 7 days after LD, whereas mice treated with BBR had significantly less thinning and disorganization. Consistent with OCT results, the mRNA levels of Rho in the NSR, and Rpe65 and Mct3 in the RPE, were significantly higher in mice treated with BBR. The numbers of TUNEL positive photoreceptors were significantly decreased in BBR-treated mice. The retinal mRNA levels of oxidative stress genes, the number of microglia/macrophages, and the malondialdehyde (MDA) immunolabeling were significantly lower in BBR-treated mice compared to controls 48 h after LD, which indicates oxidative stress was reduced by BBR in light-damaged eyes. In conclusion, systemic BBR is protective against light-induced retinal degeneration associated with diminished oxidative stress in the retina. These results suggest that BBR may be protective against retinal diseases involving oxidative stress. PMID- 26475980 TI - Cigarette smoking and risk of pancreatic cancer: a clinic-based case-control study in the San Francisco Bay Area. AB - PURPOSE: Cigarette smoking is an established risk factor for pancreatic cancer (PC). We examined the association between cigarette smoking and PC in a San Francisco Bay Area clinic-based, case-control study. METHODS: A total of 536 cases and sex and age frequency-matched controls (n = 869) were recruited predominately from the University of California San Francisco (UCSF) medical clinics between 2006 and 2011. Participants were interviewed in-person using structured questionnaires. Adjusted odds ratios (ORs) were computed. RESULTS: Forty-eight percent of cases and controls reported never having smoked cigarettes; 39% of cases and 40% of controls were former smokers; 13% of cases and 12% of controls were current smokers. No association was found for either former (OR = 0.85, 95% confidence interval [CI] = 0.66-1.1) or current cigarette smoking (men: OR = 1.0, 95% CI = 0.60-1.7; women: OR = 1.2, 95% CI = 0.73-2.1). No dose-response relationships were detected with number of cigarettes/day, smoking intensity, duration, or years since last smoked. Comparisons with a 1995 1999 population-based UCSF study demonstrated a significantly increased proportion of never smokers in this study (P < .001). CONCLUSIONS: This study revealed no significant associations between cigarette smoking and PC in the San Francisco Bay Area during 2006-2011. Data suggest a reduction in the duration of smoking within the referral population. PMID- 26475981 TI - Statins and hip fracture risk in men: a population-based case-control study. AB - PURPOSE: To estimate the association between hydroxymethylglutaryl-CoA inhibitor (statin) use and hip fracture. METHODS: We conducted a population-based case control study. Cases were 6774 male enrollees in a large managed care organization, aged 45 or more years, with an incident hip fracture from 1997 to 2006. Controls without fracture (n = 6774) were matched to cases on age, race, and medical center. Electronic information on pharmaceutical use was used to identify the dispensing of statins from 1991 forward. RESULTS: Overall, 1884 (27.8%) cases and 2150 controls (31.7%) used a statin before index date (matched odds ratio [mOR] = 0.81, 95% confidence interval [CI] = 0.74-0.87). Adjustment for comorbidity burden strengthened the magnitude of the overall association (mOR = 0.68, CI = 0.62-0.74). The adjusted association was similar across age groups but was strongest among men aged 80 years or more (mOR = 0.62, CI = 0.54-0.71) and was most pronounced in African Americans (mOR = 0.43, CI = 0.28-0.64). Greater duration of statin use did not alter the odds ratios. CONCLUSIONS: These data add to the growing evidence of a potential protective effect of statin use on bone health. However, these results need to be replicated in a prospective study that can account for confounding by indication which may explain these findings. PMID- 26475982 TI - Reproductive and lifestyle risk factors and mammographic density in Mexican women. AB - PURPOSE: Several breast cancer risk factors have been consistently associated with mammographic density (MD); however, data are limited for Hispanic women. METHODS: We examined data from 1007 premenopausal and 600 postmenopausal women in the Mexican Teachers' Cohort. Multivariable linear regression was used to estimate associations between risk factors and MD. RESULTS: Among premenopausal women, age, current body mass index (BMI), BMI at age 18 years, and weight change since age 18 years were inversely associated with percent MD, whereas benign breast disease, alcohol intake, and breastfeeding 12 months or more were associated with higher percent MD. Among postmenopausal women, age, current BMI, BMI at age 18 years, weight change since age 18 years, and speaking or having parents who speak an indigenous language were inversely associated with percent MD, whereas benign breast disease and greater age at natural menopause were positively associated with percent MD. Other breast cancer risk factors, such as age at menarche, parity, and age at first pregnancy, were not significantly associated with density in either premenopausal or postmenopausal women. CONCLUSIONS: Results from the Mexican Teachers' Cohort are generally consistent with predictors of mammographic density observed in primarily non-Hispanic white populations; however, certain risk factors (e.g., parity) were not significantly associated with MD. PMID- 26475983 TI - Role of infant sex in the association between air pollution and preterm birth. PMID- 26475984 TI - Diterpenoids from the twigs and leaves of Croton caudatus var. tomentosus. AB - One new 9,10-seco-abietane derivative, crotontomentosin A (1), four new abietane type diterpenoids, crotontomentosins B-E (2-5), one new ent-halimane-type diterpenoid, crotontomentosin F (6), along with five known diterpenoids (7-11) and one known sesquiterpenoid (12) were obtained from the twigs and leaves of Croton caudatus Geisel. var. tomentosus Hook. The structures of the compounds were established on the basis of extensive spectroscopic data. Compounds 1-4 and 11 exhibited moderate to weak inhibitory activity against the proliferation of the Hela, Hep G2, MDA-MB-231, or A549 cell lines selectively. PMID- 26475985 TI - Establishment of proprotein convertase, furinA knocked-out lines in medaka, Oryzias latipes, and unique form of medaka furin-like prorprotein convertase (mflPC). AB - Furin is a member of the subtilisin-like proprotein convertase family. Medaka furin-like proprotein convertase (mflPC), a unique form of medaka FurinA (mFurinA) (GenBank accession no. AB092685.1) was cloned from the ovary cDNA library. Compared to human furin (GenBank accession no. NM_002569.3) and mFurinA in the structural motif of mflPC, only the catalytic domain and the N-terminal region of the P domain are highly conserved, but more C-terminal domains are truncated. Based on our research, there three forms of furin, mFurinA, mflPC and mFurinB that exist in medaka. These three genes are expressed in the developing embryos and ubiquitously in adult tissues. To investigate the function of mFurinA and mflPC, as a first step, mFurinA KO lines were established. The mFurinA KO larvae with abnormal phenotypes exhibit edema, abnormal body fluid accumulation in the pericardial and yolk sacs, enlarged hearts, clogged blood vessels, structurally weak eyes, and a very short life. The data suggests that abnormal processing of TGF-beta may be one of the causes of these disorders. FurinA KO medaka is a good model for the study of human diseases such as Fraser Syndrome and Marfan syndrome. The creation of human genomic disorder models using recently advanced genome editing procedures informs us of the function of key molecules and their role in causing equivalent human disorders and will be useful as a tool to identify the mechanisms involved. PMID- 26475986 TI - Gene expression in highly sensitized dialysis patients waiting for a kidney transplant: A real-time PCR analysis. PMID- 26475987 TI - Differential T-cell subset representation in cutaneous squamous cell carcinoma arising in immunosuppressed versus immunocompetent individuals. PMID- 26475988 TI - Terrestrial Trunked Radio (TETRA) exposure and its impact on slow cortical potentials. AB - BACKGROUND: Studies have shown that exposure to radiofrequency electromagnetic fields (RF-EMF) in the mobile communication frequency range may induce physiological modifications of both spontaneous as well as event-related human electroencephalogram. So far, there are very few peer-reviewed studies on effects of Terrestrial Trunked Radio (TETRA), which is a digital radio communication standard used by security authorities and organizations in several European countries, on the central nervous system. OBJECTIVES: To analyze the impact of simulated TETRA handset signals at 385 MHz on slow cortical potentials (SCPs). METHODS: 30 young healthy males (25.2+/-2.7 years) were exposed in a double blind, counterbalanced, cross-over design to one of three exposure levels (TETRA with 10 g averaged peak spatial SAR: 1.5 W/kg, 6.0 W/kg and sham). Exposure was conducted with a body worn antenna (especially designed for this study), positioned at the left side of the head. Subjects had 9 test sessions (three per exposure condition) in which three SCPs were assessed: SCP related to a clock monitoring task (CMT), Contingent negative variation (CNV) and Bereitschaftspotential (BP). RESULTS: Neither behavioral measures nor the electrophysiological activity was significantly affected by exposure in the three investigated SCP paradigms. Independent of exposure, significant amplitude differences between scalp regions could be observed for the CMT-related SCP and for the CNV. CONCLUSIONS: The present results reveal no evidence of RF-EMF exposure-dependent brain activity modifications investigated at the behavioral and the physiological level. PMID- 26475990 TI - Interplay between self-assembled structure of bone morphogenetic protein-2 (BMP 2) and osteoblast functions in three-dimensional titanium alloy scaffolds: Stimulation of osteogenic activity. AB - Three-dimensional cellular scaffolds are receiving significant attention in bone tissue engineering to treat segmental bone defects. However, there are indications of lack of significant osteoinductive ability of three-dimensional cellular scaffolds. In this regard, the objective of the study is to elucidate the interplay between bone morphogenetic protein (BMP-2) and osteoblast functions on 3D mesh structures with different porosities and pore size that were fabricated by electron beam melting. Self-assembled dendritic microstructure with interconnected cellular-type morphology of BMP-2 on 3D scaffolds stimulated osteoblast functions including adhesion, proliferation, and mineralization, with prominent effect on 2-mm mesh. Furthermore, immunofluorescence studies demonstrated higher density and viability of osteoblasts on lower porosity mesh structure (2 mm) as compared to 3- and 4-mm mesh structures. Enhanced filopodia cellular extensions with extensive cell spreading was observed on BMP-2 treated mesh structures, a behavior that is attributed to the unique self-assembled structure of BMP-2 that effectively communicates with the cells. The study underscores the potential of BMP-2 in imparting osteoinductive capability to the 3D printed scaffolds. PMID- 26475989 TI - Eosinophil localization to the basement membrane zone is autoantibody- and complement-dependent in a human cryosection model of bullous pemphigoid. AB - Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by antibodies (IgG and IgE) targeting cell-substrate adhesion proteins. A variety of BP models suggest that autoantibody-dependent neutrophil degranulation is essential for blister formation. However, lesional biopsies reveal a predominance of eosinophils and few neutrophils. Our goal was to evaluate the role of antibodies and complement in eosinophil localization, degranulation and split formation at the dermo-epidermal junction (DEJ) utilizing a human skin cryosection model of BP paired with a human eosinophilic cell line, 15HL-60. Expression of receptors for IgG (FcgammaRII), IgE (FcepsilonRI) and complement (CR1 and CR3) was confirmed on 15HL-60 cells using flow cytometry. 15HL-60 expression of granule protein [eosinophil derived neurotoxin (EDN) and eosinophil peroxidase (EPO)] mRNA and their degranulation in vitro was confirmed using RT PCR and ELISA, respectively. For cryosection experiments, BP or control sera or IgG and IgE antibodies purified from BP sera were utilized in combination with 15HL-60 cells +/- fresh complement. Both BP serum and fresh complement were required for localization of 15-HL60 cells to the DEJ. Interestingly, eosinophil localization to the DEJ was dependent on IgG, but not IgE, and complement. However, no subepidermal split was observed. Additionally, the 15HL-60 cells did not degranulate under any experimental conditions and direct application of cell lysate to cryosections did not result in a split. Our observation that eosinophil localization to the DEJ is dependent on IgG mediated complement fixation provides additional insight into the sequence of events during the development of BP lesions. PMID- 26475991 TI - Community structure influences species' abundance along environmental gradients. AB - Species' response to abiotic environmental variation can be influenced by local community structure and interspecific interactions, particularly in restricted habitats such as islands and lakes. In temperate lakes, future increase in water temperature and run-off of terrestrial (allochthonous) dissolved organic carbon (DOC) are predicted to alter community composition and the overall ecosystem productivity. However, little is known about how the present community structure and abiotic environmental variation interact to affect the abundance of native fish populations. We used a space-for-time approach to study how local community structure interact with lake morphometric and climatic characteristics (i.e. temperature and catchment productivity) to affect brown trout (Salmo trutta L.) yield in 283 Norwegian lakes located in different biogeographical regions. Brown trout yield (based on data from standardized survey gill net fishing; g 100 m(-2) gill net night(-1)) was generally lower in lakes where other fish species were present than in lakes with brown trout only. The yield showed an overall negative relationship with increasing temperature and a positive relationship with lake shoreline complexity. Brown trout yield was also negatively correlated with DOC load (measured using Normalized Difference Vegetation Index as a proxy) and lake size and depth (measured using terrain slope as a proxy), but only in lakes where other fish species were present. The observed negative response of brown trout yield to increasing DOC load and proportion of the pelagic open-water area is likely due to restricted (littoral) niche availability and competitive dominance of more pelagic fishes such as Arctic charr (Salvelinus alpinus (L.)). Our study highlights that, through competitive interactions, the local community structure can influence the response of a species' abundance to variation in abiotic conditions. Changes in biomass and niche use of top predators (such as the brown trout), associated with predicted changes in direct and indirect climatic factors, may have further influences on the structure and function of temperate lake ecosystems. PMID- 26475992 TI - Metabolic and functional MR biomarkers of antiepileptic drug effectiveness: A review. AB - As a large number of patients with epilepsy do not respond favorably to antiepileptic drugs (AEDs), a better understanding of treatment failure and the cause of adverse side effects is required. The working mechanisms of AEDs also alter neurotransmitter concentrations and brain activity, which can be measured using MR spectroscopy and functional MR imaging, respectively. This review presents an overview of clinical research of MR spectroscopy and functional MR imaging studies to the effects of AEDs on the brain. Despite the scarcity of studies associating MR findings to the effectiveness of AEDs, the current research shows clear potential regarding this matter. Several GABAergic AEDs have been shown to increase the GABA concentration, which was related to seizure reductions, while language problems due to topiramate have been associated with altered activation patterns measured with functional MR imaging. MR spectroscopy and functional MR imaging provide biomarkers that may predict individual treatment outcomes, and enable the assessment of mechanisms of treatment failure and cognitive side effects. PMID- 26475993 TI - Prader-Willi syndrome: From genetics to behaviour, with special focus on appetite treatments. AB - Prader-Willi syndrome (PWS) is a neurodevelopmental disorder resulting from a deletion in the expression of the paternally derived alleles in the region of 15q11-q13. PWS has a prevalence rate of 1:10,000-1:30,000 and is characterized by marked endocrine abnormalities including growth hormone deficiency and raised ghrelin levels. The hyperphagic phenotype in PWS is established over a number of phases and is exacerbated by impaired satiety, low energy expenditure and intellectual difficulties including obsessive-compulsive disorder and/or autistic behaviours. Clinical management in PWS typically includes familial/carer restriction and close supervision of food intake. If the supervision of food is left unmanaged, morbid obesity eventuates, central to the risk of cardiorespiratory disorder. None of the current appetite management/intervention strategies for PWS include pharmacological treatment, though recent research shows some promise. We review the established aberrant genetics and the endocrine and neuronal attributes which may determine disturbed regulatory processes in PWS. Focusing on clinical trials for appetite behaviours in PWS, we define the effectiveness of pharmacological treatments with a view to initiating and focusing research towards possible targets for modulating appetite in PWS. PMID- 26475994 TI - Electrophysiological correlates of problematic Internet use: Critical review and perspectives for future research. AB - Problematic behaviors have emerged with the exponential development of the Internet access, with some individuals failing to constrain their Internet use despite its negative impact on their daily lives. Recent neuropsychological and neuroscience studies have suggested that problematic Internet use is notably associated with increased cue-reactivity and reduced inhibitory control. This review of the electroencephalography (EEG) literature shows that most studies have found that impaired self-control abilities (i.e., inhibition and error monitoring) are associated with underactivated frontal regions in problematic Internet users (PIUs). However, some EEG studies in the domain have also demonstrated alterations in the processing of Internet-related cues and emotional stimuli. As a whole, these data therefore suggest that both reflective (top-down) and automatic/affective (bottom-up) systems, postulated by dual-process models as being determinants in decision making, are impaired among PIUs. On this basis, new research avenues are proposed to better understand the development and maintenance of problematic Internet use, according to six main directions respectively related to (1) the identification of vulnerability biomarkers, (2) the investigation of possible lower level cognitive impairments, (3) the exploration of core reflective and automatic/affective symptoms, (4) the evaluation of Internet use heterogeneity and comorbidities, (5) the development of new neuroscience strategies and (6) the elaboration of behavioral and cognitive interventions. PMID- 26475995 TI - Defeat stress in rodents: From behavior to molecules. AB - Mood and anxiety disorders are prevalent conditions affecting one out of four people during lifetime. The development of high validity animal models to study these disorders has been a major challenge in the past. When considering experimental approaches for studying affective disorders, the social defeat paradigm has been shown to have etiological, predictive and face validity. Here, we explain the general principle of social defeat stress paradigms, with a strong focus on the resident-intruder model and compare different experimental settings as published to date. We discuss behavioral changes described in defeated animals as well as changes in the animal's physiological parameters. In addition, we provide an overview of the molecular adaptations that are found in animals subjected to defeat stress, with special attention to neural circuits and neuroendocrine signaling. Defeat produces specific behaviors resembling the signs and symptoms of humans with affective disorders, such as anhedonia, social avoidance, despair and anxiety. These can be linked to a wide range of physiological changes-ranging from cardiovascular changes to alterations in the immune system- or by disturbances in specific neurotransmitter systems, in particular serotonin and dopamine. The defeat stress model thus impacts on several functional domains of behavior and may mimic cardinal features of a multitude of psychiatric disorders including depression, post-traumatic stress disorder and schizophrenia. This manuscript critically reviews the core findings, strengths and limitations of the range of animal studies in this field and provides future perspectives. PMID- 26475996 TI - Immune suppressive activity of the influenza fusion peptide. AB - Immune suppressive domains have been identified in retro and filoviral fusion proteins. Such domains constitute small peptide motifs that are evolutionarily very well preserved within each group. We here test the hypothesis that such preservation reflects a dual selection pressure for both immune suppression and membrane fusion activity in influenza viruses for which no immune suppressive peptide motifs have been identified. We identified a conserved motif in the fusion peptide of influenza hemagglutinin as a candidate for an immune suppressive domain using comparative and phylogenetic analysis. This peptide was indeed found to exhibit immune suppressive activity in several in vitro assays. Similar to the previously reported peptides from retro and filoviruses the influenza peptide had immune suppressive activity when presented as a dimer but not as a monomer. PMID- 26475997 TI - Critical role of the lipid rafts in caprine herpesvirus type 1 infection in vitro. AB - The fusion machinery for herpesvirus entry in the host cells involves the interactions of viral glycoproteins with cellular receptors, although additional viral and cellular domains are required. Extensive areas of the plasma membrane surface consist of lipid rafts organized into cholesterol-rich microdomains involved in signal transduction, protein sorting, membrane transport and in many processes of viruses infection. Because of the extraction of cholesterol leads to disorganization of lipid microdomains and to dissociation of proteins bound to the lipid rafts, we investigated the effect of cholesterol depletion by methyl beta-cyclodextrin (MbetaCD) on caprine herpesvirus 1 (CpHV.1) in three important phases of virus infection such as binding, entry and post-entry. MbetaCD treatment did not prejudice virus binding to cells, while a dose-dependent reduction of the virus yield was observed at the virus entry stage, and 30 mM MbetaCD reduced infectivity evidently. Treatment of MDBK after virus entry revealed a moderate inhibitory effect suggesting that cholesterol is mainly required during virus entry rather than during the post-entry stage. Alteration of the envelope lipid composition affected virus entry and a noticeable reduction in virus infectivity was detected in the presence of 15 mM MbetaCD. Considering that the recognition of a host cell receptor is a crucial step in the start-up phase of infection, these data are essential for the study of CpHV.1 pathogenesis. To date virus receptors for CpHV.1 have not yet been identified and further investigations are required to state that MbetaCD treatment affects the expression of the viral receptors. PMID- 26475998 TI - Aggregatibacter actinomycetemcomitans serotypes and DGGE subtypes in Thai adults with chronic periodontitis. AB - OBJECTIVE: To investigate the distribution of Aggregatibacter actinomycetemcomitans serotypes and DGGE subtypes among isolates from Thai chronic periodontitis patients. DESIGN: Forty-four adult Thai periodontitis patients were assessed by a full mouth recording for CAL, PPD, and BOP. Seventy nine strains of A. actinomycetemcomitans were isolated from deep pockets on selective TSBV agar and 17 strains were isolated from shallow pockets. The strains were serotyped using PCR and subtyped using DGGE. RESULTS: The prevalence of A. actinomycetemcomitans was 84.1%. Non-serotypeable A. actinomycetemcomitans strains occurred equally frequent as serotypeable (54.5%); serotype a 18.2%, serotype c 15.9%, serotype e 9.1%, and serotype f 11.4%. Serotype b and d were not detected. A JP2 like strain but serotyped as c was isolated from two patients, and another two strains showed an 886bp insertion on the ltx promoter of their A. actinomycetemcomitans isolates. DGGE typing disclosed 16 different subtypes among the non-serotypeable strains. Two of them (NS1 and NS2) were more common (12.7 and 10.1%) among the strains than the other 14 subtypes (?5.1%). Most patients showed only one subtype (32.4%) but 29.7% had 2 and 3 different subtypes while 8.1% revealed 4 subtypes in one and the same deep pocket. CONCLUSION: This study showed a greater subtype diversity of A. actinomycetemcomitans predominated by non-serotypeable strains than previously reported in an adult Thai population. It was also revealed for the first time that isolates with a 530bp deletion or 886bp insertion of the ltx promoter were serotyped as serotype c. PMID- 26475999 TI - Interaction between peroxisome proliferator-activated receptor gamma and smoking on cardiovascular disease. AB - The aim of this study was to investigate the association between peroxisome proliferator-activator receptor-gamma (PPAR-gamma) genotype and additional gene smoking interaction on cardiovascular disease (CVD) based on a Chinese population. A total of 1248 subjects (613 men, 635 women), with a mean age of 55.5+/-11.8 years old, were selected, including 620 CVD patients and 628 normal controls. Logistic regression was performed to investigate association between single nucleotide polymorphism (SNP) and CVD. Generalized MDR (GMDR) was used to analysis the gene-environment interaction, cross-validation consistency, the testing balanced accuracy, and the sign test, to assess each selected interaction were calculated. The carriers of homozygous mutant of two SNP revealed increased CVD risk than those with wild-type homozygotes, OR (95% CI) were 1.31 (1.16-1.95) and 1.68 (1.29-2.06), respectively. GMDR analysis for one- to three-locus models indicated that there was a significant two-locus model (p=0.0107) involving rs1805192 and smoking, indicating a potential gene-gene interaction between rs1805192 and smoking. Overall, the two- locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 62.17%. We found that smokers with Pro/Ala or Ala/Ala genotype have highest CVD risk, compared to non smokers with Pro/Pro genotype, OR (95% CI) was 3.46 (1.31-3.42), after covariates adjustment. We found a significant association between genotypes of variants in rs10865710 and rs1805192 with increased CVD risk and a potential gene-gene interaction between rs1805192 and smoking. PMID- 26476000 TI - Daytime cold exposure and salt intake based on nocturnal urinary sodium excretion: A cross-sectional analysis of the HEIJO-KYO study. AB - Increased cardiovascular incidence in winter is partly explained by higher blood pressure due to cold exposure. Although higher salt intake induced by cold exposure has been reported in mice, the association remains unclear in humans. To investigate the association between salt intake and cold exposure in winter, a cross-sectional study was conducted among 860 elderly subjects (mean +/- standard deviation: 72.0 +/- 7.1 years). We determined ambient temperature at every 10 min according to indoor temperature measured in the subjects' home, outdoor temperature, and self-administered diary logging time spent outdoors. Salt intake was estimated by nocturnal sodium excretion rate of overnight urine collection. A 1 degrees C lower daytime ambient temperature was significantly associated with a higher urinary sodium excretion rate by 0.07 mmol/h in the subsequent night independent of age, sex, body weight, alcohol intake, calcium channel blocker use, diabetes, household income, estimated glomerular filtration rate, daytime physical activity (p=0.02). After further adjustment for outdoor temperature and day length, the lowest tertile groups of ambient daytime temperature (10.1 +/- 2.3 degrees C) showed the nocturnal urinary sodium excretion rate was higher by 14.2% (7.62 vs. 6.54 mmol/h) compared with the highest tertile group (19.3 +/- 1.8 degrees C). Higher sodium excretion rate was associated with higher nighttime ambulatory blood pressure (p<0.01) and its lower nocturnal dipping (p<0.01). Significant association between higher salt intake and daytime cold exposure partly explain the mechanism of higher blood pressure in winter, and suggest that a reduction of cold exposure might be effective to decrease salt intake. PMID- 26476001 TI - Quercetin-6-C-beta-D-glucopyranoside, natural analog of quercetin exhibits anti prostate cancer activity by inhibiting Akt-mTOR pathway via aryl hydrocarbon receptor. AB - Pre-clinical studies suggest mitigating effect of dietary flavonoid quercetin against cancer and other diseases. However, quercetin suffers from poor metabolic stability, which appears to offset its pharmacological efficacy. Recently, we isolated quercetin-6-C-beta-D-glucopyranoside (QCG) from Ulmus wallichiana planchon that has greater stability profile over quercetin. In the present study, the cytotoxic and apoptotic effects of QCG on prostate cancer cells were assessed. QCG inhibited prostate cancer cell proliferation by arresting cells at G0/G1 phase of cell cycle and induces apoptosis as evident from cytochrome c release, cleavage of caspase 3 and poly (ADP-ribose) polymerase. Mechanistic studies revealed that QCG inhibited reactive oxygen species (ROS) generation and Akt/mTOR cell survival pathways. Aryl hydrocarbon receptor (AhR) was a critical mediator of QCG action as knockdown of AhR attenuated QCG-induced cell cycle arrest, apoptosis and inhibition of Akt/mTOR pathway in prostate cancer cells. Taken together, our results suggest that QCG exhibits anti-cancer activity against prostate cancer cells via AhR-mediated down regulation of Akt/mTOR pathway in PC-3 cells. PMID- 26476003 TI - Ecological diversification associated with the pharyngeal jaw diversity of Neotropical cichlid fishes. AB - Innovations can facilitate bursts of diversification by increasing access to novel resources and the attainment of novel functional designs. Pharyngognathy, exhibited by highly diverse groups such as wrasses and cichlid fishes, is hypothesized to increase foraging capacity and efficiency. Here, I test the hypothesis that pharyngeal jaw shape and tooth morphology are adaptive in an ecologically diverse radiation of Neotropical cichlid fishes that spans North, Central and South America. I partitioned species into generalized trophic guilds using published stomach content analyses and quantified shape variation of the lower pharyngeal jaw (LPJ) using geometric morphometrics. Additionally, I tested for convergence in LPJ shape and trophic guild by mapping the phylogeny onto the principal components and testing for shifts towards similar evolutionary regimes. Major LPJ shape variation included the length and orientation (i.e. narrow or wide) of the lateral processes and length of the medial process, which varied based on the proportion of fishes and plants consumed. Pharyngeal tooth number, diversity and the frequency of tooth types were not evenly distributed among trophic guilds. There were seven distinct evolutionary regimes that converged upon four optima. Pharyngeal jaw diversification is associated with the exploitation of novel resources among Neotropical cichlids such that pharyngeal specialization has increased access to otherwise poorly accessible resources, such as resources that are difficult to crush (e.g. hard-shelled organisms) and assimilate (e.g. algae). PMID- 26476002 TI - Nutrient sensing and utilization: Getting to the heart of metabolic flexibility. AB - A central feature of obesity-related cardiometabolic diseases is the impaired ability to transition between fatty acid and glucose metabolism. This impairment, referred to as "metabolic inflexibility", occurs in a number of tissues, including the heart. Although the heart normally prefers to metabolize fatty acids over glucose, the inability to upregulate glucose metabolism under energetically demanding conditions contributes to a pathological state involving energy imbalance, impaired contractility, and post-translational protein modifications. This review discusses pathophysiologic processes that contribute to cardiac metabolic inflexibility and speculates on the potential physiologic origins that lead to the current state of cardiometabolic disease in an obesogenic environment. PMID- 26476004 TI - Heterogeneity of alcohol, tobacco, and other substance use behaviors in U.S. college students: A latent class analysis. AB - PURPOSE: To identify subgroups of college students with distinct profiles of traditional and alternative types of tobacco, alcohol, and other substance use and to examine how demographic characteristics and academic and social activities are associated with subgroup membership. METHODS: We used latent class analysis to characterize subgroups of individuals in their fourth-year of college based on their patterns of seven substance use behaviors: extreme heavy episodic drinking (HED), cigarette use, cigar/cigarillo/little cigar use, smokeless tobacco use, hookah use, marijuana use, and non-medical prescription drug use. Demographic characteristics and academic and social activities were then incorporated as predictors of these latent classes. RESULTS: We identified five classes defined by unique behavior patterns: (1) Non/Low Users, (2) Non-Hookah Tobacco Users, (3) Extreme HED & Marijuana Users, (4) Hookah and Marijuana Users, and (5) Poly Substance Users. Being male, older, and involved in sports were associated with greater odds of being in the Poly-Substance User class compared to the Low/No User class, and participating in an honors society and reporting more positive peer relationships were associated with being in the Hookah and Marijuana User class compared to the Low/No User class. CONCLUSION: Our findings of unique characteristics in the subgroups identified suggest that college substance users are a heterogeneous population requiring different targeted interventions. Of particular concern are subgroups with high rates of alternative tobacco products, as perceived risks of use may be inaccurate and this is not currently a focus of college substance use prevention interventions. PMID- 26476005 TI - Social isolation, drunkenness, and cigarette use among adolescents. AB - INTRODUCTION: This study compares isolated to sociable youth to investigate the relations between different network types of social isolation and alcohol and cigarette use. METHODS: Using data from the National Longitudinal Study of Adolescent to Adult Health we developed a network measure that includes various types of social isolation. Types of social isolation were operationalized as socially avoidant, actively isolated, and socially disinterested, with sociable youth as the reference category. Random effects ordinal logit models were fit to estimate the association between different types of social isolation and drunkenness and cigarette use. RESULTS: Different types of social isolation had varying effects on drunkenness and cigarette use. On the one hand, socially disinterested youth were at an increased risk for drunkenness and cigarette use. On the other hand, socially avoidant youth had lower odds of drunkenness and no significant differences in cigarette use when compared to sociable youth. Actively isolated youth showed no differences in drunkenness and cigarette use. CONCLUSIONS: The role played by marginalized social positions in youth substance use is an important yet overlooked problem. This study can contribute to better targeted and more effective health behavior prevention efforts for vulnerable adolescents. PMID- 26476006 TI - Nonmedical use of prescription stimulants in college students: Attitudes, intentions, and vested interest. AB - INTRODUCTION: Research on vested interest theory (VIT) indicates that the importance and hedonic relevance of attitudes moderates the link between attitudes and attitude-congruent behavior. Though largely untested in prevention research, this relationship may prove crucial in determining the success or failure of prevention efforts. The current study was designed to determine if subjectively perceived vested interest maximized the association between attitudes and intentions regarding the nonmedical use of prescription stimulants (NUPS). METHODS: A cross-sectional survey was conducted with college student respondents (N=162) using Amazon's MTurk. Participant age ranged from 19 to 49years old. A subsample analysis (n=129) was also conducted with younger respondents, as the typical college student is usually under the age of 30. RESULTS: Four-step hierarchical regression analysis indicated that both attitudes and perceived vested interest were significantly associated with NUPS behavioral intentions (p<.001). Further, vested interest moderated the relationship between stimulant-related attitudes and usage intentions (p<.001). Attitudes were significantly associated with intentions of moderately and highly vested respondents (p<.001), but not those of participants expressing low levels of perceived vested interest. CONCLUSIONS: Findings support the proposition that vested interest may be a useful target for attenuating NUPS. Rather than attempting to weaken positive attitudes toward NUPS, campaigns may prove more successful if designed to convince receivers that NUPS is not in their best interest. PMID- 26476007 TI - Nonmedical prescription opioid use among victimized women on probation and parole. AB - BACKGROUND: Nonmedical prescription opioid use (NPOU) is a major public health concern and few studies have described this phenomenon among victimized women involved in the criminal justice system. OBJECTIVE: This study will describe the relationship between victimization, psychological distress, health status and NPOU among the vulnerable population of victimized women on probation and parole. METHODS: A sample of 406 women on probation and parole responded to items assessing victimization history, self-reported health status, physical pain, psychological distress, and post-traumatic stress disorder. Multiple logistic regression analysis was utilized to differentiate NPOUs versus nonusers. RESULTS: Overall, 169 (41.6%) women reported lifetime NPOU, and 20% reported use in the past year. Compared to women who did not report NPOU, NPOUs were more likely to be White, have poorer general health, and more severe psychological distress across nine symptom domains. In multiple logistic regression models, each year of age reduced the odds of NPOU by 4%; White women were twice as likely as women of other races to report NPOU; each unit increase in the measure for physical pain was associated with a 30% increase in the odds of NPOU; and participants who met diagnostic criteria for PTSD were 60% more likely to report NPOU compared to individuals who did not. CONCLUSION: Victimized women on probation and parole report high rates of NPOU and comorbid mental and physical health problems. The criminal justice system should routinely screen for NPOU, as well as untreated or poorly managed physical pain and psychological distress, which may increase risk of NPOU. PMID- 26476008 TI - Symptoms with betel nut and betel nut with tobacco among Micronesian youth. AB - Betel nut has been stated to be addictive, but evidence is lacking. This study describes dependence symptoms among adolescents using betel alone or with tobacco. In the first study, participants were 151 9th graders in Saipan. In the second study, participants were 269 9th graders in Pohnpei and Yap. Participants completed a confidential questionnaire adapted from the U.S. National Survey of Drug Use and Health, which measured dependence symptoms. The 15 items were summed to form a scale, with a range of 0-15, where higher scores indicated greater endorsement of dependence symptoms. In the first study, 39.1% had used betel. More than two-thirds of all users (69.5%) used betel in the previous month: 87.8% also used tobacco with the betel. The mean (SD) dependence symptoms scale score among tobacco users was 8.2+/-4.0 versus 3.4+/-2.9 among those who used betel alone [t(7)=3.3, p=0.015]. In the second study, 38% from Pohnpei and 85% from Yap had used betel and most of the current users used it in the previous month (67% from Pohnpei, 91% from Yap). Among those who had used betel in the previous month, 90% from Pohnpei and 64% from Yap were using betel with tobacco. The dependence score was positively associated with frequency of tobacco use (e.g., mean (SD)=11.3 (+/-2.4) among most frequent users versus a mean (SD)=4.8 (+/-3.5) among the never users [F(3109)=28.8, p<0.001]). Betel nut users who also use tobacco may benefit from tobacco cessation strategies. PMID- 26476010 TI - Glutathione, glutathione disulfide, and S-glutathionylated proteins in cell cultures. AB - The analysis of the global thiol-disulfide redox status in tissues and cells is a challenging task since thiols and disulfides can undergo artificial oxido reductions during sample manipulation. Because of this, the measured values, in particular for disulfides, can have a significant bias. Whereas this methodological problem has already been addressed in samples of red blood cells and solid tissues, a reliable method to measure thiols and disulfides in cell cultures has not been previously reported. Here, we demonstrate that the major artifact occurring during thiol and disulfide analysis in cultured cells is represented by glutathione disulfide (GSSG) and S-glutathionylated proteins (PSSG) overestimation, due to artificial oxidation of glutathione (GSH) during sample manipulation, and that this methodological problem can be solved by the addition of N-ethylmaleimide (NEM) immediately after culture medium removal. Basal levels of GSSG and PSSG in different lines of cultured cells were 3-5 and 10-20 folds higher, respectively, when the cells were processed without NEM. NEM pre-treatment also prevented the artificial reduction of disulfides that occurs during the pre-analytical phase when cells are exposed to an oxidant stimulus. In fact, in the absence of NEM, after medium removal, GSH, GSSG and PSSG levels restored their initial values within 15-30 min, due to the activity of reductases and the lack of the oxidant. The newly developed protocol was used to measure the thiol-disulfide redox status in 16 different line cells routinely used for biomedical research both under basal conditions and after treatment with disulfiram, a thiol-specific oxidant (0-200 MUM concentration range). Our data indicate that, in most cell lines, treatment with disulfiram affected the levels of GSH and GSSG only at the highest concentration. On the other hand, PSSG levels increased significantly also at the lower concentrations of the drug, and the rise was remarkable (from 100 to 1000 folds at 200 MUM concentration) and dose dependent for almost all the cell lines. These data support the suitability of the analysis of PSSG in cultured cells as a biomarker of oxidative stress. PMID- 26476009 TI - Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning. AB - The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT(a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ~40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC. PMID- 26476011 TI - Ligation of the intersphincteric fistula tract for the treatment of fistula-in ano: experience of a tertiary care centre in South India. AB - AIM: Ligation of the intersphincteric fistula tract (LIFT) is a new sphincter sparing surgical technique increasingly used to treat fistulae-in-ano yielding good results. The aim of this study was to evaluate its effectiveness in the treatment of complex fistulae-in-ano and to determine factors associated with recurrence and its subsequent management. METHOD: A prospective observational study was performed of 167 patients with complex fistula-in-ano treated by LIFT from June 2013 to January 2014. In all patients a LIFT with partial core-out of the fistula tract was performed. RESULTS: There were 167 patients of mean age 43.6 +/- 12.8 years. Thirty-three fistulae were recurrent. 150 were trans sphincteric, 16 were intersphincteric and one was a suprasphincteric fistula. The median postoperative stay was 2 (range: 1-14) days (mean = 2.4 days). At follow up there was no change in continence. The median healing time was 4 (range: 1-8) weeks. Two patients developed an intersphincteric abscess needing surgical drainage healing uneventfully. The mean follow up was 12.8 [median = 12 (range: 4 22)] months. The healing rate was 94.1%. Ten (5.9%) patients developed a recurrent fistula that was managed by a second LIFT procedure in seven, a sinus tract excision with curettage in two and seton placement in one. Recurrence was significantly associated with diabetes mellitus and perianal collections and showed an increased incidence with tract abscesses and multiple tracts. CONCLUSION: LIFT has a high success rate in complex fistulae-in-ano. Recurrence is related to diabetes mellitus, perianal collections, tract abscesses and multiple tracts and a second LIFT procedure may be feasible and efficient. PMID- 26476012 TI - Guanine-rich DNA-based peroxidase mimetics for colorimetric assays of alkaline phosphatase. AB - DNA-based peroxidase mimetics are facilely constructed through Cu(II) coordination with different oligonucleotides involving G20, C20, A20 and T20, respectively, with high peroxidase mimicking activity as well as high stability against proteins. Peroxidase-like activities of DNA-Cu(II) complexes are greatly associated with the sequence composition of DNA templates, which decrease in the following order: G20>C20>A20>T20. G20-Cu(II) complex ([Cu(2+)]/[base]=0.05) possesses the Km value of 0.257 mM toward 3,3',5,5'-tetramethylbenzidine and 102.3mM toward hydrogen peroxide at 25 degrees C. G20-Cu(II) complexes are employed to develop a colorimetric turn-on assay of alkaline phosphatase with high sensitivity and selectivity, on the basis of pyrophosphate-induced inhibition of their intrinsic peroxidase-like activities. The limit of detection is achieved as 0.84 U/L with the linear response region of 20-200 U/L. Such colorimetric assay system is probably applicable for the quantitative determination of ALP in biological fluids. PMID- 26476013 TI - CdS/MoS2 heterojunction-based photoelectrochemical DNA biosensor via enhanced chemiluminescence excitation. AB - This work developed a CdS/MoS2 heterojunction-based photoelectrochemical biosensor for sensitive detection of DNA under the enhanced chemiluminescence excitation of luminol catalyzed by hemin-DNA complex. The CdS/MoS2 photocathode was prepared by the stepwise assembly of MoS2 and CdS quantum dots (QDs) on indium tin oxide (ITO), and achieved about 280% increasing of photocurrent compared to pure CdS QDs electrode due to the formation of heterostructure. High photoconversion efficiency in the photoelectrochemical system was identified to be the rapid spatial charge separation of electron-hole pairs by the extension of electron transport time and electron lifetime. In the presence of target DNA, the catalytic hairpin assembly was triggered, and simultaneously the dual hemin labeled DNA probe was introduced to capture DNA/CdS/MoS2 modified ITO electrode. Thus the chemiluminescence emission of luminol was enhanced via hemin-induced mimetic catalysis, leading to the physical light-free photoelectrochemical strategy. Under optimized conditions, the resulting photoelectrode was proportional to the logarithm of target DNA concentration in the range from 1 fM to 100 pM with a detection limit of 0.39 fM. Moreover, the cascade amplification biosensor demonstrated high selectivity, desirable stability and good reproducibility, showing great prospect in molecular diagnosis and bioanalysis. PMID- 26476014 TI - Potentiometric chemosensor for neopterin, a cancer biomarker, using an electrochemically synthesized molecularly imprinted polymer as the recognition unit. AB - With an established procedure of molecular imprinting, a synthetic polymer receptor for the neopterin cancer biomarker was devised and used as a recognition unit of a potentiometric chemosensor. For that, bis-bithiophene derivatized with cytosine and bithiophene derivatized with boronic acid were used as functional monomers. The open-circuit potential (OCP) based transduction under flow injection analysis conditions (FIA) determined neopterin in the concentration range of 0.15-2.5mM with the 22 uM limit of detection (LOD) and 7.01(+/-0.15) mVmM(-1) sensitivity indicating its potential suitability in clinical analysis applications. The molecularly imprinted polymer (MIP) film showed an appreciable apparent imprinting factor of ~6. The chemosensor successfully discriminated the interferences including the 6-biopterin and pterin structural analogs of neopterin as well as glucose and creatinine. Moreover, it determined neopterin in synthetic serum samples. PMID- 26476015 TI - A novel sensitive cell-based Love Wave biosensor for marine toxin detection. AB - A novel HepG2 cell-based biosensor using Love Wave sensor was developed to implement the real-time and sensitive detection of a diarrheic shellfish poisoning (DSP) toxin, Okadaic acid (OA). Detachable Love Wave sensor unit and miniaturized 8-channel recording instrument were designed for the convenient experimental preparation and sensor response signal measurement. The Love Wave sensor, whose synchronous frequency is around 160 MHz, was fabricated with ST-cut quartz substrate. To establish a cell-based biosensor, HepG2 cells as sensing elements were cultured onto the Love Wave sensor surface, and the cell attachment process was recorded by this biosensor. Results showed this sensor could monitor the cell attachment process in real time and response signals were related to the initial cell seeding densities. Furthermore, cell-based Love Wave sensor was treated with OA toxin. This biosensor presented a good performance to various OA concentrations, with a wide linear detection range (10-100 MUg/L). Based on the ultrasensitive acoustic wave platform, this cell-based biosensor will be a promising tool for real-time and convenient OA screening. PMID- 26476016 TI - Self-clearance mechanism of mitochondrial E3 ligase MARCH5 contributes to mitochondria quality control. AB - MARCH5, a mitochondrial E3 ubiquitin ligase, controls mitochondrial dynamics proteins and misfolded proteins, and has been proposed to play a role in mitochondria quality control. However, it remains unclear how mutant MARCH5 found in cancer tissues is removed from cells. Here, we show that mutation in the MARCH5 ligase domain increased its half-life fourfold, resulting in a drastic increase in its protein level. Abnormal accumulation of the E3 ligase-defective MARCH5 mutants MARCH5(H43W) and MARCH5(C65/68S) was diminished by overexpression of active MARCH5(WT) ; the mutant proteins were degraded through the ubiquitin proteasome pathway. Coimmunoprecipitation revealed that MARCH5 forms homodimers, and that substitution of Gly to Leu at the first putative GxxxG dimerization motif, but not the second, resulted in a loss of dimeric interaction. Moreover, overexpression of the dimerization-defective mutant MARCH5(4GL) could not decrease the level of accumulated MARCH5(H43W) , suggesting that dimerization of MARCH5 is necessary for self-clearance. Abnormal accumulation of MARCH5(H43W) and mitochondrial hyperfusion led to NF-KB activation, which was suppressed by overexpression of MARCH5(WT) . Together, the data reveal a self-protective mechanism involving MARCH5, which can target its own dysfunctional mutant for degradation in order to maintain mitochondrial homeostasis. PMID- 26476017 TI - Rice ASR1 and ASR5 are complementary transcription factors regulating aluminium responsive genes. AB - Rice is the most tolerant staple crop to aluminium (Al) toxicity, which is a limiting stress for grain production worldwide. This Al tolerance is the result of combined mechanisms that are triggered in part by the transcription factor ASR5. ASRs are dual target proteins that participate as chaperones in the cytoplasm and as transcription factors in the nucleus. Moreover, these proteins respond to biotic and abiotic stresses, including salt, drought and Al. Rice plants with silenced ASR genes are highly sensitive to Al. ASR5, a well characterized protein, binds to specific cis elements in Al responsive genes and regulates their expression. Because the Al sensitive phenotype found in silenced rice plants could be due to the mutual silencing of ASR1 and ASR5, we investigated the effect of the specific silencing of ASR5. Plants with artificial microRNA silencing of ASR5 present a non-transformed phenotype in response to Al because of the induction of ASR1. ASR1 has the same subcellular localization as ASR5, binds to ASR5 cis-regulatory elements, regulates ASR5 regulated genes in a non-preferential manner and might replace ASR5 under certain conditions. Our results indicate that ASR1 and ASR5 act in concert and complementarily to regulate gene expression in response to Al. PMID- 26476018 TI - On the validity of the Cerenkov limit as a criterion for precise band gap measurements by VEELS. AB - The generation of Cerenkov photons, contributions from retardation and surface effects, and the excitation of guided light modes can complicate the analysis of valence electron energy-loss spectroscopy (VEELS) data. In recent works it was argued that working below the so-called Cerenkov limit unwanted spectral contributions can be avoided, simplifying the reliable measurement of band gap energies and the extraction of the dielectric function by the Kramers-Kronig analysis. Here, relativistic simulations of valence electron energy-loss spectra of GaAs are employed in order to identify different spectral contributions. It is found that for electron energies below the Cerenkov limit the spectra can still be affected by the excitation of guided light modes and retardation effects. These spectral contributions can influence the position of the apparent band gap signal and can be problematic for the Kramers-Kronig analysis when working below or above the Cerenkov limit. PMID- 26476019 TI - Light propagation and interaction observed with electrons. AB - We discuss possibilities for a microscopic optical characterization of thin films and surfaces based on photoemission electron microscopy. We show that propagating light with wavelengths across the visible range can readily be visualized, and linear and non-linear materials properties can be evaluated non-invasively with nanometer spatial resolution. While femtosecond temporal resolution can be achieved in pump-probe-type experiments, the interferometric approach presented here has typical image frame times of ~200 fs. PMID- 26476020 TI - Increasing compliance with alcohol service laws in a developing country: intervention trial in the Kingdom of Bhutan. AB - AIM: Bhutan is a low-middle income country that, like many others, experiences significant alcohol-related harm and low compliance with laws restricting availability and promotion. This study assessed changes in compliance of alcohol outlets with sales restrictions following a multi-sector programme aimed at improving this. DESIGN: Pre-post design with covert observation of service practices. SETTING: Thimphu, Bhutan, June-November 2013. Alcohol is not permitted for sale except from 1 to 10 p.m. Wednesday-Monday. Serving minors (< 18 years old) or intoxicated patrons is illegal. PARTICIPANTS: Seventy-one outlets selected randomly from all 209 on-premises outlets in downtown Thimphu. INTERVENTION: Multi-sector programme involving visits to outlets, education of owners and staff, a toolkit and implementation checks. MEASUREMENTS: Ten mystery shopper visits were made to each outlet both before and after the intervention. We assessed compliance in five purchasing scenarios: (1) before 1 p.m., (2) after 10 p.m., (3) on Tuesdays and (4) shoppers who appeared to be underage or (5) intoxicated. Changes in compliance rates were assessed using multi-variable logistic regression models. FINDINGS: Overall compliance increased from 20 to 34% [difference: 14%; 95% confidence interval (CI) = 7-22%]. Improvement was found in refusals of service before 1 p.m.: 10-34% (difference(adj) = 24%; 95% CI = 12 37%) and on Tuesdays: 43-58% (difference(adj) = 14%; 95% CI = 1-28%). Differences in refusal to serve alcohol: after 10 p.m. (difference(adj) = 15%; 95% CI = -8 to 37%); to underage patrons (difference(adj) = -5%; 95% CI = 14 to 4%); and to intoxicated patrons (difference(adj) = 7%; 95% CI = -7-20%) were not statistically significant. Younger servers, stand-alone bars and outlets permitting indoor smoking were each less likely to comply with the alcohol service laws. CONCLUSION: A multi-sector programme to improve compliance with legal restrictions on serving alcohol in Bhutan appeared to have a modest effect but even after the programme, in two-thirds of the occasions tested, the laws were broken. PMID- 26476021 TI - Effects of nitrite exposure on haematological parameters, oxidative stress and apoptosis in juvenile turbot (Scophthalmus maximus). AB - Nitrite (NO2(-)) is commonly present as contaminant in aquatic environment and toxic to aquatic organisms. In the present study, we investigated the effects of nitrite exposure on haematological parameters, oxidative stress and apoptosis in juvenile turbot (Scophthalmus maximus). Fish were exposed to various concentrations of nitrite (0, 0.02, 0.08, 0.4 and 0.8mM) for 96 h. Fish blood and gills were collected to assay haematological parameters, oxidative stress and expression of genes after 0, 24, 48 and 96 h of exposure. In blood, the data showed that the levels of methemoglobin (MetHb), triglyceride (TG), potassium (K(+)), cortisol, heat shock protein 70 (HSP70) and glucose significantly increased in treatments with higher concentrations of nitrite (0.4 and/or 0.8mM) after 48 and 96 h, while the levels of haemoglobin (Hb) and sodium (Na(+)) significantly decreased in these treatments. In gills, nitrite (0.4 and/or 0.8mM) apparently reduced the levels of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and glutathione (GSH), increased the formation of malondialdehyde (MDA), up-regulated the mRNA levels of c-jun amino-terminal kinase (JUK1), p53, caspase-3, caspase-7 and caspase-9 after 48 and 96 h of exposure. The results suggested caspase-dependent and JUK signaling pathways played important roles in nitrite-induced apoptosis in fish. Further, this study provides new insights into how nitrite affects the physiological responses and apoptosis in a marine fish. PMID- 26476024 TI - HDAC inhibition: A novel therapeutic approach for atherosclerosis. PMID- 26476022 TI - Ischemic core and hypoperfusion volumes predict infarct size in SWIFT PRIME. AB - OBJECTIVE: Within the context of a prospective randomized trial (SWIFT PRIME), we assessed whether early imaging of stroke patients, primarily with computed tomography (CT) perfusion, can estimate the size of the irreversibly injured ischemic core and the volume of critically hypoperfused tissue. We also evaluated the accuracy of ischemic core and hypoperfusion volumes for predicting infarct volume in patients with the target mismatch profile. METHODS: Baseline ischemic core and hypoperfusion volumes were assessed prior to randomized treatment with intravenous (IV) tissue plasminogen activator (tPA) alone versus IV tPA + endovascular therapy (Solitaire stent-retriever) using RAPID automated postprocessing software. Reperfusion was assessed with angiographic Thrombolysis in Cerebral Infarction scores at the end of the procedure (endovascular group) and Tmax > 6-second volumes at 27 hours (both groups). Infarct volume was assessed at 27 hours on noncontrast CT or magnetic resonance imaging (MRI). RESULTS: A total of 151 patients with baseline imaging with CT perfusion (79%) or multimodal MRI (21%) were included. The median baseline ischemic core volume was 6 ml (interquartile range= 0-16). Ischemic core volumes correlated with 27-hour infarct volumes in patients who achieved reperfusion (r = 0.58, p < 0.0001). In patients who did not reperfuse (<10% reperfusion), baseline Tmax > 6-second lesion volumes correlated with 27-hour infarct volume (r = 0.78, p = 0.005). In target mismatch patients, the union of baseline core and early follow-up Tmax > 6 second volume (ie, predicted infarct volume) correlated with the 27-hour infarct volume (r = 0.73, p < 0.0001); the median absolute difference between the observed and predicted volume was 13 ml. INTERPRETATION: Ischemic core and hypoperfusion volumes, obtained primarily from CT perfusion scans, predict 27 hour infarct volume in acute stroke patients who were treated with reperfusion therapies. PMID- 26476025 TI - Could brain magnetic resonance imaging be of value in patients with Takotsubo syndrome without apparent brain lesions? PMID- 26476026 TI - Involvement of long noncoding RNA MALAT1 in the pathogenesis of diabetic cardiomyopathy. PMID- 26476027 TI - Endothelial microparticles after antihypertensive and lipid-lowering therapy inhibit the adhesion of monocytes to endothelial cells. PMID- 26476028 TI - Hemodynamic and echocardiographic effects of aortic regurgitation on femoro femoral veno-arterial ECMO. PMID- 26476029 TI - The role of echocardiography in the management of coronary anomaly. PMID- 26476030 TI - Atrioventricular septal defect: From embryonic development to long-term follow up. AB - Atrioventricular septal defect (AVSD) covers a spectrum of heart anomalies with a common atrioventricular connection and has an incidence of 4-5.3 per 10.000 live births. About half of the AVSDs occur in patient with Down syndrome. This review provides a bench to bedside overview of AVSD. Developmental aspects, nomenclature, anatomy, and classification of AVSD are discussed. Furthermore an overview of genetic and maternal risk factors for AVSD is provided, and available literature on (fetal) diagnosis, surgical techniques and follow-up is presented. Special attention is given to differences in developmental, anatomical and prognostic factors of AVSD between non-syndromic and Down syndrome patients. PMID- 26476031 TI - Seeking outcomes in database analyses: The good, the bad and the ugly. PMID- 26476032 TI - DPP-4 inhibitors: A potential promising therapeutic target in prevention of atherosclerosis. PMID- 26476033 TI - Response to: Relation of circumferential and longitudinal strain to other independent prognostic imaging markers in first time ST-elevation myocardial infarction. PMID- 26476034 TI - Prognostic value of abnormal P wave morphology and PR-segment displacement for mortality in ST-elevation myocardial infarction. PMID- 26476036 TI - Medical factors that predict quality of life for young adults with congenital heart disease: What matters most? AB - BACKGROUND: Identify demographic and medical status indicators that account for variability in physical and emotional health-related quality of life (QoL) among young adults with congenital heart disease (CHD) as compared to traditional lesion severity categories. METHODS: Cross-sectional study of 218 young adult survivors of CHD (mean=25.7, SD=7.1 years). Participants were recruited from pediatric and adult CHD clinics at a pediatric and an adult hospital. Stepwise linear regression examined the unique contribution of demographic (age; sex; estimated income) and medical status indicators (comorbid conditions; treatment modality; ventricular function/functional capacity) on QoL compared to traditional lesion severity categories (simple; moderate; complex). RESULTS: Lesion severity category accounted for a small portion of the variance in physical QoL (3%), but was not associated with emotional QoL. Lesion severity did not significantly contribute to the variability in physical QoL once other variables were entered. Having an estimated income of <=$30,000, taking more than one cardiac-related medication, and having a New York Heart Association (NYHA) functional class designation>I was associated with poorer physical QoL and explained 23% of the variability. NYHA class was the only variable that explained a unique proportion of variance (7%) in emotional QoL, and having a NYHA class designation>I was associated with greater risk for poorer emotional functioning. CONCLUSIONS: Findings suggested that several indicators readily available to treatment teams may provide important information about the risk for poor patient reported outcomes of physical and emotional QoL among CHD survivors. PMID- 26476035 TI - Predictive ability of the new 2014 ESC prognostic model in acute pulmonary embolism. PMID- 26476037 TI - A novel inducible cholesterol efflux peptide, FAMP, protects against myocardial ischemia reperfusion injury through a nitric oxide pathway. AB - OBJECTIVE: We evaluated whether a novel inducible cholesterol efflux (iCE) peptide [Fukuoka University Apolipoprotein A-I Mimetic Peptide (FAMP)] protects against myocardial ischemia reperfusion injury (IRI) through a nitric oxide (NO) pathway by an improvement of high-density lipoprotein (HDL) functionality. METHODS AND RESULTS: Male C57BL6/J mice were intraperitoneally injected with phosphate buffer as a control, low-dose (10 mg/kg) or high-dose (50 mg/kg) of FAMP before 18 h of IRI (n=6-12 in each group). After 30 min of ischemia followed by 6h of reperfusion, blood pressure, and infarct size were measured and cardiac function was evaluated by a Millar catheter. FAMP significantly improved stroke volume, cardiac output, left ventricular ejection fraction, and infarct size. FAMP significantly preserved cytochrome C in the mitochondrial fraction and inhibited its release into the cytosolic fraction in the heart, but did not significantly reduce mRNA levels of monocyte chemoattractant protein-1 or interluekin-6. In a TdT-mediated dUTP nick end labeling (TUNEL) assay, FAMP significantly suppressed the appearance of TUNEL-positive nuclear. We also performed same experiments with endothelial nitric oxide synthase-knockout (eNOS KO) mice and FAMP-induced improvements of cardiac function were not observed in eNOS-KO mice. CONCLUSIONS: FAMP activated HDL-functionality and improved cardiac function in a model of myocardial IRI. It may have anti-apoptotic effects by protecting mitochondria through a NO pathway as a pleiotropic effect. PMID- 26476038 TI - Cisplatin-induced bradycardia: Cardiac toxicity or cardiac hypersensitivity and Kounis syndrome? PMID- 26476039 TI - C/EBPbeta is required in pregnancy-induced cardiac hypertrophy. AB - AIM: Pregnancy is a physiological model of adaptive and reversible heart enlargement, but the molecular mechanisms determining this kind of physiologic cardiac hypertrophy are poorly known. Here, we analyzed the role of the transcription factor C/EBPbeta in the development of pregnancy-induced cardiac hypertrophy. RESULTS: C/EBPbeta+/- mice at day 18 of gestation were used as happloinsufficiency model of late pregnancy. We found that C/EBPbeta expression was specifically increased in hearts from Wt pregnant mice whereas expression of other C/EBP subtypes (alpha and delta) was not affected by gestation. Pregnancy induced changes in systemic metabolic and hormonal profiles were not essentially different in Wt versus C/EBPbeta+/- mice. However, C/EBPbeta+/- mice developed pregnancy-induced heart hypertrophy to a lower extent relative to Wt mice. Furthermore, hearts from C/EBPbeta+/- mice have alterations in fatty acid oxidation genes and reductions in the expression levels of glucose transporters that may compromise metabolic cardiac function during pregnancy. Among marker genes of inflammation, interleukin-6 (Il-6) showed a marked differential behavior in C/EBPbeta+/- pregnant mice: pregnancy strongly induced cardiac Il-6 expression in wt, a phenomenon that did not occur in C/EBPbeta+/- mice. Moreover, marker genes for M2 macrophages were decreased in C/EBPbeta+/- pregnant mice and in C/EBPbeta-/- mice subjected to LPS stimulus. CONCLUSIONS: Here we found that normal levels of C/EBPbeta are required for hypertrophy development during pregnancy. Events such as the increase in IL-6 in the heart of pregnant mice are prevented in C/EBPbeta+/- animals. Moreover, C/EBPbeta controls M2-macrophage gene expression in the heart. Thus, C/EBPbeta appears as a transcription factor required for cardiac hypertrophy response to gestation. PMID- 26476040 TI - Low-dose oral pimobendan emancipates patients with severe ischemic pump failure from intravenous catecholamine infusion for cardiogenic shock. PMID- 26476041 TI - Targeting histamine-2 receptor for prevention of cardiac remodelling in chronic pressure overload. PMID- 26476042 TI - Epicardial or transvenous leads: Controversial for the placement in implantation of cardiac resynchronization therapy. PMID- 26476043 TI - Cardiac remodeling in Galphaq and Galpha11 knockout mice. AB - BACKGROUND: Although both Galphaq- and Galpha11-protein signaling are believed to be involved in the regulation of cardiac hypertrophy, their detailed contribution to myocardial function remains elusive. METHODS AND RESULTS: We studied remodeling processes in healthy transgenic mice with genetically altered Galphaq/Galpha11-expression, in particular a global Galpha11-knockout and a novel inducible cardiac specific Galphaq-knockout, as well as a combined double knockout (dKO) mouse line. Echocardiography and telemetric ECG recordings revealed that compared with wild type mice, hearts of dKO mice showed an increased ejection fraction and a decreased heart rate, irrespective of age resulting in a maintained cardiac output. We attributed these findings to the lack of Galpha11, which the absence was associated with a decreased afterload. Histological analysis of the extracellular matrix in the heart depicted a diminished presence of collagen in aging hearts of dKO mice compared to wild-type mice. The results of a transcriptome analysis on isolated ventricular cardiac myocytes revealed alterations of the activity of genes involved in the Galphaq/Galpha11-dependent regulation of the extracellular matrix, such as the matricellular protein Cyr61. CONCLUSIONS: From our data we conclude that Galphaq/Galpha11 signaling pathways play a pivotal role in maintaining gene activity patterns. For the heart we revealed their importance in modulating the properties of the extracellular matrix, a mechanism that might be an important contributor and mechanistic basis for the development of pressure-overload induced cardiac hypertrophy. PMID- 26476044 TI - Acute coronary syndrome in the Asia-Pacific region. AB - More than 4.2 billion inhabitants populate the Asia-Pacific region. Acute coronary syndrome (ACS) is now a major cause of death and disability in this region with in-hospital mortality typically exceeding 5%. Yet, the region still lacks consensus on the best approach to overcoming its specific challenges in reducing mortality from ACS. The Asia-Pacific Real world evIdenCe on Outcome and Treatment of ACS (APRICOT) project reviewed current published and unpublished registry data, unmet needs in ACS management and possible approaches towards improving ACS-related mortality in the region. There was striking heterogeneity in the use of invasive procedures, pharmacologic practice (hospitalization/post discharge), and in short- and long-term clinical outcomes across healthcare systems; this heterogeneity was perceived to be far greater than in Western Europe or the United States. 'Benchmark' short-term clinical outcomes are preferred over long-term outcomes due to difficulties in follow-up, recording and maintenance of medication adherence in a geographically large and culturally diverse region. Key 'barriers' towards improving outcomes include patient education (pain awareness, consequences of missing medication and secondary prevention), geographical landscape (urban vs. metropolitan), limited long-term adherence to guideline-based management and widespread adoption of cost-based rather than value-based healthcare systems. Initiatives to overcome these barriers should include implementation of pre-hospital management strategies, toolkits to aid in-hospital treatment, greater community outreach with online patient/physician education and telemedicine, sustainable economic models to improve accessibility to effective pharmacotherapies and the acquisition of high quality 'real-world' regional data to tailor secondary prevention initiatives that meet the unique needs of countries in this region. PMID- 26476045 TI - Morphine in the treatment of acute pulmonary oedema--Why? AB - Morphine has for a long time, been used in patients with acute pulmonary oedema due to its anticipated anxiolytic and vasodilatory properties, however a discussion about the benefits and risks has been raised recently. A literature search in Medline and Embase using the keywords "pulmonary oedema" OR "lung oedema" OR "acute heart failure" AND "morphine" was performed. A certain vasodilation has been described after morphine administration, but the evidence for this mechanism is relatively poor and morphine-induced anxiolysis may possibly be the most important factor of morphine in pulmonary oedema and therefore some authors have suggested benzodiazepines as an alternative treatment. Respiratory depression seems to be a less relevant clinical problem according to the literature, whereas vomiting is common, which may cause aspiration. In the largest outcome study, based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4.8 (95% CI: 4.52-5.18, p<0.001). Other, smaller studies have shown a significant association between morphine administration and mortality, which was lost after adjusting for confounding factors. Morphine is still used for pulmonary oedema in spite of poor scientific background data. A randomised, controlled study is necessary in order to determine the effect--and especially the risk--when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided. PMID- 26476046 TI - A multimodality approach of a cardiac echinococcus cyst in an asymptomatic woman. PMID- 26476047 TI - Determination of Dechlorane Plus and related compounds (dechlorane 602, 603 and 604) in fish and vegetable oils. AB - Dechlorane Plus (DP) is a flame retardant used as a substitute of Mirex since 1970s, but it was not detected in the environment until 2006. Since then, this compound and its main relatives, Dechlorane 602, 603 and 604, have been mainly studied in environmental matrices for monitoring purposes, but the dietary exposure to them has been hardly investigated so far. In the present study, we determined this family of compounds in fish and vegetable oil samples from Catalonia (Spain), most of them used as health supplements. Determination was carried out by gas chromatography-high resolution mass spectrometry (GC-HRMS), after a clean up in a multilayer silica column and preparative high performance liquid chromatography (HPLC) equipped with a pyrenyl(ethyl) column. Concentrations of Dechlorane compounds were between below the limit of detection and 384.2 pg g(-1). Although there are only few studies about the presence of these pollutants in food or feed, concentrations obtained indicated that these compounds are in the same order in fish and vegetable oil health supplements as the few other food and feed studies. PMID- 26476048 TI - Adsorption of polychlorinated dibenzo-p-dioxins/dibenzofurans on activated carbon from hexane. AB - Activated carbon is widely used to abate dioxins and dioxin-like compounds from flue gas. Comparing commercial samples regarding their potential to adsorb dioxins may proceed by using test columns, yet it takes many measurements to characterise the retention and breakthrough of dioxins. In this study, commercial activated carbon samples are evaluated during tests to remove trace amounts of dioxins dissolved in n-hexane. The solution was prepared from fly ash collected from a municipal solid waste incinerator. The key variables selected were the concentration of dioxins in n-hexane and the dosage of activated carbon. Both polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) showed very high removal efficiencies (94.7%-98.0% for PCDDs and 99.7% 99.8% for PCDFs). The presence of a large excess of n-hexane solvent had little effect on the removal efficiency of PCDD/Fs. The adsorbed PCDD/Fs showed a linear correlation (R(2) > 0.98) with the initial concentrations. Comparative analysis of adsorption isotherms showed that a linear Henry isotherm fitted better the experimental data (R(2) = 0.99 both for PCDDs and PCDFs) than the more usual Freundlich isotherm (R(2) = 0.88 for PCDDs and 0.77 for PCDFs). Finally, the results of fingerprint analysis indicated that dioxin fingerprint (weight proportion of different congeners) on activated carbon after adsorption did not change from that in hexane. PMID- 26476049 TI - Fate and transport with material response characterization of green sorption media for copper removal via adsorption process. AB - Green adsorption media with the inclusion of renewable and recycled materials can be applied as a stormwater best management practice for copper removal. A green adsorption media mixture composed of recycled tire chunk, expanded clay aggregate, and coconut coir was physicochemically evaluated for its potential use in an upflow media filter. A suite of tests were conducted on the media mixture and the individual media components including studies of particle size distribution, isotherms, column adsorption and reaction kinetics. Isotherm test results revealed that the coconut coir had the highest affinity for copper (q(max) = 71.1 mg g(-1)), and that adsorption was maximized at a pH of 7.0. The coconut coir also performed the best under dynamic conditions, having an equilibrium uptake of 1.63 mg g(-1). FE-SEM imaging found a strong correlation between the porosity of the micro pore structure and the adsorptive capacity. The use of the green adsorption media mixture in isolation or the coconut coir with an expanded clay filtration chamber could be an effective and reliable stormwater best management practice for copper removal. PMID- 26476050 TI - Hydrous iron oxide modified diatomite as an active filtration medium for phosphate capture. AB - A simple method to functionalize diatomite with hydrous iron oxide was attempted and its performance as a new active filtration material to remove and recover phosphate from water was investigated under varying solution conditions. The Langmuir phosphate adsorption capacity increased from 0.6 mgP/g for raw diatomite to 4.89, 14.71, 25.02 mgP/g for hydrous iron oxide modified diatomite (HIOMD), depending on the amount of iron loaded. Loading of hydrous iron oxide caused the increase in true and bulk density and a decline in filtration rate, but to a lesser extent. It was shown that the HIOMD product with suitable iron content could retain a good filtration performance with a greatly increased adsorption capacity for phosphate. The phosphate adsorption increased by decreasing pH and by increasing ionic strength at high pH levels. The adsorption process was interpreted by ligand exchange. Coexisting oxyanions of sulfate, nitrate, citrate, carbonate, silicate and humic acid showed different effects on phosphate fixation but it was presumed that their influence at their concentrations and pH levels commonly encountered in effluent or natural waters was limited, i.e., HIOMD had a reasonably good selectivity. Results in repeated adsorption, desorption and regeneration experiment showed that the adsorbed phosphate could be recovered and the material could be reused after regeneration. The column test showed that HIOMD could be potentially utilized as an adsorption filtration medium for phosphate removal and recovery from water. PMID- 26476051 TI - Influences of graphene on microbial community and antibiotic resistance genes in mouse gut as determined by high-throughput sequencing. AB - Graphene is a promising candidate as an antibacterial material owning to its bacterial toxicity. However, little information on influence of graphene on gut microbiota is available. In this study, mice were exposed to graphene for 4 weeks, and high-throughput sequencing was applied to characterize the changes in microbial community and antibiotic resistance genes (ARGs) in mouse gut. The results showed that graphene exposure increased biodiversity of gut microbiota, and changed their community. The 1 MUg/d graphene exposure had higher influences on the gut microbiota than 10 MUg/d and 100 MUg/d graphene exposures, which might be due to higher aggregation of high-level graphene. The influence of graphene on gut microbiota might attribute to that graphene could induce oxidative stress and damage of cell membrane integrity. The results were verified by the increase of ratio of Gram-negative bacteria. Outer membrane of Gram-negative bacteria could reduce the membrane damage induced by graphene and make them more tolerance to graphene. Further, we found that graphene exposure significantly increased the abundance and types of ARGs, indicating a potential health risk of graphene. This study firstly provides new insight to the health effects of graphene on gut microbiota. PMID- 26476052 TI - Post-hepatectomy liver failure: Should we consider venous outflow? AB - INTRODUCTION: Post-hepatectomy liver failure (PHLF) is one of the most serious complications of liver resection and is associated with high morbidity and mortality rates. PRESENTATION OF CASE: We report a case of PHLF involving clinical presentation of posthepatectomy-related 'small-for-size' syndrome (SFSS) secondary to obstructed venous outflow in the liver remnant, following extended right hepatectomy. DISCUSSION: PHLF is similar to SFSS in liver transplantation (LT) in terms of pathogenesis, clinical presentation and outcomes. Although inflow hypertension is clearly implicated in the pathogenesis of SFSS some authors have suggested that outflow obstruction is a potential pathogenic factor. CONCLUSION: The present case support the hypothesis that outflow obstruction could lead symptoms similar to SFSS. PMID- 26476053 TI - Successful treatment for patients with chronic orchialgia following inguinal hernia repair by means of meshoma removal, orchiectomy and triple-neurectomy. AB - INTRODUCTION: Orchialgia following inguinal hernia repair is rare complication and still challenging since there has been no established surgical treatment because of complexity of nerve innervation to the testicular area. Herein we report a case of postoperative orchialgia following Lichtenstein repair, which was successfully treated by mesh removal, orchiectomy and triple neurectomy. CASE PRESENTATION: A 65-year-old man was referred to our department because of chronic right orchialgia following Lichtenstein hernia repair. He walked with a limp and was unable to walk a long distance. Physical examination revealed the presence of meshoma in the groin area and hypoesthesia in the anterior skin of the right scrotum. His right testis was completely atrophic and located not in the scrotum but in the subcutaneous regions of right groin. He was diagnosed as both neuropathic and nociceptive orchialgia and underwent meshoma removal, triple neurectomy, and orchiectomy to address these issues. Pathological examination revealed that meshoma was integrated with the structures of the spermatic cord, leading to foreign-body reaction and fibrosis around the genital branch of genitofemoral nerve. The resected right testis was completely-scarred without ischemic changes. Orchialgia disappeared immediately after operation and he was able to walk without a limp. DISCUSSIONS: It is important to distinguish between nociceptive and neuropathic orchialgia. Neuroanatomic understanding is essential to guide treatment options. Orchiectomy is an option but should be reserved for refractory cases with evidence of nociceptive pain accompanied by anatomical changes. CONCLUSIONS: Triple neurectomy should be considered in patients with neuropathic orchialgia. PMID- 26476054 TI - One-stage laparoscopy-assisted endorectal pull-through for late presented Hirschsprung's disease-Case series. AB - INTRODUCTION: Children with late-presenting Hirschsprung's disease (HD) are classically treated by a staged operation with enterostomy. An alternative may be one-stage laparoscopy-assisted endorectal pull-through, which has cosmetic advantages. This case-series report describes the outcomes of children with late presenting HD who underwent this procedure. PRESENTATION OF CASES: Eight older (>3 years) children (five males, three females) underwent one-stage laparoscopy assisted endorectal pull-through in 2010-2012. A retrospective review revealed their median age was 9.9 (range, 3.4-14) years. The transitional zone was rectosigmoid junction in 4 patients, and was rectum in 4 patients. For bowel preparation, five patients required rectal irrigation under general anesthesia. The median operating time was 263min. There were no intraoperative or early post operative complications. Patients started a diet a median of 5 days after the operation and were discharged a median of 11.5 days. During the median follow-up period of 37 months, seven (87.5%) had acquired voluntary bowel movements and 12.5% had grade 1 soiling. However, five (62.5%) of the patients still had constipation. The constipation was manageable with diet or laxatives in four patients but one patient continued to require regular enemas. DISCUSSION: One stage laparoscopy-assisted endorectal pull-through in late-presenting HD was feasible, even in patients with large fecaloma with obstruction. Rectal irrigation under general anesthesia and the use of laparoscopy and a bipolar coagulator help to overcome the technical difficulties of this procedure. CONCLUSION: One-stage laparoscopy-assisted endorectal pull-through in children with late-presenting short segment HD is feasible and safe. PMID- 26476055 TI - Protective effects of 3-alkyl luteolin derivatives are mediated by Nrf2 transcriptional activity and decreased oxidative stress in Huntington's disease mouse striatal cells. AB - Huntington's disease (HD) is a polyglutamine-expansion neurodegenerative disorder caused by increased number of CAG repeats in the HTT gene, encoding for the huntingtin protein. The mutation is linked to several intracellular mechanisms, including oxidative stress. Flavones are compounds with a protective role in neurodegenerative pathologies. In the present study we analyzed the protective effect of luteolin (Lut, 3',4',5,7-tetrahydroxyflavone) and four luteolin derivatives bearing 3-alkyl chains of 1, 4, 6 and 10 carbons (Lut-C1, Lut-C4, Lut C6, Lut-C10) in striatal cells derived from HD knock-in mice expressing mutant Htt (STHdh(Q111/Q111)) versus wild-type striatal cells (STHdh(Q7/Q7)). HD cells showed increased caspase-3-like activity and intracellular reactive oxygen species (ROS), which were significantly decreased following treatment with Lut-C4 and Lut-C6 under concentrations that enhanced cell viability. Interestingly, Lut C4 and Lut-C6 rose the nuclear levels of phospho(Ser40)-nuclear factor (erythroid derived-2)-like 2 (Nrf2) and Nrf2/ARE transcriptional activity. Concordantly with increased Nrf2/ARE transcription, Lut-C6 enhanced superoxide dismutase 1 (SOD1) mRNA and SOD activity and glutamate-cysteine ligase catalytic subunit (GCLc) mRNA and protein levels, while Lut-C4 induced mRNA levels of GCLc only in mutant striatal cells. Data suggest that Lut-C6 luteolin derivative (in particular) might be relevant for the development of antioxidant strategies in HD. PMID- 26476056 TI - Evolution of lung breathing from a lungless primitive vertebrate. AB - Air breathing was critical to the terrestrial radiation and evolution of tetrapods and arose in fish. The vertebrate lung originated from a progenitor structure present in primitive boney fish. The origin of the neural substrates, which are sensitive to metabolically produced CO2 and which rhythmically activate respiratory muscles to match lung ventilation to metabolic demand, is enigmatic. We have found that a distinct periodic centrally generated rhythm, described as "cough" and occurring in lamprey in vivo and in vitro, is modulated by central sensitivity to CO2. This suggests that elements critical for the evolution of breathing in tetrapods, were present in the most basal vertebrate ancestors prior to the evolution of the lung. We propose that the evolution of breathing in all vertebrates occurred through exaptations derived from these critical basal elements. PMID- 26476057 TI - The role of P2Y1 receptor signaling in central respiratory control. AB - The profile of P2 receptor signaling in respiratory control has increased substantially since the first suggestions more than 15 years ago of roles in central chemoreception and modulating inspiratory motor outflow. Part of this reflects the paradigm shift that glia participate in information processing and that ATP is a major gliotransmitter. P2 receptors are a diverse family. Here, we review ATP signaling in respiratory control, highlighting G-protein coupled P2Y1 receptors that have been a focus of recent work. Despite strong evidence of a role for glia and P2 receptor signaling in the central chemosensitivity mediated by the retotrapezoid nucleus, P2Y1 receptors do not appear to be directly involved. Evidence that central P2 receptors and glia contribute to the hypoxic ventilatory response is compelling and P2Y1 receptors are the strongest candidate. However, functional significance in vivo, details of the signaling pathways and involvement of other receptor subtypes remain important questions. PMID- 26476058 TI - Linking climate change mitigation and coastal eutrophication management through biogas technology: Evidence from a new Danish bioenergy concept. AB - The interest in sustainable bioenergy solutions has gained great importance in Europe due to the need to reduce GHG emissions and to meet environmental policy targets, not least for the protection of groundwater and surface water quality. In the Municipality of Solrod in Denmark, a novel bioenergy concept for anaerobic co-digestion of food industry residues, manure and beach-cast seaweed has been developed and tested in order to quantify the potential for synergies between climate change mitigation and coastal eutrophication management in the Koge Bay catchment. The biogas plant, currently under construction, was designed to handle an annual input of up to 200,000 t of biomass based on four main fractions: pectin wastes, carrageenan wastes, manure and beach-cast seaweed. This paper describes how this bioenergy concept can contribute to strengthening the linkages between climate change mitigation strategies and Water Framework Directive (WFD) action planning. Our assessments of the projected biogas plant indicate an annual reduction of GHG emissions of approx. 40,000 t CO2 equivalents, corresponding to approx. 1/3 of current total GHG emissions in the Municipality of Solrod. In addition, nitrogen and phosphorous loads to Koge Bay are estimated to be reduced by approx. 63 t yr.(-1) and 9 tyr.(-1), respectively, contributing to the achievement of more than 70% of the nutrient reduction target set for Koge Bay in the first WFD river basin management plan. This study shows that anaerobic co digestion of the specific food industry residues, pig manure and beach-cast seaweed is feasible and that there is a very significant, cost-effective GHG and nutrient loading mitigation potential for this bioenergy concept. Our research demonstrates how an integrated planning process where considerations about the total environment are integrated into the design and decision processes can support the development of this kind of holistic bioenergy solutions. PMID- 26476059 TI - Comparison of physicochemical properties between fine (PM2.5) and coarse airborne particles at cold season in Korea. AB - Although it has been well-known that atmospheric aerosols affect negatively the local air quality, human health, and climate changes, the chemical and physical properties of atmospheric aerosols are not fully understood yet. This study experimentally measured the physiochemical characteristics of fine and coarse aerosol particles at the suburban area to evaluate relative contribution to environmental pollution in consecutive seasons of autumn and winter, 2014-2015, using XRD, SEM-EDX, XNI, ICP-MS, and TOF-SIMS. For these experimental works, the fine and coarse aerosols were collected by the high volume air sampler for 7 days each season. The fine particles contain approximately 10 MUg m(-3) of carbonaceous aerosols consisting of 90% organic and 10% elemental carbon. The spherical-shape carbonaceous particles were observed for the coarse samples as well. Interestingly, the coarse particles in winter showed the increased frequency of carbon-rich particles with high contents of heavy metals. These results suggest that, for the cold season, the coarse particles could contribute relatively more to the conveyance of toxic contaminants compared to the fine particles in the study area. However, the fine particles showed acidic properties so that their deposition to surface may cause facilitate the increase of mobility for toxic heavy metals in soil and groundwater environments. The fine and coarse particulate matters, therefore, should be monitored separately with temporal variation to evaluate the impact of atmospheric aerosols to environmental pollution and human health. PMID- 26476060 TI - Role of an organic carbon-rich soil and Fe(III) reduction in reducing the toxicity and environmental mobility of chromium(VI) at a COPR disposal site. AB - Cr(VI) is an important contaminant found at sites where chromium ore processing residue (COPR) is deposited. No low cost treatment exists for Cr(VI) leaching from such sites. This study investigated the mechanism of interaction of alkaline Cr(VI)-containing leachate with an Fe(II)-containing organic matter rich soil beneath the waste. The soil currently contains 0.8% Cr, shown to be present as Cr(III)(OH)3 in EXAFS analysis. Lab tests confirmed that the reaction of Cr(VI) in site leachate with Fe(II) present in the soil was stoichiometrically correct for a reductive mechanism of Cr accumulation. However, the amount of Fe(II) present in the soil was insufficient to maintain long term Cr(VI) reduction at historic infiltration rates. The soil contains a population of bacteria dominated by a Mangroviflexus-like species, that is closely related to known fermentative bacteria, and a community capable of sustaining Fe(III) reduction in alkaline culture. It is therefore likely that in situ fermentative metabolism supported by organic matter in the soil produces more labile organic substrates (lactate was detected) that support microbial Fe(III) reduction. It is therefore suggested that addition of solid phase organic matter to soils adjacent to COPR may reduce the long term spread of Cr(VI) in the environment. PMID- 26476061 TI - Variability in AIRS CO2 during active and break phases of Indian summer monsoon. AB - Due to human activities, the atmospheric concentration of Carbon Dioxide (CO2) has been rising extensively since the Industrial Revolution. Indian summer monsoon (ISM) has a dominant westerly component from ocean to land with a strong tendency to ascend and hence may have role in CO2 distribution in lower and middle troposphere over Indian sub-continent. A substantial component of ISM variability arises from the fluctuations on the intra-seasonal scale between active and break phases which correspond to strong and weak monsoon circulation. In view of the above, an attempt is made in this study to examine the AIRS/AQUA satellite retrieved CO2 distribution in response to atmospheric circulation with focus on active and break phase. Correlation analysis indicates the increase in AIRS CO2 linked with strong monsoon circulation. Study also reveals that anomalous circulation pattern during active and break phase show resemblance with high and low values of AIRS CO2. Homogeneous monsoon regions of India show substantial increase in CO2 levels during active phase. Hilly regions of India show strong contrast in CO2 and vertical velocity during active and break phases. PMID- 26476062 TI - Modeling the downward transport of (210)Pb in Peatlands: Initial Penetration Constant Rate of Supply (IP-CRS) model. AB - The vertical distribution of (210)Pb is commonly used to date peat deposits accumulated over the last 100-150 years. However, several studies have questioned this method because of an apparent post-depositional mobility of (210)Pb within some peat profiles. In this study, we introduce the Initial Penetration-Constant Rate of Supply (IP-CRS) model for calculating ages derived from 210Pb profiles that are altered by an initial migration of the radionuclide. This new, two phased, model describes the distribution of atmospheric-derived (210)Pb ((210)Pbxs) in peat taking into account both incorporation of (210)Pb into the accumulating peat matrix as well as an initial flushing of (210)Pb through the uppermost peat layers. The validity of the IP-CRS model is tested in four anomalous (210)Pb peat records that showed some deviations from the typical exponential decay profile not explained by variations in peat accumulation rates. Unlike the most commonly used (210)Pb-dating model (Constant Rate of Supply (CRS)), the IP-CRS model estimates peat accumulation rates consistent with typical growth rates for peatlands from the same areas. Confidence in the IP-CRS chronology is also provided by the good agreement with independent chronological markers (i.e. (241)Am and (137)Cs). Our results showed that the IP-CRS can provide chronologies from peat records where (210)Pb mobility is evident, being a valuable tool for studies reconstructing past environmental changes using peat archives during the Anthropocene. PMID- 26476063 TI - Concentrations and patterns of organochlorines (OCs) in various fish species from the Indus River, Pakistan: A human health risk assessment. AB - The present study was conducted to reveal the concentrations and patterns of organochlorines [i.e., organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs)] in freshwater fish species collected from four ecologically important sites of the Indus River i.e., Taunsa (TAU), Rahim Yar Khan (RYK), Guddu (GUD) and Sukkur (SUK). In the fish muscle tissues, concentrations of 15 OCPs (?15OCPs) and 29 PCBs (?29PCBs) varied between 1.93-61.9 and 0.81-44.2 ng/g wet weight (ww), respectively. Overall, the rank order of OCs was DDTs>PCBs>hexachlorocyclohexanes (HCHs)>chlordanes (CHLs). The patterns of PCBs showed maximum contribution of tri-CBs (59%). Ratios of individual HCH and DDT analytes contributing to the summed values indicated both recent and past use of these chemicals in the region, depending upon fish species. To assess the associated health risks, carcinogenic and non-carcinogenic risks were calculated through hazard ratios (HRs). For carcinogenic risk, HR was >1 at both 50th and 95th percentile concentrations, suggesting that the daily exposure to OCPs and PCBs yields a lifetime cancer risk of 1 in a million. HR for non-cancerous risk was <1 at both the percentiles, signifying no adverse effect by OCs exposure in native population. PMID- 26476064 TI - Association of environmental benzo[a]pyrene exposure and DNA methylation alterations in hepatocellular carcinoma: A Chinese case-control study. AB - Epidemiological studies implicate environmental risk factors and epigenetic alterations in the multistage process of hepatocellular carcinoma (HCC) development. However, associations between environmental factors and DNA methylation of tumour suppressor genes (TSGs) in HCC development remain ambiguous. Understanding how possible interactions influence risk may provide insights into the complexity of hepato-carcinogenesis. For this study, blood samples were collected from HCC patients (n=90) and healthy volunteers (n=99) from Xiamen (China) and data for selected environmental risk factors [e.g., benzo[a]pyrene (B[a]P), hepatitis B or C virus (HBV or HCV) infection, smoking and alcohol consumption] were recorded; factors identified as significantly higher (P<0.05) amongst case subjects compared to controls were identified. In order to assess associations for epigenetic alterations and HCC risk factors, serum DNA methylation of TSGs was quantified using high-resolution melting (HRM) analysis. Our results clearly indicate elevated methylation patterns for detoxification gene [glutathione-S-transferase Pi (GSTP)] promoter regions in cases compared to control subjects. Additionally, GSTP promoter hypermethylation and B[a]P diol epoxide-albumin (BPDE-Alb) were positively correlated with HCC incidence. Our epidemiological and in vitro cell model studies indicated that GSTP promoter DNA methylation regulates this gene's expression. Moreover, GSTP also plays an important role in B[a]P detoxification and potential protective role against B[a]P-induced liver cell toxicity and hepato-carcinogenesis. PMID- 26476065 TI - Occurrence and origin of methane in groundwater in Alberta (Canada): Gas geochemical and isotopic approaches. AB - To assess potential future impacts on shallow aquifers by leakage of natural gas from unconventional energy resource development it is essential to establish a reliable baseline. Occurrence of methane in shallow groundwater in Alberta between 2006 and 2014 was assessed and was ubiquitous in 186 sampled monitoring wells. Free and dissolved gas sampling and measurement approaches yielded comparable results with low methane concentrations in shallow groundwater, but in 28 samples from 21 wells methane exceeded 10mg/L in dissolved gas and 300,000 ppmv in free gas. Methane concentrations in free and dissolved gas samples were found to increase with well depth and were especially elevated in groundwater obtained from aquifers containing coal seams and shale units. Carbon isotope ratios of methane averaged -69.7 +/- 11.10/00 (n=63) in free gas and -65.6 +/- 8.90/00 (n=26) in dissolved gas. delta(13)C values were not found to vary with well depth or lithology indicating that methane in Alberta groundwater was derived from a similar source. The low delta(13)C values in concert with average delta(2)HCH4 values of -289 +/- 440/00 (n=45) suggest that most methane was of biogenic origin predominantly generated via CO2 reduction. This interpretation is confirmed by dryness parameters typically >500 due to only small amounts of ethane and a lack of propane in most samples. Comparison with mud gas profile carbon isotope data revealed that methane in the investigated shallow groundwater in Alberta is isotopically similar to hydrocarbon gases found in 100-250 meter depths in the WCSB and is currently not sourced from thermogenic hydrocarbon occurrences in deeper portions of the basin. The chemical and isotopic data for methane gas samples obtained from Alberta groundwater provide an excellent baseline against which potential future impact of deeper stray gases on shallow aquifers can be assessed. PMID- 26476066 TI - Comparative test of ecological assessment methods of lowland streams based on long-term monitoring data of macrophytes. AB - Ecological assessment of water courses is required by the European Water Framework Directive (WFD). Assessment by means of macrophytes is impeded by insufficient knowledge on the relations between assessment scores and the dynamics of environmental parameters. Data from a long-term observation of macrophyte dynamics over 21 years in two lowland rivers were used for testing the performance of six widely used assessment methods. Six sample sites situated in two lowland streams were selected. Four sites were classified as of moderate habitat quality and two sites as of poor habitat quality in the context of WFD. Assessment methods generally showed a poor performance in recognizing the ecological status of the annual observations. Status was more often over- than underestimated. Performance of methods differed among individual rivers and among river zones. Assessment scores mostly showed a steady decline, even though all sites obviously remained in the same habitat quality class throughout the observation period. Variation of most environmental factors was largely unrelated to assessment scores. Fluctuations of assessment scores were partly related to single natural disturbance events such as high discharge. Increased shading by marginal trees was reflected negatively by most assessment scores. Assessment scores were highly correlated with species richness and total abundance. The best overall performance was shown by the North-Rhine Westphalian (NRW) method. In contrast to single metric methods it can be adapted to individual properties of a reach in a flexible way. Macrophyte assessment based on the pressure-impact framework did not lead to a satisfying result in our case study. Improvement of species assessment scores and inclusion of functional properties such as growth form may help to overcome the present difficulties. PMID- 26476067 TI - Dissolved inorganic carbon speciation in aquatic environments and its application to monitor algal carbon uptake. AB - Dissolved inorganic carbon (DIC) speciation is an important parameter that enables chemical and ecological changes in aquatic environments, such as the aquatic environmental impact of increasing atmospheric CO2 levels, to be monitored. We have examined and developed a sensitive and cost-effective 'back titration' method to determine the DIC species and abundance in aqueous environments that is more accurate and reproducible than existing methods and is applicable in a range of fresh, brackish and sea waters. We propose the use of pHHCO3 (bicarbonate-dominant pH) and pH3.5 as the titration end points in the back-titration technique to accurately determine carbonate alkalinity. The proposed method has a higher accuracy and precision than other modified Gran's methods that are currently in use. The detection limit was found to be ~5 MUmol kg(-1) with an accuracy within 1% and a precision (CV) within 0.2% and 0.5% at high and low level of carbonates, respectively. This method was successfully applied to monitor DIC in the aqueous medium of Nannochlopsis salina cultivation separately carried out with NaHCO3 and CO2 as the respective inorganic carbon source. The cells were able to grow in the NaHCO3 medium with a similar growth curve to cells with 0.039% CO2 (air). Increases in CO2 level stimulated lipid accumulation by diverting the fixed carbon from protein to lipids. The increased concentration of gaseous CO2 and the accompanying lower pH appears to significantly inhibit the growth of algae despite the presence of HCO3(-) when 20% CO2 was employed. PMID- 26476068 TI - Influence of relief on permanent preservation areas. AB - Many countries have environmental legislation to protecting natural resources on private property. In Brazil, the Brazilian Forestry Code determines specific areas to maintain with natural vegetation cover, known as areas of permanent preservation (APP). Currently, there are few studies that relate topographic variables on APP. In this context, we sought to evaluate the influence of relief on the conservation of areas of permanent preservation (APP) in the areas surrounding Caparao National Park, Brazil. By using the chi-squared statistical test, we verified that the presence of forest cover is closely associated with altitude. The classes of APP in better conservation status are slopes in addition to hilltops and mountains, whereas APP streams and springs are among the areas most affected by human activities. The most deforested areas are located at altitudes below 1100.00 m and on slopes less than 45 degrees . All orientations of the sides were significant for APP conservation status, with the southern, southeastern, and southwestern sides showing the lower degrees of impact. The methodology can be adjusted to environmental legislation to other countries. PMID- 26476069 TI - Use of physicochemical signatures to assess the sources of metals in urban road dust. AB - Road deposited dust is a complex mixture of pollutants derived from a wide range of sources. Accurate identification of these sources is seminal for effective source-oriented control measures. A range of techniques such as enrichment factor analysis (EF), principal component analysis (PCA) and hierarchical cluster analysis (HCA) are available for identifying sources of complex mixtures. However, they have multiple deficiencies when applied individually. This study presents an approach for the effective utilisation of EF, PCA and HCA for source identification, so that their specific deficiencies on an individual basis are eliminated. EF analysis confirmed the non-soil origin of metals such as Na, Cu, Cd, Zn, Sn, K, Ca, Sb, Ba, Ti, Ni and Mo providing guidance in the identification of anthropogenic sources. PCA and HCA identified four sources, with soil and asphalt wear in combination being the most prominent sources. Other sources were tyre wear, brake wear and sea salt. PMID- 26476070 TI - Calculations of 21 Lambda-S and 42 Omega states of BC molecule: Potential energy curves, spectroscopic parameters and spin-orbit coupling effect. AB - The potential energy curves (PECs) were calculated for the 42 Omega states generated from the 21 Lambda-S states (X(4)Sigma(-), A(4)Pi, B(4)Sigma(-), a(2)Pi, b(2)Sigma(-), c(2)Delta, d(2)Sigma(+), e(2)Pi, 3(2)Pi, 4(2)Pi, 5(2)Pi, 2(2)Sigma(-), 3(2)Sigma(-), 2(2)Sigma(+), 3(2)Sigma(+), 2(2)Delta, 3(2)Delta, 1(4)Sigma(+), 2(4)Pi, 1(4)Delta and 1(2)Phi), which originated from the lowest two dissociation channels, B((2)Pu)+C((3)Pg) and B((2)Pu)+C((1)Dg), of the BC molecule. The PECs were calculated for internuclear separations from 0.08 to 1.10 nm using the CASSCF method, which was followed by the icMRCI approach with the aug-cc-pV6Z basis set. Of these 21 Lambda-S states, the e(2)Pi, 2(2)Delta, 2(2)Sigma(-), 4(2)Pi, 1(2)Phi and 3(2)Delta possess the double wells. The A(4)Pi, a(2)Pi, c(2)Delta, 2(4)Pi, 4(2)Pi, 5(2)Pi, 1(4)Delta and 1(2)Phi states are inverted with the spin-orbit coupling (SOC) effect taken into account. The first well of e(2)Pi state and the second well of 4(2)Pi and 2(2)Delta states do not have any vibrational states whether with or without the SOC effect included. All the Lambda-S and Omega states involved in this paper are bound states. Scalar relativistic correction was included by the third-order Douglas-Kroll Hamiltonian approximation at the level of an aug-cc-pV5Z basis set. Core-valence correlation correction was included at the level of an aug-cc-pCV5Z basis set. The SOC effect was accounted for by the state interaction method with the Breit-Pauli Hamiltonian and the all-electron cc-pCV5Z basis set. The PECs of all the states were extrapolated to the complete basis set limit. The spectroscopic parameters were obtained. The vibrational properties of several Lambda-S and Omega states with the relatively shallow wells were evaluated. The SOC effect on the spectroscopic parameters is not obvious for almost all the states. The spectroscopic properties reported in this paper can be expected to be reliably predicted ones. PMID- 26476071 TI - Growth and characterization of novel organic 3-Hydroxy Benzaldehyde-N-methyl 4 Stilbazolium Tosylate crystals for NLO applications. AB - The 3-Hydroxy Benzaldehyde-N-methyl 4-Stilbazolium Tosylate (3- HBST) is a new organic NLO crystal and it is a new derivative in stilbazolium tosylate family. In this work we have synthesized 3-HBST and the single crystal was grown by conventional slow cooling method. The structure and lattice parameters of the grown crystal were determined by the single crystal X-ray diffraction (XRD) technique and it is exhibiting good crystalline nature which is observed from the powder XRD. In order to check the crystalline quality the rocking curve was recorded using multi crystal X-ray diffractometer. The functional groups were identified from both FTIR and NMR spectral analyses. The pi-pi* and n-pi* optical transition energy levels were estimated from the absorption peaks. The NLO property was confirmed by measuring relative SHG efficiency by Kurtz powder test; it shows 24 times higher SHG efficiency than that of urea. In order to test the mechanical stability the Vickers and Knoop micro hardness measurement were carried out and found that the micro hardness number decreases with increasing load. The melting point was determined from Differential Scanning Colorimetry (DSC). PMID- 26476072 TI - Terahertz absorption spectra and potential energy distribution of liquid crystals. AB - In this work, the terahertz (THz) absorption spectra of a set of nematic liquid crystals were studied using the density functional theories (DFT). An accurate assignment of the vibrational modes corresponding to absorption frequencies were performed using potential energy distribution (PED) in a frequency range of 0-3 THz. The impacts of different core structures on THz absorption spectra were discussed. The results indicate that scope of application must be considered in the LC-based THz device designing. This proposed work may give a useful suggestion on the design of novel liquid crystal material in THz wave. PMID- 26476073 TI - Pericarditis Associated With Human Herpesvirus-6 Reactivation in a Patient After Unrelated Cord Blood Transplant. AB - A 53-year-old woman with myelodysplastic syndrome received a cord blood transplant because she had frequent episodes of febrile neutropenia. As a conditioning regimen for transplant, she received 12 Gy total body irradiation, intravenous cytosine arabinoside 3 g/m2 every 12 hours on days -5 and -4, and cyclophosphamide 60 mg/kg/day on days -3 and -2. She received tacrolimus and short-term methotrexate treatment as prophylaxis for graft-versus-host disease. Her cardiac function was normal before transplant. She developed acute heart failure with a mild pericardial effusion 11 days after transplant, but her failure improved with a diuretic, vasodilator, and inotropic agent. She complained of dyspnea, and chest auscultation revealed pericardial friction rubs on day 28. Massive pericardial effusion was detected by echocardiography and pericarditis was diagnosed. The pericardial space was drained by pericardiocentesis. The pericardial fluid was exudative, but no bacteria or fungi were cultured. On viral polymerase chain reaction examination, human herpesvirus 6 was detected at a level of 3 * 104 copies/mL in the pericardial effusion, but not in the peripheral blood. With conservative treatment alone, that did not include antiviral therapy, her symptoms disappeared on day 56. We conclude that human herpesvirus-6 reactivation may have been associated with her pericarditis. PMID- 26476074 TI - Orthodontic bonding with and without primer: a randomized controlled trial. AB - OBJECTIVE: To evaluate the incidence of failure of brackets bonded with and without primer. DESIGN: A single-operator, cross-mouth, randomized controlled trial (RCT). SETTING: The Orthodontic Department at the Postgraduate Dental Education Centre, Orebro, Sweden. ETHICAL APPROVAL: Ethical approval was granted by the Regional Ethical Review Board, Uppsala, Sweden. PROTOCOL: The protocol was not published before trial commencement. SUBJECTS AND METHODS: Fifty consecutive patients requiring bimaxillary orthodontic treatment with fixed appliances and with an equal number of teeth on each side of the dental arch, were included in this RCT. A cross-mouth methodology was applied. In each patient, two diagonal quadrants (i.e. upper right and lower left, or vice versa) were randomly assigned to the primer group (control group) and the contralateral diagonal quadrants to the non-primer group (experimental group). The randomization process was as follows: A computer-manufactured block-randomization list was acquired and stored with a research secretary at the Postgraduate Dental Education Centre. Each time a patient gave consent, the secretary was contacted by e-mail, and information about which quadrants were to be bonded with and without primer was obtained. All incidents of bracket failure and debonding noted in patient records during the 2012-14 observation period were compiled by the other co-author, whom was blinded to the study and did not perform any orthodontic treatment on the study patients. MAIN OUTCOME MEASURES: Number of bracket failures over 18 months. RESULTS: Failure rate without primer was 5.5 per cent and with primer 3.1 per cent; P = 0.063, odds ratio (OR) 1.89 [95% confidence interval (CI) 0.97-3.68] in the adjusted model. Younger ages (10-13 years), boys, and mandible were significantly associated with higher failure rates. Interaction tests indicated that younger patients had significantly higher failure rates without (12.1 per cent) than with primer (4.1 per cent), P < 0.001, OR 3.51 (95% CI 1.93-6.38) in the adjusted model. No failure rate differences between study settings were found for older patients (14-18 years). LIMITATIONS: The difference between two groups was powered at 5 per cent. Some clinicians may consider a difference less than 5 per cent clinically significant. CONCLUSION: Bonding Victory SeriesTM brackets with TransbondTM XT with or without TransbondTM MIP primer seems overall to work equally well in a clinical setting, except in younger children where lower failure rate was found in the primer setting. PMID- 26476075 TI - Increasing the Therapeutic Ratio of Stereotactic Ablative Radiotherapy by Individualized Isotoxic Dose Prescription. AB - To obtain a favorable tradeoff between treatment benefits and morbidity ("therapeutic ratio"), radiotherapy (RT) dose is prescribed according to the tumor volume, with the goal of controlling the disease while respecting normal tissue tolerance levels. We propose a new paradigm for tumor dose prescription in stereotactic ablative radiotherapy (SABR) based on organ-at-risk (OAR) tolerance levels called isotoxic dose prescription (IDP), which is derived from experiences and limitations of conventionally fractionated radiotherapy. With IDP, the radiation dose is prescribed based on the predefined level of normal tissue complication probability of a nearby dose-limiting OAR at a prespecified dose volume constraint. Simultaneously, the prescribed total tumor dose (TTD) is maximized to the technically highest achievable level in order to increase the local tumor control probability (TCP). IDP is especially relevant for tumors located at eloquent locations or for large tumors in which severe toxicity has been described. IDP will result in a lower RT dose or a treatment scheduled with more fractions if the OAR tolerance level is exceeded, and potential dose escalation occurs when the OAR tolerance level allows it and when it is expected to be beneficial (if TCP < 90%). For patients with small tumors at noneloquent sites, the current SABR dose prescription already results in high rates of local control at low toxicity rates. In this review, the concept of IDP is described in the context of SABR. PMID- 26476076 TI - Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer. AB - STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC). Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is more effective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo. SC-43 significantly increased SHP-1 activity, downregulated p-STAT3(Tyr705) level, and induced apoptosis in CRC cells. An SHP-1 inhibitor or knockdown of SHP 1 by siRNA both significantly rescued the SC-43-induced apoptosis and decreased p STAT3(Tyr705) level. Conversely, SHP-1 overexpression increased the effects of SC 43 on apoptosis and p-STAT3(Tyr705) level. These data suggest that SC-43-induced apoptosis mediated through the loss of p-STAT3(Tyr705) was dependent on SHP-1 function. Importantly, SC-43-enhanced SHP-1 activity was because of the docking potential of SC-43, which relieved the autoinhibited N-SH2 domain of SHP-1 and inhibited p-STAT3(Tyr705) signals. Importantly, we observed that a significant negative correlation existed between SHP-1 and p-STAT3(Tyr705)expression in CRC patients (P = .038). Patients with strong SHP-1 and weak p-STAT3(Tyr705) expression had significantly higher overall survival compared with patients with weak SHP-1 and strong p-STAT3(Tyr705) expression (P = .029). In conclusion, SHP-1 is suitable to be a useful prognostic marker and a pharmacological target for CRC treatment. Targeting SHP-1-STAT3 signaling by SC-43 may serve as a promising pharmacotherapy for CRC. PMID- 26476077 TI - Inducing Oncoprotein Degradation to Improve Targeted Cancer Therapy. AB - Over the past decade, inhibition of the kinase activities of oncogenic proteins using small molecules and antibodies has been a mainstay of our anticancer drug development effort, resulting in several Food and Drug Administration-approved cancer therapies. The clinical effectiveness of kinase-targeted agents has been inconsistent, mostly because of the development of resistance. The expression and function of oncoproteins and tumor suppressors are regulated by numerous posttranslational protein modifications including phosphorylation, ubiquitination, and acetylation; hence, targeting specific posttranslational protein modifications provides for an attractive strategy for anticancer drug development. The present review discusses the hypothesis that targeted degradation of an oncoprotein may overcome many of the shortcomings seen with kinase inhibitors and that the approach would enable targeted inhibition of oncogenic proteins previously thought to be undruggable. PMID- 26476078 TI - Identification of a Selective G1-Phase Benzimidazolone Inhibitor by a Senescence Targeted Virtual Screen Using Artificial Neural Networks. AB - Cellular senescence is a barrier to tumorigenesis in normal cells, and tumor cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. One hundred and forty-seven virtual hits were acquired for validation in growth inhibition and senescence associated beta-galactosidase assays. Among the found hits, a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced senescence-associated beta-galactosidase activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1, and CDC25C. In addition, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long-term treatments. Preliminary structure-activity and structure clustering analyses are reported, and expression analysis of CB 20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT inhibitor-like profile in normal cells, with different pathways affected in cancer cells. PMID- 26476079 TI - Confirmatory Trials in the Evaluation of Anticancer Medicinal Products in Man- PFS2: A Measure of Therapeutic Action-At-A-Distance. AB - Overall survival (OS) has emerged as the definitive regulatory "be-all, end-all" for the demonstration of benefit in cancer clinical trials. The reason and the rationale for why this is so are easily appreciated: literally a "test of time," OS is a seemingly unambiguous, agenda-free end point, independent of bias-prone variables such as the frequency and methods of assessment, clinical evaluation, and the definition of progression. However, by general consensus, OS is an imperfect end point for several reasons: First, it may often be impractical because of the length, cost, and the size of clinical trials. Second, OS captures the impact of subsequent therapies, both beneficial (i.e., active) and detrimental, on survival but it does not take into account the contribution of subsequent therapies by treatment arm; the postprogression period is treated as an unknown black box (no information about the potential influence of next-line therapies on the outcome) under the implicit assumption that the clinical trial treatment is the only clinical variable that matters: what OS explicitly measures is the destination, that is, the elapsed time between the date of randomization (or intention to treat) and the date of death, not the journey, that is, what transpires in-between. In long-term maintenance strategies, patients receive treatment in temporally separated but mutually interdependent and causally linked sequences that exert a "field of influence" akin to action-at-a-distance forces like gravity, electricity, and magnetism on both the tumor and each other. Hence, in this setting, a new end point, PFS2, is required to measure this field of influence. This article reviews the definition and use in clinical trials of PFS2 and makes the case for its potential applicability as a preferred end point to measure the mutual influence of individual regimens in long-term maintenance strategies with resensitizing agents in particular. PMID- 26476080 TI - Lysophosphatidic Acid Up-Regulates Hexokinase II and Glycolysis to Promote Proliferation of Ovarian Cancer Cells. AB - Lysophosphatidic acid (LPA), a blood-borne lipid mediator, is present in elevated concentrations in ascites of ovarian cancer patients and other malignant effusions. LPA is a potent mitogen in cancer cells. The mechanism linking LPA signal to cancer cell proliferation is not well understood. Little is known about whether LPA affects glucose metabolism to accommodate rapid proliferation of cancer cells. Here we describe that in ovarian cancer cells, LPA enhances glycolytic rate and lactate efflux. A real time PCR-based miniarray showed that hexokinase II (HK2) was the most dramatically induced glycolytic gene to promote glycolysis in LPA-treated cells. Analysis of the human HK2 gene promoter identified the sterol regulatory element-binding protein as the primary mediator of LPA-induced HK2 transcription. The effects of LPA on HK2 and glycolysis rely on LPA2, an LPA receptor subtype overexpressed in ovarian cancer and many other malignancies. We further examined the general role of growth factor-induced glycolysis in cell proliferation. Like LPA, epidermal growth factor (EGF) elicited robust glycolytic and proliferative responses in ovarian cancer cells. Insulin-like growth factor 1 (IGF-1) and insulin, however, potently stimulated cell proliferation but only modestly induced glycolysis. Consistent with their differential effects on glycolysis, LPA and EGF-dependent cell proliferation was highly sensitive to glycolytic inhibition while the growth-promoting effect of IGF-1 or insulin was more resistant. These results indicate that LPA- and EGF induced cell proliferation selectively involves up-regulation of HK2 and glycolytic metabolism. The work is the first to implicate LPA signaling in promotion of glucose metabolism in cancer cells. PMID- 26476081 TI - Patient-Derived Tumor Xenografts Are Susceptible to Formation of Human Lymphocytic Tumors. AB - Patient-derived xenograft (PDX) tumor models have emerged as a new approach to evaluate the effects of cancer drugs on patients' personalized tumor grafts enabling to select the best treatment for the cancer patient and providing a new tool for oncology drug developers. Here, we report that human tumors engrafted in immunodeficient mice are susceptible to formation of B-and T-cell PDX tumors. We xenografted human primary and metastatic tumor samples into immunodeficient mice and found that a fraction of PDX tumors generated from patients' samples of breast, colon, pancreatic, bladder and renal cancer were histologically similar to lymphocytic neoplasms. Moreover, we found that the first passage of breast and pancreatic cancer PDX tumors after initial transplantation of the tumor pieces from the same human tumor graft could grow as a lymphocytic tumor in one mouse and as an adenocarcinoma in another mouse. Whereas subcutaneous PDX tumors resembling human adenocarcinoma histology were slow growing and non-metastatic, we found that subcutaneous PDX lymphocytic tumors were fast growing and formed large metastatic lesions in mouse lymph nodes, liver, lungs, and spleen. PDX lymphocytic tumors were comprised of B-cells which were Epstein-Barr virus positive and expressed CD45 and CD20. Because B-cells are typically present in malignant solid tumors, formation of B-cell tumor may evolve in a wide range of PDX tumor models. Although PDX tumor models show great promise in the development of personalized therapy for cancer patients, our results suggest that confidence in any given PDX tumor model requires careful screening of lymphocytic markers. PMID- 26476083 TI - Increased Levels of sENG and sVCAM-1 and Decreased Levels of VEGF in Severe Preeclampsia. AB - BACKGROUND: Preeclampsia (PE) is characterized by hypertension and proteinuria after the 20th week in pregnant women who have had no previous symptoms. Clinically, it is important to diagnose the severe form of the disease, in which blood pressure is much higher. Imbalance between angiogenic and antiangiogenic factors, as well as changes in adhesion molecules seem to contribute to the endothelial dysfunction and PE clinical manifestations. The aim of this study was to assess plasma levels of the angiogenic factors (free vascular endothelial growth factor (VEGF) and soluble endoglin (sEng)) and adhesion molecules (soluble forms of intercellular adhesion molecule-1 (sICAM-1) and soluble forms of vascular cell adhesion molecule-1 (sVCAM-1)) in severe PE (sPE), in order to clarify the circulating profile of these factors. METHODS: Sixty women with sPE (34 with early sPE and 26 with late sPE), and 60 normotensive pregnant were enrolled in this study. Free VEGF, sICAM-1, sVCAM-1, and sEng plasma levels were determined by ELISA. RESULTS: Increased sEng and sVCAM-1 and decreased free VEGF plasma levels were found in women with sPE, compared with normotensive pregnant group. However, no significant difference was observed comparing early and late sPE. CONCLUSION: Our data confirm the imbalance in changes in angiogenic and antiangiogenic factors, as well changes in adhesion molecule (sVCAM-1) in PE. These findings give support to the hypothesis that circulating angiogenic proteins and endothelial dysfunction may have an important biologic role in PE. Data from prospective, longitudinal studies producing serial determinations of these molecules throughout pregnancy are needed to better understanding the relevance of these markers in PE diagnosis and prognosis. PMID- 26476082 TI - SUMOylation Confers Posttranslational Stability on NPM-ALK Oncogenic Protein. AB - Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK+) T-cell lymphoma is an aggressive form of cancer that commonly affects children and adolescents. The expression of NPM-ALK chimeric oncogene results from the chromosomal translocation t(2;5)(p23;q35) that causes the fusion of the ALK and NPM genes. This translocation generates the NPM-ALK protein tyrosine kinase that forms the constitutively activated NPM-ALK/NPM-ALK homodimers. In addition, NPM-ALK is structurally associated with wild-type NPM to form NPM/NPM-ALK heterodimers, which can translocate to the nucleus. The mechanisms that sustain the stability of NPM-ALK are not fully understood. SUMOylation is a posttranslational modification that is characterized by the reversible conjugation of small ubiquitin-like modifiers (SUMOs) with target proteins. SUMO competes with ubiquitin for substrate binding and therefore, SUMOylation is believed to protect target proteins from proteasomal degradation. Moreover, SUMOylation contributes to the subcellular distribution of target proteins. Herein, we found that the SUMOylation pathway is deregulated in NPM-ALK+ T-cell lymphoma cell lines and primary lymphoma tumors from patients. We also identified Lys24 and Lys32 within the NPM domain as the sites where NPM-ALK conjugates with SUMO-1 and SUMO-3. Importantly, antagonizing SUMOylation by the SENP1 protease decreased the accumulation of NPM-ALK and suppressed lymphoma cell viability, proliferation, and anchorage-independent colony formation. One possible mechanism for the SENP1 mediated decrease in NPM-ALK levels was the increase in NPM-ALK association with ubiquitin, which facilitates its degradation. Our findings propose a model in which aberrancies in SUMOylation contribute to the pathogenesis of NPM-ALK+ T cell lymphoma. Unraveling such pathogenic mechanisms may lead to devising novel strategies to eliminate this aggressive neoplasm. PMID- 26476084 TI - The Diurnal Profile of Central Hemodynamics in a General Uruguayan Population. AB - BACKGROUND: No previous population study assessed the diurnal profile of central arterial properties. METHODS: In 167 participants (mean age, 56.1 years; 63.5% women), randomly recruited in Montevideo, Uruguay, we used the oscillometric Mobil-O-Graph 24-h PWA monitor to measure peripheral and central systolic (SBP), diastolic (DBP), and pulse (PP) pressures and central hemodynamics standardized to a heart rate of 75 bpm, including aortic pulse wave velocity, systolic augmentation (first/second peak * 100), and pressure amplification (peripheral PP/central PP). RESULTS: Over 24 hours, day and night, peripheral minus central differences in SBP/DBP and in PP averaged 12.2/-1.1, 14.0/-0.7, and 9.7/0.2mm Hg and 12.6, 14.7, and 9.5mm Hg, respectively (P < 0.001 except for nighttime DBP (P = 0.38)). The central-to-peripheral ratios of SBP, DBP, and PP were 0.89, 1.00, and 0.70 unadjusted, but after accounting for anthropometric characteristics decreased to 0.74, 0.97, and 0.63, respectively, with strong influence of height for SBP and DBP and of sex for PP. From day (10-20h) to nighttime (0-6h), peripheral (-10.4/-10.5 mm Hg) and central (-6.0/-11.3mm Hg) SBP/DBP, pulse wave velocity (-0.7 m/s) and pressure amplification (-0.05) decreased (P < 0.001), whereas central PP (+5.3mm Hg) and systolic augmentation (+2.3%) increased (P < 0.001). CONCLUSIONS: The diurnal rhythm of central pressure runs in parallel with that of peripheral pressure, but the nocturnal fall in SBP is smaller centrally than peripherally. pulse wave velocity, systolic augmentation, and pressure amplification loop through the day with high pulse wave velocity and pressure amplification but low systolic augmentation in the evening and opposite trends in the morning. PMID- 26476085 TI - Association Analysis of FOXO3 Longevity Variants With Blood Pressure and Essential Hypertension. AB - BACKGROUND: The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)- rs2802292 , rs2253310 , and rs2802288 -are associated with human longevity. The aim of the present study was to test these SNPs for association with blood pressure (BP) and essential hypertension (EHT). METHODS: In a primary study involving Americans of Japanese ancestry drawn from the Family Blood Pressure Program II we genotyped 411 female and 432 male subjects aged 40-79 years and tested for statistical association by contingency table analysis and generalized linear models that included logistic regression adjusting for sibling correlation in the data set. Replication of rs2802292 with EHT was attempted in Japanese SONIC study subjects and of each SNP in a meta-analysis of genome-wide association studies of BP in individuals of European ancestry. RESULTS: In Americans of Japanese ancestry, women homozygous for the longevity-associated (minor) allele of each FOXO3 SNP had 6mm Hg lower systolic BP and 3mm Hg lower diastolic BP compared with major allele homozygotes (Bonferroni corrected P < 0.05 and >0.05, respectively). Frequencies of minor allele homozygotes were 3.3 3.9% in women with EHT compared with 9.5-9.6% in normotensive women ( P = 0.03 0.04; haplotype analysis P = 0.0002). No association with BP or EHT was evident in males. An association with EHT was seen for the minor allele of rs2802292 in the Japanese SONIC cohort ( P = 0.03), while in European subjects the minor allele of each SNP was associated with higher systolic and diastolic BP. CONCLUSION: Longevity-associated FOXO3 variants may be associated with lower BP and EHT in Japanese women. PMID- 26476086 TI - Effect of Intensive Blood Pressure Lowering on Incident Atrial Fibrillation and P Wave Indices in the ACCORD Blood Pressure Trial. AB - BACKGROUND: There are no proven strategies to prevent atrial fibrillation (AF) in patients with type 2 diabetes (T2DM). We compared standard blood pressure (BP) lowering vs. intensive BP lowering in reducing incidence of AF or P-wave indices (PWI-ECG markers of left atrial abnormality that are considered intermediate phenotypes of AF) in patients with T2DM. METHODS: We analyzed data from the ACCORD BP trial-a randomized controlled nonblinded trial (2001-2009) which randomized patients with T2DM and systolic BP (SBP) 130-180mm Hg on <=3 antihypertensive medications aged 40-79 years with cardiovascular disease (CVD) or aged 55-79 years with subclinical CVD or >=2 CVD risk factors to standard BP lowering (SBP <140mm Hg) vs. intensive BP lowering (SBP <120mm Hg). The primary outcome was a composite of incident AF and PWI. RESULTS: Data from 3,087 participants (mean age, 62.2 years; women, 48.2%; non-White, 39.2%) were analyzed. During a mean follow-up of 4.4 years, the primary outcome occurred in 1,063 participants (incidence rate, 84.5 per 1,000 person-years in the standard therapy group vs. 73.9 per 1,000 person-years in the intensive-therapy group). The adjusted hazard ratios (95% confidence intervals) of intensive-therapy group for the primary outcome and for incident PWI alone were 0.87 (0.77-0.98), P = 0.02 and 0.87 (0.76-0.98), P = 0.02, respectively. The effect of intensive therapy on the incidence of AF alone did not reach statistical significance. CONCLUSIONS: In patients with T2DM, intensive BP lowering reduces the incidence of the composite outcome of AF and PWI, suggesting a potential benefit from stringent BP control in patients with T2DM. clinical trials registration Trial Number NCT00000620. PMID- 26476087 TI - Presence of pathogenicity islands and virulence genes of extraintestinal pathogenic Escherichia coli (ExPEC) in isolates from avian organic fertilizer. AB - Poultry litter is commonly used as fertilizer in agriculture. However, this poultry litter must be processed prior to use, since poultry have a large number of pathogenic microorganisms. The aims of this study were to isolate and genotypically and phenotypically characterize Escherichia coli from avian organic fertilizer. Sixty-four E. coli isolates were identified from avian organic fertilizer and characterized for ExPEC virulence factors, pathogenicity islands, phylogenetic groups, antimicrobial resistance, biofilm formation, and adhesion to HEp-2 cells. Sixty-three isolates (98.4%) showed at least one virulence gene (fimH, ecpA, sitA, traT, iutA, iroN, hlyF, ompT and iss). The predominant phylogenetic groups were groups A (59.3%) and B1 (34.3%). The pathogenicity island CFT073II (51.5%) was the most prevalent among the isolates tested. Thirty two isolates (50%) were resistant to at least one antimicrobial agent. Approximately 90% of isolates adhered to HEp-2 cells, and the predominant pattern was aggregative adherence (74.1%). In the biofilm assay, it was observed that 75% of isolates did not produce biofilm. These results lead us to conclude that some E. coli isolates from avian organic fertilizer could be pathogenic for humans. PMID- 26476088 TI - Association between ACTA1 candidate gene and performance, organs and carcass traits in broilers. AB - This study investigates the genetic association of the SNP present in the ACTA1 gene with performance traits, organs and carcass of broilers to help marker assisted selection of a paternal broiler line (TT) from EMBRAPA Swine and Poultry, Brazil. Genetic and phenotypic data of 1,400 broilers for 68 traits related to body performance, organ weights, weight of carcass parts, and yields as a percentage of organs and carcass parts were used. The maximum likelihood method, considering 4 analytical models, was used to analyze the genetic association between the SNP and these important economic traits. The association analysis was performed using a mixed animal model including the random effect of the animal (polygenic), and the fixed effects of sex (2 levels), hatch (5 levels) and SNP (3 levels), besides the random error. The traits significantly associated (P<0.05) with the SNP were analyzed, along with body weight at 42 days of age (BW42), by the restricted maximum likelihood method using the multi-trait animal model to estimate genetic parameters. The analysis included the residual and additive genetic random effects and the sex-hatch fixed effect. The additive effects of the SNP were associated with breast meat (BMY), liver yield (LIVY), body weight at 35 days of age (BW35); drumstick skin (DSW), drumstick (DW) and breast (BW) weights. The heritability estimates for these traits, in addition to BW42, ranged from 0.24+/-0.06 to 0.45+/-0.08 for LIVY and BW35, respectively. The genetic correlation ranged from 0.02+/-0.18 for LIVY and BMY to 0.97+/-0.01 for BW35 and BW42. Based on the results of this study, it can be concluded that ACTA1 gene is associated with performance traits BW35, LIV and BMY, DW, BW and DW adjusted for body weight at 42 days of age. Therefore, the ACTA1 gene is an important molecular marker that could be used together with others already described to increase the economically important traits in broilers. PMID- 26476089 TI - Age and adaptation to Ca and P deficiencies: 2. Impacts on amino acid digestibility and phytase efficacy in broilers. AB - A total of 1,152 straight-run hatchling Heritage 56M*fast feathering Cobb 500F broiler birds were used to determine Ca, age, and adaptation effects on apparent ileal digestibility of crude protein (AID of CP), amino acids (AID of AA) and phytase efficacy. Twelve treatments with 8 replicates, each were fed from 7 to 9 d (6 birds per replicate), 7 to 21 d (6 birds per replicate) and 19 to 21 d (3 birds per replicate) d of age. Diets were prepared with 3 Ca (0.65, 0.80, and 0.95%) and 2 non-phytate P, (0.20 and 0.40%) concentrations. A 6-phytase was added at 500 or 1,000 FTU/kg to the 0.20% nPP diet at each Ca concentration. The age and adaptation effects were determined by comparing the responses between birds fed from 7 to 9 and 19 to 21 d of age, 19 to 21, and 7 to 21 d of age, respectively. An age effect was observed regardless of Ca, nPP, or phytase concentration, with older birds (19 to 21 d) having greater apparent ileal digestibility (AID) of amino acids (AA) and CP than younger birds (7 to 9 d; P<0.05). Response to adaptation varied depending on Ca, nPP, and phytase concentrations. Constant lower AID of CP and AA was seen in adapted birds (7 to 21 d) compared to unadapted bird (19 to 21 d) when 0.20% nPP diets were fed at 0.95% Ca concentrations (P<0.05). At 0.40% nPP, there was no effect of adaptation on AID of CP and AA at any Ca concentration. Phytase efficacy was significantly lower in younger (7 to 9 d) compared to older birds (19 to 21 d; P<0.05), except at 0.65% Ca. Phytase inclusion increased AID of CP and AA regardless of Ca (P<0.05). In conclusion, the AID of CP and AA can be affected by diet, age, and adaptation. PMID- 26476090 TI - Outbreak of Listeria Monocytogenes in Pheasants. AB - Listeria monocytogenes is capable of infecting almost all animals. However, outbreaks of listeriosis are infrequent in birds. This report describes an outbreak of listeriosis in a small pheasant (Phasianus colchicus) breeder farm with more than 2,000 pheasants from Hubei province of the People's Republic of China. The affected flock consisted of adult and young birds. Approximately 300 young birds and a few adult birds were found dead within a few days of the onset of clinical signs. Twenty-five dead birds were collected for further examination. Histopathological lesions in the visceral organs were characterized by monocyte infiltration and proliferation. Localized encephalitis and meningitis were detected in the brains of dead birds. Gram-positive organisms were observed in heart blood smear, liver, and brain impression smears. The organisms were isolated from fresh liver and were identified as L. monocytogenes serotype 4b based on multiplex polymerase chain reaction (PCR) and hlyA gene sequence analysis. This is the first report describing outbreak of listeriosis in pheasant flock. PMID- 26476091 TI - The genetic basis of pectoralis major myopathies in modern broiler chicken lines. AB - This is the first report providing estimates of the genetic basis of breast muscle myopathies (BMM) and their relationship with growth and yield in broiler chickens. In addition, this paper addresses the hypothesis that genetic selection for increase breast yield has contributed to the onset of BMM. Data were analyzed from ongoing recording of BMM within the Aviagen breeding program. This study focused on three BMM: deep pectoral myopathy (DPM; binary trait), white striping (WS; 4 categories) and wooden breast (WB; 3 categories). Data from two purebred commercial broiler lines (A and B) were utilized providing greater than 40,000 meat quality records per line. The difference in selection history between these two lines has resulted in contrasting breast yield (BY): 29% for Line A and 21% for Line B. Data were analyzed to estimate genetic parameters using a multivariate animal model including six traits: body weight (BW), processing body weight (PW), BY, DPM, WB, and WS, in addition to the appropriate fixed effects and permanent environmental effect of the dam. Results indicate similar patterns of heritability and genetic correlations for the two lines. Heritabilities (h2) of BW, PW and BY ranged from 0.271-0.418; for DPM and WB h2<0.1; and for WS h2<=0.338. Genetic correlations between the BMM and BW, PW, or BY were <=0.132 in Line A and <=0.248 in Line B. This paper demonstrates the polygenic nature of these traits and the low genetic relationships with BW, PW, and BY, which facilitates genetic improvement across all traits in a balanced breeding program. It also highlights the importance of understanding the environmental and/or management factors that contribute greater than 65% of the variance in the incidence of white striping of breast muscle and more than 90% of the variance of the incidence of wooden breast and deep pectoral myopathy in broiler chickens. PMID- 26476092 TI - Temperature-associated habitat selection in a cold-water marine fish. AB - Habitat selection is a complex process, which involves behavioural decisions guided by the multiple needs and constraints faced by individuals. Climate induced changes in environmental conditions may alter those trade-offs and resulting habitat use patterns. In this study, we investigated the effect of sea temperature on habitat selection and habitat use of acoustically tagged Atlantic cod (Gadus morhua) at the Norwegian Skagerrak coast. Significant relationships between ocean temperature and habitat selection and use were found. Under favourable sea temperature thresholds (<16 degrees C), cod selected vegetated habitats, such as eelgrass and macroalgae beds, available in shallow areas. Selection for those habitats was especially high at night, when cod tended to ascend to shallower areas, presumably to feed. Selection and use of those habitats decreased significantly as temperature rose. Under increased sea surface temperature conditions, cod were absent from vegetated shallow habitats, both during the day and night, and selected instead non-vegetated rocky bottoms and sand habitats, available in deeper, colder areas. This study shows the dynamic nature of habitat selection and strongly suggests that cod in this region have to trade off food availability against favourable temperature conditions. Future increases in ocean temperature are expected to further influence the spatial behaviour of marine fish, potentially affecting individual fitness and population dynamics. PMID- 26476093 TI - Experimental white piedra: a robust approach to ultrastructural analysis, scanning electron microscopy and etiological discoveries. AB - White piedra is a fungal infection characterized by nodules comprised of Trichosporon species and restricted to the extrafollicular portion of the hair shaft. The diagnosis is based on clinical and mycological characteristics, and must be confirmed with a precise identification of the etiological agent. This research aimed to develop an in vitro infection model of white piedra and analyze its morphological and ultra-structural aspects. In the process, hair infection was induced using eight isolates of the genus Trichosporon maintained in the Culture Collection Micoteca URM. The ITS and IGS1 regions were sequenced for taxonomic confirmation. Scanning Electron Microscope (SEM) was performed at the Strategic Center for Northeast Technologies (CETENE). The scanning electron microscope was equipped with an Energy Dispersion Spectrometer (EDS). The Trichosporon isolates were identified as Trichosporon asahii (6) and Trichosporon montevideense (2) by internal transcript spacer (ITS) region and intergenic spacer 1 region (IGS1) sequencing. All eight strains were used to induce the in vitro hair infection, and nodules formed after the incubation period. Temperature variations and high humidity were not observed to be related to the development of this hair disease. The main chemical constituents detected in the nodules were carbon, nitrogen and oxygen, as well as a low level of sulfur. The absence of calcium, combined with the low level of sulfur, might explain the soft nature of the white piedra nodules. This study demonstrated that several Trichosporon species may be responsible for causing white piedra. PMID- 26476094 TI - Implications of an aging liver transplant waiting list: Survival benefit should be based upon "mile-age" and performance. PMID- 26476095 TI - Top predators and habitat complexity alter an intraguild predation module in pond communities. AB - Predator diversity and habitat complexity frequently influence species interactions at lower trophic levels, yet their joint investigation has been performed infrequently despite the demonstrated importance of each individual factor. We investigated how different top predators and varying habitat complexity influence the function of an intraguild predation module consisting of two larval salamanders, intraguild predator Ambystoma annulatum and intraguild prey A. maculatum. We manipulated predator food webs and habitat complexity in outdoor mesocosms. Top predators significantly influenced body condition and survival of A. annulatum, but habitat complexity had minimal effects on either response. A three-way interaction among the covariates top predator identity, habitat complexity and A. annulatum survival influenced body condition and survival of A. maculatum via a density-mediated indirect effect. Different top predator combinations had variable effects in different habitat complexity treatments on intraguild predator (A. annulatum) survival that subsequently influenced intraguild prey (A. maculatum) body condition and survival. Future work should consider how different top predators influence other food web components, which should vary due to predator attributes and the physical environments in which they co-occur. PMID- 26476096 TI - Sebocytes differentially express and secrete adipokines. AB - In addition to producing sebum, sebocytes link lipid metabolism with inflammation at a cellular level and hence, greatly resemble adipocytes. However, so far no analysis was performed to identify and characterize the adipocyte-associated inflammatory proteins, the members of the adipokine family in sebocytes. Therefore, we determined the expression profile of adipokines [adiponectin, interleukin (IL) 6, resistin, leptin, serpin E1, visfatin, apelin, chemerin, retinol-binding protein 4 (RBP4) and monocyte chemoattractant protein 1 (MCP1)] in sebaceous glands of healthy and various disease-affected (acne, rosacea, melanoma and psoriasis) skin samples. Sebaceous glands in all examined samples expressed adiponectin, IL6, resistin, leptin, serpin E1 and visfatin, but not apelin, chemerin, RBP4 and MCP1. Confirming the presence of the detected adipokines in the human SZ95 sebaceous gland cell line we further characterized their expression and secretion patterns under different stimuli mimicking bacterial invasion [by using Toll-like receptor (TLR)2 and 4 activators], or by 13-cis retinoic acid (13CRA; also known as isotretinoin), a key anti-acne agent. With the exception of resistin, the expression of all of the detected adipokines (adiponectin, IL6, leptin, serpin E1 and visfatin) could be further regulated at the level of gene expression, showing a close correlation with the secreted protein levels. Besides providing further evidence on similarities between adipocytes and sebocytes, our results strongly suggest that sebocytes are not simply targets of inflammation but may exhibit initiatory and modulatory roles in the inflammatory processes of the skin through the expression and secretion of adipokines. PMID- 26476097 TI - Pre-adapting parasitic phages to a pathogen leads to increased pathogen clearance and lowered resistance evolution with Pseudomonas aeruginosa cystic fibrosis bacterial isolates. AB - Recent years have seen renewed interest in phage therapy--the use of viruses to specifically kill disease-causing bacteria--because of the alarming rise in antibiotic resistance. However, a major limitation of phage therapy is the ease at with bacteria can evolve resistance to phages. Here, we determined whether in vitro experimental coevolution can increase the efficiency of phage therapy by limiting the resistance evolution of intermittent and chronic cystic fibrosis Pseudomonas aeruginosa lung isolates to four different phages. We first pre adapted all phage strains against all bacterial strains and then compared the efficacy of pre-adapted and nonadapted phages against ancestral bacterial strains. We found that evolved phages were more efficient in reducing bacterial densities than ancestral phages. This was primarily because only 50% of bacterial strains were able to evolve resistance to evolved phages, whereas all bacteria were able to evolve some level of resistance to ancestral phages. Although the rate of resistance evolution did not differ between intermittent and chronic isolates, it incurred a relatively higher growth cost for chronic isolates when measured in the absence of phages. This is likely to explain why evolved phages were more effective in reducing the densities of chronic isolates. Our data show that pathogen genotypes respond differently to phage pre-adaptation, and as a result, phage therapies might need to be individually adjusted for different patients. PMID- 26476098 TI - In vitro mineralization of MC3T3-E1 osteoblast-like cells on collagen/nano hydroxyapatite scaffolds coated carbon/carbon composites. AB - Collagen/nano-hydroxyapatite (collagen/nHA) scaffolds were successfully prepared on carbon/carbon composites as bioactive films using the layer-by-layer coating method. Surface characterizations of collagen/nHA scaffolds were detected by scanning electron microscope (SEM), X-ray diffraction (XRD), and Fourier transform infrared (FTIR) spectroscopy. Compressive strengths of the scaffolds were evaluated by a universal test machine. In vitro biological performances were determined using scaffolds seeded with MC3T3-E1 osteoblasts-like cells and cultured in mineralization medium for up to 21 days. In addition, cellular morphologies and several related gene expressions of MC3T3-E1 cells in the scaffolds were also evaluated. Chemical and morphological analysis showed that the scaffolds had uniform pore sizes and unified phase composition. Mechanical testing indicated that the collagen/nHA scaffolds had the highest compressive strength in 50% of strain condition when the proportion of collagen and nano hydroxyapatite was 1:3. Cellular morphology observations and cytology tests indicated that MC3T3-E1 cells were adhered on these scaffolds and proliferated. SEM photographs and gene expressions showed that mineralized MC3T3-E1 cells and newly formed extra cellular matrix (ECM) filled up the pores of the scaffolds after the 3-week mineralization inducement. Nano-sized apatite particles were secreted from MC3T3-E1 cells and combined with the reconstructed ECM. Collectively, collagen/nHA scaffolds provided C/C composites with a biomimetic surface for cell adhesion, proliferation and mineralized extra cellular matrices formation. PMID- 26476099 TI - Structures of the double-ring AAA ATPase Pex1-Pex6 involved in peroxisome biogenesis. AB - The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis. Recently, cryo-electron microscopy structures of the Pex1-Pex6 complex in different nucleotide states have been determined. This Structural Snapshot describes the structural features of the complex and their implications for its function, as well as questions that still await answers. PMID- 26476100 TI - Partial unfolding and refolding for structure refinement: A unified approach of geometric simulations and molecular dynamics. AB - The most successful protein structure prediction methods to date have been template-based modeling (TBM) or homology modeling, which predicts protein structure based on experimental structures. These high accuracy predictions sometimes retain structural errors due to incorrect templates or a lack of accurate templates in the case of low sequence similarity, making these structures inadequate in drug-design studies or molecular dynamics simulations. We have developed a new physics based approach to the protein refinement problem by mimicking the mechanism of chaperons that rehabilitate misfolded proteins. The template structure is unfolded by selectively (targeted) pulling on different portions of the protein using the geometric based technique FRODA, and then refolded using hierarchically restrained replica exchange molecular dynamics simulations (hr-REMD). FRODA unfolding is used to create a diverse set of topologies for surveying near native-like structures from a template and to provide a set of persistent contacts to be employed during re-folding. We have tested our approach on 13 previous CASP targets and observed that this method of folding an ensemble of partially unfolded structures, through the hierarchical addition of contact restraints (that is, first local and then nonlocal interactions), leads to a refolding of the structure along with refinement in most cases (12/13). Although this approach yields refined models through advancement in sampling, the task of blind selection of the best refined models still needs to be solved. Overall, the method can be useful for improved sampling for low resolution models where certain of the portions of the structure are incorrectly modeled. PMID- 26476101 TI - Photosynthetic response to globally increasing CO2 of co-occurring temperate seagrass species. AB - Photosynthesis of most seagrass species seems to be limited by present concentrations of dissolved inorganic carbon (DIC). Therefore, the ongoing increase in atmospheric CO2 could enhance seagrass photosynthesis and internal O2 supply, and potentially change species competition through differential responses to increasing CO2 availability among species. We used short-term photosynthetic responses of nine seagrass species from the south-west of Australia to test species-specific responses to enhanced CO2 and changes in HCO3 (-) . Net photosynthesis of all species except Zostera polychlamys were limited at pre industrial compared to saturating CO2 levels at light saturation, suggesting that enhanced CO2 availability will enhance seagrass performance. Seven out of the nine species were efficient HCO3 (-) users through acidification of diffusive boundary layers, production of extracellular carbonic anhydrase, or uptake and internal conversion of HCO3 (-) . Species responded differently to near saturating CO2 implying that increasing atmospheric CO2 may change competition among seagrass species if co-occurring in mixed beds. Increasing CO2 availability also enhanced internal aeration in the one species assessed. We expect that future increases in atmospheric CO2 will have the strongest impact on seagrass recruits and sparsely vegetated beds, because densely vegetated seagrass beds are most often limited by light and not by inorganic carbon. PMID- 26476102 TI - Endothelial Cell Viability of Donor Corneas Preserved in Eusol-C Corneal Storage Medium. AB - OBJECTIVES: To evaluate the efficacy of Eusol-C as a corneal storage medium on the survival of donor endothelium. MATERIALS AND METHODS: Twenty-seven corneas not suitable for transplant were included in this study. All donor corneas were stored in Eusol-C at 4 degrees C. Daily donor corneal endothelial cell counting was performed with an eye bank specular microscope. All corneas were discarded after the study process. RESULTS: Mean donor age was 51.3 +/- 18.8 years (range, 25-94 y). The mean duration between death and corneal excision was 9.5 +/- 6.7 hours (range, 3-23 h). Mean endothelial cell density was 2195 +/- 383 cells/mm2 at the beginning of the preservation (range, 1361-2899 cells/mm2). Donor endothelial cell density was between 1500 to 2000 cells/mm2 in 9 corneas, 2000 to 2500 in 11 corneas, 2500 to 3000 in 5, and higher than 3000 in 2 corneas at baseline. Mean endothelial cell density was found 1658 cells/mm2 on the eighth day of storage, with a mean endothelial cell loss rate of 24.5%. Corneas stored 9 to 24 days in Eusol-C had a rate of endothelial cell damage of 3.1% per day. CONCLUSIONS: Although our results revealed a higher endothelial cell loss than previous reports, overall performance of Eusol-C in preserving the donor endothelium may be satisfactory for clinical use. PMID- 26476103 TI - Influences of sampling effort on detected patterns and structuring processes of a Neotropical plant-hummingbird network. AB - Virtually all empirical ecological interaction networks to some extent suffer from undersampling. However, how limitations imposed by sampling incompleteness affect our understanding of ecological networks is still poorly explored, which may hinder further advances in the field. Here, we use a plant-hummingbird network with unprecedented sampling effort (2716 h of focal observations) from the Atlantic Rainforest in Brazil, to investigate how sampling effort affects the description of network structure (i.e. widely used network metrics) and the relative importance of distinct processes (i.e. species abundances vs. traits) in determining the frequency of pairwise interactions. By dividing the network into time slices representing a gradient of sampling effort, we show that quantitative metrics, such as interaction evenness, specialization (H2 '), weighted nestedness (wNODF) and modularity (Q; QuanBiMo algorithm) were less biased by sampling incompleteness than binary metrics. Furthermore, the significance of some network metrics changed along the sampling effort gradient. Nevertheless, the higher importance of traits in structuring the network was apparent even with small sampling effort. Our results (i) warn against using very poorly sampled networks as this may bias our understanding of networks, both their patterns and structuring processes, (ii) encourage the use of quantitative metrics little influenced by sampling when performing spatio-temporal comparisons and (iii) indicate that in networks strongly constrained by species traits, such as plant hummingbird networks, even small sampling is sufficient to detect their relative importance for the frequencies of interactions. Finally, we argue that similar effects of sampling are expected for other highly specialized subnetworks. PMID- 26476104 TI - Feasibility of deep sedation with a combination of propofol and dexmedetomidine hydrochloride for esophageal endoscopic submucosal dissection. AB - BACKGROUND AND AIM: The aim of the present study was to evaluate the efficacy and safety of sedation with a combination of propofol (PF) and dexmedetomidine (DEX) compared with sedation with benzodiazepines in esophageal endoscopic submucosal dissection (ESD). METHODS: We retrospectively reviewed clinical data for 40 consecutive patients who had undergone esophageal ESD at the Yokohama City University Hospital between July 2012 and August 2014. Of these patients, 20 were sedated with benzodiazepines (conventional group) and another 20 patients were sedated with a combination of PF and DEX (combination group). Parameters for efficacy and safety of sedation were evaluated by comparisons between the two groups. RESULTS: Median procedural times in the combination group were shorter than those in the conventional group (61 min vs. 89 min, P = 0.03), and the percentage of patients who showed restlessness in the combination group was significantly lower than that in the conventional group (25% vs. 65%, P = 0.025). Incidences of hypotension and bradycardia in the combination group were higher than those in the conventional group (60% vs. 15%, P = 0.008, and 60% vs. 15%, P = 0.008, respectively). CONCLUSION: This retrospective study suggests that a combination of PF and DEX may provide stable deep sedation with less body movement than benzodiazepines during esophageal ESD. PMID- 26476106 TI - Molecular view of the interaction of S-methyl methanethiosulfonate with DPPC bilayer. AB - We present molecular dynamics (MD) simulation studies of the interaction of a chemo preventive and protective agent, S-methyl methanethiosulfonate (MMTS), with a model bilayer of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). We analyzed and compared its diffusion mechanisms with the related molecule dimethyl sulfoxide (DMSO). We obtained spatially resolved free energy profiles of MMTS partition into a DPPC bilayer in the liquid-crystalline phase through potential of mean force (PMF) calculations using an umbrella sampling technique. These profiles showed a minimum for MMTS close to the carbonyl region of DPPC. The location of MMTS molecules in the DPPC bilayer observed in the MD was confirmed by previous SERS studies. We decomposed PMF profiles into entropic and enthalpic contributions. These results showed that the driving force for the partitioning of MMTS into the upper region of DPPC is driven by a favorable entropy change while partitioning into the acyl chains is driven by enthalpy. On the other hand, the partition of DMSO into the membrane is not favored, and is driven by entropy instead of enthalpy. Free diffusion MD simulations using all atom and coarse grained (CG) models of DPPC in presence of MMTS were used to analyze the effect of DPPC-MMTS interaction. Density profiles showed that MMTS locates preferentially in the carbonyl region, as expected according to the PMF profile and the experimental evidence. MMTS presented two differential effects over the packing of DPPC hydrocarbonate chains at low or at high molar ratios. An ordering effect was observed when a CG MMTS model was used. Finally, free diffusion MD and PMF decomposition for DMSO were used for comparison. PMID- 26476105 TI - n-3 polyunsaturated fatty acids suppress CD4(+) T cell proliferation by altering phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] organization. AB - The mechanisms by which n-3 polyunsaturated fatty acids (n-3 PUFA), abundant in fish oil, exert their anti-inflammatory effects have not been rigorously defined. We have previously demonstrated that n-3 PUFA decrease the amount of phosphatidylinositol-(4,5)-bisphosphate, [PI(4,5)P2], in CD4(+) T cells, leading to suppressed actin remodeling upon activation. Since discrete pools of PI(4,5)P2 exist in the plasma membrane, we determined whether n-3 PUFA modulate spatial organization of PI(4,5)P2 relative to raft and non-raft domains. We used Forster resonance energy transfer (FRET) to demonstrate that lipid raft mesodomains in the plasma membrane of CD4(+) T cells enriched in n-3 PUFA display increased co clustering of Lck(N10) and LAT(DeltaCP), markers of lipid rafts. CD4(+) T cells enriched in n-3 PUFA also exhibited a depleted plasma membrane non-raft PI(4,5)P2 pool as detected by decreased co-clustering of Src(N15), a non-raft marker, and PH(PLC-delta), a PI(4,5)P2 reporter. Incubation with exogenous PI(4,5)P2 rescued the effects on the non-raft PI(4,5)P2 pool, and reversed the suppression of T cell proliferation in CD4(+) T cells enriched with n-3 PUFA. Furthermore, CD4(+) T cells isolated from mice fed a 4% docosahexaenoic acid (DHA)-enriched diet exhibited a decrease in the non-raft pool of PI(4,5)P2, and exogenous PI(4,5)P2 reversed the suppression of T cell proliferation. Finally, these effects were not due to changes to post-translational lipidation, since n-3 PUFA did not alter the palmitoylation status of signaling proteins. These data demonstrate that n-3 PUFA suppress T cell proliferation by altering plasma membrane topography and the spatial organization of PI(4,5)P2. PMID- 26476107 TI - Alterations to the maternal circulating proteome after preeclampsia. AB - OBJECTIVE: The long-term maternal cardiovascular and metabolic implications associated with preeclampsia (PE) include risk of hypertension, heart disease, and metabolic syndrome. The objective of this study was to investigate if a recent history of PE was associated with detectable alterations in the circulating maternal proteome. STUDY DESIGN: Six-month postpartum plasma from women with a history of PE (n = 12) and women with uncomplicated obstetrical history (n = 12) were used for analysis. Depleted maternal plasma was analyzed by label-free liquid chromatography-mass spectrometry assay. Identified peptides were searched against the International Protein Index human database version 3.87. Exponentially modified protein abundance indices were used for comparison. Results were analyzed using pathway analysis software. RESULTS: A total of 126 eligible peptides were identified for analysis; 3 peptides were differentially expressed in the PE proteome, and an additional 5 peptides were unique to control subjects and 7 to PE subjects. PE peptide profiles were more strongly associated with markers of coagulation and complement activation compared to controls and mapped more significantly to cardiovascular disease (CVD) functions. Stratification of subjects by low (<39%) and high (>=39%) lifetime risk of CVD rather than by diagnosis produced similar findings. Comparison of controls (n = 6) to PE subjects (n = 6) without traditional cardiovascular risk factors found that while similar for body mass indices, blood pressure, and fasting lipid profiles at 6 months postpartum, PE peptide profiles continued to display stronger associations for coagulation and CVD functions. Global network analysis found that unique peptides to low-risk PE subjects were associated with cardiac infarction, CVD, and organismal injury and abnormalities. CONCLUSION: Markers of CVD risk and progression are evident in the maternal circulating proteome 6 months postpartum after PE. Augmentations in circulating peptide profiles occur in patients with previous PE who otherwise do not have clinically measurable cardiovascular risk factors. Our data highlight the need for the implementation of postpartum prevention programs in the PE population and identifies molecules that may be targeted for screening or therapeutic benefit. PMID- 26476108 TI - Efficacy of chitosan oligosaccharide as aquatic adjuvant administrated with a formalin-inactivated Vibrio anguillarum vaccine. AB - Vaccine is one of the efficient candidates to prevent fish disease through activating host immune response in aquaculture. Actually, several vaccines are often administered with adjuvants to increase immunostimulation, especially for some water-based formalin-killed vaccines. However, side effects are inevitable after vaccination of some adjuvants. Therefore, exploration for effective and harmless aquatic adjuvants is urgently needed. In this study, immunoprotection of a formalin-inactivated Vibrio anguillarum vaccine applied with chitosan oligosaccharide (COS) was analyzed. High levels of protection were achieved in zebrafish and turbot vaccinated with inactivated vaccine and COS (RPS of 89.0 +/- 4.5% and 80.0 +/- 6.9%) compared with fish vaccinated with inactivated vaccine alone (RPS of 47.8 +/- 6.6% and 64.7 +/- 5.8%) at 4 week post vaccination. Moreover, high antibody reaction and cross-protection against Vibrio alginolyticus and Vibrio harveyi were observed of turbot vaccinated with inactivated vaccine and COS. In conclusion, COS can enhance immunoprotection of a formalin-inactivated V. anguillarum vaccine, significantly activate humoral immune response of host, and be benefit for inhibition against pathogens. Therefore, COS would be a potential adjuvant for aquatic vaccine design in the future. PMID- 26476109 TI - Function analysis of fish Tollip gene in response to virus infection. AB - Toll-interacting protein (Tollip) is one of the important regulatory proteins of Toll-like receptor (TLR) signaling pathways. In previous studies, a Tollip sequence of grouper (Epinephelus coioides) was identified and the signal transduction functions of Tollip were studied. However, the response of Tollip to virus infection has not been characterized from grouper. In the present paper, the Tollip homolog (EtTollip) from grouper (Epinephelus tauvina) was cloned and its immune response to Singapore grouper iridovirus (SGIV) was investigated. EtTollip shares significant similarities to other mammalian Tollips, which contain a centrally localized protein kinase C conserved region 2 (C2) domain and a C-terminal CUE domain. After challenging with SGIV, the expression levels of EtTollip were altered in the spleen and head kidney of grouper. EtTollip mainly aggregated in the cytoplasm in a condensed state and was also distributed on the membranes of GS cells. EtTollip significantly inhibited the activities of NF kappaB and IFN-beta luciferase reporter when transfected into grouper spleen (GS) cells. SGIV can increase the activities of NF-kappaB and IFN-beta luciferase reporter, especially to IFN-beta. When transfected EtTollip with EcMyd88, the activity of NF-kappaB was increased, while transfected EtTollip with EcIRF3, the activity of IFN-beta was significantly increased. Over-expressed EtTollip inhibited the transcription of SGIV genes significantly in GS cells, and silencing of EtTollip with siRNA led to increase of SGIV genes loads. Taken together, the results provide new insights in to the importance of Tollip as evolutionarily conserved molecule for grouper innate immunity against virus infection. PMID- 26476110 TI - Nonsurgical Treatment of Urinary Incontinence in Elderly Women. AB - Urinary incontinence is a prevalent condition in elderly women with significant associated morbidity. Incontinence can by grouped into several types: stress incontinence, urgency incontinence, overflow incontinence, functional incontinence, and mixed urinary incontinence. Careful evaluation, including history and physical examination, is critical to making the correct diagnosis and guiding therapy. A variety of nonsurgical treatments, including behavioral therapies, pelvic floor muscle exercise, medications, and other treatments, are available; can be successful for many older women; and may preclude the need for surgery. Working closely with the patient, understanding her goals of care, and targeting treatments accordingly are essential for success. PMID- 26476112 TI - Evaluation and Management of Pelvic Organ Prolapse in Elderly Women. AB - Pelvic organ prolapse is a common disease in elderly patients. The most important symptom is vaginal bulge (bulge sensation or the sensation of something coming down through the vaginal introitus). This symptom is not different than in the general population. Diagnosis can be confirmed using just vaginal examinations to identify the presence of protrusion beyond the hymen, and is not different than in the general population. Different treatment options are available, including observation, nonsurgical, and surgical techniques. Pessaries and colpocleisis are the treatment options used more often in elderly patients than in the general population. PMID- 26476111 TI - Outcomes of Surgery for Stress Urinary Incontinence in the Older Woman. AB - As population demographics continue to evolve, specifics on age-related outcomes of stress urinary incontinence interventions will be critical to patient counseling and management planning. Understanding medical factors unique to older women and their lower urinary tract conditions will allow caregivers to optimize surgical outcomes, both physical and functional, and minimize complications within this population. PMID- 26476113 TI - Underactive Bladder in Older Adults. AB - Overactive bladder is one of the most common bladder problems, but an estimated 20 million Americans have underactive bladder (UAB), which makes going to the bathroom difficult, increases the risk of urinary tract infections, and even leads to institutionalization. This article provides an overview of UAB in older adults, and discusses the prevalence, predisposing factors, cause, clinical investigations, and treatments. At present, there is no effective therapy for UAB. A great deal of work still needs to be done on understanding the pathogenesis and the development of effective therapies. PMID- 26476115 TI - Functional Brain Imaging and the Neural Basis for Voiding Dysfunction in Older Adults. AB - Brain abnormalities may contribute to the increased prevalence of urinary dysfunction such as overactive bladder and urge incontinence in older individuals. Functional brain imaging suggests that 3 independent neural circuits (frontal, midcingulate, and subcortical) control voiding by suppressing the voiding reflex in the brainstem periaqueductal gray. Damage to the connecting pathways subserving these circuits (white matter hyperintensities) increases with age and is associated both with severity of urge incontinence and changes in brain function. Multicomponent therapies targeting structural and functional neural abnormalities may be more effective than any single treatment focused on the bladder. PMID- 26476116 TI - The Role of Urodynamics in Elderly Patients. AB - Urodynamic testing is the study of the function of the bladder and its outlet. Geriatric patients are at greater risk for lower urinary tract dysfunction owing to age or neurologic disease, such as Parkinson disease or stroke. Although urodynamic testing may best diagnose an individual patient's bladder storage and emptying function, the tests should be tailored to answer the question being asked and the test should only be done when the outcome of the test is going to impact decision making regarding management or treatment. PMID- 26476117 TI - Associations Between Urinary Symptoms and Sexual Health in Older Adults. AB - Fifty percent of sexually active older men and women complain of 1 or more sexual problems. Sexual dysfunction involves a complex interplay of partner factors, relationship factors, individual factors, concomitant mental health disorders, life stressors, medical comorbidity, and medication intake. Although lower urinary tract symptoms are associated with decreased sexual activity, it is unclear whether the relationship is causal or influenced by shared risk factors, or the presence of overall poor health and function. Taking a complete sexual history in patients with lower urinary tract symptoms is the first step toward detection and possible treatment. PMID- 26476114 TI - Translational Research and Functional Changes in Voiding Function in Older Adults. AB - Age-related LUT dysfunctions result from complex processes controlled by multiple genetic, epigenetic, and environmental factors and account for high costs of health care. This article discusses risk factors that may play a role in age related LUT dysfunction and presents available data comparing structural and functional changes that occur with aging in the bladder of humans and animal models. A better understanding of factors and mechanisms underlying LUT symptoms in the older population may lead to therapeutic interventions to reduce these dysfunctions. PMID- 26476118 TI - Surgical Risk and Comorbidity in Older Urologic Patients. AB - Almost two-thirds of urology operations are performed in patients 65 years and older. Older adults are at higher risk for complications and mortality compared with their younger counterparts. There are 2 primary methods to quantify surgical risk in these patients, frailty measurement and organ/comorbidity-based surgical risk calculators. A frailty assessment can be used to independently forecast the risk of postoperative complications. A paradigm shift in the preoperative assessment of the geriatric patient has occurred, which emphasizes the evaluation of frailty over more traditional surgical risk assessment, which uses comorbidities and single end-organ dysfunction to define risk. PMID- 26476119 TI - Management of Small Renal Masses in the Older Adult. AB - Small renal masses in older adults are common and usually found incidentally. Although many small renal masses are benign, most are malignant. In older patients, the small renal mass poses a challenge because the treatment paradigm has to strike the balance between competing comorbidities and a lethal cancer. Partial nephrectomy, mainly via robot-assisted technique, has gained favor over radical nephrectomy as the intervention of choice. Cryoablation and radiofrequency ablation are also viable treatment options and have a role to play in patients who desire treatment but either are not suitable surgical candidates or prefer not to have a surgical intervention. PMID- 26476120 TI - Prostate Cancer in Elderly Men: Screening, Active Surveillance, and Definitive Therapy. AB - Prostate cancer (PCa) is a common medical condition in the United States, with an estimated 16% of men receiving a diagnosis during their lifetime. Although it is the second leading cause of cancer-specific deaths among men, PCa will not be the cause of death for most men who are diagnosed with it. Although there are notable improvements recently, the relative dearth of high-quality data concerning PCa screening and treatment in older men calls for a thoughtful approach to evaluating such men for screening, diagnosis, and treatment options. This article offers guidance to an approach here. PMID- 26476121 TI - Late-Onset Hypogonadism and Testosterone Replacement in Older Men. AB - Late-onset hypogonadism is an underdiagnosed and easily treated condition defined by low serum testosterone levels in men older than 65 years. When treated, a significant improvement in quality of life may be reached in this rapidly rising sector of the population. During the evaluation, laboratory tests and a full medication review should be performed to exclude other illnesses or adverse effects from medications. The major goal of treatment in this population is treating the symptoms related to hypogonadism. There has not been clear evidence supporting universally giving older men with low serum testosterone levels and hypogonadal symptoms testosterone replacement therapy. PMID- 26476122 TI - Contemporary Systemic Therapy for Urologic Malignancies in Geriatric Patients. AB - Current data on systemic therapy in geriatric populations with genitourinary malignancies are largely derived from retrospective analyses of prospectively conducted trials or retrospective reviews. Although extrapolation of these data to real-world patients should be cautious, patients aged 65 years or older with good functional status and minimal comorbidities seem to enjoy similar survival benefit from therapy as their younger counterparts. Chronologic age alone should generally not be used to guide management decisions. Comprehensive geriatric assessment tools and prospective studies in older adults integrating comprehensive geriatric assessment can shed light on the optimal management of urologic malignancies in this population. PMID- 26476123 TI - Palliative Care of Urologic Patients at End of Life. AB - This article focuses on the issues facing patients with advanced and terminal urologic illness, from the framework of care planning based on defining patient specific and family-specific goals of care, to palliative management strategies for common symptoms and syndromes that these patients and their families experience. This article also focuses on the management of common urologic issues that may arise in the course of care for all patients at the end of life, as well as the impact of these conditions on caregivers. PMID- 26476124 TI - Urologic Issues in Geriatric Health Care. PMID- 26476125 TI - Volatile organic compounds in asthma diagnosis: a systematic review and meta analysis. AB - We aimed to assess the value and classification rate of exhaled volatile organic compounds (VOCs) in asthma diagnosis. A PRISMA-oriented systematic search for published studies regarding exhaled VOCs in asthma diagnosis was conducted based on predefined criteria. Studies presenting sensitivity and specificity values for the test were included in the meta-analysis. Pooled diagnosis odds ratios (DOR), area under the curve (AUC) and positive and negative likelihood ratios (LR) for exhaled VOC profiles were calculated; and publication bias, threshold effect and heterogeneity were estimated. Eighteen studies were selected for the qualitative analysis and six met the criteria for inclusion in the quantitative analysis. Mean (95% CI) pooled DOR, positive and negative LR were 49.3 (15.9-153.3), 5.86 (3.07-11.21) and 0.16 (0.10-0.26), respectively. The AUC value was 0.94. Only three of the 18 reviewed studies performed an external validation of the model using a different data set. The results from the revised studies suggest that exhaled VOCs are promising biomarkers for asthma diagnosis and that several compounds, mainly alkanes, may be significantly associated with asthma inflammation. However, there are still various constraints associated with standardization and externally validated studies are needed to introduce exhaled VOC profiling in a clinical scenario. PMID- 26476126 TI - Women's imaging: From symptom to diagnosis. PMID- 26476127 TI - In silico drug re-purposing against African sleeping sickness using GlcNAc-PI de N-acetylase as an experimental target. AB - Trypanosoma brucei is a protozoan that causes African sleeping sickness in humans. Many glycoconjugate compounds are present on the entire cell surface of Trypanosoma brucei to control the infectivity and survival of this pathogen. These gycoconjugates are anchored to the plasma membrane with the help of glycosyl phosphatidyl inositol (GPI) anchors. This type of anchor is much more common in protozoans than in other eukaryotes. The second step of glycosyl phosphatidyl inositol (GPI) anchor biosynthesis is catalyzed by an enzyme, which is GlcNAc-PI de-N-acetylase. GlcNAc-PI de-N-acetylase has a conserved GPI domain, which is responsible for the functionality of this enzyme. In this study, the three-dimensional structure of the target is modelled by I-TASSER and the ligand is modelled by PRODRG server. It is found that the predicted active site residues of the GPI domain are ultra-conserved for the Trypanosomatidae family. The predicted active site residues are His41, Pro42, Asp43, Asp44, Met47, Phe48, Ser74, Arg80, His103, Val144, Ser145, His147 and His150. Two hydrogen bond acceptors and four hydrogen bond donors are found in the modelled pharmacophore. All compounds of the Drugbank database and twenty three known inhibitors have been considered for structure based virtual screening. This work is focused on approved drugs because they are already tested for safety and effectiveness in humans. After the structure-based virtual screening, seventeen approved drugs and two inhibitors are found, which interact with the ligand on the basis of the designed pharmacophore. The docking has been performed for the resultant seventeen approved drugs and two known inhibitors. Two approved drugs have negative binding energy and their pKa values are similar to the selected known inhibitors. The result of this study suggests that the approved drugs Ethambutol (DB00330) and Metaraminol (DB00610) may prove useful in the treatment of African sleeping sickness. PMID- 26476128 TI - Computational exploration of microRNAs from expressed sequence tags of Humulus lupulus, target predictions and expression analysis. AB - Among computationally predicted and experimentally validated plant miRNAs, several are conserved across species boundaries in the plant kingdom. In this study, a combined experimental-in silico computational based approach was adopted for the identification and characterization of miRNAs in Humulus lupulus (hop), which is widely cultivated for use by the brewing industry and apart from, used as a medicinal herb. A total of 22 miRNAs belonging to 17 miRNA families were identified in hop following comparative computational approach and EST-based homology search according to a series of filtering criteria. Selected miRNAs were validated by end-point PCR and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), confirmed the existence of conserved miRNAs in hop. Based on the characteristic that miRNAs exhibit perfect or nearly perfect complementarity with their targeted mRNA sequences, a total of 47 potential miRNA targets were identified in hop. Strikingly, the majority of predicted targets were belong to transcriptional factors which could regulate hop growth and development, including leaf, root and even cone development. Moreover, the identified miRNAs may also be involved in other cellular and metabolic processes, such as stress response, signal transduction, and other physiological processes. The cis-regulatory elements relevant to biotic and abiotic stress, plant hormone response, flavonoid biosynthesis were identified in the promoter regions of those miRNA genes. Overall, findings from this study will accelerate the way for further researches of miRNAs, their functions in hop and shows a path for the prediction and analysis of miRNAs to those species whose genomes are not available. PMID- 26476129 TI - Collision of lymphoepithelioma-like carcinoma and adenocarcinoma of the lung: a case report. AB - We report a rare case of collision of lymphoepithelioma-like carcinoma (LELC) and adenocarcinoma (AC) in the lung. A 59-year-old woman had a history of fever and cough. A mass was found by X-ray in the left upper lung. Magnetic resonance imaging (MRI) shows a dumbbell-like mass in the fore and tongue segment of the left upper lung with irregular spiculate margin. Positron emission tomography/computed tomography (PET/CT) (18F-FDG) shows strong concentration of radioactivity (SUVmax 6.9-12.3 cm) in the lung mass only. The patient subsequently underwent resection of left upper lung and associated hilar lymph nodes. Histological examination revealed it was a collision carcinoma comprising LELC and AC. The hilar lymph nodes were tumuor free. The immunoreactions, Epstein Barr early RNA in situ hybridization and molecular analyses, such as EGFR mutation, c-Met, anaplastic lymphoma kinase were different in both tumuor components, indicating they derived from different cell origin. This rare case was discussed. PMID- 26476130 TI - Phagocyte interactions with Mycobacterium tuberculosis--Simultaneous analysis of phagocytosis, phagosome maturation and intracellular replication by imaging flow cytometry. AB - Utilization of compounds that enhance the innate immune response against Mycobacterium tuberculosis is an attractive strategy for combating tuberculosis in the post-antibiotic era. Thus, it is crucial to develop methods that can be used to screen for such compounds and to investigate their mechanisms of action. Here, we used imaging flow cytometry (ImageStreamX Mk II),which enables rapid quantification of microscopic images in flow, to study the interaction between phagocytes and M. tuberculosis. Macrophage-differentiated THP-1 cells were infected with GFP-expressing M. tuberculosis H37Ra, and methods for rapidly assessing phagocytosis, phagosome maturation, and bacterial replication inside the cells were developed and evaluated. These aspects of innate immunity are essential in determining the outcome of mycobacterial infection of phagocytes. The technique was found effective for monitoring phagocytosis of mycobacteria, phagosomal acidification and phagolysosomal fusion, as well as for measuring mycobacterial replication inside the cells. Several of these aspects could be analyzed simultaneously in the same sample, providing a great deal of information about the phagocyte-mycobacterial interaction at once. Thus, this method has great potential to be useful both for basic research questions and for evaluating compounds that enhance the innate immune response against M. tuberculosis. PMID- 26476131 TI - Keratoacanthoma: a distinct entity? AB - Keratoacanthoma (KA) are common but exceptional benign tumors, often appearing on sun-exposed areas of light skinned people and showing spontaneous resolution. The goal of this study was to review existing literature, to point out the etiological complexity of KA biology and to answer the controversial debate if or not KA is a distinct entity or a variant of squamous cell carcinoma (SCC). Relying on recent results, we highlight that KA is an individual lesion with a unique molecular signature caused by alterations in the TGFbeta signalling pathway. These recent findings will help to understand the nature of KA and to develop new reliable diagnostic tools, simplifying the discrimination of the histologically similar KA and SCC. PMID- 26476132 TI - DL0410 can reverse cognitive impairment, synaptic loss and reduce plaque load in APP/PS1 transgenic mice. AB - Cholinesterase inhibitors are first-line therapy for Alzheimer's disease (AD). DL0410 is an AChE/BuChE dual inhibitor with a novel new structural scaffold. It has been demonstrated that DL0410 could improve memory deficits in both Abeta1-42 induced and scopolamine-induced amnesia in mice. In the present study, the therapeutic effect of DL0410 and its action mechanism were investigated in APP/PS1 transgenic mice. Six-month old APP/PS1 transgenic mice were orally administered with DL0410 (3, 10, 30 mg/kg/day). After 60 days, several behavioural tests, including the Morris water maze and step-down tests, were used to investigate the effects of DL0410 on mice behaviours. All the behavioural experimental results showed that DL0410 significantly ameliorated memory deficits. Meanwhile, DL0410 attenuated neural cell damage and reduced senile plaques significantly in the hippocampus of APP/PS1 transgenic mice. In addition, DL0410 significantly decreased Abeta plaques, while increasing the number of synapses and the thickness of PSD in the hippocampus. We also found DL0410 decreased the expression of APP, NMDAR1B and the phosphorylation level of NMDAR2B, and increased the phosphorylation level of CAMKII and the expression of PSD-95. In this study, the results of behavioural tests demonstrated for the first time that DL0410 could improve learning and memory dysfunction in APP/PS1 transgenic mice. The mechanism of its beneficial effects might be related to cholinesterase inhibition, Abeta plaques inhibition, improvement of synapse loss by regulating of expression of proteins related to synapses. As a result, DL0410 could be considered as a candidate drug for the therapy of AD. PMID- 26476133 TI - Intrathecal morphine-3-glucuronide-induced nociceptive behavior via Delta-2 opioid receptors in the spinal cord. AB - Intrathecal (i.t.) injection of morphine-3-glucuronide (M3G), a major metabolite of morphine without analgesic actions, produces severe hindlimb scratching followed by biting and licking in mice. The M3G-induced behavioral response was inhibited dose-dependently by pretreatment with an antisera against dynorphin. However, the selective kappa-opioid receptor antagonist, nor-BNI did not prevent the M3G-induced behavioral response. Dynorphin is rapidly degraded by a dynorphin converting enzyme (cystein protease), to leucine-enkephalin (Leu-ENK). The M3G induced behavioral response was inhibited dose-dependently by pretreatment with the antisera against Leu-ENK. We also showed that M3G co-administered with Leu ENK-converting enzyme inhibitors, phosphoramidon and bestatin produced much stronger behavioral responses than M3G alone. Furthermore, the M3G-induced behavioral responses were inhibited dose-dependently by i.t. co-administration of the non-selective delta-opioid receptor antagonist, naltrindole or the selective delta2-opioid receptor antagonist, naltriben, whereas the selective delta1-opioid receptor antagonist, BNTX had no effect. An i.t. injection of M3G also produced a definite activation of ERK in the lumbar dorsal spinal cord. Western blotting analysis revealed that antisera against dynorphin, antisera against Leu-ENK, naltrindole or naltriben resulted in a significant blockade of ERK activation induced by M3G in the spinal cord. Taken together, these results suggest that M3G induced nociceptive responses and ERK activation may be triggered via delta2 opioid receptors activated by Leu-ENK, which is formed from dynorphin in the spinal cord. PMID- 26476134 TI - Hypothetical protein Rv3423.1 of Mycobacterium tuberculosis is a histone acetyltransferase. AB - We isolated an 8 kDa mycobacterial hypothetical protein, Rv3423.1, from the chromatin of human macrophages infected with Mycobacterium tuberculosis H37Rv. Bioinformatics predictions followed by in vitro biochemical assays with purified recombinant protein showed that Rv3423.1 is a novel histone acetyltransferase that acetylates histone H3 at the K9/K14 positions. Transient transfection of macrophages containing GFP-tagged histone H1 with RFP-tagged Rv3423.1 revealed that the protein co-localizes with the chromatin in the nucleus. Co immunoprecipitation assays confirmed that the Rv3423.1-histone interaction is specific. Rv3423.1 protein was detected in the culture filtrate of virulent but not avirulent M. tuberculosis. Infection of macrophages with recombinant Mycobacterium smegmatis constitutively expressing Rv3423.1 resulted in a significant increase in the number of intracellular bacteria. However, the protein did not seem to offer any growth advantage to free-living recombinant M. smegmatis. It is highly likely that, by binding to the host chromatin, this histone acetyltransferase from M. tuberculosis may manipulate the expression of host genes involved in anti-inflammatory responses to evade clearance and to survive in the intracellular environment. PMID- 26476135 TI - On the link between conformational changes, ligand binding and heat capacity. AB - BACKGROUND: Conformational changes coupled to ligand binding constitute the structural and energetics basis underlying cooperativity, allostery and, in general, protein regulation. These conformational rearrangements are associated with heat capacity changes. ITC is a unique technique for studying binding interactions because of the simultaneous determination of the binding affinity and enthalpy, and for providing the best estimates of binding heat capacity changes. SCOPE OF REVIEW: Still controversial issues in ligand binding are the discrimination between the "conformational selection model" and the "induced fit model", and whether or not conformational changes lead to temperature dependent apparent binding heat capacities. The assessment of conformational changes associated with ligand binding by ITC is discussed. In addition, the "conformational selection" and "induced fit" models are reconciled, and discussed within the context of intrinsically (partially) unstructured proteins. MAJOR CONCLUSIONS: Conformational equilibrium is a major contribution to binding heat capacity changes. A simple model may explain both conformational selection and induced fit scenarios. A temperature-independent binding heat capacity does not necessarily indicate absence of conformational changes upon ligand binding. ITC provides information on the energetics of conformational changes associated with ligand binding (and other possible additional coupled equilibria). GENERAL SIGNIFICANCE: Preferential ligand binding to certain protein states leads to an equilibrium shift that is reflected in the coupling between ligand binding and additional equilibria. This represents the structural/energetic basis of the widespread dependence of ligand binding parameters on temperature, as well as pH, ionic strength and the concentration of other chemical species. PMID- 26476136 TI - Long-term results following an anatomically based surgical technique for resection of colon cancer: a comparison with results from complete mesocolic excision. AB - AIM: Complete mesocolic excision (CME) has been advocated as likely to improve the long-term oncological outcome of colon cancer resection, although there is a paucity of long-term results in the literature. The aim of this study was to supplement our previously published results on colon cancer resection based on a standardized technique of precise dissection along anatomical planes with high vascular ligation and to compare our long-term results with those of recent European studies of CME. METHOD: Data were drawn from a prospective hospital registry of consecutive resections for colon cancer between 1996 and 2007, including follow-up to the end of 2012. The principal outcomes from potentially curative resections were 5-year Kaplan-Meier rates of local recurrence, systemic recurrence, overall survival and cancer-specific survival. Secondary outcomes for all resections were postoperative complications, number of lymph nodes retrieved and R0 status. RESULTS: For 779 potentially curative resections the local recurrence rate was 2.1% (95% CI 1.3-3.4), the systemic recurrence rate was 10.2% (95% CI 8.1-12.7), the 5-year overall survival rate was 76.2% (95% CI 73.0-79.0) and the cancer-specific survival rate was 89.8% (95% CI 87.3-91.9). For all 905 resections, rates of 14 surgical complications were low and not dissimilar to those in a comparable study. The median lymph node count was 15 (range 0-113). R0 status was confirmed in 883/905 patients (97.6%; 95% CI 96.4-98.5). CONCLUSION: For colon cancer, meticulous dissection along anatomical planes together with high vascular ligation results in few complications, a high R0 rate, low recurrence and high survival. PMID- 26476137 TI - Serological diagnosis of bovine brucellosis using B. melitensis strain B115. AB - Bovine brucellosis is diagnosed by official tests, such as Rose Bengal plate test (RBPT) and Complement Fixation test (CFT). Both tests detect antibodies directed against the lipolysaccharide (LPS) of Brucella cell wall. Despite their good sensitivity, those tests do not discriminate between true positive and false positive serological reactions (FPSR), the latter being generated by animals infected with other Gram negative microorganisms that share components of Brucella LPS. In this study, an antigenic extract from whole Brucella melitensis B115 strain was used to set up an ELISA assay for the serological diagnosis of bovine brucellosis. A total of 148 serum samples from five different groups of animals were tested: Group A: 28 samples from two calves experimentally infected with Yersinia enterocolitica O:9; Group B: 30 samples from bovines infected with Brucella abortus; Group C: 50 samples from brucellosis-free herds; Group D: 20 samples RBPT positive and CFT negative; Group E: 20 samples both RBPT and CFT positive. Group D and Group E serum samples were from brucellosis-free herds. Positive reactions were detected only by RBPT and CFT in calves immunized with Y. enterocolitica O:9. Sera from Group B animals tested positive also in the ELISA assay, whereas sera from the remaining groups were all negative. The results obtained encourage the use of the ELISA assay to implement the serological diagnosis of brucellosis. PMID- 26476138 TI - Microbial ecology-based methods to characterize the bacterial communities of non model insects. AB - Among the animals of the Kingdom Animalia, insects are unparalleled for their widespread diffusion, diversity and number of occupied ecological niches. In recent years they have raised researcher interest not only because of their importance as human and agricultural pests, disease vectors and as useful breeding species (e.g. honeybee and silkworm), but also because of their suitability as animal models. It is now fully recognized that microorganisms form symbiotic relationships with insects, influencing their survival, fitness, development, mating habits and the immune system and other aspects of the biology and ecology of the insect host. Thus, any research aimed at deepening the knowledge of any given insect species (perhaps species of applied interest or species emerging as novel pests or vectors) must consider the characterization of the associated microbiome. The present review critically examines the microbiology and molecular ecology techniques that can be applied to the taxonomical and functional analysis of the microbiome of non-model insects. Our goal is to provide an overview of current approaches and methods addressing the ecology and functions of microorganisms and microbiomes associated with insects. Our focus is on operational details, aiming to provide a concise guide to currently available advanced techniques, in an effort to extend insect microbiome research beyond simple descriptions of microbial communities. PMID- 26476139 TI - Bench to bedside: NK cells and control of metastasis. AB - Natural killer (NK) cells play a critical role in host immune responses against tumor growth and metastasis. The numerous mechanisms used by NK cells to regulate and control cancer metastasis include interactions with tumor cells via specific receptors and ligands as well as direct cytotoxicity and cytokine-induced effector mechanisms. NK cells also play a role in tumor immunosurveillance and inhibition of metastases formation by recognition and killing of tumor cells. In this review, we provide an overview of the molecular mechanisms of NK cell responses against tumor metastases and discuss multiple strategies by which tumors evade NK cell-mediated surveillance. With an increasing understanding of the molecular mechanisms driving NK cell activity, there is a growing potential for the development of new cancer immunotherapies. Here we provide a historical background on NK cell-based therapies and discuss the implications of recent and ongoing clinical trials using novel NK cell-based immunotherapy. PMID- 26476140 TI - Acute psychological stress induces short-term variable immune response. AB - In spite of advances in understanding the cross-talk between the peripheral immune system and the brain, the molecular mechanisms underlying the rapid adaptation of the immune system to an acute psychological stressor remain largely unknown. Conventional approaches to classify molecular factors mediating these responses have targeted relatively few biological measurements or explored cross sectional study designs, and therefore have restricted characterization of stress immune interactions. This exploratory study analyzed transcriptional profiles and flow cytometric data of peripheral blood leukocytes with physiological (endocrine, autonomic) measurements collected throughout the sequence of events leading up to, during, and after short-term exposure to physical danger in humans. Immediate immunomodulation to acute psychological stress was defined as a short-term selective up-regulation of natural killer (NK) cell-associated cytotoxic and IL-12 mediated signaling genes that correlated with increased cortisol, catecholamines and NK cells into the periphery. In parallel, we observed down-regulation of innate immune toll-like receptor genes and genes of the MyD88-dependent signaling pathway. Correcting gene expression for an influx of NK cells revealed a molecular signature specific to the adrenal cortex. Subsequently, focusing analyses on discrete groups of coordinately expressed genes (modules) throughout the time-series revealed immune stress responses in modules associated to immune/defense response, response to wounding, cytokine production, TCR signaling and NK cell cytotoxicity which differed between males and females. These results offer a spring-board for future research towards improved treatment of stress-related disease including the impact of stress on cardiovascular and autoimmune disorders, and identifies an immune mechanism by which vulnerabilities to these diseases may be gender-specific. PMID- 26476143 TI - Bifurcation structure of two coupled FHN neurons with delay. AB - This paper presents an investigation of the dynamics of two coupled non-identical FitzHugh-Nagumo neurons with delayed synaptic connection. We consider coupling strength and time delay as bifurcation parameters, and try to classify all possible dynamics which is fairly rich. The neural system exhibits a unique rest point or three ones for the different values of coupling strength by employing the pitchfork bifurcation of non-trivial rest point. The asymptotic stability and possible Hopf bifurcations of the trivial rest point are studied by analyzing the corresponding characteristic equation. Homoclinic, fold, and pitchfork bifurcations of limit cycles are found. The delay-dependent stability regions are illustrated in the parameter plane, through which the double-Hopf bifurcation points can be obtained from the intersection points of two branches of Hopf bifurcation. The dynamical behavior of the system may exhibit one, two, or three different periodic solutions due to pitchfork cycle and torus bifurcations (Neimark-Sacker bifurcation in the Poincare map of a limit cycle), of which detection was impossible without exact and systematic dynamical study. In addition, Hopf, double-Hopf, and torus bifurcations of the non trivial rest points are found. Bifurcation diagrams are obtained numerically or analytically from the mathematical model and the parameter regions of different behaviors are clarified. PMID- 26476141 TI - Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical 5-HT2A receptor and IL1-beta levels in male mice. AB - The manipulation of the enteric microbiota with specific prebiotics and probiotics, has been shown to reduce the host's inflammatory response, alter brain chemistry, and modulate anxiety behaviour in both rodents and humans. However, the neuro-immune and behavioural effects of prebiotics on sickness behaviour have not been explored. Here, adult male CD1 mice were fed with a specific mix of non-digestible galacto-oligosaccharides (Bimuno(r), BGOS) for 3 weeks, before receiving a single injection of lipopolysaccharide (LPS), which induces sickness behaviour and anxiety. Locomotor and marble burying activities were assessed 4h after LPS injection, and after 24h, anxiety in the light-dark box was assessed. Cytokine expression, and key components of the serotonergic (5 Hydroxytryptamine, 5-HT) and glutamatergic system were evaluated in the frontal cortex to determine the impact of BGOS administration at a molecular level. BGOS fed mice were less anxious in the light-dark box compared to controls 24h after the LPS injection. Elevated cortical IL-1beta concentrations in control mice 28 h after LPS were not observed in BGOS-fed animals. This significant BGOS*LPS interaction was also observed for 5HT2A receptors, but not for 5HT1A receptors, 5HT, 5HIAA, NMDA receptor subunits, or other cytokines. The intake of BGOS did not influence LPS-mediated reductions in marble burying behaviour, and its effect on locomotor activity was equivocal. Together, our data show that the prebiotic BGOS has an anxiolytic effect, which may be related to the modulation of cortical IL-1beta and 5-HT2A receptor expression. Our data suggest a potential role for prebiotics in the treatment of neuropsychiatric disorders where anxiety and neuroinflammation are prominent clinical features. PMID- 26476142 TI - Knock-down of pantothenate kinase 2 severely affects the development of the nervous and vascular system in zebrafish, providing new insights into PKAN disease. AB - Pantothenate Kinase Associated Neurodegeneration (PKAN) is an autosomal recessive disorder with mutations in the pantothenate kinase 2 gene (PANK2), encoding an essential enzyme for Coenzyme A (CoA) biosynthesis. The molecular connection between defects in this enzyme and the neurodegenerative phenotype observed in PKAN patients is still poorly understood. We exploited the zebrafish model to study the role played by the pank2 gene during embryonic development and get new insight into PKAN pathogenesis. The zebrafish orthologue of hPANK2 lies on chromosome 13, is a maternal gene expressed in all development stages and, in adult animals, is highly abundant in CNS, dorsal aorta and caudal vein. The injection of a splice-inhibiting morpholino induced a clear phenotype with perturbed brain morphology and hydrocephalus; edema was present in the heart region and caudal plexus, where hemorrhages with reduction of blood circulation velocity were detected. We characterized the CNS phenotype by studying the expression pattern of wnt1 and neurog1 neural markers and by use of the Tg(neurod:EGFP/sox10:dsRed) transgenic line. The results evidenced that downregulation of pank2 severely impairs neuronal development, particularly in the anterior part of CNS (telencephalon). Whole-mount in situ hybridization analysis of the endothelial markers cadherin-5 and fli1a, and use of Tg(fli1a:EGFP/gata1a:dsRed) transgenic line, confirmed the essential role of pank2 in the formation of the vascular system. The specificity of the morpholino induced phenotype was proved by the restoration of a normal development in a high percentage of embryos co-injected with pank2 mRNA. Also, addition of pantethine or CoA, but not of vitamin B5, to pank2 morpholino-injected embryos rescued the phenotype with high efficiency. The zebrafish model indicates the relevance of pank2 activity and CoA homeostasis for normal neuronal development and functioning and provides evidence of an unsuspected role for this enzyme and its product in vascular development. PMID- 26476144 TI - Modeling Ca(2+) currents and buffered diffusion of Ca(2+) in human beta-cells during voltage clamp experiments. AB - Macroscopic Ca(2+) currents of the human beta-cells were characterized using the Hodgkin-Huxley formalism. Expressions describing the Ca(2+)-dependent inactivation process of the L-type Ca(2+) channels in terms of the concentration of Ca(2+) were obtained. By coupling the modeled Ca(2+) currents to a three dimensional model of buffered diffusion of Ca(2+), we simulated the Ca(2+) transients formed in the immediate vicinity of the cell membrane during voltage clamp experiments performed in high buffering conditions. Our modeling approach allowed us to consider the distribution of the Ca(2+) sources over the cell membrane. The effect of exogenous (EGTA) and endogenous Ca(2+) buffers on the temporal course of the Ca(2+) transients was evaluated. We show that despite the high Ca(2+) buffering capacity, nanodomains are formed in the submembrane space, where a peak Ca(2+) concentration between ~76 and 143 uM was estimated from our simulations. In addition, the contribution of each Ca(2+) current to the formation of the Ca(2+) nanodomains was also addressed. Here we provide a general framework to incorporate the spatial aspects to the models of the pancreatic beta cell, such as a more detailed and realistic description of Ca(2+) dynamics in response to electrical activity in physiological conditions can be provided by future models. PMID- 26476145 TI - Proteomic characterization of pleural effusion, a specific host niche of Mycoplasma mycoides subsp. mycoides from cattle with contagious bovine pleuropneumonia (CBPP). AB - Mycoplasma mycoides subsp. mycoides (Mmm) is the causative agent of contagious bovine pleuropneumonia (CBPP), a severe pleuropneumonia in cattle. The abnormal accumulation of pleural fluid, called pleural effusion (PE), is one of the characteristics of this disease. We performed a proteomic analysis of seven PE samples from experimentally infected cattle and characterized their composition with respect to bovine and Mmm proteins. We detected a total of 963 different bovine proteins. Further analysis indicated a strong enrichment of proteins involved in antigen processing, platelet activation and degranulation and apoptosis and an increased abundance of acute phase proteins.With regard to the pathogen, up to 108 viable mycoplasma cells per ml were detected in the PE supernatant. The proteomic analysis revealed 350 mycoplasma proteins, including proteins involved in virulence-associated processes like hydrogen peroxide (H2O2) production and capsule synthesis. The bovine proteins detected will aid to characterize the inflammasome during an acute pleuropneumonia in cattle and the identified mycoplasma proteins will serve as baseline data to be compared with in vitro studies to improve our understanding of pathogenicity mechanisms. Based on our results, we named the pleural effusion an "in vivo niche" of Mmm during the acute phase of CBPP. Biological significance: This is the first study on bovine pleural effusions derived from an infectious disease and the first approach to characterize the proteome of Mycoplasma mycoides in vivo. This study revealed a high number of viable Mmm cells in the pleural effusion. The bovine pleural effusion proteome during Mmm infection is qualitatively similar to plasma, but differs with respect to high abundance of acute phase proteins. On the other hand,Mmm in its natural host produces proteins involved in capsule synthesis, H2O2 production and induction of inflammatory response, supporting previous knowledge on mechanisms underlying the survival and virulence of this pathogen while inside the natural host. This knowledge forms a profound basis for testing the identified protein candidates for diagnostics or vaccines. PMID- 26476146 TI - Proteomics of reproductive systems: Towards a molecular understanding of postmating, prezygotic reproductive barriers. AB - Following mating and insemination, fertility is dependent on the successful execution of a complex array of morphological, physiological and molecular interactions between male and female proteins, cells and tissues. Many of these interacting components bear hallmarks of co-evolving systems and are suspected to contribute to postmating, prezygotic (PMPZ) reproductive barriers involved in the formation of new species. Although PMPZ reproductive isolation has historically been more difficult to study than precopulatory and postzygotic barriers, recent research has highlighted its potential role in speciation and revealed the impact of molecular investigation utilizing proteomic approaches. Proteomics, in conjunction with transcriptomic and evolutionary genomic studies, has been widely used to identify rapidly evolving male and female reproductive proteins. Increased access to high-throughput and quantitative proteomic techniques, as well as the ease of generating genomic and transcriptomic resources necessary for protein identification, can facilitate the extension of proteomics from traditional model species to systems of relevance to PMPZ phenotypes and hence greatly expand our understanding of how rapidly diverging molecular systems may contribute to PMPZ barriers. Here we review the influence proteomic analyses can have on our understanding of the function and evolution of the complex cellular and molecular processes governing postcopulatory male-female interactions and the study of PMPZ reproductive isolation, with the goal of expanding our understanding of the contribution of PMPZ processes to speciation. PMID- 26476147 TI - The imprinted Phlda2 gene modulates a major endocrine compartment of the placenta to regulate placental demands for maternal resources. AB - Imprinted genes, which are expressed from a single parental allele in response to epigenetic marks first established in the germline, function in a myriad of processes to regulate mammalian development. Recent work suggests that imprinted genes may regulate the signalling function of the placenta by modulating the size of the endocrine compartment. Here we provide in vivo evidence that this hypothesis is well founded. Elevated expression of the imprinted Pleckstrin homology-like domain, family a, member 2 (Phlda2) gene drives a reduction of the spongiotrophoblast endocrine compartment, diminished placental glycogen and asymmetric foetal growth restriction. Using both loss-of-function and gain-in expression mouse models, here we further show that Phlda2 exclusively modulates the spongiotrophoblast compartment of the placenta without significantly altering the composition of the trophoblast giant cell endocrine lineages that share a common progenitor with this lineage. Additionally, we show that Phlda2 loss-of function placentae contain nearly three times more placental glycogen than non transgenic placentae. Remarkably, relative to a fully wild type scenario, wild type placentae also accumulate excessive glycogen. While loss-of-function of Phlda2 increased both placental weight and placental glycogen, the weight of both mutant and non-transgenic fetuses was lower than that found in a fully wild type scenario indicating that excessive glycogen accumulation comes at the cost of foetal growth. This work firstly highlights a novel signalling function for the spongiotrophoblast in stimulating the global accumulation of placental glycogen. Furthermore, this work suggests that Phlda2 manipulates the placenta's demands for maternal resources, a process that must be tightly regulated by epigenetic marks to ensure optimal foetal growth. PMID- 26476148 TI - Efficacy of the Ketogenic Diet for the Treatment of Refractory Childhood Epilepsy: Cerebrospinal Fluid Neurotransmitters and Amino Acid Levels. AB - OBJECTIVE: The mechanisms of the ketogenic diet remain unclear, but several predictors of response have been proposed. We aimed is to study the relationship between the etiology of epilepsy, cerebrospinal fluid neurotransmitters, pterins, and amino acids, and response to a ketogenic diet. METHODS: We studied 60 patients who began classic ketogenic diet treatment for refractory epilepsy. In 24 of 60 individuals, we analyzed cerebrospinal fluid neurotransmitters, pterins, and amino acids in baseline conditions. Mean age at epilepsy onset was 24 months, 83.3% were focal epilepsies, and in 51.7% the etiology of the epilepsy was unknown. RESULTS: Six months after initiating the ketogenic diet, it was effective (greater than a 50% reduction in seizure frequency) in 31.6% of patients. We did not find a link between rate of efficacy for the ketogenic diet and etiologies of epilepsy, nor did we find a link between the rate of efficacy for the ketogenic diet and cerebrospinal fluid pterins and biogenic amines concentrations. However, we found statistically significant differences for lysine and arginine values in the cerebrospinal fluid between ketogenic diet responders and nonresponders, but not for the other amino acids analyzed. SIGNIFICANCE: The values of some amino acids were significantly different in relationship with the ketogenic diet efficacy; however, the epilepsy etiology and the cerebrospinal fluid biogenic amine and pterin values were not. PMID- 26476149 TI - The Neurological Outcome of Isolated PVL and Severe IVH in Preterm Infants: Is It Fair to Compare? AB - OBJECTIVE: We compared the neurological outcome of isolated periventricular leukomalacia and severe intraventricular hemorrhage in a cohort of very low birth weight infants born and managed at single tertiary-care center in Saudi Arabia. METHODS: We undertook a descriptive retrospective chart review of the neurological status of very low birth weight infants who were born and managed over a 5-year period at King Abdulaziz Medical City, Riyadh. The neurological outcome of neonates with isolated periventricular leukomalacia and severe intraventricular hemorrhage (grades III and IV) was studied and compared in relation to developmental delay and cerebral palsy. RESULTS: A total of 20 patients with isolated periventricular leukomalacia and 26 with severe intraventricular hemorrhage (grades III and IV) were identified for this study. Of 20 patients with isolated periventricular leukomalacia, 9 (45%) had good developmental outcome and 11 (55%) had bad developmental outcome. Of 26 patients of severe intraventricular hemorrhage, 14 (54%) had good developmental outcome and 12 (46%) had bad developmental outcome (P = 0.55). Significant motor neurological deficit affecting function is distributed as follows: 11/20 (55%) in the isolated periventricular leukomalacia group and 7/26 (27%) in the severe intraventricular hemorrhage group (P = 0.05). Cerebral palsy was diplegic in 7/11 (64%) and quadriplegic in 4/11 (36%) in the isolated periventricular leukomalacia group, and hemiplegic 3/7 (43%), diplegic in 1/7 (14%), and quadriplegic in 3/7 (43%) in the severe intraventricular hemorrhage group (P = 0.03). Distribution of the neurological outcome according to periventricular leukomalacia grade was as follows: for periventricular leukomalacia grade I (n = 8), 6/8 (75%) had good neurological outcome and 2/8 (25%) had bad neurological outcome. In periventricular leukomalacia grade II (n = 4), good neurological outcome was seen in three patients (75%) and bad neurological outcome was seen in one patient (25%). All patients (n = 8) with periventricular leukomalacia grade III had bad outcome (P < 0.01). CONCLUSION: About half of patients with isolated periventricular leukomalacia and severe intraventricular hemorrhage had a poor developmental outcome. However, the severity of cerebral palsy was greater in the isolated periventricular leukomalacia patients and correlates highly with periventricular leukomalacia grade. Symmetrical diplegic cerebral palsy is the most common motor deficit associated with isolated periventricular leukomalacia, whereas asymmetrical hemiplegic cerebral palsy is seen exclusively with severe intraventricular hemorrhage. PMID- 26476150 TI - Unmasking right atrial fibrillation: A new indication of adenosine triphosphate test? PMID- 26476151 TI - Cervical HPV natural history among young Western Cape, South African women: The randomized control EVRI Trial. AB - OBJECTIVE: The objective of this analysis was to assess human papillomavirus (HPV) infection persistence and incidence 7-months post-enrollment by HPV vaccine study arm (vaccine or placebo). METHODS: HIV-negative, sexually active women aged 16-24 years in the Western Cape, South Africa, were enrolled in the EVRI Trial and were randomized to receive 4-valent HPV vaccine or placebo. Cervical specimens were collected at enrollment and at the 7-month visit and were genotyped for HPV. HPV prevalence, persistence, and incidence were calculated. Prevalence ratios and odds ratios were calculated to assess factors associated with a prevalent and incident HPV infection. RESULTS: HPV incidence rates were marginally higher for the placebo group (n = 163) compared to the vaccine group (n = 169). A large proportion of the prevalent high-risk (HR-HPV) HPV types (49%) persisted over the 7-month period in both arms. Prevalent HR-HPV infection was significantly associated with a prevalent gonorrhea infection and detection of Herpes simplex type 2 antibodies. Incident HR-HPV infection was significantly associated with abnormal cervical cytology at enrollment and younger age. CONCLUSIONS: Women living in geographic areas, such as southern Africa, at high risk for HPV need to receive HPV vaccination at a very young age to maximally prevent infection and subsequent disease. PMID- 26476152 TI - Characteristics of herpes zoster-associated hospitalizations in Madrid (SPAIN) before vaccine availability. AB - OBJECTIVES: This study aimed to estimate the frequency of hospitalizations due to herpes zoster (HZ) and to describe their clinical characteristics by sex and age group. METHODS: Descriptive population-based cross-sectional study of hospital admissions due to HZ from 2003 to 2013 among residents in the Autonomous Community of Madrid. Sex, age, comorbidities, length of stay and outcomes were collected and described. Crude and age-adjusted cumulative incidence rates, and stratified by sex and age, were estimated. Robust Poisson regression analysis was used to calculate the incidence rate ratios by age group. RESULTS: 2039 hospitalizations were identified (51.0% in women). Complicated HZ caused 48.7% of them (50.9% in women). The hospitalization rate was 2.98/100,000 person-years and 7.19/1000 cases of HZ in primary care. Both rates were significantly higher in men, except in the extreme age groups. An immunosuppression-associated comorbidity was identified in 32.8% of the cases and was less common in patients >=75 years of age. The median length of stay was 6 days, and in-hospital mortality was 1.4%. CONCLUSIONS: Hospitalization rates due to HZ were higher in men and increased with age. In two out of every three cases, a comorbidity that potentially caused immunosuppression could not be identified. These cases could benefit from vaccination. PMID- 26476153 TI - Using photographs to study animal social cognition and behaviour: Do capuchins' responses to photos reflect reality? AB - Behavioural responses to photos are often used to infer what animals understand about their social environment, but are rarely validated against the same stimuli in real life. If subjects' responses to photos do not reflect responses to the same live stimuli, it is difficult to conclude what happens in reality based on photo responses alone. We compared capuchins' responses to photos versus live stimuli in an identical scenario within research cubicles. Subjects had the opportunity to approach food placed in front of an alpha group member and, in a separate condition, photos depicting the same individual. Subjects' latencies to approach food when placed in front of the real alpha negatively correlated with time subjects spent in close proximity to the alpha in their main enclosure. We therefore predicted subjects' latencies to approach food in the presence of photos would positively correlate with their latencies to approach food in the presence of the real alpha inside the cubicles, but negatively correlate with time they spent in proximity to the alpha in their enclosure. Neither prediction was supported. While not necessarily surprising, we explain why these results should be an important reminder that care is needed when interpreting results from photo studies. PMID- 26476154 TI - Molecular mechanisms of rosmarinic acid from Salvia miltiorrhiza in acute lymphoblastic leukemia cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rosmarinic acid (RA), a major hydrosoluble bioactive compound found in the Chinese medicinal herb, Salvia miltiorrhiza Bunge, which has been used in traditional Chinese medicine to treat various diseases, including cancer. However, the mechanisms have not been fully elucidated. AIM OF THE STUDY: Guided by microarray hybridization and Ingenuity Pathway Analysis, we identified modes of action of rosmarinic acid (RA) isolated from S. miltiorrhiza on acute lymphoblastic leukemia cells. MATERIALS AND METHODS: Microarray data were verified by independent methods: Real-time RT-PCR (mRNA expression), resazurin assay (cytotoxicity of RA towards parental CCRF-CEM, multidrug-resistant CEM/ADR5000 cells and normal lymphocytes), flow cytometry (cell cycle arrest, apoptosis, necroptosis, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential (MMP)), single cell gel electrophoresis (DNA damage), molecular docking and gene promoter binding motif analysis (NFkappaB), Western blotting (nuclear NFkappaB translocation, PARP cleavage, caspase 3/7/9 expression), and fibronectin-based cell adhesion assay. RESULTS: RA dose-dependently inhibited CCRF-CEM and CEM/ADR5000 cells, but caused less cytotoxicity towards normal lymphocytes. RA simultaneously induced apoptosis and necrosis, as shown by cell morphology and annexin V-PI assay. DNA damage was dose-dependently induced without ROS generation, which subsequently led to cell cycle arrest. RA-stimulated MMP dysfunction activated PARP-cleavage and caspase independent apoptosis. In accordance with molecular docking and gene promoter binding motif analyses, p65 translocation from the cytosol to the nucleus was blocked by RA, indicating a mechanistic role of the NFkappaB pathway to explain RA's action. RA affected cellular movement as evaluated by ameliorating cell adhesion to fibronectin. CONCLUSIONS: RA induced apoptosis and necrosis in a ROS independent DNA damage and caspase-independent manner. These results may contribute to the rationale use of S. miltiorrhiza and RA in traditional medicine of leukemia. PMID- 26476155 TI - Risk factors for suicide in bipolar I disorder in two prospectively studied cohorts. AB - BACKGROUND: These analyses were undertaken to determine whether similar risk factors for suicide emerged across two prospectively studied cohorts of individuals with bipolar I disorder. METHODS: The NIMH Collaborative Study of Depression (CDS) recruited 288 patients with bipolar I disorder from 1978-1981 as they sought treatment. Subjects were followed semiannually and then annually for up to 30 years. The Bipolar Genomics studies identified individuals through clinical referrals and advertisement. Clinical follow-up did not occur but personal identifiers of 1748 were matched with National Death Index (NDI) records. Kaplan-Meier survival analyses tested ten potential risk factors. RESULTS: The CDS and Genomic follow-ups encompassed 12,667 and 4529 person-years, respectively. Suicides/100 person-years were 0.26 and 0.055. The demographic or clinical variables that predicted suicide differed considerably in the two cohorts. The odds ratio for suicide for those with any history of suicide attempt was 2.3 and 2.8, respectively, and was the third highest odds ratio of the tested risk factors in both studies. LIMITATIONS: CONCLUSIONS: Differences in the sources of participants in studies of suicide risk may result in marked differences across studies in both rates of suicide and in risk factors. A history of suicide attempt is a relatively robust risk factor across samples. PMID- 26476156 TI - Physiological evidence for a human-induced landscape of fear in brown bears (Ursus arctos). AB - Human persecution is a major cause of mortality for large carnivores. Consequently, large carnivores avoid humans, but may use human-dominated landscapes by being nocturnal and elusive. Behavioral studies indicate that certain ecological systems are "landscapes of fear", driven by antipredator behavior. Because behavior and physiology are closely interrelated, physiological assessments may provide insight into the behavioral response of large carnivores to human activity. To elucidate changes in brown bears' (Ursus arctos) behavior associated with human activity, we evaluated stress as changes in heart rate (HR) and heart rate variability (HRV) in 12 GPS-collared, free-ranging bears, 7 males and 5 females, 3-11 years old, using cardiac-monitoring devices. We applied generalized linear regression models with HR and HRV as response variables and chest activity, time of day, season, distance traveled, and distance to human settlements from GPS positions recorded every 30 min as potential explanatory variables. Bears exhibited lower HRV, an indication of stress, when they were close to human settlements and especially during the berry season, when humans were more often in the forest, picking berries and hunting. Our findings provide evidence of a human-induced landscape of fear in this hunted population of brown bears. PMID- 26476157 TI - Anaerobic microbial fuel cell treating combined industrial wastewater: Correlation of electricity generation with pollutants. AB - Microbial fuel cell (MFC) is a new technology that not only generates energy but treats wastewater as well. A dual chamber MFC was operated under laboratory conditions. Wastewater samples from vegetable oil industries, metal works, glass and marble industries, chemical industries and combined industrial effluents were collected and each was treated for 98h in MFC. The treatment efficiency for COD in MFC was in range of 85-90% at hydraulic retention time (HRT) of 96h and had significant impact on wastewater treatment as well. The maximum voltage of 890mV was generated when vegetable oil industries discharge was treated with columbic efficiency of 5184.7C. The minimum voltage was produced by Glass House wastewater which was 520mV. There was positive significant co-relation between COD concentration and generated voltage. Further research should be focused on the organic contents of wastewater and various ionic species affecting voltage generation in MFC. PMID- 26476158 TI - The comparison of obtaining fermentable sugars from cellulose by enzymatic hydrolysis and fast pyrolysis. AB - Sugars are one of intermediates in the biological and chemical conversion of biomass. The objective of this study was to make comparison of obtaining fermentable sugars by enzymatic hydrolysis and fast pyrolysis of ball milling pretreated cellulose. After ball milling pretreatment for 0-18h, with the accumulation of alkali and alkali earth metals (from 50.8 to 276.4ppm) and decrease of the crystalline structure (from 89.8% to 10.1%), the hydrolysis yields increased from 23.6% to 56.0% in enzymatic saccharification, while the yields of levoglucosan diminished from 61.5% to 45.6% gradually in fast pyrolysis. Both enzymatic saccharification and fast pyrolysis had unique attractive features and unfavorable limitations. The present research provided a concept for considering choices among the technologies and feedstocks currently available. PMID- 26476159 TI - Investigation on the structural effect of lignin during the hydrogenolysis process. AB - Structure has a significant effect on the lignin degradation, so the investigation of structural effect on the lignin depolymerization is important and imperative. In this study, hydrogenolysis of three typical lignins with different structures, dealkaline lignin, sodium lignosulfonate and organosolv lignin, was intensively compared over the synergistic catalyst of CrCl3 and Pd/C. The effects of reaction temperature, time, hydrogen pressure and catalyst dosage on the catalytic performance of lignin species were investigated. The structure evolution of lignins during the hydrogenolysis process was also compared. The results showed that organosolv lignin was more sensitive for hydrogenolysis than others due to its high unsaturation degree and low molecular weight. Further analysis indicated that the hydrogenolysis, hydrodeoxygenation and repolymerization reactions took place and competed intensely. Wherein, the depolymerization products with unsaturated carbonyl groups were prone to repolymerize. And the methylation was helpful to stabilize the depolymerization products and suppress the further repolymerization. PMID- 26476160 TI - Integration of mild acid hydrolysis in gamma-valerolactone/water system for enhancement of enzymatic saccharification from cotton stalk. AB - In this study, mild acid hydrolysis using gamma-valerolactone (GVL)/water system integrated with enzymatic hydrolysis was carried out for the enhancement of enzymatic saccharification efficiency. The quantitative analysis of soluble carbohydrates and structural characterizations of solid residues were conducted. Results showed that the soluble carbohydrates in the water-phase were mainly composed of monomers and oligomers from xylose and glucose, while the contents of which were depended on the ratio of GVL to water. Moreover, the inhibitors were hardly detected due to the moderate pretreatment severity. Compared with the untreated feedstock, the yields of enzymatic hydrolysis from pretreated samples increased by two-fold with the mixture of 80/20 GVL/H2O. Combined with the amount of glucose (14.6%) dissolved in the water-phase, over 92.6% of glucose in cotton stalk was released and recovered. Based on the comprehensive analysis, treatment with GVL/H2O system provided us a more effective approach for sugar production from biomass. PMID- 26476161 TI - Global transcriptional responses of Acidithiobacillus ferrooxidans Wenelen under different sulfide minerals. AB - In order to provide new information about the adaptation of Acidithiobacillus ferrooxidans during the bioleaching process, the current analysis presents the first report of the global transcriptional response of the native copper mine strain Wenelen (DSM 16786) oxidized under different sulfide minerals. Microarrays were used to measure the response of At. ferrooxidans Wenelen to shifts from iron supplemented liquid cultures (reference state) to the addition of solid substrates enriched in pyrite or chalcopyrite. Genes encoding for energy metabolism showed a similar transcriptional profile for the two sulfide minerals. Interestingly, four operons related to sulfur metabolism were over-expressed during growth on a reduced sulfur source. Genes associated with metal tolerance (RND and ATPases type P) were up-regulated in the presence of pyrite or chalcopyrite. These results suggest that At. ferrooxidans Wenelen presents an efficient transcriptional system developed to respond to environmental conditions, namely the ability to withstand high copper concentrations. PMID- 26476162 TI - Insights into the global regulation of anaerobic metabolism for improved biohydrogen production. AB - To improve the biohydrogen yield in bacterial dark fermentation, a new approach of global anaerobic regulation was introduced. Two cellular global regulators FNR and NarP were overexpressed in two model organisms: facultatively anaerobic Enterobacter aerogenes (Ea) and strictly anaerobic Clostridium paraputrificum (Cp). The overexpression of FNR and NarP greatly altered anaerobic metabolism and increased the hydrogen yield by 40%. Metabolic analysis showed that the global regulation caused more reducing environment inside the cell. To get a thorough understanding of the global metabolic regulation, more genes (fdhF, fhlA, ppk, Cb fdh1, and Sc-fdh1) were overexpressed in different Ea and Cp mutants. For the first time, it demonstrated that there were approximately linear relationships between the relative change of hydrogen yield and the relative change of NADH yield or ATP yield. It implied that cellular reducing power and energy level played vital roles in the biohydrogen production. PMID- 26476163 TI - Application of artificial neural networks to co-combustion of hazelnut husk lignite coal blends. AB - The artificial neural network (ANN) theory is applied to thermal data obtained by non-isothermal thermogravimetric analysis (TGA) from room temperature to 1000 degrees C at different heating rates in air to study co-combustion of hazelnut husk (HH)-lignite coal (LC) blends of various composition. The heating rate, blend ratio and temperature were used in the ANN analysis to predict the TG curves of the blends as parameters that affect the thermal behavior during combustion. The ANN model provides a good prediction of the TG curves for co combustion with a coefficient of determination for the developed model of 0.9995. The agreement between the experimental data and the predicted values substantiated the accuracy of the ANN calculation. PMID- 26476164 TI - Enhancing enzymatic hydrolysis of xylan by adding sodium lignosulfonate and long chain fatty alcohols. AB - Sodium lignosulfonate (SXSL) and long-chain fatty alcohols (LFAs) could enhance the enzymatic hydrolysis of xylan, and the compound of SXSL and LFAs have synergies on the enzymatic hydrolysis. SXSL shows a strong enhancement in buffer pH range from 4.0 to 6.0. The enhancement increased with the SXSL dosage and the xylanase loading. The cellulose and lignin in corncob substrate could not only adsorb xylanase nonproductively, but also seriously reduce the accessibility of xylanase on xylan to impede the enzymatic hydrolysis of xylan. Cellulase could break the plant cell wall structure of corncob and make additives work better. The xylose yield of corncob at 72h increased from 59.4% to 73.7% by adding the compound of 5g/L SXSL and 0.01% (v/v) n-decanol, which was higher than that without cellulase and additives by 30.7%. Meanwhile, the glucose yield at 72h of corncob increased from 45.8% to 62.3%. PMID- 26476165 TI - Malbranchea cinnamomea: A thermophilic fungal source of catalytically efficient lignocellulolytic glycosyl hydrolases and metal dependent enzymes. AB - This study reports thermophilic fungus Malbranchea cinnamomea as an important source of lignocellulolytic enzymes. The secretome analysis using LC-MS/MS orbitrap showed that fungus produced a spectrum of glycosyl hydrolases (cellulase/hemicellulase), polysaccharide lyases (PL) and carbohydrate esterases (CE) in addition to cellobiose dehydrogenase (CDH) indicating the presence of functional classical and oxidative cellulolytic mechanisms. The protein fractions in the secretome resolved by ion exchange chromatography were analyzed for ability to hydrolyze alkali treated carrot grass (ATCG) in the presence of Mn(2+)/Cu(2+). This strategy in tandem with peptide mass fingerprinting led to identification of metal dependent protein hydrolases with no apparent hydrolytic activity, however, showed 5.7 folds higher saccharification in presence of Mn(2+). Furthermore, adding different protein fractions to commercial cellulase (Novozymes: Cellic CTec2) resulted in enhanced hydrolysis of ATCG ranging between 1.57 and 3.43 folds indicating the enzymes from M. cinnamomea as catalytically efficient. PMID- 26476166 TI - Application of biomass pyrolytic polygeneration technology using retort reactors. AB - To introduce application status and illustrate the good utilisation potential of biomass pyrolytic polygeneration using retort reactors, the properties of major products and the economic viability of commercial factories were investigated. The capacity of one factory was about 3000t of biomass per year, which was converted into 1000t of charcoal, 950,000Nm(3) of biogas, 270t of woody tar, and 950t of woody vinegar. Charcoal and fuel gas had LHV of 31MJ/kg and 12MJ/m(3), respectively, indicating their potential for use as commercial fuels. The woody tar was rich in phenols, while woody vinegar contained large quantities of water and acetic acid. The economic analysis showed that the factory using this technology could be profitable, and the initial investment could be recouped over the factory lifetime. This technology offered a promising means of converting abundant agricultural biomass into high-value products. PMID- 26476167 TI - Replacement of sugars to hydrogen production by Rhodobacter capsulatus using dark fermentation effluent as substrate. AB - Hydrogen is a promising alternative for the increased global energy demand since it has high energy density and is a clean fuel. The aim of this work was to evaluate the photo-fermentation by Rhodobacter capsulatus, using the dark fermentation effluent as substrate. Different systems were tested by changing the type of sugar in the dark fermentation, investigating the influence of supplementing DFE with sugar and adding alternate and periodically lactose and glucose throughout the process. The supplementation of the DFE with sugar resulted in higher H2 productivity and the replacement of the sugars repeatedly during the photo-fermentation process was important to maintain the cell culture active. By controlling the residual amount of sugar, bacteria inhibition was avoided; lactic acid, that was toxic to the biomass, was consumed and the metabolic route of butyric acid production was predominant. Under optimum conditions, the H2 productivity reached 208.40mmolH2/Ld in 52h. PMID- 26476168 TI - Towards high potential magnetic biocatalysts for on-demand elimination of pharmaceuticals. AB - The present study investigated the applicability of a laccase based bioprocess for the treatment of a mixture containing 13 selected pharmaceuticals. To do so, laccase was immobilized as cross-linked enzyme aggregates (MAC-CLEAs) on amine functionalized magnetic nanoparticles using chitosan/1-ethyl-3-(3 dimethylaminopropyl)-carbodiimide hydrochloride (EDAC) as the cross-linking system. The activity recovery of laccase reached 61.4% under the optimal conditions of MAC-CLEAs formation. The latter exhibited enhanced storage stability over one year at 4 degrees C and showed better temperature resistance compared to its soluble counterpart. The biocatalysts were properly recycled and the catalytic activity recovery was good even after a hundred and fifty batch reactions. Complete removal of pharmaceuticals like acetaminophen, diclofenac, mefenamic acid, atenolol and epoxy carbamazepine and partial removal of fenofibrate, diazepam, trimethoprim, and ketoprofen by laccase was achieved within 12h of incubation, whereas efficient removal of indometacin required the presence of mediator. PMID- 26476169 TI - Modeling of biomass fractionation in a lab-scale biorefinery: Solubilization of hemicellulose and cellulose from holm oak wood using subcritical water. AB - Lignocellulose fractionation is a key biorefinery process that need to be understood. In this work, a comprehensive study on hydrothermal-fractionation of holm oak in a semi-continuous system was conducted. The aim was to develop a physicochemical model in order to reproduce the role of temperature and water flow over the products composition. The experiments involved two sets: at constant flow (6mL/min) and two different ranges of temperature (140-180 and 240 280 degrees C) and at a constant temperature range (180-260 degrees C) and different flows: 11.0, 15.0 and 27.9mL/min. From the results, temperature has main influence and flow effect was observed only if soluble compounds were produced. The kinetic model was validated against experimental data, reproducing the total organic carbon profile (e.g. deviation of 33%) and the physicochemical phenomena observed in the process. In the model, it was also considered the variations of molecular weight of each biopolymer, successfully reproducing the biomass cleaving. PMID- 26476170 TI - The pollutants removal and bacterial community dynamics relationship within a full-scale British Gas/Lurgi coal gasification wastewater treatment using a novel system. AB - The novel system of EBA (based on external circulation anaerobic (EC) process biological enhanced (BE) process-anoxic/oxic (A/O) process) was applied to treat the British Gas/Lurgi coal gasification wastewater in Erdos, China. After a long time of commissioning, the EBA system represented a stable and highly efficient performance, particularly, the concentrations of COD, NH4(+)-N, total organic carbon, total nitrogen and volatile phenols in the final effluent reached 53, 0.3, 18, 106mg/L and not detected, respectively. Both the GC-MS and fluorescence excitation-emission matrix analyses revealed significant variations of organic compositions in the effluent of different process. The results of high-throughput sequencing represented the EBA system composed 34 main bacteria which were affiliated to 7 phyla. In addition, the canonical correspondence analysis indicated high coherence among community composition, wastewater characteristics and environmental variables, in which the pH, mixed liquid suspended solids and total phenols loading were the most three significant variables. PMID- 26476171 TI - Enhancing acetone biosynthesis and acetone-butanol-ethanol fermentation performance by co-culturing Clostridium acetobutylicum/Saccharomyces cerevisiae integrated with exogenous acetate addition. AB - Acetone is the major by-product in ABE fermentations, most researches focused on increasing butanol/acetone ratio by decreasing acetone biosynthesis. However, economics of ABE fermentation industry strongly relies on evaluating acetone as a valuable platform chemical. Therefore, a novel ABE fermentation strategy focusing on bio-acetone production by co-culturing Clostridium acetobutylicum/Saccharomyces cerevisiae with exogenous acetate addition was proposed. Experimental and theoretical analysis revealed the strategy could, enhance C. acetobutylicum survival oriented amino acids assimilation in the cells; control NADH regeneration rate at moderately lower level to enhance acetone synthesis but without sacrificing butanol production; enhance the utilization ability of C. acetobutylicum on glucose and direct most of extra consumed glucose into acetone/butanol synthesis routes. By implementing the strategy using synthetic or acetate fermentative supernatant, acetone concentrations increased to 8.27-8.55g/L from 5.86g/L of the control, while butanol concentrations also elevated to the higher levels of 13.91-14.23g/L from 11.63g/L simultaneously. PMID- 26476172 TI - Sequential Fenton oxidation and hydrothermal treatment to improve the effect of pretreatment and enzymatic hydrolysis on mixed hardwood. AB - Sequential Fenton oxidation (FO) and hydrothermal treatment were performed to improve the effect of pretreatment and enzymatic hydrolysis of mixed hardwood. The molar ratio of the Fenton reagent (FeSO4.7H2O and H2O2) was 1:25, and the reaction time was 96h. During the reaction, little or no weight loss of biomass was observed. The concentration of Fe(2+) was determined and was found to increase continuously during FO. Hydrothermal treatment at 190-210 degrees C for 10-80min was performed following FO. Sequential FO and hydrothermal treatment showed positive effects on pretreatment and enzymatic hydrolysis. Xylose concentration in the hydrolysate was as high as 14.16g/L when FO-treated biomass was treated at 190 degrees C, while its concentration in the raw material was 3.72g/L. After 96h of enzymatic hydrolysis, cellulose conversion in the biomass obtained following sequential treatment was 69.58-79.54%. In contrast, the conversion in the raw material (without FO) was 64.41-67.92%. PMID- 26476173 TI - Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed. AB - Malignant pleural mesothelioma (MPM) is an aggressive cancer that proliferates in the pleural cavity. Pemetrexed (PMX) in combination with cisplatin is currently the approved standard care for MPM, but a dismal response rate persists. Recently, we prepared various liposomal PMX formulations using different lipid compositions and evaluated their in vitro cytotoxicity against human mesothelioma cells (MSTO-211H). In the present study, we investigated the in vivo therapeutic effect of our liposomal PMX formulations using an orthotopic MPM tumor mouse model. PMX encapsulated within either cholesterol-containing (PMX/Chol CL) or cholesterol-free (PMX/Non-Chol CL) cationic liposome was intrapleurally injected into tumor-bearing mice. PMX encapsulated in cholesterol-free liposomes (PMX/Non Chol CL) drastically inhibited the tumor growth in the pleural cavity, while free PMX and PMX encapsulated in cholesterol-containing liposomes (PMX/Chol CL) barely inhibited the tumor growth. The enhanced in vivo anti-tumor efficacy of PMX/Non Chol CL was credited, on the one hand, for prolonging the retention of cationic liposomes in the pleural cavity via their electrostatic interaction with the negatively charged membranes of tumor cells, but on the other hand, it was charged with contributing to a higher drug release from the "fluid" liposomal membrane following intrapleural administration. This therapeutic strategy of direct intrapleural administration of liposomal PMX, along with the great advances in CL-guided therapeutics, might be a promising therapeutic approach to conquering the poor prognosis for MPM. PMID- 26476174 TI - Intragastric pH and pressure profiles after intake of the high-caloric, high-fat meal as used for food effect studies. AB - The intraluminal conditions of the fed stomach are critical for drug release from solid oral dosage forms and thus, often associated with the occurrence of food effects on oral bioavailability. In this study, intragastric pH and pressure profiles present after the ingestion of the high-caloric, high-fat (964 kcal) FDA standard breakfast were investigated in 19 healthy human subjects by using the telemetric SmartPill(r) capsule system (26 * 13 mm). Since the gastric emptying of such large non-digestible objects is typically accomplished by the migrating motor complex phase III activity, the time required for recurrence of fasted state motility determined the gastric emptying time (GET). Following the diet recommendations of the FDA guidance on food effect studies, the mean GET of the telemetric motility capsule was 15.3 +/- 4.7 h. Thus, the high caloric value of the standard breakfast impeded gastric emptying before lunch in 18 out of 19 subjects. During its gastric transit, the capsule was exposed to highly dynamic conditions in terms of pH and pressure, which were mainly dependent on further meal and liquid intake, as well as the intragastric capsule deposition behavior. Maximum pH values in the stomach were measured immediately after capsule intake. The median pH value of the 5 min period after capsule ingestion ranged between pH 3.3 and 5.3. Subsequently, the pH decreased relatively constantly and reached minimum values of pH 0-1 after approximately 4 h. The maximum pressure within the stomach amounted to 293 +/- 109 mbar and was clearly higher than the maximum pressure measured at the ileocaecal junction (60 +/- 35 mbar). The physiological data on the intraluminal conditions within the fed stomach generated in this study will hopefully contribute to a better understanding of food effects on oral drug product performance. PMID- 26476175 TI - Stability of ethyl glucuronide in hair reference materials after accelerated aging. AB - Two different hair reference materials, one produced from authentic hair displaying an ethyl glucuronide (EtG) content of about 25 pg/mg and one obtained by fortification of blank hair to an EtG level of 85 pg/mg were submitted to accelerated aging between 4 degrees C and 60 degrees C for periods between one and 24 months. Subsequently, the EtG content was determined in the aged samples and untreated reference samples stored at -22 degrees C under repeatability conditions following the so-called isochronous approach. The EtG content remained stable even at 40 degrees C for 24 months and at 60 degrees C over six months. This is in contrast to many organic analytes contained in trace concentrations in diverse matrices. A slight but significant increase of the recovered EtG in case of authentic hair samples having been exposed for 24 months between 4 degrees C and 60 degrees C may be due to a temperature-driven process that allows increased recoveries of the physiologically embedded EtG. PMID- 26476176 TI - Daily interactions in the parent-adult child tie: Links between children's problems and parents' diurnal cortisol rhythms. AB - Studies have established that grown children's problems affect parental well being, but a dearth of research has addressed daily interactions and biological systems that may underlie these associations. This study examined whether parents have different types of daily interactions with adult children who have problems and whether those interactions are associated with variations in parents' diurnal cortisol rhythms. Middle-aged parents (n=197) reported their interactions with adult children for seven consecutive days and provided saliva, analyzed for cortisol, three times a day (wake, 30 min after wake, bedtime) for four of those days. Parents were more likely to report negative encounters but not less likely to report positive interactions or contact with adult children who suffered from problems. Interactions with adult children who had physical-emotional problems had more immediate same day associations with cortisol whereas interactions with adult children who had lifestyle-behavioral problems had more delayed, or next day associations with cortisol. Daily interactions and their associations with the hypothalamic-pituitary-adrenal-axis may be important mechanisms by which adult children with problems negatively affect parental well-being. PMID- 26476178 TI - Cortical electroconvulsive stimulation alleviates breeding-induced prepulse inhibition deficit in rats. AB - In patients with medical-refractory schizophrenia electroconvulsive therapy (ECT), i.e., the induction of therapeutic seizures via cortical surface electrodes, is effectively used. Electroconvulsive stimulation (ECS) in rodents simulates ECT in humans and is applied to investigate the mechanisms underlying this treatment. Experimentally-induced reduced prepulse inhibition (PPI) of the acoustic startle response (ASR), i.e., the reduction of the startle response to an intense acoustic stimulus when this stimulus is shortly preceded by a weaker not-startling stimulus, serves as an endophenotype for neuropsychiatric disorders that are accompanied by disturbed sensorimotor gating, such as schizophrenia. Here we used rats selectively bred for high and low PPI to evaluate whether bifrontal cortical ECS would affect PPI. For this purpose, cortical screw electrodes were stereotactically implanted above the frontal cortex. After recovery ECS was applied for five consecutive days with stimuli of 1 ms pulse width, 100 pulses/s, 1 s duration, ranging from 5.5 mA to 10 mA. PPI of ASR was measured one day before ECS, and on days 1, 7, and 14 after the last ECS. In rats with breeding-induced low PPI ECS increased PPI one week after stimulation. In contrast, ECS decreased PPI in rats with high PPI on the first day after stimulation. The reaction to the startle impulse was reduced by ECS without difference between groups. This work provides evidence that rats with breeding induced high or low PPI could be used to further investigate the underlying mechanisms of ECT in neuropsychiatric disorders with disturbed sensorimotor gating like schizophrenia. PMID- 26476180 TI - Determination of endocrine disruptors and endogenic androgens and estrogens in rat serum by high-performance liquid chromatography-tandem mass spectrometry. AB - To simultaneously measure some targeted endocrine disruptors and several forms of sex hormones in rat serum, an accurate analytical procedure was developed. First, a comparison between a polymeric-based solid-phase extraction (SPE) and a micro extraction by packed sorbent was performed to choose the optimal method to extract and concentrate the analytes: bisphenol A, atrazine, vinclozolin metabolite, testosterone, androstenedione, estrone, estradiol, estrone-sulfate and glucuronide and estradiol-sulfate and glucuronide. The analyses were then performed by high-performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with electrospray ionisation in positive and negative modes. The protocol based on SPE was validated using the ICH/2005 guidelines. The validation demonstrated good performance in terms of linearity (R(2)>0.99), recovery (71-90%) and repeatability (relative standard deviation: 1-18%). The method was sensitive with LOQ comprised between 0.1 and 0.4 ng/ml for androgens and between 0.098 and 10.2 ng/ml for estrogens. The results obtained on the serum of rats exposed to the targeted endocrine disruptors showed the suitability of this analytical strategy. PMID- 26476179 TI - Thidoredxin-2 overexpression fails to rescue chronic high calorie diet induced hippocampal dysfunction. AB - A high calorie diet (HCD) can impair hippocampal synaptic plasticity and cognitive function in animal models. Mitochondrial thioredoxin 2 (TRX-2) is critical for maintaining intracellular redox status, but whether it can protect against HCD-induced impairment of synaptic plasticity is unknown. We found that levels of TRX-2 are reduced in the hippocampus of wild type mice maintained for 8 months on a HCD, and that the mice on the HCD exhibit impaired hippocampal synaptic plasticity (long-term potentiation at CA1 synapses) and cognitive function (novel object recognition). Transgenic mice overexpressing human TRX-2 (hTRX-2) exhibit increased resistance to diquat-induced oxidative stress in peripheral tissues. However, neither the HCD nor hTRX-2 overexpression affected levels of lipid peroxidation products (F2 isoprostanes) in the hippocampus, and hTRX-2 transgenic mice were not protected against the adverse effects of the HCD on hippocampal synaptic plasticity and cognitive function. Our findings indicate that TRX-2 overexpression does not mitigate adverse effects of a HCD on synaptic plasticity, and also suggest that oxidative stress may not be a pivotal factor in the impairment of synaptic plasticity and cognitive function caused by HCDs. PMID- 26476177 TI - Technologies for controlled, local delivery of siRNA. AB - The discovery of RNAi in the late 1990s unlocked a new realm of therapeutic possibilities by enabling potent and specific silencing of theoretically any desired genetic target. Better elucidation of the mechanism of action, the impact of chemical modifications that stabilize and reduce nonspecific effects of siRNA molecules, and the key design considerations for effective delivery systems has spurred progress toward developing clinically-successful siRNA therapies. A logical aim for initial siRNA translation is local therapies, as delivering siRNA directly to its site of action helps to ensure that a sufficient dose reaches the target tissue, lessens the potential for off-target side effects, and circumvents the substantial systemic delivery barriers. While locally injected or topically applied siRNA has progressed into numerous clinical trials, an enormous opportunity exists to develop sustained-release, local delivery systems that enable both spatial and temporal control of gene silencing. This review focuses on material platforms that establish both localized and controlled gene silencing, with emphasis on the systems that show most promise for clinical translation. PMID- 26476181 TI - Effects of repeated administration of rifampicin and isoniazid on vitamin D metabolism in mice. AB - Vitamin D deficiency is prevalent in tuberculosis (TB) patients and the anti-TB drugs, especially rifampicin (RIF) and isoniazid (INH), are associated with altered endocrine actions of vitamin D. Although it is well-known that these two drugs can affect a variety of cytochrome P450 (CYP450) activity, their influence on the CYP450 enzymes involved in vitamin D metabolism remains largely unknown. To fill this critical gap, serum vitamin D status and the expression of hepatic CYP2R1 and CYP27A1 and renal CYP27B1 and CYP24A1 were assessed in mice following 3-week exposure to 100 mg/kg/day RIF or (and) 50 mg/kg/day INH. Unexpectedly, we found either RIF or co-treatment the two drugs increased the concentrations of 25 hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), without affecting 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) status. In parallel, enhanced hepatic expressions of 25-hydroxylase enzymes, CYP2R1 and (or) CYP27A1, were found in RIF and RIF+INH groups. However, co-administration of RIF and INH inhibited the expression of CYP27B1, while inducing CYP24A1 expression. Collectively, our data firstly showed that RIF and co-treatment of RIF and INH can both enhance 25-hydroxylation and 24-hydroxylation of vitamin D, providing novel evidence for the involvement of anti-TB drugs in the metabolism of vitamin D. PMID- 26476182 TI - Synthesis of A-ring halogenated 13alpha-estrone derivatives as potential 17beta HSD1 inhibitors. AB - 13alpha-Estrone and its 3-methyl or benzyl ether were halogenated in ring A with N-bromo- or N-iodosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin as electrophile triggers. The chemo- and regioselectivities of the reactions depended greatly on the nature of the substituent on C-3. Bromination of the ethers led to 2- and 4-regioisomers. Bis-halogenation occurred only in the case of the phenolic derivative. Iodination and bromination resulted in similar products, except that the 3-benzyl ether could not be iodinated under the applied conditions. The potential inhibitory action of the new halogenated 13alpha estrones on human 17beta-hydroxysteroid dehydrogenase 1 activity was investigated via in vitro radiosubstrate incubation. Some compounds proved to be effective inhibitors, with IC50 values in the submicromolar range. PMID- 26476183 TI - Sphingosine-1-phosphate receptor 1 transmits estrogens' effects in endothelial cells. AB - We have previously reported that the steroid hormone estrogens stimulate activation of sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate (S1P) receptors in breast cancer cells. Both estrogens and S1P are potent biological modulators of endothelial function in vasculature able to activate multiple effectors, including endothelial nitric oxide synthase (eNOS). In this study we report that treatment of endothelial cells (ECs) with 17beta-estradiol (E2) resulted in a rapid, transient, and dose-dependent increase in SphK activity and increased S1P production. The effect was not reproduced by the inactive E2 analogue 17alpha-E2. Expression of the dominant-negative mutant SphK1(G82D) or transfection of SphK1-targeted siRNA in ECs caused not only a defect in SphK activation by E2, but also a significant inhibition of E2-induced activation of Akt/eNOS. Furthermore, E2 treatment induced internalization of plasma membrane S1P1 receptor, accompanied with an increase in the amount of cytosolic S1P1. By down-regulating S1P1 receptor expression, the S1P1-specific antisense oligonucleotides significantly inhibited E2-induced activation of Akt/eNOS in ECs. E2-induced EC migration and tube formation were also inhibited by S1P1 down regulation. Thus, the findings indicate an important role of the SphK1/S1P1 pathway in mediating estrogen signaling and its actions in vasculature. PMID- 26476184 TI - Polyoxygenated steroids from the gorgonian Menella woodin with capabilities to modulate ROS levels in macrophages at response to LPS. AB - Four new polyoxygenated sterol derivatives (1-4) along with the compounds (5-7) previously known from other biological sources were isolated from the gorgonian Menella woodin, collected from the Vietnamese waters. Structures of 1-4 were elucidated by the detailed NMR spectroscopic and mass-spectrometric analyses as well as comparison with those reported in literature data. Compounds 1, 4, and 6 decrease the production of reactive oxygen species (ROS) by the murine macrophages of RAW 264.7 line at induction by endotoxic lipopolysaccharide (LPS) from Escherichia coli. PMID- 26476185 TI - Solid-state NMR investigation of effect of fluorination and methylation on prednisolone conformation. AB - Prednisolone (Prd) is a polymorphous synthetic corticosteroid that has three crystalline forms mediated by different solvents. In this study, we have demonstrated that solid-state {(1)H}(13)C cross-polarization/magic angle spinning (CP/MAS) NMR spectroscopy is able to resolve the effects of methylation and fluorination on the conformation of the steroidal rings in Prd. Two compounds were chosen for the study, 6-alpha-methylprednisolone (Prd-6M) and 6-alpha fluoroprednisolone (Prd-6F). The (13)C signals of Prd-6F showed primarily doublet patterns, with splittings of 40-380 Hz, indicating multiple ring conformations, whereas the (13)C signals of Prd and Prd-6M exhibited a singlet pattern, indicating a unique conformation. Using evidence from chemical shift deviation and anisotropy analysis, we have demonstrated by solid-state NMR that Prd-6F adopts two different steroidal ring conformations that are different from that of Prd-6M, and less similar to that of unsubstituted Prd. PMID- 26476186 TI - Synthetic studies towards 1alpha-hydroxysolasodine from diosgenin and the unexpected tetrahydrofuran ring opening in the Birch reduction process. AB - The synthesis of 1alpha-hydroxysolasodine from diosgenin was attempted. The Pd/C catalyst mediated dehydrogenation of diosgenin generated the 1,4,6-trien-3-one (3), which was reacted with Ac2O in pyridine in the presence of a catalytic amount of POCl3 followed by hydrolysis to give the 22-hydroxyfurostan (4) in 65% yield. Conversion of the primary 26-OH group into the azide and simultaneously 22 OH dehydration were achieved in one step by Mitsunobu reaction. Treatment of the (25R)-26-azidofurosta-1,4,6,20(22)-tetraen-3-one (5) with chlorotrimethylsilane (TMSCl)/NaI/MeCN and cyclisation in situ provided the (22R,25R)-spirosola-1,4,6 trien-3-one (6) in good yield. Stereoselective and regioselective epoxidation of trienone (6) with 30% H2O2 and 5% NaOH in methanol gave the 1alpha,2alpha-epoxy (22R,25R)-spirosola-4,6-dien-3-one (7). Birch reduction of the epoxide (7) with Li/NH3 in THF followed by the treatment with NH4Cl, however, failed to generate the expected 1alpha-hydroxysolasodine, but provided a tetrahydrofuran ring opening product, (22S,25R)-1alpha,16beta-dihydroxy-22,26-epiminocholest-4-en-3 one (8). Compounds 3 and 5-8 as well as solasodine were evaluated for their cell growth inhibitory activities against human prostate cancer PC3, human cervical carcinoma Hela, and human hepatoma HepG2 cells. At the concentration of 10 MUM, only epoxide 7 displayed moderate inhibitory rates towards these cells (40-54%). PMID- 26476187 TI - Total (1)H NMR assignment of 3beta-acetoxypregna-5,16-dien-20-one. AB - This work describes the total and unambiguous assignment of the 750 MHz (1)H NMR spectrum of 3beta-acetoxypregna-5,16-dien-20-one or 16-DPA (1), the well-known intermediate utilized in the synthesis of biological important commercial steroids. The task was accomplished by extracting the coupling constant values in the overlapped spectrum region by HSQC, and using these values in the (1)H iterative full spin analysis integrated in the PERCH NMR software. Comparison of the experimental vicinal coupling constants of 1 with the values calculated using Altona provides an excellent correlation. The same procedure, when applied to the published data of progesterone (2) and testosterone (3), afforded an acceptable correlation for 2 and a poor correlation for 3. In the last case, this suggested the reassignment of all four vicinal coupling constants for the methylene signals at the C-15 and C-16 positions, demonstrating the utility of this methodology. PMID- 26476188 TI - Predicted structures of new Vitamin D Receptor agonists based on available X-ray structures. AB - Current efforts in the field of vitamin D are to develop 1,25(OH)2D3 analogs that exhibit equal or even increased anti-proliferative activity while possessing a reduced tendency to cause hypercalcemia. The study proposes a new, rational design of vitamin D analogs based on data available in the Protein Data Bank. Undertaken approach was to minimize the electrostatic interaction energies available after the reconstruction of charge density with the aid of the pseudoatom databank, namely the University at Buffalo Pseudoatom Databank (UBDB). Analysis of 24 vitamin D analogs, bearing similar molecular structures complexed with Vitamin D Receptor enabled the design of new agonists forming all advantageous interaction to the receptor, coded TB1, TB2, TB3 and TB4. PMID- 26476189 TI - The phosphate transporters LjPT4 and MtPT4 mediate early root responses to phosphate status in non mycorrhizal roots. AB - Arbuscular mycorrhizal (AM) symbiosis improves host plant phosphorous (P) status and elicits the expression of AM-inducible phosphate transporters (PTs) in arbuscule-containing cells, where they control arbuscule morphogenesis and P release. We confirmed such functions for LjPT4 in mycorrhizal Lotus japonicus. Promoter-GUS experiments showed LjPT4 transcription not only in arbusculated cells but also in root tips, in the absence of the fungus: here LjPT4 transcription profile depended on the phosphate level. In addition, quantitative RT-PCR confirmed the expression of Lotus and Medicago truncatula PT4 in the tips of non-mycorrhizal roots. Starting from these observations, we hypothesized that AM-inducible PTs may have a regulatory role in plant development, irrespective of the fungal presence. Firstly, we focused on root development responses to different phosphate treatments in both plants demonstrating that phosphate starvation induced a higher number of lateral roots. By contrast, Lotus PT4i plants and Medicago mtpt4 mutants did not show any differential response to phosphate levels, suggesting that PT4 genes affect early root branching. Phosphate starvation-induced genes and a key auxin receptor, MtTIR1, showed an impaired expression in mtpt4 plants. We suggest PT4 genes as novel components of the P-sensing machinery at the root tip level, independently of AM fungi. PMID- 26476190 TI - Influence of arbuscular mycorrhizal fungi and treated wastewater on water relations and leaf structure alterations of Viburnum tinus L. plants during both saline and recovery periods. AB - Nowadays, irrigation with low quality water is becoming an alternative to satisfy the needs of crops. However, some plant species have to deal with high salinity of reclaimed water, by adapting their physiological behaviour during both saline and recovery periods and developing morphological changes in their leaves. The application of arbuscular mycorrhizal fungi (AMF) could also be a suitable option to mitigate the negative effects of this kind of water, although the effectiveness of plant-AMF association is influenced by many factors. In this work, during forty weeks, the combined effect of Glomus iranicum var. tenuihypharum and two types of water: control, C, EC<0.9 dS m(-1) and reclaimed water, RW (with EC: 4 dS m(-1) during a first saline period and EC: 6 dS m(-1) during a second saline period) was evaluated for laurustinus plants (Viburnum tinus L.) transplanted in soil. This was followed by a recovery period of eight weeks, when all the plants were irrigated in the control irrigation conditions. Seasonal and daily changes in stem water potential (Psistem), stomatal conductance (gs), photosynthesis (Pn) and leaf internal CO2 concentration (Ci) of laurustinus plants were evaluated. Leaf structure alterations, nutrient imbalance, height and leaf hydraulic conductivity (Kleaf) were also determined. Due to the high difficulty of absorbing water from the soil, RW plants showed a high volumetric water content (thetav) in soil. The stem water potential and the stomatal conductance (gs) values were reduced in RW plants throughout the second saline period. These decreases were also found during the day. Leaf Ca(2+)/Na(+) and K(+)/Na(+) ratios diminished in RW plants respect to the C plants due to the Na(+) accumulation, although height and chlorophyll content values did not show statistical differences. Leaves from RW plants showed a significantly thicker mesophyll than Control leaves as a consequence of high EC. The area of palisade parenchyma (PP) increased while the area of spongy parenchyma (SP) decreased in RW leaves with respect to the C leaves. These structural changes could be considered as a strategy to maximize photosynthesis potential in saline conditions. Mycorrhizal inoculation improved the water status of both C and RW plants by increasing their Psistem and gs values. As regards leaf structure, AMF showed an opposite effect to salinity for PP and SP. At the end of the recovery period, hardly any statistical differences of physiological parameters were found between treatments, although a tendency to improve them was observed in inoculated plants. In any case, the leaf structural changes and the great reduction in Kleaf observed at Psileaf below -1.5 MPa would constitute an important mechanism for laurustinus plants to reduce the water loses produced by salinity. PMID- 26476191 TI - The MERMAID study: indoor and outdoor average pollutant concentrations in 10 low energy school buildings in France. AB - Indoor air quality was characterized in 10 recently built energy-efficient French schools during two periods of 4.5 days. Carbon dioxide time-resolved measurements during occupancy clearly highlight the key role of the ventilation rate (scheduled or occupancy indexed), especially in this type of building, which was tightly sealed and equipped with a dual-flow ventilation system to provide air refreshment. Volatile organic compounds (VOCs) and inorganic gases (ozone and NO2 ) were measured indoors and outdoors by passive techniques during the occupied and the unoccupied periods. Over 150 VOC species were identified. Among them, 27 species were selected for quantification, based on their occurrence. High concentrations were found for acetone, 2-butanone, formaldehyde, toluene, and hexaldehyde. However, these concentrations are lower than those previously observed in conventional school buildings. The indoor/outdoor and unoccupied/occupied ratios are informative regarding emission sources. Except for benzene, ozone, and NO2 , all the pollutants in these buildings have an indoor source. Occupancy is associated with increased levels of acetone, 2-butanone, pentanal, butyl acetate, and alkanes. PMID- 26476192 TI - Exploring the application of latent class cluster analysis for investigating pedestrian crash injury severities in Switzerland. AB - One of the major challenges in traffic safety analyses is the heterogeneous nature of safety data, due to the sundry factors involved in it. This heterogeneity often leads to difficulties in interpreting results and conclusions due to unrevealed relationships. Understanding the underlying relationship between injury severities and influential factors is critical for the selection of appropriate safety countermeasures. A method commonly employed to address systematic heterogeneity is to focus on any subgroup of data based on the research purpose. However, this need not ensure homogeneity in the data. In this paper, latent class cluster analysis is applied to identify homogenous subgroups for a specific crash type-pedestrian crashes. The manuscript employs data from police reported pedestrian (2009-2012) crashes in Switzerland. The analyses demonstrate that dividing pedestrian severity data into seven clusters helps in reducing the systematic heterogeneity of the data and to understand the hidden relationships between crash severity levels and socio-demographic, environmental, vehicle, temporal, traffic factors, and main reason for the crash. The pedestrian crash injury severity models were developed for the whole data and individual clusters, and were compared using receiver operating characteristics curve, for which results favored clustering. Overall, the study suggests that latent class clustered regression approach is suitable for reducing heterogeneity and revealing important hidden relationships in traffic safety analyses. PMID- 26476193 TI - Towards an explanation of age-related difficulties in crossing a two-way street. AB - Crossing a two-way street is a complex task that involves visual, cognitive and motor abilities, all of which are known to decline with ageing. In particular, older pedestrians may experience difficulties when crossing two-way streets because of incorrect gap acceptance choices and impossible or unperceived evasive actions. To understand the overrepresentation of older pedestrians in crash statistics, several experimental studies have sought to identify traffic-related factors as well as those related to the abilities of the individuals themselves. However, none of these studies has required participants to actually walk across an experimental two-way street with curbs, which is a particularly challenging situation for older pedestrians. To fill this research gap, a quasi-experiment was conducted in a simulator including a total of 58 healthy aged participants (25 younger-old [age 60-72] and 33 older-old [age 72-92]) and 25 young adults (aged 18-25 years). Participants carried out a street-crossing task in a simulated two-way traffic environment; curbs were present on both sides of the experimental street. Participants also undertook a battery of tests to assess their visual and cognitive abilities. In addition, during the experiment, the participants' gait parameters were recorded. In line with earlier findings, the older-old group of participants made a higher number of decisions that led to collisions with approaching cars compared with the other groups. The two groups of older participants experienced specific difficulties when vehicles were in the far lane or when they approached rapidly. A regression analysis identified visual acuity, speed of processing (assessed using the UFOV((r)) test), and step length as significant predictors of collisions. Our results have implications for understanding the difficulties experienced by older pedestrians and allow to draw up several recommendations for improving their safety. PMID- 26476194 TI - Speeding in urban environments: Are the time savings worth the risk? AB - Perceived time savings by travelling faster is often cited as a motivation for drivers' speeding behaviour. These time savings, however, come at a cost of significant road injuries and fatalities. While it is known that drivers tend to overestimate the time savings attributable to speeding there is little empirical evidence on how much time drivers genuinely save during day-to-day urban driving and how this relates to speeding-related crashes. The current paper reports on a study to address the lack of empirical evidence on this issue using naturalistic driving data collected from 106 drivers over a period of five weeks. The results show that the average driver saves 26s/day or 2min/week by speeding. More importantly, the cost of these time savings is one fatality for every 24,450h saved by the population on 100km/h roads in dry conditions and one injury for every 2458h saved on the same roads. Full speed compliance - and consequently a dramatic reduction in the road toll - could be achieved through almost imperceptible increases in travel time by each driver. PMID- 26476195 TI - Expanding the test set: Chemicals with potential to disrupt mammalian brain development. AB - High-throughput test methods including molecular, cellular, and alternative species-based assays that examine critical events of normal brain development are being developed for detection of developmental neurotoxicants. As new assays are developed, a "training set" of chemicals is used to evaluate the relevance of individual assays for specific endpoints. Different training sets are necessary for each assay that would comprise a developmental neurotoxicity test battery. In contrast, evaluation of the predictive ability of a comprehensive test battery requires a set of chemicals that have been shown to alter brain development after in vivo exposure ("test set"). Because only a small number of substances have been well documented to alter human neurodevelopment, we have proposed an expanded test set that includes chemicals demonstrated to adversely affect neurodevelopment in animals. To compile a list of potential developmental neurotoxicants, a literature review of compounds that have been examined for effects on the developing nervous system was conducted. The search was limited to mammalian studies published in the peer-reviewed literature and regulatory studies submitted to the U.S. EPA. The definition of developmental neurotoxicity encompassed changes in behavior, brain morphology, and neurochemistry after gestational or lactational exposure. Reports that indicated developmental neurotoxicity was observed only at doses that resulted in significant maternal toxicity or were lethal to the fetus or offspring were not considered. As a basic indication of reproducibility, we only included a chemical if data on its developmental neurotoxicity were available from more than one laboratory (defined as studies originating from laboratories with a different senior investigator). Evidence from human studies was included when available. Approximately 100 developmental neurotoxicity test set chemicals were identified, with 22% having evidence in humans. PMID- 26476196 TI - Proteomic analysis of naturally-sourced biological scaffolds. AB - A key challenge to the clinical implementation of decellularized scaffold-based tissue engineering lies in understanding the process of removing cells and immunogenic material from a donor tissue/organ while maintaining the biochemical and biophysical properties of the scaffold that will promote growth of newly seeded cells. Current criteria for evaluating whole organ decellularization are primarily based on nucleic acids, as they are easy to quantify and have been directly correlated to adverse host responses. However, numerous proteins cause immunogenic responses and thus should be measured directly to further understand and quantify the efficacy of decellularization. In addition, there has been increasing appreciation for the role of the various protein components of the extracellular matrix (ECM) in directing cell growth and regulating organ function. We performed in-depth proteomic analysis on four types of biological scaffolds and identified a large number of both remnant cellular and ECM proteins. Measurements of individual protein abundances during the decellularization process revealed significant removal of numerous cellular proteins, but preservation of most structural matrix proteins. The observation that decellularized scaffolds still contain many cellular proteins, although at decreased abundance, indicates that elimination of DNA does not assure adequate removal of all cellular material. Thus, proteomic analysis provides crucial characterization of the decellularization process to create biological scaffolds for future tissue/organ replacement therapies. PMID- 26476197 TI - Billing diagnoses do not accurately identify out-of-hospital cardiac arrest patients: An analysis of a regional healthcare system. AB - BACKGROUND: International Classification of Diseases 9th Edition's Clinical Modification (ICD-9CM) codes are frequently used in health services research. We tested the operating characteristics of ICD-9CM codes for identifying out-of hospital cardiac arrest (OHCA) subjects. METHODS: We used ICD-9CM codes to generate an "administrative cohort" of subjects treated after possible OHCA at one of six emergency departments (EDs) between January 2010 and April 2014. We performed a structured chart review to determine proportion of this administrative cohort with actual OHCA (true positive rate for the ICD-9CM-based search method). The largest study site maintains a prospective registry of consecutive OHCA subjects, which we used to construct a "registry cohort". We used this cohort to calculate the sensitivity of the ICD-9CM-based search strategy at this site, and compared in-hospital mortality and discharge dispositions between the two cohorts using Chi-square tests. RESULTS: ICD-9CM codes identified 2461 subjects that comprised the administrative cohort. Of these, the true positive rate for actual OHCA on chart review was 40%. ICD9-CM code sensitivity was 100% for subjects coded as dead on arrival and 19% for subjects coded as surviving to ED disposition. There were 609 OHCA subjects in the registry cohort and 268 subjects in the administrative cohort who presented to registry site. Only 26 subjects appeared in both cohorts. In-hospital mortality was significantly higher in the administrative cohort than the registry cohort (91% vs. 61%, p<0.001), and hospital discharge disposition of survivors was less favorable (p<0.001). Neither difference persisted after excluding subjects surviving <6h. CONCLUSION: Compared to a prospective registry, ICD-9CM codes are an insensitive method to identify OHCA subjects. Moreover, ICD-9CM codes identify a biased sample of the OHCA population with higher mortality. PMID- 26476198 TI - Treatment and outcome of out-of-hospital cardiac arrest in outpatient health care facilities. AB - AIM: We evaluated the frequency and effectiveness of basic and advanced life support (ALS) interventions by medical professionals when out-of-hospital cardiac arrest (OHCA) occurred in ambulatory healthcare clinics before emergency medical services (EMS) arrival. METHODS: Non-traumatic OHCAs in adults were systematically characterized over a 15 year period by their occurrence in clinics, at home, or in non-medical public locations, and outcomes compared between matched cohorts from each group. RESULTS: Among 7784 patients, 6098 OHCA occurred at home, 1612 in non-medical public locations and 74 in clinics. Compared to non-medical public locations, clinic patients with OHCA were older, more often women and more frequently shocked; clinic arrests were more often witnessed, less likely to be of cardiac cause and to occur before EMS arrival. Compared to home, more clinic arrests were witnessed, occurred after EMS arrival, had bystander CPR, shockable rhythms and were defibrillated. When OHCA occurred before EMS arrival, 51 of 56 clinic patients (91%) received CPR, a defibrillator applied to 23 (41%), 17 (30%) were shocked, 4 (7%) intubated, and 7 (13%) received intravenous medications from facility personnel. Of these, only pre-EMS defibrillator use was associated with improved outcome. Among matched patients, OHCA survival was higher in clinics than at home (42% vs 26%, p=0.029), but comparable to other public locations. CONCLUSIONS: Survival from OHCA in clinics was comparable to non-medical public locations, and higher than at home. Alongside CPR, use of defibrillators was associated with improved survival and worth prioritizing over other interventions before EMS arrival regardless of OHCA location. PMID- 26476199 TI - Liver Transplant in Young Adults with Chronic Hepatitis C Virus: An Argument for Hepatitis C Treatment in Childhood. AB - OBJECTIVES: We sought to assess the characteristics of hepatitis C virus-positive young adults who received a liver transplant and to evaluate posttransplant outcomes. MATERIALS AND METHODS: United Network for Organ Sharing database was conducted from 1989 to 2012, and retrospective analysis was performed on all hepatitis C virus-positive young adult patients (aged, 8-35 y) who underwent a liver transplant in the United States. RESULTS: A total of 506 hepatitis C virus subjects were included. Average age at time of transplant was 30.1 +/- 4.8 years. Median follow-up after first liver transplant was 46.1 months (13, 89.3 mo). During this time, 217 patients (42.8%) died at a mean age at the time of death of 34 +/- 6.7 years including 176/ 506 (34.8%) after the first liver transplant, 34/71 (48.6%) after the second liver transplant, and 7/8 (87.5%) after the third liver transplant. The majority (65.7%) of retransplants were performed for hepatitis C virus recurrence. A mean of 1.15 liver transplants were performed per patient. Overall, 262 subjects were transplanted in the pre-Model for End-stage Liver Disease era, and 244 were transplanted post-MELD. Younger age, higher bilirubin, higher creatinine, hepatitis C carcinoma, shorter wait time, shorter cold ischemia time, nonwhite donor race, and the use of mycophenolate mofetil were significantly more common in the post-Model for End-stage Liver Disease era (all with P < .05). Importantly, 5-year patient and graft survival were not different between the pre- and post-Model for End-stage Liver Disease era. CONCLUSIONS: Liver transplant in young adults for hepatitis C virus acquired during childhood has poor outcomes that did not improve in the post-Model for End stage Liver Disease era. These findings should prompt more aggressive evaluation and treatment for hepatitis C virus in children. PMID- 26476200 TI - Hematite nanoplates: Controllable synthesis, gas sensing, photocatalytic and magnetic properties. AB - Uniform hematite (alpha-Fe2O3) nanoplates exposing {001} plane as basal planes have been prepared by a facile solvothermal method under the assistance of sodium acetate. The morphological evolution of the nanoplates was studied by adjusting the reaction parameters including the solvent and the amount of sodium acetate. The results indicated that both the adequate nucleation/growth rate and selective adsorption of alcohol molecules and acetate anions contribute to the formation of the plate-like morphology. In addition, the size of the nanoplates can be adjusted from ca. 180nm to 740nm by changing the reaction parameters. Three nanoplate samples with different size were selected to investigate the gas sensing performance, photocatalytic and magnetic properties. As gas sensing materials, all the alpha-Fe2O3 nanoplates exhibited high gas sensitivity and stability toward n-butanol. When applied as photocatalyst, the alpha-Fe2O3 nanoplates show high photodegradation efficiency towards RhB. Both the gas sensing performance and the photocatalytic property of the products exhibit obvious size-dependent effect. Magnetic measurements reveal that the plate-like alpha-Fe2O3 particles possess good room temperature magnetic properties. PMID- 26476201 TI - Ion-ion correlation, solvent excluded volume and pH effects on physicochemical properties of spherical oxide nanoparticles. AB - One major source of complexity in the implementation of nanoparticles in aqueous electrolytes arises from the strong influence that biological environments has on their physicochemical properties. A key parameter for understanding the molecular mechanisms governing the physicochemical properties of nanoparticles is the formation of the surface charge density. In this article, we present an efficient and accurate approach that combines a recently introduced classical solvation density functional theory for spherical electrical double layers with a surface complexation model to account for ion-ion correlation and excluded volume effects on the surface titration of spherical nanoparticles. We apply the proposed computational approach to account for the charge-regulated mechanisms on the surface chemistry of spherical silica (SiO2) nanoparticles. We analyze the effects of the nanoparticle size, as well as pH level and electrolyte concentration of the aqueous solution on the nanoparticle's surface charge density and Zeta potential. We validate our predictions for 580A and 200A nanoparticles immersed in acid, neutral and alkaline mono-valent aqueous electrolyte solutions against experimental data. Our results on mono-valent electrolyte show that the excluded volume and ion-ion correlations contribute significantly to the surface charge density and Zeta potential of the nanoparticle at high electrolyte concentration and pH levels, where the solvent crowding effects and electrostatic screening have shown a profound influence on the protonation/deprotonation reactions at the liquid/solute interface. The success of this approach in describing physicochemical properties of silica nanoparticles supports its broader application to study other spherical metal oxide nanoparticles. PMID- 26476202 TI - Nano interfaced biosensor for detection of choline in triple negative breast cancer cells. AB - Choline, a type of Vitamin B, is an important nutrient in the human body and is involved in key metabolic pathways. Abnormal levels of choline leads to diseased conditions. The levels of choline and its associated compounds are found to be elevated in triple negative breast cancer (TNBC) patients. The choline level ranges from 0.4 to 4.9mmol/kg in TNBC. Thus the detection of choline levels in cells can aid in diagnosing breast cancer. The present work aims to develop a nano-interfaced electrochemical biosensor for the rapid detection of choline in cancer cells. For electrochemical detection, glassy carbon electrode coated with a zinc oxide nano-interface was used as the working electrode. Zinc oxide synthesized by hydrothermal method was characterized using SEM and XRD. The choline oxidase (ChOx) enzyme was immobilized on the nano-interface by drop casting. Choline oxidase (ChOx) converts choline to betaine and H2O2 in the presence of oxygen. The H2O2 produced was determined amperometrically. The amount of H2O2 produced is directly proportional to concentration of choline present. The sensitivity, selectivity, stability and concentration studies were carried out and quantification of choline in TNBC was also carried out. The results demonstrate that this biosensor has the potential to be developed as a clinical tool for breast cancer detection. PMID- 26476203 TI - Gold nanostars: Benzyldimethylammonium chloride-assisted synthesis, plasmon tuning, SERS and catalytic activity. AB - Fabrication of Au nanostars (AuNSs) can expand the application range of Au nanoparticles because of their high electron density and localized surface plasmon resonance (LSPR) on branches. Exploiting this potential requires further refinement of length of the branches and radius of their tips. To this end, we successfully synthesized AuNSs with uniform and sharply-pointed branches by combining benzyldimethylammonium chloride (BDAC) and cetyltrimethylammonium bromide (CTAB) at low BDAC/CTAB ratios. Once mixed with CTAB, BDAC lowers the critical micelle concentration (CMC) for quick formation of the micelles, which provides favorable growth templates for AuNSs formation. Besides, BDAC increases the concentration of Cl(-), which favors Ag(+) in adsorbing on Au facets. This feature is crucial for the yield boosting and synergic shape control of AuNSs regardless of types of Au seeds used. Use of less amounts of seeds as the center of nucleation benefited sharper and longer growth of the branches. AuNSs exhibited excellent enhancement of surface-enhanced Raman scattering (SERS) intensities as the result of high electron density localized at the tips; however, the enhancement degree varied in accordance with the size of branches. In addition, AuNSs showed high catalytic performance toward the reduction of 4 nitrophenol (4-NP) to 4-aminophenol (4-AP). Efficient catalysis over AuNSs originates from their corners, stepped surfaces and high electron density at the tips. PMID- 26476204 TI - KIR2DS4 and Its Variant KIR1D Are Associated with Acute Graft-versus-Host Disease, Cytomegalovirus, and Overall Survival after Sibling-Related HLA-Matched Transplantation in Patients with Donors with KIR Gene Haplotype A. AB - Outcomes for hematopoietic stem cell transplantation (HSCT) in various donor and recipient killer immunoglobulin-like receptor (KIR) genotypes have been studied extensively. The associations between KIR2DS4 and its variant KIR1D with outcomes of HSCT from a sibling-related HLA-matched donor with KIR haplotype A have not been explored, however. To study this, we genotyped donor-recipient pairs and divided 165 recipients of HSCT from a KIR gene haplotype A donor into 3 groups: 2DS4+/2DS4+ (2 intact KIR2DS4 alleles), 2DS4+/1D+ (heterozygous), and 1D+/1D+ (homozygous for the deletion variant KIR1D). No difference in the recovery of neutrophils and platelets among the 3 groups was observed. The cumulative incidence of grade III-IV acute graft-versus-host disease (aGVHD) within day +100 was 28.94% in the 2DS4+/2DS4+ group, 14.11% in the 2DS4+/1D+ group, and 44.44% in the 1D+/1D+ group (P = .0159). Multivariate analysis identified 1D+/1D+ as an independent risk factor for aGVHD (hazard ratio [HR], 4.221; 95% confidence interval [CI], 1.470 to 12.124; P = .007). In contrast, the cumulative incidences of chronic GVHD, 3-year cumulative relapse, and treatment-related mortality did not differ significantly among the 3 groups. The rate of cytomegalovirus (CMV) reactivation was 46.96% in the 2DS4+/2DS4+ group, 20.16% in the 2DS4+/1D+ group, and 53.25% in the 1D+/1D+ group (P = .0017). Multivariate analysis identified 2DS4+/1D+ as an independent protective factor for CMV reactivation (HR, 0.268; 95% CI, 0.125 to 0.574; P = .001). Although overall survival (OS) did not differ among the groups in the first year, the 2DS4(+)/2DS4(+) group had significantly better OS than the other groups after 1 year (P = .0361). In patients with advanced-stage disease, the 3-year probability of disease-free survival was 51.06% in the 2DS4+/2DS4+ group, 34.01% in the 2DS4+/1D+ group, and 0% in the 1D+/1D+ group (P = .0314). Collectively, our data suggest that the KIR 2DS4/1D allelic variance is associated with the outcome of sibling-related HLA-matched HSCT, and that donor subclassification of KIR 2DS4/1D alleles should be considered in this setting. PMID- 26476205 TI - Comparison of Outcomes of 8/8 and 7/8 Allele-Matched Unrelated Bone Marrow Transplantation and Single-Unit Cord Blood Transplantation in Adults with Acute Leukemia. AB - To investigate an up-to-date alternative donor selection strategy, we compared the transplantation outcomes of 8/8 and 7/8 allele-matched unrelated bone marrow transplantation (UBMT) with those of umbilical cord blood transplantation (UCBT) and redefined the role of UCBT with extended analysis. Using Cox and competing risk regression analyses, we analyzed the transplantation outcomes in adult patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). A total of 2472 first myeloablative transplantations between 2000 and 2010 were included (8/8 UBMT, 1001; 7/8 UBMT, 656; UCBT, 815). For acute and chronic graft-versus-host disease (GVHD) and nonrelapse mortality (NRM), we applied the combined analyses including both AML and ALL data. In the multivariate analyses, severe acute GVHD and NRM after UCBT were comparable with 8/8 UBMT, whereas those after 7/8 UBMT were significantly higher. The incidence of extensive chronic GVHD was significantly lower with UCBT compared with after 8/8 and 7/8 UBMT. With adjusted analyses for AML, UCBT and 8/8 UBMT showed similar overall survival (OS), whereas 7/8 UBMT showed inferior OS. For ALL, we found no significant difference in OS among the 3 groups. Cord blood may be the first choice alternative to 8/8 UBMT for both AML and ALL. PMID- 26476206 TI - Quantitative and Functional Phosphoproteomic Analysis Reveals that Ethylene Regulates Water Transport via the C-Terminal Phosphorylation of Aquaporin PIP2;1 in Arabidopsis. AB - Ethylene participates in the regulation of numerous cellular events and biological processes, including water loss, during leaf and flower petal wilting. The diverse ethylene responses may be regulated via dynamic interplays between protein phosphorylation/dephosphorylation and ubiquitin/26S proteasome-mediated protein degradation and protease cleavage. To address how ethylene alters protein phosphorylation through multi-furcated signaling pathways, we performed a (15)N stable isotope labelling-based, differential, and quantitative phosphoproteomics study on air- and ethylene-treated ethylene-insensitive Arabidopsis double loss of-function mutant ein3-1/eil1-1. Among 535 non-redundant phosphopeptides identified, two and four phosphopeptides were up- and downregulated by ethylene, respectively. Ethylene-regulated phosphorylation of aquaporin PIP2;1 is positively correlated with the water flux rate and water loss in leaf. Genetic studies in combination with quantitative proteomics, immunoblot analysis, protoplast swelling/shrinking experiments, and leaf water loss assays on the transgenic plants expressing both the wild-type and S280A/S283A-mutated PIP2;1 in the both Col-0 and ein3eil1 genetic backgrounds suggest that ethylene increases water transport rate in Arabidopsis cells by enhancing S280/S283 phosphorylation at the C terminus of PIP2;1. Unknown kinase and/or phosphatase activities may participate in the initial up-regulation independent of the cellular functions of EIN3/EIL1. This finding contributes to our understanding of ethylene-regulated leaf wilting that is commonly observed during post-harvest storage of plant organs. PMID- 26476207 TI - ABO incompatible renal transplants and decreased likelihood for developing immune responses to HLA and kidney self-antigens. AB - Immune responses to HLA and tissue-restricted self-antigens (SAgs) have been proposed to play a role in the pathogenesis of renal allograft (KTx) rejection. However, ABO incompatible (ABOi) KTx recipients (KTxR) following depletion of antibodies (Abs) to blood group antigens had fewer rejections. To determine the mechanisms, pre- and post-transplant sera from ABOi (n=18) and ABO-compatible (ABOc) (n=45) KTxR were analyzed for Abs against HLA class I and II by LABScreen single antigen assay. The development of Abs to SAgs was measured by ELISA. Immunity to Collagen IV (Col-IV) and cytokines induced were measured by ELISPOT. While 8/45 (18%) ABOc KTxR developed new donor specific antibodies to HLA (DSA) following transplantation, 0/18 ABOi KTxR developed DSA. ABOi KTxR failed to develop Abs to kidney SAgs (Col-IV and fibronectin (FN)). In contrast, 7 ABOc KTxR developed Abs to both Col-IV and FN. Col-IV stimulation of lymphocytes from ABOc KTxR demonstrated increased IFNgamma, IL-17 and decreased IL-10. In contrast ABOi recipients following stimulation with antigens resulted in more IL10 and reduced IFN-gamma and IL17 production. At one year, the GFR in ABOi KTxR were significantly better (p<0.04) than ABOc KTxR. De novo DSA and immune responses to SAgs are reduced or absent in ABOi KTxR which we propose leads to less acute rejection and better long term function following ABOi KTx. PMID- 26476209 TI - Resource type influences the effects of reserves and connectivity on ecological functions. AB - Connectivity is a pivotal feature of landscapes that affects the structure of populations and the functioning of ecosystems. It is also a key consideration in conservation planning. But the potential functional effects of landscape connectivity are rarely evaluated in a conservation context. The removal of algae by herbivorous fish is a key ecological function on coral reefs that promotes coral growth and recruitment. Many reef herbivores are harvested and some use other habitats (like mangroves) as nurseries or feeding areas. Thus, the effects of habitat connectivity and marine reserves can jointly promote herbivore populations on coral reefs, thereby influencing reef health. We used a coral reef seascape in eastern Australia to test whether seascape connectivity and reserves influence herbivory. We measured herbivore abundance and rates of herbivory (on turf algae and macroalgae) on reefs that differed in both their level of connectivity to adjacent mangrove habitats and their level of protection from fishing. Reserves enhanced the biomass of herbivorous fish on coral reefs in all seascape settings and promoted consumption of turf algae. Consumption of turf algae was correlated with the biomass of surgeonfish that are exploited outside reserves. By contrast, both reserve status and connectivity influenced herbivory on macroalgae. Consumption of macroalgae was greatest on fished reefs that were far from mangroves and was not strongly correlated with any fish species. Our findings demonstrate that landscape connectivity and reserve status can jointly affect the functioning of ecosystems. Moreover, we show that reserve and connectivity effects can differ markedly depending on resource type (in this case turf algae vs. macroalgae). The effectiveness of conservation initiatives will therefore depend on our ability to understand how these multiple interactive effects structure the distribution of ecological functions. These findings have wider implications for the spatial conservation of heterogeneous environments and strengthen the case that the impact of conservation on ecosystem functioning is contingent on how reserves are positioned in landscapes. PMID- 26476208 TI - Protective effect of HLA-DQB1 alleles against alloimmunization in patients with sickle cell disease. AB - BACKGROUND: Alloimmunization or the development of alloantibodies to Red Blood Cell (RBC) antigens is considered one of the major complications after RBC transfusions in patients with sickle cell disease (SCD) and can lead to both acute and delayed hemolytic reactions. It has been suggested that polymorphisms in HLA genes, may play a role in alloimmunization. We conducted a retrospective study analyzing the influence of HLA-DRB1 and DQB1 genetic diversity on RBC alloimmunization. STUDY DESIGN: Two-hundred four multi-transfused SCD patients with and without RBC-alloimmunization were typed at low/medium resolution by PCR SSO, using IMGT-HLA Database. HLA-DRB1 and DQB1 allele frequencies were analyzed using logistic regression models, and global p-value was calculated using multiple logistic regression. RESULTS: While only trends towards associations between HLA-DR diversity and alloimmunization were observed, analysis of HLA-DQ showed that HLA-DQ2 (p=0.02), -DQ3 (p=0.02) and -DQ5 (p=0.01) alleles were significantly higher in non-alloimmunized patients, likely behaving as protective alleles. In addition, multiple logistic regression analysis showed both HLA-DQ2/6 (p=0.01) and HLA-DQ5/5 (p=0.03) combinations constitute additional predictor of protective status. CONCLUSION: Our data suggest that particular HLA-DQ alleles influence the clinical course of RBC transfusion in patients with SCD, which could pave the way towards predictive strategies. PMID- 26476210 TI - Clinical risk factors for death after release from prison in Washington State: a nested case-control study. AB - BACKGROUND AND AIMS: While mortality rates after prison release are high, little is known about clinical risk factors for death. We sought to identify risk and protective factors for all-cause and accidental poisoning (overdose) death. DESIGN: Nested case-control study of people released from prison. SETTING: Washington State Department of Corrections, Washington, USA. PARTICIPANTS: Cases (699 all-cause deaths, of which 88 were among women, and 196 additional overdose deaths, of which 76 were among women) between 1999 and 2009 matched 1 : 1 to controls on sex, age and year of release using risk set sampling. MEASUREMENTS: Prison medical charts were abstracted for clinical information. Independent associations between clinical characteristics and all-cause and overdose mortality were assessed using conditional logistic regression. FINDINGS: Key independent risk factors for all-cause mortality included homelessness [odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.06, 2.23], injection drug use (OR = 1.54, 95% CI = 1.16, 2.06), tobacco use (OR = 1.51, 95% CI = 1.07, 2.13), cirrhosis (OR = 4.42, 95% CI = 1.63, 11.98) and psychiatric medications before release (OR = 2.38, 95% CI = 1.71, 3.30). Independent risk factors for overdose mortality included substance use disorder (OR = 2.33, 95% CI = 1.32, 4.11), injection drug use (OR = 2.43, 95% CI = 1.53, 3.86), panic disorder (OR = 3.87, 95% CI = 1.62, 9.21), psychiatric prescriptions before release (OR = 2.44, 95% CI = 1.55, 3.85) and problems with opiates/sedatives (OR = 2.81, 95% CI = 1.40, 5.63). Substance use disorder treatment during the index incarceration was protective for all-cause (OR = 0.67, 95% CI = 0.49, 0.91) and overdose (OR = 0.57, 95% CI = 0.36, 0.90) mortality. CONCLUSIONS: Injection drug use and substance use disorders are risk factors for death after release from prison. In prison substance use disorder treatment services may reduce the risk. PMID- 26476211 TI - Optical Coherence Tomography Angiography in Retinal Vein Occlusion: Evaluation of Superficial and Deep Capillary Plexa. AB - PURPOSE: To evaluate the optical coherence tomography angiography (OCT angiography) appearance of the superficial and deep capillary plexa in eyes with retinal vein occlusion (RVO) and to compare these findings with those of fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD OCT). DESIGN: Retrospective observational case series. METHODS: Patients presenting with RVO to Creteil University Eye Clinic were retrospectively evaluated. All patients had undergone a comprehensive ophthalmic examination including FA, SD OCT, and OCT angiography. RESULTS: There were 54 (31 male, 57%) RVO patients with a mean age of 70 years. The perifoveal capillary arcade was visible in 52 of 54 eyes (96%) on OCT angiography and in 45 eyes (83%) on FA; this arcade was disrupted in 48 eyes (92%) and 39 eyes (72%) on OCT angiography and FA, respectively (P = .002). Perifoveal capillary arcade disruption was correlated with peripheral retinal ischemia (P = .025). Intraretinal cystoid spaces were observed in 34 eyes (68%) using FA, in 40 eyes (76%) using SD OCT, and in 49 eyes (90%) using OCT angiography (P = .008 for OCT angiography vs SD OCT and P = .001 for OCT angiography vs FA). Retinal capillary network abnormalities were observed in all patients in both superficial capillary plexus and deep capillary plexus on OCT angiography. Nonperfusion grayish areas were more frequent in the deep capillary plexus (43 eyes, 84%) than in the superficial capillary plexus (30 eyes, 59%, P < .001). CONCLUSION: OCT angiography can simultaneously evaluate both macular perfusion and edema. For the first time, an imaging technique enables the evaluation of the deep capillary plexus, which appears to be more severely affected than the superficial capillary plexus in RVO. PMID- 26476212 TI - Evaluation of Objective Vitritis Grading Method Using Optical Coherence Tomography: Influence of Phakic Status and Previous Vitrectomy. AB - PURPOSE: To evaluate a proposed method for objective measurement of vitreous inflammation using a spectral-domain optical coherence tomography (SD OCT) device in a large cohort of uveitis eyes, including pseudophakic eyes and vitrectomized eyes. DESIGN: Retrospective, observational cohort study. METHODS: One hundred five uveitis eyes (105 patients) with different vitreous haze score grades according to standardized protocols and corresponding SD OCT images (Cirrus HD OCT; Carl Zeiss Meditec, Dublin, California, USA) were included. Clinical data recorded included phakic status, previous vitreoretinal surgery, and anterior chamber (AC) cells and flare. SD OCT images were analyzed using custom software that provided absolute measurements of vitreous (VIT) and retinal pigment epithelium (RPE) signal intensities, which were compared to generate a relative optical density ratio with arbitrary units (VIT/RPE-relative intensity) and compared to VHS. RESULTS: VIT/RPE-relative intensity showed a significant positive correlation with vitreous haze score (r = 0.535, P < .001) that remained significant after adjusting for factors governing media clarity, such as AC cells, AC flare, and phakic status (R(2)-adjusted = 0.424, P < .001). Significant differences were also observed between the different vitreous haze score groups (P < .001). Preliminary observation did not observe differences in VIT/RPE relative intensity values between phakic and pseudophakic eyes (0.3522 vs 0.3577, P = .48) and between nonvitrectomized and vitrectomized eyes (0.3540 vs 0.3580, P = .52), overall and respectively for each vitreous haze score subgroup. CONCLUSIONS: VIT/RPE-relative intensity values provide objective measurements of vitreous inflammation employing an SD OCT device. Phakic status and previous vitrectomy surgery do not appear to influence these values, although these preliminary findings need validation in future studies. PMID- 26476213 TI - Clinical Clues to Predict the Presence of Parafoveal Scotoma on Humphrey 10-2 Visual Field Using a Humphrey 24-2 Visual Field. AB - PURPOSE: To investigate characteristics related to the presence of parafoveal scotoma on Humphrey 10-2 visual field (VF) in early glaucoma patients. DESIGN: Prospective, cross-sectional study. METHODS: participants: Ninety-one eyes from 91 patients with glaucomatous optic neuropathy were prospectively tested with a 10-2 VF test. OBSERVATION PROCEDURES: Glaucoma patients were classified into eyes with or without parafoveal scotoma on 10-2 VF based on pattern deviation plot. The central 10 degree region of Humphrey 24-2 VF test comprised 12 points and any abnormal VF points depressed <5%, <2%, <1%, or <0.5% from the normal database on pattern deviation plot were analyzed. Various factors related to the presence of parafoveal scotoma on 10-2 VF were analyzed. MAIN OUTCOME MEASURES: Abnormal 24-2 VF points, macular ganglion cell-inner plexiform layer thickness. RESULTS: The presence of abnormal 24-2 VF points <0.5% was significantly different between eyes with and without parafoveal scotoma on 10-2 VF (P < .01). The minimum macular ganglion cell-inner plexiform layer thickness (P = .04), any central 12 points depressed <0.5% on 24-2 VF (P < .01), and any central 12 points depressed <5% on 24-2 VF that spatially corresponds to macular ganglion cell-inner plexiform layer thinning (P < 0.01) were related factors to the presence of parafoveal scotoma on 10-2 VF. CONCLUSIONS: Glaucomatous eyes with any abnormal 24-2 VF points on the central 10 degree region that are depressed <0.5% or <5% that correlates to macular ganglion cell-inner plexiform layer thinning should receive attention and be further evaluated with a 10-2 VF test. PMID- 26476214 TI - Microchidia protein 2, MORC2, downregulates the cytoskeleton adapter protein, ArgBP2, via histone methylation in gastric cancer cells. AB - ArgBP2 is an adapter protein that plays an important role in actin-dependent processes such as cell adhesion and migration. However, its function and regulation mechanisms in gastric cancer have not yet been investigated. Here, we showed the low expression of ArgBP2 mRNA level in gastric tumor samples and its repressive function in the proliferation, migration, and invasion of gastric cancer cells. Then, we cloned and identified ArgBP2 promoter and verified that MORC2 bound to the promoter. Moreover, we demonstrated that MORC2 enhanced the recruitment of EZH2, which promoted the tri-methylation of H3K27, leading to the transcriptional repression of ArgBP2. Our results might thus contribute to understanding the molecular mechanisms of ArgBP2 regulation and suggesting ArgBP2 as a potential therapeutic target for gastric cancer. PMID- 26476215 TI - HspA1A, a 70-kDa heat shock protein, differentially interacts with anionic lipids. AB - HspA1A, a 70-kDa heat shock protein, binds to specific lipids. This interaction allows HspA1A to associate with the plasma and other cellular membranes, where it regulates many vital functions like immunity, membrane stabilization, autophagy, and apoptosis. However, the molecular mechanism of the HspA1A-lipid interactions has yet to be fully characterized. Therefore, in this study, we characterized the interaction of HspA1A with three lipids, bis-(monoacylglycero)-phosphate, cardiolipin, and sulfatide. Our results revealed that, first, HspA1A embeds in membranes when bound to liposomes composed of cardiolipin and sulfatide. Second, the binding of HspA1A to lipids is complex and although important, electrostatic interactions alone cannot fully explain the observed binding. Third, the two HspA1A domains, the nucleotide-binding domain and the substrate-binding domain, differentially bind to lipids in a lipid-specific manner. Fourth, HspA1A lipid binding is reduced by the presence of nucleotides, but it is unaffected by the presence of a peptide-substrate. These observations suggest that HspA1A binds to lipids via a multi-step mechanism and this interaction depends on the specific physicochemical properties of the lipid. We speculate that the association of HspA1A with lipids like the mitochondrial cardiolipin, which is an organelle marker, may facilitate the translocation and localized function of the molecular chaperone to particular sub-cellular compartments. PMID- 26476216 TI - Transcriptional factors p300 and MRTF-A synergistically enhance the expression of migration-related genes in MCF-7 breast cancer cells. AB - The transcriptional coactivator p300 is highly expressed in breast cancer tissues. MRTF-A is a transcription factor governed by the Rho-GTPase-actin signaling pathway. The purpose of this study was to explore the role of p300 in breast cancer metastasis. Here we showed that the motility of breast cancer cells was enhanced by the overexpression of p300, meanwhile, the transcription of migration-related genes was upregulated. Depletion of p300 downregulated the migration-related genes and slowed down the migration of breast cancer cells. p300 worked synergistically with MRTF-A to activate the transcription of MYH9, MYL9 and CYR61. As identified by co-IP, p300 interacted with the C-terminal TAD domain of MRTF-A. And together with MRTF-A, p300 was associated with the target gene promoters. Furthermore, MRTF-A was found to be acetylated in MCF-7 breast cancer cells. These results demonstrated the involvement of p300 in the MRTF-A mediated gene regulation and breast cancer cell migration. PMID- 26476217 TI - Evaluation of water content around airway in obstructive sleep apnea patients using peripharyngeal mucosal T2 magnetic resonance imaging. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is common sleep disorder characterized by repetitive episodes of airway closure which usually occurs in the retropalatal region of the oropharynx. It has been known that upper airway mucosa in OSA patients is described as edematous, but not fully clarified. OBJECTIVES: This study aimed to investigate and establish magnetic resonance imaging (MRI) parameter to estimate tissue water content at retropalatal level and its relationship with sleep parameters in OSA patients. METHODS: Forty-eight subjects with OSA underwent overnight polysomnography and cervical MRI with 1.5 tesla [mean (SD) age 55 (14) years and apnea-hypopnea index (AHI) 45.2 (26.1) events/hour, 79.2% male]. On the axial T2-weighted images from epipharynx to oropharynx, the signal intensities of masseter muscle and peripharyngeal mucosa [T2 mucous-to-masseter intensity ratio (T2MMIR)], was used as water content estimation in the retropalatal region. Partial correlation analysis was performed to examine the correlation between T2MMIR and polysomnography parameters. RESULTS: We found that there were strong and positive correlations between the T2MMIR and AHI (r = 0.545, P < 0.05), supine AHI (r = 0.553, P < 0.05) and REM AHI (r = 0.640, P < 0.01) by partial correlation analysis. Besides, in patients with less efficient sleep who had more stage 1 sleep, significantly higher T2MMIR was noted (r = 0.357, P < 0.05). CONCLUSIONS: This study confirmed that peripharyngeal T2MMIR can be a simple parameter representing peripharyngeal tissue water contents related to severe OSA. PMID- 26476219 TI - Clinical Features and Diagnostic Considerations in Psoriatic Arthritis. AB - Psoriatic arthritis is an inflammatory musculoskeletal disease affecting almost a third of patients with psoriasis. Clinical presentations are complex and varied and include peripheral arthritis, axial disease, dactylitis, and enthesitis, as well as skin and nail manifestations. We lack diagnostic biomarkers, but specific clinical and imaging features distinguish psoriatic arthritis from other forms of arthritis such as rheumatoid arthritis, gout, osteoarthritis, and other forms of spondyloarthritis. PMID- 26476220 TI - Natural History, Prognosis, and Socioeconomic Aspects of Psoriatic Arthritis. AB - Although early reports suggested psoriatic arthritis was, with the exception of arthritis mutilans, a relatively mild arthritis, later studies have challenged this view. The burden of skin disease adds to disability and impaired quality of life. Patients in secondary care manifest increased morbidity and mortality, mainly owing to cardiovascular disease. A subset of patients, primarily men with oligoarticular disease, demonstrates low levels of joint involvement without disability. The socioeconomic impact of the disease is significant. We require more information on the impact of early diagnosis and treatment on outcome, according to phenotype, to guide policy. PMID- 26476221 TI - Imaging in Psoriatic Arthritis. AB - Psoriatic arthritis (PsA) is an inflammatory joint disease characterized by arthritis and often enthesitis in patients with psoriasis, presenting a wide range of manifestations in various patterns. Imaging procedures are primarily conventional radiography, ultrasonography (US), and magnetic resonance imaging (MRI); other modalities such as computed tomography are not used routinely. Imaging is an integral part of management of PsA. In this article, we provide an overview of the status, virtues, and limitations of imaging modalities in PsA, focusing on radiography, US, and MRI. PMID- 26476222 TI - Early Psoriatic Arthritis. AB - Skin psoriasis is a major risk factor for the development of psoriatic arthritis. Recent studies have shown that delayed diagnosis is associated with long-term adverse outcomes. Screening questionnaires have revealed a potential burden of undiagnosed disease. Lifestyle factors and genetic and soluble biomarkers have come under scrutiny as risk factors. Imaging modalities may have an important role in detecting early change. With more effective treatments, it may be possible to prevent significant joint damage and associated disability. However, the precise nature of accurate and cost-effective screening strategies remains to be determined. PMID- 26476218 TI - The Epidemiology of Psoriatic Arthritis. AB - Psoriatic arthritis (PsA) is a chronic systemic inflammatory disorder characterized by joint and entheseal inflammation with a prevalence of 0.05% to 0.25% of the population and 6% to 41% of patients with psoriasis. PsA is a highly heterogeneous inflammatory arthritis. In this review, current knowledge is discussed regarding the epidemiology of PsA, including disease manifestations, classification criteria for adult and juvenile PsA, methods for recognizing early PsA, including use of screening tools and knowledge of risk factors for PsA, and medical comorbidities associated with PsA. PMID- 26476223 TI - Genetic, Epigenetic and Pharmacogenetic Aspects of Psoriasis and Psoriatic Arthritis. AB - There is a strong familial component to psoriatic disease as well as a complex array of genetic, immunologic, and environmental factors. The dominant genetic effect is located on chromosome 6p21.3 within the major histocompatibility complex region, accounting for one-third of genetic contribution. Genome-wide association studies (GWAS) identified additional genes, including skin barrier function, innate immune response, and adaptive immune response genes. To better understand disease susceptibility and progression requires replication in larger cohorts, fine-mapping efforts, new technologies, and functional studies of genetic variants, gene-gene interactions and gene-environmental interactions. New technologies available include next-generation sequencing, copy number variation analysis, and epigenetics. PMID- 26476224 TI - Etiology and Pathogenesis of Psoriatic Arthritis. AB - The current model of psoriatic arthritis implicates both the IL-23/IL-17 axis and the tumor necrosis factor (TNF) pathways in disease pathogenesis. Although specific major histocompatibility complex class I molecules are associated with the psoriatic disease phenotype, no specific antigen or autoantibody has been identified. Instead, an array of genes may code for an autoinflammatory loop, potentially activated by mechanical stress and dysbiosis in the skin or gut. Danger signals released by innate immune cells activate a Th1 and Th17 response that leads to synovitis, enthesitis, axial inflammation, and altered bone homeostasis characterized by pathologic bone resorption and new bone formation. PMID- 26476225 TI - Etiology and Pathogenesis of Psoriasis. AB - Psoriasis is a common, chronic inflammatory skin disease most often appearing in the form of well-demarcated, scaly plaques. These lesions highlight the fundamental processes underlying its pathogenesis, namely, inflammation and epidermal hyperproliferation. Both phenomena are considered consequences of an intimate interplay between the innate and the adaptive immune system. This concept is supported by results of genetic studies, pointing toward the signaling pathways of nuclear factor-kappaB, interferon-gamma, and interleukin (IL)-23 as well as antigen presentation as central axes of the psoriatic inflammation. Efficacy of biologics targeting tumor necrosis factor-alpha, IL-23, or IL-17 provides further evidence in favor of this model. PMID- 26476226 TI - Comorbidities in Psoriatic Arthritis. AB - Epidemiologic studies have shown that, in patients with psoriatic arthritis (PsA), associated comorbidities may occur more frequently than expected. This article discusses related comorbidities in patients with PsA. Identifying these comorbidities may affect the management and treatment decisions for these patients to ensure an optimal clinical outcome. All health care providers caring for patients with PsA should be aware of the relevant comorbidities and should have an understanding of how these comorbidities affect management. The common comorbidities include cardiovascular disease, metabolic syndrome, obesity, diabetes, fatty liver disease, inflammatory bowel disease, ophthalmic disease, kidney disease, osteoporosis, depression, and anxiety. PMID- 26476227 TI - Outcome Measures in Psoriatic Arthritis. AB - In the last decade, there have been significant advances in outcome measure research in psoriatic arthritis (PsA). In this article, the outcome measures for disease activity in individual key domains of PsA are reviewed, followed by the key patient-reported outcome measures of function, quality of life, fatigue, and a new measure for disease impact, the psoriatic arthritis impact of disease. New research into composite measures of psoriatic disease is summarized, including response measures and proposed cutoff points for disease activity. Finally, the key future issues in outcome measurement in PsA are addressed. PMID- 26476228 TI - Management of Psoriatic Arthritis: Traditional Disease-Modifying Rheumatic Agents and Targeted Small Molecules. AB - Traditional disease-modifying antirheumatic drugs (DMARD) remain the first-line treatment of psoriatic arthritis (PsA), despite lack of randomized controlled trials, and with evidence based on observational studies. Anti-tumor necrosis factor agents remain a top choice for biologic treatment, complemented with new biologics with different targets (IL12-23 and IL17). Unmet needs have been identified for patients who do not respond to treatment. Among targeted small molecules Apremilast is approved for the treatment of PsA and Tofactitinib is under investigation. The drugs discussed herein have the potential to address unmet needs; however, additional research is required to identify more effective therapies for PsA. PMID- 26476229 TI - Biologic Therapy for Psoriatic Arthritis. AB - Biologic medications, therapeutic proteins that inhibit or modulate proinflammatory immune cells and cytokines, have significantly altered clinicians' ability to effectively treat psoriatic arthritis (PsA). The first widely used biologics have been those targeting tumor necrosis factor alpha. Five agents (etanercept, infliximab, adalimumab, golimumab, and certolizumab) have shown significant benefit in all clinical domains of PsA as well as inhibiting progressive joint destruction. Treatment strategies such as treating PsA early in the disease course, treating to target and tight control, use of background methotrexate to reduce immunogenicity, and various cost-saving strategies are all being tested with biologic medicines for PsA. PMID- 26476230 TI - Novel Treatment Concepts in Psoriatic Arthritis. AB - The introduction of highly effective therapies and clearly defined targets has altered the treatment paradigm in psoriatic arthritis (PsA). Validated classification criteria and outcome measures specific to PsA have helped standardize a therapeutic approach to this heterogeneous disease that affects multiple clinical domains. This article discusses the importance of early intervention using a treat-to-target strategy; emerging evidence for tight control based on minimal disease activity criteria; disease considerations specific to PsA (prognostic markers, biomarkers, subclinical disease, comorbidities); and new treatment strategies to deal with refractory disease (eg, tumor necrosis factor inhibitor switching and use of novel disease-modifying therapies) and controlled disease (eg, tapering or discontinuing biologic therapy). PMID- 26476231 TI - Psoriatic Arthritis. PMID- 26476232 TI - Psoriatic Arthritis. PMID- 26476233 TI - The chloroplast NADPH thioredoxin reductase C, NTRC, controls non-photochemical quenching of light energy and photosynthetic electron transport in Arabidopsis. AB - High irradiances may lead to photooxidative stress in plants, and non photochemical quenching (NPQ) contributes to protection against excess excitation. One of the NPQ mechanisms, qE, involves thermal dissipation of the light energy captured. Importantly, plants need to tune down qE under light limiting conditions for efficient utilization of the available quanta. Considering the possible redox control of responses to excess light implying enzymes, such as thioredoxins, we have studied the role of the NADPH thioredoxin reductase C (NTRC). Whereas Arabidopsis thaliana plants lacking NTRC tolerate high light intensities, these plants display drastically elevated qE, have larger trans-thylakoid DeltapH and have 10-fold higher zeaxanthin levels under low and medium light intensities, leading to extremely low linear electron transport rates. To test the impact of the high qE on plant growth, we generated an ntrc psbs double-knockout mutant, which is devoid of qE. This double mutant grows faster than the ntrc mutant and has a higher chlorophyll content. The photosystem II activity is partially restored in the ntrc-psbs mutant, and linear electron transport rates under low and medium light intensities are twice as high as compared with plants lacking ntrc alone. These data uncover a new role for NTRC in the control of photosynthetic yield. PMID- 26476235 TI - Epigenetic modifications in mouse cerebellar Purkinje cells: effects of aging, caloric restriction, and overexpression of superoxide dismutase 1 on 5 methylcytosine and 5-hydroxymethylcytosine. AB - The aim of the present study was to assess alterations in DNA methylation and hydroxymethylation during aging in cerebellar Purkinje cells and to determine the effects of putatively preventative measures to such age-related changes. Using immunohistochemical techniques, 5-methylcytosine (5-mC) and 5 hydroxymethylcytosine (5-hmC) immunoreactivity in cerebellar Purkinje cells of 12 month- and 24-month-old mice was interrogated. Additionally, the modulatory effects of caloric restriction (CR) and normal human Cu/Zn super oxide dismutase 1 overexpression on these changes were assessed. We show that aging is associated with an increase of 5-mC and 5-hmC immunoreactivity in mouse cerebellar Purkinje cells. These age-related increases were mitigated by CR but not super oxide dismutase 1 overexpression. Additionally, the ratio between 5-mC and 5-hmC decreased with age and CR treatment, suggesting that CR has a stronger effect on DNA methylation than DNA hydroxymethylation. These findings enforce the notion that aging is closely connected to marked epigenetic changes, affecting multiple brain regions, and that CR is an effective means to prevent or counteract deleterious age-related epigenetic alterations. PMID- 26476234 TI - Mapping 3-year changes in gray matter and metabolism in Abeta-positive nondemented subjects. AB - Gray matter (GM) atrophy and brain glucose hypometabolism are already detected in the predementia stages of Alzheimer's disease (AD), but the regional and longitudinal associations between the two are not well understood. Here, we analyzed the patterns of longitudinal atrophy (magnetic resonance imaging [MRI]) and (18)F-Fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) metabolism decline in 40 cognitively healthy control (HC) and 52 mildly impaired (mild cognitive impairment [MCI]) subjects during 3 years. Based on cerebrospinal fluid and brain amyloid-PET, the subjects were divided into amyloid-beta (Abeta)- and Abeta+ subgroups. In voxel-based and region of interest analyses, we compared the 3-year rates of change in GM and glucose metabolism between Abeta-subgroups, within each diagnostic group. In joint-independent component analyses, we assessed the patterns of covariation between longitudinal change in GM volume and glucose metabolism. MCI-Abeta+ showed faster atrophy than MCI-Abeta- within the temporal, medial temporal, and medial parietal lobes. HC-Abeta+ showed faster atrophy within the precuneus than HC-Abeta-. For FDG-PET metabolism, MCI-Abeta+ exhibited faster decline than MCI-Abeta- in temporoparietal regions, whereas no differences between HC subgroups were observed. Joint-independent component analysis showed that accelerated atrophy and metabolism decline correlated across distant brain regions for MCI-Abeta+. In conclusion, abnormally increased levels of Abeta in nondemented subjects were associated with accelerated decline in both GM and glucose metabolism, where both types of neurodegeneration progress in spatially divergent patterns. PMID- 26476236 TI - TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts. AB - TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS. PMID- 26476237 TI - Lessons learned from multi-scale modeling of the failing heart. AB - Heart failure constitutes a major public health problem worldwide. Affected patients experience a number of changes in the electrical function of the heart that predispose to potentially lethal cardiac arrhythmias. Due to the multitude of electrophysiological changes that may occur during heart failure, the scientific literature is complex and sometimes ambiguous, perhaps because these findings are highly dependent on the etiology, the stage of heart failure, and the experimental model used to study these changes. Nevertheless, a number of common features of failing hearts have been documented. Prolongation of the action potential (AP) involving ion channel remodeling and alterations in calcium handling have been established as the hallmark characteristics of myocytes isolated from failing hearts. Intercellular uncoupling and fibrosis are identified as major arrhythmogenic factors. Multi-scale computational simulations are a powerful tool that complements experimental and clinical research. The development of biophysically detailed computer models of single myocytes and cardiac tissues has contributed greatly to our understanding of processes underlying excitation and repolarization in the heart. The electrical, structural, and metabolic remodeling that arises in cardiac tissues during heart failure has been addressed from different computational perspectives to further understand the arrhythmogenic substrate. This review summarizes the contributions from computational modeling and simulation to predict the underlying mechanisms of heart failure phenotypes and their implications for arrhythmogenesis, ranging from the cellular level to whole-heart simulations. The main aspects of heart failure are presented in several related sections. An overview of the main electrophysiological and structural changes that have been observed experimentally in failing hearts is followed by the description and discussion of the simulation work in this field at the cellular level, and then in 2D and 3D cardiac structures. The implications for arrhythmogenesis in heart failure are also discussed including therapeutic measures, such as drug effects and cardiac resynchronization therapy. Finally, the future challenges in heart failure modeling and simulation will be discussed. PMID- 26476238 TI - Phosphoinositide dependent protein kinase 1 is required for exercise-induced cardiac hypertrophy but not the associated mitochondrial adaptations. AB - Phosphoinositide-dependent protein kinase-1 (PDPK1) is an important mediator of phosphatidylinositol 3-kinase (PI3K) signaling. We previously reported that PI3K but not Akt signaling mediates the increase in mitochondrial oxidative capacity following physiological cardiac hypertrophy. To determine if PDPK1 regulates these metabolic adaptations we examined mice with cardiomyocyte-specific heterozygous knockout of PDPK1 (cPDPK1(+/-)) after 5 wk. exercise swim training. Akt phosphorylation at Thr308 increased by 43% in wildtype (WT) mice but not in cPDPK1(+/-) mice following exercise training. Ventricular contractile function was not different between WT and cPDPK1(+/-) mice at baseline. In addition, exercise did not influence ventricular function in WT or cPDPK1(+/-) mice. Heart weight normalized to tibia length ratios increased by 13.8% in WT mice (6.2+/-0.2 vs. 7.1+/-0.2, P=0.001), but not in cPDPK1(+/-) (6.2+/-0.3 vs. 6.5+/-0.2, P=0.20) mice after swim training. Diastolic LV dimension increased in WT mice (3.7+/-0.1 vs. 4.0+/-0.1 mm, P=0.01) but not in cPDPK1(+/-) (3.8+/-0.1 vs. 3.7+/-0.1 mm, P=0.56) following swim training. Maximal mitochondrial oxygen consumption (VADP, nmol/min/mg) using palmitoyl carnitine as a substrate was significantly increased in mice of all genotypes following swim training (WT: 13.6+/-0.6 vs.16.1+/-0.9, P=0.04; cPDPK1(+/-): 12.4+/-0.6 vs.15.9+/-1.2, P=0.04). These findings suggest that PDPK1 is required for exercise-induced cardiac hypertrophy but does not contribute to exercise-induced increases in mitochondrial function. PMID- 26476239 TI - Salinomycin encapsulated nanoparticles as a targeting vehicle for glioblastoma cells. AB - Salinomycin has been introduced as a novel alternative to traditional anti-cancer drugs. The aim of this study was to test a strategy designed to deliver salinomycin to glioblastoma cells in vitro. Salinomycin-encapsulated polysorbate 80-coated poly(lactic-co-glycolic acid) nanoparticles (P80-SAL-PLGA) were prepared and characterized with respect to particle size, morphology, thermal properties, drug encapsulation efficiency and controlled salinomycin-release behaviour. The in vitro cellular uptake of P80-SAL-PLGA (5 and 10 uM) or uncoated nanoparticles was assessed in T98G human glioblastoma cells, and the cell viability was investigated with respect to anti-growth activities. SAL, which was successfully transported to T98G glioblastoma cells via P80 coated nanoparticles (~14% within 60 min), greatly decreased (p < 0.01) the cellular viability of T98G cells. Substantial morphological changes were observed in the T98G cells with damaged actin cytoskeleton. Thus, P80-SAL-PLGA nanoparticles induced cell death, suggesting a potential therapeutic role for this salinomycin delivery system in the treatment of human glioblastoma. PMID- 26476240 TI - Tick saliva: paving the way for the stowaway Borrelia. PMID- 26476241 TI - Preparation of nanoscale Bacillus thuringiensis chitinases using silica nanoparticles for nematicide delivery. AB - A series of amino, carboxylic, and aldehydic surface-grafted silica nanoparticles (SNPs) was prepared based on SiO2 NYSi40 nanoparticles to develop an efficient, biocompatible, and cost-effective biopesticide delivery system. Bacillus thuringiensis chitinase (Chi9602) was immobilized onto SNP surface to prepare nanoscale chitinases (SNPCs) through electrostatic adsorption and covalent binding. The specimens were characterized by Fourier transform infrared, scanning electron microscopy, and zeta-potential analyses. The delivery capacity of the SNPs in Caenorhabditis elegans N2 was observed by immunofluorescence. Results demonstrated that amino-grafted SiO2 nanoparticles with Chi9602 electrostatically adsorbed onto their surface (SNPC2) exhibited a relatively high enzyme immobilization rate (80.2%) and the highest (94.1%) residual enzyme activity among all SNPCs. SNPC2 also showed wider pH tolerance and relatively higher thermostability and ultraviolet radiation resistance capacity than Chi9602. Bioassays further showed that SNPC2 synergistically enhanced the nematicidal effect of B. thuringiensis YBT-020 preparation against C. elegans, with a reduced LC50 of 8.35mg/mL and a shortened LT50 of 12.04h. Immunofluorescence assays showed that SNPC2 had considerable delivery capacity to carry a large protein into C. elegans. Therefore, SNP2 can serve as an efficient nanocarrier for the delivery of macromolecular proteic biopesticides or drugs, indicating potential agricultural or biotechnological applications. PMID- 26476242 TI - Acrosin inhibitor detection along the boar epididymis. AB - Epididymal sperm maturation represents a key step in the reproduction process. Spermatozoa are exposed to epididymal fluid components representing the natural environment essential for their post-testicular maturation. Changes in sperm membrane proteins are influenced by proteolytic, glycosylation and deglycosylation enzymes present in the epididymal fluid. Accordingly, the occurrence of inhibitors of these enzymes in the epididymis is very important for the regulation of sperm membrane protein processing. In the present study, we monitored acrosin inhibitor distribution in boar epididymal fluid and in spermatozoa from different segments of the organ. Using specific polyclonal antibody we registered increasing signal of the acrosin inhibitor (AI) from caput to cauda epididymis. Mass spectroscopy examination of the immunoprecipitated acrosin inhibitor (12 kDa) unequivocally identified sperm-associated acrosin inhibitor (SAAI) in the epididymal tissue. Lectin staining showed N-glycosylation in AI from boar epididymis. Protein detection of AI was supported by the results of semi-quantitative RT-PCR showing the presence of mRNA specifically coding for SAAI and similarly increasing throughout the epididymal duct, from its proximal to distal part. Additionally, the immunofluorescence technique showed the AI localization in the secretory tissue of caput, corpus and cauda epididymis, and in the acrosome region and midpiece of the sperm. PMID- 26476243 TI - CBLB502, an agonist of Toll-like receptor 5, has antioxidant and scavenging free radicals activities in vitro. AB - The bacterial protein flagellin is the known agonist of Toll-like receptor 5 (TLR5). It has been reported that CBLB502, a novel agonist of TLR5 derived from Salmonella flagellin, could reduce radiation toxicity in mouse and primate models, protect mice from dermatitis and oral mucositis caused by radiation, inhibit acute renal ischemic failure, and inhibit the growth of A549 lung cancer cell. The property of CBLB502 is able to bind to TLR5 and activates NF-kappaB signaling. In this study, we investigated the antioxidant potential and free radicals scavenging properties of CBLB502 in vitro. Interestingly, we found that CBLB502 has a direct and distinct antioxidant capacity and can efficiently scavenge a variety of free radicals, including superoxide anion, hydroxyl radical, and ABTS cation (ABTS(+)). Through wave scanning and kinetic evaluation of scavenging ABTS(+), we found that the ABTS(+) scavenging process of CBLB502 is relatively slow, and the ABTS(+) scavenging activity of CBLB502 has a consistently kinetics characteristics. In conclusion, our results suggested that CBLB502 has antioxidant and scavenging free radicals activities in vitro. It is implied that CBLB502 might partially promote the beneficial protective effect through its scavenging free radicals. PMID- 26476244 TI - Structure elucidation and antioxidant activity of a novel polysaccharide from Polyporus umbellatus sclerotia. AB - A novel water-soluble polysaccharide PUP60S2, with a molecular weight of 1.44*10(4)Da, was obtained from the sclerotia of Polyporus umbellatus by hot water extraction, ethanol precipitation, anion-exchange and size-exclusion chromatography. PUP60S2 was a polysaccharide comprised of about 22.3% glucuronic acid. Monosaccharide composition analysis showed that PUP60S2 was only comprised of glucose and glucuronic acid. Reduction of carboxyl groups, sugar analysis, methylation analysis, together with one and two dimension NMR spectra disclosed that the backbone of PUP60S2 consisted of (1->6)-beta-d-glucopyranosyl, every second of which was substituted at O-3 by side chains consisting of terminal beta d-Glcp, (1->3)-beta-d-Glcp, (1->3)-beta-d-GlcpA, (1->4)-beta-d-Glcp and (1->4) beta-d-GlcpA units. The antioxidant activity assay in vitro showed that PUP60S2 exerted a significant scavenging effect on DPPH, hydroxyl radical and superoxide radical in a dose-dependent manner. PMID- 26476245 TI - Degradation of konjac glucomannan by Thermobifida fusca thermostable beta mannanase from yeast transformant. AB - Native konjac glucomannan was used as the substrate for thermophilic actinomycetes, Thermobifida fusca BCRC19214, to produce beta-mannanase. The beta mannanase was purified and five internal amino acid sequences were determined by LC-MS/MS. These sequences had high homology with the beta-mannanase from T. fusca YX. The tfm gene which encoded the beta-mannanase was cloned, sequenced and heterologous expressed in Yarrowia lipolytica P01 g expression system. Recombinant heterologous expression resulted in extracellular beta-mannanase production at levels as high as 3.16 U/ml in the culture broth within 48 h cultivation. The recombinant beta-mannanase from Y. lipolytica transformant had superior thermal property. The optimal temperature of the recombinant beta mannanase from Y. lipolytica transformant (pYLSC1-tfm) was 80 degrees C. When native konjac glucomannan was incubated with the recombinant beta-mannanase from Y. lipolytica transformant (pYLSC1-tfm) at 50 degrees C, there was a fast decrease of viscosity happen during the initial phase of reaction. This viscosity reduction was accompanied by an increase of reducing sugars. The surface of konjac glucomannan film became smooth. After 24h of treatment, the DPw of native konjac glucomannan decreased from 6,435,139 to 3089. PMID- 26476246 TI - Topical Therapy Primer for Nondermatologists. AB - A representative assortment of topical therapies is discussed here with the goal of emphasizing the most commonly encountered diagnoses and treatments for nondermatologists. When using topical therapies, carefully consider the proper active ingredient, potency, vehicle, and quantity of medication. If topical therapy is ineffective, question whether the medication is being used properly, whether the diagnosis is correct, and whether the topical may be contributing to the problem. Examples of the topical contributing to the problem include tinea incognito exacerbated by topical steroid use and allergic contact dermatitis to topical steroid excipients. For some patients, even maximum topical therapy is insufficient and systemic treatment is required. At this point, consultation with a dermatologist may be helpful. PMID- 26476247 TI - The Role of Biologic Therapies in Dermatology. AB - Biologic therapy has dramatically changed the way medicine, and specifically dermatology, is practiced today. The use of biologic agents in dermatology is evolving, with psoriasis being the most common indication for which biologics are used currently. However, several other dermatologic diseases seem to be responsive to biologic therapy, and continuing research and development efforts are elucidating the benefit-risk profiles of various biologic medications in these dermatologic conditions. Although biologic agents have revolutionized the management of dermatologic conditions, cost must also be considered when evaluating management options, especially compared with traditional agents. For example, the cost of 1 year of induction and maintenance treatment of psoriasis in 2014 was estimated to be $53,909 for ustekinumab, $46,395 for etanercept, and $39,041 for adalimumab. Nonetheless, because of their efficacy, the cost of a biologic may be offset by significant reductions in the number of hospital stays, reduction in use of other systemic therapies, and increased satisfaction by patients.32 Thus, understanding their mechanisms of action, labeled and off-label uses in dermatology, and common adverse effects helps to inform clinical decision making and improve patient outcomes. PMID- 26476248 TI - Selected Disorders of Skin Appendages--Acne, Alopecia, Hyperhidrosis. AB - This article reviewed some of the more common diseases of the skin appendages that are encountered in medicine: hyperhidrosis, acne, AA, FPHL, AGA, and TE. The pathophysiology behind the conditions and their treatments were discussed so that the clinician can make logical therapeutic choices for their affected patients. PMID- 26476249 TI - Nail Disease for the Primary Care Provider. AB - Nail disorders are a common presenting complaint for both the primary care physician and the dermatologist. Nail diagnoses are broad in scope and include infectious, inflammatory, and neoplastic conditions. Onychomycosis is an especially common nail condition, and treatment should always be preceded by appropriate fungal studies for confirmation of diagnosis. Inflammatory conditions of the nail unit can mimic onychomycosis, and a dermatologist can assist with diagnosis and treatment recommendations. Likewise, subungual tumors often require biopsy, and should be evaluated by a dermatologist who is experienced in nail evaluation and treatment. PMID- 26476250 TI - Psoriasis and Cardiovascular Disease. AB - Psoriasis is a systemic inflammatory disease that confers significant risk of metabolic derangements and adverse cardiovascular outcomes. Early detection and treatment of modifiable risk factors and modulation of the systemic inflammatory response are important treatment goals. Studies have shown that there is a significant lack of awareness of the relationship between psoriasis and cardiovascular disease, so future considerations should focus on education of and collaboration with health care providers, especially those in primary care, and development of updated, rigorous screening guidelines. In addition, targeted biologic therapies such as TNF-a inhibitors have shown immense promise in targeting the systemic inflammation associated with psoriatic disease, but whether they will impact long-term cardiovascular outcomes remains to be seen. PMID- 26476251 TI - Clinical Approach to Diffuse Blisters. AB - Some blistering eruptions are self-limited, but others are life threatening, and prompt diagnosis and management are critical. The clinical presentation of vesicles and bullae suggests a broad differential and this article (1) highlights some common diagnoses that may be encountered by primary care physicians and subspecialists; (2) provides a possible systematic diagnostic approach to such patients, including history, physical examination, and relevant work-up. PMID- 26476252 TI - Atopic Dermatitis: A Common Pediatric Condition and Its Evolution in Adulthood. AB - Atopic dermatitis (AD) is a chronic and pruritic inflammatory skin disorder that has a relapsing course and can affect any age group. Patients with AD have higher rates of other allergic disorders, mental health disorders, and skin infections. An important feature of AD for practitioners to recognize is that the clinical presentation varies by age from infancy into adulthood. The goals of treatment and management of AD focuses on restoring and maintaining the skin barrier function, minimizing inflammation, breaking the itch-scratch cycle, and treating possible external triggers and secondary infections that may propagate AD. PMID- 26476253 TI - Rheumatologic Skin Disease. AB - In common rheumatologic diseases skin findings are an important diagnostic clue for astute clinicians. Skin manifestations can help identify systemic disease or may require therapy uniquely targeted at the cutaneous problem. This article discusses 3 common rheumatologic conditions seen in adults by dermatologists: cutaneous lupus, dermatomyositis, and morphea. The focus is on the cutaneous findings and clinical presentation. Some approaches to treatment are explored. Clues to help identify systemic disease are also highlighted. PMID- 26476254 TI - Common Dermatologic Procedures. AB - Dermatologists perform a wide variety of procedures on a daily basis. The skin biopsy is a fundamental technique that can be performed by all physicians who manage cutaneous conditions. Specimens should always be sent for pathologic evaluation, regardless of whether the sampled lesion appears benign. Postoperative care and education are critical for minimizing complications. PMID- 26476255 TI - Skin Cancer Epidemiology, Detection, and Management. AB - Although the signs and symptoms of the 3 most common skin malignancies are well known to physicians, any new or changing lesions should be monitored and worked up to rule out varying forms of cutaneous malignancy. Classic presenting features of each condition exist, but patients may present with overlapping or atypical features, and a biopsy is almost always required to definitively determine the true nature of each disorder. Given the intense psychosocial ramifications of skin cancer diagnosis and treatment, early detection remains the hallmark in producing favorable outcomes. PMID- 26476256 TI - Approach to the Patient with a Suspected Cutaneous Adverse Drug Reaction. AB - CADRs are common and generally have a mild, self-resolving course with minimal associated morbidity and mortality. However, subsets of CARDs are more severe, require intervention, and have significant risk of associated morbidity and mortality. For this reason, it is crucial that the clinician recognize signs and symptoms worrisome for a more severe CARD so that appropriate triage, work-up, and treatment are initiated. In all CADRs the most important first step is identification and withdrawal of the culprit medications. PMID- 26476257 TI - Inpatient Consultative Dermatology. AB - Dermatology consultation can improve diagnostic accuracy in the hospitalized patient with cutaneous disease. Dermatology consultation can streamline and improve treatment plans, and potentially lead to cost savings. Dermatology consultants can be a valuable resource for education for trainees, patients, and families. Inpatient consultative dermatology spans a breadth of conditions, including inflammatory dermatoses,infectious processes, adverse medication reactions, and neoplastic disorders, many of which can be diagnosed based on dermatologic examination alone, but when necessary, bedside skin biopsies can contribute important diagnostic information. PMID- 26476258 TI - Teledermatology. AB - This article provides an overview of teledermatology with an emphasis on the evidence most relevant to referring clinicians, who are often primary care clinicians. Discussion includes the different modalities used for teledermatology and their diagnostic reliability, diagnostic accuracy, impact on in-person dermatology visits, clinical outcomes, and user satisfaction. PMID- 26476259 TI - Dermatology. PMID- 26476260 TI - Dermatology. PMID- 26476261 TI - The alpha4 isoform of the Na+,K+-ATPase is tuned for changing extracellular environments. AB - In their journey from the male to the female reproductive tract, spermatozoa are confronted with a constantly changing environment. To cope with the associated challenges, spermatozoa express a distinct set of transporters, channels and pumps. One of the membrane proteins unique to spermatozoa is the alpha4 isoform of the Na(+) ,K(+) -ATPase. In addition to alpha4, spermatozoa express the ubiquous alpha1 variant. To get a detailed understanding of how alpha1 and alpha4 differ, and why spermatozoa need an additional Na(+) ,K(+) -ATPase, we have conducted an electrophysiological comparison of the rodent isoforms (rat alpha4 versus mouse alpha1-3) using the Xenopus oocyte expression system. We demonstrate isoform-specific differences in the voltage sensitivity of steady-state turnover, with alpha2 being the more sensitive, and alpha1 and alpha2 having faster Na(+) release kinetics than alpha3 and alpha4. Our data further show that the alpha1 and alpha2 turnover rates are fast compared with those of alpha3 and alpha4. Finally, alpha4 is less influenced by changes in extracellular Na(+) and temperature than alpha1. Based on these findings, we discuss the possibility that evolution has selected robust activity rather than rapid turnover for alpha4. PMID- 26476262 TI - Proliferating cells in the adolescent rat amygdala: Characterization and response to stress. AB - The amygdala is a heterogeneous group of nuclei that plays a role in emotional and social learning. As such, there has been increased interest in its development in adolescent animals, a period in which emotional/social learning increases dramatically. While many mechanisms of amygdala development have been studied, the role of cell proliferation during adolescence has received less attention. Using bromodeoxyuridine (BrdU) injections in adolescent and adult rats, we previously found an almost fivefold increase in BrdU-positive cells in the amygdala of adolescents compared to adults. Approximately one third of BrdU labeled cells in the amygdala contained the putative neural marker doublecortin (DCX), suggesting a potential for neurogenesis. To further investigate this possibility in adolescents, we examined the proliferative dynamics of DCX/BrdU labeled cells. Surprisingly, DCX/BrdU-positive cells were found to comprise a stable subpopulation of BrdU-containing cells across survivals up to 56 days, and there was no evidence of neural maturation by 28 days after BrdU injection. Additionally, we found that approximately 50% of BrdU+ cells within the adolescent amygdala contain neural-glial antigen (NG2) and are therefore presumptive oligodendrocyte precursors (OPCs). We next characterized the response to a short-lived stressor (3-day repeated variable stress, RVS). The total BrdU labeled cell number decreased by ~30% by 13 days following RVS (10 days post-BrdU injection) as assessed by stereologic counting methods, but the DCX/BrdU-labeled subpopulation was relatively resistant to RVS effects. In contrast, NG2/BrdU labeled cells were strongly influenced by RVS. We conclude that typical neurogenesis is not a feature of the adolescent amygdala. These findings point to several possibilities, including the possibility that DCX/BrdU cells are late developing neural precursors, or a unique subtype of NG2 cell that is relatively resistant to stress. In contrast, many proliferating OPCs are significantly impacted by a short-lived stressor, suggesting consequences for myelination in the developing amygdala. PMID- 26476263 TI - Recurrence of rectal prolapse following rectopexy: a pooled analysis of 532 patients. AB - AIM: The study was designed to address the unanswered question of the influence of the extent of rectal mobilization, the type of rectal fixation and the surgical access (open vs laparoscopic) on recurrence rates following abdominal surgery for full-thickness rectal prolapse (FTRP). METHOD: Individual patient data were pooled and data merging was performed following comparison of variable definitions to ensure similarity in definitions. Recurrence after rectopexy was defined as the presence of FTRP on physical examination. The impact of categorical factors on recurrence was assessed using Fisher's exact and the chi squared tests. Recurrence-free survival curves were generated for patients and differences in time to recurrence were compared using the log rank test. Factors passing univariate screening with a P value < 0.1 were included in a multivariate model. RESULTS: After data matching and merging, 532 patients were included. The duration of follow-up ranged from 12 to 235 months. There were 46 (8.6%) recurrences at a median follow-up of 60 months. Mean age was 53.6 +/- 17 years, 359 (67.5%) were female, the mean length of external prolapse was 6.3 +/- 4 cm, and previous abdominal surgery had taken place in 33.7%. Four variables were identified on initial univariate screening as being related to recurrence. They included a history of incontinence (P = 0.09), constipation (P = 0.018), the extent of rectal mobilization (P = 0.004) and the role of sigmoid resection (P = 0.057). Using multivariate analysis, only the degree of mobilization was independently associated with recurrence (P = 0.026). CONCLUSION: Circumferential rectal mobilization during rectopexy was associated with a decreased long-term recurrence rate. The type of rectal fixation and the type of surgical access did not influence recurrence. PMID- 26476264 TI - The Impact of Opioid Risk Reduction Initiatives on High-Dose Opioid Prescribing for Patients on Chronic Opioid Therapy. AB - Avoiding high opioid doses may reduce chronic opioid therapy (COT) risks, but the feasibility of reducing opioid doses in community practice is unknown. Washington State and a health plan's group practice implemented initiatives to reduce high dose COT prescribing. The group practice physicians were exposed to both initiatives, whereas contracted physicians were exposed only to statewide changes. Using interrupted time series analyses, we assessed whether these initiatives reduced opioid doses among COT patients in group practice (n = 16,653) and contracted care settings (n = 5,552). From 2006 to June 2014, the percentage of COT patients receiving >=120 mg morphine equivalent dose declined from 16.8% to 6.3% in the group practice versus 20.6 to 13.6% among COT patients of contracted physicians. The proportion receiving excess opioid days supplied declined from 24.0 to 10.4% among group practice COT patients and from 20.1 to 14.7% among COT patients of contracted physicians. Reductions in prescribing of high opioid dose and excess opioid days supplied followed state and health plan initiatives to change opioid prescribing. Reductions were substantially greater in the group practice setting that implemented additional initiatives to alter shared physician expectations regarding appropriate COT prescribing, compared with the contracted physicians' patients. PERSPECTIVE: Washington State and a health plan's group practice implemented initiatives to reduce high-dose COT prescribing. Group practice physicians were exposed to both initiatives, whereas the health plan's contracted physicians were exposed to only the statewide changes. Reductions in prescribing of high opioid dose, average daily dose, and excess opioid days supplied followed state and health plan initiatives to change opioid prescribing. Reductions were substantially greater in the group practice setting that implemented additional initiatives to alter shared physician expectations regarding appropriate COT prescribing, compared with the contracted physicians' patients. PMID- 26476265 TI - Chronic Back Pain Is Associated With Decreased Prefrontal and Anterior Insular Gray Matter: Results From a Population-Based Cohort Study. AB - Chronic back pain (CBP) is associated with circumscribed atrophy in gray matter (GM) predominantly localized in areas of the so-called pain matrix and the prefrontal cortex (PFC). Previous studies applying voxel-based morphometry (VBM) for identifying structural brain alterations related to CBP have reported inconsistent results, were limited to small sample sizes, and often did not control for medication. We therefore used VBM for high-resolution magnetic resonance images to investigate the association of CBP and regional GM volume in 111 individuals with CBP and 432 pain-free controls derived from the representative Study of Health in Pomerania, controlling for effects of medication. CBP was associated with decreased regional GM in the ventrolateral PFC and dorsolateral PFC, both the ventral and dorsal medial PFC, and the anterior insula. Pain intensity showed a weak negative correlation with GM volume in the left dorsolateral PFC, ventrolateral PFC, and anterior cingulate cortex. The CBP sample showed alterations in regions commonly associated with pain processing and emotional demands. To our knowledge, this is the first VBM study reporting decreased regional GM volume in the medial PFC in a CBP sample. We were unable to confirm alterations in regions other than the dorsolateral PFC and the insula. PERSPECTIVE: Previous studies reported inconsistent results for brain areas altered in chronic pain conditions, which may be in part attributable to small sample sizes, medication use, or emotional comorbidities. This study in a large and representative cohort helps to clarify these issues. PMID- 26476266 TI - Effect of Alexithymia and Emotional Repression on Postsurgical Pain in Women With Breast Cancer: A Prospective Longitudinal 12-Month Study. AB - Alexithymia, the inability to identify and express emotions, and emotional repression, a defensive mechanism used to avoid unpleasant emotional experience, have been associated with chronic pain and medical illness including breast cancer, but whether these constructs might predict pain after breast cancer surgery has not been assessed. The present study was conducted to assess the predictive value of alexithymia and emotional repression in postoperative pain. Anxiety, depression, catastrophizing, and psychological adjustment were also assessed. Data were collected before surgery, and then at 2 days and 2, 3, 6, and 12 months after surgery. We included 100 pain-free women, 96% of whom were followed for up to 12 months. Separate multivariate analyses identified anxiety as a significant predictor of postsurgical pain at 3 months, alexithymia at 3, 6, and 12 months, and body image and catastrophizing predicted acute or subacute pain at 2 months. In contrast, emotional repression was not predictive of pain. The generalized estimating equation approach was used and identified alexithymia as the only significant predictor of pain during the 12-month period after surgery. Alexithymia, but not emotional repression, predicted the development of persistent pain after breast surgery independently of anxiety and depression. Thus, alexithymia might be involved in mechanisms of pain chronicity. PERSPECTIVE: This prospective study, conducted in women with breast cancer surgery, showed that alexithymia but not emotional repression predicted postsurgical pain. These results highlight the role of dysfunction in emotional processing in the development of postsurgical pain. PMID- 26476268 TI - Abnormal N-glycosylation pattern for brain nucleotide pyrophosphatase-5 (NPP-5) in Mecp2-mutant murine models of Rett syndrome. AB - Neurological disorders can be associated with protein glycosylation abnormalities. Rett syndrome is a devastating genetic brain disorder, mainly caused by de novo loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. Although its pathogenesis appears to be closely associated with a redox imbalance, no information on glycosylation is available. Glycoprotein detection strategies (i.e., lectin-blotting) were applied to identify target glycosylation changes in the whole brain of Mecp2 mutant murine models of the disease. Remarkable glycosylation pattern changes for a peculiar 50kDa protein, i.e., the N-linked brain nucleotide pyrophosphatase-5 were evidenced, with decreased N-glycosylation in the presymptomatic and symptomatic mutant mice. Glycosylation changes were rescued by selected brain Mecp2 reactivation. Our findings indicate that there is a causal link between the amount of Mecp2 and the N-glycosylation of NPP-5. PMID- 26476267 TI - Cognitive-Behavioral-Based Physical Therapy for Patients With Chronic Pain Undergoing Lumbar Spine Surgery: A Randomized Controlled Trial. AB - The purpose of this study was to determine the efficacy of a cognitive-behavioral based physical therapy (CBPT) program for improving outcomes in patients after lumbar spine surgery. A randomized controlled trial was conducted on 86 adults undergoing a laminectomy with or without arthrodesis for a lumbar degenerative condition. Patients were screened preoperatively for high fear of movement using the Tampa Scale for Kinesiophobia. Randomization to either CBPT or an education program occurred at 6 weeks after surgery. Assessments were completed pretreatment, posttreatment and at 3-month follow-up. The primary outcomes were pain and disability measured by the Brief Pain Inventory and Oswestry Disability Index. Secondary outcomes included general health (SF-12) and performance-based tests (5-Chair Stand, Timed Up and Go, 10-Meter Walk). Multivariable linear regression analyses found that CBPT participants had significantly greater decreases in pain and disability and increases in general health and physical performance compared with the education group at the 3-month follow-up. Results suggest a targeted CBPT program may result in significant and clinically meaningful improvement in postoperative outcomes. CBPT has the potential to be an evidence-based program that clinicians can recommend for patients at risk for poor recovery after spine surgery. PERSPECTIVE: This study investigated a targeted cognitive-behavioral-based physical therapy program for patients after lumbar spine surgery. Findings lend support to the hypothesis that incorporating cognitive-behavioral strategies into postoperative physical therapy may address psychosocial risk factors and improve pain, disability, general health, and physical performance outcomes. PMID- 26476269 TI - Safety and Effectiveness of Adjunctive Intra-Arterial Abciximab in the Management of Acute Limb Ischemia. AB - BACKGROUND: Contemporary endovascular management of acute limb ischemia (ALI) generally consists of tissue plasminogen activator (tPA) based catheter-directed thrombolysis (CDT) with or without pharmacomechanical thrombectomy (PMT). Although abciximab (Reopro), a GPIIb/IIIa receptor antagonist, is widely used in coronary revascularization, its safety and effectiveness in the treatment of ALI are unknown. Here, we review our contemporary experience with the endovascular management of ALI and assess the safety and effectiveness of abciximab. METHODS: A total of 49 consecutive patients with Rutherford class II (RII) ALI undergoing CDT for ALI from 2011 to 2014 was identified. Demographics, procedural details, and outcomes were assessed and are reported. RESULTS: A total of 44 patients with RII ALI underwent tPA-based CDT in 49 discrete interventions. In 11 patients adjunctive abciximab infusion was also used. The majority (82%) of patients treated with tPA +/- PMT required overnight infusion and at least one subsequent procedure. Single-stage (on-table) thrombolysis was achieved in 91% of cases with adjunctive abciximab use versus 18% with tPA alone (P < 0.001). There was significantly less need for intensive care unit (ICU) monitoring, and there were no bleeding complications associated with adjunctive abciximab use. Overall length of stay and total operating room (OR) time favored the abciximab group but did not reach statistical significance. Overall primary patency, secondary patency, and amputation-free survival were 46 +/- 9.9%, 79 +/- 6.6%, and 78 +/- 9.2% at 1 year. CONCLUSIONS: Early results suggest adjunctive abciximab may safely facilitate on-table thrombolysis for RII ALI. This approach appears to be associated with reduced resource utilization including fewer procedures, shorter OR time, and less ICU admissions. One-year outcomes compare favorably to a similar cohort of ALI patients treated with tPA-based therapy alone. PMID- 26476270 TI - Axillary-Femoral Bypass May Provide Inadequate Distal Perfusion Compared with In Line Large Diameter Aortic Reconstruction. AB - Axillary-femoral bypass is sometimes performed for complex aortoiliac occlusive disease in patients unfit for aortic surgery or in those with aortic infection. Typically, older patients with medical comorbidities that commonly accompany atherosclerotic or aneurysmal disease are involved and can tolerate the theoretic risk of limited flow volume associated with long, small diameter, axillary femoral grafts. However, a subset of younger, healthier, more vigorous patients outside the typical atherosclerotic or aneurysmal demographic occasionally come to axillary-femoral bypass and may experience symptoms of distal hypoperfusion if flow volumes cannot meet demand. We present a series of patients with primary aortic infection treated with aortic ligation and axillary-femoral bypass, who then progressed to symptoms of visceral, spinal, or extremity ischemia from inadequate distal perfusion. PMID- 26476271 TI - Applicability of the Society for Vascular Surgery's Objective Performance Goals for Critical Limb Ischemia to Current Practice of Lower-Extremity Bypass. AB - BACKGROUND: In 2009, the Society for Vascular Surgery (SVS) established objective performance goals (OPGs) for critical limb ischemia (CLI) based on data from previous, randomized, controlled trials of lower-extremity bypass (LEB). These OPG sought to establish a benchmark of outcomes to which one could compare future endovascular therapy. However, the cohort used to develop the OPG excluded all patients who required prosthetic conduit and those with end-stage renal disease (ESRD), possibly limiting the generalizability of these results and the subsequent guidelines. The goal of this study was to determine if the SVS OPG are applicable to the current population of patients undergoing LEB. METHODS: All patients who underwent infrainguinal LEB for CLI from January 2010 to December 2013 were identified in a prospectively maintained database. Patients were stratified into OPG eligible and ineligible (non-OPG) groups based on their demographic and operative characteristics. OPG eligible patients were further stratified into high risk and average risk. Outcomes included 30-day major adverse limb events (MALEs), 30-day major adverse cardiovascular events (MACE), 1 year survival, and 1-year freedom from amputation. RESULTS: A total of 89 individual patients were identified. Only 43 (48%) patients met OPG inclusion criteria and 46 (52%) were not OPG eligible (non-OPG). The 30-day MALE was 8.7% (13.0% non-OPG vs. 7.0% OPG, P = 0.34). The 30-day MACE was 11.2% (13.0% non-OPG vs. 9.3% OPG, P = 0.58). One-year survival was 80.3% +/- 4.5% (71.2% non-OPG vs. 90.0% OPG, P = 0.21). One-year freedom from amputation was 71.7% +/- 5.5% (58.8% non-OPG vs. 84.0% OPG, P = 0.03). CONCLUSIONS: The SVS OPG for LEB are likely not generalizable to current practice as 51% of patients would have been excluded from the SVS cohort because of ESRD and prosthetic conduit. Most SVS OPG (30-day MALE, 1-year survival, and 1-year limb salvage) were attainable in patients who met SVS OPG inclusion criteria; but for the patients who are not OPG eligible, new benchmarks are needed. PMID- 26476272 TI - The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential. AB - The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention. PMID- 26476273 TI - Gamma-secretase-independent role for cadherin-11 in neurotrophin receptor p75 (p75(NTR)) mediated glioblastoma cell migration. AB - The p75 neurotrophin receptor (p75(NTR)) undergoes gamma-secretase-mediated regulated intramembrane proteolysis and is involved in glioblastoma cell migration and invasion. Consistent with previous reports, in this study we show that p75NTR increases U87-MG glioblastoma cell migration, which is reversed by inhibition of gamma-secretase activity. However, we show that expression or stabilization of the gamma-secretase-generated p75(NTR) intracellular domain (ICD) is not sufficient to induce U87-MG glioblastoma cell migration, and that exogenous expression of p75(NTR) ICD inhibits p75(NTR)-mediated glioblastoma cell (U87-MG and U373-MG) migration. To identify pathways and to determine how p75(NTR) mediates glioblastoma migration we utilized a microarray approach to assess differential gene expression profiles between parental U87-MG and cells stably expressing wild-type p75(NTR), a gamma-secretase cleavage-resistant chimeric p75(NTR) mutant (p75FasTM) and the gamma-secretase-generated p75(NTR) ICD, which mimics constitutively cleaved p75(NTR) receptor. In our microarray data analysis we identified a subset of genes that were constitutively up regulated in wild-type p75(NTR) cells, which were also repressed in p75(NTR) ICD expressing cells. Furthermore, our data revealed among the many differentially expressed genes, cadherin-11 (Cdh-11), matrix metalloproteinase 12 and relaxin/insulin-like family peptide receptor 2 as constitutively up-regulated in wild-type p75(NTR) cells, independent of gamma-secretase activity. Consistent with a role in glioblastoma migration, we found that U87-p75(NTR) cells express higher levels of Cdh-11 protein and that siRNA-mediated knockdown of Cdh-11 resulted in a significant decrease in p75(NTR)-mediated glioblastoma cell migration. Therefore, we hypothesize that p75(NTR) can impact U87-MG glioblastoma cell migration in a gamma-secretase-independent manner through modulation of specific genes, including Cdh-11, and that both gamma-secretase-independent and dependent mechanisms are involved in p75(NTR)-mediated U87-MG glioblastoma cell migration. PMID- 26476275 TI - Genetic diversity, virulence potential and antimicrobial susceptibility of Listeria monocytogenes recovered from different sources in India. AB - Listeria monocytogenes isolates (n = 36) recovered from human and animal clinical cases and foods from different geographical regions of India were characterized using multiplex PCR-based serotyping, pulsed field gel electrophoresis (PFGE), in vitro and in vivo pathogenicity tests and antibiogram profiling. Multiplex PCR based serotyping distributed L. monocytogenes isolates into 3 serogroups, of which 91.67% belonged to 4b, 4d, 4e serogroup, followed by 5.56% to 1/2a, 3a and 2.78% to 1/2b, 3b serogroups. PFGE analysis using ApaI and AscI restriction enzymes revealed 17 pulsotypes among 36 L. monocytogenes isolates with 6 major clusters having similar fingerprint profile within their cluster and 11 unique fingerprint profiles. Interestingly, PFGE analysis inferred that foods of animal origin could be a significant source of infection for spread of listeriosis among human populations. Furthermore, on comparison of in vitro and in vivo pathogenicity tests, an overall good correlation was observed between hemolytic titer assay and chick embryo inoculation test as most of the isolates with a hemolytic titer of >= 16 were found to be lethal to chick embryo. All the isolates were found to be susceptible to tested antimicrobials except for one animal isolate which showed resistance towards co-trimoxazole. PMID- 26476274 TI - Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms. AB - Bipolar disorder (BD) is associated with mood episodes and low amplitude circadian rhythms. Previously, we demonstrated that fibroblasts grown from BD patients show weaker amplification of circadian rhythms by lithium compared to control cells. Since calcium signals impact upon the circadian clock, and L-type calcium channels (LTCC) have emerged as genetic risk factors for BD, we examined whether loss of function in LTCCs accounts for the attenuated response to lithium in BD cells. We used fluorescent dyes to measure Ca(2+) changes in BD and control fibroblasts after lithium treatment, and bioluminescent reporters to measure Per2::luc rhythms in fibroblasts from BD patients, human controls, and mice while pharmacologically or genetically manipulating calcium channels. Longitudinal expression of LTCC genes (CACNA1C, CACNA1D and CACNB3) was then measured over 12 24 h in BD and control cells. Our results indicate that independently of LTCCs, lithium stimulated intracellular Ca(2+) less effectively in BD vs. control fibroblasts. In longitudinal studies, pharmacological inhibition of LTCCs or knockdown of CACNA1A, CACNA1C, CACNA1D and CACNB3 altered circadian rhythm amplitude. Diltiazem and knockdown of CACNA1C or CACNA1D eliminated lithium's ability to amplify rhythms. Knockdown of CACNA1A or CACNB3 altered baseline rhythms, but did not affect rhythm amplification by lithium. In human fibroblasts, CACNA1C genotype predicted the amplitude response to lithium, and the expression profiles of CACNA1C, CACNA1D and CACNB3 were altered in BD vs. CONTROLS: We conclude that in cells from BD patients, calcium signaling is abnormal, and that LTCCs underlie the failure of lithium to amplify circadian rhythms. PMID- 26476276 TI - On-Plant Larval Movement and Feeding Behavior of Fall Armyworm (Lepidoptera: Noctuidae) on Reproductive Corn Stages. AB - Spodoptera frugiperda J.E. Smith (fall armyworm) is considered one of the most destructive pests of corn throughout the Americas. Although this pest has been extensively studied, little is known about its larval movement and feeding behavior on reproductive compared to vegetative corn stages. Thus, we conducted studies with two corn stages (R1 and R3) and four corn plant zones (tassel, above ear, ear zone, and below ear) in the field at Concord, NE (USA), and in the field and greenhouse at Botucatu, SP (Brazil), to investigate on-plant larval movement. The effects of different corn tissues (opened tassel, closed tassel, silk, kernel, and leaf), two feeding sequence scenarios (closed tassel-leaf-silk-kernel and leaf-silk-kernel), and artificial diet (positive control) on larval survival and development were also evaluated in the laboratory. Ear zone has a strong effect on feeding choice and survival of fall armyworm larvae regardless of reproductive corn stage. Feeding site choice is made by first-instar. Corn leaves of reproductive plants were not suitable for early instar development, but silk and kernel tissues had a positive effect on survival and development of fall armyworm larvae on reproductive stage corn. PMID- 26476277 TI - Evaluation of tedizolid against Staphylococcus aureus and enterococci with reduced susceptibility to vancomycin, daptomycin or linezolid. AB - OBJECTIVES: Tedizolid displays potent activity against Gram-positive pathogens. In vitro studies against clinical isolates of Staphylococcus aureus and enterococci demonstrated improved tedizolid activity over linezolid. However, this is not well-characterized against a large collection of resistant isolates, including vancomycin-intermediate S. aureus (VISA), heterogeneous VISA (hVISA), daptomycin-non-susceptible (DNS) S. aureus, linezolid-resistant (LR) S. aureus and VRE. Therefore, our objective was to determine tedizolid activity versus other agents, against MRSA and VRE with various resistance phenotypes. METHODS: In total, 302 MRSA (75 DNS, 100 VISA, 120 hVISA and 7 LR) and 220 VRE [100 Enterococcus faecalis (all susceptible to daptomycin and linezolid) and 120 E. faecium (25 DNS and 10 LR)] were evaluated. LR isolates were analysed for the cfr gene. MICs of tedizolid, linezolid, ampicillin, clindamycin, daptomycin, gentamicin, levofloxacin, oxacillin, tigecycline, trimethoprim/sulfamethoxazole and vancomycin were determined in accordance with CLSI guidelines. RESULTS: Tedizolid MIC90 values for hVISA, VISA and DNS were 0.5 mg/L (versus 4, 4 and 2 mg/L, respectively, for linezolid). The tedizolid MIC range for LR MRSA was 0.063 1 mg/L. Two LR MRSA possessed the cfr gene with tedizolid MICs of 0.125 and 0.25 mg/L (linezolid MICs of 16 and 8 mg/L). The tedizolid MIC90 for vancomycin resistant E. faecalis and E. faecium was 0.25 and 1 mg/L, respectively; three dilutions lower for E. faecalis and two dilutions lower for E. faecium compared with linezolid. CONCLUSIONS: Tedizolid MICs demonstrate activity against isolates with decreased susceptibility to alternative agents, including linezolid. Tedizolid may be a viable treatment option in clinical situations with MDR Gram positive pathogens. PMID- 26476278 TI - A Blinded, Case-Control Trial Assessing the Value of Steady State Free Precession Magnetic Resonance Imaging in the Diagnosis of Trigeminal Neuralgia. AB - OBJECTIVE: High-resolution magnetic resonance imaging (MRI) may be a useful and readily available adjunct in identifying trigeminal neuralgia secondary to vascular contact (TNVC). This study evaluated the reliability and predictive ability of 1.5-tesla steady state free precession (SSFP) MRI sequences for the diagnosis of symptomatic vascular contact and response to operative intervention in patients with TNVC. METHODS: We performed a blinded, case-matched control trial evaluating SSFP MRI sequences in consecutive patients with unilateral TNVC with operatively proven vascular contact of the trigeminal nerve compared with healthy control subjects matched on age, sex, and laterality of the pathologic neurovascular complex. Interrater reliability was compared between 2 blinded, expert reviewers. Predictive ability of MRI was assessed in regard to accuracy, discrimination, and clinical utility. RESULTS: Inclusion criteria were met by 44 patients (22 consecutive patients with TNVC and 22 matched control subjects). Interrater reliability ranged from fair to excellent for vessel contact (kappa = 0.40), location (kappa = 0.81), type (kappa = 0.72), and multiplicity (kappa = 0.31). Vascular contact on MRI sequences did not differ significantly between cases and controls (75% vs. 82%, P = 0.30). MRI demonstrates accurate (Brier 0.15) and good discriminatory ability for clinical response after microvascular decompression (area under the receiver operating characteristic curve 0.81, 95% confidence interval = 0.6-1.0). Decision-curve analysis demonstrated that MRI could result in a net reduction of 5 cases likely to be unsuccessful per 100 patients treated. CONCLUSIONS: These results suggest the utility of SSFP MRI lies not in the diagnosis of TNVC, but rather in stratifying the likelihood of response to microvascular decompression in patients with characteristic symptoms. PMID- 26476279 TI - Delayed Deterioration in Isolated Traumatic Subarachnoid Hemorrhage. AB - BACKGROUND: Isolated traumatic subarachnoid hemorrhage (SAH) in association with mild traumatic brain injury is considered to be a less severe finding that is not likely to require surgical intervention. No previous reports have described cases warranting craniotomy for isolated traumatic SAH by itself. CASE DESCRIPTION: We report 2 cases of minor head trauma with isolated traumatic SAH that showed delayed clinical deterioration requiring immediate surgical intervention. Initial computed tomography showed isolated traumatic SAH in the basal cistern and Sylvian fissure in both cases. Angiography showed no aneurysmal source. Within 24 hours of each accident, both disturbance of consciousness and hemiparesis deteriorated. Follow-up computed tomography showed formation of intracerebral hematoma adjacent to the Sylvian fissure. Intraoperative findings showed abruption injury of a perforating branch arising from the middle cerebral artery (MCA) as the cause of bleeding. Impact at the time of injury could have caused traction on the MCA in the Sylvian fissure, resulting in abruption of the perforator. CONCLUSIONS: Isolated traumatic SAH seen in the basal cistern and Sylvian fissure carries a risk of late deterioration. A possible cause of hematoma expansion is abruption of a perforating branch arising from the MCA at the time of head injury. When hematoma expansion is identified, surgical evacuation of the hematoma is indicated. Surgical evacuation should be safely performed with the knowledge of the point of bleeding in such patients. PMID- 26476280 TI - In vivo and in vitro evaluation of novel MU-opioid receptor agonist compounds. AB - Opioids are the most effective and widely used drugs for pain treatment. Morphine is an archetypal opioid and is an opioid receptor agonist. Unfortunately, the clinical usefulness of morphine is limited by adverse effects such as analgesic tolerance and addiction. Therefore, it is important to study the development of novel opioid agonists as part of pain control. The analgesic effects of opioids are mediated by three opioid receptors, namely opioid MU-, delta-, and kappa receptors. They belong to the G protein-coupled receptor superfamily and are coupled to Gi proteins. In the present study, we developed a ligand screening system to identify novel opioid MU-receptor agonists that measures [(35)S]GTPgammaS binding to cell membrane fractions prepared from the fat body of transgenic silkworms expressing MU-receptor-Gi1alpha fusion protein. We screened the RIKEN Natural Products Depository (NPDepo) chemical library, which contains 5848 compounds, and analogs of hit compounds. We successfully identified a novel, structurally unique compound, that we named GUM1, with agonist activity for the opioid MU-receptor (EC50 of 1.2 uM). The Plantar Test (Hargreaves' Method) demonstrated that subcutaneous injection of 3mg/kg of GUM1 into wild-type rats significantly extended latency time. This extension was also observed in a rat model of morphine tolerance and was inhibited by pre-treatment of naloxone. The unique molecular skeleton of GUM1 makes it an attractive molecule for further ligand-opioid receptor binding studies. PMID- 26476281 TI - Systematic Review: Audiovisual Interventions for Reducing Preoperative Anxiety in Children Undergoing Elective Surgery. AB - OBJECTIVE: To examine the effectiveness of Audiovisual (AV) interventions at reducing preoperative anxiety and its associated outcomes in children undergoing elective surgery. METHODS: A systematic review of randomized controlled trials (RCTs) and nonrandomized studies where the primary outcome was children's preoperative anxiety was conducted. Secondary outcomes included postoperative pain, behavioral changes, recovery, induction compliance, satisfaction, and cost effectiveness. The risk of bias of each study was assessed. RESULTS: In all, 18 studies were identified. A meta-analytic approach and narrative synthesis of findings were used to summarize the results of the studies. CONCLUSIONS: This systematic review suggests that AV interventions can be effective in reducing children's preoperative anxiety. Videos, multi-faceted programs, and interactive games appear to be most effective, whereas music therapy and Internet programs are less effective. While AV interventions appear potentially useful, adequately powered RCTs are required to conclusively pinpoint the components and mechanisms of the most effective AV interventions and guide practice. PMID- 26476282 TI - Profiles of Dispositional Expectancies and Affectivity Predict Later Psychosocial Functioning in Children and Adolescents With Cancer. AB - OBJECTIVE: Examined how individual differences in disposition among pediatric cancer patients predict their later psychosocial functioning. METHODS: Patients aged 8-17 years (N = 223) reported on their disposition at baseline. One and three years later, self-reports and parent reports of patient psychosocial functioning were obtained. Latent profile analysis was used to identify subgroups that differed on baseline disposition and to compare them on later outcomes. ESULTS: Three groups were identified: The "Positive" group (59%) had high optimism and positive affectivity and low pessimism and negative affectivity; the "Moderate" group (39%) had a similar profile, with less exaggerated scores; a small, "Negative" group (2%) had the opposite profile (low optimism/positive affectivity; high pessimism/negative affectivity). These groups differed in psychosocial functioning at follow-up, generally in expected directions. CONCLUSIONS: Most patients have a disposition that may be protective. A small minority at high risk for maladjustment is distinguished by their disposition. PMID- 26476284 TI - An aid to generating figures for the American Journal of Epidemiology using SAS/GRAPH. AB - Data visualization is an important tool that epidemiologists use to communicate with others in the field. The American Journal of Epidemiology recently acknowledged the importance of data visualization by inaugurating an award for the "Figure of the Year." Yet, creating figures that adhere to the standards of the Journal is a challenge. The purpose of the present article was to provide helpful hints for creating figures in SAS/GRAPH that meet the requirements of the Journal. It stresses 3 techniques: properly sizing figures overall, sizing text within a figure, and creating acceptable file formats. This information will prove useful to authors who create data-driven figures intended to be published in the Journal. PMID- 26476283 TI - Who suffers during recessions? Economic downturns, job loss, and cardiovascular disease in older Americans. AB - Job loss in the years before retirement has been found to increase risk of cardiovascular disease (CVD), but some studies suggest that CVD mortality among older workers declines during recessions. We hypothesized that recessionary labor market conditions were associated with reduced CVD risk among persons who did not experience job loss and increased CVD risk among persons who lost their jobs. In our analyses, we used longitudinal, nationally representative data from Americans 50 years of age or older who were enrolled in the Health and Retirement Study and surveyed every 2 years from 1992 to 2010 about their employment status and whether they had experienced a stroke or myocardial infarction. To measure local labor market conditions, Health and Retirement Study data were linked to county unemployment rates. Among workers who experienced job loss, recessionary labor market conditions at the time of job loss were associated with a significantly higher CVD risk (hazard ratio = 2.54, 95% confidence interval: 1.39, 4.65). In contrast, among workers who did not experience job loss, recessionary labor market conditions were associated with a lower CVD risk (hazard ratio = 0.50, 95% confidence interval: 0.31, 0.78). These results suggest that recessions might be protective in the absence of job loss but hazardous in the presence of job loss. PMID- 26476285 TI - All-in-one dry-reagent time-resolved immunofluorometric assay for the rapid detection of HIV-1 and -2 infections. AB - An all-in-one (AIO) dry-reagent time-resolved fluorometric immunoassay that requires minimal liquid handling was developed for the detection of anti-HIV-1 and -2 antibodies. To prepare the AIO wells, in vivo biotinylated capture antigens (r-Bio-HIV-1env and r-Bio-HIV-2env) were immobilized on streptavidin coated microtitration wells and Eu(III) chelate labelled non-biotinylated tracer antigens [r-HIV-1env-Eu(III) and r-HIV-2env-Eu(III)] were dried in stable form in the same wells. The HIV AIO assay was evaluated with serum/plasma samples (n=148) from in-house and commercial panels at two different incubation times of 15 min and 1h. The overall sensitivity of the AIO assay was 98.6% and specificity was 100% for both the incubation times. The AIO assay can accept whole blood matrix. This assay is envisioned to fill the gap between the rapid point-of-care assays and traditional enzyme immunoassays (EIA) in terms of complexity and turnaround time, without compromising the performance. PMID- 26476287 TI - The T7 ejection nanomachine components gp15-gp16 form a spiral ring complex that binds DNA and a lipid membrane. AB - Bacteriophage T7 initiates infection by ejecting several internal capsid proteins into the host cell; these proteins then assemble into a nanomachine that translocates the viral genome from the phage head into the cytoplasm. The ejected proteins are thought to partially unfold as they pass through the lumen of the portal and the short stubby T7 tail during their entry into the cell. In vivo, the internal proteins gp15 and gp16 assemble into a tubular structure that spans the periplasm and cytoplasmic membrane. We show here that purified gp15 and gp16 can refold from a partially denatured state in vitro, and that gp15 interacts with gp16 to form a spiral ring structure. Purified gp15 binds to DNA, whereas gp16 binds protein-free liposomes; the gp15-gp16 complex binds both DNA and liposomes. Limited proteolysis of the liposome-bound gp16 reveals that its C terminal region is protected, suggesting a partial membrane insertion of the protein. PMID- 26476286 TI - Passing the baton: Community-based ethnography to design a randomized clinical trial on the effectiveness of oral pre-exposure prophylaxis for HIV prevention among Black men who have sex with men. AB - Although HIV interventions and clinical trials increasingly report the use of mixed methods, studies have not reported on the process through which ethnographic or qualitative findings are incorporated into RCT designs. We conducted a community-based ethnography on social and structural factors that may affect the acceptance of and adherence to oral pre-exposure prophylaxis (PrEP) among Black men who have sex with men (BMSM). We then devised the treatment arm of an adherence clinical trial drawing on findings from the community-based ethnography. This article describes how ethnographic findings informed the RCT and identifies distilled themes and findings that could be included as part of an RCT. The enhanced intervention includes in-person support groups, online support groups, peer navigation, and text message reminders. By describing key process related facilitators and barriers to conducting meaningful mixed methods research, we provide important insights for the practice of designing clinical trials for 'real-world' community settings. PMID- 26476288 TI - Prevalence of Panton-Valentine leucocidin and phenotypic and genotypic characterization of biofilm formation among Staphylococcus aureus strains isolated from children with adenoid hypertrophy. AB - Adenoids as a first line of host defense against respiratory microbes play an important role in majority of upper airway infectious and noninfectious illnesses. Bacterial pathogen can colonize on the adenoid tissue and probably act as a reservoir for them. To determine phenotypic and genotypic characterization of biofilm forming capacity of Staphylococcus aureus isolates from children with adenoid hypertrophy and prevalence of Panton-Valentine leukocidin (PVL) gene we collected 17 consecutive, clinically significant S. aureus isolates from children with adenoid hypertrophy undergoing adenoidectomy with one or more of the upper airway obstruction symptoms, nasal obstruction, mouth breathing, snoring, or sleep apnea. Biofilm formation was evaluated by colorimetric microtiter plate's assay. Gene encoding PVL and adhesion- or biofilm formation-encoding genes were targeted by polymerase chain reaction (PCR) assay. According to the results, all strains produced biofilm. Seven (41.2%) isolates produced strong biofilm whereas 7 (41.2%) isolates produced week and 3 (17.6%) isolates produced medium biofilm. Regarding the adhesion- or biofilm formation-encoding genes, 16 (94.1%) isolates were positive for the gene eno, 13(76.4%) for icaA, 13 (76.4%) for icaD, 10 (58.8%) for fib, 10 (58.8%) for fnbB, 4(23.5%) for can, and 1(5.8%) for fnbA. The high prevalence of genes encoding biofilms and adhesins and phenotypic ability to form a biofilm by S. aureus strains emphasizes the pathogenic character of strains isolated from children with adenoid hypertrophy. PMID- 26476289 TI - Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans. AB - BACKGROUND & AIMS: Cumulating evidence underlines the crucial role of aberrant lipogenesis in human hepatocellular carcinoma (HCC). Here, we investigated the oncogenic potential of fatty acid synthase (FASN), the master regulator of de novo lipogenesis, in the mouse liver. METHODS: FASN was overexpressed in the mouse liver, either alone or in combination with activated N-Ras, c-Met, or SCD1, via hydrodynamic injection. Activated AKT was overexpressed via hydrodynamic injection in livers of conditional FASN or Rictor knockout mice. FASN was suppressed in human hepatoma cell lines via specific small interfering RNA. RESULTS: Overexpression of FASN, either alone or in combination with other genes associated with hepatocarcinogenesis, did not induce histological liver alterations. In contrast, genetic ablation of FASN resulted in the complete inhibition of hepatocarcinogenesis in AKT-overexpressing mice. In human HCC cell lines, FASN inactivation led to a decline in cell proliferation and a rise in apoptosis, which were paralleled by a decrease in the levels of phosphorylated/activated AKT, an event controlled by the mammalian target of rapamycin complex 2 (mTORC2). Downregulation of AKT phosphorylation/activation following FASN inactivation was associated with a strong inhibition of rapamycin insensitive companion of mTOR (Rictor), the major component of mTORC2, at post transcriptional level. Finally, genetic ablation of Rictor impaired AKT-driven hepatocarcinogenesis in mice. CONCLUSIONS: FASN is not oncogenic per se in the mouse liver, but is necessary for AKT-driven hepatocarcinogenesis. Pharmacological blockade of FASN might be highly useful in the treatment of human HCC characterized by activation of the AKT pathway. PMID- 26476290 TI - Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12weeks. AB - BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) infection and cirrhosis have a higher risk for liver-related complications and have historically been more difficult to cure than patients without cirrhosis. We evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir, without ribavirin, for 12weeks in patients with HCV genotype 1b infection and compensated cirrhosis. METHODS: Treatment-naive and peginterferon/ribavirin treatment-experienced patients received 12weeks of ombitasvir/paritaprevir/ritonavir (25/150/100mg once daily) and dasabuvir (250mgtwicedaily). Key inclusion criteria were hemoglobin ?10g/dl, albumin ?2.8g/dl, platelet count ?25*10(9)/L, creatinine clearance ?30ml/min, and Child Pugh score ?6. Efficacy was assessed by the percentage of patients achieving SVR (HCV RNA <25IU/ml) 12weeks post-treatment (SVR12). Efficacy and safety were assessed in all patients receiving study drug. RESULTS: Sixty patients with HCV genotype 1b infection and cirrhosis received treatment. The study population comprised 62% male, 55% treatment-experienced, 83% with IL28B non-CC genotype, 22% with platelet count <90*10(9)/L, and 17% with albumin <3.5g/dl. All 60 patients completed treatment, and SVR12 was achieved in 100% (95% CI, 94.0-100%) of patients. The most common adverse events were fatigue (22%), diarrhea (20%), and headache (18%). Only one patient (1.7%) experienced a serious adverse event. Laboratory abnormalities were infrequently observed and not clinically significant. CONCLUSIONS: The HCV regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir without ribavirin for 12weeks achieved 100% SVR12 and was well tolerated in HCV genotype 1b-infected patients with cirrhosis, suggesting that this 12-week ribavirin-free regimen is sufficient in this population. PMID- 26476292 TI - Different gene expression profiles between normal and thermally selected strains of rainbow trout, Oncorhynchus mykiss, as revealed by comprehensive transcriptome analysis. AB - A high-temperature selected (HT) strain of rainbow trout was established from the Donaldson (DS) strain by traditional selective breeding in Japan. The aim of this study is to investigate genes related to upper temperature tolerance in this strain utilizing next generation sequencer (NGS), and to establish comprehensive and comparable datasets in brain, liver, muscle, heart and gill tissues between the HT and DS strains. After assembling, clustering and filtering, 242,530 contigs were obtained. Among them, 7624 transcripts had at least 10 counts in expression analysis in all tissues and used as references. BLASTX homology search showed that 7329 transcripts matched with known genes. Compared to the DS strain, the HT strain expressed 90, 775, 349, 188 and 194 genes 2 folds or more in brain, liver, muscle, heart, and gill, respectively in the case of fish before heat exposure treatment. Meanwhile, the HT strain expressed 292, 363, 433, 322 and 211 genes 2 folds or more in brain, liver, muscle, heart, and gill, respectively in case of fish after heat-exposure treatment. Many of heat shock protein family genes and transcription factor AP-1 related genes were highly expressed in all tissues of the HT strain compared with the DS strain. These results suggest that these genes play key roles in upper temperature tolerance. These comprehensive and comparable datasets will offer broad visions for upper temperature tolerance in fish species. PMID- 26476291 TI - Association of the microRNA-Single Nucleotide Polymorphism rs2910164 in miR146a with sporadic breast cancer susceptibility: A case control study. AB - BACKGROUND: Breast cancer (BC) is primarily considered a genetic disorder with a complex interplay of factors including age, gender, ethnicity, family history, personal history and lifestyle with associated hormonal and non-hormonal risk factors. The SNP rs2910164 in miR146a (a G to C polymorphism) was previously associated with increased risk of BC in cases with at least a single copy of the C allele in breast cancer, though results in other cancers and populations have shown significant variation. METHODS: In this study, we examined this SNP in an Australian sporadic breast cancer population of 160 cases and matched controls, with a replicate population of 403 breast cancer cases using High Resolution Melting. RESULTS: Our analysis indicated that the rs2910164 polymorphism is associated with breast cancer risk in both primary and replicate populations (p=0.03 and 0.0013, respectively). In contrast to the results of familial breast cancer studies, however, we found that the presence of the G allele of rs2910164 is associated with increased cancer risk, with an OR of 1.77 (95% CI 1.40-2.23). CONCLUSIONS: The microRNA miR146a has a potential role in the development of breast cancer and the effects of its SNPs require further inquiry to determine the nature of their influence on breast tissue and cancer. PMID- 26476293 TI - Massively parallel sequencing-based survey of eukaryotic community structures in Hiroshima Bay and Ishigaki Island. AB - In this study, we compared the eukaryote biodiversity between Hiroshima Bay and Ishigaki Island in Japanese coastal waters by using the massively parallel sequencing (MPS)-based technique to collect preliminary data. The relative abundance of Alveolata was highest in both localities, and the second highest groups were Stramenopiles, Opisthokonta, or Hacrobia, which varied depending on the samples considered. For microalgal phyla, the relative abundance of operational taxonomic units (OTUs) and the number of MPS were highest for Dinophyceae in both localities, followed by Bacillariophyceae in Hiroshima Bay, and by Bacillariophyceae or Chlorophyceae in Ishigaki Island. The number of detected OTUs in Hiroshima Bay and Ishigaki Island was 645 and 791, respectively, and 15.3% and 12.5% of the OTUs were common between the two localities. In the non-metric multidimensional scaling analysis, the samples from the two localities were plotted in different positions. In the dendrogram developed using similarity indices, the samples were clustered into different nodes based on localities with high multiscale bootstrap values, reflecting geographic differences in biodiversity. Thus, we succeeded in demonstrating biodiversity differences between the two localities, although the read numbers of the MPSs were not high enough. The corresponding analysis showed a clear seasonal change in the biodiversity of Hiroshima Bay but it was not clear in Ishigaki Island. Thus, the MPS-based technique shows a great advantage of high performance by detecting several hundreds of OTUs from a single sample, strongly suggesting the effectiveness to apply this technique to routine monitoring programs. PMID- 26476294 TI - A longer finger-subdomain of family A DNA polymerases found by metagenomic analysis strengthens DNA binding and primer extension abilities. AB - The family A DNA polymerases from thermophilic bacteria are useful for PCR. The DNA polymerase from Thermus aquaticus (Taq polymerase) was the original enzyme used when practical PCR was developed, and it has remained the standard enzyme for PCR to date. Knowledge gained from structure-function relationship studies of Taq polymerase is applicable to create PCR enzymes with enhanced performance. We collected the deduced amino acid sequences of the regions from motif A to motif C in the family A DNA polymerases from metagenomic sequence data, obtained by sequencing DNAs from microorganisms isolated from various hot spring areas in Japan. The corresponding regions of the polA gene for Taq polymerase were substituted with the metagenomic DNA gene fragments, and various chimeric DNA polymerases were prepared. Based on the properties of these chimeric enzymes and their sequences, we found an insertion sequence that affects the primer extension ability of the family A DNA polymerases. The insertion sequence is located in the finger subdomain, and it may enhance the affinity of the enzyme to DNA. Mutant Taq polymerases with the corresponding 9 amino acid insertion displayed enhanced PCR performance. PMID- 26476295 TI - Phytochemical screening of Artemisia arborescens L. by means of advanced chromatographic techniques for identification of health-promoting compounds. AB - Artemisia arborescens, also known as tree wormwood, is a typical species of the Mediterranean flora. It has been used in folk medicine for its antispasmodic, anti-pyretic, anti-inflammatory, and abortifacient properties. In the current study, the application of multidimensional comprehensive gas chromatography (GC*GC), allowed to obtain a detailed fingerprint of the essential oil from A. arborescens aerial parts, highlighting an abundant presence of chamazulene followed by camphor, beta-thujone, myrcene, and alpha-pinene. Moreover, flavonoids in the dichloromethane extract were analyzed by means of liquid chromatography with photodiode array and atmospheric pressure chemical ionization mass spectrometry detections (HPLC-PDA and HPLC-APCI-MS). Six polymethoxyflavones were identified and three of them, including chrysosplenetin, eupatin, and cirsilineol, were described in this species for the first time. The anti angiogenic activity was investigated in the dichloromethane extract by two in vivo models, chick chorioallantoic membrane (CAM) and zebrafish embryos. Results showed that this extract produced a strong reduction on vessel formation, both on zebrafish (57% of inhibition, 0.1 mg/mL) and chick chorioallantoic membrane (58% of inhibition, 0.8 mg/mL). The high separation power and sensitivity of the analytical methodology applied confirmed the safety of A. arborescens essential oil for human consumption, due to the very low level of the psychotrope alpha thujone determined. Moreover, the knowledge of the flavonoidic profile holds a great significance for the use of A. arborescens as a valuable source of anti angiogenic compounds that might contribute to the valorization of the phytotherapeutic potential of this plant. PMID- 26476296 TI - Selective ion monitoring of quinochalcone C-glycoside markers for the simultaneous identification of Carthamus tinctorius L. in eleven Chinese patent medicines by UHPLC/QTOF MS. AB - Current China Pharmacopoeia standards for the Chinese patent medicines (CPMs) that contain one or several the same drug(s) employ case-dependent TLC or HPLC approaches to achieve qualitative identification. A qualitative "monomethod heterotrait matrix" (MHM) strategy is thus proposed, by selective monitoring of multi-biomarkers, to achieve the identification of different CPMs. Carthamus tinctorius L. (safflower) is a reputable gynecological herbal medicine containing characteristic quinochalcone C-glycosides (QCGs) as the major bioactive components. Qualitative identification of safflower in diverse CPMs by selective monitoring of QCG markers was performed by use of the MHM strategy. Initially, 27 QCG analogs (involving 16 potentially new ones) were selectively characterized by product ion filtering (m/z 119.05) and integrated analysis of the negative mode MS(E) and Fast DDA data obtained on a UHPLC/QTOF mass spectrometer. Subsequently, by fingerprint analysis of 20 batches of safflower samples followed by a thermostable test, six QCGs (hydroxysafflor yellow A and its two isomers, anhydrosafflor yellow B, safflomin C, and isosafflomin C) were selected as the biomarkers for safflower. Then, a highly specific selective ion monitoring (SIM) method by recording centroided data was developed and applied to selectively profile six QCG biomarkers from 28 batches of CPM samples collected from versatile vendors. By reference to a standard SIM spectrum established using a home-made safflower reference extract, simultaneous identification of safflower in eleven different CPMs was accomplished with the unified sample preparation and a single UHPLC/QTOF-SIM method. The qualitative MHM strategy represents the novel methodology that facilitates the quality control of CPMs more efficiently. PMID- 26476297 TI - Multivariate data analysis and metabolic profiling of artemisinin and related compounds in high yielding varieties of Artemisia annua field-grown in Madagascar. AB - An improved liquid chromatography-tandem mass spectrometry (LC-MS/MS) protocol for rapid analysis of co-metabolites of A. annua in raw extracts was developed and extensively characterized. The new method was used to analyse metabolic profiles of 13 varieties of A. annua from an in-field growth programme in Madagascar. Several multivariate data analysis techniques consistently show the association of artemisinin with dihydroartemisinic acid. These data support the hypothesis of dihydroartemisinic acid being the late stage precursor to artemisinin in its biosynthetic pathway. PMID- 26476299 TI - Iron absorption in nonalcoholic steatohepatitis and dysmetabolic iron overload syndrome. PMID- 26476298 TI - Regulation of the plasma membrane proton pump (H(+)-ATPase) by phosphorylation. AB - In plants and fungi, energetics at the plasma membrane is provided by a large protonmotive force (PMF) generated by the family of P-type ATPases specialized for proton transport (commonly called PM H(+)-ATPases or, in Arabidopsis, AHAs for Arabidopsis H(+)-ATPases). Studies have demonstrated that this 100-kDa protein is essential for plant growth and development. Posttranslational modifications of the H(+)-ATPase play crucial roles in its regulation. Phosphorylation of several Thr and Ser residues within the carboxy terminal regulatory domain composed of ~100 amino acids change in response to environmental stimuli, endogenous hormones, and nutrient conditions. Recently developed mass spectrometric technologies provide a means to carefully quantify these changes in H(+)-ATPase phosphorylation at the different sites. These chemical modifications can then be genetically tested in planta by complementing the loss-of-function aha mutants with phosphomimetic mutations. Interestingly, recent data suggest that phosphatase-mediated changes in PM H(+)-ATPase phosphorylation are important in mediating auxin-regulated growth. Thus, as with another hormone (abscisic acid), dephosphorylation by phosphatases, rather than kinase mediated phosphorylation, may be an important focal point for regulation during plant signal transduction. Although interactions with other proteins have also been implicated in ATPase regulation, the very hydrophobic nature and high concentration of this polytopic protein presents special challenges in evaluating the biological significance of these interactions. Only by combining biochemical and genetic experiments can we attempt to meet these challenges to understand the essential molecular details by which this protein functions in planta. PMID- 26476301 TI - MicroRNA as biomarkers of mitochondrial toxicity. AB - Mitochondrial toxicity can be difficult to detect as most cells can tolerate reduced activity as long as minimal capacity for function is maintained. However, once minimal capacity is lost, apoptosis or necrosis occurs quickly. Identification of more sensitive, early markers of mitochondrial toxicity was the objective of this work. Rotenone, a mitochondrial complex I inhibitor, and 3 nitropropionic acid (3-NP), a mitochondrial complex II inhibitor, were administered daily to male Sprague-Dawley rats at subcutaneous doses of 0.1 or 0.3mg/kg/day and intraperitoneal doses of 5 or 10mg/kg/day, respectively, for 1week. Samples of kidney, skeletal muscle (quadriceps femoris), and serum were collected for analysis of mitochondrial DNA (mtDNA) copy number and microRNA (miRNA) expression patterns. MtDNA was significantly decreased with administration of rotenone at 0.3mg/kg/day and 3-NP at 5 and 10mg/kg/day in the quadriceps femoris and with 3-NP at 10mg/kg/day in the kidney. Additionally, rotenone and 3-NP treatment produced changes to miRNA expression that were similar in direction (i.e. upregulation, downregulation) to those previously linked to mitochondrial functions, such as mitochondrial damage and biogenesis (miR-122, miR-202-3p); regulation of ATP synthesis, abolished oxidative phosphorylation, and loss of membrane potential due to increased reactive oxygen species (ROS) production (miR-338-5p, miR-546, miR-34c); and mitochondrial DNA damage and depletion (miR-546). These results suggest that miRNAs may be sensitive biomarkers for early detection of mitochondrial toxicity. PMID- 26476300 TI - Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling. AB - 4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has been shown to induce apoptosis in a variety of cell lines. It appears to modulate signaling processes in more than one way because it has been suggested to have a role in signaling for differentiation and proliferation. It has been known that glutathione S-transferases (GSTs) can reduce lipid hydroperoxides through their Se-independent glutathione-peroxidase activity and that these enzymes can also detoxify LPO end-products such as 4HNE. Available evidence from earlier studies together with results of recent studies in our laboratories strongly suggests that LPO products, particularly hydroperoxides and 4HNE, are involved in the mechanisms of stress-mediated signaling and that it can be modulated by the alpha-class GSTs through the regulation of the intracellular concentrations of 4HNE. We demonstrate that 4HNE induced apoptosis in various cell lines is accompanied with c-Jun-N-terminal kinase (JNK) and caspase-3 activation. Cells exposed to mild, transient heat or oxidative stress acquire the capacity to exclude intracellular 4HNE at a faster rate by inducing GSTA4-4 which conjugates 4HNE to glutathione (GSH), and RLIP76 which mediates the ATP-dependent transport of the GSH-conjugate of 4HNE (GS-HNE). The balance between formation and exclusion promotes different cellular processes - higher concentrations of 4HNE promote apoptosis; whereas, lower concentrations promote proliferation. In this article, we provide a brief summary of the cellular effects of 4HNE, followed by a review of its GST-catalyzed detoxification, with an emphasis on the structural attributes that play an important role in the interactions with alpha-class GSTA4-4. Taken together, 4HNE is a key signaling molecule and that GSTs being determinants of its intracellular concentrations, can regulate stress-mediated signaling, are reviewed in this article. PMID- 26476303 TI - Arsenic adsorption by iron-aluminium hydroxide coated onto macroporous supports: Insights from X-ray absorption spectroscopy and comparison with granular ferric hydroxides. AB - This paper evaluates the arsenic adsorption characteristics of a macroporous polymer coated with coprecipitated iron-aluminium hydroxides (MHCMP). The MHCMP adsorbent-composite fits best with a pseudo-second order model for As(III) and a pseudo-first order kinetic model for As(V). The MHCMP shows a maximum adsorption capacity of 82.3 and 49.6 mg As/g adsorbent for As(III) and As(V) ions respectively, and adsorption followed the Langmuir model. Extended X-ray absorption fine structure showed that binding of As(III) ions were confirmed to take place on the iron hydroxides coated on the MHCMP, whereas for As(V) ions the binding specificity could not be attributed to one particular metal hydroxide. As(III) formed a bidentate mononuclear complex with Fe sites, whereas As(V) indicated on a bidentate binuclear complex with Al sites or monodentate with Fe sites on the adsorbent. The column experiments were run in a well water spiked with a low concentration of As(III) (100 MUg/L) and a commercially available adsorbent (GEH((r))102) based on granular iron-hydroxide was used for comparison. It was found that the MHCMP was able to treat 7 times more volume of well water as compared to GEH((r))102, maintaining the threshold concentration of less than 10 MUg As/L, indicating that the MHCMP is a superior adsorbent. PMID- 26476302 TI - Chronic exposure to biomass fuel smoke and markers of endothelial inflammation. AB - Indoor smoke exposure may affect cardiovascular disease (CVD) risk via lung mediated inflammation, oxidative stress, and endothelial inflammation. We sought to explore the association between indoor smoke exposure from burning biomass fuels and a selected group of markers for endothelial inflammation. We compared serum concentrations of amyloid A protein, E-selectin, soluble intercellular adhesion molecule 1 (ICAM-1) and VCAM-1, von Willebrand factor (vWF), and high sensitivity C-reactive protein (hs-CRP) in 228 biomass-exposed vs. 228 non exposed participants living in Puno, Peru. Average age was 56 years (s.d. = 13), average BMI was 26.5 kg/m(2) (s.d. = 4.4), 48% were male, 59.4% completed high school, and 2% reported a physician diagnosis of CVD. In unadjusted analysis, serum levels of soluble ICAM-1 (330 vs. 302 ng/ml; P < 0.001), soluble VCAM-1 (403 vs. 362 ng/ml; P < 0.001), and E-selectin (54.2 vs. 52.7 ng/ml; P = 0.05) were increased in biomass-exposed vs. non-exposed participants, respectively, whereas serum levels of vWF (1148 vs. 1311 mU/ml; P < 0.001) and hs-CRP (2.56 vs. 3.12 mg/l; P < 0.001) were decreased, respectively. In adjusted analyses, chronic exposure to biomass fuels remained positively associated with serum levels of soluble ICAM-1 (P = 0.03) and VCAM-1 (P = 0.05) and E-selectin (P = 0.05), and remained negatively associated with serum levels of vWF (P = 0.02) and hs-CRP (P < 0.001). Daily exposure to biomass fuel smoke was associated with important differences in specific biomarkers of endothelial inflammation and may help explain accelerated atherosclerosis among those who are chronically exposed. PMID- 26476304 TI - Biotransformation of pharmaceuticals in surface water and during waste water treatment: Identification and occurrence of transformation products. AB - Venlafaxine, gemfibrozil, ibuprofen, irbesartan and ofloxacin are highly-consumed pharmaceuticals that show considerable removal efficiencies (between 40 and 98%) in wastewater treatment plants (WWTPs). Consequently, they are expected to generate transformation products (TPs) during wastewater treatment and in surface water (SW) receiving WWTP effluent. In this work, degradation experiments for these five pharmaceuticals have been carried out with SW and WWTP activated sludge under laboratory-controlled aerobic conditions to identify their transformation products by liquid chromatography coupled to time-of-flight mass spectrometry (LC-QTOF MS). Initially, 22 pharmaceutical TPs were tentatively identified. A retrospective analysis was performed in effluent wastewater (EWW) and SW samples. All parent compounds as well as several TPs were found in some of the selected EWW and SW samples. Additionally, valsartan and 3 TPs were also detected by searching for common fragments in these waters. It is important to highlight that some TPs, such as O-desmethyl-venlafaxine and an oxidized gemfibrozil TP, were more frequently found than their corresponding parent compounds. On the basis of these results, it would be recommendable to include these TPs (at least those found in EWW and SW samples analyzed) in monitoring programs in order to gain a more realistic understanding of the impact of pharmaceuticals on water quality. PMID- 26476305 TI - Preparation of graphene oxide-wrapped carbon sphere@silver spheres for high performance chlorinated phenols sensor. AB - A template-activated strategy was developed to construct core/shell structured carbon sphere@silver composite based on one-pot hydrothermal treatment. The CS@Ag possessed a uniform three-dimensional interconnected microstructure with an enlarged surface area and catalytic activity, which was further mechanically protected by graphene oxide (GO) nanolayers to fabricate intriguing configuration, which was beneficial for efficiently preventing the aggregation and oxidation of AgNPs and improving the electrical conductivity through intimate contact. By immobilizing this special material on electrode surface, the CS@Ag@GO was further used for sensitive determination of chlorinated phenols including 2 chlorophenol, 4-chlorophenol, 2,4-dichlorophenol and 2,4,6-trichlorophenol. The tailored structure, fast electron transfer ability and facile preparation of CS@Ag@GO made it a promising electrode material for practical applications in phenols sensing. PMID- 26476306 TI - Emissions of air pollutants from indoor charcoal barbecue. AB - Ten types of commercial charcoal commonly used in Taiwan were investigated to study the potential health effects of air pollutants generated during charcoal combustion in barbecue restaurants. The charcoal samples were combusted in a tubular high-temperature furnace to simulate the high-temperature charcoal combustion in barbecue restaurants. The results indicated that traditional charcoal has higher heating value than green synthetic charcoal. The amount of PM10 and PM2.5 emitted during the smoldering stage increased when the burning temperature was raised. The EF for CO and CO2 fell within the range of 68-300 and 644-1225 g/kg, respectively. Among the charcoals, the lowest EF for PM2.5 and PM10 were found in Binchotan (B1). Sawdust briquette charcoal (I1S) emitted the smallest amount of carbonyl compounds. Charcoal briquettes (C2S) emitted the largest amount of air pollutants during burning, with the EF for HC, PM2.5, PM10, formaldehyde, and acetaldehyde being the highest among the charcoals studied. The emission of PM2.5, PM10, formaldehyde, and acetaldehyde were 5-10 times those of the second highest charcoal. The results suggest that the adverse effects of the large amounts of air pollutants generated during indoor charcoal combustion on health and indoor air quality must not be ignored. PMID- 26476307 TI - Using risk elasticity to prioritize risk reduction strategies for geographical areas and industry sectors. AB - The total quantity of chemical emissions does not take into account their chemical toxicity, and fails to be an accurate indicator of the potential impact on human health. The sources of released contaminants, and therefore, the potential risk, also differ based on geography. Because of the complexity of the risk, there is no integrated method to evaluate the effectiveness of risk reduction. Therefore, this study developed a method to incorporate the spatial variability of emissions into human health risk assessment to evaluate how to effectively reduce risk using risk elasticity analysis. Risk elasticity analysis, the percentage change in risk in response to the percentage change in emissions, was adopted in this study to evaluate the effectiveness and efficiency of risk reduction. The results show that the main industry sectors are different in each area, and that high emission in an area does not correspond to high risk. Decreasing the high emissions of certain sectors in an area does not result in efficient risk reduction in this area. This method can provide more holistic information for risk management, prevent the development of increased risk, and prioritize the risk reduction strategies. PMID- 26476308 TI - Inhibition of marine Vibrio sp. by pyoverdine from Pseudomonas aeruginosa PA1. AB - Siderophores are low-molecular-weight chemicals that are secreted by many microorganisms to chelate iron from the external environment in order to facilitate their growth and diverse metabolisms. In this study, a fluorescent siderophore, pyoverdine, secreted by Pseudomonas aeruginosa PA1 was purified by affinity chromatography using Cu-sepharose. Pyoverdine was determined to have a molecular mass of 1333.54 Da, as determined by MALDI-TOF/TOF, and belong to type I pyoverdine, as determined by PCR analysis of its corresponding outer membrane ferri-pyoverdine receptor. Pyoverdine showed different degrees of inhibitory effects on the growth of marine Vibrio sp. strains. It was also shown that the biofilm developed by Vibrio parahaemolyticus WzW1 and Wz2121 and Vibrio cyclitrophicus HS12 was significantly reduced, alone with the repressed growth in the presence of pyoverdine. Siderophore production was determined in the strains of Vibrio sp. in response to the pyoverdine-induced iron-limited conditions. The siderophore production of most Vibrio sp. was up-regulated, with the exception of the bacteria that produced little siderophore. Furthermore, Apostichopus japonicus cultured in pyoverdine pretreated seawater showed a relative percent of survival of 89% when they were challenged by Vibrio splendidus. Our results demonstrated that pyoverdine may be a promising agent that could be potentially applied to treat vibriosis. PMID- 26476309 TI - Improved WO3 photocatalytic efficiency using ZrO2 and Ru for the degradation of carbofuran and ampicillin. AB - The photocatalytic degradation of carbofuran (pesticide) and ampicillin (pharmaceutical) using synthesized WO3/ZrO2 nanoparticles under simulated solar light was investigated. Transmission electron microscopy (TEM), X-ray diffraction (XRD), and Raman spectra analyses were used to characterize the prepared catalysts. The optimum ratio of WO3 to ZrO2 was determined to be 1:1 for the degradation of both contaminants. The degradation of carbofuran and ampicillin by WO3/ZrO2 after 240 min of irradiation was 100% and 96%, respectively. Ruthenium (Ru) was employed as an additive to WO3/ZrO2 to enhance the photocatalytic degradation rate. Ru/WO3/ZrO2 exhibited faster degradation rates than WO3/ZrO2. Furthermore, 100% and 97% degradation of carbofuran and ampicillin, respectively, was achieved using Ru/WO3/ZrO2 after 180 min of irradiation. The durability of the catalyst was investigated by reusing the same suspended catalyst, which achieved 92% of its initial efficiency. The photocatalytic degradation of ampicillin and carbofuran followed pseudo-first order kinetics according to the Langmuir-Hinshelwood model. PMID- 26476310 TI - A newly isolated Pseudomonas putida S-1 strain for batch-mode-propanethiol degradation and continuous treatment of propanethiol-containing waste gas. AB - Pseudomonas putida S-1 was isolated from activated sludge. This novel strain was capable of degrading malodorous 1-propanethiol (PT). PT degradation commenced with no lag phase by cells pre-grown in nutrition-rich media, such as Luria Bertani (LB), and PT-contained mineral medium at specific growth rates of 0.10 0.19 h(-1); this phenomenon indicated the operability of a large-scale cell culture. A possible PT degradation pathway was proposed on the basis of the detected metabolites, including dipropyl disulfide, 3-hexanone, 2-hexanone, 3 hexanol, 2-hexanol, S(0), SO4(2-), and CO2. P. putida S-1 could degrade mixed pollutants containing PT, diethyl disulfide, isopropyl alcohol, and acetaldehyde, and LB-pre-cultured cells underwent diauxic growth. Waste gas contaminated with 200-400 mg/m(3) PT was continuously treated by P. putida S-1 pre-cultured in LB medium in a completely stirred tank reactor. The removal efficiencies exceeded 88% when PT stream was mixed with 200 mg/m(3) isopropanol; by contrast, the removal efficiencies decreased to 60% as the empty bed residence time was shortened from 40 s to 20 s. PMID- 26476311 TI - Experimental study on cesium immobilization in struvite structures. AB - Ceramicrete, a chemically bonded phosphate ceramic, was developed for nuclear waste immobilization and nuclear radiation shielding. Ceramicrete products are fabricated by an acid-base reaction between magnesium oxide and mono potassium phosphate that has a struvite-K mineral structure. In this study, we demonstrate that this crystalline structure is ideal for incorporating radioactive Cs into a Ceramicrete matrix. This is accomplished by partially replacing K by Cs in the struvite-K structure, thus forming struvite-(K, Cs) mineral. X-ray diffraction and thermo-gravimetric analyses are used to confirm such a replacement. The resulting product is non-leachable and stable at high temperatures, and hence it is an ideal matrix for immobilizing Cs found in high-activity nuclear waste streams. The product can also be used for immobilizing secondary waste streams generated during glass vitrification of spent fuel, or the method described in this article can be used as a pretreatment method during glass vitrification of high level radioactive waste streams. Furthermore, it suggests a method of producing safe commercial radioactive Cs sources. PMID- 26476312 TI - Efficient remediation of PAH-metal co-contaminated soil using microbial-plant combination: A greenhouse study. AB - A 2-year greenhouse study was conducted to remediate an actual wastewater irrigated soil co-contaminated with polycyclic aromatic hydrocarbons (PAHs) and heavy metals (Cd and Zn). The remediation methods included microbial remediation, phytoremediation, and microbe-assisted phytoremediation. The maximum PAH removal (96.4%), PAH mineralization, and metal phytoextraction (36.1% Cd and 12.7% Zn) were obtained by interplanting ryegrass with Seduce alfredii with regular re inoculation with Microbacterium sp. KL5 and Candida tropicalis C10 in the co contaminated soil. The plants shoots were harvested at a 4-month interval. After 2 years, the concentrations of 16 individual PAHs were reduced to below the limit of Chinese soil quality standard for agricultural use (grade II, pH 6.5-7.5), and the metal concentrations in ryegrass shoots were below the Chinese national limit for animal feeds (GB13078-2001). The exogenous microbes gradually disappeared with time, and thus a 2-month re-inoculation interval was applied for a purpose to maintain high cell density and activity of the inoculants. KL5 introduction increased soil enzyme activity, plant growth, PAH removal and metal phytoextraction, while C10 promoted soil enzyme activity and removal of high molecular-weight PAHs. Interplanting with S. alfredii reduced metal concentrations in ryegrass tissues. Ryegrass showed stronger rhizosphere effects than S. alfredii did. PMID- 26476313 TI - Kinetics and thermodynamics of interaction between sulfonamide antibiotics and humic acids: Surface plasmon resonance and isothermal titration microcalorimetry analysis. AB - The presence of sulfonamide antibiotics in the environments has been recognized as a crucial issue. Their migration and transformation in the environment is determined by natural organic matters that widely exist in natural water and soil. In this study, the kinetics and thermodynamics of interactions between humic acids (HA) and sulfamethazine (SMZ) were investigated by employing surface plasmon resonance (SPR) combined with isothermal titration microcalorimetry (ITC) technologies. Results show that SMZ could be effectively bound with HA. The binding strength could be enhanced by increasing ionic strength and decreasing temperature. High pH was not favorable for the interaction. Hydrogen bond and electrostatic interaction may play important roles in driving the binding process, with auxiliary contribution from hydrophobic interaction. The results implied that HA existed in the environment may have a significant influence on the migration and transformation of organic pollutants through the binding process. PMID- 26476314 TI - Effects of digestate on soil chemical and microbiological properties: A comparative study with compost and vermicompost. AB - Anaerobic digestion has become increasingly popular as an alternative for recycling wastes from different origins. Consequently, biogas residues, most of them with unknown chemical and biological composition, accrue in large quantities and their application into soil has become a widespread agricultural practise. The aim of this study was to evaluate the effects of digestate application on the chemical and microbiological properties of an arable soil in comparison with untreated manure, compost and vermicompost. Once in the soil matrix either the addition of compost or digestate led to an increased nitrification rate, relative to unamended and manure-treated soil, after 15 and 60 days of incubation. Faecal coliform and E. coli colony forming units (CFUs) were not detected in any of the amended soils after 60 days. The highest number of Clostridium perfringens CFUs was recorded in manure-amended soil at the beginning of the experiment and after 15 days; whilst after 60 days the lowest CFU number was registered in digestate treated soil. Denaturing gradient gel electrophoresis patterns also showed that besides the treatment the date of sampling could have contributed to modifications in the soil ammonia-oxidising bacteria community, thereby indicating that the soil itself may influence the community diversity more strongly than the treatments. PMID- 26476315 TI - Engineering metal-binding sites of bacterial CusF to enhance Zn/Cd accumulation and resistance by subcellular targeting. AB - The periplasmic protein CusF acts as a metallochaperone to mediate Cu resistance in Escherichia coli. CusF does not contain cysteine residues and barely binds to divalent cations. Here, we addressed effects of cysteine-substitution mutant (named as mCusF) of CusF on zinc/cadmium (Zn/Cd) accumulation and resistance. We targeted mCusF to different subcellular compartments in Arabidopsis. We found that plants expressing vacuole-targeted mCusF were more resistant to excess Zn than WT and plants with cell wall-targeted or cytoplasmic mCusF. Under long-term exposure to excess Zn, all transgenic lines accumulated more Zn (up to 2.3-fold) in shoots than the untransformed plants. Importantly, plants with cytoplasmic mCusF showed higher efficiency of Zn translocation from root to shoot than plants with secretory pathway-targeted-mCusF. Furthermore, the transgenic lines exhibited enhanced resistance to Cd and significant increase in root-to-shoot Cd translocation. We also found all transgenic plants greatly improved manganese (Mn) and iron (Fe) homeostasis under Cd exposure. Our results demonstrate heterologous expression of mCusF could be used to engineer a new phytoremediation strategy for Zn/Cd and our finding also deepen our insights into mechanistic basis for relieving Cd toxicity in plants through proper root/shoot partitioning mechanism and homeostatic accumulation of Mn and Fe. PMID- 26476316 TI - Genomic and molecular mechanisms for efficient biodegradation of aromatic dye. AB - Understanding the molecular mechanisms for aromatic compound degradation is crucial for the development of effective bioremediation strategies. We report the discovery of a novel phenomenon for improved degradation of Direct Red 5B azo dye by Irpex lacteus CD2 with lignin as a co-substrate. Transcriptomics analysis was performed to elucidate the molecular mechanisms of aromatic degradation in white rot fungus by comparing dye, lignin, and dye/lignin combined treatments. A full spectrum of lignin degradation peroxidases, oxidases, radical producing enzymes, and other relevant components were up-regulated under DR5B and lignin treatments. Lignin induced genes complemented the DR5B induced genes to provide essential enzymes and redox conditions for aromatic compound degradation. The transcriptomics analysis was further verified by manganese peroxidase (MnP) protein over-expression, as revealed by proteomics, dye decolorization assay by purified MnP and increased hydroxyl radical levels, as indicated by an iron reducing activity assay. Overall, the molecular and genomic mechanisms indicated that effective aromatic polymer degradation requires synergistic enzymes and radical-mediated oxidative reactions to form an effective network of chemical processes. This study will help to guide the development of effective bioremediation and biomass degradation strategies. PMID- 26476317 TI - In vivo DNA mismatch repair measurement in zebrafish embryos and its use in screening of environmental carcinogens. AB - Impairment of DNA mismatch repair (MMR) function leads to the development and progression of certain cancers. Many environmental contaminants can target DNA MMR system. Currently, measurement of MMR activity is limited to in vitro or in vivo methods at the cell line level, and reports on measurement of MMR activity at the live organism level are lacking. Here, we report an efficient method to measure DNA MMR activity in zebrafish embryos. A G-T mismatch was introduced into enhanced green fluorescent protein (EGFP) gene. Repair of the G-T mismatch to G-C in the heteroduplex plasmid generates a functional EGFP expression. The heteroduplex plasmid and a similarly constructed homoduplex plasmid were injected in parallel into the same batch of embryos at 1-cell stage and EGFP expression in EGFP positive embryos was quantified at 24 h after injection. MMR efficiency was calculated as the total fluorescence intensity of embryos injected with the heteroduplex construct divided by that of embryos injected with the homoduplex construct. Our results showed 73% reduction of MMR activity in embryos derived from MMR-deficient mlh1 mutant fish (positive control) when compared with embryos from MMR-competent wild type AB line fish, indicating feasibility of in vivo MMR activity measurement in zebrafish embryos. We further applied this novel assay for measurement of MMR efficiency in embryos exposed to environmental chemicals such as cadmium chloride (CdCl2), benzo[a]pyrene (BaP), and perfluorooctanesulphonic acid (PFOS) from 6 hpf to 24 hpf. We observed significant reductions of MMR efficiency in embryos exposed to 0.1 MUM CdCl2 (52%) and 0.5 MUM BaP (34%), but no effect in embryos exposed to PFOS. Our study for the first time provides a model system for in vivo measurement of DNA MMR activity at the organism level, which has important implications in risk assessment of various environmental carcinogens. PMID- 26476318 TI - Hexabromocyclododecane exposure induces cardiac hypertrophy and arrhythmia by inhibiting miR-1 expression via up-regulation of the homeobox gene Nkx2.5. AB - Hexabromocyclododecane (HBCD) is one of the most widely used brominated flame retardants. Although studies have reported that HBCD can cause a wide range of toxic effects on animals including humans, limited information can be found about its cardiac toxicity. In the present study, zebrafish embryos were exposed to HBCD at low concentrations of 0, 2, 20 and 200 nM. The results showed that HBCD exposure could induce cardiac hypertrophy and increased deposition of collagen. In addition, disordered calcium (Ca(2+)) handling was observed in H9C2 rat cardiomyocyte cells exposed to HBCD. Using small RNA sequencing and real-time quantitative PCR, HBCD exposure was shown to induce significant changes in the miRNA expression profile associated with the cardiovascular system. Further findings indicated that miR-1, which was depressed by Nkx2.5, might play a fundamental role in mediating cardiac hypertrophy and arrhythmia via its target genes Mef2a and Irx5 after HBCD treatment. HBCD exposure induced an arrhythmogenic disorder, which was triggered by the imbalance of Ryr2, Serca2a and Ncx1 expression, inducing Ca(2+) overload in the sarcoplasmic reticulum and high Ca(2+)-ATPase activities in the H9C2 cells. PMID- 26476320 TI - Individual and competitive removal of heavy metals using capacitive deionization. AB - This study presents the viability and preference of capacitive deionization (CDI) for removing different heavy metal ions in various conditions. The removal performance and mechanisms of three ions, cadmium (Cd(2+)), lead (Pb(2+)) and chromium (Cr(3+)) were investigated individually and as a mixture under different applied voltages and ion concentrations. It was found that CDI could effectively remove these metals, and the performance was positively correlated with the applied voltage. When 1.2 V was applied into solution containing 0.5mM individual ions, the Cd(2+), Pb(2+), and Cr(3+) removal was 32%, 43%, and 52%, respectively, and the electrosorption played a bigger role in Cd(2+) removal than for the other two ions. Interestingly, while the removal of Pb(2+) and Cr(3+) remained at a similar level of 46% in the mixture of three ions, the Cd(2+) removal significantly decreased to 14%. Similar patterns were observed when 0.05 mM was used to simulate natural contaminated water condition, but the removal efficiencies were much higher, with the removal of Pb(2+), Cr(3+), and Cd(2+) increased to 81%, 78%, and 42%, respectively. The low valence charge and lack of physical sorption of Cd(2+) were believed to be the reason for the removal behavior, and advanced microscopic analysis showed clear deposits of metal ions on the cathode surface after operation. PMID- 26476319 TI - Characterization of the biosorption and biodegradation properties of Ensifer adhaerens: A potential agent to remove polychlorinated biphenyls from contaminated water. AB - Ensifer adhaerens is a soil bacterium known for its potential to remove pollutants from the environment. We investigated the contributions of biosorption and biodegradation to the process of polychlorinated biphenyl (PCB) removal from water by living or heat-killed E. adhaerens with different incubation times. We examined the physicochemical properties of E. adhaerens, including its membrane surface moieties, extracellular polymeric substances, and defense-related enzyme activities. In addition, we measured the biosorption and biodegradation of different PCB congeners. We found that removal of PCBs by heat-killed E. adhaerens was attributed to biosorption only, while both biosorption and biodegradation were responsible for the dissipation of PCBs by live E. adhaerens. Biosorption initially plays a major role in PCB removal, but biodegradation becomes increasingly important with increased incubation time. The results of infrared spectroscopy analysis showed that bacterial lipids, proteins, and polysaccharides, which offer abundant binding sites, are responsible for the biosorption of PCBs. Biodegradation was correlated with loosely bound polysaccharides and defense-related enzyme activities that could increase the pollutant's solubility and facilitate further degradation. The PCB congeners exhibited different biosorption and biodegradation patterns, and the patterns were correlated with the octanol-water partition coefficients (Kow) of the congeners. The more hydrophobic organic compounds tended to have higher biosorption, but lower biodegradation capacities. These results indicate that E. adhaerens-mediated biosorption and biodegradation of PCBs are dependent on the status of the strain, the incubation time, and the PCB congener present, and suggest guidelines for PCB removal from water. PMID- 26476321 TI - High resolution mass spectrometry to investigate omeprazole and venlafaxine metabolites in wastewater. AB - This study reports an investigation of omeprazole and venlafaxine parent substances and metabolites in Italian municipal influent wastewaters (IWWs). These pharmaceuticals were selected because they are widely consumed in Italy, but are poorly detected in waste and surface water. The aim of the study was to identify the most relevant pharmaceuticals metabolites in wastewater in order to improve the prioritization step and choose priority pollutants for environmental monitoring campaigns. This was done by investigating omeprazole, venlafaxine and their main metabolites in 30 IWWs from ten Italian cities and by comparing results with information from pharmacokinetic studies. Analysis was performed by solid phase extraction (SPE) and high-performance liquid chromatography (HPLC) coupled to high resolution mass spectrometry (HRMS). We searched for 23 omeprazole and four venlafaxine metabolites using data-dependent and MS/MS methods. Parent omeprazole was never present in the samples. Six omeprazole metabolites were found in IWWs. Venlafaxine and two metabolites were present in all the samples. The metabolic profiles in Italian IWW agreed with results in IWW from Spain and with urinary excretion profiles from pharmacokinetic studies. Comparing results from different sources was useful to improve the identification of pharmaceuticals metabolites in environmental samples and to focus the attention of future studies on the most relevant compounds. PMID- 26476322 TI - Ce-Fe-modified zeolite-rich tuff to remove Ba(2+)-like (226)Ra(2+) in presence of As(V) and F(-) from aqueous media as pollutants of drinking water. AB - The sorption behavior of the Ba(2+)-like (226)Ra(2+) in the presence of H2AsO4( )/HAsO4(2-) and F(-) from aqueous media using Ce-Fe-modified zeolite-rich tuff was investigated in this work. The Na-modified zeolite-rich tuff was also considered for comparison purposes. The zeolite-rich tuff collected from Wyoming (US) was in contact with NaCl and CeCl3-FeCl3 solutions to obtain the Na- and Ce Fe-modified zeolite-rich tuffs (ZUSNa and ZUSCeFe). These zeolites were characterized by scanning electron microscopy and X-ray diffraction. The BET specific surface and the points of zero charge were determined as well as the content of Na, Ce and Fe by neutron activation analysis. The textural characteristics and the point of zero charge were changed by the presence of Ce and Fe species in the zeolitic network. A linear model described the Ba(2+)-like (226)Ra(2+) sorption isotherms and the distribution coefficients (Kd) varied with respect to the metallic species present in the zeolitic material. The As(V) oxianionic chemical species and F(-) affected this parameter when the Ba(2+)-like (226)Ra(2+)-As(V)-F(-) solutions were in contact with ZUSCeFe. The H2AsO4( )/HAsO4(2-) and F(-) were adsorbed by ZUSCeFe in the same amount, independent of the concentration of Ba(2+)-like (226)Ra(2+) in the initial solution. PMID- 26476323 TI - Possible ecological risk of two pharmaceuticals diclofenac and paracetamol demonstrated on a model plant Lemna minor. AB - Lemna minor is often used in environmental risk assessment and it can be supposed that usually evaluated parameters will be reliable even for assessing the risk of pharmaceuticals. Subtle changes in duckweed plant number, biomass production, and leaf area size induced by 10-day-exposure to diclofenac (DCF) and paracetamol (PCT) (0.1, 10, and 100 MUg/L), excepting 100 MUg/L DCF, are in contrast with considerable changes on biochemical and histochemical level. Both drugs caused a decrease in content of photosynthetic pigments (by up to 50%), an increase in non photochemical quenching (by 65%) and decrease in relative chlorophyll fluorescence decay values (by up to 90% with DCF). Both DCF and especially PCT increased amount of reactive nitrogen and oxygen species in roots. DCF-induced effects included mainly increased lipid peroxidation (by 78%), disturbation in membrane integrity and lowering both oxidoreductase and dehydrogenase activities (by 30%). PCT increased the content of soluble proteins and phenolics. Higher concentrations of both DCF and PCT increased the levels of oxidised ascorbate (by 30%) and oxidised thiols (by up to 84% with DCF). Glutathion-reductase activity was elevated by both pharmaceuticals (nearly by 90%), glutathion-S-transferase activity increased mainly with PCT (by 22%). The early and sensitive indicators of DCF and PCT phytotoxicity stress in duckweed are mainly the changes in biochemical processes, connected with activation of defense mechanisms against oxidative stress. PMID- 26476324 TI - An inverting beta-1,2-mannosidase belonging to glycoside hydrolase family 130 from Dyadobacter fermentans. AB - The glycoside hydrolase family (GH) 130 is composed of inverting phosphorylases that catalyze reversible phosphorolysis of beta-D-mannosides. Here we report a glycoside hydrolase as a new member of GH130. Dfer_3176 from Dyadobacter fermentans showed no synthetic activity using alpha-D-mannose 1-phosphate but it released alpha-D-mannose from beta-1,2-mannooligosaccharides with an inversion of the anomeric configuration, indicating that Dfer_3176 is a beta-1,2-mannosidase. Mutational analysis indicated that two glutamic acid residues are critical for the hydrolysis of beta-1,2-mannotriose. The two residues are not conserved among GH130 phosphorylases and are predicted to assist the nucleophilic attack of a water molecule in the hydrolysis of the beta-D-mannosidic bond. PMID- 26476325 TI - Quantitative hepatitis B surface antigen combined with hepatitis B e antigen as sustained virological response predictors during extended therapy with Peginterferon alfa-2a for hepatitis B e antigen-positive chronic hepatitis B. AB - BACKGROUND: The best strategy for chronic hepatitis B patients with poor response to 48 weeks of Peginterferon-based therapy has been controversial and the predictive value of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA levels for determining the sustained virological response (SVR) of these patients is uncertain. OBJECTIVES: To optimize management of these patients and evaluate the use of these serobiomarkers to predict SVR. STUDY DESIGN: Eighty-one patients with an unsatisfactory response after 48 weeks of Peginterferon-based therapy were treated with extended Peginterferon therapy with or without nucleo(s) tide analogues (NAs), for a total of 96 weeks of Peginterferon treatment. HBsAg, HBeAg and HBV DNA levels were measured serially during the treatment and follow-up. RESULTS AND CONCLUSIONS: Twenty-six of 81 patients (32.1%) attained SVR during the 72-week follow-up. The SVR rate was not statistically different between groups receiving 1-year prolongation of Peginterferon with or without NAs. The serum HBsAg cut-off of 1800IU/mL at week 48 had area under curve (AUC) of 0.727, and the serum HBsAg cut-off of 1500IU/mL, combined with HBeAg loss at week 72, had AUC of 0.753 to predict SVR during the follow-up. In conclusion, extended treatment with Peginterferon with or without NAs for patients with unsatisfactory response after 48 weeks of Peginterferon-based therapy is a promising strategy to achieve SVR, and quantitative serum HBsAg at week 48 and HBsAg level combined with HBeAg loss at week 72 of therapy can predict SVR to prolongation therapy with Peginterferon. PMID- 26476326 TI - Genotype distribution of norovirus around the emergence of Sydney_2012 and the antigenic drift of contemporary GII.4 epidemic strains. AB - BACKGROUND: The pattern of epochal evolution of NoV is ongoing, while novel GII.4 variants emerge and cause new pandemics. Since, the emergence in March 2012, Sydney_2012 had replaced GII.4-2009 as the primary NoV strain in most countries in the northern hemisphere by November 2012. OBJECTIVES: To determine the genotype distribution around the emergence of Sydney_2012 and to investigate the underlying evolution mechanisms of the contemporary GII.4 strains. STUDY DESIGN: From January 2012 to December 2013, molecular epidemiology of norovirus in 846 adults (>=16 years) in Shanghai were conducted. The VP1 proteins of the contemporary GII.4 strains (Den_Haag_2006b, New_Orleans_2009 and Sydney_2012) were expressed in vitro and purified. Receptor binding patterns of these three epidemic strains were determined through histo-blood group antigen (HBGA) binding assays. Convalescent serum from patients infected with GII.4 epidemic strains were employed to investigate the role of antigenic drift in the persistence of GII.4 epidemic strains through receptor-binding blockade assays. RESULTS: Epidemiological studies revealed that Sydeny_2012 has completely replaced Den_Haag_2006b and New_Orleans_2009 and has been the dominant circulating strain in Shanghai since its emergence in October 2012. Interestingly, Den_Haag_2006b and New_Orleans_2009 have been co-circulating in Shanghai before the emergence of Sydeny_2012. The contemporary GII.4 epidemic norovirus strains displayed commonly high tropism to the histo-blood group antigen receptors, whereas Sydeny_2012 was antigenically different from Den_Haag_2006b and New_Orleans_2009. CONCLUSIONS: Antigenic drift, rather than receptor switch, played a key role in the emergence and spreading of Sydney_2012. The contemporary GII.4 strains were evolving via epochal evolution without altered ligand binding profiles. PMID- 26476327 TI - Antibacterial activity of papain and bromelain on Alicyclobacillus spp. AB - Alicyclobacillus spp. are spore forming bacteria that are often related to the deterioration of acidic products such as beverages and citrus juices. After the process of industrial pasteurization, the spore produced by the bacteria can germinate and the microorganism can grow, causing sensory abnormalities in the product. Alternative biopreservatives, such as the antimicrobial compounds, are of considerable importance to the food industry. Papain and bromelain are proteolytic enzymes derived frompapaya and pineapple, respectively. These enzymes are widely used in medicine and in the pharmaceutical and food industries, but while some studies have described their antibacterial action, no studies of the Alicyclobacillus spp. exist. The aimof this studywas to analyze the antibacterial effect of papain and bromelain on Alicyclobacillus spp. through 1) determining minimum inhibitory and bactericidal concentration (MIC and MBC); 2) determining the death time curve of the micro-organism in the presence and absence of enzymes; and 3) investigating the enzymatic mechanism on the microorganism. The antibacterial activity of enzymes in combination with nisin was also evaluated. The results showed that for the Alicyclobacillus acidoterrestris strain, the MIC of papain was 0.98 MUg/mL and the MBC was 3.91 MUg/mL, while theMIC of bromelain was 62.5 MUg/mL and the MBCwas 250 MUg/mL. The concentration of 4 *MIC for both the enzymes was sufficient to eliminate 4 logs of the micro-organism after 24 h of incubation. Through the use of enzyme inhibitors specific for cysteine proteases, it was found that the antibacterial activity of papain and bromelain is not related to its proteolytic activity, butmay be related to other activities, such as amidse and esterase. The synergistic activity of the enzymes revealed a fractional inhibitory concentration (FIC) level of 0.16. Combination with nisin revealed an FIC of 0.25 for papain and 0.19 for bromelain, indicating synergism between both compounds. The application of enzymes in reconstituted orange juice contaminated with A. acidoterrestris was found to be effective, as after 48 h of incubation, at three different temperatures, the initial microbial population was eliminated. This study showed that the enzymes papain and bromelain have an antibacterial effect on A. acidoterrestris. PMID- 26476328 TI - Uptake and translocation of benzo[a]pyrene (B[a]P) in two ornamental plants and dissipation in soil. AB - Pot experiments were conducted to evaluate the phytoremediation of B[a]P contaminated soil using two ornamental plants (Tagetes patula and Mirabilis jalapa). The results showed that the dry biomass of two plants was increased at low B[a]P contaminated soil and then inhibited with increasing B[a]P concentrations. It exhibited a significantly positive linear relationship between B[a]P absorption in roots, stems, leaves and shoots of the tested plants and the concentration of B[a]P in soils (P<0.01). Meanwhile, the contents of B[a]P in different tissues of the plants increased with growing time. After planting T. patula and M. jalapa, plant-promoted biodegradation of B[a]P was account for 79.5 99.8% and 71.1-99.9%, respectively, whereas the amount of B[a]P dissipation enhancement was only 0.2-20.5% and 0.1-28.9%, respectively. Moreover, low bioaccumulation factor (BF) and translocation factor (TF) values indicated that T. patula and M. jalapa took up B[a]P from contaminated soil and transferred them to the aerial parts with low efficiency. The B[a]P removal rates in rhizosphere soils at different growing stages of T. patula and M. jalapa were 2.7-26.8% and 0.4%-33.9%, respectively, higher than those of non-rhizopshere soils. Therefore, the presence of T. patula and M. jalapa roots was effective in promoting the phytoremediation of B[a]P contaminated soils. PMID- 26476329 TI - Effects of waterborne exposure to 17beta-estradiol and 4-tert-octylphenol on early life stages of the South American cichlid fish Cichlasoma dimerus. AB - Estrogenic chemicals are often detected in the aquatic environment and can negatively affect animal development and reproduction. In teleost fishes, the hormonal regulation during a critical period of larval development has a strong influence on gonadal sex differentiation; thus this process may be affected by the exposure to environmental estrogens. In this study, we first assessed the lethal acute toxicity of the natural estrogen 17beta-estradiol (E2) and the weaker estrogen mimics 4-tert-octylphenol (OP) and 4-nonylphenol (NP) on larval stages of the South American cichlid fish Cichlasoma dimerus. In a further experiment, we analyzed the effects of chronic waterborne exposure to E2 and OP on gonad development and sex differentiation. Exposure to high concentrations of E2 had a pronounced feminizing effect directing sex differentiation towards ovarian development, while testis development was inhibited at a lower, environmentally relevant concentration. Among OP-exposed fish, 15-38.5% of the males exhibited testicular oocytes (TOs), a commonly reported biomarker of estrogenic exposure. However, since TOs were also recorded in control males and the proportion of males with TOs was not significantly higher in OP treatments, their occurrence could not be attributed to OP exposure. In addition, TOs did not seem to impair male gonad development and functionality since normal spermatogenesis was observed in testes of OP-treated fish. These results indicate that E2 occurring in the South American aquatic environment may affect male reproductive development and pose a risk for wild C. dimerus, especially under prolonged exposure, while the effects of weaker xenoestrogens such as OP would be negligible for gonad development in this species. As illustrated by this study, the natural occurrence of TOs indicates that conclusions concerning the causes of this phenomenon must be drawn with care. PMID- 26476330 TI - Microarray analysis of di-n-butyl phthalate and 17alpha ethinyl-oestradiol responses in three-spined stickleback testes reveals novel candidate genes for endocrine disruption. AB - Phthalate esters are plasticizers frequently found in wastewater effluents. Previous studies on phthalates have reported anti-androgenic activity in mammals, causing concerns of their potential effects on the reproduction of aquatic organisms. Another group of environmental endocrine disrupters, steroidal estrogens, are known to inhibit steroid biosynthesis in the gonads, but the effects related to spermatogenesis are not well understood in fish. In this study, three-spined sticklebacks were exposed to di-n-butyl phthalate (DBP) and 17alpha ethinyl-oestradiol (EE2) at nominal concentrations 35MUg/L and 40ng/L, respectively, for four days. The aim of the study was to obtain insight into the acute transcriptional responses putatively associated with endocrine disruption. RNA samples from eight individual male fish per treatment (including controls) were used in microarray analysis, covering the expression of approximately 21,000 genes. In the EE2 treatment the results show transcriptional downregulation of genes associated with steroid biosynthesis pathway and up-regulation of genes involved in pathways related to epidermal growth factor signaling and xenobiotic metabolism. The transcriptional response to DBP was in general weaker than to EE2, but based on enrichment analysis, we suggest adverse effects on retinoid metabolism, creatine kinase activity and cell adhesion. Among the genes showing highest fold changes after DBP treatment compared to control was the teleost fish -specific cytochrome P450 17A2. Overall, this study promotes our understanding on molecular responses to anti-androgens and estrogens in fish testes. PMID- 26476331 TI - Phenotypic, metabolic, and molecular genetic characterization of six patients with congenital adrenal hyperplasia caused by novel mutations in the CYP11B1 gene. AB - Congenital adrenal hyperplasia (CAH) is an autosomal recessive inherited disorder of steroidogenesis. Steroid 11beta-hydroxylase deficiency (11beta-OHD) due to mutations in the CYP11B1 gene is the second most common form of CAH. In this study, 6 patients suffering from CAH were diagnosed with 11beta-OHD using urinary GC-MS steroid metabolomics analysis. The molecular basis of the disorder was investigated by molecular genetic analysis of the CYP11B1 gene, functional characterization of splicing and missense mutations, and analysis of the missense mutations in a computer model of CYP11B1. All patients presented with abnormal clinical signs of hyperandrogenism. Their urinary steroid metabolomes were characterized by excessive excretion rates of metabolites of 11-deoxycortisol as well as metabolites of 11-deoxycorticosterone, and allowed definite diagnosis. Patient 1 carries compound heterozygous mutations consisting of a novel nonsense mutation p.Q102X (c.304C>T) in exon 2 and the known missense mutation p.T318R (c.953C>G) in exon 5. Two siblings (patient 2 and 3) were compound heterozygous carriers of a known splicing mutation c.1200+1G>A in intron 7 and a known missense mutation p.R448H (c.1343G>A) in exon 8. Minigene experiments demonstrated that the c.1200+1G>A mutation caused abnormal pre-mRNA splicing (intron retention). Two further siblings (patient 4 and 5) were compound heterozygous carriers of a novel missense mutation p.R332G (c.994C>G) in exon 6 and the known missense mutation p.R448H (c.1343G>A) in exon 8. A CYP11B1 activity study in COS-1 cells showed that only 11% of the enzyme activity remained in the variant p.R332G. Patient 6 carried a so far not described homozygous deletion g.2470_5320del of 2850 bp corresponding to a loss of the CYP11B1 exons 3-8. The breakpoints of the deletion are embedded into two typical 6 base pair repeats (GCTTCT) upstream and downstream of the gene. Experiments analyzing the influence of mutations on splicing and on enzyme function were applied as complementary procedures to genotyping and provided a rational basis for understanding the clinical phenotype of CAH. PMID- 26476332 TI - Psychophysiological effects of an iTBS modulated virtual reality challenge including participants with spider phobia. AB - Preliminary evidence suggests beneficial effects of transcranial magnetic stimulation (TMS) on anxiety. The objective of this study was to investigate the effects of intermittent theta burst stimulation (iTBS) as a form of TMS on acute anxiety provoked by a virtual reality (VR) scenario. Participants with spider phobia (n=41) and healthy controls (n=42) were exposed to a spider scenario in VR after one session of iTBS over the prefrontal cortex or sham treatment. Participants with spider phobia reacted with more anxiety compared to healthy controls. Their heart rate and skin conductance increased compared to baseline. Contrary to expectations, iTBS did not influence these reactions, but modulated heart rate variability (HRV). Sympathetic influence on HRV showed an increase in the active iTBS group only. This study does not support the idea of beneficial effects of a single session of iTBS on anxiety, although other protocols or repeated sessions might be effective. PMID- 26476333 TI - Letter to the editor: Do coagulase-negative staphylococci have no effect on the milk composition of infected mammary gland? A comment on Tomazi et al. (2015). PMID- 26476334 TI - Letter to the editor: A response to the comments of Silanikove et al. (2015). PMID- 26476335 TI - Localized hypoxia within the subgranular zone determines the early survival of newborn hippocampal granule cells. AB - The majority of adult hippocampal newborn cells die during early differentiation from intermediate progenitors (IPCs) to immature neurons. Neural stem cells in vivo are located in a relative hypoxic environment, and hypoxia enhances their survival, proliferation and stemness in vitro. Thus, we hypothesized that migration of IPCs away from hypoxic zones within the SGZ might result in oxidative damage, thus triggering cell death. Hypoxic niches were observed along the SGZ, composed of adult NSCs and early IPCs, and oxidative byproducts were present in adjacent late IPCs and neuroblasts. Stabilizing hypoxia inducible factor-1alpha with dimethyloxallyl glycine increased early survival, but not proliferation or differentiation, in neurospheres in vitro and in newly born SGZ cells in vivo. Rescue experiments in Bax(fl/fl) mutants supported these results. We propose that localized hypoxia within the SGZ contributes to the neurogenic microenvironment and determines the early, activity-independent survival of adult hippocampal newborn cells. PMID- 26476337 TI - Effects of nanocrystalline PbSe on hematopoietic system and bone marrow micronucleus rate of rats. AB - OBJECTIVE: To investigate the effect of lead selenide nanocrystals on hematopoietic system and bone marrow micronucleus rate of rats. METHOD: Specific pathogen free SD rats were randomly divided into 4 groups (8 rats in each group), and injected with of 0 (control group), 10 (low dose group), 20 (middle dose group), 30 mg/kg (high dose group) nanocrystalline PbSe, respectively. Seven weeks after injection, the blood was taken from rats for routine index detection; the number of micronucleus cells per 1000 polychromatic erythrocyte from bone marrow was counted. RESULTS: White blood cell (WBC), lymphocyte (LYM) count in low dose group rats, and WBC, LYM, granulocyte (GRN), monocytes (MOD) counts in high dose group significantly increased compared to those of control group. LYM% ratio decreased while GRN% ratio increased along with the increase of exposure dosage. Compared with those of the control group, levels of erythrocyte mean corpuscular volume (MCV) in low dose group, hemoglobin (HGB), red blood cell specific volume (HCT), MCV in middle dose group and red blood cell (RBC), HGB, HCT, MCV in high dose group, were markedly decreased. Red blood cell distribution width (RDW), blood platelet (PLT) levels in three exposure groups of were higher than those in control group. Marrow micronucleus test results showed that, the micronucleus rate rise in mid dose and high dose group compared with the control group, suggesting that nanocrystalline PbSe has genetic toxicity on rats. CONCLUSIONS: Nano PbSe can lead to changes in blood routine index and bone marrow micronucleus rate, and its toxicity was positively related to the dosage. PMID- 26476336 TI - ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure. AB - Brown adipose tissue (BAT) activation via cold exposure is increasingly scrutinized as a potential approach to ameliorate cardio-metabolic risk. Transition to cold temperatures requires changes in the partitioning of energy substrates, re-routing fatty acids to BAT to fuel non-shivering thermogenesis. However, the mechanisms behind the redistribution of energy substrates to BAT remain largely unknown. Angiopoietin-like 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL) activity, is highly expressed in BAT. Here, we demonstrate that ANGPTL4 is part of a shuttling mechanism that directs fatty acids derived from circulating triglyceride-rich lipoproteins to BAT during cold. Specifically, we show that cold markedly down-regulates ANGPTL4 in BAT, likely via activation of AMPK, enhancing LPL activity and uptake of plasma triglyceride derived fatty acids. In contrast, cold up-regulates ANGPTL4 in WAT, abolishing a cold-induced increase in LPL activity. Together, our data indicate that ANGPTL4 is an important regulator of plasma lipid partitioning during sustained cold. PMID- 26476338 TI - In vivo kinetic analysis of the penicillin biosynthesis pathway using PAA stimulus response experiments. AB - In this study we combined experimentation with mathematical modeling to unravel the in vivo kinetic properties of the enzymes and transporters of the penicillin biosynthesis pathway in a high yielding Penicillium chrysogenum strain. The experiment consisted of a step response experiment with the side chain precursor phenyl acetic acid (PAA) in a glucose-limited chemostat. The metabolite data showed that in the absence of PAA all penicillin pathway enzymes were expressed, leading to the production of a significant amount of 6-aminopenicillanic acid (6APA) as end product. After the stepwise perturbation with PAA, the pathway produced PenG within seconds. From the extra- and intracellular metabolite measurements, hypotheses for the secretion mechanisms of penicillin pathway metabolites were derived. A dynamic model of the penicillin biosynthesis pathway was then constructed that included the formation and transport over the cytoplasmic membrane of pathway intermediates, PAA and the product penicillin-G (PenG). The model parameters and changes in the enzyme levels of the penicillin biosynthesis pathway under in vivo conditions were simultaneously estimated using experimental data obtained at three different timescales (seconds, minutes, hours). The model was applied to determine changes in the penicillin pathway enzymes in time, calculate fluxes and analyze the flux control of the pathway. This led to a reassessment of the in vivo behavior of the pathway enzymes and in particular Acyl-CoA:Isopenicillin N Acyltransferase (AT). PMID- 26476339 TI - Altered resting-state functional connectivity of the amygdala in Chinese earthquake survivors. AB - Posttraumatic stress disorder (PTSD) is linked to abnormal amygdala activities. This study measured amygdala functional connectivity using DSM-5 criteria. There were 33 participants in the PTSD group and 33 participants in a trauma-exposed control (TEC) group, who did not have PTSD according to the PTSD checklist of the DSM-5 (PCL-5). Our findings are as follows: (1) In the PTSD group, the amygdala had increased positive connectivity with the medial prefrontal cortex (mPFC) and hippocampus, and decreased positive connectivity with the inferior mPFC and insula. The amygdala had increased negative connectivity with the orbital prefrontal cortex and decreased negative connectivity with the insula in comparison with TEC group. (2) PCL of all participants was correlated with the connectivity between the amygdala and the mPFC, hippocampus, and insula. These regions overlapped with those identified in the between-group comparisons. However, there was no association between PCL of the PTSD group and connectivity in these regions. Abnormal functional connectivity between the amygdala and mPFC subdivisions, hippocampus, and insula reveals their importance in PTSD pathogenesis. PMID- 26476340 TI - Preferential tumor accumulation and desirable interstitial penetration of poly(lactic-co-glycolic acid) nanoparticles with dual coating of chitosan oligosaccharide and polyethylene glycol-poly(D,L-lactic acid). AB - Despite advances in polymeric nanoparticles (NPs) as effective delivery systems for anticancer drugs, rapid clearance from blood and poor penetration capacity in heterogeneous tumors still remain to be addressed. Here, a dual coating of poly (ethylene glycol)-poly (d,l-lactic acid) (PEG-PDLLA) and water-soluble chitosan oligosaccharide (CO) was used to develop PLGA-based NPs (PCPNPs) with colloidal stability for delivery of paclitaxel (PTX). The PCPNPs were prepared by a modified nanoprecipitation process and exhibited homogeneous size of 165.5nm, and slight positive charge (+3.54mV). The single PEG-PDLLA-coated PLGA NPs (PPNPs) with negative charge (-13.42mV) were prepared as control. Human breast cancer MDA MB-231 cell and mice MDA-MB-231 xenograft model were used for in vitro and in vivo evaluation. Compared to Taxol(r), both PCPNPs and PPNPs increased the intracellular uptake and exerted stronger inhibitory effect on tumor cells in vitro, especially for PCPNPs. Particularly, due to the near neutral surface charge and shielding by the dual coating, the blank cationic NP presented low cytotoxicity. With the synergistic action of PEG-PDLLA and CO, PCPNPs not only strongly inhibited macrophage uptake and extended the blood circulation time, but also improved the selective accumulation and interstitial penetration capacity to/in tumor site. Consequently, a significantly enhanced antitumor efficacy was observed for the cationic PCPNPs. Our findings suggest that, the dual PEG PDLLA/CO coating can effective improve the tumor accumulation and interstitial penetration of NPs and, therefore may have great potential for tumor treatment. STATEMENT OF SIGNIFICANCE: Rapid clearance from blood and poor penetration capacity in heterogeneous tumors represent great challenge for polymeric nanoparticles (NPs) as effective delivery systems for anticancer drugs. This study provides a promising cationic nanoparticle (PCPNPs) with dual coating of chitosan oligosaccharide (CO) and PEG-PDLLA to address the above problem. The PCPNPs prepared with 165.5nm and slight positive charge (+3.54mV) showed an improved accumulation and interstitial penetration capacity to/in tumor site, and thus led to an enhanced antitumor efficacy. This is the first time to report the cooperative effect of PEG-PDLLA and CO on PLGA NPs in this field. This work can arouse broad interests among researchers in the fields of nanomedicine, nanotechnology, and drug delivery system. PMID- 26476341 TI - From crystalline to amorphous calcium pyrophosphates: A solid state Nuclear Magnetic Resonance perspective. AB - Hydrated calcium pyrophosphates (CPP, Ca2P2O7.nH2O) are a fundamental family of materials among osteoarticular pathologic calcifications. In this contribution, a comprehensive multinuclear NMR (Nuclear Magnetic Resonance) study of four crystalline and two amorphous phases of this family is presented. (1)H, (31)P and (43)Ca MAS (Magic Angle Spinning) NMR spectra were recorded, leading to informative fingerprints characterizing each compound. In particular, different (1)H and (43)Ca solid state NMR signatures were observed for the amorphous phases, depending on the synthetic procedure used. The NMR parameters of the crystalline phases were determined using the GIPAW (Gauge Including Projected Augmented Wave) DFT approach, based on first-principles calculations. In some cases, relaxed structures were found to improve the agreement between experimental and calculated values, demonstrating the importance of proton positions and pyrophosphate local geometry in this particular NMR crystallography approach. Such calculations serve as a basis for the future ab initio modeling of the amorphous CPP phases. STATEMENT OF SIGNIFICANCE: The general concept of NMR crystallography is applied to the detailed study of calcium pyrophosphates (CPP), whether hydrated or not, and whether crystalline or amorphous. CPP are a fundamental family of materials among osteoarticular pathologic calcifications. Their prevalence increases with age, impacting on 17.5% of the population after the age of 80. They are frequently involved or associated with acute articular arthritis such as pseudogout. Current treatments are mainly directed at relieving the symptoms of joint inflammation but not at inhibiting CPP formation nor at dissolving these crystals. The combination of advanced NMR techniques, modeling and DFT based calculation of NMR parameters allows new original insights in the detailed structural description of this important class of biomaterials. PMID- 26476342 TI - Strong poly(ethylene oxide) based gel adhesives via oxime cross-linking. AB - There is a demand for materials to replace or augment the use of sutures and staples in surgical procedures. Currently available commercial surgical adhesives provide either high bond strength with biological toxicity or polymer and protein based products that are biologically acceptable (though with potential sensitizing potential) but have much reduced bond strength. It is desirable to provide novel biocompatible and biodegradable surgical adhesives/sealants capable of high strength with minimal immune or inflammatory response. In this work, we report the end group derivatization of 8-arm star PEOs with aldehyde and amine end groups. Gels were prepared employing the Schiff-base chemistry between the aldehydes and the amines. Gel setting times, swelling behavior and rheological characterization were carried out for these gels. The mechanical-viscoelastic properties were found to be directly proportional to the crosslinking density of the gels, the 10K PEO gel was stiffer in comparison to the 20K PEO gel. The adhesive properties of these gels were tested using porcine skin and showed excellent adhesion properties. Cytotoxicity studies were carried out for the individual gel components using two different methods: (a) Crystal Violet Staining assay (CVS assay) and (b) impedance and cell index measurement by the xCELLigence system at concentrations >5%. Gels prepared by mixing 20% w/w solutions were also tested for cytotoxicity. The results revealed that the individual gel components as well as the prepared gels and their leachables were non-cytotoxic at these concentrations. STATEMENT OF SIGNIFICANCE: This work presents a new type of glue that is aimed at surgery applications using a water soluble star shaped polymer. It show excellent adhesion to skin and is tough and easy to use. We show that it is very biocompatible based on tests on live human cells, and could therefore in principle be used for internal surgery. Comparison with other reported and commercial glues shows that it is stronger than most, and does not swell in water to the same degree as many other water based bioadhesives. PMID- 26476343 TI - Homophilic interaction and deformation of E-cadherin and cadherin 7 probed by single molecule force spectroscopy. AB - Cadherin-mediated adhesion plays a crucial role in multicellular organisms. Dysfunction within this adhesion system has major consequences in many pathologies, including cancer invasion and metastasis. However, mechanisms controlling cadherin recognition and adhesive strengthening are only partially understood. Here, we investigated the homophilic interactions and mechanical stability of the extracellular (EC) domains of E-cadherin and cadherin 7 using atomic force microscopy and magnetic tweezers. Besides exhibiting stronger interactions, E-cadherin also showed more efficient force-induced self strengthening of interactions than cadherin 7. In addition, the distributions of the unbinding forces for both cadherins partially overlap with those of the unfolding forces, indicating that partial unfolding/deformation of the cadherin EC domains may take place during their homophilic interactions. These conformational changes may be involved in cadherins physiology function and contribute to the significant differences in adhesive strength mediated by type I and type II cadherins. PMID- 26476344 TI - Blood, urine and faecal metabolite profiles in the study of adult renal disease. AB - Chronic kidney disease (CKD) is a major public health burden and to date traditional biomarkers of renal function (such as serum creatinine and cystatin C) are unable to identify at-risk individuals before the disease process is well under way. To help preventive strategies and maximize the potential for effective interventions, it is important to characterise the molecular changes that take place in the development of renal damage. Metabolomics is a promising tool to identify markers of renal disease since the kidneys are involved in the handling of major biochemical classes of metabolites. These metabolite levels capture a snap-shot of the metabolic profile of the individual, allowing for the potential identification of early biomarkers, and the monitoring of real-time kidney function. In this review, we describe the current status of the identification of blood/urine/faecal metabolic biomarkers in different entities of kidney diseases including: acute kidney injury, chronic kidney disease, renal transplant, diabetic nephropathy and other disorders. PMID- 26476348 TI - TrkB Signaling in Retinal Glia Stimulates Neuroprotection after Optic Nerve Injury. AB - Brain-derived neurotrophic factor (BDNF) regulates neural cell survival mainly by activating TrkB receptors. Several lines of evidence support a key role for BDNF TrkB signaling in survival of adult retinal ganglion cells in animal models of optic nerve injury (ONI), but the neuroprotective effect of exogenous BDNF is transient. Glial cells have recently attracted considerable attention as mediators of neural cell survival, and TrkB expression in retinal glia suggests its role in neuroprotection. To elucidate this point directly, we examined the effect of ONI on TrkB(flox/flox):glial fibrillary acidic protein (GFAP)-Cre+ (TrkB(GFAP)) knockout (KO) mice, in which TrkB is deleted in retinal glial cells. ONI markedly increased mRNA expression levels of basic fibroblast growth factor (bFGF) in wild-type (WT) mice but not in TrkB(GFAP) KO mice. Immunohistochemical analysis at 7 days after ONI (d7) revealed bFGF up-regulation mainly occurred in Muller glia. ONI-induced retinal ganglion cell loss in WT mice was consistently mild compared with TrkB(GFAP) KO mice at d7. On the other hand, ONI severely decreased TrkB expression in both WT and TrkB(GFAP) KO mice after d7, and the severity of retinal degeneration was comparable with TrkB(GFAP) KO mice at d14. Our data provide direct evidence that glial TrkB signaling plays an important role in the early stage of neural protection after traumatic injury. PMID- 26476347 TI - Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs. AB - The mechanisms by which drugs induce pancreatitis are unknown. A definite cause of pancreatitis is due to the antiepileptic drug valproic acid (VPA). On the basis of three crucial observations-that VPA inhibits histone deacetylases (HDACs), HDACs mediate pancreas development, and aspects of pancreas development are recapitulated during recovery of the pancreas after injury-we hypothesized that VPA does not cause injury on its own, but it predisposes patients to pancreatitis by inhibiting HDACs and provoking an imbalance in pancreatic recovery. In an experimental model of pancreatic injury, we found that VPA delayed recovery of the pancreas and reduced acinar cell proliferation. In addition, pancreatic expression of class I HDACs (which are the primary VPA targets) increased in the midphase of pancreatic recovery. VPA administration inhibited pancreatic HDAC activity and led to the persistence of acinar-to-ductal metaplastic complexes, with prolonged Sox9 expression and sustained beta-catenin nuclear activation, findings that characterize a delay in regenerative reprogramming. These effects were not observed with valpromide, an analog of VPA that lacks HDAC inhibition. This is the first report, to our knowledge, that VPA shifts the balance toward pancreatic injury and pancreatitis through HDAC inhibition. The work also identifies a new paradigm for therapies that could exploit epigenetic reprogramming to enhance pancreatic recovery and disorders of pancreatic injury. PMID- 26476349 TI - Molecular Profiling in Lung Biopsies of Human Pulmonary Allografts to Predict Chronic Lung Allograft Dysfunction. AB - Chronic lung allograft dysfunction (CLAD) is the main reason for poor long-term outcome of lung transplantation, with bronchiolitis obliterans (BO) representing the predominant pathological feature. BO is defined as a progressive fibrous obliteration of the small airways, thought to be triggered by a combination of nonimmune bronchial injury and alloimmune and autoimmune mechanisms. Because biopsy samples are too insensitive to reliably detect BO and a decline in lung function test results, which is clinically used to define CLAD, does not detect early stages, there is need for alternative biomarkers for early diagnosis. Herein, we analyzed the cellular composition and differential expression of 45 tissue remodeling-associated genes in transbronchial lung biopsy specimens from two cohorts with 18 patients each: patients who did not develop CLAD within 3 years after transplantation (48 biopsy specimens) and patients rapidly developing CLAD within the first 3 postoperative years (57 biopsy specimens). Integrating the mRNA expression levels of the five most significantly dysregulated genes from the transforming growth factor-beta axis (BMP4, IL6, MMP1, SMAD1, and THBS1) into a score, patient groups could be confidently separated and the outcome predicted (P < 0.001). We conclude that overexpression of fibrosis-associated genes may be valuable as a tissue-based molecular biomarker to more accurately diagnose or predict the development of CLAD. PMID- 26476350 TI - Rap1 GTPase Inhibits Tumor Necrosis Factor-alpha-Induced Choroidal Endothelial Migration via NADPH Oxidase- and NF-kappaB-Dependent Activation of Rac1. AB - Macrophage-derived tumor necrosis factor (TNF)-alpha has been found in choroidal neovascularization (CNV) surgically removed from patients with age-related macular degeneration. However, the role of TNF-alpha in CNV development remains unclear. In a murine laser-induced CNV model, compared with un-lasered controls, TNF-alpha mRNA was increased in retinal pigment epithelial and choroidal tissue, and TNF-alpha colocalized with lectin-stained migrating choroidal endothelial cells (CECs). Inhibition of TNF-alpha with a neutralizing antibody reduced CNV volume and reactive oxygen species (ROS) level around CNV. In CECs, pretreatment with the antioxidant apocynin or knockdown of p22phox, a subunit of NADPH oxidase, inhibited TNF-alpha-induced ROS generation. Apocynin reduced TNF-alpha induced NF-kappaB and Rac1 activation, and inhibited TNF-alpha-induced CEC migration. TNF-alpha-induced Rac1 activation and CEC migration were inhibited by NF-kappaB inhibitor Bay11-7082. Overexpression of Rap1a prevented TNF-alpha induced ROS generation and reduced NF-kappaB and Rac1 activation. Activation of Rap1 by 8-(4-chlorophenylthio)adenosine-2'-O-Me-cAMP prevented TNF-alpha-induced CEC migration and reduced laser-induced CNV volume, ROS generation, and activation of NF-kappaB and Rac1. These findings provide evidence that active Rap1a inhibits TNF-alpha-induced CEC migration by inhibiting NADPH oxidase dependent NF-kappaB and Rac1 activation and suggests that Rap1a de-escalates CNV development by interfering with ROS-dependent signaling in several steps of the pathogenic process. PMID- 26476351 TI - Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals. AB - The continuing horrors of military conflicts and terrorism often involve the use of chemical warfare agents (CWAs) and toxic industrial chemicals (TICs). Many CWA and TIC exposures are difficult to treat due to the danger they pose to first responders and their rapid onset that can produce death shortly after exposure. While the specific mechanism(s) of toxicity of these agents are diverse, many are associated either directly or indirectly with increased oxidative stress in affected tissues. This has led to the exploration of various antioxidants as potential medical countermeasures for CWA/TIC exposures. Studies have been performed across a wide array of agents, model organisms, exposure systems, and antioxidants, looking at an almost equally diverse set of endpoints. Attempts at treating CWAs/TICs with antioxidants have met with mixed results, ranging from no effect to nearly complete protection. The aim of this commentary is to summarize the literature in each category for evidence of oxidative stress and antioxidant efficacy against CWAs and TICs. While there is great disparity in the data concerning methods, models, and remedies, the outlook on antioxidants as medical countermeasures for CWA/TIC management appears promising. PMID- 26476352 TI - Animal models of tumorigenic herpesviruses--an update. AB - Any one model system, be it culture or animal, only recapitulates one aspect of the viral life cycle in the human host. By providing recent examples of animal models for Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus, we would argue that multiple animal models are needed to gain a comprehensive understanding of the pathogenesis associated with human oncogenic herpesviruses. Transgenic mice, homologous animal herpesviruses, and tumorgraft and humanized mouse models all complement each other in the study of viral pathogenesis. The use of animal model systems facilitates the exploration of novel anti-viral and anti-cancer treatment modalities for diseases associated with oncogenic herpesviruses. PMID- 26476353 TI - Restoration of Penile Function and Patient Satisfaction with Intralesional Collagenase Clostridium Histolyticum Injection for Peyronie's Disease. AB - PURPOSE: Collagenase clostridium histolyticum is approved for the treatment of Peyronie's disease. To date, no post-release study to our knowledge has evaluated patient perceived outcomes and satisfaction. Therefore, we evaluated patient perceived experience with collagenase clostridium histolyticum injection for Peyronie's disease in a clinical practice. MATERIALS AND METHODS: From March 2014 to July 2015, 69 patients underwent 1 to 4 series of collagenase clostridium histolyticum injections for Peyronie's disease at our institution. Objective changes in penile curvature as well as patient reported functional outcomes and patient perceived curvature improvements were evaluated. RESULTS: By the time of analysis 31 patients (45%) had completed 4 trials, 47 (68%) completed 3 trials and 59 (86%) completed 2 trials. Patient reported improvements (percentage) in curvature increased with each series (trial 1-14%, trial 2-28%, trial 3-30% and trial 4-37%, p <0.05). Among those completing therapy 57% reported that collagenase clostridium histolyticum injections negated a need for surgery and 52% reported restoration of penetration. Overall 81% of men perceived collagenase clostridium histolyticum treatment as meaningful and 88% reported subjective improvements after 4 series of injections. Objective measures demonstrated a mean 23-degree curvature improvement (38%, p <0.0001). Seven patients (10%) experienced penile hematomas and no patients experienced tunical rupture. CONCLUSIONS: Collagenase clostridium histolyticum reduced the need for surgery and restored penetration in the majority of patients completing 4 series of injections. It also significantly reduced the degree of objectively measured penile curvature. Subjective improvements in curvature increased with each series of collagenase clostridium histolyticum injections as well and the majority of patients considered the therapy worthwhile. PMID- 26476354 TI - Prospective Outcomes of Ultra Mini Percutaneous Nephrolithotomy: A Consecutive Cohort Study. AB - PURPOSE: Ultra mini percutaneous nephrolithotomy is a less invasive technique of percutaneous nephrolithotomy to treat small to medium sized calculi. MATERIALS AND METHODS: We prospectively evaluated the outcomes of ultra mini percutaneous nephrolithotomy in a single surgeon, consecutive cohort study. Data on 94 patients who underwent ultra mini percutaneous nephrolithotomy were collected. RESULTS: Mean +/- SD calculus size was 15.9 +/- 4.5 mm and mean density was 1,106 +/- 167 HU. Access was achieved via the upper pole in 8 cases, interpolar in 33 and lower pole in 54. Mean operative time was 54 minutes (range 28 to 120). Mean hemoglobin loss was 0.81 gm/dl and the mean creatinine increase was 0.05 mg/dl. There were no transfusions or kidney injuries. Grade I and IIIb complications were observed in 4 and 1 patients, respectively. The most serious complication was a perinephric collection. Postoperatively oral analgesia was sufficient in 86 patients (91%). Mean length of stay was 38.2 +/- 15.9 hours. Nephrostomy drainage was used in 13 patients while 7 (7%) required a stent for 1 week. Intraoperatively 99% of renal units were stone free (absence of detectable calculi) on fluoroscopy, and 74% and 81% were stone free on day 1 postoperative ultrasound and 1-month computerized tomography, respectively. The 10 to 20 mm stones showed less bleeding, shorter operative time and a significantly lower requirement for nephrostomy or a Double-J((r)) stent. CONCLUSIONS: Ultra mini percutaneous nephrolithotomy appears to be effective and safe with a short length of stay. It may be a valuable addition to the armamentarium to treat 10 to 20 mm calculi in patients who wish to avoid routine nephrostomy or stents. Randomized, controlled trials are required. PMID- 26476355 TI - Construction of pDYN6902, a new Streptomyces integrative expression vector designed for cloning sequences interfering with Escherichia coli viability. PMID- 26476356 TI - Investigating brain functional evolution and plasticity using microelectrode array technology. AB - The aim of this work was to investigate long and short-term plasticity responsible for memory formation in dissociated neuronal networks. In order to address this issue, a set of experiments was designed and implemented in which the microelectrode array electrode grid was divided into four quadrants, two of which were chronically stimulated, every two days for one hour with a stimulation paradigm that varied over time. Overall network and quadrant responses were then analyzed to quantify what level of plasticity took place in the network and how this was due to the stimulation interruption. The results demonstrate that there were no spatial differences in the stimulus-evoked activity within quadrants. Furthermore, the implemented stimulation protocol induced depression effects in the neuronal networks as demonstrated by the consistently lower network activity following stimulation sessions. Finally, the analysis demonstrated that the inhibitory effects of the stimulation decreased over time, thus suggesting a habituation phenomenon. These findings are sufficient to conclude that electrical stimulation is an important tool to interact with dissociated neuronal cultures, but localized stimuli are not enough to drive spatial synaptic potentiation or depression. On the contrary, the ability to modulate synaptic temporal plasticity was a feasible task to achieve by chronic network stimulation. PMID- 26476357 TI - Spinal venous hypertension secondary to pelvic extra-spinal arteriovenous fistula a previously unreported cause of congestive myelopathy. PMID- 26476358 TI - A simple plasmid-based transient gene expression method using High Five cells. AB - The High Five (H5) cell line, derived from the lepidopteran Trichoplusia ni, is one of the major insect cell hosts for the production of recombinant proteins using the baculovirus expression vector system (BEVS). Here, we describe a simple polyethylenimine (PEI)-based transient gene expression (TGE) process for the rapid production of recombinant proteins from suspension-adapted H5 cells. The method was optimized using two model proteins, enhanced green fluorescent protein (EGFP) and human tumor necrosis factor receptor-Fc fusion protein (TNFR-Fc). After screening several promoter and enhancer combinations for high levels of TNFR:Fc production, an expression vector containing the Autographa californica multicapsid nucleopolyhedrovirus immediate early 1 (ie1) promoter and homologous region 5 (hr5) enhancer was selected. Cells were transfected at a density of 2*10(6) cells/mL by direct addition of DNA and PEI. Under optimized conditions, a 90% transfection efficiency (percentage of EGFP-positive cells) was obtained. In addition, we observed volumetric TNFR-Fc yields over 150MUg/mL within 4 days of transfection. The method was found to be reproducible and scalable to 300mL. This plasmid-based transient transfection process is a simple and efficient alternative to the BEVS for recombinant protein production in H5 cells. PMID- 26476359 TI - Simvastatin decreases steroid production in the H295R cell line and decreases steroids and FSH in female rats. AB - Endocrine modulating effects of Simvastatin (SV) and its metabolite, Simvastatin beta-hydroxy acid (SVA), were investigated in H295R cells and in female Sprague Dawley (SPRD) rats. H295R cells were exposed to SV and SVA concentrations from 0 to 10MUM for 48h. Four groups of SPRD rats received 0 (CT), 1.3 (L), 5.0 (M), and 20.0 (H)mg SV/kg bw/day for 14 days. 10 Steroids were investigated in H295R growth media, and in tissues and plasma from rats using GC-MS/MS. Plasma LH and FSH were quantified by ELISA. In the H295R assay, SV and SVA particularly decreased progestagens with IC50-values from 0.10-0.13MUM for SV and from 0.019 0.055MUM for SVA. In rats, SV decreased progestagens in ovaries, brain and plasma, and plasma FSH in the M (72.4% decrease) and H group (76.6% decrease). Because progestagens and gonadotropins are major players in fertility, administration of SV might exert negative effects on female reproduction. PMID- 26476360 TI - Tretinoin-loaded lipid-core nanocapsules decrease reactive oxygen species levels and improve bovine embryonic development during in vitro oocyte maturation. AB - In vitro oocyte maturation (IVM) protocols can be improved by adding chemical supplements to the culture media. Tretinoin is considered an important retinoid in embryonic development and its association with lipid-core nanocapsules (TTN LNC) represents an innovative way of improving its solubility, and chemical stability, and reducing its toxicity. The effects of supplementing IVM medium with TTN-LNC was evaluated by analyzing production of reactive oxygen species (ROS), S36-phosphorilated-p66Shc levels and caspase activity in early embryonic development, and expression of apoptosis and pluripotency genes in blastocysts. The lowest concentration tested (0.25MUM) of TTN-LNC generated higher blastocyst rate, lower ROS production and S36-p66Shc amount. Additionally, expression of BAX and SHC1 were lower in both non-encapsulated tretinoin (TTN) and TTN-LNC-treated groups. Nanoencapsulation allowed the use of smaller concentrations of tretinoin to supplement IVM medium thus reducing toxic effects related with its use, decreasing ROS levels and apoptose frequency, and improving the blastocyst rates. PMID- 26476361 TI - Vaccine approaches to malaria control and elimination: Insights from mathematical models. AB - A licensed malaria vaccine would provide a valuable new tool for malaria control and elimination efforts. Several candidate vaccines targeting different stages of the malaria parasite's lifecycle are currently under development, with one candidate, RTS,S/AS01 for the prevention of Plasmodium falciparum infection, having recently completed Phase III trials. Predicting the public health impact of a candidate malaria vaccine requires using clinical trial data to estimate the vaccine's efficacy profile--the initial efficacy following vaccination and the pattern of waning of efficacy over time. With an estimated vaccine efficacy profile, the effects of vaccination on malaria transmission can be simulated with the aid of mathematical models. Here, we provide an overview of methods for estimating the vaccine efficacy profiles of pre-erythrocytic vaccines and transmission-blocking vaccines from clinical trial data. In the case of RTS,S/AS01, model estimates from Phase II clinical trial data indicate a bi phasic exponential profile of efficacy against infection, with efficacy waning rapidly in the first 6 months after vaccination followed by a slower rate of waning over the next 4 years. Transmission-blocking vaccines have yet to be tested in large-scale Phase II or Phase III clinical trials so we review ongoing work investigating how a clinical trial might be designed to ensure that vaccine efficacy can be estimated with sufficient statistical power. Finally, we demonstrate how parameters estimated from clinical trials can be used to predict the impact of vaccination campaigns on malaria using a mathematical model of malaria transmission. PMID- 26476362 TI - Post-marketing surveillance of adverse events following immunization with inactivated quadrivalent and trivalent influenza vaccine in health care providers in Western Australia. AB - In 2015, inactivated quadrivalent influenza vaccine (QIV) was first introduced into the Australian market. A routine vaccine safety surveillance system in Western Australia was used to conduct post-licensure surveillance of adverse events following immunization with inactivated QIV and trivalent influenza vaccines (TIV) in a sample of 1685 healthcare providers (HCPs). A similar percentage of HCPs who received QIV reported having any reaction seven days post vaccination as HCPs who received TIV (13.6 vs. 12.8%, respectively; p=0.66). However, a slightly higher percentage of HCPs who received QIV reported pain or swelling at the injection site as compared to HCPs who received TIV (6.9% vs. 4.2%, respectively; p=0.02). No serious vaccine-associated adverse events were detected during follow-up of either vaccine. Acknowledging the study limitations, the results of this post-marketing surveillance support the safety of QIV, suggesting there is little difference in the reactogenicity of QIV as compared to TIV. PMID- 26476363 TI - The effect of immunization on measles incidence in the Democratic Republic of Congo: Results from a model of surveillance data. AB - BACKGROUND: Measles continues to be a leading cause of vaccine-preventable disease mortality among children under five despite a safe and efficacious vaccine being readily available. While global vaccination coverage has improved tremendously, measles outbreaks persist throughout sub-Saharan Africa. Since 2010, the Democratic Republic of Congo (DRC) has seen a resurgence of measles outbreaks affecting all 11 provinces. These outbreaks are mainly attributed to gaps in routine immunization (RI) coverage compounded with missed supplementary immunization activities (SIAs). We utilized national passive surveillance data from DRC's Integrated Disease Surveillance and Response (IDSR) system to estimate the effect of immunization on measles incidence in DRC. METHODS: We investigated the decline in measles incidence post-immunization with one dose of measles containing vaccine (MCV1) with and without the addition of supplementary immunization activities (SIAs) and outbreak response immunization (ORI) campaigns. Measles case counts by health zone were obtained from the IDSR system between January 1, 2010 and December 31, 2013. The impact of measles immunization was modeled using a random effects multi-level model for count data with RI coverage levels and mass campaign activities from one year prior. RESULTS: The presence of an SIA (aIRR [95% CI] 0.86 [0.60-1.25]) and ORI (0.28 [0.20-0.39]) in the year prior were both associated with a decrease in measles incidence. When interaction terms were included, our results suggested that the high levels of MCV1 reported in the year prior and the presence of either mass campaign was associated with a decrease in measles incidence. CONCLUSIONS: Our results highlight the importance of a two-dose measles vaccine schedule and the need for a strong routine immunization program coupled with frequent SIAs. Repeated occurrences of large-scale outbreaks in DRC suggest that vaccination coverage rates are grossly overestimated and signify the importance of the evaluation and modification of measles prevention and control strategies. PMID- 26476364 TI - Decreasing immunity to hepatitis A virus infection among US adults: Findings from the National Health and Nutrition Examination Survey (NHANES), 1999-2012. AB - BACKGROUND: The clinical course of hepatitis A virus (HAV) infection is more severe with increased age. In the United States, surveillance data reported to CDC since 2011 indicate increases in both the absolute number of cases and the mean age of cases. Total antibody to HAV (anti-HAV) is a marker of immunity. METHODS: We analyzed National Health and Nutrition Examination Survey (NHANES) data for anti-HAV from respondents aged >= 2 years collected from 2007 to 2012 and compared with data collected 10 years earlier (1999-2006). For US-born adults aged >= 20 years, we estimated age-adjusted anti-HAV prevalence by demographic and other characteristics, evaluated factors associated with anti-HAV positivity and examined anti-HAV prevalence by decade of birth. RESULTS: The prevalence of anti-HAV among adults aged >= 20 years was 24.2% (95% CI 22.5-25.9) during 2007 2012, a significant decline from 29.5% (95% CI 28.0-31.1) during 1999-2006. Prevalence of anti-HAV was consistently lower in 2007-2012 compared to 1999-2006 by all characteristics examined. In 2007-2012, the lowest age-specific prevalence was among adults aged 30-49 years (16.1-17.6%). Factors significantly associated with anti-HAV positivity among adults were older age, Mexican American ethnicity, living below poverty, less education, and not having insurance. By decade of birth, the prevalence of anti-HAV was slightly lower in 2009-2012 than in 1999 2002, except among persons born from 1980 to 1989. CONCLUSIONS: NHANES data document very low prevalence of hepatitis A immunity among U.S. adults aged 30-49 years; waning of anti-HAV over time may be minimal. Improving vaccination coverage among susceptible adults should be considered. PMID- 26476365 TI - Invasive disease potential of pneumococci before and after the 13-valent pneumococcal conjugate vaccine implementation in children. AB - BACKGROUND: Changes in serotype distribution have been induced after pneumococcal conjugate vaccines (PCV) implementation, and non-vaccine serotypes are now circulating. Among these latter serotypes, we aimed to distinguish those with high invasive disease potential before (2008-2009) and after PCV13 implementation (2012-2013). METHODS: Invasive pneumococcal disease (IPD) serotypes isolated from children 6 to 24 months were compared with nasopharyngeal-colonizing serotypes in healthy children. To assess the invasive potential of a given serotype, odds ratios (ORs) were calculated. For each serotype, OR >1 indicated increased probability of association with IPD and OR <1 decreased probability. RESULTS: In 2008/2009 and 2012/2013, 355 pneumococci were isolated from 1212 healthy children and from 569 IPD, including 166 meningitis, 114 pneumonia, and 289 other IPDs. In period 1, serotypes 7F, 3, 1, 24F, and 19A showed highly significant invasive disease potential whereas in period 2, only serotype 24F was associated with a significant high OR (6.6 [95% CI 2.6; 16.2]). Of note, for serotype 12F, OR could not be calculated because of no carrier recorded, however, if there had been a single 12F carrier, the OR would be among the highest, in period 2, 15.7 [95% 3.4; 73.0]). Only two serotypes appeared negatively associated with IPD, 11A and 23B in the period 2 as compared with nine in period 1. In the second period, pneumococcal penicillin non-susceptible isolates were mostly represented by serotypes 19A, 15A, 19F, 35B and 24F both in carriers and IPD. Only one strain was resistant to penicillin with MIC=4 MUg/ml (serotype 19A) during the first period. CONCLUSION: In children <2 years old, compared to the previous period, the number of serotypes having a high disease potential decreased after PCV13 implementation, only two non-vaccine serotypes, 24F and 12F, had high invasive disease potential. PMID- 26476367 TI - Early priming with inactivated poliovirus vaccine (IPV) and intradermal fractional dose IPV administered by a microneedle device: A randomized controlled trial. AB - INTRODUCTION: Inactivated poliovirus vaccine (IPV) introduction and phased oral poliovirus vaccine (OPV) cessation are essential for eradication of polio. METHODS: Healthy 6-week old infants in Bangladesh were randomized to one of five study arms: receipt of trivalent OPV (tOPV) or bivalent OPV (bOPV) at ages 6, 10 and 14 weeks, intramuscular IPV or intradermal one-fifth fractional dose IPV (f IPV) at ages 6 and 14 weeks, or f-IPV at ages 6 and 14 weeks with bOPV at age 10 weeks (f-IPV/bOPV). All participants received tOPV at age 18 weeks. RESULTS: Of 975 infants randomized, 95% (922) completed follow-up. Type 1 seroconversion after 3 doses at 6, 10 and 14 weeks was higher with bOPV compared with tOPV (99% vs 94%, p=0.019). Seroconversions to types 1 and 3 after 2 IPV doses at ages 6 and 14 weeks were no different than after 3 doses of tOPV or bOPV at ages 6, 10 and 14 weeks. A priming response, seroconversion 1 week after IPV at 14 weeks among those who did not seroconvert after IPV at 6 weeks, was observed against poliovirus types 1, 2 and 3 in 91%, 84% and 97%, respectively. Compared with IPV, f-IPV failed non-inferiority tests for seroconversion with 1 or 2 doses and priming after 1 dose. DISCUSSION: The findings demonstrate considerable priming with IPV at age 6 weeks, comparable immunogenicity of tOPV and bOPV, and inferior immunogenicity of one-fifth f-IPV compared with IPV. If IPV induced priming at age 6 weeks is similar to that at age 14 weeks, IPV could be administered at a younger age and possibly with a higher coverage. PMID- 26476366 TI - Progress with viral vectored malaria vaccines: A multi-stage approach involving "unnatural immunity". AB - Viral vectors used in heterologous prime-boost regimens are one of very few vaccination approaches that have yielded significant protection against controlled human malaria infections. Recently, protection induced by chimpanzee adenovirus priming and modified vaccinia Ankara boosting using the ME-TRAP insert has been correlated with the induction of potent CD8(+) T cell responses. This regimen has progressed to field studies where efficacy against infection has now been reported. The same vectors have been used pre-clinically to identify preferred protective antigens for use in vaccines against the pre-erythrocytic, blood-stage and mosquito stages of malaria and this work is reviewed here for the first time. Such antigen screening has led to the prioritization of the PfRH5 blood-stage antigen, which showed efficacy against heterologous strain challenge in non-human primates, and vectors encoding this antigen are in clinical trials. This, along with the high transmission-blocking activity of some sexual-stage antigens, illustrates well the capacity of such vectors to induce high titre protective antibodies in addition to potent T cell responses. All of the protective responses induced by these vectors exceed the levels of the same immune responses induced by natural exposure supporting the view that, for subunit vaccines to achieve even partial efficacy in humans, "unnatural immunity" comprising immune responses of very high magnitude will need to be induced. PMID- 26476368 TI - Metadata management for high content screening in OMERO. AB - High content screening (HCS) experiments create a classic data management challenge-multiple, large sets of heterogeneous structured and unstructured data, that must be integrated and linked to produce a set of "final" results. These different data include images, reagents, protocols, analytic output, and phenotypes, all of which must be stored, linked and made accessible for users, scientists, collaborators and where appropriate the wider community. The OME Consortium has built several open source tools for managing, linking and sharing these different types of data. The OME Data Model is a metadata specification that supports the image data and metadata recorded in HCS experiments. Bio Formats is a Java library that reads recorded image data and metadata and includes support for several HCS screening systems. OMERO is an enterprise data management application that integrates image data, experimental and analytic metadata and makes them accessible for visualization, mining, sharing and downstream analysis. We discuss how Bio-Formats and OMERO handle these different data types, and how they can be used to integrate, link and share HCS experiments in facilities and public data repositories. OME specifications and software are open source and are available at https://www.openmicroscopy.org. PMID- 26476369 TI - A metric and workflow for quality control in the analysis of heterogeneity in phenotypic profiles and screens. AB - Heterogeneity is well recognized as a common property of cellular systems that impacts biomedical research and the development of therapeutics and diagnostics. Several studies have shown that analysis of heterogeneity: gives insight into mechanisms of action of perturbagens; can be used to predict optimal combination therapies; and can be applied to tumors where heterogeneity is believed to be associated with adaptation and resistance. Cytometry methods including high content screening (HCS), high throughput microscopy, flow cytometry, mass spec imaging and digital pathology capture cell level data for populations of cells. However it is often assumed that the population response is normally distributed and therefore that the average adequately describes the results. A deeper understanding of the results of the measurements and more effective comparison of perturbagen effects requires analysis that takes into account the distribution of the measurements, i.e. the heterogeneity. However, the reproducibility of heterogeneous data collected on different days, and in different plates/slides has not previously been evaluated. Here we show that conventional assay quality metrics alone are not adequate for quality control of the heterogeneity in the data. To address this need, we demonstrate the use of the Kolmogorov-Smirnov statistic as a metric for monitoring the reproducibility of heterogeneity in an SAR screen, describe a workflow for quality control in heterogeneity analysis. One major challenge in high throughput biology is the evaluation and interpretation of heterogeneity in thousands of samples, such as compounds in a cell-based screen. In this study we also demonstrate that three heterogeneity indices previously reported, capture the shapes of the distributions and provide a means to filter and browse big data sets of cellular distributions in order to compare and identify distributions of interest. These metrics and methods are presented as a workflow for analysis of heterogeneity in large scale biology projects. PMID- 26476370 TI - Tracking lexical consolidation with ERPs: Lexical and semantic-priming effects on N400 and LPC responses to newly-learned words. AB - Novel words can be recalled immediately and after little exposure, but require a post-learning consolidation period to show word-like behaviour such as lexical competition. This pattern is thought to reflect a qualitative shift from episodic to lexical representations. However, several studies have reported immediate effects of meaningful novel words on semantic processing, suggesting that integration of novel word meanings may not require consolidation. The current study synthesises and extends these findings by showing a dissociation between lexical and semantic effects on the electrophysiological (N400, LPC) response to novel words. The difference in N400 amplitude between novel and existing words (a lexical effect) decreased significantly after a 24-h consolidation period, providing novel support for the hypothesis that offline consolidation aids lexicalisation. In contrast, novel words preceded by semantically related primes elicited a more positive LPC response (a semantic-priming effect) both before and after consolidation, indicating that certain semantic effects can be observed even when words have not been fully lexicalised. We propose that novel meanings immediately start to contribute to semantic processing, but that the underlying neural processes may shift from strategic to more automatic with consolidation. PMID- 26476371 TI - Early electrophysiological markers of atypical language processing in prematurely born infants. AB - Because nervous system development may be affected by prematurity, many prematurely born children present language or cognitive disorders at school age. The goal of this study is to investigate whether these impairments can be identified early in life using electrophysiological auditory event-related potentials (AERPs) and mismatch negativity (MMN). Brain responses to speech and non-speech stimuli were assessed in prematurely born children to identify early electrophysiological markers of language and cognitive impairments. Participants were 74 children (41 full-term, 33 preterm) aged 3, 12, and 36 months. Pre attentional auditory responses (MMN and AERPs) were assessed using an oddball paradigm, with speech and non-speech stimuli presented in counterbalanced order between participants. Language and cognitive development were assessed using the Bayley Scale of Infant Development, Third Edition (BSID-III). Results show that preterms as young as 3 months old had delayed MMN response to speech stimuli compared to full-terms. A significant negative correlation was also found between MMN latency to speech sounds and the BSID-III expressive language subscale. However, no significant differences between full-terms and preterms were found for the MMN to non-speech stimuli, suggesting preserved pre-attentional auditory discrimination abilities in these children. Identification of early electrophysiological markers for delayed language development could facilitate timely interventions. PMID- 26476372 TI - Concerted actions of ameliorated colitis, aberrant crypt foci inhibition and 15 hydroxyprostaglandin dehydrogenase induction by sonic hedgehog inhibitor led to prevention of colitis-associated cancer. AB - The sonic hedgehog (Shh) signaling has been known to contribute to carcinogenesis in organ, where hedgehog exerted organogenesis and in cancers, which are developed based on mutagenic inflammation. Therefore, colitis-associated cancer (CAC) can be a good model to prove whether Shh inhibitors can be applied to prevent, as the efforts to discover potent anti-inflammatory agent are active to prevent CAC. Here, under the hypothesis that Shh inhibitors can prevent CAC, mouse model was generated to develop CAC by azoxymethane (AOM)-initiated, dextran sodium sulfate-promoted carcinogenesis. Shh inhibitors, cerulenin and itraconazole were treated by oral gavage and the mice were sacrificed at early phase of 3 weeks and late phase of 16 weeks. Compared to control group, the number of aberrant crypt foci at 3 weeks and tumor incidence at 16 weeks were all significantly decreased with Shh inhibitor. Significant attenuations of macrophage infiltration accompanied with significant decreases of IL-6, COX-2, STAT3 and NF-kappaB as well as significant ameliorations of beta-catenin nuclear translocation, cyclin D1 and CDK4 were imposed with Shh inhibitors. Especially, CAC was accompanied with significant cancellation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), but their levels were significantly preserved with Shh inhibitors. Among inflammatory mediators, significantly decreased levels of IL-6 and TNF-alpha, regulated with repressed NF-kappab and STAT3, were prominent with Shh inhibitor, whereas significant inductions of apoptosis were noted with Shh inhibitors. In conclusion, Shh inhibitors significantly prevented CAC covering either ameliorating oncogenic inflammation or suppressing tumor proliferation, especially supported with significant inhibition of IL-6 and STAT3 signaling, 15 PGDH preservation and apoptosis induction. PMID- 26476373 TI - FGF23-regulated production of Fetuin-A (AHSG) in osteocytes. AB - INTRODUCTION: AHSG, a serum glycoprotein with recognized anti-calcification activity, has also been suggested to modulate both bone formation and resorption. Though the bulk of AHSG is mostly synthesized in the liver, it has been claimed that also bone cells might produce it. However, the extent of the bone AHSG production and the potential controlling factors remain to be definitively proven. A relevant number of studies support the notion that FGF23, a bone derived hormone, not only regulates the most important mineral metabolism (MM) related factors (phosphate, parathyroid hormone, vitamin D, etc.), but might be also involved in cardiovascular (CV) outcome, both in chronic kidney disease (CKD) patients and in the general population. Furthermore, in addition to some direct autocrine and paracrine effects in bone, FGF23 has been suggested to interact with AHSG. In this study we investigated if AHSG is really produced by bone cells, and if its bone production is related and/or controlled by FGF23, using cultured bone cells, according to a new method recently published by our group. RESULTS: Our data show that AHSG is consistently produced in osteocytes and to a far lesser extent in osteoblasts. Both FGF23 addition to the culture medium and its over-expression in osteocytes were associated with a consistent increase of both AHSG mRNA and protein, while FGF23 silencing was followed by opposite effects. Though most of these results were largely affected by the blockage of FGF23 receptors, the role of these receptors in the different experimental sets is still not completely clarified. In addition, we found that FGF23 and AHSG proteins co-localized both in cytoplasm and nucleus, which suggests a possible reciprocal interactivity. CONCLUSIONS: Our data not only confirm that AHSG is produced in bone, mainly in osteocytes, but show for the first time that its production is modulated by FGF23. Since both proteins play important roles in the bone and cardiovascular pathology, these results add new pieces to the puzzling relationship between bone and vascular pathology, in particular in CKD patients, prompting future investigations in this field. PMID- 26476374 TI - Quercetin reverses experimental pulmonary arterial hypertension by modulating the TrkA pathway. AB - Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation, resistance to apoptosis, and increased migration of pulmonary artery smooth muscle cells (PASMCs). We hypothesized that quercetin exerts protective effects against this disease; thus, a chronic hypoxia model of PAH was generated using male Sprague-Dawley rats, which were treated with quercetin. In this model, quercetin prevented the development of PAH, right ventricular hypertrophy, and vascular remodeling after exposure to hypoxia. Quercetin inhibited PASMC proliferation and increased the apoptosis of PASMCs in vivo. In vitro, quercetin significantly inhibited hypoxia-induced PASMC proliferation, arrested cells in G1/G0 and inhibited cell migration in a dose-dependent manner. Moreover, our results showed that quercetin increased cyclin D1 protein levels and decreased the protein expression of cyclin B1 and Cdc2. Additionally, quercetin altered the Bax/Bcl-2 ratio and reduced MMP2, MMP9, CXCR4, integrin beta1, and integrin alpha5 expression. Using genome-wide microarray analysis, we found that factors regulating proliferation, apoptosis, cell cycle, and migration were related to the tyrosine receptor kinase A (TrkA) pathway. In addition, activation of the TrkA/AKT signaling cascade during hypoxia was inhibited by quercetin in a dose-dependent manner. Moreover, quercetin alone inhibited the TrkA/AKT signaling pathway, resulting in decreased PASMC migration, cell cycle arrest and the induction of apoptosis. Our data suggest that quercetin is a potential candidate for the treatment of hypoxia-induced PAH. PMID- 26476375 TI - Targeting hepatitis B virus cccDNA using CRISPR/Cas9. AB - Despite the existence of an excellent prophylactic vaccine and the development of highly effective inhibitors of the viral polymerase, chronic hepatitis B virus (HBV) infection remains a major source of morbidity and mortality, especially in Africa and Asia. A significant problem is that, while polymerase inhibitors can effectively prevent the production of viral genomic DNA from pre-genomic RNA transcripts, they do not prevent the transcription and translation of viral mRNAs from the covalently closed circular DNA (cccDNA) templates present in the nuclei of infected cells. Moreover, because these cccDNAs are highly stable, chronic HBV infections are only very rarely cured by the use of polymerase inhibitors and these drugs clearly cannot entirely prevent the subsequent development of HBV related morbidities such as cirrhosis and hepatocellular carcinoma. As a result, there has been considerable interest in the possibility of developing treatment approaches that directly target cccDNA for elimination. Here, we discuss recent publications that analyze the ability of the bacterial CRISPR/Cas DNA editing machinery to be repurposed as a tool for the specific cleavage and destruction of HBV cccDNAs in the nuclei of infected cells and consider which steps will be necessary to make CRISPR/Cas targeting of HBV DNA a clinically feasible approach to the treatment of chronic infections in humans. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B." PMID- 26476376 TI - Current status of immunomodulatory therapy in chronic hepatitis B, fifty years after discovery of the virus: Search for the "magic bullet" to kill cccDNA. AB - Chronic hepatitis B (CHB) is currently treated with IFN-alpha and nucleos(t)ide analogues, which have many clinical benefits, but there is no ultimate cure. The major problem consists in the persistence of cccDNA in infected hepatocytes. Because no antiviral drug has been evaluated which significantly reduces copies of cccDNA, cytolytic and noncytolytic approaches are needed. Effective virus specific T- and B-cell responses remain crucial in eliminating cccDNA-carrying hepatocytes and for the long-term control of HBV infection. Reduction of viremia by antiviral drugs provides a window for reconstitution of an HBV-specific immune response. Preclinical studies in mice and woodchucks have shown that immunostimulatory strategies, such as prime-boost vaccination and PD-1 blockade, can boost a weak virus-specific T cell response and lead to effective control of HBV infection. Based on data obtained in our preclinical studies, the combination of antiviral drugs and immunomodulators may control HBV viremia during a patient's drug-off period. In this article, we review current immune-modulatory approaches for the treatment of chronic hepatitis B and the elimination of cccDNA in preclinical models. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis". PMID- 26476377 TI - Current Trends in Sinonasal Imaging. AB - As endoscopic sinus surgery (ESS) has evolved since its introduction to the United States, so has technology for imaging the sinonasal cavities. Although imaging is most frequently performed for evaluating chronic sinusitis refractory to medical therapy, its uses have expanded beyond inflammatory sinus disease. Multidetector Computed Tomography is the current workhorse for both diagnosis and preoperative planning in prospective ESS patients, while MR imaging remains a complementary tool for evaluating suspected tumors or intracranial and orbital complications of rhinosinusitis. In this article, the authors review current trends and potential future directions in the use of these modalities for sinus imaging. PMID- 26476378 TI - Normal Anatomy and Anatomic Variants of the Paranasal Sinuses on Computed Tomography. AB - It is imperative for all imaging specialists to be familiar with detailed multiplanar CT anatomy of the paranasal sinuses and adjacent structures. This article reviews the radiologically relevant embryology of this complex region and discusses the region-specific CT anatomy of the paranasal sinuses and surrounding structures. Radiologists also need to know the clinical implications of identifying preoperatively the numerous anatomic variations encountered in this region and prepare a structured report according to the expectations of the referring clinician. PMID- 26476379 TI - Imaging in Sinonasal Inflammatory Disease. AB - While most patients with inflammatory rhinosinusitis are successfully diagnosed clinically, imaging is indicated in patients with recurrent or chronic sinusitis, atypical symptoms and complicated acute sinusitis. Non-enhanced high resolution, thin section computed tomography (CT) is the reference standard in evaluating such patients. It provides superb anatomical details and enables a fairly accurate diagnosis and delineation of the disease, addressing all concerns of the endoscopic surgeon prior to intervention. Contrast MR imaging is preferred for assessing intraorbital or intracranial complications. The radiologist must have a systematic approach to sinonasal CT and generate a clinically relevant report that impacts patient management. PMID- 26476380 TI - Fungal Sinusitis. AB - Fungal sinusitis is characterized into invasive and noninvasive forms. The invasive variety is further classified into acute, chronic and granulomatous forms; and the noninvasive variety into fungus ball and allergic fungal sinusitis. Each of these different forms has a unique radiologic appearance. The clinicopathologic and corresponding radiologic spectrum and differences in treatment strategies of fungal sinusitis make it an important diagnosis for clinicians and radiologists to always consider. This is particularly true of invasive fungal sinusitis, which typically affects immuno compromised patients and is associated with significant morbidity and mortality. Early diagnosis allows initiation of appropriate treatment strategies resulting in favorable outcome. PMID- 26476381 TI - Imaging Approach to Sinonasal Neoplasms. AB - The neoplastic lesions that can be found in the sinonasal space are numerous and varied. This article describes a general approach to narrowing down the differential diagnosis and provides the treating physician sufficient information to choose and deliver the best treatment modality. Computed tomography and MR imaging together provide complete radiologic assessment of sinonasal neoplasms. PMID- 26476382 TI - Sinonasal Tumors: Computed Tomography and MR Imaging Features. AB - This article describes the computed tomography and MR imaging features of the neoplasms of the sinonasal space. Although a pathologic diagnosis may not always be possible, knowledge of the features may help in narrowing down the differentials and establishing a malignant pathology. PMID- 26476383 TI - The Skull Base in the Evaluation of Sinonasal Disease: Role of Computed Tomography and MR Imaging. AB - The median anterior and central skull base forms an interface between the sinonasal and intracranial compartments. Due to the proximity of the intracranial structures, skull base involvement is a key assessment when evaluating the spread of sinonasal disease. This review describes the pertinent anatomy and the role of computed tomography and MR imaging in evaluating the median anterior and central skull base. The imaging appearances of pathologic processes that involve and traverse the skull base between the sinonasal and intracranial compartments are discussed and illustrated. PMID- 26476384 TI - Posttreatment Imaging of the Paranasal Sinuses Following Endoscopic Sinus Surgery. AB - Endoscopic sinus surgery is a minimally invasive option for the treatment of several nonneoplastic indications, particularly for medically refractory sinusitis and polyposis. Numerous interventions can be performed through endoscopic sinus surgery, many of which may be performed together during the same procedure. There are also a variety of complications that can result from endoscopic sinus surgery. Radiological imaging plays an important role in the evaluation of patients after endoscopic sinus surgery. Thus, it is important to be familiar with the expected and complicated imaging findings associated with endoscopic sinus surgery, which are reviewed in this article. PMID- 26476386 TI - Imaging of Paranasal Sinuses. PMID- 26476387 TI - Paranasal Sinuses-Decongested! PMID- 26476385 TI - Post-treatment Evaluation of Paranasal Sinuses After Treatment of Sinonasal Neoplasms. AB - The aim of imaging in the follow-up of asymptomatic patients treated for sinonasal neoplasms is to detect submucosal relapsing lesions. The challenge is to discriminate recurrent tissue within the changes resulting from unpredictable healing of tissue after surgery and radiotherapy. Scar, inflammation, and recurrence can be better separated with a multisequence MR imaging approach. The choice of the field of view should take into account the risk of in-field intracranial recurrences, craniofacial bone metastases, and perineural spread. Fluorodeoxyglucose-PET has a role in assessing distant metastasis. Its usefulness in local and regional surveillance has yet to be established. PMID- 26476388 TI - Laparoscopic Indocyanine Green Sentinel Lymph Node Mapping in Pregnant Cervical Cancer Patients. AB - We present cases of 2 pregnant patients with early-stage cervical cancer who have undergone indocyanine green (ICG) sentinel lymph node (SLN) mapping followed by laparoscopic SLN biopsy, pelvic lymphadenectomy, and cervical conization. Eight milliliters of ICG were injected in the 4 quadrants of the cervix after having obtained an adequate pneumoperitoneum and having inspected the abdominal cavity. SLNs were identified in both hemipelvises in both patients. In the final pathologic analysis, both SLNs and non-SLNs were negative for metastatic disease. No adverse events from ICG injection were recorded. ICG SLN mapping seems to be feasible in pregnant cervical cancer patients. PMID- 26476389 TI - The effects of merit-based financial aid on drinking in college. AB - We study the effect of state-level merit aid programs (such as Georgia's HOPE scholarship) on alcohol consumption among college students. Such programs have the potential to affect drinking through a combination of channels--such as raising students' disposable income and increasing the incentive to maintain a high GPA--that could theoretically raise or lower alcohol use. We find that the presence of a merit-aid program in one's state generally leads to an overall increase in (heavy) drinking. This effect is concentrated among men, students with lower parental education, older students, and students with high college GPA's. Our findings are robust to several alternative empirical specifications including event-study analyses by year of program adoption. Furthermore, no difference in high-school drinking is observed for students attending college in states with merit-aid programs. PMID- 26476390 TI - Synthesis, evaluation and molecular docking studies of amino acid derived N glycoconjugates as antibacterial agents. AB - Six amino acid derived N-glycoconjugates of d-glucose were synthesized, characterized and tested for antibacterial activity against G(+)ve (Bacillus cereus) as well as G(-)ve (Escherichia coli and Klebsiella pneumoniae) bacterial strains. All the tested compounds exhibited moderate to good antibacterial activity against these bacterial strains. The results were compared with the antibacterial activity of standard drug Chloramphenicol, where results of A5 (Tryptophan derived glycoconjugates) against E. coli and A4 (Isoleucine derived glycoconjugates) against K. pneumoniae bacterial strains are comparable with the standard drug molecule. In silico docking studies were also performed in order to understand the mode of action and binding interactions of these molecules. The docking studies revealed that, occupation of compound A5 at the ATP binding site of subunit GyrB (DNA gyrase, PDB ID: 3TTZ) via hydrophobic and hydrogen bonding interactions may be the reason for its significant in vitro antibacterial activity. PMID- 26476392 TI - Unexpected Death on an Acute Palliative Care Unit. PMID- 26476391 TI - Initial Validation of the Daily Spiritual Experiences Scale in Chinese Immigrants With Cancer Pain. AB - CONTEXT: Evaluating religious/spiritual influences in the growing Chinese American population may inform the development of culturally relevant palliative care interventions. OBJECTIVES: We assessed the psychometric properties and acceptability of the Daily Spiritual Experiences Scale-Chinese (DSES-C) in Chinese Americans with cancer-related pain. METHODS: The translated 16-item DSES C was administered as part of a symptom intervention for Chinese-American cancer patients. Patients were recruited from four New York community oncology practices. RESULTS: Of 321 patients, 78.7% were born in Mainland China, 79.1% spoke Cantonese, and 70.2% endorsed a religious affiliation (Ancestor worship, 31.7%; Chinese God worship, 29.8%; Buddhism, 17.1%; Christianity, 14.0%). In total, 82.6% completed the DSES-C (mean age = 57.7 years; 60.8% women) and 17.4% declined (mean age = 59.3 years; 52.0% women). Reasons for declining included low religiosity or perceived relevance of the scale items and difficulties separating spirituality from religiosity terms. Individuals having a religious affiliation were more likely to complete the DSES-C, whereas those not engaging in individual spiritual/religious practices or frequent group spiritual/religious practices tended to decline (all P < 0.05). The DSES-C (mean total score = 43.6, SD = 19.3) demonstrated high reliability (alpha = 0.94). Exploratory factor analysis suggested a one-factor solution, with significant loadings (>0.40) across items except Item 14 ("Accept others"). Construct validity was suggested by a positive association between DSES-C scores and having a religious affiliation (P < 0.05). CONCLUSION: In Chinese Americans with cancer pain, the DSES-C demonstrated acceptable psychometrics. Some participants experienced linguistic or cultural barriers preventing completion. Future investigations should provide additional validation in different Asian subgroups and those with varied medical conditions. PMID- 26476393 TI - A meta-analysis of the efficacy of albendazole compared with tinidazole as treatments for Giardia infections in children. AB - Metronidazole is frequently used against Giardia infection; however, it has been associated with significant failure rates in clearing parasites from the gut; additionally, as it should be taken for 5 to 10 days, it is associated with poor compliance, probably due to side effects. Other drugs, including tinidazole (TNZ) and albendazole (ABZ) have been included in the antigiardial armamentarium. Our aim was to assess the efficacy of ABZ compared with TNZ in Giardia infections in children. A systematic review and a meta-analysis were carried out. PubMed, Medline, EMBASE, CENTRAL, and LILACS were searched electronically until February 2015. Also relevant journals and references of studies included therein were hand searched for randomised controlled trials (RCTs). The meta-analysis was limited to RCTs evaluating the use of ABZ compared with TNZ in children with Giardia infection. The assessed outcome was parasitological efficacy. Prediction intervals (PI) were computed to better express uncertainties in the effect estimates. Five RCTs including 403 children were included. Overall, TNZ significantly outperformed ABZ without differences between subgroups defined by ABZ dosages [relative risk, (RR) 1.61 (95% CI): (1.40-1.85); P<0.0001]. The 95% prediction interval range is 1.28-2.02. There was no significant heterogeneity (I(2)=0%; Q-test of heterogeneity P=0.4507. The number-needed-to-treat, the average number of patients who need to be treated with TNZ to gain one additional good outcome as compared with ABZ was 4, 95% CI: 3-5. Our results show that TNZ outperforms ABZ in the treatment of Giardia infections in children from developing countries. PMID- 26476394 TI - Breeding habitat preference of preimaginal black flies (Diptera: Simuliidae) in Peninsular Malaysia. AB - To investigate the breeding habitat preference of black flies, a comprehensive black fly survey was conducted for the first time in Peninsular Malaysia. Preimaginal black flies (pupae and larvae) were collected manually from 180 stream points encompassing northern, southern, central and east coast of the Peninsular Malaysia. A total of 47 black fly species were recorded in this study. The predominant species were Simulium trangense (36.7%) and Simulium angulistylum (33.3%). Relatively common species were Simulium cheongi (29.4%), Simulium tani (25.6%), Simulium nobile (16.2%), Simulium sheilae (14.5%) and Simulium bishopi (10.6%). Principal Component Analysis (PCA) of all stream variables revealed four PCs that accounted for 69.3% of the total intersite variance. Regression analysis revealed that high species richness is associated with larger, deeper, faster and higher discharge streams with larger streambed particles, more riparian vegetation and low pH (F=22.7, d.f.=1, 173; P<0.001). Relationship between species occurrence of seven common species (present in >10% of the sampling sites) was assessed. Forward logistic regression analysis indicated that four species were significantly related to the stream variables. S. nobile and S. tani prefer large, fast flowing streams with higher pH, large streambed particles and riparian trees. S. bishopi was commonly found at high elevation with cooler stream, low conductivity, higher conductivity and more riparian trees. In contrast, S. sheilae was negatively correlated with PC-2, thus, this species commonly found at low elevation, warmer stream with low conductivity and less riparian trees. The results of this study are consistent with previous studies from other geographic regions, which indicated that both physical and chemical stream conditions are the key factors for black fly ecology. PMID- 26476395 TI - Between sexual and apomictic: unexpectedly variable sporogenesis and production of viable polyhaploids in the pentaploid fern of the Dryopteris affinis agg. (Dryopteridaceae). AB - BACKGROUND AND AIMS: In ferns, apomixis is an important mode of asexual reproduction. Although the mechanisms of fern reproduction have been studied thoroughly, most previous work has focused on cases in which ferns reproduce either exclusively sexually or exclusively asexually. Reproduction of ferns with potentially mixed systems and inheritance of apomixis remains largely unknown. This study addresses reproduction of the pentaploid Dryopteris * critica, a hybrid of triploid apomictic D. borreri and tetraploid sexual D. filix-mas. METHODS: Spore size, abortion percentage and number of spores per sporangium were examined in pentaploid plants of D. * critica grown in an experimental garden. The sporangial content of leaf segments was cultivated on an agar medium, and DNA ploidy levels were estimated by DAPI flow cytometry in 259 gametophytes or sporophytes arising from the F2 generation of the pentaploid hybrid. KEY RESULTS: The hybrid is partly fertile (89-94% of aborted spores) and shows unstable sporogenesis with sexual and apomictic reproduction combined. The number of spores per sporangium varied from approx. 31 to 64. Within a single sporangium it was possible to detect formation of either only aborted spores or various mixtures of aborted and well-developed reduced spores and unreduced diplospores. The spores germinated in viable gametophytes with two ploidy levels: pentaploid (5x, from unreduced spores) and half of that (approx. 2.5x, from reduced spores). Moreover, 2-15% of gametophytes (both 2.5x and 5x) formed a viable sporophyte of the same ploidy level due to apogamy. CONCLUSIONS: This study documents the mixed reproductive mode of a hybrid between apomictic and sexual ferns. Both sexual reduced and apomictic unreduced spores can be produced by a single individual, and even within a single sporangium. Both types of spores give rise to viable F2 generation gametophytes and sporophytes. PMID- 26476396 TI - Functional characterization of a transition metal ion transporter, OsZIP6 from rice (Oryza sativa L.). AB - Micronutrients are important for the growth and development of plants, which deploy families of transporters for their uptake and distribution. We have functionally characterized a novel transition metal ion transporter from rice, OsZIP6 (Oryza sativa zinc regulated transporter, iron regulated transporter-like protein 6). The transporter was found to be transcriptionally activated in shoot and root tissues in response to deficiency in Fe(2+), Zn(2+) and Mn(2+). OsZIP6 was expressed in Xenopus laevis oocytes, where currents were observed on addition of Co(2+), Fe(2+) and Cd(2+) but not Zn(2+), Mn(2+) and Ni(2+). This substrate range for OsZIP6, identified using two-electrode voltage clamp electrophysiology was confirmed by atomic absorption spectroscopy. Ion transport by OsZIP6 was found to be pH dependent and enhanced transport was observed at acidic pH. Radioisotope uptake suggested that Co(2+) competitively inhibits Fe(2+) uptake by OsZIP6. Identification and characterization of ZIP family members from crop plants will contribute to an understanding of nutrient mineral homeostasis in these plants. PMID- 26476397 TI - Eating like there's no tomorrow: Public awareness of the environmental impact of food and reluctance to eat less meat as part of a sustainable diet. AB - Reducing meat consumption is central to many of the scientific debates on healthy, sustainable diets because of the high environmental impact of meat production. Missing from these debates are the public perspectives about eating less meat and consideration of cultural and social values associated with meat. The aim of this study was to explore public awareness of the environmental impact of food and their willingness to reduce meat consumption. Twelve focus groups and four individual interviews were conducted with adults from a range of socio economic groups living in both rural and urban settings in Scotland. Public understanding of the link between food, environment and climate change was explored, with a focus on meat and attitudes towards reducing meat consumption. Data were transcribed and analysed thematically. Three dominant themes emerged: a lack of awareness of the association between meat consumption and climate change, perceptions of personal meat consumption playing a minimal role in the global context of climate change, and resistance to the idea of reducing personal meat consumption. People associated eating meat with pleasure, and described social, personal and cultural values around eating meat. Some people felt they did not need to eat less meat because they had already reduced their consumption or that they only ate small quantities. Scepticism of scientific evidence linking meat and climate change was common. Changing non-food related behaviours was viewed as more acceptable and a greater priority for climate change mitigation. The study highlights the role meat plays in the diet for many people, beyond nutritional needs. If healthy, sustainable dietary habits are to be achieved, cultural, social and personal values around eating meat must be integrated into the development of future dietary recommendations. PMID- 26476398 TI - Incremental value of quantitative CMR including parametric mapping for the diagnosis of acute myocarditis. AB - AIM: Cardiac magnetic resonance (CMR) can visualize inflammatory tissue changes in acute myocarditis. Several quantitative image-derived parameters have been described to enhance the diagnostic value of CMR, but no direct comparison of these techniques is available. METHODS AND RESULTS: A total of 34 patients with suspected acute myocarditis and 50 control subjects underwent CMR. CMR protocol included quantitative assessment of T1 relaxation times using modified Look Locker inversion recovery (MOLLI) and shortened MOLLI (ShMOLLI) acquisition schemes, extracellular volume fraction (ECV), T2 relaxation times, and longitudinal strain. Established Lake-Louise criteria (LLC) consisting of T2 weighted signal intensity ratio (T2-ratio), early gadolinium enhancement ratio (EGEr), and late gadolinium enhancement (LGE) were assessed. Receiver operating characteristics analysis was performed to compare diagnostic performance. Areas under the curve of native T1 (MOLLI: 0.95; ShMOLLI: 0.92) and T2 relaxation times (0.92) were higher compared with those of the other CMR parameters (T2-ratio: 0.71, EGEr: 0.71, LGE: 0.87, LLC: 0.90, ECV MOLLI: 0.77, ECV ShMOLLI: 0.80, longitudinal strain: 0.83). Combined with LGE, each native mapping technique outperformed the diagnostic performance of LLC (P < 0.01, respectively). A combination of native parameters (T1, T2, and longitudinal strain) significantly increased the diagnostic performance of CMR compared with LLC without need of contrast media application (0.99 vs. 0.90; P = 0.008). CONCLUSION: In patients suspected of having acute myocarditis, diagnostic performance of CMR can be improved by implementation of quantitative CMR parameters. Especially, native mapping techniques have the potential to replace current LLC. CLINICALTRIALS. GOV NUMBER: NCT02299856. PMID- 26476399 TI - Impact of exercise-induced mitral regurgitation on hypertrophic cardiomyopathy outcomes. AB - AIMS: Rest echocardiography plays a role in hypertrophic cardiomyopathy (HCM) diagnosis and risk stratification because left atrial enlargement, severe left ventricle (LV) hypertrophy, and rest LV outflow tract (LVOT) gradients >=50 mmHg are sudden cardiac death risk factors that have been highlighted in recent guidelines. Conversely, the lack of evidence makes that exercise-echocardiography findings play a limited role. In clinical practice, LVOT gradient, but also mitral regurgitation (MR) or pulmonary pressure, seems relevant parameters to look for, during the exercise. Therefore, we sought to determine whether exercise induced changes in myocardial and valvular functions could improve HCM risk stratification. METHODS AND RESULTS: Consecutive primitive HCM patients with a preserved LV ejection fraction underwent standardized exercise echocardiography (including the assessment of myocardial function, dynamic left intraventricular gradient, and valvular regurgitations) at baseline and were clinically followed for a median of 29.3 months. The primary endpoint was a composite criterion that included death from any cause, cardiorespiratory arrest, and hospitalization for a cardiovascular event. A total of 126 patients were included. Eighteen patients reached the primary endpoint. According to univariate Cox regression analysis, exercise LVOT gradient >=50 mmHg [hazard ratio (HR) = 3.31, P = 0.01] and significant (>=2/4) exercise MR (HR = 3.64, P < 0.01) were associated with the primary endpoint. Patients with significant MR had significantly higher rest and exercise LVOT gradients (P = 0.001 and P = 0.001) and larger left atria volumes (P < 0.001). CONCLUSION: Significant exercise-induced MR appears to significantly impact the prognoses of HCM patients, and it is also associated with higher LVOT rest and exercise gradients. PMID- 26476400 TI - The role of gamma-aminobutyric acid/glycinergic synaptic transmission in mediating bilirubin-induced hyperexcitation in developing auditory neurons. AB - Hyperbilirubinemia is a common clinical phenomenon observed in human newborns. A high level of bilirubin can result in severe jaundice and bilirubin encephalopathy. However, the cellular mechanisms underlying bilirubin excitotoxicity are unclear. Our previous studies showed the action of gamma aminobutyric acid (GABA)/glycine switches from excitatory to inhibitory during development in the ventral cochlear nucleus (VCN), one of the most sensitive auditory nuclei to bilirubin toxicity. In the present study, we investigated the roles of GABAA/glycine receptors in the induction of bilirubin hyperexcitation in early developing neurons. Using the patch clamp technique, GABAA/glycine receptor mediated spontaneous inhibitory synaptic currents (sIPSCs) were recorded from bushy and stellate cells in acute brainstem slices from young mice (postnatal day 2-6). Bilirubin significantly increased the frequency of sIPSCs, and this effect was prevented by pretreatments of slices with either fast or slow Ca(2+) chelators BAPTA-AM and EGTA-AM suggesting that bilirubin can increase the release of GABA/glycine via Ca(2+)-dependent mechanisms. Using cell-attached recording configuration, we found that antagonists of GABAA and glycine receptors strongly attenuated spontaneous spiking firings in P2-6 neurons but produced opposite effect in P15-19 neurons. Furthermore, these antagonists reversed bilirubin evoked hyperexcitability in P2-6 neurons, indicating that excitatory action of GABA/glycinergic transmission specifically contribute to bilirubin-induced hyperexcitability in the early stage of development. Our results suggest that bilirubin-induced enhancement of presynaptic release GABA/Glycine via Ca(2+) dependent mechanisms may play a critical role in mediating neuronal hyperexcitation associated with jaundice, implicating potential new strategies for predicting, preventing, and treating bilirubin neurotoxicity. PMID- 26476401 TI - Biochemical and toxicological evaluation of nano-heparins in cell functional properties, proteasome activation and expression of key matrix molecules. AB - The glycosaminoglycan heparin and its derivatives act strongly on blood coagulation, controlling the activity of serine protease inhibitors in plasma. Nonetheless, there is accumulating evidence highlighting different anticancer activities of these molecules in numerous types of cancer. Nano-heparins may have great biological significance since they can inhibit cell proliferation and invasion as well as inhibiting proteasome activation. Moreover, they can cause alterations in the expression of major modulators of the tumor microenvironment, regulating cancer cell behavior. In the present study, we evaluated the effects of two nano-heparin formulations: one isolated from porcine intestine and the other from the sea squirt Styela plicata, on a breast cancer cell model. We determined whether these nano-heparins are able to affect cell proliferation, apoptosis and invasion, as well as proteasome activity and the expression of extracellular matrix molecules. Specifically, we observed that nano-Styela compared to nano-Mammalian analogue has higher inhibitory role on cell proliferation, invasion and proteasome activity. Moreover, nano-Styela regulates cell apoptosis, expression of inflammatory molecules, such as IL-6 and IL-8 and reduces the expression levels of extracellular matrix macromolecules, such as the proteolytic enzymes MT1-MMP, uPA and the cell surface proteoglycans syndecan-1 and -2, but not on syndecan-4. The observations reported in the present article indicate that nano-heparins and especially ascidian heparin are effective agents for heparin-induced effects in critical cancer cell functions, providing an important possibility in pharmacological targeting. PMID- 26476403 TI - Evaluating the initial impact of the Riyadh Epilepsy Awareness Campaign. AB - OBJECTIVE: We determine the impact of an educational awareness campaign on the level of knowledge and the attitude of the Saudi population in Riyadh, Saudi Arabia in an attempt to improve the awareness and reduce the social stigma associated with epilepsy. METHODS: The Saudi Epilepsy Society organized a citywide awareness campaign in 2013. A survey consisting of 11 questions pertaining to epilepsy awareness was distributed to Saudi citizens living in Riyadh, aged 15 years and above, in malls, health clubs, mosques, universities, and schools during that campaign. The same questionnaire was administered before and after the awareness campaign to the same individuals on the same day to assess the impact of the campaign (n=2118). RESULTS: The epilepsy awareness campaign significantly raised the general knowledge about epilepsy: 1519 before vs. 1944 after (P<0.001) would allow their children to interact with an individual who had epilepsy; 1567 before vs. 688 after (P<0.001) would not want their children to marry an individual with epilepsy. Eight hundred twenty six before vs. 47 after (P<0.001) thought that epilepsy is untreatable. Regarding the causes of epilepsy, 1663 before vs. 896 after (P<0.001) believed that epilepsy is caused by supernatural powers, and 1224 before vs. 1874 after (P<0.001) chose brain disease as a cause of epilepsy. CONCLUSION: These findings suggest that epilepsy awareness campaigns can close knowledge gaps. A long-term reevaluation may be needed to assess awareness sustainability. PMID- 26476402 TI - Visual search in Dementia with Lewy Bodies and Alzheimer's disease. AB - Visual search is an aspect of visual cognition that may be more impaired in Dementia with Lewy Bodies (DLB) than Alzheimer's disease (AD). To assess this possibility, the present study compared patients with DLB (n = 17), AD (n = 30), or Parkinson's disease with dementia (PDD; n = 10) to non-demented patients with PD (n = 18) and normal control (NC) participants (n = 13) on single-feature and feature-conjunction visual search tasks. In the single-feature task participants had to determine if a target stimulus (i.e., a black dot) was present among 3, 6, or 12 distractor stimuli (i.e., white dots) that differed in one salient feature. In the feature-conjunction task participants had to determine if a target stimulus (i.e., a black circle) was present among 3, 6, or 12 distractor stimuli (i.e., white dots and black squares) that shared either of the target's salient features. Results showed that target detection time in the single-feature task was not influenced by the number of distractors (i.e., "pop-out" effect) for any of the groups. In contrast, target detection time increased as the number of distractors increased in the feature-conjunction task for all groups, but more so for patients with AD or DLB than for any of the other groups. These results suggest that the single-feature search "pop-out" effect is preserved in DLB and AD patients, whereas ability to perform the feature-conjunction search is impaired. This pattern of preserved single-feature search with impaired feature conjunction search is consistent with a deficit in feature binding that may be mediated by abnormalities in networks involving the dorsal occipito-parietal cortex. PMID- 26476404 TI - High intensity interval exercise decreases IL-8 and enhances the immunomodulatory cytokine interleukin-10 in lean and overweight-obese individuals. AB - PURPOSE: To compare the effects of two interval exercises with different intensities on acute inflammatory response in lean and overweight-obese subjects. METHODS: Ten lean (BMI<24.9kg/m(2)) and 12 overweight-obese (BMI 25 to <34.9kg/m(2)) males performed two conditions in randomly assigned: (1) high intensity interval exercise (HIIE) 10*60s (85-90%PMax)/75s (50%PMax); (2) moderate intensity interval exercise (MIIE) 10*60s (70-75%PMax)/60s (50%PMax), with blood collections at pre, immediately and 30min post each exercise bouts to evaluate total and differential leukocyte counts, serum creatine kinase (CK), lactate dehydrogenase (LDH) and systemic levels of IL-1ra, IL-6, IL-8, IL-10, IL 17a and CCL2. RESULTS: In lean group, HIIE induced a significant increase in total leukocytes and monocyte, while MIIE session did not change the number of leukocytes. Overweight-obese group presented similar increase in leukocytes, monocytes and lymphocytes in both HIIE and MIIE sessions. At baseline, overweight obese group showed high levels of CK, IL-8, IL-6 and CCL2 and lower concentrations of IL-10 compared to lean group. The MIIE did not alter the cytokine concentrations in both groups, independently of the time analysis. The HIIE induced significant decrease in IL-8 levels 30min post session in both the groups, and a progressive elevation in IL-10 levels immediately and 30min post in lean and overweight-obese. Regarding IL-6, overweight-obese subjects presented progressive increase either immediately and 30min after HIIE, while lean individuals presented significant increase only 30min after exercise. CONCLUSIONS: The acute inflammatory response to interval exercise is intensity dependent. Although obesity influences the basal concentrations of several cytokines, only HIIE induced important alterations in IL-8 and IL-10 levels, which may have important implications in the control of chronic low-grade inflammation in obesity. PMID- 26476405 TI - Long-term Impact of Androgen-deprivation Therapy on Cardiovascular Morbidity After Radiotherapy for Clinically Localized Prostate Cancer. AB - OBJECTIVE: To characterize the impact of androgen-deprivation therapy (ADT) on the incidence of cardiovascular events (CE) in prostate cancer patients treated with radiotherapy (RT). MATERIALS AND METHODS: There were 2211 patients with localized prostate cancer treated with RT from 1988 to 2008 at our institution. There were 991 patients (44.8%) who received ADT at the time of RT for a median of 6.1 months. Salvage ADT was initiated prior to CE in 365 men (16.5%) at a median of 5.5 years (range: 0.6 to 18.4 years) after RT and continued for a median of 4.3 years. A nomogram was constructed to predict the 10-year risk of CE "post-RT" (i.e., after RT). RESULTS: Patients receiving ADT at the time of RT exhibited significantly higher 10-year incidence of CE (19.6%, 95% CI 17.0% 22.6%) than those not receiving ADT (14.3%, 95% CI 12.2%-16.7%, P = .005). On multivariate analysis, both ADT at the time of RT (P = .007) and the time of salvage (P = .0004) were associated with increased CE risk, as were advanced age (P = .02), smoking (P = .0007), history of diabetes (P = .0007), and history of CE before RT (P < .0001). A nomogram using patient age, smoking status, history of pre-RT CE, history of diabetes, and ADT use at the time of RT predicted the rate of 10-year CE with a C-index of 0.81 (95% CI, 0.72-0.88). CONCLUSION: While ADT is often an essential part of prostate cancer treatment, patients should be counseled regarding increased risks of CE and prophylactic efforts should be considered to mitigate that risk. PMID- 26476406 TI - An insoluble frontotemporal lobar degeneration-associated TDP-43 C-terminal fragment causes neurodegeneration and hippocampus pathology in transgenic mice. AB - Frontotemporal dementia (FTD) causes progressive personality, behavior and/or language disturbances and represents the second most common form of dementia under the age of 65. Over half of all FTD cases are classified pathologically as frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein of 43 kDa (TDP-43) pathology (FTLD-TDP). In FTLD-TDP brains, TDP-43 is phosphorylated, C terminally cleaved, lost from the nucleus and accumulates in the cytoplasm and processes of neurons and glia. However, the contribution of TDP-43 C-terminal fragments (CTFs) to pathogenesis remains poorly understood. Here, we developed transgenic (Tg) mice with forebrain Camk2a-controlled doxycycline-suppressible expression of a TDP-43 CTF (amino acids 208-414, designated 208 TDP-43 CTF), previously identified in FTLD-TDP brains. In these 208 TDP-43 Tg mice, detergent insoluble 208 TDP-43 CTF was present in a diffuse punctate pattern in neuronal cytoplasm and dendrites without forming large cytoplasmic inclusions. Remarkably, the hippocampus showed progressive neuron loss and astrogliosis in the dentate gyrus (DG). This was accompanied by phosphorylated TDP-43 in the CA1 subfield, and ubiquitin and mitochondria accumulations in the stratum lacunosum moleculare (SLM) layer, without loss of endogenous nuclear TDP-43. Importantly, 208 TDP-43 CTF and phosphorylated TDP-43 were rapidly cleared when CTF expression was suppressed in aged Tg mice, which ameliorated neuron loss in the DG despite persistence of ubiquitin accumulation in the SLM. Our results demonstrate that Camk2a-directed 208 TDP-43 CTF overexpression is sufficient to cause hippocampal pathology and neurodegeneration in vivo, suggesting an active role for TDP-43 CTFs in the pathogenesis of FTLD-TDP and related TDP-43 proteinopathies. PMID- 26476408 TI - An essential role for UBE2A/HR6A in learning and memory and mGLUR-dependent long term depression. AB - UBE2A deficiency syndrome (also known as X-linked intellectual disability type Nascimento) is an intellectual disability syndrome characterized by prominent dysmorphic features, impaired speech and often epilepsy. The syndrome is caused by Xq24 deletions encompassing the UBE2A (HR6A) gene or by intragenic UBE2A mutations. UBE2A encodes an E2 ubiquitin-conjugating enzyme involved in DNA repair and female fertility. A recent study in Drosophila showed that dUBE2A binds to the E3 ligase Parkin, which is required for mitochondrial function and responsible for juvenile Parkinson's disease. In addition, these studies showed impairments in synaptic transmission in dUBE2A mutant flies. However, a causal role of UBE2A in of cognitive deficits has not yet been established. Here, we show that Ube2a knockout mice have a major deficit in spatial learning tasks, whereas other tested phenotypes, including epilepsy and motor coordination, were normal. Results from electrophysiological measurements in the hippocampus showed no deficits in synaptic transmission nor in the ability to induce long-term synaptic potentiation. However, a small but significant deficit was observed in mGLUR-dependent long-term depression, a pathway previously implied in several other mouse models for neurodevelopmental disorders. Our results indicate a causal role of UBE2A in learning and mGLUR-dependent long-term depression, and further indicate that the Ube2a knockout mouse is a good model to study the molecular mechanisms underlying UBE2A deficiency syndrome. PMID- 26476407 TI - DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. AB - Null mutations in genes involved in V(D)J recombination cause a block in B- and T cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease-all with severely impaired T cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naive T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients. PMID- 26476410 TI - Distribution and source of (129)I, (239)(,240)Pu, (137)Cs in the environment of Lithuania. AB - Fifty five soil samples collected in the Lithuania teritory in 2011 and 2012 were analyzed for (129)I, (137)Cs and Pu isotopes in order to investigate the level and distribution of artificial radioactivity in Lithuania. The activity and atomic ratio of (238)Pu/((239,24)0)Pu, (129)I/(127)I and (131)I/(137)Cs were used to identify the origin of these radionuclides. The (238)Pu/(239+240)Pu and (240)Pu/(239)Pu ratios in the soil samples analyzed varied in the range of 0.02 0.18 and 0.18-0.24, respectively, suggesting the global fallout as the major source of Pu in Lithuania. The values of 10(-9) to 10(-6) for (129)I/(127)I atomic ratio revealed that the source of (129)I in Lithuania is global fallout in most cases though several sampling sites shows a possible impact of reprocessing releases. Estimated (129)I/(131)I ratio in soil samples from the southern part of Lithuania shows negligible input of the Chernobyl fallout. No correlation of the (137)Cs and Pu isotopes with (129)I was observed, indicating their different sources terms. Results demonstrate uneven distribution of these radionuclides in the Lithuanian territory and several sources of contamination i.e. Chernobyl accident, reprocessing releases and global fallout. PMID- 26476409 TI - Developmental effects of vasotocin and nonapeptide receptors on early social attachment and affiliative behavior in the zebra finch. AB - Zebra finches demonstrate selective affiliation between juvenile offspring and parents, which, like affiliation between pair partners, is characterized by proximity, vocal communication and contact behaviors. This experiment tested the hypothesis that the nonapeptide arginine vasotocin (AVT, avian homologue of vasopressin) and nonapeptide receptors play a role prior to fledging in the development of affiliative behavior. Zebra finch hatchlings of both sexes received daily intracranial injections (post-hatch days 2-8) of either AVT, Manning Compound (MC, a potent V1a receptor antagonist) or saline (vehicle control). The social development of both sexes was assessed by measuring responsiveness to isolation from the family and subsequent reunion with the male parent after fledging. In addition, we assessed the changes in affiliation with the parents, unfamiliar males, and unfamiliar females each week throughout juvenile development. Compared to controls, MC subjects showed decreased attachment to the parents and MC males did not show the normal increase in affiliative interest in opposite sex individuals as they reached reproductive maturity. In contrast, AVT subjects showed a sustained affiliative interest in parents throughout development, and males showed increased interest in opposite sex conspecifics as they matured. These results provide the first evidence suggesting that AVT and nonapeptide receptors play organizational roles in social development in a bird. PMID- 26476411 TI - Origin of radon concentration of Csaloka Spring in the Sopron Mountains (West Hungary). AB - We examined the Csaloka Spring, which has the highest radon concentration in the Sopron Mountains (West Hungary) (, yearly average of 227 +/- 10 Bq L(-1)). The main rock types here are gneiss and micaschist, formed from metamorphism of former granitic and clastic sedimentary rocks respectively. The aim of the study was to find a likely source of the high radon concentration in water. During two periods (2007-2008 and 2012-2013) water samples were taken from the Csaloka Spring to measure its radon concentration (from 153 +/- 9 Bq L(-1) to 291 +/- 15 Bq L(-1)). Soil and rock samples were taken within a 10-m radius of the spring from debrish and from a deformed gneiss outcrop 500 m away from the spring. The radium activity concentration of the samples (between 24.3 +/- 2.9 Bq kg(-1) and 145 +/- 6.0 Bq kg(-1)) was measured by gamma-spectroscopy, and the specific radon exhalation was determined using radon-chamber measurements (between 1.32 +/- 0.5 Bq kg(-1) and 37.1 +/- 2.2 Bq kg(-1)). Based on these results a model calculation was used to determine the maximum potential radon concentration, which the soil or the rock may provide into the water. We showed that the maximum potential radon concentration of these mylonitic gneissic rocks (cpot = 2020 Bq L(-1)) is about eight times higher than the measured radon concentration in the water. However the maximum potential radon concentration for soils are significantly lower (41.3 Bq L(-1)) Based on measurements of radon exhalation and porosity of rock and soil samples we concluded that the source material can be the gneiss rock around the spring rather than the soil there. We determined the average radon concentration and the time dependence of the radon concentration over these years in the spring water. We obtained a strong negative correlation (-0.94 in period of 2007-2008 and -0.91 in 2012-2013) between precipitation and radon concentration. PMID- 26476412 TI - Diurnal variation of apoplastic ascorbate in winter wheat leaves in relation to ozone detoxification. AB - Besides stomatal closure, biological detoxification is an important protection mechanism for plants against ozone (O3). This study investigated the diurnal changes of ascorbate (a major detoxification agent) in the apoplast and leaf tissues of winter wheat grown under ambient air field conditions. Results showed the reduced ascorbate in the apoplast (ASCapo) exhibited a peak in late morning or midday, mismatching with either the maximum external O3 concentrations in mid afternoon or the maximum stomatal O3 uptake between late morning and mid afternoon. In contrast, the ASC in leaf tissues remained stable throughout the day. The investigations conducted in a Free-Air Concentration Elevation of O3 system confirmed that the diurnal variations of the ASCapo were induced more by the daily variations of O3 concentrations rather than the cumulative O3 effects. In conclusion, the O3-stress detoxification should be a dynamic variable rather than a fixed threshold as assumed in the stomatal flux-based O3 dose metrics. PMID- 26476414 TI - Prediction of recombinant protein overexpression in Escherichia coli using a machine learning based model (RPOLP). AB - Recombinant protein overexpression, an important biotechnological process, is ruled by complex biological rules which are mostly unknown, is in need of an intelligent algorithm so as to avoid resource-intensive lab-based trial and error experiments in order to determine the expression level of the recombinant protein. The purpose of this study is to propose a predictive model to estimate the level of recombinant protein overexpression for the first time in the literature using a machine learning approach based on the sequence, expression vector, and expression host. The expression host was confined to Escherichia coli which is the most popular bacterial host to overexpress recombinant proteins. To provide a handle to the problem, the overexpression level was categorized as low, medium and high. A set of features which were likely to affect the overexpression level was generated based on the known facts (e.g. gene length) and knowledge gathered from related literature. Then, a representative sub-set of features generated in the previous objective was determined using feature selection techniques. Finally a predictive model was developed using random forest classifier which was able to adequately classify the multi-class imbalanced small dataset constructed. The result showed that the predictive model provided a promising accuracy of 80% on average, in estimating the overexpression level of a recombinant protein. PMID- 26476413 TI - Probing the chemical mechanism and critical regulatory amino acid residues of Drosophila melanogaster arylalkylamine N-acyltransferase like 2. AB - Arylalkylamine N-acyltransferase like 2 (AANATL2) catalyzes the formation of N acylarylalkylamides from the corresponding acyl-CoA and arylalkylamine. The N acylation of biogenic amines in Drosophila melanogaster is a critical step for the inactivation of neurotransmitters, cuticle sclerotization, and melatonin biosynthesis. In addition, D. melanogaster has been used as a model system to evaluate the biosynthesis of fatty acid amides: a family of potent cell signaling lipids. We have previously showed that AANATL2 catalyzes the formation of N acylarylakylamides, including long-chain N-acylserotonins and N-acyldopamines. Herein, we define the kinetic mechanism for AANATL2 as an ordered sequential mechanism with acetyl-CoA binding first followed by tyramine to generate the ternary complex prior to catalysis. Bell shaped kcat,app - acetyl-CoA and (kcat/Km)app - acetyl-CoA pH-rate profiles identified two apparent pKa,app values of ~7.4 and ~8.9 that are critical to catalysis, suggesting the AANATL2-catalyzed formation of N-acetyltyramine occurs through an acid/base chemical mechanism. Site-directed mutagenesis of a conserved glutamate that corresponds to the catalytic base for other D. melanogaster AANATL enzymes did not produce a substantial depression in the kcat,app value nor did it abolish the pKa,app value attributed to the general base in catalysis (pKa ~7.4). These data suggest that AANATL2 catalyzes the formation of N-acylarylalkylamides using either different catalytic residues or a different chemical mechanism relative to other D. melanogaster AANATL enzymes. In addition, we constructed other site-directed mutants of AANATL2 to help define the role of targeted amino acids in substrate binding and/or enzyme catalysis. PMID- 26476415 TI - Cytoprotective role of autophagy against BH3 mimetic gossypol in ATG5 knockout cells generated by CRISPR-Cas9 endonuclease. AB - Previously, we demonstrated the association between autophagy and gossypol induced growth inhibition of mutant BRAF melanoma cells. Here, we investigate the role of autophagy in ATG5 knockout cell lines generated by the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas-mediated genome editing. The MTT assay revealed that the inhibitory effect of gossypol was weaker on ATG5 knockout cells than that on the wild type (WT) cells. The conversion of non-autophagic LC3-I to autophagic LC3-II and RT-PCR confirmed the functional gene knockout. However, Cyto-ID autophagy assay revealed that gossypol induced ATG5- and LC3-independent autophagy in ATG5 knockout cells. Moreover, gossypol acts as an autophagy inducer in ATG5 knockout cells while blocking the later stages of the autophagy process in WT cells, which was determined by measuring autophagic flux after co-treatment of gossypol with chloroquine (late-stage autophagy inhibitor). On the other hand, inhibition of autophagy with 3-MA or Beclin-1 siRNA caused a partial increase in the sensitivity to gossypol in ATG5 knockout cells, but not in the WT cells. Together, our findings suggest that the resistance to gossypol in ATG5 knockout cells is associated with increased cytoprotective autophagy, independent of ATG5. PMID- 26476417 TI - Understanding surgeon decision making in the use of radiotherapy as neoadjuvant treatment in rectal cancer. AB - BACKGROUND: Strong evidence supports the use of neoadjuvant radiotherapy in rectal cancer to improve local control. This randomised controlled trial aimed to determine the effect of clinical and non-clinical factors on decision making by colorectal surgeons in patients with rectal cancer. METHODS: Two surveys comprising vignettes of alternating short (4) and long (12) cues identified previously as important in rectal cancer, were randomly assigned to all members of the CSSANZ. Respondents chose from three possible treatments: long course chemoradiotherapy (LC), short course radiotherapy (SC) or surgery alone to investigate the effects on surgeon decision and confidence in decisions. Choice data were analysed using multinomial logistic regression models. RESULTS: 106 of 165 (64%) surgeons responded. LC was the preferred treatment choice in 73% of vignettes. Surgeons were more likely to recommend LC over SC (OR 1.79) or surgery alone (OR 1.99) when presented with the shorter, four-cue scenarios. There was no significant difference in confidence in decisions made when surgeons were presented with long cue vignettes (P = 0.57). Significant effects on the choice between LC, SC and surgery alone were tumour stage (P < 0.001), nodal status (P < 0.001), tumour position in the rectum (P < 0.001) and the circumferential location of the tumour (P < 0.001). A T4 tumour was the factor most likely associated with a recommendation against surgery alone (OR 335.96) or SC (OR 61.73). CONCLUSIONS: This study shows that clinical factors exert the greatest influence on surgeon decision making, which follows a "fast and frugal" heuristic decision making model. PMID- 26476416 TI - Susceptibility of restorations and adjacent enamel/dentine to erosion under different salivary flow conditions. AB - OBJECTIVES: The aim of this study was to investigate the effect of erosion on direct tooth-coloured restorations and adjacent enamel/dentine under low and normal simulated salivary flow rates. METHODS: Bovine enamel and dentine specimens were prepared (n=16) and restored with the following materials: resin composite (FiltekZ250), resin-modified glass ionomer cement (Fuji II LC), high viscosity glass ionomer cement (Fuji IX), and conventional glass ionomer cement (Fuji II). They were submitted to in vitro erosion-remineralisation cycling simulating normal (0.5 ml/min) and low (0.05 ml/min) salivary flow rates, for 5 days. The restorative material, enamel and dentine substrates were assessed with optical profilometry for surface loss. Mixed-model ANOVAs were used for statistical comparisons (alpha=0.05). RESULTS: Low-salivary flow significantly increased surface loss for all tested substrates (p<0.05), except FiltekZ250. Surface loss (mean+/-SD, in micrometres) under low-salivary flow was significantly higher in enamel (19.75+/-4.27) and dentine (23.08+/-3.48) adjacent to FiltekZ250 compared to Fuji II LC (16.33+/-2.30 and 20.47+/-2.58, respectively) and Fuji IX (15.79+/-2.41 and 20.63+/-2.34, respectively). Restoration surface degradation was significantly lower for Fuji II LC (2.17+/ 0.73) than for both Fuji II (13.03+/-6.79), and Fuji IX (16.74+/-7.72) under low salivary flow condition; whereas FiltekZ250 exhibited no meaningful surface loss (-0.35+/-0.19). CONCLUSION: Limited to these in vitro conditions, low-salivary flow promoted higher erosive conditions for teeth and restorations. Some fluoride containing restorative materials may reduce erosive wear on adjacent enamel and dentine. FiltekZ250 resisted erosive surface loss. Fuji II LC showed both reduced acid degradation and protection of adjacent dental surfaces to erosion. CLINICAL SIGNIFICANCE: Patients at risk for erosion and in need of restorations may benefit from fluoride-containing restorative materials that resist erosive degradation. The data of this study suggest that resin-modified glass ionomer may be a suitable restoration for patients at higher risk of erosion with low exposure to fluoride. PMID- 26476418 TI - Extent of lymph node dissection and overall survival in patients with uterine carcinosarcoma, papillary serous and endometrioid adenocarcinoma: A retrospective cohort study. AB - OBJECTIVE: To evaluate the interaction between extent of lymph node dissection (LND) and overall survival (OS) in patients with various histologic types of uterine cancer. METHODS: We retrospectively identified 834 patients who had primary surgery in our institution for uterine carcinosarcoma (CS), papillary serous (UPSC) and endometrioid adenocarcinoma between 1984 and 2009. Stage, grade, total lymph node count (LNC), positive LNC, adjuvant therapy, age, race and OS were collected. OS was calculated using the Kaplan-Meier method. Predictive factors were compared with the log rank test and Cox regression analysis. RESULTS: Our cohort included 158 patients with CS, 115 patients with UPSC and 561 patients with endometrioid adenocarcinoma. Of the cohort, 38% of the patients had Stage III or IV disease. LND was performed in 73% of patients with CS, 68% of patients with UPSC and 79% of patients with endometrioid adenocarcinoma. LND was performed in 82% of Stage I-II and in 68% of Stage III-IV cases. The median total LNC was 13 (range 1-75) and there was no significant difference in the total LNC between the different histologies. Median OS was 21 months for CS, 18 months for UPSC and 200 months for patients with endometrioid adenocarcinoma. A positive association between the total and positive LNC was present in all three histologic types (Spearman coefficient, p < 0.001). The cohort was divided in quartiles based on the total LNC and a Kaplan-Meier survival analysis was performed. A continuum of improved OS was noted in correlation with increased LNC. OS was 27 months for the group with 0 nodes, 112 months for the group with 1-8 nodes, 117 months for the group with 9-16 nodes and 196 months for the group with >17 nodes. Doubling the total LNC was associated with 28% risk of death reduction (HR 0.724, CI 0.66-0.794, p < 0.001) for the first year and 14% risk reduction (HR 0.858, CI 0.761-0.967, p = 0.012) for the second year. CONCLUSIONS: In our cohort, the performance of LND is associated with improved OS. This effect appears to be uniform across pathology types. The extent of the LND is inversely correlated with the risk of death for the first 2 years. PMID- 26476420 TI - Association between serum 25-hydroxyvitamin D concentrations and depressive symptoms in an older Korean population: A cross-sectional study. AB - BACKGROUND: This study aims to examine associations between serum 25 hydroxyvitamin D [25(OH)D] concentrations and depressive symptoms in an older Korean population. METHODS: The study used data from the Korean Urban Rural Elderly study, which enrolled 2942 participants aged 65 years or older from urban and rural communities. After excluding those treated with antidepressants, we conducted cross-sectional analysis of 2853 participants (962 men and 1891 women). Serum 25(OH)D was analyzed as both a continuous and categorized variable. Depressive symptoms were assessed using the Korean version of the Geriatric Depression Scale - Short Form. Multivariate logistic regression analyses were conducted to examine relationships between serum 25(OH)D and depressive symptoms for men and women separately. RESULTS: In men, ORs (95% CIs) for depressive symptoms were 1.74 (0.85, 3.58), 2.50 (1.20, 5.18), and 2.81 (1.15, 6.83) for those with a 25(OH)D concentration of 20.0-29.9, 10.0-19.9, and <10.0ng/mL, respectively (P-trend=0.013), compared with those with a 25(OH)D concentration of >=30.0ng/mL, after adjustment for study year, month of assay, age, parathyroid hormone, body mass index, number of comorbidities, smoking status, alcohol intake, exercise, sleep duration, income, education, cohabitation status, and residential area. In women, the associations between 25(OH)D and depressive symptoms were significant neither before nor after adjustment. LIMITATIONS: Due to the cross-sectional study design, causal association is uncertain. Intake of vitamin D supplements and outdoor activity were not examined. CONCLUSIONS: Our findings suggest that lower concentrations of vitamin D are independently associated with depressive symptoms in older Korean adults. PMID- 26476419 TI - Non-fatal suicidal behaviours in French Polynesia: Results of the WHO/START study and its implications for prevention. AB - OBJECTIVES: This is the first research article examining non-fatal suicidal behaviours (NFSB) in French Polynesia. The study was conducted in the frames of the WHO/START Study in 2008-2010. The main objective of the investigation was to obtain reliable data in order to develop evidence-based suicide prevention strategies. METHOD: Interviews with people presenting with NFSB at the Emergency Department (ED) of the French Polynesia Hospital (CHPF) were conducted by emergency and psychiatry departments' staff examining socio-demographic and clinical information and motives triggering suicidal behaviour. Odds ratios and rate ratios with 95% confidence intervals were calculated. RESULTS: There were 556 presentations of NFSB by 515 persons at the ED of CHPF (ratio 1.08) with the average rate of 75 per 100,000 for those treated in the hospital. An estimate of cases occurring in remote islands might bring the rate for the whole French Polynesia around 94 per 100,000. NFSB was more prevalent in females; rates for both genders were highest in the age group 25-35 years and 15-24 years. The main suicide method was drug poisoning by psychotropic drugs. The most frequent psychiatric disorder was mood disorder (45.3%); however, 26% of subjects had no 'major' psychiatric disorders, with 14.5% without a psychiatric diagnosis or only reactive disorders (F43-11.7%). There was a high prevalence of previous NFSB (52.1%). LIMITATIONS: Study includes only NFSB seeking medical help from the biggest hospital in the country. CONCLUSION: Suicide prevention activities specific to the findings and the socio-cultural context of French Polynesia should be considered. PMID- 26476421 TI - Construct validity of a proposed new diagnostic entity: Acute Suicidal Affective Disturbance (ASAD). AB - BACKGROUND: The current study presents initial support for the construct validity of Acute Suicidal Affective Disturbance (ASAD), a clinical entity consisting of acute suicide risk and several related features. METHODS: Participants (N=195) were university students who were recruited for a history of suicide attempt(s), history of suicidal ideation, or no history of suicide attempts or suicidal ideation. Participants completed study measures online. RESULTS: Factor analytic results indicated a one factor solution for a lifetime measure of ASAD symptoms. The measure demonstrated strong convergent and divergent validity with common correlates of suicide-related outcomes and incremental predictive validity, as lifetime occurrence of ASAD symptoms predicted number of past suicide attempts above and beyond a host of suicide risk factors. Lifetime ASAD symptoms differed between those with multiple suicide attempts, those with a single attempt, and participants without a history of attempts, as well as between participants with a history of both suicidal ideation and attempts and those with a history of suicidal ideation but not suicide attempts. LIMITATIONS: The cross-sectional research design limits the ability to infer causation between ASAD symptoms and suicidal behavior. Only past ASAD symptoms (not current symptoms) were measured. CONCLUSIONS: ASAD appears to be a unified clinical entity that characterizes acute suicide risk which may assist clinicians in determining a client's potential for death by suicide. PMID- 26476422 TI - Does collaborative care improve social functioning in adults with depression? The application of the WHO ICF framework and meta-analysis of outcomes. AB - BACKGROUND: Collaborative care has proven efficacy in improving symptoms of depression, yet patients value improvements in their social function also. We used the World Health Organisation's International classification of functioning, disability, and health (WHO ICF) to robustly identify measures of social function and explored whether collaborative care interventions improve social functioning using meta-analysis. METHODS: We performed a secondary data analysis on studies identified from our previous Cochrane review of collaborative care interventions for depression and search update (December 2013). The WHO ICF framework was applied to identify studies that included self-report measures of social functioning. Outcomes were extracted at short-term (6 months) and medium-term (>=7 months) and analysed using random-effects meta-analysis. The relationship between improvements in depression outcomes and improvements in social functioning was also explored using bivarable meta-regression. RESULTS: Eighteen trials were identified that measured social functioning and met our remaining inclusion criteria. Collaborative care was associated with small improvements in social functioning in the short (Standardised Mean Difference, SMD=0.23, 95% confidence interval 0.12 to 0.34) and medium term (SMD=0.19, 95% confidence interval 0.09 to 0.29). Improvements in depressive symptoms were associated with moderate improvements in social function (beta=-0.55, 95% confidence interval 0.82 to -0.28) but cross-sectionally only. LIMITATIONS: The small number of studies (N=18) prevented more complex analyses to explore moderators of social functioning outcomes. CONCLUSIONS: Collaborative care improves social functioning but the mechanisms through which this occurs are unknown. Future depression interventions need to consider a person's degree of social function equally alongside their depressive symptoms. PMID- 26476431 TI - Multi-scale perturbations of protein interactomes reveal their mechanisms of regulation, robustness and insights into genotype-phenotype maps. AB - Cellular architectures and signaling machineries are organized through protein protein interactions (PPIs). High-throughput methods to study PPIs in yeast have opened a new perspective on the organization of the cell by allowing the study of whole protein interactomes. Recent investigations have moved from the description of this organization to the analysis of its dynamics by experimenting how protein interaction networks (PINs) are rewired in response to perturbations. Here we review studies that have used the budding yeast as an experimental system to explore these altered networks. Given the large space of possible PPIs and the diversity of potential genetic and environmental perturbations, high-throughput methods are an essential requirement to survey PIN perturbations on a large scale. Network perturbations are typically conceptualized as the removal of entire proteins (nodes), the modification of single PPIs (edges) or changes in growth conditions. These studies have revealed mechanisms of PPI regulation, PIN architectural organization, robustness and sensitivity to perturbations. Despite these major advances, there are still inherent limits to current technologies that lead to a trade-off between the number of perturbations and the number of PPIs that can be considered simultaneously. Nevertheless, as we exemplify here, targeted approaches combined with the existing resources remain extremely powerful to explore the inner organization of cells and their responses to perturbations. PMID- 26476429 TI - Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study. AB - OBJECTIVE: To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes. DESIGN: Metaepidemiological study. ELIGIBILITY CRITERIA: Meta-analyses of randomised controlled trials with mortality outcomes comparing the effectiveness of exercise and drug interventions with each other or with control (placebo or usual care). DATA SOURCES: Medline and Cochrane Database of Systematic Reviews, May 2013. MAIN OUTCOME MEASURE: Mortality. DATA SYNTHESIS: We combined study level death outcomes from exercise and drug trials using random effects network meta-analysis. RESULTS: We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339,274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14,716 participants were randomised to physical activity interventions in 57 trials. No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise vanticoagulants 0.09, 95% credible intervals 0.01 to 0.70 and exercise v antiplatelets 0.10, 0.01 to 0.62). Diuretics were more effective than exercise in heart failure (exercise v diuretics 4.11,1.17 to 24.76). Inconsistency between direct and indirect comparisons was not significant. CONCLUSIONS: Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes. PMID- 26476432 TI - Suppression of TGFbeta and Angiogenesis by Type VII Collagen in Cutaneous SCC. AB - BACKGROUND: Individuals with severe generalized recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering disorder caused by mutations in the COL7A1 gene, develop unexplained aggressive squamous cell carcinomas (SCC). Here we report that loss of type VII collagen (Col7) in SCC results in increased TGFbeta signaling and angiogenesis in vitro and in vivo. METHODS: Stable knockdown (KD) of Col7 was established using shRNA, and cells were used in a mouse xenograft model. Angiogenesis was assessed by immunohistochemistry, endothelial tube-forming assays, and proteome arrays. Mouse and zebrafish models were used to examine the effect of recombinant Col7 on angiogenesis. Findings were confirmed in anonymized, archival human tissue: RDEB SCC tumors, non-EB SCC tumors, RDEB skin, normal skin; and two human RDEB SCC cell lines. The TGFbeta pathway was examined using immunoblotting, immunohistochemistry, biochemical inhibition, and siRNA. All statistical tests were two-sided. RESULTS: Increased numbers of cross-cut blood vessels were observed in Col7 KD compared with control xenografts (n = 4 to 7 per group) and in RDEB tumors (n = 21) compared with sporadic SCC (n = 24, P < .001). Recombinant human Col7 reversed the increased SCC angiogenesis in Col7 KD xenografts in vivo (n = 7 per group, P = .04). Blocking the interaction between alpha2beta1 integrin and Col7 increased TGFB1 mRNA expression 1.8-fold and p Smad2 levels two-fold. Increased TGFbeta signaling and VEGF expression were observed in Col7 KD xenografts (n = 4) compared with control (n = 4) and RDEB tumors (TGFbeta markers, n = 6; VEGF, n = 17) compared with sporadic SCC (TGFbeta markers, n = 6; VEGF, n = 21). Inhibition of TGFbeta receptor signaling using siRNA resulted in decreased endothelial cell tube formation (n = 9 per group, mean tubes per well siC = 63.6, SD = 17.1; mean tubes per well siTbetaRII = 29.7, SD = 6.1, P = .02). CONCLUSIONS: Type VII collagen suppresses TGFbeta signaling and angiogenesis in cutaneous SCC. Patients with RDEB SCC may benefit from anti angiogenic therapy. PMID- 26476430 TI - An overview of bioinformatics methods for modeling biological pathways in yeast. AB - The advent of high-throughput genomics techniques, along with the completion of genome sequencing projects, identification of protein-protein interactions and reconstruction of genome-scale pathways, has accelerated the development of systems biology research in the yeast organism Saccharomyces cerevisiae In particular, discovery of biological pathways in yeast has become an important forefront in systems biology, which aims to understand the interactions among molecules within a cell leading to certain cellular processes in response to a specific environment. While the existing theoretical and experimental approaches enable the investigation of well-known pathways involved in metabolism, gene regulation and signal transduction, bioinformatics methods offer new insights into computational modeling of biological pathways. A wide range of computational approaches has been proposed in the past for reconstructing biological pathways from high-throughput datasets. Here we review selected bioinformatics approaches for modeling biological pathways inS. cerevisiae, including metabolic pathways, gene-regulatory pathways and signaling pathways. We start with reviewing the research on biological pathways followed by discussing key biological databases. In addition, several representative computational approaches for modeling biological pathways in yeast are discussed. PMID- 26476433 TI - The Temporal Risk of Heart Failure Associated With Adjuvant Trastuzumab in Breast Cancer Patients: A Population Study. AB - BACKGROUND: The late cardiac effect of adjuvant trastuzumab and its potential interaction with anthracycline have not been well-studied on a population level. METHODS: In this retrospective population-based cohort study, female breast cancer patients in Ontario, diagnosed between 2003 and 2009, were identified by the Ontario Cancer Registry and linked to administrative databases to ascertain demographics, cardiac risk factors, comorbidities, and use of adjuvant trastuzumab and other chemotherapy. Patients with pre-existing heart failure (HF) were excluded. The main endpoint was new diagnosis of HF. Analyses included Kaplan-Meier (KM) survival analysis, multivariable piecewise Cox regression, and competing risk and propensity score analyses. All statistical tests were two sided. RESULTS: Nineteen thousand seventy-four women with breast cancer treated with adjuvant chemotherapy were identified, of whom 3371 (17.7%) also received adjuvant trastuzumab. Anthracycline use was 84.9% overall. After a median follow up of 5.9 years, patients treated with trastuzumab and chemotherapy were more likely to develop HF than patients on chemotherapy alone (5-year cumulative incidences of 5.2% vs 2.5%; log-rank P < .001). After adjusting for confounders, adjuvant trastuzumab remained independently associated with incident HF in the first 1.5 years (HR = 5.77, 95% CI = 4.38 to 7.62, P < .001), but not thereafter (HR = 0.87, 95% CI = 0.57 to 1.33, P = .53). Anthracycline use did not increase the risk of HF with trastuzumab synergistically, neither within (P interaction = .92) nor beyond 1.5 years (P interaction = .23). CONCLUSION: Adjuvant trastuzumab was associated with increased risk of new incidence of HF in breast cancer survivors during the period of adjuvant treatment but not thereafter. Routine intensive monitoring may not be necessary after completing adjuvant therapy. PMID- 26476434 TI - RE: Detecting Overall Survival Benefit Derived From Survival Postprogression Rather Than Progression-Free Survival. PMID- 26476435 TI - RE: A Proposal to Standardize Reporting Units for Fecal Immunochemical Tests for Hemoglobin. PMID- 26476436 TI - Exposure to 915 MHz radiation induces micronuclei in Vicia faba root tips. AB - The increasing use of mobile phones and wireless networks raised a great debate about the real carcinogenic potential of radiofrequency-electromagnetic field (RF EMF) exposure associated with these devices. Conflicting results are reported by the great majority of in vivo and in vitro studies on the capability of RF-EMF exposure to induce DNA damage and mutations in mammalian systems. Aimed at understanding whether less ambiguous responses to RF-EMF exposure might be evidenced in plant systems with respect to mammalian ones, in the present work the mutagenic effect of RF-EMF has been studied through the micronucleus (MN) test in secondary roots of Vicia faba seedlings exposed to mobile phone transmission in controlled conditions, inside a transverse electro magnetic (TEM) cell. Exposure of roots was carried out for 72h using a continuous wave (CW) of 915 MHz radiation at three values of equivalent plane wave power densities (23, 35 and 46W/m(2)). The specific absorption rate (SAR) was measured with a calorimetric method and the corresponding values were found to fall in the range of 0.4-1.5W/kg. Results of three independent experiments show the induction of a significant increase of MN frequency after exposure, ranging from a 2.3-fold increase above the sham value, at the lowest SAR level, up to a 7-fold increase at the highest SAR. These findings are in agreement with the limited number of data on cytogenetic effects detected in other plant systems exposed to mobile phone RF-EMF frequencies and clearly show the capability of radiofrequency exposure to induce DNA damage in this eukaryotic cell system. PMID- 26476437 TI - Effects of the Synthetic Neurosteroid: 3beta-Methoxypregnenolone (MAP4343) on Behavioral and Physiological Alterations Provoked by Chronic Psychosocial Stress in Tree Shrews. AB - BACKGROUND: Most currently available active antidepressant drugs are selective serotonin/noradrenaline reuptake inhibitors. However, as their clinical efficacy is not immediate, long-term administration is often accompanied by substantial side effects, and numerous patients remain non- or partial responders. We have recently found that the synthetic neurosteroid derivative 3beta methoxypregnenolone, which binds to the microtubule-associated protein-2, can provide a novel therapeutic approach in experimental model of depressive disorders in rats. To further validate the antidepressant-like efficacy of 3beta methoxypregnenolone, we investigated effects of a longer treatment (4-week oral administration; 50mg/kg/d) in a nonrodent species, the tree shrew, exposed to psychosocial stress that elicits close-to-human alterations observed in patients with depressive disorders. METHODS: During the experimental period, physiological parameters were registered, including core body temperature and electroencephalogram, while animals were videotaped to analyze their avoidance behavior. Morning urine samples were collected for measurements of cortisol and noradrenaline levels. RESULTS: We found that treatment with 3beta methoxypregnenolone abolished stress-triggered avoidance behavior and prevented hormone hypersecretion, hypothermia, and sleep disturbances, further suggesting its antidepressant-like efficacy. Comparative treatment with fluoxetine also prevented some of the physiological alterations, while the hypersecretion of cortisol and sleep disturbances were not or partially restored by fluoxetine, suggesting a better efficacy of 3beta-methoxypregnenolone. Alpha-tubulin isoforms were measured in hippocampi: we found that 3beta-methoxypregnenolone reversed the specific decrease in acetylation of alpha-tubulin induced by psychosocial stress, while it did not modify the psychosocial stress-elicited reduction of tyrosinated alpha-tubulin. CONCLUSIONS: Taken together, these data strongly suggest a potent antidepressant-like effect of 3beta-methoxypregnenolone on translational parameters. PMID- 26476439 TI - Notice of Retraction. PMID- 26476438 TI - Mitochondrial DNA copy number in colorectal cancer: between tissue comparisons, clinicopathological characteristics and survival. AB - Low mitochondrial DNA (mtDNA) copy number in tumors has been associated with worse prognosis in colorectal cancer (CRC). This study further deciphers the role of mtDNA copy number in CRC by comparing mtDNA copy number between healthy, adenoma and carcinoma tissue, by investigating its association according to several clinicopathological characteristics in CRC, and by relating it to CRC specific survival in CRC patients. A hospital-based series of samples including cancer, adenoma and adjacent histologically normal tissue from primary CRC patients (n = 56) and recurrent CRC (n = 16) was studied as well as colon mucosa samples from healthy subjects (n = 76). Furthermore, mtDNA copy number was assessed in carcinomas of 693 CRC cases identified from the population-based Netherlands Cohort Study (NLCS). MtDNA copy number was significantly lower in carcinoma tissue (P = 0.011) and adjacent tissue (P < 0.001) compared to earlier resected adenoma tissue and in primary CRC tissue compared to recurrent CRC tissue (P = 0.011). Within both study populations, mtDNA copy number was significantly lower in mutated BRAF (P = 0.027 and P = 0.006) and in microsatellite unstable (MSI) tumors (P = 0.033 and P < 0.001) and higher in KRAS mutated tumors (P = 0.004). Furthermore, the association between mtDNA and survival seemed to follow an inverse U-shape with the highest HR observed in the second quintile of mtDNA copy number (HR = 1.70, 95% CI = 1.18, 2.44) compared to the first quintile. These results might reflect an association of mtDNA copy number with various malignant processes in cancer cells and warrants further research on tumor energy metabolism in CRC prognosis. PMID- 26476440 TI - Promoting lifestyle behaviour change and well-being in hospital patients: a pilot study of an evidence-based psychological intervention. AB - BACKGROUND: Lifestyle risk behaviours show an inverse social gradient, clustering in vulnerable groups. We designed and piloted an intervention to address barriers to lifestyle behaviour change among hospital patients. METHODS: We designed our intervention using effective components of behaviour change interventions informed by psychological theory. Delivered by a health psychologist based at the Royal Free London NHS Foundation Trust, the 4-week intervention included detailed baseline assessment, personalized goal setting, psychological skills development, motivation support and referral to community services. Primary outcomes were feasibility and patient acceptability. We also evaluated changes to health and well-being. RESULTS: From 1 July 2013 to 31 September 2014, 686 patients were referred, 338 (49.3%) attended a first appointment and 172 (25.1%) completed follow-up. Furthermore, 72.1% of attenders were female with the median age 55 years and poor self-reported baseline health. After 4 weeks, self-efficacy, health and well-being scores significantly improved: 63% of lifestyle goals and 89% of health management goals were fully achieved; 58% of referrals to community lifestyle behaviour change services and 79% of referrals to other services (e.g. Citizen's Advice Bureau) were accepted; 99% were satisfied/very satisfied with the service. CONCLUSIONS: Our hospital-based intervention was feasible, acceptable and showed preliminary health and well-being gains. PMID- 26476441 TI - Dose-Response Functions for the Olfactory, Nasal Trigeminal, and Ocular Trigeminal Detectability of Airborne Chemicals by Humans. AB - We gathered from the literature 47 odor and 37 trigeminal (nasal and ocular) chemesthetic psychometric (i.e., detectability or dose-response) functions from a group of 41 chemicals. Vapors delivered were quantified by analytical methods. All functions were very well fitted by the sigmoid (logistic) equation: y = 1 / (1 + e({-(x-C)/D})), where parameter C quantifies the detection threshold concentration and parameter D the steepness of the function. Odor and chemesthetic functions showed no concentration overlap: olfactory functions grew along the parts per billion (ppb by volume) range or lower, whereas trigeminal functions grew along the part per million (ppm by volume) range. Although, on average, odor detectability rose from chance detection to perfect detection within 2 orders of magnitude in concentration, chemesthetic detectability did it within one. For 16 compounds having at least 1 odor and 1 chemesthetic function, the average gap between the 2 functions was 4.6 orders of magnitude in concentration. A quantitative structure-activity relationship (QSAR) using 5 chemical descriptors that had previously described stand-alone odor and chemesthetic threshold values, also holds promise to describe, and eventually predict, olfactory and chemesthetic detectability functions, albeit functions from additional compounds are needed to strengthen the QSAR. PMID- 26476442 TI - The structure of Erb1-Ytm1 complex reveals the functional importance of a high affinity binding between two beta-propellers during the assembly of large ribosomal subunits in eukaryotes. AB - Ribosome biogenesis is one of the most essential pathways in eukaryotes although it is still not fully characterized. Given the importance of this process in proliferating cells, it is obvious that understanding the macromolecular details of the interactions that take place between the assembly factors, ribosomal proteins and nascent pre-rRNAs is essentially required for the development of new non-genotoxic treatments for cancer. Herein, we have studied the association between the WD40-repeat domains of Erb1 and Ytm1 proteins. These are essential factors for the biogenesis of 60S ribosomal subunits in eukaryotes that form a heterotrimeric complex together with the also essential Nop7 protein. We provide the crystal structure of a dimer formed by the C-terminal part of Erb1 and Ytm1 from Chaetomium thermophilum at 2.1 A resolution. Using a multidisciplinary approach we show that the beta-propeller domains of these proteins interact in a novel manner that leads to a high-affinity binding. We prove that a point mutation within the interface of the complex impairs the interaction between the two proteins and negatively affects growth and ribosome production in yeast. Our study suggests insights into the association of the Erb1-Ytm1 dimer with pre ribosomal particles. PMID- 26476443 TI - CauloBrowser: A systems biology resource for Caulobacter crescentus. AB - Caulobacter crescentus is a premier model organism for studying the molecular basis of cellular asymmetry. The Caulobacter community has generated a wealth of high-throughput spatiotemporal databases including data from gene expression profiling experiments (microarrays, RNA-seq, ChIP-seq, ribosome profiling, LC-ms proteomics), gene essentiality studies (Tn-seq), genome wide protein localization studies, and global chromosome methylation analyses (SMRT sequencing). A major challenge involves the integration of these diverse data sets into one comprehensive community resource. To address this need, we have generated CauloBrowser (www.caulobrowser.org), an online resource for Caulobacter studies. This site provides a user-friendly interface for quickly searching genes of interest and downloading genome-wide results. Search results about individual genes are displayed as tables, graphs of time resolved expression profiles, and schematics of protein localization throughout the cell cycle. In addition, the site provides a genome viewer that enables customizable visualization of all published high-throughput genomic data. The depth and diversity of data sets collected by the Caulobacter community makes CauloBrowser a unique and valuable systems biology resource. PMID- 26476444 TI - PDBe: improved accessibility of macromolecular structure data from PDB and EMDB. AB - The Protein Data Bank in Europe (http://pdbe.org) accepts and annotates depositions of macromolecular structure data in the PDB and EMDB archives and enriches, integrates and disseminates structural information in a variety of ways. The PDBe website has been redesigned based on an analysis of user requirements, and now offers intuitive access to improved and value-added macromolecular structure information. Unique value-added information includes lists of reviews and research articles that cite or mention PDB entries as well as access to figures and legends from full-text open-access publications that describe PDB entries. A powerful new query system not only shows all the PDB entries that match a given query, but also shows the 'best structures' for a given macromolecule, ligand complex or sequence family using data-quality information from the wwPDB validation reports. A PDBe RESTful API has been developed to provide unified access to macromolecular structure data available in the PDB and EMDB archives as well as value-added annotations, e.g. regarding structure quality and up-to-date cross-reference information from the SIFTS resource. Taken together, these new developments facilitate unified access to macromolecular structure data in an intuitive way for non-expert users and support expert users in analysing macromolecular structure data. PMID- 26476445 TI - Directly lighting up RNA G-quadruplexes from test tubes to living human cells. AB - RNA G-quadruplexes (G4s) are one of the key components of the transcriptome that act as efficient post-transcriptional regulatory elements in living cells. To conduct further studies of the unique biological functions of RNA G4s, techniques need to be developed that can efficiently recognize RNA G4 structures under various conditions, in fixed cells and living cells, as well as in vitro. This paper presents the development of such a method, a new technique using a cyanine dye called CyT, which can detect both canonical and non-canonical RNA G4 structures from test tubes to living human cells. The ability of CyT to distinguish between G4 and nonG4 RNA offers a promising tool for future RNA G4 based biomarker discovery and potential diagnostic applications. PMID- 26476446 TI - Full-length RNA structure prediction of the HIV-1 genome reveals a conserved core domain. AB - A distance constrained secondary structural model of the ~10 kb RNA genome of the HIV-1 has been predicted but higher-order structures, involving long distance interactions, are currently unknown. We present the first global RNA secondary structure model for the HIV-1 genome, which integrates both comparative structure analysis and information from experimental data in a full-length prediction without distance constraints. Besides recovering known structural elements, we predict several novel structural elements that are conserved in HIV-1 evolution. Our results also indicate that the structure of the HIV-1 genome is highly variable in most regions, with a limited number of stable and conserved RNA secondary structures. Most interesting, a set of long distance interactions form a core organizing structure (COS) that organize the genome into three major structural domains. Despite overlapping protein-coding regions the COS is supported by a particular high frequency of compensatory base changes, suggesting functional importance for this element. This new structural element potentially organizes the whole genome into three major domains protruding from a conserved core structure with potential roles in replication and evolution for the virus. PMID- 26476447 TI - FLOR-ID: an interactive database of flowering-time gene networks in Arabidopsis thaliana. AB - Flowering is a hot topic in Plant Biology and important progress has been made in Arabidopsis thaliana toward unraveling the genetic networks involved. The increasing complexity and the explosion of literature however require development of new tools for information management and update. We therefore created an evolutive and interactive database of flowering time genes, named FLOR-ID (Flowering-Interactive Database), which is freely accessible at http://www.flor id.org. The hand-curated database contains information on 306 genes and links to 1595 publications gathering the work of >4500 authors. Gene/protein functions and interactions within the flowering pathways were inferred from the analysis of related publications, included in the database and translated into interactive manually drawn snapshots. PMID- 26476448 TI - Selection of 2'-deoxy-2'-fluoroarabinonucleotide (FANA) aptamers that bind HIV-1 reverse transcriptase with picomolar affinity. AB - Using a Systematic Evolution of Ligands by Exponential Enrichment (SELEX) protocol capable of selecting xeno-nucleic acid (XNA) aptamers, a 2'-deoxy-2' fluoroarabinonucleotide (FANA) aptamer (referred to as FA1) to HIV-1 reverse transcriptase (HIV-1 RT) was selected. FA1 bound HIV-1 RT with KD,app values in the low pM range under different ionic conditions. Comparisons to published HIV-1 RT RNA and DNA aptamers indicated that FA1 bound at least as well as these aptamers. FA1 contained a 20 nucleotide 5' DNA sequence followed by a 57 nucleotide region of FANA nucleotides. Removal of the fourteen 5' DNA nucleotides did not affect binding. FA1's predicted structure was composed of four stems and four loops. All stem nucleotides could be modified to G-C base pairs (14 total changes) with a small effect on binding. Eliminating or altering most loop sequences reduced or abolished tight binding. Overall, results suggested that the structure and the sequence of FA1 were important for binding. FA1 showed strong inhibition of HIV-1 RT in extension assays while no specific binding to avian myeloblastosis or Moloney murine leukemia RTs was detected. A complete DNA version of FA1 showed low binding to HIV-1 RT, emphasizing the unique properties of FANA in HIV-1 RT binding. PMID- 26476449 TI - PhytoPath: an integrative resource for plant pathogen genomics. AB - PhytoPath (www.phytopathdb.org) is a resource for genomic and phenotypic data from plant pathogen species, that integrates phenotypic data for genes from PHI base, an expertly curated catalog of genes with experimentally verified pathogenicity, with the Ensembl tools for data visualization and analysis. The resource is focused on fungi, protists (oomycetes) and bacterial plant pathogens that have genomes that have been sequenced and annotated. Genes with associated PHI-base data can be easily identified across all plant pathogen species using a BioMart-based query tool and visualized in their genomic context on the Ensembl genome browser. The PhytoPath resource contains data for 135 genomic sequences from 87 plant pathogen species, and 1364 genes curated for their role in pathogenicity and as targets for chemical intervention. Support for community annotation of gene models is provided using the WebApollo online gene editor, and we are working with interested communities to improve reference annotation for selected species. PMID- 26476450 TI - PlantPAN 2.0: an update of plant promoter analysis navigator for reconstructing transcriptional regulatory networks in plants. AB - Transcription factors (TFs) are sequence-specific DNA-binding proteins acting as critical regulators of gene expression. The Plant Promoter Analysis Navigator (PlantPAN; http://PlantPAN2.itps.ncku.edu.tw) provides an informative resource for detecting transcription factor binding sites (TFBSs), corresponding TFs, and other important regulatory elements (CpG islands and tandem repeats) in a promoter or a set of plant promoters. Additionally, TFBSs, CpG islands, and tandem repeats in the conserve regions between similar gene promoters are also identified. The current PlantPAN release (version 2.0) contains 16 960 TFs and 1143 TF binding site matrices among 76 plant species. In addition to updating of the annotation information, adding experimentally verified TF matrices, and making improvements in the visualization of transcriptional regulatory networks, several new features and functions are incorporated. These features include: (i) comprehensive curation of TF information (response conditions, target genes, and sequence logos of binding motifs, etc.), (ii) co-expression profiles of TFs and their target genes under various conditions, (iii) protein-protein interactions among TFs and their co-factors, (iv) TF-target networks, and (v) downstream promoter elements. Furthermore, a dynamic transcriptional regulatory network under various conditions is provided in PlantPAN 2.0. The PlantPAN 2.0 is a systematic platform for plant promoter analysis and reconstructing transcriptional regulatory networks. PMID- 26476451 TI - Epigenetic program and transcription factor circuitry of dendritic cell development. AB - Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC. Specific histone marks in CDP reveal a DC-primed epigenetic signature, which is maintained and reinforced during DC differentiation. Epigenetic marks and transcription factor PU.1 occupancy increasingly coincide upon DC differentiation. By integrating PU.1 occupancy and gene expression we devised a transcription factor regulatory circuitry for DC commitment and subset specification. The circuitry provides the transcription factor hierarchy that drives the sequel MPP-CDP-cDC/pDC, including Irf4, Irf8, Tcf4, Spib and Stat factors. The circuitry also includes feedback loops inferred for individual or multiple factors, which stabilize distinct stages of DC development and DC subsets. In summary, here we describe the basic regulatory circuitry of transcription factors that drives DC development. PMID- 26476452 TI - The ubiquitin ligase HERC3 attenuates NF-kappaB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation. AB - Activation of NF-kappaB-dependent transcription represents an important hallmark of inflammation. While the acute inflammatory response is per se beneficial, it can become deleterious if its spatial and temporal profile is not tightly controlled. Classically, NF-kappaB activity is limited by cytoplasmic retention of the NF-kappaB dimer through binding to inhibitory IkappaB proteins. However, increasing evidence suggests that NF-kappaB activity can also be efficiently contained by direct ubiquitination of NF-kappaB subunits. Here, we identify the HECT-domain ubiquitin ligase HERC3 as novel negative regulator of NF-kappaB activity. We find that HERC3 restricts NF-kappaB nuclear import and DNA binding without affecting IkappaBalpha degradation. Instead HERC3 indirectly binds to the NF-kappaB RelA subunit after liberation from IkappaBalpha inhibitor leading to its ubiquitination and protein destabilization. Remarkably, the regulation of RelA activity by HERC3 is independent of its inherent ubiquitin ligase activity. Rather, we show that HERC3 and RelA are part of a multi-protein complex containing the proteasome as well as the ubiquitin-like protein ubiquilin-1 (UBQLN1). We present evidence that HERC3 and UBQLN1 provide a link between NF kappaB RelA and the 26S proteasome, thereby facilitating RelA protein degradation. Our findings establish HERC3 as novel candidate regulating the inflammatory response initiated by NF-kappaB. PMID- 26476453 TI - Inner nuclear envelope protein SUN1 plays a prominent role in mammalian mRNA export. AB - Nuclear export of messenger ribonucleoproteins (mRNPs) through the nuclear pore complex (NPC) can be roughly classified into two forms: bulk and specific export, involving an nuclear RNA export factor 1 (NXF1)-dependent pathway and chromosome region maintenance 1 (CRM1)-dependent pathway, respectively. SUN proteins constitute the inner nuclear envelope component of the l I: nker of N: ucleoskeleton and C: ytoskeleton (LINC) complex. Here, we show that mammalian cells require SUN1 for efficient nuclear mRNP export. The results indicate that both SUN1 and SUN2 interact with heterogeneous nuclear ribonucleoprotein (hnRNP) F/H and hnRNP K/J. SUN1 depletion inhibits the mRNP export, with accumulations of both hnRNPs and poly(A)+RNA in the nucleus. Leptomycin B treatment indicates that SUN1 functions in mammalian mRNA export involving the NXF1-dependent pathway. SUN1 mediates mRNA export through its association with mRNP complexes via a direct interaction with NXF1. Additionally, SUN1 associates with the NPC through a direct interaction with Nup153, a nuclear pore component involved in mRNA export. Taken together, our results reveal that the inner nuclear envelope protein SUN1 has additional functions aside from being a central component of the LINC complex and that it is an integral component of the mammalian mRNA export pathway suggesting a model whereby SUN1 recruits NXF1-containing mRNP onto the nuclear envelope and hands it over to Nup153. PMID- 26476454 TI - KEGG as a reference resource for gene and protein annotation. AB - KEGG (http://www.kegg.jp/ or http://www.genome.jp/kegg/) is an integrated database resource for biological interpretation of genome sequences and other high-throughput data. Molecular functions of genes and proteins are associated with ortholog groups and stored in the KEGG Orthology (KO) database. The KEGG pathway maps, BRITE hierarchies and KEGG modules are developed as networks of KO nodes, representing high-level functions of the cell and the organism. Currently, more than 4000 complete genomes are annotated with KOs in the KEGG GENES database, which can be used as a reference data set for KO assignment and subsequent reconstruction of KEGG pathways and other molecular networks. As an annotation resource, the following improvements have been made. First, each KO record is re-examined and associated with protein sequence data used in experiments of functional characterization. Second, the GENES database now includes viruses, plasmids, and the addendum category for functionally characterized proteins that are not represented in complete genomes. Third, new automatic annotation servers, BlastKOALA and GhostKOALA, are made available utilizing the non-redundant pangenome data set generated from the GENES database. As a resource for translational bioinformatics, various data sets are created for antimicrobial resistance and drug interaction networks. PMID- 26476455 TI - H3K23me2 is a new heterochromatic mark in Caenorhabditis elegans. AB - Genome-wide analyses in Caenorhabditis elegans show that post-translational modifications (PTMs) of histones are evolutionary conserved and distributed along functionally distinct genomic domains. However, a global profile of PTMs and their co-occurrence on the same histone tail has not been described in this organism. We used mass spectrometry based middle-down proteomics to analyze histone H3 N-terminal tails from C. elegans embryos for the presence, the relative abundance and the potential cross-talk of co-existing PTMs. This analysis highlighted that the lysine 23 of histone H3 (H3K23) is extensively modified by methylation and that tri-methylated H3K9 (H3K9me3) is exclusively detected on histone tails with di-methylated H3K23 (H3K23me2). Chromatin immunoprecipitation approaches revealed a positive correlation between H3K23me2 and repressive marks. By immunofluorescence analyses, H3K23me2 appears differentially regulated in germ and somatic cells, in part by the action of the histone demethylase JMJD-1.2. H3K23me2 is enriched in heterochromatic regions, localizing in H3K9me3 and heterochromatin protein like-1 (HPL-1)-positive foci. Biochemical analyses indicated that HPL-1 binds to H3K23me2 and interacts with a conserved CoREST repressive complex. Thus, our study suggests that H3K23me2 defines repressive domains and contributes to organizing the genome in distinct heterochromatic regions during embryogenesis. PMID- 26476456 TI - BiGG Models: A platform for integrating, standardizing and sharing genome-scale models. AB - Genome-scale metabolic models are mathematically-structured knowledge bases that can be used to predict metabolic pathway usage and growth phenotypes. Furthermore, they can generate and test hypotheses when integrated with experimental data. To maximize the value of these models, centralized repositories of high-quality models must be established, models must adhere to established standards and model components must be linked to relevant databases. Tools for model visualization further enhance their utility. To meet these needs, we present BiGG Models (http://bigg.ucsd.edu), a completely redesigned Biochemical, Genetic and Genomic knowledge base. BiGG Models contains more than 75 high-quality, manually-curated genome-scale metabolic models. On the website, users can browse, search and visualize models. BiGG Models connects genome-scale models to genome annotations and external databases. Reaction and metabolite identifiers have been standardized across models to conform to community standards and enable rapid comparison across models. Furthermore, BiGG Models provides a comprehensive application programming interface for accessing BiGG Models with modeling and analysis tools. As a resource for highly curated, standardized and accessible models of metabolism, BiGG Models will facilitate diverse systems biology studies and support knowledge-based analysis of diverse experimental data. PMID- 26476457 TI - Universal digital high-resolution melt: a novel approach to broad-based profiling of heterogeneous biological samples. PMID- 26476458 TI - GlyTouCan 1.0--The international glycan structure repository. AB - Glycans are known as the third major class of biopolymers, next to DNA and proteins. They cover the surfaces of many cells, serving as the 'face' of cells, whereby other biomolecules and viruses interact. The structure of glycans, however, differs greatly from DNA and proteins in that they are branched, as opposed to linear sequences of amino acids or nucleotides. Therefore, the storage of glycan information in databases, let alone their curation, has been a difficult problem. This has caused many duplicated efforts when integration is attempted between different databases, making an international repository for glycan structures, where unique accession numbers are assigned to every identified glycan structure, necessary. As such, an international team of developers and glycobiologists have collaborated to develop this repository, called GlyTouCan and is available at http://glytoucan.org/, to provide a centralized resource for depositing glycan structures, compositions and topologies, and to retrieve accession numbers for each of these registered entries. This will thus enable researchers to reference glycan structures simply by accession number, as opposed to by chemical structure, which has been a burden to integrate glycomics databases in the past. PMID- 26476460 TI - Mealtime interruptions, assistance and nutritional intake in subacute care. AB - Protected mealtimes is an initiative to support increased nutritional intake for all hospitalised patients, particularly those who are malnourished. The increased focus on maximising independence of patients in the subacute setting may provide a supportive environment for implementing these strategies. The aim of the present study was to gain insight into subacute ward practices at mealtimes under usual conditions (i.e. at baseline) where no protected mealtimes policy was implemented. Participants were patients aged >=65 years recruited from subacute care facilities at a large healthcare network in Victoria, Australia. Participants were observed at mealtimes and mid meals (i.e. morning tea, afternoon tea and supper) to determine daily energy and protein intake, provision of mealtime assistance and mealtime interruptions. Almost all participants received assistance when it was needed, with positive and negative interruptions experienced by 56.2% and 76.2% of participants, respectively. There was an energy deficit of approximately 2 MJ per day between average intake and estimated requirements. In conclusion, mealtime practices were suboptimal, with particularly high rates of negative interruptions. Protected mealtimes is one strategy that may improve the mealtime environment to support patients' dietary intake. Prospective studies are needed to evaluate its implementation and effects. PMID- 26476459 TI - Zonisamide Reduces Withdrawal Symptoms But Does Not Enhance Varenicline-Induced Smoking Cessation. AB - INTRODUCTION: Varenicline (Chantix) is a first-line treatment for smoking cessation but does not produce cessation in many individuals. It may be possible to improve abstinence by co-administering varenicline with other medications. Zonisamide (Zonegran) has a similar pharmacologic profile to topiramate, which has been shown to reduce smoking, but is better tolerated. This study evaluated whether combined zonisamide and varenicline reduced tobacco withdrawal and increased abstinence among smokers trying to quit, relative to varenicline and placebo. METHODS: This was a double-blind, randomized, placebo-controlled pilot trial of zonisamide + varenicline versus placebo + varenicline for smoking cessation. Smokers received brief counseling and study medications, and completed weekly assessments for 10 consecutive weeks. The primary outcome was continuous abstinence rates (biochemically verified) during the final 4 weeks of treatment. RESULTS: Results are presented as intent-to-treat and completer analyses. Seventy four individuals were enrolled; 45 completed the study. Overall, 14.9% (intent-to treat) and 25.0% (completer) of participants maintained sustained abstinence during the final 4 weeks of treatment. There were no differences between groups for biochemically-verified smoking, but zonisamide + varenicline reduced self reported smoking, nicotine withdrawal, and craving compared to placebo + varenicline. CONCLUSIONS: Zonisamide decreased nicotine withdrawal and craving, though not of sufficient magnitude to modify smoking behavior. The sample size was small and low rates of abstinence across groups suggest the study population was difficult to treat. Additional evaluation of zonisamide or other medications that increase GABA or decrease glutamate in larger or more diverse populations may yield positive clinical benefit for nicotine/tobacco cessation. IMPLICATIONS: This study provides support for layering novel medications with varenicline for smoking cessation, for investigating medications that target the GABA and glutamate system, and for assessing the contribution that reductions in nicotine withdrawal have on ultimate cessation outcomes. PMID- 26476461 TI - Restless leg syndrome in patients with spinal cord injury. AB - BACKGROUND: The presence of restless leg syndrome (RLS) in patients with spinal cord injury (SCI) is not well established. We studied the frequency and severity of RLS in a population of patients with SCI and the effect of treatment with dopaminergic drugs when clinically indicated. METHODS: Consecutive patients with SCI admitted to an out-patient clinic of a neurorehabilitation hospital (n:195) were evaluated for the presence of RLS between February 2013 and May 2014. A diagnosis of RLS was made according to the criteria of the International RLS Study Group, and severity was assessed by the RLS rating scale. Information on gender, age, time since SCI, level and severity of SCI, was obtained. RESULT: The mean age was 54.7 +/- 15.6 years (range: 22-81 year); with time since SCI: 16.9 +/- 11.4 years (range: 1-50 years). Thirty-five of 195 patients (17.9%) presented RLS. Twenty-two out of 154 (14.3%) patients with cervicothoracic SCI and 13 out of 41 (31.7%) patients with lumbosacral SCI presented RLS. Restless leg symptoms were mild in 2 patients, moderate in 10 patients, severe in 12 patients and very severe in 11. Ten patients received dopaminergic agonist treatment with a significant reduction in RLS severity scale from 29.1 +/- 5.9 to 10.2 +/- 7.9. DISCUSSION: RLS occurs frequently in SCI patients and responds to dopaminergic treatment. Physicians have to be aware of this diagnosis to avoid unnecessary suffering in this patient population. PMID- 26476462 TI - On the relationship between side of onset and cognition in Parkinson disease: Response from the authors. PMID- 26476463 TI - Measuring online interpretations and attributions of social situations: Links with adolescent social anxiety. AB - OBJECTIVE: We evaluated the utility of a novel, picture-based tool to measure how adolescents interpret and attribute cause to social exchanges and whether biases in these processes relate to social anxiety. Briefly presented ambiguous visual social scenes, each containing a photograph of the adolescent as the protagonist, were followed by three possible interpretations (positive, negative, neutral/unrelated) and two possible causal attributions (internal, external) to which participants responded. METHOD: Ninety-five adolescents aged 14 to 17 recruited from mainstream schools, with varying levels of social anxiety rated the likelihood of positive, negative and unrelated interpretations before selecting the single interpretation they deemed as most likely. This was followed by a question prompting them to decide between an internal or external causal attribution for the interpreted event. RESULTS: Across scenarios, adolescents with higher levels of social anxiety rated negative interpretations as more likely and positive interpretations as less likely compared to lower socially anxious adolescents. Higher socially anxious adolescents were also more likely to select internal attributions to negative and less likely to select internal attributions for positive events than adolescents with lower levels of social anxiety. CONCLUSIONS: Adolescents with higher social anxiety display cognitive biases in interpretation and attribution. This tool is suitable for measuring cognitive biases of complex visual-social cues in youth populations with social anxiety and simulates the demands of daily social experiences more closely. LIMITATIONS: As we did not measure depressive symptoms, we cannot be sure that biases linked to social anxiety are not due to concurrent low mood. PMID- 26476464 TI - Evaluation of focused ultrasound algorithms: Issues for reducing pre-focal heating and treatment time. AB - BACKGROUND: Due to the heating in the pre-focal field the delay between successive movements in high intensity focused ultrasound (HIFU) are sometimes as long as 60s, resulting to treatment time in the order of 2-3h. Because there is generally a requirement to reduce treatment time, we were motivated to explore alternative transducer motion algorithms in order to reduce pre-focal heating and treatment time. MATERIALS AND METHODS: A 1 MHz single element transducer with 4 cm diameter and 10 cm focal length was used. A simulation model was developed that estimates the temperature, thermal dose and lesion development in the pre focal field. The simulated temperature history that was combined with the motion algorithms produced thermal maps in the pre-focal region. Polyacrylimde gel phantom was used to evaluate the induced pre-focal heating for each motion algorithm used, and also was used to assess the accuracy of the simulation model. RESULTS: Three out of the six algorithms having successive steps close to each other, exhibited severe heating in the pre-focal field. Minimal heating was produced with the algorithms having successive steps apart from each other (square, square spiral and random). The last three algorithms were improved further (with small cost in time), thus eliminating completely the pre-focal heating and reducing substantially the treatment time as compared to traditional algorithms. CONCLUSIONS: Out of the six algorithms, 3 were successful in eliminating the pre-focal heating completely. Because these 3 algorithms required no delay between successive movements (except in the last part of the motion), the treatment time was reduced by 93%. Therefore, it will be possible in the future, to achieve treatment time of focused ultrasound therapies shorter than 30 min. The rate of ablated volume achieved with one of the proposed algorithms was 71 cm(3)/h. The intention of this pilot study was to demonstrate that the navigation algorithms play the most important role in reducing pre-focal heating. By evaluating in the future, all commercially available geometries, it will be possible to reduce the treatment time, for thermal ablation protocols intended for oncological targets. PMID- 26476465 TI - Numerical comparison of acoustic wedge models, with application to ultrasonic telemetry. AB - Ultrasonic telemetry imaging systems are used to monitor such immersed structures as main vessels of nuclear reactors. The interaction between acoustic beams and targets involves scattering phenomena, mainly specular reflection and tip diffraction. In order to assist in the design of imaging systems, a simulation tool is required for the accurate modeling of such phenomena. Relevant high frequency scattering models have been developed in electromagnetic applications, in particular, the geometrical optics (GO), Geometrical Theory of Diffraction (GTD) and its uniform corrections (UAT and UTD), Kirchhoff approximation (KA) and Physical Theory of Diffraction (PTD). Before adopting any of them for simulation of scattering of acoustic waves by edged immersed rigid bodies, it is important to realize that in acoustics the characteristic dimension to the wave length ratio is usually considerably smaller than in electromagnetics and a further study is required to identify models' advantages, disadvantages and regions of applicability. In this paper their numerical comparison is carried out. As the result, the most suitable algorithm is identified for simulating ultrasonic telemetry of immersed rigid structures. PMID- 26476466 TI - Impact of a primary care based intervention on breast cancer knowledge, risk perception and concern: A randomized, controlled trial. AB - PURPOSE: To estimate the effects of a tablet-based, breast cancer risk education intervention for use in primary care settings (BreastCARE) on patients' breast cancer knowledge, risk perception and concern. METHODS: From June 2011-August 2012, we enrolled women from two clinics, aged 40-74 years with no personal breast cancer history, and randomized them to the BreastCARE intervention group or to the control group. All patients completed a baseline telephone survey and risk assessment (via telephone for controls, via tablet computer in clinic waiting room prior to visit for intervention). All women were categorized as high or average risk based on the Referral Screening Tool, the Gail model or the Breast Cancer Surveillance Consortium model. Intervention patients and their physicians received an individualized risk report to discuss during the visit. All women completed a follow-up telephone survey 1-2 weeks after risk assessment. Post-test comparisons estimated differences at follow-up in breast cancer knowledge, risk perception and concern. RESULTS: 580 intervention and 655 control women completed follow-up interviews. Mean age was 56 years (SD = 9). At follow up, 73% of controls and 71% of intervention women correctly perceived their breast cancer risk and 22% of controls and 24% of intervention women were very concerned about breast cancer. Intervention patients had greater knowledge (>=75% correct answers) of breast cancer risk factors at follow-up (24% vs. 16%; p = 0.002). In multivariable analysis, there were no differences in correct risk perception or concern, but intervention patients had greater knowledge ([OR] = 1.62; 95% [CI] = 1.19-2.23). CONCLUSIONS: A simple, practical intervention involving physicians at the point of care can improve knowledge of breast cancer without increasing concern. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01830933. PMID- 26476468 TI - Endovascular Treatment of Femoropopliteal Lesions: So Many Options, Little Consensus. PMID- 26476467 TI - Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions: 24-Month Results of IN.PACT SFA. AB - BACKGROUND: Evidence from large, randomized, controlled peripheral artery disease trials reporting long-term outcomes using drug-coated balloons (DCBs) is limited. Previously, the DCB showed favorable 1-year outcomes compared with conventional percutaneous transluminal angioplasty (PTA), yet durability of the treatment effect with DCBs remains unknown. OBJECTIVES: This study sought to investigate the longer-term outcomes of a paclitaxel-eluting DCB compared to PTA for femoropopliteal lesions. METHODS: We enrolled 331 patients with symptomatic (Rutherford 2 to 4) femoropopliteal lesions up to 18 cm in length. Patients were randomly assigned in a 2:1 ratio to treatment with DCB or PTA. The 24-month assessments included primary patency, freedom from clinically driven target lesion revascularization (CD-TLR), major adverse events, and quality of life and functional outcomes as assessed by the EuroQOL-5D quality-of-life questionnaire, walking impairment questionnaire, and 6-min walk test. RESULTS: At 24 months, patients treated with DCB showed significantly higher primary patency when compared with PTA (78.9% vs. 50.1%; p < 0.001). The rates of CD-TLR were 9.1% and 28.3% (p < 0.001) for the DCB and PTA groups, respectively. The overall mortality rate in the DCB group was 8.1% versus 0.9% in the PTA group (p = 0.008). There were no device- or procedure-related deaths and no major amputations in either group through 24-month follow-up. The rate of vessel thrombosis was low (1.5% DCB vs. 3.8% PTA; p = 0.243), with no new events reported between 1 and 2 years. Both groups showed similar functional improvement at 2 years, although DCB patients achieved this level of function with 58% fewer reinterventions. CONCLUSIONS: The 24-month outcomes from the trial demonstrate a durable and superior treatment effect of DCB versus PTA with significantly higher primary patency, lower CD-TLR, and similar functional status improvement with fewer repeat interventions. (Randomized Trial of IN.PACT Admiral Drug Eluting Balloon vs Standard PTA for the Treatment of SFA and Proximal Popliteal Arterial Disease [INPACT SFA I]; NCT01175850; and IN.PACT Admiral Drug-Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Superficial Femoral Artery [SFA] and Proximal Popliteal Artery [PPA] [INPACT SFA II]; NCT01566461). PMID- 26476470 TI - In Reply. PMID- 26476469 TI - Effect of Posterior Tibial Slope on Flexion and Anterior-Posterior Tibial Translation in Posterior Cruciate-Retaining Total Knee Arthroplasty. AB - Reduced posterior tibial slope (PTS) and posterior tibiofemoral translation (PTFT) in posterior cruciate-retaining (PCR) total knee arthroplasty (TKA) may result in suboptimal flexion. We evaluated the relationship between PTS, PTFT, and total knee flexion after PCR TKA in a cadaveric model. We performed a balanced PCR TKA using 9 transfemoral cadaver specimens and changed postoperative PTS in 1 degrees increments. We measured maximal flexion and relative PTFT at maximal flexion. We determined significant changes in flexion and PTFT as a function of PTS. Findings showed an average increase in flexion of 2.3 degrees and average PTFT increase of 1mm per degree of PTS increase when increasing PTS from 1 degrees to 4 degrees (P<.05). Small initial increases in PTS appear to significantly increase knee flexion and PTFT. PMID- 26476471 TI - Shorter Hospital Stay and Lower 30-Day Readmission After Unicondylar Knee Arthroplasty Compared to Total Knee Arthroplasty. AB - BACKGROUND: Reducing hospital stay and unplanned hospital readmission of arthroplasty patients has been a topic of recent interest. The aim of the present study was to query the National Surgical Quality Improvement Program database to compare the length of hospital stay (LOS) and the subsequent 30-day hospital readmission rates in patients undergoing primary unicondylar knee arthroplasty (UKA) and total knee arthroplasty (TKA). METHODS: We identified 1340 UKAs and 36,274 TKAs over a 2-year period (2011-2012). Patient demographics, comorbidities, LOS, 30-day postoperative complications, and readmission rates were compared between the groups. Multivariate regression analysis was used to determine the effect of procedure type on LOS and readmission rates. RESULTS: Unicondylar knee arthroplasty patients had a median LOS of 2 days compared to 3 days for TKAs (P < .001). The readmission rate in the TKA group was nearly double that of the UKA group (4.1% vs 2.2%) (P < .0001). Multivariate regression analysis identified that undergoing a UKA was predictive for a shorter LOS (coefficient -1 day) and was protective for 30-day readmission (odds ratio, 0.60; 95% confidence interval, 0.41-0.88). CONCLUSION: Patients undergoing UKA had a shorter LOS and a lower 30-day readmission rate compared to TKA patients. After adjusting for selected cofounders, we demonstrated that undergoing a UKA is a protective factor for 30-day readmission. PMID- 26476472 TI - Meralgia paresthetica with lumbar neurinoma: Case report. PMID- 26476473 TI - Epidemiology of urinary tract infections in type 2 diabetes mellitus patients: An analysis based on a large sample of 456,586 German T2DM patients. AB - INTRODUCTION: This analysis was conducted to investigate urinary tract infection (UTI) incidence among Type 2 Diabetes mellitus (T2DM) patients in Germany in a real-world setting and to identify risk factors associated with UTI incidence/recurrence. METHODS: Our cohort study was conducted based on an anonymized dataset from a regional German sickness fund (2010-2012). A UTI event was mainly identified through observed outpatient/inpatient UTI diagnoses. We reported the number of UTI events per 1000 patient-years. Furthermore, the proportion of patients affected by >=1 and >=2 UTI events in the observational period was separately reported. Finally, three multivariate Cox regression analyses were conducted to identify factors that may be associated with UTI event risk or recurrent UTI event risk. RESULTS: A total of 456,586 T2DM-prevalent patients were identified (mean age 72.8years, 56.1% female, mean Charlson Comorbidity Index (CCI) of 7.3). Overall, the UTI event rate was 87.3 events per 1000 patient-years (111.8/55.8 per 1000 patient-years for women/men (p<0.001)). The highest UTI event rates were observed for those aged >89years. After 730days after first observed T2DM diagnosis, the proportion of women/men still UTI-event free was 80.9%/90.2% (p<0.001). Most important factors associated with UTI risk in our three models were older age (Hazard Ratio (HR)=1.56-1.70 for >79years), female gender (HR=1.38-1.57), UTIs in the previous two years (HR=2.77-5.94), number of comorbidities as measured by the CCI (HR=1.32-1.52 for CCI>6) and at least one cystoscopy in the previous year (HR=2.06-5.48). Furthermore, high HbA1c values in the previous year (HR=1.29-1.4 referring to HbA1c>9.5%) and a poor kidney function (HR=1.11-1.211 referring to glomerular filtration rate (GFR)<60ml/min) increased the UTI event risk. DISCUSSION: Our study confirms that UTI event risk is high in T2DM patients. Older female patients having experienced previous UTIs face an above-average UTI risk, especially if these risk factors are associated with poor glycemic control and poor kidney function. PMID- 26476475 TI - Lycopene protects against atrazine-induced hepatic ionic homeostasis disturbance by modulating ion-transporting ATPases. AB - The aim of this study was to evaluate the possible chemoprotective role of lycopene (LYC) against atrazine (ATR)-induced ionic disorder and hepatotoxicity in mice. Male kunming mice were treated with LYC (5mg/kg) and/or ATR (50mg/kg or 200mg/kg) by lavage administration for 21days. Ionic disorder was assessed by determining the Na(+), K(+) and Ca(2+) content and the alteration in ATP enzymes (ATPases) including Na(+)-K(+)-ATPase, Ca(2+)-ATPase, Mg(2+)-ATPase and Ca(2+) Mg(2+)-ATPase and the mRNA levels of ATPase's subunits in liver. ATR caused the increases of alanine aminotransferase and aspartate aminotransferase activities and histological changes. LYC pretreatment significantly protected liver against ATR-caused alternation. The significant effect of ATR and LYC on the K(+) and Mg(2+) content in liver was not observed, but ATR increased hepatic Na(+)-K(+) ATPase activity and decreased Mg(2+)-ATPase and Ca(2+)-Mg(2+)-ATPase activity. The mRNA expressions of Na(+)-K(+)-ATPase subunits were regulated significantly by ATR. A significant increase of Ca(2+) content and seven down-regulated mRNA expressions of Ca(2+)-ATPase subunits and a decrease of Ca(2+)-ATPase activity were observed in the ATR-treated mice. Notably, LYC modulated these ATR-induced alterations of ATPase activity and mRNA expression of their subunits. These results suggest that ATR presents hepatotoxicity via regulating hepatic ATPase's activities and their subunit transcriptions and inducing ionic disorder. LYC protects liver against ATR-induced hepatotoxicity, significantly. LYC modulated hepatic ionic homeostasis disturbance via regulation of ATPase activities and their subunits' (1a1, 1b3, 1b4 and 2b4) transcriptions. In summary, these effects play a critical role of LYC-mediated chemoprevention against ATR-induced hepatotoxicity. PMID- 26476474 TI - Associations between anxiety and depression symptoms and cognitive testing and neuroimaging in type 2 diabetes. AB - AIMS: Anxiety, depression, accelerated cognitive decline, and increased risk of dementia are observed in individuals with type 2 diabetes. Anxiety and depression may contribute to lower performance on cognitive tests and differences in neuroimaging observed in individuals with type 2 diabetes. METHODS: These relationships were assessed in 655 European Americans with type 2 diabetes from 504 Diabetes Heart Study families. Participants completed cognitive testing, brain magnetic resonance imaging, the Brief Symptom Inventory Anxiety subscale, and the Center for Epidemiologic Studies Depression-10. RESULTS: In analyses adjusted for age, sex, educational attainment, and use of psychotropic medications, individuals with comorbid anxiety and depression symptoms had lower performance on all cognitive testing measures assessed (p<=0.005). Those with both anxiety and depression also had increased white matter lesion volume (p=0.015), decreased gray matter cerebral blood flow (p=4.43*10(-6)), decreased gray matter volume (p=0.002), increased white and gray matter mean diffusivity (p<=0.001), and decreased white matter fractional anisotropy (p=7.79*10(-4)). These associations were somewhat attenuated upon further adjustment for health status related covariates. CONCLUSIONS: Comorbid anxiety and depression symptoms were associated with cognitive performance and brain structure in a European American cohort with type 2 diabetes. PMID- 26476476 TI - Gastric cancer incidence in the Romagna Region of Italy: A spatial and temporal analysis. AB - BACKGROUND: The worldwide decrease in gastric cancer incidence is due to a birth cohort-dependent decrease in exposure to major risk factors. METHODS: In an area of northern Italy with a historically strong internal geographical gradient in gastric cancer incidence, variations in rates by municipality and age group between 1987 and 2008 were evaluated. The study period was divided into three nonadjacent periods. End points included: age- and sex-standardised incidence rates; incidence rate ratio between age- and sex-standardised incidence rates; smoothed relative risks of gastric cancer incidence, and posterior probabilities of the relative risk being >1. RESULTS: In 1987-1990, the estimate of posterior probabilities of relative risk being >1 showed a higher incidence in hilly/mountainous areas. Between 1987-1990 and 2005-2008, a uniform decrease of more than 50% was observed (incidence rate ratio: plain, 0.45 (95% confidence interval 0.40-0.51); hill, 0.44 (0.34-0.58); mountain, 0.48 (0.22-1.02)). The decrease in the mountainous area was weak in the middle time period, with an incidence rate ratio of 0.92 (0.46-1.84), and intensified afterwards. The decrease occurred earlier and was more pronounced among younger people. In 2005 2008, gastric cancer risk was uniform across ages and municipalities. CONCLUSIONS: The observed changes in gastric cancer incidence is the epilogue of a birth-cohort-dependent decrease in exposure to major risk factors. PMID- 26476477 TI - A novel method for estimating the track-soil parameters based on Kalman and improved strong tracking filters. AB - A tracked vehicle has been widely used in exploring unknown environments and military fields. In current methods for suiting soil conditions, soil parameters need to be given and the traction performance cannot always be satisfied on soft soil. To solve the problem, it is essential to estimate track-soil parameters in real-time. Therefore, a detailed mathematical model is proposed for the first time. Furthermore, a novel algorithm which is composed of Kalman filter (KF) and improved strong tracking filter (STF) is developed for online track-soil estimation and named as KF-ISTF. By this method, the KF is used to estimate slip parameters, and the ISTF is used to estimate motion states. Then the key soil parameters can be estimated by using a suitable soil model. The experimental results show that equipped with the estimation algorithm, the proposed model can be used to estimate the track-soil parameters, and make the traction performance satisfied with soil conditions. PMID- 26476478 TI - Caregiver's functional status during a young child's asthma exacerbation: A validated instrument. AB - BACKGROUND: Few instruments exist to measure caregivers' functional status during a young child's asthma exacerbation. OBJECTIVE: We sought to develop and validate a measure of caregivers' functional status during a preschooler's asthma exacerbation. METHODS: The psychometric properties of the 21-item questionnaire Effects of a Young Child's Asthma Flare-up on the Parents (ECAP) were tested in a randomized placebo-controlled trial of pre-emptive high-dose fluticasone in preschoolers with virus-induced asthma. Caregivers completed the ECAP questionnaire on the last day their child exhibited symptoms of an upper respiratory tract infection or asthma exacerbation (episode). The mean of each item, scored on a scale of 1 (best) to 7 (worst), provided the ECAP score. RESULTS: Ninety-three preschoolers (2.5 +/- 1.0 years old; 62.4% male) experienced 878 episodes. Feasibility (80% questionnaire return rate; 90% completion) and internal consistency (Cronbach alpha = 0.97) were high. Of 628 episodes with a completed ECAP questionnaire, 621 (98.9%) had data on exacerbations, and 609 (97.0%) had data on health care use. The ECAP score was significantly higher for children experiencing an asthma exacerbation versus those who were not (mean difference, 0.8; 95% CI, 0.6-1.0) and for episodes resulting versus not resulting in an emergency visit (mean difference, 1.2; 95% CI, 1.0-1.4), systemic corticosteroid use (mean difference, 1.4; 95% CI, 1.1 1.7), or hospitalization (mean difference, 1.9; 95% CI, 1.4-2.5). The ECAP score was significantly lower in children treated with fluticasone versus those treated with placebo (mean difference, -0.7; 95% CI, -1.1 to -0.3). CONCLUSIONS: The 21 item ECAP questionnaire, showing high feasibility, internal consistency, discriminative validity, and responsiveness, has the psychometric properties to serve as a validated outcome to measure the burden of preschoolers' asthma exacerbations on their caregivers' functional status. PMID- 26476479 TI - Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. AB - Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma. PMID- 26476481 TI - An Internet-Based Intervention (Mamma Mia) for Postpartum Depression: Mapping the Development from Theory to Practice. AB - BACKGROUND: As much as 10-15% of new mothers experience depression postpartum. An Internet-based intervention (Mamma Mia) was developed with the primary aims of preventing depressive symptoms and enhancing subjective well-being among pregnant and postpartum women. A secondary aim of Mamma Mia was to ease the transition of becoming a mother by providing knowledge, techniques, and support during pregnancy and after birth. OBJECTIVE: The aim of the paper is to provide a systematic and comprehensive description of the intervention rationale and the development of Mamma Mia. METHODS: For this purpose, we used the intervention mapping (IM) protocol as descriptive tool, which consists of the following 6 steps: (1) a needs assessment, (2) definition of change objectives, (3) selection of theoretical methods and practical strategies, (4) development of program components, (5) planning adoption and implementation, and (6) planning evaluation. RESULTS: Mamma Mia is a fully automated Internet intervention available for computers, tablets, and smartphones, intended for individual use by the mother. It starts in gestational week 18-24 and lasts up to when the baby becomes 6 months old. This intervention applies a tunneled design to guide the woman through the program in a step-by-step fashion in accordance with the psychological preparations of becoming a mother. The intervention is delivered by email and interactive websites, combining text, pictures, prerecorded audio files, and user input. It targets risk and protective factors for postpartum depression such as prepartum and postpartum attachment, couple satisfaction, social support, and subjective well-being, as identified in the needs assessment. The plan is to implement Mamma Mia directly to users and as part of ordinary services at well-baby clinics, and to evaluate the effectiveness of Mamma Mia in a randomized controlled trial and assess users' experiences with the program. CONCLUSIONS: The IM of Mamma Mia has made clear the rationale for the intervention, and linked theories and empirical evidence to the contents and materials of the program. This meets the recent calls for intervention descriptions and may inform future studies, development of interventions, and systematic reviews. PMID- 26476482 TI - [Assessment of exercise capacity in congenital heart disease]. AB - For many years, the treatment of congenital heart diseases has been a field in which, based on the seriousness of these conditions, treatment options were viewed with the greatest deference. This has conditioned, in many cases, the interventions to be undertaken in each. In this sense, exercise was thought to have a negative impact and thus the practise of almost any physical activity was limited. Although there has recently been a change in the paradigm with respect to exercise, this idea continues to hold sway. For many cardiopathies, the information obtained through a stress test is essential in order to implement and supervise an exercise program. The aim of this study is to analyze the parameters within the stress test which allow for an adequate stratification of the risk to subjects with congenital heart diseases who undertake exercise, as well as their values in accordance with the type of pathology, the gravity of such, and the age of the patients. Furthermore, these parameters will be analyzed for both their survival markers and the protocols that can best be adjusted for patients with these characteristic. PMID- 26476480 TI - Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association. AB - BACKGROUND: Coronin-1A (CORO1A) is a regulator of actin dynamics important for T cell homeostasis. CORO1A deficiency causes T(-)B(+) natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections. However, because all known human mutations in CORO1A abrogate protein expression, the role of the protein's functional domains in host immunity is unknown. OBJECTIVE: We sought to identify the cause of the primary immunodeficiency in 2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia. METHODS: We performed immunologic, genetic, and biochemical studies in the patients, family members, and healthy control subjects. RESULTS: Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens. IgG, IgM, IgA, and specific antibody responses were normal. Whole-genome sequencing identified a homozygous frameshift mutation in CORO1A disrupting the last 2 C-terminal domains by replacing 61 amino acids with a novel 91-amino-acid sequence. The CORO1A(S401fs) mutant was expressed in the patients' lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes but did not oligomerize and had impaired cytoskeletal association. CORO1A(S401fs) was associated with increased filamentous actin accumulation in T cells, severely defective thymic output, and impaired T-cell survival but normal calcium flux and cytotoxicity, demonstrating the importance of CORO1A oligomerization and subcellular localization in T-cell homeostasis. CONCLUSIONS: We describe a truncating mutation in CORO1A that permits protein expression and survival into young adulthood. Our studies demonstrate the importance of intact CORO1A C terminal domains in thymic egress and T-cell survival, as well as in defense against viral pathogens. PMID- 26476483 TI - [Primary angioplasty in diabetic and non-diabetic patients with acute myocardial infarction: Predictors of mortality]. AB - BACKGROUND AND AIMS: Diabetes mellitus is one of the major risk factors for coronary artery disease. The aim of this study was to evaluate in-hospital mortality and during follow-up of diabetic patients with acute myocardial infarction treated with primary angioplasty and to determine its predictors. MATERIALS AND METHODS: Eight hundred and sixty six patients were retrospectively enrolled from January 1993 to December 2013. A hundred patients with a diagnosis of diabetes were evaluated. The median follow-up was 121 months in 90% of the population. RESULTS: Of the 100 diabetic patients included (11.56%) 86% were male and 50% older than 70 years. Overall, 76% presented with a Killip-Kimball grade of 1 at admission and 16% presented with a Killip-Kimball 4. The most frequent location of myocardial infarction was anterior and 65% had 2 or more coronary vessel disease. In-hospital mortality was 15%. The only independent variable significantly associated was the Killip-Kimball at admission. Mortality during follow up was 35% and its independent predictors were: age, Killip-Kimball at admission and use of angiotensin-converting enzyme inhibitors Interestingly, in the non-diabetic group, Killip-kimball at admission failed to predict long-term mortality CONCLUSION: This group of diabetic patients was older, and with a higher prevalence of 2 or more vessel disease. Cardiogenic shock on admission was the only independent predictor of in-hospital death and along with age and angiotensin-converting enzyme inhibitor use, an independent predictor of mortality during long term follow-up. PMID- 26476484 TI - Measuring happiness in individuals with profound multiple disabilities. AB - This quantitative study assessed whether presentation of preferred items and activities during multiple periods of the day (and over multiple days) increased indices of happiness (over time/sustained) in individuals with PMD. A multiple baseline design across participants was utilized to measure changes in indices of happiness of the participants. Participants were recruited from an adult day activity program specializing in providing assistance to individuals with disabilities. For Mary, baseline indices of happiness were 26.67% of intervals, increasing 6.76% during intervention to 33.43%. For Caleb, baseline indices of happiness were 20.84% of intervals, increasing 6.34% during intervention to 27.18%. For Mark, baseline indices of happiness were 40.00% of intervals, increasing 12.75% during intervention to 52.75%. Overall interobserver agreement was 82.8%, with interobserver agreement observations occurring during 63.04% of the observations. The results of the investigation demonstrated that presenting preferred items and activities increased the indices of happiness compared to baseline rates of indices of happiness. Results may have been more robust if the participants were assessed for overall responsiveness patterns prior to the initiation of measurement of indices of happiness. PMID- 26476485 TI - Systematic review of sensory integration therapy for individuals with disabilities: Single case design studies. AB - Sensory integration therapy (SIT) is a controversial intervention that is widely used for people with disabilities. Systematic analysis was conducted on the outcomes of 17 single case design studies on sensory integration therapy for people with, or at-risk of, a developmental or learning disability, disorder or delay. An assessment of the quality of methodology of the studies found most used weak designs and poor methodology, with a tendency for higher quality studies to produce negative results. Based on limited comparative evidence, functional analysis-based interventions for challenging behavior were more effective that SIT. Overall the studies do not provide convincing evidence for the efficacy of sensory integration therapy. Given the findings of the present review and other recent analyses it is advised that the use of SIT be limited to experimental contexts. Issues with the studies and possible improvements for future research are discussed including the need to employ designs that allow for adequate demonstration of experimental control. PMID- 26476486 TI - Metabolic effects of supplementation with vitamin D in type 2 diabetic patients with vitamin D deficiency. AB - AIM: Epidemiological studies suggest that vitamin D status influences type 2 diabetes mellitus. We investigate the metabolic effects of vitamin D. MATERIAL AND METHODS: We studied consecutive type 2 diabetic patients without insulin therapy with vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) lower than 20ng/ml). They were treated with 16,000IU of calcifediol orally once a week for a minimum of 8 weeks. RESULTS: Twenty eight patients were treated for a mean time of 84.1 days (range 56 to 120 days). All patients achieved serum levels of 25(OH)D higher than 20ng/ml. There was a significant reduction in fasting glucose (145.6+/-35.5 vs. 131.7+/-30.4mg/dl, p<0.001). There were small non-significant reductions in HbA1c, fasting insulin and Homeostasis Model Assesment (HOMA) insulin resistance (IR). There were small non-significant increases in HOMA insulin sensitivity (S) and HOMA-beta cell function (B) and a small significant increase in Quantitative Insulin Sensitivity Check Index (QUICKI). CONCLUSIONS: Correction of vitamin D deficiency in type 2 diabetic patients decreases fasting glucose. Our results do not rule out improvements in metabolic control, insulin resistance and function of the beta cell. PMID- 26476487 TI - The relationship of the apolipoprotein E gene polymorphism in Turkish Type 2 Diabetic Patients with and without diabetic foot ulcers. AB - AIMS: The aim of this study was to investigate the association between Apolipoprotein E (ApoE) gene polymorphism in the development of diabetic foot ulcers in Type 2 diabetes Turkish patients. MATERIALS AND METHODS: The ApoE genotypes were determined retrospectively in 50 patients with diabetic foot and 50 without diabetic foot and a control group of 50 healthy individuals. RESULTS: The genotype ApoE distribution did differ between the control group (E2E3 44%, E3E3 38%, E3E4 18%) and Type 2 Diabetic Patients (E2E3 6%, E3E3 81%, E3E4 16%) (p<0.001). The genotype ApoE distribution did not differ between Type 2 Diabetic Patients group (E2E3 4%, E3E3 86%, E3E4 4%) and diabetic foot ulcers (E2E3 8%, E3E3 76%, E3E4 16%) (p>0.05). The frequency of the E2,E3,E4 allele in between the control group and Type 2 Diabetic Patients were no similar for the groups (E2 22%, E3 69%, E4 9% and E2 3%, E3 90.5%, E4 6.5%, respectively) (p<0.001). The frequency of the E2-E4 allele in between the Type 2 Diabetic Patients and diabetic foot ulcers were similar for the groups (E2 2%, E3 93%, E4 5% and E2 4%, E3 88%, E4 8%, respectively) (p>0.05). CONCLUSIONS: The gene polymorphism of ApoE and E3 allele are a risk factor for diabetes, but gene polymorphism of ApoE is not an independent risk factor for diabetic foot. Lack of association between ApoE gene polymorphism and Type 2 diabetic foot ulcers might be due to ethnic differences. PMID- 26476488 TI - Evaluation of prevalence and risk factors of gestational diabetes in a tertiary care hospital in Kerala. AB - AIMS: The prospective study was conducted with the aim to evaluate the prevalence and risk factors of gestational diabetes mellitus in a tertiary care referral hospital in Kerala. MATERIALS AND METHODS: A prospective observational study was conducted with the aim to study the prevalence, risk factors, complications, treatment pattern and cost analysis of GDM. The study was carried out in the Obstetrics & Gynecology dDepartment of Al Shifa hHospital located in northern Kerala. RESULTS: Over an eight-month period, 201 patients who met the inclusion criteria were enrolled for study from which prevalence of GDM was estimated at 15.9%. The study revealed higher prevalence of risk factors and complications such as age >25 years, BMI >26kg/m(2), family history of DM, past history GDM, history of big baby, gestational hypertension, vaginal candidiasis, premature rupture of membranes and hyperbilirubinemia in GDM group as compared to non-GDM group. The study also demonstrated that modern life-style was a major influencing factor for development of diabetes in the study population. CONCLUSION: The study reveals the necessity of proper screening diagnosis and management of GDM in pregnant women by the clinicians so as to prevent the future burden of type 2 diabetes. PMID- 26476489 TI - A clinical measure of suicidal ideation, suicidal behavior, and associated symptoms in bipolar disorder: Psychometric properties of the Concise Health Risk Tracking Self-Report (CHRT-SR). AB - OBJECTIVE: People with bipolar disorder are at high risk of suicide, but no clinically useful scale has been validated in this population. The aim of this study was to evaluate the psychometric properties in bipolar disorder of the 7- and 12-item versions of the Concise Health Risk Tracking Self-Report (CHRT-SR), a scale measuring suicidal ideation, suicidal behavior, and associated symptoms. METHODS: The CHRT was administered to 283 symptomatic outpatients with bipolar I or II disorder who were randomized to receive lithium plus optimized personalized treatment (OPT), or OPT without lithium in a six month longitudinal comparative effectiveness trial. Participants were assessed using structured diagnostic interviews, clinician-rated assessments, and self-report questionnaires. RESULTS: The internal consistency (Cronbach alpha) was 0.80 for the 7-item CHRT-SR and 0.90 for the 12-item CHRT-SR with a consistent factor structure, and three independent factors (current suicidal thoughts and plans, hopelessness, and perceived lack of social support) for the 7-item version. CHRT-SR scores are correlated with measures of depression, functioning, and quality of life, but not with mania scores. CONCLUSIONS: The 7- and 12-item CHRT-SR both had excellent psychometric properties in a sample of symptomatic subjects with bipolar disorder. The scale is highly correlated with depression, functioning, and quality of life, but not with mania. Future research is needed to determine whether the CHRT-SR will be able to predict suicide attempts in clinical practice. PMID- 26476490 TI - Neopterin as a potential cytoprotective brain molecule. AB - Neopterin, a byproduct of the tetrahydrobiopterin de novo pathway, is found in increased levels in cerebrospinal fluid and plasma and significantly increases upon damage, infection or during immune system activation. The production of this compound seems almost restricted to the monocyte/macrophage linage cells, in response to interferon-gamma stimulation. However, it is unclear whether and which nervous cells are able to synthesize neopterin, respond to any stressor applied extracellularly, or even the role of the compound in the central nervous system. Here we propose a potential cytoprotective role of neopterin in the brain, and show evidence that cultured rat astrocytes are responsive to the molecule; the pterin elicited increased hemeoxygenase-1 cellular content and decreased oxidative stress induced by mitochondrial dysfunction. Further studies are needed to clarify neopterin's cytoprotective effects in the central nervous system, and its potential role in different neuroinflammatory diseases. PMID- 26476491 TI - Conversion from gastric bypass to sleeve gastrectomy for complications of gastric bypass. AB - BACKGROUND: Complications after gastric bypass (RYGB) are well documented. Reversal of RYGB is indicated in select cases but can lead to weight gain. Conversion from RYGB to sleeve gastrectomy (SG) has been proposed for correction of complications of RYGB without associated weight gain. However, little is known about outcomes after this procedure. OBJECTIVES: To examine outcomes after conversion from RYGB to SG. SETTING: University hospital. METHODS: A retrospective study of patients who underwent RYGB to SG conversion was undertaken. RESULTS: Twelve patients underwent RYGB to SG conversion for refractory marginal ulceration, stricture, dumping, gastrogastric fistula, hypoglycemia, and failed weight loss. No deaths occurred. Four patients experienced 7 major complications, including portal vein thrombosis, bleeding, pancreatic leak, pulmonary embolus, seroma, anastomotic leak, and stricture. Two required reoperation, and 6 were readmitted within 30 days. Four required nasoenteric feeding postoperatively because of prolonged nausea. The complication of RYGB resolved in 11 of 12 patients. At 14.7 months, change in body mass index for all patients was a decrease of 2.2 kg/m(2). In 5 patients with morbid obesity at conversion, the change in body mass index was a decrease of 6.4 kg/m(2) at 19 months. CONCLUSIONS: Laparoscopic conversion from RYGB to SG is successful in resolving certain complications of RYGB and does not result in short-term weight gain. However, conversion has a high rate of major complications as well as a high rate of readmission and need for supplemental nutrition. Although conversion to SG may be appropriate in carefully-selected patients, other options for patients with severe chronic complications after RYGB should be considered. PMID- 26476492 TI - Relationships between type 2 diabetes remission after gastric bypass and different weight loss metrics: arguments against excess weight loss in metabolic surgery. AB - BACKGROUND: Percentage excess weight loss (%EWL) outcome of bariatric surgery is distorted by deviations in baseline body mass index (BMI). It has been reported that this can lead to false conclusions, most likely because bariatric weight loss in fact is baseline-BMI independent. OBJECTIVES: If the metabolic effect of bariatric surgery is baseline-BMI independent as well, could %EWL also lead to false conclusions on metabolic surgery? SETTING: Bariatric Center of Excellence, general hospital, Netherlands. METHODS: Retrospective analysis of 1-year outcome of all consecutive primary gastric bypass patients with type 2 diabetes (T2DM). Metabolic outcome (glycated hemoglobin [HbA1c], T2DM medication) was compared with bariatric outcome (weight loss) using 3 different metrics: %EWL, the most popular weight loss metric among bariatric surgeons; percentage (total) weight loss (%WL), most commonly used by nonsurgical professionals; and percentage alterable weight loss (%AWL), the only metric rendering weight loss outcome independent of baseline BMI. Metabolic success (HbA1c<=6.0%, T2DM remission) was compared with different definitions of bariatric success (>=50 %EWL, BMI<35 kg/m(2), %AWL percentiles; Mann-Whitney test; P< .05). RESULTS: Until May 2014, 2001 patients underwent primary laparoscopic Roux-en-Y gastric bypass (LRYGB), of whom 449 had T2DM with baseline BMI 43.3 kg/m(2), mean 1.6 number of T2DM medication and HbA1c 7.5%. At 1 year 95% follow-up, with BMI 30.5 kg/m(2), 52.1% T2DM remission, 86.9% HbA1c<7.0%, and 63.6% without T2DM medication. No significant differences in T2DM outcome and weight loss were found with different baseline BMI, except for %EWL (P<.001). Weight loss was significantly better with better T2DM outcome, but for %EWL contradictory relationships were found in baseline-BMI subgroups. T2DM outcome was not less successful for patients with<50 %EWL. CONCLUSION: In T2DM patients, weight loss after gastric bypass does not depend on BMI, HbA1c, or T2DM medication at baseline. The popular %EWL metric and the 50 %EWL success criterion are problematic in comparing bariatric and metabolic outcome of gastric bypass surgery. They should be abandoned. The %WL metric is the best and most commonly used alternative, whereas %AWL is ideal for selected logistics in bariatric research. Weight loss percentiles are best suited for defining bariatric success in metabolic surgery. PMID- 26476493 TI - American Society for Metabolic and Bariatric Surgery estimation of bariatric surgery procedures in the United States, 2011-2014. PMID- 26476494 TI - Successful adult-to-adult living donor liver transplantation using liver allograft after the resection of hemangioma: A suggestive case for a further expansion of living donor pool. AB - INTRODUCTION: Hepatic hemangioma is one of the most common benign liver tumors. There are few published reports regarding liver transplantation using liver allografts with hemangioma. PRESENTATION OF CASE: A 45-year-old man was evaluated as a living donor for 19-year-old son with cirrhosis due to hepatic fibrosis. Preoperative investigations revealed 20 and 7mm hemangiomas, at segment 2 (S2) and 4 (S4) respectively. Considering the anatomical relation of S2 hemangioma and Glisson 2, liver graft was designed as left lobe excluded S2 hemangioma by partial resection. Estimated graft recipient weight ratio (GRWR) even after partial resection of hemangioma was reasonable. During the donor operation, a partial hepatic resection of S2 hemangioma was performed. Intraoperative pathologic findings revealed a cavernous hemangioma, and then, the left hepatic graft with the caudate lobe was harvested. Actual GRWR was 0.90%. Donor's postoperative course was uneventful. Recipient's post-operative course was almost uneventful. Postoperative computed tomography of the recipient showed the graft regeneration without increase or recurrence of hemangioma. DISCUSSION: Organ shortage is a major concern in the field of liver transplantation. A novel donor source with a further option is extremely crucial for a guarantee of liver transplantation. We experienced the first case of adult-to-adult living donor liver transplantation using liver allograft after the resection of hemangioma. CONCLUSION: We advocate that the use of liver allograft with hemangiomas in adult to-adult LDLT settings can be remarkable strategy to reduce the problem of organ shortage without any unfavorable consequences in both living donor and recipient. PMID- 26476495 TI - Improving operating room cleaning results with microfiber and steam technology. AB - Microfiber and steam technology is a novel cleaning method that has advantages for clinical applications. We describe its use in the operating room. The benefits include improved cleaning for every patient regardless of known or perceived risk, occupational health and safety advantages, and reduced cost of cleaning, allowing for expansion of cleaning activity without the need for additional human resources. Continuous surgical site infection surveillance demonstrated that infections remained at previously low levels. PMID- 26476496 TI - Physiologic and fit factor profiles of N95 and P100 filtering facepiece respirators for use in hot, humid environments. AB - BACKGROUND: To determine if hot, humid ambient conditions impact filtering facepiece respirators' (FFRs') fit, and to evaluate differences in physiologic and subjective responses between N95 FFRs and P100 FFRs. METHODS: Twelve subjects had physiologic monitoring and subjective perceptions monitored over 1 hour of treadmill exercise (5.6 km/h) in an environmental chamber (35 degrees C, relative humidity 50%) wearing an N95 FFR, P100 FFR, or no respirator. Respirator quantitative fit testing was done before and after exercise. RESULTS: There was no significant difference in pass rates for both FFRs on initial fit testing, but subjects who passed were more likely to fail the postexercise test with N95 FFRs (P = .01). Wearing FFRs increased the temperature of facial skin covered by the FFR (P = .009) and breathing discomfort (P = .002). No significant differences were noted in other measured variables (heart rate, respiratory rate, oxygen saturation, transcutaneous carbon dioxide level, rectal temperature, global skin temperature, core temperature, and subjective perceptions) between controls and FFRs and between FFR models. CONCLUSION: After 1 hour of exercise in hot, humid ambient conditions, P100 FFRs retained better fit than N95 FFRs, without additional physiologic or subjective impact. Wearing FFRs under these conditions does not add to the body's thermophysiologic or perceptual burdens. PMID- 26476497 TI - Consequences for overcrowding in the emergency room of a change in bed management policy on available in-hospital beds. AB - Objective Emergency rooms play an important role by providing continuous access to healthcare 24 h a day, 7 days a week, but the lack of available hospital beds has become a major difficulty. Changing bed management policy could improve patient flow. The aim of the present study was to evaluate the consequences of a change in patient prioritisation on available beds. Methods The study consisted of a computerised bed management simulation based on day-by-day data collected from 1 to 31 January 2013 in a teaching hospital. Real hospital data were used to power the computer simulation. The scenarios tested were: (1) priority for emergency and surgery; (2) priority for emergency and medicine; (3) priority for planned admissions and surgery; and (4) priority for planned admissions and medicine. The results of these scenarios were compared with each other and to actual data. Results This study included 2347 patients. The scenario that proved to be the least efficient was the one that gave priority to emergency patients presenting with a medical condition. The scenario that exhibited the best efficiency was the one that gave priority to planned admissions and surgery. Conclusions Changing policies for hospital bed management is worth exploring to improve hospital patient flow and length of stay. What is known about the topic? The lack of available hospital beds is a major difficulty in managing patient flow in emergency rooms (ERs). The ER patient flow competes against a flow of planned hospital admissions for the same beds and the lack of a clearly defined policy on either prioritising ER patient flow over planned admissions or vice versa contributes to a disordered system. What does this paper add? We compared several simulated scenarios corresponding to different bed management policies. The scenario that gave priority to planned admissions and surgery gave the most suitable results. What are the implications for practitioners? Postponing scheduled surgical patients was not an efficient procedure to solve hospital overcrowding. PMID- 26476498 TI - Motoric Cognitive Risk Syndrome: Prevalence and Risk Factors in Japanese Seniors. AB - OBJECTIVES: Motoric cognitive syndrome (MCR), a newly described predementia syndrome characterized by cognitive complaints and slow gait, is associated with increased risk of developing dementia. Due to the potential differences in health, behavioral, and lifestyle factors between races that can influence dementia risk, it is important to examine risk factors for MCR in different countries. This study aimed to report the prevalence as well as modifiable factors associated with MCR in Japanese community-dwelling older adults. DESIGN: A cross-sectional design. SETTING: General community. PARTICIPANTS: A total of 9683 older adults (52% women, mean age: 73.6 years) participating in the National Center for Geriatrics and Gerontology Study of Geriatric Syndromes. MEASUREMENTS: Participants were screened for presence of MCR at baseline. The association of selected modifiable risk factors (medical illness, depressive symptoms, and falls) and lifestyle variables (obesity, physical inactivity, smoking, and alcohol consumption) with MCR was examined using multivariate logistic regression analysis. RESULTS: At cross-section, 619 participants met criteria for MCR, with an overall prevalence 6.4% (95% CI 5.9-6.9). A higher prevalence of MCR was seen with advancing age (P < .001), but there were no sex differences. Diabetes (adjusted odds ratio [OR] 1.47, P = .001), depressive symptoms (OR 3.57, P < .001), and falls (OR 1.45, P < .001) were associated with increased risk of MCR. Among the lifestyle factors, obesity (OR 1.26, P = .018) and physical inactivity (OR 1.57, P < .001) were associated with increased risk of MCR. CONCLUSION: MCR is common in the elderly Japanese population. The potentially modifiable risk and lifestyle factors identified for MCR should be further studied to develop interventions. PMID- 26476499 TI - Natriuretic peptides for perioperative management of cardiac surgery. AB - Atrial natriuretic peptide (carperitide) is used to treat heart failure in Japan, while brain natriuretic peptide (nesiritide) is employed in Europe/USA. Patients undergoing cardiac surgery have a complex underlying pathologic state that features increased levels of neurohumoral factors due to activation of the renin angiotensin-aldosterone system and/or increased sympathetic activity. We considered that perioperative administration of carperitide could be beneficial for cardiac surgery patients, and we have conducted clinical investigations of its use. This article reviews the effects of natriuretic peptides in cardiac surgery patients based on our experience and on previous reports about perioperative management with carperitide or nesiritide. PMID- 26476500 TI - Sutureless aortic valve replacement may improve early mortality compared with transcatheter aortic valve implantation: A meta-analysis of comparative studies. AB - OBJECTIVES: To determine which improves clinical outcomes more, sutureless (including rapid-deployment) aortic valve replacement (AVR) or transcatheter aortic valve implantation (TAVI), we performed a meta-analysis of comparative studies. METHODS: MEDLINE and EMBASE were searched through June 2015 using Web based search engines (PubMed and OVID). Studies considered for inclusion met the following criteria: the design was a comparative study; the study population included patients with severe aortic valve stenosis, patients were assigned to sutureless AVR versus TAVI; and main outcomes included at least early (in hospital or 30-day) all-cause mortality. RESULTS: Of 87 potentially relevant articles screened initially, no randomized controlled trials and 7 observational comparative studies of sutureless AVR versus TAVI (enrolling a total of 945 patients) were identified and included. The first pooled analysis demonstrated a statistically significant reduction in mortality with sutureless AVR over TAVI [2.5% versus 7.3%; odds ratio (OR), 0.33; 95% confidence interval (CI), 0.16 to 0.69; p=0.003; risk difference (RD), -5.23%; 95% CI, -8.12% to -2.33%; p=0.0004]. The second pooled analyses demonstrated no statistically significant difference in bleeding complications, acute kidney injury, and conduction disturbance between sutureless AVR and TAVI. The third pooled analysis demonstrated a statistically significant reduction in paravalvular aortic regurgitation (AR) with sutureless AVR over TAVI (3.5% versus 33.2%; OR, 0.09; 95% CI, 0.05 to 0.16, p<0.00001; MD, -22.56%; 95% CI, -36.59% to -8.53%; p=0.002). CONCLUSIONS: Compared with TAVI, sutureless AVR may be associated with a reduction in early mortality and postoperative paravalvular AR. PMID- 26476501 TI - Noninvasive Follow-Up of Patients With Spontaneous Coronary Artery Dissection With CT Angiography. PMID- 26476502 TI - 3D Intracardiac Echocardiography During TAVR Without Endotracheal Intubation. PMID- 26476503 TI - Echocardiographic Algorithm for Post-Myocardial Infarction LV Thrombus: A Gatekeeper for Thrombus Evaluation by Delayed Enhancement CMR. AB - OBJECTIVES: The goal of this study was to determine the prevalence of post myocardial infarction (MI) left ventricular (LV) thrombus in the current era and to develop an effective algorithm (predicated on echocardiography [echo]) to discern patients warranting further testing for thrombus via delayed enhancement (DE) cardiac magnetic resonance (CMR). BACKGROUND: LV thrombus affects post-MI management. DE-CMR provides thrombus tissue characterization and is a well validated but an impractical screening modality for all patients after an MI. METHODS: A same-day echo and CMR were performed according to a tailored protocol, which entailed uniform echo contrast (irrespective of image quality) and dedicated DE-CMR for thrombus tissue characterization. RESULTS: A total of 201 patients were studied; 8% had thrombus according to DE-CMR. All thrombi were apically located; 94% of thrombi occurred in the context of a left anterior descending (LAD) infarct-related artery. Although patients with thrombus had more prolonged chest pain and larger MI (p <= 0.01), only 18% had aneurysm on echo (cine-CMR 24%). Noncontrast (35%) and contrast (64%) echo yielded limited sensitivity for thrombus on DE-CMR. Thrombus was associated with stepwise increments in basal -> apical contractile dysfunction on echo and quantitative cine-CMR; the echo-measured apical wall motion score was higher among patients with thrombus (p < 0.001) and paralleled cine-CMR decrements in apical ejection fraction and peak ejection rates (both p < 0.005). Thrombus-associated decrements in apical contractile dysfunction were significant even among patients with LAD infarction (p < 0.05). The echo-based apical wall motion score improved overall performance (area under the curve 0.89 +/- 0.44) for thrombus compared with ejection fraction (area under the curve 0.80 +/- 0.61; p = 0.01). Apical wall motion partitions would have enabled all patients with LV thrombus to be appropriately referred for DE-CMR testing (100% sensitivity and negative predictive value), while avoiding further testing in more than one-half (56% to 63%) of patients. CONCLUSIONS: LV thrombus remains common, especially after LAD MI, and can occur even in the absence of aneurysm. Although DE-CMR yielded improved overall thrombus detection, apical wall motion on a noncontrast echocardiogram can be an effective stratification tool to identify patients in whom DE-CMR thrombus assessment is most warranted. (Diagnostic Utility of Contrast Echocardiography for Detection of LV Thrombi Post ST Elevation Myocardial Infarction; NCT00539045). PMID- 26476504 TI - Coronary Artery Calcium Improves Risk Classification in Younger Populations. AB - OBJECTIVES: This study sought to assess the effect of coronary artery calcium (CAC) on coronary heart disease (CHD) risk prediction in a younger population. BACKGROUND: CAC measured by computed tomography improves CHD risk classification in older adults, but the effectiveness of CAC in younger populations has not been fully assessed. METHODS: In the DHS (Dallas Heart Study), a multiethnic probability-based population sample, traditional CHD risk factors and CAC were measured in participants without baseline cardiovascular disease or diabetes. Incident CHD-defined as CHD death, myocardial infarction, or coronary revascularization-was assessed over a median follow-up of 9.2 years. Predicted CHD risk was assessed with a Weibull model inclusive of traditional risk factors before and after the addition of CAC as ln(CAC + 1). Participants were divided into 3 10-year risk categories, <6%, 6% to <20%, and >=20%, and the net reclassification improvement (NRI) was calculated. We also performed a random effects meta-analysis of NRI from previous studies inclusive of older individuals. RESULTS: The analysis comprised 2,084 participants; mean age was 44.4 +/- 9.0 years. CAC was independently associated with incident CHD (hazard ratio per SD: 1.90, 95% confidence interval [CI] 1.51 to 2.38; p < 0.001). The addition of CAC to the traditional risk factor model resulted in significant improvement in the C-statistic (delta = 0.03; p = 0.003). Among participants with CHD events, the addition of CAC resulted in net correct upward reclassification of 21%, and among those without CHD, a net correct downward reclassification of 0.5% (NRI: 0.216, p = 0.012). Results remained significant when the outcome was restricted to CHD death and myocardial infarction and when individuals with diabetes were included. The NRI observed in this study was similar to the pooled estimate from previous studies (0.200, 95% CI: 0.140 to 0.258) and the addition of our study to the meta-analysis did not result in significant heterogeneity (I(2) = 0%). CONCLUSIONS: CAC scoring also improves CHD risk classification in younger adults. PMID- 26476505 TI - Precursors of Hypertensive Heart Phenotype Develop in Healthy Adults: A High Resolution 3D MRI Study. AB - OBJECTIVES: This study used high-resolution 3-dimensional cardiac magnetic resonance to define the anatomical and functional left ventricular (LV) properties associated with increasing systolic blood pressure (SBP) in a drug naive cohort. BACKGROUND: LV hypertrophy and remodeling occur in response to hemodynamic stress but little is known about how these phenotypic changes are initiated in the general population. METHODS: In this study, 1,258 volunteers (54% women, mean age 40.6 +/- 12.8 years) without self-reported cardiovascular disease underwent 3-dimensional cardiac magnetic resonance combined with computational modeling. The relationship between SBP and wall thickness (WT), relative WT, end-systolic wall stress (WS), and fractional wall thickening were analyzed using 3-dimensional regression models adjusted for body surface area, sex, race, age, and multiple testing. Significantly associated points in the LV model (p < 0.05) were identified and the relationship with SBP reported as mean beta coefficients. RESULTS: There was a continuous relationship between SBP and asymmetric concentric hypertrophic adaptation of the septum and anterior wall that was associated with normalization of wall stress. In the lateral wall an increase in wall stress with rising SBP was not balanced by a commensurate hypertrophic relationship. In normotensives, SBP was positively associated with WT (beta = 0.09) and relative WT (beta = 0.07) in the septal and anterior walls, and this regional hypertrophic relationship was progressively stronger among pre hypertensives (beta = 0.10) and hypertensives (beta = 0.30). CONCLUSIONS: These findings show that the precursors of the hypertensive heart phenotype can be traced to healthy normotensive adults and that an independent and continuous relationship exists between adverse LV remodeling and SBP in a low-risk population. These adaptations show distinct regional variations with concentric hypertrophy of the septum and eccentric hypertrophy of the lateral wall, which challenge conventional classifications of LV remodeling. PMID- 26476507 TI - Use of alginate beads as carriers for lactic acid bacteria in a structured system and preliminary validation in a meat product. AB - This paper proposes the microencapsulation into alginate beads of 4 isolates of lactic acid bacteria (Lactobacillus spp.), previously isolated from pork meat. First, the beads were studied in relation to the encapsulation yield (EY), kinetic of cell release in a structured system, and survival throughout bead storage at 4 degrees C. EY was 93-96% and the survival of the encapsulated microorganisms was variable, with two isolates showing a bacterial population of 6.1-6.9 log cfu/g after 35 days under refrigerated conditions. Thereafter, the paper addressed a preliminary validation in a meat model system, containing salt, nitrites and nitrates, lactose, pepper, and then in a commercial preparation of pork meat. For the validation in pork meat, free cells were used as controls. Cell released from beads were able to achieve a significant acidification; in particular, after 7 days they showed the same results of free cells. PMID- 26476506 TI - hs-Troponin I Followed by CT Angiography Improves Acute Coronary Syndrome Risk Stratification Accuracy and Work-Up in Acute Chest Pain Patients: Results From ROMICAT II Trial. AB - OBJECTIVES: This study compared diagnostic accuracy of conventional troponin/traditional coronary artery disease (CAD) assessment and highly sensitive troponin (hsTn) I/advanced CAD assessment for acute coronary syndrome (ACS) during the index hospitalization. BACKGROUND: hsTnI and advanced assessment of CAD using coronary computed tomography angiography (CTA) are promising candidates to improve the accuracy of emergency department evaluation of patients with suspected ACS. METHODS: We performed an observational cohort study in patients with suspected ACS enrolled in the ROMICAT II (Rule Out Myocardial Infarction/Ischemia using Computer Assisted Tomography) trial and randomized to coronary CTA who also had hsTnI measurement at the time of the emergency department presentation. We assessed coronary CTA for traditional (no CAD, nonobstructive CAD, >=50% stenosis) and advanced features of CAD (>=50% stenosis, high-risk plaque features: positive remodeling, low <30-Hounsfield units plaque, napkin-ring sign, spotty calcium). RESULTS: Of 160 patients (mean age: 53 +/- 8 years, 40% women) 10.6% were diagnosed with ACS. The ACS rate in patients with hsTnI below the limit of detection (n = 9, 5.6%), intermediate (n = 139, 86.9%), and above the 99th percentile (n = 12, 7.5%) was 0%, 8.6%, and 58.3%, respectively. Absence of >=50% stenosis and high-risk plaque ruled out ACS in patients with intermediate hsTnI (n = 87, 54.4%; ACS rate 0%), whereas patients with both >=50% stenosis and high-risk plaque were at high risk (n = 13, 8.1%; ACS rate 69.2%) and patients with either >=50% stenosis or high-risk plaque were at intermediate risk for ACS (n = 39, 24.4%; ACS rate 7.7%). hsTnI/advanced coronary CTA assessment significantly improved the diagnostic accuracy for ACS as compared to conventional troponin/traditional coronary CTA (area under the curve 0.84, 95% confidence interval [CI]: 0.80 to .88 vs. 0.74, 95% CI: 0.70 to 0.78; p < 0.001). CONCLUSIONS: hsTnI at the time of presentation followed by early advanced coronary CTA assessment improves the risk stratification and diagnostic accuracy for ACS as compared to conventional troponin and traditional coronary CTA assessment. (Multicenter Study to Rule Out Myocardial Infarction/Ischemia by Cardiac Computed Tomography [ROMICAT-II]; NCT01084239). PMID- 26476509 TI - Milia en plaque on the posterior surface of both auricules following radiation therapy. PMID- 26476508 TI - First-time whole blood donation: A critical step for donor safety and retention on first three donations. AB - AIM OF THE STUDY: Whole blood donation is generally safe although vasovagal reactions can occur (approximately 1%). Risk factors are well known and prevention measures are shown as efficient. This study evaluates the impact of the donor's retention in relation to the occurrence of vasovagal reaction for the first three blood donations. MATERIAL AND METHODS: Our study of data collected over three years evaluated the impact of classical risk factors and provided a model including the best combination of covariates predicting VVR. The impact of a reaction at first donation on return rate and complication until the third donation was evaluated. RESULTS: Our data (523,471 donations) confirmed the classical risk factors (gender, age, donor status and relative blood volume). After stepwise variable selection, donor status, relative blood volume and their interaction were the only remaining covariates in the model. Of 33,279 first-time donors monitored over a period of at least 15 months, the first three donations were followed. Data emphasised the impact of complication at first donation. The return rate for a second donation was reduced and the risk of vasovagal reaction was increased at least until the third donation. CONCLUSION: First-time donation is a crucial step in the donors' career. Donors who experienced a reaction at their first donation have a lower return rate for a second donation and a higher risk of vasovagal reaction at least until the third donation. Prevention measures have to be processed to improve donor retention and provide blood banks with adequate blood supply. PMID- 26476510 TI - Psychosocial factors and excessive gestational weight gain: The effect of parity in an Australian cohort. AB - OBJECTIVES: psychosocial variables can be protective or risk factors for excessive gestational weight gain (GWG). Parity has also been associated with GWG; however, its effect on psychosocial risk factors for GWG is yet to be determined. The aim of this study was to investigate if, and how, psychosocial factors vary in their impact on the GWG of primiparous and multiparous women. DESIGN/PARTICIPANTS: pregnant women were recruited in 2011 via study advertisements placed in hospitals, online, in parenting magazines, and at baby and children's markets, resulting in a sample of 256 women (113 primiparous, 143 multiparous). Participants completed questionnaires at 16-18 weeks' gestation and their pregravid BMI was recorded. Final weight before delivery was measured and used to calculate GWG. FINDINGS: the findings revealed that primiparous women had significantly higher feelings of attractiveness (a facet of body attitude; p=0.01) than multiparous women. Hierarchical regressions revealed that in the overall sample, increased GWG was associated significantly with lower pre pregnancy BMI (standardised coefficient beta=-0.39, p<0.001), higher anxiety symptoms (beta=0.25, p=0.004), and reduced self-efficacy to eat a healthy diet (beta=-0.20, p=0.02). Although higher GWG was predicted significantly by decreased feelings of strength and fitness for primiparous women (beta=-0.25, p=0.04) and higher anxiety was related significantly to greater GWG for multiparous women (beta=0.43, p<0.001), statistical comparison of the model across the two groups suggested the magnitude of these effects did not differ across groups (p>0.05). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: the findings suggest that psychosocial screening and interventions by healthcare professionals may help to identify women who are at risk of excessive GWG, and there may be specific psychosocial factors that are more relevant for each parity group. PMID- 26476512 TI - [Importance of diffusion weighted magnetic resonance imaging at differentiation of cholesteatoma and granulation tissue in patients with chronic suppurative otitis media]. AB - OBJECTIVES: This study aims to report the significance of echo-planar diffusion weighted imaging (EP-DWI) in preoperative magnetic resonance imaging of patients with surgically corrected cholesteatoma and granulation tissue according to DWI and apparent diffusion coefficient (ADC) values. PATIENTS AND METHODS: Ninety-one patients (52 males, 39 females; mean age 40.7+/-15.8 years; range 3 to 77 years) who admitted to radiology clinic of our hospital between December 2009 and May 2011 with a pre-diagnosis of chronic otitis media with primary acquired cholesteatoma and assessed preoperatively in our clinic by ear magnetic resonance imaging and DWI were included in the study. Diffusion-weighted imaging results were compared with operative findings and pathology results. Patients were retrospectively evaluated using picture archiving and communication system. Diffusion-weighted imaging and ADC images were examined qualitatively and quantitatively. RESULTS: Ninety-one patients suspected of cholesteatoma were operated. According to the results of operations, 50 patients had cholesteatoma and 41 patients had granulation tissue. The mean DWI values of patients with cholesteatoma were significantly higher than patients with granulation tissue (p<0.05). The mean ADC values of patients with cholesteatoma were significantly lower than patients with granulation tissue (p<0.05). The sensitivity and specificity of EP-DWI in detection of cholesteatoma were 97.6% and 92.0%, respectively. CONCLUSION: Echo-planar diffusion-weighted imaging by using ADC and DWI is a valuable tool with high sensitivity and specificity rates in detecting cholesteatoma particularly bigger than 5 mm and in differentiating them from other pathologies. PMID- 26476511 TI - A critical review of nitrogen mineralization in biosolids-amended soil, the associated fertilizer value for crop production and potential for emissions to the environment. AB - International controls for biosolids application to agricultural land ensure the protection of human health and the environment, that it is performed in accordance with good agricultural practice and that nitrogen (N) inputs do not exceed crop requirements. Data from the scientific literature on the total, mineral and mineralizable N contents of biosolids applied to agricultural land under a wide range of climatic and experimental conditions were collated. The mean concentrations of total N (TN) in the dry solids (DS) of different biosolids types ranged from 1.5% (air-dried lime-treated (LT) biosolids) to 7.5% (liquid mesophilic anaerobic digestion (LMAD) biosolids). The overall mean values of mineralizable N, as a proportion of the organic N content, were 47% for aerobic digestion (AeD) biosolids, 40% for thermally dried (TD) biosolids, 34% for LT biosolids, 30% for mesophilic anaerobic digestion (MAD) biosolids, and 7% for composted (Com) biosolids. Biosolids air-dried or stored for extended periods had smaller total and mineralizable N values compared to mechanically dewatered types. For example, for biosolids treated by MAD, the mean TN (% DS) and mineralizable N (% organic N) contents of air-dried materials were 3% and 20%, respectively, compared to 5% and 30% with mechanical dewatering. Thus, mineralizable N declined with the extent of biological stabilization during sewage sludge treatment; nevertheless, overall plant available N (PAN=readily available inorganic N plus mineralizable N) was broadly consistent across several major biosolids categories within climatic regions. However, mineralizable N often varied significantly between climatic regions for similar biosolids types, influencing the overall PAN. This may be partly attributed to the increased rate, and also the greater extent of soil microbial mineralization of more stable, residual organic N fractions in biosolids applied to soil in warmer climatic zones, which also raised the overall PAN, compared to cooler temperate areas. It is also probably influenced by differences in upstream wastewater treatment processes that affect the balance of primary and secondary, biological sludges in the final combined sludge output from wastewater treatment, as well as the relative effectiveness of sludge stabilization treatments at specific sites. Better characterization of biosolids used in N release and mineralization investigations is therefore necessary to improve comparison of system conditions. Furthermore, the review suggested that some international fertilizer recommendations may underestimate mineralizable N in biosolids, and the N fertilizer value. Consequently, greater inputs of supplementary mineral fertilizer N may be supplied than are required for crop production, potentially increasing the risk of fertilizer N emissions to the environment. Thus greater economic and environmental savings in mineral N fertilizer application are potentially possible than are currently realized from biosolids recycling programmes. PMID- 26476513 TI - Influence of nasal pack removal on patients' anxiety after septoplasty. AB - OBJECTIVES: This study aims to investigate the effects of the removal of Merocel nasal packs on patients' anxiety after septoplasty. PATIENTS AND METHODS: Fifty patients (26 males, 24 females; mean age 30 years; range 18 to 56 years) who underwent septoplasty in the Department of Ear Nose and Throat of our hospital between January 2013 and January 2015 were enrolled in this prospective study. Patients' anxiety was measured using the State-Trait Anxiety Inventory. Anxiety levels were measured 24 hours preoperatively, 48 hours postoperatively before nasal pack removal, and 60 minutes after nasal pack removal. RESULTS: The State Trait Anxiety Inventory scores were 44.2+/-7.4 preoperatively, 45.1+/-7.1 postoperatively before pack removal, and 37.4+/-6.7 after pack removal. There was no statistically significant difference between pre- and postoperative evaluations. However, patients' anxiety decreased statistically significantly in the evaluation 60 minutes after pack removal (p=0.0). CONCLUSION: We recommend administering soluble packs or sewing techniques without nasal packs after septoplasty due to concerns related to quality of life after surgery. PMID- 26476514 TI - Establishment and reliability test of a "Vertigo Council Diagnosis Questionnaire" for patients with chronic vestibular dysfunction: preliminary study. AB - OBJECTIVES: This study aims to establish a "Vertigo Council Diagnosis Questionnaire" for patients with chronic vestibular dysfunction and show the reliability of this questionnaire. MATERIALS AND METHODS: A "Vertigo Council Diagnosis Questionnaire" consisting of 10 questions was prepared by 15 specialist physicians and analyzed for reliability using the "translation-back-translation" method. RESULTS: When all the items of our questionnaire were evaluated, the content validity ratio ranged from 0.6 to 0.87, and the content validity index was 0.676. The conformity ratio between the real diagnosis and the diagnosis based on the questionnaire was 63.19%, and the kappa was 0.441 (moderate). No significant difference was found between the first and second responses to any of the questions (p>0.05). There was no significant difference between question conformity (conformity between the first and second responses) and diagnostic conformity (conformity between the real diagnosis and the diagnosis based on the questionnaire) (p>0.05) in any of the questions. No relationship was found between diagnostic conformity and sociodemographic data (age, sex, education, occupation) (p>0.05). CONCLUSION: Our study results suggest that, in Turkish patients, diagnosis of vertigo should be based on face-to-face interviews, and clinical and laboratory evaluations rather than a questionnaire. PMID- 26476515 TI - Pack free septoplasty: functional outcomes and complications. AB - OBJECTIVES: This study aims to evaluate the functional outcomes and complications of pack free septoplasty in adults. PATIENTS AND METHODS: Forty-nine consecutive patients (35 males, 14 females; mean age 37.7 years; range 18 to 63 years) who underwent septoplasty in our clinic between January 2011 and June 2013 were prospectively included in the study. Preoperative nasal obstruction was scored using the Nasal Obstruction Symptom Evaluation (NOSE). Nasal obstruction was reevaluated in the first and the third postoperative months. Postoperative complications were recorded. Pre- and postoperative NOSE scores were compared. RESULTS: Recovery rate was 81.63%. There was a statistically significant difference between preoperative NOSE scores and postoperative first and third month NOSE scores (p<0.05). We observed minor hemorrhage in 17 patients (34.7%), nasal synechiae in three patients (6.1%), and flap overposition in two patients (4.1%). CONCLUSION: Pack free septoplasty performed with transseptal suture technique is effective in the treatment of septum deviation and may be performed confidently in septum surgery. PMID- 26476516 TI - Prevalence of benign paroxysmal positional vertigo among motocross racers: a case control study. AB - OBJECTIVES: This study aims to investigate the prevalence of benign paroxysmal positional vertigo (BPPV) among motocross racers after cross-country up and downhill activities. PATIENTS AND METHODS: This case-control study included 40 motocross racers (39 males, 1 female; mean age 26 years; range 21 to 43 years) and 40 healthy controls (30 males, 10 females; mean age 28 years; range 22 to 43 years) who had no hearing or balance problems. The Dix-Hallpike maneuver was applied to confirm the diagnosis of BPPV. Patients with BPPV were administered the Epley maneuver every week for one month and followed-up for treatment response assessment. RESULTS: Motocross and control groups were similar in terms of demographic and laboratory parameters. While BPPV was detected in four motocross racers (10%) according to Dix-Hallpike maneuver outcome and clinical findings, there was no BPPV in the control group. Of the motocross racers with BPPV, three had unilateral, one had bilateral disease. Of these patients, Epley maneuver was applied two times in two patients and three times in the other two patients. There was no vertigo or nystagmus in any of the patients with BPPV in one month. CONCLUSION: Intensive motocross activity is a cause of post-traumatic BPPV developing without head trauma. Large-scale, randomized controlled studies are needed to establish the post-traumatic etiology of BPPV in motocross racers. PMID- 26476517 TI - [Impact of markedly nasal septal deviation on 24-hour rhythm Holter findings]. AB - OBJECTIVES: This study aims to investigate any impact of nasal septal deviations on cardiac arrhythmias and heart rates by performing 24-hour rhythm Holter analysis before and after septoplasty accompanied by Nasal Obstruction Symptom Evaluation (NOSE) scale. PATIENTS AND METHODS: The study included 21 male patients (mean age 33 years; range 18 to 55 years) who underwent septoplasty between September 2013 and August 2014. Patients were performed 24-hour rhythm Holter electrocardiography analysis preoperatively and at postoperative third month. Supraventricular and ventricular extrasystoles were recorded pre- and postoperatively. Operation efficiency was measured with NOSE scale. RESULTS: Of the 21 patients, ventricular and supraventricular extrasystoles were observed in seven patients (33%) in the preoperative period. Mean age of patients with arrhythmia (mean age 51 years; range 18 to 55 years) was statistically significant higher compared to patients without arrhythmia (mean age 30 years; range 23 to 55 years) (p=0.012). Extrasystoles decreased in seven patients in the postoperative period. Average, minimum, and maximum heart rates did not change statistically significant in the postoperative period. CONCLUSION: The fact that septoplasty decreased arrhythmias indicates that nasal septum deviations may be associated with cardiac arrhythmias. Septoplasty had no effect on heart rates. Performing septoplasty in the early period may prevent future cardiac complications in indicated patients. PMID- 26476518 TI - [The relationship between platelet count and mean platelet volume with obstructive sleep apnea syndrome]. AB - OBJECTIVES: This study aims to investigate the relationship between platelet count and mean platelet volume (MPV) with obstructive sleep apnea syndrome (OSAS). PATIENTS AND METHODS: This retrospective study included 417 OSAS patients (284 males, 133 females; mean age 47.9+/-10.0; range 23 to 75 years) who were performed polisomnography (PSG) in our clinic between January 2013 and December 2014. Patients were divided into two groups according to apnea-hipopnea index (AHI). Apnea-hipopnea index <5 was assumed as normal, while AHI >=5 was assumed as OSAS. Platelet count and MPV values of group with normal AHI and group with OSAS were statistically compared. Apnea-hipopnea index, REM AHI, non-REM AHI, minimum oxygen saturation, and duration of oxygen saturation remaining below 90% were statistically compared with platelet count and MPV. RESULTS: The mean of platelet count in non-OSAS and OSAS groups were 262.31+/-65.78 and 252.77+/ 61.86, respectively, with no statistically significant difference between the groups. Mean platelet volume in non-OSAS and OSAS groups were 9.56+/-1.88 and 9.71+/-1.57, respectively; however, the difference was not statistically significant. Platelet count increased statistically significantly as AHI, REM AHI, non-REM AHI, and minimum oxygen saturation parameters got impaired. CONCLUSION: As PSG parameters get impaired, platelet count increases in OSAS patients. PMID- 26476520 TI - Adenoid cystic carcinoma of the accessory parotid gland. AB - Accessory parotid gland is a small salivary gland tissue separated from main part of parotid gland. It is located on the masseter muscle anterior to the Stensen's duct. Tumors of accessory parotid gland are rare. In this article, we report an unusual case of adenoid cystic carcinoma involving accessory parotid gland. The patient presented with a progressively growing mass in the middle portion of her cheek. She underwent a partial parotidectomy including both the superficial and accessory lobes. The histopathologic diagnosis was adenoid cystic carcinoma of cribriform type. PMID- 26476519 TI - [Rhino-orbito-cerebral mucormycosis: two case reports in the light of the literature]. AB - Rhino-orbito-cerebral mucormycosis is an acute onset and often fatal disease. Risk factors include uncontrolled diabetes mellitus, hematological malignancies, and long-term corticosteroid use. Early diagnosis and treatment are important. The underlying causes should be treated, surgical debridement should be performed and appropriate antifungal drugs should be given. In this article, we report two diabetic ketoacidosis patients who developed rhino-orbito-cerebral mucormycosis and were treated with surgical debridement and amphotericin B therapy. PMID- 26476521 TI - A rare, incidental submandibular hydatid cyst. AB - Hydatid cyst disease is a parasitic infestation caused by Echinococcus granulosus. It is transmitted via oral ingestion of eggs excreted by dog's stool. Liver and lungs are the most commonly involved organs. Primary involvement of submandibular region by hydatid cyst is extremely rare. In this article, we report a case of a lesion excised from submandibular region with an initial diagnosis of branchial cleft cyst, but shown to be a hydatid cyst in histopathological evaluation. PMID- 26476522 TI - Hyoid osteoradionecrosis accompanied by candida infection. AB - Osteoradionecrosis of the hyoid bone is a rare complication of therapeutic irradiation performed for head and neck cancer. In this article, we present a 52 year-old male patient who admitted with severe odynophagia following chemo radiotherapy administration for tonsil carcinoma. Fluorine-18-fluorodeoxy-glucose positron emission tomography-computed tomography revealed a metabolic activity in hyoid bone. The pathological findings were consistent with fungal infection and hyoid bone necrosis. Hyoid osteoradionecrosis should be kept in mind in patients with intractable dysphagia following irradiation for head and neck tumors. PMID- 26476523 TI - [Submucosal lingual schwannoma]. AB - Schwannoma or neurilemmoma is a slow growing, solitary, and encapsulated benign tumor originating from Schwann cells of the peripheral nerves. Lingual schwannomas are rare. A 46-year-old male patient admitted with a complaint of swelling on the right half of the tongue for one year. An approximately 1x1 cm submucosal mass was detected on the right side of the tongue. The submucosal mass was totally excised under local anesthesia. Pathological examination was consistent with schwannoma. Lingual schwannomas should be considered in the differential diagnosis of tongue masses. PMID- 26476524 TI - Assessment of adaptability of zebu cattle (Bos indicus) breeds in two different climatic conditions: using cytogenetic techniques on genome integrity. AB - The aim of this study was to evaluate the genome integrity so as to assess the adaptability of three breeds of indigenous cattle reared under arid and semi-arid regions of Rajasthan (Bikaner) and Haryana (Karnal) India. The cattle were of homogenous group (same age and sex) of indigenous breeds viz. Sahiwal, Tharparkar and Kankrej. A total of 100 animals were selected for this study from both climatic conditions. The sister chromatid exchanges (SCE's), chromosomal gaps and chromatid breaks were observed in metaphase plates of chromosome preparations obtained from in vitro culture of peripheral blood lymphocytes. The mean number of breaks and gaps in Sahiwal and Tharparkar of semi-arid zone were 8.56 +/- 3.16, 6.4 +/- 3.39 and 8.72 +/- 2.04, 3.52 +/- 6.29, respectively. Similarly, the mean number of breaks and gaps in Tharparkar and Kankrej cattle of arid zone were 5.26 +/- 1.76, 2.74 +/- 1.76 and 5.24 +/- 1.84, 2.5 +/- 1.26, respectively. The frequency of SCEs in chromosomes was found significantly higher (P < 0.05) in Tharparkar of semi-arid region (4.72 +/- 1.55) compared to arid region (2.83 +/- 1.01). Similarly, the frequency of SCEs was found to be 4.0 +/- 1.41 in the Sahiwal of semi-arid region and 2.69 +/- 1.12 in Kankrej of arid zone. Statistical analysis revealed significant differences (P < 0.05) amongst the different zones, i.e. arid and semi-arid, whereas no significant difference (P > 0.05) was observed in the same zone. The analysis of frequency of CAs and SCEs revealed significant effects of environmental conditions on the genome integrity of animals, thereby indicating an association with their adaptability. PMID- 26476525 TI - Filobacterium rodentium gen. nov., sp. nov., a member of Filobacteriaceae fam. nov. within the phylum Bacteroidetes; includes a microaerobic filamentous bacterium isolated from specimens from diseased rodent respiratory tracts. AB - Strain SMR-CT, which was originally isolated from rats as the SMR strain, had been named 'cilia-associated respiratory bacillus' ('CAR bacillus'). 'CAR bacillus' was a Gram-stain-negative, filamentous argentophilic bacterium without flagella. SMR-CT grew at 37 degrees C under microaerobic conditions, showed gliding activity, hydrolysed urea and induced chronic respiratory diseases in rodents. The dominant cellular fatty acids detected were iso-C15 : 0 and anteiso C15 : 0. The DNA G+C content was 47.7 mol%. 16S rRNA gene sequence analysis revealed SMR-CT and other strains of 'CAR bacillus' isolated from rodents all belonged to the phylum Bacteroidetes. The nearest known type strain, with 86 % 16S rRNA gene sequence similarity, was Chitinophaga pinensis DSM 2588T in the family Chitinophagaceae. Strain SMR-CT and closely related strains of 'CAR bacillus' rodent-isolates formed a novel family-level clade in the phylum Bacteroidetes with high bootstrap support (98-100 %). Based on these results, we propose a novel family, Filobacteriaceae fam. nov., in the order Sphingobacteriales as well as a novel genus and species, Filobacterium rodentium gen. nov., sp. nov., for strain SMR-CT. The type strain is SMR-CT ( = JCM 19453T = DSM 100392T). PMID- 26476526 TI - Warmer temperatures reduce the costs of inducible defences in the marine toad, Rhinella marinus. AB - Many of the far-reaching impacts of climate change on ecosystem function will be due to alterations in species interactions. However, our understanding of the effects of temperature on the dynamics of interactions between species is largely inadequate. Inducible defences persist in prey populations because defensive traits increase survival in the presence of predators but are costly when they are absent. Large-scale changes in the thermal climate are likely to alter the costs or benefits of these defences for ectotherms, whose physiological processes are driven by environmental temperature. A shift in costs of defensive traits would affect not only predator-prey interactions, but also the strength of selection for inducible defences in natural populations. We investigate the effect of temperature on the costs of behavioural defences in larvae of the marine toad, Rhinella marinus. Larvae were reared in the presence or absence of predator cues at both 25 and 30 degrees C. When exposed to predation cues, larvae reduced activity and spent less time feeding. Exposure to predation cues also reduced metabolic rate, presumably as a by-product of reducing activity levels. Larvae exposed to predation cues also grew more slowly, were smaller at metamorphosis and were poorer jumpers after metamorphosis--three traits associated with fitness in post-metamorphic anurans. We found that the costs of behavioural defences, in terms of larval growth, post-metamorphic size and jumping performance, were exacerbated at cooler temperatures. The thermal sensitivity of costs associated with defensive traits may explain geographic variation in plasticity of defensive traits in other species and suggests that changes in environmental temperature associated with climate change may affect predator-prey interactions in subtle ways not previously considered. PMID- 26476527 TI - Engineering the intracellular metabolism of Escherichia coli to produce gamma aminobutyric acid by co-localization of GABA shunt enzymes. AB - OBJECTIVES: To direct the carbon flux from Krebs cycle into the gamma aminobutyric acid (GABA) shunt pathway for the production of GABA by protein scaffold introduction in Escherichia coli. RESULTS: Escherichia coli was engineered to produce GABA from glucose by the co-localization of enzymes succinate semialdehyde dehydrogenase (GadD), GABA aminotransferase (PuuE) and GABA transporter (GadC) by protein scaffold. 0.7 g GABA l(-1) was produced from 10 g glucose l(-1) while no GABA was produced in wild type E. coli. pH 6 and 30 degrees C were optimum for GABA production, and GABA concentration increased to 1.12 g GABA l(-1) when 20 g glucose l(-1) was used. When competing metabolic networks were inactivated, GABA increased by 24 % (0.87 g GABA l(-1)). CONCLUSIONS: The novel GABA production system was constructed by co-localization of GABA shunt enzymes. PMID- 26476528 TI - PLA nanovectors with encapsulated betulin: plant leaf extract-synthesized nanovectors are more efficacious than PVA-synthesized nanovectors. AB - OBJECTIVES: Betulin (BT) is an abundant triterpene found predominantly in the bark of Himalayan birch. It is difficult to deliver it in vivo because of its low aqueous solubility. We have therefore developed novel formulations of BT for improving its solubility, bioavailability and therapeutic efficacy. RESULTS: Poly D,L-lactide nanovectors (PLA NVs) were synthesized using poly(vinyl alcohol) and Lonicera japonica leaf extract (LE) as a stabiliser and named as PLA-1 NVs and PLA-2 NVs. PLA-1 NVs and PLA-2 NVs were used for the encapsulation of betulin (BT) and named as BT-En-1 and BT-En-2 NVs. The encapsulation efficiency of BT-En 1 and BT-En-2 NVs were 99.3 and 100 % respectively. Prepared nanoformulations were physically stable. An in vitro study revealed 45 % BT was released over 24 h. BT had a prolonged release from BT-En-2 NVs as compared to BT-En-1 NVs. BT-En 2 NVs had better anticancerous activity against SiHa cells than BT-En-1 NVs. CONCLUSIONS: Developed BT-EN-2 NVs had better biocompatibility, excellent stability and enhanced release characteristics than BT-En-1 NVs. PMID- 26476529 TI - Enhancement of medium-chain-length polyhydroxyalkanoates biosynthesis from glucose by metabolic engineering in Pseudomonas mendocina. AB - OBJECTIVES: To enhance the biosynthesis of medium-chain-length polyhydroxyalkanoates (PHAMCL) from glucose in Pseudomonas mendocina NK-01, metabolic engineering strategies were used to block or enhance related pathways. RESULTS: Pseudomonas mendocina NK-01 produces PHAMCL from glucose. Besides the alginate oligosaccharide biosynthetic pathway proved by our previous study, UDP-D glucose and dTDP-L-rhamnose biosynthetic pathways were identified. These might compete for glucose with the PHAMCL biosynthesis. First, the alg operon, galU and rmlC gene were deleted one by one, resulting in NK-U-1(?alg), NK-U-2 (?alg?galU), NK-U-3(alg?galU?rmlC). After fermentation for 36 h, the cell dry weight (CDW) and PHAMCL production of these strains were determined. Compared with NK-U: 1) NK-U-1 produced elevated CDW (from 3.19 +/- 0.16 to 3.5 +/- 0.11 g/l) and equal PHAMCL (from 0.78 +/- 0.06 to 0.79 +/- 0.07 g/l); 2) NK-U-2 produced more CDW (from 3.19 +/- 0.16 to 3.55 +/- 0.23 g/l) and PHAMCL (from 0.78 +/- 0.06 to 1.05 +/- 0.07 g/l); 3) CDW and PHAMCL dramatically decreased in NK-U-3 (1.53 +/- 0.21 and 0.41 +/- 0.09 g/l, respectively). Additionally, the phaG gene was overexpressed in strain NK-U-2. Although CDW of NK-U-2/phaG decreased to 1.29 +/- 0.2 g/l, PHA titer (%CDW) significantly increased from 24.5 % up to 51.2 %. CONCLUSION: The PHAMCL biosynthetic pathway was enhanced by blocking branched metabolic pathways in combination with overexpressing phaG gene. PMID- 26476530 TI - SSR markers: a tool for species identification in Psidium (Myrtaceae). AB - Molecular DNA markers are used for detection of polymorphisms in individuals. As they are independent of developmental stage of the plant and environmental influences, they can be useful tools in taxonomy. The alleles of simple sequence repeat (SSR) markers (or microsatellites) are traditionally used to identify taxonomic units. This application demands the laborious and costly delimitation of exclusive alleles in order to avoid homoplasy. Here, we propose a method for identification of species based on the amplification profile of groups of SSR markers obtained by a transferability study. The approach considers that the SSR are conserved among related species. In this context, using Psidium as a model, 141 SSR markers developed for Psidium guajava were transferred to 13 indigenous species of Psidium from the Atlantic Rainforest. Transferability of the markers was high and 28 SSR were conserved in all species. Four SSR groups were defined and they can help in the identification of all 13 Psidium species studied. A group of 31 SSR was genotyped, with one to six alleles each. The H0 varied from 0.0 to 0.46, and PIC from 0.0 to 0.74. Cluster analysis revealed shared alleles among species. The high percentage of SSR transferability found in Psidium evidences the narrow phylogenetic relationship existing among these species since transferability occurs by the preservation of the microsatellites and anchoring regions. The proposed method was useful for distinguishing the species of Psidium, being useful in taxonomic studies. PMID- 26476531 TI - Looking for a Symphony: A Sort of Essay with a Perspective on Activity Theories and the Ontology of Psychology: Learning from Danish and Russian Experiences by Jens Mammen & Irina Mironenko. AB - As a perspective on Mammen and Miroenkos the article is reflecting on the possibility of Activity Theory being a foundation on which Psychology could be integrated. Mammen and Miroenkos point that directed activity not only is towards objects "defined as a sum of qualities, but by individual reference" is a starting point. As a specific example the phenomenon Love, as "significant object relations", is related to the concept "choice categories". It is stated that relations of affection and love can't be understood independent of history of common activity, and that this makes the concept "choice categories" central in a psychological understanding of what love is. PMID- 26476532 TI - Modulation of protease-activated receptor expression by Porphyromonas gingivalis in human gingival epithelial cells. AB - BACKGROUND: Protease-activated receptors (PARs) are G-protein-coupled receptors with an active role in mediating inflammation, pain and other functions. The oral pathogen Porphyromonas gingivalis (P. gingivalis) secretes proteases that activate PARs. The aim of this study was to elucidate the role of PARs in the pathogenesis of chronic periodontitis by expression analysis of PARs in human gingival epithelial cells (GECs) before and after P. gingivalis supernatants treatment. METHODS: GECs were isolated from healthy human gingival tissue samples. The expression of PARs in GECs was determined by reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. The effect of P. gingivalis proteases was investigated by quantitative real-time reverse transcription polymerase chain reaction (QRT-PCR) and flow cytometry. RESULTS: PAR-1, PAR-2, and PAR-3 were expressed in GECs. PAR-4 was not found by both RT PCR and flow cytometry. Analysis of gene expression using QRT-PCR showed an up regulation of PAR-2 mRNA in comparison to the untreated control cells (P < 0.05). In contrast, the mRNA expressions of PAR-1 and PAR-3 were significantly down regulated (P > 0.05) in response to P. gingivalis supernatant compared to that in unstimulated control cells. This effect was abrogated by the protease inhibitor TLCK (P < 0.05). The results of flow cytometry indicated PARs protein levels consistent with mRNA levels in the results of QRT-PCR. CONCLUSIONS: Our study shows that PAR-1, PAR-2 and PAR-3 are expressed in GECs. P. gingivalis proteases play a role in the regulation of innate immune responses in GECs. GECs use PARs to recognize P. gingivalis and mediate cell responses involved in innate immunity. PMID- 26476533 TI - Naringin suppresses the metabolism of A375 cells by inhibiting the phosphorylation of c-Src. AB - Elevation of glycolysis, increase in lactic acid production, and enhancement of mitochondrial biogenesis are all the changes of energy metabolism of melanoma cells. Melanoma cells' metabolism and energy production networks play an important role in cancer proliferation, survival, motility, invasiveness, metastasis, and angiogenesis. Since the Warburg theory was put forward in the 1930s, more researchers focus on finding new ways for effectively eliminating cancer cells by targeting their energy metabolism. In this study, we found naringin has the inhibitory effects on the glucose metabolism of A375 cells, a melanoma cell line, in a concentration-dependent manner. We also found that naringin could significantly reduce the phosphorylation of c-Src. In summary, we demonstrated that naringin inhibits the malignant phenotype of A375 cells by suppressing c-Src and its downstream signaling pathway. More importantly, we provide the novel mechanism that, as a natural inhibitor of c-Src, naringin could be an effective candidate for the treatment of melanoma. PMID- 26476534 TI - TAB3 overexpression promotes cell proliferation in non-small cell lung cancer and mediates chemoresistance to CDDP in A549 cells via the NF-kappaB pathway. AB - Transforming growth factor-activated kinase 1 (TAK1)-binding protein 3 (TAB3) is essential for the activation of the nuclear factor kappa B (NF-kappaB) pathway and has important roles in cell survival. However, the contribution of TAB3 to non-small cell lung cancer (NSCLC) remains elusive. In the present study, Western blotting and immunohistochemistry assays demonstrated that TAB3 expression was frequently increased in NSCLC tissues and cells. In addition, chi-square test and Kaplan-Meier analysis revealed that upregulation of TAB3 expression correlated with a more invasive tumor phenotype and poor prognosis. In addition, a series of experiments, including serum starvation-refeeding experiment and TAB3-siRNA transfection assay, showed that TAB3 expression promoted NSCLC cell proliferation. Furthermore, the effect of TAB3 expression on the sensitivity to cis-diamminedichloroplatinum (CDDP) and possible signaling transduction pathways was investigated. When the expression of TAB3 was inhibited by siRNA transfection, the sensitivity to CDDP was enhanced. Moreover, it showed that downregulation of TAB3 enhanced CDDP-induced A549 cell apoptosis through the inhibition of the NF-kappaB pathway. These results suggest that TAB3 plays a critical role in NSCLC progression and chemoresistance and that TAB3 depletion may be a promising approach to lung cancer therapy. PMID- 26476535 TI - Interaction between p53 codon 72 and MDM2 309T>G polymorphisms and the risk of hepatocellular carcinoma. AB - The p53 tumor suppressor and its negative regulator, murine double minute 2 (MDM2), play critical roles in carcinogenesis. P53 codon 72 and MDM2 309T>G polymorphisms could influence p53 and MDM2 function, respectively, and might affect cancer susceptibility. We therefore investigated the association between these two SNPs, alone or in combination, and the risk of hepatocellular carcinoma (HCC) in Chinese. In this case-control study, we genotyped p53 codon 72 and MDM2 309T>G polymorphisms in 985 HCC cases and 992 cancer-free age- and sex-matched controls and evaluated their associations with the risk of HCC. Although no significant main effects were found for these two SNPs in the single-locus analysis and stratified analysis by age, sex, smoking, drinking, and hepatitis B virus (HBV) infection, we found that individuals carrying at least one G allele of the MDM2 309T>G polymorphism had statistically significant increased risk of HCC among those with the p53 Pro/Pro genotype (adjusted odds ratio (OR) = 2.23, 95 % confidence interval (95%CI) = 1.20-4.14 for TG genotype; adjusted OR = 2.67, 95%CI = 1.32-5.42 for GG genotype), and the interaction between p53 codon 72 and MDM2 309T>G was significant (P interaction = 0.017). Our findings suggest that the interaction of p53 codon 72 and MDM2 309T>G may play an important role in the etiology of HCC. More studies with well-designed and large sample sizes are required to validate these observations. PMID- 26476536 TI - Comparison of (18)F-fluorodeoxyglucose PET/CT findings with vascular endothelial growth factors and receptors in colorectal cancer. AB - The purpose of this study was to evaluate the association of (18)F fluorodeoxyglucose (FDG)-PET/CT findings with the vascular endothelial growth factor (VEGF) family and its receptor (VEGFR) levels in metastatic and nonmetastatic colorectal cancer (CRC). Fluorine-18 FDG-PET/CT scans were performed for initial staging and restaging of patients with CRC. FDG-PET/CT findings of tumor (such as the presence of a primary tumor, the lymphatic or distance metastases, and the maximum standardized uptake value (SUVmax) of the primary tumor), serum VEGF A-C-D-E levels, and serum VEGF receptor 1-2-3 levels were analyzed. A total of 63 patients were included into the study (35 males, mean age 61.3 +/- 11.9 years). Patients were divided into two groups, based on positive and negative PET/CT findings. Patients were also categorized according to the presence of metastasis. All evaluated parameters were significantly higher in the PET/CT-positive group than the PET/CT-negative group (p < 0.001). All those parameters were also positively correlated with each other. The highest correlation for SUVmax of primary tumor was found with VEGFR-3 (p < 0.001, r = 0.665). Patients with metastases had high levels of VEGF-D, VEGF-A, VEGF-C, VEGF E, and VEGFR-3 than those without metastases. These parameters had better specificity and sensitivity values than the SUVmax of the primary tumor for detection of metastases. However, VEGF-D was the best indicator of metastasis in all of those parameters (VEGF-D vs SUVmax; sensitivity 100 vs 100 %; specificity 76 vs 76 %; AUC 0.903 vs 0.835; p < 0.001, respectively). Vascular endothelial growth factor family and its receptors were significantly higher in metastatic CRC patients. VEGF-D was the best indicator of metastasis than all VEGF family, VEGFR-3, and primary tumor SUVmax. VEGF family (A-C-D-E) and VEGFR-3 may help to determine the prognosis and management of CRC. PMID- 26476537 TI - P50-associated COX-2 extragenic RNA (PACER) overexpression promotes proliferation and metastasis of osteosarcoma cells by activating COX-2 gene. AB - P50-associated cyclooxygenase-2 (COX-2) extragenic RNA (PACER) is a novel long noncoding RNA that has been found to activate the COX-2 gene, which may function as an oncogene in osteosarcoma. However, the role of PACER and the relationship between PACER and COX-2 in osteosarcoma progression have been unknown until now. Here, we examined the expression levels of PACER in clinical tumor samples and human osteosarcoma cell lines, assessed the functions of PACER in osteosarcoma cell proliferation and invasion, and then explored the mechanism of PACER dysregulation in osteosarcoma. The results showed that PACER was overexpressed in osteosarcoma tissues and cell lines compared with normal tissues and osteoblasts, respectively. PACER knockdown inhibited the proliferation and invasion of human osteosarcoma cells. Downregulation of PACER significantly suppressed the expression of COX-2, and the effects of PACER on cell proliferation and invasion were rescued by COX-2 overexpression. Furthermore, COX-2 activation by PACER was NF-kappaB-dependent. The regulation of PACER by CCCTC-binding factor (CTCF) was associated with DNA methylation status. Taken together, these findings suggest that PACER promotes proliferation and metastasis of osteosarcoma cells by activating the COX-2 gene and its own expression was influenced by DNA methylation. PMID- 26476538 TI - Overexpression of Hexokinase 1 as a poor prognosticator in human colorectal cancer. AB - It has been suggested that hexokinase 1 (HK1) is involved in tumorigenesis. However, the expression dynamics of HK1 and its prognostic significance in human colorectal cancer (CRC) still remain unclear. The aim of the present study was to investigate the expression of HK1 and its prognostic significance in CRC. In this study, immunohistochemical analysis was used to examine the expression dynamics of HK1 in CRC tissues from two independent cohorts. Receiver operating characteristic curve analysis, Kaplan-Meier curves, and Cox regression analysis were utilized to investigate the prognostic significance. Results showed that a high expression of HK1 was observed in 106 of 393 (27.0 %) and 69 of 229 (30.1 %) of CRC in the training cohort and validation cohort, respectively. Further correlation analyses indicated that the increased HK1 expression was strongly correlated with the pN classification and TNM stage. Both cohorts showed a close association between the overexpression of HK1 and poorer overall survival. Importantly, multivariate analysis identified HK1 expression in CRC as an independent prognostic factor. Overexpression of HK1 may act as a significant biomarker of poor prognosis for patients with CRC. PMID- 26476539 TI - Apoptotic effects of salinomycin on human ovarian cancer cell line (OVCAR-3). AB - In this study, we studied the apoptotic and cytotoxic effects of salinomycin on human ovarian cancer cell line (OVCAR-3) as salinomycin is known as a selectively cancer stem cell killer agent. We used immortal human ovarian epithelial cell line (IHOEC) as control group. Ovarian cancer cells and ovarian epithelial cells were treated by different concentrations of salinomycin such as 0.1, 1, and 40 MUM and incubated for 24, 48, and 72 h. Dimethylthiazol (MTT) cell viability assay was performed to determine cell viability and toxicity. On the other hand, the expression levels of some of the apoptosis-related genes, namely anti apoptotic Bcl-2, apoptotic Bax, and Caspase-3 were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, Caspase-3 protein level was also determined. As a result, we concluded that incubation of human OVCAR-3 by 0.1 MUM concentration of salinomycin for 24 h killed 40 % of the cancer cells by activating apoptosis but had no effect on normal cells. The apoptotic Bax gene expression was upregulated but anti-apoptotic Bcl-2 gene expression was downregulated. Active Caspase-3 protein level was increased significantly (p < 0.05). PMID- 26476540 TI - T cells in tumor microenvironment. AB - Tumors progress in a specific area, which supports its development, spreading or shrinking in time with the presence of different factors that effect the fate of the cancer cells. This specialized site is called "tumor microenvironment" and has a composition of heterogenous materials. The immune cells are also residents of this stromal, cancerous, and inflammatory environment, and their types, densities, or functional differences are one of the key factors that mediate the fate of a tumor. T cells as a vital part of the immune system also are a component of tumor microenvironment, and their roles have been elucidated in many studies. In this review, we focused on the immune system components by focusing on T cells and detailed T helper cell subsets in tumor microenvironment and how their behaviors affect either the tumor or the patient's outcome. PMID- 26476541 TI - Low pretreatment serum globulin may predict favorable prognosis for gastric cancer patients. AB - An elevated serum albumin (ALB) and albumin/globulin ratio (AGR) have been reported to be associated with a favorable prognosis for several types of cancer. However, little is known about prognostic significance of globulin (GLB) in gastric cancer patients. The purpose of this study was to evaluate whether GLB, ALB, and AGR analysis could predict the prognosis of patients with gastric cancer. A retrospective cohort of 186 patients with gastric cancer followed by radical surgery was recruited between January 2007 and December 2010. Levels for preoperative GLB and ALB were obtained and used to calculate the AGR. Survival analysis was used to evaluate the predictive value of GLB, ALB, and AGR. X-tile program determined 37.6, 33.4, and 1.33 as the optimal cutoff value for ALB, GLB, and AGR in terms of survival. Univariate analysis revealed that low GLB levels were significantly associated with favorable survival (P = 0.045). Conversely, low ALB levels were associated with a significantly worse survival (P = 0.000). In conclusion, low preoperative GLB level may serve as a valuable marker to predict the prognosis of gastric cancer patients. PMID- 26476542 TI - Epidemiology of Patients with Ovarian Cancer with and Without a BRCA1/2 Mutation. AB - Ovarian cancer survival rates have improved only slightly in recent decades; however, treatment of this disease is expected to undergo rapid change as strategies incorporating molecular-targeted therapies enter clinical practice. Carriers of deleterious mutations (defined as a harmful mutation) in either the BRCA1 or BRCA2 gene (BRCAm) have a significantly increased risk of developing ovarian cancer. Epidemiology data in large (>500 patients) unselected ovarian cancer populations suggest that the expected incidence rate for BRCAm in this population is 12-14 %. Patients with a BRCAm are typically diagnosed at a younger age than those without a BRCAm. Associations with BRCAm vary according to ethnicity, with women of Ashkenazi Jewish descent being 10 times more likely to have a BRCAm than the general population. In terms of survival, patients with invasive epithelial ovarian cancer who have a BRCAm may have improved overall survival compared with patients who do not carry a BRCAm. Although genetic testing for BRCAm remains relatively uncommon in ovarian cancer patients, testing is becoming cheaper and increasingly accessible; however, this approach is not without numerous social, ethical and policy issues. Current guidelines recommend BRCAm testing in specific ovarian cancer patients only; however, with the emergence of treatments that are targeted at patients with a BRCAm, genetic testing of all patients with high-grade serous ovarian cancer may lead to improved patient outcomes in this patient population. Knowledge of BRCAm status could, therefore, help to inform treatment decisions and identify relatives at increased risk of developing cancer. PMID- 26476543 TI - Clinical Evaluation of a Novel Nine-Gene Panel for Ion Torrent PGM Sequencing of Myeloid Malignancies. AB - BACKGROUND AND OBJECTIVE: In the last decade, a number of genes have been reported to be recurrently associated with myeloid malignancies. While some mutations are easily detectable by conventional molecular genetics methods, other mutations are more difficult to screen because of lower frequency and being scattered along large genomic ranges. However, newly developed approaches for next-generation sequencing provide an affordable solution for targeted multiplex resequencing of up to several hundreds of amplicons. Here, we aimed to develop and validate a novel custom panel for targeted resequencing of myeloid malignancy samples using the Ion PGM(TM) System (Ion Torrent, Paisley, UK). METHODS: We designed a pool of 424 primers for the amplification of 212 amplicons covering 99.46 % of the exonic regions of nine human genes as follows: ASXL1, EZH2, CALR, RUNX1, SETBP1, SF3B1, SRSF2, TET2, and U2AF1. Initial testing of the panel performance was performed on an Ion PGM(TM) machine using PGM(TM) 316 v2 chips on 16 DNA samples from patients with myeloid malignancies. Sequence alignment, variant calling, and annotation were performed using Ion Reporter software. RESULTS: We identified a total of 14 nonsynonymous somatic coding variants in seven samples affecting six of the genes in the panel (ASXL1, CALR, RUNX1, SRSF2, TET2, and U2AF1). Notably, three of the identified mutations were not present in the Cosmic v.67 release. CONCLUSION: This proof-of-concept study confirms the feasibility of Ion Torrent systems for resequencing of clinically relevant mutations in myeloid malignancies. It can be particularly useful in cases without the most frequent clonal markers. PMID- 26476545 TI - Determination of the maximum rate of eccrine sweat glands' ion reabsorption using the galvanic skin conductance to local sweat rate relationship. AB - PURPOSE: The purpose of the present study was to develop and describe a simple method to evaluate the rate of ion reabsorption of eccrine sweat glands in human using the measurement of galvanic skin conductance (GSC) and local sweating rate (SR). This purpose was investigated by comparing the SR threshold for increasing GSC with following two criteria of sweat ion reabsorption in earlier studies such as (1) the SR threshold for increasing sweat ion was at approximately 0.2-0.5 mg/cm2/min and (2) exercise heat acclimation improved the sweat ion reabsorption ability and would increase the criteria 1. METHODS: Seven healthy non-heat acclimated male subjects received passive heat treatment both before and after 7 days of cycling in hot conditions (50% maximum oxygen uptake, 60 min/day, ambient temperature 32 degrees C, and 50% relative humidity). RESULTS: Subjects became partially heat-acclimated, as evidenced by the decreased end-exercise heart rate (p < 0.01), rate of perceived exhaustion (p < 0.01), and oesophageal temperature (p = 0.07), without alterations in whole body sweat loss, from the first to the last day of training. As hypothesized, we confirmed that the SR threshold for increasing GSC was near the predicted SR during passive heating before exercise heat acclimation, and increased significantly after training (0.19 +/- 0.09-0.32 +/- 0.10 mg/cm2/min, p < 0.05). CONCLUSIONS: The reproducibility of sweat ion reabsorption by the eccrine glands in the present study suggests that the relationship between GSC and SR can serve as a new index for assessing the maximum rate of sweat ion reabsorption of eccrine sweat glands in humans. PMID- 26476544 TI - Association of Vascular Endothelial Growth Factor A (VEGFA) and its Receptor (VEGFR2) Gene Polymorphisms with Risk of Chronic Myeloid Leukemia and Influence on Clinical Outcome. AB - INTRODUCTION: Vascular endothelial growth factor A (VEGFA) and its kinase insert domain receptor (VEGFR2/KDR) were reported to be upregulated in chronic myeloid leukemia (CML); however, the influence of polymorphisms in VEGFA and VEGFR2 in CML pathogenesis and therapeutic response, have not yet been elucidated. METHODS: We aimed to analyze these polymorphisms in 212 CML patients and 212 healthy controls by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. RESULTS: The VEGFA+936C>T polymorphism did not differ significantly between the CML patients and controls. The frequency of CT genotype was higher in CML patients than in controls (25 vs. 18%), higher in males than in females (29 vs. 18%), was more prevalent in the patients with splenomegaly (p = 0.03), and was negatively associated with lactate dehydrogenase (LDH) levels (p = 0.01). The frequency of VEGFR2 mutant T-allele was higher in CML patients than controls (p < 0.0001). In the dominant model, patients having the combined AT and TT genotypes were associated with 2.6-fold higher risk of CML [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.71-3.97, p < 0.0001]. VEGFR2 AT genotype was significantly associated with high blast count (p = 0.006), minor hematological response (p = 0.03) and poor cytogenetic response (p = 0.003), indicating its role in therapeutic resistance. In contrast, poor molecular response was observed in patients with TT genotype (p = 0.02). VEGFA+936C>T polymorphism was found to have synergistic interaction with VEGFR2+1416A>T in inflating the risk for CML further (P(interaction) = 0.0002). CONCLUSION: Our results indicate that VEGFR2+1416A>T polymorphism may be a useful marker in assessing the disease progression in CML patients. In addition, VEGFA+936C>T was observed to have additive effect in inflating the risk further. PMID- 26476546 TI - Gender differences in power production, energetic capacity and efficiency of elite cross-country skiers during whole-body, upper-body, and arm poling. AB - PURPOSE: To characterize gender differences in power output, energetic capacity and exercise efficiency during whole-body (WP), upper-body (UP), and arm poling (AP). METHODS: Ten male and ten female elite cross-country skiers, matched for international performance level, completed three incremental submaximal tests and a 3-min self-paced performance test on a Concept2 SkiErg. Power output, cardiorespiratory and kinematic variables were monitored. Body composition was determined by dual-energy X-ray absorptiometry. RESULTS: The men demonstrated 87, 97 and 103% higher power output, and 51, 65 and 71% higher VO2peak (L min(-1)) than the women during WP, UP and AP, respectively, while utilizing ~10% more of their running VO2max in all modes (all P < 0.001). The men had 35, 38 and 59% more lean mass in the whole body, upper body and arms (all P < 0.001). The men exhibited greater shoulder and elbow extension at the start of poling and greater trunk flexion at the end of poling (all P < 0.05). The relationship between VO2 and power output did not differ between the men and women. CONCLUSIONS: Gender differences in power production and peak aerobic capacity increased sequentially from WP to UP to AP, coinciding with a greater portion of the muscle mass in the arms of the men. Although the men and women employed each poling technique differently, the estimated efficiency of double poling was independent of gender. PMID- 26476547 TI - Effect of APAP and heated humidification with a heated breathing tube on adherence, quality of life, and nasopharyngeal complaints. PMID- 26476548 TI - Response to "Effect of APAP and heated humidification with a heated breathing tube on adherence, quality of life, and nasopharyngeal complaints". PMID- 26476549 TI - Severe community-acquired pneumonia and positive urinary antigen test for S. pneumoniae: amoxicillin is associated with a favourable outcome. AB - Positive urinary antigen tests (UAT) for pneumococcal infection in community acquired pneumonia (CAP) may lead to targeted antibiotic therapy. We report an audit aimed at defining the link between mortality and targeted therapy. We conducted a retrospective multicentre audit of patients with severe CAP for whom a UAT was positive for S. pneumoniae. Patients admitted from January 2010 to December 2013 to 8 medical centres (from A to H) were included. Co-morbidities were defined by the specific treatment administered before hospital care, or if the diagnosis was newly established during the hospital stay. We used the Pneumonia Severity Index (PSI) to assess disease severity. Only patients with PSI > 90 were included. Antibiotic treatments and the PSI were extracted from patients' charts. Amoxicillin had to be prescribed as a targeted antibiotic treatment or at the time of antibiotic reassessment. A total of 389 patients were included. The mean (+/-STD) PSI score was 128 +/- 29; 38.9% of the patients had a class 5 PSI score. Intensive care was required for 36.6% of the patients. Amoxicillin was initially prescribed in 47 cases (12.1%) and in 34 cases after reassessment (8.7%). In logistic regression analysis, we found three parameters associated with mortality: being hospitalised in institution D, class 5 PSI score, and metastatic cancer. In contrast, three antibiotic regimens were protective factors, including targeted therapy: OR = 0.09, p < 0.001. In the context of severe CAP with positive UAT for S. pneumoniae, targeted therapy was associated with a reduction in mortality. PMID- 26476551 TI - Amplicon-Based Pyrosequencing Reveals High Diversity of Protistan Parasites in Ships' Ballast Water: Implications for Biogeography and Infectious Diseases. AB - Ships' ballast water (BW) commonly moves macroorganisms and microorganisms across the world's oceans and along coasts; however, the majority of these microbial transfers have gone undetected. We applied high-throughput sequencing methods to identify microbial eukaryotes, specifically emphasizing the protistan parasites, in ships' BW collected from vessels calling to the Chesapeake Bay (Virginia and Maryland, USA) from European and Eastern Canadian ports. We utilized tagged amplicon 454 pyrosequencing with two general primer sets, amplifying either the V4 or V9 domain of the small subunit (SSU) of the ribosomal RNA (rRNA) gene complex, from total DNA extracted from water samples collected from the ballast tanks of bulk cargo vessels. We detected a diverse group of protistan taxa, with some known to contain important parasites in marine systems, including Apicomplexa (unidentified apicomplexans, unidentified gregarines, Cryptosporidium spp.), Dinophyta (Blastodinium spp., Euduboscquella sp., unidentified syndinids, Karlodinium spp., Syndinium spp.), Perkinsea (Parvilucifera sp.), Opisthokonta (Ichthyosporea sp., Pseudoperkinsidae, unidentified ichthyosporeans), and Stramenopiles (Labyrinthulomycetes). Further characterization of groups with parasitic taxa, consisting of phylogenetic analyses for four taxa (Cryptosporidium spp., Parvilucifera spp., Labyrinthulomycetes, and Ichthyosporea), revealed that sequences were obtained from both known and novel lineages. This study demonstrates that high-throughput sequencing is a viable and sensitive method for detecting parasitic protists when present and transported in the ballast water of ships. These data also underscore the potential importance of human-aided dispersal in the biogeography of these microbes and emerging diseases in the world's oceans. PMID- 26476550 TI - Recommendations for the diagnosis of pediatric tuberculosis. AB - Tuberculosis (TB) is still the world's second most frequent cause of death due to infectious diseases after HIV infection, and this has aroused greater interest in identifying and managing exposed subjects, whether they are simply infected or have developed one of the clinical variants of the disease. Unfortunately, not even the latest laboratory techniques are always successful in identifying affected children because they are more likely to have negative cultures and tuberculin skin test results, equivocal chest X-ray findings, and atypical clinical manifestations than adults. Furthermore, they are at greater risk of progressing from infection to active disease, particularly if they are very young. Consequently, pediatricians have to use different diagnostic strategies that specifically address the needs of children. This document describes the recommendations of a group of scientific societies concerning the signs and symptoms suggesting pediatric TB, and the diagnostic approach towards children with suspected disease. PMID- 26476552 TI - Quantifying landscape pattern and assessing the land cover changes in Piatra Craiului National Park and Bucegi Natural Park, Romania, using satellite imagery and landscape metrics. AB - Protected areas of Romania have enjoyed particular importance after 1989, but, at the same time, they were subject to different anthropogenic and natural pressures which resulted in the occurrence of land cover changes. These changes have generally led to landscape degradation inside and at the borders of the protected areas. In this article, 12 landscape metrics were used in order to quantify landscape pattern and assess land cover changes in two protected areas, Piatra Craiului National Park (PCNP) and Bucegi Natural Park (BNP). The landscape metrics were obtained from land cover maps derived from Landsat Thematic Mapper (TM) and Landsat Enhanced Thematic Mapper Plus (ETM+) images from 1987, 1993, 2000, 2009 and 2010. Three land cover classes were analysed in PCNP and five land cover map classes in BNP. The results show a landscape fragmentation trend for both parks, affecting different types of land covers. Between 1987 and 2010, in PCNP fragmentation was, in principle, the result not only of anthropogenic activities such as forest cuttings and illegal logging but also of natural causes. In BNP, between 1987 and 2009, the fragmentation affected the pasture which resulted in the occurrence of bare land and rocky areas because of the erosion on the Bucegi Plateau. PMID- 26476553 TI - Our red-green world. PMID- 26476554 TI - Evaluation of the Synergistic Effect Between Ethyl Formate and Phospine for Control of Aphis gossypii (Homoptera: Aphididae). AB - Cotton aphid, Aphis gossypii Glover, is known as a quarantine pest that is hard to control with short periods of fumigation with phosphine (PH(3)) or low concentrations of ethyl formate. Moreover, low-temperature fumigation with ethyl formate can lead to phototoxic damage of some perishable commodities. Therefore, a laboratory study was conducted to evaluate the synergistic effect of mixing ethyl formate and PH(3) for the treatment of adults and nymphs of A. gossypii. Combined toxicity was observed and compared with a single dose of eitherrethyl formate or PH(3). When insects were exposed to 0.5 g/m(3) of PH(3) combined with different levels of ethyl formate from 1.6 to 16.3 g/m(3) at 5 and 20C for 2 h, L(Ct)(50) and L(Ct)(99) values were greatly reduced in comparison with a single dose of either ethyl formate or PH(3). The synergistic ratio (SR) is described as L(Ct) of ethyl formate alone/L(Ct) of ethyl formate + PH(3). The SR values of L(Ct)(50) and L(Ct)(99) for adult A. gossypii at 5C were 4.55 and 2.33, respectively. However, at 20C the SR levels of L(Ct)(50) and L(Ct)(99) were 2.22 and 1.45, respectively, but still showed significant synergism (significant difference, P<0.5). This new technology could meet quarantine and preshipment requirements for shorter exposure times and less damage of perishable commodities, and could also be extended for controlling other quarantine pests and thereby be a useful alternative to methyl bromide for fruit and vegetable applications. PMID- 26476555 TI - Comparative Growth and Survival of Hylurgus ligniperda (Coleoptera: Scolytinae) and Arhopalus ferus (Coleoptera: Cerambycidae) Reared on Artificial or Natural Diet at 15 or 25 degrees C. AB - Two saproxylic forest insects, Hylurgus ligniperda (F.) (Coleoptera: Scolytinae) and Arhopalus ferus (Mulsant)(Coleoptera: Cerambycidae), were reared on artificial or natural diet at 15 or 25 degrees C to compare larval growth rates and survival. A significant diet by temperature interaction was observed in the growth of H. ligniperda larvae,which developed faster when reared on natural diet at 15 degrees C, but grew faster and pupated significantly earlier when reared on artificial diet at 25 degrees C. However, H. ligniperda survival by the end of the experiment was low on both diets when reared at 25 degrees C (10.1%, 95% CI: 5.2-15.1%), which suggests that rearing at lower temperatures may be required. A. ferus larvae gained significantly larger body size when reared on artificial diet than on natural diet at both temperatures. Survival of A. ferus reared on artificial diet was significantly lower than larvae reared on natural diet at 25 degrees C. The significant differences between A. ferus larval development rates when reared on artificial and natural diets preclude the use of artificial diet to collect meaningful data to construct temperature development models for ecological comparisons. Artificial diet provided a suitable medium for mass production of individuals for research purposes, e.g., test mortality in response to treatments. However, additional rearing studies are needed to determine whether the larger artificially reared larvae result in adults that are healthier, more productive, and live longer. PMID- 26476556 TI - Pollen Contaminated With Field-Relevant Levels of Cyhalothrin Affects Honey Bee Survival, Nutritional Physiology, and Pollen Consumption Behavior. AB - Honey bees are exposed to a variety of environmental factors that impact their health, including nutritional stress, pathogens, and pesticides. In particular, there has been increasing evidence that sublethal exposure to pesticides can cause subtle, yet important effects on honey bee health and behavior. Here, we add to this body of knowledge by presenting data on bee-collected pollen containing sublethal levels of cyhalothrin, a pyrethroid insecticide, which, when fed to young honey bees, resulted in significant changes in lifespan, nutritional physiology,and behavior. For the first time, we show that when young, nest-aged bees are presented with pollen containing field-relevant levels of cyhalothrin, they reduce their consumption of contaminated pollen. This indicates that, at least for some chemicals, young bees are able to detect contamination in pollen and change their behavioral response, even if the contamination levels do not prevent foraging honey bees from collecting the contaminated pollen. PMID- 26476557 TI - The Effect of an Interspersed Refuge on Aphis glycines (Hemiptera: Aphididae), Their Natural Enemies, and Biological Control. AB - Soybean production in the north central United States has relied heavily on the use of foliar and seed applied insecticides to manage Aphis glycines (Hemiptera: Aphididae). An additional management strategy is the use soybean cultivars containing A. glycines resistance genes (Rag). Previous research has demonstrated that Rag cultivars are capable of preventing yield loss equivalent to the use of foliar and seed-applied insecticides.However, the presence of virulent biotypes in North America has raised concern for the durability of Rag genes. A resistance management program that includes a refuge for avirulent biotypes could limit the frequency at which virulent biotypes increase within North America. To what extent such a refuge reduces the effectiveness of aphid-resistant soybean is not clear. We conducted an experiment to determine whether a susceptible refuge mixed into resistant soybean (i.e., interspersed refuge or refuge-in-a-bag) affects the seasonal exposure of aphids, their natural enemies, biological control, and yield protection provided by aphid resistance. We compared three ratios of interspersed refuges (resistant: susceptible; 95:5, 90:10, 75:25) to plots grown with 100%susceptible or resistant soybean. We determined that an interspersed refuge of at least 25% susceptible seed would be necessary to effectively produce avirulent individuals. Interspersed refuges had negligible effects onyield and the natural enemy community. However, there was evidence that they increased the amount of biological control that occurred within a plot. We discuss the compatibility of interspersed refuges for A. glycines management and whether resistance management can prolong the durability of Rag genes. PMID- 26476558 TI - Insecticide Efficacy and Timing for Control of Western Bean Cutworm (Lepidoptera: Noctuidae) in Dry and Snap Beans. AB - The western bean cutworm, Striacosta albicosta (Smith) (Lepidoptera: Noctuidae), is a recent pest of corn, dry,and snap beans, in the Great Lakes region, and best practices for its management in beans need to be established.Insecticide efficacy and application timing field studies, conducted in 2011-2013, determined that lambda-cyhalothrin and chlorantraniliprole were capable of reducing western bean cutworm feeding damage in dry beans from 2.3 to 0.4% in preharvest samples, and in snap beans from 4.8 to 0.1% of marketable pods, respectively. The best application timing in dry beans was determined to be 4-18 d after 50% egg hatch. No economic benefit was found when products were applied to dry beans, and despite high artificial inoculation rates, damage to marketable yield was relatively low. Thiamethoxam, methoxyfenozide, and spinetoram were also found to be effective at reducing western bean cutworm damage in dry bean to as low as 0.3% compared to an untreated control with 2.5% damaged pods. In snap beans, increased return on investment between CAD$400 and CAD$600 was seen with multiple applications of lambda-cyhalothrin, and with chlorantraniliprole applied 4 d after egg mass infestation. PMID- 26476559 TI - Dry Dog Food Integrity and Mite Strain Influence the Density-Dependent Growth of the Stored-Product Mite Tyrophagus putrescentiae (Acari: Acaridida). AB - The infestation of foodstuffs by mites is connected to health risks and economic losses. The cosmopolitan stored-product mite Tyrophagus putrescentiae (Schrank, 1781) is an emerging and predominant pest of dry dog food. In this study, the influences on mite population growth of 1) the different dry dog food kernels present in the package; 2) the integrity of the dry dog food kernel, whether intact or crushed; 3) the initial population density of 10 or 100 specimens; and 4) the four mite strains used were investigated under laboratory conditions. The population growth tests were performed for 28 d at 85% relative humidity and 25 degrees C. The intrinsic growth rates of the mites were compared. The population growth was higher on the brown and green kernels than on the red and white kernels. The kernel integrity affected the population growth, and the integrity effect was highly influenced by the initial mite population density. The mites showed density-dependent growth in three of the four mite strains tested. The initial population density changed the population growth ranking among the mite strains, thereby indicating strain-specific density-dependent growth. The results of this study have important implications for predictive models of stored-product mite populations in dry dog food. One practical recommendation is that the growth of mites should be considered with regard to the mite strains and according to the strain-specific density dependent growth. Next, the integrity of the kernels should be maintained because disrupted or crushed kernels promote increases in mite populations. PMID- 26476560 TI - Urinary symptoms following external beam radiotherapy of the prostate: Dose symptom correlates with multiple-event and event-count models. AB - BACKGROUND AND PURPOSE: This study aimed to compare urinary dose-symptom correlates after external beam radiotherapy of the prostate using commonly utilised peak-symptom models to multiple-event and event-count models which account for repeated events. MATERIALS AND METHODS: Urinary symptoms (dysuria, haematuria, incontinence and frequency) from 754 participants from TROG 03.04 RADAR trial were analysed. Relative (R1-R75 Gy) and absolute (A60-A75Gy) bladder dose-surface area receiving more than a threshold dose and equivalent uniform dose using exponent a (range: a ?[1 ... 100]) were derived. The dose-symptom correlates were analysed using; peak-symptom (logistic), multiple-event (generalised estimating equation) and event-count (negative binomial regression) models. RESULTS: Stronger dose-symptom correlates were found for incontinence and frequency using multiple-event and/or event-count models. For dysuria and haematuria, similar or better relationships were found using peak-symptom models. Dysuria, haematuria and high grade (? 2) incontinence were associated to high dose (R61-R71 Gy). Frequency and low grade (? 1) incontinence were associated to low and intermediate dose-surface parameters (R13-R41Gy). Frequency showed a parallel behaviour (a=1) while dysuria, haematuria and incontinence showed a more serial behaviour (a=4 to a ? 100). Relative dose-surface showed stronger dose symptom associations. CONCLUSIONS: For certain endpoints, the multiple-event and event-count models provide stronger correlates over peak-symptom models. Accounting for multiple events may be advantageous for a more complete understanding of urinary dose-symptom relationships. PMID- 26476561 TI - Impact of tumour invasion on seminal vesicles mobility in radiotherapy of prostate cancer. AB - PURPOSE: Mobility of the seminal vesicles relative to the prostate challenges adequate dose coverage. The aim of this study was to assess the impact of tumour invasion on SV mobility. METHODS AND MATERIALS: Three groups of 30 prostate cancer patients with (1) no invasion on MR, (2) minimal invasion (<5mm), and (3) extensive invasion (>5mm) were studied. Translations and rotations of the SV were measured with CBCT and compared between the three groups. RESULTS: In the extensive group the random SV translations were significantly lower in comparison with the no invasion group in the LR: 0.15 vs 0.16 cm (p=0.015), CC: 0.17 vs 0.23 cm (p=0.004) and AP direction: 0.19 vs 0.26 cm (p=0.002). Also the random SV rotation on the LR axis was significantly lower: 5.2 vs 6.3 degrees (p=0.035). In comparison with the minimal invasion group the random SV translations were significantly lower in the extensive group in the CC: 0.17 vs 0.24 cm (p=0.001) and AP direction 0.19 vs 0.31 cm (p=0.007) and for the rotation on the LR axis: 5.2 vs 6.5 degrees (p=0.043). CONCLUSION: Increasing tumour invasion in the SV reduces the mobility of the SV, however the mobility remains considerable. PMID- 26476562 TI - Dynamics of the HPA axis and inflammatory cytokines: Insights from mathematical modeling. AB - In the work presented here, a novel mathematical model was developed to explore the bi-directional communication between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory cytokines in acute inflammation. The dynamic model consists of five delay differential equations 5D for two main pro-inflammatory cytokines (TNF-alpha and IL-6) and two hormones of the HPA axis (ACTH and cortisol) and LPS endotoxin. The model is an attempt to increase the understanding of the role of primary hormones and cytokines in this complex relationship by demonstrating the influence of different organs and hormones in the regulation of the inflammatory response. The model captures the main qualitative features of cytokine and hormone dynamics when a toxic challenge is introduced. Moreover, in this work a new simple delayed model of the HPA axis is introduced which supports the understanding of the ultradian rhythm of HPA hormones both in normal and infection conditions. Through simulations using the model, the role of key inflammatory cytokines and cortisol in transition from acute to persistent inflammation through stability analysis is investigated. Also, by employing a Markov chain Monte Carlo (MCMC) method, parameter uncertainty and the effects of parameter variations on each other are analyzed. This model confirms the important role of the HPA axis in acute and prolonged inflammation and can be a useful tool in further investigation of the role of stress on the immune response to infectious diseases. PMID- 26476563 TI - Live poultry market workers are susceptible to both avian and swine influenza viruses, Guangdong Province, China. AB - Guangdong Province is recognized for dense populations of humans, pigs, poultry and pets. In order to evaluate the threat of viral infection faced by those working with animals, a cross-sectional, sero-epidemiological study was conducted in Guangdong between December 2013 and January 2014. Individuals working with swine, at poultry farms, or live poultry markets (LPM), and veterinarians, and controls not exposed to animals were enrolled in this study and 11 (4 human, 3 swine, 3 avian, and 1 canine) influenza A viruses were used in hemagglutination inhibition (HI) assays (7 strains) and the cross-reactivity test (9 strains) in which 5 strains were used in both tests. Univariate analysis was performed to identify which variables were significantly associated with seropositivity. Odds ratios (OR) revealed that swine workers had a significantly higher risk of elevated antibodies against A/swine/Guangdong/L6/2009(H1N1), a classical swine virus, and A/swine/Guangdong/SS1/2012(H1N1), a Eurasian avian-like swine virus than non-exposed controls. Poultry farm workers were at a higher risk of infection with avian influenza H7N9 and H9N2. LPM workers were at a higher risk of infection with 3 subtypes of avian influenza, H5N1, H7N9, and H9N2. Interestingly, the OR also indicated that LPM workers were at risk of H1N1 swine influenza virus infection, perhaps due to the presence of pigs in the LPM. While partial confounding by cross-reactive antibodies against human viruses or vaccines cannot be ruled out, our data suggests that animal exposed people as are more likely to have antibodies against animal influenza viruses. PMID- 26476564 TI - Effect of age and inoculation route on the infection of duck Tembusu virus in Goslings. AB - Duck Tembusu virus (TMUV) is an emerging flavivirus that has caused variable levels of outbreaks in poultry in recent years. In order to study the effect of age and inoculation routes on the TMUV infection, one hundred healthy domestic 5 day-old and 20-day-old goslings were equally divided into five groups and four experimental groups of goslings were infected with the TMUV-SDSG strain by intravenous and intranasal routes, respectively. Severe clinical signs were observed in goslings infected at 5 days of age, including listlessness, growth retardation, severe neurological dysfunction and even death. However, goslings infected at 20 days of age showed mild symptoms and no mortality. The severity of gross lesions gradually reduced as goslings matured. The severe histopathological changes were observed in 5-day-old infected goslings, including cerebral edema, viral encephalitis, myocardial necrosis, hepatic steatosis, spleen lymphoid cell depletion, pancreatic epithelial cell shedding and interstitial hemorrhage. However, 20-day-old infected goslings showed mild histopathological changes. Viral loads in different tissues were detected by the SYBR Green I real-time PCR assay. The level of viral loads in most of tissues 5-day-old infected goslings was higher than that of 20-day-old infected goslings, correlating with the severity of clinical symptoms and lesions in these tissues. 20-day-old infected goslings developed significantly higher serum neutralizing antibody titers than 5 day-old infected goslings. Furthermore, goslings infected with TMUV intravenously demonstrated more severe clinical signs, lesions and higher viral loads in tissues than those of goslings infected with TMUV intranasally. Therefore, age and inoculation routes can affect the pathogenicity of TMUV in geese and younger geese are more susceptible to the virus. Age and inoculation route factors should be considered in study of the pathogenicity, pathogenesis, folumation of prevention and therapy strategies of TMUV infection in geese. PMID- 26476568 TI - Tumor budding in colorectal cancer--ready for diagnostic practice? AB - Tumor budding is an important additional prognostic factor for patients with colorectal cancer (CRC). Defined as the presence of single tumor cells or small clusters of up to 5 cells in the tumor stroma, tumor budding has been likened to an epithelial-mesenchymal transition. Based on well-designed retrospective studies, tumor budding is linked to adverse outcome of CRC patients in 3 clinical scenarios: (1) in malignant polyps, detection of tumor buds is a risk factor for lymph node metastasis indicating the need for colorectal surgery; (2) tumor budding in stage II CRC is a highly adverse prognostic indicator and may aid patient selection for adjuvant therapy; (3) in the preoperative setting, presence of tumor budding in biopsy material may help to identify high-risk rectal cancer patients for neoadjuvant therapy. However, lack of consensus guidelines for standardized assessment still limits reporting in daily diagnostic practice. This article provides a practical and comprehensive overview on tumor budding aimed at the practicing pathologist. First, we review the prognostic value of tumor budding for the management of colon and rectal cancer patients. Second, we outline a practical, evidence-based proposal for the assessment of tumor budding in the daily sign-out. Last, we summarize the current knowledge of the molecular characteristics of high-grade budding tumors in the context of personalized treatment approaches and biomarker discovery. PMID- 26476567 TI - Renal carcinoma associated with a novel succinate dehydrogenase A mutation: a case report and review of literature of a rare subtype of renal carcinoma. AB - Renal cell carcinoma (RCC) linked to germline mutation of succinate dehydrogenase subunits A, B, C, and D (SDHA, SDHB, SDHC, and SDHD, respectively) has been recently included as a provisional entity in the 2013 International Society of Urological Pathology Vancouver classification. Most SDH-deficient tumors show SDHB mutation, with only a small number of RCC with SDHC or SDHD having been reported to date. Only one case of SDH-deficient renal carcinoma known to be SDHA mutated has been previously reported. Here we report an additional RCC harboring an SDHA mutation occurring in a 62-year-old man with right flank pain and nodal metastasis. The tumor was characterized by an infiltrative pattern with solid, acinar, and papillary components. Loss of SDHA and SDHB protein by immunohistochemistry confirmed the diagnosis. Hybrid capture-based comprehensive genomic profiling identified 3 genomic alterations in tumor tissue: (i) a novel single-nucleotide splice site deletion in SDHA gene, (ii) single-nucleotide deletion in NF2 gene, and (iii) EGFR gene amplification of 19 copies. This is the second report of SDHA-mutated RCC. With increased awareness, this rare tumor can be recognized on the basis of distinctive morphology and confirmation by immunohistochemistry and genomic profiling. PMID- 26476570 TI - Development of an affordable typing method for Meyerozyma guilliermondii using microsatellite markers. AB - Despite previously published methods, there is still a lack of rapid and affordable methods for genotyping the Meyerozyma guilliermondii yeast species. The development of microsatellite markers is a useful genotyping method in several yeast species. Using the Tandem Repeat Finder Software, a total of 19 microsatellite motifs (di-, tri-, and tetra- repetition) were found in silico in seven of the nine scaffolds published so far. Primer pairs were designed for all of them, although only four were used in this work. All microsatellite amplifications showed size polymorphism, and the results were identical when repeated. The combination of three microsatellite markers (sc15F/R, sc32 F/R and sc72 F/R) produced a different pattern for each of the Type Culture Collection strains of M. guilliermondii used to optimize the method. The three primer pairs can be used in the same PCR reaction, which reduces costs, in tandem with the fluorescent labeling of only the forward primer in each primer pair. Microsatellite typing was applied on 40 more M. guilliermondii strains. The results showed that no pattern is repeated between the different environmental niches. Four M. guilliermondii strains were only amplified with primer pair sc32 F/R, and subsequently identified as Meyerozyma caribbica by Taq I-RFLP of the 5.8S ITS rDNA. Most out-group species gave negative results even for physiologically similarly species such as Debaryomyces hansenii. The microsatellite markers used in this work were stable over time, which enables their use as a traceability tool. PMID- 26476571 TI - Efficacy of two Staphylococcus aureus phage cocktails in cheese production. AB - Staphylococcus aureus is one of the most prevalent pathogenic bacteria contaminating dairy products. In an effort to reduce food safety risks, virulent phages are investigated as antibacterial agents to control foodborne pathogens. The aim of this study was to compare sets of virulent phages, design phage cocktails, and use them in a cocktail to control pathogenic staphylococci in cheese. Six selected phages belonging to the three Caudovirales families (Myoviridae, Siphoviridae, Podoviridae) were strictly lytic, had a broad host range, and did not carry genes coding for virulence traits in their genomes. However, they were sensitive to pasteurization. At MOI levels of 15, 45, and 150, two anti-S. aureus phage cocktails, each containing three phages, one from each of the three phage families, eradicated a 10(6)CFU/g S. aureus population after 14 days of Cheddar cheese curd ripening at 4 degrees C. The use of these phages did not trigger over-production of S. aureus enterotoxin C. The use of phage cocktails and their rotation may prevent the emergence of phage resistant bacterial strains. PMID- 26476566 TI - Application of classification based cognitive functional therapy for a patient with lumbar spinal stenosis: A case report. AB - This report describes the case of a 52 year old male administrative assistant presenting with symptomatic lumbar spinal stenosis (LSS). Despite patho anatomical considerations, the patient's pain related functional behaviour, mal adapted presentation, motor control strategies, incorrect belief system, and faulty cognition of associating disc healing with a lordotic posture adversely contributed to his presentation. With limited specific guidelines in the literature for this specific lumbar spine condition, the patient response during the assessment guided the intervention. Treatment that incorporated a cognitive functional therapy resulted in a successful outcome. The patient attended for twelve treatment sessions in three months and demonstrated improvement in overall function. By week 12, the Oswestry Disability Index (ODI) reduced from 68% to 19% and further reduced to 15% at three months following discharge. The patient's self-reported tolerance for standing improved from 10 min to 60 min and his self reported tolerance of walking improved from 200 m to three kilometres. The effects were maintained three months post discharge. This case report supports the clinical utility of a patient-centred multidimensional classification system that utilised cognitive functional therapy in a patient with LSS. PMID- 26476569 TI - Synchronous pituitary adenoma and pituicytoma. AB - Pituicytoma is a rare benign neoplasm arising in the sellar region, usually found in the posterior lobe and/or pituitary stalk. Here, we report the case of a 67 year-old woman who presented with bitemporal hemianopsia and visual impairment accompanied by mildly elevated prolactin. Pathologic and molecular examination of the tissue removed transsphenoidally revealed 2 distinct tumors: pituitary adenoma and pituicytoma. To the best of our knowledge, histologically proven pituicytoma and pituitary adenoma have never been reported together. PMID- 26476572 TI - Virus recovering from strawberries: Evaluation of a skimmed milk organic flocculation method for assessment of microbiological contamination. AB - Skimmed milk organic flocculation method was adapted, optimized and compared with polyethylene glycol (PEG) precipitation and filtration methods for recovering viruses from a strawberry matrix. Spiking experiments with norovirus genogroup II genotype 4 (NoV GII.4) and murine norovirus 1 (MNV-1) demonstrated that the organic flocculation method associated with a glycine elution buffer, filter bag and cetyltrimethylammonium bromide (CTAB) showed a recovery percentage of 2.5 and 32 times higher than PEG precipitation and filtration methodologies for NoV recovering. Furthermore, this method was used for investigating NoV and human adenoviruses (HAdVs) in 90 samples of fresh strawberries commercialized in Rio de Janeiro markets. NoV GI and GII were not detected in those samples and MNV-1, used as internal process control (IPC), was recovered in 95.5% (86) of them. HAdVs were detected in 18 (20.0%) samples and characterized by nucleotide sequencing as Human Mastadenovirus specie F and as type specie HAdV-2. Bacterial analysis did not detect Salmonella spp. and Listeria monocytogenes, however, 3.3% of fecal coliforms were detected in those samples. These results indicate the organic flocculation method as an alternative for recovering enteric viruses from strawberries, emphasizing a need for virus surveillance in food matrices. PMID- 26476574 TI - Increased radiosensitivity of HPV-positive head and neck cancers: Molecular basis and therapeutic perspectives. AB - Human papillomavirus driven head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal squamous cell carcinoma (OPSCC), are characterized by a significant survival advantage over their HPV-negative counterparts. Although the reasons behind this are still not fully elucidated, it is widely accepted that these tumors have a higher response to ionizing radiation that might explain their favorable outcomes. Potential underlying intrinsic mechanisms include impaired DNA repair abilities, differences in activated repopulation-signaling pathways and cell cycle control mechanisms. The role of the microenvironment is increasingly highlighted, particularly tumor oxygenation and the immune response. Recent studies have shown a distinct pattern of intratumoral immune cell infiltrates, according to HPV status, and have suggested that an increased cytotoxic T-cell based antitumor immune response is involved in improved prognosis of patients with HPV-positive OPSCC. These significant milestones, in the understanding of HPV-induced HNSCC, pave the way to new therapeutic opportunities. This article reviews the current evidence on the biological basis of increased radiosensitivity in HPV-positive HNSCC and discusses potential therapeutic implications. PMID- 26476573 TI - Inhibition of bacterial growth in sweet cheese whey by carbon dioxide as determined by culture-independent community profiling. AB - Whey is a valuable co-product from cheese making that serves as a raw material for a wide range of products. Its rich nutritional content lends itself to rapid spoilage, thus it typically needs to be pasteurised and refrigerated promptly. Despite the extensive literature on milk spoilage bacteria, little is known about the spoilage bacteria of whey. The utility of carbon dioxide (CO2) to extend the shelf-life of raw milk and cottage cheese has been well established, but its application in whey preservation has not yet been explored. This study aims to characterise the microbial populations of fresh and spoiled sweet whey by culture independent community profiling using 454 pyrosequencing of 16S rRNA gene amplicons and to determine whether carbonation is effective in inhibiting bacterial growth in sweet whey. The microbiota of raw Cheddar and Mozzarella whey was dominated by cheese starter bacteria. After pasteurisation, two out of the three samples studied became dominated by diverse environmental bacteria from various phyla, with Proteobacteria being the most dominant. Diverse microbial profiles were maintained until spoilage occurred, when the entire population was dominated by just one or two genera. Whey spoilage bacteria were found to be similar to those of milk. Pasteurised Cheddar and Mozzarella whey was spoiled by Bacillus sp. or Pseudomonas sp., and raw Mozzarella whey was spoiled by Pseudomonas sp., Serratia sp., and other members of the Enterobacteriaceae family. CO2 was effective in inhibiting bacterial growth of pasteurised Cheddar and Mozzarella whey stored at 15 degrees C and raw Mozzarella whey stored at 4 degrees C. The spoilage bacteria of the carbonated samples were similar to those of the non-carbonated controls. PMID- 26476575 TI - Working in tandem: The contribution of remedial programs and roadside licence suspensions to drinking and driving deterrence in Ontario. AB - In 1998, Ontario implemented a remedial program called "Back On Track" (BOT) for individuals convicted of alcohol-impaired driving. Drivers convicted before October 2000 were exposed to a single-component program ("Edu BOT"); those convicted after participated in a multi-component program ("Full BOT"). We evaluated the impact of BOT, and the preceding 90-day roadside licence suspension, on drinking and driving recidivism, an outcome yet to be examined, using population-wide driver records. A Chi Square Test was used to compare the three-year cumulative incidence of recidivism between three historically-defined cohorts: No BOT, Edu BOT, and Full BOT. Stratified analyses by completion status and by age were also conducted. Analyses of the roadside suspension were conducted using an interrupted time series approach based on segmented Poisson/negative binomial regression. The roadside suspension was associated with a 65.2% reduction in drinking driving recidivism. In combination with indefinite suspensions for non-completion, the BOT program was also associated with a 21% decrease in drinking and driving recidivism in the three years following a CCC driving prohibition, from 8.5% to 6.7%. This reduction cannot be explained by pre existing trends in recidivism. Conversion of the BOT program from the single component version to the multi-component program further reduced the three-year cumulative incidence of recidivism to 5.5% (a total reduction of 35% from pre BOT). Results provide strong converging evidence that remedial alcohol education/treatment programs in combination with other sanctions can produce substantial increases in road safety. PMID- 26476576 TI - Flipping a Lipid-Linked Oligosaccharide? You Must Whip It! AB - The mechanism for flipping large lipid-linked oligosaccharides across membranes has remained a paradox. Perez et al. now report the structure of the PglK protein of C. jejuni, a flippase for a bacterial lipid-linked oligosaccharide, and reveal an unexpected whip-like mechanism. PMID- 26476577 TI - Radial pseudoaneurysm after a puncture for blood gas analysis. AB - Radial pseudoaneurysm (PA) is a rare complication of the transradial approach for the arterial catheterization. PMID- 26476578 TI - Who is prescribing controlled medications to patients who die of prescription drug abuse? AB - BACKGROUND: Prescription drug-related fatalities remain a significant issue in the United States, yet there is a relative lack of knowledge on the specialty specific prescription patterns for drug-related deaths. METHODS: We designed a study that investigated medical examiner reports of prescription drug-related deaths that occurred in San Diego County during 2013. A Prescription Drug Monitoring Program search was performed on each of these cases to ascertain which physician specialties had prescribed controlled substances to these patients. The data were analyzed for each specialty, including pills per prescription, type of prescription, doctor shoppers (4 physicians + 4 pharmacies over 1 year), and chronic users (>=3 consecutive months of medications). MAIN FINDINGS: In 2013, 4.5% of all providers in San Diego County wrote a prescription for a patient who died a prescription-related death. There were a total of 713 providers who prescribed 4366 medications totaling 328928 pills. Overall, emergency physicians gave the lowest number of prescriptions per provider (1.6), whereas pain management provided the highest amount per provider (12.9). Most prescriptions went to doctor shoppers (>50%) and chronic users (95.8%). Hydrocodone was the most frequently prescribed medication to those patients whose deaths were related to prescription drugs. CONCLUSIONS: Emergency physicians appear to provide fewer prescriptions to those patients who die due to prescription drugs. Emergency physicians do, however, account for a significant proportion of total providers in this study. These results highlight the need to use Prescription Drug Monitoring Program data to closely monitor prescription patterns and to intervene when necessary. PMID- 26476579 TI - Progressive increase in D-dimer levels during extracorporeal membrane oxygenation can predict membrane oxygenator failure in children given hematopoietic stem cell transplantation? PMID- 26476580 TI - Multipronged strategy to reduce routine-priority blood testing in intensive care unit patients. AB - PURPOSE: The purpose of the study is to reduce unnecessary ordering of routine priority blood tests. METHODS: In this before-after study, we studied all patients admitted to a 15-bed tertiary intensive care unit (ICU) from July 1, 2011, to June 27, 2013. Based on input from intensivists, acceptable indications for ordering routine-priority complete blood counts (CBCs) and electrolyte/renal panels were developed. Sequential interventions were (1) education sessions for ICU housestaff about the lack of evidence for routine-priority blood tests; (2) an item on the ICU rounds checklist to ask if routine-priority blood tests were indicated; (3) a rubber stamp, "routine bloodwork NOT indicated for tomorrow," was used in the chart; (4) a prompt in the electronic ordering system to allow only accepted indications; and (5) a second educational session for ICU housestaff. We measured numbers of tests done before and after these interventions. RESULTS: After introduction of interventions, there were 0.14 fewer routine-priority CBCs and 0.13 fewer routine-priority electrolyte/renal panels done per patient-day. Nonroutine CBCs and nonroutine electrolyte/renal panels increased by 0.03 and 0.02 tests per patient-day, respectively. This overall reduction in tests equates to an adjusted savings of $11,200.24 over 1 year in 1 ICU. There were no differences in demographics, severity of illness, length of stay, or number of red cell transfusions between the 2 periods. CONCLUSION: Sequential interventions to discourage the ordering of routine priority blood tests in an ICU were associated with a significant decrease in the number of tests ordered. PMID- 26476581 TI - Evaluation of parturient perception and aversion before and after primary cesarean delivery in a low-resource country. AB - OBJECTIVE: To determine the perception of and aversion to cesarean delivery (CD) and their determinants before and after primary CD. METHODS: A prospective cross sectional survey of pregnant women undergoing primary CD (elective or emergency) was conducted in six health facilities in Ilorin, Nigeria. All participants completed an interviewer-administered questionnaire before the operation and 3 4days thereafter. The statistical analysis included the calculation of odds ratios (ORs) with 95% confidence intervals (CIs) and a logistic regression. RESULTS: Of the 254 participants, 182 (71.7%) and 53 (20.9%) had an aversion to CD before and after the procedure, respectively. A woman's personal decision was the overriding factor influencing acceptance of the operation. Preoperative predictors of aversion were prenatal admission (OR 2.86 [95% CI,1.07-7.66]; P=0.030) and a history of previous surgery (OR 0.42 [95% CI, 0.24-0.75]; P=0.003), whereas postoperatively a low number of prenatal clinic visits (less than four; OR 3.05 [95% CI,1.63-5.69]; P=0.001) and a history of previous surgery (OR 0.51 [95% CI, 0.27-0.96]; P=0.034) were significant. Postprocedure, 164 (64.6%) women said they would accept a repeat CD. CONCLUSION: Patient education, prenatal care, and previous surgical experiences were important in determining women's perception of and aversion to CD. PMID- 26476582 TI - Maternal age and outcome of preterm infants at discharge from the neonatal intensive care unit. AB - OBJECTIVE: To assess the effect of maternal age on preterm neonates' survival free from major morbidity at discharge from two neonatal intensive care units in Jerusalem, Israel. METHODS: A retrospective chart review of two hospitals from 2009-2010 was performed. Eligible neonates were born at less than 35 weeks of gestation and survived to discharge. Major morbidity included at least one of the following: chronic lung disease, at least grade 3 intraventricular hemorrhage, periventricular leukomalacia, at least stage 3 retinopathy of prematurity, at least stage 2 necrotizing enterocolitis, or sepsis. RESULTS: The analysis was performed on 380 neonates of 294 mothers. Mean maternal age was 30.5 years (range, 17-52), mean gestational age was 31.5 weeks (range, 24-34), and mean birth weight was 1705.5 g (range, 460-3150). Of the neonates, 90 (23.7%) had major morbidity, which was associated with lower mean gestational age (29.5 weeks vs 32.3 weeks, P<0.001), birth weight (1326.5g vs 1822.2g, P<0.001), and the need for resuscitation at birth (P<0.001) in comparison with neonates without major morbidity. A comparison of maternal age between the two outcome groups yielded a nonsignificant result. A logistic regression model revealed that maternal age does not contribute significantly to poor neonatal outcomes. CONCLUSION: Advanced maternal age was not associated with major morbidity of preterm neonates at discharge from the neonatal intensive care units. PMID- 26476583 TI - Cardiac Regeneration Therapies - Targeting Neuregulin 1 Signalling. PMID- 26476584 TI - Effect of the Inhibition of Hydrogen Sulfide Synthesis on Ischemic Injury and Oxidative Stress Biomarkers in a Transient Model of Focal Cerebral Ischemia in Rats. AB - OBJECTIVE: Hydrogen sulfide (H2S) plays multiple roles in the function of the central nervous system in physiological and pathological conditions, such as cerebral ischemia. Recent studies have reported controversial results about the role of H2S in cerebral ischemia. The aim of this study was to evaluate the effects of amino-oxyacetic acid (AOAA), an inhibitor of H2S synthesis, on ischemic injury in an experimental model of stroke. METHODS: Using laser Doppler monitoring, cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAO) for 1 hour in rats. AOAA (.025, .05, .1, and .5 mmol/kg intraperitoneally [i.p.]) was injected at the beginning of MCAO. Infarct volume, cerebral edema, and activity of antioxidant enzymes were measured using the standard methods 24 hours after ischemia. RESULTS: The administration of AOAA at doses .025, .05, and .1 mmol/kg significantly reduced the infarct volume (P < .001). Furthermore, .025 and .05 mmol/kg of AOAA significantly reduced brain edema and improved the neurological outcome (P < .001). The administration of AOAA did not significantly change the malondialdehyde content, activities of superoxide dismutase, or glutathione peroxidase antioxidant enzymes in the brain tissue (P > .05). CONCLUSION: The results showed that AOAA administered at a low dose has protective effects; however, at higher doses it did not exert any protective effect against cerebral ischemia and even worsened the ischemic injury. This finding suggests that H2S might be both beneficial and harmful in cerebral ischemic injury depending on its concentration in transient model of focal cerebral ischemia. PMID- 26476585 TI - Short-Term Trajectories of Depressive Symptoms in Stroke Survivors and Their Family Caregivers. AB - GOAL: We utilize group-based trajectory modeling (GBTM) to delineate depressive symptom trajectories among stroke survivor-caregiver dyads, to identify predictors of the delineated trajectories, and to assess the influence of time varying covariates (stroke survivor depressive symptoms and functional disability, caregiver depressive symptoms, and foreign domestic worker [FDW] assistance) on the level of the depressive symptom trajectories. METHODS: Data on 172 stroke survivor-caregiver dyads in Singapore, for whom depressive symptoms were assessed thrice (baseline/3 months/6 months), were utilized. GBTM was applied to delineate depressive symptom trajectories, and to identify their predictors and time-varying covariates. FINDINGS: Three stroke survivor depressive symptom trajectories (low and decreasing [47.6%], low and increasing [43.1%], and high and increasing [9.3%]) and 2 caregiver depressive symptom trajectories (low and stable [71.5%] and high and decreasing [28.5%]) were delineated. Caregivers with chronic diseases were more likely (odds ratio [95% confidence interval]: 8.09[2.04-32.07]) and those caring for older stroke survivors (0.94[0.90-0.98]) were less likely to follow the high and decreasing than the low and stable depressive symptom trajectory. An increase in stroke survivor functional disability and caregiver depressive symptoms led to a rise (~worsening) in stroke survivor depressive symptom trajectories. Whereas an increase in stroke survivor depressive symptoms led to a rise in caregiver depressive symptom trajectories, FDW assistance led to a decline (~improvement). CONCLUSION: Care professionals should be mindful of heterogeneity in depressive symptom patterns over time among stroke survivor-caregiver dyads. Reciprocal association of depressive symptoms in the stroke survivor-caregiver dyad suggests that addressing mood problems in 1 member may benefit the other member, and calls for dyadic mental health interventions. PMID- 26476586 TI - Diffuse Fluid-Attenuated Inversion Recovery Hyperintensity in Subarachnoid Space Following Cerebral Angiography and Intravenous Thrombolysis. AB - OBJECTIVE: Transient cortical blindness (TCB) is a relatively rare but well recognized complication following cardiovascular and cerebral angiography. METHODS: A 68-year-old male developed TCB following cerebral angiography along with punctate diffusion lesion evident on emergent magnetic resonance imaging (MRI). The patient received intravenous tissue plasminogen activator (IV-tPA) for suspected stroke. RESULTS: Follow-up MRI revealed diffuse hyperintensities in subarachnoid space in fluid-attenuated inversion recovery (FLAIR) sequence mostly in bilateral occipital lobes. CONCLUSION: The finding on the FLAIR as described in this case is an indication of diffuse disruption of the blood-brain barrier perhaps secondary to cerebral angiography, high blood pressure, and IV-tPA. To the best of our knowledge, this is the first reported case of TCB with diffuse postcontrast FLAIR changes. PMID- 26476587 TI - A Simple Geometric Assessment of Perfusion Lesion Volume at Hyperacute Stage of Ischemic Stroke in Patients with Symptomatic Steno-Occlusion of Major Cerebral Arteries and Risk of Subsequent Cerebral Ischemic Events. AB - Our objective is to elucidate the association of baseline perfusion lesion volume on perfusion-weighted magnetic resonance imaging (PWI) obtained at hyperacute stage of ischemic stroke with subsequent cerebral ischemic events (SIEs) in patients with symptomatic steno-occlusion of major cerebral arteries. Using a prospective stroke registry database, patients arriving within 24 hours of onset with symptomatic steno-occlusion of major supratentorial cerebral arteries were identified. On baseline PWI, time-to-peak lesion volume (TTP-LV) was determined by a simple geometric method and dichotomized into the highest tertile (large) and the other tertiles (small to medium) according to the vascular territory of occluded arteries. Primary outcome was a time to SIE up to 1 year after stroke onset. A total of 385 patients (a median time delay from onset to arrival, 2.2 hours) were enrolled. During the first year of stroke, the SIE rate of the large TTP-LV group was twice that of the small-to-medium TTP-LV group (35.7% versus 17.4%; P < .001). Large TTP-LV independently raised the hazard of SIE (hazard ratio, 2.24; 95% confidence interval, 1.45-3.44). This study demonstrates that TTP-LV on PWI measured through a simple geometric method at an emergency setting can be used to predict progression or recurrence of ischemic stroke in patients with symptomatic steno-occlusion of major cerebral arteries. PMID- 26476588 TI - Atrial Cardiopathy and Cryptogenic Stroke: A Cross-sectional Pilot Study. AB - BACKGROUND: There is increasing evidence that left atrial dysfunction or cardiopathy is associated with ischemic stroke risk independently of atrial fibrillation. We aimed to determine the prevalence of atrial cardiopathy biomarkers in patients with cryptogenic stroke. METHODS: We included consecutive patients with ischemic stroke enrolled in the New York Columbia Collaborative Specialized Program of Translational Research in Acute Stroke registry between December 1, 2008, and April 30, 2012. Medical records were reviewed and patients with a diagnosis of cryptogenic stroke were identified. Atrial cardiopathy was defined as at least one of the following: serum N-terminal probrain natriuretic peptide (NT-proBNP) level greater than 250 pg/mL, P-wave terminal force velocity in lead V1 (PTFV1) on electrocardiogram (ECG) greater than 5000 uV?ms, or severe left atrial enlargement (LAE) on echocardiogram. We compared clinical, echocardiographic, and radiological characteristics between patients with and without atrial cardiopathy. RESULTS: Among 40 patients with cryptogenic stroke, 63% had at least one of the biomarkers of atrial cardiopathy; 49% had elevated NT proBNP levels, 20% had evidence of increased PTFV1 on ECG, and 5% had severe LAE. Patients with atrial cardiopathy were more likely to be older (76 versus 62 years, P = .012); have hypertension (96% versus 33%, P < .001), hyperlipidemia (60% versus 27%, P = .05), or coronary heart disease (28% versus 0%, P = .033); and less likely to have a patent foramen ovale (4% versus 40%, P = .007). CONCLUSION: There is a high prevalence of biomarkers indicative of atrial cardiopathy in patients with cryptogenic stroke. Clinical trials are needed to determine whether these patients may benefit from anticoagulation to prevent stroke. PMID- 26476589 TI - A Phase II Study of AT-101 to Overcome Bcl-2--Mediated Resistance to Androgen Deprivation Therapy in Patients With Newly Diagnosed Castration-Sensitive Metastatic Prostate Cancer. AB - In a phase II multicenter study, men with castration sensitive metastatic prostate cancer were treated with AT-101, a small molecule Bcl-2 inhibitor, and androgen deprivation therapy. At the end of 7 cycles of therapy in 55 patients, an undetectable PSA was achieved in 31%. However, the combination did not meet the pre-specified level of activity for further development. BACKGROUND: We conducted a phase II study in men with castration-sensitive metastatic prostate cancer to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, has clinical activity in patients initiating androgen deprivation therapy (ADT) for metastatic prostate cancer. MATERIALS AND METHODS: Patients with metastatic prostate cancer scheduled to start, or who had recently (within 6 weeks) initiated, ADT were enrolled. ADT with a luteinizing hormone-releasing hormone agonist and bicalutamide was started 6 weeks before initiation of oral AT-101, 20 mg/day for 21 days of a 28-day cycle. The primary endpoint of the study was the percentage of patients with an undetectable prostate-specific antigen (PSA) level (<= 0.2 ng/mL) after 7.5 months (1.5 months of ADT alone plus 6 months of combined ADT and AT-101). To assess for an association between chromodomain helicase DNA binding protein 1 (CHD1) and drug sensitivity, fluorescence in situ hybridization with confocal microscopy was assessed in a subgroup of patients. RESULTS: A total of 55 patients were enrolled, with median age of 61 years and a median PSA level of 27.6 ng/dL. Of the 55 patients, 72% had a Gleason score >= 8. Three patients had visceral metastases, and the remaining patients had bone or nodal metastasis. An undetectable PSA level was achieved in 31% of the patients. Of the 31 patients, 12 experienced serious adverse events, 7 of which were considered related to study therapy. Most of the related adverse events were gastrointestinal and nervous system disorders. CHD1 assessment was feasible, with a nonsignificant association with therapeutic sensitivity in a small number of patients. CONCLUSION: The combination of ADT and AT-101 did not meet the prespecified level of activity for further development of this combination. PMID- 26476590 TI - Psychological consequences and quality of life among medical rescuers who responded to the 2010 Yushu earthquake: A neglected problem. AB - A comprehensive study was conducted 8 months after the 2010 Yushu earthquake to assess the prevalence of posttraumatic stress disorder (PTSD) among medical rescuers and the rescuers' quality of life. Additionally, the study examines differences between local and supporting forces, as well as the relationship between PTSD and lower quality of life (QoL), and the risk factors for both. A total of 338 rescuers (including 123 local rescuers and 215 supporting ones) were randomly selected from Yushu County (the epicenter) and Xining City using multistage systematic sampling. Two standardized instruments, the PTSD Checklist Civilian Version (PCL-C) and the Chinese version of the WHOQOL-BREF, were used to evaluate the prevalence of PTSD and obtain the rescuers' QoL. Being between 40 and 50 years old, a nurse, Tibetan, having been in serious danger or having received mental health training before this earthquake were significantly and independently associated with PTSD symptoms. Compared with supporting rescuers, local rescuers were more likely to develop PTSD and to report a lower QoL. Additional mental health services and training should be available to at-risk medical rescuers and groups to ensure they are adequately prepared for relief efforts and to maintain their mental health after assistance in disaster relief. PMID- 26476591 TI - Effects of antidepressant treatment on total antioxidant capacity and free radical levels in patients with major depressive disorder. AB - In this prospective study, we investigated the effects of antidepressant therapy on total antioxidant capacity and free radical levels in patients with major depressive disorder (MDD). We recruited thirty-five first-episode patients who met the criteria of the Fourth Edition of Diagnostic and Statistical Manual of Mental Disorders of MDD and 35 age- and sex-matched healthy controls. Superoxide and hydroxyl radicals were measured to investigate oxidative status and the total radical-trapping antioxidant parameter (TRAP) assay was performed to evaluate antioxidant capacity in healthy controls and in patients before and after receiving a 12-week regimen of sertraline. The severity of depression was evaluated using the 17-item Hamilton Depression Rating Scale (HDRS). Before treatment, the mean HDRS score in patients with MDD was 26.11+/-4.93. Of the 35 patients with MDD, 19 (54.29%) completed the 12-week treatment regimen and all achieved remission. Patients with MDD had significantly lower TRAP baseline values than healthy controls. After adjusting for age, sex, occupation, education and marital status, we found that HDRS score was negatively correlated with TRAP value and level of superoxide radicals. After treatment, the MDD group demonstrated significantly higher TRAP values and significantly lower levels of superoxide and hydroxyl radicals. In conclusion, MDD patients are accompanied by lowered antioxidant capacity than healthy individuals. Antidepressant treatment for 12 weeks results in increased antioxidant capacity and a decrease in circulating free radicals. PMID- 26476592 TI - Effect of ash content on the combustion process of simulated MSW in the fixed bed. AB - This paper experimentally and numerically investigates the effects of ash content on the combustion process of simulated Municipal Solid Waste (MSW). A fixed-bed experimental reactor was utilized to reveal the combustion characteristics. Temperature distributions, ignition front velocity, and the characteristics of gas species' release were measured and simulated during the combustion process. In the present work, the two-dimensional unsteady mathematical heterogeneous model was developed to simulate the combustion process in the bed, including the process rate model as well as NOx production model. The simulation results in the bed are accordant with the experimental results. The results show that as ash content increases, the lower burning rate of fuel results in char particles leaving the grate without being fully burned, causing a loss of combustible material in the MSW in a fixed bed and therefore reducing the combustion efficiency and increasing the burning time of the MSW. PMID- 26476593 TI - Age-Dependent Pleiotropy Between General Cognitive Function and Major Psychiatric Disorders. AB - BACKGROUND: General cognitive function predicts psychiatric illness across the life course. This study examines the role of pleiotropy in explaining the link between cognitive function and psychiatric disorder. METHODS: We used two large genome-wide association study data sets on cognitive function-one from older age, n = 53,949, and one from childhood, n = 12,441. We also used genome-wide association study data on educational attainment, n = 95,427, to examine the validity of its use as a proxy phenotype for cognitive function. Using a new method, linkage disequilibrium regression, we derived genetic correlations, free from the confounding of clinical state between psychiatric illness and cognitive function. RESULTS: We found a genetic correlation of .711 (p = 2.26e-12) across the life course for general cognitive function. We also showed a positive genetic correlation between autism spectrum disorder and cognitive function in childhood (rg = .360, p = .0009) and for educational attainment (rg = .322, p = 1.37e-5) but not in older age. In schizophrenia, we found a negative genetic correlation between older age cognitive function (rg = -.231, p = 3.81e-12) but not in childhood or for educational attainment. For Alzheimer's disease, we found negative genetic correlations with childhood cognitive function (rg = -.341, p = .001), educational attainment (rg = -.324, p = 1.15e-5), and with older age cognitive function (rg = -.324, p = 1.78e-5). CONCLUSIONS: The pleiotropy exhibited between cognitive function and psychiatric disorders changed across the life course. These age-dependent associations might explain why negative selection has not removed variants causally associated with autism spectrum disorder or schizophrenia. PMID- 26476594 TI - ROCK inhibitor Y27632 promotes proliferation and diminishes apoptosis of marmoset induced pluripotent stem cells by suppressing expression and activity of caspase 3. AB - Previous studies reported that Rho-associated kinase inhibitor Y27632 markedly diminishes human embryonic stem cell and induced pluripotent stem cell (iPSC) dissociation-induced apoptosis and increases cloning efficiency in a feeder-free culture system. However, the mechanisms by which Y27632 protects pluripotent stem cells from apoptosis remain unknown. In the present study, we tested the effects of Y27632 on single dissociated marmoset iPSCs in a feeder-free culture. The results showed that Y27632 promoted the number of cells proliferating after passage by single-cell dissociation in a dose-dependent manner. The Rho associated kinase inhibitor Y27632 markedly increased the cloning efficiency of marmoset iPSCs without affecting their karyotype and the expression of pluripotency markers. Meanwhile, Y27632 markedly diminished apoptosis of the marmoset iPSCs under even more severe conditions by suppressing the expression and activity of caspase 3. Taken together, the present results suggest that this reagent is effective in improving the cultural system of primate iPSCs. PMID- 26476595 TI - Expression of angiogenic factors and luteinizing hormone receptors in the corpus luteum of mares induced to ovulate with deslorelin acetate. AB - The effects of deslorelin acetate use in inducing ovulation need to be clarified to improve the results of equine embryo transfer. The mRNA abundance for angiogenic factors and LH receptor (LHR) in corpus luteum (CL) was studied in mares with natural (control group [CG]) and induced ovulation with deslorelin acetate (treatment group [TG]; follicles: >= 35 mm). Transrectal ultrasonography was used to verify the ovulation day, and on Days 4, 8, and 12 after ovulation (Day 0), CL samples were obtained through ultrasound-guided biopsy. The messenger RNA expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and LHR genes were analyzed by real-time polymerase chain reaction. A positive correlation was observed between VEGF and LHR (P < 0.00001, r = 0.78), and it was possible to detect higher LHR expression in the TG than in the CG on Day 4 (P < 0.05). Moreover, this expression was higher on Days 4 and 8 than on Day 12 in the TG. Basic fibroblast growth factor was also expressed in luteal tissue on all days for both groups; however, these differences were not significant. In conclusion, deslorelin acetate was effective for the induction of ovulation in mares, resulting in higher expression of LHR, especially on the fourth day after ovulation. In addition, VEGF expression was influenced by induced ovulation, with a lower level on Day 12, which is expected in nonpregnant mares. PMID- 26476596 TI - Safety impacts of platform tram stops on pedestrians in mixed traffic operation: A comparison group before-after crash study. AB - Tram stops in mixed traffic environments present a variety of safety, accessibility and transport efficiency challenges. In Melbourne, Australia the hundred year-old electric tram system is progressively being modernized to improve passenger accessibility. Platform stops, incorporating raised platforms for level entry into low floor trams, are being retro-fitted system-wide to replace older design stops. The aim of this study was to investigate the safety impacts of platform stops over older design stops (i.e. Melbourne safety zone tram stops) on pedestrians in the context of mixed traffic tram operation in Melbourne, using an advanced before-after crash analysis approach, the comparison group (CG) method. The CG method evaluates safety impacts by taking into account the general trends in safety and the unobserved factors at treatment and comparison sites that can alter the outcomes of a simple before-after analysis. The results showed that pedestrian-involved all injury crashes reduced by 43% after platform stop installation. This paper also explores a concern that the conventional CG method might underestimate safety impacts as a result of large differences in passenger stop use between treatment and comparison sites, suggesting differences in crash risk exposure. To adjust for this, a modified analysis explored crash rates (crash counts per 10,000 stop passengers) for each site. The adjusted results suggested greater reductions in pedestrian-involved crashes after platform stop installation: an 81% reduction in pedestrian-involved all injury crashes and 86% reduction in pedestrian-involved FSI crashes, both are significant at the 95% level. Overall, the results suggest that platform stops have considerable safety benefits for pedestrians. Implications for policy and areas for future research are explored. PMID- 26476598 TI - Gold-coated carbon nanotube electrode arrays: Immunosensors for impedimetric detection of bone biomarkers. AB - C-terminal telopeptide (cTx), a fragment generated during collagen degradation, is a key biomarker of bone resorption during the bone remodeling process. The presence of varying levels of cTx in the bloodstream can hence be indicative of abnormal bone metabolism. This study focuses on the development of an immunosensor utilizing carbon nanotube (CNT) electrodes coated with gold nanoparticles for the detection of cTx, which could ultimately lead to the development of an inexpensive and rapid point-of-care (POC) tool for bone metabolism detection and prognostics. Electrochemical impedance spectroscopy (EIS) was implemented to monitor and detect the antigen-antibody binding events occurring on the surface of the gold-deposited CNT electrode. Type I cTx was used as the model protein to test the developed sensor. The sensor was accordingly characterized at various stages of development for evaluation of the optimal sensor performance. The biosensor could detect cTx levels as low as 0.05 ng/mL. The feasibility of the sensor for point-of-care (POC) applications was further demonstrated by determining the single frequency showing maximum changes in impedance, which was determined to be 18.75 Hz. PMID- 26476597 TI - Can NMR solve some significant challenges in metabolomics? AB - The field of metabolomics continues to witness rapid growth driven by fundamental studies, methods development, and applications in a number of disciplines that include biomedical science, plant and nutrition sciences, drug development, energy and environmental sciences, toxicology, etc. NMR spectroscopy is one of the two most widely used analytical platforms in the metabolomics field, along with mass spectrometry (MS). NMR's excellent reproducibility and quantitative accuracy, its ability to identify structures of unknown metabolites, its capacity to generate metabolite profiles using intact bio-specimens with no need for separation, and its capabilities for tracing metabolic pathways using isotope labeled substrates offer unique strengths for metabolomics applications. However, NMR's limited sensitivity and resolution continue to pose a major challenge and have restricted both the number and the quantitative accuracy of metabolites analyzed by NMR. Further, the analysis of highly complex biological samples has increased the demand for new methods with improved detection, better unknown identification, and more accurate quantitation of larger numbers of metabolites. Recent efforts have contributed significant improvements in these areas, and have thereby enhanced the pool of routinely quantifiable metabolites. Additionally, efforts focused on combining NMR and MS promise opportunities to exploit the combined strength of the two analytical platforms for direct comparison of the metabolite data, unknown identification and reliable biomarker discovery that continue to challenge the metabolomics field. This article presents our perspectives on the emerging trends in NMR-based metabolomics and NMR's continuing role in the field with an emphasis on recent and ongoing research from our laboratory. PMID- 26476599 TI - Diamond encapsulated photovoltaics for transdermal power delivery. AB - A safe, compact and robust means of wireless energy transfer across the skin barrier is a key requirement for implantable electronic devices. One possible approach is photovoltaic (PV) energy delivery using optical illumination at near infrared (NIR) wavelengths, to which the skin is highly transparent. In the work presented here, a subcutaneously implantable silicon PV cell, operated in conjunction with an external NIR laser diode, is developed as a power delivery system. The biocompatibility and long-term biostability of the implantable PV is ensured through the use of an hermetic container, comprising a transparent diamond capsule and platinum wire feedthroughs. A wavelength of 980 nm is identified as the optimum operating point based on the PV cell's external quantum efficiency, the skin's transmission spectrum, and the wavelength dependent safe exposure limit of the skin. In bench-top experiments using an external illumination intensity of 0.7 W/cm(2), a peak output power of 2.7 mW is delivered to the implant with an active PV cell dimension of 1.5 * 1.5 * 0.06 mm(3). This corresponds to a volumetric power output density of ~20 mW/mm(3), significantly higher than power densities achievable using inductively coupled coil-based approaches used in other medical implant systems. This approach paves the way for further ministration of bionic implants. PMID- 26476601 TI - Changes to transtibial amputee gait with a weighted backpack on multiple surfaces. AB - BACKGROUND: Modern prosthetic technology and rehabilitation practices have enabled people with lower extremity amputations to participate in almost all occupations and physical activities. Carrying backpack loads can be an essential component for many of these jobs and activities; however, amputee gait with backpack loads is poorly understood. This knowledge gap must be addressed in order to further improve an individual's quality of living through changes in rehabilitation programs and prosthesis development. METHODS: Ten male, unilateral, K4-level (ability or potential for prosthetic ambulation that exceeds basic ambulation skills, exhibiting high impact, stress, or energy levels), transtibial amputees completed ten walking trials at a self-selected pace on simulated uneven ground, ramp ascent, and ramp descent. Five trials were with a 24.5 kg backpack load and five trials without. Temporal-spatial parameters and kinematic peak values for the ankle, knee, hip, pelvis, and trunk were collected and analyzed for differences between backpack conditions. FINDINGS: Each surface had novel findings not found on the other surfaces. However differences in temporal-spatial parameters were congruent with the literature on able bodied individuals. Pelvis and trunk angular velocities decreased with the backpack. Hip flexion on both limbs increased during weight acceptance while wearing the backpack, a common adaptation seen in able-bodied individuals on level ground. INTERPRETATION: A 24.5 kg backpack load can be accommodated by transtibial amputees at the K4 functional level. Future studies on load carriage and gait training programs should include incline and descent due to the increased difficulty. Rehabilitation programs should verify hip and knee flexor strength and work to reduce intact limb reliance. PMID- 26476600 TI - Physiological fluctuations in white matter are increased in Alzheimer's disease and correlate with neuroimaging and cognitive biomarkers. AB - The objective of this study was to determine whether physiological fluctuations in white matter (PFWM) on resting-state functional magnetic resonance images could be used as an index of neurodegeneration and Alzheimer's disease (AD). Using resting-state functional magnetic resonance image data from participants in the Alzheimer's Disease Neuroimaging Initiative, PFWM was compared across cohorts: cognitively healthy, mild cognitive impairment, or probable AD. Secondary regression analyses were conducted between PFWM and neuroimaging, cognitive, and cerebrospinal fluid biomarkers. There was an effect of cohort on PFWM (t = 5.08, degree of freedom [df] = 424, p < 5.7 * 10(-7)), after accounting for nuisance effects from head displacement and global signal (t > 6.16). From the neuroimaging data, PFWM was associated with glucose metabolism (t = -2.93, df = 96, p = 0.004) but not ventricular volume (p < 0.49) or hippocampal volume (p > 0.44). From the cognitive data, PFWM was associated with composite memory (t = 3.24, df = 149, p = 0.0015) but not executive function (p > 0.21). PFWM was not associated with cerebrospinal fluid biomarkers. In one final omnibus model to explain PFWM (n = 124), glucose metabolism (p = 0.04) and cohort (p = 0.008) remained significant, as were global and head motion root-mean-square terms, whereas memory was not (p = 0.64). PFWM likely reflects end-arteriole intracranial pulsatility effects that may provide additional diagnostic potential in the context of AD neurodegeneration. PMID- 26476602 TI - Obesity is associated with higher absolute tibiofemoral contact and muscle forces during gait with and without knee osteoarthritis. AB - BACKGROUND: Obesity is an important risk factor for knee osteoarthritis initiation and progression. However, it is unclear how obesity may directly affect the mechanical loading environment of the knee joint, initiating or progressing joint degeneration. The objective of this study was to investigate the interacting role of obesity and moderate knee osteoarthritis presence on tibiofemoral contact forces and muscle forces within the knee joint during walking gait. METHODS: Three-dimensional gait analysis was performed on 80 asymptomatic participants and 115 individuals diagnosed with moderate knee osteoarthritis. Each group was divided into three body mass index categories: healthy weight (body mass index<25), overweight (25<=body mass index<=30), and obese (body mass index>30). Tibiofemoral anterior-posterior shear and compressive forces, as well as quadriceps, hamstrings and gastrocnemius muscle forces, were estimated based on a sagittal plane contact force model. Peak contact and muscle forces during gait were compared between groups, as well as the interaction between disease presence and body mass index category, using a two-factor analysis of variance. FINDINGS: There were significant osteoarthritis effects in peak shear, gastrocnemius and quadriceps forces only when they were normalized to body mass, and there were significant BMI effects in peak shear, compression, gastrocnemius and hamstrings forces only in absolute, non-normalized forces. There was a significant interaction effect in peak quadriceps muscle forces, with higher forces in overweight and obese groups compared to asymptomatic healthy weight participants. INTERPRETATION: Body mass index was associated with higher absolute tibiofemoral compression and shear forces as well as posterior muscle forces during gait, regardless of moderate osteoarthritis presence or absence. The differences found may contribute to accelerated joint damage with obesity, but with the osteoarthritic knees less able to accommodate the high loads. PMID- 26476604 TI - Anomalous Origin of the "Nonculprit" Right Coronary Artery From the Left Anterior Descending Artery in a Patient With Anterolateral ST-Segment Elevation Myocardial Infarction. PMID- 26476605 TI - Severe Neointimal Hyperplasia of Neoplastic Carina Following Bioresorbable Scaffold Implantation Using T-Stenting and Small Protrusion Technique: Insights From Optical Frequency Domain Imaging. PMID- 26476606 TI - Thrombus in the Aorta: Late Complication After Percutaneous Closure of Ruptured Sinus of Valsalva Aneurysm. PMID- 26476603 TI - Genetics and biology of primary ciliary dyskinesia. AB - Ciliopathies are a growing class of disorders caused by abnormal ciliary axonemal structure and function. Our understanding of the complex genetic and functional phenotypes of these conditions has rapidly progressed. Primary ciliary dyskinesia (PCD) remains the sole genetic disorder of motile cilia dysfunction. However, unlike many Mendelian genetic disorders, PCD is not caused by mutations in a single gene or locus, but rather, autosomal recessive mutation in one of many genes that lead to a similar phenotype. The first reported PCD mutations, more than a decade ago, identified genes encoding known structural components of the ciliary axoneme. In recent years, mutations in genes encoding novel cytoplasmic and regulatory proteins have been discovered. These findings have provided new insights into the functions of the motile cilia, and a better understanding of motile cilia disease. Advances in genetic tools will soon allow more precise genetic testing, mandating that clinicians must understand the genetic basis of PCD. Here, we review genetic mutations, their biological impact on cilia structure and function, and the implication of emerging genetic diagnostic tools. PMID- 26476607 TI - Anterior Mitral Leaflet Perforation During Transcatheter Aortic Valve Replacement in a Patient With Mitral Annular Calcification. PMID- 26476608 TI - Transcatheter Aortic and Mitral Valve-in-Valve Implantation for Failed Surgical Bioprosthetic Valves: An 8-Year Single-Center Experience. AB - OBJECTIVES: We report our 8-year experience in transcatheter aortic and mitral valve-in-valve (VinV) implantation. BACKGROUND: Feasibility and good early outcomes associated with transcatheter aortic and mitral VinV implantation into failed surgical bioprostheses have been confirmed, but the mid-term and long-term outcomes of transcatheter aortic and mitral VinV is unknown. METHODS: A total of 73 patients with aortic (n = 42) and mitral (n = 31) bioprosthetic valve dysfunction underwent transcatheter VinV implantation between April 2007 and December 2013. Edwards balloon-expandable transcatheter valves (Edwards Lifesciences Inc., Irvine, California) were used. Median follow-up was 2.52 years with a maximum of 8 years. RESULTS: Seventy-two patients (mean age 79.7 +/- 9.4 years, 32 women) underwent successful VinV implantation (success rate 98.6%). At 30 days, all-cause mortality was 1.4%, disabling stroke 1.4%, life-threatening bleeding 4.1%, acute kidney injury requiring hemodialysis 2.7%, and coronary artery obstruction requiring intervention 1.4%. No patient had greater than mild paravalvular leak. Estimated survival rates were 88.9%, 79.5%, 69.8%, 61.9%, and 40.5% at 1, 2, 3, 4, and 5 years, respectively. The small surgical valve size (19 and 21 mm) was an independent risk factor for reduced survival in aortic VinV patients. At 2-year follow-up, 82.8% of aortic and 100% of mitral VinV patients were in New York Heart Association functional class I or II. CONCLUSIONS: Transcatheter VinV for failed surgical bioprostheses can be performed safely with a high success rate and minimal early mortality and morbidity. Transcatheter VinV provides encouraging mid-term clinical outcomes in this high-risk elderly cohort of patients. Transcatheter VinV is an acceptable alternative therapy for failed aortic or mitral bioprostheses in selected high-risk patients. PMID- 26476611 TI - Safety and Efficacy of Stent Retrievers for the Management of Acute Ischemic Stroke: Comprehensive Review and Meta-Analysis. AB - OBJECTIVES: This study sought to evaluate the safety and efficacy of stent retriever for the management of acute ischemic stroke. BACKGROUND: Stroke is the third leading cause of death and the most common cause of disability in the United States. Early reperfusion has been associated with favorable outcomes. Stent retrievers are novel endovascular devices that provide vessel recanalization via thrombus retrieval mechanical thrombectomy. METHODS: The authors performed a literature search using PubMed, EMBASE, and Cochrane Central Register of Controlled Trials from May 2005 to May 2015. Randomized controlled trails (RCTs) comparing endovascular therapy (ET) with the use of retrievable stents against standard therapy (ST) for the management of acute stroke were included. RESULTS: Five RCTs (the MR CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME, and REVASCAT studies) with 634 patients in the ET group and 653 patients in the ST group met inclusion criteria. The frequency of a low 90-day modified Rankin Score (0 to 2) in the intervention group was 42.6% compared with 26.1% in the control group (odds ratio: 2.43; 95% confidence interval [CI]: 1.9 to 3.09; p < 0.0001). The frequency of intracranial bleeding was 4.2% in the ET group compared with 4.3% in the ST group (risk ratio: 1.08; 95% CI: 0.64 to 1.82; p = 0.78). 90-day mortality was 15.1% in the ET group compared with 18.7% in the ST group (risk ratio: 0.81; 95% CI: 0.58 to 1.12; p = 0.19). There was no evidence of significant heterogeneity or publication bias for any of the endpoints. CONCLUSIONS: On the basis of the results of this meta-analysis of RCTs, ET with stent retrievers appears as a safe and effective therapeutic option for acute ischemic stroke due to large vessel occlusion. PMID- 26476609 TI - Long-Term Outcomes After Treatment With a Paclitaxel-Coated Balloon Versus Balloon Angioplasty: Insights From the PEPCAD-DES Study (Treatment of Drug eluting Stent [DES] In-Stent Restenosis With SeQuent Please Paclitaxel-Coated Percutaneous Transluminal Coronary Angioplasty [PTCA] Catheter). AB - OBJECTIVES: The intention this PEPCAD-DES (Treatment of Drug-eluting Stent [DES] In-Stent Restenosis With SeQuent Please Paclitaxel Eluting Percutaneous Transluminal Coronary Angioplasty [PTCA] Catheter) study update was to demonstrate the safety and efficacy of paclitaxel-coated balloon (PCB) angioplasty in patients with DES-ISR at 3 years. BACKGROUND: In the PEPCAD-DES trial late lumen loss and the need for repeat target lesion revascularization (TLR) was significantly reduced with PCB angioplasty compared with plain old balloon angioplasty (POBA) in patients with drug-eluting stent in-stent restenosis (DES-ISR) at 6 months. We evaluated whether the clinical benefit of reduced TLR and major adverse cardiac events (MACE) was maintained up to 3 years. METHODS: A total of 110 patients with DES-ISR in native coronary arteries with reference diameters ranging from 2.5 mm to 3.5 mm and lesion lengths <=22 mm were randomized to treatment with either PCB or POBA in a multicenter, randomized, single-blind clinical study. With a 2:1 randomization, 72 patients were randomized to the PCB group and 38 patients to the POBA group. At baseline, there were lesions with at least 2 stent layers in PCB (52.8%, 38 of 72) and POBA (55.3%, 21 of 38) patients. RESULTS: At 36 months, the TLR rates were significantly lower in the PCB group compared with the POBA control group (19.4% vs. 36.8%; p = 0.046). Multiple TLRs in individual patients were more frequent in the POBA group compared with the PCB group (more than 1 TLR: POBA, 13.2%; PCB, 1.4%; p = 0.021). The 36-month MACE rate was significantly reduced in the PCB group compared with the POBA group (20.8% vs. 52.6%, log-rank p = 0.001). CONCLUSIONS: PCB angioplasty was superior to POBA for the treatment of DES-ISR patients in terms of MACE and TLR for up to 36 months. There was no late catch-up phenomenon. (Treatment of Drug-eluting Stent [DES] In-Stent Restenosis With SeQuent(r) Please Paclitaxel Eluting Percutaneous Transluminal Coronary Angioplasty [PTCA] Catheter [PEPCAD-DES]; NCT00998439). PMID- 26476610 TI - Incidence, Causes, and Predictors of Early (<=30 Days) and Late Unplanned Hospital Readmissions After Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: The aim of this study was to determine the incidence, causes, and predictors of unplanned hospital readmissions after transcatheter aortic valve replacement (TAVR). BACKGROUND: Data regarding unplanned hospital readmissions after TAVR in a real-world all-comers population are scarce. METHODS: A total of 720 consecutive patients undergoing TAVR at 2 centers who survived the procedure, were included. Median follow-up was 23 months (interquartile range [IQR]: 12 to 39 months), available in 99.9% of the initial population. The occurrence, timing, and causes of hospital readmission within the first year post-TAVR were obtained in all cases. Early and late readmissions were defined as those occurring <=30 days and >30 days to 1 year post-TAVR, respectively. RESULTS: There were 506 unplanned readmissions in 316 patients (43.9%) within the first year post-TAVR (median time: 63 days; IQR: 19 to 158 days post-discharge). Of these, early readmission occurred in 105 patients (14.6%), and 118 patients (16.4%) had multiple (>=2) readmissions. Readmissions were due to noncardiac and cardiac causes in 59% and 41% of cases, respectively. Noncardiac readmissions included, in order of decreasing frequency, respiratory, infection, and bleeding events as the main causes, whereas heart failure and arrhythmias accounted for most cardiac readmissions. The predictors of early readmission were periprocedural major bleeding complications (p = 0.001), anemia (p = 0.019), lower left ventricular ejection fraction (p = 0.042), and the combined presence of antiplatelet and anticoagulation therapy at hospital discharge (p = 0.014). The predictors of late readmission were chronic obstructive pulmonary disease (p = 0.001), peripheral vascular disease (p = 0.023), chronic renal failure (p = 0.013), and atrial fibrillation (p = 0.012). Early readmission was an independent predictor of mortality during the follow-up period (hazard ratio: 1.56, 95% confidence interval: 1.02 to 2.39, p = 0.043). CONCLUSIONS: The readmission burden after TAVR in an all-comers population was high. Nearly one-fifth of the patients were readmitted early after hospital discharge, increasing the risk of mortality at follow-up. Reasons for readmission were split between noncardiac and cardiac causes, with respiratory causes and heart failure as the main diagnoses in each group, respectively. Whereas early readmissions were mainly related to periprocedural bleeding events, most late readmissions were secondary to baseline patient comorbidities. These results underscore the importance of and provide the basis for implementing specific preventive measures to reduce readmission rates after TAVR. PMID- 26476612 TI - A Strategy of Underexpansion and Ad Hoc Post-Dilation of Balloon-Expandable Transcatheter Aortic Valves in Patients at Risk of Annular Injury: Favorable Mid Term Outcomes. AB - OBJECTIVES: The aim of this study was to evaluate a strategy of intentional underexpansion of excessively oversized balloon-expandable transcatheter heart valves (THVs) in terms of clinical outcomes, valve function, and frame durability at 1 year. BACKGROUND: Transcatheter aortic valve replacement requires the selection of an optimally sized THV to ensure paravalvular sealing and fixation without risking annular injury. However, some patients have "borderline" annular dimensions that require choosing between a THV that may be too small or another that may be too large. METHODS: We evaluated 47 patients at risk of annular injury who underwent transcatheter aortic valve replacement (TAVR) with an oversized, but deliberately underexpanded, THV followed by post-dilation if required. Clinical evaluation, echocardiography, and cardiac computed tomography were performed pre-TAVR, post-TAVR, and at 1 year. RESULTS: Deployment of oversized THVs with modest underfilling of the deployment balloon (<10% by volume) was not associated with significant annular injury. Paravalvular regurgitation was mild or less in 95.7% of patients, with post-dilation required in 10.7%. THV hemodynamic function was excellent and remained stable at 1 year. Computed tomography documented stent frame circularity in 87.5%. Underexpansion was greatest within the intra-annular THV inflow (stent frame area 85.8% of nominal). There was no evidence of stent frame recoil, deformation, or fracture at 1 year. CONCLUSIONS: In carefully selected patients with borderline annulus dimensions and in whom excessive oversizing of a balloon-expandable SAPIEN XT valve (Edwards Lifesciences, Inc., Irvine, California) is a concern, a strategy of deliberate underexpansion, with ad hoc post-dilation, if necessary, may reduce the risk of annular injury without compromising valve performance. PMID- 26476613 TI - Very Late Scaffold Thrombosis Due to Insufficient Strut Apposition. PMID- 26476614 TI - Investigating biofilm structure developing on carriers from lab-scale moving bed biofilm reactors based on light microscopy and optical coherence tomography. AB - This study focused on characterizing the structure of biofilms developed on carriers used in lab-scale moving bed biofilm reactors. Both light microscopy (2D) and optical coherence tomography (OCT) were employed to track the biofilm development on carriers of different geometry and under different aeration rates. Biofilm structure was further characterized with respect to average biofilm thickness, biofilm growth velocity, biomass volume, compartment filling degree, surface area, etc. The results showed that carriers with a smaller compartment size stimulated a quick establishment of biofilms. Low aeration rates favored fast development of biofilms. Comparison between the results derived from 2D and 3D images revealed comparable results with respect to average biofilm thickness and compartment filling degree before the carrier compartments were fully willed with biomass. However, 3D imaging with OCT was capable of visualizing and quantifying the heterogeneous structure of biofilms, which cannot be achieved using 2D imaging. PMID- 26476615 TI - Optimization of sugarcane bagasse autohydrolysis for methane production from hemicellulose hydrolyzates in a biorefinery concept. AB - This study aimed to optimize through design of experiments, the process variables (temperature - T, time - t and solid-to-liquid ratio - SLR) for sugarcane bagasse (SB) autohydrolysis (AH) to obtain hemicellulose hydrolyzates (HH) prone to anaerobic digestion (AD) and biochemical methane production (BMP). The results indicated that severe AH conditions, which lead to maximum hemicelluloses dissolution and sugar content in the HH, were not the best for BMP, probably due to the accumulation of toxic/recalcitrant compounds (furans and lignin). Mild AH conditions (170 degrees C, 35min and SLR=0.33) led to the highest BMP (0.79Nm(3)kg TOC(-1)), which was confirmed by the desirability tool. HH produced by AH carried out at the desired condition DC2 (178.6 degrees C, 43.6min and SLR=0.24) showed the lowest accumulation of inhibitory compounds and volatile fatty acids (VFA) and highest BMP (1.56Nm(3)kg TOC(-1)). The modified Gompertz model best fit the experimental data and led to a maximum methane production rate (R) of 2.6mmol CH4d(-1) in the best condition. PMID- 26476616 TI - Haematococcus pluvialis soluble proteins: Extraction, characterization, concentration/fractionation and emulsifying properties. AB - A water-soluble matrix was extracted from green vegetative Haematococcus pluvialis through high-pressure cell disruption either at native pH (5.7) or with pH shifting to neutral (7). The resulting supernatant is mainly composed of carbohydrates and proteins, with the highest yield of proteins obtained at neutral pH (73+/-2% of total biomass proteins). The key emulsification properties of the proteins isolated in neutral supernatant (emulsification capacity (EC): 534+/-41mLoilg(-1) protein, emulsification stability (ES): 94+/-3% and emulsification activity index (EAI): 80+/-1m(2)g(-1)) were comparable to the native supernatant values (EC: 589+/-21mLoilg(-1) protein, ES: 84+/-3% and EAI: 75+/-1m(2)g(-1)). Confronted to sodium caseinate (EC: 664+/-30mLoilg(-1) protein, ES: 63+/-4%, and EAI: 56+/-4m(2)g(-1)) these results highlighted the strong potential of proteins isolated from H. pluvialis as emulsifier agent. Moreover, experiments have shown that the stability of emulsions obtained from supernatants is due to the proteins rather than the carbohydrates. PMID- 26476617 TI - Histone H3 phosphorylation is upregulated in PBMCs of schizophrenia patients in comparison to healthy controls. PMID- 26476618 TI - Neurophysiological evidence for a processing bias towards schizophrenia associated communication abnormalities. AB - BACKGROUND: The current study aimed to examine the effects of diagnostic and symptomatic information on auditory linguistic event-related potentials (ERPs) in the listener, in response to speech containing schizophrenia-associated communication abnormalities. METHODS: 73 participants listened to conversation segments while continuous EEG was recorded. Participants were told that the responder in the conversation was either a university student, had symptoms from a stroke, had symptoms from schizophrenia, or had recovered from schizophrenia. The final word of the response was randomly presented as a typical ending, word approximation, neologism, or filler ending. RESULTS: A significant N400 was observed over centro-parietal electrode sites in response to word approximations and neologisms in the university student condition only. There were no differences between conditions in the N100 ERP, and EEG measures were not related to either subjective or objective measures of stigmatizing attitudes. CONCLUSIONS: The N400 effect may represent disengagement, at a semantic level, from what an individual is saying based on symptomatic or diagnostic information about schizophrenia. PMID- 26476619 TI - Ramadan and diabetes: What we see, learn and understand from continuous glucose monitoring. AB - Abstinence from eating and drinking from dawn to sunset characterizes the holy month of Ramadan. For the 50 million Muslims worldwide with diabetes who adhere to this religious fast, the practice results in marked changes in glucose homoeostasis. The sunset meal (Iftar) that breaks the fasting state is followed by exaggerated surges in blood glucose and sustained overnight hyperglycaemia in cases of nocturnal overfeeding. The predawn meal (Suhoor) frequently results in prolonged glucose decay over the daylight hours. These glycaemic disturbances are particularly marked in insulin-treated patients, in those with unsatisfactory diabetes control during the pre-Ramadan period and in patients who are poorly compliant with lifestyle recommendations. Whether such patients should be exempt from the Islamic fast remains an open debate, which might be partially resolved by long-term controlled studies using the technology of continuous glucose monitoring in large populations of patients with diabetes. PMID- 26476620 TI - Pyruvatibacter mobilis gen. nov., sp. nov., a marine bacterium from the culture broth of Picochlorum sp. 122. AB - A Gram-stain-negative, aerobic bacterium, designated strain GYP-11T, was isolated from the culture broth of a marine microalga, Picochloruma sp. 122. Cells were dimorphic rods; free living cells were motile by means of a single polar flagellum, and star-shaped-aggregate-forming cells were attached with stalks and non-motile. Sodium pyruvate or Tween 20 was required for growth on marine agar 2216.16S rRNA gene sequence analysis revealed that this isolate shared 94.07 % similarity with its closest type strain, Parvibaculum hydrocarboniclasticum EPR92T. Phylogenetic analyses indicated that strain GYP-11T represents a distinct lineage in a robust clade consisting of strain GYP-11T, alphaproteobacterium GMD21A06 and Candidatus Phaeomarinobacter ectocarpi Ec32. This clade was close to the genera Parvibaculum and Tepidicaulis in the order Rhizobiales. Chemotaxonomic and physiological characteristics, including cellular fatty acids and carbon source profiles, also readily distinguished strain GYP-11T from all established genera and species. Thus, it is concluded that strain GYP-11T represents a novel species of a new genus in the order Rhizobiales, for which the name Pyruvatibacter mobilis gen. nov., sp. nov. is proposed. The type strain of Pyruvatibacter mobilis is GYP-11T ( = CGMCC 1.15125T = KCTC 42509T). PMID- 26476621 TI - Frequent condom use with casual partners varies by sexual position among younger gay and bisexual men in New Zealand: national behavioural surveillance 2006-2011. AB - Background Condom promotion remains a cornerstone of HIV/STI control, but must be informed by evidence of uptake and address disparities in use. This study sought to determine the prevalence of, and demographic, behavioural and relational factors associated with, condom use during insertive and receptive anal intercourse with casual partners among younger gay, bisexual and other men who have sex with men (YMSM) in New Zealand. METHODS: The 2006-2011 national HIV behavioural surveillance data for YMSM aged 16-29 years was pooled. Separately for each sexual position, frequent (always/almost always) versus infrequent condom use was regressed onto explanatory variables using manual backward stepwise multivariable logistic regression analysis. RESULTS: Three-quarters of YMSM reported frequent condom use during insertive (76.0%) and receptive (73.8%) anal intercourse. YMSM who were exclusively insertive were more likely to report frequent condom use than versatile YMSM. Factors positively associated with frequent condom use, irrespective of sexual position were: in-person versus web based recruitment, testing HIV negative versus never testing or testing HIV positive, having no recent sex with women, reporting two to five versus one male sexual partner in the past 6 months, reporting no current regular partner, but if in a regular relationship, reporting a boyfriend-type versus fuckbuddy-type partner, and frequent versus infrequent regular partner condom use. Pacific ethnicity and less formal education were negatively associated with frequent condom use only during receptive anal intercourse. CONCLUSIONS: The findings from this study demonstrate that condom norms can be actively established and maintained among YMSM. Condom promotion efforts must increase YMSM's capacity, agency and skills to negotiate condom use, especially for the receptive partner. PMID- 26476622 TI - 3D Bridged Carbon Nanoring/Graphene Hybrid Paper as a High-Performance Lateral Heat Spreader. AB - Graphene paper (GP) has attracted great attention as a heat dissipation material due to its unique thermal transfer property exceeding the limit of graphite. However, the relatively poor thermal transfer properties in the normal direction of GP restricts its wider applications in thermal management. In this work, a 3D bridged carbon nanoring (CNR)/graphene hybrid paper is constructed by the intercalation of polymer carbon source and metal catalyst particles, and the subsequent in situ growth of CNRs in the confined intergallery spaces between graphene sheets through thermal annealing. Further investigation demonstrates that the CNRs are covalently bonded to the graphene sheets and highly improve the thermal transport in the normal direction of the CNR/graphene hybrid paper. This full-carbon architecture shows excellent heat dissipation ability and is much more efficient in removing hot spots than the reduced GP without CNR bridges. This highly thermally conductive CNR/graphene hybrid paper can be easily integrated into next generation commercial high-power electronics and stretchable/foldable devices as high-performance lateral heat spreader materials. This full-carbon architecture also has a great potential in acting as electrodes in supercapacitors or hydrogen storage devices due to the high surface area. PMID- 26476623 TI - Multiple suburethral and subvesical abscesses. PMID- 26476624 TI - Do Plants Eavesdrop on Floral Scent Signals? AB - Plants emit a diverse array of volatile organic compounds that can function as cues to other plants. Plants can use volatiles emitted by neighbors to gain information about their environment, and respond by adjusting their phenotype. Less is known about whether the many different volatile signals that plants emit are all equally likely to function as cues to other plants. We review evidence for the function of floral volatile signals and conclude that plants are as likely to perceive and respond to floral volatiles as to other, better-studied volatiles. We propose that eavesdropping on floral volatile cues is particularly likely to be adaptive because plants can respond to these cues by adjusting traits that directly affect pollination and mating. PMID- 26476625 TI - Defining the efficacy of neurokinin-1 receptor antagonists in controlling chemotherapy-induced nausea and vomiting in different emetogenic settings-a meta analysis. AB - PURPOSE: This meta-analysis was performed to evaluate the efficacy of neurokinin 1 receptor antagonists (NK1RAs) for the prevention of chemotherapy-induced nausea and vomiting (CINV) across different categories of chemotherapeutic emetogenicity. METHODS: A systematic review of MEDLINE (via PubMed) and OVID databases, plus major oncology conferences, identified randomized, controlled trials evaluating NK1RAs in combination with a 5-HT3 RA plus a glucocorticoid for management of CINV. Efficacy end points were no emesis, no nausea, and complete response (CR) rates. Data were analyzed using a random effects model. RESULTS: Twenty-three trials (N = 11,814) were identified. Based on absolute differences (AD) for no emesis (21 %), no nausea (8 %), CR (16 %), and odd ratios (OR) of 2.62, 1.43, and 2.16, respectively, NK1RA regimens provided better CINV protection versus control groups (all p < 0.00001) in patients receiving cisplatin-based highly emetogenic chemotherapy (HEC). In patients receiving anthracycline/cyclophosphamide (AC)-based HEC, respective ADs and ORs were 14, 4, and 11 % and 1.97 (p < 0.0001), 1.17 (p = 0.04), and 1.62 (p < 0.00001). In patients receiving moderately emetogenic chemotherapy (3 trials), no statistically significant benefit of NK1RAs was found; however, positive trends were detected for CR and no emesis. NK1RAs were effective for CINV prevention in a small number of studies using high-dose chemotherapy as conditioning prior to stem cell transplant and cisplatin-based multiple-day chemotherapy (MDC). CONCLUSIONS: This meta-analysis demonstrated the efficacy of NK1RA in preventing vomiting in patients receiving HEC (including AC), with smaller effects on prevention of nausea. Efficacy is also seen with high-dose chemotherapy and cisplatin-based MDC. PMID- 26476626 TI - Hope, emotion regulation, and psychosocial well-being in patients newly diagnosed with cancer. AB - PURPOSE: Patients newly diagnosed with cancer are often confronted with feelings of uncertainty and life threat. A significant proportion may report impairments in psychosocial well-being. Previous studies examining protective psychological factors such as hope and emotion regulation (ER) have yet to investigate these processes concurrently within a common self-regulation framework and/or focus on newly diagnosed patients. The present study aimed to examine how hope and ER may relate to psychosocial outcomes of patients newly diagnosed with cancer. METHODS: The present study used a cross-sectional design with self-report questionnaires. Participants were newly diagnosed patients (N = 101) recruited from three cancer therapy clinics in a hospital. Patients completed measures of hope, ER (cognitive reappraisal and expressive suppression), and psychosocial well-being (life satisfaction and negative affectivity). RESULTS: Findings showed that (1) hope and reappraisal, but not suppression, were associated with well-being and (2) the interaction between hope and reappraisal was associated with well-being; reappraisal was not associated with well-being in high hope patients, while high reappraisal was associated with better well-being in low hope patients. CONCLUSION: Individual differences in hope and reappraisal appeared to be associated with psychosocial outcomes in newly diagnosed cancer patients. Hopeful thinking appeared to benefit patients' psychosocial well-being. In addition, an interaction effect between hope and reappraisal suggested that reappraisal as an ER strategy may be particularly adaptive for patients with low hope. PMID- 26476627 TI - "Undressing" distress among cancer patients living in urban, regional, and remote locations in Western Australia. AB - PURPOSE: People diagnosed with cancer from rural and remote locations may experience heightened distress because of distance from cancer treatment and support services. We examined whether remoteness and other factors are associated with psychosocial distress and explored commonly reported problems among cancer patients in Western Australia (WA). METHODS: In a cross-sectional study, cancer patients newly referred to a Cancer Council WA Cancer Support Coordinator (CSC) were screened and assessed using the Distress Thermometer (DT) and Problem List (PL) and a standardized form, respectively. The index of remoteness was the Australian Standard Geographical Classification. The association between remoteness, demographic variables, and the frequency of problems endorsed on the PL was analyzed using bivariate analyses and a generalized linear mixed model (GLMM) regression. RESULTS: Of 1032 patients referred to a CSC, 466 were screened (45.2 %) with complete data available for 441 patients. Patients from remote areas reported fewer problems than patients from urban and regional locations. Increasing remoteness was not associated with higher distress (r = -0.04, p = 0.43). Concerns reported differed by remoteness category and included worry, sadness, fears, finances, transportation, and physical symptoms. More emotional problems were independently associated with higher distress (beta = 0.47, p < 0.001), explaining 17.31 % of the variance. CONCLUSIONS: There is no evidence that increasing remoteness is associated with higher distress. Emotional concerns and physical problems appear to be prevalent among cancer patients irrespective of urban or rural location. Specific concerns detected by distress screening, particularly emotional concerns, may warrant further assessment and targeted referrals. PMID- 26476628 TI - Informal caregivers of advanced-stage cancer patients: Every second is at risk for psychiatric morbidity. AB - PURPOSE: Informal caregivers of advanced cancer patients are known to suffer from high distress due to their caregiving responsibilities. Nevertheless, a comprehensive evaluation of psychiatric morbidity is often missing in clinical practice due to time resources, and mental health problems may be unnoticed in this population. A feasible approach is needed to identify caregivers at risk for psychiatric disorders to offer targeted interventions and enhance their well being. METHODS: This cross-sectional, multi-institutional study screened 345 caregivers of advanced cancer patients for psychiatric disorders (i.e., depression, anxiety, posttraumatic stress disorder, and alcohol abuse/dependence) and assessed factors potentially associated with mental health diagnoses (including socio-demographic factors, burden, hope, caring-related quality of life, and coping preferences). RESULTS: Overall, almost 52 % of participants had one or more suspected psychiatric disorders, with anxiety being the most prevalent. Perceived hope, higher burden, and more emotion-oriented coping were associated with psychiatric morbidity in this sample. Spouses and parents showed significantly more symptoms of psychiatric disorders than other relatives. CONCLUSIONS: This study confirms the high risk of informal caregivers of advanced cancer patients to develop psychiatric disorders and suggests a practically feasible approach to identify at risk caregivers to offer support. PMID- 26476629 TI - Study design and population pharmacokinetic analysis of a phase II dose-ranging study of interleukin-1 receptor antagonist. AB - Interleukin-1 receptor antagonist, a naturally-occurring antagonist to the pro inflammatory cytokine Interleukin-1, is already in clinical use. In experimental models of stroke, Interleukin-1 receptor antagonist in cerebrospinal fluid has been associated with cerebral neuroprotection and in a phase I clinical trial in patients with subarachnoid haemorrhage it crosses the blood-cerebrospinal fluid barrier. The aims of the current work were to design a dose-ranging clinical study in patients and to analyse the plasma and cerebrospinal fluid data obtained using a population pharmacokinetic modelling approach. The study was designed using prior information: a published population pharmacokinetic model and associated parameter estimates. Simulations were carried out to identify combinations of intravenous bolus and 4 h infusion doses that could achieve a concentration of 100 ng/ml in cerebrospinal fluid within approximately 30 min. The most informative time points for plasma and cerebrospinal fluid were obtained prospectively; optimisation identified five sampling time points that were included in the 15 time points in the present study design. All plasma and cerebrospinal fluid concentration data from previous and current studies were combined for updated analysis. The result of the simulations showed that a dosage regimen of 500 mg intravenous bolus and 10 mg/kg/h could achieve the target concentration, however four other regimens that represent a stepwise increase in maximum concentration were also selected. Analysis of the updated data showed improvement in parameter accuracy and predictive performance of the model; the percentage relative standard errors for fixed and random-effects parameters were <15 and 35% respectively. A dose-ranging study was successfully designed using modelling and simulation. PMID- 26476630 TI - Totally laparoscopic gastrectomy for gastric cancer after endoscopic submucosal dissection: a propensity score matching analysis. AB - PURPOSE: A recently developed endoscopic mucosal resection (EMR) procedure, endoscopic submucosal dissection (ESD), makes en bloc resection possible for mucosal cancer regardless of lesion size. ESD involves deeper and wider dissection of the gastric wall and may therefore increase the difficulty of subsequent totally laparoscopic gastrectomy (TLG) and the risk of complications. However, the influence of ESD on subsequent TLG has yet to be demonstrated. The purpose of the present study was to clarify the influence of ESD on subsequent TLG. METHODS: Between March 2006 and December 2013, we retrospectively collected data of 38 patients undergoing TLG with ESD (ESD group) and propensity score matched 38 patients undergone TLG without ESD (non-ESD group) for treatment of gastric cancer at Tonan Hospital and Hokkaido University Hospital. The covariates for propensity score matching were as follows: age, sex, American Society of Anesthesiologists score, body mass index, and type of surgery. Clinicopathologic characteristics and surgical outcomes were compared between the two groups. RESULTS: Operative times for TLG in ESD group and non-ESD group were 228.2 +/- 53.9 and 228.1 +/- 52.7 min (P = 0.989), and blood loss was 45.7 +/- 83.0 and 71.3 +/- 74.5 g, respectively (P = 0.161). There were no significant differences between the groups of ESD and non-ESD in postoperative recovery and postoperative complications. In totally laparoscopic distal gastrectomy (TLDG), the patients with ESD-resected specimens of more than 50 mm in diameter had significantly longer operative times (P = 0.009). CONCLUSIONS: In this study, TLG is a feasible procedure treatment of gastric cancer regardless of ESD. However, TLDG is more difficult in cases where the ESD-resected specimen is more than 50 mm in diameter. PMID- 26476631 TI - A possible link between hepatic mitochondrial dysfunction and diet-induced insulin resistance. AB - BACKGROUND: Mitochondria are the main cellular sites devoted to ATP production and lipid oxidation. Therefore, the mitochondrial dysfunction could be an important determinant of cellular fate of circulating lipids, that accumulate in the cytoplasm, if they are not oxidized. The ectopic fat accumulation is associated with the development of insulin resistance, and a link between mitochondrial dysfunction and insulin resistance has been proposed. METHODS: Recent data on the possible link existing between mitochondrial dysfunction in the liver and diet induced obesity will be summarized, focusing on the three factors that affect the mitochondrial oxidation of metabolic fuels, i.e. organelle number, organelle activity, and energetic efficiency of the mitochondrial machinery in synthesizing ATP. Search in PubMed relevant articles from 2003 to 2014 was conducted, by using query "liver mitochondria and obesity" "hepatic mitochondria and obesity" "liver mitochondria and high fat diet" and "hepatic mitochondria and high fat diet" and including related articles by the same groups. RESULTS: Several works, by using different physiological approaches, have dealt with alteration in mitochondrial function in obesity and diabetes. Most results show that hepatic mitochondrial function is impaired in models of obesity and insulin resistance induced by high-fat or highfructose feeding. CONCLUSIONS: Since mitochondria are the main producers of both cellular energy and free radicals, dysfunctional mitochondria could play an important role in the development of insulin resistance and ectopic fat storage in the liver, thus supporting the emerging idea that mitochondrial dysfunction is closely related to the development of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis. PMID- 26476632 TI - Food supplementation with rice bran enzymatic extract prevents vascular apoptosis and atherogenesis in ApoE-/- mice. AB - PURPOSE: Atherosclerosis is associated with reduced mononuclear cell (MNC) telomere length, and senescent cells have been detected in atherosclerotic plaques. Rice bran is a source of gamma-oryzanol, phytosterols and tocols with potential lipid-lowering, antioxidant and anti-inflammatory activities. Here, we tested the hypothesis that rice bran enzymatic extract (RBEE) impacts on apoptosis, telomere length and atherogenesis in mice. METHODS: Seven-week-old male ApoE-/- mice were fed high-fat diet (HFD) or isocaloric HFD supplemented with 5 % (w/w) RBEE for 23 weeks. Wild-type mice of the same age were kept under standard diet as controls. RESULTS: RBEE treatment reduced total cholesterol (19.24 +/- 1.63 vs 24.49 +/- 1.71 mmol/L) and triglycerides (1.13 +/- 0.18 vs 1.75 +/- 0.22 mmol/L) and augmented HDL-cholesterol (1.86 +/- 0.20 vs 1.07 +/- 0.20 mmol/L). RBEE attenuated macrophage infiltration by 56.69 +/- 4.65 % and plaque development (7737 +/- 836 vs 12,040 +/- 1001 MUm2) in the aortic sinus. In the aorta, RBEE treatment reduced expression of the apoptosis pathway components p16, p53 and bax/bcl-2 ratio. RBEE prevented apoptosis of aortic endothelial cells (2.81 +/- 0.71-1.14 +/- 0.35 apoptotic nuclei/ring for ApoE-/- HFD and ApoE /- HFD 5 % RBEE, respectively). In contrast, MNC of RBEE-fed mice exhibited enhanced apoptosis marker expression with increased p53 and bax/bcl-2 protein levels. Compared to WT, ApoE-/- mice on HFD were characterized by significant telomere shortening in aorta (11 +/- 2 %) and MNC (73 +/- 7 %), which was reduced by supplementation with RBEE (aorta: 40 +/- 7 %; MNC: 105 +/- 10 %). Expression of telomere repeat-binding factor 2 was increased in RBEE-fed mice. CONCLUSION: Long-term food supplementation with RBEE lowers cholesterol and prevents atherosclerotic plaque development in ApoE-/- mice. Differential regulation of vascular and MNC apoptosis and senescence were identified as potential mechanisms. PMID- 26476634 TI - Vinegar decreases blood pressure by down-regulating AT1R expression via the AMPK/PGC-1alpha/PPARgamma pathway in spontaneously hypertensive rats. AB - PURPOSE: Vinegar has been reported to lower blood pressure, but its mechanism is unclear. This study explored whether vinegar plays antihypertensive effect by activating AMP-activated protein kinase (AMPK) pathway. METHODS: Male spontaneously hypertensive rats (SHRs) were assigned to vinegar, acetic acid, nifedipine, nifedipine + vinegar, or distilled water by oral gavage for 8 weeks. Blood and aortas were analyzed for biochemical indices and protein expression levels. Sv40-transformed aortic rat endothelia cell line (SVAREC) cells were treated with acetate at different doses for 24 h; protein expression levels were assessed. RESULTS: Vinegar and acetic acid decreased blood pressure in SHRs on weeks 6 and 8, and nifedipine + vinegar had a better effect on blood pressure control than vinegar or nifedipine alone. Vinegar and acetic acid could decrease serum renin and angiotensin-converting enzyme (ACE) activities, angiotensin II and aldosterone concentrations in SHRs. Vinegar and acetic acid also increased AMP/ATP ratios and expression levels of pAMPK, PPARgamma coactivator-1alpha (PGC 1alpha), and PPARgamma while inhibited angiotensin II type 1 receptor (AT1R) expression in SHRs. The changes in these protein expressions were also found in SVAREC cells treated with 200 or 400 MUmol/L acetate. In the presence of AMPK inhibitor or PGC-1alpha small interfering RNA, the effects of acetate on their downstream protein expression in SVAREC cells were abolished, respectively. CONCLUSION: Vinegar activates AMPK by increasing AMP/ATP ratios, thereby increases PGC-1alpha and PPARgamma expressions, and inhibits AT1R expression in SHRs. Acetic acid is responsible for the antihypertensive effects of vinegar. There is a joint effect between vinegar and nifedipine in blood pressure control. PMID- 26476633 TI - Inhibition of pancreatic cancer cell migration by plasma anthocyanins isolated from healthy volunteers receiving an anthocyanin-rich berry juice. AB - PURPOSE: Pancreatic cancer is an aggressive cancer type, of which the most important characteristics are migration and metastasis. Anthocyanins (ACN) are discussed to be protective phytochemicals; however, up to now only scarce data are available regarding their effects on cancer prevention. In this study, we aimed to determine whether ACN and their metabolites from plasma (PAM), isolated from blood of healthy volunteers after ingestion of an ACN-rich juice, are effective in modulating cancer cell migration in vitro. METHODS: PAM were isolated from blood of healthy volunteers (n = 10) after consumption of an ACN rich berry juice. Before ingestion (PAM0min) and after 60 min (PAM60min), blood was taken and PAM were isolated from plasma by solid-phase extraction. Migration of pancreatic cancer cells PANC-1 and AsPC-1 was assayed in a Boyden chamber. The influence of PAM on cellular reactive oxygen species (ROS) or mitochondria specific ROS was measured fluorimetrically. mRNA expression levels of matrix metalloproteinases (MMP-2 and MMP-9) and NF-kappaB mRNA were determined by real time PCR. RESULTS: After application of PAM60min to PANC-1, we observed a reduced cell migration, which was associated with reduced levels of endogenously generated ROS concomitant with reduced NF-kappaB as well as MMP-2 and MMP-9 mRNA expression levels. In AsPC-1 cells, however, migration was not affected by PAM60min. CONCLUSION: It can be assumed that physiologically relevant ACN and their metabolites were able to inhibit pancreatic cancer cell migration in dependency of the phenotype of cells and may thus deserve further attention as potential bioactive phytochemicals in cancer prevention. PMID- 26476635 TI - Enhanced Early Posterior Negativity to Fearful Faces in Patients with Anxiety Disorder. AB - Patients with anxiety disorders (AnDs) have distinct patterns of threat-related emotional processing compared to healthy controls (HCs). The current study investigated the temporal course of emotional processing in AnDs by examining Event-related potential (ERP) components. Twenty-three AnDs and twenty-four age- and gender-matched HCs viewed emotional (fearful, happy) and neutral faces while their electroencephalograms were recorded. Early (P100, N170), middle (early posterior negativity; EPN), and late ERP components late positive potential were analyzed. To localize ERP source activity, standardized low-resolution brain electromagnetic tomography (sLORETA) was used. AnDs displayed significantly enhanced mean amplitude of the EPN compared to HCs when fearful faces were presented. In addition, the EPN's mean amplitude elicited by fearful faces was more pronounced than for happy and neutral faces in AnDs, whereas in HCs the EPN elicited by fearful faces was only augmented compared to neutral faces. Finally, sLORETA analysis revealed that the source activity of the EPN (fearful minus happy face condition) was increased in the cuneus and precuneus in AnDs compared to HCs. Our results indicate that the EPN is a distinct ERP component modulated by facial emotional processing in AnDs. Furthermore, the results show that anxiety symptoms enhance selective attention for fearful faces. Finally, it revealed that the cuneus and precuneus are involved in fearful face processing in AnDs. PMID- 26476636 TI - Comparison of anterograde versus retrograde percutaneous screw fixation of anterior column acetabular fractures. AB - PURPOSE: Percutaneous screw fixation is an effective technique in addressing minimally displaced anterior column acetabular fractures. The aim of this study is to evaluate the ease of percutaneous screw insertion for acetabular anterior column fracture, as it pertains to anterograde versus retrograde insertion techniques. METHOD: From 2009 to 2013, CT imaging from 30 adult volunteers (15 males, 15 females) without history of pelvic disruption and/or morphologic abnormalities were evaluated. From these images, virtual 3D pelvic models were generated. The differences area of screw starting points, limitation position of anterior column screws, and range of screw directions were analyzed. CONCLUSION: We found in our analysis that anterograde and retrograde had not only variations in their starting points, but differences in areas of insertion. Typically, anterograde portals have a larger area for insertion. Additionally, given the limitations we noted in screw position and the severity of the acetabular fractures, this will allow the treating surgeon to determine the most optimal technique for percutaneous anterior column screw fixation. RESULTS: In our analysis, we found two areas for effective percutaneous anterograde insertion and one area for effective retrograde insertion. They both possess geometries with different shapes. Additionally, the area of anterograde insertion is larger than the retrograde area of insertion. The limitations in screw positions were shown in the AP, inlet, outlet, iliac oblique, obturator oblique, and lateral views. The direction range between superior and inferior and between medial and lateral were measured and recorded. In area of anterograde, the angle between the superior and inferior limits was 29.2 degrees +/- 2.7 degrees , while the angle limit between medial and lateral was 18.5 degrees +/- 1.8 degrees . In area of retrograde, the angle between the superior and inferior limits was 8.32 degrees +/- 1.3 degrees , while the angle limit between medial and lateral was 7.5 degrees +/- 0.8 degrees PMID- 26476638 TI - Optimal classification for the diagnosis of duchenne muscular dystrophy images using support vector machines. AB - BACKGROUND: This study aimed to investigate the optimal support vector machines (SVM)-based classifier of duchenne muscular dystrophy (DMD) magnetic resonance imaging (MRI) images. METHODS: T1-weighted (T1W) and T2-weighted (T2W) images of the 15 boys with DMD and 15 normal controls were obtained. Textural features of the images were extracted and wavelet decomposed, and then, principal features were selected. Scale transform was then performed for MRI images. Afterward, SVM based classifiers of MRI images were analyzed based on the radical basis function and decomposition levels. The cost (C) parameter and kernel parameter [Formula: see text] were used for classification. Then, the optimal SVM-based classifier, expressed as [Formula: see text]), was identified by performance evaluation (sensitivity, specificity and accuracy). RESULTS: Eight of 12 textural features were selected as principal features (eigenvalues [Formula: see text]). The 16 SVM based classifiers were obtained using combination of (C, [Formula: see text]), and those with lower C and [Formula: see text] values showed higher performances, especially classifier of [Formula: see text]). The SVM-based classifiers of T1W images showed higher performance than T1W images at the same decomposition level. The T1W images in classifier of [Formula: see text]) at level 2 decomposition showed the highest performance of all, and its overall correct sensitivity, specificity, and accuracy reached 96.9, 97.3, and 97.1 %, respectively. CONCLUSION: The T1W images in SVM-based classifier [Formula: see text] at level 2 decomposition showed the highest performance of all, demonstrating that it was the optimal classification for the diagnosis of DMD. PMID- 26476639 TI - Tendon-driven continuum robot for neuroendoscopy: validation of extended kinematic mapping for hysteresis operation. AB - PURPOSE: The hysteresis operation is an outstanding issue in tendon-driven actuation--which is used in robot-assisted surgery--as it is incompatible with kinematic mapping for control and trajectory planning. Here, a new tendon-driven continuum robot, designed to fit existing neuroendoscopes, is presented with kinematic mapping for hysteresis operation. METHODS: With attention to tension in tendons as a salient factor of the hysteresis operation, extended forward kinematic mapping (FKM) has been developed. In the experiment, the significance of every component in the robot for the hysteresis operation has been investigated. Moreover, the prediction accuracy of postures by the extended FKM has been determined experimentally and compared with piecewise constant curvature assumption. RESULTS: The tendons were the most predominant factor affecting the hysteresis operation of the robot. The extended FKM including friction in tendons predicted the postures in the hysteresis operation with improved accuracy (2.89 and 3.87 mm for the single and the antagonistic-tendons layouts, respectively). The measured accuracy was within the target value of 5 mm for planning of neuroendoscopic resection of intraventricle tumors. CONCLUSION: The friction in tendons was the most predominant factor for the hysteresis operation in the robot. The extended FKM including this factor can improve prediction accuracy of the postures in the hysteresis operation. The trajectory of the new robot can be planned within target value for the neuroendoscopic procedure by using the extended FKM. PMID- 26476637 TI - Clinical evaluation of a model-updated image-guidance approach to brain shift compensation: experience in 16 cases. AB - PURPOSE: Brain shift during neurosurgical procedures must be corrected for in order to reestablish accurate alignment for successful image-guided tumor resection. Sparse-data-driven biomechanical models that predict physiological brain shift by accounting for typical deformation-inducing events such as cerebrospinal fluid drainage, hyperosmotic drugs, swelling, retraction, resection, and tumor cavity collapse are an inexpensive solution. This study evaluated the robustness and accuracy of a biomechanical model-based brain shift correction system to assist with tumor resection surgery in 16 clinical cases. METHODS: Preoperative computation involved the generation of a patient-specific finite element model of the brain and creation of an atlas of brain deformation solutions calculated using a distribution of boundary and deformation-inducing forcing conditions (e.g., sag, tissue contraction, and tissue swelling). The optimum brain shift solution was determined using an inverse problem approach which linearly combines solutions from the atlas to match the cortical surface deformation data collected intraoperatively. The computed deformations were then used to update the preoperative images for all 16 patients. RESULTS: The mean brain shift measured ranged on average from 2.5 to 21.3 mm, and the biomechanical model-based correction system managed to account for the bulk of the brain shift, producing a mean corrected error ranging on average from 0.7 to 4.0 mm. CONCLUSIONS: Biomechanical models are an inexpensive means to assist intervention via correction for brain deformations that can compromise surgical navigation systems. To our knowledge, this study represents the most comprehensive clinical evaluation of a deformation correction pipeline for image-guided neurosurgery. PMID- 26476640 TI - A clinically applicable laser-based image-guided system for laparoscopic liver procedures. AB - PURPOSE: Laser range scanners (LRS) allow performing a surface scan without physical contact with the organ, yielding higher registration accuracy for image guided surgery (IGS) systems. However, the use of LRS-based registration in laparoscopic liver surgery is still limited because current solutions are composed of expensive and bulky equipment which can hardly be integrated in a surgical scenario. METHODS: In this work, we present a novel LRS-based IGS system for laparoscopic liver procedures. A triangulation process is formulated to compute the 3D coordinates of laser points by using the existing IGS system tracking devices. This allows the use of a compact and cost-effective LRS and therefore facilitates the integration into the laparoscopic setup. The 3D laser points are then reconstructed into a surface to register to the preoperative liver model using a multi-level registration process. RESULTS: Experimental results show that the proposed system provides submillimeter scanning precision and accuracy comparable to those reported in the literature. Further quantitative analysis shows that the proposed system is able to achieve a patient-to-image registration accuracy, described as target registration error, of [Formula: see text]. CONCLUSIONS: We believe that the presented approach will lead to a faster integration of LRS-based registration techniques in the surgical environment. Further studies will focus on optimizing scanning time and on the respiratory motion compensation. PMID- 26476642 TI - Polysialic acid biosynthesis and production in Escherichia coli: current state and perspectives. AB - Polysialic acid (PSA) is a unique polysaccharide that plays critical roles in many bioprocesses, which makes it useful in a wide range of biomedical applications. The increased demand for PSA has led to considerable efforts to improve its production using bacteria, such as Escherichia coli. Bioprocess optimization and metabolic engineering have allowed the efficient production of PSA. This review aims to summarize the metabolism of PSA with an emphasis on the importance of the key pathway components. In addition, this review provides an update on state of the art PSA production using E. coli with a special emphasis on strategies of strain engineering and process development for the enhanced production of PSA. PMID- 26476641 TI - Predicting children's behaviour during dental treatment under oral sedation. AB - AIMS: The primary aim of this study was to assess whether parents' own anxiety and their perception of their child's dental fear and child's general fear can predict preoperatively their child's behaviour during dental treatment under oral sedation. The secondary aim was to assess whether the child's age, gender and ASA classification grade are associated with a child's behaviour under oral sedation. STUDY DESIGN: Cross-sectional prospective study. METHODS: The Corah's Dental Anxiety Scale (DAS), Children's Fear Survey Schedule Dental-Subscale (CFSS-DS) and Children's Fear Survey Schedule Short-Form (CFSS-SF) questionnaires were completed by parents of children undergoing dental treatment with oral midazolam. Behaviour was rated by a single clinician using the overall behaviour section of the Houpt-Scale and scores dichotomised into acceptable or unacceptable behaviour. Data were analysed using chi (2), t test and logistic regression analysis. RESULTS: In total 404 children (215 girls, 53 %) were included, with the mean age of 4.57 years, SD = 1.9. Behaviour was scored as acceptable in 336 (83 %) and unacceptable in 68 (17 %) children. STATISTICS: The level of a child's dental fear, as perceived by their parent, was significantly associated with the behaviour outcome (p = 0.001). Logistic regression analysis revealed that if the parentally perceived child's dental fear (CFSS-DS) rating was high, the odds of the child exhibiting unacceptable behaviour under oral sedation was two times greater than if their parents scored them a low dental fear rating (OR 2.27, 95 % CI 1.33-3.88, p = 0.003). CONCLUSIONS: CFSS-DS may be used preoperatively to help predict behaviour outcome when children are treated under oral sedation and facilitate treatment planning. PMID- 26476643 TI - The blue-light receptor CmWC-1 mediates fruit body development and secondary metabolism in Cordyceps militaris. AB - Light is an essential factor for pigment formation and fruit body development in Cordyceps militaris, a well-known edible and medicinal fungus. Cmwc-1, a homolog of the blue-light receptor gene white collar-1 (wc-1) in Neurospora crassa, was cloned from the C. militaris genome in our previous study. Here, Cmwc-1 gene inactivation results in thicker aerial hyphae, disordered fruit body development, a significant reduction in conidial formation, and carotenoid and cordycepin production. These characteristics were restored when the DeltaCmwc-1 strains were hybridized with wild-type strains of the opposite mating type. A genome-wide expression analysis revealed that there were 1042 light-responsive genes in the wild-type strain and only 458 in the DeltaCmwc-1 strain. Among five putative photoreceptors identified, Vivid, cryptochrome-1, and cyclobutane pyrimidine dimer photolyase are strongly induced by light in a Cmwc-1-dependent manner, while phytochrome and cryptochrome-2 were not induced. The transcription factors involved in the fungal light reaction were mainly of the Zn2Cys6 type. CmWC-1 regulates adenylosuccinate synthase, an important enzyme for adenosine de novo synthesis, which could explain the reduction in cordycepin production. Some G protein-coupled receptors that control fungal fruit body formation and the sexual cycle were regulated by CmWC-1, and the cAMP pathway involved in light signal transduction in N. crassa was not critical for the photoreaction in the fungus here. A transcriptional analysis indicated that steroid biosynthesis was more active in the DeltaCmwc-1 strain, suggesting that CmWC-1 might switch the vegetative growth state to primordia differentiation by suppressing the expression of related genes. PMID- 26476644 TI - Improving alkane synthesis in Escherichia coli via metabolic engineering. AB - Concerns about energy security and global petroleum supply have made the production of renewable biofuels an industrial imperative. The ideal biofuels are n-alkanes in that they are chemically and structurally identical to the fossil fuels and can "drop in" to the transportation infrastructure. In this work, an Escherichia coli strain that produces n-alkanes was constructed by heterologous expression of acyl-acyl carrier protein (ACP) reductase (AAR) and aldehyde deformylating oxygenase (ADO) from Synechococcus elongatus PCC7942. The accumulation of alkanes ranged from 3.1 to 24.0 mg/L using different expressing strategies. Deletion of yqhD, an inherent aldehyde reductase in E. coli, or overexpression of fadR, an activator for fatty acid biosynthesis, exhibited a nearly twofold increase in alkane titers, respectively. Combining yqhD deletion and fadR overexpression resulted in a production titer of 255.6 mg/L in E. coli, and heptadecene was the most abundant product. PMID- 26476645 TI - Ferulic acid transformation into the main vanilla aroma compounds by Amycolatopsis sp. ATCC 39116. AB - The wild strain Amycolatopsis sp. ATCC 39116 was explored in ferulic acid-based media to produce naturally the aroma components of the cured vanilla pod, namely vanillin,vanillic acid, and vanillyl alcohol. Other phenolic compounds(4-vinyl guaiacol, guaiacol, and protocatechuic acid) were also evaluated. The influence of medium composition,fermentation technology (batch or fed-batch), supplementation with vanillic acid, and inoculum concentration on ferulic acid biotransformation were evaluated. The results postulate the initial concentration of cell mass as the variable with the strongest impact on ferulic acid metabolization under the studied conditions. The highest amounts of vanillin and vanillic acid were achieved at intermediate values of cell mass.Vanillyl alcohol and protocatechuic acid were more closely linked to high cell mass concentrations. Conversely, 4-vinyl guaiacol reached its highest amount at the lowest amount of cell mass. Guaiacol was not detected in any case. Therefore,the initial cell concentration must be considered a critical parameter when using Amycolaptosis sp. ATCC 39116 for the production of vanillin and related compounds. PMID- 26476646 TI - Enhanced production of leech hyaluronidase by optimizing secretion and cultivation in Pichia pastoris. AB - Leech hyaluronidase (LHAase) was recently cloned and successfully expressed in Pichia pastoris. To increase its secretory expression level, four signal peptides (nsB, YTP1, SCS3, and HKR1) and six amphipathic peptides (APs) were comparatively investigated. After substitution with nsB and fusion with AP2, the production of LHAase was significantly increased, from 8.42 * 10(5) to 1.24 * 10(6) U/ml. Compared with the parental LHAase, the variant AP2-LHAase showed a lower optimum pH (5.0), higher optimum temperature (50 degrees C), and a broader range of thermal stability (20-60 degrees C). To further promote fermentative production of the variant AP2-LHAase, the cultivation temperature was systematically optimized according to cell viability and alcohol oxidase activity. Eventually, through a combination of N-terminal engineering and optimization of cultivation, the production of LHAase was improved to 1.68 * 10(6) U/ml, with a high productivity of 1.87 * 10(4) U/ml/h. PMID- 26476647 TI - AA9 and AA10: from enigmatic to essential enzymes. AB - The lignocellulosic biomass, comprised mainly of cellulose, hemicellulose, and lignin, is a strong competitor for petroleum to obtain fuels and other products because of its renewable nature, low cost, and non-competitiveness with food production when obtained from agricultural waste. Due to its recalcitrance, lignocellulosic material requires an arsenal of enzymes for its deconstruction and the consequent release of fermentable sugars. In this context, enzymes currently classified as auxiliary activity 9 (AA9/formerly GH61) and 10 (AA10/formerly CBM 33) or lytic polysaccharide monooxygenases (LPMO) have emerged as cellulase boosting enzymes. AA9 and AA10 are the new paradigm for deconstruction of lignocellulosic biomass by enhancing the activity and decreasing the loading of classical enzymes to the reaction and, consequently, reducing costs of the hydrolysis step in the second-generation ethanol production chain. In view of that disclosed above, the goal of this work is to review experimental data that supports the relevance of AA9 and AA10 for the biomass deconstruction field. PMID- 26476648 TI - Mycoremediation with mycotoxin producers: a critical perspective. AB - Filamentous fungi that produce mycotoxins also demonstrate the ability to degrade a wide variety of naturally occurring and anthropogenically generated hazardous wastes. Hence, these are emerging as excellent candidates for bioremediation. Their mycelia exhibit the robustness of adapting to highly restrictive environmental conditions often experienced in the presence of persistent pollutants, which makes them more useful compared to other microbes. However, it now appears that several regulatory factors that govern mycotoxin synthesis in these toxigenic strains also regulate their bioremediation abilities. To this end, mycoremediation and mycotoxin synthesis have been thoroughly but independently investigated; hence, much less is understood about the overlaps between the two processes. This review aims to shed light on this critical knowledge gap and provide some useful insights into the future research that might overcome the challenges associated with these shared regulatory modules. This will enable the harnessing of the full potential of mycoremediation by minimizing mycotoxin contamination. PMID- 26476649 TI - Reactor performances and microbial communities of biogas reactors: effects of inoculum sources. AB - Anaerobic digestion is a very complex process that is mediated by various microorganisms, and the understanding of the microbial community assembly and its corresponding function is critical in order to better control the anaerobic process. The present study investigated the effect of different inocula on the microbial community assembly in biogas reactors treating cellulose with various inocula, and three parallel biogas reactors with the same inoculum were also operated in order to reveal the reproducibility of both microbial communities and functions of the biogas reactors. The results showed that the biogas production, volatile fatty acid (VFA) concentrations, and pH were different for the biogas reactors with different inocula, and different steady-state microbial community patterns were also obtained in different biogas reactors as reflected by Bray Curtis similarity matrices and taxonomic classification. It indicated that inoculum played an important role in shaping the microbial communities of biogas reactor in the present study, and the microbial community assembly in biogas reactor did not follow the niche-based ecology theory. Furthermore, it was found that the microbial communities and reactor performances of parallel biogas reactors with the same inoculum were different, which could be explained by the neutral-based ecology theory and stochastic factors should played important roles in the microbial community assembly in the biogas reactors. The Bray-Curtis similarity matrices analysis suggested that inoculum affected more on the microbial community assembly compared to stochastic factors, since the samples with different inocula had lower similarity (10-20 %) compared to the samples from the parallel biogas reactors (30 %). PMID- 26476650 TI - Transposon sequencing: methods and expanding applications. AB - A comprehensive understanding of genotype-phenotype links in bacteria is the primary theme of bacterial functional genomics. Transposon sequencing (Tn-seq) or its equivalent methods that combine random transposon mutagenesis and next generation sequencing (NGS) represent a powerful approach to understand gene functions in bacteria on a genome-wide scale. This approach has been utilized in a variety of bacterial species to provide comprehensive information on gene functions related to various phenotypes or biological processes of significance. With further improvements in the molecular protocol for specific amplification of transposon junction sequences and increasing capacity of next generation sequencing technologies, the applications of Tn-seq have been expanding to tackle questions that are important yet difficult to address in the past. In this review, we will discuss the technical aspects of different Tn-seq methods along with their pros and cons to provide a helpful guidance for those who want to implement or improve Tn-seq for their own research projects. In addition, we also provide a comprehensive summary of recent published studies based on Tn-seq methods to give an updated perspective on the current and emerging applications of Tn-seq. PMID- 26476651 TI - Dihydroxylation of four- and five-ring aromatic hydrocarbons by the naphthalene dioxygenase from Sphingomonas CHY-1. AB - The naphthalene dioxygenase from Sphingomonas CHY-1 exhibits extremely broad substrate specificity toward polycyclic aromatic hydrocarbons (PAHs). In a previous study, the catalytic rates of oxidation of nine PAHs were determined using the purified dioxygenase, but the oxidation products formed from four- to five-ring hydrocarbons were incompletely characterized. Here, we reexamined PAH oxygenation reactions using Escherichia coli recombinant cells overproducing strain CHY-1 dioxygenase. Hydroxylated products generated by the dioxygenase were purified and characterized by means of GC-MS, UV absorbance as well as 1H- and 13C-NMR spectroscopy. Fluoranthene was converted to three dihydrodiols, the most abundant of which was identified as cis-7,8-dihydroxy-7,8-dihydrofluoranthene. This diol turned out to be highly unstable, converting to 8-hydroxyfluoranthene by spontaneous dehydration. The dioxygenase also catalyzed dihydroxylations on the C2-C3 and presumably the C1-C2 positions, although at much lower rates. Benz[a]anthracene was converted into three dihydrodiols, hydroxylated in positions C1-C2, C8-C9, and C10-C11, and one bis-cis-dihydrodiol. The latter compound was identified as cis,cis-1,2,10,11-tetrahydroxy-1,2,10,11 tetrahydrobenz[a]anthracene, which resulted from the subsequent dioxygenation of the 1,2- or 10,11-dihydrodiols. Chrysene dioxygenation yielded a single diol identified as cis-3,4-dihydroxy-3,4-dihydrochrysene, which underwent further oxidation to give cis,cis-3,4,9,10 chrysene tetraol. Pyrene was a poor substrate for the CHY-1 dioxygenase and gave a single dihydrodiol hydroxylated on C4 and C5, whereas benzo[a}pyrene was converted to two dihydrodiols, one of which was identified as cis-9,10-dihydrodiol. The selectivity of the dioxygenase is discussed in the light of the known 3D structure of its catalytic component and compared to that of the few enzymes able to attack four- and five-ring PAHs. PMID- 26476652 TI - Three-step biocatalytic reaction using whole cells for efficient production of tyramine from keratin acid hydrolysis wastewater. AB - Tyramine has been paid more attention in recent years as a significant metabolite of tyrosine and catecholamine drug and an intermediate of medicinal material and some drugs. In this study, an effective, green, and three-step biocatalytic synthesis method for production of tyramine starting from serine in keratin acid hydrolysis wastewater was developed and investigated. Serine deaminase from Escherichia coli was first combined with tyrosine phenol-lyase from Citrobacter koseri, to convert L-serine to L-tyrosine. L-Tyrosine can then be decarboxylated to tyramine by tyrosinede carboxylase from Lactobacillus brevis. All these enzymes originated from recombinant whole cells. Serine deaminaseand tyrosine phenol-lyase could efficiently convert L-serine in wastewater to L-tyrosine at pH 8.0, 37 degrees C, and Triton X-100 of 0.04% when tyrosine phenol-lyase and its corresponding substrates were sequentially added. Tyrosine conversion rate reached 98 % by L-tyrosine decarboxylase. In scale-up study, the conversion yield of L-serine in wastewater to tyrosine was up to 89 %. L-Tyrosine was decarboxylated to tyramine with a high yield 94 %. Tyramine hydrochloride was obtained with a total yield 84 %. This study has provided an efficient way of recycling keratin acid hydrolysis wastewater to produce tyramine. PMID- 26476653 TI - Mutations improving production and secretion of extracellular lipase by Burkholderia glumae PG1. AB - Burkholderia glumae is a Gram-negative phytopathogenic bacterium known as the causative agent of rice panicle blight. Strain B. glumae PG1 is used for the production of a biotechnologically relevant lipase, which is secreted into the culture supernatant via a type II secretion pathway. We have comparatively analyzed the genome sequences of B. glumae PG1 wild type and a lipase overproducing strain obtained by classical strain mutagenesis. Among a total number of 72 single nucleotide polymorphisms (SNPs) identified in the genome of the production strain, two were localized in front of the lipAB operon and were analyzed in detail. Both mutations contribute to a 100-fold overproduction of extracellular lipase in B. glumae PG1 by affecting transcription of the lipAB operon and efficiency of lipase secretion. We analyzed each of the two SNPs separately and observed a stronger influence of the promoter mutation than of the signal peptide modification but also a cumulative effect of both mutations. Furthermore, fusion of the mutated LipA signal peptide resulted in a 2-fold increase in secretion of the heterologous reporter alkaline phosphatase from Escherichia coli. PMID- 26476654 TI - Identification of novel anti-inflammatory probiotic strains isolated from pulque. AB - Probiotics are live microorganisms which when administered in adequate amounts, confer health benefits on the host. Their use is more and more widespread for both prevention and treatment of diseases, including traveler's diarrhea and inflammatory bowel diseases (IBDs). In this work, we isolated and characterized novel candidate probiotic strains from pulque (xaxtle), a traditional Mexican alcoholic fermented beverage. A total of 14 strains were obtained from xaxtle samples isolated from three different Mexican regions. Species identification was performed by biochemical methods and 16S rRNA gene targeted PCR. The isolates belonged to the Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus brevis, and Lactobacillus composti phylogenetic groups, with L. brevis being the most dominant group. Bacteria were tested for lysozyme, low pH, and bile acid resistance. Moreover, the strains were tested for adherence to human intestinal epithelial cells and screened for their immunomodulatory properties using a cellular model. Selected bacterial strains with anti-inflammatory properties were then tested in vivo in a dinitro-benzene sulfonic acid (DNBS)-induced chronic colitis mouse model, and weight loss, gut permeability, and cytokine profiles were measured as readouts of inflammation. One of the selected strains, Lactobacillus sanfranciscensis LBH1068, improved mice health as observed by a reduction of weight loss, significant decreases in gut permeability, and cytokine modulation. Altogether, our results highlighted the potential of lactobacilli isolated from pulque and in particular the strain L. sanfranciscensis LBH1068 as a novel probiotic to treat IBD. PMID- 26476655 TI - Phaeohyphomycosis Due to Exophiala jeanselmei: An Emerging Pathogen in India- Case Report and Review. AB - We present a rare case of a 30-year-old woman who presented with a swelling on the lateral aspect of her left forearm, present since 6 months, adjacent to a 16 year-old burn scar. X-ray of elbow joint and forearm revealed the subcutaneous nature of the swelling. Giemsa and periodic acid-Schiff-stained smears and potassium hydroxide mount of fine-needle aspirate of the swelling revealed dematiaceous, branching, and septate fungal hyphae. Fungal culture of the aspirated pus showed growth of Exophiala jeanselmei. Histopathological examination revealed brown-coloured hyphae with foreign body giant cell reaction and palisading granulomas in the surrounding tissue. The patient was successfully treated with surgical excision of the swelling. All the cases of phaeohyphomycosis due to Exophiala spp. in India are also reviewed. PMID- 26476657 TI - Sinus pericranii and myoclonic epilepsy: novel features of 3q29 microdeletion syndrome. PMID- 26476656 TI - Sister Mary Joseph's nodule: a very useful indicator of significant internal pathology. PMID- 26476658 TI - Bilateral anterior fornix infarction: the "amnestic syndrome of the subcallosal artery". PMID- 26476659 TI - Novel approach to treat fecal incontinence with muscle stem cell-based therapy. PMID- 26476660 TI - Glutathione and its related enzymes in the gonad of Nile Tilapia (Oreochromis niloticus). AB - Glutathione (GSH) concentration, the activity of its metabolizing enzymes, glutathione transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), and the antioxidant enzyme catalase (CAT) in O. niloticus ovary and testis were examined. GSH concentration of O. niloticus testis exhibited high concentration (129 +/- 21 nmol/g tissue) compared with GSH concentration (49.2 +/ 8.3 nmol/g tissue) in the ovary. GST, GPx, GR, and CAT activities of O. niloticus testis exhibited high values compared with their corresponding values in ovary homogenates. However, protein concentration in ovary homogenates exhibited higher values (175 +/- 40.6 mg) compared with testis homogenates (27.1 +/- 3.7 mg). O. niloticus ovary was less effective in excretion of xenobiotices compared with the testis, where its function is mainly in increasing the protein content of the eggs; however, in O. niloticus testis, the glutathione cycle operated in accelerated way in the direction of reduced GSH production in order to protect the maturation stages in a save way. A simple reproducible procedure for the purification of GST from O. niloticus ovary was established. The enzymes proved to be homogenous as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and its molecular weight was calculated to be 25.1 kDa. GST of O. niloticus ovary exhibited maximum activity at pH 7.5. The Michaelis-Menten constant (K(m)) of the purified ovary GST for GSH and CDNB was 0.076 mM and 1.0 mM, respectively. Cibacron blue was the most potent inhibitor of ovary GST activity (IC50 value, concentration of inhibitor that will give 50% inhibition, equal 0.002 MUM). The specific activity of GST toward different electrophilic substrates was determined. GST activity toward benzyl isothiocyanate was the highest compared with phenethyl isothiocyanate and allyl isothiocyanate. PMID- 26476662 TI - New insights into phosphorus management in agriculture--A crop rotation approach. AB - This manuscript presents research results examining phosphorus (P) management in a soil-plant system for three variables: i) internal resources of soil available phosphorus, ii) cropping sequence, and iii) external input of phosphorus (manure, fertilizers). The research was conducted in long-term cropping sequences with oilseed rape (10 rotations) and maize (six rotations) over three consecutive growing seasons (2004/2005, 2005/2006, and 2006/2007) in a production farm on soils originated from Albic Luvisols in Poland. The soil available phosphorus pool, measured as calcium chloride extractable P (CCE-P), constituted 28% to 67% of the total phosphorus input (PTI) to the soil-plant system in the spring. Oilseed rape and maize dominant cropping sequences showed a significant potential to utilize the CCE-P pool within the soil profile. Cropping sequences containing oilseed rape significantly affected the CCE-P pool, and in turn contributed to the P(TI). The P(TI) uptake use efficiency was 50% on average. Therefore, the CCE P pool should be taken into account as an important component of a sound and reliable phosphorus balance. The instability of the yield prediction, based on the P(TI), was mainly due to an imbalanced management of both farmyard manure and phosphorus fertilizer. Oilseed rape plants provide a significant positive impact on the CCE-P pool after harvest, improving the productive stability of the entire cropping sequence. This phenomenon was documented by the P(TI) increase during wheat cultivation following oilseed rape. The Unit Phosphorus Uptake index also showed a higher stability in oilseed rape cropping systems compared to rotations based on maize. Cropping sequences are a primary factor impacting phosphorus management. Judicious implementation of crop rotations can improve soil P resources, efficiency of crop P use, and crop yield and yield stability. Use of cropping sequences can reduce the need for external P sources such as farmyard manure and chemical fertilizers. PMID- 26476661 TI - Quercetin protects HCT116 cells from Dichlorvos-induced oxidative stress and apoptosis. AB - The present study was designed to assess the possible protective effects of Quercetin (QUER), a flavonoid with well-known pharmacological effects, against Dichlorvos (DDVP)-induced toxicity in vitro using HCT116 cells. The cytotoxicity was monitored by cell viability, reactive oxygen species (ROS) generation, anti oxidant enzyme activities, malondialdehyde (MDA) production, and DNA fragmentation. The apoptosis was assessed through the measurement of the mitochondrial transmembrane potential (DeltaPsim) and caspase activation. The results indicated that pretreatment of HCT116 cells with QUER, 2 h prior to DDVP exposure, significantly decreased the DDVP-induced cell death, inhibited the ROS generation, modulated the activities of catalase (CAT) and superoxide dismutase (SOD), and reduced the MDA level. The reductions in mitochondrial membrane potential, DNA fragmentation, and caspase activation were also attenuated by QUER. These findings suggest that dietary QUER can protect HCT116 cells against DDVP-induced oxidative stress and apoptosis. PMID- 26476663 TI - Significant increase in prostatectomy and decrease in radiation for clinical T3 prostate cancer from 1998 to 2012. AB - PURPOSE: We aimed to describe changes in treatment patterns for clinical T3 prostate cancer (PCa) from 1998 to 2012, specifically investigating what factors influence receipt of prostatectomy or radiation. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results database, we studied 11,604 men with clinical T3N0M0 PCa from 1998 to 2012, with treatment categorized as radiation, radical prostatectomy (RP), or no curative therapy. We calculated rate of treatment type by year of diagnosis to investigate trends in treatment patterns, further stratifying by clinical T3a, defined as unilateral and bilateral extracapsular extension (n = 3,842), vs. T3b (defined as extension to seminal vesicles (n = 3,665). Finally, a multivariable logistic regression analysis measured association of demographic and clinical variables with type of treatment received for years 2010 to 2011. RESULTS: Rates of prostatectomy increased significantly from 1998 to 2012 (12.5% vs. 44.4%), radiation decreased significantly (55.8% vs. 38.4%), and receipt of no treatment also decreased (31.7% vs. 17.2%, all P<0.001). These trends were similar for clinical T3a and T3b. Rates of prostatectomy surpassed radiation by 2008 in clinical T3a, reaching 49.8% vs. 37.1%, respectively, in 2012 (P = 0.002), and were statistically similar to radiation in 2012 for clinical T3b, reaching 41.6% vs. 42.1% (P = 0.92). Multivariable logistic regression analysis demonstrated that patients were less likely to receive prostatectomy than radiation if biopsy Gleason scores of 8 to 10 (adjusted odds ratio [AOR] = 0.41, 0.32-0.53), higher initial prostate specific antigen (AOR = 0.97, 0.97-0.98), and older age (AOR = 0.92, 0.90-0.03, all P<0.01). The likelihood of RP was similar among cT3b vs. cT3a (AOR = 0.95, 0.71-1.26, P = 0.74). CONCLUSIONS: Since 1998, there has been a significant increase in the use of RP for clinical T3 PCa and a significant decrease in the use of radiation such that in 2012, the use of prostatectomy exceeded the use of radiation. PMID- 26476664 TI - Electrophysiological studies in Internet addiction: A review within the dual process framework. PMID- 26476665 TI - The isolation and synthesis of a novel benzofuran compound from Tephrosia purpurea, and the synthesis of several related derivatives, which suppress histamine H1 receptor gene expression. AB - A novel naturally occurring compound with a benzofuran skeleton was isolated from a plant, Tephrosia purpurea collected in Bangladesh. The chemical synthesis of this compound confirmed its structure, and preliminary biological results showed its suppressive activity towards histamine H1 gene expression. One isomer and four derivatives were also synthesized, and their suppression activity was investigated. Although only small quantities of this compound can be isolated from its natural source, a 10 g scale synthesis was demonstrated by the newly developed method. PMID- 26476666 TI - Synthesis and biological activity of amino acid derivatives of avarone and its model compound. AB - A series of eighteen derivatives of marine sesquiterpene quinone avarone and its model system tert-butylquinone with amino acids has been synthesized by nucleophilic addition of amino acids to the quinones. In vitro cytotoxic activity toward human cancer cell lines (HeLa, A549, Fem-X, K562, MDA-MB-453) and normal MRC-5 cell line was determined. Several compounds showed very strong inhibitory activity with IC50 values less than 10 MUM. Avarone derivatives were more active than the corresponding tert-butylquinone derivatives. The results of the cytofluorimetric analysis of cell cycle of HeLa cells showed that apoptosis might be one of possible mechanism of action of these compounds in cancer cells. In order to examine the influence of caspases on cell death, the apoptotic mechanisms induced by the tested compounds were determined using specific caspases 3, 8 and 9 inhibitors. For all compounds antibacterial activities against six strains of Gram-positive and four strains of Gram-negative bacteria were determined, as well as antifungal activity against three fungal species. PMID- 26476667 TI - 1,2,3-Triazole-based analogue of benznidazole displays remarkable activity against Trypanosoma cruzi. AB - The current treatment of Chagas disease is based on the use of two drugs, nifurtimox and benznidazole, which present limited efficacy in the chronic stage of the disease and toxic side effects. Although some progress has been made in the development of new drugs to treat this disease, the discovery of novel compounds is urgently required. In this work we report the synthesis and biological evaluation of 1,2,3-triazole-based analogues of benznidazole. A small series of 27 compounds was successfully synthesized via microwave-assisted copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) from N-benzyl-2-azidoacetamide (1) and a set of commercial terminal alkynes. Analogues 24 (IC50 40 MUM) and 28 (IC50 50 MUM) showed comparable activities to benznidazole (IC50 34 MUM) against trypomastigote form and analogue 15 (IC50 7 MUM) was found to be the most active. Regarding the cytotoxicity assessment of the series, most compounds were not cytotoxic. This work shows that the designed strategy is efficiently capable of generating novel benzindazole analogues and reveals one analogue is more active than benznidazole. PMID- 26476668 TI - Poly(amidoamine) dendrimers show carbonic anhydrase inhibitory activity against alpha-, beta-, gamma- and eta-class enzymes. AB - Four generations of poly(amidoamine) (PAMAM) dendrimers incorporating benzenesulfonamide moieties were investigated as inhibitors of carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the alpha-, beta-, gamma- and eta classes which are present in pathogenic bacteria, fungi or protozoa. The following bacterial, fungal and protozoan organisms were included in the study: Vibrio cholerae, Trypanosoma cruzi, Leishmania donovani chagasi, Porphyromonas gingivalis, Cryptococcus neoformans, Candida glabrata, and Plasmodium falciparum. The eight pathozymes present in these organisms were efficiently inhibited by the four generations PAMAM-sulfonamide dendrimers, but multivalency effects were highly variable among the different enzyme classes. The Vibrio enzyme VchCA was best inhibited by the G3 dendrimer incorporating 32 sulfamoyl moieties. The Trypanosoma enzyme TcCA on the other hand was best inhibited by the first generation dendrimer G0 (with 4 sulfamoyl groups), whereas for other enzymes the optimal inhibitory power was observed for the G1 or G2 dendrimers, with 8 and 16 sulfonamide functionalities. This study thus proves that the multivalency may be highly relevant for enzyme inhibition for some but not all CAs from pathogenic organisms. On the other hand, some dendrimers investigated here showed a better inhibitory power compared to acetazolamide for enzymes from widespread pathogens, such as the eta-CA from Plasmodium falciparum. Overall, the main conclusion is that this class of molecules may lead to important developments in the field of anti-infective CA inhibitors. PMID- 26476669 TI - Influence of stereoscopic vision on task performance with an operating microscope. AB - PURPOSE: To determine the extent to which stereoscopic depth perception influences the performance of tasks executed under an operating microscope. SETTING: Laboratory of Experimental Ophthalmology, University Medical Center Groningen, the Netherlands. DESIGN: Experimental study. METHODS: Medical students were assigned (on the basis of their stereoacuity) to a stereo-sufficient group (depth perception <=240 seconds of arc [arcsec]) or stereo-deficient group (>=480 arcsec). They performed a bead-stringing task (a mockup surgical test) under an operating microscope or a task on a cataract surgery simulator. The stereo sufficient subjects also performed the bead-stringing task under artificial stereo-deficient conditions (binocular and monocular viewing). RESULTS: The study comprised 77 medical students. The stereo-sufficient subjects performed both tasks faster than the stereo-deficient subjects and artificially stereo-deficient subjects (P <= .024). In addition, a within-group analysis established that the stereo-sufficient subjects were faster at the bead-stringing task with stereoscopic viewing than under artificial stereo-deficient conditions with binocular viewing (P <= .011). CONCLUSIONS: Having stereovision resulted in better initial performance on certain tasks involving the use of an operating microscope or cataract surgery simulator. However, this study did not show that stereo deficiency necessarily results in an inability to perform such tasks properly. Hence, it was not evident that for admission to an ophthalmology residency program, stereovision should be judged more stringently than other traits. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26476670 TI - Discussion. PMID- 26476671 TI - The PROTAGORAS study to evaluate the performance of the Endurant stent graft for patients with pararenal pathologic processes treated by the chimney/snorkel endovascular technique. AB - OBJECTIVE: The chimney/snorkel endovascular aortic repair (ch-EVAR) is gaining ever-greater acceptance in the treatment of pararenal pathologic processes. However, the published experience includes mainly short-term clinical results with combinations of several abdominal devices and types of chimney grafts. The aim of this study was the midterm evaluation of the Endurant stent graft (Medtronic, Santa Rosa, Calif) as a standard abdominal device for ch-EVAR. METHODS: Between January 2009 and January 2013, prospectively collected data of high-risk patients with pararenal pathologic processes who underwent ch-EVAR with placement of the Endurant abdominal device were analyzed. The chimney graft intended for use was a balloon-expandable covered stent. Main outcome measures were aneurysm sac regression and chimney graft patency. RESULTS: A total of 187 snorkel/chimney grafts were successfully placed in 128 patients (mean age, 76.6 years). The technical success was 100%. The mean preoperative proximal neck length and aneurysm size were 4.7 mm and 64.8 mm (range, 48-135 mm), respectively. The postoperative new neck length after use of chimney grafts was 18.7 +/- 6.3 mm. The mean aneurysm sac decreased significantly (60.8 mm; 95% confidence interval, 2.036-7.084; P = .001) after a mean radiologic follow up of 24.6 +/- 17.4 months. Thirty-day mortality and midterm mortality were 0.8% and 17.2%, respectively. Two patients (1.6%) with single chimneys presented with late new onset of type Ia endoleak and underwent additional tube and multiple chimney placement. Primary chimney graft patency was 95.7%. Freedom from chimney graft related reinterventions was 93.1%. CONCLUSIONS: Standard use of the Endurant abdominal device for ch-EVAR in >120 patients is associated with high technical success, significant aneurysm sac regression, and low incidence of secondary procedures after 2-year radiologic follow-up. These results will give significant impetus to device selection, facilitating the standardization of technique. PMID- 26476673 TI - Circular stapling for Roux-en-Y esophagojejunal anastomosis using a transorally inserted anvil. PMID- 26476674 TI - Prognostic value of sarcopenia in liver surgery. AB - Current knowledge indicates that malnutrition increases the rate of post operative complications, particularly respiratory and infectious, after major surgery. Almost all liver surgery is performed in patients with cancer, a factor that increases the risk of malnutrition. The primary risk factors for post operative complications are pre-operative hypo-albuminemia and a body mass index less than 20 kg/m(2). To improve the prediction of complications in these patients, some teams have suggested measurement of muscle thickness by computed tomography. Muscular mass can thus be quantified by measuring the total surface of the psoas muscle or the total surface of all muscles (i.e. external and internal oblique, transverse, psoas and paravertebral muscles) seen on an axial CT slice at L3. As well, data exist suggesting that sarcopenia is an independent predictive factor of post-operative morbidity and poor long-term survival after resection for cancer. Nonetheless, the literature on the subject is limited, there are no standardized definitions for sarcopenia, and the need of special software to calculate the surfaces limits its usefulness. Lastly, there are little if any data concerning the nutritional or pharmacologic means to treat sarcopenia. This update, based on a literature review, deals with the value and the prognostic impact of sarcopenia in surgery for liver tumors. The current definition of sarcopenia, validated internationally, the methods of measurement, and the consequences of sarcopenia on the outcome of liver resections are detailed in this review. PMID- 26476672 TI - Wnt signaling in age-related macular degeneration: human macular tissue and mouse model. AB - BACKGROUND: The wingless-type MMTV integration site (Wnt) signaling is a group of signal transduction pathways. In canonical Wnt pathway, Wnt ligands bind to low density lipoprotein receptor-related protein 5 or 6 (LRP5 or LRP6), resulting in phosphorylation and activation of the receptor. We hypothesize that canonical Wnt pathway plays a role in the retinal lesion of age-related macular degeneration (AMD), a leading cause of irreversible central visual loss in elderly. METHODS: We examined LRP6 phosphorylation and Wnt signaling cascade in human retinal sections and plasma kallistatin, an endogenous inhibitor of the Wnt pathway in AMD patients and non-AMD subjects. We also used the Ccl2 (-/-) /Cx3cr1 (-/-) /rd8 and Ccl2 (-/-) /Cx3cr1 (gfp/gfp) mouse models with AMD-like retinal degeneration to further explore the involvement of Wnt signaling activation in the retinal lesions in those models and to preclinically evaluate the role of Wnt signaling suppression as a potential therapeutic option for AMD. RESULTS: We found higher levels of LRP6 (a key Wnt signaling receptor) protein phosphorylation and transcripts of the Wnt pathway-targeted genes, as well as higher beta-catenin protein in AMD macula compared to controls. Kallistatin was decreased in the plasma of AMD patients. Retinal non-phosphorylated-beta-catenin and phosphorylated-LRP6 were higher in Ccl2 (-/-) /Cx3cr1 (-/-) /rd8 mice than that in wild type. Intravitreal administration of an anti-LRP6 antibody slowed the progression of retinal lesions in Ccl2 (-/-) /Cx3cr1 (-/-) /rd8 and Ccl2 (-/-) /Cx3cr1 (gfp/gfp) mice. Electroretinography of treated eyes exhibited larger amplitudes compared to controls in both mouse models. A2E, a retinoid byproduct associated with AMD was lower in the treated eyes of Ccl2 (-/-) /Cx3cr1 (-/-) /rd8 mice. Anti-LRP6 also suppressed the expression of Tnf-alpha and Icam-1 in Ccl2 (-/-) /Cx3cr1 (-/-) /rd8 retinas. CONCLUSIONS: Wnt signaling may be disturbed in AMD patients, which could contribute to the retinal inflammation and increased A2E levels found in AMD. Aberrant activation of canonical Wnt signaling might also contribute to the focal retinal degenerative lesions of mouse models with Ccl2 and Cx3cr1 deficiency, and intravitreal administration of anti-LRP6 antibody could be beneficial by deactivating the canonical Wnt pathway. PMID- 26476675 TI - Glisson capsulectomy for extensive superficial liver involvement in peritoneal carcinomatosis (with video). PMID- 26476676 TI - Laparoscopic pancreaticoduodenectomy: How I do it? (with video). PMID- 26476677 TI - Institutional research and biomedical journals: Poor quality articles and honest researchers! PMID- 26476678 TI - Isolated pancreatic injuries: An analysis of 49 consecutive patients treated at a Level 1 Trauma Centre. AB - BACKGROUND: This study interrogated a large prospectively documented institutional database to determine morbidity and mortality after an isolated pancreatic injury (IPI). METHOD: Complications were graded according to the Clavien-Dindo classification and the International Study Group of Pancreatic Surgery (ISGPS) definitions. The degree of the pancreatic duct injury was graded using a modified Takishima duct injury classification. Primary endpoints were general and pancreas-specific morbidity and mortality. RESULTS: Four hundred and forty-eight consecutive patients were treated between 1990 and 2014 for pancreatic injuries of whom 49 (median age: 30, range: 13-68 years, 41 men, blunt injuries: n=43) had an IPI. Thirty-four (70%) patients underwent urgent surgery, 20 of whom had a distal pancreatectomy and 14 had external drainage of the pancreatic injury. Fifteen (30%) patients presented with a non-resolving pancreatic pseudocyst or fistula; five had grade 4A or 4B ductal injuries and underwent surgery, 10 with 3A and 3B ductal injuries were successfully managed endoscopically. Fifty-five percent had postoperative morbidity. Two patients (4%) died of non-pancreatic-related causes. CONCLUSION: While overall mortality is low after an IPI, morbidity is high. Two thirds of patients required operative intervention and one third were treated endoscopically. The degree of pancreatic ductal injury determined whether endoscopic intervention was effective. PMID- 26476679 TI - Evaluation of a sequencing batch reactor sewage treatment rig for investigating the fate of radioactively labelled pharmaceuticals: Case study of propranolol. AB - Pharmaceuticals are frequently detected in the aquatic environment, and have potentially damaging effects. Effluents from sewage treatment plants (STPs) are major sources of these substances. The use of sequencing batch reactor (SBR) STPs, involving cycling between aerobic and anoxic conditions to promote nitrification and denitrification, is increasing but these have yet to be understood in terms of removal of pharmaceutical residues. This study reports on the development of a laboratory rig to simulate a SBR. The rig was used to investigate the fate of radiolabelled propranolol. This is a commonly prescribed beta blocker, but with unresolved fate in STPs. The SBR rig (4.5 L) was operated on an 8 h batch cycle with settled sewage. Effective treatment was demonstrated, with clearly distinct treatment phases and evidence of nitrogen removal. Radiolabelled (14)C-propranolol was dosed into both single (closed) and continuous (flow-through) simulations over 13 SBR cycles. Radioactivity in CO2 off-gas, biomass and liquid was monitored, along with the characteristics of the sewage. This allowed apparent rate constants and coefficients for biodegradation and solid:water partitioning to be determined. Extrapolation from off-gas radioactivity measurements in the single dose 4-d study suggested that propranolol fell outside the definitions of being readily biodegradable (DegT50 = 9.1 d; 60% biodegradation at 12.0 d). During continuous dosing, 63-72% of propranolol was removed in the rig, but less than 4% of dose recovered as (14)CO2, suggesting that biodegradation was a minor process (Kbiol(M) L kg d(-1) = 22-49) and that adsorption onto solids dominated, giving rise to accumulations within biomass during the 17 d solid retention time in the SBR. Estimations of adsorption isotherm coefficients were different depending on which of three generally accepted denominators representing sorption sites was used (mixed liquor suspended solids, reactor COD or mass of waste activated sludge). With further development and evaluation, the rig developed for simulating SBR processes has potential to be used for informing better environmental risk assessments for those pharmaceuticals showing ambiguous results in field fate studies. PMID- 26476680 TI - Migration and distribution of water and organic matter for activated sludge during coupling magnetic conditioning-horizontal electro-dewatering (CM-HED). AB - Magnetic micro-particles (MMPs) and magnetic field (MF) were utilized as a coupling conditioning unit before dewatering activated sludge (AS) under a horizontal electric field. The removal and migration of free and bound water in AS during coupling magnetic conditioning-horizontal electro-dewatering (CM-HED) were determined. The organic matter migration between the solid and liquid phases of AS biosolids was also analyzed. Results show that MMPs dosage and MF intensity were determined as 0.15 g/g dry solids and 0.065 T for the best dewaterability, respectively. The optimum dewatering conditions for CM-HED with the final water content of 89.98% were 40 V and 120 min as determined using the response surface methodology. MMPs conditioning could induce a slight coagulation among AS flocs, increase the particle size from 85.9 MUm to 92.3 MUm and decrease mass fractal dimension from 2.18 to 2.07. The MMPs-conditioned AS also showed a network-like structure, banded cells with shrunk surfaces. CM-HED process effectively reduced the free water content (FWC) and bound water content (BWC) but increased the portion of BWC in AS. The corresponding removal ratios of bound water and free water were 52.89% and 95.86% at the anode side and 46.28% and 92.75% at the cathode side, respectively. The coupling magnetic conditioning led to the largest BWC reduction of 23.14% in CM-HED process, and most of this reduction approaching 92.83% occurred during magnetic micro-particle conditioning stage. Gravity field caused the largest sludge reduction of 87.45%. During HED stage, the removal ratio of free water in AS was 63.73% at the anode side and 36.54% at the cathode side, while it was 21.9% and 10.96% for bound water, respectively. Along with water removed by CM-HED process, the organic matter in supernatant/filtrate increased, and a sharp rise occurred during HED stage. Meanwhile, the extracellular polymeric substance (EPS) contents initially decreased at MMPs-MF conditioning stage and then increased at the HED stage. Lower EPS contents in AS indicated better dewaterability. The largest reduction in the EPS content of AS at MMPs-MF conditioning stage corresponded to the largest decline in BWC. Furthermore, the protein-like substances in the supernatant/filtrate increased from 30% to 50%, whereas the fulvic acid-like and humic acid-like substances decreased from 54% to 27% at the HED stage. MMPs significantly reduced the polysaccharide and protein contents in the slime-EPS by 90.26% and 99.25%, respectively. Approximately 92.35% of humic acid-like materials in tightly bound EPS were reduced by MMPs. Thus, coupling magnetic conditioning should be selected as pretreatment prior to HED. PMID- 26476681 TI - Steady-state analysis of activated sludge processes with a settler model including sludge compression. AB - A reduced model of a completely stirred-tank bioreactor coupled to a settling tank with recycle is analyzed in its steady states. In the reactor, the concentrations of one dominant particulate biomass and one soluble substrate component are modelled. While the biomass decay rate is assumed to be constant, growth kinetics can depend on both substrate and biomass concentrations, and optionally model substrate inhibition. Compressive and hindered settling phenomena are included using the Burger-Diehl settler model, which consists of a partial differential equation. Steady-state solutions of this partial differential equation are obtained from an ordinary differential equation, making steady-state analysis of the entire plant difficult. A key result showing that the ordinary differential equation can be replaced with an approximate algebraic equation simplifies model analysis. This algebraic equation takes the location of the sludge-blanket during normal operation into account, allowing for the limiting flux capacity caused by compressive settling to easily be included in the steady-state mass balance equations for the entire plant system. This novel approach grants the possibility of more realistic solutions than other previously published reduced models, comprised of yet simpler settler assumptions. The steady-state concentrations, solids residence time, and the wastage flow ratio are functions of the recycle ratio. Solutions are shown for various growth kinetics; with different values of biomass decay rate, influent volumetric flow, and substrate concentration. PMID- 26476682 TI - Nanoparticle scattering characterization and mechanistic modelling of UV-TiO2 photocatalytic reactors using computational fluid dynamics. AB - A computational fluid dynamic (CFD) model was developed to describe the process performance of a semi-batch annular TiO2-UV photoreactor in an Eulerian framework. The model accounted for the optical behaviour of titanium dioxide (TiO2) suspensions, the flow distribution and the oxalic acid degradation in the reactor. The scattering component of the optical model, explicitly included in the CFD simulations using a TiO2-specific scattering phase function integrated in the radiative transfer equation, was calibrated using an optical goniometer by comparing simulated scattering light profiles against irradiance measurements collected for various TiO2 concentrations and UV wavelengths and subsequently solved by the discrete ordinate (DO) radiation model. Several scattering phase functions were tested against the goniometric measurements confirming that the Henyey-Greenstein (HG) equation was the most appropriate angular distribution function at 254 and 355 nm, irrespective of the TiO2 concentration. Using the calibrated HG function, a new approach for quantifying the absolute values of absorption and scattering coefficients in TiO2 suspensions was proposed. It consists of iteratively solving, using the DO model, the radiative transfer equation for various combinations of absorption and scattering coefficients until the error between observed and predicted angular irradiance measurements is minimized. The accuracy of the optical parameters was verified with independent CFD simulations carried out for an annular photoreactor and already available in the literature. Predicted and simulated irradiance and oxalic acid degradation data were found to be in excellent agreement, confirming the considerable potential of the integrated modelling approach presented in this paper for the design, optimization and scale-up of photocatalytic technologies for water and wastewater treatment applications. PMID- 26476683 TI - "Why are the Saturations Dropping?" The Blalock-Taussig Shunt Revisited. PMID- 26476684 TI - Interleukin 19 reduces inflammation in chemically induced experimental colitis. AB - Inflammatory bowel disease results from chronic dysregulation of the mucosal immune system and aberrant activation of both the innate and adaptive immune responses. Interleukin (IL)-19, a member of the IL-10 family, functions as an anti-inflammatory cytokine. Here, we investigated the contribution of IL-19 to intestinal inflammation in a model of T cell-mediated colitis in mice. Inflammatory responses in IL-19-deficient mice were assessed using the 2,4,6 trinitrobenzene sulfonic acid (TNBS) model of acute colitis. IL-19 deficiency aggravated TNBS-induced colitis and compromised intestinal recovery in mice. Additionally, the exacerbation of TNBS-induced colonic inflammation following genetic ablation of IL-19 was accompanied by increased production of interferon gamma, IL-12 (p40), IL-17, IL-22, and IL-33, and decreased production of IL-4. Moreover, the exacerbation of colitis following IL-19 knockout was also accompanied by increased production of CXCL1, G-CSF and CCL5. Using this model of induced colitis, our results revealed the immunopathological relevance of IL-19 as an anti-inflammatory cytokine in intestinal inflammation in mice. PMID- 26476685 TI - Wire assisted sigmoid intubation: An alternative approach to overcome technically difficult colonic angulations. AB - Complete colonoscopy can sometimes prove technically challenging. Sharp colonic angulation can be one of the contributing factors. With the advancement in technology, various modalities have been employed to overcome technical difficulties. Here we describe a guidewire assisted sigmoid intubation to overcome this hurdle with limited resources. PMID- 26476686 TI - Microtubules and cellulose biosynthesis: the emergence of new players. AB - Microtubules determine the orientation of newly formed cellulose microfibrils in expanding cells. There are many hypotheses regarding how the information is transduced across the plasma membrane from microtubules to cellulose microfibrils. However, the molecular mechanisms underlying the co-alignment between microtubules and cellulose microfibrils were not revealed until the recent discovery of cellulose synthase interacting (CSI) proteins. Characterization of CSIs and additional cellulose synthase-associated proteins will greatly advance the knowledge of how cellulose microfibrils are organized. PMID- 26476687 TI - Novel links in the plant TOR kinase signaling network. AB - Nutrient and energy sensing and signaling mechanisms constitute the most ancient and fundamental regulatory networks to control growth and development in all life forms. The target of rapamycin (TOR) protein kinase is modulated by diverse nutrient, energy, hormone and stress inputs and plays a central role in regulating cell proliferation, growth, metabolism and stress responses from yeasts to plants and animals. Recent chemical, genetic, genomic and metabolomic analyses have enabled significant progress toward molecular understanding of the TOR signaling network in multicellular plants. This review discusses the applications of new chemical tools to probe plant TOR functions and highlights recent findings and predictions on TOR-mediate biological processes. Special focus is placed on novel and evolutionarily conserved TOR kinase effectors as positive and negative signaling regulators that control transcription, translation and metabolism to support cell proliferation, growth and maintenance from embryogenesis to senescence in the plant system. PMID- 26476688 TI - Is physical exercise harmful to liver transplantation recipients? Review of literature. AB - Liver transplantation is a treatment that significantly improves the patients' quality of life. However, we should be more ambitious and seek an improvement in their fitness through training protocols allowing them to fully return to daily activities. English and Spanish-language articles on PubMed and the Cochrane Library were searched untill 2014. Articles were reviewed by 2 of the authors to determine if they were suitable for inclusion. It is shown a compilation of studies that included patients who have participated in aerobic, strength, or both combined training programs, without implying a risk for the graft function. There is a lack of studies with high scientific evidence that stablish a proper exercise program methodology, supervised by specialists in physical activity and sports. PMID- 26476689 TI - Identification of two isoforms of CYP4 in Marsupenaeus japonicus and their mRNA expression profile response to benzo[a]pyrene. AB - CYP4 enzymes are essential components of cellular detoxification systems and play important roles in monitoring persistent organic pollutants in marine environments. However, there are few studies on CYP4 in shrimp. In this study, two CYP4 isoforms, CYP4V28 and CYP4V29, were cloned from Marsupenaeus japonicus for the first time, and the tissue distributions and mRNA expression profile in response to benzo[a]pyrene (B[a]P) were analyzed by quantitative real-time PCR (QRT-PCR). The full lengths of CYP4V28 and CYP4V29 were 1771 bp and 1647 bp respectively, with deduced amino acid sequences of 511 and 515 amino acids. The two CYP4s were predominantly expressed in the hepatopancreas and weakly expressed in other six tested tissues. As demonstrated by QRT-PCR, the mRNA levels of the two CYP4s show both a time- and dose-dependent response to B[a]P. The mRNA expression levels of CYP4V28 and CYP4V29 peaked at 12 h and 6 h respectively, and the peak level exhibited a tendency of positive correlation with the concentration of B[a]P. This study provides clues for further elucidating the function and regulation mechanisms of the two CYP4s in M. japonicas and evaluating of the biomarker potential of the two CYP4 isoforms. PMID- 26476690 TI - Complete genome sequence of a giant Vibrio bacteriophage VH7D. AB - A Vibrio sp. lytic phage VH7D was isolated from seawater of an abalone farm in Xiamen, China. The phage was capable of lysing Vibrio rotiferianus DSM 17186(T) and Vibrio harveyi DSM 19623(T). The complete genome of this phage consists of 246,964 nucleotides with a GC content of 41.31%, which characterized it as a giant vibriophage. Here we report the complete genome sequence and major findings from the genomic annotation. PMID- 26476691 TI - Delimitation of the Earliness per se D1 (Eps-D1) flowering gene to a subtelomeric chromosomal deletion in bread wheat (Triticum aestivum). AB - Earliness per se (Eps) genes account for the variation in flowering time when vernalization and photoperiod requirements are satisfied. Genomics and bioinformatics approaches were used to describe allelic variation for 40 Triticum aestivum genes predicted, by synteny with Brachypodium distachyon, to be in the 1DL Eps region. Re-sequencing 1DL genes revealed that varieties carrying early heading alleles at this locus, Spark and Cadenza, carry a subtelomeric deletion including several genes. The equivalent region in Rialto and Avalon is intact. A bimodal distribution in the segregating Spark X Rialto single seed descent (SSD) populations enabled the 1DL QTL to be defined as a discrete Mendelian factor, which we named Eps-D1. Near isogenic lines (NILs) and NIL derived key recombinants between markers flanking Eps-D1 suggest that the 1DL deletion contains the gene(s) underlying Eps-D1. The deletion spans the equivalent of the Triticum monoccocum Eps-A (m) 1 locus, and hence includes MODIFIER OF TRANSCRIPTION 1 (MOT1) and FTSH PROTEASE 4 (FTSH4), the candidates for Eps-A (m) 1. The deletion also contains T. aestivum EARLY FLOWERING 3-D1 (TaELF3-D1) a homologue of the Arabidopsis thaliana circadian clock gene EARLY FLOWERING 3. Eps D1 is possibly a homologue of Eps-B1 on chromosome 1BL. NILs carrying the Eps-D1 deletion have significantly reduced total TaELF3 expression and altered TaGIGANTEA (TaGI) expression compared with wild type. Altered TaGI expression is consistent with an ELF3 mutant, hence we propose TaELF3-D1 as the more likely candidate for Eps-D1. This is the first direct fine mapping of Eps effect in bread wheat. PMID- 26476692 TI - Histone modifications controlling native and induced neural stem cell identity. AB - During development, neural progenitor cells (NPCs) that are capable of self renewing maintain a proliferative cellular pool while generating all differentiated neural cell components. Although the genetic network of transcription factors (TFs) required for neural specification has been well characterized, the unique set of histone modifications that accompanies this process has only recently started to be investigated. In vitro neural differentiation of pluripotent stem cells is emerging as a powerful system to examine epigenetic programs. Deciphering the histone code and how it shapes the chromatin environment will reveal the intimate link between epigenetic changes and mechanisms for neural fate determination in the developing nervous system. Furthermore, it will offer a molecular framework for a stringent comparison between native and induced neural stem cells (iNSCs) generated by direct neural cell conversion. PMID- 26476693 TI - Long-term exposure to traffic pollution and hospital admissions in London. AB - Evidence on the effects of long-term exposure to traffic pollution on health is inconsistent. In Greater London we examined associations between traffic pollution and emergency hospital admissions for cardio-respiratory diseases by applying linear and piecewise linear Poisson regression models in a small-area analysis. For both models the results for children and adults were close to unity. In the elderly, linear models found negative associations whereas piecewise models found non-linear associations characterized by positive risks in the lowest and negative risks in the highest exposure category. An increased risk was observed among those living in areas with the highest socioeconomic deprivation. Estimates were not affected by adjustment for traffic noise. The lack of convincing positive linear associations between primary traffic pollution and hospital admissions agrees with a number of other reports, but may reflect residual confounding. The relatively greater vulnerability of the most deprived populations has important implications for public health. PMID- 26476694 TI - Cognitive disorders in children associated with urban vehicular emissions. AB - This review introduces recent advances in an emerging research area that is focussed on studying the effect of exposure to vehicular emissions on cognition, with specific attention to children from urban environments. Today, air pollution is a global environmental issue, especially in urban environments, emitting particulate matter (PM), nitrogen dioxide (NO2), carbon monoxide (CO), volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) into the surroundings. The association of exposure to urban air pollution and cognitive disorders in children is a major cause of concern. We review recent findings associated with exposure to air pollutants and explained the potential mechanisms driving oxidative stress in living systems. An attempt has been made to investigate the cognitive effects of air pollutants leading to neurodegeneration, neurodysfunction, attention deficit/hypersensitivity deficiencies and autism in children. Accumulating evidence suggests that urban air pollution may have significant impact on central nervous system (CNS) of the developing brain. PMID- 26476695 TI - Evidence for differential effects of reduced and oxidised nitrogen deposition on vegetation independent of nitrogen load. AB - Nitrogen (N) deposition impacts natural and semi-natural ecosystems globally. The responses of vegetation to N deposition may, however, differ strongly between habitats and may be mediated by the form of N. Although much attention has been focused on the impact of total N deposition, the effects of reduced and oxidised N, independent of the total N deposition, have received less attention. In this paper, we present new analyses of national monitoring data in the UK to provide an extensive evaluation of whether there are differences in the effects of reduced and oxidised N deposition across eight habitat types (acid, calcareous and mesotrophic grasslands, upland and lowland heaths, bogs and mires, base-rich mires, woodlands). We analysed data from 6860 plots in the British Countryside Survey 2007 for effects of total N deposition and N form on species richness, Ellenberg N values and grass:forb ratio. Our results provide clear evidence that N deposition affects species richness in all habitats except base-rich mires, after factoring out correlated explanatory variables (climate and sulphur deposition). In addition, the form of N in deposition appears important for the biodiversity of grasslands and woodlands but not mires and heaths. Ellenberg N increased more in relation to NHx deposition than NOy deposition in all but one habitat type. Relationships between species richness and N form were habitat specific: acid and mesotrophic grasslands appear more sensitive to NHx deposition while calcareous grasslands and woodlands appeared more responsive to NOy deposition. These relationships are likely driven by the preferences of the component plant species for oxidised or reduced forms of N, rather than by soil acidification. PMID- 26476696 TI - Efficacy of TachoSil((r)) in preventing hemorrhage after loop electrosurgical excision procedure. AB - STUDY OBJECTIVE: To assess the utility of TachoSil for achieving hemostasis after loop electrosurgical excision procedure (LEEP). DESIGN: Case-control study (Canadian Task Force Classification II-2). SETTING: University hospital. PATIENTS: One hundred seventy-three patients who underwent LEEP. INTERVENTIONS: Patients were managed by LEEP with application of TachoSil (TachoSil group, n=75) or without application of TachoSil (control group, n=94). MEASUREMENTS AND MAIN RESULTS: Patient characteristics (age, specimen depth, resection margin, LEEP histopathology, or use of TachoSil) except for parity were similar between the two study groups. Severe bleeding requiring any intervention developed in 14% of patients (24 of 169 patients), without any statistically significant difference between the two groups (11% in the TachoSil group vs. 17% in the control group; P=0.274). On the logistic regression analysis, other potential clinico-pathologic parameters, including age, parity, specimen depth, involvement of the resection margin, and LEEP histopathology, were not correlated with severe bleeding after LEEP. CONCLUSION: The use of TachoSil may not reduce the incidence of severe bleeding after LEEP. PMID- 26476697 TI - Design and evaluation of a bioreactor with application to forensic burial environments. AB - Existing forensic taphonomic methods lack specificity in estimating the postmortem interval (PMI) in the period following active decomposition. New methods, such as the use of citrate concentration in bone, are currently being considered; however, determining the applicability of these methods in differing environmental contexts is challenging. This research aims to design a forensic bioreactor that can account for environmental factors known to impact decomposition, specifically temperature, moisture, physical damage from animals, burial depth, soil pH, and organic matter content. These forensically relevant environmental variables were characterized in a soil science context. The resulting metrics were soil temperature regime, soil moisture regime, slope, texture, soil horizon, cation exchange capacity, soil pH, and organic matter content. Bioreactor chambers were constructed using sterilized thin-walled polystyrene boxes housed in calibrated temperature units. Gravesoil was represented using mineral soil (Ultisols), and organic soil proxy for Histosols, horticulture mix. Gravesoil depth was determined using mineral soil horizons A and Bt2 to simulate surface scatter and shallow grave burial respectively. A total of fourteen different environmental conditions were created and controlled successfully over a 90-day experiment. These results demonstrate successful implementation and control of forensic bioreactor simulating precise environments in a single research location, rather than site-specific testing occurring in different geographic regions. Bone sections were grossly assessed for weathering characteristics, which revealed notable differences related to exposure to different temperature regimes and soil types. Over the short 90-day duration of this experiment, changes in weathering characteristics were more evident across the different temperature regimes rather than the soil types. Using this methodology, bioreactor systems can be created to replicate many different clandestine burial contexts, which will allow for the more rapid understanding of environmental effects on skeletal remains. PMID- 26476698 TI - Lipid deposition in liver cells: The influence of short form augmenter of liver regeneration. AB - BACKGROUND AND OBJECTIVE: The short form augmenter of liver regeneration (sfALR) is a novel human hepatotrophic growth factor. The aim of this study was to investigate the potential role of sfALR in NAFLD. METHODS: The free fatty acids (FFA) induced lipid accumulation in mouse liver parenchymal cells was examined by Oil Red O staining and triglyceride level determination. The cell cycle was determined by flow cytometry and the proliferation was assessed by CCK8. The expression levels of gfer, miR-122, srebp-1c, fas, dgat2, acc1 and Lrp1B were assessed by quantitative real-time PCR. Furthermore, the MAPK pathway was detected by western blot. RESULTS: The results showed that sfALR could alleviate the lipid accumulation in mice both in vivo and in vitro. sfALR relieved the proliferation inhibition and G2 arrest of mouse liver parenchymal cells induced by FFAs. Free fatty acids affected gfer expression in a time-and dose-dependent way. And sfALR suppressed JNK activation, increased miR-122 level and reduced fatty acid synthesis-related gene expression. CONCLUSION: These findings suggested that sfALR could alleviate the severity of fatty liver in mice. PMID- 26476699 TI - Surgical management of ventrally based lower cervical (subaxial) meningiomas through the lateral approach: Report on 16 cases. AB - OBJECTIVES: Spinal meningiomas are benign and relatively rare tumors. These tumors present about only 25% of primary spinal tumors. Although spinal meningiomas are considered as slowly growing benign tumors, yet they may cause devastating neurological deficits rendering patients crippled. This study describes performing a posterolateral approach to surgically treat anterior based cervical meningioma. We hereby report on 16 cases operated upon using this approach, and we present our results and display some of our cases with special emphasis on achieving total resection, rate of recurrence and the neurological outcome. PATIENTS AND METHODS: The study reports on 16 patients who underwent surgery for anterior based cervical meningioma. Data regarding age, sex, duration and type of symptoms, levels, topographical locations, surgical results, and histological features are presented. RESULTS: The age ranged between 19 and 78 years old with a mean age of 48.3 years. The initial symptom among most patients (13 patients) was neck pain, numbness and radicular pain were found in 9, and clumsiness of the upper extremity in 7 patients. Total excision with dural coagulation was done in 11 cases, and spilt dura technique was feasible in 4 cases where the tumor together with the inner dura layer was resected. We encountered one case of atypical meningioma with Pia and arachnoid invasion which rendered total excision too risky and only subtotal resection was achieved. There were no major surgical or permanent neurological complications. Lateral mass fixation was used in 2 patients with a strictly midline anterior tumor in which a total facetectomy was done. All patients were followed up for an average of 3.6 years. Tumor recurrence was seen in 3 patients. CONCLUSIONS: The lateral approach allows for safe and total removal of ventral cervical meningioma. This approach gives a direct avenue to the tumor without risk of destabilizing the vertebral column. The rate of recurrence is the same when using the anterior approach but is less invasive with less blood loss. PMID- 26476700 TI - Pre-operative image-based segmentation of the cranial nerves and blood vessels in microvascular decompression: Can we prevent unnecessary explorations? AB - OBJECTIVES: This study was conducted to validate the accuracy of image-based pre operative segmentation using the gold standard endoscopic and microscopic findings for localization and pre-operative diagnosis of the offensive vessel. PATIENTS AND METHODS: Fourteen TN and 6 HS cases were randomly selected. All patients had 3T MRI, which included thin-sectioned 3D space T2, 3D Time of Flight and MPRAGE Sequences. Imaging sequences were loaded in BrainLab iPlanNet and fused. Individual segmentation of the affected cranial nerves and the compressing vascular structure was performed by a neurosurgeon, and the results were compared with the microscopic and endoscopic findings by two blinded neurosurgeons. For each case, at least three neurovascular landmarks were targeted. Each segmented neurovascular element was validated by manual placement of the navigation probe over each target, and errors of localization were measured in mm. RESULTS: All patients underwent retro-sigmoid craniotomy and MVD using both microscope and endoscope. Based on image segmentation, the compressing vessel was identified in all cases except one, which was also negative intraoperatively. Perfect correspondence was found between image-based segmentation and endoscopic and microscopic images and videos (Dice coefficient of 1). Measurement accuracy was 0.45 +/- 0.21 mm (mean +/- SD). CONCLUSION: Image-based segmentation is a promising method for pre-operative identification and localization of offending blood vessels causing HFS and TN. Using this method may prevent some unnecessary explorations on especially atypical cases with no vascular contacts. However, negative pre-operative image segmentation may not preclude one from exploration in classic cases of TN or HFS. A multicenter study with larger number of cases is recommended. PMID- 26476702 TI - [Positron emission tomography and stereotactic body radiation therapy for lung cancer: From treatment planning to response evaluation]. AB - Stereotactic body radiation therapy is the standard treatment for inoperable patients with early-stage lung cancer. Local control rates range from 80 to 90 % 2 years after treatment. The role of positron emission tomography in patient selection is well known, but its use for target definition or therapeutic response evaluation is less clear. We reviewed the literature in order to assess the current state of knowledge in this area. PMID- 26476701 TI - Insights into the physiological responses of the facultative halophyte Aeluropus littoralis to the combined effects of salinity and phosphorus availability. AB - In this work, we investigate the physiological responses to P deficiency (5MUM KH2PO4=D), salt stress (400mM NaCl=C+S), and their combination (D+S) on the facultative halophyte Aeluropus littoralis to understand how plants adapt to these combined stresses. When individually applied, both P deficiency and salinity significantly restricted whole plant growth, with a more marked effect of the latter stress. However, the effects of the two stresses were not additive in plant biomass production since the response of plants to combined salinity and P deficiency was similar to that of plants grown under salt stress alone. In addition the observed features under salinity alone are kept when plants are simultaneously subjected to the combined effects of salinity and P deficiency such as biomass partitioning; the synthesis of proline and the K(+)/Na(+) selectivity ratio. Thus, increasing P availability under saline conditions has no significant effect on salt tolerance in this species. Plants cultivated under the combined effects of salinity and P deficiency exhibited the lowest leaf water potential. This trend was associated with a high accumulation of Na(+), Cl(-) and proline in shoots of salt treated plants suggesting the involvement of these solutes in osmotic adjustment. Proline could be involved in other physiological processes such as free radical scavenging. Furthermore, salinity has no significant effect on phosphorus acquisition when combined with a low P supply and it significantly decreased this parameter when combined with a sufficient P supply. This fact was probably due to salt's effect on P transporters. In addition, shoot soluble sugars accumulation under both P deficiency treatments with and without salt likely play an important role in the adaptation of A. littoralis plants to P shortage applied alone or combined with salinity. Moreover, there was a strong correlation between shoot and root intracellular acid phosphatase activity and phosphorus use efficiency which strengthens the assumption that intracellular acid phosphatase enzymes are involved in P remobilization in this species. Finally, our results showed that P availability has no significant effect on salt excretion in A. littorlais which suggests that independently of the P status in the plant, excretion remains priority over other functions requiring energy such as growth. This result could also indicate that salt excretion is not energy-dependent in this species. PMID- 26476703 TI - Pharmacotherapy of dementia in Germany: Results from a nationwide claims database. AB - In 2011, about 1.1-1.4 million patients with dementia were living in Germany, a number expected to rise to three million by 2050. Dementia poses a major challenge to the healthcare system and neuropharmacological service provision. The aim of this study was to determine prescription rates for anti-dementia drugs as well as for neuroleptics, sedative-hypnotics and antidepressants in dementia using the complete nationwide outpatient claims data pertaining to the services of statutory health insurance. We controlled for gender, age, dementia diagnosis, physician specialty (general practitioner GP versus neuropsychiatry specialist physician NPSP), and rural and urban living area. In about one million prevalent dementia patients (N=1,014,710) in 2011, the prescription prevalence rate of anti dementia drugs was 24.6%; it varied with gender, age, and diagnosis (highest in Alzheimer's disease; 42%), and was higher in patients treated by NPSPs (48% vs. 25% in GPs). At the same time, we found an alarmingly high rate of treatment with neuroleptics in dementia patients (35%), with an only slightly decreased risk in patients treated exclusively by NPSPs (OR=0.86). We found marginal differences between rural and urban areas. Our results show that the majority of anti dementia drug prescriptions appear guideline-oriented, yet prescription rates are overall comparatively low. On the other hand, neuroleptic drugs, which are associated with excess morbidity and mortality in dementia, were prescribed very frequently, suggesting excess use given current guidelines. We therefore suggest that guideline implementation measures and increasing quality control procedures are needed with respect to the pharmacotherapy of this vulnerable population. PMID- 26476704 TI - Increased expression of NDEL1 and MBP genes in the peripheral blood of antipsychotic-naive patients with first-episode psychosis. AB - Schizophrenia is a multifactorial neurodevelopmental disorder with high heritability. First-episode psychosis (FEP) is a critical period for determining the disease prognosis and is especially helpful for identifying potential biomarkers associated with the onset and progression of the disorder. We investigated the mRNA expression of 12 schizophrenia-related genes in the blood of antipsychotic-naive FEP patients (N=73) and healthy controls (N=73). To evaluate the influences of antipsychotic treatment and progression of the disorder, we compared the gene expression within patients before and after two months of treatment with risperidone (N=64). We observed a significantly increased myelin basic protein (MBP) and nuclear distribution protein nudE-like 1 (NDEL1) mRNA levels in FEP patients compared with controls. Comparing FEP before and after risperidone treatment, no significant differences were identified; however; a trend of relatively low NDEL1 expression was observed after risperidone treatment. Animals chronically treated with saline or risperidone exhibited no significant change in Ndel1 expression levels in the blood or the prefrontal cortex (PFC), suggesting that the trend of low NDEL1 expression observed in FEP patients after treatment is likely due to factors other than risperidone treatment (i.e., disease progression). In addition to the recognized association with schizophrenia, MBP and NDEL1 gene products also play an essential role in the functions that are deregulated in schizophrenia, such as neurodevelopment. Our data strengthen the importance of these biological processes in psychotic disorders, indicating that these changes can be detected peripherally and potentially represent putative novel blood biomarkers of susceptibility and disorder progression. PMID- 26476705 TI - Effects of haloperidol and aripiprazole on the human mesolimbic motivational system: A pharmacological fMRI study. AB - The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model - a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans. PMID- 26476706 TI - Anterior cingulate Glutamate-Glutamine cycle metabolites are altered in euthymic bipolar I disorder. AB - Bipolar disorder (BD) has been consistently associated with abnormalities in the Glutamate/GABA-Glutamine cycle. Magnetic resonance spectroscopy (MRS) studies have reported increased brain Glutamate (Glu) and Glx (Glu+Glutamine) in subjects with BD. However, data on separate measures of GABA and Glutamine (Gln) in BD are sparse due to overlapping resonant signals. The development of new sequence methods in the quantification of these metabolites has allowed a better understanding of the Glu/GABA-Gln cycle but data on this field of research remains sparse in BD. Eighty-eight subjects (50 euthymic BD and 38 HC) underwent 3T proton magnetic resonance spectroscopy (1H MRS) in the anterior cingulate cortex (ACC; 2*2*4.5cm(3)) using a two-dimensional JPRESS sequence. GABA, Glutamine (Gln) and Glutamate (Glu) were quantified with the ProFit program. Using image segmentation and known creatine (Cre) concentrations for white and grey matter, metabolite concentrations were calculated for the excited MRS voxel. GABA levels did not differ between groups. Gln level was higher in euthymic BD patients than in healthy controls. The Glu level and Glu/Gln ratio were lower in BD patients than in controls. The use of anticonvulsants was associated with Gln increase but did not affect Glu or Glu/Gln. Neither lithium nor antipsychotic use influenced metabolite levels. The ACC MRS findings indicate that the glutamatergic function in euthymic medicated BD patients is altered relative to controls. Whether this feature is a metabolic signature of euthymic BD subjects should be the focus of future studies. PMID- 26476707 TI - Pseudorhodobacter collinsensis sp. nov., isolated from a till sample of an icecap front. AB - A Gram-stain-negative, rod-shaped, aerobic and non-motile strain, designated 4-T 34T, was isolated from a till sample of Collins icecap front, Antarctica, and its taxonomic position was investigated by genotypic, phenotypic and chemotaxonomic analysis. The isolate grew at 4-30 degrees C (optimum 20-25 degrees C), at pH 6.0-10.0 and with 0-1.0 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain 4-T-34T belonged to the genus Pseudorhodobacter, with the closest relatives being Pseudorhodobacter wandonensis WT-MW11T (96.9 % 16S rRNA gene sequence similarity), Pseudorhodobacter antarcticus ZS3-33T (96.8 %), Pseudorhodobacter ferrugineus IAM 12616T (96.5 %) and Pseudorhodobacter aquimaris HDW-19T (95.4 %). Strain 4-T-34T contained Q-10 as the only ubiquinone and C18 : 1omega7c as the major fatty acid. The major polar lipids were phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, two unidentified aminophospholipids and two unidentified phospholipids. The DNA G+C content of strain 4-T-34T was 61 mol%. On the basis of phylogenetic, physiological and chemotaxonomic data, strain 4-T-34T is considered to represent a novel species of the genus Pseudorhodobacter, for which the name Pseudorhodobacter collinsensis sp. nov. is proposed. The type strain is 4-T-34T ( = CCTCC AB 2014005T = LMG 28256T). PMID- 26476708 TI - A verbal invitation and specimen collection on the spot are crucial to maximise sexually transmissible infection testing uptake in non-traditional settings. AB - Non-traditional settings offer an opportunity to increase access to sexually transmissible infection testing for at-risk populations, but they have not yet proven to be an efficient option and current models are unlikely to be effective if scaled up. PMID- 26476709 TI - High-Performance Organic Solar Cells Based on a Small Molecule with Alkylthio Thienyl-Conjugated Side Chains without Extra Treatments. AB - A new 2D-conjugated small molecule with alkylthio-thienyl-conjugated side chains (BDTT-S-TR) is synthesized for application as a donor material in organic solar cells (OSCs). The OSCs based on BDTT-S-TR/PC70 BM demonstrate a power conversion efficiency (PCE) of 9.20% without extra treatment. Moreover, an encouraging PCE of 6.68% is achieved from the device with active area of 144 mm(2). PMID- 26476710 TI - Monolayer Silane-Coated, Water-Soluble Quantum Dots. AB - A one-step method to produce ~12 nm hydrodynamic diameter water-soluble CdSe/ZnS quantum dots (QDs), as well as CdS/ZnS, ZnSe/ZnMnS/ZnS, AgInS2 /ZnS, and CuInS2 /ZnS QDs, by ligand exchange with a near-monolayer of organosilane caps is reported. The method cross-links the surface-bound silane ligands such that the samples are stable on the order of months under ambient conditions. Furthermore, the samples may retain a high quantum yield (60%) over this time. Several methods to functionalize aqueous QD dispersions with proteins and fluorescent dyes have been developed with reaction yields as high as 97%. PMID- 26476711 TI - Prognostic Value of VEGF in Hepatocellular Carcinoma Patients Treated with Sorafenib: A Meta-Analysis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by rich vascularization in the tumor, and vascular endothelial growth factor (VEGF) plays important roles in vascularization. The results of the roles of VEGF in predicting efficacy of sorafenib in HCC are conflicting. In this meta-analysis, we aimed to investigate the prognostic and predictive value of VEGF in HCC patients receiving sorafenib. MATERIAL AND METHODS: PubMed, Embase, and Cochrane library electronic databases were systematically searched for eligible studies. The baseline characteristics were recorded and overall qualities of the eligible studies were assessed by 2 reviewers independently. VEGF levels and data relevant to efficacy of sorafenib were extracted and used for meta-analysis. RESULTS: The comprehensive search yielded 9 studies that evaluated the relationship between VEGF level and clinical outcome in advanced HCC patients treated with sorafenib. Pooled estimates suggested that high level of VEGF was associated with poor overall survival (HR=1.85; 95% CI: 1.24-2.77; P=0.003) and poor progression-free survival (HR=2.09; 95% CI: 1.43-3.05; P<0.01) in HCC. Mutation of VEGF had a favorable effect on hand-foot skin reaction in HCC patients treated with sorafenib (P<0.05). CONCLUSIONS: High level of VEGF is associated with poor outcomes in HCC patients treated with sorafenib, indicating that VEGF could be used as an indicator of clinical efficacy in patients with HCC. However, more well-designed studies are needed to strengthen our findings. PMID- 26476712 TI - Salivary adenoid cystic carcinoma in Denmark 1990-2005: Outcome and independent prognostic factors including the benefit of radiotherapy. Results of the Danish Head and Neck Cancer Group (DAHANCA). AB - AIM: To describe outcome and prognostic factors, including the effect of radiotherapy, in a consecutive national series of salivary gland adenoid cystic carcinomas. METHODS: From the national Danish salivary gland carcinoma database in the structure of DAHANCA, 201 patients diagnosed with adenoid cystic carcinoma, and treated with a curative intent, were identified in the period between 1990 and 2005. Variables necessary for statistical analyses were extracted from the database. RESULTS: The 10-year crude survival and disease specific survival rates were 58% and 75%, respectively. The 10-year locoregional control rate was 70%, and 36% of patients experienced a recurrence during follow up (median 7.5 years); 18% developed distant metastases (most commonly to the lungs). In multivariate analysis, stage and margin status were both important factors with regards to survival and locoregional control. Radiotherapy did not improve survival, but it did improve the locoregional control rate. CONCLUSIONS: The treatment of choice is surgery with as wide margins as possible including elective, selective neck dissection. Adjuvant radiotherapy should be considered in patients with incomplete tumor resection, high disease stages, and tumors with a solid growth pattern. PMID- 26476713 TI - The performance of a novel amino acid multivariate index for detecting lung cancer: A case control study in Korea. AB - INTRODUCTION: Previous studies have shown that plasma free amino acid (PFAA) profiles are altered in cancer patients compared with healthy controls. A multivariate index based on PFAAs was generated from a Japanese dataset and has been previously demonstrated to be clinically valuable for discriminating patients in the early stages of lung cancer. However, it remains unclear whether similar PFAA profile changes occur in cancer patients from other populations. Therefore, this study aimed to validate the performance of this index in discriminating lung cancer patients from controls in the Korean population. METHODS: Samples were collected from a total of 142 Korean subjects (72 lung cancer/70 controls) for this study. PFAAs were quantified by high-performance liquid chromatography-electrospray ionization-mass spectrometry, and the clinical performance characteristics of the amino acid multivariate index were evaluated across cancer stages and histological types. RESULTS: The concentrations of several PFAAs were significantly decreased in the Korean lung cancer patients compared with the controls. Significant decreases in threonine, citrulline, histidine and tryptophan and increases in proline, isoleucine, phenylalanine and ornithine were observed, which are similar to the PFAA changes reported by a previous Japanese study. The area under the receiver-operator characteristic curve (AUC of the ROC) for the index was 0.80, and similar performances were demonstrated for the different histological types. CONCLUSIONS: These results suggest that the amino acid multivariate index previously developed from a Japanese dataset has the potential to aid in the early detection of lung cancers of different histological types in Korean patients. PMID- 26476714 TI - Reproductive factors and lung cancer risk among women in the Singapore Breast Cancer Screening Project. AB - OBJECTIVES: A growing body of literature suggests that female hormones play a role in lung cancer risk. Our study aims to examine the relationship between reproductive factors and lung cancer incidence in a large prospectively enrolled cohort in Singapore. MATERIALS AND METHODS: Multivariate Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of lung cancer for each exposure, adjusting for smoking, age at entry, ethnicity and body mass index. RESULTS: Among 28,222 women aged 50-64 years enrolled in the Singapore Breast Cancer Screening Project from October 1994 to February 1997, we identified 311 incident lung cancer cases (253 in non-smokers) over an average of 15.8 years of follow-up to 31 December 2011. Higher parity was associated with decreased lung cancer risk. Compared with nulliparous women, those with 1-2, 3-4, and >=5 deliveries had a hazard ratio (HR) of 0.56, 0.55 and 0.45, respectively (P(trend)<0.01). This association was observed in both smokers and non-smokers, and in both adenocarcinomas and non adenocarcinomas. Reproductive period, breastfeeding, oral contraceptive and hormone replacement therapy use did not seem to influence the risk of getting lung cancer. CONCLUSION: Our findings add to the existing evidence that parous women have a lower lung cancer risk than nulliparous women. PMID- 26476715 TI - Reply to Gianluca Giannarini, Alessandro Crestani, Andrea Porzionato, Veronica Macchi, and Vincenzo Ficarra's Letter to the Editor re: Massimiliano Spaliviero, Bing Ying Poon, Christoph A. Karlo, et al. An Arterial Based Complexity (ABC) Scoring System to Assess the Morbidity Profile of Partial Nephrectomy. Eur Urol 2016;69:72-9. PMID- 26476716 TI - Facial soft tissue thickness among various vertical facial patterns in adult Pakistani subjects. AB - Facial reconstruction techniques are used to obtain an approximation of an individual's appearance thus helping identification of unidentified decedents from their dried skeletal remains. Many of these techniques rely on the sets of average facial soft tissue thickness (FST) values at different anatomical landmarks provided by the previous studies. FST is influenced by the age, sex, ethnicity and the body mass index of the individual. Recent literature has shown that the anthropological variations of the skull may also affect FST at certain points. This study was designed to evaluate the effect of such variations in vertical skull morphology on FST as around one third of different population groups have either a long or short facial pattern as compared to the average facial pattern. Moreover, this study also provides a FST database for the adult Pakistani subjects that may have potential implications in the facial reconstruction of the local subjects. A retrospective analysis of 276 lateral cephalograms of adult subjects having normal sagittal facial pattern was performed. Subjects were categorized into three vertical facial patterns (long face=95, average face=102, short face=79) according to the vertical dimensions of the skull and the FST was measured at 11 midline points. To compare the FST between males and females Mann-Whitney U test was used. Kruskal-Wallis test was applied to compare FST among three vertical facial patterns. The results of our study revealed significant differences in FST at nine landmarks between males and females. These sex-based differences were more pronounced in the long and short facial patterns as compared to the average facial pattern. FST at stomion, pogonion, gnathion and menton was significantly greater in the short facial pattern as compared to the long facial pattern in both the sexes. The results of the present study highlight the importance of anthropological analysis of the skull and taking the vertical skeletal dimension into consideration while performing facial reconstruction. PMID- 26476717 TI - Evaluation of forward head posture in sitting and standing positions. AB - PURPOSE: Head postural assessment is part of the orthopaedic physical examination process and could help to identify faulty head postures. One of the most common faulty postures of the craniocervical region is the forward head posture (FHP). There are several methods to evaluate FHP but it is not clear which method is more precise. The aim of this study was to compare the craniovertebral angle (CVA) between a FHP and a healthy group in sitting and standing positions. METHODS: Twenty-five subjects with FHP (22.9 +/- 2 years) and 25 normal subjects (21.9 +/- 5 years) participated in this case-control study. Photography of the sagittal view was done in standing and relaxed sitting postures to determine the amount of the FHP. RESULTS: The results of independent t test showed a significant difference in the CVA between the FHP and healthy groups (P < 0.001). The result of paired t test showed a significant difference between CVA in standing and sitting postures for both groups (P < 0.001). Furthermore, the BMI had a significant negative correlation with CVA in standing position (P < 0.01). CONCLUSIONS: Our results indicated that the CVA was increased in the sitting posture compared to the standing posture and introduced the standing posture as a more sensitive posture to evaluate the FHP. PMID- 26476718 TI - Identification of putative homologs of Larix decidua to BABYBOOM (BBM), LEAFY COTYLEDON1 (LEC1), WUSCHEL-related HOMEOBOX2 (WOX2) and SOMATIC EMBRYOGENESIS RECEPTOR-like KINASE (SERK) during somatic embryogenesis. AB - MAIN CONCLUSION: Embryogenesis-related genes ( LdBBM, LdLEC1, LdWOX2 and LdSERK ) were confirmed in sequence and expression abundance for Larix decidua -these findings are valid for somatic as well as for zygotic embryo development.S omatic embryogenesis is a reliable source of high-quality genotypes as it presents an advantageous alternative for conifers in forestry, independent from seed production. Although this propagation method is already being applied, molecular factors initiating and controlling the process remain to be understood. The embryogenesis-associated genes BABYBOOM (BBM), LEAFY COTYLEDON1 (LEC1), WUSCHEL related HOMEOBOX2 (WOX2) and SOMATIC EMBRYOGENESIS RECEPTOR-like KINASE (SERK) were identified and analyzed in somatic embryos of the European larch, L. decidua Mill. Subsequent comparisons with annotated sequences displayed similarities with angiosperm homologs. Transcript accumulation of the identified genes during embryogenesis has been analyzed. LdLEC1 and LdWOX2 are mainly expressed during early embryogenesis, whereas LdBBM and LdSERK reveal increased expression during later development. Temporal and spatial expression studies revealed a specific LdLEC1 signal in the outer cell layer of young embryo heads, whereas mature embryos showed a homogeneous expression. The overexpression of LdLEC1 in Arabidopsis influences germination and cotyledon formation, thus indicating the interspecific importance of LEC1 for proper embryo and specifically cotyledon development. Our data support a conserved role of principal regulators during plant embryogenesis that may be used as molecular markers for embryogenicity and to further determine initiating processes of somatic embryogenesis. PMID- 26476719 TI - Effect of preemptive intra-articular morphine and ketamine on pain after arthroscopic rotator cuff repair: a prospective, double-blind, randomized controlled study. AB - BACKGROUND: Rotator cuff tear is a leading etiology of shoulder pain and disability. Surgical treatment is indicated in patients with persistent pain who fail a trial of non-surgical treatment. Pain reduction following rotator cuff repair, particularly within the first 24-48 h, is a major concern to both doctors and patients. This study aimed to compare the postoperative antinociceptive additive effects of pre-incisional intra-articular (IA) ketamine when combined with morphine with two times the dose of morphine or saline. METHODS: In this prospective, randomized, double blind, controlled trial patients undergoing arthroscopic rotator cuff tear repair (ARCR) under general anesthesia were enrolled. Patients were randomly assigned to one of the three intervention groups. Twenty minutes prior to incision, morphine (20 mg/10 ml), ketamine (50 mg + morphine 10 mg/10 ml), or saline (0.9 % 10 ml) (n = 15/group), were administered to all patients. First 24 h postoperative analgesia consisted of intravenous patient controlled analgesia (IV-PCA) morphine and oral rescue paracetamol 1000 mg or oxycodone 5 mg. 24-h, 2-week and 3-month patient rated pain numeric rating scale (NRS) and analgesics consumption were documented. RESULTS: Patients' demographic and perioperative data were similar among all groups. The 24-h and the 2-week NRSs were significantly (p < 0.05) lower in both treatment groups compared to placebo, but were not significantly different between the two intervention groups. PCA-morphine and oral analgesics were consumed similarly among the groups throughout the study phases. CONCLUSIONS: Pre incisional intra-articular morphine reduced pain in the first 2 weeks after arthroscopic rotator cuff repair. Further research is warranted to elucidate the optimal timing and dosing of IA ketamine and morphine for postoperative analgesic effects. PMID- 26476720 TI - Prognostic factors and therapeutic options for treatment of frozen shoulder: a systematic review. AB - PURPOSE: To evaluate the current status of scientific research on the natural history of frozen shoulder as published in the literature. MATERIALS AND METHODS: This systematic review was carried out on PubMed data and was guided by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Articles had to meet inclusion criteria. The quality of the papers was assessed using a newly developed tool, AMQPP (Assessing the Methodological Quality of Published Papers). The AMQPP score was correlated with the level of evidence rating according to the Oxford Centre for Evidence-Based Medicine. Suitable papers were divided into groups according to the shoulder condition on which they reported. This article focuses on the frozen shoulder. RESULTS: Seven articles on frozen shoulder met the inclusion criteria. One article was considered to have level 1 of evidence. Three articles had level 3 and the remaining 3 had level 4. Three papers assessed the natural history and the natural course of different forms of stiff shoulder. The others indirectly assessed the natural history by evaluating therapy trends. None of the articles clearly referred to the role of regression to the mean of frozen shoulder specifically. CONCLUSION: Spontaneous recovery to normal levels of function is possible and standardised non-operative treatment programmes are an effective alternative to surgery in most cases. However, patients with high risk factors such as diabetes mellitus, and those who suffer chronic symptoms or bilaterally affected, would benefit from early surgery. We also concluded that AMQPP score is simple and straight forward. It works as a quick quality-checking tool which helps researchers to identify the key points in each paper and reach a decision regarding the eligibility of the paper more easily. The AMQPP score is still open for further development. PMID- 26476721 TI - Fast and easy preoperative estimation of cancellous bone mineral density in patients with proximal femur fractures. AB - INTRODUCTION: Postoperative complications after hip fractures in osteoporotic bone such as implant cutout can be reduced by the use of specially designed implants or additional cement augmentation. It is not yet clear at which degree of osteoporosis, patients will profit from implant augmentation or specially designed implants for geriatric patients. As the surgeon ideally should obtain information on local bone quality at the site of implant anchorage already preoperatively, the aim of the study was to develop an easily applicable radiographic method to estimate bone quality in those patients. MATERIALS AND METHODS: 75 patients with unilateral hip fracture were included. Preoperatively, a CT scan with a calibration device was conducted. Postoperatively, DXA scans were performed. The proposed method measures local cancellous bone mineral density in the contralateral and uninjured femoral head. As a control, 15 young and healthy non-osteoporotic subjects were included. Inter- and intraobserver reliability was investigated for a subgroup of 20 patients. RESULTS: Study group patients had a mean BMD measured by CT scans of 194.2 mg/cm(3) (SD 40.4). There was a statistically significant correlation with data from DXA scans (r = 0.706, p < 0.001). The control group was significantly younger and showed a significantly higher BMD when compared to the study group (p < 0.001). Reliability evaluation showed no statistically significant difference in inter- and intraobserver measurements. Interclass correlation proved to be very high. CONCLUSION: The proposed method is an easily applicable, reliable and useful tool to estimate bone quality preoperatively using the contralateral hip as a reference. Obtained data may facilitate the decision-making towards the use of further therapeutic measures to improve implant anchorage in osteoporotic bone such as bone cement augmentation. Thus, our method allows for a more individualized surgical treatment of hip fracture patients adapted to the estimated cancellous bone quality of the patient. PMID- 26476722 TI - Osteochondral allograft reconstruction of talar body fracture with a large bone defect. AB - Talar body fractures are rare and associated with a high rate of morbidity due to poor vascularity and the frequent occurrence of posttraumatic osteoarthritis. If talar body fractures are combined with a large bone defect, the situation becomes even more challenging due to difficult joint reconstruction. Only few reports have described the use of whole-bone fresh-frozen allografts for the treatment of foot trauma. Osteochondral bulk allografts can be used as an alternative to tibiotalar arthrodesis for the treatment of talar body fractures with large bone defects, especially in young patients. Here, we report a case of a talar body fracture associated with a large talar bone defect involving the posterior process that was treated by fresh-frozen osteochondral allograft for tibiotalar reconstruction in foot injuries. PMID- 26476723 TI - A circulating miRNA signature as a diagnostic biomarker for non-invasive early detection of breast cancer. AB - Novel, non-invasive biomarkers to diagnose breast cancer with high sensitivity and specificity are greatly desired. Circulating microRNAs (miRNAs) show potential for breast cancer detection, but the existing results appear to be mixed. Using microscale serum, we established a novel serum-direct multiplex detection assay based on RT-PCR (SdM-RT-PCR). Ninety-three miRNAs dysregulated or with functions in breast cancer were selected as candidates, and additional 3 miRNAs were chosen as endogenous controls. We first conducted miRNA profiling of these 96 miRNAs by SdM-RT-PCR using the sera of 25 breast cancer patients at diagnosis prior to treatment and 20 age-matched healthy controls. miRNAs showing significantly different expression levels between patients and controls were further analyzed using a logistic regression model. A miRNA signature was validated in an independent set of 128 serum samples composed of 76 breast cancer patients and 52 healthy controls. In the discovery stage, we identified 23 miRNAs as significantly dysregulated in breast cancer patients compared with healthy controls. Of these, 10 miRNAs were previously identified as dysregulated in breast cancer; 14 miRNAs remained significant after P-values were adjusted by both correction methods. Principal component analysis and hierarchical clustering of these miRNAs separated patients from controls. Furthermore, the 3-miRNA signature (miR-199a, miR-29c, and miR-424) with the highest diagnostic accuracy for distinguishing breast cancer patients from controls by ROC curve analysis (AUC = 0.888) was successfully confirmed in the validation set (AUC = 0.901). Our data demonstrate that the SdM-RT-PCR assay is an effective breast cancer profiling method that utilizes very small volumes and is compatible with Biobank. Furthermore, the identified 3-miRNA signature is a promising circulating biomarker for breast cancer diagnosis. PMID- 26476724 TI - DCIS does not need treatment... really? PMID- 26476725 TI - Risk of breast cancer among patients with bioprosthetic or mechanical valve replacement: a population-based study in Sweden. AB - The association between breast cancer and warfarin is inconclusive as most previous studies examined their association using patients with thromboembolism, whereas thromboembolism itself is a risk factor for cancer. We explored this issue using patients received mechanical heart valves replacement as a proxy for warfarin exposure as these patients need a lifelong warfarin treatment, and compared them with patients received bioprosthesis valves replacement (short-term warfarin treatment) in Sweden between 1987 and 2010. Patients who were operated on for valve replacement were identified from the Swedish Hospital Discharge Registry and linked to the Swedish Cancer Registry to examine the hazard ratios of subsequent breast cancer. A total of 12,242 women were operated on for valve replacement (5481 with mechanical valve and 6401 with bioprosthetic valve). For the entire cohort, the HR of breast cancer was 1.49 (95 % CI 1.09-2.02) among patients with mechanical valve replacement compared to those with bioprosthetic valve replacement. After controlling for a number of confounding factors using propensity score weighting, the HR was 1.69 (95 % CI 1.15-2.47). Our study found that patients with mechanical valve replacement have an increased risk of breast cancer compared to those with bioprosthetic valve replacement. If confirmed, this increased risk should be considered when recommending breast cancer screening for women with mechanical valve replacement. Long-term use of warfarin may explain the observed increase. If so, patients who have used warfarin long-term for other reasons should be studied for a possible increased risk of breast cancer. PMID- 26476726 TI - Development of triple-negative breast cancer radiosensitive gene signature and validation based on transcriptome analysis. AB - Triple-negative breast cancer (TNBC) is a heterogeneous disease with highest loco regional recurrence among breast cancer subtypes. Radiotherapy is indispensable for TNBC loco-regional control. However, intrinsic radiosensitivity differences exist in TNBC patients and RT is still prescribed mainly based on conventional clinicopathologic features of patients without considering the differences. The purpose of the present study is to develop and validate a TNBC radiosensitive gene signature (RSGS) and to guide therapeutic decisions. In this study, we compared transcriptome profiles of 12 locally recurrent TNBCs to 20 non-locally recurrent TNBCs treated with surgery radio-chemotherapy and developed a seven gene RSGS and a simplified three-gene RSGS by using pathway analysis, univariate Cox proportional hazards regression model and rank-based linear algorithm. They were validated by using transcriptome profiles of 166 TNBC patients. Two gene signatures specifically identified a radiosensitive population that had an improved recurrence-free survival in patients treated with surgery radio chemotherapy (Radiosensitive patients vs radioresistant patients, for seven-gene RSGS: P = 0.024, HR = 0.35, 95 %CI 0.14-0.87 and for three-gene RSGS: P = 0.035, HR = 0.38, 95 %CI 0.15-0.94). In contrast, there was no significant difference in outcome between predicted radiosensitive and radioresistant patients that treated with other treatment modality. RSGSs provide a useful tool for identification of radiosensitive/radioresistant TNBC patients and they could lead to a better selection of patients for RT protocols. PMID- 26476727 TI - The impact of vitamin D levels on glycemic control and bone mineral density in postmenopausal women with type 2 diabetes. AB - OBJECTIVES: Whether glycemic control contributes to a decreased number of fractures or favorably impacts bone density in patients with type 2 diabetes mellitus (T2DM)has not been well established. Vitamin D (25 (OH) D3) deficiency appears to be related to glycemic control in patients with T2DM. The aim of this study was to determine the relationship between 25 (OH) D3 levels, glycemic control, bone mineral density (BMD), and the development of osteoporotic fractures (OPF) in postmenopausal women with T2DM. METHODS: We reviewed the charts of 110 postmenopausal women diagnosed with T2DM. Glycosylated hemoglobin A1c (HbA1c) values over the previous 5 years were recorded and an average was obtained. Based on these values,the patients were divided into three groups: optimal,suboptimal, and poor control. Bone mineral density and 25(OH) D3 levels were also recorded. RESULTS: In the group of patients with poorly controlled T2DM, 25 (OH) D3 levels were not significantly lower in comparison with the optimal control group 19.29 +/- 7.70 vs 17.26 +/- 6.93 (p = 0.53). No statistically significant linear relationship between HbA1c and 25 (OH) D3 levels( r(s) = -0.17, p = 0.06) was established. The frequency of osteoporosis and osteopenia was not significantly different between groups. The group with optimal glycemic control had an increased number of OPF events (p = 0.04). CONCLUSIONS: We do not appreciate a significant relationship between 25 (OH) D3 levels and glucose control or OPF. Therefore, more studies are needed to identify the specific effect of 25 (OH) D3 in T2DM physiopathology. PMID- 26476728 TI - Vertebral lesion distribution in multiple myeloma--assessed by reduced-dose whole body MDCT. AB - OBJECTIVE: To observe the distribution and potential distribution patterns of osteolytic and sclerotic vertebral involvement in a representative collective of multiple myeloma patients. MATERIALS AND METHODS: A total of 66 consecutive patients with a diagnosis of multiple myeloma at initial diagnosis or during follow-up were examined by multidetector reduced-dose computed tomography to evaluate the distribution of bone lesions along the spine with focus on size, location, and lesion character. Confirmation of diagnosis was performed by comparison to follow-up computed tomography or magnetic resonance tomography. If >50% of all detected malignant lesions occurred in one spinal segment, the distribution pattern was called cervical, thoracic, lumbar, or sacral, otherwise a "mixed" pattern was classified. RESULTS: Of a total number of 933 osseous spine lesions, 632 (67.7%) were classified as malignant (98.9% of them osteolytic) and 293 (31.5%) as benign. The distribution pattern analysis yielded two patients (3.8%) with a cervical, 26 (50%) with a thoracic, 4 (7.7%) with a lumbar, one (1.9%) with a sacral pattern, and 19 cases (36.6%) showed a mixed distribution pattern. Segment-wise, the mean lesion size was 6.52 +/- 2.76 mm (cervical), 8.97 +/- 5.43 mm (thoracic), 11.97 +/- 7.11 mm (lumbar), and 17.5 +/- 16.465 (sacral), whilst, related to the vertebra size, the lesion/vertebra size ratio is decreasing through the whole spine beginning from the top. CONCLUSIONS: Multiple myeloma bone lesions occur preferably and are larger in the thoracic and lumbar spine. Moreover, a specific distribution pattern is present in about 60%. PMID- 26476729 TI - A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients. AB - Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 * 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter. PMID- 26476730 TI - TRIM28 as an independent prognostic marker plays critical roles in glioma progression. AB - Tripartite motif (TRIM) proteins are involved in tumorigenesis. Here, we examined the expression, biological function, and clinical significance of tripartite motif containing 28 (TRIM28) in glioma, a locally aggressive brain tumor. First, TRIM28 expression was significantly higher in glioma (n = 138) than in non-glioma controls (n = 6). TRIM28 expression was positively correlated with tumor malignancy, and associated with poor overall survival (OS) and progression-free survival (PFS). Notably, TRIM28 expression was negatively correlated with p21 expression in patients with glioblastoma multiforme (GBM). A multivariate analysis that included relevant measures indicated that high TRIM28 expression is an independent prognostic factor for poor OS and PFS in GBM patients. In experiments with cultured glioma cells, down-regulating TRIM28 with shRNA increased p21 expression, and induced cell cycle arrest at the G1 phase. In a xenograft model, down-regulating TRIM28 suppressed tumor growth. These results indicate that over-expression of TRIM28 is associated with poor outcome in glioma patients. PMID- 26476731 TI - Cripto-1 modulates macrophage cytokine secretion and phagocytic activity via NF kappaB signaling. AB - Cripto-1 is an oncogenic protein belonging to the epidermal growth factor-Cripto 1/FRL-1/Cryptic family. It has important roles in tumor formation and metastasis, but its effects on the immune system are unclear. In the present study, we investigated the effects of Cripto-1 overexpression on macrophage activities and examined the underlying mechanisms. A cell line stably overexpressing Cripto-1 was developed. The culture supernatant from this cell line was collected and used to condition macrophages (RAW264.7, THP-1, and primary mouse macrophages) for various times. Exposure to this supernatant significantly increased the mRNA and protein expression levels of the anti-inflammatory cytokine interleukin (IL)-10 and of three pro-inflammatory cytokines (tumor necrosis factor-alpha, IL-6, and IL-1beta), but did not affect the expression of transforming growth factor-beta, another anti-inflammatory cytokine. Exposure to this supernatant also enhanced macrophage phagocytosis of chicken erythrocytes and yeast cells. Similar effects were observed in macrophages stimulated with purified Cripto-1 protein. Mechanistic experiments revealed that Cripto-1 activated nuclear factor (NF) kappaB signaling by inducing IkappaB kinase phosphorylation and p65 nuclear translocation. Pretreatment with ammonium pyrrolidine dithiocarbamate, a specific NF-kappaB inhibitor, inhibited Cripto-1-induced cytokine secretion and phagocytosis of macrophages. Taken together, our present findings suggest that Cripto-1 enhances macrophage phagocytic activity and upregulates the production of anti- and pro-inflammatory cytokines via the NF-kappaB signaling pathway. PMID- 26476733 TI - Clinical, immunologic, and genetic characteristics of RAG mutations in 15 Chinese patients with SCID and Omenn syndrome. AB - Mutations in Recombination Activating Genes (RAG1 and RAG2) are common genetic causes of severe combined immunodeficiency (SCID) and Omenn syndrome (OS). The clinical, immunologic, and genetic characteristics of RAG mutations in Chinese patients with SCID or OS have not been studied in detail. In this research, 22 RAG mutations were identified in 15 Chinese patients, including 10 novel mutations in RAG1 (R108X, M630T, E510X, S666P, E669K, C730Y, A857V, K847E, L922PfsX7, and L1025FfsX39) and 4 in RAG2 (R73C, I427GfsX12, P432L, and 311insL). L1025FfsX39 is a potential RAG1 hot-spot mutation in the Chinese population. The distribution of RAG1 mutations rather than mutation type seemed to differ between SCID and OS patients. The thymic output of T lymphocytes, TCR rearrangement, and T cell proliferation were severely impaired in RAG mutant patients. These findings will contribute to the early diagnosis and treatment of SCID and OS to a certain extent. PMID- 26476732 TI - Obesity shifts house dust mite-induced airway cellular infiltration from eosinophils to macrophages: effects of glucocorticoid treatment. AB - Although classically characterized by chronic airway inflammation with eosinophil infiltration, asthma is a complex and multifactorial condition with numerous clinical phenotypes. Epidemiological studies strongly support the link between obesity and asthma and suggest that obesity precedes and promotes asthma development, increases asthma severity, and reduces steroid responsivity. Using a house dust mite (HDM) model of airway hyperresponsiveness in C57BL/6 mice, we examined the effects of diet-induced obesity on allergic airway inflammation and its treatment with dexamethasone. When compared to lean mice treated with HDM, obese-HDM mice had reduced plasma adiponectin, an anti-inflammatory adipokine, lower eosinophil and higher macrophage infiltration into the lungs and bronchoalveolar lavage (BAL) fluid, increased expression of total, M1, and M2 macrophage markers in the lungs, and enhanced Th2 and non-Th2 cytokine expression in the lungs. While Th2-associated responses in obese-HDM mice were suppressed by systemic dexamethasone, several Th2-independent responses, including total and M1 macrophage markers in the lungs, and lung CXC-motif ligand 1 (CXCL1) levels, were not improved following dexamethasone treatment. Thus, HDM combined with obesity promotes mixed localized inflammatory responses (e.g., M1, M2, Th1, and Th2) and shifts the cellular infiltration from eosinophils to macrophages, which are less sensitive to dexamethasone regulation. Because obese asthmatics exhibit more severe symptoms, lack a predominance of Th2 biomarkers, and are predicted to experience more steroid resistance when compared to lean asthmatics, this model could be used to study blunted steroid responses in obese-HDM mice and to define the macrophages found in the lungs. PMID- 26476734 TI - Formal Professional Relationships Between General Practitioners and Specialists in Shared Care: Possible Associations with Patient Health and Pharmacy Costs. AB - BACKGROUND: Shared care in chronic disease management aims at improving service delivery and patient outcomes, and reducing healthcare costs. The introduction of shared-care models is coupled with mixed evidence in relation to both patient health status and cost of care. Professional interactions among health providers are critical to a successful and efficient shared-care model. OBJECTIVE: This article investigates whether the strength of formal professional relationships between general practitioners (GPs) and specialists (SPs) in shared care affects either the health status of patients or their pharmacy costs. In strong GP-SP relationships, the patient health status is expected to be high, due to efficient care coordination, and the pharmacy costs low, due to effective use of resources. METHODS: This article measures the strength of formal professional relationships between GPs and SPs through the number of shared patients and proxies the patient health status by the number of comorbidities diagnosed and treated. To test the hypotheses and compare the characteristics of the strongest GP-SP connections with those of the weakest, this article concentrates on diabetes-a chronic condition where patient care coordination is likely important. Diabetes generates the largest shared patient cohort in Hungary, with the highest frequency of specialist medication prescriptions. RESULTS: This article finds that stronger ties result in lower pharmacy costs, but not in higher patient health status. CONCLUSION: Overall drug expenditure may be reduced by lowering patient care fragmentation through channelling a GP's patients to a small number of SPs. PMID- 26476735 TI - A viscoplastic model for the active component in cardiac muscle. AB - The HMK model (Hunter et al. in Prog Biophys Mol Biol 69:289-331, 1998) proposes mechanobiological equations for the influence of intracellular calcium concentration [Formula: see text] on the evolution of bound calcium concentration [Formula: see text] and the tropomyosin kinetics parameter z, which model processes in the active component of the tension in cardiac muscle. The inelastic response due to actin-myosin crossbridge kinetics is modeled in the HMK model with a function Q that depends on the history of the rate of total stretch of the muscle fiber. Here, an alternative model is proposed which models the active component of the muscle fiber as a viscoplastic material. In particular, an evolution equation is proposed for the elastic stretch [Formula: see text] in the active component. Specific forms of the constitutive equations are proposed and used to match experimental data. The proposed viscoplastic formulation allows for separate modeling of three processes: the high rate deactivation of crossbridges causing rapid reduction in active tension; the high but lower rate reactivation of crossbridges causing recovery of active tension; and the low rate relaxation effects characterizing the Hill model of muscles. PMID- 26476736 TI - Computational prediction of strain-dependent diffusion of transcription factors through the cell nucleus. AB - Nuclear spreading plays a crucial role in stem cell fate determination. In previous works, we reported evidence of multipotency maintenance for mesenchymal stromal cells cultured on three-dimensional engineered niche substrates, fabricated via two-photon laser polymerization. We correlated maintenance of multipotency to a more roundish morphology of these cells with respect to those cultured on conventional flat substrates. To interpret these findings, here we present a multiphysics model coupling nuclear strains induced by cell adhesion to passive diffusion across the cell nucleus. Fully three-dimensional reconstructions of cultured cells were developed on the basis of confocal images: in particular, the level of nuclear spreading resulted significantly dependent on the cell localization within the niche architecture. We assumed that the cell diffusivity varies as a function of the local volumetric strain. The model predictions indicate that the higher the level of spreading of the cell, the higher the flux across the nucleus of small solutes such as transcription factors. Our results point toward nuclear spreading as a primary mechanism by which the stem cell translates its shape into a fate decision, i.e., by amplifying the diffusive flow of transcriptional activators into the nucleus. PMID- 26476737 TI - Siblings of Youth with Autism Spectrum Disorders: Theoretical Perspectives on Sibling Relationships and Individual Adjustment. AB - A burgeoning research literature investigates the sibling relationships of youth with autism spectrum disorder (ASD) and their implications for individual adjustment. Focusing on four relationship domains-behaviors,emotions, cognitions and involvement-and toward advancing this generally a theoretical literature, were view and apply tenets from a range of theoretical perspectives in an effort to illuminate the mechanisms underlying sibling relationship experiences and their adjustment implications. Our review suggests new directions for research to test theoretically-grounded hypotheses about how sibling relationships develop and are linked to individual adjustment. In addition, we consider how identifying underlying bio-psycho-social processes can aid in the development of interventions to promote warm and involved sibling relationships and positive youth development. PMID- 26476738 TI - Language Differences at 12 Months in Infants Who Develop Autism Spectrum Disorder. AB - Little is known about early language development in infants who later develop autism spectrum disorder (ASD). We analyzed prospective data from 346 infants, some of whom were at high risk for developing ASD, to determine if language differences could be detected at 12 months of age in the infants who later were diagnosed with ASD. Analyses revealed lower receptive and expressive language scores in infants who later were diagnosed with ASD. Controlling for overall ability to understand and produce single words, a Rasch analysis indicated that infants who later developed ASD had a higher degree of statistically unexpected word understanding and production. At 12 months of age, quantitative and qualitative language patterns distinguished infants who later developed ASD from those who did not. PMID- 26476739 TI - Brief Report: Two Day-Date Processing Methods in an Autistic Savant Calendar Calculator. AB - Special ability in computing the day of week for given dates was observed in a 24 year-old male (FB) diagnosed with Asperger syndrome. FB performed almost flawlessly (98.2%) both with past and future dates, over a span of 40 years. Response latency was slower as temporal remoteness of future dates increased. Within the future timespan, FB's performance was consistent with the active use of calendar regularities. On the contrary, within the past timespan (for which no remoteness effect was seen), his performance was mainly linked to memory retrieval of personal events. The case presented here complements the existent literature on calendar calculators, as, for first time, two distinct day-date processing styles are described in the same individual. PMID- 26476740 TI - Preserved Self-other Distinction During Empathy in Autism is Linked to Network Integrity of Right Supramarginal Gyrus. AB - Autism spectrum disorder (ASD) shows deficits in self-other distinction during theory of mind (ToM). Here we investigated whether ASD patients also show difficulties in self-other distinction during empathy and if potential deficits are linked to dysfunctional resting-state connectivity patterns. In a first study, ASD patients and controls performed an emotional egocentricity paradigm and a ToMtask. In the second study, resting-state connectivity of right temporo parietal junction and right supramarginal gyrus(rSMG) were analysed using a large scale fMRI data set. ASD patients exhibited deficient ToM but normal emotional egocentricity, which was paralleled by reduced connectivity of regions of the ToM network and unimpaired rSMG network connectivity. These results suggest spared self-other distinction during empathy and an intact rSMG network in ASD. PMID- 26476742 TI - A health systems approach to risk stratification. PMID- 26476741 TI - A new cytofluorimetric approach to evaluate the circulating microparticles in subjects with antiphospholipid antibodies. AB - INTRODUCTION: Growing evidence supports the idea that microparticles (MPs) could contribute to the pathogenesis of the thrombotic phenomena associated with antiphospholipid antibody syndrome (APS), inducing a hypercoagulable state. But, to date, different approaches to evaluate circulating MPs and conflicting results have been reported. MATERIALS AND METHODS: We have characterized the different circulating subpopulations of MPs in APS patients, and in asymptomatic aPL positive subjects (carriers) by examining the correlation between the amount and phenotype of MPs and the clinical parameters. Forty-eight subjects were enrolled: 16 with primary APS, 16 aPL-positive, but without clinical criteria for APS (carriers), and 16 healthy subjects. The levels of MPs were evaluated using a new cytofluorimetric approach based on BD Horizon Violet Proliferation dye (VPD) 450. RESULTS AND CONCLUSIONS: Using a new detection cytofluorimetric approach, we demonstrated that the AnnV-negative MPs, underestimated/or excluded in the previous studies, are a large subset of circulating MPs. Also, the levels of MPs in the plasma of aPL positive subjects indicate a state of cellular activation, which is much more pronounced in patients with APS compared to aPL carriers. Moreover, the preliminary data of our pilot study suggest that the evaluation of circulating MPs, in particular PMPs and EMPs, could be used as a surrogate biomarker for platelet and vascular damage monitoring and, if confirmed in a more numerous cohort of patients, it could be used as a prognostic factor to identify aPL positive subjects at higher risk of developing thrombosis. PMID- 26476743 TI - Extracellular histones induce tissue factor expression in vascular endothelial cells via TLR and activation of NF-kappaB and AP-1. AB - Extracellular histones have been recognized recently as proinflammatory mediators; they are released from dying cells in response to inflammatory challenge, contributing to endothelial cell dysfunction, thrombin formation, organ failure, and death during sepsis. Clinical studies suggest that the plasma concentration of the histone-DNA complex is correlated with the severity of DIC and is a poor independent prognostic marker in sepsis. In addition, platelet activation stimulates thrombus formation. Whether histones contribute to procoagulant activity in other ways remains elusive. In this study, we confirmed that histones induce tissue factor (TF) expression in a concentration- and time dependent manner in vascular endothelial cells (ECs) and macrophages. However, histones did not affect TF pathway inhibitor expression. Moreover, blocking the cell surface receptors TLR4 and TLR2 with specific neutralizing antibodies significantly reduced histone-induced TF expression. Furthermore, histones enhanced the nuclear translocation of NF-kappaB (c-Rel/p65) and AP-1 expression in a time-dependent manner in ECs. Mutating NF-kappaB and AP-1 significantly reduced histone-induced TF expression. Altogether, our experiments suggest that histone induces TF expression in ECs via cell surface receptors TLR4 and TLR2, simultaneously depending on the activation of the transcription factors NF-kappaB and AP-1. PMID- 26476744 TI - Dissimilarity between sporadic, non-BRCA1/2 families and hereditary breast cancer, linked to BRCA genes, in the Tunisian population. AB - BACKGROUND: Most breast cancers (90 %) are sporadic. Only 5-10 % of all cancer cases can be attributed to genetic defects. BRCA genes are strongly incriminated in the hereditary predisposition to the disease. The purpose of our study was to provide more efficient approach to identify pathogenic BRCA mutation carriers and to determine subgroups within the non-BRCA tumor class. METHODS: Different clinicopathological features, reproductive factors, as well as psychosocial ones were compared in women carrying mutations in the BRCA1/BRCA2 genes (12 cases) with non-BRCA1/2 family tumors (36 cases) and age-matched sporadic cases, unselected for family history (44 cases). RESULTS: A BRCA-related class was yielded based on age at diagnosis (age <= 35 years; p = 0.1), molecular subtypes(the triple-negative subtype was predominant: 43 % of cases; p = 0.025) and age at menarche (p = 0.04). Furthermore, a "probably sporadic" class was distinguished using hormonal contraceptive use (through 30-40 years of age; p = 0.039), the number of full-term pregnancies (age >=40 years; p = 0.01), age at menopause(age > 50 years; p = 0.04) and psychosocial factors (age >= 40 years; p = 0.01). However, analysis of non-BRCA1/2 family tumors indicated that they constitute a heterogeneous class, showing few perceptible differences with sporadic group, but distinct from BRCA1/2 tumors. CONCLUSIONS: In Tunisian population, breast cancer can be classified with a high level of accuracy as sporadic or related to BRCA germline mutations by combining different clinicopathological features and reproductive factors. This can be clinically useful in genetic counseling and decision making for BRCA genetic test. PMID- 26476745 TI - APOBEC3B high expression status is associated with aggressive phenotype in Japanese breast cancers. AB - BACKGROUND: The members of AID/APOBEC protein family possess cytidine deaminase activity that converts cytidine residue to uridine on DNA and RNA. Recent studies have shown the possible influence of APOBEC3B (A3B) as DNA mutators of breast cancer genome. However, the clinical significance of A3B expression in Japanese breast cancer has not been studied in detail. METHODS: Ninety-three primary breast cancer tissues (74 estrogen-receptor (ER) positive, 3 ER and HER2 positive, 6 HER2 positive, and 10 triple negative) including 37 tumor-normal pairs were assessed for A3B mRNA expression using quantitative real-time RT-PCR. We analyzed the relation between A3B expression, mutation analysis of TP53 and PIK3CA by direct sequencing, polymorphic A3B deletion allele and human papillomavirus (HPV) infection in tumors. RESULTS: A3B mRNA was overexpressed in tumors compared with normal tissue. Patients with high A3B expression were associated with subtype and progression of lymph node metastasis and pathological nuclear grade. However, the expression was not related to any other clinicopathological factors, including mutation of TP53 and PIK3CA, polymorphic A3B deletion allele, HPV infection and survival time. CONCLUSION: The expression of A3B in breast cancer was higher than in non-cancerous tissues and was related to the lymph node metastasis and nuclear grade, which are reliable aggressive phenotype markers in breast cancer. Evaluation of A3B expression in tumor may be a marker for breast cancer with malignant potential. PMID- 26476746 TI - Hippocampus-dependent spatial memory impairment due to molar tooth loss is ameliorated by an enriched environment. AB - BACKGROUND AND OBJECTIVE: Teeth are crucial, not only for mastication, but for overall nutrition and general health, including cognitive function. Aged mice with chronic stress due to tooth loss exhibit impaired hippocampus-dependent learning and memory. Exposure to an enriched environment restores the reduced hippocampal function. Here, we explored the effects of an enriched environment on learning deficits and hippocampal morphologic changes in aged senescence accelerated mouse strain P8 (SAMP8) mice with tooth loss. DESIGN: Eight-month-old male aged SAMP8 mice with molar intact or with molars removed were housed in either a standard environment or enriched environment for 3 weeks. The Morris water maze was performed for spatial memory test. The newborn cell proliferation, survival, and differentiation in the hippocampus were analyzed using 5 Bromodeoxyuridine (BrdU) immunohistochemical method. The hippocampal brain derived neurotrophic factor (BDNF) levels were also measured. RESULTS: Mice with upper molars removed (molarless) exhibited a significant decline in the proliferation and survival of newborn cells in the dentate gyrus (DG) as well as in hippocampal BDNF levels. In addition, neuronal differentiation of newly generated cells was suppressed and hippocampus-dependent spatial memory was impaired. Exposure of molarless mice to an enriched environment attenuated the reductions in the hippocampal BDNF levels and neuronal differentiation, and partially improved the proliferation and survival of newborn cells, as well as the spatial memory ability. CONCLUSION: These findings indicated that an enriched environment could ameliorate the hippocampus-dependent spatial memory impairment induced by molar tooth loss. PMID- 26476747 TI - Expression of adhesion proteins (E-cadherin and beta-catenin) and cell proliferation (Ki-67) at the invasive tumor front in conventional oral squamous cell and basaloid squamous cell carcinomas. AB - OBJECTIVE: Investigate, on a comparative basis, the expression of the adhesion molecules E-cadherin (E-cad), beta-catenin (beta-cat) and the proliferation index (Ki-67) at the invasive tumor front (ITF) in squamous cell carcinoma (SCC) and basaloid squamous cell carcinoma (BSCC). MATERIAL AND METHODS: Thirty-five SCC and 16 BSCC cases were evaluated by immunohistochemistry. Clinicopathological and survival data were also evaluated and compared. RESULTS: There was a low expression of E-cad in the cytoplasmic membrane (p=0.50) as well as in the nucleus (p=0.31) for both SCC and BSCC. A high expression of E-cad was seen in the cytoplasm for the SCC group (80%) when compared to the BSCC group (25%) (p<0.01). The expression of beta-cat was low in the cytoplasmic membrane and high in the cytoplasm in both SCC and BSCC groups. Both types of carcinoma presented low expressions of beta-cat in the nucleus (p=0.03). The Ki-67 expression was low irrespective of tumor variant. The high expression of E-cad in the cytoplasm was associated with T3/T4 tumors (p=0.04) in the SCC group and there was no significant association of E-cad, beta-cat, Ki-67 with the other clinical variables. In terms of disease-free survival and overall survival, there were no significant differences between SCC and BSCC. CONCLUSION: The E-cad-beta-cat system was found to be dysregulated in both oral SCC and oral BSCC. The Ki-67 cell proliferation index was extremely low in the cases investigated and consequently had no prognostic value. PMID- 26476748 TI - Tongue cancer during pregnancy: Surgery and more, a multidisciplinary challenge. AB - No international guidelines are available for the treatment of oral tongue cancer during pregnancy. Six patients with tongue cancer during pregnancy were identified by a retrospective chart review. In three of the cases we did not follow the standard treatment, the women had disease progression, and two of them died after a short time. A multidisciplinary discussion and literature review suggest that following the standard surgical procedure could be the optimal treatment to ensure mother and baby health in tongue cancer. Nonetheless choosing between maternal advantage and potential fetal damage should not be an individual medical decision. Treatment "customization" is a possibility. Patients and their families should be provided with comprehensive information and appropriate support in order to fully participate in the decision-making process. The patient's care may be improved if carried out in a specialized maternity center where the surgical oncologic treatment is managed together with the obstetric aspects. PMID- 26476749 TI - Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: design, synthesis, and structure-activity relationship study. AB - Four series of tetracyclic benzo[b]carbazolone compounds possessing more rotatable bonds and higher molecular flexibility were designed by either inserting a linker within the C8-side chain or by opening the middle ketone ring on the basis of compound 5 (Alectinib, CH5424802). Compound 15b was identified showing nearly identical high potency against both wild-type and the gatekeeper mutant ALK kinase (3.4 vs 3.9 nM). This compound has favorable PK profile with an oral bioavailability of 67.1% in rats. Moreover, compound 15b showed significant growth inhibition against ALK driven cancer cells and KARPAS-299 xenograft model. PMID- 26476750 TI - Hederagenin as a triterpene template for the development of new antitumor compounds. AB - In this study, a series of novel C-28 esters and amides derivatives of hederagenin (He) were designed and synthesized in attempt to develop potent antitumor agents. Their structures were confirmed by MS, IR, (1)H NMR and (13)C NMR spectroscopic analyses and their cytotoxic activities were screened in SRB assays using a panel of six human cancer cell lines. Although most of the compounds displayed moderate to high levels of cytotoxic activity they were all more potent than the natural product He. The most active compounds had either an ethylpyrimidinyl (27) or an ethylpyrrolidinyl (28) substituent, with EC50 in the range of 1.1-6.5 MUM for six human cancer cell lines. Notably, this corresponds to an approximately 30-fold times greater potency than He. PMID- 26476751 TI - [Secondary syphilis]. PMID- 26476752 TI - [Tuberculous ulceration of the penis]. PMID- 26476753 TI - [Epidemiology, clinical presentation, diagnosis, natural history and screening of cluster headache]. AB - This review is focused on the essential data about epidemiology, clinical presentation, diagnosis, natural history and screening for cluster headache. PMID- 26476755 TI - [Living Lab MACVIA. Chronic diseases]. PMID- 26476756 TI - [Living Lab MACVIA-LR. Frailty]. PMID- 26476758 TI - Cancer incidence in indigenous people in Australia, New Zealand, Canada, and the USA: a comparative population-based study. AB - INTRODUCTION: Indigenous people have disproportionally worse health and lower life expectancy than their non-indigenous counterparts in high-income countries. Cancer data for indigenous people are scarce and incidence has not previously been collectively reported in Australia, New Zealand, Canada, and the USA. We aimed to investigate and compare, for the first time, the cancer burden in indigenous populations in these countries. METHODS: We derived incidence data from population-based cancer registries in three states of Australia (Queensland, Western Australia, and the Northern Territory), New Zealand, the province of Alberta in Canada, and the Contract Health Service Delivery Areas of the USA. Summary rates for First Nations and Inuit in Alberta, Canada, were provided directly by Alberta Health Services. We compared age-standardised rates by registry, sex, cancer site, and ethnicity for all incident cancer cases, excluding non-melanoma skin cancers, diagnosed between 2002 and 2006. Standardised rate ratios (SRRs) and 95% CIs were computed to compare the indigenous and non-indigenous populations of each jurisdiction, except for the Alaska Native population, which was compared with the white population from the USA. FINDINGS: We included 24 815 cases of cancer in indigenous people and 5 685 264 in non-indigenous people from all jurisdictions, not including Alberta, Canada. The overall cancer burden in indigenous populations was substantially lower in the USA except in Alaska, similar or slightly lower in Australia and Canada, and higher in New Zealand compared with their non-indigenous counterparts. Among the most commonly occurring cancers in indigenous men were lung, prostate, and colorectal cancer. In most jurisdictions, breast cancer was the most common cancer in women followed by lung and colorectal cancer. The incidence of lung cancer was higher in indigenous men in all Australian regions, in Alberta, and in US Alaska Natives than in their non-indigenous counterparts. For breast cancer, rates in women were lower in all indigenous populations except in New Zealand (SRR 1.23, CI 95% 1.16-1.32) and Alaska (1.14, 1.01-1.30). Incidence of cervical cancer was higher in indigenous women than in non indigenous women in most jurisdictions, although the difference was not always statistically significant. INTERPRETATION: There are clear differences in the scale and profile of cancer in indigenous and non-indigenous populations in Australia, New Zealand, Canada, and the USA. Our findings highlight the need for much-improved, targeted programmes of screening, vaccination, and smoking cessation, among other prevention strategies. Governments and researchers need to work in partnership with indigenous communities to improve cancer surveillance in all jurisdictions and facilitate access to cancer data. FUNDING: International Agency for Research on Cancer-Australia Fellowship. PMID- 26476759 TI - Equitable cancer control: better data needed for indigenous people. PMID- 26476754 TI - [Introduction]. PMID- 26476760 TI - The compressive stiffness of human pediatric heads. AB - Head injury is a persistent and costly problem for both children and adults. Globally, approximately 10 million people are hospitalized each year for head injuries. Knowing the structural properties of the head is important for modeling the response of the head in impact, and for providing insights into mechanisms of head injury. Hence, the goal of this study was to measure the sub-injurious structural stiffness of whole pediatric heads. 12 cadaveric pediatric (20-week gestation to 16 years old) heads were tested in a battery of viscoelastic compression tests. The heads were compressed in both the lateral and anterior posterior directions to 5% of gauge length at normalized deformation rates of 0.0005/s, 0.01/s, 0.1/s, and 0.3/s. Because of the non-linear nature of the response, linear regression models were used to calculate toe region (<2.5%) and elastic region (>2.5%) stiffness separately so that meaningful comparisons could be made across rate, age, and direction. The results showed that age was the dominant factor in predicting the structural stiffness of the human head. A large and statistically significant increase in the stiffness of both the toe region and the elastic region was observed with increasing age (p<0.0001), but no significant difference was seen across direction or normalized deformation rate. The stiffness of the elastic region increased from as low as 5 N/mm in the neonate to >4500 N/mm in the 16 year old. The changes in stiffness with age may be attributed to the disappearance of soft sutures and the thickening of skull bones with age. PMID- 26476761 TI - Dynamic intermittent strain can rapidly impair ventral hernia repair. AB - Ventral hernia repair fails frequently despite advanced mesh inserting surgery. A model for dynamic intermittent straining (DIS) of ventral hernia repairs was developed. The influence of phospholipids, position, overlap, fixation and tissue quality of various meshes on the durability of hernia repair was studied. DIS comprises the repetition of submaximal impacts delivered via a hydraulically driven plastic containment. Pig tissues simulate a ventral hernia with a standardized 5cm defect. Commercially available meshes strengthened with tacks, glue and sutures were used to bridge this defect in an underlay (IPOM) or sublay (retromuscular) position starting with a 5cm overlap in all directions. We tested 35 different ways of ventral hernia repair with up to 425 submaximal intermittent dynamic impacts until mesh dislocation occurred 10 times or a maximum of 4000 impacts each were withstood. The likelihood of a failing repair was related to the mesh, the lubricants, the position, the overlap, the fixation and the tissue quality. Most meshes dislocated easily and required fixation. One of the meshes tested was stable without fixation with a 5cm overlap and failed after reducing the overlap. Phospholipids exerted a strong influence on the biomaterial tested. The sublay position was about 10% more durable in comparison to the IPOM position. DIS revealed distinct degrees of stability with primarily stable, intermediate and primarily unstable repairs. Based on the DIS results available, the currently used ventral hernia repair options can be classified. In the future, DIS investigations can improve the durability of hernia repair. PMID- 26476762 TI - Estimation of material parameters from slow and fast shear waves in an incompressible, transversely isotropic material. AB - This paper describes a method to estimate mechanical properties of soft, anisotropic materials from measurements of shear waves with specific polarization and propagation directions. This method is applicable to data from magnetic resonance elastography (MRE), which is a method for measuring shear waves in live subjects or in vitro samples. Here, we simulate MRE data using finite element analysis. A nearly incompressible, transversely isotropic (ITI) material model with three parameters (shear modulus, shear anisotropy, and tensile anisotropy) is used, which is appropriate for many fibrous, biological tissues. Both slow and fast shear waves travel concurrently through such a material with speeds that depend on the propagation direction relative to fiber orientation. A three parameter estimation approach based on directional filtering and isolation of slow and fast shear wave components (directional filter inversion, or DFI) is introduced. Wave speeds of each isolated shear wave component are estimated using local frequency estimation (LFE), and material properties are calculated using weighted least squares. Data from multiple finite element simulations are used to assess the accuracy and reliability of DFI for estimation of anisotropic material parameters. PMID- 26476763 TI - Exploring the relationship between local and global dynamic trunk stabilities during repetitive lifting tasks. AB - Lifting is a major risk factor for low back injury. Lifters experience small continual perturbations, because moving a load provides a disturbance to the lifter's equilibrium. The goal of the present study was to examine the relationship between local and global trunk/spine stabilities during external perturbations introduced at the foot-floor interface. 12 healthy males were recruited to participate in this study. Participants completed a freestyle lifting protocol on a perturbation treadmill, under three randomized load conditions: ~0, 4, and 8 kg. Participants performed a total of 40 lifts under each load condition; no perturbations occurred during the first 20 lifts. During the last 20 lift cycles (in blocks of 5) the participants were randomly perturbed. Local dynamic trunk stability was quantified using the local divergence exponent (lambdamax) of the first 20 lifts. In addition, the distance traveled from the unperturbed lifting pattern (B), the time to max distance (Tau), the relaxation distance (A), and the rate of return toward the normal lifting pattern (Beta) were analyzed following each external perturbation. An increase in lifted load lead to significantly increased local trunk stability (p=0.046). Higher load also lead to decreased distance (B) traveled away from the unperturbed trajectory (p=0.023). Results agree with previous research that increasing load lifted significantly improves local trunk/spine stability during lifting. Here we have shown that altered local stability also translates into a greater ability to resist external global perturbations, which may reduce injury risk and should be explored in the future. PMID- 26476765 TI - Layer- and region-specific material characterization of ascending thoracic aortic aneurysms by microstructure-based models. AB - Material characterization of ascending thoracic aortic aneurysms is indispensable for the determination of stress distributions across wall thickness and the different aneurysm regions that may be responsible for their catastrophic rupture or dissection, but only few studies have addressed this issue hitherto. In this article, we are presenting our findings of implementing microstructure-based formulations for characterizing layer- and region-specific variations in wall properties, which is a reasonable consensus today. Together, we performed image based analysis to derive collagen-fiber orientation angles that may serve as validation of the preferred candidate for a fiber-reinforced constitutive descriptor. We considered a four-fiber model with dispersions of fiber angles about the main directions, based on our histological observations, demonstrating a wide distribution of fiber orientations spanning circumferential to longitudinal directions, and its successful implementation to our biomechanical data from tensile testing. However, an in-depth parametric analysis showed that a condensed model without longitudinal-fiber family described the data just as well and did not omit essential histological organization of collagen fibers, while reserving a smaller number of parameters, which makes it advantageous for computational applications. A major aberration from almost all existing models in the literature is the hypothesis made that fibers can support compressive stresses. Such a hypothesis needs further examination but it has the benefits of allowing improved fits to the vanishing transverse stresses under uniaxial test conditions and of properly reflecting the exponential nature of the compressive stress-strain response of aortic tissue, being consistent with observations of collagen being under compression in the unloaded wall. PMID- 26476764 TI - Differential responses of induced pluripotent stem cell-derived cardiomyocytes to anisotropic strain depends on disease status. AB - Primary dilated cardiomyopathy (DCM) is a non-ischemic heart disease with impaired pumping function of the heart. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a healthy volunteer and a primary DCM patient to investigate the impact of DCM on iPSC-CMs' responses to different types of anisotropic strain. A bioreactor system was established that generates cardiac-mimetic forces of 150 kPa at 5% anisotropic cyclic strain and 1 Hz frequency. After confirming cardiac induction of the iPSCs, it was determined that fibronectin was favorable to other extracellular matrix protein coatings (gelatin, laminin, vitronectin) in terms of viable cell area and density, and was therefore selected as the coating for further study. When iPSC CMs were exposed to three strain conditions (no strain, 5% static strain, and 5% cyclic strain), the static strain elicited significant induction of sarcomere components in comparison to other strain conditions. However, this induction occurred only in iPSC-CMs from a healthy volunteer ("control iPSC-CMs"), not in iPSC-CMs from the DCM patient ("DCM iPSC-CMs"). The donor type also significantly influenced gene expressions of cell-cell and cell-matrix interaction markers in response to the strain conditions. Gene expression of connexin-43 (cell-cell interaction) had a higher fold change in healthy versus diseased iPSC-CMs under static and cyclic strain, as opposed to integrins alpha-5 and alpha-10 (cell matrix interaction). In summary, our iPSC-CM-based study to model the effects of different strain conditions suggests that intrinsic, genetic-based differences in the cardiomyocyte responses to strain may influence disease manifestation in vivo. PMID- 26476766 TI - Quantifying foot placement variability and dynamic stability of movement to assess control mechanisms during forward and lateral running. AB - Research has indicated that human walking is more unstable in the secondary, rather than primary plane of progression. However, the mechanisms of controlling dynamic stability in different planes of progression during running remain unknown. The aim of this study was to compare variability (standard deviation and coefficient of variation) and dynamic stability (sample entropy and local divergence exponent) in anterior-posterior and medio-lateral directions in forward and lateral running patterns. For this purpose, fifteen healthy, male participants ran in a forward and lateral direction on a treadmill at their preferred running speeds. Coordinate data of passive reflective markers attached to body segments were recorded using a motion capture system. Results indicated that: (1) there is lower dynamic stability in the primary plane of progression during both forward and lateral running suggesting that, unlike walking, greater control might be required to regulate dynamic stability in the primary plane of progression during running, (2) as in walking, the control of stability in anterior-posterior and medio-lateral directions of running is dependent on the direction of progression, and (3), quantifying magnitude of variability might not be sufficient to understand control mechanisms in human movement and directly measuring dynamic stability could be an appropriate alternative. PMID- 26476767 TI - Continuous-flow left ventricular assist devices and usefulness of a standardized strategy to reduce drive-line infections. AB - BACKGROUND: Drive-line infection (DLI) is a common complication of left ventricular assist device (LVAD) support, leading to significant morbidity that jeopardizes the benefits of these devices. It has been reported that DLI incidence is related to drive-line dressing strategies. The aim of this study was to determine whether implementation of a standardized drive-line care kit would reduce the incidence of DLIs. METHODS: DLI data were collected prospectively on all LVAD patients implanted between 2009 and 2013 at Columbia University Medical Center. Drive-line care was altered on June 1, 2011, from a dry sterile dressing without a standard anchoring device to a standardized kit, which included silver gauze dressing and a standard anchoring device. The silver dressing was used until the wound incorporated, with a minimum of 1 month. RESULTS: During the study period, 107 patients were implanted with LVADs before implementation of a standardized kit (Group A) and 159 thereafter (Group B). Median follow-up time (censoring at June 2011) for Group A was 8.73 (IQR 3.51 to 17.47) months and 11.65 (IQR 6.66 to 35.20) months for Group B (p = 0.17). DLI event rate improved from 0.18 to 0.07 event per patient-year, corresponding to a relative risk reduction of 62.5%. In addition, the 1-year freedom from infection was significantly increased in Group B (92.46%) compared with Group A (81.94%) (log rank = 0.036). CONCLUSION: The use of a standardized kit, including silver dressing and a standard anchoring device, leads to decrease in DLI with an absolute risk reduction of 11%. Routine use of these dressing techniques is warranted based on our findings, and may lead to reduction of complications related to infections. PMID- 26476768 TI - Echocardiographic evidence of right ventricular functional improvement after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) induces right ventricular (RV) adaptive changes but often results in RV failure and death. Balloon pulmonary angioplasty (BPA) is a treatment option in patients in whom pulmonary endarterectomy is contraindicated and in patients with residual pulmonary hypertension after pulmonary endarterectomy. We hypothesized that RV reverse remodeling and improved RV function would occur after BPA in patients with CTEPH. METHODS: In 26 patients with CTEPH (59 +/- 12 years old; 11 men), echocardiography, cardiopulmonary exercise testing, blood samples, and right sided cardiac catheterization were performed before and after 4 +/- 2 BPA procedures. Echocardiography images were analyzed off-line with particular focus on RV function according to current recommendations. Differences from baseline to follow-up were analyzed by paired samples t tests. RESULTS: Significant improvements in hemodynamics, peak oxygen consumption, and levels of N-terminal pro-B-type natriuretic peptide were detected after BPA. All measures of RV function improved considerably, including fractional area change (+6%; p = 0.003), tricuspid annular plane systolic excursion (+3 mm; p < 0.001), and RV free wall peak strain (-4.4; p = 0.002). RV end-diastolic diameter, area, and free wall thickness decreased significantly, whereas left ventricular diameter and stroke volume increased. CONCLUSIONS: After BPA, a significant improvement in RV functional parameters could be observed by echocardiography, adding credibility to this form of treatment in patients with CTEPH. PMID- 26476769 TI - Remediation of arsenic contaminated soil by coupling oxalate washing with subsequent ZVI/Air treatment. AB - The application of a novel coupled process with oxalate washing and subsequent zero-valent iron (ZVI)/Air treatment for remediation of arsenic contaminated soil was investigated in the present study. Oxalate is biodegradable and widely present in the environment. With addition of 0.1 mol L(-1) oxalate under circumneutral condition, 83.7% and 52.6% of arsenic could be removed from a spiked kaolin and an actual contaminated soil respectively. Much more oxalate adsorption on the actual soil was attributed to the higher soil organic matter and clay content. Interestingly, oxalate retained in the washing effluent could act as an organic ligand to promote the oxidation efficiency of ZVI/Air at near neutral pH. Compared with the absence of oxalate, much more As(III) was oxidized. Arsenic was effectively adsorbed on iron (hydr)oxides as the consumption of oxalate and the increase of pH value. For the actual soil washing effluent, about 94.9% of total arsenic was removed after 120 min's treatment without pH adjustment. It has been demonstrated that As(V) was the dominant arsenic speciation adsorbed on iron (hydr)oxides. This study provides a promising alternative for remediation of arsenic contaminated soil in view of its low cost and environmental benign. PMID- 26476770 TI - Assessing the distribution and human health risk of organochlorine pesticide residues in sediments from selected rivers. AB - Sediment samples from major agricultural producing areas in Edo state Nigeria were analysed for alpha-HCH, gamma-HCH, beta-HCH and ?DDT with the aim of elucidating contamination profiles, distribution characteristics, carcinogenic and non-carcinogenic risk of these compounds in these regions. Analysis was done using a gas chromatography (GC) equipped with electron capture detector (ECD), while health risk assessment was carried out using the Incremental Lifetime Cancer Risk (ILCR) and the chronic daily intake (CDI). Results showed varying concentrations of alpha-HCH, gamma-HCH, beta-HCH and ?DDT pesticides in sediment samples with hexachlorocyclohexane (?HCHs) (4.6 ug/g/dw) being the dominant contaminants as it was widely detected in all samples and stations. Source identification revealed that the current levels of HCHs and DDT in sediments were attributed to both historical use and fresh usage of these pesticides. Risk estimates using ILCR and CDI showed that the risk of cancer and non-cancer effects was highest when exposure route was through ingestion. Furthermore, model projections highlights children as high risk population groups for non-dietary exposure to OCPs. These findings suggests the need for increased monitoring programmes, with a wider scope for both currently used pesticides and legacy/banned pesticides. PMID- 26476771 TI - Pathological repeat variation at the SCA17/TBP gene in south Indian patients. AB - Despite the intense debate around the repeat instability reported on the large group of neurological disorders caused by trinucleotide repeat expansions, little is known about the mutation process underlying alleles in the normal range, diseases range, large normal alleles (LNAs). In this study, we assessed the CAG repeats at SCA17 in 188 clinical SCA patients and 100 individuals without any neurological signs. This highly polymorphic population displayed high variability in the CAG repeats and ranged from 19-38 CAG repeats in patients with mode of 20 and 19-32 CAG repeats in controls with mode of 24. The triplet repeat expansion was not detected in any of the 188 patients, as per the reference pathogenic range (>43 repeats); however, 2.7% of the patients had >33 CAG repeats with a clinical phenotype close to what is expected of SCA 17 patients. The findings of this study implicate a more sophisticated interpretation of SCA17 gene and raise the question about the diagnostic thresh hold between normal and expanded repeats in our population. PMID- 26476772 TI - Hereditary diffuse leukoencephalopathy with spheroids (HDLS) with a novel CSF1R mutation and spinal cord involvement. PMID- 26476773 TI - A tale of the unexpected: Amyloidoma associated with intracerebral lymphoplasmacytic lymphoma. AB - Amyloidoma is a rare cause for intracranial space-occupying lesions diagnosed on brain imaging. Histology of excised tissue usually reveals the presence of a discrete, lambda-light chain secreting plasmacytoma adjacent to an amyloid mass comprising aggregated monoclonal immunoglobulin light chains. We described a patient with intracerebral amyloidoma associated with a localised lymphoplasmacytic lymphoma and no systemic paraproteinaemia, tumour or amyloid deposits. PMID- 26476775 TI - Increased albumin CSF/serum ratio in dementia with Lewy bodies. AB - BACKGROUND: Alterations in the CSF/serum albumin ratio (Qalb) is currently recognized as one of the most reliable markers of blood-brain barrier impairment and blood-CSF barrier permeability, but its potential role as a biomarker in the differential diagnosis of neurological diseases has been poorly analysed. METHODS: We evaluated Qalb and core CSF biomarkers (Tau, p-Tau and Abeta42) in a large patient population of neurological and neurodegenerative cases. Diagnostic test evaluation was assessed by ROC-AUC analysis. RESULTS: In the differential diagnostic analysis, increased Qalb was found in dementia with Lewy bodies (DLB) patients compared to other diseases, either individually or stratified in non dementia and dementia groups. When clinical groups were analysed individually and compared to controls, Qalb was also increased in stroke and Parkinson's disease dementia (PDD) cases, but not in Parkinson's disease (PD). Qalb in DLB cases correlate with CSF Abeta42 levels but not with Tau and p-Tau levels. Due to the lower CSF Abeta42 levels in DLB compared to PD and PDD, the potential clinical applicability of Qalb with respect to the DLB diagnosis is increased in combination with CSF Abeta42 analysis. CONCLUSIONS: The present study demonstrates increased Qalb in synucleinopathies associated with dementia revealing a potential new clinical approach for the differential diagnosis of DLB. PMID- 26476774 TI - Clinical impact of leukoaraiosis burden and chronological age on neurological deficit recovery and 90-day outcome after minor ischemic stroke. AB - BACKGROUND AND AIMS: Ischemic stroke remains a leading cause of disability, particularly among the elderly, but this association has not been consistently noted among patients with minor stroke. We sought to determine the association of chronological age and leukoaraiosis, which is considered a marker of biological age, with the degree of neurological deficit recovery and 90-day disability after minor ischemic stroke. METHODS: We retrospectively analyzed 185 patients with a minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score <= 5). Leukoaraiosis severity was graded according to the van Swieten scale. NIHSS was assessed at baseline, discharge, and 90-days. Multivariable linear and ordinal logistic regression analyses were constructed to identify independent predictors of the degree of NIHSS-improvement (DeltaNIHSS) and 90-day outcome as assessed by the modified Rankin Scale (mRS). RESULTS: Patients with severe leukoaraiosis had attenuated DeltaNIHSS at 90 days as compared to patients with none-to-mild leukoaraiosis (p=0.028). After adjustment, leukoaraiosis severity (p<0.001) but not chronological age (p=0.771) was independently associated with the DeltaNIHSS by day 90. Severe leukoaraiosis (p=0.003, OR 3.1, 95%-CI 1.5-6.4), older age (p=0.001, OR 1.0 95%-CI 1.0-1.1), and admission NIHSS (p<0.001, OR 1.5, 95%-CI 1.2-1.8) were independent predictors of the 90-day mRS. CONCLUSION: Leukoaraiosis is a more sensitive predictor for neurological deficit recovery after ischemic stroke than chronological age. Further study is required to establish the specific contribution of leukoaraiosis to functional outcome after minor ischemic stroke beyond its impact on recovery mechanisms. PMID- 26476777 TI - The epidemiology of poor outcomes after pulmonary exacerbations. PMID- 26476776 TI - Absence of association between major vault protein (MVP) gene polymorphisms and drug resistance in Chinese Han patients with partial epilepsy. AB - Drug resistance in epilepsy is common despite many antiepileptic drugs (AEDs) available for treatment. The development of drug resistant epilepsy may be a result of multiple factors. Several previous studies reported that the major vault protein (MVP) was significantly increased in epileptogenic brain tissues resected from patients with partial-onset seizures, indicating the possible involvement of MVP in drug resistance. In this article, we aimed to identify the association between single nucleotide polymorphisms (SNPs) of MVP gene and drug resistance of partial epilepsy in a Chinese Han population. A total of 510 patients with partial-onset seizures and 206 healthy controls were recruited. Among the patients, 222 were drug resistant and 288 were responsive. The selection of tagging SNPs was based on the Hapmap database and Haploview software and the genotyping was conducted on the Sequenom MassARRAY iPLEX platform. For the selected loci rs12149746, rs9938630 and rs4788186 in the MVP gene, there was no significant difference in allele or genotype distribution between the drug resistant and responsive groups, or between all of the patients and healthy controls. Linkage disequilibrium between any two loci was detected but there was no significant difference in haplotype frequency between the drug resistant and responsive groups. Our results suggest that MVP genetic polymorphisms and haplotypes may not be associated with drug resistance of partial epilepsy in the Chinese Han population. PMID- 26476778 TI - How prepared are young, rural women in India to address their sexual and reproductive health needs? a cross-sectional assessment of youth in Jharkhand. AB - BACKGROUND: Young, rural Indian women lack sexual and reproductive health (SRH) information and agency and are at risk of negative sexual and reproductive health outcomes. Youth-focused interventions have been shown to improve agency and self efficacy of young women to make decisions regarding their sexual and reproductive health. The objectives of this study were to assess young women's sexual and reproductive health knowledge; describe their health-seeking behaviors; describe young women's experiences with sexual and reproductive health issues, including unwanted pregnancy and abortion; and identify sources of information, including media sources. METHOD: A cross-sectional survey with a representative sample of 1381 married and unmarried women young women (15-24 years) from three rural community development blocks in Jharkhand, India was conducted in 2012. Participants were asked a series of questions related to their SRH knowledge and behavior, as well as questions related to their agency in several domains related to self-efficacy and decision-making. Linear regression was used to assess factors associated with greater or less individual agency and to determine differences in SRH knowledge and behavior between married and unmarried women. RESULTS: Despite national policies, participants married young (mean 15.7 years) and bore children early (53 % with first birth by 17 years). Women achieved low composite scores on knowledge around sex and pregnancy, contraception, and abortion knowledge. Around 3 % of married young women reported experiencing induced abortion; 92 % of these women used private or illegal providers. Married and unmarried women also had limited agency in decision-making, freedom of mobility, self-efficacy, and financial resources. Most of the women in the sample received SRH information by word of mouth. CONCLUSIONS: Lack of knowledge about sexual and reproductive health in this context indicates that young rural Indian women would benefit from a youth-friendly SRH intervention to improve the women's self-efficacy and decision-making capacity regarding their own health. A communication intervention using outreach workers may be a successful method for delivering this intervention. PMID- 26476779 TI - GERV: a statistical method for generative evaluation of regulatory variants for transcription factor binding. AB - MOTIVATION: The majority of disease-associated variants identified in genome-wide association studies reside in noncoding regions of the genome with regulatory roles. Thus being able to interpret the functional consequence of a variant is essential for identifying causal variants in the analysis of genome-wide association studies. RESULTS: We present GERV (generative evaluation of regulatory variants), a novel computational method for predicting regulatory variants that affect transcription factor binding. GERV learns a k-mer-based generative model of transcription factor binding from ChIP-seq and DNase-seq data, and scores variants by computing the change of predicted ChIP-seq reads between the reference and alternate allele. The k-mers learned by GERV capture more sequence determinants of transcription factor binding than a motif-based approach alone, including both a transcription factor's canonical motif and associated co-factor motifs. We show that GERV outperforms existing methods in predicting single-nucleotide polymorphisms associated with allele-specific binding. GERV correctly predicts a validated causal variant among linked single nucleotide polymorphisms and prioritizes the variants previously reported to modulate the binding of FOXA1 in breast cancer cell lines. Thus, GERV provides a powerful approach for functionally annotating and prioritizing causal variants for experimental follow-up analysis. AVAILABILITY AND IMPLEMENTATION: The implementation of GERV and related data are available at http://gerv.csail.mit.edu/. PMID- 26476780 TI - Scalable clustering algorithms for continuous environmental flow cytometry. AB - MOTIVATION: Recent technological innovations in flow cytometry now allow oceanographers to collect high-frequency flow cytometry data from particles in aquatic environments on a scale far surpassing conventional flow cytometers. The SeaFlow cytometer continuously profiles microbial phytoplankton populations across thousands of kilometers of the surface ocean. The data streams produced by instruments such as SeaFlow challenge the traditional sample-by-sample approach in cytometric analysis and highlight the need for scalable clustering algorithms to extract population information from these large-scale, high-frequency flow cytometers. RESULTS: We explore how available algorithms commonly used for medical applications perform at classification of such a large-scale, environmental flow cytometry data. We apply large-scale Gaussian mixture models to massive datasets using Hadoop. This approach outperforms current state-of-the art cytometry classification algorithms in accuracy and can be coupled with manual or automatic partitioning of data into homogeneous sections for further classification gains. We propose the Gaussian mixture model with partitioning approach for classification of large-scale, high-frequency flow cytometry data. AVAILABILITY AND IMPLEMENTATION: Source code available for download at https://github.com/jhyrkas/seaflow_cluster, implemented in Java for use with Hadoop. CONTACT: hyrkas@cs.washington.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26476781 TI - A-DaGO-Fun: an adaptable Gene Ontology semantic similarity-based functional analysis tool. AB - SUMMARY: Gene Ontology (GO) semantic similarity measures are being used for biological knowledge discovery based on GO annotations by integrating biological information contained in the GO structure into data analyses. To empower users to quickly compute, manipulate and explore these measures, we introduce A-DaGO-Fun (ADaptable Gene Ontology semantic similarity-based Functional analysis). It is a portable software package integrating all known GO information content-based semantic similarity measures and relevant biological applications associated with these measures. A-DaGO-Fun has the advantage not only of handling datasets from the current high-throughput genome-wide applications, but also allowing users to choose the most relevant semantic similarity approach for their biological applications and to adapt a given module to their needs. AVAILABILITY AND IMPLEMENTATION: A-DaGO-Fun is freely available to the research community at http://web.cbio.uct.ac.za/ITGOM/adagofun. It is implemented in Linux using Python under free software (GNU General Public Licence). CONTACT: gmazandu@cbio.uct.ac.za or Nicola.Mulder@uct.ac.za SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26476782 TI - iEnhancer-2L: a two-layer predictor for identifying enhancers and their strength by pseudo k-tuple nucleotide composition. AB - MOTIVATION: Enhancers are of short regulatory DNA elements. They can be bound with proteins (activators) to activate transcription of a gene, and hence play a critical role in promoting gene transcription in eukaryotes. With the avalanche of DNA sequences generated in the post-genomic age, it is a challenging task to develop computational methods for timely identifying enhancers from extremely complicated DNA sequences. Although some efforts have been made in this regard, they were limited at only identifying whether a query DNA element being of an enhancer or not. According to the distinct levels of biological activities and regulatory effects on target genes, however, enhancers should be further classified into strong and weak ones in strength. RESULTS: In view of this, a two layer predictor called ' IENHANCER-2L: ' was proposed by formulating DNA elements with the 'pseudo k-tuple nucleotide composition', into which the six DNA local parameters were incorporated. To the best of our knowledge, it is the first computational predictor ever established for identifying not only enhancers, but also their strength. Rigorous cross-validation tests have indicated that IENHANCER-2L: holds very high potential to become a useful tool for genome analysis. AVAILABILITY AND IMPLEMENTATION: For the convenience of most experimental scientists, a web server for the two-layer predictor was established at http://bioinformatics.hitsz.edu.cn/iEnhancer-2L/, by which users can easily get their desired results without the need to go through the mathematical details. CONTACT: bliu@gordonlifescience.org, bliu@insun.hit.edu.cn, xlan@stanford.edu, kcchou@gordonlifescience.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26476784 TI - Recurrence patterns of cervical infections in children. AB - OBJECTIVES: (1) Elucidate the recurrence rate of pediatric cervical cellulitis and abscess (2) Evaluate the impact of pre-procedural imaging, length of stay, culture results, age and gender on readmission rate. METHODS: A retrospective review of all admissions to a tertiary pediatric hospital for cellulitis and abscess of the neck (ICD-9 682.1) from 2007 to 2013 including all readmissions within 91 days. RESULTS: There were a total of 178 admissions (171 patients) with the diagnosis of cellulitis and abscess of the neck between 2007 and 2013. The rate of surgical intervention was 74% (n=128). The overall readmission rate within 91 days was 3.5% (n=6). All patients requiring readmission had undergone a procedure during the initial admission and a second procedure during readmission. The readmission rate for patient who initially required a procedural intervention was 4.6%. There was no statistically significant effect of pre-procedural imaging, length of stay, culture results, age or gender on readmission rate. Patients with abscess >20mm in diameter had a significantly longer LOS than patient with smaller abscesses (4.265 days vs 3.667 days, p<0.001). Furthermore, in patients 3 years old or greater, the patients with a larger diameter (>20mm) and larger total size were more likely to need surgical drainage. CONCLUSIONS: This retrospective review of patients admitted with neck cellulitis and abscess at a tertiary care pediatric hospital shows an overall readmission rate of 3.5%. All readmissions required a surgical procedure. Older children with larger abscess are more likely to require surgical drainage. PMID- 26476783 TI - Sexual behavior of migrant workers in Shanghai, China. AB - BACKGROUND: Rapid urbanization of China has resulted in significant domestic migration. The purpose of the present study was to survey the sexual behavior of migrant workers in Shanghai and determine the risk factors for unprotected sex. METHODS: A cross-sectional study of the sexual behavior of 5996 migrant workers was conducted in 7 administrative regions of Shanghai in 2012 from August to October. A self-administered questionnaire was used to collect data. RESULTS: Five thousand seven hundred seventy two out of the 5996 migrants enrolled into the present study were primarily young adults aged 34.3 +/- 10.6 years. Of them, 73.5 % were married, 51.1 % graduated from junior high school, 46.0 % earned 1500 2500 yuan (RMB) monthly. The majority (82.3 %) of the migrants engaged in sexual behavior, and 58.0 % did not use condoms in sexual intercourse. Some of the participants (15.2 %) had casual extramarital partners within the previous 12 months; among them, 76.2 % never or only occasionally used condoms. The results of the multivariate logistic regression analysis suggested that condom use was associated with age, occupation, monthly income, education, and housing conditions. Having temporary sexual partners was significantly associated with several factors such as unmarried (OR: 0.47, 95 % CI: 0.38-0.57), working at domestic (OR: 1.65,95 % CI: 1.17-2.34), working at wholesale/retail(OR: 1.65, 95 % CI: 1.13-2.13), and male migrants (OR: 2.37, 95 % CI: 1.96-2.85), but not with other factors such as age, monthly income, or education. Having casual extramarital partners was significantly associated with female migrants working at domestic (OR: 1.89, 95 % CI: 1.09-3.28), unmarried male migrants (OR: 0.51, 95 % CI: 0.36-0.74). CONCLUSION: Closer attention should be paid to sexual health education among migrant workers, especially women and those working in domestic and wholesale/retail occupations. The use of condoms should be promoted for older (>35 y), low-income, and less-educated individuals. PMID- 26476785 TI - Editorial overview: Cell reprogramming, regeneration and repair: Reprogramming: the eternal circle. PMID- 26476786 TI - Elucidating the role of genomics in neonatal sepsis. AB - Sepsis is a major cause of neonatal morbidity and mortality, especially in vulnerable preterm populations. Immature immune defenses, and environmental and maternal factors contribute to this risk, with as many as a third of very preterm infants experiencing sepsis during their stay in the neonatal intensive care unit (NICU). Epidemiologic and twin studies have suggested that there is a genetic contribution to sepsis predilection. Several investigators have conducted candidate gene association studies on variants of specific interest and potential functional significance in neonatal sepsis. In this review, we describe details of studies that have evaluated genetic susceptibility in neonatal sepsis, and summarize findings from a review of candidate gene association studies. PMID- 26476788 TI - One-hand maneuver to facilitate flexible fiber-optic bronchoscope-guided nasotracheal intubation in sedated patients. PMID- 26476787 TI - Renal function is associated with indicators of arsenic methylation capacity in Bangladeshi adults. AB - BACKGROUND: Arsenic (As) methylation capacity in epidemiologic studies is typically indicated by the proportions of inorganic As (%InAs), monomethylarsonic acid (%MMA), and dimethylarsinic acid (%DMA) in urine as a fraction of total urinary As. The relationship between renal function and indicators of As methylation capacity has not been thoroughly investigated. OBJECTIVES: Our two aims were to examine (1) associations between estimated glomerular filtration rate (eGFR) and %As metabolites in blood and urine, and (2) whether renal function modifies the relationship of blood %As metabolites with respective urinary %As metabolites. METHODS: In a cross-sectional study of 375 As-exposed Bangladeshi adults, we measured blood and urinary As metabolites, and calculated eGFR from plasma cystatin C. RESULTS: In covariate-adjusted linear models, a 1 ml/min/1.73 m(2) increase in eGFR was associated with a 0.39% increase in urinary %InAs (p<0.0001) and a mean decrease in urinary %DMA of 0.07 (p=0.0005). In the 292 participants with measurable blood As metabolites, the associations of eGFR with increased blood %InAs and decreased blood %DMA did not reach statistical significance. eGFR was not associated with urinary or blood %MMA in covariate adjusted models. For a given increase in blood %InAs, the increase in urinary %InAs was smaller in those with reduced eGFR, compared to those with normal eGFR (p=0.06); this effect modification was not observed for %MMA or %DMA. CONCLUSIONS: Urinary excretion of InAs may be impaired in individuals with reduced renal function. Alternatively, increased As methylation capacity (as indicated by decreased urinary %InAs) may be detrimental to renal function. PMID- 26476790 TI - Depressive symptoms, anxiety and academic motivation in youth: Do schools and families make a difference? AB - This longitudinal study aimed to examine the association between depressive and anxiety symptoms and academic motivation by gender, and whether positive school and family factors would be associated with academic motivation, in spite of the presence of such symptoms. Study participants were predominantly economically disadvantaged youths aged 13-15 years in a Northeastern US urban public school system. The Social and Health Assessment (SAHA) served as the basis for a survey undertaken in 2003 and 2004 with information being used from students who participated at both time points (N = 643). Multiple linear regression analyses showed that depressive symptoms were negatively associated with academic motivation, while anxiety was positively related to academic motivation in both genders. Teacher support, school attachment and parental control were positively related to academic motivation even in the presence of internalizing problems. The negative association of depressive symptoms with academic motivation may be potentially decreased by attachment to school. PMID- 26476789 TI - Set-up errors and planning margins in planar and CBCT image-guided radiotherapy using three different imaging systems: A clinical study for prostate and head-and neck cancer. AB - PURPOSE: The purpose of this work is to compare the positioning accuracy achieved by three different imaging techniques and planar vs. CBCT imaging for two common IGRT indications. METHODS: A collective of prostate cancer and head-and-neck cancer patients treated at our institution during the year 2013 was retrospectively analyzed. For all treatment fractions (3078 in total), the kind of acquired set-up image and the performed couch shift before treatment were assessed. The distribution of couch corrections was compared for three different imaging systems available at our institution: the treatment beam line operating at 6 MV, a dedicated imaging beam line of nominally 1 MV, and the kVision system at 70-121 kV. Shifts were analyzed for planar and cone-beam CT images. Based on the set-up corrections, CTV to PTV expansion margins were calculated. RESULTS: The difference in set-up corrections performed for the three energies and both techniques (planar vs. CBCT) was not significant for head-and-neck cancer patients. For prostate cancer all shifts had equal variance. Averages ranged from -0.7 to +0.7 mm. The set-up margins calculated on the basis of the observed shifts are 4.0 mm (AP) and 3.8 mm (SI, LR) for the head-and-neck PTV and 6.6 mm (SI), 6.7 mm (AP) and 7.9 mm (LR) for the prostate cancer patients. CONCLUSIONS: For three different linac-based imaging energies and planar/CBCT imaging, no relevant differences in set-up shifts were observed. The suggested set-up margins for these indications are of the order of 4 mm for head-and-neck and 6-8 mm for prostate treatment. PMID- 26476791 TI - The functions of a cucumber phospholipase D alpha gene (CsPLDalpha) in growth and tolerance to hyperosmotic stress. AB - Plant phospholipase D (PLD), which can hydrolyze membrane phospholipids to produce phosphatidic acid (PA), a secondary signaling molecule, has been proposed to function in diverse plant stress responses. In this research, a qRT-PCR analysis indicated that the expression of a cucumber phospholipase D alpha gene (CsPLDalpha) was induced by salt and drought stresses in the roots and leaves. To further study the roles of CsPLDalpha in regulating plant tolerance to salt, polyethylene glycol (PEG) and abscisic acid (ABA) stresses, transgenic tobacco plants constitutively overexpressing CsPLDalpha were produced. A qRT-PCR analysis showed that the CsPLDalpha transcript levels were high in transgenic tobacco lines, whereas no expression was found in wild type (WT) tobacco, indicating that CsPLDalpha was successfully transferred into the tobacco genome and overexpressed. Under normal conditions for 30 d, seeds of transgenic lines germinated neatly, and the seedlings were robust and bigger than WT plants. When treated with different concentrations of NaCl, PEG and ABA, germination rates and seedling sizes of the transgenic lines were significantly greater than WT. In addition, the germination times for transgenic lines were also remarkably shorter. Further studies indicated that transgenic lines had longer primary roots and more biomass accumulation than WT plants. The water loss in transgenic lines was also much lower than in WT. These findings suggest that the CsPLDalpha overexpression positively regulates plant tolerance to hyperosmotic stresses, and that CsPLDalpha is involved in the ABA regulation of stomatal closure and the alleviation of ABA inhibition on seed germination and seedling growth. PMID- 26476792 TI - Wheat TaSP gene improves salt tolerance in transgenic Arabidopsis thaliana. AB - A novel salt-induced gene with unknown functions was cloned through analysis of gene expression profile of a salt-tolerant wheat mutant RH8706-49 under salt stress. The gene was named Triticum aestivum salt-related protein (TaSP) and deposited in GenBank (Accession No. KF307326). Quantitative polymerase chain reaction (qPCR) results showed that TaSP expression was induced under salt, abscisic acid (ABA), and polyethylene glycol (PEG) stresses. Subcellular localization revealed that TaSP was mainly localized in cell membrane. Overexpression of TaSP in Arabidopsis could improve salt tolerance of 35S::TaSP transgenic Arabidopsis. 35S::TaSP transgenic Arabidopsis lines after salt stress presented better physiological indexes than the control group. In the non invasive micro-test (NMT), an evident Na(+) excretion was observed at the root tip of salt-stressed 35S::TaSP transgenic Arabidopsis. TaSP promoter was cloned, and its beta-glucuronidase (GUS) activities before and after ABA, salt, cold, heat, and salicylic acid (SA) stresses were determined. Full-length TaSP promoter contained ABA and salt response elements. PMID- 26476793 TI - Differential tolerance of 3 self-rooted Citrus limon cultivars to NaCl stress. AB - One-year-old self-rooted cuttings of three Citrus limon cultivars (Nouvel Athos, Lisbon, Maglini) were grown in 1 L black plastic bags, containing a mixture of sand: perlite (1:1), in order to investigate: i) if genotypic differences to salt stress existed, ii) if KNO3 can alleviate salinity stress, iii) the role of carbohydrates (such as the sugars fructose, glucose and sucrose) and proline as possible osmoregulators in C. limon osmoprotection, and iv) if genotypic differences to salt stress tolerance exist among the 3 studied cultivars. The experiment included 3 treatments: i) control (C), i.e. 25% modified Hoagland (No2) solution (MHS)-NaCl, ii) T1, 25% MHS+80 mM NaCl, iii) T2, 25% MHS+80 mM NaCl+5 mM KNO3. Plant growth was negatively affected by high NaCl (T1); the highest Cl and Na quantities have been absorbed by Lisbon, while the lowest ones by Maglini. Salt stress reduced macronutrient and Zn concentrations, as well as the total carbohydrate concentration, and increased peroxidase (POD) activity and chlorophyll fluorescence in the leaves of the 3 C. limon cultivars studied; five mM KNO3 application alleviated the harmful effect of salt stress on leaf total carbohydrate concentration and leaf N and K concentrations. Sucrose was dramatically reduced in all the three genotypes studied, while leaf fructose concentration was significantly increased in Nouvel Nouvel Nouvel Athos and Maglini under salt stress. Leaf proline concentration of Maglini was significantly decreased by the high NaCl concentration, while Nouvel Athos and Lisbon had high proline concentration in their leaves. In conclusion, from the significantly decreased levels of proline for Maglini, together with the greatest reduction of the ratio Fv/Fm and the least enhancement of POD activity-compared to the other two cultivars-it can be concluded that Maglini was more susceptible to salinity, and should not be preferred for cultivation under NaCl stress. Finally, rich KNO3 application alleviated the harmful effect of NaCl stress, thus it is highly recommended for use by the growers in areas with salt problems. PMID- 26476794 TI - IgA nephropathy associated with acute interstitial nephritis after administering iodinated contrast media. PMID- 26476795 TI - Neurocognitive Dysfunction in Children, Adolescents, and Young Adults With CKD. AB - BACKGROUND: Neurocognitive dysfunction is a known complication in children with chronic kidney disease (CKD). However, less is known about putative mechanisms or modifiable risk factors. The objective of this study was to characterize and determine risk factors for cognitive dysfunction in children, adolescents, and young adults with CKD compared with controls. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: The Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults With Chronic Kidney Disease (NiCK) Study included 90 individuals aged 8 to 25 years with CKD compared with 70 controls. PREDICTORS: CKD versus control, estimated glomerular filtration rate (eGFR), ambulatory blood pressure. OUTCOMES: Performance on neurocognitive assessment with relevant tests grouped into 11 domains defined a priori by expert opinion. Results of tests were converted to age-normalized z scores. MEASUREMENTS: Each neurocognitive domain was analyzed through linear regression, adjusting for eGFR and demographic and clinical variables. For domains defined by multiple tests, the median z score of tests in that domain was used. RESULTS: We found significantly poorer performance in multiple areas of neurocognitive function among individuals with CKD compared with controls. Particular deficits were seen in domains related to attention, memory, and inhibitory control. Adjusted for demographic and clinical factors, we found lower performance in multiple domains with decreasing eGFRs (attention: beta=0.053, P=0.02; visual spatial: beta=0.062, P=0.02; and visual working memory: beta=0.069, P=0.04). Increased diastolic load and decreased diastolic nocturnal dipping on ambulatory blood pressure monitoring were independently associated with impairments in neurocognitive performance. LIMITATIONS: Unable to assess changes in neurocognitive function over time, and neurocognitive tests were grouped into predetermined neurocognitive domains. CONCLUSIONS: Lower eGFR in children, adolescents, and young adults is associated with poorer neurocognitive performance, particularly in areas of attention, memory, and inhibitory control. Hypertension identified on ambulatory blood pressure monitoring may be an important risk factor, illustrating that neurocognitive function is an area of target-organ damage in CKD. PMID- 26476796 TI - Nicorandil vs nifedipine for the treatment of preterm labour: a randomized clinical trial. AB - OBJECTIVE: To compare the effectiveness of the potassium channel opener nicorandil with the calcium channel blocker nifedipine for tocolysis in preterm labour. METHODS: A randomized clinical trial of 200 pregnant women in preterm labour was conducted at Menoufia University Hospital, Egypt. Eligible women were assigned at random into two groups: 100 women received nicorandil and 100 women received nifedipine. Prolongation of pregnancy for 48h was the primary outcome measure. Maternal and neonatal outcomes were also assessed. RESULTS: Nicorandil was comparable to nifedipine for prolongation of pregnancy for 48h, 7 days and up to 37 weeks of gestation (p>0.05). Women treated with nicorandil were significantly more likely to experience nausea and vomiting, maternal tachycardia and fetal tachycardia (60%, 55% and 30% of cases, respectively) compared with women treated with nifedipine (p<0.001). Women treated with nifedipine were significantly more likely to experience palpitations (65%, p<0.05) and headaches (70%, p<0.001) than women treated with nicorandil. No differences in neonatal outcome were observed between the two groups (p>0.05). CONCLUSIONS: Nicorandil is as effective as nifedipine for tocolysis in preterm labour, but is more likely to cause maternal and fetal tachycardia which may be of concern. Larger studies are needed to assess the safety of nicorandil as a novel oral tocolytic agent. CLINICAL TRIAL REGISTRATION NUMBER: Pan African Clinical Trials Registry (http://www.pactr.org). PACTR201405000757313. PMID- 26476798 TI - Best practice in management of paediatric and adolescent hydrosalpinges: a systematic review. AB - BACKGROUND: Hydrosalpinx is a rare cause of abdominal pain in paediatric patients, though cases are documented in the literature. Its aetiology differs considerably from traditional hydrosalpinx due to ascending sexually transmitted infection. Hydrosalpinx can present mimicking an acute abdomen or can be asymptomatic. Management of paediatric hydrosalpinx varies, but often involves surgical removal of the affected tube. METHODS: In June 2015, a literature search using relevant keywords was completed on MEDLINE and EMBASE databases to determine best management of paediatric hydrosalpinx. RESULTS: We found 66 cases from 38 articles. Surgical intervention took place in 74% of cases (n=49). The most common surgical intervention was salpingectomy. In 3% of cases (n=2), nonsurgical medical management with hormonal therapy was utilized, with post operative improvement in symptomology. In 23% of cases (n=15), conservative management was utilized: 2 of these cases torted, 4 cases persisted and 9 cases resolved. CONCLUSION: Overall, the results of this review demonstrate that there are comparable outcomes between surgical, medical and conservative management. However, medical and conservative management was not often offered, and more research is needed on the subject. PMID- 26476797 TI - The expression of thyroid hormone receptors (THR) is regulated by the progesterone receptor system in first trimester placental tissue and in BeWo cells in vitro. AB - BACKGROUND: Thyroid hormones are essential for the maintenance of pregnancy and a deficiency in maternal thyroid hormones has been associated with early pregnancy losses. The aim of this study was a systematic investigation of the influence of mifepristone (RU 486) on the expression of the thyroid hormone receptor (THR) isoforms THRalpha1, THRalpha2, THRbeta1 and THRbeta2 on protein and mRNA-level. METHODS: Samples of placental tissue were obtained from patients with mifepristone induced termination of pregnancy (n=13) or mechanical induced termination of normal pregnancy (n=20), each from the 4th to 13th week of pregnancy. Expression of THRalpha1, THRalpha2, THRbeta1 and THRbeta2 was analysed on protein level by immunohistochemistry and on mRNA level by real time RT-PCR (TaqMan). The influence of progesterone on THR gene expression was analysed in the trophoblast tumour cell line BeWo by real time RT-PCR (TaqMan). RESULTS: Nuclear expression of THRalpha1, THRalpha2 and THRbeta1 is downregulated on protein level in mifepristone (RU 486) treated villous trophoblast tissue. In decidual tissue, we found a significant downregulation only for THRalpha1 in mifepristone treated tissue. On mRNA level, we also found a significantly reduced expression of THRA but no significant downregulation for THRB in placental tissue. The gene THRA encodes the isoform THRalpha and the gene THRB encodes the isoform THRbeta. The majority of cells expressing the thyroid hormone receptors in the decidua are decidual stromal cells. In addition, in vitro experiments with trophoblast tumour cells showed that progesterone significantly induced THRA but not THRB expression. CONCLUSIONS: Termination of pregnancy with mifepristone (RU 486) leads to a downregulation of THRalpha1, THRalpha2 and THRbeta1 in villous trophoblasts and in addition to a decreased expression of THRA in placental tissue. Decreased expression of THRalpha1 induced by RU486 could also be found in the decidua. Therefore inhibition of the progesterone receptor may be responsible for this downregulation. This assumption is supported by the finding, that stimulation of the progesterone receptor by progesterone itself up-regulated THRA in trophoblast cells in vitro. PMID- 26476799 TI - Does fertility treatment increase the risk of uterine cancer? A meta-analysis. AB - An ongoing debate over the last two decades has focused on whether fertility treatment in women may lead to an increased risk of developing uterine cancer over a period of time. Uterine cancer (including mainly endometrial carcinoma and the less common uterine sarcoma) is the commonest reproductive tract cancer and the fourth commonest cancer in women in the UK. Our objective was to assess the association between fertility drugs used in the treatment of female infertility (both as an independent therapy and during in vitro fertilization cycles) and the development of uterine cancer. A literature search was performed using Medline, Embase, Cochrane Library and Google Scholar databases for comparative studies until December 2014 to investigate a clinical significance of fertility treatment on the incidence of developing uterine cancer. General and MESH search headings, as well as the 'related articles' function were applied. All comparative studies of 'fertility treatment' versus 'non-fertility treatment' reporting the incidence of uterine cancer as an outcome were included. Uterine cancer incorporated the following terms: uterine cancer, uterine body tumours, uterine sarcomas and endometrial cancers. The primary outcome of interest was the uterine cancer incidence in all 'fertility treatment' versus 'non-fertility treatment' patient groups. Secondary outcomes of interest were: (a) uterine cancer incidence in 'IVF' versus 'non-IVF' patient groups; and (b) uterine cancer incidence according to type of fertility drug used. Odds ratio was the summary statistic. Random effects modelling, graphical exploration and sensitivity analysis were used to evaluate the consistency of the calculated treatment effect. We included six studies in our final analysis, which comprised 776,224 patients in total. Of these, 103,758 had undergone fertility treatment and 672,466 had not. There was 100% agreement between the two reviewers regarding the data extraction. All the studies contained groups that were comparable in age, although the criteria of reporting age varied. Taking all studies into account, the incidence of uterine cancer was 0.14% (150 of 103,758) in the fertility treatment group and 2.22% (14,918 of 672,466) in the non-fertility treatment group. Using the random-effect model to analyze uterine cancer incidence, this difference was not found to be of statistical significance: OR 0.78 (95% CI, 0.39-1.57). The degree of heterogeneity was high (I(2)=68%). The risk for the development of uterine and in particular endometrial cancer posed by infertility and an unopposed oestrogen state is widely recognized. The present analysis aimed to perceive whether standard fertility drugs were also a risk to future uterine cancer development. The treatment does increase the concentrations of unopposed oestrogen for a short periods of time but if successful leads to fertility. This meta-analysis points to a non-deleterious effect of fertility drugs towards the development of uterine cancer, a conclusion strongly supported by our sub-group analysis. PMID- 26476800 TI - Fertility-sparing management of low-grade endometrial stromal sarcoma: analysis of an institutional series and review of the literature. AB - OBJECTIVE: Low-grade endometrial stromal sarcoma (LG-ESS) is a rare malignancy, often occurring before menopause. There is no consensus regarding its optimal management. Total hysterectomy and bilateral salpingo-oophorectomy precludes future fertility and may thus be undesirable by women wishing to maintain their reproductive potential. However, experience of fertility-sparing management in LG ESS is very limited. In this paper, the disease outcome is presented in six young women with LG-ESS conservatively treated by combined hysteroscopic resection and hormonal therapy. STUDY DESIGN: From October 2009 to February 2013, at the Gynecologic Oncology Department of the National Cancer Institute of Naples, six women, with early-stage LG-ESS aged 18-40 years who desired childbearing and/or retaining their fertility, were enrolled into a pilot study of fertility-sparing management. Diagnosis of LG-ESS was made on specimens from hysteroscopic resection performed on a presumed benign lesion. All patients were planned to be treated with adjuvant megestrol acetate for two years. Hormonal therapy was started within 6 weeks from the hysteroscopic resection, with orally megestrol acetate at 40mg daily, increasing gradually according to patient's tolerance to the recommended total dose of 160mg daily. RESULTS: All patients were submitted to hysteroscopic resection in a one-step procedure. Five patients started megestrol acetate within 6 weeks from the hysteroscopic resection (one patient did not start hormonal therapy because of early pregnancy after the hysteroscopic resection). Hormonal therapy was well tolerated; one patient stopped megestrol acetate after 12 months because of self-supporting strong desire to conceive; the other four patients regularly completed the hormonal therapy. To date, all patients show no evidence of disease. CONCLUSIONS: Although fertility-sparing management is not the current standard of care for young women with early-stage LG-ESS, our preliminary data are promising. Larger series with a longer follow-up are needed to further assess safety and efficacy of combined hysteroscopic resection and hormonal therapy. PMID- 26476801 TI - Addressing preservation of elastic contrast in energy-filtered transmission electron microscopy. AB - Energy-filtered transmission electron microscopy (EFTEM) images with resolutions of the order of an Angstrom can be obtained using modern microscopes corrected for chromatic aberration. However, the delocalized nature of the transition potentials for atomic ionization often confounds direct interpretation of EFTEM images, leading to what is known as "preservation of elastic contrast". In this paper we demonstrate how more interpretable images might be obtained by scanning with a focused coherent probe and incoherently averaging the energy-filtered images over probe position. We dub this new imaging technique energy-filtered imaging scanning transmission electron microscopy (EFISTEM). We develop a theoretical framework for EFISTEM and show that it is in fact equivalent to precession EFTEM, where the plane wave illumination is precessed through a range of tilts spanning the same range of angles as the probe forming aperture in EFISTEM. It is demonstrated that EFISTEM delivers similar results to scanning transmission electron microscopy with an electron energy-loss spectrometer but has the advantage that it is immune to coherent aberrations and spatial incoherence of the probe and is also more resilient to scan distortions. PMID- 26476802 TI - Differential phase-contrast dark-field electron holography for strain mapping. AB - Strain mapping is an active area of research in transmission electron microscopy. Here we introduce a dark-field electron holographic technique that shares several aspects in common with both off-axis and in-line holography. Two incident and convergent plane waves are produced in front of the specimen thanks to an electrostatic biprism in the condenser system of a transmission electron microscope. The interference of electron beams diffracted by the illuminated crystal is then recorded in a defocused plane. The differential phase recovered from the hologram is directly proportional to the strain in the sample. The strain can be quantified if the separation of the images due to the defocus is precisely determined. The present technique has the advantage that the derivative of the phase is measured directly which allows us to avoid numerical differentiation. The distribution of the noise in the reconstructed strain maps is isotropic and more homogeneous. This technique was used to investigate different samples: a Si/SiGe superlattice, transistors with SiGe source/drain and epitaxial PZT thin films. PMID- 26476803 TI - Diesel cars and health: the Volkswagen emissions scandal. PMID- 26476804 TI - Cross-regulation of Pseudomonas motility systems: the intimate relationship between flagella, pili and virulence. AB - Pseudomonas aeruginosa navigates using two distinct forms of motility, swimming and twitching. A polar flagellum and Type 4 pili power these movements, respectively, allowing P. aeruginosa to attach to and colonize surfaces. Single cell imaging and particle tracking algorithms have revealed a wide range of bacterial surface behaviors which are regulated by second messengers cyclic-di GMP and cAMP; the production of these signals is, in turn, responsive to the engagement of motility organelles with a surface. Innate immune defense systems, long known to recognize structural components of flagella, appear to respond to motility itself. The association of motility with both upregulation of virulence and induction of host defense mechanisms underlies the complex contributions of flagella and pili to P. aeruginosa pathogenesis. PMID- 26476805 TI - Interplay between flagellation and cell cycle control in Caulobacter. AB - The assembly of the flagellum, a sophisticated nanomachine powering bacterial locomotion in liquids and across surfaces, is highly regulated. In the synchronizable alpha-Proteobacterium Caulobacter crescentus, the flagellum is built at a pre-selected cell pole and flagellar transcript abundance oscillates during the cell cycle. Conserved regulators not only dictate when the transcripts encoding flagellar structural proteins peak, but also those encoding polarization factors. Additionally, post-transcriptional cell cycle cues facilitate flagellar (dis-)assembly at the new cell pole. Because of this regulatory complexity and the power of bacterial genetics, motility is a suitable and simple proxy for dissecting how bacteria implement cell cycle progression and polarity, while also providing clues on how bacteria might decide when and where to display other surface structures. PMID- 26476807 TI - Comparative study of carbon nanotubes and granular activated carbon: Physicochemical properties and adsorption capacities. AB - The overall goal was to determine an optimum pre-treatment condition for carbon nanotubes (CNTs) to facilitate air pollutant adsorption. Various combinations of heat and chemical pre-treatment were explored, and toluene was tested as an example hazardous air pollutant adsorbate. Specific objectives were (1) to characterize raw and pre-treated single-wall (SW) and multi-wall (MW) CNTs and compare their physical/chemical properties to commercially available granular activated carbon (GAC), (2) to determine the adsorption capacities for toluene onto pre-treated CNTs vs. GAC. CNTs were purified via heat-treatment at 400 degrees C in steam, followed by nitric acid treatment (3N, 5N, 11N, 16N) for 3-12 h to create openings to facilitate adsorption onto interior CNT sites. For SWNT, Raman spectroscopy showed that acid treatment removed impurities up to a point, but amorphous carbon reformed with 10h-6N acid treatment. Surface area of SWNTs with 3 h-3N acid treatment (1347 m(2)/g) was higher than the raw sample (1136 m(2)/g), and their toluene maximum adsorption capacity was comparable to GAC. When bed effluent reached 10% of inlet concentration (breakthrough indicating time for bed cleaning), SWNTs had adsorbed 240 mg/g of toluene, compared to 150 mg/g for GAC. Physical/chemical analyses showed no substantial difference for pre treated vs. raw MWNTs. PMID- 26476806 TI - Towards a model for Flavobacterium gliding. AB - Cells of Flavobacterium johnsoniae, a rod-shaped bacterium about 6 MUm long, do not have flagella or pili, yet they move over surfaces at speeds of about 2 MUm/s. This motion is called gliding. Recent advances in F. johnsoniae research include the discovery of mobile cell-surface adhesins and rotary motors. The puzzle is how rotary motion leads to linear motion. We suggest a possible mechanism, inspired by the snowmobile. PMID- 26476808 TI - Surgical Treatment of Primary Cardiac Sarcomas: Review of a Single-Institution Experience. AB - BACKGROUND: Primary cardiac sarcomas are rare, aggressive, and usually lethal. Surgical management protocols are not defined because of the lack of extensive experience in treating these patients. In this study, we reviewed our outcomes with primary cardiac sarcoma, and we make recommendations regarding management. METHODS: Review of the Houston Methodist Hospital cardiac tumor database from 1990 to 2015 (25 years) yielded 131 primary cardiac evaluations of possible cardiac sarcoma. From these we identified 95 patients who underwent surgical excision. A computer search of cardiac sarcomas yielded 131 tumors that were coded as primary cardiac sarcoma or possible primary cardiac sarcoma. Retrospective data collection and clinical outcomes were evaluated for all 95 patients. Medical records and follow-up material were requested for all patients through clinic visits and contacting the physician of the patient, the hospital record department, and the cardiac tumor board after previous approval. The procedures were performed using an institutional review board-approved cardiac tumor protocol, and the patients gave full consent. RESULTS: All 95 patients were diagnosed as having primary cardiac sarcoma by histologic appearance. Age ranged from 15 to 84 years at the time of presentation (mean, 44 years). Male patients made up 57% of the sample. The most common site for the cardiac sarcoma was the right atrium (37 patients) followed by the left atrium (31 patients). Postoperative 1-year mortality was 35% (33 patients). The most common tumor histologic type was angiosarcoma (40%) followed by spindle cell sarcoma (11%). CONCLUSIONS: Primary cardiac sarcoma is a rare but lethal disease. Surgical intervention is associated with acceptable surgical mortality in this high-risk group of patients. PMID- 26476809 TI - Binding assessment of two arachidonic-based synthetic derivatives of adrenalin with beta-lactoglobulin: Molecular modeling and chemometrics approach. AB - A computational approach to predict the main binding modes of two adrenalin derivatives, arachidonoyl adrenalin (AA-AD) and arachidonoyl noradrenalin (AA NOR) with the beta-lactoglubuline (BLG) as a nano-milk protein carrier is presented and assessed by comparison to the UV-Vis absorption spectroscopic data using chemometric analysis. Analysis of the spectral data matrices by using the multivariate curve resolution-alternating least squares (MCR-ALS) algorithm led to the pure concentration calculation and spectral profiles resolution of the chemical constituents and the apparent equilibrium constants computation. The negative values of entropy and enthalpy changes for both compound indicated the essential role of hydrogen bonding and van der Waals interactions as main driving forces in stabilizing protein-ligand complex. Computational studies predicted that both derivatives are situated in the calyx pose and remained in that pose during the whole time of simulation with no any significant protein structural changes which pointed that the BLG could be considered as a suitable carrier for these catecholamine compounds. PMID- 26476810 TI - Evolution of CPMAS under fast magic-angle-spinning at 100 kHz and beyond. AB - This article describes recent trends of high-field solid-state NMR (SSNMR) experiments for small organic molecules and biomolecules using (13)C and (15)N CPMAS under ultra-fast MAS at a spinning speed (nuR) of 80-100kHz. First, we illustrate major differences between a modern low-power RF scheme using UFMAS in an ultra-high field and a traditional CPMAS scheme using a moderate sample spinning in a lower field. Features and sensitivity advantage of a low-power RF scheme using UFMAS and a small sample coil are summarized for CPMAS-based experiments. Our 1D (13)C CPMAS experiments for uniformly (13)C- and (15)N labeled alanine demonstrated that the sensitivity per given sample amount obtained at nuR of 100kHz and a (1)H NMR frequency (nuH) of 750.1MHz is ~10 fold higher than that of a traditional CPMAS experiment obtained at nuR of 20kHz and nuH of 400.2MHz. A comparison of different (1)H-decoupling schemes in CPMAS at nuR of 100kHz for the same sample demonstrated that low-power WALTZ-16 decoupling unexpectedly displayed superior performance over traditional low-power schemes designed for SSNMR such as TPPM and XiX in a range of decoupling field strengths of 5-20kHz. Excellent (1)H decoupling performance of WALTZ-16 was confirmed on a protein microcrystal sample of GB1 at nuR of 80kHz. We also discuss the feasibility of a SSNMR microanalysis of a GB1 protein sample in a scale of 1nmol to 80nmol by (1)H-detected 2D (15)N/(1)H SSNMR by a synergetic use of a high field, a low-power RF scheme, a paramagnetic-assisted condensed data collection (PACC), and UFMAS. PMID- 26476811 TI - Solid-state (13)C NMR and synchrotron SAXS/WAXS studies of uniaxially-oriented polyethylene. AB - We report solid-state (13)C NMR and synchrotron wide-and small-angle X-ray scattering experiments (WAXS, SAXS) on metallocene linear low density polyethylene films (e.g., ExceedTM 1018 mLLDPE; nominally 1MI, 0.918 density ethylene-hexene metallocene copolymer) as a function of uniaxial draw ratio, lambda. Combined, these experiments provide an unambiguous, quantitative molecular view of the orientation of both the crystalline and amorphous phases in the samples as a function of draw. Together with previously reported differential scanning calorimetry (DSC), gas transport measurements, transmission electron microscopy (TEM), optical birefringence, small angle X-ray scattering (SAXS) as well as other characterization techniques, this study of the state of orientation in both phases provides insight concerning the development of unusually high barrier properties of the most oriented samples (lambda=10). In this work, static (non-spinning) solid-state NMR measurements indicate that in the drawn Exceed(TM) films both the crystalline and amorphous regions are highly oriented. In particular, chemical shift data show the amorphous phase is comprised increasingly of so-called "taut tie chains" (or tie chains under any state of tautness) in the mLLDPE with increasing draw ratio - the resonance lines associated with the amorphous phase shift to where the crystalline peaks are observed. In the sample with highest total draw (lambda=10), virtually all of the chains in the non-crystalline region have responded and aligned in the machine (draw) direction. Both monoclinic and orthorhombic crystalline peaks are observed in high-resolution, solid-state magic-angle spinning (MAS) NMR measurements of the oriented PE films. The orientation is comparable to that obtained for ultra high molecular weight HDPE fibers described as "ultra-oriented" in the literature. Furthermore, the presence of a monoclinic peak in cold-drawn samples suggests that there is an appreciable internal stress associated with the LLDPE. The results are confirmed and independently quantified by Herman's Orientation Function values derived from the WAXS measurements. The degree of orientation approaches theoretically perfect alignment of chains along the draw direction. We deduce from this observation that a high fraction of the non-crystalline chains are either tie chains that directly connect adjacent lamellae or are interlocking loops from adjacent lamellae. In either case, the chains are load-bearing and are consistent with the idea of "taut tie chains". We note that transmission electron micrographs recorded for the ultra-oriented Exceed showed the lamellae are often appreciably thinner and shorter than they are for cast or blown Exceed 1018. Combined with higher crystallinity, the thinner lamellae statistically favor more tie chains. Finally, the remarkably large decrease in permeability of the lambda=10 film is primarily attributed to the high degree of orientation (and loss of entropy) of the amorphous phase. PMID- 26476812 TI - Alicyclobacillus fodiniaquatilis sp. nov., isolated from acid mine water. AB - Two novel, Gram-stain-variable, moderately thermophilic, acidophilic, rod-shaped, endospore-forming bacteria, G45-16T and G45-17, were isolated from acid mine water of Zijin copper mine in Fujian Province, China. Phylogenetic analysis of 16S rRNA gene sequences showed that they were closely related to Alicyclobacillus acidoterrestris ATCC 49025T with sequence similarities of 96.8 %. Cells grew aerobically at 20-45 degrees C (optimum, 40 degrees C), at pH 2.5-5.5(optimum, pH 3.5) and in the presence of 0-4.0 % (w/v) NaCl. Strains contained MK-7 as the major menaquinone and the major cellular fatty acids were omega-cyclohexane C19 : 0 and omega-cyclohexane C17 : 0. The DNA G+C content was 51.3 and 49.8 mol% (Tm) for G45-16T and G45-17, respectively. On the basis of phenotypic, chemotaxonomic and phylogenetic comparisons with their relatives and DNA-DNA relatedness values, it is concluded that strains G45-16T and G45-17 represent a novel species within the genus Alicyclobacillus, for which the name Alicyclobacillus fodiniaquatilis sp. nov. is proposed; the type strain is G45-16T(=CGMCC 1.15049T=NBRC 111483T). PMID- 26476813 TI - Towards future archives and historiographies of 'big biology'. PMID- 26476814 TI - Plant Thermoregulation: Energetics, Trait-Environment Interactions, and Carbon Economics. AB - Building a more predictive trait-based ecology requires mechanistic theory based on first principles. We present a general theoretical approach to link traits and climate. We use plant leaves to show how energy budgets (i) provide a foundation for understanding thermoregulation, (ii) explain mechanisms driving trait variation across environmental gradients, and (iii) guide selection on functional traits via carbon economics. Although plants are often considered to be poikilotherms, the data suggest that they are instead limited homeotherms. Leaf functional traits that promote limited homeothermy are adaptive because homeothermy maximizes instantaneous and lifetime carbon gain. This theory provides a process-based foundation for trait-climate analyses and shows that future studies should consider plant (not only air) temperatures. PMID- 26476815 TI - Rapid Anthropocene Speciation Reveals Pull of the Recent: A Response to Thomas. PMID- 26476816 TI - Controlling the Behavior of Single Live Cells with High Density Arrays of Microscopic OLEDs. PMID- 26476817 TI - Jack Rodney Robertson (1917-2015): IUGA loses its second founding father. PMID- 26476818 TI - A survey of prolapse practice in UK women's health physiotherapists: what has changed in the last decade? AB - INTRODUCTION AND HYPOTHESIS: Prolapse is a common female problem, and conservative treatments such as pelvic floor muscle training (PFMT) are important options for women. Evidence supporting the effectiveness of PFMT for prolapse has grown over the last decade, and it was hypothesised that practice and practice guidelines would have developed in line with the evidence. To assess this, up-to date information about the practice of physiotherapists working in women's health regarding their treatment of prolapse was required. METHODS: An online survey sent to members of the Association of Chartered Physiotherapists in Women's Health and the Chartered Physiotherapists Promoting Continence. Results were compared with those of an earlier survey undertaken in 2002. RESULTS: A 49 % response rate was achieved. The majority of respondents were senior physiotherapists (55 %) and had worked in women's health for more than 10 years. Respondents were treating significantly more women with prolapse than a decade before: 36 % vs 14 % treated more than 50 women per year in 2002 and 2013 respectively (p < 0.001). Individualised PFMT (93 %), lifestyle advice (92 %) and biofeedback-assisted PFMT (83 %) were the most common treatment elements, with four being the average number of appointments. Forty-eight percent had changed their practice as a result of recent research; however, scepticism amongst medics, the referral of women directly for surgery, and constraints on resources were thought to be barriers to wider implementation of the evidence of PFMT for prolapse. CONCLUSIONS: There has been uptake of evidence-based prolapse practice by UK specialist physiotherapists in the last decade. Further research targeting the implementation of this evidence would be valuable in addressing potential barriers, and in supporting the need for physiotherapy in the treatment of prolapse. PMID- 26476819 TI - Uterus-preserving laparoscopic lateral suspension with mesh for pelvic organ prolapse: a patient-centred outcome report and video of a continuous series of 245 patients. AB - INTRODUCTION AND HYPOTHESIS: Changes in the psychological value of reproductive organs have led to a growing interest in uterine-preserving surgery for pelvic organ prolapse (POP). Sacral hysteropexy is considered as gold standard, although dissection of the promontory may be challenging. We show a video and present a report on a series of patients operated by laparoscopic lateral suspension with mesh as an alternative. METHODS: Clinical evaluation was performed using the simplified Pelvic Organ Prolapse Quantification System (POP-Q). Primary outcomes were subjective and objective cure; secondary outcomes were rates for reoperation and complications. We assessed patient's satisfaction in a telephone interview using a visual analogue scale and the Patient Global Impression of Improvement Scale (PGI-I) scale. RESULTS: Two hundred and fifty-four patients were treated between 2004 and 2011 with a median follow-up of 7.5 years. At 1 year 82.7 % of patients were asymptomatic, and anatomic success rates were 88.2 % for the anterior, 86.1 % for the apical and 80.8 % for the posterior compartment; 1.2 % had mesh exposure, and the reoperation rate was 7.4 %. More than 80 % of patients were highly satisfied with the outcome. CONCLUSIONS: Uterine-preserving laparoscopic lateral suspension with mesh is a safe technique with promising results and low complication rates. It may be an alternative to sacral hysteropexy for high-morbidity patients. PMID- 26476820 TI - Surface electromyography and ultrasound evaluation of pelvic floor muscles in hyperandrogenic women. AB - INTRODUCTION: High levels of androgens increase muscle mass. Due to the characteristics of hyperandrogenism in polycystic ovary syndrome (PCOS), it is plausible that women with PCOS may have increased pelvic floor muscle (PFM) thickness and neuromuscular activity levels compared with controls. The aim of this study was to assess PFM thickness and neuromuscular activity among hyperandrogenic women with PCOS and controls. METHODS: This was an observational, cross-sectional, case-control study evaluating PFM by ultrasound (US) and surface electromyography (sEMG) in nonobese women with and without PCOS. Seventy-two women were divided into two groups: PCOS (n = 33) and controls (n = 39). PFM thickness during contraction was assessed by US (Vingmed CFM 800). Pelvic floor muscle activity was assessed by sEMG (MyoTrac Infinit) during contractions at different time lengths: quick, and 8 and 60 s. Descriptive analysis, analysis of variance (ANOVA), and Student's t test were used for statistical analyses. RESULTS: There were no significant differences in PFM sEMG activity between PCOS and controls in any of the contractions: quick contraction (73.23 mV/ 71.56 mV; p = 0.62), 8 s (55.77 mV/ 54.17 mV; p = 0.74), and 60 s (49.26 mV/ 47.32 mV; p = 0.68), respectively. There was no difference in PFM thickness during contractions evaluated by US between PCOS and controls (12.78 mm/ 13.43 mm; p = .48). CONCLUSIONS: This study did not find statistically significant differences in pelvic floor muscle thickness or in muscle activity between PCOS women and controls. PMID- 26476821 TI - Prepubic abscess related to retropubic sling sutures placed 18 years earlier. PMID- 26476822 TI - Presentation and management of rectovaginal fistulas after delivery. AB - INTRODUCTION: Obstetric trauma leading to rectovaginal fistula (RVF) formation results from perineal laceration and/or from prolonged ischemia and necrosis following obstructed labor. Due to modern obstetric care fistulas are rare in industrialized countries. METHODS: Patients undergoing surgery for a RVF between January 2005 and December 2014 at the Department of Obstetrics and Gynecology, Tuebingen, Germany, were identified and their records were reviewed retrospectively. RESULTS: Of 48 patients, 13 developed RVF of obstetric etiology. Parity ranged from 2 to 4. RVF repair was performed in all patients using a transvaginal approach: fistula excision and multilayer closure (7 of 13) with Martius flap interposition (1 of 7) and sphincteroplasty (5 of 13). One RVF closed spontaneously. Due to significant destruction of the anal canal, large RVF and RVF recurrence, 4 of the 13 patients needed a temporary protective ileostomy. Fistula closure was achieved in 12 of 13 patients. CONCLUSION: The choice of RVF repair should be tailored to the underlying pathology and type of repair done previously and the patient's wishes. PMID- 26476823 TI - Shoulder dystocia and associated manoeuvres as risk factors for perineal trauma. AB - INTRODUCTION AND HYPOTHESIS: Shoulder dystocia (SD) is an obstetric emergency that can be associated with serious neonatal morbidity and mortality. The aim of this study was to identify the incidence and risk factors for obstetric anal sphincter injuries (OASIS) in women who sustained SD at birth. METHODS: This was a retrospective observational study over a 5-year period whereby 403 cases of SD were identified. The primary outcome measure was to identify the incidence of OASIS in women with SD. We also evaluated the role of the manoeuvres used for the management of SD and aimed to identify possible correlations between specific manoeuvres and OASIS by univariate and multivariate regression analysis. RESULTS: Shoulder dystocia was associated with a three-fold increase in the risk of OASIS in our population. The use of internal manoeuvres (OR 2.182: 95 % CI 1.173 4.059), an increased number of manoeuvres >= 4 (OR 4.667: 95 % CI 1.846-11.795), Woods' screw manoeuvre (OR 3.096: 95 % CI 1.554-6.169), reverse Woods' screw manoeuvre (OR 4.848: 95 % CI 1.647-14.277) and removal of the posterior arm (OR 2.222: 95 % CI 1.117-4.421) were all associated with a significant increase in the likelihood of OASIS. CONCLUSIONS: In our study, instrumental deliveries, the use of internal manoeuvres (Woods' screw and reverse Woods' screw) and four or more manoeuvres for the management of SD were independently associated with a higher incidence of OASIS. To effectively manage shoulder dystocia with lower risks of perineal trauma, these factors could be considered when designing further prospective studies and developing management protocols. PMID- 26476824 TI - Calcifications and tungsten deposits after breast-conserving surgery and intraoperative radiotherapy for breast cancer. AB - AIM: To describe the presence of atypical calcifications on post-operative mammography after breast-conserving surgery (BCS) and intraoperative radiotherapy (IORT). MATERIALS AND METHODS: We retrospectively include all patients followed after BCS and IORT for breast cancer (n=271). All follow-up mammograms at 6 months after surgery were retrospectively evaluated by two board-certified radiologists. The radiologists had to notify the presence or the absence of atypical calcifications. RESULTS: Five patients had on follow-up mammography the presence of atypical calcifications. Two patients had a stereotactic breast biopsy. The pathologic examination showed the presence of small tungsten particles located in the breast parenchyma. CONCLUSION: The presence of atypical calcifications after BCS and IORT, presenting as multiple, scattered, round calcifications, should be rated as BIRADS 2 and do not require biopsy. They corresponded on tungsten deposits. PMID- 26476825 TI - Vascular uterine abnormalities: Comparison of imaging findings and clinical outcomes. AB - OBJECTIVE: To retrospectively compare the imaging findings and the outcomes for patients with vascular uterine abnormalities (VUA) and to identify prognostic factors. MATERIAL AND METHODS: Between 2007 and 2012, 38 patients with vaginal bleeding and abnormal ultrasonographic (US) findings consistent with acquired VUA were consecutively included (mean age 31.6 years, range 19-62). Follow-up was 32 months in mean (1-78 months). Seventeen women (44.7%) started bleeding immediately after curettage, spontaneous miscarriage, trophoblastic disease, or section scars, with the remainder starting bleeding after 8 days to 2 years. All US, CT (n=2), MR (n=5) and angiographic (n=26) images were reviewed and compared to medical reports in order to identify severe VUA requiring treatment, and predictive factors. RESULTS: No information about severity was provided by US, MRI or CT. Twelve patients were successfully managed conservatively. Angiography identified 6 non-severe VUA, corresponding to an isolated uterine hyperemia, and 20 severe VUA, corresponding to an association of a nidus and early venous drainage. Recurrences were more often observed for severe VUA (p=0.001). The hemoglobin level was significantly lower (below 11 g/L) in these cases (p=0.004). Recurrences were significantly more frequently observed for patients with history of dilatation and curettage (p=0.02). Hysterectomy was performed for three patients only (8%). Among the women who wished to have children, 14 (77.8%) were pregnant after 9 months in mean (range 2-23). CONCLUSIONS: Recurrence happens more frequently after curettage and in case of anemia or severe VUA findings on angiography, justifying adequate embolization for these patients. PMID- 26476826 TI - Minimal impact of calcimimetics on the management of hyperparathyroidism in chronic dialysis. AB - BACKGROUND: The calcimimetic drug cinacalcet has changed the prescription patterns in patients with secondary hyperparathyroidism, despite the lack of randomized studies that compare cinacalcet with conventional treatment, including parathyroidectomy. The aim of this study was to evaluate current management of patients on chronic dialysis with incidental and parathyroid hormone (PTH) levels >= 500 ng/L. METHODS: Prospective pharmacoepidemiologic study of chronic dialysis patients with PTH level >= 500 ng/L. RESULTS: We studied 269 patients. Among the 186 patients who had 2-year follow-up, 125 (67%) were managed using cinacalcet. At 2 years, when comparing the cinacalet with the noncinacalet groups, we found that mean PTH values were 400 +/- 318 versus 388 +/- 251 ng/L (P = ns) and the percentage of patients following 2009 PTH Kidney Disease Improving Global Outcomes (KDIGO) guidelines were 79 versus 85% (P = ns). Eight patients (4%) underwent parathyroidectomy. On multivariate analysis, the use of cinacalcet was not a predictor for PTH within KDIGO guidelines at 2-year follow-up. CONCLUSION: Cinacalcet was used in the majority (67%) of patients on chronic dialysis with secondary hyperparathyroidism, but the use of cinacalcet did not affect mean PTH values nor the proportion of patients following KDIGO guidelines compared with patients not using calcimimetics. PMID- 26476827 TI - Discussion. PMID- 26476828 TI - Clinical characteristics and follow-up of intracranial metastases from thyroid cancer. AB - BACKGROUND: Intracranial metastasis from thyroid cancer is extremely rare. However, less is known about the risk factors for intracranial metastasis and its treatment from few retrospective studies. The aim of this study was to contribute to the understanding of this disease by analyzing patients with intracranial metastases from thyroid cancer. METHODS: Between 2001 and 2014, the database of the National Cancer Center of Korea was searched for thyroid cancer patients. The clinical characteristics and site of distant metastasis according to the histological type were evaluated in the thyroid cancer cohort. Among the patients with intracranial metastases, the characteristics, histological type of primary cancer and metastatic brain tumor, additional synchronous or previous distant metastasis, treatment modalities, locations and characteristics on radiologic findings, time interval between the first diagnosis of the primary thyroid cancer and brain metastasis, thyroglobulin level at the first detection of intracranial metastasis and survival were reviewed. RESULTS: A total of 10 (0.032 %) out of 3,090 thyroid cancer patients in the National Cancer Center database were identified as having intracranial metastases. The histological types of the primary thyroid cancers were papillary for six patients, follicular for three, and poorly differentiated carcinoma for one. Six of these ten patients underwent surgical resection for intracranial lesions. Whole-brain radiotherapy or tyrosine kinase inhibitors were applied to the patients as postoperative adjuvant treatment, and stereotactic radiosurgery was considered for recurrent or surgically inoperable lesions. The overall median survival time was 33 months (range, 0.5-78 months) after diagnosis of intracranial metastasis. CONCLUSIONS: Surgical resection and adjuvant treatments in the contemporary era seem to result in improved survival after intracranial metastases compared with what has been reported in past studies. Considering the grave course of intracranial metastasis, the early detection and aggressive treatment of patients with a good performance status are crucial. PMID- 26476829 TI - Repeated bouts of fast velocity eccentric contractions induce atrophy of gastrocnemius muscle in rats. AB - One bout of exercise consisting of fast velocity eccentric contractions has been shown to increase muscle protein degradation in rats. The present study tested the hypothesis that muscle atrophy would be induced after four bouts of fast velocity eccentric contractions, but not after four bouts of slow velocity eccentric contractions. Male Wistar rats were randomly placed into 3 groups; fast (180 degrees /s) velocity (180EC, n = 7), slow (30 degrees /s) velocity eccentric exercise (30EC, n = 7), or sham-treatment group (control, n = 7). The 180EC and 30EC groups received 4 sessions of 4 sets of 5 eccentric contractions of triceps surae muscles by extending the ankle joint during evoked electrical stimulation of the muscles, and the control group had torque measures, every 2 days, and all rats were sacrificed 1 day after the fourth session. Medial and lateral gastrocnemius wet mass were 4-6 % smaller, cross-sectional area of medial gastrocnemius was 6-7% smaller, and isometric tetanic torque of triceps surae muscles was 36 % smaller (p < 0.05) for 180EC than control at 1 day after the fourth session, but no such differences were evident between 30EC and control. The expressions of atrophy-related molecules such as FoxO1, FoxO3 and myostatin were upregulated (78-229 %) only for 180EC, but an increase in phosphorylated p70s6k (227%) was found only for 30EC at 1 day after the fourth session (p < 0.05). The level of Bax, a pro-apoptotic protein, was greater (p < 0.05) for 180EC than control. These results support the hypothesis that muscles are atrophied by repeated bouts of fast but not slow velocity eccentric contractions. PMID- 26476830 TI - Differential growth and responsiveness to cancer therapy of tumor cells in different environments. AB - Tumor metastasis often confers poor prognosis for cancer patients due to lack of comprehensive strategy in dealing with cells growing in different environment. Current anticancer therapies have incomplete effectiveness because they were designed assuming metastatic tumors behave similarly in different organs. We hypothesize that tumors growing in different sites are biologically heterogeneous in growth potential, as well as in tumor response to anti-cancer therapies. To test this hypothesis, we have developed a multi-organ tumor growth model using the hydrodynamic cell delivery method to establish simultaneous and quantifiable tumor growth in the liver, lungs and kidneys of mice. We demonstrated that growth rate of melanoma tumor in the liver is higher than that of the lungs and kidneys. Tumors in the lungs and kidneys grew minimally at the early stage and aggressively thereafter. Tumors in different organs were also heterogeneous in response to chemotherapy and immune gene therapy using dacarbazine and interferon beta gene, respectively. Lung tumors responded to chemotherapy better than tumors in the liver, but showed minimal response to interferon beta gene therapy, compared to tumors in the liver and kidneys. We also confirmed differential tumor growth of the metastatic colon cancer in mice. Our results point out the importance of a better understanding of the differences in tumor growing in diverse environments. The biological heterogeneity of metastatic tumors demonstrated in this study necessitates establishing new drug screening strategies that take into account the environmental difference at the sites of tumor growth. PMID- 26476831 TI - Pregnancy outcomes among women with beta-thalassemia trait. AB - OBJECTIVE: To compare the obstetric outcomes between pregnant women affected by beta-thalassemia trait and normal controls. METHODS: A retrospective cohort study was conducted on singleton pregnant women complicated by beta-thalassemia trait and normal controls, randomly selected with the controls-to-case ratio of 2:1. All were low-risk pregnancies without underlying medical diseases and fetal anomalies. The pregnancies undergoing invasive prenatal diagnosis were excluded. RESULTS: A total of 597 pregnant women with beta-thalassemia trait and 1194 controls were recruited. Baseline characteristics and maternal outcomes in the two groups were similar, except that hemoglobin levels were slightly lower in the study group. The prevalence of small for gestational age and preterm birth tended to be higher in the study group but not reached the significant levels but the rate of low birth weight was significantly higher in the study group (relative risk 1.25; 95 % CI 1.00-1.57). Additionally, abortion rate was also significantly higher in the study group (relative risk 3.25; 95 % CI 1.35-7.80). CONCLUSION: Beta-thalassemia trait could minimally, but significantly, increase risk of low birth weight but did not increase rates of maternal adverse outcomes. PMID- 26476833 TI - The anterolateral ligament of the knee: a radiologic and histotopographic study. AB - PURPOSE: Recent anatomic investigations of the lateral structures of the knee have rediscovered a ligament, called the antero-lateral ligament (ALL). METHODS: Ten specimens of ALL (6 M, 4 F, mean age 82.3) were sampled from bodies of the Body Donation program of the University of Padova for histological and immuno histochemical studies. Moreover, a retrospective magnetic resonance (MR) study was carried out in 50 patients (30 M, 20 F, mean age 37.5). MR exams with a normal anatomo-radiological report were selected. RESULTS: From the microscopic point of view the ALL corresponds to a dense connective tissue (mean thickness 893 +/- 423 um), and is composed by collagen I (90 %), collagen III (5 %) and collagen VI (3 %) and scarce elastic fibers (<1 %). On MR exams, ALL appears as a thin linear structure, originating at the lateral epicondyle, running obliquely downwards and forwards, and inserting in the middle third (46 %) or inferior third (14 %) of lateral meniscus and in the lateral aspect of the proximal tibia. It was observed in 47 cases (93 %), with a mean length of 32 +/- 4.6 mm and mean thickness of 1.1 +/- 0.4 mm. The ALL showed low signal intensity on both T1- and T2-weighted sequences. CONCLUSION: The ALL shows the typical structure of a fibrous ligament. From the anatomo-radiological point of view the ALL is almost constantly depicted by routine 1.5-T MR scan. PMID- 26476834 TI - Wernicke Encephalopathy: a Future Problem Even After Sleeve Gastrectomy? A Systematic Literature Review. AB - Wernicke encephalopathy (WE) is a serious complication of bariatric surgery with significant morbidity and mortality. A few cases have been reported in the literature, mainly in patients after a Roux-en-Y gastric bypass. Since sleeve gastrectomy (SG) has become a more established and popular bariatric procedure, WE is expected to appear more frequently after SG. We performed a literature review on WE after SG, and 13 cases have been found to be sufficiently documented. The risk of WE needs to be considered in patients with a prolonged vomiting episode and any type of neurological symptoms, independent of the presence of any surgical complications. PMID- 26476835 TI - Monitoring of Diabetic Retinopathy in relation to Bariatric Surgery: a Prospective Observational Study. AB - BACKGROUND: To investigate the need for closer perioperative monitoring of diabetic retinopathy in patients with type 2 diabetes undergoing bariatric surgery. METHODS: Prospective observational clinical study of 56 patients with type 2 diabetes undergoing bariatric surgery. The patients were examined with 7 field fundus images and optical coherence tomography scans 2 weeks before and 1, 3, 6 and 12 months after bariatric surgery. Worsening was defined as a two-step change in the Wisconsin Epidemiologic Study of Diabetic Retinopathy scale or appearance or worsening of macular edema. Postoperative changes were analyzed in a mixed model. RESULTS: Six patients (11 %) had any worsening at any visit, and three (5 %) persisted at 1 year. Of the 24 patients with preoperative retinopathy, 4-13 % worsened and 9-22 % improved, with significant overall improvement at 6 months (p = 0.01). Only one (3%) of the 32 patients without preoperative diabetic retinopathy had a transient worsening at 6 months. No patients developed macular edema, but the whole cohort had a minor increase in center point foveal thickness that peaked 6 months postoperatively. The patients were required to have good glucose control preoperatively where HbA1c was 6.4 +/- 1.9 %. CONCLUSIONS: Diabetic retinopathy was clinically stable after bariatric surgery, and none of the observed changes would have resulted in a changed screening interval at our center. This supports adherence to regular diabetic retinopathy screening guidelines following bariatric surgery in well-controlled patients. A clinically negligible but statistically significant foveal thickening 6 months postoperatively warrants further study. PMID- 26476836 TI - Symptom clusters in women with breast cancer: an analysis of data from social media and a research study. AB - PURPOSE: User-generated content on social media sites, such as health-related online forums, offers researchers a tantalizing amount of information, but concerns regarding scientific application of such data remain. This paper compares and contrasts symptom cluster patterns derived from messages on a breast cancer forum with those from a symptom checklist completed by breast cancer survivors participating in a research study. METHODS: Over 50,000 messages generated by 12,991 users of the breast cancer forum on MedHelp.org were transformed into a standard form and examined for the co-occurrence of 25 symptoms. The k-medoid clustering method was used to determine appropriate placement of symptoms within clusters. Findings were compared with a similar analysis of a symptom checklist administered to 653 breast cancer survivors participating in a research study. RESULTS: The following clusters were identified using forum data: menopausal/psychological, pain/fatigue, gastrointestinal, and miscellaneous. Study data generated the clusters: menopausal, pain, fatigue/sleep/gastrointestinal, psychological, and increased weight/appetite. Although the clusters are somewhat different, many symptoms that clustered together in the social media analysis remained together in the analysis of the study participants. Density of connections between symptoms, as reflected by rates of co-occurrence and similarity, was higher in the study data. CONCLUSIONS: The copious amount of data generated by social media outlets can augment findings from traditional data sources. When different sources of information are combined, areas of overlap and discrepancy can be detected, perhaps giving researchers a more accurate picture of reality. However, data derived from social media must be used carefully and with understanding of its limitations. PMID- 26476837 TI - Religion as problem, religion as solution: religious buffers of the links between religious/spiritual struggles and well-being/mental health. AB - PURPOSE: Previous studies have established robust links between religious/spiritual struggles (r/s struggles) and poorer well-being and psychological distress. A critical issue involves identifying the religious factors that buffer this relationship. This is the first study to empirically address this question. Specifically, it examines four religious factors (i.e., religious commitment, life sanctification, religious support, religious hope) as potential buffers of the links between r/s struggle and one indicator of subjective well-being (i.e., happiness) and one indicator of psychological distress (i.e., depressive symptoms). METHOD: We utilized a cross-sectional design and a nationally representative sample of American adults (N = 2140) dealing with a wide range of major life stressors. RESULTS: We found that the interactions between r/s struggle and all potential moderators were significant in predicting happiness and/or depression. The linkage between r/s struggle and lower levels of happiness was moderated by higher levels of each of the four proposed religious buffers. Religious commitment and life sanctification moderated the ties between r/s struggles and depressive symptoms. CONCLUSIONS: The findings underscore the multifaceted character of religion: Paradoxically, religion may be a source of solutions to problems that may be an inherent part of religious life. PMID- 26476838 TI - Anesthetic Ketamine-Induced DNA Damage in Different Cell Types In Vivo. AB - The use of a combination of ketamine and xylazine is broadly used either for anesthesia or euthanasia in rodent animal models in research. However, the genotoxicity and mutagenic effects of these drugs are unknown. Therefore, the aim of this study was to evaluate these effects to help the understanding of elevated values in negative controls in genotoxic/mutagenic assays. Sixty CF-1 mice were divided into ten groups of six mice per group: negative control (saline), positive control (doxorubicin, 40 mg/kg), ketamine at 80 mg/kg and xylazine at 10 mg/kg, ketamine at 100 mg/kg and xylazine at 10 mg/kg, ketamine at 140 mg/kg and xylazine at 8 mg/kg, ketamine at 80 mg/kg, ketamine at 100 mg/kg, ketamine at 140 mg/kg, xylazine at 8 mg/kg, and xylazine at 10 mg/kg. After drug induction, the blood cells were analyzed at 1, 12, and 24 h by the comet assay, while the brain cortex, liver, and kidney cells were verified just at 24 h by the comet assay and bone marrow was tested at 24 h by micronucleus test. The positive control was significantly different in relation to the negative control in all times and tissue analyzed. The dose of ketamine at 140 mg/kg plus xylazine at 8 mg/kg and only ketamine at 140 mg/kg exhibited a genotoxic effect in blood and brain cells at all the times analyzed. The doses of ketamine at 80 and 100 mg/kg in association or not with xylazine showed increased DNA damage at 1 and 12 h, but this effect was reversed after 24 h of drug administration. The liver, kidney, and bone marrow cells of animals treated with ketamine or xylazine isolated or combined did not differ when compared with the negative control. Then, our findings emphasize the necessity of more studies that prove safety of the ketamine use, since that anesthetic can be able to induce false-negative results in genotoxic experimental studies. PMID- 26476839 TI - Acute Carnosine Administration Increases Respiratory Chain Complexes and Citric Acid Cycle Enzyme Activities in Cerebral Cortex of Young Rats. AB - Carnosine (beta-alanyl-L-histidine) is an imidazole dipeptide synthesized in excitable tissues of many animals, whose biochemical properties include carbonyl scavenger, anti-oxidant, bivalent metal ion chelator, proton buffer, and immunomodulating agent, although its precise physiological role(s) in skeletal muscle and brain tissues in vivo remain unclear. The aim of the present study was to investigate the in vivo effects of acute carnosine administration on various aspects of brain bioenergetics of young Wistar rats. The activity of mitochondrial enzymes in cerebral cortex was assessed using a spectrophotometer, and it was found that there was an increase in the activities of complexes I-III and II-III and succinate dehydrogenase in carnosine-treated rats, as compared to vehicle-treated animals. However, quantitative real-time RT-PCR (RT-qPCR) data on mRNA levels of mitochondrial biogenesis-related proteins (nuclear respiratory factor 1 (Nrf1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (Ppargc1alpha), and mitochondrial transcription factor A (Tfam)) were not altered significantly and therefore suggest that short-term carnosine administration does not affect mitochondrial biogenesis. It was in agreement with the finding that immunocontent of respiratory chain complexes was not altered in animals receiving carnosine. These observations indicate that acute carnosine administration increases the respiratory chain and citric acid cycle enzyme activities in cerebral cortex of young rats, substantiating, at least in part, a neuroprotector effect assigned to carnosine against oxidative-driven disorders. PMID- 26476840 TI - Selective Aryl Hydrocarbon Receptor Modulator 3,3'-Diindolylmethane Impairs AhR and ARNT Signaling and Protects Mouse Neuronal Cells Against Hypoxia. AB - The neuroprotective potential of 3,3'-diindolylmethane (DIM), which is a selective aryl hydrocarbon receptor modulator, has recently been shown in cellular and animal models of Parkinson's disease and lipopolysaccharide-induced inflammation. However, there are no data concerning the protective capacity and mechanisms of DIM action in neuronal cells exposed to hypoxia. The aim of the present study was to investigate the neuroprotective potential of DIM against the hypoxia-induced damage in mouse hippocampal cells in primary cultures, with a particular focus on DIM interactions with the aryl hydrocarbon receptor (AhR), its nuclear translocator ARNT, and estrogen receptor beta (ERbeta). In the present study, 18 h of hypoxia induced apoptotic processes, in terms of the mitochondrial membrane potential, activation of caspase-3, and fragmentation of cell nuclei. These effects were accompanied by substantial lactate dehydrogenase release and neuronal cell death. The results of the present study demonstrated strong neuroprotective and anti-apoptotic actions of DIM in hippocampal cells exposed to hypoxia. In addition, DIM decreased the Ahr and Arnt mRNA expression and stimulated Erbeta mRNA expression level. DIM-induced mRNA alterations were mirrored by changes in protein levels, except for ERbeta, as detected by ELISA, Western blotting, and immunofluorescence labeling. We also demonstrated that DIM decreased the expression of AhR-regulated CYP1A1. Using specific siRNAs, we provided evidence that impairment of AhR and ARNT, but not ERbeta plays a key role in the neuroprotective action of DIM against hypoxia-induced cell damage. This study may have implication for identifying new agents that could protect neurons against hypoxia by targeting AhR/ARNT signaling. PMID- 26476841 TI - BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury. AB - For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF (Pax2) -KO) versus the auditory cortex and hippocampus (BDNF (TrkC) -KO). We demonstrate that BDNF (Pax2) -KO but not BDNF (TrkC) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF (Pax2) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF (Pax2) -KO, but not of BDNF (TrkC) -KO mice. Also, BDNF (Pax2) -WT but not BDNF (Pax2) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise. PMID- 26476842 TI - Cell and Context-Dependent Effects of the Heat Shock Protein DNAJB6 on Neuronal Survival. AB - Previous studies performed in cell lines have shown that the heat shock protein, DNAJB6, protects against the proteotoxic effects of mutant huntingtin (mut-Htt) via direct interaction with mut-Htt. However, these studies were performed primarily using in vitro models and cell lines. We report that when expressed in primary neurons, DNAJB6 induces cell death. Neurotoxicity is observed with both the DNAJB6a isoform, which is strictly nuclear, and the DNAJB6b isoform, which is predominantly cytoplasmic, suggesting that neurotoxicity is mediated in the nucleus. However, when co-expressed in primary neurons with mut-Htt, DNAJB6 protects against mut-Htt neurotoxicity. This suggests that the contrasting effect of DNAJB6 on neuronal viability depends on the presence or absence of proteotoxic stress. Neurotoxicity of DNAJB6 cannot be prevented by inhibition of glycogen synthase kinase 3 beta (GSK3beta) or c-Jun N-terminal kinase (JNK) but is prevented by pharmacological inhibition of cyclin-dependent kinases (CDKs). Expression of dominant-negative forms of CDK2 or CDK4, or of p21(CIP1), the physiological inhibitor of CDKs, also inhibits DNAJB6 neurotoxicity. DNAJB6 neurotoxicity can also be inhibited by histone deacetylase-4 (HDAC4), which interacts with DNAJB6 and which has previously been described to inhibit cell cycle progression. These results conclude that neurotoxicity resulting from elevated DNAJB6 is cell cycle dependent. PMID- 26476845 TI - Building a Radiology Service Line: Key Elements and Necessary Actions. AB - Building a radiology service line is a challenge. Beyond the science of imaging and pathophysiology of disease, there are a number of key elements and necessary actions--related to personnel, communication, and resources--that must be taken to make the service line successful and sustainable. Although there is no single best way to build an imaging-based service line, there are a number of essential components. The purpose of this article is to delineate these components and describe how ambitious radiologists may successfully build and sustain a radiology service line. PMID- 26476844 TI - Prevalence of Drug Combinations Increasing Bleeding Risk Among Warfarin Users With and Without Alzheimer's Disease. AB - PURPOSE: The aim of this study was to analyse the prevalence and predictors of drug combinations increasing bleeding risk among warfarin users with and without Alzheimer's disease (AD). METHODS: This retrospective observational study utilised data from the Finnish MEDALZ-2005 cohort. The MEDALZ-2005 study included all community-dwelling persons with a clinically verified diagnosis of AD at the end of 2005, and one comparison person without AD for each case. Data on drug use was collected from the Prescription Register. We included persons who were warfarin users during the study period 2006-2009. Drug combinations increasing bleeding risk with warfarin included selective serotonin reuptake inhibitors (SSRIs), non-steroidal anti-inflammatory agents (NSAIDs), other antithrombotic drugs and tramadol. Factors associated with combination use were investigated with logistic regression. RESULTS: During the follow-up, 3385 persons with AD and 4830 persons without AD used warfarin. Drug combinations increasing bleeding risk were more common in warfarin users with AD than without AD [35.9 and 30.5%, respectively (p < 0.0001)]. The most common combination was SSRIs and warfarin, which was more common among persons with AD (23.8%) than among persons without AD (10.9%). NSAIDs and warfarin combination was more common among persons without AD. Combination use was associated with AD, female gender, younger age, diabetes mellitus, rheumatoid arthritis and asthma/chronic obstructive pulmonary disease (COPD). CONCLUSIONS: Use of drug combinations increasing bleeding risk was more common among warfarin users with AD. Special attention should be paid to minimise the duration of concomitant use and to find safer alternatives without increased bleeding risk. PMID- 26476843 TI - Myelodysplastic Syndromes in the Elderly: Treatment Options and Personalized Management. AB - Myelodysplastic syndromes (MDS) are typical diseases of the elderly, with a median age of 68-75 years at initial diagnosis. Demographic changes producing an increased proportion of elderly in our societies mean the incidence of MDS will rise dramatically. Considering the increasing number of treatment options, ranging from best supportive care to hematopoietic stem cell transplantation (HSCT), decision making is rather complex in this cohort of patients. Moreover, aspects of the aging process also have to be considered in therapy planning. Treatment of elderly MDS patients is dependent on the patient's individual risk and prognosis. Comorbidities play an essential role as predictors of survival and therapy tolerance. Age-adjusted models and the use of geriatric assessment scores are described as a basis for individualized treatment algorithms. Specific treatment recommendations for the different groups of patients are given. Currently available therapeutic agents, including supportive care, erythropoiesis stimulating agents (ESAs), immune-modulating agents, hypomethylating agents, and HSCT are described in detail and discussed with a special focus on elderly MDS patients. The inclusion of elderly patients in clinical trials is of utmost importance to obtain data on efficacy and safety in this particular group of patients. Endpoints relevant for the elderly should be integrated, including maintenance of quality of life and functional activities as well as evaluation of use of healthcare resources. PMID- 26476846 TI - Epidemiology of Search and Rescue in Baxter State Park: Dangers of Descent and Fatigue. AB - OBJECTIVE: The purpose of this study was to determine the epidemiology of injury in Baxter State Park, Maine, and to better tailor search and rescue (SAR) resources, personnel, and training to acute needs in the park. METHODS: We conducted a retrospective review of all SAR incident reports in Baxter State Park from July 1992 through June 2014. For each event, demographics, location, time, activity before the incident, incident details, and evacuation means were recorded and analyzed. RESULTS: In all, 754 incidents of SAR or medical need were identified. Mean age was 38.9 years; mean age for subjects with fatigue as the primary complaint was 48.7 years. A majority (60.5%) of victims were male. Nineteen fatalities occurred during the study. Traumatic injuries precipitated 51% of SAR incidents, and an additional 30% were initiated for late or lost parties. Slips or falls while hiking were the most common causes of injury (67%), with the lower extremity being the most common injury site (31%). When applicable, 84.4% of acute need occurred while descending, as opposed to ascending, a mountain. Fatigue was the most commonly reported medical emergency, causative in 66% of medical SAR events. CONCLUSIONS: Fatigue is a major factor in SAR events, both as a discreet cause and as a contributor to other injuries. Search and rescue need is more likely to occur during mountain descent, and lower extremity injuries are the most common etiology. Efforts should be focused on training rescuers in lower extremity and fatigue treatment, and more rescuers should be available when many are descending. PMID- 26476848 TI - Vibratory Dynamics of Four Types of Excised Larynx Phonations. AB - OBJECTIVES: There are four types of signals that are typical representations of vocal fold vibratory patterns. Type 1 signals are nearly periodic, type 2 signals contain subharmonic properties, type 3 signals are chaotic, and type 4 signals are characterized as white noise. High-speed imaging allows detailed observation of these vocal fold vibratory patterns. Therefore, high-speed imaging can explore the vibratory mechanism behind each of the four types of signals. METHODS: The glottal area time series of the four types of vocal fold vibrations were calculated from high-speed images of 10 excised canine larynges. Nonlinear dynamic parameters of correlation dimension (D2) and Kolmogorov entropy (K2) were used to quantify the characteristics of the glottal areas and acoustical signals for each voice signal type. RESULTS: The correlation dimension and Kolmogorov entropy of the glottal areas and acoustical signals for type 1, 2, and 3 voice signals were consistent with the results of previous studies. Interestingly, there was a difference between the glottal area and acoustical signals of type 4 voice signals (P < 0.001). Both the correlation dimension and Kolmogorov entropy of the type 4 glottal area were close to 0. In contrast, the type 4 acoustical signals had an infinite correlation dimension and a Kolmogorov entropy that was close to 1. CONCLUSIONS: Turbulence in the vocal tract creates high-frequency breathiness, causing noise in the acoustical signal of type 4 voice, proving that the acoustical signal does not represent the motion mechanism behind type 4 voice. The results of this study demonstrate that high-speed imaging can provide a more accurate representation of the type 4 vocal fold vibratory pattern, and a more effective method to explore the mechanism of type 4 signals. PMID- 26476847 TI - Statistical analysis of EGFR structures' performance in virtual screening. AB - In this work the ability of EGFR structures to distinguish true inhibitors from decoys in docking and MM-PBSA is assessed by statistical procedures. The docking performance depends critically on the receptor conformation and bound state. The enrichment of known inhibitors is well correlated with the difference between EGFR structures rather than the bound-ligand property. The optimal structures for virtual screening can be selected based purely on the complex information. And the mixed combination of distinct EGFR conformations is recommended for ensemble docking. In MM-PBSA, a variety of EGFR structures have identically good performance in the scoring and ranking of known inhibitors, indicating that the choice of the receptor structure has little effect on the screening. PMID- 26476849 TI - Stress, diabetes, and infection: Syndemic suffering at an urban Kenyan hospital. AB - The complexity of sickness among Kenya's urban poor cannot be dissociated from how social and health problems become syndemic. Increasingly diabetes and other non-communicable diseases (NCDs) are emerging among low-income populations that also are most afflicted by social stress and infection. This article examines how social stress, psychological distress, and physical illness among patients in a public hospital in Nairobi, Kenya, produce syndemic suffering, defined by lived experiences of syndemic clustering such as diabetes with depression and infection. We recruited 100 urban public hospital patients, of which half were women, and half had type 2 diabetes from June to August 2014. We administered written informed consent and collected anthropometrics and blood samples before we conducted lengthy mixed qualitative and survey interviews. We analyzed social stress in narrative interviews using content analysis and evaluated social and physical contributors to mental distress with frequency tables and logistic regression. We found that people experienced diabetes through a complex social and medical framework, where social problems were cause and consequence to psychological and physical suffering. Women's narratives revealed more social suffering as well as more mental distress and somatic symptoms, including multi morbidities, than men's. People with diabetes reported not only concurrent anxiety and depression but also common infections, including malaria, tuberculosis, and HIV/AIDS. Narratives reveal how NCDs concurrent with infections, and HIV in particular, produce financial challenges for patients, especially when HIV treatment is free and patients must pay out-of-pocket for diabetes care. Future studies should investigate syndemic clustering of infections and NCDs among low-income populations at the population-level. PMID- 26476850 TI - Evidence-Based Anticoagulation Decision Making for Atrial Fibrillation--How We Are Doing? (Maybe Not So Well?). PMID- 26476851 TI - The Risk Stratification and Stroke Prevention Therapy Care Gap in Canadian Atrial Fibrillation Patients. AB - BACKGROUND: Canadian atrial fibrillation (AF) guidelines recommend that all AF patients be risk stratified with respect to stroke and bleeding, and that most should receive antithrombotic therapy. METHODS: As part of the Canadian Facilitating Review and Education to Optimize Stroke Prevention in Atrial Fibrillation (FREEDOM AF) chart audit, data were collected on 4670 patients >= 18 years old without significant valvular heart disease from the primary care practices of 474 physicians (February to September, 2011). RESULTS: Physicians did not provide an estimate of stroke and bleeding risk in 15% and 25% of patients, respectively. When risks were provided, they were on the basis of a predictive stroke and bleeding risk index in only 50% and 26% of patients, respectively. There were over- and underestimation of stroke and bleeding risk in a large proportion of patients. Antithrombotic therapy included warfarin (90%); 24% of patients had a time in the therapeutic range (TTR) < 50%, 9% between 50% and 60%, 11% between 60% and 70%, and 56% had a TTR >= 70%. CONCLUSIONS: In a large Canadian AF population, primary care physicians did not provide a stroke or bleeding risk in a substantial proportion of their AF patients. When estimates were provided, they were on the basis of a predictive stroke and bleeding risk index in less than half of the patients. Furthermore, there was under- and overestimation of stroke and bleeding risk in a substantial proportion of patients. As many as 1 in 3 patients receiving warfarin have their TTR < 60%. These findings suggest an opportunity to enhance knowledge translation to primary care physicians. PMID- 26476852 TI - Multi-Modal Optical Imaging of the Cerebellum in Animals. AB - Thanks to their flexibility, optical techniques could be the key to explore anatomy, plasticity, and functionality of the cerebellum. As an example, an in vivo analysis of the dynamic remodeling of cerebellar axons by nonlinear microscopy can provide fundamental insights of the mechanism that promotes neuronal regeneration. Several studies showed that damaged climbing fibers are capable of regrowing also in adult animals. The investigation of the time-lapse dynamics of degeneration and regeneration of these axons within their complex environment can be performed by time-lapse two-photon fluorescence (TPF) imaging in vivo. Here, we show that single axonal branches can be dissected by laser axotomy, thus avoiding collateral damage to the adjacent dendrite and the formation of a persistent glial scar. Despite the very small denervated area, the injured axons consistently reshaped the connectivity with surrounding neurons and sprouted new branches through the intact surroundings. Correlative light and electron microscopy revealed that the sprouted branch contains large numbers of vesicles, with varicosities in the close vicinity of Purkinje dendrites. By using an RNA interference approach, we found that downregulating GAP-43 causes a significant increase in the turnover of presynaptic boutons and hampers the generation of reactive sprouts. Further, we report how nonlinear microscopy in combination with novel voltage sensitive dyes or transgenic mice allow optical registrations of action potential across a population of neurons opening promising prospective in understanding brain functionality. Finally, we describe novel implementations of light-sheet microscopy to resolve neuronal anatomy in whole cerebellum with cellular resolution. The understanding gained from these complementary optical methods may provide a deeper comprehension of the cerebellum. PMID- 26476853 TI - Using the column wall itself as resistive heater for fast temperature gradients in liquid chromatography. AB - A new system is proposed for applying fast temperature gradients in liquid chromatography. It consists of a 0.7 mm * 150 mm fused-silica column coated with a 50 MUm Nickel-layer, which is connecting with a power source and a temperature control system to perform fast and reproducible temperature gradients using the column wall itself as a resistive heater. Applying a current of 4A and passive cooling results in a maximal heating and cooling rate of, respectively, 71 and 21 degrees C/min. Multi-segment temperature gradients were superimposed on mobile phase gradients to enhance the selectivity for three sets of mixtures (pharmaceutical compounds, a highly complex mixture and an insecticide sample). This resulted in a higher peak count or better selectivities for the various mixtures. PMID- 26476854 TI - Insight into the composition and evolution of compost-derived dissolved organic matter using high-performance liquid chromatography combined with Fourier transform infrared and nuclear magnetic resonance spectra. AB - Size exclusion chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC) were combined with Fourier transform infrared spectra (FTIR) and nuclear magnetic resonance (NMR) based on two dimensional (2D) hetero spectral correlation spectra techniques to fractionate compost-derived dissolved organic matter (DOM) and determine how size- and hydrophobicity-distinguished fractions differ in the composition and evolution. The results showed that the compost-derived DOM was comprised of protein- and humic-like species. The low apparent molecule weight (AMW) protein-like components were enriched in C-C=H3 and N-C=O, and showed more bioreactivity compared with the high AMW counterpart. The hydrophobic and hydrophilic protein-like components both consisted of CCH3 and N-C=O. However, the relatively hydrophilic protein-like components were more easily consumed. As to the humic-like species, the relatively hydrophilic components were slightly larger than the relatively hydrophobic ones. The high AMW and relatively hydrophilic humic-like components were high in C-H, OCH3, N C=O, N-H, COO, O-H and aromatic C. The low AMW and relatively hydrophobic humic like components were enriched in CCH3 and N-C=O, and were easily biodegraded during composting. 2D hetero-spectral correlation spectra techniques enhance the characterization of DOM and provide a promising way to elucidate the environmental behaviors of DOM. PMID- 26476855 TI - Predictors of Sustained Prescription Opioid Use After Admission for Trauma in Adolescents. AB - PURPOSE: The study objectives are to describe the longitudinal trajectory of prescription opioid use among adolescents requiring a trauma admission and then identify predictors of sustained opioid use. METHODS: Randomly sampled adolescents (12-18 years) admitted to a Level I trauma center were surveyed. Follow-up assessments were obtained at 2, 5, and 12 months. Self-reported prescription opioid use, defined as "taking an opioid prescribed by a physician," was obtained at baseline and every follow-up time point. At the baseline interview, validated mental health measures and pain scales were obtained as well as preinjury substance use. A fixed-effects mixed Poisson regression analysis was performed to predict prescription opioid use over time. RESULTS: A total of 120 adolescents (mean age 15.5 years [1.9 standard deviation], 75% male) completed the baseline interview with 98% follow-up at 12 months. At baseline, 7% of adolescents reported prescription opioid use before their trauma, with rates of prescription opioid use of 52% at 2 months, 13.3% at 5 months, and 12.5% at 12 months after discharge. After adjusting for demographic characteristics and injury severity score, those with sustained prescription opioid use were more likely to report preinjury marijuana use and higher baseline pain scores. CONCLUSIONS: Approximately one in eight adolescents (12.5%) was using prescription opioids 12 months after injury hospitalization. Readily identifiable risk factors predicted sustained prescription opioid use, including preinjury marijuana use and baseline pain score. Screening for substance use including marijuana at the time of injury could help identify patients at risk for both substance use problems and sustained prescription opioid use. PMID- 26476856 TI - Structural Determinants of Youth Bullying and Fighting in 79 Countries. AB - PURSPOSE: The prevention of youth violence is a public health priority in many countries. We examined the prevalence of bullying victimization and physical fighting in youths in 79 high- and low-income countries and the relations between structural determinants of adolescent health (country wealth, income inequality, and government spending on education) and international differences in youth violence. METHODS: Cross-sectional surveys were administered in schools between 2003 and 2011. These surveys provided national prevalence rates of bullying victimization (n = 334,736) and four or more episodes of physical fighting in the past year (n = 342,312) in eligible and consenting 11-16 year olds. Contextual measures included per capita income, income inequality, and government expenditures on education. We used meta-regression to examine relations between country characteristics and youth violence. RESULTS: Approximately 30% of adolescents reported bullying victimization and 10.7% of males and 2.7% of females were involved in frequent physical fighting. More youth were exposed to violence in African and Eastern Mediterranean countries than in Europe and Asia. Violence directly related to country wealth; a 1 standard deviation increase in per capita income corresponded to less bullying (-3.9% in males and -4.2% in females) and less fighting (-2.9% in males and -1.0% in females). Income inequality and education spending modified the relation between country wealth and fighting; where inequality was high, country wealth related more closely to fighting if education spending was also high. CONCLUSIONS: Country wealth is a robust determinant of youth violence. Fighting in affluent but economically unequal countries might be reduced through increased government spending on education. PMID- 26476857 TI - The Therapeutic Promise of Mesenchymal Stem Cells for Liver Restoration. AB - Hepatocyte transplantation aims to provide a functional substitution of liver tissue lost due to trauma or toxins. Chronic liver diseases are associated with inflammation, deterioration of tissue homeostasis, and deprivation of metabolic capacity. Recent advances in liver biology have focused on the pro-regenerative features of mesenchymal stem cells (MSCs). We argue that MSCs represent an attractive therapeutic option to treat liver disease. Indeed, their pleiotropic actions include the modulation of immune reactions, the stimulation of cell proliferation, and the attenuation of cell death responses. These characteristics are highly warranted add-ons to their capacity for hepatocyte differentiation. Undoubtedly, the elucidation of the regenerative mechanisms of MSCs in different liver diseases will promote their versatile and disease-specific therapeutic use. PMID- 26476858 TI - Mapping the spatial dimensions of participatory practice: A discussion of context in evaluation. AB - In participatory or collaborative evaluation practice, context is considered a complex, relational and social phenomenon that frames the parameters of the inquiry process in profound ways. To help us expand upon our understanding of context, we borrow the concept of "space" from the critical geographers, as it provides a bridge between the social and geographic complexities of context, enabling us to more fully capture the social and relational dynamic that fundamentally defines participatory evaluation. Our focus is on understanding context and relationships as two interconnected, dynamic and constituent parts of evaluation practices that feature participatory spaces. We then turn to a comparative analysis of participatory practice across two published reviews of distinct sets of empirical studies as a way to extend our understanding of participatory evaluation in relation to its practical, and frequently complex, contextual expressions in the field. This comparative analysis enables us to develop a set of five dimensions (epistemic, temporal/historical, cultural, economic/organizational, political) that we believe captures the spatial and contextual characteristics and contours of participatory practice. PMID- 26476859 TI - Utilization of internal evaluation results by community mental health organizations: Credibility in different forms. AB - Internal evaluations are numerous but the literature is largely focused on external evaluations. There have been few explorations of the factors affecting the use of findings from internal evaluations that are carried out by program staff in community organizations. This study examined the instrumental use of internal evaluation findings within 19 community mental health organizations in Ontario, Canada. All but one respondent reported instrumental use in their organization, using the evaluation findings to make program-related decisions. For these non-controversial programs, qualities such as the ability of internal evaluators to identify relevant information, their role/expertise within the organization and the consistency of evaluation findings with current understanding appeared to influence use more strongly than evaluator objectivity. PMID- 26476861 TI - Characterization of spatial and temporal variability in hydrochemistry of Johor Straits, Malaysia. AB - Characterization of hydrochemistry changes in Johor Straits within 5 years of monitoring works was successfully carried out. Water quality data sets (27 stations and 19 parameters) collected in this area were interpreted subject to multivariate statistical analysis. Cluster analysis grouped all the stations into four clusters ((Dlink/Dmax) * 100<90) and two clusters ((Dlink/Dmax) * 100<80) for site and period similarities. Principal component analysis rendered six significant components (eigenvalue>1) that explained 82.6% of the total variance of the data set. Classification matrix of discriminant analysis assigned 88.9 92.6% and 83.3-100% correctness in spatial and temporal variability, respectively. Times series analysis then confirmed that only four parameters were not significant over time change. Therefore, it is imperative that the environmental impact of reclamation and dredging works, municipal or industrial discharge, marine aquaculture and shipping activities in this area be effectively controlled and managed. PMID- 26476862 TI - Evaluation of the status and distributions of heavy metal pollution in surface sediments of the Langat River Basin in Selangor Malaysia. AB - The concentration of four metals: Cd, Ni, Cr, and Sn, in the surface sediment samples from the Langat River were evaluated. Multivariate techniques were used to apportion the sources of the metals. The results showed that the highest concentration of metals in the Langat River were found at Jenjarom station, with the concentration of these metals decreasing in the order of Sn>Cr>Ni>Cd (114.27, 21.03, 7.84, 0.59 MUg g(-1) dry weight). The level of pollution in the sediment was assessed using contamination factor (CF), pollution load index (PLI), geo accumulation index (Igeo), and enrichment factor (EF). The results of the pollution assessment showed that the Langat River sediments have severe enrichment of Sn and moderate to severe enrichment of Cd. The results of the PLI for the Langat River suggest that the sampling stations are not polluted with the exception of the Jugra, Jenjarom, and Jalan Hulu Langat stations. PMID- 26476860 TI - The power of a collaborative relationship between technical assistance providers and community prevention teams: A correlational and longitudinal study. AB - BACKGROUND: Historically, effectiveness of community collaborative prevention efforts has been mixed. Consequently, research has been undertaken to better understand the factors that support their effectiveness; theory and some related empirical research suggests that the provision of technical assistance is one important supporting factor. The current study examines one aspect of technical assistance that may be important in supporting coalition effectiveness, the collaborative relationship between the technical assistance provider and site lead implementer. METHODS: Four and one-half years of data were collected from technical assistance providers and prevention team members from the 14 community prevention teams involved in the PROSPER project. RESULTS: Spearman correlation analyses with longitudinal data show that the levels of the collaborative relationship during one phase of collaborative team functioning associated with characteristics of internal team functioning in future phases. CONCLUSIONS: Results suggest that community collaborative prevention work should consider the collaborative nature of the technical assistance provider - prevention community team relationship when designing and conducting technical assistance activities, and it may be important to continually assess these dynamics to support high quality implementation. PMID- 26476863 TI - Plastic pollution in five urban estuaries of KwaZulu-Natal, South Africa. AB - Monitoring plastic concentrations in estuaries is vital in assessing the magnitude of terrestrial inputs to oceanic environments. Data on plastics <= 5 mm in estuaries are scant. This study determined microplastic levels within five estuaries along the Durban coastline and on intervening beaches. Plastics were isolated from estuarine sediment, beach sediment and the surface water of each estuary and characterised. Sediment at the Bayhead area of Durban harbour had the highest average plastic concentrations (745.4 +/- 129.7 particles per 500 ml) and an attenuating concentration trend away from the city centre was found. Prevailing south to north longshore drift was hypothesised to result in plastic accumulation on the northern shores of beaches with estuarine effluents, however, this was not found. Fragments composed the largest percent of plastics (59%) found in Bayhead, whereas fibres dominated other estuaries with proportions ranging from 38% of total plastics in the uMgeni estuary to 66% in the Mdloti. PMID- 26476864 TI - Current status of coral reefs in the United Arab Emirates: Distribution, extent, and community structure with implications for management. AB - Coral reefs of the United Arab Emirates were once extensive, but have declined dramatically in recent decades. Marine management and policy have been hampered by outdated and inaccurate habitat maps and habitat quality information. We combined existing recent datasets with our newly mapped coral habitats to provide a current assessment of nation-wide extent, and performed quantitative surveys of communities at 23 sites to assess coral cover and composition. Over 132 km(2) of coral habitat was mapped, averaging 28.6 +/- 3.8% live coral cover at surveyed sites. In the Arabian Gulf low cover, low richness Porites dominated communities characterized western Abu Dhabi, while reefs northeast of Abu Dhabi city generally contained higher richness and cover, and were dominated by merulinids (formerly faviids). Distinct communities occur in the Sea of Oman, where cover and richness were low. We provide management recommendations to enhance conservation of vulnerable coral reefs in the UAE. PMID- 26476865 TI - Lessons Learned from a Cross-Model Validation between a Discrete Event Simulation Model and a Cohort State-Transition Model for Personalized Breast Cancer Treatment. AB - OBJECTIVES: Breast cancer is the most common malignancy among women in developed countries. We developed a model (the Oncotyrol breast cancer outcomes model) to evaluate the cost-effectiveness of a 21-gene assay when used in combination with Adjuvant! Online to support personalized decisions about the use of adjuvant chemotherapy. The goal of this study was to perform a cross-model validation. METHODS: The Oncotyrol model evaluates the 21-gene assay by simulating a hypothetical cohort of 50-year-old women over a lifetime horizon using discrete event simulation. Primary model outcomes were life-years, quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). We followed the International Society for Pharmacoeconomics and Outcomes Research Society for Medical Decision Making (ISPOR-SMDM) best practice recommendations for validation and compared modeling results of the Oncotyrol model with the state-transition model developed by the Toronto Health Economics and Technology Assessment (THETA) Collaborative. Both models were populated with Canadian THETA model parameters, and outputs were compared. RESULTS: The differences between the models varied among the different validation end points. The smallest relative differences were in costs, and the greatest were in QALYs. All relative differences were less than 1.2%. The cost-effectiveness plane showed that small differences in the model structure can lead to different sets of nondominated test-treatment strategies with different efficiency frontiers. We faced several challenges: distinguishing between differences in outcomes due to different modeling techniques and initial coding errors, defining meaningful differences, and selecting measures and statistics for comparison (means, distributions, multivariate outcomes). CONCLUSIONS: Cross-model validation was crucial to identify and correct coding errors and to explain differences in model outcomes. In our comparison, small differences in either QALYs or costs led to changes in ICERs because of changes in the set of dominated and nondominated strategies. PMID- 26476866 TI - Molecular insight in the purification of immunoglobulin by pseudobiospecific ligand l-histidine and histidyl moieties in histidine ligand affinity chromatography (HLAC) by molecular docking. AB - Pseudobiospecific ligand l-histidine is an inexpensive, highly stable, non-toxic ligand explored successfully over the last twenty years for the purification of immunoglobulins in immobilised histidine ligand affinity chromatography. It is of great interest to know the molecular recognition sites of IgG to immobilized l histidine. Here, we have used an in silico approach to explore the molecular recognition of l-histidine by IgG. We have assessed the feasible binding modes of histidine and its moieties at different sites of IgG and considered only those binding conformations which are exhibited via the imidazole ring NH group or any other OH donating group apart from the ones which are terminally conjugated with the support matrix. We categorised binding site into two categories; category I: inner binding groove and category II: surface binding groove and observed that the hinge region of IgG has most favourable binding pocket for l-histidine and histidyl moieties. Ser and Tyr residues on the hinge region make several significant interactions with l-histidine and histidyl moieties. In case of Fc region of IgG, l-histidine and histidyl moieties closely resemble the binding modes of Protein A, biomimetic ligand 22/8 and B domain of SpA to IgG. In addition to these we have also observed a significant binding site for l histidine and histidyl moieties at Fab region of IgG. PMID- 26476867 TI - Disease related knowledge, medication adherence and glycaemic control among patients with type 2 diabetes mellitus in Pakistan. AB - AIMS: The purpose of this study was to investigate the association of diabetes related knowledge and treatment adherence with glycaemic control among patients with type 2 diabetes mellitus (T2DM) in Pakistan. METHODS: The study was designed as a questionnaire-based, cross-sectional analysis. T2DM patients attending a public outpatient clinic in Sargodha, Pakistan, were targeted for the study. In addition to the demographic information, the Urdu version of Michigan Diabetes Knowledge Test and Morisky Medication Adherence Scale was used for data collection. Patients' medical records were reviewed for glycated haemoglobin levels (HbA1c). Descriptive statistics were used to elaborate sociodemographic characteristics. The Spearman's Rho correlation was used to measure association of disease-related knowledge and treatment adherence with glycaemic control. SPSS V 20.0 was used for data analysis and p<0.05 was taken as significant. RESULT: In total, 392 T2DM patients were included in the study. The mean age (SD) of these patients was 50.77+/-9.671 years, 56.6% were males and 90% (n=353) of respondents were married. The mean (SD) duration of disease was 5.58 (4.09) years with median HbA1c of 9.00 (IQR=8.20-10.40). The median knowledge score was 8.0 (IQR=6.0 10.0), while the median adherence score was 4.7 (IQR=3.0-6.0). HbA1c had non significant and weak negative association with diabetes-related knowledge (r= 0.036, p=0.404) and treatment adherence (r=-0.071, p=0.238). CONCLUSION: There was negative association reported between HbA1c, treatment adherence and diabetes related knowledge. Greater efforts are clearly required to investigate other factors affecting glycaemic control among T2DM patients in Pakistan. PMID- 26476868 TI - Measurement of ageing effects on muscle tone and mechanical properties of rectus femoris and biceps brachii in healthy males and females using a novel hand-held myometric device. AB - BACKGROUND: Age and gender effects on muscle tone and mechanical properties have not been studied using hand-held myometric technology. Monitoring changes in muscle properties with ageing in community settings may provide a valuable assessment tool for detecting those at risk of premature decline and sarcopenia. OBJECTIVE: This study aimed to provide objective data on the effects of ageing and gender on muscle tone and mechanical properties of quadriceps (rectus femoris) and biceps brachii muscles. METHODS: In a comparative study of 123 healthy males and females (aged 18-90 years; n=61 aged 18-35; n=62 aged 65-90) muscle tone, elasticity and stiffness were measured using the MyotonPRO device. RESULTS: Stiffness was greater and elasticity lower in older adults for BB and RF (p<0.001). Tone was significantly greater in older adults for BB but not for RF when data for males and females were combined (p=0.28). There were no gender differences for BB in either age group. In RF, males had greater stiffness (young males 292 vs females 233 N/m; older males 328 vs females 311 N/m) and tone (young 16.4 vs 13.6 Hz; older 16.7 vs 14.9 Hz). Elasticity in RF was lower in young males than females but did not differ between the older groups (both males and females log decrement 1.6). CONCLUSIONS: Stiffness and tone increased with ageing and elasticity decreased. These findings have implications for detecting frailty using a novel biomarker. Age and gender differences are important to consider when assessing effects of pathological conditions on muscle properties in older people. PMID- 26476869 TI - Using a brain-machine interface to control a hybrid upper limb exoskeleton during rehabilitation of patients with neurological conditions. AB - BACKGROUND: As a consequence of the increase of cerebro-vascular accidents, the number of people suffering from motor disabilities is raising. Exoskeletons, Functional Electrical Stimulation (FES) devices and Brain-Machine Interfaces (BMIs) could be combined for rehabilitation purposes in order to improve therapy outcomes. METHODS: In this work, a system based on a hybrid upper limb exoskeleton is used for neurological rehabilitation. Reaching movements are supported by the passive exoskeleton ArmeoSpring and FES. The movement execution is triggered by an EEG-based BMI. The BMI uses two different methods to interact with the exoskeleton from the user's brain activity. The first method relies on motor imagery tasks classification, whilst the second one is based on movement intention detection. RESULTS: Three healthy users and five patients with neurological conditions participated in the experiments to verify the usability of the system. Using the BMI based on motor imagery, healthy volunteers obtained an average accuracy of 82.9 +/- 14.5 %, and patients obtained an accuracy of 65.3 +/- 9.0 %, with a low False Positives rate (FP) (19.2 +/- 10.4 % and 15.0 +/- 8.4 %, respectively). On the other hand, by using the BMI based on detecting the arm movement intention, the average accuracy was 76.7 +/- 13.2 % for healthy users and 71.6 +/- 15.8 % for patients, with 28.7 +/- 19.9 % and 21.2 +/- 13.3 % of FP rate (healthy users and patients, respectively). CONCLUSIONS: The accuracy of the results shows that the combined use of a hybrid upper limb exoskeleton and a BMI could be used for rehabilitation therapies. The advantage of this system is that the user is an active part of the rehabilitation procedure. The next step will be to verify what are the clinical benefits for the patients using this new rehabilitation procedure. PMID- 26476870 TI - Recent advances in alcohol and organic acid fractionation of lignocellulosic biomass. AB - Organosolv fractionation is a promising process to separate lignocellulosic biomass for the preparation of multiply products including biofuels, chemicals, and materials. This review presents the state of art of different processes applying alcohols and organic acids to treat lignocellulosic biomass for the production of ethanol, lignin, xylose, etc. The major organosolv technologies using ethanol, formic acid, and acetic acid, are intensively introduced and discussed in depth. In addition, the structural modifications of the major components of lignocelluloses, the technical processes, and the applications of the products were also summarized. The object of the review is to provide recent information in the field of organosolv process for the integrated biorefinery. The perspectives of the challenge and opportunity related to this topic are also presented. PMID- 26476871 TI - Fabrication of porosity-enhanced MgO/biochar for removal of phosphate from aqueous solution: Application of a novel combined electrochemical modification method. AB - A novel combined electrochemical modification (CEM) method, using a graphite electrode-based electric field and MgCl2 as electrolyte, was newly developed to prepare porosity-enhanced biochar containing periclase (MgO) nanocomposites (PE MgO/biochar). During the CEM method, the dried marine macroalgae was immersed in the MgCl2 solution, and a voltage of 20V was then applied for 10min prior to pyrolysis. Morphological and chemical analyses results showed that nano-sized MgO particles with a highly crystalline structure were dispersed and enriched on the surface of the PE-MgO/biochar, which enabled higher phosphate adsorption capability. In an adsorption equilibrium test, among various biochars, PE MgO/biochar exhibited the highest phosphate adsorption capacity from aqueous solution with a Langmuir-Freundlich maximum adsorption capacity as high as 620mg Pg(-1). It can be concluded that the newly introduced CEM method is a potent additional technique to effectively prepare modified-biochar in terms of a simple and time-saving modification method. PMID- 26476873 TI - Effects of halide ions on the acceptor phase in spontaneous chemical oscillations in donor/membrane/acceptor systems. AB - The effects of halide ions on the acceptor phase in the chemical oscillation in donor/membrane/acceptor systems were examined. The transfer of cetyltrimethylammonium (CTA(+)) ions from the donor phase and their adsorption and desorption at the membrane/acceptor interface led to spontaneous, nonlinear oscillations of the electric potential. Chloride ions stabilized the adsorption of CTA(+) ions and gave rise to a large-amplitude, long-interval, and a long relaxation-time constant. On the contrary, iodide ions, which are more hydrophobic than chloride ions, demonstrated opposite results. This mechanism was proposed based on the simultaneous time-resolved measurements of the interfacial tensions at both the donor/membrane and membrane/acceptor interfaces and observation of the convective flow due to Marangoni instability. PMID- 26476872 TI - Epidemiology of human immunodeficiency virus-1 and hepatitis B virus co-infection and risk factors for acquiring these infections in the Fako division of Southwest Cameroon. AB - BACKGROUND: Past studies have demonstrated that a large population of Cameroonians are afflicted with human immunodeficiency virus (HIV) and/or hepatitis B virus (HBV) demonstrating a need for better prevention programs. We aim to describe the prevalence of HIV, HBV and HIV/HBV co-infection; examine the association between HIV and HBV; and determine risk correlates associated with HIV and HBV transmission in Southwest Cameroon. METHODS: A cross-sectional, community-based surveillance study was conducted among adults in five hospitals , one in each of the five health districts of the Fako division of the Southwest region of Cameroon. Participants underwent pre- and post-test counselling, a 30 question survey and blood draw for HIV and HBV serologic testing. To construct a final model, chi-squared tests and logistic regression were used to investigate associations. RESULTS: Among 761 participants, 40.32 % were male, mean age was 35.21 +/- 12.42 years, and the prevalence of HIV, HBV and HIV/HBV co-infection was 10.69 % , 9.86 % , and 1.16 % , respectively. There was no association between HIV and HBV infection. However, there was a statistically significant crude associated (p-value < 0.05) between HIV and three high-risk sexual behaviour variables: condom use, number of lifetime sexual partners, and age at first sexual intercourse. After adjustment, HIV status continued to be associated with number of lifetime sexual partners (adjusted odds ratio (AOR) = 2.26; 95 % confidence interval (CI) =1.22-4.17) and age at first sexual intercourse (AOR = 2.63; 95 % CI =1.44-4.81). In contrast, none of the high-risk sexual behaviours was associated with HBV. CONCLUSIONS: The prevalence of HIV and HBV was relatively high in the Southwest region of Cameroon, emphasizing the importance of intervention and treatment programs in this country. Additionally, the results from this study suggest that unlike HIV, HBV is not associated with sexual risk factors and may provide evidence that HBV is acquired through routes other than sexual transmission, warranting further investigation in this region. PMID- 26476874 TI - Angiogenic Factors in Bronchopulmonary Dysplasia. PMID- 26476875 TI - [Failure mode effect analysis applied to preparation of intravenous cytostatics]. AB - OBJECTIVE: To proactively identify risks in the preparation of intravenous cytostatic drugs, and to prioritise and establish measures to improve safety procedures. MATERIAL AND METHODS: Failure Mode Effect Analysis methodology was used. A multidisciplinary team identified potential failure modes of the procedure through a brainstorming session. The impact associated with each failure mode was assessed with the Risk Priority Number (RPN), which involves three variables: occurrence, severity, and detectability. Improvement measures were established for all identified failure modes, with those with RPN>100 considered critical. The final RPN (theoretical) that would result from the proposed measures was also calculated and the process was redesigned. RESULTS: A total of 34 failure modes were identified. The initial accumulated RPN was 3022 (range: 3-252), and after recommended actions the final RPN was 1292 (range: 3 189). RPN scores >100 were obtained in 13 failure modes; only the dispensing sub process was free of critical points (RPN>100). A final reduction of RPN>50% was achieved in 9 failure modes. CONCLUSIONS: This prospective risk analysis methodology allows the weaknesses of the procedure to be prioritised, optimize use of resources, and a substantial improvement in the safety of the preparation of cytostatic drugs through the introduction of double checking and intermediate product labelling. PMID- 26476876 TI - [Evaluation of adherence to treatment with calcium and vitamin D in the elderly in a basic health area]. AB - BACKGROUND AND OBJECTIVE: The vitamin D deficiency is high in the elderly population. Calcium and vitamin D supplements is a frequently used measure in individuals at risk for falls and/or fractures. However, this practice has achieved a low level of compliance. The aim is to assess the adherence to treatment with calcium and vitamin D in elders with hypovitaminosis D in an urban area of Madrid. PATIENTS AND METHODS: Intervention study performed on 438 individuals >=65years from the 'Penagrande Cohort' with hypovitaminosis D that were treated with calcium and vitamin D. Adherence at 3 and 12 months was assessed using the Morisky-Green and counting of prescriptions written. RESULTS: A total of 413 of the 438 individuals with hypovitaminosis D were analysed (18 patients were not treated because of contraindications, and 7 were considered lost). At 3 and 12 months, 63.9% and 47.2%, respectively, were adherents. After a brief educational intervention, 19.3% of individuals without adherence at 3 months became good compliers when measured at one year. Comorbidity was associated with lower rates of adherence to treatment after one year (46.3% versus 35.2%, P=.027). The main cause of non-adherence to calcium was digestive intolerance, and due to oversights for vitamin D. Concordance between adherence assessed by the Morisky test and counting of prescriptions written was high (Kappa index=69.8%). CONCLUSIONS: Non-adherence to chronic treatment with calcium and vitamin D is a relevant problem in elderly. It is important to assess adherence and implement health education strategies in clinical practice. PMID- 26476877 TI - Quantitatively assessing the health risk of exposure to PAHs from intake of smoked meats. AB - Smoked meat and meat products represent a significant part of the daily diet in south-west China and many other parts of the world. In this study, we evaluated the health risks of long-term exposure to polycyclic aromatic hydrocarbons (PAHs) in a daily low dose exposures (from intake of PAH-containing smoked meats) in south-west China for eight groups of people based on a Monte Carlo simulation. Total concentrations of PAHs in smoked meats from south-west China ranged from 14.4 to 56.3MUgkg(-1). The 95th percentile carcinogenic risk (CR) values of eight groups in four cities and provinces were lower than the acceptable value (1.00E 5), indicating no significant risk. The 95th percentile Hazard Index (HI) values were below 1, suggesting no obvious non-carcinogenic effects developed. This study was the first attempt to provide information on the potential health risk for daily intake of PAH-containing smoked meat. PMID- 26476878 TI - Exposure to low pH induces molecular level changes in the marine worm, Platynereis dumerilii. AB - Fossil fuel emissions and changes in net land use lead to an increase in atmospheric CO2 concentration and a subsequent decrease of ocean pH. Noticeable effects on organisms' calcification rate, shell structure and energy metabolism have been reported in the literature. To date, little is known about the molecular mechanisms altered under low pH exposure, especially in non-calcifying organisms. We used a suppression subtractive hybridisation (SSH) approach to characterise differentially expressed genes isolated from Platynereis dumerilii, a non-calcifying marine polychaeta species, kept at normal and low pH conditions. Several gene sequences have been identified as differentially regulated. These are involved in processes previously considered as indicators of environment change, such as energy metabolism (NADH dehydrogenase, 2-oxoglutarate dehydrogenase, cytochrome c oxidase and ATP synthase subunit F), while others are involved in cytoskeleton function (paramyosin and calponin) and immune defence (fucolectin-1 and paneth cell-specific alpha-defensin) processes. This is the first study of differential gene expression in a non-calcifying, marine polychaete exposed to low pH seawater conditions and suggests that mechanisms of impact may include additional pathways not previously identified as impacted by low pH in other species. PMID- 26476880 TI - Association Between Prenatal Exposure to Maternal Infection and Offspring Mood Disorders: A Review of the Literature. AB - The purpose of this article is to provide a systematic review of studies that have examined the association between prenatal exposure to maternal infection and development of mood disorders across the life course. Drawing from both human- and animal-based studies, we give an overview of hypothesized biological mechanisms by which exposure to maternal infection during critical periods of gestation may contribute to fetal programming of mood disorders in offspring. We discuss studies examining the association between prenatal exposure to maternal infection with pathogens including influenza as well as other respiratory viruses, herpesviruses, hepatitis viruses, and Toxoplasma gondii and mood disorders in human populations. Moreover, we outline strengths and limitations of the current body of evidence and make recommendations for future research. We also discuss findings in the context of well-documented gender and socioeconomic disparities in the prevalence and severity of mood disorders, particularly major depression, and the role that early exposure to infection may play in explaining the perpetuation of such disparities across generations. Overall, this review of the current knowledge on this topic has important implications for determining future research directions, designing interventions as well as prenatal care guidelines targeted at prevention or treatment of infection during pregnancy, and clinical practice for the identification of individuals that may be at increased risk for mood disorders beginning early in life. Importantly, such efforts may not only lower the overall burden of mood disorders but also serve to address social disparities in these adverse mental health conditions in the U.S. PMID- 26476879 TI - Oral application of freeze-dried yeast particles expressing the PCV2b Cap protein on their surface induce protection to subsequent PCV2b challenge in vivo. AB - Porcine circovirus type 2 (PCV2) is now endemic in every major pig producing country, causing PCV-associated disease (PCVAD), linked with large scale economic losses. Current vaccination strategies are based on the capsid protein of the virus and are reasonably successful in preventing PCVAD but fail to induce sterile immunity. Additionally, vaccinating whole herds is expensive and time consuming. In the present study a "proof of concept" vaccine trial was employed to test the effectiveness of powdered freeze-dried recombinant Saccharomyces cerevisiae yeast stably expressing the capsid protein of PCV2b on its surface as an orally applied vaccine. PCV2-free pigs were given 3 doses of vaccine or left un-vaccinated before challenge with a defined PCV2b strain. Rectal temperatures were measured and serum and faeces samples were collected weekly. At the end of the study, pigs were euthanized, tissue samples taken and tested for PCV2b load by qPCR and immunohistochemistry. The peak of viraemia in sera and faeces of unvaccinated pigs was higher than that of vaccinated pigs. Additionally more sIgA was found in faeces of vaccinated pigs than unvaccinated. Vaccination was associated with lower serum concentrations of TNFalpha and IL-1beta but higher concentrations of IFNalpha and IFNgamma in comparison to the unvaccinated animals. At the end of the trial, a higher viral load was found in several lymphatic tissues and the ileum of unvaccinated pigs in comparison to vaccinated pigs. The difference between groups was especially apparent in the ileum. The results presented here demonstrate a possible use for recombinant S. cerevisiae expressing viral proteins as an oral vaccine against PCV2. A powdered freeze dried recombinant S. cerevisiae used as an oral vaccine could be mixed with feed and may offer a cheap and less labour intensive alternative to inoculation with the additional advantage that no cooling chain would be required for vaccine transport and storage. PMID- 26476881 TI - Development of a validated LC-APCI-MS/MS method to study the plasma and tumor distribution of CHO-PTX intravenous lipid emulsion. AB - Conjugation of a cholesterol moiety to active compounds for cancer treatment or diagnosis is an attractive approach for increasing lipophilicity and improving loading into lipid carriers. We developed a highly sensitive and specific liquid chromatography atmospheric-pressure chemical ionization tandem mass spectrometry (LC-APCI-MS/MS) analytical method to investigate the in vivo plasma and tumor distribution characteristic of a cholesterol-paclitaxel conjugate (CHO-PTX) in nude mice with MDA-MB-231 human breast cancer xenografts. The samples were analyzed in positive ion, multiple reaction monitoring mode. The plasma and tumor tissue samples were processed by liquid-liquid extraction with methyl tert-butyl ether (MTBE). Docetaxel was used as the internal standard (IS) for sample processing and analysis. MS/MS detection was carried out by monitoring the transitions of m/z 1266.7->369.4 and 330.3 for CHO-PTX, and m/z 808.7->226.4 and 509.1 for IS. The calibration curves were linear over 100-25,000 ng/mL in mouse plasma and tumor homogenate samples. The limit of quantitation of CHO-PTX was 100 ng/mL in both matrices. The intra-day and inter-day precisions were less than 15%, and the accuracy was between -8.0% and 8.6% for both matrices. The developed method was successfully applied to measure CHO-PTX levels in plasma and tumor tissues in nude mice. The mean tumor concentrations in mice tumor tissues after intravenous administration of CHO-PTX emulsion at a dose equivalent to 20 mg/kg paclitaxel were 2022+/-630 ng/mL ng/mL, 2516+/-982 ng/mL, 3056+/-1438 ng/mL, and 2367+/-1029 ng/mL at 0.25, 3, 24, and 120 h, respectively. The accumulation of CHO-PTX in the tumor suggests that cholesteryl drug conjugates are a promising approach for medical treatment of various human cancers. PMID- 26476882 TI - Application of (1)H NMR-based serum metabolomic studies for monitoring female patients with rheumatoid arthritis. AB - Rheumatoid arthritis is a chronic autoimmune-based inflammatory disease that leads to progressive joint degeneration, disability, and an increased risk of cardiovascular complications, which is the main cause of mortality in this population of patients. Although several biomarkers are routinely used in the management of rheumatoid arthritis, there is a high demand for novel biomarkers to further improve the early diagnosis of rheumatoid arthritis, stratification of patients, and the prediction of a better response to a specific therapy. In this study, the metabolomics approach was used to provide relevant biomarkers to improve diagnostic accuracy, define prognosis and predict and monitor treatment efficacy. The results indicated that twelve metabolites were important for the discrimination of healthy control and rheumatoid arthritis. Notably, valine, isoleucine, lactate, alanine, creatinine, GPC APC and histidine relative levels were lower in rheumatoid arthritis, whereas 3-hydroxyisobutyrate, acetate, NAC, acetoacetate and acetone relative levels were higher. Simultaneously, the analysis of the concentration of metabolites in rheumatoid arthritis and 3 months after induction treatment revealed that L1, 3-hydroxyisobutyrate, lysine, L5, acetoacetate, creatine, GPC+APC, histidine and phenylalanine were elevated in RA, whereas leucine, acetate, betaine and formate were lower. Additionally, metabolomics tools were employed to discriminate between patients with different IL-17A genotypes. Metabolomics may provide relevant biomarkers to improve diagnostic accuracy, define prognosis and predict and monitor treatment efficacy in rheumatoid arthritis. PMID- 26476884 TI - Getting to the heart of the matter in type 2 diabetes. PMID- 26476885 TI - Arsenic and human health effects: A review. AB - Arsenic (As) is ubiquitous in nature and humans being exposed to arsenic via atmospheric air, ground water and food sources are certain. Major sources of arsenic contamination could be either through geological or via anthropogenic activities. In physiological individuals, organ system is described as group of organs that transact collectively and associate with other systems for conventional body functions. Arsenic has been associated with persuading a variety of complications in body organ systems: integumentary, nervous, respiratory, cardiovascular, hematopoietic, immune, endocrine, hepatic, renal, reproductive system and development. In this review, we outline the effects of arsenic on the human body with a main focus on assorted organ systems with respective disease conditions. Additionally, underlying mechanisms of disease development in each organ system due to arsenic have also been explored. Strikingly, arsenic has been able to induce epigenetic changes (in utero) and genetic mutations (a leading cause of cancer) in the body. Occurrence of various arsenic induced health effects involving emerging areas such as epigenetics and cancer along with their respective mechanisms are also briefly discussed. PMID- 26476886 TI - Ampelopsin induces apoptosis in HepG2 human hepatoma cell line through extrinsic and intrinsic pathways: Involvement of P38 and ERK. AB - Our results showed that ampelopsin significantly inhibited cell viability of hepatoma HepG2 cells using MTT assay. We further investigated the mechanism of anticancer activity by ampelopsin, it showed that ampelopsin induced apoptosis of HepG2 cells using DAPI assay and flow cytometry, which was confirmed by activation of PARP. Next, activation of the caspase cascades were demonstrated, including caspase-8, -9 and -3. We also found that ampelopsin increased the levels of death receptor 4 (DR4), death receptor 5 (DR5) and decreased the expression of Bcl-2 protein, which led to an increase of the Bax/Bcl-2 ratio. Meanwhile, the release of cytochrome c from mitochondria was observed. Ampelopsin decreased the levels of iNOS and COX-2 but had no impact on the level of reactive oxygen species (ROS). In addition, ampelopsin activated ERK1/2 and P38, but little JNK1/2 activation was detected. Further investigation showed that suppression of P38 activation by SB203580 increased the cell viability and also prevented cleavage of caspase-3 and PARP, inhibition of ERK1/2 with U0126 had the opposite action. In conclusion, our results indicated that ampelopsin mainly elicited apoptosis through extrinsic and intrinsic pathway and that ERK1/2 and P38 had opponent effects on the apoptosis. PMID- 26476887 TI - The in vitro effect of Lambda-cyhalothrin on quality and antioxidant responses of rainbow trout Oncorhynchus mykiss spermatozoa. AB - There is little information in the scientific literature about effect of in vitro exposure of fish spermatozoa to pesticides. In vitro effect of Lambda-cyhalothrin (LCT) on sperm quality and oxidative stress has not been fully explored yet. The effects of LCT, which is a synthetic pyrethroid insecticide, on quality and oxidative stress of spermatozoa were investigated in vitro due to extensively use to control a wide range of insect pests in agriculture, public health, and homes and gardens. To explore the potential in vitro toxicity of LCT, fish spermatozoa were incubated with different concentrations of LCT (0.6, 1.2 and 2.4 MUg/L) for 2h. Reduced glutathione (GSH), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA) in spermatozoa were analyzed for determination of oxidant and antioxidant balance. Our results indicated that the percentage and duration of sperm motility significantly decreased with exposure to LCT. Activity of GSH-Px and MDA (P<0.05) and GSH levels (P<0.05) increased in a concentration dependent manner while CAT activity decreased (P<0.05). In conclusion, the oxidant and antioxidant status and sperm quality were affected by increasing concentrations of LCT. PMID- 26476888 TI - Blocking TGF-beta expression inhibits silica particle-induced epithelial mesenchymal transition in human lung epithelial cells. AB - The main characteristic of silicosis is irreversible fibrosis. Certain studies have shown that epithelial-mesenchymal transition (EMT) regulated by transforming growth factor-beta (TGF-beta) is involved in fibrosis. Thus, we suggest that TGF beta regulated EMT may play an important role in silicosis. In this study, we determined the expression of TGF-beta-Smad2/3, EMT- and ECM-related markers in lung epithelial cells treated with silica particle by RT-PCR, western-blot and ELISA. In order to explore the role of TGF-beta, we used TGF-beta inhibitor in the cell model. We found that the cells lost the expression of epithelial phenotypic markers and acquired increased expression of mesenchymal cells markers with ECM deposition after treatment with silica particle. Moreover, the changes of EMT-related event was restricted in response to TGF-beta inhibitor. These findings suggest that EMT is essentially involved in the pathogenesis of fibrosis induced by silica particles and down-regulating the TGF-beta expression can inhibit the process of EMT. PMID- 26476889 TI - [Fertility preservation and endometriosis: When medical borders on social]. PMID- 26476890 TI - [Should a systematic fertility preservation be proposed to healthy women carrying a BRCA1/2 mutation?]. AB - Should all women with BRCA1 or BRCA2 genes mutations be considered at risk of prematurely impaired fertility, and thus should a fertility preservation systematically be proposed? Women carrying mutations of BRCA1 or BRCA2 are at high risk for breast and tubo-ovarian cancer. The treatment of a breast cancer at a young age, unrare in this population, is associated with a risk of infertility, due to the ovarian toxicity of chemotherapy, to the recommended duration of hormonotherapy when indicated, and to the time advised before starting a pregnancy. Furthermore, some data in the literature suggest a higher risk of premature ovarian failure among women with BRCA1/2 mutation: advance of the age at menopause and poorer response to ovarian stimulation have been observed. Several pathophysiological hypotheses support this finding, as the involvement of the BRCA genes in maintaining telomere length, the DNA repair anomalies promoting oocyte apoptosis, differences in FMR1 genotype. Current fertility preservation techniques have limitations, some of them being specific to BRCA1/2 women: absence of oncological risk due to stimulation in BRCA1/2 women not clearly demonstrated, oocyte vitrification techniques limited rentability, graft of ovarian cortex not suitable in these women at high risk. Thus, data on the increased risk of premature ovarian failure remaining weak, such a systematic proposal seems questionable. PMID- 26476891 TI - [Oxidative stress and preeclampsia: A review]. AB - Preeclampsia is a leading cause of pregnancy complications and affects 3-7% of pregnant women. Pathophysiology of preeclampsia is still unclear. According to the two-stage model of preeclampsia, the abnormal and hypoperfused placenta (stage 1) releases factors to the bloodstream, which are responsible for the maternal symptoms (stage 2), characterised by a systemic inflammation and endothelial dysfunction. Oxidative stress plays an important role in the pathophysiology of the preeclampsia and could be the common denominator between the two. This review summarizes the current knowledge of a new potential etiology of the disease, with a special focus on oxidative stress. We also review the different factors that have been proposed to cause endothelial cell dysfunction in preeclampsia, and trials investigating the role of antioxidant supplementation in preeclampsia. PMID- 26476892 TI - [A simple self-assessment tool for the first-trimester ultrasound images]. AB - OBJECTIVES: The objective of this study was to establish a minimum subset of simple criteria for the self-assessment of the quality of first-trimester ultrasound images of nuchal translucency (NT) and crown-rump length (CRL). METHODS: We designed 162 simplified image-scoring methods (ISM) based on 1, 2, 3 or 4 binary criteria derived from the 8 criteria of the original image scoring method of the French College of Fetal Ultrasound (CFEF). These ISM were assessed on 68,250 consecutive scans of the French national audit conducted by the CFEF on NT and CRL images. The ISM associated with the best precision to identify excellent/reasonable quality scans were selected. RESULTS: Simplified ISM based on 1, 2, 3 and 4 criteria showed maximum positive predictive values of 95.3% (95.11-95.50) 98.0% (97.87-98.14), 99.3% (99.17-99.35) and 99.7% (99.68-99.79), respectively, to identify excellent/reasonable quality scans. The proportion of excellent/reasonable scans was 2.8 to 16.7% when three criteria among the 8 were insufficient, and 0.17 to 3.95% when four criteria were insufficient. CONCLUSIONS: The best performing ISM was based on the following four quality criteria: (i) sagittal plane of the NT, (ii) calipers placement for measuring the NT, (iii) image magnification of NT images and (iv) CRL measurement. This score might be the most relevant in clinical practice in the first-trimester screening. PMID- 26476893 TI - Thoracic and lumbar posture behaviour in sitting tasks and standing: Progressing the biomechanics from observations to measurements. AB - Few studies quantify spinal posture behaviour at both the thoracolumbar and lumbar spinal regions. This study compared spontaneous spinal posture in 50 asymptomatic participants (21 males) during three conditions: 10-min computer task in sitting (participants naive to the measure), during their perceived 'correct' sitting posture, and standing. Three-dimensional optical tracking quantified surface spinal angles at the thoracolumbar and lumbar regions, and spinal orientation with respect to the vertical. Despite popular belief that lordotic lumbar angles are 'correct' for sitting, this was rarely adopted for 10 min sitting. In 10-min sitting, spinal angles flexed 24(7-9)deg at lumbar and 12(6-8)deg at thoracolumbar regions relative to standing (P < 0.001). When participants 'corrected' their sitting posture, their thoracolumbar angle 2(7)deg was similar to the angle in standing -1(6)deg (P = 1.00). Males were flexed at the lumbar angle relative to females for 10-min sitting, 'correct' sitting and standing, but showed no difference at the thoracolumbar region. PMID- 26476894 TI - Application of Opuntia ficus-indica in bioremediation of wastewaters. A critical review. AB - Heavy metal ion, pesticide and dye wastewaters cause severe ecological contamination with conventional treatment methods proving inadequate, unsuccessful or expensive to apply. Several biomaterials have recently been explored for the biosorption and biocoagulation-flocculation of pollutants from wastewaters. In the past 10 years, there has been an extensive research output on the use of biological materials such as agricultural wastes, chitosan, Moringa Oleifera, Eichhornia crassipes, bacteria, algae, Cactus plants etc. in environmental remediation. The present paper reviews the scattered information about the green technology involving Opuntia ficus-indica derived biomaterials in wastewater decontamination. Its characterization, physicochemical compositions, its application in biosorption and flocculation of dyes, pesticides and metallic species focussing on equilibrium, kinetics and thermodynamic properties are reviewed. The main results obtained in the depollution of a variety of contaminated wastewaters using cladodes, fruit pulp and peels mucilage and electrolytes show very high and promising pollutant maximum sorption capacities and removal percentages in the range -125.4-1000 mg/g and 0.31-2251.56 mg/g for the biosorption of dyes and metallic species respectively and removal % ranges of 50-98.7%, 11-93.62% and 17-100% for turbidity, chemical oxygen demand and heavy metals respectively by coagulation-flocculation process. The biomaterials proved to be efficient in pollutant removal that there is need to explore the scaling up of the study from the laboratory scale to community pilot plants and eventually to industrial levels. PMID- 26476895 TI - Brachybacterium horti sp. nov., isolated from garden soil. AB - A bacterial strain, THG-S15-4T, was isolated from garden soil taken from the Guro gu district of Seoul, Republic of Korea. Strain THG-S15-4T was Gram-stain positive, facultatively anaerobic, coccus-shaped and non-motile, forming white colonies. The strain grew optimally at 25-37 degrees C, at pH 7.0 and in the presence of 0-2.0 % (w/v) NaCl. Phylogenetic analysis, based on 16S rRNA gene sequences, showed that strain THG-S15-4T was affiliated to species of the genus Brachybacterium, and the most closely related species were Brachybacterium rhamnosum KCTC 9917 T (98.5 % sequence similarity) and Brachybacterium squillarum KCTC 19899T (96.9 % sequence similarity). The DNA-DNA relatedness between strain THG-S15-4T and B. rhamnosum KCTC 9917 T was found to be below 20.0 %. The DNA G+C content was determined to be 69.5 mol%. The major isoprenoid quinone detected was MK-7. Strain THG-S15-4T was characterized chemotaxonomically as having meso diaminopimelic acid in the cell-wall peptidoglycan. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, unidentified glycolipids and an unidentified polar lipid. The major fatty acids were found to be iso-C16 : 0 and anteiso-C15 : 0. The results of physiological and biochemical tests enabled strain THG-S15-4T to be differentiated phenotypically from species of the genus Brachybacterium with validly published names. Therefore, it is suggested that this newly isolated organism represents a novel species, for which the name Brachybacterium horti sp. nov. is proposed. The type strain is THG-S15 4T ( = KCTC 39563T = CCTCC AB 2015116T). PMID- 26476896 TI - Using Arden Syntax Medical Logic Modules to reduce overutilization of laboratory tests for detection of bacterial infections-Success or failure? AB - OBJECTIVE: Bacterial infections frequently cause prolonged intensive care unit (ICU) stays. Repeated measurements of the procalcitonin (PCT) biomarker are typically used for early detection and follow up of bacterial infections and sepsis, but those PCT measurements are costly. To avoid overutilization, we developed and evaluated a clinical decision support system (CDSS) in Arden Syntax which computes necessary and preventable PCT orders. METHODS: The CDSS implements a rule set based on the latest PCT value, the time period since this measurement, and the PCT trend scenario. We assessed the CDSS effects on the daily rate of ordered PCT tests within a prospective study having two ON and two OFF phases in a surgical ICU. In addition, we performed interviews with the participating physicians to investigate their experience with the CDSS advice. RESULTS: Prior to the deployment of the CDSS, 22% of the performed PCT tests were potentially preventable according to the rule set. During the first ON phase the daily rate of ordered PCT tests per patient decreased significantly from 0.807 to 0.662. In subsequent OFF, ON and OFF phases, however, PCT utilization reached again daily rates of 0.733, 0.803, and 0.792, respectively. The interviews demonstrated that the physicians were aware of the problem of PCT overutilization, which they primarily attributed to acute time constraints. The responders assumed that the majority of preventable measurements are indiscriminately ordered for patients during longer ICU stays. CONCLUSION: We observed an 18% reduction of PCT tests within the first four weeks of CDSS support in the investigated ICU. This reduction may have been influenced by raised awareness of the overutilization problem; the extent of this influence cannot be determined in our study design. No reduction of PCT tests could be observed during the second ON phase. The physician interviews indicated that time critical ICU situations can prevent extensive reflection about the necessity of individual tests. In order to achieve an enduring effect on PCT utilization, we will have to proceed to electronic order entry. PMID- 26476897 TI - Immobilized sialyltransferase fused to a fungal biotin-binding protein: Production, properties, and applications. AB - A beta-galactoside alpha2,6-sialyltransferase (ST) from the marine bacterium Photobacterium sp. JT-ISH-224 with a broad acceptor substrate specificity was fused to a fungal biotin-binding protein tamavidin 2 (TM2) to produce immobilized enzyme. Specifically, a gene for the fusion protein, in which ST from Photobacterium sp. JT-ISH-224 and TM2 were connected via a peptide linker (ST-L TM2) was constructed and expressed in Escherichia coli. The ST-L-TM2 was produced in the soluble form with a yield of approximately 15,000 unit/300 ml of the E. coli culture. The ST-L-TM2 was partially purified and part of it was immobilized onto biotin-bearing magnetic microbeads. The immobilized ST-L-TM2 onto microbeads could be used at least seven consecutive reaction cycles with no observed decrease in enzymatic activity. In addition, the optimum pH and temperature of the immobilized enzyme were changed compared to those of a free form of the ST. Considering these results, it was strongly expected that the immobilized ST-L-TM2 was a promising tool for the production of various kind of sialoligosaccharides. PMID- 26476899 TI - Crude Coal Tar and Ultraviolet (UV) A radiation (Modified Goeckerman Technique) in Treatment of Psoriasis. AB - Psoriasis is a chronic inflammatory dermatosis that has a substantial impact on the quality of life. Goeckerman's technique (GT) has been implemented for the treatment of psoriasis with high clearance rates and long periods of remission. The objective of this article was to evaluate the efficacy and safety of modified GT (crude coal tar 2.5% plus UVA) as an alternative therapeutic modality for psoriatic patients with skin types III-V. Twenty two patients with moderate, severe, and erythrodermic psoriasis were included in this study. All patients received modified GT (crude coal tar 2.5% plus UVA) six days per week for a period of 3 months. Assessment of the rate of reduction of psoriasis area severity index (PASI) was performed, as well as photographic documentation of each patient at baseline and after completion of therapy. There was a significant reduction in PASI scores after therapy in all patients (P=0.001). The rate of PASI reduction after therapy was >50% in 63.6% of patients; 27.3% of patients achieved >75% reduction and 9.1% of patients achieved 26-50% reduction. No serious side effects were reported in any of the patients. Modified GT is a safe and effective therapeutic option for patients with moderate and severe psoriasis. PMID- 26476898 TI - Leonine facies (LF) and mycosis fungoides (MF): A single-center study and systematic review of the literature. AB - BACKGROUND: Leonine facies (LF) is defined as displaying facial features similar to that of a lion with prominent convexities and furrowed creases. LF develops in a very small population of patients with cutaneous T-cell lymphoma. OBJECTIVE: We aimed to study the clinicopathologic features and overall prognosis associated with LF in patients with mycosis fungoides and Sezary syndrome. METHODS: We conducted a single-center retrospective study, reviewing 1338 patients with mycosis fungoides seen from 1987 to 2015 at a tertiary referral center for cutaneous T-cell lymphoma, and a systematic review of 14 patients in the literature. RESULTS: We identified 10 patients with mycosis fungoides who developed LF. Folliculotropism was seen in all patients with LF who had facial biopsy specimens. Radiation was a beneficial therapy. Complete remission was achieved in 1 patient and overall 5-year survival was 26%. Systematic review of 10 additional patients showed that all patients with LF, including ours, had stage-IV disease and some degree of blood involvement, but not all met criteria for Sezary syndrome. LIMITATIONS: This was a retrospective study with a small sample size. CONCLUSION: LF is associated with stage-IV cutaneous T-cell lymphoma, is often accompanied by folliculotropism and blood involvement, and can be treated with local electron beam therapy. PMID- 26476901 TI - Health-related Quality of Life in Children with Moderate to Severe Atopic Dermatitis. AB - Atopic dermatitis (AD) is a common, chronic skin disease in children that may affect their quality of life (QoL). The aim of this study was to assess QoL in children in Montenegro with moderate to severe AD. A cross-sectional study was conducted at the Clinic of Dermatology and Venereology, Clinical Center of Montenegro, Podgorica, between January and December 2014. The study group included 200 children (97 boys and 103 girls) with the diagnosis of AD. The Infants' Dermatitis Quality of Life Index (IDQOL) and the Children's Dermatology Life Quality Index (CDLQI) were used to determine QoL for 90 infants (<4 years old) and 110 children (4-16 years old), respectively. Severity of disease was measured by the three-item severity (TIS) score. The mean scores were 14.38+/ 5.57 for IDQOL and 18.43+/-4.88 for CDLQI. A positive correlation was observed between AD clinical severity (TIS) and all the items of IDQOL with Spearman's correlation coefficient (rho) ranging from 0.31 to 0.74, and between AD clinical severity and all domains of CDLQI (rho=0.31-0.69). The impact of AD on health related quality of life (HRQoL) was more severe for younger girls, but only in some domains (IDQOL), and for older boys (CDLQI). The linguistically validated Serbian versions of both IDQOL and CDLQI questionnaires showed good internal consistency with Cronbach's alpha values of 0.88 and 0.73, respectively. In conclusion, our results demonstrate that AD has a great impact on QoL. A positive correlation between clinical severity and quality of life was seen. PMID- 26476900 TI - Relationship Between Serum Fetuin-A Levels and Carotid Intima-media Thickness in Turkish Patients with Mild to Moderate Psoriasis. A Case-control Study. AB - Previous studies have associated severe psoriasis and psoriatic arthritis with an increased risk of atherosclerosis. However, the association between patients with mild-to-moderate plaque-type psoriasis and atherosclerosis has yet to be studied in depth. This study investigates a) possible correlations between carotid intima media thickness (CIMT) and serum fetuin-A levels in patients with mild-to moderate psoriasis and b) correlations between psoriasis severity index (PASI) and fetuin-A levels. The latter correlation was recently reported to be important for wound healing and vascular calcification. In this prospective study, a total of 70 patients with mild-to-moderate psoriasis and 66 control participants were included. PASI, CIMT, and serum fetuin-A levels were examined in all patients. Although the difference in fetuin-A values was not statistically significant between patients with mild-to-moderate plaque-type psoriasis and control groups (P=0.401), the CIMT levels in the psoriasis group were significantly higher than the control group (P=0.002). There were no correlations among fetuin-A levels, CIMT, and PASI. This study establishes an association between mild to moderate psoriasis and atherosclerosis. This study also concludes that, similarly to patients with severe psoriasis, CIMT levels are a better indicator of cardiovascular risk than serum fetuin-A levels in patients diagnosed with mild-to moderate plaque-type psoriasis. PMID- 26476902 TI - Clinical Features, Dermoscopic Patterns, and Histological Diagnostic Model for Melanocytic Tumors of Uncertain Malignant Potential (MELTUMP). AB - Cutaneous melanocytic lesions with atypical histological features can be difficult to categorize as benign or malignant. In the diagnosis of melanocytic lesions, the melanocytic tumor of uncertain malignant potential (MELTUMP) category has been widely used. Although one may favor a benign or malignant interpretation, a definitive diagnosis is not always possible, and long term clinical follow-up remains the only true evidence of biological behavior. We report 14 cases of MELTUMP with expert second opinion. Clinical pictures were available in 8 cases; dermoscopy was available in 5 cases. Accurate guidelines are delineated in the formulation of the diagnosis. We think that the histological diagnosis should be accompanied by a note in which the pathologist describes the histological pattern that has generated diagnostic uncertainty. Since the MELTUMP term does not exclude the malignant nature of the lesion, all microstaging attributes for melanoma should be added. Moreover, superficial atypical melanocytic proliferation of uncertain significance (SAMPUS) and MELTUMP categories should be included in the WHO classification of melanocytic tumors of the skin. The role of sentinel lymph node biopsy in MELTUMP has not yet been established. Recent studies have looked at concurrent tumor deposits in lymph nodes of MELTUMP, mostly of atypical Spitzoid lesions, and shown that these lesions rarely progress to overt malignancy. In our study, sentinel node metastasis was found in only one case. The follow-up period of this case and of the others has shown that the clinical outcome of MELTUMP tends to be favorable. PMID- 26476903 TI - Scabies in a Patient with Rheumatoid Arthritis Treated with Adalimumab - A Case Report. AB - Rheumatoid arthritis is a chronic systemic inflammatory disease characterized by synovitis, erosions, and destruction of affected joints. If untreated, it leads to severe disability and premature mortality. Tumor necrosis factor alpha (TNF alpha) inhibitors are biological drugs used in treatment of rheumatoid arthritis. Possible side effects include skin allergic reactions, which, if generalized, are the reason for discontinuation of the drug. We report the case of a 46-year-old female patient with rheumatoid arthritis who presented with pruritus and erythematous papular exanthema after administration of the second dose of adalimumab. At first, we suspected a drug hypersensitivity reaction. As the signs and symptoms persisted for 2 months after discontinuation of adalimumab and despite continuous administration of antihistamines and glucocorticoids, further work-up was performed, and scabies was diagnosed. The patient was treated with topical 10% crotamiton. The symptoms were persistent and additional applications of the preparation were needed. After clinical remission of scabies, treatment of active rheumatoid arthritis with adalimumab was restarted without any complications. PMID- 26476904 TI - Tinea Incognita in a Patient with Crest Syndrome: Case Report. AB - Tinea incognita is a dermatophytic infection that is difficult to diagnose, usually modified by inappropriate topical or systemic corticosteroid therapy. We report an extensive case of tinea incognita caused by the zoophilic dermatophyte Trichophyton mentagrophytes (var. granulosa) in a 49-year-old female patient with CREST (Calcinosis; Raynaud phenomenon; Esophageal involvement; Sclerodactyly; Teleangiectasia) syndrome. Immunocompromised patients, as well as patients with keratinization disorders, seem to be especially susceptible to dermatophytic infections with atypical clinical presentation that is sometimes bizarre and difficult to recognize. Therefore, close monitoring and mycological skin examination is recommended in order to avoid misdiagnosis and to give the patient the best chance of recovery. PMID- 26476905 TI - Nodular Prurigo Associated with Mycosis Fungoides - Case Report. AB - Mycosis fungoides (MF) is the most common type of cutaneous lymphoma and accounts for approximately 50% of all lymphomas arising primarily in the skin. The three types of MF lesions are patches, plaques, and tumors, according to which the disease is traditionally divided into three clinical stages. The clinical course can be protracted and take years or decades. In the final stage, MF evolves to a systemic form of the disease. Nodular prurigo (NP) is still a condition of unknown etiology characterized by papulonodular eruption and intense pruritus. Multiple diseases, including dermatological, systemic, and psychiatric diseases, have been assumed to cause NP. Pruritic skin lesions have been known to precede clinically evident B and T cell lymphomas for years. In the literature, pruritus and NP have been reported in patients affected by systemic Hodgkin and non Hodgkin lymphomas. Only two cases of cutaneous lymphoma as underlying disease in patients with PN have been reported in the literature. We report a rare case of a patient with concomitant non-Hodgkin skin lymphoma - MF and NP. Our female patient with a 10-year history of MF stage IIb during the last three years had been presenting for regular check-up with itchy, newly formed, rarely disseminated nodules 5-8 mm in diameter on the forearms and lower legs. Sharply limited erythematosquamous, slightly infiltrated foci (as part of MF as the underlying disease) were visible on the trunk and extremities. Extracutaneous involvement of MF was excluded. We performed a biopsy on a nodule from the lower leg to rule out tumor stage MF; the biopsy confirmed NP. We conclude that prurigo nodules should not be confused with tumor stage MF. NP is a therapeutic challenge for any dermatologist. Any underlying diseases should be treated first. PMID- 26476906 TI - Advanced Pyoderma Gangrenosum Previously Treated as Squamous Cell Carcinoma. AB - Pyoderma gangrenosum is a rare, neutrophilic ulcerative skin disease of unknown etiology often associated with an underlying systemic disease. We present a case of a pyoderma gangrenosum that was initially misdiagnosed and treated as squamous cell carcinoma in another hospital. Multiple surgical treatments triggered postoperative exacerbations and further rapid progression of the lesions. History of pathergy, clinical findings, and histopathological features examined at our Department indicated pyoderma gangrenosum. The diagnosis was confirmed by excluding other diseases that could cause similar-appearing cutaneous lesions. No associated underlying disease was determined. After the diagnosis was confirmed, corticosteroid therapy was initiated until complete remission of ulcerations. PMID- 26476907 TI - Successful Management of a Chronic Refractory Leg Ulcer in an Adolescent with Sickle Cell Anemia. AB - Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by a wide range of clinical manifestations. Chronic leg ulcers are a disabling complication with repercussions on the quality of life. We report the case of a 14-year-old girl with a diagnosis of SCD who developed a chronic leg ulcer that was successfully treated with a multi-disciplinary approach, including local and systemic therapies. The role of different treatments, in particular low molecular weight heparin, in the refractory chronic leg ulcer healing process will be discussed. PMID- 26476908 TI - Darier's Disease with Esophageal Involvement. PMID- 26476909 TI - A Case of Iatrogenic Cutaneous Lipomatosis. PMID- 26476910 TI - Enoxaparin-induced Skin Necrosis. PMID- 26476911 TI - Atypical Spitz Tumor of Uncertain Biologic Potential with Inopportune Localization in a 7-year-old Boy. PMID- 26476912 TI - Familial Case of White Sponge Nevus - Diagnosis and Therapeutical Challenges. PMID- 26476913 TI - Recipient Site Necrosis After Tumescent Infiltration with Adrenaline in Hair Transplantation. PMID- 26476914 TI - IN MEMORIAM OF PROFESSOR MLADEN RUPEC. PMID- 26476915 TI - Lungworms in Alpine ibex (Capra ibex) in the eastern Alps, Italy: An ecological approach. AB - Host-parasite relationships have been frequently investigated in mountain dwelling ungulates, though mostly focusing on gastrointestinal nematodes. On the contrary, very few studies were conducted on broncopulmonary nematodes, which may result in severe parenchymal lesions and act as predisposing factor for multifactorial pneumonia. The epidemiological and ecological features of lungworms infecting an Alpine ibex population in the Eastern Alps, Italy, were non-invasively investigated by means of a modified Baermann technique with an original quantitative methodology. Out of a total of 269 samples collected monthly from July to November 2013 and from July to October 2014, 212 (78.8%) were positive for Muellerius and 26 (9.7%) for Protostrongylus, whereas Neostrongylus and Cystocaulus were less prevalent (4.1% and 0.7%, respectively). None of the investigated samples tested positive for dictyocaulids. The genus Muellerius showed the highest larval output intensity (134.2 L1/g), followed by Protostrongylus with 33.8 L1/g. A contrasting age-related pattern of Muellerius and Protostrongylus was revealed, with the former significantly more prevalent and abundant in adult animals, while the latter in kids. Due to the limited accessibility of the study area during winter and spring, it was difficult to describe clear seasonal trends in larval output, although Muellerius showed a minimum in the late summer and a rise in the autumn. The newly developed diagnostic method showed a fair repeatability, thus representing an interesting tool to investigate the ecology of lungworms in protected species, such as the A. ibex. Based on results, ibex in the Marmolada massif seem to have an ecologically stable relationship with their lungworm community. PMID- 26476916 TI - DNA sequence analyses reveal co-occurrence of novel haplotypes of Fasciola gigantica with F. hepatica in South Africa and Zimbabwe. AB - The aim of this study was to identify and determine the genetic diversity of Fasciola species in cattle from Zimbabwe, the KwaZulu-Natal and Mpumalanga provinces of South Africa and selected wildlife hosts from Zimbabwe. This was based on analysis of DNA sequences of the nuclear ribosomal internal transcribed spacer (ITS1 and 2) and mitochondrial cytochrome oxidase 1 (CO1) regions. The sample of 120 flukes was collected from livers of 57 cattle at 4 abattoirs in Zimbabwe and 47 cattle at 6 abattoirs in South Africa; it also included three alcohol-preserved duiker, antelope and eland samples from Zimbabwe. Aligned sequences (ITS 506 base pairs and CO1 381 base pairs) were analyzed by neighbour joining, maximum parsimony and Bayesian inference methods. Phylogenetic trees revealed the presence of Fasciola gigantica in cattle from Zimbabwe and F. gigantica and Fasciola hepatica in the samples from South Africa. F. hepatica was more prevalent (64%) in South Africa than F. gigantica. In Zimbabwe, F. gigantica was present in 99% of the samples; F. hepatica was found in only one cattle sample, an antelope (Hippotragus niger) and a duiker (Sylvicapra grimmia). This is the first molecular confirmation of the identity Fasciola species in Zimbabwe and South Africa. Knowledge on the identity and distribution of these liver flukes at molecular level will allow disease surveillance and control in the studied areas. PMID- 26476917 TI - Modular Integration of Upconverting Nanocrystal-Dendrimer Composites for Folate Receptor-Specific NIR Imaging and Light-Triggered Drug Release. AB - Upconversion nanocrystals (UCNs) display near-infrared (NIR)-responsive photoluminescent properties for NIR imaging and drug delivery. The development of effective strategies for UCN integration with other complementary nanostructures for targeting and drug conjugation is highly desirable. This study reports on a core/shell-based theranostic system designed by UCN integration with a folate (FA)-conjugated dendrimer for tumor targeting and with photocaged doxorubicin as a cytotoxic agent. Two types of UCNs (NaYF4:Yb/Er (or Yb/Tm); diameter = ~50 to 54 nm) are described, each displaying distinct emission properties upon NIR (980 nm) excitation. The UCNs are surface modified through covalent attachment of photocaged doxorubicin (ONB-Dox) and a multivalent FA-conjugated polyamidoamine (PAMAM) dendrimer G5(FA)6 to prepare UCN@(ONB-Dox)(G5FA). Surface plasmon resonance experiments performed with G5(FA)6 dendrimer alone show nanomolar binding avidity (KD = 5.9 * 10(-9) M) to the folate binding protein. This dendrimer binding corresponds with selective binding and uptake of UCN@(ONB Dox)(G5FA) by FAR-positive KB carcinoma cells in vitro. Furthermore, UCN@(ONB Dox)(G5FA) treatment of FAR(+) KB cells inhibits cell growth in a light dependent manner. These results validate the utility of modularly integrated UCN-dendrimer nanocomposites for cell type specific NIR imaging and light-controlled drug release, thus serving as a new theranostic system. PMID- 26476919 TI - Development of a label-free gold nanoparticle-based colorimetric aptasensor for detection of human estrogen receptor alpha. AB - The increasing demand for easily available and low-cost diagnostics has fuelled the development of aptasensors as platforms for rapid, sensitive, and point-of care testing of target analytes. Recently, gold nanoparticle (AuNP)-based aptasensors have attracted wide recognition owing to their color transition properties which allow real-time rapid sensing of targets. In this study, we utilized the color transition property of aptamer-functionalized AuNPs to detect and quantify estrogen receptor alpha (ERalpha), a key biomarker protein in breast cancer. We found that the coating of AuNPs with unmodified ERalpha-RNA aptamer (GGGGUCAAGGUGACCCC) makes them resistant to salt-induced aggregation. However, addition of ERalpha to the aptamer-protected AuNPs results in their spontaneous aggregation as evident from a color transition from wine red to deep blue. On the basis of this, we developed an ERalpha aptasensor, with limits of detection and quantification of 0.64 and 2.16 ng/mL, respectively; the aptasensor can efficiently detect and quantify ERalpha in a working range of 10 ng/mL-5MUg/mL protein. Validation of the aptasensor on cellular extracts of ERalpha-positive MCF-7 and ERalpha-deficient MDA-MB-231 breast cancer cells showed a target selective response in ERalpha-positive samples but not in cellular extracts of ERalpha-deficient breast cancer cells. Further, the small size and simple fabrication chemistry of aptamers provide an additional benefit to make the ERalpha aptasensor a potentially useful and cost-effective tool in point-of-care analyses of ERalpha. PMID- 26476920 TI - In situ ionic liquid dispersive liquid-liquid microextraction and direct microvial insert thermal desorption for gas chromatographic determination of bisphenol compounds. AB - A new procedure based on direct insert microvial thermal desorption injection allows the direct analysis of ionic liquid extracts by gas chromatography and mass spectrometry (GC-MS). For this purpose, an in situ ionic liquid dispersive liquid-liquid microextraction (in situ IL DLLME) has been developed for the quantification of bisphenol A (BPA), bisphenol Z (BPZ) and bisphenol F (BPF). Different parameters affecting the extraction efficiency of the microextraction technique and the thermal desorption step were studied. The optimized procedure, determining the analytes as acetyl derivatives, provided detection limits of 26, 18 and 19 ng L(-1) for BPA, BPZ and BPF, respectively. The release of the three analytes from plastic containers was monitored using this newly developed analytical method. Analysis of the migration test solutions for 15 different plastic containers in daily use identified the presence of the analytes at concentrations ranging between 0.07 and 37 MUg L(-1) in six of the samples studied, BPA being the most commonly found and at higher concentrations than the other analytes. PMID- 26476918 TI - Susceptibility to quantum dot induced lung inflammation differs widely among the Collaborative Cross founder mouse strains. AB - Quantum dots (QDs) are engineered semiconductor nanoparticles with unique physicochemical properties that make them potentially useful in clinical, research and industrial settings. However, a growing body of evidence indicates that like other engineered nanomaterials, QDs have the potential to be respiratory hazards, especially in the context of the manufacture of QDs and products containing them, as well as exposures to consumers using these products. The overall goal of this study was to investigate the role of mouse strain in determining susceptibility to QD-induced pulmonary inflammation and toxicity. Male mice from 8 genetically diverse inbred strains (the Collaborative Cross founder strains) were exposed to CdSe-ZnS core-shell QDs stabilized with an amphiphilic polymer. QD treatment resulted in significant increases in the percentage of neutrophils and levels of cytokines present in bronchoalveolar lavage fluid (BALF) obtained from NOD/ShiLtJ and NZO/HlLtJ mice relative to their saline (Sal) treated controls. Cadmium measurements in lung tissue indicated strain-dependent differences in disposition of QDs in the lung. Total glutathione levels in lung tissue were significantly correlated with percent neutrophils in BALF as well as with lung tissue Cd levels. Our findings indicate that QD-induced acute lung inflammation is mouse strain dependent, that it is heritable, and that the choice of mouse strain is an important consideration in planning QD toxicity studies. These data also suggest that formal genetic analyses using additional strains or recombinant inbred strains from these mice could be useful for discovering potential QD-induced inflammation susceptibility loci. PMID- 26476921 TI - Analytical strategy to investigate 3,4-methylenedioxypyrovalerone (MDPV) metabolites in consumers' urine by high-resolution mass spectrometry. AB - The potential of high-resolution mass spectrometry (HRMS) for the investigation of human in vivo metabolism of 3,4-methylenedioxypyrovalerone (MDPV) using urine collected from a consumer (this is, in non-controlled experiments) has been investigated. As a control sample was not available, the common approach based on the comparison of a control/blank sample and samples collected after drug intake could not be used. Alternatively, an investigation based on common fragmentation pathways was applied, assuming that most metabolites share some fragments with the parent drug. An extension of this approach was also applied based on the fragmentation pathway of those metabolites identified in urine samples in the first step. The use of MS(E) experiments (sequential acquisition of mass spectra at low and high collision energy) has been crucial to this aim as it allowed promoting fragmentation in the collision cell without any previous precursor ion selection. MDPV belongs to the group of new psychoactive substances (NPS), being known as the "cannibal drug". This substance is being abused more and more and is associated with dangerous side effects. The human metabolites (both phase I and phase II) were detected and tentatively identified by accurate mass full-spectrum measurements using ultra-high performance liquid chromatography coupled to hybrid quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Following this strategy, up to 10 phase I metabolites, together with some glucuronides and sulphates, were detected and tentative structures were proposed. Several compounds identified in this work have not been previously reported in the literature. PMID- 26476922 TI - Quantification and characterization of alkaloids from roots of Rauwolfia serpentina using ultra-high performance liquid chromatography-photo diode array mass spectrometry. AB - A new UHPLC-UV method has been developed for the simultaneous analysis of seven alkaloids [ajmaline (1), yohimbine (2), corynanthine (3), ajmalicine (4), serpentine (5), serpentinine (6), and reserpine (7)] from the root samples of Rauwolfia serpentina (L.) Benth. ex Kurz. The chromatographic separation was achieved using a reversed phase C18 column with a mobile phase of water and acetonitrile, both containing 0.05% formic acid. The seven compounds were completely separated within 8 min at a flow rate of 0.2 mL/min with a 2-MUL injection volume. The method is validated for linearity, accuracy, repeatability, limits of detection (LOD), and limits of quantification (LOQ). Seven plant samples and 21 dietary supplements claiming to contain Rauwolfia roots were analyzed and content of total alkaloids (1-7) varied, namely, 1.57-12.1 mg/g dry plant material and 0.0-4.5 mg/day, respectively. The results indicated that commercial products are of variable quality. The developed analytical method is simple, economic, fast, and suitable for quality control analysis of Rauwolfia samples and commercial products. The UHPLC-QToF-mass spectrometry with electrospray ionization (ESI) interface method is described for the confirmation and characterization of alkaloids from plant samples. This method involved the detection of [M + H](+) or M(+) ions in the positive mode. PMID- 26476923 TI - Atomic force microscopy based investigations of anti-inflammatory effects in lipopolysaccharide-stimulated macrophages. AB - A new method based on atomic force microscopy (AFM) was developed to investigate the anti-inflammatory effects of drugs on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The LPS-stimulated RAW264.7 macrophage cell line is a widely used in vitro cell model for the screening of anti-inflammatory drugs or the study of anti-inflammatory mechanisms. In this work, the inhibitory effects of dexamethasone and quercetin on LPS-CD14 receptor binding in RAW264.7 macrophages was probed by LPS-functionalized tips for the first time. Both dexamethasone and quercetin were found to inhibit LPS-induced NO production, iNOS expression, IkappaBalpha phosphorylation, and IKKalpha/beta phosphorylation in RAW264.7 macrophages. The morphology and ultrastructure of RAW264.7 macrophages were determined by AFM, which indicated that dexamethasone and quercetin could inhibit LPS-induced cell surface particle size and roughness increase in RAW264.7 macrophages. The binding of LPS and its receptor in RAW264.7 macrophages was determined by LPS-functionalized AFM tips, which demonstrated that the binding force and binding probability between LPS and CD14 receptor on the surface of RAW264.7 macrophages were also inhibited by dexamethasone or quercetin treatment. The obtained results imply that AFM, which is very useful for the investigation of potential targets for anti-inflammatory drugs on native macrophages and the enhancement of our understanding of the anti-inflammatory effects of drugs, is expected to be developed into a promising tool for the study of anti-inflammatory drugs. PMID- 26476924 TI - Leucine-induced anabolic-catabolism: two sides of the same coin. AB - Leucine is an essential nutrient with potent abilities to stimulate both muscle protein synthesis as well as increased oxidative metabolism supported by mitochondrial biogenesis. Few studies have simultaneously investigated anabolic and catabolic responses following leucine treatment with the exception of master regulator of cellular energetics, AMPK. The unique ability of leucine to stimulate both favorable anabolic and catabolic processes in highly metabolically active tissues suggests leucine consumption/supplementation may provide benefits beyond hypertrophic gains. This review highlights original investigations reporting leucine's ability to stimulate both anabolic and catabolic processes in muscle. Additionally, this report discusses potential explanations for the simultaneous activation of two seemingly opposing processes, as well as the interplay between them. The role of cellular energetics is of undeniable importance in sustaining increased protein synthesis following leucine administration; however, the dependence of leucine-induced mitochondrial biogenesis on heightened energy expenditure from elevated protein synthesis remains to be defined experimentally. PMID- 26476925 TI - Id1 modulates endothelial progenitor cells function through relieving the E2-2 mediated repression of FGFR1 and VEGFR2 in vitro. AB - The migration and proliferation of EPCs are crucial for re-endothelialization in vascular repair and development. Id1 has a regulatory role in the regulation of EPCs migration and proliferation. Based on these findings, we hypothesized that Id1 plays a regulatory role in modulating the migration and proliferation of EPCs by interaction with other factors. Herein, we report that the Id1 protein and E box protein E2-2 regulate EPCs function with completely opposite effects. Id1 plays a positive role in the regulation of EPC proliferation and migration, while endogenous E2-2 appears to be a negative regulator. Immunoprecipitation and immunofluorescence assay revealed that the Id1 protein interacts and co-localizes with the E2-2 protein in EPCs. Further, endogenous E2-2 protein was found to block EPCs function via the inhibition of FGFR1 and VEGFR2 expression. The overexpression and silencing of Id1 have no direct regulatory role on VEGFR2 and FGFR1 expression. On the other hand, Id1 relieves the E2-2-mediated repression of FGFR1 and VEGFR2 expression to modulate EPCs proliferation, migration, and tube formation in vitro. In summary, we demonstrated that Id1 and E2-2 are critical regulators of EPCs function in vitro. Id1 interacts with E2-2 and relieves the E2 2-mediated repression of FGFR1 and VEGFR2 expression to modulate EPCs functions. Id1 and E2-2 may represent novel therapeutic targets for re-endothelialization in vascular damage and repair. PMID- 26476926 TI - Macular function measured by binocular mfERG and compared with macular structure in healthy children. AB - PURPOSE: To create normative data in children from binocular multifocal ERG (mfERG) recordings and compare results with the macular thickness. METHODS: Forty nine 5- to 15-year-old healthy, full-term children were examined with Espion Multifocal System, using DTL electrodes. The stimulus matrix consisted of 37 hexagonal elements. Amplitudes, implicit times and response densities (presented in three rings) of the first-order component P1 were analyzed. Measurements of macular thickness were performed with spectral-domain Cirrus OCT. RESULTS: There were no significant differences between right and left eyes regarding mfERG recordings. Median P1 implicit times of Rings 1-3 of the 46 right eyes were 30.0, 30.0 and 30.8 ms and response densities 20.5, 10.9 and 7.6 nV/deg(2), respectively. Implicit time was longer in boys than in girls (p = 0.009, 0.039, 0.005 in Rings 1-3) and was correlated with age (r s = 0.417, 0.316, 0.274 in Rings 1-3). Implicit time in Ring 1 correlated significantly with the inner circle of the OCT measurements (p = 0.014). CONCLUSION: Binocular mfERG with DTL electrodes is a reliable test of the central macular function in children and correlates with macular structure. As previously not shown, there was a significant difference in implicit time between boys and girls. PMID- 26476927 TI - Clinical evaluation of the xDP output compression strategy for cochlear implants. AB - Technological advances in the domain of digital signal processing adapted to cochlear implants (CI) are partially responsible for the ever-improving outcomes observed with this neural prosthesis. The goal of the present study was to evaluate audiometric outcomes with a new signal processing strategy implemented in Oticon Medical-Neurelec cochlear implant systems, the xDP strategy. The core of this approach is a preset-based back-end output compression system, modulating a multi-channel transfer function depending on the intensity and information content of input sounds. Twenty adult CI patients, matched for age and CI experience, were included in this study. Pure-tone thresholds and vocal audiometry scores were measured with their former signal processing strategy and with xDP. Speech perception was assessed using dissyllabic words presented in quiet, at different intensity levels: 40, 55, 70, and 85 dB SPL, and in a cocktail party noise at a signal-to-noise ratio of +10 dB. Results with the xDP strategy showed, as awaited, no major modification of pure-tone thresholds. A global increase of speech perception scores was observed after a 1-month habituation period, with significant improvements for speech perception in quiet for moderate (55 dB SPL), loud speech sounds (85 dB SPL), and speech-in-noise comprehension. Subjective signal quality assessment showed a preference for Crystalis(xDP) over the former strategy. These results allow the quantification of improvements provided by the xDP signal processing strategy. PMID- 26476928 TI - Graph-guided joint prediction of class label and clinical scores for the Alzheimer's disease. AB - Accurate diagnosis of Alzheimer's disease and its prodromal stage, i.e., mild cognitive impairment, is very important for early treatment. Over the last decade, various machine learning methods have been proposed to predict disease status and clinical scores from brain images. It is worth noting that many features extracted from brain images are correlated significantly. In this case, feature selection combined with the additional correlation information among features can effectively improve classification/regression performance. Typically, the correlation information among features can be modeled by the connectivity of an undirected graph, where each node represents one feature and each edge indicates that the two involved features are correlated significantly. In this paper, we propose a new graph-guided multi-task learning method incorporating this undirected graph information to predict multiple response variables (i.e., class label and clinical scores) jointly. Specifically, based on the sparse undirected feature graph, we utilize a new latent group Lasso penalty to encourage the correlated features to be selected together. Furthermore, this new penalty also encourages the intrinsic correlated tasks to share a common feature subset. To validate our method, we have performed many numerical studies using simulated datasets and the Alzheimer's Disease Neuroimaging Initiative dataset. Compared with the other methods, our proposed method has very promising performance. PMID- 26476930 TI - The biochemistry, enzymology and pharmacology of non-vitamin K anticoagulant drug reversal agents and antidotes. PMID- 26476929 TI - Developmental changes in the morphology of mouse hypoglossal motor neurons. AB - Hypoglossal motor neurons (XII MNs) innervate tongue muscles important in breathing, suckling and vocalization. Morphological properties of 103 XII MNs were studied using NeurobiotinTM filling in transverse brainstem slices from C57/Bl6 mice (n = 34) from embryonic day (E) 17 to postnatal day (P) 28. XII MNs from areas thought to innervate different tongue muscles showed similar morphology in most, but not all, features. Morphological properties of XII MNs were established prior to birth, not differing between E17-18 and P0. MN somatic volume gradually increased for the first 2 weeks post-birth. The complexity of dendritic branching and dendrite length of XII MNs increased throughout development (E17-P28). MNs in the ventromedial XII motor nucleus, likely to innervate the genioglossus, frequently (42 %) had dendrites crossing to the contralateral side at all ages, but their number declined with postnatal development. Unexpectedly, putative dendritic spines were found in all XII MNs at all ages, and were primarily localized to XII MN somata and primary dendrites at E18-P4, increased in distal dendrites by P5-P8, and were later predominantly found in distal dendrites. Dye-coupling between XII MNs was common from E18 to P7, but declined strongly with maturation after P7. Axon collaterals were found in 20 % (6 of 28) of XII MNs with filled axons; collaterals terminated widely outside and, in one case, within the XII motor nucleus. These results reveal new morphological features of mouse XII MNs, and suggest that dendritic projection patterns, spine density and distribution, and dye-coupling patterns show specific developmental changes in mice. PMID- 26476932 TI - PKCs in thrombus formation. AB - The protein kinase C (PKC) family has been implicated in several physiological processes regulating platelet activation. Each isoform of PKC expressed on platelets, may have a positive and/or negative role depending on the nature and concentration of the agonist. Mice lacking PKCalpha show much reduced thrombus formation in vivo, while PKCtheta(-/-) showed inhibition of aggregation in response to PAR4. On the other hand, PKCdelta by associating with Fyn, inhibits platelet aggregation. In addition, PKCbeta by interacting with its receptor RACK1 has been implicated in the primary phases of signaling via the alphaIIbbeta3 and finally PKCE appears to be involved in platelet function downstream GPVI. The present review discusses the latest observations relevant to the role of individual PKC isoforms in platelet activation and thrombus formation. PMID- 26476933 TI - Improving Immunization Rates at an Urban Charter School. AB - A midwestern children's hospital operates a school-based clinic in an urban charter school. The clinic provides the expertise and knowledge of an advanced practice registered nurse (APRN) and offers a structure permitting care coordination and continuity. The APRN created a systematic process for immunization record maintenance. This process identifies students needing recommended vaccines for their age group and provides opportunities for students to update their record or receive immunizations. This initiative demonstrated that improved vaccination compliance can be sustained through systematic methods to identify immunization gaps and support the administration of necessary vaccines. PMID- 26476931 TI - Double Bond Position Plays an Important Role in Delta-9 Desaturation and Lipogenic Properties of Trans 18:1 Isomers in Mouse Adipocytes. AB - The objective of this research was to study the delta-9 desaturation of individual trans (t) fatty acids that can be found in ruminant fat or partially hydrogenated vegetable oils (PHVO) and determine their effects on lipogenic gene expression in adipocytes. It was hypothesized that delta-9 desaturation and lipogenic properties of t-18:1 isomers depend on the position of double bond. Differentiated 3T3-L1 adipocytes were treated with 200 uM of t6-18:1, t9-18:1, t11-18:1, t13-18:1 or t16-18:1, cis (c)-9 18:1 or bovine serum albumin (BSA) vehicle control for 48 h. Cells were then harvested for fatty acid and gene expression analyses using gas chromatography and quantitative PCR respectively. Among t-18:1 isomers, t13-18:1 and t11-8:1 had the greatest percent delta-9 desaturation (44 and 41 % respectively) followed by t16-18:1 and t6-18:1 (32 and 17 % respectively), while c9-18:1 and t9-18:1 did not undergo delta-9 desaturation. Trans9-18:1 up-regulated (P < 0.05) the expression of lipogenic genes including fatty acid synthase and stearoyl-CoA desaturase-1 (P < 0.05), whereas the expression of these genes were not affected with other t-18:1 isomers (P > 0.05). Consistent with gene expression results, t9-18:1 increased the de novo lipogenic index (16:0/18:2n-6) compared with control cells and increased delta-9 desaturation index (c9-16:1/18:0) compared to other t-18:1 isomers (P < 0.05). The current study provides further evidence that the predominant trans fatty acid in PHVO (t9-18:1) has isomer specific lipogenic properties. PMID- 26476934 TI - The Persian version of satisfaction assessment module of Orthotics and Prosthetics Users' Survey. AB - BACKGROUND: Orthotics and Prosthetics User's Survey (OPUS) was developed to measure patient satisfaction in Prosthetic and Orthotic (P&O) field. OBJECTIVE: To translate the satisfaction assessment module of OPUS (OPUS-SM) into Persian language (Persian OPUS-SM) and investigate its psychometric properties. METHODS: For cross-cultural adaptation of the OPUS-SM, the guideline suggested by the World Health Organization was recruited. A sample of 116 Persian-speaking people who received P&O devices and services, participated in this study. During the first session, participants filled out the Persian OPUS-SM and the Visual Analog Scale (VAS) regarding their satisfaction from delivered devices and services. Drawing from the above sample of 116 participants, 41 participants retook the Persian OPUS-SM 5-7 days after their first time. The results of the first and second administration sessions were analyzed to assess internal consistency, test retest reliability, item-subscale correlation, minimal detectable change, floor and ceiling effects, criterion validity, and dimensionality of the Persian OPUS SM. RESULTS: The Cronbach's alphas of the Persian OPUS-SM were 0.71 and 0.89 for device and service satisfaction subscales, respectively. The intraclass correlation coefficients were 0.76 and 0.90 for device and service satisfaction subscales, respectively. The SEM and MDC for device satisfaction were 6.21 and +/ 17.21, respectively. The SEM and MDC for service satisfaction were 2.25 and +/ 6.22, respectively. There was a strong correlation between VAS and satisfaction subscales of the Persian OPUS-SM. Dimensionality assessment revealed that Persian OPUS-SM is a unidimensional measure. CONCLUSIONS: The adapted and translated Persian OPUS-SM is a reliable and validated measure. PMID- 26476935 TI - Men with disabilities - A cross sectional survey of health promotion, social inclusion and participation at community Men's Sheds. AB - BACKGROUND: The intersections between chronicity, disability and social inequality are well understood. Novel ways to counter the social determinants of health and disability are needed. Men's Sheds are a community space where men can participate in a range of shared activities and potentially experience a health and social benefits. OBJECTIVE: This cross-sectional survey was conducted to inform future research by determining who attended Men's Sheds and the range of health, social, community, and educational activities undertaken there. This paper explores the membership of people with disabilities (PWD) at Men's Sheds and the factors that predict their membership. METHODS: An online survey link was sent to all known Men's Sheds internationally in 2012. Data were analyzed using descriptive and inferential (univariate and multivariate) statistics. RESULTS: 32.2% of international sheds and 29% of Australian sheds specifically targeted the inclusion of PWD. 80% of these sheds have significantly more members with disabilities than sheds who do no target PWD. Factors associated with greater membership of PWD included the provision of transport, social outings and promoting occupational skills. CONCLUSIONS: PWD are being encouraged to join and are joining Men's Sheds. This is significant as the value of participation and inclusion toward better health and wellbeing is well known. Men's Sheds offer a community space where the social determinants of chronicity and disability can potentially be countered. PMID- 26476936 TI - Smart sampling and incremental function learning for very large high dimensional data. AB - Very large high dimensional data are common nowadays and they impose new challenges to data-driven and data-intensive algorithms. Computational Intelligence techniques have the potential to provide powerful tools for addressing these challenges, but the current literature focuses mainly on handling scalability issues related to data volume in terms of sample size for classification tasks. This work presents a systematic and comprehensive approach for optimally handling regression tasks with very large high dimensional data. The proposed approach is based on smart sampling techniques for minimizing the number of samples to be generated by using an iterative approach that creates new sample sets until the input and output space of the function to be approximated are optimally covered. Incremental function learning takes place in each sampling iteration, the new samples are used to fine tune the regression results of the function learning algorithm. The accuracy and confidence levels of the resulting approximation function are assessed using the probably approximately correct computation framework. The smart sampling and incremental function learning techniques can be easily used in practical applications and scale well in the case of extremely large data. The feasibility and good results of the proposed techniques are demonstrated using benchmark functions as well as functions from real-world problems. PMID- 26476937 TI - Antimicrobial activity and partial characterization of bacteriocin-like inhibitory substances produced by Lactobacillus spp. isolated from artisanal Mexican cheese. AB - Lactobacillus spp. from Mexican Cocido cheese were shown to produce bacteriocin like substances (BLS) active against Staphylococcus aureus,Listeria innocua,Escherichia coli, andSalmonella typhimurium by using the disk diffusion method. Crude extracts of Lactobacillus fermentum showed strong inhibitory activity against Staph. aureus, L. innocua, E. coli, and Salmonella cholerae. Complete inactivation of antimicrobial activity was observed after treatment of crude extracts with proteinase K, pronase, papain, trypsin, and lysozyme, confirming their proteinaceous nature. However, antimicrobial activity was partly lost for some of the crude extracts when treated with alpha-amylase, indicating that carbohydrate moieties were involved. The antimicrobial activity of the crude extracts was stable at 65 degrees C for 30min over a wide pH range (2-8), and addition of potassium chloride, sodium citrate, ethanol, and butanol did not affect antibacterial activity. However, antimicrobial activity was lost after heating at 121 degrees C for 15min, addition of methanol or Tween 80. Fourteen out of 18 Lactobacillus spp. showed antimicrobial activity against different test microorganisms, and 12 presented bacteriocin-like substances. Generation time and growth rate parameters indicated that the antimicrobial activity of crude extracts from 3 different strains was effective against the 4 indicator microorganisms. One of the crude extracts showed inhibition not only against gram positive but also against gram-negative bacteria. Bacteriocin-like substances produced by this specific Lactobacillus strain showed potential for application as a food biopreservative. PMID- 26476938 TI - MicroRNA-24 can control triacylglycerol synthesis in goat mammary epithelial cells by targeting the fatty acid synthase gene. AB - In nonruminants it has been demonstrated that microRNA-24 (miR-24) is involved in preadipocyte differentiation, hepatic lipid, and plasma triacylglycerol synthesis. However, its role in ruminant mammary gland remains unclear. In this study we measured miR-24 expression in goat mammary gland tissue at 4 different stages of lactation and observed that it had highest expression at peak lactation when compared with the dry period. Overexpression or downregulation of miR-24 in goat mammary epithelial cells (GMEC) strongly affected fatty acid profiles; in particular, miR-24 enhanced unsaturated fatty acid concentration. Additional effects of miR-24 included changes in triacylglycerol content and the expression of fatty acid synthase, sterol regulatory element binding transcription protein 1, stearoyl-CoA desaturase, glycerol-3-phosphate acyltransferase mitochondrial, and acetyl-CoA carboxylase. Luciferase reporter assay confirmed that fatty acid synthase is a target of miR-24. Taken together, these results not only highlight the physiological importance of miR-24 in fatty acid metabolism in GMEC, but also laid the foundation for further research on regulatory mechanisms among miR-24 and other microRNA expressed in GMEC. PMID- 26476939 TI - Occurrence of Salmonella, Listeria monocytogenes, and enterotoxigenic Staphylococcus in goat milk from small and medium-sized farms located in Minas Gerais State, Brazil. AB - Consumption of goat milk has been increasing due to its nutritional characteristics and health benefits. Therefore, assessment of the presence of foodborne pathogens in this product is critical to ensure its safety to consumers. The present study aimed to identify common foodborne pathogens in raw goat milk. Fifty-three samples of raw goat milk from 11 farms were collected and cultured for the presence of Salmonella spp. and Listeria monocytogenes, as well as for enumeration and isolation of coagulase-positive and coagulase-negative Staphylococcus (CPS and CNS, respectively). All samples tested negative for Salmonella spp. and L. monocytogenes. The CPS counts in raw goat milk samples were predominantly less than 2 log cfu/mL (n=39), and CNS counts were predominantly higher than 3 log cfu/mL (n=42). Based on Staphylococcus counts, 51 isolates were selected (CPS=26; CNS=25) and tested by PCR for the presence of classic enterotoxin-encoding genes (sea, seb, sec, sed, and see). Only 3 isolates (CPS=2, CNS=1) were negative for all enterotoxin-encoding genes tested, and the genotype sec and see was the most frequent (n=16), followed by sea, sec, and see (n=13) and sec (n=13); sed was not detected in any isolate. The frequencies of enterotoxin-encoding genes for CPS and CNS were similar, demonstrating the equivalence of both groups in harboring these virulent markers. These results suggest that Salmonella and L. monocytogenes are not frequent contaminants of raw goat milk, but that Staphylococcus spp. that are capable of producing enterotoxins are prevalent; therefore, consumers of raw goat milk and products made from raw milk are at risk. PMID- 26476940 TI - Prevalence, seasonality, and growth of enterococci in raw and pasteurized milk in Victoria, Australia. AB - This study investigated the prevalence, seasonality, and species variety of enterococci present in raw milk factory silos and pasteurized milk in 3 dairying regions in Victoria, Australia, over a 1-yr period. Additionally, the growth ability of thermoduric enterococci isolated in this study (Enterococcus faecalis, E. faecium, E. hirae, and E. durans) was determined in milk at temperatures likely to occur during storage, transport, and distribution, and before domestic consumption (4 and 7 degrees C). Enterococci were detected in 96% of 211 raw milk samples, with an average count of 2.48 log10 cfu/mL. Counts were significantly lower in winter than summer (average 1.84 log10 cfu/mL) and were different between factories but not regions. Enterococcus faecalis was the most prevalent species isolated from raw milk in every factory, comprising between 61.5 and 83.5% of enterococcal species across each season. Enterococci were detected in lower numbers in pasteurized milk than in raw milk and were below the limit of detection on spread plates (<10 cfu/mL) after factory pasteurization. Residual viable cells were only detected following enrichment using 100-mL samples of milk, with 20.8% of the samples testing positive; this equated to a decrease in the average raw milk enterococci count of >4 log10 cfu/mL following pasteurization. Although E. faecalis predominated in raw milk and E. durans was found in only 2.9% of raw milk samples, E. durans was the most prevalent species detected in pasteurized milk. The detection of enterococci in the pasteurized milk did not correlate with higher enterococci counts in the raw milk. This suggested that the main enterococci populations in raw milk were heat-sensitive and that thermoduric enterococci survived pasteurization in a small numbers of instances. All of the thermoduric enterococci that were assessed for growth at likely refrigeration temperatures were able to grow at both 4 and 7 degrees C in sterile milk, with generation times of 35 to 41h and 16 to 22h, respectively. Thermoduric enterococci were detected in pasteurized milk stored at 4 degrees C for 2 wk (typically 1 to 9 cells/100mL, up to 2.82 log10 cfu/mL), demonstrating the potential of enterococci to survive pasteurization and contribute to milk spoilage at refrigeration temperatures. This is particularly relevant for milk that is aseptically packaged to exclude gram-negative psychrotrophic bacteria and kept above the recommended storage temperature of <=5 degrees C. PMID- 26476942 TI - Identification and quantification of triacylglycerols containing n-3 long-chain polyunsaturated fatty acids in bovine milk. AB - The n-3 long-chain polyunsaturated fatty acids (LC-PUFA) are low-abundance components in milk fat, but have great potential in promoting human health. A comprehensive survey on triacylglycerol (TAG) molecular species in milk that contain at least one type of n-3 LC-PUFA, namely eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid, was conducted in this work using HPLC-linear trap quadrupole-Orbitrap and HPLC-triple quadrupole mass spectrometry techniques. A total of 51 TAG species that contain n-3 LC-PUFA have been identified in bovine milk and their structures assigned. The TAG species containing docosahexaenoic acid were found in much smaller number and at much lower abundance compared with the other 2 types of TAG. An HPLC-triple quadrupole mass spectrometry-based method was developed, which provides relative quantification of all these TAG species in a run of 36 min. Application of this method to the quantification of n-3 LC-PUFA-incorporated TAG in 32 individual animal milk samples allowed us to determine variation between animals, identify strong metabolic relationships between TAG species, and reveal negative effect of a grape marc supplement on the accumulation of eicosapentaenoic acid in milk. PMID- 26476941 TI - Evolution of phagocytic function in monocytes and neutrophils blood cells of healthy calves. AB - The immune system of newborn calves is immature and must mature gradually. Understanding how this immunity is established may define different profiles. Twelve healthy calves were monitored during 8 time periods to assess the innate immune system during the first 90d. Blood samples were collected, and the blood phagocytes, identified by the expression of CD14 and CH138 surface molecules, were evaluated for phagocytic functionality (Staphylococcus aureus and Escherichia coli stained with propidium iodide) and the intracellular production of reactive oxygen species (2,7'-dichlorofluorescein diacetate oxidation). Functional changes in the CD14+ and CH138+ cells occurred at 40d of age, with sporadic increases in phagocytosis intensity and reactive oxygen species production, and decreased phagocytosis occurred at 60d of age. Therefore, fewer phagocytes were active from 40d of age, although those that were active performed their roles with greater efficacy. That change presumably occurred because the calf phagocytes began to support the immune response without the influence of passive immunity. The animals failed to reach the stability needed to complete the maturation of the innate immune response by 90d of age. These data are applicable for healthy calves only. PMID- 26476943 TI - Effects of human visitation on calf growth and performance of calves fed different milk replacer feeding levels. AB - Twenty-eight newborn Holstein heifer calves from the university herd and 8 newborn Holstein heifer calves from a commercial herd were blocked by birth and herd into 1 of 4 treatments: conventional [20% crude protein (CP), 20% fat] milk replacer (MR; treatment C) with (1) or without (0) human visitation, or a higher plane of MR nutrition (28% CP, 20% fat) regimen (treatment A) with (1) or (0) without human visitation. Calves on C MR treatments received 454g of MR from d 2 to 41. Calves on A MR received 916g of MR from d 2 to 8 and 1134g of MR from d 9 to 41. Visitation with calves occurred at 1030 and 1430h daily from d 1 to 56 and comprised verbal stimulation and stirring of starter grain. An opaque curtain divided the calf nursery, with calves in the front half assigned to visitation treatments and those in the rear half not assigned to visitation treatments. Calves were fed their MR treatment until d 43 (preweaning), after which all calves received half of their allotment of MR until d 49 (weaning). Calves were tracked for the next week until d 56 (postweaning). Starter grain and MR intakes were measured daily along with weekly body weight and skeletal measurements. One half of the calves on each treatment had blood samples taken via jugular venipuncture on d 41 (preweaning), 43, 45, 47, 49, and 51 (postweaning) to evaluate blood glucose, urea, nonesterified fatty acids, and cortisol concentrations. During the preweaning and weaning phases, calves on A0 and A1 treatments consumed more MR, less starter, and weighed more than the C0 and C1 calves. Calves on A0 and A1 had greater average daily gain (ADG), hip and withers gain, were taller at the hip, and had larger girths during the preweaning phase. Overall, body weight, withers and hip heights, and heart girths were greater in A0 andA1 calves during the weaning week. Efficiency of utilization of estimated metabolizable energy (ME) intake (ADG/ME) were similar. Glucose and nonesterified fatty acids concentrations were greater in visited calves preweaning. An interaction for glucose was observed during weaning, with A1 calves having the highest concentration and A0 calves having the lowest concentrations during weaning. Cortisol tended to be higher in visited calves during weaning. Postweaning, calves formerly fed A0 and A1 treatments had lower blood glucose and tended to have higher urea and cortisol concentrations than C0 and C1 treatments. The higher plane of nutrition fed calves tended to have higher cortisol concentrations indicating that they experienced more stress due to the removal of MR more than calves fed conventionally. Calves fed the higher plane of MR nutrition consumed more dry matter, ME, and water weighed more, had a greater ADG, and were taller than calves fed the conventional MR. These calves were more efficient (ADG/dry matter intake) when expressed on a dry matter basis, but had similar efficiency when expressed on an ME basis (ADG/ME). Visiting calves did little to reduce the stress of weaning when calves are fed the higher plane of nutrition MR feeding regimen. PMID- 26476944 TI - Sensitivity of solid culture, broth culture, and real-time PCR assays for milk and colostrum samples from Mycobacterium avium ssp. paratuberculosis-infectious dairy cows. AB - Mycobacterium avium ssp. paratuberculosis (MAP) can be shed in feces, milk, and colostrum. The goal of this study was to assess assays that detect MAP in these sample types, including effects of lactation stage or season. Understanding the performance of these assays could improve how they are used, limiting the risk of infection to calves. Forty-six previously confirmed MAP-positive cows from 7 Atlantic Canadian dairy farms were identified for colostrum sampling and monthly sampling of milk and feces over a 12-mo period. Samples were assayed for MAP using solid culture, broth culture, and direct real-time PCR (qPCR). Across assay types, test sensitivity when applied to milk samples averaged 25% of that when applied to fecal samples. For colostrum samples, sensitivity depended on assay type, with sensitivity of qPCR being approximately 46% of that in feces. Across sample types, sensitivity of qPCR was higher than that of the other assays. Sensitivity of qPCR, when applied to milk samples, was significantly higher in summer than in other seasons. Summer was also the season with highest agreement between milk and fecal samples collected within the same month. Our results suggest that qPCR would detect more cows shedding MAP in their milk and colostrum than solid or broth culture assays, particularly during the summer, thus providing better management information to limit exposure of calves to this infectious organism. PMID- 26476945 TI - Evaluation of bacterial contamination in raw milk, ultra-high temperature milk and infant formula using single molecule, real-time sequencing technology. AB - The Pacific Biosciences (Menlo Park, CA) single molecule, real-time sequencing technology (SMRT) was reported to have some advantages in analyzing the bacterial profile of environmental samples. In this study, the presence of bacterial contaminants in raw milk, UHT milk, and infant formula was determined by SMRT sequencing of the full length 16S rRNA gene. The bacterial profiles obtained at different taxonomic levels revealed clear differences in bacterial community structure across the 16 analyzed dairy samples. No indicative pathogenic bacteria were found in any of these tested samples. However, some of the detected bacterial species (e.g., Bacillus cereus, Enterococcus casseliflavus, and Enterococcus gallinarum) might potentially relate with product quality defects and bacterial antibiotic gene transfer. Although only a limited number of dairy samples were analyzed here, our data have demonstrated for the first time the feasibility of using the SMRT sequencing platform in detecting bacterial contamination. Our paper also provides interesting reference information for future development of new precautionary strategies for controlling the dairy safety in large-scale industrialized production lines. PMID- 26476946 TI - Short communication: Changes in fluorescence intensity induced by soybean soluble polysaccharide-milk protein interactions during acidification. AB - Interactions between stabilizer and milk protein are believed to influence the stabilizing behavior of the milk system. We investigated changes in fluorescence intensity induced by interactions of soybean soluble polysaccharide (SSPS) and milk protein (Mp) during acidification. The fluorescence intensity (If) of Mp increased as pH decreased from 6.8 to 5.2. Compared with Mp alone, If of SSPS-Mp mixtures increased as the pH decreased from 6.8 to 5.2. We found that the If of the SSPS-Mp mixture decreased in a pH range from 5.2 to 3.6, which indicated a change in the polarity microenvironment around the Trp residues. We also found that the maximum emission wavelength (lambdamax) shifted from 337 to 330nm as pH decreased from 6.8 to 3.6, in further support of SSPS interacting with the polar portion of Mp during acidification. Furthermore, an excited monomeric molecule (pyrene exciplex) was found as a ground-state pyrene formed and a broad band was shown at about 450nm. The intensity ratio of the first peak to the third peak (I1:I3) of Mp increased slightly, and the ratio of intensity of pyrene exciplex to monomer (Ie:Im) decreased because pyrene molecules were located in a less hydrophobic microenvironment during acidification. However, the ratio of I1:I3 decreased clearly at pH below 5.6 and the ratio of Ie:Im showed the opposite trend in the SSPS-Mp mixture. Changes in intrinsic and exogenous fluorescence intensity confirmed that interactions of SSPS and Mp could change the polarity of the microenvironment and that SSPS probably interacted with the polar portion of Mp. These results could give insight into the behavior of stabilizers in acid milk products. PMID- 26476947 TI - Dairy farm cost efficiency in leading milk-producing regions in Poland. AB - This paper examines the cost efficiency of dairy farms in 2 important regions of commercial milk production in Poland (i.e., Wielkopolskie and Podlaskie). Both regions gained importance following the market-driven resource allocation mechanism adopted after Poland's transition to the market economy in 1989 and accession to the European Union (EU) in 2004. The elimination of the dairy quota system in the EU in 2015 offers new expansion opportunities. The analysis of trends in cow numbers, milk production, and yield per cow shows different patterns of expansion of the dairy sector in the 2 regions. We selected dairy farm data from the Farm Accounts Data Network database for both regions and applied the cost frontier estimation model to calculate the relative cost efficiency index for the period 2004 to 2009. The indexes compare each farm in the sample to the most efficient dairy farm in each region separately. Additionally, the top 5% of dairy farms with the highest relative cost efficiency index from each region were compared in terms of production costs with published results from a study using the representative farm approach. The comparison of results from 2 different studies permits a conclusion that Wielkopolskie and Podlaskie dairy farms are able to compete with farms from the 4 largest milk producing countries in the EU. Although both regions can improve yields per cow, especially Podlaskie, both regions are likely to take advantage of the expansion opportunities offered by the 2015 termination of the milk quota system. PMID- 26476948 TI - Water-lactose behavior as a function of concentration and presence of lactic acid in lactose model systems. AB - The presence of high amounts of lactic acid in acid whey restricts its ability to be further processed because lactose appears to remain in its amorphous form. A systematic study is lacking in this regard especially during the concentration step. Hence, the main aim of the study was to establish the structure and behavior of water molecules surrounding lactose in the presence of 1% (wt/wt) lactic acid at a concentration up to 50% (wt/wt). Furthermore, the crystallization nature of freeze-dried lactose with or without lactic acid was established using differential scanning calorimetry and Fourier transform infrared spectroscopy. Two mechanisms were proposed to describe the behavior of water molecules around lactose molecules during the concentration of pure lactose and lactose solutions with lactic acid. Pure lactose solution exhibited a water evaporation enthalpy of ~679 J.g(-1), whereas lactose+ lactic acid solution resulted in ~965 J.g(-1) at a 50% (wt/wt) concentration. This indicates a greater energy requirement for water removal around lactose in the presence of lactic acid. Higher crystallization temperatures were observed with the presence of lactic acid, indicating a delay in crystallization. Furthermore, less crystalline lactose (~12%) was obtained in the presence of lactic acid, indicating high amorphous nature compared with pure lactose where ~50% crystallinity was obtained. The Fourier transform infrared spectra revealed that the strong hydration layer consisting lactic acid and H3O(+) ions surrounded lactose molecules via strong H bonds, which restricted water mobility, induced a change in structure of lactose, or both, creating unfavorable conditions for lactose crystallization. Thus, partial or complete removal of lactic acid from acid whey may be the first step toward improving the ability of acid whey to be processed. PMID- 26476949 TI - Corn silage from corn treated with foliar fungicide and performance of Holstein cows. AB - Foliar fungicide application to corn plants is used in corn aimed for corn silage in the dairy industry, but questions regarding frequency of application and its effect on corn silage quality and feed conversion when fed to dairy cows remain prevalent. The objective of this study was to evaluate the effects of various foliar fungicide applications to corn on dry matter intake (DMI), milk production, and milk composition when fed to dairy cows. Sixty-four Holstein cows with parity 2.5+/-1.5, 653+/-80kg of body weight, and 161+/-51d in milk were blocked and randomly assigned to 1 of 4 corn silage treatments (total mixed ration with 35% of the dry matter as corn silage). Treatments were as follows: control (CON), corn silage with no applications of foliar fungicide; treatment 1 (1X), corn silage from corn that received 1 application of pyraclostrobin (PYR) foliar fungicide (Headline; BASF Corp.) at corn vegetative stage 5; treatment 2 (2X), corn silage from corn that received the same application as 1X plus another application of a mixture of PYR and metconazole (Headline AMP; BASF Corp.) at corn reproductive stage 1 ("silking"); and treatment 3 (3X), corn silage from corn that received the same applications as 2X as well as a third application of PYR and metconazole at reproductive stage 3 ("milky kernel"). Corn was harvested at about 32% dry matter and 3/4 milk line stage of kernel development and ensiled for 200d. Treatments were fed to cows for 5wk, with the last week being used for statistical inferences. Week -1 was used as a covariate in the statistical analysis. Dry matter intake tended to be lower for cows fed corn silage treated with fungicide than CON (23.8, 23.0, 19.5, and 21.3kg for CON, 1X, 2X, and 3X, respectively). A linear treatment effect for DMI was observed, with DMI decreasing as foliar fungicide applications increased. Treatments CON, 1X, 2X, and 3X did not differ for milk yield (34.5, 34.5, 34.2, and 34.4kg/d, respectively); however, a trend for increased feed conversion represented by fat corrected milk/DMI (1.65 vs. 1.47) and energy-corrected milk/DMI (1.60 vs. 1.43) was noted for cows fed corn silage with fungicide compared with CON. In conclusion, cows receiving corn silage treated with foliar fungicide had better conversion of feed dry matter to milk than those receiving CON silage. PMID- 26476950 TI - Proton transfer reaction time-of-flight mass spectrometry: A high-throughput and innovative method to study the influence of dairy system and cow characteristics on the volatile compound fingerprint of cheeses. AB - The aim of this work was to study the effect of dairy system and individual cow related factors on the volatile fingerprint of a large number of individual model cheeses analyzed by proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS). A total of 1,075 model cheeses were produced using milk samples collected from individual Brown Swiss cows reared in 72 herds located in mountainous areas of Trento province (Italy). The herds belonged to 5 main dairy systems ranging from traditional to modern and the cows presented different daily milk yields (24.6+/-7.9kg * d(-1)), stages of lactation (199+/-138 d in milk), and parities (2.7+/-1.8). The PTR-ToF-MS revealed 619 peaks, of which the 240 most intense were analyzed, and 61 of these were tentatively attributed to relevant volatile organic compounds on the basis of their fragmentation patterns and data from the literature. Principal component analysis was used to convert the multiple responses characterizing the PTR-ToF-MS spectra into 5 synthetic variables representing 62% of the total information. These principal components were related to groups of volatile compounds tentatively attributed to different peaks and used to investigate the relationship of the volatile compound profile obtained by PTR-ToF-MS to animal and farm characteristics. Lactation stage is related to 4 principal components which brought together 52.9% of the total variance and 57.9% of the area of analyzed peaks. In particular, 2 principal components were positively related to peaks tentatively attributed to aldehydes and ketones and negatively related to alcohols, esters, and acids, which displayed a linear increase during lactation. The second principal component was affected by dairy system; it was higher in the modern system in which cows received total mixed rations. The third principal component was positively related to daily milk production. In summary, we report the first application of this innovative, high-throughput technique to study the effects of dairy system and individual animal factors on volatile organic compounds of model cheeses. Individual cheesemaking procedures together with this spectrometric technique open new avenues for genetic selection of dairy species with respect to both milk and cheese quality. PMID- 26476951 TI - A decision-making tool to determine economic feasibility and break-even prices for artisan cheese operations. AB - Artisan cheese makers lack access to valid economic data to help them evaluate business opportunities and make important business decisions such as determining cheese pricing structure. The objective of this study was to utilize an economic model to evaluate the net present value (NPV), internal rate of return, and payback period for artisan cheese production at different annual production volumes. The model was also used to determine the minimum retail price necessary to ensure positive NPV for 5 different cheese types produced at 4 different production volumes. Milk type, cheese yield, and aging time all affected variable costs. However, aged cheeses required additional investment for aging space (which needs to be larger for longer aging times), as did lower yield cheeses (by requiring larger-volume equipment for pasteurization and milk handling). As the volume of milk required increased, switching from vat pasteurization to high temperature, short-time pasteurization was necessary for low-yield cheeses before being required for high-yield cheeses, which causes an additional increase in investment costs. Because of these differences, high-moisture, fresh cow milk cheeses can be sold for about half the price of hard, aged goat milk cheeses at the largest production volume or for about two-thirds the price at the lowest production volume examined. For example, for the given model assumptions, at an annual production of 13,608kg of cheese (30,000 lb), a fresh cow milk mozzarella should be sold at a minimum retail price of $27.29/kg ($12.38/lb), whereas a goat milk Gouda needs a minimum retail price of $49.54/kg ($22.47/lb). Artisan cheese makers should carefully evaluate annual production volumes. Although larger production volumes decrease average fixed cost and improve production efficiency, production can reach volumes where it becomes necessary to sell through distributors. Because distributors might pay as little as 35% of retail price, the retail price needs to be higher to compensate. An artisan cheese company that has not achieved the recognition needed to achieve a premium price may not find distribution through distributors profitable. PMID- 26476952 TI - Spore populations among bulk tank raw milk and dairy powders are significantly different. AB - To accommodate stringent spore limits mandated for the export of dairy powders, a more thorough understanding of the spore species present will be necessary to develop prospective strategies to identify and reduce sources (i.e., raw materials or in-plant) of contamination. We characterized 1,523 spore isolates obtained from bulk tank raw milk (n=33 farms) and samples collected from 4 different dairy powder-processing plants producing acid whey, nonfat dry milk, sweet whey, or whey protein concentrate 80. The spores isolated comprised 12 genera, at least 44 species, and 216 rpoB allelic types. Bacillus and Geobacillus represented the most commonly isolated spore genera (approximately 68.9 and 12.1%, respectively, of all spore isolates). Whereas Bacillus licheniformis was isolated from samples collected from all plants and farms, Geobacillus spp. were isolated from samples from 3 out of 4 plants and just 1 out of 33 farms. We found significant differences between the spore population isolated from bulk tank raw milk and those isolated from dairy powder plant samples, except samples from the plant producing acid whey. A comparison of spore species isolated from raw materials and finished powders showed that although certain species, such as B. licheniformis, were found in both raw and finished product samples, other species, such as Geobacillus spp. and Anoxybacillus spp., were more frequently isolated from finished powders. Importantly, we found that 8 out of 12 genera were isolated from at least 2 different spore count methods, suggesting that some spore count methods may provide redundant information if used in parallel. Together, our results suggest that (1) Bacillus and Geobacillus are the predominant spore contaminants in a variety of dairy powders, implying that future research efforts targeted at elucidating approaches to reduce levels of spores in dairy powders should focus on controlling levels of spore isolates from these genera; and (2) the spore populations isolated from bulk tank raw milk and some dairy powder products are significantly different, suggesting that targeting in-plant sources of contamination may be important for achieving low spore counts in the finished product. These data provide important insight regarding the diversity of spore populations isolated from dairy powders and bulk tank raw milk, and demonstrate that several spore genera are detected by multiple spore count methods. PMID- 26476953 TI - Detrimental effect of selection for milk yield on genetic tolerance to heat stress in purebred Zebu cattle: Genetic parameters and trends. AB - In an attempt to determine the possible detrimental effects of continuous selection for milk yield on the genetic tolerance of Zebu cattle to heat stress, genetic parameters and trends of the response to heat stress for 86,950 test-day (TD) milk yield records from 14,670 first lactations of purebred dairy Gir cows were estimated. A random regression model with regression on days in milk (DIM) and temperature-humidity index (THI) values was applied to the data. The most detrimental effect of THI on milk yield was observed in the stage of lactation with higher milk production, DIM 61 to 120 (-0.099kg/d per THI). Although modest variations were observed for the THI scale, a reduction in additive genetic variance as well as in permanent environmental and residual variance was observed with increasing THI values. The heritability estimates showed a slight increase with increasing THI values for any DIM. The correlations between additive genetic effects across the THI scale showed that, for most of the THI values, genotype by environment interactions due to heat stress were less important for the ranking of bulls. However, for extreme THI values, this type of genotype by environment interaction may lead to an important error in selection. As a result of the selection for milk yield practiced in the dairy Gir population for 3 decades, the genetic trend of cumulative milk yield was significantly positive for production in both high (51.81kg/yr) and low THI values (78.48kg/yr). However, the difference between the breeding values of animals at high and low THI may be considered alarming (355kg in 2011). The genetic trends observed for the regression coefficients related to general production level (intercept of the reaction norm) and specific ability to respond to heat stress (slope of the reaction norm) indicate that the dairy Gir population is heading toward a higher production level at the expense of lower tolerance to heat stress. These trends reflect the genetic antagonism between production and tolerance to heat stress demonstrated by the negative genetic correlation between these components ( 0.23). Monitoring trends of the genetic component of heat stress would be a reasonable measure to avoid deterioration in one of the main traits of Zebu cattle (i.e., high tolerance to heat stress). On the basis of current genetic trends, the need for future genetic evaluation of dairy Zebu animals for tolerance to heat stress cannot be ruled out. PMID- 26476954 TI - From cold to hot: Climatic effects and productivity in Wisconsin dairy farms. AB - This study examined the effects of climatic conditions on dairy farm productivity using panel data for the state of Wisconsin along with alternative stochastic frontier models. A noteworthy feature of this analysis is that Wisconsin is a major dairy-producing area where winters are typically very cold and snowy and summers are hot and humid. Thus, it is an ideal geographical region for examining the effects of a range of climatic factors on dairy production. We identified the effects of temperature and precipitation, both jointly and separately, on milk output. The analysis showed that increasing temperature in summer or in autumn is harmful for dairy production, whereas warmer winters and warmer springs are beneficial. In contrast, more precipitation had a consistent adverse effect on dairy productivity. Overall, the analysis showed that over the past 17 yr, changes in climatic conditions have had a negative effect on Wisconsin dairy farms. Alternative scenarios predict that climate change would lead to a 5 to 11% reduction in dairy production per year between 2020 and 2039 after controlling for other factors. PMID- 26476955 TI - Endogenous C1-inhibitor production and expression in the heart after acute myocardial infarction. AB - BACKGROUND: Complement activation contributes significantly to inflammation related damage in the heart after acute myocardial infarction. Knowledge on factors that regulate postinfraction complement activation is incomplete however. In this study, we investigated whether endogenous C1-inhibitor, a well-known inhibitor of complement activation, is expressed in the heart after acute myocardial infarction. MATERIALS AND METHODS: C1-inhibitor and complement activation products C3d and C4d were analyzed immunohistochemically in the hearts of patients who died at different time intervals after acute myocardial infarction (n=28) and of control patients (n=8). To determine putative local C1 inhibitor production, cardiac transcript levels of the C1-inhibitor-encoding gene serping1 were determined in rats after induction of acute myocardial infarction (microarray). Additionally, C1-inhibitor expression was analyzed (fluorescence microscopy) in human endothelial cells and rat cardiomyoblasts in vitro. RESULTS: C1-inhibitor was found predominantly in and on jeopardized cardiomyocytes in necrotic infarct cores between 12h and 5days old. C1-inhibitor protein expression coincided in time and colocalized with C3d and C4d. In the rat heart, serping1 transcript levels were increased from 2h up until 7days after acute myocardial infarction. Both endothelial cells and cardiomyoblasts showed increased intracellular expression of C1-inhibitor in response to ischemia in vitro (n=4). CONCLUSIONS: These observations suggest that endogenous C1-inhibitor is likely involved in the regulation of complement activity in the myocardium following acute myocardial infarction. Observations in rat and in vitro suggest that C1 inhibitor is produced locally in the heart after acute myocardial infarction. PMID- 26476957 TI - Infant twins' social interactions with caregivers and same-age siblings. AB - The study of twin behavior offers the opportunity to study differential patterns of social and communicative interactions in a context where the adult partner and same-age peer are equally familiar. We investigated the development of social engagement, communicative gestures, and imitation in 7- to 25-month-old twins. Twin dyads (N=20 pairs) participated in 10-min, semi-structured play sessions, with the mother seated in a chair completing paperwork for half the session, and on the floor with her children for the other half. Overall, twins engaged more with their mothers than with their siblings: they showed objects and imitated speech and object use more frequently when interacting with their mothers than with their siblings. When the mother was otherwise engaged, the twins played with toys separately, observed each other's toy play, or were unengaged. These results demonstrate that adult scaffolding of social interactions supports increased communicative bids even in a context where both familiar peers and adults are available as communicative partners. PMID- 26476958 TI - Extracting protein dynamics information from overlapped NMR signals using relaxation dispersion difference NMR spectroscopy. AB - Protein dynamics plays important roles in many biological events, such as ligand binding and enzyme reactions. NMR is mostly used for investigating such protein dynamics in a site-specific manner. Recently, NMR has been actively applied to large proteins and intrinsically disordered proteins, which are attractive research targets. However, signal overlap, which is often observed for such proteins, hampers accurate analysis of NMR data. In this study, we have developed a new methodology called relaxation dispersion difference that can extract conformational exchange parameters from overlapped NMR signals measured using relaxation dispersion spectroscopy. In relaxation dispersion measurements, the signal intensities of fluctuating residues vary according to the Carr-Purcell Meiboon-Gill pulsing interval, whereas those of non-fluctuating residues are constant. Therefore, subtraction of each relaxation dispersion spectrum from that with the highest signal intensities, measured at the shortest pulsing interval, leaves only the signals of the fluctuating residues. This is the principle of the relaxation dispersion difference method. This new method enabled us to extract exchange parameters from overlapped signals of heme oxygenase-1, which is a relatively large protein. The results indicate that the structural flexibility of a kink in the heme-binding site is important for efficient heme binding. Relaxation dispersion difference requires neither selectively labeled samples nor modification of pulse programs; thus it will have wide applications in protein dynamics analysis. PMID- 26476960 TI - Developing Guidance on Ethics for Patient Groups Collecting and Reporting Patient Information for Health Technology Assessments. PMID- 26476959 TI - A case-control study: Association between serum neuregulin 4 level and non alcoholic fatty liver disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a great health burden. Neuregulin 4 (Nrg4) is a recently identified secret factor that may be associated with NAFLD. AIM: To investigate the association between serum Nrg4 level and NAFLD by conducting a case-control study. METHOD: A total of 174 subjects were included. 87 NAFLD subjects and 87 age- and sex-matched non-NAFLD controls were identified by hepatic ultrasound examination. Anthropometric and biochemical data were measured and recorded. Serum Nrg4 level was evaluated by using enzyme-linked immunosorbent assay. SPSS software was used for statistical analyses. RESULTS: Compared to the controls, subjects with NAFLD presented with reduced level of serum Nrg4 (0.40 (0.27, 0.55) vs. 0.50 (0.30, 0.81)ng/mL (median (interquartile range)), P=0.029). By multivariate logistic regression analysis, reduced serum levels of Nrg4 were associated with higher NAFLD odds (OR=0.251, 95% confidence interval=0.081-0.779, P=0.017). By dividing the distribution of serum Nrg4 level into quartiles, there was borderline statistical difference of NAFLD prevalence among the four groups (P=0.058). There was no significant difference of serum Nrg4 levels in subjects according to the grades of fatty liver by ultrasound (P=0.080). No statistical difference of serum Nrg4 level was observed between obese and non-obese subjects (P=0.932). CONCLUSION: Decreased serum Nrg4 level is prevalent in NAFLD subjects compared to non-NAFLD controls, and is an independent risk factor associated with NAFLD, indicating that Nrg4 might have a protective role in the development of NAFLD. PMID- 26476961 TI - The Impact of Chronic Urticaria from the Patient's Perspective: A Survey in Five European Countries. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is associated with considerable burden, but data from European patients are limited. METHODS: This study is a retrospective, cross-sectional analysis of National Health and Wellness Survey data from the five largest EU countries (5EU: France, Germany, Italy, Spain, and the UK) collected between 2010 and 2013. Burden of disease for patients with CSU was estimated by comparing individuals currently treated for chronic urticaria (proxy CSU cases) with controls selected from respondents without chronic urticaria. Matching and regression models were used to quantify the impact of chronic urticaria on health-related quality of life, self-reported psychological complaints, work and activity impairment, and healthcare use. RESULTS: The sample included 175,923 respondents. Prevalence of diagnosed chronic urticaria was 0.5 and 0.2% were treating the condition with a prescription. Cases (N = 369) had substantially lower (worse) regression-adjusted mean Mental Component Summary (40.2 vs. 45.4), Physical Component Summary (44.6 vs. 49.9), and SF-6D health utility scores (0.63 vs. 0.71; all p < 0.001) relative to controls (N = 1476), differences that exceed accepted minimally important differences for these measures. Depression, anxiety, and sleep difficulties were approximately twice as prevalent among those currently receiving treatment for chronic urticaria (all p < 0.001). Cases also had elevated presenteeism (31 vs. 17%), overall work impairment (37 vs. 20%), and impairment in non-work activities (42 vs. 26%; all p < 0.01) relative to controls. Physician visits (9.1 vs. 4.9), emergency room visits (0.8 vs. 0.3), and hospitalizations (0.3 vs. 0.2) were more frequent than in controls (all p < 0.01). CONCLUSIONS: This research adds to the existing evidence showing significant burden of CSU. PMID- 26476962 TI - Adenocarcinoma of the cervical esophagus arising from ectopic gastric mucosa: report of two cases and review of the literature. AB - Esophageal adenocarcinoma arising from ectopic gastric mucosa (EGM) is extremely rare. We describe here two Japanese patients with adenocarcinoma of the cervical esophagus arising from EGM. Case 1 is a 62-year-old man who had slightly red EGM in the cervical esophagus on upper gastrointestinal endoscopy (UGE). Because the biopsy showed atypical glands that were suspicious for adenocarcinoma, endoscopic submucosal dissection was performed. Histopathological examination revealed that the lesion was a well-differentiated adenocarcinoma (pT1a MM). Lymphovascular invasion was absent, and the margins were free from carcinoma. Case 2 is a 57 year-old man who had an elevated lesion with a bleeding tendency in an area of EGM in the cervical esophagus on UGE. Adenocarcinoma was diagnosed in the biopsy. Because of the presence of enlarged lymph nodes (#106recL), preoperative chemoradiotherapy was performed to reduce the size of the adenocarcinoma and lymph nodes prior to resection of the cervical esophagus and reconstruction with free jejunal grafts. Histopathological examination revealed moderately differentiated adenocarcinoma (0-I, pT2N1M0, pStage II). In both cases, adenocarcinoma was surrounded by EGM, which led to the diagnosis of EGM-derived esophageal adenocarcinoma. Here, we report its immunohistochemical characteristics in the present cases and discuss the histogenesis. PMID- 26476963 TI - Differences in quality standards when prescribing nutritional support: Differences between specialist and non-specialist physicians. AB - Adequate nutritional support includes many different aspects, but poor understanding of clinical nutrition by health care professionales often results in an inadequate prescription. MATERIAL AND METHODS: A study was conducted to compare enteral and parenteral nutritional support plans prescribed by specialist and non-specialist physicians. RESULTS: Non-specialist physicians recorded anthropometric data from only 13.3% of patients, and none of them performed nutritional assessments. Protein amounts provided by non-specialist physicians were lower than estimated based on ESPEN (10.29g of nitrogen vs 14.62; P<.001). Differences were not statistically significant in the specialist group (14.88g of nitrogen; P=.072). Calorie and glutamine provision and laboratory controls prescribed by specialists were significantly closer to those recommended by clinical guidelines. CONCLUSION: Nutritional support prescribed by specialists in endocrinology and nutrition at San Pedro de Alcantara Hospital was closer to clinical practice guideline standards and of higher quality as compared to that prescribed by non-specialists. PMID- 26476964 TI - Simpson's method of discs in Salukis and Whippets: Echocardiographic reference intervals for end-diastolic and end-systolic left ventricular volumes. AB - BACKGROUND: Sighthound breeds are known to have different cardiac sizes and dimensions from other breeds; therefore, breed-specific references are required to avoid misinterpretation of echocardiographic findings. End-diastolic volume (EDV) and end-systolic volume (ESV) reference intervals derived from Simpson's method of discs (SMOD) do not exist for Salukis or Whippets. OBJECTIVES: To establish EDV and ESV reference intervals for SMOD in Salukis and Whippets. ANIMALS: 110 Salukis and 119 Whippets. METHODS: Reference intervals for SMOD with and without normalization to body surface area (BSA) were established using the right parasternal and left apical views in 93 healthy Salukis and 82 healthy Whippets. Volumes were compared between both echocardiographic views, genders, and racing and show pedigree dogs. The 90% reference intervals were calculated using the robust method. RESULTS: Agreement between right-sided and left-sided echocardiographic views was good. Reference intervals indexed to body surface area (BSA) for Whippets were 59-109 mL/m2 for end-diastolic volume index and 18 53 mL/m2 for end-systolic volume index. Corresponding values for Salukis were 68 126 mL/m2 for end-diastolic volume index and 27-64 mL/m2 for end-systolic volume index. There were no indexed volume differences between male and female or racing and show pedigree dogs in both breeds. The non-normalized volumes significantly differed between genders. CONCLUSIONS AND CLINICAL IMPORTANCE: Whippets and Salukis had larger systolic and diastolic left ventricular volumes compared with other breeds. This study provided echocardiographic reference intervals for SMOD derived left ventricular volumes for these athletic breeds. PMID- 26476965 TI - Control of the micromovements of a composite-material nail design: A finite element analysis. AB - BACKGROUND: Intramedullary nail fixation is the most accepted modality for stabilizing long bone midshaft fractures. The commercially used nails are fabricated from Stainless Steel or Titanium. Composite-materials (CM) mainly carbon-fiber reinforced polymers (CFRP) have been gaining more interest and popularity due to their properties, such as modulus of elasticity close to that of bone, increased fatigue strength, and radio-opacity to irradiation that permits a better visualization of the healing process. The use of CFRP instead of metals allows better control of different directional movements along a fracture site. The purpose of this analysis was to design a CM intramedullary nail to enable micromovements as depicted on a finite element analysis method. METHODS: We designed a three-dimentional femoral nail model. Three CFRP with different laminates arrangements, were included in the analysis. The finite element analysis involved applying vertical and horizontal loads on each of the designed and tested nails. RESULTS: The nails permitted a transverse micromovement of 0.75mm for the 45 degrees lay-up and 1.5mm for the 90 degrees lay-up for the CM, 1.38mm for the Titanium and 0.74mm for the Stainless Steel nails. The recorded axial movements were 0.53mm for the 45 degrees lay-up, 0.87mm for the 90 degrees lay-up, 0.46mm for the unsymmetrical lay-up CM, 0.046 for the Titanium and 0.02 for the Stainless Steel nails. Overall, the simulations showed that nail transverse micromovements can be reduced by using 45 degrees carbon fiber orientations. Similar results were observed with each metal nails. INTERPRETATION: We found that nail micromovements can be controlled by changing the directional stiffness using different lay-up orientations. These results can be useful for predicting nail micromovements under specified loading conditions which are crucial for stimulating callus formation in the early stages of healing. PMID- 26476966 TI - Characterizing liver capsule microstructure via in situ bulge test coupled with multiphoton imaging. AB - The characterization of biological tissue at the microscopic scale is the starting point of many applications in tissue engineering and especially in the development of structurally based constitutive models. In the present study, focus is made on the liver capsule, the membrane encompassing hepatic parenchyma, which takes a huge part in liver mechanical properties. An in situ bulge test experiment under a multiphoton microscope has been developed to assess the microstructure changes that arise with biaxial loading. Multiphoton microscopy allows to observe the elastin and collagen fiber networks simultaneously. Thus a description of the microstructure organization of the capsule is given, characterizing the shapes, geometry and arrangement of fibers. The orientation of fibers is calculated and orientation distribution evolution with loading is given, in the case of an equibiaxial and two non equibiaxial loadings, thanks to a circular and elliptic set up of the bulge test. The local strain fields have also been computed, by the mean of a photobleaching grid, to get an idea of what the liver capsule might experience when subjected to internal pressure. Results show that strain fields present some heterogeneity due to anisotropy. Reorientation occurs in non equibiaxial loadings and involves fibers layers from the inner to the outer surface as expected. Although there is a fiber network rearrangement to accommodate with loading in the case of equibiaxial loading, there is no significant reorientation of the main fibers direction of the different layers. PMID- 26476967 TI - On intrinsic stress fiber contractile forces in semilunar heart valve interstitial cells using a continuum mixture model. AB - Heart valve interstitial cells (VICs) play a critical role in the maintenance and pathophysiology of heart valve tissues. Normally quiescent in the adult, VICs can become activated in periods of growth and disease. When activated, VICs exhibit increased levels of cytokines and extracellular matrix (ECM) synthesis, and upregulated expression and strong contraction of alpha-smooth muscle actin (alpha SMA) fibers. However, it remains unknown how expression and contraction of the alpha-SMA fibers, which vary among different VIC types, contribute to the overall VIC mechanical responses, including the nucleus and cytoskeleton contributions. In the present study, we developed a novel solid-mixture model for VIC biomechanical behavior that incorporated 1) the underlying cytoskeletal network, 2) the oriented alpha-SMA stress fibers with passive elastic and active contractile responses, 3) a finite deformable elastic nucleus. We implemented the model in a full 3D finite element simulation of a VIC based on known geometry. Moreover, we examined the respective mechanical responses of aortic and pulmonary VICs (AVICs and PVICs, respectively), which are known to have different levels of alpha-SMA expression levels and contractile behaviors. To calibrate the model, we simulated the combined mechanical responses of VICs in both micropipette aspiration (MA) and atomic force microscopy (AFM) experiments. These two states were chosen as the VICs were under significantly different mechanical loading conditions and activation states, with the alpha-SMA fibers inactivated in the MA studies while fully activated in the AFM studies. We also used the AFM to study the mechanical property of the nucleus. Our model predicted that the substantial differences found in stiffening of the AVIC compared to the PVICs was due to a 9 to 16 times stronger intrinsic AVIC alpha-SMA stress fiber contractile force. Model validation was done by simulating a traction force microscopy experiment to estimate the forces the VICs exert on the underlying substrate, and found good agreement with reported traction force microscopy results. Further, estimated nuclear stiffness for both AVICs and PVICs were similar and comparable to the literature, and were both unaffected by VIC activation level. These results suggest substantial functional differences between AVICs and PVICs at the subcellular level. Moreover, this first VIC computational biomechanical model is but a first step in developing a comprehensive, integrated view of the VIC pathophysiology and interactions with the valve ECM micro-environment based on simulation technologies. PMID- 26476968 TI - Application of UVA-riboflavin crosslinking to enhance the mechanical properties of extracellular matrix derived hydrogels. AB - Hydrogels derived from extracellular matrix (ECM) have become increasing popular in recent years, particularly for use in tissue engineering. One limitation with ECM hydrogels is that they tend to have poor mechanical properties compared to native tissues they are trying to replicate. To address this problem, a UVA (ultraviolet-A) riboflavin crosslinking technique was applied to ECM hydrogels to determine if it could be used to improve their elastic modulus. Hydrogels fabricated from corneal, cardiac and liver ECM were used in this study. The mechanical properties of the hydrogels were characterized using a spherical indentation technique. The microstructure of the hydrogels and the cytotoxic effect of crosslinking on cell seeded hydrogels were also evaluated. The combination of UVA light and riboflavin solution led to a significant increase in elastic modulus from 6.8kPa to 24.7kPa, 1.4kPa to 6.9kPa and 0.9kPa to 1.6kPa for corneal, cardiac and liver ECM hydrogels respectively. The extent of this increase was dependent on a number of factors including the UVA exposure time and the initial hydrogel concentration. There were also a high percentage of viable cells within the cell seeded hydrogels with 94% of cells remaining viable after 90min exposure to UVA light. These results suggest that UVA-riboflavin crosslinking is an effective approach for improving the mechanical properties of ECM hydrogels without resulting in a significant reduction of cell viability. PMID- 26476969 TI - Possible causes of the gradient decrease in the right ventricular outflow tract in biventricular hypertrophic cardiomyopathy. PMID- 26476970 TI - Synthesis, antimycobacterial and antibacterial activity of l-[(1R,2S)-2 fluorocyclopropyl]naphthyridone derivatives containing an oxime-functionalized pyrrolidine moiety. AB - A series of novel 1-[(1R,2S)-2-fluorocyclopropyl]naphthyridone derivatives 21-24 containing an oxime-functionalized pyrrolidine moiety were designed, synthesized and evaluated for their biological activity. Our results reveal that compounds 21a, 21e and 21j show considerable activity against MTB H37Rv ATCC 27294 (MICs: <0.25 MUg/mL) and MDR-MTB 6133 (MICs: 0.03-0.054 MUg/mL). The target compounds 21 24 are generally poor against the Gram-negative strains, but 21a-j and 22a-c have potent potency (MICs: <0.008-32 MUg/mL) against all of the tested Gram-positive strains including MRSA and MRSE with a few exceptions, and the most active compounds 21d, 21e and 22a-c (MICs: <0.008-32 MUg/mL) were found to be comparable to or better than moxifloxacin, and 2->250 times more potent than ciprofloxacin and levofloxacin. PMID- 26476971 TI - Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 1: SAR of modifications to the central aryl core. AB - This Letter describes the lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs). While first generation PAMs from Roche were reported in the late 1990s, little effort has focused on the development of mGlu1 PAMs since. New genetic data linking loss-of-function mutant mGlu1 receptors to schizophrenia, bipolar disorder and other neuropsychiatric disorders has rekindled interest in the target, but the ideal in vivo probe, for example, with good PK, brain penetration and low plasma protein binding, for robust target validation has been lacking. Here we describe the first modifications to the central aryl core of the VU0486321 series, where robust SAR was noted. Moreover, structural variants were identified that imparted selectivity (up to >793-fold) versus mGlu4. PMID- 26476972 TI - Compared fixation and survival of 280 lateralised vs 527 standard cementless stems after two years (1-7). AB - BACKGROUND: Restoring the native hip anatomy increases hip prosthesis survival, whereas increased femoral lateralisation creates high torque stresses that may alter prosthesis fixation. After finding lucent lines around cementless lateralised stems (CorailTM, DePuy Synthes, St Priest, France) in several patients, we evaluated the effects of lateralisation in a large case-series. The objective of our study was to compare lateralised vs standard stems of identical design in terms of radiological osteo-integration and survival. HYPOTHESIS: Lateralised stems, despite being used only when indicated by the anatomical parameters, carry a higher risk of impaired osteo-integration. MATERIALS AND METHODS: A retrospective study was conducted in 807 primary total hip arthroplasties (THAs) performed between 2006 and 2010 in 798 patients with a mean age of 65 +/- 14.2 years. Lateralised stems were used in 280 cases (Corail High Offset KHO, n = 169; and Corail coxa vara KLA, n = 111 cases) and standard stems in 527 cases (Corail KA). Mean follow-up was 2.3 years (range, 1-7 years). The clinical evaluation included determination of the Postel-Merle d'Aubigne (PMA) score. Bone fixation and stability of the implants were assessed by determining the Engh and Massin score and the ARA score on the radiographs at last follow-up. Femoral, acetabular and global offset values were determined before and after THA. Nobles's Canal Flare Index was computed. Survival was estimated using the Kaplan-Meier method with surgical revision for aseptic loosening as the end point. RESULTS: The PMA score improved from 12 (10-15) pre-operatively to 17.7 (14-18) (P < 0.05). After THA, in the lateralised stem group, femoral offset was restored in 217 (77%) hips and the mean change vs the pre-operative offset value was -2 mm; in the standard stem group, femoral offset was restored in 440 (83.5%) hips and the mean change was +1 mm. The Engh and Massin score values were similar in the standard stem and lateralised stem groups (24.4 +/- 2.2 and 22.6 +/- 2.4, respectively, NS). Revision for aseptic loosening was required in 5 patients with lateralised stems (3 KHO and 2 KLA) versus none of the patients with standard stems. There were no cases of excessive femoral offset and the mean change in offset was -2.3mm (-5.3 to -1.1). Noble's index was increased (4.27 +/- 0.5 for the loosened lateralised stems, 3.65 +/- 0.8 for the well-fixed lateralised stems and 3.82 +/- 0.6 for the standard stems), with no significant difference across groups. Overall survival after 3.5 years of follow-up was 94.6% (95% confidence interval, 88.4-100%) with lateralised stems and 100% with standard stems (P < 0.05). DISCUSSION: The risk of aseptic loosening was significantly higher with the lateralised stem (5/280, 1.8%) than with the standard stem (n = 0). Our findings indicate a need for careful preparation to obtain primary fixation of lateralised stems. LEVEL OF EVIDENCE: III, retrospective case-control study. PMID- 26476973 TI - Did I say dog or cat? A study of semantic error detection and correction in children. AB - Although naturalistic studies of spontaneous speech suggest that young children can monitor their speech, the mechanisms for detection and correction of speech errors in children are not well understood. In particular, there is little research on monitoring semantic errors in this population. This study provides a systematic investigation of detection and correction of semantic errors in children between the ages of 5 and 8years as they produced sentences to describe simple visual events involving nine highly familiar animals (the moving animals task). Results showed that older children made fewer errors and corrected a larger proportion of the errors that they made than younger children. We then tested the prediction of a production-based account of error monitoring that the strength of the language production system, and specifically its semantic-lexical component, should be correlated with the ability to detect and repair semantic errors. Strength of semantic-lexical mapping, as well as lexical-phonological mapping, was estimated individually for children by fitting their error patterns, obtained from an independent picture-naming task, to a computational model of language production. Children's picture-naming performance was predictive of their ability to monitor their semantic errors above and beyond age. This relationship was specific to the strength of the semantic-lexical part of the system, as predicted by the production-based monitor. PMID- 26476974 TI - [The actions of the Editorial Committee]. PMID- 26476975 TI - [Eight years of experience with HIFU for prostate cancer: Oncological and functional results]. AB - OBJECTIVE: To study the oncologic and functional results of HIFU as a first-line treatment for localized prostate cancer. MATERIAL AND METHOD: Enrolment of patients between 2006 and 2011 for the first treatment against localized prostate cancer with HIFU (Integrated Imaging((r)), EDAP-TMS, Vaulx-en-Velin, France). The biochemical recurrence-free survival was calculated by using the Phoenix criterion (PSA>nadir+2 ng/mL). The functional complications were assessed clinically and through standardised questionnaires. RESULTS: The condition of 191 patients was assessed at a mean follow-up of 55.5 +/- 22.7 months. In 10,1% of the treatments, an incident during the medical procedure was observed with the volume of the prostate (P=0.026) as risk factor. The overall survival, the survival and the metastatic free survival rate were respectively 89.5%, 98.4% and 97.4%. The biochemical free survival rate for 5 years was 87.5%, 69% and 39% respectively for the low, medium and high-risk groups of d'Amico classification. Eighty-six percent of the patients with a PSA nadir <= 0.3 ng/mL were relapse free at 5 years. Whereas only 48% of the patients with a nadir>0.3 ng/mL did not. Only 17.8% of the patients had a rescue treatment with an average delay of 31.1 months. The urinary and sexual impairment was significant but 78.1% of the patients were dry at the end of the study. The most common complication found in 18.3% of the patients was the prostatic obstruction. CONCLUSION: The oncologic and functional results of the HIFU seem similar to the other first-line treatments results and reveal that the HIFU is a therapeutic option for the treatment of prostate cancer in men over 70 years. LEVEL OF EVIDENCE: 5. PMID- 26476976 TI - [Does laparoscopic nephrectomy with vaginal extraction affect the sexual quality of life of patients?]. AB - OBJECTIVES: To evaluate the consequences of laparoscopic nephrectomy with vaginal extraction on sexual quality of life. METHODS: Sixteen patients (mean age: 53.8 years) who underwent laparoscopic nephrectomy with vaginal extraction between September 2010 and February 2014 were included in this monocentric prospective study. All patients underwent a preoperative gynecological examination to evaluate the feasibility of vaginal extraction. The sexual function of the patients was evaluated using the French version of the Female Sexual Function Index (FSFI). The patients completed an initial FSFI preoperatively then another postoperatively after the resumption of sexual activities. RESULTS: The mean hospital stay was 2.2 days (0-5 days). No postoperative complications were observed except for one case of bleeding at the vaginal incision 4 days after surgery, resolved with a single suture under local anesthesia. Fifteen patients (94%) completed both the pre- and postoperative FSFIs. Three patients were sexually inactive and one was a virgin. The pre- and postoperative mean FSFI overall scores were 24.2 and 24.3 respectively (p=0.39). Scores were comparable in all six of the domains assessed by the questionnaire. Particularly, the pre- and postoperative scores for satisfaction were 4.5 and 4.4 respectively. No increase in dyspareunia was observed after surgery, nor was it more difficult for our patients to reach orgasm after the intervention. No statistically significant differences were observed between the pre- and postoperative FSFI scores. CONCLUSIONS: Although preliminary, our results suggest that laparoscopic nephrectomy with vaginal extraction has no effect on the sexual quality of life of patients. PMID- 26476977 TI - [Comparison Bricker's and Wallace's anastomoses in ileal conduit: Retrospective, multicenter study]. AB - OBJECTIVES: To compare Bricker and Wallace anastomosis in ileal conduit and search other risk factors of hydronephrosis. METHODS: Retrospective study in two French Hospitals with two different surgical practices. Hydronephrosis are separated in two groups: complicated hydronephrosis requiring reoperation and no complicated hydronephrosis. RESULTS: One hundred and sixty patients were included in the study and 317 renal units were explored (141 in Bricker's group and 176 in Wallace's group). The rate of complicated and non-complicated hydronephrosis are respectively 9.9 and 20.6% in Bricker's group against 10.8 and 13.6% in Wallace's group, without significant difference (P=0.8 and 0.1). In the other risk factors, only body mass index over 25 kg/m(2) was found as significant for complicated hydronephrosis. The left side and preoperative hydronephrosis are only associated to a risk of no complicated hydronephrosis (P=0.006 and 0.026). CONCLUSION: We found no difference between the two most common types of ureteroenteric anastomotic techniques. However, a high body mass index increases the rate of reoperation for hydronephrosis. LEVEL OF EVIDENCE: 5. PMID- 26476978 TI - Peptide motif analysis predicts alphaviruses as triggers for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) develops in response to both genetic and environmental factors. The strongest genetic determinant is HLA-DR, where polymorphisms within the P4 and P6 binding pockets confer elevated risk. However, low disease concordance across monozygotic twin pairs underscores the importance of an environmental factor, probably infectious. The goal of this investigation was to predict the microorganism most likely to interact with HLA-DR to trigger RA under the molecular mimicry hypothesis. A set of 185 structural proteins from viruses or intracellular bacteria was scanned for regions of sequence homology with a collagen peptide that binds preferentially to DR4; candidates were then evaluated against a motif required for T cell cross-reactivity. The plausibility of the predicted agent was evaluated by comparison of microbial prevalence patterns to epidemiological characteristics of RA. Peptides from alphavirus capsid proteins provided the closest fit. Variations in the P6 position suggest that the HLA binding preference may vary by species, with Ross River virus, Chikungunya virus, and Mayaro virus peptides binding preferentially to DR4, and peptides from Sindbis/Ockelbo virus showing stronger affinity to DR1. The predicted HLA preference is supported by epidemiological studies of post-infection chronic arthralgia. Parallels between the cytokine profiles of RA and chronic alphavirus infection are discussed. PMID- 26476979 TI - Risk factors for kidney injury during vancomycin and piperacillin/tazobactam administration, including increased odds of injury with combination therapy. AB - BACKGROUND: Acute kidney injury (AKI) occurs frequently in hospitalized patients and has been associated with the administration of certain medications. Concerns have been raised in recent reports that the antibiotic combination of vancomycin and piperacillin/tazobactam (combV/P) may be more associated with AKI than monotherapy with either drug. METHODS: To compare the incidence of and risk factors for AKI in patients receiving combV/P versus monotherapy with either drug, a retrospective study was conducted in non-critically ill inpatients at a large urban teaching hospital. AKI was defined as either: (1) Increase in serum creatinine >=0.5 mg/dl OR (2) >=1.5-fold creatinine increase from admission baseline. In addition to standard multivariable regression adjustment, propensity score weighting was used as a robust approach to reduce the effects of covariate confounding when estimating the adjusted odds of AKI. RESULTS: A total of 228 patients were evaluated. The overall incidence of AKI was 11.8 % (27 of 228 patients). AKI occurred in 4 of 101 patients in the vanc group (4.0 %), 4 of 26 patients in the piptazo group (15.4 %), and 19 of 101 patients in the combV/P group (18.8 %). The univariable odds of AKI was significantly lower in the vanc group compared to both the combV/P group (OR 0.178, 95 % CI 0.058-0.544, p = 0.003) and piptazo (OR 0.227, 95 % CI 0.053-0.978, p = 0.047) group. A multivariable model accounting for baseline characteristics again showed that vanc monotherapy was associated with lower odds of AKI than combV/P (OR 0.14, 95 % CI 0.04-0.52, p = 0.004). Male sex was also associated with lower odds of AKI (OR 0.28, 95 % CI 0.10-0.79, p = 0.02) in the multivariable model. In the propensity score analysis using inverse probability of treatment weighting (IPTW), vanc monotherapy and male sex were again associated with lower odds of AKI (OR 0.17; 95 % CI 0.04-0.62, p = 0.008 and OR 0.28, 95 % CI 0.09-0.89, p = 0.03, respectively). CONCLUSION: This study substantiates recent reports that combV/P may be more associated with AKI than vanc monotherapy in hospital inpatients. AKI also appears to be more likely in females during therapy with these antimicrobials. While severity of illness is difficult to account for, these findings are further justification for narrowing antibiotic coverage when possible after this combination has been initiated in hospitalized patients. PMID- 26476980 TI - A gloomy picture: a meta-analysis of randomized controlled trials reveals disappointing effectiveness of programs aiming at preventing child maltreatment. AB - BACKGROUND: Consistent findings about the effectiveness of parent programs to prevent or reduce child maltreatment are lacking. METHODS: In the present meta analysis we synthesized findings from 27 independent samples from randomized controlled trials (RCTs) on the effectiveness of 20 different intervention programs aimed at (i) preventing the occurrence of child maltreatment in the general population or with at-risk but non-maltreating families, or (ii) reducing the incidence of child maltreatment in maltreating families. RESULTS: A significant combined effect on maltreatment (d = 0.13; N = 4883) disappeared after the trim-and-fill approach that takes into account publication bias against smaller studies without significant outcomes. However, moderator analyses showed that larger effect sizes were found for more recent studies, studies with smaller samples, programs that provide parent training instead of only support, programs that target maltreating instead of at-risk families, and programs with a moderate length (6-12 months) or a moderate number of sessions (16-30). CONCLUSIONS: More RCTs are needed to further unravel which factors are associated with program effectiveness. Because currently existing programs appeared to only reduce and not prevent child maltreatment, efforts in the field of preventive intervention should also focus on the development and testing of preventive programs for families at risk for child maltreatment. PMID- 26476981 TI - Renal failure induces atrial arrhythmogenesis from discrepant electrophysiological remodeling and calcium regulation in pulmonary veins, sinoatrial node, and atria. AB - BACKGROUND: Renal failure (RF) increases the risk of atrial fibrillation (AF), but arrhythmogenic mechanism is unclear. The present study investigated the electrophysiological effects of RF on AF trigger (pulmonary veins, PVs) and substrate (atria) and evaluated potential underlying mechanisms. METHODS: Electrocardiographic, echocardiographic, and biochemical studies were conducted in rabbits with and without antibiotic-induced mild (creatinine=1.5-6.0 mg/dl) and advanced (creatinine>6.0 mg/dl) RF. Conventional microelectrode techniques, western blotting, and histological examinations were performed using the isolated rabbit PV, left atrium (LA), right atrium (RA) and sinoatrial node (SAN). RESULTS: Advanced RF rabbits (n=18) had a higher incidence (33.3% vs. 11.1% and 0%, p<0.05) of atrial arrhythmia than mild RF (n=18) and control (n=18) rabbits. Advanced RF rabbits exhibited faster PV spontaneous activities, longer action potential duration (APD) in the LA, higher fibrosis in the LA, and slower SAN beating rates than control rabbits, but had a similar APD and fibrosis in the RA. Caffeine (1 mM) increased advanced RF PV arrhythmogenesis, which is blocked by flecainide (10 MUM), or KB-R7943 (10 MUM). Moreover, advanced RF rabbits had a higher expression of the Na+/Ca2+ exchanger, protein kinase A, phosphorylated ryanodine receptor (Serine 2808), and phosphorylated phospholamban (Serine 16) in PVs, and a higher expression of Cav 1.2 in the LA, and a lower expression of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 in the SAN. CONCLUSIONS: Advanced RF increases atrial arrhythmia by modulating the distinctive electrophysiological characteristics of the PV, LA, and SAN. PMID- 26476982 TI - Takotsubo cardiomyopathy triggered by ischemic injury: When lateralmyocardial infarction precipitate apical ballooning syndrome. PMID- 26476983 TI - Arrhythmia ablation using the Amigo Robotic Remote Catheter System versus manual ablation: One year follow-up results. PMID- 26476984 TI - Focal form of left ventricular non-compaction cardiomyopathy with congestive form of heart failure. PMID- 26476985 TI - The effect of transesophageal echocardiography on the incidence of thromboembolism after electrical cardioversion in atrial fibrillation: A multicenter analysis. PMID- 26476986 TI - Statin use and incident erectile dysfunction--A nationwide propensity-matched cohort study in Taiwan. AB - BACKGROUND: Statins are commonly prescribed for cardiovascular diseases which have been reported to share many contributory underlying mechanisms with erectile dysfunction (ED). However, the correlation between statin use and incident ED is uncertain. METHODS: We conducted a population-based propensity-matched cohort study by identifying new statin users among male patients 40-79 years of age in the period 2000 to 2010. A statin nonuser control cohort matched for age, propensity score, and index year at a 3:1 ratio was selected for comparison. Cohorts were tracked for the occurrence of any type of incident ED according to the registry of ED diagnosis in the database. The association between statin use and the risk of ED was evaluated by Cox proportional hazard model and adjusted by age, PS, socioeconomic status, comorbidities, and medications. RESULTS: Compared with nonusers, statin users had a significantly lower risk of incident ED (HR, 0.75; 95% CI, 0.63-0.90, p=0.002). Further analysis demonstrated that statin users in the group of middle-aged (40-49 years old) or high-potency statin treated (i.e., rosuvastatin, atorvastatin, and simvastatin) had lower HR for incident ED. Analysis in the patterns of cumulative statin exposure also showed that high-potency statins could decrease the HR for incident ED in dose- and duration-dependent manners. CONCLUSIONS: Statin use was associated with a reduced risk of incident ED in the middle-aged men in Taiwan. The potency and the cumulative exposure of statin utilized played critical roles. PMID- 26476987 TI - Tako-tsubo cardiomyopathy may lead to permanent changes in left ventricular geometry: Potential implications in the setting of pre-existing myocardial disease? PMID- 26476988 TI - Incidence and distribution of thin-high signals detected by coronary optical coherence tomography in patients treated with paclitaxel-coated balloon angioplasty for in-stent restenosis. PMID- 26476989 TI - Experience from a randomized controlled trial with Impella 2.5 versus IABP in STEMI patients with cardiogenic pre-shock. Lessons learned from the IMPRESS in STEMI trial. PMID- 26476990 TI - Difficulty in closing eyelid after local upper dental infiltration anaesthesia with articaine: case report. PMID- 26476991 TI - Featherstone gag: WHO checklist is not enough. PMID- 26477005 TI - A method for quantitative analysis of clump thickness in cervical cytology slides. AB - Knowledge of the spatial distribution and thickness of cytology specimens is critical to the development of digital slide acquisition techniques that minimise both scan times and image file size. In this paper, we evaluate a novel method to achieve this goal utilising an exhaustive high-resolution scan, an over-complete wavelet transform across multi-focal planes and a clump segmentation of all cellular materials on the slide. The method is demonstrated with a quantitative analysis of ten normal, but difficult to scan Pap stained, Thin-prep, cervical cytology slides. We show that with this method the top and bottom of the specimen can be estimated to an accuracy of 1 MUm in 88% and 97% of the fields of view respectively. Overall, cellular material can be over 30 MUm thick and the distribution of cells is skewed towards the cover-slip (top of the slide). However, the median clump thickness is 10 MUm and only 31% of clumps contain more than three nuclei. Therefore, by finding a focal map of the specimen the number of 1 MUm spaced focal planes that are required to be scanned to acquire 95% of the in-focus material can be reduced from 25.4 to 21.4 on average. In addition, we show that by considering the thickness of the specimen, an improved focal map can be produced which further reduces the required number of 1 MUm spaced focal planes to 18.6. This has the potential to reduce scan times and raw image data by over 25%. PMID- 26477006 TI - Tuning the sphere-to-rod transition in the self-assembly of thermoresponsive polymer hybrids. AB - Nano-scale drug delivery systems have undergone extensive development, and control of size and structure is critical for regulation of their biological responses and therapeutic efficacy. Amphiphilic polymers that form self-assembled structures in aqueous media have been investigated and used for the diagnosis and therapy of various diseases, including cancer. Here, we report the design and fabrication of thermoresponsive polymeric micelles from alginate conjugated with poly(N-isopropylacrylamide) (PNIPAAm). Alginate-PNIPAAm hybrids formed self aggregated structures in response to temperature changes near body temperature. A structural transition from micellar spheres to rods of alginate-PNIPAAm hybrids was observed depending on the molecular weight of PNIPAAm and the polymer concentration. Additionally, hydrogels with nanofibrous structures were formed by simply increasing the polymer concentration. This approach to controlling the structure of polymer micelles from nanoparticles to fibrous hydrogels may be useful in applications in drug delivery and tissue engineering. PMID- 26477007 TI - Thymine-functionalized amphiphilic biodegradable copolymers for high-efficiency loading and controlled release of methotrexate. AB - In this study, a novel thymine-functionalized six-membered cyclic carbonate monomer (TAC) was synthesized by the Michael-addition reaction between thymine and acryloyl carbonate (AC). The corresponding functional amphiphilic block copolymer mPEG-b-PTAC was further successfully synthesized by ring-opening polymerization using immobilized porcine pancreas lipase (IPPL) as the catalyst and mPEG as the macroinitiator. Meanwhile, mPEG-b-P(TAC-co-DTC) and mPEG-b-PDTC were also synthesized by the same enzymatic methods for comparison on different TAC contents. The structures of monomer and copolymers were characterized by (1)H NMR, (13)C-NMR and FTIR. All the amphiphilic block copolymers could self-assemble to form nano-sized micelles in aqueous solution. Transmission electron microscopy (TEM) observation showed that the micelles dispersed in spherical shape with nano size before and after MTX loading. (1)H-NMR and FTIR results confirmed the successful formation of multiple hydrogen-bonding interactions between exposed thymine groups of hydrophobic PTAC segments and 2,6-diaminopyridine (DAP) groups of MTX molecules, which resulting in the higher drug loading capacity and the pH sensitive drug release behavior. MTT assays also indicated lower toxicity of copolymer but higher potent cytotoxic activity of MTX-loaded copolymer against HeLa cells. PMID- 26477008 TI - Magneto-thermally responsive hydrogels for bladder cancer treatment: Therapeutic efficacy and in vivo biodistribution. AB - Bladder cancer is one of the deadliest forms of cancer in modern medicine which despite recent progress has remained incurable and challenging for researchers. There is unmet need to address this endemic as the number of patients are growing by about 10,000 every year world-wide. Here, we report a minimally invasive magnetic chemotherapy method to address this problem where polyethylene glycol (PEG) functionalized Fe3O4 magnetic nanostructures (MNS) are homogeneously embedded in thermally responsive poly(N-isopropylacrylamide, NIPAAm) hydrogels (HG). The system (HG-MNS) loaded with anti-cancer drug doxorubicin (DOX) incubated with cancer cell lines subjected to external radiofrequency (RF) field can remotely stimulate the release of drug smartly at the site. The in vitro efficacy investigated on bladder cancer (T-24) cell lines showed the potential of the system in dealing with the disease successfully. Further, the materials preferential accumulation via systemic delivery was studied using swiss mice model. Vital tissue organs like liver, lung and heart were analysed by magnetic resonance imaging (MRI). A detail accounts of the materials optimization, cytotoxicity and anti-proliferation activity tests with apoptosis analysis by flow cytometry after RF exposure (250 kHz) to the cells and in vivo biodistribution data are discussed in the paper. PMID- 26477009 TI - Is identification of smoking, risky alcohol consumption and overweight and obesity by General Practitioners improving? A comparison over time. AB - BACKGROUND: Detection of lifestyle risk factors by GPs is the first step required for intervention. Despite significant investment in preventive health care in general practice, little is known about whether GP detection of lifestyle risk factors have improved over time. OBJECTIVES: To examine whether sensitivity and specificity of GP detection of smoking, risky alcohol consumption and overweight and obesity has increased in patients presenting to see their GP, by comparing results from four Australian studies conducted between 1982 and 2011. METHODS: Demographic characteristics of patient and GP samples and the prevalence, sensitivity and specificity of detection of each risk factor were extracted from published studies. Differences between GP and patient sample characteristics were examined. To identify trends over time in prevalence of risk factors, sensitivity and specificity of detection across studies and the Cochran-Armitage test for trend were calculated for each risk factor for the overall sample and by male and female subgroups. RESULTS: There were no statistically significant changes in the sensitivity of GP detection of smoking or overweight or obesity over time. Specificity of detection of smoking increased from 64.7% to 98% (P < 0.0001) and decreased for overweight or obesity from 92% to 89% (P = 0.01). There was a small decrease in the sensitivity of detection of alcohol consumption (P = 0.02) and an increase in specificity (P = 0.01). CONCLUSIONS: Despite significant investment to increase GP detection and intervention for lifestyle risk factors, accurate detection of smoking, risky alcohol consumption and overweight and obesity occurs for less than two-thirds of all patients. PMID- 26477010 TI - Overweight can be used as a tool to guide case-finding for cardiovascular risk assessment. AB - BACKGROUND: In general practice, it is too time-consuming to invite all patients for cardiovascular risk assessment. OBJECTIVE: To examine how many patients with an indication for treatment with cardiovascular medication can be identified by ad hoc case-finding when all patients with overweight/obesity are invited for risk assessment. METHODS: A cross-sectional analysis of the baseline measurements of the Netherlands Epidemiology of Obesity study, a population-based prospective cohort study in 6673 persons aged 45-65 years. We calculated the proportion of participants with a treatment indication using the risk prediction Systematic COronary Risk Evaluation (SCORE-NL 2011), for lean, overweight and obese participants. Participants with a history of cardiovascular disease, diabetes mellitus or rheumatoid arthritis or using cardiovascular medication were not eligible for ad hoc case-finding because they were already identified as being at risk and/or had been treated. RESULTS: Of the study population, 30% had already been identified and/or treated with cardiovascular medication and were therefore not eligible for ad hoc case-finding. Of the eligible participants, 47% were lean, 41% overweight and 12% obese. Of the participants with overweight, 12% had a treatment indication and of the participants with obesity, 19% had a treatment indication. Of all participants with a treatment indication 24% were not yet treated. Of all participants with a new treatment indication, 70% had overweight or obesity. CONCLUSIONS: Of the participants with a treatment indication, 24% were not yet treated. Inviting patients with overweight/obesity for cardiovascular risk assessment may help to detect 70% of these residual patients with a treatment indication. PMID- 26477011 TI - Interferon-gamma promotes phagocytosis of Cryptococcus neoformans but not Cryptococcus gattii by murine macrophages. AB - Among invasive fungal infections, cryptococcosis caused by inhalation of Cryptococcus neoformans or Cryptococcus gattii is particularly dangerous because it can disseminate to the central nervous system and cause life-threatening meningitis or meningoencephalitis. Previous reports described significant differences in the histopathological features of C. neoformans and C. gattii infection, such as greater pathogen proliferation and a limited macrophage response in mouse lung infected by C. gattii. To elucidate the difference in pathogenicity of these two Cryptococcus species, we investigated the interaction of C. neoformans and C. gattii with murine macrophages, the first line of host defense, by confocal laser microscopy. Only thin-capsulated, and not thick capsulated C. neoformans and C. gattii were phagocytosed by macrophages. Preactivation with interferon-gamma increased the phagocytic rate of thin capsulated C. neoformans up to two-fold, but did not promote phagocytosis of thin capsulated C. gattii. Lipopolysaccharide preactivation or Aspergillus fumigatus conidia co-incubation had no effect on internalization of thin-capsulated C. neoformans or C. gattii by macrophages. Phagocytosis of live thin-capsulated C. neoformans, but not that of live thin-capsulated C. gattii, induced interleukin 12 release from macrophages. However, phagocytosis of heat-killed or paraformaldehyde-fixed thin-capsulated C. neoformans did not increase IL-12 release, showing that the internalization of live yeast is important for initiating the immune response during C. neoformans-macrophage interactions. Our data suggest that macrophage response to C. gattii is limited compared with that to C. neoformans and that these results may partially explain the limited immune response and the greater pathogenicity of C. gattii. PMID- 26477012 TI - Substance use in incarcerated male offenders: Predictive validity of a personality typology of substance misusers. AB - INTRODUCTION: Substance use and misuse is highly prevalent in offenders, and a significant proportion of convicted offenders continue to use controlled substances during incarceration. Few studies have focused on the identification of variables, especially personality characteristics, that may be predictive of institutional substance use. The purpose of this study is to assess the validity of the Substance Use Risk Profile (SURP) personality typology in a sample of male offenders and to determine whether it may have utility in identifying offenders at risk for substance use during incarceration. METHODS: A total of 118 offenders across all provincial and federal institutions in New Brunswick, Canada completed questionnaires assessing personality, mental health symptoms, substance use motives, and substance use. RESULTS: Latent class cluster analysis revealed the presence of three distinct clusters of offenders based on severity of substance use, personality, and mental health symptoms. Survival analysis indicated a significant effect of levels of sensation seeking, a trend of cluster membership, and anxiety sensitivity on days until first institutional substance use. CONCLUSION: High levels of sensation seeking and low anxiety sensitivity appear to indicate increased risk for substance misuse in this population. PMID- 26477013 TI - Trajectories of perceived discrimination from adolescence to emerging adulthood and substance use among Hispanic youth in Los Angeles. AB - Previous studies have documented associations between perceptions of racial/ethnic discrimination and adverse health outcomes among Hispanics and other minority groups. However, these studies have not examined change in perceived discrimination over the lifecourse and whether trajectories of perceived discrimination affect outcomes differently. This study of 2722 Hispanic students identified trajectories of perceived discrimination from 9th grade through emerging adulthood (approximately ages 14-23), and compared these trajectory groups on substance use outcomes. Four distinct trajectory groups were identified: (1) low and stable discrimination, (2) increasing discrimination, (3) initially high but decreasing discrimination, and (4) high and stable discrimination. Compared with the low and stable discrimination group, the groups that experienced higher levels of discrimination were at higher risk of cigarette, alcohol, marijuana, and hard drug use. Specifically, the group with increasing discrimination (group 2) had a higher risk of alcohol, marijuana, and hard drug use; the group with initially high but decreasing discrimination (group 3) had a higher risk of cigarette smoking and alcohol use; and the group with high and stable discrimination (group 4) had a higher risk of alcohol, marijuana, and hard drug use. Results indicate that experiencing discrimination during adolescence, emerging adulthood, or both, regardless of whether the discrimination increases or decreases, could place Hispanic youth at risk for substance use. Health education programs are needed to help Hispanic youth learn effective skills to cope with discrimination without resorting to substance use. PMID- 26477014 TI - I like people who drink like me: Perceived appeal as a function of drinking status. AB - INTRODUCTION: Individuals rate opposite sex faces as more attractive after consuming or being primed with alcohol. However, other traits such as intelligence and likeability have not been examined and might vary as a function of information about one's drinking habits. We expected social drinkers to be rated more positively than heavy drinkers, abstainers, or recovering alcoholics. We further hypothesized that faces with similar drinking habits to participants would be rated as more appealing. METHODS: Five hundred ninety-four undergraduates viewed 25 opposite sex faces randomly paired with drinking information, and rated each face on perceived appeal. RESULTS: Hierarchical linear models revealed that social drinkers were rated as most appealing, as expected. Unexpectedly, recovering alcoholics were rated as the next most appealing, followed by abstainers, then heavy drinkers. The interaction between drinker type and participants' own drinking predicting ratings indicated that the heavier the participant drinks, the more favorably they rated heavy drinkers compared to other types of drinkers. Thus, as expected, ratings varied as a function of participants' own drinking; however, ratings did not vary as a function of participants' alcohol-related problems. CONCLUSIONS: Findings support hypotheses in that social drinkers were generally perceived as appealing compared to other drinker types, and ratings tended to be influenced by participants' own drinking. Individuals' prototypes and norms regarding drinking may influence how they perceive others when others' drinking habits are known. This might be especially important to consider with heavy drinkers who may seek out others who drink similarly, which could reinforce problematic drinking. PMID- 26477015 TI - Social deprivation and hospital admission rates, length of stay and readmissions in emergency medical admissions. AB - BACKGROUND: Patients from deprived backgrounds have a higher in-patient mortality following an emergency medical admission. How deprivation relates to the admission or readmission incidence rates, episode length of stay (LOS) and ancillary resource utilization is less clear. METHODS: All emergency medical admissions (66,861 episodes in 36,214 patients) between 2002 and 2013, categorized by quintile of Irish National Deprivation Index were assessed against admission or readmission incidence rates (/1000 local population by electoral division), LOS and utilization of five ancillary services. Univariate and multi variable risk estimates (odds ratios (OR) or incidence rate ratios (IRR)) were calculated, using truncated Poisson regression. RESULTS: The deprivation index quintile was strongly correlated with the emergency medical admission rate with IRR (as compared with quintile 1) as follows: Q2 1.99 (95% CI: 1.96, 2.01), Q3 3.45 (95% CI: 3.41, 3.49), Q4 3.27 (95% CI: 3.23, 3.31) and Q5 4.29 (95% CI: 4.23, 4.35). LOS was not influenced by deprivation status; although increasing deprivation resulted in increased utilization of social services (OR 1.04: 95% CI: 1.03, 1.06), with a lower requirement for occupational therapy (OR 0.94: 95% CI: 0.93, 0.96) and speech/language services (OR 0.83: 95% CI: 0.80, 0.86). There was a rather decreased use of ancillary services with increasing deprivation; however, the readmission rate was strongly predicted by deprivation status. CONCLUSION: Deprivation status strongly influenced the admission and readmission rates for medical patients admitted as emergencies; however, ancillary resource utilization was not increased. Deprivation index will increase demand on hospital resources due to the aggregate effect on both admission and readmission incidence rates. PMID- 26477016 TI - Acute and chronic diseases as part of multimorbidity in acutely hospitalized older patients. AB - BACKGROUND: To describe the prevalence of multimorbidity and to study the association between acute and chronic diseases in acutely hospitalized older patients METHODS: Prospective cohort study conducted between 2006 and 2008 in three teaching hospitals in the Netherlands. 639 patients aged 65 years and older, hospitalized for >48 h were included. Two physicians scored diseases, using ICD-9 codes. Chronic multimorbidity was defined as the presence of >=2 chronic diseases, and acute multimorbidity as >=1 acute diseases upon pre existent chronic diseases. Logistic regression analyses were conducted to analyse cluster associations between a chronic index disease and the concurrent chronic or acute disease, corrected for age and sex. RESULTS: The mean age of patients was 78 years, over 50% had ADL impairments. Prevalence of chronic multimorbidity was 69%, and acute multimorbidity was present in 88%. Hypertension (OR 1.16; 95% CI 1.08-1.24), diabetes (type I or type 2) (OR 1.12; 95% CI 1.04-1.21), heart failure (OR 1.25; 95% CI 1.14-1.38) and COPD (OR 1.19; 95% CI 1.05-1.34) were associated with acute renal failure. Hypertension (OR 1.10; 95% CI 1.04-1.17) and atrial fibrillation (OR 1.17; 95% CI 1.08-1.27) were associated with an adverse drug event. Gastro-intestinal bleeding was clustered with atrial fibrillation (OR 1.11; 95% CI 1.04-1.19) and gastric ulcer (OR 1.16; 95% CI 1.07-1.25). CONCLUSION: Both acute and chronic multimorbidity was frequently present in hospitalized older patients. We identified specific associations between acute and chronic diseases. There is a need for strategies addressing multimorbidity during the exacerbation of chronic diseases. PMID- 26477017 TI - Patient satisfaction with a hospital-based neuropsychology service. AB - Objective The aim of the present study was to develop and pilot a measure of patient satisfaction that encompasses themes, activities, settings and interactions specific to the neuropsychological assessment process. Methods A focus group of out-patients (n=15) was surveyed to identify the factors commonly associated with a satisfactory neuropsychological experience. Responses informed a purposely designed 14-item patient satisfaction scale (alpha=0.88) that was completed by 66 hospital out-patients with mild to moderate cognitive impairment. Results Satisfaction with the neuropsychological assessment process was generally reported, with the testing phase (85%) rated significantly more favourably than the pre-assessment (79%) and feedback (70%) phases. Commentaries provided by 32 respondents identified interpersonal facilitators to a satisfactory neuropsychological assessment experience, but also dissatisfaction with physical aspects of the testing environment in addition to service availability. Conclusions The patient satisfaction scale can be used as a quality assurance tool to evaluate neuropsychological service delivery. Large-scale research is needed to confirm the scale's psychometric properties. Further research may also include a broader perspective on the consumers' experience of neuropsychological services. PMID- 26477018 TI - Caring for parents: a consequentialist approach. AB - In this paper, I explain the demands of filial obligations from act and rule consequentialism. More specifically, I defend a rule-consequentialist explanation of filial obligations, and identify a few factors in relation to the determination of filial demands; they include the costs of internalization of filial obligations, and the proportions of the young and the old generations in a population pyramid. I believe that in a society with an aging population, we may accept a strong view of filial obligation. Towards the end of the paper, I explain that rule-consequentialism is compatible with certain special views of filial obligations, such as the gratitude theory and the special goods theory; these theories represent ways in which adult children and their parents may obtain special goods from engaging in the relationship. PMID- 26477019 TI - A question of origin: dioxin-like PCBs and their relevance in stock management of European eels. AB - The stock of European Eel (Anguilla anguilla L.) has reached an all-time low in 2011. Spawner quality of mature eels in terms of health status and fitness is considered one of the key elements for successful migration and reproduction. Dioxin-like Polychlorinated Biphenyls (dl-PCBs) are known persistent organic pollutants potentially affecting the reproductive capability and health status of eels throughout their entire lifetime. In this study, muscle tissue samples of 192 European eels of all continental life stages from 6 different water bodies and 13 sampling sites were analyzed for contamination with lipophilic dl-PCBs to investigate the potential relevance of the respective habitat in light of eel stock management. Results of this study reveal habitat-dependent and life history stage-related accumulation of targeted PCBs. Sum concentrations of targeted PCBs differed significantly between life stages and inter-habitat variability in dl PCB levels and -profiles was observed. Among all investigated life stages, migrant silver eels were found to be the most suitable life history stage to represent their particular water system due to habitat dwell-time and their terminal contamination status. With reference to a possible negative impact of dl PCBs on health and the reproductive capability of eels, it was hypothesized that those growing up in less polluted habitats have a better chance to produce healthy offspring than those growing up in highly polluted habitats. We suggest that the contamination status of water systems is fundamental for the life cycle of eels and needs to be considered in stock management and restocking programs. PMID- 26477020 TI - Alemtuzumab use in neuromyelitis optica spectrum disorders: a brief case series. AB - Alemtuzumab is an anti-CD52 monoclonal antibody recently licensed for use in relapsing-remitting multiple sclerosis. Here, we report our experience of its use in neuromyelitis optica (NMO) spectrum disorders. A retrospective case review of patients treated with alemtuzumab in Cambridge, UK, was conducted to identify those who fulfil the criteria for NMO spectrum disorder. Three cases were identified. Case 1, 9-year-old female, presented with transverse myelitis and bilateral optic neuritis,with one lower medullary and several longitudinally extensive cord lesions. Despite immunosuppression including two courses of alemtuzumab, she continued to relapse, was wheelchair bound and registered blind by age 12, and died at age 18. Case 2, 41-year-old female, presented with bilateral optic neuritis and transverse myelitis with longitudinally extensive cervical cord lesions. Despite three courses of alemtuzumab, she had five relapses with visual impairment and new cord lesions. She later developed tumefactive white matter lesions and died aged 51.Case 3, 31-year-old female, presented with transverse myelitis with longitudinally extensive cervical cord lesions and positive aquaporin-4 antibody. After one course of alemtuzumab, she relapsed with 4 episodes of myelitis with new enhancing lesions and accumulating disability. She became relapse free after rituximab and mycophenolate mofetil. From this case series, we conclude that alemtuzumab failed to prevent disabling relapses and poor outcome in NMO. We hypothesise that rituximab is more effective, as in case 3, because it causes much more prolonged B lymphocyte depletion than alemtuzumab. We therefore caution against the use of alemtuzumab in NMO. PMID- 26477021 TI - "Orbiting around" the orbital myositis: clinical features, differential diagnosis and therapy. AB - Orbital myositis (OM) is a rare disease whose clinical heterogeneity and different treatment options represent a diagnostic and therapeutic challenge. We aim to review the state of knowledge on OM, also describing a cohort of patients diagnosed in our centre, to highlight some remarkable clinical features. A literature review was conducted in PubMed and Medline databases. The herein described cohort is composed of seven OM patients, diagnosed according to clinical, laboratory and neuroradiological features, whose clinical data were retrospectively analysed. OM is a non-infectious, inflammatory process primarily involving extraocular eye-muscles. It typically presents as an acute to sub acute, painful ophthalmoplegia with signs of ocular inflammation, but atypical cases without pain or with a chronic progression have been described. The wide range of OM mimicking diseases make a prompt diagnosis challenging but orbit MRI provides valuable clues for differential diagnosis. Timely treatment is greatly important as OM promptly responds to steroids; nevertheless, partial recovery or relapses often occur. In refractory, recurrent or steroid-intolerant cases other therapeutic options (radiotherapy, immunosuppressants, immunoglobulins) can be adopted, but the most effective therapeutic management is yet to be established. In this review, we provide a detailed clinical description of OM, considering the main differential diagnoses and suggesting the most useful investigations. In light of the currently available data on therapy efficacy, we propose a therapeutic algorithm that may guide neurologists in OM patients' management. PMID- 26477022 TI - Spectrum of cerebral spinal fluid findings in patients with posterior reversible encephalopathy syndrome. AB - The purpose of this study is to characterize the spectrum of cerebrospinal fluid (CSF) findings in patients with posterior reversible encephalopathy syndrome (PRES)and determine its associations with severity of edema. In this retrospective cross-sectional study electronic medical reports were screened for patients with PRES. Clinical and laboratory data closest to onset of clinical symptoms were collected. Neuroimaging reports from all patients were categorized according to the presence of vasogenic edema,cytotoxic edema and contrast enhancement. From Jan 1999to Feb 2015, 87 patients with PRES and CSF findings were included. Mean total protein levels were 793 +/- 929 mg/l. Median cell counts were 2/MUl (IQR 1-4). Eight patients had cell counts[6/MUl with a maximum of 41/MUl. In 31 patients with extended CSF analysis, mean CSF/serum albuminquotient (QAlb) was 10.1 (IQR 6-17.3). An elevated QAlb (age-adjusted) was found in 74 % of these 31 patients. PRES patients with severe edema had higher mean total protein levels in CSF (mean difference = 407 mg/l; 95 %CI 187-628). Significant correlations were found for edema severity with levels of CSF protein (r = 0.48, p<0.001) as well with QAlb (r = 0.44, p = 0.013). This study shows that total protein in CSF and QAlb are elevated and correlate with severity of edema in PRES patients, whereas pleocytosis was rare in our cohort. This supports the theory that PRES is caused by a dysfunctional blood brain barrier. PMID- 26477023 TI - A pilot study of cognitive behavioural therapy and relaxation for migraine headache: a randomised controlled trial. AB - Headache is being viewed more commonly in a biopsychosocial framework, which introduces the possible utilisation of psychological treatment options, such as cognitive behavioural therapy and relaxation. No such treatments have been trialled in the UK. We conducted a randomised controlled pilot trial, comparing a brief guided self-help CBT and relaxation treatment with standard medical care (SMC), in a UK NHS setting. Participants were recruited from specialist headache clinics across London. Participants were randomised to receive either treatment or standard medical care. Our objective was to provide design information necessary for a future definitive trial of the SHE treatment, including, recruitment/retention rates, acceptability of randomisation, treatment fidelity and estimations of mean and variances of outcome measures. From the initial 275 patients identified, 73 were randomised. There was no difference in drop-out rates between SMC and treatment groups. Of the 36 participants randomised to receive treatment, 72% attended all sessions. Findings show that a future definitive trial of the SHE treatment is feasible, with small modifications of protocol, within a UK NHS context. PMID- 26477025 TI - Nerve ultrasound in the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis with predominant lower motor neuron disease (ALS/LMND). AB - The objective of the study was to investigate nerve ultrasound (US) in comparison to nerve conduction studies (NCS) for differential diagnosis of amyotrophic lateral sclerosis with predominant lower motoneuron disease(ALS/LMND) and multifocal motor neuropathy(MMN). A single-center, prospective, examiner-blinded cross-sectional diagnostic study in two cohorts was carried out. Cohort I: convenience sample of subjects diagnosed with ALS/LMND or MMN (minimal diagnostic criteria:possible ALS (revised EL-Escorial criteria), possible MMN (European Federation of Neurosciences guidelines).Cohort II: consecutive subjects with suspected diagnosis of either ALS/LMND or MMN. Diagnostic US and NCS models were developed based on ROC analysis of 28 different US and 32 different NCS values measured in cohort I. Main outcome criterion was sensitivity/specificity of these models between ALS/LMND and MMN in cohort II.Cohort I consisted of 16 patients with ALS/LMND and 8 patients with MMN. For cohort II, 30 patients were recruited, 8 with ALS/LMND, 5 with MMN, and 17 with other diseases. In cohort I, the three best US measures showed higher mean +/- SD areas under the curve than the respective NCS measures (0.99 +/- 0.01 vs. 0.79 +/- 0.03, p<0.001; two-sided t test). The US model with highest measurement efficacy (8 values) and diagnostic quality reached 100 % sensitivity and 92 % specificity for MMN in cohort II, while the respective NCS model (6 values, including presence of conduction blocks) reached 100 and 52 %. Nerve US is of high diagnostic accuracy for differential diagnosis of ALS/LMND and MMN. It might be superior to NCS in the diagnosis of MMN in hospital-admitted patients with this differential diagnosis. PMID- 26477024 TI - Strategies to target drugs to gliomas and CNS metastases of solid tumors. AB - The treatment for central nervous system metastases of solid tumors and gliomas is limited as the blood-brain barrier (BBB) is an obstacle to systemic therapy. Here, we review the physiochemical properties of the BBB and both current and new drug strategies to penetrate brain tumors. We focus on targeting receptor- or carrier-mediated transport mechanisms over the BBB used by drug conjugates, nanoparticles, polymer-based nanocarriers, siRNA, and antibodies. PMID- 26477026 TI - Risk factors for the recurrence of post-semicircular canal benign paroxysmal positional vertigo after canalith repositioning. AB - This retrospective study was conducted to determine the relationship between variable factors and the recurrence rate of post-semicircular canal benign paroxysmal positional vertigo (PSC-BPPV) after canalith repositioning procedure (CRP). Patients with PSC-BPPV were diagnosed by history and the presence of a positive Dix-Hallpike maneuver between 2008 and 2010. In total, 243 patients (47 males and 196 females, average age = 57.5 -years) treated with Epley's maneuver or canalith repositioning procedure (CRP) were included in the study. The demographic factors studied were age, sex, sleep disorders, inner ear diseases, head trauma history, and cardiovascular diseases. Multivariate statistics using SPSS version 15, Pearson's Chi-squared test (chi2), Kaplan-Meier analysis, log rank test, and Cox proportional hazards regression model were used for the analysis. The success rate of vertigo control after the initial CRP was 83.1 %. Pearson's chi2 test results showed that females and participants with sleep disorders exhibited a significant difference in the recurrence of vertigo after the initial CRP. In addition, the Kaplan-Meier analysis and log-rank test survival analysis revealed that the recurrence was associated with females and participants with sleep disorders and inner ear diseases.However, Cox proportional hazards regression showed no differences in recurrences associated with old age, sex, sleep disorders, inner ear diseases, head trauma, and cardiovascular diseases. Epley's maneuver or CRP is an effective, safe, and simple treatment for BPPV. Females and participants with sleep disorders and inner ear diseases are likely associated with the recurrence of BPPV after CRP. PMID- 26477027 TI - Strictly monitored exercise programs reduce motor deterioration in ALS: preliminary results of a randomized controlled trial. AB - The objective of our study was to perform a randomized controlled trial (RCT) aimed to evaluate the effects of three strictly monitored exercise programs(SMEP) compared to "usual care" (UCP) in a cohort of ALS patients. We included patients with definite and probable ALS and disease duration <=24 months. Patients were randomized to receive a SMEPs or a UCP. SMEPs included three subgroups of treatment: active exercises associated with cycloergometer activity (1A), only active (1B) and passive (1C) exercises, respectively. Moreover, SMEP patients and their caregivers were trained to a daily home-based passive exercise program. The UCP group was treated with passive and stretching exercises twice weekly. The treatment period for both groups was 6 months (T180), and patients were assessed by revised ALS Functional Rating Scale (ALSFRS-R), % Forced Vital Capacity (FVC %), and McGill Quality of Life (MGQoL) questionnaire. ALSFRS-R score was also evaluated at 6 months after the treatment period (T360). Sixty ALS patients were randomly assigned to one of two arms: SMEP Group included 30 patients, ten subjects for each subgroup (1A, 1B, and 1C); 30 patients were included in the UCP Group.At T180 and T360, SMEPs group had significantly higher ALSFRS-R score compared to the UCP group (32.8 +/- 6.5 vs 28.7 +/- 7.5, p = 0.0298; 27.5 +/- 7.6 vs 23.3 +/- 7.6, p = 0.0338, respectively). No effects of SMEPs on survival, respiratory decline and MGQol were found. In conclusion, although no effect on survival was demonstrated,our data suggest that a strictly monitored exercise program may significantly reduce motor deterioration in ALS patients. PMID- 26477028 TI - Characteristic diffusion tensor tractography in multiple system atrophy with predominant cerebellar ataxia and cortical cerebellar atrophy. AB - The objective of this study is to determine whether diffusion tensor imaging (DTI) tractography analysis is a potential method for differentiating cerebellar ataxia patients with multiple system atrophy with predominant cerebellar ataxia (MSA-C) and cortical cerebellar atrophy (CCA). Forty-one MSA-C patients (62.7 +/- 8.1 years old, mean +/- SD) and age- and gender-matched 15 CCA patients (63.0 +/- 8.6 years old) were examined.Tractography was performed using the DTI track module provided in the MedINRIA version 1.9.4, and regions of interest were drawn manually to reconstruct an efferent fiber tract and two afferent fiber tracts via the cerebellum. Compared with CCA, MSA-C patients showed significant declines of fractional anisotropy (FA) values of afferent 1 and 2 (p<0.01, respectively) and a significant increase of the radial diffusivity (RD) value in afferent 1 (p<0.05). Receiver-operator characteristic curve analysis showed 85.7 % sensitivity and 75.0 % specificity of FA values in afferent 1 (cutoff value 0.476). Linear regressions showed strong correlations between FA value and disease duration in CCA patients (efferent 1, r = -0.466; afferent 2, r = -0.543; both p<0.05), and between the FA value and the ratio of the standardized scale for the assessment and rating of ataxia (SARA)/disease duration in MSA-C patients (afferent 1, r = -0.407; p<0.01). The present DTI tractography newly showed that the FA values of two afferent fiber tracts showed significant declines in MSA-C patients, and afferent 1 showed good diagnostic sensitivity and specificity. When combining the FA values of efferent 1 with disease duration, the present DTI tractography analysis could be useful for differentiating MSA-C and CCA patients. PMID- 26477030 TI - Reproductive seasonality in creole hair sheep in the tropic. AB - The objective of the present study was to evaluate the annual ovulatory activity of hair sheep at 15 degrees N. Nineteen Creole ewes with body weight of 40.8 +/- 0.3 kg were used. The ovulatory activity was monitored for a year by quantifying progesterone concentrations in blood samples obtained from all the ewes every 7 days. The differences in monthly proportions of ewes with ovulatory activity were analyzed by the chi-square test. Ovulatory activity decreased from May to July and in September, and 42% of ewes ovulated year round. It is concluded that at 15 degrees N, a high proportion of ewes is capable of ovulating throughout the year in the tropical southeastern region of Mexico. PMID- 26477029 TI - Clinical utility of 18F-FDG-PET/MR for preoperative breast cancer staging. AB - OBJECTIVE: To evaluate the performance of 18F-fluorodeoxyglucose (FDG) positron emission tomography magnetic resonance imaging (PET/MR) for preoperative breast cancer staging. METHODS: Preoperative PET/MR exams of 58 consecutive women with breast cancer were retrospectively reviewed. Histology and mean follow-up of 26 months served as gold standard. Four experienced readers evaluated primary lesions, lymph nodes and distant metastases with contrast-enhanced MRI, qualitative/quantitative PET, and combined PET/MR. ROC curves were calculated for all modalities and their combinations. RESULTS: The study included 101 breast lesions (83 malignant, 18 benign) and 198 lymph node groups, (34 malignant, 164 benign). Two patients had distant metastases. Areas under the curve (AUC) for breast cancer were 0.9558, 0.8347 and 0.8855 with MRI, and with qualitative and quantitative PET/MR, respectively (p = 0.066). Sensitivity for primary cancers with MRI and quantitative PET/MR was 100 % and 77 % (p = 0.004), and for lymph nodes 88 % and 79 % (p = 0.25), respectively. Specificity for MRI and PET/MR for primary cancers was 67 % and 100 % (p = 0.03) and for lymph nodes 98 % and 100 % (p = 0.25). CONCLUSIONS: In breast cancer patients, MRI alone has the highest sensitivity for primary tumours. For nodal metastases, both MRI and PET/MR are highly specific. KEY POINTS: * MRI alone and PET/MR have a similar overall diagnostic performance. * MRI alone has a higher sensitivity than PET/MR for local tumour assessment. * Both MRI and PET/MR have a limited sensitivity for nodal metastases. * Positive lymph nodes on MRI or PET/MR do not require presurgical biopsy. PMID- 26477031 TI - Body weight and reproductive parameters in fast and weak growing Awassi ram lambs during different age stages. AB - This study was carried out on 30 Syrian Awassi ram lambs around 3 months of age. Lambs were divided equally in 2 groups as fast growing (FG) and weak growing (WG) lambs to identify body weight and reproductive parameters in each group during different age stages. Blood samples were collected to determine testosterone and leptin concentrations using radioimmunoassay. At puberty, average body weight and age of FG and WG lambs was 52.4 and 43.1 kg, and 225.9 and 248.0 days, respectively, with a significant (P < 0.05) difference between them in both parameters. Testosterone concentration was very low at 3 months of age (below 1.0 nmol L(-1)) and increased with advancing age with a sharp increase occurring at 7 months of age and at puberty, averages were 12.58 and 11.86 nmol L(-1) for FG and WG groups, respectively, with no significant (P > 0.05) differences. At puberty, average leptin concentration was 3.16 and 2.98 ng mL(-1) for FG and WG groups, respectively, with no significant (P > 0.05) difference. PMID- 26477032 TI - Investigation of major cattle production constraints in Kembata Tambaro zone of Southern Ethiopia using participatory epidemiology methods. AB - Ethiopia has enormous livestock resources from which rural households derive their livelihoods. A cross-sectional study based on participatory appraisal methods was conducted in Kembata Tambaro zone to assess major constraints to livestock production and major diseases of cattle and their treatment options. Four districts were selected purposively for this study, and 18 peasant associations were randomly sampled from the selected districts. Focus group discussion, semistructured interviews, simple ranking and scoring, proportional piling, pairwise ranking, and matrix scoring were the participatory epidemiological tools used in the study. Feed and free grazing land shortages and diseases were found to be the major constraints to cattle production in the area. Mastitis was ranked as the most serious disease of cattle. Modern veterinary treatments are used alongside traditional herbal remedies. Matrix scoring showed strong agreement between focus groups in identifying the major diseases using their indicators (clinical signs). Hence, it was concluded that indigenous knowledge complemented with participatory methods and approaches allow community and field researchers to jointly study specific livestock problems and help identify appropriate solutions. PMID- 26477033 TI - 2014 Conway review lecture, Royal Academy of Medicine in Ireland: "S6, drugs and RCK and Bowl". AB - BACKGROUND: The Conway Review Lecture is held annually by the Royal Academy of Medicine in Ireland Biomedical Sciences Section, to remember the life and scientific work of a world class Irish scientist, Professor Edward J Conway. AIMS: This years lecture will focus on large conductance Ca2+ activated K+ (BK) channels and aims to describe how a combination of techniques can be used to unravel drug effects on ion channels at a molecular level. METHODS: Experiments were performed using a range of techniques including patch clamp electrophysiology, mutagenesis, structural biology and mathematical modeling. RESULTS: Our data suggest that the novel BK channel opener GoSlo-SR-5-6 mediates its effects via an interaction with 2 residues on S6 (S317 and I326) and a residue on the S4/S5 linker (L227). CONCLUSIONS: We hypothesize that this novel opener activates BK channels by altering an interaction between the S4/S5 linker and the pore-forming S6 transmembrane helix. PMID- 26477034 TI - Hybrid Intercalated Duct Lesion of the Parotid: Diagnostic Challenges of a Recently Described Entity with Fine Needle Aspiration Findings. AB - Intercalated duct lesions (IDL) of the salivary glands are recently described, and encompass both hyperplasia and benign neoplasms that remain incompletely understood. IDLs have been linked to various benign and low-grade malignant salivary gland neoplasms. We herein present a case of a 77 year old woman with an IDL of the parotid composed of both a hyperplastic and an adenomatous component and report, for the first time, the fine needle aspiration findings of such a lesion. This case illustrates the morphologic spectrum of an IDL, as well as challenges in rendering an accurate cytological and histologic diagnosis. The potential diagnostic pitfalls presented by the hybrid pattern of this lesion are also discussed. PMID- 26477035 TI - Simultaneous Triple Primary Head and Neck Malignancies: A Rare Case Report. AB - The occurrences of multiple primary malignant tumours in the head and neck region are reported as simultaneous, synchronous, or metachronous based on their chronology of presentation. Lymphoid malignancies presenting in association with squamous cell carcinoma in the head and neck region are extremely rare. We report a case of a 71 year old male patient with simultaneous triple primary malignancies of different histologic origin, involving larynx (squamous cell carcinoma), thyroid (papillary thyroid carcinoma) and lymph nodes (non-Hodgkin's lymphoma). PMID- 26477036 TI - Low intraoperative heart rate volatility is associated with early postoperative mortality in general surgical patients: a retrospective case-control study. AB - Heart rate volatility (HRVO) is hypothesized to be a physiological measure of sympathetic activity and is defined by the standard deviation (SD) of the heart rate (HR) in beats per minutes (BPM) over fixed time intervals. To investigate the relationship between low HRVO (SD < 0.5 BPM) during surgical procedures and mortality within 48 h post-procedure. We retrospectively reviewed all adult general surgical procedures performed at our center from January 1, 2003 through July 1, 2013 to identify patients who died within 48 h post-procedure. Demographic, heart rate, and mortality data were extracted from the electronic anesthesia record. Propensity score analysis was used to find matching controls based on age, gender, ASA score, anesthesia type, Charlson index, procedure type, emergency status, year, use of preoperative beta blocker, hypertension, diabetes, atrial fibrillation and heart failure. HRVO was calculated for each 5 min interval as the SD of all HR's within that interval. Negative binomial regression was then used to model the count of intervals with HRVO < 0.5 BPM for the duration of the surgery. During the 10 year study period, 283 patients died within 48 h of procedure finish. These patients were matched to 566 patients who did not die within 48 h after procedure. Patients who died had a 39 % increase in frequency of low HRVO episodes compared to patients who survived (RR 1.39, 95 % CI 1.13-1.72; p = 0.003). Low HRVO during surgical procedure is associated with increased mortality risk within 48 h after procedure. Strategies to identify HRVO early and modify it may lead to improvement in outcomes. PMID- 26477037 TI - Phenology and structure of a phytoseiid community in an insecticide-free apple orchard. AB - Commercial orchards have acarine communities that are reduced in biological diversity compared to their undisturbed counterparts. Examining the phenology of an unsprayed orchard allows for the examination of non-pesticide factors that drive changes in populations. This study examined the mite community in a largely unsprayed research orchard in 2013-2014. The phytoseiids Galendromus flumenis (Chant), Amblydromella caudiglans (Schuster), Kampimodromus corylosus Kolodochka, and Galendromus occidentalis (Nesbitt) were found, in addition to Zetzellia mali (Ewing) and Aculus schlechtendali (Nalepa). Although G. occidentalis is typically the dominant phytoseiid in commercial orchards, G. flumenis was much more abundant in this unsprayed block. Aculus schlechtendali appeared to be the main source of prey for all predator species. The availability of this prey item and the lack of pesticides are likely the factors that allowed for G. flumenis to reach high abundances. Tetranychids were scarce, emphasizing the role of these mites as induced pests; without the application of disruptive sprays, the predatory mite community was able to maintain biological control. This study demonstrates that the species complex of generalist phytoseiids that is present in orchard systems undisturbed by pesticides is sufficient to maintain spider mite populations below damaging levels throughout the season. PMID- 26477038 TI - The natural infection of birds and ticks feeding on birds with Rickettsia spp. and Coxiella burnetii in Slovakia. AB - Ixodid ticks (Acari: Ixodidae) are known as primary vectors of many pathogens causing diseases in humans and animals. Ixodes ricinus is a common ectoparasite in Europe and birds are often hosts of subadult stages of the tick. From 2012 to 2013, 347 birds belonging to 43 species were caught and examined for ticks in three sites of Slovakia. Ticks and blood samples from birds were analysed individually for the presence of Rickettsia spp. and Coxiella burnetii by PCR based methods. Only I. ricinus was found to infest birds. In total 594 specimens of bird-attached ticks were collected (451 larvae, 142 nymphs, 1 female). Altogether 37.2% (16/43) of bird species were infested by ticks and some birds carried more than one tick. The great tit, Parus major (83.8%, 31/37) was the most infested species. In total, 6.6 and 2.7% of bird-attached ticks were infected with Rickettsia spp. and C. burnetii, respectively. Rickettsia helvetica predominated (5.9%), whereas R. monacensis (0.5%) was only sporadically detected. Coxiella burnetii was detected in 0.9%, Rickettsia spp. in 8.9% and R. helvetica in 4.2% of bird blood samples. The great tit was the bird species most infested with I. ricinus, carried R. helvetica and C. burnetti positive tick larvae and nymphs and was found to be rickettsaemic in its blood. Further studies are necessary to define the role of birds in the circulation of rickettsiae and C. burnetii in natural foci. PMID- 26477040 TI - Vedolizumab for the Treatment of Adults with Moderate-to-Severe Active Ulcerative Colitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to severe active ulcerative colitis (UC). The Evidence Review Group (ERG) produced a critical review of the evidence for the clinical effectiveness and cost effectiveness of the technology, based upon the company's submission to NICE. The evidence was derived mainly from GEMINI 1, a Phase 3, multicentre, randomised, double-blinded, placebo-controlled study of the induction and maintenance of clinical response and remission by vedolizumab (MLN0002) in patients with moderate-to-severe active UC with an inadequate response to, loss of response to or intolerance of conventional therapy or anti-tumour necrosis factor (TNF) alpha. The clinical evidence showed that vedolizumab performed significantly better than placebo in both the induction and maintenance phases. In the post hoc subgroup analyses in patients with or without prior anti-TNF-alpha therapy, vedolizumab performed better then placebo (p value not reported). In addition, a greater improvement in health-related quality of life was observed in patients treated with vedolizumab, and the frequency and types of adverse events were similar in the vedolizumab and placebo groups, but the evidence was limited to short-term follow-up. There were a number of limitations and uncertainties in the clinical evidence base, which warrants caution in its interpretation--in particular, the post hoc subgroup analyses and high dropout rates in the maintenance phase of GEMINI 1. The company also presented a network meta-analysis of vedolizumab versus other biologic therapies indicated for moderate-to-severe UC. However, the ERG considered that the results presented may have underestimated the uncertainty in treatment effects, since fixed-effects models were used, despite clear evidence of heterogeneity among the trials included in the network. Results from the company's economic evaluation (which included price reductions to reflect the proposed patient access scheme for vedolizumab) suggested that vedolizumab is the most effective option compared with surgery and conventional therapy in the following three populations: (1) a mixed intention-to treat population, including patients who have previously received anti-TNF-alpha therapy and those who are anti-TNF-alpha naive; (2) patients who are anti-TNF alpha naive only; and (3) patients who have previously failed anti-TNF-alpha therapy only. The ERG concluded that the results of the company's economic evaluation could not be considered robust, because of errors in model implementation, omission of relevant comparators, deviations from the NICE reference case and questionable model assumptions. The ERG amended the company's model and demonstrated that vedolizumab is expected to be dominated by surgery in all three populations. PMID- 26477039 TI - Methods for Health Economic Evaluation of Vaccines and Immunization Decision Frameworks: A Consensus Framework from a European Vaccine Economics Community. AB - BACKGROUND: Incremental cost-effectiveness and cost-utility analyses [health economic evaluations (HEEs)] of vaccines are routinely considered in decision making on immunization in various industrialized countries. While guidelines advocating more standardization of such HEEs (mainly for curative drugs) exist, several immunization-specific aspects (e.g. indirect effects or discounting approach) are still a subject of debate within the scientific community. OBJECTIVE: The objective of this study was to develop a consensus framework for HEEs of vaccines to support the development of national guidelines in Europe. METHODS: A systematic literature review was conducted to identify prevailing issues related to HEEs of vaccines. Furthermore, European experts in the field of health economics and immunization decision making were nominated and asked to select relevant aspects for discussion. Based on this, a workshop was held with these experts. Aspects on 'mathematical modelling', 'health economics' and 'decision making' were debated in group-work sessions (GWS) to formulate recommendations and/or--if applicable--to state 'pros' and 'contras'. RESULTS: A total of 13 different aspects were identified for modelling and HEE: model selection, time horizon of models, natural disease history, measures of vaccine induced protection, duration of vaccine-induced protection, indirect effects apart from herd protection, target population, model calibration and validation, handling uncertainty, discounting, health-related quality of life, cost components, and perspectives. For decision making, there were four aspects regarding the purpose and the integration of HEEs of vaccines in decision making as well as the variation of parameters within uncertainty analyses and the reporting of results from HEEs. For each aspect, background information and an expert consensus were formulated. CONCLUSIONS: There was consensus that when HEEs are used to prioritize healthcare funding, this should be done in a consistent way across all interventions, including vaccines. However, proper evaluation of vaccines implies using tools that are not commonly used for therapeutic drugs. Due to the complexity of and uncertainties around vaccination, transparency in the documentation of HEEs and during subsequent decision making is essential. PMID- 26477041 TI - Occupational sunscreen use among US Hispanic outdoor workers. AB - BACKGROUND: Occupational ultraviolet radiation (UVR) exposure is a risk factor for skin cancer, and Hispanic individuals are over-represented in a number of outdoor occupations (e.g., farming, landscaping). This study examined predictors of occupational sunscreen use in a group of US Hispanic adults who work outdoors. RESULTS: A population-based sample of outdoor workers (n = 149, 85 % male) completed survey measures regarding their demographics, melanoma risk, perceived skin cancer risk, skin cancer knowledge, and their occupational sunscreen use. Sixty-nine percent of the sample reported never or rarely wearing sunscreen while working outdoors. Being female (p = .02), having a higher level of education (p = .03), and residing at a higher latitude (p = .04) were associated with more frequent sunscreen use. CONCLUSIONS: This study highlights the importance of interventions to promote sun protection behaviors among US Hispanic outdoor workers, and identifies potential intervention targets. PMID- 26477042 TI - Iodine Nutritional Status among Adolescent Girls in Uttarakhand, India. AB - INTRODUCTION: Uttarakhand (UK) state is a known endemic region for Iodine deficiency. OBJECTIVE: To assess iodine nutritional status among adolescent girls in districts: Udham Singh Nagar (USN), Nainital (N) and Pauri (P) of UK state. METHODS: In each district, 30 clusters (schools) were identified by using population proportionate to size cluster sampling. In each school, 60 girls (12 18 years) attending the schools were included. Total of 5430 girls from USN (1823), N (1811) and P (1796) were studied. Clinical examination of thyroid of each girl was conducted. From each cluster, spot urine and salt samples were collected. RESULTS: Total goiter rate was found to be 6.8% (USN), 8.2% (N) and 5.6% (P). Median urinary iodine concentration levels were 250 MUg/l (USN), 200 MUg/l (N) and 183 MUg/l (P). CONCLUSION: Findings of the study documented that adolescent girls had adequate iodine nutritional status in the three districts of UK. PMID- 26477043 TI - Angina Severity, Depression, and Response to Percutaneous Revascularization in Patients With Chronic Total Occlusion of Coronary Arteries. AB - OBJECTIVES: This study sought to quantify depression rates in patients referred for percutaneous coronary intervention (PCI) for chronic total occlusion (CTO), assess its relationship to baseline angina symptoms, and compare angina improvement after CTO-PCI between depressed and non-depressed patients. BACKGROUND: Depression is common among patients with chronic angina, and portends poor prognosis. CTOs are a common cause of angina. The relationships between angina, depression, and CTO intervention are unknown. METHODS: We collected baseline and 30-day post-PCI data on angina (Seattle Angina Questionnaire [SAQ7]), dyspnea (Rose Dyspnea Scale [RDS]), and depression status (Patient Health Questionnaire [PHQ-2]) on 45 consecutive patients referred for CTO-PCI between October 2013 and October 2014. RESULTS: Depression (PHQ-2 score >=3) was present in 18/45 patients (40%) at baseline. Baseline SAQ7 Summary and SAQ7 Angina Frequency scores for depressed patients were 35.4 (range, 28.4-42.4) and 54.4 (range, 43.0-65.8), compared with 67.3 (range, 57.5-77.1) and 77.8 (range, 68.5-87.1) for non-depressed patients (P<.001 and P=.01, respectively). Following CTO-PCI, the mean improvement in SAQ7 Summary and SAQ7 Angina Frequency scores was 48.5 (range, 35.4-61.5) and 32.8 (range, 21.0-44.5) for patients with depression, compared with 16.5 (range, 5.87-27.2) and 12.6 (range, 3.0-22.2) for patients without depression (P<.001 and P=.01, respectively). Following PCI, the presence of depression was reduced (72% relative reduction vs. baseline; P=.01). CONCLUSIONS: Depression identifies patients more limited by angina and more likely to respond to CTO-PCI compared with non-depressed patients. Depression screening may be indicated for patients with CTO, as 67% of CTO patients were not receiving treatment for depression. PMID- 26477044 TI - Feasibility of Left Atrial Appendage Occlusion Without Preprocedural Transesophageal Echocardiography or CT Scanning. AB - OBJECTIVE: To assess the success rate and safety outcomes of left atrial appendage occlusion (LAAO) procedures in a cohort of patients who had not undergone preprocedural imaging. BACKGROUND: LAAO patients usually undergo imaging with either transesophageal echocardiography (TEE) or computed tomography (CT) prior to the procedure itself. This preprocedural imaging may not be necessary. METHODS: The procedural success and major complication rates were assessed in a cohort of 52 patients who underwent LAAO without preprocedural imaging. RESULTS: Mean patient age was 75 +/- 8 years. Median CHA2DS2-VASc score was 4 and median HASBLED score was 3. The LAAO procedure was successful in 51/52 cases (98.1%). In 1 case, the LAAO procedure did not proceed because the LAA was too large for the available occlusion devices. No patient had left atrial appendage thrombus, despite the fact that only 4 patients were taking oral anticoagulation therapy at the time. Major complications occurred in 2/52 cases (3.8%), both due to vascular injuries causing pseudoaneurysm formation. CONCLUSION: LAAO in this series was not adversely affected by lack of preprocedural imaging. Omitting preprocedural imaging reduces risk attributable to the modality, reduces patient inconvenience and discomfort, reduces cost, and does not appear to significantly reduce the proportion of patients who can undergo a successful procedure. Further larger studies are warranted. PMID- 26477045 TI - Percutaneous Left Atrial Appendage Closure: How Easy Can it Get? PMID- 26477046 TI - The Long (and Sometimes Endless) Road to Murine Lupus Genes. PMID- 26477047 TI - Pillars Article: Polygenic Control of Susceptibility to Murine Systemic Lupus Erythematosus. Immunity. 1994. 1: 219-229. PMID- 26477050 TI - The Influence of Ambient Temperature on the Susceptibility of Aedes aegypti (Diptera: Culicidae) to the Pyrethroid Insecticide Permethrin. AB - Insecticides are the most common strategy used for the management of mosquitoes. Changes in ambient temperature can alter the toxicity of insecticides to ectothermic organisms. Studies show organophosphate insecticides exhibit a positive correlation between ambient temperature and mortality for many insect species, and carbamate insecticides exhibit a slightly negative correlation between ambient temperature and mortality. Pyrethroid insecticides exhibit a distinctly negative correlation between increasing ambient temperature and mortality for insects. However, this relationship has not been systematically studied for adult mosquitoes. Therefore, we examined the influence of temperature on the susceptibility of adult Aedes aegypti L. (Diptera: Culicidae) when exposed to permethrin. The median lethal concentration, LC50, was estimated for adult Ae. aegypti when exposed to eight concentrations of permethrin (ranging from 0.06 0.58 ng/cm2) at each of the following temperatures-16, 23, 26, 30, 32, and 34C for 24 h in bottle assays. The estimated LC50 for each temperature was 0.26, 0.36, 0.36, 0.45, 0.27, and 0.31 ng/cm2, respectively. Results indicated a negative correlation between temperature and mortality from 16 to 30C, a positive correlation between temperature and mortality from 30 to 32C, and a negative correlation between temperature and mortality from 32 to 34C. If mosquito populations are expanding in space and time because of increased ambient temperatures and cannot be managed as effectively with pyrethroids, the spread of mosquito-borne diseases may pose considerable additional risk to public health. PMID- 26477048 TI - Cohabitation in the Intestine: Interactions among Helminth Parasites, Bacterial Microbiota, and Host Immunity. AB - Both intestinal helminth parasites and certain bacterial microbiota species have been credited with strong immunomodulatory effects. Recent studies reported that the presence of helminth infection alters the composition of the bacterial intestinal microbiota and, conversely, that the presence and composition of the bacterial microbiota affect helminth colonization and persistence within mammalian hosts. This article reviews recent findings on these reciprocal relationships, in both human populations and mouse models, at the level of potential mechanistic pathways and the implications these bear for immunomodulatory effects on allergic and autoimmune disorders. Understanding the multidirectional complex interactions among intestinal microbes, helminth parasites, and the host immune system allows for a more holistic approach when using probiotics, prebiotics, synbiotics, antibiotics, and anthelmintics, as well as when designing treatments for autoimmune and allergic conditions. PMID- 26477049 TI - How do Nutritional Stress and La Crosse Virus Infection Interact? Tests for Effects on Willingness to Blood Feed and Fecundity in Aedes albopictus (Diptera: Culicidae). AB - Evolutionary theory predicts that vector-borne pathogens should have low virulence for their vector because of selection against pathogens that harm the vector sufficiently to reduce transmission. Environmental factors such as nutritional stress can alter vector-pathogen associations by making the vectors more susceptible to pathogens (condition-dependent competence) and vulnerable to the harm caused by pathogen replication (condition-dependent virulence). We tested the hypotheses of condition-dependent competence and condition-dependent virulence by examining the interactive effects of short-term sugar deprivation and exposure to La Crosse virus (LACV) in female Aedes albopictus (Skuse). We predicted that infection status interacts with sugar deprivation to alter willingness to blood feed and fecundity in the second gonotrophic cycle (condition-dependent virulence). Sugar deprivation had no effect on body infection or disseminated infection rates. Infection status, sugar treatment, and their interaction had no effect on fecundity. Mosquitoes that had intermittent access to sugar were significantly more willing to take a second bloodmeal compared with those that had continuous access to sugar. Infection status and the interaction with sugar treatment had no effect on blood-feeding behavior. Thus, we found no evidence of short-term sugar deprivation leading to condition dependent competence for, or condition-dependent virulence of, LACV in Ae. albopictus. PMID- 26477052 TI - ERRATA. PMID- 26477051 TI - Long-Term Ecological Study of Host-Seeking Adults of Hyalomma lusitanicum (Acari: Ixodidae) in a Meso-Mediterranean Climate. AB - From January 2007 to December 2014, three representative meso-Mediterranean bioclimatic environment types were sampled monthly using blanket-dragging techniques to determine the tick abundance rate. Hyalomma lusitanicum Koch, 1844 was the most prevalent species (96.58%) followed by Dermacentor marginatus Sulzer, 1776; Rhipicephalus pusillus Gil Collado, 1936; and Rhipicephalus bursa Canestrini and Fanzago, 1878. H. lusitanicum adults begin questing activity around March, numbers rising quickly reaching their peak in May-June and then diminishing until the end of the year, with a small increase in September October. This pattern was clear and constant throughout the years, irrespective of the microclimate or biotope tested. PMID- 26477055 TI - Bridging the Gap Between Knowledge and Practice in Complementary and Alternative Medicine in Saudi Arabia. PMID- 26477057 TI - Oral Cancer: You Be the Judge. PMID- 26477056 TI - GRS Nubes Supra Lunam, a New Lunula Shape. PMID- 26477058 TI - Narrow-Diameter Overdenture Implants: A Sensible Option for Growing a Practice. PMID- 26477060 TI - Chikungunya disease: gaps and opportunities in public health and research in the Americas. PMID- 26477059 TI - Antigenic and genetic characteristics of zoonotic influenza viruses and development of candidate vaccine viruses for pandemic preparedness. PMID- 26477061 TI - More Than Just Bond Strength: Clinical Success Is a Multifaceted Endeavor. PMID- 26477062 TI - The (Technical) Revolution Is On. PMID- 26477063 TI - 2015 Edition Health Information Technology (Health IT) Certification Criteria, 2015 Edition Base Electronic Health Record (EHR) Definition, and ONC Health IT Certification Program Modifications. Final rule. AB - This final rule finalizes a new edition of certification criteria (the 2015 Edition health IT certification criteria or "2015 Edition'') and a new 2015 Edition Base Electronic Health Record (EHR) definition, while also modifying the ONC Health IT Certification Program to make it open and accessible to more types of health IT and health IT that supports various care and practice settings. The 2015 Edition establishes the capabilities and specifies the related standards and implementation specifications that Certified Electronic Health Record Technology (CEHRT) would need to include to, at a minimum, support the achievement of meaningful use by eligible professionals (EPs), eligible hospitals, and critical access hospitals (CAHs) under the Medicare and Medicaid EHR Incentive Programs (EHR Incentive Programs) when such edition is required for use under these programs. PMID- 26476565 TI - Asymmetric somatic hybridization induces point mutations and indels in wheat. AB - BACKGROUND: Allopolyploid genome needs wide structural variation to deal with genomic shock. The introgression line, generated via asymmetric somatic hybridization, is introgressed with a minimum of exogenous chromatin, which also leads to genomic shock to induce genetic variation. However, the extent of its genomic variation and its difference from allopolyploidies remains unknown. METHODS: Here, we explored this issue using the bread wheat cultivar SR3, a derivative of an asymmetric somatic hybrid between the cultivar JN177 and an accession of tall wheatgrass (Thinopyrum elongatum). The ESTs (expressed sequence taqs) were large-scale sequenced using the cDNA library constructed in each of SR3 and JN177. Point mutations and indels (insertions and deletions) of SR3 were calculated, and their difference from the genetic variation of bread wheat and its ancestors were compared, with aim to analyze the extent and pattern of sequence variation induced by somatic hybridization. RESULTS: Both point mutations and indels (insertions and deletions) were frequently induced by somatic hybridization in the coding sequences. While the genomic shock caused by allopolyploidization tends to favor deletion over insertion, there was no evidence for such a preference following asymmetric somatic hybridization. The GC content of sequence adjacent to indel sites was also distinct from what has been observed in allopolyploids. CONCLUSIONS: This study demonstrates that asymmetric somatic hybridization induces high frequency of genetic variation in a manner partially different from allopolipoidization. Asymmetric somatic hybridization provides appropriate material to comprehensively explore the nature of the genetic variation induced by genomic shock. PMID- 26477064 TI - Medicare and Medicaid Programs; Electronic Health Record Incentive Program- Stage 3 and Modifications to Meaningful Use in 2015 Through 2017. Final rules with comment period. AB - This final rule with comment period specifies the requirements that eligible professionals (EPs), eligible hospitals, and critical access hospitals (CAHs) must meet in order to qualify for Medicare and Medicaid electronic health record (EHR) incentive payments and avoid downward payment adjustments under the Medicare EHR Incentive Program. In addition, it changes the Medicare and Medicaid EHR Incentive Programs reporting period in 2015 to a 90-day period aligned with the calendar year. This final rule with comment period also removes reporting requirements on measures that have become redundant, duplicative, or topped out from the Medicare and Medicaid EHR Incentive Programs. In addition, this final rule with comment period establishes the requirements for Stage 3 of the program as optional in 2017 and required for all participants beginning in 2018. The final rule with comment period continues to encourage the electronic submission of clinical quality measure (CQM) data, establishes requirements to transition the program to a single stage, and aligns reporting for providers in the Medicare and Medicaid EHR Incentive Programs. PMID- 26477065 TI - [Age-related Strabismus]. PMID- 26477067 TI - [Long-Term Follow-up of Age-related Strabismus Patients 50 Years-old and Over]. AB - PURPOSE: To characterize age-related strabismus by long term observation. METHODS: Clinical Characteristics were collected at two institutions from patients 50 years-old and over with age-related strabismus, who complained of diplopia and were followed up longer than 2 years without surgical intervention. RESULTS: The cohort consisted of one case of near exotropia (convergence insufficiency, exotropia angle at near was 11.3 degrees), eight cases of distance esotropia (divergence insufficiency, average esotropia angle at distance was 5.8 degrees), and 15 cases of hypertropia (average hypertropia angle at distance was 3.6 degrees). In 14 patients more than one year passed from the onset of diplopia to date of visiting one of the two clinics. The strabismus angle slowly increased (0.3 per year in average; Wicoxon signed-rank test, p < 0.01). 17 patients successfully used prism incorporated glasses. Diplopia was intermittent at first and became more frequent in most cases. Hypertropic patients often showed extorsion of the lower eye. CONCLUSION: Age-related strabismus eyes slowly develop diplopia and very slowly get worse in deviation angle. Prism incorporated glasses are useful in this condition. PMID- 26477070 TI - The Saints Among Us. PMID- 26477069 TI - [Bilateral Endogenous Fungal Subretinal Abscesses due to Scedosporium prolificans: a Case Report]. AB - BACKGROUND: We report a case with bilateral endogenous fungal subretinal abscesses. To our knowledge, this is the first report from Japan in which Scedosporium prolificans (S. prolificans) was cultured from intraocular tissue. CASE: A 74-year-old man, receiving chemotherapy for acute myeloid leukemia, complained of visual loss in both eyes. Best-corrected visual acuity was hand motion in the right and 2/200 in the left eye. His right eye showed exophthalmos, inflammation in the anterior chamber and iris neovascularization. Funduscopy revealed no details as there was vitreous opacity in the right eye, and irregular round yellowish-white subretinal lesions involving the macula in the left eye. Blood culture was negative, and C-reactive protein (CRP) and beta-D glucan titers were high. An antifungal drug and broad-spectrum antibiotics were initiated. Two days after the initial visit, right visual acuity had deteriorated to light perception. Enucleation of the right eye was performed for diagnosis and treatment. Fungi were cultured from the subretinal lesion, confirming a diagnosis of S. prolificans infection. After systemic administration and intravitreal injections of antifungal agents, the subretinal abscess in the left eye gradually diminished. At present, six months after the first visit, left visual acuity is 20/200. CONCLUSION: Although S. prolificans endophthalmitis can be intractable, this case suggests that repeated intravitreal antifungal agent injections can be effective. PMID- 26477066 TI - [Clinical Results of Diffractive Multifocal Intraocular Lens Implantation after Laser In Situ Keratomileusis]. AB - PURPOSE: To evaluate the visual performance in eyes with diffractive intraocular lenses (IOLs) after laser in situ keratomileusis (LASIK). METHODS: This single center retrospective study evaluated eyes that had diffractive multifocal IOL implantation after previous LASIK or not treated with LASIK (controls). The outcomes' measures were the visual acuities (VAs) at distance and near, spherical equivalent (SE) and contrast sensitivity at one month postoperatively. RESULTS: The study evaluated 40 eyes of 33 patients. The mean uncorrected logMAR VAs were 0.05 +/- 0.13/0.00 +/- 0.14 (LASIK group/control group) at distance and 0.10 +/- 0.13/0.16 +/- 0.18 at near. There was no statistically significant difference between the 2 groups at the VAs. The SE of the LASIK group was -0.06 +/- 0.39 D, significantly lower than the control group (0.22 +/- 0.45 D) (p < 0.05). The contrast sensitivity of the LASIK group at high spatial frequency was lower than the control group (p < 0.05). CONCLUSION: After LASIK, the diffractive multifocal IOL provided good uncorrected distance and near VAs. However, decrease in contrast sensitivity should be considered. PMID- 26477071 TI - A Discerning Heart: Saint Paul's Dr. Vacharee Peterson. PMID- 26477072 TI - Minnesota Dental Association 2015 Guest of Honor Stephen F. Litton. PMID- 26477068 TI - [Factors Affecting Outcomes of Repeated Penetrating Keratoplasty]. AB - PURPOSE: To investigate prognosis for repeated penetrating keratoplasty (PKP) and factors that affect the outcome. METHODS: We retrospectively investigated graft survival rates, 1-year postoperative best-corrected visual acuity and irreversible rejection rates in 108 eyes of 106 patients that had repeated PKP. Factors that might affect the outcome were, age, number of previous PKP, original diseases, history of glaucoma and rejection and the use of postoperative immunosuppressant were also studied. RESULTS: Individual-factor analysis showed that history of rejection and postoperative immunosuppressant significantly increased the risk of postoperative rejection. Multi-factor analysis showed that graft survival rate was significantly lower among cases that had systemic immunosuppressants (steroids and cyclosporine). One year postoperative best corrected visual acuity was significantly worse in cases that had history of glaucoma. In cases with history of rejection, systemic administration of postoperative immunosuppressants was significantly associated with postoperative irreversible rejection. CONCLUSION: History of rejection and glaucoma tend to have poor outcome, and the outcome might not improve by postoperative immunosuppressants. PMID- 26477073 TI - Modern Trends in Indirect Restorations. PMID- 26477074 TI - The Generational Rainbow in Organized Dentistry. PMID- 26477075 TI - Can We Run Out of Compassion? PMID- 26477076 TI - Understanding Compassion Fatigue. PMID- 26477077 TI - A Place at the Table: The 2015 MDA President's Interview. PMID- 26477078 TI - The Incidence of Furcation Region Patency in Molars Before and After Simulated Periodontal Therapy. AB - PURPOSE: To determine if there is increased bacterial communication through the furcation region in molar teeth after simulated periodontal therapy. METHODS: Sixty-five extracted first and second molars were accessed and the roots were sectioned 4 mm apical to the furcation. The canals and external suface of the root were sealed except the furcation region. In Phase I, the teeth were sterilized and then suspended in Rogosa SL broth. A broth containing Lactobacillus casei was placed in the pulp chamber. The Rogosa SL broth in the bottom chamber was monitored daily for 30 days for turbidity, and once turbidly was noted, the broth was plated to confirm the presence of L. casei. In Phase II, the furcation regions were scaled and cementum removed, the teeth were sterilized, and the microbial leakage was repeated. RESULTS: The Phase I and Phase II median times to turbidity were 9.5 days and 4 days, respectively, and the difference was statistically significant (p = 0.0035). Phase I turbidity rate was 86.5%, and Phase II was 92.3%, which was not statistically significant (p = 0.25). CONCLUSIONS: The root canal system communicated with the furcation region an average of 86.5% and 92.5% after scaling and root planing during the 30 days of the experiment. The time of leakage between the two groups decreased from 9.5 to 4 days (p = 0.0035). CLINICAL SIGNIFICANCE: Periodontal instrumentation of the furcation region in molar teeth can increase the risk of bacterial contamination by 39% while shortening the time for bacterial penetration in teeth with exposed dentin or furcation canals. accessory canals, scaling, and root planing. PMID- 26477079 TI - Recent Update on Antibiotic Prophylaxis for Prosthetic Joints for Dental Patients. PMID- 26477080 TI - FDA's Investigation into Patients Being Injected with Simulated IV Fluids Continues. PMID- 26477081 TI - Nursing Cultural Competencies: Improving Patient Care Quality and Satisfaction. PMID- 26477082 TI - Down But Not Out--The United States Healthcare System Ranks Last ... Again. PMID- 26477083 TI - The Future of Medicaid Expansion in Ohio. PMID- 26477084 TI - Where Are the Nurses in Nursing Homes? PMID- 26477085 TI - [Prospcts of application of implantable microkelectromechanical systems for monitoring and analysis of parameters of blood circulation system]. PMID- 26477086 TI - [Application of a low-inertia medicl hammer to traumatologic and orthopedic surgery]. PMID- 26477087 TI - [Use of duplex scanning in estimation of liver fibrosis]. PMID- 26477088 TI - [Adaptive stress-testing system SAKR-VELO]. PMID- 26477089 TI - [Remote measurement of respiratory rate labratory mice in studies of mdx model of Duchenne muscular dystrophy]. PMID- 26477090 TI - [Effect of pulsatile flow and back washing on the plasma flow rate in plasmapheresis. Part 2. Experiment]. PMID- 26477091 TI - [Screening diagnostics of stomach cancer on the basis of fuzzy models of blood structure and composition and patients anamnesis]. PMID- 26477092 TI - [Prospcts of application of the radio-frequency idrffmon tedmologY with passive tags in invasive biosensor systems]. PMID- 26477093 TI - [A driver support system based on analysis of pulse and vehicle motion parameters]. PMID- 26477094 TI - [Comparison of characteristics of trapezoidal, rectilinear and Gurwich-Venin bipolar defibrillation pulses]. PMID- 26477095 TI - [Modeling of atrial defibrillation sources on a triangulated sphere]. PMID- 26477096 TI - [Equipment for thermal treatment and storage of blood prearations and components]. PMID- 26477097 TI - [Evaluation of the condition of ultrasonic medical diagnostic devices in hospitals and dinics of the Moscow Health Care Department]. PMID- 26477098 TI - Prevention: It's Up to Us to Educate Our Patients. PMID- 26477099 TI - Do I Have to Provide Staff Time Off for Religious Holidays? PMID- 26477100 TI - Bad-Mouthed on Facebook--What's a Practice to Do? PMID- 26477101 TI - 3.8 Million Americans Will Face Cognitive Disabilities; Plan Ahead. PMID- 26477102 TI - How Race and Ethnicity Affect Your Patients' Heart Disease Risk. PMID- 26477103 TI - The MDA Health Plan: Find Out If It's the Right Plan for You. Created by dentists ... for dentists. PMID- 26477104 TI - Fractured Endodontic Instrument: A Clinical Dilemma Retrieve, Bypass or Entomb? AB - A common clinical complication of root canal treatment is fracture of an endodontic file. The risk of treatment failure because of incomplete cleaning and shaping encourages the dentist to retrieve the fractured part. Several techniques have been offered to remove the fractured file, yet those techniques sacrifice sound dentin, which may lead to increased risk for perforations and root fractures. The aim of this article is to describe a clinical approach to accessing fractured files, depending on their location in the canal and stage of cleaning and shaping. This prudent approach may decrease complications from unnecessary dentin removal, while respecting the biological aspects of cleaning the canals. PMID- 26477105 TI - UDM School of Dentistry: A Year in Reflection. The Legacy of Clinical Excellence Continues. PMID- 26477106 TI - U-M School of Dentistry: A Commitment to Core Values. PMID- 26477107 TI - [PULMONARY TUBERCULOSIS TREATMENT OUTCOME AMONG FOREIGN NATIONALS RESIDING IN OSAKA CITY]. AB - Abstract PURPOSE: In this study, we analyzed pulmonary tuberculosis treatment outcomes among foreign nationals of different backgrounds. METHODS: The research was conducted between January 2006 and December 2011. One hundred fifty nine foreign nationals residing in Osaka city had pulmonary tuberculosis during this period. Patients were grouped according to treatment outcomes. We conducted three different types of comparisons. First, we compared backgrounds of patients with treatment success or default. Second, backgrounds of patients who continued treatment in Japan or who moved overseas (transfer out) were compared. Third, treatment outcomes of foreign nationals between 20 and 39 years of age were compared with those of age-matched Japanese patients registered between 2010 and 2011. RESULTS: (1) The treatment outcomes were as follows: cured, 53 cases (33.3%); treatment completed, 55 cases (34.6 %); treatment failure, 0 cases (0.0%); treatment default, 14 cases (8.8%); moved overseas, 17 cases (10.7%); moved to another location inside Japan, 13 cases (8.2%); died, 6 cases (3.8%); and under treatment, 1 case (0.6%). (2) Comparison of treatment success and default among foreign nationals with pulmonary tuberculosis revealed a default rate among smear-negative cases of 14.5%, significantly higher than in smear positive cases (2.1%; P < 0.05). (3) We compared backgrounds between foreign nationals with pulmonary tuberculosis who continued taking treatment in Japan and those who moved abroad (transfer out). The rate of overseas transfer out (44.4%) was higher among patients not covered by health insurance. This was significantly higher than among patients covered by public insurance or assistance (9.0%; P < 0.01). (4) Comparison of foreign and Japanese nationals between 20 and 39 years of age revealed a default rate in foreign nationals with pulmonary tuberculosis of 13.6%. This was significantly higher than that of Japanese patients (4.0%; P < 0.01). The rate of transfer out among foreign nationals with pulmonary tuberculosis was 19.1%, also significantly higher than that of Japanese patients (5.3%; P < 0.001). DISCUSSION: The rates of treatment default and transfer out among patients between 20 to 39 years of age were significantly higher among foreign nationals than in Japanese patients. Lack of knowledge about treatment and language problems may contribute to this finding. This suggests that adequate support and definitive directly observed treatment short-course programs are needed for foreign nationals. Patients who moved abroad (overseas transfer out) may also be ultimately categorized as treatment default. However, it is difficult to determine final treatment outcomes of patients who moved abroad. Further measures are needed to ensure that foreign nationals continue to receive treatment when they transfer overseas. PMID- 26477108 TI - [RISK GROUPS FOR TUBERCULOSIS IN JAPAN: ANALYSIS OF RELATIVE RISK AND POPULATION ATTRIBUTABLE FRACTION]. AB - OBJECTIVE: Despite the decreasing trend in tuberculosis (TB) cases reported within the general population, TB incidence remains high in certain high-risk groups in Japan. Many of the previous discussions and studies have concentrated mainly on the elderly and those with clinical risks; however, no comprehensive evaluation has been conducted to date. Our study thus sought to estimate the relative risk (RR) and the population attributable fraction (PAF) of selected risk groups in Japan and discuss their relevance to programming future research needs and policies. METHOD: PAF and RR were calculated for patients with human immunodeficiency virus infection, diabetes, rheumatoid arthritis, those on dialysis, the elderly, health care workers, the homeless, people receiving public assistance, foreigners, prisoners, smokers, and those with alcohol problems, and were grouped into "high PAF" (PAF >= 5%), "middle PAF" (5% > PAF >= 1%), and "low PAF" (PAF < 1%) groups. RESULTS: The elderly and patients with diabetes showed the highest PAF and RR and should thus be prioritized for policies. PMID- 26477109 TI - [DRUG-INDUCED LIVER INJURY AND PYRAZINAMIDE USE]. AB - BACKGROUND: In the 1950s, high doses (40-70 mg/kg/day) of pyrazinamide were reported to cause drug-induced liver injury (DILI). It remains unclear whether adding pyrazinamide (Z) at the currently accepted low dose (20-25 mg/kg/day) to a regimen of isoniazid (H), rifampicin (R), and ethambutol (E) increases the risk of DILI. METHOD: We reviewed adult patients admitted for smear-positive tuberculosis who were treated with a daily HRE or HRZE regimen. A Cox model was used to analyze the impact of pyrazinamide on the occurrence of DILI. RESULTS: We reviewed 195 patients (123 men [63%], 72 women [37%], average age 65 +/- 19 years, 65 HRE patients [33%], 130 HRZE patients [67%]). The incidence of DILI in the first two months was 15% (29/195). The HRZE regimen was not associated with DILI (hazard ratio 0.55, P = 0.263). CONCLUSION: Addition of low-dose (20-25 mg/kg/day) pyrazinamide to the HRE regimen does not appeared to be associated with increased DILI incidence during the first two months of treatment. PMID- 26477110 TI - [A STUDY OF SURGICAL TREATMENT FOR PATIENTS WITH MYCOBACTERIUM ABSCESSUS PULMONARY DISEASE AND A COMPARATIVE EXAMINATION OF MYCOBACTERIUM AVIUM COMPLEX DISEASE]. AB - OBJECTIVE: This is a retrospective study on six surgical cases of Mycobacterium abscessus pulmonary disease, including a comparison with M. avium complex (MAC) disease. SUBJECTS AND METHODS: We performed surgery for six cases of M. abscessus pulmonary disease between July 2012 and June 2014. In all the cases, video assisted thoracic surgery alone was performed. Age, sex, bacillus identification method, disease type, preoperative anti-glycopeptidolipid core immunoglobulin A antibody value, preoperative chemotherapy, preoperative chemotherapy period, adaptation of the operation, surgical method, result of the bacillus culture of an organization that was extracted at operation, postoperative hospitalization period, surgical complications, and postoperative relapse were examined for the six cases of M. abscessus pulmonary disease. In addition, the cases were compared with 36 cases of MAC disease for which operation was performed during the same period. RESULT: None of the patients had major surgical complications or in hospital death. Although three patients survived for more than 1 postoperative year and completed chemotherapy, relapses are not accepted in all cases at present. In the comparison with MAC disease, the mean preoperative chemotherapy period for M. abscessus pulmonary disease was 5.5 months, which was 18.9 months shorter than that for MAC disease, with a statistically significant difference. CONCLUSION AND CONSIDERATION: Surgery for M. abscessus pulmonary disease may be considered a safe and effective therapeutic procedure. Moreover, some physicians believe that surgical treatment is required at an earlier stage of M. abscessus pulmonary disease compared with MAC disease. PMID- 26477111 TI - [HISTOLOGICAL ANALYSIS OF BONE DESTRUCTION IN SPINAL TUBERCULOSIS]. AB - PURPOSE: To investigate the mechanism of bone destruction in spinal tuberculosis (TB) by immunohistochemical analysis of the pathway that includes receptor activator of NF-kappaB (RANK), receptor activator of NF-kappaB ligand (RANKL), osteoprotegerin (OPG), and osteocalcin (OCN) in affected tissues. MATERIALS AND METHODS: TB bone specimens were obtained from 30 surgically treated spinal TB patients (13 males and 17 females; average age, 67 years). Normal bone specimens were also obtained from 30 osteoarthritis patients (12 males and 18 females; average age, 70 years) who had undergone knee arthroplasty, wherein a piece of the non-weight-bearing part of the femur was obtained as a part of the resected bone for surgery. The two groups of specimens were examined for the expression of RANK, RANKL, OPG, and OCN by immunohistochemistry. RESULTS: Spinal TB specimens were significantly infiltrated by inflammatory cells, and bone resorption by multinucleated osteoclasts was observed. RANKL was predominantly expressed in lymphocytes and osteoblasts, whereas RANK was expressed in mononucleated osteoclast precursors among the inflammatory cells. In contrast, there was no infiltration of the inflammatory cells, and the expression of RANKL/RANK was poor in the control specimens. OCN, a bone formation marker, was expressed in the osteoblasts and in part of the bone matrix in normal tissues; however, it was poorly expressed in the tissues of the spinal TB patients. OPG, a neutralizer of the RANK-RANKL pathway, was expressed in the osteoblasts and stromal cells, and there was no significant difference in the expression between the two groups. DISCUSSION: In the tissues from spinal TB patients, the RANK-RANKL pathway was strongly activated, whereas the expression of its neutralizer OPG was not sufficiently induced. In addition, the bone formation marker OCN was poorly expressed, indicating a paucity of reactive bone formation. These findings are consistent with bone-resorption-predominant destruction, which is commonly observed in osteoarticular TB. Activation of the RANK-RANKL pathway has been considered to be caused by cytokines such as tumor necrosis factor-alpha and interleukin-6, which also play important roles in the immune response against TB. In severe pulmonary TB, an intense and prolonged immune reaction sometimes leads to tissue destruction and the formation of cavity lesions. Therefore, such an immune reaction against spinal TB may also cause activation of the RANK-RANKL pathway, thereby leading to bone destruction. PMID- 26477112 TI - [INCREASE IN THE NUMBER OF INFANTS WITH KOCH PHENOMENON AFTER BCG VACCINATION]. AB - PURPOSE: To investigate the trends in the number of infants diagnosed with Koch phenomenon after BCG vaccination following the change in the timing of the vaccination. METHOD: We extracted and analyzed data from infants aged <= 1 year diagnosed with latent tuberculosis infection (LTBI) or active tuberculosis, registered in the Japanese tuberculosis surveillance system, from May 2012 to the end of the year, and from May 2013 to the end of the year. RESULT: There was no increase in active tuberculosis cases between the two periods (5 patients each). However, the number of infants with LTBI doubled (45 to 90), presumably because Koch phenomenon developed after BCG vaccination. CONCLUSION: After changing the timing of vaccination, the number of infants experiencing Koch phenomenon appears to have increased. However, more in-depth analysis of this finding is required. PMID- 26477113 TI - [DISSEMINATED MYCOBACTERIUM INTRACELLULARE INFECTION IN A PATIENT WITH MYELODYSPLASTIC SYNDROME]. AB - A 71-year-old man with myelodysplastic syndrome (MDS) was admitted to our hospital because of recurrent high-grade fever. He was examined for bacterial and fungal infections and treated with antibiotics and antifungal agents. However, he did not achieve a definitive diagnosis and had no apparent improvement for more than a month. Bone marrow aspiration revealed transformation of MDS to acute myeloid leukemia and hemophagocytosis. In addition, Mycobacterium intracellulare was isolated from both a bone marrow specimen and a blood sample. Therefore, he was diagnosed with disseminated Mycobacterium avium complex (MAC) infection with hemophagocytosis. An antibody test was negative for human immunodeficiency virus (HIV). His general condition improved with anti-mycobacterial drug and steroid treatments. Clinicians should suspect disseminated nontuberculous mycobacterial infections in unexplained febrile patients with hematological disorders. PMID- 26477114 TI - [RATES OF COMPLETION AND TREATMENT OUTCOMES FOR TYPE OF COMMUNITY DOTS]. AB - AIM: To investigate the relationship between completion rates for community directly observed treatment short-course (DOTS) and treatment outcomes, according to implementation tactics, to improve the treatment outcomes. METHODS AND SUBJECTS: We evaluated 529 newly registered patients with smear-positive pulmonary tuberculosis who underwent community DOTS (checking medication at least once per week) during 2010 and 2011 in Osaka City. DOTS completion was defined as checking medication 3 times or more per month, with checking medication missed less than 3 consecutive times. DOTS was implemented using the following 4 tactics: healthcare staff visited the patients' home or workplace (visiting type), the patients visited a health and welfare center (HWC type), the patients visited a pharmacy (P type), or the patients visited an outpatient department at a medical center (MC type). Regarding treatment outcomes, resolution of the tuberculosis or treatment completion was defined as "successful treatment", and treatment failure or default was defined as "unsuccessful treatment". We then analyzed the DOTS completion rate for each DOTS implementation tactic. RESULTS: DOTS was completed in 417 (78.8%) of the 529 patients. The completion rates were 79.7%, 75.4%, 75.9%, and 81.3% for patients who underwent visiting (n= 394), HWC (n = 61), P (n = 58), and MC (n = 16) DOTS, respectively; no significant difference was observed. The mean ages for each group were 62.8 years, 53.6 years, 45.0 years, and 56.6 years for patients who underwent visiting, HWC, P, and MC DOTS, respectively; patients who underwent P DOTS were significantly younger (P < 0.001). Among the 4 groups, the visiting DOTS group had the lowest percentage of full-time employees (16.2%) and the highest percentage of unemployed individuals (67.3%). In contrast, the percentage of full-time employees was 63.8% and 50.0% in the P and MC DOTS groups, respectively. The P DOTS group had the lowest unemployment percentage (19.0%) among the 4 groups. Thus, a significant correlation existed between the DOTS implementation tactics and the presence/ absence of the patients' occupations (P < 0.001). Among the 417 patients who completed DOTS, 99.8% achieved successful treatment. Among the 112 patients who did not complete DOTS, 89.3% achieved successful treatment, and this success rate was significantly lower than that for the group who completed DOTS (P < 0.00 1). Among the visiting, HWC, and P DOTS groups, the completion of DOTS resulted in a high treatment success rate. DISCUSSION: Patients who completed DOTS achieved better treatment outcomes; therefore, it is important to provide patients with medication support until their tuberculosis is resolved. The P DOTS group contained a higher percentage of full-time employees and had a significantly lower mean age; this was likely because pharmacies are accessible at night and during the weekend. There was no significant difference in the DOTS completion rates according to implementation tactic, which suggests that it is important to assist patients with their medication according to their needs. PMID- 26477116 TI - [Nursing knowledge and theory: where is the economic value]. PMID- 26477115 TI - [TUBERCULOSIS ANNUAL REPORT 2013--(1) Summary of Tuberculosis Notification Statistics and Foreign-born Tuberculosis Patients]. AB - This is the first in a 4-series report based on the Tuberculosis Annual Report 2013. It summarizes general tuberculosis (TB) statistics and gives an overview of foreign-born TB patients notified and registered in Japan in 2013. TB notification has continued to decline since 2000, and a total of 20,495 patients with all forms of TB were notified in 2013, with a rate per 100,000 population of 16.1. The age of TB patients has increased, with 57.4% of all TB patients in 2013 more than 70 years old. The number of patients with latent TB infection drastically increased from 4,930 in 2010 to 10,046 in 2011, but has been declining since. The number of foreign-born TB patients increased from 739 in 1998 to 1,064 in 2013; similarly, the proportion of foreign-born patients among all TB patients increased from 2.1% in 1998 to 5.4% in 2013. Foreign-born TB patients aged 20-29 years accounted for 42.7% of all new TB patients in the same age group in 2013. Among foreign-born TB patients, more than half were from China (27.4%) and the Philippines (24.1%). Younger patients were more likely to have entered Japan within the previous 5 years (61.5% and 61.3% of foreign-born patients in their teens and twenties, respectively). The largest occupational category was "regular employees" (25%), which excluded service workers, health care workers, and teachers, followed by students (24%) and unemployed people (21 %). With the government relaxing restrictions on entry of foreign workers to cope with labor shortage in the construction industry ahead of the 2020 Tokyo Olympics, both the number and proportion of foreign-born TB patients is also expected to rise. Comprehensive programs are urgently required to ensure early diagnosis and treatment completion among one of the vulnerable populations in Japan. PMID- 26477117 TI - Nurse-Managed Clinics: Barriers and Benefits Toward Financial Sustainability when Integrating Primay Care and Mental Health. AB - Nurse-managed, integrated clinics offer access, affordability, and quality to the health care environment. The integration of mental health and primary care is a holistic, comprehensive model that addresses the complicated needs of those with mental illness. As nurses increase their education in leadership, financial management, and business, there is a correlating increase in the number of nurse managed clinics. More research is needed to determine the financial structures that benefit sustainability of nurse-managed, integrated clinics. However, in an integrated review of the literature between 2000 and 2012, the data indicate nurse-managed health centers receive less federal financial support than the medically modeled federally qualified health center. PMID- 26477118 TI - The Effect of Hardiness Education on Hardiness and Burnout on Registered Nurses. AB - Nurse leaders need to be aware of the costly implications of staff retention, unit finances, and patient satisfaction caused by unmanaged stress and burnout as well as staff disengagement. It is vital to the organizational behavior of the health care facility for nurse managers to promote, educate, and screen for hardiness in their staff. Hardiness education can lessen the effects of stress and burnout. Nurse managers and executives can give their staff valuable tools and resources to enhance hardiness and coping abilities through hardiness education. PMID- 26477119 TI - A Cost-Effective Mindfulness Stress Reduction Program: A Randomized Control Trial for Breast Cancer Survivors. AB - Many breast cancer survivors continue to experience residual symptoms including anxiety, cognitive impairment, depression, fatigue, and pain. In this study, the cost-effectiveness of a Mindfulness-Based Stress Reduction intervention for breast cancer survivors was examined. The cost of the program was assessed from the societal perspective, accounting for both direct medical and patient opportunity costs. The cost per quality-adjusted life year was relatively low compared to the cost-utility findings of other published breast cancer interventions. The program appears to provide for significantly improved health related quality of life at a comparativelv low cost. PMID- 26477120 TI - Documentation of Preventive Nursing Measures in the Elderly Trauma Patient: Potential financial Impact and the Health Record. AB - Hospital-acquired complications in older adults are significantly higher than in younger patients. Nursing measures to prevent hospital-acquired complications are generally mandated by nursing policy and are required documentation in hospital record systems. In this study, gaps in the nursing documentation of measures intended to prevent hospital-acquired complications in elderly trauma patients may be related to the documentation of these measures not being required entries in the system used by the facility. These findings highlight the importance of the relationship between nursing documentation requirements and the system used for the expedient documentation of nursing care. PMID- 26477121 TI - The Impact of Prolonged Economic Downturns and Economic Crises on the Nursing Profession. AB - Prolonged economic downturns and economic crises are affecting nations around the world, including developed countries such as Portugal, Spain, and Greece. In the United States, recovery from the latest economic crisis has been accompanied by a persistently high rate of unemployment. To a large extent, the impacts on the nursing profession may depend on the severity of economic downturns and their duration in the country of employment of nurses. Nurses in certain areas of patient care (such as mental health) may also be more strongly affected because of the impact of economic crises and high unemployment on morbidity patterns. Emigration of nurses may also increase as a result of prolonged economic crisis. PMID- 26477122 TI - The Importance of the Partner: Supporting Nurse Leaders' Journey to Executive Roles. AB - Having a fully committed partner is an asset some nurse executives celebrate. The life partner can play a critical role in the nurse executive's career from a personal perspective. The importance of being flexible and balancing "who does what" and how to manage through life's challenges is reported through three nurse executives' stories and one spouse. Having a partner enriches the life journey, according to these leaders. PMID- 26477124 TI - Increasing survival, enhancing citizen resilience. PMID- 26477123 TI - The World Health Organization's Sixty-Eighth World Health Assembly: Updates and Opportunities. AB - The World Health Assembly (WHA) is the decision-making body of the World Health Organization. Delegates attending the Sixty-Eighth WHA, May 2015, covered a wide range of global challenges and agreed on several key resolutions of importance to nurse leaders. Some of the resolutions adopted relevant for nurse leaders and nursing care such as air pollution, strategies to strengthen epilepsy care, antimicrobial drug resistance, and strategies to strengthen surgical care, are highlighted. Nurse leaders should consider attending the World Health Assembly, as the topics discussed are critical for the future directions of strengthening human resources for health worldwide and, in particular, nursing and midwifery services. PMID- 26477125 TI - Letter from the Vice-President. Equipping citizens with the skills to respond to mass casualty incidents. PMID- 26477126 TI - Presidential Policy Directive: National preparedness. PMID- 26477127 TI - A systematic response to mass trauma: The public, organized first responders, and the American College of Surgeons. PMID- 26477128 TI - Strategies to enhance survival in active shooter and intentional mass casualty events. PMID- 26477129 TI - Physicians roundtable--February 10, 2015. Bystanders: Our nation's immediate responders. PMID- 26477130 TI - The military experience and integration with the civilian sector. PMID- 26477131 TI - The Department of Homeland Security's role in enhancing and implementing the response to active shooter and intentional mass casualty events. PMID- 26477132 TI - Initial management of mass-casualty incidents due to firearms: Improving survival. PMID- 26477133 TI - Improving Survival from Active Shooter Events: The Hartford Consensus. PMID- 26477134 TI - Active Shooter and International Mass-Casualty Events: The Hartford Consensus II. PMID- 26477135 TI - The Hartford Consensus III: Implementation of Bleeding Control: If you see something do something. PMID- 26477136 TI - The continuing threat of intentional mass casualty events in the U.S.: Observations of federal law enforcement. PMID- 26477137 TI - Public health education: The use of unique strategies to educate the public in the principles of the Hartford Consensus. PMID- 26477138 TI - The continuing threat of active shooter and intentional mass casualty events: Local law enforcement and hemorrhage control. PMID- 26477139 TI - Military history of increasing survival: The U.S. military experience with tourniquets and hemostatic dressings in the Afghanistan and Iraq conflicts. PMID- 26477140 TI - Hemorrhage control devices: Tourniquets and hemostatic dressings. PMID- 26477141 TI - Intentional mass casualty events: Implications for prehospital emergency medical services systems. PMID- 26477142 TI - Role of the American College of Surgeons Committee on Trauma in the care of the injured. PMID- 26477143 TI - Integrated education of all responders. PMID- 26477144 TI - Implementation of the Hartford Consensus initiative to increase survival from active shooter and intentional mass casualty events and to enhance the resilience of citizens. PMID- 26477145 TI - The Presidential Directive. Strengthening U.S. citizen resilience in mass casualty incidents. PMID- 26477146 TI - [SCREW-BASED INTERMAXILLARY TRACTION COMBINED WITH OCCLUSAL SPLINT FOR TREATMENT OF PEDIATRIC MANDIBULAR CONDYLAR FRACTURE]. AB - OBJECTIVE: To evaluate the effectiveness of the screw-based intermaxillary traction combined with occlusal splint in the treatment of pediatric mandibular condylar fracture. METHODS: Between June 2005 and December 2013, 35 pediatric patients with 49 mandibular condylar fractures were treated, and the clinical data were retrospectively reviewed. There were 25 boys and 10 girls, aged 3-13 years (mean, 7.3 years). The injury causes included falling (18 cases), traffic accident (14 cases), and violence (3 cases). The time between injury and treatment was 2-30 days (mean, 6.8 days). Restricted mouth opening was observed, and the maximal mouth opening was (22.74 +/- 7.22) mm except 3 patients who were too young to measure. Condylar fractures were located at the left (12 cases), at the right (9 cases), at bilateral (14 cases) based on the sites; and fractures were classified as intracapsular (35 fractures), neck (10 fractures), and subcondylar (4 fractures) based on the fracture line. Four self-drilling titanium screws were inserted into the alveolar bone of both maxilla and mandible. After screw inserting, an occlusal splint with a fulcrum was used on the affected side and elastic band was put to perform anterior intermaxillary traction. After 1 month, the screws and splint were removed. Follow-up examinations were carried out on schedule. RESULTS: All the patients were followed up from 6 months to 8 years and 10 months (median, 71 months). No screw-related complication occurred in the others except one case of screw loosening. The postoperative maximal mouth opening was (38.82 +/- 2.02) nim. Mild joint noise was found in 4 cases and opening deviation occurred in 6 cases. Radiographic results demonstrated complete condyle remodeling was achieved in 24 cases (32 fractures), and moderate remodeling in 11 cases (17 fractures) at last follow-up. CONCLUSION: The screw based intermaxillary traction combined with occlusal splint might be an effective method for pediatric mandibular condylar fracture. The screw-related complications may be avoided by careful preoperative investigations. PMID- 26477147 TI - [EFFECTIVENESS OF DIGITAL CUSTOMIZED STEEL PLATE IN TREATMENT OF COMPLEX FRACTURES OF LIMBS]. AB - OBJECTIVE: To observe the effectiveness of digital customized plate in the treatment of complex limb fracture. METHODS: Between January 2012 and May 2013, CT raw data of complex limb fracture were used to establish the fracture three dimensional simulation model after reduction, and a customized personalized anatomic plate was designed and used for internal fixation after open reduction in 42 cases. There were 22 males and 20 females, aged 16-53 years (average, 37.4 years). The causes of injury were traffic accident in 21 cases, falling from height in 18 cases, crush by heavy objects in 3 cases, including 26 cases of fresh closed fracture and 16 cases of open fracture (9 cases of type I and 7 cases of type II according to Gustilo classification). According to AO classification, there were 15 cases of humerus comminuted fracture, 4 cases of radial comminuted fracture, 8 cases of femoral comminuted fracture, and 15 cases of tibia comminuted fracture. The interval of injury and operation was 6-28 days (mean, 10 days). RESULTS: Reduction and internal fixation of fracture were successfully performed on 42 patients. The length and position of digital customized plate, direction and length of screw implant, number of screw were basically identical with preoperative design. The operation time was 35-120 minutes (mean, 70 minutes); the blood loss volume was 30-500 mL (mean, 180 mL); and X ray fluoroscopy frequency was 2-6 times (mean, 3 times). Superficial infection occurred in 2 cases, and was cured after dressing change; primary healing of incision was obtained in the other patients. Forty-two cases were followed up 6-24 months with an average of 11.5 months. The fracture healing time was 8-19 weeks (mean, 14 weeks) in 41 cases; delayed union occurred in 1 case at 44 weeks after operation. The fracture anatomical reduction was achieved in 19 cases, malunion in 3 cases, and functional reduction in the other patients. At last follow-up, no plate and screw loosening and breakage was observed. CONCLUSION: Digital customized plate in treatment of complex fractures of limbs, especially for the multiple comminuted fracture of long bones of the limbs has the advantages of convenient operation, less trauma, fewer complications, and good effectiveness. PMID- 26477148 TI - [TREATING SACROILIAC JOINT TUBERCULOSIS WITH RIFAMPICIN-LOADED OsteoSet]. AB - OBJECTIVE: To assess the safety, feasibility, and effectiveness of medical calcium sulfate (OsteoSet) mixed with powder for injection of rifampicin after radical debridement in the treatment of sacroiliac joint tuberculosis. METHODS: A retrospective analysis was made on the clinical data from 27 patients with sacroiliac joint tuberculosis who underwent debridement surgery and local bone graft of OsteoSet artificial bone impregnated with powder for injection of rifampicin between August 2006 and August 2010. There were 10 males and 17 females with an average age of 35.2 years (range, 16-64 years). The mean disease duration was 7.5 months (range, 1.5-16 months). The left sacroiliac joint was involved in 16 cases, the right side in 10 cases, and both sides in 1 case; Of them, 18 cases had iliac fossa abscess and 6 cases of buttocks abscess. According to the classification system by Kim, there were 9 cases of type III and 18 cases of type IV. The preoperative Majeed score was 61.23?6.49, including good in 4 patients, general in 19 patients, and poor in 4 patients. RESULTS: All patients achieved wound healing by first intention; no complications of pelvic infection, peripheral nerve injury, and lower extremity deep vein thrombosis occurred. Twenty-six patients were followed up 16 months on average (range, 12-24 months). All the patients had normal sense and movement of both lower limbs; no perineum sensory disturbance was found. One case of multi-drug resistant had local recurrence at 3 months after operation, which was cured after adjusting anti tuberculosis drugs, nutritional support, enhancing immunity with thymopentin, and second operation. Bone union was observed at 10.5 months on average (range, 9-12 months) in 25 patients, and clinical symptoms disappeared with no recurrence or complication, and they returned to previous work. The Majeed score at last follow up was 92.31 +/- 3.36, showing significant difference when compared with preoperative score (t = -32.76, P=0.00). The results were excellent in 22 patients, good in 4 patients, and the excellent and good rate was 100%, showing signi.ficant difference compared with the preoperative one (chi2=31.93, P=0.00). CONCLUSION: Bone graft interbody fusion surgery with rifampicin loaded OsteoSet is one of the effective methods to treat sacroiliac joint tuberculosis. PMID- 26477149 TI - [PROCEDURE OF RECONSTRUCTING TRANSVERSE ARCH OF THE FOREFOOT BY TRANSFERING TENDONS FOR CORRECTING HALLUX VALGUS]. AB - OBJECTIVE: To explore the effectiveness of the procedure of reconstructing the transverse arch of the forefoot by anastomosing adductor hallucis and abductor hallucis tendons in correcting hallux valgus. METHODS: A retrospective analysis was made on the clinical data from 28 patients (40 feet) with hallux valgus treated with the procedure of reconstructing the transverse arch of the forefoot by anastomosing adductor hallucis and abductor hallucis tendons between January 2010 and January 2014. There were 3 males (6 feet) and 25 females (34 feet), with an average age of 51.7 years (range, 20-71 years). The unilateral foot was involved in 16 cases and bilateral feet in 12 cases. The mean disease duration was 8.9 years (range, 1-30 years). All the cases had pain of the first metacarpophalangeal joint; 22 feet had collapsed transverse arch of the forefoot combined with plantar callus, and 8 feet had collapsed transverse arch of the forefoot combined with hammer toe deformity. American Orthopaedic Foot and Ankle Society (AOFAS) score was 59.07 +/- 8.49. Preoperative X-ray showed that the hallux valgus angle (HVA) was (33.68 +/- 8.10) degrees, and the intermetatarsal angle (IMA) was (15.60 +/- 4.07) degrees. According to classification of the hallux valgus by Mann, 9 feet were rated as mild, 23 feet as moderate, and 8 feet as severe. RESULTS: Superficial infection of incision occurred in 1 case (1 foot) after surgery, and healing by first intention was obtained in the others. Two cases (3 feet) had numbness in the toes. All of 28 cases were followed up from 6 months to 4 years (1.8 years on average). Based on the AOFAS score, the results were excellent in 24 feet, good in 9 feet, fair in 4 feet, and poor in 3 feet, and the excellent and good rate was 82.5%. At last follow-up, the HVA, IMA, and AOFAS score were (15.10 +/- 5.28), (9.05 +/- 2.42) degrees, and 86.03 +/- 7.45 respectively, showing significant differences compared with preoperative ones (P=0.00). The collapsed transverse arch of the forefoot was recovered to some extent, plantar callus disappeared (14 feet), or decreased (8 feet). Recurrence of hallux valgus deformity was observed in 2 cases (3 feet) at 2 and 3 months after surgery respectively, and no hallux varus was found. CONCLUSION: This procedure not only can effectively reduce the increased hallux valgus angle, and narrow the angle between the 1st and 2nd metatarsal, but also can relocate the sesamoid system, reconstruct the transverse arch of the forefoot, and effectively restore the physiological anatomy structure and biological function of the forefoot. PMID- 26477150 TI - [EFFECTIVENESS OF SURGERY IN TREATMENT OF ANKLE FRACTURES ASSOCIATED WITH DELTOID LIGAMENT INJURY]. AB - OBJECTIVE: To evaluate the effectiveness of repairing the deltoid ligament with ankle fracture. METHODS: Between January 2010 and January 2013, 11 patients with ankle fractures associated with deltoid ligament injury were treated. There were 7 males and 4 females, with an average age of 38.2 years (range, 18-72 years). The interval between injury and operation was 6 hours to 7 days (mean, 4 days). According to Lauge-Hansen classification, ankle fracture was rated as pronation external rotation type in 5 cases, as supination-external rotation type in 4 cases, and as pronation-abduction type in 2 cases. The MRI and color Doppler ultrasound showed deltoid ligament rupture. The results of valgus stress test, talus valgus tilt test, and anterior drawer test after anesthesia were all positive. Fracture was treated by open reduction and internal fixation, and deltoid injury was repaired. RESULTS: All incisions healed primarily. All patients were followed up 12-18 months (mean, 13.3 months). The X-ray films showed anatomical reduction, good position of internal fixation and stable distal tibiofibular syndesmosis. The mean fracture union time was 7.6 weeks (range, 6-8 weeks). MRI at 3 months after operation showed normal shape of the deltoid ligament. According to American Orthopaedic Foot and Ankle Society (AOFAS) score, the results were excellent in 6 cases, good in 3 cases, fair in 1 case, and poor in 1 case, with an excellent and good rate of 81.8%. CONCLUSION: It is an effective method to treat ankle fracture with deltoid ligament injury by open reduction and internal fixation of ankle fracture and repair of the deltoid ligament injury, which can effectively rebuild medial instability and has satisfactory effectiveness. PMID- 26477151 TI - [ANTIBIOTIC-IMPREGNATED ARTICULAR CEMENT SPACER FOR TREATMENT OF PERIPROSTHETIC JOINT INFECTION]. AB - OBJECTIVE: To investigate the current problems and corresponding solutions regarding the use of antibiotic-impregnated cement spacer for the treatment of periprosthetic joint infection (PJI). METHODS: A retrospective analysis was made on the clinical data of 27 patients with PJI who underwent two-stage revision with antibiotic-impregnated cement spacer between January 2001 and January 2013. There were 12 males and 15 females, with an average age of 62.7 years (range, 25 81 years). All arthroplasties were unilateral, including 19 hip PJI and 8 knee PJI. The mean duration from primary arthroplasty to PJI was 25 months (range, 3 252 months). After infection was controlled with the antibiotic-impregnated cement spacer combined with systematic antibiotics treatment, two-stage revision was performed. The effectiveness was evaluated. Results One patient died of myocardial infarction at 2 days after surgery. Infection was controlled, and two stage revision was successfully performed in 19 patients; deep venous thrombosis occurred in 1 of 3 patients who experienced hip spacer fractures, which was cured after conservative management. The spacers were removed and bacteria-sensitive antibiotics was used because of recurrent infections after the first-stage surgery in 7 patients; 3 patients gave up treatment because infection was not controlled, 4 patients received revision after infection was controlled. Twenty three patients were followed up 1-5 years (mean, 2.3 years). The average Harris hip score and KSS score at 1 years after revision were significantly improved when compared with preoperative ones (P<0.05). In the 8 patients with gram negative or fungus infection, 7 were found to have recurrent infection after the first-stage surgery; in the 12 patients with gram-positive infection, no recurrent infection was found. Failed treatment was observed in 1 patient with gram-positive and gram-negative infections and 2 with fungus infection, respectively. CONCLUSION: Antibiotic- impregnated cement spacer has a satisfactory effectiveness for PJI. However, complication of spacer fracture should be noted, especially hip spacers. If the pathogen is gram-negative bacteria or fungus, the implanted spacer may increase the possibility of recurrent infection. PMID- 26477152 TI - [RESEARCH OF ACETABULAR ORIENTATION DETERMINATION AND ACCURACY IN TOTAL HIP ARTHROPLASTY FOR BONY ANKYLOSED HIP]. AB - OBJECTIVE: To explore the method of acetabular orientation determination in total hip arthroplasty (THA) for bony ankylosed hip and the accuracy of the postoperative evaluation. METHODS: Between January 2009 and March 2013, 33 consecutive patients (49 hips) underwent THA. There were 25 males and 8 females with a mean age of 35.8 years (range, 18-69 years). The left hip was involved in 10 cases, the right hip in 7 cases, and bilateral hips in 16 cases. The causes were ankylosing spondylitis in 18 patients, tuberculosis in 6 patients, traumatic arthritis in 6 patients, osteoarthritis in 2 patients, and suppurative infection in 1 patient. The disease duration was 7-15 years with an average of 10.8 years. The acetabular orientation was determined with periacetabular bone marks (the upper margin of the obturator foramen, acetabular notch etc.) and soft tissue signs (acetabulum transverse ligament etc.). The hip or pelvic radiograph was taken to measure the acetabular prosthesis anteversion and abduction angle, and upward or downward, inward or outward acetabular migration degree. The acetabular anteversion angle of 15 degrees, the abduction angle of 45 degrees, and upward or downward, inward or outward acetabular migration degree of 0 served as a reference value to evaluate the accuracy of acetabular position. RESULTS: There was no complications of neurovascular injury, fracture, joint dislocation, and infection. All of patients were followed up 13-63 months (mean, 30.3 months). The anteversion angle and abduction angle were (13.904 +/- 4.034) degrees and (42.898 +/- 7.474) degrees at last follow-up, showing no significant difference when compared with reference value (t=1.386, P=0.178; t=1.969, P=0.055). The inward or outward and upward or downward acetabulum migration degree were (2.530 +/- 2.261) mm and (3.886 +/- 3.334) mm respectively, showing significant differences when compared with reference value (t=7.830, P=0.000; t=8.159, P=0.000); it was less than 5 mm in 29 hips, 5-10 mm in 18 hips, and more than 10 mm in 2 hips; the acetabulum center coincidence rate was 59.2%. CONCLUSION: For bony ankylosed hip having loss of normal anatomy structure, intraoperative residues and permanent anatomical structure should be used for acetabular positioning. PMID- 26477153 TI - [EFFECTIVENESS OF ANATOMIC FEMORAL COMPONENT PROSTHESIS FOR SEVERE DEVELOPMENTAL DYSPLASIA OF THE HIP IN TOTAL HIP ARTHROPLASTY]. AB - OBJECTIVE: To evaluate the effectiveness of anatomic femoral component prosthesis for severe development dysplasia of the hip (DDH) in total hip arthroplasty (THA). METHODS: Between September 2009 and September 2013, 48 patients (51 hips) with severe DDH underwent THA with cementless anatomic femoral component prosthesis. There were 5 males (5 hips) and 43 females (46 hips) with an average age of 51 years (range, 28-67 years). The left hip was involved in 25 cases, the right hip in 20 cases, and bilateral hips in 3 cases. There were 39 cases (44 hips) of Crowe type III and 9 cases (7 hips) of Crowe type IV. The visual analogue scale (VAS) score was 5.72 +/- 1.84, and Harris score was 41.66 +/- 4.87 at preoperation. All patients had leg discrepancy with a length difference of (4.31 +/- 0.84) cm. RESULTS: The duration of surgery was 59-110 minutes (mean, 78.6 minutes), and the hospitalization days were 6-20 days (mean, 12.3 days). All patients obtained primary healing of incision without wound related complications of swelling, effusion, and infection. Two patients were found to have intramuscular venous thrombosis. All patients were followed up 10-54 months (mean, 29 months). Limp was observed at the early stage after operation in 9 patients and disappeared after 1 year, the other patients had normal gait. The VAS score 1.46?0.47, Harris score 88.66 +/- 3.48, and the leg length difference (1.15 +/- 0.33) cm at last follow-up all showed significant differences when compared with the preoperative values (P<0.05). No prosthesis loosening or subsidence, heterotopic ossification, dislocation, and infection occurred. CONCLUSION: Anatomic femoral component prosthesis for severe DDH in THA can relieve pain, and improve the hip joint function and limb discrepancy. Short-term effectiveness was satisfactory, but the long-term effectiveness should still be observed in future. PMID- 26477154 TI - [CLINGING LESSER TROCHANTER OSTEOTOMY WITH WAGNER CONE IN TREATMENT OF CROWE TYPE IV DEVELOPMENTAL DYSPLASIA OF THE HIP IN ADULT]. AB - OBJECTIVE: To investigate the effectivness of the clinging lesser trochanter osteotomy with the Wagner cone in total hip arthroplasty (THA) for Crowe type IV developmental dysplasia of the hip (DDH) in adult. METHODS: Between November 2009 and September 2012, 7 female patients (9 hips) with Crowe type IV DDH were treated by THA procedures of clinging lesser trochanter osteotomy with Wagner cone, aged 24-62 years (mean, 42 years). All patients experienced severe pain and claudication. The left hip was involved in 2 cases, the right hip in 3 cases, and bilateral hips in 2 cases. The Harris score of involved hip was 50.00?7.04. The both limps were discrepancy with an average length difference of 3.4 cm (range, 3 4 cm). The results of Trendelenburg sign were positive. X-ray films showed high complete dislocation of the involved hips. RESULTS: The incisions healed by first intention. There was no complication such as infection, dislocation, prosthesis loosening, neurovascular injury. The average follow-up was 36.4 months (range, 25 48 months). Pain and claudication were improved and all patients could restore to work. The Harris score was improved to 83.42 +/- 6.47, showing significant difference when compared with preoperative score (t=8.90, P=0.00). The results of Trendelenburg sign were negative. X-ray films showed that all patients got a bony union at osteotomy site of greater trochanter at 3-6 months after operation. And the interface between prosthesis and bone was stable. There was no prosthesis loosening or sinking during the follow-up. CONCLUSION: Clinging lesser trochanter osteotomy with Wagner cone could be an option to shorten the femur in THA for patients with Crowe type IV DDH. It is effective in decreasing the risk of neurovascular injury. PMID- 26477155 TI - [A COMPARATIVE STUDY ON TWO OSTEOTOMIES IN TOTAL HIP ARTHROPLASTY FOR CROWE TYPE IV DEVELOPMENTAL DYSPLASIA OF THE HIP]. AB - OBJECTIVE: To assess the effectiveness of two osteotomy methods in total hip arthroplasty (THA) for treating Crowe type IV adult developmental dysplasia of the hip (DDH), trochanteric osteotomy and subtrochanteric osteotomy. METHODS: A retrospective analysis was made on the clinical data of 36 patients (43 hips) with Crowe type IV DDH undergoing THA between June 2007 and December 2013. In THA, 19 patients (23 hips) underwent trochanteric osteotomy (group A) and 17 patients (20 hips) underwent subtrochanteric osteotomy (group B). There was no significant difference in age, gender, body mass index, side, preoperative Harris score, and limb length difference between 2 groups (P>0.05). The operation duration, bleeding volume, hospitalization duration, intraoperative and postoperative complications were compared between 2 groups. RESULTS: There was no significant difference in operation duration, bleeding volume, and hospitalization days between 2 groups (P>0.05). The rate of intraoperative complication was 21.7% (5/23) in group A and 5.0% (1/20) in group B, showing no significant difference between 2 groups (P>0.05). The rate of postoperative complications was 10.5% (2/19) in group A and 22.2% (4/18) in group B, showing no significant difference between 2 groups (P>0.05). Thirty-one patients (37 hips) were followed up 1-7 years (mean, 3 years), including 16 cases (19 hips) in group A and 15 cases (18 hips) in group B. X-ray films showed good position of the prostheses. The Harris score at last follow-up was significantly increased when compared with preoperative score in 2 groups (P<0.05), but there was no significant difference between 2 groups (P>0.05). The postoperative discrepancy of bilateral lower limbs had no significant difference (t = -1.343, P=0.188). CONCLUSION: THA with trochanteric osteotomy or subtrochanteric osteotomy both can effectively treat Crowe type IV DDH. THA with subtrochanteric osteotomy has an advantage in correcting lower limb discrepancy. PMID- 26477157 TI - [MINIMALLY INVASIVE PROCEDURE FOR CORRECTION OF PECTUS CARINATUM]. AB - OBJECTIVE: To explore the method and experience in correction of pectus carinatum with minimally invasive procedure. METHODS: Between June 2010 and January 2014, 30 patients with pectus carinatum were corrected by minimally invasive procedure. There were 21 boys and 9 girls whose average age was 13 years and 2 months (range, from 8 years and 10 months to 18 years and 9 months), including 24 cases of first operation, 2 recurrence after traditional pectus carinatum correction, and 4 cases secondary to median thoracotomy. Thirty patients had symmetric and asymmetric mild pectus carinatum. RESULTS: The operation was performed successfully in all patients, and no severe complication occurred. The operation time was 42-95 minutes (mean, 70 minutes). The bleeding volume during operation was 4-30 mL (mean, 10 mL). The time from operation to discharge was 6-10 days (mean, 7 days). The average time of follow-up was 25 months (range, 9-54 months). All surgical wound healed primarily with no infection. The X-ray films showed slight pneumothorax in 7 cases, and it was absorbed after 1 month without treatment. Loosening of internal fixation was found in 1 patient because of trauma at 6 months, and operation was performed again. The bar was removed at 2 years in 21 patients. The patients had good thoracic contour and normal activity. CONCLUSION: Minimally invasive procedure for correction of pectus carinatum is safe and will get satisfactory effect in maintaining thoracic contour. It has also less trauma and shorter operation time. PMID- 26477156 TI - [RESEARCH PROGRESS OF OSTEOTOMY IN TOTAL HIP ARTHROPLASTY TO TREAT CROWE TYPE IV DEVELOPMENTAL DYSPLASIA OF THE HIP]. AB - OBJECTIVE: To summarize the methods and complications of osteotomy in total hip arthroplasty (THA) to treat Crowe type IV developmental dysplasia of the hip (DDH) so as to provide the reference for selection of surgical procedures. METHODS: The literature concerning THA for DDH was reviewed, and the effectiveness and complications were summarized in different methods. RESULTS: At present, four osteotomies are commonly used in DDH, including transtrochanteric osteotomy, subtrochanteric osteotomy, lesser trochanteric osteotomy, and distal femoral osteotomy. Transtrochanteric osteotomy and subtrochanteric osteotomy can effectively adjust leg length, correct femoral anteversion and avoid nerve injury, but transtrochanteric osteotomy may cause bone fracture and abductor injury. Lesser trochanteric osteotomy is scarcely used because of its poor effectiveness. Distal femoral osteotomy is usually used in patients with knee deformity. CONCLUSION: For patients with Crowe type IV DDH complicated by severe femoral dislocation and soft tissue spasm, subtrochanteric osteotomy should be selected, whereas it needs an associated standard focusing on how to select the osteotomy shape and length in subtrochanteric ostetomy, which needs an advanced research. PMID- 26477158 TI - [EVALUATION OF TWO-DIMENSION COMPUTER-AIDED SURGERY NAVIGATION SYSTEM FOR LUMBAR PEDICLE SCREW FIXATION ON RECOMBINANT CT SECTION AFTER OPERATION]. AB - OBJECTIVE: To investigate the accuracy of the two-dimension computer-aided surgery navigation system in the lumbar pedicle screw fixation on recombinant CT section after operation. METHODS: Between February 2011 and April 2013, 218 patients undergoing lumbar spinal pedicle screw fixation were divided into 2 groups: two-dimension computer-aided surgery navigation system was used in 95 cases (the navigation group) and X-ray fluoroscopy assistant technology in 123 cases (the fluoroscopy assistant group). There was no significant difference in age, gender, and type of disease between 2 groups (P>0.05). The mean operating time, blood loss volume, and fluoroscopy times, and the one-time success rate of pedicle screw implant were observed. The sagittal screw angle (SSA), the relationship between the pedicle cortex and screw, the accuracy rate of pedicle screw, and the sagittal angle on both sides (SBA) were observed. RESULTS: A total of 504 screws were inserted in navigation group, 432 (85.7%) were inserted successfully at first time and 472 (85.7%) were inserted successfully at end time. A total of 656 screws were inserted in fluoroscopy assistant group, 474 (72.3%) were successfully inserted at first time, and 563 (85.8%) were inserted successfully at end time. There were significant differences in the one-time success rate and final success rate of pedicle screw implant between 2 groups (chi2=30.19, P=0.00; chi2=18.16, P=0.00). There was no significant difference in the mean operating time and the blood loss volume of pedicle screw implant between 2 groups (t=0.88, P=0.38; t=1.47, P=0.14); but the fluoroscopy times of pedicle screw implant in navigation group 0.7?0.3 were significantly less than that in fluoroscopy assistant group 1.5 +/- 1.0 (t = -8.09, P = 0.00). The SSA and SBA in navigation group [(3.7 +/- 0.9)0 and (1.7 +/- 0.8)] were significantly less than those in fluoroscopy assistant group [ (6.0 +/- 1.7) degrees and (3.5 +/- 1.6) degrees] (t = -26.92, P = 0.00; t = -22.49, P=0.00). CONCLUSION: The sagittal screw angle and accuracy of pedicle screw implant can be significantly improved using the two-dimension computer-aided surgery navigation system in lumbar posterior fixation. PMID- 26477159 TI - [APPLICATION OF WRIST CREASE ISLAND FLAP BASED ON THE SUPERFICIAL PALMAR BRANCH OF THE RADIAL ARTERY FOR THUMB RECONSTRUCTION]. AB - OBJECTIVE: To investigate the effectiveness of the island flaps based on the superficial palmar branch of the radial artery (SPBRA) to repair the thumb wound. METHODS: Between February 2012 and November 2013, 8 cases of thumb defects and bilateral artery defect were treated. There were 5 males and 3 females with an average age of 30.5 years (range, 19-51 years). The injury was caused by crush (4 cases), avulsion (3 cases), and twist (1 case). The injury located at the metacarpophalangeal joints in 3 cases, at the proximal palmar side in 2 cases, and at the interphalangeal joints in 3 cases. The defect size ranged from 3.5 cm x 1.5 cm to 6.5 cm x 2.0 cm. The digital artery defect was 2.5-8.5 cm (mean, 5.3 cm). The disease duration was 2.0-4.5 hours (mean, 3.2 hours). The reversed island flaps based on the SPBRA were designed, which size was 4.0 cm x 2.0 cm to 7.5 cm x 3.0 cm. The donor sites were closed directly. RESULTS: The operation was successfully completed in 7 patients except 1 patient having vascular variation. All flaps survived completely. Wound and incision at the donor site healed by first intention. All patients were followed up 6-18 months (mean, 13 months). The flaps had similar color and texture to adjacent skin. Linear scar was seen at the donor site in 1 patient, with no functional limitation. According to the functional assessment criteria of upper limb by the Hand Surgery Branch of Chinese Medical Association, the results were excellent in 6 cases, good in 1 case, and fair in 1 case, with an excellent and good rate of 87.5%. CONCLUSION: The reversed island flap based on the SPBRA is an ideal flap for the thumb reconstruction because the advantages of reliable blood supply, easy dissection, less injury at donor site, and good repair results. PMID- 26477160 TI - [SEQUENTIAL THERAPY OF VACUUM SEALING DRAINAGE AND PEDICLED FLAP TRANSPLANTATION FOR CHILDREN WITH MOTORCYCLE SPOKE HEEL INJURY]. AB - OBJECTIVE: To investigate the clinical characteristics of motorcycle spoke heel injury and the effectiveness of sequential therapy of vacuum sealing drainage (VSD) and pedicled flap transplantation for treating motorcycle spoke heel injury in children. METHODS: Between January 2010 and January 2014, 15 children (aged from 3 to 8 years, 5.7 years on average) with motorcycle spoke heel injury received sequential therapy of VSD and pedicled flap transplantation. The interval from injury to admission was 3-7 days, with an average of 4.9 days. The locations were the heel in 8 cases, the heel and lateral malleolus in 2 cases, and the medial malleolus and medial heel in 4 cases, and the medial and lateral malleolus and heel in 1 case. The patients had different degrees of defects of the skin, tendon, and bone. The skin defect size ranged from 3 cm x 3 cm to 13 cm x 6 cm. VSD was applied for twice in 13 cases and three times in 2 cases. Reversed flow sural flap was applied in 8 cases, lateral supramalleolar flap in 2 cases, medial supramalleolar perforator-based flaps in 4 cases, and posterior tibial artery flap in 1 case. Eight pedicled flaps with neuroanastomosis were selected according to the wound characteristics. The flap size ranged from 4 cm x 4 cm to 14 cm x 7 cm. RESULTS: Of 15 cases, 13 flaps survived well except that two had partial skin necrosis at the distal site. Primary healing was obtained, and skin graft at donor site survived. The patients were followed up 9-21 months (mean, 13 months). Mild and moderate bulky flaps were observed in 9 cases and 6 cases respectively. Of 15 cases, 13 could walk with weight loading, and 2 had slight limping. Superficial sensation recovered to S3 in 8 patients undergoing neuroanastomosis, and recovered to S2 in 7 patients not undergoing neuroanastomosis at 6 months after operation. According to AOFAS evaluation system for Ankle-Hindfoot, the results were excellent in 13 cases and good in 2 cases, with an excellent and good rate of 100% at 8 months after operation. CONCLUSION: The main characteristic of motorcycle spoke heel injury lies in a combination of high energy damage and thermal damage. Sequential therapy of VSD and pedicled flap transplantation can be regarded as a reliable option to obtain good outcome of wound healing and satisfactory functional recovery for the management of motorcycle spoke heel injury. PMID- 26477161 TI - [REACTION OF HUMAN FIBROBLASTS FROM DIFFERENT SITES TO THE MECHANICAL STRESS]. AB - OBJECTIVE: To explore the reaction of normal skin fibroblasts from different sites of human body to cyclic stretch. METHODS: The normal skin tissues from scapular upper back and medial side of upper arm of 3 patients were cultured in vitro. Fibroblasts of experimental group were loaded by cyclic stretch with 10% amplitude for 24, 36, and 48 hours respectively. Fibroblasts of control group were cultured without cyclic stretch. The morphologic changes were observed using inverted microscope. CCK-8 method was used to detect the proliferation of the fibroblasts. The expressions of integrin beta1 mRNA, p130Crk-associated substance (P130Cas) mRNA, transform growth factor beta1 (TGF-beta1) mRNA, and collagen type I alpha1 chain (COL1A1) mRNA were detected by real-time quantitative PCR. The protein levels of collagen type I and TGF-beta1 were detected by ELISA. RESULTS: The cultured cells showed a significantly increased cell proliferation ability, and apparent orientation after the applied strain. The proliferation activity, mRNA expression levels of integrin beta1, P130Cas, and TGF-beta1, protein levels of TGF-beta1 in back skin were significantly higher than those in arm skin (P<0.05) when the fibroblasts were loaded for 36 and 48 hours, but no significant difference between back skin and arm skin at 24 hours (P>0.05). There was no significant difference in mRNA expression level of COL1A1 and protein level of collagen type I between back skin and arm skin at 24, 36, and 48 hours (P>0.05). There was no significant difference in all above indexes between back skin and arm skin in control group (P>0.05). CONCLUSION: Fibroblasts from scapular upper back and medial side of upper arm display different reactions to cyclic stretch, which indicates that there exists site difference in the reactions of fibroblasts to cyclic stretch. It might be related with the incidence of hypertrophic scar in different sites of the body. PMID- 26477162 TI - [EFFECT OF RECOMBINANT ADENOVIRUS-BONE MORPHOGENETIC PROTEIN 12 TRANSFECTION ON DIFFERENTIATION OF PERIPHERAL BLOOD MESENCHYMAL STEM CELLS INTO TENDON/LIGAMENT CELLS]. AB - OBJECTIVE: To research the effect of recombinant adenovirus-bone morphogenetic protein 12 (Ad-BMP-12) transfection on the differentiation of peripheral blood mesenchymal stem cells (MSCs) into tendon/ligament cells. METHODS: Peripheral blood MSCs were isolated from New Zealand rabbits (3-4 months old) and cultured in vitro until passage 3. The recombinant adenoviral vector system was prepared using AdEasy system, then transfected into MSCs at passage 3 (transfected group); untransfected MSCs served as control (untransfected group). The morphological characteristics and growth of transfected cells were observed under inverted phase contrast microscope. The transfection efficiency and green fluorescent protein (GFP) expression were detected by flow cytometry (FCM) and fluorescence microscopy. After cultured for 14 days in vitro, the expressions of tendon/ligament-specific markers were determined by immunohistochemistry and real time fluorescent quantitative PCR. RESULTS: GFP expression could be observed in peripheral blood MSCs at 8 hours after transfection. At 24 hours after transfection, the cells had clear morphology and grew slowly under inverted phase contrast microscope and almost all expressed GFP at the same field under fluorescence microscopy. FCM analysis showed that the transfection efficiency of the transfected group was 99.57%, while it was 2.46% in the untransfected group. The immunohistochemistry showed that the expression of collagen type I gradually increased with culture time in vitro. Real-time fluorescent quantitative PCR results showed that the mRNA expressions of the tendon/ligament-specific genes (Tenomodulin, Tenascin-C, and Decorin) in the transfected group were significantly higher than those in untransfected group (0.061+/- 0.013 vs. 0.004 +/- 0.002, t = -7.700, P=0.031; 0.029 +/- 0.008 vs. 0.003 +/- 0.001, t = -5.741, P=0.020; 0.679 +/- 0.067 vs. 0.142 +/- 0.024, t = -12.998, P=0.000). CONCLUSION: Ad-BMP-12 can significantly promote differentiation of peripheral blood MSCs into tendon/ligament fibroblasts and enhance the expressions of tendon/ligament specific phenotypic differentiation, which would provide the evidence for peripheral blood MSCs applied for tendon/ligament regeneration. PMID- 26477163 TI - [INDUCTING DIFFERENTIATION EFFECT OF SCIATIC NERVE EXTRACTS ON RABBIT ADIPOSE DERIVED STEM CELLS IN VITRO]. AB - OBJECTIVE: To study the inducting differentiation effect of the sciatic nerve extracts on rabbit adipose-derived stem cells (ADSCs) in vitro. METHODS: The ADSCs were isolated from 2 healthy 4-month-old New Zealand rabbits (weighing, 2.0 2.5 kg) and cultured to passage 3, which were pretreated with 10 ng/mL basic fibroblast growth factor (bFGF) for 24 hours before induction. Then the induction media containing the extracts of normal sciatic nerve (group B) and injured sciatic nerve at 3, 7, and 14 days (group C, group D, and group E) were used, and D-Hank was used in group A as blank control group. The morphological changes of the cells were observed. At 7 days of induction, the gene expressions of neuron specific enolase (NSE), nestin (NES), and S-100 were detected by real-time fluorescent quantitative PCR. The S-100 protein expression was tested by immunocytochemical staining. RESULTS: At 4 days after induction, some ADSCs of groups C, D, and E showed the morphology of Schwann-like cells or neuron-like cells, the change of group D was more obvious; and the ADSCs of group A and B had no obvious change, which were still spindle. The S-100 immunocytochemical staining showed positive expression in groups C, D, and E (more obvious in group D) and negative expression in groups A and B. The gene expression of S-100 displayed time-dependent increases in groups C and D, which was significantly higher than that of groups A, B, and E (P<0.05), but no significant difference was found between groups C and D (P>0.05). The gene expression of NSE showed the same tendency to S-100, which reached the peak in group D; the gene expression of NSE in groups D and E was significantly higher than that of groups A, B, and C (P<0.05), and groups D and E showed significant difference (P<0.05). However, the gene expression of Nestin showed no significant difference among different groups (P>0.05). CONCLUSION: The ADSCs can be induced to differentiate into Schwann-like cells or neuron-like cells with sciatic nerve extracts; and the early stage (3-7 days) after injury is the best time for stem cell transplantation. PMID- 26477164 TI - [ISOLATION, CULTURE AND IDENTIFICATION OF CARTILAGE DERIVED STEM CELLS FROM THREE SUBTYPES OF CARTILAGES]. AB - OBJECTIVE: To isolate and culture cartilage derived stem cells from different subtypes of cartilages, and to identify their characteristics. METHODS: Cartilage derived stem cells were isolated from different subtypes of cartilages (auricle cartilage, articular cartilage, and intervertebral cartilage) by using adhesive method of fibronectin. The expressions of positive surface markers (CD29 and CD90) and negative surface markers (CD34 and CD45) in cartilage derived stem cells were detected via flow cytometry. The single cell colony-forming efficiency of cartilage derived stem cells was determined by clonal formation unit test; the multipotent differentiation capacity was identified by chondrogensis, osteogenesis, and adipogenesis induction. RT-PCR was used to test the expression of osteogenic, chondrogenic, and adipogenic genes; and bone marrow mesenchymal stem cells (BMSCs) served as control. RESULTS: Three cell populations were successfully isolated from different subtypes of cartilages, which could express CD29 and CD 90 highly, but did not express CD34 and CD45. After 2 weeks of culture, single cartilage derived stem cell could form single cell colony. In addition, cartilage derived stem cells had high chondrogenesis, osteogenesis, and adipogenesis potentials. After osteogenic induction, the expressions of collagen type I and collagen type X in articular and intervertebral cartilage stem cells were significantly higher than those in BMSCs (P<0.05), while there was no significant difference between auricular cartilage stem cells and BMSCs (P>0.05). The expressions of Aggrecan and collagen type II in cartilage derived stem cells after chondrogenic induction were significantly higher than those in BMSCs (P<0.05). While the ability of adipogenic differentiation was lower than that in BMSCs, but no significant difference was found (P>0.05). CONCLUSION: Cartilage derived stem cells in different subtypes of cartilages possess typical characteristics of stem cells. PMID- 26477165 TI - [EFFECT OF VITAMIN C ON APOPTOSIS OF NUCLEUS PULPOSUS CELLS INDUCED BY TUMOR NECROSIS FACTOR a AND SERUM DEPRIVATION]. AB - OBJECTIVE: To explore the effect of Vitamin C (Vit C) on the apoptosis of human nucleus pulposus (NP) cells induced by tumor necrosis factor a (TNF-alpha) and serum deprivation. METHODS: The NP cells were isolated from patients undergoing spine corrective operation by collagenase trypsin. The experiment was divided into 3 groups: Vit C group (group A), TNF-alpha group (group B), and serum deprivation group (group C). Group A was reassigned to Al subgroup (basic medium), A2 subgroup (100 pg/mL Vit C), and A3 subgroup (200 pg/mL Vit C). Group B was reassigned to B0 subgroup (control group), Bi subgroup (100 ng/mL TNF alpha), B2 subgroup (100 microg/mL Vit C+100 ng/mL TNF-alpha), and B3 subgroup (200 microg/mL Vit C+100 ng/mL TNF-alpha). Group C was reassigned to C0 subgroup (Control group), C1 subgroup (2% FBS), C2 subgroup (2% FBS+100 microg/mL Vit C), and C3 subgroup (2% FBS+200 microg/mL Vit C). After application of 100 pg/mL or 200 microg/mL Vit C for 24 hours, NP cells were stimulated by TNF-alpha and serum deprivation, then the apoptosis rate of NP cells was detected by a flow cytometry, and the gene expressions of the extracellular matrix of NP cells (collagen type I, collagen type II, aggrecan, and Sox9) and apoptosis related genes (p53, FAS, and Caspase 3) were detected by real-time fluoroscent quantitative PCR. Results Group A: Vit C could significantly reduce the apoptosis rate and gene expressions of p53, FAS, and Caspase 3 of NP cells in A2 and A3 subgroups when compared with Al subgroup (P<0.05), but there was no significant difference between A2 subgroup and A3 subgroup (P>0.05); Vit C could promote the expressions of the extracellular matrix (collagen type I, collagen type II, aggrecan, and Sox9) of NP cells in a concentration dependent manner (P<0.05). Group B: TNF-alpha significantly increased the apoptosis rate and the gene expressions of p53, FAS, and Caspase 3 in B1 subgroup when compared with B0 subgroup (P<0.05); however, Vit C significantly increased the apoptosis rate and the gene expressions in B2 subgroup, and significantly decreased them in B3 subgroup when compared with B1 subgroup (P<0.05). Group C: 2% FBS significantly increased the apoptosis rate of NP cells and significantly reduced the gene expressions of p53, FAS, and Caspase 3 in C1 subgroup when compared with C0 subgroup (P<0.05); Vit C could significantly reduce the apoptosis rate and gene expressions of p53, FAS, and Caspase 3 in C3 subgroup, but it could significantly increase them in C2 subgroup when compared with C1 subgroup (P<0.05). CONCLUSION: Vit C can promote the synthesis and secretion of extracellular matrix of NP cells. 200 microg/mL Vit C may delay the apoptosis induced by TNF-alpha and serum deprivation, indicating the potential therapeutic effect of Vit C on intervertebral disc degeneration. PMID- 26477166 TI - [DEVELOPMENT AND CHALLENGES OF ANNULUS FIBROSUS TISSUE ENGINEERING]. AB - OBJECTIVE: To review the biomaterial and clinical prospects of annulus tibrosus tissue engineering. METHODS: The recent literature concerning annulus fibrosus tissue engineering, including cell source, bioactive molecules, and biomaterial was extensively reviewed and summarized. RESULTS: Mesenchymal stem cells (MSCs) is an ideal seed cells. When annulus fibrosus cells and MSCs in the ratio of 2:1 are cultured, it shows the closest mRNA expression levels of annulus fibrosus related markers. Bioactive molecules can be divided into 4 types: growth factors, morphogens, catabolic enzyme inhibitors, and intracellular regulators. They play an active role in promoting the synthesis of extracellular matrix, and maintaining intervertebral disc homeostasis and a balance between anabolic- and catabolic process in the disc. Based on the source, biological materials can be divided into natural materials, synthetic materials, and composite materials. The mechanical properties of the annulus fibrosus is an important basis for material design. Up to now, none of these scaffold materials is accepted as the most suitable one. The selection of scaffold materials is still to be further studied. The development of novel composite biomaterials is a trend. CONCLUSION: The annulus fibrosus tissue engineering for the anulus fibrosus regeneration and repair will bring very broad prospects for clinical application in future. PMID- 26477167 TI - [ROLE OF STEM CELL NICHES IN MAINTAINING CARDIAC STEM CELLS HOMEOSTASIS]. AB - OBJECTIVE: To review the role of stem cell niches in maintaining cardiac stem cells homeostasis, and to foresee its prospects. METHODS: The literature on cardiac stem cells niches was extensively reviewed. The roles of stem cell niches components, extracellular matrix, and secretory factors in maintaining cardiac stem cell homeostasis were analysed and reviewed. RESULTS: Lots of experiments reveal that stem cell niches are able to delay the aging of cardiac stem cells, protect from external damage, keep stem properties, and improve the purity and quantity. However, the mechanism is not fully understood. CONCLUSION: The stem cell niches have a very bright application prospect in homeostasis, purification, and amplification for the cardiac stem cells, and it needs further study. PMID- 26477168 TI - [PROGRESS OF ALGINATE DERIVATIVES BASED ON BIOMEDICAL MATERIALS]. AB - OBJECTIVE: To summarize the current research status of alginate derivatives based on biomedical materials, and analyze several key points as novel clinical products. METHODS: The general preparation and application methods of alginate derivatives based on biomedical materials at home and abroad were reviewed. The present status and problems were analyzed. RESULTS: The derivation methods to prepare alginate derivatives include crosslink, sulfation, biological factors derivatization, hydrophobic modification, and graft copolymerization. With excellent bionic performance of structure and properties, many alginate derivatives are available for tissue engineering scaffolds, artificial organs, and drug delivery systems etc. However, more systematic applied basic research data should be collected and statistically analyzed for risk managements. CONCLUSION: Alginate derivatives have good feasibility as novel medical products, meanwhile, systematic evaluation and verification should be executed for their safety, effectiveness, and suitability. PMID- 26477169 TI - [RESEARCH PROGRESS OF DIAGNOSIS AND TREATMENT OF HANGMAN FRACTURE]. AB - OBJECTIVE: To review the research progress of the diagnosis and treatment of Hangman fracture. METHODS: The original articles about the diagnosis and treatment of Hangman fracture were extensively reviewed and analyzed. RESULTS: Not only X-ray, but also MRI and CT scans are necessory for the diagnosis and assessment of Hangman fractures. The treatment of unstable Hangman fracture included posterior C2, C3 fixation, anterior C2, C3 fixation, and anterior C2, C3 fixation combined with posterior C2 pedicle screw fixation. The anterior surgical fixation is used by the anterior retropharyngeal approach or subaxial anterior approach, and it has the advantages of directly resecting the injured C2, C3 discs, getting a satisfactory cervical spine alignment, and avoiding the postoperative axial pain. However, posterior surgical fixation using C2 pedicle screw has the risks of neurovascular injuries. CONCLUSION: The surgical technique of Hangman fracture should be determined based on the patient's injury and surgeon's experience. Randomized control trials of different surgical techniques should be performed. PMID- 26477170 TI - "Training more nurses is only answer to crisis". PMID- 26477171 TI - Trusts lose their overseas recruits. PMID- 26477172 TI - Ex-CNO calls for commitment on staff levels. PMID- 26477173 TI - NHS faces wave of criticism over spiralling agency staff bill. PMID- 26477174 TI - Trust warned about nurse shortage. PMID- 26477175 TI - Midlands trust pilots dementia patient booklet. PMID- 26477176 TI - Government pushes ahead with plans that may see NMC fee rise. PMID- 26477177 TI - Talking to nurse during surgery calms patients. PMID- 26477179 TI - "Consider the excellence of daily care to be inspirational". PMID- 26477178 TI - "Well intended, but five year view omits majority of nurses". PMID- 26477180 TI - Leadership philosophy of care home managers. AB - BACKGROUND: Care home managers have a significant influence on staff morale and care delivery. Training methods underpinned by transformational leadership theory (TLT) have been used successfully to develop leaders in healthcare services. AIM: The aim of this preliminary study was to establish which aspects of TLT were apparent in care home managers' philosophies of leadership. METHOD: A qualitative research design was used and 25 care home managers in the north-east of England took part. Participants were asked to provide their philosophies of leadership by completing a questionnaire; a thematic analysis of the responses was then conducted. RESULTS: Development of philosophy, enablement and interpersonal impact emerged as key themes. DISCUSSION: The findings suggested that elements of TLT were apparent in the participants' philosophies of leadership. However, the importance of gaining the support of senior management when attempting to apply a philosophy of eadership in practice was lacking. CONCLUSION: Aspects of TLT, such as supporting frontline employees to engage in education and establishing trust, were embedded in care home managers' philosophies. To develop leadership skills, managers may benefit from training programmes that involve both structured teaching and guided learning through experience. PMID- 26477181 TI - Managing and treating chronic kidney disease. AB - Chronic kidney disease is a long-term condition that commonly exists with other conditions such as diabetes, hypertension and heart failure. The majority of people with CKD are managed in the community by a GP and community nursing team rather than a nephrologist. This article provides an overview of its stages, management and treatment. PMID- 26477182 TI - A strategy for maintaining student wellbeing. AB - Pre-registration nursing programmes place many challenges on students and these can affect their health and wellbeing. The wellness recovery action plan (WRAP) is a strengths-focused technique to reduce stress and improve health and wellbeing that was initially used in mental health care. This article discusses the potential for using WRAPs to support student nurses, as well as those studying other health professions. They can be used to enhance students' educational and clinical self-awareness, reduce anxiety and vulnerability, and enhance resilience, enabling them to cope more effectively with educational and personal challenges. PMID- 26477183 TI - Adherence to CPAP in obstructive sleep apnoea. PMID- 26477184 TI - 60 seconds with Angela Reed-Fox. PMID- 26477185 TI - Big change from small ideas. PMID- 26477186 TI - CMS building its own Superbowl. PMID- 26477187 TI - And in the 15th year.... PMID- 26477188 TI - Collaboration, focus drive transplant success rate at Northwest Kidney Centers. AB - The first step toward creating a successful transplant culture like we have in Seattle is having leaders who understand that transplant truly is the best option for certain patients. A dialysis organization must create infrastructure that addresses patients' needs before, during and after transplant. Patient education and IDT involvement are essential. And working in collaboration with local transplant programs, other health care providers and community partners can propel such an initiative to success. PMID- 26477189 TI - Survival comparison of daily home hemodialysis vs. conventional in the nursing home setting. AB - Nursing home patients on dialysis are higher-acuity compared to the broader end stage renal disease population, and historically have poor outcomes. The objective of this epidemiological study was to compare outcomes in ESRD patients in the nursing home setting treated with daily home hemodialysis versus conventional three-day-a-week hemodialysis. Health status was evaluated for 3,919 patients (n=3391 conventional, n=528 daily home dialysis; April 2007 to June 2013 for conventional; April 2011 to June 2013 for daily home hemodialysis). Analyses included monthly mortality rates, Kaplan-Meier survival analysis, and laboratory values. Results showed monthly mortality rates were consistently lower in the daily home hemodialysis population over the same time period vs. conventional dialysis care. In the incident three months of treatment, annualized monthly mortality rates were 70%, 72%, and 64% in the conventional dialysis population vs. 50%, 24%, and 17% in the daily home population. Patients treated with daily home dialysis had generally similar or higher albumin and hemoglobin values and lower ferritin values over the same time period. Patients treated with daily home hemodialysis had lower monthly mortality rates and generally improved health status compared to patients treated with conventional dialysis. The results of this study are provocative and should be evaluated in a prospective study. PMID- 26477190 TI - CMOs look at need for blood cultures before prescribing antibiotics. PMID- 26477191 TI - Five easy steps to ensure patients are prepared for emergencies. PMID- 26477194 TI - The elephant in the room: Violence in the workplace. PMID- 26477195 TI - Technologies of stage magic: Simulation and dissimulation. AB - The craft of stage magic is presented in this article as a site to study the interplay of people and technology. The focus is on conjuring in the 19th and early 20th centuries, a time when magicians eagerly appropriated new optical, mechanical and electrical technologies into their acts. Also at this time, a modern style of conjuring emerged, characterized by minimal apparatus and a natural manner of performance. Applying Lucy Suchman's perspective of human machine reconfigurations, conjuring in this modern style is interpreted as an early form of simulation, coupled with techniques of dissimulation. Magicians simulated the presence of supernational agency for public audiences, while dissimulating the underlying methods and mechanisms. Dissimulation implies that the secret inner workings of apparatus were not simply concealed but were rendered absent. This, in turn, obscured the production of supernatural effects in the translation of agencies within an assembly of performers, assistants, apparatus, apparatus-builders, and so on. How this was achieved is investigated through an analysis of key instructional texts written by and for magicians working in the modern style. Techniques of dissimulation are identified in the design of apparatus for three stage illusions, and in the new naturalness of the performer's manner. To explore the significance of this picture of stage magic, and its reliance on techniques of dissimulation, a parallel is drawn between conjuring and recent performances of computerized life forms, especially those of social robotics. The paper concludes by considering what is revealed about the production of agency in stage magic's peculiar human-machine assemblies. PMID- 26477196 TI - Trading twitter: Amateur recorders and economies of scientific exchange at the Cornell Library of Natural Sounds. AB - Scientists have long engaged in collaborations with field collectors, but how are such collaborations established and maintained? This article examines structures of collaborative data collection between professional scientists and various field recorders around the Cornell Library of Natural Sounds. The Library collects animal sound recordings for use in education, preservation, and entertainment, but primarily in the scientific field of bio-acoustics. Since 1945, the Library has enlisted academic researchers, commercial recorders and broadcasters (such as the British Broadcasting Corporation), and amateur sound hunters in its expansion. I argue that the Cornell Library of Natural Sounds managed to craft and sustain a crucial network of contributors through creative and strategic brokering with its collection of recordings/data. Drawing on notions from exchange theory, I show that sound recordings were valued not just as scientific data, but also as copyrighted commodities that could be bought, sold, traded, and converted in a range of economic, social, and symbolic capitals within collaborators' respective social fields. Thus, aligning collaborators' interests, these exchange relations enabled the Cornell Library of Natural Sounds to negotiate amateur recorders' reliability, willingness to share work, and commitment to scientific standards, as well as the bonds that solidified their collaboration with the Cornell Library of Natural Sounds. Attending to the micro economics of data exchange, this article thus brings into perspective the multi dimensional processes through which data-flows are managed. PMID- 26477197 TI - Crafting the group: Care in research management. AB - This article reports findings from an interview study with group leaders and principal investigators in Denmark, the United Kingdom and the United States. Taking as our starting point current interest in the need to enhance 'responsible research and innovation', we suggest that these debates can be developed through attention to the talk and practices of scientists. Specifically, we chart the ways in which interview talk represented research management and leadership as processes of caring craftwork. Interviewees framed the group as the primary focus of their attention (and responsibilities), and as something to be tended and crafted; further, this process required a set of affective skills deployed flexibly in response to the needs of individuals. Through exploring the presence of notions of care in the talk of principal investigators and group leaders, we discuss the relation between care and craft, reflect on the potential implications of the promotion of a culture of care and suggest how mundane scientific understandings of responsibility might relate to a wider discussion of responsible research and innovation. PMID- 26477198 TI - The little death: Rigoni-Stern and the problem of sex and cancer in 20th-century biomedical research. AB - Approaches to the organization and conduct of cancer research changed dramatically throughout the 20th century. Despite marked differences between the epidemiological approaches of the first half of the century and molecular techniques that gained dominance in the 1980s, prominent 20th-century researchers investigating the link between sexual activity and anogenital cancers continuously invoked the same 1842 treatise by Italian surgeon Domenico Rigoni Stern, who is said to originate the problem of establishing a causal link between sex and cancer. In this article, I investigate 20th-century references to Rigoni Stern as a case of a broader phenomenon: scientists situating their work through narratives of venerated ancestors, or originators. By explaining shifting versions of originator narratives in light of their authors' cultural context and research practices, we can reimagine as meaningful cultural symbols the references that previous scholars have treated as specious rhetorical maneuvers. In this case, references to Rigoni-Stern provide an interpretive anchor for American scientists to construct continuity between their work and a diverse historical legacy of cancer research. PMID- 26477199 TI - Formalization and separation: A systematic basis for interpreting approaches to summarizing science for climate policy. AB - In studies of environmental issues, the question of how to establish a productive interplay between science and policy is widely debated, especially in relation to climate change. The aim of this article is to advance this discussion and contribute to a better understanding of how science is summarized for policy purposes by bringing together two academic discussions that usually take place in parallel: the question of how to deal with formalization (structuring the procedures for assessing and summarizing research, e.g. by protocols) and separation (maintaining a boundary between science and policy in processes of synthesizing science for policy). Combining the two dimensions, we draw a diagram onto which different initiatives can be mapped. A high degree of formalization and separation are key components of the canonical image of scientific practice. Influential Science and Technology Studies analysts, however, are well known for their critiques of attempts at separation and formalization. Three examples that summarize research for policy purposes are presented and mapped onto the diagram: the Intergovernmental Panel on Climate Change, the European Union's Science for Environment Policy initiative, and the UK Committee on Climate Change. These examples bring out salient differences concerning how formalization and separation are dealt with. Discussing the space opened up by the diagram, as well as the limitations of the attraction to its endpoints, we argue that policy analyses, including much Science and Technology Studies work, are in need of a more nuanced understanding of the two crucial dimensions of formalization and separation. Accordingly, two analytical claims are presented, concerning trajectories, how organizations represented in the diagram move over time, and mismatches, how organizations fail to handle the two dimensions well in practice. PMID- 26477200 TI - Ontological turns, turnoffs and roundabouts. AB - There has been much talk of an 'ontological turn' in Science and Technology Studies. This commentary explores some recent work on multiple and historical ontologies, especially articles published in this journal, against a background of constructivism. It can be tempting to read an ontological turn as based and promoting a version of perspectivism, but that is inadequate to the scholarly work and opens multiple ontologies to serious criticisms. Instead, we should read our ontological turn or turns as being about multiplicities of practices and the ways in which these practices shape the material world. Ontologies arise out of practices through which people engage with things; the practices are fundamental and the ontologies derivative. The purchase in this move comes from the elucidating power of the verbs that scholars use to analyze relations of practices and objects--which turn out to be specific cases of constructivist verbs. The difference between this ontological turn and constructivist work in Science and Technology Studies appears to be a matter of emphases found useful for different purposes. PMID- 26477201 TI - Performing ontology. AB - Ontology, and in particular, the so-called ontological turn, is the topic of a recent themed issue of Social Studies of Science (Volume 43, Issue 3, 2013). Ontology, or metaphysics, is in philosophy concerned with what there is, how it is, and forms of being. But to what is the science and technology studies researcher turning when he or she talks of ontology? It is argued that it is unclear what is gained by arguing that ontology also refers to constructed elements. The 'ontological turn' comes with the risk of creating a pseudo-debate or pseudo-activity, in which energy is used for no end, at the expense of empirical studies. This text rebuts the idea of an ontological turn as foreshadowed in the texts of the themed issue. It argues that there is no fundamental qualitative difference between the ontological turn and what we know as constructivism. PMID- 26477202 TI - Stuck with/in a 'turn': Can we metaphorize better in Science and Technology Studies? AB - This contribution encourages loosening the cast-iron mould of the 'turn' metaphor that the practices of general and ontology-related turn-talking/making in Science and Technology Studies forge and fortify. Could framing novel themes and thinking in terms of 'turn' be as good as fettering? Not specific to the 'ontological turn' or 'turn to ontology', but haunting Science and Technology Studies across the board to signify supposed tidal change, the metaphor warrants dissection. Thus, this commentary expounds four distinct yet not unrelated versions of 'turn' -rotation, change of course/direction, change in general and occasion/opportunity to act--together with the worlds they beget. Then, the operation of these 'turns' in the debates on the 'ontological turn' is pursued. Enactments of the first three modes/moulds of 'turn', all entailing and tainted by the inexorable directedness of change the coupled 'turn to' framing imparts, either debunk or qualify the extent of the professed 'turn', with the effect of betraying its conceptual and methodological offerings. The fourth version, less substitutable with 'turn to' and thus less infected by intransigent directedness, escapes the rigidity that diminishes the value of ontology-minded studies. Clear of either a resolution to the debate or an alternative trope to cure the maladies of 'turn', the conclusion wishes to open space for pondering how to metaphorize more consciously and judiciously evolution and innovation in Science and Technology Studies. PMID- 26477203 TI - Missing the (question) mark? What is a turn to ontology? AB - Our introductory essay in this journal's 2013 Special Issue on the 'turn to ontology' examined the shift from epistemology to ontology in science and technology studies and explored the implications of the notion of enactment. Three responses to that Special Issue argue that (I) there is no fundamental qualitative difference between the ontological turn and social constructivism, (2) we need to be wary of overly generic use of the term 'ontology' and (3) the language of 'turns' imposes constraints on the richness and diversity of science and technology studies. In this brief reply, we show how each of those critiques varies in its commitment to circumspection about making objective determinations of reality and to resisting reification. We illustrate our point by considering overlapping discussions in anthropology. This brings out the crucial difference between the science and technology studies slogan 'it could be otherwise' and the multinaturalist motto 'it actually is otherwise'. PMID- 26477204 TI - Prospecting for dinosaurs on the mining frontier: The value of information in America's Gilded Age. AB - How much is a dinosaur worth? This essay offers an account of the way vertebrate fossils were priced in late 19th-century America to explore the process by which monetary values are established in science. Examining a long and drawn-out negotiation over the sale of an unusually rich dinosaur quarry in Wyoming, I argue that, on their own, abstract market principles did not suffice to mediate between supply and demand. Rather, people haggling over the price of dinosaur bones looked to social norms from the mineral industry for cues on how to value these rare and unusual objects, adopting a set of negotiation tactics that exploited asymmetries in the distribution of scarce information to secure the better end of the deal. On the mining frontier in America's Gilded Age, dinosaurs were thus valued in much the same way as any other scarce natural resource one could dig out of the ground, including gold, silver, and coal. PMID- 26477205 TI - 'For men arousal is orientation': Bodily truthing, technosexual scripts, and the materialization of sexualities through the phallometric test. AB - We trace the history of the phallometric test--which measures erections of men exposed to visual erotic stimuli to characterize sexualities--in order to account for its functioning as a 'truthing technology'. On the basis of a content analysis of 410 key scientific journal article abstracts, we argue that since its invention in Czechoslovakia in the 1950s, phallometry has been employed within three distinct assemblages: as a test of predominance of sexual desire, as a test for therapeutic efficacy, and as a threshold test of sexual risk. Drawing on works of theorists of materialization and proponents of script theory, we argue that within each assemblage phallometric testing materializes male desire and renders it measurable via a 'technosexual script'. We consider the performative effects of phallometry in establishing scientific conceptions of normal and abnormal sexualities. At the same time, through attention to debates among practitioners and broader controversies surrounding the employment of phallometry, we examine the limits of researchers' abilities to establish the broader credibility of the test and capture the phenomenon of sexual desire. This analysis contributes to the study of truthing technologies (or 'truth machines') as a class, while also helping to build bridges between science and technology studies and sexuality studies. PMID- 26477206 TI - Organizing for ontological change: The kernel of an AIDS research infrastructure. AB - Is it possible to prepare and plan for emergent and changing objects of research? Members of the Multicenter AIDS Cohort Study have been investigating AIDS for over 30 years, and in that time, the disease has been repeatedly transformed. Over the years and across many changes, members have continued to study HIV disease while in the process regenerating an adaptable research organization. The key to sustaining this technoscientific flexibility has been what we call the kernel of a research infrastructure: ongoing efforts to maintain the availability of resources and services that may be brought to bear in the investigation of new objects. In the case of the Multicenter AIDS Cohort Study, these resources are as follows: specimens and data, calibrated instruments, heterogeneous experts, and participating cohorts of gay and bisexual men. We track three ontological transformations, examining how members prepared for and responded to changes: the discovery of a novel retroviral agent (HIV), the ability to test for that agent, and the transition of the disease from fatal to chronic through pharmaceutical intervention. Respectively, we call the work, 'technologies', and techniques of adapting to these changes, 'repurposing', 'elaborating', and 'extending the kernel'. PMID- 26477207 TI - Thinking science with thinking machines: The multiple realities of basic and applied knowledge in a research border zone. AB - Some scholars dismiss the distinction between basic and applied science as passe, yet substantive assumptions about this boundary remain obdurate in research policy, popular rhetoric, the sociology and philosophy of science, and, indeed, at the level of bench practice. In this article, I draw on a multiple ontology framework to provide a more stable affirmation of a constructivist position in science and technology studies that cannot be reduced to a matter of competing perspectives on a single reality. The analysis is grounded in ethnographic research in the border zone of Artificial Intelligence science. I translate in situ moments in which members of neighboring but differently situated labs engage in three distinct repertoires that render the reality of basic and applied science: partitioning, flipping, and collapsing. While the essences of scientific objects are nowhere to be found, the boundary between basic and applied is neither illusion nor mere propaganda. Instead, distinctions among scientific knowledge are made real as a matter of course. PMID- 26477208 TI - Understanding policy research in liminal spaces: Think tank responses to diverging principles of legitimacy. AB - Research on scientific, social scientific, and technical knowledge is increasingly focused on changes in institutionalized fields, such as the commercialization of university-based knowledge. Much less is known about how organizations produce and promote knowledge in the 'thick boundaries' between fields. In this article, I draw on 53 semi-structured interviews with Canadian think-tank executives, researchers, research fellows, and communication officers to understand how think-tank knowledge work is linked to the liminal spaces between institutionalized fields. First, although think-tank knowledge work has a broadly utilitarian epistemic culture, there are important differences between organizations that see intellectual simplicity and political consistency as the most important marker of credibility, versus those that emphasize inconsistency. A second major difference is between think tanks that argue for the separation of research and communication strategies and those that conflate them from beginning to end, arguably subordinating research to demands from more powerful fields. Finally, think tanks display different degrees of instrumentalism toward the public sphere, with some seeking publicity as an end in itself and others using it as a means to influence elite or public opinion. Together, we can see these differences as responses to diverging principles of legitimacy. PMID- 26477209 TI - Tensions in agnotology: Normativity in the studies of commercially driven ignorance. AB - As scientific research moves increasingly to the private sector, the social organization of science undergoes important transformations. Focusing on the production of ignorance, agnotology has been a fruitful approach to understanding the social and epistemic consequences of the recent commercialization of scientific research. Despite their important contributions, scholars working on agnotology seem to hold implicit normative commitments that are in tension with their descriptive accounts of ignorance-constructive practices. The main aim of this article is to uncover these commitments and to expose the emerging tensions. Thus, this article begins an exploration into normative aspects of the studies of ignorance. In particular, it shows that agnotology still needs the support of a well-articulated normative approach capable of identifying and evaluating the epistemic and social concerns raised by the private funding and performance of science. PMID- 26477210 TI - Survey marks 25 years with rise in volume and open positions. PMID- 26477211 TI - Learn from hybrid OR experts at annual conference Town Hall. PMID- 26477212 TI - Hiding in plain sight: Surgical smoke threatens health of OR staff. PMID- 26477213 TI - New AAMI standard for endoscope reprocessing. PMID- 26477214 TI - Quality reports to determine pay rise or fall. PMID- 26477215 TI - Staffing at most ASCs stays stable despite recruitment challenges. PMID- 26477216 TI - Successful recruitment and retention of engaged employees--Part 1. PMID- 26477217 TI - Financial Incentives, Workplace Wellness Program Participation, and Utilization of Health Care Services and Spending. AB - This paper analyzes data from a large employer that enhanced financial incentives to encourage participation in its workplace wellness programs. It examines, first, the effect of financial incentives on wellness program participation, and second, it estimates the impact of wellness program participation on utilization of health care services and spending. The Patient Protection and Affordable Care Act of 2010 (PPACA) allows employers to provide financial incentives of as much as 30 percent of the total cost of coverage when tied to participation in a wellness program. Participation in health risk assessments (HRAs) increased by 50 percentage points among members of unions that bargained in the incentive, and increased 22 percentage points among non-union employees. Participation in the biometric screening program increased 55 percentage points when financial incentives were provided. Biometric screenings led to an average increase of 0.31 annual prescription drug fills, with related spending higher by $56 per member per year. Otherwise, no significant effects of participation in HRAs or biometric screenings on utilization of health care services and spending were found. The largest increase in medication utilization as a result of biometric screening was for statins, which are widely used to treat high cholesterol. This therapeutic class accounted for one-sixth of the overall increase in prescription drug utilization. Second were antidepressants, followed by ACE inhibitors (for hypertension), and thyroid hormones (for hypothyroidism). Biometric screening also led to significantly higher utilization of biologic response modifiers and immunosuppressants. These specialty medications are used to treat autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, and are relatively expensive compared with non-specialty medications. The added spending associated with the combined increase in fills of 0.02 was $27 per member per year--about one-half of the overall increase in prescription drug spending from those who participated in biometric screenings. PMID- 26477218 TI - "I'll take competency over compassion. PMID- 26477219 TI - Student funding at centre of row. PMID- 26477220 TI - Workforce plan to train 23,000 new nurses in England by 2019. PMID- 26477221 TI - Care homes in staffing crisis as nurses leave to work in NHS. PMID- 26477222 TI - Key government target for new health visitors missed. PMID- 26477224 TI - Risks of urethral sling surgery methods differ. PMID- 26477223 TI - Mental health safe staffing guide 'lacks rigour and independence'. PMID- 26477225 TI - Red armbands show patients who's in charge of the ward. PMID- 26477226 TI - Reusable sharps bins linked to higher C Diff rate. PMID- 26477227 TI - Nurse-led general practice gains top rating from CQC inspectors. PMID- 26477228 TI - "Care practitioner role would reverse nursing staff shortage". PMID- 26477229 TI - "Frontline leadership model is the way forward to boost care". PMID- 26477230 TI - The nurse's role in patient nutrition and hydration. AB - Abstract Evans L, Best C (2015) Meeting patients' nutrition and hydration needs. The Nursing and Midwifery Council's new code was introduced in March 2015. For the first time, nutrition and hydration are mentioned specifically within the code. This article explores why this has become necessary and how nursing responsibility for the nutritional care of the patient has changed over the past 150 years. It also looks in more depth at how the nutritional care can meet the standards of the code. PMID- 26477231 TI - Caring from a distance: the role of telehealth. AB - BACKGROUND: Telehealth is used to help people manage their heath and maintain independence, but has proved difficult to integrate into routine practice. AIM: To explore the barriers to telehealth and find out what helps to improve its adoption among nursing staff. METHOD: Case studies were compiled from four community health services in the Yorkshire and Humber region that were using telehealth to monitor patients. The case studies used interviews with 84 community nursing, technical and support staff, and 21 managers. Some 40 telehealth users and 12 carers were also interviewed. RESULTS: Factors serving as barriers to the use of telehealth, including lack of planning, insufficient training, lack of time and technological problems. Factors encouraging uptake included giving nurses time to experiment with the technology, a clear service pathway, establishing telehealth champions to troubleshoot and disseminate information, and successful care using telehealth. DISCUSSION: Factors improving the adoption of telehealth in community nursing include: better planning of how the service operates and installing appropriate technology, good communication with nurses and service users, establishing telehealth champions and providing ongoing training and support. CONCLUSION: Many of the barriers in using telehealth can be avoided with better planning and collaboration. PMID- 26477233 TI - Patients' expectations of treatments and tests. PMID- 26477232 TI - Reducing the risk of baby falls in maternity units. AB - During a 12-month period there were 17 baby falls on the maternity wards at Nottingham University Hospitals Trust; two of the babies who fell were injured. By collecting information about the baby falls and how they happened, we were able to compile a guideline for both preventing and managing baby falls. This formed part of the trust's patient safety programme. We then piloted and implemented risk-prevention strategies for baby falls. These involved a risk assessment to identify women needing closer observation and the installation of bedside cots. These strategies brought about a marked reduction of baby falls and are now being established across all the maternity units across the trust. PMID- 26477234 TI - 60 second with Nick Birchall.. PMID- 26477235 TI - Prime promotor of talent. PMID- 26477236 TI - Supporting the crucial role of carers. PMID- 26477237 TI - The Use of Complementary and Alternative Medical Care in a Psychiatric Nursing Practice. PMID- 26477238 TI - Telling Stories: A Powerful Grassroots Tool. PMID- 26477239 TI - Nursing Health Policy. PMID- 26477240 TI - Consider Assisted Suicide. PMID- 26477241 TI - YMCA Diabetes Prevention Program. PMID- 26477242 TI - Effect of age, family history of diabetes, and antipsychotic drug treatment on risk of diabetes in people with psychosis: a population-based cross-sectional study. AB - BACKGROUND: Psychosis is associated with an increased risk of diabetes mellitus. A positive synergy between antipsychotic drug effects and a pre-existing liability to diabetes mellitus might explain the especially high relative risk of diabetes mellitus in young adults with psychosis. We aimed to assess the individual and joint effect of age, family history of diabetes mellitus, and currently prescribed antipsychotic drug treatment on risk for diabetes mellitus. METHODS: In this study, we used data from the 2010 Australian National Survey of Psychosis-an observational study done at seven sites in five Australian states. We included data from 1155 people with psychosis aged 18-64 years who were in contact with psychiatric services and who gave a fasting blood sample to test for current diabetes mellitus. Using logistic regression, we modelled the association of diabetes mellitus with age, family history of diabetes mellitus, and current antipsychotic drug treatment. We compared model fit with and without two-way and three-way interaction terms and used likelihood ratio tests to establish which terms to include in the final model. FINDINGS: After adjustment for older age, which was an independent risk factor, compared with not taking antipsychotic drugs, antipsychotic drug treatment was associated with diabetes mellitus only in those without a family history of diabetes mellitus (clozapine adjusted odds ratio [OR] 7.22, 95% CI 1.62-32.20, p=0.01; quetiapine 5.91, 1.33-26.30, p=0.02; aripiprazole 5.06, 0.86-29.64, p=0.07; risperidone 4.17, 0.90-19.24, p=0.07; and olanzapine 2.23, 0.45-11.06, p=0.32). Antipsychotic drug treatment was not associated with additional risk of diabetes mellitus in those with a family history (clozapine adjusted OR 1.51, 95% CI 0.64-3.54, p=0.34; quetiapine 1.09, 0.49-2.43, p=0.82; aripiprazole 0.43, 0.12-1.49, p=0.18; risperidone 1.12, 0.48 2.63, p=0.79; and olanzapine 0.67, 0.26-1.71, p=0.39). INTERPRETATION: People with psychosis are at increased risk of diabetes mellitus if they have a family history of diabetes mellitus or if they have no family history of diabetes mellitus but are taking antipsychotic drugs. Increasing age increases risk but independently of family history or antipsychotic drug treatment. Clinicians should not think the absence of a family history of diabetes mellitus protects their patients from the diabetic side-effects of antipsychotics. FUNDING: Australian Federal Government and Orygen. PMID- 26477243 TI - Genetic vulnerability in antipsychotic drug-induced diabetes. PMID- 26477244 TI - The impact of childhood sexual abuse on the mental and physical health, and healthcare utilization of older adults. AB - BACKGROUND: The aim of this study is to examine the long-term association between childhood sexual abuse (CSA) and mental and physical health, especially with conditions related to hypothalamic-pituitary-adrenal axis dysfunction such as mood disorders, cardiovascular disorders, gastrointestinal disorders, pain disorders, and measures of frailty and functional mobility. In addition, we examined the impact of CSA on self-reported health and healthcare utilization. METHODS: Data from the Irish Longitudinal Study on Ageing were employed (N = 8,178). The effects of CSA on mental health, physical health, and healthcare utilization in old age population were estimated by ordinal least square, logistic regression, and Poisson regression, controlling for demographic factors, childhood adversities, and behavioral health. RESULTS: Six percent of respondents reported CSA with little variation by gender. A significant association was found between CSA and mental health. Those who reported CSA were more likely to have depression, anxiety, worry, loneliness, and low quality of life. Poor self reported health, lung disease, arthritis, peptic ulcer, chronic pain as well as high levels of total cholesterol and low-density lipoprotein were associated with CSA. Further, those who reported CSA were more likely to report doctor and hospital visits than those without a history of CSA. CONCLUSIONS: Findings from the present study show that CSA has significant long-term mental and physical consequences, whereby early life events are linked to later life health outcomes. PMID- 26477245 TI - Identification of Fatty Acid Glucose Esters as Os9BGlu31 Transglucosidase Substrates in Rice Flag Leaves. AB - Rice Os9BGlu31 transglucosidase transfers glucosyl moieties between various carboxylic acids and alcohols, including phenolic acids and flavonoids, in vitro. The role of Os9BGlu31 transglucosidase in rice plant metabolism has only been suggested to date. Methanolic extracts of rice bran and leaves were found to contain oleic acid and linoleic acid to which Os9BGlu31 could transfer glucose from the 4-nitrophenyl beta-D-glucoside (4NPGlc) donor to form 1-O-acyl glucose esters. Os9BGlu31 showed higher activity with oleic acid (18:1) and linoleic acid (18:2) than with stearic acid (18:0) and had both a higher kcat and a higher Km for linoleic than oleic acid in the presence of 8 mM 4NPGlc donor. Os9BGlu31 knockout mutant rice lines were found to have significantly larger amounts of fatty acid glucose esters than wild-type control lines. Because the transglucosylation reaction is reversible, these data suggest that fatty acid glucose esters act as glucosyl donor substrates for Os9BGlu31 transglucosidase in rice. PMID- 26477246 TI - Saturation Recovery EPR and Nitroxide Spin Labeling for Exploring Structure and Dynamics in Proteins. AB - Experimental techniques capable of determining the structure and dynamics of proteins are continuously being developed in order to understand protein function. Among existing methods, site-directed spin labeling in combination with saturation recovery (SR) electron paramagnetic resonance spectroscopy contributes uniquely to the determination of secondary and tertiary protein structure under physiological conditions, independent of molecular weight and complexity. In addition, SR of spin labeled proteins was recently demonstrated to be sensitive to conformational exchange events with characteristic lifetimes on the order of MUs, a time domain that presents a significant challenge to other spectroscopic techniques. In this chapter, we present the theoretical background necessary to understand the capabilities of SR as applied to spin labeled proteins, the instrumental requirements, and practical experimental considerations necessary to obtain interpretable data, and the use of SR to obtain information on protein: (1) secondary structure via solvent accessibility measurements, (2) tertiary structure using interspin distance measurements, and (3) conformational exchange. PMID- 26477247 TI - High-Pressure EPR and Site-Directed Spin Labeling for Mapping Molecular Flexibility in Proteins. AB - High hydrostatic pressure is a powerful probe of protein conformational flexibility. Pressurization reveals regions of elevated compressibility, and thus flexibility, within individual conformational states, but also shifts conformational equilibria such that "invisible" excited states become accessible for spectroscopic characterization. The central aim of this chapter is to describe recently developed instrumentation and methodologies that enable high pressure site-directed spin labeling electron paramagnetic resonance (SDSL-EPR) experiments on proteins and to demonstrate the information content of these experiments by highlighting specific recent applications. A brief introduction to the thermodynamics of proteins under pressure is presented first, followed by a discussion of the principles underlying SDSL-EPR detection of pressure effects in proteins, and the suitability of SDSL-EPR for this purpose in terms of timescale and ability to characterize conformational heterogeneity. Instrumentation and practical considerations for variable-pressure continuous wave EPR and pressure resolved double electron-electron resonance (PR DEER) experiments are reviewed, and finally illustrations of data analysis using recent applications are presented. Although high-pressure SDSL-EPR is in its infancy, the recent applications presented highlight the considerable potential of the method to (1) identify compressible (flexible) regions in a folded protein; (2) determine thermodynamic parameters that relate conformational states in equilibrium; (3) populate and characterize excited states of proteins undetected at atmospheric pressure; (4) reveal the structural heterogeneity of conformational ensembles and provide distance constraints on the global structure of pressure-populated states with PR DEER. PMID- 26477248 TI - Exploring Structure, Dynamics, and Topology of Nitroxide Spin-Labeled Proteins Using Continuous-Wave Electron Paramagnetic Resonance Spectroscopy. AB - Structural and dynamical characterization of proteins is of central importance in understanding the mechanisms underlying their biological functions. Site-directed spin labeling (SDSL) combined with continuous-wave electron paramagnetic resonance (CW EPR) spectroscopy has shown the capability of providing this information with site-specific resolution under physiological conditions for proteins of any degree of complexity, including those associated with membranes. This chapter introduces methods commonly employed for SDSL and describes selected CW EPR-based methods that can be applied to (1) map secondary and tertiary protein structure, (2) determine membrane protein topology, (3) measure protein backbone flexibility, and (4) reveal the existence of conformational exchange at equilibrium. PMID- 26477249 TI - Bifunctional Spin Labeling of Muscle Proteins: Accurate Rotational Dynamics, Orientation, and Distance by EPR. AB - While EPR allows for the characterization of protein structure and function due to its exquisite sensitivity to spin label dynamics, orientation, and distance, these measurements are often limited in sensitivity due to the use of labels that are attached via flexible monofunctional bonds, incurring additional disorder and nanosecond dynamics. In this chapter, we present methods for using a bifunctional spin label (BSL) to measure muscle protein structure and dynamics. We demonstrate that bifunctional attachment eliminates nanosecond internal rotation of the spin label, thereby allowing the accurate measurement of protein backbone rotational dynamics, including microsecond-to-millisecond motions by saturation transfer EPR. BSL also allows for accurate determination of helix orientation and disorder in mechanically and magnetically aligned systems, due to the label's stereospecific attachment. Similarly, labeling with a pair of BSL greatly enhances the resolution and accuracy of distance measurements measured by double electron-electron resonance (DEER). Finally, when BSL is applied to a protein with high helical content in an assembly with high orientational order (e.g., muscle fiber or membrane), two-probe DEER experiments can be combined with single probe EPR experiments on an oriented sample in a process we call BEER, which has the potential for ab initio high-resolution structure determination. PMID- 26477250 TI - EPR Distance Measurements in Deuterated Proteins. AB - Pulsed electron double resonance technique, also known as double electron electron resonance, jointly with site-directed spin labeling (SDSL) have been used extensively for studying structures and structural change. During the last decades, significant enhancements have been made by optimization of the experimental protocols, introducing new techniques for artifact suppression, and developing data analysis programs for extracting more reliable distance distributions. However, the distance determination by pulsed electron paramagnetic resonance is still facing some limitations, especially when studying spin-labeled proteins, due mainly to the fast relaxation time that imposes severe limitations on the maximum distances measurable and upon the sensitivity of such experiments. In the present work, we demonstrate the impact of the deuteration of the underlying protein, in addition to the solvent, on relaxation times, sensitivity, and on distance measurements. PMID- 26477251 TI - Spin labeling and Double Electron-Electron Resonance (DEER) to Deconstruct Conformational Ensembles of HIV Protease. AB - An understanding of macromolecular conformational equilibrium in biological systems is oftentimes essential to understand function, dysfunction, and disease. For the past few years, our lab has been utilizing site-directed spin labeling (SDSL), coupled with electron paramagnetic resonance (EPR) spectroscopy, to characterize the conformational ensemble and ligand-induced conformational shifts of HIV-1 protease (HIV-1PR). The biomedical importance of characterizing the fractional occupancy of states within the conformational ensemble critically impacts our hypothesis of a conformational selection mechanism of drug-resistance evolution in HIV-1PR. The purpose of the following chapter is to give a timeline perspective of our SDSL EPR approach to characterizing conformational sampling of HIV-1PR. We provide detailed instructions for the procedure utilized in analyzing distance profiles for HIV-1PR obtained from pulsed electron-electron double resonance (PELDOR). Specifically, we employ a version of PELDOR known as double electron-electron resonance (DEER). Data are processed with the software package "DeerAnalysis" (http://www.epr.ethz.ch/software), which implements Tikhonov regularization (TKR), to generate a distance profile from electron spin-echo amplitude modulations. We assign meaning to resultant distance profiles based upon a conformational sampling model, which is described herein. The TKR distance profiles are reconstructed with a linear combination of Gaussian functions, which is then statistically analyzed. In general, DEER has proven powerful for observing structural ensembles in proteins and, more recently, nucleic acids. Our goal is to present our advances in order to aid readers in similar applications. PMID- 26477252 TI - Ionizable Nitroxides for Studying Local Electrostatic Properties of Lipid Bilayers and Protein Systems by EPR. AB - Electrostatic interactions are known to play a major role in the myriad of biochemical and biophysical processes. Here, we describe biophysical methods to probe local electrostatic potentials of proteins and lipid bilayer systems that are based on an observation of reversible protonation of nitroxides by electron paramagnetic resonance (EPR). Two types of probes are described: (1) methanethiosulfonate derivatives of protonatable nitroxides for highly specific covalent modification of the cysteine's sulfhydryl groups and (2) spin-labeled phospholipids with a protonatable nitroxide tethered to the polar head group. The probes of both types report on their ionization state through changes in magnetic parameters and degree of rotational averaging, thus, allowing the electrostatic contribution to the interfacial pKa of the nitroxide, and, therefore, the local electrostatic potential to be determined. Due to their small molecular volume, these probes cause a minimal perturbation to the protein or lipid system. Covalent attachment secures the position of the reporter nitroxides. Experimental procedures to characterize and calibrate these probes by EPR, and also the methods to analyze the EPR spectra by simulations are outlined. The ionizable nitroxide labels and the nitroxide-labeled phospholipids described so far cover an exceptionally wide range of ca. 2.5-7.0 pH units, making them suitable to study a broad range of biophysical phenomena, especially at the negatively charged lipid bilayer surfaces. The rationale for selecting proper electrostatically neutral interface for probe calibration, and examples of lipid bilayer surface potential studies, are also described. PMID- 26477253 TI - Peptide-Membrane Interactions by Spin-Labeling EPR. AB - Site-directed spin labeling (SDSL) in combination with electron paramagnetic resonance (EPR) spectroscopy is a well-established method that has recently grown in popularity as an experimental technique, with multiple applications in protein and peptide science. The growth is driven by development of labeling strategies, as well as by considerable technical advances in the field, that are paralleled by an increased availability of EPR instrumentation. While the method requires an introduction of a paramagnetic probe at a well-defined position in a peptide sequence, it has been shown to be minimally destructive to the peptide structure and energetics of the peptide-membrane interactions. In this chapter, we describe basic approaches for using SDSL EPR spectroscopy to study interactions between small peptides and biological membranes or membrane mimetic systems. We focus on experimental approaches to quantify peptide-membrane binding, topology of bound peptides, and characterize peptide aggregation. Sample preparation protocols including spin-labeling methods and preparation of membrane mimetic systems are also described. PMID- 26477254 TI - Structural Characterization of Membrane-Curving Proteins: Site-Directed Spin Labeling, EPR, and Computational Refinement. AB - Endocytosis and other membrane remodeling processes require the coordinated generation of different membrane shapes. Proteins capable of manipulating lipid bilayers mediate these events using mechanisms that are not fully understood. Progress is limited by the small number of structures solved for proteins bound to different membrane shapes and tools capable of resolving such information. However, recent studies have shown site-directed spin labeling (SDSL) in combination with electron paramagnetic resonance (EPR) to be capable of obtaining high-resolution structural information for proteins bound to different membrane shapes. This technique can be applied to proteins with no known structure or proteins with structures known in solution. By refining the data obtained by EPR with computational modeling, 3D structures or structural models of membrane-bound proteins can be generated. In this chapter, we highlight the basic considerations and steps required to investigate the structures of membrane-bound proteins using SDSL, EPR, and computational refinement. PMID- 26477255 TI - Determining the Secondary Structure of Membrane Proteins and Peptides Via Electron Spin Echo Envelope Modulation (ESEEM) Spectroscopy. AB - Revealing detailed structural and dynamic information of membrane embedded or associated proteins is challenging due to their hydrophobic nature which makes NMR and X-ray crystallographic studies challenging or impossible. Electron paramagnetic resonance (EPR) has emerged as a powerful technique to provide essential structural and dynamic information for membrane proteins with no size limitations in membrane systems which mimic their natural lipid bilayer environment. Therefore, tremendous efforts have been devoted toward the development and application of EPR spectroscopic techniques to study the structure of biological systems such as membrane proteins and peptides. This chapter introduces a novel approach established and developed in the Lorigan lab to investigate membrane protein and peptide local secondary structures utilizing the pulsed EPR technique electron spin echo envelope modulation (ESEEM) spectroscopy. Detailed sample preparation strategies in model membrane protein systems and the experimental setup are described. Also, the ability of this approach to identify local secondary structure of membrane proteins and peptides with unprecedented efficiency is demonstrated in model systems. Finally, applications and further developments of this ESEEM approach for probing larger size membrane proteins produced by overexpression systems are discussed. PMID- 26477256 TI - Spin Labeling Studies of Transmembrane Signaling and Transport: Applications to Phototaxis, ABC Transporters and Symporters. AB - Membrane proteins still represent a major challenge for structural biologists. This chapter will focus on the application of continuous wave and pulsed EPR spectroscopy on spin-labeled membrane proteins. Site-directed spin labeling EPR spectroscopy has evolved as a powerful tool to study the structure and dynamics of proteins, especially membrane proteins, as this method works largely independently of the size and complexity of the biological system under investigation. This chapter describes applications of this technique to three different systems: the archaeal photoreceptor/-transducer complex SRII/HtrII as an example for transmembrane signaling and two transport systems, the histidine ATP-binding cassette transporter HisQMP, and the sodium-proline symporter PutP. PMID- 26477258 TI - Spin Labeling of Potassium Channels. AB - Potassium channels are the ion channels most extensively studied by structural techniques. Whereas high-resolution crystal structures have provided key insights into the molecular architecture of these channels, spin labeling studies have helped to unveil the dynamic structural aspects underlying their function. From a practical standpoint, the popularity of spin labeling studies of potassium channels lies in their small size and relative ease of overexpression. The inherent fourfold symmetry of most potassium channels has also greatly facilitated spin labeling studies. This chapter focuses on the overexpression, purification, spin labeling, and subsequent reconstitution of modified potassium channels. It will discuss the general methods used to produce a suitable spin labeled potassium channel sample and highlight some of the common pitfalls that can occur along the way. At the end of the chapter, we provide detailed methods to produce spin-labeled samples of KcsA and KvAP, the two most commonly studied potassium channels. PMID- 26477257 TI - Navigating Membrane Protein Structure, Dynamics, and Energy Landscapes Using Spin Labeling and EPR Spectroscopy. AB - A detailed understanding of the functional mechanism of a protein entails the characterization of its energy landscape. Achieving this ambitious goal requires the integration of multiple approaches including determination of high-resolution crystal structures, uncovering conformational sampling under distinct biochemical conditions, characterizing the kinetics and thermodynamics of transitions between functional intermediates using spectroscopic techniques, and interpreting and harmonizing the data into novel computational models. With increasing sophistication in solution-based and ensemble-oriented biophysical approaches such as electron paramagnetic resonance (EPR) spectroscopy, atomic resolution structural information can be directly linked to conformational sampling in solution. Here, we detail how recent methodological and technological advances in EPR spectroscopy have contributed to the elucidation of membrane protein mechanisms. Furthermore, we aim to assist investigators interested in pursuing EPR studies by providing an introduction to the technique, a primer on experimental design, and a description of the practical considerations of the method toward generating high quality data. PMID- 26477259 TI - Advanced EPR Methods for Studying Conformational Dynamics of Nucleic Acids. AB - Pulsed electron paramagnetic resonance (EPR) spectroscopy has become an important tool for structural characterization of biomolecules allowing measurement of the distances between two paramagnetic spin labels attached to a biomolecule in the 2 8 nm range. In this chapter, we will focus on applications of this approach to investigate tertiary structure elements as well as conformational dynamics of nucleic acid molecules. Both aspects take advantage of using specific spin labels that are rigidly attached to the nucleobases, as they allow obtaining not only the distance but also the relative orientation between both nitroxide moieties with high accuracy. Thus, not only the distance but additionally the three Euler angles between both the nitroxide axis systems and the two polar angles of the interconnecting vector with respect to the nitroxide axis systems can be extracted from a single pair of spin labels. To extract all these parameters independently and unambiguously, a set of multifrequency/multifield pulsed EPR experiments have to be performed. We will describe the experimental procedure as well as newly developed spin labels, which are helpful to disentangle all these parameters, and tools which we have developed to analyze such data sets. The procedures and analyses will be illustrated by examples from our laboratory. PMID- 26477261 TI - Overhauser Dynamic Nuclear Polarization Studies on Local Water Dynamics. AB - Overhauser dynamic nuclear polarization (ODNP) is an emerging technique for quantifying translational water dynamics in the vicinity (<1 nm) of stable radicals that can be chemically attached to macromolecules of interest. This has led to many in-depth and enlightening studies of hydration water of biomolecules, revolving around the role of solvent dynamics in the structure and function of proteins, nucleic acids, and lipid bilayer membranes. Still to date, a complete and fully automated ODNP instrument is not commercialized. The purpose of this chapter is to share the technical know-how of the hardware, theory, measurement, and data analysis method needed to successfully utilize and disseminate the ODNP technique. PMID- 26477260 TI - An Integrated Spin-Labeling/Computational-Modeling Approach for Mapping Global Structures of Nucleic Acids. AB - The technique of site-directed spin labeling (SDSL) provides unique information on biomolecules by monitoring the behavior of a stable radical tag (i.e., spin label) using electron paramagnetic resonance (EPR) spectroscopy. In this chapter, we describe an approach in which SDSL is integrated with computational modeling to map conformations of nucleic acids. This approach builds upon a SDSL tool kit previously developed and validated, which includes three components: (i) a nucleotide-independent nitroxide probe, designated as R5, which can be efficiently attached at defined sites within arbitrary nucleic acid sequences; (ii) inter-R5 distances in the nanometer range, measured via pulsed EPR; and (iii) an efficient program, called NASNOX, that computes inter-R5 distances on given nucleic acid structures. Following a general framework of data mining, our approach uses multiple sets of measured inter-R5 distances to retrieve "correct" all-atom models from a large ensemble of models. The pool of models can be generated independently without relying on the inter-R5 distances, thus allowing a large degree of flexibility in integrating the SDSL-measured distances with a modeling approach best suited for the specific system under investigation. As such, the integrative experimental/computational approach described here represents a hybrid method for determining all-atom models based on experimentally-derived distance measurements. PMID- 26477262 TI - Practical Aspects of Paramagnetic Relaxation Enhancement in Biological Macromolecules. AB - In this brief review, we summarize various aspects of NMR paramagnetic relaxation enhancement (PRE). We discuss the types of spin labels used in NMR studies, describe the relevant theory used to accurately calculate PREs from coordinates, including how to take into account the fact that paramagnetic labels tend to be highly mobile and sample a wide range of conformational space, and outline methods to refine structures or ensembles of structures directly against PRE data using simulated annealing. Finally, we show how the PRE can be used to detect, characterize, and visualize sparsely populated states of proteins and their complexes that are invisible to all other biophysical techniques. PMID- 26477263 TI - In Vivo pO2 Imaging of Tumors: Oxymetry with Very Low-Frequency Electron Paramagnetic Resonance. AB - For over a century, it has been known that tumor hypoxia, regions of a tumor with low levels of oxygenation, are important contributors to tumor resistance to radiation therapy and failure of radiation treatment of cancer. Recently, using novel pulse electron paramagnetic resonance (EPR) oxygen imaging, near absolute images of the partial pressure of oxygen (pO2) in tumors of living animals have been obtained. We discuss here the means by which EPR signals can be obtained in living tissues and tumors. We review development of EPR methods to image the pO2 in tumors and the potential for the pO2 image acquisition in human subjects. PMID- 26477264 TI - Direct and Repeated Measurement of Heart and Brain Oxygenation Using In Vivo EPR Oximetry. AB - Low level of oxygen (hypoxia) is a critical factor that defines the pathological consequence of several pathophysiologies, particularly ischemia, that usually occur following the blockage of a blood vessel in vital organs, such as brain and heart, or abnormalities in the microvasculature, such as peripheral vascular disease. Therefore, methods that can directly and repeatedly quantify oxygen levels in the brain and heart will significantly improve our understanding of ischemic pathologies. Importantly, such oximetry capability will facilitate the development of strategies to counteract low levels of oxygen and thereby improve outcome following stroke or myocardial infarction. In vivo electron paramagnetic resonance (EPR) oximetry has the capability to monitor tissue oxygen levels in real time. The method has largely been tested and used in experimental animals, although some clinical measurements have been performed. In this chapter, a brief overview of the methodology to repeatedly quantify oxygen levels in the brain and heart of experimental animal models, ranging from mice to swine, is presented. EPR oximetry requires a one-time placement of an oxygen-sensitive probe in the tissue of interest, while the rest of the procedure for reliable, accurate, and repeated measurements of pO2 (partial pressure of oxygen) is noninvasive and can be repeated as often as desired. A multisite oximetry approach can be used to monitor pO2 at many sites simultaneously. Building on significant advances in the application of EPR oximetry in experimental animal models, spectrometers have been developed for use in human subjects. Initial feasibility of pO2 measurement in solid tumors of patients has been successfully demonstrated. PMID- 26477265 TI - Free Radical Imaging Using In Vivo Dynamic Nuclear Polarization-MRI. AB - Redox reactions that generate free radical intermediates are essential to metabolic processes, and their intermediates can produce reactive oxygen species, which may promote diseases related to oxidative stress. The development of an in vivo electron spin resonance (ESR) spectrometer and its imaging enables us noninvasive and direct measurement of in vivo free radical reactions in living organisms. The dynamic nuclear polarization magnetic resonance imaging (DNP-MRI), also called PEDRI or OMRI, is also a new imaging method for observing free radical species in vivo. The spatiotemporal resolution of free radical imaging with DNP-MRI is comparable with that in MRI, and each of the radical species can be distinguished in the spectroscopic images by changing the frequency or magnetic field of ESR irradiation. Several kinds of stable nitroxyl radicals were used as spin probes to detect in vivo redox reactions. The signal decay of nitroxyl probes, which is determined with in vivo DNP-MRI, reflects the redox status under oxidative stress, and the signal decay is suppressed by prior administration of antioxidants. In addition, DNP-MRI can also visualize various intermediate free radicals from the intrinsic redox molecules. This noninvasive method, in vivo DNP-MRI, could become a useful tool for investigating the mechanism of oxidative injuries in animal disease models and the in vivo effects of antioxidant drugs. PMID- 26477266 TI - Preface. PMID- 26477267 TI - Theranostic, pH-Responsive, Doxorubicin-Loaded Nanoparticles Inducing Active Targeting and Apoptosis for Advanced Gastric Cancer. AB - This study developed a kind of magnetic-polymer nanocarrier with folate receptor targeting and pH-sensitive multifunctionalities to carry doxorubicin (DOX) for treatment of advanced gastric cancer (AGC). Folate-conjugated, pH-sensitive, amphiphilic poly(beta-aminoester) self-assembled with hydrophobic oleic acid modified iron oxide nanoparticles, and the resulting hydrophobic interaction area is a reservoir for lipophilic DOX (F-P-DOX). Confocal microscopy illustrated that F-P-DOX treatment could keep higher DOX accumulation in cells than P-DOX (without folate conjugation), and therefore get a higher efficiency of DOX internalization at pH 6.5 than at pH 7.4. Electron microscope characterization and real-time polymerase chain reaction revealed cell apoptosis promoted by F-P-DOX. The better efficacy of F-P-DOX on GC than free DOX and P-DOX was determined by MTT assay and xenograft model. Moreover, the accumulation of F-P-DOX in the tumor site was detected by magnetic resonance imaging (MRI). All those observations suggest F-P DOX could be a promising theranostic candidate for AGC treatment. PMID- 26477269 TI - Non-alcoholic fatty liver disease and risk of cardiovascular disease. AB - Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liver-related mortality and morbidity. During the past decade, it has also become increasingly evident that NAFLD is a multisystem disease that affects many extra-hepatic organ systems, including the heart and the vascular system. In this updated clinical review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong association of NAFLD with cardiovascular diseases (CVDs) and other functional and structural myocardial abnormalities. We also discuss some recently published data that correlate NAFLD due to specific genetic polymorphisms with the risk of CVDs. Finally, we briefly examine the assessment tools for estimating the global CVD risk in patients with NAFLD as well as the conventional and the more innovative pharmacological approaches for the treatment of CVD risk in this group of patients. PMID- 26477268 TI - Oxygen- and Nitrogen-Enriched 3D Porous Carbon for Supercapacitors of High Volumetric Capacity. AB - Efficient utilization and broader commercialization of alternative energies (e.g., solar, wind, and geothermal) hinges on the performance and cost of energy storage and conversion systems. For now and in the foreseeable future, the combination of rechargeable batteries and electrochemical capacitors remains the most promising option for many energy storage applications. Porous carbonaceous materials have been widely used as an electrode for batteries and supercapacitors. To date, however, the highest specific capacitance of an electrochemical double layer capacitor is only ~200 F/g, although a wide variety of synthetic approaches have been explored in creating optimized porous structures. Here, we report our findings in the synthesis of porous carbon through a simple, one-step process: direct carbonization of kelp in an NH3 atmosphere at 700 degrees C. The resulting oxygen- and nitrogen-enriched carbon has a three-dimensional structure with specific surface area greater than 1000 m(2)/g. When evaluated as an electrode for electrochemical double layer capacitors, the porous carbon structure demonstrated excellent volumetric capacitance (>360 F/cm(3)) with excellent cycling stability. This simple approach to low-cost carbonaceous materials with unique architecture and functionality could be a promising alternative to fabrication of porous carbon structures for many practical applications, including batteries and fuel cells. PMID- 26477270 TI - Cord blood copeptin concentrations in fetal macrosomia. AB - BACKGROUND/AIM: Excessive fetal growth is associated with increased adiposity and reduced insulin sensitivity at birth. Copeptin, a surrogate marker of arginine vasopressin (AVP) secretion, is upregulated in states of hyperinsulinemia and is considered one of the mediators of insulin resistance. We aimed to investigate cord blood concentrations of copeptin (C-terminal fragment of AVP pro-hormone) in healthy large-for-gestational-age (LGA) infants at term. METHODS: This prospective study was conducted on 30 LGA (n=30) and 20 appropriate-for gestational-age (AGA, n=20) singleton full-term healthy infants. Cord blood copeptin and insulin concentrations were determined by ELISA and IRMA, respectively. Infants were classified as LGA or AGA, based on customized birth weight standards adjusted for significant determinants of fetal growth. RESULTS: Cord blood copeptin concentrations were similar in LGA cases, compared to AGA controls, after adjusting for delivery mode. However, in the LGA group, cord blood copeptin concentrations positively correlated with birth-weight (r=0.422, p=0.020). In the AGA group, cord blood copeptin concentrations were elevated in cases of vaginal delivery vs elective cesarean section (p=0.003). Cord blood insulin concentrations were higher in LGA cases, compared to AGA controls (p=0.036). No association was recorded between cord blood copeptin concentrations and maternal age, parity, gestational age or fetal gender in both groups. CONCLUSIONS: Cord blood copeptin concentrations may not be up-regulated in non distressed LGA infants. However, the positive correlation between cord blood copeptin concentrations and birth-weight in the LGA group may point to the documented association between AVP release and increased fat deposition. Vaginal delivery vs elective cesarean section is accompanied by a marked stress-related increase of cord blood copeptin concentrations. PMID- 26477271 TI - Enhancer repertoires are reshaped independently of early priming and heterochromatin dynamics during B cell differentiation. AB - A widely accepted model posits that activation of enhancers during differentiation goes through a priming step prior to lineage commitment. To investigate the chronology of enhancer repertoire establishment during hematopoiesis, we monitored epigenome dynamics during three developmental stages representing hematopoietic stem cells, B-cell progenitors and mature B-cells. We find that only a minority of enhancers primed in stem cells or progenitors become active at later stages. Furthermore, most enhancers active in differentiated cells were not primed in earlier stages. Thus, the enhancer repertoire is reshaped dynamically during B-cell differentiation and enhancer priming in early stages does not appear to be an obligate step for enhancer activation. Furthermore, our data reveal that heterochromatin and Polycomb-mediated silencing have only a minor contribution in shaping enhancer repertoires during cell differentiation. Together, our data revisit the prevalent model about epigenetic reprogramming during hematopoiesis and give insights into the formation of gene regulatory networks. PMID- 26477273 TI - Molecular Mechanisms Underlying Urate-Induced Enhancement of Kv1.5 Channel Expression in HL-1 Atrial Myocytes. AB - BACKGROUND: Hyperuricemia induces endothelial dysfunction, oxidative stress and inflammation, increasing cardiovascular morbidities. It also raises the incidence of atrial fibrillation; however, underlying mechanisms are unknown. METHODS AND RESULTS: The effects of urate on expression of Kv1.5 in cultured mouse atrial myocytes (HL-1 cells) using reverse transcriptase-PCR, immunoblots, flow cytometry and patch-clamp experiments were studied. Treatment with urate at 7 mg/dl for 24 h increased the Kv1.5 protein level, enhanced ultra-rapid delayed rectifier K(+)channel currents and shortened action potential duration in HL-1 cells. HL-1 cells expressed the influx uric acid transporter (UAT), URATv1, and the efflux UATs, ABCG2 and MRP4. An inhibitor against URATv1, benzbromarone, abolished the urate effects, whereas an inhibitor against ABCG2, KO143, augmented them. Flow cytometry showed that urate induced an increase in reactive oxygen species, which was abolished by the antioxidant, N-acetylcysteine (NAC), and the NADPH-oxidase inhibitor, apocynin. Both NAC and apocynin abolished the enhancing effects of urate on Kv1.5 expression. A urate-induced increase in the Kv1.5 proteins was accompanied by phosphorylation of extracellular signal-regulated kinase (ERK), and was abolished by an ERK inhibitor, PD98059. NAC abolished phosphorylation of ERK by urate. CONCLUSIONS: Intracellular urate taken up by UATs enhanced Kv1.5 protein expression and function in HL-1 atrial myocytes, which could be attributable to ERK phosphorylation and oxidative stress derived from nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase. PMID- 26477272 TI - Exercise Performance Is a Prognostic Indicator in Elderly Patients With Chronic Heart Failure--Application of Metabolic Exercise Cardiac Kidney Indexes Score. AB - BACKGROUND: In patients with chronic heart failure (HF) the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score, is a predictor of cardiovascular death and urgent heart transplantation. We investigated the relationship between age, exercise tolerance and the prognostic value of the MECKI score. METHODS AND RESULTS: We analyzed data from 3,794 patients with chronic systolic HF. The primary endpoint was a composite of cardiovascular death and urgent heart transplantation. Older patients had higher prevalence of comorbidities and lower exercise performance compared with younger subjects (peak VO2, 925 vs. 1,351 L/min; P<0.0001; VE/VCO2slope, 33.2 vs. 28.3; P>0.0001). The rate of the primary endpoint was 19% in the highest age quartile and 14% in the lowest quartile. At multivariable analysis, the independent predictors of the primary endpoint were left ventricular ejection fraction (LVEF), eGFR, peak VO2, serum Na(+)and the use of beta-blockers in patients aged >=70 years, and LVEF, eGFR and peak VO2in younger subjects. The MECKI risk score increased across age subgroups, but on receiver operating characteristic curve analysis its prognostic power was similar in both patients aged >=70 and <70 years. CONCLUSIONS: Older patients with HF are a high-risk population with lower exercise performance. The MECKI score increased according to age and maintained its prognostic value also in older patients. PMID- 26477274 TI - Quantitative Assessment of Fluid Accumulation Using Bioelectrical Impedance Analysis in Patients With Acute Decompensated Heart Failure. AB - BACKGROUND: Acute decompensated heart failure (ADHF) is generally considered to be a problem of fluid volume overload, therefore accurately quantifying the degree of fluid accumulation is of critical importance in assessing whether adequate decongestion has been achieved. The aim of this study was to develop and validate a method to quantify the degree of fluid accumulation in patients with ADHF. METHODS AND RESULTS: Using multi-frequency bioelectrical impedance analysis (BIA), we measured extracellular water (ECW) volume in 130 ADHF patients on admission and at discharge. We also predicted optimal ECW volume using original equations based on data from 60 control subjects without the signs of HF. Measured/predicted (M/P) ratio of ECW in ADHF patients was observed to decrease from 1.26+/-0.25 to 1.04+/-0.17 during hospitalization (P<0.001). The amount of ECW volume reduction was significantly correlated with reduction in body weight (r=0.766, P<0.001). On multivariate analysis, higher M/P ratio of ECW at discharge was associated with increased risk of ADHF readmission or cardiac death within 6 months after discharge. CONCLUSIONS: Multi-frequency BIA-measured ECW was found to offer valuable information for analyzing the pathophysiology of ADHF, and may be a useful guide in the management of this disease. PMID- 26477275 TI - [Supportive care for malignant ascites in palliative phase: Place of paracentesis and diuretics]. AB - Malignant ascites, occurring in advanced stages of cancer, is linked with poor prognosis and can cause invalidating symptoms. Physiopathological mechanisms of ascites formation are complex and have yet to be fully elucidated. In most cases, ascites is due to peritoneal carcinomatosis in which vascular permeability is enhanced by VEGF production while lymphatic drainage decreases. Ascites can also be secondary to portal hypertension, for example in case of multiple liver metastases, or due to lymphatic obstruction. While paracentesis and diuretics are commonly used, their efficiency has never been compared in a randomized controlled study. Paracentesis brings immediate but temporary relief in over 90% of cases, and implies multiple hospitalizations. Literature reports ascites control by aldosterone alone or in association with furosemide. But, available data is controversial, and there is no predictive factor to identify patients that respond to diuretic treatment. The indication of diuretic treatment is left to the appreciation of physicians. Existing recommendations are old, and practices influenced by results obtained in non-neoplastic ascites. Additional evidences are required before guidelines can be established for the palliative management of malignant ascites. PMID- 26477276 TI - Derivatization methods for LC-MS analysis of endogenous compounds. AB - Sensitive and reliable analysis of endogenous compounds is critically important for many physiological and pathological studies. Methods based on LC-MS have progressed to become the method of choice for analyzing endogenous compounds. However, the analysis can be challenging due to various factors, including inherent low concentrations in biological samples, low ionization efficiency, undesirable chromatographic behavior and interferences of complex biological. The integration of chemical derivatization with LC-MS could enhance its capabilities in sensitivity and selectivity, and extend its application to a wider range of analytes. In this article, we will review the derivatization strategies in the LC MS analysis of various endogenous compounds, and provide applications highlighting the impact of these important techniques in the evaluation of pathological events. PMID- 26477277 TI - Transient dual-energy lasing in a semiconductor microcavity. AB - We demonstrate sequential lasing at two well-separated energies in a highly photoexcited planar microcavity at room temperature. Two spatially overlapped lasing states with distinct polarization properties appear at energies more than 5 meV apart. Under a circularly polarized nonresonant 2 ps pulse excitation, a sub-10-ps transient circularly polarized high-energy (HE) state emerges within 10 ps after the pulse excitation. This HE state is followed by a pulsed state that lasts for 20-50 ps at a low energy (LE) state. The HE state is highly circularly polarized as a result of a spin-preserving stimulated process, while the LE state shows a significantly reduced circular polarization because of a diminishing spin imbalance. PMID- 26477278 TI - Comparison of the larvicidal efficacies of moxidectin or a five-day regimen of fenbendazole in horses harboring cyathostomin populations resistant to the adulticidal dosage of fenbendazole. AB - Despite widespread acknowledgement of cyathostomin resistance to adult icidal dosages of benzimidazole (BZD) anthelmintics, many strongyle control programs continue to feature regularly scheduled larvicidal treatment with fenbendazole (FBZ). However, no studies have been conducted to evaluate the efficacy of larvicidal regimens against encysted cyathostomins in a BZD-resistant (BZD-R) population. A masked, randomized, controlled clinical study was conducted with 18 juvenile horses harboring populations of cyathostomins that were considered BZD-R on the basis of fecal egg count reduction (FECR). Horses were blocked by prior history, ranked by egg counts, and allocated randomly to one of three treatment groups: 1--control, 2--FBZ >10mg/kg once daily for five consecutive days, or 3- moxidectin (MOX) >0.4 mg/kg once. Fecal samples were collected prior to treatment and seven and 14 days after the final dose of anthelmintic. On Days 18-20, complete replicates of horses were euthanatized and necropsied, and 1% aliquots of large intestinal contents were recovered for determination of complete worm counts. The cecum and ventral colon were weighed, and measured proportions of the respective organ walls were processed for quantitation and characterization of encysted cyathostomin populations. The five-day regimen of FBZ achieved 44.6% fecal egg count reduction, had 56.4% activity against luminal adults and larvae, and was 38.6% and 71.2% effective against encysted early third stage (EL3) and late third stage/ fourth stage (LL3/L4) cyathostomin larvae, respectively. In contrast, MOX provided 99.9% FECR, removed 99.8% of luminal stages, and exhibited 63.6% and 85.2% efficacy against EL3 and LL3/L4 mucosal cyathostomins, respectively. Although BZD-R was the most feasible explanation for the lower larvicidal efficacies of FBZ, mean larval counts of moxidectin-treated horses were not significantly different from controls or those treated with FBZ. The lack of significant differences between larvicidal treatments was partially attributed to a small sample size and high variability among worm burdens. Historical differences in the time intervals between treatment and necropsy were identified as a confounding factor for accurate estimation of larvicidal efficacy. Determining appropriate post-treatment intervals for measuring larvicidal efficacy remains a critical regulatory and scientific challenge for this therapeutic area. PMID- 26477279 TI - Elucidation of Leucaena leucocephala anthelmintic-like phytochemicals and the ultrastructural damage generated to eggs of Cooperia spp. AB - Leucaena leucocephala is a tropical forage legume suggested as an alternative method to control gastrointestinal parasitism in ruminants. This study: (1) performed a bio-guided fractionation of an aqueous extract of L. leucocephala using the egg hatch assay (EHA) to identify the anthelmintic (AH)-like phytochemicals present in fresh leaves, and (2) assessed the ultrastructural damage to eggs of Cooperia spp. after incubation with the final fraction. Phytochemicals were isolated using silica gel columns and identified using high performance liquid chromatography and standards for comparison. The final fraction was evaluated using EHA at 0.06, 0.125, 0.250, 0.500 and 1.1 mg ml(-1). The lethal concentration to inhibit 50% of Cooperia spp. egg hatching (LC50) was calculated using a Probit analysis. Scanning and transmission electron microscopy revealed the ultrastructural changes present in Cooperia spp. eggs. Bio-guided isolation procedures led to the recognition of an active fraction (LlC1F3) mainly composed of quercetin (82.21%) and caffeic acid (13.42%) which inhibited 90.49 +/ 2.8% of Cooperia spp. egg hatching (P<0.05), and an LC50 of 0.06 +/- 0.14 mg ml( 1). Scanning electron microscopy (SEM) showed eggs exposed to the active fraction had an irregular external layer with small projections and ruptures of lateral eggshell walls. Transmission electron microscopy (TEM) showed changes to Cooperia spp. eggs in electro-density, including the thickness of the eggshell layers and fractures after incubation with the final fraction (LlC1F3). Changes in bioactivity after purification suggest synergistic interactions between quercetin and caffeic acid. PMID- 26477280 TI - Tuberculosis case burden and treatment outcomes in children, adults and older adults, Vanuatu, 2007-2011. AB - SETTING: All five DOTS centres in Vanuatu. OBJECTIVES: To determine across the age spectrum the tuberculosis (TB) case burden, disease pattern and treatment outcomes in patients registered between 2007 and 2011. DESIGN: Retrospective cohort study involving reviews of TB registers and treatment cards. RESULTS: Of 588 TB patients, 142 (24%) were children (aged 0-14 years), 327 (56%) adults (aged 15-54 years) and 119 (20%) were older adults (aged ?55 years; subdivided into 55-64 and ?65 years); 568 were new patients, 13 had been treated previously and 7 had unknown status. Compared with adults, children with new TB had a higher prevalence of extra-pulmonary TB (75% vs. 34%, OR 5.7, 95%CI 3.6-9.0) and a lower prevalence of smear-positive pulmonary TB (11% vs. 45%, OR 0.15, 95%CI 0.1-0.3), while older adults with new TB had a higher prevalence of smear-negative pulmonary TB (38% vs. 21%, OR 2.4, 95%CI 1.5-3.8). Overall TB treatment success was 83%, but in the second category of older adults (?65 years) treatment success was 67% and case fatality was 18%. CONCLUSION: Children and older adults constitute 45% of the TB burden in Vanuatu. Differences in disease patterns and poorer treatment outcomes in older adults have implications for policy and practice. PMID- 26477281 TI - Profile of tuberculosis patients with delayed sputum smear conversion in the Pacific island of Vanuatu. AB - SETTING: National tuberculosis control programme, Vanuatu. OBJECTIVE: To assess tuberculosis (TB) trends, characterise sputum smear-positive patients with non conversion at 2 months and assess their treatment outcomes. DESIGN: Evaluation of programme data over a 9-year period (2004-2012), comparing 2-month sputum non converters (delayed converters) with sputum smear converters diagnosed in 2011 and 2012. RESULTS: Annual TB case numbers were similar over the study period, with an average TB notification rate of 58 per 100 000 population. Of 417 sputum smear-positive cases, 74 (18%) were delayed converters. Delayed converters were more likely than converters (88% vs. 79%) to have had high pre-treatment sputum smear grades (OR 2.5, 95%CI 0.97-6.45). Among delayed converters, treatment adherence was high (99% good adherence), outcomes were generally good (90% treatment success, 85% cure, 4% treatment failure) and no drug resistance was detected. Deaths were unexpectedly common among converters (11/80, 14%), with significantly more deaths in Tafea than in Shefa Province (7/58 vs. 2/80, OR 5.35, 95%CI 1.07-26.79). Tafea Province also had the greatest number of delayed converters (30/74, 40.5%) and the highest TB incidence rate. CONCLUSION: Delayed sputum conversion was relatively uncommon, and was not associated with adverse outcomes or drug resistance. Regional differences require further investigation to better understand local factors that may compromise patient management. PMID- 26477282 TI - Building operational research capacity in the Pacific. AB - Operational research (OR) in public health aims to investigate strategies, interventions, tools or knowledge that can enhance the quality, coverage, effectiveness or performance of health systems. Attention has recently been drawn to the lack of OR capacity in public health programmes throughout the Pacific Islands, despite considerable investment in implementation. This lack of ongoing and critical reflection may prevent health programme staff from understanding why programme objectives are not being fully achieved, and hinder long-term gains in public health. The International Union Against Tuberculosis and Lung Disease (The Union) has been collaborating with Pacific agencies to conduct OR courses based on the training model developed by The Union and Medecins Sans Frontieres Brussels-Luxembourg in 2009. The first of these commenced in 2011 in collaboration with the Fiji National University, the Fiji Ministry of Health, the World Health Organization and other partners. The Union and the Secretariat of the Pacific Community organised a second course for participants from other Pacific Island countries and territories in 2012, and an additional course for Fijian participants commenced in 2013. Twelve participants enrolled in each of the three courses. Of the two courses completed by end 2013, 18 of 24 participants completed their OR and submitted papers by the course deadline, and 17 papers have been published to date. This article describes the context, process and outputs of the Pacific courses, as well as innovations, adaptations and challenges. PMID- 26477283 TI - Tuberculosis notifications, characteristics and treatment outcomes: urban vs. rural Solomon Islands, 2000-2011. AB - SETTING: All provincial tuberculosis (TB) management units in the Solomon Islands. OBJECTIVE: To compare TB notifications, characteristics and treatment outcomes in urban vs. rural areas. DESIGN: A retrospective descriptive cohort study involving record review and data extraction from provincial TB and laboratory registers and treatment charts from 2000 to 2011. RESULTS: Of 4137 TB cases notified, 1364 (33%) were from urban and 3227 (67%) from rural areas. Notification rates per year of study were consistently higher in urban areas (104 150 per 100 000 population) than in rural areas (49-70/100 000). Cases in rural areas were more likely to have smear-negative pulmonary TB and less likely to have extra-pulmonary TB (P < 0.001). TB cases in rural areas were more likely to die from TB than those from urban areas (3.2% vs. 5.9%). In contrast, TB cases in rural areas were less likely to default (2.8% vs. 1.8%). CONCLUSION: TB notification rates were much higher in urban than in rural areas in the Solomon Islands. Rural patients are more likely to die from the disease but are slightly less likely to default. Further research is required to explore the possibility of under-reporting in rural areas and to improve treatment outcomes. PMID- 26477284 TI - Sputum smear microscopy referral rates and turnaround time in the Tonga Islands. AB - SETTING: The National Tuberculosis Programme and the National Reference Laboratory, located on the main island of Tonga, Tongatapu, and three district hospital laboratories located on the outer islands. OBJECTIVES: To compare Tongatapu with Tonga's outer islands with respect to sputum referral rates, numbers of samples per patient, sample quality, test results and time from sending sample to obtaining results and from obtaining results to treatment initiation. DESIGN: Retrospective study involving record review of laboratory and TB treatment registers in Tonga's four hospitals from 2003 to 2012. RESULTS: Of 3078 sputum samples submitted, 71.7% were of good quality. Sputum referral rates on Tongatupu were nearly twice as high as those on the outer islands (353 vs. 180 per 100 000 population). The mean smear turnaround times on Tongatapu and the outer islands were respectively 4.02 and 4.11 days. Of 83 positive cases, 91.2% were treated within a day in Tongatapu compared with 80% in the outer islands. CONCLUSIONS: Referral rates for sputum smear testing differed in the main and the outer islands in Tonga, but turnaround times did not. Records of sputum quality and dates had limitations, necessitating interventions with TB-specific laboratory guidelines and registers. Further research is required to understand the differences in referral rates. PMID- 26477285 TI - Characteristics of government workers and association with diabetes and hypertension in the Cook Islands. AB - SETTING: Twenty government departments in Rarotonga, Cook Islands. OBJECTIVE: To determine the characteristics, presence of selected non-communicable disease (NCD) risk factors and prevalence of diabetes mellitus (DM) and hypertension among government workers who participated in 'wellness checks' in 2012. DESIGN: Cross-sectional study involving analysis of survey data. RESULTS: Of 598 employees, 70% were aged 25-54 years and 55% were female. Two thirds were obese (body mass index ?30 kg/m(2)), and 76% had low levels of fruit and vegetable consumption. Of 50 (8.4%) participants diagnosed with DM (random blood glucose ?11 mmol/l, fasting ?7 mmol/l), 30 were self-reported and 20 were based on blood glucose. Of the 206 (34.4%) diagnosed with hypertension (systolic ?140 and/or diastolic ?90), 71 were self-reported and 135 were based on blood pressure measurements. Obesity was associated with hypertension (OR 2.79, 95%CI 1.4-5.4), but not with DM. No relationship was observed between fruit and vegetable consumption and presence or absence of DM or hypertension. CONCLUSION: This study identified a high prevalence of obesity and hypertension among government employees in the Cook Islands, risk factors that are associated with NCDs such as DM and cardiovascular disease. 'Wellness checks' pave the way for interventions in workplace settings to prevent and better manage these diseases through early diagnosis, risk management, treatment and supportive public health policies. PMID- 26477286 TI - Describing the burden of non-communicable disease risk factors among adults with diabetes in Wallis and Futuna. AB - BACKGROUND: The South Pacific Territory of Wallis and Futuna has a high burden of non-communicable diseases (NCD): 18% of adults have diabetes mellitus (DM) and 87% are classified as overweight or obese. OBJECTIVE: To characterise the burden of additional World Health Organization (WHO) recognised NCD risk factors, such as smoking, obesity, high blood pressure, eating less than five fruit or vegetable servings per day and a sedentary lifestyle, among adults with DM. DESIGN: Re-analysis of cross-sectional data from a 2009 national survey. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Of 487 adults sampled, 87 (18%) had DM. Nearly 99% of individuals with DM had at least one additional NCD risk factor, and 62% had three or more concurrent NCD risk factors. Individuals with DM were more likely to be obese (OR 1.66, 95%CI 1.01 2.74) and had a much higher prevalence of high blood pressure (OR 3.02, 95%CI 1.87-4.86). CONCLUSION: DM is rarely identified in the absence of other NCD risk factors. We recommend an integrated approach to the management of DM and other NCD risk factors in routine care rather than a disease-specific approach. PMID- 26477287 TI - Burden and spectrum of disease in people with diabetes in Tonga. AB - SETTING: National Diabetes Centre, Tonga. OBJECTIVE: To describe the diabetes patient profile and disease spectrum, assess the impact of diabetic care and evaluate diabetes-attributable adverse outcomes. DESIGN: Retrospective descriptive study of patients registered in the National Diabetes Registry from its inception in May 2004 to 2012, and review of the National Deaths Registry (2011-2012). RESULTS: Of 4653 patients with diabetes mellitus (DM) identified, 95.8% had type 2 DM, 0.2% type 1, 1.2% gestational DM and 2.9% pre-DM. Of the 4409 patients with type 2 DM, 64.7% were female, 82.7% were aged ?40 years, 25.3% had hypertension and 53.3% were obese. Among those in care for >2 years, no positive impact on body mass index or glycosylated haemoglobin could be demonstrated, but there was significant improvement in hypertension control. Morbidity included lower limb amputations in 272 (6.1%) patients. DM was listed as a contributory cause of death due to sepsis (15/30, 50.0%), kidney failure (16/28, 57.1%), stroke (7/16, 43.8%) and ischaemic heart disease (20/59, 33.9%). CONCLUSION: DM was associated with high levels of morbidity and mortality. DM care improved hypertension control, but had little impact on other comorbid conditions. Enhanced monitoring and greater patient involvement should improve care; creative strategies are required to prevent and reduce obesity. PMID- 26477288 TI - Screening adult tuberculosis patients for diabetes mellitus in Ebeye, Republic of the Marshall Islands. AB - A retrospective cohort study was conducted to evaluate the screening of adult TB patients for diabetes (DM) using glycated haemoglobin (HbA1C) in Ebeye, Republic of the Marshall Islands. Of 62 patients registered between July 2010 and December 2012, 28 (45%) had DM. The only significant difference in baseline characteristics between those with and those without DM was higher age in those with DM. Two-month sputum smears and cultures were also not different between the two groups. Despite the limited sample size, this study shows that screening TB patients for DM in Ebeye is feasible and worthwhile and that it should be continued. PMID- 26477289 TI - Screening for tuberculosis and LTBI in diabetes patients, Pohnpei, Federated States of Micronesia. AB - A retrospective cohort study was performed in Pohnpei, a small Pacific Island, to evaluate the feasibility and results of screening adult diabetes (DM) patients for tuberculosis (TB) and latent tuberculous infection (LTBI) using a symptom screen, tuberculin skin testing and chest radiography. Of 79 patients, 65 (82%) completed screening. Two (3%) patients with active TB and 16 (25%) with LTBI were referred for anti-tuberculosis treatment and isoniazid preventive therapy, respectively. It is feasible and worthwhile to screen diabetes patients for TB, but a number of changes are needed to improve both the screening process and the diagnostic yield. PMID- 26477290 TI - Mentorship for operational research capacity building: hands-on or hands-off? AB - Mentorship is a key feature of operational research training courses run by the International Union Against Tuberculosis and Lung Disease and Medecins Sans Frontieres. During the recent South Pacific paper writing module, the faculty discussed 'hands-on' mentorship (direct technical assistance) vs. 'hands-off' mentorship (technical advice). This article explores the advantages and disadvantages of each approach. Our collective experience indicates that 'hands on' mentorship is a valuable learning experience for the participant and a rewarding experience for the mentor. This approach increases the likelihood of successful course completion, including publishing a well written paper. However, mentors must allow participants to lead and take ownership of the paper, in keeping with a first author position. PMID- 26477291 TI - beta-CD-dextran polymer for efficient sequestration of cholesterol from phospholipid bilayers: Mechanistic and safe-toxicity investigations. AB - The aim of this work was to investigate the suitability of beta-cyclodextrin dextran (BCD-dextran) polymer as cholesterol sequestering agent in vitro. For this purpose, BCD-dextran-cholesterol complexation was studied by phase solubility studies as well as with a specifically designed in vitro model based on giant unilamellar vesicles (GUVs) to evaluate the ability of this polymer to sequestrate cholesterol from phospholipid bilayers. Cholesterol-sequestering ability of BCD-dextran was also investigated on different cell lines relevant for the hematopoietic system and results were correlated to cells toxicity. BCD dextran polymer was capable of extracting significant amount of cholesterol from phospholipid bilayers and to a higher extent in comparison to available beta cyclodextrins (BCDs). The ability of BCD-dextran in sequestering cholesterol resulted also very high on cell lines relevant for the hematopoietic system. Moreover, BCD-dextran resulted less toxic on cell cultures due to higher selectivity in sequestering cholesterol in comparison to MBCD (that sequestrated also significant amounts of cholesteryl esters). In conclusion, BCD-dextran resulted an extremely efficient cholesterol-sequestering agent and BCD-dextran resulted more selective to cholesterol extraction in comparison to other BCDs (therefore of lower cytotoxicity). This phenomenon might play a key role to develop an efficient treatment for hypercholesterolemia based on cholesterol segregation. PMID- 26477292 TI - Cilostazol blocks pregnancy in naturally cycling swine: An animal model. AB - AIMS: Cilostazol (CLZ) is an FDA approved therapeutic that is indicated for patients with intermittent claudication disease. CLZ is a selective inhibitor for phosphodiesterase 3A (PDE3A); an enzyme that controls oocyte maturation in many mammals including humans. Recently, CLZ has been reported to block pregnancy and oocyte maturation in mice. The objective of the present work was to evaluate the potential non-steroidal contraceptive capacity of CLZ using a more advanced translational model for humans. MAIN METHODS: Three groups of naturally cycling sows were treated orally with 0, 100, or 200mg CLZ, twice a day (bid), for 6days before estrus and continued for three days after estrus. Each sow was mated by one of two proven fertile boars on alternate days during estrus. KEY FINDINGS: CLZ dose of 100mg, bid, completely blocked pregnancy in sows when compared to control sows (P<0.01). However, the 200mg dose of CLZ, bid, failed to significantly block pregnancy in pigs. No significant differences were observed in heart rates of treated and control animals. Re-mating of the previously treated sows exhibited normal pregnancies and litter sizes. SIGNIFICANCE: This study shows that CLZ is capable of producing a reversible non-steroidal contraceptive effect without adverse effects on the heart rate in pigs. The observed contraceptive effect of CLZ was at doses similar to those indicated to humans. This FDA approved agent, for treatment of patients with intermittent claudication, may have an additional therapeutic effect as a non-steroidal contraceptive agent. Cilostazol merits further evaluation in women and might be useful for controlling the population of homeless animals. PMID- 26477293 TI - Short-term hyperprolactinemia decreases allergic inflammatory response of the lungs. AB - AIMS: Prolactin is a major immunomodulator. The present study evaluated the effects of short-term hyperprolactinemia induced by domperidone before ovalbumin antigenic challenge on the lung's allergic inflammatory response. MAIN METHODS: To induce hyperprolactinemia, domperidone was injected in rats at a dose of 5.1mg.kg(-1) per day, i.p., for 5days from 10th to 14th day after OVA immunization. Total and differential leukocyte counts from bronchoalveolar lavage (BAL), femoral marrow lavage (FML), and blood were analyzed. The percentages of mucus and collagen production were evaluated. Levels of corticosterone and prolactin in serum, interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha) in lung explants supernatants were measured and interferon gamma (IFN-gamma) in bronchiolar lavage cells suspensions (BAL) was measured. KEY FINDINGS: The rats that were subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, cellularity decrease in femoral marrow lavage fluid, a lower percentage of mucus, and an increase in lung IL-4, IL-6, IL-10, TNF-alpha and IFN-gamma expression. SIGNIFICANCE: Hyperprolactinemia induced before antigenic challenge decreased allergic lung inflammation. These data suggest that prolactin may play a role in the pathophysiology of asthma. The present study demonstrates a prospective beneficial side effect of domperidone for asthmatic patients. PMID- 26477294 TI - A computational chemistry perspective on the current status and future direction of hepatitis B antiviral drug discovery. AB - Computational chemical biology, applied to research on hepatitis B virus (HBV), has two major branches: bioinformatics (statistical models) and first-principle methods (molecular physics). While bioinformatics focuses on statistical tools and biological databases, molecular physics uses mathematics and chemical theory to study the interactions of biomolecules. Three computational techniques most commonly used in HBV research are homology modeling, molecular docking, and molecular dynamics. Homology modeling is a computational simulation to predict protein structure and has been used to construct conformers of the viral polymerase (reverse transcriptase domain and RNase H domain) and the HBV X protein. Molecular docking is used to predict the most likely orientation of a ligand when it is bound to a protein, as well as determining an energy score of the docked conformation. Molecular dynamics is a simulation that analyzes biomolecule motions and determines conformation and stability patterns. All of these modeling techniques have aided in the understanding of resistance mutations on HBV non-nucleos(t)ide reverse-transcriptase inhibitor binding. Finally, bioinformatics can be used to study the DNA and RNA protein sequences of viruses to both analyze drug resistance and to genotype the viral genomes. Overall, with these techniques, and others, computational chemical biology is becoming more and more necessary in hepatitis B research. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B." PMID- 26477295 TI - Experimental and theoretical optical properties of methylammonium lead halide perovskites. AB - The optical constants of methylammonium lead halide single crystals CH3NH3PbX3 (X = I, Br, Cl) are interpreted with high level ab initio calculations using the relativistic quasiparticle self-consistent GW approximation (QSGW). Good agreement between the optical constants derived from QSGW and those obtained from spectroscopic ellipsometry enables the assignment of the spectral features to their respective inter-band transitions. We show that the transition from the highest valence band (VB) to the lowest conduction band (CB) is responsible for almost all the optical response of MAPbI3 between 1.2 and 5.5 eV (with minor contributions from the second highest VB and the second lowest CB). The calculations indicate that the orientation of [CH3NH3](+) cations has a significant influence on the position of the bandgap suggesting that collective orientation of the organic moieties could result in significant local variations of the optical properties. The optical constants and energy band diagram of CH3NH3PbI3 are then used to simulate the contributions from different optical transitions to a typical transient absorption spectrum (TAS). PMID- 26477296 TI - Target discrimination delays attentional benefit for grouped contexts: An ERP study. AB - Searching a target was shown to be facilitated when embedded in a homogeneous compared to a heterogeneous context. This study investigated extended attention deployment after visual search for a target that observers had to discriminate in contexts of varying heterogeneity. Results showed more efficient attention deployment towards targets in homogeneous contexts as evident in higher accuracy and larger N2pc amplitudes than in random contexts. RTs to subsequently presented probes were shorter and a larger posterior positivity was observed in the ERP when probes were presented at the target location compared to other locations. This on-target advantage was larger for homogeneous contexts at ISIs of 90ms, but not for shorter (30ms) or longer (150ms) ISIs. These results show that visual search tasks induce an accelerated attention deployment after homogeneous contexts, however with a delay after target discrimination compared to less demanding target detection. PMID- 26477297 TI - What haplodiploids can teach us about hybridization and speciation. AB - Most evolutionary theory focuses on species that reproduce through sexual reproduction where both sexes have a diploid chromosome count. Yet a substantial proportion of multicellular species display complex life cycles, with both haploid and diploid life stages. A classic example is haplodiploidy, where females develop from fertilized eggs and are diploid, while males develop from unfertilized eggs and are haploid. Although haplodiploids make up about 15% of all animals (de la Filia et al. ), this type of reproduction is rarely considered in evolutionary theory. In this issue of Molecular Ecology, Patten et al. () develop a theoretical model to compare the rate of nuclear and mitochondrial introgression in haplodiploid and diploid species. They show that when two haplodiploid species hybridize, nuclear genes are much less likely to cross the species barrier than if both species were to be diploids. The reason for this is that only half of the offspring resulting from matings between haplodiploid species are true hybrids: sons from such mating only inherit their mother genes and therefore only contain genes of the maternal species. Truly, hybrid males can only occur through backcrossing of a hybrid female to a male of one of the parental species. While this twist of haplodiploid transmission genetics limits nuclear introgression, mitochondrial genes, which are maternally inherited, are unaffected by the scarcity of hybrid males. In other words, the rate of mitochondrial introgression is the same for haplodiploid and diploid species. As a result, haplodiploid species on average show a bias of mitochondrial compared to nuclear introgression. PMID- 26477298 TI - Open-Source, Platform-Independent Library and Online Scripting Environment for Accessing Thermo Scientific RAW Files. AB - Mass spectrometers typically output data in proprietary binary formats. While converter suites and standardized XML formats have been developed in response, these conversion steps come with non-negligible computational time and storage space overhead. As a result, simple, everyday data inspection tasks are often beyond the skills of the mass spectrometrist, who is unable to freely access the acquired data. We therefore here describe the unthermo library for convenient, platform-independent access to Thermo Scientific RAW files and the associated online playground to transform small and easily understandable scriptlets into executable programs for end-users. By fostering the provision of code examples and snippet exchange, the interested mass spectrometrist or researcher can use this playground to quickly assemble custom scripts for their particular purpose. In this way, the data in these RAW files can be mined much more readily and directly by the user, and fast, automated raw data extraction or analysis can finally become part of the daily routine of the mass spectrometrist. PMID- 26477299 TI - Hypomyelinating disorders: An MRI approach. AB - In recent years, the concept of hypomyelinating disorders has been proposed as a group of disorders with varying systemic manifestations that are identified by MR findings of absence or near absence of the T2 hypointensity that develops in white matter as a result of myelination. Initially proposed as a separate group because they were the largest single category of undiagnosed leukodystrophies, their separation as a distinct group that can be recognized by looking for a specific MRI feature has resulted in a marked increase in their diagnosis and a better understanding of the different causes of hypomyelination. This review will discuss the clinical presentations, imaging findings on standard MRI, and new MRI related techniques that allow a better understanding of these disorders and proposed methods for quantifying the myelination as a potential means of assessing disease course and the effects of proposed treatments. Disorders with hypomyelination of white matter, or hypomyelinating disorders (HMDs), represent the single largest category among undiagnosed genetic leukoencephalopathies (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010). This group of inborn errors of metabolism is characterized by a magnetic resonance imaging (MRI) appearance of reduced or absent myelin development: delay in the development of T2 hypointensity and, often, T1 hyperintensity in the white matter of the brain. The concept of hypomyelination was first conceptualized by (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010; Schiffmann et al., 1994) in a series of papers that showed that these MRI characteristics were easily recognized, were different from the MRI characteristics of dysmyelinating and demyelinating disorders, and that the combination of these imaging findings with specific other clinical and imaging features could be used to make diagnoses with some confidence. In this manuscript, we will discuss the physiologic and genetic bases of hypomyelinating disorders, as well as their classification, clinical manifestations and imaging characteristics. PMID- 26477302 TI - Sequence-selective DNA recognition and enhanced cellular up-take by peptide steroid conjugates. AB - Several GCN4 bZIP TF models have previously been designed and synthesized. However, the synthetic routes towards these constructs are typically tedious and difficult. We here describe the substitution of the Leucine zipper domain of the protein by a deoxycholic acid derivative appending the two GCN4 binding region peptides through an optimized double azide-alkyne cycloaddition click reaction. In addition to achieving sequence specific dsDNA binding, we have investigated the potential of these compounds to enter cells. Confocal microscopy and flow cytometry show the beneficial influence of the steroid on cell uptake. This unique synthetic model of the bZIP TF thus combines sequence specific dsDNA binding properties with enhanced cell-uptake. Given the unique properties of deoxycholic acid and the convergent nature of the synthesis, we believe this work represents a key achievement in the field of TF mimicry. PMID- 26477301 TI - Mini-review: Retarding aging in murine genetic models of neurodegeneration. AB - Retardation of aging processes is a plausible approach to delaying the onset or slowing the progression of common neurodegenerative disorders. We review the results of experiments using murine genetic models of Alzheimer disease and Huntington disease to evaluate the effects of retarding aging. While positive results are reported in several of these experiments, there are several discrepancies in behavioral and pathologic outcomes both within and between different experiments. Similarly, different experiments yield varying assessments of potential proximate mechanisms of action of retarding aging. The anti-aging interventions used for some experiments include some that show only modest effects on lifespan, and others that have proven hard to reproduce. Several experiments used aggressive transgenic neurodegenerative disease models that may be less relevant in the context of age-related diseases. The experience with these models and interventions may be useful in designing future experiments assessing anti-aging interventions for disease-modifying treatment of neurodegenerative diseases. PMID- 26477300 TI - Controversies in preterm brain injury. AB - In this review, we highlight critical unresolved questions in the etiology and mechanisms causing preterm brain injury. Involvement of neurons, glia, endogenous factors and exogenous exposures is considered. The structural and functional correlates of interrupted development and injury in the premature brain are under active investigation, with the hope that the cellular and molecular mechanisms underlying developmental abnormalities in the human preterm brain can be understood, prevented or repaired. PMID- 26477303 TI - Steam explosion pretreatment of triticale (* Triticosecale Wittmack) straw for sugar production. AB - Triticale, a non-food based, low-cost and well-adapted crop in marginal lands has been considered as a potential 1G and 2G feedstock for bio-ethanol production. In this work, triticale straw was evaluated as a source of fermentable sugars by combination of uncatalyzed steam explosion and enzymatic hydrolysis. Pretreatment conditions with severities from 3.05 to 4.12 were compared in order to identify conditions that favour the recovery of hemicellulose-derived sugars, cellulose digestibility or the combined sugars yield (CSY) from the pretreatment-enzymatic hydrolysis. Xylose oligosaccharide was the major sugar in hydrolysates from all pretreatment conditions. Maximum hemicellulose-sugars recovery (52% of the feedstock content) was obtained at 200 degrees C and 5 min. The highest cellulose digestibility (95%) was found at 200 degrees C - 15 min, although glucose recovery from hydrolysis was maximised at 200 degrees C - 10 min (digestibility >92%) due to higher mass yield of pretreated solids. The maximum CSY (nearly 77% of theoretical content) was obtained at 200 degrees C - 5 min. Sugar loss after pretreatment was observed to higher extent at harsher severities. However, the concentrations of sugar degradation products and acetic acid were at levels below tolerance limits of the downstream biological conversions. Steam explosion pretreatment without acid impregnation is a good technology for production of fermentable sugars from triticale straw. This work provides foundation for future autohydrolysis steam explosion optimization studies to enhanced sugars recovery and digestibility of triticale straw. PMID- 26477304 TI - The changing model of big pharma: impact of key trends. AB - Recent years have seen exciting breakthroughs in biomedical sciences that are producing truly novel therapeutics for unmet patient needs. However, the pharmaceutical industry is also facing significant barriers in the form of pricing and reimbursement, continued patent expirations and challenging market dynamics. In this article, we have analyzed data from the 1995-2015 period, on key aspects such as revenue distribution, research units, portfolio mix and emerging markets to identify four key trends that help to understand the change in strategic focus, realignment of R&D footprint, the shift from primary care toward specialty drugs and biologics and the growth of emerging markets as major revenue drivers for big pharma. PMID- 26477305 TI - Free-standing ultrathin CoMn2O4 nanosheets anchored on reduced graphene oxide for high-performance supercapacitors. AB - Ultrathin CoMn2O4 nanosheets supported on reduced graphene oxide (rGO) are successfully synthesized through a simple co-precipitation method with a post annealing treatment. With the assistance of citrate, the free-standing CoMn2O4 ultrathin nanosheets can form porous overlays on both sides of the rGO sheets. Such a novel hybrid nanostructure can effectively promote charge transport and accommodate volume variation upon prolonged charge/discharge cycling. When evaluated as a promising electrode for supercapacitors in a 6 M KOH solution electrolyte, the hybrid nanocomposites demonstrate highly enhanced capacitance and excellent cycling stability. PMID- 26477306 TI - Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma. AB - While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy. PMID- 26477307 TI - Positive regulation of beta-catenin-PROX1 signaling axis by DBC1 in colon cancer progression. AB - Aberrant activation of Wnt/beta-catenin pathway contributes to colorectal cancer (CRC) progression. However, little is known about regulatory mechanisms of the beta-catenin activity in cancer progression. Here we investigated the role of DBC1, which was recently reported as a negative regulator of SIRT1 and a transcriptional coactivator, in the regulation of Wnt/beta-catenin signaling. We identified the genome-wide targets of DBC1 and found that loss of DBC1 inhibits the expression of beta-catenin target genes including PROX1, a transcription factor linked to CRC progression. Mechanistically, DBC1 stabilizes LEF1-beta catenin interaction by inhibiting SIRT1-mediated beta-catenin deacetylation, thereby enhancing LEF1-beta-catenin complex formation and long-range chromatin looping at the PROX1 locus. Furthermore, DBC1 is also required for the transcriptional activity of PROX1, suggesting that DBC1 has a dual function in regulating beta-catenin-PROX1 signaling axis: as a coactivator for both beta catenin and PROX1. Importantly, loss of DBC1 inhibited growth and tumorigenic potential of colon cancer cells, and DBC1 expression correlated with shorter relapse-free survival in patients with advanced CRC. Our results firmly establish DBC1 as a critical positive regulator of beta-catenin-PROX1 signaling axis and a key factor in beta-catenin-PROX1-mediated CRC progression. PMID- 26477308 TI - TGF-beta signaling links E-cadherin loss to suppression of nucleotide excision repair. AB - E-cadherin is a cell adhesion molecule best known for its function in suppressing tumor progression and metastasis. Here we show that E-cadherin promotes nucleotide excision repair through positively regulating the expression of xeroderma pigmentosum complementation group C (XPC) and DNA damage-binding protein 1 (DDB1). Loss of E-cadherin activates the E2F4 and p130/107 transcription repressor complexes to suppress the transcription of both XPC and DDB1 through activating the transforming growth factor-beta (TGF-beta) pathway. Adding XPC or DDB1, or inhibiting the TGF-beta pathway, increases the repair of ultraviolet (UV)-induced DNA damage in E-cadherin-inhibited cells. In the mouse skin and skin tumors, UVB radiation downregulates E-cadherin. In sun-associated premalignant and malignant skin neoplasia, E-cadherin is downregulated in association with reduced XPC and DDB1 levels. These findings demonstrate a crucial role of E-cadherin in efficient DNA repair of UV-induced DNA damage, identify a new link between epithelial adhesion and DNA repair and suggest a mechanistic link of early E-cadherin loss in tumor initiation. PMID- 26477309 TI - Sp100A is a tumor suppressor that activates p53-dependent transcription and counteracts E1A/E1B-55K-mediated transformation. AB - Human adenoviruses (HAdV) are used as a model system to investigate tumorigenic processes in mammalian cells where the viral oncoproteins E1A and E1B-55K are absolutely required for oncogenic transformation, because they simultaneously accelerate cell cycle progression and inhibit tumor suppressor proteins such as p53, although the underlying mechanism is still not understood in detail. In our present study, we provide evidence that E1B-55K binding to the PML-NB component Sp100A apparently has an essential role in regulating adenovirus-mediated transformation processes. Specifically, when this E1B-55K/Sp100A complex recruits p53, Sp100A-induced activation of p53 transcriptional activity is effectively abolished. Hence, Sp100A exhibits tumor-suppressive activity, not only by stabilizing p53 transactivation but also by depressing E1A/E1B-55K-mediated transformation. E1B-55K counteracts this suppressive activity, inducing Sp100A SUMOylation and sequestering the modified cellular factor into the insoluble matrix of the nucleus or into cytoplasmic inclusions. These observations provide novel insights into how E1B-55K modulates cellular determinants to maintain growth-promoting activity during oncogenic processes and lytic infection. PMID- 26477311 TI - Targeting tumor-stroma crosstalk: the example of the NT157 inhibitor. AB - Recent clinical research has provided evidence that cancer progression and therapy resistance is driven not only by tumor's genetic profile but also by complex paracrine interactions within the tumor microenvironment (TME). The role of TME in modulating tumor drug sensitivity is increasingly recognized and targeting TME has been the focus of novel therapeutic approaches. Two recent reports show that a new anti-cancer drug, the inhibitor NT157 has the potential to inhibit IGF-1R and STAT3 signaling pathways in cancer cells and stroma cells of TME leading to a decrease in cancer cell survival. PMID- 26477310 TI - Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells. AB - Dysregulated microRNA (miRNA) mediate malignant phenotypes, including metabolic reprogramming. By performing an integrative analysis of miRNA and metabolome data for the NCI-60 cell line panel, we identified an miRNA cluster strongly associated with both c-Myc expression and global metabolic variation. Within this cluster the cancer-associated and cardioprotective miR-22 was shown to repress fatty acid synthesis and elongation in tumour cells by targeting ATP citrate lyase and fatty acid elongase 6, as well as impairing mitochondrial one-carbon metabolism by suppression of methylene tetrahydrofolate dehydrogenase/cyclohydrolase. Across several data sets, expression of these target genes were associated with poorer outcomes in breast cancer patients. Importantly, a beneficial effect of miR-22 on clinical outcomes in breast cancer was shown to depend on the expression levels of the identified target genes, demonstrating the relevance of miRNA/mRNA interactions to disease progression in vivo. Our systematic analysis establishes miR-22 as a novel regulator of tumour cell metabolism, a function that could contribute to the role of this miRNA in cellular differentiation and cancer development. Moreover, we provide a paradigmatic example of effect modification in outcome analysis as a consequence of miRNA-directed gene targeting, a phenomenon that could be exploited to improve patient prognosis and treatment. PMID- 26477312 TI - NFATc1 promotes prostate tumorigenesis and overcomes PTEN loss-induced senescence. AB - Despite recent insights into prostate cancer (PCa)-associated genetic changes, full understanding of prostate tumorigenesis remains elusive owing to complexity of interactions among various cell types and soluble factors present in prostate tissue. We found the upregulation of nuclear factor of activated T cells c1 (NFATc1) in human PCa and cultured PCa cells, but not in normal prostates and non tumorigenic prostate cells. To understand the role of NFATc1 in prostate tumorigenesis in situ, we temporally and spatially controlled the activation of NFATc1 in mouse prostate and showed that such activation resulted in prostatic adenocarcinoma with features similar to those seen in human PCa. Our results indicate that the activation of a single transcription factor, NFATc1 in prostatic luminal epithelium to PCa can affect expression of diverse factors in both cells harboring the genetic changes and in neighboring cells through microenvironmental alterations. In addition to the activation of oncogenes c-MYC and STAT3 in tumor cells, a number of cytokines and growth factors, such as IL1beta, IL6 and SPP1 (osteopontin, a key biomarker for PCa), were upregulated in NFATc1-induced PCa, establishing a tumorigenic microenvironment involving both NFATc1 positive and negative cells for prostate tumorigenesis. To further characterize interactions between genes involved in prostate tumorigenesis, we generated mice with both NFATc1 activation and Pten inactivation in prostate. We showed that NFATc1 activation led to acceleration of Pten null-driven prostate tumorigenesis by overcoming the PTEN loss-induced cellular senescence through inhibition of p21 activation. This study provides direct in vivo evidence of an oncogenic role of NFATc1 in prostate tumorigenesis and reveals multiple functions of NFATc1 in activating oncogenes, in inducing proinflammatory cytokines, in oncogene addiction, and in overcoming cellular senescence, which suggests calcineurin-NFAT signaling as a potential target in preventing PCa. PMID- 26477313 TI - TSH overcomes Braf(V600E)-induced senescence to promote tumor progression via downregulation of p53 expression in papillary thyroid cancer. AB - The BRAF(V600E) mutation is found in approximately 40% of papillary thyroid cancers (PTC). Mice with thyroid-specific expression of Braf(V600E) (TPO Braf(V600E)) develop PTC rapidly with high levels of serum thyroid-stimulating hormone (TSH). It is unclear to what extent the elevated TSH contributes to tumor progression. To investigate the progression of Braf(V600E)-induced PTC (BVE-PTC) under normal TSH, we transplanted BVE-PTC tumors subcutaneously into nude and TPO Braf(WT) mice. Regression of the transplanted tumors was observed in both nude and TPO-Braf(WT) mice. They were surrounded by heavy lymphocyte infiltration and oncogene-induced senescence (OIS) was demonstrated by strong beta-gal staining and absence of Ki-67 expression. In contrast, BVE-PTC transplants continued to grow when transplanted into TPO-Braf(V600E) mice. The expression of Trp53 was increased in tumor transplants undergoing OIS. Trp53 inactivation reversed OIS and enabled tumor transplants to grow in nude mice with characteristic cell morphology of anaplastic thyroid cancer (ATC). PTC-to-ATC transformation was also observed in primary BVE-PTC tumors. ATC cells derived from Trp53 knockout tumors had increased PI3K/AKT signaling and became resistant to Braf(V600E) inhibitor PLX4720, which could be overcome by combined treatment of PI3K inhibitor LY294002 and PLX4720. In conclusion, BVE-PTC progression could be contained via p53 dependent OIS and TSH is a major disruptor of this balance. Simultaneous targeting of both MAPK and PI3K/AKT pathways offer a better therapeutic outcome against ATC. The current study reinforces the importance of rigorous control of serum TSH in PTC patients. PMID- 26477314 TI - A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells. AB - The MST1R gene is overexpressed in pancreatic cancer producing elevated levels of the RON tyrosine kinase receptor protein. While mutations in MST1R are rare, alternative splice variants have been previously reported in epithelial cancers. We report the discovery of a novel RON isoform discovered in human pancreatic cancer. Partial splicing of exons 5 and 6 (P5P6) produces a RON isoform that lacks the first extracellular immunoglobulin-plexin-transcription domain. The splice variant is detected in 73% of xenografts derived from pancreatic adenocarcinoma patients and 71% of pancreatic cancer cell lines. Peptides specific to RON P5P6 detected in human pancreatic cancer specimens by mass spectrometry confirm translation of the protein isoform. The P5P6 isoform is found to be constitutively phosphorylated, present in the cytoplasm, and it traffics to the plasma membrane. Expression of P5P6 in immortalized human pancreatic duct epithelial (HPDE) cells activates downstream AKT, and in human pancreatic epithelial nestin-expressing cells, activates both the AKT and MAPK pathways. Inhibiting RON P5P6 in HPDE cells using a small molecule inhibitor BMS 777607 blocked constitutive activation and decreased AKT signaling. P5P6 transforms NIH3T3 cells and induces tumorigenicity in HPDE cells. Resultant HPDE P5P6 tumors develop a dense stromal compartment similar to that seen in pancreatic cancer. In summary, we have identified a novel and constitutively active isoform of the RON tyrosine kinase receptor that has transforming activity and is expressed in human pancreatic cancer. These findings provide additional insight into the biology of the RON receptor in pancreatic cancer and are clinically relevant to the study of RON as a potential therapeutic target. PMID- 26477315 TI - Murine melanomas accelerated by a single UVR exposure carry photoproduct footprints but lack UV signature C>T mutations in critical genes. AB - Ultraviolet radiation (UVR) exposure increases malignant melanoma (MM) risk, but in the context of acute, not cumulative exposure. C>T and CC>TT changes make up the overwhelming majority of single base substitutions (SBS) in MM DNA, as both precursor melanocytes and melanocytic lesions have incurred incidental exposures to sunlight. To study the mutagenic mechanisms by which acute sunburn accelerates MM, we sequenced the exomes of spontaneous and neonatal UVB-induced Cdk4 R24C::Tyr-NRASQ61K mouse MMs. UVR-induced MMs carried more SBSs than spontaneous MMs, but the levels of genomic instability, reflected by translocations and copy number changes, were not different. C>T/G>A was the most common SBS in spontaneous and UVR-induced MMs, only modestly increased in the latter. However, they tended to occur at the motif A/GpCpG (reflecting C>T transition due to spontaneous deamination of cytosine at CpG) in spontaneous MMs, and T/CpCpC/T (reflecting the effects of pyrimidine dimers on either side of the mutated C) in UVR-induced MMs. Unlike MMs associated with repetitive exposures, we observed no CC>TT changes. In addition, we also found UVR 'footprints' at T>A/A>Ts (at NpTpT) and T>C/A>G (at CpTpC). These footprints are also present in MMs from a chronic UVR mouse model, and in some human MMs, suggesting that they may be minor UVR signature changes. We found few significantly somatically mutated genes (~6 per spontaneous and 15 per UVR-induced melanoma) in addition to the Cdk4 and NRAS mutations already present. Trp53 was the most convincing recurrently mutated gene; however, in the UVR-induced MMs no Trp53 mutations were at C>T/G>A, suggesting that it was probably mutated during tumour progression, not directly induced by UVR photoproducts. The very low load of recurrent mutations convincingly induced by classical UVB-induced dimer photoproducts may support a role for cell extrinsic mechanisms, such as photoimmunosuppression and inflammation in driving MM after acute UVB exposure. PMID- 26477316 TI - Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer. AB - Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a catecholamine that binds to five G protein-coupled receptors. We discovered expression of DA type-1 receptors (D1Rs) in breast cancer, thereby identifying these receptors as novel therapeutic targets in this disease. Strong to moderate immunoreactive D1R expression was found in 30% of 751 primary breast carcinomas, and was associated with larger tumors, higher tumor grades, node metastasis and shorter patient survival. DA and D1R agonists, signaling through the cGMP/protein kinase G (PKG) pathway, suppressed cell viability, inhibited invasion and induced apoptosis in multiple breast cancer cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in two mouse models with D1R-expressing xenografts by increasing both necrosis and apoptosis. D1R-expressing primary tumors and metastases in mice were detected by fluorescence imaging. In conclusion, D1R overexpression is associated with advanced breast cancer and poor prognosis. Activation of the D1R/cGMP/PKG pathway induces apoptosis in vitro and causes tumor shrinkage in vivo. Fenoldopam, which is FDA (Food and Drug Administration) approved to treat renal hypertension, could be repurposed as a novel therapeutic agent for patients with D1R-expressing tumors. PMID- 26477318 TI - N-cadherin functions as a growth suppressor in a model of K-ras-induced PanIN. AB - Cadherin subtype switching from E-cadherin to N-cadherin is associated with the epithelial-to-mesenchymal transition (EMT), a process required for invasion and dissemination of carcinoma cells. We found that N-cadherin is expressed in human and mouse pancreatic intraepithelial neoplasia (PanIN), suggesting that N cadherin may also have a role in early-stage pancreatic cancer. To investigate the role of N-cadherin in mouse PanIN (mPanIN), we simultaneously activated oncogenic K-ras(G12D) and deleted the N-cadherin (Cdh2) gene in the murine pancreas. Genetic ablation of N-cadherin (N-cad KO) caused hyperproliferation, accelerated mPanIN progression, and early tumor development in K-ras(G12D) mice. Decreased E-cadherin and redistribution of beta-catenin accompanied the loss of N cadherin in pancreatic ductal epithelial cells (PDEC). Nuclear accumulation of beta-catenin and its transcription co-activator Tcf4 led to activation of Wnt/beta-catenin target genes. Unexpectedly, loss of N-cadherin in the K ras(G12D) model resulted in increased mPanIN progression and tumor incidence. These in vivo results demonstrate for the first time that N-cadherin functions as a growth suppressor in the context of oncogenic K-ras. PMID- 26477317 TI - The p53 tetramer shows an induced-fit interaction of the C-terminal domain with the DNA-binding domain. AB - The Trp53 gene is the most frequently mutated gene in all human cancers. Its protein product p53 is a very powerful transcription factor that can activate different biochemical pathways and affect the regulation of metabolism, senescence, DNA damage response, cell cycle and cell death. The understanding of its function at the molecular level could be of pivotal relevance for therapy. Investigation of long-range intra- and interdomain communications in the p53 tetramer-DNA complex was performed by means of an atomistic model that included the tetramerization helices in the C-terminal domain, the DNA-binding domains and a consensus DNA-binding site of 18 base pairs. Nonsymmetric dynamics are illustrated in the four DNA-binding domains, with loop L1 switching from inward to outward conformations with respect to the DNA major groove. Direct intra- and intermonomeric long-range communications between the tetramerization and DNA binding domains are noted. These long-distance conformational changes link the C terminus with the DNA-binding domain and provide a biophysical rationale for the reported functional regulation of the p53 C-terminal region. A fine characterization of the DNA deformation caused by p53 binding is obtained, with 'static' deformations always present and measured by the slide parameter in the central thymine-adenine base pairs; we also detect 'dynamic' deformations switched on and off by particular p53 tetrameric conformations and measured by the roll and twist parameters in the same base pairs. These different conformations can indeed modulate the electrostatic potential isosurfaces of the whole p53-DNA complex. These results provide a molecular/biophysical understanding of the evident role of the C terminus in post-translational modification that regulates the transcriptional function of p53. Furthermore, the unstructured C terminus is able to facilitate contacts between the core DNA binding domains of the tetramer. PMID- 26477319 TI - Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses. AB - Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Ialpha and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2 cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA. PMID- 26477320 TI - Identifying the Minimal Enzymes Required for Biosynthesis of Epoxyketone Proteasome Inhibitors. AB - Epoxyketone proteasome inhibitors have attracted much interest due to their potential as anticancer drugs. Although the biosynthetic gene clusters for several peptidyl epoxyketone natural products have recently been identified, the enzymatic logic involved in the formation of the terminal epoxyketone pharmacophore has been relatively unexplored. Here, we report the identification of the minimal set of enzymes from the eponemycin gene cluster necessary for the biosynthesis of novel metabolites containing a terminal epoxyketone pharmacophore in Escherichia coli, a versatile and fast-growing heterologous host. This set of enzymes includes a non-ribosomal peptide synthetase (NRPS), a polyketide synthase (PKS), and an acyl-CoA dehydrogenase (ACAD) homologue. In addition to the in vivo functional reconstitution of these enzymes in E. coli, in vitro studies of the eponemycin NRPS and (13) C-labeled precursor feeding experiments were performed to advance the mechanistic understanding of terminal epoxyketone formation. PMID- 26477321 TI - Combination of six enzymes of a marine Novosphingobium converts the stereoisomers of beta-O-4 lignin model dimers into the respective monomers. AB - Lignin, an aromatic polymer of phenylpropane units joined predominantly by beta-O 4 linkages, is the second most abundant biomass component on Earth. Despite the continuous discharge of terrestrially produced lignin into marine environments, few studies have examined lignin degradation by marine microorganisms. Here, we screened marine isolates for beta-O-4 cleavage activity and determined the genes responsible for this enzymatic activity in one positive isolate. Novosphingobium sp. strain MBES04 converted all four stereoisomers of guaiacylglycerol-beta guaiacyl ether (GGGE), a structural mimic of lignin, to guaiacylhydroxypropanone as an end metabolite in three steps involving six enzymes, including a newly identified Nu-class glutathione-S-transferase (GST). In silico searches of the strain MBES04 genome revealed that four GGGE-metabolizing GST genes were arranged in a cluster. Transcriptome analysis demonstrated that the lignin model compounds GGGE and (2-methoxyphenoxy)hydroxypropiovanillone (MPHPV) enhanced the expression of genes in involved in energy metabolism, including aromatic-monomer assimilation, and evoked defense responses typically expressed upon exposure to toxic compounds. The findings from this study provide insight into previously unidentified bacterial enzymatic systems and the physiological acclimation of microbes associated with the biological transformation of lignin-containing materials in marine environments. PMID- 26477322 TI - Nanoscale surface modification by anodic oxidation increased bone ingrowth and reduced fibrous tissue in the porous coating of titanium-alloy femoral hip arthroplasty implants. AB - Hip arthroplasty femoral stems coated with Ti6Al4V beads were treated by anodic oxidation in H3 PO4 for enhanced bioactivity and were studied in a 6-month canine model to determine the effects of the treated surface on the ingrowth of bone and soft tissues. The area fractions of bone, marrow, and fibrous tissue in the porous coating of seven treated and seven untreated control implants were determined using histomorphological techniques. The area fraction of bone within the porous coating was greater for anodic oxide treated (23.6 +/- 8.3%) compared to control implants (l2.7 +/- 4.7%) (p = 0.013), and there was less fibrous tissue in the treated implants (18.0 +/- 9.5%) compared to the controls (33.1 +/- 7.9%) (p = 0.006). XPS, XRD, TEM, and SEM analyses of the treated implants revealed a 400 nm-thick titanium oxide layer of low crystallinity with an undulating surface, populated with more than 25 nm-size pores per square micrometer. There was no detectable increase in serum titanium or in generation of particulates locally compared to the control implants. Micro and nanoscale surface modification by anodic oxidation increased bone ingrowth and reduced fibrous tissue, which may extend the longevity of fixation, limiting pathways for particle migration, and impeding the progression of osteolysis and aseptic loosening of arthroplasty components. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 283-290, 2017. PMID- 26477323 TI - Therapeutic outcomes in patients undergoing surgery after diagnosis of Cushing's disease: A single-center study. AB - This study aimed to investigate early and late outcomes of patients who underwent neurosurgical procedures for the preoperative diagnosis of Cushing's disease (CD). Clinical, endocrine, imaging, and histologic data from 252 patients undergoing pituitary surgery at Toranomon Hospital through the end of 2012 were entered into a database and statistically analyzed. In 22 of these patients (8.7%; positive venous sampling in 15 and negative venous sampling in 7 patients), tumors were invisible on magnetic resonance imaging (MRI) and 42.9% of them achieved remission. In the remaining 230 patients, 93.5% of those with microadenomas (n=154) and 71.1% of those with macroadenomas (n=76) achieved early postoperative remission, with recurrence rates of 2.7% and 14.8%, respectively, during a 72.5-month median follow-up. In multivariate analyses, cavernous sinus invasion (CSI; odds ratio [OR], 13.0), type of surgery (OR, 4.0), and tumor size (OR, 2.7) were significant preoperative factors affecting early postoperative results, whereas peak cortisol levels >=9.4 MUg/dL in response to corticotropin releasing hormone (CRH) and CSI were significant factors predicting recurrence. Tumor recurrence was more common in patients with non-densely granulated adenomas than in patients with densely granulated adenomas. We propose that the higher remission and lower recurrence rates in this series are due to our surgical strategies, including extracapsular tumor removal, aggressive resection of tumors with CSI, extended transsphenoidal surgery (TSS), or a combined approach for large/giant adenomas. Appropriate multimodal treatments, including radiotherapy, medication, and repeated surgery in patients with persistent or recurrent CD, could result in better overall outcomes than previously achieved. PMID- 26477324 TI - A 1-year safety study of dulaglutide in Japanese patients with type 2 diabetes on a single oral hypoglycemic agent: an open-label, nonrandomized, phase 3 trial. AB - The goal of this study was to assess the safety and efficacy of 0.75 mg of dulaglutide, a once weekly glucagon-like peptide-1 receptor agonist, in Japanese patients with type 2 diabetes (T2D) on a single oral hypoglycemic agent (OHA). In this phase 3, nonrandomized, open-label, parallel-group, 52-week study, safety and efficacy of once weekly dulaglutide 0.75 mg were assessed in Japanese patients with T2D on a single OHA (sulfonylureas [SU], biguanides [BG], alpha glucosidase inhibitors [AGI], thiazolidinedione [TZD], or glinides [GLN]). A total of 394 patients were treated with study drug, and 92.9% completed the 52 week treatment period. The most frequent treatment-emergent adverse events were nasopharyngitis and gastrointestinal disorders, including constipation, diarrhea, and nausea. Incidences of hypoglycemia varied across the combination therapy groups: incidence was greater in patients receiving SU compared with other combinations. No severe hypoglycemic episodes occurred during the study. Increases from baseline in pancreatic and total amylase, lipase, and pulse rate were observed in all 5 combination therapy groups. Significant reductions from baseline in HbA1c were observed in all 5 combination therapy groups (-1.57% to 1.69%, p < 0.001 for all). Mean body weight changes from baseline varied across the combination therapy groups: a significant increase was observed in combination with TZD, there were no significant changes in combination with SU or GLN, and significant reductions were observed in combination with BG or AGI. Once weekly dulaglutide 0.75 mg in combination with a single OHA was overall well tolerated and improved glycemic control in Japanese patients with T2D. PMID- 26477325 TI - De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. AB - The voltage-gated Kv2.1 potassium channel encoded by KCNB1 produces the major delayed rectifier potassium current in pyramidal neurons. Recently, de novo heterozygous missense KCNB1 mutations have been identified in three patients with epileptic encephalopathy and a patient with neurodevelopmental disorder. However, the frequency of KCNB1 mutations in infantile epileptic patients and their effects on neuronal activity are yet unknown. We searched whole exome sequencing data of a total of 437 patients with infantile epilepsy, and found novel de novo heterozygous missense KCNB1 mutations in two patients showing psychomotor developmental delay and severe infantile generalized seizures with high-amplitude spike-and-wave electroencephalogram discharges. The mutation located in the channel voltage sensor (p.R306C) disrupted sensitivity and cooperativity of the sensor, while the mutation in the channel pore domain (p.G401R) selectively abolished endogenous Kv2 currents in transfected pyramidal neurons, indicating a dominant-negative effect. Both mutants inhibited repetitive neuronal firing through preventing production of deep interspike voltages. Thus KCNB1 mutations can be a rare genetic cause of infantile epilepsy, and insufficient firing of pyramidal neurons would disturb both development and stability of neuronal circuits, leading to the disease phenotypes. PMID- 26477326 TI - Pityriasis Alba--Common Disease, Enigmatic Entity: Up-to-Date Review of the Literature. AB - Pityriasis alba (PA) is a skin disorder that affects children and adolescents. Although it is common worldwide, its incidence is markedly higher in darker skin phototypes. Its characteristic features include an extended, multistage course and spontaneous remissions and recurrences. Preceded by erythematous changes, patches of hypopigmented skin of up to a few centimeters in diameter appear on the upper body. Pruritus may accompany it. Even though its etiology is unknown, possible reported triggering factors include sunlight, beauty treatments, and microorganisms, among others. Calcineurin inhibitors play the most crucial role in PA pharmacotherapy. PA often coexists with atopic dermatitis and is considered one of its milder forms. PMID- 26477327 TI - Moving ahead: what will a renewed Countdown to 2030 for Women and Children look like? PMID- 26477329 TI - Hierarchy concepts: classification and preparation strategies for zeolite containing materials with hierarchical porosity. AB - 'Hierarchy' is a property which can be attributed to a manifold of different immaterial systems, such as ideas, items and organisations or material ones like biological systems within living organisms or artificial, man-made constructions. The property 'hierarchy' is mainly characterised by a certain ordering of individual elements relative to each other, often in combination with a certain degree of branching. Especially mass-flow related systems in the natural environment feature special hierarchically branched patterns. This review is a survey into the world of hierarchical systems with special focus on hierarchically porous zeolite materials. A classification of hierarchical porosity is proposed based on the flow distribution pattern within the respective pore systems. In addition, this review might serve as a toolbox providing several synthetic and post-synthetic strategies to prepare zeolitic or zeolite containing material with tailored hierarchical porosity. Very often, such strategies with their underlying principles were developed for improving the performance of the final materials in different technical applications like adsorptive or catalytic processes. In the present review, besides on the hierarchically porous all zeolite material, special focus is laid on the preparation of zeolitic composite materials with hierarchical porosity capable to face the demands of industrial application. PMID- 26477328 TI - Countdown to 2015: a decade of tracking progress for maternal, newborn, and child survival. AB - Conceived in 2003 and born in 2005 with the launch of its first report and country profiles, the Countdown to 2015 for Maternal, Newborn, and Child Survival has reached its originally proposed lifespan. Major reductions in the deaths of mothers and children have occurred since Countdown's inception, even though most of the 75 priority countries failed to achieve Millennium Development Goals 4 and 5. The coverage of life-saving interventions tracked in Countdown increased steadily over time, but wide inequalities persist between and within countries. Key drivers of coverage such as financing, human resources, commodities, and conducive health policies also showed important, yet insufficient increases. As a multistakeholder initiative of more than 40 academic, international, bilateral, and civil society institutions, Countdown was successful in monitoring progress and raising the visibility of the health of mothers, newborns, and children. Lessons learned from this initiative have direct bearing on monitoring progress during the Sustainable Development Goals era. PMID- 26477330 TI - Addressing governance challenges in the provision of animal health services: A review of the literature and empirical application transaction cost theory. AB - Providing adequate animal health services to smallholder farmers in developing countries has remained a challenge, in spite of various reform efforts during the past decades. The focuses of the past reforms were on market failures to decide what the public sector, the private sector, and the "third sector" (the community based sector) should do with regard to providing animal health services. However, such frameworks have paid limited attention to the governance challenges inherent in the provision of animal health services. This paper presents a framework for analyzing institutional arrangements for providing animal health services that focus not only on market failures, but also on governance challenges, such as elite capture, and absenteeism of staff. As an analytical basis, Williamson's discriminating alignment hypothesis is applied to assess the cost-effectiveness of different institutional arrangements for animal health services in view of both market failures and governance challenges. This framework is used to generate testable hypotheses on the appropriateness of different institutional arrangements for providing animal health services, depending on context-specific circumstances. Data from Uganda and Kenya on clinical veterinary services is used to provide an empirical test of these hypotheses and to demonstrate application of Williamson's transaction cost theory to veterinary service delivery. The paper concludes that strong public sector involvement, especially in building and strengthening a synergistic relation-based referral arrangement between paraprofessionals and veterinarians is imperative in improving animal health service delivery in developing countries. PMID- 26477331 TI - On the structure and bonding in the B4O4(+) cluster: a boron oxide analogue of the 3,5-dehydrophenyl cation with pi and sigma double aromaticity. AB - Boron oxide clusters offer intriguing molecular models for the electron-deficient system, in which the boronyl (BO) group plays a key role and the interplay between the localized BO triple bond and the multicenter electron delocalization dominates the chemical bonding. Here we report the structural, electronic, and bonding properties of the B4O4(+) cationic cluster on the basis of unbiased Coalescence Kick global-minimum searches and first-principles electronic structural calculations at the B3LYP and single-point CCSD(T) levels. The B4O4(+) cluster is shown to possess a Cs (1, (2)A') global minimum. It represents the smallest boron oxide species with a hexagonal boroxol (B3O3) ring as the core, terminated by a boronyl group. Chemical bonding analyses reveal double (pi and sigma) aromaticity in Cs B4O4(+), which closely mimics that in the 3,5 dehydrophenyl cation C6H3(+) (D3h, (1)A1'), a prototypical molecule with double aromaticity. Alternative D2h (2, (2)B3g) and C2v (3, (2)A1) isomeric structures of B4O4(+) are also analyzed, which are relevant to the global minima of B4O4 neutral and B4O4(-) anion, respectively. These three structural motifs vary drastically in terms of energetics upon changing the charge state, demonstrating an interesting case in which every electron counts. The calculated ionization potentials and electron affinities of the three corresponding neutral isomers are highly uneven, which underlie the conformational changes in the B4O4(+/0/-) series. The current work presents the smallest boron oxide species with a boroxol ring, establishes an analogy between boron oxides and the 3,5-dehydrophenyl cation, and enriches the chemistry of boron oxides and boronyls. PMID- 26477332 TI - Synthesis of stable C-linked ferrocenyl amino acids and their use in solution phase peptide synthesis. AB - Incorporation of ferrocenyl group to peptides is an efficient method to alter their hydrophobicity. Ferrocenyl group can also act as an electrochemical probe when incorporated onto functional peptides. Most often, ferrocene is incorporated onto peptides post-synthesis via amide, ester or triazole linkages. Stable amino acids containing ferrocene as a C-linked side chain are potentially useful building units for the synthesis of ferrocene-containing peptides. We report here an efficient route to synthesize ferrocene-containing amino acids that are stable and can be used in peptide synthesis. Coupling of 2-ferrocenyl-1,3-dithiane and iodides derived from aspartic acid or glutamic acid using n-butyllithium leads to the incorporation of a ferrocenyl unit to the delta-position or epsilon-position of an alpha-amino acid. The reduction or hydrolysis of the dithiane group yields an alkyl or an oxo derivative. The usability of the synthesized amino acids is demonstrated by incorporating one of the amino acids in both C-terminus and N terminus of tripeptides in solution phase. PMID- 26477333 TI - Factors affecting burnout in female nurses who have preschool-age children. AB - AIM: This prospective cohort study aims to clarify the factors affecting burnout in female nurses who have preschool-age children. METHODS: The subjects were 2151 female nurses who have preschool-age children and work at 70 city hospitals across Japan. The questionnaires were completed by 1644 female nurses with preschool-age children in October 2010, and they were divided into a cohort to observe the incidence of burnout, which was investigated in October 2011. RESULTS: At the baseline, the authors obtained responses from 1802 subjects (83.8%) who had agreed to join the study. The subjects the authors were able to investigate totaled 523, of whom 117 (22.4%) had experienced burnout. Multiple logistic regression analysis showed that influencing or predictive factors in burnout were years at the present workplace, will to continue work, assertiveness, overtime work, and spanking children. CONCLUSION: Female nurses who have preschool-age children tend to burnout easily if they have been at their present workplace for less than 3 years, wish to quit working, respond to a child's misbehavior with spanking, are "very low" in assertiveness, or work 4-6 h of overtime per week. PMID- 26477334 TI - Hazard Analysis and Critical Control Points System for a Bull Semen Production Centre. AB - Bull semen production centres (SPC) generally present satisfactory quality control for sperm processing, but non-standardized hygiene procedures. This study describes a Hazard Analysis and Critical Control Points (HACCP) system developed for bull SPC and subsequently implemented in a commercial SPC. After the identification of hazards at each step of semen processing and the determination of their risk and severity, monitoring and corrective procedures were designed to assess the system's efficiency. The HACCP system identified six microbiological hazards, 10 physical hazards, four chemical hazards and three critical control points. After the establishment of Good Processing Practices, Standard Operating Procedures and Standard Sanitizing Operating Procedures, the system was validated through an audit, to identify eventual failures and to define measures to correct them. PMID- 26477337 TI - Effect of Treatment on Body Fluid in Patients with Unilateral Aldosterone Producing Adenoma: Adrenalectomy versus Spironolactone. AB - Aldosterone affects fluid retention in the body by affecting how much salt and water that the kidney retains or excretes. There is limited information about the effect of prolonged aldosterone excess and treatment on body fluid in primary aldosteronism (PA) patients. In this study, body composition changes of 41 PA patients with unilateral aldosterone producing adenoma (APA) were assessed by a bio-impedance spectroscopy device. Patients with APA receiving adrenalectomy, as compared with those treated with spironolactone, had significantly lower relative overhydration (OH) and urine albumin excretion, and significantly higher urine sodium excretion four weeks after treatment. These differences dissipated 12 weeks after the initial treatment. Independent factors to predict decreased relative OH four weeks after treatment were male patients and patients who experienced adrenalectomy. Patients who underwent adrenaelctomy had significantly decreased TNF-alpha and increased serum potassium level when compared to patients treated with spironolactone 4 and 12 weeks after treatment. In this pilot study, we found that adrenalectomy leads to an earlier increase in renal sodium excretion and decreases in body fluid content, TNF-alpha, and urine albumin excretion. Adrenalectomy yields a therapeutic effect more rapidly, which has been shown to ameliorate overhydration in PA patients. PMID- 26477338 TI - Functional and association studies of the cholesteryl ester transfer protein (CETP) gene in a Wannan Black pig model. AB - Some polymorphisms of the human CETP gene are causally and significantly associated with serum lipids levels; however, the information regarding this gene in pigs is sparse. To evaluate the effects of CETP on blood lipid traits and fat deposition in pig, porcine CETP tissue expression patterns were observed by quantitative real-time polymerase chain reaction (qPCR) first. High expression was detected in liver, spleen, gluteus medius (GM) muscle and backfat. A de novo polymorphism (AF333037:g.795C>T) in the intron 1 region of porcine CETP was identified. This polymorphism was further genotyped by direct sequencing of the PCR products of 390 Wannan Black pigs, a Chinese native breed population. Association analyses at 45 and 300 days of age revealed highly significant associations between CETP genotypes and serum lipid traits. Furthermore, this polymorphism was proved to be associated with differences in liver CETP mRNA levels: pigs at 300 days of age with the TT genotype had higher levels than did those with other genotypes (P = 0.021). Additionally, analysis at 300 days of age showed that GM CETP mRNA expression correlated positively with serum lipids levels as well as with carcass backfat thickness and intramuscular fat content in GM. These results indicate that CETP is involved in serum, adipose and muscle lipid metabolism in pigs. The mechanisms underlying such relationships and their functional implications are worthy of further research. PMID- 26477339 TI - Does the legacy of historical biogeography shape current invasiveness in pines? AB - Why are some introduced species more successful at establishing and spreading than others? Until now, characteristics of extant species have been intensively investigated to answer this question. We propose to gain new insights on species invasiveness by exploring the long-term biogeographic and evolutionary history of lineages. We exemplify our approach using one of the best-studied invasive plant genera, Pinus. We notably estimated the historical biogeography of pines and the rates of trait evolution in pines. These estimates were analysed with regard to species invasiveness status. The results revealed that currently invasive species belong to lineages that were particularly successful at colonizing new regions in the past. We also showed that highly mobile lineages had faster rates of niche evolution, but that these rates are poor proxies for species adaptive potential in invaded regions (estimated by niche shift among native and invaded regions). In summary, working at the interface of ecology, historical biogeography and evolutionary history offers stimulating perspectives to improve our understanding of the drivers of invasion success. PMID- 26477340 TI - Effect of electrolytes on the microstructure and yielding of aqueous dispersions of colloidal clay. AB - Na-montmorillonite is a natural clay mineral and is available in abundance in nature. The aqueous dispersions of charged and anisotropic platelets of this mineral exhibit non-ergodic kinetically arrested states ranging from soft glassy phases dominated by interparticle repulsions to colloidal gels stabilized by salt induced attractive interactions. When the salt concentration in the dispersing medium is varied systematically, viscoelasticity and yield stress of the dispersion show non-monotonic behavior at a critical salt concentration, thus signifying a morphological change in the dispersion microstructures. We directly visualize the microscopic structures of these kinetically arrested phases using cryogenic scanning electron microscopy. We observe the existence of honeycomb like network morphologies for a wide range of salt concentrations. The transition of the gel morphology, dominated by overlapping coin (OC) and house of cards (HoC) associations of clay particles at low salt concentrations to a new network structure dominated by face-face coagulation of platelets, is observed across the critical salt concentration. We further assess the stability of these gels under gravity using electroacoustics. This study, performed for concentrated clay dispersions for a wide concentration range of externally added salt, is useful in our understanding of many geophysical phenomena that involve the salt induced aggregation of natural clay minerals. PMID- 26477341 TI - Classroom Enters the Courtroom: Stereochemistry of SN1 and SN2 Reactions in Enantiomer Patent Litigations of the Antidepressant Escitalopram. AB - The role of elementary stereochemistry is illustrated in the patent litigations of the blockbuster antidepressant drug escitalopram oxalate. An undergraduate student of organic chemistry would recognize the stereochemical courses of the intramolecular SN 2 and SN 1 reactions of the single-enantiomer (S)-diol intermediate in the synthesis of the blockbuster antidepressant drug escitalopram oxalate: retention of configuration of the chiral carbon atom under basic conditions and racemization under acidic conditions, respectively. He/she, in searching for a stereoselective ring-closure reaction of the enantiomeric diol, will think of an SN 2 reaction in a basic medium. From these points of view, the process claim in the enantiomer patents of escitalopram is obvious/lacks an inventive step. An organic chemistry examination problem based on this scenario is offered. PMID- 26477342 TI - Pre-operative Waterlow score: Predicts risk of post-operative infection in patients with neck of femur fractures. AB - INTRODUCTION: Nursing staff prospectively collect Waterlow scores (Ws) on all inpatients across most NHS hospitals, identifying patients at risk of pressure ulcers. This bedside score has not been applied in predicting other negative outcomes in patients with neck of femur (NOF) fractures. OBJECTIVES: To investigate the relationship between increasing Waterlow score and 30-day post operative infection in patients with NOF fracture. PATIENTS AND METHODS: Pre operative Ws and 30-day clinical outcome data were collected on 97 consecutive operatively treated NOF fracture patients at our institution (level one trauma centre). RESULTS: 30-day infection rate was 36%, which manifested as hospital acquired pneumonia (66%) and urinary tract infection (34%). For every one point increase in Ws, the odds of having an infection increased by 1.68 times (95% CI 1.37-2.08). The relationship between Ws and 30-day infection was similar when adjusted for potential confounders: patient demographics (age and gender), number of medical comorbidities, ASA grade, and days to surgery. For our data, the Ws predictive of infection was >=17. This has a sensitivity of 84.9% (95% CI 68.1 94.9%) and a specificity of 84.1% (95% CI 74.7-92.1%). The area under the curve was 0.89 (95% CI 0.82-0.96). CONCLUSION: Our study demonstrates a strong relationship between increasing Ws and post-operative infection risk. This raises the interesting yet controversial question of using Ws to identify patients at high-risk of developing post-operative infections and the potential benefit of an extended period of antibiotic prophylaxis. PMID- 26477343 TI - The use of gentamicin-coated nails in complex open tibia fracture and revision cases: A retrospective analysis of a single centre case series and review of the literature. AB - INTRODUCTION: Despite modern advances in fracture care, deep (implant-related) infection remains a problem in the treatment of tibia fractures. There is some evidence that antibiotic-coated implants are beneficial in the prevention of this sometimes devastating complication. In the following study we describe our results using a gentamicin-coated intramedullary tibia nail (Expert Tibia Nail (ETN) PROtectTM) for the surgical treatment of complex open tibia fracture and revision cases. MATERIALS AND METHODS: We describe the outcome of patients treated between January 2012 and September 2013, using a gentamicin-coated intramedullary tibia nail. Treatment indications included acute, Gustilo grade II III, open tibia fractures or closed tibia fractures with long-term external fixation prior to intramedullary nailing and complex tibia fracture revision cases with a mean of three prior surgical interventions. Outcome parameters in this study were deep infection and nonunion. RESULTS: In total, 16 consecutive patients with 16 tibia fractures were treated with a gentamicin-coated intramedullary nail. The overall patient population was subdivided into two groups. The first group consisted of 11 patients (68.8%) with acute fractures who were treated with a gentamicin-coated intramedullary nail. The second group consisted of 5 complex revision cases (31.2%). In our patient population no deep infections could be noted after the treatment with a gentamicin-coated tibia nail. Nonunion was diagnosed in 4 patients (25.0%), 1 of these was a revision case. CONCLUSIONS: Musculoskeletal complications place a cost burden on total healthcare expenditure. Better understanding of the epidemiology and pathogenesis is essential because this can lead to prevention rather than treatment strategies. The purpose of the study was to evaluate a gentamicin-coated tibia nail in the prevention of deep (implant-related) infection. In our patient population no deep infections occurred after placement of the gentamicin-coated nail. Following this study and literature data, antibiotic-coated implants seem a potential option for prevention of deep infection in trauma patients. In the future this statement needs to be confirmed by large randomised clinical trials. PMID- 26477344 TI - High revision rate but good healing capacity of atypical femoral fractures. A comparison with common shaft fractures. AB - INTRODUCTION: Healing of complete, atypical femoral fractures is thought to be impaired, but the evidence is weak and appears to be based on the delayed healing observed in patients with incomplete atypical fractures. Time until fracture healing is difficult to assess, therefore we compared the reoperation rates between women with complete atypical femoral fractures and common femoral shaft fractures. METHODS: We searched the orthopaedic surgical registry in Ostergotland County for patients with subtrochanteric and femoral shaft fractures (ICD-10 diagnosis codes S72.2, S72.3 and M84.3F) between January 1st 2007 and December 31st 2013. Out of 895 patients with surgically treated femoral shaft fractures, 511 were women 50 years of age or older. Among these we identified 24 women with atypical femoral shaft fractures, and 71 with common shaft fractures. RESULTS: Reoperations were performed in 6 and 5 patients, respectively, odds ratio 4.4 (95% CI 1.2 to 16.1). However, 5 reoperations in the atypical fracture group could not be ascribed to poor healing. In 3 patients the reoperation was due to a new fracture proximal to a standard intramedullary nail. In 2 patients the distal locking screws were removed due to callus formation that was deemed incomplete 5 months post-operatively. The one patient with poor healing showed faint callus formation at 5 months when the fracture was dynamised and callus remained sparse at 11 months. Among patients with common shaft fractures, 2 reoperations were performed to remove loose screws, 2 because of peri-implant fractures and 1 reoperation due to infection. DISCUSSION: Reoperation rates in patients with complete atypical femoral fractures are higher than in patients with common shaft fractures. The main reason for failure was peri-implant fragility fractures which might be prevented with the use of cephalomedullary nails at the index surgery. Fracture healing however, seems generally good. A watchful waiting approach is advocated in patients with fractures that appear to heal slowly. PMID- 26477345 TI - Improving early identification of the high-risk elderly trauma patient by emergency medical services. AB - STUDY OBJECTIVE: We sought to (1) define the high-risk elderly trauma patient based on prognostic differences associated with different injury patterns and (2) derive alternative field trauma triage guidelines that mesh with national field triage guidelines to improve identification of high-risk elderly patients. METHODS: This was a retrospective cohort study of injured adults >=65 years transported by 94 EMS agencies to 122 hospitals in 7 regions from 1/1/2006 through 12/31/2008. We tracked current field triage practices by EMS, patient demographics, out-of-hospital physiology, procedures and mechanism of injury. Outcomes included Injury Severity Score>=16 and specific anatomic patterns of serious injury using abbreviated injury scale score >=3 and surgical interventions. In-hospital mortality was used as a measure of prognosis for different injury patterns. RESULTS: 33,298 injured elderly patients were transported by EMS, including 4.5% with ISS>=16, 4.8% with serious brain injury, 3.4% with serious chest injury, 1.6% with serious abdominal-pelvic injury and 29.2% with serious extremity injury. In-hospital mortality ranged from 18.7% (95% CI 16.7-20.7) for ISS>=16 to 2.9% (95% CI 2.6-3.3) for serious extremity injury. The alternative triage guidelines (any positive criterion from the current guidelines, GCS<=14 or abnormal vital signs) outperformed current field triage practices for identifying patients with ISS>=16: sensitivity (92.1% [95% CI 89.6 94.1%] vs. 75.9% [95% CI 72.3-79.2%]), specificity (41.5% [95% CI 40.6-42.4%] vs. 77.8% [95% CI 77.1-78.5%]). Sensitivity decreased for individual injury patterns, but was higher than current triage practices. CONCLUSIONS: High-risk elderly trauma patients can be defined by ISS>=16 or specific non-extremity injury patterns. The field triage guidelines could be improved to better identify high risk elderly trauma patients by EMS, with a reduction in triage specificity. PMID- 26477346 TI - Necessity for fibular fixation associated with distal tibia fractures. AB - INTRODUCTION: Intramedullary (IM) nailing is a well-accepted treatment for distal third tibia fractures in combination with injury to the fibula. However, the indications for operative stabilisation of the fibula remain controversial. METHODS: The authors performed a retrospective review on a consecutive series of patients who underwent intramedullary nailing of a non-comminuted distal third tibia fracture with or without fibular fixation at a Level I urban trauma centre. A review of surgical records identified 120 patients who initially were included in this study, while a total of 98 patients who met the inclusion criteria were included in the final analysis. RESULTS: Our results found no difference in the mean value of coronal and sagittal plane alignment in both the immediate post operative and follow-up time periods. We also saw no statistically significant difference when comparing malalignment between patients treated with or without fibula fixation. There were no deep infections between the two groups. No significant differences were seen between the fibular fixation group and the non fixation group. Distal screw removal due to prominence or pain was the most common reason for future surgery in both groups. CONCLUSION: These findings suggest that the addition of fibular fixation does not affect whether or not alignment is maintained in either the immediate post-operative or short-term follow-up period. PMID- 26477347 TI - Silver-polysaccharide antimicrobial nanocomposite coating for methacrylic surfaces reduces Streptococcus mutans biofilm formation in vitro. AB - OBJECTIVES: The aim of this study was to determine the in vitro microbiological performances of a lactose-modified chitosan (Chitlac) coating inside which silver nanoparticles were embedded (Chitlac-nAg) for BisGMA/TEGDMA methacrylic specimens. METHODS: Different concentrations of nAg inside Chitlac coating were tested (1 mM, 2 mM, 5 mM). Specimen surface was analyzed by means of field emission scanning electron microscopy (FEISEM) and energy-dispersive X-ray spectroscopy (EDS). A 48 h monospecific Streptococcus mutans biofilm was developed over the specimen surfaces using a modified drip-flow bioreactor; adherent viable biomass was assessed by MTT test and biofilm was imaged by confocal laser-scanning microscopy (CLSM). RESULTS: The presence of finely dispersed nanoparticles inside the Chitlac coating was confirmed by FEISEM and EDS analysis. All nanoparticles were embedded in the Chitlac coating layer. Chitlac-nAg coatings were able to significantly decrease biofilm formation depending on the nAg concentration, reaching a -80% viable biomass decrease when the 5 mM nAg-Chitlac group was confronted to non-coated control specimens. CLSM analysis did not provide evidence of a contact-killing activity, however the antibacterial Chitlac-nAg coating was able to alter biofilm morphology preventing the development of mature biofilm structures. CONCLUSIONS: The microbiological model applied in this study helped in assessing the antibacterial properties of a coating designed for methacrylate surfaces. CLINICAL SIGNIFICANCE: A microbiological model based on a bioreactor-grown biofilm is useful for preliminary in vitro tests of dental materials. In translational terms, an antibacterial nanocomposite coating based on Chitlac-nAg and designed to be applied to methacrylic surfaces may be a promising way to obtain dental materials able to actively prevent secondary caries. PMID- 26477348 TI - Global aerial flyways allow efficient travelling. AB - Birds migrate over vast distances at substantial costs. The highly dynamic nature of the air makes the selection of the best travel route difficult. We investigated to what extent migratory birds may optimise migratory route choice with respect to wind, and if route choice can be subject to natural selection. Following the optimal route, calculated using 21 years of empirical global wind data, reduced median travel time by 26.5% compared to the spatially shortest route. When we used a time-dependent survival model to quantify the adaptive benefit of choosing a fixed wind-optimised route, 84.8% of pairs of locations yielded a route with a higher survival than the shortest route. This suggests that birds, even if incapable of predicting wind individually, could adjust their migratory routes at a population level. As a consequence, this may result in the emergence of low-cost flyways representing a global network of aerial migratory pathways. PMID- 26477349 TI - Factors associated with suicide completion: A comparison between suicide attempters and completers. AB - INTRODUCTION: The objective of this study was to compare the sociodemographic and clinical variables of suicide attempters and completers and to identify risk and protective factors for suicide completion. METHODS: Subjects (n = 320) visiting to the emergency room were classified into two groups: suicide attempters (n = 222) and suicide completers (n = 98). Univariate analyses and logistic regression models were used to explore the differences between suicide attempters and completers and to identify risk factors for suicide completion. RESULTS: The results showed that compared with suicide attempters, suicide completers were older, male, having alcohol use disorders, having comorbid health problems, having severe suicide ideation, and using severe suicide methods such as hanging and jumping from a height. Using multiple logistic regression model, risk factors predicting suicide completion were comorbid medical illness, and intense suicide ideation. Factor that served as protective factors against suicide completion was female. DISCUSSION: This study demonstrated that suicide completers have more severe clinical profile than suicide attempters. Decreasing intensity of suicide ideation and treating comorbid medical illness of suicide attempters might be important in preventing them from suicide completion. It is important that the implementation of suicide preventive programs focused on alcoholism is useful in decreasing suicide rates further. Moreover, suicide completers used highly lethal methods, our results indicate that our country should make greater efforts to decrease hanging and jumping from a height. PMID- 26477350 TI - MRI Customized Play Therapy in Children Reduces the Need for Sedation--A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effectiveness of an MRI-specific play therapy intervention on the need for sedation in young children. METHODS: All children in the age group of 4-10 y, who were advised an MRI scan over a period of one year were randomized. Exclusion criteria included children with neurodevelopmental disorders impairing cognition and children who had previously undergone diagnostic MRI. A total of 79 children were randomized to a control or an intervention condition. The intervention involved familiarizing the child with the MRI model machine, listing the steps involved in the scan to the child in vivid detail, training the child to stand still for 5 min, and conducting several dry runs with a doll or a favorite toy. The study was approved by the Institute ethical committee. RESULTS: The need for sedation was 41 % (n = 16) in the control group and this declined to 20 % (n = 8) in the intervention group (chi(2) = 4.13; P = 0.04). The relative risk of sedation decreased by 49 % in the intervention group as compared to the control group (RR 0.49; 95 % CI: 0.24-1.01) and this difference was statistically significant (P = 0.04). The absolute risk difference in sedation use between intervention and control group was 21 % (95 % CI 1.3 %-40.8 %). Even on adjusting for age, relative risk of sedation remained significantly lower in children undergoing play therapy as compared to the control (RR 0.57, 95 % CI: 0.32-0.98) with P value of 0.04. CONCLUSIONS: The use of an MRI customized play therapy with pediatric patients undergoing diagnostic MRI resulted in significant reduction of the use of sedation. PMID- 26477351 TI - Network Pharmacology of Ayurveda Formulation Triphala with Special Reference to Anti-Cancer Property. AB - Network pharmacology is an emerging technique, which integrates systems biology and computational biology to study multi-component and multi-targeted formulations. Ayurveda, the traditional system of Indian medicine, uses intelligent formulations; however, their scientific rationale and mechanisms remain largely unexplored. This paper presents the potential of network pharmacology to understand the rationale of a commonly used Ayurveda formulation known as Triphala. We have developed pharmacology networks of Triphala based on the information gathered from different databases and using the software Cytoscape. The networks depict the interaction of bioactives with molecular targets and their relation with diseases, especially cancer. The network pharmacology analysis of Triphala has offered new relationships among bioactives, targets and putative applications of cancer etiology. This pioneering effort might open new possibilities to know pharmacodynamics of Ayurvedic drugs like Triphala and also help in the discovery of new leads and targets for various diseases. PMID- 26477352 TI - Establishment of a Primary Screening Assay for the DHX9 Helicase. AB - The RNA helicase DHX9 is an ATP-dependent DExH box helicase that can unwind DNA and RNA. Much evidence has implicated DHX9 at multiple levels of gene expression regulation ranging from genome stability and replication, to transcriptional control and translation regulation. Its association with the EWS-FLI1 fusion product, as well as the finding that its suppression can be synthetic lethal with the BCL-2 family inhibitor ABT-737 indicates a potential role in tumor maintenance. Hence, to identify small molecules that could interfere with its activity, we developed a homogenous RNA-dependent ATPase assay. We show that aurintricarboxylic acid, a promiscuous protein-nucleic acid inhibitor prevents DHX9-mediated hydrolysis demonstrating that the assay is also capable of detecting compounds that impinge on DHX9:RNA association. PMID- 26477353 TI - Unravelling the Impact of Reaction Paths on Mechanical Degradation of Intercalation Cathodes for Lithium-Ion Batteries. AB - The intercalation compounds are generally considered as ideal electrode materials for lithium-ion batteries thanks to their minimum volume expansion and fast lithium ion diffusion. However, cracking still occurs in those compounds and has been identified as one of the critical issues responsible for their capacity decay and short cycle life, although the diffusion-induced stress and volume expansion are much smaller than those in alloying-type electrodes. Here, we designed a thin-film model system that enables us to tailor the cation ordering in LiNi(0.5)Mn(1.5)O4 spinels and correlate the stress patterns, phase evolution, and cycle performances. Surprisingly, we found that distinct reaction paths cause negligible difference in the overall stress patterns but significantly different cracking behaviors and cycling performances: 95% capacity retention for disordered LiNi(0.5)Mn(1.5)O4 and 48% capacity retention for ordered LiNi(0.5)Mn(1.5)O4 after 2000 cycles. We were able to pinpoint that the extended solid-solution region with suppressed phase transformation attributed to the superior electrochemical performance of disordered spinel. This work envisions a strategy for rationally designing stable cathodes for lithium-ion batteries through engineering the atomic structure that extends the solid-solution region and suppresses phase transformation. PMID- 26477354 TI - Systematic Engineering of Escherichia coli for d-Lactate Production from Crude Glycerol. AB - Crude glycerol resulting from biodiesel production is an abundant and renewable resource. However, the impurities in crude glycerol usually make microbial fermentation problematic. This issue was addressed by systematic engineering of Escherichia coli for the production of d-lactate from crude glycerol. First, mgsA and the synthetic pathways of undesired products were eliminated in E. coli, rendering the strain capable of homofermentative production of optically pure d lactate. To direct carbon flux toward d-lactate, the resulting strain was endowed with an enhanced expression of glpD-glpK in the glycerol catabolism and of a heterologous gene encoding d-lactate dehydrogenase. Moreover, the strain was evolved to improve its utilization of cruder glycerol and subsequently equipped with the FocA channel to export intracellular d-lactate. Finally, the fed-batch fermentation with two-phase culturing was carried out with a bioreactor. As a result, the engineered strain enabled production of 105 g/L d-lactate (99.9% optical purity) from 121 g/L crude glycerol at 40 h. The result indicates the feasibility of our approach to engineering E. coli for the crude glycerol-based fermentation. PMID- 26477355 TI - Nocturia in Patients With Sleep-Disordered Breathing and Cardiovascular Disease. AB - BACKGROUND: Sleep apnea is a common condition and a cardiovascular risk factor. Continuous positive airway pressure (CPAP) reduces cardiovascular events and sleep apnea-related symptoms, especially in patients with obstructive sleep apnea (OSA), who occasionally experience nocturia, a common problem in individuals of advanced age. METHODS AND RESULTS: The present study was a prospective, observational study including 1,429 consecutive patients with cardiovascular disease (CVD). A questionnaire on nocturia was administered and nocturnal pulse oximetry was performed. Patients with moderate-to-severe sleep-disordered breathing (SDB) underwent polysomnography, and patients with OSA received CPAP therapy. Nocturia was observed in 561 of 666 patients included in the analysis. A multiple logistic regression analysis revealed that nocturia was associated with oxygen desaturation defined as a 3% decrease (P=0.0335) independent of age (P<0.0001), male sex (P=0.0078), hypertension (P=0.0139), and B-type natriuretic peptide (BNP) level (P=0.0185). Nocturia was reduced in patients who continued CPAP treatment and they also showed a decrease in the apnea-hypopnea index (45.3+/-13.6 vs. 2.5+/-3.7 events/h, P<0.0001), systolic blood pressure (121.6+/ 11.9 vs. 113.4+/-8.8 mmHg, P=0.0002), and BNP level (57.7 [15.0-144.4] vs. 27.4 [8.5-111.7] pg/ml, P=0.0006). CONCLUSIONS: CPAP has the potential to reduce nocturia and risk factors for SDB such as increased blood pressure and BNP level, which may be beneficial in older men with CVD and OSA. PMID- 26477356 TI - Diagnosis and Detection of Myocardial Injury in Active Cardiac Sarcoidosis- Significance of Myocardial Fatty Acid Metabolism and Myocardial Perfusion Mismatch. AB - BACKGROUND: Myocardial injury can be detected more sensitively using (123)I radioiodinated 15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) than thallium-201 (TL). The present study investigated whether (18)F fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake as an index of active inflammation in patients with cardiac sarcoidosis (CS) is associated with BMIPP and TL findings, and whether dual single-photon emission computed tomography (SPECT) can facilitate diagnosis of CS. METHODS AND RESULTS: We retrospectively enrolled 52 consecutive patients with suspected CS who were assessed on FDG-PET/computed tomography (CT) and BMIPP/TL dual SPECT. The SPECT images were divided into 17 segments and then BMIPP and TL total defect scores (BMDS, TLDS) as well as mismatch scores (BMDS-TLDS: sumMS) were calculated. Maximum standardized uptake value (SUVmax) in the entire myocardium was obtained from FDG-PET/CT. SUVmax was much higher in patients with, than without CS (P<0.0001). BMDS was higher and sumMS much higher in CS (P<0.05 and P<0.0001, respectively). The sensitivity and specificity of sumMS to detect CS were 74% and 80%, respectively. SUVmax was not associated with either BMDS or sumMS in the patients with CS. On multivariate analysis, the combination of sumMS and SUVmax had greater prognostic significance compared with each parameter on its own. CONCLUSIONS: BMIPP and TL dual-tracer mismatch is a useful finding to diagnose CS, and adds greater diagnostic value to SUVmax on FDG-PET/CT. PMID- 26477357 TI - Lead-Free alpha-La2WO6 Ferroelectric Thin Films. AB - (001)-Epitaxial La2WO6 (LWO) thin films are grown by pulsed laser deposition on (001)-oriented SrTiO3 (STO) substrates. The alpha-phase (high-temperature phase in bulk) is successfully stabilized with an orthorhombic structure (a = 16.585(1) A, b = 5.717(2) A, c = 8.865(5) A). X-ray-diffraction pole-figure measurements suggest that crystallographic relationships between the film and substrate are [100]LWO ? [110]STO, [010]LWO ? [110]STO and [001]LWO ? [001]STO. From optical properties, investigated by spectroscopic ellipsometry, we extract a refractive index value around 2 (at 500 nm) along with the presence of two absorption bands situated, respectively at 3.07 and 6.32 eV. Ferroelectricity is evidenced as well on macroscale (standard polarization measurements) as on nanoscale, calling for experiments based on piezo-response force-microscopy, and confirmed with in situ scanning-and-tunneling measurements performed with a transmission electron microscope. This work highlights the ferroelectric behavior, at room temperature, in high-temperature LWO phase when stabilized in thin film and opens the way to new functional oxide thin films dedicated to advanced electronic devices. PMID- 26477358 TI - Effect of Polyelectrolyte Film Stiffness on Endothelial Cells During Endothelial to-Mesenchymal Transition. AB - Endothelial-to-mesenchymal transition (EndMT), during which endothelial cells (ECs) transdifferentiate into mesenchymal phenotype, plays a key role in the development of vascular implant complications such as endothelium dysfunction and in-stent restenosis. Substrate stiffness has been confirmed as a key factor to influence EC behaviors; however, so far, the relationship between substrate stiffness and EndMT has been rarely studied. Here, ECs were cultured on the (poly(L-lysine)/hyaluronate acid) (PLL/HA) multilayer films with controlled stiffness for 2 weeks, and their EndMT behaviors were studied. We demonstrated that ECs lost their markers (vWf and CD31) in a stiffness-dependent manner even without supplement of growth factors, and the softer film favored the maintaining of EC phenotype. Further, induced by transforming growth factor beta1 (TGF beta1), ECs underwent EndMT, as characterized by losing their typical cobblestone morphology and markers and gaining smooth muscle cell markers (alpha-smooth muscle actin and calponin). Interestingly, stronger EndMT was observed when ECs were cultured on the stiffer film. Collectively, our findings suggest that substrate stiffness has significant effects on EndMT, and a softer substrate is beneficial to ECs by keeping their phenotype and inhibiting EndMT, which presents a new strategy for surface design of vascular implant materials. PMID- 26477359 TI - White Matter Changes in Tinnitus: Is It All Age and Hearing Loss? AB - Tinnitus is a condition characterized by the perception of auditory phantom sounds. It is known as the result of complex interactions between auditory and nonauditory regions. However, previous structural imaging studies on tinnitus patients showed evidence of significant white matter changes caused by hearing loss that are positively correlated with aging. Current study focused on which aspects of tinnitus pathologies affect the white matter integrity the most. We used the diffusion tensor imaging technique to acquire images that have higher contrast in brain white matter to analyze how white matter is influenced by tinnitus-related factors using voxel-based methods, region of interest analysis, and deterministic tractography. As a result, white matter integrity in chronic tinnitus patients was both directly affected by age and also mediated by the hearing loss. The most important changes in white matter regions were found bilaterally in the anterior corona radiata, anterior corpus callosum, and bilateral sagittal strata. In the tractography analysis, the white matter integrity values in tracts of right parahippocampus were correlated with the subjective tinnitus loudness. PMID- 26477360 TI - The Two-Brains Hypothesis: Towards a guide for brain-brain and brain-machine interfaces. AB - Great advances have been made in signaling information on brain activity in individuals, or passing between an individual and a computer or robot. These include recording of natural activity using implants under the scalp or by external means or the reverse feeding of such data into the brain. In one recent example, noninvasive transcranial magnetic stimulation (TMS) allowed feeding of digitalized information into the central nervous system (CNS). Thus, noninvasive electroencephalography (EEG) recordings of motor signals at the scalp, representing specific motor intention of hand moving in individual humans, were fed as repetitive transcranial magnetic stimulation (rTMS) at a maximum intensity of 2.0[Formula: see text]T through a circular magnetic coil placed flush on each of the heads of subjects present at a different location. The TMS was said to induce an electric current influencing axons of the motor cortex causing the intended hand movement: the first example of the transfer of motor intention and its expression, between the brains of two remote humans. However, to date the mechanisms involved, not least that relating to the participation of magnetic induction, remain unclear. In general, in animal biology, magnetic fields are usually the poor relation of neuronal current: generally "unseen" and if apparent, disregarded or just given a nod. Niels Bohr searched for a biological parallel to complementary phenomena of physics. Pertinently, the two-brains hypothesis (TBH) proposed recently that advanced animals, especially man, have two brains i.e., the animal CNS evolved as two fundamentally different though interdependent, complementary organs: one electro-ionic (tangible, known and accessible), and the other, electromagnetic (intangible and difficult to access) a stable, structured and functional 3D compendium of variously induced interacting electro-magnetic (EM) fields. Research on the CNS in health and disease progresses including that on brain-brain, brain-computer and brain-robot engineering. As they grow even closer, these disciplines involve their own unique complexities, including direction by the laws of inductive physics. So the novel TBH hypothesis has wide fundamental implications, including those related to TMS. These require rethinking and renewed research engaging the fully complementary equivalence of mutual magnetic and electric field induction in the CNS and, within this context, a new mathematics of the brain to decipher higher cognitive operations not possible with current brain-brain and brain-machine interfaces. Bohr may now rest. PMID- 26477362 TI - Simultaneous detection of multiple mycotoxins in broiler feeds using a liquid chromatography tandem-mass spectrometry. AB - Mycotoxins are secondary fungal metabolites that are typically present in grain and feed ingredients used for animal feeds. An analytical method using LC-ESI MS/MS was developed to quantify nine mycotoxins, consisting of aflatoxin B1 (AFB1), AFB2, AFG1, AFG2, T-2 toxin, deoxynivalenol (DON), nivalenol (NIV), zearalenone (ZEA) and ochratoxin A (OTA) in broiler feeds. In total, 100 samples of broiler feeds were collected from poultry farms in Central Thailand. The survey found that AFB1 and ZEA were the most prevalent mycotoxins in the feed samples at percentages of 93% and 63%, respectively. The limit of detections (LODs) of investigated mycotoxins was 0.20-0.78 ng/g. AFB2, DON, AFG1, NIV and T 2 toxin were also detectable at low contamination levels with percentages of 20%, 9%, 7%, 5% and 1%, respectively, whereas OTA and AFG2 were not detected in any of the feed samples. These results suggest that there is a very low level of risk of the exposure to mycotoxins in feeds obtained from broiler farms in Central Thailand. PMID- 26477361 TI - Biofunctionalization of Large Gold Nanorods Realizes Ultrahigh-Sensitivity Optical Imaging Agents. AB - Gold nanorods (GNRs, ~ 50 * 15 nm) have been used ubiquitously in biomedicine for their optical properties, and many methods of GNR biofunctionalization have been described. Recently, the synthesis of larger-than-usual GNRs (LGNRs, ~ 100 * 30 nm) has been demonstrated. However, LGNRs have not been biofunctionalized and therefore remain absent from biomedical literature to date. Here we report the successful biofunctionalization of LGNRs, which produces highly stable particles that exhibit a narrow spectral peak (FWHM ~100 nm). We further demonstrated that functionalized LGNRs can be used as highly sensitive scattering contrast agents by detecting individual LGNRs in clear liquids. Owing to their increased optical cross sections, we found that LGNRs exhibited up to 32-fold greater backscattering than conventional GNRs. We leveraged these enhanced optical properties to detect LGNRs in the vasculature of live tumor-bearing mice. With LGNR contrast enhancement, we were able to visualize tumor blood vessels at depths that were otherwise undetectable. We expect that the particles reported herein will enable immediate sensitivity improvements in a wide array of biomedical imaging and sensing techniques that rely on conventional GNRs. PMID- 26477363 TI - Current use and perspective of indocyanine green clearance in liver diseases. AB - Indocyanine green (ICG) is a water-soluble anionic compound that binds to plasma proteins after intravenous administration. It is selectively taken up at the first pass by hepatocytes and excreted unchanged into the bile. With the development of ICG elimination measurement by spectrophotometry, the ICG retention test has become a safe, rapid, reproducible, inexpensive and noninvasive tool for the assessment of liver function. Clinical evidence suggests that the ICG retention test can enable the establishment of tailored management strategies by providing prognostic information. In particular, this method has been evaluated as a prognostic marker in patients with advanced cirrhosis or awaiting liver transplantation. In addition, it is used as a marker of portal hypertension in cirrhotic patients, as a prognostic factor in intensive care units and for the assessment of liver function in patients undergoing liver surgery. Since recent technology enables ICG-PDR to be measured noninvasively at the bedside, this parameter is an attractive addition to liver function and regional haemodynamic monitoring. However, the current state-of-the-art as concerns this technology remains at a low level of evidence and thorough assessment is required. PMID- 26477364 TI - Regulation and Evolution of the RAG Recombinase. AB - The modular, noncontiguous architecture of the antigen receptor genes necessitates their assembly through V(D)J recombination. This program of DNA breakage and rejoining occurs during early lymphocyte development, and depends on the RAG1 and RAG2 proteins, whose collaborative endonuclease activity targets specific DNA motifs enriched in the antigen receptor loci. This essential gene shuffling reaction requires lymphocytes to traverse several developmental stages wherein DNA breakage is tolerated, while minimizing the expense to overall genome integrity. Thus, RAG activity is subject to stringent temporal and spatial regulation. The RAG proteins themselves also contribute autoregulatory properties that coordinate their DNA cleavage activity with target chromatin structure, cell cycle status, and DNA repair pathways. Even so, lapses in regulatory restriction of RAG activity are apparent in the aberrant V(D)J recombination events that underlie many lymphomas. In this review, we discuss the current understanding of the RAG endonuclease, its widespread binding in the lymphocyte genome, its noncleavage activities that restrain its enzymatic potential, and the growing evidence of its evolution from an ancient transposase. PMID- 26477365 TI - Chromatin Interactions in the Control of Immunoglobulin Heavy Chain Gene Assembly. AB - Expression of antibody heavy chain occurs via precisely timed developmental activation of the immunoglobulin heavy chain (IgH) gene locus during B cell development. IgH locus activation permits coordinated gene rearrangements that assemble variable (VH), diversity (DH), and joining (JH) gene segments into functional genes. Chromosomal conformation changes and epigenetic mechanisms play critical roles in ensuring rearrangement fidelity while minimizing hazardous consequences of broken DNA ends generated during recombination. In this review, we summarize the current status of regulatory mechanisms that underpin effective IgH gene assembly. For this, the germline locus is divided into two parts: a 2.4Mb 5' part that contains all VH gene segments and a 300kb 3' domain that contains DH and JH gene segments, as well as exons that encode IgH isotypes. Structural features of each part are discussed individually, followed by consideration of how the two parts come together to complete IgH recombination. Throughout we emphasize current insights, propose plausible mechanisms, and highlight key questions for future studies. PMID- 26477366 TI - Spatial Regulation of V-(D)J Recombination at Antigen Receptor Loci. AB - Lymphocytes express a diverse repertoire of antigen receptors, which are able to recognize a large variety of foreign pathogens. Functional antigen receptor genes are assembled by V(D)J recombination in immature B cells (Igh and Igk) and T cells (Tcr b and Tcra/d). V(D)J recombination takes place in the 3' proximal domain containing the D, J, and C gene segments, whereas 31 (Tcrb) to 200 (Igh) V genes are spread over a large region of 0.67 (Tcrb) to 3 (Igk) megabase pairs. The spatial regulation of V(D)J recombination has been best studied for the Igh locus, which undergoes reversible contraction by long-range looping in pro-B cells. This large-scale contraction brings distantly located VH genes into close proximity of the DJH-rearranged gene segment, which facilitates VH-DJH recombination. The B-cell-specific Pax5, ubiquitous YY1, and architectural CTCF/cohesin proteins regulate Igh locus contraction in pro-B cells by binding to multiple sites in the VH gene cluster. These regulators also control the pro-B cell-specific activity of the distally located PAIR elements, which may be involved in the regulation of VH-DJH recombination by promoting locus contraction. Moreover, the large VH gene cluster of the Igh locus undergoes flexible long-range looping, which guarantees similar participation of all VH genes in VH-DJH recombination to generate a diverse antibody repertoire. Importantly, long-range looping is a more general regulatory principle, as other antigen receptor loci also undergo reversible contraction at the developmental stage, where they engage in V-(D)J recombination. PMID- 26477368 TI - Dynamic Control of Long-Range Genomic Interactions at the Immunoglobulin kappa Light-Chain Locus. AB - The Igkappa locus, which is spread over 3Mb of genomic DNA and contains >100 variable (V) genes, serves as an important model system to study long-range chromatin interactions. Here, we will discuss how in developing B cells in the bone marrow the accessibility of individual Vkappa segments is controlled by many lineage-specific and ubiquitously expressed transcription factors that act on various cis-regulatory elements, including promoters, enhancers, and insulators. This dynamic control furthermore involves changes in subnuclear localization, histone modification, DNA demethylation, and three-dimensional locus compaction. In pro-B cells, the Igkappa locus adopts a poised conformation as full contraction has been achieved and many key transcription factors already occupy the locus. Subsequently, the combined activation of pre-B cell antigen receptor signaling pathways and attenuation of IL-7R signaling in small resting pre-B cells dramatically modifies the transcription factor landscape, supporting the induction of monoallelic Igkappa gene rearrangements. Hereby, the intronic and 3' Igkappa enhancer elements coordinately focus their activities in the Vkappa region toward frequently used Vkappa genes. Recent work has drawn attention to the intriguing role of the CTCF-associated regulatory elements Cer and Sis, which are located in the Vkappa-Jkappa intervening region and control Igkappa locus contraction and Vkappa repertoire diversity. This involves CTCF-mediated locus insulation, restricting enhancer activity to the Vkappa region and suppressing the preferential recombination to proximal Vkappa genes. A picture emerges in which the dynamic control of long-range genomic interactions ensures correct timing of Igkappa locus recombination and provides appropriate opportunities for individual Vkappa gene segments to engage in Vkappa-Jkappa rearrangement. PMID- 26477369 TI - Regulation of Tcrb Gene Assembly by Genetic, Epigenetic, and Topological Mechanisms. AB - The adaptive immune system endows mammals with an ability to recognize nearly any foreign invader through antigen receptors that are expressed on the surface of all lymphocytes. This defense network is generated by V(D)J recombination, a set of sequentially controlled DNA cleavage and repair events that assemble antigen receptor genes from physically separated variable (V), joining (J), and sometimes diversity (D) gene segments. The recombination process itself must be stringently regulated to minimize oncogenic translocations involving chromosomes that harbor immunoglobulin and T cell receptor loci. Indeed, V(D)J recombination is controlled at several levels, including tissue-, developmental stage-, allele-, and gene segment-specificity. These levels of control are imposed by a collection of architectural and regulatory elements that are distributed throughout each antigen receptor locus. Together, the genetic elements regulate developmental changes in chromatin, transcription, and locus topology that promote or disfavor long-range recombination. This chapter focuses on the cross talk between these mechanisms at the T cell receptor beta (Tcrb) locus, and how they sculpt a diverse TCRbeta repertoire while maintaining monospecificity of this antigen receptor on each mature T lymphocyte. We also discuss how insights obtained from studies of Tcrb are more generally relevant to our understanding of gene regulation strategies employed by mammals. PMID- 26477370 TI - Chromatin Dynamics and the Development of the TCRalpha and TCRdelta Repertoires. AB - The adaptive immune system allows vertebrates to orchestrate highly specific responses to a virtually unlimited milieu of antigens. Effective adaptive immune responses depend on the capacity of T and B lymphocytes to generate diverse repertoires of antigen receptors through the recombination of variable (V), diversity (D), and joining (J) gene segments at antigen receptor loci. V(D)J recombination must be carefully regulated during the early stages of T and B lymphocyte development to ensure the proper development of lymphocyte subsets and to maximize antigen receptor combinatorial diversity. Among all T cell receptor (TCR) and immunoglobulin loci, the TCRalpha/delta (Tcra/Tcrd) locus is unique in its complexity since it undergoes recombination at two distinct stages of T cell development to create distinct TCR proteins that are used by different lineages of T cells. Here, we review the mechanisms that regulate V(D)J recombination at the Tcra/Tcrd locus, with a focus on the dynamic chromatin environment and how it instructs the assembly of the Tcra and Tcrd repertoires. We discuss the dynamics of Tcra and Tcrd repertoire formation in the context of T cell development, and we consider how the recombination program is directed by localized changes in chromatin structure that regulate the accessibility of Tcra and Tcrd gene segments to the V(D)J recombinase. We then move beyond local to address spatial relationships in the nucleus, emphasizing the three-dimensional organization of the Tcra/Tcrd locus as a critical player in understanding long-distance interactions between chromatin regulatory elements as well as long-distance interactions between recombination substrates. PMID- 26477367 TI - Long-Range Regulation of V(D)J Recombination. AB - Given their essential role in adaptive immunity, antigen receptor loci have been the focus of analysis for many years and are among a handful of the most well studied genes in the genome. Their investigation led initially to a detailed knowledge of linear structure and characterization of regulatory elements that confer control of their rearrangement and expression. However, advances in DNA FISH and imaging combined with new molecular approaches that interrogate chromosome conformation have led to a growing appreciation that linear structure is only one aspect of gene regulation and in more recent years, the focus has switched to analyzing the impact of locus conformation and nuclear organization on control of recombination. Despite decades of work and intense effort from numerous labs, we are still left with an incomplete picture of how the assembly of antigen receptor loci is regulated. This chapter summarizes our advances to date and points to areas that need further investigation. PMID- 26477371 TI - Long-Range Control of V(D)J Recombination & Allelic Exclusion: Modeling Views. AB - Allelic exclusion of immunoglobulin (Ig) and T-cell receptor (TCR) genes ensures the development of B and T lymphocytes operating under the mode of clonal selection. This phenomenon associates asynchronous V(D)J recombination events at Ig or TCR alleles and inhibitory feedback control. Despite years of intense research, however, the mechanisms that sustain asymmetric choice in random Ig/TCR dual allele usage and the production of Ig/TCR monoallelic expressing B and T lymphocytes remain unclear and open for debate. In this chapter, we first recapitulate the biological evidence that almost from the start appeared to link V(D)J recombination and allelic exclusion. We review the theoretical models previously proposed to explain this connection. Finally, we introduce our own mathematical modeling views based on how the developmental dynamics of individual lymphoid cells combine to sustain allelic exclusion. PMID- 26477372 TI - Preface. PMID- 26477373 TI - Cholesterol-lowering effects and potential mechanisms of different polar extracts from Cyclocarya paliurus leave in hyperlipidemic mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cyclocarya paliurus Batal., native only to China, is widely consumed as a Chinese traditional folk medicine for the prevention and treatment of hyperlipidemia, obesity, and diabetes. The aim of the study is to investigate the cholesterol-lowering effect and potential mechanisms of different polar extracts from Cyclocarya paliurus leaves in mice fed with high-fat-diet. MATERIALS AND METHODS: Cyclocarya paliurus leaves extracts were orally administered to diet-induced hyperlipidemic mice for 4 weeks. Simvastatin was used as a positive control. Body weight, food intake, histopathology of liver and adipose tissues, hepatic and renal function indices, lipid profiles in the serum and liver were evaluated. Total bile acid concentrations of the liver and feces were also measured. Furthermore, the activities and mRNA expression of cholesterol metabolism-related enzymes including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7alpha-hydroxylase (CYP7A1) and acyl CoA cholesterol acyltransferase 2 (ACAT2) in the livers of the mice were analyzed. LC-MS detection was performed to identify the components in the active fraction of Cyclocarya paliurus extracts. RESULTS: Different Cyclocarya paliurus polar extracts, especially ChE reduced the levels of serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and hepatic TC and TG, enhanced the level of serum high-density lipoprotein cholesterol (HDL C), restored hepatic and renal function indices and histomorphology. HMG-CoA reductase activity and mRNA expression were decreased, while CYP7A1 activity and mRNA expression as well as the level of fecal and hepatic bile acid were increased by ChE. LC-MS analysis of ChE revealed the presence of six main triterpenoids, which might be responsible for its antihyperlipidemic bioactivity. CONCLUSIONS: Evidently ChE possesses the best antihyperlipidemic activity, and the cholesterol-lowering effect is at least partly attributed to its role in promoting the conversion of cholesterol into bile acids by upgrading the activity and mRNA expression of CYP7A1 and inhibiting those of HMG-CoA reductase to lower the cholesterol biosynthesis. PMID- 26477374 TI - Inhibition of alpha-glucosidase by new prenylated flavonoids from euphorbia hirta L. herb. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia hirta L. (Euphorbiaceae) is a pantropical medicinal rhizomatous herb, traditionally used in the treatment of diabetes, respiratory and gastro-intestinal disorders. AIM OF THE STUDY: To isolate and characterize the constituents of Euphorbia hirta and evaluate their in-vitro alpha-glucosidase inhibitory activity. The study is also aimed at describing structural activity relationship, type of alpha-glucosidase inhibition and in-vivo potential to regulate post prandial hyperglycemia in Wistar rats. MATERIALS AND METHODS: Methanolic extract of whole plant was suspended in water, and sequentially fractionated with n-hexane and ethyl acetate. Further ethyl acetate fraction was subjected to medium pressure liquid chromatography (MPLC) to isolate the active molecules under the following experimental conditions, pressure (up to 5 kg/cm(2)) and flow rate (2 in./min). The structural elucidation of isolated compounds was done on the basis of detailed spectral analysis. The alpha-glucosidase inhibitory potential of isolated compounds was evaluated and compared with standard drug acarbose. In addition, type of inhibition was dwelled by Lineweaver-Burk plot analysis. Further, sucrose tolerance test was performed in Wistar rats pre-treated with the isolated compounds and acarbose (0.015 mM) followed by a sucrose load (2g/kg, p.o.) and blood glucose level was measured up to 120 min by the glucose oxidase method. RESULTS: The ethyl acetate fraction afforded quercetrin (1), dimethoxy quercetrin (2), along with two new prenylated flavonosides designated as hirtacoumaroflavonoside (3) and hirtaflavonoside-B (4) characterized as 7-O-(p-coumaroyl)-5,7,4'-trihydroxy-6-(3,3-dimethyl allyl) flavonol-3-O-beta-D-glucopyranosyl-(2" -> 1"')-O-alpha-L-rhamnopyranoside and 5, 7, 3', 4'-trihydroxy-6-(3, 3-dimethyl allyl)-8-(iso-butenyl)-flavonol-3-C-beta-d glucopyranoside, respectively. All the isolated compounds showed dose dependent inhibition of alpha-glucosidase which was found to be comparable to acarbose. Maximum alpha-glucosidase inhibition was achieved with compound 3 (IC50 0.022 mM) followed by 4 (IC50 0.071 mM) in comparison to acarbose (IC50 0.092 mM). The results revealed that 5,7,4'- trihydroxyflavone structure is imperative for the inhibitory activity. The prenylation in the flavonoids increase the potency and p coumaroyl substitution at C-7 further enriched the alpha-glucosidase inhibition. Compound 3 exhibited non-competitive inhibition while compounds 1, 2 and 4 showed mixed non-competitive inhibitory pattern. The results of sucrose tolerance test corresponded well with the in vitro studies. CONCLUSION: alpha-Glucosidase inhibitory activity and sucrose tolerance test demonstrated by the prenylated flavonoids present in E. hirta provide credence to the ethnomedicinal use of the plant in the management of diabetes in folk medicine. PMID- 26477375 TI - [Choledochal cyst during pregnancy. Report of 3 cases and a literature review]. AB - BACKGROUND: Choledochal cysts are rare. They usually present during childhood in women, but it can also be seen during pregnancy. Clinical signs and symptoms are obscured during this time, thus it can complicate the diagnosis and represent a life threatening complication for both the mother and the child. OBJECTIVE: To communicate the case of 3 pregnant patients with choledochal cyst. CLINICAL CASES: Three pregnant women in which choledochal cyst were diagnosed. Two developed signs of cholangitis. The first one underwent a hepatic-jejunostomy, but had an abortion and died on postoperative day 10. The second one had a preterm caesarean operation due to foetal distress and underwent a hepatic jejunostomy 4 weeks later; during her recovery she had a gastric perforation and died of septic complications. The third one did not develop cholangitis or jaundice. She had an uneventful pregnancy and had a hepatic-jejunostomy 4 weeks later with good results. CONCLUSIONS: Management of choledochal cysts during pregnancy is related to the presence of cholangitis. When they do not respond to medical treatment, decompression of the biliary tree is indicated. Definitive treatment should be performed after resolution of the pregnancy. PMID- 26477377 TI - N270 sensitivity to conflict strength and working memory: A combined ERP and sLORETA study. AB - The event-related potential N270 component is known to be an electrophysiological marker of the supramodal conflict processing. However little is know about the factors that may modulate its amplitude. In particular, among all studies that have investigated the N270, little or no control of the conflict strength and of the load in working memory have been done leaving a lack in the understanding of this component. We designed a spatial audiovisual conflict task with simultaneous target and cross-modal distractor to evaluate the N270 sensitivity to the conflict strength (i.e., visual target with auditory distractor or auditory target with visual distractor) and the load in working memory (goal task maintenance with frequent change in the target modality). In a first session, participants had to focus on one modality for the target position to be considered (left-hand or right-hand) while the distractor could be at the same side (compatible) or at opposite side (incompatible). In a second session, we used the same set of stimuli as in the first session with an additional distinct auditory signal that clued the participants to frequently switch between the auditory and the visual targets. We found that (1) reaction times and N270 amplitudes for conflicting situations were larger within the auditory target condition compared to the visual one, (2) the increase in target maintenance effort led to equivalent increase of both reaction times and N270 amplitudes within all conditions and (3) the right dorsolateral prefrontal cortex current density was higher for both conflicting and active maintenance of the target situations. These results provide new evidence that the N270 component is an electrophysiological marker of the supramodal conflict processing that is sensitive to the conflict strength and that conflict processing and active maintenance of the task goal are two functions of a common executive attention system. PMID- 26477379 TI - The influence of assumptions on generation time distributions in epidemic models. AB - A simple class of stochastic models for epidemic spread in finite, but large, populations is studied. The purpose is to investigate how assumptions about the times between primary and secondary infections influences the outcome of the epidemic. Of particular interest is how assumptions of individual variability in infectiousness relates to variability of the epidemic curve. The main concern is the final size of the epidemic and the time scale at which it evolves. The theoretical results are illustrated by simulations. PMID- 26477378 TI - The neural substrates for the rewarding and dopamine-releasing effects of medial forebrain bundle stimulation have partially discrepant frequency responses. AB - Midbrain dopamine neurons have long been implicated in the rewarding effect produced by electrical brain stimulation of the medial forebrain bundle (MFB). These neurons are excited trans-synaptically, but their precise role in intracranial self-stimulation (ICSS) has yet to be determined. This study assessed the hypothesis that midbrain dopamine neurons are in series with the directly stimulated substrate for self-stimulation of the MFB and either perform spatio-temporal integration of synaptic input from directly activated MFB fibers or relay the results of such integration to efferent stages of the reward circuitry. Psychometric current-frequency trade-off functions were derived from ICSS performance, and chemometric trade-off functions were derived from stimulation-induced dopamine transients in the nucleus accumbens (NAc) shell, measured by means of fast-scan cyclic voltammetry. Whereas the psychometric functions decline monotonically over a broad range of pulse frequencies and level off only at high frequencies, the chemometric functions obtained with the same rats and electrodes are either U-shaped or level off at lower pulse frequencies. This discrepancy was observed when the dopamine transients were recorded in either anesthetized or awake subjects. The lack of correspondence between the psychometric and chemometric functions is inconsistent with the hypothesis that dopamine neurons projecting to the NAc shell constitute an entire series stage of the neural circuit subserving self-stimulation of the MFB. PMID- 26477376 TI - Cross-activation and detraining effects of tongue exercise in aged rats. AB - Voice and swallowing deficits can occur with aging. Tongue exercise paired with a swallow may be used to treat swallowing disorders, but may also benefit vocal function due to cross-system activation effects. It is unknown how exercise-based neuroplasticity contributes to behavior and maintenance following treatment. Eighty rats were used to examine behavioral parameters and changes in neurotrophins after tongue exercise paired with a swallow. Tongue forces and ultrasonic vocalizations were recorded before and after training/detraining in young and old rats. Tissue was analyzed for neurotrophin content. Results showed tongue exercise paired with a swallow was associated with increased tongue forces at all ages. Gains diminished after detraining in old rats. Age-related changes in vocalizations, neurotrophin 4 (NT4), and brain derived neurotrophic factor (BDNF) were found. Minimal cross-system activation effects were observed. Neuroplastic benefits were demonstrated with exercise in old rats through behavioral improvements and up-regulation of BDNF in the hypoglossal nucleus. Tongue exercise paired with a swallow should be developed, studied, and optimized in human clinical research to treat swallowing and voice disorders in elderly people. PMID- 26477380 TI - Malony-CoA inhibits the S113L variant of carnitine-palmitoyltransferase II. AB - Carnitine palmitoyltransferases (CPT), located both in the outer (CPT I) and inner membrane (CPT II) of mitochondria, are the key players for an efficient transport of long chain fatty acids into this cell compartment. The metabolite malonyl-CoA is known to inhibit CPT I, but not CPT II. His6-N-hCPT2 (wild type) and His6-N-hCPT2/ S113L (variant) were produced recombinantly in prokaryotic host, purified and characterized according to their functional and regulatory properties. The wild type and the variant showed the same enzymatic activity and were both inhibited by malonyl-CoA and malonate in a time-dependent manner. The inhibition was, however, significantly more pronounced in the mutated enzyme. The residual activities were 40% and 5% at temperatures of 4 degrees C and 30 degrees C, respectively. The inhibitory effect proceeded irreversibly with no recovery after postincubation of palmitoyl-CoA (Pal-CoA) as native substrate. A model of malonyl-CoA and malonate binding to human CPT II was suggested by docking studies to explain the action of the inhibitors regarding to the effect of the mutation on the protein conformation. Results indicated that not only CPT I, but also CPT II can be inhibited by malonyl-CoA. Thus, the complete inhibition of total CPT (i.e. CPT I and CPT II) in muscle homogenates by an established assay is not due to a lack of enzymatically active CPT II, but rather due to an abnormal regulation of the enzyme. PMID- 26477381 TI - N-3PUFA differentially modulate palmitate-induced lipotoxicity through alterations of its metabolism in C2C12 muscle cells. AB - Excessive energy intake leads to fat overload and the formation of lipotoxic compounds mainly derived from the saturated fatty acid palmitate (PAL), thus promoting insulin resistance (IR) in skeletal muscle. N-3 polyunsaturated fatty acids (n-3PUFA) may prevent lipotoxicity and IR. The purpose of this study was to examine the differential effects of n-3PUFA on fatty acid metabolism and insulin sensitivity in muscle cells. C2C12 myotubes were treated with 500 MUM of PAL without or with 50 MUM of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) for 16 h. PAL decreased insulin-dependent AKT activation and glucose uptake and increased the synthesis of ceramides and diglycerides (DG) derivatives, leading to protein kinase Ctheta activation. EPA and DHA, but not ALA, prevented PAL-decreased AKT activation but glucose uptake was restored to control values by all n-3PUFA vs. PAL. Total DG and ceramide contents were decreased by all n-3PUFA, but only EPA and DHA increased PAL beta oxidation, decreased PAL incorporation into DG and reduced protein kinase Ctheta activation. EPA and DHA emerge as better candidates than ALA to improve fatty acid metabolism in skeletal muscle cells, notably via their ability to increase mitochondrial beta-oxidation. PMID- 26477382 TI - Ceramide signaling targets the PP2A-like protein phosphatase Sit4p to impair vacuolar function, vesicular trafficking and autophagy in Isc1p deficient cells. AB - The vacuoles play important roles in cellular homeostasis and their functions include the digestion of cytoplasmic material and organelles derived from autophagy. Conserved nutrient signaling pathways regulate vacuolar function and autophagy, ensuring normal cell and organismal development and aging. Recent evidence implicates sphingolipids in the modulation of these processes, but the impact of ceramide signaling on vacuolar dynamics and autophagy remains largely unknown. Here, we show that yeast cells lacking Isc1p, an orthologue of mammalian neutral sphingomyelinase type 2, exhibit vacuolar fragmentation and dysfunctions, namely decreased Pep4p-mediated proteolysis and V-ATPase activity, which impairs vacuolar acidification. Moreover, these phenotypes are suppressed by downregulation of the ceramide-activated protein phosphatase Sit4p. The isc1Delta cells also exhibit defective Cvt and vesicular trafficking in a Sit4p-dependent manner, ultimately contributing to a reduced autophagic flux. Importantly, these phenotypes are also suppressed by downregulation of the nutrient signaling kinase TORC1, which is known to inhibit Sit4p and autophagy, or Sch9p. These results support a model in which Sit4p functions downstream of Isc1p in a TORC1 independent, ceramide-dependent signaling branch that impairs vacuolar function and vesicular trafficking, leading to autophagic defects in yeast. PMID- 26477384 TI - Long term effect of telmisartan in HIV-positive male patients with high blood pressure. PMID- 26477385 TI - Impaired bone mineral accrual in prepubertal HIV-infected children: a cohort study. AB - OBJECTIVE: To evaluate bone mass accrual and determine the influence of clinical, anthropometric, dietary and biochemical parameters on bone mass. METHODS: A cohort study including 35 prepubertal HIV-infected children, between 7 and 12 years, attended at a referral center. At time 1 (T1) and time 2 (T2), patients were assessed according to clinical, anthropometric, dietary, biochemical parameters and bone mineral density (BMD). At T2, patients were divided into prepubertal and pubertal. RESULTS: Despite the increase in bone mass absolute values, there was no improvement in lumbar spine BMD (LSBMD) Z-score (p=0.512) and worsening in total body BMD (TBMD) Z-score (p=0.040). Pubertal patients (n=19) showed higher bone mineral content (BMC) (p=0.001), TBMD (p=0.006) and LSBMD (p=0.002) compared to prepubertal patients. After multivariate linear regression analysis, the predictors of bone mass in T1 were age, BMI and HA Z scores for BMC; BMI Z-score, adequate serum magnesium concentration and dietary calcium intake for TBMD; adequate serum concentration of magnesium, BMI and HA Z scores for LSBMD. In T2, age, total body fat and lean body mass (kg) for BMC; BMI Z-score and puberty for TBMD; dietary fat intake, BMI Z-score for BMD and puberty for LSBMD. CONCLUSION: HIV-infected children have compromised bone mass and the presence of puberty seems to provide suitability of these parameters. Adequate intake of calcium and fat appears to be protective for proper bone mass accumulation factor, as well as monitoring nutritional status and serum magnesium concentration. PMID- 26477383 TI - Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity. AB - The generation of reactive metabolites from therapeutic agents is one of the major mechanisms of drug-induced liver injury (DILI). In order to evaluate metabolism-related toxicity and improve drug efficacy and safety, we generated a battery of HepG2-derived cell lines that express 14 cytochrome P450s (CYPs) (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5 and 3A7) individually using a lentiviral expression system. The expression/production of a specific CYP in each cell line was confirmed by an increased abundance of the CYP at both mRNA and protein levels. Moreover, the enzymatic activities of representative CYPs in the corresponding cell lines were also measured. Using our CYP-expressed HepG2 cells, the toxicity of three drugs that could induce DILI (amiodarone, chlorpromazine and primaquine) was assessed, and all of them showed altered (increased or decreased) toxicity compared to the toxicity in drug treated wild-type HepG2 cells. CYP-mediated drug toxicity examined in our cell system is consistent with previous reports, demonstrating the potential of these cells for assessing metabolism-related drug toxicity. This cell system provides a practical in vitro approach for drug metabolism screening and for early detection of drug toxicity. It is also a surrogate enzyme source for the enzymatic characterization of a particular CYP that contributes to drug-induced liver toxicity. PMID- 26477387 TI - Cyanidin 3-glucoside improves diet-induced metabolic syndrome in rats. AB - Increased consumption of dark-coloured fruits and vegetables may mitigate metabolic syndrome. This study has determined the changes in metabolic parameters, and in cardiovascular and liver structure and function, following chronic administration of either cyanidin 3-glucoside (CG) or Queen Garnet plum juice (QG) containing cyanidin glycosides to rats fed either a corn starch (C) or a high-carbohydrate, high-fat (H) diet. Eight to nine-week-old male Wistar rats were randomly divided into six groups for 16-week feeding with C, C with CG or QG, H or H with CG or QG. C or H were supplemented with CG or QG at a dose of ~ 8 mg/kg/day cyanidin glycosides from week 8 to 16. H rats developed signs of metabolic syndrome including visceral adiposity, impaired glucose tolerance, hypertension, cardiovascular remodelling, increased collagen deposition in left ventricle, non-alcoholic fatty liver disease, increased plasma liver enzymes and increased inflammatory cell infiltration in the heart and liver. Both CG and QG reversed these cardiovascular, liver and metabolic signs. However, no intact anthocyanins or common methylated/conjugated metabolites could be detected in the plasma samples and plasma hippuric acid concentrations were unchanged. Our results suggest CG is the most likely mediator of the responses to QG but that further investigation of the pharmacokinetics of oral CG in rats is required. PMID- 26477388 TI - A novel proteomics sample preparation method for secretome analysis of Hypocrea jecorina growing on insoluble substrates. AB - Analysis of the secretomes of filamentous fungi growing on insoluble lignocellulosic substrates is of major current interest because of the industrial potential of secreted fungal enzymes. Importantly, such studies can help identifying key enzymes from a large arsenal of bioinformatically detected candidates in fungal genomes. We describe a simple, plate-based method to analyze the secretome of Hypocrea jecorina growing on insoluble substrates that allows harsh sample preparation methods promoting desorption, and subsequent identification, of substrate-bound proteins, while minimizing contamination with non-secreted proteins from leaking or lysed cells. The validity of the method was demonstrated by comparative secretome analysis of wild-type H.jecorina strain QM6a growing on bagasse, birch wood, spruce wood or pure cellulose, using label fee quantification. The proteomic data thus obtained were consistent with existing data from transcriptomics and proteomics studies and revealed clear differences in the responses to complex lignocellulosic substrates and the response to pure cellulose. This easy method is likely to be generally applicable to filamentous fungi and to other microorganisms growing on insoluble substrates. PMID- 26477389 TI - Comparative proteome analysis of rubber latex serum from pathogenic fungi tolerant and susceptible rubber tree (Hevea brasiliensis). AB - Many cultivated rubber trees (Hevea brasiliensis) are invaded by various Phytophthora species fungi, especially in tropical regions which result in crop yield losses. Comparative proteome analysis coupled with liquid chromatography electrospray/ionization (LC-ESI) mass spectrometry identification was employed to investigate the relative abundance of defense related proteins in Phytophthora sp. susceptible (RRIM600) and tolerant (BPM24) clones of rubber tree. Proteome maps of non-rubber constituent of these two model clones show similar protein counts, although some proteins show significant alterations in their abundance. Most of the differentially abundant proteins found in the serum of BPM24 illustrate the accumulation of defense related proteins that participate in plant defense mechanisms such as beta-1,3-glucanase, chitinase, and lectin. SDS-PAGE and 2-D Western blot analysis showed greater level of accumulation of beta-1,3 glucanase and chitinase in latex serum of BPM24 when compared to RRIM600. A functional study of these two enzymes showed that BPM24 serum had greater beta 1,3-glucanase and chitinase activities than that of RRIM600. These up-regulated proteins are constitutively expressed and would serve to protect the rubber tree BPM24 from any fungal invader. The information obtained from this work is valuable for understanding of defense mechanisms and plantation improvement of H. brasiliensis. BIOLOGICAL SIGNIFICANCE: Non-rubber constituents (latex serum) have almost no value and are treated as waste in the rubber agricultural industry. However, the serum of natural rubber latex contains biochemical substances. The comparative proteomics analysis of latex serum between tolerant and susceptible clones reveals that the tolerant BPM24 clone contained a high abundance of several classes of fungal pathogen-responsive proteins, such as glucanase and chitinase. Moreover, other proteins identified highlighted the accumulation of defensive-associated proteins participating in plant fungal immunity. The isolation of beta-1,3-glucanase, chitinase, and lectin from latex serum should be further investigated and may provide a therapeutic application. This investigation will lead to possible use of latex serum as a great biotechnological resource due to the large quantity of serum produced and the biochemicals contained therein. PMID- 26477390 TI - Purely organic electroluminescent material realizing 100% conversion from electricity to light. AB - Efficient organic light-emitting diodes have been developed using emitters containing rare metals, such as platinum and iridium complexes. However, there is an urgent need to develop emitters composed of more abundant materials. Here we show a thermally activated delayed fluorescence material for organic light emitting diodes, which realizes both approximately 100% photoluminescence quantum yield and approximately 100% up-conversion of the triplet to singlet excited state. The material contains electron-donating diphenylaminocarbazole and electron-accepting triphenyltriazine moieties. The typical trade-off between effective emission and triplet-to-singlet up-conversion is overcome by fine tuning the highest occupied molecular orbital and lowest unoccupied molecular orbital distributions. The nearly zero singlet-triplet energy gap, smaller than the thermal energy at room temperature, results in an organic light-emitting diode with external quantum efficiency of 29.6%. An external quantum efficiency of 41.5% is obtained when using an out-coupling sheet. The external quantum efficiency is 30.7% even at a high luminance of 3,000 cd m(-2). PMID- 26477391 TI - A new method for achieving enhanced dielectric response over a wide temperature range. AB - We report a novel approach for achieving high dielectric response over a wide temperature range. In this approach, multilayer ceramic heterostructures with constituent compositions having strategically tuned Curie points (T(C)) were designed and integrated with varying electrical connectivity. Interestingly, these multilayer structures exhibited different dielectric behavior in series and parallel configuration due to variations in electrical boundary conditions resulting in the differences in the strength of the electrostatic coupling. The results are explained using nonlinear thermodynamic model taking into account electrostatic interlayer interaction. We believe that present work will have huge significance in design of high performance ceramic capacitors. PMID- 26477392 TI - The Impact of Environmental Fluctuations on Evolutionary Fitness Functions. AB - The concept of fitness as a measure for a species' success in natural selection is central to the theory of evolution. We here investigate how reproduction rates which are not constant but vary in response to environmental fluctuations, influence a species' prosperity and thereby its fitness. Interestingly, we find that not only larger growth rates but also reduced sensitivities to environmental changes substantially increase the fitness. Thereby, depending on the noise level of the environment, it might be an evolutionary successful strategy to minimize this sensitivity rather than to optimize the reproduction speed. Also for neutral evolution, where species with exactly the same properties compete, variability in the growth rates plays a crucial role. The time for one species to fixate is strongly reduced in the presence of environmental noise. Hence, environmental fluctuations constitute a possible explanation for effective population sizes inferred from genetic data that often are much smaller than the census population size. PMID- 26477394 TI - Domain control of carrier density at a semiconductor-ferroelectric interface. AB - Control of charge carrier distribution in a gated channel via a dielectric layer is currently the state of the art in the design of integrated circuits such as field effect transistors. Replacing linear dielectrics with ferroelectrics would ultimately lead to more energy efficient devices as well as the added advantage of the memory function of the gate. Here, we report that the channel-off/channel on states in a metal/ferroelectric/semiconductor stack are actually transitions from a multi domain state to a single domain state of the ferroelectric under bias. In our approach, there is no a priori assumption on the single or multi domain nature of the ferroelectric layer that is often neglected in works discussing the ferroelectric-gate effect on channel conductivity interfacing a ferroelectric. We also predict that semiconductor/ferroelectric/semiconductor stacks can function at even lower gate voltages than metal/ferroelectric/semiconductor stacks when an n-type semiconductor is placed between the ferroelectric and the gate metal. Our results suggest the ultimate stability of the multidomain state whenever it interfaces a semiconductor electrode and that a switchable single domain state may not be necessary to achieve effective control of conductivity in a p-type channel. Finally, we discuss some experimental results in the literature in light of our findings. PMID- 26477393 TI - Impact Of Environmental Variation On Host Performance Differs With Pathogen Identity: Implications For Host-Pathogen Interactions In A Changing Climate. AB - Specialist and generalist pathogens may exert different costs on their hosts; thereby altering the way hosts cope with environmental variation. We examined how pathogen-challenge alters the environmental conditions that maximize host performance by simultaneously varying temperature and nutrition (protein to carbohydrate ratio; P:C) after exposure to two baculoviruses; one that is specific to the cabbage looper, Trichoplusia ni (TnSNPV) and another that has a broad host range (AcMNPV). Virus-challenged larvae performed better on more protein-biased diets, primarily due to higher survival, whereas unchallenged larvae performed best on a balanced diet. The environmental conditions that maximized host performance differed with virus identity because TnSNPV-challenge inflicted fitness costs (reduced pupal weight and prolonged development) whereas AcMNPV-challenge did not. The performance of TnSNPV-challenged larvae rose with increasing P:C across all temperatures, whereas temperature modulated the optimal P:C in AcMNPV-challenged larvae (slightly protein-biased at 16 degrees C to increasingly higher P:C as temperature increased). Increasing temperature reduced pupal size, but only at more balanced P:C ratios, indicating that nutrition moderates the temperature-size rule. Our findings highlight the complex environmental interactions that can alter host performance after exposure to pathogens, which could impact the role of entomopathogens as regulators of insect populations in a changing climate. PMID- 26477395 TI - Effectiveness of an (18)F-FDG-PET based strategy to optimize the diagnostic trajectory of suspected recurrent laryngeal carcinoma after radiotherapy: The RELAPS multicenter randomized trial. AB - PURPOSE: The purpose of this study is to evaluate the efficacy of (18)F-FDG-PET as first-line diagnostic investigation, prior to performing a direct laryngoscopy with biopsy under general anesthesia, in patients suspected of recurrent laryngeal carcinoma after radiotherapy. PATIENTS AND METHODS: 150 patients suspected of recurrent T2-4 laryngeal carcinoma at least two months after prior (chemo)radiotherapy with curative intent for resectable disease were randomized to direct laryngoscopy (CWU: conventional workup strategy) or to (18)F-FDG-PET only followed by direct laryngoscopy if PET was assessed 'positive' or 'equivocal' (PWU: PET based workup strategy), to compare the effectiveness of these strategies. Primary endpoint was the number of indications for direct laryngoscopies classified as unnecessary based on absence of recurrence, both on direct laryngoscopy and on six month follow up. Safety endpoints comprised resectability of recurrent lesions and completeness of surgical margins following salvage laryngectomy. RESULTS: Intention-to-treat analyses were performed on all randomized patients (CWU: n=74, PWU: n=76). Tumor recurrence was similar in both groups: 45 patients (30%; 21 CWU, 24 PWU) within six months. In 53 patients in the CWU arm (72%, 95% CI: 60-81) unnecessary direct laryngoscopies were performed compared to 22 in the PWU arm (29%, 95% CI: 19-40) (p<0.0001). The percentage of salvage laryngectomies (resectability) and positive surgical margins were similar between CWU and PWU (81%, 63% respectively, p=0.17, and 29%, 7%, respectively, p=0.20). The prevalence of the combination of local unresectability and positive margins is in the CWU group 24% and in the PWU group 8%. No difference (p=0.32) in disease specific survival between both groups was found. CONCLUSION: In patients with suspected laryngeal carcinoma after radiotherapy, PET as the first diagnostic procedure can reduce the need for direct laryngoscopy by more than 50% without jeopardizing quality of treatment. PMID- 26477396 TI - Validation of the total dysphagia risk score (TDRS) in head and neck cancer patients in a conventional and a partially accelerated radiotherapy scheme. AB - BACKGROUND AND PURPOSE: A risk model, the total dysphagia risk score (TDRS), was developed to predict which patients are most at risk to develop grade ?2 dysphagia at 6 months following radiotherapy (RT) for head and neck cancer. The purpose of this study was to validate this model at 6 months and to investigate the power at earlier and later time-points. A second aim was to see if this model can be used in a partially accelerated RT regimen. MATERIALS AND METHODS: 164 patients from 3 different centres treated with RT between 2008 and 2014 were included in the current study. Both physician-scored dysphagia and QoL data were prospectively obtained. The TDRS of all patients was correlated with the physician-scored dysphagia and the QoL data. To validate this prediction model, we tested the validity in terms of calibration and discrimination. RESULTS: Partial acceleration had no influence on the TDRS. Regarding physician-scored dysphagia, there was a significant correlation with dysphagia grade ?2 at 1, 3, 6 and 9 months. The area-under-the-curve at 1 month was 0.85; at 3 months 0.80; at 6 months 0.85; at 9 months 0.86 and 0.79 at 12 months. Regarding QoL, TDRS correlates with PEG-tube usage at 6 and 12 months. CONCLUSION: We found significant correlations between TDRS and dysphagia grade ?2 and PEG-tube usage. PMID- 26477398 TI - Theoretical description of efficiency enhancement in DSSCs sensitized by newly synthesized heteroleptic Ru complexes. AB - Recently, some new series of heteroleptic ruthenium-based dyes, the so-called RD dyes, were designed and synthesized showing better performances compared to the well-known homoleptic N719. In this work, using the density-functional theory and its time-dependent extension, we have investigated the electronic structure and absorption spectra of these newly synthesized dyes, and compared the results to those of N3 dye to describe the variations of the properties due to the molecular engineering of the ancillary ligand. We have shown that the calculation results of the absorption spectra for these dyes using the PBE0 for the exchange correlation functional are in better agreement with the experiment than using B3LYP or range-separated CAM-B3LYP. We have also derived a formula based on the DFT and used it to visually describe the level shifts in a solvent. The higher Jsc observed in these new dyes is explained by the fact that here, in contrast to N3, the excitation charge was effectively transferred to the anchoring ligand. Furthermore, we have shown that the difference dipole moment vectors of the ground and excited states can be used to determine the charge-transfer direction in an excitation process. Finally, different electron lifetimes observed in these dyes are explained by investigating the adsorption geometries and the relative orientations of iodine molecules in different "dyeI2" complexes. PMID- 26477397 TI - Impaired climbing and flight behaviour in Drosophila melanogaster following carbon dioxide anaesthesia. AB - Laboratories that study Drosophila melanogaster or other insects commonly use carbon dioxide (CO2) anaesthesia for sorting or other work. Unfortunately, the use of CO2 has potential unwanted physiological effects, including altered respiratory and muscle physiology, which impact motor function behaviours. The effects of CO2 at different levels and exposure times were examined on the subsequent recovery of motor function as assessed by climbing and flight assays. With as little as a five minute exposure to 100% CO2, D. melanogaster exhibited climbing deficits up to 24 hours after exposure. Any exposure length over five minutes produced climbing deficits that lasted for days. Flight behaviour was also impaired following CO2 exposure. Overall, there was a positive correlation between CO2 exposure length and recovery time for both behaviours. Furthermore, exposure to as little as 65% CO2 affected the motor capability of D. melanogaster. These negative effects are due to both a CO2-specific mechanism and an anoxic effect. These results indicate a heretofore unconsidered impact of CO2 anaesthesia on subsequent behavioural tests revealing the importance of monitoring and accounting for CO2 exposure when performing physiological or behavioural studies in insects. PMID- 26477399 TI - Iridium-catalyzed enantioselective allylation of silyl enol ethers derived from ketones and alpha,beta-unsaturated ketones. AB - The unified Ir-catalyzed enantioselective allylic substitution reactions of silyl enol ethers derived from ketones and alpha,beta-unsaturated ketones with branched, racemic allylic alcohols are described. This transformation is catalyzed by the Carreira system and proceeds without fluoride, and with high ee and b : l ratio. The synthetic utility of this method was illustrated by the concise enantioselective total synthesis of marine natural products calyxolane A, B and by the assignment of the absolute configuration of calyxolane A. PMID- 26477400 TI - Advances in nanoscale alloys and intermetallics: low temperature solution chemistry synthesis and application in catalysis. AB - Based on the bottom-up chemistry techniques, the size, shape, and composition controlled synthesis of nanoparticles can now be achieved uniformly, which is of great importance to the nanoscience community as well as in modern catalysis research. The low-temperature solution-phase synthesis approach represents one of the most attractive strategies and has been utilized to synthesize nanoscale metals, alloys and intermetallics, including a number of new metastable phases. This perspective will highlight the solution-based nanoparticle synthesis techniques, a low-temperature platform, for the synthesis of size and shape tunable nanoscale transition metals, alloys, and intermetallics from the literature, keeping a focus on the utility of these nanomaterials in understanding the catalysis. For each solution-based nanoparticle synthesis technique, a comprehensive overview has been given for the reported nanoscale metals, alloys, and intermetallics, followed by critical comments. Finally, their enhanced catalytic activity and durability as novel catalysts have been discussed towards several hydrogenation/dehydrogenation reactions and also for different inorganic to organic reactions. Hence, the captivating advantages of this controllable low-temperature solution chemistry approach have several important implications and together with them this approach provides a promising route to the development of next-generation nanostructured metals, alloys, and intermetallics since they possess fascinating properties as well as outstanding catalytic activity. PMID- 26477401 TI - Theoretical prediction of silicene as a new candidate for the anode of lithium ion batteries. AB - Using density functional theory calculations, we determine the band structure and DOS of graphene and silicene supercell models. We also study the adsorption mechanism of Li metal atoms and Li-ions onto free-standing silicene (buckled, theta = 101.7 degrees ) and compare the results with those of graphene. In contrast to graphene, interactions between Li metal atoms and Li-ions with the silicene surface are quite strong due to its highly reactive buckled hexagonal structure. As a consequence of structural properties the adsorption height, the most stable adsorption site and energy barrier against Li diffusion are also discussed here to outline the prospects of using silicene in electronic devices such as Li ion batteries (LiBs), hydrogen storage and molecular machines. However, in most LiBs, graphene layers are used as anode electrodes. Here, it is shown that graphene has very limited Li storage capacity and low surface area than silicene. As our models are in good agreement with previous predictions, this finding presents a possible avenue for creating better anode materials that can replace graphene for higher capacity and better cycling performance of LiBs. PMID- 26477402 TI - Radionuclide (131)I-labeled multifunctional dendrimers for targeted SPECT imaging and radiotherapy of tumors. AB - We report the synthesis, characterization, and utilization of radioactive (131)I labeled multifunctional dendrimers for targeted single-photon emission computed tomography (SPECT) imaging and radiotherapy of tumors. In this study, amine terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) were sequentially modified with 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO) and folic acid (FA) linked with polyethylene glycol (PEG), followed by acetylation modification of the dendrimer remaining surface amines and labeling of radioactive iodine-131 ((131)I). The generated multifunctional (131)I-G5.NHAc-HPAO-PEG-FA dendrimers were characterized via different methods. We show that prior to (131)I labeling, the G5.NHAc-HPAO-PEG-FA dendrimers conjugated with approximately 9.4 HPAO moieties per dendrimer are noncytotoxic at a concentration up to 20 MUM and are able to target cancer cells overexpressing FA receptors (FAR), thanks to the modified FA ligands. In the presence of a phenol group, radioactive (131)I is able to be efficiently labeled onto the dendrimer platform with good stability and high radiochemical purity, and render the platform with an ability for targeted SPECT imaging and radiotherapy of an FAR-overexpressing xenografted tumor model in vivo. The designed strategy to use the facile dendrimer nanotechnology may be extended to develop various radioactive theranostic nanoplatforms for targeted SPECT imaging and radiotherapy of different types of cancer. PMID- 26477403 TI - Viscoelastic polymer flows and elastic turbulence in three-dimensional porous structures. AB - Viscoelastic polymer solutions flowing through reservoir rocks have been found to improve oil displacement efficiency when the aqueous-phase shear-rate exceeds a critical value. A possible mechanism for this enhanced recovery is elastic turbulence that causes breakup and mobilization of trapped oil ganglia. Here, we apply nuclear magnetic resonance (NMR) pulsed field gradient (PFG) diffusion measurements in a novel way to detect increased motion of disconnected oil ganglia. The data are acquired directly from a three-dimensional (3D) opaque porous structure (sandstone) when viscoelastic fluctuations are expected to be present in the continuous phase. The measured increase in motion of trapped ganglia provides unequivocal evidence of fluctuations in the flowing phase in a fully complex 3D system. This work provides direct evidence of elastic turbulence in a realistic reservoir rock - a measurement that cannot be readily achieved by conventional laboratory methods. We support the NMR data with optical microscopy studies of fluctuating ganglia in simple two-dimensional (2D) microfluidic networks, with consistent apparent rheological behaviour of the aqueous phase, to provide conclusive evidence of elastic turbulence in the 3D structure and hence validate the proposed flow-fluctuation mechanism for enhanced oil recovery. PMID- 26477405 TI - Mechanical testing of internal fixation devices: A theoretical and practical examination of current methods. AB - Successful healing of long bone fractures is dependent on the mechanical environment created within the fracture, which in turn is dependent on the fixation strategy. Recent literature reports have suggested that locked plating devices are too stiff to reliably promote healing. However, in vitro testing of these devices has been inconsistent in both method of constraint and reported outcomes, making comparisons between studies and the assessment of construct stiffness problematic. Each of the methods previously used in the literature were assessed for their effect on the bending of the sample and concordant stiffness. The choice of outcome measures used in in vitro fracture studies was also assessed. Mechanical testing was conducted on seven hole locked plated constructs in each method for comparison. Based on the assessment of each method the use of spherical bearings, ball joints or similar is suggested at both ends of the sample. The use of near and far cortex movement was found to be more comprehensive and more accurate than traditional centrally calculated interfragmentary movement values; stiffness was found to be highly susceptible to the accuracy of deformation measurements and constraint method, and should only be used as a within study comparison method. The reported stiffness values of locked plate constructs from in vitro mechanical testing is highly susceptible to testing constraints and output measures, with many standard techniques overestimating the stiffness of the construct. This raises the need for further investigation into the actual mechanical behaviour within the fracture gap of these devices. PMID- 26477404 TI - Microvesicles released from tumor cells disrupt epithelial cell morphology and contractility. AB - During tumor progression, cancer cells interact and communicate with non malignant cells within their local microenvironment. Microvesicles (MV) derived from human cancer cells play an important role in mediating this communication. Another critical aspect of cancer progression involves widespread ECM remodeling, which occur both at the primary and metastatic sites. ECM remodeling and reorganization within the tumor microenvironment is generally attributed to fibroblasts. Here, using MCF10a cells, a well-characterized breast epithelial cell line that exhibits a non-malignant epithelial phenotype, and MVs shed by aggressive MDA-MB-231 carcinoma cells, we show that non-malignant epithelial cells can participate in ECM reorganization of 3D collagen matrices following their treatment with cancer cell-derived MVs. In addition, MVs trigger several changes in epithelial cells under 3D culture conditions. Furthermore, we show that this ECM reorganization is associated with an increase in cellular traction force following MV treatment, higher acto-myosin contractility, and higher FAK activity. Overall, our findings suggest that MVs derived from tumor cells can contribute to ECM reorganization occurring within the tumor microenvironment by enhancing the contractility of non-malignant epithelial cells. PMID- 26477406 TI - Estimation of local anisotropy of plexiform bone: Comparison between depth sensing micro-indentation and Reference Point Indentation. AB - The recently developed Reference Point Indentation (RPI) allows the measurements of bone properties at the tissue level in vivo. The goal of this study was to compare the local anisotropic behaviour of bovine plexiform bone measured with depth sensing micro-indentation tests and with RPI. Fifteen plexiform bone specimens were extracted from a bovine femur and polished down to 0.05um alumina paste for indentations along the axial, radial and circumferential directions (N=5 per group). Twenty-four micro-indentations (2.5um in depth, 10% of them were excluded for testing problems) and four RPI-indentations (~50um in depth) were performed on each sample. The local indentation modulus Eind was found to be highest for the axial direction (24.3+/-2.5GPa) compared to the one for the circumferential indentations (19% less stiff) and for the radial direction (30% less stiff). RPI measurements were also found to be dependent on indentation direction (p<0.001) with the exception of the Indentation Distance Increase (IDI) (p=0.173). In particular, the unloading slope US1 followed similar trends compared to the Eind: 0.47+/-0.03N/um for axial, 11% lower for circumferential and 17% lower for radial. Significant correlations were found between US1 and Eind (p=0.001; R(2)=0.58), while no significant relationship was found between IDI and any of the micro-indentation measurements (p>0.157). In conclusion some of the RPI measurements can provide information about local anisotropy but IDI cannot. Moreover, there is a linear relationship between most local mechanical properties measured with RPI and with micro-indentations, but IDI does not correlate with any micro-indentation measurements. PMID- 26477407 TI - Effects of lower-limb muscular fatigue on stair gait. AB - The objective of the present study was to determine the effects of lower-limb muscular fatigue on stair gait. Twelve healthy young male adults between 20 and 30 years old participated in the experiment. There were two experimental sessions corresponding to a no fatigue condition and a lower-limb muscular fatigue condition, respectively. Lower-limb muscular fatigue was induced using repetitive lower-limb pushing exertions. Both ascent and descent were studied. Stair gait was assessed by lower-limb joints and trunk kinematics, and postural stability measures. It was found that lower-limb muscular fatigue compromised stair gait during descent, but did not make any difference during ascent. These findings highlighted the importance of minimizing exposures to lower-limb muscular fatigue during descent in stair accident prevention. PMID- 26477408 TI - Microfluidic deformability analysis of the red cell storage lesion. AB - A key challenge in transfusion medicine research and clinical hematology is to develop a simple and non-destructive method to measure the quality of each blood unit prior to use. RBC deformability has long been proposed as an indicator of blood quality. We measured RBC deformability using the pressure required for single cells to transit through a micrometer scale constriction to examine longitudinal changes in RBC deformability, as well as the variability in blood quality and storage capacity across donors. We used a microfluidic device to monitor deformability changes in RBCs stored in plastic tubes and in blood bags over 14 and 56 days respectively. We found consistent storage based degradation of RBC deformability with statistically significant variability in both the initial RBC deformability and storage capacity among donors. Furthermore, all samples exhibited a transient recovery phenomenon. Deformability profiling of stored RBCs using transiting pressure showed significant donor variability in initial quality and storage capacity. This measurement approach shows promise as a rapid method to individually assess the quality of stored RBC units. PMID- 26477409 TI - Effects of external helmet accessories on biomechanical measures of head injury risk: An ATD study using the HYBRIDIII headform. AB - Competitive cycling is a popular activity in North America for which injuries to the head account for the majority of hospitalizations and fatalities. In cycling, use of helmet accessories (e.g. cameras) has become widespread. As a consequence, standards organizations and the popular media are discussing the role these accessories could play in altering helmet efficacy and head injury risk. We conducted impacts to a helmeted anthropomorphic headform, with and without camera accessories, at speeds of 4m/s and 6m/s, and measured head accelerations, forces on the head-form skull, and used the Simulated Injury Monitor to estimate brain tissue strain. The presence of the camera reduced peak linear head acceleration (51% - 4m/s impacts, 61% - 6m/s, p<0.05). Skull fracture risk based on kinematics was always less than 1%. For 4m/s impacts, peak angular accelerations were lower (47%, p<0.05), as were peak angular velocities (14%) with the velocity effect approaching significance (p=0.06), with the camera accessory. For 6m/s impacts, accelerations were on average higher (5%, p>0.05) as were velocities (77%, p<0.05). Skull forces were never greater than 443.2N, well below forces associated with fracture. Brain tissue strain, the cumulative strain damage measure at 25% (CSDM-25), was lower (56%, p<0.05) in 4m/s but higher (125%, p>0.05) in 6m/s impacts with the camera accessory. Based on CSDM-25 for 4m/s tests, the risk of severe concussion was reduced (p<0.05) from 25% (no camera) to 7% (camera). For 6m/s tests, risks were on average increased (p>0.05) from 18% (no camera) to 58% (camera). PMID- 26477414 TI - European Resuscitation Council Guidelines for Resuscitation 2015: Section 6. Paediatric life support. PMID- 26477410 TI - European Resuscitation Council Guidelines for Resuscitation 2015: Section 1. Executive summary. PMID- 26477412 TI - European Resuscitation Council Guidelines for Resuscitation 2015: Section 4. Cardiac arrest in special circumstances. PMID- 26477415 TI - European Resuscitation Council Guidelines for Resuscitation 2015: Section 7. Resuscitation and support of transition of babies at birth. PMID- 26477416 TI - European Resuscitation Council Guidelines for Resuscitation 2015 Section 8. Initial management of acute coronary syndromes. PMID- 26477417 TI - European Resuscitation Council Guidelines for Resuscitation 2015 Section 9. First aid. PMID- 26477418 TI - European Resuscitation Council Guidelines for Resuscitation 2015: Section 10. Education and implementation of resuscitation. PMID- 26477419 TI - European Resuscitation Council Guidelines for Resuscitation 2015: Section 11. The ethics of resuscitation and end-of-life decisions. PMID- 26477420 TI - European Resuscitation Council Guidelines for Resuscitation 2015: Section 2. Adult basic life support and automated external defibrillation. PMID- 26477423 TI - Part 6: Pediatric basic life support and pediatric advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 26477424 TI - Part 7: Neonatal resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 26477426 TI - Part 9: First aid: 2015 International Consensus on First Aid Science with Treatment Recommendations. PMID- 26477427 TI - Part 2: Evidence evaluation and management of conflicts of interest: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 26477428 TI - Part 3: Adult basic life support and automated external defibrillation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 26477430 TI - Error in the editorial entitled "Frequency and number of resuscitation related rib and sternum fractures are higher than generally considered". PMID- 26477429 TI - Part 4: Advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 26477432 TI - Efficient Electrocatalytic Water Oxidation at Neutral and High pH by Adventitious Nickel at Nanomolar Concentrations. AB - Electrolytic water oxidation using earth-abundant elements is a key challenge in the quest to develop cheap, large surface area arrays for solar-to-hydrogen conversion. There have been numerous studies in this area in recent years, but there remains an imperative to demonstrate that the current densities reported are indeed due to the species under consideration and not due to the presence of adventitious (yet possibly highly active) contaminants at low levels. Herein, we show that adventitious nickel at concentrations as low as 17 nM can act as a water oxidation catalyst in mildly basic aqueous solutions, achieving stable (tens of hours) current densities of 1 mA cm(-2) at overpotentials as low as 540 mV at pH 9.2 and 400 mV at pH 13. This nickel was not added to the electrolysis baths deliberately, but it was found to be present in the electrolytes as an impurity by ICP-MS. The presence of nickel on anodes from extended-time bulk electrolysis experiments was confirmed by XPS. In showing that such low levels of nickel can perform water oxidation at overpotentials comparable to many recently reported water oxidation catalysts, this work serves to raise the burden of proof required of new materials in this field: contamination by adventitious metal ions at trace loadings must be excluded as a possible cause of any observed water oxidation activity. PMID- 26477433 TI - Protein/polysaccharide interactions and their impact on haze formation in white wines. AB - Proteins in white wines may aggregate and form hazes at room temperature. This was previously shown to be related to pH-induced conformational changes and to occur for pH <3.5. The aim of the present work was to study the impact of wine polysaccharides on pH-induced haze formation by proteins but also the consequences of their interactions with these proteins on the colloidal stability of white wines. To this end, model systems and purified global pools of wine proteins and polysaccharides were used first. Kinetics of aggregation, proteins involved, and turbidities related to final hazes were monitored. To further identify the impact of each polysaccharide, fractions purified to homogeneity were used in a second phase. These included two neutral (mannoprotein and arabinogalactan) and two negatively charged (rhamnogalacturonan II dimer (RG-II) and arabinogalactan) polysaccharides. The impact of major wine polysaccharides on wine protein aggregation at room temperature was clearly less marked than those of the pH and the ionic strength. Polysaccharides modulated the aggregation kinetics and final haziness, indicating that they interfere with the aggregation process, but could not prevent it. PMID- 26477434 TI - Studying Policy Changes in Disaster Management in India: A Tale of Two Cyclones. AB - OBJECTIVE: The mainstay of India's disaster management policy until the early 2000s had been relief and rescue operations. The Odisha Super Cyclone (1999) with 10,000 deaths and US $3 billion economic damage provided a rude awakening. Recognizing the importance of preemptive preparedness, the government initiated systematic steps to implement a national framework interlinking economic, environmental, and overall developmental issues for efficient response to and mitigation of disasters. METHODS: We attempted a critical analysis of this paradigm shift in India's disaster management policy through the prism of 2 cyclones, 14 years apart in time. RESULTS: With improved preparedness and response measures, the death toll in 2013 Cyclone Phailin was 0.5% and the economic loss was about one-third of that during 1999. Concomitant improvements in the technological expertise of the early warning system, an integrated approach at all levels of administration including joint planning with major nongovernmental organizations, and improved community participation were identified as game-changers. An unbelievable 1 million people were evacuated to safety. CONCLUSIONS: Our essay aims to highlight key steps in this success and calls for futuristic approaches like insurance programs and gender-sensitive recovery plans. With thorough scrutiny, India's model may well stand to be replicated in resource-restricted settings. PMID- 26477438 TI - Evidence for the introduction of the Asian red alga Neosiphonia japonica and its introgression with Neosiphonia harveyi (Ceramiales, Rhodophyta) in the Northwest Atlantic. AB - There is currently conflict in the literature on the taxonomic status of the reportedly cosmopolitan species Neosiphonia harveyi, a common red alga along the coast of Atlantic Canada and New England, USA. Neosiphonia harveyi sensu lato was assessed using three molecular markers: COI-5P, ITS and rbcL. All three markers clearly delimited three genetic species groups within N. harveyi sensu lato in this region, which we identified as N. harveyi, N. japonica and Polysiphonia akkeshiensis (here resurrected from synonymy with N. japonica). Although Neosiphonia harveyi is considered by some authors to be introduced to the Atlantic from the western Pacific, it was only confirmed from the North Atlantic suggesting it is native to this area. In contrast, Neosiphonia japonica was collected from only two sites in Rhode Island, USA, as well as from its reported native range in Asia (South Korea), which when combined with data in GenBank indicates that this species was introduced to the Northwest Atlantic. The GenBank data further indicate that N. japonica was also introduced to North Carolina, Spain, Australia and New Zealand. Despite the fact that all three markers clearly delimited N. harveyi and N. japonica as distinct genetic species groups, the ITS sequences for some N. harveyi individuals displayed mixed patterns and additivity indicating introgression of nuclear DNA from N. japonica into N. harveyi in the Northwest Atlantic. Introgression of DNA from an introduced species to a native species (i.e. 'genetic pollution') is one of the possible consequences of species introductions, and we believe this is the first documented evidence for this phenomenon in red algae. PMID- 26477441 TI - An Approach to Preparing Ni-P with Different Phases for Use as Supercapacitor Electrode Materials. AB - Herein, we describe a simple two-step approach to prepare nickel phosphide with different phases, such as Ni2 P and Ni5 P4 , to explain the influence of material microstructure and electrical conductivity on electrochemical performance. In this approach, we first prepared a Ni-P precursor through a ball milling process, then controlled the synthesis of either Ni2 P or Ni5 P4 by the annealing method. The as-prepared Ni2 P and Ni5 P4 are investigated as supercapacitor electrode materials for potential energy storage applications. The Ni2 P exhibits a high specific capacitance of 843.25 F g(-1) , whereas the specific capacitance of Ni5 P4 is 801.5 F g(-1) . Ni2 P possesses better cycle stability and rate capability than Ni5 P4 . In addition, the Fe2 O3 //Ni2 P supercapacitor displays a high energy density of 35.5 Wh kg(-1) at a power density of 400 W kg(-1) and long cycle stability with a specific capacitance retention rate of 96 % after 1000 cycles, whereas the Fe2 O3 //Ni5 P4 supercapacitor exhibits a high energy density of 29.8 Wh kg(-1) at a power density of 400 W kg(-1) and a specific capacitance retention rate of 86 % after 1000 cycles. PMID- 26477440 TI - Novel emergency department registration kiosk for HIV screening is cost effective. AB - High operating costs challenge sustainability of successful US emergency department (ED) HIV screening programs. Free-standing registration kiosks could potentially reduce the marginal costs of ED HIV screening. We investigated incremental cost-effectiveness ratio (CER) per new HIV diagnosis for a kiosk based approach for offering screening at ED registration versus a testing staff based approach to offer testing at the bedside. A rapid oral-fluid HIV screening program, instituted in a US ED since 2005, had a rate of new HIV diagnosis 0.16% in 2012. A two-phase quasi experimental design, including a testing staff-based approach to offer testing at the bedside (Phase I, August and September 2011) and a kiosk-based approach to offer testing at ED registration (Phase II, December 2011 and January 2012), was performed. CER per new HIV diagnosis was defined as total cost of the screening program divided by number of newly diagnosed cases. Costs included screening program personnel (study coordinator, testing staff, and kiosk helpers), diagnostic assays (rapid and confirmatory tests), and kiosks (2 kiosks, software, and IT consulting fees). Sensitivity analyses were performed. Data from our dedicated testing staff (DTS) program (Phase I) resulted in an estimated 5434 patients tested in one year and 9 newly diagnosed HIV-infected patients (95% CI: 3, 18). Data from the kiosk program (Phase II), resulted in a projected 4571 ED patients tested in one year and 21 newly diagnosed HIV-infected patients (95% CI: 4, 70). The overall cost was $ 201,433 for the DTS program, versus $292,008 for the kiosk program. Incremental CER per new HIV diagnosis for kiosk-based approach was $7523 (range: $1780-90,025 by sensitivity analysis). Our pilot data demonstrated that the use of kiosks for HIV screening was potentially more cost-effective than a testing staff-based bedside approach. PMID- 26477443 TI - NICE guidelines must reflect consensus and be up-to-date. PMID- 26477442 TI - Helicobacter Species Identified in Captive Sooty Mangabeys (Cercocebus atys) with Metastatic Gastric Adenocarcinoma. AB - BACKGROUND: Of all human cancers, gastric carcinoma is the one of the leading causes of death. Helicobacter pylori is considered a major etiologic agent of this disease. Spontaneously occurring gastric carcinoma is a rare diagnosis in nonhuman primates. A 2011 case report documented a high incidence of gastric adenocarcinoma in a closed colony of captive sooty mangabeys (Cercebus atys). However, H. pylori infection was not detected in these animals. MATERIALS AND METHODS: In this study, using archived formalin-fixed, paraffin-embedded stomach sections of these animals alternative methodologies were used to identify H. pylori and other non-H. pylori Helicobacter species. In addition, two additional cases of sooty mangabeys with metastatic gastric carcinoma are characterized. RESULTS: Using fluorescent in situ hybridization, we identified gastric H. suis in 75% of archived and new gastric carcinoma cases. In the two newly reported cases, H. suis and a novel Helicobacter species were detected via PCR and sequence analysis of the 16S rRNA gene. H. pylori was not identified in any of the gastric carcinoma cases via FISH and/or PCR and sequence analysis of Helicobacter spp. in DNA from of available tissues. CONCLUSIONS: This report is the first to characterize Helicobacter species infection in spontaneous gastric carcinoma with metastatic potential in nonhuman primates. PMID- 26477444 TI - Evaluating a tablet application and differential reinforcement to increase eye contact in children with autism. AB - We tested the effectiveness of a tablet application and differential reinforcement to increase eye contact in 3 children with autism. The application required the child to look at a picture of a person's face and identify the number displayed in the person's eyes. Eye contact was assessed immediately after training, 1 hr after training, and in a playroom. The tablet application was not effective; however, differential reinforcement was effective for all participants. PMID- 26477445 TI - Editorial Comment on "A Comparison of Sexual Health History and Practices among Monogamous and Consensually Nonmonogamous Sexual Partners"-Moving Ahead: Accepting (and Funding) Research That Critically Examines Monogamy. PMID- 26477446 TI - Does chronic raise of metal ion levels induce oxidative DNA damage and hypoxia like response in patients with metal-on-metal hip resurfacing? AB - Metal-on-metal hip resurfacing (MOM-HR) represents a viable alternative to traditional arthroplasty. Nevertheless, in MOM coupling both metal nanoparticles and ions are released, whose toxicity remains a matter of concern. We investigated whether 'endogenous' chronic exposure to cobalt and chromium induced a state of oxidative stress, DNA damage and a hypoxia-like response in patients with well-functioning MOM-HR. Twenty-two patients with unilateral MOM-HR were recruited at long-term. Twenty-one osteoarthritic subjects were enrolled for comparison. Serum ion levels were measured and correlated with 8 hydroxydeoxyguanosine and circulating-free-DNA, as markers of oxidative DNA damage. Moreover, the hypoxia-inducible factor-1alpha, marker of hypoxic state, was evaluated. Ion concentrations were found to be 5-to-15 times higher in MOM-HR patients than in presurgery subjects (p < 0.001); circulating-free-DNA, 8 hydroxydeoxyguanosine, and hypoxia-inducible factor-1alpha levels were not significantly different between groups and did not correlate with ion levels. Analyzing the results according to gender, MOM-HR males had higher 8 hydroxydeoxyguanosine levels (p = 0.01) compared with MOM-HR females. Similarly, circulating-free-DNA values were higher in males than females, even if this difference did not reach statistical significance. This research is the first that attempted to investigate the long-term effects of ion dissemination in subjects with well-fixed MOM implants. A significant correlation between biomarkers increase and ion levels was not demonstrated. Nevertheless, both circulating-free-DNA and 8-hydroxydeoxyguanosine showed a tendency to increase in MOM-HR males. Further studies with a larger sample size should be performed to detect the clinical relevance of biomarkers increase especially in younger subjects, where a chronic moderately elevated exposure has to be faced. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 460-466, 2017. PMID- 26477447 TI - Utility of texture analysis for quantifying hepatic fibrosis on proton density MRI. AB - PURPOSE: To evaluate the potential utility of texture analysis of proton density maps for quantifying hepatic fibrosis in a murine model of hepatic fibrosis. MATERIALS AND METHODS: Following Institutional Animal Care and Use Committee (IACUC) approval, a dietary model of hepatic fibrosis was used and 15 ex vivo murine liver tissues were examined. All images were acquired using a 30 mm bore 11.7T magnetic resonance imaging (MRI) scanner with a multiecho spin-echo sequence. A texture analysis was employed extracting multiple texture features including histogram-based, gray-level co-occurrence matrix-based (GLCM), gray level run-length-based features (GLRL), gray level gradient matrix (GLGM), and Laws' features. Texture features were correlated with histopathologic and digital image analysis of hepatic fibrosis. RESULTS: Histogram features demonstrated very weak to moderate correlations (r = -0.29 to 0.51) with hepatic fibrosis. GLCM features correlation and contrast demonstrated moderate-to-strong correlations (r = -0.71 and 0.59, respectively) with hepatic fibrosis. Moderate correlations were seen between hepatic fibrosis and the GLRL feature short run low gray-level emphasis (SRLGE) (r = -0. 51). GLGM features demonstrate very weak to weak correlations with hepatic fibrosis (r = -0.27 to 0.09). Moderate correlations were seen between hepatic fibrosis and Laws' features L6 and L7 (r = 0.58). CONCLUSION: This study demonstrates the utility of texture analysis applied to proton density MRI in a murine liver fibrosis model and validates the potential utility of texture-based features for the noninvasive, quantitative assessment of hepatic fibrosis. PMID- 26477449 TI - Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning. AB - Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning. PMID- 26477450 TI - Copper-Intercalated Birnessite as a Water Oxidation Catalyst. AB - We report a synthetic method to increase the catalytic activity of birnessite toward water oxidation by intercalating copper in the interlayer region of the layered manganese oxide. Intercalation of copper, verified by XRD, XPS, ICP, and Raman spectroscopy, was accomplished by exposing a suspension of birnessite to a Cu(+)-bearing precursor molecule that underwent disproportionation in solution to yield Cu(0) and Cu(2+). Electrocatalytic studies showed that the Cu-modified birnessite exhibited an overpotential for water oxidation of ~490 mV (at 10 mA/cm(2)) and a Tafel slope of 126 mV/decade compared to ~700 mV (at 10 mA/cm(2)) and 240 mV/decade, respectively, for birnessite without copper. Impedance spectroscopy results suggested that the charge transfer resistivity of the Cu modified sample was significantly lower than Cu-free birnessite, suggesting that Cu in the interlayer increased the conductivity of birnessite leading to an enhancement of water oxidation kinetics. Density functional theory calculations show that the intercalation of Cu(0) into a layered MnO2 model structure led to a change of the electronic properties of the material from a semiconductor to a metallic-like structure. This conclusion from computation is in general agreement with the aforementioned impedance spectroscopy results. X-ray photoelectron spectroscopy (XPS) showed that Cu(0) coexisted with Cu(2+) in the prepared Cu modified birnessite. Control experiments using birnessite that was decorated with only Cu(2+) showed a reduction in water oxidation kinetics, further emphasizing the importance of Cu(0) for the increased activity of birnessite. The introduction of Cu(0) into the birnessite structure also increased the stability of the electrocatalyst. At a working current of 2 mA, the Cu-modified birnessite took ~3 times longer for the overpotential for water oxdiation to increase by 100 mV compared to when Cu was not present in the birnessite. PMID- 26477451 TI - Language changes in bilingual individuals with Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) in those who are bilingual is becoming increasingly prevalent in modern society, yet little is known about the impact of AD on the bilingual's two languages. AIMS: To gather information from the available literature on AD and bilingual individuals. METHODS & PROCEDURES: The first author searched three electronic databases for relevant articles and retrieved 186 articles. Nine articles met the inclusion criteria and were selected for this review. Various research methods employed in assessing language changes in bilingual individuals with AD were captured. MAIN CONTRIBUTION: Preliminary findings suggest that both controls and bilingual individuals with Alzheimer's disease (BIAD) were more able on language-related tasks in their dominant language compared with their non-dominant language. The current literature would suggest that both languages in bilingual individuals are equally affected by AD; however, there is room to explore preliminary data on the fact that the non-dominant language, and indeed the dominant language, is more sensitive to AD. CONCLUSIONS & IMPLICATIONS: More robust, clinically relevant research designs that test current theoretical frameworks are needed to inform the development of appropriate assessments, diagnosis and person-centred care for bilingual individuals with AD. PMID- 26477454 TI - Bottom-up regulation of malaria population dynamics in mice co-infected with lung migratory nematodes. AB - When and how populations are regulated by bottom up vs. top down processes, and how those processes are affected by co-occurring species, are poorly characterised across much of ecology. We are especially interested in the community ecology of parasites that must share a host. Here, we quantify how resources and immunity affect parasite propagation in experiments in near replicate 'mesocosms'' - i.e. mice infected with malaria (Plasmodium chabaudi) and nematodes (Nippostrongylus brasiliensis). Nematodes suppressed immune responses against malaria, and yet malaria populations were smaller in co infected hosts. Further analyses of within-host epidemiology revealed that nematode co-infection altered malaria propagation by suppressing target cell availability. This is the first demonstration that bottom-up resource regulation may have earlier and stronger effects than top-down immune mechanisms on within host community dynamics. Our findings demonstrate the potential power of experimental ecology to disentangle mechanisms of population regulation in complex communities. PMID- 26477455 TI - Knowledge, attitude and practices for design for safety: A study on civil & structural engineers. AB - Design for safety (DfS) (also known as prevention through design, safe design and Construction (Design and Management)) promotes early consideration of safety and health hazards during the design phase of a construction project. With early intervention, hazards can be more effectively eliminated or controlled leading to safer worksites and construction processes. DfS is practiced in many countries, including Australia, the UK, and Singapore. In Singapore, the Manpower Ministry enacted the DfS Regulations in July 2015, which will be enforced from August 2016 onwards. Due to the critical role of civil and structural (C&S) engineers during design and construction, the DfS knowledge, attitude and practices (KAP) of C&S engineers have significant impact on the successful implementation of DfS. Thus, this study aims to explore the DfS KAP of C&S engineers so as to guide further research in measuring and improving DfS KAP of designers. During the study, it was found that there is a lack of KAP studies in construction management. Therefore, this study also aims to provide useful lessons for future applications of the KAP framework in construction management research. A questionnaire was developed to assess the DfS KAP of C&S engineers. The responses provided by 43 C&S engineers were analyzed. In addition, interviews with experienced construction professionals were carried out to further understand perceptions of DfS and related issues. The results suggest that C&S engineers are supportive of DfS, but the level of DfS knowledge and practices need to be improved. More DfS guidelines and training should be made available to the engineers. To ensure that DfS can be implemented successfully, there is a need to study the contractual arrangements between clients and designers and the effectiveness of different implementation approaches for the DfS process. The questionnaire and findings in this study provided the foundation for a baseline survey with larger sample size, which is currently being planned. In contrast to earlier studies, the study showed that the responding C&S engineers were supportive of the DfS. The study showed that the key to improving the DfS KAP of C&S engineers is by improving clients' motivation for DfS. PMID- 26477456 TI - Serological Evidence of Pandemic H1N1 Influenza Virus Infections in Greek Swine. AB - The introduction of the 2009 pandemic H1N1 (pH1N1) influenza virus in pigs changed the epidemiology of influenza A viruses (IAVs) in swine in Europe and the rest of the world. Previously, three IAV subtypes were found in the European pig population: an avian-like H1N1 and two reassortant H1N2 and H3N2 viruses with human-origin haemagglutinin (HA) and neuraminidase proteins and internal genes of avian decent. These viruses pose antigenically distinct HAs, which allow the retrospective diagnosis of infection in serological investigations. However, cross-reactions between the HA of pH1N1 and the HAs of the other circulating H1 IAVs complicate serological diagnosis. The prevalence of IAVs in Greek swine has been poorly investigated. In this study, we examined and compared haemagglutination inhibition (HI) antibody titres against previously established IAVs and pH1N1 in 908 swine sera from 88 herds, collected before and after the 2009 pandemic. While we confirmed the historic presence of the three IAVs established in European swine, we also found that 4% of the pig sera examined after 2009 had HI antibodies only against the pH1N1 virus. Our results indicate that pH1N1 is circulating in Greek pigs and stress out the importance of a vigorous virological surveillance programme. PMID- 26477458 TI - Emerging Targets For Prostate Adenocarcinoma Therapy: How Molecular Biology May Drive Towards a More Tailored Approach. AB - Prostate adenocarcinoma is the most diagnosed male cancer in the Western world and the second leading cause of cancer-related mortality. Albeit most of the patients with prostate adenocarcinoma are currently treated by surgery and/or radiation therapy, more than 30-40% of affected subjects will eventually progress and develop advanced disease. To date, management decisions depend on the clinical stage of the patient and the histological diagnosis which unfortunately often lack to predict the real prognosis. Current therapies have shown to be insufficient, mainly in the metastatic disease. For clear-cut diagnosis and follow-up, we promptly need molecular markers also useful in predicting patient's outcome. Advances in cancer genomics have led to a plethora of biomarkers, which must now to be rigorously validated in the clinical setting. Recent insights on prostate adenocarcinoma biology which unveiled some of the biological mechanisms leading to this tumour, have managed in devising novel strategies for therapy. Immunotherapeutic agents, selective adrenal inhibitors, anti-angiogenic molecules, newly engineered androgen receptor inhibitors, compounds targeting the bone microenvironment are demonstrated to limit cancer growth by blocking specific signaling pathways. Such strategies can be complemented to existing therapeutic paradigm in improving beneficial outcome. Moreover, other emerging pharmacological compounds have shown encouraging results and several clinical trials are ongoing. This review summarizes the developing targeted therapies for prostate adenocarcinoma and discuss their potential benefit mainly in the castration- resistant forms. PMID- 26477457 TI - Cell Death and microRNAs in Cholestatic Liver Diseases: Update on Potential Therapeutic Applications. AB - Cholestasis is the main pathogenic event in a wide range of genetic or acquired disorders of bile acid synthesis or bile flow, resulting in intrahepatic and systemic accumulation of bile acids. In turn, augmented levels of bile acids lead to hepatocellular injury and progressive liver damage, eventually culminating in fibrosis and end-stage liver disease. In the injured cholestatic liver, apoptosis has long been recognized as a direct consequence of bile acid-mediated injury. It is now apparent that inflammation and necrosis play an equal or even more prevalent role. Ursodeoxycholic acid is the mainstream treatment for several cholestatic syndromes, but has limited efficacy in certain circumstances. With the notion that miRNAs play key roles in basic biological processes and that their deregulation is common in human liver disease, prospective use of miRNAs as either therapeutic targets or disease biomarkers is now being increasingly documented. Deciphering the exact contribution of each player is crucial for directing efforts toward finding much needed novel therapeutic strategies for cholestasis. PMID- 26477459 TI - Targeting Transient Receptor Potential Channels in Cardiometabolic Diseases and Myocardial Ischemia Reperfusion Injury. AB - BACKGROUND: Cardiovascular disease is still the most frequent cause of death in both developed and developing countries while metabolic syndrome and myocardial ischemia reperfusion (I/R) injury are the common risk factors responsible for the impaired cardiac function. Transient receptor potential (TRP) channels are non selective cation channels, that sense a broad range of stimuli from physical conditions such as stretch, to chemicals including capsaicin. OBJECTIVE: The diverse studies have revealed multifunctional roles of TRP channels in the physiological conditions and various diseases while some members of TRP channel superfamily are demonstrated to participate in the pathophysiology of cardiometabolic diseases and myocardial ischemia reperfusion injury. Here we discuss the roles of TRP channels in myocardial ischemia reperfusion and cardiometabolic diseases and their potential use in treating these diseases. RESULTS: Regulation of TRP channels facilitates the control of metabolic syndrome such as obesity, diabetes mellitus, hypertension, and atherosclerosis. This review presents an overview of our current knowledge regarding the physiological functions of TRP channels in the metabolic and cardiovascular systems and their contributions to cardiometabolic diseases and I/R injury. CONCLUSION: On the basis of these discoveries, the therapeutic potential of targeting novel TRP channels can be proposed for the treatment of cardiometabolic diseases and I/R injury. PMID- 26477460 TI - Mechanism of Action: How Nano-Antimicrobials Act? AB - Escalating resistance to almost every class of antibiotics is reducing the utility of currently available antimicrobial drugs. A part of this menace is attributed to poor pharmacokinetics and pharmacodynamics of the drug. Improvement in drug delivery is the most challenging task encountered by the pharmaceutical industries; however nanotechnology can bring a revolution in drug delivery design. Nano-antimicrobials (NAMs) have their own intrinsic antimicrobial activity (nanoparticles) or augment overall efficacy of enclosed antibiotics (nano-carriers), thus contribute in mitigating or reversing the resistance phenomenon. Nano-particles (NPs) having their own intrinsic antimicrobial activity kill microbes by mimicking natural course of killing by phagocytic cells i.e., by producing large quantity of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS). It is believed that NPs kill microbes by simultaneously acting on many essential life processes or metabolic routes of microbes; that as many genetic mutations to develop resistance against them seems to be impossible. Nano carriers improve the pharmacokinetics of the enclosed drug. Moreover, one of the major techniques by which NAMs can overcome resistance is targeted drug delivery to the site of disease. In this review, a comprehensive detail about the mechanism of action of NAMs are presented in context to multi drug resistance phenomenon. PMID- 26477461 TI - Substance P and its Inhibition in Ocular Inflammation. AB - Neuropeptides, and specifically Substance P (SP), can crucially contribute to the ocular inflammatory response. SP is an undecapeptide that is secreted from sensory nerve endings and from various immune cells during inflammation. SP modulates ocular inflammation through its binding with the high-affinity neurokinin-1 receptor (NK-1R). This receptor is expressed on nerves, immune cells, and epithelial cells. SP is a key mediator of neurogenic inflammation as it induces increased microvascular permeability, vasodilatation, plasma extravasation, and subsequent tissue edema. In addition, macrophages can release inflammatory mediators such as interleukins, chemokines, and growth factors in response to SP stimulation. Inhibition of SP activity, either through blockade of the neuropeptide release or the use of SP receptor antagonists, ameliorates ocular inflammation, it restores immune privilege and improves a number of clinical endpoints associated with inflammation, such as corneal opacity, ocular perforation, and angiogenesis. This review of the literature will summarize the role of SP in the ocular inflammatory response (with an emphasis on the ocular surface). In addition, it will review the therapeutic effects of SP blockade to control ocular inflammation (i) in animal models and (ii) in highly prevalent human diseases. PMID- 26477462 TI - The Application of Chitosan and Its Derivatives as Nanosized Carriers for the Delivery of Chemical Drugs and Genes or Proteins. AB - The carrier technology provides an intelligent approach for drug delivery by entrapping the drug into a carrier, such as nanoparticles, microspheres, hydrogels, and so on, which can increase the bioavailability of drug, enhance targeting, reduce toxicity and side effects of drug. The polysaccharides, e.g., chitosan and its derivatives, as carriers for delivery of chemical drugs and genes or proteins were summed up herein. PMID- 26477463 TI - Sirtuins: Possible Clinical Implications in Cardio and Cerebrovascular Diseases. AB - Mammalian sirtuins (SIRT1-7) are NAD+-dependent deacetylases, which play an important role in aging and in a wide range of cellular functions. SIRT1, the best-characterized member of the family, acts as a sensor of the redox state and triggers in the cell the appropriate defense response. A large body of evidence has showed that SIRT1 induces both cellular and systemic protective effects in the cardiovascular system by preventing stress-induced apoptosis and senescence, and mitigating endothelial dysfunction. Hence, SIRT1 is now foreseen as a potential therapeutic target for a growing number of cardiovascular diseases. Recently, it has been suggested that SIRT1 activation could also be considered as a neuroprotective strategy. Indeed, SIRT1 protects against ischemia/reperfusion injury both in vitro and in vivo and avoids severe ischemic damage by preserving cerebral blood flow. In the last years it was suggested that others sirtuins, in particular SIRT3 and SIRT6, could exert beneficial effects in vascular syndromes. The aim of this review was to describe and discuss recent experimental evidence on the effects of SIRT1 and other sirtuins on the pathophysiology of cardio- and cerebrovascular diseases, underlying a potential therapeutic effect of these enzymes in the treatment and/or prevention of such conditions. PMID- 26477464 TI - Topical and Transdermal Delivery of Drug-Loaded Nano/ Microsystems with Application of Physical Enhancement Techniques. AB - Topical and transdermal delivery has been studied over last decades and it presents advantages for the treatment of several disorders, macromolecules delivery and vaccination. The greatest challenge is to overcome the stratum corneum (SC) barrier. Compared to traditional topical formulation strategies, nano /microsystems offer advantages such as increased stability, increased loading dose, coverage of undesired colors, reduced toxicity and prolonged release of active agents. However, there are no conclusive studies demonstrating the ability of such systems to penetrate the skin in relevant therapeutic amounts. The use of physical methods holds great promise for enhancing skin permeation through the SC and for targeting hair follicles. This review discusses the characteristics and feasibility of using a dual approach employing the application of physical methods of permeation enhancement to enable the topical or transdermal delivery of drug-loaded nano/microsystems. PMID- 26477465 TI - Morphological and Functional Characteristic of Senescent Cancer Cells. AB - Cellular senescence is the state of permanent proliferation cessation. There are two types of cell senescence. One is replicative senescence, which relies on telomere length-dependent limit of cell divisions. The second is stress-induced premature senescence (SIPS) which is telomere- independent. Cell senescence is a barrier to cancer. Paradoxically senescent cells, which are metabolically active secrete factors which can be procancerogenic. The main culprit of cell senescence is DNA damage and DNA damage response. Although cancer cells frequently possess mutations in two main signalling pathways involved in cell senescence, namely p53/p21 and p16/Rb, they still preserve the ability to undergo DNA damage-induced senescence. Cancer cell senescence is a new promising target for anticancer therapy. It was shown that many types of cancer cells can undergo SIPS. Senescent cancer cells have generally the same features as normal cells, such as enlarged size, accumulation of DNA damage foci and increased activity of Senescence Associated beta- galactosidase. Moreover senescent cancer cells are frequently polyploid and it was shown that polyploidy might be connected with abnormal cell division, which leads to the appearance of small descendants. In this review we will focus on morphological hallmarks of senescent cancer cells as well as their functional capabilities, such as secretion, polyploidization, and stemness. We will also discuss links with autophagy, mitotic catastrophe and the propensity of senescent cells to regain proliferative activities. We would like to show the complexity of cancer cell phenotype arising after anticancer treatment and difficulties in interpretation of the experimental data. PMID- 26477466 TI - Dynamic Behavior of Clobazam on High-Performance Liquid Chromatography Chiral Stationary Phases. AB - Clobazam, a 1,5-benzodiazepin-2,4-dione, is a chiral molecule because its ground state conformation features a nonplanar seven-membered ring lacking reflection symmetry elements. The two conformational enantiomers of clobazam interconvert at room temperature by a simple ring-flipping process. Variable temperature HPLC on the Pirkle type (R)-N-(3,5-dinitronenzoyl)phenylglycine and (R,R)-Whelk-O1 chiral stationary phases (CSPs) allowed us to separate for the first time the conformational enantiomers of clobazam and to observe peak coalescence decoalescence phenomena due to concomitant separation and interconversion processes occurring on the same time scale. Clobazam showed temperature dependent dynamic high-performance liquid chromatography (HPLC) profiles with interconversion plateaus on the two CSPs indicative of on-column enantiomer interconversion. (enantiomerization) in the column temperature range between Tcol = 10 degrees C and Tcol = 30 degrees C, whereas on-column interconversion was absent at temperature close to or lower than Tcol = 5 degrees C. Computer simulation of exchange-deformed HPLC profiles using a program based on the stochastic model yielded the apparent rate constants for the on-column enantiomerization and the corresponding free energy activation barriers. At Tcol = 20 degrees C the averaged enantiomerization barriers, DeltaG(?), for clobazam were found in the range 21.08-21.53 kcal mol(-1) on the two CSPs. The experimental dynamic chromatograms and the corresponding interconversion barriers reported in this article are consistent with the literature data measured by DNMR at higher temperatures and in different solvents. PMID- 26477467 TI - Sexual polymorphisms of vomeronasal 1 receptor family gene expression in bulls, steers, and estrous and early luteal-phase heifers. AB - Vomeronasal 1 receptors (V1R) are a family of receptors for intraspecies chemosignals, including pheromones, and are expressed in the olfactory epithelium (OE) and vomeronasal organ (VO). Even in the well-studied rodents, it is unclear which members of the V1R family cause sexual polymorphisms, as there are numerous genes and it is difficult to quantify their expressions individually. Bovine species carry only 34 V1R homologs, and the OE and VOs are large enough to sample. Here, V1R expression was quantified in the OE and VOs of individual bovines. Based on the 34 gene sequences, we obtained a molecular dendrogram consisting of four clusters and six independent branches. Semi-quantitative RT PCR was used to obtain gene expression profiles in the VOs and OE of 5 Japanese Black bulls, 5 steers, 7 estrous heifers and 6 early luteal-phase heifers. Ten genes showed significant between-group differences, and 22 showed high expression in VOs than in OE. The bulls showed higher expression of one gene more in OE and another in VOs (both P<0.05) than did steers; both genes belonged to the first cluster. No genes were expressed more abundantly in steers than in bulls. The estrous heifers showed higher expression of a gene of the second cluster in OE, and a gene of the third cluster in VOs (both P<0.05) than did early luteal-phase heifers. These results suggest V1R expression exhibits sexual polymorphisms in cattle. PMID- 26477468 TI - Alzheimer's disease: a report from the 7th Kuopio Alzheimer symposium. AB - The 7th Kuopio Alzheimer symposium was held on 11-13 June, 2015, in Kuopio, Finland and attracted ~250 attendees from 14 different countries around the world. The theme for the symposium in its seventh year was 'From mechanisms to prevention and intervention of Alzheimer's disease'. The 3-day international scientific symposium composed of seven oral sessions and a poster session. The program, spanning from molecular mechanisms to prevention, prediction, diagnosis and treatment of Alzheimer's disease, provided a forum for the attendees to share their research, network and to obtain a comprehensive overview of the current status and future directions of research into Alzheimer's disease. PMID- 26477469 TI - Advances in Immuno-Oncology: Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer-Introduction. PMID- 26477470 TI - Current Perspectives in Immunotherapy for Non-Small Cell Lung Cancer. AB - In non-small cell lung cancer (NSCLC), the first immune checkpoint inhibitor to be approved by the US Food and Drug Administration was nivolumab, based on a survival advantage over docetaxel in recurrent squamous NSCLC, a difficult-to treat histology. In addition, several other immune checkpoint inhibitors are also in late-stage development. Most of these agents inhibit the programmed cell death protein 1 (PD-1) pathway, targeting either the PD-1 receptor or its ligand, programmed cell death ligand 1 (PD-L1). In addition to nivolumab, pembrolizumab is a PD-1 inhibitor under investigation in NSCLC, and atezolizumab (MPDL3280A), durvalumab (MEDI4736), and avelumab (MSB0010718C) are PD-L1 inhibitors under investigation. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint inhibitors ipilimumab and tremelimumab are also under investigation in NSCLC, largely as part of combination approaches rather than as monotherapy. PD L1 expression as a potential biomarker to select patients most likely to respond to inhibitors of the PD-1 pathway has been widely studied. PMID- 26477471 TI - Incorporating Immunotherapy Into the Treatment of Non-Small Cell Lung Cancer: Practical Guidance for the Clinic. AB - Immunotherapy provides unique challenges in the clinic, as nivolumab is a first in-class agent for non-small cell lung cancer (NSCLC). Unlike other NSCLC therapies, immunotherapy cannot currently be selected based on a patient's clinical characteristics or a tumor's molecular characteristics, although some evidence suggests that programmed death ligand 1 (PD-L1) may be useful as a molecular biomarker in the future. Histology is currently important to the use of nivolumab because it is only approved in squamous cell NSCLC. However, recent evidence shows a similar survival benefit of nivolumab in nonsquamous disease, so histology will likely not be a distinguishing factor in the future. It has been discovered that immunotherapy often has delayed response kinetics, leading to the development of immune-related response criteria (irRC) in 2009. The irRC have distinguishing characteristics from traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria that prevent physicians from prematurely discontinuing immunotherapy. In addition to these differences in response criteria, the safety profiles of immunotherapeutic agents are distinct from other NSCLC therapies. The toxicities frequently associated with immunotherapies are unlike common chemotherapy toxicities because they are autoimmune in nature. Thus, physicians are presented with the challenge of appropriately identifying and managing these unfamiliar immune-related adverse events. PMID- 26477472 TI - Understanding the Rationale for Immunotherapy in Non-Small Cell Lung Cancer. AB - Although immunotherapy has been used for decades in immunogenic tumor types, such as melanoma and renal cell carcinoma, historically immunotherapeutic approaches in other tumor types, including non-small cell lung cancer (NSCLC), have met with failure. Nonetheless, evidence exists supporting the role of the immune system in tumor suppression, even in tumor types believed to be non-immunogenic. In NSCLC, immune checkpoint molecules have recently proven to be successful targets, with nivolumab, the first immune checkpoint inhibitor indicated for NSCLC, approved by the US Food and Drug Administration in March 2015. Several other immune checkpoint inhibitors are currently in phase III development in NSCLC. PMID- 26477473 TI - Superior Catalytic Activity of Electrochemically Reduced Graphene Oxide Supported Iron Phthalocyanines toward Oxygen Reduction Reaction. AB - Structure and surface properties of supporting materials are of great importance for the catalytic performance of the catalysts. Herein, we prepared the iron phthalocyanine (FePc) functionalized electrochemically reduced graphene oxide (ERGO) by the electrochemical reduction of FePc/GO. The resultant FePc/ERGO exhibits higher catalytic activity toward ORR than that of FePc/graphene. More importantly, the onset potential for ORR at FePc/ERGO positively shifts by 45 mV compared with commercial Pt/C in alkaline media. Besides, FePc/ERGO displays enhanced durability and selectivity toward ORR. The superior catalytic performance of FePc/ERGO for ORR are ascribed to the self-supported structure of ERGO, uniformly morphology and size of FePc nanoparticles. PMID- 26477474 TI - Outcome of salvage surgery for colorectal cancer initially treated by upfront endoscopic therapy. AB - BACKGROUND: Recent advances in endoscopic therapy, including conventional endoscopic resection and endoscopic submucosal dissection (ESD), have led to a large number of patients with early colorectal cancer (CRC) being cured; however, when resected specimens obtained by these procedures manifest risk factors for lymph node metastasis, additional treatments need to be considered. The aim of our study was to evaluate the outcomes of salvage surgery in CRC patients treated initially by advanced therapeutic endoscopy. METHODS: We investigated 145 patients who underwent salvage surgery in our department after endoscopic therapy for CRC between April 2006 and March 2015. Demographic and pathological data, endoscopic procedures, reasons for surgery, and operative outcomes, including perioperative details and recurrence-free and disease-specific survival after surgery, were analyzed. These data were further compared with those of 59 patients with submucosal invasive CRC treated by conventional endoscopic resection/ESD alone and 133 patients treated by surgery alone. RESULTS: Overall lymph node metastases were observed in 14% of patients who underwent salvage surgery after therapeutic endoscopy and 16% of those who received abdominal surgery alone. In analyses of surgical cases, patients with lymph node metastases more frequently included cases with lymphatic infiltration (63%) and ESD-treated cases (45%) than those without metastases (21%, P < .0001 and 22%, P = .02; respectively). A logistic regression analysis identified lymphatic infiltration as an independent predictive factor for lymph node metastases (odds ratio: 8.77, 95% confidence interval: 2.90-33.31, P < .0001). Long-term outcomes were favorable in both lymphatic infiltration-negative and positive cases. Moreover, survivals were comparable among the different treatment groups. CONCLUSION: Because of the high rate of nodal involvement, adequate lymphadenectomy need to be performed in salvage surgery after upfront endoscopic therapy. PMID- 26477475 TI - Clinical predictors of prolonged postresection hypotension after laparoscopic adrenalectomy for pheochromocytoma. AB - BACKGROUND: Although the perioperative management of patients with pheochromocytoma has been improving recently, severe hypotensive episodes can occur that require postoperative catecholamine support and are challenging to manage. Our aim was to identify the clinical factors that predict prolonged postresection hypotension in patients after laparoscopic adrenalectomy for pheochromocytoma. METHODS: The records of 73 Japanese patients who underwent unilateral laparoscopic adrenalectomy for pheochromocytoma were surveyed retrospectively. Patients were divided into 2 groups according to whether catecholamine support was needed after postoperatively. Clinical and biochemical data were evaluated at baseline and after operation. RESULTS: Thirty-four of 73 patients (47%) required continuous infusion of catecholamine to maintain systolic blood pressure >90 mm Hg at the end of the operation. The median duration of postoperative catecholamine support was 17 hours (range, 3-130) in these 34 patients. On multivariate analysis, tumor size >60 mm, urinary epinephrine levels >200 MUg/day, and urinary norepinephrine levels >600 MUg/day were independent predictors of prolonged hypotension requiring postoperative catecholamine support. Tumor size and urinary norepinephrine levels were significantly correlated with the duration of postoperative catecholamine support. CONCLUSION: Larger tumor size and greater values of urinary epinephrine and norepinephrine levels were significant predictors of prolonged hypotension requiring postoperative catecholamine support. Moreover, tumor size and urinary norepinephrine levels were positively correlated with the duration of postoperative catecholamine support. Clinicians can identify and manage patients more effectively with a greater risk of prolonged hypotension after tumor resection using these preoperative clinical variables. PMID- 26477476 TI - Survival benefit of repeat resection of successive recurrences after the initial hepatic resection for colorectal liver metastases. AB - BACKGROUND: Relapse is common after the resection of colorectal liver metastases (CLM); however, the optimal treatment for such recurrent disease remains uncertain. We investigated whether repeat resections for successive recurrences of CLM provide survival benefit on the postrecurrence survival. METHODS: We reviewed patients who underwent upfront, curative resection for CLM at our center during a 15-year period. Of these, 263 patients who had not received any other perioperative treatment for the metastases were eligible for our analysis. The recurrence-free survival (RFS0) after the initial hepatic resection and after the first (n = 108), second (n = 43), and third (n = 15) repeat resections for recurrent disease were assessed (RFS1-3). The overall survival after the initial hepatic resection and the postrecurrence survival (n = 198) also was assessed. RESULTS: The median RFS0 was 0.8 years, and RFS1, RFS2, and RFS3 were 1.3, 1.1, and 2.0 years, respectively. The hazard ratio for RFS for the first, second, and third resections versus the initial hepatic resection was 0.9 (95% confidence interval [95% CI] 0.7-1.1; P = .34), 1.00 (95% CI 0.7-1.4; P = .97), and 0.7 (95% CI 0.4-1.3; P = .29). The 5-year and 10-year OS rates were 54.6% and 42.2%, and the 5-year and 10-year postrecurrence survival was 34.3% and 28.6%, respectively. CONCLUSION: Repeat resection in patients with recurrent disease after CLM resection is beneficial, offering the potential for cure in a small proportion of patients with recurrent disease. PMID- 26477477 TI - Patient cost-sharing and insurance arrangements are associated with hospital readmissions after abdominal surgery: Implications for access and quality health care. AB - BACKGROUND: Readmission rates after operative procedures are used increasingly as a measure of hospital care quality. Patient access to care may influence readmission rates. The objective of this study was to determine the relationship between patient cost-sharing, insurance arrangements, and the risk of postoperative readmissions. METHODS: Using the MarketScan Research Database (n = 121,002), we examined privately insured, nonelderly patients who underwent abdominal surgery in 2010. The main outcome measures were risk-adjusted unplanned readmissions within 7 days and 30 days of discharge. Odds of readmissions were compared with multivariable logistic regression models. RESULTS: In adjusted models, $1,284 increase in patient out-of-pocket payments during index admission (a difference of one standard deviation) was associated with 19% decrease in the odds of 7-day readmission (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.78-0.85) and 17% decrease in the odds of 30-day readmission (OR 0.83, 95% CI 0.81-0.86). Patients in the noncapitated point-of-service plans (OR 1.19, 95% CI 1.07-1.33), preferred provider organization plans (OR 1.11, 95% CI 1.03-1.19), and high-deductible plans (OR 1.12, 95% CI 1.00-1.26) were more likely to be readmitted within 30 days compared with patients in the capitated health maintenance organization and point-of-service plans. CONCLUSION: Among privately insured, nonelderly patients, increased patient cost-sharing was associated with lower odds of 7-day and 30-day readmission after abdominal surgery. Insurance arrangements also were significantly associated with postoperative readmissions. Patient cost sharing and insurance arrangements need consideration in the provision of equitable access for quality care. PMID- 26477478 TI - Breast Cancer Survivor Advocacy at a University Hospital: Development of a Peer Support Program with Evaluation by Patients, Advocates, and Clinicians. AB - Peer-to-peer support programs provide unique psychosocial and educational support for breast cancer patients. A Patient Survivor Advocacy (PSA) program was developed by the University of Wisconsin Breast Center (UWBC) to provide support for newly diagnosed patients from peers who had completed primary treatment. In this study, we evaluated patient, advocate, and clinician experience with the PSA program. A program matching volunteer peer advocates at least 1 year removed from primary treatment with newly diagnosed patients was developed. Peer advocates were recruited from the practices of UWBC clinicians and received in-person training on six dimensions of peer advocacy. Trained advocates were then paired based on demographic and medical history with new patients referred to the program. Survey assessment tools were distributed to assess peer advocate and patient satisfaction, as well as clinician experience. Forty patients have been matched with seven advocates, with contact largely by email (53 %) or phone (36 %). Patients and peer advocates reported satisfaction with the program. The majority of patients (92.9 %) reported that the program was "helpful" and that they would recommend the PSA program to another woman with breast cancer. All peer advocates (100 %) responded with a sense of achievement in their advocate roles. Clinicians noted challenges in referral to the program. Peer advocates can provide key emotional and psychosocial support to newly diagnosed breast cancer patients. The peer advocate, patient, and clinician feedback collected in this study will inform the future development of this program at our and peer institutions. PMID- 26477479 TI - A novel mutation and a known mutation in the CLCN7 gene associated with relatively stable infantile malignant osteopetrosis in a Chinese patient. AB - Osteopetrosis is a group of heterogeneous disorders caused by the dysfunction of osteoclasts. The CLCN7 and TCIRG1 genes are the major obligate genes responsible for infantile malignant osteopetrosis (IMO). IMO patients usually die in infancy or before three years of age. In this study, we report a patient who was diagnosed with IMO at seven months of age. The patient presented with classical radiological features of IMO. She also exhibited erythropenia, thrombocytopenia, hepatosplenomegaly and neurodegeneration. The parents discontinued any medical treatment for the patient. Surprisingly, the patient's condition did not deteriorate when she was admitted a second time at the age of four years and nine months, despite not receiving any medical support during the untreated period. We sequenced the CLCN7 and TCIRG1 genes of the patient and her parents and identified a novel c.285+1G>A (IVS3+1G>A) mutation and the known c.896C>T (p.Ala299Val) mutation. The novel c.285+1G>A mutation occurred on the splice donor of the third intron of CLCN7. This mutation was predicted to interfere with normal splicing between exons 3 and 4, thereby truncating 711 amino acids from the C terminus and resulting in the loss of all of the functional domains of the encoded protein. The c.896C>T (p.Ala299Val) mutation was a previously known pathogenic mutation. We did not find any pathogenic mutations in the TCIRG1 gene. CLCN7-related osteopetrosis is known to have a high phenotype heterogeneity. Our study demonstrates a wide heterogeneity in the progression of the phenotypes and expanded the mutational spectrum for the CLCN7 gene. PMID- 26477480 TI - A functional genomics tool for the Pacific bluefin tuna: Development of a 44K oligonucleotide microarray from whole-genome sequencing data for global transcriptome analysis. AB - Bluefin tunas are one of the most important fishery resources worldwide. Because of high market values, bluefin tuna farming has been rapidly growing during recent years. At present, the most common form of the tuna farming is based on the stocking of wild-caught fish. Therefore, concerns have been raised about the negative impact of the tuna farming on wild stocks. Recently, the Pacific bluefin tuna (PBT), Thunnus orientalis, has succeeded in completing the reproduction cycle under aquaculture conditions, but production bottlenecks remain to be solved because of very little biological information on bluefin tunas. Functional genomics approaches promise to rapidly increase our knowledge on biological processes in the bluefin tuna. Here, we describe the development of the first 44K PBT oligonucleotide microarray (oligo-array), based on whole-genome shotgun (WGS) sequencing and large-scale expressed sequence tags (ESTs) data. In addition, we also introduce an initial 44K PBT oligo-array experiment using in vitro grown peripheral blood leukocytes (PBLs) stimulated with immunostimulants such as lipopolysaccharide (LPS: a cell wall component of Gram-negative bacteria) or polyinosinic:polycytidylic acid (poly I:C: a synthetic mimic of viral infection). This pilot 44K PBT oligo-array analysis successfully addressed distinct immune processes between LPS- and poly I:C- stimulated PBLs. Thus, we expect that this oligo-array will provide an excellent opportunity to analyze global gene expression profiles for a better understanding of diseases and stress, as well as for reproduction, development and influence of nutrition on tuna aquaculture production. PMID- 26477481 TI - Risk assessment for neonatal RDS/TTN using gestational age and the amniotic lamellar body count in twin pregnancies. AB - BACKGROUND: The amniotic lamellar body count (LBC) is useful for predicting respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN) in twin pregnancies. However, the risk of neonatal respiratory complications varies with gestational age (GA). We herein created a model to predict the risk for RDS and TTN using GA and the LBC in twin pregnancies. METHODS: Six hundred thirty-two amniotic fluid samples, comprising 169 dichorionic twin (DCT) and 147 monochorionic twin (MCT) gestations, were obtained at Cesarean section. The samples were analyzed immediately without centrifugation. A logistic regression model including the LBC and GA was used to develop the prediction model for RDS/TTN. RESULTS: There were 101 neonates (16.0%) with RDS/TTN. The GA and LBC were significant independent factors affecting RDS/TTN. According to the logistic regression model, we determined the probability of RDS/TTN given the values of GA and the LBC. The overall diagnostic accuracy for predicting neonatal RDS/TTN using GA and the LBC was higher than the use of the LBC alone. CONCLUSIONS: GA specific LBC cutoffs for the risk assessment of neonatal RDS/TTN have been considered to be more accurate in twin pregnancies. Our findings provide valuable, new information for the management of twin pregnancies. PMID- 26477482 TI - Is glycated albumin useful for differential diagnosis between fulminant type 1 diabetes mellitus and acute-onset autoimmune type 1 diabetes mellitus? AB - BACKGROUND: Markedly elevated plasma glucose and relatively low HbA1c compared to plasma glucose is one diagnostic criterion for fulminant type 1 diabetes mellitus (FT1DM). Glycated albumin (GA) is a glycemic control marker that reflects glycemic control in shorter period than HbA1c. This study investigated whether GA is useful for differential diagnosis between FT1DM and acute-onset autoimmune type 1 diabetes mellitus (T1ADM) or not. METHODS: This study included 38 FT1DM patients and 31 T1ADM patients in whom both HbA1c and GA were measured at the time of diagnosis. RESULTS: In FT1DM patients, as compared to T1ADM patients, both HbA1c and GA were significantly lower (HbA1c; 6.6+/-0.9% vs. 11.7+/-2.6%, P<0.0001, GA; 22.9+/-4.8% vs. 44.3+/-8.3%, P<0.0001). For differential diagnosis between FT1DM and T1ADM, ROC analysis showed that the optimum cut-off value for GA was 33.5% with sensitivity and specificity of 97.4% and 96.8%, respectively, while the optimum cut-off value for HbA1c was 8.7% with sensitivity and specificity of 100% and 83.9%, respectively. CONCLUSIONS: GA also may be useful for the differential diagnosis between FT1DM and T1ADM when the cut-off value can be set at 33.5%. PMID- 26477483 TI - Role of CHI3L1 in neuroinflammation. PMID- 26477484 TI - Natural killer cells from psoriasis vulgaris patients have reduced levels of cytotoxicity associated degranulation and cytokine production. AB - Psoriasis vulgaris is a chronic inflammatory disease of the skin with a strong genetic component and immune system involvement. Although some evidence suggests that Natural Killer (NK) cells may play a part in psoriasis, their role is relatively unstudied and results are controversial. In this current study, NK cells from psoriasis patients exhibited reduced degranulation and produced lower levels of the pro-inflammatory cytokines IFN-gamma and TNF-alpha. Further investigation found that NK cells from psoriasis patients and healthy controls expressed similar levels of activation markers, NK cell receptors and apoptosis inducing molecules. In addition, comparable levels of several cytokines important in NK cell biology were found in the serum of psoriasis patients and healthy controls. Genotyping analysis revealed that HLA-C2, which provides a ligand for killer-cell immunoglobulin-like receptors (KIR) expressed by NK cells, was strongly associated with psoriasis susceptibility. However, no link between the KIR genes themselves and disease was found. PMID- 26477485 TI - Response to "Breaking-up sedentary time is associated with impairment in activities of daily living". PMID- 26477486 TI - Molecular genomics resource for the parasitic nematode Spirocerca lupi: Identification of 149 microsatellite loci using FIASCO and next generation sequencing. AB - Understanding genetic diversity and movement patterns in parasitic organisms is paramount to establish control and management strategies. In this study we developed a microsatellite resource as well as a diagnostic multiplex for the cosmopolitan parasitic nematode Spirocerca lupi, known to cause spirocercosis in canids. A combination of microsatellite enrichment and 454 sequencing was used to identify 149 unique microsatellite loci in S. lupi. Twenty loci were characterized further in two sampling sites in South Africa, with 10 loci identified as polymorphic (allele ranges from 4 to 17). These loci were designed into a single diagnostic multiplex suitable for species identification and population genetics studies. The markers were also successful in cross-species amplification in Cylicospirura felineus, Philonema oncorhynchi and Gongylonema pulchrum. Our resource provides a large set of candidate loci for a number of nematode studies as well as loci suitable for diversity and population genetics studies of S. lupi within the South African context as well as globally. PMID- 26477487 TI - Cavity-less on-chip optomechanics using excitonic transitions in semiconductor heterostructures. AB - The hybridization of semiconductor optoelectronic devices and nanomechanical resonators provides a new class of optomechanical systems in which mechanical motion can be coupled to light without any optical cavities. Such cavity-less optomechanical systems interconnect photons, phonons and electrons (holes) in a highly integrable platform, opening up the development of functional integrated nanomechanical devices. Here we report on a semiconductor modulation-doped heterostructure-cantilever hybrid system, which realizes efficient cavity-less optomechanical transduction through excitons. The opto-piezoelectric backaction from the bound electron-hole pairs enables us to probe excitonic transition simply with a sub-nanowatt power of light, realizing high-sensitivity optomechanical spectroscopy. Detuning the photon energy from the exciton resonance results in self-feedback cooling and amplification of the thermomechanical motion. This cavity-less on-chip coupling enables highly tunable and addressable control of nanomechanical resonators, allowing high-speed programmable manipulation of nanomechanical devices and sensor arrays. PMID- 26477488 TI - The mucin MUC4 is a transcriptional and post-transcriptional target of K-ras oncogene in pancreatic cancer. Implication of MAPK/AP-1, NF-kappaB and RalB signaling pathways. AB - The membrane-bound mucinMUC4 is a high molecularweight glycoprotein frequently deregulated in cancer. In pancreatic cancer, one of the most deadly cancers in occidental countries, MUC4 is neo-expressed in the preneoplastic stages and thereafter is involved in cancer cell properties leading to cancer progression and chemoresistance. K-ras oncogene is a small GTPase of the RAS superfamily, highly implicated in cancer. K-ras mutations are considered as an initiating event of pancreatic carcinogenesis and K-ras oncogenic activities are necessary components of cancer progression. However, K-ras remains clinically undruggable. Targeting early downstream K-ras signaling in cancer may thus appear as an interesting strategy and MUC4 regulation by K-ras in pancreatic carcinogenesis remains unknown. Using the Pdx1-Cre; LStopL-K-rasG12D mouse model of pancreatic carcinogenesis, we show that the in vivo early neo-expression of the mucin Muc4 in pancreatic intraepithelial neoplastic lesions (PanINs) induced by mutated K ras is correlated with the activation of ERK, JNK and NF-kappaB signaling pathways. In vitro, transfection of constitutively activated K-rasG12V in pancreatic cancer cells led to the transcriptional upregulation of MUC4. This activation was found to be mediated at the transcriptional level by AP-1 and NF kappaB transcription factors via MAPK, JNK and NF-kappaB pathways and at the posttranscriptional level by a mechanism involving the RalB GTPase. Altogether, these results identify MUC4 as a transcriptional and post-transcriptional target of K-ras in pancreatic cancer. This opens avenues in developing new approaches to target the early steps of this deadly cancer. PMID- 26477489 TI - H1-nucleosome interactions and their functional implications. AB - Linker histones are three domain proteins and consist of a structured (globular) domain, flanked by two likely non-structured NH2- and COOH-termini. The binding of the linker histones to the nucleosome was characterized by different methods in solution. Apparently, the globular domain interacts with the linker DNA and the nucleosome dyad, while the binding of the large and rich in lysines COOH terminus results in "closing" the linker DNA of the nucleosome and the formation of the "stem" structure. What is the mode of binding of the linker histones within the chromatin fiber remains still elusive. Nonetheless, it is clear that linker histones are essential for both the assembly and maintenance of the condensed chromatin fiber. Interestingly, linker histones are post translationally modified and how this affects both their binding to chromatin and functions is now beginning to emerge. In addition, linker histones are highly mobile in vivo, but not in vitro. No explanation of this finding is reported for the moment. The higher mobility of the linker histones should, however, have strong impact on their function. Linker histones plays an important role in gene expression regulation and other chromatin related process and their function is predominantly regulated by their posttranslational modifications. However, the detailed mechanism how the linker histones do function remains still not well understood despite numerous efforts. Here we will summarize and analyze the data on the linker histone binding to the nucleosome and the chromatin fiber and will discuss its functional consequences. PMID- 26477490 TI - Specificities and genomic distribution of somatic mammalian histone H1 subtypes. AB - Histone H1 is a structural component of chromatin that may have a role in the regulation of chromatin dynamics. Unlike core histones, the linker histone H1 family is evolutionarily diverse and many organisms have multiple H1 variants or subtypes, distinguishable between germ-line and somatic cells. In mammals, the H1 family includes seven somatic H1 variants with a prevalence that varies between cell types and over the course of differentiation, H1.1 to H1.5 being expressed in a replication-dependent manner, whereas H1.0 and H1X are replication independent. Until recently, it has not been known whether the different variants had specific roles in the regulation of nuclear processes or were differentially distributed across the genome. To address this, an increasing effort has been made to investigate divergent features among H1 variants, regarding their structure, expression patterns, chromatin dynamics, post-translational modifications and genome-wide distribution. Although H1 subtypes seem to have redundant functions, several reports point to the idea that they are also differently involved in specific cellular processes. Initial studies investigating the genomic distribution of H1 variants have started to suggest that despite a wide overlap, different variants may be enriched or preferentially located at different chromatin types, but this may depend on the cell type, the relative abundance of the variants, the differentiation state of the cell, or whether cells are derived from a neoplastic process. Understanding the heterogeneity of the histone H1 family is crucial to elucidate their role in chromatin organization, gene expression regulation and other cellular processes. PMID- 26477491 TI - Identification of GATA-4 as a novel transcriptional regulatory component of regenerating islet-derived family members. AB - Intestinal epithelial cells are exposed to luminal bacterial threat and require adequate defense mechanisms to ensure host protection and epithelium regeneration against possible deleterious damage. Differentiated intestinal epithelial cells produce antimicrobial and regenerative components that protect against such challenges. Few intestinal specific transcription factors have been identified to control the switching from repression to activation of this class of gene. Herein, we show that gene transcription of some regenerating islet-derived (REG) family members is dependent on the transcription factor GATA-4. Silencing of GATA 4 expression in cultured intestinal epithelial cells identified Reg3beta as a target gene using an unbiased approach of gene expression profiling. Co transfection and RNA interference assays identified complex GATA-4-interactive transcriptional components required for the activation or repression of Reg3beta gene activity. Conditional deletion of Gata4 in the mouse intestinal epithelium supported its regulatory role for Reg1, Reg3alpha, Reg3beta and Reg3gamma genes. Reg1 dramatic down-modulation of expression in Gata4 conditional null mice was associated with a significant decrease in intestinal epithelial cell migration. Altogether, these results identify a novel and complex role for GATA-4 in the regulation of REG family members gene expression. PMID- 26477492 TI - Discovery and functional analysis of lncRNAs: Methodologies to investigate an uncharacterized transcriptome. AB - It is known that more than 70% of mammalian genomes are transcribed, yet the vast majority of transcripts do not code for proteins. Are these noncoding transcripts merely transcriptional noise, or do they serve a biological purpose? Recent developments in genomic analysis technologies, especially sequencing methods, have allowed researchers to create a large atlas of transcriptomes, study subcellular localization, and investigate potential interactions with proteins for a growing number of transcripts. Here, we review the current methodologies available for discovering and investigating functions of long noncoding RNAs (lncRNAs), which require a wide variety of applications to study their potential biological roles. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. PMID- 26477493 TI - Genomics in the neonatal nursery: Focus on ROP. AB - Retinopathy of prematurity (ROP) is a complex disease that is influenced by both genetic and environmental factors. Several small studies have found genetic variants in EPAS1, VEGF, SOD, and members of the WNT family in association with ROP. Design in genetic studies is challenging because of changing recommendations for the management of prematurity and ROP, the fact ROP is rare, and that availability of resources for managing premature infants can vary throughout the world. In addition, there is a shortage of ophthalmologists with the ability to diagnose and characterize severe ROP. Careful determination of the degree of prematurity is important when evaluating genetic studies. Controlling for significant epidemiologic factors and multiple comparisons is also important to consider when evaluating genetic studies. One large candidate gene study controlled for degree of prematurity, significant epidemiologic factors, and multiple comparisons and found variants within the intron of BDNF associated with severe ROP. Future studies using unbiased techniques to assess genetic risk are important as are in-depth study of BDNF through deep sequencing and associated mechanistic studies using appropriate experimental models. PMID- 26477494 TI - Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy. AB - Autophagy is an important homeostatic mechanism that eliminates long-lived proteins, protein aggregates and damaged organelles. Its dysregulation is involved in many neurodegenerative disorders. Autophagy is therefore a promising target for blunting neurodegeneration. We searched for novel autophagic pathways in primary neurons and identified the cytosolic sphingosine-1-phosphate (S1P) pathway as a regulator of neuronal autophagy. S1P, a bioactive lipid generated by sphingosine kinase 1 (SK1) in the cytoplasm, is implicated in cell survival. We found that SK1 enhances flux through autophagy and that S1P-metabolizing enzymes decrease this flux. When autophagy is stimulated, SK1 relocalizes to endosomes/autophagosomes in neurons. Expression of a dominant-negative form of SK1 inhibits autophagosome synthesis. In a neuron model of Huntington's disease, pharmacologically inhibiting S1P-lyase protected neurons from mutant huntingtin induced neurotoxicity. These results identify the S1P pathway as a novel regulator of neuronal autophagy and provide a new target for developing therapies for neurodegenerative disorders. PMID- 26477496 TI - Long-term medical management of uterine fibroids with ulipristal acetate. AB - OBJECTIVE: To investigate the efficacy and safety of repeated 12-week courses of 5 or 10 mg daily ulipristal acetate for intermittent treatment of symptomatic uterine fibroids. DESIGN: Double-blind, randomized administration of four 12-week courses of ulipristal acetate. SETTING: Gynecology centers. PATIENT(S): Four hundred fifty-one subjects with symptomatic uterine fibroid(s) and heavy menstrual bleeding. INTERVENTION(S): Four repeated 12-week treatment courses of daily 5 or 10 mg ulipristal acetate. MAIN OUTCOME MEASURE(S): Endometrial safety and general safety, laboratory parameters, amenorrhea, controlled bleeding, fibroid volume, quality of life (QoL), and pain. RESULT(S): Efficacy results, such as bleeding control and fibroid volume reduction, were in line with previously published data. Pain and QoL showed marked improvements from screening, even during the off-treatment intervals. The safety profile of ulipristal acetate was confirmed, and repeated treatment courses did not increase the occurrence of adverse reactions. There were no significant changes in laboratory parameters during the study. The percentage of subjects with endometrial thickness >= 16 mm was 7.4% (all subjects) after the first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses. As in previous studies, ulipristal acetate did not increase the occurrence of endometrial features of concern. The frequency of nonphysiological changes did not increase with repeated treatment. They were observed in 17.8% and 13.3% of biopsies after treatment courses 2 and 4, respectively, and were reversible after treatment cessation. CONCLUSION(S): The results of this study demonstrate the efficacy and further support the safety profile of repeated intermittent treatment of symptomatic fibroids with ulipristal acetate. CLINICAL TRIAL REGISTRATION NUMBER: NCT01629563. PMID- 26477497 TI - Levels of antimullerian hormone in serum during the normal menstrual cycle. AB - OBJECTIVE: To determine whether levels of antimullerian hormone (AMH) in serum vary during the normal menstrual cycle, using the most recently developed immunoassay method. DESIGN: Prospective cohort study. SETTING: Local community. PATIENT(S): Women with normal menstrual cycles and between the ages of 18 and 45 years were recruited (n = 45). Blood samples were collected on 5 days within each cycle: two in the follicular phase and three after confirmed ovulation. Exclusion criteria were anovulatory cycles, incomplete sample collection, insufficient blood volume, or non-Caucasian ethnicity. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum samples were tested for levels of AMH using a new immunoassay method (Ansh Labs). The effects of body mass index (BMI) and smoking on serum AMH levels were considered. RESULT(S): Serum AMH levels varied significantly during the menstrual cycle, with the highest levels in the follicular phase. When the analysis was stratified by age, AMH variation during the menstrual cycle was significant only for women older than 30 years. Serum AMH levels were not significantly altered by BMI or smoking. CONCLUSION(S): The new AMH immunoassay revealed a follicular phase rise in serum levels, particularly in women over the age of 30 years. This is consistent with other reports finding an interaction of menstrual cycle variation in AMH and chronological age. Nonetheless, the extent of variation is small, and sampling on any day of the menstrual cycle is expected to adequately reflect ovarian reserve. CLINICAL TRIAL REGISTRATION NUMBER: NCT01337999. PMID- 26477495 TI - Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases. AB - Aging is one of the most important biological processes and is a known risk factor for many age-related diseases in human. Studying age-related transcriptomic changes in tissues across the whole body can provide valuable information for a holistic understanding of this fundamental process. In this work, we catalogue age-related gene expression changes in nine tissues from nearly two hundred individuals collected by the Genotype-Tissue Expression (GTEx) project. In general, we find the aging gene expression signatures are very tissue specific. However, enrichment for some well-known aging components such as mitochondria biology is observed in many tissues. Different levels of cross tissue synchronization of age-related gene expression changes are observed, and some essential tissues (e.g., heart and lung) show much stronger "co-aging" than other tissues based on a principal component analysis. The aging gene signatures and complex disease genes show a complex overlapping pattern and only in some cases, we see that they are significantly overlapped in the tissues affected by the corresponding diseases. In summary, our analyses provide novel insights to the co-regulation of age-related gene expression in multiple tissues; it also presents a tissue-specific view of the link between aging and age-related diseases. PMID- 26477499 TI - Psychological stress and testicular function: a cross-sectional study of 1,215 Danish men. AB - OBJECTIVE: To study the associations between self-reported psychological stress, semen quality, and serum reproductive hormones among young Danish men. DESIGN: Cross-sectional study. SETTING: University hospital-based research center. PARTICIPANT(S): Danish men (median age 19 years) from the general population were investigated from 2008 to 2012. INTERVENTION(S): Participants completed a questionnaire on health and lifestyle, including a four-item questionnaire about self-rated stress, had a physical examination performed, delivered a semen sample, and had a blood sample drawn. MAIN OUTCOME MEASURE(S): Semen parameters (semen volume, sperm concentration, and percentages of motile and morphologically normal spermatozoa) and serum levels of reproductive hormones (LH, FSH, T, calculated free T, sex hormone-binding globulin, and inhibin B). RESULT(S): Poorer semen quality was detected among men with self-reported stress scores above an intermediate stress level, in a dose-response manner. For example, men with the highest stress levels had 38% (95% confidence interval [CI] 3%; 61%) lower sperm concentration, 34% (95% CI 59%; 106%) lower total sperm count, and 15% (95% CI 1%; 27%) lower semen volume than men with intermediate stress levels. No significant associations between self-reported stress and levels of reproductive hormones were detected. CONCLUSION(S): A negative association between self-reported stress and semen quality was detected. If causal, stress may be a contributing factor for suboptimal semen quality among otherwise healthy men. PMID- 26477500 TI - Solubility of the catalytic domains of Botulinum neurotoxin serotype E subtypes. AB - The Clostridium botulinum neurotoxins (BoNTs) are the most potent protein toxins known to humans. There are seven serotypes of the BoNTs (A-G), among which serotypes A, B, E and F are known to cause natural human intoxication. To date, eleven subtypes of LC/E, termed E1~E11, have been identified. The LCs of BoNT/E were insoluble, prohibiting studies towards understanding the mechanisms of toxin action and substrate recognition. In this work, the molecular basis of insolubility of the recombinant LCs of two representative subtypes of BoNT/E, E1(Beluga) and E3 (Alaska), was determined. Hydrophobicity profile and structural modeling predicted a C-terminal candidate region responsible for the insolubility of LC/Es. Deletion of C-terminal 19 residues of LC/E(1-400) resulted in enhanced solubility, from 2 to ~50% for LC/EAlaska and from 16 to ~95% for LC/EBeluga. In addition, resides 230-236 were found to contribute to a different solubility level of LC/EAlaska when compared to LC/EBeluga. Substituting residues (230)TCI(232) in LC/EAlaska to the corresponding residues of (230)KYT(232) in LC/EBeluga enhanced the solubility of LC/EAlaska to a level approaching that of LC/EBeluga. Among these LC/Es and their derivatives, LC/EBeluga 1-400 was the most soluble and stable protein. Each LC/E derivative possessed similar catalytic activity, suggesting that the C-terminal region of LC/Es contributed to protein solubility, but not catalytic activity. In conclusion, this study generated a soluble and stable recombinant LC/E and provided insight into the structural components that govern the solubility and stability of the LCs of other BoNT serotypes and Tetanus toxin. PMID- 26477501 TI - Functional characterization of p7 viroporin from hepatitis C virus produced in a cell-free expression system. AB - Using a cell-free expression system we produced the p7 viroporin embedded into a lipid bilayer in a single-step manner. The protein quality was assessed using different methods. We examined the channel forming activity of p7 and verified its inhibition by 5-(N,N-Hexamethylene) amiloride (HMA). Fourier transformed infrared spectroscopy (FTIR) experiments further showed that when p7 was inserted into synthetic liposomes, the protein displayed a native-like conformation similar to p7 obtained from other sources. Photoactivable amino acid analogs used for p7 protein synthesis enabled oligomerization state analysis in liposomes by cross-linking. Therefore, these findings emphasize the quality of the cell-free produced p7 proteoliposomes which can benefit the field of the hepatitis C virus (HCV) protein production and characterization and also provide tools for the development of new inhibitors to reinforce our therapeutic arsenal against HCV. PMID- 26477502 TI - Extended endoscopic endonasal transclival clipping of posterior circulation aneurysms--an alternative to the transcranial approach. AB - BACKGROUND: Transcranial clipping of most posterior circulation aneurysms is one of the most difficult procedures, with high morbidity, and endovascular coiling is an alternative with less risk, but is not devoid of complications and not suitable for all aneurysms. Here we describe four cases of posterior circulation aneurysms clipped via the extended endoscopic endonasal transclival route. To the best of our knowledge, this is the first report of basilar top and posterior cerebral artery aneurysms being clipped endonasally. METHODS AND RESULTS: Four patients with posterior circulation aneurysms underwent extended endoscopic endonasal transclival clipping of the aneurysm. The age range was 35-70 years. There were two males and two females. Three of the four patients presented after the rupture of aneurysms, and the other patient presented with sudden-onset left hemiparesis probably due to thromboembolism from a large unruptured left posterior cerebral artery (PCA) aneurysm. On evaluation with four-vessel digital subtraction angiography (DSA), two patients had a basilar apex aneurysm, one had a basilar trunk aneurysm, and the other had a PCA (P1) aneurysm. Postoperatively, two patients had good recovery. One patient with a PCA aneurysm and another with a basilar apex aneurysm had fresh postoperative deficits. One patient developed postoperative CSF rhinorrhea. CONCLUSION: Endoscopic extended transnasal surgery is an expanding field in neurosurgery with a steep learning curve. With improvement in techniques and instrumentation the use of this approach for clipping posterior circulation aneurysms can become an effective alternative in the treatment of aneurysms. PMID- 26477503 TI - How I do it: shoelace watertight dural closure in extended transsphenoidal surgery. AB - BACKGROUND: Skull base reconstruction after extended transsphenoidal surgery is essential to prevent postoperative cerebrospinal fluid leakage. METHODS: A novel and simple technique for skull base reconstruction termed "shoelace dural closure" was devised. The dura mater was closed with a fat graft using a continuous running suture with both ends of a double-armed suture. CONCLUSIONS: The shoelace dural closure is an effective method for achieving watertight closure of the anterior skull base without the use of lumbar drains, fascia lata grafts, or nasoseptal flaps. PMID- 26477504 TI - Superoxide dismutase 1 and glutathione peroxidase 1 are involved in the protective effect of sulodexide on vascular endothelial cells exposed to oxygen glucose deprivation. AB - Sulodexide (SDX) is widely used in the treatment of both arterial and venous thrombotic disorders. In addition to its recognized antithrombotic action, SDX has endothelial protective potential, which is independent of the coagulation/fibrinolysis system. However, the detailed molecular mechanisms of the endothelioprotective action of the drug are still unresolved. The aim of the present study was to determine whether treatment with SDX at concentrations of 0.125-0.5 lipase releasing unit (LRU)/ml have on the expression and activity of antioxidant enzymes in ischemic endothelial cells and how these effects might be related to the antiapoptotic properties of SDX. In the present study, human umbilical vein endothelial cells (HUVECs) were subjected to ischemia-simulating conditions (combined oxygen and glucose deprivation, OGD) for 6h to determine the protective effects of SDX. SDX (0.25 and 0.5LRU/ml) in OGD significantly increased the cell viability and prevented mitochondrial depolarization in the HUVECs. Moreover, SDX protected the HUVECs against OGD-induced apoptosis. At concentrations of 0.25 and 0.5LRU/ml, the drug increased both superoxide dismutase 1 (SOD1) and glutathione peroxidase 1 (GPx1) mRNA/protein expression together with a significant attenuation of oxidative stress in ischemic HUVECs. Our findings also demonstrate that an increase in both SOD and GPx activity is involved in the protective effect of SDX on ischemic endothelial cells. Altogether, these results suggest that SDX has a positive effect on ischemia induced endothelial damage because of its antioxidant and antiapoptotic properties. PMID- 26477498 TI - Evidence of a genetic link between endometriosis and ovarian cancer. AB - OBJECTIVE: To evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer. DESIGN: Pooled genetic analysis. SETTING: University hospital. PATIENT(S): Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Endometriosis-associated genetic variation and ovarian cancer. RESULT(S): There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected. CONCLUSION(S): By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions. PMID- 26477505 TI - Heat shock protein 60 stimulates the migration of vascular smooth muscle cells via Toll-like receptor 4 and ERK MAPK activation. AB - Accumulating evidence indicates that heat shock protein (HSP) 60 is strongly associated with the pathology of atherosclerosis (AS). However, the precise mechanisms by which HSP60 promotes atherosclerosis remain unclear. In the present study, we found that HSP60 mRNA and protein expression levels in the thoracic aorta are enhanced not only in a mouse model of AS but also in high-fat diet (HFD) mice. HSP60 expression and secretion was activated by platelet-derived growth factor-BB (PDGF-BB) and interleukin (IL)-8 in both human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs). HSP60 was found to induce VSMC migration, and exposure to HSP60 activated ERK MAPK signaling. U0126, an inhibitor of ERK, reduced VSMC migration. The HSP60 stimulated VSMCs were found to express TLR4 mRNA but not TLR2 mRNA. Knockdown of TLR4 by siRNA reduced HSP60-induced VSMC migration and HSP60-induced ERK activation. Finally, HSP60 induced IL-8 secretion in VSMCs. Together these results suggest that HSP60 is involved in the stimulation of VSMC migration, via TLR4 and ERK MAPK activation. Meanwhile, activation of HSP60 is one of the most powerful methods of sending a 'danger signal' to the immune system to generate IL 8, which assists in the management of an infection or disease. PMID- 26477506 TI - Coarse-grained treatment of the self-assembly of colloids suspended in a nematic host phase. AB - The complex interplay of molecular scale effects, nonlinearities in the orientational field and long-range elastic forces makes liquid-crystal physics very challenging. A consistent way to extract information from the microscopic, molecular scale up to the meso- and macroscopic scale is still missing. Here, we develop a hybrid procedure that bridges this gap by combining extensive Monte Carlo (MC) simulations, a local Landau-de Gennes theory, classical density functional theory, and finite-size scaling theory. As a test case to demonstrate the power and validity of our novel approach we study the effective interaction among colloids with Boojum defect topology immersed in a nematic liquid crystal. In particular, at sufficiently small separations colloids attract each other if the angle between their center-of-mass distance vector and the far-field nematic director is about 30 degrees . Using the effective potential in coarse-grained two-dimensional MC simulations we show that self-assembled structures formed by the colloids are in excellent agreement with experimental data. PMID- 26477508 TI - South Pacific Environmental Radioactivity Association (SPERA): 2014 conference. PMID- 26477509 TI - Complexes of (eta(6)-benzene)ruthenium(II) with 1,4-bis(phenylthio/seleno-methyl) 1,2,3-triazoles: synthesis, structure and applications in catalytic activation of oxidation and transfer hydrogenation. AB - 1,4-Bis(phenylthio/seleno methyl)-1,2,3-triazoles (L1-L4) synthesized by a 'Click' reaction react with [{(eta(6)-C6H6)RuCl(MU-Cl)}]2 and NH4PF6 resulting in complexes [(eta(6)-C6H6)RuClL]PF6 (1-4 for L = L1-L4) in which the ligands coordinate in a bidentate mode through S/Se and N of triazole. The CH2EPh (E = S or Se) attached to nitrogen of triazole remains pendent. Ligands and complexes have been authenticated with multinuclei NMR, IR and HR-MS. Single crystal structures of complexes 1-4 have been solved. The Ru-S and Ru-Se bond lengths (A) are respectively 2.388(2)/2.3902(19) and 2.5007(4)/2.5262(19). The disposition of benzene ring, N, S/Se and Cl around Ru is of a piano stool type. For catalytic oxidation of alcohols [Oppenauer-type and with N-methylmorpholine-N-oxide (NMO)] and transfer hydrogenation (TH) of carbonyl compounds [with 2-propanol and glycerol] all the four complexes have been found efficient. The optimum catalyst loadings (in mol%) are: 0.01 (NMO), 0.1 (Oppenauer), 0.01 (TH with 2-propanol) and 0.5 (TH with glycerol). Interestingly, time profiles (under optimum conditions) of two catalytic oxidations and TH's are almost similar, suggesting that they are competitive on appropriate catalyst loading. DFT calculations are consistent with somewhat low reactivity of 1 in comparison to those of 2-4. PMID- 26477507 TI - Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease. AB - Stroke and vascular dementia are leading causes of morbidity and mortality. Neuroprotective therapies have been proposed but none have proven clinically tolerated and effective. While overstimulation of N-methyl-d-aspartate-type glutamate receptors (NMDARs) is thought to contribute to cerebrovascular insults, the importance of NMDARs in physiological function has made this target, at least in the view of many in 'Big Pharma,' 'undruggable' for this indication. Here, we describe novel NitroMemantine drugs, comprising an adamantane moiety that binds in the NMDAR-associated ion channel that is used to target a nitro group to redox mediated regulatory sites on the receptor. The NitroMemantines are both well tolerated and effective against cerebral infarction in rodent models via a dual allosteric mechanism of open-channel block and NO/redox modulation of the receptor. Targeted S-nitrosylation of NMDARs by NitroMemantine is potentiated by hypoxia and thereby directed at ischemic neurons. Allosteric approaches to tune NMDAR activity may hold therapeutic potential for cerebrovascular disorders. PMID- 26477510 TI - A rapid and facile preparation of novel macroporous silicone-based cryogels via photo-induced thiol-ene click chemistry. AB - Novel poly(dimethylsiloxane) based macroporous gels (cryogels) were prepared via a simple and rapid photo-induced thiol-ene click reaction at low temperatures. The cryogels formed were able to float on a water surface and selectively remove oils or organic solvents with excellent recyclability. PMID- 26477512 TI - Multicomponent kinetic analysis and theoretical studies on the phenolic intermediates in the oxidation of eugenol and isoeugenol catalyzed by laccase. AB - Laccase catalyzes the oxidation of natural phenols and thereby is believed to initialize reactions in lignification and delignification. Numerous phenolic mediators have also been applied in laccase-mediator systems. However, reaction details after the primary O-H rupture of phenols remain obscure. In this work two types of isomeric phenols, EUG (eugenol) and ISO (trans-/cis-isoeugenol), were used as chemical probes to explore the enzymatic reaction pathways, with the combined methods of time-resolved UV-Vis absorption spectra, MCR-ALS, HPLC-MS, and quantum mechanical (QM) calculations. It has been found that the EUG consuming rate is linear to its concentration, while the ISO not. Besides, an o methoxy quinone methide intermediate, (E/Z)-4-allylidene-2-methoxycyclohexa-2,5 dienone, was evidenced in the case of EUG with the UV-Vis measurement, mass spectra and TD-DFT calculations; in contrast, an ISO-generating phenoxyl radical, a (E/Z)-2-methoxy-4-(prop-1-en-1-yl) phenoxyl radical, was identified in the case of ISO. Furthermore, QM calculations indicated that the EUG-generating phenoxyl radical (an O-centered radical) can easily transform into an allylic radical (a C centered radical) by hydrogen atom transfer (HAT) with a calculated activation enthalpy of 5.3 kcal mol(-1) and then be fast oxidized to the observed eugenol quinone methide, rather than an O-radical alkene addition with barriers above 12.8 kcal mol(-1). In contrast, the ISO-generating phenoxyl radical directly undergoes a radical coupling (RC) process, with a barrier of 4.8 kcal mol(-1), while the HAT isomerization between O- and C-centered radicals has a higher reaction barrier of 8.0 kcal mol(-1). The electronic conjugation of the benzyl type radical and the aromatic allylic radical leads to differentiation of the two pathways. These results imply that competitive reaction pathways exist for the nascent reactive intermediates generated in the laccase-catalyzed oxidation of natural phenols, which is important for understanding the lignin polymerization and may shed some light on the development of efficient laccase-mediator systems. PMID- 26477513 TI - A comparative first principles study on trivalent ion incorporated SSZ-13 zeolites. AB - The dispersion-corrected density functional theory has been used to study the trivalent ions B, Al, Ga, and Fe incorporated SSZ-13-type zeolites. The associated structure and Bronsted/Lewis acidity change caused by the incorporation ions were comparatively studied. It was found that the smaller the radius differences of the incorporation ions are, the smaller the changes in the structure will be and the less acidity will be enhanced for the Bronsted sites. The trivalent Al is found to be the most favorable trivalent incorporation ion and Na is found to be the most favorable charge balanced ion for the synthesis of SSZ-13-type zeolites due to size comparability, which are in line with the experimental observation. The substitution energies which show the relative synthesis difficulty level were also applied for B, Al, Ga, and Fe incorporated zeolites and found that the difficulty decreases with order of Fe > B > Ga ? Al, also in good agreement with the experimental observations. Adsorption studies for the NH3 and pyridine molecules indicate that adsorption on the Bronsted acid sites is more stable than on the Lewis acid sites. The Bronsted acidity was found to follow the order of HAl-SSZ-13 > HGa-SSZ-13 ~ HFe-SSZ-13 > HB-SSZ-13 where the Lewis acidity was found to follow the order of HGa-SSZ-13 ~ HFe-SSZ-13 > HAl-SSZ 13 > HB-SSZ-13. Our results provide new insights for the synthesis of the SSZ-13 type zeolites and fundamental information for the zeolitic catalyst designation to enhance the catalytic performance. PMID- 26477511 TI - Lifespan and Stress Resistance in Drosophila with Overexpressed DNA Repair Genes. AB - DNA repair declines with age and correlates with longevity in many animal species. In this study, we investigated the effects of GAL4-induced overexpression of genes implicated in DNA repair on lifespan and resistance to stress factors in Drosophila melanogaster. Stress factors included hyperthermia, oxidative stress, and starvation. Overexpression was either constitutive or conditional and either ubiquitous or tissue-specific (nervous system). Overexpressed genes included those involved in recognition of DNA damage (homologs of HUS1, CHK2), nucleotide and base excision repair (homologs of XPF, XPC and AP-endonuclease-1), and repair of double-stranded DNA breaks (homologs of BRCA2, XRCC3, KU80 and WRNexo). The overexpression of different DNA repair genes led to both positive and negative effects on lifespan and stress resistance. Effects were dependent on GAL4 driver, stage of induction, sex, and role of the gene in the DNA repair process. While the constitutive/neuron-specific and conditional/ubiquitous overexpression of DNA repair genes negatively impacted lifespan and stress resistance, the constitutive/ubiquitous and conditional/neuron-specific overexpression of Hus1, mnk, mei-9, mus210, and WRNexo had beneficial effects. This study demonstrates for the first time the effects of overexpression of these DNA repair genes on both lifespan and stress resistance in D. melanogaster. PMID- 26477514 TI - Cross-linked Polymer-Blend Gate Dielectrics through Thermal Click Chemistry. AB - New cross-linking reagents were synthesized and mixed with polystyrene (PS) in solution to form a blend. Thin-films were spin-coated from the blend and then cross-linked by thermal activation at relatively low temperature (100 degrees C) to form cross-linked gate dielectrics. This new method is compatible with plastic substrates in flexible electronics. The azide and alkyne cross-linking reagents are kinetically stable at room temperature, so any premature cross-linking is avoided during processing. This method also significantly improved the dielectric performances of PS thin films. Solution-processed top-gate organic field-effect transistor devices with indacenodithiophene-benzothiadiazole copolymer as semiconductor layer and the cross-linked PS blend as dielectric layer showed improved performances with lower gate leakages and higher operation stabilities than devices with neat PS film as dielectric layer. PMID- 26477515 TI - Discovery of Novel Inhibitor Scaffolds against the Metallo-beta-lactamase VIM-2 by Surface Plasmon Resonance (SPR) Based Fragment Screening. AB - Metallo-beta-lactamase (MBL) inhibitors can restore the function of carbapenem antibiotics and therefore help to treat infections of antibiotic resistant bacteria. In this study, we report novel fragments inhibiting the clinically relevant MBL Verona integron-encoded metallo-beta-lactamase (VIM-2). The fragments were identified from a library of 490 fragments using an orthogonal screening approach based on a surface plasmon resonance (SPR) based assay combined with an enzyme inhibition assay. The identified fragments showed IC50 values between 14 and 1500 MUM and ligand efficiencies (LE) between 0.48 and 0.23 kcal/mol per heavy atom. For two of the identified fragments, crystal structures in complex with VIM-2 were obtained. The identified fragments represent novel inhibitor scaffolds and are good starting points for the design of potent MBL inhibitors. Furthermore, the established SPR based assay and the screening approach can be adapted to other MBLs and in this way improve the drug discovery process for this important class of drug targets. PMID- 26477516 TI - Simulation of the dissolved nitrogen and phosphorus loads in different land uses in the Three Gorges Reservoir Region--based on the improved export coefficient model. AB - Nonpoint source pollution is one of the primary causes of eutrophication of water bodies. The concentrations and loads of dissolved pollutants have a direct bearing on the environmental quality of receiving water bodies. Based on the Johnes export coefficient model, a pollutant production coefficient was established by introducing the topographical index and measurements of annual rainfall. A pollutant interception coefficient was constructed by considering the width and slope of present vegetation. These two coefficients were then used as the weighting factors to modify the existing export coefficients of various land uses. A modified export coefficient model was created to estimate the dissolved nitrogen and phosphorus loads in different land uses in the Three Gorges Reservoir Region (TGRR) in 1990, 1995, 2000, 2005, and 2010. The results show that the new land use export coefficient was established by the modification of the production pollution coefficient and interception pollution coefficient. This modification changed the single numerical structure of the original land use export coefficient and takes into consideration temporal and spatial differentiation features. The modified export coefficient retained the change structure of the original single land use export coefficient, and also demonstrated that the land use export coefficient was not only impacted by the change of land use itself, but was also influenced by other objective conditions, such as the characteristics of the underlying surface, amount of rainfall, and the overall presence of vegetation. In the five analyzed years, the simulation values of the dissolved nitrogen and phosphorus loads in paddy fields increased after applying the modification in calculation. The dissolved nitrogen and phosphorus loads in dry land comprised the largest proportions of the TGRR's totals. After modification, the dry land values showed an initial increase and then a decrease over time, but the increments were much smaller than those of the paddy field. The dissolved nitrogen and phosphorus loads in the woodland and meadow decreased after modification. The dissolved nitrogen and phosphorus loads in the building lot were the lowest but showed an increase with the progression of time. These results demonstrate that the modified export coefficient model significantly improves the accuracy of dissolved pollutant load simulation for different land uses in the TGRR, especially the accuracy of dissolved nitrogen load simulation. PMID- 26477517 TI - Helix Sense-Selective Supramolecular Polymerization Seeded by a One-Handed Helical Polymeric Assembly. AB - Helix sense-selective supramolecular polymerization was achieved using a one handed helical nanotubular polymeric assembly as a seed. First, bipyridine (BPY) appended achiral hexabenzocoronene ((BPY)HBC) was copolymerized noncovalently with chiral (BPY)HBC(S) (or (BPY)HBC(R)) at a molar ratio of 9:1, which, via the sergeants-and-soldiers effect, afforded a P-helical (or M-helical) nanotube, which was then treated with Cu(2+) to transform into structurally robust ((BPY)Cu)NT(P) (or ((BPY)Cu)NT(M)) with a Cu(2+)/BPY coordination polymer shell. Helical seeds ((BPY)Cu)NT(P) and ((BPY)Cu)NT(M) brought about the controlled assembly of fluorinated chiral FHBC(S) and FHBC(R) as well as achiral FHBC to yield one-handed helical nanotubular supramolecular block copolymers, in which the helical senses of the newly formed block segments were solely determined by those of the helical seeds employed. Noteworthy, FHBC(S) and FHBC(R) alone without the helical seeds form ill-defined agglomerates. Attempted supramolecular polymerization of a racemic mixture of FHBC(S) and FHBC(R) from ((BPY)Cu)NT(P) (or ((BPY)Cu)NT(M)) resulted in its chiral separation, affording P-helical (or M helical) diastereomeric block segments composed of FHBC(S)and FHBC(R) with different thermodynamic properties. PMID- 26477518 TI - A microsimulation cost-utility analysis of alcohol screening and brief intervention to reduce heavy alcohol consumption in Canada. AB - BACKGROUND AND AIMS: Screening and brief intervention (SBI) is a public health intervention that has been shown to be effective in reducing heavy alcohol consumption. The aim of this study is to estimate the cost-effectiveness of implementing universal alcohol SBI in primary care in Canada. DESIGN: We developed a microsimulation model of alcohol consumption and its effects on 18 alcohol-related causes of death. SETTING: The model simulates a Canadian population. PARTICIPANTS: The model simulates individuals and their alcohol consumption on a continuous scale starting from age 17 years to death. INTERVENTIONS: The reference case assumes no SBI in Canada. The base case assumes screening was conducted using the Alcohol Use Disorders Identification Test (AUDIT) at a threshold score of 8. Additional analyses included evaluating SBI using the AUDIT at threshold scores between 4 and 8 or the Derived Alcohol Use Disorders Identification Test (AUDIT-C) at threshold scores between 3 and 7. MEASUREMENTS: The model estimates the direct health-care costs, life years gained and quality-adjusted life years (QALY) gained, which are then used to estimate the incremental cost-effectiveness ratio (ICER) of SBI versus no SBI. FINDINGS: SBI with AUDIT (at a threshold score of 8) had an ICER of $8729/QALY. Our results suggest that using AUDIT thresholds between 8 and 4, inclusive, would be cost effective for the whole population, as well as for men and women individually. Our results suggest that the AUDIT-C would be cost-effective at thresholds of 7 to 3, inclusive, for men, women and the whole population. CONCLUSIONS: In Canada, screening and brief intervention via Alcohol Use Disorders Identification Test (AUDIT) and Derived Alcohol Use Disorders Identification Test (AUDIT-C) to reduce heavy alcohol consumption appears to be cost-effective for men and women at Alcohol Use Disorders Identification Test (AUDIT) thresholds of 8 and lower and at Derived Alcohol Use Disorders Identification Test (AUDIT-C) thresholds of 7 and lower. PMID- 26477519 TI - Rapid screening of edible oils for phthalates using phase-transfer catalyst assisted hydrolysis and liquid phase microextraction coupled to high performance liquid chromatography-tandem mass spectrometry. AB - Edible oil is easily contaminated with phthalic acid esters (PAEs). Conventional procedures to analyze individual PAEs require very rigorous experimental conditions that are extremely labor-intensive due to significant procedural contaminations generated by the ubiquitous presence of PAEs in the laboratory environment. In this study, a rapid screening method for PAEs in edible oil was successfully developed. Using a phase-transfer catalyst (terabutylammonium bromide) during oil/water biphasic base hydrolysis of PAEs, the hydrolysis time was decreased from a previously reported time of 20 h to 10 min (80 degrees C). The resulting phthalic acid in the acidified hydrolysate was extracted with 600 MUL of tributyl phosphate and then analyzed by high performance liquid chromatography-tandem mass spectrometry in 6 min. Parameters affecting the hydrolysis of PAEs and the extraction of phthalic acid were optimized, and the analytical method was validated. No obvious matrix effect existed in the edible oils whether an external or internal standard method was used. The detection limit was 1.0 MUmol kg(-1), and the quantification limit was 1.3 MUmol kg(-1). The recovery rates varied from 86 to 107% with relative standard deviations equal to or lower than 9.9% in all of the tested conditions. Twenty-six samples were analyzed, and the background corrected total PAE content was found to be in the range of = 5, respectively. Depressive symptoms were defined as a BDI >= 10. RESULTS: The frequency of ED did not differ significantly according to OSA severity. In Spearman's correlation analysis, the BDI and the ESS were inversely correlated with the KIIEF-5, whereas the SAQLI was positively correlated with the KIIEF-5. The RDI and the lowest oxygen saturation (SaO2 ) did not exhibit significant correlations with the KIIEF-5. A multivariate logistic regression analysis adjusted for possible confounding factors showed that ED was independently associated with the SAQLI and depressive symptoms, but there was no significant association of ED with either the RDI or the lowest SaO2 . CONCLUSIONS: The present study demonstrated that depressive symptoms and a low quality of life specific to sleep apnea are independent risk factors for ED in OSA patients. PMID- 26477544 TI - Vaginal epithelial cells regulate membrane adhesiveness to co-ordinate bacterial adhesion. AB - Vaginal epithelium is colonized by different bacterial strains and species. The bacterial composition of vaginal biofilms controls the balance between health and disease. Little is known about the relative contribution of the epithelial and bacterial cell surfaces to bacterial adhesion and whether and how adhesion is regulated over cell membrane regions. Here, we show that bacterial adhesion forces with cell membrane regions not located above the nucleus are stronger than with regions above the nucleus both for vaginal pathogens and different commensal and probiotic lactobacillus strains involved in health. Importantly, adhesion force ratios over membrane regions away from and above the nucleus coincided with the ratios between numbers of adhering bacteria over both regions. Bacterial adhesion forces were dramatically decreased by depleting the epithelial cell membrane of cholesterol or sub-membrane cortical actin. Thus, epithelial cells can regulate membrane regions to which bacterial adhesion is discouraged, possibly to protect the nucleus. PMID- 26477543 TI - High-throughput microanalysis of large lignocellulosic sample sets by pyrolysis gas chromatography/mass spectrometry. AB - High-throughput analytical techniques to assess the chemistry of lignocellulosic plant material are crucial to plant cell-wall research. We have established an analytical platform for this purpose and demonstrated its usefulness with two applications. The system is based on analytical pyrolysis, coupled to gas chromatography/mass spectrometry - a technique particularly suited for analysis of lignocellulose. Automated multivariate-based data-processing methods are used to obtain results within a few hours after analysis, with an experimental batch of 500 analyzed samples. The usefulness of multivariate sample discrimination methods and hierarchical clustering of samples is demonstrated. We have analyzed an Arabidopsis mutant collection consisting of 300 samples representing 31 genotypes. The mutant collection is presented through cluster analysis, based on chemotypic difference, with respect to wild type. Further, we have analyzed 500 thin sections from five biological replicate trees to create a spatial highly resolved profile of the proportions of syringyl-, guaiacyl- and p-hydroxyphenyl lignin across phloem, developing and mature wood in aspen. The combination of biologically easy to interpret information, the low demand of sample amount and the flexibility in sample types amenable to analysis makes this technique a valuable extension to the range of established high-throughput biomaterial analytical platforms. PMID- 26477545 TI - The ABC's of dopamine receptor partial agonists - aripiprazole, brexpiprazole and cariprazine: the 15-min challenge to sort these agents out. PMID- 26477547 TI - Electrospun Ultrafine Fiber Composites Containing Fumed Silica: From Solution Rheology to Materials with Tunable Wetting. AB - Fumed silica (FS) particles with hydrophobic (R805) or hydrophilic (A150) surface functionalities are incorporated in polyacrylonitrile (PAN) fibers by electrospinning to produce mats with controlled wettability. Rheological measurements are conducted to elucidate the particle-polymer interactions and characterize the system while microscopic and analytic tools are used to examine FS location within both fibers and films to aid in the fundamental understanding of wetting behavior. Unlike traditional polymers, we find these systems to be gel like, yet electrospinnable; the fumed silica networks break down into smaller aggregates during the electrospinning process and disperse both within and on the surface of the fibers. Composite nanofiber mats containing R805 FS exhibit an apparent contact angle over 130 degrees and remain hydrophobic over 30 min, while similar mats with A150 display rapid surface-wetting with a static contact angle of ~30 degrees . Wicking experiments reveal that the water absorption properties can be further manipulated, with R805 FS-impregnated mats taking up only 8% water relative to mat weight in 15 min. In contrast, PAN fibers containing A150 FS absorb 425% of water in the same period, even more than the pure PAN fiber (371%). The vastly different responses to water demonstrate the versatility of FS in surface modification, especially for submicron fibrous mats. The role of fumed silica in controlling wettability is discussed in terms of their surface functionality, placement on nanofibers and induced surface roughness. PMID- 26477548 TI - Ultraviolet radiation, vitamin D and multiple sclerosis. AB - There is compelling epidemiological evidence that the risk of developing multiple sclerosis is increased in association with low levels of sun exposure, possibly because this is associated with low vitamin D status. Recent work highlights both vitamin D and non-vitamin D effects on cellular immunity that suggests that higher levels of sun exposure and/or vitamin D status are beneficial for both MS risk and in ameliorating disease progression. Here we review this recent evidence, focusing on regulatory cells, dendritic cells, and chemokines and cytokines released from the skin following exposure to ultraviolet radiation. PMID- 26477546 TI - Joubert Syndrome in French Canadians and Identification of Mutations in CEP104. AB - Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population. PMID- 26477549 TI - Self-emulsifying drug delivery systems in oral (poly)peptide drug delivery. AB - INTRODUCTION: Oral administration of most therapeutic peptides and proteins is mainly restricted due to the enzymatic and absorption membrane barrier of the GI tract. In order to overcome these barriers, various technologies have been explored. Among them, self-emulsifying drug delivery systems (SEDDS) received considerable attention as potential carriers to facilitate oral peptide and protein delivery in recent years. AREAS COVERED: This review article intends to summarize physiological barriers which limit the bioavailability of orally administrated peptide and protein drugs. Furthermore, the potential of SEDDS to protect incorporated peptides and proteins towards peptidases and proteases and to penetrate the mucus layer is reviewed. Their permeation-enhancing properties and their ability to release the drug in a controlled way are described. Moreover, this review covers the results of in vivo studies providing evidence for this promising approach. EXPERT OPINION: As SEDDS can: i) provide a protective effect towards a presystemic metabolism; ii) efficiently permeate the intestinal mucus gel layer in order to reach the absorption membrane; and iii) be produced in a very simple and cost-effective manner, they are a promising tool for oral peptide and protein drug delivery. PMID- 26477550 TI - Contrast Media Extravasation of Computed Tomography and Magnetic Resonance Imaging: Management Guidelines for the Radiologist. AB - Intravenous contrast administration has been of great importance in diagnostic radiology, but it is not without risks either due to the local, systemic allergic reactions or due to subcutaneous extravasation of contrast media. Subcutaneous contrast medium extravasationis an infrequent, yet a well-recognized complication. However, most incidents are minor and can be managed conservatively, but there are a few cases that require immediate surgical intervention. This article discusses the risks factors, clinical manifestations, and conservative and surgical approaches of subcutaneous contrast media extravasation for both computed tomography and magnetic resonance imaging. PMID- 26477551 TI - A new identity for asthma. PMID- 26477552 TI - Reframing the varenicline question: have anecdotes and emotional filters clouded our decision making? PMID- 26477553 TI - Decision making in long-term ventilation for children. PMID- 26477554 TI - Life in a bubble. PMID- 26477555 TI - A systems approach to burnout. PMID- 26477556 TI - Structure, Optical Absorption, and Performance of Organic Solar Cells Improved by Gold Nanoparticles in Buffer Layers. AB - 11-Mercaptoundecanoic acid (MUA)-stabilized gold nanoparticles (AuNPs) embedded in copper phthalocyanine (CuPc) were used as a buffer layer between a poly(3 hexyl-thiophene) (P3HT)/[6,6]-phenyl C61-butyric acid methyl ester (PCBM) bulk heterojunction and anodic indium-tin oxide (ITO) substrate. As systematic synchrotron-based grazing incidence X-ray diffraction (GIXRD) experiments demonstrated that the AuNPs present in the buffer layer can improve the microstructure of the active layer with a better lamella packing of P3HT from the surface to the interior, UV-visible absorption spectrum measurements revealed enhanced optical absorption due to the localized surface plasma resonance (LSPR) generated by the AuNPs. The device of ITO/poly(3,4 ethylenedioxythiophene):polystyrenesulfonate/CuPc:MUA-stabilized AuNPs/P3HT:PCBM/LiF/Al was found with over 24% enhancement of power conversion efficiency (PCE) in comparison with reference devices without AuNPs. This remarkable improvement in PCE should be partially attributed to LSPR generated by the AuNPs and partially to improved crystallization as well as preferred orientation order of P3HT due to the presence of the AuNPs, which would promote more applications of metal NPs in the organic photovoltaic devices and other organic multilayer devices. PMID- 26477557 TI - Omovertebral bone associated with Sprengel deformity presented with chronic cervical pain. PMID- 26477558 TI - Patterning mechanisms of the sub-intestinal venous plexus in zebrafish. AB - Despite considerable interest in angiogenesis, organ-specific angiogenesis remains less well characterized. The vessels that absorb nutrients from the yolk and later provide blood supply to the developing digestive system are primarily venous in origin. In zebrafish, these are the vessels of the Sub-intestinal venous plexus (SIVP) and they represent a new candidate model to gain an insight into the mechanisms of venous angiogenesis. Unlike other vessel beds in zebrafish, the SIVP is not stereotypically patterned and lacks obvious sources of patterning information. However, by examining the area of vessel coverage, number of compartments, proliferation and migration speed we have identified common developmental steps in SIVP formation. We applied our analysis of SIVP development to obd mutants that have a mutation in the guidance receptor PlexinD1. obd mutants show dysregulation of nearly all parameters of SIVP formation. We show that the SIVP responds to a unique combination of pathways that control both arterial and venous growth in other systems. Blocking Shh, Notch and Pdgf signaling has no effect on SIVP growth. However Vegf promotes sprouting of the predominantly venous plexus and Bmp promotes outgrowth of the structure. We propose that the SIVP is a unique model to understand novel mechanisms utilized in organ-specific angiogenesis. PMID- 26477560 TI - Selective chromatid segregation mechanism proposed for the human split hand/foot malformation development by chromosome 2 translocations: A perspective. AB - Three unrelated chromosome 2q14.1-14.2 region translocations caused the split hand/foot limb malformation development in humans by an unknown mechanism. Their etiology was described by the autosomal dominant inheritance with incomplete penetrance genetic model although authors stated, "the understanding of the genotype-to-phenotype relationship has been most challenging". The conundrums are that no mutation was found in known genes located at or near the translocation breakpoints, some limbs were malformed while others were not in the same patient and surprisingly breakpoints lie at relatively large distance of more than 2.5 million bases to have caused disorder-causing gene mutations in a single gene. To help understand translocations etiology for limb development, we invoke the selective DNA strand/chromatid-specific epigenetic imprinting and segregation mechanism employed by the two highly diverged fission yeasts to produce daughter cells of different cell types by mitosis. By this mechanism, an anterior- and posterior-limb-tissues-generating pair of daughter cells is produced by a single deterministic cell dividing in the anlagen of the limb bud. Accordingly, malformation develops simply because translocations hinder the proper distribution of chromatid-specific epialleles of a limb developmental gene during the deterministic cell's mitosis. It is tempting to speculate that such a mechanism might involve the HOXD-cluster genes situated centromere-distal to the translocation breakpoints many million bases away at the 2q31.1 region. Further genetic tests of the hypothesis are proposed for the human and mouse limb development. In sum, genetic analysis of translocations suggests that the sequence asymmetry of strands in the double-helical DNA structure of a developmental gene forms the physical basis of daughter cells' developmental asymmetry, thus opposing the morphogen-gradient research paradigm of limb development. PMID- 26477559 TI - Dynamic membrane depolarization is an early regulator of ependymoglial cell response to spinal cord injury in axolotl. AB - Salamanders, such as the Mexican axolotl, are some of the few vertebrates fortunate in their ability to regenerate diverse structures after injury. Unlike mammals they are able to regenerate a fully functional spinal cord after injury. However, the molecular circuitry required to initiate a pro-regenerative response after spinal cord injury is not well understood. To address this question we developed a spinal cord injury model in axolotls and used in vivo imaging of labeled ependymoglial cells to characterize the response of these cells to injury. Using in vivo imaging of ion sensitive dyes we identified that spinal cord injury induces a rapid and dynamic change in the resting membrane potential of ependymoglial cells. Prolonged depolarization of ependymoglial cells after injury inhibits ependymoglial cell proliferation and subsequent axon regeneration. Using transcriptional profiling we identified c-Fos as a key voltage sensitive early response gene that is expressed specifically in the ependymoglial cells after injury. This data establishes that dynamic changes in the membrane potential after injury are essential for regulating the specific spatiotemporal expression of c-Fos that is critical for promoting faithful spinal cord regeneration in axolotl. PMID- 26477561 TI - Ribbon regulates morphogenesis of the Drosophila embryonic salivary gland through transcriptional activation and repression. AB - Transcription factors affect spatiotemporal patterns of gene expression often regulating multiple aspects of tissue morphogenesis, including cell-type specification, cell proliferation, cell death, cell polarity, cell shape, cell arrangement and cell migration. In this work, we describe a distinct role for Ribbon (Rib) in controlling cell shape/volume increases during elongation of the Drosophila salivary gland (SG). Notably, the morphogenetic changes in rib mutants occurred without effects on general SG cell attributes such as specification, proliferation and apoptosis. Moreover, the changes in cell shape/volume in rib mutants occurred without compromising epithelial-specific morphological attributes such as apicobasal polarity and junctional integrity. To identify the genes regulated by Rib, we performed ChIP-seq analysis in embryos driving expression of GFP-tagged Rib specifically in the SGs. To learn if the Rib binding sites identified in the ChIP-seq analysis were linked to changes in gene expression, we performed microarray analysis comparing RNA samples from age matched wild-type and rib null embryos. From the superposed ChIP-seq and microarray gene expression data, we identified 60 genomic sites bound by Rib likely to regulate SG-specific gene expression. We confirmed several of the identified Rib targets by qRT-pCR and/or in situ hybridization. Our results indicate that Rib regulates cell growth and tissue shape in the Drosophila salivary gland via a diverse array of targets through both transcriptional activation and repression. Furthermore, our results suggest that autoregulation of rib expression may be a key component of the SG morphogenetic gene network. PMID- 26477562 TI - Visualizing functional pathways in the human brain using correlation tensors and magnetic resonance imaging. AB - Functional magnetic resonance imaging usually detects changes in blood oxygenation level dependent (BOLD) signals from T2*-sensitive acquisitions, and is most effective in detecting activity in brain cortex which is irrigated by rich vasculature to meet high metabolic demands. We recently demonstrated that MRI signals from T2*-sensitive acquisitions in a resting state exhibit structure specific temporal correlations along white matter tracts. In this report we validate our preliminary findings and introduce spatio-temporal functional correlation tensors to characterize the directional preferences of temporal correlations in MRI signals acquired at rest. The results bear a remarkable similarity to data obtained by diffusion tensor imaging but without any diffusion encoding gradients. Just as in gray matter, temporal correlations in resting state signals may reflect intrinsic synchronizations of neural activity in white matter. Here we demonstrate that functional correlation tensors are able to visualize long range white matter tracts as well as short range sub-cortical fibers imaged at rest, and that evoked functional activities alter these structures and enhance the visualization of relevant neural circuitry. Furthermore, we explore the biophysical mechanisms underlying these phenomena by comparing pulse sequences, which suggest that white matter signal variations are consistent with hemodynamic (BOLD) changes associated with neural activity. These results suggest new ways to evaluate MRI signal changes within white matter. PMID- 26477565 TI - Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex. AB - We have analyzed the distribution of mitochondrial contact site and cristae organizing system (MICOS) complex proteins and mitochondrial intermembrane space bridging complex (MIB) proteins over (sub)complexes and over species. The MICOS proteins are associated with the formation and maintenance of mitochondrial cristae. Indeed, the presence of MICOS genes in genomes correlates well with the presence of cristae: all cristae containing species have at least one MICOS gene and cristae-less species have none. Mic10 is the most widespread MICOS gene, while Mic60 appears be the oldest one, as it originates in the ancestors of mitochondria, the proteobacteria. In proteobacteria the gene occurs in clusters with genes involved in heme synthesis while the protein has been observed in intracellular membranes of the alphaproteobacterium Rhodobacter sphaeroides. In contrast, Mic23 and Mic27 appear to be the youngest MICOS proteins, as they only occur in opisthokonts. The remaining MICOS proteins, Mic10, Mic19, Mic25 and Mic12, the latter we show to be orthologous to human C19orf70/QIL1, trace back to the root of the eukaryotes. Of the remaining MIB proteins, also DNAJC11 shows a high correlation with the presence of cristae. In mitochondrial protein complexome profiles, the MIB complex occurs as a defined complex and as separate subcomplexes, potentially reflecting various assembly stages. We find three main forms of the complex: A) The MICOS complex, containing all the MICOS proteins, B) a membrane bridging subcomplex, containing in addition SAMM50, MTX2 and the previously uncharacterized MTX3, and C) the complete MIB complex containing in addition DNAJC11 and MTX1. PMID- 26477563 TI - An Xist-activating antisense RNA required for X-chromosome inactivation. AB - The transcriptional imbalance due to the difference in the number of X chromosomes between male and female mammals is remedied through X-chromosome inactivation, the epigenetic transcriptional silencing of one of the two X chromosomes in females. The X-linked Xist long non-coding RNA functions as an X inactivation master regulator; Xist is selectively upregulated from the prospective inactive X chromosome and is required in cis for X inactivation. Here we discover an Xist antisense long non-coding RNA, XistAR (Xist Activating RNA), which is encoded within exon 1 of the mouse Xist gene and is transcribed only from the inactive X chromosome. Selective truncation of XistAR, while sparing the overlapping Xist RNA, leads to a deficiency in Xist RNA expression in cis during the initiation of X inactivation. Thus, the Xist gene carries within its coding sequence an antisense RNA that drives Xist expression. PMID- 26477566 TI - Agonist-induced changes in RalA activities allows the prediction of the endocytosis of G protein-coupled receptors. AB - GTP binding proteins are classified into two families: heterotrimeric large G proteins which are composed of three subunits, and one subunit of small G proteins. Roles of small G proteins in the intracellular trafficking of G protein coupled receptors (GPCRs) were studied. Among various small G proteins tested, GTP-bound form (G23V) of RalA inhibited the internalization of dopamine D2 receptor independently of the previously reported downstream effectors of RalA, such as Ral-binding protein 1 and PLD. With high affinity for GRK2, active RalA inhibited the GPCR endocytosis by sequestering the GRK2 from receptors. When it was tested for several GPCRs including an endogenous GPCR, lysophosphatidic acid receptor 1, agonist-induced conversion of GTP-bound to GDP-bound RalA, which presumably releases the sequestered GRK2, was observed selectively with the GPCRs which have tendency to undergo endocytosis. Conversion of RalA from active to inactive state occurred by translocation of RGL, a guanine nucleotide exchange factor, from the plasma membrane to cytosol as a complex with Gbetagamma. These results suggest that agonist-induced Gbetagamma-mediated conversion of RalA from the GTP-bound form to the GDP-bound form could be a mechanism to facilitate agonist-induced internalization of GPCRs. PMID- 26477568 TI - Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain. AB - Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, "decoy" antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling. PMID- 26477570 TI - Dissociation in control of physiological and behavioral responses to emotional stress by cholinergic neurotransmission in the bed nucleus of the stria terminalis in rats. AB - The bed nucleus of the stria terminalis (BNST) is a forebrain structure implicated in physiological and behavioral responses to emotional stress. However, the local neurochemical mechanisms mediating the BNST control of stress responses are not fully known. Here, we investigated the involvement of BNST cholinergic neurotransmission, acting via muscarinic receptors, in cardiovascular (increase in blood pressure and heart rate and fall in tail skin temperature) and neuroendocrine (increase in plasma corticosterone) responses and behavioral consequences (anxiogenic-like effect in the elevated plus-maze) evoked by acute restraint stress in rats. Bilateral microinjection into the BNST of either the choline uptake inhibitor hemicholinium-3 (3 nmol/100 nl) or the muscarinic receptor antagonist methylatropine (3 nmol/100 nl) enhanced the heart rate increase and inhibited the anxiogenic-like effect observed in the elevated plus maze evoked by restraint. However, neither hemicholinium-3 nor methylatropine affected the increase in blood pressure and plasma corticosterone levels and the fall in tail skin temperature. Facilitation of local cholinergic signaling by microinjection of the acetylcholinesterase inhibitor neostigmine (0.1 nmol/100 nl) into the BNST reduced restraint-evoked pressor and tachycardiac responses and the fall in tail cutaneous temperature, without affecting the increase in plasma corticosterone. All effects of neostigmine were completely abolished by local BNST pretreatment with methylatropine. These findings indicate an opposite role of BNST cholinergic neurotransmission, acting via local muscarinic receptor, in control of cardiovascular responses (inhibitory influence) and emotional consequences (facilitatory influence) evoked by restraint stress. Furthermore, present findings provide evidence that BNST control of neuroendocrine responses to stress is mediated by mechanisms others than local cholinergic signaling. PMID- 26477571 TI - The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT(1A) and 5-HT(2A) receptors. AB - 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen, acting as a non-selective serotonin 5-HT(1A)/5-HT(2A)-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT(1A)-R and 5-HT(2A)-R, using wild type (WT) and 5-HT(2A)-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT(1A)-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT(1A)-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT(1A)-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT(1A)-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT(2A)-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development. PMID- 26477567 TI - Phosphorylation and isoform use in p120-catenin during development and tumorigenesis. AB - P120-catenin is essential to vertebrate development, modulating cadherin and small-GTPase functions, and growing evidence points also to roles in the nucleus. A complexity in addressing p120-catenin's functions is its many isoforms, including optional splicing events, alternative points of translational initiation, and secondary modifications. In this review, we focus upon how choices in the initiation of protein translation, or the earlier splicing of the RNA transcript, relates to primary sequences that harbor established or putative regulatory phosphorylation sites. While certain p120 phosphorylation events arise via known kinases/phosphatases and have defined outcomes, in most cases the functional consequences are still to be established. In this review, we provide examples of p120-isoforms as they relate to phosphorylation events, and thereby to isoform dependent protein-protein associations and downstream functions. We also provide a view of upstream pathways that determine p120's phosphorylation state, and that have an impact upon development and disease. Because other members of the p120 subfamily undergo similar processing and phosphorylation, as well as related catenins of the plakophilin subfamily, what is learned regarding p120 will by extension have wide relevance in vertebrates. PMID- 26477569 TI - Estrogen accelerates the resolution of inflammation in macrophagic cells. AB - Although 17beta-estradiol (E2) anti-inflammatory activity has been well described, very little is known about the effects of this hormone on the resolution phase of the inflammatory process. Here, we identified a previously unreported ERalpha-mediated effect of E2 on the inflammatory machinery. The study showed that the activation of the intracellular estrogen receptor shortens the LPS-induced pro-inflammatory phase and, by influencing the intrinsic and extrinsic programs, triggers the resolution of inflammation in RAW 264.7 cells. Through the regulation of the SOCS3 and STAT3 signaling pathways, E2 facilitates the progression of the inflammatory process toward the IL10-dependent "acquired deactivation" phenotype, which is responsible for tissue remodeling and the restoration of homeostatic conditions. The present study may provide an explanation for increased susceptibility to chronic inflammatory diseases in women after menopause, and it suggests novel anti-inflammatory treatments for such disorders. PMID- 26477574 TI - Development of a new integrative toxicity index based on an improvement of the sea urchin embryo toxicity test. AB - The sea urchin embryo toxicity test is classically used to assess the noxious effects of contaminated marine waters and sediments. In Italian guidelines on quality of dredged sediments, the standard toxicity criteria used for this assay are based on a single endpoint at 48 hours of development, corresponding to the pluteus stage. Different typologies of abnormalities, including those which occur at earlier stages, are not categorized, thus preventing the evaluation of the actual teratogenic hazards. A new integrative toxicity index has been developed in this study based on the analysis of two developmental stages, at 24 and 48h post-fertilization, and the differentiation between development delays and germ layers impairments: the new toxicity index is calculated by integrating the frequency of abnormal embryos with the severity of such abnormalities. When tested on dredged sediments, the evaluation of increasing levels of toxicity affecting embryonic outcomes enhanced the capability to discriminate different samples, appearing particularly relevant to validate the sea urchin embryo toxicity assay, and supporting its utility in practical applications such as the sediments classification in harbor areas. PMID- 26477573 TI - Neurobehavioral Anomalies in the Pitx3/ak Murine Model of Parkinson's Disease and MPTP. AB - Pitx3/ak null mutants are characterized by basal ganglia pathology in a manner resembling Parkinson's disease (PD), with decline in substantia nigra cell numbers as well as striatal tyrosine hydroxylase expression. Although young adult Pitx3/ak mutants were deficient in motor coordination tests, they were more active than non-transgenic controls in the open-field, unlike PD-related bradykinesia. On the SHIRPA primary screen, the mutants displayed body tremor, hyperactivity in the viewing jar, anomalies in eye morphology as well as a higher degree of hindlimb clasping and myoclonic jumping. Increased hindlimb clasping time and rotorod deficits seen in mutants were also exhibited by mice injected with MPTP, indicating an influence of dopamine on these behaviors. PMID- 26477572 TI - Genetic and Environmental Contributions to Behavioral Stability and Change in Children 6-36 months of Age Using Louisville Twin Study Data. AB - The Infant Behavior Record (IBR) from the Bayley Scales of Infant Development has been used to study behavioral development since the 1960s. Matheny (1983) examined behavioral development at 6, 12, 18, and 24 months from the Louisville Twin Study (LTS). The extracted temperament scales included Task Orientation, Affect-Extraversion, and Activity. He concluded that monozygotic twins were more similar than same-sex dizygotic twins on these dimensions. Since this seminal work was published, a larger LTS sample and more advanced analytical methods are available. In the current analyses, Choleksy decomposition was applied to behavioral data (n = 1231) from twins 6-36 months. Different patterns of genetic continuity vs genetic innovations were identified for each IBR scale. Single common genetic and shared environmental factors explained cross-age twin similarity in the Activity scale. Multiple shared environmental factors and a single genetic factor coming on line at age 18 months contributed to Affect Extraversion. A single shared environmental factor and multiple genetic factors explained cross-age twin similarity in Task Orientation. PMID- 26477575 TI - The first mollusk spatzle homolog gene in the clam, Paphia undulate. AB - Spatzle, is the only identified endogenous Toll receptor ligand, plays a critical role in initiatinge innate immune responses and controlling dorsal-ventral axis formation in Drosophila. Here we identified the first spatzle gene homolog, Pu Spz, in the marine mollusk Paphia undulate. The full-length of Pu-Spz cDNA is 1248 bp, including an open reading frame (ORF) of 702 bp, a 5'-untranslated region (UTR) of 26 bp and a 3'-UTR of 203 bp. The ORF encodes a 233-amino-acid protein with conserved domains; it includes a putative signal peptide and a C terminal cystine-knot. Sequence alignment revealed that the cystine-knot domain of Pu-Spz contains six highly conserved Cys residues, which maintain a molecular conformation suitable for Toll receptor binding. Unlike Spatzle, Pu-Spz lacks a seventh Cys residue, which is essential for forming intermolecular disulfide bridge. Phylogenetic analysis revealed that Pu-Spz is closer to the homologs found in crustaceans than to those in the insect branch. Transcript abundance of Pu-Spz was increased after challenging P. undulate with either heat-killed Listeria monocytogenes or heat-killed Vibrio alginolyticus, suggesting Spatzle is involved in P. undulate host defense. Our results demonstrate convergent evolution of the spatzle-Toll system between the mollusk and arthropod lineages. PMID- 26477576 TI - Molecular structure and functional characterization of the gamma-interferon inducible lysosomal thiol reductase (GILT) gene in largemouth bass (Microptenus salmoides). AB - The enzyme gamma-interferon-inducible lysosomal thiol reductase (GILT) plays a role in facilitating the processing and presentation of major histocompatibility complex (MHC) class II-restricted antigens and is also involved in MHC I restricted antigens in adaptive immunity catalyzing disulfide bond reduction in mammals. In this study, we cloned a GILT gene homolog from largemouth bass (designated 'lbGILT'), a freshwater fish belonging to Perciformes and known for its nutritive value. We obtained the full-length cDNA of lbGILT by reverse transcription PCR and rapid amplification of cDNA ends. This cDNA is comprised of a 5'-untranslated region (UTR) of 87 bp, a 3'-UTR of 189 bp, and an open reading frame of 771 bp. It encodes a protein of 256 amino acids with a deduced molecular weight of 28.548 kDa and a predicted isoelectric point of 5.62. The deduced protein possesses the typical structural features of known GILTs, including an active site motif, two potential N-linked glycosylation sites, a GILT signature sequence, and six conserved cysteines. Tissue-specific expression of lbGILT was shown by real-time quantitative PCR. The expression of lbGILT mRNA was obviously up regulated in spleen and kidney after induction with lipopolysaccharide. Recombinant lbGILT was produced as an inclusion body with a His6 tag in ArcticExpress (DE3), and the protein was then washed, solubilized, and refolded. The refolded lbGILT showed reduction activity against an IgG substrate. These results suggest that lbGILT plays a role in innate immunity. PMID- 26477578 TI - Multi-phase functionalization of titanium for enhanced photon absorption in the vis-NIR region. AB - Inadequate absorption of Near Infrared (NIR) photons by conventional silicon solar cells has been a major stumbling block towards the attainment of a high efficiency "full spectrum" solar cell. An effective enhancement in the absorption of such photons is desired as they account for a considerable portion of the tappable solar energy. In this work, we report a remarkable gain observed in the absorption of photons in the near infrared and visible region (400 nm-1000 nm) by a novel multi-phased oxide of titanium. Synthesised via a single step ultra-fast laser pulse interaction with pure titanium, characterisation studies have identified this oxide of titanium to be multi-phased and composed of Ti3O, (TiO.716)3.76 and TiO2 (rutile). Computed to have an average band gap value of 2.39 eV, this ultrafast laser induced multi-phased titanium oxide has especially exhibited steady absorption capability in the NIR range of 750-1000 nm, which to the best of our knowledge, was never reported before. The unique NIR absorption properties of the laser functionalised titanium coupled with the simplicity and versatility of the ultrafast laser interaction process involved thereby provides tremendous potential towards the photon sensitization of titanium and thereafter for the inception of a "full spectrum" solar device. PMID- 26477577 TI - Eltrombopag enhances platelet adhesion by upregulating the expression of glycoprotein VI in patients with chronic immune thrombocytopenic purpura. AB - Eltrombopag, a thrombopoietin receptor agonist, has been approved for the treatment of patients with immune thrombocytopenia because of its abilities to enhance platelet production and reduce hemorrhage. Both platelet count and platelet adhesion are crucial to stop bleeding. Although eltrombopag is known to improve platelet counts, its effects on platelet adhesion are not yet known. This study aimed to assess the efficacy of eltrombopag on platelet production and platelet adhesive affinity. To evaluate the efficacy of low-dose eltrombopag (25 mg) for patients with chronic refractory immune thrombocytopenic purpura (ITP) and to determine the ex vivo platelet adhesion ability before and after treatment with eltrombopag, we conducted an open-label, multicenter study in which 25 Taiwanese patients with chronic ITP were enrolled. During the 6-month evaluation, the starting and maximum doses of eltrombopag were 25 and 50 mg, respectively, to maintain the platelet count of >=50,000 per MUL. Flow-based adhesion assay was used to detect the percentage of platelets adhering to immobilized von Willebrand factor-collagen on microslides. Of the enrolled patients, 48% achieved a platelet count of >=50,000 per MUL. Interestingly, 83% of all responders required 25 mg of eltrombopag daily to achieve the target platelet count. In addition, the percentage of bleeding patients was significantly reduced in both responders and nonresponders by 50% from the baseline level throughout the treatment period. The ex vivo platelet adhesion capacity was elevated after the 6-month eltrombopag treatment in both responders and nonresponders. Furthermore, glycoprotein VI (GPVI) expression was significantly upregulated after treatment with eltrombopag. Low-to-intermediate dose of eltrombopag showed good efficacy to expedite platelet production and augment platelet adhesion. These 2 factors might explain the efficacy of eltrombopag in ameliorating hemorrhage in patients with ITP. PMID- 26477579 TI - Microwave axial dielectric properties of carbon fiber. AB - Randomly distributed carbon fibers (CFs) reinforced epoxy resin composites are prepared by the pouring method, the dielectric properties of CF composites with different fiber content and length have been performed in the frequency range from 8.2 to 12.4 GHz. The complex permittivity of the composite increases with the fiber length, which is attributed to the decrease of depolarization field, and increases with the volume fraction, which is attributed to the increase of polarization. A formula, based on the theory of Reynolds-Hugh, is proposed to calculate the effective permittivity of CF composites, and validated by the experiments. The proposed formula is further applied to derive the axial permittivity of CF and analyze the effect of fiber length on the axial permittivity. PMID- 26477580 TI - Multi-step control over self-assembled hydrogels of peptide-derived building blocks and a polymeric cross-linker. AB - We present a detailed study of self-assembled hydrogels of bundled and cross linked networks consisting of positively charged amyloid-like nanofibers and a triblock copolymer with negatively charged end blocks as a cross-linker. In a first step small oligopeptides self-assemble into macrocycles which are held together by reversible disulfide bonds. Interactions between the peptides cause the macrocycles to assemble into nanofibers, which form a reversible hydrogel. The physical properties of the hydrogel are tuned using various methods such as control over the fibre length, addition of a cross-linking copolymer, and addition of salt. We establish a relationship between the bulk mechanical properties, the properties of the individual fibers and the hydrogel morphology using characterization techniques operating at different length scales such as rheology, atomic force microscopy (AFM) and cryo transmission electron microscopy (Cryo-TEM). This allows for a precise control of the elastic behaviour of these networks. PMID- 26477582 TI - Dipyrrolyphenol as a precursor of pi-electronic anion that forms ion pairs with cations. AB - A nitro-substituted dipyrrolylphenol was synthesized as a precursor of a pi electronic anion, whose phenolate (phenoxide) moiety upon deprotonation was stabilized by the hydrogen-bond-donating pyrrole NH, thus forming solid-state ion pairs with various cationic species. PMID- 26477581 TI - Bioaccessibility of Ba, Cu, Pb, and Zn in urban garden and orchard soils. AB - Exposure of young children to toxic metals in urban environments is largely due to soil and dust ingestion. Soil particle size distribution and concentrations of toxic metals in different particle sizes are important risk factors in addition to bioaccessibility of these metals in the particles. Analysis of particle size distribution and metals concentrations for 13 soils, 12 sampled from urban gardens and 1 from orchard found that fine particles (<105 MUm) comprised from 22 to 66% by weight of the tested soils, with Ba, Cu, Pb and Zn generally at higher concentrations in the finer particles. However, metal bioaccessibility was generally lower in finer particles, a trend most pronounced for Ba and Pb. Gastric was higher than gastrointestinal bioaccessibility for all metals except Cu. The lower bioaccessibility of Pb in urban garden soils compared to orchard soil is attributable to the higher organic matter content of the garden soils. PMID- 26477584 TI - Ionogel based on biopolymer-silica interpenetrated networks: dynamics of confined ionic liquid with lithium salt. AB - Obtaining solid-state electrolytes with good electrochemical performances remains challenging. Ionogels, i.e. solid host networks confining an ionic liquid, are promising as they keep the macroscopic properties of the liquid. However, confinement of an ionic liquid can imply important changes in its molecular dynamics, depending on the route of synthesis and on the confining network. We studied this effect on an imidazolium based ionic liquid with its lithium salt confined in a hybrid biopolymer-silica matrix. Dynamics of bulk and confined solution was probed by quasi-elastic neutron scattering (QENS) which revealed a weakly slowed dynamics of imidazolium-based ionic liquid inside the polymer silica host network. PMID- 26477585 TI - Multifunctional pure and Eu(3+) doped beta-Ag2MoO4: photoluminescence, energy transfer dynamics and defect induced properties. AB - Pure and Eu(3+) doped beta-Ag2MoO4 were synthesized using a co-precipitation method at room temperature. The as prepared compounds were characterized systematically using X-ray diffraction (XRD), photoluminescence (PL) spectroscopy, cyclic voltammetry (CV) and positron annihilation lifetime spectroscopy (PALS). It is observed that pure beta-Ag2MoO4 gives blue (445 nm) and green (550 nm) emission when irradiated with UV light. The origin of the green band was qualitatively explained from density functional theory (DFT) calculations using a suitable distortion model. It was observed that on doping europium ions, efficient energy transfer from molybdate to europium takes place. The excitation spectrum depicting f-f transitions (particularly 395 nm and 465 nm peaks) is much more intense than the CTB showing that Eu(3+) ions can be effectively excited by near UV-light. Based on DFT calculations it is proposed that due to the occurrence of Eu(3+) d-states in the conduction band (CB) as well as the strong contribution of Eu(3+) d-states to the impurity level present in the vicinity of the Fermi level, the host (beta-Ag2MoO4) to dopant (Eu(3+)) energy transfer is preferable. beta-Ag2MoO4 is also explored as a potential candidate for electrocatalysis of the oxygen reduction reaction (ORR). It was observed that the doping of europium ions in beta-Ag2MoO4 enhances the electrocatalytic activity toward the ORR. The presence of a large concentration of cation vacancies and large surface defects as suggested by positron annihilation lifetime spectroscopy (PALS) seem to be aiding the ORR. PMID- 26477583 TI - Bv8/prokineticin 2 is involved in Abeta-induced neurotoxicity. AB - Bv8/Prokineticin 2 (PROK2) is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Among multiple biological roles demonstrated for PROK2, it was recently established that PROK2 is an insult inducible endangering mediator for cerebral damage. Aim of the present study was to evaluate the PROK2 and its receptors' potential involvement in amyloid beta (Abeta) neurotoxicity, a hallmark of Alzheimer's disease (AD) and various forms of traumatic brain injury (TBI). Analyzing primary cortical cultures (CNs) and cortex and hippocampus from Abeta treated rats, we found that PROK2 and its receptors PKR1 and PKR2 mRNA are up-regulated by Abeta, suggesting their potential involvement in AD. Hence we evaluated if impairing the prokineticin system activation might have protective effect against neuronal death induced by Abeta. We found that a PKR antagonist concentration-dependently protects CNs against Abeta(1-42)-induced neurotoxicity, by reducing the Abeta-induced PROK2 neuronal up-regulation. Moreover, the antagonist completely rescued LTP impairment in hippocampal slices from 6 month-old Tg2576 AD mice without affecting basal synaptic transmission and paired pulse-facilitation paradigms. These results indicate that PROK2 plays a role in cerebral amyloidosis and that PROK2 antagonists may represent a new approach for ameliorating the defining pathology of AD. PMID- 26477586 TI - Ordered growth of vanadyl phthalocyanine (VOPc) on an iron phthalocyanine (FePc) monolayer. AB - The growth and characterisation of a non-planar phthalocyanine (vanadyl phthalocyanine, VOPc) on a complete monolayer (ML) of a planar phthalocyanine (Iron(II) phthalocyanine, FePc) on an Au(111) surface, has been investigated using ultra-high vacuum (UHV) scanning tunnelling microscopy (STM) and low energy electron diffraction (LEED). The surface mesh of the initial FePc monolayer has been determined and shown to correspond to an incommensurate overlayer, not commensurate as previously reported. Ordered islands of VOPc, with (1 * 1) epitaxy, grow on the FePc layer at submonolayer coverages. The individual VOPc molecules occupy sites directly atop the underlying FePc molecules, indicating that significant intermolecular bonding must occur. It is proposed that this interaction implies that the V[double bond, length as m-dash]O points down into the surface, allowing a Fe-O bond to form. The detailed appearance of the STM images of the VOPc molecules is consistent with previous studies in other VOPc growth studies in which this molecular orientation has been proposed. PMID- 26477587 TI - Synthesis and photophysics of selective functionalized pi-conjugated, blue light emitting, highly fluorescent C7-imidazo indolizine derivatives. AB - A new family of novel highly fluorescent pi-conjugated, C7-imidazole based indolizine derivatives has been prepared in good to excellent yields, catalysed by l-proline in acetonitrile. These are pi-conjugated, C7-imidazole based indolizine derivatives covering the emission wavelength range 423-449 nm in acetonitrile with high quantum yields at 25 degrees C. A thorough photophysical study of all the compounds has been carried out to understand the pi-conjugated electronic effect of the imidazole moiety fused at the C7 position on the indolizine motif. In addition, a comparative photophysical study of three selective fluorophores was also carried out in a wide variety of solvents at 25 degrees C. Finally, the molecular orbitals of the two representative compounds were investigated through DFT calculations to illustrate the pi-conjugate effect. PMID- 26477588 TI - Comprehensive Cytomorphologic Analysis of Pulmonary Adenoid Cystic Carcinoma: Comparison to Small Cell Carcinoma and Non-pulmonary Adenoid Cystic Carcinoma. AB - BACKGROUND: Cytologic diagnosis of pulmonary adenoid cystic carcinoma (AdCC) is frequently challenging and differential diagnosis with small cell carcinoma is often difficult. METHODS: Eleven cytologically diagnosed cases of pulmonary AdCC were collected and reviewed according to fifteen cytomorphologic characteristics: small cell size, cellular uniformity, coarse chromatin, hyperchromasia, distinct nucleolus, frequent nuclear molding, granular cytoplasm, organoid cluster, sheet formation, irregular border of cluster, hyaline globule, hyaline basement membrane material, individual cell necrosis or apoptotic body, and necrotic background. Twenty cases of small cell carcinoma and fifteen cases of non pulmonary AdCC were also reviewed for the comparison. RESULTS: Statistically significant differences were identified between pulmonary AdCC and small cell carcinoma in fourteen of the fifteen cytomorphologic criteria (differences in sheet formation were not statistically significant). Cellular uniformity, distinct nucleolus, granular cytoplasm, distinct cell border, organoid cluster, hyaline globule, and hyaline basement membrane material were characteristic features of AdCC. Frequent nuclear molding, individual cell necrosis, and necrotic background were almost exclusively identified in small cell carcinoma. Although coarse chromatin and irregular cluster border were observed in both, they favored the diagnosis of small cell carcinoma. Hyaline globules were more frequently seen in non-pulmonary AdCC cases. CONCLUSIONS: Using the fifteen cytomorphologic criteria described by this study, pulmonary AdCC could be successfully distinguished from small cell carcinoma. Such a comprehensive approach to an individual case is recommended for the cytologic diagnosis of pulmonary AdCC. PMID- 26477589 TI - Combination of Optimization and Metalated-Ligand Exchange: An Effective Approach to Functionalize UiO-66(Zr) MOFs for CO2 Separation. AB - The strategy to functionalize water-stable metal-organic frameworks (MOFs) in order to improve their CO2 uptake capacities for efficient CO2 separation remains limited and challenging. We herein present an effective approach to functionalize a prominent water-stable MOF, UiO-66(Zr), by a combination of optimization and metalated-ligand exchange. In particular, by systematic optimization, we have successfully obtained UiO-66(Zr) of the highest BET surface area reported so far (1730 m(2) g(-1) ). Moreover, it shows a hybrid Type I/IV N2 isotherm at 77 K and a mesopore size of 3.9 nm for the first time. The UiO-66 MOF underwent a metalated-ligand-exchange (MLE) process to yield a series of new UiO-66-type MOFs, among which UiO-66-(COONa)2 -EX and UiO-66-(COOLi)4 -EX MOFs have both enhanced CO2 working capacity and IAST CO2 /N2 selectivity. Our approach has thus suggested an alternative design to achieve water-stable MOFs with high crystallinity and gas uptake for efficient CO2 separation. PMID- 26477590 TI - Microfluidic cell-phoresis enabling high-throughput analysis of red blood cell deformability and biophysical screening of antimalarial drugs. AB - Changes in red blood cell (RBC) deformability are associated with the pathology of many diseases and could potentially be used to evaluate disease status and treatment efficacy. We developed a simple, sensitive, and multiplexed RBC deformability assay based on the spatial dispersion of single cells in structured microchannels. This mechanism is analogous to gel electrophoresis, but instead of transporting molecules through nano-structured material to measure their length, RBCs are transported through micro-structured material to measure their deformability. After transport, the spatial distribution of cells provides a readout similar to intensity bands in gel electrophoresis, enabling simultaneous measurement on multiple samples. We used this approach to study the biophysical signatures of falciparum malaria, for which we demonstrate label-free and calibration-free detection of ring-stage infection, as well as in vitro assessment of antimalarial drug efficacy. We show that clinical antimalarial drugs universally reduce the deformability of RBCs infected by Plasmodium falciparum and that recently discovered PfATP4 inhibitors, known to induce host mediated parasite clearance, display a distinct biophysical signature. Our process captures key advantages from gel electrophoresis, including image-based readout and multiplexing, to provide a functional screen for new antimalarials and adjunctive agents. PMID- 26477591 TI - Batch and Flow Synthesis of Pyrrolo[1,2-a]-quinolines via an Allene-Based Reaction Cascade. AB - An efficient reaction cascade delivering a series of pyrrolo[1,2-a]quinolines bearing phosphonate or phosphine oxide moieties is presented. This sequence exploits the in situ transformation of propargylic alcohols into transient allenes by means of a strategic [2,3]-sigmatropic rearrangement followed by trapping of the resulting allenes by an adjacent pyrrole ring. Furthermore, the initial small scale batch process was successfully translated into a continuous flow process allowing efficient preparation of selected pyrrolo[1,2-a]quinolines on multigram scale without any safety concerns due to the reaction's inherent exothermic profile. PMID- 26477592 TI - The contribution of education, social class and economic activity to the income mortality association in alcohol-related and other mortality in Finland in 1988 2012. AB - AIMS: First, to quantify trends in the contribution of alcohol-related mortality to mortality disparity in Finland by income quintiles. Secondly, to estimate the degree to which education, social class and economic activity explain the income mortality association in alcohol-related and other mortality in four periods within 1988-2012. DESIGN: Register-based longitudinal study using an 11% random sample of Finnish residents linked to socio-economic and mortality data in 1988 2012 augmented with an 80% sample of all deaths during 1988-2007. Mortality rates and discrete time survival regression models were used to assess the income mortality association following adjustment for covariates in 6-year periods after baseline years of 1988, 1994, 2001, and 2007. SETTING: Finland. PARTICIPANTS: Individuals aged 35-64 years at baselines. For the four study periods for men/women, the final data set comprised, respectively, 26,360/12,825, 22,561/11,423, 20,342/11,319 and 2651/1514 deaths attributable to other causes and 7517/1217, 8199/1450, 9807/2116, 1431/318 deaths attributable to alcohol related causes. MEASUREMENTS: Alcohol-related deaths were analysed with household income, education, social class and economic activity as covariates. FINDINGS: The income disparity in mortality originated increasingly from alcohol-related causes of death, in the lowest quintile the contribution increasing from 28 to 49% among men and from 11 to 28% among women between periods 1988-93 and 2007-12. Among men, socio-economic characteristics attenuated the excess mortality during each study period in the lowest income quintile by 51-62% in alcohol-related and other causes. Among women, in the lowest quintile the attenuation was 47-76% in other causes, but there was a decreasing tendency in the proportion explained by the covariates in alcohol-related mortality. CONCLUSIONS: The income disparity in mortality among working-age Finns originates increasingly from alcohol-related causes of death. Roughly half the excess mortality in the lowest income quintile during 2007-12 is explained by the covariates of household income, education, social class and economic activity. PMID- 26477594 TI - The changing face of atherosclerotic plaque inflammation. PMID- 26477595 TI - Genetics of coronary heart disease: towards causal mechanisms, novel drug targets and more personalized prevention. AB - Coronary heart disease (CHD) is an archetypical multifactorial disorder that is influenced by genetic susceptibility as well as both modifiable and nonmodifiable risk factors, and their interactions. Advances during recent years in the field of multifactorial genetics, in particular genomewide association studies (GWASs) and their meta-analyses, have provided the statistical power to identify and replicate genetic variants in more than 50 risk loci for CHD and in several hundreds of loci for cardiometabolic risk factors for CHD such as blood lipids and lipoproteins. Although for a great majority of these loci both the causal variants and mechanisms remain unknown, progress in identifying the causal variants and underlying mechanisms has already been made for several genetic loci. Furthermore, identification of rare loss-of-function variants in genes such as PCSK9, NPC1L1, APOC3 and APOA5, which cause a markedly decreased risk of CHD and no adverse side effects, illustrates the power of translating genetic findings into novel mechanistic information and provides some optimism for the future of developing novel drugs, given the many genes associated with CHD in GWASs. Finally, Mendelian randomization can be used to reveal or exclude causal relationships between heritable biomarkers and CHD, and such approaches have already provided evidence of causal relationships between CHD and LDL cholesterol, triglycerides/remnant particles and lipoprotein(a), and indicated a lack of causality for HDL cholesterol, C-reactive protein and lipoprotein associated phospholipase A2. Together, these genetic findings are beginning to lead to promising new drug targets and novel interventional strategies and thus have great potential to improve prevention, prediction and therapy of CHD. PMID- 26477597 TI - Impact of attention biases to threat and effortful control on individual variations in negative affect and social withdrawal in very young children. AB - Early temperamental sensitivity may form the basis for the later development of socioemotional maladjustment. In particular, temperamental negative affect places children at risk for the development of anxiety. However, not all children who show negative affect go on to develop anxiety or extreme social withdrawal. Recent research indicates that reactive control, in the form of attention to threat, may serve as a bridge between early temperament and the development of later social difficulties. In addition, variation in effortful control may also modulate this trajectory. Children (mean age=5.57 years) were assessed for attention bias to threatening and pleasant faces using a dot-probe paradigm. Attention bias to threatening (but not happy) faces moderated the direct positive relation between negative affect and social withdrawal. Children with threat biases showed a significant link between negative affect and social withdrawal, whereas children who avoided threat did not. In contrast, effortful control did not moderate the relation between negative affect and social withdrawal. Rather, there was a direct negative relation between effortful control and social withdrawal. The findings from this short report indicate that the relations among temperament, attention bias, and social withdrawal appears early in life and point to early emerging specificity in reactive and regulatory functioning. PMID- 26477598 TI - Language complexity modulates 8- and 10-year-olds' success at using their theory of mind abilities in a communication task. AB - Basic competence in theory of mind is acquired during early childhood. Nonetheless, evidence suggests that the ability to take others' perspectives in communication improves continuously from middle childhood to the late teenage years. This indicates that theory of mind performance undergoes protracted developmental changes after the acquisition of basic competence. Currently, little is known about the factors that constrain children's performance or that contribute to age-related improvement. A sample of 39 8-year-olds and 56 10-year olds were tested on a communication task in which a speaker's limited perspective needed to be taken into account and the complexity of the speaker's utterance varied. Our findings showed that 10-year-olds were generally less egocentric than 8-year-olds. Children of both ages committed more egocentric errors when a speaker uttered complex sentences compared with simple sentences. Both 8- and 10 year-olds were affected by the demand to integrate complex sentences with the speaker's limited perspective and to a similar degree. These results suggest that long after children's development of simple visual perspective-taking, their use of this ability to assist communication is substantially constrained by the complexity of the language involved. PMID- 26477599 TI - CAUTI Surveillance: Opportunity or Opportunity Cost? PMID- 26477596 TI - The small leucine-rich repeat proteoglycans in tissue repair and atherosclerosis. AB - Proteoglycans consist of a protein core with one or more covalently attached glycosaminoglycan (GAG) side chains and have multiple roles in the initiation and progression of atherosclerosis. Here we discuss the potential and known functions of a group of small leucine-rich repeat proteoglycans (SLRPs) in atherosclerosis. We focus on five SLRPs, decorin, biglycan, lumican, fibromodulin and PRELP, because these have been detected in atherosclerotic plaques or demonstrated to have a role in animal models of atherosclerosis. Decorin and biglycan are modified post-translationally by substitution with chondroitin/dermatan sulphate GAGs, whereas lumican, fibromodulin and PRELP have keratan sulphate side chains, and the core proteins have leucine-rich repeat (LRR) motifs that are characteristic of the LRR superfamily. The chondroitin/dermatan sulphate GAG side chains have been implicated in lipid retention in atherosclerosis. The core proteins are discussed here in the context of (i) interactions with collagens and their implications in tissue integrity, fibrosis and wound repair and (ii) interactions with growth factors, cytokines, pathogen-associated molecular patterns and cell surface receptors that impact normal physiology and disease processes such as inflammation, innate immune responses and wound healing (i.e. processes that are all important in plaque development and progression). Thus, studies of these SLRPs in the context of wound healing are providing clues about their functions in early stages of atherosclerosis to plaque vulnerability and cardiovascular disease at later stages. Understanding of signal transduction pathways regulated by the core protein interactions is leading to novel roles and therapeutic potential for these proteins in wound repair and atherosclerosis. PMID- 26477600 TI - Reply to Roady. PMID- 26477601 TI - Global redox cycle of biospheric carbon: Interaction of photosynthesis and earth crust processes. AB - A model of the natural global redox cycle of biospheric carbon is introduced. According to this model, carbon transfer between biosphere and geospheres is accompanied by a conversion of the oxidative forms, presented by CO2, bicarbonate and carbonate ions, into the reduced forms, produced in photosynthesis. The mechanism of carbon transfer is associated with two phases of movement of lithospheric plates. In the short-term orogenic phase, CO2 from the subduction (plates' collisions) zones fills the "atmosphere-hydrosphere" system, resulting in climate warming. In the long-term quiet (geosynclynal) phase, weathering and photosynthesis become dominant depleting the oxidative forms of carbon. The above asymmetric periodicity exerts an impact on climate, biodiversity, distribution of organic matter in sedimentary deposits, etc. Along with photosynthesis expansion, the redox carbon cycle undergoes its development until it reaches the ecological compensation point, at which CO2 is depleted to the level critical to support the growth and reproduction of plants. This occurred in the Permo-Carboniferous time and in the Neogene. Shorter-term perturbations of the global carbon cycle in the form of glacial-interglacial oscillations appear near the ecological compensation point. PMID- 26477603 TI - Medical Cost Impact of Intrathecal Baclofen Therapy for Severe Spasticity. PMID- 26477602 TI - "Just take your medicine and everything will be fine": Responsibilisation narratives in accounts of transitioning young people with HIV into adult care services in Australia. AB - Young people who have grown up with perinatally acquired HIV in wealthy nations are increasingly transitioning into adult care settings which expect more independence and self-regulation than paediatric care. Drawing on the first qualitative study on growing up with HIV in Australia, this paper examines "responsibilisation" narratives in semi-structured interviews conducted with young people with HIV and their paediatric and adult care providers. Three dominant narratives were identified: responsibilisation as imperative, practice and contest. This suggests that while young people growing up with HIV in an advanced liberal setting such as Australia may value the independence of adult care, and appreciate the need to take responsibility for their health, the practices involved in becoming a responsible health citizen are shaped by individual histories and circumstances, and in some cases, can lead to serious contestation and conflict with care providers. Placing a stronger emphasis on what young people can gain from taking an active role in managing their health may more successfully foster responsibilisation, rather than focusing on what they will lose. Clinicians could benefit from greater support regarding how to engage young people with the elements of responsibilisation likely to resonate more meaningfully at different points in their lives. PMID- 26477604 TI - Effect of Iron(II) on Arsenic Sequestration by delta-MnO2: Desorption Studies Using Stirred-Flow Experiments and X-Ray Absorption Fine-Structure Spectroscopy. AB - Arsenic (As) mobility in the environment is greatly affected by its oxidation state and the degree to which it is sorbed on metal oxide surfaces. Manganese (Mn) and iron (Fe) oxides are ubiquitous solids in terrestrial systems and have high sorptive capacities for many trace metals, including As. Although numerous studies have studied the effects of As adsorption and desorption onto Fe and Mn oxides individually, the fate of As within mixed systems representative of natural environments has not been resolved. In this research, As(III) was initially reacted with a poorly crystalline phyllomanganate (delta-MnO2) in the presence of Fe(II) prior to desorption. This initial reaction resulted in the sorption of both As(III) and As(V) on mixed Fe/Mn-oxides surfaces. A desorption study was carried out using two environmentally significant ions, phosphate (PO4(3-)) and calcium (Ca(2+)). Both a stirred-flow technique and X-ray absorption fine-structure spectroscopy (XAFS) analysis were used to investigate As desorption behavior. Results showed that when As(III)/Fe(II) = 1:1 in the initial reaction, only As(V) was desorbed, agreeing with a previous study showing that As(III) is not associated with the Fe/Mn-oxides. When As(III)/Fe(II) = 1:10 in the initial reaction, both As(III) and As(V) can be desorbed from the Fe/Mn oxide surface, and more As(III) is desorbed than As(V). Neither of the desorbents used in this study completely removed As(III) or As(V) from the Fe/Mn-oxides surface. However, the As desorption fraction decreases with increasing Fe(II) concentration in the initial reactions. PMID- 26477605 TI - Spin Noise Detection of Nuclear Hyperpolarization at 1.2 K. AB - We report proton spin noise spectra of a hyperpolarized solid sample of commonly used "DNP (dynamic nuclear polarization) juice" containing TEMPOL (4-hydroxy 2,2,6,6-tetramethylpiperidine N-oxide) and irradiated by a microwave field at a temperature of 1.2 K in a magnetic field of 6.7 T. The line shapes of the spin noise power spectra are sensitive to the variation of the microwave irradiation frequency and change from dip to bump, when the electron Larmor frequency is crossed, which is shown to be in good accordance with theory by simulations. Small but significant deviations from these predictions are observed, which can be related to spin noise and radiation damping phenomena that have been reported in thermally polarized systems. The non-linear dependence of the spin noise integral on nuclear polarization provides a means to monitor hyperpolarization semi-quantitatively without any perturbation of the spin system by radio frequency irradiation. PMID- 26477606 TI - Exogenous isoprene modulates gene expression in unstressed Arabidopsis thaliana plants. AB - Isoprene is a well-studied volatile hemiterpene that protects plants from abiotic stress through mechanisms that are not fully understood. The antioxidant and membrane stabilizing potential of isoprene are the two most commonly invoked mechanisms. However, isoprene also affects phenylpropanoid metabolism, suggesting an additional role as a signalling molecule. In this study, microarray-based gene expression profiling reveals transcriptional reprogramming of Arabidopsis thaliana plants fumigated for 24 h with a physiologically relevant concentration of isoprene. Functional enrichment analysis of fumigated plants revealed enhanced heat- and light-stress-responsive processes in response to isoprene. Isoprene induced a network enriched in ERF and WRKY transcription factors, which may play a role in stress tolerance. The isoprene-induced up-regulation of phenylpropanoid biosynthetic genes was specifically confirmed using quantitative reverse transcription polymerase chain reaction. These results support a role for isoprene as a signalling molecule, in addition to its possible roles as an antioxidant and membrane thermoprotectant. PMID- 26477607 TI - PTH Promotes Bone Anabolism by Stimulating Aerobic Glycolysis via IGF Signaling. PMID- 26477610 TI - Noise robust spatially regularized myelin water fraction mapping with the intrinsic B1-error correction based on the linearized version of the extended phase graph model. AB - PURPOSE: To improve the quantification accuracy of transverse relaxometry by accounting for B1 -error, after minimizing slice profile imperfections. MATERIALS AND METHODS: The slice profile of refocusing pulses was optimized by setting refocusing slice thicknesses three times that of the excitation pulse. The first step of data processing combined the L-curve approach with the linearized version of the extended phase graph model to jointly estimate the temporal regularization constant map and the flip angle error (FAE)-map. The second step improved the noise robustness of the reconstruction by imposing a spatial smoothness constraint on T2 -distributions. The proposed method (spatial-regularization-with FAE-correction) was evaluated against methods without FAE-correction (conventional-regularization-without-FAE-correction, spatial-regularization without-FAE-correction) and conventional-regularization-with-FAE-correction using relevant statistics (simulated data: mean square myelin reconstruction error [MSMRE] and averaged-symmetric-Kullbeck-Leibler score [SKL] between returned distributions and ground truths; experimental data: median of mean square error [MMSE] of fitting across entire data-set and coefficient of variation [COV] in white-matter [WM] regions of interest [ROIs]). RESULTS: In simulation, our method resulted in reduced MSMRE (at signal-to-noise ratio [SNR] = 200: MSMRESpatial regularization-without-FAEC = 0.057; MSMRESpatial-regularization-with-FAEC = 0.0107) and reduced SKL scores (at SNR = 200: SKLSpatial-regularization-without FAEC = 0.061; SKLSpatial-regularization-with-FAEC = 0.0143). In human volunteers, our method yielded a reduced MSE of fitting (MMSESpatial regularization-without-FAEC = (2.26 +/- 0.60) * 10(-3) ; MMSESpatial regularization-with-FAEC = (1.57 +/- 0.44) * 10(-4) )and also resulted in reduced COV (COVSpatial-regularization-without-FAEC = 0.08-0.19; COVSpatial regularization-with-FAEC = 0.09-0.12). In a water-phantom, a good correlation between the absolute value of measured B1 -map and FAE-map was found (regression analysis: slope = 1.04; R(2) = 0.66). CONCLUSION: The proposed method resulted in more accurate and noise robust myelin water fraction maps with improved depiction of subcortical WM structures. PMID- 26477611 TI - Monitoring Serum Levels of Sorafenib and Its N-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma. AB - Sorafenib, an oral multi-kinase inhibitor, is the final therapy prior to palliative care for advanced hepatocellular carcinoma (HCC). However, due to its adverse effects, 20% of patients must discontinue sorafenib within 1 month after first administration. To identify ways to predict the adverse effects and administer the drug for longer periods, we explored the relationship between the duration of sorafenib treatment and the pharmacokinetics of sorafenib and its major metabolite, sorafenib N-oxide. Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17). We evaluated early sorafenib accumulation as the area under the curve of sorafenib and sorafenib N-oxide concentrations during days 1-7 (AUC(sorafenib) and AUC(N-oxide), respectively). Inter-group comparison revealed that AUC(N-oxide) and AUC ratio (AUC(N-oxide)/AUC(sorafenib)) were significantly higher in the dosage reduction/withdrawal group (P = 0.031 and P = 0.0022, respectively). Receiver operating characteristic analysis indicated that AUC(N-oxide) and AUC ratio were reliable predictors of adverse effects. When patients were classified by cut-off points (AUC(N-oxide:) 2.0 MUg ? day/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUC(N-oxide) <= 2.0 MUg ? day/mL (P = 0.0048, log-rank test). In conclusion, we recommend to simultaneously monitor serum levels of sorafenib and its N-oxide during the early stage after the first administration, which enables us to provide safe and long-term therapy for each HCC patient with sorafenib. PMID- 26477609 TI - Multidisciplinary intervention of early, lethal metastatic prostate cancer: Report from the 2015 Coffey-Holden Prostate Cancer Academy Meeting. AB - BACKGROUND: The 2015 Coffey-Holden Prostate Cancer Academy Meeting, themed: "Multidisciplinary Intervention of Early, Lethal Metastatic Prostate Cancer," was held in La Jolla, California from June 25 to 28, 2015. METHODS: The Prostate Cancer Foundation (PCF) sponsors an annual, invitation-only, action-tank structured meeting on a critical topic concerning lethal prostate cancer. The 2015 meeting was attended by 71 basic, translational, and clinical investigators who discussed the current state of the field, major unmet needs, and ideas for addressing earlier diagnosis and treatment of men with lethal prostate cancer for the purpose of extending lives and making progress toward a cure. RESULTS: The questions addressed at the meeting included: cellular and molecular mechanisms of tumorigenesis, evaluating, and targeting the microenvironment in the primary tumor, advancing biomarkers for clinical integration, new molecular imaging technologies, clinical trials, and clinical trial design in localized high-risk and oligometastatic settings, targeting the primary tumor in advanced disease, and instituting multi-modal care of high risk and oligometastatic patients. DISCUSSION: This article highlights the current status, greatest unmet needs, and anticipated field changes that were discussed at the meeting toward the goal of optimizing earlier interventions to potentiate cures in high-risk and oligometastatic prostate cancer patients. PMID- 26477612 TI - Beneficial role of spermidine in chlorophyll metabolism and D1 protein content in tomato seedlings under salinity-alkalinity stress. AB - Polyamines are important in protecting plants against various environmental stresses, including protection against photodamage to the photosynthetic apparatus. The molecular mechanism of this latter effect is not completely understood. Here, we have investigated the effects of salinity-alkalinity stress and spermidine (Spd) on tomato seedlings at both physiological and transcriptional levels. Salinity-alkalinity stress decreased leaf area, net photosynthetic rate, maximum net photosynthetic rate, light saturation point, apparent quantum efficiency, total chlorophyll, chlorophyll a and chlorophyll a:chlorophyll b relative to the control. The amount of D1 protein, an important component of photosystem II, was reduced compared with the control, as was the expression of psbA, which codes for D1. Expression of the chlorophyll biosynthesis gene porphobilinogen deaminase (PBGD) was reduced following salinity alkalinity stress, whereas the expression of Chlase, which codes for chlorophyllase, was increased. These negative physiological effects of salinity alkalinity stress were alleviated by exogenous Spd. Expression of PBGD and psbA were enhanced, whereas the expression of Chlase was reduced, when exogenous Spd was included in the stress treatment compared with when it was not. The protective effect of Spd on chlorophyll and D1 protein content during stress may maintain the photosynthetic apparatus, permitting continued photosynthesis and growth of tomato seedlings (Solanum lycopersicum cv. Jinpengchaoguan) under salinity-alkalinity stress. PMID- 26477613 TI - Digestive enzymatic activity during ontogenetic development in zebrafish (Danio rerio). AB - Despite the growing importance of zebrafish (Danio rerio) as an experimental model in biomedical research, some aspect of physiological and related morphological age dependent changes in digestive system during larval development are still unknown. In this paper, a biochemical and morphological study of the digestive tract of zebrafish was undertaken to record the functional changes occurring in this species during its ontogenetic development, particularly from 24 hr to 47 days post fertilization (dpf). Endo- and exo-proteases, as well as alpha-amylase enzymes, were quantified in zebrafish larvae before first feeding (7 dpf). The most morphologically significant events during the ontogenesis of the gut occurred between 3 dpf (mouth opening) and 7 dpf (end of exocrine pancreas differentiation). The presence of a wide range of digestive enzymes, already active at earlier zebrafish larval stages, closely related with the omnivorous diet of this species. Increasing enzyme activities were found with increasing age, probably in relation with intestinal mucosa folding and consequent absorption surface increase. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 699 706, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26477614 TI - Expression profiling of heat shock genes in a scuttle fly Megaselia scalaris (Diptera, Phoridae). AB - The Phoridae are a family of small, hump-backed flies, dominating in post-fire areas. Some of these flies are probably able to survive a fire as an egg, larva, or pupa, and may be adapted to the fire-altered environment at the genomic level. In this study, we describe the influence of short-term temperature treatment on the expression of seven heat shock protein genes in the third-instar larvae and imagoes of a scuttle fly Megaselia scalaris-one of the cosmopolitan and polyphagous phorids. In terms of the response to temperature treatment, these genes tested against tubulin as a reference split into three classes. The first class consists of hsp22 (larvae), hsp23 (larvae), and hsp26 (both larvae and imagoes), and is upregulated at the lowest temperature (33 degrees C). The second class consists of hsp22 (imagoes), hsp23 (imagoes), hsp40 (larvae and imagoes), and hsp70 (larvae and imagoes), and is upregulated or induced at 37 degrees C. Expression of genes of the third class (hsp27 and hsp83-larvae and imagoes) increased after treatment at 41 degrees C temperature. Expression of the first two classes of genes occurred at a temperature lower than the LT50 of larvae and imagoes. The fact that there is a gap between the temperature upregulating hsp genes and the temperature leading to the loss of viability suggests that not only the level of hsp gene expression but also the temperature at which gene expression increased is important in an adaptation of M. scalaris to harsh environment. J. Exp. Zool. 323A: 704-713, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26477615 TI - [Recent echocardiographic examination of the left ventricle - from M-mode to 3D speckle-tracking imaging]. AB - The left ventricle has a vital role in maintaining circulation of the body, therefore, its non-invasive assessment is essential. The aim of the present review is to demonstrate clinical relevance of different echocardiographic methods in the evaluation of left ventricle emphasizing the importance of the most recent three-dimensional (and) speckle-tracking methodologies. PMID- 26477616 TI - [Lactose intolerance: past and present. Part II]. AB - The author summarises the interrelations between lactose intolerance, calcium and vitamin D metabolism and osteoporosis. Lactose intolerance enhances the risk of forearm and hip fractures in some patients. Lactase gene genotype and fracture risk are related in some populations. Calcium and vitamin D supplementation increase bone mineral content and they are justified in children, during pregnancy and lactation, and in postmenopausal women. The intake of milk and milk products could increase the risk of ovarian carcinoma. CC genotype of the lactase gene increased the risk of colorectal carcinoma in Finns; no such effect was observed in British, Spanish and Italian patients. Even small quantities of lactose in drugs (10-750 mg) could elicit intolerance symptoms due to individual susceptibility. In spite of public knowledge and advertising, controlled studies did not prove the beneficial effect of either a lactose-free diet, enzyme supplementation or probiotics in an evidence-based manner. While accepted guidelines are lacking, a personalised therapy is mandatory. In spite of increasing public interest in lactose intolerance, many unknown factors must still be studied. PMID- 26477617 TI - [Associations between concurrent use of tobacco and alcohol and symptoms of attention-deficit hyperactivity disorder among ninth grader students]. AB - INTRODUCTION: Attention-deficit hyperactivity disorder is a risk factor of smoking and alcohol drinking in adolescence. Since attention-deficit hyperactivity disorder and smoking and alcohol drinking in adolescence are predictors for the development of substance use disorders in adulthood, it is important to understand the nature of these associations. AIM: The aim of the authors was to investigate associations between attention-deficit hyperactivity disorder symptoms and the joint use of alcohol and nicotine among 9th graders. METHOD: A representative sample of 944 pupils attending state-run secondary schools in Budapest were recruited. Generalized Linear Mixed Model and logistic regression analyses have been conducted. RESULTS: The prevalence was 29.6% and 41.4% for current smoking and current alcohol drinking, respectively. The prevalence of their concurrent-use was 21.7%. Alcohol drinking and smoking showed a significant positive association with the total scores of Attention-Deficit Hyperactivity Disorder Scale and with the Attention Deficit and Hyperactivity/Impulsivity subscales. CONCLUSIONS: The findings highlight the potential importance of attention-deficit hyperactivity disorder in the development of the joint use of these substances. PMID- 26477618 TI - [Excessive energy drink consumption caused marked QT prolongation. Case report]. AB - The authors report a case of a 22-year-old man with atypical chest pain after consumption of six energy drinks (1.5 liter containing 470 mg coffein) with vodka. On admission ECG showed marked QT/QTc prolongation (QT/QTc, 520/580 msec). Next day the QT/QTc returned to fully normal (QT/QTc, 360/430 msec). It was assumed that the patient had a silent long QT syndrome and that high dose of highly caffeinated energy drink triggered the (paradoxical) prolonged QT/QTc. The authors conclude that excessive energy drink intake with alcohol or during physical exercise should be avoided. PMID- 26477619 TI - Complete mitochondrial genome of Ochetobius elongatus (Cyprinidae, Leuciscinae). AB - In this study, the complete mitochondrial genome of Ochetobius elongatus was first sequenced and annotated. The entire mitogenome is 16 613 bp in length and has a typical vertebrate mitochondrial genetic trait, consisting of 13 protein coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and a control region. The overall nucleotide composition of O. elongatus mt genome is A: 30.96%, T: 25.38%, G: 16.26% and C: 27.40%, with the A + T content of 56.34%, showing an obvious anti-G bias. Phylogenetic analyses suggest that Leuciscinae formed a clade first and then clustered with Cultrinae. The complete mitochondrial genome of O. elongatus will benefit to a better understanding of population genetics, molecular systematics and stock evaluation, further serving the germplasm resources conservation and management of O. elongatus. PMID- 26477620 TI - Advancing cerebrospinal fluid biomarker discovery by mass spectrometry. PMID- 26477621 TI - Advances in Stem Cell Therapy for Leukemia. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective post remission treatment for leukemia, resulting in lower relapse rates than alternative therapies. However, it is limited by the lack of suitable human leukocyte antigen (HLA) matched donors and high rates of transplant-related morbidity and mortality. Cord blood transplantation (CBT) and haploidentical SCT (haplo-SCT) expand the potential donor pool but are also associated with major complications. Co-infusion of third-party donor stem cells with a CBT/haplo-SCT, which is called "dual transplantation," has been reported to improve the outcome of HSCT by accelerating hematopoietic reconstitution and reducing the incidence of graft-versus-host disease (GVHD). In addition, infusion of HLA-mismatched donor granulocyte colony-stimulating factor-mobilized donor peripheral blood stem cells after chemotherapy, the so called "microtransplantation", has been shown to promote the graft-versus-leukemia effect and hasten hematopoietic recovery without amplifying GVHD. Herein, we review recent advances in stem cell therapy for leukemia with a specific focus on dual transplantation and microtransplantation. PMID- 26477622 TI - Current and Future Chemotherapy for Chagas Disease. AB - Human American trypanosomiasis, commonly called Chagas disease, is one of the most neglected illnesses in the world and remains one of the most prevalent chronic infectious diseases of Latin America with thousands of new cases every year. The only treatments available have been introduced five decades ago. They have serious, undesirable side effects and disputed benefits in the chronic stage of the disease - a characteristic and debilitating cardiomyopathy and/or megavisceras. Several laboratories have therefore focused their efforts in finding better drugs. Although recent years have brought new clinical trials, these are few and lack diversity in terms of drug mechanism of action, thus resulting in a weak drug discovery pipeline. This fragility has been recently exposed by the failure of two candidates; posaconazole and E1224, to sterilely cure patients in phase 2 clinical trials. Such setbacks highlight the need for continuous, novel and high quality drug discovery and development efforts to discover better and safer treatments. In this article we will review past and current findings on drug discovery for Trypanosoma cruzi made by academic research groups, industry and other research organizations over the last half century. We also analyze the current research landscape that is now better placed than ever to deliver alternative treatments for Chagas disease in the near future. PMID- 26477623 TI - Osteoclasts and Remodeling Based Bone Formation. AB - Osteoclasts are multinuclear cells of the monocyte macrophage lineage. They are responsible for bone remodeling by first resorbing packets of bone, which are subsequently replaced by new bone produced by osteoblasts. Osteoblasts are derived from mesenchymal stem cells, and thus osteogenesis can also be induced in various tissues at extra skeletal sites. Fifty years ago it was discovered that demineralized bone matrix is able to induce ectopic bone formation. Since that time the differentiation of bone cells has been studied intensively. The aim was to produce bone for the repair of bone defects. The molecular basis of bone remodeling has been established in great detail and the mechanism of how bone resorption and bone formation are coupled in bone remodeling sites has been delineated. Osteoclasts resorb bone, but they also secrete anabolic signals that induce mesenchymal stem cells and osteoblasts to initiate osteogenesis in resorption lacuna (remodeling) or another nonresorbed site (modeling). It is this osteoclast derived influence on mesenchymal stem cells and osteoblasts that could be utilized in tissue engineering. So far investigators have tried to find ways to induce bone formation by activating mesenchymal stem cells, but a better understanding of the remodeling paradigm of bone, the intrinsic regulation of bone formation through osteoclastic resorption, could be utilized for tissue engineering. Scaffold materials like decellularized natural tissue extracellular matrices or bone type resorbable mineral matrices induce resorption and simultaneously induce bone formation. PMID- 26477627 TI - [Evaluation of the interest of procalcitonin in the diagnosis of chorioamnionitis in preterm premature rupture of membranes. An observational and prospective study]. AB - INTRODUCTION: Diagnosis of chorioamnionitis (CA) is difficult because all clinical and biological signs are rarely concordant. According to recent literature, PCT could act as a specific marker of bacterial infection. Our main objective was to assess whether PCT could improve our management of patients with preterm premature rupture of membranes (pPROM), allowing earlier and more specific diagnosis for CA. METHODS: Patients with pPROM from 24 and 34weeks of amenorrhea were included, from November 2013 to October 2014. PCT was collected twice a week, from pPROM until delivery. Obstetricians were blinded from PCT results, in order not to influence the management of the patients. PCT values were then compared to clinical and other biological diagnostic markers (CRP and white blood cells count [WBC]). RESULTS: Thirty patients were included, with 11 cases of histological CA and 5 early-onset neonatal sepsis. With a cut-off value of 0.05ng/mL, the sensitivity of PCT to detect histological CA was 54%, the specificity was 79% and the positive and negative predictive value were respectively 60% and 75%. The positive likelihood ratio was 2.57 and the negative likelihood ratio was 0.58. Using PCT values, our medical decision of foetal extraction would have change in 5 cases (in a wrong way in 3 of them). CONCLUSION: PCT in the diagnostic of CA is not useful in the management of patients. PMID- 26477631 TI - Atomic Layer Deposition of Pd Nanoparticles on TiO2 Nanotubes for Ethanol Electrooxidation: Synthesis and Electrochemical Properties. AB - Palladium nanoparticles are grown on TiO2 nanotubes by atomic layer deposition (ALD), and the resulting three-dimensional nanostructured catalysts are studied for ethanol electrooxidation in alkaline media. The morphology, the crystal structure, and the chemical composition of the Pd particles are fully characterized using scanning and transmission electron microscopies, X-ray diffraction, and X-ray photoelectron spectroscopy. The characterization revealed that the deposition proceeds onto the entire surface of the TiO2 nanotubes leading to the formation of well-defined and highly dispersed Pd nanoparticles. The electrooxidation of ethanol on Pd clusters deposited on TiO2 nanotubes shows not only a direct correlation between the catalytic activity and the particle size but also a steep increase of the response due to the enhancement of the metal-support interaction when the crystal structure of the TiO2 nanotubes is modified by annealing at 450 degrees C in air. PMID- 26477632 TI - Interventions for varicose veins and leg oedema in pregnancy. AB - BACKGROUND: Pregnancy is presumed to be a major contributory factor in the increased incidence of varicose veins in women, which can in turn lead to venous insufficiency and leg oedema. The most common symptom of varicose veins and oedema is the substantial pain experienced, as well as night cramps, numbness, tingling, the legs may feel heavy, achy, and possibly be unsightly. Treatments for varicose veins are usually divided into three main groups: surgery, pharmacological and non-pharmacological treatments. Treatments of leg oedema comprise mostly symptom reduction rather than cure and use of pharmacological and non-pharmacological approaches. OBJECTIVES: To assess any form of intervention used to relieve the symptoms associated with varicose veins and leg oedema in pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials of treatments for varicose veins or leg oedema, or both, in pregnancy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: We included seven trials (involving 326 women). The trials were largely unclear for selection bias and high risk for performance and detection bias.Two studies were placebo-controlled trials. The first one compared a phlebotonic (rutoside) with placebo for the reduction in symptoms of varicose veins; the second study evaluated the efficacy of troxerutin in comparison to placebo among 30 pregnant women in their second trimester with symptomatic vulvar varicosities and venous insufficiency in their lower extremities. Data from this study were not in useable format, so were not included in the analysis. Two trials compared either compression stockings with resting in left lateral position or reflexology with rest for 15 minutes for the reduction of leg oedema. One trial compared standing water immersion for 20 minutes with sitting upright in a chair with legs elevated for 20 minutes. Women standing in water were allowed to stand or walk in place. One trial compared 20 minutes of daily foot massage for five consecutive days and usual prenatal care versus usual prenatal care. The final trial compared three treatment groups for treating leg oedema in pregnancy. The first group was assigned to lateral supine bed rest at room temperature, women in the second group were asked to sit in a bathtub of waist-deep water at 32 +/- 0.5 C with their legs horizontal and the third group included the women who were randomised to sitting immersed in shoulder-deep water at 32 +/- 0.5 C with legs extended downward. We did not include this study in the analysis as outcomes reported in the paper were not pre specified outcomes of this review.We planned to use GRADE methods to assess outcomes for two different comparisons and assign a quality rating. However, only two out of three outcomes for one comparison were reported and could be assessed. Evidence from one trial (rutoside versus placebo) for the outcomes of reduction in symptoms and incidence of complications associated with varicose veins and oedema was assessed as of moderate quality. Rutoside versus placeboOne trial involving 69 women, reported that rutoside significantly reduced the symptoms associated with varicose veins (risk ratio (RR) 1.89, 95% confidence interval (CI) 1.11 to 3.22; moderate quality evidence). The incidence of complications (deep vein thrombosis) did not differ significantly between the two groups (risk ratio (RR) 0.17, 95% CI 0.01 to 3.49; moderate quality evidence). There were no significant differences in side-effects (RR 1.30, 95% CI 0.23 to 7.28). Women's perception of pain was not reported in this trial. External pneumatic intermittent compression versus restOne trial, involving 35 women, reported no significant difference in lower leg volume when compression stockings were compared against rest (mean difference (MD) -258.80, 95% CI -566.91 to 49.31). Reflexology versus restingAnother trial, involving 55 women, compared reflexology with rest. Reflexology significantly reduced the symptoms associated with oedema (reduction in symptoms: RR 9.09, 95% CI 1.41 to 58.54). The same study showed a trend towards satisfaction and acceptability with the intervention (RR 6.00, 95% CI 0.92 to 39.11). Water immersion versus leg elevationThere was evidence from one trial, involving 32 women, to suggest that water immersion for 20 minutes in a swimming pool reduces leg volume (RR 0.43, 95% CI 0.22 to 0.83). Foot massage versus routine careOne trial, involving 80 women reported no significant difference in lower leg circumference when foot massage was compared against routine care (MD -0.11, 95% CI -1.02 to 0.80).No other primary or secondary outcomes were reported in the trials. AUTHORS' CONCLUSIONS: There is moderate quality evidence to suggest that rutosides appear to help relieve the symptoms of varicose veins in late pregnancy. However, this finding is based on one study (69 women) and there are not enough data presented in the study to assess its safety in pregnancy. Reflexology or water immersion appears to help improve symptoms for women with leg oedema, but again this is based on two small studies (43 and 32 women, respectively). PMID- 26477633 TI - Combining Fourier and lagged k-nearest neighbor imputation for biomedical time series data. AB - Most clinical and biomedical data contain missing values. A patient's record may be split across multiple institutions, devices may fail, and sensors may not be worn at all times. While these missing values are often ignored, this can lead to bias and error when the data are mined. Further, the data are not simply missing at random. Instead the measurement of a variable such as blood glucose may depend on its prior values as well as that of other variables. These dependencies exist across time as well, but current methods have yet to incorporate these temporal relationships as well as multiple types of missingness. To address this, we propose an imputation method (FLk-NN) that incorporates time lagged correlations both within and across variables by combining two imputation methods, based on an extension to k-NN and the Fourier transform. This enables imputation of missing values even when all data at a time point is missing and when there are different types of missingness both within and across variables. In comparison to other approaches on three biological datasets (simulated and actual Type 1 diabetes datasets, and multi-modality neurological ICU monitoring) the proposed method has the highest imputation accuracy. This was true for up to half the data being missing and when consecutive missing values are a significant fraction of the overall time series length. PMID- 26477634 TI - Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis. AB - BACKGROUND: Current guidelines generally recommend watchful waiting until symptoms emerge for aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS). OBJECTIVES: The study sought to compare the long term outcomes of initial AVR versus conservative strategies following the diagnosis of asymptomatic severe AS. METHODS: We used data from a large multicenter registry enrolling 3,815 consecutive patients with severe AS (peak aortic jet velocity >4.0 m/s, or mean aortic pressure gradient >40 mm Hg, or aortic valve area <1.0 cm(2)) between January 2003 and December 2011. Among 1,808 asymptomatic patients, the initial AVR and conservative strategies were chosen in 291 patients, and 1,517 patients, respectively. Median follow-up was 1,361 days with 90% follow-up rate at 2 years. The propensity score-matched cohort of 582 patients (n = 291 in each group) was developed as the main analysis set for the current report. RESULTS: Baseline characteristics of the propensity score-matched cohort were largely comparable, except for the slightly younger age and the greater AS severity in the initial AVR group. In the conservative group, AVR was performed in 41% of patients during follow-up. The cumulative 5-year incidences of all-cause death and heart failure hospitalization were significantly lower in the initial AVR group than in the conservative group (15.4% vs. 26.4%, p = 0.009; 3.8% vs. 19.9%, p < 0.001, respectively). CONCLUSIONS: The long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in this real-world analysis and might be substantially improved by an initial AVR strategy. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140). PMID- 26477636 TI - The Multidimensionality of Cardiovascular Procedures. PMID- 26477635 TI - Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial. AB - BACKGROUND: Anticoagulation is required during transcatheter aortic valve replacement (TAVR) procedures. Although an optimal regimen has not been determined, heparin is mainly used. Direct thrombin inhibition with bivalirudin may be an effective alternative to heparin as the procedural anticoagulant agent in this setting. OBJECTIVES: The goal of this study was to determine whether bivalirudin offers an alternative to heparin as the procedural anticoagulant agent in patients undergoing TAVR. METHODS: A total of 802 patients with aortic stenosis were randomized to undergo transfemoral TAVR with bivalirudin versus unfractionated heparin during the procedure. The 2 primary endpoints were major bleeding within 48 h or before hospital discharge (whichever occurred first) and 30-day net adverse clinical events, defined as the combination of major adverse cardiovascular events (all-cause mortality, myocardial infarction, or stroke) and major bleeding. RESULTS: Anticoagulation with bivalirudin versus heparin did not meet superiority because it did not result in significantly lower rates of major bleeding at 48 h (6.9% vs. 9.0%; relative risk: 0.77; 95% confidence interval [CI]: 0.48 to 1.23; p = 0.27) or net adverse cardiovascular events at 30 days (14.4% vs. 16.1%; relative risk: 0.89; 95% CI: 0.64 to 1.24; risk difference: 1.72; 95% CI: -6.70 to 3.25; p = 0.50); regarding the latter, the prespecified noninferiority hypothesis was met (pnoninferiority < 0.01). Rates of major adverse cardiovascular events at 48 h were not significantly different (3.5% vs. 4.8%; relative risk: 0.73; 95% CI: 0.37 to 1.43; p = 0.35). At 48 h, the bivalirudin group had significantly fewer myocardial infarctions but more acute kidney injury events than the heparin group; at 30 days, these differences were no longer significant. CONCLUSIONS: In this randomized trial of TAVR procedural pharmacotherapy, bivalirudin did not reduce rates of major bleeding at 48 h or net adverse cardiovascular events within 30 days compared with heparin. Although superiority was not shown, the noninferiority hypothesis was met with respect to the latter factor. Given the lower cost, heparin should remain the standard of care, and bivalirudin can be an alternative anticoagulant option in patients unable to receive heparin in TAVR. (International, Multi-center, Open-label, Randomized Controlled Trial in Patients Undergoing TAVR to Determine the Treatment Effect [Both Safety and Efficacy] of Using Bivalirudin Instead of UFH [BRAVO-2/3]; NCT01651780). PMID- 26477637 TI - NDP-alpha-MSH attenuates heart and liver responses to myocardial reperfusion via the vagus nerve and JAK/ERK/STAT signaling. AB - Melanocortin peptides afford cardioprotection during myocardial ischemia/reperfusion via janus kinases (JAK), extracellular signal-regulated kinases (ERK) and signal transducers/activators of transcription (STAT) pathways. Here we investigated whether melanocortin-induced modulation of the JAK/ERK/STAT signaling occurs via the cholinergic anti-inflammatory pathway, focusing our study on cardiac and hepatic responses to prolonged myocardial ischemia/reperfusion. Ischemia was produced in rats by ligature of the left anterior descending coronary artery for 30min; effects of ischemia/reperfusion were evaluated using Western blot of heart and liver proteins. Intravenous treatment, during coronary artery occlusion, with the melanocortin analog (Nle(4), D-Phe(7))alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) induced a left ventricle up-regulation of the cardioprotective transcription factors pJAK2, pERK1/2 and pTyr-STAT3 (JAK-dependent), and a reduction in the levels of the inflammatory mediators tumor necrosis factor-alpha (TNF-alpha) and pJNK (a transcription factor also involved in apoptosis), as assessed at the end of the 2 h reperfusion period. Further, these beneficial effects of NDP-alpha-MSH were associated with heart over-expression of the pro-survival proteins heme oxygenase 1 (HO-1) and Bcl-XL, and decrease of ventricular arrhythmias and infarct size. In the liver NDP-alpha-MSH induced a decrease in the pJAK2 and pTyr-STAT3 levels, and strongly reduced pERK1/2 expression. In the liver of ischemic rats NDP-alpha MSH also blunted pJNK activity and TNF-alpha expression, and up-regulated Bcl-XL. Bilateral cervical vagotomy prevented all effects of NDP-alpha-MSH, both in the heart and liver. These results indicate that melanocortins inhibit heart and liver damage triggered by prolonged myocardial ischemia/reperfusion likely, as main mechanism, via the vagus nerve-mediated modulation of the JAK/STAT/ERK signaling pathways. PMID- 26477638 TI - Protective effects of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside in the MPTP-induced mouse model of Parkinson's disease: Involvement of reactive oxygen species-mediated JNK, P38 and mitochondrial pathways. AB - Parkinson's disease (PD) is characterized by the selective death of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress-induced neuron loss is thought to play a crucial role in the pathogenesis of PD. Previous work from our group suggests that 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside (TSG), an active component extracted from a traditional Chinese herb, Polygonum multiflorum thunb, can attenuate 1-methyl-4-phenyl pyridium-induced apoptosis in the neuronal cell line PC12, by inhibiting reactive oxygen species generation and modulating c-Jun N-terminal kinases (JNK) activation. Here, we investigated the protective effects of TSG against 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP)-induced loss of tyrosine hydroxylase positive cells in mice and the underlying mechanisms. The results showed that MPTP-induced loss of tyrosine hydroxylase positive cells and reactive oxygen species generation were prevented by TSG in a dose-dependent manner. The reactive oxygen species scavenger N acetylcysteine could also mitigate reactive oxygen species generation. Moreover, JNK and P38 were activated by MPTP, but extracellular signal-regulated protein kinases phosphorylation did not change after MPTP treatment. TSG at different doses blocked the activation of JNK and P38. The protective effect of TSG was also associated with downregulation of the bax/bcl-2 ratio, reversed the release of cytochrome c and smac, and inhibited the activation of caspase-3, -6, and -9 induced by MPTP. In conclusion, our studies demonstrated that the protective effects of TSG in the MPTP-induced mouse model of PD are involved, at least in part, in controlling reactive oxygen species-mediated JNK, P38, and mitochondrial pathways. PMID- 26477641 TI - Haemophilus influenzae isolates survive for up to 20 years at -70 degrees C in skim milk tryptone glucose glycerol broth (STGGB) if thawing is avoided during re culture. AB - Haemophilus influenzae remains a major cause of disease worldwide requiring continued study. Recently, isolates of Streptococcus pneumoniae and Moraxella catarrhalis, but not H. influenzae, were reported to survive long-term ultra freeze storage in STGGB. We show that nontypeable H. influenzae isolates survive for up to 20 years when thawing is avoided. PMID- 26477639 TI - Observation of a phononic Mollow triplet in a multimode hybrid spin nanomechanical system. AB - Reminiscent of the bound character of a qubit's dynamics confined on the Bloch sphere, the observation of a Mollow triplet in the resonantly driven qubit fluorescence spectrum represents one of the founding signatures of quantum electrodynamics. Here we report on its observation in a hybrid spin nanomechanical system, where a nitrogen-vacancy spin qubit is magnetically coupled to the vibrations of a silicon carbide nanowire. A resonant microwave field turns the originally parametric hybrid interaction into a resonant process, where acoustic phonons are now able to induce transitions between the dressed qubit states, leading to synchronized spin-oscillator dynamics. We further explore the vectorial character of the hybrid coupling to the bidimensional deformations of the nanowire. The demonstrated microwave assisted synchronization of the spin-oscillator dynamics opens novel perspectives for the exploration of spin-dependent forces, the key ingredient for quantum state transfer. PMID- 26477642 TI - Incidence and predictors of unplanned non-target lesion revascularisation up to three years after drug-eluting stent implantation: insights from a pooled analysis of the RESOLUTE Global Clinical Trial Program. AB - AIMS: To compare the incidence and predictors of target lesion revascularisation (TLR) and non-TLR after percutaneous coronary intervention with drug-eluting stents (DES). METHODS AND RESULTS: We pooled patient-level data on 6,137 patients (Resolute zotarolimus-eluting stent: 5,016, XIENCE everolimus-eluting stent: 1,121) in the RESOLUTE Global Program. At three years, clinically driven TLR, unplanned non-TLR, and no revascularisation occurred in 186, 618, and 5,333 patients, respectively. On multivariate analysis, predictors of both TLR and non TLR were pre-procedure diameter stenosis (%) (odds ratio [OR] 1.01, 95% confidence interval [CI] [1.01-1.02], and OR 0.99 [0.99-1.00]), diabetes (OR 1.46 [1.07-1.99], and OR 1.37 [1.15-1.64]), and prior PCI (OR 1.42 [1.01-2.00], and OR 1.41 [1.18-1.68]). Baseline characteristics associated with TLR only were prior coronary artery bypass graft surgery (OR 2.85 [1.91-4.27]), in-stent restenosis (OR 2.35 [1.43-3.83]), age (OR 0.98 per year [0.97-1.00]), hypertension (OR 1.64 [1.10-2.44]), and pre-procedure reference vessel diameter (OR 0.74 per mm [0.55 0.99]). Baseline characteristics associated with non-TLR only were lesion location (left anterior descending vs. all others) (OR 0.70 [0.59-0.83]), and hyperlipidaemia (OR 1.42 [1.15-1.75]). CONCLUSIONS: The cumulative incidence of non-TLR at three years in patients treated with current-generation DES was almost three times higher than TLR. PMID- 26477643 TI - Implantable atrial flow regulator for severe, irreversible pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a severe, progressive and fatal disease. The creation of an interatrial right-to-left shunt in patients with PAH may enhance systemic ventricular output at the expense of desaturation. However, creating sustainable restricted interatrial communication is challenging. We describe the successful use of an atrial flow regulator, a novel implantable atrial communication device, in a 54-year-old female with severe irreversible PAH. PMID- 26477644 TI - Percutaneous Melody valve implantation for tricuspid valve regurgitation with very large annulus: the diabolo-shaped bridge for valve-in-stent technique. PMID- 26477645 TI - A novel IgY-Aptamer hybrid system for cost-effective detection of SEB and its evaluation on food and clinical samples. AB - In the present study, we introduce a novel hybrid sandwich-ALISA employing chicken IgY and ssDNA aptamers for the detection of staphylococcal enterotoxin B (SEB). Cloning, expression and purification of the full length recombinant SEB was carried out. Anti-SEB IgY antibodies generated by immunizing white leg-horn chickens with purified recombinant SEB protein and were purified from the immunized egg yolk. Simultaneously, ssDNA aptamers specific to the toxin were prepared by SELEX method on microtiter well plates. The sensitivity levels of both probe molecules i.e., IgY and ssDNA aptamers were evaluated. We observed that the aptamer at 250 ngmL(-1) concentration could detect the target antigen at 50 ngmL(-1) and the IgY antibodies at 250 ngmL(-1), could able to detect 100 ngmL(-1) antigen. We further combined both the probes to prepare a hybrid sandwich aptamer linked immune sorbent assay (ALISA) wherein the IgY as capturing molecule and biotinylated aptamer as revealing probe. Limit of detection (LOD) for the developed method was determined as 50 ngmL(-1). Further, developed method was evaluated with artificially SEB spiked milk and natural samples and obtained results were validated with PCR. In conclusion, developed ALISA method may provide cost-effective and robust detection of SEB from food and environmental samples. PMID- 26477646 TI - Affibody-mediated PET imaging of HER3 expression in malignant tumours. AB - Human epidermal growth factor receptor 3 (HER3) is involved in the progression of various cancers and in resistance to therapies targeting the HER family. In vivo imaging of HER3 expression would enable patient stratification for anti-HER3 immunotherapy. Key challenges with HER3-targeting are the relatively low expression in HER3-positive tumours and HER3 expression in normal tissues. The use of positron-emission tomography (PET) provides advantages of high resolution, sensitivity and quantification accuracy compared to SPECT. Affibody molecules, imaging probes based on a non-immunoglobulin scaffold, provide high imaging contrast shortly after injection. The aim of this study was to evaluate feasibility of PET imaging of HER3 expression using (68)Ga-labeled affibody molecules. The anti-HER3 affibody molecule HEHEHE-Z08698-NOTA was successfully labelled with (68)Ga with high yield, purity and stability. The agent bound specifically to HER3-expressing cancer cells in vitro and in vivo. At 3 h pi, uptake of (68)Ga-HEHEHE-Z08698-NOTA was significantly higher in xenografts with high HER3 expression (BT474, BxPC-3) than in xenografts with low HER3 expression (A431). In xenografts with high expression, tumour-to-blood ratios were >20, tumour-to-muscle >15, and tumour-to-bone >7. HER3-positive xenografts were visualised using microPET 3 h pi. In conclusion, PET imaging of HER3 expression is feasible using (68)Ga-HEHEHE-Z08698-NOTA shortly after administration. PMID- 26477648 TI - Cost-effectiveness of Apixaban Compared With Edoxaban for Stroke Prevention in Nonvalvular Atrial Fibrillation. AB - PURPOSE: The purpose of this analysis was to assess the cost-effectiveness of apixaban 5 mg BID versus high- and low-dose edoxaban (60 mg and 30 mg once daily) as intended starting dose strategies for stroke prevention in patients from a UK National Health Service perspective. METHODS: A previously developed and validated Markov model was adapted to evaluate the lifetime clinical and economic impact of apixaban 5 mg BID versus edoxaban (high and low dose) in patients with nonvalvular atrial fibrillation. A pairwise indirect treatment comparison was conducted for clinical end points, and price parity was assumed between apixaban and edoxaban. Costs in 2012 British pounds, life-years, and quality-adjusted life years (QALYs) gained, discounted at 3.5% per annum, were estimated. FINDINGS: Apixaban was predicted to increase life expectancy and QALYs versus low- and high dose edoxaban. These gains were achieved at cost-savings versus low-dose edoxaban, thus being dominant and nominal increases in costs versus high-dose edoxaban. The incremental cost-effectiveness ratio of apixaban versus high-dose edoxaban was L6763 per QALY gained. IMPLICATIONS: Apixaban was deemed to be dominant (less costly and more effective) versus low-dose edoxaban and a cost effective alternative to high-dose edoxaban. PMID- 26477647 TI - Amygdala responses to salient social cues vary with oxytocin receptor genotype in youth. AB - Depression, anxiety, and posttraumatic stress disorder are linked to altered limbic morphology, dysregulated neuroendocrine function, and heightened amygdala responses to salient social cues. Oxytocin appears to be a potent modulator of amygdala reactivity and neuroendocrine responses to psychosocial stress. Given these stress regulatory effects, there is increasing interest in understanding the role of oxytocin in vulnerability to stress-related clinical disorders. The present study examines the impact of a common functional variant within the oxytocin receptor (OXTR) gene (rs2254298) on structure and function of the amygdala in a high-risk sample of urban, low-income, minority youth with a high incidence of early life stress (ELS). Compared to G/G homozygotes, youth carrying the OXTR A-allele showed increased amygdala volume, reduced behavioral performance, and heightened amygdala response during two functional magnetic resonance imaging (fMRI) tasks that involved viewing socially-relevant face stimuli. Higher amygdala response was related to ELS in A-allele carriers but not G/G homozygotes. These findings underscore a series of relations among a common oxytocin system gene variant, ELS exposure, and structure and function of the amygdala in early life. Heightened amygdala response to salient social cues in OXTR A-allele carriers may elevate risk for emotional psychopathology by increasing amygdala involvement in disambiguating environmental cues, particularly for individuals with ELS. PMID- 26477649 TI - A perspective on the future role of brain pet imaging in exercise science. AB - Positron Emission Tomography (PET) bears a unique potential for examining the effects of physical exercise (acute or chronic) within the central nervous system in vivo, including cerebral metabolism, neuroreceptor occupancy, and neurotransmission. However, application of Neuro-PET in human exercise science is as yet surprisingly sparse. To date the field has been dominated by non-invasive neuroelectrical techniques (EEG, MEG) and structural/functional magnetic resonance imaging (sMRI/fMRI). Despite PET having certain inherent disadvantages, in particular radiation exposure and high costs limiting applicability at large scale, certain research questions in human exercise science can exclusively be addressed with PET: The "metabolic trapping" properties of (18)F-FDG PET as the most commonly used PET-tracer allow examining the neuronal mechanisms underlying various forms of acute exercise in a rather unconstrained manner, i.e. under realistic training scenarios outside the scanner environment. Beyond acute effects, (18)F-FDG PET measurements under resting conditions have a strong prospective for unraveling the influence of regular physical activity on neuronal integrity and potentially neuroprotective mechanisms in vivo, which is of special interest for aging and dementia research. Quantification of cerebral glucose metabolism may allow determining the metabolic effects of exercise interventions in the entire human brain and relating the regional cerebral rate of glucose metabolism (rCMRglc) with behavioral, neuropsychological, and physiological measures. Apart from FDG-PET, particularly interesting applications comprise PET ligand studies that focus on dopaminergic and opioidergic neurotransmission, both key transmitter systems for exercise-related psychophysiological effects, including mood changes, reward processing, antinociception, and in its most extreme form 'exercise dependence'. PET ligand displacement approaches even allow quantifying specific endogenous neurotransmitter release under acute exercise interventions, to which modern PET/MR hybrid technology will be additionally fruitful. Experimental studies exploiting the unprecedented multimodal imaging capacities of PET/MR in human exercise sciences are as yet pending. PMID- 26477651 TI - Previous exposure to intact speech increases intelligibility of its digitally degraded counterpart as a function of stimulus complexity. AB - Recent studies have shown that acoustically distorted sentences can be perceived as either unintelligible or intelligible depending on whether one has previously been exposed to the undistorted, intelligible versions of the sentences. This allows studying processes specifically related to speech intelligibility since any change between the responses to the distorted stimuli before and after the presentation of their undistorted counterparts cannot be attributed to acoustic variability but, rather, to the successful mapping of sensory information onto memory representations. To estimate how the complexity of the message is reflected in speech comprehension, we applied this rapid change in perception to behavioral and magnetoencephalography (MEG) experiments using vowels, words and sentences. In the experiments, stimuli were initially presented to the subject in a distorted form, after which undistorted versions of the stimuli were presented. Finally, the original distorted stimuli were presented once more. The resulting increase in intelligibility observed for the second presentation of the distorted stimuli depended on the complexity of the stimulus: vowels remained unintelligible (behaviorally measured intelligibility 27%) whereas the intelligibility of the words increased from 19% to 45% and that of the sentences from 31% to 65%. This increase in the intelligibility of the degraded stimuli was reflected as an enhancement of activity in the auditory cortex and surrounding areas at early latencies of 130-160ms. In the same regions, increasing stimulus complexity attenuated mean currents at latencies of 130-160ms whereas at latencies of 200-270ms the mean currents increased. These modulations in cortical activity may reflect feedback from top-down mechanisms enhancing the extraction of information from speech. The behavioral results suggest that memory-driven expectancies can have a significant effect on speech comprehension, especially in acoustically adverse conditions where the bottom-up information is decreased. PMID- 26477650 TI - Automatic segmentation of the striatum and globus pallidus using MIST: Multimodal Image Segmentation Tool. AB - Accurate segmentation of the subcortical structures is frequently required in neuroimaging studies. Most existing methods use only a T1-weighted MRI volume to segment all supported structures and usually rely on a database of training data. We propose a new method that can use multiple image modalities simultaneously and a single reference segmentation for initialisation, without the need for a manually labelled training set. The method models intensity profiles in multiple images around the boundaries of the structure after nonlinear registration. It is trained using a set of unlabelled training data, which may be the same images that are to be segmented, and it can automatically infer the location of the physical boundary using user-specified priors. We show that the method produces high-quality segmentations of the striatum, which is clearly visible on T1 weighted scans, and the globus pallidus, which has poor contrast on such scans. The method compares favourably to existing methods, showing greater overlap with manual segmentations and better consistency. PMID- 26477652 TI - Mapping multidimensional pain experience onto electrophysiological responses to noxious laser heat stimuli. AB - The origin of the conscious experience of pain in the brain is a continuing enigma in neuroscience. To shed light on the brain representation of a multifaceted pain experience in humans, we combined multivariate analysis of subjective aspects of pain sensations with detailed, single-trial analysis of electrophysiological brain responses. Participants were asked to fully focus on any painful or non-painful sensations occurring in their left hand during an interval surrounding the onset of noxious laser heat stimuli, and to rate their sensations using a set of visual analogue scales. Statistical parametric mapping was used to compute a multivariate regression analysis of subjective responses and single-trial laser evoked potentials (LEPs) at subject and group levels. Standardized Low Resolution Electromagnetic Tomography method was used to reconstruct sources of LEPs. Factor analysis of subjective responses yielded five factors. Factor 1, representing pain, mapped firstly as a negative potential at the vertex and a positive potential at the fronto-temporal region during the 208 260ms interval, and secondly as a strong negative potential in the right lateral frontal and prefrontal scalp regions during the 1292-1340ms interval. Three other factors, labelled "anticipated pain", "stimulus onset time", and "body sensations", represented non-specific aspects of the pain experience, and explained portions of LEPs in the latency range from 200ms to 700ms. The subjective space of pain during noxious laser stimulation is represented by one large factor featuring pain intensity, and by other factors accounting for non specific parts of the sensory experience. Pain is encoded in two separate latency components with different scalp and brain representations. PMID- 26477653 TI - Tracer kinetic modelling for DCE-MRI quantification of subtle blood-brain barrier permeability. AB - There is evidence that subtle breakdown of the blood-brain barrier (BBB) is a pathophysiological component of several diseases, including cerebral small vessel disease and some dementias. Dynamic contrast-enhanced MRI (DCE-MRI) combined with tracer kinetic modelling is widely used for assessing permeability and perfusion in brain tumours and body tissues where contrast agents readily accumulate in the extracellular space. However, in diseases where leakage is subtle, the optimal approach for measuring BBB integrity is likely to differ since the magnitude and rate of enhancement caused by leakage are extremely low; several methods have been reported in the literature, yielding a wide range of parameters even in healthy subjects. We hypothesised that the Patlak model is a suitable approach for measuring low-level BBB permeability with low temporal resolution and high spatial resolution and brain coverage, and that normal levels of scanner instability would influence permeability measurements. DCE-MRI was performed in a cohort of mild stroke patients (n=201) with a range of cerebral small vessel disease severity. We fitted these data to a set of nested tracer kinetic models, ranking their performance according to the Akaike information criterion. To assess the influence of scanner drift, we scanned 15 healthy volunteers that underwent a "sham" DCE-MRI procedure without administration of contrast agent. Numerical simulations were performed to investigate model validity and the effect of scanner drift. The Patlak model was found to be most appropriate for fitting low-permeability data, and the simulations showed vp and K(Trans) estimates to be reasonably robust to the model assumptions. However, signal drift (measured at approximately 0.1% per minute and comparable to literature reports in other settings) led to systematic errors in calculated tracer kinetic parameters, particularly at low permeabilities. Our findings justify the growing use of the Patlak model in low-permeability states, which has the potential to provide valuable information regarding BBB integrity in a range of diseases. However, absolute values of the resulting tracer kinetic parameters should be interpreted with extreme caution, and the size and influence of signal drift should be measured where possible. PMID- 26477654 TI - Laminar microvascular transit time distribution in the mouse somatosensory cortex revealed by Dynamic Contrast Optical Coherence Tomography. AB - The transit time distribution of blood through the cerebral microvasculature both constrains oxygen delivery and governs the kinetics of neuroimaging signals such as blood-oxygen-level-dependent functional Magnetic Resonance Imaging (BOLD fMRI). However, in spite of its importance, capillary transit time distribution has been challenging to quantify comprehensively and efficiently at the microscopic level. Here, we introduce a method, called Dynamic Contrast Optical Coherence Tomography (DyC-OCT), based on dynamic cross-sectional OCT imaging of an intravascular tracer as it passes through the field-of-view. Quantitative transit time metrics are derived from temporal analysis of the dynamic scattering signal, closely related to tracer concentration. Since DyC-OCT does not require calibration of the optical focus, quantitative accuracy is achieved even deep in highly scattering brain tissue where the focal spot degrades. After direct validation of DyC-OCT against dilution curves measured using a fluorescent plasma label in surface pial vessels, we used DyC-OCT to investigate the transit time distribution in microvasculature across the entire depth of the mouse somatosensory cortex. Laminar trends were identified, with earlier transit times and less heterogeneity in the middle cortical layers. The early transit times in the middle cortical layers may explain, at least in part, the early BOLD fMRI onset times observed in these layers. The layer-dependencies in heterogeneity may help explain how a single vascular supply manages to deliver oxygen to individual cortical layers with diverse metabolic needs. PMID- 26477655 TI - Fast ventral stream neural activity enables rapid visual categorization. AB - Primates can recognize objects embedded in complex natural scenes in a glimpse. Rapid categorization paradigms have been extensively used to study our core perceptual abilities when the visual system is forced to operate under strong time constraints. However, the neural underpinning of rapid categorization remains to be understood, and the incredible speed of sight has yet to be reconciled with modern ventral stream cortical theories of object recognition. Here we recorded multichannel subdural electrocorticogram (ECoG) signals from intermediate areas (V4/PIT) of the ventral stream of the visual cortex while monkeys were actively engaged in a rapid animal/non-animal categorization task. A traditional event-related potential (ERP) analysis revealed short visual latencies (<50-70ms) followed by a rapidly developing visual selectivity (within ~20-30ms) for most electrodes. A multi-variate pattern analysis (MVPA) technique further confirmed that reliable animal/non-animal category information was possible from this initial ventral stream neural activity (within ~90-100ms). Furthermore, this early category-selective neural activity was (a) unaffected by the presentation of a backward (pattern) mask, (b) generalized to novel (unfamiliar) stimuli and (c) co-varied with behavioral responses (both accuracy and reaction times). Despite the strong prevalence of task-related information on the neural signal, task-irrelevant visual information could still be decoded independently of monkey behavior. Monkey behavioral responses were also found to correlate significantly with human behavioral responses for the same set of stimuli. Together, the present study establishes that rapid ventral stream neural activity induces a visually selective signal subsequently used to drive rapid visual categorization and that this visual strategy may be shared between human and non-human primates. PMID- 26477656 TI - A systematic review of MRI studies examining the relationship between physical fitness and activity and the white matter of the ageing brain. AB - Higher levels of physical fitness or activity (PFA) have been shown to have beneficial effects on cognitive function and grey matter volumes in older adults. However, the relationship between PFA and the brain's white matter (WM) is not yet well established. Here, we aim to provide a comprehensive and systematic review of magnetic resonance imaging studies examining the effects of PFA on the WM of the ageing brain. Twenty-nine studies were included in the review: eleven examined WM volume, fourteen WM lesions, and nine WM microstructure. While many studies found that higher levels of PFA were associated with greater WM volumes, reduced volume or severity of WM lesions, or improved measures of WM microstructure, a number of negative findings have also been published. Meta analyses of global measures of WM volume and WM lesion volume yielded significant, but small, effect sizes. Overall, we found evidence for cautious support of links between PFA and WM structure, and highlighted key areas for future research including the extent to which the relationship between PFA and WM structure is anatomically specific, the influence of possible confounding factors, and the relationship between PFA, WM and cognition. PMID- 26477657 TI - The absolute CBF response to activation is preserved during elevated perfusion: Implications for neurovascular coupling measures. AB - Functional magnetic resonance imaging (fMRI) techniques in which the blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) response to a neural stimulus are measured, can be used to estimate the fractional increase in the cerebral metabolic rate of oxygen consumption (CMRO2) that accompanies evoked neural activity. A measure of neurovascular coupling is obtained from the ratio of fractional CBF and CMRO2 responses, defined as n, with the implicit assumption that relative rather than absolute changes in CBF and CMRO2 adequately characterise the flow-metabolism response to neural activity. The coupling parameter n is important in terms of its effect on the BOLD response, and as potential insight into the flow-metabolism relationship in both normal and pathological brain function. In 10 healthy human subjects, BOLD and CBF responses were measured to test the effect of baseline perfusion (modulated by a hypercapnia challenge) on the coupling parameter n during graded visual stimulation. A dual-echo pulsed arterial spin labelling (PASL) sequence provided absolute quantification of CBF in baseline and active states as well as relative BOLD signal changes, which were used to estimate CMRO2 responses to the graded visual stimulus. The absolute CBF response to the visual stimuli were constant across different baseline CBF levels, meaning the fractional CBF responses were reduced at the hyperperfused baseline state. For the graded visual stimuli, values of n were significantly reduced during hypercapnia induced hyperperfusion. Assuming the evoked neural responses to the visual stimuli are the same for both baseline CBF states, this result has implications for fMRI studies that aim to measure neurovascular coupling using relative changes in CBF. The coupling parameter n is sensitive to baseline CBF, which would confound its interpretation in fMRI studies where there may be significant differences in baseline perfusion between groups. The absolute change in CBF, as opposed to the change relative to baseline, may more closely match the underlying increase in neural activity in response to a stimulus. PMID- 26477658 TI - White matter tract covariance patterns predict age-declining cognitive abilities. AB - Previous studies investigating the relationship of white matter (WM) integrity to cognitive abilities and aging have either focused on a global measure or a few selected WM tracts. Ideally, contribution from all of the WM tracts should be evaluated at the same time. However, the high collinearity among WM tracts precludes systematic examination of WM tracts simultaneously without sacrificing statistical power due to stringent multiple-comparison corrections. Multivariate covariance techniques enable comprehensive simultaneous examination of all WM tracts without being penalized for high collinearity among observations. METHOD: In this study, Scaled Subprofile Modeling (SSM) was applied to the mean integrity of 18 major WM tracts to extract covariance patterns that optimally predicted four cognitive abilities (perceptual speed, episodic memory, fluid reasoning, and vocabulary) in 346 participants across ages 20 to 79years old. Using expression of the covariance patterns, age-independent effects of white matter integrity on cognition and the indirect effect of WM integrity on age-related differences in cognition were tested separately, but inferences from the indirect analyses were cautiously made given that cross-sectional data set was used in the analysis. RESULTS: A separate covariance pattern was identified that significantly predicted each cognitive ability after controlling for age except for vocabulary, but the age by WM covariance pattern interaction was not significant for any of the three abilities. Furthermore, each of the patterns mediated the effect of age on the respective cognitive ability. A distinct set of WM tracts was most influential in each of the three patterns. The WM covariance pattern accounting for fluid reasoning showed the most number of influential WM tracts whereas the episodic memory pattern showed the least number. CONCLUSION: Specific patterns of WM tracts make significant contributions to the age-related differences in perceptual speed, episodic memory, and fluid reasoning but not vocabulary. Other measures of brain health will need to be explored to reveal the major influences on the vocabulary ability. PMID- 26477659 TI - Behavioral correlates of changes in hippocampal gray matter structure during acquisition of foreign vocabulary. AB - Experience can affect human gray matter volume. The behavioral correlates of individual differences in such brain changes are not well understood. In a group of Swedish individuals studying Italian as a foreign language, we investigated associations among time spent studying, acquired vocabulary, baseline performance on memory tasks, and gray matter changes. As a way of studying episodic memory training, the language learning focused on acquiring foreign vocabulary and lasted for 10weeks. T1-weighted structural magnetic resonance imaging and cognitive testing were performed before and after the studies. Learning behavior was monitored via participants' use of a smartphone application dedicated to the study of vocabulary. A whole-brain analysis showed larger changes in gray matter structure of the right hippocampus in the experimental group (N=33) compared to an active control group (N=23). A first path analyses revealed that time spent studying rather than acquired knowledge significantly predicted change in gray matter structure. However, this association was not significant when adding performance on baseline memory measures into the model, instead only the participants' performance on a short-term memory task with highly similar distractors predicted the change. This measure may tap similar individual difference factors as those involved in gray matter plasticity of the hippocampus. PMID- 26477660 TI - Structural and functional neuroplasticity in human learning of spatial routes. AB - Recent findings with both animals and humans suggest that decreases in microscopic movements of water in the hippocampus reflect short-term neuroplasticity resulting from learning. Here we examine whether such neuroplastic structural changes concurrently alter the functional connectivity between hippocampus and other regions involved in learning. We collected both diffusion-weighted images and fMRI data before and after humans performed a 45min spatial route-learning task. Relative to a control group with equal practice time, there was decreased diffusivity in the posterior-dorsal dentate gyrus of the left hippocampus in the route-learning group accompanied by increased synchronization of fMRI-measured BOLD signal between this region and cortical areas, and by changes in behavioral performance. These concurrent changes characterize the multidimensionality of neuroplasticity as it enables human spatial learning. PMID- 26477662 TI - Tunable optical limiting optofluidic device filled with graphene oxide dispersion in ethanol. AB - An optofluidic device with tunable optical limiting property is proposed and demonstrated. The optofluidic device is designed for adjusting the concentration of graphene oxide (GO) in the ethanol solution and fabricated by photolithography technique. By controlling the flow rate ratio of the injection, the concentration of GO can be precisely adjusted so that the optical nonlinearity can be changed. The nonlinear optical properties and dynamic excitation relaxation of the GO/ethanol solution are investigated by using Z-scan and pump-probe measurements in the femtosecond regime within the 1.5 MUm telecom band. The GO/ethanol solution presents ultrafast recovery time. Besides, the optical limiting property is in proportion to the concentration of the solution. Thus, the threshold power and the saturated power of the optical limiting property can be simply and efficiently manipulated by controlling the flow rate ratio of the injection. Furthermore, the amplitude regeneration is demonstrated by employing the proposed optofluidic device. The signal quality of intensity-impaired femtosecond pulse is significantly improved. The optofluidic device is compact and has long interaction length of optical field and nonlinear material. Heat can be dissipated in the solution and nonlinear material is isolated from other optical components, efficiently avoiding thermal damage and mechanical damage. PMID- 26477664 TI - Anisotropic reversible piezoresistivity in magnetic-metallic/polymer structured elastomeric composites: modelling and experiments. AB - Structured elastomeric composites (SECs) with electrically conductive fillers display anisotropic piezoresistivity. The fillers do not form string-of-particle structures but pseudo-chains formed by grouping micro-sized clusters containing nanomagnetic particles surrounded by noble metals (e.g. silver, Ag). The pseudo chains are formed when curing or preparing the composite in the presence of a uniform magnetic field, thus pseudo-chains are aligned in the direction of the field. The electrical conduction through pseudo-chains is analyzed and a constitutive model for the anisotropic reversible piezoresistivity in SECs is proposed. Several effects and characteristics, such as electron tunnelling, conduction inside the pseudo-chains, and chain-contact resistivity, are included in the model. Experimental results of electrical resistance, R, as a function of the normal stress applied in the direction of the pseudo-chains, P, are very well fitted by the model in the case of Fe3O4[Ag] microparticles magnetically aligned while curing in polydimethylsiloxane, PDMS. The cross sensitivity of different parameters (like the potential barrier and the effective distance for electron tunnelling) is evaluated. The model predicts the presence of several gaps for electron tunnelling inside the pseudo-chains. Estimates of those parameters for the mentioned experimental system under strains up to 20% are presented. Simulations of the expected response for other systems are performed showing the influence of Young's modulus and other parameters on the predicted piezoresistivity. PMID- 26477661 TI - From Protecting the Heart to Improving Athletic Performance - the Benefits of Local and Remote Ischaemic Preconditioning. AB - Remote Ischemic Preconditioning (RIPC) is a non-invasive cardioprotective intervention that involves brief cycles of limb ischemia and reperfusion. This is typically delivered by inflating and deflating a blood pressure cuff on one or more limb(s) for several cycles, each inflation-deflation being 3-5 min in duration. RIPC has shown potential for protecting the heart and other organs from injury due to lethal ischemia and reperfusion injury, in a variety of clinical settings. The mechanisms underlying RIPC are under intense investigation but are just beginning to be deciphered. Emerging evidence suggests that RIPC has the potential to improve exercise performance, via both local and remote mechanisms. This review discusses the clinical studies that have investigated the role of RIPC in cardioprotection as well as those studying its applicability in improving athletic performance, while examining the potential mechanisms involved. PMID- 26477663 TI - Glycolipid dynamics in generation and differentiation of induced pluripotent stem cells. AB - Glycosphingolipids (GSLs) are glycoconjugates that function as mediators of cell adhesion and modulators of signal transduction. Some well-defined markers of undifferentiated human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) are glycoconjugates, such as SSEA-3, SSEA-4, TRA-1-60 and TRA 1-81. However, Comprehensive GSL profiles of hiPSCs have not yet been elucidated. The global images of GSLs from the parental cells, hiPSCs, and differentiated cells revealed that there are parental cell-independent specific glycolipids, including Globo H (fucosyl-Gb5Cer) and H type1 antigen (fucosyl-Lc4Cer) that are novel markers for undifferentiated hiPSCs. Interestingly, undifferentiated hiPSCs expressed H type 1 antigen, specific for blood type O, regardless of the cells' genotypes. Thus, in this study, we defined the dynamics of GSL remodeling during reprogramming from parental cell sets to iPSC sets and thence to iPSC-neural cells. PMID- 26477665 TI - Metabolic Acidosis of CKD: An Update. AB - The kidney has the principal role in the maintenance of acid-base balance. Therefore, a decrease in renal ammonium excretion and a positive acid balance often leading to a reduction in serum bicarbonate concentration are observed in the course of chronic kidney disease (CKD). The decrease in serum bicarbonate concentration is usually absent until glomerular filtration rate decreases to <20 to 25mL/min/1.73 m(2), although it can develop with lesser degrees of decreased kidney function. Non-anion gap acidosis, high-anion gap acidosis, or both can be found at all stages of CKD. The acidosis can be associated with muscle wasting, bone disease, hypoalbuminemia, inflammation, progression of CKD, and increased mortality. Administration of base may decrease muscle wasting, improve bone disease, and slow the progression of CKD. Base is suggested when serum bicarbonate concentration is <22 mEq/L, but the target serum bicarbonate concentration is unclear. Evidence that increments in serum bicarbonate concentration > 24 mEq/L might be associated with worsening of cardiovascular disease adds complexity to treatment decisions. Further study of the mechanisms through which metabolic acidosis contributes to the progression of CKD, as well as the pathways involved in mediating the benefits and complications of base therapy, is warranted. PMID- 26477666 TI - The relationship between educational attainment and waiting time among the elderly in Norway. AB - We investigate whether educational attainment affects waiting time of elderly patients in somatic hospitals. We consider three distinct pathways; that patients with different educational attainment have different disease patterns, that patients with different levels of education receive treatments at different hospitals, and that patient choice and supply of local health services within hospital catchment areas explain unequal waiting time of different educational groups. We find evidence of an educational gradient in waiting time for male patients, but not for female patients. Conditional on age, male patients with tertiary education wait 45% shorter than male patients with secondary or primary education. The first pathway is not quantitatively important as controlling for disease patters has little effect on relative waiting times. The second pathway is important. Relative to patients with primary education, variation in waiting time and education level across local hospitals contributes to higher waiting time for male patients with secondary education and female patients with secondary or tertiary education and lower waiting time for male patients with tertiary education. These effects are in the order of 15-20%. The third pathway is also quantitatively important. The educational gradients within catchment areas disappear when we control for travel distance and supply of private specialists. PMID- 26477667 TI - Patients' perceptions of generic drugs in Greece. AB - The use of generic drugs is growing increasingly around the world and in Greece, in particular, in order to reduce pharmaceutical expenditure. However, patients' perceptions and attitudes about generics have only partially been studied so far in Greece. OBJECTIVE: This study aimed to examine the factors that influence the attitude of patients and consumers regarding generic drugs. METHODS: A questionnaire survey of 364 patients visiting a pharmacy was conducted. The questionnaire consisted of 29 questions, including questions regarding their knowledge about generics, the reasons for using them, their previous experience, their willingness for generic substitution, and the factors behind these choices. RESULTS: Nearly half of the participants in the survey know the term 'generic' and that it has a lower price compared to the brand name drug. Their views on safety and efficacy vary significantly and the main source of information on generics is the media and the internet. The lack of knowledge is the main barrier for attitudes of doctors. Health professionals play the most influential role for the substitution of a branded drug by a generic, followed by the cost of the generic. CONCLUSIONS: Almost half of the patients know about generic drugs, with their lower price being the most popular feature which most patients are familiar with. It seems that primarily the doctor and, subsequently the pharmacist play the most important role in a patient's decision to replace his/her medicine with a generic. PMID- 26477668 TI - Stereospecific S(N)2@P reactions: novel access to bulky P-stereogenic ligands. AB - The stereospecific hydrolysis of bulky aminophosphine boranes is reported for the first time. The resulting phosphinous acid boranes, upon activation, undergo stereospecific nucleophilic substitution reaction at the phosphorous center with amine nucleophiles. The combination of these two processes provides a novel access to bulky P*-ligands. PMID- 26477669 TI - Route to Topological Superconductivity via Magnetic Field Rotation. AB - The verification of topological superconductivity has become a major experimental challenge. Apart from the very few spin-triplet superconductors with p-wave pairing symmetry, another candidate system is a conventional, two-dimensional (2D) s-wave superconductor in a magnetic field with a sufficiently strong Rashba spin-orbit coupling. Typically, the required magnetic field to convert the superconductor into a topologically non-trivial state is however by far larger than the upper critical field H(c2), which excludes its realization. In this article, we argue that this problem can be overcome by rotating the magnetic field into the superconducting plane. We explore the character of the superconducting state upon changing the strength and the orientation of the magnetic field and show that a topological state, established for a sufficiently strong out-of-plane magnetic field, indeed extends to an in-plane field orientation. We present a three-band model applicable to the superconducting interface between LaAlO3 and SrTiO3, which should fulfil the necessary conditions to realize a topological superconductor. PMID- 26477670 TI - Nonlinear optical chromophores based on Dewar's rules: enhancement of electro optic activity by introducing heteroatoms into the donor or bridge. AB - In this work, we investigated the enhancement of the electro-optic response by introducing electron-rich heteroatoms as additional donors into the donor or bridge of a conventional second-order nonlinear optical chromophore. A series of chromophores C2-C4 based on the same tricyanofuran acceptor (TCF) but with different heteroatoms in the alkylamino phenyl donor (C2 or C3) or thiophene bridge (C4) have been synthesized and systematically investigated. Density functional theory calculations suggested that chromophores C2-C4 had a smaller energy gap and larger first-order hyperpolarizability (beta) than traditional chromophore C1 due to the additional heteroatoms. Single crystal structure analyses and optimized configurations indicate that the rationally introduced heteroatom group would bring larger beta and weaker intermolecular interactions which were beneficial for translating molecular beta into macro-electro-optic activity in electric field poled films. The electro-optic coefficient of poled films containing 25 wt% of these new chromophores doped in amorphous poly carbonate afforded values of 83 and 91 pm V(-1) at 1310 nm for chromophores C3 and C4, respectively, which are two times higher than that of the traditional chromophore C1 (39 pm V(-1)). High r33 values indicated that introducing heteroatoms to the donor and bridge of a conventional molecular structure can efficiently improve the electron-donating ability, which improves the beta. The long-chain on the donor or bridge part, acting as the isolation group, may reduce inter-molecular electrostatic interactions, thus enhancing the macroscopic EO activity. These results, together with good solubility and compatibility with the polymer, show the new chromophore's potential application in electro-optic devices. PMID- 26477671 TI - Functional metal-bipyridinium frameworks: self-assembly and applications. AB - Metal-organic frameworks (MOFs) as newly emerged materials have experienced rapid development in the last few years. The modular synthesis procedure allows integrating functional groups in their frameworks with varied applications. Due to the easy modification of the backbone and highly charged characteristics with interesting electron-active properties, the use of bipyridinium derivatives as synthons for the fabrication of functional metal-bipyridinium frameworks (MBPFs) has attracted increased interest over the past few years. Various bipyridinium bearing ligands have been designed for the construction of functional MBPFs, and some of them present intriguing properties for potential applications including photochromism and photoswitching, sensing, molecule adsorption and separation. This perspective aims to highlight the recent progress in this area, and seeks to uncover promising ideas that will underscore future advancements at both the fundamental and applied levels. PMID- 26477672 TI - Nature of flocculation and tactoid formation in montmorillonite: the role of pH. AB - The dissolution and swelling properties of montmorillonite at different pH have been studied, using small angle X-ray scattering (SAXS), imaging and osmotic stress methods combined with Monte Carlo simulations. The acidity of montmorillonite dispersions has been varied as well as the counterions to the net negatively charged platelets. At low pH, Na montmorillonite dissolves and among other species Al(3+) is released, hydrated, polymerized and then it replaces the counterions in the clay. This dramatically changes the microstructure of Na montmorillonite, which instead of having fully exfoliated platelets, turns into a structure of aggregated platelets, so-called tactoids. Montmorillonite dispersion still has a significant extra-lamellar swelling among the tactoids due to the presence of very small nanoplatelets. PMID- 26477673 TI - An efficient one-pot two catalyst system in the construction of 2-substituted benzimidazoles: synthesis of benzimidazo[1,2-c]quinazolines. AB - The benzimidazole core is a common moiety in a large number of natural products and pharmacologically active small molecules. The synthesis of novel benzimidazole derivatives remains a main focus in medicinal research. In continuation of the efforts towards Ce(III) catalysts for organic transformations, we observed for the first time the activity of the iodide ion and copper cation in activating CeCl3.7H2O in the selective formation of prototypical 2-substituted benzimidazoles. The one-pot CeCl3.7H2O-CuI catalytic system procedure includes the cyclo-dehydrogenation of aniline Schiff's bases, generated in situ from the condensation of 1,2-phenylenediamine and aldehydes, followed by the oxidation with iodine, which works as a hydrogen sponge. Mild reaction conditions, good to excellent yields, and clean reactions make the procedure a useful contribution to the synthesis of biologically active fused heterocycles containing benzimidazoquinazolines. PMID- 26477674 TI - Attitudes Concerning Postmortem Organ Donation: A Multicenter Survey in Various German Cohorts. AB - BACKGROUND: The aim of this study was to characterize postmortem organ donation attitudes in various German cohorts. MATERIAL AND METHODS: Employees of 2 German cities and 2 German university hospitals, employees of a German automobile enterprise, and members of a German Medical Society were administered a questionnaire about postmortem organ and tissue donation attitudes. Demographic data and general attitudes were questioned and focused on: I) willingness to donate organs, II) holding a donor card, and III) having discussed the topic with the family. RESULTS: Of 5291 participants, 65.2% reported favoring postmortem organ donation. Missing negative experiences, the idea that donation is helpful, a non-medical professional environment, excellent general health, gender, agreement with the brain-death paradigm, and age significantly influenced the participants' attitudes. Participants were more likely to possess donor cards and had discussed more often with family members if they agreed with the brain-death paradigm and considered donation to be helpful. Males and older participants were the most likely to neglect donor cards, and Catholics, Protestants, and participants with poor health were the least likely to donate organs. Interest in receiving more information was expressed by 38.1% and 50.6% of participants refusing donation of all or of specific organs, respectively, and suggested the internet (60.0%) and family doctors (35.0%) as preferred sources of information. CONCLUSIONS: Public campaigns in Germany should focus on males and older people as regards donor cards, and females, younger, and religiously affiliated persons as regards the general willingness to donate organs postmortem. PMID- 26477675 TI - Fibril Film Formation of Pseudoenantiomeric Oxymethylenehelicene Oligomers at the Liquid-Solid Interface: Structural Changes, Aggregation, and Discontinuous Heterogeneous Nucleation. AB - Oxymethylenehelicene (P)- and (M)-oligomers up to a nonamer were synthesized by a building block method. The oligomers formed dimeric homoaggregates in trifluoromethylbenzene. A mixture of the pseudoenantiomeric (P)-pentamer and (M) hexamer formed a heteroaggregate, which self-assembled into one-dimensional fibril films at the liquid-solid interface. Discontinuous heterogeneous nucleation occurred, which involved the formation of particles that were 50 nm in diameter and subsequent fibril growth from these particles. The fibril film was formed on the solid surface and the molecules remained dissociated in solution. The fibril film formation was affected by seeding and the solid surface materials. PMID- 26477676 TI - Two-ply channels for faster wicking in paper-based microfluidic devices. AB - This article describes the development of porous two-ply channels for paper-based microfluidic devices that wick fluids significantly faster than conventional, porous, single-ply channels. The two-ply channels were made by stacking two single-ply channels on top of each other and were fabricated entirely out of paper, wax and toner using two commercially available printers, a convection oven and a thermal laminator. The wicking in paper-based channels was studied and modeled using a modified Lucas-Washburn equation to account for the effect of evaporation, and a paper-based titration device incorporating two-ply channels was demonstrated. PMID- 26477677 TI - Solving Kinetic Equations for the Laser Flash Photolysis Experiment on Nitric Oxide Synthases: Effect of Conformational Dynamics on the Interdomain Electron Transfer. AB - The production of nitric oxide by the nitric oxide synthase (NOS) enzyme depends on the interdomain electron transfer (IET) between the flavin mononucleotide (FMN) and heme domains. Although the rate of this IET has been measured by laser flash photolysis (LFP) for various NOS proteins, no rigorous analysis of the relevant kinetic equations was performed so far. In this work, we provide an analytical solution of the kinetic equations underlying the LFP approach. The derived expressions reveal that the bulk IET rate is significantly affected by the conformational dynamics that determines the formation and dissociation rates of the docking complex between the FMN and heme domains. We show that in order to informatively study the electron transfer across the NOS enzyme, LFP should be used in combination with other spectroscopic methods that could directly probe the docking equilibrium and the conformational change rate constants. The implications of the obtained analytical expressions for the interpretation of the LFP results from various native and modified NOS proteins are discussed. The mathematical formulas derived in this work should also be applicable for interpreting the IET kinetics in other modular redox enzymes. PMID- 26477678 TI - False-positive findings, multiple comparisons and the strength of hypotheses. PMID- 26477679 TI - Processing of Facial Emotion in Bipolar Depression and Euthymia. AB - Previous studies of facial emotion processing in bipolar disorder (BD) have reported conflicting findings. In independently conducted studies, we investigate facial emotion labeling in euthymic and depressed BD patients using tasks with static and dynamically morphed images of different emotions displayed at different intensities. Study 1 included 38 euthymic BD patients and 28 controls. Participants completed two tasks: labeling of static images of basic facial emotions (anger, disgust, fear, happy, sad) shown at different expression intensities; the Eyes Test (Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001), which involves recognition of complex emotions using only the eye region of the face. Study 2 included 53 depressed BD patients and 47 controls. Participants completed two tasks: labeling of "dynamic" facial expressions of the same five basic emotions; the Emotional Hexagon test (Young, Perret, Calder, Sprengelmeyer, & Ekman, 2002). There were no significant group differences on any measures of emotion perception/labeling, compared to controls. A significant group by intensity interaction was observed in both emotion labeling tasks (euthymia and depression), although this effect did not survive the addition of measures of executive function/psychomotor speed as covariates. Only 2.6-15.8% of euthymic patients and 7.8-13.7% of depressed patients scored below the 10th percentile of the controls for total emotion recognition accuracy. There was no evidence of specific deficits in facial emotion labeling in euthymic or depressed BD patients. Methodological variations-including mood state, sample size, and the cognitive demands of the tasks-may contribute significantly to the variability in findings between studies. PMID- 26477680 TI - Do Subjective Memory Complaints Lead or Follow Objective Cognitive Change? A Five Year Population Study of Temporal Influence. AB - The relationship between subjective memory complaints (SM) and objective memory (OM) performance in aging has been variably characterized in a substantial literature, to date. In particular, cross-sectional studies often observe weak or no associations. We investigated whether subjective memory complaints and objectively measured cognition influence each other over time, and if so, which is the stronger pathway of change-objective to subjective, or subjective to objective-or whether they are both important. Using bivariate latent change score modeling in data from a population study (N=1980) over 5 annual assessment cycles, we tested four corresponding hypotheses: (1) no coupling between SM and OM over time; (2) SM as leading indicator of change in OM; (3) OM as leading indicator of change in SM; (4) dual coupling over time, with both SM and OM leading subsequent change in the other. We also extended objective cognition to two other domains, language and executive functions. The dual-coupling models best fit the data for all three objective cognitive domains. The SM-OM temporal dynamics differ qualitatively compared to other domains, potentially reflecting changes in insight and self-awareness specific to memory impairment. Subjective memory and objective cognition reciprocally influence each other over time. The temporal dynamics between subjective and objective cognition in aging are nuanced, and must be carefully disentangled to shed light on the underlying processes. PMID- 26477684 TI - Pain-related anxiety in relation to anxiety and depression among persons living with HIV/AIDS. AB - Persons living with HIV/AIDS (PLHA) experience clinically significant pain as a result of HIV and such pain is often related to increased levels of anxiety/depression. Pain-related anxiety has been identified as a mechanism in the onset and progression of pain experience and associated affective distress. However, there has not been empirical study of pain-related anxiety in relation to affective processes among PLHA. To address this gap, hierarchical multiple regressions were conducted using SPSS v.21 to examine pain-related anxiety (as measured using the Pain Anxiety Symptoms Scale) in relation to anxiety and depressive symptoms (as measured using the Mood and Anxiety Symptoms Questionnaire) among 93 PLHA (10.8% female; Mean age = 49.63, SD = 8.89). Pain related anxiety was significantly related to anxious arousal symptoms (beta = .43) and anhedonic depressive symptoms (beta = .25); effects were evident beyond the variance accounted for by CD4 count, race, sex, income level, and current level of bodily pain. The present results suggest that pain-related anxiety may play a role in the experience of anxiety and depressive symptoms among PLHA. PMID- 26477683 TI - Immunotherapy and tumor microenvironment. AB - Recent exciting progress in cancer immunotherapy has ushered in a new era of cancer treatment. Immunotherapy can elicit unprecedented durable responses in advanced cancer patients that are much greater than conventional chemotherapy. However, such responses only occur in a relatively small fraction of patients. A positive response to immunotherapy usually relies on dynamic interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). Depending on the context of these interactions, the TME may play important roles to either dampen or enhance immune responses. Understanding the interactions between immunotherapy and the TME is not only critical to dissect the mechanisms of action but also important to provide new approaches in improving the efficiency of current immunotherapies. In this review, we will highlight recent work on how the TME can influence the efficacy of immunotherapy as well as how manipulating the TME can improve current immunotherapy regimens in some cases. PMID- 26477685 TI - Trialing and Maintenance Dosing Using a Low-Dose Intrathecal Opioid Method for Chronic Nonmalignant Pain: A Prospective 36-Month Study. AB - OBJECTIVE: To evaluate low-dose intrathecal opioid trialing and maintenance with regard to analgesia and psychometric functional capacity. MATERIALS AND METHODS: Prospective cohort of subjects offered, trialed and maintained using low-dose opioid therapy via an intrathecal drug delivery system. Analgesia, measured by visual analog scale and the Global Pain Scale, and function, measured by Multidimensional Pain Inventory and Global Pain Scale, are evaluated. Population analysis by age, gender, oral opioid dose, diagnosis, and pain type is reported. RESULTS: Fifty-eight subjects enrolled in the 36-month evaluation period with mean opioid intrathecal opioid dose less than 350 MUg per day of morphine equivalent utilized. Primary nociceptive pain type were associated with lower intrathecal opioid doses and improved visual analog scale pain rating and improved pain severity and interference on the Multidimensional Pain Inventory. CONCLUSIONS: This study adds to the growing body of literature suggesting that low-dose intrathecal analgesia without oral opioid supplementation can be efficacious. It appears that this approach may achieve analgesia with lower doses in those with primary nociceptive pain type. PMID- 26477686 TI - Substrate-Deposited Sea Spray Aerosol Particles: Influence of Analytical Method, Substrate, and Storage Conditions on Particle Size, Phase, and Morphology. AB - Atmospheric aerosols are often collected on substrates and analyzed weeks or months after the initial collection. We investigated how the selection of substrate and microscopy method influence the measured size, phase, and morphology of sea spray aerosol (SSA) particles and how sample storage conditions affect individual particles using three common microscopy techniques: optical microscopy, atomic force microscopy, and scanning electron microscopy. Micro Raman spectroscopy was used to determine changes in the water content of stored particles. The results show that microscopy techniques operating under ambient conditions provide the most relevant and robust measurement of particle size. Samples stored in a desiccator and at ambient conditions leads to similar sizes and morphologies, while storage that involves freezing and thawing leads to irreversible changes due to phase changes and water condensation. Typically, SSA particles are deposited wet and, if possible, samples used for single-particle analysis should be stored at or near conditions at which they were collected in order to avoid dehydration. However, if samples need to be dry, as is often the case, then this study found that storing SSA particles at ambient laboratory conditions (17-23% RH and 19-21 degrees C) was effective at preserving them and reducing changes that would alter samples and subsequent data interpretation. PMID- 26477687 TI - Diagnosis and management of thrombotic thrombocytopenic purpura (TTP) in Australia: findings from the first 5 years of the Australian TTP/thrombotic microangiopathy registry. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA). In 2009, the Australian TTP/TMA registry was established to collect data on patients presenting with TTP/TMA throughout Australia. AIM: To summarise information on the diagnosis and management of patients with TTP collected in the first 5 years (2009-2014) of the Australian TTP registry. METHODS: Registry data from June 2009 to October 2014 were reviewed. RESULTS: Fifty-seven patients were identified with TTP (defined as ADAMTS13 activity <10%), accounting for 72 clinical episodes. ADAMTS13 inhibitor testing was performed in nine out of 57 patients (16%), reflecting the limited availability of accredited testing facilities. Sixty-seven out of 72 episodes were treated with therapeutic plasma exchange (PEx) using cryodepleted plasma (40% of episodes), fresh frozen plasma (36%) or a mixture (22%). Median exposure to plasma products was 55.9 L. PEx was commenced >=2 days from stated diagnosis in 15% of episodes. Adverse reactions to PEx were common with documented allergic reactions (including life threatening) in 21% of episodes. Adjunctive immunosuppression was documented in 76% of episodes (corticosteroid 71% and rituximab 39%). Platelet transfusion was administered in 15% of episodes. CONCLUSIONS: Data from the Australian TTP/TMA registry suggest a heterogenous approach to the diagnosis and management of TTP in Australia over the assessed period. These observations highlight areas for improvement and standardisation of practice, including comprehensive diagnostic testing, more immediate access to PEx and a more uniform approach to adjunctive immunosuppression and supportive care. PMID- 26477688 TI - The key regulator of submergence tolerance, SUB1A, promotes photosynthetic and metabolic recovery from submergence damage in rice leaves. AB - The submergence-tolerance regulator, SUBMERGENCE1A (SUB1A), of rice (Oryza sativa L.) modulates gene regulation, metabolism and elongation growth during submergence. Its benefits continue during desubmergence through protection from reactive oxygen species and dehydration, but there is limited understanding of SUB1A's role in physiological recovery from the stress. Here, we investigated the contribution of SUB1A to desubmergence recovery using the two near-isogenic lines, submergence-sensitive M202 and tolerant M202(Sub1). No visible damage was detected in the two genotypes after 3 d of submergence, but the sublethal stress differentially altered photosynthetic parameters and accumulation of energy reserves. Submergence inhibited photosystem II photochemistry and stimulated breakdown of protein and accumulation of several amino acids in both genotypes at similar levels. Upon desubmergence, however, more rapid return to homeostasis of these factors was observed in M202(Sub1). Submergence considerably restrained non photochemical quenching (NPQ) in M202, whereas the value was unaltered in M202(Sub1) during the stress. Upon reaeration, submerged plants encounter sudden exposure to higher light. A greater capability for NPQ-mediated photoprotection can benefit the rapid recovery of photosynthetic performance and energy reserve metabolism in M202(Sub1). Our findings illuminate the significant role of SUB1A in active physiological recovery upon desubmergence, a component of enhanced tolerance to submergence. PMID- 26477689 TI - Efficient Fludarabine-Activating PNP From Archaea as a Guidance for Redesign the Active Site of E. Coli PNP. AB - The combination of the gene of purine nucleoside phosphorylase (PNP) from Escherichia coli and fludarabine represents one of the most promising systems in the gene therapy of solid tumors. The use of fludarabine in gene therapy is limited by the lack of an enzyme that is able to efficiently activate this prodrug which, consequently, has to be administered in high doses that cause serious side effects. In an attempt to identify enzymes with a better catalytic efficiency than E. coli PNP towards fludarabine to be used as a guidance on how to improve the activity of the bacterial enzyme, we have selected 5'-deoxy-5' methylthioadenosine phosphorylase (SsMTAP) and 5'-deoxy-5'-methylthioadenosine phosphorylase II (SsMTAPII), two PNPs isolated from the hyperthermophilic archaeon Sulfolobus solfataricus. Substrate specificity and catalytic efficiency of SsMTAP and SsMTAPII for fludarabine were analyzed by kinetic studies and compared with E. coli PNP. SsMTAP and SsMTAPII share with E. coli PNP a comparable low affinity for the arabinonucleoside but are better catalysts of fludarabine cleavage with k(cat)/K(m) values that are 12.8-fold and 6-fold higher, respectively, than those reported for the bacterial enzyme. A computational analysis of the interactions of fludarabine in the active sites of E. coli PNP, SsMTAP, and SsMTAPII allowed to identify the crucial residues involved in the binding with this substrate, and provided structural information to improve the catalytic efficiency of E. coli PNP by enzyme redesign. PMID- 26477690 TI - Reply: Mutations in TUBB4A and spastic paraplegia. PMID- 26477691 TI - Age-related changes in aortic 3D blood flow velocities and wall shear stress: Implications for the identification of altered hemodynamics in patients with aortic valve disease. AB - PURPOSE: To investigate age-related changes in peak systolic aortic 3D velocity and wall shear stress (WSS) in healthy controls and to investigate the importance of age-matching for 3D mapping of abnormal aortic hemodynamics in bicuspid aortic valve disease (BAV). MATERIALS AND METHODS: 4D flow MRI (fields strengths = 1.5 3T; resolution = 2.2-3.9 * 1.7-2.6 * 2.2-4.0 mm(3) ; Venc = 150-250 cm/s; TE/TR/FA = 2.3-2.8/4.7-5.4msec/7-15 degrees ) was performed in 56 controls (age range: 19-78 years) and in two BAV patient groups each consisting of 10 subjects (group 1: 20-29 years, group 2: 52-57 years). Heat maps showing abnormal 3D velocity and WSS were created for the BAV patients by comparison with an age matched and with an unmatched control group. The fraction of the aorta exposed to abnormal velocity/WSS was calculated relative to the total aortic volume/surface. RESULTS: Significant inverse relationships between age and healthy velocity/WSS were found (R(2) = 0.32/0.39, P < 0.001). For BAV group 1, abnormally elevated velocity/WSS was overestimated when compared with older controls (51-60 years) than when correctly age-matched (~25 +/- 14% vs. ~8 +/- 5%). For BAV group 2, abnormally decreased velocity/WSS was overestimated when compared with younger controls (21-30 years) than when correctly age-matched (~9 +/- 7% vs. 1 +/- 1%). CONCLUSION: Significant correlations exist between age and peak systolic velocity and WSS. Therefore, robust age-matching is important when creating abnormal 3D aortic velocity and WSS maps for patients with BAV. PMID- 26477692 TI - Blueberry Improves the Therapeutic Effect of Etanercept on Patients with Juvenile Idiopathic Arthritis: Phase III Study. AB - Juvenile idiopathic arthritis (JIA) is the most common arthritis in the adolescents under the age of 16. Etanercept, an inhibitor of tumor necrosis factor, is often used to treat JIA despite its significant side effects. Homeopathic remedies, such as blueberries, have anti-inflammatory properties with fewer unwanted effects and should be considered as a primary treatment. We aimed to explore the efficacy and safety of combination therapy of blueberry and etanercept for JIA. Two hundred and one JIA patients were selected, and randomly and evenly assigned to three groups: ETA (50 mg of etanercept twice weekly), ETABJ (matched etanercept and 50 ml blueberry juice daily) and ETAPJ (matched etanercept and placebo juice). The severity of JIA was measured using American College of Rheumatology scales (ACR) 20, 50 and 70. The levels of pro inflammatory cytokines, interleukin-1 (IL1) alpha and IL1 beta, and interleukin-1 receptor antagonist (IL1RA) were measured by qRT-PCR and ELISA. After a 6-month follow-up, the ACR20, ACR50 and ACR70 in an ETABJ group were higher than those in other two groups (P < 0.05), suggesting clinically meaningful improvement in JIA. Meanwhile, the symptoms and side effects were reduced significantly or absent in an ETABJ group, including mental diseases, retrobulbar optic neuritis, gaining weight, infection, cutaneous vasculitis, diarrhea, uveitis and pancytopenia. Blueberries reduced the levels of IL1 alpha and beta, and increased the level of IL1RA. Thus, a combination therapy of blueberry and etanercept can reduce the severity of JIA and should be developed as a new method for JIA therapy. PMID- 26477693 TI - RNA interference targeting PSCA suppresses primary tumor growth and metastasis formation of human prostate cancer xenografts in SCID mice. AB - BACKGROUND AND OBJECTIVES: Prostate stem cell antigen (PSCA) is a cell surface, glycosylphosphatidylinositol (GPI)-anchored glycoprotein. Its overexpression has been detected in both local and metastatic prostate cancer (PCa), making it a potential therapeutic target. We previously reported that silencing PSCA by small interfering RNA targeting human PSCA (siRNA-PSCA) inhibited biological activity of PSCA-positive PCa cells leading to reduced proliferation, motility and invasion in vitro. In this study, we extended this in vitro findings to in vivo settings in order to investigate the effects of this specific siRNA on the tumor growth and metastasis development of PCa in vivo. MATERIALS AND METHODS: The siRNA-PSCA and ectopically overexpressed-PSCA vector were constructed and transfected into human PCa PC-3M and LNCaP cells, respectively, and were subcutaneously inoculated into the male SCID mice. Tumor growth was measured with a caliper, and formation of metastasis in mice bearing xenograft tumors was studied by magnetic resonance imaging (MRI) and autopsy analysis. Western blot and immunohistochemistry were used to assess the expression levels of PSCA protein in tumor tissues from xenograft and distant metastases. RESULTS: Consistent with our previous in vitro findings, the subcutaneous xenografts of PC 3M-siPSCA exhibited the almost completely inhibited expression of PSCA protein in their tumors tissues (P < 0.001 and P < 0.001, respectively), and consequently had a significant reduction in tumor growth volumes (P < 0.05 for all), and metastasis onset and sites (P < 0.001 for all) compared to those of PC-3M and PC 3M-siScrm. Conversely, LNCaP-PSCA showed significantly enhanced primary tumor growth and metastasis formation of xenografts compared to LNCaP-vehicle and LNCaP cells (P < 0.001 for all). Moreover, the up-regulated expression of PSCA protein was detected in the distant metastases of xenograft tumors from all groups. CONCLUSIONS: Taken together, these observations suggest that PSCA has a promoting role in the growth and metastasis of PCa and siRNA-PSCA may be a potential therapeutic strategy for PSCA-positive PCa. PMID- 26477694 TI - Pigmented naevi and sun protection behaviour among primary and secondary school students in an Eastern Hungarian city. AB - BACKGROUND: The most important risk factors for malignant melanoma are skin type I or II, large number of atypical naevi and a history of sunburn in childhood and adolescence. METHODS: A cross-sectional study was performed to assess skin type, number of pigmented lesions and sun protection behaviour in 1157 12- to 19-year old Hungarian students at 20 primary and secondary schools in Debrecen, Hungary. After receiving dermatological training, 18 school doctors examined the students' skin. A questionnaire was completed by the students with the assistance of their parents about sun protection, sunburns and the use of sunbed. Data from 612 questionnaires were evaluated. RESULTS: Based on the doctors' evaluation, most of the pupils were classified as having skin type II and majority of them had 5-20 naevi, particularly on the trunk. Based on the student's response, 5.2% purposely sunbathed daily, 10.1% did not use any form of sun protection, 32.2% wore sun protective clothing and 65.7% applied sunscreen generally. 6.9% used sunbed, and 74.0% previously experienced serious sunburn at least once. Indoor tanning statistically correlated with the number of melanocytic naevi. CONCLUSION: A high prevalence of sunburn was reported by the students and some of them did not apply any sun protection methods but used sunbed at a critical age for developing melanoma at a later time. These data highlight the importance of educating children and parents about appropriate sun protection. PMID- 26477695 TI - Pro-permeability Factors After Dexamethasone Implant in Retinal Vein Occlusion; The Ozurdex for Retinal Vein Occlusion (ORVO) Study. PMID- 26477696 TI - Cysteamine in renal transplantation: A report of two patients with nephropathic cystinosis and the successful re-initiation of cysteamine therapy during the immediate post-transplant period. AB - Nephropathic cystinosis is a rare disorder causing the accumulation of intracellular cystine crystals in tissues. The damage to the proximal tubules of the kidneys results in Fanconi syndrome, and patients with cystinosis experience the progression of chronic kidney disease, resulting in the need for kidney transplantation. Treatment of cystinosis with cysteamine has proven to be effective; however, it has many gastrointestinal side effects that are concerning for transplant specialists during the immediate post-transplant period. Transplant specialists routinely discontinue cysteamine therapy for up to six weeks to ensure proper immunosuppressant absorption. This practice is worrisome because it communicates the acceptability of lapses of cysteamine treatment to patients. It may be better to re-initiate cysteamine therapy shortly after transplantation while the patient is followed more closely by the transplant team. This report presents two pediatric patients with nephropathic cystinosis who successfully restarted cysteamine therapy in the immediate post-transplant period without issue in regard to immunosuppression absorption or gastrointestinal side effects. These cases challenge current practice of discontinuing cysteamine therapy during kidney transplantation, and immediate re initiation of cysteamine therapy in cystinosis patients post-transplant should be considered. PMID- 26477697 TI - In Situ Visualization of Block Copolymer Self-Assembly in Organic Media by Super Resolution Fluorescence Microscopy. AB - Analytical methods that enable visualization of nanomaterials derived from solution self-assembly processes in organic solvents are highly desirable. Herein, we demonstrate the use of stimulated emission depletion microscopy (STED) and single molecule localization microscopy (SMLM) to map living crystallization driven block copolymer (BCP) self-assembly in organic media at the sub diffraction scale. Four different dyes were successfully used for single-colour super-resolution imaging of the BCP nanostructures allowing micelle length distributions to be determined in situ. Dual-colour SMLM imaging was used to measure and compare the rate of addition of red fluorescent BCP to the termini of green fluorescent seed micelles to generate block comicelles. Although well established for aqueous systems, the results highlight the potential of super resolution microscopy techniques for the interrogation of self-assembly processes in organic media. PMID- 26477699 TI - The complete mitochondrial genome of the Madagascar ground gecko Paroedura picta (Squamata: Gekkonidae). AB - We sequenced the complete mitochondrial genome of the Madagascar ground gecko Paroedura picta (Squamata: Gekkonidae). The mitogenome is 17 220 base pairs long and conforms to the typical vertebrate gene composition and arrangement, i.e. 13 protein-coding genes, 22 tRNA genes, 2 ribosomal RNA genes and 1919 bp long control region. We reconstructed phylogenetic relationships of P. picta and representatives of nine other genera from the family Gekkonidae and calculated mean p-distances for all 13 protein-coding mitochondrial genes. The lowest mean p distances were found in cytochrome oxidase subunit I and III genes (COI and COIII) indicating their usefulness for elucidating deeper phylogenetic relationships. PMID- 26477698 TI - Effects of 96 Weeks of Rosuvastatin on Bone, Muscle, and Fat in HIV-Infected Adults on Effective Antiretroviral Therapy. AB - Heightened inflammation and immune activation are associated with lower bone mineral density (BMD) and lean body mass (LBM) among HIV-infected persons. We hypothesized that a reduction in inflammation with rosuvastatin would be associated with improvements in BMD and LBM. HIV-infected participants on stable antiretroviral therapy without statin indication and with heightened immune activation (>=19% CD8(+)CD38(+)HLA-DR(+) T cells) or inflammation (hsCRP >=2 mg/liter) were randomized to rosuvastatin 10 mg daily or placebo for 96 weeks. Among 72 participants randomized to rosuvastatin and 75 to placebo, there were no significant differences in the relative changes in BMD (p > 0.29) or in fat (p >= 0.19). A trend toward increased LBM (p = 0.059) was seen in the rosuvastatin arm without differences in creatinine kinase or self-reported physical activity (p >= 0.10). In a multivariable regression model, rosuvastatin was associated with a significant positive effect on LBM after adjusting for age, sex, race, smoking status, and detectable HIV-1 viral load. Higher baseline sCD163 correlated with increases in LBM from weeks 0 to 96 (p = 0.023); greater changes in total and leg lean mass were seen among statin users with higher compared to lower baseline IP 10 levels (LBM 1.8 vs. -0.3%; p = 0.028 and leg lean mass 2.9 vs. -1.7%; p = 0.012). Rosuvastatin is associated with an absence of toxicity on BMD and a potential benefit on LBM over 96 weeks of therapy. The preservation of LBM in the rosuvastatin arm over the 2 years of the study is of major clinical relevance in delaying loss of muscle mass with aging. PMID- 26477700 TI - Restoring calcium homeostasis to treat Alzheimer's disease: a future perspective. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that primarily compromises memory formation and storage. Several hypotheses regarding the pathogenesis of AD have been proposed; however, no cure is available to date. Here we describe the calcium hypothesis of AD, which is gaining popularity. We present data supporting this hypothesis and focus on a recently discovered calcium-signaling pathway that is dysregulated in AD and propose targets for the development of disease-modifying therapies. PMID- 26477701 TI - European Resuscitation Council Guidelines for Resuscitation 2015: Section 3. Adult advanced life support. PMID- 26477702 TI - European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015: Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015. PMID- 26477703 TI - Part 1: Executive summary: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 26477704 TI - Part 5: Acute coronary syndromes: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 26477705 TI - Part 8: Education, implementation, and teams: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. PMID- 26477707 TI - Growth Factors and Astrocytes Metabolism: Possible Roles for Platelet Derived Growth Factor. AB - Astrocytes exert multiple functions in the brain such as the development of blood brain barrier characteristics, the promotion of neurovascular coupling, attraction of cells through the release of chemokines, clearance of toxic substances and generation of antioxidant molecules and growth factors. In this aspect, astrocytes secrete several growth factors (BDNF, GDNF, NGF, and others) that are fundamental for cell viability, oxidant protection, genetic expression and modulation of metabolic functions. The platelet derived growth factor (PDGF), which is expressed by many SNC cells, including astrocytes, is an important molecule that has shown neuroprotective potential, improvement of wound healing, regulation of calcium metabolism and mitochondrial function. Here we explore some of these astrocyte-driven functions of growth factors and their possible therapeutic uses in the context of neurodegeneration. PMID- 26477708 TI - Construction of Training Sets for Valid Calibration of in Vivo Cyclic Voltammetric Data by Principal Component Analysis. AB - Principal component regression, a multivariate calibration technique, is an invaluable tool for the analysis of voltammetric data collected in vivo with acutely implanted microelectrodes. This method utilizes training sets to separate cyclic voltammograms into contributions from multiple electroactive species. The introduction of chronically implanted microelectrodes permits longitudinal measurements at the same electrode and brain location over multiple recordings. The reliability of these measurements depends on a consistent calibration methodology. One published approach has been the use of training sets built with data from separate electrodes and animals to evaluate neurochemical signals in multiple subjects. Alternatively, responses to unpredicted rewards have been used to generate calibration data. This study addresses these approaches using voltammetric data from three different experiments in freely moving rats obtained with acutely implanted microelectrodes. The findings demonstrate critical issues arising from the misuse of principal component regression that result in significant underestimates of concentrations and improper statistical model validation that, in turn, can lead to inaccurate data interpretation. Therefore, the calibration methodology for chronically implanted microelectrodes needs to be revisited and improved before measurements can be considered reliable. PMID- 26477709 TI - Epstein-Barr virus-associated inflammatory pseudotumor presenting as a colonic mass. AB - Epstein-Barr virus (EBV)-positive inflammatory pseudotumor (IPT) commonly involves spleen and liver and has only rarely been reported in the gastrointestinal (GI) tract. The spindle cells may express myofibroblastic or follicular dendritic cell markers. We report a challenging case of EBV-positive IPT arising in the ascending colon. The lesion was composed of spindle cells positive for smooth muscle actin but negative for all follicular dendritic cell markers tested and was associated with an exuberant lymphoid proliferation containing reactive follicles, abundant plasma cells, and small lymphocytes. We further discuss pitfalls for possible misdiagnosis as ALK-positive inflammatory myofibroblastic tumor, IgG4-related disease, and peripheral T-cell lymphoma. Our case represents the first EBV-positive inflammatory pseudotumor of the GI tract in the Western literature. Awareness of this rare entity in GI tract is essential for correct diagnosis and appropriate patient management. PMID- 26477711 TI - Spinal cord injury is associated with an increased risk of atrial fibrillation: A population-based cohort study. AB - BACKGROUND: Spinal cord injury (SCI) can result in substantial sensorimotor and autonomic dysfunctions and an adverse prognosis. Cardiovascular disease is the leading cause of death in patients with chronic SCI. OBJECTIVE: We conducted a retrospective cohort study to investigate the association between atrial fibrillation (AF) and SCI. METHODS: Using the National Health Insurance Research Database, we identified 41,691 patients without a history of AF who were newly hospitalized for SCI between 2000 and 2011. The comparison group included 166,724 patients without AF or SCI who were matched to the SCI group according to age, sex, and index year at a ratio of 4:1. Both cohorts were followed up until the end of 2011, and the cumulative incidence of AF was calculated. Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier curve analysis were used to compare differences in the cumulative incidence of AF between the 2 groups. RESULTS: During the mean follow-up periods of 5.69 years for the SCI group and 6.17 years for the non-SCI group, the overall incidence rates were 2.70 and 1.99 cases per 1000 person-years, respectively (crude hazard ratio 1.36; 95% confidence interval 1.24-1.48). After adjusting for age, sex, and all comorbidities, the risk of AF remained significantly higher in the SCI group than in the non-SCI group (adjusted hazard ratio 1.28; 95% confidence interval 1.17-1.40). CONCLUSION: SCI is associated with an increased risk of AF in a long term follow-up period. PMID- 26477710 TI - Ventricular antitachycardia pacing therapy in patients with heart failure implanted with a cardiac resynchronization therapy defibrillator device: Efficacy, safety, and impact on mortality. AB - BACKGROUND: Cardiac resynchronization therapy defibrillator can terminate ventricular tachycardia (VT) and fast VT (FVT) via antitachycardia pacing (ATP). OBJECTIVES: We evaluated efficacy and safety of ATP, whether ATP induces ventricular arrhythmias after inappropriate ATP or atrial fibrillation (AF) after appropriate ATP, and whether ATP is associated with mortality. METHODS: A total of 1404 patients with a cardiac resynchronization therapy defibrillator were followed in a prospective multicenter observational research. All-cause mortality rates were estimated in patient subgroups in order to uncouple the trigger (VT/FVT or other rhythms causing inappropriate detections) from ATP therapy. RESULTS: Over a median follow-up of 31 months, 2938 VT/FVT episodes were treated with ATP in 360 patients. The adjusted ATP success rate was 63% (95% confidence interval [CI] 57%-69%) on FVTs and 68% (95% CI 62%-74%) on VTs. Acceleration occurred in 55 (1.87%) and syncope in 4 (0.14%) of all ATP-treated episodes. In 14 true VT/FVT episodes in 5 patients, AF followed ATP therapy. In 4 episodes in 2 patients, VT followed ATP inappropriately applied during AF. Death rate per 100 patient-years was 5.6 (95% CI 4.3-7.5) in patients with appropriate ATP and 1.5 (95% CI 0.4-6.1) in patients with inappropriate ATP (P = .045). CONCLUSION: ATP was effective in terminating VT/FVT episodes and displayed a good safety profile. ATP therapies by themselves did not increase death risk; prognosis was indeed better in patients without arrhythmic episodes, even if they received inappropriate ATP, than in patients with ATP on VT/FVT episodes. Adverse outcomes observed in patients receiving implantable cardioverter-defibrillator therapies are probably related to the arrhythmia itself, a marker of disease progression, rather than to adverse effects of ATP. PMID- 26477713 TI - PCR-sequencing is a complementary method to amplification refractory mutation system for EGFR gene mutation analysis in FFPE samples. AB - Amplification Refractory Mutation System (ARMS) is the most popular technology for EGFR gene mutation analysis in China. Cutoff Ct or DeltaCt values were used to differentiate low mutation abundance cases from no mutation cases. In this study, all of 359 NSCLC samples were tested by ARMS. Seventeen samples with larger Ct or DeltaCt than cutoff values were retested by PCR-sequencing. TKI treatment responses were monitored on the cases with ARMS negative and PCR sequencing positive results. One exon 18 G719X case, 67 exon 19 deletion cases, 2 exon 20 insertion cases, 1 exon 20 T790M case, 60 exon 21 L858R cases, 5 exon 21 L861Q cases and 201 wild type cases were identified by ARMS. Another 22 cases were evaluated as wild type but had later amplification fluorescent curves. Seventeen out of these 22 cases were retested by PCR-sequencing. It turns out that 3 out of 3 cases with exon 19 deletion later amplifications, 2 out of 2 cases with L858R later amplifications and 4 out of 12 cases with T790M later amplifications were identified as mutation positive. Two cases with exon 19 deletion and L858R respectively were treated by TKI and got responses. Our study indicated that PCR-sequencing might be a complementary way to confirm ARMS results with later amplifications. PMID- 26477712 TI - Prevalence and distribution of focal triggers in persistent and long-standing persistent atrial fibrillation. AB - BACKGROUND: The relevance of focal triggers in persistent atrial fibrillation (PerAF) and long-standing persistent atrial fibrillation (LSPAF) has not been previously investigated. OBJECTIVE: We prospectively evaluated the prevalence and distribution of AF triggers in patients referred for catheter ablation of PerAF and LSPAF. METHODS: We analyzed consecutive patients undergoing first time AF ablation who underwent a standardized trigger protocol including cardioversion of induced or spontaneous AF and infusion of up to 20 MUg of isoproterenol for 15-20 minutes either before or after pulmonary vein (PV) isolation accomplished. Triggers were defined as AF/sustained atrial tachyarrhythmia or repetitive atrial premature depolarizations. RESULTS: A total of 2168 patients were included (mean age 57 +/- 11 years; 1636 [75%] men), with 1531 patients having paroxysmal AF (PAF) (71%), 496 having PerAF (23%), and 141 having LSPAF (7%). PV triggers were found in 1398 patients with PAF (91%), 449 patients with PerAF (91%), and 129 patients with LSPAF (91%) (P = .856 for comparison across groups). Non-PV triggers were elicited in a total of 234 patients (11%), and the prevalence was similar across the different types of AF (PAF, 165 [11%]; PerAF, 54 [11%]; LSPAF, 15 [11%]; P = .996 for comparison across groups). CONCLUSION: PVs are the main AF trigger site in patients with PerAF and LSPAF, with an overall prevalence similar to that found in patients with PAF. These results support the current recommendations for PV isolation as the cornerstone of catheter ablation to eliminate AF triggers in PerAF and LSPAF. PMID- 26477714 TI - Candida glabrata induced infection of rat tracheal epithelial cells is mediated by TLR-2 induced activation of NF-kappaB. AB - An increasing number of reports identified Candida glabrata (C. glabrata) as the important causative agent of invasive pulmonary fungal infection. However, little is known about immune responses to C. glabrata in rat tracheal epithelial cell (RTEC). Here, the effect of C. glabrata on RTEC and the role of TLR-2 and NF kappaB in the immune response were investigated by treatment with TLR-2 siRNA and NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC), respectively. Our results showed that the knockdown of TLR-2 and pretreatment of PDTC led to inhibition of cell proliferation by C. glabrata, further enhanced cells in G0/G1 phases, and promoted C. glabrata -induced apoptosis. C. glabrata infection induced the expression or secretion of TLR-2, NF-kappaB, TNF-alpha, and IL-6, and its effect was inhibited by knockdown of TLR-2. Pretreatment with PDTC inhibited the C. glabrata -induced expression of TLR2, and also inhibited the expression of p65 subunit of NF-kappaB in the first 4 h. Although the expression of p65 subunit at 6 h was elevated compared to baseline, the C. glabrata -induced expression of TNF alpha and IL-6 remained attenuated by PDTC pretreatment. Therefore, C. glabrata recognized the TLR-2 in rat tracheal epithelial cell (RTEC), and then activated the transcription factor NF-kappaB and further promoted the secretion of TNF alpha and IL-6 to contribute to the immune response and inflammation. PMID- 26477715 TI - Directly measuring mean and variance of infinite-spectrum observables such as the photon orbital angular momentum. AB - The standard method for experimentally determining the probability distribution of an observable in quantum mechanics is the measurement of the observable spectrum. However, for infinite-dimensional degrees of freedom, this approach would require ideally infinite or, more realistically, a very large number of measurements. Here we consider an alternative method which can yield the mean and variance of an observable of an infinite-dimensional system by measuring only a two-dimensional pointer weakly coupled with the system. In our demonstrative implementation, we determine both the mean and the variance of the orbital angular momentum of a light beam without acquiring the entire spectrum, but measuring the Stokes parameters of the optical polarization (acting as pointer), after the beam has suffered a suitable spin-orbit weak interaction. This example can provide a paradigm for a new class of useful weak quantum measurements. PMID- 26477716 TI - An event-related potential investigation of sentence processing in adults who stutter. AB - The purpose of this study was to investigate characteristics of the semantic processing of sentences' final verbs in stutterers using event-related potential (ERP). ERPs elicited from semantically violating and non-violating verbs in Japanese sentences were compared between 13 adults who stutter (AWS) and 13 adults who do not stutter (AWNS). The stimulus sentences elicited the N400 and the late positive component (LPC) in both groups. The amplitude of the N400, however, was attenuated in AWS. Regarding the LPC, the LPC in the 450-700ms time window (the early LPC) was evident in both groups, but the LPC in the 700-850 time window (the late LPC) was only apparent in AWS. Because AWS judged sentence congruency as accurately as AWNS did, it is assumed that AWS depended more on the LPC for semantic processing, resulting in the enhancement of the late LPC. We speculate that semantic processing of sentences for AWS is more time consuming than that for AWNS. PMID- 26477717 TI - Characteristics of fast-spiking neurons in the striatum of behaving monkeys. AB - Inhibitory interneurons are the fundamental constituents of neural circuits that organize network outputs. The striatum as part of the basal ganglia is involved in reward-directed behaviors. However, the role of the inhibitory interneurons in this process remains unclear, especially in behaving monkeys. We recorded the striatal single neuron activity while monkeys performed reward-directed hand or eye movements. Presumed parvalbumin-containing GABAergic interneurons (fast spiking neurons, FSNs) were identified based on narrow spike shapes in three independent experiments, though they were a small population (4.2%, 42/997). We found that FSNs are characterized by high-frequency and less-bursty discharges, which are distinct from the basic firing properties of the presumed projection neurons (phasically active neurons, PANs). Besides, the encoded information regarding actions and outcomes was similar between FSNs and PANs in terms of proportion of neurons, but the discharge selectivity was higher in PANs than that of FSNs. The coding of actions and outcomes in FSNs and PANs was consistently observed under various behavioral contexts in distinct parts of the striatum (caudate nucleus, putamen, and anterior striatum). Our results suggest that FSNs may enhance the discharge selectivity of postsynaptic output neurons (PANs) in encoding crucial variables for a reward-directed behavior. PMID- 26477719 TI - Highlights form ESC 2015. PMID- 26477718 TI - g-force induced giant efficiency of nanoparticles internalization into living cells. AB - Nanotechnology plays an increasingly important role in the biomedical arena. Iron oxide nanoparticles (IONPs)-labelled cells is one of the most promising approaches for a fast and reliable evaluation of grafted cells in both preclinical studies and clinical trials. Current procedures to label living cells with IONPs are based on direct incubation or physical approaches based on magnetic or electrical fields, which always display very low cellular uptake efficiencies. Here we show that centrifugation-mediated internalization (CMI) promotes a high uptake of IONPs in glioblastoma tumour cells, just in a few minutes, and via clathrin-independent endocytosis pathway. CMI results in controllable cellular uptake efficiencies at least three orders of magnitude larger than current procedures. Similar trends are found in human mesenchymal stem cells, thereby demonstrating the general feasibility of the methodology, which is easily transferable to any laboratory with great potential for the development of improved biomedical applications. PMID- 26477720 TI - Arterial stiffness in assessment of impaired left atrial function. PMID- 26477721 TI - Surgical and transcatheter management alternatives in refractory pulmonary hypertension: Potts shunt. AB - Despite advances in the medical treatment of children with pulmonary arterial hypertension that have resulted in improved health quality and life expectancy, the progression of the disease is still the main problem for some patients. Because of this undesirable condition, the search for new treatment strategies continues for pediatric cardiologists. At this point, the Eisenmenger physiology is the main target because of the long-life expectancy and more stable hemodynamics of patients with Eisenmenger syndrome. Therefore, some invasive procedures may be used for conversion to Eisenmenger physiology with the aim of decompressing the right ventricle. PMID- 26477722 TI - Multifaceted impact of caffeic acid phenethyl ester (CAPE) in experimental myocardial injuries. PMID- 26477723 TI - Prognostic marker of nonfatal pulmonary thromboembolism: decreased glomerular filtration rate or increased age? PMID- 26477724 TI - Analysis of heart rate variability seems to be one step ahead of cardiac reflex tests for investigating cardiovascular autonomic neuropathy. PMID- 26477725 TI - Predictors of successful percutaneous transvenous mitral commissurotomy using the Bonhoeffer Multi-Track system in patients with moderate to severe mitral stenosis: Can we see beyond the Wilkins score? PMID- 26477726 TI - Should we consider serum potassium level as a mortality predictor in ST-elevation myocardial infarction? PMID- 26477727 TI - Mean platelet volume: When the size does matter. PMID- 26477728 TI - Is atrial septal defect alone able to affect the cardiac autonomic function or are there different factors that influence this function? PMID- 26477729 TI - Potential benefits of oral pentoxifylline before coronary artery bypass surgery. PMID- 26477730 TI - Atrial fibrillation after cardiac surgery. PMID- 26477731 TI - Cardiac problem and MERS. PMID- 26477734 TI - The rewarding properties of methamphetamine in an invertebrate model of drug addiction. AB - The rewarding properties of drugs in the mammalian system depend on their ability to activate appetitive motivational states. The associated underlying mechanism is strongly conserved in evolution and invertebrates have recently emerged as a powerful new model in addiction research. The natural reward system in crayfish has surprisingly proven sensitive to human drugs of abuse, providing a new model for research into the basic biological mechanisms of drug addiction. In this study, we examined the presence of natural reward systems in crayfish, and then characterized its sensitivity to 2.5 MUg/g, 5.0 MUg/g and 10.0 MUg/g doses of methamphetamine (METH). Using the conditioned place preference (CPP) paradigm, we demonstrated that irrespective of the number of doses of METH injected into the pericardial system, crayfish seek out a particular tactile environment that had previously been paired with the METH. This study demonstrates that crayfish offer a comparative and complementary approach in addiction research. It contributes an evolutionary context to our understanding of a key component in learning and of natural reward as an important life-sustaining process. PMID- 26477733 TI - A transcriptional reference map of defence hormone responses in potato. AB - Phytohormones are involved in diverse aspects of plant life including the regulation of plant growth, development and reproduction, as well as governing biotic and abiotic stress responses. We have generated a comprehensive transcriptional reference map of the early potato responses to exogenous application of the defence hormones abscisic acid, brassinolides (applied as epibrassinolide), ethylene (applied as the ethylene precursor aminocyclopropanecarboxylic acid), salicylic acid and jasmonic acid (applied as methyl jasmonate). Of the 39000 predicted genes on the microarray, a total of 2677 and 2473 genes were significantly differentially expressed at 1 h and 6 h after hormone treatment, respectively. Specific marker genes newly identified for the early hormone responses in potato include: a homeodomain 20 transcription factor (DMG400000248) for abscisic acid; a SAUR gene (DMG400016561) induced in epibrassinolide treated plants; an osmotin gene (DMG400003057) specifically enhanced by aminocyclopropanecarboxylic acid; a gene weakly similar to AtWRKY40 (DMG402007388) that was induced by salicylic acid; and a jasmonate ZIM-domain protein 1 (DMG400002930) which was specifically activated by methyl jasmonate. An online database has been set up to query the expression patterns of potato genes represented on the microarray that can also incorporate future microarray or RNAseq-based expression studies. PMID- 26477735 TI - Dehydrodiconiferyl alcohol (DHCA) modulates the differentiation of Th17 and Th1 cells and suppresses experimental autoimmune encephalomyelitis. AB - Dehydrodiconiferyl alcohol (DHCA), originally isolated from the stems of Cucurbita moschata, has previously been shown to exhibit anti-adipogenic and anti lipogenic effects in 3T3-L1 cells and primary mouse embryonic fibroblasts (MEFs) (Lee et al., 2012). Here, we investigated whether synthetic DHCA could suppress the CD4 T helper 17 (Th17)-mediated production of the interleukin (IL)-17 protein. The results from RT-qPCR suggest that DHCA-mediated down-regulation of IL-17 occurred at the transcriptional level by suppressing the expression of RAR related orphan receptor (ROR)gammat, the master transcription factor involved in the differentiation of Th17 cells. Furthermore, such inhibition was mediated by the suppression of NF-kappaB activity. DHCA also inhibited the Th1-mediated production of interferon (IFN) gamma by controlling the expression of a key transcription factor known to regulate the production of this cytokine, T-bet. In the mouse experimental autoimmune encephalomyelitis (EAE) model, DHCA showed significant therapeutic effects by inhibiting the infiltration of immune cells into the spinal cords, decreasing the differentiation of pathogenic Th17 and Th1 cells, suppressing the expression of various pro-inflammatory cytokines, and eventually ameliorating the clinical symptoms of EAE mice. Taken together, our data indicate that DHCA may be a potential candidate as an agent for the control of Th17 and Th1-mediated inflammatory diseases. PMID- 26477736 TI - A novel antimicrobial peptide derived from fish goose type lysozyme disrupts the membrane of Salmonella enterica. AB - In aquaculture, accumulation of antibiotics resulted in development of resistance among bacterial pathogens. Consequently, it became mandatory to find alternative to synthetic antibiotics. Antimicrobial peptides (AMPs) which are described as evolutionary ancient weapons have been considered as promising alternates in recent years. In this study, a novel antimicrobial peptide had been derived from goose type lysozyme (LyzG) which was identified from the cDNA library of freshwater fish Channa striatus (Cs). The identified lysozyme cDNA contains 585 nucleotides which encodes a protein of 194 amino acids. CsLyzG was closely related to Siniperca chuatsi with 92.8% homology. The depicted protein sequence contained a GEWL domain with conserved GLMQ motif, 7 active residues and 2 catalytic residues. Gene expression analysis revealed that CsLyzG was distributed in major immune organs with highest expression in head kidney. Results of temporal expression analysis after bacterial (Aeromonas hydrophila) and fungal (Aphanomyces invadans) challenges indicated a stimulant-dependent expression pattern of CsLyzG. Two antimicrobial peptides IK12 and TS10 were identified from CsLyzG and synthesized. Antibiogram showed that IK12 was active against Salmonella enterica, a major multi-drug resistant (MDR) bacterial pathogen which produces beta lactamase. The IK12 induced loss of cell viability in the bacterial pathogen. Flow cytometry assay revealed that IK12 disrupt the membrane of S. enterica which is confirmed by scanning electron microscope (SEM) analysis that reveals blebs around the bacterial cell membrane. Conclusively, CsLyzG is a potential innate immune component and the identified antimicrobial peptide has great caliber to be used as an ecofriendly antibacterial substance in aquaculture. PMID- 26477737 TI - Phylogenetic analysis reveals an evolutionary transition from internal to external brooding in Epiactis Verrill (Cnidaria: Anthozoa: Actiniaria) and rejects the validity of the genus Cnidopus Carlgren. AB - Reproductive behaviors in the sea anemone genus Epiactis provide an opportunity for investigating the evolution of reproductive phenomena such as brooding and sex allocation (hermaphroditic vs. gonochoric) in a group of closely related and easily accessible species. However, given its broad geographic distribution, the striking diversity in reproductive behaviors, and the lack of synapomorphy for the genus, the monophyly of Epiactis is questionable. Here we perform phylogenetic analyses to test the monophyly of Epiactis and the validity of Cnidopus, which consists entirely of species once assigned to Epiactis. We use the large number of brooding species in Epiactis to investigate evolutionary patterns in brooding modes and characteristics associated with them. We find a monophyletic group of North Pacific Epiactis species: this group includes the type species of the genus and species that brood internally or externally, and that are hermaphroditic or gonochoric. Based on the results, we reject the genus Cnidopus because its circumscription renders Epiactis sensu stricto paraphyletic. Ancestral character state reconstruction indicates that in the North Pacific, externally brooding species evolved from internally brooding ancestors and that sex allocation is highly labile. Species relationships in Epiactis and Aulactinia appear to conform to geographic patterns more strongly than to taxonomic hypotheses. Contrary to expectations based on other invertebrates, we fail to find a strong correlation between brooding and hermaphroditism. PMID- 26477738 TI - Phylogeny of the island archipelago frog genus Sanguirana: Another endemic Philippine radiation that diversified 'Out-of-Palawan'. AB - Recent higher-level frog phylogenetic analyses have included a few members of the endemic Philippine frog genus Sanguirana. Although the monophyly of the group has never been disputed, the recent phylogenetically-supported inclusion of the Palawan Wood Frog (Sanguirana sanguinea) in this clade was highly unexpected. In addition, species boundaries and relationships remain unclear and new species continue to be discovered. We estimate the phylogeny for this endemic Philippine genus using two mitochondrial gene regions and six nuclear loci and complete sampling for all known species. We use a time-calibrated Bayesian estimate of phylogeny and model-testing approach to biogeographic inference to infer ancestral areas and probable means of diversification. These analyses identify Sanguirana as an additional clade for which the 'Out-of-Palawan' biogeographic scenario is unambiguously preferred. This study lends additional support to recent work suggesting that a substantial portion of Philippine vertebrate megadiversity originated via colonization of the archipelago from the Palawan microcontinent, with subsequent invasion of oceanic islands (e.g., range expansion over Huxley's Modification of Wallace's Line), numerous instances of overwater dispersal, and geographic radiation across the archipelago. PMID- 26477739 TI - The Effects and Stigma of Mental Illness in Turkey. AB - This study was planned to determine internalized stigma of patients who were monitored in the psychiatry clinics due to mental problems. It was determined that there was significant difference between the patients' mean internalized stigma total scores between subscale scores and their gender, job, the place that the patient was raised in, educational status, working status, income level, the period spent after the diagnosis, hospitalization status, the hospital monitoring the patient and the diagnosis. It is suggested that counseling services should be planned in order to identify negative impact of the factors that influence coping with internalized stigma. PMID- 26477740 TI - Ultra-wideband microwave absorber by connecting multiple absorption bands of two different-sized hyperbolic metamaterial waveguide arrays. AB - Microwave absorbers have important applications in various areas including stealth, camouflage, and antenna. Here, we have designed an ultra-broadband light absorber by integrating two different-sized tapered hyperbolic metamaterial (HMM) waveguides, each of which has wide but different absorption bands due to broadband slow-light response, into a unit cell. Both the numerical and experimental results demonstrate that in such a design strategy, the low absorption bands between high absorption bands with a single-sized tapered HMM waveguide array can be effectively eliminated, resulting in a largely expanded absorption bandwidth ranging from 2.3 to 40 GHz. The presented ultra-broadband light absorber is also insensitive to polarization and robust against incident angle. Our results offer a further step in developing practical artificial electromagnetic absorbers, which will impact a broad range of applications at microwave frequencies. PMID- 26477741 TI - Optimizing Field Emission Properties of the Hybrid Structures of Graphene Stretched on Patterned and Size-controllable SiNWs. AB - Graphene is one of the ideal nanomaterials to be paired with silicon, and their complementary properties can be exploited in field emission (FE) devices. We reported an efficient way to produce and adjust the dimension of uniform protrusions within graphene. First, a multistep template replication process was utilized to fabricate highly periodic and well-aligned silicon nanowires (SiNWs) of different diameters (400, 500 and 600 nm). Then, large-scale and uniform graphene, fabricated by chemical vapor deposition (CVD), was transferred onto these size-controlled SiNWs to obtain the nanoscale and uniform undulations. As compared to the nanowires alone, the hybrid structures lead to higher FE performance due to electron conductivity enhancement, high-density emmison protrusions and band bending. These hybrid SiNWs/graphene structures could provide a promising class of field emission cathodes. PMID- 26477742 TI - Hydrodynamic fluctuation-induced forces in confined fluids. AB - We study thermal, fluctuation-induced hydrodynamic interaction forces in a classical, compressible, viscous fluid confined between two rigid, planar walls with no-slip boundary conditions. We calculate hydrodynamic fluctuations using the linearized, stochastic Navier-Stokes formalism of Landau and Lifshitz. The mean fluctuation-induced force acting on the fluid boundaries vanishes in this system, so we evaluate the two-point, time-dependent force correlations. The equal-time correlation function of the forces acting on a single wall gives the force variance, which we show to be finite and independent of the plate separation at large inter-plate distances. The equal-time, cross-plate force correlation, on the other hand, decays with the inverse inter-plate distance and is independent of the fluid viscosity at large distances; it turns out to be negative over the whole range of plate separations, indicating that the two bounding plates are subjected to counter-phase correlations. We show that the time-dependent force correlations exhibit damped temporal oscillations for small plate separations and a more irregular oscillatory behavior at large separations. The long-range hydrodynamic correlations reported here represent a "secondary Casimir effect", because the mean fluctuation-induced force, which represents the primary Casimir effect, is absent. PMID- 26477744 TI - Highly Crystalline CVD-grown Multilayer MoSe2 Thin Film Transistor for Fast Photodetector. AB - Hexagonal molybdenum diselenide (MoSe2) multilayers were grown by chemical vapor deposition (CVD). A relatively high pressure (>760 Torr) was used during the CVD growth to achieve multilayers by creating multiple nuclei based on the two dimensional crystal growth model. Our CVD-grown multilayer MoSe2 thin-film transistors (TFTs) show p-type-dominant ambipolar behaviors, which are attributed to the formation of Se vacancies generated at the decomposition temperature (650 degrees C) after the CVD growth for 10 min. Our MoSe2 TFT with a reasonably high field-effect mobility (10 cm(2)/V . s) exhibits a high photoresponsivity (93.7 A/W) and a fast photoresponse time (tau(rise) ~ 0.4 s) under the illumination of light, which demonstrates the practical feasibility of multilayer MoSe2 TFTs for photodetector applications. PMID- 26477745 TI - A KISS (keep it simple, sensor) array for glycosaminoglycans. AB - Herein, we demonstrate that it is possible to design a sensor array with one multivalent cationic receptor (a dendrigraft of lysine) and one fluorescent anionic indicator (a fluorescein-labeled peptide). Depending on the loading of the indicator on the receptor, negatively charged glycosaminoglycans (GAGs) induce a positive or negative variation of the fluorescent signal as they displace the indicators from the receptor or they compact the indicators on the receptor's surface, respectively. This unique strategy allows not only the blind identification of pure GAGs with a level of accuracy of 100%, but also the differentiation of mixtures. PMID- 26477743 TI - Drosophila Chemoreceptors: A Molecular Interface Between the Chemical World and the Brain. AB - Chemoreception is essential for survival. Feeding, mating, and avoidance of predators depend on detection of sensory cues. Drosophila contains diverse families of chemoreceptors that detect odors, tastants, pheromones, and noxious stimuli, including receptors of the odor receptor (Or), gustatory receptor (Gr), ionotropic receptor (IR), Pickpocket (Ppk), and Trp families. We consider recent progress in understanding chemoreception in the fly, including the identification of new receptors, the discovery of novel biological functions for receptors, and the localization of receptors in unexpected places. We discuss major unsolved problems and suggest areas that may be particularly ripe for future discoveries, including the roles of these receptors in driving the circuits and behaviors that are essential to the survival and reproduction of the animal. PMID- 26477746 TI - Remarkable enhancement in the Kapitza resistance and electron potential barrier of chemically modified In2O3(ZnO)9 natural superlattice interfaces. AB - Superlattice interfaces can efficiently scatter phonons and filter low-energy electrons, thereby reducing the thermal conductivity to the "alloy limit" of crystalline solids and increasing the Seebeck coefficient substantially. In this paper, we report a two-fold reduction in the thermal conductivity and an improvement of about 170% in the Seebeck coefficient of an existing In2O3(ZnO)9 superlattice by chemically modifying the interface with small additions of aluminum. Using a classical model for the interface transport, we attribute such significant changes to the increase in both the Kapitza (thermal) resistance and the electron potential barrier height of the InO2(-) superlattice interfaces that are modified by Al(3+). The present work opens a new avenue of research showing that the superlattice interfaces can be chemically tuned for specific properties, which can be investigated in both experimental and computational ways, and also suggests a new route for material design for applications in areas like thermoelectrics. PMID- 26477747 TI - Compositional dependence of anomalous thermal expansion in perovskite-like ABX3 formates. AB - The compositional dependence of thermal expansion behaviour in 19 different perovskite-like metal-organic frameworks (MOFs) of composition [A(I)][M(II)(HCOO)3] (A = alkylammonium cation; M = octahedrally-coordinated divalent metal) is studied using variable-temperature X-ray powder diffraction measurements. While all systems show essentially the same type of thermomechanical response-irrespective of their particular structural details-the magnitude of this response is shown to be a function of A(I) and M(II) cation radii, as well as the molecular anisotropy of A(I). Flexibility is maximised for large M(II) and small A(I), while the shape of A(I) has implications for the direction of framework hingeing. PMID- 26477748 TI - Reproducible, stable and fast electrochemical activity from easy to make graphene on copper electrodes. AB - The electrochemical activity of graphene is of fundamental importance to applications from energy storage to sensing, but has proved difficult to unambiguously determine due to the challenges innate to fabricating well defined graphene electrodes free from contamination. Here, we report the electrochemical activity of chemical vapour deposition (CVD) graphene grown on copper foil without further treatment, through appropriate choice of electrolyte. Fast electron transfer kinetics are observed for both inner and outer sphere redox couples with fully covered graphene on copper electrodes (k degrees = 0.014 +/- 0.001 cm s(-1) or k degrees = 0.012 +/- 0.001 cm s(-1) for potassium ferrocyanide(II) and hexaamineruthenium(III) chloride, respectively). Unlike highly oriented pyrolytic graphite electrodes, the electrochemical response of the graphene on copper electrodes is stable, with no apparent electrode fouling even with inner sphere redox couples, and reproducible independent of the time between growth and measurement. Comparison between fully covered electrodes, and partial coverage of graphene with varying graphene grain sizes (from roughly 50 MUm to <10 MUm) shows that in this instance the basal plane of graphene is electrochemically active. These CVD grown graphene on copper electrodes are quick, cheap and reproducible to make and hence provide a convenient platform for further investigation of graphene electrochemistry and the effect of covalent and non-covalent modification. PMID- 26477749 TI - NIS-catalyzed oxidative cyclization of alcohols with amidines: a simple and efficient transition-metal free method for the synthesis of 1,3,5-triazines. AB - An efficient method for the synthesis of 1,3,5-triazines by NIS-catalyzed oxidative cyclization of alcohols with amidines has been developed. The reaction works smoothly under transition-metal free and phosphine-free conditions to afford a wide range of 1,3,5-triazine derivatives in moderate to good yields. The synthetic methodology was achieved via in situ oxidation of alcohols to aldehydes. PMID- 26477750 TI - Chromobacterium Violaceum Sepsis: Rethinking Conventional Therapy to Improve Outcome. AB - BACKGROUND: Chromobacterium violaceum (C. violaceum) is a facultative anaerobic gram-negative bacterium found in soil and water, especially in tropical and subtropical areas. Although infection in humans is rare, it is associated with significant morbidity. The bacterium is known for its resistance to multiple antimicrobials, and the possibility of relapse and reinfection. Presence of bacteremia, disseminated infection, and ineffective antimicrobial agents are predictors of mortality. CASE REPORT: We report the case of a previously healthy 11-year-old male with C. violaceum sepsis who was exposed to stagnant water. He presented with severe septic shock and developed multi-organ system failure. Initial presumptive diagnosis was staphylococcal infection secondary to presence of skin abscesses resulting in antibiotic coverage with vancomycin, clindamycin, nafcillin and ceftriaxone. He also had multiple lung and liver abscesses. Once C. violaceum was identified, he received meropenem and ciprofloxacin, and was later discharged on ertapenem and trimethoprim-sulfamethoxazole (TMP-SMX) to complete a total of six months of antibiotics. He was diagnosed with chronic granulomatous disease (CGD) and is currently on prophylactic TMP-SMX and itraconazole. He has not had any relapses since his initial presentation. CONCLUSIONS: This case highlights the importance of considering C. violaceum as a relevant human pathogen, and considering it early in temperate regions, particularly in cases of fulminant sepsis associated with multi-organ abscesses. Once C. violaceum is identified, appropriate antimicrobial therapy should be started promptly, and sufficient duration of treatment is necessary for successful therapy. PMID- 26477751 TI - Quantitative imaging of platinum based on laser ablation-inductively coupled plasma-mass spectrometry to investigate toxic side effects of cisplatin. AB - This work presents a quantitative bioimaging method for platinum based on laser ablation-inductively coupled plasma-mass spectrometry and its application for a biomedical study concerning toxic side effects of cisplatin. To trace the histopathology back to cisplatin, platinum was localized and quantified in major functional units of testicle, cochlea, kidney, nerve and brain sections from cisplatin treated mice. The direct consideration of the histology enables precise interpretation of the Pt images and the novel quantitative evaluation approach allows significantly more precise investigations than the pure image. For the first time, platinum was detected and quantified in all major injured structures including organ of Corti of cochlea and seminiferous tubule of testicle. In this way, proximal tubule in kidney, Leydig cells in testicle, stria vascularis and organ of Corti in cochlea and nerve fibers in sciatic nerves are confirmed as targets of cisplatin in these organs. However, the accumulation of platinum in almost all investigated structures also raises questions about more complex pathogenesis including direct and indirect interruption of several biological processes. PMID- 26477752 TI - Understanding the Thermodynamics of Hydrogen Bonding in Alcohol-Containing Mixtures: Self Association. AB - The perturbed chain form of the polar statistical associating fluid theory (Polar PC-SAFT) was used to model lower 1-alcohol + n-alkane mixtures. The ability of the equation of state to predict accurate activity coefficients at infinite dilution was demonstrated as a function of temperature. Investigations show that the association term in SAFT plays an important role in capturing the right composition dependence of the activity coefficients in comparison with nonassociating models (UNIQUAC). Results also show that considering long-range polar interactions can significantly improve the fractions of free monomers predicted by PC-SAFT in comparison with spectroscopic data and molecular dynamic (MD) simulations carried out in this work. Furthermore, evidence of hydrogen bonding cooperativity in 1-alcohol + n-alkane systems is discussed using spectroscopy, simulation, and theory. In general, results demonstrate the theory's predictive power, limitations of first-order perturbation theories, as well as the importance of considering long-range polar interactions for better hydrogen-bonding thermodynamics. PMID- 26477754 TI - Alcohol and the heart. PMID- 26477753 TI - Variation in Carotenoid Content of Kale and Other Vegetables: A Review of Pre- and Post-harvest Effects. AB - Lutein and zeaxanthin are carotenoids that are selectively taken up into the macula of the eye, where they are thought to protect against the development of age-related macular degeneration. They are obtained from dietary sources, with the highest concentrations found in dark green leafy vegetables, such as kale and spinach. In this Review, compositional variations due to variety/cultivar, stage of maturity, climate or season, farming practice, storage, and processing effects are highlighted. Only data from studies which report on lutein and zeaxanthin content in foods are reported. The main focus is kale; however, other predominantly xanthophyll containing vegetables such as spinach and broccoli are included. A small amount of data about exotic fruits is also referenced for comparison. The qualitative and quantitative composition of carotenoids in fruits and vegetables is known to vary with multiple factors. In kale, lutein and zeaxanthin levels are affected by pre-harvest effects such as maturity, climate, and farming practice. Further research is needed to determine the post-harvest processing and storage effects of lutein and zeaxanthin in kale; this will enable precise suggestions for increasing retinal levels of these nutrients. PMID- 26477755 TI - A new 2-step risk-stratification clinical score for suspected appendicitis in children. AB - AIM: The aim of this study was to develop a new Children's Appendicitis Score (CAS) by combining 3 inflammatory markers and a set of predictors for suspected appendicitis in children. METHODS: 374 children aged 4-16years with suspicion of appendicitis were prospectively enrolled for the derivation cohort. Demographic characteristics, clinical features, laboratory, and histology data were collected. The outcome measure was the histological presence or absence of appendicitis. Backward logistic regression was employed to select predictors for construction of a score. Diagnostic performance of CAS was compared with the Pediatric Appendicitis Score (PAS) on a separate validation cohort. RESULTS: The combination of normal white blood cell count (WBC), neutrophil percentage, and C reactive protein (CRP) had a 100% negative predictive value for appendicitis. We assigned 'coefficient A' as 'zero' when all triple markers were negative and 'one' when any one markers was positive. A second component of 6 predictors was identified for construction of the 'raw score': Localized right-lower-quadrant pain, generalized guarding, constant characteristic of pain, pain on percussion or coughing, WBC>=14000/L and CRP>=24g/L. CAS was generated by multiplying 'coefficient A' by 'raw score'. CONCLUSION: CAS is superior to PAS in ruling out appendicitis. Risk stratification of equivocal patients could guide the need for further diagnostic imaging examination. PMID- 26477756 TI - [The guidelines for diagnosis and treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma in China (2015 edition)]. PMID- 26477757 TI - [A multicenter study on the revalidation of validated conversion factor for the conversion of BCRABL(P210)transcript levels to the international scale in chronic myeloid leukemia]. AB - OBJECTIVE: To revalidate the conversion factor(CF)for the conversion of BCR-ABL (P210)transcript levels to the international scale(BCR- ABLIS)in chronic myeloid leukemia(CML) which validated before. METHODS: Peking University People's Hospital(PKUPH)prepared the exchange samples for revalidation of CFs of 15 laboratories which validated nine or eighteen months ago. The fresh BCR ABL(P210)(+)bone morrow or peripheral blood nucleated cells were diluted with BCR ABL (P210)(-)cells to achieve different BCR- ABL levels, totally 16 sets and 24 samples per set were prepared. TRIzol reagent was added in each tube. Each laboratory tested BCR-ABL transcript levels of one set of samples. Agreement between BCR-ABLIS of each laboratory and PKUPH was assessed by the Bland- Altman method. For laboratories which did not meet the criteria of revalidation, linear regression equation was derived after the samples with maximum BCR-ABL deviation were removed until R2>0.98, then new CF was calculated. RESULTS: 10 laboratories met the revalidation criteria with both bias within +/-1.4 fold and 95% limits of agreement within +/-6 folds, and their CFs still could be used for accurately conversion of BCR-ABLIS. New CFs were recalculated as of 1.8-6.3 folds of their previous CFs in 5 laboratories not met the criteria. CONCLUSION: Revalidation of CF by sample exchange among laboratories was necessary for accurate and continuous application of BCR-ABLIS, which not only tested the validity of CF acquired before but also calculated new available CFs for those with invalid CFs. PMID- 26477758 TI - [Clinical and cytogenetic study of chromosome 1 abnormality in myelodysplastic syndrome]. AB - OBJECTIVE: To explore the incidence of chromosome 1 abnormality in myelodysplastic syndrome(MDS)to couple its association with clinical presentation and prognosis. METHODS: R- band karyotype analyses were performed in 672 cases of MDS between 2010 and 2013. Clinical data of those with abnormal chromosome l were collected and then analyzed factors affecting the prognosis. RESULTS: Of 672 cases of patients with MDS, chromosome 1 aberration[der(1), dup(1), -1 were most frequent] were found in 41(6.1%)cases. 1q trisomy was found in 18/41(43.9%)cases, and the most common patterns were duplication of the long arm as well as unbalanced translocation with other chromosomes. Of 41 patients with chromosomal 1 abnormality, 32 cases were accompanied with other chromosomal aberration, usually involving 3 or more abnormal chromosomal karyotypes, e.g., chromosome 8, 7 abnormalities. According to IPSS-R scoring system, 19 patients were diagnosed with very high risk, 10 patients high risk, 10 patients intermediate risk and 2 patients low risk MDS. 9 patients transformed into acute leukemia with median transforming time of 7.18(0.56-54.28)months. Median survival of 36 cases after 2010 was 17.48(95% CI 14.38-20.58)months. There were significant differences on median survival between RAEB and non-RAEB groups(chi2=10.398, P=0.001), and between with more than 3 chromosome abnormalities and with less than 3 groups(chi2=3.939, P=0.047). RAEB was identified as an independent risk factor for the prognosis of MDS with chromosome 1 abnormality. CONCLUSION: Chromosome 1 aberration was not rare in MDS. 1q trisomy was the most common abnormal karyotype in China, which often accompanied with other chromosomal abnormalities. The prognosis of MDS patients with chromosome 1 abnormality was poor, especially worse in those diagnosed with RAEB-1, RAEB-2 and with more than 3 chromosome abnormality. For patients whose percentage of bone marrow blasts less than 5%, the prognosis of patients with 1q trisomy was better than those without 1q trisomy. RAEB was identified as an independent risk factor for the prognosis of MDS with chromosome 1 abnormality. PMID- 26477759 TI - [The prognosis value of early and interim 18F-FDG-PET/CT scans in patients with diffuse large B-cell lymphoma]. AB - OBJECTIVE: To investigate the prognosis value of early and interim 18F-FDG-PET/CT scan in patients with diffuse large B- cell lymphoma (DLBCL) to establish the suitable criteria for evaluating posttherapeutic lesions in scans. METHODS: Fifty six newly diagnosed DLBCL patients were enrolled in the study, and underwent baseline, early and interim 18F- FDG PET/CT scans. Five- point and % DeltaSUVmax criteria were used separately to interpret 18F- FDG PET/CT images. Interobserver reproducibility was assessed with the kappa test(kappa), and thresholds of %DeltaSUVmax were calculated via receiver operating characteristic curve(ROC). Survival curves were obtained using Kaplan-Meier curves and log-rank test. Cox regression analysis was used for multi-factor analysis. RESULTS: Median follow-up was 24 months(6 to 42 months). The kappa value of the five- point scale was above 0.600 with the reference background set in the liver(Score>=4). The optimal threshold of %DeltaSUVmax was 81% for early PET/CT and 74% for interim PET/CT. Survival analysis showed both early and interim PET/CT scans could predict the outcome of 56 patients with DLBCL, and 3-year PFS and OS of PET-negative patients were significantly higher than those of PET-positive ones(P<0.05). Five-score criteria were more accurate in evaluating 3- year PFS of DLBCL patients in the interim PET/CT scan(76.79%). %DeltaSUVmax criteria were better for interpreting 3 year OS(76.79% and 83.93%). Multi-factor analysis demonstrated that early and interim PET/CT were solid predicting factors for DLBCL patients. CONCLUSION: Early and interim PET/CT scans could predict the outcome of patients with DLBCL, treated with R-CHOP/CHOP. Three-year OS was more accurate in early and interim PET/CT using 66 %DeltaSUVmax criteria as an interpretation, while 3-year PFS was more accurate in interim PET/CT by five scores criteria. PMID- 26477760 TI - [Therapeutic effect of CY-fTBI and BMM conditioning regimen in the process of allo-HSCT treating III,IV non-Hodgkin lymphoma: 15 years analysis of single center]. AB - OBJECTIVE: To investigate the efficacy of allogeneic hematopoietic stem cell transplantation(allo-HSCT)in the treatment of patients with III,IV non-Hodgkin lymphoma(NHL), and compared the efficacy between Cy- fractionated to talbody irradiation(fTBI)based conditioning regimen and Maryland, horse flange and mitoxantrone(BMM). METHODS: The clinical data of 47 patients with III, IV NHL after allo- HSCT from November 1998 to May 2014 were collected and retrospectively analyzed. To observe the hematopoietic reconstruction recovery after transplantation, cumulative incidence of acute graft- versus- host- disease (aGVHD) and chronic graft- versus- host- disease (cGVHD), transplantation related mortality (TRM), recurrence rate (RR), disease- free survival (DFS), overall survival(OS). Compare the efficacy of fTBI and BMM conditioning regimen at the same time. RESULTS: Neutrophils achieving 0.5*109/L and platelets achieving 50*109/L on day 17 (range, 10- 72) post transplantation. Acute GVHD occurred in 53.19%, among them, grade I-II occurred in 42.55%, grade III-IV occurred in 10.65%, and cGVHD occurred in 21.28%. 21 patients were alive with a median follow up of 9.7 months(0.2-149.1 months). Overall survival(OS)was 73.5%, 49.3%, 40.1% respectively in the first, third and fifth year in Cy-fTBI group; in BMM group it was 67.8%, 32.9% and 31.4% respectively, and disease-free survival(DFS)was 65.3%, 45.6%, 30.2% respectively in the first, third and fifth year. In Cy-fTBI group, the recurrence rate(RR)and transplantation related mortality(TRM)in the first year were 18.9%, 23.0% respectively, the third year were 19.5%, 38.3% and the fifth year were 35.2%, 39.2%. In BMM group, RR and TRM in the first year were 27.4%, 24.5% respectively, the third year were 38.9%, 46.4% and the fifth year were 39.2%, 48.2%. However, there was no significant difference in the indicator of OS, DFS, RR, TRM in the two groups. CONCLUSION: Allo-HSCT could make some III,IV NHL patients achieve long-term disease- free survival, but the TRM was still high relatively. Moreover, compared with the program of BMM conditioning regimen, Cy-fTBI might reduce the TRM and RR, meanwhile, increase the DFS and OS. However, due to the small number cases of two groups, there was no statistical significant difference. PMID- 26477761 TI - [Control study of melphalan instead of cyclophosphamide as a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation for treatment of myeloid malignancies]. AB - OBJECTIVE: To evaluate melphalan instead of cyclophosphamide in modified busulfancyclophosphamide regimen as a new myeloablative conditioning regimen for the treatment of myeloid malignancies patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: The clinic data of 94 myeloid malignancies patients undergoing allogeneic HSCT were analyzed, of which 48 patients received Bu+Cy+Flu+Ara-C, 46 cases Bu+Mel+Flu+Ara-C regimens. Rregimen related toxicity, engraftment, graft- versus-host disease(GVHD), infection condition, non- relapse mortality, and overall survival were compared between the two groups. RESULTS: All patients achieved neutrophil engraftment. The incidence of grade III-IV oral mucositis and diarrhea in BMFA group was higher than in BCFA group(P<0.05). The incidence of acute GVHD in BMFA group was also higher than in BCFA group but without statistically significant difference(36.5% over 56.5%, P=0.100). With a median follow up of 42 months, the incidence of no relapse mortality in BCFA group was 12.5% and 19.6% in BMFA group(P=0.400). The relapse rate in BMFA group(4.3%)was significantly lower than in BCFA group (25.0%, P=0.009). The overall survival rates were(71.8+/-6.7)% and(76.1+/-6.3)%(P=0.852), and diseasefree survival rates were(67.8+/-8.9)% and(76.1+/-6.3)%(P=0.567)were comparable between BCFA group and BMFA group. CONCLUSION: Melphalan instead of cyclophosphamide as a new myeloablative conditioning regimen had lower relapse and satisfied disease-free survival rates, but the risk of regimenrelated toxicity and GVHD should be taken into consideration. PMID- 26477762 TI - [Clinical features and prognosis in MLL-AF10 positive acute leukemia]. AB - OBJECTIVE: To analyze the clinical features and prognosis of acute leukemia patients with the mixed lineage leukemia(MLL)gene rearrangements AF10 positive. METHODS: 6 cases with MLL-AF10 positive were analyzed retrospectively, related literatures were reviewed to clarify MLL-AF10 patients'clinical features and prognosis. RESULTS: The median age of 6 cases was 19.5 years old, 5 patients with fever onset, the onset white blood cells of 4 patients were less than 10*109/L. 5 cases were as M5 and 1 case M4 according to FAB classification, the level of fusion gene(RQ-PCR)was 0.23%-22.60% when diagnosed, 4 cases had concomitant WT1 gene mutation, flow cytometry disclosed myeloid phenotype. Of 5 evaluated patients achieved the first complete remission after conventional chemotherapy, 2 cases of complex karyotype died, one case died of sepsis in induction, another died from failing of transplantation. 4 out of 5 transplant recipients gained long term survival. CONCLUSION: The MLL-AF10 positive patients were mostly young men, the majority FAB classification was M5 or M4, often onset with fever, low white blood cells and low level of fusion gene, usually associated with WT1 mutation. Conventional chemotherapy produced a high response rate, but easy to relapse, while the complex karyotype had a poor prognosis, allo-HSCT may have the potential to improve the prognosis of MLL-AF10 positive patients. PMID- 26477763 TI - [Identification of genetic defects in a Chinese pedigree with factor XIII deficiency: case report and literature review]. AB - OBJECTIVE: To perform phenotypic diagnosis, genetic diagnosis and prenatal diagnosis of inherited coagulation factor XIII (FXIII)deficiency in a Chinese family also provide a review of inherited coagulation F XIII deficiency. METHODS: The activity levels of F XIII (F XIII:C) of proband and family members were measured by clot solubility test and REA-chrom F XIII kit. The antigen levels of F XIII(FXIII:Ag) were measured by enzyme-linked immunosorbent assay. Thrombelastography (TEG) test was used to make a comprehensive evaluation of coagulation status in the proband. All 15 exons and exon-intron boundaries of the F13A1 gene were amplified by PCR, and DNA sequencing was performed then. The mutation identified in the proband was screened in the family members. Furthermore, the related literatures were reviewed to provide a profile of clinical manifestation, gene mutations, the relationship between the mutations and phenotype, and treatments of inherited coagulation F XIII deficient cases. RESULTS: The clot solubility test was positive in the proband. The FXIII:Ag level of the proband was less than 1% and the FXIII:C level was below the lower limit of detection (<3%). Two compound heterozygous missense mutations (p.Arg662* and p.Trp665*) were identified in the proband. Family study showed that the two mutations were both inherited from the parents. The fetus also carried two compound heterozygous mutations, the same as the proband, and was diagnosed with severe F XIII deficiency. As reported in the literatures, most mutations were missense mutations and nonsense mutations, and no hot spot was found. The clinical pattern of F XIII deficiency varied among patients, with potentially fatal consequences from severe bleeding complications. CONCLUSION: Better understanding of F XIII biochemical properties and function and developing of FXIII laboratory assays and genetic detection could prevent missed diagnosis, and patients moght benefit from better care. PMID- 26477764 TI - [Clinical characteristics and outcome of patients with primary central nervous system lymphoma]. AB - OBJECTIVE: To investigate the characteristics, treatment and outcome of patients with primary central nervous system lymphoma (PCNSL). METHODS: A total of 37 patients with PCNSL treated in Peking Union Medical College Hospital from June 1999 to June 2012 were enrolled into this retrospective study. The clinical characteristics, results of treatment and prognostic factors were analyzed. RESULTS: The median age of 37 patients with PCNSL at diagnosis was 57 years(range 17 to 78 years) with a male to female ratio of 2.7:1. The symptoms or signs of elevated intracranial pressure and cognitive dysfunction were the most common initial manifestations. The median time period between onset of symptoms and diagnosis was 1.5 months. The majority of lesions were located in the cerebral hemisphere. At a median follow-up of 50 months, the median overall survival for all treated patients was 36.0 months (95% CI 21.7-50.3 months), with a progression-free survival of 18.0 months(95% CI 9.1-26.9 months). The 3-year cumulative survival rate was 46.9%. Compared to chemotherapy alone, combined modality regimens which did not improve outcome were associated with a greater risk of neurotoxicity. CONCLUSION: The prognosis of PCNSL was still poor, and the optimal treatment strategy for these patients should be explored in the future clinical trials. PMID- 26477765 TI - [Primary breast diffuse large B-cell lymphoma-report of 21 cases from China with literatures review]. AB - OBJECTIVE: To evaluateclinical features, treatment and outcomes of patients diagnosed with primary breast diffuse large B-cell lymphoma(DLBCL). METHODS: Clinical data were analyzed for all patients diagnosed with primary breast DLBCL(n=21). Kaplan-Meier method was used to estimate 5- year overall survival(OS)rate, and the difference was compared by Log- rank test. RESULTS: The 21 cases of patients with primary breast DLBCL were all female with median age at diagnosis as 48 years (range 21-64 years). 13 patients had International Prognostic Index(IPI)of 0, 6 IPI 1, and 2 IPI 2. The 5- year OS rates of CHOP/R- CHOP and R+/-DICE after R+/-EPOCH groups were 40.0% and 72.2% , respectively(P=0.035). The central nervous system relapse rate of CHOP/R-CHOP and R+/-DICE after R+/- EPOCH groups were 16.7% and 6.7%(P=0.500), respectively. The 5- year OS rates of patients with primary breast DLBCL staging II E-III E and I E were 21.4% and 83.3% , respectively(P=0.025). CONCLUSION: Primary breast DLBCL was rare. The patients of primary breast DLBCL with chemotherapy regimen of R+/ DICE after R+/-EPOCH might have a better prognosis and lower relapse rate of central nervous system; the primary breast DLBCL patients staging IIE-IIIE might have a poor prognosis. PMID- 26477766 TI - [Influence of RNA interference on MSI-2 gene in THP-1 cell and expression of NUMB]. AB - OBJECTIVE: To investigate the effect of small interfering RNA(siRNA)for MSI-2 on the growth, apoptosis and NUMB expression of THP-1 cells. METHODS: Three siRNA for MSI-2 gene was designed and transfected into THP- 1 cells. The cell inhibition, colony formation and apoptosis were determined. The protein expression of NUMB, caspase- 3 and PARP were detected by Western blotting. RESULTS: After MSI- 2 expression of THP- 1 cells was down- regulated for 24 hours, cell inhibition of siRNA MSI-2 group was(47.89+/-7.64)%, obviously higher than that of negative control group(P=0.005). After 9 days, cell colony count of siRNA MSI-2 group was 7.50+/-1.53, also lower than that of negative control group(35.75+/-7.46, P<0.001). In addition, apoptotic rates of siRNA MSI- 2 group at 24 hours [(15.22+/-1.52)%]and 48 hours[(33.83+/-3.96)%]were significantly higher than those of negative control group(P=0.008 and P=0.001, respectively). Accordingly, activations of caspase-3 and PARP and increased NUMB were observed in siRNA MSI- 2 group. CONCLUSION: siRNA for MSI- 2 gene could increase the expressions of NUMB to inhibit the proliferation and induce apoptosis of THP-1 cells. PMID- 26477767 TI - [Primary cardiac plasmablastic lymphoma: report of a case and literature review]. AB - OBJECTIVE: To report a case of primary cardiac plasmablastic lymphoma to investigate its clinical feature, diagnosis, therapy and prognosis. METHODS: A case of primary cardiac plasmablastic lymphoma was studied. The imaging examination, conventional histopathological and immunohistochemical staining of this case were detected. The clinical feature, pathogenesis, diagnosis, therapy and prognosis of primary cardiac plasmablastic lymphoma were further investigated through literatures review. RESULTS: The tumor was located in the right atrium. Microscopic examination showed diffuse proliferation of large lymphoid cells. The neoplastic cells were positive for CD38 and CD79a. The patient was treated with chemotherapy combined with autologous stem cell transplantation. CONCLUSION: Primary cardiac plasmablastic lymphoma was extremely rare. Its pathogenesis remained to be unclear. With non- specific clinical manifestations, the diagnosis was mainly confirmed by histopathological and immunohistochemical staining method. Without standard treatment, more patients were treated with chemithreapy regimens similar to the treatment used in aggressine lymphoma. Patients usually had a poor prognosis. PMID- 26477768 TI - [Treatment of adult acute lymphoblastie leukemia with eosinophilia and abnormality of PDGFRA by autologous hematopoietic stem cell transplantation and imatinib: one case report and literatures review]. PMID- 26477769 TI - [Expression of IL- 32 in serum with acute leukemia and its clinical significance]. PMID- 26477770 TI - [Laboratory diagnosis and ultrastructure in a case with Niemann-Pick disease]. PMID- 26477771 TI - [Clinical significance of NF-kappaB/p65 expression in patients with diffuse large B-cell lymphoma]. PMID- 26477772 TI - [Combination of thrombosis and coagulation disorder as first manifestation of bromadiolone toxicity: a case report and literature review]. PMID- 26477773 TI - [Heterogeneity of hematopoietic stem cell]. PMID- 26477774 TI - [The function and clinical value of Von Willebrand factor propeptide]. PMID- 26477775 TI - [De novo CD5- positive diffuse large B- cell lymphoma in leukemic phase with highly chromosome complex aberrations and splenic infarction: a case report and literatures review]. PMID- 26477776 TI - [Advances in leukemia inhibitors targeting PI3K/AKT/mTOR pathway]. PMID- 26477777 TI - [Advances in microRNA and graft-versus-host disease]. PMID- 26477778 TI - Persistent neuropathic pain increases synaptic GluA1 subunit levels in core and shell subregions of the nucleus accumbens. AB - The nucleus accumbens (NAc) is a key component of the brain reward system, and it is composed of core and shell subregions. Glutamate transmission through AMPA type receptors in both core and shell of the NAc has been shown to regulate reward- and aversion-type behaviors. Previous studies have additionally demonstrated a role for AMPA receptor signaling in the NAc in chronic pain states. Here, we show that persistent neuropathic pain, modeled by spared nerve injury (SNI), selectively increases the numbers of GluA1 subunits of AMPA receptors at the synapse of both core and shell subregions. Such increases are not observed, however, for the GluA2 subunits. Furthermore, we find that phosphorylation at Ser845-GluA1 is increased by SNI at both core and shell subregions. These results demonstrate that persistent neuropathic pain increases AMPA receptor delivery to the synapse in both NAc core and shell, implying a role for AMPA receptor signaling in these regions in pain states. PMID- 26477780 TI - Decrease in CA3 inhibitory network activity during Theiler's virus encephalitis. AB - Viral infections of the central nervous system are often associated with seizures, and while patients usually recover from the infection and the seizures cease, there is an increased lifetime incidence of epilepsy. These viral infections can result in mesial temporal sclerosis, and, subsequently, a type of epilepsy that is difficult to treat. In previous work, we have shown that Theiler's murine encephalomyelitis virus (TMEV) infections in C57B/6 mice, an animal model of virus-induced epilepsy, results in changes in excitatory currents of CA3 neurons both during the acute infection and two months later, at a time when seizure thresholds are reduced and when spontaneous seizures can occur. The changes in the excitatory system differ at these two time points, suggesting different mechanisms for seizure generation. In the present paper, we examine GABAergic mediated inhibition in CA3 pyramidal cells at these two time points following TMEV infection. We found that amplitudes of sIPSCs and mIPSCs were reduced during the acute infection, but recovered at the two-month time point. These observations are consistent with previous measurements of excitatory currents suggesting different mechanisms of seizure generation during the acute infection and during chronic epilepsy. PMID- 26477781 TI - Factors associated with sex work among at-risk female youth in Cambodia: a cross sectional study. AB - In Cambodia, despite great achievements in reducing the prevalence of HIV in the general population, reducing new HIV infections among young at-risk women remains a challenge. This study was designed to examine the prevalence of risky behaviors of sexually active female youth in Cambodia and to explore risk factors associated with engagement in transactional sex. We surveyed sexually active female youth aged 10-24 enrolled at risk "hotspots" in eight provinces in Cambodia. We collected data on demographic factors, sexual behavior, and factors hypothesized to be associated with transactional sex. Multivariable logistic regression was used to identify associations between demographic and sexual behavior and transactional sex. Of the 280 respondents, the mean age was 21.2, and 48.1% had been paid for sex in the past year. After adjustment, at-risk females who were never have been married (adjusted odds ratio (AOR) 3.40, 95% confidence interval (CI) = 1.65-6.97), have completed less than 6 years of school (AOR 3.26, 95% CI = 1.60-6.66), have 1 or more parents who had died (AOR 4.34, 95% CI = 2.00-9.38), be a heavy alcohol drinker (AOR 3.58, 95% CI = 1.78-7.18), have used a condom with their boyfriend during last sexual encounter (AOR 3.50, 95% CI = 1.68-7.32), and have ever had an HIV test (AOR 3.51, 95% CI = 1.68-7.32) were more likely to engage in sex work. Our findings suggest that prevention strategies for female youth at risk of engagement in sex work should include upstream structural interventions that aim to encourage girls' education and empowerment. In addition, tailored sex education and behavior change messaging about the risks of heavy drinking, condom use with romantic partners, and the importance of frequent HIV testing for at-risk youth and sex workers should be designed and delivered to youth currently engaging in sex work. PMID- 26477779 TI - Caspase-dependent degradation of MDMx/MDM4 cell cycle regulatory protein in amyloid beta-induced neuronal damage. AB - MDMx/MDM4 is a negative regulator of the p53 tumor suppressor protein and is necessary for survival in dividing cells. MDMx is also expressed in postmitotic neurons, with prosurvival roles that are independent of its extensively described roles in carcinogenesis. We and others have shown a role for MDMx loss in neuronal death in vitro and in vivo in several neurodegenerative diseases. Further, we have recently shown that MDMx is targeted for proteolytic degradation by calcium-dependent proteases, calpains, in neurons in vitro, and that MDMx overexpression provided partial neuroprotection in a model of HIV-associated neurodegeneration. Here, we assessed whether amyloid beta (Abeta)-induced MDMx degradation occurred in Alzheimer's Disease (AD) models. Our data shows an age dependent reduction in MDMx levels in cholinergic neurons within the cortex of adult mice expressing the swedish mutant of the amyloid precursor protein, APP in the Tg2576 murine model of AD. In vitro, Abeta treatment of primary cortical neurons led to the caspase-dependent MDMx degradation. Our findings suggest that MDMx degradation associated with neuronal death occurs via caspase activation in neurons, and that the progressive loss of MDMx protein represents a potential mechanism of Abeta-induced neuronal death during disease progression in AD. PMID- 26477782 TI - Architectonic mapping of somatosensory areas involved in skilled forelimb movements and tool use. AB - Cebus monkeys stand out from other New World monkeys by their ability to perform fine hand movements, and by their spontaneous use of tools in the wild. Those behaviors rely on the integration of somatosensory information, which occurs in different areas of the parietal cortex. Although a few studies have examined and parceled the somatosensory areas of the cebus monkey, mainly using electrophysiological criteria, very little is known about its anatomical organization. In this study we used SMI-32 immunohistochemistry, myelin, and Nissl stains to characterize the architecture of the parietal cortical areas of cebus monkeys. Seven cortical areas were identified between the precentral gyrus and the anterior bank of the intraparietal sulcus. Except for areas 3a and 3b, distinction between different somatosensory areas was more evident in myelin stained sections and SMI-32 immunohistochemistry than in Nissl stain, especially for area 2 and subdivisions of area 5. Our results show that cebus monkeys have a relatively complex somatosensory cortex, similar to that of macaques and humans. This suggests that, during primate evolution, the emergence of new somatosensory areas underpinned complex manual behaviors in most Old World simians and in the New World cebus monkey. J. Comp. Neurol. 524:1399-1423, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26477783 TI - Differential neutrophil activation in viral infections: Enhanced TLR-7/8-mediated CXCL8 release in asthma. AB - BACKGROUND AND OBJECTIVE: Respiratory viral infections are a major cause of asthma exacerbations. Neutrophils accumulate in the airways and the mechanisms that link neutrophilic inflammation, viral infections and exacerbations are unclear. This study aims to investigate anti-viral responses in neutrophils from patients with and without asthma and to investigate if neutrophils can be directly activated by respiratory viruses. METHODS: Neutrophils from peripheral blood from asthmatic and non-asthmatic individuals were isolated and stimulated with lipopolysaccharide (LPS) (1 MUg/mL), f-met-leu-phe (fMLP) (100 nM), imiquimod (3 MUg/mL), R848 (1.5 MUg/mL), poly I:C (10 MUg/mL), RV16 (multiplicity of infection (MOI)1), respiratory syncytial virus (RSV) (MOI1) or influenza virus (MOI1). Cell-free supernatants were collected after 1 h of neutrophil elastase (NE) and matrix metalloproteinase (MMP)-9 release, or after 24 h for CXCL8 release. RESULTS: LPS, fMLP, imiquimod and R848 stimulated the release of CXCL8, NE and MMP-9 whereas poly I:C selectively induced CXCL8 release only. R848 induced CXCL8 release was enhanced in neutrophils from asthmatics compared with non-asthmatic cells (P < 0.01). RSV triggered the release of CXCL8 and NE from neutrophils, whereas RV16 or influenza had no effect. CONCLUSION: Neutrophils release CXCL8, NE and MMP-9 in response to viral surrogates with R848-induced CXCL8 release being specifically enhanced in asthmatic neutrophils. Toll-like receptor (TLR7/8) dysregulation may play a role in neutrophilic inflammation in viral-induced exacerbations. PMID- 26477784 TI - The association between chronic hepatitis C infection and cardiovascular risk. AB - BACKGROUND: Vascular disease is a common cause of death in patients with chronic hepatitis C (CHC) infection; however, the association between CHC and atherosclerosis is unclear. AIMS: To determine whether patients with CHC have increased subclinical vascular disease and whether genotype or antiviral treatment modifies this risk. METHODS: Fifty CHC patients and 22 age-matched and sex-matched healthy controls underwent clinical and biochemical assessment for vascular risk factors. In addition, vascular risk was assessed by measuring arterial stiffness (aortic augmentation index and carotid-femoral pulse wave velocity (PWV)), endothelial dysfunction (brachial artery flow-mediated dilatation (FMD) and dilatation post-glycerol trinitrate administration) and carotid intima-media thickness (CIMT). Assessment was repeated in subset of CHC patients (n = 12) undergoing antiviral treatment 18 months after initiation of treatment. RESULTS: Baseline vascular risk factors and measures of arterial stiffness, endothelial dysfunction and CIMT were not different between cases and controls (P > 0.2 for all). Genotype 1 CHC patients had greater endothelial dysfunction with lower FMD (8.2 +/- 3.5% vs 10.9 +/- 5.2%, P = 0.03) and higher right CIMT (0.6 +/- 0.1 mm vs 0.5 +/- 0.07 mm, P = 0.04) compared with non genotype 1. Patients who achieved sustained virological response (7/12) showed significant improvement in insulin resistance (homeostasis model of assessment of insulin resistance 2.3 +/- 1.2 vs 1.8 +/- 0.8, P = 0.02) and arterial stiffness (PWV 7.4 +/- 1.1 m/s vs 6.5 +/- 0.6 m/s, P = 0.04). CONCLUSIONS: Subclinical vascular disease is not greater in CHC subjects compared with controls. However, among CHC subjects, genotype 1 infection is associated with greater endothelial dysfunction and increased carotid-intima medial thickness compared with non genotype 1 infection. Successful viral eradication may improve insulin resistance and arterial stiffness. PMID- 26477785 TI - Continuous Seasonal River Ebullition Measurements Linked to Sediment Methane Formation. AB - Laboratory sediment incubations and continuous ebullition monitoring over an annual cycle in the temperate Saar River, Germany confirm that impounded river zones can produce and emit methane at high rates (7 to 30 (g CH4 m(-3) d(-1)) at 25 degrees C and 270 to 700 (g CH4 m(-2) yr(-1)), respectively). Summer methane ebullition (ME) peaks were a factor of 4 to 10 times the winter minima, and sediment methane formation was dominated by the upper sediment (depths of 0.14 to 0.2 m). The key driver of the seasonal ME dynamics was temperature. An empirical model relating methane formation to temperature and sediment depth, derived from the laboratory incubations, reproduced the measured daily ebullition from winter to midsummer, although late summer and autumn simulated ME exceeded the observed ME. A possible explanation for this was substrate limitation. We recommend measurements of methanogenically available carbon sources to identify substrate limitation and help characterize variation in methane formation with depth and from site to site. PMID- 26477786 TI - Mutations in TUBB4A and spastic paraplegia. PMID- 26477787 TI - Metabolic profiling of a novel antithrombotic compound, S002-333 and enantiomers: metabolic stability, species comparison and in vitro-in vivo extrapolation. AB - OBJECTIVE: The aim of this research work was to characterize the metabolism of S002-333, (2-(4'-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide) and its enantiomers, S004-1032 (R-form) and S007 1558 (S-form) in pooled human liver microsomes (PHLM) and pooled liver microsomes (LM) of rat (RLM), rabbit (RABLM), dog (DLM) and monkey (MLM). Another objective of this study was to identify suitable surrogate species to humans for further development of lead candidates. METHOD: In vitro metabolic stability and metabolite identification of S002-333 and enantiomers were carried out in PHLM and LM of various species. The prediction of surrogate species and in vitro in vivo extrapolation were performed based upon the calculated in vitro intrinsic clearance (CLint ). RESULTS/CONCLUSION: The in vitro CLint values for S002-333, S004-1032 and S007-1558 were 0.027 +/- 0.005, 0.025 +/- 0.004 and 0.036 +/- 0.005 ml/min/mg, respectively, in PHLM, indicating that S007-1558 was the most metabolically unstable of the three. The LM of other species showed similar results. A common surrogate species to humans for S002-333 and enantiomers was predicted as rabbit where the extrapolated hepatic clearance (CLH ) did not show a significant difference to the in vivo CLH values. However, none of the species closely mimic humans with respect to the proportion of major metabolites (M-1-M 4) formed in vitro. Likewise, the CLH values were also predicted in humans for S002-333 and enantiomers using various mathematical models. During analysis, there was no chiral inversion evident among the individual isomers throughout in vitro and in vivo experiments. In conclusion, the in vitro results indicate a prominent role of phase I metabolism in the degradation of S002-333 and enantiomers and predict rabbit as an alternative species to conduct further safety and efficacy studies. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26477788 TI - Gender differences in caregiver burden and its determinants in family members of terminally ill cancer patients. AB - OBJECTIVE: Female family caregivers consistently report higher levels of stress and burden compared to male caregivers. Explanations for the apparently higher psychological vulnerability of female caregivers are largely missing to date. This study assesses the correlates and determinants of caregiver burden in family caregivers of advanced cancer patients with a specific focus on gender differences. METHODS: Three hundred and eight self-identified main informal caregivers of advanced cancer patients were cross-sectionally assessed using structured questionnaires for caregiver burden and hypothesised determinants of burden, including sociodemographic characteristics, caring arrangements, support needs, hope and coping style. Gender differences and predictors of burden were assessed using t-tests, chi-squared tests and univariate linear regression. Significant univariate predictors were entered in an analysis of covariance separately for men and women. RESULTS: Burden was significantly higher in women. Hope was the most significant protective factor against burden in both genders, together with perceived fulfilment of support needs. Only in women emotion oriented coping and being in employment while caring were significantly predictive of higher burden in the multivariate analysis. The model explained 36% of the variance in burden in men and 29% in women. CONCLUSION: Psychological support interventions for family caregivers should take gender-specific risk factors into account. Interventions focusing on keeping up hope while caring for a terminally ill family member may be a valuable addition to palliative services to improve support for family carers. Women may benefit from interventions that address adaptive coping and strategies to deal with the dual demands of employment and caring. Copyright (c) 2015 John Wiley & Sons, Ltd. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26477789 TI - The relationship between perineural invasion, tumor grade, reactive stroma and prostate cancer-specific mortality: A clinicopathologic study on a population based cohort. AB - BACKGROUND: In vitro and in vivo studies have shown that nerves, tumor epithelium, and stroma interact and promote prostate cancer (PC) progression. Perineural invasion (PNI) is established amidst these interactions and may therefore indicate an aggressive PC phenotype. The purpose of the present study was to determine the relationship between PNI, tumor grade, reactive stroma, and PC-specific mortality. METHODS: A population-based study on 318 patients, encompassing all cases of PC diagnosed by needle biopsies and without evidence of systemic metastasis at the time of diagnosis in Aust-Agder County in the period of 1991-1999. Patients were identified by cross-referencing the Cancer Registry of Norway. Clinical data were obtained by review of medical charts. Diagnostic prostate needle biopsies were reviewed with respect to presence of PNI, percentage of biopsy cores with PNI, Gleason score (GS), and reactive stromal grade (RSG). The endpoint was PC-specific mortality. RESULTS: The presence of PNI was significantly associated with high tumor grade and abundant reactive stroma. The 10-year PC-specific survival for patients with and without PNI was 72% and 91%, respectively (P = 0.001, log rank). PNI predicted PC-specific mortality independently of clinical factors, though the effect of PNI was attenuated when adjusting for GS and RSG. However, a percentage of biopsy cores with PNI >50% was found to predict PC-specific mortality independently of other clinicopathologic parameters. CONCLUSIONS: The present population-based study shows that PNI on diagnostic prostate needle biopsy is associated with increased risk of PC specific mortality. Our findings demonstrate that the prognostic effect of PNI is dependent on an association with high grade carcinoma and reactive stroma. However; the impact of PNI on clinical outcome becomes stronger and independent of other clinicopathologic factors upon increased percentage of PNI positive biopsy cores. Thus, our study highlights the importance of PNI and microenvironmental interactions for the long-term outcome of PC. PMID- 26477790 TI - Cellular Response of Sinorhizobium sp. Strain A2 during Arsenite Oxidation. AB - Arsenic (As) is a widely distributed toxic element in the environment and microorganisms have developed resistance mechanisms in order to tolerate it. The cellular response of the chemoorganotrophic arsenite (As[III])-oxidizing alpha Proteobacteria, Sinorhizobium sp. strain A2, to arsenic was examined in the present study. Several proteins associated with arsenite oxidase and As resistance were shown to be accumulated in the presence of As(III). A shift in central carbon metabolism from the tricarboxylic acid pathway to glyoxylate pathway was also observed in response to oxidative stress. Our results revealed the strategy of the As(III)-oxidizing Sinorhizobium strain to mitigate arsenic toxicity and oxidative damage by multiple metabolic adaptations. PMID- 26477791 TI - Prolonged auditory brainstem responses in infants with autism. AB - Numerous studies have attempted to identify early physiological abnormalities in infants and toddlers who later develop autism spectrum disorder (ASD). One potential measure of early neurophysiology is the auditory brainstem response (ABR), which has been reported to exhibit prolonged latencies in children with ASD. We examined whether prolonged ABR latencies appear in infancy, before the onset of ASD symptoms, and irrespective of hearing thresholds. To determine how early in development these differences appear, we retrospectively examined clinical ABR recordings of infants who were later diagnosed with ASD. Of the 118 children in the participant pool, 48 were excluded due to elevated ABR thresholds, genetic aberrations, or old testing age, leaving a sample of 70 children: 30 of which were tested at 0-3 months, and 40 were tested at toddlerhood (1.5-3.5 years). In the infant group, the ABR wave-V was significantly prolonged in those who later developed ASD as compared with case matched controls (n = 30). Classification of infants who later developed ASD and case-matched controls using this measure enabled accurate identification of ASD infants with 80% specificity and 70% sensitivity. In the group of toddlers with ASD, absolute and interpeak latencies were prolonged compared to clinical norms. Findings indicate that ABR latencies are significantly prolonged in infants who are later diagnosed with ASD irrespective of their hearing thresholds; suggesting that abnormal responses might be detected soon after birth. Further research is needed to determine if ABR might be a valid marker for ASD risk. Autism Res 2016, 9: 689-695. (c) 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research. PMID- 26477792 TI - Trauma-associated pneumonia: time to redefine ventilator-associated pneumonia in trauma patients. AB - BACKGROUND: The high prevalence of ventilator-associated pneumonia (VAP) in trauma patients has been reported in the literature, but the reasons for this observation remain unclear. We hypothesize that trauma factors play critical roles in VAP etiology. METHODS: In this retrospective study, 1,044 ventilated trauma patients were identified from December 2010 to December 2013. Patient level trauma factors were used to predict pneumonia as study endpoint. RESULTS: Ninety-five of the 1,044 ventilated trauma patients developed pneumonia. Rib fractures, pulmonary contusion, and failed prehospital intubation were significant predictors of pneumonia in a multivariate model. CONCLUSIONS: It is time to redefine VAP in trauma patients based on the effect of rib fractures, pulmonary contusions, and failed prehospital intubations. The Centers for Disease Control and Prevention definition of VAP needs to be modified to reflect the effect of trauma factors in the etiology of trauma-associated pneumonia. PMID- 26477794 TI - Antrodia cinnamomea Extract Inhibits Th17 Cell Differentiation and Ameliorates Imiquimod-Induced Psoriasiform Skin Inflammation. AB - Antrodia cinnamomea (A. cinnamomea) is a Chinese medicinal herb that possesses a broad range of bioactivities, including anti-inflammation. Given that the proinflammatory cytokine IL-17 plays a critical role in the pathogenesis of autoimmune diseases, we investigated whether A. cinnamomea could inhibit the development of Th17 cells, the main producer of IL-17, and exhibit therapeutic effects on an animal model of psoriasis. We found that A. cinnamomea extract (AC) inhibited the differentiation of Th17 cells as well as the production of IL-17A, IL-21, and IL-22 from these cells. This effect was associated with the inhibition of STAT3 phosphorylation and RORgammat expression. Notably, the oral administration of AC reduced psoriasis-like inflammation in imiquimod-mediated dermal damage, repressed the expression of IL-17A, IL-22, and TNF-alpha in skin lesions, and decreased the infiltration of CD4+ T cells, CD8+ T cells, and neutrophils into the dermis. Finally, serum levels of IL-17A were decreased in AC treated mice with psoriasis-like skin inflammation. Taken together, these findings indicate that AC inhibits Th17 cell differentiation, suggesting a role for A. cinnamomea in the treatment of psoriasis and other Th17 cell-mediated inflammatory diseases. PMID- 26477795 TI - Cancer Chemoprevention Effects of Ginger and its Active Constituents: Potential for New Drug Discovery. AB - Ginger is a commonly used spice and herbal medicine worldwide. Besides its extensive use as a condiment, ginger has been used in traditional Chinese medicine for the management of various medical conditions. In recent years, ginger has received wide attention due to its observed antiemetic and anticancer activities. This paper reviews the potential role of ginger and its active constituents in cancer chemoprevention. The phytochemistry, bioactivity, and molecular targets of ginger constituents, especially 6-shogaol, are discussed. The content of 6-shogaol is very low in fresh ginger, but significantly higher after steaming. With reported anti-cancer activities, 6-shogaol can be served as a lead compound for new drug discovery. The lead compound derivative synthesis, bioactivity evaluation, and computational docking provide a promising opportunity to identify novel anticancer compounds originating from ginger. PMID- 26477793 TI - Decreased brain PME/PDE ratio in bipolar disorder: a preliminary (31) P magnetic resonance spectroscopy study. AB - OBJECTIVES: The aim of the present study was to measure brain phosphorus-31 magnetic resonance spectroscopy ((31) P MRS) metabolite levels and the creatine kinase reaction forward rate constant (kf ) in subjects with bipolar disorder (BD). METHODS: Subjects with bipolar euthymia (n = 14) or depression (n = 11) were recruited. Healthy comparison subjects (HC) (n = 23) were recruited and matched to subjects with BD on age, gender, and educational level. All studies were performed on a 3-Tesla clinical magnetic resonance imaging system using a (31) P/(1) H double-tuned volume head coil. (31) P spectra were acquired without (1) H-decoupling using magnetization-transfer image-selected in vivo spectroscopy. Metabolite ratios from a brain region that includes the frontal lobe, corpus callosum, thalamus, and occipital lobe are expressed as a percentage of the total phosphorus (TP) signal. Brain pH was also investigated. RESULTS: Beta-nucleoside-triphosphate (beta-NTP/TP) in subjects with bipolar depression was positively correlated with kf (p = 0.039, r(2) = 0.39); similar correlations were not observed in bipolar euthymia or HC. In addition, no differences in kf and brain pH were observed among the three diagnostic groups. A decrease in the ratio of phosphomonoesters to phosphodiesters (PME/PDE) was observed in subjects with bipolar depression relative to HC (p = 0.032). We also observed a trend toward an inverse correlation in bipolar depression characterized by decreased phosphocreatine and increased depression severity. CONCLUSIONS: In our sample, kf was not altered in the euthymic or depressed mood state in BD. However, decreased PME/PDE in subjects with bipolar depression was consistent with differences in membrane turnover. These data provide preliminary support for alterations in phospholipid metabolism and mitochondrial function in bipolar depression. PMID- 26477796 TI - Cudraxanthone H Induces Growth Inhibition and Apoptosis in Oral Cancer Cells via NF-kappaB and PIN1 Pathways. AB - Cudraxanthone H (CH) is a natural compound isolated from a methanol extract of the root bark of Cudrania tricuspidata, a herbal plant also known as Moraceae. However, the effect of CH on human cancer cells has not been reported previously. The aim of this study was to investigate the anticancer effects and mechanism of action of CH on oral squamous cell carcinoma (OSCC) cells. CH exerted significant antiproliferative effects on OSCC cells in dose- and time-dependent manners. CH also induced apoptosis in OSCC cells, as evidenced by an increased percentage of cells in the sub-G1 phase of the cell cycle, annexin V-positive/propidium iodide negative cells, and nuclear morphology. This antiproliferative effect of CH was associated with a marked reduction in the expression of cyclin D1 and cyclin E, with a concomitant induction of cyclin-dependent kinase inhibitor (CDKI) expression (p21 and p27). CH inhibited the phosphorylation and degradation of IkappaB-alpha and the nuclear translocation of NF-kappaB p65. Furthermore, CH treatment down-regulated PIN1 mRNA and protein expression in a dose-dependent manner. PIN1 overexpression by infection with adenovirus-PIN1 (Ad-PIN1) attenuated the CH-induced growth-inhibiting and apoptosis-inducing effects, blocked CH-enhanced CDKI expression and restored cyclin levels. In contrast, inhibiting PIN1 expression via juglone exerted the opposite effects. The present study is the first to demonstrate antiproliferative and apoptosis-inducing effects of CH, which exerts its effects by inhibiting NF-kappaB and PIN1. These data suggest that it might be a novel alternative chemotherapeutic agent for use in the treatment of oral cancer. PMID- 26477797 TI - Chloroform Extract of Solanum lyratum Induced G0/G1 Arrest via p21/p16 and Induced Apoptosis via Reactive Oxygen Species, Caspases and Mitochondrial Pathways in Human Oral Cancer Cell Lines. AB - Solanum lyratum (SLEC) Thunberg (Solanaceae) has been used as a traditional herbal medicine in China for centuries. Numerous studies have shown that SLEC Thunberg (Solanaceae) extract inhibited cancer cell growth in vitro. Herein, we investigated cell death-induced by EcoAc, water, chloroform, butanol extract of SLEC in human oral cancer cell lines (HSC-3, SAS, and CAL-27) in vitro. Different SLEC extract induced cytotoxic effects in human oral cancer cells were examined by contrast phase microscopy. We selected the chloroform extract of SLEC to examine the cytotoxic effects by using DAPI staining, comet assays, flow cytometric assay, Western blotting and examination of confocal laser microscopy. SLEC decreased the percentage of viable cells, induced G0/G1 arrest and apoptosis. These effects were concentration- and time-dependent manners. SLEC increased protein levels of p21, p16, CDK2, and cyclin D1 in HSC-3, SAS, and CAL 27 cells. Also, SLEC increased CDK6 in HSC-3 and CAL-27 cells, but inhibited CDK6 in SAS cells. Cyclin E in HSC-3 and SAS cells was increased by SLEC, but it was inhibited in CAL-27 cells. SLEC suppressed the anti-apoptotic proteins Bcl-2 and Bcl-xl, but increased the pro-apoptotic proteins Bax and Bad in HSC-3, SAS, and CAL-27 cells. SLEC promoted the production of reactive oxygen species (ROS) and Ca2+, decreased the mitochondrial membrane potential (Deltapsim) and stimulated NO production in HSC-3, SAS, and CAL-27 cells. Specific caspase inhibitors (caspase-8 inhibitor: Z-IETD-FMK; caspase-9 inhibitor: Z-LEHD-FMK and caspase-3 inhibitor: Z-DEVD-FMK) for caspase-8, -9, and -3 blocked SLE-activated caspase-8, -9, and -3 activities which were associated with an increase in the percentage of viable cells. Taken together, SLE induced G0/G1 arrest and apoptosis via extrinsic- and intrinsic-dependent pathways in HSC-3, SAS, and CAL-27 cells. PMID- 26477798 TI - Therapeutic Potential of Young Green Barley Leaves in Prevention and Treatment of Chronic Diseases: An Overview. AB - Medicinal plants have played a major role as a functional food and pharmacological source of active substances. Barley grass (BG) is young green barley leaves. It is the young grass of the common barley plant Hordeum vulgare L. of the family Poeaceae (Graminae). It is a type of green grasses, and the only vegetation on the earth that can supply sole nutritional support from birth to old age. It contains a wide spectrum of vitamins, minerals, as well as eight essential amino acids that we must get from our diets. BG possesses several pharmacological activities as anticancer activity, anti-oxidant activity and anti inflammatory activity. It has been argued that BG helps blood flow, digestion and general detoxification of the body. The major pharmacologic interest of BG is its use in the treatment of chronic diseases. The beneficial effects observed in chronic disease may be related to bioactive compounds contained in BG such as superoxide dismutase (SOD) and bioflavonoids (lutonarin and saponarin). Thus, this paper is focused on the various studies that emphasize the therapeutic potential of BG in the prevention and treatment of chronic diseases. PMID- 26477799 TI - Effects of the Combination of the Main Active Components of Astragalus and Panax notoginseng on Inflammation and Apoptosis of Nerve Cell after Cerebral Ischemia Reperfusion. AB - Astragalus and Panax notoginseng are commonly used to treat cardio cerebrovascular diseases in China and are often combined together to promote curative effect. We speculate that the enhancement of the combination on anticerebral ischemia injury may come from the main active components. The purpose of this work was to probe the effects and mechanisms of Astragaloside IV (the active component of Astragalus) combined with Ginsenoside Rg1, Ginsenoside Rb1, and Notoginsenoside R1 (the active components of P. notoginseng) to antagonize ischemia/reperfusion (I/R) injury via inflammation and apoptosis. C57BL/6 mice were randomly divided into sham, model, Astragaloside IV, Ginsenoside Rg1, Ginsenoside Rb1, Notoginsenoside R1, four active components combination, and Edaravone groups. After administration for 3 days, bilateral common carotid arteries (CCA) were occluded with artery clip for 20[Formula: see text]min followed by reperfusion for 24[Formula: see text]h. Our results showed that the survival rate of nerve cell in hippocampal CA1 decreased while the apoptotic rate increased, and the level of caspase-3 protein in brain tissues was elevated, the expressions of TNF-a, IL-1, and ICAM-1 mRNA as well as phosphorylated nuclear factor kappa B (NF-kappaB) inhibitor protein alpha (p IkappaBa) in brain tissues were up-regulated, and the nuclear translocation rate of NF-kappaB was raised. Additionally, the protein expressions of phosphorylated tyrosine kinase 1 (p-JAK1), phosphorylated signal transducer and activator of transcription-1 (p-STAT1), glucose regulated protein 78 (GRP78), caspase-12, and phosphorylated c-Jun N-terminal kinases 1/2 (p-JNK1/2) in brain tissues were also significantly strengthened after I/R for 24 h. All drugs could increase neurocyte survival rate in hippocampal CA1, decrease the apoptotic rate, and inhibit caspase-3 protein expression, in contrast, the effects of four active components combination were better than those of active components alone. In addition, Astragaloside IV and Ginsenoside Rg1 could down-regulate the level of TNF-alpha, and ICAM-1 mRNA, respectively, Notoginsenoside R1 reduced both TNF-alpha and ICAM 1 mRNA, and the combination of the 4 effective components had inhibitory effects on the expressions of TNF-alpha, IL-1beta, and ICAM-1 mRNA. Astragaloside IV, Ginsenoside Rg1, Notoginsenoside R1, and 4 effective components combination were able to restrain the phosphorylation of IkappaBalpha, and relieve the nuclear translocation rate of NF-kappaB. Moreover, the effects of the combination are greater than those of active components alone. All drugs could suppress the phosphorylation of JAK1 induced by I/R; meanwhile the expression of p-STAT1 exhibited a decrease in Ginsenoside Rg1 and four active components combination groups. The decreases of p-JAK1 and p-STAT1 in the four active components combination group were more obvious than those in active components alone groups. Astragaloside IV, Ginsenoside Rg1, and Notoginsenoside R1 further augmented GRP78 expression caused by I/R, Notoginsenoside R1 attenuated caspase-12 protein expression, Astragaloside IV and Ginsenoside Rg1 lessened the phosphorylation of JNK1/2, and the four active components combination was capable of up-regulating GRP78 protein while down-regulating the expressions of caspase-12 and p-JNK1/2. Similarly, the effects of the four active components combination were greater than those of effective components alone. These suggested that the combination of the main active components of Astragalus and Panax notoginseng could strengthen protective effects on cerebral ischemia injury via anti-apoptosis and anti inflammation, and the mechanisms might be associated with restraining the activation of NF-kappaB and JAK1/STAT1 signal pathways and regulating endoplasmic reticulum stress (ERS) after cerebral ischemia. PMID- 26477800 TI - The Progress of Metabolomics Study in Traditional Chinese Medicine Research. AB - Traditional Chinese medicine (TCM) has played important roles in health protection and disease treatment for thousands of years in China and has gained the gradual acceptance of the international community. However, many intricate issues, which cannot be explained by traditional methods, still remain, thus, new ideas and technologies are needed. As an emerging system biology technology, the holistic view adopted by metabolomics is similar to that of TCM, which allows us to investigate TCM with complicated conditions and multiple factors in depth. In this paper, we tried to give a timely and comprehensive update about the methodology progression of metabolomics, as well as its applications, in different fields of TCM studies including quality control, processing, safety and efficacy evaluation. The herbs investigated by metabolomics were selected for detailed examination, including Anemarrhena asphodeloides Bunge, Atractylodes macrocephala Kidd, Pinellia ternate, etc.; furthermore, some valuable results have been obtained and summarized. In conclusion, although the study of metabolomics is at the early phase and requires further scrutiny and validation, it still provides bright prospects to dissect the synergistic action of multiple components from TCM. Overall, with the further development of analytical techniques, especially multi-analysis techniques, we expect that metabolomics will greatly promote TCM research and the establishment of international standards, which is beneficial to TCM modernization. PMID- 26477801 TI - Chinese Herbal Products for Ischemic Stroke. AB - Traditional Chinese herbal products (CHPs) have been described in ancient medicine systems as treatments for various stroke-associated ailments. This study is aimed to investigate the prescription patterns and combinations of CHPs for ischemic stroke in Taiwan. Prescriptions of CHPs for ischemic stroke were obtained from the National Health Insurance Research Database (NHIRD) of Taiwan. Every prescription with a leading diagnosis of ischemic stroke made during 2000 2010 was analyzed. Descriptive statistics were applied to the pattern of co prescriptions. Multiple logistic regression models were used to assess demographic and risk factors that are correlated with CHP use. The dataset of inpatient claims data contained information on 15,896 subjects who experienced ischemic stroke from 2000 to 2010. There was an average of 5.82 CHPs in a single prescription for subjects with ischemic stroke. Bu-yang-huan-wu-tang (BYHWT) (40.32%) was by far the most frequently prescribed formula CHP for ischemic stroke, and the most commonly used combination of two-formula-CHP was BYHWT with Shu-jin-huo-xue-tang (SJHXT) (4.40%). Dan Shen (16.50%) was the most commonly used single CHP for ischemic stroke, and the most commonly used combination of two single CHPs was Shi Chang Pua with Yuan Zhi (4.79%). We found that BYHWT and Dan Shen were the most frequently prescribed formula and single CHP for ischemic stroke, respectively. These results provide information about individualized therapy and may contribute to further pharmacologic experiments and clinical trials. PMID- 26477802 TI - Mitochondrial genome diversity among six laboratory zebrafish (Danio rerio) strains. AB - The mitochondrial genome (mtDNA) is distinct from the nuclear genome and is known to play a significant role in several disease phenotypes, such as longevity and fertility. Here we characterize the complete mitochondrial genomes (~16 590 bp), and the extent of within and between strain variation for 27 adult zebrafish, representing five commonly used laboratory strains (AB, TL, HL, WIK, and SJD) and one line acquired from a local pet shop. These data were subsequently analyzed to determine the phylogenetic relationships between strains and ascertain if positive selection might be operating on any mtDNA genes. Relationships between strains are not entirely consistent with those observed previously using nuclear DNA. Further there is a substantial body of variation within current zebrafish lines, with 172 variants described across lines. Of these, 27 changes are non synonymous and there is nominal evidence for positive selection in the mtDNA sequences at some of these sites. We further identify novel frameshift mutations in eight genes, which are all predicted to have functional consequences. Our study provides the first information on mtDNA diversity in zebrafish, identifies multiple non-synonymous substitutions and other mutations expected to have functional effects, and represents an important first step in establishing zebrafish as a model for investigating the phenotypic effects of mtDNA mutations. PMID- 26477803 TI - Does the gut drive amyotrophic lateral sclerosis progress? PMID- 26477804 TI - Economics of Team-based Care in Controlling Blood Pressure: A Community Guide Systematic Review. AB - CONTEXT: High blood pressure is an important risk factor for cardiovascular disease and stroke, the leading cause of death in the U.S., and a substantial national burden through lost productivity and medical care. A recent Community Guide systematic review found strong evidence of effectiveness of team-based care in improving blood pressure control. The objective of the present review is to determine from the economic literature whether team-based care for blood pressure control is cost beneficial or cost effective. EVIDENCE ACQUISITION: Electronic databases of papers published January 1980-May 2012 were searched to find economic evaluations of team-based care interventions to improve blood pressure outcomes, yielding 31 studies for inclusion. EVIDENCE SYNTHESIS: In analyses conducted in 2012, intervention cost, healthcare cost averted, benefit-to-cost ratios, and cost effectiveness were abstracted from the studies. The quality of estimates for intervention and healthcare cost from each study were assessed using three elements: intervention focus on blood pressure control, incremental estimates in the intervention group relative to a control group, and inclusion of major cost-driving elements in estimates. Intervention cost per unit reduction in systolic blood pressure was converted to lifetime intervention cost per quality adjusted life-year (QALY) saved using algorithms from published trials. CONCLUSIONS: Team-based care to improve blood pressure control is cost effective based on evidence that 26 of 28 estimates of $/QALY gained from ten studies were below a conservative threshold of $50,000. This finding is salient to recent U.S. healthcare reforms and coordinated patient-centered care through formation of Accountable Care Organizations. PMID- 26477806 TI - Clinical Decision Support Systems Recommended to Prevent Cardiovascular Disease. PMID- 26477805 TI - Clinical Decision Support Systems and Prevention: A Community Guide Cardiovascular Disease Systematic Review. AB - CONTEXT: Clinical decision support systems (CDSSs) can help clinicians assess cardiovascular disease (CVD) risk and manage CVD risk factors by providing tailored assessments and treatment recommendations based on individual patient data. The goal of this systematic review was to examine the effectiveness of CDSSs in improving screening for CVD risk factors, practices for CVD-related preventive care services such as clinical tests and prescribed treatments, and management of CVD risk factors. EVIDENCE ACQUISITION: An existing systematic review (search period, January 1975-January 2011) of CDSSs for any condition was initially identified. Studies of CDSSs that focused on CVD prevention in that review were combined with studies identified through an updated search (January 2011-October 2012). Data analysis was conducted in 2013. EVIDENCE SYNTHESIS: A total of 45 studies qualified for inclusion in the review. Improvements were seen for recommended screening and other preventive care services completed by clinicians, recommended clinical tests completed by clinicians, and recommended treatments prescribed by clinicians (median increases of 3.8, 4.0, and 2.0 percentage points, respectively). Results were inconsistent for changes in CVD risk factors such as systolic and diastolic blood pressure, total and low-density lipoprotein cholesterol, and hemoglobin A1C levels. CONCLUSIONS: CDSSs are effective in improving clinician practices related to screening and other preventive care services, clinical tests, and treatments. However, more evidence is needed from implementation of CDSSs within the broad context of comprehensive service delivery aimed at reducing CVD risk and CVD-related morbidity and mortality. PMID- 26477807 TI - 2010 National and State Costs of Excessive Alcohol Consumption. AB - INTRODUCTION: Excessive alcohol use cost the U.S. $223.5 billion in 2006. Given economic shifts in the U.S. since 2006, more-current estimates are needed to help inform the planning of prevention strategies. METHODS: From March 2012 to March 2014, the 26 cost components used to assess the cost of excessive drinking in 2006 were projected to 2010 based on incidence (e.g., change in number of alcohol attributable deaths) and price (e.g., inflation rate in cost of medical care). The total cost, cost to government, and costs for binge drinking, underage drinking, and drinking while pregnant were estimated for the U.S. for 2010 and allocated to states. RESULTS: Excessive drinking cost the U.S. $249.0 billion in 2010, or about $2.05 per drink. Government paid for $100.7 billion (40.4%) of these costs. Binge drinking accounted for $191.1 billion (76.7%) of costs; underage drinking $24.3 billion (9.7%) of costs; and drinking while pregnant $5.5 billion (2.2%) of costs. The median cost per state was $3.5 billion. Binge drinking was responsible for >70% of these costs in all states, and >40% of the binge drinking-related costs were paid by government. CONCLUSIONS: Excessive drinking cost the nation almost $250 billion in 2010. Two of every $5 of the total cost was paid by government, and three quarters of the costs were due to binge drinking. Several evidence-based strategies can help reduce excessive drinking and related costs, including increasing alcohol excise taxes, limiting alcohol outlet density, and commercial host liability. PMID- 26477808 TI - The Role of Clinical Decision Support Systems in Preventing Cardiovascular Disease. PMID- 26477809 TI - Letter Regarding Indoor Ultraviolet Radiation Tanning and Skin Cancer. PMID- 26477810 TI - Response to Letter Regarding Indoor Ultraviolet Radiation Tanning and Skin Cancer. PMID- 26477818 TI - The Role of Mast Cells in Bacterial Infection. AB - Mast cells (MCs) are particularly abundant at host-environment interfaces, such as skin and intestinal mucosa. Because of their location, it has been hypothesized that MCs can act as sentinel cells that sense microbial attacks and initiate a protective immune response. Several studies have suggested that animals deficient in MCs exhibit a worsened pathology in various experimental models of bacterial infection. However, other studies have indicated that MCs under certain circumstances may have a detrimental impact on bacterial disease, and there are also recent studies indicating that MCs are dispensable for the clearance of bacterial pathogens. Herein, we review the current knowledge of the role of MCs in bacterial infection. PMID- 26477819 TI - Gas-Phase Chemical Separation of Phosphatidylcholine and Phosphatidylethanolamine Cations via Charge Inversion Ion/Ion Chemistry. AB - The [M + H](+) cations formed upon electrospray ionization of the glycerophospholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE) show distinct reactivities upon gas-phase reactions with doubly deprotonated 1,4 phenylenedipropionic acid (PDPA). PC cations undergo charge inversion via adduct formation with subsequent methyl cation and proton transfer to the acid to yield [PC - CH3](-) anions. These demethylated PC anions fragment upon ion trap collision-induced dissociation (CID) to yield products that reveal fatty acid chain lengths and degrees of unsaturation. PE cations, on the other hand, undergo charge inversion via double proton transfer to the two carboxylate moieties in doubly deprotonated PDPA to yield [PE - H](-) anions. These anions also fragment upon ion trap CID to yield product ions indicative of chain lengths and degrees of unsaturation in the fatty acyl moieties. Advantage is taken of this distinct reactivity to separate isomeric and isobaric PC and PE cations present in mass spectra of lipid mixtures. A cation precursor ion population containing a mixture of PE and PC cations is mass-selected and subjected to ion/ion charge inversion reactions that result in separation of PC and PE anions into different mass-to charge ratios. Mass selection and subsequent ion trap CID of the lipid anions allows for the characterization of the isomeric lipids within each subclass. The charge inversion approach described here is demonstrated to provide increased signal-to-noise ratios for detection of PCs and PEs relative to the standard negative ionization approach as well as improved mixture analysis performance. PMID- 26477820 TI - Associations between single nucleotide polymorphisms in the FAS pathway and acute kidney injury. AB - INTRODUCTION: To determine whether single nucleotide polymorphisms (SNPs) in FAS and related genes are associated with acute kidney injury (AKI) in patients with acute respiratory distress syndrome (ARDS). METHODS: We studied 401 (Caucasian N = 310 and African-American N = 91) patients aged >= 13 years with ALI who enrolled in the Fluid and Catheter Treatment Trial (FACTT) between 2000 and 2005 from 20 North American centers. We genotyped 367 SNPs in 45 genes of the Fas/Fas ligand pathway to identify associations between SNPs in Fas pathway genes and the development of AKI by day 2 after enrollment in FACTT, adapting Acute Kidney Injury Network (AKIN) criteria. Written informed consent was obtained from participants or legally authorized surrogates in the original FACTT study and available to use for secondary analysis. RESULTS: In Caucasian patients, we identified associations between two SNPs and the incidence of AKI (stage 1 and above): rs1050851 and rs2233417; both are found within the gene for nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA). For rs1050851 and rs2233417, the odds ratios (ORs) were 2.34 (95 % confidence interval (CI) = 1.58-3.46, p = 1.06 * 10(-5), FDR = 0.003) and 2.46 (CI = 1.61-3.76, p = 1.81 * 10(-5), FDR = 0.003) for each minor allele, respectively. The associations were stronger still for AKIN stage 2-3 with respective ORs 4.00 (CI = 2.10-7.62, p = 1.05 * 10(-5), FDR = 0.003) and 4.03 (CI = 2.09-7.77, p = 1.88 * 10(-5), FDR = 0.003) for each minor allele homozygote. We observed no significant association between these SNPs and AKI in the smaller subset of African Americans. CONCLUSION: In Caucasian patients with ALI, the presence of minor alleles in two SNPs in NFKBIA was strongly associated with the development of AKI. TRIAL REGISTRATION: NCT00281268 . Registered 20/01/2006. PMID- 26477821 TI - Thrombophilia testing patterns amongst patients with acute venous thromboembolism. AB - BACKGROUND: Thrombophilia testing has limited value in determining the selection and duration of anticoagulation therapy for venous thromboembolism (VTE), yet is commonly performed. This study describes the patterns and appropriateness of thrombophilia testing in a large cohort of patients with acute VTE. MATERIALS AND METHODS: This was a retrospective study of a random sample of patients with a validated diagnosis of acute VTE diagnosed between January 1, 2004 and December 31, 2010. Events were identified from administrative data and verified via manual review. Patients were grouped by thrombophilia testing status and compared on patient characteristics and thrombophilia testing results and appropriateness. RESULTS: Of 1314 patients with validated VTE, 315 (24%) underwent thrombophilia testing, 62 (20%) of whom had >= 1 positive test. Tested patients were younger and more likely to have had a family history of VTE. Factor V Leiden (17%) and prothrombin G20210A mutation (4%) were the most commonly detected thrombophilias. Only 31 (10%) of tested patients met eligibility criteria for thrombophilia testing (i.e., at least one strong thrombophilic risk factor present) and were tested at least 90 days following unprovoked index VTE. CONCLUSIONS: Thrombophilia is commonly evaluated in patients without a clear indication for testing and during times where results may be unreliable. Future studies are needed to assess interventions aimed at reducing inappropriate thrombophilia testing without adversely affecting patient outcomes. PMID- 26477822 TI - Pelvic Pain Associated With Essure Perforation. PMID- 26477823 TI - Plant stilbenes induce endoplasmic reticulum stress and their anti-cancer activity can be enhanced by inhibitors of autophagy. AB - BACKGROUND: Environmental conditions or chemical agents can interfere with the function of the endoplasmic reticulum, and the resulting endoplasmic reticulum (ER) stress can be toxic to the cell if it is not relieved. The classical compensatory response to ER stress is the unfolded protein response (UPR) that reduces protein load in the ER. However, autophagy may also compensate by removing large insoluble protein aggregates. Agents that stress the ER can have anti-cancer activity, and novel applications of ER stress inducing agents are being investigated. Plant stilbenes are a class of stress responsive molecules that includes resveratrol, which are being investigated as potential therapeutics in humans for conditions such as aging or cancer. RESULTS: We performed a screen of 1726 small, drug like molecules to identify those that could activate an ER stress responsive luciferase gene. After secondary screening, we determined that the plant stilbenes pterostilbene and piceatannol were the most potent inducers of ER stress from this group. ER stress can be particularly toxic to cells with high ER load, so we examined their effect on cells expressing the Wnt family of secreted glycoprotein growth factors. Molecular analysis determined that these ER stress-inducing stilbenes could block Wnt processing and also induce autophagy in acute lymphoblastic leukemia cells expressing Wnt16. Combining pterostilbene (to induce ER stress) with chloroquine (to inhibit autophagy) lead to significant cellular toxicity in cells from aggressive acute lymphoblastic leukemia. CONCLUSIONS: Plant stilbenes are potent inducers of ER stress. However, their toxicity is more pronounced in cancer cells expressing Wnt growth factors. The toxicity of stilbenes in these ALL cells can be potentiated by the addition of autophagy inhibitors, suggesting a possible therapeutic application. PMID- 26477824 TI - miR-92a regulates angiogenic activity of adipose-derived mesenchymal stromal cells. AB - Mesenchymal stromal cells including those from adipose tissue (MSCs) regulate angiogenesis in adult tissues. MicroRNAs (miRs), small noncoding RNAs that control gene expression by binding to target mRNAs, reducing their stability and/or inhibiting translation, appear to be important regulators of blood vessel growth. In this study, we examined the impact of angio-miRs on paracrine activities of MSCs. Using Illumina microarrays we found that miR-92a is one of the most abundant angio-miRs in human MSCs. We transfected MSC with pre-miR-92a or anti-miR-92a which led to the coordinated changes of known miR-92a target mRNA levels. Then we tested the ability of conditioned medium from transfected cells to stimulate tube formation by HUVECs. MSC overexpressing miR-92a completely lost the ability to stimulate tubes formation by endothelial cells. However, knocking out miR-92a by transfection with anti-miR-92a did not increase the ability of MSC to stimulate tube formation. Secretion of hepatocyte growth factor (HGF) and angiopoetin-1 was significantly lower in the medium of miR-92a overexpressing MSC, whereas VEGF secretion did not change significantly. The replenishment of HGF but not angiopoietin-1 has restored the ability of conditioned medium from miR-92a overexpressing MSC to stimulate the tube formation. We conclude that overexpression of miR-92a in MSC suppresses angiogenic properties of these cells by down-regulation of HGF secretion. PMID- 26477825 TI - Macrophages derived from THP-1 promote the osteogenic differentiation of mesenchymal stem cells through the IL-23/IL-23R/beta-catenin pathway. AB - Abnormal bone formation is a clinically significant dilemma for many conditions in response to injury, inflammation or genetic disease. However, the effects of inflammation on the osteogenic differentiation of mesenchymal stem cells (MSCs) remain unclear. IL-23 secretion from macrophages might contribute to the development of bone formation. Here, we investigated the stimulatory effects of THP-1 macrophage conditioned medium (MPhi CM) on the osteogenic differentiation of human MSCs and the associated signaling pathways. The osteogenic differentiation of MSCs was induced after exposure to osteogenic differentiation medium (OM). MPhi CM significantly increased alkaline phosphate (ALP) activity and calcium mineralization in MSCs. Osteogenic marker genes, including RUNX2, ALP and osteocalcin (OCN), were also up-regulated in MSCs after exposure to MPhi CM. Moreover, western blotting revealed that MPhi CM treatment induced STAT3 and beta catenin activation in MSCs. Furthermore, blockade of IL-23 in MPhi CM not only impaired the osteogenic-promotion effects of macrophage but also decreased the expression of osteogenic maker genes. However, IL-23R silencing suppressed MPhi CM-induced calcium mineralization and osteogenic maker gene expression in MSCs. These data suggest that macrophages derived from THP-1 promote the osteoblastic differentiation of MSCs through the IL-23/IL-23R/beta-catenin pathway and macrophages might contribute to the development of bone formation in inflammation. PMID- 26477826 TI - Aquablation - image-guided robot-assisted waterjet ablation of the prostate: initial clinical experience. AB - OBJECTIVE: To assess the safety and feasibility of aquablation in a first-in-man study. Aquablation is a novel minimally invasive water ablation therapy combining image guidance and robotics (AquaBeam((r)) ) for the targeted and heat-free removal of prostatic tissue in men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: A prospective, non-randomised, single-centre trial in men aged 50-80 years with moderate-to-severe LUTS was conducted. Under real-time image-based ultrasonic guidance, AquaBeam technology enables surgical planning and mapping, and leads to a controlled heat-free resection of the prostate using a high-velocity saline stream. Patients were evaluated at 1, 3, and 6 months after aquablation. RESULTS: In all, 15 patients were treated with aquablation under general anaesthesia. The mean (range) age was 73 (59-86) years and prostate size was 54 (27-85) mL. A substantial median lobe was present in six of the 15 patients. The mean International Prostate Symptom Score (IPSS) was 23 and the maximum urinary flow rate (Qmax ) was 8.4 mL/s at baseline. The mean procedural time was 48 min with a mean aquablation treatment time of 8 min. All procedures were technically successful with no serious or unexpected adverse events (AEs). All but one patient had removal of catheter on day 1, and most of the patients were discharged on the first postoperative day. No patient required a blood transfusion, and postoperative sodium changes were negligible. There were no serious 30-day AEs. One patient underwent a second aquablation treatment within 90 days of the first procedure. The mean IPSS score statistically improved from 23.1 at baseline to 8.6 at 6 months (P < 0.001) and the Qmax increased from 8.6 mL/s at baseline to 18.6 mL/s at the 6-month follow-up (P < 0.001). At 6 months, the mean detrusor pressure at Qmax decreased to 45 cmH2 0 from 66 cmH2 0 at baseline (P < 0.05), and the mean prostate size was reduced to 36 mL, a 31% reduction in size vs baseline (P < 0.001). No cases of urinary incontinence or erectile dysfunction were reported. CONCLUSIONS: These preliminary results from this initial study show aquablation of the prostate is technically feasible with a safety profile comparable to other BPH technologies. The combination of surgical mapping by the operating surgeon and the high-velocity saline provides a promising technique delivering a conformal, quantifiable, and standardised heat free ablation of the prostate. Advantages of this technique include reduction in resection time compared with other endoscopic methods, as well as the potential to preserve sexual function. PMID- 26477827 TI - POST Forms More Than Advance Directives Associated With Out-of-Hospital Death: Insights From a State Registry. AB - CONTEXT: Patients' end-of-life care outcomes often do not reflect their preferences. Ninety-two percent of West Virginians prefer to die outside the hospital, yet only 58.8% do. OBJECTIVES: To compare out-of-hospital death (OHD) between those with completed advance directive (AD) and Physician Orders for Scope of Treatment (POST) forms. METHODS: This was a retrospective cohort study of 2027 West Virginians who submitted AD and/or POST forms to the West Virginia e Directive Registry and died between October 1, 2010 and December 31, 2013. A multivariable logistic regression model examined the relationship between OHD by form type while adjusting for age and enrollment in hospice. RESULTS: Patients who completed an AD were significantly less likely to have an OHD (56.9%) than those who completed a POST form with comfort measures orders or a POST form with limited/full intervention orders (88.4% and 75.9%, respectively, P < 0.001). The odds of OHD were significantly higher for patients with POST forms with comfort measures orders than for those with ADs (OR 4.239, P < 0.001). CONCLUSION: A prospective study is needed to validate that a statewide POST program and registry provide a more effective way than ADs to express, document, and honor patients' preferences for an OHD. PMID- 26477828 TI - Using Markov Multistate Models to Examine the Progression of Symptom Severity Among an Ambulatory Population of Cancer Patients: Are Certain Symptoms Better Managed Than Others? AB - CONTEXT: Patient-reported assessments of symptom severity can assist providers in monitoring and managing symptoms for cancer patients, which is important for offering patients optimal cancer care. Understanding which symptoms deteriorate at a faster rate over time can help identify areas for improving symptom management. OBJECTIVES: This article aimed to longitudinally examine the transitions in symptom severity over time and determine which symptoms deteriorate most rapidly. METHODS: This was an Ontario-wide cohort study from 2007 to 2011 of adult outpatients diagnosed with cancer. During every symptom assessment at the cancer center, patients reported their level of severity for each of nine symptoms. A Markov multistate model under an intermittent observation scheme was implemented to examine the progression of symptom severity over time among cancer patients. RESULTS: This study included 55,883 patients with over 280,000 symptom assessments. The median time between assessments was 29 days, and the majority of patients had at least three assessments. The symptoms deteriorating most rapidly over time were fatigue and well-being, whereas the symptom deteriorating least rapidly over time was nausea. CONCLUSION: The availability of numerous medications for treating nausea, compared to fatigue and well-being, may be a reasonable explanation for our findings. Alternate management for these symptoms, such as exercise for reducing fatigue, should be investigated to improve patients' quality of life. The use of multistate modeling methods is also unique in the study of symptom progression and provides a more in depth understanding of the likelihood of symptom deterioration and improvement over time. PMID- 26477829 TI - A semi-multifunctional sialyltransferase from Bibersteinia trehalosi and its comparison to the Pasteurella multocida ST1 mutants. AB - Sialic acids are well known for their crucial roles in many physiological and pathological processes. Improvement in the efficacy of protein drugs, an increase in the anti-inflammatory activity of intravenous immunoglobulin, preparation of infant milk and the diagnosis of diseases are examples of why there is a need for efficient in vitro sialylation. Sialyltransferases are crucial enzymes for the synthesis of sialo-oligosaccharides. Here, we introduce a new alpha2,3 sialyltransferase from bacteria Bibersteinia trehalosi (BtST1), which is homological to sialyltransferase from Pasteurella multocida (PmST1), Pasteurella dagmatis (PdST1) and Haemophilus ducreyi (Hd0053). BtST1 is active in a wide pH range and shows considerable acceptor flexibility. Very good specific activities have been detected with lactose and LacNAc as acceptors, and these activities were comparable to those of efficient multifunctional PmST1 and higher than PdST1, Hd0053 and also PmST1 M144D which was constructed to decrease the high sialidase activity of PmST1. Testing of PmST1 mutant forms revealed that mutations that included S143 caused only the restriction of sialyltransferase activity, whereas mutations including G142 resulted in the loss of activity with lactose. BtST1 possesses only low sialidase and trans-sialidase activities that are comparable to mutant PmST1 M144D, which are detected only in the presence of CMP. The combination of large acceptor flexibility, high activity for lactose and LacNAc and naturally low sialidase activity make BtST1 an attractive enzyme for biotechnological applications. PMID- 26477830 TI - Molecular Screen Identifies Cardiac Myosin-Binding Protein-C as a Protein Kinase G-Ialpha Substrate. AB - BACKGROUND: Pharmacological activation of cGMP-dependent protein kinase G I (PKGI) has emerged as a therapeutic strategy for humans with heart failure. However, PKG-activating drugs have been limited by hypotension arising from PKG induced vasodilation. PKGIalpha antiremodeling substrates specific to the myocardium might provide targets to circumvent this limitation, but currently remain poorly understood. METHODS AND RESULTS: We performed a screen for myocardial proteins interacting with the PKGIalpha leucine zipper (LZ)-binding domain to identify myocardial-specific PKGI antiremodeling substrates. Our screen identified cardiac myosin-binding protein-C (cMyBP-C), a cardiac myocyte-specific protein, which has been demonstrated to inhibit cardiac remodeling in the phosphorylated state, and when mutated leads to hypertrophic cardiomyopathy in humans. GST pulldowns and precipitations with cGMP-conjugated beads confirmed the PKGIalpha-cMyBP-C interaction in myocardial lysates. In vitro studies demonstrated that purified PKGIalpha phosphorylates the cMyBP-C M-domain at Ser 273, Ser-282, and Ser-302. cGMP induced cMyBP-C phosphorylation at these residues in COS cells transfected with PKGIalpha, but not in cells transfected with LZ mutant PKGIalpha, containing mutations to disrupt LZ substrate binding. In mice subjected to left ventricular pressure overload, PKGI activation with sildenafil increased cMyBP-C phosphorylation at Ser-273 compared with untreated mice. cGMP also induced cMyBP-C phosphorylation in isolated cardiac myocytes. CONCLUSIONS: Taken together, these data support that PKGIalpha and cMyBP-C interact in the heart and that cMyBP-C is an anti remodeling PKGIalpha kinase substrate. This study provides the first identification of a myocardial-specific PKGIalpha LZ dependent antiremodeling substrate and supports further exploration of PKGIalpha myocardial LZ substrates as potential therapeutic targets for heart failure. PMID- 26477831 TI - Differentiation of oral bacteria in in vitro cultures and human saliva by secondary electrospray ionization - mass spectrometry. AB - The detection of bacterial-specific volatile metabolites may be a valuable tool to predict infection. Here we applied a real-time mass spectrometric technique to investigate differences in volatile metabolic profiles of oral bacteria that cause periodontitis. We coupled a secondary electrospray ionization (SESI) source to a commercial high-resolution mass spectrometer to interrogate the headspace from bacterial cultures and human saliva. We identified 120 potential markers characteristic for periodontal pathogens Aggregatibacter actinomycetemcomitans (n = 13), Porphyromonas gingivalis (n = 70), Tanerella forsythia (n = 30) and Treponema denticola (n = 7) in in vitro cultures. In a second proof-of-principle phase, we found 18 (P. gingivalis, T. forsythia and T. denticola) of the 120 in vitro compounds in the saliva from a periodontitis patient with confirmed infection with P. gingivalis, T. forsythia and T. denticola with enhanced ion intensity compared to two healthy controls. In conclusion, this method has the ability to identify individual metabolites of microbial pathogens in a complex medium such as saliva. PMID- 26477832 TI - Genetic discovery for oil production and quality in sesame. AB - Oilseed crops are used to produce vegetable oil. Sesame (Sesamum indicum), an oilseed crop grown worldwide, has high oil content and a small diploid genome, but the genetic basis of oil production and quality is unclear. Here we sequence 705 diverse sesame varieties to construct a haplotype map of the sesame genome and de novo assemble two representative varieties to identify sequence variations. We investigate 56 agronomic traits in four environments and identify 549 associated loci. Examination of the major loci identifies 46 candidate causative genes, including genes related to oil content, fatty acid biosynthesis and yield. Several of the candidate genes for oil content encode enzymes involved in oil metabolism. Two major genes associated with lignification and black pigmentation in the seed coat are also associated with large variation in oil content. These findings may inform breeding and improvement strategies for a broad range of oilseed crops. PMID- 26477833 TI - Insurance Status and Differences in Treatment and Survival of Testicular Cancer Patients. AB - OBJECTIVE: To explore the relationship between insurance status and differences in treatment and survival of testicular cancer patients. The Surveillance, Epidemiology, and End Results (SEER) database was utilized for this study. MATERIALS AND METHODS: Between 2007 and 2011, 5986 testicular cancer patients were included in the SEER database. Patients were classified into nonseminoma and seminoma groups. We compared mortality rates, metastasis (M+) at diagnosis, and rates of adjuvant treatments between the uninsured (UI) and insured (I) populations. RESULTS: Overall, 2.64% of UI vs 1.36% of I died from testicular cancer (P = .025) and 16.73% of UI vs 10.52% of I had M+ at diagnosis (P <.0001). In the nonseminoma group, 4.19% of UI vs 2.79% of I died from testicular cancer (P = .326) and 25.92% of UI vs 18.46% of I had M+ at diagnosis (P = .0007). Also 17.28% of UI vs 20.88% of I had retroperitoneal lymph node dissection (RPLND; P = .1). In the seminoma group, 1.06% of UI vs 0.33% of I died from testicular cancer (P = .030) and 7.43% of UI vs 4.81% of I had M+ at diagnosis (P = .029). Also 34.75% of UI vs 48.4% of I received adjuvant radiation (P = .0083). The lack of health insurance predicted poor survival after adjusting for tumor stage, receiving adjuvant radiation or RPLND. CONCLUSION: UI testicular cancer patients present with more advanced cancer stages and have higher mortality rates than I patients. UI seminoma patients received less adjuvant radiation. This may be related to lack of access to care or more advanced cancer stage at diagnosis. PMID- 26477834 TI - Evidence for glycinergic GluN1/GluN3 NMDA receptors in hippocampal metaplasticity. AB - Hebbian, or associative, forms of synaptic plasticity are considered the molecular basis of learning and memory. However, associative synaptic modifications, including long-term potentiation (LTP) and depression (LTD), can form positive feedback loops which must be constrained for neural networks to remain stable. One proposed constraint mechanism is metaplasticity, a process whereby synaptic changes shift the threshold for subsequent plasticity. Metaplasticity has been functionally observed but the molecular basis is not well understood. Here, we report that stimulation which induces LTP recruits GluN2B lacking GluN1/GluN3 NMDA receptors (NMDARs) to excitatory synapses of hippocampal pyramidal neurons. These unconventional receptors may compete against conventional GluN1/GluN2 NMDARs to favor synaptic depotentiation in response to subsequent "LTP-inducing" stimulation. These results implicate glycinergic GluN1/GluN3 NMDAR as molecular brakes on excessive synaptic strengthening, suggesting a role for these receptors in the brain that has previously been elusive. PMID- 26477835 TI - How to become an expert: A new perspective on the role of sleep in the mastery of procedural skills. AB - How do you get to Carnegie Hall? Practice, sleep, practice. With enough practice and sleep - we adopt new strategies that eventually become automatic, and subsequently require only the refinement of the existing skill to become an "expert". It is not known whether sleep is involved in the mastery and refinement of new skills that lead to expertise, nor is it known whether this may be primarily dependent on rapid eye movement (REM), non-REM stage 2 (NREM2) or slow wave sleep (SWS). Here, we employed behavioural and scalp-recorded electroencephalography (EEG) techniques to investigate the post-learning changes in the architecture (e.g., REM, NREM2 and SWS duration) and the electrophysiological features (e.g., rapid eye movements, sleep spindles and slow wave activity) that characterize these sleep states as individuals progress from night to night, from "Novice" to "Experts" on a cognitive procedural task (e.g., the Tower of Hanoi task). Here, we demonstrate that speed of movements improves over the course of training irrespective of whether sleep or wake intervenes training sessions, whereas accuracy improves gradually, but only significantly over a night of sleep immediately prior to mastery of the task. On the night that subjects are first exposed to the task, the density of fast spindles increased significantly during both NREM2 and SWS accompanied by increased NREM2 sigma power and SWS delta power, whereas, on the night that subjects become experts on the task, they show increased REM sleep duration and spindles became larger in terms of amplitude and duration during SWS. Re-exposure to the task one-week after it had already been mastered resulted in increased NREM sleep duration, and again, increased spindle density of fast spindles during SWS and NREM2 and increased NREM2 sigma power and SWS delta power. Importantly, increased spindle density was correlated with overnight improvement in speed and accuracy. Taken together, these results help to elucidate how REM and NREM sleep are uniquely involved in memory consolidation over the course of the mastery of a new cognitively complex skill, and help to resolve controversies regarding sequential nature of memory processing during sleep in humans, for which consistent evidence is currently lacking. PMID- 26477836 TI - Physicochemical Investigation of 2,4,5-Trimethoxybenzylidene Propanedinitrile (TMPN) Dye as Fluorescence off-on Probe for Critical Micelle Concentration (CMC) of SDS and CTAB. AB - 2,4,5-trimethoxybenzylidene propanedinitrile (TMPN) was synthesized by Knoevenagel condensation. Structure of the TMPN was conformed by the elemental analysis and EI-MS, FT-IR, (1)H-NMR, (13)C-NMR spectroscopy. Absorbance and emission spectrum of the TMPN was studied in different solvent provide that TMPN is good absorbent and emission red shift in absorbance and emission spectra as polarity of the solvents increase. Photophysical properties including, oscillator strength, extinction coefficient, transition dipole moment, stokes shift and fluorescence quantum yield were investigated in order to investigate the physicochemical behaviors of TMPN. Dye undergoes solubilization in different micelles and may be used as a probe to determine the critical micelle concentration (CMC) of SDS and CTAB. PMID- 26477837 TI - Synthesis, and Fluorescence Properties of Coumarin and Benzocoumarin Derivatives Conjugated Pyrimidine Scaffolds for Biological Imaging Applications. AB - Series of coumarin and 5,6-benzomcomarin substituted pyrimidine derivatives 11-15 and 22-25 were synthesized, aiming to develop new imaging fluorescent agents. Analogously, treatment of 4-chloropyrimidine analog 16 with coumarin 3 carbohyrazide 5 under MWI condition followed by boiling with NH4OAc in HOAc furnished coumarin-1,2,4-triazolo-pyrimidine analog 18. The fluorescence property was investigated spectrophotometrically in MeOH with Rhodamine 6G as standard dye. All the compounds showed emission in the region between 331 and 495 nm. The quantum yield of all the compounds were found to be weak, except methyl benzocoumarin 3-carboxylate 22 which showed (PhiF = 0.98) in comparison to Rhodamine 6G as standard (PhiF = 0.95). PMID- 26477838 TI - Fluorescence Determination of Warfarin Using TGA-capped CdTe Quantum Dots in Human Plasma Samples. AB - In this study, some effort has been performed to provide low temperature, less time consuming and facile routes for the synthesis of CdTe quantum dots using ultrasound and water soluble capping agent thioglycolic acid. TGA-capped CdTe quantum dots were characterized through x-ray diffraction, transmission electron microscopy, Fourier transform infrared, ultraviolet-visible and fluorescence spectroscopy. The prepared quantum dots were used for warfarin determination based on the quenching of the fluorescence intensity in aqueous solution. Under the optimized conditions, the linear range of quantum dots fluorescence intensity versus the concentration of warfarin was 0.1-160.0 MUM, with the correlation coefficient of 0.9996 and a limit of detection of 77.5 nM. There was no interference to coexisting foreign substances. The selectivity of the sensor was also tested and the results show that the developed method possesses a high selectivity for warfarin. PMID- 26477839 TI - A scanning acoustic microscope discriminates cancer cells in fluid. AB - Scanning acoustic microscopy (SAM) discriminates lesions in sections by assessing the speed of sound (SOS) or attenuation of sound (AOS) through tissues within a few minutes without staining; however, its clinical use in cytological diagnosis is unknown. We applied a thin layer preparation method to observe benign and malignant effusions using SAM. Although SAM is inferior in detecting nuclear features than light microscopy, it can differentiate malignant from benign cells using the higher SOS and AOS values and large irregular cell clusters that are typical features of carcinomas. Moreover, each single malignant cell exhibits characteristic cytoplasmic features such as a large size, irregular borders and secretory or cytoskeletal content. By adjusting the observation range, malignant cells are differentiated from benign cells easily using SAM. Subtle changes in the functional and structural heterogeneity of tumour cells were pursuable with a different digital data of SAM. SAM can be a useful tool for screening malignant cells in effusions before light microscopic observation. Higher AOS values in malignant cells compared with those of benign cells support the feasibility of a novel sonodynamic therapy for malignant effusions. PMID- 26477840 TI - Scheduled versus Pro Re Nata Dosing in the VIEW Trials. AB - PURPOSE: To analyze visual acuity (VA) outcomes before and after preplanned treatment regimen change in the VIEW studies at week 52 (W52). DESIGN: Multiple post hoc analyses for retrospectively defined subgroups in 2 multicenter, multinational, double-masked trials. PARTICIPANTS: Two thousand four hundred fifty-seven neovascular age-related macular degeneration (AMD) patients. METHODS: Patients were randomized to treatment with 0.5 mg ranibizumab given monthly, a 0.5-mg or 2-mg intravitreal aflibercept injection given monthly, or 2 mg intravitreal aflibercept given every other month, after 3 initial monthly doses, up to W52. From W52 through W96, patients received their original dosing assignment using a capped pro re nata (PRN) regimen, with defined retreatment criteria based on VA and morphologic signs of disease activity and mandatory dosing at least every 12 weeks. MAIN OUTCOME MEASURES: Best-corrected VA (BCVA) and optical coherence tomography assessments were mandatory at all visits from baseline to W96. Outcomes were changes in BCVA and central retinal thickness. Outcomes were evaluated in all patients who completed 2 years of the VIEW studies using the last observation carried forward method for missing data at interim visits. RESULTS: After W52, approximately 20% of patients lost 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more across all treatment arms with PRN treatment. Patients who met the retreatment criterion of loss of 5 ETDRS letters or more in the first quarter of the PRN dosing phase did not recover; mean final VA loss across the 4 study arms was -4.4 to -5.8 letters. Outcomes of these patients up to W52 were indistinguishable from those of the overall population. There were no differences between groups in serious ocular adverse events or Anti-Platelet Trialists' Collaboration arterial thromboembolic events through W96. CONCLUSIONS: These analyses suggest that there are subgroups of patients for whom VA outcomes in the second year of the VIEW studies were less stable than in the first year and for whom W52 seems to be an important inflection point. Although alternate reasons specific to the nature of the underlying AMD cannot be fully excluded, the switch in treatment regimen at W52 is a plausible explanation. PMID- 26477841 TI - African Ancestry Is Associated with Higher Intraocular Pressure in Latinos. AB - PURPOSE: Intraocular pressure (IOP) is a major risk factor, as well as the only modifiable risk factor, for glaucoma. Racial differences have been observed in IOP measurements with individuals of African descent experiencing the highest IOP when compared with other ethnic groups. The purpose of this study was to examine the relationship between genetic ancestry and IOP in Latinos. DESIGN: Population based genetic association study. PARTICIPANTS: A total of 3541 participants recruited from the Los Angeles Latino Eye Study. METHODS: Study participants were genotyped using the Illumina OmniExpress BeadChip (~730K markers). We used STRUCTURE to estimate individual genetic ancestry. Simple and multiple linear regression, as well as quantile regression, analyses were performed to investigate the relationship between genetic ancestry and IOP. MAIN OUTCOME MEASURES: The relationship between genetic ancestry and IOP in Latinos. RESULTS: African ancestry was significantly associated with higher IOP in Latinos in our simple linear regression analysis (P = 0.002). After adjusting for age, gender, body mass index, systolic blood pressure, central corneal thickness, and type 2 diabetes, this association remained significant (P = 0.0005). The main association was modified by a significant interaction between African ancestry and hypertension (P = 0.037), with hypertensive individuals experiencing a greater increase in IOP with increasing African ancestry. CONCLUSIONS: To our knowledge, we demonstrate for the first time that African ancestry and its interaction with hypertension are associated with higher IOP in Latinos. PMID- 26477842 TI - Ranibizumab or Bevacizumab for Neovascular Age-Related Macular Degeneration According to the Lucentis Compared to Avastin Study Treat-and-Extend Protocol: Two-Year Results. AB - PURPOSE: To compare the efficacy and safety of bevacizumab (Avastin; F. Hoffmann La Roche Ltd, Basel, Switzerland) versus ranibizumab (Lucentis; Novartis Pharma AG, Basel, Switzerland) for neovascular age-related macular degeneration (nAMD) after 2 years when using a treat-and-extend protocol. DESIGN: Multicenter, randomized, noninferiority trial with a noninferiority limit of 5 letters. PARTICIPANTS: Patients 50 years of age or older with previously untreated nAMD in 1 eye and best-corrected visual acuity 20/25 to 20/320. METHODS: Patients were assigned randomly to receive intravitreal injections with either ranibizumab 0.5 mg or bevacizumab 1.25 mg. Injections were given every 4 weeks until inactive disease was achieved. The treatment interval then was extended by 2 weeks at a time up to a maximum of 12 weeks. In the event of a recurrence, the treatment interval was shortened by 2 weeks at a time. MAIN OUTCOME MEASURE: Mean change in visual acuity at 2 years. RESULTS: Of a total of 441 randomized patients, 339 patients (79%) completed the 2-year visit. According to per-protocol analysis at 2 years, bevacizumab was equivalent to ranibizumab, with 7.4 and 6.6 letters gained, respectively (95% confidence interval [CI] of mean difference, -4.1 to 2.5; P = 0.634). Intention-to-treat analysis was concordant, with a gain of 7.8 letters for bevacizumab and 7.5 letters for ranibizumab (95% CI of mean difference, -3.2 to 2.7; P = 0.873). The 2-year results did not show any significant difference in mean central retinal thickness, with a decrease of -113 MUm for bevacizumab and -122 MUm for ranibizumab (95% CI of mean difference, -32 to 15; P = 0.476). There was a statistically significant difference between the drugs regarding the number of treatments given, with 18.2 injections for bevacizumab and 16.0 injections for ranibizumab (95% CI of mean difference, -3.4 to -1.0; P <= 0.001). The number of serious adverse events was similar between the groups over the course of the study. CONCLUSIONS: At 2 years, bevacizumab and ranibizumab had an equivalent effect on visual acuity and reduction of central retinal thickness when administered according to a treat-and-extend protocol for nAMD. There was no significant difference in the number of serious adverse events between the treatment groups. PMID- 26477843 TI - Intravitreal Bevacizumab Versus Ranibizumab for Treatment of Neovascular Age Related Macular Degeneration: Findings from a Cochrane Systematic Review. AB - TOPIC: To summarize the relative effects of bevacizumab (Avastin; Genentech, Inc, South San Francisco, CA) and ranibizumab (Lucentis; Genentech, Inc.), using findings from a Cochrane Eyes and Vision Group systematic review. CLINICAL RELEVANCE: Neovascular age-related macular degeneration (NVAMD) is the most common cause of uncorrectable vision loss among the elderly in developed countries. Bevacizumab and ranibizumab are the most frequently used anti-vascular endothelial growth factor (VEGF) agents injected intravitreally to treat NVAMD. METHODS: For this systematic review, we included only randomized controlled trials in which the 2 anti-VEGF agents had been compared directly. The primary outcome was 1-year gain in best-corrected visual acuity (BCVA) of >=15 letters. We followed Cochrane methods for trial selection, data extraction, and data analyses. Relative effects of bevacizumab versus ranibizumab are presented as estimated risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: We identified 6 eligible randomized controlled trials with 2809 participants. The proportion of eyes that gained >=15 letters of BCVA by 1 year was similar for the 2 agents when the same regimens were compared (RR, 0.90; 95% CI, 0.73-1.11). The mean change in BCVA from baseline also was similar (MD, -0.5 letter; 95% CI, -1.6 to +0.6). Other BCVA and quality of life outcomes were similar for the 2 agents. One-year treatment cost with ranibizumab was 5.1 and 25.5 times the cost for bevacizumab in the 2 largest trials. Ocular adverse events were uncommon (<1%), and rates were similar for the 2 agents. CONCLUSIONS: We found no important difference in effectiveness or safety between bevacizumab and ranibizumab for NVAMD treatment, but there was a large cost difference. PMID- 26477844 TI - Episcleral Venous Fluid Wave Correlates with Trabectome Outcomes: Intraoperative Evaluation of the Trabecular Outflow Pathway. AB - PURPOSE: To determine whether the characteristics of an intraoperative episcleral venous fluid wave (EVFW), a potential indicator of trabecular outflow patency, correlates with Trabectome (NeoMedix Corp, Tustin, CA) outcomes. DESIGN: Retrospective, observational study. PARTICIPANTS: A total of 68 eyes of 49 patients with glaucoma who underwent phaco-Trabectome (63 eyes) or Trabectome alone (5 eyes). METHODS: The EVFW was evaluated in a masked fashion for wave degree (0-4) and clock hours (0-6). A diffuse EVFW (4, 5, 6 clock hours) was a near complete blanching of the episcleral vasculature, and a poorly defined wave was minimal change in the vasculature. Patients were grouped into wave categories to determine whether there was a correlation with postoperative intraocular pressure (IOP). Patients requiring further glaucoma surgery were considered failures. MAIN OUTCOME MEASURES: Degree and extent of EVFW, IOP, and glaucoma medications. RESULTS: For all eyes, there was a statistically significant correlation between wave clock hours and postoperative IOP at month 1 (P = 0.043) and month 3 (P = 0.002), but not a statistically significant correlation at month 6 (P = 0.12) or 1 year (P = 0.86). A strong correlation was found among IOP, medications, and EVFW in eyes with an extensive EVFW when compared with eyes with a poorly defined EVFW. At 12 months, the mean IOP in the extensive EVFW group was 13.3+/-2.7 mmHg on 1.4+/-1.2 medications compared with an IOP of 18.4+/-3.1 mmHg on 2.9+/-0.9 medications in the poorly defined group (both P = 0.001). Overall, 5 of 68 eyes (7%), required further glaucoma surgery. Eyes with a poorly defined EVFW had a higher likelihood of further glaucoma surgery (36%). CONCLUSIONS: The EVFW is an intraoperative gauge of patency through the trabecular outflow pathway. Absence of the EVFW implies obstruction in the collector channel intrascleral aqueous outflow pathway, preventing flow to the visible episcleral veins. In contrast, eyes with a diffuse EVFW had sufficient flow through their collector channels, had a lower IOP, required fewer glaucoma medications, and had a lower requirement for further glaucoma surgery. The characteristics of an EFVW may be able to predict surgical outcomes after Trabectome surgery. PMID- 26477845 TI - Structure and Morphology of Radial Retinal Folds with Familial Exudative Vitreoretinopathy. PMID- 26477846 TI - Combined Persistent Fetal Vasculature: A Classification Based on High-Resolution B-Mode Ultrasound and Color Doppler Imaging. AB - PURPOSE: The purpose of this study was to classify combined persistent fetal vasculature (PFV) on the basis of the ultrasonographic and Doppler characteristics. The potential clinical significance for both surgery design and prognosis determination was discussed. DESIGN: A cross-sectional case series. PARTICIPANTS: The eyes of 54 children diagnosed with unilateral combined PFV were evaluated using B-mode ultrasound and color Doppler imaging (CDI). METHODS: Each participant's age at first presentation, diagnosis for referral, gender, family history, and systemic or other ocular anomalies were recorded. Retinal detachment, optic nerve abnormalities, and macular dislocation were also recorded in detail according to the RetCam (Clarity Medical Systems, Pleasanton, CA), ultrasound, and Doppler findings. The PFV eyes were divided into 4 groups on the basis of the ultrasound and CDI findings. Intergroup analysis was performed. MAIN OUTCOME MEASURES: Overall and intergroup analyses of the demographic features of the children with PFV were performed. The axial length, depth of the anterior chamber, and lens thickness were compared between the affected eyes and the fellow healthy eyes among the 4 groups. RESULTS: Some 22.2%, 18.5%, 33.3%, and 25.9% of the eyes were grouped into type I ("I" shape), II ("Y" shape), III (inverted "Y" shape), and IV ("X" shape) combined PFV, respectively. The age at first presentation for type I was older than that for the other groups (P = 0.014). The axial length was reduced (P = 0.012) and the anterior chamber more shallow (P = 0.011) than in fellow healthy eyes for type IV eyes, but not for the other 3 groups. CONCLUSIONS: Ultrasound and CDI are informative screening and diagnostic tools that show characteristic flow patterns in the 4 types of combined PFV. This novel classification system provides new and important information for the diagnosis of PFV and, if validated, may play a role in guiding treatment recommendations in the future. PMID- 26477847 TI - Phenology and host preferences Phlebotomus perniciosus (Diptera: Phlebotominae) in a focus of Toscana virus (TOSV) in South of France. AB - This paper reports on an entomological survey performed over the period 2009-2011 in endemic focus of peri-urban TOSV in South of France located from 24km east of Marseille. Sand flies were captured using CDC light traps set in sand fly resting places overnight, and temperature, relative humidity and wind were recorded to establish possible relations between meteorological factors and vector densities. The most common species, of 5,432 specimens collected and identified, was Phlebotomus perniciosus (74%), followed by Sergentomyia minuta (6%) and Phlebotomus ariasi (1%). Male flies were highly predominant for all Larroussius species instead of S. minuta which counted (85%) of females. The results shed light on the wide population's dynamic of P. perniciosus in France showing a diphasic seasonal trend with two abundance peaks at the beginning of July and late August, when a mean temperature is from 23.3 to 25.7 degrees C. Interestingly, these two peaks are corresponding to the peaks of occurrence of human TOSV cases. Among the 1724 females collected, 549 (32%) were blood-fed. Based on the results of blood meal analyses, P. perniciosus fed on large animal's diversity (man, chicken, rabbit, others mammalians, etc.), including bats that are the only species found naturally infected by TOSV. Results indicate that host choice was probably related to its availability than specific attractiveness. Data presented confirm that sand flies easily adapted to the periurban sites like, P. perniciosus may represent a public health concern for pathogen transmission in similar Mediterranean environments. PMID- 26477848 TI - Venom from Opisthacanthus elatus scorpion of Colombia, could be more hemolytic and less neurotoxic than thought. AB - We report the first biochemical, biological, pharmacological and partial proteomic characterization studies of the Opisthancanthus elatus venom (Gervais, 1844) from Colombia. The Reverse Phase High-Performance Liquid Chromatography venom profile showed 28 main well-defined peaks, most eluting between 20 and 45min (18-30% of acetonitrile, respectively). High-resolution mass analysis indicates the presence of 106 components ranging from 806.59742Da to 16849.4139Da. O. elatus venom showed hemolytic activity and hydrolyzed the specific substrate BapNa suggesting the presence of proteins with serine-protease activity. Collected RP-HPLC fractions eluting at 52.6, 55.5, 55.8, 56.2, and 63.9min (PLA2 region between 33 and 40% of acetonitrile), showed hemolytic activity and hydrolyzed the synthetic substrate 4-nitro-3-octanoyloxy-benzoic acid, indicating the presence of compounds with phospholipases A2 activity. These RP-HPLC fractions, showed molecular masses values up to 13978.19546Da, corroborating the possible presence of the mentioned enzymes. Tryptic digestion and MS/MS analysis showed the presence of a phospholipase like fragment, similar to on described in other Opisthacanthus genus studies. No coagulant activity was observed. No larvicidal or antimicrobial activity was observed at concentrations evaluated. Lethal and toxic activity is expected at doses above 100mg/kg, no neurotoxic effects were detected at lower doses. In conclusion, O. elatus exhibits a venom with a predominant phospholipase A2 activity than thought; mammal's neurotoxic activity is expected above the 100mg/kg, which is very high compared to the venom from other neurotoxic scorpions. PMID- 26477849 TI - Characterization of asymptomatic Plasmodium falciparum infection and its risk factors in pregnant women from the Republic of Congo. AB - Malaria in pregnancy remains a serious public health problem in the Republic of Congo despite the implementation of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) in 2006. The aim of this cross-sectional study was to characterize Plasmodium falciparum infections and determine possible risk factors in pregnant Congolese women attending an antenatal clinic in a periurban area of southern Brazzaville. This study was conducted from March 2012 to December 2013 in a site where several years ago, high malaria resistance to SP was reported. Pregnant women were enrolled during antenatal visits and the number of received IPTp-SP doses was recorded as well as individual sociodemographic data. Peripheral blood was collected and P. falciparum infection was checked by microscopy and by PCR targeting P. falciparum merozoite surface protein gene (msp2). Haemoglobin concentration was measured and P. falciparum positive samples were typed for msp2 allelic diversity. A total of 363 pregnant women were recruited. The prevalence of asymptomatic P. falciparum infection was 7% and 19% by microscopy and by PCR, respectively. More than one half (51.5%) of the pregnant women were anaemic. Multivariate analysis indicated that P. falciparum infection was associated with anaemia. It was also observed that women who have received IPTp-SP have significantly lower prevalence of infection. The administration of IPTp-SP did not influence the multiplicity of infection (MOI). This first study investigating asymptomatic malaria infection on pregnant women of the Republic of Congo shows that P. falciparum infections were clearly associated with maternal anaemia, and use of IPTp-SP reduced the risk of carrying asymptomatic infections. PMID- 26477850 TI - Novel method for immunofluorescence staining of mammalian eggs using non-contact alternating-current electric-field mixing of microdroplets. AB - Recently, a new technique was developed for non-catalytically mixing microdroplets. In this method, an alternating-current (AC) electric field is used to promote the antigen-antibody reaction within the microdroplet. Previously, this technique has only been applied to histological examinations of flat structures, such as surgical specimens. In this study, we applied this technique for the first time to immunofluorescence staining of three-dimensional structures, specifically, mammalian eggs. We diluted an antibody against microtubules from 1:1,000 to 1:16,000, and compared the chromatic degree and extent of fading across dilutions. In addition, we varied the frequency of AC electric-field mixing from 5 Hz to 46 Hz and evaluated the effect on microtubule staining. Microtubules were more strongly stained after AC electric-field mixing for only 5 minutes, even when the concentration of primary antibody was 10 times lower than in conventional methods. AC electric-field mixing also alleviated microtubule fading. At all frequencies tested, AC electric-field mixing resulted in stronger microtubule staining than in controls. There was no clear difference in a microtubule staining between frequencies. These results suggest that the novel method could reduce antibody consumption and shorten immunofluorescence staining time. PMID- 26477851 TI - Seasonal Expression of Prolactin Receptor in the Scented Gland of Male Muskrat (Ondatra zibethicus). AB - Prolactin (PRL) has numerous actions in mammalian biological systems including mammary development and biological processes. The aim of this study was to investigate the seasonal changes of prolactin receptor (PRLR) expression in the scented gland of muskrat during the breeding and nonbreeding seasons. Histologically, glandular cells, interstitial cells and excretory tubules were identified in the scented glands in both seasons, whereas epithelial cells were sparse in the nonbreeding season. PRLR was observed in glandular cells of scented glands during the breeding and nonbreeding seasons with stronger immunostaining during the breeding season. Consistent with the immunohistochemical results, both the mean of protein and mRNA levels of PRLR were higher in the scented glands of the breeding season, and relatively lower level in the nonbreeding season. In addition, differential seasonal changes were also detected in the expression profile of microRNAs (miRNAs) in the scented gland of muskrat. Besides, plasma PRL concentration was remarkably higher in the breeding season than that in the nonbreeding season. These results suggested that muskrat scented gland was the direct target organ of PRL, and stronger expression of PRLR in scented glands during the breeding season indicated that PRL may directly regulate scented glandular function of the muskrats. PMID- 26477852 TI - Accumulation of small protein molecules in a macroscopic complex coacervate. AB - To obtain insight into the accumulation of proteins into macroscopic complex coacervate phases, the lysozyme concentration in complex coacervates containing the cationic polyelectrolyte poly-(N,N dimethylaminoethyl methacrylate) and the anionic polyelectrolyte polyacrylic acid was investigated as a function of the mixing ratio, protein concentration and ionic strength. Maximal protein enrichment of the complex coacervate phase was observed to require the presence of all three macromolecules. Under optimized conditions the protein concentrations in the complex coacervate were as high as 200 g L(-1). Such high concentrations are comparable to the protein concentration in the cytosol, suggesting that these interesting liquid phases may serve a suitable model system for the phase behavior of the cytosol and genesis and function of membrane-less organelles. The high stability of the complexes and the salt dependent uptake of protein suggest that complex coacervates may provide a way to store hydrated proteins at high concentrations and might therefore be of interest in the formulation of high protein foods. PMID- 26477853 TI - Negotiating health and life: Syrian refugees and the politics of access in Lebanon. AB - In the context of ongoing armed conflicts in Libya, Syria, Yemen, and Iraq, it is vital to foster nuanced understandings of the relationship between health, violence, and everyday life in the Middle East and North Africa. In this article, we explore how healthcare access interacts with humanitarian bureaucracy and refugees' daily experiences of exile. What are the stakes involved with accessing clinical services in humanitarian situations? How do local conditions structure access to healthcare? Building on the concept of "therapeutic geographies," we argue for the integration of local socio-political context and situated knowledge into understandings of humanitarian healthcare systems. Using evidence gathered from participant observation among Syrian and Palestinian refugees in Lebanon, we demonstrate how procedures developed to facilitate care-such as refugee registration and insurance contracting-can interact with other factors to simultaneously prevent and/or disincentivize refugees' accessing healthcare services and expose them to structural violence. Drawing on two interconnected ethnographic encounters in a Palestinian refugee camp and in a Lebanese public hospital, we demonstrate how interactions surrounding the clinical encounter reveal the social, political, and logistical complexities of healthcare access. Moreover, rather than hospital visits representing discrete encounters with the Lebanese state, we contend that they reveal important moments in an ongoing process of negotiation and navigation within and through the constraints and uncertainties that shape refugee life. As a result, we advocate for the incorporation of situated forms of knowledge into humanitarian healthcare practices and the development of an understanding of healthcare access as nested in the larger experience of everyday refugee life. PMID- 26477854 TI - The impact of neighborhood disorganization on neighborhood exposure to violence, trauma symptoms, and social relationships among at-risk youth. AB - Previous research has demonstrated that exposure to violence (ETV) is a serious concern across the north-south socioeconomic divide. While studies have found that social support is a protective factor for youth exposed to violence and trauma, little is known about the impact of trauma symptoms on forming and maintaining social relationships which are key to accessing a vital social resource that fosters resilience in youth experiencing trauma symptomatology. Building on previous models that examine the impact of neighborhoods on exposure to violence and trauma, the current study examines the impact of neighborhood disorganization on ETV among youth and ETV's effects on trauma symptoms and social relationships. Data were collected on 2242 juvenile justice-involved youth with behavioral health issues in 11 urban and rural counties in the Midwestern United States. Using structural equation modeling (SEM), our data demonstrated that living in highly disorganized neighborhoods was associated with higher levels of ETV and that ETV was positively associated with trauma symptoms. Mediational analysis showed that trauma symptoms strongly mediated the effect of ETV on social relationships. Freely estimating structural paths by gender revealed that hypothesized associations between these variables were stronger for females than males. Findings here highlight the need to provide trauma-informed care to help youth to build and maintain social relationships. Identification and treatment of trauma symptoms that is culturally informed is a critical first step in ensuring that identified protective factors in local contexts, such as social relations and social support, have opportunities to minimize the impact of ETV among youth across northern and southern nations. PMID- 26477855 TI - Long-bone fracture detection in digital X-ray images based on digital-geometric techniques. AB - Automated fracture detection is an essential part of a computer-aided tele medicine system. In this paper, we have proposed a unified technique for the detection and evaluation of orthopaedic fractures in long-bone digital X-ray image. We have also developed a software tool that can be conveniently used by paramedics or specialist doctors. The proposed tool first segments the bone region of an input digital X-ray image from its surrounding flesh region and then generates the bone-contour using an adaptive thresholding approach. Next, it performs unsupervised correction of bone-contour discontinuities that might have been generated because of segmentation errors, and finally detects the presence of fracture in the bone. Moreover, the method can also localize the line-of-break for easy visualization of the fracture, identify its orientation, and assess the extent of damage in the bone. Several concepts from digital geometry such as relaxed straightness and concavity index are utilized to correct contour imperfections, and to detect fracture locations and type. Experiments on a database of several long-bone digital X-ray images show satisfactory results. PMID- 26477856 TI - Going far beyond the near-field diffraction limit via plasmonic cavity lens with high spatial frequency spectrum off-axis illumination. AB - For near-field imaging optics, minimum resolvable feature size is highly constrained by the near-field diffraction limit associated with the illumination light wavelength and the air distance between the imaging devices and objects. In this study, a plasmonic cavity lens composed of Ag-photoresist-Ag form incorporating high spatial frequency spectrum off-axis illumination (OAI) is proposed to realize deep subwavelength imaging far beyond the near-field diffraction limit. This approach benefits from the resonance effect of the plasmonic cavity lens and the wavevector shifting behavior via OAI, which remarkably enhances the object's subwavelength information and damps negative imaging contribution from the longitudinal electric field component in imaging region. Experimental images of well resolved 60-nm half-pitch patterns under 365 nm ultra-violet light are demonstrated at air distance of 80 nm between the mask patterns and plasmonic cavity lens, approximately four-fold longer than that in the conventional near-field lithography and superlens scheme. The ultimate air distance for the 60-nm half-pitch object could be theoretically extended to 120 nm. Moreover, two-dimensional L-shape patterns and deep subwavelength patterns are illustrated via simulations and experiments. This study promises the significant potential to make plasmonic lithography as a practical, cost effective, simple and parallel nano-fabrication approach. PMID- 26477857 TI - The interactions between TiO2 and graphene with surface inhomogeneity determined using density functional theory. AB - TiO2/graphene composites have shown promise as photocatalysts, leading to improved electronic properties. We have modeled using density functional theory TiO2/graphene interfaces formed between graphene with various defects/functional groups (C vacancy, epoxide, and hydroxyl) and TiO2 clusters of various sizes. We considered clusters from 3 to 45 atoms, the latter a nanoparticle of ~1 nm in size. Our results show that binding to pristine graphene is dominated by van der Waals forces, and that C vacancies or epoxide groups lead to much stronger binding between the graphene and TiO2. Such sites may serve to anchor TiO2 to graphene. Graphene surfaces with hydroxyls however lead to OH transfer to TiO2 and weak interactions between the graphene and the hydroxylated TiO2 cluster. Charge transfer may occur between TiO2 and graphene in various directions (graphene to TiO2 or TiO2 to graphene), depending on the state of the graphene surface, based on overlap of the density of states. Our work indicates that graphene surface defects or functional groups may have a significant effect on the stability, structure, and photoactivity of these materials. PMID- 26477858 TI - Raman/fluorescence dual-sensing and imaging of intracellular pH distribution. AB - Herein, a pH-sensitive probe has been designed based on DNA modified gold nanoparticles (AuNPs) for Raman/fluorescence dual-imaging of the intracellular pH distribution. In the acidic environment of cancer cells, the configuration change of DNA on the probe surface could turn "on" Raman/fluorescence signals simultaneously. PMID- 26477859 TI - Counter-ligand control of the electronic structure in dinuclear copper tetrakisguanidine complexes. AB - The redox-active GFA (Guanidino-Functionalized Aromatic compound) 1,4,5,8 tetrakis(tetramethylguanidino)-naphthalene (6) is used to synthesize new dinuclear copper complexes of the formula [6(CuX2)2] with different electronic structures. With X = OAc, a dinuclear Cu(II) complex of the neutral GFA is obtained (electronic structure [Cu(II)-GFA-Cu(II)], two unpaired electrons), and with X = Br a diamagnetic dinuclear Cu(I) complex of the dicationic GFA (electronic structure [Cu(I)-GFA(2+)-Cu(I)], closed-shell singlet state). The different electronic structures lead to significant differences in the optical, structural and magnetic properties of the complexes. Furthermore, the complex [6(CuI)2](2+) (electronic structure [Cu(I)-GFA(2+)-Cu(I)], closed-shell singlet state) is synthesized by reaction of 6(2+) with two equivalents of CuI. Slow decomposition of this complex in solution leads to the fluorescent dye 2,7 bis(dimethylamino)-1,3,6,8-tetraazapyrene. In an improved synthesis of this tetraazapyrene, 6 is reacted with CuBr in the presence of dioxygen. Quantum chemical calculations show that the addition of counter-ligands to the trigonal planar Cu(I) atoms of [6(CuI)2](2+) favors or disfavors one of the electronic structures, depending on the nature of the counter-ligand. PMID- 26477860 TI - Design, synthesis and DNA interactions of a chimera between a platinum complex and an IHF mimicking peptide. AB - Conjugation of metal complexes with peptide scaffolds possessing high DNA binding affinity has shown to modulate their biological activities and to enhance their interaction with DNA. In this work, a platinum complex/peptide chimera was synthesized based on a model of the Integration Host Factor (IHF), an architectural protein possessing sequence specific DNA binding and bending abilities through its interaction with a minor groove. The model peptide consists of a cyclic unit resembling the minor grove binding subdomain of IHF, a positively charged lysine dendrimer for electrostatic interactions with the DNA phosphate backbone and a flexible glycine linker tethering the two units. A norvaline derived artificial amino acid was designed to contain a dimethylethylenediamine as a bidentate platinum chelating unit, and introduced into the IHF mimicking peptides. The interaction of the chimeric peptides with various DNA sequences was studied by utilizing the following experiments: thermal melting studies, agarose gel electrophoresis for plasmid DNA unwinding experiments, and native and denaturing gel electrophoresis to visualize non covalent and covalent peptide-DNA adducts, respectively. By incorporation of the platinum metal center within the model peptide mimicking IHF we have attempted to improve its specificity and DNA targeting ability, particularly towards those sequences containing adjacent guanine residues. PMID- 26477862 TI - Kinetic and thermodynamic characterization of C-N bond rotation by N methylacetohydroxamic acid in aqueous media. AB - Hydroxamic acids (HAs) perform tasks in medicine and industry that require bidentate metal binding. The two favored conformations of HAs are related by rotation around the C(=O)-N bond. The conformations are unequal in stability. Recently, we reported that the most stable conformation of a small secondary HA in water places the oxygen atoms anti to one another. The barrier to C-N bond rotation may therefore modulate metal binding by secondary HAs in aqueous media. We have now determined the activation barrier to C-N rotation from major to minor conformation of a small secondary HA in D2O to be 67.3 kJ/mol. The HA rotational barrier scales with solvent polarity, as is observed in amides, although the HA barrier is less than that of a comparable tertiary amide in aqueous solution. Successful design of new secondary HAs to perform specific tasks requires solid understanding of rules governing HA structural behavior. Results from this work provide a more complete foundation for HA design efforts. PMID- 26477861 TI - MiR-1271 Inhibits Ovarian Cancer Growth by Targeting Cyclin G1. AB - BACKGROUND: Ovarian cancer is the most lethal gynecological malignant cancer in the female genital system. The dysfunction of miRNA contributes to ovarian cancer development. MATERIAL AND METHODS: The miR-1271 level in ovarian cancer tissues and cells was assayed by qRT-PCR. The miR-1271 expression in cells was overexpressed by miRNA-mimic transfection and reduced by miRNA-antisense oligonucleotide (ASO) transfection. Cell proliferation was analyzed by an MTT assay. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The protein level was assayed by Western blotting. RESULTS: The ovarian cancer tissue and cell lines showed low levels of miR-1271. Low levels of miR-1271 in ovarian cancer tissues were correlated with a low rate of patient survival, and the overexpression of miR 1271 inhibited the proliferation of ovarian cancer cells. The 3' UTR of cyclin G1 (CCNG1) was targeted by miR-1271. CONCLUSIONS: Low levels of miR-1271 in ovarian cancer tissues promoted cancer cell growth. MiR-1271 may be a new predictor of prognosis in ovarian cancer. MiR-1271 exerted its role by targeting CCNG1. PMID- 26477863 TI - Homeowner and homebuyer impressions of visitable features. AB - BACKGROUND: Though visitable house features (32+" wide doors; no-step or low slope entries; and a usable half- or full bathroom on the main floor) have benefits, many developers and builders oppose them because they believe homebuyers do not want them. OBJECTIVE: The present study sought to test the accuracy of developer and builder perceived barriers to including visitable features in new houses. Specifically, we tested the desirability of houses with and without such features to homeowners and homebuyers. We hypothesized that homeowners and homebuyers would prefer to buy homes with visitable features even if they believed such homes would cost more. METHODS: In a cross-sectional study, we surveyed 96 homeowners and 107 homebuyers in Ohio. For photos of nine matched pairs of visitable and non-visitable features, respondents assessed home would sell faster, which they preferred to buy, and which had an older inhabitant. They also rated effects of each visitable feature on qualities that might affect the marketability of the home, such as good design, aesthetics, appeal to young, appeal to old, ease of hosting visitors, and resale value. RESULTS: Both homeowners and homebuyers preferred to buy houses with visitable features, thought they would sell faster, and rated each visitable feature as having favorable effects on the qualities, even though they expected houses with visitable feature to cost more and to house an older person or a person with difficulty walking. CONCLUSIONS: Contrary to developer and builder beliefs, homeowners and homebuyers may prefer houses with visitable features. PMID- 26477864 TI - Use of food and packaging model matrices to investigate the antioxidant properties of biorefinery grass lignins. AB - The antioxidant properties of grass lignins recovered from an alkaline industrial process and from different ethanol organosolv pretreatment processes were compared using two types of tests: (i) classical radical 2,2'-diphenyl-1 picrylhydrazyl (DPPH(*)) scavenging tests in dioxane/water or ethanol and (ii) tests involving multiphasic systems (lipid dispersion in water or cellulose film suspended in ethanol). These multiphasic systems were representative of food and packaging matrices in view of high-value applications. All lignins, in solution or in the film, effectively scavenged radicals. Moreover, they were competitive with a food commercial rosemary extract to protect linoleic acid against oxidation. Whereas the DPPH(*) test in dioxane was not discriminant, differences appeared between lignins when the test was performed in ethanol or with the multiphasic systems. Moreover, radical scavenging activity was preserved in the film even after its immersion in ethanol. Structural analysis of lignins revealed that low-molar-mass phenolics, namely p-hydroxycinnamic acids and lignin depolymerization products, governed lignin antioxidant properties in the multiphasic systems. PMID- 26477865 TI - Fat is the new normal. PMID- 26477866 TI - Cohort Analysis of a Pharmacokinetic-Modeled Methadone Weaning Optimization for Neonatal Abstinence Syndrome. AB - OBJECTIVE: To evaluate neonatal abstinence syndrome (NAS) treatment outcomes achieved using an optimized methadone weaning protocol developed using pharmacokinetic (PK) modeling compared with standard methadone weaning. STUDY DESIGN: This pre-post cohort study evaluated 360 infants who completed pharmacologic treatment for NAS with methadone as inpatients at 1 of 6 nurseries in southwest Ohio between January 2012 and March 2015. Infants were initially treated with a standard methadone weaning protocol (n = 267). Beginning in July 2014, infants were treated with a revised methadone weaning protocol developed using PK modeling (n = 93). Linear mixed models were used to calculate adjusted mean primary outcomes, including total duration of methadone treatment, total administered methadone dosage, and length of inpatient hospital stay, which were compared between weaning protocols. The use of adjunctive therapy for NAS treatment was examined as a secondary outcome. RESULTS: Infants who received NAS treatment with the revised protocol experienced a shorter duration of methadone treatment (13.1 vs 16.4 days; P < .001) and shorter duration of inpatient treatment (18.3 vs 21.7 days; P < .001) compared with infants receiving standard methadone weaning. No difference was observed in total methadone dosage administered (0.52 vs 0.52 mg/kg; P = .97) or in the use of adjunctive therapy (22.6% vs 25.5%; P = .68) between groups. CONCLUSION: Refinement of a standard methadone weaning protocol using PK modeling was associated with reduced duration of opioid weaning and shortened length of stay for pharmacologic treatment of NAS. PMID- 26477868 TI - A Cost-Effectiveness Analysis of a Pilot Neonatal Screening Program for Sickle Cell Anemia in the Republic of Angola. AB - OBJECTIVE: To assess the cost-effectiveness of a pilot newborn screening (NBS) and treatment program for sickle cell anemia (SCA) in Luanda, Angola. STUDY DESIGN: In July 2011, a pilot NBS and treatment program was implemented in Luanda, Angola. Infants identified with SCA were enrolled in a specialized SCA clinic in which they received preventive care and sickle cell education. In this analysis, the World Health Organization (WHO) and generalized cost-effectiveness analysis methods were used to estimate gross intervention costs of the NBS and treatment program. To determine healthy life-years (HLYs) gained by screening and treatment, we assumed NBS reduced mortality to that of the Angolan population during the first 5 years based upon WHO and Global Burden of Diseases Study 2010 estimates, but provided no significant survival benefit for children who survive through age 5 years. A secondary sensitivity analysis with more conservative estimates of mortality benefits also was performed. The costs of downstream medical costs, including acute care, were not included. RESULTS: Based upon the costs of screening 36,453 infants and treating the 236 infants with SCA followed after NBS in the pilot project, NBS and treatment program is projected to result in the gain of 452-1105 HLYs, depending upon the discounting rate and survival assumptions used. The corresponding estimated cost per HLY gained is $1380-$3565, less than the gross domestic product per capita in Angola. CONCLUSIONS: These data demonstrate that NBS and treatment for SCA appear to be highly cost effective across all scenarios for Angola by the WHO criteria. PMID- 26477867 TI - When Participants in Genomic Research Grow Up: Contact and Consent at the Age of Majority. PMID- 26477869 TI - Primary Care Providers' Initial Evaluation of Children with Global Developmental Delay: A Clinical Vignette Study. AB - OBJECTIVE: To examine the decisions of pediatric primary care physicians about their diagnostic evaluation for a child with suspected global developmental delay (GDD). STUDY DESIGN: A survey was mailed to a sample of pediatricians (n = 600) and family physicians (n = 600) randomly selected from the American Medical Association Physician Masterfile. The survey contained a clinical vignette describing a 9-month-old nondysmorphic boy with GDD. Participants were asked their initial evaluation steps (test, refer, or both test and refer) and what types of referral and/or testing they would pursue. We examined bivariate associations between physician/clinical practice characteristics and participants' evaluation decision. RESULTS: More pediatricians than family physicians completed the survey (response rates: 55% vs 38%). Almost three quarters of the respondents (74%) reported that their first step in a diagnostic evaluation would be to refer the child without testing, 22% would test only, and 4% would both test and refer. As their initial step, most physicians referred to a developmental pediatrician (58%), and only 5% would refer to a geneticist. The most commonly ordered test was general biochemical testing (64%). The most commonly ordered genetic test was a karyotype (39%). CONCLUSIONS: When evaluating a child with GDD, few primary care physicians would order genetic testing or refer to a genetics specialist as a first evaluation step. Future studies should examine both barriers to and utilization of a genetic evaluation for children with GDD. PMID- 26477870 TI - Association between Clinical Outcomes and Hospital Guidelines for Cerebrospinal Fluid Testing in Febrile Infants Aged 29-56 Days. AB - OBJECTIVE: To describe the association between clinical outcomes and clinical practice guidelines (CPGs) recommending universal cerebrospinal fluid (CSF) testing in the emergency department for febrile infants aged 29-56 days. STUDY DESIGN: Using 2007-2013 administrative data from 32 US children's hospitals, we performed a difference-in-differences analysis comparing 7 hospitals with CPGs recommending universal CSF testing for older febrile infants aged 29-56 days (CPG group) with 25 hospitals without such CPGs (control group). We compared differences in clinical outcomes between older febrile infants with the corresponding differences among younger febrile infants aged 7-28 days. The primary outcome was the occurrence of an adverse event, defined as a delayed diagnosis of bacterial meningitis, mechanical ventilation, placement of a central venous catheter, extracorporeal membrane oxygenation, or in-hospital mortality. Analyses were adjusted for race/ethnicity, sex, median annual household income by zip code, primary insurance source, discharge season, and discharge year. RESULTS: The proportion of older febrile infants undergoing CSF testing was higher (P < .001) in the CPG group (64.8%) than the control group (47.8%). CPGs recommending universal CSF testing for older febrile infants were not associated with significant differences in adverse events (difference-in-differences: +0.31 percentage points, 95% CI -0.18 to 0.85; P = .22). CONCLUSIONS: Hospital CPGs recommending universal CSF testing for febrile infants aged 29-56 days were not associated with significant differences in clinical outcomes. PMID- 26477871 TI - Potential Impact of a Validated Screening Tool for Pediatric Abusive Head Trauma. AB - OBJECTIVE: To conduct a retrospective, theoretical comparison of actual pediatric intensive care unit (PICU) screening for abusive head trauma (AHT) vs AHT screening guided by a previously validated 4-variable clinical prediction rule (CPR) in datasets used by the Pediatric Brain Injury Research Network to derive and validate the CPR. STUDY DESIGN: We calculated CPR-based estimates of abuse probability for all 500 patients in the datasets. Next, we demonstrated a positive and very strong correlation between these estimates of abuse probability and the overall diagnostic yields of our patients' completed skeletal surveys and retinal examinations. Having demonstrated this correlation, we applied mean estimates of abuse probability to predict additional, positive abuse evaluations among patients lacking skeletal survey and/or retinal examination. Finally, we used these predictions of additional, positive abuse evaluations to extrapolate and compare AHT detection (and 2 other measures of AHT screening accuracy) in actual PICU screening for AHT vs AHT screening guided by the CPR. RESULTS: Our results suggest that AHT screening guided by the CPR could theoretically increase AHT detection in PICU settings from 87%-96% (P < .001), and increase the overall diagnostic yield of completed abuse evaluations from 49%-56% (P = .058), while targeting slightly fewer, though not significantly less, children for abuse evaluation. CONCLUSIONS: Applied accurately and consistently, the recently validated, 4-variable CPR could theoretically improve the accuracy of AHT screening in PICU settings. PMID- 26477872 TI - Left Ventricular Myxoma. PMID- 26477873 TI - Prospective Surveillance of Extreme Neonatal Hyperbilirubinemia in Australia. AB - OBJECTIVES: To determine the incidence, causes, associated factors, and short term outcomes of extreme neonatal hyperbilirubinemia in Australia in order to identify opportunities for prevention. STUDY DESIGN: This was a prospective population-based surveillance study in collaboration with the Australian Pediatric Surveillance Unit between April 1, 2010, and March 31, 2013. Case definition was: infants >34 weeks gestation with a peak total serum bilirubin >=450 MUmol/L and or clinical evidence of bilirubin encephalopathy. Clinicians completed questionnaires detailing demographic and clinical data including: peak serum bilirubin, signs of bilirubin encephalopathy, etiology, associated pathology, management, and short-term outcomes. RESULTS: The questionnaire return rate was 95%, and 87 infants met the case definition. The Australian incidence of extreme neonatal hyperbilirubinemia is estimated to be 9.4/100,000 live births. Main etiologies were: idiopathic ABO blood group incompatibility, glucose-6 phosphate dehydrogenase deficiency, and Rhesus isoimmunization. There were no significant differences in short-term outcomes between inpatient and outpatient cases. Cases with a hemolytic etiology were significantly more likely to have extremely high levels of hyperbilirubinemia (P < .002). CONCLUSION: The incidence of extreme neonatal hyperbilirubinemia in Australia is comparable with previous studies. Robust pre- and post-discharge assessment and management strategies of neonatal hyperbilirubinemia are essential to prevent neurodisability. Universal glucose-6-phosphate dehydrogenase screening and serial bilirubin monitoring may optimize preventative strategies. PMID- 26477874 TI - HIV-related stigma experiences: Understanding gender disparities in Thailand. AB - This paper assesses the relationship between gender and HIV-related stigma experiences among people living with HIV (PLHIV) - enacted and anticipated stigma - and PLHIV caregivers - courtesy stigma - in Northern Thailand, along with the underlying reasons for stigmatising attitudes towards PLHIV - instrumental and symbolic stigma - expressed in the general population. We used data from the Living With Antiretrovirals (LIWA) study conducted on all PLHIV receiving antiretroviral treatment in four district hospitals in Northern Thailand (n = 513) and on a community sample of adults from the general population (n = 500). Women living with HIV and female caregivers of PLHIV reported higher rates of HIV related stigma experiences than men. Gender interacted with other predictors - the period of HIV diagnosis and age - to increase the level of stigma experienced. Among the general population, attitudes of contact avoidance were infrequent. However, stereotypes depicting PLHIV as blameworthy were highly pervasive, with women perceived as the "victims" of their spouse's irresponsible sexual behaviours. In this context, women were yet more often subjected to HIV related stigma than men, in particular women diagnosed in the pre-antiretroviral therapy era and younger female caregivers. The role of gender in shaping disparities in HIV-related stigma experiences is discussed. PMID- 26477875 TI - Optimizing isothermal titration calorimetry protocols for the study of 1:1 binding: Keeping it simple. AB - BACKGROUND: Successful ITC experiments require conversion of cell reagent (titrand M) to product and production or consumption of heat. These conditions are quantified for 1:1 binding, M+X <=> MX. METHODS: Nonlinear least squares is used in error-propagation mode to predict the precisions with which the key quantities - binding constant K, reaction enthalpy DeltaH degrees , and stoichiometry number n - can be estimated over a wide range of the dimensionless quantity that governs isotherm shape, c=K[M]0. The measurement precision sigmaq is estimated from analysis of water-water blanks. RESULTS: When the product conversion exceeds 90%, the parameter relative standard errors are proportional to sigmaq/qtot, where the total heat qtot ~ DeltaH degrees [M]0V0. Specifically, sigmaK/K*qtot/sigmaq ~ 25 for c=10(-3)-10, ~ 11 c(1/3) for c=10-10(4). For c>1, n and DeltaH degrees are more precise than K; this holds also at smaller c for the product n*DeltaH degrees and for DeltaH degrees when n can be held fixed. Use of as few as 10 titrant injections can outperform the customary 20-40 while also improving productivity. CONCLUSION: These principles are illustrated in experiment design using the program ITC-PLANNER15. GENERAL SIGNIFICANCE: Simple quantitative guidelines replace the "c rules" that have dominated the literature for decades. PMID- 26477876 TI - Locard's Principle of Exchange, Dental Examination and Fragments of Skin. AB - The transfer of materials between victim and perpetrator was first reported by Locard in the nineteenth century. While in recent years DNA testing has been very successful in matching biological material from crime scenes to perpetrators, the following cases demonstrate that other more time-honored methods remain useful. Two cases of lethal assault are reported where the victims had bitten their assailants resulting in fragments of the perpetrators' skin being wedged between their teeth which were discovered during post mortem oral examinations. As the fragments were able to be matched to injuries in the perpetrators, identification was established prior to confirmatory DNA testing. In case 1 a criminal conviction for manslaughter resulted, and in case 2 the identity of the assailant was confirmed. Examination of a properly exposed and illuminated oral cavity may provide useful evidence in assault cases. These cases represent an unusual dental variant of Locard's principle. PMID- 26477877 TI - The long-term risk of upper-extremity lymphedema is two-fold higher in breast cancer patients than in melanoma patients. AB - BACKGROUND AND OBJECTIVES: We assessed the cumulative incidence, symptoms, and risk factors for upper-extremity lymphedema in breast cancer and melanoma patients undergoing sentinel lymph node biopsy or axillary lymph node dissection. METHODS: Patients were recruited preoperatively (time 0) and assessed at 6, 12, and 18 months postoperatively. Limb volume change (LVC) was measured by perometry. Lymphedema was categorized as none, mild (LVC 5-9.9%), or moderate/severe (LVC>=10%). Symptoms were assessed with a validated lymphedema instrument. Longitudinal logistic regression analyses were conducted to identify risk factors associated with moderate/severe lymphedema. RESULTS: Among 205 breast cancer and 144 melanoma patients, the cumulative incidence of moderate/severe lymphedema at 18 months was 36.5% and 35.0%, respectively. However, in adjusted analyses, factors associated with moderate/severe lymphedema were breast cancer (OR 2.0, P = 0.03), body mass index >= 30 kg/m(2) (OR 1.6, P = 0.04), greater number of lymph nodes removed (OR 1.05, P < 0.01), and longer interval since surgery (OR 2.33 at 18 months, P < 0.01). CONCLUSIONS: Lymphedema incidence increased over time in both cohorts. However, the adjusted risk of moderate/severe lymphedema was two-fold higher in breast cancer patients. These results may be attributed to surgical treatment of the primary tumor in the breast and more frequent use of radiation. PMID- 26477879 TI - In Vitro and In Vivo Anti-Melanoma Effects of Pituranthos tortuosus Essential Oil Via Inhibition of FAK and Src Activities. AB - A large number of plants used in traditional medicines have been shown to possess antitumor activities. The aims of this study were to evaluate any anticancer effect of the essential oil (EO) extracted from P. tortuosus against B16F10 melanoma cancer cells in vitro as well as in vivo. In vitro, EO was shown to induce apoptosis and to inhibit migration and invasion processes. Further investigation revealed that EO decreased focal adhesion and invadopodia formation which was accompanied by a drastic downregulation of FAK, Src, ERK, p130Cas and paxillin. Moreover, EO treatment decreased the expression level of p190RhoGAP, and Grb2, which impair cell migration and actin assembly. Mice bearing the melanoma cells were used to confirm any in vivo effectiveness of the EO as an anti-tumor promoting agent. In mice dosed with 100 mg EO/kg/d (for 27 days), tumor weight was inhibited by 98% compared to that in mice that did not receive the product. In conclusion, these data suggested to us that an EO of P. tortuosus could evolve to be a potential medicinal resource for use in the treatment of cancers. PMID- 26477878 TI - Indirect consequences of extreme weather and climate events and their associations with physical health in coastal Bangladesh: a cross-sectional study. AB - BACKGROUND: Bangladesh is one of the countries in the world which is most prone to natural disasters. The overall situation is expected to worsen, since extreme weather and climate events (EWCE) are likely to increase in both frequency and intensity. Indirect consequences caused in the events' aftermath widen the range of possible adverse health outcomes. OBJECTIVE: To assess the association of indirect consequences of EWCE and physical health. DESIGN: We used recent cross sectional self-reported data from 16 coastal villages in Bangladesh. A total of 980 households were surveyed using a structured questionnaire. The outcome of physical health was categorized into three groups, reflecting the severity of reported diseases by the respective source of treatment as a proxy variable (hospital/clinic for severe disease, other source/no treatment for moderate disease, and no disease). The final statistical analysis was conducted using multinomial logistic regression. RESULTS: Severe diseases were significantly associated with drinking water from open sources [odds ratio (OR): 4.26, 95% confidence interval (CI): 2.25-8.09] and tube wells (OR: 2.39, 95% CI: 1.43 4.01), moderate harm by river erosion (OR: 6.24, 95% CI: 2.76-14.11), food scarcity (OR: 1.98, 95% CI: 1.16-3.40), and the perception of increased employment problems (OR: 2.19, 95% CI: 1.18-4.07). Moderate diseases were significantly associated with moderate harm by river erosion (OR: 2.65, 95% CI: 1.28-5.48) and fully experienced food scarcity (OR: 1.75, 95% CI: 1.16-2.63). For both categories, women and the elderly had higher chances for diseases. CONCLUSIONS: Indirect consequences of EWCE were found to be associated with adverse health outcomes. Basic needs such as drinking water, food production, and employment opportunities are particularly likely to become threatened by EWCE and, thus, may lead to a higher likelihood of ill-health. Intervention strategies should concentrate on protection and provision of basic needs such as safe drinking water and food in the aftermath of an event. PMID- 26477880 TI - Comparison of outcomes between minimally invasive oesophagectomy and open oesophagectomy for oesophageal cancer. AB - BACKGROUND: A systematic review with meta-analysis was performed to compare perioperative outcomes between minimally invasive oesophagectomy (MIE) and open oesophagectomy (OE). METHODS: PubMed and Cochrane databases were searched up to January 2015 using keywords: esophageal cancer, MIE, OE, hybrid MIE. Randomized controlled trials or prospective studies comparing the efficacy of OE with MIE or hybrid MIE in oesophageal cancer patients were included. Sensitivity analysis and quality assessment were performed. RESULTS: MIE required longer operation time (pooled standardized difference in means = 0.565; 95% confidence interval (CI) = 0.272, 0.858; P < 0.001) than OE, but resulted in less blood loss, shorter hospital stays, lower incidence of pneumonia and vocal cord palsy (P values <=0.026). There was no difference between MIE and OE regarding lymph node yield (pooled standardized difference in means = 0.078; 95% CI = -0.111, 0.267; P = 0.419). Length of intensive care unit stay, in-hospital mortality and 30-day mortality were also similar (P values >=0.419) in both groups. CONCLUSIONS: Regarding certain clinical outcomes, MIE may be more beneficial than OE. PMID- 26477882 TI - Characterization of a Mixture of CO2 Adsorption Products in Hyperbranched Aminosilica Adsorbents by (13)C Solid-State NMR. AB - Hyperbranched amine polymers (HAS) grown from the mesoporous silica SBA-15 (hereafter "SBA-15-HAS") exhibit large capacities for CO2 adsorption. We have used static in situ and magic-angle spinning (MAS) ex situ (13)C nuclear magnetic resonance (NMR) to examine the adsorption of CO2 by SBA-15-HAS. (13)C NMR distinguishes the signal of gas-phase (13)CO2 from that of the chemisorbed species. HAS polymers possess primary, secondary, and tertiary amines, leading to multiple chemisorption reaction outcomes, including carbamate (RnNCOO(-)), carbamic acid (RnNCOOH), and bicarbonate (HCO3(-)) moieties. Carbamates and bicarbonate fall within a small (13)C chemical shift range (162-166 ppm), and a mixture was observed including carbamic acid and carbamate, the former disappearing upon evacuation of the sample. By examining the (13)C-(14)N dipolar coupling through low-field (B0 = 3 T) (13)C{(1)H} cross-polarization MAS NMR, carbamate is confirmed through splitting of the (13)C resonance. A third species that is either bicarbonate or a second carbamate is evident from bimodal T2 decay times of the ~163 ppm peak, indicating the presence of two species comprising that single resonance. The mixture of products suggests that (1) the presence of amines and water leads to bicarbonate being present and/or (2) the multiple types of amine sites in HAS permit formation of chemically distinct carbamates. PMID- 26477881 TI - Hepatitis C virus seroprevalence in adults in Africa: a systematic review and meta-analysis. AB - With the introduction of more efficient treatments for hepatitis C virus (HCV), improved epidemiological information is required at the country level to allow evidence-based policymaking for elaboration of national strategies and HCV resources planning. We present a systematic review with meta-analysis of HCV seroprevalence data in adults in African countries. We conducted a systematic review of all HCV seroprevalence estimates reported in African countries from 2000 to 2014 in MEDLINE, AJOL and grey literature. We assessed studies performed in the general population and among blood donors, pregnant women and HIV-positive patients. A meta-regression analysis was used to provide adjusted estimates of HCV seroprevalence in the general adult population in each country, accounting for the heterogeneity in sample age structure and population types in the included studies. We identified 775 national-level estimations, among which 184 were included. Estimates of HCV seroprevalence were produced for 38 countries, in addition to the results from nationwide representative surveys available in Egypt and Libya. Next to Egypt, which clearly stands out, the highest levels of seroprevalence were found in Middle Africa (e.g. Cameroon, Gabon and Angola) and some West African countries (e.g. Burkina Faso, Benin), and the largest absolute numbers of infected adults were found in Nigeria, Ethiopia and Democratic Republic of Congo. This study exposes the diversity of HCV epidemiology among African countries. Egypt and several countries of West and Middle Africa present a HCV burden that will require strong governmental commitment to promote efficient preventive and curative interventions. PMID- 26477883 TI - Clinical and scientific perspectives on movement disorders: Stanley Fahn's contributions. AB - Dr. Stanley Fahn, the H. Houston Merritt Professor of Neurology and Director Emeritus of the Center for Parkinson's Disease and Other Movement Disorders at Columbia University, one of the founders of the field of movement disorders, was the first president of the Movement Disorders Society (subsequently renamed as the International Parkinson and Movement Disorder Society). Together with his friend and colleague, Professor David Marsden, he also served as the first co editor of the journal Movement Disorders. By emphasizing phenomenology as the key element in differentiating various hypokinetic and hyperkinetic movement disorders, Dr. Fahn drew attention to the clinical history and the power of observation in the diagnosis of movement disorders. Dr. Fahn had major influence on the development of classifications and assessments of various movement disorders and in organizing various research groups such as the Parkinson Study Group. As the founder and president of the World Parkinson Coalition and an organizer of the initial three World Parkinson Congresses, he has demonstrated his long-standing commitment to the cause of including patients as partners. The primary goal and objective of this invited review is to highlight some of Dr. Fahn's most impactful scientific and clinical contributions to the understanding and treatment of Parkinson's disease, dystonia, and other movement disorders. PMID- 26477884 TI - Comparison of the effect of MTAD and conventional irrigation agents on apical leakage and push-out bond strength of root canal filling. AB - The aim of this study was to evaluate the effect of MTAD (a mixture of tetracycline isomer, an acid, and a detergent) and conventional irrigation agents on the apical leakage and push-out bond strength of root canal filling and to correlate the apical leakage and push-out bond strength. Root canals of 120 maxillary central incisors were prepared with a ProTaper file up to F3 and distributed to six groups. Saline, 1% NaOCl, 17% EDTA, 17% EDTA/1% NaOCl, and 2% chlorhexidine (CHX) solutions were used between each file change, and 5 mL of the same irrigating solution was used for the final flush. In the MTAD group, the root canals were irrigated with 1.3% NaOCl between each file and 5 mL of MTAD for the final flush. All the root canals were filled with AH Plus sealer and gutta percha cones. Apical leakage was evaluated using a fluid transport system. After the apical leakage test, each tooth was prepared for the push-out assessment. The statistical analysis revealed that the irrigation solutions had no effect on the apical leakage of the root canal fillings (p = 0.258). The root fillings of the groups irrigated with MTAD showed significantly lower push-out bond strength values than the other groups (p < 0.001). These commonly used irrigating solutions did not affect the apical leakage of the root canal sealer. MTAD reduced the bond strength of the root canal sealer to the root canal dentin. PMID- 26477885 TI - Prey from the eyes of predators: Color discriminability of aposematic and mimetic butterflies from an avian visual perspective. AB - Predation exerts strong selection on mimetic butterfly wing color patterns, which also serve other functions such as sexual selection. Therefore, specific selection pressures may affect the sexes and signal components differentially. We tested three predictions about the evolution of mimetic resemblance by comparing wing coloration of aposematic butterflies and their Batesian mimics: (a) females gain greater mimetic advantage than males and therefore are better mimics, (b) due to intersexual genetic correlations, sexually monomorphic mimics are better mimics than female-limited mimics, and (c) mimetic resemblance is better on the dorsal wing surface that is visible to predators in flight. Using a physiological model of avian color vision, we quantified mimetic resemblance from predators' perspective, which showed that female butterflies were better mimics than males. Mimetic resemblance in female-limited mimics was comparable to that in sexually monomorphic mimics, suggesting that intersexual genetic correlations did not constrain adaptive response to selection for female-limited mimicry. Mimetic resemblance on the ventral wing surface was better than that on the dorsal wing surface, implying stronger natural and sexual selection on ventral and dorsal surfaces, respectively. These results suggest that mimetic resemblance in butterfly mimicry rings has evolved under various selective pressures acting in a sex- and wing surface-specific manner. PMID- 26477886 TI - Low Carotid Artery Wall Shear Stress is Associated with Significant Coronary Artery Disease in Patients with Chest Pain. AB - AIM: To investigate the relationships among carotid wall shear stress (WSS), carotid intima-media thickness (IMT), and total plaque area (TPA) using ultrasound (US) in the common carotid artery (CCA) in patients with suspected coronary artery disease (CAD). METHODS: Carotid artery US was performed in 950 patients with suspected CAD, and mean IMT, TPA, and hemodynamic parameters of CCA, including peak and mean WSS, were measured. We analyzed the carotid parameters according to the presence of CAD and the predictive values of WSS and TPA for the presence of significant CAD. RESULTS: Compared with patients without CAD (n=667), patients with CAD (n=283) demonstrated significantly higher mean IMT (0.66 vs. 0.74 mm, p < 0.001), TPA (0.13 vs. 0.20 cm(2), p=0.002), and beta stiffness index (5.12 vs. 5.60, p=0.045) and lower mean WSS (2.59 vs. 2.23 dyne/cm(2), p < 0.001). Mean WSS revealed significant negative correlations with the beta stiffness index (r=-0.116, p < 0.001), mean IMT (r=-0.193, p=0.007), and TPA (r =-0.296, p < 0.001). Mean WSS, mean IMT and TPA revealed significant difference with respect to CAD severity (for all p < 0.001). Age [OR, 1.038 (95% CI, 1.010-1.066), p=0.007], diabetes mellitus [1.606 (1.194-1.807), p= 0.011], smoking [1.758 (1.564-1.866), p < 0.001], carotid TPA [2.615 (1.320-5.183), p=0.006], and mean WSS [0.554 (0.371-0.838), p=0.005] were significant CAD predictors. CONCLUSIONS: In patients with chest pain, low local shear stress and high plaque burden in the carotid arteries were significant CAD predictors. These findings indicate that carotid WSS has a role as an index of atherosclerosis and serves as a predictor of significant coronary atherosclerosis. PMID- 26477887 TI - The Impact of Population, Contact, and Spatial Heterogeneity on Epidemic Model Predictions. AB - Our objective was to evaluate the effect that complexity in the form of different levels of spatial, population, and contact heterogeneity has in the predictions of a mechanistic epidemic model. A model that simulates the spatiotemporal spread of infectious diseases between animal populations was developed. Sixteen scenarios of foot-and-mouth disease infection in cattle were analyzed, involving combinations of the following factors: multiple production-types (PT) with heterogeneous contact and population structure versus single PT, random versus actual spatial distribution of population units, high versus low infectivity, and no vaccination versus preemptive vaccination. The epidemic size and duration was larger for scenarios with multiple PT versus single PT. Ignoring the actual unit locations did not affect the epidemic size in scenarios with multiple PT/high infectivity, but resulted in smaller epidemic sizes in scenarios using multiple PT/low infectivity. In conclusion, when modeling fast-spreading epidemics, knowing the actual locations of population units may not be as relevant as collecting information on population and contact heterogeneity. In contrast, both population and spatial heterogeneity might be important to model slower spreading epidemic diseases. Our findings can be used to inform data collection and modeling efforts to inform health policy and planning. PMID- 26477889 TI - Isolation and assessment of gut bacteria from the Formosan subterranean termite, Coptotermes formosanus (Isoptera: Rhinotermitidae), for paratransgenesis research and application. AB - Paratransgenesis targeting the gut protozoa is being developed as an alternative method for the control of the Formosan subterranean termite (FST). This method involves killing the cellulose-digesting gut protozoa using a previously developed antiprotozoal peptide consisting of a target specific ligand coupled to an antimicrobial peptide (Hecate). In the future, we intend to genetically engineer termite gut bacteria as "Trojan Horses" to express and spread ligand Hecate in the termite colony. The aim of this study was to assess the usefulness of bacteria strains isolated from the gut of FST as "Trojan Horses." We isolated 135 bacteria from the guts of workers from 3 termite colonies. Sequencing of the 16S rRNA gene identified 20 species. We tested 5 bacteria species that were previously described as part of the termite gut community for their tolerance against Hecate and ligand-Hecate. Results showed that the minimum concentration required to inhibit bacteria growth was always higher than the concentration required to kill the gut protozoa. Out of the 5 bacteria tested, we engineered Trabulsiella odontotermitis, a termite specific bacterium, to express green fluorescent protein as a proof of concept that the bacteria can be engineered to express foreign proteins. Engineered T. odontotermitis was fed to FST to study if the bacteria are ingested. This feeding experiment confirmed that engineered T. odontotermitis is ingested by termites and can survive in the gut for at least 48 h. Here we report that T. odontotermitis is a suitable delivery and expression system for paratransgenesis in a termite species. PMID- 26477888 TI - CO2 -dependent metabolic modulation in red blood cells stored under anaerobic conditions. AB - BACKGROUND: Anaerobic red blood cell (RBC) storage reduces oxidative damage, maintains adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (DPG) levels, and has superior 24-hour recovery at 6 weeks compared to standard storage. This study will determine if removal of CO2 during O2 depletion by gas exchange may affect RBCs during anaerobic storage. STUDY DESIGN AND METHODS: This is a matched three-arm study (n = 14): control, O2 and CO2 depleted with Ar (AN), and O2 depleted with 95%Ar/5%CO2 (AN[CO2 ]). RBCs in additives AS-3 or OFAS-3 were evenly divided into three bags, and anaerobic conditions were established by gas exchange. Bags were stored at 1 to 6 degrees C in closed chambers under anaerobic conditions or ambient air, sampled weekly for up to 9 weeks for a panel of in vitro tests. A full metabolomics screening was conducted for the first 4 weeks of storage. RESULTS: Purging with Ar (AN) results in alkalization of the RBC and increased glucose consumption. The addition of 5% CO2 to the purging gas prevented CO2 loss with an equivalent starting and final pH and lactate to control bags (p > 0.5, Days 0-21). ATP levels are higher in AN[CO2 ] (p < 0.0001). DPG was maintained beyond 2 weeks in the AN arm (p < 0.0001). Surprisingly, DPG was lost at the same rate in both control and AN[CO2 ] arms (p = 0.6). CONCLUSION: Maintenance of ATP in the AN[CO2 ] arm demonstrates that ATP production is not solely a function of the pH effect on glycolysis. CO2 in anaerobic storage prevented the maintenance of DPG, and DPG production appears to be pH dependent. CO2 as well as O2 depletion provides metabolic advantage for stored RBCs. PMID- 26477890 TI - Adenine supplement delays senescence in cultured human follicle dermal papilla cells. PMID- 26477892 TI - Work for sustainability: Case studies of Brazilian companies. AB - The introduction of strategic corporate sustainability policies is expected to result in the improvement of several issues in companies. One of these issues is work, which should involve greater well-being for workers. Within the context of production engineering, this research connects sustainability and work-related issues, the latter seen in light of the discipline of ergonomics. Based on case studies conducted at four companies considered sustainability benchmarks, we examined how the introduction of the theme of sustainability has influenced work related issues. The elements analyzed here were the corporate sustainability strategy, organizational practices for deploying the strategy, and the work design phase. The last element is the moment in which work is prescribed in the organization. The results show that, despite the announcement of the inclusion of changes in work, there is not any explicit evidence confirming that such changes are considered as a requirement for corporate sustainability projects. PMID- 26477891 TI - Sleep Apnea and the Risk of Incident Gout: A Population-Based, Body Mass Index Matched Cohort Study. AB - OBJECTIVE: Sleep apnea is associated with hyperuricemia owing to hypoxia-induced nucleotide turnover. We undertook this study to assess the relationship between incident sleep apnea and the risk of incident gout. METHODS: Using data from The Health Improvement Network in the UK, we identified individuals with a first-ever physician diagnosis of sleep apnea. For each patient with sleep apnea, up to 5 individuals without sleep apnea were matched by sex, age, birth year, and body mass index (within +/-0.5 kg/m(2) ). We estimated the incidence rates of gout and examined the relationship between sleep apnea and the risk of incident gout using a Cox proportional hazards model, adjusting for potential confounders. In addition, we assessed the rate difference in gout due to sleep apnea using an additive hazard model. RESULTS: Among 9,865 patients with newly diagnosed sleep apnea and 43,598 matched individuals without sleep apnea, we identified 270 incident cases of gout over 1 year of followup, resulting in incidence rates of 8.4 per 1,000 person-years and 4.8 per 1,000 person-years, respectively. The crude and multivariable rate ratios of incident gout in patients with sleep apnea were 1.7 (95% confidence interval [95% CI] 1.3, 2.2) and 1.5 (95% CI 1.1, 2.1), respectively. The corresponding rate differences between patients with sleep apnea and the comparison cohort were 3.6 (95% CI 1.6, 5.6) and 2.8 (95% CI 0.7, 4.9) per 1,000 person-years. The effect of sleep apnea persisted across subgroups. CONCLUSION: This general population-based study indicates that sleep apnea is independently associated with an increased risk of incident gout. Future research should examine the potential benefits of correcting sleep apnea-induced hypoxia on the risk of hyperuricemia and gout flares. PMID- 26477894 TI - Computer modeling with randomized-controlled trial data informs the development of person-centered aged care homes. AB - AIM: To answer questions on the essential components (services, operations and resources) of a person-centered aged care home (iHome) using computer simulation. MATERIALS & METHODS: iHome was developed with AnyLogic software using extant study data obtained from 60 Australian aged care homes, 900+ clients and 700+ aged care staff. Bayesian analysis of simulated trial data will determine the influence of different iHome characteristics on care service quality and client outcomes. Interim results: A person-centered aged care home (socio-cultural context) and care/lifestyle services (interactional environment) can produce positive outcomes for aged care clients (subjective experiences) in the simulated environment. CONCLUSION: Further testing will define essential characteristics of a person-centered care home. PMID- 26477895 TI - The complete mitochondrial genome of the butterfly Herona marathus (Lepidoptera: Nymphalidae). AB - The complete mitochondrial genome (mitogenome) of Herona marathus was sequenced and analyzed in the study. The mitogenome is 15 487 bp in size, including 37 genes and a putative control region. Thirteen protein-coding genes (PCGs) all start with a typical ATN codon, expect that COI gene uses CGA as its initial codon. Majority of the 13 PCGs have a complete termination codon (TAA or TAG) except for COII and ND4 have a single T-- residue. All tRNAs have typical clover leaf secondary structure, except for tRNASer(AGN), in which the dihydrouridine (DHU) arm is a simple loop. Bayesian analyses support the monophyly of butterflies and recover high supports for the following family level relationships: (Papilionidae + Hesperioidea + (Pieridae + Lycaenidae + (Danaidae + Nymphalidae))). PMID- 26477896 TI - Preventive Medicine Training: The Case for Integrating Integrative Medicine. PMID- 26477897 TI - Integrative Medicine in Preventive Medicine Education: Competency and Curriculum Development for Preventive Medicine and Other Specialty Residency Programs. AB - During 2012, the USDHHS's Health Resources and Services Administration funded 12 accredited preventive medicine residencies to incorporate an evidence-based integrative medicine curriculum into their training programs. It also funded a national coordinating center at the American College of Preventive Medicine, known as the Integrative Medicine in Preventive Medicine Education (IMPriME) Center, to provide technical assistance to the 12 grantees. To help with this task, the IMPriME Center established a multidisciplinary steering committee, versed in integrative medicine, whose primary aim was to develop integrative medicine core competencies for incorporation into preventive medicine graduate medical education training. The competency development process was informed by central integrative medicine definitions and principles, preventive medicine's dual role in clinical and population-based prevention, and the burgeoning evidence base of integrative medicine. The steering committee considered an interdisciplinary integrative medicine contextual framework guided by several themes related to workforce development and population health. A list of nine competencies, mapped to the six general domains of competence approved by the Accreditation Council of Graduate Medical Education, was operationalized through an iterative exercise with the 12 grantees in a process that included mapping each site's competency and curriculum products to the core competencies. The competencies, along with central curricular components informed by grantees' work presented elsewhere in this supplement, are outlined as a roadmap for residency programs aiming to incorporate integrative medicine content into their curricula. This set of competencies adds to the larger efforts of the IMPriME initiative to facilitate and enhance further curriculum development and implementation by not only the current grantees but other stakeholders in graduate medical education around integrative medicine training. PMID- 26477899 TI - Integrative Medicine in Preventive Medicine Education: Implementation Analysis. AB - In September 2012, the Health Resources and Services Administration funded 12 preventive medicine residency programs to participate in a 2-year project aimed at incorporating integrative medicine (IM) into their residency training programs. The grantees were asked to incorporate competencies for IM into their respective preventive medicine residency curricula and to provide for faculty development in IM. The analysis conducted in 2014-2015 used the following evidence to assess residency programs' achievements and challenges in implementation: progress and performance measures reports, curriculum mapping of program activities to IM competencies, records of webinar participation, and post project individual semi-structured phone interviews with the 12 grantee project leaders. Key findings are: (1) IM activities offered to residents increased by 50% during the 2 years; (2) Accessing IM resources already in existence at local grantee sites was the primary facilitator of moving the integration of IM into preventive medicine residencies forward; (3) Among all activities offered residents, rotations were perceived by grantees as by far the most valuable contributor to acquiring IM competencies; (4) Online training was considered a greater contributor to preventive medicine residents' medical knowledge in IM than faculty lectures or courses; (5) Faculty were offered a rich variety of opportunities for professional development in IM, but some programs lacked a system to ensure faculty participation; and (6) Perceived lack of evidence for IM was a barrier to full program implementation at some sites. Grantees expect implemented programs to continue post-funding, but with decreased intensity owing to perceived faculty and curriculum time constraints. PMID- 26477900 TI - Implementation of an Integrative Medicine Curriculum for Preventive Medicine Residents. AB - The University of Maryland Department of Epidemiology and Public Health collaborated with the Center for Integrative Medicine at the same institution to develop and implement a unique integrative medicine curriculum within a preventive medicine residency program. Between October 2012 and July 2014, Center for Integrative Medicine faculty provided preventive medicine residents and faculty, and occasionally other Department of Epidemiology and Public Health faculty, with comprehensive exposure to the field of integrative medicine, including topics such as mind-body medicine, nutrition and nutritional supplements, Traditional Chinese Medicine, massage, biofield therapies, manual medicine, stress management, creative arts, and the use of integrative medicine in the inpatient setting. Preventive medicine residents, under the supervision of Department of Epidemiology and Public Health faculty, led integrative medicine themed journal clubs. Resident assessments included a case-based knowledge evaluation, the Integrative Medicine Attitudes Questionnaire, and a qualitative evaluation of the program. Residents received more than 60 hours of integrative medicine instruction, including didactic sessions, experiential workshops, and wellness retreats in addition to clinical experiences and individual wellness mentoring. Residents rated the program positively and recommended that integrative medicine be included in preventive medicine residency curricula. The inclusion of a wellness-focused didactic, experiential, and skill-based integrative medicine program within a preventive medicine residency was feasible and well received by all six preventive medicine residents. PMID- 26477898 TI - Disease Prevention and Health Promotion: How Integrative Medicine Fits. AB - As a discipline, preventive medicine has traditionally been described to encompass primary, secondary, and tertiary prevention. The fields of preventive medicine and public health share the objectives of promoting general health, preventing disease, and applying epidemiologic techniques to these goals. This paper discusses a conceptual approach between the overlap and potential synergies of integrative medicine principles and practices with preventive medicine in the context of these levels of prevention, acknowledging the relative deficiency of research on the effectiveness of practice-based integrative care. One goal of integrative medicine is to make the widest array of appropriate options available to patients, ultimately blurring the boundaries between conventional and complementary medicine. Both disciplines should be subject to rigorous scientific inquiry so that interventions that are efficacious and effective are systematically distinguished from those that are not. Furthermore, principles of preventive medicine can be infused into prevalent practices in complementary and integrative medicine, promoting public health in the context of more responsible practices. The case is made that an integrative preventive approach involves the responsible use of science with responsiveness to the needs of patients that persist when conclusive data are exhausted, providing a framework to make clinical decisions among integrative therapies. PMID- 26477901 TI - Interprofessional Integrative Medicine Training for Preventive Medicine Residents. AB - Integrative medicine training was incorporated into the Rutgers New Jersey Medical School Preventive Medicine residency at the Rutgers Biomedical and Health Sciences Newark Campus as a collaboration between the Rutgers New Jersey Medical School and the School of Health Related Professions. Beginning in 2012, an interdisciplinary faculty team organized an Integrative Medicine program in a Preventive Medicine residency that leveraged existing resources across Rutgers Biomedical and Health Sciences. The overarching aim of the programs was to introduce residents and faculty to the scope and practice of integrative medicine in the surrounding Newark community and explore evidence-based research on integrative medicine. The faculty team tapped into an interprofessional network of healthcare providers to organize rotations for the preventive medicine residents that reflected the unique nature of integrative medicine in the greater Newark area. Residents provided direct care as part of interdisciplinary teams at clinical affiliates and shadowed health professionals from diverse disciplines as they filled different roles in providing patient care. The residents also participated in research projects. A combination of formal and informal programs on integrative medicine topics was offered to residents and faculty. The Integrative Medicine program, which ran from 2013 through 2014, was successful in exposing residents and faculty to the unique nature of integrative medicine across professions in the community served by Rutgers Biomedical and Health Sciences. PMID- 26477902 TI - Assimilating Traditional Healing Into Preventive Medicine Residency Curriculum. AB - Comprehensive cultural competency includes knowledge and awareness of culturally based healing and wellness practices. Healthcare providers should be aware of the individual patient's beliefs, culture, and use of culturally based health practices because patients may adopt such practices for general wellness or as adjunct therapies without the benefit of discussion with their healthcare provider. This article describes the culturally based traditional healing curriculum that has been implemented in the University of New Mexico Public Health and General Preventive Medicine Residency Program in order to fulfill this knowledge necessity. Curricular elements were added in a stepwise manner starting in 2011, with the full content as described implemented starting in 2013. Data were collected annually with evaluation of the full curriculum occurring in 2015. New Mexico has a diverse population base that includes predominantly Hispanic and Native American cultures, making the inclusion of curriculum regarding traditional healing practices very pertinent. Residents at the University of New Mexico were educated through several curricular components about topics such as Curanderismo, the art of Mexican Folk Healing. An innovative approach was used, with a compendium of training methods that included learning directly from traditional healers and participation in healing practices. The incorporation of this residency curriculum resulted in a means to produce physicians well trained in approaching patient care and population health with knowledge of culturally based health practices in order to facilitate healthy patients and communities. PMID- 26477903 TI - Public Health and Preventive Medicine Meet Integrative Health: Applications of Competency Mapping to Curriculum Education at the University of Michigan. AB - The University of Michigan School of Public Health Preventive Medicine Residency (UMSPH PMR) Integrative Medicine Program (IMP) was developed to incorporate integrative medicine (IM), public health, and preventive medicine principles into a comprehensive curriculum for preventive medicine residents and faculty. The objectives of this project were to (1) increase the preventive medicine workforce skill sets based in complementary and alternative medicine and IM that would address individual and population health issues; (2) address the increasing demand for evidence-based IM by training physicians to implement cost-effective primary and secondary prevention services and programs; and (3) share lessons learned, curriculum evaluations, and best practices with the larger cohort of funded IM PMR programs. The UMSPH PMR collaborated with University of Michigan IM faculty to incorporate existing IM competencies with those already established for preventive medicine and public health residency training as the first critical step for IMP curriculum integration. Essential teaching strategies incorporated didactic and practicum methods, and made use of seasoned IM faculty, along with newly minted preventive medicine integrative teaching faculty, and PMR resident learners as IM teachers. The major components of the IMP curriculum included resident participation in IMP Orientation Sessions, resident leadership in epidemiology graduate IM seminars, resident rotations in IM month-long clinical practicums, resident participation in interprofessional health system wide IM clinical case conferences, and PMR faculty enrollment in the renowned Faculty Scholars Program in Integrative Healthcare. This paper describes the novel interdisciplinary collaborations and key curriculum components that resulted in the IMP, as well as evaluation of strengths, weaknesses, and lessons learned. PMID- 26477904 TI - Training on Exercise is Medicine(r) Within an Integrative Medicine Curriculum. AB - Physicians are increasingly approached by individuals seeking integrative approaches to health care and well-being. Many integrative modalities include a physical activity component. Patients seek guidance from primary and specialty care providers on the safe and effective incorporation of these modalities into their lifestyle. Physicians and other health professionals receive very limited training in the clinical applications of exercise science. This paper reports on a curriculum designed to teach health professionals key exercise constructs for application to clinical practice for prevention and management of lifestyle related disease, and incorporating the curriculum into a preventive medicine residency training program. The course was developed in 2012-2013, data collected in 2013-2015, and analysis was done in 2015. Six modules were developed as part of a 24-hour course. Each module included didactic, laboratory, and case examples. The modules included energetics, exercise and cardiorespiratory health, bone health, obesity and sarcopenia, balance and fall prevention, and behavior change and the use of technologies. The delivery was found feasible for all three components, delivered in 2-4-hour segments. The incorporation into the residency curriculum was feasible, efficacious, well received, and easily incorporated into the existing curriculum. This comprehensive curriculum has the potential to close the gap in medical school, residency, graduate, nursing, and integrative curricula on this important topic. Current practitioners would benefit in primary care and geriatric settings. This curriculum would also be useful for cross disciplinary researchers, including public health, health behaviors, and integrative medicine practitioners. PMID- 26477905 TI - Teaching Integrative Medicine to Residents: A Focus on Populations Rather Than Individual Patients. AB - INTRODUCTION: Integrative medicine (IM) is by its very definition patient centric: "It reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic approaches." Best methods for teaching IM in residency have not been well described. METHODS: An IM curriculum for preventive medicine (PM) residents was thoughtfully developed and iteratively revised using Kern's six-step approach. The centerpiece of this curriculum was to have learners work collaboratively within teams on projects that would facilitate IM-focused care within primary care practices. Before embarking on specific IM-related projects, residents immersed themselves within the practices to understand the needs of the community. RESULTS: Forty-eight PM residents have participated in the curriculum in the last 3 years, and 27 unique physician preceptors served as mentors for the projects. Both residents and preceptors enjoyed working on the projects, and both groups considered the work to be a valuable educational pursuit. Common IM content areas covered by the projects dealt with interprofessional collaboration, health promotion, and population-based prevention. Although there were challenges associated with implementation of the projects, overcoming these enhanced the PM residents' confidence and ability to serve as agents of change. CONCLUSIONS: An IM curriculum was successfully incorporated into a PM residency program. The focus on serving the community, or a population health approach, may not be the most common approach in IM, but it worked effectively to enhance the IM knowledge and skills of PM residents. PMID- 26477906 TI - Integrative Medicine in a Preventive Medicine Residency: A Program for the Urban Underserved. AB - The Preventive Medicine Residency Program collaborated with the Department of Family Medicine's Program for Integrative Medicine and Health Disparities at Boston Medical Center to create a new rotation for preventive medicine residents starting in autumn 2012. Residents participated in integrative medicine group visits and consults, completed an online curriculum in dietary supplements, and participated in seminars all in the context of an urban safety net hospital. This collaboration was made possible by a federal Health Resources and Services Administration grant for integrative medicine in preventive medicine residencies and helped meet a need of the program to increase residents' exposure to clinical preventive medicine and integrative health clinical skills and principles. The collaboration has resulted in a required rotation for all residents that continues after the grant period and has fostered additional collaborations related to integrative medicine across the programs. PMID- 26477907 TI - Project ASPIRE: Incorporating Integrative Medicine Into Residency Training. AB - Griffin Hospital, a community hospital affiliated with Yale School of Public Health and Yale School of Medicine, received Health Resources and Services Administration funding to strengthen and improve its combined internal medicine and general preventive medicine residency program by incorporating an integrative medicine curriculum. The purpose of project ASPIRE (Advancing Skills of Preventive medicine residents through Integrative medicine Education, Research and Evaluation) was to create, implement, and evaluate a needs-based, innovative training curriculum in integrative medicine. Through this robust new training, the authors aimed to produce preventive medicine-trained physicians with competencies in integrative medicine to collaboratively work with other integrative medicine practitioners in interdisciplinary teams to provide holistic, patient-centered care. The multifaceted collaborative curriculum was composed of didactics, grand rounds, journal club, objective structured clinical examinations, and two new practicum rotations in integrative medicine. The new practicum rotations included block rotations at the Integrative Medicine Center at Griffin Hospital and the Yale Stress Center. Between 2012 and 2014, three cohorts participated in the curriculum; two of these cohorts included three advanced preventive medicine residents each and the fourth included four residents. Project faculty conducted 14 lectures and journal clubs, and two grand rounds. Six of the ten participating residents (60%) completed integrative medicine clinical rotations. Residents' attitudes toward integrative medicine were evaluated through self-assessment using the Complementary, Alternative, and Integrative Medicine Attitudes Questionnaire; data were analyzed in 2015. This article describes the results of this prospective observational study based on single-institution experience over the course of the 2-year project period. PMID- 26477908 TI - Adaptation to Acute and Regular Exercise: From Reductionist Approaches to Integrative Biology. AB - This chapter serves as an introduction to the volume focused on the molecular and cellular regulation of adaptation to acute and chronic exercise exposure. It begins with a definition of the overall content of the "sedens-physical activity exercise training-fitness" domain. One conclusion from this brief overview is that past and current studies have primarily dealt with very limited subsets of the traits and parameters of interest to exercise biologists. Molecular and cellular studies have focused more on adaptation to exercise and less on variable levels of cardiorespiratory fitness even though the latter is a powerful indicator of current and future health status and longevity. In this regard, molecular profiling of intrinsic versus acquired cardiorespiratory fitness would seem to be an area of research deserving more attention. Although molecular and cellular studies are clearly reductionist by nature, they constitute the primary material allowing systems biology to draw inferences about pathways, networks, and systems. Integrative physiology can be substantially enriched by taking advantage of the findings and lessons from molecular studies and systems biology approaches. DNA sequence variation within and between populations as well as recent advances in the definition of the functional elements in the human and other genomes offer unique opportunities to pursue new and more powerful molecular studies, and to reconcile reductionist and integrative approaches. PMID- 26477910 TI - Exercise and Regulation of Lipid Metabolism. AB - The increased prevalence of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, and fatty liver disease has provided increasingly negative connotations toward lipids. However, it is important to remember that lipids are essential components supporting life. Lipids are a class of molecules defined by their inherent insolubility in water. In biological systems, lipids are either hydrophobic (containing only polar groups) or amphipathic (possess polar and nonpolar groups). These characteristics lend lipids to be highly diverse with a multitude of functions including hormone and membrane synthesis, involvement in numerous signaling cascades, as well as serving as a source of metabolic fuel supporting energy production. Exercise can induce changes in the lipid composition of membranes that effect fluidity and cellular function, as well as modify the cellular and circulating environment of lipids that regulate signaling cascades. The purpose of this chapter is to focus on lipid utilization as metabolic fuel in response to acute and chronic exercise training. Lipids utilized as an energy source during exercise include circulating fatty acids bound to albumin, triglycerides stored in very-low-density lipoprotein, and intramuscular triglyceride stores. Dynamic changes in these lipid pools during and after exercise are discussed, as well as key factors that may be responsible for regulating changes in fat oxidation in response to varying exercise conditions. PMID- 26477911 TI - Exercise and Regulation of Protein Metabolism. AB - Skeletal muscles exhibit radical changes in physiology and metabolism in response to exercise. While exercise induces highly specific physiological changes, e.g., hypertrophy, associated with weightlifting or oxygen utilization associated with aerobic-type exercises, the foundation of these changes is driven by the summation of exercise-induced alterations in muscle protein metabolism. Practically, any type of exercise stimulates muscle protein turnover, the purpose being both to renew, and also modify, the myocellular composition of proteins in line with adaptations according to the mechanical and metabolic demands imposed. The mechanism(s) by which exercise stimulates protein turnover has been the subset of intense study. These studies have been led by the use of stable isotopically labeled amino acids. Essentially, use of these heavier variants (e.g., (13)C AA vs. (12)C) coupled to mass spectrometry has enabled study of the dynamic responses of muscle protein turnover to exercise. Using these techniques, it has become patently clear that exercise stimulates muscle protein turnover, i.e., muscle protein synthesis (MPS) and breakdown (MPB). Moreover, intake of specific nutrients (i.e., dietary proteins) potentiates MPS while attenuating MPB, facilitating maintenance of proteostasis and exercise adaptation. The mechanisms driving these protein metabolic responses to exercise include the coordinated activation of mRNA translation pathways (e.g., mechanistic target of rapamycin) and multiple MPB pathways (e.g., autophagy and ubiquitin-proteasome). These processes are triggered by exercise-induced hormone, auto/paracrine-acting growth factors, mechanical transduction, and intramyocellular second messenger pathways. Finally, there remains poor understanding of how distinct exercise modes (e.g., resistance vs. endurance) lead to such distinct adaptations from a protein metabolic and molecular standpoint. PMID- 26477909 TI - Exercise and Regulation of Carbohydrate Metabolism. AB - Carbohydrates are the preferred substrate for contracting skeletal muscles during high-intensity exercise and are also readily utilized during moderate intensity exercise. This use of carbohydrates during physical activity likely played an important role during the survival of early Homo sapiens, and genes and traits regulating physical activity, carbohydrate metabolism, and energy storage have undoubtedly been selected throughout evolution. In contrast to the life of early H. sapiens, modern lifestyles are predominantly sedentary. As a result, intake of excessive amounts of carbohydrates due to the easy and continuous accessibility to modern high-energy food and drinks has not only become unnecessary but also led to metabolic diseases in the face of physical inactivity. A resulting metabolic disease is type 2 diabetes, a complex endocrine disorder characterized by abnormally high concentrations of circulating glucose. This disease now affects millions of people worldwide. Exercise has beneficial effects to help control impaired glucose homeostasis with metabolic disease, and is a well established tool to prevent and combat type 2 diabetes. This chapter focuses on the effects of exercise on carbohydrate metabolism in skeletal muscle and systemic glucose homeostasis. We will also focus on the molecular mechanisms that mediate the effects of exercise to increase glucose uptake in skeletal muscle. It is now well established that there are different proximal signaling pathways that mediate the effects of exercise and insulin on glucose uptake, and these distinct mechanisms are consistent with the ability of exercise to increase glucose uptake in the face of insulin resistance in people with type 2 diabetes. Ongoing research in this area is aimed at defining the precise mechanism by which exercise increases glucose uptake and insulin sensitivity and the types of exercise necessary for these important health benefits. PMID- 26477912 TI - Exercise and the Regulation of Mitochondrial Turnover. AB - Exercise is a well-known stimulus for the expansion of the mitochondrial pool within skeletal muscle. Mitochondria have a remarkable ability to remodel their networks and can respond to an array of signaling stimuli following contractile activity to adapt to the metabolic demands of the tissue, synthesizing proteins to expand the mitochondrial reticulum. In addition, when they become dysfunctional, these organelles can be recycled by a specialized intracellular system. The signals regulating this mitochondrial life cycle of synthesis and degradation during exercise are still an area of great research interest. As mitochondrial turnover has valuable consequences in physical performance, in addition to metabolic health, disease, and aging, consideration of the signals which control this cycle is vital. This review focuses on the regulation of mitochondrial turnover in skeletal muscle and summarizes our current understanding of the impact that exercise has in modulating this process. PMID- 26477913 TI - Endurance Exercise and the Regulation of Skeletal Muscle Metabolism. AB - Almost a half century ago, regular endurance exercise was shown to improve the capacity of skeletal muscle to oxidize substrates to produce ATP for muscle work. Since then, adaptations in skeletal muscle mRNA level were shown to happen with a single bout of exercise. Protein changes occur within days if daily endurance exercise continues. Some of the mRNA and protein changes cause increases in mitochondrial concentrations. One mitochondrial adaptation that occurs is an increase in fatty acid oxidation at a given absolute, submaximal workload. Mechanisms have been described as to how endurance training increases mitochondria. Importantly, Pgc-1alpha is a master regulator of mitochondrial biogenesis by increasing many mitochondrial proteins. However, not all adaptations to endurance training are associated with increased mitochondrial concentrations. Recent evidence suggests that the energetic demands of muscle contraction are by themselves stronger controllers of body weight and glucose control than is muscle mitochondrial content. Endurance exercise has also been shown to regulate the processes of mitochondrial fusion and fission. Mitophagy removes damaged mitochondria, a process that maintains mitochondrial quality. Skeletal muscle fibers are composed of different phenotypes, which are based on concentrations of mitochondria and various myosin heavy chain protein isoforms. Endurance training at physiological levels increases type IIa fiber type with increased mitochondria and type IIa myosin heavy chain. Endurance training also improves capacity of skeletal muscle blood flow. Endurance athletes possess enlarged arteries, which may also exhibit decreased wall thickness. VEGF is required for endurance training-induced increases in capillary-muscle fiber ratio and capillary density. PMID- 26477914 TI - Exercise and the Regulation of Skeletal Muscle Hypertrophy. AB - Skeletal muscle is a critical organ serving as the primary site for postprandial glucose disposal and the generation of contractile force. The size of human skeletal muscle mass is dependent upon the temporal relationship between changes in muscle protein synthesis (MPS) and muscle protein breakdown. The aim of this chapter is to review our current understanding of how resistance exercise influences protein turnover with a specific emphasis on the molecular factors regulating MPS. We also will discuss recent data relating to the prescription of resistance exercise to maximize skeletal muscle hypertrophy. Finally, we evaluate the impact of age and periods of disuse on the loss of muscle mass and the controversy surround the etiology of muscle disuse atrophy. PMID- 26477915 TI - Exercise and the Regulation of Adipose Tissue Metabolism. AB - Adipose tissue is a major regulator of metabolism in health and disease. The prominent roles of adipose tissue are to sequester fatty acids in times of energy excess and to release fatty acids via the process of lipolysis during times of high-energy demand, such as exercise. The fatty acids released during lipolysis are utilized by skeletal muscle to produce adenosine triphosphate to prevent fatigue during prolonged exercise. Lipolysis is controlled by a complex interplay between neuro-humoral regulators, intracellular signaling networks, phosphorylation events involving protein kinase A, translocation of proteins within the cell, and protein-protein interactions. Herein, we describe in detail the cellular and molecular regulation of lipolysis and how these processes are altered by acute exercise. We also explore the processes that underpin adipocyte adaptation to endurance exercise training, with particular focus on epigenetic modifications, control by microRNAs and mitochondrial adaptations. Finally, we examine recent literature describing how exercise might influence the conversion of traditional white adipose tissue to high energy-consuming "brown-like" adipocytes and the implications that this has on whole-body energy balance. PMID- 26477917 TI - Molecular Mechanisms for Exercise Training-Induced Changes in Vascular Structure and Function: Skeletal Muscle, Cardiac Muscle, and the Brain. AB - Compared with resting conditions, during incremental exercise, cardiac output in humans is elevated from ~5 to 25 L min(-1). In conjunction with this increase, the proportion of cardiac output directed toward skeletal muscle increases from ~20% to 85%, while blood flow to cardiac muscle increases 500% and blood flow to specific brain structures increases nearly 200%. Based on existing evidence, researchers believe that blood flow in these tissues is matched to the increases in metabolic rate during exercise. This phenomenon, the matching of blood flow to metabolic requirement, is often referred to as functional hyperemia. This chapter summarizes mechanical and metabolic factors that regulate functional hyperemia as well as other exercise-induced signals, which are also potent stimuli for chronic adaptations in vascular biology. Repeated exposure to exercise-induced increases in shear stress and the induction of angiogenic factors alter vascular cell gene expression and mediate changes in vascular volume and blood flow control. The magnitude and regulation of this coordinated response appear to be tissue specific and coupled to other factors such as hypertrophy and hyperplasia. The cumulative effects of these adaptations contribute to increased exercise capacity, reduced relative challenge of a given submaximal exercise bout and ameliorated vascular outcomes in patient populations with pathological conditions. In the subsequent discussion, this chapter explores exercise as a regulator of vascular biology and summarizes the molecular mechanisms responsible for exercise training-induced changes in vascular structure and function in skeletal and cardiac muscle as well as the brain. PMID- 26477918 TI - Exercise and Regulation of Bone and Collagen Tissue Biology. AB - The musculoskeletal system and its connective tissue include the intramuscular connective tissue, the myotendinous junction, the tendon, the joints with their cartilage and ligaments, and the bone; they all together play a crucial role in maintaining the architecture of the skeletal muscle, ensuring force transmission, storing energy, protecting joint surface and stability, and ensuring the transfer of muscular forces into resulting limb movement. The musculoskeletal connective tissue structure is relatively stable, but mechanical loading and subsequent mechanotransduction and molecular anabolic signaling can result in some adaptation of the connective tissue, its size, its strength, and its mechanical properties, whereby it can improve its capacity by 5-20% with regular physical activity. For several of the mechanically loaded connective tissues, only limited information regarding molecular and cellular signaling pathways and their adaptation to exercise is available. In contrast to tissue responses with exercise, lack of mechanical tissue loading through inactivity or immobilization of the human body will result in a dramatic loss of connective tissue content, structure, and tolerable load within weeks, to a degree (30-40%) that mimics that of contractile skeletal musculature. This illustrates the importance of regular mechanical load in order to preserve the stabilizing role of the connective tissue for the overall function of the musculoskeletal system in both daily activity and exercise. PMID- 26477916 TI - Exercise and the Regulation of Hepatic Metabolism. AB - The accelerated metabolic demands of the working muscle cannot be met without a robust response from the liver. If not for the hepatic response, sustained exercise would be impossible. The liver stores, releases, and recycles potential energy. Exercise would result in hypoglycemia if it were not for the accelerated release of energy as glucose. The energetic demands on the liver are largely met by increased oxidation of fatty acids mobilized from adipose tissue. Adaptations immediately following exercise facilitate the replenishment of glycogen stores. Pancreatic glucagon and insulin responses orchestrate the hepatic response during and immediately following exercise. Like skeletal muscle and other physiological systems, liver adapts to repeated demands of exercise by increasing its capacity to produce energy by oxidizing fat. The ability of regular physical activity to increase fat oxidation is protective and can reverse fatty liver disease. Engaging in regular physical exercise has broad ranging positive health implications including those that improve the metabolic health of the liver. PMID- 26477919 TI - Exercise and the Regulation of Endocrine Hormones. AB - The endocrine system has profound regulatory effects within the human body and thus the ability to control and maintain appropriate function within many physiological systems (i.e., homeostasis). The hormones associated with the endocrine system utilize autocrine, paracrine, or endocrine actions on the cells of their target tissues within these physiologic systems to adjust homeostasis. The introduction of exercise as a stressor to disrupt homeostasis can greatly amplify and impact the actions of these hormones. To that end, the endocrine response to an acute exercise session occurs in a progression of phases with the magnitude of the response being relative to the exercise work intensity or volume. Various physiologic mechanisms are considered responsible for these responses, although not all are completely understood or elucidated. Chronic exercise training does not eliminate the acute exercise response but may attenuate the overall effect of the responsiveness as the body adapts in a positive fashion to the training stimulus. Regrettably, an excessive intensity and/or volume of training may lead to maladaptation and is associated with inappropriate endocrine hormonal responses. The mechanisms leading to a deleterious maladaptive state are not well understood and require additional research for elucidation. PMID- 26477920 TI - Exercise and Regulation of Adipokine and Myokine Production. AB - Skeletal muscle and white adipose tissue are the largest organs in the human body and both tissues act as endocrine organs capable of secreting many bioactive molecules. There has been some confusion about nomenclature and we suggest that the name myokine should be restricted to a protein or molecule secreted from myocytes, whereas the term adipokine should be used to describe proteins and molecules secreted from adipocytes. In fact, many myokines are also produced by adipocytes and we propose to name them adipo-myokines. Many adipo-myokines produced by skeletal muscle or adipose tissue are influenced by exercise. Therefore, it is likely that adipo-myokines may contribute in the mediation of the health benefits of exercise and physical inactivity probably leads to an altered adipo-myokine profile, which could provide a potential mechanism for the association between sedentary behavior and many chronic diseases. Within this review, we evaluate the effects of acute and chronic exercise on myokine, adipokine, and adipo-myokine production. By using the adipo-myokine concept and including both skeletal muscle and adipose tissue, an attempt is made to gain a global view on the beneficial effects of different exercise programs and the underlying pathways. PMID- 26477921 TI - Exercise and the Regulation of Inflammatory Responses. AB - Exercise initiates a cascade of inflammatory events, which ultimately lead to long-term effects on human health. During and after acute exercise in skeletal muscle, interactions between immune cells, cytokines, and other intracellular components, create an inflammatory milieu responsible for the recovery and adaption from an exercise bout. In the systemic circulation, cytokines released from muscle (myokines) mediate metabolic and inflammatory processes. Moderate exercise training results in improvements in systemic inflammation, evident by reductions in acute phase proteins. The anti-inflammatory effects of regular exercise include actions dependent and independent of changes in adipose tissue mass. Future research should encompass approaches, which attempt to integrate other, less-recognized physiological processes with acute and long-term inflammatory changes. This will include investigation into metabolic, endocrine, and immune components of various tissues and organs. PMID- 26477922 TI - Exercise and the Regulation of Immune Functions. AB - Exercise has a profound effect on the normal functioning of the immune system. It is generally accepted that prolonged periods of intensive exercise training can depress immunity, while regular moderate intensity exercise is beneficial. Single bouts of exercise evoke a striking leukocytosis and a redistribution of effector cells between the blood compartment and the lymphoid and peripheral tissues, a response that is mediated by increased hemodynamics and the release of catecholamines and glucocorticoids following the activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. Single bouts of prolonged exercise may impair T-cell, NK-cell, and neutrophil function, alter the Type I and Type II cytokine balance, and blunt immune responses to primary and recall antigens in vivo. Elite athletes frequently report symptoms associated with upper respiratory tract infections (URTI) during periods of heavy training and competition that may be due to alterations in mucosal immunity, particularly reductions in secretory immunoglobulin A. In contrast, single bouts of moderate intensity exercise are "immuno-enhancing" and have been used to effectively increase vaccine responses in "at-risk" patients. Improvements in immunity due to regular exercise of moderate intensity may be due to reductions in inflammation, maintenance of thymic mass, alterations in the composition of "older" and "younger" immune cells, enhanced immunosurveillance, and/or the amelioration of psychological stress. Indeed, exercise is a powerful behavioral intervention that has the potential to improve immune and health outcomes in the elderly, the obese, and patients living with cancer and chronic viral infections such as HIV. PMID- 26477923 TI - Exercise Regulation of Cognitive Function and Neuroplasticity in the Healthy and Diseased Brain. AB - Regular exercise broadly enhances physical and mental health throughout the lifespan. Animal models have provided us with the tools to gain a better understanding of the underlying biochemical, physiological, and morphological mechanisms through which exercise exerts its beneficial cognitive effects. One brain region in particular, the hippocampus, is especially responsive to exercise. It is critically involved in learning and memory and is one of two regions in the mammalian brain that continues to generate new neurons throughout life. Exercise prevents the decline of the hippocampus from aging and ameliorates many neurodegenerative diseases, in part by increasing adult hippocampal neurogenesis but also by activating a multitude of molecular mechanisms that promote brain health. In this chapter, we first describe some rodent models used to study effects of exercise on the brain. Then we review the rodent work focusing on the mechanisms behind which exercise improves cognition and brain health in both the normal and the diseased brain, with emphasis on the hippocampus. PMID- 26477924 TI - Exercise, Autophagy, and Apoptosis. AB - Exercise is a form of physiological stress which is known to induce an adaptational response. It is proposed that both apoptosis and autophagy are processes which are necessary for adaptation to exercise. Apoptosis and autophagy are induced during exercise to limit tissue damage, restore tissue integrity, terminate inflammatory responses, or induce direct signals for adaptation. Apoptosis is induced by specific mediators like reactive oxygen species, cytokines, and hormones. Autophagic pathways are activated by altered proteins/organelles with the aim to conserve and recycle the cellular resources. In this case, the cell is flooded with damaged molecules, the repairing mechanisms are overtaxed, and apoptosis is induced. In conclusion, autophagy seems to be necessary for adaptation by providing locally the conditions for muscle plasticity and apoptosis systemically by mobilizing progenitor cells. PMID- 26477925 TI - Exercise and Stem Cells. AB - Stem cells are traditionally studied in the context of embryonic development, yet studies confirm that a fraction remains in the adult organism for the purpose of daily remodeling and rejuvenation of multiple tissues following injury. Adult stem cells (ASCs) are found in close proximity to vessels and respond to tissue specific cues in the microenvironment that dictate their fate and function. Exercise can dramatically alter strain sensing, extracellular matrix composition, and inflammation, and such changes in the niche likely alter ASC quantity and function postexercise. The field of stem cell biology is still in its infancy and identification and terminology of ASCs continues to evolve; thus, current information regarding exercise and stem cells is lacking. This chapter summarizes the literature that reports on the ASC response to acute exercise and exercise training, with particular emphasis on hematopoietic stem cells, endothelial progenitor cells, and mesenchymal stem cells. PMID- 26477926 TI - Exercise and Gene Expression. AB - Acute and transient changes in gene transcription following a single exercise bout, if reinforced by repeated exercise stimuli, result in the longer lasting effects on protein expression and function that form the basis of skeletal muscle training adaptations. Changes in skeletal muscle gene expression occur in response to multiple stimuli associated with skeletal muscle contraction, various signaling kinases that respond to these stimuli, and numerous downstream pathways and targets of these kinases. In addition, DNA methylation, histone acetylation and phosphorylation, and micro-RNAs can alter gene expression via epigenetic mechanisms. Contemporary studies rely upon "big omics data," in combination with computational and systems biology, to interrogate, and make sense of, the complex interactions underpinning exercise adaptations. The exciting potential is a greater understanding of the integrative biology of exercise. PMID- 26477927 TI - Exercise, Skeletal Muscle and Circulating microRNAs. AB - Regular exercise stimulates numerous structural, metabolic, and morphological adaptations in skeletal muscle. These adaptations are vital to maintain human health over the life span. Exercise is therefore seen as a primary intervention to reduce the risk of chronic disease. Advances in molecular biology, biochemistry, and bioinformatics, combined with exercise physiology, have identified many key signaling pathways as well as transcriptional and translational processes responsible for exercise-induced adaptations. Noncoding RNAs, and specifically microRNAs (miRNAs), constitute a new regulatory component that may play a role in these adaptations. The short single-stranded miRNA sequences bind to the 3' untranslated region of specific messenger RNAs (mRNAs) on the basis of sequence homology. This results in the degradation of the target mRNA or the inhibition of protein translation causing repression of the corresponding protein. While tissue specificity or enrichment of certain miRNAs makes them ideal targets to manipulate and understand tissue development, function, health, and disease, other miRNAs are ubiquitously expressed; however, it is uncertain whether their mRNA/protein targets are conserved across different tissues. miRNAs are stable in plasma and serum and their altered circulating expression levels in disease conditions may provide important biomarker information. The emerging research into the role that miRNAs play in exercise induced adaptations has predominantly focused on the miRNA species that are regulated in skeletal muscle or in circulation. This chapter provides an overview of these current research findings, highlights the strengths and weaknesses identified to date, and suggests where the exercise-miRNA field may move into the future. PMID- 26477929 TI - Preface. PMID- 26477928 TI - Exercise as a Polypill for Chronic Diseases. AB - Exercise may be described as a polypill to prevent and/or treat almost every chronic disease, with obvious benefits such as its low cost and practical lack of adverse effects. Implementing physical activity interventions in public health is therefore a goal at the medical, social, and economic levels. This chapter describes the importance of health promotion through physical activity and discusses the impacts of exercise on the most prevalent chronic diseases, namely metabolic syndrome-related disorders, cardiovascular diseases, cancer, and Alzheimer's disease. For each of these chronic conditions, we discuss the epidemiological evidence supporting a beneficial role of exercise, provide guidelines for exercise prescription, and describe the biological mechanisms whereby exercise exerts its modulatory effects. PMID- 26477930 TI - Cesium Speciation in Dust from Municipal Solid Waste and Sewage Sludge Incineration by Synchrotron Radiation Micro-X-ray Analysis. AB - The chemical behavior of Cs in waste incineration processes is important to consider when disposing of radionuclide-contaminated waste from the Fukushima Daiichi nuclear power plant accident in Japan. To determine the speciation of Cs, we attempted the direct speciation of trace amounts of stable Cs in the dust from municipal solid waste incineration (MSWI) and sewage sludge incineration (SSI) by micro-X-ray fluorescence (MU-XRF) and micro-X-ray absorption fine structure (MU XAFS) at the SPring-8 facility. The MU-XRF results revealed that locally produced Cs was present in MSWI and SSI dust within the cluster size range of 2-10 MUm. The MU-XAFS analysis confirmed that the speciation of Cs in MSWI dust was similar to that of CsCl, while in SSI dusts it was similar to pollucite. The solubility of Cs was considered to be influenced by the exact Cs species present in incineration residue. PMID- 26477931 TI - A comparative study on worldwide genetic diversity and population structure analysis of Plasmodium vivax thrombospondin-related adhesive protein (PvTRAP) and its implications for the vivax vaccine design. AB - Plasmodium vivax thrombospondin-related anonymous protein (PvTRAP) is a promising malaria vaccine candidate; however, it exhibits sequence heterogeneity. Therefore, to design a broadly protective vivax vaccine, it is essential to have adequate information on signatures of selection and geospatial genetic diversity of global PvTRAP. For this purpose, 50 Iranian pvtrap were sequenced and compared with related available global sequences in GenBank. The nucleotide sequence analysis of Iranian pvtrap in comparison with the Sal-1 sequence showed the occurrence of 15 SNPs, and all sites were dimorphic. In total, 12 amino acid substitutions were detected and 2 of which were novel, resulting in 10 haplotypes that 8 of them were not reported in any other geographic regions. In comparison with global population, haplotype and nucleotide diversities were lowest in South Korean populations while higher levels of diversities were observed in Thai and Brazilian P. vivax populations. All 12 amino acid replacements in ectodomain of Iranian PvTRAP were distributed in predicted either B- or T-cells epitope as well as intrinsically unstructured/disordered regions (IURs). The present results revealed that observing the relatively low-level diversity in PvTRAP protein might actually be selected by immune response. In summary, the present analysis in parallel to the limited available published data has shown that genetic diversity in the global pvtrap exhibits low-level diversity and geographic variation. These results are of practical significance for the strategic development and deployment of control measures in particular for development of PvTRAP-based malaria vaccine. PMID- 26477932 TI - Rediscovery of Trypanosoma (Pycnomonas) suis, a tsetse-transmitted trypanosome closely related to T. brucei. AB - The African tsetse-transmitted trypanosomes are considered to be a well-known group of parasitic protozoa, but in 2008 a novel and distinctive trypanosome related to Trypanosoma brucei was discovered among tsetse isolates from Msubugwe in Tanzania. The host range, distribution and potential pathogenicity of this new trypanosome remain to be elucidated; such studies would be facilitated by a sensitive and specific identification method. Here, we identified two highly repetitive elements in the genome of the new trypanosome: a 177 bp repeat, which was located predominantly on the highly abundant minichromosomes, and a 138 bp repeat, which was widely dispersed in the genome. A PCR test based on each repeat was specific for the new trypanosome and sensitive to <0.1 trypanosome equivalent. These PCR tests were used to identify trypanosomes in archival pig blood smears from the 1950's, confirming the identity of the Msubugwe trypanosome as Trypanosoma (Pycnomonas) suis. We also present data on the molecular karyotype and spliced leader (SL, miniexon) repeat of the new trypanosome, both of which distinguish T. suis from other, better-known African tsetse-transmitted trypanosomes. The rediscovery of T. suis opens new lines of research into the evolution and biology of the African trypanosomes. PMID- 26477933 TI - Deep sequencing reveals the viral adaptation process of environment-derived H10N8 in mice. AB - The H10N8 virus was isolated from the water of Dongting Lake, China. Mice were infected while showing no obvious symptoms and replication was restricted to the lungs. When the wild-type virus was serially passaged in the lungs of mice, the resulting viruses became lethal and capable of replication in many other organs. This offered an applicable model for the exploration of viral genome gradual mutation during adaptation in mice. The different passage viruses from mice lung lavage were named P1, P3, P5, and P7, respectively. We sequenced the four viruses using next-generation sequencing (NGS) to analyze the dynamics of the H10N8 viral genome, polymorphism, and amino acid mutation of related proteins. We aimed to demonstrate how a mutant strain of low pathogenicity could become lethal to mice. Using Illumina high-throughput data, we detected the gradual mutations of F277S, C278Q, F611S and L653P in the polymerase acidic (PA) protein, and of L207V and E627K in the PB2 protein during adaptation. Interestingly, many amino acid sites mutated quickly; the others did so more slowly and remained in a heterozygous state for several generations. The PA amino acids S277 and Q278 have previously been found in clinical wild-type strains, including the human-H10N8 isolate in 2013. This demonstrates that the wild-type H10N8 virus had mutated to adapt to mammalian hosts. These data provide important reference information for influenza virus research. PMID- 26477934 TI - Molecular characterization of pig epidemic diarrhoea viruses isolated in Japan from 2013 to 2014. AB - Since October 2013, approximately 1000 outbreaks of porcine epidemic diarrhoea (PED) have occurred, spanning almost all prefectures of Japan, after a period of seven years without a reported case. In order to consider occurrence factor of PED outbreaks, we determined the whole-genome sequences of 38 PED virus (PEDV) strains from diarrheal samples collected at swine farms in 18 prefectures between 2013 and 2014 using next-generation sequencing technology. Using these data, we investigated genetic variation among the recent Japanese PEDV strains and the genetic relationships between these strains and global PEDV strains isolated recently from multiple swine-industrial countries. Eleven out of 38 PEDV strains were isolated successfully on Vero cells with trypsin treatment and subjected to genome sequence analysis. In a comparative genome analysis, we detected two novel PEDV variants, TTR-2/JPN/2014 and MYG-1/JPN/2014, with large deletions in the spike and ORF3 genes, respectively. A phylogenetic analysis based on the spike gene showed that the 38 Japanese PEDV strains were classified into two PEDV types: the North American type with high virulence (n=34) and the INDEL type (n=4). In addition, the recent Japanese PEDV isolates had a close relationship to global PEDV strains isolated in recent years than to the classical PEDV strains detected in Japan the past decades ago. Moreover, the phylogenetic dendrogram of the complete genomes also indicated that the 38 Japanese PEDV strains, including the two novel PEDV variants discovered in this study, are closely related to the PEDV strains that were widespread in the United States and Korea in 2013-2014. These findings suggest that the re-emergence of PED outbreaks since the last reported case in 2006 was caused by the introduction of recent PEDV strains to Japan from overseas. PMID- 26477935 TI - Papillary adenoma arising from an extensive biliary low-grade intraepithelial neoplasia. PMID- 26477936 TI - Pushing the Boundaries of Chemical Protein Synthesis: The Case of Ubiquitin Chains and Polyubiquitinated Peptides and Proteins. AB - Chemical synthesis offers unique opportunities to prepare proteins with precise control of the atomic composition. Thanks to recent breakthroughs in synthetic methods, the preparation of large and complex proteins composed of 200-300 residues has now become possible. With these advances, a unique toolbox has been created to enable chemical biologists to investigate proteins that are difficult or even impossible to achieve otherwise, such as posttranslationally modified proteins and proteins composed of d-amino acids. In this review we describe the latest achievements in constructing protein conjugates of record sizes, such as those that are involved in the ubiquitin system. PMID- 26477937 TI - Embryological exposure to valproic acid induces social interaction deficits in zebrafish (Danio rerio): A developmental behavior analysis. AB - Changes in social behavior are associated with brain disorders, including mood disorders, stress, schizophrenia, Alzheimer's disease, and autism spectrum disorders (ASD). Autism is a complex neurodevelopmental disorder characterized by deficits in social interaction, impaired communication, anxiety, hyperactivity, and the presence of restricted interests. Zebrafish is one of the most social vertebrates used as a model in biomedical research, contributing to an understanding of the mechanisms that underlie social behavior. Valproic acid (VPA) is used as an anti-epileptic drug and mood stabilizer; however, prenatal VPA exposure in humans has been associated with an increased incidence of autism and it can also affect fetal brain development. Therefore, we conducted a behavioral screening at different periods of zebrafish development at 6, 30, 70, and 120dpf (days postfertilization) after VPA exposure in the early development stage to investigate social behavior, locomotion, aggression, and anxiety. VPA (48MUM) exposure during the first 48hpf (hours postfertilization) did not promote changes on survival, morphology, and hatching rate at 24hpf, 48hpf, and 72hpf. The behavioral patterns suggest that VPA exposure induces changes in locomotor activity and anxiety at different developmental periods in zebrafish. Furthermore, a social interaction deficit is present at 70dpf and 120dpf. VPA exposure did not affect aggression in the adult stage at 70dpf and 120dpf. This is the first study that demonstrated zebrafish exposed to VPA during the first 48h of development exhibit deficits in social interaction, anxiety, and hyperactivity at different developmental periods. PMID- 26477938 TI - Taxonomy, biogeography and importance of Heterobasidion viruses. AB - The genus Heterobasidion consists of several species of necrotrophic and saprotrophic fungi, and includes some of the most detrimental organisms in boreal conifer forests. These fungi host a widespread and diverse mycovirus community composed of more than 16 species of Partitiviridae, a species of Narnaviridae and one taxonomically unassigned virus related to the Curvularia thermal tolerance virus. These viruses are able to cross species borders, co-infect single host strains and cause phenotypic changes in their hosts. The abundance of viruses increases over time in Heterobasidion infection centers, and they are targeted by fungal RNA interference. Long-term field studies are essential for obtaining a comprehensive view of virus effects in the nature. PMID- 26477939 TI - Unveiling transient protein-protein interactions that modulate inhibition of alpha-synuclein aggregation by beta-synuclein, a pre-synaptic protein that co localizes with alpha-synuclein. AB - Pathology in Parkinson's disease is linked to self-association of alpha-Synuclein (alphaS) into pathogenic oligomeric species and highly ordered amyloid fibrils. Developing effective therapeutic strategies against this debilitating disease is critical and betaS, a pre-synaptic protein that co-localizes with alphaS, can act as an inhibitor of alphaS assembly. Despite the potential importance of betaS as an inhibitor of alphaS, the nature, location and specificity of the molecular interactions between these two proteins is unknown. Here we use NMR paramagnetic relaxation enhancement experiments, to demonstrate that betaS interacts directly with alphaS in a transient dimer complex with high specificity and weak affinity. Inhibition of alphaS by betaS arises from transient alphaS/betaS heterodimer species that exist primarily in head- to- tail configurations while alphaS aggregation arises from a more heterogeneous and weaker range of transient interactions that include both head-to-head and head-to-tail configurations. Our results highlight that intrinsically disordered proteins can interact directly with one another at low affinity and that the transient interactions that drive inhibition versus aggregation are distinct by virtue of their plasticity and specificity. PMID- 26477940 TI - Spectromicroscopic insights for rational design of redox-based memristive devices. AB - The demand for highly scalable, low-power devices for data storage and logic operations is strongly stimulating research into resistive switching as a novel concept for future non-volatile memory devices. To meet technological requirements, it is imperative to have a set of material design rules based on fundamental material physics, but deriving such rules is proving challenging. Here, we elucidate both switching mechanism and failure mechanism in the valence change model material SrTiO3, and on this basis we derive a design rule for failure-resistant devices. Spectromicroscopy reveals that the resistance change during device operation and failure is indeed caused by nanoscale oxygen migration resulting in localized valence changes between Ti(4+) and Ti(3+). While fast reoxidation typically results in retention failure in SrTiO3, local phase separation within the switching filament stabilizes the retention. Mimicking this phase separation by intentionally introducing retention-stabilization layers with slow oxygen transport improves retention times considerably. PMID- 26477941 TI - Fully-sialylated alpha-chain of complement 4-binding protein: Diagnostic utility for ovarian clear cell carcinoma. AB - OBJECTIVE: While a certain fraction of endometriomas can develop de novo epithelial ovarian cancer (EOC) such as clear cell carcinoma (OCCC), there is currently no useful biomarker available for early detection of OCCC from endometriomas. The aim of this study was to describe the diagnostic utility of a novel biomarker for EOC especially for OCCC to distinguish from endometrioma. METHODS: More than 100,000 glycan structures of serum glycoproteins obtained from 134 pretreatment all stage EOC patients (including 45 OCCCs) and 159 non-cancer control women (including 36 endometriomas) were explored for a mass spectrum approach. Diagnostic accuracy of identified biomarker was compared to the one of CA-125 by comparing area under curve (AUC) and positive/negative predictive values (PPV and NPV). RESULTS: A2160, a fully-sialylated alpha-chain of complement 4-binding protein, was identified as a candidate target marker. A2160 was significantly elevated in all stages of OCCC compared to with endometriomas. Diagnostic accuracy of A2160 (cutoff 1.6U/mL) to distinguish early stage OCCC from endometrioma is significantly higher than that of CA-125 (cutoff 35IU/L): AUC for A2160 versus CA-125, 0.92 versus 0.67; PPV 95% versus 64%; and NPV 85% versus 58%. In addition, fully-sialylated glycans had a higher accuracy for diagnosing EOC as compared to partially-sialylated glycans of alpha-chain of complement 4-binding protein. CONCLUSION: Our study suggested that A2160 may be a useful biomarker to distinguish early-stage OCCC from endometrioma. This new biomarker can be potentially applied for the monitoring of endometrioma patients, making possible the early diagnosis of OCCC. PMID- 26477942 TI - A Qualitative Study of Factors That Influence Contraceptive Choice among Adolescent School-Based Health Center Patients. AB - STUDY OBJECTIVE: Long-acting reversible contraceptive (LARC) methods can prevent teen pregnancy yet remain underutilized by adolescents in the United States. Pediatric providers are well positioned to discuss LARCs with adolescents, but little is known about how counseling should occur in pediatric primary care settings. We explored adolescent womens' attitudes and experiences with LARCs to inform the development of adolescent-centered LARC counseling strategies. DESIGN: Qualitative analysis of one-on-one interviews. SETTING: Participants were recruited from 2 urban school-based, primary care centers. PARTICIPANTS: Thirty adolescent women aged 14-18 years, diverse in race/ethnicity, and sexual experience. INTERVENTIONS: Interviews were audio-recorded, transcribed, and coded using inductive and deductive coding. MAIN OUTCOME MEASURE: Major themes were identified to integrate LARC-specific adolescent preferences into existing counseling approaches. RESULTS: Participants (mean age, 16.2 years; range, 14-18 years) represented a diverse range of racial and/or ethnic identities. Half (15/30) were sexually active and 17% (5/30) reported current or past LARC use. Five themes emerged regarding key factors that influence LARC choice, including: (1) strong preferences about device-specific characteristics; (2) previous exposure to information about LARCs from peers, family members, or health counseling sessions; (3) knowledge gaps about LARC methods that affect informed decision-making; (4) personal circumstances or experiences that motivate a desire for effective and/or long-acting contraception; and (5) environmental constraints and supports that might influence adolescent access to LARCs. CONCLUSION: We identified 5 factors that influence LARC choice among adolescent women and propose a framework for incorporating these factors into contraceptive counseling services in pediatric primary care settings. PMID- 26477943 TI - Robust orthogonal recombination system for versatile genomic elements rearrangement in yeast Saccharomyces cerevisiae. AB - Rearrangement of genomic DNA elements in a dynamic controlled fashion is a fundamental challenge. Site-specific DNA recombinases have been tamed as a powerful tool in genome editing. Here, we reported a DNA element rearrangement on the basis of a pairwise orthogonal recombination system which is comprised of two site-specific recombinases of Vika/vox and Cre/loxp in yeast Saccharomyces Creevisiae. Taking the advantage of the robust pairwise orthogonality, we showed that multi gene elements could be organized in a programmed way, in which rationally designed pattern of loxP and vox determined the final genotype after expressing corresponding recombinases. Finally, it was demonstrated that the pairwise orthogonal recombination system could be utilized to refine synthetic chromosome rearrangement and modification by loxP-mediated evolution, SCRaMbLE, in yeast cell carrying a completely synthesized chromosome III. PMID- 26477944 TI - Chromium supplementation improved post-stroke brain infarction and hyperglycemia. AB - Hyperglycemia is common after acute stroke and is associated with a worse outcome of stroke. Thus, a better understanding of stress hyperglycemia is helpful to the prevention and therapeutic treatment of stroke. Chromium is an essential nutrient required for optimal insulin activity and normal carbohydrate and lipid metabolism. Beyond its nutritional effects, dietary supplement of chromium causes beneficial outcomes against several diseases, in particular diabetes-associated complications. In this study, we investigated whether post-stroke hyperglycemia involved chromium dynamic mobilization in a rat model of permanent focal cerebral ischemia and whether dietary supplement of chromium improved post-stroke injury and alterations. Stroke rats developed brain infarction, hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Post-stroke hyperglycemia was accompanied by elevated secretion of counter-regulatory hormones including glucagon, corticosterone, and norepinephrine, decreased insulin signaling in skeletal muscles, and increased hepatic gluconeogenesis. Correlation studies revealed that counter-regulatory hormone secretion showed a positive correlation with chromium loss and blood glucose increased together with chromium loss. Daily chromium supplementation increased tissue chromium levels, attenuated brain infarction, improved hyperglycemia, and decreased plasma levels of glucagon and corticosterone in stroke rats. Our findings suggest that stroke rats show disturbance of tissue chromium homeostasis with a net loss through urinary excretion and chromium mobilization and loss might be an alternative mechanism responsible for post-stroke hyperglycemia. PMID- 26477945 TI - Accumulation of reactivity to MBP sensitizes TRAIL mediated oligodendrocyte apoptosis in adult sub cortical white matter in a model for human multiple sclerosis. AB - Reactivity to myelin associated proteins is the hallmark of human multiple sclerosis (M.S) and its experimental counterparts. However, the nature of such reactivity has not been described fully. Herein, we report that myelin basic protein (MBP) reactivity accumulates in a rat model for M.S. over a period of time and sensitizes TRAIL mediated progressive oligodendrocyte apoptosis. We used active immunization by Myelin Oligodendrocyte Glycoprotein (MOG, 50 MUg) to study chronic remitting relapsing encephalomyelitis in rats. A time point analysis of the progressive disease revealed cumulative accumulation of anti myelin basic protein antibodies during the disease progression with minimal change in the anti MOG antibodies. Increased reactivity to MBP was studied to sensitize TNF related apoptosis-inducing ligand (TRAIL) and other proinflammatory cytokines in a cumulative fashion leading to the Caspase dependent apoptosis of oligodendrocytes and myelin loss. In a rescue experiment, we could limit the demyelination and prevent disease progression by neutralizing the effector, TRAIL in an early stage of the disease. This is the first study to identify the accumulation of MBP antibodies in MOG induced EAE which possibly leads to TRAIL sensitized oligodendrocyte apoptosis in the white mater of EAE rats. This finding stresses on the need to study MBP antibody titers in M.S. patients and therefore might serve as an alternate marker for progressive demyelination. PMID- 26477947 TI - Giant electro-optic effect in Ge/SiGe coupled quantum wells. AB - Silicon-based photonics is now considered as the photonic platform for the next generation of on-chip communications. However, the development of compact and low power consumption optical modulators is still challenging. Here we report a giant electro-optic effect in Ge/SiGe coupled quantum wells. This promising effect is based on an anomalous quantum-confined Stark effect due to the separate confinement of electrons and holes in the Ge/SiGe coupled quantum wells. This phenomenon can be exploited to strongly enhance optical modulator performance with respect to the standard approaches developed so far in silicon photonics. We have measured a refractive index variation up to 2.3 * 10(-3) under a bias voltage of 1.5 V, with an associated modulation efficiency V(pi)L(pi) of 0.046 V cm. This demonstration paves the way for the development of efficient and high speed phase modulators based on the Ge/SiGe material system. PMID- 26477946 TI - Response to peripheral immune stimulation within the brain: magnetic resonance imaging perspective of treatment success. AB - Chronic peripheral inflammation in diseases such as rheumatoid arthritis leads to alterations in central pain processing and consequently to mood disorders resulting from sensitization within the central nervous system and enhanced vulnerability of the medial pain pathway. Proinflammatory cytokines such as tumor necrosis factor (TNF) alpha play an important role herein, and therapies targeting their signaling (i.e., anti-TNF therapies) have been proven to achieve good results. However, the phenomenon of rapid improvement in the patients' subjective feeling after the start of TNFalpha neutralization remained confusing, because it was observed long before any detectable signs of inflammation decline. Functional magnetic resonance imaging (fMRI), enabling visualization of brain activity upon peripheral immune stimulation with anti-TNF, has helped to clarify this discrepancy. Moreover, fMRI appeared to work as a reliable tool for predicting prospective success of anti-TNF therapy, which is valuable considering the side effects of the drugs and the high therapy costs. This review, which is mainly guided by neuroimaging studies of the brain, summarizes the state-of-the art knowledge about communication between the immune system and the brain and its impact on subjective well-being, addresses in more detail the outcome of the abovementioned anti-TNF fMRI studies (rapid response to TNFalpha blockade within the brain pain matrix and differences in brain activation patterns between prospective therapy responders and nonresponders), and discusses possible mechanisms for the latter phenomena and the predictive power of fMRI. PMID- 26477948 TI - The Masquerading Cyst: Extraparenchymal Neurocysticercosis Presenting as Acute Meningitis. PMID- 26477949 TI - Radiation Effects on Cognitive Function Among Atomic Bomb Survivors Exposed at or After Adolescence. AB - BACKGROUND: The objective of this study was to investigate radiation effects on longitudinal pre-dementia cognitive decline among participants who developed dementia as well as on those who did not develop dementia during follow-up. METHODS: Measuring cognitive function with the Cognitive Abilities Screening Instrument approximately every 2 years, we followed 1844 atomic bomb survivors participating in the Adult Health Study of the Radiation Effects Research Foundation from 1992 to 2011. Participants were adolescents or older when exposed to between 0 and 4 Gy. Approximately 15% and 40% of participants were exposed to >=1 Gy and <5 mGy, respectively. At study start, participants were dementia-free and between 60 and 80 years old. Three-quarters of the participants returned after baseline, averaging 8.4 years of follow-up. During follow-up, 313 developed dementia. We used cognitive scores before dementia onset for analysis and a mixed effects model to estimate radiation effects on longitudinal change of cognition, adjusting for dementia occurrence, age, sex, and education. RESULTS: Cognition level was significantly associated with age, education, and dementia occurrence but not with radiation dose or sex. Cognitive decline accelerated with increasing age, especially among participants who developed dementia. Neither radiation nor education was significantly associated with the degree of deterioration with age. Radiation did not modify the different cognitive decline by dementia occurrence. CONCLUSIONS: Radiation did not significantly affect cognition among atomic bomb survivors exposed at or after adolescence. PMID- 26477950 TI - Cardiovascular Disease Prevention in Men with Vascular Erectile Dysfunction: The View of the Preventive Cardiologist. AB - Vascular erectile dysfunction is a powerful marker of increased cardiovascular risk. However, current guidelines lack specific recommendations on the role that the evaluation of vascular erectile dysfunction should play in cardiovascular risk assessment, as well on the risk stratification strategy that men with vascular erectile dysfunction should undergo. In the last 3 years, erectile dysfunction experts have made a call for more specific guidance and have proposed the selective use of several prognostic tests for further cardiovascular risk assessment in these patients. Among them, stress testing has been prioritized, whereas other tests are considered second-line tools. In this review, we provide additional perspective from the viewpoint of the preventive cardiologist. We discuss the limitations of current risk scores and the potential interplay between erectile dysfunction assessment and the use of personalized prognostic tools, such as the coronary artery calcium score, in the cardiovascular risk stratification and management of men with vascular erectile dysfunction. Finally, we present an algorithm for primary care physicians, urologists, and cardiologists to aid clinical decision-making. PMID- 26477951 TI - Reversal of Fortune: Central Nervous System Blastomycosis. PMID- 26477952 TI - Global Landscape of Total Organic Carbon, Nitrogen and Phosphorus in Lake Water. AB - Human activities continue to increase the amount of carbon (C), nitrogen (N) and phosphorus (P) in lakes, which may cause serious environmental and human health problems. Global landscape of total organic C (TOC), N and P in lake water is still poorly known. Using a global data set that covers ~8300 lakes from 68 countries/regions spanning six continents, we estimate that global mean concentrations and storage in lake water are 5.578 mg L(-1) and 984.0 Tg for TOC, 0.526 mg L(-1) and 92.8 Tg for TN, and 0.014 mg L(-1) and 2.5 Tg for TP. These lake elements are significantly interrelated and in uneven distribution, being associated with morphological characteristics and climate conditions. We proposed that global C, N and P cycles should be considered as a whole in biogeochemical studies and policy-making related to environmental protection. PMID- 26477953 TI - Theory of mind ability predicts prognosis of outpatients with major depressive disorder. AB - A theory of mind (ToM) deficit in patients with major depressive episodes is associated with difficulty in social adjustment, and thus may indicate a poorer prognosis. We investigated the association between ToM deficits and the outcome in patients who had recovered from major depressive episodes. We evaluated ToM abilities of 100 patients with major depressive disorder during a period of remission. The patients were followed up for one year and their outcomes observed. After one year, patients who had a ToM deficit according to a second order false belief question relapsed significantly more frequently than did patients who did not have a deficit (Fisher's exact test P<0.0001; relative risk (RR)=8.286; CI 2.608, 26.324). Significant differences between these two groups were shown in scores of the Global Assessment of Functioning Scale (P<0.0001). Our results suggest that a ToM deficit after symptom remission in patients with major depressive disorder predicts a higher relapse rate and lower social function one year after recovering from a major depressive episode. PMID- 26477954 TI - Evidence against mood-congruent attentional bias in Major Depressive Disorder. AB - Depression is consistently associated with biased retrieval and interpretation of affective stimuli, but evidence for depressive bias in earlier cognitive processing, such as attention, is mixed. In five separate experiments, individuals with depression (three experiments with clinically diagnosed major depression, two experiments with dysphoria measured via the Beck Depression Inventory) completed three tasks designed to elicit depressive biases in attention, including selective attention, attentional switching, and attentional inhibition. Selective attention was measured using a modified emotional Stroop task, while attentional switching and inhibition was examined via an emotional task-switching paradigm and an emotional counter task. Results across five different experiments indicate that individuals with depression perform comparably with healthy controls, providing corroboration that depression is not characterized by biases in attentional processes. PMID- 26477956 TI - Divergent de novo synthesis of all eight stereoisomers of 2,3,6 trideoxyhexopyranosides and their oligomers. AB - All eight possible stereoisomers of 2,3,6-trideoxyhexopyranosides are prepared systematically from furan derivatives by a sequence of Achmatowicz rearrangement, Pd-catalysed glycosidation, and chiral catalyst-controlled tandem reductions. This sequence provides access to all possible stereoisomers of naturally occurring rhodinopyranosides, amicetopyranosides, disaccharide narbosine B, and other unnatural oligomeric 2,3,6-trideoxyhexopyranosides. It comprises a unique and systematic strategy for the de novo synthesis of deoxysugars. PMID- 26477957 TI - A supercell approach to the doping effect on the thermoelectric properties of SnSe. AB - We study the thermoelectric properties of tin selenide (SnSe) by using first principles calculations coupled with the Boltzmann transport theory. A recent experimental study showed that SnSe gives an unprecedented thermoelectric figure of merit ZT of 2.6 +/- 0.3 in the high-temperature (>750 K) phase, while ZT in the low-temperature phase (<750 K) is much smaller than that of the high temperature phase. Here we explore the possibility of increasing ZT in the low temperature regime by carrier doping. For this purpose, we adopt a supercell approach to model the doped systems. We first examine the validity of the conventional rigid-band approximation (RBA), and then investigate the thermoelectric properties of Ag or Bi doped SnSe as p- or n-type doped materials using our supercell method. We found that both types of doping improve ZT and/or the power factor of the low-temperature phase SnSe, but only after the adjustment of the appropriate doping level is achieved. PMID- 26477955 TI - First-episode bipolar disorder is associated with erythrocyte membrane docosahexaenoic acid deficits: Dissociation from clinical response to lithium or quetiapine. AB - Deficits in long-chain omega-3 (LCn-3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be associated with the pathophysiology of bipolar disorder. However, LCn-3 fatty acid status at the initial onset of mania and its association with treatment response are not known. Erythrocyte membrane fatty acid composition was determined in first-episode bipolar manic or mixed (n=40) and healthy (n=40) subjects. Mood symptom ratings were obtained with the Young Mania Rating Scale (YMRS) and the Hamilton Depression Rating Scale (HDRS). Erythrocyte fatty acid composition and clinical ratings were also determined within a sub-group of bipolar subjects following 8-week (n=19) or 52-week (n=11) open-label treatment with lithium or quetiapine. At baseline bipolar subjects exhibited significantly lower erythrocyte docosahexaenoic acid (DHA, 22:6n-3) composition compared with healthy subjects (-23%, p<0.0001). EPA (20:5n-3) and docosapentanoic acid (22:5n-3), and LCn-6 fatty acids including arachidonic acid were not different. Following 8- or 52-week treatment with lithium or quetiapine, YMRS and HDRS total scores decreased significantly whereas erythrocyte fatty acids including DHA did not change. These data indicate that selective erythrocyte DHA deficits coincide with the initial onset of manic symptoms, and reductions in mood symptoms following treatment are not mediated by changes in fatty acid status. PMID- 26477958 TI - Angiotensin 2 Type 1 Receptor Blockade with Neprilysin Inhibition for Chronic Heart Failure: A New Paradigm? PMID- 26477959 TI - Electrocardiographic Criteria for Left Ventricular Hypertrophy in Asians Differs from Criteria Derived from Western Populations--Community-based Data from an Asian Population. AB - INTRODUCTION: Electrocardiographic (ECG) criteria for left ventricular hypertrophy (LVH), such as the Cornell and Sokolow-Lyon voltage criteria were derived from Western populations. However, their utility and accuracy for diagnosing echocardiographic LVH in Asian populations is unclear. The objective of this study was to assess the accuracy of ECG criteria for LVH in Asians and to determine if alternative gender-specific ECG cut-offs may improve its diagnostic accuracy. MATERIALS AND METHODS: ECG and echocardiographic assessments were performed on 668 community-dwelling Asian adults (50.9% women; 57 +/- 10 years) in Singapore. The accuracy of ECG voltage criteria was compared to echocardiographic LVH criteria based on the American Society of Echocardiography guidelines, and Asian ethnicity and gender-specific partition values. RESULTS: Echocardiographic LVH was present in 93 (13.6%) adults. Cornell criteria had low sensitivity (5.5%) and high specificity (98.9%) for diagnosing LVH. Modified gender specific cut-offs (18 mm in women, 22 mm in men) improved sensitivity (8.8% to 17.5%, 0% to 14.7%, respectively) whilst preserving specificity (98.2% to 94.2%, 100% to 95.8%). Similarly, Sokolow-Lyon criteria had poor sensitivity (7.7%) and high specificity (96.1%) for diagnosing LVH. Lowering the cut-off value from 35 mm to 31 mm improved the sensitivity in women from 3.5% to 14% while preserving specificity at 94.2%. A cut-off of 36 mm was optimal in men (sensitivity of 14.7%, specificity of 95.5%). CONCLUSION: Current ECG criteria for LVH derived in Western cohorts have limited sensitivity in Asian populations. Our data suggests that ethnicity- and gender-specific ECG criteria may be needed. PMID- 26477960 TI - Thyroid Autoimmune Antibodies and Major Depressive Disorder in Women. AB - INTRODUCTION: Anti-thyroid antibodies are associated with extra-thyroid diseases such as Graves' ophthalmopathy and Hashimoto's encephalopathy. Some evidence suggests that anti-thyroid antibodies are also associated with depression. Interleukin (IL)-17 appears to play an important role in autoimmune thyroid disease. This study investigated whether specific thyroid autoantibodies and IL 17 distinguished persons with depression from non-depressed controls. MATERIALS AND METHODS: Forty-seven adult females with non-psychotic, current major depressive disorder and 80 healthy female controls participated in this study. Thyroid peroxidase antibodies, thyroglobulin antibodies, thyroid-stimulating hormone (TSH) receptor antibodies, free T3 and T4, TSH and IL-17 were measured from the serum. Measurements were repeated to assess test-retest reliability. Receiver operating characteristic (ROC) curves were used to estimate discriminatory values of the measurements. Differences between groups and associations between the clinical and biochemical assessments were analysed. RESULTS: Median TSH receptor antibody concentration was significantly higher in the depressed than control group (P <0.001). Area under the ROC curve was 0.80 (95% CI, 0.73 to 0.88). Higher TSH receptor antibody titres were associated with greater depression severity scores (r = 0.33, P <0.05). IL-17 levels were not associated with TSH receptor antibody levels or depression severity scores. Thyroid function and other thyroid autoantibodies were not associated with depression severity. CONCLUSION: TSH receptor antibodies might be a biomarker of immune dysfunction in depression. PMID- 26477961 TI - Genomics of Hereditary Colorectal Cancer: Lessons Learnt from 25 Years of the Singapore Polyposis Registry. AB - INTRODUCTION: The Singapore Polyposis Registry (SPR) was established in 1989 in Singapore General Hospital (SGH). The aims were to provide a central registry service to facilitate identification, surveillance and management of families and individuals at high risk of colorectal cancer. MATERIALS AND METHODS: This is a review of published literature in the department. RESULTS: The registry currently has 253 families with several genetic conditions-93 familial adenomatous polyposis (FAP) families, 138 Amsterdam-criteria positive presumed Lynch syndrome (LS) families, 12 families with Peutz Jeghers syndrome, 2 families with Cowden's syndrome, and 8 families with hereditary mixed polyposis syndrome (HMPS). There are also 169 families with a strong family history of colorectal cancer but no abnormal genes yet identified. In FAP, a diagnostic tool developed has allowed a 94% local APC germline detection rate in FAP families. Knowledge obtained studying the phenotype of FAP patients has allowed better choice of surgery between ileal pouch anal anastomosis (IPAA) against an ileal-rectal anastomosis (IRA). In LS, our review has noted a highly heterogenous mutational spectrum and novel variants made up 46.7% (28/60) of all variants identified in this cohort. This may suggest that our Southeast Asian ethnic groups have distinct mutational variants from Western populations. Pathogenic mutations were only confined to MLH1 and MSH2, and identified in 28.8% of families. CONCLUSION: The impact of predictive gene testing for hereditary cancer risk in clinical practice has allowed evolution of care. Risk-reducing surgery and aggressive surveillance allows reduction in morbidity and mortality of patients. The SPR will continue to grow and improve outcomes in hereditary colorectal cancer patients and families. PMID- 26477962 TI - Disseminated Bacillus Calmette-Guerin and Susceptibility to Mycobacterial Infections-Implications on Bacillus Calmette-Guerin Vaccinations. AB - Bacillus Calmette-Guerin (BCG) is a live vaccine and has the potential to cause local disease and systemic dissemination in immunocompromised hosts, including infants who are infected with human immunodeficiency virus (HIV) through vertical transmission, and patients with primary immunodeficiencies (PID) such as severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), hyper-IgM syndrome, and defects of the IL12- IFNgamma axis (Mendelian susceptibility to mycobacterial diseases, MSMD). Disseminated BCG is extremely difficult to treat. The chance of complete eradication is low unless functional immune response is restored by haematopoietic stem cell transplant. Prolonged use of anti mycobacterial drugs often causes organ toxicities and drug resistance. Inflammatory complications which develop upon immunoreconstitution post transplant may necessitate immunosuppressive treatment, which adversely affect immune recovery and increases risks of opportunistic infections. Multiple BCG reactivations can occur in patients with CGD and MSMD, and BCG can remain latent until reactivations take place in adulthood and manifest as disease. It is important for neonatologists, general practitioners, primary care clinicians and nurses working in maternal and child care centres to be aware of BCG-related complications, which may be the first sign of an underlying immunodeficiency. As neonatal BCG is included in standard vaccination schedule in many countries, it is a challenge to identify and avoid administration of BCG to infants who potentially have PIDs. Deferring BCG vaccination is recently advocated to protect highly vulnerable populations, but the appropriate strategy is yet to be determined. Newborn screening for SCID offers a potential to avoid this complication, if an integrated system of screening and vaccination can be organised. PMID- 26477963 TI - Does Limited Tourniquet Usage in Primary Total Knee Arthroplasty Result in Better Functional Outcomes? PMID- 26477964 TI - A Tribute to Tham Cheok Fai, "Founding Father" of Singapore Neurosurgery. PMID- 26477965 TI - Dr Tan Ngoh Chuan (1931 - 2015). PMID- 26477966 TI - Improvement of the electron collection efficiency in porous hematite using a thin iron oxide underlayer: towards efficient all-iron based photoelectrodes. AB - Different approaches have been explored to increase the water oxidation activity of nanostructured hematite (alpha-Fe2O3) photoanodes, including doping with various elements, surface functionalization with both oxygen evolving catalysts (OEC) and functional overlayers and, more recently, the introduction of ultrathin oxide underlayers as tunneling back contacts. Inspired by this latter strategy, we present here a photoanode design with a nanometric spin-coated iron oxide underlayer coupled with a mesoporous hematite film deposited by electrophoresis. The electrodes equipped with the thin underlayer exhibit a four-fold improvement in photoactivity over the simple hematite porous film, reaching a stable photocurrent density of ca. 1 mA cm(-2) at 0.65 V versus the saturated calomel electrode (SCE) at pH 13.3 (NaOH 0.1 M) under air mass (AM) 1.5G illumination. A further improvement to 1.5 mA cm(-2) is observed after decoration of the hematite surface with a Fe(iii)-OEC. These results demonstrate that by combining different iron oxide morphologies, it is possible to improve the selectivity of the interfaces towards both electron collection at the back contact and hole transfer to the electrolyte, obtaining an efficient all-iron based photoelectrode entirely realized with simple wet solution scalable procedures. PMID- 26477967 TI - Endosonography for lung cancer staging: predictors for false-negative outcomes. AB - OBJECTIVES: Non-small cell lung cancer (NSCLC) guidelines recommend endosonography (endobronchial [EBUS] and/or transesophageal ultrasound [EUS]) as the initial step for mediastinal tissue staging. Identifying predictors for false negative results could help establish which patients should undergo confirmatory surgical staging. MATERIALS AND METHODS: 775 NSCLC patients staged negative by EBUS, EUS or combined EUS/EBUS were retrospectively analyzed. Predictors of false negative outcomes were identified by logistic regression analysis. RESULTS AND CONCLUSION: Three predictors for false-negative outcomes were identified: central location of the lung tumor (OR 3.7/4.5/3.6 for EBUS, EUS and EUS/EBUS respectively, p<0.05), nodal enlargement on CT (OR 3.2/2.5/4.9 for EBUS, EUS and EUS/EBUS respectively, p<0.05) and FDG-avidity of N2/N3 lymph node stations on PET (OR 4.2/4.0/7.5 for EBUS, EUS and EUS/EBUS respectively, p<0.05). One subgroup (peripheral lung tumor, nodal enlargement on CT without FDG-avidity for N2/N3) had a low predicted probability (7.8%) for false-negative EUS. For combined EUS/EBUS, two subgroups were identified: peripheral located tumor with nodal enlargement on CT but without FDG-avidity for N2/N3 (predicted probability 4.7%) and centrally located tumor without affected lymph nodes on CT or PET (predicted probability 3.4%). In conclusion, for specific well-defined subsets of NSCLC patients the low predicted probability of metastasis after negative endosonography might justify omitting confirmatory surgical staging. PMID- 26477968 TI - Treatment of isolated mediastinal and hilar recurrence of lung cancer with bronchoscopic endobronchial ultrasound guided intratumoral injection of chemotherapy with cisplatin. AB - PURPOSE: A common pattern of recurrence in lung cancer after receiving full dose external beam radiation therapy (EBRT) to targeted sites is isolated mediastinal and hilar recurrence (IMHR). Treatment options for these patients are limited to palliative radiation, chemotherapy, and/or best supportive care. We describe our experience with treating IMHR with bronchoscopic endobronchial ultrasound (EBUS) guided intratumoral injection of cisplatin (ITC). METHODS: Patients treated between Jan 2009-September 2014 with ITC for IMHR were included. Patient demographics, tumor histology, size, concurrent therapy, location, number of sites treated, treatment sessions, and encounters were abstracted. Responses were analyzed on follow-up scans 8-12 weeks after the last treatment session using RECIST 1.1 criteria. Locoregional recurrence, progression-free survival (PFS), and overall survival were measured. RESULTS: 50 sites were treated in 36 patients (19 males, 17 females) with mean age 61.9+/-8.5 years. Eight sites treated on subsequent encounters were excluded and one patient had an unevaluable response, leaving 35 patients and 41 sites for final analysis. 24/35 (69%) had complete or partial response (responders), whereas 11/35 (31%) had stable or progressive disease (non-responders). There were no significant differences in response based on histology, size, and concurrent therapy. Median survival for the group was 8 months (95% CI of 6-11 mo). Responders had significantly higher survival and PFS than non-responders. Two patients treated with concurrent EBRT, developed broncho mediastinal fistula. CONCLUSION: EBUS guided intratumoral cisplatin for IMHR appears to be safe and effective, and may represent a new treatment paradigm for this patient population. PMID- 26477969 TI - Comparing four different ALK antibodies with manual immunohistochemistry (IHC) to screen for ALK-rearranged non-small cell lung cancer (NSCLC). AB - OBJECTIVES: Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) screening is essential to its treatment such as crizotinib. Different assays have been developed to detect ALK rearrangements, such as fluorescence in situ hybridization (FISH), reverse transcriptase-PCR (RT-PCR), and immunohistochemistry (IHC). However, ALK detection has not been applied widely in all hospitals. Moreover, IHC has been proposed to be a pre-screening tool because of its wide application in clinics. Since the low expression of ALK protein, the sensitivity and specificity of ALK antibody are the keys to the success of IHC screening. Therefore, we compared different antibodies to find the best one for IHC detection. MATERIALS AND METHODS: We evaluated ALK expression by four different ALK antibodies: clone D5F3 (Ventana), clone D5F3 (CST), clone 1A4/1H7 (OriGene Tech.), and clone 5A4 (Abcam) based on manual IHC in a cohort of 60 NSCLCs. The results were compared with those from automated IHC (clone D5F3, Ventana). All cases were evaluated independently by ALK FISH. RESULTS: 32 ALK positive and 28 ALK-negative NSCLCs were identified by automated IHC (D5F3, Ventana) and FISH analysis. Based on conventional manual IHC, the sensitivity of four antibodies-D5F3 (Ventana), D5F3 (CST), 1A4/1H7 (OriGene Tech.), and 5A4 (Abcam)-was 93.8%, 84.4%, 93.8%, and 56.3%, respectively. Their specificities and positive predictive values were 100%. The percentage of strong-moderate staining was 65.6%, 62.5%, 68.8%, and 21.9%, respectively. Compared with automated IHC (D5F3, Ventana), each staining concordance was 96.7%, 91.7%, 96.7%, and 76.7%, respectively, and each presented staining heterogeneity (weak-moderate-strong intensity). CONCLUSION: These data indicated that manual IHC with a more reliable ALK antibody might provide an effective strategy for screening ALK gene rearrangements in all NSCLC patients, followed by confirmatory FISH analysis in IHC-positive cases. PMID- 26477970 TI - Rhodium(iii)-catalyzed annulation of arenes with alkynes assisted by an internal oxidizing N-O bond. AB - Rh(iii)-catalyzed C-H activation of 3-aryl-dihydroisoxazoles in the coupling with diarylacetylenes has been developed under redox-neutral conditions. This reaction occurred under mild conditions with no by-product, and the N-O bond functions as an oxidizing directing group, leading to efficient synthesis of isoquinolines functionalized with a proximal secondary alcohol. PMID- 26477971 TI - Rhenium complexes of bidentate, bis-bidentate and tridentate N-heterocyclic carbene ligands. AB - A series of eight Rhenium(I)-N-heterocyclic carbene (NHC) complexes of the general form [ReCl(CO)3(C^C)] (where C^C is a bis(NHC) bidentate ligand), [ReCl(CO)3(C^C)]2 (where C^C is a bis-bidentate tetra-NHC ligand) and [Re(CO)3(C^N^C)](+)[X](-) (where C^N^C is a bis(NHC)-amine ligand and the counter ion X is either the ReO4(-) or PF6(-)) have been synthesised using a Ag2O transmetallation protocol. The novel precursor imidazolium salts and Re(I) complexes were characterized by elemental analysis, (1)H and (13)C NMR spectroscopy and the molecular structures for two imidazolium salt and six Re(I) complexes were determined by single crystal X-ray diffraction. These NHC ligand systems are of interest for possible applications in the development of Tc-99m or Re-186/188 radiopharmaceuticals and as such the stability of two complexes of the form [ReCl(CO)3(C^C)] and [Re(CO)3(C^N^C)][ReO4] were evaluated in ligand challenge experiments using the metal binding amino acids L-histidine or L cysteine. These studies showed that the former was unstable, with the chloride ligand being replaced by either cysteine or histidine, while no evidence for transchelation was observed for the latter suggesting that bis(NHC)-amine ligands of this type may be suitable for biological applications. PMID- 26477972 TI - Enantioselective Guest Effect on the Spin State of a Chiral Coordination Framework. AB - The diversity of spin crossover (SCO) complexes that, on the one hand, display variable temperature, abruptness and hysteresis of the spin transition, and on the other hand, are spin-sensitive to the various guest molecules, makes these materials unique for the detection of different organic and inorganic compounds. We have developed a homochiral SCO coordination polymer with a spin transition sensitive to the inclusion of the guest 2-butanol, and these solvates with (R)- and (S)-alcohols demonstrate different SCO behaviours depending on the chirality of the organic analyte. A stereoselective response to the guest inclusion is detected as a shift in the temperature of the transition both from dia- to para- and from para- to diamagnetic states in heating and cooling modes respectively. Furthermore, the Mossbauer spectroscopy directly visualizes how the metallic centres in a chiral coordination framework differently sense the interaction with guests of different chiralities. PMID- 26477974 TI - Does the ethanolammonium acetate ionic liquid mix homogeneously with molecular solvents? AB - In order to study micro-structural heterogeneities in the solutions of ionic liquids (ILs), ethanolammonium acetate (EOAA) IL has been synthesized and (1) H NMR spectra of its binary solutions, namely EOAA/DMSO and EOAA/n-butanol, have been measured at 298.15 K. Then the concentration-dependent chemical shifts delta (-CH3 , EOAA), delta (-CH3 , DMSO) and delta (-CH3 , n-butanol) have been correlated separately using the local composition (LC) model. The results indicated that self-association of EOAA played the leading role within EOAA-rich region in mixtures. However with the molecular solvents increasing, the interactions between EOAA and solvents gradually predominated. Moreover the comparisons between DMSO and n-butanol have demonstrated that DMSO could break the network of IL more easily, indicating that the influence of DMSO on the properties of EOAA should be more obvious, which was consistent with experimental results of viscosity and conductivity. Furthermore the maximum difference between the local and the bulk appeared at x(EOAA) ~ 0.5 for both systems, which reflected remarkable nonideality of mixtures at this concentration. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26477973 TI - Low doses of neonicotinoid pesticides in food rewards impair short-term olfactory memory in foraging-age honeybees. AB - Neonicotinoids are often applied as systemic seed treatments to crops and have reported negative impact on pollinators when they appear in floral nectar and pollen. Recently, we found that bees in a two-choice assay prefer to consume solutions containing field-relevant doses of the neonicotinoid pesticides, imidacloprid (IMD) and thiamethoxam (TMX), to sucrose alone. This suggests that neonicotinoids enhance the rewarding properties of sucrose and that low, acute doses could improve learning and memory in bees. To test this, we trained foraging-age honeybees to learn to associate floral scent with a reward containing nectar-relevant concentrations of IMD and TMX and tested their short (STM) and long-term (LTM) olfactory memories. Contrary to our predictions, we found that none of the solutions enhanced the rate of olfactory learning and some of them impaired it. In particular, the effect of 10 nM IMD was observed by the second conditioning trial and persisted 24 h later. In most other groups, exposure to IMD and TMX affected STM but not LTM. Our data show that negative impacts of low doses of IMD and TMX do not require long-term exposure and suggest that impacts of neonicotinoids on olfaction are greater than their effects on rewarding memories. PMID- 26477975 TI - Perceptions of Adolescents with Overweight and Obesity for the Development of User-Centered Design Self-Management Tools within the Context of the Chronic Care Model: A Qualitative Study. AB - BACKGROUND: The Chronic Care Model (CCM) is helpful to illustrate multiple levels of influence in the management of chronic disease, such as overweight and obesity in adolescents. Unfortunately, various constraints create gaps in the management process activities performed within the CCM. Consumer health technologies (CHT) may serve as a linkage between adolescents with overweight or obesity, their parents, and their pediatricians. OBJECTIVE: To conduct formative research to qualitatively identify views of adolescents with overweight and obesity on use of consumer health technologies to manage weight loss across chronic care management settings. DESIGN: As part of a multi-perspective qualitative study, 10 focus groups were conducted with adolescents with overweight and obesity. PARTICIPANTS/SETTING: Forty-eight adolescents (15 male, 33 female) aged 12 to 17 years who were current participants of an intensive lifestyle change camp in the summer of 2012 participated in focus groups. All adolescents were classified as overweight (21%) or obese (79%) according to body mass index (BMI) for age charts published by the Centers for Disease Control and Prevention. ANALYSIS: All focus groups were recorded, transcribed verbatim, and checked for accuracy. Predefined and open coding were used to analyze transcripts for emerging themes. RESULTS: Adolescents perceive CHT, with its functional requirements of assistance with restaurant food selection, teaching cooking skills, and providing encouragement and motivation, to be helpful with overweight and obesity self-management. Desired features to carry out these functional requirements included avatars, self-monitoring capabilities, social networking, and rewards. CONCLUSION: Our findings largely agree with previously reported parental perceptions of the benefit of CHT for adolescent overweight and obesity self-management and strengthen support for the design and implementation of CHT within the CCM. PMID- 26477976 TI - Seamless lamination of a concave-convex architecture with single-layer graphene. AB - Graphene has been used as an electrode and channel material in electronic devices because of its superior physical properties. Recently, electronic devices have changed from a planar to a complicated three-dimensional (3D) geometry to overcome the limitations of planar devices. The evolution of electronic devices requires that graphene be adaptable to a 3D substrate. Here, we demonstrate that chemical-vapor-deposited single-layer graphene can be transferred onto a silicon dioxide substrate with a 3D geometry, such as a concave-convex architecture. A variety of silicon dioxide concave-convex architectures were uniformly and seamlessly laminated with graphene using a thermal treatment. The planar graphene was stretched to cover the concave-convex architecture, and the resulting strain on the curved graphene was spatially resolved by confocal Raman spectroscopy; molecular dynamic simulations were also conducted and supported the observations. Changes in electrical resistivity caused by the spatially varying strain induced as the graphene-silicon dioxide laminate varies dimensionally from 2D to 3D were measured by using a four-point probe. The resistivity measurements suggest that the electrical resistivity can be systematically controlled by the 3D geometry of the graphene-silicon dioxide laminate. This 3D graphene-insulator laminate will broaden the range of graphene applications beyond planar structures to 3D materials. PMID- 26477977 TI - Elimination of murine and human T-cell epitopes in recombinant immunotoxin eliminates neutralizing and anti-drug antibodies in vivo. AB - Antibodies against the toxin portion of recombinant immunotoxins (RIT) reduce their efficacy and pose a potential safety risk. To overcome this problem we mutated the very immunogenic immunotoxin SS1P to produce LMB-T20, a de-immunized RIT that has the eight human T-cell epitopes in SS1P modified or removed. To determine the effect of T-cell epitope removal in vivo we mapped the T-cell epitopes in immune-competent BALB/c mice and found that these mice recognize two epitopes. One corresponds to the human immunodominant T-cell epitope and the other to a human subdominant epitope; both were eliminated in LMB-T20. We found that mice immunized with LMB-T20 did not have T-cell activation and did not develop anti-drug antibodies (ADA), whereas mice immunized with SS1P, showed T cell activation, and developed ADA detected by both ELISA and drug neutralizing assays. The ability of the mice treated with LMB-T20 to respond to other antigens was not compromised. We conclude that elimination of T-cell epitopes is sufficient to prevent formation of antibodies to an immunogenic foreign protein. PMID- 26477978 TI - Maslinic Acid Protected PC12 Cells Differentiated by Nerve Growth Factor against beta-Amyloid-Induced Apoptosis. AB - beta-Amyloid peptide (Abeta) was used to induce apoptosis in PC12 cells differentiated by nerve growth factor, and the protective activities of maslinic acid (MA) at 2-16 MUM were examined. Abeta treatment lowered Bcl-2 expression, raised Bax expression, and decreased cell viability. MA pretreatments decreased Bax expression, raised the Bcl-2/Bax ratio, and increased cell viability. MA pretreatments retained glutathione content and decreased subsequent Abeta-induced release of reactive oxygen species, tumor necrosis factor-alpha, interleukin (IL) 1beta, and IL-6. Abeta treatment up-regulated protein expression of p47(phox), gp91(phox), mitogen-activated protein kinase, advanced glycation end product receptor (RAGE), and nuclear factor-kappa B (NF-kappaB). MA pretreatments at 2-16 MUM suppressed the expression of proteins including gp91(phox), p47(phox), p-p38, and NF-kappaB p65, at 4-16 MUM down-regulated RAGE and NF-kappaB p50 expression, and at 8 and 16 MUM reduced p-ERK1/2 expression. These novel findings suggest that maslinic acid is a potent compound against Abeta-induced cytotoxicity. PMID- 26477979 TI - Developing a brief depression screen and identifying associations with comorbid physical and psychological illness in Australian Gulf War veterans. AB - OBJECTIVE: Major depression occurs frequently in veterans, and is associated with comorbid psychological and physical disorders and poorer quality of life. Depression can be difficult to detect in primary care, while lengthy assessment instruments can deter use. Our study aimed to develop a brief depression screen that could be used by veterans and caregivers, and then to compare the association between the brief screen and comorbidities and quality of life with that of a longer instrument. METHODS: Our dataset comprised 1204 male Royal Australian Navy veterans of the 1990/91 Gulf War. Depressive symptoms were assessed using the General Health Questionnaire (GHQ-12), health-related quality of life by the Short-Form Health Survey (SF-12), major depression and comorbid psychiatric diagnoses such as posttraumatic disorder (PTSD) using Diagnostic and Statistical Manual (DSM-IV) criteria. Comorbid physical illnesses including musculoskeletal disorders, chronic fatigue and diabetes were examined. RESULTS: A brief depression screen of three key self-reported symptoms was identified. Veterans with major depression present according to the screen were over four times more likely to have multisymptom illness or PTSD, and almost twice as likely to have musculoskeletal disorders. Having depression according to the brief screen and having at least one other physical or psychological condition was associated with poorer quality of life. Similar results were obtained for a longer screen based on all GHQ-12 items. CONCLUSION: A 3 item depression screen performed as well as a 12 item one in identifying major depression, comorbid physical and psychological illness and poorer quality of life in veterans. PMID- 26477980 TI - Radiation therapy and grade II/III oligodendroglial tumors. AB - Radiotherapy has been a longstanding treatment option for low-grade glioma. Improvements in tumor control and radiation-related toxicity may be attributed to advances in neuroimaging as well as radiotherapy planning and delivery. The discovery of various molecular prognostic factors have aided in patient selection for radiotherapy. These prognostic and predictive factors may also play a key role in determining which patients are likely to benefit most from combined systemic therapy and radiation. PMID- 26477981 TI - The Effect of Temperature and Laboratory Rearing Conditions on the Development of Dermestes maculatus (Coleoptera: Dermestidae). AB - Experiments were conducted to study the life cycle of Dermestes maculatus and to establish the total developmental time and the developmental time of immature stages, in relation with six different temperatures. We also analyzed the variations in size, morphology, and other indicators of temporal variation during life cycle of D. maculatus, in relation with temperature. One hundred larvae were selected per experiment, reared individually. The remaining larvae were reared to evaluate and establish temporal variations among the instars (length, cephalic width, and dry weight). In all trials, survivorship was greater than 50% and seven larval instars were found. Data of the average developmental time of immature stages and of the total cycle, at different temperatures, are provided. This is of relevance when estimating particularly, a minimum PMI. No relation between morphometric parameters and temperature was found, suggesting that other random factors may have been involved. Thus, this indicates that the method of isomegalen diagrams could not be used for calculating PMI. PMID- 26477982 TI - The impact of combined administration of paraquat and maneb on motor and non motor functions in the rat. AB - Paraquat (PQ) and maneb (MB) are potential risk factors for Parkinson's disease. However, their impact on non-motor disorders, monoamine neurotransmission and basal ganglia function is not clearly determined. Here we investigated the effects of combined treatment with PQ/MB on motor behavior, anxiety and "depressive-like" disorders, tissue content of monoamines, and subthalamic nucleus (STN) neuronal activity. Male Sprague-Dawley rats were intoxicated by PQ (10 mg/kg) and MB (30 mg/kg) twice a week. Two weeks later, the majority of animals (group 1, 16/26) showed a severe loss of body weight with tremor and respiratory distress and others (group 2, 6/26) showed only tremor. Animals of group 2 received PQ/MB during four weeks before developing weight loss. A last group (group 3, 4/26) was insensitive to PQ/MB after 6 weeks of injections. Groups 1 and 2 displayed a failure of motor activity and motor coordination. Group 3 showed slight motor deficits only after the last injection of PQ/MB. Moreover, PQ/MB induced anxiety and "depressive-like" behaviors in animals of groups 2 and 3. Biochemical analysis showed that PQ/MB reduced striatal dopamine (DA) tissue content paralleled by changes in the activity of STN neurons without changing the content of norepinephrine and serotonin in the cortex. Our data provide evidence that individuals are not equally sensitive to PQ/MB and show that the motor deficits in vulnerable animals, are not only a result of DA neuron degeneration, but may also be a consequence of peripheral disabilities. Nevertheless, the parkinsonian-like non-motor impairments may be a direct consequence of the bilateral DA depletion. PMID- 26477983 TI - Mastication induces long-term increases in blood perfusion of the trigeminal principal nucleus. AB - Understanding mechanisms for vessel tone regulation within the trigeminal nuclei is of great interest because some headache syndromes are due to dysregulation of such mechanisms. Previous experiments on animal models suggest that mastication may alter neuron metabolism and blood supply in these nuclei. To investigate this hypothesis in humans, arterial spin-labeling magnetic resonance imaging (MRI) was used to measure blood perfusion within the principal trigeminal nucleus (Vp) and in the dorsolateral-midbrain (DM, including the mesencephalic trigeminal nucleus) in healthy volunteers, before and immediately after a mastication exercise consisting of chewing a gum on one side of the mouth for 1 h at 1 bite/s. The side preference for masticating was evaluated with a chewing test and the volume of the masseter muscle was measured on T1-weighted MRI scans. The results demonstrated that the mastication exercise caused a perfusion increase within the Vp, but not in the DM. This change was correlated to the preference score for the side where the exercise took place. Moreover, the basal Vp perfusion was correlated to the masseter volume. These results indicate that the local vascular tone of the trigeminal nuclei can be constitutively altered by the chewing practice and by strong or sustained chewing. PMID- 26477984 TI - The effects of facial color and inversion on the N170 event-related potential (ERP) component. AB - Faces are important for social interaction because much can be perceived from facial details, including a person's race, age, and mood. Recent studies have shown that both configural (e.g. face shape and inversion) and surface information (e.g. surface color and reflectance properties) are important for face perception. Therefore, the present study examined the effects of facial color and inverted face properties on event-related potential (ERP) responses, particularly the N170 component. Stimuli consisted of natural and bluish-colored faces. Faces were presented in both upright and upside down orientations. An ANOVA was used to analyze N170 amplitudes and verify the effects of the main independent variables. Analysis of N170 amplitude revealed the significant interactions between stimulus orientation and color. Subsequent analysis indicated that N170 was larger for bluish-colored faces than natural-colored faces, and N170 to natural-colored faces was larger in response to inverted stimulus as compared to upright stimulus. Additionally, a multivariate pattern analysis (MVPA) investigated face-processing dynamics without any prior assumptions. Results distinguished, above chance, both facial color and orientation from single-trial electroencephalogram (EEG) signals. Decoding performance for color classification of inverted faces was significantly diminished as compared to an upright orientation. This suggests that processing orientation is predominant over facial color. Taken together, the present findings elucidate the temporal and spatial distribution of orientation and color processing during face processing. PMID- 26477986 TI - Event-related brain potentials during the visuomotor mental rotation task: The contingent negative variation scales to angle of rotation. AB - Perceptual judgments about the angular disparity of a character from its standard upright (i.e., mental rotation task) result in a concurrent increase in reaction time (RT) and modulation of the amplitude of the P300 event-related brain potential (ERP). It has therefore been proposed that the P300 represents the neural processes associated with a visual rotation. In turn, the visuomotor mental rotation (VMR) task requires reaching to a location that deviates from a target by a predetermined angle. Although the VMR task exhibits a linear increase in RT with increasing oblique angles of rotation, work has not examined whether the task is supported via a visual rotation analogous to its mental rotation task counterpart. This represents a notable issue because seminal work involving non human primates has ascribed VMR performance to the motor-related rotation of directionally tuned neurons in the primary motor cortex. Here we examined the concurrent behavioral and ERP characteristics of a standard reaching task and VMR tasks of 35 degrees , 70 degrees , and 105 degrees of rotation. Results showed that the P300 amplitude was larger for the standard compared to each VMR task--an effect independent of the angle of rotation. In turn, the amplitude of the contingent negative variation (CNV)--an ERP related to cognitive and visuomotor integration for movement preparation--was systematically modulated with angle of rotation. Thus, we propose that the CNV represents an ERP correlate related to the cognitive and/or visuomotor transformation demands of increasing the angular separation between a stimulus and a movement goal. PMID- 26477985 TI - Inhibition of Drp1 by Mdivi-1 attenuates cerebral ischemic injury via inhibition of the mitochondria-dependent apoptotic pathway after cardiac arrest. AB - Mitochondrial fission is predominantly controlled by the activity of dynamin related protein1 (Drp1), which has been reported to be involved in mitochondria apoptosis pathways. However, the role of Drp1 in a rat model of cardiac arrest remains unknown. In this study, we found that activation of Drp1 in the mitochondria was increased after cardiac arrest and inhibition of Drp1 by 1.2 mg/kg of mitochondrial division inhibitor-1 (Mdivi-1) administration after the restoration of spontaneous circulation (ROSC) significantly protected against cerebral ischemic injury, shown by the increased 72-h survival rate and improved neurological function. Moreover, the increase of the vital neuron and the reduction of cytochrome c (CytC) release, apoptosis-inducing factor (AIF) translocation and caspase-3 activation in the brain indicate that this protection might result from the suppression of neuron apoptosis. Altogether, these results indicated that Drp1 is activated after cardiac arrest and the inhibition of Drp1 is protective against cerebral ischemic injury in a rat of cardiac arrest model via inhibition of the mitochondrial apoptosis pathway. PMID- 26477987 TI - Statins Modulate Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 in Human Hepatic Myofibroblasts. AB - Statins have been shown to exert anti-inflammatory and anti-fibrogenic properties in the liver. In the present study, we explored the mechanisms underlying anti fibrogenic effects of statins in isolated hepatic myofibroblasts and focused on cyclooxyegnase-2, a major anti-proliferative pathway in these cells. We show that simvastatin and fluvastatin inhibit thymidine incorporation in hMF in a dose dependent manner. Pretreatment of cells with NS398, a COX-2 inhibitor, partially blunted this effect. cAMP levels, essential to the inhibition of hMF proliferation, were increased by statins and inhibited by non-steroidal anti inflammatory drugs. Since statins modify prenylation of some important proteins in gene expression, we investigated the targets involved using selective inhibitors of prenyltransferases. Inhibition of geranylgeranylation resulted in the induction of COX-2 and mPGES-1. Using gel retardation assays, we further demonstrated that statins potentially activated the NFkappaB and CRE/E-box binding for COX-2 promoter and the binding of GC-rich regions and GATA for mPGES 1. Together these data demonstrate that statin limit hepatic myofibroblasts proliferation via a COX-2 and mPGES-1 dependent pathway. These data suggest that statin-dependent increase of prostaglandin in hMF contributes to its anti fibrogenic effect. PMID- 26477988 TI - Management of adrenocortical carcinoma. PMID- 26477989 TI - Fission yeast meets a legend in Kobe: report of the Eighth International Fission Yeast Meeting. AB - The Eighth International Fission Yeast Meeting, which was held at Ikuta Shrine Hall in Kobe, Japan, from 21 to 26 June 2015, was attended by 327 fission yeast researchers from 25 countries (190 overseas and 137 domestic participants). At this meeting, 124 talks were held and 145 posters were presented. In addition, newly developed database tools were introduced to the community during a workshop. Researchers shared cutting-edge knowledge across broad fields of study, ranging from molecules to evolution, derived from the superior model organism commonly used within the fission yeast community. Intensive discussions and constructive suggestions generated in this meeting will surely advance the understanding of complex biological systems in fission yeast, extending to general eukaryotes. PMID- 26477990 TI - Kinetics and Mechanism of the Oxidation of Cyclic Methylsiloxanes by Hydroxyl Radical in the Gas Phase: An Experimental and Theoretical Study. AB - The ubiquitous presence of cyclic volatile methylsiloxanes (cVMS) in the global atmosphere has recently raised environmental concern. In order to assess the persistence and long-range transport potential of cVMS, their second-order rate constants (k) for reactions with hydroxyl radical ((*)OH) in the gas phase are needed. We experimentally and theoretically investigated the kinetics and mechanism of (*)OH oxidation of a series of cVMS, hexamethylcyclotrisiloxane (D3), octamethycyclotetrasiloxane (D4), and decamethycyclopentasiloxane (D5). Experimentally, we measured k values for D3, D4, and D5 with (*)OH in a gas-phase reaction chamber. The Arrhenius activation energies for these reactions in the temperature range from 313 to 353 K were small (-2.92 to 0.79 kcal.mol(-1)), indicating a weak temperature dependence. We also calculated the thermodynamic and kinetic behaviors for reactions at the M06-2X/6-311++G**//M06-2X/6-31+G** level of theory over a wider temperature range of 238-358 K that encompasses temperatures in the troposphere. The calculated Arrhenius activation energies range from -2.71 to -1.64 kcal.mol(-1), also exhibiting weak temperature dependence. The measured k values were approximately an order of magnitude higher than the theoretical values but have the same trend with increasing size of the siloxane ring. The calculated energy barriers for H-atom abstraction at different positions were similar, which provides theoretical support for extrapolating k for other cyclic siloxanes from the number of abstractable hydrogens. PMID- 26477991 TI - Dr. Stanley Fahn's contributions to Movement Disorders. PMID- 26477993 TI - Marginal and internal analysis of preheated dental fissure-sealing materials using optical coherence tomography. AB - OBJECTIVES: This study aimed to evaluate the influence of pre-photoactivation temperature on the marginal and internal integrity (occurrence of voids) of fissure-sealing materials on occlusal fissures using optical coherence tomography (OCT). METHODS: Occlusal fissures of 40 human third molars were sealed using a resin-based fissure sealant (Fluroshield) and a flowable composite (Permaflo) photoactivated at 68 degrees C (preheated) or at room temperature (25 degrees C) (n=10). After sealing, the teeth were subjected to thermocycling (500 cycles, 5-55 degrees C) and 14 days of pH cycling (demineralisation for 6 hours/day and remineralisation for 18 hours/day). The occlusal surfaces were scanned in a buccolingual direction, and 20 tomographic images parallel to the long axis of each tooth were obtained. Images presenting marginal gaps and internal voids were counted and statistically analysed using analysis of variance and Tukey's test (P<0.05). RESULTS: There were statistically significant differences between materials and temperatures (P<0.01). The flowable composite had a lower percentage of gaps and internal voids than the resin-based sealant. Preheated materials had a lower percentage of gaps and internal voids than the materials at room temperature. CONCLUSION: Therefore, preheated flowable composite provided the best marginal sealing of fissures, and internal homogeneity of the material. PMID- 26477992 TI - Declines in violence and police arrest among female sex workers in Karnataka state, south India, following a comprehensive HIV prevention programme. AB - INTRODUCTION: Female sex workers (FSWs) frequently experience violence, harassment and arrest by the police or their clients, but there is little evidence as to the impact that such factors may have on HIV risk or whether community interventions could mitigate this impact. METHODS: As part of the evaluation of the Avahan programme in Karnataka, serial integrated behavioural and biological assessment (IBBA) surveys (four districts) (2005 to 2011) and anonymous polling booth surveys (PBS) (16 districts) (2007 to 2011) were conducted with random samples of FSWs. Logistic regression analysis was used to assess 1) changes in reported violence and arrests over time and 2) associations between violence by non-partners and police arrest and HIV/STI risk and prevalence. Mediation analysis was used to identify mediating factors. RESULTS: 5,792 FSWs participated in the IBBAs and 15,813 participated in the PBS. Over time, there were significant reductions in the percentages of FSWs reporting being raped in the past year (PBS) (30.0% in 2007, 10.0% in 2011, p<0.001), being arrested in the past year [adjusted odds ratio (AOR) 0.57 (0.35, 0.93), p=0.025] and being beaten in the past six months by a non-partner (clients, police, pimps, strangers, rowdies) [AOR 0.69 (0.49, 0.95), p=0.024)] (IBBA). The proportion drinking alcohol (during the past week) also fell significantly (32.5% in 2005, 24.9% in 2008, 16.8% in 2011; p<0.001). Violence by non-partners (being raped in the past year and/or beaten in the past six months) and being arrested in the past year were both strongly associated with HIV infection [AOR 1.59 (1.18, 2.15), p=0.002; AOR 1.91 (1.17, 3.12), p=0.01, respectively]. They were also associated with drinking alcohol (during the past week) [AOR 1.98 (1.54, 2.53), p<0.001; AOR 2.79 (1.93, 4.04), p<0.001, respectively], reduced condom self efficacy with clients [AOR 0.36 (0.27, 0.47), p<0.001; AOR 0.62 (0.39, 0.98), p=0.039, respectively], symptomatic STI (during the past year) [AOR 2.62 (2.07, 3.30), p<0.001; AOR 2.17 (1.51, 3.13), p<0.001, respectively], gonorrhoea infection [AOR 2.79 (1.51, 5.15), p=0.001; AOR 2.69 (0.96, 7.56), p=0.060, respectively] and syphilis infection [AOR 1.86 (1.04, 3.31), p=0.036; AOR 3.35 (1.78, 6.28), p<0.001, respectively], but not with exposure to peer education, community mobilization or HIV testing uptake. Mediation analysis suggests that alcohol use and STIs may partially mediate the association between violence or arrests and HIV prevalence. DISCUSSION: Violence by non-partners and arrest are both strongly associated with HIV infection among FSWs. Large-scale, comprehensive HIV prevention programming can reduce violence, arrests and HIV/STI infection among FSWs. PMID- 26477994 TI - Salty Food Preference and Intake and Risk of Gastric Cancer: The JACC Study. AB - BACKGROUND: High sodium intake is a potential risk factor of gastric cancer. However, limited information is available on the relationship between salty food preference or intake and risk of gastric cancer. The aim of the present study was to determine the association between these variables among the Japanese population. METHODS: Between 1988 and 1990, 15,732 men and 24,997 women aged 40 79 years old with no history of cancer or cardiovascular disease completed a lifestyle questionnaire that included information about food intake. The subjects were enrolled in the Japan Collaborative Cohort (JACC) Study for Evaluation of Cancer Risk Sponsored by Monbusho. After a median follow-up of 14.3 years, 787 incident gastric cancers were documented. We examined the associations between salty food preference and intake and gastric cancer incidence using the Cox proportional hazard model. RESULTS: The risk of gastric cancer among subjects with a strong preference for salty food was approximately 30% higher than among those who preferred normal-level salty food (hazard ratio [HR] 1.31; 95% confidence interval [CI], 1.02-1.67). The risk of gastric cancer in subjects who consumed 3 and >= 4 bowls/day of miso soup was approximately 60% higher than in those who consumed less miso soup (HR 1.67; 95% CI, 1.16-2.39 and HR 1.64; 95% CI, 1.11-2.42, respectively). Sodium intake correlated positively and linearly with risk of gastric cancer (P for trend = 0.002). CONCLUSIONS: The present study showed that salty food preference, consumption of large quantities of miso soup, and high sodium intake were associated with increased risk of gastric cancer among Japanese people. PMID- 26477995 TI - Comparison of Prevalence- and Smoking Impact Ratio-Based Methods of Estimating Smoking-Attributable Fractions of Deaths. AB - BACKGROUND: Smoking is a major modifiable risk factor for premature mortality. Estimating the smoking-attributable burden is important for public health policy. Typically, prevalence- or smoking impact ratio (SIR)-based methods are used to derive estimates, but there is controversy over which method is more appropriate for country-specific estimates. We compared smoking-attributable fractions (SAFs) of deaths estimated by these two methods. METHODS: To estimate SAFs in 2012, we used several different prevalence-based approaches using no lag and 10- and 20 year lags. For the SIR-based method, we obtained lung cancer mortality rates from the Korean Cancer Prevention Study (KCPS) and from the United States-based Cancer Prevention Study-II (CPS-II). The relative risks for the diseases associated with smoking were also obtained from these cohort studies. RESULTS: For males, SAFs obtained using KCPS-derived SIRs were similar to those obtained using prevalence based methods. For females, SAFs obtained using KCPS-derived SIRs were markedly greater than all prevalence-based SAFs. Differences in prevalence-based SAFs by time-lag period were minimal among males, but SAFs obtained using longer-lagged prevalence periods were significantly larger among females. SAFs obtained using CPS-II-based SIRs were lower than KCPS-based SAFs by >15 percentage points for most diseases, with the exceptions of lung cancer and chronic obstructive pulmonary disease. CONCLUSIONS: SAFs obtained using prevalence- and SIR-based methods were similar for males. However, neither prevalence-based nor SIR-based methods resulted in precise SAFs among females. The characteristics of the study population should be carefully considered when choosing a method to estimate SAF. PMID- 26477996 TI - Concurrent Associations of Physical Activity and Screen-Based Sedentary Behavior on Obesity Among US Adolescents: A Latent Class Analysis. AB - BACKGROUND: Independent associations of physical activity (PA) and sedentary behavior (SB) with obesity are well documented. However, little is known about the combined associations of these behaviors with obesity in adolescents. The present study examines the prevalence of concurrent levels of PA and SB, and their associations with obesity among US adolescents. METHODS: Data from a total of 12 081 adolescents who participated in the Youth Risk Behaviors Survey during 2012-2013 were analyzed. A latent class analysis was performed to identify latent subgroups with varying combined levels of subjectively measured PA and screen based SB. Follow-up analysis examined the changes in the likelihood of being obese as determined by the Center for Disease Control and Prevention Growth Chart between latent subgroups. RESULTS: Four latent subgroups with varying combined levels of PA and SB were identified across gender. The likelihood of being obese was significantly greater for the subgroups featuring either or both Low PA or High SB when compared with High PA/Low SB across genders (odds ratio [OR] ranges, 2.1-2.7 for males and 9.6-23.5 for females). Low PA/High SB showed the greater likelihood of being obese compared to subgroups featuring either or both High PA and Low SB (OR ranges, 2.2-23.5) for female adolescents only. CONCLUSIONS: The findings imply that promoting sufficient levels of PA while reducing SB should be encouraged in order to reduce obesity risk among adolescents, particularly for males. The risk of obesity for female adolescents can be reduced by engaging in either high levels of PA or low levels of SB. PMID- 26477997 TI - Development of Dose-Response Models to Predict the Relationship for Human Toxoplasma gondii Infection Associated with Meat Consumption. AB - Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States. It is thought that a substantial portion of human T. gondii infections is acquired through the consumption of meats. The dose-response relationship for human exposures to T. gondii-infected meat is unknown because no human data are available. The goal of this study was to develop and validate dose-response models based on animal studies, and to compute scaling factors so that animal derived models can predict T. gondii infection in humans. Relevant studies in literature were collected and appropriate studies were selected based on animal species, stage, genotype of T. gondii, and route of infection. Data were pooled and fitted to four sigmoidal-shaped mathematical models, and model parameters were estimated using maximum likelihood estimation. Data from a mouse study were selected to develop the dose-response relationship. Exponential and beta-Poisson models, which predicted similar responses, were selected as reasonable dose response models based on their simplicity, biological plausibility, and goodness fit. A confidence interval of the parameter was determined by constructing 10,000 bootstrap samples. Scaling factors were computed by matching the predicted infection cases with the epidemiological data. Mouse-derived models were validated against data for the dose-infection relationship in rats. A human dose response model was developed as P (d) = 1-exp (-0.0015 * 0.005 * d) or P (d) = 1 (1 + d * 0.003 / 582.414)(-1.479) . Both models predict the human response after consuming T. gondii-infected meats, and provide an enhanced risk characterization in a quantitative microbial risk assessment model for this pathogen. PMID- 26477998 TI - Transcatheter Treatment of Thrombosis in the Single Ventricle Pathway: An Institutional Experience. AB - BACKGROUND: Shunt or conduit thrombosis in a single ventricle circuit is a life threatening complication that requires prompt treatment to rapidly restore shunt/conduit patency. Transcatheter interventions represent an attractive alternative to systemic thrombolysis or open surgical procedures. We report our center's experience with catheter-based approaches in patients with palliated single ventricle who present with shunt/conduit thrombosis. METHODS: A retrospective review was performed of all patients with palliated single ventricle physiology who were diagnosed over a 5-year period with shunt/conduit thrombosis and received catheter-based interventions. Patients were followed up to hospital discharge. RESULTS: Thirteen patients were identified that were diagnosed with thrombosis of a modified Blalock-Taussig shunt (five patients), bidirectional cavopulmonary shunt (one patient), and total cavopulmonary pathway (seven patients). Shunt/conduit thrombosis occurred both early and late after palliation surgery. Catheter-based interventions included balloon angioplasty (one patient), stent implantation (12 patients), and mechanical thrombectomy (one patient). Thrombophilia was identified in seven patients. Technical and clinical success with restoration of normal shunt flow and improvement in clinical status was achieved in 12 patients. Reversible procedure-related complications occurred in three patients with no significant sequelae. CONCLUSIONS: Our experience suggests that percutaneous catheter-based interventions are safe and effective in managing shunt/conduit thrombosis in infants and children with palliated single ventricle circulation. PMID- 26477999 TI - Mechanistic target of rapamycin (mTOR) expression is increased in acne patients' skin. PMID- 26478000 TI - Camellia sinensis Mediated Enhancement of Humoral Immunity to Particulate and Non particulate Antigens. AB - The most common drinking beverage in large portion of the world is Camellia sinensis (green tea). In the present study, we evaluated the adjuvant effect of green tea and tea polyphenols to particulate and non-particulate antigens. BALB/c mice were immunized with particulate and non-particulate antigens. Modulation of immunoglobulin-secreting splenocytes, IgG-mediated and IgM-mediated immunity, was evaluated by hemolytic plaque assay and enzyme-linked immunosorbent assay, respectively. Dose-dependent response of tea polyphenols was also assayed. Phenolic content was measured in crude preparations of green tea. We observed a stimulatory effect of green tea preparations on humoral immune response mediated by the increased number of antibody-secreted cells in spleen. A significant increase in IgM-mediated and IgG-mediated immune response to non-particulate antigen was also observed in green tea-treated animals. A dose-dependent adjuvant effect was seen in the case of tea polyphenols for a longer period of time compared with crude tea preparations. This study indicates polyphenols as major constituents responsible for the enhanced and sustained adjuvant activity of green tea. We suggest that tea polyphenols might be considered for real-life evaluation during adjuvant-mediated vaccination trial programs. PMID- 26478001 TI - Ligand Controlled Regiodivergent C1 Insertion on Arynes for Construction of Phenanthridinone and Acridone Alkaloids. AB - A palladium-catalyzed regiodivergent C1 insertion multicomponent reaction involving aryne, CO, and 2-iodoaniline is established to construct the scaffolds of phenanthridinone and acridone alkaloids. Regioselective control is achieved under the guidance of selective ligands. The phenanthridinones are solely obtained under ligand-free condition. In comparison, application of the electron abundant bidentate ligand dppm afforded the acridones with high efficiency. The release rate of the aryne from the precursor assists the regioselectivity of insertion as well, which was revealed through interval NMR tracking. A plausible mechanism was suggested based on the control experiments. Representative natural products and two types of natural product analogues were synthesized divergently through this tunable method. PMID- 26478002 TI - VEGF: inflammatory paradoxes. PMID- 26478003 TI - The mitochondrial genome of Sinibotia robusta of pearl river (Cypriniformes: Cobitidae). AB - We present the complete mitochondrial genome of Sinibotia robusta in this study. The mitochondrial genome is 16 575 bp in length and consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a control region. The nucleotide compositions of the light strand are 31.9% A, 25.7% T, 26.9% C and 15.5% G. Except ND6 and eight tRNA genes, all other mitochondrial genes are encoded on the heavy strand. The genus most related to Botia Gray was Leptobotia Bleeker and Parabotia Sauvage, as revealed by phylogenetic relationships derived using a maximum likelihood tree. This mitogenome will help elucidate the morphological systematic complexity and phylogenetic structure of Cobitidae and related species. PMID- 26478004 TI - Selective Fluorescence Detection of Cysteine over Homocysteine and Glutathione Based on a Cysteine-Triggered Dual Michael Addition/Retro-aza-aldol Cascade Reaction. AB - In this work, a cysteine (Cys)-triggered dual Michael addition/retro-aza-aldol cascade reaction has been exploited and utilized to construct a fluorescent probe for Cys for the first time. The resulting fluorescent probe 8-alkynylBodipy 1 contains an activated alkynyl unit as Michael receptor and a Bodipy dye as fluorescence reporter and can highly selectively detect Cys over homocysteine (Hcy)/glutathione (GSH) as well as other amino acids with a significant fluorescence off-on response (~4500-fold) and an ultralow detection limit (0.38 nM). The high selectivity of 1 for Cys could be attributed to a kinetically favored five-membered cyclic intermediate produced by the dual Michael addition of Cys with the activated alkynyl unit of 1. The big fluorescence off-on response is due to the subsequent retro-aza-aldol reaction of the five-membered cyclic intermediate that results in the release of a highly fluorescent 8-methylBodipy dye 2. The probe has been successfully used to detect and image Cys in serum and cells, respectively. PMID- 26478005 TI - Emerging role of P2X7 receptors in CNS health and disease. AB - Purinergic signalling in the brain is becoming an important focus in the study of CNS health and disease. Various purinergic receptors are found to be present in different brain cells in varying extent, which get activated upon binding of ATP or its analogues. Conventionally, ATP was considered only as a major metabolic fuel of the cell but its recognition as a neurotransmitter in early 1970s, brought meaningful insights in neuron glia crosstalk, participating in various physiological functions in the brain. P2X7R, a member of ligand gated purinergic receptor (P2X) family, is gaining attention in the field of neuroscience because of its emerging role in broad spectrum of ageing and age related neurological disorders. The aim of this review is to provide an overview about the structure and function of P2X7R highlighting its unique features which distinguish it from the other members of its family. This review critically analyzes the literature mentioning the details about the agonist and antagonist of the P2X7R. It also emphasizes the advancements in understanding the dual role of P2X7R in brain development and disorders inviting meaningful insights about its involvement in Alzheimer's disease, Huntington's disease, Multiple Sclerosis, Neuropathic pain, Spinal Cord Injury and NeuroAIDS. Exploring the roles of P2X7R in detail is critical to identify its therapeutic potential in the treatment of acute and chronic neurodegenerative diseases. Moreover, this review also helps to raise more interest in the neurobiology of the purinergic receptors and thus providing new avenues for future research. PMID- 26478007 TI - Tryptase levels in children presenting with anaphylaxis: Temporal trends and associated factors. AB - BACKGROUND: The diagnosis of anaphylaxis currently relies on suggestive clinical history after exposure to a potential triggering factor because no reliable diagnostic marker is available to confirm the diagnosis. OBJECTIVES: We aimed to evaluate tryptase levels in children with anaphylaxis and to examine predictors of elevated tryptase level (defined as >=11.4 MUg/L during reaction and for those with a baseline level, defined as a reaction level of at least 2 ng/mL + 1.2 * [postreaction tryptase level]). METHODS: Children presenting with anaphylaxis to the Montreal Children's Hospital were recruited over a 4-year period. Symptoms, triggers, and management of anaphylaxis were documented. Levels during the reaction and approximately 9 months after the reaction were compared on the basis of paired means using the t distribution. Multivariate linear and logistic regressions were used to evaluate the association between tryptase levels and risk factors. RESULTS: Over a 4-year period, 203 children had serum tryptase levels measured. Among these, 39 children (19.2%; 95% CI, 14.1%-25.4%) had elevated levels. Only severe reactions were associated with reaction levels of 11.4 MUg/L or more (odds ratio, 6.5; 95% CI, 2.2-19.0). Milk-induced anaphylaxis and severe reactions were more likely associated with increased tryptase levels (beta-adjusted, 4.0; 95% CI, 0.95-7.0, and 7.5; 95% CI, 4.8-10.3, respectively). Reaction levels exceeding the threshold level of 2 ng/mL + 1.2 * (postreaction tryptase level) detected most of the anaphylactic reactions, particularly if baseline levels were taken within 2 months of the reaction. CONCLUSIONS: Tryptase levels are particularly useful for the diagnosis of severe and/or milk-induced anaphylaxis. Assessing the difference between reaction and postreaction tryptase levels may improve diagnostic sensitivity. PMID- 26478006 TI - Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells. AB - BACKGROUND: Mutations in lysosomal trafficking regulator (LYST) cause Chediak Higashi syndrome (CHS), a rare immunodeficiency with impaired cytotoxic lymphocyte function, mainly that of natural killer (NK) cells. Our understanding of NK cell function deficiency in patients with CHS and how LYST regulates lytic granule exocytosis is very limited. OBJECTIVE: We sought to delineate cellular defects associated with LYST mutations responsible for the impaired NK cell function seen in patients with CHS. METHODS: We analyzed NK cells from patients with CHS with missense mutations in the LYST ARM/HEAT (armadillo/huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) or BEACH (beige and Chediak-Higashi) domains. RESULTS: NK cells from patients with CHS displayed severely reduced cytotoxicity. Mutations in the ARM/HEAT domain led to a reduced number of perforin-containing granules, which were significantly increased in size but able to polarize to the immunologic synapse; however, they were unable to properly fuse with the plasma membrane. Mutations in the BEACH domain resulted in formation of normal or slightly enlarged granules that had markedly impaired polarization to the IS but could be exocytosed on reaching the immunologic synapse. Perforin-containing granules in NK cells from patients with CHS did not acquire certain lysosomal markers (lysosome-associated membrane protein 1/2) but were positive for markers of transport vesicles (cation independent mannose 6-phosphate receptor), late endosomes (Ras-associated binding protein 27a), and, to some extent, early endosomes (early endosome antigen 1), indicating a lack of integrity in the endolysosomal compartments. NK cells from patients with CHS had normal cytokine compartments and cytokine secretion. CONCLUSION: LYST is involved in regulation of multiple aspects of NK cell lytic activity, ranging from governance of lytic granule size to control of their polarization and exocytosis, as well as regulation of endolysosomal compartment identity. LYST functions in the regulated exocytosis but not in the constitutive secretion pathway. PMID- 26478009 TI - Live and heat-treated probiotics differently modulate IL10 mRNA stabilization and microRNA expression. PMID- 26478008 TI - CD19 controls Toll-like receptor 9 responses in human B cells. AB - BACKGROUND: CD19 is a B cell-specific molecule that serves as a major costimulatory molecule for amplifying B-cell receptor (BCR) responses. Biallelic CD19 gene mutations cause common variable immunodeficiency in human subjects. BCR and Toll-like receptor (TLR) 9-induced B-cell responses are impaired in most patients with common variable immunodeficiency. OBJECTIVE: We sought to analyze whether CD19 is required for TLR9 function in human B cells. METHODS: Expression of surface activation markers was assessed after anti-IgM or CpG stimulation by using flow cytometry on B cells from patients with 1 or 2 defective CD19 alleles, which decrease or abrogate CD19 expression, respectively. The phosphorylation or interaction of signaling molecules was analyzed by using phospho flow cytometry, immunoblotting, or co-immunoprecipitation in CD19-deficient or control B cells and in a B-cell line in which CD19 has been knocked down with lentivirus transduced short hairpin RNA. RESULTS: B cells from subjects with 1 or 2 defective CD19 alleles showed defective upregulation in vitro of CD86, transmembrane activator and CAML interactor (TACI), and CD23 activation markers after TLR9 stimulation. TLR9 ligands normally induce phosphorylation of CD19 through myeloid differentiation primary response gene-88 (MYD88)/proline-rich tyrosine kinase 2 (PYK2)/LYN complexes, which allows recruitment of phosphoinositide 3-kinase (PI3K) and phosphorylation of Bruton tyrosine kinase (BTK) and AKT in human B cells with a different kinetic than that of BCRs. In addition, inhibition of PI3K, AKT, or BTK, as well as BTK deficiency, also resulted in TLR9 activation defects in B cells similar to those in patients with CD19 deficiency. CONCLUSION: CD19 is required for TLR9-induced B-cell activation. Hence CD19/PI3K/AKT/BTK is an essential axis integrating BCRs and TLR9 signaling in human B cells. PMID- 26478010 TI - Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. PMID- 26478011 TI - One size does not fit all: Monitoring faecal glucocorticoid metabolites in marsupials. AB - Marsupial research, conservation, and management can benefit greatly from knowledge about glucocorticoid (GC) secretion patterns because GCs influence numerous aspects of physiology and play a crucial role in regulating an animal's response to stressors. Faecal glucocorticoid metabolites (FGM) offer a non invasive tool for tracking changes in GCs over time. To date, there are relatively few validated assays for marsupials compared with other taxa, and those that have been published generally test only one assay. However, different assays can yield very different signals of adrenal activity. The goal of this study was to compare the performance of five different enzyme immunoassays (EIAs) for monitoring adrenocortical activity via FGM in 13 marsupial species. We monitored FGM response to two types of events: biological stressors (e.g., transport, novel environment) and pharmacological stimulation (ACTH injection). For each individual animal and assay, FGM peaks were identified using the iterative baseline approach. Performance of the EIAs for each species was evaluated by determining (1) the percent of individuals with a detectable peak 0.125-4.5days post-event, and (2) the biological sensitivity of the assay as measured by strength of the post-event response relative to baseline variability (Z-score). Assays were defined as successful if they detected a peak in at least 50% of the individuals and the mean species response had a Z?2. By this criterion, at least one assay was successful in 10 of the 13 species, but the best-performing assay varied among species, even those species that were closely related. Furthermore, the ability to confidently assess assay performance was influenced by the experimental protocols used. We discuss the implications of our findings for biological validation studies. PMID- 26478012 TI - Thyroid development in zebrafish lacking Taz. AB - Taz is a signal-responsive transcriptional coregulator implicated in several biological functions, from chondrogenesis to regulation of organ size. Less well studied, however, is its role in thyroid formation. Here, we explored the in vivo effects on thyroid development of morpholino (MO)-mediated knockdown of wwtr1, the gene encoding zebrafish Taz. The wwtr1 gene is expressed in the thyroid primordium and pharyngeal tissue of developing zebrafish. Compared to mammalian cells, in which Taz promotes expression of thyroid transcription factors and thyroid differentiation genes, wwtr1 MO injection in zebrafish had little or no effect on the expression of thyroid transcription factors, and differentially altered the expression of thyroid differentiation genes. Analysis of wwtr1 morphants at later stages of development revealed that the number and the lumen of thyroid follicles, and the number of thyroid follicle cells, were significantly smaller. In addition, Taz-depleted larvae displayed patterning defects in ventral cranial vessels that correlate with lateral displacement of thyroid follicles. These findings indicate that the zebrafish Taz protein is needed for the normal differentiation of the thyroid and are the first to suggest that Taz confers growth advantage to the endocrine gland. PMID- 26478014 TI - siRNA-lipid nanoparticles with long-term storage stability facilitate potent gene silencing in vivo. AB - Considerable efforts have been directed towards discovering and developing delivery vehicles for RNA therapeutics. While most studies emphasize the efficacy and safety of these delivery vehicles, few reports conduct a comprehensive assessment of their storage stability, a critical property for practical applications. Here, we report a potent and safe lipid nanoparticle with long-term storage stability. Through chemical synthesis and screening of cationic lipids, a formulation has been identified that enables potent knockdown of hepatocyte proteins in mice upon intravenous administration (siRNA ED50 ~0.02 mg/kg). Toxicity studies revealed that a dose of 2mg/kg was well tolerated in rats, the most sensitive rodent model. We identified that a cyclic chemical structure in cationic lipids improved particle stability. The nanoparticles showed over 1.5 year storage stability as a liquid, with over 90% siRNA encapsulation without any changes in particle size. This novel delivery material has promising potential as a drug product that could bring RNA therapeutics to the treatment of liver related disorders. PMID- 26478013 TI - Minimizing biases associated with tracking analysis of submicron particles in heterogeneous biological fluids. AB - Tracking the dynamic motion of individual nanoparticles or viruses offers quantitative insights into their real-time behavior and fate in different biological environments. Indeed, particle tracking is a powerful tool that has facilitated the development of drug carriers with enhanced penetration of mucus, brain tissues and other extracellular matrices. Nevertheless, heterogeneity is a hallmark of nanoparticle diffusion in such complex environments: identical particles can exhibit strongly hindered or unobstructed diffusion within microns of each other. The common practice in 2D particle tracking, namely analyzing all trackable particle traces with equal weighting, naturally biases towards rapidly diffusing sub-populations at shorter time scales. This in turn results in misrepresentation of particle behavior and a systematic underestimate of the time necessary for a population of nanoparticles to diffuse specific distances. We show here via both computational simulation and experimental data that this bias can be rigorously corrected by weighing the contribution by each particle trace on a 'frame-by-frame' basis. We believe this methodology presents an important step towards objective and accurate assessment of the heterogeneous transport behavior of submicron drug carriers and pathogens in biological environments. PMID- 26478015 TI - Heparin desulfation modulates VEGF release and angiogenesis in diabetic wounds. AB - While vascular endothelial growth factor (VEGF) has been shown to be one of the key players in wound healing by promoting angiogenesis current clinical applications of this growth factor to the wound environment are poorly controlled and not sustainable. Hydrogels made of sulfated glycosaminoglycans (GAG) allow for the sustained release of growth factors since GAGs engage in electrostatic complexation of biomolecules. In here, we explore a set of hydrogels formed of selectively desulfated heparin derivatives and star-shaped poly(ethylene glycol) with respect to VEGF binding and release and anticoagulant activity. As a proof of concept, supportive effects on migration and tube formation of human umbilical vein endothelial cells were studied in vitro and the promotion of wound healing was followed in genetically diabetic (db/db) mice. Our data demonstrate that the release of VEGF from the hydrogels is modulated in dependence on the GAG sulfation pattern. Hydrogels with low sulfate content (11% of initial heparin) were found to be superior in efficacy of VEGF administration, low anticoagulant activity and promotion of angiogenesis. PMID- 26478016 TI - Drug delivery into microneedle-porated nails from nanoparticle reservoirs. AB - This study demonstrates the potential of polymeric nanoparticles as drug reservoirs for sustained topical drug delivery into microneedle-treated human nail. Laser scanning confocal microscopy was used to image the delivery of a fluorescent model compound from nanoparticles into the nail. A label-free imaging technique, stimulated Raman scattering microscopy, was applied, in conjunction with two-photon fluorescence imaging, to probe the disposition of nanoparticles and an associated lipophilic 'active' in a microneedle-porated nail. The results provide clear evidence that the nanoparticles function as immobile reservoirs, sequestered on the nail surface and in the microneedle-generated pores, from which the active payload can be released and diffuse laterally into the nail over an extended period of time. PMID- 26478017 TI - Amifostine-conjugated pH-sensitive calcium phosphate-covered magnetic-amphiphilic gelatin nanoparticles for controlled intracellular dual drug release for dual targeting in HER-2-overexpressing breast cancer. AB - We developed a surfactant-free method utilizing amifostine to stably link a targeting ligand (Herceptin) to amphiphilic gelatin (AG)-iron oxide@calcium phosphate (CaP) nanoparticles with hydrophobic curcumin (CUR) and hydrophilic doxorubicin (DOX) encapsulated in the AG core and CaP shell (AGIO@CaP-CD), respectively. This multi-functional nanoparticle system has a pH-sensitive CaP shell and degradable amphiphilic gelatin (AG) core, which enables controllable sequential release of the two drugs. The dual-targeting system of AGIO@CaP-CD (HER-AGIO@CaP-CD) with a bioligand and magnetic targeting resulted in significantly elevated cellular uptake in HER2-overexpressing SKBr3 cells and more efficacious therapy than delivery of targeting ligand alone due to the synergistic cell multi-drug resistance/apoptosis-inducing effect of the CUR and DOX combination. This nanoparticle combined with Herceptin and iron oxide nanoparticles not only provided a dual-targeting functionality, but also encapsulated CUR and DOX as a dual-drug delivery system for the combination therapy. This study further demonstrated that the therapeutic efficacy of this dual-targeting co-delivery system can be improved by modifying the application duration of magnetic targeting, which makes this combination therapy system a powerful new tool for in vitro/in vivo cancer therapy, especially for HER2 positive cancers. PMID- 26478041 TI - Re: Should Prophylactic Anti-Incontinence Procedures be Performed at the Time of Prolapse Repair? Systematic Review. PMID- 26478018 TI - Mucoadhesive microparticles with a nanostructured surface for enhanced bioavailability of glaucoma drug. AB - Topical drug administration to the eye is limited by low drug bioavailability due to its rapid clearance from the preocular surface. Thus, multiple daily administrations are often needed, but patient compliance is low, hence a high chance of unsatisfactory treatment of ocular diseases. To resolve this, we propose mucoadhesive microparticles with a nanostructured surface as potential carriers for delivery of brimonidine, an ocular drug for glaucoma treatment. For sustained drug delivery, the microparticles were composed mainly of a diffusion wall material, poly(lactic-co-glycolic acid) and a mucoadhesive polymer, polyethylene glycol, was used as an additive. Due to their nanostructured surface, the microparticles with a mucoadhesive material exhibited a 13-fold increase in specific surface area and could thus adhere better to the mucous layer on the eye, as compared with the conventional spherical microparticles. When loaded with brimonidine, the mucoadhesive microparticles with a nanostructured surface increased both drug bioavailability and its activity period by a factor of more than 2 over Alphagan P, a marketed eye drop of brimonidine. PMID- 26478089 TI - Quantum-secure covert communication on bosonic channels. AB - Computational encryption, information-theoretic secrecy and quantum cryptography offer progressively stronger security against unauthorized decoding of messages contained in communication transmissions. However, these approaches do not ensure stealth--that the mere presence of message-bearing transmissions be undetectable. We characterize the ultimate limit of how much data can be reliably and covertly communicated over the lossy thermal-noise bosonic channel (which models various practical communication channels). We show that whenever there is some channel noise that cannot in principle be controlled by an otherwise arbitrarily powerful adversary--for example, thermal noise from blackbody radiation--the number of reliably transmissible covert bits is at most proportional to the square root of the number of orthogonal modes (the time-bandwidth product) available in the transmission interval. We demonstrate this in a proof-of-principle experiment. Our result paves the way to realizing communications that are kept covert from an all-powerful quantum adversary. PMID- 26478088 TI - Fructose 1,6-bisphosphate, a high-energy intermediate of glycolysis, attenuates experimental arthritis by activating anti-inflammatory adenosinergic pathway. AB - Fructose 1,6-bisphosphate (FBP) is an endogenous intermediate of the glycolytic pathway. Exogenous administration of FBP has been shown to exert protective effects in a variety of ischemic injury models, which are attributed to its ability to sustain glycolysis and increase ATP production. Here, we demonstrated that a single treatment with FBP markedly attenuated arthritis, assessed by reduction of articular hyperalgesia, joint swelling, neutrophil infiltration and production of inflammatory cytokines, TNF and IL-6, while enhancing IL-10 production in two mouse models of arthritis. Our mechanistic studies showed that FBP reduces joint inflammation through the systemic generation of extracellular adenosine and subsequent activation of adenosine receptor A2a (A2aR). Moreover, we showed that FBP-induced adenosine generation requires hydrolysis of extracellular ATP through the activity of the ectonucleosides triphosphate diphosphohydrolase-1 (ENTPD1, also known as CD39) and ecto-5'-nucleotidase (E5NT, also known as CD73). In accordance, inhibition of CD39 and CD73 abolished anti arthritic effects of FBP. Taken together, our findings provide a new insight into the molecular mechanism underlying the anti-inflammatory effect of FBP, showing that it effectively attenuates experimental arthritis by activating the anti inflammatory adenosinergic pathway. Therefore, FBP may represent a new therapeutic strategy for treatment of rheumatoid arthritis (RA). PMID- 26478090 TI - Folding thermodynamics of c-Myb DNA-binding domain in correlation with its alpha helical contents. AB - The conformational and thermal stabilities of the minimum functional unit for c Myb DNA-binding domain, tandem repeat 2 and 3 (R2R3), were analyzed under different pH conditions, ranging from 4.0 to 7.5, using circular dichroism and differential scanning calorimetry. Secondary structure analysis showed that the solution pH largely affects the conformational stability of the protein domain. Of all conditions analyzed, the alpha-helical content was maximal at pH 6.5, and the thermal stability was highest at pH 5.0. Thermodynamic parameters for thermal unfolding of R2R3 were determined using differential scanning calorimetry, and the origin of folding thermodynamics at the different pHs and its correlation with the alpha-helical content were further analyzed. It should be noted that the alpha-helical content correlates well with the enthalpy change in the pH range from 4.5 to 7.5, suggesting that the strength of hydrogen bonds and salt bridges needed for maintenance of helical structure is related to enthalpy in the native state. Under physiological pH conditions, c-Myb R2R3 exists in the enthalpically unstable but entropically stable state. Due to loss of rigid structure and high stability, the protein can now obtain structural flexibility, befitting its function. PMID- 26478091 TI - Rapana thomasiana hemocyanin modified with ionic liquids with enhanced anti breast cancer activity. AB - This is the first study on the surface modification of a hemocyanin from marine snail Rapana thomasiana (RtH) with series of imidazolium-based amino acid ionic liquids [emim][AA]. We monitored the induced by [emim][AA] conformational changes in RtH molecule and evaluated the effect of these ionic liquids (ILs) on the protein thermal stability. The cytotoxicity of all obtained RtH-[emim][AA] complexes was assessed toward breast cancer cells (MCF-7) and murine fibroblasts (3T3). As a whole, even small amounts of the tested ILs altered the secondary structure of RtH. The thermal denaturation of RtH in presence of [emim][AA] displayed multi-component transitions, which were shifted toward lower temperatures in comparison to those estimated for the native RtH. The profiles of the RtH-IL calorimetric curves show a clear dependence on the structure of the added salts. In addition, all RtH-[emim][AA] complexes exhibited an enhanced antiprofilerative activity of toward MCF-7 cells in comparison to that of the native RtH. The best results are observed for RtH-[emim][Leu], RtH-[emim][Trp] or RtH-[emim][Ile], which applied in concentration of 700 MUg/mL inhibited the MCF-7 cell viability (for 24h) by 66, 63 and 53%, respectively. In addition, these IL RtH complexes were less cytotoxic to 3T3 cells, i.e. they exhibited some cell specificity. PMID- 26478092 TI - Synthesis and antimicrobial activity of polysaccharide alginate derived cationic surfactant-metal(II) complexes. AB - New natural polysaccharide carbohydrate derivatives of sodium alginate surfactant and its cobalt, copper and zinc complexes were synthesized. Structures of the synthesized compounds are reported using FTIR, (1)H NMR and UV-vis. The critical micelle concentration (CMC) value of the alginate surfactant and its metal complexes in aqueous solution was found out from surface tension measurements. Surface tension data at different temperatures served for the evaluation of the temperature-dependent CMC and the thermodynamics of micellization (DeltaGmic, DeltaHmic, DeltaSmic) and adsorption (DeltaGads, DeltaGads, DeltaSads). The surface activities of the synthesized polymeric surfactant and its metal complexes were influenced by their chemical structures and the type of the transition metals. These compounds were evaluated against Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and fungi (Candida albicans and Asperigllus niger). The antibacterial and antifungal screening tests of the alginate surfactant metal complexes have shown good results compared to its precursor alginate surfactant. PMID- 26478093 TI - Assessment of structure, stability and aggregation of soluble lens proteins and alpha-crystallin upon non-enzymatic glycation: The pathomechanisms underlying cataract development in diabetic patients. AB - Total soluble lens proteins (TSPs) and alpha-crystallin (alpha-Cry) were individually subjected to the long-term glycation in the presence of d-glucose. The glycated and non-glycated protein counterparts were incubated under different stress conditions and compared according to their structure, stability and aggregation propensity by various spectroscopic techniques and gel mobility shift analyses. Extensive glycation of the lens proteins was accompanied with structural alteration, reduction in their surface hydrophobicity and increment of their surface tension. Our results suggest that glycation causes lens crystallins to partially resist against structural alteration and aggregation/fibrillation under both thermal and thermochemical systems. The conformational stability of lens crystallins was increased upon glycation, showing the reason behind resistance of glycated proteins against stress-induced structural alteration and aggregation. Due to the resistance of glycated lens crystallins against aggregation, the role of this modification in development of senile cataract can be explained with the associated damaging consequences highlighted in this article. PMID- 26478094 TI - Identification and characterization of a cytotoxic polysaccharide from the flower of Abelmoschus manihot. AB - A low molecular weight polysaccharide was identified from the flower of Abelmoschus manihot (Linn.) Medicus, a popular herbal medicine also known as Flos A. manihot. The polysaccharide, AMPS-a, was obtained from the ethanol-extracted debris of Flos A. manihot by successive purification through DEAE-cellulose-52 and Sephadex G-100 column. AMPS-a has an estimated molecular weight of 8.8*10(3)Da and is mainly composed of beta-d-glucose, alpha-d-mannose, alpha-d galactose and alpha-l-fucose at a molar ratio of 1.00:0.91:2.14:1.09. The preliminary structural features were studied by hydrolysis-methylation analysis, GC-MS, FT-IR and (1)H and (13)C NMR spectroscopy. AMPS-a contains a backbone composed of repeating units of ->6)alpha-d-Galp-(1->6)alpha-d-Manp-(1->6)alpha-d Galp-(1-> with beta-d-Glcp (1->3)alpha-Fucp-(1-> branching at O-3 of mannose. AMPS-a exhibited potent inhibitory effects on the proliferation of hepatic (SMMC 7721, HepG2) and gastric (MGC-803, MKN-45) cancer cells in vitro, and the sugar branches were indispensible for the cytotoxicity. Our work contributes to the first report of a novel cytotoxic polysaccharide from Flos A. manihot that may provide a potential source of anti-tumor agent. PMID- 26478095 TI - Estrogen Secreted by Mesenchymal Stem Cells Necessarily Determines Their Feasibility of Therapeutical Application. AB - Mesenchymal stem cells are therapeutically applicable and involved in the development of some types of diseases including estrogen (E2)-related ones. Little is known about E2 secretion by mesenchymal stem cells and its potential influence on their therapeutical applications. Our in vitro experiments showed that BMSCs cultured from C57BL/6J mice secreted E2 in a time-dependent manner. In vivo study identified a significantly increased E2 level in serum after a single administration of BMSCs, and a sustained elevation of E2 level upon a repetitive administration. Morris water maze test in the ovariectomised (OVX) mouse model revealed BMSCs transplantation ameliorated OVX-induced memory deficits by secreted E2. On the contrary, in endometriosis model, BMSCs transplantation aggravated endometriotic lesions because of E2 secretion. Mechanistically, the aromatase cytochrome P450 appeared to be critical for the biosynthesis and exerted effects of estrogen secretion by BMSCs. Our findings suggested that BMSCs transplantation is on the one hand an attractive option for the therapeutic treatment of diseases associated with E2 deficits in part through E2 secretion, on the other hand a detrimental factor for the E2-exasperated diseases largely via E2 production. It is important and necessary to monitor serum E2 level before and after the initiation of BMSCs therapy. PMID- 26478096 TI - Correspondence Regarding the Consensus Statement from the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues. PMID- 26478097 TI - Liver fibrosis and Gd-EOB-DTPA-enhanced MRI: A histopathologic correlation. AB - Gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) is a hepatocyte-specific MRI contrast agent. Because the hepatic uptake of Gd-EOB-DTPA depends on the integrity of the hepatocyte mass, this uptake can be quantified to assess liver function. We report the relationship between the extent of Gd-EOB DTPA uptake and the degree of liver fibrosis. T1-weighted volume-interpolated breath-hold examination (VIBE) sequences with fat suppression were acquired before and 20 minutes after contrast injection. Strong correlations of the uptake characteristics of Gd-EOB-DTPA with the relative enhancement (RE) of the liver parenchyma and the grade of fibrosis/cirrhosis, classified using the Ishak scoring system, were observed. The subdivisions between the grades of liver fibrosis based on RE were highly significant for all combinations, and a ROC revealed sensitivities >=82% and specificities >=87% for all combinations. MR imaging is a satisfactorily sensitive method for the assessment of liver fibrosis/cirrhosis. PMID- 26478099 TI - Medical screening in dental settings: a qualitative study of the views of authorities and organizations. AB - BACKGROUND: The practice of identifying individuals with undiagnosed diabetes mellitus type II or undiagnosed hypertension by medical screening in dental settings has been received positively by both patients and dentistry professionals. This identification has also shown to be cost-effective by achieving savings and health benefits, but no investigation has been made of the attitudes of authorities and organizations. The aim of this study was to describe the views of authorities and organizations. RESULTS: Thirteen authorities and organizations were interviewed of the sample of 20 requested. Seven approached authorities and organizations did not believe it was relevant to participate in the study. The manifest analysis resulted in four categories: medical screening ought to be established in the society; dentistry must have relevant competence to perform medical screening; medical screening requires cooperation between dentistry and health care; and dentistry is not the only context where medical screening could be performed. The latent analysis resulted in an emerging theme: positive to, but uncertain about, the concept of medical screening in dental settings. The spokespersons for the approached authorities and organizations had a positive view of medical screening but the respondents experienced a lack of facts concerning the scientific communities' position, guidelines and procedures in the topic. CONCLUSIONS AND IMPLICATIONS: Approached authorities and organizations generally had a positive view of medical screening in dental settings but were uncertain about the concept. Further scientific knowledge and guidelines concerning the topic are needed before it can be commonly introduced and additional research on implementation strategies and long-term follow-up of medical screening are needed. PMID- 26478100 TI - Maintenance of Certification for Gastroenterologists. PMID- 26478102 TI - The economic impact of surgical care for morbidly obese endometrial cancer patients: a nationwide study. AB - BACKGROUND: Obesity significantly impacts the cost of cancer treatment, yet the impact of morbid obesity on inpatient hospital charges related to endometrial cancer treatment is not well-defined. OBJECTIVES: The purpose of this study was to determine the charges that are associated with inpatient surgery, hospitalization, and postoperative care of morbidly obese patients with endometrial cancer. STUDY DESIGN: Data were obtained from the National Inpatient Sample from 2010. Chi-square test, t-test, and linear regression were used for statistical analyses. RESULTS: Six thousand five hundred sixty patients who underwent hysterectomy for endometrial cancer were identified. Mean age was 62 years (range, 22-99 years). The majority were white (78%), and the remainder were black (10%), Hispanic, (8%), Asian (3%), and Native American (1%). Insurance types were private (45%), Medicare (45%), Medicaid (5%), and uninsured (7%). One thousand eighty-eight of these patients (17%) were coded as morbidly obese. The mean postoperative stay for the morbidly obese was 4.0 days (range, 0-46 days) compared with 3.5 days (range, 0-81 days) for the non-morbidly obese patients (P < .01). Morbidly obese patients required more intensive care with mechanical ventilation (5.5% vs 1.6%; P < .01). The median hospital charges were higher for morbidly obese patients compared with their counterparts ($46,654 vs $41,164; P < .01). After adjustment for charges that were associated with insurance type, hospital type, and the surgery that was performed, the incremental increase in hospital charges that were associated with treating the morbidly obese patient was $5096 per patient (95% confidence interval, $2593-$7598; P < .01). CONCLUSION: In this economic analysis, the health care charges that were associated with inpatient endometrial cancer treatment in the morbidly obese patient was significantly higher compared the non-morbidly obese patient. Resources are needed to support the needs of this population, and programs to encourage weight loss and optimize general health should be encouraged. PMID- 26478103 TI - Assessing first-stage labor progression and its relationship to complications. AB - BACKGROUND: New labor curves have challenged the traditional understanding of the general pattern of dilation and descent in labor. They also revealed wide variation in the time to advance in dilation. An interval of arrest such as 4 hours did not fall beyond normal limits until dilation had reached 6 cm. Thus, the American College of Obstetricians and Gynecologists/Society for Maternal Fetal Medicine first-stage arrest criteria, based in part on these findings, are applicable only in late labor. The wide range of time to dilate is unavoidable because cervical dilation has neither a precise nor direct relationship to time. Newer statistical techniques (multifactorial models) can improve precision by incorporating several factors that are related directly to labor progress. At each examination, the calculations adapt to the mother's current labor conditions. They produce a quantitative assessment that is expressed in percentiles. Low percentiles indicate potentially problematic labor progression. OBJECTIVE: The purpose of this study was to assess the relationship between first stage labor progress- and labor-related complications with the use of 2 different assessment methods. The first method was based on arrest of dilation definitions. The other method used percentile rankings of dilation or station based on adaptive multifactorial models. STUDY DESIGN: We included all 4703 cephalic presenting, term, singleton births with electronic fetal monitoring and cord gases at 2 academic community referral hospitals in 2012 and 2013. We assessed electronic data for route of delivery, all dilation and station examinations, newborn infant status, electronic fetal monitoring tracings, and cord blood gases. The labor-related complication groups included 272 women with cesarean delivery for first-stage arrest, 558 with cesarean delivery for fetal heart rate concerns, 178 with obstetric hemorrhage, and 237 with neonatal depression, which left 3004 women in the spontaneous vaginal birth group. Receiver operating characteristic curves were constructed for each assessment method by measurement of the sensitivity for each complication vs the false-positive rate in the normal reference group. RESULTS: The duration of arrest at >=6 cm dilation showed poor levels of discrimination for the cesarean delivery interventions (area under the curve, 0.55-0.65; P < .01) and no significant relationship to hemorrhage or neonatal depression. The dilation and station percentiles showed high discrimination for the cesarean delivery-related outcomes (area under the curve, 0.78-0.93; P < .01) and low discrimination for the clinical outcomes of hemorrhage and neonatal depression (area under the curve, 0.58-0.61; P < .01). CONCLUSIONS: Duration of arrest of dilation at >=6 cm showed little or no discrimination for any of the complications. In comparison, percentile rankings that were based on the adaptive multifactorial models showed much higher discrimination for cesarean delivery interventions and better, but low discrimination for hemorrhage. Adaptive multifactorial models present a different method to assess labor progress. Rather than "pass/fail" criteria that are applicable only to dilation in late labor, they produce percentile rankings, assess 2 essential processes for vaginal birth (dilation and descent), and can be applied from 3 cm onward. Given the limitations of labor-progress assessment based solely on the passage of time and because of the extreme variation in decision-making for cesarean delivery for labor disorders, the types of mathematic analyses that are described in this article are logical and promising steps to help standardize labor assessment. PMID- 26478101 TI - Maternal and fetal roles in bacterially induced preterm labor in the mouse. AB - BACKGROUND: The relative roles of the mother and fetus in signaling for labor remain poorly understood. OBJECTIVE: We previously demonstrated using gene knockout (KO) mice that Escherichia coli-induced preterm delivery is completely dependent on MyD88, a toll-like receptor adaptor protein. Here we leveraged this finding to conduct a genetic experiment testing whether the mother, the fetus, or both signal for parturition in bacterially induced labor. STUDY DESIGN: Six different maternal/fetal genotype combinations for MyD88 were studied: wild-type (WT) dams carrying one of the following: (1) WT or (2) MyD88 heterozygous (het) fetuses (generated by mating WT females with WT or MyD88-knockout [KO] males, respectively); (3) WT dams carrying MyD88-KO fetuses (generated by replacing the ovaries of WT females with MyD88-KO ovaries, followed by mating with MyD88-KO males); a similar strategy was used to generate MyD88-KO dams carrying (4) MyD88 KO, (5) MyD88 het, or (6) WT fetuses. On day 14.5 of gestation, mice received intrauterine injections of either 1 * 10(9) killed E coli or sterile medium. Delivery of >= 1 fetus within 48 hours was considered preterm. A separate group of similarly treated pregnant mice was euthanized 5 hours after surgery for gene expression and tissue analysis. RESULTS: E coli-induced preterm delivery is dependent on maternal and not fetal genotype: > 95% of WT and < 5% of MyD88-KO dams deliver prematurely, regardless of fetal genotype (P = .0001). In contrast, fetal survival in utero is influenced by fetal genotype: in MyD88-KO dams, in which premature birth rarely occurs, only 81% of WT and 86% of MyD88-heterozygous fetuses were alive 48 hours after surgery compared with 100% of MyD88-KO fetuses (P < .01). Messenger ribonucleic acids for the inflammatory mediators interleukin 1beta, tumor necrosis factor, interleukin-6, and cyclooxygenase-2 were elevated in uterine tissues only in WT mothers treated with E coli and were low or undetectable in the uteri of KO mothers or in animals treated with saline. Serum progesterone levels were lower in KO mothers with WT ovaries than in WT mothers with KO ovaries, but bacterial exposure did not have an impact on these levels. CONCLUSION: In the murine E coli-induced labor model, preterm delivery and uterine expression of inflammatory mediators is determined by the mother and not the fetus and is not attributable to a decline in serum progesterone. PMID- 26478105 TI - Triggers, bundles, protocols, and checklists--what every maternal care provider needs to know. AB - The rise in maternal morbidity and mortality has resulted in national and international attention at optimally organizing systems and teams for pregnancy care. Given that maternal morbidity and mortality can occur unpredictably in any obstetric setting, specialists in general obstetrics and gynecology along with other primary maternal care providers should be integrally involved in efforts to improve the safety of obstetric care delivery. Quality improvement initiatives remain vital to meeting this goal. The evidence-based utilization of triggers, bundles, protocols, and checklists can aid in timely diagnosis and treatment to prevent or limit the severity of morbidity as well as facilitate interdisciplinary, patient-centered care. The purpose of this document is to summarize the pertinent elements from this forum to assist primary maternal care providers in their utilization and implementation of these safety tools. PMID- 26478104 TI - Effectiveness and short-term safety of modified sodium hyaluronic acid carboxymethylcellulose at cesarean delivery: a randomized trial. AB - BACKGROUND: The rising cesarean birth rate has drawn attention to risks associated with repeat cesarean birth. Prevention of adhesions with adhesion barriers has been promoted as a way to decrease operative difficulty. However, robust data demonstrating effectiveness of such interventions are lacking. OBJECTIVE: We report data from a multicenter trial designed to evaluate the short term safety and effectiveness of a modified sodium hyaluronic acid (HA) carboxymethylcellulose (CMC) absorbable adhesion barrier for reduction of adhesions following cesarean delivery. STUDY DESIGN: Patients who underwent primary or repeat cesarean delivery were included in this multicenter, single blinded (patient), randomized controlled trial. Patients were randomized into either HA-CMC (N = 380) or no treatment (N = 373). No other modifications to their treatment were part of the protocol. Short-term safety data were collected following randomization. The location and density of adhesions (primary outcome) were assessed at their subsequent delivery using a validated tool, which can also be used to derive an adhesion score that ranges from 0-12. RESULTS: No differences in baseline characteristics, postoperative course, or incidence of complications between the groups following randomization were noted. Eighty patients from the HA-CMC group and 92 controls returned for subsequent deliveries. Adhesions in any location were reported in 75.6% of the HA-CMC group and 75.9% of the controls (P = .99). There was no significant difference in the median adhesion score; 2 (range 0-10) for the HA-CMC group vs 2 (range 0-8) for the control group (P = .65). One third of the HA-CMC patients met the definition for severe adhesions (adhesion score >4) compared to 15.5% in the control group (P = .052). There were no significant differences in the time from incision to delivery (P = .56). Uterine dehiscence in the next pregnancy was reported in 2 patients in HA-CMC group vs 1 in the control group (P = .60). CONCLUSION: Although we did not identify any short-term safety concerns, HA-CMC adhesion barrier applied at cesarean delivery did not reduce adhesion formation at the subsequent cesarean delivery. PMID- 26478106 TI - Phase Transformation in Tantalum under Extreme Laser Deformation. AB - The structural and mechanical response of metals is intimately connected to phase transformations. For instance, the product of a phase transformation (martensite) is responsible for the extraordinary range of strength and toughness of steel, making it a versatile and important structural material. Although abundant in metals and alloys, the discovery of new phase transformations is not currently a common event and often requires a mix of experimentation, predictive computations, and luck. High-energy pulsed lasers enable the exploration of extreme pressures and temperatures, where such discoveries may lie. The formation of a hexagonal (omega) phase was observed in recovered monocrystalline body centered cubic tantalum of four crystallographic orientations subjected to an extreme regime of pressure, temperature, and strain-rate. This was accomplished using high-energy pulsed lasers. The omega phase and twinning were identified by transmission electron microscopy at 70 GPa (determined by a corresponding VISAR experiment). It is proposed that the shear stresses generated by the uniaxial strain state of shock compression play an essential role in the transformation. Molecular dynamics simulations show the transformation of small nodules from body centered cubic to a hexagonal close-packed structure under the same stress state (pressure and shear). PMID- 26478107 TI - Salivary botulinum toxin injection may reduce aspiration pneumonia in neurologically impaired children. AB - OBJECTIVES: Neurologically impaired children often drool and aspirate saliva leading to recurrent aspiration pneumonia and frequent hospitalizations. Salivary botulinum toxin injection is known to reduce sialorrhea. This study evaluates whether this intervention affects the frequency and duration of respiratory infections including aspiration pneumonia and hospitalizations in neurologically impaired children. METHODS: Retrospective review of patients treated with salivary botulinum toxin at a tertiary care pediatric hospital from January 2009 to December 2013. Each patient was their own control and 180 day pre-injection and post-injection time periods were compared. Outcomes evaluated included: number of hospital days, intensive care unit days, days of antibiotic treatment, chest X-rays, and infiltrates on chest X-ray. RESULTS: 13 patients accumulated 539 hospital days. All children were gastrostomy tube dependent. 54% were tracheostomy tube dependent. Amongst all patients, the total hospital days decreased from 385 to 154 (P=0.02), the mean days treated with antibiotics decreased from 214 to 47 (P=0.02), and the number of chest X-ray confirmed infiltrates decreased from 20 to 6 (P=0.02) after injection. CONCLUSION: In this review, there was a decrease in hospitalized days, antibiotic usage, and chest X ray infiltrates after the salivary botulinum toxin injection. A prospective study is needed to evaluate whether this treatment can prevent aspiration pneumonia in neurologically impaired children. PMID- 26478108 TI - Adenoids and clinical symptoms: Epidemiology of a cohort of 795 pediatric patients. AB - OBJECTIVE: Adenoid hypertrophy (AH) is very common in children and can cause airway obstruction. The aim of this retrospective study was to investigate the relationship between AH and other factors, including age, possible related symptoms, and allergies. METHODS: Seven hundred and ninety-five patients (460 males, 335 females; mean age=5.9 years; range age: 1-14 years) were seen in an ENT clinic for nasal symptoms. Nasal endoscopy was performed with a pediatric flexible endoscope. One hundred and sixty-nine patients had documented allergy sensitization. Patients were divided into two groups according to their age: group 1 included children aged 1-7 years, and group 2 included subjects aged 8-14 years. RESULTS: Adenoid size was related to age (p<0.0001). A logistic regression model - performed to evaluate adenoid grade considering, as dependent variables, age, sex, and the presence or absence of symptoms - was statistically significant (p<0.001). Moreover, AH was more common (p=0.0104) in patients with allergy sensitization, in particular in patients aged 8-14 years (p=0.0043). Nasal obstruction (OR=3.27) significantly predicted AH, whereas major age was not associated with pathological AH (OR=0.81). CONCLUSIONS: The present retrospective study described the relationship between AH and other demographic and clinical factors. In conclusion, our findings demonstrated a significant association among pathological AH, age, and nasal obstruction. PMID- 26478109 TI - Day-case adenotonsillectomy for sleep apnoea in children? AB - OBJECTIVES: Many clinicians are concerned about possible airway or respiratory complications following adenotonsillectomy for sleep related breathing disorder (SRBD), and routinely admit such patients for overnight monitoring. However, published guidelines suggest this is unnecessary in some cases. This study firstly aimed to establish current UK practice, and secondly to investigate whether children with mild/moderate SRBD experience respiratory problems during the first post-operative night. METHODS: To establish current UK practice, we carried out a telephone survey asking if the procedure was carried out as a day case, and admission criteria. For the second aim, a prospective study of children admitted following adenotonsillectomy for mild/moderate SRBD was carried out to investigate occurrence of respiratory complications on first post-operative night. RESULTS: Forty-two UK ENT doctors responded to the telephone survey, 50% routinely admitted patients having adenotonsillectomy for SRBD. Discharge criteria included stable observations and eating and drinking (14 hospitals), no bleeding (1), stable oxygen saturations (1) and age above 5 years (1); four had no specific criteria. Of 51 children admitted following adenotonsillectomy for mild/moderate SRBD, 11 (21.6%) experienced oxygen desaturations overnight. Of these, nine were under 4 years old, and two older children had asthma. Irrespective of comorbidities, 9/27 (33.2%) children under 4 years old experienced desaturations. The only children aged more than 4 years that had desaturations were ones that had additional comorbidities. CONCLUSION: Half of surveyed doctors admit all children following surgery for SRBD. The number of admissions could be reduced, because same-day discharge for otherwise-healthy children over 4 years old having adenotonsillectomy for mild/moderate SRBD appears to be safe. PMID- 26478116 TI - Solid state p-type dye-sensitized solar cells: concept, experiment and mechanism. AB - Solid state p-type dye-sensitized solar cells (p-ssDSCs) have been proposed and fabricated for the first time, using the organic dye P1 as the sensitizer on mesoporous NiO and phenyl-C61-butyric acid methyl ester (PCBM) as the electron conductor. The p-ssDSC has shown an impressive open circuit photovoltage of 620 mV. Femtosecond and nanosecond transient absorption spectroscopy has given evidence for sub-ps hole injection from the excited P1 to NiO, followed by electron transfer from P1(-) to PCBM. PMID- 26478115 TI - Dynamic assembly of a zinc-templated bifunctional organocatalyst in the presence of water for the asymmetric aldol reaction. AB - A bifunctional organocatalytic system consisting of simple pyridine ligands containing separate catalytic functionalities was assembled using ZnCl2. This novel metal-templated catalyst furnished high yields and stereoselectivities towards the aldol reaction. The addition of controlled amounts of water turned out to be crucial to dissolve the system and achieve optimal results. PMID- 26478117 TI - Discovery of rhenium and masurium (technetium) by Ida Noddack-Tacke and Walter Noddack. Forgotten heroes of nuclear medicine. AB - The history of the early identification of elements and their designation to the Mendeleev Table of the Elements was an important chapter in German science in which Ida (1896-1978) and Walter (1893-1960) Noddack played an important role in the first identification of rhenium (element 75, 1925) and technetium (element 43, 1933). In 1934 Ida Noddack was also the first to predict fission of uranium into smaller atoms. Although the Noddacks did not for some time later receive the recognition for the first identification of technetium-99m, their efforts have appropriately more recently been recognized. The discoveries of these early pioneers are even more astounding in light of the limited technologies and resources which were available during this period. The Noddack discoveries of elements 43 and 75 are related to the subsequent use of rhenium-188 (beta/gamma emitter) and technetium-99m (gamma emitter) in nuclear medicine. In particular, the theranostic relationship between these two generator-derived radioisotopes has been demonstrated and offers new opportunities in the current era of personalized medicine. PMID- 26478118 TI - The Anthropocene Speciation Hypothesis Remains Valid: Reply to Hulme et al. PMID- 26478119 TI - Metal-free methylation of a pyridine N-oxide C-H bond by using peroxides. AB - Metal-free methylation of a pyridine N-oxide C-H bond was developed using peroxide as a methyl reagent under neat conditions. Pyridine N-oxide derivatives with various groups (e.g., Cl, NO2, and OCH3) were all suitable substrates, and the desired products were obtained in moderate to excellent yields under standard conditions. Moreover, the methylation can be performed with a good yield on the gram-scale experiment. Tentative mechanistic studies show that the methylation is a classical radical process. PMID- 26478120 TI - De facto methodologies toward the synthesis and scale-up production of UiO-66 type metal-organic frameworks and membrane materials. AB - Metal-organic frameworks (MOFs) are architected via coordination bonds between inorganic metal nodes and organic ligands. They have become emerging advanced porous materials and gained ever-increasing attention in the past decade. In particular, overwhelming studies have been devoted to those hydrostable MOFs which are suggested to be highly promising for industrial applications. UiO-66 is such a unique MOF because of its superior thermal/chemical stability and structural tunability. However, its repeatable, green, and scale-up synthesis remains a challenge for its commercialization and implementation in industrial applications. This perspective mainly summarises the recent development in the synthesis of UiO-66-type MOFs and their related composites. From a scale-up viewpoint, we also present some important advances in the batch and continuous reactor synthesis toward their massive production (226 references). PMID- 26478121 TI - Steady-state photoconductivity and multi-particle interactions in high-mobility organic semiconductors. AB - Fundamental understanding of photocarrier generation, transport and recombination under a steady-state photoexcitation has been an important goal of organic electronics and photonics, since these processes govern such electronic properties of organic semiconductors as, for instance, photoconductivity. Here, we discovered that photoconductivity of a highly ordered organic semiconductor rubrene exhibits several distinct regimes, in which photocurrent as a function of cw (continuous wave) excitation intensity is described by a power law with exponents sequentially taking values 1, 1/3 and 1/4. We show that in pristine crystals this photocurrent is generated at the very surface of the crystals, while the bulk photocurrent is drastically smaller and follows a different sequence of exponents, 1 and 1/2. We describe a simple experimental procedure, based on an application of "gauge effect" in high vacuum, that allows to disentangle the surface and bulk contributions to photoconductivity. A model based on singlet exciton fission, triplet fusion and triplet-charge quenching that can describe these non-trivial effects in photoconductivity of highly ordered organic semiconductors is proposed. Observation of these effects in photoconductivity and modeling of the underlying microscopic mechanisms described in this work represent a significant step forward in our understanding of electronic properties of organic semiconductors. PMID- 26478122 TI - C.S. Greene continues his biased accusations. PMID- 26478123 TI - Osteolytic expansile lesion of the mandible in a 60-year-old male. PMID- 26478124 TI - Historical: early multi-component FT-PGSE NMR self-diffusion measurements-some personal reflections. PMID- 26478125 TI - A high energy output nanogenerator based on reduced graphene oxide. AB - In this paper, we report a novel graphene-based nanogenerator for high energy harvesting. Experimental and theoretical results revealed that the energy output mechanism is the joint action of the strain effect (band engineering) and the triboelectric effect of reduced graphene oxide. It was found that the current could be adjusted by experimental parameters, such as the electrolyte concentration and rotation rate. Furthermore, the voltage output could be amplified by series connection of the system. Compared with other nanogenerators, the present graphene-based nanogenerator provides advantages, such as simple assembly, flexibility and high structural stability. It is expected that this nanogenerator will be of potential application in active sensors and sustainable power sources. PMID- 26478126 TI - Antioxidants Inhibit Formation of 3-Monochloropropane-1,2-diol Esters in Model Reactions. AB - The capacities of six antioxidants to inhibit the formation of 3 monochloropropane-1,2 diol (3-MCPD) esters were examined in this study. Inhibitory capacities of the antioxidants were investigated both in chemical models containing the precursors (tripalmitoyl glycerol, 1,2-dipalmitoyl-sn glycerol, monopalmitoyl glycerol, and sodium chloride) of 3-MCPD esters and in oil models (rapeseed oil and sodium chloride). Six antioxidants, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tert-butyl hydroquinone (TBHQ), propyl gallate (PG), L-ascorbyl palmitate (AP), and alpha-tocopherol (VE), were found to exhibit inhibiting capacities on 3-MCPD ester formation both in chemical models and in oil models. TBHQ provided the highest inhibitory capacity both in chemical models and in oil models; 44% of 3-MCPD ester formation was inhibited in the presence of TBHQ (66 mg/kg of oil) after heating of rapeseed oil at 230 degrees C for 30 min, followed by PG and AP. BHT, BHA, and VE appeared to have weaker inhibitory abilities in both models. VE exhibited the lowest inhibition rate; 22% of 3-MCPD esters were inhibited in the presence of VE (172 mg/kg of oil) after heating of rapeseed oil at 230 degrees C for 30 min. In addition, the inhibition rates of PG and VE decreased dramatically with an increase in temperature or heating time. The results suggested that some antioxidants, such as TBHQ, PG, and AP, could be the potential inhibitors of 3 MCPD esters in practice. PMID- 26478128 TI - Are PrP(C)s involved in some human myelin diseases? Relating experimental studies to human pathology. AB - We have experimentally demonstrated that cobalamin (Cbl) deficiency increases normal cellular prion (PrP(C)) levels in rat spinal cord (SC) and cerebrospinal fluid (CSF), and decreases PrP(C)-mRNA levels in rat SC. Repeated intracerebroventricular administrations of anti-octapeptide repeat-PrP(C)-region antibodies to Cbl-deficient (Cbl-D) rats prevent SC myelin lesions, and the administrations of PrP(C)s to otherwise normal rats cause SC white matter lesions similar to those induced by Cbl deficiency. Cbl positively regulates SC PrP(C) synthesis in rat by stimulating the local synthesis of epidermal growth factor (EGF), which also induces the local synthesis of PrP(C)-mRNAs, and downregulating the local synthesis of tumor necrosis factor(TNF)-alpha, thus preventing local PrP(C) overproduction. We have clinically demonstrated that PrP(C) levels are increased in the CSF of patients with subacute combined degeneration (SCD), unchanged in the CSF of patients with Alzheimer's disease and amyotrophic lateral sclerosis, and decreased in the CSF and SC of patients with multiple sclerosis (MS), regardless of its clinical course. We conclude that SCD (human and experimental) is a neurological disease due to excess PrP(C) without conformational change and aggregation, that the increase in PrP(C) levels in SCD and Cbl-D polyneuropathy and their decrease in MS CNS make them antipodian myelin diseases in terms of quantitative PrP(C) abnormalities, and that these abnormalities are related to myelin damage in the former, and impede myelin repair in the latter. PMID- 26478127 TI - Hydrogen peroxide activates store-operated Ca(2+) entry in coronary arteries. AB - BACKGROUND AND PURPOSE: Abnormal Ca(2+) metabolism has been involved in the pathogenesis of vascular dysfunction associated with oxidative stress. Here, we have investigated the actions of H2 O2 on store-operated Ca(2+) (SOC) entry in coronary arteries and assessed whether it is impaired in arteries from a rat model of metabolic syndrome. EXPERIMENTAL APPROACH: Simultaneous measurements of intracellular Ca(2+) concentration and contractile responses were made in coronary arteries from Wistar and obese Zucker rats, mounted in microvascular myographs, and the effects of H2 O2 were assessed. KEY RESULTS: H2 O2 raised intracellular Ca(2+) concentrations, accompanied by simultaneous vasoconstriction that was markedly reduced in a Ca(2+) -free medium. Upon Ca(2+) re-addition, a nifedipine-resistant sustained Ca(2+) entry, not coupled to contraction, was obtained in endothelium-denuded coronary arteries. The effect of H2 O2 on this voltage-independent Ca(2+) influx was concentration-dependent, and high micromolar H2 O2 concentrations were inhibitory and reduced SOC entry evoked by inhibition of the sarcoplasmic reticulum ATPase (SERCA). H2 O2 -induced increases in Fura signals were mimicked by Ba(2+) and reduced by heparin, Gd(3+) ions and by Pyr6, a selective inhibitor of the Orai1-mediated Ca(2+) entry,. In coronary arteries from obese Zucker rats, intracellular Ca(2+) mobilization and SOC entry activated by acute exposure to H2 O2 were augmented and associated with local oxidative stress. CONCLUSION AND IMPLICATIONS: H2 O2 exerted dual concentration dependent stimulatory/inhibitory effects on store-operated, IP3 receptor-mediated and Orai1-mediated Ca(2+) entry, not coupled to vasoconstriction in coronary vascular smooth muscle. SOC entry activated by H2 O2 was enhanced and associated with vascular oxidative stress in coronary arteries in metabolic syndrome. PMID- 26478129 TI - Spatial navigation in elderly healthy subjects, amnestic and non amnestic MCI patients. AB - INTRODUCTION: Mild cognitive impairment (MCI) is considered an early stage of cognitive impairment. Therefore, it is important to identify early cognitive markers of MCI conversion to dementia and topographical disorientation (TD) may help differentiate normal aging from MCI and prodromal Alzheimer's disease (AD). Our aim was to propose a new instrument in elderly healthy subjects and MCI patients of amnestic (aMCI) and non-amnestic (naMCI) type. METHOD: We observed 18 healthy subjects and 18 MCI patients (9 aMCI and 9 naMCI). All participants were submitted to a neuropsychological battery and to a new experimental small-scale spatial navigation test reproducing an ideal city. RESULTS: a-MCI patients performed worse in learning a new route, in replacing landmarks in the city and in drawing a map of the city. Na-MCI patients' performance was not different from that observed in healthy subjects, except for a longer time span in Route Forward learning. MCI and healthy samples showed different correlations between experimental subtests and neuropsychological tests. CONCLUSIONS: Our task seems to be sensitive in pointing out differences in spatial abilities of MCI subtypes, especially with regard to the following subtests: learning a new route, retrieving a landmark's place and building a map of the environment. In comparison with more complex tests, these results allow us to consider the new tool as useful to evaluate spatial navigation in healthy elderly subjects and MCI patients. PMID- 26478130 TI - Sleep hygiene and its association with daytime sleepiness, depressive symptoms, and quality of life in patients with mild obstructive sleep apnea. AB - PURPOSE: To investigate the direct and indirect associations of sleep hygiene with daytime sleepiness, depressive symptoms, and quality of life (QoL), in newly diagnosed, untreated patients with mild obstructive sleep apnea (OSA). METHODS: Data were collected from adults with mild OSA. The Sleep Hygiene Index (SHI), Sleep Problems Index-1 (SPI-1) of the Medical Outcomes Study-Sleep Scale, Epworth Sleepiness Scale (ESS), Beck Depression Inventory (BDI), and Medical Outcomes Study Short-Form Health survey (SF-36) were used to evaluate patients. To determine the indirect and direct associations between SHI and disease outcomes, the Sobel test and multiple linear regression analyses were used, respectively. When we evaluated the direct associations, we excluded 3 items of the original SHI which were more reflective of general health rather than sleep-specific habits and environments. RESULTS: In total, 260 patients with mild OSA participated in this study. The average age, AHI, and SHI scores were 49.1 years (SD 12.5), 9.3/h (SD 2.9), and 24.7 (SD 6.0), respectively. Here, >= 10% of participants indicated poor sleep hygiene behaviors on 7 of 13 items. Young age and men were associated with higher SHI scores (both p<0.01). The 13-item SHI scores were indirectly related to ESS, BDI, and SF-36 scores via SPI-1 (all p<0.05). The 10-item SHI scores were related to ESS (p=0.049) and SF-36 (p=0.001), but not to BDI, independently of SPI-1 or other confounding factors in mild OSA patients. Age, sex, AHI, and body mass index were not related to ESS, BDI, or total SF-36 scores. CONCLUSIONS: Sleep hygiene is indirectly related to daytime sleepiness, depressive symptoms, QoL via sleep quality and also related to daytime sleepiness and QoL independent of sleep quality in mild OSA patients. PMID- 26478131 TI - Usefulness of arterial spin-labeling images in periictal state diagnosis of epilepsy. AB - PURPOSE: Arterial spin-labeling (ASL) perfusion MRI, a noninvasive method of assessing cerebral blood flow, is becoming a diagnostic tool of epilepsy. This study was undertaken to evaluate the diagnostic validity of ASL in patients with status epilepticus (SE) in a periictal state. METHOD: Twenty cases with SE were studied. Patients were imaged at a 3T MRI including ASL and diffusion-weighted imaging (DWI), and were also examined using electroencephalography (EEG). The abnormal findings of ASL were compared with those obtained from DWI and EEG. RESULT: Focal hyperperfusion was found in the cortical territory of 13 cases (65%). In 10 of those 13 cases, the ASL hyperperfusion region corresponded to DWI high intensity and EEG abnormality. Two cases showed hyperperfusion corresponding to EEG abnormalities in ASL despite the absence of high intensity in DWI. The remaining single case showed hyperperfusion in ASL despite the absence of high intensity in DWI and EEG abnormalities. Hyperperfusion in the subcortical territory was observed in the ipsilateral thalamus in three cases and in the contralateral cerebellum in one case. CONCLUSION: Our results suggest that ASL is a useful tool to diagnose status epilepticus and localization of the epilepsy focus. PMID- 26478132 TI - Amnestic syndrome of the subcallosal artery with additional penetrating vessel involvement. PMID- 26478133 TI - The role of surgery in grade II/III oligodendroglial tumors. AB - Supratentorial gliomas WHO grade II and III with an oligodendroglial phenotype are highly infiltrative lesions that preferentially originate in lobar location. Open tumor resection represents one of the mainstays of management as beneficial decompressive effects for large space-occupying lesions and oncologically relevant cytoreductive effects from complete resection can be expected. In patients not eligible for safe tumor resection meticulous histological and molecular-genetic evaluation can be obtained from advanced stereotactic biopsy techniques. In this perspective, important aspects of open tumor surgery and stereotactic biopsy are discussed within the context of diagnosis, prognosis and treatment of oligodendrogliomas and oligoastrocytomas WHO grade II and III. Practical considerations are provided in order to integrate the place of surgery into an increasingly personalized management concept. For highly selected patients interstitial brachytherapy is introduced as an alternative surgically performed treatment option. PMID- 26478134 TI - Cue-reactivity in experienced electronic cigarette users: Novel stimulus videos and a pilot fMRI study. AB - Some individuals who try electronic cigarettes (e-cigarettes) continue to use long-term. Previous research has investigated the safety of e-cigarettes and their potential for use in smoking cessation, but comparatively little research has explored chronic or habitual e-cigarette use. In particular, the relationship between e-cigarette cues and craving is unknown. We sought to bridge this gap by developing a novel set of e-cigarette (salient) and electronic toothbrush (neutral) videos for use in cue-reactivity paradigms. Additionally, we demonstrate the utility of this approach in a pilot fMRI study of 7 experienced e cigarette users. Participants were scanned while viewing the cue videos before and after 10min use of their own e-cigarettes (producing an 11.7ng/ml increase in plasma nicotine concentration). A significant session (pre- and post-use) by video type (salient and neutral) interaction was exhibited in many sensorimotor areas commonly activated in other cue-reactivity paradigms. We did not detect significant cue-related activity in other brain regions notable in the craving literature. Possible reasons for this discrepancy are discussed, including the importance of matching cue stimuli to participants' experiences. PMID- 26478135 TI - Survival Time of Cross-Match Incompatible Red Blood Cells in Adult Horses. AB - BACKGROUND: There is a markedly reduced half-life of transfused RBCs when donor and recipient cats or humans are cross-match incompatible. Only 10-20% of horses have naturally occurring alloantibodies. Therefore, cross-match testing before blood transfusion is not always performed. HYPOTHESIS: Cross-match incompatibility predicts shortened RBC survival time as compared to that of compatible or autologous blood. ANIMALS: Twenty healthy adult horses. METHODS: Prospective trial. Blood type, anti-RBC antibody screen (before and 1 month after transfusion) and major and minor cross-match determined 10 donor-recipient pairs. Two pairs were cross-match compatible, the remainder incompatible. Donor blood (4 L) was collected into citrate phosphate dextrose adenine-1, labeled with NHS biotin, and transfused into recipients. Samples were collected at 1 hour and 1, 2, 3, 5, 7, 14, 21, 28, and 35 days after transfusion, and biotinylated RBCs were detected by flow cytometry. Horses were monitored for transfusion reaction during transfusion and daily for 5 days. RESULTS: Cross-match incompatibility was significantly associated with decreased RBC survival time (P < .001). The half life of transfused incompatible (cross-match >1+) allogenic equine RBCs was 4.7 (95% CI, 3.2-6.2) days versus 33.5 (24-43) days for compatible pairings. Cross match incompatibility was associated with acute febrile transfusion reaction (P = .0083). At day 30, only 1 horse had developed novel anti-RBC antibodies. CONCLUSIONS AND CLINICAL IMPORTANCE: Cross-match incompatibility was predictive of febrile transfusion reaction and shortened transfused RBC survival, but did not result in production of anti-RBC antibodies at 30 days. Cross-match testing before transfusion is recommended. PMID- 26478137 TI - Ligand Design Virtual Issue. PMID- 26478136 TI - Quantification of Osteon Morphology Using Geometric Histomorphometrics. AB - Many histological methods in forensic anthropology utilize combinations of traditional histomorphometric parameters which may not accurately describe the morphology of microstructural features. Here, we report the novel application of a geometric morphometric method suitable when considering structures without anatomically homologous landmarks for the quantification of complete secondary osteon size and morphology. The method is tested for its suitability in the measurement of intact secondary osteons using osteons digitized from transverse femoral diaphyseal sections prepared from two human individuals. The results of methodological testing demonstrate the efficacy of the technique when applied to intact secondary osteons. In providing accurate characterization of micromorphology within the robust mathematical framework of geometric morphometrics, this method may surpass traditional histomorphometric variables currently employed in forensic research and practice. A preliminary study of the intersectional histomorphometric variation within the femoral diaphysis is made using this geometric histomorphometric method to demonstrate its potential. PMID- 26478138 TI - Lithic Technological Approaches to the African Late Pleistocene Later Stone Age. PMID- 26478139 TI - How did bonobos come to range south of the congo river? Reconsideration of the divergence of Pan paniscus from other Pan populations. AB - While investigating the genetic structure in wild bonobos,(1) we realized that the widely accepted scenario positing that the Pleistocene appearance of the Congo River separated the common ancestor of chimpanzees (Pan troglodytes) and bonobos (P. paniscus) into two species is not supported by recent geographical knowledge about the formation of the Congo River. We explored the origin of bonobos using a broader biogeographical perspective by examining local faunas in the central African region. The submarine Congo River sediments and paleotopography of central Africa show that the Congo River has functioned as a geographical barrier for the last 34 million years. This evidence allows us to hypothesize that when the river was first formed, the ancestor of bonobos did not inhabit the current range of the species on the left bank of the Congo River but that, during rare times when the Congo River discharge decreased during the Pleistocene, one or more founder populations of ancestral Pan paniscus crossed the river to its left bank. The proposed scenario for formation of the Congo River and the corridor hypothesis for an ancestral bonobo population is key to understanding the distribution of great apes and their evolution. PMID- 26478141 TI - How to do a jejunal interposition reconstruction in pancreas-sparing segmental duodenectomy. PMID- 26478140 TI - Early hominin biogeography in Island Southeast Asia. AB - Island Southeast Asia covers Eurasia's tropical expanse of continental shelf and active subduction zones. Cutting between island landmasses, Wallace's Line separates Sunda and the Eastern Island Arc (the Arc) into distinct tectonic and faunal provinces. West of the line, on Sunda, Java Island yields many fossils of Homo erectus. East of the line, on the Arc, Flores Island provides one skeleton and isolated remains of Homo floresiensis. Luzon Island in the Philippines has another fossil hominin. Sulawesi preserves early hominin archeology. This insular divergence sets up a unique regional context for early hominin dispersal, isolation, and extinction. The evidence is reviewed across three Pleistocene climate periods. Patterns are discussed in relation to the pulse of global sea level shifts, as well as regional geo-tectonics, catastrophes, stegodon dispersal, and paleogenomics. Several patterns imply evolutionary processes typical of oceanic islands. Early hominins apparently responded to changing island conditions for a million-and-a-half years, likely becoming extinct during the period in which Homo sapiens colonized the region. PMID- 26478142 TI - Clinical simulation training improves the clinical performance of Chinese medical students. AB - BACKGROUND: Modern medical education promotes medical students' clinical operating capacity rather than the mastery of theoretical knowledge. To accomplish this objective, clinical skill training using various simulations was introduced into medical education to cultivate creativity and develop the practical ability of students. However, quantitative analysis of the efficiency of clinical skill training with simulations is lacking. METHODS: In the present study, we compared the mean scores of medical students (Jinan University) who graduated in 2013 and 2014 on 16 stations between traditional training (control) and simulative training groups. In addition, in a clinical skill competition, the objective structured clinical examination (OSCE) scores of participating medical students trained using traditional and simulative training were compared. The data were statistically analyzed and qualitatively described. RESULTS: The results revealed that simulative training could significantly enhance the graduate score of medical students compared with the control. The OSCE scores of participating medical students in the clinical skill competition, trained using simulations, were dramatically higher than those of students trained through traditional methods, and we also observed that the OSCE marks were significantly increased for the same participant after simulative training for the clinical skill competition. CONCLUSIONS: Taken together, these data indicate that clinical skill training with a variety of simulations could substantially promote the clinical performance of medical students and optimize the resources used for medical education, although a precise analysis of each specialization is needed in the future. PMID- 26478150 TI - Abstracts of the 24th Annual Meeting of the German Transplantation Society Dresden, Germany, 22-24 October 2015. PMID- 26478143 TI - The application of 3D printing in anatomy education. PMID- 26478152 TI - Poultry Femoral Head Separation and Necrosis: A Review. AB - Femoral head separation (FHS) is a degenerative skeletal problem in fast-growing poultry wherein the growth plate of the proximal femur separates from its articular cartilage. At its early phase, FHS may remain asymptomatic but lead to epiphyseal breakage, infection, and femoral head necrosis (FHN). Healthy femoral head is viewed as a positive trait for genetic selection. However, the etiology of FHS is poorly understood for use in noninvasive diagnosis and genetic selection. Focal cell death and atrophic changes are likely associated with separation of tissues and necrotic changes. Fibrotic thickening of the articular surface can also impair free movement of the proximal epiphysis in the acetabulum, leading to FHS, under strain. The major limitation to understanding the pathophysiology of FHN is the lack of suitable experimental models and biomarkers to diagnose the problem. In this review, we discuss the possible etiologic factors, anatomic features of the chicken femoral head, biomarkers, and molecular mechanisms relevant to FHN. PMID- 26478151 TI - Ginkgo biloba Extract (EGb 761(r)) Inhibits Glutamate-induced Up-regulation of Tissue Plasminogen Activator Through Inhibition of c-Fos Translocation in Rat Primary Cortical Neurons. AB - EGb 761((r)) , a standardized extract of Ginkgo biloba leaves, has antioxidant and antiinflammatory properties in experimental models of neurodegenerative disorders such as stroke and Alzheimer's disease. Tissue plasminogen activator (tPA) acts a neuromodulator and plays a crucial role in the manifestation of neurotoxicity leading to exaggerated neuronal cell death in neurological insult conditions. In this study, we investigated the effects of EGb 761 on the basal and glutamate-induced activity and expression of tPA in rat primary cortical neurons. Under basal condition, EGb 761 inhibited both secreted and cellular tPA activities, without altering tPA mRNA level, as modulated by the activation of p38. Compared with basal condition, EGb 761 inhibited the glutamate-induced up regulation of tPA mRNA resulting in the normalization of overt tPA activity and expression. c-Fos is a component of AP-1, which plays a critical role in the modulation of tPA expression. Interestingly, EGb 761 inhibited c-Fos nuclear translocation without affecting c-Fos expression in glutamate-induced rat primary cortical neurons. These results demonstrated that EGb 761 can modulate tPA activity under basal and glutamate-stimulated conditions by both translational and transcriptional mechanisms. Thus, EGb 761 could be a potential and effective therapeutic strategy in tPA-excessive neurotoxic conditions. PMID- 26478153 TI - Quantitative Estimation of the Number of Contaminated Hatching Eggs Released from an Infected, Undetected Turkey Breeder Hen Flock During a Highly Pathogenic Avian Influenza Outbreak. AB - The regulatory response to an outbreak of highly pathogenic avian influenza (HPAI) in the United States may involve quarantine and stop movement orders that have the potential to disrupt continuity of operations in the U.S. turkey industry--particularly in the event that an uninfected breeder flock is located within an HPAI Control Area. A group of government-academic-industry leaders developed an approach to minimize the unintended consequences associated with outbreak response, which incorporates HPAI control measures to be implemented prior to moving hatching eggs off of the farm. Quantitative simulation models were used to evaluate the movement of potentially contaminated hatching eggs from a breeder henhouse located in an HPAI Control Area, given that active surveillance testing, elevated biosecurity, and a 2-day on-farm holding period were employed. The risk analysis included scenarios of HPAI viruses differing in characteristics as well as scenarios in which infection resulted from artificial insemination. The mean model-predicted number of internally contaminated hatching eggs released per movement from an HPAI-infected turkey breeder henhouse ranged from 0 to 0.008 under the four scenarios evaluated. The results indicate a 95% chance of no internally contaminated eggs being present per movement from an infected house before detection. Sensitivity analysis indicates that these results are robust to variation in key transmission model parameters within the range of their estimates from available literature. Infectious birds at the time of egg collection are a potential pathway of external contamination for eggs stored and then moved off of the farm; the predicted number of such infectious birds was estimated to be low. To date, there has been no evidence of vertical transmission of HPAI virus or low pathogenic avian influenza virus to day-old poults from hatching eggs originating from infected breeders. The application of risk analysis methods was beneficial for evaluating outbreak measures developed through emergency response planning initiatives that consider the managed movement of hatching eggs from monitored premises in an HPAI Control Area. PMID- 26478154 TI - Evaluating Protection Against Infectious Bronchitis Virus by Clinical Signs, Ciliostasis, Challenge Virus Detection, and Histopathology. AB - In this study, we examined the association among clinical signs, ciliostasis, virus detection, and histopathology for evaluating protection of vaccinated chickens against homologous and heterologous infectious bronchitis virus (IBV) challenge. At 5 days following challenge with IBV, we found a good correlation among clinical signs, ciliostasis in the trachea, challenge virus detection, and microscopic lesions in the trachea, with all four criteria being negative in fully protected birds and positive in fully susceptible birds. In partially protected birds we observed clinical signs and detected challenge virus; however, the ciliated epithelium was intact. In a second experiment, we challenged fully protected, partially protected, and fully susceptible birds with IBV, and then at 5 days postchallenge we gave the birds an opportunistic bacterium intranasally. Twenty Bordetella avium colonies were recovered from one of five fully protected birds, and only five colonies were isolated from two of five partially protected birds without ciliostasis, whereas in birds with ciliostasis, numerous colonies were isolated. Obviously, decreasing IBV infection and replication in the upper respiratory tract will decrease transmission and mutations, leading to variant viruses, and herein we demonstrate that protection of the cilia will decrease secondary bacterial infections, which have been shown to lead to condemnations and increased mortality. Thus, it appears that examining both criteria would be important when evaluating IBV vaccine efficacy. PMID- 26478156 TI - Runting Stunting Syndrome Associated with Transmissible Viral Proventriculitis in Broiler Chickens. AB - This report describes an outbreak of transmissible viral proventriculitis (TVP) associated with runting stunting syndrome (RSS) in 25- and 28-day-old broiler chickens, in which chicken proventricular necrosis virus (CNPV) was detected. Clinical signs included poor uniformity, very small birds for their age, increased mortality, and culling of smaller birds. Almost all birds necropsied exhibited moderate to severely enlarged proventriculi with diffusely pale serosa and thickened walls. Microscopically the proventriculi had lesions of degeneration and necrosis of the epithelium of the proventricular glands, accompanied by lymphocytic inflammation and glandular hyperplasia, with occasional formation of lymphoid nodules within the glandular parenchyma. Immunohistochemistry staining for CPNV was positive. Positive staining was generally found in the cytoplasm of glandular epithelial cells in the form of finely granular brown pigment. CPNV RNA was detected in the proventriculi by reverse transcriptase-PCR (RT-PCR). Other findings included mild enteritis in a few birds and small bursa of Fabricius. Direct electron microscopy performed on the intestinal samples was negative for viral particles. RT-PCR analysis of bursae was positive for infectious bursal disease virus (IBDV). In conclusion, this report associates TVP with RSS by describing an outbreak in which TVP attributable to CPNV was the most commonly found lesionin chickens with a clinical history compatible with RSS. Therefore, TVP should be considered as a possible differential diagnosis in cases compatible with RSS. PMID- 26478155 TI - In Ovo Vaccination with Turkey Herpesvirus Hastens Maturation of Chicken Embryo Immune Responses in Specific-Pathogen-Free Chickens. AB - Administration of Marek's disease (MD) vaccines in ovo has become a common practice for the poultry industry. Efficacy of MD vaccines is very high, even though they are administered to chicken embryos that are immunologically immature. We have recently demonstrated that in ovo vaccination with turkey herpesvirus (HVT) results in increased activation of T cells at hatch. Our previous results suggested that in ovo vaccination with HVT might have a positive impact not only on MD protection but also on the overall maturity of the developing immune system of the chicken (Gallus gallus domesticus). The objective of this study was to evaluate the effect of administration of HVT at 18 days of embryonation (ED) on the maturation of the embryo immune system. Four experiments were conducted in Specific-Pathogen-Free Avian Supplies (SPAFAS) chickens to evaluate the effect of administration of HVT at 18 ED on the splenic cell phenotypes at day of age (experiment 1) and on the ability of 1-day-old chickens to respond to various antigens compared with older birds (experiments 2 and 3). In addition, a fourth experiment was conducted to elucidate whether administration of other serotype's MD vaccines (CVI988 and SB-1) at 18 ED had the same effect as HVT on the spleen cell phenotypes at day of age. Our results demonstrated that 1-day-old chickens that had received HVT in ovo (1-day HVT) had higher percentages of CD45+, MHC-I+, CD45+MHC-I+, CD3+, MHC-II+, CD3+MHC-II+, CD4+, CD8+, and CD4+CD8+ cells in the spleen than 1-day-old sham-inoculated chickens (1-day sham). Moreover, spleens of 1-day HVT chickens had greater percentages of CD45+MHC-I+ cells and equal or greater numbers of CD4+CD8- and CD4 CD8+ cells than older unvaccinated chickens. In addition, administration of HVT at 18 ED rendered chicks at hatch more responsive to unrelated antigens such as concavalin A, phytohemagglutinin-L, and keyhole limpet hemocyanin. Administration of MD vaccines of other serotypes had an effect, although less remarkable than HVT, on the spleen cell phenotypes at hatch. Vaccines of all three serotypes resulted in an increased percentage of MHC-I+, CD45-MHC-I+, CD4-CD8+, and CD8+ cells, but only HVT resulted in a higher percentage of CD45+, CD45+MHC-I+, CD3+MHC-II+, and CD4+CD8- cells. Results of this study show that it is possible to hasten maturation of the chicken embryo immune system by administering HVT in ovo and open new avenues to optimize the procedure to improve and strengthen the immunocompetency of commercial chickens at hatch. PMID- 26478157 TI - Avian Hepatitis E Virus Infection in Organic Layers. AB - Between 2012 and 2014, 141 chickens from 10 organic layer flocks with a history of severe drop in egg production (up to 40%) and slight increased mortality (up to 1% per week) were submitted to the Avian Health and Food Safety Laboratory (Puyallup, WA). At necropsy, the most common finding was pinpoint white foci on the liver and regressed ova without any other remarkable lesions. Histologically, there was multifocal mild-to-severe acute necrotizing hepatitis present. No significant bacteria were recovered from liver samples, and tests for mycotoxins were negative. Twenty-six serum samples from four affected flocks tested were positive for avian hepatitis E virus (HEV) immunoglobulin Y antibodies. Avian HEV RNA was detected in 10 livers of chickens from two different affected flocks. The avian HEV was characterized by sequencing and determined to belong to genotype 2. The diagnosis of a clinical manifest HEV was based solely on the demonstration of specific viral RNA and the absence of other causative agents in samples from flocks, as the clinical sings and pathologic lesions were atypical. PMID- 26478158 TI - Infection of Broilers with Two Virulent Strains of Infectious Laryngotracheitis Virus: Criteria for Evaluation of Experimental Infections. AB - Infectious laryngotracheitis (ILT) is a highly contagious disease of chickens and is responsible for significant economic losses in the poultry industry worldwide; it is caused by Gallid herpesvirus-1 (GaHV-1), commonly known as infectious laryngotracheitis virus (ILTV). Experimental evaluation of ILTV strains is fundamental to identify changes in virulence that can contribute to the severity and spread of outbreaks and consequently influence the efficacy of vaccination. Several criteria had been utilized to determine the degree of virulence associated with ILTV strains. The objectives of this study were to compare the levels of virulence of the standard United States Department of Agriculture (USDA) challenge strain with a contemporary outbreak-related strain (63140) and to evaluate the efficacy of individual criteria to identify changes in virulence. Broilers were inoculated with increasing infectious doses of each strain. The criteria utilized to evaluate virulence were clinical signs of the disease, mortality, microscopic tracheal lesions, trachea genome viral loads, and antibody titers. Clinical signs scores were a useful parameter to define the peak of clinical disease but did not reveal differences in virulence between strains. Similarly, trachea microscopic lesion scores or levels of serum antibody titers were parameters that did not reveal obvious differences in virulence between strains. However, mortalities and increased viral genome loads in trachea of chickens inoculated with lower (log10 1 to 2) infectious doses clearly differentiated 63140 as a more-virulent ILTV strain. This study provides the framework to compare the virulence level of emerging ILTV isolates to the now characterized USDA and 63140 strains. PMID- 26478159 TI - Evaluation of Factors Influencing Efficacy of Vaccine Strain CVI988 Against Marek's Disease in Meat-Type Chickens. AB - Marek's disease (MD) strain CVI988 is the most-protective commercially available vaccine against very virulent plus (vv+) Marek's disease virus (MDV). However, its use in meat-type chickens has been controversial. While several countries have been using CVI988 for more than 40 yr, others do not authorize its use or it is restricted mainly to layers. The use of CVI988 in meat-type chickens will be necessary in the future in areas where other vaccine protocols fail. The objective of this study was to evaluate factors (vaccine dose, vaccine origin, chicken genetics, age and route of vaccination, and combination with other MD vaccines) influencing the efficacy of CVI988 against MD in meat-type chickens. Three animal experiments were conducted in which various vaccine protocols using CVI988 were tested for their protection against challenge with vv+ strain 648A by contact at day of age. Experiments 1 and 2 were to compare the efficacy of CVI988 vaccines from three different origins (CVI988-A, CVI988-B, and CVI988-C) and evaluate the effect of vaccine dose and chicken genetics. Experiment 3 was to evaluate the effect of adding CVI988 vaccine to various vaccine protocols using other MD vaccines of serotypes 2 (SB-1) and 3 (rHVT). Our results show that, regardless of the origin of the vaccine, protection against early challenge with 648A was good when vaccines were administered at a high dose (>3000 plaque forming units [PFU]). Differences among vaccines, however, were detected even when using a high dose in experiment 2 (vaccine CVI988-B conferred higher protection than did CVI988-C) but not in Experiment 1 (CVI988-B was compared to CVI988-A). The use of a fixed low dose (2000 PFU) of vaccine resulted in reduction in protection, and such reduction was more remarkable when using CV1988 A. No statistically significant differences were found when we compared the efficacy of CVI988 in two different genetic lines of broiler chickens (G1 and G2). Vaccination protocols that included CVI988 had better protection than protocols that only included MD vaccines of serotypes 2 and 3. This was true regardless of the vaccine protocol used (CVI988/rHVT+SB-1; CVI988+rHVT+SB-1/None; rHVT+SB-1/CVI988; wherein the vaccine before the slash (/) was administered in ovo at embryonation day 18 and the vaccine after the slash was administered at day of age, subcutaneously). When only vaccines of serotypes 2 and 3 were used, protection against early challenge with vv+MDV was higher when vaccines were administered in ovo (rHVT+SB-1/None) than if vaccines were administered at hatch (None/rHVT+SB-1). Monitoring vaccine DNA load in feather pulp (FP) samples at 1 wk was used to monitor vaccination, and results showed that differences in vaccine replication exist among vaccines but such differences were not necessarily related to protection (r = 0.41, P > 0.05). Monitoring load of challenge MDV DNA in FP at 21 days was conducted, and results correlated (r = 0.85, P < 0.05) with the percentage of chickens with MD lesions at the termination of the study, confirming that early diagnosis is a very powerful tool with which to evaluate protection. PMID- 26478160 TI - Histopathologic and Myogenic Gene Expression Changes Associated with Wooden Breast in Broiler Breast Muscles. AB - The wooden breast condition is a myopathy affecting the pectoralis major (p. major) muscle in fast-growing commercial broiler lines. Currently, wooden breast affected birds are phenotypically detected by palpation of the breast area, with affected birds having a very hard p. major muscle that is of lower value. The objective of this study was to compare the wooden breast myopathy in two fast growing broiler lines (Lines A and B) with incidence of wooden breast to a slower growing broiler Line C with no phenotypically observable wooden breast. One of the characteristics of the wooden breast condition is fibrosis of the p. major muscle. Morphologic assessment of Lines A and B showed significant fibrosis in both lines, but the collagen distribution and arrangement of the collagen fibrils was different. In Line A, the collagen fibrils were tightly packed, whereas in Line B the collagen fibrils were diffuse. This difference in collagen organization may be due to the expression of the extracellular matrix proteoglycan decorin. Decorin is a regulator of collagen crosslinking and is expressed at significantly higher levels in Line A wooden breast-affected p. major muscle, which would lead to tightly packed collagen fibers due to high levels of collagen crosslinking. Furthermore, expression of the muscle-specific transcriptional regulatory factors for proliferation and differentiation of muscle cells leading to the regeneration of muscle in response to muscle damage was significantly elevated in Line A, and only the factor for differentiation, myogenin, was increased in Line B. The results from this study provide initial evidence that the etiology of the wooden breast myopathy may vary between fast growing commercial broiler lines. PMID- 26478161 TI - Vaccination of 1-Day-Old Turkey Poults with Fowlpox Vaccine by Subcutaneous Route. AB - In high-challenge areas, 1-day-old chicks are often vaccinated with fowlpox vaccine to provide early protection against the disease. However, we were unable to find any information in the published literature on the safety and efficacy of live fowlpox virus vaccine in 1-day-old turkeys. In this study, we evaluated a freeze-dried chicken-embryo-origin live fowlpox virus vaccine for its safety and efficacy in 1-day-old turkey poults by administering the vaccine subcutaneously in the upper back of the neck. Following vaccination, the turkeys were observed for 3 wk for vaccine-associated mortality and adverse reactions. Efficacy was evaluated by challenging the turkeys against a standard challenge strain of fowlpox virus. The results of this study indicated that the vaccine was safe and efficacious for subcutaneous administration in 1-day-old turkeys. None of the vaccinated turkeys revealed any adverse reactions or mortality associated with the vaccine. The vaccine protected more than 98% of the turkeys against fowlpox virus challenge. PMID- 26478163 TI - Epidemiology of Avian Infectious Bronchitis Virus Genotypes in Iran (2010-2014). AB - Infectious bronchitis virus (IBV) in vaccinated chicken flocks continues to cause enormous economic losses to the poultry industry in Iran. A molecular surveillance of IBV genotypes involved in outbreaks of disease was performed. Specimens of trachea, kidney, and cecal tonsil were collected from 250 suspected flocks (more than 2500 samples) and identified between 2010 and 2014. Partial spike glycoprotein gene sequences revealed seven distinct genotypes, including Mass, 793/B, IS720, Variant 2, QX, IR-I, and IR-II, to be circulating in the chicken farms. The majority of flocks (67.6%) experienced infection with an IBV variant unrelated to the vaccine strains. These variants displayed homologies ranging from 54.1% to 78.5% and from 53% to 86% with H120 and 4/91, respectively. These findings reveal the existence of IBV variants genetically different from the vaccine strains currently in use and explain the outbreaks of disease observed in the field. The current work constitutes the first comprehensive survey of IBV in Iran and emphasizes the need for continuous monitoring and rethinking of current preventative measures. PMID- 26478162 TI - Characterization of Avian Influenza and Newcastle Disease Viruses from Poultry in Libya. AB - On March 2013, the Libyan poultry industry faced severe outbreaks due to mixed infections of APMV-1 (Newcastle disease) and low pathogenic avian influenza (AI) of the H9N2 subtype which were causing high mortality and great economic losses. APMV-1 and H9N2 were isolated and characterized. Genetic sequencing of the APMV 1/chicken/Libya/13VIR/ 7225-1/2013 isolate revealed the presence of a velogenic APMV-1 belonging to lineage 5 (GRRRQKR*F Lin.5) or genotype VII in class II, according to the nomenclature in use. Three AI viruses of the H9N2 subtype, namely A/avian/Libya/13VIR7225-2/2013, A/avian/Libya/13VIR7225-3/2013, and A/avian/Libya/13VIR7225-5/2013, were isolated and found to belong to the G1 lineage. Analysis of amino acid sequences showed that the analyzed H9N2 viruses contained the amino acid Leu at position 226 (H3 numbering) at the receptor binding site of the HA, responsible for human virus-like receptor specificity. On March 2014, an outbreak of highly pathogenic avian influenza (HPAI) virus of the H5N1 subtype was diagnosed in a backyard poultry farm in an eastern region of Libya. The H5N1 isolate (A/chicken/Libya/14VIR2749-16/2014) was detected by real time RT-PCR (rRT-PCR). Genetic characterization of the HA gene revealed that the identified subtype was highly pathogenic, belonged to the 2.2.1 lineage, and clustered with recent Egyptian viruses. This study revealed the presence of a velogenic APMV-1 genotype and of two influenza subtypes, namely HPAI H5N1 and H9N2, which are of major interest for public and animal health. Considering these findings, more investigations must be undertaken to establish and implement adequate influenza surveillance programs; this would allow better study of the epidemiology of APMV-1 genotype VII in Libya and evaluation of the current vaccination strategies. PMID- 26478164 TI - Erysipelas Outbreaks in Flocks of Geese in Poland--Biochemical and Genetic Analyses of the Isolates. AB - Erysipelothrix rhusiopathiae causes erysipelas in many vertebrate species. Severe disease outbreaks have been noted in many poultry species--chickens, ducks, emus, pheasants, pigeons, and geese. This article describes the biochemical and genetic analyses of six E. rhusiopathiae strains isolated from geese for meat production. The isolates came from birds kept in different poultry houses on one farm, and were collected during two erysipelas outbreaks. We analyzed and compared the isolates by random amplified polymorphic DNA with the use of NK6 primer and pulsed-field gel electrophoresis, with the restriction enzyme SmaI. Biochemical examination was performed with API Coryne test. Analyses showed that the three strains isolated during the first outbreak differed, whereas the three isolates from the second outbreak were identical to one another, but distinct from the isolates from the first outbreak. The results of biochemical and genetic analyses of E. rhusiopathiae strains isolated from geese suggest different sources of infection for the erysipelas outbreaks. PMID- 26478165 TI - Co-infection with Multiple Respiratory Pathogens Contributes to Increased Mortality Rates in Algerian Poultry Flocks. AB - Respiratory infections are a common cause for increased mortality rates in poultry worldwide. To improve intervention strategies, circulating pathogens have to be identified and further characterized. Because of the lack of diagnostic tools, it was not known what pathogens contribute to the high mortality rates in association with respiratory disease in Algeria. Our objective was to determine if primary pathogens including Mycoplasma gallisepticum (MG), Mycoplasma synoviae (MS), avian influenza virus (AIV), infectious bronchitis virus (IBV), and avian metapneumovirus (aMPV), known to be present in neighboring countries, can also be detected in Algerian chicken and turkey flocks. Results demonstrate the circulation of the investigated pathogens in Algerian poultry flocks as multi infections. Phylogenetic characterization of the Algerian IBV strains confirmed the circulation of nephropathogenic viruses that are different from the strains isolated in neighboring countries. This could suggest the existence of a new IBV genotype in North Africa. Additionally, we detected for the first time an aMPV subtype B field strain and avian influenza virus. Interestingly, all viral pathogens were present in co-infections with MG, which could exacerbate clinical disease. Additional pathogens may be present and should be investigated in the future. Our results suggest that multiple respiratory infections may be responsible for high mortality in Algerian poultry flocks and very probably also in other regions of the world, which demonstrates the need for the establishment of more comprehensive control strategies. PMID- 26478166 TI - Necrotic Enteritis in Chickens Associated with Clostridium sordellii. AB - Three outbreaks of necrotic enteritis-like disease associated with Clostridium sordelii were diagnosed in commercial broiler chicken flocks with 18,000 to 31,000 birds between 18 and 26 days old. Clinical signs in the affected flocks included high mortality up to 2% a day, depression, and diarrhea. The main gross changes included segmental dilation of the small intestine with watery contents, gas, mucoid exudate, and roughened and uneven mucosa, occasionally covered with a pseudomembrane. Microscopic lesions in the small intestine were characterized by extensive areas of coagulative necrosis of the villi, fibrinous exudate in the lumen, and high numbers of large, Gram-positive rods, occasionally containing subterminal spores, seen in the necrotic tissue and lumen. These rods were identified as C. sordellii by immunohistochemistry. Clostridium sordellii was isolated in an almost pure culture from the intestine of affected birds. A retrospective study of commercial broiler chicken and turkey submissions to the California Animal Health and Food Safety Laboratory System revealed that C. sordellii had been isolated from intestinal lesions in outbreaks of necrotic enteritis-like disease in 8 of 39 cases, 5 times together with Clostridium perfringens and 3 times alone. The latter three cases are reported here. PMID- 26478167 TI - Aberrant Clinical Appearance and Pathomorphology Noticed During an Outbreak of Histomonosis Indicates a Different Pathogenesis of Histomonas meleagridis Genotype 2. AB - The present case report describes a remarkable feature of Histomonas meleagridis characterized by aberrant clinical appearance and pathomorphologic lesions, which were mainly confined to the ceca, noticed during a field outbreak of histomonosis. In a flock of meat turkey toms, sudden death was noticed at the end of week 5 in the absence of specific clinical signs. Instead of the well-known sulfur-colored feces, some caseous cores were found in the litter. Mortality up to 17% per week was noticed in the first 2 wk of observation, after which it declined to approximately 1% per week. In the 10th week of life roughly 31% of the birds had died before the remaining birds were killed to preclude further economic losses due to insufficient growth or continuing mortality. Necropsy of affected birds on the farm and during a more detailed investigation of 15 birds prior to the killing of the flock revealed severe lesions in the ceca characterized by thickened cecal walls filled with necrotic and caseous material. Additionally, some ruptured and necrotic ceca were noticed together with localized peritonitis. Despite such severe typhlitis, only one of the sectioned birds showed pathomorphologic changes in the liver. Test tube flotation from collected fecal samples revealed only sporadic occurrence of coccidial oocysts and no nematodes. However, the presence of H. meleagridis was confirmed by PCR and/or immunohistochemistry, with specific antibodies against the parasite in a majority of the investigated ceca and in four liver samples. Remarkably, genetic characterization revealed H. meleagridis genotype 2, about which no detailed investigations have been reported so far. Although PCR detected a concurrent presence of Tetratrichomonas gallinarum, an involvement in the lesions could be excluded based upon histologic investigations. Finally, infection with Escherichia coli and Gallibacterium anatis was demonstrated by bacteriologic smears of internal organs, most likely a secondary infection. Altogether, the results demonstrate an aberrant clinical appearance and pathomorphology in turkeys suffering from histomonosis. Pathomorphologic changes were characterized by severe inflammation of the ceca with minimal liver involvement, indicating a different pathogenesis of H. meleagridis genotype 2. PMID- 26478168 TI - Erratum. PMID- 26478174 TI - Recent advances of thermally responsive nanogels for cancer therapy. AB - Thermally responsive nanogel drug delivery systems (TRNDDS) have been widely investigated as a new strategy for active targeting tumor therapy, as these can accumulate on the tumor site and/or release the payload at the desired site by structure changes rapidly once stimulated by temperature changes. In this review, we discuss the evolution of TRNDDS and future perspectives for antitumor drug and gene delivery. With further understanding of the specificity of tumor site at the cellular and molecular level, in parallel with the development of nanomaterial design and preparation, TRNDDS show great potential for tumor targeting therapy. PMID- 26478175 TI - Phylogenetic relationships of Hemiptera inferred from mitochondrial and nuclear genes. AB - Here, we reconstructed the Hemiptera phylogeny based on the expanded mitochondrial protein-coding genes and the nuclear 18S rRNA gene, separately. The differential rates of change across lineages may associate with long-branch attraction (LBA) effect and result in conflicting estimates of phylogeny from different types of data. To reduce the potential effects of systematic biases on inferences of topology, various data coding schemes, site removal method, and different algorithms were utilized in phylogenetic reconstruction. We show that the outgroups Phthiraptera, Thysanoptera, and the ingroup Sternorrhyncha share similar base composition, and exhibit "long branches" relative to other hemipterans. Thus, the long-branch attraction between these groups is suspected to cause the failure of recovering Hemiptera under the homogeneous model. In contrast, a monophyletic Hemiptera is supported when heterogeneous model is utilized in the analysis. Although higher level phylogenetic relationships within Hemiptera remain to be answered, consensus between analyses is beginning to converge on a stable phylogeny. PMID- 26478177 TI - Ferrocyanide-Ferricyanide Redox Couple Induced Electrochemiluminescence Amplification of Carbon Dots for Ultrasensitive Sensing of Glutathione. AB - Here we report a novel solid-state ECL sensor for ultrasensitive sensing of glutathione (GSH) based on ferrocyanide-ferricyanide redox couple (Fe(CN)6(3-/4 )) induced electrochemiluminescence (ECL) amplification of carbon dots (C-dots). The electropolymerization of C-dots and (11-pyrrolyl-1-yl-undecyl) triethylammonium tetrafluoroborate (A2) enabled immobilization of the hydrophilic C-dots on the surface of glassy carbon electrode (GCE) perfectly, while the excellent conductivity of polypyrrole was exploited to accelerate electron transfer between them. The Fe(CN)6(3-/4-) can expeditiously convert the C-dots and S2O8(2-) to C-dot(*-) and SO4(*-), respectively. High yields of the excited state C-dots (C-dots*) were obtained, and a ~10-fold ECL amplification was realized. The C-dots* obtained through the recombination of electron-injected and hole-injected processes may be impeded due to the interference of GSH to K2S2O8. Therefore, the constructed sensor for GSH showed a detection limit down to 54.3 nM (S/N = 3) and a wide linear range from 0.1-1.0 MUM with a correlation coefficient of 0.997. PMID- 26478178 TI - Reassessment of chemical control of breathing in undisturbed bullfrogs, Lithobates catesbeianus, using measurements of pulmonary ventilation. AB - Despite the importance of bullfrogs (Lithobates catesbeianus) as models in respiratory control, chemical control of breathing in conscious bullfrogs has never been assessed with methods that measure the tidal volume (VT). This has precluded the calculation of important respiratory variables like minute ventilation (V.E) and air convection requirement. To address this, we adapted airflow pneumotachography for use in bullfrogs and reassessed chemical control of breathing. We show that V.E measured with pneumotachography produces breathing pattern and metabolism values consistent with anurans. Second, we confirm that bullfrogs have small ventilatory responses to hypercarbia that include increases in tidal volume and a post-hypercarbic hyperpnea. We observed that the magnitude of the post-hypercarbic hyperpnea does not depend on ventilatory responses during hypercarbia. Finally, we showed that increases in breathing frequency and VT during hypoxia are differentially regulated with time. These findings comprise the first complete assessment of hypercarbic and hypoxic V.E responses in intact bullfrogs and emphasize the importance of measuring VT. PMID- 26478179 TI - Global brain dynamics embed the motor command sequence of Caenorhabditis elegans. AB - While isolated motor actions can be correlated with activities of neuronal networks, an unresolved problem is how the brain assembles these activities into organized behaviors like action sequences. Using brain-wide calcium imaging in Caenorhabditis elegans, we show that a large proportion of neurons across the brain share information by engaging in coordinated, dynamical network activity. This brain state evolves on a cycle, each segment of which recruits the activities of different neuronal sub-populations and can be explicitly mapped, on a single trial basis, to the animals' major motor commands. This organization defines the assembly of motor commands into a string of run-and-turn action sequence cycles, including decisions between alternative behaviors. These dynamics serve as a robust scaffold for action selection in response to sensory input. This study shows that the coordination of neuronal activity patterns into global brain dynamics underlies the high-level organization of behavior. PMID- 26478180 TI - Structural and Mechanistic Basis of PAM-Dependent Spacer Acquisition in CRISPR Cas Systems. AB - Bacteria acquire memory of viral invaders by incorporating invasive DNA sequence elements into the host CRISPR locus, generating a new spacer within the CRISPR array. We report on the structures of Cas1-Cas2-dual-forked DNA complexes in an effort toward understanding how the protospacer is sampled prior to insertion into the CRISPR locus. Our study reveals a protospacer DNA comprising a 23-bp duplex bracketed by tyrosine residues, together with anchored flanking 3' overhang segments. The PAM-complementary sequence in the 3' overhang is recognized by the Cas1a catalytic subunits in a base-specific manner, and subsequent cleavage at positions 5 nt from the duplex boundary generates a 33-nt DNA intermediate that is incorporated into the CRISPR array via a cut-and-paste mechanism. Upon protospacer binding, Cas1-Cas2 undergoes a significant conformational change, generating a flat surface conducive to proper protospacer recognition. Here, our study provides important structure-based mechanistic insights into PAM-dependent spacer acquisition. PMID- 26478183 TI - The good and the bad. PMID- 26478181 TI - Evolving new protein-protein interaction specificity through promiscuous intermediates. AB - Interacting proteins typically coevolve, and the identification of coevolving amino acids can pinpoint residues required for interaction specificity. This approach often assumes that an interface-disrupting mutation in one protein drives selection of a compensatory mutation in its partner during evolution. However, this model requires a non-functional intermediate state prior to the compensatory change. Alternatively, a mutation in one protein could first broaden its specificity, allowing changes in its partner, followed by a specificity restricting mutation. Using bacterial toxin-antitoxin systems, we demonstrate the plausibility of this second, promiscuity-based model. By screening large libraries of interface mutants, we show that toxins and antitoxins with high specificity are frequently connected in sequence space to more promiscuous variants that can serve as intermediates during a reprogramming of interaction specificity. We propose that the abundance of promiscuous variants promotes the expansion and diversification of toxin-antitoxin systems and other paralogous protein families during evolution. PMID- 26478182 TI - Molecular logic of neuronal self-recognition through protocadherin domain interactions. AB - Self-avoidance, a process preventing interactions of axons and dendrites from the same neuron during development, is mediated in vertebrates through the stochastic single-neuron expression of clustered protocadherin protein isoforms. Extracellular cadherin (EC) domains mediate isoform-specific homophilic binding between cells, conferring cell recognition through a poorly understood mechanism. Here, we report crystal structures for the EC1-EC3 domain regions from four protocadherin isoforms representing the alpha, beta, and gamma subfamilies. All are rod shaped and monomeric in solution. Biophysical measurements, cell aggregation assays, and computational docking reveal that trans binding between cells depends on the EC1-EC4 domains, which interact in an antiparallel orientation. We also show that the EC6 domains are required for the formation of cis-dimers. Overall, our results are consistent with a model in which protocadherin cis-dimers engage in a head-to-tail interaction between EC1-EC4 domains from apposed cell surfaces, possibly forming a zipper-like protein assembly, and thus providing a size-dependent self-recognition mechanism. PMID- 26478184 TI - An optimised perfusion technique for extracting murine gastric leukocytes. AB - The stomach is a difficult tissue to analyse by flow cytometry, largely due to the difficulty of isolating viable leukocytes. Here we present the re optimization of a perfusion technique that compares favourably against two other methods of enzymatic digestion for the release of gastric leukocytes. We believe that this technique could greatly assist the analysis of immune cells basally present in the murine stomach and that infiltrate during infection or disease. PMID- 26478186 TI - Effect of beta-cyclodextrin on the internalization of nanoparticles into intestine epithelial cells. AB - The influence of beta-cyclodextrin on the interaction and internalization of PLGA nanoparticles into intestine epithelial cells was assessed. For this purpose beta cyclodextrin was adsorbed on PLGA nanoparticles. Interaction of nanoparticles with Caco-2 cells, determined by fluorescence, was expressed as the number of particles per cell. Confocal microscopy confirmed the localization of the particles in the cell monolayer. The results showed that adsorption of beta cyclodextrin on the surface of PLGA nanoparticles reduces interaction with mucin, enhancing in this way the internalization into the Caco-2 cells. PMID- 26478185 TI - In vitro release studies of insulin from lipid implants in solution and in a hydrogel matrix mimicking the subcutis. AB - Widely accepted in vitro methodologies for sustained release parenteral drug formulations remain to be established. Hydrogels have been proposed as a release matrix more closely resembling the in vivo conditions for formulations intended for subcutaneous administration. The perspective of the current work was to investigate the feasibility of developing UV imaging-based in vitro methods enabling visualization and characterization of drug release and transport of protein therapeutics intended for subcutaneous administration. Specifically, the objectives were to prepare lipid implants providing sustained release of the model protein insulin and investigate the release into 0.5% (w/v) agarose hydrogels, pH7.40, using UV imaging- and a gel sampling-based release testing method. These results were compared to insulin release into well agitated buffer solution. Irrespective of the applied in vitro release method, the insulin release from Sterotex implants with a drug load of 20% (w/w) was faster as compared to the release from implants with a load of 10% (w/w), most likely due to the higher porosity of the implants with increasing drug load. Insulin release from 10% (w/w) implants into agitated solution was faster as compared to release into agarose hydrogel. This was ascribed to the additional mass transfer resistance provided by the agarose hydrogel. Interestingly, the release profiles of insulin from implants with an initial drug load of 20% (w/w) obtained by the three in vitro methods were relatively similar. The gel-based methods, in particular UV imaging, enable monitoring local drug concentrations in the vicinity of the implant over time thereby facilitating assessment of, e.g., sink conditions. The study highlights that the selection of the in vitro release method should take into account various factors including mass transport, drug stability, data analysis and simplicity of the methodology. PMID- 26478187 TI - Post-exercise appetite was affected by fructose content but not glycemic index of pre-exercise meals. AB - The purpose of this study was to investigate whether both glycemic index (GI) and breakfast fructose content affect appetite during the postprandial period and recovery period after 1 hr of brisk walking. Ten healthy young men (age: 21.7 +/- 1.5 y, body mass index: 20.9 +/- 1.1 kg?m(-2), VO2max: 53.7 +/- 3.7 mL?kg( 1)?min(-1)) completed 1 hr of brisk walking at 46% VO2max 2 hr after eating one of three isocaloric breakfasts: a low-GI breakfast not including fructose content (LGI), a low-GI breakfast including fructose beverage (LGIF) and a high-GI breakfast (HGI). All breakfasts provided 1.0 g?kg(-1) body weight carbohydrates, and the calculated GI values for the three breakfasts were 41, 39, and 72, respectively. In the LGIF and HGI trials, approximately 25% of participants' energy was derived from either fructose or glucose beverage. Appetite scores were measured every 30 min during the 2-hr postprandial period and 1-hr recovery period. During the postprandial period, the incremental areas under the blood response curve values of glucose and insulin were higher in the HGI trial, compared with those in the LGI and LGIF trials. At 30 and 60 min during the recovery period, the appetite scores were lower in the LGIF trial than those in the LGI and HGI trials. No differences were observed between the LGI and HGI trials. Breakfast fructose content, rather than GI, seems to affect appetite during the recovery period after 1 hr of brisk walking. PMID- 26478189 TI - Hybrid Surface Acoustic Wave-Electrohydrodynamic Atomization (SAW-EHDA) For the Development of Functional Thin Films. AB - Conventional surface acoustic wave - electrostatic deposition (SAW-ED) technology is struggling to compete with other thin film fabrication technologies because of its limitation in atomizing high density solutions or solutions with strong inter particle bonding that requires very high frequency (100 MHz) and power. In this study, a hybrid surface acoustic wave - electrohydrodynamic atomization (SAW EHDA) system has been introduced to overcome this problem by integrating EHDA with SAW to achieve the deposition of different types of conductive inks at lower frequency (19.8 MHZ) and power. Three materials, Poly [2-methoxy-5-(2 ethylhexyloxy)-1, 4-phenylenevinylene] (MEH-PPV), Zinc Oxide (ZnO), and Poly(3, 4 ethylenedioxythiophene):Polystyrene Sulfonate ( PEDOT: PSS) have been successfully deposited as thin films through the hybrid SAW-EHDA. The films showed good morphological, chemical, electrical, and optical characteristics. To further evaluate the characteristics of deposited films, a humidity sensor was fabricated with active layer of PEDOT: PSS deposited using the SAW-EHDA system. The response of sensor was outstanding and much better when compared to similar sensors fabricated using other manufacturing techniques. The results of the device and the films' characteristics suggest that the hybrid SAW-EHDA technology has high potential to efficiently produce wide variety of thin films and thus predict its promising future in certain areas of printed electronics. PMID- 26478188 TI - A Designed Angiopoietin-1 Variant, Dimeric CMP-Ang1 Activates Tie2 and Stimulates Angiogenesis and Vascular Stabilization in N-glycan Dependent Manner. AB - Angiopoietin-1 (Ang1), a potential growth factor for therapeutic angiogenesis and vascular stabilization, is known to specifically cluster and activate Tie2 in high oligomeric forms, which is a unique and essential process in this ligand receptor interaction. However, highly oligomeric native Ang1 and Ang1 variants are difficult to produce, purify, and store in a stable and active form. To overcome these limitations, we developed a simple and active dimeric CMP-Ang1 by replacing the N-terminal of native Ang1 with the coiled-coil domain of cartilage matrix protein (CMP) bearing mutations in its cysteine residues. This dimeric CMP Ang1 effectively increased the migration, survival, and tube formation of endothelial cells via Tie2 activation. Furthermore, dimeric CMP-Ang1 induced angiogenesis and suppressed vascular leakage in vivo. Despite its dimeric structure, the potencies of such Tie2-activation-induced effects were comparable to those of a previously engineered protein, COMP-Ang1. We also revealed that these effects of dimeric CMP-Ang1 were affected by specified N-glycosylation in its fibrinogen-like domain. Taken together, our results indicate that dimeric CMP Ang1 is capable of activating Tie2 and stimulating angiogenesis in N-glycan dependent manner. PMID- 26478190 TI - CsTNF1, a teleost tumor necrosis factor that promotes antibacterial and antiviral immune defense in a manner that depends on the conserved receptor binding site. AB - Tumor necrosis factor (TNF) is one of the most important cytokines involved in inflammation, apoptosis, cell proliferation, and stimulation of the immune system. The TNF gene has been cloned in teleost fish; however, the in vivo function of fish TNF is essentially unknown. In this study, we report the identification of a TNF homologue, CsTNF1, from tongue sole (Cynoglossus semilaevis) and analysis of its expression and biological effect. CsTNF1 is composed of 242 amino acid residues and possesses a TNF domain and conserved receptor binding sites. Expression of CsTNF1 was detected in a wide range of tissues and up-regulated in a time-dependent manner by experimental challenge with bacterial and viral pathogens. Bacterial infection of peripheral blood leukocytes (PBL) caused extracellular secretion of CsTNF1. Purified recombinant CsTNF1 (rCsTNF1) was able to bind to PBL and stimulate the respiratory burst activity of PBL. In contrast, rCsTNF1M1 and rCsTNF1M2, the mutant CsTNF1 bearing substitutions at the receptor binding site, failed to activate PBL. Fish administered with rCsTNF1, but not with rCsTNF1M1 and rCsTNF1M2, exhibited enhanced expression of IL-1, IL-6, IL-8, IL-27, TLR9 and G3BP in a time-dependent manner and augmented resistance against bacterial and viral infection. These results provide the first evidence that the receptor binding sites are essential to a fish TNF, and that CsTNF1 is involved in the innate immune defense of fish against microbial pathogens. PMID- 26478191 TI - Differential distribution of lipids in epidermis, gastrodermis and hosted Symbiodinium in the sea anemone Anemonia viridis. AB - Cnidarian-dinoflagellate symbiosis mainly relies on nutrient recycling, thus providing both partners with a competitive advantage in nutrient-poor waters. Essential processes related to lipid metabolism can be influenced by various factors, including hyperthermal stress. This can affect the lipid content and distribution in both partners, while contributing to symbiosis disruption and bleaching. In order to gain further insight into the role and distribution of lipids in the cnidarian metabolism, we investigated the lipid composition of the sea anemone Anemonia viridis and its photosynthetic dinoflagellate endosymbionts (Symbiodinium). We compared the lipid content and fatty acid profiles of the host cellular layers, non-symbiotic epidermal and symbiont-containing gastrodermal cells, and those of Symbiodinium, in a mass spectrometry-based assessment. Lipids were more concentrated in Symbiodinium cells, and the lipid class distribution was dominated by polar lipids in all tissues. The fatty acid distribution between host cell layers and Symbiodinium cells suggested potential lipid transfers between the partners. The lipid composition and distribution was modified during short-term hyperthermal stress, mainly in Symbiodinium cells and gastrodermis. Exposure to elevated temperature rapidly caused a decrease in polar lipid C18 unsaturated fatty acids and a strong and rapid decrease in the abundance of polar lipid fatty acids relative to sterols. These lipid indicators could therefore be used as sensitive biomarkers to assess the physiology of symbiotic cnidarians, especially the effect of thermal stress at the onset of cnidarian bleaching. Overall, the findings of this study provide some insight on key lipids that may regulate maintenance of the symbiotic interaction. PMID- 26478192 TI - Sexual dimorphism in baseline urinary corticosterone metabolites and their association with body-condition indices in a peri-urban population of the common Asian toad (Duttaphrynus melanostictus). AB - Field endocrinology research through the quantification of glucocorticoids or stress hormones in free-living wildlife is crucial for assessing their physiological responses towards pervasive environmental changes. Urinary corticosterone metabolite (UCM) enzyme-immunoassay (EIA) has been validated for numerous amphibian species as a non-invasive measure of physiological stress. Body-condition indices (BCIs) have also been widely used in amphibians as an indirect measure of animal health. Field endocrinology research on amphibian species in Asia is limited. In this study, we validated a UCM EIA in a peri-urban sub-population of the common Asian toad (Duttaphrynus melanostictus) in Pune, Maharashtra, India. We determined the baseline levels of UCMs in male (n=39) and female (n=19) toads. Secondly, we used a standard capture handling protocol to quantify changes in UCMs during short-term captivity. We also determined BCIs in the male and female toads using Fulton's index (K) and residual condition index (RCI). The results showed that mean baseline levels of UCMs were significantly higher in male toads than in females. There was no significant change in mean levels of UCMs of males and females between capture and captivity (0-12h). This highlights plausible habituation of the species to the peri-urban environment. Associations between UCMs with BCIs (K and R) were positive in male toads but negative in females. In conclusion, our UCMs EIA can be applied with BCIs to assess health of the Asian toads. We also suggest that direct fitness parameters such as sperm and oocyte quality, reproductive ecology and immunocompetence measurements should be applied in combination with these conservation physiology tools to quantify the fitness consequences of pervasive environmental changes on native amphibians. PMID- 26478193 TI - Metabolic activity and behavior of the invasive amphipod Dikerogammarus villosus and two common Central European gammarid species (Gammarus fossarum, Gammarus roeselii): Low metabolic rates may favor the invader. AB - The Ponto-Caspian amphipod Dikerogammarus villosus is one of the most successful invaders in Central European rivers. Contrary to studies on its ecology, ecophysiological studies comparing the species' physiological traits are scarce. In this context, in particular the metabolic activity of the invasive species has rarely been considered and, moreover, the few existing studies on this species report strongly deviating results. The purpose of this study was to assess the metabolic activity and behavior of D. villosus and other common European amphipod species (Gammarus fossarum, Gammarus roeselii) in relation to temperatures covering the thermal regime of the invaded habitats. Based on direct calorimetric measurements of metabolic heat dissipation at three temperature levels (5 degrees C, 15 degrees C and 25 degrees C), we found the routine metabolic rate of D. villosus to be significantly lower than that of the other studied gammarid species at the medium temperature level. The estimated resting metabolic rate indicated a similar trend. At 5 degrees C and 25 degrees C, both routine and resting metabolic rate did not differ between species. Compared to G. fossarum and G. roeselii, D. villosus exhibited lower locomotor activity at the low and medium temperatures (5 degrees C and 15 degrees C). In contrast, its locomotor activity increased at the high experimental temperature (25 degrees C). G. fossarum and G. roeselii were apparently more active than D. villosus at all studied temperatures. We conclude that D. villosus has both physiological and behavioral adaptations that lead to a reduction in metabolic energy expenditure, which is assumed to be beneficial and might contribute to its invasive success. PMID- 26478194 TI - Observing in space and time the ephemeral nucleation of liquid-to-crystal phase transitions. AB - The phase transition of crystalline ordering is a general phenomenon, but its evolution in space and time requires microscopic probes for visualization. Here we report direct imaging of the transformation of amorphous titanium dioxide nanofilm, from the liquid state, passing through the nucleation step and finally to the ordered crystal phase. Single-pulse transient diffraction profiles at different times provide the structural transformation and the specific degree of crystallinity (eta) in the evolution process. It is found that the temporal behaviour of eta exhibits unique 'two-step' dynamics, with a robust 'plateau' that extends over a microsecond; the rate constants vary by two orders of magnitude. Such behaviour reflects the presence of intermediate structure(s) that are the precursor of the ordered crystal state. Theoretically, we extend the well known Johnson-Mehl-Avrami-Kolmogorov equation, which describes the isothermal process with a stretched-exponential function, but here over the range of times covering the melt-to-crystal transformation. PMID- 26478195 TI - Chronobiological Therapy for Mood Disorders. AB - Chronobiological therapies for mood disorders include manipulations of the sleep wake cycle such as sleep deprivation and sleep phase advance and the controlled exposure to light and darkness. Their antidepressant efficacy can overcome drug resistance and targets the core depressive symptoms including suicide, thus making them treatment options to be tried either alone or as adjunctive treatments combined with common psychopharmacological interventions. The specific pattern of mood change observed with chronobiological therapies is characterized by rapid and sustained effects, when used among themselves or combined with drugs. Effects sizes are the same reported for the most effective psychiatric treatments, but side effects are usually marginal or absent. New treatment protocols are developed to adapt them in different clinical settings. This review deals with the general principles of clinical chronobiology and the latest findings in this rapidly developing field. PMID- 26478196 TI - Genetic Similarities between Compulsive Overeating and Addiction Phenotypes: A Case for "Food Addiction"? AB - There exists a continuous spectrum of overeating, where at the extremes there are casual overindulgences and at the other a 'pathological' drive to consume palatable foods. It has been proposed that pathological eating behaviors may be the result of addictive appetitive behavior and loss of ability to regulate the consumption of highly processed foods containing refined carbohydrates, fats, salt, and caffeine. In this review, we highlight the genetic similarities underlying substance addiction phenotypes and overeating compulsions seen in individuals with binge eating disorder. We relate these similarities to findings from neuroimaging studies on reward processing and clinical diagnostic criteria based on addiction phenotypes. The abundance of similarities between compulsive overeating and substance addictions puts forth a case for a 'food addiction' phenotype as a valid, diagnosable disorder. PMID- 26478197 TI - Sleep, Cognition and Dementia. AB - The older patient population is growing rapidly around the world and in the USA. Almost half of seniors over age 65 who live at home are dissatisfied with their sleep, and nearly two-thirds of those residing in nursing home facilities suffer from sleep disorders. Chronic and pervasive sleep complaints and disturbances are frequently associated with excessive daytime sleepiness and may result in impaired cognition, diminished intellect, poor memory, confusion, and psychomotor retardation all of which may be misinterpreted as dementia. The key sleep disorders impacting patients with dementia include insomnia, hypersomnolence, circadian rhythm misalignment, sleep disordered breathing, motor disturbances of sleep such as periodic leg movement disorder of sleep and restless leg syndrome, and parasomnias, mostly in the form of rapid eye movement (REM) sleep behavior disorder (RBD). RBD is a pre-clinical marker for a class of neurodegenerative diseases, the "synucleinopathies", and requires formal polysomnographic evaluation. Untreated sleep disorders may exacerbate cognitive and behavioral symptoms in patients with dementia and are a source of considerable stress for bed partners and family members. When left untreated, sleep disturbances may also increase the risk of injury at night, compromise health-related quality of life, and precipitate and accelerate social and economic burdens for caregivers. PMID- 26478199 TI - A role for vector control in dengue vaccine programs. AB - Development and deployment of a successful dengue virus (DENV) vaccine has confounded research and pharmaceutical entities owing to the complex nature of DENV immunity and concerns over exacerbating the risk of DENV hemorrhagic fever (DHF) as a consequence of vaccination. Thus, consensus is growing that a combination of mitigation strategies will be needed for DENV to be successfully controlled, likely involving some form of vector control to enhance a vaccine program. We present here a deterministic compartmental model to illustrate that vector control may enhance vaccination campaigns with imperfect coverage and efficacy. Though we recognize the costs and challenges associated with continuous control programs, simultaneous application of vector control methods coincident with vaccine roll out can have a positive effect by further reducing the number of human cases. The success of such an integrative strategy is predicated on closing gaps in our understanding of the DENV transmission cycle in hyperedemic locations. PMID- 26478198 TI - Improvement of BCG protective efficacy with a novel chimpanzee adenovirus and a modified vaccinia Ankara virus both expressing Ag85A. AB - A replication-deficient chimpanzee adenovirus expressing Ag85A (ChAdOx1.85A) was assessed, both alone and in combination with modified vaccinia Ankara also expressing Ag85A (MVA85A), for its immunogenicity and protective efficacy against a Mycobacterium tuberculosis (M.tb) challenge in mice. Naive and BCG-primed mice were vaccinated or boosted with ChAdOx1.85A and MVA85A in different combinations. Although intranasally administered ChAdOx1.85A induced strong immune responses in the lungs, it failed to consistently protect against aerosol M.tb challenge. In contrast, ChAdOx1.85A followed by MVA85A administered either mucosally or systemically, induced strong immune responses and was able to improve the protective efficacy of BCG. This vaccination regime has consistently shown superior protection over BCG alone and should be evaluated further. PMID- 26478200 TI - Correlates of protection of serotype-specific capsular antibody and invasive Group B Streptococcus disease in South African infants. AB - BACKGROUND: Vaccinating pregnant women may prevent invasive Group B Streptococcus (GBS) disease in their young infants. In a low-middle income setting, we sought to determine an association between natural maternal antibody responses and the development of invasive GBS disease. METHODS: We undertook a matched case-control study in Johannesburg, South Africa. Maternal and infant antibody concentrations were compared between serotype-specific Ia and III GBS cases and well-baby controls in which the mother was colonized with the same serotype. RESULTS: The median maternal serotype Ia and III antibody concentrations (in MUg/mL) were 0.05 (IQR: 0.02-0.24; n=27) and 0.14 (IQR: 0.08-0.33; n=29) in cases, and 0.29 (IQR: 0.06-1.60; n=43) and 0.29 (IQR: 0.13-0.58; n=31) in homotypic controls, respectively. A smaller proportion of cases as compared to homotypic controls had higher serotype Ia and III maternal antibody concentrations. Using Bayesian modeling, we demonstrated that the risk of invasive GBS disease was less than 10% with maternal antibody concentrations >= 6 MUg/mL and >= 3 MUg/mL for serotypes Ia and III, respectively. CONCLUSIONS: Maternal capsular antibody concentrations are associated with the risk of invasive GBS disease in infants. In a low-middle income setting with a high burden of invasive disease, we have demonstrated a sero-correlate of protection for GBS serotypes Ia and III which could facilitate vaccine licensure. PMID- 26478202 TI - Intention to receive influenza vaccination prior to the summer influenza season in adults of Hong Kong, 2015. AB - Following a severe winter epidemic of drifted influenza A(H3N2) during January March 2015, the Hong Kong government purchased vaccines of southern hemisphere formulation for administration prior to the anticipated summer influenza epidemic. This is the first time that seasonal influenza vaccines will be delivered twice within the same year in Hong Kong. We conducted a household telephone survey to investigate the acceptance of Hong Kong adults to pre-summer influenza vaccination. We found that the proportion of people reporting intention to receive vaccination was 37.8, 24.0, 31.4, and 34.4% in the age groups of 18 39, 40-59, 60-69, and 70 years or above. Only 31.3% of respondents who claimed they were parents or guardians said they would take their children to receive vaccination if the new vaccine was available. These findings suggested that intention to receive pre-summer vaccination was low even among the priority group of older people. PMID- 26478203 TI - Report on the second WHO integrated meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses: Geneva, Switzerland, 5-7 May 2014. AB - On 5-7 May 2014, the World Health Organization (WHO) convened the second integrated meeting on "influenza vaccines that induce broadly protective and long lasting immune responses". Around 100 invited experts from academia, the vaccine industry, research and development funders, and regulatory and public health agencies attended the meeting. Areas covered included mechanisms of protection in natural influenza-virus infection and vaccine-induced immunity, new approaches to influenza-vaccine design and production, and novel routes of vaccine administration. A timely focus was on how this knowledge could be applied to both seasonal influenza and emerging viruses with pandemic potential such as influenza A (H7N9), currently circulating in China. Special attention was given to the development of possible universal influenza vaccines, given that the Global Vaccine Action Plan calls for at least one licensed universal influenza vaccine by 2020. This report highlights some of the topics discussed and provides an update on studies published since the report of the previous meeting. PMID- 26478201 TI - Mouse models of dengue virus infection for vaccine testing. AB - Dengue is a mosquito-borne disease caused by four serologically and genetically related viruses termed DENV-1 to DENV-4. With an annual global burden of approximately 390 million infections occurring in the tropics and subtropics worldwide, an effective vaccine to combat dengue is urgently needed. Historically, a major impediment to dengue research has been development of a suitable small animal infection model that mimics the features of human illness in the absence of neurologic disease that was the hallmark of earlier mouse models. Recent advances in immunocompromised murine infection models have resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice that are deficient in both the interferon-alpha/beta receptor (IFN-alpha/beta R) and the interferon-gamma receptor (IFN-gammaR). These models mimic many hallmark features of dengue disease in humans, such as viremia, thrombocytopenia, vascular leakage, and cytokine storm. Importantly AG129 mice develop lethal, acute, disseminated infection with systemic viral loads, which is characteristic of typical dengue illness. Infected AG129 mice generate an antibody response to DENV, and antibody-dependent enhancement (ADE) models have been established by both passive and maternal transfer of DENV-immune sera. Several steps have been taken to refine DENV mouse models. Viruses generated by peripheral in vivo passages incur substitutions that provide a virulent phenotype using smaller inocula. Because IFN signaling has a major role in immunity to DENV, mice that generate a cellular immune response are desired, but striking the balance between susceptibility to DENV and intact immunity is complicated. Great strides have been made using single-deficient IFN-alpha/betaR mice for DENV-2 infection, and conditional knockdowns may offer additional approaches to provide a panoramic view that includes viral virulence and host immunity. Ultimately, the DENV AG129 mouse models result in reproducible lethality and offer multiple disease parameters to evaluate protection by candidate vaccines. PMID- 26478204 TI - Recessive Mutations in POLR3B Encoding RNA Polymerase III Subunit Causing Diffuse Hypomyelination in Patients with 4H Leukodystrophy with Polymicrogyria and Cataracts. AB - The diagnosis of 4H leukodystrophy (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) is based on clinical findings and magnetic resonance imaging (MRI). Recently, mutations of the genes encoding Pol III (RNA polymerase III) subunit A (POLR3A) and subunit B (POL3B) have been identified as the genetic causes of hypomyelination. We describe two Polish female siblings aged 5 and 10 years with compound heterozygous mutations in POLR3B. They both presented with similar clinical symptoms and MRI findings presenting as 4H leukodystrophy, and the association of polymicrogyria and cataract. According to our observation in young children with the absence of hypogonadotropic hypogonadism, brain MRI pattern is very essential in proper early diagnosis of 4H leukodystrophy. All clinical and radiological results are of course helpful, however genetic conformation is always necessary. PMID- 26478208 TI - Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study. AB - BACKGROUND: While oral antidepressants reach efficacy after weeks, single-dose intravenous (i.v.) ketamine has rapid, yet time-limited antidepressant effects. We aimed to determine the efficacy and safety of single-dose i.v. ketamine augmentation of escitalopram in major depressive disorder (MDD). METHOD: Thirty outpatients with severe MDD (17-item Hamilton Rating Scale for Depression total score ? 24) were randomized to 4 weeks double-blind treatment with escitalopram 10 mg/day+single-dose i.v. ketamine (0.5 mg/kg over 40 min) or escitalopram 10 mg/day + placebo (0.9% i.v. saline). Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR). Suicidal ideation was evaluated with the QIDS-SR item 12. Adverse psychopathological effects were measured with the Brief Psychiatric Rating Scale (BPRS)-positive symptoms, Young Mania Rating Scale (YMRS) and Clinician Administered Dissociative States Scale (CADSS). Patients were assessed at baseline, 1, 2, 4, 24 and 72 h and 7, 14, 21 and 28 days. Time to response (? 50% MADRS score reduction) was the primary outcome. RESULTS: By 4 weeks, more escitalopram + ketamine-treated than escitalopram + placebo-treated patients responded (92.3% v. 57.1%, p = 0.04) and remitted (76.9% v. 14.3%, p = 0.001), with significantly shorter time to response [hazard ratio (HR) 0.04, 95% confidence interval (CI) 0.01-0.22, p < 0.001] and remission (HR 0.11, 95% CI 0.02-0.63, p = 0.01). Compared to escitalopram + placebo, escitalopram + ketamine was associated with significantly lower MADRS scores from 2 h to 2 weeks [(peak = 3 days-2 weeks; effect size (ES) = 1.08 1.18)], QIDS-SR scores from 2 h to 2 weeks (maximum ES = 1.27), and QIDS-SR suicidality from 2 to 72 h (maximum ES = 2.24). Only YMRS scores increased significantly with ketamine augmentation (1 and 2 h), without significant BPRS or CADSS elevation. CONCLUSIONS: Single-dose i.v. ketamine augmentation of escitalopram was safe and effective in severe MDD, holding promise for speeding up early oral antidepressant efficacy. PMID- 26478209 TI - The Scaling of Human Contacts and Epidemic Processes in Metapopulation Networks. AB - We study the dynamics of reaction-diffusion processes on heterogeneous metapopulation networks where interaction rates scale with subpopulation sizes. We first present new empirical evidence, based on the analysis of the interactions of 13 million users on Twitter, that supports the scaling of human interactions with population size with an exponent gamma ranging between 1.11 and 1.21, as observed in recent studies based on mobile phone data. We then integrate such observations into a reaction- diffusion metapopulation framework. We provide an explicit analytical expression for the global invasion threshold which sets a critical value of the diffusion rate below which a contagion process is not able to spread to a macroscopic fraction of the system. In particular, we consider the Susceptible-Infectious-Recovered epidemic model. Interestingly, the scaling of human contacts is found to facilitate the spreading dynamics. This behavior is enhanced by increasing heterogeneities in the mobility flows coupling the subpopulations. Our results show that the scaling properties of human interactions can significantly affect dynamical processes mediated by human contacts such as the spread of diseases, ideas and behaviors. PMID- 26478210 TI - Resolution Pharmacology: Opportunities for Therapeutic Innovation in Inflammation. AB - Current medicines for the clinical management of inflammatory diseases act by inhibiting specific enzymes or antagonising specific receptors or blocking their ligands. In the past decade, a new paradigm in our understanding of the inflammatory process has emerged with the appreciation of genetic, molecular, and cellular mechanisms that are engaged to actively resolve inflammation. The 'resolution of acute inflammation' is enabled by counter-regulatory checkpoints to terminate the inflammatory reaction, promoting healing and repair. It may be possible to harness this knowledge for innovative approaches to the treatment of inflammatory pathologies. Here we discuss current translational attempts to develop agonists at proresolving targets as a strategy to rectify chronic inflammatory status. We reason this new approach will lead to the identification of better drugs that will establish a new branch of pharmacology, 'resolution pharmacology'. PMID- 26478212 TI - L1-CAM and N-CAM: From Adhesion Proteins to Pharmacological Targets. AB - L1 cell adhesion molecule (L1-CAM) and neural cell adhesion molecule (N-CAM), key members of the immunoglobulin-like CAM (Ig-CAM) family, were first recognized to play critical roles in surface interactions of neurons, by binding with each other and with extracellular matrix (ECM) proteins. Subsequently, adhesion was recognized to include signaling due to both activation of beta-integrin, with the generation of intracellular cascades, and integration with the surface cytoskeleton. The importance of the two Ig-CAMs was revealed by their activation of the tyrosine kinase receptors of fibroblast growth factor (FGF), epidermal growth factor (EGF), and nerve growth factor (NGF). Based on these complex signaling properties, L1-CAM and N-CAM have become of great potential pharmacological interest in neurons and cancers. Treatment of neurodegenerative disorders and cognitive deficits of neurons is aimed to increase the cell Ig-CAM tone, possibly provided by synthetic/mimetic peptides. In cancer cells, where Ig CAMs are often overexpressed, the proteins are employed for prognosis. The approaches to therapy are based on protein downregulation, antibodies, and adoptive immunotherapy. PMID- 26478213 TI - Commentary: To improve melanoma detection, help teach our colleagues. PMID- 26478214 TI - Thermodynamic holography. AB - The holographic principle states that the information about a volume of a system is encoded on the boundary surface of the volume. Holography appears in many branches of physics, such as optics, electromagnetism, many-body physics, quantum gravity, and string theory. Here we show that holography is also an underlying principle in thermodynamics, a most important foundation of physics. The thermodynamics of a system is fully determined by its partition function. We prove that the partition function of a finite but arbitrarily large system is an analytic function on the complex plane of physical parameters, and therefore the partition function in a region on the complex plane is uniquely determined by its values along the boundary. The thermodynamic holography has applications in studying thermodynamics of nano-scale systems (such as molecule engines, nano generators and macromolecules) and provides a new approach to many-body physics. PMID- 26478211 TI - Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy. AB - Polo-like kinase 1 (Plk1) plays key roles in regulating mitotic processes that are crucial for cellular proliferation. Overexpression of Plk1 is tightly associated with the development of particular cancers in humans, and a large body of evidence suggests that Plk1 is an attractive target for anticancer therapeutic development. Drugs targeting Plk1 can potentially be directed at two distinct sites: the N-terminal catalytic kinase domain (KD), which phosphorylates substrates, and the C-terminal polo-box domain (PBD) which is essential for protein-protein interactions. In this review we summarize recent advances and new challenges in the development of Plk1 inhibitors targeting these two domains. We also discuss novel strategies for designing and developing next-generation inhibitors to effectively treat Plk1-associated human disorders. PMID- 26478215 TI - Unimolecular antiparallel G-quadruplex folding topology of 2'-5'-isoTBA sequences remains unaltered by loop composition. AB - A 2'-5'-linked isoTBA 15 mer sequence with (232) loop composition formed stable antiparallel quadruplex structures similar to the SELEX derived 15 mer TBA sequence with (232) loop composition. A parallel versus antiparallel topology of 3'-5'-G-quadruplexes is largely dictated by the loop length, and it is known that the truncated loops favour parallel quadruplexes. In contrast to TBA, systematic reduction of the loop length in isoTBA from (232) to (222), (131) or even (111) did not alter the antiparallel topology of the resulting 14 mer, 13 mer and 11 mer G-rich modified isoTBA-like sequences. PMID- 26478216 TI - Identifying and avoiding singularity-induced local traps over control landscapes of spin chain systems. AB - The wide success of quantum optimal control in experiments and simulations is attributed to the properties of the control landscape, defined by the objective value as a functional of the controls. Prior analysis has shown that on satisfaction of some underlying assumptions, the landscapes are free of suboptimal traps that could halt the search for a global optimum with gradient based algorithms. However, violation of one particular assumption can give rise to a so-called singular control, possibly bringing about local traps on the corresponding landscapes in some particular situations. This paper theoretically and experimentally demonstrates the existence of singular traps on the landscape in linear spin-1/2 chains with Ising couplings between nearest neighbors and with certain field components set to zero. The results in a two-spin example show how a trap influences the search trajectories passing by it, and how to avoid encountering such traps in practice by choosing sufficiently strong initial control fields. The findings are also discussed in the context of the generally observed success of quantum control. PMID- 26478218 TI - Reaction and degradation mechanism in all-solid-state lithium-air batteries. AB - The reaction and degradation mechanism in all-solid-state Li-air batteries was investigated to improve the cycling performance. It is suggested that Li2O2 is first produced by the H2O-mediated electrochemical reactions during discharging and Li2CO3 is produced by the following chemical reactions. Disruption of the CNTs and residual discharge products, which cause the capacity degradation during cycling, were observed. PMID- 26478217 TI - Outcome of Treating Pediatric Uveitis With Dexamethasone Implants. AB - PURPOSE: To describe the outcome in children of eyes with uveitis following repeated treatment with dexamethasone (Ozurdex) implants. DESIGN: Retrospective, interventional study. METHODS: Twenty-two eyes of 16 pediatric patients with uveitis were treated with 35 dexamethasone implants at a tertiary referral center. Following implantations, anatomic and functional outcomes, as well as ocular complications, were noted. Main outcome measures included best-corrected visual acuity, central retinal thickness, number and dosage of systemic immunosuppression drugs, vitreous haze score, and presence of raised intraocular pressure or cataract. RESULTS: Following the first implantation, average best corrected visual acuity improved significantly from 0.55 +/- 0.08 logMAR to 0.37 +/- 0.08 logMAR (P = .024), central retinal thickness decreased by 219 +/- 55 MUm (P = .01), and the percentage of eyes achieving a vitreous haze score of 0 increased from 41% to 88% (P = .006). The median time to relapse following the first injection was 9 months, with a similar response achieved after each repeat implantation. Children previously requiring systemic immunosuppression at the time of the first implantation were able to stop or significantly reduce the dose and number of drugs. In total there were 4 instances of cataract progression that were not visually significant and did not require surgical treatment and 6 cases of raised IOP, 5 of which were treated pharmacologically with no surgical intervention required and 1 that required revision of a previous filtration surgery. There were no cases of implant migration into the anterior chamber, endophthalmitis, or retinal detachment. CONCLUSIONS: The use of dexamethasone implants in children results in improved retinal thickness and reduction in ocular inflammation, which can improve vision for several months. Repeat implantations result in continued control of the inflammation, allowing for reduction of systemic immunosuppression with few ocular complications. PMID- 26478219 TI - Genetics and imaging of oligodendroglial tumors. AB - Oligodendroglial tumors are chemosensitive with a favorable prognosis compared with other histological subtypes. The genetic hallmark of co-deletion of 1p and 19q determines both treatment response and prognosis. While this test now forms part of routine histopathology diagnosis in many laboratories, alternative noninvasive imaging biomarkers of tumor genotype remain an attractive proposition. This review will focus on imaging biomarkers of molecular genetics in oligodendroglial tumors. PMID- 26478220 TI - The content and effectiveness of home-based nursing interventions to promote health and well-being in families with small children: a systematic review. AB - BACKGROUND: Although the use of preventive family nursing interventions in the home is increased, the literature on the content and effectiveness of these interventions remains fragmented. AIM: The aim of this review was to identify and describe the content of preventive family nursing interventions in families' homes and the effectiveness they had on the families' health and well-being. METHODS: A systematic review was conducted using searches on the databases CINAHL, PubMed, Scopus and Web of Science (2003-2014). RESULTS: Altogether, 2077 articles were identified, and 11 were selected based on the inclusion and exclusion criteria. The main types of interventions were discussions and practical exercises to help parents cope with parenthood and relationships and interactions in the family, together with health, well-being, social relations and socio-economic situations. The effectiveness of family interventions was reported in all the selected studies. CONCLUSIONS: Greater knowledge of interventions is needed in the future, to develop program content and to explore the validity and reliability of used measurements. In addition, more effort is needed to develop quality appraisal tools for preventive interventions in families' homes. PMID- 26478222 TI - Structure of Zeste-DNA Complex Reveals a New Modality of DNA Recognition by Homeodomain-Like Proteins. AB - Drosophila Zeste is a DNA binding protein important for chromatin-targeted regulation of gene expression. It is best studied in the context of transvection a mechanism of interallelic gene regulation involving paired chromosomes-and repression of the expression of white by Zeste mutants. Both of these functions depend on the DNA binding and self-association properties of Zeste, but the underlying structural basis remains unknown. Here we report the crystal structure of the DNA binding domain of Zeste in complex with a 19-bp DNA duplex containing the consensus recognition sequence motif. The structure reveals a helix-turn helix Myb/homeodomain-like fold with the Zeste-specific insertion sequence forming a short helix and a long loop. Direct base contacts by the major groove binding helix principally account for the sequence-specific recognition, and backbone contacts via the Zeste-specific insertion are mainly responsible for the length requirement and the orientation of DNA. Our structural and biochemical characterizations of the DNA binding property of Zeste uncover an altered DNA binding modality of homeodomain-like proteins, and the structural information should facilitate the unraveling of the intricate mechanism of Zeste in regulation of gene expression. PMID- 26478221 TI - Syringomyelia in a Newborn Male Simmental Calf. PMID- 26478223 TI - Predicting Large RNA-Like Topologies by a Knowledge-Based Clustering Approach. AB - An analysis and expansion of our resource for classifying, predicting, and designing RNA structures, RAG (RNA-As-Graphs), is presented, with the goal of understanding features of RNA-like and non-RNA-like motifs and exploiting this information for RNA design. RAG was first reported in 2004 for cataloging RNA secondary structure motifs using graph representations. In 2011, the RAG resource was updated with the increased availability of RNA structures and was improved by utilities for analyzing RNA structures, including substructuring and search tools. We also classified RNA structures as graphs up to 10 vertices (~200 nucleotides) into three classes: existing, RNA-like, and non-RNA-like using clustering approaches. Here, we focus on the tree graphs and evaluate the newly founded RNAs since 2011, which also support our refined predictions of RNA-like motifs. We expand the RAG resource for large tree graphs up to 13 vertices (~260 nucleotides), thereby cataloging more than 10 times as many secondary structures. We apply clustering algorithms based on features of RNA secondary structures translated from known tertiary structures to suggest which hypothetical large RNA motifs can be considered "RNA-like". The results by the PAM (Partitioning Around Medoids) approach, in particular, reveal good accuracy, with small error for the largest cases. The RAG update here up to 13 vertices offers a useful graph-based tool for exploring RNA motifs and suggesting large RNA motifs for design. PMID- 26478224 TI - Vine Nitrogen Status Does Not Have a Direct Impact on 2-Methoxy-3 isobutylpyrazine in Grape Berries and Wines. AB - Methoxypyrazines (MP) constitute a large family of compounds that contribute to the vegetative varietal aroma of many grapevine varieties and wines. The berry content in 2-methoxy-3-isobutylpyrazine (IBMP), a major MP reminiscent of green pepper aroma, can be influenced by environmental factors or cultural practices such as water status or mineral nutrition. To date, no study has investigated a possible direct effect of nitrogen (N) on IBMP synthesis without possible interference from water status and vigor variations. In this study, only vine nitrogen status was significantly different among treatments. Water status was controlled during the season, and vine vigor was similar among treatments. IBMP level was maximal at bunch closure and decreased during the season. There was no significant effect of nitrogen nutrition on this metabolite. Moreover, the expression profiles of VvOMT3 and VvOMT4, key genes in the IBMP biosynthetic pathway, were similar between treatments. This result indicates that when an effect of N on IBMP was found in previous studies, it was likely mediated through the modification of bunch-zone microclimate, induced by the higher vigor of high N-status vines. PMID- 26478225 TI - Renal Phosphate Reabsorption is Correlated with the Increase in Lumbar Bone Mineral Density in Patients Receiving Once-Weekly Teriparatide. AB - In order to assess the changes in serum calcium and phosphate and the changes in renal tubular phosphate reabsorption (TmP/GFR) and to evaluate the association between these indices and the increase in bone mineral density (BMD) with once weekly intermittent administration of teriparatide (TPTD), the results from the teriparatide once-weekly efficacy research (TOWER) trial were re-analyzed. The TOWER trial studied postmenopausal women and older men with osteoporosis. Patients were randomly assigned to receive TPTD 56.5 MUg or placebo for 72 weeks. Of these patients, the present study investigated those whose calcium and phosphate levels and lumbar BMD (L-BMD) were measured (TPTD group, n = 153 and Placebo group, n = 137). The TPTD group had significantly lower serum phosphate, calcium-phosphate product, and TmP/GFR at weeks 4, 24, 48, and 72 and urinary fractional calcium excretion (FECa) at weeks 12, 48, and 72 (p < 0.05). In the TPTD group, the serum phosphate and TmP/GFR during early treatment (4, and 12 weeks) showed a significant positive correlation with the percent change in L-BMD at weeks 48 and 72. Based on multivariate analysis corrected for age, BMI, and L BMD at the start of treatment, serum phosphate and TmP/GFR at week 4 showed a significant correlation with the percent change in L-BMD. This study suggests that the L-BMD response to once-weekly long-term TPTD treatment is associated with circulating phosphate or with the status of its renal reabsorption. Preventing decrease in serum phosphate levels may be important in acquiring greater L-BMD with once-weekly TPTD. PMID- 26478226 TI - Osteogenesis Imperfecta Type I Caused by COL1A1 Deletions. AB - Osteogenesis imperfecta (OI) type I is usually caused by COL1A1 stop or frameshift mutations, leading to COL1A1 haploinsufficiency. Here we report on 12 individuals from 5 families who had OI type I due to an unusual cause heterozygous deletions of the entire COL1A1 gene. The deletions were initially detected by semiconductor-based sequencing of genomic DNA and confirmed by quantitative PCR. Array comparative genomic hybridization in DNA of the index patient in each family showed that deletion size varied from 18.5 kb to 2.23 Mb between families, encompassing between 1 and 47 genes (COL1A1 included). The skeletal phenotype of the affected individuals was similar to that of patients with haploinsufficiency caused by COL1A1 stop or frameshift mutations. However, one individual with a deletion that included also DLX3 and DLX4 had tooth discoloration and bone fragility. Three individuals from 2 families had deletions that included also CACNA1G, and these individuals had learning disabilities. These features are not usually observed in COL1A1 haploinsufficiency, but are in accordance with previously described individuals in whom deletions included the same genes. In summary, we found deletions of COL1A1 in 5 out of 161 families (3 %) with OI type I that were evaluated. Deletions encompassing not only COL1A1 but also neighboring genes can lead to contiguous gene syndromes that may include dental involvement and learning disability. PMID- 26478228 TI - Mechanical properties of zirconium alloys and zirconium hydrides predicted from density functional perturbation theory. AB - The elastic properties and mechanical stability of zirconium alloys and zirconium hydrides have been investigated within the framework of density functional perturbation theory. Results show that the lowest-energy cubic Pn3[combining macron]m polymorph of delta-ZrH1.5 does not satisfy all the Born requirements for mechanical stability, unlike its nearly degenerate tetragonal P42/mcm polymorph. Elastic moduli predicted with the Voigt-Reuss-Hill approximations suggest that mechanical stability of alpha-Zr, Zr-alloy and Zr-hydride polycrystalline aggregates is limited by the shear modulus. According to both Pugh's and Poisson's ratios, alpha-Zr, Zr-alloy and Zr-hydride polycrystalline aggregates can be considered ductile. The Debye temperatures predicted for gamma-ZrH, delta ZrH1.5 and epsilon-ZrH2 are thetaD = 299.7, 415.6 and 356.9 K, respectively, while thetaD = 273.6, 284.2, 264.1 and 257.1 K for the alpha-Zr, Zry-4, ZIRLO and M5 matrices, i.e. suggesting that Zry-4 possesses the highest micro-hardness among Zr matrices. PMID- 26478229 TI - 29th Annual Meeting of the Austrian Society of Transplantation, Transfusion and Genetics - Austrotransplant 2015, Kitzbuehel, Austria, 21-24 October 2015. PMID- 26478227 TI - Cell-Free Protein Synthesis: Pros and Cons of Prokaryotic and Eukaryotic Systems. AB - From its start as a small-scale in vitro system to study fundamental translation processes, cell-free protein synthesis quickly rose to become a potent platform for the high-yield production of proteins. In contrast to classical in vivo protein expression, cell-free systems do not need time-consuming cloning steps, and the open nature provides easy manipulation of reaction conditions as well as high-throughput potential. Especially for the synthesis of difficult to express proteins, such as toxic and transmembrane proteins, cell-free systems are of enormous interest. The modification of the genetic code to incorporate non canonical amino acids into the target protein in particular provides enormous potential in biotechnology and pharmaceutical research and is in the focus of many cell-free projects. Many sophisticated cell-free systems for manifold applications have been established. This review describes the recent advances in cell-free protein synthesis and details the expanding applications in this field. PMID- 26478231 TI - Work-life balance: The female cardiothoracic surgeon's perspective. PMID- 26478230 TI - Transient unidirectional energy flow and diode-like phenomenon induced by non Markovian environments. AB - Relying on an exact time evolution scheme, we identify a novel transient energy transfer phenomenon in an exactly-solvable quantum microscopic model consisting of a three-level system coupled to two non-Markovian zero-temperature bosonic baths through two separable quantum channels. The dynamics of this model can be solved exactly using the quantum-state-diffusion equation formalism, demonstrating finite intervals of unidirectional energy flow across the system, typically, from the non-Markovian environment towards the more Markovian bath. Furthermore, when introducing a spatial asymmetry into the system, an analogue of the rectification effect is realized. In the long time limit, the dynamics arrives at a stationary state and the effects recede. Understanding temporal characteristics of directional energy flow will aid in designing microscopic energy transfer devices. PMID- 26478232 TI - Can patients with congenitally corrected transposition of the great arteries live better electrically? PMID- 26478233 TI - How to develop a niche: Focus on adult cardiac surgery. PMID- 26478234 TI - Is there any role for positron emission tomography-computed tomography after induction therapy for locally advanced non-small cell lung cancer? PMID- 26478235 TI - Mechanical versus biologic valves: Clicking engines or quiet electrics or hybrids? PMID- 26478236 TI - Historical perspectives of The American Association for Thoracic Surgery: William Elias Adams, MD (May 1, 1902-November 25, 1973). PMID- 26478237 TI - Prometheus' predicament: How to address contemporary left ventricular assist devices in patients with liver dysfunction. PMID- 26478238 TI - Calpain inhibition improves collateral-dependent perfusion in a hypercholesterolemic swine model of chronic myocardial ischemia. AB - PURPOSE: Calpain overexpression is implicated in aberrant angiogenesis. We hypothesized that calpain inhibition (MDL28170) would improve collateral perfusion in a swine model with hypercholesterolemia and chronic myocardial ischemia. METHODS: Yorkshire swine fed a high cholesterol diet for 4 weeks underwent surgical placement of an ameroid constrictor to their left circumflex coronary artery. Three weeks later, animals received no drug, high cholesterol control group (n = 8); low-dose calpain inhibition (0.12 mg/kg; n = 9); or high dose calpain inhibition (0.25 mg/kg; n = 8). The heart was harvested after 5 weeks. RESULTS: Myocardial perfusion in ischemic myocardium significantly improved with high-dose calpain inhibition at rest and with demand pacing (P = .016 and .011). Endothelium-dependent microvessel relaxation was significantly improved with low-dose calpain inhibition (P = .001). There was a significant increase in capillary density, with low-dose calpain inhibition and high-dose calpain inhibition (P = .01 and .01), and arteriolar density with low-dose calpain inhibition (P = .001). Calpain inhibition significantly increased several proangiogenic proteins, including vascular endothelial growth factor (P = .02), vascular endothelial growth factor receptor 1 (P = .003), vascular endothelial growth factor receptor 2 (P = .003), and talin, a microvascular structural protein (P = .0002). There was a slight increase in proteins implicated in endothelial-dependent (nitric oxide mediated) relaxation, including extracellular signal-regulated kinase, phosphorylated extracellular signal-regulated kinase, and inducible nitric oxide synthase with calpain inhibition. CONCLUSIONS: In the setting of hypercholesterolemia, calpain inhibition improved perfusion, with a trend toward increased collateralization on angiography and increased capillary and arteriolar densities in ischemic myocardium. Calpain inhibition also improved endothelium-dependent microvessel relaxation and increased expression of proteins implicated in angiogenesis and vasodilatation. PMID- 26478239 TI - Postoperative atrial fibrillation: Is there a need for prevention? PMID- 26478240 TI - It's time to get to the root of things. PMID- 26478241 TI - An important first step in the evaluation of venous thromboembolism after pulmonary resection. PMID- 26478242 TI - Don't miss the plenary sessions. PMID- 26478243 TI - Zone 0 hybrid arch exclusion: What for? PMID- 26478244 TI - Importance of Glu53 in the C-terminal region of brazzein, a sweet-tasting protein. AB - BACKGROUND: The sweetness of brazzein, one of the known sweet proteins, is dependent on charges and/or structures of its specific amino acid side chains. As the residues in the C-terminus of brazzein are known to play a critical role in sweetness, the currently unknown function of Glu53 requires further study. RESULTS: To identify important residues responsible for the sweetness of the protein brazzein, four mutants of the Glu53 residue in the C-terminal region of des-pE1M-brazzein, which lacks the N-terminal pyroglutamate, were constructed using site-directed mutagenesis. Mutations of Glu53 substitution to Ala or Asp significantly decreased the sweetness. On the other hand, a Lys mutation resulted in a molecule with sweetness similar to that of des-pE1M-brazzein. Mutation of Glu53 to Arg resulted in a molecule significantly sweeter than des-pE1M-brazzein, which agrees with previous findings showing that mutation with positively charged residues results in a sweeter protein. CONCLUSION: Our results suggest that the residue at position 53 is crucial for the sweetness of brazzein, which may be interacting with the sweet-taste receptor. (c) 2015 Society of Chemical Industry. PMID- 26478245 TI - Monitoring of physical health in services for young people at ultra-high risk of psychosis. AB - AIM: People with schizophrenia have poor physical health and high rates of premature mortality. Risk factors for later cardiovascular disease are present from an early stage, and recording of these factors is recommended in first episode services. However, it is unclear whether cardiometabolic risk factors are monitored prior to first-episode psychosis. METHODS: A retrospective analysis was conducted on case notes of individuals accepted into a specialized early detection service for young people at ultra-high risk for psychosis. Notes were assessed to determine whether the following physical health measures were recorded: height, weight, body mass index, blood pressure, blood glucose and lipids, physical activity levels, smoking status, substance use and alcohol intake. RESULTS: Forty individuals were deemed at ultra-high risk for psychosis and accepted into the service. The two measures reported most frequently were whether a person used substances (82.5%) or alcohol (72.5%), but more specific details were not commonly reported. A minority of case files contained information on height (2.5%), weight (7.5%), body mass index (5%), blood glucose (2.5%), smoking status (15%) and physical activity (7.5%). Six case files had no measure of physical health. CONCLUSIONS: Physical health and unhealthy lifestyle factors were not assessed routinely in the specialized service. Clear monitoring guidelines should be developed to establish routine assessment of common metabolic risk factors present in this population. PMID- 26478246 TI - (1) H and (13) C NMR spectral assignments of novel naphthalenylphenylpyrazolines. PMID- 26478247 TI - Blood Pressure Management After Intracerebral Hemorrhage. AB - OPINION STATEMENT: Elevated blood pressure (BP), which presents in approximately 80 % of patients with acute intracerebral hemorrhage (ICH), is associated with increased risk of poor outcome. The Second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) study, a multinational, multicenter, randomized controlled trial published in 2013, demonstrated better functional outcomes with no harm for patients with acute spontaneous ICH within 6 h of onset who received target-driven, early intensive BP lowering (systolic BP target <140 mmHg within 1 h, continued for 7 days) and suggested that greater and faster reduction in BP might enhance the treatment effect by limiting hematoma growth. The trial resulted in revisions of guidelines for acute management of ICH, in which intensive BP lowering in patients with acute ICH is recommended as safe and effective treatment for improving functional outcome. BP lowering is also the only intervention that is proven to reduce the risk of recurrent ICH. Current evidences from several randomized trials, including PROGRESS and SPS3, indicate that long-term strict BP control in patients with ICH is safe and could offer additional benefits in major reduction in risk of recurrent ICH. The latest American Heart Association/American Stroke Association (AHA/ASA) guidelines recommended a target BP of <130/80 mmHg after ICH, but supporting evidence is limited. Randomized controlled trials are needed that focus on strict BP control, initiated early after onset of the disease and continued long-term, to demonstrate effective prevention of recurrent stroke and other major vascular events without additional harms in the ICH population. PMID- 26478250 TI - Glucocorticoid Cell Priming Enhances Transfection Outcomes in Adult Human Mesenchymal Stem Cells. AB - Human mesenchymal stem cells (hMSCs) are one of the most widely researched stem cell types with broad applications from basic research to therapeutics, the majority of which require introduction of exogenous DNA. However, safety and scalability issues hinder viral delivery, while poor efficiency hinders nonviral gene delivery, particularly to hMSCs. Here, we present the use of a pharmacologic agent (glucocorticoid) to overcome barriers to hMSC DNA transfer to enhance transfection using three common nonviral vectors. Glucocorticoid priming significantly enhances transfection in hMSCs, demonstrated by a 3-fold increase in efficiency, 4-15-fold increase in transgene expression, and prolonged transgene expression when compared to transfection without glucocorticoids. These effects are dependent on glucocorticoid receptor binding and caused in part by maintenance of normal metabolic function and increased cellular (5-fold) and nuclear (6-10-fold) DNA uptake over hMSCs transfected without glucocorticoids. Results were consistent across five human donors and in cells up to passage five. Glucocorticoid cell priming is a simple and effective technique to significantly enhance nonviral transfection of hMSCs that should enhance their clinical use, accelerate new research, and decrease reliance on early passage cells. PMID- 26478251 TI - Context-dependent third-party intervention in agonistic encounters of male Przewalski horses. AB - One mechanism to resolve conflict among group members is third party intervention, for which several functions, such as kin protection, alliance formation, and the promotion of group cohesion have been proposed. Still, empirical research on the function of intervention behaviour is rare. We studied 40 cases of intervention behaviour in a field study on 13 semi-wild bachelor horses (Equus ferus przewalskii) in (a) standard social situations, and (b) when new horses joined the group (i.e. introductions). Only interventions in agonistic encounters were analysed. Eight of 13 animals directed intervention behaviour toward threatening animal in agonistic encounters of group members. One stallion was particularly active. The stallions did not intervene to support former group mates or kin and interventions were not reciprocated. In introduction situations and in standard social situations, the interveners supported animals which were lower in rank, but targeted, threatening animals of comparable social rank. After introductions, stallions received more affiliative behaviour from animals they supported and thus appeared to intervene for alliance formation. In standard social situations, interveners did not receive more affiliative behaviour from animals they supported and may primarily have intervened to promote group cohesion and to reduce social disruption within the group. PMID- 26478253 TI - Behavioral effects of fluoxetine on aggression and associative learning in Siamese fighting fish (Betta splendens). AB - Past research has implicated serotonin as an important neurotransmitter in the facilitation of aggressive behavior. In Siamese fighting fish (Betta splendens), the SSRI fluoxetine has been demonstrated to reduce both frequency and duration of aggressive displays across a variety of concentration exposure procedures. While this multi-method approach has provided strong evidence for fluoxetine's impact on aggression, no study has sought to examine the behavioral mechanism by which fluoxetine exerts its anti-aggressive effect. To address this question, a Go-No Go discrimination task utilizing mirror presentations as a reinforcer was designed. Consistent with previous reports, the results indicated that fluoxetine may exert a sedative effect upon aggressive behavior via decreased arousal to external stimuli. PMID- 26478252 TI - Target-invariant aggressive display in a tephritid fly. AB - Fruit flies of the family Tephritidae (Diptera) use specialized wing displays in aggressive encounters with conspecifics and predators. These displays, called supination displays, have been thought to deter attacks from one of their main predators, spiders of the family Salticidae. However, there is no information whether the display is qualitatively or quantitatively different when the target is a conspecific or a predator. In this study, we sought to determine whether flies vary their displays depending on the display target. Using the Mexican fruit fly Anastrepha ludens, we compared the characteristics of the display that male and female flies use against conspecifics and spiders. Flies did not distinguish between spiders and conspecifics in terms of display rates and bout duration. In general, flies are more likely to retreat faster from spiders after performing a display. We suggest that supination is a generalized aggressive behavior that is independent of the target. PMID- 26478249 TI - Development of Novel Adenoviral Vectors to Overcome Challenges Observed With HAdV 5-based Constructs. AB - Recombinant vectors based on human adenovirus serotype 5 (HAdV-5) have been extensively studied in preclinical models and clinical trials over the past two decades. However, the thorough understanding of the HAdV-5 interaction with human subjects has uncovered major concerns about its product applicability. High vector-associated toxicity and widespread preexisting immunity have been shown to significantly impede the effectiveness of HAdV-5-mediated gene transfer. It is therefore that the in-depth knowledge attained working on HAdV-5 is currently being used to develop alternative vectors. Here, we provide a comprehensive overview of data obtained in recent years disqualifying the HAdV-5 vector for systemic gene delivery as well as novel strategies being pursued to overcome the limitations observed with particular emphasis on the ongoing vectorization efforts to obtain vectors based on alternative serotypes. PMID- 26478254 TI - Chemoreception of hunger levels alters the following behaviour of a freshwater snail. AB - Chemically-mediated orientation is essential for many animals that must locate sites containing resources such as mates or food. One way to find these areas is by using publically-available information from other individuals. We tested a freshwater snail, Physa gyrina, for chemoreception of conspecific cues and predicted they could discriminate between cues based on information regarding hunger levels. We placed 'tracker' snails into a 2-arm arena where they could either follow or avoid an area previously used by a 'marker' snail. The hunger levels of both trackers and markers was manipulated, being either starved or fed. Starved and fed trackers did not differ in their following response when markers were hungry, but starved trackers were significantly more likely to follow fed markers, compared to fed trackers that tended to avoid areas used by fed markers. This outcome suggests that P. gyrina uses conspecific chemical cues to find food and potentially in some situations to avoid intra-specific food competition. PMID- 26478255 TI - Fluorescent nanoparticles based on AIE fluorogens for bioimaging. AB - Fluorescent nanoparticles (FNPs) have recently attracted increasing attention in the biomedical field because of their unique optical properties, easy fabrication and outstanding performance in imaging. Compared with conventional molecular probes including small organic dyes and fluorescent proteins, FNPs based on aggregation-induced emission (AIE) fluorogens have shown significant advantages in tunable emission and brightness, good biocompatibility, superb photo- and physical stability, potential biodegradability and facile surface functionalization. In this review, we summarize the latest advances in the development of fluorescent nanoparticles based on AIE fluorogens including polymer nanoparticles and silica nanoparticles over the past few years, and the various biomedical applications based on these fluorescent nanoparticles are also elaborated. PMID- 26478256 TI - Influence of MPEP (a selective mGluR5 antagonist) on the anticonvulsant action of novel antiepileptic drugs against maximal electroshock-induced seizures in mice. AB - The aim of this study was to determine the effects of 2-methyl-6 (phenylethynyl)pyridine (MPEP - a selective antagonist for the glutamate metabotropic receptor subtype mGluR5) on the protective action of some novel antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) against maximal electroshock-induced seizures in mice. Brain concentrations of antiepileptic drugs were measured to determine whether MPEP altered pharmacokinetics of antiepileptic drugs. Intraperitoneal injection of 1.5 and 2mg/kg of MPEP significantly elevated the threshold for electroconvulsions in mice, whereas MPEP at a dose of 1mg/kg considerably enhanced the anticonvulsant activity of pregabalin and topiramate, but not that of lamotrigine or oxcarbazepine in the maximal electroshock-induced seizures in mice. Pharmacokinetic results revealed that MPEP (1mg/kg) did not alter total brain concentrations of pregabalin and topiramate, and the observed effect in the mouse maximal electroshock seizure model was pharmacodynamic in nature. Collectively, our preclinical data suggest that MPEP may be a safe and beneficial adjunct to the therapeutic effects of antiepileptic drugs in human patients. PMID- 26478257 TI - ProTSAV: A protein tertiary structure analysis and validation server. AB - Quality assessment of predicted model structures of proteins is as important as the protein tertiary structure prediction. A highly efficient quality assessment of predicted model structures directs further research on function. Here we present a new server ProTSAV, capable of evaluating predicted model structures based on some popular online servers and standalone tools. ProTSAV furnishes the user with a single quality score in case of individual protein structure along with a graphical representation and ranking in case of multiple protein structure assessment. The server is validated on ~64,446 protein structures including experimental structures from RCSB and predicted model structures for CASP targets and from public decoy sets. ProTSAV succeeds in predicting quality of protein structures with a specificity of 100% and a sensitivity of 98% on experimentally solved structures and achieves a specificity of 88%and a sensitivity of 91% on predicted protein structures of CASP11 targets under 2A.The server overcomes the limitations of any single server/method and is seen to be robust in helping in quality assessment. ProTSAV is freely available at http://www.scfbio iitd.res.in/software/proteomics/protsav.jsp. PMID- 26478258 TI - The complete mitochondrial genome of the Qinghai Plateau yak Bos grunniens (Cetartiodactyla: Bovidae). AB - The Qinghai Plateau yak Bos grunniens (Cetartiodactyla: Bovidae) is an important primitive local breed in the Qinghai-Tibetan Plateau and adjacent regions. In this study, its complete mitochondrial genome sequence has been assembled and characterized from high-throughput Illumina sequencing data. This genome is 16 322 bp in length, and contains 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and a non-coding D-loop or control region. The nucleotide composition is asymmetric (33.73% A, 25.79% C, 13.19% G, and 27.29% T) with an overall A + T content of 61.02%. The gene arrangement and the composition are similar to most other vertebrates. These data would contribute to our better understanding its population genetics and evolutionary history. PMID- 26478259 TI - Long-term outcomes following laparoscopic anterior and Nissen fundoplication. AB - BACKGROUND: Limited evidence exists to which operation gives best long-term outcomes for gastro-oesophageal reflux disease. This study aimed to assess long term symptomatic outcome and satisfaction following laparoscopic anterior (LA) or Nissen fundoplication in a specialist upper gastrointestinal unit. METHODS: Patients who underwent primary LA or Nissen (LN) fundoplication between May 1994 and June 2010 were identified from a prospectively collected database. DeMeester, modified DeMeester, 'Gastrointestinal Symptom Rating Scale' scores and patient satisfaction were assessed by questionnaire. RESULTS: A total of 387 patients underwent surgery and 246 patients (65%) completed questionnaires, with 181 LA patients and 65 LN patients. Median follow-up was 83 months for LA and 179 months for LN (P < 0.001). A total of 218/245 (89%) reported major improvement in symptoms and 27 (11%) reported poor outcomes. There was no differences between LA and LN for symptom scores at short (<5 years) or long-term follow-up (>5 years). Women reported significantly higher DeMeester scores and lower satisfaction (P = 0.012). One hundred and eighteen (48%) patients were taking proton pump inhibitors (PPI) at follow-up despite high satisfaction rates. CONCLUSION: LA and LN have similar long-term results with patients reporting high satisfaction levels. Women reported more symptoms and less satisfaction than men. Despite high satisfaction rates a high percentage of patients take PPIs. PMID- 26478260 TI - Excited state nonadiabatic dynamics of bare and hydrated anionic gold clusters Au3(-)[H2O]n (n = 0-2). AB - We present a joint theoretical and experimental study of excited state dynamics in pure and hydrated anionic gold clusters Au3(-)[H2O]n (n = 0-2). We employ mixed quantum-classical dynamics combined with femtosecond time-resolved photoelectron spectroscopy in order to investigate the influence of hydration on excited state lifetimes and photo-dissociation dynamics. A gradual decrease of the excited state lifetime with the number of adsorbed water molecules as well as gold cluster fragmentation quenching by two or more water molecules are observed both in experiment and in simulations. Non-radiative relaxation and dissociation in excited states are found to be responsible for the excited state population depletion. Time constants of these two processes strongly depend on the number of water molecules leading to the possibility to modulate excited state dynamics and fragmentation of the anionic cluster by adsorption of water molecules. PMID- 26478262 TI - Genome-Wide Tuning of Protein Expression Levels to Rapidly Engineer Microbial Traits. AB - The reliable engineering of biological systems requires quantitative mapping of predictable and context-independent expression over a broad range of protein expression levels. However, current techniques for modifying expression levels are cumbersome and are not amenable to high-throughput approaches. Here we present major improvements to current techniques through the design and construction of E. coli genome-wide libraries using synthetic DNA cassettes that can tune expression over a ~10(4) range. The cassettes also contain molecular barcodes that are optimized for next-generation sequencing, enabling rapid and quantitative tracking of alleles that have the highest fitness advantage. We show these libraries can be used to determine which genes and expression levels confer greater fitness to E. coli under different growth conditions. PMID- 26478261 TI - Comparison of acute non-visual bright light responses in patients with optic nerve disease, glaucoma and healthy controls. AB - This study examined the effect of optic nerve disease, hence retinal ganglion cell loss, on non-visual functions related to melanopsin signalling. Test subjects were patients with bilateral visual loss and optic atrophy from either hereditary optic neuropathy (n = 11) or glaucoma (n = 11). We measured melatonin suppression, subjective sleepiness and cognitive functions in response to bright light exposure in the evening. We also quantified the post-illumination pupil response to a blue light stimulus. All results were compared to age-matched controls (n = 22). Both groups of patients showed similar melatonin suppression when compared to their controls. Greater melatonin suppression was intra individually correlated to larger post-illumination pupil response in patients and controls. Only the glaucoma patients demonstrated a relative attenuation of their pupil response. In addition, they were sleepier with slower reaction times during nocturnal light exposure. In conclusion, glaucomatous, but not hereditary, optic neuropathy is associated with reduced acute light effects. At mild to moderate stages of disease, this is detected only in the pupil function and not in responses conveyed via the retinohypothalamic tract such as melatonin suppression. PMID- 26478263 TI - [Blind]. PMID- 26478264 TI - Homophyly/Kinship Model: Naturally Evolving Networks. AB - It has been a challenge to understand the formation and roles of social groups or natural communities in the evolution of species, societies and real world networks. Here, we propose the hypothesis that homophyly/kinship is the intrinsic mechanism of natural communities, introduce the notion of the affinity exponent and propose the homophyly/kinship model of networks. We demonstrate that the networks of our model satisfy a number of topological, probabilistic and combinatorial properties and, in particular, that the robustness and stability of natural communities increase as the affinity exponent increases and that the reciprocity of the networks in our model decreases as the affinity exponent increases. We show that both homophyly/kinship and reciprocity are essential to the emergence of cooperation in evolutionary games and that the homophyly/kinship and reciprocity determined by the appropriate affinity exponent guarantee the emergence of cooperation in evolutionary games, verifying Darwin's proposal that kinship and reciprocity are the means of individual fitness. We propose the new principle of structure entropy minimisation for detecting natural communities of networks and verify the functional module property and characteristic properties by a healthy tissue cell network, a citation network, some metabolic networks and a protein interaction network. PMID- 26478265 TI - Cloning and functional characterization of Delta6 fatty acid desaturase (FADS2) in Eurasian perch (Perca fluviatilis). AB - The Eurasian perch (Perca fluviatilis) is a freshwater carnivorous species of high interest to diversify inland aquaculture. However, little is known about its ability to bioconvert polyunsaturated fatty acids (PUFAs) from plant oils into long chain polyunsaturated fatty acids (LC-PUFAs). In this study, special attention has been given to the fatty acid desaturase 2 (FADS2) which is commonly described to be a rate-limiting enzyme of the LC-PUFA biosynthesis. This work reports on the cloning, tissue expression and functional characterization of the Eurasian perch fads2, but also on the cloning of two alternative splicing transcripts named fads2-AS1 and fads2-AS2. The fads2 cDNA cloned is composed of an open reading frame (ORF) of 1338 nucleotides (nt) and encodes a protein of 445 amino acids. This deduced amino acid sequence displays the typical structure of microsomal FADS2 including two transmembrane domains and an N-terminal cytochrome b5 domain with the "HPGG" motif. Quantitative real-time PCR assay of fads2, fads2 AS1 and fads2-AS2 expressions revealed that the fads2 transcript was mainly expressed in the liver and intestine and exhibited a typical gene expression pattern of freshwater species while fads2-AS1 and fads2-AS2 genes were highly expressed in the brain, followed by the liver and intestine. Functional characterization of Eurasian perch FADS2 in transgenic yeast showed a fully functional Delta6 desaturation activity toward C18 PUFA substrates, without residual Delta5 and Delta8 desaturase activities. PMID- 26478266 TI - Identification of a soluble leptin receptor in crucian carp with different binding affinity to leptin-a and leptin-b. AB - Soluble leptin receptor (sLepR) is the main leptin-binding protein in plasma and contributes to activation of circulating leptin. In this study, we identified a sLepR in plasma of crucian carp (Carassius carassius) using a pull-down assay, and the interaction of sLepR with its ligand is confirmed by a cross-linking study. In addition, we found that leptin-a has higher affinity than leptin-b for sLepR. According to our knowledge, this is the first experimental report about the main ligand of sLepR in teleost. PMID- 26478267 TI - Magnesium Transporter 5 plays an important role in Mg transport for male gametophyte development in Arabidopsis. AB - During anther development the male gametophyte develops inside the locule and the tapetal cells provide all nutrients for its development. Magnesium Transporter 5 (MGT5) is a member of the MGT family and has dual functions of Mg export and import. Here, we show that male gametophyte mitosis and intine formation are defective in a mgt5 mutant. The transient expression of GFP-MGT5 revealed that MGT5 is localized in the plasma membrane. These findings suggest that in the male gametophyte MGT5 plays a role in importing Mg from the locule and that Mg is essential for male gametophyte development. The expression of MGT5 in the knockout ABORTED MICROSPORES (AMS) mutant (AMS being an essential regulator of tapetum) is tremendously reduced. Chromatin immunoprecipitation and mobility shift assay experiments demonstrated that AMS can directly bind the promoter of MGT5. An immunoelectron microscopy assay revealed that MGT5-His is localized to the plasma membrane of the tapetum. These findings suggest that AMS directly regulates MGT5 in the tapetum and thus induces export of Mg into the locule. The mgt5 plant exhibits severe male sterility while the expression of MGT5 under the tapetum-specific promoter A9 partly rescued mgt5 fertility. mgt5 fertility was restored under high-Mg conditions. These findings suggest that the mgt5 tapetum still has the ability to export Mg and that a sufficient supply of Mg from the tapetum can improve the importation of Mg in the mgt5 male gametophyte. Therefore, MGT5 plays an important role in Mg transport from the tapetum to the microspore. PMID- 26478268 TI - Unique insight into phase separation in polymer solar cells from their electric characteristics. AB - A series of polymer solar cells (PSCs) were fabricated with indene-C60 bisadduct (ICBA) or [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM) as an electron acceptor and with PBDT-TS1 as an electron donor. The donor/acceptor (D/A) phase separation was adjusted with different solution processing methods, consisting of cool (room temperature, 20 degrees C) solution, hot (70 degrees C) solution and the solutions with solvent additive 1,8-diiodideoctane (DIO). The champion PCE of PSCs with ICBA or PC61BM as an electron acceptor is 4.32% or 5.97% for the active layers prepared from hot solution with DIO additive or cool solution with DIO additive, respectively. The improved PCEs should be attributed to the optimized D/A phase separation in the active layers by adjusting the redistribution of PC61BM or the ICBA among the PBDT-TS1 networks. The degree of phase separation of the active layers with different acceptors was evaluated according to the current density-voltage (J-V) curves of hole-only and electron-only devices. The distribution of PC61BM or ICBA molecules in the normal direction can be simply judged from the symmetry degree of J-V curves of electron-only devices measured under the forward and reverse bias. PMID- 26478269 TI - Transatrial Pericardial Insufflation of Carbon Dioxide to Facilitate Percutaneous Pericardial Access for Ablation of Ventricular Tachycardia. PMID- 26478271 TI - Derivatization of steroids in biological samples for GC-MS and LC-MS analyses. AB - The determination of steroids in biological samples is essential in different areas of knowledge. MS combined with either GC or LC is considered the best analytical technique for specific and sensitive determinations. However, due to the physicochemical properties of some steroids, and the low concentrations found in biological samples, the formation of a derivative prior to their analysis is required. In GC-MS determinations, derivatization is needed for generating volatile and thermally stable compounds. The improvement in terms of stability and chromatographic retention are the main reasons for selecting the derivatization agent. On the other hand, derivatization is not compulsory in LC MS analyses and the derivatization is typically used for improving the ionization and therefore the overall sensitivity achieved. PMID- 26478270 TI - Human Mitochondrial DNA-Protein Complexes Attach to a Cholesterol-Rich Membrane Structure. AB - The helicase Twinkle is indispensable for mtDNA replication in nucleoids. Previously, we showed that Twinkle is tightly membrane-associated even in the absence of mtDNA, which suggests that Twinkle is part of a membrane-attached replication platform. Here we show that this platform is a cholesterol-rich membrane structure. We fractionated mitochondrial membrane preparations on flotation gradients and show that membrane-associated nucleoids accumulate at the top of the gradient. This fraction was shown to be highly enriched in cholesterol, a lipid that is otherwise low abundant in mitochondria. In contrast, more common mitochondrial lipids, and abundant inner-membrane associated proteins concentrated in the bottom-half of these gradients. Gene silencing of ATAD3, a protein with proposed functions related to nucleoid and mitochondrial cholesterol homeostasis, modified the distribution of cholesterol and nucleoids in the gradient in an identical fashion. Both cholesterol and ATAD3 were previously shown to be enriched in ER-mitochondrial junctions, and we detect nucleoid components in biochemical isolates of these structures. Our data suggest an uncommon membrane composition that accommodates platforms for replicating mtDNA, and reconcile apparently disparate functions of ATAD3. We suggest that mtDNA replication platforms are organized in connection with ER-mitochondrial junctions, facilitated by a specialized membrane architecture involving mitochondrial cholesterol. PMID- 26478272 TI - Fluorescence polarization measures energy funneling in single light-harvesting antennas--LH2 vs conjugated polymers. AB - Numerous approaches have been proposed to mimic natural photosynthesis using artificial antenna systems, such as conjugated polymers (CPs), dendrimers, and J aggregates. As a result, there is a need to characterize and compare the excitation energy transfer (EET) properties of various natural and artificial antennas. Here we experimentally show that EET in single antennas can be characterized by 2D polarization imaging using the single funnel approximation. This methodology addresses the ability of an individual antenna to transfer its absorbed energy towards a single pool of emissive states, using a single parameter called energy funneling efficiency (epsilon). We studied individual peripheral antennas of purple bacteria (LH2) and single CP chains of 20 nm length. As expected from a perfect antenna, LH2s showed funneling efficiencies close to unity. In contrast, CPs showed lower average funneling efficiencies, greatly varying from molecule to molecule. Cyclodextrin insulation of the conjugated backbone improves EET, increasing the fraction of CPs possessing epsilon = 1. Comparison between LH2s and CPs shows the importance of the protection systems and the protein scaffold of LH2, which keep the chromophores in functional form and at such geometrical arrangement that ensures excellent EET. PMID- 26478274 TI - Desymmetrized Vertex Design for the Synthesis of Covalent Organic Frameworks with Periodically Heterogeneous Pore Structures. AB - Two novel porous 2D covalent organic frameworks (COFs) with periodically heterogeneous pore structures were successfully synthesized through desymmetrized vertex design strategy. Condensation of C(2v) symmetric 5-(4 formylphenyl)isophthalaldehyde or 5-((4-formylphenyl)ethylene)isophthalaldehyde with linear hydrazine linker under the solvothermal or microwave heating conditions yields crystalline 2D COFs, HP-COF-1 and HP-COF-2, with high specific surface areas and dual pore structures. PXRD patterns and computer modeling study, together with pore size distribution analysis confirm that each of the resulting COFs exhibits two distinctively different hexagonal pores. The structures were characterized by FT-IR, solid state (13)C NMR, gas adsorption, SEM, TEM, and theoretical simulations. Such rational design and synthetic strategy provide new possibilities for preparing highly ordered porous polymers with heterogeneous pore structures. PMID- 26478273 TI - High-performance mussel-inspired adhesives of reduced complexity. AB - Despite the recent progress in and demand for wet adhesives, practical underwater adhesion remains limited or non-existent for diverse applications. Translation of mussel-inspired wet adhesion typically entails catechol functionalization of polymers and/or polyelectrolytes, and solution processing of many complex components and steps that require optimization and stabilization. Here we reduced the complexity of a wet adhesive primer to synthetic low-molecular-weight catecholic zwitterionic surfactants that show very strong adhesion (~50 mJ m(-2)) and retain the ability to coacervate. This catecholic zwitterion adheres to diverse surfaces and self-assembles into a molecularly smooth, thin (<4 nm) and strong glue layer. The catecholic zwitterion holds particular promise as an adhesive for nanofabrication. This study significantly simplifies bio-inspired themes for wet adhesion by combining catechol with hydrophobic and electrostatic functional groups in a small molecule. PMID- 26478275 TI - Applying a novel electrostatic dry powder coating technology to pellets. AB - The present study aimed to apply a novel dry powder technology to coat pellets with different coating materials grounded into fine powders. Piroxicam, a non steroidal anti-inflammatory drug, was used as the active pharmaceutical ingredient (API). Eudragit(r) EPO, Eudragit(r) RS/RL and Acryl EZE were used as the coating materials to achieve immediate release, sustained release and delayed release, respectively. Three steps including preheating, powder adhesion and curing were carried out to form the coating film while liquid plasticizers were used to decrease the glass transition temperature of coating powders and also served to reduce the electrical resistance of pellets. Results of SEM indicated coating film could be better formed by increasing curing temperature or extending curing time. Dissolution tests showed that three different drug release profiles, including immediate release, sustained release and delayed release, were achieved by this coating technology with different coating formulations. And the dry powder coated pellets using this developed technology exhibited an excellent stability with 1 month at 40 degrees C/75% RH. The coating procedure could be shortened to within 120 min and the use of fluidized hot air was minimized, both cutting down the overall cost dramatically compared to organic solvent coating and aqueous coating. All results demonstrated that the novel electrostatic dry powder coating method is a promising technology in the pharmaceutical coating industry. PMID- 26478276 TI - In vivo efficacy and bioavailability of lumefantrine: Evaluating the application of Pheroid technology. AB - The oral absorption of compounds with low aqueous solubility, such as lumefantrine, is typically limited by the dissolution rate in the gastro intestinal tract, resulting in erratic absorption and highly variable bioavailability. In previous studies we reported on the ability of Pheroid vesicles to improve the bioavailability of poorly soluble drugs. In the present study a Pro-Pheroid formulation, a modification of the previous formulation, was applied to improve the solubility of lumefantrine after oral administration and compared to lumefantrine in DMSO:water (1:9 v/v) solution (reference solution). A bioavailability study of lumefantrine was conducted in a mouse model in fed and fasted states. When using the reference solution, the bioavailability of the lumefantrine heavily depended on food intake, resulting in a 2.7 times higher bioavailability in the fed state when compared to the fasted state. It also showed large between-subject variability. When formulated using Pro-Pheroid, the bioavailability of lumefantrine was 3.5 times higher as compared to lumefantrine in the reference solution and fasting state. Pro-Pheroid also dramatically reduced the effects of food intake and the between-subject variability for bioavailability observed with the reference. In vivo antimalarial efficacy was also evaluated with lumefantrine formulated using Pro-Pheroid technology compared to the reference solution. The results indicated that lumefantrine in Pro-Pheroid formulation exhibited improved antimalarial activity in vitro by 46.8%, when compared to the reference. The results of the Peters' 4-day suppressive test indicated no significant difference in the efficacy or mean survival time of the mice in the Pro-Pheroid formulation and reference test groups when compared to the positive control, chloroquine. These findings suggest that using the Pro Pheroid formulation improves the bioavailability of lumefantrine, eliminates the food effect associated with lumefantrine as well as significantly reduces the between subject variability in bioavailability when compared to the reference solution. PMID- 26478277 TI - Training of resistance to proactive interference and working memory in older adults: a randomized double-blind study. AB - BACKGROUND: Working memory (WM) performance is often decreased in older adults. Despite the growing popularity of WM trainings, underlying mechanisms are still poorly understood. Resistance to proactive interference (PI) constitutes a candidate process that contributes to WM performance and might influence training or transfer effects. Here, we investigated whether PI resistance can be enhanced in older adults using a WM training with specifically increased PI-demands. Further, we investigated whether potential effects of such a training were stable and entailed any transfer on non-trained tasks. METHOD: Healthy old adults (N = 25, 68.8 +/- 5.5 years) trained with a recent-probes and an n-back task daily for two weeks. Two different training regimens (high vs. low PI-amount in the tasks) were applied as between-participants manipulation, to which participants were randomly assigned. Near transfer tasks included interference tasks; far transfer tasks assessed fluid intelligence (gF) or speed. Immediate transfer was assessed directly after training; a follow-up measurement was conducted after two months. RESULTS: Both groups similarly improved in PI resistance in both training tasks. Thus, PI susceptibility was generally reduced in the two training groups and there was no difference between WM training with high versus low PI demands. Further, there was no differential near or far transfer on non-trained tasks, neither immediately after the training nor in the follow-up. CONCLUSION: PI demands in WM training tasks do not seem critical for enhancing WM performance or PI resistance in older adults. Instead, improved resistance to PI appears to be an unspecific side-effect of a WM training. PMID- 26478278 TI - Unseeded Inertial Cavitation for Enhancing the Delivery of Chemotherapies: A Safety Study. AB - Acoustic cavitation can improve local drug delivery in tumors. Without injected external nucleation agents, initiating inertial cavitation requires high negative pressures, which can lead to biological damage. In the present study, unseeded inertial cavitation was obtained in vivo using confocal beams, and the effect of these exposure conditions was assessed on drug structure and activity, shallow tissues and growth of breast tumors. No change was observed in the structure and cytotoxicity of doxorubicin. Experiments were conducted on healthy rats, exposing the thigh and abdomen. Histologic analyses at 72 h and 2 weeks post-treatment demonstrated a modest impact on tissues. Syngeneic 4 T1 breast tumors in mice were sonicated. Immunohistochemical analyses showed that ultrasound did not impact vascular density, proliferation and apoptosis of cancer cells. In addition, ultrasound did not negatively modify cancer cell spreading to the lungs and bone marrow. This provides evidence that these particular parameters can be used safely in vivo. PMID- 26478279 TI - Clinical Application of Superior Vena Cava Spectra in Evaluation of Pulmonary Hypertension: A Comparative Echocardiography and Catheterization Study. AB - This study was designed to assess whether superior vena cava (SVC) Doppler flow velocities are associated with invasive measures of pulmonary arterial pressure. Eighty patients with unrepaired congenital heart disease who underwent cardiac catheterization were included (31 men, 49 women; mean age: 37.3 +/- 14.7 y). Compared with the non-pulmonary hypertension group, the moderate and severe pulmonary hypertension groups had decreased SVC ventricular reserve flow velocity and a significantly increased ratio of atrial reverse flow to systolic flow (AR/S). AR/S correlated significantly with invasive pulmonary arterial systolic pressure (r = 0.426, p < 0.0001). A cutoff of 0.45 had a sensitivity and specificity of 74% and 80%, respectively, for prediction of pulmonary hypertension. Good correlation also existed between SVC AR/S and pulmonary arterial systolic pressure in cases without tricuspid regurgitation (r = 0.706, p = 0.034). These results indicate that SVC AR/S may be an alternative method for assessing pulmonary hypertension. PMID- 26478280 TI - Formation of carrageenan-CaCO3 bioactive membranes. AB - The high biocompatibility and resorbability of polymeric membranes have encouraged their use to manufacture medical devices. Here, we report on the preparation of membranes consisting of carrageenan, a naturally occurring sulfated polysaccharide that forms helical structures in the presence of calcium ions. We incorporated CaCO3 particles into the membranes to enhance their bioactivity and mechanical properties. Infrared spectroscopy and X-ray diffraction data confirmed CaCO3 incorporation into the polymeric matrix. We tested the bioactivity of the samples by immersing them in a solution that mimics the ionic composition and pH of the human body fluid. The hybrid membranes generated hydroxyapatite, as attested by X-ray diffraction data. Scanning electron and atomic force microscopies aided investigation of membrane topography before and after CaCO3 deposition. The wettability and surface free energy, evaluated by contact angle measures, increased in the presence of CaCO3 particles. These parameters are important for membrane implantation in the body. Moreover, membrane stiffness was up to 110% higher in the presence of the inorganic particles, as revealed by Young's modulus. PMID- 26478281 TI - The organic interlamellar layer in abalone nacre: Formation and mechanical response. AB - The interlamellar organic layer plays a key role in establishing the tensile mechanical response of nacre, while changing the compressive response in only a marginal manner. We conduct observations on the epithelial layer of the abalone foot in direct contact with the extrapallial layer where the deposition process takes place and identify cilia, microvilli, and secretory cells which determine the deposition of chitin to form the interlamellar organic layer. On the basis of these observations we propose a mechanism for the deposition of interlamellar organic layers. We show that the fraction of pores, as well as their diameter, grow rapidly as the interlamellar layer is extended uniaxially or biaxially, and compare these calculations with the observed values. In the calculations we assume a Poisson's ratio equal to zero in the plane of the lamellae. This assumption is justified by the thickness of the organic layer (20-50 nm) being equal to twice the diameter of the chitin fibrils; consequently the expansion of the membrane occurs at a constant thickness. As an illustration of this effect, an externally applied strain of 0.5 increases the initial pore diameter (typically equal to 20-50 nm) to a value of ten times (0.2-0.5 MUm). These calculations explain the observations of large pores reported in the literature and interpret them as the result of externally applied loads. PMID- 26478282 TI - Enhanced growth of neural networks on conductive cellulose-derived nanofibrous scaffolds. AB - The problem of recovery from neurodegeneration needs new effective solutions. Tissue engineering is viewed as a prospective approach for solving this problem since it can help to develop healthy neural tissue using supportive scaffolds. This study presents effective and sustainable tissue engineering methods for creating biomaterials from cellulose that can be used either as scaffolds for the growth of neural tissue in vitro or as drug screening models. To reach this goal, nanofibrous electrospun cellulose mats were made conductive via two different procedures: carbonization and addition of multi-walled carbon nanotubes. The resulting scaffolds were much more conductive than untreated cellulose material and were used to support growth and differentiation of SH-SY5Y neuroblastoma cells. The cells were evaluated by scanning electron microscopy and confocal microscopy methods over a period of 15 days at different time points. The results showed that the cellulose-derived conductive scaffolds can provide support for good cell attachment, growth and differentiation. The formation of a neural network occurred within 10 days of differentiation, which is a promising length of time for SH-SY5Y neuroblastoma cells. PMID- 26478283 TI - Structure, mechanical characteristics and in vitro degradation, cytotoxicity, genotoxicity and mutagenicity of novel biodegradable Zn-Mg alloys. AB - Zn-(0-1.6)Mg (in wt.%) alloys were prepared by hot extrusion at 300 degrees C. The structure, mechanical properties and in vitro biocompatibility of the alloys were investigated. The hot-extruded magnesium-based WE43 alloy was used as a control. Mechanical properties were evaluated by hardness, compressive and tensile testing. The cytotoxicity, genotoxicity (comet assay) and mutagenicity (Ames test) of the alloy extracts and ZnCl2 solutions were evaluated with the use of murine fibroblasts L929 and human osteosarcoma cell line U-2 OS. The microstructure of the Zn alloys consisted of recrystallized Zn grains of 12 MUm in size and fine Mg2Zn11 particles arranged parallel to the hot extrusion direction. Mechanical tests revealed that the hardness and strength increased with increasing Mg concentration. The Zn-0.8 Mg alloys showed the best combination of tensile mechanical properties (tensile yield strength of 203 MPa, ultimate tensile strength of 301 MPa and elongation of 15%). At higher Mg concentrations the plasticity of Zn-Mg alloys was deteriorated. Cytotoxicity tests with alloy extracts and ZnCl2 solutions proved the maximum safe Zn(2+) concentrations of 120 MUM and 80 MUM for the U-2 OS and L929 cell lines, respectively. Ames test with extracts of alloys indicated that the extracts were not mutagenic. The comet assay demonstrated that 1-day extracts of alloys were not genotoxic for U-2 OS and L929 cell lines after 1-day incubation. PMID- 26478285 TI - Bark extract mediated green synthesis of silver nanoparticles: Evaluation of antimicrobial activity and antiproliferative response against osteosarcoma. AB - In the current investigation we report the biosynthesis potentials of bark extracts of Ficus benghalensis and Azadirachta indica for production of silver nanoparticle without use of any external reducing or capping agent. The appearance of dark brown color indicated the complete nanoparticle synthesis which was further validated by absorbance peak by UV-vis spectroscopy. The morphology of the synthesized particles was characterized by Field emission- scanning electron microscopy (Fe-SEM) and atomic force microscopy (AFM). The X ray diffraction (XRD) patterns clearly illustrated the crystalline phase of the synthesized nanoparticles. ATR-Fourier Transform Infrared (ATR-FTIR) spectroscopy was performed to identify the role of various functional groups in the nanoparticle synthesis. The synthesized nanoparticles showed promising antimicrobial activity against Gram negative (Escherichia coli, Pseudomonas aeruginosa and Vibrio cholerae) and Gram positive (Bacillus subtilis) bacteria. The synthesized nano Ag also showed antiproliferative activity against MG-63 osteosarcoma cell line in a dose dependent manner. Thus, these synthesized Ag nanoparticles can be used as a broad spectrum therapeutic agent against osteosarcoma and microorganisms. PMID- 26478284 TI - Green synthesis of silver nanoparticles using Coffea arabica seed extract and its antibacterial activity. AB - A novel green source was opted to synthesize silver nanoparticles using dried roasted Coffea arabica seed extract. Bio-reduction of silver was complete when the mixture (AgNO3+extract) changed its color from light to dark brown. UV-vis spectroscopy result showed maximum adsorption at 459 nm, which represents the characteristic surface plasmon resonance of nanosilver. X-ray crystal analysis showed that the silver nanoparticles are highly crystalline and exhibit a cubic, face centered lattice with characteristic (111), (200), (220) and (311) orientations. Particles exhibit spherical and ellipsoidal shaped structures as observed from TEM. Composition analysis obtained from SEM-EDXA confirmed the presence of elemental signature of silver. FTIR results recorded a downward shift of absorption bands between 800-1500 cm(-1) indicting the formation of silver nanoparticles. The mean particle size investigated using DLS was found to be in between 20-30 nm respectively. Anti-bacterial activity of silver nanoparticles on E. coli and S. aureus demonstrated diminished bacterial growth with the development of well-defined inhibition zones. PMID- 26478286 TI - Construction of a sensitive and selective sensor for morphine using chitosan coated Fe3O4 magnetic nanoparticle as a modifier. AB - A simple and sensitive sensor based on carbon paste electrode (CPE) modified by chitosan-coated magnetic nanoparticle (CMNP) was developed for the electrochemical determination of morphine (MO). The proposed sensor was characterized with scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS). The electrooxidation of MO was studied on modified carbon paste electrode using cyclic voltammetry, chronoamperometry and differential pulse voltammetry as diagnostic techniques. The oxidation peak potential of morphine on the CMNP/CPE appeared at 380 mV which was accompanied with smaller overpotential and increase in oxidation peak current compared to that obtained on the bare carbon paste electrode (CPE). Under optimum conditions the sensor provides two linear DPV responses in the range of 10-2000 nM and 2-720 MUM for MO with a detection limit of 3 nM. The proposed sensor was successfully applied for monitoring of MO in serum and urine samples and satisfactory results were obtained. PMID- 26478288 TI - Square wave voltammetric determination of paracetamol at chitosan modified carbon paste electrode: Application in natural water samples, commercial tablets and human urines. AB - A novel analytical approach has been developed and evaluated for the quantitative analysis of paracetamol (PCT). The anodic peak currents of paracetamol on the CS CPE were about 200 fold higher than that of the unmodified electrodes. The influence of various parameters on the CS-CPE was investigated. Under the optimized working conditions, the oxidation peak current is linear to the paracetamol concentration in the ranges of 1.0 * 10(-3)-4.0 * 10(-4)mol L(-1) and 2.0 * 10(-4)-8.0 * 10(-7)mol L(-1) with a detection limit of 5.08 * 10(-7)mol L( 1). The repeatability of the method expressed as relative standard deviation (RSD) is 1.73% (n=8). Possible interferences were tested and evaluated in 1.0 * 10(-4)mol L(-1) paracetamol in the presence of inorganic ions, dopamine, ibuprofen, ascorbic acid and uric acid. The proposed method was successfully applied to PCT determination in natural waters, tablets and urine samples. PMID- 26478287 TI - Policaprolactone/polyvinylpyrrolidone/siloxane hybrid materials: Synthesis and in vitro delivery of diclofenac and biocompatibility with periodontal ligament fibroblasts. AB - In this paper, we report the synthesis of polycaprolactone (PCL) based hybrid materials containing hydrophilic domains composed of N-vinylpyrrolidone (VP), and gamma-methacryloxypropyltrimethoxysilane (MPS). The hybrid materials were obtained by RAFT copolymerization of N-vinylpyrrolidone and MPS using a pre formed dixanthate-end-functionalized PCL as macro-chain transfer agent, followed by a post-reaction crosslinking step. The composition of the samples was determined by elemental and thermogravimetric analyses. Differential scanning calorimetry and X-ray diffraction indicated that the crystallinity of PCL decreases in the presence of the hydrophilic domains. Scanning electron microscopy images revealed that the samples present an interconnected porous structure on the swelling. Compared to PCL, the hybrid materials presented low water contact angle values and higher elastic modulus. These materials showed controlled release of diclofenac, and biocompatibility with human periodontal ligament fibroblasts. PMID- 26478289 TI - Covalent immobilization of lysozyme onto woven and knitted crimped polyethylene terephthalate grafts to minimize the adhesion of broad spectrum pathogens. AB - Graft-associated infections entirely determine the short-term patency of polyethylene terephthalate PET cardiovascular graft. We attempted to enzymatically inhibit the initial bacterial adhesion to PET grafts using lysozyme. Lysozyme was covalently immobilized onto woven and knitted forms of crimped PET grafts by the end-point method. Our figures of merit revealed lysozyme immobilization yield of 15.7 MUg/cm(2), as determined by the Bradford assay. The activity of immobilized lysozyme on woven and knitted PET manifested 58.4% and 55.87% using Micrococcus lysodeikticus cells, respectively. Noteworthy, the adhesion of vein catheter-isolated Staphylococcus epidermidis decreased by 6- to 8-folds and of Staphylococcus aureus by 11- to 12-folds, while the Gram negative Escherichia coli showed only a decrease by 3- to 4-folds. The anti adhesion efficiency was specific for bacterial cells and no significant effect was observed on adhesion and growth of L929 cells. In conclusion, immobilization of lysozyme onto PET grafts can inhibit the graft-associated infection. PMID- 26478290 TI - Changes in the drug release pattern of fresh and set simvastatin-loaded brushite cement. AB - Calcium phosphate cements are synthetic bone graft substitutes able to set at physiological conditions. They can be applied by minimally invasive surgery and can also be used as drug delivery systems. Consequently, the drug release pattern from the cement paste (fresh cement) is of high clinical interest. However, previous studies have commonly evaluated the drug release using pre-set cements only. Therefore, the aim of this work was to determine if the time elapsed from cement preparation until immersion in the solution (3 min for fresh cements, and 1h and 15 h for pre-set cements) had an influence on its physical properties, and correlating these to the drug release profile. Simvastatin was selected as a model drug, while brushite cement was used as drug carrier. This study quantified how the setting of a material reduces the accessibility of the release media to the material, thus preventing drug release. A shift in the drug release pattern was observed, from a burst-release for fresh cements to a sustained release for pre-set cements. PMID- 26478291 TI - Direct electrochemistry of hemoglobin and biosensing for hydrogen peroxide using a film containing silver nanoparticles and poly(amidoamine) dendrimer. AB - A new architecture for a biosensor is proposed using a glassy carbon electrode (GCE) modified with hemoglobin (Hb) and silver nanoparticles (AgNPs) encapsulated in poly(amidoamine) dendrimer (PAMAM). The biosensors were characterized using ultraviolet-visible spectroscopy, zeta-potential and cyclic voltammetry to investigate the interactions between Hb, AgNPs and the PAMAM film. The biosensor exhibited a well-defined cathodic peak attributed to reduction of the Fe(3+) present in the heme group in Hb, as revealed by cyclic voltammetry in the presence of O2. An apparent heterogeneous electron transfer rate of 4.1s(-1) was obtained. The Hb-AgNPs-PAMAM/GCE third generation biosensor was applied in the amperometric determination of hydrogen peroxide over the linear range from 6.0 * 10(-6) to 9.1 * 10(-5)mol L(-1) with a detection limit of 4.9 * 1 0(-6)mol L(-1). The proposed method can be extended to immobilize and evaluate the direct electron transfer of other redox enzymes. PMID- 26478292 TI - Phenylboronic acid functionalized reduced graphene oxide based fluorescence nano sensor for glucose sensing. AB - Reduced graphene has emerged as promising tools for detection based application of biomolecules as it has high surface area with strong fluorescence quenching property. We have used the concept of fluorescent quenching property of reduced graphene oxide to the fluorescent probes which are close vicinity of its surface. In present work, we have synthesized fluorescent based nano-sensor consist of phenylboronic acid functionalized reduced graphene oxide (rGO-PBA) and di-ol modified fluorescent probe for detection of biologically important glucose molecules. This fluorescent graphene based nano-probe has been characterized by high resolution transmission electron microscope (HRTEM), Atomic force microscope (AFM), UV-visible, Photo-luminescence (PL) and Fourier transformed infrared (FT IR) spectroscopy. Finally, using this PBA functionalized reduced GO based nano sensor, we were able to detect glucose molecule in the range of 2 mg/mL to 75 mg/mL in aqueous solution of pH7.4. PMID- 26478293 TI - Bioactivity response of Ta1-xOx coatings deposited by reactive DC magnetron sputtering. AB - The use of dental implants is sometimes accompanied by failure due to periimplantitis disease and subsequently poor esthetics when soft-hard tissue margin recedes. As a consequence, further research is needed for developing new bioactive surfaces able to enhance the osseous growth. Tantalum (Ta) is a promising material for dental implants since, comparing with titanium (Ti), it is bioactive and has an interesting chemistry which promotes the osseointegration. Another promising approach for implantology is the development of implants with oxidized surfaces since bone progenitor cells interact with the oxide layer forming a diffusion zone due to its ability to bind with calcium which promotes a stronger bond. In the present report Ta-based coatings were deposited by reactive DC magnetron sputtering onto Ti CP substrates in an Ar+O2 atmosphere. In order to assess the osteoconductive response of the studied materials, contact angle and in vitro tests of the samples immersed in Simulated Body Fluid (SBF) were performed. Structural results showed that oxide phases where achieved with larger amounts of oxygen (70 at.% O). More compact and smooth coatings were deposited by increasing the oxygen content. The as-deposited Ta coating presented the most hydrophobic character (100 degrees ); with increasing oxygen amount contact angles progressively diminished, down to the lowest measured value, 63 degrees . The higher wettability is also accompanied by an increase on the surface energy. Bioactivity tests demonstrated that highest O-content coating, in good agreement with wettability and surface energy values, showed an increased affinity for apatite adhesion, with higher Ca/P ratio formation, when compared to the bare Ti substrates. PMID- 26478294 TI - The outermost surface properties of silk fibroin films reflect ethanol-treatment conditions used in biomaterial preparation. AB - Silk fibroin has attracted interest as a biomaterial, given its many excellent properties. Cell attachment to silk substrates is usually weaker than to standard culture dishes, and cells cultured on silk films or hydrogels typically form spheroids and micro-aggregates. However, too little is known about the higher order structures and behavior of fibroin under different conditions to explain the features of silk fibroin as a culture substrate. For instance, different biomaterial surfaces, with distinct effects on cell culture, can be achieved by varying the conditions of crystallization by alcohol immersion. Here, we show that treatment of fibroin film with <80% ethanol results in a jelly-like, hydrated hydrogel as the outermost surface layer; fibroblasts preferably aggregate, rather than attach individually to such a hydrogel surface, and therefore aggregate into spheroids. In contrast, a fibroin film treated with >90% ethanol has a harder surface than the <80% ethanol-treated fibroin, to which individual cells prefer to attach (and then expand on the surface), rather than to aggregate. We discuss the influence of alcohol concentration on the surface properties, based on surface analysis of the films. The surface analysis involved assessment of static and dynamic contact angles, zeta potential, changes in crystallinity and microscopic morphology of electrospun fibers, and texture changes of the outermost surface at a nanometer-scale captured by a scanning probe microscope. PMID- 26478295 TI - Formation of stacked luminescent complex of 8-hydroxyquinoline molecules on hydroxyapatite coating by using cold isostatic pressing. AB - Cold isostatic pressing successfully formed a chelate complex of 8 hydroxyquinoline (8 Hq) molecules on plasma-sprayed hydroxyapatite (HAp) coating by solid-state reaction. The complex emits a fluorescence peak at approximately 500 nm by UV irradiation. The red shift of the fluorescence was newly observed in the cases of highly compressed complex due to pi - pi stacking of aromatic ring in the molecular structure of 8 Hq. The immersed complex coating in Simulated Body Fluid (SBF) demonstrated amorphous apatite precipitation and kept its fluorescence property. PMID- 26478296 TI - Improving blood-compatibility via surface heparin-immobilization based on a liquid crystalline matrix. AB - Blood compatibility is of considerable importance in developing medical materials and devices that are in contact with blood. In this work, we successfully developed a novel liquid crystalline heparin-immobilized material (Hep-OPPC) by two-step modification for further improvement of hydrophilicity and hemocompatibility of the liquid crystalline hydroxypropyl cellulose ester (OPCL). The results showed that Hep-immobilization on the OPCL led to dramatic changes in the surface morphology and crystallinity, whereas, the Hep-OPPCs also maintained the liquid crystalline feature at room temperature after heparinization. Furthermore, the hemocompatibility of the Hep-OPPCs was markedly enhanced at low levels of hemolysis assay (HR) with unimpaired erythrocytomorphology, significantly lower concentrations of C3a in blood plasma and remarkable increases in plasma re-calcification time (PRT). This suggests that the heparinized surface could restrict the transformation of fibrinogen with less activation of the intrinsic coagulation system. Moreover, the activated partial thromboplastin time (APTT) and prothrombin time (PT) values of the Hep-OPPCs with low heparin density could also be prolonged in this study suggesting that the liquid crystal feature of the matrix might be blocking the clotting factors. We concluded that the heparin-immobilized liquid crystalline material has the potential to be used in blood-contact materials. PMID- 26478297 TI - Role of heat on the development of electrochemical sensors on bare and modified Co3O4/CuO composite nanopowder carbon paste electrodes. AB - The Co3O4/CuO composite nanopowder (NP) was synthesized by a mechanochemical method and characterized by using powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS). The synthesized Co3O4/CuO NP was used as a modified carbon paste electrode (MCPE) and further the bare carbon paste and Co3O4/CuO NP modified carbon paste was heated at different temperatures (100, 150, 200 and 250 degrees C) for 10 min. The Co3O4/CuO NP MCPE was used to study the consequences of scan rate and dopamine concentration. Furthermore the preheated modified electrodes were used to study the electrochemical response to dopamine (DA), ascorbic acid (AA) and uric acid (UA). PMID- 26478298 TI - Time-dependent rheological behaviour of bacterial cellulose hydrogel. AB - This work focuses on time-dependent rheological behaviour of bacterial cellulose (BC) hydrogel. Due to its ideal biocompatibility, BC hydrogel could be employed in biomedical applications. Considering the complexity of loading conditions in human body environment, time-dependent behaviour under relevant conditions should be understood. BC specimens are produced by Gluconacetobacter xylinus ATCC 53582 at static-culture conditions. Time-dependent behaviour of specimens at several stress levels is experimentally determined by uniaxial tensile creep tests. We use fraction-exponential operators to model the rheological behaviour. Such a representation allows combination of good accuracy in analytical description of viscoelastic behaviour of real materials and simplicity in solving boundary value problems. The obtained material parameters allow us to identify time-dependent behaviour of BC hydrogel at high stress level with sufficient accuracy. PMID- 26478299 TI - Electrochemical & osteoblast adhesion study of engineered TiO2 nanotubular surfaces on titanium alloys. AB - TiO2 nanotubes were grafted on the surface of cpTi, Ti6Al4V and Ti6Al4V-ELI with the aim to provide a new podium for human pre-osteoblast cell (MC3T3) adhesion and proliferation. The surface morphology and chemistry of these alloys were examined with scanning electron microscopy and energy dispersive x-ray spectroscopy. TiO2 nanotubes were further characterized by cyclic potentiodynamic polarization tests and electrochemical impedance spectroscopy. The vertically aligned nanotubes were subjected to pre-osteoblast cell proliferation in order to better understand cell-material interaction. The study demonstrated that these cells interact differently with nanotubes of different titanium alloys. The significant acceleration in the growth rate of pre-osteoblast cell adhesion and proliferation is also witnessed. Additionally, the cytotoxicity of the leached metal ions was evaluated by using a tetrazolium-based bio-assay, MTS. Each group of data was operated for p<0.05, concluded one way ANOVA to investigate the significance difference. PMID- 26478300 TI - Sustained release of hydrophilic drug from polyphosphazenes/poly(methyl methacrylate) based microspheres and their degradation study. AB - Drug delivery system is referred as an approach to deliver the therapeutic agents to the target site safely in order to achieve the maximum therapeutic effects. In this perspective, synthesis of three new polyphosphazenes and their blend fabrication system with poly(methyl methacrylate) is described and characterized with (1)H NMR, (31)P NMR, GPC and DSC. Furthermore, these novel blends were used to fabricate microspheres and evaluated for sustain release of hydrophilic drug (aspirin as model drug). Microspheres of the two blends showed excellent encapsulation efficacy (about 93%), controlled burst release (2.3% to 7.93%) and exhibited sustain in vitro drug release (13.44% to 32.77%) up to 218 h. At physiological conditions, the surface degradation of microspheres and diffusion process controlled the drug release sustainability. Furthermore, it was found that the degree of porosity was increased with degradation and the resulting porous network was responsible for water retention inside the microspheres. The percentage water retention was found to be interrelated with degradation time and percentage drug release. PMID- 26478301 TI - Physicochemical properties and bioactivity of freeze-cast chitosan nanocomposite scaffolds reinforced with bioactive glass. AB - Chitosan based nanocomposite scaffolds were prepared by freeze casting method through blending constant chitosan concentration with different portions of synthesized bioactive glass nanoparticles (BGNPs). Transmission Electron Microscopy (TEM) image showed that the particles size of bioactive glass (64SiO2.28CaO.8P2O5) prepared by sol-gel method was approximately less than 20 nm. Fourier Transform Infrared Spectroscopy (FT-IR) and X-ray Diffraction (XRD) analysis showed proper interfacial bonding between BGNPs and chitosan polymers. Scanning Electron Microscopy (SEM) images depicted a unidirectional structure with homogenous distribution of BGNPs among chitosan matrix associated with the absence of pure chitosan scaffold's wall pores after addition of only 10 wt.% BGNPs. As the BGNP content increased from 0 to 50 wt.%, the compressive strength and compressive module values increased from 0.034 to 0.419 MPa and 0.41 to 10.77 MPa, respectively. Biodegradation study showed that increase in BGNP content leads to growth of weight loss amount. The in vitro biomineralization studies confirmed the bioactive nature of all nanocomposites. Amount of 30 wt.% BGNPs represented the best concentration for absorption capacity and bioactivity behaviors. PMID- 26478302 TI - Ferrimagnetic nanocrystal assemblies as versatile magnetic particle hyperthermia mediators. AB - Colloidal nanocrystal assemblies (nanoclusters), consisting of 13 nm iron oxide nanocrystals, were synthesized in various sizes (45-98 nm), and were investigated as heating mediators for magnetic particle hyperthermia. The colloidal nanocrystal clusters show enhanced heating efficiency in comparison with their constituent primary iron oxide nanocrystals due to collective magnetic features. The fine tuning of intra-cluster magnetic interactions results to the domination of the hysteresis losses mechanism over the relaxation loss heating contributions and eventually to a versatile magnetic particle hyperthermia mediator. PMID- 26478303 TI - Influence of Cu doping in borosilicate bioactive glass and the properties of its derived scaffolds. AB - Copper doped borosilicate glasses (BG-Cu) were studied by means of FT-IR, Raman, UV-vis and NMR spectroscopies to investigate the changes that appeared in the structure of borosilicate glass matrix by doping copper ions. Micro-fil and immunohistochemistry analysis were applied to study the angiogenesis of its derived scaffolds in vivo. Results indicated that the Cu ions significantly increased the B-O bond of BO4 groups at 980 cm(-1), while they decrease that of BO2O(-) groups at 1440-1470 cm(-1) as shown by Raman spectra. A negative shift was observed from (11)B and (29)Si NMR spectra. The (11)B NMR spectra exhibited a clear transformation from BO3 into BO4 groups, caused by the agglutination effect of the Cu ions and the charge balance of the agglomerate in the glass network, leading to a more stable glass network and lower ions release rate in the degradation process. Furthermore, the BG-Cu scaffolds significantly enhanced blood vessel formation in rat calvarial defects at 8 weeks post-implantation. Generally, it suggested that the introduction of Cu into borosilicate glass endowed glass and its derived scaffolds with good properties, and the cooperation of Cu with bioactive glass may pave a new way for tissue engineering. PMID- 26478304 TI - Functionalization of polycaprolactone/hydroxyapatite scaffolds with Usnea lethariiformis extract by using supercritical CO2. AB - Investigation of an integrated supercritical fluid extraction and supercritical solvent impregnation process for fabrication of microporous polycaprolactone hydroxyapatite (PCL-HA) scaffolds with antibacterial activity is presented. The HA content and particle size as well as the operating conditions of the integrated process is optimized regarding the amount of impregnated antibacterial agent (Usnea lethariiformis extract) in the PCL-HA matrix, scaffold morphology and antibacterial activity against methicillin resistant Staphylococcus aureus (MRSA) strains. High pressure differential scanning calorimetry (HP-DSC) assay reveals that an increasing amount of HA results in decreasing melting temperature as well as crystallinity at an operating pressure of 17 MPa. The PCL-HA composites with micrometric sizes of the HA particles are convenient for being processed by the integrated process due to the simple preparation, a good interaction between the PCL matrix and filler and the advantageous impact on sorption. The scaffold obtained from PCL-HA with 20% of the HA shows the highest impregnation yield at 17 MPa and 35 degrees C (5.9%) and subsequently also the best bactericidal effect on the tested MRSA strains at an initial bacterial inoculum of 2 * 10(-4)CFU/mL. PMID- 26478305 TI - Tuning anatase and rutile phase ratios and nanoscale surface features by anodization processing onto titanium substrate surfaces. AB - Both the anatase (A) and rutile (R) phases of titanium oxide have shown enhanced antimicrobial and bioactivity levels but the specific A/R phase ratio needed for the best results is still unknown. In this study titanium samples were anodized to produce specific ratios of anatase and rutile phases within the oxide layers. Specific ratios produced included maximum A minimum R, minimum A maximum R, 50% A 50% R, minimum A minimum R, and a non-anodized titanium control group. Samples were characterized for phase distributions within the oxide layers, surface porosity, corrosion resistance, and bioactivity. Results indicated the targeted phase ratios were reproducibly achieved during the anodization process. Samples containing the highest levels of anatase showed the largest individual pore sizes, but a lower overall percent porosity value compared to samples containing higher rutile levels. EBSD examination of the anodized layer cross-sections provided valuable new spatial information on the distribution of anatase and rutile phases within the anodized layers. Highly porous oxide layers showed significantly higher corrosion rates compared to non-anodized titanium, but no significant differences were shown in the icorr values between samples containing primarily anatase phase, samples containing primarily rutile phase, and samples containing an approximate 50:50 mixture of the two phases. Minimum A minimum R samples showed substantially less porosity compared to the other anodization groups, a significantly lower oxide thickness, and comparable corrosion rates to non-anodized titanium. All samples within the study showed apatite production in simulated body fluid within the seven day test period indicating enhanced bioactivity. PMID- 26478306 TI - Effect of preparation processes and structural insight into the supermolecular system: Bisacodyl and beta-cyclodextrin inclusion complex. AB - In this study, beta-cyclodextrin (beta-CD) and bisacodyl were chosen as model host and guest molecule to explore the effect of preparation processes on the physicochemical properties of inclusion complexes (ICs) and to gain an insight into the structure of ICs. The influence of temperature and pH on complexation was studied by multiple temperature-pH phase solubility analysis. The most favorable conformation was predicted by molecular modeling using AutoDock. (1)H nuclear magnetic resonance and rotating frame nuclear Overhauser effect spectroscopy further confirmed the structure. Moreover, bisacodyl . beta-CD ICs in solid state were successfully prepared via three different procedures (co crystallization, co-evaporation, and co-grinding) and fully characterized by several solid-state techniques, namely, Fourier transform infrared spectroscopy, X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, solid-state NMR spectroscopy, and scanning electron microscopy. It was found that acid solution and low temperature were unfavorable for formation of bisacodyl . beta-CD. The pyridine moiety was suggested to be enclosed in the hydrophobic cavity of beta-CD. The complexes prepared using co-crystallization showed properties similar to those prepared using co-evaporation. Moreover, ICs obtained by co-evaporation and co-grinding had higher loading efficiency, water solubility, and dissolution rate than ICs obtained by co-crystallization. PMID- 26478307 TI - Nanostructured material formulated acrylic bone cements with enhanced drug release. AB - To improve antibiotic properties, poly(methyl methacrylate) (PMMA)-based bone cements are formulated with antibiotic and nanostructured materials, such as hydroxyapatite (HAP) nanorods, carbon nanotubes (CNT) and mesoporous silica nanoparticles (MSN) as drug carriers. For nonporous HAP nanorods, the release of gentamicin (GTMC) is not obviously improved when the content of HAP is below 10%; while the high content of HAP shows detrimental to mechanical properties although the release of GTMC can be substantially increased. As a comparison, low content of hollow nanostructured CNT and MSN can enhance drug delivery efficiency. The presence of 5.3% of CNT in formulation can facilitate the release of more than 75% of GTMC in 80 days, however, its mechanical strength is seriously impaired. Among nanostructured drug carriers, antibiotic/MSN formulation can effectively improve drug delivery and exhibit well preserved mechanical properties. The hollow nanostructured materials are believed to build up nano-networks for antibiotic to diffuse from the bone cement matrix to surface and achieve sustained drug release. Based on MSN drug carrier in formulated bone cement, a binary delivery system is also investigated to release GTMC together with other antibiotics. PMID- 26478308 TI - Development and characterization of cefazolin loaded zinc oxide nanoparticles composite gelatin nanofiber mats for postoperative surgical wounds. AB - Systemic antibiotic therapy in post-operative wound care remain controversial leading to escalation in levels of multi-resistant bacteria with unwanted morbidity and mortality. Recently zinc (Zn) because of multiple biophysiological functions, gain considerable interest for wound care. Based on our current understanding, the present study was designed with an intent to produce improve therapeutic approaches for post-operative wound management using composite multi functional antibiotic carrier. The study involved the fabrication, characterization and pre-clinical evaluation of cefazolin nanofiber mats loaded with zinc oxide (ZnO) and comparing co-formulated mats with individual component, enable a side by side comparison of the benefits of our intervention. Minimum inhibitory concentration (MIC) of the drug, ZnO nanoparticles (ZnONPs) and drug ZnONP mixture against Staphylococcus aureus was determined using micro dilution assay. The fabricated nanofibers were then evaluated for in-vitro antimicrobial activity and the mechanism of inhibition was predicted by scanning electron microscopy (SEM). Further these nanofiber mats were evaluated in-vivo for wound healing efficacy in Wistar rats. Study revealed that the average diameter of the nanofibers is around 200-900 nm with high entrapment efficiency and display sustained drug release behavior. The combination of ZnO and cefazolin in 1:1 weight ratio showed higher anti-bacterial activity of 1.9 +/- 0.2 MUg/ml. Transmission electron microscopy of bacterial cells taken from the zone of inhibition revealed the phenomenon of cell lysis in tested combination related to cell wall disruption. Further composite medicated nanofiber mats showed an accelerated wound healing as compared to plain cefazolin and ZnONP loaded mats. Macroscopical and histological evaluations demonstrated that ZnONP hybrid cefazolin nanofiber showed enhanced cell adhesion, epithelial migration, leading to faster and more efficient collagen synthesis. Hence the fabricated composite nanofiber mats have the potential to be used as a postoperative antimicrobial wound dressings. PMID- 26478309 TI - Osteogenesis of human adipose-derived stem cells on poly(dopamine)-coated electrospun poly(lactic acid) fiber mats. AB - Electrospinning is a versatile technique to generate large quantities of micro- or nano-fibers from a wide variety of shapes and sizes of polymer. The aim of this study is to develop functionalized electrospun nano-fibers and use a mussel inspired surface coating to regulate adhesion, proliferation and differentiation of human adipose-derived stem cells (hADSCs). We prepared poly(lactic acid) (PLA) fibers coated with polydopamine (PDA). The morphology, chemical composition, and surface properties of PDA/PLA were characterized by SEM and XPS. PDA/PLA modulated hADSCs' responses in several ways. Firstly, adhesion and proliferation of hADSCs cultured on PDA/PLA were significantly enhanced relative to those on PLA. Increased focal adhesion kinase (FAK) and collagen I levels and enhanced cell attachment and cell cycle progression were observed upon an increase in PDA content. In addition, the ALP activity and osteocalcin of hADSCs cultured on PDA/PLA were significantly higher than seen in those cultured on a pure PLA mat. Moreover, hADSCs cultured on PDA/PLA showed up-regulation of the ang-1 and vWF proteins associated with angiogenesis differentiation. Our results demonstrate that the bio-inspired coating synthetic degradable PLA polymer can be used as a simple technique to render the surfaces of synthetic biodegradable fibers, thus enabling them to direct the specific responses of hADSCs. PMID- 26478310 TI - Evaluation of cystamine-modified hyaluronic acid/chitosan polyplex as retinal gene vector. AB - PURPOSE: A successful gene therapy approach can prevent or treat congenital and acquired diseases. However, there is still no ideal non-viral vector for gene delivery in a safe and timely manner. In this report the anionic polymer hyaluronic acid (HA) was investigated as a potential vector for gene therapy. Due to its intrinsic characteristics it constitutes an excellent candidate to deliver therapeutic genes, pending the modification of its surface charge. METHODS: To modify its charge, HA was modified with cystamine. Several formulations were prepared using modified HA combined with sodium sulfate, sodium triphosphate, K carrageenan and chitosan. Vectors were characterized with respect to size, charge, DNA load and its protection, and effect on cell viability. The better performing formulations were further evaluated in vitro for their transfection efficiency in HEK293T and ARPE-19 cells. RESULTS: Cell viability assays showed low cytotoxicity for both polymers. Gene transfer efficiency depended on cell line and formulation, but no increased transfection efficiency was observed with the modified polymer. CONCLUSIONS: HA has great potential as a gene therapy vector, but further optimization, including incorporation of a higher percentage of positive groups in HA, is needed before its use as a gene delivery vector. PMID- 26478311 TI - Control-release microcapsule of famotidine loaded biomimetic synthesized mesoporous silica nanoparticles: Controlled release effect and enhanced stomach adhesion in vitro. AB - In the present work, control-release microcapsule of famotidine (FMT) loaded biomimetic synthesized mesoporous silica nanoparticles (B-MSNs) was developed, and controlled release effect and stomach adhesion of this formulation in vitro were mainly investigated. B-MSN was previously synthesized and it was amorphous mesoporous nanoparticles with helical channels. Cytotoxicity of B-MSN was studied using human breast cancer cells (MCF-7) and the result indicated that cytotoxicity of B-MSN can be neglected. After loading FMT into B-MSN, specific surface area, pore volume and pore diameter of B-MSN were obviously reduced. In vitro dissolution test showed that B-MSN had the ability to slow down FMT release for 15 min. In order to prolong controlled release effect and remained the advantage of B-MSN (improve drug stability due to its rigid silica framework), the combined application of control-release microcapsule (using cellulose and hydroxypropyl methylcellulose K15M as excipients) with B-MSN was designed. It was obvious that newly designed formulation significantly controlled FMT release with Fickian diffusion mechanism and showed enhanced stomach adhesion in vitro, which has significant value in widening the application of B-MSN in formulation design. PMID- 26478312 TI - Electrospun PDLLA/PLGA composite membranes for potential application in guided tissue regeneration. AB - With the aim to explore a membrane system with appropriate degradation rate and excellent cell-occlusiveness for guided tissue regeneration (GTR), a series of poly(D, L-lactic acid) (PDLLA)/poly(D, L-lactic-co-glycolic acid) (PLGA) (100/0, 70/30, 50/50, 30/70, 0/100, w/w) composite membranes were fabricated via electrospinning. The fabricated membranes were evaluated by morphological characterization, water contact angle measurement and tensile test. In vitro degradation was characterized in terms of the weight loss and the morphological change. Moreover, in vitro cytologic research revealed that PDLLA/PLGA composite membranes could efficiently inhibit the infiltration of 293 T cells. Finally, subcutaneous implant test on SD rat in vivo showed that PDLLA/PLGA (70/30, 50/50) composite membranes could function well as a physical barrier to prevent cellular infiltration within 13 weeks. These results suggested that electrospun PDLLA/PLGA (50/50) composite membranes could serve as a promising barrier membrane for guided tissue regeneration due to suitable biodegradability, preferable mechanical properties and excellent cellular shielding effects. PMID- 26478313 TI - A novel cysteine sensor based on modification of carbon paste electrode by Fe(II) exchanged zeolite X nanoparticles. AB - An electrochemical sensor based on carbon paste electrode (CPE) modified with iron(II) doped into a synthesized nano-particles of zeolite X (Fe(II)-NX/ZCME) was constructed, which is highly sensitive for detection of cysteine (Cys). The modified electrode showed an excellent electro-activity for oxidation of Cys in phosphate buffer at pH7.4. It has been found that anodic peak potential of Cys oxidation, compared with the unmodified CPE (UCPE), was shifted towards negative values at the surface of the modified electrode under the optimum condition. The peak current increased linearly with the Cys concentration in the wide range of 5.0 * 10(-9)-3.0 * 10(-3) mol L(-1). The very low detection limit was obtained to be 1.5 * 10(-10) mol L(-1). Finally, the modified electrode was used as a selective, simple and precise new electrochemical sensor for the determination of Cys in the real samples, such as pharmaceutical and biological fluids. PMID- 26478314 TI - Investigating composite systems based on poly L-lactide and poly L lactide/triclosan nanoparticles for tissue engineering and medical applications. AB - In this study, the encapsulated triclosan with a low molecular weight PLLA (LATC30) is dispersed into a PLLA having higher molecular weight via melt blending to increase the overall properties and particularly antibacterial activity of the system. The proposed method results in a completely homogenous composite as 5% LATC30 improved mechanical properties. For instance, the elongation at break was increased ca. 3%. The mechanical properties of the fabricated composites were also affected by the plasticizing role of LATC30. The kinetics of hydrolytic degradation in an accelerated condition was obtained using a novel method by the Beer-Lambert equation. It was found that the incorporation of LATC30 into the composite increases the rate of hydrolytic degradation. The calorimetry showed a reduction in crystallinity upon addition of LATC30. Moreover, the degradation of the composites was studied and fully described the kinetic analysis by the Flynn-Wall-Ozawa (FWO) method. From which, it was found that the activation energy of the system was decreased. As the LATC30 content of the composite was increased, the hydrophilicity of the composite was increased. The fabricated scaffolds with 5% LATC30 demonstrated a good osteoblast cell attachment and mineralization on the composite scaffolds. This composite is a suitable antibacterial candidate for the bone tissue engineering and medical applications since the real dosage of triclosan stays at ca. 1.5%. PMID- 26478315 TI - Monoamine oxidase B layer-by-layer film fabrication and characterization toward dopamine detection. AB - In this work nanostructured film composites of the monoamine oxidase B (MAO-B) enzyme, free or encapsulated in liposomes, were fabricated by the layer-by-layer (LbL) self-assembly technique, employing polyethylene imine (PEI) as polycation. Initially, the MAO-B enzyme was incorporated into liposomes in order to preserve its enzymatic structure ensuring their activity and catalytic stability. The LbL film growth was monitored by surface plasmon resonance (SPR) by gold resonance angle shift analysis after each bilayer deposition. Subsequently, the films were applied as amperometric biosensors for dopamine detection using Prussian Blue (PB) as the electron mediator. The biosensor fabricated by MAO-B incorporated into liposomes composed of DPPG:POPG in the ratio (1:4) (w/w) showed the best performance with a sensitivity of 0.86 (MUA cm(-2))/(mmol L(-1)) and a detection limit of 0.33 mmol L(-1). PMID- 26478316 TI - Polyacrylic acids-bovine serum albumin complexation: Structure and dynamics. AB - The study of the mixture of BSA with polyacrylic acids at different masses versus pH allowed highlighting the existence of two regimes of weak and strong complexation. These complexes were studied in diluted regime concentration, by turbidimetry, dynamic light scattering (DLS), zeta-potential measurements and nuclear magnetic resonance (NMR). We have followed the pH effect on the structure and properties of the complex. This allowed refining the interpretation of the phase diagram and understanding the observed phenomena. The NMR measurements allowed probing the dynamics of the constituents versus the pH. The computational method was used to precisely determine the electrostatic potential of BSA and how the polyelectrolyte binds to it at different pH. PMID- 26478317 TI - In vitro culture and harvest of BMMSCs on the surface of a novel thermosensitive glass microcarrier. AB - Traditional two-dimensional (2D) static culture environment for stem cells followed by enzymatic cell detachment or mechanical treatment is routinely used in research laboratories. However, this method is not ideal as stem cells expand slowly, with cell damage and partial loss of specific stemness. For this reason, a better culture condition is urgently needed to improve stem cell recovery. A novel thermosensitive P(NIPAAm-co-HPM)-g-TMSPM-g-microcarrier was prepared here as a three-dimensional (3D) culture substitute. This novel microcarrier was prepared by grafting NIPAAm and HPM to the surface of glass microcarrier using TMSPM through surface free radical copolymerization. The prepared material was tested in cell culture and via cooling harvest method. We found that NIPAAm was successfully grafted on to the surface of the microcarriers, providing an excellent biocompatible environment for BMMSC adhesion and growth. More importantly, BMMSCs could be fully removed from the thermosensitive glass microcarriers with remained cell viability. PMID- 26478318 TI - Formulation optimization and characterization of transdermal film of simvastatin by response surface methodology. AB - Matrix type of simvastatin transdermal film (SSTF) was developed with poly(vinyl alcohol) (PVA) and eudragit RL100 (EG) using response surface methodology (RSM) to investigate combined effect of the selected process variables like SS concentration, PVA:EG ratio and the dibutyl phthalate (DBT) concentration at different levels on dependent variables such as tensile strength and flux, with an aim to optimize a suitable combination of drug, polymer and plasticizer ratio. The study reveals that the effect of DBT concentration was highest on tensile strength, while SS concentration exhibited pronounced effect on SS flux through the abdominal skin of rat. According to Derringer's desirability prediction tool, the composition of optimized film was found to be 2% of SS, 2:1 ratio of PVA:EG and 40% of DBT. Under these conditions, the SSTF exhibited a predicted value of tensile strength and flux of 11.871 MPa and 43.569 MUg/cm(2)/h, respectively. The in vivo hypolipidemic study conducted for 14 days in hyperlipidemia induced Sprague-Dawley rats reveals that the optimized SSTF exhibited significant lowering of blood lipid level. The absence of skin irritation indicates that the prepared film was safe and well tolerated as transdermal formulation. Thus, the film may serve as an alternative therapy to oral dosage form of SS. PMID- 26478319 TI - Coaxial electrospun aligned tussah silk fibroin nanostructured fiber scaffolds embedded with hydroxyapatite-tussah silk fibroin nanoparticles for bone tissue engineering. AB - The bone is a composite of inorganic and organic materials and possesses a complex hierarchical architecture consisting of mineralized fibrils formed by collagen molecules and coated with oriented hydroxyapatite. To regenerate bone tissue, it is necessary to provide a scaffold that mimics the architecture of the extracellular matrix in native bone. Here, we describe one such scaffold, a nanostructured composite with a core made of a composite of hydroxyapatite and tussah silk fibroin. The core is encased in a shell of tussah silk fibroin. The composite fibers were fabricated by coaxial electrospinning using green water solvent and were characterized using different techniques. In comparison to nanofibers of pure tussah silk, composite notably improved mechanical properties, with 90-fold and 2-fold higher initial modulus and breaking stress, respectively, obtained. Osteoblast-like MG-63 cells were cultivated on the composite to assess its suitability as a scaffold for bone tissue engineering. We found that the fiber scaffold supported cell adhesion and proliferation and functionally promoted alkaline phosphatase and mineral deposition relevant for biomineralization. In addition, the composite were more biocompatible than pure tussah silk fibroin or cover slip. Thus, the nanostructured composite has excellent biomimetic and mechanical properties and is a potential biocompatible scaffold for bone tissue engineering. PMID- 26478320 TI - Probing the surface microstructure of layer-by-layer self-assembly chitosan/poly(l-glutamic acid) multilayers: A grazing-incidence small-angle X-ray scattering study. AB - This study characterized the surface structure of layer-by-layer self-assembly chitosan/poly(L-glutamic acid) multilayers through grazing-incidence small-angle X-ray scattering (GISAXS), X-ray reflectivity (XRR), and atomic force microscopy (AFM). A weakly long-period ordered structure along the in-plane direction was firstly observed in the polyelectrolyte multilayer by the GISAXS technique. This structure can be attributed to the specific domains on the film surface. In the domain, nanodroplets that were formed by polyelectrolyte molecules were orderly arranged along the free surface of the films. This ordered structure gradually disappeared with the increasing bilayer number because of the complex merging behavior of nanodroplets into large islands. Furthermore, resonant diffuse scattering became evident in the GISAXS patterns as the number of bilayers in the polyelectrolyte multilayer was increased. Notably, the lateral cutoff length of resonant diffuse scattering for these polyelectrolyte films was comparable with the long-period value of the ordered nanodroplets in the polyelectrolyte multilayer. Therefore, the nanodroplets could be considered as a basic transmission unit for structure propagation from the inner interface to the film surface. It suggests that the surface structure with length scale larger than the size of nanodroplets was partially complicated from the interface structure near the substrate, but surface structure smaller than the cutoff length was mainly depended on the conformation of nanodroplets. PMID- 26478321 TI - Green synthesis and characterization of silver nanoparticles using Artemisia absinthium aqueous extract--A comprehensive study. AB - Unlike chemical synthesis, biological synthesis of nanoparticles is gaining tremendous interest, and plant extracts are preferred over other biological sources due to their ample availability and wide array of reducing metabolites. In this project, we investigated the reducing potential of aqueous extract of Artemisia absinthium L. for synthesizing silver nanoparticles (AgNPs). Optimal synthesis of AgNPs with desirable physical and biological properties was investigated using ultra violet-visible spectroscopy (UV-vis), dynamic light scattering (DLS), transmission electron microscopy (TEM) and energy-dispersive X ray analysis (EDX). To determine their appropriate concentrations for AgNP synthesis, two-fold dilutions of silver nitrate (20 to 0.62 mM) and aqueous plant extract (100 to 0.79 mg ml(-1)) were reacted. The results showed that silver nitrate (2mM) and plant extract (10 mg ml(-1)) mixed in different ratios significantly affected size, stability and yield of AgNPs. Extract to AgNO3 ratio of 6:4v/v resulted in the highest conversion efficiency of AgNO3 to AgNPs, with the particles in average size range of less than 100 nm. Furthermore, the direct imaging of synthesized AgNPs by TEM revealed polydispersed particles in the size range of 5 to 20 nm. Similarly, nanoparticles with the characteristic peak of silver were observed with EDX. This study presents a comprehensive investigation of the differential behavior of plant extract and AgNO3 to synthesize biologically stable AgNPs. PMID- 26478322 TI - Self-assembled semi-crystallinity at parallel beta-sheet nanocrystal interfaces in clustered MaSp1 (spider silk) proteins. AB - In this communication, we use molecular dynamics methods to model the self assembly of semi-crystalline domains at beta-sheet nanocrystal interfaces in clusters of spider silk (MaSp1) proteins. Our research elucidates that the energetics at interfaces between crystalline and amorphous domains control effectively, the extent to which semi-crystalline domains can form at interfaces. Stability at nanocrystal interfaces is not linearly related to the internal (bulk) stability of the beta-sheet nanocrystal. Rather, interfacial stability is found to be highly sensitive to the number of alanine repeat units that make up each sheet. Intriguingly, the most stable interface for the development of semi crystallinity is built up of polyalanine beta-sheets of a length similar to that which is spun naturally in spider dragline silk. PMID- 26478323 TI - Degradation of bioabsorbable Mg-based alloys: Assessment of the effects of insoluble corrosion products and joint effects of alloying components on mammalian cells. AB - This work is focused on the processes occurring at the bioabsorbable metallic biomaterial/cell interfaces that may lead to toxicity. A critical analysis of the results obtained when degradable metal disks (pure Mg and rare earth-containing alloys (ZEK100 alloys)) are in direct contact with cell culture and those obtained with indirect methods such as the use of metal salts and extracts was made. Viability was assessed by Acridine Orange dye, neutral red and clonogenic assays. The effects of concentration of corrosion products and possible joint effects of the binary and ternary combinations of La, Zn and Mg ions, as constituents of ZEK alloys, were evaluated on a mammalian cell culture. In all cases more detrimental effects were found for pure Mg than for the alloys. Experiments with disks showed that gradual alterations in pH and in the amount of corrosion products were better tolerated by cells and resulted in higher viability than abrupt changes. In addition, viability was dependent on the distance from the source of ions. Experiments with extracts showed that the effect of insoluble degradation products was highly detrimental. Indirect tests with Zn ions revealed that harmful effects may be found at concentrations >= 150 MUM and at >= 100 MUM in mixtures with Mg. These mixtures lead to more deleterious effects than single ions. Results highlight the need to develop a battery of tests to evaluate the biocompatibility of bioabsorbable biomaterials. PMID- 26478324 TI - Optimizing thickness of ceramic coatings on plastic components for orthopedic applications: A finite element analysis. AB - Realizing hard ceramic coatings on the plastic component of a joint prosthesis can be strategic for the mechanical preservation of the whole implant and to extend its lifetime. Recently, thanks to the Plasma Pulsed Deposition (PPD) method, zirconia coatings on ultra-high molecular weight polyethylene (UHMWPE) substrates resulted in a feasible outcome. Focusing on both the highly specific requirements defined by the biomedical application and the effective possibilities given by the deposition method in the perspectives of technological transfer, it is mandatory to optimize the coating in terms of load bearing capacity. The main goal of this study was to identify through Finite Element Analysis (FEA) the optimal coating thickness that would be able to minimize UHMWPE strain, possible insurgence of cracks within the coating and stresses at coating-substrate interface. Simulations of nanoindentation and microindentation tests were specifically carried out. FEA findings demonstrated that, in general, thickening the zirconia coating strongly reduced the strains in the UHMWPE substrate, although the 1 MUm thickness value was identified as critical for the presence of high stresses within the coating and at the interface with the substrate. Therefore, the optimal thickness resulted to be highly dependent on the specific loading condition and final applications. PMID- 26478325 TI - Dental glass ionomer cement reinforced by cellulose microfibers and cellulose nanocrystals. AB - The aim of this work was to evaluate if the addition of cellulose microfibers (CmF) or cellulose nanocrystals (CNC) would improve the mechanical properties of a commercial dental glass ionomer cement (GIC). Different amounts of CmF and CNC were previously prepared and then added to reinforce the GIC matrix while it was being manipulated. Test specimens with various concentrations of CmF or CNC in their total masses were fabricated and submitted to mechanical tests (to evaluate their compressive and diametral tensile strength,modulus, surface microhardness and wear resistance) and characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). The incorporation of CmF in the GIC matrix did not greatly improve the mechanical properties of GIC. However, the addition of a small amount of CNC in the GIC led to significant improvements in all of the mechanical properties evaluated: compressive strength (increased up to 110% compared with the control group), elastic modulus increased by 161%, diametral tensile strength increased by 53%, and the mass loss decreased from 10.95 to 3.87%. Because the composites presented a considerable increase in mechanical properties, the modification of the conventional GIC with CNC can represent a new and promising dental restorative material. PMID- 26478326 TI - New antimony(III) halide complexes with dithiocarbamate ligands derived from thiuram degradation: The effect of the molecule's close contacts on in vitro cytotoxic activity. AB - Antimony(III) halide complexes of the formulae {[SbBr(Me2DTC)2]n} (1), {[SbI(Me2DTC)2]n} (2) and {[(Me2DTC)2Sb(MU2-I)Sb(Me2DTC)2](+).I3(-)} (3) (Me2DTC = dimethyldithiocarbomate) were synthesized from SbX3, (X = Br or I) and tetramethylthiuram monosulfide (Me4tms) or tetramethylthiuram disulfide (Me4tds). The complexes were characterized by melting point (m.p.), elemental analysis (e.a.), Fourier-transform Infra-Red (FT-IR), Fourier-transform Raman (FT-Raman), Nuclear Magnetic Resonance ((1)H,(13)C-NMR) spectroscopy and Thermogravimetric Differential Thermal Analysis (TG-DTA). Crystal structures of complexes 1-3 were determined with single crystal X-ray diffraction analysis. Complexes 1 and 2 are polymers with distorted square pyramidal (SP) geometry in each monomeric unit, whereas complex 3 is ionic, containing an iodonium linkage Sb-I(+)-Sb and an I3( ) counter anion; to the best of our knowledge, this is the first ionic antimony(III) iodide complex. The in vitro cytotoxic activity of 1-3 against human adenocarcinoma cells: breast (MCF-7) and cervix (HeLa) cells and non cancerous cells: MRC-5 (normal human fetal lung fibroblast cells) was evaluated with trypan blue (TB) and sulforhodamine B (SRB) assays. Among antimony(III) compounds with sulfur containing ligand, those of dithiocarbamates exhibit significant cytotoxic activity. Hirshfeld surface volumes were analyzed to clarify the nature of the intermolecular interactions by the 2D fingerprint plot. Molecules with lower H-all atoms inter-molecular interactions exhibit the higher activity against MCF-7 cells. The in vivo genotoxicity of 1-3 was evaluated by the mean of Allium cepa test. Alterations in the mitotic index values due to the chromosomal aberrations were observed in the case of complexes 2 and 3. Since, no such alteration is caused by 1, it makes this compound candidate for further study as potential drug. PMID- 26478327 TI - Biomimetic synthesis of hollow calcium carbonate with the existence of the agar matrix and bovine serum albumin. AB - Proteins play important roles in the process of biomineralization. Vaterite and calcite have been synthesized by the reaction of Na2CO3 and CaCl2 in the bovine serum albumin (BSA) and agar system. The samples have been characterized by Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). The shape of CaCO3 crystal has been analyzed by scanning electronic microscopy (SEM). The results show that calcite is a single product in the absence of BSA, but the product is a mixture of calcite and vaterite in the presence of BSA. The spheral shell of CaCO3 crystal was obtained when the concentration of BSA increased to 9.0mg/mL. PMID- 26478328 TI - Full factorial design optimization of anti-inflammatory drug release by PCL-PEG PCL microspheres. AB - A biodegradable triblock poly(epsilon-caprolactone)-poly(ethylene glycol) poly(epsilon-caprolactone) copolymer was successfully synthesized by ring-opening polymerization of epsilon-caprolactone, and was characterized by intrinsic viscosimetry, (1)H nuclear magnetic resonance, infrared spectroscopy and X-ray diffraction. Copolymer microparticles loaded with ibuprofen were prepared by an oil-in-water (o/w) emulsion solvent evaporation process. They were carefully weighted and characterized through their zeta potential. In this work, 4 selected process parameters (shaking speed X1, time of contact X2, poly(vinyl alcohol) concentration X3, and ibuprofen concentration X4) were adjusted at 2 different values. For each of the 16 experimental conditions, repeated twice, the drug encapsulation efficiency of the microspheres was determined, according to the following definition: EE (X1, X2, X3, X4)=mass of encapsulated ibuprofen/total weight of ibuprofen. A "full factorial design method" was applied to analyze the results statistically according to a polynomial fit and to determine the optimal conditions for the microencapsulation of the ibuprofen through an accurate statistical protocol. The microparticles obtained exhibit a spherical shape as shown by electron microscopy. PMID- 26478329 TI - Synthesis and characterization of Ti-Ta-Nb-Mn foams. AB - The unprecedented increase in human life expectancy have produced profound changes in the prevailing patterns of disease, like the observed increased in degenerative disc diseases, which cause degradation of the bones. Ti-Nb-Ta alloys are promising materials to replace the damaged bone due to their excellent mechanical and corrosion resistance properties. In general metallic foams are widely used for medical application due to their lower elastic moduli compare to bulk materials. In this work we studied the synthesis of 34Nb-29Ta-xMn (x: 2, 4 and 6 wt.% Mn) alloy foams (50% v/v) using ammonium hydrogen carbonate as a space holder. Alloys were produced through mechanical alloying in a planetary mill for 50h. Green compacts were obtained by applying 430 MPa pressure. To remove the space holder from the matrix the green compacts were heated to 180 degrees C for 1.5h and after sintered at 1300 degrees C for 3h. Foams were characterized by x ray diffraction, scanning, transmission electron microscopy and optical microscopy. The elastic modulus of the foam was measured as ~30 GPa, and the values are almost equal to the values predicted using various theoretical models. PMID- 26478330 TI - Nanostructured SnO2 encapsulated guar-gum hybrid nanocomposites for electrocatalytic determination of hydrazine. AB - The present article deals with synthesis of sol-gel derived tin dioxide (SnO2) nanoparticles encapsulated in to guar gum (GG) biopolymer as the organic inorganic hybrid materials for the determination of hydrazine. The organic inorganic hybrid combines the perfunctory strength offered by the inorganic SnO2 nanoparticles with flexible binding sites provided by the organic biopolymer (GG) solution by the ultrasonication. The phase identification, crystalline size, surface morphology and optical properties of prepared SnO2 and SnO2-GG nanocomposites has been investigated through FT-IR, XRD, SEM, AFM, TEM, UV-Vis, and PL techniques. The colloidal solution of SnO2 and GG is electrophoretically deposited (EPD) onto the indium tin-oxide (ITO) glass substrate and studied for the electrooxidation of hydrazine. Under the optimized experimental conditions, the linearity between the current response and the hydrazine concentration has been obtained in the range of 2-22 mM, with a low detection limit of 2.76 mM and a high sensitivity of 5.72 MUA cm(-2). Based on the linear increase in amperometric current, a sensitive hydrazine electrochemical sensor is constructed. The proposed SnO2-GG/ITO electrode shows a good response time (35s), reproducibility, and long-term stability. The obtained results suggest that SnO2 GG nanocomposites electrode provides a favorable sensing platform for the electrochemical studies. In addition, the cyclic voltammetry (CV) studies are used to evaluate the kinetic parameters. PMID- 26478331 TI - Modeling capillary formation in calcium and copper alginate gels. AB - Alginate solutions in the presence of bivalent ions can form ionic cross-linked gels. In particular gelation conditions the gel structure can be characterized by great anisotropy with the presence of straight capillaries along a preferential direction. These materials can find applications mainly in high-tech sectors, like tissue engineering, where the gel characteristics play a crucial role. Despite the need of mastering the capillary formation and properties, the process remains a poorly known problem, and its development is left to trial and error procedures. In this work a quantitative approach to the description of the capillary formation process has been developed. The theory proposed by Treml et al. (2003) has been implemented and extended to an alginate different from the one used in that study and two different ions (calcium and copper). Some of the model parameters have been derived through simple measurements; others have been scaled using proper scaling equations. Experiments have been performed in different gelation conditions, varying alginate and ionic solution concentrations, to highlight the effects of these parameters on the anisotropic structure and to validate the model. In all the analyses done, the model has performed nicely showing a good reliability in the prediction of gel characteristics like capillary formation, capillary length and process time. PMID- 26478332 TI - Application of three-dimensional reduced graphene oxide-gold composite modified electrode for direct electrochemistry and electrocatalysis of myoglobin. AB - In this paper a three-dimensional (3D) reduced graphene oxide (RGO) and gold (Au) composite was synthesized by electrodeposition and used for the electrode modification with carbon ionic liquid electrode (CILE) as the substrate electrode. Myoglobin (Mb) was further immobilized on the surface of 3D RGO Au/CILE to obtain an electrochemical sensing platform. Direct electrochemistry of Mb on the modified electrode was investigated with a pair of well-defined redox waves appeared on cyclic voltammogram, indicating the realization of direct electron transfer of Mb with the modified electrode. The results can be ascribed to the presence of highly conductive 3D RGO-Au composite on the electrode surface that accelerate the electron transfer rate between the electroactive center of Mb and the electrode. The Mb modified electrode showed excellent electrocatalytic activity to the reduction of trichloroacetic acid in the concentration range from 0.2 to 36.0 mmol/L with the detection limit of 0.06 mmol/L (3sigma). PMID- 26478333 TI - Synthesis and characterization of the antitubercular phenazine lapazine and development of PLGA and PCL nanoparticles for its entrapment. AB - The aim of this work was to develop and characterize nanoparticles as carriers of lapazine, a phenazine derived from beta-lapachone; its antimycobacterial activity is described for the first time as a potential treatment for tuberculosis. The lapazine was synthesized, and by using gas chromatography coupled to a flame ionization detector, it was possible to evaluate its purity degree of almost 100%. For better elucidation of the molecular structure, mass spectroscopy and 1H NMR were carried out and compared to the literature values. Lapazine was assayed in vitro against H37Rv Mycobacterium tuberculosis and a rifampicin-resistant strain, with minimum inhibitory concentration values of 3.00 and 1.56 MUg mL(-1), respectively. The nanoparticles showed a polydispersity index of 0.16,mean diameter of 188.5 +/- 1.7 mm, zeta potential of -15.03 mV, and drug loading of 54.71 mg g(-1) for poly-epsilon-caprolactone (PCL) nanoparticles and a polydispersity index of 0.318,mean diameter of 197.4 +/- 2.7 mm, zeta potential of -13.43 mV and drug loading of 137.07 mg g(-1) for poly(DL-lactide-co glycolide) (PLGA) nanoparticles. These results indicate that both polymeric formulations have good characteristics as potential lapazine carriers in the treatment of tuberculosis. PMID- 26478334 TI - Strontium incorporation to optimize the antibacterial and biological characteristics of silver-substituted hydroxyapatite coating. AB - Infection in primary total joint prostheses is attracting considerable attention. In this study, silver (Ag) was incorporated into hydroxyapatite (HA) using a hydrothermal method in order to improve its antimicrobial properties. Strontium (Sr) was added as a second binary element to improve the biocompatibility. The substituted HA samples were fixed on titanium (Ti) substrates by dopamine assisted immobilization in order to evaluate their antibacterial and biological properties. The results showed that Ag and Sr were successfully incorporated into HA without affecting their crystallinity. Further, the antibacterial tests showed that all the Ag-substituted samples had good anti-bacterial properties against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Despite their good antibacterial ability, the Ag-substituted samples showed evidence of cytotoxicity on MG63 cells, characterized by low cell density and poor spreadability. The addition of Sr to the Ag-substituted samples considerably reduced the cytotoxicity of Ag. Although the viability of the cells grown on the surfaces of co-substituted HA was not as high as that of the cells grown on the HA surfaces, it is believed that excellent antibacterial properties and good biological activity can be achieved by balancing the dosage of Sr and Ag. PMID- 26478335 TI - Preparation and characterization of a novel sodium alginate incorporated self assembled Fmoc-FF composite hydrogel. AB - Dipeptides and their derivatives have attracted tremendous attention owning to their excellent abilities of self-assemble assembling into various structures which have great potentials for applications in biology and/or nanotechnology. In the present study, we dedicate to fabricate a rigid and structure controllable Fmoc-FF/SA composite hydrogel. We found that the modified dipeptide, fluorenyl-9 methoxycarbonyl (Fmoc)-diphenylalanine (Phe-Phe) can self-assemble into rigid hydrogels with structures of nanowires, layered thin films or honeycombs as the change of sodium alginate (SA) concentration. Meanwhile, CD-spectroscopy demonstrated that SA appeared to control the process, but it did not change the arrangement of the Fmoc-FF peptide. Our results demonstrated that the formed hydrogel showed physical and chemical stability as well as possessing good biocompatibility. Rheological measurements showed that the addition of SA could improve the stability of the hydrogel. Cell viability assay revealed that the Fmoc-FF and Fmoc-FF/SA hydrogels are both beneficial for cell proliferation in vitro. Our results indicated that the fabricated Fmoc-FF/SA composite hydrogels could be used in tissue engineering and drug delivery in the future. PMID- 26478336 TI - Effects of a low-shrinkage methacrylate monomer and monoacylphosphine oxide photoinitiator on curing efficiency and mechanical properties of experimental resin-based composites. AB - This study investigated the degree of conversion, depth of cure, Vickers hardness, flexural strength, flexural modulus and volumetric shrinkage of experimental composite containing a low shrinkage monomer FIT-852 (FIT; Esstech Inc.) and photoinitiator 2,4,6-trimethylbenzoyldiphenylphosphine oxide (TPO; Sigma Aldrich) compared to conventional composite containing Bisphenol A-glycidyl methacrylate (BisGMA) and camphorquinone-amine photoinitiator system. The degree of conversion was generally higher in FIT-based composites (45-64% range) than in BisGMA-based composites (34-58% range). Vickers hardness, flexural strength and modulus were higher in BisGMA-based composites. A polywave light-curing unit was generally more efficient in terms of conversion and hardness of experimental composites than a monowave unit. FIT-based composite containing TPO showed the depth of cure below 2mm irrespective of the curing light. The depth of cure of FIT-based composite containing CQ and BisGMA-based composites with either photoinitiator was in the range of 2.8-3.0mm. Volumetric shrinkage of FIT-based composite (0.9-5.7% range) was lower than that of BisGMA-based composite (2.2-12% range). FIT may be used as a shrinkage reducing monomer compatible with the conventional CQ-amine system as well as the alternative TPO photoinitiator. However, the depth of cure of FIT_TPO composite requires boosting to achieve clinically recommended thickness of 2mm. PMID- 26478337 TI - Aminolysis of polyethylene terephthalate surface along with in situ synthesis and stabilizing ZnO nanoparticles using triethanolamine optimized with response surface methodology. AB - This research concerned the simultaneous polyester surface modification and synthesis of zinc oxide nano-reactors to develop durable photo-bio-active fabric with variable hydrophobicity/hydrophilicity under sunlight. For this purpose, triethanolamine (TEA) was applied as a stabilizer and pH adjusting chemical for the aminolysis of polyester surface and enhancing the surface reactivity along with synthesis and deposition of ZnO nanoparticles on the fabric. Therefore, TEA played a crucial role in providing the alkaline condition for the preparation of zinc oxide nanoparticles and acting as stabilizer controlling the size of the prepared nanoparticles. The stain-photodegradability regarded as self-cleaning efficiency, wettability and weight change under the process was optimized based on zinc acetate and TEA concentrations, using central composite design (CCD). Findings also suggested the potential of the prepared fabric in inhibiting Staphylococcus aureus and Escherichia coli bacteria growth with greater than 99.99% antibacterial efficiency. Besides, the proposed treatment had no detrimental effect on tensile strength and hand feeling of the polyester fabric. PMID- 26478338 TI - Development of a novel carbon paste sensor for determination of micromolar amounts of sulfaquinoxaline in pharmaceutical and biological samples. AB - A potentiometric carbon paste sensor was fabricated for determination of sulfaquinoxaline (SQX) based on the use of ion-association complex of sulfaquinoxaline sodium with 2,3,5-triphenyltetrazolium chloride. The proposed sensor exhibited Nernstian slope of 58.4 +/- 0.3 mV per decade for sulfaquinoxaline over a wide concentration range of 5.0 * 10(-6) to 1.0 * 10( 2)M, with a low detection limit of 3.0 * 10(-6)M. The sensor manifested advantages of fast response time, satisfactory reproducibility, long life time, high thermal stability and, most importantly, excellent selectivities for sulfaquinoxaline relative to a wide variety of common foreign inorganic cations, anions, sugars and amino acids. The sensor was successfully used for determination of sulfaquinoxaline in pharmaceutical solution, blood serum, urine and milk samples. The isothermal coefficient of the electrode was calculated by the investigation of temperature effects on the electrode potential response. PMID- 26478339 TI - Modification of carbon paste electrode with Fe(III)-clinoptilolite nano-particles for simultaneous voltammetric determination of acetaminophen and ascorbic acid. AB - A novel carbon paste electrode (CPE) modified with Fe(III)-exchanged clinoptilolite nano-particles (Fe(III)-NClino/CPE) was constructed and used for simultaneous voltammetric (CV, SqW and chronoamperometry) determination of ascorbic acid and acetaminophen. Raw and modified zeolites were characterized by X-ray diffraction (XRD) and transmission electron microscope (TEM). The square wave peak current was linearly increased in the concentration ranges of 1.0 * 10( 9)-1.0 * 10(-2) mol L(-1) for ascorbic acid and 1.0 * 10(-10-)1.0 * 10(-2) mol L( 1) for acetaminophen with detection limits of 1.8 * 10(-9) mol L(-1) and 9.9 * 10(-10) mol L(-1), respectively. The detection limits of 2.4 * 10(-10) mol L(-1) and 2.5 * 10(-11) mol L(-1) were also obtained for AA and AC in chronoamperometric measurements, respectively. The diffusion coefficients of 7.5 * 10(-5) cm(2) s(-1) and 2.4 * 10(-5) cm(2) s(-1) were respectively calculated for the oxidation of AC and AA by chronoamperometry. The proposed electrode exhibited high sensitivity and good stability, and would be valuable for the clinical assay of ascorbic acid and acetaminophen. PMID- 26478341 TI - Application of a thin film of poly(solochrome black T) as a redox mediator for the electro-catalytic simultaneous determination of dopamine and acetaminophen in the pharmaceutical and biological samples. AB - Glassy carbon electrode was successfully modified with a thin film of poly(solochrome black T) and applied for the sensitive and selective voltammetric simultaneous determination of dopamine and acetaminophen. The preparation and basic electrochemical behavior of poly(solochrome black T) film on the glassy carbon electrode were investigated in details. The modified electrode with polymeric thin film exhibits excellent electro-catalytic activity toward the oxidation of dopamine and acetaminophen. The anodic peaks of the both species were well defined with lowered oxidation potential and enhanced oxidation peak currents. The modified electrode was used as a voltammetric sensor for sensitive simultaneous determination of dopamine and acetaminophen free from ascorbic acid and uric acid interferences. Under the optimum conditions, the detection limits were 0.092 and 0.142 MUmol L(-1) for DA and AP, respectively. The proposed sensor has been successfully used in analysis of pharmaceutical and biological samples. PMID- 26478340 TI - Electrospinning of PLGA/gum tragacanth nanofibers containing tetracycline hydrochloride for periodontal regeneration. AB - Controlled drug release is a process in which a predetermined amount of drug is released for longer period of time, ranging from days to months, in a controlled manner. In this study, novel drug delivery devices were fabricated via blend electrospinning and coaxial electrospinning using poly lactic glycolic acid (PLGA), gum tragacanth (GT) and tetracycline hydrochloride (TCH) as a hydrophilic model drug in different compositions and their performance as a drug carrier scaffold was evaluated. Scanning electron microscopy (SEM) results showed that fabricated PLGA, blend PLGA/GT and core shell PLGA/GT nanofibers had a smooth and bead-less morphology with the diameter ranging from 180 to 460 nm. Drug release studies showed that both the fraction of GT within blend nanofibers and the core shell structure can effectively control TCH release rate from the nanofibrous membranes. By incorporation of TCH into core-shell nanofibers, drug release was sustained for 75 days with only 19% of burst release within the first 2h. The prolonged drug release, together with proven biocompatibility, antibacterial and mechanical properties of drug loaded core shell nanofibers make them a promising candidate to be used as drug delivery system for periodontal diseases. PMID- 26478342 TI - Effect of surface roughness on performance of magnetoelastic biosensors for the detection of Escherichia coli. AB - Escherichia coli are bacteria that must be controlled in the food industry and the hospital sector. Magnetoelastic biosensors offer the promise of rapid identification of these and other harmful antigens. In this work, strips of amorphous Metglas 2826MB3 were cut to size (5 mm * 1 mm) with a microdicing saw and were then coated with thin layers of Cr and Au, as verified by Rutherford backscattering spectroscopy (RBS). Several sensor surfaces were studied: 1) as cast strip, wheel side; 2) as-cast strip, free surface; and 3) thinned and polished surface. A layer of cystamine was applied to the Au-covered magnetoelastic substrate, forming a self-assembledmonolayer (SAM), followed by antibodies, using a modified Hermanson protocol. The cystamine layer growth was verified by Fourier transform infrared spectroscopy (FTIR) and scanning electronmicroscopy (SEM). The biosensors were exposed to solutions of bacteria and the resonant frequency of the sensors was measured with an impedance analyzer for times up to 100 min. Reductions in the resonant frequency, corresponding to bacteria capture, were measured after optimizing the signal amplitude. For times up to 40 min, high capture rates were observed and thereafter saturation occurred. Saturation values of the frequency shifts were compared with the number of bacteria observed on the sensor using fluorescence microscopy. Parameters associated with capture kinetics were studied for different sensor surfaces. The rough surfaces were found to show a faster response, while the thinned and polished sensors showed the largest frequency shift. PMID- 26478343 TI - The anion recognition properties of a novel hydrazone based on colorimetric and potentiometric studies. AB - A novel hydrazone, 1,3-bis (2-formylphenoxy) propane bis (2,4-dinitrophenyl hydrazine) (S) has been synthesized and characterized by the NMR, IR, CHNS, UV Vis, Raman, TEM and XPS analysis. Upon the addition of monohydrogen phosphate (MHP) ion, sudden color change from light yellow to dark violet has occurred. The binding constant of S-MHP was determined by Hill plot. Hydrazone also showed potential response with MHP ion. A number of polymeric membrane electrodes (PME) and coated graphite electrode (CGE) were also fabricated and found that the CGE has revealed better results in comparison to PME in terms of the detection limit of 7.58 * 10(-9) mol L(-1) and Nernstian response. PMID- 26478344 TI - Fluorescent molecularly imprinted polymers based on 1,8-naphthalimide derivatives for efficiently recognition of cholic acid. AB - Fluorescent molecularly imprinted polymers (MIPs) have attracted increasing attentions in recent years due to their high selectivity and sensitivity for target molecules. In this study, two cholic acid imprinted fluorescent polymers, i.e., MIP1 and MIP2, were prepared using 4-dimethylamino-N-allylnaphthalimide (F1) and 4-piperazinyl-N-allylnaphthalimide (F2) as the fluorescent functional monomers, respectively. The fluorescence intensity of MIP1 decreased linearly with the increase of the template concentration in the range of 1.50-120.0 MUM, while the fluorescence intensity of MIP2 increased linearly with the increase of the template concentration in the range of 0.40-110.0 MUM. The detection limits of MIP1 and MIP2 for cholic acid were 0.42 and 0.083 MUM, respectively. The mechanisms of the fluorescence responsive of the imprinted polymers were discussed. The results of fluorescence measurement and binding experiments demonstrated that both imprinted polymers have high recognition abilities and binding affinities for the template. The imprinted polymers have been successfully applied to the determination of cholic acid in human serums. The present study indicated that 1,8-naphthalimide can be used as a modular building block for design and construction of various fluorogenic molecularly imprinted materials for practical sensing and separation. PMID- 26478345 TI - Multifunctional nanotube-like Fe3O4/PANI/CDs/Ag hybrids: An efficient SERS substrate and nanocatalyst. AB - In this paper, the stable and environment-friendly Fe3O4 nanotubes with polyaniline (Fe3O4 NTs/PANI hybrids) have been prepared via mesoporous anodic alumina oxide (AAO) template, sol-gel method and in-situ polymerization. Then multifunctional Fe3O4 NTs/PANI/Ag hybrids have been obtained by decorating Ag nanoparticles by glucose reduction on surface of Fe3O4 NTs/PANI hybrids. The morphologies and structures of these hybrids were subsequently investigated by SEM, XRD, TEM and XPS measurements. The Fe3O4 NTs/PANI/Ag hybrids presented high catalytic activity due to the template-assisted presence, preventing Ag particulate agglomeration. Importantly, the Fe3O4 NTs/PANI/Ag hybrids achieve sensitive surface-enhanced Raman scattering (SERS) signals. Furthermore, the introduction of carbon dots (CDs) endows these hybrids good dispersion and stable photoluminescence (PL). Therefore, the obtained hybrids may have potential applications in waste water treatment, biomedicine, photocatalyst, and environmental analysis. PMID- 26478346 TI - Radiation damage on Langmuir monolayers of the anionic 1.2-dipalmitoyl-sn-glycero 3-[phospho-rac-(1-glycerol)] (sodium salt)(DPPG) phospholipid at the air-DNA solution interface. AB - The resilience of cells to ultraviolet (UV) irradiation is probably associated with the effects induced in biological molecules such as DNA and in the cell membrane. In this study, we investigated UV damage to the anionic 1.2-dipalmitoyl sn-glycero-3-[phospho-rac-(1-glycerol)] (sodium salt) (DPPG) phospholipid, which is an important component of cell membranes. In films cast from DPPG emulsions, UV irradiation induced cleavage of C-O, C=O and -PO(2-) bonds, while in Langmuir monolayers at the air/water interface representing the cell membrane this irradiation caused the monolayer stability to decrease. When DNA was present in the subphase, however, the effects from UV irradiation were smaller, since the ionic products from degradation of either DPPG or DNA stabilize the intact DPPG molecules. This mechanism may explain why UV irradiation does not cause immediate cell collapse, thus providing time for the cellular machinery to repair elements damaged by UV. PMID- 26478347 TI - Construction of polymer-paclitaxel conjugate linked via a disulfide bond. AB - Covalently linked amphiphilic polymer-paclitaxel (PTX) could self-assemble into micelles to overcome many drawbacks of existing delivery systems of PTX by virtue of tunable compositions, variable sizes, high drug loading content and zero burst release. Moreover, a reduction-responsive system based on glutathione (GSH) can be established by introducing disulfide bonds into the polymeric carriers to improve the selectivity for cancer cells. Herein, we reported a disulfide bond linked polymer-PTX, P(PEGMEA)-co-P(PDPHEMA)-g-PTX with a high PTX loading content of 43.7 wt.%. In vitro cell assay showed that the polymer carrier has almost no cytotoxicity. The half maximal inhibitory concentration (IC50) values of the polymer-PTX conjugate against HEK-293 cells was about 10 times higher than that of HeLa cells after incubation for 72 h. Such a dramatic selectivity for cancer and normal cells provides a promising strategy to improve the therapeutic efficacy and decrease the side effects of PTX in chemotherapy. PMID- 26478348 TI - Efficient protein immobilization on polyethersolfone electrospun nanofibrous membrane via covalent binding for biosensing applications. AB - In this paper we introduce novel strategy for antibody immobilization using high surface area electrospun nanofibrous membrane based on ethyl-3-(3 dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling chemistry. To present the high performance of proposed biosensors, anti staphylococcus enterotoxin B (anti-SEB) was used as a model to demonstrate the utility of our proposed system. Polymer solution of polyethersolfone was used to fabricate fine nanofibrous membrane. Moreover, industrial polyvinylidene fluoride membrane and conventional microtiter plate were also used to compare the efficiency of antibody immobilization. Scanning electron microscopy images were taken to study the morphology of the membranes. The surface activation of nanofibrous membrane was done with the help of O2 plasma. PES nanofibrous membrane with carboxyl functional groups for covalent attachment of antibodies were treated by EDC/NHS coupling agent. The quantity of antibody immobilization was measured by enzyme-linked immuno sorbent assay (ELISA) method. Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) spectroscopy was performed to confirm the covalent immobilization of antibody on membrane. Atomic force microscopy, scanning electron microscopy and invert fluorescence microscopy were used to analyze the antibody distribution pattern on solid surfaces. Results show that oxygen plasma treatment effectively increased the amount of antibody immobilization through EDC/NHS coupling chemistry. It was found that the use of nanofibrous membrane causes the improved detection signal of ELISA based biosensors in comparison to the standard assay carried out in the 96-well microtiter plate. This method has the potential to improve the ELISA based biosensor and we believe that this technique can be used in various biosensing methods. PMID- 26478349 TI - Thermally processed polymeric microparticles for year-long delivery of dexamethasone. AB - Dexamethasone-releasing poly(lactic-co-glycolic acid) (PLGA) microparticles were formulated using a solvent displacement technique with the addition of distillation aiming to increase drug delivery lifetime. Two PLGA copolymer ratios (50:50 and 75:25) were used to determine the influence of lactic acid and glycolic acid ratio on microparticle characteristics. The addition of distillation significantly slows the release of dexamethasone compared to traditional solvent removal via evaporation while still maintaining a therapeutic dosage. Microparticles formulated with PLGA 50:50 controllably release dexamethasone up to one year and 75:25 release up to two years in-vitro. The ratio of lactic acid to glycolic acid plays a significant role in microparticle stability, drug loading efficiency, and thermal properties. In all, this formulation technique offers new prospects for inflammation suppression in pediatric vascular and airway diseases. PMID- 26478350 TI - Photocurable bioadhesive based on lactic acid. AB - Novel photocurable and low molecular weight oligomers based on l-lactic acid with proven interest to be used as bioadhesive were successfully manufactured. Preparation of lactic acid oligomers with methacrylic end functionalizations was carried out in the absence of catalyst or solvents by self-esterification in two reaction steps: telechelic lactic acid oligomerization with OH end groups and further functionalization with methacrylic anhydride. The final adhesive composition was achieved by the addition of a reported biocompatible photoinitiator (Irgacure(r) 2959). Preliminary in vitro biodegradability was investigated by hydrolytic degradation in PBS (pH=7.4) at 37 degrees C. The adhesion performance was evaluated using glued aminated substrates (gelatine pieces) subjected to pull-to-break test. Surface energy measured by contact angles is lower than the reported values of the skin and blood. The absence of cytoxicity was evaluated using human fibroblasts. A notable antimicrobial behaviour was observed using two bacterial models (Staphylococcus aureus and Escherichia coli). The cured material exhibited a strong thrombogenic character when placed in contact with blood, which can be predicted as a haemostatic effect for bleeding control. This novel material was subjected to an extensive characterization showing great potential for bioadhesive or other biomedical applications where biodegradable and biocompatible photocurable materials are required. PMID- 26478351 TI - Biomimetic composite microspheres of collagen/chitosan/nano-hydroxyapatite: In situ synthesis and characterization. AB - The collagen/chitosan/hydroxyapatite (COL/CS/HA) composite microspheres with a good spherical form and a high dispersity were successfully obtained using an in situ synthesis method. The FT-IR and XRD results revealed that the inorganic phase in the microspheres was crystalline HA containing carbonate ions. The morphology of the composite microspheres was dependent on the HA content, and a more desirable morphology was achieved when 20 wt.% HA was contained. The composite microspheres exhibited a narrow particle distribution, most of which ranged from 5 to 10 MUm. In addition, the needle-like HA nano-particles were uniformly distributed in the composite microspheres, and their crystallinity and crystal size decreased with the HA content. PMID- 26478352 TI - Growth of hydroxyapatite on the cellular membrane of the bacterium Bacillus thuringiensis for the preparation of hybrid biomaterials. AB - This study aimed to grow hydroxyapatite (HAp) crystals on the cellular wall of the Gram-positive bacterium Bacillus thuringiensis using a bio-mimetic method. Several strains were phenotypically and genotypically characterized using multilocus sequence typing (MLST) gene markers to differentiate the strains and confirm the identity of the isolated species to guarantee that the selected species was not harmful to human health or the environment. Three of the analyzed strains were selected because they exhibited the best nucleation and growth of HAp on the bacterial surface. This innovative method to grow HAp crystals on a cellular membrane helps to elucidate the mechanisms by which osseous tissue is formed in nature. The optimum concentration for the simulated physiological fluid (SPF) was 1.5*. The hybrid materials were characterized by optical microscopy, atomic force microscopy (AFM), scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). PMID- 26478353 TI - Stimuli-responsive weak polyelectrolyte multilayer films: A thin film platform for self triggered multi-drug delivery. AB - Polyelectrolyte multilayer (PEM) thin film composed of weak polyelectrolytes was designed by layer-by-layer (LbL) assembly of poly(allylamine hydrochloride) (PAH) and poly(methacrylic acid) (PMA) for multi-drug delivery applications. Environmental stimuli such as pH and ionic strength showed significant influence in changing the film morphology from pore-free smooth structure to porous structure and favored triggered release of loaded molecules. The film was successfully loaded with bovine serum albumin (BSA) and ciprofloxacin hydrochloride (CH) by modulating the porous polymeric network of the film. Release studies showed that the amount of release could be easily controlled by changing the environmental conditions such as pH and ionic strength. Sustained release of loaded molecules was observed up to 8h. The fabricated films were found to be biocompatible with epithelial cells during in-vitro cell culture studies. PEM film reported here not only has the potential to be used as self responding thin film platform for transdermal drug delivery, but also has the potential for further development in antimicrobial or anti-inflammatory coatings on implants and drug-releasing coatings for stents. PMID- 26478354 TI - Delivery system for mefenamic acid based on the nanocarrier layered double hydroxide: Physicochemical characterization and evaluation of anti-inflammatory and antinociceptive potential. AB - PURPOSE: The anionic form of the drug mefenamic acid intercalated into the nanocarrier layered double hydroxide (LDH-Mef) was evaluated by anti-inflammatory and antinociceptive assays. METHODS: The LDH-Mef material was characterized by a set of physicochemical techniques, which was supported by Density Functional Theory calculations. The pharmacological effects of LDH-Mef (40 wt% of drug) were evaluated by hemolytic, anti-inflammatory activity and antinociceptive assays. RESULTS: In vivo assays were conducted for the first time in order to assess the LDH-Mef potential. The hemolytic effects decreased for the intercalated Mef as demonstrated by the higher tolerated hemolytic concentration (1.83 mM) compared to mefenamic acid (MefH), 0.48 mM. Pretreatment of animals with MefH or LDH-Mef reduced carrageenan-, dextran sulfate- and PGE2-induced paw edema. MefH or LDH Mef also decrease total leucocytes and neutrophil counts of the peritoneal cavity after inflammation induction with carrageenan. In the nociception model, oral pretreatment with LDH-Mef reduced mechanical hypernociception carrageenan-induced after 3-4h and also the number of writhings induced by acetic acid. CONCLUSIONS: This work shows the increase of the anti-inflammatory and antinociceptive potential of the drug confined into the LDH, as well as, its hemolytic effect. PMID- 26478355 TI - Structural analysis of xSrO-(50 - x)CaO-50P2O5 glasses with x=0, 5, or 10 mol% for potential use in a local delivery system for osteomyelitis treatment. AB - The introduction of ions into a local delivery matrix is one method of managing degradation and subsequent release of the incorporated therapeutic agents. Of interest in this study was whether we could modify the structural nature of calcium polyphosphate (CPP) glass and the subsequent therapeutic potential of this local delivery matrix with inclusion of strontium (Sr). We found that adding 10 mol% Sr significantly increased the density and chain length of the glass. There was no significant impact of Sr doping on the subsequent loading of vancomycin into the matrix, or the matrix porosity. The noted differences in structural stability, ion release, and vancomycin release between the un-doped CPP matrices and 10 mol% Sr-doped CPP matrices in vitro are likely a result of a decrease in glass disorder upon Sr addition to the glass and preferential retention of Sr over Ca during matrix degradation. This study has provided further evidence that Sr incorporation may serve to both manipulate antibiotic release from the amorphous CPP matrix and provide a potential source of therapeutic ions for enhanced bone regeneration. PMID- 26478356 TI - Cobalt doped proangiogenic hydroxyapatite for bone tissue engineering application. AB - The present study delineates the synthesis and characterization of cobalt doped proangiogenic-osteogenic hydroxyapatite. Hydroxyapatite samples, doped with varying concentrations of bivalent cobalt (Co(2+)) were prepared by the ammoniacal precipitation method and the extent of doping was measured by ICP-OES. The crystalline structure of the doped hydroxyapatite samples was confirmed by XRD and FTIR studies. Analysis pertaining to the effect of doped hydroxyapatite on cell cycle progression and proliferation of MG-63 cells revealed that the doping of cobalt supported the cell viability and proliferation up to a threshold limit. Furthermore, such level of doping also induced differentiation of the bone cells, which was evident from the higher expression of differentiation markers (Runx2 and Osterix) and better nodule formation (SEM study). Western blot analysis in conjugation with ELISA study confirmed that the doped HAp samples significantly increased the expression of HIF-1alpha and VEGF in MG-63 cells. The analysis described here confirms the proangiogenic-osteogenic properties of the cobalt doped hydroxyapatite and indicates its potential application in bone tissue engineering. PMID- 26478357 TI - Lower cytotoxicity, high stability, and long-term antibacterial activity of a poly(methacrylic acid)/isoniazid/rifampin nanogel against multidrug-resistant intestinal Mycobacterium tuberculosis. AB - To overcome the undesirable side effects and reduce the cytotoxicity of isoniazid (INH) and rifampin (RMP) in the digestive tract, a poly(methacrylic acid) (PMAA) nanogel was developed as a carrier of INH and RMP. This PMAA/INH/RMP nanogel was prepared as a treatment for intestinal tuberculosis caused by multidrug-resistant Mycobacterium tuberculosis (MTB). The morphology, size, and in vitro release properties were evaluated in a simulated gastrointestinal medium, and long-term antibacterial performance, cytotoxicity, stability, and activity of this novel PMAA/INH/RMP nanogel against multidrug-resistant MTB in the intestine were investigated. Our results indicate that the PMAA/INH/RMP nanogel exhibited extended antibacterial activity by virtue of its long-term release of INH and RMP in the simulated gastrointestinal medium. Further, this PMAA/INH/RMP nanogel exhibited lower cytotoxicity than did INH or RMP alone, suggesting that this PMAA/INH/RMP nanogel could be a more useful dosage form than separate doses of INH and RMP for intestinal MTB. The novel aspects of this study include the cytotoxicity study and the three-phase release profile study, which might be useful for other researchers in this field. PMID- 26478358 TI - Fabrication of graphene/gold-modified screen-printed electrode for detection of carcinoembryonic antigen. AB - Immunosensors based on gold nanoparticles and reduced graphene oxide (AuNPs/rGO) modified screen-printed electrodes (SPEs) were successfully synthesized using an electrochemical deposition method. The modified SPEs were characterized using a field emission scanning electron microscope (FESEM) and Raman spectroscopy to analyze the morphology and composition of AuNPs and rGO. Both the FESEM and Raman spectroscopy revealed that the AuNPs were successfully anchored on the thin film of rGO deposited on the surface of the SPEs. Characterization with a ferri ferrocyanide couple [Fe(CN)6(3-/4-)] showed that the electron transfer kinetic between the analyte and electrode was enhanced after the modification with the AuNPs/rGO composite on the electrode surface, in addition to increasing the effective surface area of the electrode. The modified SPE was immobilized with a sandwich type immunosensor to mimic the ELISA (enzyme-linked immunosorbent assay) immunoassay. The modified SPE that was fortified with the sandwich type immunosensor exhibited double electrochemical responses in the detection of carcinoembryonic antigen (CEA), with linear ranges of 0.5-50 ng/mL and 250-2000 ng/mL and limits of detection of 0.28 ng/mL and 181.5 ng/mL, respectively. PMID- 26478359 TI - Synthesis of nano-hydroxyapatite and its rapid mediated surface functionalization by silane coupling agent. AB - In this work, hydroxyapatite (HA) nanorods were synthesized by simple one step wet precipitation method followed by their rapid surface functionalization via aminopropyltriethoxysilane (APTS) to give modified (HA-APTS) product. Functionalized hydroxyapatite (HA-APTS) holds amino groups on their surface that can be further functionalized with other bioactive molecules. The extent of functionalization of HA was studied under three different processing conditions; at room temperature, at 80 degrees C and under microwave condition (600 W). Three different temperatures have been use for the purpose of comparison between the functionalized products so that we can judge that whether there is any effect of temperature on the final products. In the last we conclude that temperature has no effect. So microwave condition is best to carried out the functionalization in just 5 min. PMID- 26478360 TI - Acute toxicity and in vivo biodistribution of monodispersed mesoporous bioactive glass spheres in intravenously exposed mice. AB - The use of biomaterials from laboratories to clinics requires exhaustive and elaborate studies involving the biodistribution, clearance, and biocompatibility of biomaterials for in vivo biomedical applications. This study aimed to evaluate the acute toxicity and biodistribution of intravenously administrated sub micrometer mesoporous bioactive glass spheres (SMBGs) in mice. The lethal dose 50 (LD50) of SMBGs was higher than 250 mg/kg. The acute toxicity was evaluated at 14 days after intravenous injection of SMBGs at 20, 100 and 180 mg/kg in ICR mice. The mortality, coefficients of major organs, hematology data and blood biochemical indexes revealed the low in vivo toxicity of SMBGs at all doses. However, the histological examination showed lymphocytic infiltration and granuloma formation in hepatocyte and megakaryocyte hyperplasia in the spleen at high dose. The silicon content analysis using ICP-OES and TEM results indicated that SMBGs mainly distributed in the resident macrophages of the liver and spleen, and could be cleared from the body more than 2 weeks. These findings can be important for the toxicity assessment of sub-micrometer particles and the development of bioactive glass based drug delivery system for biomedical applications. PMID- 26478361 TI - Effect of drug precursor in cell uptake and cytotoxicity of redox-responsive camptothecin nanomedicines. AB - Novel redox-responsive nanomedicines have been synthesized by conjugating camptothecin prodrugs ((pyridine-2-yldisulfanil)alkyl carbonate derivatives) to hybrid porous silica nanoparticles through disulfide bond. After disulfide reduction, camptothecin may be released by an intramolecular cyclization mechanism or by carbonate bond hydrolysis. Samples have been characterized by physico-chemical techniques, and stability and drug release in PBS and human serum have been determined. Moreover, cell uptake was studied by fluorescence microscopy and flow cytometry, whilst cytotoxic activity was validated by MTT test. Obtained results indicate that prodrug side chain carbon number (n=1,2,3) determines material hydrophobic properties and, as a consequence, its stability in aqueous medium. When n value increases, the negative surface charge decreases dramatically due to a shielding effect provoked by hydrophobic ligands, which promotes particle aggregation and favors cell internalization. Furthermore, the n value determines the type of products released and, subsequently, the cytotoxic activity. Full disulfide bridge reduction takes place in all cases, but quick delivery of the free drug by intramolecular cyclization is only possible with the shortest linker (n=1), whereas other nanomedicines only present slow discharge of camptothecin by carbonate hydrolysis. Overall, the drug precursor incorporated to the inorganic nanoplatform modulates both cell uptake rate and cytotoxicity according to the different functionalization. PMID- 26478362 TI - Enhanced apatite-forming ability and antibacterial activity of porous anodic alumina embedded with CaO-SiO2-Ag2O bioactive materials. AB - In this study, to provide porous anodic alumina (PAA) with bioactivity and anti bacterial properties, sol-gel derived bioactive CaO-SiO2-Ag2O materials were loaded onto and into PAA nano-pores (termed CaO-SiO2-Ag2O/PAA) by a sol-dipping method and subsequent calcination of the gel-glasses. The in vitro apatite forming ability of the CaO-SiO2-Ag2O/PAA specimens was evaluated by soaking them in simulated body fluid (SBF). The surface microstructure and chemical property before and after soaking in SBF were characterized. Release of ions into the SBF was also measured. In addition, the antibacterial properties of the samples were tested against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The results showed that CaO-SiO2-Ag2O bioactive materials were successfully decorated onto and into PAA nano-pores. In vitro SBF experiments revealed that the CaO-SiO2-Ag2O/PAA specimens dramatically enhanced the apatite-forming ability of PAA in SBF and Ca, Si and Ag ions were released from the samples in a sustained and slow manner. Importantly, E. coli and S. aureus were both killed on the CaO-SiO2-Ag2O/PAA (by 100%) samples compared to PAA controls after 3 days of culture. In summary, this study demonstrated that the CaO-SiO2-Ag2O/PAA samples possess good apatite-forming ability and high antibacterial activity causing it to be a promising bioactive coating candidate for implant materials for orthopedic applications. PMID- 26478363 TI - Evaluation of the factors influencing the resultant diameter of the electrospun gelatin/sodium alginate nanofibers via Box-Behnken design. AB - This article presented a study on the effects of solution properties (i.e., gelatin concentration, alginate concentration, content of alginate solution in the blend solution, and content of acetic acid in the solvent of gelatin solution) on the average diameter of electrospun gelatin/sodium alginate nanofibers, as well as its standard deviation. For this purpose, blend solutions of two natural polymers (gelatin and sodium alginate) were prepared both in the absence and presence of ethanol. Response surface methodology based on a three level, four-variable Box-Benkhen design was employed to define quadratic relationships between the responses and the solution properties. The individual and interactive effects of the solution properties were determined. Moreover, the adequacy of the models was verified by the validation experiments. Results showed that the average diameters of the resultant nanofibers were 68-166 nm and 90-155 nm in the absence and presence of ethanol, respectively. The experimental results were in good agreement with the predicted response values. Hence, this study provides an overview on the fabrication of gelatin/sodium alginate nanofibers with targeted diameter, which may have potential to be used in the field of tissue engineering. PMID- 26478364 TI - Preparation of polyelectrolyte complex nanoparticles of chitosan and poly(2 acry1amido-2-methylpropanesulfonic acid) for doxorubicin release. AB - A new kind of polyelectrolyte complex (PEC) based on cationic chitosan (CS) and anionic poly(2-acry1amido-2-methylpropanesulfonic acid) (PAMPS) was prepared using a polymer-monomer pair reaction system. Chitosan was mixed with 2 acry1amido-2-methylpropanesulfonic acid) (AMPS) in an aqueous solution, followed by polymerization of AMPS. The complex was formed by electrostatic interaction of NH3(+) groups of CS and SO3(-) groups of AMPS, leading to a formation of complex nanoparticles of CS-PAMPS. A series of nanoparticles were obtained by changing the weight ratio of CS to AMPS, the structure and properties of nanoparticles were investigated. It was observed that the nanoparticles possessed spherical morphologies with average diameters from 255 nm to 390 nm varied with compositions of the nanoparticles. The nanoparticles were used as drug vehicles for doxorubicin, displaying relative high drug loading rate and encapsulation rate. The vitro release profiles revealed that the drug release could be controlled by adjusting pH of the release media. The nanoparticles demonstrated apparent advantages such as simple preparation process, free of organic solvents, size controllable, good biodegradability and biocompatibility, and they could be potentially used in drug controlled release field. PMID- 26478365 TI - Easy synthesis of highly fluorescent carbon dots from albumin and their photoluminescent mechanism and biological imaging applications. AB - A simple and green approach was developed to synthesize highly fluorescent carbon dots (CDs) using albumin as a carbon source in aqueous solution at room temperature. The CDs were characterized by excellent monodispersion, superior photostability, pH-independent emission, long fluorescence lifetime and high quantum yield (QY). The photoluminescent (PL) mechanism of CDs was explored by means of time-resolved PL decay, and the results revealed that PL originated from the emission of both defect state and intrinsic state. In addition, biological imaging with the application of CDs was carried out in human breast cancer Bcap 37 cell, which demonstrated that CDs were provided with an excellent biocompatibility, low cytotoxicity and good transmembrane ability. Besides, CDs could be considered as a potential substitute for organic dyes or semiconductor quantum dots (SQDs) in biological imaging. PMID- 26478366 TI - Surfactant-assisted sol-gel synthesis of forsterite nanoparticles as a novel drug delivery system. AB - In the present study, forsterite nanoparticles were synthesized via surfactant assisted sol-gel method using cetyltrimethyl ammonium bromide (CTAB) as a surfactant. The effects of CTAB contents and heat treatment on the textural properties and drug release from nanoparticles were investigated. The synthesized powders were studied by X-ray diffraction, Fourier transform infrared spectra, Brunauer-Emmett-Teller surface area analysis and transmission electron microscope images. Mg2SiO4 materials demonstrated mesoporous characteristics and large specific surface area ranging from 159 to 30 m(2)/g. The TEM results showed that forsterite nanorods had diameters about 4 nm and lengths ranging from 10 to 60 nm. It was found that the samples with 6g CTAB show slower drug release rate than the other specimens, which is due to smaller pore size. This study revealed that the drug delivery of forsterite can be tailored by changing the amount of surfactant. PMID- 26478367 TI - Flexible fiber-reinforced composites with improved interfacial adhesion by mussel inspired polydopamine and poly(methyl methacrylate) coating. AB - To obtain a kind of light-curable fiber-reinforced composite for dental restoration, an excellent interfacial adhesion between the fiber and the acrylate resin matrix is quite essential. Herein, surface modification on glass fibers were carried out by coating them with poly(methyl methacrylate) (PMMA), polydopamine (PDA), or both. The PMMA or PDA coating was performed by soaking fibers in PMMA/acetone solution or dopamine aqueous solution. PDA/PMMA co-coated glass fibers were obtained by further soaking PDA-coated fibers in PMMA/acetone solution. These modified fibers were impregnated with bisphenol A glycidyl methacrylate (Bis-GMA)/triethylene glycol dimethacrylate (TEGDMA) (5:5, w/w) dental resin at a volume fraction of 75%, using unmodified fibers as reference. Light-cured specimens were submitted to evaluations including flexural properties, morphological observation, dynamic mechanical thermal analysis (DMTA) and pull-out test. In comparison with unmodified glass fibers, all the modified glass fibers showed enhancements in flexural strength and modulus of Bis GMA/TEGDMA resin composites. Results of DMTA and pull-out tests confirmed that surface modification had significantly improved the interfacial adhesion between the glass fiber and the resin matrix. Particularly, the PDA/PMMA co-coated glass fibers displayed the most efficient reinforcement and the strongest interfacial adhesion due to the synergetic effects of PDA and PMMA. It indicated that co coating method was a promising approach in modifying the interfacial compatibility between inorganic glass fiber and organic resin matrix. PMID- 26478368 TI - Regenerated collagen fibers with grooved surface texture: Physicochemical characterization and cytocompatibility. AB - A novel type of protein fibers, regenerated collagen fibers (RC) from cattle skin, was prepared through wet-spinning. Due to the combined effect of solvent exchange and subsequent drawing process, the fibers were found to have a grooved surface texture. The grooves provided not only ordered topographical cues, but also increased surface area. Protein content of the RC fibers was confirmed by Fourier Transform infrared spectroscopy (FTIR) and ninhydrin color reaction. The fibers could be readily fabricated into nonwovens or other textiles, owning to their comparable physical properties to other commercialized fibers. Cell growth behavior on RC nonwovens suggested both early adhesion and prompt proliferation. The high moisture regain, good processability, along with the excellent cytocompatibility indicated that the RC fibers and nonwovens developed in this study might offer a good candidate for biomedical and healthcare applications. PMID- 26478369 TI - Poly(hydroxybutyrate)/cellulose acetate blend nanofiber scaffolds: Preparation, characterization and cytocompatibility. AB - Poly(hydroxybutyrate) (PHB)/cellulose acetate (CA) blend nanofiber scaffolds were fabricated by electrospinning using the blends of chloroform and DMF as solvent. The blend nanofiber scaffolds were characterized by SEM, FTIR, XRD, DSC, contact angle and tensile test. The blend nanofibers exhibited cylindrical, uniform, bead free and random orientation with the diameter ranged from 80-680 nm. The scaffolds had very well interconnected porous fibrous network structure and large aspect surface areas. It was found that the presence of CA affected the crystallization of PHB due to formation of intermolecular hydrogen bonds, which restricted the preferential orientation of PHB molecules. The DSC result showed that the PHB and CA were miscible in the blend nanofiber. An increase in the glass transition temperature was observed with increasing CA content. Additionally, the mechanical properties of blend nanofiber scaffolds were largely influenced by the weight ratio of PHB/CA. The tensile strength, yield strength and elongation at break of the blend nanofiber scaffolds increased from 3.3 +/- 0.35 MPa, 2.8 +/- 0.26 MPa, and 8 +/- 0.77% to 5.05 +/- 0.52 MPa, 4.6 +/- 0.82 MPa, and 17.6 +/- 1.24% by increasing PHB content from 60% to 90%, respectively. The water contact angle of blend nanofiber scaffolds decreased about 50% from 112 +/- 2.1 degrees to 60 +/- 0.75 degrees . The biodegradability was evaluated by in vitro degradation test and the results revealed that the blend nanofiber scaffolds showed much higher degradation rates than the neat PHB. The cytocompatibility of the blend nanofiber scaffolds was preliminarily evaluated by cell adhesion studies. The cells incubated with PHB/CA blend nanofiber scaffold for 48 h were capable of forming cell adhesion and proliferation. It showed much better biocompatibility than pure PHB film. Thus, the prepared PHB/CA blend nanofiber scaffolds are bioactive and may be more suitable for cell proliferation suggesting that these scaffolds can be used for wound dressing or tissue engineering scaffolds. PMID- 26478370 TI - Influence of the different carbon nanotubes on the development of electrochemical sensors for bisphenol A. AB - Different methods of functionalisation and the influence of the multi-walled carbon nanotube sizes were investigated on the bisphenol A electrochemical determination. Samples with diameters of 20 to 170 nmwere functionalized in HNO3 5.0 mol L(-1) and a concentrated sulphonitric solution. The morphological characterisations before and after acid treatment were carried out by scanning electron microscopy and cyclic voltammetry. The size and acid treatment affected the oxidation of bisphenol A. The multi-walled carbon nanotubes with a 20-40 nm diameter improved the method sensitivity and achieved a detection limit for determination of bisphenol A at 84.0 nmol L(-1). PMID- 26478371 TI - In vivo behaviors of Ca(OH)2 activated nano SiO2 (nCa/nSi=3) cement in rabbit model. AB - In vivo behaviors of Ca(OH)2 activated nano SiO2 (nCa/nSi=3, TCS) cement were investigated in the rabbit femoral defects using the poly(methyl methacrylate) (PMMA) as control. The deposited apatite and CaCO3 layers round TCS paste surfaces were completely used to construct the new bone tissue. TCS paste could stimulate the formation of new bone tissue in marrow tissue. The osteostimulation was mainly attributed to the proliferation and differentiation effects of Ca and Si ions released from TCS paste on the osteoprogenitor cells. However, Calcium Silicate-Hydrate (C-S-H) gel in TCS paste was harder to degradate than Ca(OH)2. TCS paste kept the original shape during implantation, and could not provide the pores or spaces for further formation of bone tissue. Osteolytic defects induced by wear particles from TCS paste surface could not be completely avoided, because of the interfacial strain and the extensive micromotion between TCS paste surface and new bone tissue. Overall, our results indicated that Ca(OH)2 activated nano SiO2 cement was bioactivity and osteostimulation. The further improvements of Ca(OH)2 activated nano SiO2 cement should be done by achieving a balance between biological properties and mechanical performances. PMID- 26478372 TI - Pulse electrodeposited nickel-indium tin oxide nanocomposite as an electrocatalyst for non-enzymatic glucose sensing. AB - Nickel and nickel-ITO nanocomposite on mild steel substrate were prepared by pulse electrodeposition method from nickel sulphamate electrolyte and were examined as electrocatalysts for non-enzymatic glucose sensing. The surface morphology, chemical composition, preferred orientation and oxidation states of the nickel metal ion in the deposits were characterized by SEM, EDAX, XRD and XPS. Electrochemical sensing of glucose was studied by cyclic voltammetry and amperometry. The modified Ni-ITO nanocomposite electrode showed higher electrocatalytic activity for the oxidation of glucose in alkaline medium and exhibited a linear range from 0.02 to 3.00 mM with a limit of detection 3.74 MUM at a signal-to-noise ratio of 3. The higher selectivity, longer stability and better reproducibility of this electrode compared to nickel in the sensing of glucose are pointers for exploitation in practical clinical applications. PMID- 26478373 TI - Electrochemical sensing platforms based on the different carbon derivative incorporated interface. AB - their effects on the properties of these biosensors. Biosensors were prepared by Horseradish peroxidase (HRP) immobilization on the composite electrodes composed of carbon black, carbon nanofiber (CNF), extended graphite, multiwalled carbon nanotube (MWCNT), reduced graphene oxide (REGO) and poly(glycidyl methacrylateco vinylferrocene) (P(GMA-co-VFc)) as mediator, covalent linker, and host matrix for carbon derivatives. The modified pencil graphite electrode (PGE) was used for the detection of hydrogen peroxide and to follow electrochemical behavior of different carbon derivatives which were recorded. The electrochemical characterization was investigated by cyclic voltammetry and electrochemical impedance spectroscopy methods. Amperometric measurements showed that the REGO and MWCNT modified electrodes have excellent performance in comparison with other carbon derivatives studied. PMID- 26478374 TI - Tailoring the degradation and biological response of a magnesium-strontium alloy for potential bone substitute application. AB - Bone defects are very challenging in orthopedic practice. There are many practical and clinical shortcomings in the repair of the defect by using autografts, allografts or xenografts, which continue to motivate the search for better alternatives. The ideal bone grafts should provide mechanical support, fill osseous voids and enhance the bone healing. Biodegradable magnesium strontium (Mg-Sr) alloys demonstrate good biocompatibility and osteoconductive properties, which are promising biomaterials for bone substitutes. The aim of this study was to evaluate and pair the degradation of Mg-Sr alloys for grafting with their clinical demands. The microstructure and performance of Mg-Sr alloys, in vitro degradation and biological properties including in vitro cytocompatibility and in vivo implantation were investigated. The results showed that the as-cast Mg-Sr alloy exhibited a rapid degradation rate compared with the as-extruded alloy due to the intergranular distribution of the second phase and micro-galvanic corrosion. However, the initial degradation could be tailored by the coating protection, which was proved to be cytocompatible and also suitable for bone repair observed by in vivo implantation. The integrated fracture calluses were formed and bridged the fracture gap without gas bubble accumulation, meanwhile the substitutes simultaneously degraded. In conclusion, the as-cast Mg-Sr alloy with coating is potential to be used for bone substitute alternative. PMID- 26478375 TI - Novel glass-like coatings for cardiovascular implant application: Preparation, characterization and cellular interaction. AB - Glass coatings are of great interest for biomedical implant application due to their excellent properties. Nowadays they are used in different fields including drug delivery, for bone tissue regeneration or as implant. Nevertheless they can only be applied using high temperatures. Therefore their usage in the field of cardiovascular implant application is still restricted. Accordingly new developments in this field have been carried out to overcome this problem and to coat cardiovascular implants. Here, novel glass-like coatings have been developed and applied using sol-gel technique at moderate temperatures. The biocompatibility and selectivity have been analyzed using human endothelial cells. The obtained results clarify that the developed compositions can either promote or suppress endothelial cell growth only by altering the sintering atmosphere. A later application as thin layer on cardiovascular implants like stents is conceivable. PMID- 26478376 TI - Magnesium degradation influenced by buffering salts in concentrations typical of in vitro and in vivo models. AB - Magnesium and its alloys have considerable potential for orthopedic applications. During the degradation process the interface between material and tissue is continuously changing. Moreover, too fast or uncontrolled degradation is detrimental for the outcome in vivo. Therefore in vitro setups utilizing physiological conditions are promising for the material/degradation analysis prior to animal experiments. The aim of this study is to elucidate the influence of inorganic salts contributing to the blood buffering capacity on degradation. Extruded pure magnesium samples were immersed under cell culture conditions for 3 and 10 days. Hank's balanced salt solution without calcium and magnesium (HBSS) plus 10% of fetal bovine serum (FBS) was used as the basic immersion medium. Additionally, different inorganic salts were added with respect to concentration in Dulbecco's modified Eagle's medium (DMEM, in vitro model) and human plasma (in vivo model) to form 12 different immersion media. Influences on the surrounding environment were observed by measuring pH and osmolality. The degradation interface was analyzed by electron-induced X-ray emission (EIXE) spectroscopy, including chemical-element mappings and electron microprobe analysis, as well as Fourier transform infrared reflection micro-spectroscopy (FTIR). PMID- 26478377 TI - Formulation of cyclodextrin inclusion complex-based orally disintegrating tablet of eslicarbazepine acetate for improved oral bioavailability. AB - The present investigation was aimed towards developing a beta-cyclodextrin (beta CD) solid dispersion (SD) based orally disintegrating tablet (ODT) of eslicarbazepine acetate (ESL), for improving the dissolution and providing fast onset of anti-epileptic action. Optimum ratio of ESL and beta-CD was determined by Job's plot. Thereafter, solid dispersions were prepared by solvent evaporation method and evaluated for yield, assay, Differential scanning calorimetry (DSC), Fourier transform infra red spectroscopy (FTIR), X-ray diffraction (XRD), and in vitro dissolution. Optimized SD was compressed into ODT by direct compression using super disintegrants and evaluated for wetting time, drug content, in vitro drug release and in vivo studies. The results of DSC, FTIR and XRD analysis supported the formation of inclusion complex. An improved dissolution with 99.95 +/- 2.80% drug release in 60 min was observed in comparison to 24.85 +/- 2.96% release from a plain drug suspension. Tablets with crosspovidone as a super disintegrant showed the least disintegration time of 24.66 +/- 1.52 s and higher in vitro drug release against marketed tablets. In vivo studies indicated that the formulated tablets had 2 times higher bioavailability than marketed tablets. Thus, the developed beta-CD-ESL SD-ODT could provide faster onset of action and higher bioavailability, which would be beneficial in case of epileptic seizures. PMID- 26478378 TI - Glassy carbon electrode modified with horse radish peroxidase/organic nucleophilic-functionalized carbon nanotube composite for enhanced electrocatalytic oxidation and efficient voltammetric sensing of levodopa. AB - A novel and selective enzymatic biosensor was designed and constructed for voltammetric determination of levodopa (L-Dopa) in aqueous media (phosphate buffer solution, pH=7). Biosensor development was on the basis of to physically immobilizing of horse radish peroxidase (HRP) as electrochemical catalyst by sol gel on glassy carbon electrode modified with organic nucleophilic carbon nanotube composite which in this composite p-phenylenediamine (pPDA) as organic nucleophile chemically bonded with functionalized MWCNT (MWCNT-COOH). The results of this study suggest that prepared bioorganic nucleophilic carbon nanotube composite (HRP/MWCNT-pPDA) shows fast electron transfer rate for electro oxidation of L-Dopa because of its high electrochemical catalytic activity toward the oxidation of L-Dopa, more--NH2 reactive sites and large effective surface area. Also in this work we measured L-Dopa in the presence of folic acid and uric acid as interferences. The proposed biosensor was characterized by scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), FT-IR spectroscopy and cyclic voltammetry (CV). The differential pulse voltammetry (DPV) was used for determination of L-Dopa from 0.1 MUM to 1.9 MUM with a low detection limit of 40 nM (for S/N=3) and sensitivity was about 35.5 MUA/MUM. Also this biosensor has several advantages such as rapid response, high stability and reproducibility. PMID- 26478380 TI - Optimizing the release process and modelling of in vitro release data of cis dichlorodiamminoplatinum (II) encapsulated into poly(2-hydroxyethyl methacrylate) nanocarriers. AB - Drug encapsulated nanocarriers are vehicles to transport the drug molecules and release them at the immediate vicinity of the diseased sites. The aim of this study was to design poly (2-hydroxyethyl methacrylate) nanoparticles (PHEMANPs) as a swelling and diffusion controlled drug release system for achieving sustained release of (cis-dichlorodiamminoplatinum II) CDDP. The study undertakes designing and characterization of nanocarriers, optimization of drug encapsulation, and investigating release dynamics of the CDDP drug. PHEMANPs were prepared by suspension polymerization method followed by post loading of the CDDP onto the nanocarriers. The physicochemical and biopharmaceutical properties were evaluated by FTIR, TEM, FESEM, EDX, DLS, surface charge, water intake studies, in vitro cytotoxicity, protein adsorption and percent haemolysis. Chemical stability of the drug was assessed and in vitro release experiments were performed to optimize formulation by UV spectral analysis. The obtained cumulative release data were fitted to zero, first and Korsmeyer-Peppas kinetic models to gain insights into release kinetics and prevailing drug transport mechanisms. The successful encapsulation of CDDP was achieved in different PHEMANP formulations with maximum drug encapsulation efficiency of approx. 60% and the release kinetics was found to follow the Korsmeyer-Peppas model having non-Fickian mechanism. The results indicated that the CDDP can be formulated with a high payload of PHEMANPs which can serve as promising nanomedicine and help in achieving sustained delivery of drug for targeting tumour. PMID- 26478379 TI - Coatings of titanium substrates with xCaO . (1 - x)SiO2 sol-gel materials: characterization, bioactivity and biocompatibility evaluation. AB - The objective of this study has been to develop low temperature sol-gel coatings to modify the surface of commercially pure titanium grade 4 (a material generally used in dental application) and to evaluate their bioactivity and biocompatibility on the substrate. Glasses of composition expressed by the following general formula xCaO . (1 - x)SiO2 (0.099.99%) and rapid pathogen deactivation efficiency (antimicrobial rate >99.99% even within 15s of contact time). The water washing and ring diffusion tests demonstrated that the antimicrobial film was a non-leaching product. Inspiringly, the antimicrobial PBAT films with an excellent antimicrobial activity can be obtained even at a very low dosage of PHGH (1.0 mg/g PBAT film). PMID- 26478396 TI - Effect of the addition CNTs on performance of CaP/chitosan/coating deposited on magnesium alloy by electrophoretic deposition. AB - CaP/chitosan/carbon nanotubes (CNTs) coating on AZ91D magnesium alloy was prepared via electrophoretic deposition (EPD) followed by conversion in a phosphate buffer solution (PBS). The bonding between the layer and the substrate was studied by an automatic scratch instrument. The phase compositions and microstructures of the composite coatings were determined by using X-ray diffraction (XRD), Fourier-transformed infrared spectroscopy (FTIR), Raman spectroscopy and scanning electron microscope (SEM). The element concentration and gentamicin concentration were respectively determined by inductively coupled plasma optical emission spectrometer (ICP-OES) test and ultraviolet spectrophotometer (UV). The cell counting kit (CCK) assay was used to evaluate the cytotoxicity of samples to SaOS-2 cells. The results showed that a few CNTs with their original tubular morphology could be found in the CaP/chitosan coating and they were beneficial for the crystal growth of phosphate and improvement of the coating bonding when the addition amount of CNTs in 500 ml of electrophoretic solution was from 0.05 g to 0.125 g. The loading amount of gentamicin increased and the releasing speed of gentamicin decreased after CNTs was added into the CaP/chitosan coating for immersion loading and EPD loading. The cell viability of Mg based CaP/chitosan/CNTs was higher than that of Mg based CaP/chitosan from 16 days to 90 days. PMID- 26478397 TI - Assembly of AuNRs and eugenol for trace analysis of eugenol using resonance light scattering technique. AB - A new resonance light scattering (RLS) method for determining eugenol was developed using gold nanorods (AuNRs) as probes which were synthesized in our lab. The weak RLS intensity of eugenol was obviously enhanced by the use of AuNRs. All of the results from the SEM, RLS and UV spectra indicated that eugenol induced the assembly of AuNRs; thus, a new complex of AuNRs-eugenol was formed. The assembly of this new complex was achieved through a coordination bond between eugenol and AuNRs. Under optimum experimental conditions, a direct linear relationship was established between the enhancement of RLS intensity and the concentration of eugenol in the range of 0.043-10.60 MUg ml(-1) (r=0.9927). Moreover, the limit of detection (LOD) was found at a nanogram level (7.28 ng ml( 1) by 3S0/S). The recovery and RSD (n=5) of three synthetic samples were 99.7 104.2% and 0.81-1.19%, respectively. The method was successfully employed for the analysis of eugenol in curry powder samples. PMID- 26478398 TI - Effect of bimodal harmonic structure design on the deformation behaviour and mechanical properties of Co-Cr-Mo alloy. AB - In the present work, Co-Cr-Mo alloy compacts with a unique bimodal microstructural design, harmonic structure design, were successfully prepared via a powder metallurgy route consisting of controlled mechanical milling of pre alloyed powders followed by spark plasma sintering. The harmonic structured Co-Cr Mo alloy with bimodal grain size distribution exhibited relatively higher strength together with higher ductility as compared to the coarse-grained specimens. The harmonic Co-Cr-Mo alloy exhibited a very complex deformation behavior wherein it was found that the higher strength and the high retained ductility are derived from fine-grained shell and coarse-grained core regions, respectively. Finally, it was observed that the peculiar spatial/topological arrangement of stronger fine-grained and ductile coarse-grained regions in the harmonic structure promotes uniformity of strain distribution, leading to improved mechanical properties by suppressing the localized plastic deformation during straining. PMID- 26478399 TI - CdS/ZnS nanocomposites: from mechanochemical synthesis to cytotoxicity issues. AB - CdS/ZnS nanocomposites have been prepared by a two-step solid-state mechanochemical synthesis. CdS has been prepared from cadmium acetate and sodium sulfide precursors in the first step. The obtained cubic CdS (hawleyite, JCPDS 00 010-0454) was then mixed in the second step with the cubic ZnS (sphalerite, JCPDS 00-005-0566) synthesized mechanochemically from the analogous precursors. The crystallite sizes of the new type CdS/ZnS nanocomposite, calculated based on the XRD data, were 3-4 nm for both phases. The synthesized nanoparticles have been further characterized by high-resolution transmission electron microscopy (HRTEM) and micro-photoluminescence (MUPL) spectroscopy. The PL emission peaks in the PL spectra are attributed to the recombination of holes/electrons in the nanocomposites occurring in depth associated with Cd, Zn vacancies and S interstitials. Their photocatalytic activity was also measured. In the photocatalytic activity tests to decolorize Methyl Orange dye aqueous solution, the process is faster and its effectivity is higher when using CdS/ZnS nanocomposite, compared to single phase CdS. Very low cytotoxic activity (high viability) of the cancer cell lines (selected as models of living cells) has been evidenced for CdS/ZnS in comparison with CdS alone. This fact is in a close relationship with Cd(II) ions dissolution tested in a physiological solution. The concentration of cadmium dissolved from CdS/ZnS nanocomposites with variable Cd:Zn ratio was 2.5-5.0 MUg.mL(-1), whereas the concentration for pure CdS was much higher - 53 MUg.ml(-1). The presence of ZnS in the nanocrystalline composite strongly reduced the release of cadmium into the physiological solution, which simulated the environment in the human body. The obtained CdS/ZnS quantum dots can serve as labeling media and co-agents in future anti-cancer drugs, because of their potential in theranostic applications. PMID- 26478400 TI - Influence of microstructural modifications induced by ultrasonic impact treatment on hardening and corrosion behavior of wrought Co-Cr-Mo biomedical alloy. AB - In this work, biomedical Co-28Cr-6Mo alloy is subjected to ultrasonic impact treatment (UIT). XRD, TEM and SAED analyses show that the plastic deformation induced by the UIT process results in a complex microstructural formation in surface layer of Co-28Cr-6Mo alloy. The peculiar feature observed in the alloy structure by TEM is the formation of Lomer-Cottrell locks originated by simultaneous sliding of Shockley partial dislocations in intersecting planes. At the beginning of the UIT process (till the strain extent e ~ 0.2), dislocation pile-ups are gathered in front of the Lomer-Cottrell locks stimulating the formation of a great number of chaotic stacking faults (SFs) packets (incompletely transformed martensite), which are predominant with regard to the occurrence of epsilon-martensite and micro-twins. The incompletely transformed martensite hinders the shear translation through the twin boundaries and suppresses grain subdivision in surface layer of Co-28Cr-6Mo alloy at the UIT process used. On-going deformation to e ~ 0.4 leads to further modification of microstructure in the micron-scale gamma-grains, which consists of numerous Lomer Cottrell locks, chaotic subtraction SFs, intersected nano-twins and fine lathes of epsilon-martensite with average size of approx. 50-100 nm. The observed structural features (at e ~ 0.4) allow adequately explaining noticeable increase in microhardness without any cracks/cleavages in surface layer. Enhanced corrosion resistance of Co-28Cr-6Mo alloy, which manifests itself with less negative corrosion potential and lower corrosion and passivity currents in potentiodynamic curve, is promoted by the UIT induced oxide films and the following structural features: the CSL type of gamma/epsilon interfacial boundaries, uniformly distributed fine carbides, and high fraction of the grains oriented with close packed (111)gamma and (0002)epsilon planes parallel to the surface of the UIT-processed specimen. PMID- 26478401 TI - Differentiation potential of SHEDs using biomimetic periosteum containing dexamethasone. AB - Mimicking the architecture of the natural environment in vivo is an effective strategy for tissue engineering. The periosteum has an important function in bone regeneration. However, the harvesting of autogenous periosteum has the disadvantages of donor site morbidity and limited donor sources. This study uses an innovative artificial periosteum that forms dexamethasone (DEX)-containing polyvinyl alcohol (PVA) nanofiber obtained from skin fibrous scaffold. The aim was to evaluate the effect on bone healing of osteogenic differentiation in stems originating from human exfoliated deciduous teeth (SHEDs) in vitro. The microstructure of fabricated periosteum was observed through SEM, and results showed the apparent homogenous distribution of porous structures. DEX was also found to be continuously released into the culture medium from the periosteum for 28 days. MTT results further revealed that fabricated periosteum was cytocompatible and non-toxic to SHEDs. After 21 days of induced culture, the expression of alkaline phosphatase activity and calcium mineralization notably increased. Osteogenic results showed high early and late osteoblast gene expression by RT-PCR analysis, such as collagen type I, Runx2, OPN, and OCN. The osteoblastic protein expression of BMP-2 and OCN was clearly observed as well under fluorescence microscopy. The results, which could be applied to bone regeneration, demonstrated that skin fibrous scaffold provided an osteoinductive environment for stem cells to differentiate and that PVA nanofiber was a suitable reservoir for osteogenic factors with controlled release profile. PMID- 26478402 TI - HLC/pullulan and pullulan hydrogels: their microstructure, engineering process and biocompatibility. AB - New locally injectable biomaterials that are suitable for use as soft tissue fillers are needed to address a significant unmet medical need. In this study, we used pullulan and human-like collagen (HLC) based hydrogels with various molecular weights (MWs) in combination therapy against tissue defects. Briefly, pullulan was crosslinked with NaIO4 to form a pullulan hydrogel and then may coupled with HLC using the reaction between the -NH2 end-group of HLC and the CHO group present on the aldehyde pullulan to form the HLC/pullulan hydrogel, wherein the NaIO4 acted as the crosslinking and oxidizing agent. The good miscibility of pullulan and HLC in the hydrogels was confirmed via Fourier transform infrared spectroscopy, scanning electron microscopy, compression testing, enzyme degradation testing, cell adhesions, live/dead staining and subcutaneous filling assays. Here, pullulan hydrogels with various MWs were fabricated and physicochemically characterized. Limitations of the pullulan hydrogels included inflammation, poor mechanical strength, and degradation. By contrast, the properties of the HLC/pullulan hydrogels strongly enhanced. The efficacy of these hydrogels was evaluated both in vitro and in vivo. Our results indicate that HLC/pullulan hydrogels may have therapeutic value as efficient soft tissue fillers, with reduced inflammation, improved cell adhesion and delayed hydrogel degradation. PMID- 26478403 TI - Effect of nanocomposite packaging containing ZnO on growth of Bacillus subtilis and Enterobacter aerogenes. AB - Recent advances in nanotechnology have opened new windows in active food packaging. Nano-sized ZnO is an inexpensive material with potential antimicrobial properties. The aim of the present study is to evaluate the antibacterial effect of low density Polyethylene (LDPE) containing ZnO nanoparticles on Bacillus subtilis and Enterobacter aerogenes. ZnO nanoparticles have been synthesized by facil molten salt method and have been characterized by X-ray diffraction (XRD), and scanning electron microscopy (SEM). Nanocomposite films containing 2 and 4 wt.% ZnO nanoparticles were prepared by melt mixing in a twin-screw extruder. The growth of both microorganisms has decreased in the presence of ZnO containing nanocomposites compared with controls. Nanocomposites with 4 wt.% ZnO nanoparticles had stronger antibacterial effect against both bacteria in comparison with the 2 wt.% ZnO containing nanocomposites. B. subtilis as Gram positive bacteria were more sensitive to ZnO containing nanocomposite films compared with E. aerogenes as Gram-negative bacteria. There were no significant differences between the migration of Zn ions from 2 and 4 wt.% ZnO containing nanocomposites and the released Zn ions were not significantly increased in both groups after 14 days compared with the first. Regarding the considerable antibacterial effects of ZnO nanoparticles, their application in active food packaging can be a suitable solution for extending the shelf life of food. PMID- 26478404 TI - Enhancement of the antimicrobial properties of orthorhombic molybdenum trioxide by thermal induced fracturing of the hydrates. AB - The oxides of the transition metal molybdenum exhibit excellent antimicrobial properties. We present the preparation of molybdenum trioxide dihydrate (MoO3 * 2H2O) by an acidification method and demonstrate the thermal phase development and morphological evolution during and after calcination from 25 degrees C to 600 degrees C. The thermal dehydration of the material was found to proceed in two steps. Microbiological roll-on tests using Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa were performed and exceptional antimicrobial activities were determined for anhydrous samples with orthorhombic lattice symmetry and a large specific surface area. The increase in the specific surface area is due to crack formation and to the loss of the hydrate water after calcination at 300 degrees C. The results support the proposed antimicrobial mechanism for transition metal oxides, which based on a local acidity increase as a consequence of the augmented specific surface area. PMID- 26478405 TI - Enhancement of chondrogenic differentiation of rabbit mesenchymal stem cells by oriented nanofiber yarn-collagen type I/hyaluronate hybrid. AB - Cartilage defects cause joint pain and loss of mobility. It is crucial to induce the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by both biological and structural signals in cartilage tissue engineering. Sponge like scaffolds fabricated using native cartilage extracellular matrix components can induce the BMSC differentiation by biological signals and limited structural signals. In this study, an oriented poly(L-lactic acid)-co-poly(epsilon caprolactone) P(LLA-CL)/collagen type I (Col-I) nanofiber yarn mesh, fabricated by dynamic liquid electrospinning served as a skeleton for a freeze-dried Col I/hyaluronate (HA) chondral phase (SPONGE) containing both structural and biological signals to guide BMSC chondrogenic differentiation. In vitro results show that the Yarn Col-I/HA hybrid scaffold (Yarn-CH) promotes orientation, adhesion and proliferation of BMSCs better than SPONGE. Furthermore, BMSCs seeded on the Yarn-CH scaffold demonstrated a large increase in the glycosaminoglycan content and expression of collagen type II following a 21-day culture. PMID- 26478406 TI - Effect of autoclaving and sintering on the formation of beta-wollastonite. AB - beta-wollastonite (beta-CaSiO3) was synthesized from rice husk ash and calcium carbonate, and a study of the effects of the autoclaving and sintering steps is presented here. Autoclaving and sintering at 8h and 2h yielded the beta wollastonite phase in full, with improved crystallinity. Nucleation between rice husk ash and calcium oxide occurred around 135 degrees C, pressure 0.24 MPa, and growth proved to be more crystalline after the ripening period. For shorter processing times, and for both unsintered and unautoclaved samples, cristobalite and unstable tricalcium silicate phases were present. Crystallite size was increased by longer sintering times but reduced by longer autoclaving times. The beta-wollastonite obtained had a random branch-like structure. In conclusion, the introduction of the autoclaving step successfully obtained beta-wollastonite from a reaction between rice husk ash and calcium oxide. PMID- 26478407 TI - Study of the boron levels in serum after implantation of different ratios nano hexagonal boron nitride-hydroxy apatite in rat femurs. AB - Boron and its derivatives are effective in bone recovery and osteointegration. However, increasing the boron levels in body liquids may cause toxicity. The aim of our study is to investigate serum boron levels using ICP-MS after implantation of different ratios of nano-hBN-HA composites in rat femurs. All rats were (n=126) divided into five experimental groups (n=24) and one healthy group (6 rats); healthy (Group1), femoral defect + %100 HA (Group2), femoral defect + %2.5 hBN + %97.5 HA (Group3), femoral defect + %5 hBN + %95 HA (Group4), femoral defect + %10 hBN + %90 HA (Group5), femoral defect + %100 hBN (Group6). The femoral defect was created in the distal femur (3mm drill-bit). Each implant group was divided into four different groups (n=24) also 6 rats sacrificed for each groups in one week intervals during four weeks. In our results; at 1, 2, 3, and 4 weeks after implantation near bone tissue, serum levels of boron were evaluated using ICP-MS. We demonstrated that neither short-term nor long-term implantation of hBN-HA composite resulted in statistically increased serum boron levels in experimental groups compared to healthy group. In conclusion, this study investigated the implant material produced form hBN-HA for the first time. Our data suggest that hBN is a new promising target for biomaterial and implant bioengineers. PMID- 26478408 TI - Gold nanorods contained polyvinyl alcohol/chitosan nanofiber matrix for cell imaging and drug delivery. AB - Gold nanorods (AuNRs) that contained polyvinyl alcohol/chitosan (PVA/CS) hybrid nanofibers with dual functions are successfully fabricated by a simple electrospinning method. The results of transmission electron microscopy (TEM), X ray diffraction (XRD) and energy dispersive X-ray (EDX) spectroscopy indicate that AuNRs are indeed encapsulated into the PVA/CS hybrid nanofibers. FTIR spectra results demonstrate that the chemical structures of PVA and CS are not affected when the AuNRs are introduced into the fibers. In vitro cytotoxicity test reveals that the hybrid fibers involving AuNRs are completely biocompatible. The as-prepared fibers can be used as a carrier for anticancer agent doxorubicin (DOX), and the drug is delivered into the cell nucleus. The AuNRs and DOX incorporated fibers are effective for inhibiting the growth and proliferation of ovary cancer cells and they can also be used as the cell imaging agent due to the unique optical properties of AuNRs. The nanofiber matrix combining two functions of cell imaging and drug delivery may be of great application potential in biomedical-related areas. PMID- 26478409 TI - Voltammetric studies of Azathioprine on the surface of graphite electrode modified with graphene nanosheets decorated with Ag nanoparticles. AB - By using graphene nanosheets decorated with Ag nanoparticles (AgNPs-G) as an effective approach for the surface modification of pyrolytic graphite electrode (PGE), a sensing platform was fabricated for the sensitive voltammetric determination of Azathioprine (Aza). The prepared AgNPs-G nanosheets were characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), UV-vis and Raman spectroscopy techniques. The electrochemical behavior of Aza was investigated by means of cyclic voltammetry. Comparing to the bare PGE, a remarkable enhancement was observed in the response characteristics of Aza on the surface of the modified electrode (AgNPs-G/PGE) as well as a noticeable decrease in its reduction overpotential. These results can be attributed to the incredible enlargement in the microscopic surface area of the electrode due to the presence of graphene nanosheets together with strong adsorption of Aza on its surface. The effect of experimental parameters such as accumulation time, the amount of modifier suspension and pH of the supporting electrolyte were also optimized toward obtaining the maximum sensitivity. Under the optimum conditions, the calibration curve studies demonstrated that the peak current increased linearly with Aza concentrations in the range of 7 * 10(-7) to 1 * 10(-4)mol L(-1) with the detection limit of 68 nM. Further experiments revealed that the modified electrode can be successfully applied for the accurate determination of Aza in pharmaceutical preparations. PMID- 26478410 TI - Biomimetic synthesized bimodal nanoporous silica: Bimodal mesostructure formation and application for ibuprofen delivery. AB - The present paper innovatively reports bimodal nanoporous silica synthesized using biomimetic method (B-BNS) with synthesized polymer (C16-L-serine) as template. Formation mechanism of B-BNS was deeply studied and exploration of its application as carrier of poorly water-soluble drug ibuprofen (IBU) was conducted. The bimodal nanopores and curved mesoscopic channels of B-BNS were achieved due to the dynamic self-assembly of C16-L-serine induced by silane coupling agent (3-aminopropyltriethoxysilane, APTES) and silica source (tetraethoxysilane, TEOS). Characterization results confirmed the successful synthesis of B-BNS, and particularly, nitrogen adsorption/desorption measurement demonstrated that B-BNS was meso-meso porous silica material. In application, B BNS loaded IBU with high drug loading content due to its enlarged nanopores. After being loaded, IBU presented amorphous phase because nanoporous space and curved mesoscopic channels of B-BNS prevented the crystallization of IBU. In vitro release result revealed that B-BNS controlled IBU release with two release phases based on bimodal nanopores and improved dissolution in simulated gastric fluid due to crystalline conversion of IBU. It is convincible that biomimetic method provides novel theory and insight for synthesizing bimodal nanoporous silica, and unique functionalities of B-BNS as drug carrier can undoubtedly promote the application of bimodal nanoporous silica and development of pharmaceutical science. PMID- 26478411 TI - Study of biomechanical, anatomical, and physiological properties of scorpion stingers for developing biomimetic materials. AB - Through natural selection, many animal organs have evolved superior mechanical properties and elegant hierarchical structures adaptive to their multiple biological functions. We combine experiments and theory to investigate the composition-structure-property-function relations of scorpion stingers. Their hierarchical structures and functionally gradient mechanical properties were revealed. Slow motion analysis of the penetration process of a scorpion stinger was performed to examine the refined survival skills of scorpions. An experiment based mechanics model of the stinger was proposed, the results of which revealed an optimized range of penetration angle in an insertion event. Both theoretical and numerical results are in good agreement with our experimental measurements. The analysis method and physical insights of this work are potentially important for investigating a general class of sharp-edge biological materials, e.g., cattle horns, spider fangs, cat claws, and plant thorns. PMID- 26478412 TI - Porous poly(DL-lactic acid) matrix film with antimicrobial activities for wound dressing application. AB - Poly(lactic acid) (PLA) is polymeric biomaterial that has been used for wound dressing due to its biodegradability and biocompatibility. However, PLA has some limitations including poor toughness, low degradation rate and high hydrophobicity. The aim of this study is to develop an antibiotic drug-loaded PLA porous film as wound dressing with antibacterial activity. PLA porous film was fabricated by temperature change technique using solvent casting method. Polyethylene glycol (PEG) 400 was added for improving the pore interconnectivity of film. Gentamicin sulfate (GS) or metronidazole (MZ) was incorporated into PLA porous films. PLA containing PEG 400 exhibited the more amorphous form than plain PLA film and contained 55.31 +/- 2.85% porosity and 20 MUm of the pore size which significantly improved the water vapor transmission rate, oxygen transmission rate, degradation rate and percentage of drug release, respectively. Drug-loaded porous films efficiently inhibited the bacteria growth. GS-loaded film inhibited Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, whereas MZ loaded film inhibited Bacteroides fragilis and the sustainable antibacterial activity was attained for 7 days. PMID- 26478413 TI - Development of a novel starch with a three-dimensional ordered macroporous structure for improving the dissolution rate of felodipine. AB - In this study, silica nanospheres with different particle sizes were used as hard template for synthesis of a starch with a novel three-dimensional ordered macroporous structure (3DOMTS). As a pharmaceutical adjuvant, 3DOMTS was used to improve the dissolution rate and oral relative bioavailability of water-insoluble drugs. Felodipine (FDP) was chosen as a model drug and was loaded into the 3DOMTS by solvent evaporation. FDP loading into 3DOMTS with different pore sizes was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimeter (DSC), powder X-ray diffractometer (PXRD) and Fourier-Transform Infrared (FTIR). The results obtained showed that FDP was present in the pores in an amorphic or microcrystalline state. The in vitro dissolution results showed that 3DOMTS could effectively improve the dissolution rate of FDP in comparison with commercial common tablets. Pharmacokinetic results indicated that the oral relative bioavailability of self made FDP-3DOMTS tablets were 184%, showing that 3DOMTS produced a significantly increased oral absorption of FDP. In conclusion, 3DOMTS exhibits the dual potential of improving the dissolution rate of poorly water soluble drugs and the novel filler produced by direct compression technology confirming that 3DOMTS will be useful for many applications in the field of pharmaceutics. PMID- 26478415 TI - One-pot synthesize of dendritic hyperbranched PAMAM and assessment as a broad spectrum antimicrobial agent and anti-biofilm. AB - Hyperbranched poly(amidoamine) (h-PAMAM) compound was synthesized from diethylene triamine and different moles percent of methyl acrylate using simple one-pot and commercial synthesis method. The synthesized h-PAMAM was provided with ester and amine terminations. Chemical structure of the synthesized h-PAMAM, with different terminations, was confirmed by Fourier Transform Infrared (FTIR) spectroscopy. In addition, the size and the distribution of the synthesized h-PAMAM were evaluated using Dynamic Light Scattering (DLS) analysis. The molecular weights of the synthesized modified hyperbranched polymer, with different terminations, were measured using Gel-permeation chromatograph. The ill-structure of the h-PAMAM with different molar feed methyl acrylate:diethylene triamine (MA:DETA) ratios was designed as h-PAMAM-amine, h-PAMAM-ester and h-PAMAM-amine plus (sharing similar chemical and physical properties with well-defined poly(amidoamine) (PAMAM) dendrimers in generation 2, 2.5 or 3, respectively). Moreover, the synthesized compound expressed broad spectrum antimicrobial and anti-biofilms activity. PMID- 26478414 TI - Modified silk fibroin scaffolds with collagen/decellularized pulp for bone tissue engineering in cleft palate: Morphological structures and biofunctionalities. AB - Cleft palate is a congenital malformation that generates a maxillofacial bone defect around the mouth area. The creation of performance scaffolds for bone tissue engineering in cleft palate is an issue that was proposed in this research. Because of its good biocompatibility, high stability, and non-toxicity, silk fibroin was selected as the scaffold of choice in this research. Silk fibroin scaffolds were prepared by freeze-drying before immerging in a solution of collagen, decellularized pulp, and collagen/decellularized pulp. Then, the immersed scaffolds were freeze-dried. Structural organization in solution was observed by Atomic Force Microscope (AFM). The molecular organization of the solutions and crystal structure of the scaffolds were characterized by Fourier transform infrared (FT-IR) and X-ray diffraction (XRD), respectively. The weight increase of the modified scaffolds and the pore size were determined. The morphology was observed by a scanning electron microscope (SEM). Mechanical properties were tested. Biofunctionalities were considered by seeding osteoblasts in silk fibroin scaffolds before analysis of the cell proliferation, viability, total protein assay, and histological analysis. The results demonstrated that dendrite structure of the fibrils occurred in those solutions. Molecular organization of the components in solution arranged themselves into an irregular structure. The fibrils were deposited in the pores of the modified silk fibroin scaffolds. The modified scaffolds showed a beta-sheet structure. The morphological structure affected the mechanical properties of the silk fibroin scaffolds with and without modification. Following assessment of the biofunctionalities, the modified silk fibroin scaffolds could induce cell proliferation, viability, and total protein particularly in modified silk fibroin with collagen/decellularized pulp. Furthermore, the histological analysis indicated that the cells could adhere in modified silk fibroin scaffolds. Finally, it can be deduced that modified silk fibroin scaffolds with collagen/decellularized pulp had the performance for bone tissue engineering and a promise for cleft palate treatment. PMID- 26478416 TI - Antibacterial nanocarriers of resveratrol with gold and silver nanoparticles. AB - This study focused on the preparation of resveratrol nanocarrier systems and the evaluation of their in vitro antibacterial activities. Gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) for resveratrol nanocarrier systems were synthesized using green synthetic routes. During the synthesis steps, resveratrol was utilized as a reducing agent to chemically reduce gold and silver ions to AuNPs and AgNPs. This system provides green and eco-friendly synthesis routes that do not involve additional chemical reducing agents. Resveratrol nanocarriers with AuNPs (Res-AuNPs) and AgNPs (Res-AgNPs) were observed to be spherical and to exhibit characteristic surface plasmon resonance at 547 nm and at 412-417 nm, respectively. The mean size of the nanoparticles ranged from 8.32 to 21.84 nm, as determined by high-resolution transmission electron microscopy. The face-centered cubic structure of the Res-AuNPs was confirmed by high-resolution X-ray diffraction. Fourier-transform infrared spectra indicated that the hydroxyl groups and C=C in the aromatic ring of resveratrol were involved in the reduction reaction. Res-AuNPs retained excellent colloidal stability during ultracentrifugation and re-dispersion, suggesting that resveratrol also played a role as a capping agent. Zeta potentials of Res-AuNPs and Res-AgNPs were in the range of -20.58 to -48.54 mV. Generally, against Gram-positive and Gram-negative bacteria, the Res-AuNPs and Res-AgNPs exhibited greater antibacterial activity compared to that of resveratrol alone. Among the tested strains, the highest antibacterial activity of the Res-AuNPs was observed against Streptococcus pneumoniae. The addition of sodium dodecyl sulfate during the synthesis of Res AgNPs slightly increased their antibacterial activity. These results suggest that the newly developed resveratrol nanocarrier systems with metallic nanoparticles show potential for application as nano-antibacterial agents with enhanced activities. PMID- 26478417 TI - In vitro study of bioactivity of homemade tissue-engineered periosteum. AB - This study was aimed to evaluate in vitro bioactivity of tissue-engineered periosteum (TEP) which was fabricated by coupling either rabbits' MSCs or osteodifferentiated MSCs (O-MSCs) with porcine small intestinal submucosa (SIS), and that produced two kinds of TEPs (M1=MSCs+SIS and M2=Osteoblast+SIS). The cell adherence was observed under scanning electronic microscopy (SEM). Cell proliferation was measured by 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl-2 H tetrazoliumbromide (MTT) test. In vitro osteogenetic potential of TEPs was evaluated kinetically at 0, 5, 10 and 15 d by measuring alkaline phosphatase (ALP) activity, and semi-quantitative assay of osteocalcin and collagen type I expression with Western blot. SEM indicated that either MSCs or O-MSCs could adhere and survive on SIS, but MTT test revealed that SIS was more preferable for O-MSCs than MSCs in proliferative aspect. In contrast, ALP activity, osteocalcin and collagen type I expression of M2 were higher than M1 in general. Kinetically, osteocalcin and collagen type I expression demonstrated a continuous increase, while ALP activity of both groups was displayed an early peak around the fifth day, followed a decrease trend. In conclusion, TEP, especially M2, has an active osteogenesis and is promising for in vivo bone defect reparation via a supposed biomimetic procedure of intramembranous ossification. PMID- 26478418 TI - Development of porous Ti6Al4V/chitosan sponge composite scaffold for orthopedic applications. AB - A novel composite scaffold consisting of porous Ti6Al4V part filled with chitosan sponge was fabricated using a combination of electron beam melting and freeze drying. The mechanical properties of porous Ti6Al4V part were examined via compressive test. The ultimate compressive strength was 85.35 +/- 8.68 MPa and the compressive modulus was 2.26 +/- 0.42 GPa. The microstructure of composite scaffold was characterized using scanning electron microscopy. The chitosan sponge filled in Ti6Al4V part exhibited highly porous and well-interconnected micro-pore architecture. The osteoblastic cells were seeded on scaffolds to test their seeding efficiency and biocompatibility. Significantly higher cell seeding efficiency was found on composite scaffold. The biological response of osteoblasts on composite scaffolds was superior in terms of improved cell attachment, higher proliferation, and well-spread morphology in relation to porous Ti6Al4V part. These results suggest that the Ti6Al4V/chitosan composite scaffold is potentially useful as a biomedical scaffold for orthopedic applications. PMID- 26478419 TI - Chitosan nanoparticles enhance the antibacterial activity of chlorhexidine in collagen membranes used for periapical guided tissue regeneration. AB - Endodontic failure is mainly associated with the persistence of microbial infection in the root canal system and/or the periradicular area. Microorganisms and their toxins located in the root canal system may trigger apical periodontitis and tissue destruction. Tissue regeneration in periapical surgery by using membrane barriers has shown an improved healing and bone closure. However, bacterial membrane contamination is a main reason of failure. In this in vitro study, different brands of chlorhexidine, a combination of chitosan nanoparticles containing chlorhexidine were tested against Enterococcus faecalis on agar plate's cultures and infected collagen membranes. Our results indicated that chitosan nanoparticles acted synergistically with chlorhexidine, inhibiting and eliminating significantly a greater amount of colony former units in both BHI agar cultures and infected collagen membranes. These results suggested that chitosan nanoparticles could be used to improve regenerative procedures in periapical surgery. PMID- 26478420 TI - Investigating actinomycin D binding to G-quadruplex, i-motif and double-stranded DNA in 27-nt segment of c-MYC gene promoter. AB - c-MYC DNA is an attractive target for drug design, especially for cancer chemotherapy. Around 90% of c-MYC transcription is controlled by NHE III1, whose 27-nt purine-rich strand has the ability to form G-quadruplex structure. In this investigation, interaction of ActD with 27-nt G-rich strand (G/c-MYC) and its equimolar mixture with the complementary sequence, (GC/c-MYC) as well as related C-rich oligonucleotide (C/c-MYC) was evaluated. Molecular dynamic simulations showed that phenoxazine and lactone rings of ActD come close to the outer G tetrad nucleotides indicating that ActD binds through end-stacking to the quadruplex DNA. RMSD and RMSF revealed that fluctuation of the quadruplex DNA increases upon interaction with the drug. The results of spectrophotometry and spectrofluorometry indicated that ActD most probably binds to the c-MYC quadruplex and duplex DNA via end-stacking and intercalation, respectively and polarity of ActD environment decreases due to the interaction. It was also found that binding of ActD to the GC-rich DNA is stronger than the two other forms of DNA. Circular dichroism results showed that the type of the three forms of DNA structures doesn't change, but their compactness alters due to their interaction with ActD. Finally, it can be concluded that ActD binds differently to double stranded DNA, quadruplex DNA and i-motif. PMID- 26478421 TI - Neurotypic cell attachment and growth on III-nitride lateral polarity structures. AB - III-nitride materials have recently received increasing levels of attention for their potential to successfully interface with, and sense biochemical interactions in biological systems. Expanding on available sensing schemes (including transistor-based devices,) a III-N lateral polarity structure capable of introducing quasi-phase matching through a periodic polarity grating presents a novel platform for second harmonic generation. This platform constitutes a non linear optical phenomenon with exquisite sensitivity to the chemical state of a surface or interface. To characterize the response of a biological system to the nanostructured lateral polarity structures, we cultured neurotypic PC12 cells on AlGaN with varying ratios of Al:Ga - 0, 0.4, 0.6, and 1 - and on surfaces of varying pitch to the III-polar vs. N-polar grating - 5, 10, 20 and 50 MUm. While some toxicity associated with increasing Al is observed, we documented and quantified trends in cell responses to the local material polarity and nanoscale roughness. The nitrogen-polar material has a significantly higher nanoscale roughness than III-polar regions, and a 80-200 nm step height difference between the III-polar and N-polar materials in the lateral polarity configuration generates adequate changes in topography to influence cell growth, improves cell adhesion and promotes cell migration along the direction of the features. As the designed material configuration is further explored for biochemical sensing, the lateral polarity scheme may provide a route in assessing the non-specific protein adsorption to this varying nano-topography that drives the subsequent cell response. PMID- 26478422 TI - Photochemically modified diamond-like carbon surfaces for neural interfaces. AB - Diamond-like carbon (DLC) was modified using a UV functionalization method to introduce surface-bound amine and aldehyde groups. The functionalization process rendered the DLC more hydrophilic and significantly increased the viability of neurons seeded to the surface. The amine functionalized DLC promoted adhesion of neurons and fostered neurite outgrowth to a degree indistinguishable from positive control substrates (glass coated with poly-L-lysine). The aldehyde functionalized surfaces performed comparably to the amine functionalized surfaces and both additionally supported the adhesion and growth of primary rat Schwann cells. DLC has many properties that are desirable in biomaterials. With the UV functionalization method demonstrated here it may be possible to harness these properties for the development of implantable devices to interface with the nervous system. PMID- 26478423 TI - Thermogelling chitosan-collagen-bioactive glass nanoparticle hybrids as potential injectable systems for tissue engineering. AB - Recently, stimuli-responsive nanocomposite-derived hydrogels have gained prominence in tissue engineering because they can be applied as injectable scaffolds in bone and cartilage repair. Due to the great potential of these systems, this study aimed to synthesize and characterize novel thermosensitive chitosan-based composites, chemically modified with collagen and reinforced by bioactive glass nanoparticles (BG) on the development of injectable nanohybrids for regenerative medicine applications. Thus, the composite hydrogels were extensively characterized by structural, morphological, rheological, and biological testing. The composites showed thermosensitive response with the gelation temperature at approximately 37 degrees C, which is compatible with the human body temperature. In addition, scanning electron microscopy (SEM) analysis indicated that the chitosan hydrogels exhibited 3D-porous structures, and the incorporation of collagen in the system caused increase on the average pore size. Fourier transform infrared spectroscopy (FTIR) analysis indicated the main functional groups of each component of the composite system and their chemical interactions forming the scaffold. Moreover, rheological measurements were employed to assess the viscoelastic behavior of the hydrogels as a function of the temperature. The results demonstrated that the addition of collagen and bioactive glass increases the mechanical properties after the gelation process. The addition of 2 wt.% of BG nanoparticles caused an increase of approximately 39% on stiffness compared to pure chitosan and the addition of 30 wt.% collagen caused a further increase on the stiffness by 95%. The cytotoxicity and cell viability of the hydrogels were assessed by MTT and LIVE/DEAD(r) assays, where the results demonstrated no toxic effect of the composites on the human osteosarcoma cell culture (SAOS) and kidney cells line of human embryo (HEK 293 T). Hence, it can be stated that innovative composites were successfully designed and synthesized in this research with promising potential to be used as thermoresponsive biomaterials for bone-tissue bioapplications. PMID- 26478424 TI - Bonding and bio-properties of hybrid laser/magnetron Cr-enriched DLC layers. AB - Chromium-enriched diamond-like carbon (DLC) layers were prepared by a hybrid technology using a combination of pulsed laser deposition (PLD) and magnetron sputtering. XRD revealed no chromium peaks, indicating that the layers are mostly amorphous. Carbon (sp(2) and sp(3) bonds) and chromium bonds were determined by XPS from C 1s, O 1s, and Cr 2p photoelectron peaks. Depending on the deposition conditions, the concentration of Cr in DLC layers moved from zero to 10 at.% for as-received sample surfaces, and to about 31 at.% after mild sputter-cleaning by argon ion cluster beam. It should be noted that the most stable Cr(3+) bonding state is in Cr2O3 and Cr(OH)3, and that there is the toxic Cr(6+) state in CrO3. The surface content of hexavalent chromium in the Cr 2p3/2 spectra is rather low, but discernible. The population density of Saos-2 cells was the highest in samples containing higher concentrations of chromium 7.7 and 10 at.%. This means that higher concentrations of chromium supported the cell adhesion and proliferation. In addition, as revealed by a LIVE/DEAD viability/cytotoxicity kit, the cells on all Cr-containing samples maintained high viability (96 to 99%) on days 1 and 3 after seeding. However, this seemingly positive cell behavior could be associated with the risk of dedifferentiation and oncogenic transformation of cells. PMID- 26478425 TI - Biomimetic synthesis of ribbon-like hydroxyapatite employing poly(l-arginine). AB - Binding of a polypeptide on colloidal particles can affect the dissolution of mineral, initiate crystal nucleation and change the growth kinetics of the precipitated crystal. In this study the synthesis of hydroxyapatite nanocrystals was performed in the presence of poly(L-arginine), PA. Aqueous solutions of Ca(2+), phosphate, and PA were employed at calcium:PA molar ratios ranging from 2:1 to 1:2 and the resulting suspensions were hydrothermally treated at 80 degrees C for 16 h, or at 130 degrees C for 6h. The resulting nanomaterials were characterized by XRD, FTIR, TEM, SEM, and TGA. It was found that the presence of PA promotes HAP formation and affects its crystal size and morphology possibly through a rather specific interaction between the homopeptide that is positively charged and also that adopts a beta-sheet conformation and the negatively charged c-plane of the growing HAP crystal. In all cases, hexagonal HAP crystals with thin ribbon-like morphology were obtained. Increase of the PA ratio and of the hydrothermal temperature leads to more homogeneous and narrower size distributions with crystallites having widths ranging between 5 to 50 nm and lengths ranging from 50 to 450 nm. PMID- 26478426 TI - Biocorrosion behavior of biodegradable nanocomposite fibers coated layer-by-layer on AM50 magnesium implant. AB - This article demonstrates the use of hybrid nanofibers to improve the biodegradation rate and biocompatibility of AM50 magnesium alloy. Biodegradable hybrid membrane fiber layers containing nano-hydroxyapatite (nHA) particles and poly(lactide)(PLA) nanofibers were coated layer-by-layer (LbL) on AM50 coupons using a facile single-step air jet spinning (AJS) approach. The corrosion performance of coated and uncoated coupon samples was investigated by means of electrochemical measurements. The results showed that the AJS 3D membrane fiber layers, particularly the hybrid membrane layers containing a small amount of nHA (3 wt.%), induce a higher biocorrosion resistance and effectively decrease the initial degradation rate compared with the neat AM50 coupon samples. The adhesion strength improved highly due to the presence of nHA particles in the AJS layer. Furthermore, the long biodegradation rates of AM50 alloy in Hank's balanced salt solution (HBSS) were significantly controlled by the AJS-coatings. The results showed a higher cytocompatibility for AJS-coatings compared to that for neat Mg alloys. The nanostructured nHA embedded hybrid PLA nanofiber coating can therefore be a suitable coating material for Mg alloy as a potential material for biodegradable metallic orthopedic implants. PMID- 26478427 TI - Rapid determination of furosemide in drug and blood plasma of wrestlers by a carboxyl-MWCNT sensor. AB - A novel method is developed for the quantification of furosemide in biological fluids. The method is based on the electro-reduction of Zn(II)-furosemide complex at carboxyl-MWCNT modified glassy carbon electrode. It is shown that, in Britton Robinson buffer (pH5.7) the reduction peak of Zn(II)-furosemide complex formed at -1.0 V (versus, Ag/AgCl). The increment of current signal obtained from the reduction peak current of the Zn(II)-furosemide complex was rectilinear with furosemide concentration in the range of 0.03 to 140.0 MUg ml(-1), with a detection limit of 0.007 MUg ml(-1). The drug recovery ranged between 97.8% and 100.8% and the mean drug recovery was 98.89%. The accuracies (relative error% and RSD%) were less than 15% and are acceptable according to the US FDA guideline for bioanalytical method validation. The sensor was used for quantification of furosemide in drug and biological fluid samples. The data of drug analysis were compared with the standard method. PMID- 26478429 TI - Inorganic hemostats: The state-of-the-art and recent advances. AB - Hemorrhage is the most common cause of death both in hospitals and on the battlefield. The need for an effective hemostatic agent remains, since all injuries are not amenable to tourniquet use. There are many topical hemostatic agents and dressings available to control severe bleeding. This article reviews the most commonly used inorganic hemostats, subcategorized as zeolite and clay based hemostats. Their hemostatic functions as well as their structural properties that are believed to induce hemostasis are discussed. The most important findings from in vitro and in vivo experiments are also covered. PMID- 26478428 TI - Nano-assemblies consisting of Pd/Pt nanodendrites and poly (diallyldimethylammonium chloride)-coated reduced graphene oxide on glassy carbon electrode for hydrogen peroxide sensors. AB - Non-enzymatic hydrogen peroxide (H2O2) sensors were fabricated on the basis of glassy carbon (GC) electrode modified with palladium (Pd) core-platinum (Pt) nanodendrites (Pt-NDs) and poly (diallyldimethylammonium chloride) (PDDA)-coated reduced graphene oxide (rGO). A facile wet-chemical method was developed for preparing Pd core-Pt nanodendrites. In this approach, the growth of Pt NDs was directed by Pd nanocrystal which could be regarded as seed. The PDDA-coated rGO could form uniform film on the surface of GC electrode, which provided a support for Pd core- Pt NDs adsorption by self-assembly. The morphologies of the nanocomposites were characterized by transmission electron microscopy, energy dispersive X-ray spectroscopy and X-ray diffraction (spectrum). Electrocatalytic ability of the nanocomposites was evaluated by cyclic voltammetry and chronoamperometric methods. The sensor fabricated by Pd core-Pt NDs/PDDA-rGO/GCE exhibited high sensitivity (672.753 MUA mM(-1) cm(-2)), low detection limit (0.027 MUM), wider linear range (0.005-0.5mM) and rapid response time (within 5s). Besides, it also exhibited superior reproducibility, excellent anti interference performance and long-term stability. The present work could afford a viable method and efficient platform for fabricating all kinds of amperometric sensors and biosensors. PMID- 26478430 TI - Nanoparticles for antimicrobial purposes in Endodontics: A systematic review of in vitro studies. AB - INTRODUCTION: Antimicrobial nanoparticles with enhanced physiochemical properties have attracted attention as modern antimicrobials, especially in the complicated oral cavity environment. The goal of the present article is to review the current state of nanoparticles used for antimicrobial purposes in root canal infections. METHODS: A review was conducted in electronic databases using MeSH keywords to identify relevant published literature in English. The analysis and eligibility criteria were documented according to the Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA-guidelines). No restrictions on publication date were imposed. Data regarding root canal disinfections, general antimicrobial mechanisms of nanoparticles, type of nanoparticles as antimicrobial agent and antimicrobial effect of nanoparticles in endodontics were collected and subjected to descriptive data analysis. RESULTS: The literature search in electronic databases according to the inclusion criteria provided 83 titles and abstracts. Among them 15 papers were related to antimicrobial effect of nanoparticles in Endodontics. Silver nanoparticles with sustainable activity were the most studied agent for its antimicrobial behavior in root canal infection. Aided polymeric nanoparticles with photo or ultrasound, glass bioactive nanoparticles as well as Calcium derivative based nanoparticles, with improved activity in comparison with the non-nano counterparts, are of importance in infection control of dental root canal. Bioactive Non-organic nanoparticles with structural capabilities present enhanced antimicrobial activity in root canal infections. DISCUSSION: All included studies showed an enhanced or at least equal effect of nanoparticulate systems to combat dental root canal infections compared to conventional antimicrobial procedures. However, it is crucial to understand their shortcomings and their probable cellular effects and toxicity as well as environmental effects. PMID- 26478431 TI - Fluoride-containing bioactive glasses: Glass design, structure, bioactivity, cellular interactions, and recent developments. AB - Bioactive glasses (BGs) are known to bond to both hard and soft tissues. Upon exposure to an aqueous environment, BG undergoes ion exchange, hydrolysis, selective dissolution and precipitation of an apatite layer on their surface, which elicits an interfacial biological response resulting in bioactive fixation, inhibiting further dissolution of the glass, and preventing complete resorption of the material. Fluorine is considered one of the most effective in-vivo bone anabolic factors. In low concentrations, fluoride ions (F(-)) increase bone mass and mineral density, improve the resistance of the apatite structure to acid attack, and have well documented antibacterial properties. F(-) ions may be incorporated into the glass in the form of calcium fluoride (CaF2) either by part substitution of network modifier oxides, or by maintaining the ratios of the other constituents relatively constant. Fluoride-containing bioactive glasses (FBGs) enhance and control osteoblast proliferation, differentiation and mineralisation. And with their ability to release fluoride locally, FBGs make interesting candidates for various clinical applications, dentinal tubule occlusion in the treatment of dentin hypersensitivity. This paper reviews the chemistry of FBGs and the influence of F(-) incorporation on the thermal properties, bioactivity, and cytotoxicity; and novel glass compositions for improved mechanical properties, processing, and bioactive potential. PMID- 26478432 TI - CTCF negatively regulates HOXA10 expression in breast cancer cells. AB - HOX genes not only play important roles in defining body patterning during embryonic development, but also control numerous cellular events in adult cells. Deregulated HOX gene expression in different cancers including breast cancer is now increasingly being reported. Given that human HOXA cluster is marked with several CTCF binding sites, we investigated whether the presence of CTCF is associated directly with expression of HOXA genes in breast cancer cells. Several HOX genes, such as HOXA4, HOXA5 and HOXA10, were deregulated by CTCF overexpression and knockdown in MCF-7 cells. Among these genes, HOXA10 is an emerging tumor suppressor for its role in activation of p53 and in countering tumorigenesis in breast cancer. Here we provided evidences that CTCF functions as a negative regulator of HOXA10 in breast cancer cells. The putative promoter region of HOXA10 lies between 5.3 and 6.1 kb upstream of its start codon and its promoter activity was negatively regulated by CTCF. Together with in-silico analysis and in vitro mutation assay we identified a 20 bp CTCF binding motif flanking with core promoter element of HOXA10. HOXA10 promoter region was kept inactivated by maintaining H3K27me3 inactivation marks in the presence of CTCF. Epigenetic silencing of HOXA10 by CTCF in breast cancer cells may contribute towards tumorigenesis by decreasing apoptosis and promoting metastasis. PMID- 26478433 TI - Lactoferrin acts as an adjuvant during influenza vaccination of neonatal mice. AB - Health policy precludes neonatal vaccination against influenza. Hence, morbidity and mortality are high under 6 months of age. Lactoferrin may activate diminished numbers of dysfunctional dendritic cells and reverse neonatal vaccine failures. Aluminum hydroxide/ALUM recruits neutrophils that secrete lactoferrin at deposition sites of antigen. We theorized lactoferrin + influenza antigen initiates an equivalent antibody response compared to ALUM. Three-day-old mice received subcutaneously 30 MUg of H1N1 hemagglutinin + 200 MUg of bovine lactoferrin versus hemagglutinin + ALUM. Controls received hemagglutinin, lactoferrin, or ALUM. After 21 days, sera measured anti-H1N1 (ELISA) and neutralizing antibody (plaque assays). ELISA detected equal antibody production with lactoferrin + hemagglutinin compared to hemagglutinin + ALUM; both sera also neutralized H1N1 virus at a 1:20 dilution (p < 0.01). Controls had no anti-H1N1 antibody. Neonates given lactoferrin had no anaphylaxis when challenged four weeks later. Lactoferrin is a safe and effective adjuvant for inducing antibody against influenza in neonates. PMID- 26478434 TI - Set1/MLL complex is indispensable for the transcriptional ability of heat shock transcription factor 2. AB - Heat shock transcription factor 2 (HSF2) is one of four mammalian HSFs, and it is essential in neurogenesis and gametogenesis. However, other aspects of this transcription factor have not been thoroughly characterized. We recently demonstrated that HSF2 suppresses the aggregation caused by polyglutamine (polyQ) protein, and that the cell protective ability of HSF2 is mediated through the induction of the small HSP alphaB-crystallin (CRYAB). In the present study, we investigated the mechanism of HSF2-induced CRYAB expression. We demonstrated that HSF2 interacted with the core component of the Set1/MLL H3K4 histone methyltransferase complex, WDR5. Indeed, HSF2 up-regulated the H3K4me3, H3K14Ac, and H3K27Ac (active histone marks) of the CRYAB promoter. WDR5 bound to the HSF2 central domain (Domain X) in vitro and in vivo, and Cys278 of HSF2 was indispensable for HSF2-WDR5 interaction. HSF2 also interacted with the Set1/MLL complex. These results suggest that the interaction with the Set1/MLL complex via binding to WDR5 is critical for the transcriptional ability of HSF2. PMID- 26478435 TI - MicroRNA-128b suppresses tumor growth and promotes apoptosis by targeting A2bR in gastric cancer. AB - MicroRNAs (miRNAs) play crucial roles in the development and progression of human cancers, including gastric cancer (GC). The discovery of miRNAs may provide a new and powerful tool for studying the mechanism, diagnosis, and treatment of GC. In this study, we aimed to investigate the role and mechanism of miR-128b in the development and progression of GC. Quantitative real-time PCR (qRT-PCR) was used to measure the expression level of miR-128b in GC tissues and cell lines. We found that miR-128b was significantly down-regulated in GC tissues and cell lines. In addition, over-expression of miR-128b inhibited GC cell proliferation, migration and invasion of GC cells in vitro. Gain-of-function in vitro experiments further showed that the miR-128b mimic significantly promoted GC cell apoptosis. Subsequent dual-luciferase reporter assay identified one of the proto oncogene A2bR as direct target of miR-128b. Therefore, our results indicate that miR-128b is a proto-oncogene miRNA that can suppresses GC proliferation and migration through down-regulation of the oncogene gene A2bR. Taken together, our results indicate that miR-128b could serve as a potential diagnostic biomarker and therapeutic option for human GC in the near future. PMID- 26478436 TI - Large Reactional Osteogenesis in Maxillary Sinus Associated with Secondary Root Canal Infection Detected Using Cone-beam Computed Tomography. AB - Inflammatory injuries in the maxillary sinus may originate from root canal infections and lead to bone resorption or regeneration. This report describes the radiographic findings of 4 asymptomatic clinical cases of large reactional osteogenesis in the maxillary sinus (MS) associated with secondary root canal infection detected using cone-beam computed tomographic (CBCT) imaging. Apical periodontitis, a consequence of root canal infection, may lead to a periosteal reaction in the MS and osteogenesis seen as a radiopaque structure on imaging scans. The use of a map-reading strategy for the longitudinal and sequential slices of CBCT images may contribute to the definition of diagnoses and treatment plans. Root canal infections may lead to reactional osteogenesis in the MS. High resolution CBCT images may reveal changes that go unnoticed when using conventional imaging. Findings may help define initial diagnoses and therapeutic plans, but only histopathology provides a definitive diagnosis. Surgical enucleation of the periapical lesion is recommended if nonsurgical root canal treatment fails to control apical periodontitis. PMID- 26478437 TI - Use of Cone-beam Computed Tomography during Retreatment of a 2-rooted Maxillary Central Incisor: Case Report of a Complex Diagnosis and Treatment. AB - A double-rooted maxillary incisor is an extremely rare anatomic variation. Only a few case reports describe this abnormal anatomy. In recent decades, cone-beam computed tomographic (CBCT) imaging has become more common for endodontic purposes. This case report describes the retreatment of double-rooted maxillary central incisors using CBCT imaging. In 2012, a 20-year-old man was referred to our department because of asymptomatic periapical lesions in teeth #8, #9, and #10. During the evaluation of a periapical radiograph, a rare anatomic variation, in the form of an additional root of tooth #9, was detected, and it was impossible to decide about the source of the lesion between teeth #9 and #10. During retreatment, after gutta-percha removal, CBCT imaging was performed; this allowed proper treatment of the additional root and a final diagnosis of normal periapical tissue of tooth #10 with no treatment needed. The 18-month follow-up revealed a healing lesion in tooth #9 and normal periapical tissue in tooth #10. During the treatment of teeth with an anatomic variation, CBCT imaging can serve as an auxiliary tool for 3-dimensional evaluation that influences treatment steps and techniques. CBCT scanning can be very useful in assessing the actual location of a periapical lesion, which influences diagnosis and treatment planning. PMID- 26478438 TI - Comparisons of the Retreatment Efficacy of Calcium Silicate and Epoxy Resin-based Sealers and Residual Sealer in Dentinal Tubules. AB - INTRODUCTION: The aim of this study was to evaluate the retreatment efficacy and amount of residual sealer in a single canal filled with either EndoSequence BC (Brasseler, Savannah, GA) or AH Plus (Dentsply DeTrey, Konstanz, Germany). METHODS: Canal obturation with gutta-percha and sealer was performed in 28 human teeth using the continuous wave technique. Group 1 (n = 13) used AH Plus sealer, and group 2 (n = 15) used EndoSequence BC sealer. After 7 days, the root fillings were removed using Gates Glidden drills and a nickel-titanium rotary system. Retreatment time was measured in seconds. Canal cleanliness was examined by scanning electron microscopy. The remaining debris in the canal space and penetration into dentinal tubules were evaluated by confocal microscopy. Retreatment time was compared using the Student t test, and differences in sealer penetration and remaining debris between the groups were analyzed using the Mann Whitney U test (P < .05). RESULTS: There was no significant difference between the 2 groups in the amount of dentin penetration, amount of debris, or retreatment time. With respect to penetration depth, the AH Plus group showed a slightly higher percentage than the BC group, with a significant difference only in the portion 6 mm from the apex (P < .05). Scanning electron microscopic images showed significant debris remaining on canal walls in both groups, whereas canal patency in retreatment was achieved in every specimen. CONCLUSIONS: The present study shows that EndoSequence BC sealer and AH Plus sealer have similar efficacy in dentin penetration and retreatment efficacy. PMID- 26478439 TI - Influence of Heat Treatment of Nickel-Titanium Rotary Endodontic Instruments on Apical Preparation: A Micro-Computed Tomographic Study. AB - INTRODUCTION: The aim of this study was to make a 3-dimensional comparison of the canal transportation and changes in apical geometry using micro-computed tomographic imaging after canal preparation with K3 (SybronEndo, Orange, CA) and K3XF (SybronEndo) file systems. METHODS: Twenty-eight mandibular molars were randomly divided into 2 groups according to the rotary system used in instrumentation: K3 or K3XF. The specimens were scanned by micro-computed tomographic imaging before and after instrumentation. Images before and after instrumentation from each group were compared with regard to canal volume, surface area, and structure model index (SMI) (paired t test, P < .05). After instrumentation, the canals from each group were compared regarding the changes in volume, surface area, SMI, and canal transportation in the last 4 apical mm (t test, P < .05). RESULTS: Instrumentation with the 2 rotary systems significantly changed the canal volume, surface area, and SMI (P < .05). There were no significant differences between instrument types concerning these parameters (P > .05). There were no significant differences between the 2 groups with regard to canal transportation in the last 4 apical mm (P > .05). CONCLUSIONS: Both rotary systems showed adequate canal preparations with reduced values of canal transportation. Heat treatment did not influence changes in root canal geometry in the apical region. PMID- 26478440 TI - The biosynthesis of allelopathic di-C-glycosylflavones from the roots of Desmodium incanum (G. Mey.) DC. AB - The allelopathic root exudate of the drought-tolerant subsistence cereal intercrop D. incanum, protecting against the parasitic weed Striga hermonthica, comprises a number of di-C-glycosylflavones specifically containing C-glucosyl, C galactosyl and C-arabinosyl moieties. Here we demonstrate that the biosynthesis of all compounds containing a C-glucose involves C-glucosylation of 2 hydroxynaringenin with subsequent C-galactosylation, C-glucosylation or C arabinosylation. In addition, the crude soluble enzyme extract converts two fluorinated 2-hydroxyflavanone analogues to corresponding mono- and di-C glycosylflavones demonstrating that some differences in C-ring substitution can be tolerated by the plant enzymes. Elucidating the biosynthesis of these C glycosylflavones (CGFs) has the potential to open up opportunities for transferring the enzymic and genetic basis for the S. hermonthica inhibiting allelopathic trait to food crop plants. PMID- 26478441 TI - Targeting transcription factor STAT3 for cancer prevention and therapy. AB - Signal Transducers and Activators of Transcription (STATs) comprise an important class of transcription factors that have been implicated in a wide variety of essential cellular functions related to proliferation, survival, and angiogenesis. Among various STAT members, STAT3 is frequently overexpressed in tumor cells as well as tissue samples, and regulates the expression of numerous oncogenic genes controlling the growth and metastasis of tumor cells. The current review briefly discusses the importance of STAT3 as a potential target for cancer therapy and also provides novel insights into various classes of existing pharmacological inhibitors of this transcription factor that can be potentially developed as anti-cancer drugs. PMID- 26478442 TI - Allosteric small-molecule kinase inhibitors. AB - Small-molecule kinase inhibitors are invaluable targeted therapeutics for the treatment of various human diseases, especially cancers. While the majority of approved and developed preclinical small-molecule inhibitors are characterized as type I or type II inhibitors that target the ATP-binding pocket of kinases, the remarkable sequential and structural similarity among ATP pockets renders the selective inhibition of kinases a daunting challenge. Therefore, targeting allosteric pockets of kinases outside the highly conversed ATP pocket has been proposed as a promising alternative to overcome current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small number of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA approval of the first small-molecule allosteric inhibitor trametinib in 2013, the progress of more than 10 other allosteric inhibitors in clinical trials, and the emergence of a pipeline of highly selective and potent preclinical molecules, have been reported in the past decade. In this article, we present the current knowledge on allosteric inhibition in terms of conception, classification, potential advantages, and summarized debatable topics in the field. Recent progress and allosteric inhibitors that were identified in the past three years are highlighted in this paper. PMID- 26478443 TI - Novel pharmacotherapy of sarcoidosis. AB - Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs. Treatment of sarcoidosis can be challenging as it is often difficult to measure disease activity and distinguish active inflammation from fibrosis. Identifying the inflammatory mediators in sarcoidosis has led to the development and use of novel therapeutic agents. The goal of pharmacotherapy is to decrease granuloma accumulation, ameliorate symptoms and improve organ function. Systemic corticosteroids remain the first line treatment. Other immunosuppressive agents may be considered for the patients who respond poorly to corticosteroids or who experience significant adverse effects. An overview of pharmacotherapy of sarcoidosis is provided here. PMID- 26478444 TI - Seizures in oligodendroglial tumors. AB - Epilepsy develops in more than 70-90% of oligodendroglial tumors and represents a favorable indicator for long-term survival if present as the first clinical sign. Presence of IDH1 mutation is frequently associated with seizures in oligodendrogliomas, next to alterations of glutamate and GABA metabolism in the origin of glioma-associated epilepsy. Treatment by surgery or radiotherapy results in seizure freedom in about two-thirds of patients, and chemotherapy to a seizure reduction in about 50%. Symptomatic anticonvulsive therapy with levetiracetam and valproic acid as monotherapy are both evidence-based drugs for the partial epilepsies, and their effective use in brain tumors is supported by a large amount of additional data. Pharmacoresistance against anticonvulsants is more prevalent among oligodendrogliomas, occurring in about 40% despite polytherapy with two anticonvulsants or more. Toxic signs of anticonvulsants in brain tumors involve cognition, bone marrow and skin. Previous neurosurgery, radiation therapy or chemotherapy add to the risks of cognitive dysfunction. PMID- 26478446 TI - Evidence of Nonuniformity in Urothelium Barrier Function between the Upper Urinary Tract and Bladder. AB - PURPOSE: We compared the relative permeability of upper urinary tract and bladder urothelium to mitomycin C. MATERIALS AND METHODS: Ex vivo porcine bladder, ureters and kidneys were dissected out and filled with 1 mg ml(-1) mitomycin C. At 60 minutes the organs were emptied and excised tissue samples were sectioned parallel to the urothelium. Sectioned tissue was homogenized and extracted mitomycin C was quantified. Transurothelial permeation across the different urothelia was calculated by normalizing the total amount of drug extracted to the surface area of the tissue sample. Average mitomycin C concentrations at different tissue depths (concentration-depth profiles) were calculated by dividing the total amount of drug recovered by the total weight of tissue. RESULTS: Mitomycin C permeation across the ureteral urothelium was significantly greater than across the bladder and renal pelvis urothelium (9.07 vs 0.94 and 3.61 MUg cm(-2), respectively). Concentrations of mitomycin C in the ureter and kidney were markedly higher than those achieved in the bladder at all tissue depths. Average urothelial mitomycin C concentrations were greater than 6.5-fold higher in the ureter and renal pelvis than in the bladder. CONCLUSIONS: To our knowledge we report for the first time that the upper urinary tract and bladder show differing permeability to a single drug. Ex vivo porcine ureter is significantly more permeable to mitomycin C than bladder urothelium and consequently higher mitomycin C tissue concentrations can be achieved after topical application. Data in this study correlate with the theory that mammalian upper tract urothelium represents a different cell lineage than that of the bladder and it is innately more permeable to mitomycin C. PMID- 26478445 TI - Association of Gallbladder Mucocele Histologic Diagnosis with Selected Drug Use in Dogs: A Matched Case-Control Study. AB - BACKGROUND: The cause of gallbladder mucocele (GBM) formation in dogs currently is unknown. Many available drugs represent a newer generation of xenobiotics that may predispose dogs to GBM formation. OBJECTIVE: To determine if there is an association between the histologic diagnosis of GBM in dogs and administration of selected drugs. ANIMALS: Eighty-one dogs with a histologic diagnosis of GBM and 162 breed, age, and admission date-matched control dogs from a single referral institution. METHODS: Medical records of dogs with GBM and control dogs from 2001 to 2011 were reviewed. Owner verification of drug history was sought by a standard questionnaire. Reported use of heartworm, flea, and tick preventatives as well as nonsteroidal anti-inflammatory drugs, analgesics, corticosteroids, or medications for treatment of osteoarthritis was recorded. RESULTS: Dogs with GBM were 2.2 times as likely to have had reported use of thyroxine (as a proxy for the diagnosis of hypothyroidism) as control dogs (95% confidence interval [CI], 0.949-5.051), 3.6 times as likely to have had reported treatment for Cushing's disease (95% CI, 1.228-10.612), and 2.3 times as likely to have had reported use of products containing imidacloprid (95% CI, 1.094-4.723). Analysis of a data subset containing only Shetland sheepdogs (23 GBM and 46 control) indicated that Shetland sheepdogs with GBM formation were 9.3 times as likely to have had reported use of imidacloprid as were control Shetland sheepdogs (95% CI, 1.103 78.239). CONCLUSIONS AND CLINICAL IMPORTANCE: This study provides evidence for an association between selected drug use and GBM formation in dogs. A larger epidemiologic study of Shetland sheepdogs with GBM formation and exposure to imidacloprid is warranted. PMID- 26478447 TI - Experience, Expertise and Dedication are Requirements for Successful Outcome in Bladder Exstrophy Care. PMID- 26478448 TI - Female Urethral Reconstruction. AB - PURPOSE: Female urethral reconstruction can be used successfully to treat a heterogeneous group of urethral disorders through an expanding number of unique approaches. Understanding the diverse etiologies of female urethral stricture and loss is essential in evaluating and diagnosing patients. Although there is an appreciable body of literature addressing female urethral reconstruction individually, there is a paucity of resources that approach this issue holistically. We discuss the relevant female urethral anatomy, pathophysiology, diagnosis and evaluation of female urethral disorders, and current reconstructive techniques, as well as published outcomes data and potential future directions for female urethral reconstruction. MATERIALS AND METHODS: We reviewed articles published in English and indexed in the PubMed(r), Embase(r) and Google ScholarTM databases, and consulted textbooks. Key search terms used were female, urethra, urethral reconstruction, urethroplasty, pathology, stricture, vaginal flap, bladder flap, graft, dilation, pubovaginal sling, catheterization, imaging, tissue engineering and bioscaffold. We created a synopsis of relevant articles, including original research studies and reviews. RESULTS: Urethral tissue loss and strictures are caused by traumatic injuries, iatrogenic injuries and, rarely, infections and malignancies. A comprehensive patient history and physical examination are critical for diagnosis. Flexible cystoscopy, voiding cystourethrography and endovaginal magnetic resonance imaging can help to determine the surgical method of repair. Minimally invasive approaches to female urethral reconstruction are associated with poor outcomes. Definitive treatment options for repair of female urethral stricture include vaginal flap/wall urethroplasty, graft urethroplasty and distal urethrectomy with advancement meatoplasty. Repair techniques for urethral loss include primary closure, vaginal flap/wall urethroplasty and bladder flap urethroplasty. Vaginal flap approaches with well vascularized grafts and buccal mucosal grafts have high success rates. Tissue engineered grafts are being investigated as a novel treatment modality. CONCLUSIONS: Female urethral reconstruction is complex, and one must carefully evaluate patients afflicted with urethral disorders. Urethral stricture and urethral loss have different etiologies. Variations of a standard approach might best address the condition of an individual patient. Long-term outcomes data are not available for contemporary techniques of female urethral reconstruction. The highest success rates have been reported with vaginal flap and buccal mucosal graft urethroplasty. Further studies focusing on newer reconstruction techniques and long-term outcomes are warranted. PMID- 26478449 TI - Identification of Oxidation Compounds of 1-Stearoyl-2-linoleoyl-sn-glycero-3 phosphoethanolamine during Thermal Oxidation. AB - Heat-induced oxidative modification of phosphatidylethanolamine molecular species as potential functional food components was investigated. 1-Stearoyl-2-linoleoyl sn-glycero-3-phosphoethanolamine (SLPE) was chosen as a model. The optimal temperature for hydroperoxide formation was determined by mass spectrometry. The maximal level of formation of this compound was obtained at 125 degrees C. The structures of nonvolatile organic compounds (non-VOCs) were identified using liquid chromatography-electrospray ionization mass spectrometry combined with an acid treatment. Kinetics of formation of non-VOCs was monitored over time. Results showed that the level of the SLPE precursor rapidly decreased during thermal oxidation and oxygenated products, such as hydroxyl, oxo, or epoxy groups, were formed. The VOCs formed from oxidized SLPE were determined by headspace solid-phase microextraction followed by gas chromatography-mass spectrometry analysis. The result showed that a saturated methyl ketone (2 heptanone) was the most predominant VOC of SLPE. Kinetics indicated that the formation of VOCs was related not only to the decomposition of hydroperoxides but also to the further decomposition of non-VOCs. PMID- 26478450 TI - Electropolymerizable peripherally tetra-{2-[3-(diethylamino)phenoxy]ethoxy} substituted as well as axially (4-phenylpiperazin-1-yl)propanoxy-disubstituted silicon phthalocyanines and their electrochemistry. AB - A novel type of peripherally tetra-substituted as well as axially disubstituted silicon(iv) phthalocyanine containing electropolymerizable ligands was designed and synthesized for the first time. Axial bis-hydroxy silicon phthalocyanine 2 was prepared from 2(3),9(10),16(17),23(24)-tetrakis-{2-[3 (diethylamino)phenoxy]ethoxy}phthalocyanine 1 in dichloromethane by using 1.8 diazabicyclo[5.4.0]undec-7-ene (DBU) and trichlorosilane. Peripherally tetra and axially di-substituted silicon phthalocyanine 4 was synthesized from 2(3),9(10),16(17),23(24)-tetrakis-{2-[3 (diethylamino)phenoxy]ethoxy}silicon(iv)phthalocyanine dihydroxide 2 with 1-(3 chloropropyl)-4-phenylpiperazine 3 in toluene in the presence of NaH at 120 degrees C. These complexes were fully characterized by various spectroscopy techniques such as (1)H-NMR, (13)C-NMR, IR, UV-Vis, and MALDI-TOF spectroscopy and elemental analysis as well. Electropolymerization properties of silicon(IV) phthalocyanine complexes were investigated by cyclic and square wave voltammetry. Electrochemical studies reveal that silicon(IV) phthalocyanine complexes were electropolymerized on the working electrode during the anodic potential scan. This study is the first example of electropolymerization of both peripherally tetra and axially di-substituted silicon phthalocyanines on the same molecule. PMID- 26478451 TI - Biomimetic Replication of Microscopic Metal-Organic Framework Patterns Using Printed Protein Patterns. AB - It is demonstrated that metal-organic frameworks (MOFs) can be replicated in a biomimetic fashion from protein patterns. Bendable, fluorescent MOF patterns are formed with micrometer resolution under ambient conditions. Furthermore, this technique is used to grow MOF patterns from fingerprint residue in 30 s with high fidelity. This technique is not only relevant for crime-scene investigation, but also for biomedical applications. PMID- 26478452 TI - Optical coherency matrix tomography. AB - The coherence of an optical beam having multiple degrees of freedom (DoFs) is described by a coherency matrix G spanning these DoFs. This optical coherency matrix has not been measured in its entirety to date--even in the simplest case of two binary DoFs where G is a 4 * 4 matrix. We establish a methodical yet versatile approach--optical coherency matrix tomography--for reconstructing G that exploits the analogy between this problem in classical optics and that of tomographically reconstructing the density matrix associated with multipartite quantum states in quantum information science. Here G is reconstructed from a minimal set of linearly independent measurements, each a cascade of projective measurements for each DoF. We report the first experimental measurements of the 4 * 4 coherency matrix G associated with an electromagnetic beam in which polarization and a spatial DoF are relevant, ranging from the traditional two point Young's double slit to spatial parity and orbital angular momentum modes. PMID- 26478453 TI - The implications of recurrent disturbances within the world's hottest coral reef. AB - Determining how coral ecosystems are structured within extreme environments may provide insights into how coral reefs are impacted by future climate change. Benthic community structure was examined within the Persian Gulf, and adjacent Musandam and northern Oman regions across a 3-year period (2008-2011) in which all regions were exposed to major disturbances. Although there was evidence of temporal switching in coral composition within regions, communities predominantly reflected local environmental conditions and the disturbance history of each region. Gulf reefs showed little change in coral composition, being dominated by stress-tolerant Faviidae and Poritidae across the 3 years. In comparison, Musandam and Oman coral communities were comprised of stress-sensitive Acroporidae and Pocilloporidae; Oman communities showed substantial declines in such taxa and increased cover of stress-tolerant communities. Our results suggest that coral communities may persist within an increasingly disturbed future environment, albeit in a much more structurally simple configuration. PMID- 26478454 TI - Screening for contaminant hotspots in the marine environment of Kuwait using ecotoxicological and chemical screening techniques. AB - Kuwait is a country with low rainfall and highly concentrated industrial and domestic effluents entering its coastal waters. These can be both treated and untreated. In this study we sampled a series of coastal and open-sea sites and used a variety of analyses to identify those sites requiring the most attention. We used a high throughput GC-MS screen to look for over 1000 chemicals in the samples. Estrogen and androgen screens assessed the potential to disrupt endocrine activity. An oyster embryo development screen was used to assess biological effect potential. The chemical screen identified sites which had high numbers of identified industrial and domestic chemicals. The oyster screen showed that these sites had also caused high levels of developmental abnormalities with 100% of embryos affected at some sites. The yeast screen showed that estrogenic chemicals were present in outfalls at 2-3 ng/l E2 equivalent, and detectable even in some open water sites. PMID- 26478455 TI - Heavy metal contamination and ecological risk in Futian mangrove forest sediment in Shenzhen Bay, South China. AB - Surface sediments in the Futian mangrove forest (South China) were analyzed for heavy metals including cadmium (Cd), chromium (Cr), copper (Cu), lead (Pb) and zinc (Zn). The heavy metal distributions varied greatly in surface sediments, reflecting some sediment heterogeneity. The heavy metal concentrations decreased in the order of Zn>Cr>Pb>Cu>Cd. According to the mean probable effects level quotient, the combination of studied metals had a 21% probability of being toxic. The potential ecological risk index and geo-accumulation index also revealed high metal contamination. Cd was of primary concern due to its higher assessment values and potential for adverse biological effects. Multivariate analysis implied that clay and silt played a significant role in raising the levels of Cr, Cu and Zn. The percentage of mobile heavy metals was relatively higher, without considerable ecological risk to the biota based on the risk assessment code. PMID- 26478456 TI - Mercury and selenium in seston, marine plankton and fish (Sardinella brasiliensis) as a tool for understanding a tropical food web. AB - Mercury (Hg) and selenium (Se) concentrations were evaluated in a planktivorous fish and four size classes of organisms (FSCO), collected at an oligotrophic bay in the Southeastern Brazilian coast. No significant spatial differences between Hg and Se were found in the FSCO within the five sampling points in the bay. Hg and Se concentrations increased with successive increases in the size class of the analyzed plankton, i.e. approximately 3-and 2-fold, respectively, from microplankton to macroplankton. Hg and Se biomagnified throughout the planktonic food web. The smallest size class of organism, seston, composed of both biotic and abiotic portions, and fish showed the highest Hg concentrations. This indicates that Hg is not biomagnifying in the base of the bay food web. Selenium concentrations in fish were approximately 5.9 times higher than those in seston. Hg and Se concentrations in fish were approximately 3.5 and 14.6 times higher than those found in the plankton, respectively. PMID- 26478457 TI - Baseline distribution and sources of linear alkyl benzenes (LABs) in surface sediments from Brunei Bay, Brunei. AB - Sewage pollution is one of major concerns of coastal and shoreline settlements in Southeast Asia, especially Brunei. The distribution and sources of LABs as sewage molecular markers were evaluated in surface sediments collected from Brunei Bay. The samples were extracted, fractionated and analyzed using gas chromatography- mass spectrometry (GC-MS). LABs concentrations ranged from 7.1 to 41.3 ng g(-1) dry weight (dw) in surficial sediments from Brunei Bay. The study results showed LABs concentrations variably due to the LABs intensity and anthropogenic influence along Brunei Bay in recent years. The ratio of Internal to External isomers (I/E ratio) of LABs in sediment samples from Brunei Bay ranged from 0.56 to 2.17 along Brunei Bay stations, indicating that the study areas were receiving primary and secondary effluents. This is the first study carried out to assess the distribution and sources of LABs in surface sediments from Brunei Bay, Brunei. PMID- 26478458 TI - Methyl mercury concentrations in edible fish and shellfish from Dunedin, and other regions around the South Island, New Zealand. AB - Methyl mercury (MeHg) concentrations were determined in edible fish and shellfish available in local markets in Dunedin, New Zealand. While most of the fish species were sourced in Dunedin, some specimens of fish were also collected from waters off Picton, around Stewart Island and also off-shore of the South Island in the Puysegur and Subantarctic regions. The concentrations of MeHg were analysed in 25 different fish species and shellfish (103 muscle tissue samples). Total mercury (HgT) levels were also analysed in a few (n=12) selected fish samples. Most of the Hg was in the form of MeHg (>= 96%). Higher MeHg concentrations were found in fish at higher trophic levels, particularly in predatory fish species such as ling, school shark, spiny dogfish and albacore tuna. Concentrations of MeHg in all samples ranged from 0.002 to 2.515 MUg MeHg/g. PMID- 26478459 TI - Mussel farming in Maliakos Gulf and quality indicators of the marine environment: Good benthic below poor pelagic ecological status. AB - Biological and geochemical variables in the water column and sediments were monitored along a transect of a mussel farm located in a transitional environment in Maliakos Gulf, a semi-enclosed gulf in eastern Mediterranean. Analyses of water, sediment and macrofauna samples were used to calculate ecological status indicators in the context of the European Water Framework Directive. The water column ecological status was "Poor" or "Bad" showing little change with distance from the farm, but the ecological status of the benthic communities was found to be "Good," although there were quantitative changes in macrofaunal indices with distance from the farm. PMID- 26478460 TI - Sources and distribution of polycyclic aromatic hydrocarbons in a an urbanized tropical estuary and adjacent shelf, Northeast of Brazil. AB - Located in Northeastern Brazil, the Capibaribe Estuarine System is an important ecosystem that supplies food and protection for nursery of several species with ecological and economic importance. It is located inside an urbanized area, receives untreated domestic and industrial effluents, and houses some marinas and the Harbor of Recife, which are very important to national and international communities. The distribution and sources of PAHs were investigated in sediments from CES and adjacent shelf. Total PAH concentrations ranged from non-detectable to 497.6 MUg g(-1). Pyrolytic sources predominated in most of sites, but petrogenic PAHs were also recorded. The concentration decrease of PAHs toward adjacent shelf suggests that the main source of these compounds is in the upper portion of estuary, where there is an intense discharge of sewage, but atmospheric input also seems to be relevant to the area. The results reinforce the important role of an estuary in contaminant retention. PMID- 26478462 TI - Comparison of experimental and DFT-calculated NMR chemical shifts of 2-amino and 2-hydroxyl substituted phenyl benzimidazoles, benzoxazoles and benzothiazoles in four solvents using the IEF-PCM solvation model. AB - A comparative study of experimental and calculated NMR chemical shifts of six compounds comprising 2-amino and 2-hydroxy phenyl benzoxazoles/benzothiazoles/benzimidazoles in four solvents is reported. The benzimidazoles showed interesting spectral characteristics, which are discussed. The proton and carbon chemical shifts were similar for all solvents. The largest chemical shift deviations were observed in benzene. The chemical shifts were calculated with density functional theory using a suite of four functionals and basis set combinations. The calculated chemical shifts revealed a good match to the experimentally observed values in most of the solvents. The mean absolute error was used as the primary metric. The use of an additional metric is suggested, which is based on the order of chemical shifts. The DP4 probability measures were also used to compare the experimental and calculated chemical shifts for each compound in the four solvents. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26478461 TI - Inhibition of the regulator of G protein signalling RGS4 in the spinal cord decreases neuropathic hyperalgesia and restores cannabinoid CB1 receptor signalling. AB - BACKGROUND AND PURPOSE: Regulators of G protein signalling (RGS) are major determinants of metabotropic receptor activity, reducing the lifespan of the GTP bound state of G proteins. Because the reduced potency of analgesic agents in neuropathic pain may reflect alterations in RGS, we assessed the effects of CCG 63802, a specific RGS4 inhibitor, on pain hypersensitivity and signalling through cannabinoid receptors, in a model of neuropathic pain. EXPERIMENTAL APPROACH: The partial sciatic nerve ligation (PSNL) model in male Sprague Dawley rats was used to measure paw withdrawal thresholds to mechanical (von Frey hairs) or thermal (Hargreaves method) stimuli, during and after intrathecal injection of CCG 63802. HEK293 cells expressing CB1 receptors and conditional expression of RGS4 were used to correlate cAMP production and ERK phosphorylation with receptor activation and RGS4 action. KEY RESULTS: Treatment of PSNL rats with CCG 63802, twice daily for 7 days after nerve injury, attenuated thermal hyperalgesia during treatment. Spinal levels of anandamide were higher in PSNL animals, irrespective of the treatment. Although expression of CB1 receptors was unaffected, HU210 induced CB1 receptor signalling was inhibited in PSNL rats and restored after intrathecal CCG 63802. In transfected HEK cells expressing CB1 receptors and RGS4, inhibition of cAMP production, a downstream effect of CB1 receptor signalling, was blunted after RGS4 overexpression. RGS4 expression also attenuated the CB1 receptor-controlled activation of ERK1/2. CONCLUSIONS AND IMPLICATIONS: Inhibition of spinal RGS4 restored endogenous analgesic signalling pathways and mitigated neuropathic pain. Signalling through CB1 receptors may be involved in this beneficial effect. PMID- 26478463 TI - Molecular characterisation of a bio-based active packaging containing Origanum vulgare L. essential oil using pyrolysis gas chromatography-mass spectrometry. AB - BACKGROUND: Environmental, economic and safety challenges motivate shift towards safer materials for food packaging. New bioactive packaging techniques, i.e. addition of essential plant oils (EOs), are gaining attention by creating barriers to protect products from spoilage. Analytical pyrolysis gas chromatography-mass spectrometry (Py-GC-MS) was used to fingerprint a bioactive polylactic acid (PLA) with polybutylene succinate (PBS) (950 g kg(-1) :50 g kg( 1) ) film extruded with variable quantities (0, 20, 50 and 100 g kg(-1) ) of Origanum vulgare EO. RESULTS: Main PLA:PBS pyrolysis products were lactide enantiomers and monomer units from the major PLA fraction and succinic acid anhydride from the PBS fraction. Oregano EO pyrolysis released cymene, terpinene and thymol/carvacrol peaks as diagnostic peaks for EO. In fact, linear correlation coefficients better than 0.950R(2) value (P < 0.001) were found between the chromatographic area of the diagnostic peaks and the amount of oregano EO in the bioplastic. CONCLUSION: The pyrolytic behaviour of a bio-based active package polymer including EO is studied in detail. Identified diagnostic compounds provide a tool to monitor the quantity of EO incorporated into the PLA:PBS polymeric matrix. Analytical pyrolysis is proposed as a rapid technique for the identification and quantification of additives within bio-based plastic matrices. (c) 2015 Society of Chemical Industry. PMID- 26478464 TI - Cationic cluster formation versus disproportionation of low-valent indium and gallium complexes of 2,2'-bipyridine. AB - Group 13 M(I) compounds often disproportionate into M(0) and M(III). Here, however, we show that the reaction of the M(I) salt of the weakly coordinating alkoxyaluminate [Ga(I)(C6H5F)2](+)[Al(OR(F))4](-) (R(F)=C(CF3)3) with 2,2' bipyridine (bipy) yields the paramagnetic and distorted octahedral [Ga(bipy)3](2+)(*){[Al(OR(F))4](-)}2 complex salt. While the latter appears to be a Ga(II) compound, both, EPR and DFT investigations assign a ligand-centred [Ga(III){(bipy)3}(*)](2+) radical dication. Surprisingly, the application of the heavier homologue [(I)n(I)(C6H5F)2](+)[Al(OR(F))4](-) leads to aggregation and formation of the homonuclear cationic triangular and rhombic [In3(bipy)6](3+), [In3(bipy)5](3+) and [In4(bipy)6](4+) metal atom clusters. Typically, such clusters are formed under strongly reductive conditions. Analysing the unexpected redox-neutral cationic cluster formation, DFT studies suggest a stepwise formation of the clusters, possibly via their triplet state and further investigations attribute the overall driving force of the reactions to the strong In-In bonds and the high lattice enthalpies of the resultant ligand stabilized [M3](3+){[Al(OR(F))4](-)}3 and [M4](4+){[Al(OR(F))4](-)}4 salts. PMID- 26478465 TI - In vivo evaluation of injectable calcium phosphate cement composed of Zn- and Si incorporated beta-tricalcium phosphate and monocalcium phosphate monohydrate for a critical sized defect of the rabbit femoral condyle. AB - Zinc (Zn) enhances bone formation with mineralization and is an essential element of osteoblastic proliferation. Silicon (Si) is important in apatite formation coupled with the promotion of osteogenesis. The primary focus of this work was the assessment of the bone healing capacity of calcium phosphate cements (CPC) composed of Zn- and Si-incorporated beta-tri calcium phosphate (TCP) and mono calcium phosphate mono hydrate (MCPM). Zn- and Si-incorporated beta-TCP was synthesized through a sol gel process with varying amounts of Zn: (3, 6, or 9% w/w) and 15% w/w Si. Fabricated CPC samples were characterized by scanning electron microscopy, setting time, injectability, compressive strength and initial pH change with time. Compositional analysis and the effects of Zn and Si on cellular interaction were evaluated by energy dispersive X-ray spectroscopy mapping, viability determination and F-actin assay. The data were used to optimize the CPC formulation. The efficacy of bone healing was investigated via implantation into critical sized rabbit femoral condyle defects for 4 and 8 weeks. CPC cement with 6% (w/w) Zn content was the best candidate for faster bone healing (bone to tibial volume ratio in 8 weeks: 22.78% +/- 0.02). Significantly faster degradation was also revealed. Bone healing was significantly delayed when CPC cement with 9% (w/w) Zn was used. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 260-271, 2017. PMID- 26478466 TI - Myosin superfamily: The multi-functional and irreplaceable factors in spermatogenesis and testicular tumors. AB - Spermatogenesis is a fundamental process in sexual development and reproduction, in which the diploid spermatogonia transform into haploid mature spermatozoa. This process is under the regulation of multiple factors and pathway. Myosin has been implicated in various aspects during spermatogenesis. Myosins constitute a diverse superfamily of actin-based molecular motors that translocate along microfilament in an ATP-dependent manner, and six kinds of myosins have been proved that function during spermatogenesis. In mitosis and meiosis, myosins play an important role in spindle assembly and positioning, karyokinesis and cytokinesis. During spermiogenesis, myosins participate in acrosomal formation, nuclear morphogenesis, mitochondrial translocation and spermatid individualization. In this review, we summarize current understanding of the functions of myosin in spermatogenesis and some reproductive system diseases such as testicular tumors and prostate cancer, and discuss the roles of possible upstream molecules which regulate myosin in these processes. PMID- 26478467 TI - Effective de novo assembly of fish genome using haploid larvae. AB - Recent improvements in next-generation sequencing technology have made it possible to do whole genome sequencing, on even non-model eukaryote species with no available reference genomes. However, de novo assembly of diploid genomes is still a big challenge because of allelic variation. The aim of this study was to determine the feasibility of utilizing the genome of haploid fish larvae for de novo assembly of whole-genome sequences. We compared the efficiency of assembly using the haploid genome of yellowtail (Seriola quinqueradiata) with that using the diploid genome obtained from the dam. De novo assembly from the haploid and the diploid sequence reads (100 million reads per each datasets) generated by the Ion Proton sequencer (200 bp) was done under two different assembly algorithms, namely overlap-layout-consensus (OLC) and de Bruijn graph (DBG). This revealed that the assembly of the haploid genome significantly reduced (approximately 22% for OLC, 9% for DBG) the total number of contigs (with longer average and N50 contig lengths) when compared to the diploid genome assembly. The haploid assembly also improved the quality of the scaffolds by reducing the number of regions with unassigned nucleotides (Ns) (total length of Ns; 45,331,916 bp for haploids and 67,724,360 bp for diploids) in OLC-based assemblies. It appears clear that the haploid genome assembly is better because the allelic variation in the diploid genome disrupts the extension of contigs during the assembly process. Our results indicate that utilizing the genome of haploid larvae leads to a significant improvement in the de novo assembly process, thus providing a novel strategy for the construction of reference genomes from non-model diploid organisms such as fish. PMID- 26478468 TI - 2D nanosheet molybdenum disulphide (MoS2) modified electrodes explored towards the hydrogen evolution reaction. AB - We explore the use of two-dimensional (2D) MoS2 nanosheets as an electrocatalyst for the Hydrogen Evolution Reaction (HER). Using four commonly employed commercially available carbon based electrode support materials, namely edge plane pyrolytic graphite (EPPG), glassy carbon (GC), boron-doped diamond (BDD) and screen-printed graphite electrodes (SPE), we critically evaluate the reported electrocatalytic performance of unmodified and MoS2 modified electrodes towards the HER. Surprisingly, current literature focuses almost exclusively on the use of GC as an underlying support electrode upon which HER materials are immobilised. 2D MoS2 nanosheet modified electrodes are found to exhibit a coverage dependant electrocatalytic effect towards the HER. Modification of the supporting electrode surface with an optimal mass of 2D MoS2 nanosheets results in a lowering of the HER onset potential by ca. 0.33, 0.57, 0.29 and 0.31 V at EPPG, GC, SPE and BDD electrodes compared to their unmodified counterparts respectively. The lowering of the HER onset potential is associated with each supporting electrode's individual electron transfer kinetics/properties and is thus distinct. The effect of MoS2 coverage is also explored. We reveal that its ability to catalyse the HER is dependent on the mass deposited until a critical mass of 2D MoS2 nanosheets is achieved, after which its electrocatalytic benefits and/or surface stability curtail. The active surface site density and turn over frequency for the 2D MoS2 nanosheets is determined, characterised and found to be dependent on both the coverage of 2D MoS2 nanosheets and the underlying/supporting substrate. This work is essential for those designing, fabricating and consequently electrochemically testing 2D nanosheet materials for the HER. PMID- 26478469 TI - Effects of perinatal exposure to lead (Pb) on purine receptor expression in the brain and gliosis in rats tolerant to morphine analgesia. AB - The aim of the present study was to investigate the molecular effects of perinatal exposure to lead (Pb) on protein and mRNA expression of purine receptors: P2X4, P2X7, adenosine receptor A1; and astrocytes (GFAP mRNA expression) and on microglia activation (Iba1 mRNA expression) in several structures of the mesolimbic system (striatum, hippocampus, prefrontal cortex) in rats expressing tolerance to the antinociceptive effect of morphine. Rat mothers were orally treated with 0.1% lead acetate from conception, through gestation, and postnatally, as well as to offspring up to day (PND) 28; subsequently molecular studies were conducted on adult (PND 60) male rats. Morphine tolerance developed more strongly in rats perinatally exposed to Pb. The analysis revealed a significant up-regulation of protein and mRNA P2X4 receptor expression in the striatum and prefrontal cortex but not in the hippocampus; P2X7 protein and mRNA receptor expression in the striatum and hippocampus, but not in the prefrontal cortex; A1 protein receptor expression in all investigated structures and A1 mRNA expression in the striatum and hippocampus; Iba1 mRNA expression in the striatum and hippocampus; and GFAP mRNA expression in the striatum and prefrontal cortex. Immunohistochemical analysis has also revealed significant alterations. Strong expressions of P2X4, P2X7, A1 receptors, astrocytes and microglia activation were observed in the hippocampus in Pb and/or morphine treated rats. The higher expression of purine receptors and glial cell activation are important markers of neuroinflammatory processes. Therefore, we conclude that Pb-induced neuroinflammation may be responsible for the intensification of morphine tolerance in the Pb-treated rats. Additionally, the dysregulation of A1 adenosine receptors, mainly in the hippocampus, may also be involved in the intensification of morphine tolerance in Pb-treated rats. Our study demonstrates the significant participation of environmental factors in addictive process; additionally, it shows the necessity of modification of addictive disorder with neuroprotective agents. PMID- 26478470 TI - Production of ascorbic acid releasing biomaterials for pelvic floor repair. AB - OBJECTIVE: An underlying abnormality in collagen turnover is implied in the occurrence of complications and recurrences after mesh augmented pelvic floor repair surgeries. Ascorbic acid is a potent stimulant of collagen synthesis. The aim of this study is to produce ascorbic acid releasing poly-lactic acid (PLA) scaffolds and evaluate them for their effects on extracellular matrix production and the strength of the materials. MATERIALS AND METHODS: Scaffolds which contained either l-ascorbic acid (AA) and Ascorbate-2-Phosphate (A2P) were produced with emulsion electrospinning. The release of both drugs was measured by UV spectrophotometry. Human dermal fibroblasts were seeded on scaffolds and cultured for 2weeks. Cell attachment, viability and total collagen production were evaluated as well as mechanical properties. RESULTS: No significant differences were observed between AA, A2P, Vehicle and PLA scaffolds in terms of fibre diameter and pore size. The encapsulation efficiency and successful release of both AA and A2P were demonstrated. Both AA and A2P containing scaffolds were significantly more hydrophilic and stronger in both dry and wet states compared to PLA scaffolds. Fibroblasts produced more collagen on scaffolds containing either AA or A2P compared to cells grown on control scaffolds. CONCLUSION: This study is the first to directly compare the two ascorbic acid derivatives in a tissue engineered scaffold and shows that both AA and A2P releasing electrospun PLA scaffolds increased collagen production of fibroblasts to similar extents but AA scaffolds seemed to be more hydrophilic and stronger compared to A2P scaffolds. STATEMENT OF SIGNIFICANCE: Mesh augmented surgical repair of the pelvic floor currently relies on non-degradable materials which results in severe complications in some patients. There is an unmet and urgent need for better pelvic floor repair materials. Our current understanding suggests that the ideal material should be able to better integrate into sites of implantation both biologically and mechanically. The impact of vitamin C on extracellular matrix production is well established but we in this study have undertaken a critical comparison of two derivatives of vitamin C as they are released from a biodegradable scaffold. This strategy proved to be equally useful with both derivatives in terms of new tissue production yet we observed significant differences in mechanical properties of these biomaterials. PMID- 26478471 TI - A combinatorial approach towards achieving an injectable, self-contained, phosphate-releasing scaffold for promoting biomineralization in critical size bone defects. AB - An injectable, guanosine 5'-diphosphate (GDP)-crosslinked chitosan sponge was investigated as a drug delivery system (DDS) for accelerating biomineralization in critical size bone defects (CSBDs). Two approaches were examined both individually, and in combination, in order to achieve this goal. The first approach involved the encapsulation and release of Bone Morphogenetic Protein 7 (BMP-7), a powerful mineralization stimulant. Results confirmed that the rapid gelation of the chitosan sponge prompted high encapsulation of BMP-7 and provided a controlled release over a period of 30 days with no burst release. The second approach was aimed at encapsulating pyrophosphatase (PPtase) in the chitosan sponge to cleave pyrophosphate (PPi) - a mineralization inhibitor and a degradation by-product of the chitosan sponge - into phosphate ions (Pi). PPtase was successfully encapsulated in the chitosan sponge and was able to completely eliminate PPi from the media by cleaving them to Pi. Chitosan sponges releasing Pi into the media were shown to increase overall biomineralization fourfold as compared to controls, an amount equivalent to biomineralization caused by direct injection of 1MUg of free BMP-7 to the cells. Even though the combined encapsulation of 1MUg BMP-7 and PPtase in the sponges did not demonstrate an additional increase in biomineralization, encapsulation of low concentrations of BMP-7 can promote mesenchymal stem cell migration into the sponge after application in vivo. The findings suggest that the sponge-PPtase system likely allows excellent bone regeneration with lower concentrations of BMP-7, reducing risks and expense of the treatment. STATEMENT OF SIGNIFICANCE: There are bone defects, known as critical size defects, which do not heal on their own and require a therapeutic intervention. The current commercially-available therapies use large quantities of growth factors, such as Bone Morphogenetic Proteins (BMPs), which makes them expensive and a source for a myriad of unwanted side effects. In this manuscript we demonstrate, for the first time, the use of an injectable chitosan-based sponge that contains no inorganic components, but can nonetheless act as a source of phosphate ions to improve bone mineralization. We also demonstrate that this sponge can entrap small concentrations of BMP-7 and provide controlled release over time. The ability to release phosphate ions and low concentrations of BMP-7 makes this therapeutic intervention clinically relevant, affordable, and safe. PMID- 26478472 TI - Anti-biofilm action of nitric oxide-releasing alkyl-modified poly(amidoamine) dendrimers against Streptococcus mutans. AB - The effect of nitric oxide (NO)-releasing dendrimer hydrophobicity on Streptococcus mutans killing and biofilm disruption was examined at pH 7.4 and 6.4, the latter relevant to dental caries. Generation 1 (G1) poly(amidoamine) (PAMAM) dendrimers were modified with alkyl epoxides to generate propyl-, butyl-, hexyl-, octyl-, and dodecyl-functionalized dendrimers. The resulting secondary amines were reacted with NO to form N-diazeniumdiolate NO donor-modified dendrimer scaffolds (total NO ~1MUmol/mg). The bactericidal action of the NO releasing dendrimers against both planktonic and biofilm-based S. mutans proved greatest with increasing alkyl chain length and at lower pH. Improved bactericidal efficacy at pH 6.4 was attributed to increased scaffold surface charge that enhanced dendrimer-bacteria association and ensuing membrane damage. For shorter alkyl chain (i.e., propyl and butyl) dendrimer modifications, increased antibacterial action at pH 6.4 was due to faster NO-release kinetics from proton-labile N-diazeniumdiolate NO donors. Octyl- and dodecyl-modified PAMAM dendrimers proved most effective for eradicating S. mutans biofilms with NO release mitigating dendrimer scaffold cytotoxicity. STATEMENT OF SIGNIFICANCE: We report the antibacterial and anti-biofilm efficacy of dual-action nitric oxide (NO)-releasing dendrimers against S. mutans, an etiological agent in dental caries. This work was undertaken to enhance the anti-biofilm action of these scaffolds by employing various alkyl chain modifications. Furthermore, we evaluated the ability of NO to eradicate cariogenic biofilms. We found that at the lower pH associated with dental caries (pH ~6.4), NO has a more pronounced antibacterial effect for alkyl modifications less capable of biofilm penetration and membrane disruption. Of greatest significance, we introduce dendrimers as a new macromolecular antibacterial agent against the cariogenic bacteria S. mutans. PMID- 26478473 TI - Evaluation of Trace Elements and Their Relationship with Growth and Development of Young Children. AB - This study was conducted to assess the levels of trace elements and their relationship with growth and development of children in Shanghai, China, to offer scientific evidence for supplementing trace elements in children. A stratified, clustered, random sampling method was used in the study. Blood samples were taken from 2141 Shanghai children from 0 to 6.0 years old, and the concentrations of zinc (Zn), calcium (Ca), iron (Fe), copper (Cu), and magnesium (Mg) were measured using inductively coupled plasma mass spectrometry (ICP-MS). Nutritional status was determined and Z-scores of anthropometric parameters, such as height for age (HFA), weight for age (WFA), and body mass index (BMI) were calculated, indicated by HAZ, WAZ, and BMIZ, respectively. The overall median blood levels of Zn, Ca, Fe, Cu, and Mg were 8.83, 79.02, 9.49, 1.04, and 15.45 mg/L, respectively. Fe, Cu, and Mg increased with age and Zn, Fe, and Cu differed by sex. HAZ and WAZ were positively correlated with Zn (r (2) = 0.072 and 0.053, respectively; P < 0.05). Trace elements were significantly related to children's growth and development. Dietary supplementation and screening of nutritional states are potential solutions to improve children's growth and development. PMID- 26478474 TI - A call for the better utilization of physical activity and exercise training in the defense against cardiovascular disease. AB - Statins, also known as 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, effectively reduce elevated levels of serum LDL-C concentration and in turn lower cardiovascular morbidity and mortality. Regular exercise and physical activity also have significant preventive effects against cardiovascular diseases by simultaneously reducing multiple risk factors. However, statins also produce a number of adverse events, including muscle pain, which increases dramatically in statin users who also exercise, likely limiting the cardiovascular benefits. Most importantly, reduced physical activity participation due to statin-related side effects can cancel out the benefits of the pharmacological treatment. Although exercise training offers more modest benefits compared to pharmacological therapy against traditional risk factors, considering the total impact of exercise on cardiovascular health, it is now evident that this intervention may offer a greater reduction of risks compared to statin therapy alone. However, primary recommendations regarding cardiovascular therapy still center around pharmacological approaches. Thus a new outlook is called for in clinical practice that provides room for physical activity and exercise training, thus lipid targets can be reached by a combined intervention along with improvements in other cardiovascular parameters, such as endothelial function and low-grade inflammation. Databases such as Pubmed and Google Scholar as well as the reference list of the relevant articles were searched to collect information for this opinion article. PMID- 26478475 TI - Robust H(infinity) positional control of 2-DOF robotic arm driven by electro hydraulic servo system. AB - In this paper an Hinfinity positional feedback controller is developed to improve the robust performance under structural and parametric uncertainty disturbance in electro-hydraulic servo system (EHSS). The robust control model is described as the linear state-space equation by upper linear fractional transformation. According to the solution of Hinfinity sub-optimal control problem, the robust controller is designed and simplified to lower order linear model which is easily realized in EHSS. The simulation and experimental results can validate the robustness of this proposed method. The comparison result with PI control shows that the robust controller is suitable for this EHSS under the critical condition where the desired system bandwidth is higher and the external load of the hydraulic actuator is closed to its limited capability. PMID- 26478476 TI - Choroid Plexus Tumors: Experience of 10 Cases with Special References to Adult Cases. AB - Choroid plexus tumors (CPTs) are rare intraventricular neoplasms accounting for about 0.3-0.6% of all intracranial tumors. This retrospective study on CPTs presents clinico-pathological features and management strategies based on a 20 year single-institutional experience. This series included 10 consecutive patients with pathologically proven CPTs; 5 choroid plexus papillomas (CPPs), 3 atypical CPPs (ACPPs), and 2 choroid plexus carcinomas (CPCs). Their clinical, radiological, and histopathological features as well as management including follow-up studies were reviewed. The patients included five males and five females, aging from 0 years to 61 years with median of 28 years. The affected site was lateral ventricle in two adults and fourth ventricle in eight patients; four children and four adults. The most common symptoms were gait disturbance and memory disturbance. All the patients underwent craniotomy with total, subtotal, and partial removals achieved in 50%, 40%, and 10% of the patients, respectively. The occurrence of the high grade subtypes was 50% in both the adult and pediatric groups. The Ki-67/MIB-1 index increased across the three histological subtypes, from CPP to ACPP and then to CPC. Adjuvant therapy was administered in three patients. The two patients (one adult and one child) with CPC died of whole central nervous system dissemination. At a median of 62-month follow-up, the other eight patients were alive, with only one patient having recurrence and reoperation. The results demonstrate that gross total resection is usually curative for CPP and ACPP, and adjuvant chemoradiotherapy would be required for CPC and incompletely resected ACPP. PMID- 26478477 TI - Laparoscopic adjustable gastric band revisional surgery: a single surgeon series. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is a safe and proven surgical option for morbid obesity; however, the need for revisional surgery is being increasingly reported. This study reports outcomes and incidence for a large cohort of patients requiring revisional LAGB surgery for various indications. METHODS: A retrospective review of prospectively collected data for 1524 primary LAGB placed between 2003 and 2013 by a single surgeon at a single institution was performed, analysing data for all patients in this cohort requiring revisional LAGB surgery. RESULTS: A total of 434 revisions were performed on 349 patients. A total of 278 patients had a single revision, with 71 patients having two or more revisions. Revisions amounting to 213 were band repositions, 68 were band removal only and 153 were band removal with conversion to another bariatric procedure, mostly Roux-en-Y gastric bypass (n = 143). A total of 47 (35.1%) 'band-to-band' revision patients were lost to follow-up. Patients undergoing 'band-to-band' revision for a slipped band, patient intolerance and mechanical band failure had mean excess weight loss (EWL) at 4 years of 49.9% (n = 35), 38.6% (n = 10) and 67.4% (n = 6), respectively. Port or tubing revisions were not included. Mean follow-up for 'band-to-band' revision patients was 33.4 months (standard deviation 26.4 months). 22.9% of patients required one or more band revision procedures by 2013, increased from 13% in 2008. CONCLUSION: Continued EWL is achieved with repositioning or replacement of a LAGB. However, a significant and increasing rate of re-operation over time exists. PMID- 26478478 TI - Direct versus hydrogen-assisted CO dissociation over stepped Ni and Ni3Fe surfaces: a computational investigation. AB - The adsorption and dissociation of CO over stepped Ni and Ni3Fe surfaces were systematically studied using density functional theory slab calculations. Both (211)-like surface structure terminations (NiNi step and NiFe step, denoted as Ni3Fe(211)-AA and Ni3Fe(211)-AB) are considered for Ni3Fe. Direct scission of the C-O bond in CO is identified as the least likely one among the three proposed dissociation pathways and CO dissociation via a CHO intermediate appears to be most feasible at low CO coverage on pure and alloyed Ni(211) surfaces. The priority of H-assisted CO dissociation might originate from the more activated C O bond in COH and CHO. Compared to Ni(211), the Ni3Fe(211)-AB surface could facilitate CO activation especially for the most possible CHO intermediate mechanism, whose rate-limiting step is found to be altered. The d-band center theory and Mulliken charge analysis are also employed to explain the activity difference between Ni3Fe(211)-AB and Ni3Fe(211)-AA. The significant structural sensitivity of CO dissociation highlights the importance of Fe locating in the step edge and the high reactivity of Ni3Fe(211)-AB is largely ascribed to the synergistic effect between Ni and Fe at the step edge. PMID- 26478480 TI - Fourier Deconvolution Methods for Resolution Enhancement in Continuous-Wave EPR Spectroscopy. AB - An overview of resolution enhancement of conventional, field-swept, continuous wave electron paramagnetic resonance spectra using Fourier transform-based deconvolution methods is presented. Basic steps that are involved in resolution enhancement of calculated spectra using an implementation based on complex discrete Fourier transform algorithms are illustrated. Advantages and limitations of the method are discussed. An application to an experimentally obtained spectrum is provided to illustrate the power of the method for resolving overlapped transitions. PMID- 26478479 TI - Rapid-Scan EPR of Nitroxide Spin Labels and Semiquinones. AB - Rapid-scan electron paramagnetic resonance is based on continuous direct detection of the spin response as the magnetic field is scanned upfield and downfield through resonance thousands of times per second. The method provides improved signal-to-noise for a wide range of samples, including rapidly tumbling and immobilized radicals. This chapter provides an introduction to the method and practical examples of implementation for organic radicals. PMID- 26478481 TI - Multifrequency Pulsed EPR and the Characterization of Molecular Dynamics. AB - In fluid solution, motion-dependent processes dominate electron spin-lattice relaxation for nitroxides and semiquinones at frequencies between 250 MHz and 34 GHz. For triarylmethyl radicals, motion-dependent processes dominate spin-lattice relaxation at frequencies below about 3 GHz. The frequency dependence of relaxation provides invaluable information about dynamic processes occurring with characteristic times on the order of the electron Zeeman frequency. Relaxation mechanisms, methods of measuring spin-lattice relaxation, and motional processes for nitroxide, semiquinone, and triarylmethyl radicals are discussed. PMID- 26478483 TI - 230/115 GHz Electron Paramagnetic Resonance/Double Electron-Electron Resonance Spectroscopy. AB - Electron paramagnetic resonance (EPR) and double electron-electron resonance (DEER) spectroscopies are powerful and versatile tools for studying local structures and dynamic properties of biological molecules. Similar to nuclear magnetic resonance (NMR) spectroscopy, EPR/DEER spectroscopies become more advantageous at higher frequencies and higher magnetic fields because of better spectral resolution as well as higher spin polarization. Here, we describe development of a high-frequency (HF) EPR/DEER spectrometer operating in the frequency range of 107-120 and 215-240 GHz and in the magnetic field range of 0 12.1 T, which has unique experimental capabilities such as enabling the complete spin polarization and wide-band DEER spectroscopy. Emphasis is given on the application of HF EPR/DEER techniques, and specific examples of HF EPR spectroscopy to drastically increase spin coherence in nanodiamonds as well as HF DEER spectroscopy to extract spin concentration in a diamond crystal are presented. PMID- 26478484 TI - CW-EPR Spectral Simulations: Solid State. AB - This chapter summarizes the core concepts underlying the simulation of EPR spectra from biological samples in the solid state, from a user perspective. The key choices and decisions that have to be made by a user when simulating an experimental EPR spectrum are outlined. These include: the choice of the simulation model (the network of spins and the associated spin Hamiltonian), the dynamic regime (solid, liquid, slow motion), the level of theory used in the simulation (matrix diagonalization, perturbation theory, etc.), the treatment of orientational order and disorder (powder, crystal, partial ordering), the inclusion of the effects of structural disorder (strains), the effects of other line broadening mechanisms (unresolved hyperfine couplings, relaxation), and the inclusion of experimental distortions (field modulation, power saturation, filtering). Additionally, the salient aspects of utilizing least-squares fitting algorithms to aid the analysis of experimental spectra with the help of simulations are outlined. Although drawing from the experience gained from implementing EasySpin and from interacting with EasySpin's user base, this chapter applies to any EPR simulation software. PMID- 26478482 TI - Resolution and Characterization of Chemical Steps in Enzyme Catalytic Sequences by Using Low-Temperature and Time-Resolved, Full-Spectrum EPR Spectroscopy in Fluid Cryosolvent and Frozen Solution Systems. AB - Approaches to the resolution and characterization of individual chemical steps in enzyme catalytic sequences, by using temperatures in the cryogenic range of 190 250 K, and kinetics measured by time-resolved, full-spectrum electron paramagnetic resonance spectroscopy in fluid cryosolvent and frozen solution systems, are described. The preparation and performance of the adenosylcobalamin dependent ethanolamine ammonia-lyase enzyme from Salmonella typhimurium in the two systems exemplifies the biochemical and spectroscopic methods. General advantages of low-temperature studies are (1) slowing of reaction steps, so that measurements can be made by using straightforward T-step kinetic methods and commercial instrumentation, (2) resolution of individual reaction steps, so that first-order kinetic analysis can be applied, and (3) accumulation of intermediates that are not detectable at room temperatures. The broad temperature range from room temperature to 190 K encompasses three regimes: (1) temperature independent mean free energy surface (corresponding to native behavior); (2) the narrow temperature region of a glass-like transition in the protein, over which the free energy surface changes, revealing dependence of the native reaction on collective protein/solvent motions; and (3) the temperature range below the glass transition region, for which persistent reaction corresponds to nonnative, alternative reaction pathways, in the vicinity of the native configurational envelope. Representative outcomes of low-temperature kinetics studies are portrayed on Eyring and free energy surface (landscape) plots, and guidelines for interpretations are presented. PMID- 26478485 TI - CW-EPR Spectral Simulations: Slow-Motion Regime. AB - This chapter reviews the range of methods currently available for calculating the electron paramagnetic resonance (EPR) spectrum of nitroxide spin-labeled biomolecules undergoing slow motion. The two major approaches include the stochastic Liouville equation (SLE) which represents the spin label motion using diffusion operators, and the dynamic trajectory (DT) approach, which enables the EPR spectrum to be calculated from molecular dynamics simulations. The basic model parameters needed for each approach are described, together with a broad outline of the theoretical approaches underlying the methods, sufficient to allow their comparison for different applications. Hybrid methods utilizing a combination of SLE and DT approaches are briefly discussed. PMID- 26478486 TI - Quantitative Interpretation of Multifrequency Multimode EPR Spectra of Metal Containing Proteins, Enzymes, and Biomimetic Complexes. AB - Electron paramagnetic resonance (EPR) spectroscopy has long been a primary method for characterization of paramagnetic centers in materials and biological complexes. Transition metals in biological complexes have valence d-orbitals that largely define the chemistry of the metal centers. EPR spectra are distinctive for metal type, oxidation state, protein environment, substrates, and inhibitors. The study of many metal centers in proteins, enzymes, and biomimetic complexes has led to the development of a systematic methodology for quantitative interpretation of EPR spectra from a wide array of metal containing complexes. The methodology is now contained in the computer program SpinCount. SpinCount allows simulation of EPR spectra from any sample containing multiple species composed of one or two metals in any spin state. The simulations are quantitative, thus allowing determination of all species concentrations in a sample directly from spectra. This chapter will focus on applications to transition metals in biological systems using EPR spectra from multiple microwave frequencies and modes. PMID- 26478487 TI - Pulse Double-Resonance EPR Techniques for the Study of Metallobiomolecules. AB - Electron paramagnetic resonance (EPR) spectroscopy exploits an intrinsic property of matter, namely the electron spin and its related magnetic moment. This can be oriented in a magnetic field and thus, in the classical limit, acts like a little bar magnet. Its moment will align either parallel or antiparallel to the field, giving rise to different energies (termed Zeeman splitting). Transitions between these two quantized states can be driven by incident microwave frequency radiation, analogous to NMR experiments, where radiofrequency radiation is used. However, the electron Zeeman interaction alone provides only limited information. Instead, much of the usefulness of EPR is derived from the fact that the electron spin also interacts with its local magnetic environment and thus can be used to probe structure via detection of nearby spins, e.g., NMR-active magnetic nuclei and/or other electron spin(s). The latter is exploited in spin labeling techniques, an exciting new area in the development of noncrystallographic protein structure determination. Although these interactions are often smaller than the linewidth of the EPR experiment, sophisticated pulse EPR methods allow their detection. A number of such techniques are well established today and can be broadly described as double-resonance methods, in which the electron spin is used as a reporter. Below we give a brief description of pulse EPR methods, particularly their implementation at higher magnetic fields, and how to best exploit them for studying metallobiomolecules. PMID- 26478488 TI - Mapping the Structure of Metalloproteins with RIDME. AB - Distance measurements in biological macromolecules represent a very active field of application of pulsed electron paramagnetic resonance (EPR) spectroscopy. The relatively recently introduced pulsed EPR method of relaxation-induced dipolar modulation enhancement (RIDME) is conceptually similar to the popular double electron-electron resonance (DEER), but is much more suitable for studying the structures of metalloproteins while using their native paramagnetic metal centers as structural reference points. In particular, RIDME can largely alleviate the sensitivity and orientational selectivity problems that limit the application of DEER to such systems. In this contribution, the theoretical principles, implementation, optimization, and available experimental examples of RIDME are described with the purpose of enhancing the familiarity with this technique and promoting its application. PMID- 26478489 TI - Structural Characterization of the Catalytic Sites of Mononuclear Nonheme Fe Hydroxylases Using 2H-ESEEM. AB - Aromatic amino acid hydroxylases are members of a larger group of enzymes that use a mononuclear nonheme Fe center to catalyze a variety of thermodynamically challenging reactions in which O2 is used in the oxidative transformation of substrates. The hydroxylase enzymes are catalytically active in the ferrous oxidation state and are high-spin. To render the catalytic site EPR-active, we have used nitric oxide (NO) as a surrogate for substrate O2 to form an S=3/2 paramagnetic center. While the continuous-wave (cw)-EPR spectra of NO-enzyme adducts are rather generic, they provide electron spin echo envelope modulation (ESEEM) data that are rich with structural information derived from ligand hyperfine couplings. This chapter will focus on (2)H-ESEEM spectroscopy, an approach that we have taken for assigning these spectra and harvesting the unique information on Fe(II) coordination chemistry that they provide. While these spectroscopic measurements are routine, an emphasis will be placed on the analysis of cw-EPR and (2)H-ESEEM data using an unconstrained nonlinear optimization approach. These analysis methods are based on simple custom "scripts" that run in the MATLAB environment and that use EasySpin, a public domain EPR simulation package, as their calculation engine. The examples provided here use a strategy that can be adapted for the treatment of most EPR measurements. PMID- 26478490 TI - Pulsed EPR in the Study of Drug Binding in Cytochrome P450 and NOS. AB - Pulsed EPR methods for the study of drug binding to heme-thiolate enzymes such as cytochrome P450 and nitric oxide synthase are discussed. HYSCORE and ENDOR methods to measure (1)H of axial ligands of the heme group are described with illustrations of water serving as the axial ligand in the drug-free enzyme and ligands coordinating directly to the heme or through one or more bridging water molecules. Some practical aspects of measurement and data processing are discussed along with prospects for use with other nuclei and at other EPR bands. PMID- 26478492 TI - Development and Application of Spin Traps, Spin Probes, and Spin Labels. AB - This chapter focuses on major achievements of the last decade in the synthesis and applications of spin traps, spin probes, and spin labels. Our discussion on spin trapping is mainly concerned with novel aspects of nitrones used as spin traps and with the kinetics caused by bioreductants. The second part of the chapter deals with recent developments in site-directed spin labeling (SDSL) for studying structure and functions of proteins and nucleic acids. We focus on SDSL EPR distance measurements using advanced trityl and nitroxide labels, on new approaches for incorporation of spin labels in biomolecules, and finally, on recent room/physiological temperature measurements made feasible by these novel spin labels. PMID- 26478491 TI - EPR Methods for Biological Cu(II): L-Band CW and NARS. AB - Copper has many roles in biology that involve the change of coordination sphere and/or oxidation state of the copper ion. Consequently, the study of copper in heterogeneous environments is an important area in biophysics. EPR is a primary technique for the investigation of paramagnetic copper, which is usually the isolated Cu(II) ion, but sometimes as Cu(II) in different oxidation states of multitransition ion clusters. The gross geometry of the coordination environment of Cu(II) can often be determined from a simple inspection of the EPR spectrum, recorded in the traditional X-band frequency range (9-10 GHz). Identification and quantitation of the coordinating ligand atoms, however, is not so straightforward. In particular, analysis of the superhyperfine structure on the EPR spectrum, to determine the number of coordinated nitrogen atoms, is fraught with difficulty at X-band, despite the observation that the overwhelming number of EPR studies of Cu(II) in the literature have been carried out at X-band. Greater reliability has been demonstrated at S-band (3-4 GHz), using the low field parallel (gz) features. However, analysis relies on clear identification of the outermost superhyperfine line, which has the lowest intensity of all the spectral features. Computer simulations have subsequently indicated that the much more intense perpendicular region of the spectrum can be reliably interpreted at L-band (2 GHz). The present work describes the development of L-band EPR of Cu(II) into a routine method that is applicable to biological samples. PMID- 26478493 TI - Site-Directed Spin Labeling of RNA by Postsynthetic Modification of 2'-Amino Groups. AB - To elucidate mechanisms that govern functions of nucleic acids, it is essential to understand their structure and dynamics. Electron paramagnetic resonance (EPR) spectroscopy is a valuable technique that is routinely used to study those aspects of nucleic acids. A prerequisite for most EPR studies of nucleic acids is incorporation of spin labels at specific sites, known as site-directed spin labeling (SDSL). There are two main strategies for SDSL through formation of covalent bonds, i.e., the phosphoramidite approach and postsynthetic spin labeling. After describing briefly the advantages and disadvantages of these two strategies, postsynthetic labeling of 2'-amino groups in RNA is delineated. Postsynthetic labeling of 2'-amino groups in RNA using 4-isocyanato-TEMPO has long been established as a useful approach. However, this method has some drawbacks, both with regard to the spin-labeling protocol and the flexibility of the spin label itself. Recently reported isothiocyanate-substituted aromatic isoindoline-derived nitroxides can be used to quantitatively and selectively modify 2'-amino groups in RNA and do not have the drawbacks associated with 4 isocyanato-TEMPO. This chapter provides a detailed description of the postsynthetic spin-labeling methods of 2'-amino groups in RNA with a special focus on using the aromatic isothiocyanate spin labels. PMID- 26478494 TI - Gd3+ Spin Labeling for Measuring Distances in Biomacromolecules: Why and How? AB - Applications of distance measurements by pulse dipolar electron-paramagnetic resonance (PD-EPR) spectroscopy to structural biology are based on introducing spin labels (SLs) at well-defined locations in the biomacromolecule. The most commonly used SLs are nitroxyl radicals, but recently SLs based on high-spin Gd(3+) (S=7/2) complexes have been shown to be an attractive alternative for PD EPR, particularly double electron-electron resonance (DEER), at spectrometer frequencies higher than 30 GHz. In this chapter, we describe the advantage of using this new family of SLs in terms of sensitivity, stability, and chemical diversity. We present current labeling strategies for proteins, discuss the approximations under which DEER data analysis of a pair of Gd(3+) SLs (GdSLs) is equivalent to that of a pair of S=1/2 SLs, and discuss the reduction in multispin effects in a cluster of GdSLs, as opposed to a cluster of nitroxide labels, which can be found in oligomeric systems. In addition, we provide a brief overview of the current, rather limited, knowledge of Gd(3+) phase relaxation behavior and describe experimental strategies in terms of optimizing sensitivity. The possibility of using several types of SLs in a system allows one to isolate effects due to the chemical nature of the SL itself; several such examples are presented, focusing on comparing nitroxide and GdSLs. Finally, we will discuss the initial results on in-cell DEER with GdSLs. PMID- 26478495 TI - Cu2+ as an ESR Probe of Protein Structure and Function. AB - Electron spin resonance (ESR) spectroscopy in combination with site-directed spin labeling has been widely used to determine the structure and dynamics of proteins and other biomolecules. The most popular spin label is a nitroxide-based radical which can be attached to a protein via a site-specific reaction with either native cysteines or cysteines engineered into the system via site-directed mutagenesis. Paramagnetic transition metals, including Cu(2+), often serve as cofactors of metalloproteins, and have already been realized as ESR probes to report structural information in these proteins. This chapter summarizes recent methodological development from our laboratory in utilizing Cu(2+) as an ESR spin probe to determine distance information. We focus on detailed experimental procedures, optimized instrumental parameters, and data analysis approaches in order to guide one who is new to the field. Theory and applications of metal ESR have been reviewed in literature and are not the focus of this chapter. A few examples of applications of the methods are listed in the end. PMID- 26478496 TI - Genetically Encoded Spin Labels for In Vitro and In-Cell EPR Studies of Native Proteins. AB - Electron paramagnetic resonance (EPR) spectroscopy in combination with site directed spin labeling (SDSL) is a powerful approach to study the structure, dynamics, and interactions of proteins. The genetic encoding of the noncanonical amino acid spin-labeled lysine 1 (SLK-1) eliminates the need for any chemical labeling steps in SDSL-EPR studies and enables the investigation of native, endogenous proteins with minimal structural perturbation, and without the need to create unique reactive sites for chemical labeling. We report detailed experimental procedures for the efficient synthesis of SLK-1, the expression and purification of SLK-1-containing proteins under conditions that ensure maximal integrity of the nitroxide radical moiety, and procedures for intramolecular EPR distance measurements in proteins by double electron-electron resonance. PMID- 26478497 TI - Genetic Incorporation of the Unnatural Amino Acid p-Acetyl Phenylalanine into Proteins for Site-Directed Spin Labeling. AB - Site-directed spin labeling (SDSL) is a powerful tool for the characterization of protein structure and dynamics; however, its application in many systems is hampered by the reliance on unique and benign cysteine substitutions for the site specific attachment of the spin label. An elegant solution to this problem involves the use of genetically encoded unnatural amino acids (UAAs) containing reactive functional groups that are chemically orthogonal to those of the 20 amino acids found naturally in proteins. These unique functional groups can then be selectively reacted with an appropriately functionalized spin probe. In this chapter, we detail the genetic incorporation of the ketone-bearing amino acid p acetyl phenylalanine (pAcPhe) into recombinant proteins expressed in E. coli. Incorporation of pAcPhe is followed by chemoselective reaction of the ketone side chain with a hydroxylamine-functionalized nitroxide to afford the spin-labeled side chain "K1," and we present two protocols for successful K1 labeling of proteins bearing site-specific pAcPhe. We outline the basic requirements for pAcPhe incorporation and labeling, with an emphasis on practical aspects that must be considered by the researcher if high yields of UAA incorporation and efficient labeling reactions are to be achieved. To this end, we highlight recent advances that have led to increased yields of pAcPhe incorporation, and discuss the use of aniline-based catalysts allowing for facile conjugation of the hydroxylamine spin label under mild reaction conditions. To illustrate the utility of K1 labeling in proteins where traditional cysteine-based SDSL methods are problematic, we site-specifically K1 label the cellular prion protein at two positions in the C-terminal domain and determine the interspin distance using double electron-electron resonance EPR. Recent advances in UAA incorporation and ketone-based bioconjugation, in combination with the commercial availability of all requisite reagents, should make K1 labeling an increasingly viable alternative to cysteine-based methods for SDSL in proteins. PMID- 26478499 TI - Computer Modeling of Spin Labels: NASNOX, PRONOX, and ALLNOX. AB - Measurement of distances between spin labels using electron paramagnetic resonance with the double electron-electron resonance (DEER) technique is an important method for evaluation of biomolecular structures. Computation of interlabel distances is of value for experimental planning, validation of known structures using DEER-measured distances, and determination of theoretical data for comparison with experiment. This requires steps of building labels at two defined sites on proteins, DNA or RNA; calculation of allowable label conformers based on rotation around torsional angles; computation of pairwise interlabel distances on a per conformer basis; and calculation of an average distance between the two label ensembles. We have described and validated two programs for this purpose: NASNOX, which permits computation of distances between R5 labels on DNA or RNA; and PRONOX, which similarly computes distances between R1 labels on proteins. However, these programs are limited to a specific single label and single target types. Therefore, we have developed a program, which we refer to as ALLNOX (Addition of Labels and Linkers), which permits addition of any label to any site on any target. The main principle in the program is to break the molecular system into a "label," a "linker," and a "target." The user can upload a "label" with any chemistry, define a "linker" based on a SMILES-like string, and then define the "target" site. The flexibility of ALLNOX facilitates theoretical evaluation of labels prior to synthesis and accommodates evaluation of experimental data in biochemical complexes containing multiple molecular types. PMID- 26478498 TI - A Straightforward Approach to the Analysis of Double Electron-Electron Resonance Data. AB - Double electron-electron resonance (DEER) is now widely utilized to measure distance distributions in the 20-70A range. DEER is frequently applied to biological systems that have multiple conformational states leading to complex distance distributions. These complex distributions raise issues regarding the best approach to analyze DEER data. A widely used method utilizes a priori background correction followed by Tikhonov regularization. Unfortunately, the underlying assumptions of this approach can impact the analysis. In this chapter, a method of analyzing DEER data is presented that is ideally suited to obtain these complex distance distributions. The approach allows the fitting of raw experimental data without a priori background correction as well as the rigorous determination of uncertainties for all fitting parameters. This same methodological approach can be used for the simultaneous or global analysis of multiple DEER data sets using variable ratios of a common set of components, thus allowing direct correlation of distance components with functionally relevant conformational and biochemical states. Examples are given throughout to highlight this robust fitting approach. PMID- 26478500 TI - mtsslSuite: Probing Biomolecular Conformation by Spin-Labeling Studies. AB - EPR long-range distance measurements on spin-labeled macromolecules have recently become a popular tool in structural biology. The method can be used to obtain coarse-grained structures of biomolecules, to track conformational changes and dynamics, to dock macromolecular complexes, or to localize spin centers within macromolecules using trilateration. Because the conformation of the spin label is usually unknown, it is often necessary to construct conformational models of the spin label on the macromolecules for data interpretation. For this purpose, so called in silico spin-labeling approaches have been developed. In this chapter, a comprehensive summary of the mtsslSuite is provided, one of the in silico spin labeling software packages. The package currently contains three programs: mtsslWizard, mtsslDock, and mtsslTrilaterate. Worked examples for the usage of all three programs during the planning- and interpretation stages of the EPR experiment are given. PMID- 26478501 TI - Full Atom Simulations of Spin Label Conformations. AB - Interpretation of EPR measurables from spin labels in terms of structure and dynamics requires knowledge of label behavior. General strategies were developed for simulation of labels used in EPR of proteins. The criteria for those simulations are (a) exhaustive sampling of rotamer space, (b) consensus of results independent of starting points, and (c) inclusion of entropy. These criteria are satisfied only when the number of transitions in any dihedral angle exceeds 100 and the simulation maintains thermodynamic equilibrium. Methods such as conventional MD do not efficiently cross energetic barriers, simulated anealing, Monte Carlo or popular Rotamer Library methodologies are potential energy based and ignore entropy (in addition to their specific shortcomings: environment fluctuations, fixed environment, or electrostatics). The Simulated scaling method avoids the above flaws by modulating the force fields between a reduced (allowing crossing energy barriers) and full potential (sampling minima). Spin label diffuses on this surface while remaining in thermodynamic equilibrium. Simulations show that (a) adopting a single conformation is rare, often there are two to four populated rotamers and (b) position of the NO varies up to 16 A. These results illustrate necessity for caution when interpreting EPR signals in terms of molecular structure. For example, the 10-16 A distance change in DEER should not be interpreted as a large conformational change, it can well be a flip about Calpha-Cbeta bond. Rigorous exploration of possible rotamer structures of a spin label is paramount in signal interpretation. We advocate use of bifunctional labels, motion of which is restricted 10,000-fold and the NO position is restricted to 2-5 A. PMID- 26478502 TI - Preface. PMID- 26478505 TI - Electronic Structure and Ferromagnetism Modulation in Cu/Cu2O Interface: Impact of Interfacial Cu Vacancy and Its Diffusion. AB - Cu/Cu2O composite structures have been discovered to show sizable ferromagnetism (FM) with the potential applications in spintronic devices. To date, there is no consensus on the FM origin in Cu/Cu2O systems. Here, first principles calculations are performed on the interface structure to explore the microscopic mechanism of the FM. It is found that only the Cu vacancy (V(Cu)) adjacent to the outermost Cu2O layer induces a considerable magnetic moment, mostly contributed by 2p orbitals of the nearest-neighbor oxygen atom (O(NN)) with two dangling bonds and 3d orbitals of the Cu atoms bonding with the O(NN). Meanwhile, the charge transfer from Cu to Cu2O creates higher density of states at the Fermi level and subsequently leads to the spontaneous FM. Furthermore, the FM could be modulated by the amount of interfacial V(Cu), governed by the interfacial Cu diffusion with a moderate energy barrier (~1.2 eV). These findings provide insights into the FM mechanism and tuning the FM via interfacial cation diffusion in the Cu/Cu2O contact. PMID- 26478506 TI - Post-earthquake Nepal: the way forward. PMID- 26478504 TI - Heme Binding by Corynebacterium diphtheriae HmuT: Function and Heme Environment. AB - The heme uptake pathway (hmu) of Corynebacterium diphtheriae utilizes multiple proteins to bind and transport heme into the cell. One of these proteins, HmuT, delivers heme to the ABC transporter HmuUV. In this study, the axial ligation of the heme in ferric HmuT is probed by examination of wild-type (WT) HmuT and a series of conserved heme pocket residue mutants, H136A, Y235A, and M292A. Characterization by UV-visible, resonance Raman, and magnetic circular dichroism spectroscopies indicates that H136 and Y235 are the axial ligands in ferric HmuT. Consistent with this assignment of axial ligands, ferric WT and H136A HmuT are difficult to reduce while Y235A is reduced readily in the presence of dithionite. The FeCO Raman shifts in WT, H136A, and Y235A HmuT-CO complexes provide further evidence of the axial ligand assignments. Additionally, these frequencies provide insight into the nonbonding environment of the heme pocket. Ferrous Y235A and the Y235A-CO complex reveal that the imidazole of H136 exists in two forms, one neutral and one with imidazolate character, consistent with a hydrogen bond acceptor on the H136 side of the heme. The ferric fluoride complex of Y235A reveals the presence of at least one hydrogen bond donor on the Y235 side of the heme. Hemoglobin utilization assays showed that the axial Y235 ligand is required for heme uptake in HmuT. PMID- 26478507 TI - Does decentralisation of tuberculosis care influence treatment outcomes? The case of Oromia Region, Ethiopia. AB - SETTING: Oromia Region, Ethiopia. OBJECTIVE: To investigate the effect of decentralised care on anti-tuberculosis treatment outcomes and identify factors affecting outcome among new smear-positive tuberculosis (TB) patients. DESIGN: This was a retrospective cohort study comparing patients treated in the community during the continuation phase with those managed throughout treatment in health facilities. Data were collected from TB registers and patient cards using a pre tested data capture form. RESULTS: Of the 2226 new smear-positive TB patients registered from July 2010 to June 2012 who were included in the study, 1599 (72.6%) received treatment in health facilities, and the rest in the community. Overall treatment success was 94.7%. Patients treated in the community had comparable treatment success with those managed in health facilities (aOR 1.7, 95%CI 0.80-3.57). Missing doses (OR 0.22, 95%CI 0.08-0.55), supervision during the continuation phase (OR 2.6, 95%CI 1.34-5.05), positive sputum at month 2 (OR 0.07, 95%CI 0.04-0.13) and human immunodeficiency virus infection (OR 0.25, 95%CI 0.13-0.46) were independent predictors of treatment success. CONCLUSION: Overall treatment success is high in new smear-positive TB patients in Oromia. Patients receiving treatment in the community during the continuation phase have treatment success comparable with that of patients managed in health facilities. PMID- 26478508 TI - Assigning focal persons to notify more tuberculosis patients: lessons learned in southern Ethiopia. AB - SETTING: Health centres in Southern Ethiopia. OBJECTIVE: To determine factors contributing to the large variations in the notification of smear-positive tuberculosis (TB) cases. DESIGN: A cross-sectional study in selected health centres from areas with high and low case notification was conducted and health system and health care worker (HCW) related determinants were examined. RESULTS: A total of 50 (61.0%) health centres and 172 (65.2%) HCWs from high case notification areas, and 32 (39.0%) health centres and 92 (33.8%) HCWs from low case notification areas were included in the study. Assignment of a full-time TB focal person at the TB clinic (adjusted odds ratio [aOR] 5.8, 95%CI 1.5-22.4) and availability of TB recording tools (aOR 7.0, 95%CI 1.5-32.5) were independent predictors of high case notification rates. HCW knowledge about TB screening, diagnosis and treatment was positively associated with case notification (aOR 2.53, 95%CI 1.42-4.48). CONCLUSION: Increased TB case notification was associated with the presence of a full-time focal person, availability of TB recording tools and good knowledge about TB among HCWs. Putting in place these measures in all health centres could increase TB notification in the region. PMID- 26478509 TI - The Ethiopian initiative to build sustainable capacity for operational research: overview and lessons learned. AB - SETTING: Programme-based operational research is instrumental for the enhancement of tuberculosis (TB) control. In 2012, the Ethiopian Federal Ministry of Health launched an initiative for capacity building in operational research (OR). OBJECTIVE: To develop sustainable capacity for OR in Ethiopia in a multiyear initiative. DESIGN: The initiative was developed in collaboration with regional, national and international experts. Teams representing regions in Ethiopia conducted OR addressing national and regional priorities. To make use of local expertise and increase sustainability, a domestic mentor training programme was included. Existing capacity was enhanced through a competitive grant scheme providing TB researchers with financial and technical support. The Ethiopian Tuberculosis Research Advisory Committee was also supported in its functions. Regional ethics review bodies were strengthened or established where they did not exist. RESULTS: Fifty-two people were trained and conducted 13 OR projects, of which six have been published to date. In addition, eight protocols were supported through grants. Ethics review bodies were strengthened in all regions. CONCLUSION: The initiative trained participants from all regions and succeeded in the completion of all stages of the OR process. The success of the programme can be attributed to the team approach, 'learning while doing', integrated mentorship programme and strong national ownership. PMID- 26478510 TI - Documentation and treatment outcomes of smear-negative and extra-pulmonary tuberculosis in Ethiopia. AB - BACKGROUND: Smear-negative and extra-pulmonary tuberculosis (TB) comprise two thirds of TB cases reported in Ethiopia. Neither treatment outcomes nor underlying associated factors are routinely reported for these cases. OBJECTIVE: To assess treatment outcomes and associated risk factors of smear-negative and extra-pulmonary TB in comparison with smear-positive cases. DESIGN: Record review of all TB cases registered in 14 randomly selected public and private health facilities in Addis Ababa, Ethiopia, over a 1-year period. RESULTS: Percentages of smear-negative and extra-pulmonary TB were independent of human immunodeficiency virus (HIV) status, and were not evenly distributed among health facilities. Extra-pulmonary TB was overrepresented in the private sector, and smear-negative TB was more frequent in health clinics than in hospitals. Outcomes reported by clinics were more favourable than those of the hospitals; no differences were observed when comparing public and private health facilities. Only 54% of the TB registers were complete; missing information correlated with unfavourable outcomes. Younger age, but not sex or HIV status, was associated with favourable outcomes. CONCLUSION: The uneven distribution of smear-negative and extra-pulmonary TB among different health facilities requires further study and may provide important insight into diagnosis and care of these patients. Incomplete TB register information may be an underappreciated factor contributing to unfavourable outcomes. PMID- 26478511 TI - Adherence to anti-tuberculosis treatment in Tigray, Northern Ethiopia. AB - SETTING: Tuberculosis (TB) patients in Mekelle Zone, Tigray Region, in Ethiopia. OBJECTIVE: To investigate adherence to anti-tuberculosis treatment. DESIGN: A cross-sectional study in health facilities providing anti-tuberculosis treatment was conducted. Adherence was measured in three ways: through self-reported missed doses, by visual analogue scale whereby patients rate their own adherence and by record review. A patient was considered to be adherent if 90% or more of the prescribed medication was taken. RESULT: Of 278 TB patients included, 101 were in the intensive and 177 in the continuation phase. Respectively 67 (24.1%), 130 (46.8%) and 80 (28.8%) patients had smear-positive, smear-negative and extra pulmonary TB. Self-report of missed doses and record review indicated adherence of respectively 273 (97.3%) and 271 (97.5%) patients. By visual analogue scale, 250 (91.6%) patients rated themselves as adherent. History of drug side effects (aOR 0.25, 95%CI 0.08-0.77) and knowledge about TB prevention (aOR 0.19, 95%CI 0.05-0.8) were independently associated with being adherent in this setting. CONCLUSION: Adherence to anti-tuberculosis treatment was high in our study. Adherence support should be given to the poor, the elderly, patients co-infected with the human immunodeficiency virus, alcohol abusers and smokers. Health education on TB prevention should be given to all TB patients regularly. PMID- 26478512 TI - Ambulatory care for multidrug-resistant tuberculosis: lessons learned in Addis Ababa, Ethiopia. AB - SETTING: Ethiopia is one of the high multidrug-resistant tuberculosis (MDR-TB) burden countries. Efforts by the National TB Programme to control MDR-TB include expanding ambulatory care. OBJECTIVE: To investigate the opportunities and challenges faced by treatment follow-up health centres (TFCs) when managing MDR TB patients, with greater focus on recording, TB infection control (IC) and supervision practices. METHODS: A facility-based cross-sectional study was conducted by reviewing the records of all MDR-TB cases in all 25 TFCs in Addis Ababa, Ethiopia. The TB focal point, pharmacy and laboratory heads were also interviewed. RESULT: A total of 221 MDR-TB patients were registered; 157 (71%) patients had been referred from one of the two treatment initiating centres. While some TFCs oversaw up to 41 patients, others had just one patient. The majority of the TFCs (n = 21, 84%) followed standardised TB IC procedures. Poor documentation of patient information was observed at all sites; for example, human immunodeficiency virus and current treatment status was not indicated for respectively 86 (38%) and 41 (18%) patients. CONCLUSION: The study revealed that infection prevention practices were largely adhered to. Documentation of patient related information was a major challenge, and regular supervision of the TFCs should be emphasised. Record keeping is critical. PMID- 26478514 TI - Investigating the choriocapillaris and choroidal vasculature with new optical coherence tomography technologies. AB - The body of knowledge of in vivo investigation of the choroid has been markedly enhanced by recent technological advances in optical coherence tomography (OCT). New insights elucidating the morphological features of the choriocapillaris and choroidal vasculature, in both physiological and pathological conditions, indicate that the choroid plays a pivotal role in many posterior segment diseases. In this article, a review of the histological characteristics of the choroid, which must be considered for the proper interpretation of in vivo imaging, is followed by a comprehensive discussion of fundamental principles of the current state-of-the-art in OCT, including cross-sectional OCT, en face OCT, and OCT angiography using both spectral domain OCT and swept source OCT technologies. A detailed review of the tomographic features of the choroid in the normal eye is followed by relevant findings in prevalent chorioretinal diseases, focusing on major causes of vision loss such as typical early and advanced age related macular degeneration, polypoidal choroidal vasculopathy, central serous chorioretinopathy, pachychoroid spectrum disorders, diabetic choroidopathy, and myopia. PMID- 26478513 TI - Poor symptomatic tuberculosis screening practices in a quarter of health centres in Amhara Region, Ethiopia. AB - SETTING: In 2011, Ethiopia introduced a strategy of symptomatic tuberculosis (TB) screening for patients attending out-patient services to increase identification of presumptive TB. OBJECTIVE: To assess implementation and factors affecting symptomatic TB screening at out-patient departments in health centres in the Amhara Region, Ethiopia. DESIGN: Using a cross-sectional study design, 86 randomly selected public health centres providing DOTS were included in the study. Data were captured by reviewing TB registers and interviewing key informants at out-patient services. RESULTS: Of 86 health centres, 24 (28%) had poor symptomatic TB screening practices, defined as screening <80% of attending out-patients. Having an actively functioning multidisciplinary health centre team to assess TB services (aOR 2.29, 95%CI 2.23-30.80) and partner support for TB activities (aOR 4.84, 95%CI 1.05-22.40) were associated with higher TB screening rates, whereas availability of antiretroviral therapy was negatively associated. In all health centres combined, 1.6% of out-patient department attendees were identified as having presumptive TB. CONCLUSION: A quarter of health centres had poor symptomatic TB screening practices in the out-patient services in this study. Strengthening multidisciplinary teams and expanding partner support are recommended to improve TB screening practices at out-patient services in Ethiopia. PMID- 26478516 TI - Interfacial band alignment for photocatalytic charge separation in TiO2 nanotube arrays coated with CuPt nanoparticles. AB - n-Type anatase-phase one-dimensional TiO2 nanostructure arrays coated with nanoparticles of Cu or CuPt have emerged as high performance photocatalysts for both photooxidation and photoreduction. The properties of the catalyst-promoter interface are recognized to be critical to this high performance but are largely unknown. Using X-ray and ultraviolet photoelectron spectroscopies (XPS/UPS), we probed the electronic properties of the CuPt-TiO2 interface in transparent TiO2 nanotube arrays (TTNTAs) coated with photodeposited CuPt nanoparticles (CuPt TTNTA hybrids) as well as those coated with sputtered CuPt (Sput-CuPt-TTNTA hybrids). XPS and UPS spectra provided the evidence of a Schottky barrier with a band-bending of 0.49-0.67 eV at the CuPt-TiO2 interface in CuPt-TTNTA hybrids due to which photoexcited electrons are expected to be retained in the TiO2 while photoexcited holes will be collected by the CuPt nanoparticles. For Sput-CuPt TTNTA hybrids, no such band-bending was observed. These results point to the importance of the metal nanoparticle preparation technique on interfacial band alignments and challenge the conventional understanding of the promoting action of noble metal nanoparticles on TiO2 photocatalysts as sinks for photoexcited electrons. PMID- 26478515 TI - Sam68 regulates cell proliferation and cell adhesion-mediated drug resistance (CAM-DR) via the AKT pathway in non-Hodgkin's lymphoma. AB - OBJECTIVES: Sam68 (Src-associated in mitosis 68 kDa), a substrate for tyrosine kinase c-Src during mitosis, is up-regulated in a variety of human cancers and acts oncogenically promoting tumour progression. This study has explored biological function and clinical significance of Sam68 in non-Hodgkin's lymphoma (NHL). MATERIALS AND METHODS: To examine Sam68 expression in NHL, clinically, eight diffuse large B-cell lymphomas and four reactive lymphoid hyperplasia fresh frozen tissues were obtained for western blot and quantitative real-time PCR analyses. Using immunohistochemical staining, paraffin wax embedded sections from 164 cases of NHL patients were used to evaluate prognostic value of Sam68. Cell Counting Kit-8 (CCK-8) and soft agar colony assays were conducted to investigate the role of Sam68 in cell viability and cell proliferation respectively. Furthermore, effects of Sam68 on cell adhesion-mediated drug resistance (CAM-DR) was determined by CCK-8 assay and flow cytometric analysis. RESULTS: Expression status of Sam68 inversely correlated with clinical outcomes of patients with NHL, and it was also an independent prognostic factor for the outcomes. In addition, Sam68 was associated with proliferation of NHL cells. Knock-down of its gene inhibited cell proliferation and colony formation by delaying cell cycle progression. Furthermore, OCI-Ly8 and Jeko-1 cells adhering to FN and HS-5 expressed higher Sam68 protein, compared to their suspension counterparts. Sam68 promoted cell adhesion-mediated drug resistance (CAM-DR) via the AKT pathway. CONCLUSIONS: Increased Sam68 expression in NHL resulted in poor prognosis, and it promoted CAM-DR in NHL via AKT. PMID- 26478517 TI - Chronic Endometritis: Potential Cause of Infertility and Obstetric and Neonatal Complications. AB - Chronic endometritis (CE) is a local inflammatory disease characterized by unusual plasmacyte infiltration in the endometrial stromal areas. CE has been neglected in gynecologic practice, as it is a less symptomatic benign disease that requires demanding and time-consuming histopathologic examinations for the definite diagnosis. Recent studies, however, suggest the association of CE with infertility and obstetric and neonatal complications. In this review article, we aimed to update the knowledge on epidemiology, etiology, and pathogenesis of CE as well as discuss its clinical management from diagnosis to treatment. PMID- 26478518 TI - Prioritization of candidate genes in "QTL-hotspot" region for drought tolerance in chickpea (Cicer arietinum L.). AB - A combination of two approaches, namely QTL analysis and gene enrichment analysis were used to identify candidate genes in the "QTL-hotspot" region for drought tolerance present on the Ca4 pseudomolecule in chickpea. In the first approach, a high-density bin map was developed using 53,223 single nucleotide polymorphisms (SNPs) identified in the recombinant inbred line (RIL) population of ICC 4958 (drought tolerant) and ICC 1882 (drought sensitive) cross. QTL analysis using recombination bins as markers along with the phenotyping data for 17 drought tolerance related traits obtained over 1-5 seasons and 1-5 locations split the "QTL-hotspot" region into two subregions namely "QTL-hotspot_a" (15 genes) and "QTL-hotspot_b" (11 genes). In the second approach, gene enrichment analysis using significant marker trait associations based on SNPs from the Ca4 pseudomolecule with the above mentioned phenotyping data, and the candidate genes from the refined "QTL-hotspot" region showed enrichment for 23 genes. Twelve genes were found common in both approaches. Functional validation using quantitative real-time PCR (qRT-PCR) indicated four promising candidate genes having functional implications on the effect of "QTL-hotspot" for drought tolerance in chickpea. PMID- 26478519 TI - Recent development of chemical derivatization in LC-MS for biomedical approaches. AB - LC-MS/MS is currently the most powerful system in biomedical analysis. At the same time, chemical derivatization is a useful technique to enhance the detection sensitivity of nonionizable or poorly ionizable molecules in LC-MS/MS. Derivatization improves the ionization efficiency, the chromatographic separation and/or the chemical stability. This article presents an overview of the recent development of chemical derivatization reagents and reactions for the quantitative analysis of xenobiotic and endogenous molecules such as pharmaceuticals, amino acids, peptides, proteins, steroids, biomarkers and industrial products by LC-MS. PMID- 26478520 TI - Stepwise evolution of pandrug-resistance in Klebsiella pneumoniae. AB - Carbapenem resistant Enterobacteriaceae (CRE) pose an urgent risk to global human health. CRE that are non-susceptible to all commercially available antibiotics threaten to return us to the pre-antibiotic era. Using Single Molecule Real Time (SMRT) sequencing we determined the complete genome of a pandrug-resistant Klebsiella pneumoniae isolate, representing the first complete genome sequence of CRE resistant to all commercially available antibiotics. The precise location of acquired antibiotic resistance elements, including mobile elements carrying genes for the OXA-181 carbapenemase, were defined. Intriguingly, we identified three chromosomal copies of an ISEcp1-bla(OXA-181) mobile element, one of which has disrupted the mgrB regulatory gene, accounting for resistance to colistin. Our findings provide the first description of pandrug-resistant CRE at the genomic level, and reveal the critical role of mobile resistance elements in accelerating the emergence of resistance to other last resort antibiotics. PMID- 26478521 TI - 15,16-dihydrotanshinone I Induces Apoptosis and Inhibits the Proliferation, Migration of Human Osteosarcoma Cell Line 143B in vitro. AB - BACKGROUND: 15,16-dihydrotanshinone I (DHTI), a lipophilic tanshinone extracted from Danshen root (Salvia miltiorrhiza Bunge), has been reported to function as an antitumor agent. However, its activity on osteosarcoma (OS), the most common primary malignant bone tumor, is unclear. OBJECTIVE: This study aimed to determine the effects of DHTI treatment on proliferation, apoptosis and migration of human OS cell line 143B and investigate the possible underlying molecular mechanisms. METHOD: Human cell line 143B was used as a model for investigation of the inhibitory effects of DHTI on osteosarcoma. Cell proliferation was evaluated by MTT assays, while cell cycle progression, apoptosis and cell migration were analyzed by flow cytometer, caspase activity assays and scratch migration assays. qRT-PCR and western blot were carried out to detect the expression levels of representative genes and proteins during physiological processes examined above. RESULTS: DHTI treatment inhibited the proliferation of 143B cells in a dose- and time-dependent manner through arresting cells in G1 phase by reducing the expression of cyclin D1, cyclin E1, CDK2, CDK4, CDK6, p-Rb, E2F1, SKP2 and increasing the expression of P53, P21cip1, P27kip1. In addition, DHTI induced apoptosis of 143B cells through caspase pathways to activate caspase-3, caspase 8, caspase-9, Bax, and PARP cleavage but reduce the expression of Bcl-2. Furthermore, DHTI treatment attenuated cell migration by down-regulating adhesion molecules VCAM-1 and ICAM-1. CONCLUSION: These findings suggest that DHTI could be a novel and efficient therapeutic candidate for OS treatment and further detailed investigation is warranted. PMID- 26478522 TI - Interleukin-17 in atherosclerosis: Still a long road ahead. PMID- 26478523 TI - Atrioventricular block associated with ticagrelor therapy may require permanent pacemaker. PMID- 26478524 TI - Cardiac atrial appendage stem cells therapy: a novel and promising approach for myocardial reparation after MI. PMID- 26478530 TI - Care participation and burden among informal caregivers of older adults with care needs and associations with dementia. AB - BACKGROUND: Few studies have estimated care burden in large, representative, multi-ethnic Asian population-based informal caregivers of older adults with care needs. This study describes informal caregivers' care participation for a population-based sample of older adults with care needs in Singapore, investigates differences by dementia status, and examines correlates of caregivers' burden. METHODS: Data collected from 693 pairs of older adults, aged 60 to 100 years, having any care needs, and their informal caregivers, who were aged 21 to 88 years, closely involved in their care and "knew the older resident best," and were interviewed during a cross-sectional national survey, were used. Clinical characteristics of older adults, including behavioral and psychological symptoms of dementia (BPSD) and dementia diagnosis, care needs, and socio demographic characteristics of participants were obtained. Care burden was assessed with the Zarit Burden Interview. RESULTS: Informal caregivers' participation was highest in activities related to communication (35.1%), feeding (32%), and bathing (21.1%). Among the older adults with any care need, 356 (51.4%) had dementia. Care burden was significantly associated with married caregivers (odds ratio (OR) 2.4 vs. never married), when their relative belonged to a younger cohort (OR 2.5 vs. >84 years), needed care much of the time (OR 2.5 vs. no care needed), exhibited BPSD (OR 3.5 vs. no BPSD), and had dementia (OR 2.52 vs. no dementia). CONCLUSIONS: Factors related to older adults--more care needs, presence of BPSD, and dementia--were significant contributors to informal caregivers' burden, and these should be considered while planning interventions to alleviate care burden. PMID- 26478531 TI - Conversion to Belatacept based regimen does not change T-cell phenotype and function in renal transplantation. AB - Belatacept offers a new option for renal allograft recipients who are suffering from side effects of calcineurin inhibitors or mTOR inhibitors,which may result in renal and extrarenal benefits.We prospectively performed flow cytometric immunophenotyping with a T-cell panel. In total we were able to fully investigate the immunophenotypic change in 8 patients before and after conversion from calcineurin inhibitor (n = 5) or mTOR inhibitor (n=2) to Belatacept or additional administration (n=1). Cells were analysed pre conversion, 1 month, 3 months, 6 months and 12 months after first Belatacept administration. The percentage of central memory, naive, effector memory and terminally differentiated effector memory CD4+ and CD4- T-cells was determined. CD28, CD25 and CD69 expression on CD4+ and CD4- T-cells was measured ex vivo and also after 3 days of mitogen stimulation. Intracellular cytokines IFNgamma and IL-2 were measured after polyclonal cellular stimulation. The expression of activation markers and intracellular cytokines as well as the percentage of T-cell subsets did not change significantly during the observation period compared to the time-point pre conversion. Therefore the conversion of calcineurin inhibitor or mTOR inhibitor to Belatacept seems to have no obvious impact on the immunophenotype of T-cells in patients after kidney transplantation. PMID- 26478532 TI - Brief report: When does identity lead to negative affective experiences? A comparison of Turkish-Bulgarian and Turkish-German adolescents. AB - We examine relationships between social identity domains (ethnic, national, and religious) and negative affect among Turkish-Bulgarian and Turkish-German youth. Path analysis confirmed a multiple social identities (MSI) factor that has negative relations to experiencing negative affect for Turkish youth in both countries. Beyond this negative relationship, the component of national identity showed a positive relationship to negative affect for Turkish-Bulgarians, but not for Turkish-Germans. Our findings indicate that beyond the generally adaptive effect of MSI on youth development, unique components of social identity may not always be an asset: In an assimilative acculturation context (i.e., Bulgaria), the endorsement of national identity was not adaptive. Our research therefore highlights the need for a contextually differentiated view on "healthy" identity formation among immigrants for research and practice. PMID- 26478533 TI - Unravelling intrinsic efficacy and ligand bias at G protein coupled receptors: A practical guide to assessing functional data. AB - Stephenson's empirical definition of an agonist, as a ligand with binding affinity and intrinsic efficacy (the ability to activate the receptor once bound), underpins classical receptor pharmacology. Quantifying intrinsic efficacy using functional concentration response relationships has always presented an experimental challenge. The requirement for realistic determination of efficacy is emphasised by recent developments in our understanding of G protein coupled receptor (GPCR) agonists, with recognition that some ligands stabilise different active conformations of the receptor, leading to pathway-selective, or biased agonism. Biased ligands have potential as therapeutics with improved selectivity and clinical efficacy, but there are also pitfalls to the identification of pathway selective effects. Here we explore the basics of concentration response curve analysis, beginning with the need to distinguish ligand bias from other influences of the functional system under study. We consider the different approaches that have been used to quantify and compare biased ligands, many of which are based on the Black and Leff operational model of agonism. Some of the practical issues that accompany these analyses are highlighted, with opportunities to improve estimates in future, particularly in the separation of true agonist intrinsic efficacy from the contributions of system dependent coupling efficiency. Such methods are by their nature practical approaches, and all rely on Stephenson's separation of affinity and efficacy parameters, which are interdependent at the mechanistic level. Nevertheless, operational analysis methods can be justified by mechanistic models of GPCR activation, and if used wisely are key elements to biased ligand identification. PMID- 26478534 TI - Cooperation is related to dispersal patterns in Sino-Tibetan populations. AB - There is growing recognition in both evolutionary biology and anthropology that dispersal is key to establishing patterns of cooperation. However, some models predict that cooperation is more likely to evolve in low dispersal (viscous) populations, while others predict that local competition for resources inhibits cooperation. Sex-biased dispersal and extra-pair mating may also have an effect. Using economic games in Sino-Tibetan populations with strikingly different dispersal patterns, we measure cooperation in 36 villages in southwestern China; we test whether social structure is associated with cooperative behaviour toward those in the neighbourhood. We find that social organization is associated with levels of cooperation in public goods and dictator games and a resource dilemma; people are less cooperative towards other villagers in communities where dispersal by both sexes is low. This supports the view that dispersal for marriage played an important role in the evolution of large-scale cooperation in human society. PMID- 26478535 TI - Excision Versus Ablation in Renal Cancer: Optimising Outcome and Minimising Risk. PMID- 26478536 TI - Learning to Fly: There's no sensation to compare with this Suspended animation, a state of bliss--Pink Floyd. PMID- 26478537 TI - Quantification of Fluoroquinolone Uptake through the Outer Membrane Channel OmpF of Escherichia coli. AB - Decreased drug accumulation is a common cause of antibiotic resistance in microorganisms. However, there are few reliable general techniques capable of quantifying drug uptake through bacterial membranes. We present a semiquantitative optofluidic assay for studying the uptake of autofluorescent drug molecules in single liposomes. We studied the effect of the Escherichia coli outer membrane channel OmpF on the accumulation of the fluoroquinolone antibiotic, norfloxacin, in proteoliposomes. Measurements were performed at pH 5 and pH 7, corresponding to two different charge states of norfloxacin that bacteria are likely to encounter in the human gastrointestinal tract. At both pH values, the porins significantly enhance drug permeation across the proteoliposome membranes. At pH 5, where norfloxacin permeability across pure phospholipid membranes is low, the porins increase drug permeability by 50-fold on average. We estimate a flux of about 10 norfloxacin molecules per second per OmpF trimer in the presence of a 1 mM concentration gradient of norfloxacin. We also performed single channel electrophysiology measurements and found that the application of transmembrane voltages causes an electric field driven uptake in addition to concentration driven diffusion. We use our results to propose a physical mechanism for the pH mediated change in bacterial susceptibility to fluoroquinolone antibiotics. PMID- 26478538 TI - Straightforward synthesis and catalytic applications of rigid N,O-type calixarene ligands. AB - Here, we report a simple one-step access to new rigid N,O-calixarene ligands which is based on copper-catalyzed amination at the lower rim. We also present the coordination properties of these ligands with some main group and transition metals leading to new complexes with superior catalytic activity, in several organic transformations, compared with calixarene metal complexes reported in the literature. PMID- 26478539 TI - A new method for simultaneous detection and discrimination of Bovine herpesvirus types 1 (BoHV-1) and 5 (BoHV-5) using real time PCR with high resolution melting (HRM) analysis. AB - Bovine herpesvirus types 1 (BoHV-1) and 5 (BoHV-5) are antigenically and genetically similar. The aim of this study was to develop a simple and reliable one-step real time PCR assay with high resolution melting (HRM) analysis for the simultaneous detection and differentiation of BoHV-1 and BoHV-5. Optimization of assay conditions was performed with DNA from reference strains. Then, DNA from field isolates, clinical samples and tissue samples of experimentally infected animals were studied by real time PCR-HRM. An efficient amplification of real time PCR products was obtained, and a clear melting curve and appropriate melting peaks for both viruses were achieved in the HRM curve analysis for BoHV type identification. BoHV was identified in all of the isolates and clinical samples, and BoHV types were properly differentiated. Furthermore, viral DNA was detected in 12/18 and 7/18 samples from BoHV-1- and BoHV-5-infected calves, respectively. Real time PCR-HRM achieved a higher sensitivity compared with virus isolation or conventional PCR. In this study, HRM was used as a novel procedure. This method provides rapid, sensitive, specific and simultaneous detection of bovine alpha herpesviruses DNA. Thus, this technique is an excellent tool for diagnosis, research and epidemiological studies of these viruses in cattle. PMID- 26478540 TI - Construction of infectious cDNA clone derived from a classical swine fever virus field isolate in BAC vector using in vitro overlap extension PCR and recombination. AB - To develop reverse genetics system of RNA viruses, cloning of full-length viral genome is required which is often challenging due to many steps involved. In this study, we report cloning of full-length cDNA from an Indian field isolate (CSFV/IVRI/VB-131) of classical swine fever virus (CSFV) using in vitro overlap extension PCR and recombination which drastically reduced the number of cloning steps. The genome of CSFV was amplified in six overlapping cDNA fragments, linked by overlap extension PCR and cloned in a bacterial artificial chromosome (BAC) vector using in vitro recombination method to generate full-length cDNA clone. The full-length CSFV cDNA clone was found stable in E. coli Stellar and DH10B cells. The full-length RNA was transcribed in vitro using T7 RNA polymerase and transfected in PK15 cells using Neon-tip electroporator to rescue infectious CSFV. The progeny CSFV was propagated in PK15 cells and found indistinguishable from the parent virus. The expression of CSFV proteins were detected in cytoplasm of PK15 cells infected with progeny CSFV at 72 h post-infection. We concluded that the in vitro overlap extension PCR and recombination method is useful to construct stable full-length cDNA clone of RNA virus in BAC vector. PMID- 26478541 TI - Immunization of Mice with a Live Transconjugant Shigella Hybrid Strain Induced Th1 and Th17 Cell-Mediated Immune Responses and Confirmed Passive Protection Against Heterologous Shigellae. AB - An avirulent, live transconjugant Shigella hybrid (LTSHDeltastx) strain was constructed in our earlier study by introducing a plasmid vector, pPR1347, into a Shiga toxin gene deleted Shigella dysenteriae 1. Three successive oral administrations of LTSHDeltastx to female adult mice produced comprehensive passive heterologous protection in their offspring against challenge with wild type shigellae. Production of NO and different cytokines such asIL-12p70, IL 1beta and IL-23 in peritoneal mice macrophages indicated that LTSHDeltastx induced innate and adaptive immunity in mice. Furthermore, production of IFN gamma, IL-10 and IL-17 in LTSH-primed splenic CD4+ T cell suggested that LTSHDeltastx may induce Th1 and Th17 cell-mediated immune responses. Exponential increase of the serum IgG and IgA titre against whole shigellae was observed in immunized adult mice during and after the immunization with the highest peak on day 35. Antigen-specific sIgA was also determined from intestinal lavage of immunized mice. The stomach extracts of neonates from immunized mice, mainly containing mother's milk, contained significant levels of anti-LTSHDeltastx immunoglobulin. These studies suggest that the LTSHDeltastx could be a new live oral vaccine candidate against shigellosis in the near future. PMID- 26478543 TI - A Novel Recombinant Chlorophyllase1 from Chlamydomonas reinhardtii for the Production of Chlorophyllide Derivatives. AB - Natural chlorophyll metabolites have exhibited physiological activity in vitro. In this study, a recombinant chlorophyllase1 gene from Chlamydomonas reinhardtii (CrCLH1) was isolated and characterized. Recombinant CrCLH1 can perform chlorophyll dephytylation and produce chlorophyllide and phytol. In a transient assay, the subcellular localization of CrCLH1-green fluorescent protein was determined to be outside the chloroplast. Biochemical analyses of the activity of recombinant CrCLH1 indicated that its optimal pH value and temperature are 6.0 and 40 degrees C, respectively. Enzyme kinetic data revealed that the recombinant CrCLH1 had a higher catalytic efficiency for chlorophyll a than for chlorophyll b and bacteriochlorophyll a. According to high-performance liquid chromatography analysis of chlorophyll hydrolysis, recombinant CrCLH1 catalyzed the conversion of chlorophyll a to pheophorbide a at pH 5. Therefore, recombinant CrCLH1 can be used as a biocatalyst to produce chlorophyllide derivatives. PMID- 26478542 TI - Molecular Genetic Characterization of Thyroid Dyshormonogenesis in a French Bulldog. AB - BACKGROUND: A case of congenital hypothyroidism with goiter (CHG) in a juvenile French bulldog was identified and hypothesized to be caused by dyshormonogenesis of genetic etiology. OBJECTIVES: To describe case management, unusual phenotypic aspects, and a CHG-causing mutation in a French bulldog. ANIMALS: Thyroid tissue and blood from a CHG-affected French bulldog and 4 normal control dogs and buccal brush samples of 125 French bulldogs were studied. METHODS: Standard clinical assessment and laboratory tests were applied. Thyroid peroxidase (TPO) iodide oxidation activity was measured in vitro, and TPO protein was assessed on Western blots. Thyroid peroxidase exons and flanking splice sites were amplified from genomic DNA and sequenced. Thyroid peroxidase cDNA was amplified from thyroid RNA and sequenced. RESULTS: At 9 months of age, the affected dog had signs of cretinism, but near-normal skeletal maturation. The enlarged thyroid glands exhibited noninflammatory fibrosis and aberrant follicular organization. Thyroid peroxidase activity and immunocrossreactive protein were undetectable. There was a T>C mutation of the intron 12 splice donor consensus that caused abnormally spliced mRNA, consistent with absent TPO function. The mutant allele was not observed in 125 clinically normal French bulldogs. CONCLUSIONS: Presumptive CHG in a French bulldog with unusual clinical presentation is described. Genetic etiology was confirmed by identifying the underlying TPO mutation. PMID- 26478544 TI - Direct oral anticoagulants: to switch or not to switch? PMID- 26478545 TI - Review of current and emerging treatment options in acromegaly. AB - In almost every patient, acromegaly is caused by a growth hormone secreting pituitary adenoma. Clinical features are the result of excessive growth hormone secretion and the consecutive excess in insulin-like growth factor I levels. This results in somatic overgrowth and metabolic disturbances with a higher morbidity and mortality than in the general population. With optimal disease management, mortality can be reduced to that seen in the general population. The current treatment of acromegaly is based on a combination of surgery, radiotherapy and medical therapy. This review provides an overview of the current and upcoming therapies with a focus on medical therapy. PMID- 26478546 TI - When do patients prefer a direct oral anticoagulant over a vitamin K antagonist? AB - BACKGROUND: The reasons for patients to change their usual vitamin K antagonist (VKA) treatment to a direct oral anticoagulant (DOAC) are unexplored. METHOD: A random sample of 200 patients treated with VKAs for the indication of atrial fibrillation from the Thrombosis Service in Amsterdam was selected. A survey, using the treatment trade-off technique, was sent to participants. The trade-off included four scenarios: 1 (no need for laboratory controls); 2 (less bleeding); 3 (less interactions); 4 (more effective). RESULTS: Under scenario 1, 57% of the patients would have made the switch, with a further increase to 65% with scenario 2 (trend value, p = 0.006, 95% CI 1.11-1.85). In addition, in each scenario patients who were less satisfied with their current treatment were more likely to switch to a DOAC compared with satisfied patients. The variables duration of treatment, gender, age and educational level did not affect the preference for a DOAC. CONCLUSION: Patients considered no requirement for regular laboratory control and a lower risk of bleeding the most important arguments to switch to a DOAC. PMID- 26478547 TI - No accumulation of a prophylactic dose of nadroparin in moderate renal insufficiency. AB - BACKGROUND: Low-molecular-weight heparins (LMWHs) have been shown to accumulate in patients with renal insufficiency, especially in therapeutic dosages. Although no appropriate studies have been conducted for prophylactic dosages of nadroparin, dose reduction is sometimes recommended, especially for high prophylactic dosages. We assessed accumulation of a prophylactic dose of 5700 IU subcutaneous nadroparin once daily in patients with renal insufficiency. METHODS: We conducted a prospective cohort study and measured peak anti-Xa activity four hours after subcutaneous nadroparin injection on day 1, 3, 5 and if possible day 10 in adults with and without renal insufficiency defined as a glomerular filtration rate (GFR) below or above 50 ml/min/1.73 m2. Patients with a GFR below 10 ml/min/1.73 m2 were excluded. RESULTS: We included 14 patients in each group. In the group with renal failure 12 patients had a GFR between 30 and 50 ml/min/1.73 m2. Peak anti-Xa activity showed a high interindividual variability, but was fairly constant within each patient. There was no rise in peak anti-Xa activity on day 3 and 5 after consecutive administration. In the group with normal renal function, peak anti-Xa activity declined on day 5 compared with day 1 (p = 0.005). CONCLUSION: Prophylactic dosages of nadroparin showed no accumulation in patients with a GFR between 30-50 ml/min/1.73 m2. Dose reduction in this group could lead to suboptimal thromboprophylaxis. Due to underrepresentation of patients with a GFR < 30 ml/min/1.73 m2 (n = 2), we cannot give recommendations for this group. PMID- 26478548 TI - Acute episode of cyclic vomiting syndrome preceded by arterial hypertension – Case presentation and review. AB - Cyclic vomiting syndrome (CVS) is a functional disorder with recurrent episodes of vomiting. Between these episodes patients recover to well-being. Lack of awareness often leads to a delay in making the diagnosis. The diagnosis is based on a typical medical history and exclusion of other causes. We present a case report of a middle-aged patient who had recurrent episodes of vomiting for 12 years coinciding with hypertension. After excluding other causes, CVS was diagnosed. The episodes of acute vomiting were stopped by administration of antiemetic and sedative drugs and urapidil reduced the hypertension. Treatment with sedatives stops vomiting caused by the emetic centre of the central nervous system. PMID- 26478549 TI - Non-myeloablative allogeneic stem cell transplantation: a new treatment option for acquired angioedema? AB - INTRODUCTION: Acquired angioedema is a rare disorder causing recurrent life threatening angioedema, due to decreased activity of C1 esterase inhibitor. CASE REPORT: A 57-year-old man presented to our hospital with recurrent swelling of the hands, lips, tongue, scrotum and throat. Lab examination showed the presence of an IgM kappa monoclonal antibody. Additional analysis showed that in the IgM fraction autoantibody activity against C1 esterase inhibitor was present. This confirmed the diagnosis of acquired angioedema in the presence of lymphoplasmacytic lymphoma. Despite standard therapy, there was an increase in the episodes of laryngeal oedema. Therefore it was decided to perform a non myeloablative allogeneic haematopoietic stem cell transplantation, with his HLA identical brother as donor. The post-transplantation course was without complications. Five years following alloSCT he is in complete remission without symptoms and with increased C1 esterase inhibitor activity. DISCUSSION: In this case all other known treatment options for severe acquired angioedema failed. This is the first case describing treatment of severe acquired angioedema, caused by lymphoplasmacytic lymphoma, with an alloSCT. PMID- 26478550 TI - A patient with right-sided deep venous thrombosis and lymphadenopathy on ultrasound. PMID- 26478552 TI - Hypertension at a young age: beware of the unexpected. PMID- 26478554 TI - Chronic diarrhoea and repeated bowel obstruction in an 84-year-old woman. PMID- 26478556 TI - Severe abdominal pain three weeks after a hemi-hepatectomy. PMID- 26478558 TI - Is hyperhomocysteinaemia a minor risk factor for venous thrombosis or subject to publication bias? PMID- 26478559 TI - Employing a new 12-connected topological open-framework copper borovanadate as an effective heterogeneous catalyst for oxidation of benzyl-alkanes. AB - A new 12-connected topological open-framework copper borovanadate with a unique B/V ratio (20/12) and a -B3O7(OH)-Na(MU-OH)[B(OH)2]-B3O7(OH)- connection mode has been hydrothermally obtained and characterized. It not only features the first 3 D copper(II) borovanadate which possesses the largest ratio of TM(2+) and borovanadate anion, but also displays highly catalytic activities for the oxidation of benzyl-alkanes. PMID- 26478560 TI - Substrate Hunting for the Myxobacterial CYP260A1 Revealed New 1alpha-Hydroxylated Products from C-19 Steroids. AB - Cytochromes P450 catalyze a variety of synthetically useful reactions. However, it is difficult to determine their physiological or artificial functions when a plethora of orphan P450 systems are present in a genome. CYP260A1 from Sorangium cellulosum So ce56 is a new member among the 21 available P450s in the strain. To identify putative substrates for CYP260A1 we used high-throughput screening of a compound library (ca. 17,000 ligands). Structural analogues of the type I hits were searched for biotechnologically relevant compounds, and this led us to select C-19 steroids as potential substrates. We identified efficient surrogate redox partners for CYP260A1, and an Escherichia coli-based whole-cell biocatalyst system was developed to convert testosterone, androstenedione, and their derivatives methyltestosterone and 11-oxoandrostenedione. A detailed (1) H and (13) C NMR characterization of the product(s) from C-19 steroids revealed that CYP260A1 is the very first 1alpha-steroid hydroxylase. PMID- 26478561 TI - Detection, Localization and Tyrosine Phosphorylation Status of Ser/Thr Protein Phosphatase1gamma in Freshly Ejaculated, In Vitro Capacitated and Cryopreserved Buffalo Spermatozoa. AB - Several recent studies have indicated the important roles of Ser/Thr protein phosphatase1gamma (PP1gamma) in regulating the motility and capacitation of mammalian spermatozoa. Here, we report the presence and distribution of PP1gamma protein in freshly ejaculated, in vitro capacitated and cryopreserved buffalo spermatozoa. The presence of PP1gamma and its distribution were assessed by Western blotting and indirect immunofluorescence techniques, whereas the isoforms of PP1gamma and their tyrosine phosphorylation status were identified by using 2D electrophoresis. The number of isoforms and the status of tyrosine phosphorylation of PP1gamma were increased in capacitated spermatozoa when compared with freshly ejaculated spermatozoa. Differential pattern of expression and tyrosine phosphorylation of PP1gamma were observed in cryopreserved spermatozoa, wherein some isoforms were degraded and some were tyrosine phosphorylated. In addition, immunofluorescence technique revealed that PP1gamma was localized to principle, mid-piece, post-acrosomal and equatorial regions of buffalo spermatozoa. Differential distribution of tyrosine-phosphorylated proteins were observed in fresh, capacitated and cryopreserved spermatozoa. The tyrosine phosphorylation of several proteins (20, 37, 38, 52, 60, 79 and 100 kDa) were increased when sperm cells were incubated with PP1gamma inhibitor, okadaic acid. Together, our results suggest that buffalo spermatozoa express different isoforms of PP1gamma protein. The protein expression and tyrosine phosphorylation of PP1gamma were increased during capacitation. Furthermore, the differential pattern of expression and tyrosine phosphorylation of PP1gamma were observed in cryopreserved spermatozoa. In addition, the inhibition of PP1gamma protein increases protein tyrosine phosphorylation in capacitation. PMID- 26478562 TI - Risk factors for major amputation in hospitalised diabetic foot patients. AB - Diabetic foot ulcers are the main cause of non-traumatic lower extremity amputation. The objective of this study was to evaluate the risk factors for major amputation in diabetic foot patients. Eight hundred and sixty diabetic patients were admitted to the diabetic wound centre of the Korea University Guro Hospital for foot ulcers between January 2010 and December 2013. Among them, 837 patients were successfully monitored until complete healing. Ulcers in 809 patients (96.7%) healed without major amputation and those in 28 patients (3.3%) healed with major amputation. Data of 88 potential risk factors including demographics, ulcer condition, vascularity, bioburden, neurology and serology were collected from patients in the two groups and compared. Among the 88 potential risk factors, statistically significant differences between the two groups were observed in 26 risk factors. In the univariate analysis, which was carried out for these 26 risk factors, statistically significant differences were observed in 22 risk factors. In a stepwise multiple logistic analysis, six of the 22 risk factors remained statistically significant. Multivariate-adjusted odds ratios were 11.673 for ulcers penetrating into the bone, 8.683 for dialysis, 6.740 for gastrointestinal (GI) disorders, 6.158 for hind foot ulcers, 0.641 for haemoglobin levels and 1.007 for fasting blood sugar levels. The risk factors for major amputation in diabetic foot patients were bony invasions, dialysis, GI disorders, hind foot locations, low levels of haemoglobin and elevated fasting blood sugar levels. PMID- 26478563 TI - Improved Slow Light Capacity In Graphene-based Waveguide. AB - We have systematically investigated the wideband slow light in two-dimensional material graphene, revealing that graphene exhibits much larger slow light capability than other materials. The slow light performances including material dispersion, bandwidth, dynamic control ability, delay-bandwidth product, propagation loss, and group-velocity dispersion are studied, proving graphene exhibits significant advantages in these performances. A large delay-bandwidth product has been obtained in a simple yet functional grating waveguide with slow down factor c/v(g) at 163 and slow light bandwidth Deltaomega at 94.4 nm centered at 10.38 MUm, which is several orders of magnitude larger than previous results. Physical explanation of the enhanced slow light in graphene is given. Our results indicate graphene is an excellent platform for slow light applications, promoting various future slow light devices based on graphene. PMID- 26478564 TI - Are Pets in the Bedroom a Problem? AB - The presence of pets in the bedroom can alter the sleep environment in ways that could affect sleep. Data were collected by questionnaire and interview from 150 consecutive patients seen at the Center for Sleep Medicine, Mayo Clinic in Arizona. Seventy-four people (49%) reported having pets, with 31 (41% of pet owners) having multiple pets. More than half of pet owners (56%) allowed their pets to sleep in the bedroom. Fifteen pet owners (20%) described their pets as disruptive, whereas 31 (41%) perceived their pets as unobtrusive or even beneficial to sleep. Health care professionals working with patients with sleep concerns should inquire about the presence of companion animals in the sleep environment to help them find solutions and optimize their sleep. PMID- 26478565 TI - Platelet secretion of CXCL4 is Rac1-dependent and regulates neutrophil infiltration and tissue damage in septic lung damage. AB - BACKGROUND AND PURPOSE: Platelets are potent regulators of neutrophil accumulation in septic lung damage. We hypothesized that platelet-derived CXCL4 might support pulmonary neutrophilia in a murine model of abdominal sepsis. EXPERIMENTAL APPROACH: Polymicrobial sepsis was triggered by coecal ligation and puncture (CLP) in C57BL/6 mice. Platelet secretion of CXCL4 was studied by using confocal microscopy. Plasma and lung levels of CXCL4, CXCL1 and CXCL2 were determined by elisa. Flow cytometry was used to examine surface expression of Mac 1 on neutrophils. KEY RESULTS: CLP increased CXCL4 levels in plasma, and platelet depletion reduced plasma levels of CXCL4 in septic animals. Rac1 inhibitor NSC23766 decreased the CLP-enhanced CXCL4 in plasma by 77%. NSC23766 also abolished PAR4 agonist-induced secretion of CXCL4 from isolated platelets. Inhibition of CXCL4 reduced CLP-evoked neutrophil recruitment, oedema formation and tissue damage in the lung. However, immunoneutralization of CXCL4 had no effect on CLP-induced expression of Mac-1 on neutrophils. Targeting CXCL4 attenuated plasma and lung levels of CXCL1 and CXCL2 in septic mice. CXCL4 had no effect on neutrophil chemotaxis in vitro, indicating it has an indirect effect on pulmonary neutrophilia. Intratracheal CXCL4 enhanced infiltration of neutrophils and formation of CXCL2 in the lung. CXCR2 antagonist SB225002 markedly reduced CXCL4-provoked neutrophil accumulation in the lung. CXCL4 caused secretion of CXCL2 from isolated alveolar macrophages. CONCLUSIONS AND IMPLICATIONS: Rac1 controls platelet secretion of CXCL4 and CXCL4 is a potent stimulator of neutrophil accumulation in septic lungs via generation of CXCL2 in alveolar macrophages. Platelet-derived CXCL4 plays an important role in lung inflammation and tissue damage in polymicrobial sepsis. PMID- 26478567 TI - In reference to A new theory on the pathogenesis of acquired cholesteatoma: Mucosal traction. PMID- 26478569 TI - Pathogen-nematode interaction: Nitrogen supply of Listeria monocytogenes during growth in Caenorhabditis elegans. AB - Listeria monocytogenes is a Gram-positive facultatively intracellular human pathogen. Due to its saprophytic lifestyle, L. monocytogenes is assumed to infect and proliferate within soil organisms such as Caenorhabditis elegans. However, little is known about the nutrient usages and metabolite fluxes in this bacterium nematode interaction. Here, we established a nematode colonization model for L. monocytogenes and a method for the efficient separation of the pathogen from the nematodal gut. Following (15)N labelling of C. elegans and gas chromatography mass spectrometry-based (15)N isotopologue analysis, we detected a high basal metabolic rate of the nematode, and observed a significant metabolic flux from nitrogenous compounds of the nematode to listerial proteins during proliferation of the pathogen in the worm's intestine. For comparison, we also measured the N fluxes from the gut content into listerial proteins using completely (15)N labelled Escherichia coli OP50 as food for C. elegans. In both settings, L. monocytogenes prefers the direct incorporation of histidine, arginine and lysine over their de novo biosynthesis. Our data suggest that colonization of nematodes is a strategy of L. monocytogenes to increase its access to N-rich nutrients. PMID- 26478568 TI - Biological and mechanical characterization of chitosan-alginate scaffolds for growth factor delivery and chondrogenesis. AB - Chitosan-alginate (Ch-Al) natural polysaccharide blends have been used for wound healing, tissue engineering, and drug delivery due to their ability to form pH dependent ionic chain-chain interactions. Yet, the biomechanical properties and growth factor (GF) release kinetics of Ch-Al, which are important in controlling the microenvironment during tissue regeneration, have not been fully explored. This study examines the compressive elastic modulus of many Ch-Al scaffold formulations and crosslinking conditions, and also the strain recovery after compressive deformation of Ch-Al scaffolds, both of which make Ch-Al an attractive composite for reproducing articular cartilage's resistance to and resiliency under compression. Cell viability, proliferation, and in vitro cartilaginous matrix production (collagen type II, glycosaminoglycans, aggrecan) without supplemental GFs are also investigated, demonstrating the polymer blend's inherent chondrogenic properties. Additionally, this study explores the ability of Ch-Al chain functional groups to control and extend GF delivery and minimize GF burst release, using model proteins BSA and histone at high loading dose and chondrogenic protein TGF-beta1 at low loading dose in complete media. Expedited cartilaginous matrix synthesis on Ch-Al with low dose TGF-beta1 release is evaluated, with Ch-Al supporting homogeneous matrix deposition and lacunae formation as early as 3 weeks due to Ch-Al's maintenance of GF bioactivity and sustained GF delivery. These results illustrate the potential to focus the formulational range of Ch-Al to provide enhanced mechanical performance and controlled, bioactive GF release to cooperatively promote cartilage regeneration. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 272-282, 2017. PMID- 26478572 TI - Fano-resonant aluminum and gold nanostructures created with a tunable, up scalable process. AB - An up-scalable approach for creating Fano-resonant nanostructures on large surfaces at visible wavelengths is demonstrated. The use of processes suitable for high throughput fabrication and the choice of aluminum as a cost-efficient plasmonic material ensure that the presented insights are valuable even in consideration of typical industrial constraints. In particular, wafer-scale fabrication and the process compatibility with roll-to-roll embossing are demonstrated. It is shown that through adjustment of readily accessible evaporation parameters, the shape and position of the optical resonance can be tuned within a spectral band of more than 70 nm. The experimental data are complemented with rigorous coupled wave analysis and surface integral equation simulations. Calculated electric fields as well as surface charges shed light onto the physics behind the present resonances. In particular, a surface plasmon polariton is found to couple to a localized plasmonic mode with a hexapolar charge distribution, leading to a Fano-like resonance. Further understanding of the interactions at hand is gained by considering both aluminum and gold nanostructures. PMID- 26478570 TI - Inflammatory mechanisms of pulmonary injury induced by mustards. AB - Exposure of humans and animals to vesicants, including sulfur mustard (SM) and nitrogen mustard (NM), causes severe and debilitating damage to the respiratory tract. Both acute and long term pathological consequences are observed in the lung following a single exposure to these vesicants. Evidence from our laboratories and others suggest that macrophages and the inflammatory mediators they release play an important role in mustard-induced lung injury. In this paper, the pathogenic effects of SM and NM on the lung are reviewed, along with the potential role of inflammatory macrophages and mediators they release in mustard-induced pulmonary toxicity. PMID- 26478566 TI - Medical treatments of elderly, French patients with type 2 diabetes: results at inclusion in the GERODIAB Cohort. AB - Prevalence of diabetes in the elderly increases, and half of the French diabetics are over the age of 75 years. The GERODIAB study is the first French multicentre, prospective, observational study designed to analyse over 5 years the influence of glycaemic control on morbidity-mortality in type 2 diabetics patients 70 years old and over. This study analysed the diabetic and geriatric factors associated with the treatment modalities, particularly insulin, at inclusion in the cohort. The cohort of 987 type 2 diabetics was divided into three groups according to the method of treatment. Slightly fewer than one-third of these patients (26.4%) were treated with insulin alone, 31% received insulin and oral antidiabetic drugs, and 42.7% oral antidiabetic drugs alone. The patients that received insulin alone were significantly older, had poorer glycaemic control (HbA1c = 7.9 +/- 1.4, 7.8 +/- 1.0 and 7.1 +/- 1.2%, respectively; P < 0.001) and had greater alterations of glomerular filtration rate (GFR). HbA1c was below 6.5% in 15% of patients and 37.3% of patients had a GFR below 60 mL/min. The patients treated with insulin alone had significantly more hypoglycaemic episodes (respectively 53.3, 36.3 and 19.5%, P < 0.001), retinopathy, cardiovascular involvement and more specific geriatric complications, such as cognitive disorders (respectively 34.1, 31.4 and 23.6%, P = 0.006). In this specific population of elderly type 2 diabetic patients, diabetic and geriatric conditions significantly differed between the types of drug treatments. Considering low values of HbA1c and GFR, some patients seemed overtreated and other patients received inappropriate drugs. PMID- 26478571 TI - Berberine promotes bone marrow-derived mesenchymal stem cells osteogenic differentiation via canonical Wnt/beta-catenin signaling pathway. AB - Berberine (BBR) has recently been reported to be extensively used for musculoskeletal disorders such as osteoporosis through enhancing osteogenic differentiation, inhibiting osteoclastogenesis and bone resorption and repressing adipogenesis. Although canonical Wnt signaling plays a crucial role in suppressing bone marrow-derived mesenchymal stem cells (MSCs) commitment to the chondrogenic and adipogenic lineage and enhancing osteogenic differentiation, no previous reports have shown an association between BBR-induced osteogenesis and Wnt/beta-catenin signaling pathway. In this study, we aimed to investigate the stimulatory effect and the mechanism of BBR on osteogenic differentiation of human bone marrow-derived MSCs. MSCs were isolated from bone marrow specimens and treated with different concentration of BBR. Cell viability was measured by the WST-8 assay. Effects of BBR on osteogenic differentiation of MSCs were assessed by von Kossa staining, ALP staining and ALP activity. Osteogenic specific genes, chondrogenic and adipogenic related marker genes were determined by quantitative real-time polymerase chain reaction analysis. Western blot and Immunofluorescence staining were performed to analyze OCN and OPN, and beta-catenin expression in the presence or absence of BBR combined with DKK-1 or beta-catenin siRNA transfection. Increasing concentration of BBR (3, 10 and 30 MUM) promoted osteogenic differentiation and osteogenic genes expression after incubation for various days compared with DMSO group, whereas expression levels of chondrogenic and adipogenic related marker genes were dramatically suppressed. After treated with 10MUM BBR for 7 days, beta-catenin, OPN and OCN expression were significantly induced, which could be effectively suppressed by the addition of DKK-1 or beta-catenin siRNA beta-catenin. Interestingly, the expression level of Runx2 gene was also decreased by inhibiting the transduction of Wnt/beta-catenin signaling. These findings suggest that BBR can stimulate osteogenic differentiation of MSCs not only by enhancing Runx2 expression but also by activating canonical Wnt/beta-catenin signaling pathway, and canonical Wnt/beta catenin signaling pathway is in part responsible for BBR-induced osteogenic differentiation of MSCs in vitro. BBR is a potential pharmaceutical medicine by enhancing osteogenic differentiation for bone disorders, such as osteoporosis. PMID- 26478573 TI - Identification and characterization of distinct IL-17F expression patterns and signaling pathways in chronic lymphocytic leukemia and normal B lymphocytes. AB - Chronic lymphocytic leukemia (CLL) is characterized by a progressive accumulation of B lymphocytes. T cell abnormalities are a common feature of CLL and contribute to impaired immune function in these patients. T cells are ineffective in eliminating the leukemic clone and may actually promote tumor growth and survival. Previous work from our laboratory documented elevated circulating levels of IL-17A-producing Th17 cells in CLL patients as compared to healthy age matched control subjects. These high circulating Th17 levels associated with better prognostic markers and significantly longer overall survival, even among patients whose clones used unmutated IGHVs (U-CLL). Recent studies suggest that Th17 cells are heterogeneous, expressing different profiles of cytokines, and that different subsets of Th17s mediate different biological functions. In the present study, we found significantly higher levels of IL-17F-expressing CD4(+) T cells in CLL versus healthy peripheral blood mononuclear cells following in vitro stimulation in the presence of Th17-promoting cytokines. Furthermore, the differentiation of IL-17F-expressing Th17 cells was significantly enhanced when purified CD4(+) T cells from CLL patients were cultured in the presence of autologous CLL B cells. Lastly, single-cell network profiling revealed that IL 17F triggers NFkappaB phosphorylation in T and B cells from patients with CLL, but not age-matched healthy controls. Taken together, our data suggest that the phenotype of Th17 cells in CLL patients is distinct from healthy individuals, expressing higher levels of IL-17F, and that B and T cells from CLL patients are particularly responsive to IL-17F, as compared to healthy age-matched control individuals. PMID- 26478574 TI - Objective assessment of delayed gastric emptying using gastric scintigraphy in post pancreaticoduodenectomy patients. AB - BACKGROUND: No objective assessment of delayed gastric emptying is carried out in patients undergoing Whipple's procedure. All definitions and criteria along with evaluation of incidence of delayed gastric emptying are based on subjective assessment of the patient with clinical overview, so this study was carried out for an objective and accurate assessment of delayed gastric emptying in post Whipple's patients using gastric scintigraphy. METHODS: Twenty-one patients undergoing Whipple's procedure performed by a single surgeon in a tertiary referral centre were included in the study. Gastric scintigraphy was performed preoperatively and on post-operative 10th and 21st days. Preoperative and post operative gastric scintigraphy findings were used for the diagnosis of delayed gastric emptying and it was correlated with the incidence of clinical diagnosis of delayed gastric emptying. RESULTS: Thirteen out of 21 patients had clinical delayed gastric emptying. When compared with clinical delayed gastric emptying, the sensitivity, specificity, positive and negative predictive values of post operative 10th day gastric scintigraphy were 61.53, 100, 100 and 61.53%, respectively (P = 0.004). The sensitivity, specificity, positive and negative predictive values of post-operative 21st day gastric scintigraphy were 38.46, 100, 100 and 50%, respectively (P = 0.04). Reflux across the gastrojejunal anastomosis was noted in 28.5% on dynamic scintigraphy with the severity of clinical symptoms related directly with the degree of reflux. No correlation was seen between delayed gastric emptying and variables such as diabetes mellitus, hypertension and pancreaticojejunal anastomotic leaks. CONCLUSIONS: Gastric scintigraphy may be used to diagnose delayed gastric emptying more objectively in post Whipple's patients. PMID- 26478575 TI - In situ spectroelectrochemical and theoretical study on the oxidation of a 4H imidazole-ruthenium dye adsorbed on nanocrystalline TiO2 thin film electrodes. AB - Terpyridine 4H-imidazole-ruthenium(II) complexes are considered promising candidates for use as sensitizers in dye sensitized solar cells (DSSCs) by displaying broad absorption in the visible range, where the dominant absorption features are due to metal-to-ligand charge transfer (MLCT) transitions. The ruthenium(III) intermediates resulting from photoinduced MLCT transitions are essential intermediates in the photoredox-cycle of the DSSC. However, their photophysics is much less studied compared to the ruthenium(II) parent systems. To this end, the structural alterations accompanying one-electron oxidation of the RuIm dye series (including a non-carboxylic RuIm precursor, and, carboxylic RuImCOO in solution and anchored to a nanocrystalline TiO2 film) are investigated via in situ experimental and theoretical UV-Vis absorption and resonance Raman (RR) spectroelectrochemistry. The excellent agreement between the experimental and the TDDFT spectra derived in this work allows for an in-depth assignment of UV-Vis and RR spectral features of the dyes. A concordant pronounced wavelength dependence with respect to the charge transfer character has been observed for the model system RuIm, and both RuImCOO in solution and attached on the TiO2 surface. Excitation at long wavelengths leads to the population of ligand-to metal charge transfer states, i.e. photoreduction of the central ruthenium(III) ion, while high-energy excitation features an intra-ligand charge transfer state localized on the 4H-imidazole moiety. Therefore, these 4H-imidazole ruthenium complexes investigated here are potential multi-photoelectron donors. One electron is donated from MLCT states, and additionally, the 4H-imidazole ligand reveals electron-donating character with a significant contribution to the excited states of the ruthenium(III) complexes upon blue-light irradiation. PMID- 26478576 TI - Naturally occurring genetic mutations in the 5'-upstream regulatory region of bovine FSHB generate a novel cis-regulatory element that affects its expression. AB - We previously reported that numerous naturally occurring genetic mutations in the 5'-upstream regulatory region (5'-URR) of the bovine follicle-stimulating hormone beta-subunit gene (FSHB) were associated with reduced serum follicle-stimulating hormone (FSH) levels, poor-quality semen and low fertility in bulls. In addition, two different FSHB mRNA transcripts resulting from the linked mutations of genomic DNA were discovered in mutation-bearing bull pituitaries. Here, using electrophoretic mobility shift assay, we identified c.-1539_-1538delGGinsTTAACT mutations in the 5'-URR that generated a novel cis-regulatory element in bovine FSHB. Moreover, this novel element seemed to play a role in repressing FSHB transcription based on a promoter activity analysis in LbetaT2 gonadotrope cells. Quantitative assays of FSHB mRNA in the bovine pituitaries suggested that the levels of FSHB wild-type transcripts in the mutation-bearing bulls were significantly lower (P < 0.05) than in those of bulls without FSHB genetic mutations and that the levels of FSHB-mutated transcripts were significantly lower (P < 0.05) than that of wild-type transcripts in the mutation-bearing bulls. Altogether, our results suggest that decreased serum FSH levels and male fertility in bulls with the c.-1539_-1538delGGinsTTAACT mutation likely result from the alteration of cis-regulatory elements and induction of FSHB transcription. PMID- 26478577 TI - A regular yoga intervention for staff nurse sleep quality and work stress: a randomised controlled trial. AB - AIMS AND OBJECTIVES: Although many studies have assessed the efficacy of yoga in older individuals, minimal research has focused on how nurses use yoga to improve sleep quality and to reduce work stress after work hours. We used the Pittsburgh Sleep Quality Index in Chinese and the Questionnaire on Medical Worker's Stress in Chinese to determine the impact of yoga on the quality of sleep and work stress of staff nurses employed by a general hospital in China. BACKGROUND: Disturbances in the circadian rhythm interrupt an individual's pattern of sleep. STUDY DESIGN: Convenient sampling method. METHODS: One hundred and twenty nurses were randomised into two groups: a yoga group and a non-yoga group. The yoga group performed yoga more than two times every week for 50-60 minutes each time after work hours. The NG group did not participate in yoga. After six months, self-reported sleep quality and work stress were compared between the two groups, and then we used linear regression to confirm the independent factors related to sleep quality. RESULTS: Nurses in the yoga group had better sleep quality and lower work stress compared with nurses in the non-yoga group. The linear regression model indicated that nursing experience, age and yoga intervention were significantly related to sleep quality. CONCLUSION: Regular yoga can improve sleep quality and reduce work stress in staff nurses. RELEVANCE TO CLINICAL PRACTICE: This study provides evidence that hospital management should pay attention to nurse sleep quality and work stress, thereby taking corresponding measures to reduce work pressure and improve health outcomes. PMID- 26478578 TI - Diagnostic accuracy of CERAD total score in a Colombian cohort with mild cognitive impairment and Alzheimer's disease affected by E280A mutation on presenilin-1 gene. AB - BACKGROUND: This study aimed to determine Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychological Assessment Battery total score diagnostic accuracy in the diagnosis of mild cognitive impairment (MCI) and dementia in familial Alzheimer's disease (FAD) with E280A mutation on presenilin 1 gene (PSEN1). METHODS: A cross-sectional study was conducted in a cohort of PSEN1 E280A carriers and non-carriers assessed between January 1995 and February 2013. During the first neuropsychological assessment, 76 were having dementia, 46 had MCI, and 1,576 were asymptomatic. CERAD cut-off points were established for MCI and dementia using a Receiver Operating Characteristics (ROC) analysis, and were further analyzed according to education level in two groups: low education level (eight years or less), and high education level (over eight years). RESULTS: The area under curve-ROC CERAD total score for dementia was 0.994 (95% CI = 0.989-0.999), and that for MCI was 0.862 (95% CI = 0.816-0.908). The dementia diagnosis cut-off point for the low education group was 54, (98.4% sensitivity, 92.6% specificity), and that for the high education group was 67 (100% sensitivity, 94.1% specificity). The MCI diagnosis cut-off point for the low education group was 66 (91.2% sensitivity, 56.4% specificity), and that for the high education group was 72 (91.7% sensitivity, 76.3% specificity). CONCLUSIONS: The CERAD total score is a useful screening tool for dementia and MCI in a population at risk of FAD. PMID- 26478579 TI - Family Complexity, the Family Safety Net, and Public Policy. PMID- 26478580 TI - Multiplicity of Terms Related to Patient Safety: A Hindrance to Progress. PMID- 26478581 TI - [Not Available]. PMID- 26478582 TI - Utilization of Dabigatran for Atrial Fibrillation at 3 Tertiary Care Centres. AB - BACKGROUND: The outpatient management of stroke prevention for patients with atrial fibrillation has recently been published and provides insight into the benefits and risks of the new direct-acting oral anti-coagulants. However, real world use of these agents for hospital inpatients requires additional study. OBJECTIVE: To determine prescribing patterns for dabigatran at 3 Canadian hospitals, specifically adherence with the hospitals' prescribing restriction limiting dabigatran to patients with nonvalvular atrial fibrillation and creatinine clearance above 30 mL/min (primary outcome) and assessment of age related prescribing, prescribing of medications with defined contraindications or potential for interaction when given concurrently with dabigatran, and use of risk stratification tools (secondary outcomes). METHODS: A retrospective chart review of patients for whom dabigatran was prescribed from August to October 2011 was performed at 3 hospitals in Toronto, Ontario. Descriptive statistics were used for all outcomes assessed. RESULTS: Overall, dabigatran was prescribed for 69 inpatients, of whom 16 (23%) were new users (dabigatran initiated during hospital admission) and 53 (77%) were prior users (dabigatran prescribed before admission to hospital). Fifty-eight patients (84%; 14 new users and 44 prior users) received dabigatran according to the hospitals' prescribing restriction. For the remaining 11 patients, dabigatran therapy did not meet prescribing restrictions for use because of valvular disease or presence of prosthetic valve (10 patients [14% of the total sample]) and impaired renal function (1 patient [1%]). Among those whose dabigatran therapy met the prescribing restrictions for use, amiodarone and acetylsalicylic acid were the most common concurrently prescribed medications (17 patients [29%] and 14 patients [24%], respectively). Stroke and bleeding risk were documented for only 27 patients (47%) and 10 patients (17%), respectively. CONCLUSION: At the study hospitals, dabigatran was appropriately prescribed for the indication of nonvalvular atrial fibrillation in patients without renal impairment in most cases. However, greater consideration of cardiac history (including valvular disease and presence of prosthetic valves), drug interactions, and documentation of risks and benefits is warranted. These research findings highlight the importance of and opportunity for pharmacist review and involvement in assessment and selection of patients with indications for anticoagulant therapy, particularly when agents are new to the market. PMID- 26478583 TI - Pharmacists' Perceptions of the Influence of Interactions with the Pharmaceutical Industry on Clinical Decision-Making. AB - BACKGROUND: There is a paucity of literature examining the perceptions of Canadian pharmacists toward drug promotion by the pharmaceutical industry and pharmacist-industry interactions. OBJECTIVES: To determine whether hospital pharmacists perceive their interactions with the pharmaceutical industry as influencing their clinical decision-making or that of their colleagues and whether hospital pharmacists perceive that interactions with the pharmaceutical industry create a conflict of interest. METHODS: A cross-sectional survey of the complete sample of hospital pharmacists practising in 3 large health authorities in a single Canadian province was conducted from February to April 2010. RESULTS: A total of 224 responses were received from the approximately 480 pharmacists in the target health authorities (response rate approximately 47%). Fifty-eight percent of respondents (127/218) did not believe that information received at industry-sponsored events influenced their clinical decision-making. Most (142/163 [87%]) disagreed that small gifts influenced their clinical decision making, whereas responses were divided for large gifts. Respondents were also divided on the issue of whether their interactions created conflicts of interest, with most of those who had received gifts agreeing that large gifts would create a conflict of interest (134/163 [82%]) whereas small gifts would not (100/163 [61%]). There were positive correlations between respondents' beliefs about their own susceptibility to influence from sponsored events or receipt of small or large gifts and the susceptibility of others, but 22% of respondents (28/127) expressed a different perception about sponsored events, all believing themselves to be less influenced than their colleagues. Only 6% (4/64) of those who received large gifts and 4% (5/142) of those who received small gifts and felt they were not influenced by these gifts reported that it was likely others would be influenced by the receipt of such gifts. CONCLUSIONS: Most hospital pharmacists who responded to this survey had attended industry-sponsored events, and the majority felt that it did not influence their clinical decision-making, despite recognition that the information received is unbalanced. Respondents were divided on the notion of whether these interactions led to conflicts of interest. Respondents generally felt that large and small gifts had different effects on influence and conflict of interest. PMID- 26478584 TI - Outcomes in Documented Pseudomonas aeruginosa Bacteremia Treated with Intermittent IV Infusion of Ceftazidime, Meropenem, or Piperacillin-Tazobactam: A Retrospective Study. AB - BACKGROUND: Pseudomonas aeruginosa, one of the leading causes of nosocomial gram negative bloodstream infections, is particularly difficult to treat because of its multiple resistance mechanisms combined with a lack of novel antipseudomonal antibiotics. Despite knowledge of time-dependent killing with beta-lactam antibiotics, most hospitals in Canada currently administer beta-lactam antibiotics by intermittent rather than extended infusions. OBJECTIVES: To determine clinical outcomes, microbiological outcomes, total hospital costs, and infection-related costs for patients with P. aeruginosa bacteremia who received intermittent IV administration of antipseudomonal beta-lactam antibiotics in a tertiary care institution. METHODS: For this retrospective descriptive study, data were collected for patients who were admitted between March 1, 2005, and March 31, 2013, who had P. aeruginosa bacteremia during their admission, and who received at least 72 h of treatment with ceftazidime, meropenem, or piperacillin tazobactam. Clinical and microbiological outcomes were determined, and total and infection-related hospital costs were calculated. RESULTS: A total of 103 patients were included in the analysis, of whom 79 (77%) experienced clinical cure. In addition, bacterial eradication was achieved in 41 (87%) of the 47 patients with evaluable data for this outcome. Twenty-eight (27%) of the 103 patients died within 30 days of discontinuation of antipseudomonal beta-lactam antibiotic therapy. The median total cost of the hospital stay was $121 718, and the median infection-related cost was $29 697. CONCLUSIONS: P. aeruginosa bacteremia is a clinically significant nosocomial infection that continues to cause considerable mortality and health care costs. To the authors' knowledge, no previous studies have calculated total and infection-related hospital costs for treatment of P. aeruginosa bacteremia with intermittent infusion of antipseudomonal beta-lactam antibiotics, with characterization of cost according to site of acquisition of the infection. This study may provide important baseline data for assessing the impact of implementing extended-infusion beta lactam therapy, antimicrobial stewardship, and infection control strategies targeting P. aeruginosa infection in hospitalized patients. PMID- 26478585 TI - A Qualitative Analysis of Implementation of Antimicrobial Stewardship at 3 Academic Hospitals: Understanding the Key Influences on Success. AB - BACKGROUND: Inappropriate use of antimicrobials is linked to the development and spread of drug-resistant pathogens and is associated with increased morbidity, mortality, lengths of hospital stay, and health care costs. "Antimicrobial stewardship" is the umbrella term for an evidence-based knowledge translation strategy involving comprehensive quality improvement activities to optimize the use of antimicrobials, improve patient outcomes, reduce the development of antimicrobial resistance and hospital-acquired infections such as Clostridium difficile, and decrease health care costs. OBJECTIVE: To assess the perceptions and experiences of antimicrobial stewardship program leaders in terms of clinicians' attitudes toward and behaviours related to antimicrobial prescribing. METHODS: In this qualitative study, semistructured interviews were conducted with 6 antimicrobial stewards (2 physicians and 4 pharmacists) at 3 academic hospitals between June and August 2013. RESULTS: The following 3 key themes emerged from the interviews: getting the right people on board, building collegial relationships, and rapidly establishing a track record. The study results elucidated the role and mechanisms that the program leader and other antimicrobial stewards used to influence other clinicians to engage in effective utilization of antimicrobials. The results also highlighted the methods employed by members of the antimicrobial stewardship team to tailor their strategies to the local context and to stakeholders of participating units; to gain credibility by demonstrating the impact of the antimicrobial stewardship program on clinical outcomes and cost; and to engage senior leaders to endorse and invest in the antimicrobial stewardship program, thereby adding to the antimicrobial stewards' credibility and their ability to influence the uptake of effective antimicrobial use. CONCLUSIONS: Collectively, these results offer insight into processes and mechanisms of influence employed by antimicrobial stewards to enhance antimicrobial use among clinicians, which can in turn inform future implementation of antimicrobial stewardship and strategies for organizational change in hospitals. PMID- 26478586 TI - Playing in the Sandbox: Considerations When Leading or Participating on a Multidisciplinary Research Team. PMID- 26478588 TI - Implementation of Radio Frequency Identification for Medication Tray Management. PMID- 26478587 TI - [Not Available]. PMID- 26478589 TI - Widening Our Horizons: Pharmacy Practice from a Global Perspective. PMID- 26478590 TI - Pharmacy Practice in Australia. PMID- 26478591 TI - Erratum: Outcomes Associated with Conventional Accelerated versus Once-Weekly IV Iron Therapy in Outpatients Undergoing Hemodialysis - Correction. AB - [This corrects the article on p. 304 in vol. 68, PMID: 26327704.]. PMID- 26478592 TI - Clozapine-Associated Myocarditis: Case Report and Literature Review. PMID- 26478593 TI - Has the Drug of Choice for Treating Critical Illness Delirium Been Established? PMID- 26478594 TI - Nourishing the Soul of Pharmacy: Stories of Reflection. PMID- 26478595 TI - [Not Available]. PMID- 26478596 TI - A Change of Seasons-A New Beginning! PMID- 26478597 TI - Porous Structures in Stacked, Crumpled and Pillared Graphene-Based 3D Materials. AB - Graphene, an atomically thin material with the theoretical surface area of 2600 m2g-1, has great potential in the fields of catalysis, separation, and gas storage if properly assembled into functional 3D materials at large scale. In ideal non-interacting ensembles of non-porous multilayer graphene plates, the surface area can be adequately estimated using the simple geometric law ~ 2600 m2g-1/N, where N is the number of graphene sheets per plate. Some processing operations, however, lead to secondary plate-plate stacking, folding, crumpling or pillaring, which give rise to more complex structures. Here we show that bulk samples of multilayer graphene plates stack in an irregular fashion that preserves the 2600/N surface area and creates regular slot-like pores with sizes that are multiples of the unit plate thickness. In contrast, graphene oxide deposits into films with massive area loss (2600 to 40 m2g-1) due to nearly perfect alignment and stacking during the drying process. Pillaring graphene oxide sheets by co-deposition of colloidal-phase particle-based spacers has the potential to partially restore the large monolayer surface. Surface areas as high as 1000 m2g-1 are demonstrated here through colloidal-phase deposition of graphene oxide with water-dispersible aryl-sulfonated ultrafine carbon black as a pillaring agent. PMID- 26478598 TI - A Search for the Optimum Lithium Rich Layered Metal Oxide Cathode Material for Li Ion Batteries. AB - We report the results of a comprehensive study of the relationship between electrochemical performance in Li cells and chemical composition of a series of Li rich layered metal oxides of the general formula xLi2MnO3 . (1 x)LiMn0.33Ni0.33Co0.33O2 in which x = 0,1, 0.2, 0,3, 0.5 or 0.7, synthesized using the same method. In order to identify the cathode material having the optimum Li cell performance we first varied the ratio between Li2MnO3 and LiMO2 segments of the composite oxides while maintaining the same metal ratio residing within their LiMO2 portions. The materials with the overall composition 0.5Li2MnO3 . 0.5LiMO2 containing 0.5 mole of Li2MnO3 per mole of the composite metal oxide were found to be the optimum in terms of electrochemical performance. The electrochemical properties of these materials were further tuned by changing the relative amounts of Mn, Ni and Co in the LiMO2 segment to produce xLi2MnO3 . (1-x)LiMn0.50Ni0.35Co0.15O2 with enhanced capacities and rate capabilities. The rate capability of the lithium rich compound in which x = 0.3 was further increased by preparing electrodes with about 2 weight-percent multiwall carbon nanotube in the electrode. Lithium cells prepared with such electrodes were cycled at the 4C rate with little fade in capacity for over one hundred cycles. PMID- 26478599 TI - First-Pass Angiography in Mice Using FDG-PET: A Simple Method of Deriving the Cardiovascular Transit Time Without the Need of Region-of-Interest Drawing. AB - In this study, we developed a simple and robust semi-automatic method to measure the right ventricle to left ventricle (RV-to-LV) transit time (TT) in mice using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). The accuracy of the method was first evaluated using a 4-D digital dynamic mouse phantom. The RV-to-LV TTs of twenty-nine mouse studies were measured using the new method and compared to those obtained from the conventional ROI-drawing method. The results showed that the new method correctly separated different structures (e.g., RV, lung, and LV) in the PET images and generated corresponding time activity curve (TAC) of each structure. The RV-to-LV TTs obtained from the new method and ROI method were not statistically different (P = 0.20; r = 0.76). We expect that this fast and robust method is applicable to the pathophysiology of cardiovascular diseases using small animal models such as rats and mice. PMID- 26478600 TI - A DOI Detector With Crystal Scatter Identification Capability for High Sensitivity and High Spatial Resolution PET Imaging. AB - A new phoswich detector is being developed at the Crump Institute, aiming to provide improvements in sensitivity, and spatial resolution for PET. The detector configuration is comprised of two layers of pixelated scintillator crystal arrays, a glass light guide and a light detector. The annihilation photon entrance (top) layer is a 48 * 48 array of 1.01 * 1.01 * 7 mm3 LYSO crystals. The bottom layer is a 32 * 32 array of 1.55 * 1.55 * 9 mm3 BGO crystals. A tapered, multiple-element glass lightguide is used to couple the exit end of the BGO crystal array (52 * 52 mm2) to the photosensitive area of the Position Sensitive Photomultiplier Tube (46 * 46 mm2), allowing the creation of flat panel detectors without gaps between the detector modules. Both simulations and measurements were performed to evaluate the characteristics and benefits of the proposed design. The GATE Monte Carlo simulation indicated that the total fraction of the cross layer crystal scatter (CLCS) events in singles detection mode for this detector geometry is 13.2%. The large majority of these CLCS events (10.1% out of 13.2%) deposit most of their energy in a scintillator layer other than the layer of first interaction. Identification of those CLCS events for rejection or correction may lead to improvements in data quality and imaging performance. Physical measurements with the prototype detector showed that the LYSO, BGO and CLCS events were successfully identified using the delayed charge integration (DCI) technique, with more than 95% of the LYSO and BGO crystal elements clearly resolved. The measured peak-to-valley ratios (PVR) in the flood histograms were 3.5 for LYSO and 2.0 for BGO. For LYSO, the energy resolution ranged from 9.7% to 37.0% full width at half maximum (FWHM), with a mean of 13.4 +/- 4.8%. For BGO the energy resolution ranged from 16.0% to 33.9% FWHM, with a mean of 18.6 +/- 3.2%. In conclusion, these results demonstrate that the proposed detector is feasible and can potentially lead to a high spatial resolution, high sensitivity and DOI PET system. PMID- 26478601 TI - Hybrid approaches for multiple-species stochastic reaction-diffusion models. AB - Reaction-diffusion models are used to describe systems in fields as diverse as physics, chemistry, ecology and biology. The fundamental quantities in such models are individual entities such as atoms and molecules, bacteria, cells or animals, which move and/or react in a stochastic manner. If the number of entities is large, accounting for each individual is inefficient, and often partial differential equation (PDE) models are used in which the stochastic behaviour of individuals is replaced by a description of the averaged, or mean behaviour of the system. In some situations the number of individuals is large in certain regions and small in others. In such cases, a stochastic model may be inefficient in one region, and a PDE model inaccurate in another. To overcome this problem, we develop a scheme which couples a stochastic reaction-diffusion system in one part of the domain with its mean field analogue, i.e. a discretised PDE model, in the other part of the domain. The interface in between the two domains occupies exactly one lattice site and is chosen such that the mean field description is still accurate there. In this way errors due to the flux between the domains are small. Our scheme can account for multiple dynamic interfaces separating multiple stochastic and deterministic domains, and the coupling between the domains conserves the total number of particles. The method preserves stochastic features such as extinction not observable in the mean field description, and is significantly faster to simulate on a computer than the pure stochastic model. PMID- 26478602 TI - Immigration and the New Racial Diversity in Rural America. AB - This article highlights the new racial and ethnic diversity in rural America, which may be the most important but least anticipated population shift in recent demographic history. Ethnoracial change is central to virtually every aspect of rural America over the foreseeable future: agro-food systems, community life, labor force change, economic development, schools and schooling, demographic change, intergroup relations, and politics. The goal here is to plainly illustrate how America's racial and ethnic transformation has emerged as an important dimension of ongoing U.S. urbanization and urbanism, growing cultural and economic heterogeneity, and a putative "decline in community" in rural America. Rural communities provide a natural laboratory for better understanding the implications of uneven settlement and racial diversity, acculturation, and economic and political incorporation among Hispanic newcomers. This article raises the prospect of a new racial balkanization and outlines key impediments to full incorporation of Hispanics into rural and small town community life. Immigration and the new ethnoracial diversity will be at the leading edge of major changes in rural community life as the nation moves toward becoming a majority-minority society by 2042. PMID- 26478603 TI - Transition-metal free umpolung carbon-nitrogen vs. carbon-chlorine bond formation. AB - The formation of carbon-nitrogen (C-N) bonds via an umpolung substitution reaction has been achieved at -78 degrees C without the need for catalysts, ligands, or additives. The scope is limited to aryl Grignard reagents with N chloroamines. The findings in this manuscript serve as a reference point for all C-N bond formation involving N-chloroamines and organometallic reagents. Knowing the yields of uncatalyzed reactions will be useful when determining the success of future catalytic methods. PMID- 26478605 TI - Gross national happiness and health: lessons from Bhutan. PMID- 26478606 TI - IHR Review Committee to discuss Ebola report. PMID- 26478607 TI - Boosting health skills in Ukraine. AB - Health workers in conflict-hit eastern Ukraine are gaining new skills that may prove invaluable in peacetime too. Andrei Shukshin reports. PMID- 26478608 TI - Space technologies for health. AB - Space science and satellite technologies hold untapped potential for public health, according to a new expert group that will deliver its proposals to the United Nations General Assembly in New York next month. Pascal Michel talks to Fiona Fleck. PMID- 26478609 TI - New indicators for delay in initiation of antiretroviral treatment: estimates for Cameroon. AB - OBJECTIVE: To propose two new indicators for monitoring access to antiretroviral treatment (ART) for human immunodeficiency virus (HIV); (i) the time from HIV seroconversion to ART initiation, and (ii) the time from ART eligibility to initiation, referred to as delay in ART initiation. To estimate values of these indicators in Cameroon. METHODS: We used linear regression to model the natural decline in CD4+ T-lymphocyte (CD4+ cell) numbers in HIV-infected individuals over time. The model was fitted using data from a cohort of 351 people in Cote d'Ivoire. We used the model to estimate the time from seroconversion to ART initiation and the delay in ART initiation in a representative sample of 4154 HIV infected people who started ART in Cameroon between 2007 and 2010. FINDINGS: In Cameroon, the median CD4+ cell counts at ART initiation increased from 140 cells/MUl (interquartile range, IQR: 66 to 210) in 2007-2009 to 163 cells/MUl (IQR: 73 to 260) in 2010. The estimated average time from seroconversion to ART initiation decreased from 10.4 years (95% confidence interval, CI: 10.3 to 10.5) to 9.8 years (95% CI: 9.6 to 10.0). Delay in ART initiation increased from 3.4 years (95% CI: 3.1 to 3.7) to 5.8 years (95% CI: 5.6 to 6.2). CONCLUSION: The estimated time to initiate ART and the delay in ART initiation indicate that progress in Cameroon is insufficient. These indicators should help monitor whether public health interventions to accelerate ART initiation are successful. PMID- 26478610 TI - Monitoring of HIV treatment in seven countries in the WHO Region of the Americas. AB - OBJECTIVE: To determine the prevalence of adequate monitoring and the costs of measuring CD4+ T-lymphocytes (CD4+ cell) and human immunodeficiency virus (HIV) viral load in people receiving antiretroviral therapy (ART) in seven countries in the WHO Region of the Americas. METHODS: We obtained retrospective, longitudinal data for 14 476 adults who started a first ART regimen at seven HIV clinics in Argentina, Brazil, Chile, Haiti, Honduras, Mexico and Peru between 2000 and 2011. We estimated the proportion of 180-day periods with adequate monitoring, which we defined as at least one CD4+ cell count and one viral load measurement. Factors associated with adequate monitoring were analysed using regression methods. The costs of the tests were estimated. FINDINGS: The median follow-up time was 50.4 months; the proportion of 180-day periods with adequate CD4+ cell counts was 69% while the proportion with adequate monitoring was 62%. Adequate monitoring was more likely in participants who were older, who started ART more recently, whose first regimen included a non-nucleoside reverse transcriptase inhibitor or who had a CD4+ cell count less than 200 cells/ul at ART initiation. The cost of one CD4+ cell count ranged from 7.37 United States dollars (US$) in Argentina to US$ 64.09 in Chile; the cost of one viral load measurement ranged from US$ 20.34 in Brazil to US$ 186.28 in Haiti. CONCLUSION: In HIV-infected participants receiving ART in the WHO Region of the Americas, CD4+ cell count and viral load monitoring was often carried out less frequently than regional guidelines recommend. The laboratory costs of monitoring varied greatly. PMID- 26478612 TI - Effectiveness of emergency water treatment practices in refugee camps in South Sudan. AB - OBJECTIVE: To investigate the concentration of residual chlorine in drinking water supplies in refugee camps, South Sudan, March-April 2013. METHODS: For each of three refugee camps, we measured physical and chemical characteristics of water supplies at four points after distribution: (i) directly from tapstands; (ii) after collection; (iii) after transport to households; and (iv) after several hours of household storage. The following parameters were measured: free and total residual chlorine, temperature, turbidity, pH, electrical conductivity and oxidation reduction potential. We documented water handling practices with spot checks and respondent self-reports. We analysed factors affecting residual chlorine concentrations using mathematical and linear regression models. FINDINGS: For initial free residual chlorine concentrations in the 0.5-1.5 mg/L range, a decay rate of ~5x10(-3) L/mg/min was found across all camps. Regression models showed that the decay of residual chlorine was related to initial chlorine levels, electrical conductivity and air temperature. Covering water storage containers, but not other water handling practices, improved the residual chlorine levels. CONCLUSION: The concentrations of residual chlorine that we measured in water supplies in refugee camps in South Sudan were too low. We tentatively recommend that the free residual chlorine guideline be increased to 1.0 mg/L in all situations, irrespective of diarrhoeal disease outbreaks and the pH or turbidity of water supplies. According to our findings, this would ensure a free residual chlorine level of 0.2 mg/L for at least 10 hours after distribution. However, it is unknown whether our findings are generalizable to other camps and further studies are therefore required. PMID- 26478611 TI - Estimating the burden of foodborne diseases in Japan. AB - OBJECTIVE: To assess the burden posed by foodborne diseases in Japan using methods developed by the World Health Organization's Foodborne Disease Burden Epidemiology Reference Group (FERG). METHODS: Expert consultation and statistics on food poisoning during 2011 were used to identify three common causes of foodborne disease in Japan: Campylobacter and Salmonella species and enterohaemorrhagic Escherichia coli (EHEC). We conducted systematic reviews of English and Japanese literature on the complications caused by these pathogens, by searching Embase, the Japan medical society abstract database and Medline. We estimated the annual incidence of acute gastroenteritis from reported surveillance data, based on estimated probabilities that an affected person would visit a physician and have gastroenteritis confirmed. We then calculated disability-adjusted life-years (DALYs) lost in 2011, using the incidence estimates along with disability weights derived from published studies. FINDINGS: In 2011, foodborne disease caused by Campylobacter species, Salmonella species and EHEC led to an estimated loss of 6099, 3145 and 463 DALYs in Japan, respectively. These estimated burdens are based on the pyramid reconstruction method; are largely due to morbidity rather than mortality; and are much higher than those indicated by routine surveillance data. CONCLUSION: Routine surveillance data may indicate foodborne disease burdens that are much lower than the true values. Most of the burden posed by foodborne disease in Japan comes from secondary complications. The tools developed by FERG appear useful in estimating disease burdens and setting priorities in the field of food safety. PMID- 26478613 TI - Climate change, cash transfers and health. AB - The forecast consequences of climate change on human health are profound, especially in low- and middle-income countries and among the most disadvantaged populations. Innovative policy tools are needed to address the adverse health effects of climate change. Cash transfers are established policy tools for protecting population health before, during and after climate-related disasters. For example, the Ethiopian Productive Safety Net Programme provides cash transfers to reduce food insecurity resulting from droughts. We propose extending cash transfer interventions to more proactive measures to improve health in the context of climate change. We identify promising cash transfer schemes that could be used to prevent the adverse health consequences of climatic hazards. Cash transfers for using emission-free, active modes of transport - e.g. cash for cycling to work - could prevent future adverse health consequences by contributing to climate change mitigation and, at the same time, improving current population health. Another example is cash transfers provided to communities that decide to move to areas in which their lives and health are not threatened by climatic disasters. More research on such interventions is needed to ensure that they are effective, ethical, equitable and cost-effective. PMID- 26478614 TI - National health accounts data from 1996 to 2010: a systematic review. AB - OBJECTIVE: To collect, compile and evaluate publicly available national health accounts (NHA) reports produced worldwide between 1996 and 2010. METHODS: We downloaded country-generated NHA reports from the World Health Organization global health expenditure database and the Organisation for Economic Co-operation and Development (OECD) StatExtract website. We also obtained reports from Abt Associates, through contacts in individual countries and through an online search. We compiled data in the four main types used in these reports: (i) financing source; (ii) financing agent; (iii) health function; and (iv) health provider. We combined and adjusted data to conform with OECD's first edition of A system of health accounts manual, (2000). FINDINGS: We identified 872 NHA reports from 117 countries containing a total of 2936 matrices for the four data types. Most countries did not provide complete health expenditure data: only 252 of the 872 reports contained data in all four types. Thirty-eight countries reported an average not-specified-by-kind value greater than 20% for all data types and years. Some countries reported substantial year-on-year changes in both the level and composition of health expenditure that were probably produced by data generation processes. All study data are publicly available at http://vizhub.healthdata.org/nha/. CONCLUSION: Data from NHA reports on health expenditure are often incomplete and, in some cases, of questionable quality. Better data would help finance ministries allocate resources to health systems, assist health ministries in allocating capital within the health sector and enable researchers to make accurate comparisons between health systems. PMID- 26478616 TI - Aggression in mental health settings: a case study in Ghana. PMID- 26478618 TI - Maximizing the impact of community-based practitioners in the quest for universal health coverage. PMID- 26478619 TI - Monitoring inequality: an emerging priority for health post-2015. PMID- 26478615 TI - Emergency care in 59 low- and middle-income countries: a systematic review. AB - OBJECTIVE: To conduct a systematic review of emergency care in low- and middle income countries (LMICs). METHODS: We searched PubMed, CINAHL and World Health Organization (WHO) databases for reports describing facility-based emergency care and obtained unpublished data from a network of clinicians and researchers. We screened articles for inclusion based on their titles and abstracts in English or French. We extracted data on patient outcomes and demographics as well as facility and provider characteristics. Analyses were restricted to reports published from 1990 onwards. FINDINGS: We identified 195 reports concerning 192 facilities in 59 countries. Most were academically-affiliated hospitals in urban areas. The median mortality within emergency departments was 1.8% (interquartile range, IQR: 0.2-5.1%). Mortality was relatively high in paediatric facilities (median: 4.8%; IQR: 2.3-8.4%) and in sub-Saharan Africa (median: 3.4%; IQR: 0.5 6.3%). The median number of patients was 30 000 per year (IQR: 10 296-60 000), most of whom were young (median age: 35 years; IQR: 6.9-41.0) and male (median: 55.7%; IQR: 50.0-59.2%). Most facilities were staffed either by physicians-in training or by physicians whose level of training was unspecified. Very few of these providers had specialist training in emergency care. CONCLUSION: Available data on emergency care in LMICs indicate high patient loads and mortality, particularly in sub-Saharan Africa, where a substantial proportion of all deaths may occur in emergency departments. The combination of high volume and the urgency of treatment make emergency care an important area of focus for interventions aimed at reducing mortality in these settings. PMID- 26478621 TI - Prevention is better than treatment. PMID- 26478622 TI - Realizing nurses' full potential. PMID- 26478624 TI - Transitioning to a national health system in Cyprus: a stakeholder analysis of pharmaceutical policy reform. AB - OBJECTIVE: To review the pharmaceutical sector in Cyprus in terms of the availability and affordability of medicines and to explore pharmaceutical policy options for the national health system finance reform expected to be introduced in 2016. METHODS: We conducted semi-structured interviews in April 2014 with senior representatives from seven key national organizations involved in pharmaceutical care. The captured data were coded and analysed using the predetermined themes of pricing, reimbursement, prescribing, dispensing and cost sharing. We also examined secondary data provided by the Cypriot Ministry of Health; these data included the prices and volumes of prescription medicines in 2013. FINDINGS: We identified several key issues, including high medicine prices, underuse of generic medicines and high out-of-pocket drug spending. Most stakeholders recommended that the national government review existing pricing policies to ensure medicines within the forthcoming national health system are affordable and available, introduce a national reimbursement system and incentivize the prescribing and dispensing of generic medicines. There were disagreements over how to (i) allocate responsibilities to governmental agencies in the national health system, (ii) reconcile differences in opinion between stakeholders and (iii) raise awareness among patients, physicians and pharmacists about the benefits of greater generic drug use. CONCLUSION: In Cyprus, if the national health system is going to provide universal health coverage in a sustainable fashion, then the national government must address the current issues in the pharmaceutical sector. Importantly, the country will need to increase the market share of generic medicines to contain drug spending. PMID- 26478623 TI - Psychological distress and the perception of radiation risks: the Fukushima health management survey. AB - OBJECTIVE: To assess relationships between the perception of radiation risks and psychological distress among evacuees from the Fukushima nuclear power plant disaster. METHODS: We analysed cross-sectional data from a survey of evacuees conducted in 2012. Psychological distress was classified as present or absent based on the K6 scale. Respondents recorded their views about the health risks of exposure to ionizing radiation, including immediate, delayed and genetic (inherited) health effects, on a four-point Likert scale. We examined associations between psychological distress and risk perception in logistic regression models. Age, gender, educational attainment, history of mental illness and the consequences of the disaster for employment and living conditions were potential confounders. FINDINGS: Out of the 180,604 people who received the questionnaire, we included 59,807 responses in our sample. There were 8717 respondents reporting psychological distress. Respondents who believed that radiation exposure was very likely to cause health effects were significantly more likely to be psychologically distressed than other respondents: odds ratio (OR) 1.64 (99.9% confidence interval, CI: 1.42-1.89) for immediate effects; OR: 1.48 (99.9% CI: 1.32-1.67) for delayed effects and OR: 2.17 (99.9% CI: 1.94-2.42) for genetic (inherited) effects. Similar results were obtained after controlling for individual characteristics and disaster-related stressors. CONCLUSION: Among evacuees of the Fukushima nuclear disaster, concern about radiation risks was associated with psychological distress. PMID- 26478625 TI - Eliminating artificial trans fatty acids in Argentina: estimated effects on the burden of coronary heart disease and costs. AB - OBJECTIVE: To estimate the impact of Argentine policies to reduce trans fatty acids (TFA) on coronary heart disease (CHD), disability-adjusted life years (DALYs) and associated health-care costs. METHODS: We estimated the baseline intake of TFA before 2004 to be 1.5% of total energy intake. We built a policy model including baseline intake of TFA, the oils and fats used to replace artificial TFAs, the clinical effect of reducing artificial TFAs and the costs and DALYs saved due to averted CHD events. To calculate the percentage of reduction of CHD, we calculated CHD risks on a population-based sample before and after implementation. The effect of the policies was modelled in three ways, based on projected changes: (i) in plasma lipid profiles; (ii) in lipid and inflammatory biomarkers; and (iii) the results of prospective cohort studies. We also estimated the present economic value of DALYs and associated health-care costs of coronary heart disease averted. FINDINGS: We estimated that projected changes in lipid profile would avert 301 deaths, 1066 acute CHD events, 5237 DALYs and 17 million United States dollars (US$) in health-care costs annually. Based on the adverse effects of TFA intake reported in prospective cohort studies, 1517 deaths, 5373 acute CHD events, 26 394 DALYs and US$ 87 million would be averted annually. CONCLUSION: Even under the most conservative scenario, reduction of TFA intake had a substantial effect on public health. These findings will help inform decision-makers in Argentina and other countries on the potential public health and economic impact of this policy. PMID- 26478626 TI - Errors generated by a point-of-care CD4+ T-lymphocyte analyser: a retrospective observational study in nine countries. AB - OBJECTIVE: To estimate the proportion of invalid results generated by a CD4+ T lymphocyte analyser used by Medecins Sans Frontieres (MSF) in field projects and identify factors associated with invalid results. METHODS: We collated 25,616 CD4+ T-lymphocyte test results from 39 sites in nine countries for the years 2011 to 2013. Information about the setting, user, training, sampling technique and device repair history were obtained by questionnaire. The analyser performs a series of checks to ensure that all steps of the analysis are completed successfully; if not, an invalid result is reported. We calculated the proportion of invalid results by device and by operator. Regression analyses were used to investigate factors associated with invalid results. FINDINGS: There were 3354 invalid test results (13.1%) across 39 sites, for 58 Alere PimaTM devices and 180 operators. The median proportion of errors per device and operator was 12.7% (interquartile range, IQR: 10.3-19.9) and 12.1% (IQR: 7.1-19.2), respectively. The proportion of invalid results varied widely by country, setting, user and device. Errors were not associated with settings, user experience or the number of users per device. Tests performed on capillary blood samples were significantly less likely to generate errors compared to venous whole blood. CONCLUSION: The Alere Pima CD4+ analyser generated a high proportion of invalid test results, across different countries, settings and users. Most error codes could be attributed to the operator, but the exact causes proved difficult to identify. Invalid results need to be factored into the implementation and operational costs of routine CD4+ T-lymphocyte testing. PMID- 26478627 TI - Cost-effectiveness of community-based practitioner programmes in Ethiopia, Indonesia and Kenya. AB - OBJECTIVE: To assess the cost-effectiveness of community-based practitioner programmes in Ethiopia, Indonesia and Kenya. METHODS: Incremental cost effectiveness ratios for the three programmes were estimated from a government perspective. Cost data were collected for 2012. Life years gained were estimated based on coverage of reproductive, maternal, neonatal and child health services. For Ethiopia and Kenya, estimates of coverage before and after the implementation of the programme were obtained from empirical studies. For Indonesia, coverage of health service interventions was estimated from routine data. We used the Lives Saved Tool to estimate the number of lives saved from changes in reproductive, maternal, neonatal and child health-service coverage. Gross domestic product per capita was used as the reference willingness-to-pay threshold value. FINDINGS: The estimated incremental cost per life year gained was 82 international dollars ($)in Kenya, $999 in Ethiopia and $3396 in Indonesia. The results were most sensitive to uncertainty in the estimates of life-years gained. Based on the results of probabilistic sensitivity analysis, there was greater than 80% certainty that each programme was cost-effective. CONCLUSION: Community-based approaches are likely to be cost-effective for delivery of some essential health interventions where community-based practitioners operate within an integrated team supported by the health system. Community-based practitioners may be most appropriate in rural poor communities that have limited access to more qualified health professionals. Further research is required to understand which programmatic design features are critical to effectiveness. PMID- 26478628 TI - Road traffic crashes, injury and fatality trends in Sri Lanka: 1938-2013. AB - OBJECTIVE: To analyse trends in road traffic crashes, injuries and fatalities over 75 years in Sri Lanka. METHODS: Data on road traffic crashes, injuries and fatalities between 1938 and 2013 were obtained from the Police Statistics Unit. Rates per 100,000 population were calculated and trends were analysed using joinpoint regression analysis. FINDINGS: Road traffic crashes and injuries rose substantially between 1938 and 2013: annual crashes increased from 61.2 to 183.6 per 100,000 people; injuries, from 35.1 to 98.6 per 100,000; and fatalities, from 3.0 to 10.8 per 100,000 people per year. Joinpoint analysis showed large fluctuations in crashes and injuries over time but the fatalities rose almost continuously. These fluctuations paralleled the country's political and economic development. In some years, better traffic law enforcement and improved public transportation may have been associated with reduced crashes and injuries, whereas rapid growth in vehicle numbers, especially two- and three-wheeled vehicles, may have contributed to increased crashes and injuries. In addition, insurance policies that did not require a police report to claim may have led to underreporting of crashes and allowed drivers to avoid prosecution. CONCLUSION: Fluctuations over time in road traffic crashes and injuries in Sri Lanka are associated with changes in political, economic and traffic policy. There is potential for reducing road traffic crashes and injuries through better traffic law enforcement, restrictions on the importation of two- and three-wheeled vehicles and policies to improve road safety and prevent underreporting of crashes. PMID- 26478630 TI - Disclosure of medical errors to patients in China. PMID- 26478631 TI - Honouring the value of people in public health: a different kind of p-value. PMID- 26478632 TI - Achieving universal health coverage. PMID- 26478629 TI - Data collection tools for maternal and child health in humanitarian emergencies: a systematic review. AB - OBJECTIVE: To describe tools used for the assessment of maternal and child health issues in humanitarian emergency settings. METHODS: We systematically searched MEDLINE, Web of Knowledge and POPLINE databases for studies published between January 2000 and June 2014. We also searched the websites of organizations active in humanitarian emergencies. We included studies reporting the development or use of data collection tools concerning the health of women and children in humanitarian emergencies. We used narrative synthesis to summarize the studies. FINDINGS: We identified 100 studies: 80 reported on conflict situations and 20 followed natural disasters. Most studies (76/100) focused on the health status of the affected population while 24 focused on the availability and coverage of health services. Of 17 different data collection tools identified, 14 focused on sexual and reproductive health, nine concerned maternal, newborn and child health and four were used to collect information on sexual or gender-based violence. Sixty-nine studies were done for monitoring and evaluation purposes, 18 for advocacy, seven for operational research and six for needs assessment. CONCLUSION: Practical and effective means of data collection are needed to inform life-saving actions in humanitarian emergencies. There are a wide variety of tools available, not all of which have been used in the field. A simplified, standardized tool should be developed for assessment of health issues in the early stages of humanitarian emergencies. A cluster approach is recommended, in partnership with operational researchers and humanitarian agencies, coordinated by the World Health Organization. PMID- 26478633 TI - Biological Activity Assessment in Mexican Tropical Soils with Different Hydrocarbon Contamination Histories. AB - The use of soil health indicators linked to microbial activities, such as key enzymes and respirometric profiles, helps assess the natural attenuation potential of soils contaminated with hydrocarbons. In this study, the intrinsic physicochemical characteristics, biological activity and biodegradation potential were recorded for two soils with different contamination histories (>5 years and <1 months). The enzymatic activity (lipase and dehydrogenase) as well as microbiological and mineralisation profiles were measured in contaminated soil samples. Soil suspensions were tested as microbial inocula in biodegradation potential assays using contaminated perlite as an inert support. The basal respiratory rate of the recently contaminated soil was 15-38 mg C-CO2 kg-1 h-1, while the weathered soil presented a greater basal mineralisation capacity of 55 70 mg C-CO2 kg-1 h-1. The basal levels of lipase and dehydrogenase were significantly greater than those recorded in non-contaminated soils (551 +/- 21 MUg pNP g-1). Regarding the biodegradation potential assessment, the lipase (1000 3000 MUg pNP g-1 of perlite) and dehydrogenase (~3000 MUg INF g-1 of perlite) activities in the inoculum of the recently contaminated soil were greater than those recorded in the inoculum of the weathered soil. This was correlated with a high mineralisation rate (~30 mg C-CO2 kg-1 h-1) in the recently contaminated soil and a reduction in hydrocarbon concentration (~30 %). The combination of an inert support and enzymatic and respirometric analyses made it possible to detect the different biodegradation capacities of the studied inocula and the natural attenuation potential of a recently contaminated soil at high hydrocarbon concentrations. PMID- 26478635 TI - Soil Dehydrogenases as an Indicator of Contamination of the Environment with Petroleum Products. AB - The aim of the research was to compare the effects of various petroleum products, biodiesel, diesel oil, fuel oil and unleaded petrol on soil dehydrogenases, and to evaluate biostimulation with compost and urea in the restoration of homeostasis of the soil contaminated with these products. The obtained results allowed for defining the weight of dehydrogenases in monitoring of the environment subjected to pressure from petroleum hydrocarbons. The studies were carried out under laboratory conditions for 180 days, and loamy sand was the soil formation used in the experiment. The petroleum products were used in the following amounts: 0, 2, 4, 8 and 16 g kg-1 DM of soil. Indices of the influence of the petroleum product and the stimulating substance on the activity of dehydrogenases were calculated. It was proved that the petroleum products affect soil dehydrogenases in various ways. Biodiesel, diesel oil and fuel oil stimulate these enzymes, while petrol acts as an inhibitor. Among the substances tested regarding biostimulation of soils contaminated with petroleum products, compost is definitely more useful than urea, and therefore, the former should be used for the remediation of such soils. Stimulation of dehydrogenases by compost, both in contaminated and non-contaminated soils, proves that it may accelerate microbiological degradation of petroleum-derived contaminants. PMID- 26478636 TI - A note on recovering the distributions from exponential moments. AB - The problem of recovering a cumulative distribution function of a positive random variable via the scaled Laplace transform inversion is studied. The uniform upper bound of proposed approximation is derived. The approximation of a compound Poisson distribution as well as the estimation of a distribution function of the summands given the sample from a compound Poisson distribution are investigated. Applying the simulation study, the question of selecting the optimal scaling parameter of the proposed Laplace transform inversion is considered. The behavior of the approximants are demonstrated via plots and table. PMID- 26478634 TI - Over-the-Counter Monocyclic Non-Steroidal Anti-Inflammatory Drugs in Environment Sources, Risks, Biodegradation. AB - Recently, the increased use of monocyclic non-steroidal anti-inflammatory drugs has resulted in their presence in the environment. This may have potential negative effects on living organisms. The biotransformation mechanisms of monocyclic non-steroidal anti-inflammatory drugs in the human body and in other mammals occur by hydroxylation and conjugation with glycine or glucuronic acid. Biotransformation/biodegradation of monocyclic non-steroidal anti-inflammatory drugs in the environment may be caused by fungal or bacterial microorganisms. Salicylic acid derivatives are degraded by catechol or gentisate as intermediates which are cleaved by dioxygenases. The key intermediate of the paracetamol degradation pathways is hydroquinone. Sometimes, after hydrolysis of this drug, 4 aminophenol is formed, which is a dead-end metabolite. Ibuprofen is metabolized by hydroxylation or activation with CoA, resulting in the formation of isobutylocatechol. The aim of this work is to attempt to summarize the knowledge about environmental risk connected with the presence of over-the-counter anti inflammatory drugs, their sources and the biotransformation and/or biodegradation pathways of these drugs. PMID- 26478637 TI - QUANTIFIERS UNDONE: REVERSING PREDICTABLE SPEECH ERRORS IN COMPREHENSION. AB - Speakers predictably make errors during spontaneous speech. Listeners may identify such errors and repair the input, or their analysis of the input, accordingly. Two written questionnaire studies investigated error compensation mechanisms in sentences with doubled quantifiers such as Many students often turn in their assignments late. Results show a considerable number of undoubled interpretations for all items tested (though fewer for sentences containing doubled negation than for sentences containing many-often, every-always or few seldom.) This evidence shows that the compositional form-meaning pairing supplied by the grammar is not the only systematic mapping between form and meaning. Implicit knowledge of the workings of the performance systems provides an additional mechanism for pairing sentence form and meaning. Alternate accounts of the data based on either a concord interpretation or an emphatic interpretation of the doubled quantifier don't explain why listeners fail to apprehend the 'extra meaning' added by the potentially redundant material only in limited circumstances. PMID- 26478638 TI - Research: The Power of Collaboration. PMID- 26478639 TI - Education: Integrating PTD Into Undergraduate Curricula. PMID- 26478640 TI - Do cognitive interventions alter the rate of age-related cognitive change? AB - There has recently been a great deal of interest in cognitive interventions, particularly when applied in older adults with the goal of slowing or reversing age-related cognitive decline. Although seldom directly investigated, one of the fundamental questions concerning interventions is whether the intervention alters the rate of cognitive change, or affects the level of certain cognitive measures with no effect on the trajectory of change. This question was investigated with a very simple intervention consisting of the performance of three versions (treatment) or one version (control) of the relevant cognitive tests at an initial occasion. Participants were retested at intervals ranging from less than 1 to 12 years, which allowed rates of change to be examined in the control and treatment groups. Although the intervention can be considered modest, participants in the treatment group had about .25 standard deviations less negative cognitive change over an interval of approximately three years than those in the control group, which is comparable to effect sizes reported with more intensive interventions. However, there were no interactions of the intervention with length of the interval between occasions, and thus there was no evidence that the intervention affected the course of age-related cognitive decline. PMID- 26478641 TI - A Statistical Framework for the Analysis of ChIP-Seq Data. AB - Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) has revolutionalized experiments for genome-wide profiling of DNA-binding proteins, histone modifications, and nucleosome occupancy. As the cost of sequencing is decreasing, many researchers are switching from microarray-based technologies (ChIP-chip) to ChIP-Seq for genome-wide study of transcriptional regulation. Despite its increasing and well-deserved popularity, there is little work that investigates and accounts for sources of biases in the ChIP-Seq technology. These biases typically arise from both the standard pre-processing protocol and the underlying DNA sequence of the generated data. We study data from a naked DNA sequencing experiment, which sequences non-cross-linked DNA after deproteinizing and shearing, to understand factors affecting background distribution of data generated in a ChIP-Seq experiment. We introduce a background model that accounts for apparent sources of biases such as mappability and GC content and develop a flexible mixture model named MOSAiCS for detecting peaks in both one- and two sample analyses of ChIP-Seq data. We illustrate that our model fits observed ChIP Seq data well and further demonstrate advantages of MOSAiCS over commonly used tools for ChIP-Seq data analysis with several case studies. PMID- 26478643 TI - Estimating and interpreting latent variable interactions: A tutorial for applying the latent moderated structural equations method. AB - Latent variables are common in psychological research. Research questions involving the interaction of two variables are likewise quite common. Methods for estimating and interpreting interactions between latent variables within a structural equation modeling framework have recently become available. The latent moderated structural equations (LMS) method is one that is built into Mplus software. The potential utility of this method is limited by the fact that the models do not produce traditional model fit indices, standardized coefficients, or effect sizes for the latent interaction, which renders model fitting and interpretation of the latent variable interaction difficult. This article compiles state-of-the-science techniques for assessing LMS model fit, obtaining standardized coefficients, and determining the size of the latent interaction effect in order to create a tutorial for new users of LMS models. The recommended sequence of model estimation and interpretation is demonstrated via a substantive example and a Monte Carlo simulation. Finally, extensions of this method are discussed, such as estimating quadratic effects of latent factors and interactions between latent slope and intercept factors, which hold significant potential for testing and advancing developmental theories. PMID- 26478642 TI - The role of early visual attention in social development. AB - Faces convey important information about the social environment, and even very young infants are preferentially attentive to face-like over non-face stimuli. Eye-tracking studies have allowed researchers to examine which features of faces infants find most salient across development, and the present study examined scanning of familiar (i.e., mother) and unfamiliar (i.e., stranger) static faces at 6-, 9-, and 12-months-of-age. Infants showed a preference for scanning their mother's face as compared to a stranger's face, and displayed increased attention to the eye region as compared to the mouth region. Infants also showed patterns of decreased attention to eyes and increased attention to mouths between 6 and 12 months. Associations between visual attention at 6, 9, and 12 months and the Communication and Symbolic Behavior Scales DP (CSBS-DP) at 18 months were also examined, and a significant positive relation between attention to eyes at 6 months and the social subscale of the CSBS-DP at 18 months was found. This effect was driven by infants' attention to their mother's eyes. No relations between face scanning in 9- and 12-month-olds and social outcome at 18 months were found. The potential for using individual differences in early infant face processing to predict later social outcome is discussed. PMID- 26478644 TI - Analyses of geological and hydrodynamic controls on methane emissions experienced in a Lower Kittanning coal mine. AB - This paper presents a study assessing potential factors and migration paths of methane emissions experienced in a room-and-pillar mine in Lower Kittanning coal, Indiana County, Pennsylvania. Methane emissions were not excessive at idle mining areas, but significant methane was measured during coal mining and loading. Although methane concentrations in the mine did not exceed 1% limit during operation due to the presence of adequate dilution airflow, the source of methane and its migration into the mine was still a concern. In the course of this study, structural and depositional properties of the area were evaluated to assess complexity and sealing capacity of roof rocks. Composition, gas content, and permeability of Lower Kittanning coal, results of flotation tests, and geochemistry of groundwater obtained from observation boreholes were studied to understand the properties of coal and potential effects of old abandoned mines within the same area. These data were combined with the data obtained from exploration boreholes, such as depths, elevations, thicknesses, ash content, and heat value of coal. Univariate statistical and principal component analyses (PCA), as well as geostatistical simulations and co-simulations, were performed on various spatial attributes to reveal interrelationships and to establish area wide distributions. These studies helped in analyzing groundwater quality and determining gas-in-place (GIP) of the Lower Kittanning seam. Furthermore, groundwater level and head on the Lower Kittanning coal were modeled and flow gradients within the study area were examined. Modeling results were interpreted with the structural geology of the Allegheny Group of formations above the Lower Kittanning coal to understand the potential source of gas and its migration paths. Analyses suggested that the source of methane was likely the overlying seams such as the Middle and Upper Kittanning coals and Freeport seams of the Allegheny Group. Simulated ground-water water elevations, gradients of groundwater flow, and the presence of recharge and discharge locations at very close proximity to the mine indicated that methane likely was carried with groundwater towards the mine entries. Existing fractures within the overlying strata and their orientation due to the geologic conditions of the area, and activation of slickensides between shale and sandstones due to differential compaction during mining, were interpreted as the potential flow paths. PMID- 26478645 TI - Tobacco Use among Foster Youth: Evidence of Health Disparities. AB - Youth aging out of foster care face a challenging road to independence. Following exposure to myriad risk factors such as abuse, neglect, parental substance use, and severe housing mobility, supportive services decrease upon exit from care, often increasing risk for substance use, homelessness, and unemployment. Although tobacco use is also highly prevalent, little attention has been paid to screening, assessment, and treatment of tobacco use in this vulnerable group. The current study (N = 116) reports on tobacco use prevalence, consequences, and co occurrence with other substances in a sample of youth (ages 18 to 19) exiting the foster care system. In the face of an overall decrease in tobacco use among general population adolescents and young adults, results suggest disproportionate levels of lifetime, recent, and daily use among foster youth. Prevalence of recent tobacco use (46%) is nearly triple national rates, while daily smoking (32%) is almost four times that of general population young adults. Tobacco users were more likely than non-users to drink (70% vs. 40%) and to smoke marijuana (72% vs. 25%). We strongly encourage researchers and practitioners to increase attention to this tobacco-related health disparity. PMID- 26478646 TI - Implicit versus Explicit Rejection Self-Perceptions and Adolescents' Interpersonal Functioning. AB - We investigated associations between implicit and explicit self-perceptions of rejection with interpersonal functioning in close relationships. Adolescents (N=124) reported their explicit rejection self-perceptions on a questionnaire and completed the Implicit Association Test to assess their implicit rejection self perceptions. After controlling for implicit self-perceptions, adolescents' explicit rejection self-perceptions were associated with the adolescents self reporting more negative relationship quality with close friends and self reporting more negative behaviors with romantic partners. After controlling for explicit self-perceptions, adolescents' implicit rejection self-perceptions were associated with their romantic partners reporting more negative relationship quality with them, and observations of adolescents displaying more negative behaviors with romantic partners. Implicit and explicit rejection self perceptions uniquely explain individual differences in interpersonal behaviors. PMID- 26478647 TI - Contemporary Work and Family Issues Affecting Marriage and Cohabitation Among Low Income Single Mothers. AB - In this paper, we advance and test an integrative model of the effects of employment status, nonstandard work schedules, male employment, and women's perceptions of economic instability on union formation among low-income single mothers. Based on longitudinal data from 1,299 low-income mothers from the 3-city Welfare Study, results indicate that employment status alone is not significantly associated with whether women marry or cohabit. We find that nonemployed mothers and mothers working nonstandard schedules were less likely to marry compared to those working standard schedules. Mothers' perceptions of economic well-being were associated with marriage at Wave 2. In contrast, cohabitation outcomes were not explained by economic factors, but were related to the perception of child care support. The policy implications of these results are discussed, in particular, as they relate to welfare reform's work and family goals. PMID- 26478648 TI - Parental Incarceration as a Risk Factor for Children in Homeless Families. AB - The current study aimed to describe the prevalence of children of incarcerated parents (COIP) in a sample of homeless/highly mobile children, examine the relationship between parental incarceration and other risk factors, and investigate the effect of parental incarceration on child academic and mental health outcomes. The authors compared COIP (n = 45) to children whose parents were never incarcerated (n = 93) within a sample of 138, 4- to 7-year-old ethnically diverse children residing in emergency homeless shelters. Children's caregivers provided information about children's history of parental incarceration and other family experiences. Children's teachers reported academic and mental health outcomes in the subsequent school year. Compared to children with no history of parental incarceration, COIP experienced more negative life events. Regression models revealed that a history of parental incarceration was a significant predictor of teacher-reported internalizing problems. These results have implications for the identification and treatment of the highest risk homeless/highly mobile children. PMID- 26478649 TI - ASSIMILATION CHOICES AMONG IMMIGRANT FAMILIES: DOES SCHOOL CONTEXT MATTER? AB - This paper explores the relationship between social context, measured in terms of school characteristics, and the assimilation of immigrant adolescents. First, it develops a measure of assimilation based on comparing immigrant adolescents to native peers within the same school. Second, it investigates whether immigrant adolescents' degree of assimilation varies systematically according to school SES. Third, it explores the role of parental and adolescent behavior in creating such variation. Results show that both Asian and Hispanic immigrant youth are less assimilated to native youths' substance use and delinquency patterns in lower-SES schools. This association can be explained by parenting behaviors and adolescent friendship choices for Asian youth, but not Hispanic youth. PMID- 26478650 TI - Genus Ranges of Chord Diagrams. AB - A chord diagram consists of a circle, called the backbone, with line segments, called chords, whose endpoints are attached to distinct points on the circle. The genus of a chord diagram is the genus of the orientable surface obtained by thickening the backbone to an annulus and attaching bands to the inner boundary circle at the ends of each chord. Variations of this construction are considered here, where bands are possibly attached to the outer boundary circle of the annulus. The genus range of a chord diagram is the genus values over all such variations of surfaces thus obtained from a given chord diagram. Genus ranges of chord diagrams for a fixed number of chords are studied. Integer intervals that can be, and those that cannot be, realized as genus ranges are investigated. Computer calculations are presented, and play a key role in discovering and proving the properties of genus ranges. PMID- 26478651 TI - Why does Income Relate to Depressive Symptoms? Testing the Income Rank Hypothesis Longitudinally. AB - This paper reports a test of the relative income rank hypothesis of depression, according to which it is the rank position of an individual's income amongst a comparison group, rather than the individual's absolute income, that will be associated with depressive symptoms. A new methodology is developed to test between psychosocial and material explanations of why income relates to well being. This method was used to test the income rank hypothesis as applied to depressive symptoms. We used data from a cohort of 10,317 individuals living in Wisconsin who completed surveys in 1992 and 2003. The utility assumed to arise from income was represented with a constant relative risk aversion function to overcome limitations of previous work in which inadequate specification of the relationship between absolute income and well-being may have inappropriately favoured relative income specifications. We compared models in which current and future depressive symptoms were predicted from: (a) income utility alone, (b) income rank alone, (c) the transformed difference between the individual's income and the mean income of a comparison group and (d) income utility, income rank and distance from the mean jointly. Model comparison overcomes problems involving multi-collinearity amongst the predictors. A rank-only model was consistently supported. Similar results were obtained for the association between depressive symptoms and wealth and rank of wealth in a cohort of 32,900 British individuals who completed surveys in 2002 and 2008. We conclude that it is the rank of a person's income or wealth within a social comparison group, rather than income or wealth themselves or their deviations from the mean within a reference group, that is more strongly associated with depressive symptoms. PMID- 26478652 TI - Formal Laurent series in several variables. AB - We explain the construction of fields of formal infinite series in several variables, generalizing the classical notion of formal Laurent series in one variable. Our discussion addresses the field operations for these series (addition, multiplication, and division), the composition, and includes an implicit function theorem. PMID- 26478653 TI - Measurement of Behavioral and Emotional Outcomes of Youth in Foster Care: Investigation of the Roles of Age and Placement Type. AB - The Behavioral Assessment System for Children-2 (BASC-2) is used to assess behavioral and emotional outcomes for youth. Research providing evidence for use of the BASC-2 parent-report form historically has included biological parents reporting on their children (Reynolds and Kamphaus 2004). For youth residing in out-of-home placements through enrollment in foster care, caregivers reporting on their functioning may include foster parents or residential staff. Given the significant adverse mental health outcomes for youth in foster care and the need to adequately assess adjustment in foster care, the purpose of the study was to evaluate the measurement properties of caregivers' report on the parent report form (PRS) of the BASC-2 in foster care youth. Using 479 respondents, a measurement model was fit to the data demonstrating adequate fit across Internalizing Problems, Externalizing Problems, and Adaptive Skills. Further, a comparison of measurement properties across child and adolescent groups and groups of youth residing in residential facilities versus foster homes was conducted. Factorial invariance and latent means also were assessed. The BASC-2 PRS was found to be an adequate assessment of psychological outcomes for youth in foster care when completed by foster parents or residential facility staff. PMID- 26478654 TI - Identifying Shared Latent Dimensions of Psychological Symptoms: Implications for the Psychological Correlates of Smoking. AB - Shared latent dimensions may account for the co-occurrence of multiple forms of psychological dysfunction. However, this conceptualization has rarely been integrated into the smoking literature, despite high levels of psychological symptoms in smokers. In this study, we used confirmatory factor analysis to compare three models (1-factor, 2-factor [internalizing-externalizing], and 3 factor [low positive affect-negative affect-disinhibition]) of relations among nine measures of affective and behavioral symptoms implicated in smoking spanning depression, anxiety, happiness, anhedonia, ADHD, aggression, and alcohol use disorder symptoms. We then examined associations of scores from each of the manifest scales and the latent factors from the best-fitting model to several smoking characteristics (i.e., experimentation, lifetime established smoking [>=100 cigarettes lifetime], age of smoking onset, cigarettes/day, nicotine dependence, and past nicotine withdrawal). We used two samples: (1) College Students (N =288; mean age =20; 75 % female) and (2) Adult Daily Smokers (N=338; mean age=44; 32 % female). In both samples, the 3-factor model separating latent dimensions of deficient positive affect, negative affect, and disinhibition fit best. In the college students, the disinhibition factor and its respective indicators significantly associated with lifetime smoking. In the daily smokers, low positive and high negative affect factors and their respective indicators positively associated with cigarettes/day and nicotine withdrawal symptom severity. These findings suggest that shared features of psychological symptoms may be parsimonious explanations of how multiple manifestations of psychological dysfunction play a role in smoking. Implications for research and treatment of co occurring psychological symptoms and smoking are discussed. PMID- 26478655 TI - Childhood adversities and adult use of potentially injurious physical discipline in Japan. AB - Using data derived from the World Mental Health Japan Survey (n = 1,186), this study examined the intergenerational continuity of potentially injurious physical discipline of children in a community sample from Japan with a special focus on the confounding effects of 11 other types of childhood adversities (CAs) and the intervening effects of mental disorders and socioeconomic status. Bivariate analyses revealed that having experienced physical discipline as children and five other CAs was significantly associated with the use of physical discipline as parents in the Japanese community examined. However, childhood physical discipline was the only CA that remained significant after adjusting for the other CAs. The association of childhood physical discipline with adult perpetration was independent of the respondents' mental disorders and household income. No significant gender differences were found in the associations between childhood physical discipline and adult perpetration. The current study on Japan provided empirical support consistent with results found in other countries regarding the intergenerational transmission of child physical abuse. PMID- 26478656 TI - The Comorbid and Individual Impacts of Maternal Depression and Substance Dependence on Parenting and Child Behavior Problems. AB - Maternal depression, substance dependence, and the comorbidity of these conditions are highly prevalent risk factors among families involved with Child Protective Services (CPS). Data from the National Survey of Child and Adolescent Well-Being I (NSCAW I) were analyzed to examine the influence of maternal substance dependence, depression, and comorbidity on parenting and child behavior over 36-months among children reported to CPS who remained in the home at all waves. Although neglect and child behavior problems were highest for mothers with comorbidity at baseline, mothers with substance dependence had the poorest self reported parenting and child behavior problems over time. Results indicate a need for intensive targeted services to address the complex needs of CPS-involved mothers with substance dependence and their in-home children. PMID- 26478657 TI - Discrepant Alcohol Use, Intimate Partner Violence, and Relationship Adjustment among Lesbian Women and their Relationship Partners. AB - This study examined the association between relationship adjustment and discrepant alcohol use among lesbian women and their same-sex intimate partners after controlling for verbal and physical aggression. Lesbian women (N = 819) who were members of online marketing research panels completed an online survey in which they reported both their own and same-sex intimate partner's alcohol use, their relationship adjustment, and their own and their partner's physical aggression and psychological aggression (i.e., verbal aggression and dominance/isolation). Partners' alcohol use was moderately correlated. Discrepancy in alcohol use was associated with poorer relationship adjustment after controlling for psychological aggression and physical aggression. Results are discussed in terms of the similarity and differences with previous literature primarily focused on heterosexual couples. PMID- 26478658 TI - Statistical Learning is Related to Early Literacy-Related Skills. AB - It has been demonstrated that statistical learning, or the ability to use statistical information to learn the structure of one's environment, plays a role in young children's acquisition of linguistic knowledge. Although most research on statistical learning has focused on language acquisition processes, such as the segmentation of words from fluent speech and the learning of syntactic structure, some recent studies have explored the extent to which individual differences in statistical learning are related to literacy-relevant knowledge and skills. The present study extends on this literature by investigating the relations between two measures of statistical learning and multiple measures of skills that are critical to the development of literacy-oral language, vocabulary knowledge, and phonological processing-within a single model. Our sample included a total of 553 typically developing children from prekindergarten through second grade. Structural equation modeling revealed that statistical learning accounted for a unique portion of the variance in these literacy-related skills. Practical implications for instruction and assessment are discussed. PMID- 26478659 TI - Modern diagnostics for type B aortic dissection. AB - BACKGROUND: Undifferentiated chest pain is one of the most common complaints in the acute care setting. Type B aortic dissection is an important cause of chest pain and a complex clinical entity, which carries significant morbidity and mortality and requires accurate clinical and radiological evaluation. METHODS: Imaging technologies have become an irreplaceable tool to establish the diagnosis of aortic dissection and to plan treatment strategies. Computed tomography is an important component in this process, replacing catheter-based angiography as the most commonly used preoperative and postoperative imaging modality for the thoracic aorta. The use of functional imaging methods, such as magnetic resonance imaging and echocardiography is evolving. These methods are able to provide the clinically relevant anatomical, hemodynamic and biomechanical information that is necessary for accurate diagnosis, risk stratification and patient selection for treatment. CONCLUSION: Advanced image acquisition equipment and expertise are increasingly available in a growing number of institutions and as a consequence, existing strategies for the management of type B dissection are rapidly evolving. PMID- 26478660 TI - Chimpanzee Cognitive Control. AB - Cognitive control processes are a feature of human cognition. Recent comparative tests have shown that some nonhuman animals also might share aspects of cognitive control with humans. Two of the executive processes that constitute cognitive control are metacognition and self-control, and recent experiments with chimpanzees are described that demonstrate metacognitive monitoring and control when these animals engage in an information-seeking task. Chimpanzees also show strategic responding in a self-control task by exhibiting self-distraction as an aid to delay of gratification. These demonstrations indicate continuity with similar human cognitive capacities, and the performances of chimpanzees in these kinds of tests have implications for considering the nature of the intelligence of these animals. PMID- 26478661 TI - Modification of Bacterial Cellulose with Organosilanes to Improve Attachment and Spreading of Human Fibroblasts. AB - Bacterial Cellulose (BC) synthesized by Acetobacter xylinum has been a promising candidate for medical applications. Modifying BC to possess the properties needed for specific applications has been reported. In this study, BCs functionalized by organosilanes were hypothesized to improve the attachment and spreading of Normal Human Dermal Fibroblast (NHDF). The BC gels obtained from biosynthesis were dried by either ambient-air drying or freeze drying. The surfaces of those dried BCs were chemically modified by grafting methyl terminated octadecyltrichlorosilane (OTS) or amine terminated 3-aminopropyltriethoxysilane (APTES) to expectedly increase hydrophobic or electrostatic interactions with NHDF cells, respectively. NHDF cells improved their attachment and spreading on the majority of APTES modified BCs (~70-80% of area coverage by cells) with more rapid growth (~2.6 2.8* after incubations from 24 to 48h) than on tissue culture polystyrene (~2*); while the inverse results (< 5% of area coverage and stationary growth) were observed on the OTS-modified BCs. For organosilane modified BCs, the drying method had no effect on in vitro cell attachment/spreading behaviors. PMID- 26478662 TI - Advanced pancreatic cancer - how to choose an adequate treatment option. AB - The prognosis of pancreatic adenocarcinoma is poor, making it one of the leading causes of cancer-related death. The 5-year overall survival rate remains below 5% and little progress is made during the past decade. Only about 10%-20% of patients are eligible for curative-intent surgery and the majority end up having recurring disease even after radical surgery and postoperative adjuvant chemotherapy. Chemotherapy in metastatic disease is palliative at best, aiming at disease and symptom control and prolongation of life. Treatment always causes side effects, the degree of which varies from patient to patient, depending on the patient's general condition, concomitant morbidities as well as on the chosen treatment modality. Why is pancreatic cancer so resistant to treatment? How to best help the patient to reach the set treatment goals? PMID- 26478663 TI - Hepatitis B virus infection in Indonesia. AB - Approximately 240 million people are chronically infected with hepatitis B virus (HBV), 75% of whom reside in Asia. Approximately 600000 of infected patients die each year due to HBV-related diseases or hepatocellular carcinoma (HCC). The endemicity of hepatitis surface antigen in Indonesia is intermediate to high with a geographical difference. The risk of HBV infection is high in hemodialysis (HD) patients, men having sex with men, and health care workers. Occult HBV infection has been detected in various groups such as blood donors, HD patients, and HIV infected individuals and children. The most common HBV subgenotype in Indonesia is B3 followed by C1. Various novel subgenotypes of HBV have been identified throughout Indonesia, with the novel HBV subgenotypes C6-C16 and D6 being successfully isolated. Although a number of HBV subgenotypes have been discovered in Indonesia, genotype-related pathogenicity has not yet been elucidated in detail. Therefore, genotype-related differences in the prognosis of liver disease and their effects on treatments need to be determined. A previous study conducted in Indonesia revealed that hepatic steatosis was associated with disease progression. Pre-S2 mutations and mutations at C1638T and T1753V in HBV/B3 have been associated with advanced liver diseases including HCC. However, drug resistance to lamivudine, which is prominent in Indonesia, remains obscure. Although the number of studies on HBV in Indonesia has been increasing, adequate databases on HBV infection are limited. We herein provided an overview of the epidemiology and clinical characteristics of HBV infection in Indonesia. PMID- 26478664 TI - Restoring homeostasis of CD4+ T cells in hepatitis-B-virus-related liver fibrosis. AB - Immune-mediated liver injury is widely seen during hepatitis B virus (HBV) infection. Unsuccessful immune clearance of HBV results in chronic hepatitis and increases the risk of liver cirrhosis and hepatocellular carcinoma. HBV-related liver fibrosis (HBVLF), occurring as a result of HBV-induced chronic hepatitis, is a reversible, intermediate stage of chronic hepatitis B (CHB) and liver cirrhosis. Therefore, defining the pathogenesis of HBVLF is of practical significance for achieving better clinical outcomes. Recently, the homeostasis of CD4(+) T cells was considered to be pivotal in the process of HBVLF. To better uncover the underlying mechanisms, in this review, we systematically retrospect the impacts of different CD4(+) T-cell subsets on CHB and HBVLF. We emphasize CD4(+) T-cell homeostasis and the important balance between regulatory T (Treg) and T helper 17 (Th17) cells. We discuss some cytokines associated with Treg and Th17 cells such as interleukin (IL)-17, IL-22, IL-21, IL-23, IL-10, IL-35 and IL 33, as well as surface molecules such as programmed cell death protein 1, cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin domain and mucin domain-containing molecule 3 and cannabinoid receptor 2 that have potential therapeutic implications for the homeostasis of CD4(+) T cells in CHB and HBVLF. PMID- 26478665 TI - Molecular mechanism of hepatitis B virus X protein function in hepatocarcinogenesis. AB - Many factors are considered to contribute to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), including products of HBV, HBV integration and mutation, and host susceptibility. HBV X protein (HBx) can interfere with several signaling pathways associated with cell proliferation and invasion, and HBx C terminal truncation has been suggested to impact the development of HCC. This review focuses on the pathological functions of HBx in HBV-induced hepatocarcinogenesis. As a transactivator, HBx can affect regulatory non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs. HBx is also involved in epigenetic modification and DNA repair. HBx interacts with various signal transduction pathways, such as the p53, Wnt, and nuclear factor-kappaB pathways. We conclude that HBx hastens the development of hepatoma. PMID- 26478666 TI - Immune and non-immune responses to hepatitis C virus infection. AB - The host innate and adaptive immune systems are involved in nearly every step of hepatitis C virus (HCV) infection. In patients, the outcome is determined by a series of complex host-virus interactions, whether it is a natural infection or results from clinical intervention. Strong and persistent CD8(+) and CD4(+) T cell responses are critical in HCV clearance, as well as cytokine-induced factors that can directly inhibit virus replication. Newly available direct-acting antivirals (DAAs) are very effective in viral clearance in patients. DAA treatment may further result in the down-regulation of programmed death-1, leading to rapid restoration of HCV-specific CD8(+) T cell functions. In this review, we focus on recent studies that address the host responses critical for viral clearance and disease resolution. Additional discussion is devoted to the prophylactic vaccine development as well as to current efforts aimed at understanding the host innate responses against HCV infection. Current theories on how the ubiquitin system and interferon-stimulated genes may affect HCV replication are also discussed. PMID- 26478667 TI - Hepatitis C virus markers in infection by hepatitis C virus: In the era of directly acting antivirals. AB - About 130-170 million people are infected with the hepatitis C virus (HCV) worldwide and more than 350000 people die each year of HCV-related liver diseases. The combination of pegylated interferon (Peg-IFN) and ribavirin (RBV) was recommended as the treatment of choice for chronic hepatitis C for nearly a decade. In 2011 the directly acting antivirals (DAA) HCV NS3/4A protease inhibitors, telaprevir and boceprevir, were approved to treat HCV-genotype-1 infection, each in triple combination with Peg-IFN and RBV. These treatments allowed higher rates of SVR than the double Peg-IFN + RBV, but the low tolerability and high pill burden of these triple regimes were responsible for reduced adherence and early treatment discontinuation. The second and third wave DAAs introduced in 2013-2014 enhanced the efficacy and tolerability of anti-HCV treatment. Consequently, the traditional indicators for disease management and predictors of treatment response should be revised in light of these new therapeutic options. This review article will focus on the use of the markers of HCV infection and replication, of laboratory and instrumental data to define the stage of the disease and of predictors, if any, of response to therapy in the DAA era. The article is addressed particularly to physicians who have patients with hepatitis C in care in their everyday clinical practice. PMID- 26478669 TI - Modulation of host lipid metabolism by hepatitis C virus: Role of new therapies. AB - It is well established that hepatitis C virus (HCV) infection and replication relies on host lipid metabolism. HCV proteins interact and associate with lipid droplets to facilitate virion assembly and production. Besides, circulating infective particles are associated with very low-density lipoprotein. On the other hand, higher serum lipid levels have been associated with sustained viral response to pegylated interferon and ribavirin therapy in chronic HCV infection, suggesting a relevant role in viral clearance for host proteins. Host and viral genetic factors play an essential role in chronic infection. Lipid metabolism is hijacked by viral infection and could determine the success of viral replication. Recently development of direct acting antiviral agents has shown a very high efficacy (> 90%) in sustained viral response rates even for cirrhotic patients and most of the viral genotypes. HCV RNA clearance induced by Sofosbuvir has been associated with an increased concentration and size of the low-density lipoprotein particles. In this review, host genetic factors, viral factors and the interaction between them will be depicted to clarify the major issues involved in viral infection and lipid metabolism. PMID- 26478668 TI - Impact of new treatment options for hepatitis C virus infection in liver transplantation. AB - Liver transplant candidates and recipients with hepatitis C virus (HCV)-related liver disease greatly benefit from an effective antiviral therapy. The achievement of a sustained virological response before transplantation can prevent the recurrence of post-transplant HCV disease that occurs universally and correlates with enhanced progression to graft cirrhosis. Previous standard-of care regimens (e.g., pegylated-interferon plus ribavirin with or without first generation protease inhibitors, boceprevir and telaprevir) displayed suboptimal results and poor tolerance in liver transplant recipients. A new class of potent direct-acting antiviral agents (DAA) characterized by all-oral regimens with minimal side effects has been approved and included in the recent guidelines for the treatment of liver transplant recipients with recurrent HCV disease. Association of sofosbuvir with ribavirin and/or ledipasvir is recommended in liver transplant recipients and patients with decompensated cirrhosis. Other regimens include simeprevir, daclatasvir, and combination of other DAA. Possible interactions should be monitored, especially in coinfected human immunodeficiency virus/HCV patients receiving antiretrovirals. PMID- 26478670 TI - What's new in hepatitis C virus infections in children? AB - The number of hepatitis C virus (HCV) infection cases is relatively low in children. This low number may be connected with the lack of screening tests and the asymptomatic course of infection. Currently, mother-to-infant transmission is the most common cause of HCV infection amongst children in developed countries. It is important to introduce routine screening tests for HCV in pregnant women. The risk of vertical transmission of HCV is estimated at approximately 5% (3% 10%). Currently, we do not have HCV transmission prevention methods. Some factors could potentially be eliminated by elective caesarean section. Currently, the method of prevention of perinatal HCV infection is the early identification and effective treatment of infections in young women in the preconception period. We describe genetic tests (IL-28B single nucleotide polymorphisms) to identify children with an increased chance of spontaneous clearance or sustained virologic response achievement and vitamin D level as a potential predictor of treatment response in children. It is also important to develop non-invasive tests that can predict liver fibrosis. The existence of differences in the mechanisms leading to liver injury between children and adults creates new perspectives of action to reduce liver disease progression in children in the early years of life. PMID- 26478671 TI - Epidemiology of hepatitis C virus in Iran. AB - In Iran, the prevalence of hepatitis C virus (HCV) infection is relatively low according to the population-based epidemiological studies. However, the epidemiology of HCV is changing and the rate of HCV infection is increasing due to the growth in the number of injecting drug users in the society. In addition, a shift has occurred in the distribution pattern of HCV genotypes among HCV infected patients in Iran. Genotype 1a is the most prevalent genotype in Iran, but in recent years, an increase in the frequency of 3a and a decrease in 1a and 1b have been reported. These variations in the epidemiology of HCV reflect differences in the routes of transmission, status of public health, lifestyles, and risk factors in different groups and geographic regions of Iran. Health policy makers should consider these differences to establish better strategies for control and prevention of HCV infection. Therefore, this review was conducted to present a clear view regarding the current epidemiology of HCV infection in Iran. PMID- 26478673 TI - Review of single incision laparoscopic surgery in colorectal surgery. AB - As surgical techniques continue to move towards less invasive techniques, single incision laparoscopic surgery (SILS), a hybrid between traditional multiport laparoscopy and natural orifice transluminal endoscopic surgery, was introduced to further the enhanced outcomes of multiport laparoscopy. The safety and feasibility of SILS for both benign and malignant colorectal disease has been proven. SILS provides the potential for improved cosmesis, postoperative pain, recovery time, and quality of life at the drawback of higher technical skill required. In this article, we review the history, describe the available technology and techniques, and evaluate the benefits and limitations of SILS for colorectal surgery in the published literature. PMID- 26478672 TI - Injecting drug use: A vector for the introduction of new hepatitis C virus genotypes. AB - Hepatitis C virus (HCV) genotypes' monitoring allows real-time insight into the dynamic changes that occur in the global epidemiological picture of HCV infection. Intravenous drug use is currently the primary driver for HCV transmission in developed and developing countries. The distribution of HCV genotypes/subtypes differs significantly between people who inject drugs (PWID) and the general population. HCV genotypes that previously exhibited a limited geographical distribution (3a, 4) are becoming more prevalent in this high-risk group. Immigration from HCV-endemic countries and the evolving networks of HCV transmission in PWID influence HCV genotypes distribution in Europe. Social vulnerabilities (e.g., unemployment, homelessness, and limited access to social and healthcare insurances systems) are important triggers for illicit drug use, which increases the associated risks of HCV infection and the frequent emergence of less prevalent genotypes. Genotype/subtype determination bears important clinical consequences in the progression of liver disease, susceptibility to antiviral therapies and the emergence of resistance-associated variants. An estimated half of the chronically HCV-infected PWID are unaware of their infection, and only one in ten of those diagnosed enter treatment. Nevertheless, PWID exhibit high response rates to new antiviral regimens, and the level of HCV reinfection is unexpectedly low. The focus of the healthcare system must be on the early detection and treatment of infection, to avoid late presentations that are associated with high levels of viremia and liver fibrosis, which may diminish the therapeutic success rate. PMID- 26478674 TI - Data analyses and perspectives on laparoscopic surgery for esophageal achalasia. AB - In general, the treatment methods for esophageal achalasia are largely classified into four groups, including drug therapy using nitrite or a calcium channel blocker, botulinum toxin injection, endoscopic therapy such as endoscopic balloon dilation, and surgery. Various studies have suggested that the most effective treatment of esophageal achalasia is surgical therapy. The basic concept of this surgical therapy has not changed since Heller proposed esophageal myotomy for the purpose of resolution of lower esophageal obstruction for the first time in 1913, but the most common approach has changed from open-chest surgery to laparoscopic surgery. Currently, the laparoscopic surgery has been the procedure of choice for the treatment of esophageal achalasia. During the process of the transition from open-chest surgery to laparotomy, to thoracoscopic surgery, and to laparoscopic surgery, the necessity of combining antireflux surgery has been recognized. There is some debate as to which type of antireflux surgery should be selected. The Toupet fundoplication may be the most effective in prevention of postoperative antireflux, but many medical institutions have selected the Dor fundoplication which covers the mucosal surface exposed by myotomy. Recently, a new endoscopic approach, peroral endoscopic myotomy (POEM), has received attention. Future studies should examine the long-term outcomes and whether POEM becomes the gold standard for the treatment of esophageal achalasia. PMID- 26478675 TI - Aberrant expression of peroxiredoxin 1 and its clinical implications in liver cancer. AB - AIM: To investigate the expression characteristics of peroxiredoxin 1 (PRDX1) mRNA and protein in liver cancer cell lines and tissues. METHODS: The RNA sequencing data from 374 patients with liver cancer were obtained from The Cancer Genome Atlas. The expression and clinical characteristics of PRDX1 mRNA were analyzed in this dataset. The Kaplan-Meier and Cox regression survival analysis was performed to determine the relationship between PRDX1 levels and patient survival. Subcellular fractionation and Western blotting were used to demonstrate the expression of PRDX1 protein in six liver cancer cell lines and 29 paired fresh tissue specimens. After bioinformatics prediction, a putative post translational modification form of PRDX1 was observed using immunofluorescence under confocal microscopy and immunoprecipitation analysis in liver cancer cells. RESULTS: The mRNA of PRDX1 gene was upregulated about 1.3-fold in tumor tissue compared with the adjacent non-tumor control (P = 0.005). Its abundance was significantly higher in men than women (P < 0.001). High levels of PRDX1 mRNA were associated with a shorter overall survival time (P = 0.04) but not with recurrence-free survival. The Cox regression analysis demonstrated that patients with high PRDX1 mRNA showed about 1.9-fold increase of risk for death (P = 0.03). In liver cancer cells, PRDX1 protein was strongly expressed with multiple different bands. PRDX1 in the cytosol fraction existed near the theoretical molecular weight, whereas two higher molecular weight bands were present in the membrane/organelle and nuclear fractions. Importantly, the theoretical PRDX1 band was increased, whereas the high molecular weight form was decreased in tumor tissues. Subsequent experiments revealed that the high molecular weight bands of PRDX1 might result from the post-translational modification by small ubiquitin like modifier-1 (SUMO1). CONCLUSION: PRDX1 was overexpressed in the tumor tissues of liver cancer and served as an independent poor prognostic factor for overall survival. PRDX1 can be modified by SUMO to play specific roles in hepatocarcinogenesis. PMID- 26478676 TI - Dimethyl sulfoxide inhibits zymosan-induced intestinal inflammation and barrier dysfunction. AB - AIM: To investigate whether dimethyl sulfoxide (DMSO) inhibits gut inflammation and barrier dysfunction following zymosan-induced systemic inflammatory response syndrome and multiple organ dysfunction syndrome. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham with administration of normal saline (SS group); sham with administration of DMSO (SD group); zymosan with administration of normal saline (ZS group); and zymosan with administration of DMSO (ZD group). Each group contained three subgroups according to 4 h, 8 h, and 24 h after surgery. At 4 h, 8 h, and 24 h after intraperitoneal injection of zymosan (750 mg/kg), the levels of intestinal inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-10] and oxides (myeloperoxidase, malonaldehyde, and superoxide dismutase) were examined. The levels of diamine oxidase (DAO) in plasma and intestinal mucosal blood flow (IMBF) were determined. Intestinal injury was also evaluated using an intestinal histological score and apoptosis of intestinal epithelial cells was determined by deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The intestinal epithelial tight junction protein, ZO-1, was observed by immunofluorescence. RESULTS: DMSO decreased TNF-alpha and increased IL-10 levels in the intestine compared with the ZS group at the corresponding time points. The activity of intestinal myeloperoxidase in the ZS group was higher than that in the ZD group 24 h after zymosan administration (P < 0.05). DMSO decreased the content of malondialdehyde (MDA) and increased the activity of superoxide dehydrogenase (SOD) 24 h after zymosan administration. The IMBF was lowest at 24 h and was 49.34% and 58.26% in the ZS group and ZD group, respectively (P < 0.05). DMSO alleviated injury in intestinal villi, and the gut injury score was significantly lower than the ZS group (3.6 +/- 0.2 vs 4.2 +/- 0.3, P < 0.05). DMSO decreased the level of DAO in plasma compared with the ZS group (65.1 +/- 4.7 U/L vs 81.1 +/- 5.0 U/L, P < 0.05). DMSO significantly preserved ZO-1 protein expression and localization 24 h after zymosan administration. The TUNEL analysis indicated that the number of apoptotic intestinal cells in the ZS group was much higher than the ZD group (P < 0.05). CONCLUSION: DMSO inhibited intestinal cytokines and protected against zymosan-induced gut barrier dysfunction. PMID- 26478677 TI - Clinical characteristics of hepatoduodenal lymph node metastasis in gastric cancer. AB - AIM: To assess the clinical features of hepatoduodenal lymph node (HDLN) metastasis and to clarify the optimal indication of HDLN dissection. METHODS: We investigated a total of 276 patients who underwent gastrectomy with extended lymphadenectomy, including HDLN dissection, for gastric cancer between 1999 and 2012. Of these, 26 patients (9.4%) had HDLN metastasis. First, we investigated the clinicopathological characteristics, their perioperative clinical outcomes, such as postoperative complications, and prognostic outcomes between patients with and without HDLN metastasis. Second, we detected the prognostic factors, particularly in patients with HDLN metastasis. Third, we assessed the therapeutic value of HDLN dissection to determine its optimal indication. RESULTS: The five year overall survival rate of the patients with HDLN metastasis was 29%. Univariate and multivariate logistic regression analyses revealed that the tumour location (the middle or lower stomach [P = 0.005, OR = 5.88 (95%CI: 1.61-38.1)] and pT category [T3 or T4, P = 0.017, OR = 4.45 (95%CI: 1.28-21.3)] were independent risk factors for HDLN metastasis. Cox proportional hazard analysis identified pN3 as an independent poor prognostic factor in the patients with HDLN metastasis [P = 0.021, HR = 5.17 (95%CI: 1.8-292)]. For patients who underwent radical HDLN dissection, HDLN metastasis was a prognostic indicator in pN3 gastric cancer (P < 0.0001), but not pN1-2 (P = 0.602). Furthermore, the index of therapeutic value of HDLN dissection for gastric cancer in the middle or lower stomach and the upper stomach was 3.4 and 0.0, respectively. CONCLUSION: We suggest that HDLN dissection should be indicated for pN1 or pN2 gastric cancers located at the middle or lower stomach. PMID- 26478678 TI - Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies. AB - AIM: To evaluate the long-term efficacy adefovir (ADV)-based combination therapies in entecavir (ETV)-resistant chronic hepatitis B (CHB) patients. METHODS: Fifty CHB patients with genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV (ADV/ETV, n = 23) or ADV plus lamivudine (LMV) (ADV/LMV, n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus (HBV) DNA levels were measured by real-time PCR and logarithmically transformed for analysis. Cumulative rates of virologic response (VR; HBV DNA < 20 IU/mL) were calculated using the Kaplan-Meier method, and the difference was determined by a log-rank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR, respectively. RESULTS: Baseline median HBV DNA levels were 5.53 (2.81-7.63) log10 IU/mL. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27 (12-45) mo. Overall, cumulative VR rates at 6, 12, 24, and 36 mo were 26%, 36%, 45%, and 68%, respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates (35%, 43%, 65%, and 76%, respectively) than those with the ADV/LAM combination (18%, 30%, 30%, and 62%, respectively; P = 0.048). In the multivariate analysis, low baseline HBV DNA levels (< 5.2 log10 IU/mL) and initial virologic response at 3 mo (IVR-3; HBV DNA < 3.3 log10 IU/mL after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period, the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors. CONCLUSION: If tenofovir is not available, ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers, and may be continued if IVR-3 is achieved. PMID- 26478679 TI - Geographical distribution of the incidence of gastric cancer in Bhutan. AB - AIM: To estimate the prevalence of gastric cancer (GC) in a cohort of patients diagnosed with GC and to compare it with patients diagnosed with all other types of gastro-intestinal (GI) cancer during the same period. METHODS: Between 2008 and 2013, five-year period, the medical records of all GI cancer patients who underwent medical care and confirm diagnosis of cancer were reviewed at the National Referral Hospital, Thimphu which is the only hospital in the country where surgical and cancer diagnosis can be made. Demographic information, type of cancer, and the year of diagnosis were collected. RESULTS: There were a total of 767 GI related cancer records reviewed during the study period of which 354 (46%) patients were diagnosed with GC. There were 413 patients with other GI cancer including; esophagus, colon, liver, rectum, pancreas, gall bladder, cholangio carcinoma and other GI tract cancers. The GC incidence rate is approximately 0.9/10000 per year (367 cases/5 years per 800000 people). The geographic distribution of GC was the lowest in the south region of Bhutan 0.3/10000 per year compared to the central region 1.4/10000 per year, Eastern region 1.2/10000 per year, and the Western region 1.1/10000 per year. Moreover, GC in the South part was significantly lower than the other GI cancer in the same region (8% vs 15%; OR = 1.8, 95%CI: 1.3-3.1, P = 0.05). Among GC patients, 38% were under the age of 60 years, mean age at diagnosis was 62.3 (+/- 12.1) years with male-to female ratio 1:0.5. The mean age among patients with all other type GI cancer was 60 years (+/- 13.2) and male-to-female ratio of 1:0.7. At time of diagnosis of GC, 342 (93%) were at stage 3 and 4 of and by the year 2013; 80 (23%) GC patients died compared to 31% death among patients with the all other GI cancer (P = 0.08). CONCLUSION: The incidence rate of GC in Bhutan is twice as high in the United States but is likely an underestimate rate because of unreported and undiagnosed cases in the villages. The high incidence of GC in Bhutan could be attributed to the high prevalence of Helicobacter pylori infection that we previously reported. The lowest incidence of GC in Southern part of the country could be due to the difference in the ethnicity as most of its population is of Indian and Nepal origin. Our current study emphasizes on the importance for developing surveillance and prevention strategies for GC in Bhutan. PMID- 26478680 TI - Upper gastrointestinal bleeding in Scotland 2000-2010: Improved outcomes but a significant weekend effect. AB - AIM: To assess numbers and case fatality of patients with upper gastrointestinal bleeding (UGIB), effects of deprivation and whether weekend presentation affected outcomes. METHODS: Data was obtained from Information Services Division (ISD) Scotland and National Records of Scotland (NRS) death records for a ten year period between 2000-2001 and 2009-2010. We obtained data from the ISD Scottish Morbidity Records (SMR01) database which holds data on inpatient and day-case hospital discharges from non-obstetric and non-psychiatric hospitals in Scotland. The mortality data was obtained from NRS and linked with the ISD SMR01 database to obtain 30-d case fatality. We used 23 ICD-10 (International Classification of diseases) codes which identify UGIB to interrogate database. We analysed these data for trends in number of hospital admissions with UGIB, 30-d mortality over time and assessed effects of social deprivation. We compared weekend and weekday admissions for differences in 30-d mortality and length of hospital stay. We determined comorbidities for each admission to establish if comorbidities contributed to patient outcome. RESULTS: A total of 60643 Scottish residents were admitted with UGIH during January, 2000 and October, 2009. There was no significant change in annual number of admissions over time, but there was a statistically significant reduction in 30-d case fatality from 10.3% to 8.8% (P < 0.001) over these 10 years. Number of admissions with UGIB was higher for the patients from most deprived category (P < 0.05), although case fatality was higher for the patients from the least deprived category (P < 0.05). There was no statistically significant change in this trend between 2000/01-2009/10. Patients admitted with UGIB at weekends had higher 30-d case fatality compared with those admitted on weekdays (P < 0.001). Thirty day mortality remained significantly higher for patients admitted with UGIB at weekends after adjusting for comorbidities. Length of hospital stay was also higher overall for patients admitted at the weekend when compared to weekdays, although only reached statistical significance for the last year of study 2009/10 (P < 0.0005). CONCLUSION: Despite reduction in mortality for UGIB in Scotland during 2000-2010, weekend admissions show a consistently higher mortality and greater lengths of stay compared with weekdays. PMID- 26478681 TI - Lymphocyte-to-monocyte ratio predicts survival of patients with hepatocellular carcinoma after curative resection. AB - AIM: To investigate the prognostic value of preoperative lymphocyte-to-monocyte ratio (LMR) in patients with hepatocellular carcinoma (HCC) undergoing curative hepatectomy. METHODS: Clinicopathological data of 210 hepatitis B virus (HBV) associated HCC patients who were treated by radical hepatic resection between 2003 and 2010 were retrospectively analyzed. None of the patients received any preoperative anticancer therapy or intraoperative radiofrequency ablation. The diagnosis was confirmed by pathological examination after surgery. Absolute peripheral blood lymphocyte and monocyte counts were derived from serum complete blood cell count before surgery, and LMR was calculated by dividing lymphocyte count by monocyte count. The best cutoff was determined by receiver operating characteristics (ROC) curve analysis. Correlations between LMR levels and clinicopathological features were assessed using the chi(2) test. Survival outcomes were estimated using the Kaplan-Meier method and compared by the log rank test. Univariate and multivariate analyses were performed to evaluate the prognostic impact of LMR and other clinicopathological factors on overall survival (OS) and recurrence-free survival (RFS), using the Cox proportional hazards model. RESULTS: The optimal cutoff value of LMR for survival analysis was 3.23, which resulted in the most appropriate sensitivity of 55.3% and specificity of 74.7%, with the area under the curve (AUC) of 0.66 (95%CI: 0.593-0.725). All patients were dichotomized into either a low (<= 3.23) LMR group (n = 66) or a high (> 3.23) LMR group (n = 144). A low preoperative LMR level was significantly correlated with the presence of cirrhosis, elevated levels of total bilirubin and larger tumor size. Patients with a low LMR level had significantly reduced 5-year OS (61.9% vs 83.2%, P < 0.001) and RFS (27.8% vs 47.6%, P = 0.009) compared to those with a high LMR level. Multivariate analyses indicated that a lower LMR level was a significantly independent predictor of inferior OS (P = 0.003) and RFS (P = 0.006). Subgroup analysis indicated that survival outcome was significantly more favorable in cirrhotic patients with LMR > 3.23. However, there were no differences between low and high LMR groups for OS and RFS in non cirrhotic patients. CONCLUSION: Preoperative LMR was demonstrated for the first time to serve as an independent prognostic factor in HBV-associated HCC patients after curative resection. Prospective studies with larger cohorts for validation are warranted. PMID- 26478682 TI - Gastroenterologist perceptions of faecal microbiota transplantation. AB - AIM: To explore gastroenterologist perceptions towards and experience with faecal microbiota transplantation (FMT). METHODS: A questionnaire survey consisting of 17 questions was created to assess gastroenterologists' attitude towards and experience with FMT. This was anonymously distributed in hard copy format amongst attendees at gastroenterology meetings in Australia between October 2013 and April 2014. Basic descriptive statistical analyses were performed. RESULTS: Fifty two clinicians participated. Twenty one percent had previously referred patients for FMT, 8% more than once. Ninety percent would refer patients with Clostridium difficile infection (CDI) for FMT if easily available, 37% for ulcerative colitis, 13% for Crohn's disease and 6% for irritable bowel syndrome. Six percent would not refer any indication, including recurrent CDI. Eighty-six percent would enroll patients in FMT clinical trials. Thirty-seven percent considered the optimal mode of FMT administration transcolonoscopic, 17% nasoduodenal, 13% enema and 8% oral capsule. The greatest concerns regarding FMT were: 42% lack of evidence, 12% infection risk, 10% non infectious adverse effects/lack of safety data, 10% aesthetic, 10% lack of efficacy, 4% disease exacerbation, and 2% inappropriate use; 6% had no concerns. Seventy seven percent believed there is a lack of accessibility while 52% had an interest in learning how to provide FMT. Only 6% offered FMT at their institution. CONCLUSION: Despite general enthusiasm, most gastroenterologists have limited experience with, or access to, FMT. The greatest concerns were lack of supportive evidence and safety issues. However a significant proportion would refer indications other than CDI for FMT despite insufficient evidence. These data provide guidance on where education and training are required. PMID- 26478683 TI - Systematic analysis of the safety and benefits of transvaginal hybrid-NOTES cholecystectomy. AB - AIM: To evaluate transvaginal hybrid-NOTES cholecystectomy (TVC) during its clinical establishment and compare it with the traditional laparoscopic technique (LC). METHODS: The specific problems and benefits of TVC were reviewed using a registry analysis, a comparative cohort study and a randomized clinical trial. At first, feasibility, safety and specific complications of the TVC were analyzed based on the first 488 data sets of the German NOTES Registry (GNR). Hereafter, we compared the early postoperative results of our first 50 TVC-patients with those of 50 female LC-patients matched by age, BMI and ASA classification. The same cohort was contacted an average of two years later to evaluate long-term results concerning pain and satisfaction with the aesthetic results and the overall postoperative results as well as sexual intercourse by means of two domains of the German version of the Female Sexual Function Index (FSFI-d). Consequently, we performed a randomized clinical trial comparing 20 TVC-patients with 20 needlescopic/3-trocar cholecystectomies (NC) also concerning the early postoperative results as well as pain, satisfaction and quality of life by means of the Eypasch Gastrointestinal Quality of Life Index (GIQLI) in the later course. Finally, we discussed the results in accordance with other published studies. RESULTS: The complication (3.5%) and conversion rates (4.1%) for TVC were low in the GNR and comparable to those of the LC. Access related intraoperative complications included injuries to the bladder (n = 4; 0.8%) and bowel (n = 3; 0.6%). The study cohort revealed less postoperative pain after TVC comparing to the LC-patients on the day of surgery (NRS, 1.5/10 vs 3.1/10, P = 0.003), in the morning (NRS, 1.9/10 vs 2.8/10, P = 0.047) and in the evening (NRS, 1.1/10 vs 1.8/10, P = 0.025) of postoperative day (POD) one. The randomized clinical trial consistently found less cumulative pain until POD 2 (NRS, 8/40 vs 14/40, P = 0.043), as well as until POD 10 (NRS, 22/190 vs 41/190, P = 0.010). Furthermore, the TVC-patients had a better quality of life on POD 10 than did the LC-patients (GIQLI, 124/144 vs 107/144, P = 0.028). The complication rates were comparable and no specific problems were detected in the long-term follow-up for sexual intercourse for either group. The TVC-patients were more satisfied with the aesthetic result in the long-term course in the matched cohort analysis (1.00 vs 1.88, P < 0.001) as well as in the randomized clinical trial (1.00 vs 1.70, P < 0.001) when compared with the LC-patients. CONCLUSION: TVC is a feasible procedure with a high safety profile and has advantages in regard to postoperative pain and aesthetic results when compared with LC or NC. PMID- 26478684 TI - Hilar cholangiocarcinoma with intratumoral calcification: A case report. AB - This report describes a rare case of hilar cholangiocarcinoma with intratumoral calcification that mimicked hepatolithiasis. A 73-year-old man presented to a local hospital with a calcified lesion in the hepatic hilum. At first, hepatolithiasis was diagnosed, and he underwent endoscopic stone extraction via the trans-papillary route. This treatment strategy failed due to biliary stricture. He was referred to our hospital, and further examination suggested the existence of cholangiocarcinoma. He underwent left hepatectomy with caudate lobectomy and extrahepatic bile duct resection. Pathological examination revealed hilar cholangiocarcinoma with intratumoral calcification, while no stones were found. To the best of our knowledge, only one case of calcified hilar cholangiocarcinoma has been previously reported in the literature. Here, we report a rare case of calcified hilar cholangiocarcinoma and reveal its clinicopathologic features. PMID- 26478685 TI - Statistical coherence of primary schooling in IPUMS-International integrated population samples for China, India, Vietnam, and ten other Asia-Pacific countries. AB - IPUMS-International www.ipums.org/international disseminates harmonized census microdata for more than 80 countries at no cost, although access is restricted to bona-fide researchers and students who agree to the stringent conditions of use license. Currently over 270 samples are available, totalling more than 600 million person records. Each year 15-20 additional samples are released, as more countries cooperate with the IPUMS initiative and the integration of 2010 round census samples is completed. With so much microdata so readily available, questions of data quality naturally arise. This paper focusses on the concept of statistical coherence over time for a single concept, primary schooling completed. From an analysis of the percentage completing primary schooling by birth year for pairs of samples for thirteen Asia-Pacific countries, we find outstanding coherence for four-China, Mongolia, Vietnam, and Indonesia-with mean differences of less than 0.5 percentage points, regression coefficient (b) ranging from 0.93 to 1.07 and R2 =.99. For the thirteen countries as a group there is considerable variation overall with mean absolute difference as high as 16 percentage points, b ranging from 0.62-1.44 and R2=.65-.99. As a whole, statistical coherence of primary schooling is outstanding. Nonetheless, to make expert use of the harmonized microdata, researchers are cautioned to carefully study the IPUMS integrated metadata as well as the original source documentation. National Statistical Offices not currently cooperating or that have not yet entrusted 2010 round census microdata are invited to do so. PMID- 26478686 TI - A Hybrid Approach for Efficient Modeling of Medium-Frequency Propagation in Coal Mines. AB - An efficient procedure for modeling medium frequency (MF) communications in coal mines is introduced. In particular, a hybrid approach is formulated and demonstrated utilizing ideal transmission line equations to model MF propagation in combination with full-wave sections used for accurate simulation of local antenna-line coupling and other near-field effects. This work confirms that the hybrid method accurately models signal propagation from a source to a load for various system geometries and material compositions, while significantly reducing computation time. With such dramatic improvement to solution times, it becomes feasible to perform large-scale optimizations with the primary motivation of improving communications in coal mines both for daily operations and emergency response. Furthermore, it is demonstrated that the hybrid approach is suitable for modeling and optimizing large communication networks in coal mines that may otherwise be intractable to simulate using traditional full-wave techniques such as moment methods or finite-element analysis. PMID- 26478687 TI - Sex Work, Heroin Injection, and HIV Risk in Tijuana: A Love Story. AB - The relationships between female sex workers and their non-commercial male partners are typically viewed as sites of HIV risk rather than meaningful unions. This ethnographic case study presents a nuanced portrayal of the relationship between Cindy and Beto, a female sex worker who injects drugs and her intimate, non-commercial partner who live in Tijuana, Mexico. Based on ethnographic research in Tijuana and our long term involvement in a public health study, we suggest that emotions play a central role in sex workers' relationships and contribute in complex ways to each partner's health. We conceptualize Cindy and Beto's relationship as a "dangerous safe haven" in which HIV risk behaviors such as unprotected sex and syringe sharing convey notions of love and trust and help sustain emotional unity amidst broader uncertainties, but nevertheless carry very real health risks. Further attention to how emotions shape vulnerable couples' health remains a task for anthropology. PMID- 26478689 TI - Parenting Practices Among Biological Mothers of Drug Involved Truant Youth: A Latent Profile Analysis. PMID- 26478688 TI - A Typology of Violence against Self and Others and Its Associations with Drinking and Other Drug Use among High School Students in a U.S. General Population Survey. AB - This study examined associations between binge drinking and other substance use and perpetration of violence against self and others. Data were pooled from the 2003, 2005, and was constructed to reflect four categories of behaviors: other directed violence only, self-directed violence only, combined other- and self directed violence, and no violence. Results from multinomial logistic regressions show that the frequency of binge drinking and other substance use were significant risk factors for each of the violence categories relative to no violence. However, the strengths of these associations varied across the violence categories. PMID- 26478690 TI - Improving parenting and parent-teen communication to delay or prevent the onset of alcohol and drug use in young adolescents with emotional/behavioral disorders: A pilot trial. PMID- 26478691 TI - The Validity of Truant Youths' Marijuana Use and Its Impact on Alcohol Use and Sexual Risk Taking. AB - Few studies investigating the validity of marijuana use have used samples of truant youth. In the current study, self-reports of marijuana use are compared with urine test results for marijuana to identify marijuana underreporting among adolescents participating in a longitudinal Brief Intervention for drug-involved truant youth. It was hypothesized that marijuana underreporting would be associated with alcohol underreporting and engaging in sexual risk behaviors. The results indicated marijuana underreporting was significantly associated with self denial of alcohol use, but not associated with sexual risk behavior. Also, there was an age effect in marijuana use underreporting such that younger truant youth were more likely to underreport marijuana use, compared to older truant youth. Implications for policy and future research are discussed. PMID- 26478692 TI - Sectarian and Nonsectarian Violence: Mothers' Appraisals of Political Conflict in Northern Ireland. AB - Past research on peace and conflict in Northern Ireland has focused on politically-motivated violence. However, other types of crime (i.e., nonsectarian) also impact community members. To study the changing nature of violence since the signing of the Belfast Agreement in Northern Ireland the current study used qualitative methods to distinguish between nonsectarian and sectarian antisocial behavior. Analyses were conducted using the Constant Comparative Method to illuminate thematic patterns in focus groups with Catholic and Protestant mothers from segregated Belfast neighborhoods. Participants differentiated between nonsectarian and sectarian violence; the latter was further distinguished into two dimensions - overt acts and intergroup threat. Although both nonsectarian and sectarian antisocial behavior related to insecurity, participants described pulling together and increased ingroup social cohesion in response to sectarian threats. The findings have implications for the study of violence and insecurity as experienced in the everyday lives of mothers, youth, and families in settings of protracted conflict. PMID- 26478693 TI - An Automated Mouse Tail Vascular Access System by Vision and Pressure Feedback. AB - This paper develops an automated vascular access system (A-VAS) with novel vision based vein and needle detection methods and real-time pressure feedback for murine drug delivery. Mouse tail vein injection is a routine but critical step for preclinical imaging applications. Due to the small vein diameter and external disturbances such as tail hair, pigmentation, and scales, identifying vein location is difficult and manual injections usually result in poor repeatability. To improve the injection accuracy, consistency, safety, and processing time, A VAS was developed to overcome difficulties in vein detection noise rejection, robustness in needle tracking, and visual servoing integration with the mechatronics system. PMID- 26478694 TI - Communication Assessment of the Most Frequented Breast Cancer Websites: Evaluation of Design and Theoretical Criteria. AB - : The internet is a prominent source of health information for the public. This research evaluated both basic use and design tenets and the presence of theoretical components to motivate healthy breast cancer behavior for users of the most frequented breast cancer websites. METHODOLOGY: Each website was evaluated with 2 sets of questions. The first attends to the basic use and design tenets of the website. The second coding form assessed the websites use of 3 behavior change theories. RESULTS: The majority of the websites fared well with regards to their use of basic tenet and design principles. Theoretical components were used sparingly on the majority of websites. DISCUSSION: The most frequented breast cancer websites are currently well equipped with basic use and design tenets. However, their lack of behavioral change components is likely to impede users' motivations to protect themselves against breast cancer. PMID- 26478695 TI - Why You Really Should Consider Using Palladium-Catalyzed Cross-Coupling of Silanols and Silanolates. AB - The transition metal-catalyzed cross-coupling of organometallic nucleophiles derived from tin, boron, and zinc with organic electrophiles enjoys a preeminent status among modern synthetic methods for the formation of carbon-carbon bonds. In recent years, organosilanes have emerged as viable alternatives to the conventional reagents, with the added benefits of low cost, low toxicity and high chemical stability. However, silicon-based cross-coupling reactions often require heating in the presence of a fluoride source, which has significantly hampered their widespread acceptance. To address the "fluoride problem", a new paradigm for palladium-catalyzed, silicon-based cross-coupling reactions has been developed that employs a heretofore underutilized class of silicon reagents, the organosilanols. The use of organosilanols, either in the presence of Bronsted bases or as their silanolate salts, represents an operationally simple and mild alternative to the fluoride-based activation method. Organosilanols are readily available by many well-established methods for introducing carbon-silicon bonds onto alkenes, alkynes, arenes and heteroarenes. Moreover, several different protocols for the generation of alkali metal salts of, vinyl-, alkenyl-, alkynyl , aryl-, and heteroarylsilanolates have been developed and the advantages of each of these methods have been demonstrated for a number of different coupling classes. This review will describe the development and implementation of cross coupling reactions of organosilanols and their conjugate bases, silanolates, with a wide variety of substrate classes. In addition, application of these transformations in the total synthesis of complex natural products will also be highlighted. Finally, the unique advantages of organosilicon coupling strategies vis a vis organoboron reagents are discussed. PMID- 26478696 TI - Sex Rules: Emerging Adults' Perceptions of Gender's Impact on Sexuality. AB - Past research often explains gender differences in sexual behavior according to differences in social norms for men and women. Yet, individuals' perceptions and internalizations of current social norms are not well understood. This study aimed to examine emerging adults' perceptions of how being male or female impacts their sexuality and how their perceptions would differ if they were another gender. Participants (N = 205) were college students, 61% female, and ranged from age 18-25 (M = 20.5, SD = 1.7). Participants answered open-ended questions about gender and responses were coded for content, positive tone, and negative tone. In describing how being female affected their sexual thoughts and feelings, women were more likely than men to focus on reputation concerns and describe limits and contexts in which sexual behavior was acceptable. In describing how being male affected their sexual thoughts and feelings, men were more likely than women to focus on issues of desire. Women's perceptions about how their sexual thoughts and feelings would differ if they were male were consistent with men's perceptions of their own gender's actual impact on sexuality, and vice versa. Women's descriptions of their own gender's impact on sexuality were more emotionally laden than men's. Finally, being older was associated with less negative and more positive emotional tone in men's and women's responses respectively. PMID- 26478697 TI - Checklist of the helminth parasites of the genus Profundulus Hubbs, 1924 (Cyprinodontiformes, Profundulidae), an endemic family of freshwater fishes in Middle-America. AB - From December 2012 to November 2014, 267 fish belonging to the family Profundulidae (representing nine of the 11 species of the genus Profundulus) were collected in 26 localities of Middle-America, across southern Mexico, Guatemala, and Honduras, comprising the distribution range of the genus, and analyzed for helminth parasites. Additionally, a database with all ten available published accounts of the helminth parasite fauna of this genus (the only genus within the family) was assembled. Based on both sources of information, a checklist containing all the records was compiled as a tool to address future questions in the areas of evolutionary biology, biogeography, ecology and phylogeography of this host-parasite association. The helminth parasite fauna of this fish group consists of 20 nominal species, classified in 17 genera and 14 families. It includes six species of adult digeneans, five metacercariae, two monogeneans, one adult cestode, three adult nematodes and three larval nematodes. The profundulid fishes are parasitized by a specialized group of helminth species (e.g. Paracreptotrema blancoi sensu Salgado-Maldonado et al. (2011b), Paracreptotrema profundulusi Salgado-Maldonado, Caspeta-Mandujano & Martinez Ramirez, 2011, Phyllodistomum spinopapillatum Perez-Ponce de Leon, Pinacho-Pinacho, Mendoza Garfias & Garcia-Varela, 2015, Spinitectus humbertoi Mandujano-Caspeta & Moravec, 2000, Spinitectus mariaisabelae Caspeta-Mandujano Cabanas-Carranza & Salgado Maldonado, 2007 and Rhabdochona salgadoi Mandujano-Caspeta & Moravec, 2000), representing the core helminth fauna that are not shared with other Middle American fish species. PMID- 26478698 TI - Seven new hypselostomatid species from China, including some of the world's smallest land snails (Gastropoda, Pulmonata, Orthurethra). AB - Seven new species of Hypselostomatidae are described from the Chinese province Guangxi: Angustopila dominikae Pall-Gergely & Hunyadi, sp. n., Angustopila fabella Pall-Gergely & Hunyadi, sp. n., Angustopila subelevata Pall-Gergely & Hunyadi, sp. n., Angustopila szekeresi Pall-Gergely & Hunyadi, sp. n., Hypselostoma socialis Pall-Gergely & Hunyadi, sp. n., Hypselostoma lacrima Pall Gergely & Hunyadi, sp. n. and Krobylos sinensis Pall-Gergely & Hunyadi, sp. n. The latter species is reported from three localities. All other new species are known only from the type locality. Specimens nearly identical to the type specimens of Angustopila huoyani Jochum, Slapnik & Pall-Gergely, 2014 were found in a cave in northern Guangxi, 500 km from the type locality. Adult individuals of Angustopila subelevata sp. n. (shell height = 0.83-0.91 mm, mean = 0.87 mm) and Angustopila dominikae sp. n. (shell height of the holotype = 0.86 mm) represent the smallest known members of the Hypselostomatidae, and thus are amongst the smallest land snails ever reported. We note that Pyramidula laosensis Saurin, 1953 might also belong to Krobylos. Paraboysidia neglecta van Benthem Jutting, 1961, which was previously included in Angustopila, is classified in Hypselostoma. PMID- 26478699 TI - Five new cryptic freshwater gastropod species from New Caledonia (Caenogastropoda, Truncatelloidea, Tateidae). AB - During the course of a project aiming at the reconstruction of the colonization of the South Pacific islands by tateid gastropods based on molecular data we discovered five new species on New Caledonia belonging to the genera Hemistomia and Leiorhagium, respectively. We describe these species based on morphological, anatomical and genetic data. All five species are morphologically cryptic as they closely resemble or are even indistinguishable from known species stressing the importance of a comprehensive taxonomic approach integrating several methods. As a consequence of their small and fragmented geographic ranges and the rapidly progressing anthropogenic land cover changes on New Caledonia, all five species qualify as critically endangered according to the criteria of the IUCN. PMID- 26478700 TI - On Afromantispa and Mantispa (Insecta, Neuroptera, Mantispidae): elucidating generic boundaries. AB - The genus Afromantispa Snyman & Ohl, 2012 was recently synonymised with Mantispa Illiger, 1798 by Monserrat (2014). Here morphological evidence is presented in support of restoring the genus Afromantispa stat. rev. to its previous status as a valid and morphologically distinct genus. Twelve new combinations (comb. n.) are proposed as species of Afromantispa including three new synonyms. PMID- 26478701 TI - Croatian mayflies (Insecta, Ephemeroptera): species diversity and distribution patterns. AB - Knowledge of the mayfly biodiversity in the Balkan Peninsula is still far from complete. Compared to the neighbouring countries, the mayfly fauna in Croatia is very poorly known. Situated at the crossroads of central and Mediterranean Europe and the Balkan Peninsula, Croatia is divided into two ecoregions: Dinaric western Balkan and Pannonian lowland. Mayflies were sampled between 2003 and 2013 at 171 sites, and a total of 66 species was recorded. Combined with the literature data, the Croatian mayfly fauna reached a total of 79 taxa. Of these, 29 species were recorded for the first time in Croatia while 15 species were not previously recorded in Dinaric western Balkan ecoregion. Based on the mayfly assemblage, sampling sites were first structured by ecoregion and then by habitat type. In comparison with the surrounding countries, the Croatian mayfly fauna is the most similar to the Hungarian and Bosnian fauna. Some morphologically interesting taxa such as Baetis cf. nubecularis Eaton, 1898 and Rhithrogena from the diaphana group were recorded. Ephemera cf. parnassiana Demoulin, 1958, the species previously recorded only from Greece, was also recorded. PMID- 26478702 TI - Redescription of Temnothorax antigoni (Forel, 1911) and description of its new social parasite Temnothorax curtisetosus sp. n. from Turkey (Hymenoptera, Formicidae). AB - Temnothorax antigoni (Forel, 1911) is redescribed basing on a new material from southwestern Turkey (Antalya province), Lesbos and Rhodes (Greece, Aegean and Dodecanese islands). The gyne of this species is described for the first time. Temnothorax curtisetosus, a new species of social parasite collected in a nest of Temnothorax antigoni, is described. Colour photos of both taxa are given. A key to the worker caste of the eastern Mediterranean species belonging to both Temnothorax recedens and Temnothorax muellerianus groups are provided. PMID- 26478703 TI - The cushion-star Parvulastra exigua in South Africa: one species or more? AB - The cushion-star Parvulastra exigua (Lamarck, 1816) is a widely distributed member of the temperate intertidal fauna in the southern hemisphere. In South Africa, it occurs in sympatry with the endemic Parvulastra dyscrita (Clark, 1923), the two species being differentiated predominantly by gonopore placement. Several recent studies have suggested that there may be additional cryptic species within the Parvulastra exigua complex in South Africa, based variously on color morphology, genetic evidence and the differential placement of the gonopores. This paper attempts to resolve whether one or more species are represented within Parvulastra exigua. A total of 346 Parvulastra exigua and 8 Parvulastra dyscrita were collected from sites on the west and south-west coasts of South Africa; morphological, anatomical and genetic analyses were performed to determine whether cryptic species and/or Parvulastra exigua specimens with aboral gonopores were present. Results show that neither cryptic species nor Parvulastra exigua specimens with aboral gonopores occur at these sites. This study thus refutes previous claims of the existence of aboral gonopores in South African Parvulastra exigua, and suggests that a single species is represented. The distinction between Parvulastra exigua and Parvulastra dyscrita is also confirmed, and features separating these two species are clarified and documented. PMID- 26478704 TI - Taxonomy and distribution of some katydids (OrthopteraTettigoniidae) from tropical Africa. AB - Results of the study of specimens collected in tropical Africa and preserved in different European collections and museums are reported and extensively illustrated. The following three new species are described: Horatosphaga aethiopica sp. n., Dapanera occulta sp. n. and Cestromoecha laeglae sp. n. In addition, new diagnostic characters or distributional data for Ruspolia differens (Serville, 1838), Thyridorhoptrum senegalense Krauss, 1877, Horatosphaga leggei (Kirby, 1909), Horatosphaga linearis (Rehn, 1910), Preussia lobatipes Karsch, 1890 and Dapanera eidmanni Ebner, 1943 are reported. Finally, Symmetropleura plana (Walker, 1869) is proposed to be transferred to the genus Symmetrokarschia Massa, 2015, Conocephalus carbonarius (Redtenbacher, 1891) to the genus Thyridorhoptrum Rehn & Hebard, 1915; the genus Gonatoxia Karsch, 1889 is proposed to be synonymized with Dapanera Karsch, 1889. PMID- 26478705 TI - A new species of Mollitrichosiphum Suenaga from Taiwan Island (Hemiptera, Aphididae), based on morphological characteristics and DNA sequences. AB - A new species of Mollitrichosiphum Suenaga, Mollitrichosiphum tumorisiphum Qiao & Jiang, sp. n., from Fagus longipetiolata in Taiwan island is described. Siphunculi of Mollitrichosiphum tumorisiphum in alatae are distinctly swollen on the distal part, unlike those of the other known species in the genus. Updated keys to apterous and alate viviparous females of all known Chinese species of Mollitrichosiphum are provided. The specimens studied are deposited in the National Zoological Museum of China, Institute of Zoology, Chinese Academy of Sciences, Beijing, China and the Natural History Museum, London, United Kingdom. PMID- 26478706 TI - Immatures of the New World treehopper tribe Amastrini (Hemiptera, Membracidae, Smiliinae) with a key to genera. AB - The immatures stages of 8 of the 11 genera (Amastris Stal, Bajulata Ball, Erosne Stal, Harmonides Kirkaldy, Idioderma Van Duzee, Neotynelia Creao-Duarte & Sakakibara, Tynelia Stal, and Vanduzea Goding) of the tribe Amastrini are described for the first time along with brief diagnoses of Membracidae and the subfamily Smiliinae. A key to genera and notes on biology are provided. Multiple species of most genera are illustrated. Based on its distinct nymphal morphology, Vanduzea laeta nolina Ball is elevated to specific rank as Vanduzea nolina stat. n., and Bajulata, despite the superficial similarity of its adults to those of Vanduzea, is confirmed as warranting generic rank based on its unique nymphal morphology. Colombia is a new country record for Tynelia. PMID- 26478707 TI - Pseudofornicia gen. n. (Hymenoptera, Braconidae, Microgastrinae), a new Indo Australian genus and one new species from Vietnam. AB - Pseudofornicia gen. n. (Hymenoptera: Braconidae: Microgastrinae) is described (type species: Pseudofornicia nigrisoma sp. n. from Vietnam) including three Oriental (type species, Pseudofornicia flavoabdominis (He & Chen, 1994), comb. n. and Pseudofornicia vanachterbergi Long, (nom. n. for Fornicia achterbergi Long, 2007; not Fornicia achterbergi Yang & Chen, 2006) and one Australian species (Pseudofornicia commoni (Austin & Dangerfield, 1992), comb. n.). Keys to genera with similar metasomal carapace and to species of the new genus are provided. The new genus shares the curved inner middle tibial spur, the comparatively small head, the median carina of the first metasomal tergite and the metasomal carapace with Fornicia Brulle, 1846, but has the first tergite movably joined to the second tergite and the third tergite 1.1-1.6 * as long as the second tergite medially and is flattened in lateral view. One of the included species is a primary homonym and is renamed in this paper. PMID- 26478708 TI - A review of Canadian and Alaskan species of the genera Clusiota Casey and Atheta Thomson, subgenus Microdota Mulsant & Rey (Coleoptera, Staphylinidae, Aleocharinae). AB - This paper treats 13 species of the subgenus Microdota Mulsant & Rey of Atheta Thomson and 3 species of the genus Clusiota Casey in Canada and Alaska. We report here 4 species new to science, and 3 new provincial records. The following species are new to science: Atheta (Microdota) curtipenis Klimaszewski & Webster, sp. n., Atheta (Microdota) formicaensis Klimaszewski & Webster, sp. n., Atheta (Microdota) macesi Klimaszewski & Webster, sp. n., and Clusiota grandipenis Klimaszewski & Webster, sp. n. The new provincial records are: Atheta (Microdota) pseudosubtilis Klimaszewski & Langor, new to AB, and Atheta (Microdota) subtilis (Scriba), an adventive Palaearctic species new to North America, first reported in LB and NB. The two Clusiota Casey species are reviewed, and their distribution is revised. A female Clusiota impressicollis was discovered in Ontario and is illustrated here for the first time. A key to all Canadian species of the subgenus Microdota and genus Clusiota are provided. Atheta (Microdota) holmbergi Bernhauer and Atheta (Microdota) alesi Klimaszewski & Brunke are transferred here to the subgenus Dimetrota Mulsant & Rey. PMID- 26478709 TI - The Register of Antarctic Marine Species (RAMS): a ten-year appraisal. AB - The Register of Antarctic Marine Species (RAMS) is a marine species database that manages an authoritative taxonomic list of species occurring in the Southern Ocean. RAMS links with several other initiatives managing biogeographic or genomics information. The current paper aims to briefly present RAMS and provides an updated snapshot of its contents, in the form of a DarwinCore checklist (available through http://ipt.biodiversity.aq/resource.do?r=rams) and illustrative barplots. Moreover, this article presents a ten year appraisal (since the creation of RAMS). This appraisal first focuses on RAMS bibliometrics. We observed that RAMS was cited (Google Scholar) in 50 distinct publications among which 32 were peer-reviewed in 18 different journals. Three journals (Antarctic Science, Polar Biology, ZooKeys) represent almost 40% of these peer review publications. The second appraisal focuses on the evolution of new RAMS records. We observed an important decrease in data additions since 2011. As a case study, we focused on an original dataset for a specific group (Asteroidea, Echinodermata). It appears that around one hundred species of asteroids are lacking in RAMS despite the relatively high availability of these data. This suggests that the users' community (or collaborative projects such as AquaRES) could be helpful in order to maintain the RAMS database over the long term. PMID- 26478710 TI - The wealth, health and wellbeing of Ireland's older people before and during the economic crisis. AB - The economic crisis of 2008/9 was felt more acutely in Ireland relative to elsewhere and culminated in the international bailout in 2010. Given the economic collapse, Ireland provides an ideal case-study of the link between wealth collapses and movements in variables such as health and well-being. Using nationally-representative samples of older people collected before and during the crisis, we show that mean net assets fell by 45 percent between 2006/7 and 2012/13. In spite of this massive fall in wealth, measures of health and well being remained broadly unchanged. However, expectations about future living standards became less optimistic. The results tend to support the findings of other recent studies that recessions do not have widespread negative effects on health and well-being. PMID- 26478711 TI - Chess players' fame versus their merit. AB - We investigate a pool of international chess title holders born between 1901 and 1943. Using Elo ratings, we compute for every player his expected score in a game with a randomly selected player from the pool. We use this figure as the player's merit. We measure players' fame as the number of Google hits. The correlation between fame and merit is 0.38. At the same time, the correlation between the logarithm of fame and merit is 0.61. This suggests that fame grows exponentially with merit. PMID- 26478712 TI - In vitro and in vivo toxicity of urban and rural particulate matter from California. AB - Particulate matter (PM) varies in chemical composition and mass concentration based on location, source, and particle size. This study sought to evaluate the in vitro and in vivo toxicity of coarse (PM10-2.5) and fine (PM25) PM samples collected at 5 diverse sites within California. Coarse and fine PM samples were collected simultaneously at 2 rural and 3 urban sites within California during the summer. A human pulmonary microvascular endothelial cell line (HPMEC-ST1.6R) was exposed to PM suspensions (50 MUg/mL) and analyzed for reactive oxygen species (ROS) after 5 hours of treatment. In addition, FVB/N mice were exposed by oropharyngeal aspiration to 50 MUg PM, and lavage fluid was collected 24 hrs post exposure and analyzed for total protein and %PMNs. Correlations between trace metal concentrations, endotoxin, and biological endpoints were calculated, and the effect of particle size range, locale (urban vs. rural), and location was determined. Absolute principal factor analysis was used to identify pollution sources of PM from elemental tracers of those sources. Ambient PM elicited an ROS and pro-inflammatory-related response in the cell and mouse models, respectively. These responses were dependent on particle size, locale, and location. Trace elements associated with soil and traffic markers were most strongly linked to the adverse effects in vitro and in vivo. Particle size, location, source, and composition of PM collected at 5 locations in California affected the ROS response in human pulmonary endothelial cells and the inflammatory response in mice. PMID- 26478713 TI - Anomalous segregation dynamics of self-propelled particles. AB - A number of novel experimental and theoretical results have recently been obtained on active soft matter, demonstrating the various interesting universal and anomalous features of this kind of driven systems. Here we consider the adhesion difference-driven segregation of actively moving units, a fundamental but still poorly explored aspect of collective motility. In particular, we propose a model in which particles have a tendency to adhere through a mechanism which makes them both stay in touch and synchronize their direction of motion - but the interaction is limited to particles of the same kind. The calculations corresponding to the related differential equations can be made in parallel, thus a powerful GPU card allows large scale simulations. We find that in a very large system of particles, interacting without explicit alignment rule, three basic segregation regimes seem to exist as a function of time: i) at the beginning the time dependence of the correlation length is analogous to that predicted by the Cahn-Hillard theory, ii) next rapid segregation occurs characterized with a separation of the different kinds of units being faster than any previously suggested speed, finally, iii) the growth of the characteristic sizes in the system slows down due to a new regime in which self-confined, rotating, splitting and re-joining clusters appear. Our results can explain recent observations of segregating tissue cells in vitro. PMID- 26478714 TI - Distribution of the Height of Local Maxima of Gaussian Random Fields. AB - Let {f(t) : t ? T} be a smooth Gaussian random field over a parameter space T, where T may be a subset of Euclidean space or, more generally, a Riemannian manifold. We provide a general formula for the distribution of the height of a local maximum [Formula: see text] is a local maximum of f(t)} when f is non stationary. Moreover, we establish asymptotic approximations for the overshoot distribution of a local maximum [Formula: see text] is a local maximum of f(t) and f(t0) > v} as v -> infinity. Assuming further that f is isotropic, we apply techniques from random matrix theory related to the Gaussian orthogonal ensemble to compute such conditional probabilities explicitly when T is Euclidean or a sphere of arbitrary dimension. Such calculations are motivated by the statistical problem of detecting peaks in the presence of smooth Gaussian noise. PMID- 26478715 TI - Location in ASL: Insights from phonetic variation. AB - Recent work on location variation led us to investigate whether phonetic effects influence the lowering of certain forehead located signs in American Sign Language. We found that signing speed and the location of adjacent signs did affect these forehead signs in ways that conform to general principals of coarticulation. In this paper, we use those results as a basis to illustrate additional approaches to the evaluation of the phonetics of location. In particular, we suggest that finer grained analyses of location values may provide insights into directionality of coarticulatory effects, that changes in body posture assist in the achievement of location values, and that kinematic data can be used to describe the use of the signing space in a global sense. Previous work in sign phonetics has provided a solid foundation and new research is progressing well, but there is much work yet to be done. PMID- 26478716 TI - Effect of Carbon Nanotubes Upon Emissions From Cutting and Sanding Carbon Fiber Epoxy Composites. AB - Carbon nanotubes (CNTs) are being incorporated into structural composites to enhance material strength. During fabrication or repair activities, machining nanocomposites may release CNTs into the workplace air. An experimental study was conducted to evaluate the emissions generated by cutting and sanding on three types of epoxy-composite panels: Panel A containing graphite fibers, Panel B containing graphite fibers and carbon-based mat, and Panel C containing graphite fibers, carbon-based mat, and multi-walled CNTs. Aerosol sampling was conducted with direct-reading instruments, and filter samples were collected for measuring elemental carbon (EC) and fiber concentrations. Our study results showed that cutting Panel C with a band saw did not generate detectable emissions of fibers inspected by transmission electron microscopy but did increase the particle mass, number, and EC emission concentrations by 20% to 80% compared to Panels A and B. Sanding operation performed on two Panel C resulted in fiber emission rates of 1.9*108 and 2.8*106 fibers per second (f/s), while no free aerosol fibers were detected from sanding Panels A and B containing no CNTs. These free CNT fibers may be a health concern. However, the analysis of particle and EC concentrations from these same samples cannot clearly indicate the presence of CNTs, because extraneous aerosol generation from machining the composite epoxy material increased the mass concentrations of the EC. PMID- 26478717 TI - Knowledge and skills needed to improve as preceptor: development of a continuous professional development course - a qualitative study part I. AB - BACKGROUND: Preceptors are expected to have the skills to be able to form an effective learning environment and facilitate a constructive clinical learning experience for students and new employees. Internationally, access to education for preceptors varies, with preceptors worldwide requesting more education in preceptorship. This article is based on a two-part study focusing on both the development and evaluation of a continuous, credit-bearing professional development course. The aim of this part of the study was to investigate and include preceptors' requests and educational needs when developing a continuous professional development course on an advanced level. METHODS: This study used a qualitative research approach. In total, 64 preceptors (62 women and two men) answered one single written, self-administered global question online. The participants were all interested in teaching and had completed an undergraduate training in preceptorship. The collected data was analysed by content analysis inspired by Burnard's description of the method. RESULTS: The participating preceptors illuminated two main themes: 'Tools for effective precepting of students and healthcare professionals' and 'in-depth knowledge and understanding of preceptorship in an academic setting'. The results suggest that vital components for preceptor preparation could be a) teaching and learning strategies, b) reflective and critical reasoning, c) communication models, d) the role of the preceptor, and e) preceptorship. CONCLUSION: Using the results from this study as a guide, a continuous professional development course was designed to assist preceptors in deepening their knowledge of preceptorship in regard to planning, leading and implementing educational activities directed at students, healthcare professionals, patients and their families. The course content focuses on skills needed for preceptorship and is based on adult learning principles. A continuous, credit-bearing professional development course must include an exam by which participants are formally assessed and graded; therefore, a written assignment was included as part of the course. PMID- 26478718 TI - The pluripotency factor LIN28B is involved in oral carcinogenesis and associates with tumor aggressiveness and unfavorable prognosis. AB - OBJECTIVE: LIN28B is a conserved RNA-binding protein critically involved in development, cellular metabolism and tumorigenesis. It is frequently overexpressed in human cancers and correlates with tumor aggressiveness as well as unfavorable prognosis. However, the expression pattern and oncogenic roles of LIN28B during oral squamous cell carcinoma (OSCC) development and progression has not been well established yet. Here, we sought to determine the expression of LIN28B and its clinical significance using chemical-induced OSCC animal model, cell lines and primary specimens. METHOD: The OSCC animal model was induced using 7,12-dimethyl-1,2-bezan-tracene (DMBA) painting in the hamster buccal pouch. Buccal lesions from animals were obtained from different time points and subjected to routine histological analyses and immunohistochemical staining of LIN28B. The mRNA, protein abundance and subcellular localization of LIN28B was determined in a panel of OSCC cell lines by real-time RT-PCR, western blot and immunofluorescence. The expression levels of LIN28B in human primary OSCC samples were further evaluated by immunohistochemical staining. Moreover, the relationship between LIN28B and several clinicopathological parameters as well as patients' prognosis were also assessed. RESULTS: Our results revealed that negative or low LIN28B expression was commonly observed in normal epithelial, whereas more LIN28B abundance was identified in epithelial dysplasia and invasive SCC in the DMBA-induced OSCC animal model. Overexpression of LIN28B was identified in a major fraction of OSCC samples(39/58) and significantly associated with tumor size (P = 0.049) and advanced clinical stages (P = 0.0286). Patients with increased LIN28B had markedly reduced overall survival as compared to those with low LIN28B. Multivariate survival analyses further indicated that LIN28B abundance served as an independent prognostic factor for patients' overall survival. CONCLUSIONS: Our findings reveal that LIN28B is critically involved in OSCC initiation and progression and aberrantly overexpressed in human OSCC. It might represent a novel diagnostic and prognostic biomarker for oral cancer. PMID- 26478719 TI - Effects of Looking Behavior on Listening and Understanding in a Simulated Classroom. AB - Audiovisual cues can improve speech perception in adverse acoustical environments when compared to auditory cues alone. In classrooms, where acoustics often are less than ideal, the availability of visual cues has the potential to benefit children during learning activities. The current study evaluated the effects of looking behavior on speech understanding of children (8-11 years) and adults during comprehension and sentence repetition tasks in a simulated classroom environment. For the comprehension task, results revealed an effect of looking behavior (looking required versus looking not required) for older children and adults only. Within the looking-behavior conditions, age effects also were evident. There was no effect of looking behavior for the sentence-repetition task (looking versus no looking) but an age effect also was found. The current findings suggest that looking behavior may impact speech understanding differently depending on the task and the age of the listener. In classrooms, these potential differences should be taken into account when designing learning tasks. PMID- 26478720 TI - Contribution of Adolescence to the Life Course: What Matters Most in the Long Run? AB - Our wish is for more long-term longitudinal studies specifically designed to demonstrate the importance of adolescence in the life course. Specifically, we wish for our science to document as rigorously as possible the individual and contextual characteristics and experiences that matter the most during adolescence for long-term adult health and well-being. Recent research has shown the early childhood effects on adult outcomes, including effects from intervention programs, bringing needed scientific evidence to inform social policy about the importance of optimizing early development. In most of these efforts, there is little emphasis on adolescence, and thus there is little understanding about the effects of adolescence over and above the effects of childhood on adult outcomes. Our view is that adolescence matters a great deal for long-term health and well-being and we summarize what it will take to make our wish come true. PMID- 26478721 TI - SOCIO-EMOTIONAL AND CHARACTER DEVELOPMENT: A Theoretical Orientation. AB - More and more researchers are studying socio-emotional and character development (SECD). The rise and progress in SECD research is encouraging, but there is a critical issue with such a multidisciplinary and fast-developing field: SECD research and evaluation can be more consistent to prevent heterogeneity in definitions and disparate theoretical, measurement, and program models. After summarizing SECD-related literature, I recommend the theory of triadic influence (TTI) as a force to generate consistency and a resource to assist in guiding the design and evaluation of SECD-related programs. The theory fills a gulf in the literature that seeks an ecological theory aligned with SECD-related programs and etiology. The recommendation of the TTI stems from 3 main advantages: (1) The TTI integrates a full range of risk and protective factors in a detailed mediation and moderation framework; (2) it takes a comprehensive view of all the stakeholders in the educational system (i.e., youth, schools, families, and communities); (3) and its utility has been substantiated by empirical evidence from a variety of fields. I discuss applications of the TTI in SECD-related work and suggest improvements for etiology research and the design and evaluation of SECD programs. PMID- 26478723 TI - Metabolic responses induced by DNA damage and poly (ADP-ribose) polymerase (PARP) inhibition in MCF-7 cells. AB - Genomic instability is one of the hallmarks of cancer. Several chemotherapeutic drugs and radiotherapy induce DNA damage to prevent cancer cell replication. Cells in turn activate different DNA damage response (DDR) pathways to either repair the damage or induce cell death. These DDR pathways also elicit metabolic alterations which can play a significant role in the proper functioning of the cells. The understanding of these metabolic effects resulting from different types of DNA damage and repair mechanisms is currently lacking. In this study, we used NMR metabolomics to identify metabolic pathways which are altered in response to different DNA damaging agents. By comparing the metabolic responses in MCF-7 cells, we identified the activation of poly (ADP-ribose) polymerase (PARP) in methyl methanesulfonate (MMS)-induced DNA damage. PARP activation led to a significant depletion of NAD+. PARP inhibition using veliparib (ABT-888) was able to successfully restore the NAD+ levels in MMS-treated cells. In addition, double strand break induction by MMS and veliparib exhibited similar metabolic responses as zeocin, suggesting an application of metabolomics to classify the types of DNA damage responses. This prediction was validated by studying the metabolic responses elicited by radiation. Our findings indicate that cancer cell metabolic responses depend on the type of DNA damage responses and can also be used to classify the type of DNA damage. PMID- 26478724 TI - Detecting Sudden Gains during Treatment of Major Depressive Disorder: Cautions from a Monte Carlo Analysis. AB - Sudden gains are relatively large, quick, stable drops in symptom scores during treatment of depression that may (or may not) signal important therapeutic events. We review what is known and unknown currently about the prevalence, causes, and outcomes of sudden gains. We argue that valid identification of sudden gains (vs. random fluctuations in symptoms and gradual gains) is prerequisite to their understanding. In Monte Carlo simulations, three popular criterion sets showed inadequate power to detect sudden gains and many false positives due to (a) testing multiple intervals for sudden gains, (b) finite retest reliability of symptom measures, and (c) failure to account for gradual gains. Sudden gains in published clinical datasets appear similar in form and frequency to false positives in the simulations. We discuss the need to develop psychometrically sound methods to detect sudden gains and to differentiate sudden from random and gradual gains. PMID- 26478722 TI - Energy Minimization on Manifolds for Docking Flexible Molecules. AB - In this paper, we extend a recently introduced rigid body minimization algorithm, defined on manifolds, to the problem of minimizing the energy of interacting flexible molecules. The goal is to integrate moving the ligand in six dimensional rotational/translational space with internal rotations around rotatable bonds within the two molecules. We show that adding rotational degrees of freedom to the rigid moves of the ligand results in an overall optimization search space that is a manifold to which our manifold optimization approach can be extended. The effectiveness of the method is shown for three different docking problems of increasing complexity. First, we minimize the energy of fragment-size ligands with a single rotatable bond as part of a protein mapping method developed for the identification of binding hot spots. Second, we consider energy minimization for docking a flexible ligand to a rigid protein receptor, an approach frequently used in existing methods. In the third problem, we account for flexibility in both the ligand and the receptor. Results show that minimization using the manifold optimization algorithm is substantially more efficient than minimization using a traditional all-atom optimization algorithm while producing solutions of comparable quality. In addition to the specific problems considered, the method is general enough to be used in a large class of applications such as docking multidomain proteins with flexible hinges. The code is available under open source license (at http://cluspro.bu.edu/Code/Code_Rigtree.tar) and with minimal effort can be incorporated into any molecular modeling package. PMID- 26478726 TI - Hereditary xanthinuria and urolithiasis in a domestic shorthair cat. AB - A 2-year-old domestic shorthair cat was presented with a history of hematuria, stranguria and intermittent urethral obstruction. Urine sediment showed hematuria, pyuria, and yellow-brown, amorphous and spherical crystals. Upon surgical correction of the obstructed urethra by perineal urethrostomy, many dark yellow to grey, irregular, gravel-like to millet grain-sized uroliths, consisting of 100% xanthine by crystallography were found. The urinary xanthine concentration was high. The cat subsequently developed bilateral nephroliths, recurrent urinary tract infection, and chronic kidney failure. Dietary management with a low-purine diet failed in part due to poor compliance, and the cat was euthanized at 6 years of age. Xanthinuria is rare inborn error of metabolism in cats and other species but should be considered as a differential diagnosis in cases of feline urolithiasis. No associated molecular genetic defect has been elucidated, and management of these cases is difficult. In the absence of calculi for analysis, measuring urinary xanthine concentration can help in diagnosing this metabolic defect. PMID- 26478727 TI - Influence of Human Pressure on Forest Resources and Productivity at Stand and Tree Scales: The Case Study of Yunnan Pine in SW China. AB - This paper examines human impact on stands and individual trees of Pinus yunnanensis growing near the small mountain villages of Pianshui and Yangjuan in southwestern Sichuan Province, China. In an effort to assess whether use of these forests was sustainable, we examined the effects of human use in two ways. First, we directly measured the effect of cutting branches, for fuel and fodder, on tree growth. We hypothesized that branch cutting would negatively impact tree growth. We established 12 plots on four hills and compared 14 pairs of trees, one tree in each pair with an apparently full crown and the other with a considerable portion of the crown removed. Second, we assessed stand and tree properties over a 500 m elevation gradient above the villages where we hypothesized that as elevation increases, stand and tree properties should show fewer human impacts. Although extensive branch cutting reduced the live crown, tree height and diameter, compensatory processes likely enabled trees to recover and to add basal area increments (BAIs) similar to those added by trees with full crowns. Trees and stands close to villages showed less growth and lower basal areas, respectively, than stands and trees at intermediate or distant elevations from villages. Areas relatively close to the villages showed considerable effects of human-related disturbances such as branch cutting, grazing, tree and shrub removal, losses of litter, and human and animal trails. Such areas had increased soil erosion and often loss of the 'A' horizon. Stands close to villages had younger trees, lower stand basal areas, smaller basal area increments, and more stumps. Our results suggest an increasingly vulnerable interface between occupants of these two villages and their surrounding forests. PMID- 26478725 TI - Treatment of Insomnia, Insomnia Symptoms, and Obstructive Sleep Apnea During and After Menopause: Therapeutic Approaches. AB - Understanding sleep complaints among menopausal women is an emerging area of clinical and research interest. Several recent reviews have focused on mechanisms of menopausal insomnia and symptoms. In this review, we present a discussion on the most relevant and recent publications on the treatment of sleep disorders for menopausal women, with a focus on menopause-related insomnia, insomnia symptoms, and obstructive sleep apnea. We discuss both nonpharmacological and pharmacological treatments, including cognitive-behavioral therapy for insomnia (CBT-I), complementary and alternative medicine, hormone replacement therapy, sedative hypnotics, antidepressants, and continuous positive airway pressure. In addition, we briefly discuss methods and considerations of assessment of sleep disorders in menopausal women. PMID- 26478728 TI - The effects of occupational noise on blood pressure and heart rate of workers in an automotive parts industry. AB - BACKGROUND: One of the most important impacts of industrial noise is physiological and psychological effects. The increases in workers' blood pressure and heart rate were detected during and after exposure to high levels of noise. The objectives of this research were to determine whether the noise exposures have any effects on blood pressure and heart rate of workers in the automotive parts industry. METHODS: This case study was done in 2011 at different units of an automotive parts manufacturing in Tehran. Sound pressure level was measured at different units of the factory with a calibrated instrument. Demographic features of workers were gathered with an appropriate questionnaire. Heart rate and blood pressure were measured twice in a day in the start time of work day (before exposure to noise) and middle shift hours (during exposure to noise) in the occupational physician office. For analyzing data, chi-square, independent sample t-test, paired t-test, and analysis of covariance (ANCOVA) were used. P < 0.050 was considered statistically significant. RESULTS: The average age of workers in the case and control groups was 35.71 +/- 8.10 and 33.40 +/- 10.41 years, respectively. There was no difference between the average age of case and control groups (P = 0.436). The results of ANCOVA revealed the significant differences between the mean changes of heart rate F (1, 37) = 26.68, P < 0.001, systolic blood pressure F (1, 37) = 21.70, P < 0.001, and diastolic blood pressure F (1, 37) = 26.20, P < 0.001 of workers in the case and control groups. CONCLUSION: Exposure to industrial noise may increase the heart rate of workers. Although rises in heart rate, systolic, and diastolic blood pressure of workers in the case group were observed after exposure to noise, the values of heart rate, systolic, and diastolic blood pressure were in the normal range. Further experimental investigations are needed to determine the relationships between these variables. PMID- 26478729 TI - Development and validation of cardiac patient competence questionnaire, Iranian version. AB - BACKGROUND: The aim was to translate and develop a patient competence (PC) questionnaire in the context of cardiology and test its validity and reliability. METHODS: In total, 148 cardiac patients who have inclusion criteria of the study were completed cardiac PC (CPC) questionnaire. Hospital Anxiety and Depression Scale and self-administered instrument European quality of life 5-dimensions were used to further validate the CPC questionnaire. The CPC was translated according to the recommended methodology for translating questionnaires, and psychometric properties including internal consistency, factor analysis, discriminant validity, construct validity, and concurrent criterion validity were tested. RESULTS: Five domains in problem-focused task including search for information, self-regulation, being assertive, independent decision-making, and looking for social services, and three domains in emotion-focused task including stress management, confronting the threat, and avoidance were obtained by factor analysis. The standardized Cronbach's alpha of all domains were statistically significant (P < 0.001) and internal consistency for all domains was acceptable. Significant intercorrelations of CPC domains also indicated good criterion validity. As there were no cross-loadings, the domains have demonstrated good construct validity and discriminant validity. CONCLUSION: The results of this study show that the Persian version of the CPC is a reliable and valid questionnaire. Although further improvement of this measure is clearly required, it suggests being a potential basis for investigating the determinants and health effects of CPC. PMID- 26478730 TI - Comparison of N-acetylcysteine, ascorbic acid, and normal saline effect in prevention of contrast-induced nephropathy. AB - BACKGROUND: Considering the crucial role of appropriate preventative strategies in reducing the rate of contrast-induced nephropathy (CIN) occurrence and its related morbidity and mortality, the effect of N-acetylcysteine (NAC), ascorbic acid (AA), and normal saline (NS) was investigated in the patient's undergone coronary angiography. METHODS: In this clinical trial, 120 patients scheduled for elective coronary angiography with serum creatinine (Cr) level > 1.5 mg/dl or glomerular filtration rate (GFR) >= 60 selected by convenience method. Selected patients were allocated in three treatment groups randomly to receive oral NAC (600 mg/twice daily) plus NS (100 ml/hour) (Group A), oral AA (250 mg/twice daily) plus NS (100 ml/hour) (Group B) and NS (100 ml/hour) (Group C), respectively. The occurrence of CIN was evaluated based on serum Cr and GFR in three studied groups, before and after angiography procedure. The analysis of variance and paired t-test were used for data analysis by SPSS. RESULTS: The serum Cr increased and GFR decreased significantly during the intervention in three groups (P < 0.010). However, the amounts of these changes were equal between groups (P > 0.050). CONCLUSION: The study showed that nor the addition of NAC neither the addition of AA to sodium chloride infusion has more beneficial effect than hydration with sodium chloride, in the prevention of CIN. PMID- 26478731 TI - Trends of 28 days case fatality rate after first acute myocardial infarction in Isfahan, Iran, from 2000 to 2009. AB - BACKGROUND: The purpose of the present study was the analysis of the trends in case fatality rate of acute myocardial infarction (AMI) in Isfahan, Iran. This analysis was performed based on gender, age groups, and type of AMI according to the International Classification of Diseases, version 10, during 2000-2009. METHODS: Disregarding the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA), this cohort study considered all AMI events registered between 2000 and 2009 in 13 hospitals in Isfahan. All patients were followed for 28 days. In order to assess the case fatality rate, the Kaplan-Meier analysis, and to compare survival rate, log-rank test were used. Using the Cox regression model, 28 days case fatality hazard ratio (HR) was calculated. RESULTS: In total, 12,900 patients with first AMI were entered into the study. Among them, 9307 (72.10%) were men and 3593 (27.90%) women. The mean age in all patients increased from 61.36 +/- 12.19 in 2000-2001 to 62.15 +/- 12.74 in 2008 2009, (P = 0.0070); in women, from 65.38 +/- 10.95 to 67.15 +/- 11.72 (P = 0.0200), and in men, from 59.75 +/- 12.29 to 59.84 +/- 12.54 (P = 0.0170),. In addition, the 28 days case fatality rate in 2000-2009 had a steady descending trend. Thus, it decreased from 11.20% in 2000-2001 to 07.90% in 2008-2009; in men, from 09.20% to 06.70%, and in women, from 16.10% to 10.90%. During the study, HR of case fatality rate in 2000-2001 declined; therefore, in 2002-2003, it was 0.93 [95% confidence interval (CI) = 0.77-1.11], in 2004-2005, 0.88 (95% CI = 0.73-1.04), in 2006-2007, 0.67 (95% CI = 0.56-0.82), and in 2008-2009, 0.69 (95% CI = 0.56-0.82). CONCLUSION: In Isfahan, a reduction was observable in the trend of case fatality rate in both genders and all age groups. Thus, there was a 29.46% reduction in case fatality rate (27.17% in men, 32.29% in women) during the study period. PMID- 26478733 TI - Left ventricular dysfunction: Neither a matter of atherosclerosis nor an anomalous originated right coronary artery from left anterior descending artery. AB - BACKGROUND: Abnormal separation of right coronary artery (RCA) from the left coronary system is an extremely rare variation among coronary artery anomalies. The compressions on the anomalous route of this artery may lead to arrhythmia, chest pain, or left ventricular dysfunction or may enhance formation of atherosclerotic plaques. CASE REPORT: Here, we have reported a patient presented with heart failure who had an anomalous atherosclerotic RCA originating from left anterior descending artery. Interestingly, neither the anomalous origin nor the atherosclerosis was the cause of the patient's problems and she suffered from a hypertensive cardiomyopathy. CONCLUSION: This reminds that encountering an anomaly should not solely be interpreted as the cause of cardiac disease. PMID- 26478732 TI - Herbs with anti-lipid effects and their interactions with statins as a chemical anti- hyperlipidemia group drugs: A systematic review. AB - BACKGROUND: The present systematic review aimed to express the clinical anti lipid effects of different types of herbs, as well as described studied interactions between herbal remedies and prescribed drugs for hyperlipidemic patients which were based on in vitro experiments, animal studies, and empirical clinical experiences. METHODS: For this systematic review, we explored 2183 published papers about herbal drugs interactions from November 1967 to August 2014, fulfilling eligibility criteria by searching in some databases such as Web of Science, Medline, Scopus, Embase, Cinahl, and the Cochrane database. The main keywords used for searching included: herbal medicine, herbs, statin, lipid, and herb-drug interaction. RESULTS: Among published articles about herb-drug interactions, 185 papers met the initial search criteria and among them, 92 papers were potentially retrievable including a description of 17 herbs and medicinal plants. In first step and by reviewing all published manuscripts on beneficial effects of herbs on serum lipids level, 17 herbs were described to be effective on lipid profile as lowering serum triglyceride, total cholesterol, low density lipoprotein cholesterol as well as increasing serum high-density lipoprotein level. Some herbs such as celery could even affect the hepatic triglyceride concentrations. The herbal reaction toward different types of statins is varied so that grapefruit or pomegranate was interacted with only some types of statins, but not with all statin types. In this context, administration of herbal materials can lead to decreased absorption of statins or decreased the plasma concentration of these drugs. CONCLUSION: Various types of herbs can potentially reduce serum lipid profile with the different pathways; however, the herb-drug interactions may decrease pharmacological therapeutic effects of anti hyperlipidemic drugs that should be considered when approved herbs are prescribed. PMID- 26478734 TI - Influence of nandrolone decanoate administration on serum lipids and liver enzymes in rats. AB - BACKGROUND: Anabolic-androgenic steroids have been associated with several side effects range. This experimental study was conducted to evaluate the effects of nandrolone decanoate (ND, an anabolic steroid) on lipid profile and liver enzymes in rats in Iran. METHODS: Forty adult male and female of Wistar strain rats were randomly assigned to four groups of 10 animals each: male control, female control, ND-male treated (15 mg/kg b.w./day), and ND-female treated (15 mg/kg b.w./day). Serum concentrations of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured in all studied groups. RESULTS: Treating rats with ND (case group) resulted in a significant elevation of TC (69.4 +/- 8.7), TG (101.6 +/- 32.9) and ALT (72.2 +/- 13.8) and significant reduction of LDL (6.4 +/- 2.6) and AST (138.7 +/- 19.4) as compared to control group in female rats. ND supplementation (case group) significantly increased TC (64.4 +/- 6.2), AST (255.0 +/- 32.0), and ALT (84.3 +/- 3.8) in comparison with the control group in male rats. CONCLUSION: Overall, our result indicated that the ND use can cause a negative effect on lipid profile and liver enzyme in rats. PMID- 26478735 TI - Effect of peroxisome proliferator-activated receptor gamma on inflammatory markers. PMID- 26478736 TI - Retracted: Pulmonary hypertension due to a pulmonary artery leiomyosarcoma: A case report. AB - [This retracts the article on p. 133 in vol. 10.]. PMID- 26478737 TI - Illustrative case studies in the return of exome and genome sequencing results. AB - Whole genome and exome sequencing tests are increasingly being ordered in clinical practice, creating a need for research exploring the return of results from these tests. A goal of the Clinical Sequencing and Exploratory Research (CSER) consortium is to gain experience with this process to develop best practice recommendations for offering exome and genome testing and returning results. Genetic counselors in the CSER consortium have an integral role in the return of results from these genomic sequencing tests and have gained valuable insight. We present seven emerging themes related to return of exome and genome sequencing results accompanied by case descriptions illustrating important lessons learned, counseling challenges specific to these tests and considerations for future research and practice. PMID- 26478739 TI - A whole-plant chamber system for parallel gas exchange measurements of Arabidopsis and other herbaceous species. AB - BACKGROUND: Photosynthetic assimilation of carbon is a defining feature of the plant kingdom. The fixation of large amounts of carbon dioxide supports the synthesis of carbohydrates, which make up the bulk of plant biomass. Exact measurements of carbon assimilation rates are therefore crucial due to their impact on the plants metabolism, growth and reproductive success. Commercially available single-leaf cuvettes allow the detailed analysis of many photosynthetic parameters, including gas exchange, of a selected leaf area. However, these cuvettes can be difficult to use with small herbaceous plants such as Arabidopsis thaliana or plants having delicate or textured leaves. Furthermore, data from single leaves can be difficult to scale-up for a plant shoot with a complex architecture and tissues in different physiological states. Therefore, we constructed a versatile system-EGES-1-to simultaneously measure gas exchange in the whole shoots of multiple individual plants. Our system was designed to be able record data continuously over several days. RESULTS: The EGES-1 system yielded comparable measurements for eight plants for up to 6 days in stable, physiologically realistic conditions. The chambers seals have negligible permeability to carbon dioxide and the system is designed so as to detect any bulk-flow air leaks. We show that the system can be used to monitor plant responses to changing environmental conditions, such as changes in illumination or stress treatments, and to compare plants with phenotypically severe mutations. By incorporating interchangeable lids, the system could be used to measure photosynthetic gas exchange in several genera such as Arabidopsis, Nicotiana, Pisum, Lotus and Mesembryanthemum. CONCLUSION: EGES-1 can be introduced into a variety of growth facilities and measure gas exchange in the shoots diverse plant species grown in different growth media. It is ideal for comparing photosynthetic carbon assimilation of wild-type and mutant plants and/or plants undergoing selected experimental treatments. The system can deliver valuable data for whole plant growth studies and help understanding mutant phenotypes. Overall, the EGES 1 is complementary to the readily-available single leaf systems that focus more on the photosynthetic process in within the leaf lamina. PMID- 26478738 TI - Genes associated with RSV lower respiratory tract infection and asthma: the application of genetic epidemiological methods to understand causality. AB - Infants with respiratory syncytial virus (RSV) lower respiratory tract infections (LRIs) are at increased risk for childhood asthma. The objectives of this article are to review the genes associated with both RSV LRI and asthma, review analytic approaches to assessing shared genetic risk and propose a future perspective on how these approaches can help us to understand the role of infant RSV infection as both an important risk factor for asthma and marker of shared genetic etiology between the two conditions. The review of shared genes and thus pathways associated with severity of response to RSV infection and asthma risk can help us to understand mechanisms of disease and ultimately propose new and novel targets for primary prevention of both diseases. PMID- 26478741 TI - Feasibility of 3-dimensional video-assisted thoracic surgery (3D-VATS) for pulmonary resection. AB - BACKGROUND: Two-dimensional video-assisted thoracic surgery (2D-VATS) has gained its position in daily practise. Although very useful, its two-dimensional view has its drawbacks when performing pulmonary resections. We report our first experience with 3-dimensional video-assisted surgery (3D-VATS). Advantages and differences with 2D-VATS and robotic surgery (RS) are discussed. METHODS: To evaluate feasibility, we scheduled patients for surgery by 3D-VATS who would normally be treated with 2D-VATS. The main difference of the equipment in 3D-VATS compared with former VATS equipment, is the flexible camera-tip (100-degrees) and the necessary 3D-glasses. RESULTS: Four patients were successfully operated for anatomic pulmonary resections. On-the-structure dissection was easily performed and with the flexible camera-tip, a perfect view can be obtained, with clear visualisation of important (hilar) structures. These features highly facilitate the surgeon in tissue preparation and recognition of the dissection planes. CONCLUSION: In our opinion, 3D-VATS is superior to 2D-VATS for performing anatomic pulmonary resection and we expect an improvement in terms of operation time and learning curve. Furthermore, it is a valuable alternative for RS at lower costs. PMID- 26478740 TI - Caustic ingestion management: world society of emergency surgery preliminary survey of expert opinion. AB - Caustic material ingestion injuries (CMI) are uncommon. Only 5,000 cases are reported in the United States each year and most acute care healthcare facilities admit only a few cases annually. Accordingly, no single institution can claim extensive experience, and management protocols are most probably based on either expert opinion or literature reports. In this study, we will attempt to review opinions and practices of representatives of the board members of the World Society of Emergency Surgery and compare them to the current literature. PMID- 26478742 TI - Investments in blood safety improve the availability of blood to underserved areas in a sub-Saharan African country. AB - BACKGROUND AND OBJECTIVES: Since 2004, several African countries, including Namibia, have received assistance from the U.S. President's Emergency Plan for AIDS Relief (PEPFAR). Gains have been documented in the safety and number of collected units in these countries, but the distribution of blood has not been described. MATERIALS AND METHODS: Nine years of data on blood requests and issues from Namibia were stratified by region to describe temporal and spatial changes in the number and type of blood components issued to Namibian healthcare facilities nationally. RESULTS: Between 2004 and 2007 (early years of PEPFAR support) and 2008-2011 (peak years of PEPFAR support), the average number of red cell units issued annually increased by 23.5% in seven densely populated but less developed regions in northern Namibia; by 30% in two regions with urban centres; and by 35.1% in four sparsely populated rural regions. CONCLUSION: Investments in blood safety and a policy decision to emphasize distribution of blood to underserved regions improved blood availability in remote rural areas and increased the proportion of units distributed as components. However, disparities persist in the distribution of blood between Namibia's urban and rural regions. PMID- 26478743 TI - Using water-solvent systems to estimate in vivo blood-tissue partition coefficients. AB - BACKGROUND: Blood-tissue partition coefficients indicate how a chemical will distribute throughout the body and are an important part of any pharmacokinetic study. They can be used to assess potential toxicological effects from exposure to chemicals and the efficacy of potential novel drugs designed to target certain organs or the central nervous system. In vivo measurement of blood-tissue partition coefficients is often complicated, time-consuming, and relatively expensive, so developing in vitro systems that approximate in vivo ones is desirable. We have determined such systems for tissues such as brain, muscle, liver, lung, kidney, heart, skin, and fat. RESULTS: Several good (p < 0.05) blood tissue partition coefficient models were developed using a single water-solvent system. These include blood-brain, blood-lung, blood-heart, blood-fat, blood skin, water-skin, and skin permeation. Many of these partition coefficients have multiple water-solvent systems that can be used as models. Several solvents methylcyclohexane, 1,9-decadiene, and 2,2,2-trifluoroethanol-were common to multiple models and thus a single measurement can be used to estimate multiple blood-tissue partition coefficients. A few blood-tissue systems require a combination of two water-solvent partition coefficient measurements to model well (p < 0.01), namely: blood-muscle: chloroform and dibutyl ether, blood-liver: N methyl-2-piperidone and ethanol/water (60:40) volume, and blood-kidney: DMSO and ethanol/water (20:80) volume. CONCLUSION: In vivo blood-tissue partition coefficients can be easily estimated through water-solvent partition coefficient measurements.Graphical abstract:Predicted blood-brain barrier partition coefficients coloured by measured log BB value. PMID- 26478744 TI - Improving transitions of care for complex pediatric trauma patients from inpatient rehabilitation to home: an observational pilot study. AB - BACKGROUND: Patients requiring inpatient pediatric rehabilitation following trauma or disabling illness often require complex care after hospital discharge. The patients and their families are at risk for loss of continuity of care and increased stress which can adversely affect functional and medical outcomes. This pilot study assesses the complexity of need and difficulty with obtaining services at the time of transition from inpatient to outpatient care for pediatric rehabilitation. Additionally we explored the intervention of a post discharge phone call from an experienced rehabilitation nurse to address any issues identified in this period. METHODS: A rehabilitation nurse made scripted post discharge phone calls to patients and families 1-2 weeks after discharge from inpatient pediatric rehabilitation inquiring about medical appointments, medications, therapies, adaptive equipment and transition back to school. Results were recorded by the nurse then analyzed and tabulated by a rehabilitation physician. RESULTS: Eighty two percent of patients had needs in 4-5 of the areas assessed as part of their discharge recommendations. Eighty four percent of those families contacted had difficulty with at least one area at discharge. In all cases of confusion or difficulty with the recommendations, the nurse was able to provide needed guidance to ameliorate the situation. CONCLUSIONS: This pilot study indicates that pediatric rehabilitation patient require complex care as they transition to an outpatient setting. There is significant confusion and families often have difficulty obtaining necessary care in an efficient and effective way during this transition. A post discharge phone call from an experienced rehabilitation nurse could address most of the issues that arise during the transition. This pilot study indicates a need for more investigation into interventions to improve the transition process for pediatric rehabilitation patients and suggests a post discharge phone call program could be useful intervention for pediatric rehabilitation patients and other patient populations requiring complex care such as polytrauma patients. PMID- 26478745 TI - Long contiguous stretches of homozygosity spanning shortly the imprinted loci are associated with intellectual disability, autism and/or epilepsy. AB - BACKGROUND: Long contiguous stretches of homozygosity (LCSH) (regions/runs of homozygosity) are repeatedly detected by single-nucleotide polymorphism (SNP) chromosomal microarrays. Providing important clues regarding parental relatedness (consanguinity), uniparental disomy, chromosomal recombination or rearrangements, LCSH are rarely considered as a possible epigenetic cause of neurodevelopmental disorders. Additionally, despite being relevant to imprinting, LCSH at imprinted loci have not been truly addressed in terms of pathogenicity. In this study, we examined LCSH in children with unexplained intellectual disability, autism, congenital malformations and/or epilepsy focusing on chromosomal regions which harbor imprinted disease genes. RESULTS: Out of 267 cases, 14 (5.2 %) were found to have LCSH at imprinted loci associated with a clinical outcome. There were 5 cases of LCSH at 15p11.2, 4 cases of LCSH at 7q31.2, 3 cases of LCSH at 11p15.5, and 2 cases of LCSH at 7q21.3. Apart from a case of LCSH at 7q31.33q32.3 (~4 Mb in size), all causative LCSH were 1-1.5 Mb in size. Clinically, these cases were characterized by a weak resemblance to corresponding imprinting diseases (i.e., Silver-Russell, Beckwith-Wiedemann, and Prader-Willi/Angelman syndromes), exhibiting distinctive intellectual disability, autistic behavior, developmental delay, seizures and/or facial dysmorphisms. Parental consanguinity was detected in 8 cases (3 %), and these cases did not exhibit LCSH at imprinted loci. CONCLUSIONS: This study demonstrates that shorter LCSH at chromosomes 7q21.3, 7q31.2, 11p15.5, and 15p11.2 occur with a frequency of about 5 % in the children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations appears to be the most common one among children with neurodevelopmental diseases. Finally, since LCSH less than 2.5-10 Mb in size are generally ignored in diagnostic SNP microarray studies, one can conclude that an important epigenetic cause of intellectual disability, autism or epilepsy is actually overlooked. PMID- 26478746 TI - Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro esophageal junctional carcinoma. AB - BACKGROUND: Clinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small. A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC. RESULTS: Dual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6). EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 %) tumours, with high polysomy in 22 (13.8 %) and amplification in 10 (6.3 %). Two independent operator scores for FISH positivity were 100 % concordant. EGFR FISH positive status was not associated with clinic-pathological features. EGFR amplification was associated with worse survival (HR = 2.64, 95 % CI 1.04 to 6.71, p = 0.03). CONCLUSION: Our FISH scoring system for EGFR in advanced EC identifies a significant subgroup (20.0 %) of FISH positive patients. EGFR amplification, which is found in 6.3 %, is associated with poor survival. It is not known if there is a role for EGFR targeted treatment in this subgroup of patients, however we are now utilising this EGFR FISH assay and scoring system in biopsies from clinical trials utilising anti-EGFR targeted therapies. PMID- 26478747 TI - Prediction of protein solvent accessibility using PSO-SVR with multiple sequence derived features and weighted sliding window scheme. AB - BACKGROUND: The prediction of solvent accessibility could provide valuable clues for analyzing protein structure and functions, such as protein 3-Dimensional structure and B-cell epitope prediction. To fully decipher the protein-protein interaction process, an initial but crucial step is to calculate the protein solvent accessibility, especially when the tertiary structure of the protein is unknown. Although some efforts have been put into the protein solvent accessibility prediction, the performance of existing methods is far from satisfaction. METHODS: In order to develop the high-accuracy model, we focus on some possible aspects concerning the prediction performance, including several sequence-derived features, a weighted sliding window scheme and the parameters optimization of machine learning approach. To address above issues, we take following strategies. Firstly, we explore various features which have been observed to be associated with the residue solvent accessibility. These discriminative features include protein evolutionary information, predicted protein secondary structure, native disorder, physicochemical propensities and several sequence-based structural descriptors of residues. Secondly, the different contributions of adjacent residues in sliding window are observed, thus a weighted sliding window scheme is proposed to differentiate the contributions of adjacent residues on the central residue. Thirdly, particle swarm optimization (PSO) is employed to search the global best parameters for the proposed predictor. RESULTS: Evaluated by 3-fold cross-validation, our method achieves the mean absolute error (MAE) of 14.1% and the person correlation coefficient (PCC) of 0.75 for our new-compiled dataset. When compared with the state-of-the-art prediction models in the two benchmark datasets, our method demonstrates better performance. Experimental results demonstrate that our PSAP achieves high performances and outperforms many existing predictors. A web server called PSAP is built and freely available at http://59.73.198.144:8088/SolventAccessibility/. PMID- 26478748 TI - Implementation of guidelines for metabolic syndrome control in kidney transplant recipients: results at a single center. AB - BACKGROUND: Cardiovascular disease is a leading cause of death among kidney transplant recipients. Metabolic syndrome increases the risk for cardiovascular events and decreases graft survival. Lately, guidelines for management of the metabolic syndrome, primarily hypertension, diabetes mellitus (DM) and hypercholesterolemia have dramatically changed in an attempt to decrease cardiovascular risks among kidney transplant recipients. In the present study we examined whether these guideline changes had impact on our management of post transplantation patients and the subsequent treatment outcomes for these diseases. METHODS: Data were obtained from kidney transplant clinic files from two follow-up (FU) periods-between 1994-1997 and between 2008-2011. Demographic data, monitoring and screening frequency for cardiovascular risk factors, immunosuppression regimen, treatment for hypertension, diabetes and hyperlipidemia, treatment outcomes and graft function changes were compared between the two follow-up periods. RESULTS: There was a significant increase in the percentage of patients undergoing transplantation due to renal failure secondary to diabetes and/or hypertension. Patient monitoring and screening during the second FU period were less frequent, but more targeted, reflecting changes in clinic routines. Blood pressure was better controlled in the second FU period (p < 0.01), as was hypercholesterolemia (p < 0.001). High fasting glucose levels were more prevalent among patients in the second group (p < 0.005), although more patients received treatment for DM (p < 0.001). Significantly, fewer patients experienced deterioration of kidney functions during the second FU period (p < 0.001). CONCLUSIONS: We found that guideline changes had impact on clinical practice, which translated to better control of the metabolic syndrome. DM control is challenging. Overall, stability of kidney function improved. PMID- 26478749 TI - Lymphangioleiomyomatosis. PMID- 26478750 TI - Perceiving the Black female body: Race and gender in police constructions of body weight. AB - Representations of Black women in United States popular culture and public discourse frequently depict them stereotypically as fat and in need of policing for moral failures. As well, research has shown that Black women are perceived and constructed as non-prototypical for their gender. Taken together, observers within a White dominant social frame could be said to have difficulty correctly seeing Black women's bodies and gender presentations. In this study we examined how Black women are seen in the context of New York City Police Department (NYPD) stops and searches (known as Stop & Frisk). We examined how officers categorized Black women's body weight; investigated whether stops took place in public or private space; and assessed the extent to which body weight brought additional sanctions (i.e., being frisked). We used publicly available datasets from the NYPD's Stop & Frisk program, in which stops numbering in the hundreds of thousands were recorded in yearly databases from 2003 to 2012. For each stop, officers record a number of attributes about the potential suspect and context, including race, gender, physique, date, and precinct. We conducted logistic regressions to model the odds of being categorized as heavy by race and gender, controlling for age, calculated BMI, location in a Black precinct, and season of the year. Results showed that across 10 years of data, Black women were more likely than White women to be labeled heavy. Black women were also much more likely than all other subgroups to be stopped inside rather than outside. Body size showed little association with stop locations or frisks. We interpret these findings as a reflection of Black women's positioning with regard to racial and gender representations and the disciplinary projects of the state. PMID- 26478751 TI - Estimation After a Group Sequential Trial. AB - Group sequential trials are one important instance of studies for which the sample size is not fixed a priori but rather takes one of a finite set of pre specified values, dependent on the observed data. Much work has been devoted to the inferential consequences of this design feature. Molenberghs et al (2012) and Milanzi et al (2012) reviewed and extended the existing literature, focusing on a collection of seemingly disparate, but related, settings, namely completely random sample sizes, group sequential studies with deterministic and random stopping rules, incomplete data, and random cluster sizes. They showed that the ordinary sample average is a viable option for estimation following a group sequential trial, for a wide class of stopping rules and for random outcomes with a distribution in the exponential family. Their results are somewhat surprising in the sense that the sample average is not optimal, and further, there does not exist an optimal, or even, unbiased linear estimator. However, the sample average is asymptotically unbiased, both conditionally upon the observed sample size as well as marginalized over it. By exploiting ignorability they showed that the sample average is the conventional maximum likelihood estimator. They also showed that a conditional maximum likelihood estimator is finite sample unbiased, but is less efficient than the sample average and has the larger mean squared error. Asymptotically, the sample average and the conditional maximum likelihood estimator are equivalent. This previous work is restricted, however, to the situation in which the the random sample size can take only two values, N = n or N = 2n. In this paper, we consider the more practically useful setting of sample sizes in a the finite set {n1, n2, ..., nL }. It is shown that the sample average is then a justifiable estimator , in the sense that it follows from joint likelihood estimation, and it is consistent and asymptotically unbiased. We also show why simulations can give the false impression of bias in the sample average when considered conditional upon the sample size. The consequence is that no corrections need to be made to estimators following sequential trials. When small sample bias is of concern, the conditional likelihood estimator provides a relatively straightforward modification to the sample average. Finally, it is shown that classical likelihood-based standard errors and confidence intervals can be applied, obviating the need for technical corrections. PMID- 26478752 TI - High levels of 5-hydroxymethylcytosine (5hmC) is an adverse predictor of biochemical recurrence after prostatectomy in ERG-negative prostate cancer. AB - BACKGROUND: Prostate cancer (PC) can be stratified into distinct molecular subtypes based on TMPRSS2-ERG gene fusion status, but its potential prognostic value remains controversial. Likewise, routine clinicopathological features cannot clearly distinguish aggressive from indolent tumors at the time of diagnosis; thus, new prognostic biomarkers are urgently needed. The DNA methylation variant 5-hydroxymethylcytosine (5hmC, an oxidized derivative of 5 methylcytosine) has recently emerged as a new diagnostic and/or prognostic biomarker candidate for several human malignancies. However, this remains to be systematically investigated for PC. In this study, we determined 5hmC levels in 311 PC (stratified by ERG status) and 228 adjacent non-malignant (NM) prostate tissue specimens by immunohistochemical analysis of a tissue microarray, representing a large radical prostatectomy (RP) cohort with long clinical follow up. We investigated possible correlations between 5hmC and routine clinicopathological variables and assessed the prognostic potential of 5hmC by Kaplan-Meier and uni- and multivariate Cox regression analyses in ERG+ (n = 178) vs. ERG- (n = 133) PCs using biochemical recurrence (BCR) as endpoint. RESULTS: We observed a borderline significant (p = 0.06) reduction in 5hmC levels in PC compared to NM tissue samples, which was explained by a highly significant (p < 0.001) loss of 5hmC in ERG- PCs. ERG status was not predictive of BCR in this cohort (p = 0.73), and no significant association was found between BCR and 5hmC levels in ERG+ PCs (p = 0.98). In contrast, high 5hmC immunoreactivity was a significant adverse predictor of BCR after RP in ERG- PCs, independent of Gleason score, pathological tumor stage, surgical margin status, and pre-operative prostate-specific antigen (PSA) level (hazard ratio (HR) (95 % confidence interval (CI)): 1.62 (1.15-2.28), p = 0.006). CONCLUSIONS: This is the first study to demonstrate a prognostic potential for 5hmC in PC. Our findings highlight the importance of ERG stratification in PC biomarker studies and suggest that epigenetic mechanisms involving 5hmC are important for the development and/or progression of ERG- PC. PMID- 26478753 TI - Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. AB - Epigenetic modulation of gene activity occurs in response to non-genetic factors such as body weight status, physical activity, dietary factors, and environmental toxins. In addition, each of these factors is thought to affect and be affected by the gut microbiome. A primary mechanism that links these various factors together in mediating control of gene expression is the production of metabolites that serve as critical cofactors and allosteric regulators of epigenetic processes. Here, we review the involvement of the gut microbiota and its interactions with dietary factors, many of which have known cellular bioactivity, focusing on particular epigenetic processes affected and the influence they have on human health and disease, particularly cancer and response to treatment. Advances in DNA sequencing have expanded the capacity for studying the microbiome. Combining this with rapidly improving techniques to measure the metabolome provides opportunities to understand complex relationships that may underlie the development and progression of cancer as well as treatment-related sequelae. Given broad reaching and fundamental biology, both at the cellular and organismal levels, we propose that interactive research programs, which utilize a wide range of mutually informative experimental model systems-each one optimally suited for answering particular questions-provide the best path forward for breaking ground on new knowledge and ultimately understanding the epigenetic significance of the gut microbiome and its response to dietary factors in cancer prevention and therapy. PMID- 26478754 TI - DNA methylation changes of whole blood cells in response to active smoking exposure in adults: a systematic review of DNA methylation studies. AB - Active smoking is a major preventable public health problem and an established critical factor for epigenetic modification. In this systematic review, we identified 17 studies addressing the association of active smoking exposure with methylation modifications in blood DNA, including 14 recent epigenome-wide association studies (EWASs) and 3 gene-specific methylation studies (GSMSs) on the gene regions identified by EWASs. Overall, 1460 smoking-associated CpG sites were identified in the EWASs, of which 62 sites were detected in multiple (>=3) studies. The three most frequently reported CpG sites (genes) in whole blood samples were cg05575921 (AHRR), cg03636183 (F2RL3), and cg19859270 (GPR15), followed by other loci within intergenic regions 2q37.1 and 6p21.33. These significant smoking-related genes were further assessed by specific methylation assays in three GSMSs and reflected not only current but also lifetime or long term exposure to active smoking. In conclusion, this review summarizes the evidences for the use of blood DNA methylation patterns as biomarkers of smoking exposure for research and clinical practice. In particular, it provides a reservoir for constructing a smoking exposure index score which could be used to more precisely quantify long-term smoking exposure and evaluate the risks of smoking-induced diseases. PMID- 26478755 TI - Roadside increments in PM10, NOx and NO2 concentrations observed over 2 months at a major highway in New Zealand. AB - Continuous and simultaneous observational particulate matter (measured as PM10), nitrogen dioxide (NO2) and oxides of nitrogen (NOx) data were captured at a kerbside site alongside a major highway in Auckland, New Zealand, and at a pair of setback sites within 250 m of the highway, day and night over 8 weeks. The three measurement sites were intended to allow emissions from the highway to be largely isolated from other sources. By filtering the data and subtracting upwind concentrations, the average roadside increment was calculated to be 1.8, 7.2 and 101.4 MUg m-3 for PM10, NO2 and NOx, respectively, relative to a predominantly upwind setback site, and -0.1, 9.4 and 98.5 MUg m-3 for PM10, NO2 and NOx, respectively, relative to a downwind setback site. The negative value for PM10 was attributed to local evening heating sources impacting the setback site. On days when peak 24 h PM10 concentrations were observed, the absolute kerbside increment was 2.1 MUg m-3. The absolute roadside 24 h average PM10 increment varied diurnally, peaking (on average) at 2.4 MUg m-3 during peak traffic hours. The largest observed 24-h average PM10 roadside increment was 6.9 MUg m-3 and exceeded 5 MUg m-3 on nine occasions. On each of these occasions, the daily mean wind speed was less than 2 m s-1. The diurnally averaged difference in NOx concentrations between the kerbside site and the setback sites clearly resembled the diurnal cycle in traffic volume, and peaked during the morning traffic peak at around 180 MUg m-3. Background NOx concentrations were slightly higher in our study compared to a similar study in Las Vegas but absolute roadside concentrations were higher. This may be consistent with higher NOx emission factors in Auckland, but differences in the precise distance of the monitor from the road lanes and differences in meteorology need to be considered. PMID- 26478756 TI - Attention-Deficit/Hyperactivity Disorder Symptom Profiles in Medication-Treated Adults Entering a Psychosocial Treatment Program. AB - BACKGROUND: Although medications are the most widely studied effective treatments for adults with attention-deficit/hyperactivity disorder (ADHD), patients treated with medications often have significant residual symptoms that may be amenable to psychosocial intervention. Few studies, however, report on the structure and severity of specific residual ADHD symptoms in adult patients who have been treated with medications. This information may be important in identifying the most important psychosocial treatment targets for medicated adults with ADHD with residual symptoms. OBJECTIVES: Identify which symptoms of ADHD are most frequent and severe for medication-treated adults. Identify meaningful factors underlying self-report and clinician ratings in this group. METHODS: Self-reported and clinician-rated ADHD symptom data from 105 adults in the community already receiving medication treatment who were entering cognitive behavioral therapy studies were examined. First, we examined the frequency and severity of each of the 18 ADHD symptoms that were present in the sample. Second, we conducted exploratory factor analyses of self-reported and clinician-rated ADHD symptoms to best describe the structure of residual symptoms in medication-treated adults, Lastly, we examined the association of the resulting factor scores with clinician rated global ADHD severity (Clinical Global Impressions) and functional impairment (Global Assessment of Functioning) scales to determine which factors relate to overall severity. RESULTS: The 2 most frequent (self-reported and clinician-rated) residual symptoms were disorganization (85%-88%) and distractibility (74%-83%). Exploratory factor analyses for both self-reported and clinician-rated data yielded a 3-factor model: (1) Hyperactivity/Restlessness, (2) Impulsivity/Poor Prospective Memory, and (3) Inattention. Using multiple regression, the Inattention factor from self-reported and clinician-rated data was most strongly, consistently, and uniquely related to clinician ratings of both illness severity and functioning. CONCLUSIONS: In this sample, disorganization and distractibility were the most frequent and clinically significant residual symptoms; therefore, these should be important targets in psychosocial treatments for this population. Scoring symptom rating scales in medication-treated adults with ADHD using Hyperactivity. Restlessness, Impulsivity/Poor Prospective Memory, and Inattention factors may be more informative with respect to evaluating psychosocial treatment outcome than overall scale scores alone. PMID- 26478757 TI - Measurement of ADAMTS13. AB - ADAMTS13, encoded on chromosome 9q34, is a member of the ADAMTS (a disintegrin and metalloprotease with thrombospondin type 1 motif) metalloprotease family, containing the common domain structure of (from the amino terminus) signal peptide, propeptide, reprolysin type metalloprotease, thrombospondin type 1 motif, cysteine-rich region, and spacer domain. ADAMTS13 cleaves von Willebrand factor (VWF) in a shear stress dependent manner. Deficiency of the enzyme causes the platelet aggregation of thrombotic thrombocytopenic purpura (TTP). Inhibitory antibodies of ADAMTS13 are detected in patients with acquired TTP, while homozygous or double heterozygous mutations of the ADAMTS13 gene cause the hereditary form of the disease 1. Targeting of the ADAMTS13 gene by recombinant technology has reproduced the phenotype of human TTP in ADAMTS13-null mice 2. Despite these advances, intense controversy and confusion persist regarding the role of ADAMTS13 assays in the diagnosis of TTP. This brief review highlights some of the contentious issues and proposes steps to improve the diagnostic value of ADAMTS13 assays. PMID- 26478758 TI - Metacognition in animals: Trends and challenges. AB - There is widespread agreement that metacognition is not demonstrated if alternative explanations account for putative meta-cognition data. However, there is less agreement on which studies are protected from alternative explanations. We have argued that existing experiments on uncertainty monitoring can be explained by low-level explanations without assuming metacognition (Crystal & Foote, 2009). The field would benefit from the development of accepted standards for what is required to produce a convincing example of metacognition in animals. PMID- 26478759 TI - Structure Activity Relationships (SARs) Using a Structurally Diverse Drug Database: Validating Success of Predictor Tools. AB - ADME/Tox (absorption, distribution, metabolism, elimination and toxicity) technology is traditionally associated as a tool in the drug discovery process which is often used to predict the efficiency of drug adsorption, distribution, metabolic pathways, and elimination. For the past four years we have been involved in an effort to evaluate readily available Food and Drug Administration (FDA) consumer drug profiles and pharmacological data. Portable Document Format (PDF) data from drug profiles available on the FDA Drug Information website were used to create a searchable FDA Consumer Drug Database(c) using Bio-Rad's KnowItAll(r) platform which includes ADME/Tox in silico predictors. 14 pertinent pharmaceutical and pharmacological properties were collected for 75 structurally diverse consumer prescription drugs, and for several drugs, not all properties were completely populated. The major objective of this investigation was to validate the platforms prediction models for plasma protein binding (PPB) and bioavailability (BIO). PMID- 26478760 TI - Particle Size Distribution in Aluminum Manufacturing Facilities. AB - As part of exposure assessment for an ongoing epidemiologic study of heart disease and fine particle exposures in aluminum industry, area particle samples were collected in production facilities to assess instrument reliability and particle size distribution at different process areas. Personal modular impactors (PMI) and Minimicro-orifice uniform deposition impactors (MiniMOUDI) were used. The coefficient of variation (CV) of co-located samples was used to evaluate the reproducibility of the samplers. PM2.5 measured by PMI was compared to PM2.5 calculated from MiniMOUDI data. Mass median aerodynamic diameter (MMAD) and concentrations of sub-micrometer (PM1.0) and quasi-ultrafine (PM0.56) particles were evaluated to characterize particle size distribution. Most of CVs were less than 30%. The slope of the linear regression of PMI_PM2.5 versus MiniMOUDI_PM2.5 was 1.03 mg/m3 per mg/m3 (+/- 0.05), with correlation coefficient of 0.97 (+/- 0.01). Particle size distribution varied substantively in smelters, whereas it was less variable in fabrication units with significantly smaller MMADs (arithmetic mean of MMADs: 2.59 MUm in smelters vs. 1.31 MUm in fabrication units, p = 0.001). Although the total particle concentration was more than two times higher in the smelters than in the fabrication units, the fraction of PM10 which was PM1.0 or PM0.56 was significantly lower in the smelters than in the fabrication units (p < 0.001). Consequently, the concentrations of sub-micrometer and quasi-ultrafine particles were similar in these two types of facilities. It would appear, studies evaluating ultrafine particle exposure in aluminum industry should focus on not only the smelters, but also the fabrication facilities. PMID- 26478761 TI - Promoting an Alcohol-free Childhood: A Novel Home-Based Parenting Program. PMID- 26478763 TI - Factors Influencing Care Decisions for Patients With Advanced Cancer. PMID- 26478762 TI - BAYESIAN GROUP LASSO FOR NONPARAMETRIC VARYING-COEFFICIENT MODELS WITH APPLICATION TO FUNCTIONAL GENOME-WIDE ASSOCIATION STUDIES. AB - Although genome-wide association studies (GWAS) have proven powerful for comprehending the genetic architecture of complex traits, they are challenged by a high dimension of single-nucleotide polymorphisms (SNPs) as predictors, the presence of complex environmental factors, and longitudinal or functional natures of many complex traits or diseases. To address these challenges, we propose a high-dimensional varying-coefficient model for incorporating functional aspects of phenotypic traits into GWAS to formulate a so-called functional GWAS or fGWAS. Bayesian group lasso and the associated MCMC algorithms are developed to identify significant SNPs and estimate how they affect longitudinal traits through time varying genetic actions. The model is generalized to analyze the genetic control of complex traits using subject-specific sparse longitudinal data. The statistical properties of the new model are investigated through simulation studies. We use the new model to analyze a real GWAS data set from the Framingham Heart Study, leading to the identification of several significant SNPs associated with age-specific changes of body mass index. The fGWAS model, equipped with Bayesian group lassso, will provide a useful tool for genetic and developmental analysis of complex traits or diseases. PMID- 26478764 TI - Reconsidering the logical structure of the theory of natural selection. AB - Natural selection has been criticized as a tautology. This would be a major problem for evolutionary biology, if true, because tautological statements can't be falsified and, therefore, can't be scientific. There is merit to this critique insofar as the theory of natural selection is indeed generally described in a tautological manner. However, natural selection can be described non tautologically if we're careful. Natural selection should be defined as the theory that attempts to predict and retrodict evolutionary change through environmental forces acting upon organisms. However, this re-framing comes at a cost: it reveals, based on our current knowledge of evolutionary forces, the lack of ability to make accurate predictions about expected changes except in the most simple of circumstances. I suggest that evolutionary biologists should work to develop "principles of evolution," based on an expanded and more focused research program designed to identify common trends in evolution, which will ultimately allow us to make more accurate predictions and retrodictions about evolution. PMID- 26478765 TI - MICAL-L1-related and unrelated mechanisms underlying elongated tubular endosomal network (ETEN) in human dendritic cells. AB - The endosomal pathway constitutes a highly dynamic intracellular transport system, which is composed of vesicular and tubular compartments. Endosomal tubules enable geometry-based discrimination between membrane and luminal content. Extended tubular endosomes were suggested to deliver a steady stream of membrane proteins to one location more reliable and effective than vesicular endosomes. Recently, we demonstrated that human dendritic cells (DCs) form a large elongated tubular endosomal network, e.g. ETEN, upon distinct triggers. LPS stimulation triggered late endosomal tubulation. Additional clustering of class I MHC and ICAM-1 by a cognate interaction between antigen-laden DC and antigen specific CD8(+) T-cells induces formation of transferrin-positive tubules emanating from the endosomal recycling compartment (ERC). We here discuss cell biological mechanisms that are involved in membrane bending and possibly underlie initiation, elongation, and stabilization of ETEN in human DCs. Using a knock down approach we demonstrate that MICAL-L1 is necessary for ETEN remodeling originating from ERC in human DCs. PMID- 26478766 TI - Evolutionary thinking: "A conversation with Carter Phipps about the role of evolutionary thinking in modern culture". AB - Evolution as an idea has a lengthy history, even though the idea of evolution is generally associated with Darwin today. Rebecca Stott provides an engaging and thoughtful overview of this history of evolutionary thinking in her 2013 book, Darwin's Ghosts: The Secret History of Evolution. Since Darwin, the debate over evolution-both how it takes place and, in a long war of words with religiously oriented thinkers, whether it takes place-has been sustained and heated. A growing share of this debate is now devoted to examining how evolutionary thinking affects areas outside of biology. How do our lives change when we recognize that all is in flux? What can we learn about life more generally if we study change instead of stasis? Carter Phipps' book, Evolutionaries: Unlocking the Spiritual and Cultural Potential of Science's Greatest Idea, delves deep into this relatively new development. Phipps generally takes as a given the validity of the Modern Synthesis of evolutionary biology. His story takes us into, as the subtitle suggests, the spiritual and cultural implications of evolutionary thinking. Can religion and evolution be reconciled? Can evolutionary thinking lead to a new type of spirituality? Is our culture already being changed in ways that we don't realize by evolutionary thinking? These are all important questions and Phipps book is a great introduction to this discussion. Phipps is an author, journalist, and contributor to the emerging "integral" or "evolutionary" cultural movement that combines the insights of Integral Philosophy, evolutionary science, developmental psychology, and the social sciences. He has served as the Executive Editor of EnlightenNext magazine (no longer published) and more recently is the co-founder of the Institute for Cultural Evolution, a public policy think tank addressing the cultural roots of America's political challenges. What follows is an email interview with Phipps. PMID- 26478767 TI - The genealogy of genealogy of neurons. AB - Two scenarios of neuronal evolution (monophyly and polyphyly) are discussed in the historical timeline starting from the 19th century. The recent genomic studies on Ctenophores re-initiated a broad interest in the hypotheses of independent origins of neurons. However, even earlier work on ctenophores suggested that their nervous systems are unique in many aspects of their organization and a possibility of the independent origin of neurons and synapses was introduced well before modern advances in genomic biology. PMID- 26478768 TI - Assembly of actin filaments and microtubules in Nwk F-BAR-induced membrane deformations. AB - F-BAR domains form crescent-shaped dimers that bind to and deform lipid bilayers, and play a role in many cellular processes requiring membrane remodeling, including endocytosis and cell morphogenesis. Nervous Wreck (NWK) encodes an F BAR/SH3 protein that regulates synapse growth in Drosophila. Unlike conventional F-BAR proteins that assemble tip-to-tip into filaments and helical arrays around membrane tubules, the Nwk F-BAR domain instead assembles into zigzags, creating ridges and periodic scallops on membranes in vitro. In cells, this membrane deforming activity generates small buds, which can lengthen into extensive protrusions upon actin cytoskeleton polymerization. Here, we show that Nwk induced cellular protrusions contain dynamic microtubules, distinguishing them from conventional filopodia, and further do not depend on actin filaments or microtubules for their maintenance. Our results indicate new ways in which close cooperation between the membrane remodeling and cytoskeletal machinery underlies large-scale changes in cellular morphology. PMID- 26478769 TI - In wild tobacco, Nicotiana attenuata, variation among bacterial communities of isogenic plants is mainly shaped by the local soil microbiota independently of the plants' capacity to produce jasmonic acid. AB - The phytohormone jasmonic acid (JA) plays a central role in defense against necrotrophic pathogens and herbivores in Nicotiana attenuata. Recently Santhanam et al.(1) showed that JA does not have a major role in shaping the root- and shoot associated bacterial communities, though a few taxa differed among control (empty vector, EV) plants and plants impaired in their capacity to produce JA (irAOC). In this addendum, we provide additional data showing that the composition of the plant bacterial communities is mainly shaped by tissue type. The qualitative data analysis revealed that at the order level, 5 bacterial OTUs formed a core community found in all tissues irrespective of genotypes, while 9 OTUs were different among roots and shoots. The heterogeneity among individual plants was high masking the potential genotype effect on bacterial communities. Using a culture-dependent approach, 3 of 18 bacterial taxa retrieved either only from one of the genotypes or from both had a growth promoting effect on EV and irAOC seedlings. The data suggest that the local soil niche in which the roots grows is a major driver of the variability in root bacterial communities recruited by different individuals, and the plant growth-promoting effects of some taxa are independent of the genotype. PMID- 26478770 TI - Subcellular neuronal quasicrystals: Implications for consciousness. AB - Neuron neurotransmitter receptors are in general pentameric. This enables them to form pentagonal components in biological quasicrystals (similar to mathematical aperiodic tilings). As quasicrystals have been proposed to require quantum effects to exist this might introduce such effects as a component of neurotransmission and thus consciousness. Microtubules may play a role in the clustering of the receptors into quasicrystals, thus modulating their function and may even form quasicrystals themselves. Other quaiscrystals in neurons are potentially formed by water, cholera toxin complexes, and the cytoskeletal components actin and ankyrin. PMID- 26478771 TI - The Microcosm within: An interview with William B. Miller, Jr., on the Extended Hologenome theory of evolution. AB - There is a singular unifying reality underlying every biologic interaction on our planet. In immunology, that which does not kill you makes you different. -William B. Miller, Jr. We are experiencing a revolution in our understanding of inner space on a par with our exponentially increasing understanding of outer space. In biology, we are learning that the genetic and epigenetic complexity within organisms is far deeper than suspected. This is a key theme in William B. Miller Jr.'s book, The Microcosm Within: Evolution and Extinction in the Hologenome. We are learning also that a focus on the human genome alone is misleading when it comes to who we really are as biological entities, and in terms of how we and other creatures have evolved. Rather than being defined by the human genome alone, we are instead defined by the "hologenome," the sum of the human genome and the far larger genetic endowment of the microbiome and symbiotic communities that reside within and around us. Miller is a medical doctor previously in private practice in Pennsylvania and Phoenix, Arizona. This book is his first foray into evolutionary theory. His book could have been titled "The Origin of Variation" because this is his primary focus. He accepts that natural selection plays a role in evolution, but he demotes this mechanism to a less important role than the Modern Synthesis suggests. His main gripe, however, concerns random variation. He argues that random variation is unable to explain the origin and evolution of biological forms that we see in the world around us and in the historical record. Miller suggests that, rather than random variation as the engine of novelty, there is a creative impulse at the heart of cellular life, and even at the level of the genetic aggregate, that generates novelty on a regular basis. I probe this assertion in the interview below. He also highlights the strong role of "exogenous genetic assault" in variation and in his immunological model of evolution. PMID- 26478772 TI - Why so many sperm cells? AB - A key limiting step in fertility is the search for the oocyte by spermatozoa. Initially, there are tens of millions of sperm cells, but a single one will make it to the oocyte. This may be one of the most severe selection processes designed by evolution, whose role is yet to be understood. Why such a huge redundancy is required and what does that mean for the search process? we discuss here these questions and consequently new lines of interdisciplinary research needed to find possible answers. PMID- 26478773 TI - Intranasal administration of oxytocin promotes social play in domestic dogs. AB - In a recent paper,(1) we examined whether oxytocin in the domestic dog modulates the maintenance of close social bonds in non-reproductive contexts. We found that exogenous oxytocin promotes positive social behaviors not only toward conspecifics, but also toward human partners. Here we examined in further detail the effect that oxytocin manipulation has on social play. When sprayed with oxytocin, subjects initiated play sessions more often and played for longer periods of time than when sprayed with saline. Furthermore, after oxytocin nasal intake dogs displayed play signals more often than after saline administration, suggesting that oxytocin enhances dogs' play motivation. To our knowledge, this study provides the first evidence that oxytocin promotes social play in the domestic dog. We use these results to hypothesize on the potential therapeutic use of oxytocin for promoting social behaviors and treating social deficits in the domestic dog. PMID- 26478774 TI - Bacterial microcompartment assembly: The key role of encapsulation peptides. AB - Bacterial microcompartments (BMCs) are proteinaceous organelles used by a broad range of bacteria to segregate and optimize metabolic reactions. Their functions are diverse, and can be divided into anabolic (carboxysome) and catabolic (metabolosomes) processes, depending on their cargo enzymes. The assembly pathway for the beta-carboxysome has been characterized, revealing that biogenesis proceeds from the inside out. The enzymes coalesce into a procarboxysome, followed by encapsulation in a protein shell that is recruited to the procarboxysome by a short (~17 amino acids) extension on the C-terminus of one of the encapsulated proteins. A similar extension is also found on the N- or C termini of a subset of metabolosome core enzymes. These encapsulation peptides (EPs) are characterized by a primary structure predicted to form an amphipathic alpha-helix that interacts with shell proteins. Here, we review the features, function and widespread occurrence of EPs among metabolosomes, and propose an expanded role for EPs in the assembly of diverse BMCs. PMID- 26478775 TI - Time-related expression profiles for heat shock protein gene transcripts (HSP40, HSP70) in the central nervous system of Lymnaea stagnalis exposed to thermal stress. AB - Organisms exposed to environmental stressors respond by rapidly synthesising a suite of highly conserved proteins called heat shock proteins (HSPs). Environmental stress can also enhance and/or block memory formation, with long term memory formation requiring gene activation and protein synthesis. Thermal stress in the pond snail Lymnaea stagnalis can enhance memory formation, and, in this study, the effect of thermal stress on HSP gene expression in the nervous system was investigated. Time-related expression profiles for HSP40 and HSP70 indicated rapid (<30 min) induction for both transcripts. For HSP40, induction was <20 fold relative to control and expression returned to control levels within 8 h, whereas HSP70 induction was >100 fold and expression did not return to control levels within 8 h. PMID- 26478776 TI - Can subcellular organization be explained only by physical principles? AB - In a recent forum article, Dan Needleman and Jan Brugues argue that, despite the astonishing advances in cell biology, a fundamental understanding of even the most well-studied subcellular biological processes is lacking.(1) This lack of understanding is evidenced by our inability to make precise predictions of subcellular and cellular behaviors. They suggest that to achieve such an understanding, we need to apply a combination of quantitative experiments with new theoretical concepts and determine the physical principles of subcellular biological organization.(1) We discuss these issues and suggest that, besides biophysics, we need strong theoretical inputs from biocommunication theory in order to understand all the core agents of the cellular life and subcellular organization. PMID- 26478777 TI - Investigating animal cognition with the Aesop's Fable paradigm: Current understanding and future directions. AB - The Aesop's Fable paradigm - in which subjects drop stones into tubes of water to obtain floating out-of-reach rewards - has been used to assess causal understanding in rooks, crows, jays and human children. To date, the performance of corvids suggests that they can recognize the functional properties of a variety of objects including size, weight and solidity, and they seem to be more capable of learning from causal information than arbitrary information. However, 2 alternative explanations for their performance have yet to be ruled out. The perceptual-motor feedback hypothesis suggests that subjects may attend solely to the movement of the reward, repeating actions which bring the reward closer, while the object-bias hypothesis suggests that subjects could pass certain tasks by preferring to handle objects that resemble natural stones. Here we review our current understanding of performance on the Aesop's Fable tasks, and suggest that studies controlling for feedback and object preferences will help us determine exactly what animals understand about the cause and effect of water displacement. PMID- 26478779 TI - A Charge Swap mutation E461K in the yeast dynamin Vps1 reduces endocytic invagination. AB - Vps1 is the yeast dynamin-like protein that functions during several membrane trafficking events including traffic from Golgi to vacuole, endosomal recycling and endocytosis. Vps1 can also function in peroxisomal fission indicating that its ability to drive membrane fission is relatively promiscuous. It has been of interest therefore that several mutations have been identified in Vps1 that only disrupt its endocytic function. Most recently, disruption of the interaction with actin through mutation of residues in one of the central stalk alpha helices (RR457,458 EE) has been shown to disrupt endocytosis and cause an accumulation of highly elongated invaginations in cells. This data supports the idea that an interaction between Vps1 and actin is important to drive the scission stage in endocytosis. Another Vps1 mutant generated in the study was vps1 E461K. Here we show data demonstrating that the E461K mutation also disrupts endocytosis but at an early stage, resulting in inhibition of the invagination step itself. PMID- 26478778 TI - The natural history of consciousness, and the question of whether plants are conscious, in relation to the Hameroff-Penrose quantum-physical 'Orch OR' theory of universal consciousness. PMID- 26478780 TI - Differences in color learning between pollen- and sucrose-rewarded bees. AB - What bees learn during pollen collection, and how they might discriminate between flowers on the basis of the quality of this reward, is not well understood. Recently we showed that bees learn to associate colors with differences in pollen rewards. Extending these findings, we present here additional evidence to suggest that the strength and time-course of memory formation may differ between pollen- and sucrose-rewarded bees. Color-naive honeybees, trained with pollen or sucrose rewards to discriminate colored stimuli, were found to differ in their responses when recalling learnt information after reversal training. Such differences could affect the decision-making and foraging dynamics of individual bees when collecting different types of floral rewards. PMID- 26478781 TI - Anchored PKA as a gatekeeper for gap junctions. AB - Anchored protein kinase A (PKA) bound to A Kinase Anchoring Protein (AKAP) mediates effects of localized increases in cAMP in defined subcellular microdomains and retains the specificity in cAMP-PKA signaling to distinct extracellular stimuli. Gap junctions are pores between adjacent cells constituted by connexin proteins that provide means of communication and transfer of small molecules. While the PKA signaling is known to promote human trophoblast cell fusion, the gap junction communication through connexin 43 (Cx43) is a prerequisite for this process. We recently demonstrated that trophoblast fusion is regulated by ezrin, a known AKAP, which binds to Cx43 and delivers PKA in the vicinity gap junctions. We found that disruption of the ezrin-Cx43 interaction abolished PKA-dependent phosphorylation of Cx43 as well as gap junction communication and subsequently cell fusion. We propose that the PKA-ezrin-Cx43 macromolecular complex regulating gap junction communication constitutes a general mechanism to control opening of Cx43 gap junctions by phosphorylation in response to cAMP signaling in various cell types. PMID- 26478782 TI - On the role of the plasmodial cytoskeleton in facilitating intelligent behavior in slime mold Physarum polycephalum. AB - The plasmodium of slime mold Physarum polycephalum behaves as an amorphous reaction-diffusion computing substrate and is capable of apparently 'intelligent' behavior. But how does intelligence emerge in an acellular organism? Through a range of laboratory experiments, we visualize the plasmodial cytoskeleton-a ubiquitous cellular protein scaffold whose functions are manifold and essential to life-and discuss its putative role as a network for transducing, transmitting and structuring data streams within the plasmodium. Through a range of computer modeling techniques, we demonstrate how emergent behavior, and hence computational intelligence, may occur in cytoskeletal communications networks. Specifically, we model the topology of both the actin and tubulin cytoskeletal networks and discuss how computation may occur therein. Furthermore, we present bespoke cellular automata and particle swarm models for the computational process within the cytoskeleton and observe the incidence of emergent patterns in both. Our work grants unique insight into the origins of natural intelligence; the results presented here are therefore readily transferable to the fields of natural computation, cell biology and biomedical science. We conclude by discussing how our results may alter our biological, computational and philosophical understanding of intelligence and consciousness. PMID- 26478783 TI - Cell-based inhibitor screening identifies multiple protein kinases important for circadian clock oscillations. AB - Molecular oscillation of the circadian clock is based on E-box-mediated transcriptional feedback loop formed with clock genes and their encoding products, clock proteins. The clock proteins are regulated by post-translational modifications such as phosphorylation. We investigated the effects of a series of kinase inhibitors on gene expression rhythms in Rat-1 fibroblasts. The period of the cellular circadian rhythm in culture was lengthened by treatment with SB203580 (p38 MAPK inhibitor), SP600125 (JNK inhibitor), IC261 (CKI inhibitor) and Roscovitine (CDK inhibitor). On the other hand, the period was shortened by SB216763 (GSK-3 inhibitor) or KN93 (CaMKII inhibitor) treatment. Application of 20 MUM KN93 completely abolished the rhythmic gene expression. The activity of CaMKII exhibited circadian variation in a phase close to the E-box-mediated transcriptional rhythms. In vitro kinase assay revealed that CaMKII directly phosphorylates N-terminal and Ser/Pro-rich domains of CLOCK, an activator of E box-mediated transcription. These results indicate a phosphorylation-dependent tuning of the period length by a regulatory network of multiple kinases and reveal an essential role of CaMKII in the cellular oscillation mechanism. PMID- 26478784 TI - Autopoiesis + extended cognition + nature = can buildings think? AB - To incorporate metabolic, bioremedial functions into the performance of buildings and to balance generative architecture's dominant focus on computational programming and digital fabrication, this text first discusses hybridizing Maturana and Varela's biological theory of autopoiesis with Andy Clark's hypothesis of extended cognition. Doing so establishes a procedural protocol to research biological domains from which design could source data/insight from biosemiotics, sensory plants, and biocomputation. I trace computation and botanic simulations back to Alan Turing's little-known 1950s Morphogenetic drawings, reaction-diffusion algorithms, and pioneering artificial intelligence (AI) in order to establish bioarchitecture's generative point of origin. I ask provocatively, Can buildings think? as a question echoing Turing's own, "Can machines think?" PMID- 26478785 TI - High-quality permanent draft genome sequence of the Lebeckia ambigua-nodulating Burkholderia sp. strain WSM4176. AB - Burkholderia sp. strain WSM4176 is an aerobic, motile, Gram-negative, non-spore forming rod that was isolated from an effective N2-fixing root nodule of Lebeckia ambigua collected in Nieuwoudtville, Western Cape of South Africa, in October 2007. This plant persists in infertile, acidic and deep sandy soils, and is therefore an ideal candidate for a perennial based agriculture system in Western Australia. Here we describe the features of Burkholderia sp. strain WSM4176, which represents a potential inoculant quality strain for L. ambigua, together with sequence and annotation. The 9,065,247 bp high-quality-draft genome is arranged in 13 scaffolds of 65 contigs, contains 8369 protein-coding genes and 128 RNA-only encoding genes, and is part of the GEBA-RNB project proposal (Project ID 882). PMID- 26478786 TI - High-quality permanent draft genome sequence of the Mimosa asperata - nodulating Cupriavidus sp. strain AMP6. AB - Cupriavidus sp. strain AMP6 is an aerobic, motile, Gram-negative, non-spore forming rod that was isolated from a root nodule of Mimosa asperata collected in Santa Ana National Wildlife Refuge, Texas, in 2005. Mimosa asperata is the only legume described so far to exclusively associates with Cupriavidus symbionts. Moreover, strain AMP6 represents an early-diverging lineage within the symbiotic Cupriavidus group and has the capacity to develop an effective nitrogen-fixing symbiosis with three other species of Mimosa. Therefore, the genome of Cupriavidus sp. strain AMP6 enables comparative analyses of symbiotic trait evolution in this genus and here we describe the general features, together with sequence and annotation. The 7,579,563 bp high-quality permanent draft genome is arranged in 260 scaffolds of 262 contigs, contains 7,033 protein-coding genes and 97 RNA-only encoding genes, and is part of the GEBA-RNB project proposal. PMID- 26478787 TI - Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport. AB - A potent class of indolinyl-thiazole based inhibitors of cellular lipid uptake mediated by scavenger receptor, class B, type I (SR-BI) was identified via a high throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) in an assay measuring the uptake of the fluorescent lipid DiI from HDL particles. This class of compounds is represented by ML278 (17-11), a potent (average IC50 = 6 nM) and reversible inhibitor of lipid uptake via SR-BI. ML278 is a plasma-stable, noncytotoxic probe that exhibits moderate metabolic stability, thus displaying improved properties for in vitro and in vivo studies. Strikingly, ML278 and previously described inhibitors of lipid transport share the property of increasing the binding of HDL to SR-BI, rather than blocking it, suggesting there may be similarities in their mechanisms of action. PMID- 26478789 TI - Expression of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) in Patients With Serous Ovarian Carcinoma and Their Clinical Significance. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) has an essential role in tumor metastasis by inducing the construction of abnormal blood vessels. Epidermal growth factor receptor (EGFR) is involved in different parts of cancer growth such as tumor initiation, angiogenesis and metastasis. OBJECTIVES: The aim of this study was to evaluate the expression of VEGF and EGFR in ovarian cancer in southern Iran and to assess the correlation between expression of these two markers and patients' age, tumor stage, and grade. PATIENTS AND METHODS: In this cross-sectional study, 50 paraffin blocks of serous ovarian adenocarcinomas and 50 paraffin-embedded specimens from control individuals operated for reasons other than malignancy were immunohistochemically stained using anti-human VEGF and EGFR antibodies. RESULTS: A significant difference in the frequency of positive expression of VEGF was observed in ovarian cancer patients (25.0%) compared with the control group (8.0%) (P = 0.023). A significant difference between EGFR expression in patients (56.8%) and controls (24.0%) was also obtained (P = 0.001). No significant correlation between VEGF and EGFR expression and patients' age, tumor grade and stage were detected (P > 0.05). CONCLUSIONS: The significant increase in both VEGF and EGFR in the patients with ovarian cancer compared to healthy individuals could have prognostic value. Identifying these markers may be useful for chemopreventive and chemotherapeutic strategies for patients with serous ovarian cancer. PMID- 26478790 TI - Awareness, Attitude, and Practice of Breast Cancer Screening Women, and the Associated Socio-Demographic Characteristics, in Northern Iran. AB - BACKGROUND: Breast cancer is the most common malignancy among women, with a high rate of mortality. The burden of disease and its serious outcome could be prevented by early detection. OBJECTIVES: Thus, the objective of this study was investigation the awareness, attitude and practice of breast cancer screening women. PATIENTS AND METHODS: This cross-sectional study has conducted on 500 representative samples of women aged 20 - 65 years who referred to urban area of Babol health centers in 2012. The data have collected with standard questionnaire. The demographic data, the knowledge of risk factors and symptoms and sign, the health belief, and the practice of women in breast cancer screening have collected by interview. RESULTS: The results show that only 14.8% of participants had a high level of knowledge for breast cancer risk factors and 33.8% at high level of awareness of symptoms and signs. The level of awareness has significantly associated with higher age (P = 0.03) and higher educational level (P = 0.04). Only 10.2% and 8.4% of women have performed breast self- examination (BSE) monthly and breast clinical examination (BCE) annually respectively. The practice of women with BSE has significantly associated with aging (P = 0.005), higher educational level (P = 0.007), higher knowledge (P = 0.001) and positive attitude toward perceived benefits and confidence and health motivation (P = 0.001). CONCLUSIONS: The low level of awareness and practice of breast cancer screening have found in this study, emphasized an extension of framework health educational program, particularly in younger and low educated women. PMID- 26478791 TI - Epidemiological Evaluation of Head and Neck Sarcomas in Iran (the Study of 105 Cases Over 13 Years). AB - BACKGROUND: Head and neck sarcomas are exceedingly rare and they include 4% - 10% of all sarcomas and less than 1% of all neoplasm of head and neck. OBJECTIVES: The aim of this study is to evaluate the epidemiological characteristics of head and neck sarcomas of patients in Isfahan, Iran. PATIENTS AND METHODS: In this retrospective study, from the 16000 patients whose files were evaluated, the total number of 105 head and neck sarcomas were collected. They were evaluated with due attention to age, gender of the patients and the most common location of the lesion. RESULTS: From the total number of 105 (0.6%) patients with sarcomas, 56 were men (53.33%) and 49 women (46.66%). The most common head and neck sarcomas among this population were Osteosarcoma (32 cases, 30.47%), Chondrosarcoma (14 cases, 13.33%), and Ewing sarcoma (11 cases, 10.47%).The most common soft tissue sarcoma was Rabdomiosarcoma. Mandible was the most common location for these lesions. CONCLUSIONS: In this study, the hard tissue sarcomas were more prevalent than soft tissue ones. Hence, special attention should be paid to the patients when being diagnosed. PMID- 26478788 TI - Tumor-Induced Osteomalacia. PMID- 26478792 TI - A Common SNP of IL-10 (-1082A/G) is Associated With Increased Risk of Premenopausal Breast Cancer in South Indian Women. AB - BACKGROUND: Evading the immune destruction and angiogenesis has been the two hallmarks of cancer. Interleukin-10 (IL-10) is a cytokine with immune suppressing (pro-tumorigenic) and anti-angiogenic (anti-tumorigenic) properties, thus making the role of IL-10 in tumorigenesis enigmatic. Previous studies have suggested a critical role of IL10 altered expression in complex process of tumor microenvironment, co-evolution and tumorigenesis. OBJECTIVES: Evaluating the role of IL10 (-1082A/G) gene promoter polymorphism in breast cancer patients from South India. PATIENTS AND METHODS: A case-control study was conducted with a total of 285 individuals, these include 125 histologically confirmed breast cancer patients and 160 age and sex matched controls. Genotypes were determined by allele-specific polymerase chain reaction (AS-PCR), followed by agarose gel electrophoresis. Statistical analysis was done to test the significance of results obtained. RESULTS: Statistical analysis revealed that AA genotype of the Il-10 -1082A/G polymorphism is significantly associated with breast cancer (AA vs. AG: chi(2) = 14.46, P = 0.0001432, OR = 2.854, 95% CI = 1.68 - 4.849). Up on stratifying subjects based on cancer stage, age at onset, menopausal status, AA genotype has associated with all the sub groups, except for post-menopausal women. There was no significant association which was observed with respected to hormonal status (ER, PR) and Her2/neu status. CONCLUSIONS: The present study suggests that IL-10 AA genotype as a risk factor in the etiology of breast cancer in the South Indian population. PMID- 26478793 TI - The Effect of Stress Management Model in Quality of Life in Breast Cancer Women. AB - BACKGROUND: Breast cancer associates with severs severe distress and stress. Since Because of that, the stress management program can train necessary skills to cope with stress; therefore, the current study investigates the effectiveness of stress management on enhancement of quality of life. OBJECTIVES: The aim of the current study is to examine the effectiveness of stress management model in quality of life for breast cancer patients. PATIENTS AND METHODS: This research is a quasi-experimental study with pre and post-tests. The 21 subjects were selected from cancer institute of Imam Khomeini in Tehran in 2014. The participants were allocated to two matched groups based on their pre-test scores. They were assigned randomly to the control and experimental groups. Stress management was conducted with the experimental group during 10 sessions. Then the questionnaire was administered at post-test. Statistical analysis was conducted by using the independent t-test and analysis of variance. The research instrument was the core quality of life questionnaire QLQ-C30. RESULTS: The results of the independent t-test showed that there is a significant difference between the pretest and post-test scores in the experimental group (P < 0.05). Also, there is no significant difference between means of quality of life subscales and socio demographic of the patients such as; age, education and disease stage (P < 0.05). CONCLUSIONS: The results indicate that stress management can change the irrational and distortion thoughts. So, it enhances the quality of life in breast cancer patients. PMID- 26478795 TI - Association of Systemic Anaplastic Large Cell Lymphoma and Active Toxoplasmosis in a Child. AB - INTRODUCTION: Anaplastic large cell lymphoma is a subset of non-Hodgkin lymphoma and an unusual disease in children. CASE PRESENTATION: Herein we have reported a 7- year- old girl with a large necrotic skin ulcer on the chest caused by systemic form of anaplastic large-cell lymphoma and simultaneous active toxoplasmosis diagnosed by PCR on lymph node specimen. There were few reports showing a role for toxoplasma infection to cause some malignancies such as lymphoma in adults. CONCLUSIONS: Based to our knowledge, this has been the first report of simultaneous systemic anaplastic large cell lymphoma and active toxoplasmosis, documented by positive PCR on tissue biopsy in a child. This case report has suggested more attention to the accompanying Toxoplasma gondii infection as a probable cause of some types of lymphomas. PMID- 26478794 TI - Pituitary Glioblastoma: A Case Report. AB - INTRODUCTION: Pituitary adenomas have been the most common sellaturcica tumors. There have been many unusual types of pituitary tumors that might neglect by radiologists and clinicians. One of these tumors would be the malignant glioma. CASE PRESENTATION: A 62-year-old male has complained from sudden frontal headache, nausea, vomiting, decreased vision, blurred vision and double vision. In skull radiographic, there was an expansion of sellaturcica and a lesion with clear border on T1; heterogeneous; iso - to hypotense; size about 3/5 * 2/5 cm with no surrounding edema that it has homogeneously attracted contrast Lesion, that shown a signal hypointensity on T2 with heterogeneous enhancement. In the coronal sections, the tumor expanded to the suprasellar region and optic chiasmatic that has compressed especially on the left side. Partial tumor resection has conducted. The surgery has done by a transsphenoidal approach. The pathologist has diagnosed a glioblastoma. This diagnosis has confirmed using immunohistochemistry technique. CONCLUSIONS: There have been many unusual types of pituitary tumors that might neglect by radiologists and clinicians. One of these tumors would be the malignant glioma. PMID- 26478796 TI - Recurrence and Five -Year Survival in Colorectal Cancer Patients After Surgery. AB - BACKGROUND: Colorectal cancer (CRC) is a common malignancyworldwide and its outcome is most closely related to the extent of disease at presentation. Early diagnosis of an asymptomatic recurrence increases the likelihood of a complete surgical resection. OBJECTIVES: The aim of this study was to evaluate the incidence of colorectal cancer recurrence and survival rate within 5 years, after surgery. PATIENTS AND METHODS: During the 9-year period since 21st Mar, 2004 to 20th Mar, 2013, patients whose primary colorectal cancer were resected in Taleghani hospital, Tehran, Iran were selected in a historical cohort. The necessary data such as demographic, age, gender, family history of CRC, site and size of tumor, stage of tumor, operation details, histological results, treatment method, histopathologic, etc. were collected. Then the recurrence and survival of colorectal cancer within 5 years after operation and their risk factors were evaluated. P value less than 0.05 were considered significant. All analysis was done using SPSS software. RESULTS: A total of 107 patients underwent resection for colorectal cancer during the study period, with mean age of 53.50 +/- 12.68 years (range 24 - 76 years), survival rate of 73.8% (rectum 70.0% and colon 75.9%), and mean survival time of 142.17 +/- 21.60 month. The recurrence rate of CRC patients, during five years after surgery was 5.7%. Regional lymph nodes, Distance metastasis and Adjuvant therapy were significant prognosis factors of survival after surgery. CONCLUSIONS: The rate of recurrence in Iranian patients was low, which could be due to improvement of exactness and expertise of surgeons or better adjuvant therapy. The significant association between survival and adjuvant therapy clarifies this finding. Early diagnosis and primary detection could increase the rate of survival. PMID- 26478797 TI - Germ Cell Tumor's Survival Rate in Young Patients. AB - BACKGROUND: Germ cell tumors are neoplasms that originate from multi potential germ cells and can be intra or extra gonadal. According to pathologic classification, they have different subtypes. They account for 3% of pediatric malignancies and most commonly happen in children before the age of 15 years old. Epidemiologic evidence about pediatric germ cell tumors is scant in our region. OBJECTIVES: The aim of current study was to determine demographic characteristics, recurrence and survival rate of germ cell tumor patients under the age of 21 years. PATIENTS AND METHODS: During a 10-year period (1996 - 2006), 106 patients under the age of 21 years suffering from germ cell tumor were admitted to our centers. We extracted the data needed for our study from patients' medical records in the hospitals. RESULTS: Thirty seven boys and 69 girls with a mean age of 8.4 +/- 7.8 years were included. Most tumors were diagnosed before the age of one year (37%). The most common pathologic subtype was mature teratoma (44%). Ovary (35%) was the most common primary site. Surgery plus chemotherapy were used to treat 54 patients and BEP was the most common chemotherapy regimen. Metastasis and recurrent tumor were seen in 22% and 8% of cases, respectively. Four-year overall survival was 89%. CONCLUSIONS: Our study showed that demographic characteristics of GCT patients in our population are similar to patients of other geographic regions in the world. Primary tumor site, histologic subtype and metastasis were significant prognostic factors for survival. PMID- 26478798 TI - Evaluation of Survival and Treatment Toxicity With High-Dose-Rate Brachytherapy With Cobalt 60 in Carcinoma of Cervix. AB - BACKGROUND: Cervical cancer remains to be a major health problem and cancer related cause of death among women in developing countries such as Iran where the most cases are diagnosed in locally advanced stage. OBJECTIVES: This cross sectional-analytic study aims to report outcome 154 patients with carcinoma of cervix were treated with external beam radiation therapy (EBRT) and high-dose rate (HDR) brachytherapy with cobalt 60 (Co-6o) remote after loading system. PATIENTS AND METHODS: A total of 154 patients with the international federation of gynecologist and oncologist (FIGO) stages I-IVA with histopathologically confirmed carcinoma of cervix, followed by the radiation-oncology ward of Shohada e-Tajrish Hospital in Tehran, Iran, between February 2008 and March 2015. They were completed their scheduled EBRT and HDR brachytherapy with Co-60 remote after loading system. Out of this, 132 patients completed their standard follow up protocol. They were analyzed for 3-year disease-free survival (DFS), 3-year overall survival (OS) incidence of acute and late complications for HDR brachytherapy. RESULTS: Fourteen patients (9.1 %) were in stage I (FIGO classification), 8 (5.2%) were in stage IIA, 26 (16.9%) were in stage IIB, 100 (64.9%) were in stage III, and 6 (3.9 %) were in stage IVA. The follow up duration was between 6 - 60 months with a median of 38 months. Overall rectal and bladder treatment toxicity rates were 33.7%. The 3-year DFS rate was 85.7%, 70.7 %, 41% and 16.6% for stages I, II, III, IVA respectively. Favorable prognostic factors in univariate and multivariate analysis were early stage, tumor size < 4 cm (after adjusting for the residual disease after radiation), no pelvic lymph node involvement and 1 week Gap between EBRT and HDR brachytherapy in 3-year DFS (P = 0.001, P = 0.012, P = 0.005, P = 0.005, respectively). The 3-year OS rate was 85.7%, 76.4%, 42%, and 33.3% for stages I, II, III, and IVA, respectively. Favorable prognostic factors in univariate and multivariate analysis were early stage, tumor size < 4 cm, no pelvic lymph node involvement, 1 week gap between EBRT and HDR brachytherapy and no distant metastasis (during the follow up) in 3 year OS (P = 0.001, P = 0.002, P = 0.002, P = 0.002, P = 0.001, respectively). CONCLUSIONS: HDR brachytherapy with Co-60 remote after loading system was successful and it showed HDR brachytherapy in treating patients with carcinoma of cervix was effective after EBRT with acceptable rectal and bladder complications. PMID- 26478799 TI - The Role of Patient in Patient Management. PMID- 26478800 TI - Erratum: Association of cigarette smoking and metabolic syndrome in a Puerto Rican adult population: Erratum. AB - [This corrects the article on p. 849 in vol. 5, PMID: 25104996.]. PMID- 26478801 TI - Erratum: Pathologic Analysis of Control Plans for Air Pollution Management in Tehran Metropolis: A Qualitative Study: Erratum. AB - [This corrects the article on p. 995 in vol. 4, PMID: 24130939.]. PMID- 26478802 TI - Erratum: Can French paradox hypothesis explain the observed different trends of mortality from ischemic Heart disease and stroke in Western Europe?: Erratum. AB - [This corrects the article on p. 1345 in vol. 4, PMID: 24498488.]. PMID- 26478803 TI - One-pot synthesis of MWW zeolite nanosheets using a rationally designed organic structure-directing agent. AB - A new material MIT-1 comprised of delaminated MWW zeolite nanosheets is synthesized in one-pot using a rationally designed organic structure-directing agent (OSDA). The OSDA is comprised of a hydrophilic head segment that resembles the OSDA used to synthesize the zeolite precursor MCM22(P), a hydrophobic tail segment that resembles the swelling agent used to swell MCM22(P), and a di quaternary ammonium linker that connects both segments. MIT-1 features high crystallinity and surface areas exceeding 500 m2g-1, and can be synthesized over a wide synthesis window that includes Si/Al ratios ranging from 13 to 67. Characterization data reveal high mesoporosity and acid strength with no detectable amorphous silica phases. Compared to MCM-22 and MCM-56, MIT-1 shows a three-fold increase in catalytic activity for the Friedel-Crafts alkylation of benzene with benzyl alcohol. PMID- 26478805 TI - Pharmacists in Australian general practice: an opportunity for expertise in precision medicine. PMID- 26478804 TI - Dermestes maculatus: an intermediate-germ beetle model system for evo-devo. AB - BACKGROUND: Understanding how genes change during evolution to direct the development of diverse body plans is a major goal of the evo-devo field. Achieving this will require the establishment of new model systems that represent key points in phylogeny. These new model systems must be amenable to laboratory culture, and molecular and functional approaches should be feasible. To date, studies of insects have been best represented by the model system Drosophila melanogaster. Given the enormous diversity represented by insect taxa, comparative studies within this clade will provide a wealth of information about the evolutionary potential and trajectories of alternative developmental strategies. RESULTS: Here we established the beetle Dermestes maculatus, a member of the speciose clade Coleoptera, as a new insect model system. We have maintained a continuously breeding culture in the lab and documented Dermestes maculatus embryogenesis using nuclear and phalloidin staining. Anterior segments are specified during the blastoderm stage before gastrulation, and posterior segments are added sequentially during germ band elongation. We isolated and studied the expression and function of the pair-rule segmentation gene paired in Dermestes maculatus. In this species, paired is expressed in stripes during both blastoderm and germ band stages: four primary stripes arise prior to gastrulation, confirming an intermediate-germ mode of development for this species. As in other insects, these primary stripes then split into secondary stripes. To study gene function, we established both embryonic and parental RNAi. Knockdown of Dmac-paired with either method resulted in pair-rule-like segmentation defects, including loss of Engrailed expression in alternate stripes. CONCLUSIONS: These studies establish basic approaches necessary to use Dermestes maculatus as a model system. Methods are now available for use of this intermediate-germ insect for future studies of the evolution of regulatory networks controlling insect segmentation, as well as of other processes in development and homeostasis. Consistent with the role of paired in long-germ Drosophila and shorter-germ Tribolium, paired functions as a pair-rule segmentation gene in Dermestes maculatus. Thus, paired retains pair-rule function in insects with different modes of segment addition. PMID- 26478806 TI - Suvorexant in insomnia: efficacy, safety and place in therapy. AB - Insomnia is a highly prevalent disorder that can occur in conjunction with other medical or psychiatric conditions or can occur in the absence of a coexisting disorder. Regardless, treatment of insomnia is beneficial to the patient and may benefit comorbidities if they exist. Nonpharmacologic modalities such as sleep hygiene and stimulus controls are important mainstays of insomnia therapy, but may not be sufficient to treat the disorder. Dual orexin receptor antagonists (DORAs) are a new class of insomnia medication that target wakefulness-promoting neuropeptides to regulate the sleep-wake cycle. Suvorexant is the first DORA to be approved and has demonstrated efficacy at decreasing both time to sleep onset and increasing total sleep time compared with placebo. Suvorexant has a novel mechanism of action and may represent an alternative for patients who cannot tolerate or do not receive benefit from traditional sleep agents. Suvorexant is generally effective and well tolerated, but has not been compared head to head with traditional sleep agents and being only newly available, lacks a longer-term 'real-world' experience base. PMID- 26478807 TI - Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety. PMID- 26478809 TI - Upcoming drug safety and pharmacovigilance conferences 2016/2016. PMID- 26478808 TI - Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety-reply. PMID- 26478810 TI - Sex-specific cardiac cardiolipin remodelling after doxorubicin treatment. AB - BACKGROUND: Imbalance in lipid metabolism and membrane lipid homeostasis has been observed in numerous diseases including heart failure and cardiotoxicity. Growing evidence links phospholipid alterations especially cardiolipins (CLs) to defects in mitochondrial function and energy metabolism in heart failure. We have shown recently that doxorubicin cardiotoxicity is more severe in male than female Wistar rats. We aimed to study whether this sex specificity is linked to differences in cardiac phospholipid profiles. RESULTS: Adult male and female rats were injected 2 mg/kg doxorubicin weekly for 7 weeks. Cardiac phospholipid molecular species were determined by liquid chromatography coupled with mass spectrometry fragmentation (LC)/MS(n). Sex difference in phosphatidylethanolamine and phosphatidylcholine species containing docosahexaenoic and docosapentaenoic acyl chains was observed, females having more than males. In both sexes, doxorubicin induced an important loss of the main CL(18:2)4, while the level of monolysocardiolipin MLCL(18:2)3 remained stable. However, a severe remodelling appeared in treated rats with the longest CL acyl chains in doxorubicin-treated females, which might compensate for the loss of tetra-linoleoyl CL. The level of oxidized cardiolipin was not particularly increased after doxorubicin treatment. Finally, expression of genes involved in the biosynthesis of fatty acid appeared to be decreased in doxorubicin-treated males. CONCLUSIONS: These results emphasize for the first time the cardiac remodelling in the phospholipid classes after doxorubicin treatment. These observations suggest that doxorubicin has a sex-specific impact on the heart phospholipidome especially on cardiolipin, an essential mitochondrial lipid. Further studies are needed to better understand the roles of lipids in the anthracycline cardiotoxicity and sex differences, but phospholipid cardioprotection seems a valuable new additive therapeutic strategy for anthracycline cardiotoxicity. PMID- 26478811 TI - Solving the worldwide emergency department crowding problem - what can we learn from an Israeli ED? AB - ED crowding is a prevalent and important issue facing hospitals in Israel and around the world, including North and South America, Europe, Australia, Asia and Africa. ED crowding is associated with poorer quality of care and poorer health outcomes, along with extended waits for care. Crowding is caused by a periodic mismatch between the supply of ED and hospital resources and the demand for patient care. In a recent article in the Israel Journal of Health Policy Research, Bashkin et al. present an Ishikawa diagram describing several factors related to longer length of stay (LOS), and higher levels of ED crowding, including management, process, environmental, human factors, and resource issues. Several solutions exist to reduce ED crowding, which involve addressing several of the issues identified by Bashkin et al. This includes reducing the demand for and variation in care, and better matching the supply of resources to demands in care in real time. However, what is needed to reduce crowding is an institutional imperative from senior leadership, implemented by engaged ED and hospital leadership with multi-disciplinary cross-unit collaboration, sufficient resources to implement effective interventions, access to data, and a sustained commitment over time. This may move the culture of a hospital to facilitate improved flow within and across units and ultimately improve quality and safety over the long term. PMID- 26478812 TI - Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules. AB - Mycobacterium tuberculosis, the causative agent of human tuberculosis, has two proteins belonging to the truncated hemoglobin (trHb) family. Mt-trHbN presents well-defined internal hydrophobic tunnels that allow O 2 and (*)NO to migrate easily from the solvent to the active site, whereas Mt-trHbO possesses tunnels that are partially blocked by a few bulky residues, particularly a tryptophan at position G8. Differential ligand migration rates allow Mt-trHbN to detoxify (*)NO, a crucial step for pathogen survival once under attack by the immune system, much more efficiently than Mt-trHbO. In order to investigate the differences between these proteins, we performed experimental kinetic measurements, (*)NO decomposition, as well as molecular dynamics simulations of the wild type Mt-trHbN and two mutants, VG8F and VG8W. These mutations introduce modifications in both tunnel topologies and affect the incoming ligand capacity to displace retained water molecules at the active site. We found that a single mutation allows Mt-trHbN to acquire ligand migration rates comparable to those observed for Mt-trHbO, confirming that ligand migration is regulated by the internal tunnel architecture as well as by water molecules stabilized in the active site. PMID- 26478813 TI - Synthesis and Protein Incorporation of Azido-Modified Unnatural Amino Acids. AB - Two new azidophenylalanine residues (3 and 4) have been synthesized and, in combination with 4-azido-L-phenylalanine (1) and 4-azidomethyl-L-phenylalanine (2), form a series of unnatural amino acids (UAAs) containing the azide vibrational reporter at varying distances from the aromatic ring of phenylalanine. These UAAs were designed to probe protein hydration with high spatial resolution by utilizing the large extinction coefficient and environmental sensitivity of the azide asymmetric stretch vibration. The sensitivity of the azide reporters was investigated in solvents that mimic distinct local protein environments. Three of the four azido-modified phenylalanine residues were successfully genetically incorporated into a surface site in superfolder green fluorescent protein (sfGFP) utilizing an engineered, orthogonal aminoacyl-tRNA synthetase in response to an amber codon with high efficiency and fidelity. SDS-PAGE and ESI-Q-TOF mass analysis verified the site specific incorporation of these UAAs. The observed azide asymmetric stretch in the linear IR spectra of these UAAs incorporated into sfGFP indicated that the azide groups were hydrated in the protein. PMID- 26478815 TI - Quantitative assessment of damage during MCET: a parametric study in a rodent model. AB - BACKGROUND: Myocardial cavitation-enabled therapy (MCET) has been proposed as a means to achieve minimally invasive myocardial reduction using ultrasound to produce scattered microlesions by cavitating contrast agent microbubbles. METHODS: Rats were treated using burst mode focused ultrasound at 1.5 MHz center frequency and varying envelope and pressure amplitudes. Evans blue staining indicated lethal cardiomyocytic injury. A previously developed quantitative scheme, evaluating the histologic treatment results, provides an insightful analysis for MCET treatment parameters. Such include ultrasound exposure amplitude and pulse modulation, contrast agent dose, and infusion rate. RESULTS: The quantitative method overcomes the limitation of visual scoring and works for a large dynamic range of treatment impact. Macrolesions are generated as an accumulation of probability driven microlesion formations. Macrolesions grow radially with radii from 0.1 to 1.6 mm as the ultrasound exposure amplitude (peak negative) increases from 2 to 4 MPa. To shorten treatment time, a swept beam was investigated and found to generate an acceptable macrolesion volume of about 40 MUL for a single beam position. CONCLUSIONS: Ultrasound parameters and administration of microbubbles directly influence lesion characteristics such as microlesion density and macrolesion dimension. For lesion generation planning, control of MCET is crucial, especially when targeting larger pre-clinical models. PMID- 26478814 TI - Nitrergic Mechanisms for Management of Recurrent Priapism. AB - INTRODUCTION: Priapism is a condition involving prolonged penile erection unrelated to sexual interest or desire. The ischemic type, including its recurrent variant, is often associated with both physical and psychological complications. As such, management is of critical importance. Ideal therapies for recurrent priapism should address its underlying pathophysiology. AIM: To review the available literature on priapism management approaches particularly related to nitrergic mechanisms. METHODS: A literature review of the pathophysiology and management of priapism was performed using PubMed. MAIN OUTCOME MEASURE: Publications pertaining to mechanisms of the molecular pathophysiology of priapism. RESULTS: Nitrergic mechanisms are characterized as major players in the molecular pathophysiology of priapism. PDE5 inhibitors represent an available therapeutic option with demonstrated ability in attenuating these underlying nitrergic derangements. Several additional signaling pathways have been found to play a role in the molecular pathophysiology of priapism and have also been associated with these nitrergic mechanisms. CONCLUSION: An increasing understanding of the molecular pathophysiology of priapism has led to the discovery of new potential targets. Several mechanism-based therapeutic approaches may become available in the future. PMID- 26478816 TI - Synthesis of bulk-size transparent gadolinium oxide-polymer nanocomposites for gamma ray spectroscopy. AB - Heavy element loaded polymer composites have long been proposed to detect high energy X- and gamma-rays upon scintillation. The previously reported bulk composite scintillators have achieved limited success because of the diminished light output resulting from fluorescence quenching and opacity. We demonstrate the synthesis of a transparent nanocomposite comprising gadolinium oxide nanocrystals uniformly dispersed in bulk-size samples at a high loading content. The strategy to avoid luminescence quenching and opacity in the nanocomposite was successfully deployed, which led to the radioluminescence light yield of up to 27 000/MeV, about twice as much as standard commercial plastic scintillators. Nanocomposites monoliths (14 mm diameter by 3 mm thickness) with 31 wt% loading of nanocrystals generated a photoelectric peak for Cs-137 gamma (662 keV) with 11.4% energy resolution. PMID- 26478817 TI - Safety, efficacy, and immunogenicity of Flublok in the prevention of seasonal influenza in adults. AB - Flublok is the first recombinant hemagglutinin (HA) vaccine licensed by the US Food and Drugs Administration for the prevention of influenza in adults aged 18 and older. The HA proteins produced in insect cell culture using the baculovirus expression system technology are exact analogues of wild type circulating influenza virus HAs. The universal HA manufacturing process that has been successfully scaled to the 21,000L contributes to rapid delivery of a substantial number of doses. This review discusses the immunogenicity, efficacy and safety data from five pivotal clinical studies used to support licensure of trivalent Flublok for adults 18 years of age and older in the United States. The trial data demonstrate that the higher antigen content in Flublok results in improved immunogenicity. Data further suggest improved efficacy and a slightly lower local reactogenicity compared with standard inactivated influenza vaccine, despite the presence of more antigen (statistically significant). Flublok influenza vaccine can include HAs designed to mimic 'drift' in influenza viruses as the process of predicting antigenic drift advances and, at a minimum, could address late appearing influenza viruses. The implementation of the latter will require support from regulatory authorities. PMID- 26478818 TI - Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective. AB - Herpes zoster (HZ) is primarily a disease of nerve tissue but the acute and longer-term manifestations require multidisciplinary knowledge and involvement in their management. Complications may be dermatological (e.g. secondary bacterial infection), neurological (e.g. long-term pain, segmental paresis, stroke), ophthalmological (e.g. keratitis, iridocyclitis, secondary glaucoma) or visceral (e.g. pneumonia, hepatitis). The age-related increased incidence of HZ and its complications is thought to be a result of the decline in cell-mediated immunity (immunosenescence), higher incidence of comorbidities with age and social environmental changes. Individuals who are immunocompromised as a result of disease or therapy are also at increased risk, independent of age. HZ and its complications (particularly postherpetic neuralgia) create a significant burden for the patient, carers, healthcare systems and employers. Prevention and treatment of HZ complications remain a therapeutic challenge despite recent advances. This is an overview of the multidisciplinary implications and management of HZ in which the potential contribution of vaccination to reducing the incidence HZ and its complications are also discussed. PMID- 26478819 TI - Nickel-Catalyzed Decarboxylative Arylation of Azoles with Perfluoro- and Nitrobenzoates. AB - This manuscript describes a Ni-catalyzed method for the direct arylation of azoles using benzoates. Perfluorophenyl and 2-nitrobenzoates participate in these reactions to afford the corresponding products in modest to good yields. The efficiency of the arylations with perfluorobenzoates is highly dependent on both the degree and position of fluorine atoms in the benzoates. PMID- 26478821 TI - An unusual coronary pseudo-obstruction image due to competitive blood flow between critical stenosis in proximal LAD and collateral vessels from RCA. AB - This case illustrates an unusual coronary pseudo-obstruction due to competitive coronary flows from critical proximal left anterior descending (LAD) coronary artery stenosis and collateral vessels from distal right coronary artery. The flow dynamics of both antegrade and retrograde flows counterbalanced each other at the second diagonal branch level of LAD causing a total pseudo-obstruction image. PMID- 26478820 TI - Renocardiac syndromes: physiopathology and treatment stratagems. AB - PURPOSE OF REVIEW: Bidirectional inter-organ interactions are essential for normal functioning of the human body; however, they may also promote adverse conditions in remote organs. This review provides a narrative summary of the epidemiology, physiopathological mechanisms and clinical management of patients with combined renal and cardiac disease (recently classified as type 3 and 4 cardiorenal syndrome). Findings are also discussed within the context of basic research in animal models with similar comorbidities. SOURCES OF INFORMATION: Pertinent published articles were identified by literature search of PubMed, MEDLINE and Google Scholar. Additional data from studies in the author's laboratory were also consulted. FINDINGS: The prevalence of renocardiac syndrome throughout the world is increasing in part due to an aging population and to other risk factors including hypertension, diabetes and dyslipidemia. Pathogenesis of this disorder involves multiple bidirectional interactions between the kidneys and heart; however, participation of other organs cannot be excluded. Our own work supports the hypothesis that the uremic milieu, caused by kidney dysfunction, produces major alterations in vasoregulatory control particularly at the level of the microvasculature that results in impaired oxygen delivery and blood perfusion. LIMITATIONS: Recent clinical literature is replete with articles discussing the necessity to clearly define or characterize what constitutes cardiorenal syndrome in order to improve clinical management of affected patients. Patients are treated after onset of symptoms with limited available information regarding etiology. While understanding of mechanisms involved in pathogenesis of inter-organ crosstalk remains a challenging objective, basic research data remains limited partly because of the lack of animal models. IMPLICATIONS: Preservation of microvascular integrity may be the most critical factor to limit progression of multi-organ disorders including renocardiac syndrome. More fundamental studies are needed to help elucidate physiopathological mechanisms and for development of treatments to improve clinical outcomes. PMID- 26478822 TI - Social Support Can Buffer against Stress and Shape Brain Activity. AB - Social support from close relationship partners is an important resource for coping with stress, particularly during childhood. We discuss ethical challenges associated with studying stress and its social buffering in the laboratory, as well as emerging evidence regarding two potential neural substrates for the social buffering of stress: hypothalamic oxytocin activity and activation of areas in the prefrontal cortex associated with effective self-regulation. We also address the role of early-life social experiences in shaping brain development, as well as recommendations for practice and policy that would advance the ethical treatment of children and reduce social inequalities in early-life experiences and opportunities-e.g., investing in programs that prevent child maltreatment and facilitating access to high-quality child care for economically disadvantaged families. We also debate the ethical implications of using oxytocin nasal sprays to simulate the stress-reducing properties of social support and advise waiting for more evidence before recommending their use. PMID- 26478824 TI - Finger Tendon Travel Associated with Sequential Trigger Nail Gun Use. AB - BACKGROUND: Pneumatic nail guns used in wood framing are equipped with one of two triggering mechanisms. Sequential actuation triggers have been shown to be a safer alternative to contact actuation triggers because they reduce traumatic injury risk. However, the sequential actuation trigger must be depressed for each individual nail fired as opposed to the contact actuation trigger, which allows the trigger to be held depressed as nails are fired repeatedly by bumping the safety tip against the workpiece. As such, concerns have been raised about risks for cumulative trauma injury, and reduced productivity, due to repetitive finger motion with the sequential actuation trigger. PURPOSE: This study developed a method to predict cumulative finger flexor tendon travel associated with the sequential actuation trigger nail gun from finger joint kinematics measured in the trigger actuation and productivity standards for wood-frame construction tasks. METHODS: Finger motions were measured from six users wearing an instrumented electrogoniometer glove in a simulation of two common framing tasks wall building and flat nailing of material. Flexor tendon travel was calculated from the ensemble average kinematics for an individual nail fired. RESULTS: Finger flexor tendon travel was attributable mostly to proximal interphalangeal and distal interphalangeal joint motion. Tendon travel per nail fired appeared to be slightly greater for a wall-building task than a flat nailing task. The present study data, in combination with construction industry productivity standards, suggest that a high-production workday would be associated with less than 60 m/day cumulative tendon travel per worker (based on 1700 trigger presses/day). CONCLUSION AND APPLICATIONS: These results suggest that exposure to finger tendon travel from sequential actuation trigger nail gun use may be below levels that have been previously associated with high musculoskeletal disorder risk. PMID- 26478823 TI - Factors that determine local control with gamma knife radiosurgery: The role of primary histology. AB - BACKGROUND: Stereotactic radiosurgery for the treatment of brain metastases is commonly delivered without regard to primary cancer histology. This study sought to determine if the primary site of origin for brain metastases affected the propensity for local failure. METHODS: A total of 83 patients with 200 brain metastases were examined retrospectively for predictors of infield failure. Tumor, patient, and treatment characteristics were analyzed including primary tumor histology, radiosurgical dose and age. Cox proportional hazards models, univariate and multivariate analyses were used to identify predictors of local failure. RESULTS: Freedom from local failure for the entire population was 83% and 65% at 6 and 12 months, respectively. Multivariate analysis revealed that breast cancer brain metastases have a significantly lower risk of local failure than melanoma (HR = 0.31, p< 0.001). Additionally, multivariate analysis revealed that increasing dose lowered risk for local failure (HR = 0.87, p<0.001). CONCLUSIONS: Melanoma histology leads to a higher rate of local failure. Higher prescription dose results in higher incidence of local control. PMID- 26478825 TI - Yoga in public school improves adolescent mood and affect. AB - The purpose of the present study was to directly compare the acute effects of participating in a single yoga class versus a single standard physical education (PE) class on student mood. Forty-seven high school students completed self report questionnaires assessing mood and affect immediately before and after participating in a single yoga class and a single PE class one week later. Data were analyzed using paired-samples t tests and Wilcoxon-signed ranks tests and by comparing effect sizes between the two conditions. Participants reported significantly greater decreases in anger, depression, and fatigue from before to after participating in yoga compared to PE. Significant reductions in negative affect occurred after yoga but not after PE; however, the changes were not significantly different between conditions. In addition, after participating in both yoga and PE, participants reported significant decreases in confusion and tension, with no significant difference between groups. Results suggest that school-based yoga may provide unique benefits for students above and beyond participation in PE. Future research should continue to elucidate the distinct psychological and physiological effects of participating in yoga compared to PE activities. PMID- 26478826 TI - A Cross Cultural Comparison of Disability and Symptomatology Associated with CFS. AB - Few studies have compared symptomatology and functional differences experienced by patients with chronic fatigue syndrome (CFS) across cultures. The current study compared patients with CFS from the United States (US) to those from the United Kingdom (UK) across areas of functioning, symptomatology, and illness onset characteristics. Individuals in each sample met criteria for CFS as defined by Fukuda et al. (1994). These samples were compared on two measures of disability and impairment, the DePaul Symptom Questionnarie (DSQ) and the Medical outcomes study 36-item short-form health survey (SF-36). Results revealed that the UK sample was significantly more impaired in terms of mental health and role emotional functioning, as well as specific symptoms of pain, neurocognitive difficulties, and immune manifestations. In addition, the UK sample was more likely to be working rather than on disability. Individuals in the US sample reported more difficulties falling asleep, more frequently reported experiencing a sudden illness onset (within 24 hours), and more often reported that the cause of illness was primarily due to physical causes. These findings suggest that there may be important differences in illness characteristics across individuals with CFS in the US and the UK, and this has implications for the comparability of research findings across these two countries. PMID- 26478827 TI - Synthesis and Characterization of L-Lysine Conjugated Silver Nanoparticles Smaller Than 10 nM. AB - A rapid and convenient batch method for synthesizing lysine-conjugated silver nanoparticles of approximately 5 nm of size was developed. Nanoparticles of size less than 100 nm exhibit significant medical potential. L-Lysine demonstrates potential for therapeutic applications and silver nanoparticles are an optimal choice for drug delivery because of its intrinsic anti-platelet, anti-bacterial and anti-inflammatory capabilities. Current synthesis protocols for Lysine-capped particles under 10 nm are time consuming and tedious and allow only for the sythesis of small quantities of particles. The synthesis of Lysin-capped silver nanoparticles was based on the reaction in which AgNO3 was reduced by excess NaBH4. L-Lysine, a known essential amino acid, served as the capping agent to minimize initial aggregation. The particles were then separated by size chromatography. Capping occurred through the amide bond on L-Lysine as determined by FT-IR. The conjugation of the particle to the amide bond is important, since this leaves the amino group of Lysine open to further modifications. The particles were further characterized in regards to their shape, size and stability. Finally we demonstrated that the synthesized particles exhibit limited to no toxicity in cells, using HEK 293 cell line as a model system. Our sythesis protocol can be successfully used for scale-up and synthesis of high quantities of nanoparticles. PMID- 26478828 TI - The Implications of Rapid Economic Growth for Health-Related Behaviors and Chronic Metabolic Diseases: An Exploratory Study in Post-Earthquake West China. AB - A devastating earthquake struck west China in 2008. Reconstruction efforts have focused on urbanization and modernization, hastening economic growth in the area. This rapid growth provides a unique opportunity to explore the potential impact of rapid environmental changes on metabolic disease risk. The study objective was to gather qualitative information from residents of a rapidly changing area in China to determine perceived changes in food- and physical activity-related aspects of the environment and their perceived effects on health. We conducted extensive interviews with 30 residents of an area where towns were rapidly rebuilt after being destroyed by the 2008 Wenchuan earthquake. Findings suggest that a longitudinal investigation of children and their families in this rapidly developing region may identify mechanisms by which environmental factors influence the development of diet-related chronic illnesses. PMID- 26478829 TI - Portrayal of medical decision making around medical interventions life-saving encounters on three medical television shows. AB - INTRODUCTION: Previous literature has shown that patients obtain information about the medical system from television shows. Additionally, shared decision making is regularly cited as the ideal way to make decisions during a medical encounter. Little information exists surrounding the characteristics of medical decision-making, such as who makes the decision, on medical television shows. We evaluate the characteristics of medical decisions in lifesaving encounters on medical television shows and evaluate if these characteristics were different on staged and reality television shows. METHODS: We coded type of medical intervention, patient's ability to participate in decision, presence of patient advocate during decision, final decision maker, decision to use intervention, and controversy surrounding decision on three television shows. Frequencies by show were calculated and differences across the three television shows and between staged (ER) and reality (BostonMed and Hopkins) television shows were assessed with chi-square tests. RESULTS: The final data set included 37 episodes, 137 patients and 593 interventions. On ER, providers were significantly more likely to make the decision about the medical intervention without informing the patient when a patient was capable of making a decision compared to BostonMed or Hopkins (p<0.001). Across all shows, 99% of all decisions on whether to use a medical intervention resulted in the use of that intervention. DISCUSSION: Medical interventions are widely portrayed in the medical television shows we analyzed. It is possible that what patients see on television influences their expectations surrounding the decision making process and the use of medical interventions in everyday healthcare encounters. PMID- 26478831 TI - A Practical One-Pot Synthesis of Positron Emission Tomography (PET) Tracers via Nickel-Mediated Radiofluorination. AB - Invited for this months cover picture is the group of Professor Bernd Neumaier at the Institute of Radiochemistry and Experimental Molecular Imaging at the University Clinic of Cologne. The cover picture shows the differences in brain metabolism of a healthy young and a healthy old subject, as well as a patient suffering from Parkinsons disease (left to right) uncovered by 6-[(18)F]FDOPA positron emission tomography (PET). Morbus Parkinson occurs when nerve cells that produce dopamine begin to die. The shortage of dopamine leads to movement problems in affected individuals. 6-[(18)F]FDOPA is extensively used to evaluate the progression of Parkinsons disease. Bold stick projections of this PET tracer, as well as a neuronal network, are seen in the background. Unfortunately, conventional procedures to produce 6-[(18)F]FDOPA are cumbersome. Thus, several recent developments aim at the simplification of this radiosynthesis. In our work, we studied the applicability of the recently reported Ni-mediated radiofluorination approach for daily routine production of 6-[(18)F]FDOPA. For more details, see the Full Paper on p. 457 ff. PMID- 26478832 TI - Graphical Abstract: ChemistryOpen 4/2015. PMID- 26478834 TI - Spotlights on our sister journals: ChemistryOpen 4/2015. PMID- 26478835 TI - Advanced Developments in Cyclic Polymers: Synthesis, Applications, and Perspectives. AB - Due to the topological effect, cyclic polymers demonstrate different and unique physical and biological properties in comparison with linear counterparts having the same molecular-weight range. With advanced synthetic and analytic technologies, cyclic polymers with different topologies, e.g. multicyclic polymers, have been reported and well characterized. For example, various cyclic DNA and related structures, such as cyclic duplexes, have been prepared conveniently by click chemistry. These types of DNA have increased resistance to enzymatic degradation and have high thermodynamic stability, and thus, have potential therapeutic applications. In addition, cyclic polymers have also been used to prepare organic-inorganic hybrids for applications in catalysis, e.g. catalyst supports. Due to developments in synthetic technology, highly pure cyclic polymers could now be produced in large scale. Therefore, we anticipate discovering more applications in the near future. Despite their promise, cyclic polymers are still less explored than linear polymers like polyolefins and polycarbonates, which are widely used in daily life. Some critical issues, including controlling the molecular weight and finding suitable applications, remain big challenges in the cyclic-polymer field. This review briefly summarizes the commonly used synthetic methodologies and focuses more on the attractive functional materials and their biological properties and potential applications. PMID- 26478836 TI - Morphological Transformation Reactions of Photocatalytic Metalloporphyrin Containing Coordination Polymer Particles from Seed Structures. AB - Coordination polymer particles have attracted a great deal of attention due to their characteristic properties and diverse applications in the fields of gas storage, catalysis, optics, sensing, electronics, photochemistry, and biology. Herein, we investigated shape transformation reactions of zinc 5, 10, 15, 20 tetra(4-pyridyl)-21 H, 23 H-porphine (ZnTPyP)-containing coordination polymer particles (ZnTPyP-CPPs) from seed structures by delicately controlling the Gibbs energy of the self-assembly system. We obtained a morphological transformation from 1 D short nanorods to 1 D long nanorods and 3 D nano-octahedral structures, and from 3 D nano-octahedral structures to 1 D nanorod structures. We illustrated a new method to design and synthesize metalloporphyrin-containing CPPs in a controllable manner. Furthermore, photocatalytic properties of ZnTPyP-CPPs were tested, showing good catalytic abilities towards the photodegradation of methylene blue (MB) under visible light illumination. PMID- 26478837 TI - Lithium Insertion Mechanism in Iron-Based Oxyfluorides with Anionic Vacancies Probed by PDF Analysis. AB - The mechanism of lithium insertion that occurs in an iron oxyfluoride sample with a hexagonal-tungsten-bronze (HTB)-type structure was investigated by the pair distribution function. This study reveals that upon lithiation, the HTB framework collapses to yield disordered rutile and rock salt phases followed by a conversion reaction of the fluoride phase toward lithium fluoride and nanometer sized metallic iron. The occurrence of anionic vacancies in the pristine framework was shown to strongly impact the electrochemical activity, that is, the reversible capacity scales with the content of anionic vacancies. Similar to FeOF type electrodes, upon de-lithiation, a disordered rutile phase forms, showing that the anionic chemistry dictates the atomic arrangement of the re-oxidized phase. Finally, it was shown that the nanoscaling and structural rearrangement induced by the conversion reaction allow the in situ formation of new electrode materials with enhanced electrochemical properties. PMID- 26478838 TI - Development of a Chemical Methodology for the Preparation of Peptide Thioesters Applicable to Naturally Occurring Peptides Using a Sequential Quadruple Acyl Transfer System. AB - Peptide thioesters are very useful in protein chemistry, and chemistry- and biochemistry-based protocols are used for the preparation of thioesters. Among such protocols, only a few biochemistry-based approaches have been use for naturally occurring peptide sequences. The development of chemistry-based protocols applicable to natural sequences remains a challenge, and the development of such methods would be a major contribution to protein science. Here, we describe the preparation of peptide thioesters using innovative methodology that features nickel(II)-mediated alcoholysis of a naturally occurring peptide sequence, followed by O-N and N-S acyl transfers. This protocol involves sequential quadruple acyl transfer, termed SQAT. Notably, the SQAT system consists of sequential chemical reactions that allow naturally occurring peptide sequences to be converted to thioesters without requiring an artificial chemical unit. PMID- 26478839 TI - Synthesis of Arylamine Tribenzopentaphenes and Investigation of their Hole Mobility. AB - We report the versatile synthesis of two tribenzo[fj,ij,rst]pentaphene (TBP) derivatives bearing two diarylamine substituents attached at the opposite ends of the aromatic core. Field effect transistor (FET) devices of the bis-diarylamine TBP compounds were fabricated using spin coating under different concentrations, spin speed, and solvent conditions. Emission spectra and surface investigation by atomic force microscopy (AFM) reveal the formation of aggregates induced by the strong pi-pi stacking of the aromatic core leading to island features, and thus, unexpected low hole mobilities. The synthetic strategy we show herein, however, offers the possibility to decorate the TBP core structure with various charge carrier peripheral groups and optimized alkyl chains, which should improve the crystalline property of their thin films upon deposition, leading consequently to a better hole transport mobility. PMID- 26478840 TI - A Practical One-Pot Synthesis of Positron Emission Tomography (PET) Tracers via Nickel-Mediated Radiofluorination. AB - Recently a novel method for the preparation of (18)F-labeled arenes via oxidative [(18)F]fluorination of easily accessible and sufficiently stable nickel complexes with [(18)F]fluoride under exceptionally mild reaction conditions was published. The suitability of this procedure for the routine preparation of clinically relevant positron emission tomography (PET) tracers, 6-[(18)F]fluorodopamine (6 [(18)F]FDA), 6-[(18)F]fluoro-l-DOPA (6-[(18)F]FDOPA) and 6-[(18)F]fluoro-m tyrosine (6-[(18)F]FMT), was evaluated. The originally published base-free method was inoperative. However, a "low base" protocol afforded protected radiolabeled intermediates in radiochemical conversions (RCCs) of 5-18 %. The subsequent deprotection step proceeded almost quantitatively (>95 %). The simple one-pot two step procedure allowed the preparation of clinical doses of 6-[(18)F]FDA and 6 [(18)F]FDOPA within 50 min (12 and 7 % radiochemical yield, respectively). In an unilateral rat model of Parkinsons disease, 6-[(18)F]FDOPA with high specific activity (175 GBq MUmol(-1)) prepared using the described nickel-mediated radiofluorination was compared to 6-[(18)F]FDOPA with low specific activity (30 MBq MUmol(-1)) produced via conventional electrophilic radiofluorination. Unexpectedly both tracer variants displayed very similar in vivo properties with respect to signal-to-noise ratio and brain distribution, and consequently, the quality of the obtained PET images was almost identical. PMID- 26478841 TI - Functionalization of a Rigid Divalent Ligand for LecA, a Bacterial Adhesion Lectin. AB - The bacterial adhesion lectin LecA is an attractive target for interference with the infectivity of its producer P. aeruginosa. Divalent ligands with two terminal galactoside moieties connected by an alternating glucose-triazole spacer were previously shown to be very potent inhibitors. In this study, we chose to prepare a series of derivatives with various new substituents in the spacer in hopes of further enhancing the LecA inhibitory potency of the molecules. Based on the binding mode, modifications were made to the spacer to enable additional spacer protein interactions. The introduction of positively charged, negatively charged, and also lipophilic functional groups was successful. The compounds were good LecA ligands, but no improved binding was seen, even though altered thermodynamic parameters were observed by isothermal titration calorimetry (ITC). PMID- 26478842 TI - Tetra- versus Pentavalent Inhibitors of Cholera Toxin. AB - The five B-subunits (CTB5) of the Vibrio cholerae (cholera) toxin can bind to the intestinal cell surface so the entire AB5 toxin can enter the cell. Simultaneous binding can occur on more than one of the monosialotetrahexosylganglioside (GM1) units present on the cell surface. Such simultaneous binding arising from the toxins multivalency is believed to enhance its affinity. Thus, blocking the initial attachment of the toxin to the cell surface using inhibitors with GM1 subunits has the potential to stop the disease. Previously we showed that tetravalent GM1 molecules were sub-nanomolar inhibitors of CTB5. In this study, we synthesized a pentavalent version and compared the binding and potency of penta- and tetravalent cholera toxin inhibitors, based on the same scaffold, for the first time. The pentavalent geometry did not yield major benefits over the tetravalent species, but it was still a strong inhibitor, and no major steric clashes occurred when binding the toxin. Thus, systems which can adopt more geometries, such as those described here, can be equally potent, and this may possibly be due to their ability to form higher-order structures or simply due to more statistical options for binding. PMID- 26478843 TI - Multistimuli-Responsive Luminescence of Naphthalazine Based on Aggregation Induced Emission. AB - Stimuli-responsive luminescent materials, which are dependent on changes in physical molecular packing modes, have attracted more and more interest over the past ten years. In this study, 2,2-dihydroxy-1,1-naphthalazine was synthesized and shown to exhibit different fluorescence emission in solution and solid states with characteristic aggregation-induced emission (AIE) properties. A remarkable change in the fluorescence of 2,2-dihydroxy-1,1-naphthalazine occurred upon mechanical grinding, heating, or exposure to solvents. According to the characterization by solid-state fluorescence spectroscopy, X-ray crystallography, differential scanning calorimetry, and X-ray powder diffraction, the fluorescence change could be attributed to transitions between two structurally different polymorphs. These significant properties could also give 2,2-dihydroxy-1,1 naphthalazine more potential applications as a multifunctional material. PMID- 26478844 TI - Highly Efficient Synthesis of Optically Pure (S)-1-phenyl-1,2-ethanediol by a Self-Sufficient Whole Cell Biocatalyst. AB - Terminal vicinal diols are important chiral building blocks and intermediates in organic synthesis. Reduction of alpha-hydroxy ketones provides a straightforward approach to access these important compounds. In this study, it has been found that asymmetric reduction of a series of alpha-hydroxy aromatic ketones and 1 hydroxy-2-pentanone, catalyzed by Candida magnolia carbonyl reductase (CMCR) with glucose dehydrogenase (GDH) from Bacillus subtilis for cofactor regeneration, afforded 1-aryl-1,2-ethanediols and pentane-1,2-diol, respectively, in up to 99 % ee. In order to evaluate the efficiency of the bioreduction, lyophilized recombinant Escherichia coli whole cells coexpressing CMCR and GDH genes were used as the biocatalyst and alpha-hydroxy acetophenone as the model substrate, and the reaction conditions, such as pH, cosolvent, the amount of biocatalyst and the presences of a cofactor (i.e., NADP(+)), were optimized. Under the optimized conditions (pH 6, 16 h), the bioreduction proceeded smoothly at 1.0 m substrate concentration without the external addition of cofactor, and the product (S)-1 phenyl-1,2-ethanediol was isolated with 90 % yield and 99 % ee. This offers a practical biocatalytic method for the preparation of these important vicinal diols. PMID- 26478845 TI - Novel Carbazole (Cbz)-Based Carboxylated Functional Monomers: Design, Synthesis, and Characterization. AB - A series of novel functional carbazole (Cbz)-based carboxylated monomers were synthesized and characterized. A Clauson-Kaas procedure, a deprotection step, amide coupling, and hydrolysis were utilized as key chemical reactions towards the multistep synthesis of monomers in good to excellent isolated yields. The design strategy was further extended to complex carbazole-COOH monomers incorporated arylazo groups as photoreactive moieties. In addition, photoreactive hybrid carbazole (Cbz)-pyrrole (Pyr)-based carboxylated monomers, comprising a pyrrole core linking a carbazole and a photoreactive phenylazide or benzophenone moiety through an amide spacer in the molecular structure, were also synthesized. The latter can be utilized for surface modification of polymeric films in their monomeric form or as polymeric microparticles (MPs). PMID- 26478846 TI - Picking Out Logic Operations in a Naphthalene beta-Diketone Derivative by Using Molecular Encapsulation, Controlled Protonation, and DNA Binding. AB - On-off switching and molecular logic in fluorescent molecules are associated with what chemical inputs can do to the structure and dynamics of these molecules. Herein, we report the structure of a naphthalene derivative, the fashion of its binding to beta-cyclodextrin and DNA, and the operation of logic possible using protons, cyclodextrin, and DNA as chemical inputs. The compound crystallizes out in a keto-amine form, with intramolecular N-H???O bonding. It shows stepwise formation of 1:1 and 1:2 inclusion complexes with beta-cyclodextrin. The aminopentenone substituents are encapsulated by beta-cyclodextrin, leaving out the naphthalene rings free. The binding constant of the beta-cyclodextrin complex is 512 m(-1). The pKa value of the guest molecule is not greatly affected by the complexation. Dual input logic operations, based on various chemical inputs, lead to the possibility of several molecular logic gates, namely NOR, XOR, NAND, and Buffer. Such chemical inputs on the naphthalene derivative are examples of how variable signal outputs based on binding can be derived, which, in turn, are dependent on the size and shape of the molecule. PMID- 26478847 TI - Thermodynamics of Self-Assembly of Dicarboxylate Ions with Binuclear Lanthanide Complexes. AB - Self-assembly of a range of carboxylic acids (benzoic acid, dinicotinic acid, nicotinic acid, and isophthalic acid) with the europium complex of 5-nitro alpha,alpha'-bis(DO3Ayl)-m-xylene (where DO3A is 1,4,7,10-tetraazacyclododecane 1,4,7-triacetic acid) has been explored to establish the thermodynamics of binding in a range of solvent systems and in a range of aqueous buffer solutions. In this system, profound effects are observed as a consequence of competition by the hydroxide ion, which outcompetes even dinicotinate at high pH. In the case of isophthalate, which binds most strongly, and dinicotinate, both enthalpic and entropic contributions to binding have been identified. The europium complex with 5-nitro-alpha,alpha'-bis(DO3Ayl)-m-xylene is found to have a solution structure significantly different from the related europium complex of 5-amino-alpha,alpha' bis(DO3Ayl)-m-xylene. It is found that phosphate binds strongly to the europium complex of the nitro derivate but not to the europium complex of amino derivative. Lactate, citrate, and pyruvate also bind strongly to 5-nitro alpha,alpha'-bis(Eu?DO3Ayl)-m-xylene, and it is concluded that the solution structure of this binuclear lanthanide complex is significantly different from that of the amino-substituted complex. PMID- 26478848 TI - Solvent-Tuned Self-Assembled Nanostructures of Chiral l/d-Phenylalanine Derivatives of Protoporphyrin IX. AB - Protoporphyrin IX is a naturally occurring amphiphilic porphyrin with a rigid hydrophobic nonpolar core and two polar propionic acid substitutions on the porphyrin ring. This molecule can be modified on the hydrophilic group, which can lead to strengthened pi-pi-stacking and spontaneous self-assembly into novel nanostructures. Herein, we use l- phenylalanine and d-phenylalanine to modify protoporphyrin IX, and use the two derivatives for solvophobic-controlled self assembly. Both derivatives possess two important features: 1) the aromatic core of the porphyrin for dispersive interactions and 2) a chiral amino acid to maximize the influence of chirality on selfassembly. These derivatives lead to the formation of a variety of nanostructure morphologies, such as spheres, nanofibers, lamellar structures, and thread-like and spherical shells. Solution based self-assembly was determined by UV/Vis, fluorescence, and circular dichroism spectroscopy, and the formed nanostructures were characterized by scanning electron microscopy (SEM). Such engineered porphyrin derivatives could have potential applications in energy transport and storage, supramolecular chemistry, materials science, and medicine. PMID- 26478849 TI - Metal-Organic Chemical Vapor Deposition (MOCVD) Synthesis of Heteroepitaxial Pr0.7Ca0.3MnO3 Films: Effects of Processing Conditions on Structural/Morphological and Functional Properties. AB - Calcium-doped praseodymium manganite films (Pr0.7Ca0.3MnO3, PCMO) were prepared by metal-organic chemical vapor deposition (MOCVD) on SrTiO3 (001) and SrTiO3 (110) single-crystal substrates. Structural characterization through X-ray diffraction (XRD) measurements and transmission electron microscopy (TEM) analyses confirmed the formation of epitaxial PCMO phase films. Energy dispersive X-ray (EDX) and X-ray photoelectron spectroscopy (XPS) characterization was used to confirm lateral and vertical composition and the purity of the deposited films. Magnetic measurements, obtained in zero-field-cooling (ZFC) and field cooling (FC) modes, provided evidence of the presence of a ferromagnetic (FM) transition temperature, which was correlated to the transport properties of the film. The functional properties of the deposited films, combined with the structural and chemical characterization collected data, indicate that the MOCVD approach represents a suitable route for the growth of pure, good quality PCMO for the fabrication of novel spintronic devices. PMID- 26478850 TI - Responsive Polymer Photonics. PMID- 26478851 TI - New Synthetic Receptors for Molecular Recognition of Anions and Their Practical Applications. PMID- 26478852 TI - Towards immersive virtual reality (iVR): a route to surgical expertise. AB - Surgery is characterized by complex tasks performed in stressful environments. To enhance patient safety and reduce errors, surgeons must be trained in environments that mimic the actual clinical setting. Rasmussen's model of human behavior indicates that errors in surgical procedures may be skill-, rule-, or knowledge-based. While skill-based behavior and some rule-based behavior may be taught using box trainers and ex vivo or in vivo animal models, we posit that multimodal immersive virtual reality (iVR) that includes high-fidelity visual as well as other sensory feedback in a seamless fashion provides the only means of achieving true surgical expertise by addressing all three levels of human behavior. While the field of virtual reality is not new, realization of the goals of complete immersion is challenging and has been recognized as a Grand Challenge by the National Academy of Engineering. Recent technological advances in both interface and computational hardware have generated significant enthusiasm in this field. In this paper, we discuss convergence of some of these technologies and possible evolution of the field in the near term. PMID- 26478853 TI - Finding the loopholes: a cross-sectional qualitative study of systemic barriers to treatment access for women drug court participants. AB - BACKGROUND: Therapeutic diversion courts seek to address justice-involved participants' underlying problems leading to their legal system involvement, including substance use disorder, psychiatric illness, and intimate partner violence. The courts have not addressed systemic hurdles, which can contribute to a cycle of substance use disorder and recidivism, which in turn hinder health and wellness. The study purpose is to explore the systemic issues faced by women participants in drug treatment court from multiple perspectives to understand how these issues may relate to health and wellness in their lives. METHODS: Qualitative thematic framework analysis of five separate focus groups consisting of female drug treatment court participants, community providers, and court staff (n = 25). Themes were mapped across the socio-ecological framework and contextualized according to social determinants of health. RESULTS: Numerous systemic factors impacted women's access to treatment. Laws and legal policies (governance) excluded those who could potentially have benefitted from therapeutic court and did not allow consideration of parenting issues. Macroeconomic policies limit housing options for those with convictions. Social policies limited transportation, education, and employment options. Public policies limited healthcare and social protection and ability to access available resources. Culture and societal values, including stigma, limited treatment options. CONCLUSIONS: By understanding the social determinant of health for women in drug treatment court and stakeholder's perceptions, the legal system can implement public policy to better address the health needs of women drug court participants. PMID- 26478854 TI - Children and unintentional firearm death. AB - BACKGROUND: Children in the United States are at far greater risk of unintentional gun death than children in other developed countries. The relative figures may even be worse since the estimates for US child unintentional gun deaths are derived from the Vital Statistics which have been shown to be underestimates. No study has used a national data system to investigate the circumstances of fatal child gun accidents. METHODS: We use data from the National Violent Death Reporting System for 16 states from 2005 to 2012. We examine the cases of unintentional gun death involving children in five age groups, 0-1, 2-4, 5-10, 11-12, and 13-14, where the child was either the victim or shooter. RESULTS: We estimate that there were 110 unintentional firearm deaths to children 0-14 annually in the U.S. during this 8 year time period, 80 % higher than reported by the Vital Statistics. The victims were predominantly male (81 %). Approximately two thirds of the shootings were other-inflicted, and in 97 % of those cases the shooter was a male. The typical shooter in other-inflicted shootings is a brother or friend. Indeed, children aged 11-14 are often shot in the home of friends. The large majority of children are shot by other children or by themselves. It is rare for a child accidentally to be shot by or accidentally to shoot an adult who is not a family member. CONCLUSIONS: Our study highlights the fact that unintentional firearm death to children is a problem of children shooting children and thus the importance of keeping guns away from children, their siblings, and their friends. PMID- 26478855 TI - Resveratrol and Malignancies. AB - Carcinogenesis is a multifactorial process, frequently encompassing 3 stages: initiation, promotion and progression. It is characterized by multiple deviations from normal both at the cell and organism levels. Although most people have a small number of cells that present deviations from normal, most of those cells will not cause cancer. However, some will. What tips the balance between normal and abnormal is the subject of intense scientific research as well as unfounded speculations. Chronic inflammation is one of the risk factors for cancer. Resveratrol is consumed by the population as a dietary supplement in the hope of decreasing the risk of inflammation and cancer and other chronic diseases such as diabetes and vascular diseases. There is a discrepancy between the doses used in the animal studies showing that resveratrol decreases all three stages of carcinogenesis, and the doses ingested by the population either as supplements or in the diet. While there is health benefit from using high resveratrol doses, it might be also of practical and scientific benefit to focus future effort in understanding the effects of normal dietary resveratrol levels. PMID- 26478856 TI - Influence of the MCT1 rs1049434 on Indirect Muscle Disorders/Injuries in Elite Football Players. AB - BACKGROUND: The aim of this study was to investigate the association between MCT1 rs1049434 polymorphism and indirect muscle injuries in elite football players. One hundred and seventy-three male elite Italian football players (age = 19.2 +/- 5.3 years) were recruited from a first-league football club participating at the Official National Italian Football Championship (Serie A, Primavera, Allievi, Giovanissimi). The cohort was genotyped for the MCT1 rs1049434 polymorphism, and muscle injuries data were collected during the period of 2009-2014 (five football seasons). METHODS: Genomic DNA was extracted using a buccal swab, and genotyping was performed using PCR method. Structural-mechanical injuries and functional muscle disorder were included in the acute indirect muscle injury group. RESULTS: Participants with the MCT1 AA (AA = 1.57 +/- 3.07, n = 69) genotype exhibit significantly higher injury incidents compared to participants with the TT genotype (TT = 0.09 +/- 0.25, n = 22, P = 0.04). CONCLUSIONS: The MCT1 rs1049434 polymorphism is associated with the incidence of muscle injuries in elite football players. We anticipate that the knowledge of athletes' genetic predisposition to sports-related injuries might aid in individualizing training programs. PMID- 26478857 TI - Increased Insulin mRNA Binding Protein-3 Expression Correlates with Vascular Enhancement of Renal Cell Carcinoma by Intravenous Contrast-CT and is Associated with Bone Metastasis. AB - PURPOSE: To: 1) assess the correlation between CT vascularity and a candidate molecular marker of RCC metastasis (insulin-like mRNA binding protein-3 (IMP3)); and 2) demonstrate the differential expression of IMP3 in high vs. low vascular tumors. EXPERIMENTAL DESIGN: Retrospectively obtained contrast CT from 72 patients with primary RCC were used to establish threshold values for Low, Intermediate and High tumor vascularity. Paired histopathology specimens from 33 of these patients were used for immunohistochemistry (IHC) to correlate CT with IMP-3 expression. IMP-3 gene expression studies were performed on RCC and poorly vascular prostate cancer (PC) human bone metastases samples to confirm presence of IMP3 in metastatic samples from RCC. Gene expression studies were performed on RCC 786-O and PC3 cell lines to confirm the presence of high expression of IMP3 in the RCC cell line. RESULTS: IMP-3 expression positively correlated with CT vascular enhancement (p<0.01). IMP3 expression by IHC was strongly positive in all RCC, but weak in PC bone metastases. Real time RT-PCR demonstrated a significant 4-fold increase in imp-3 expression in RCC 786-O vs. PC3 cells in vitro (p<0.001). CONCLUSION: Quantitation of pre-operative CT is a feasible method to phenotype primary RCC vascularity, which correlates with IMP-3 expression. In situ and cell line studies demonstrate an association between high IMP-3 expression and RCC bone metastasis. Studies aimed at defining the diagnostic potential of biomarkers for RCC bone metastasis, and functional significance of IMP-3 in RCC vascularity and tumor progression are warranted. PMID- 26478858 TI - Changing plasmid types responsible for extended spectrum cephalosporin resistance in Escherichia coli O157:H7 in the United States, 1996-2009. AB - Escherichia coli O157 is a major cause of foodborne illness. Plasmids are genetic elements that mobilize antimicrobial resistance determinants including blaCMY beta-lactamases that confer resistance to extended-spectrum cephalosporins (ESC). ESCs are important for treating a variety of infections. IncA/C plasmids are found among diverse sources, including cattle, the principal source of E. coli O157 infections in humans. IncI1 plasmids are common among E. coli and Salmonella from poultry and other avian sources. To broaden our understanding of reservoirs of blaCMY, we determined the types of plasmids carrying blaCMY among E. coli O157. From 1996 to 2009, 3742 E. coli O157 isolates were tested. Eleven (0.29%) were ceftriaxone resistant and had a blaCMY-2-containing plasmid. All four isolates submitted before 2001 and a single 2001 isolate had blaCMY encoded on IncA/C plasmids, while all five isolates submitted after 2001 and a single 2001 isolate had blaCMY carried on IncI1 plasmids. The IncI1 plasmids were ST2, ST20, and ST23. We conclude that cephalosporin resistance among E. coli O157:H7 is due to plasmid-encoded blaCMY genes and that plasmid types appear to have shifted from IncA/C to IncI1. This shift suggests either a change in plasmid type among animal reservoirs or that the organism has expanded into avian reservoirs. More analysis of human, retail meat, and food animal isolates is necessary to broaden our understanding of the antimicrobial resistance determinants of ESC resistance among E. coli O157. PMID- 26478859 TI - Improvement of glucaric acid production in E. coli via dynamic control of metabolic fluxes. AB - D-glucaric acid can be used as a building block for biopolymers as well as in the formulation of detergents and corrosion inhibitors. A biosynthetic route for production in E. coli has been developed (Moon et al., 2009), but previous work with the glucaric acid pathway has indicated that competition with endogenous metabolism may limit carbon flux into the pathway. Our group has recently developed an E. coli strain where phosphofructokinase (Pfk) activity can be dynamically controlled and demonstrated its use for improving yields and titers of the glucaric acid precursor myo-inositol on glucose minimal medium. In this work, we have explored the further applicability of this strain for glucaric acid production in a supplemented medium more relevant for scale-up studies, both under batch conditions and with glucose feeding via in situ enzymatic starch hydrolysis. It was found that glucaric acid titers could be improved by up to 42% with appropriately timed knockdown of Pfk activity during glucose feeding. The glucose feeding protocol could also be used for reduction of acetate production in the wild type and modified E. coli strains. PMID- 26478860 TI - The Effect of Gynecologic Oncologist Availability on Ovarian Cancer Mortality. AB - AIM: To determine the association between the distribution of gynecologic oncologist (GO) and population-based ovarian cancer death rates. MATERIALS AND METHODS: Data on ovarian cancer incidence and mortality in the United States (U.S.) was supplemented with U.S. census data, and analyzed in relation to practicing GOs. GO locations were geocoded to link association between county variables and GO availability. Logistic regression was used to measure areas of high and low ovarian cancer mortality, adjusting for contextual variables. RESULTS: Practicing GOs were unevenly distributed in the United States, with the greatest numbers in metropolitan areas. Ovarian cancer incidence and death rates increased as distance to a practicing GO increased. A relatively small number (153) of counties within 24 miles of a GO had high ovarian cancer death rates compared to 577 counties located 50 or more miles away with high ovarian cancer death rates. Counties located 50 or more miles away from a GO practice had an almost 60% greater odds of high ovarian cancer mortality compared to those with closer practicing GOs (OR 1.59, 95% CI 1.18-2.15). CONCLUSION: The distribution of GOs across the United States appears to be significantly associated with ovarian cancer mortality. Efforts that facilitate outreach of GOs to certain populations may increase geographic access. Future studies examining other factors associated with lack of GO access (e.g. insurance and other socioeconomic factors) at the individual level will assist with further defining barriers to quality ovarian cancer care in the United States. PMID- 26478861 TI - Anesthesia Experience for Open Gastrostomy With Ultrasound-Guided Unilateral Subcostal Transversus Abdominis Plane Block in a High Risk Elderly Patient: A Case Report. AB - INTRODUCTION: Many papers have reported that TAP block provides effective postoperative analgesia, but the sole use of TAP block for surgical anesthesia has been rarely reported. CASE PRESENTATION: Therefore, we presented an 80-year old male undergoing ultrasound-guided unilateral subcostal TAP block providing surgical anesthesia for open gastrostomy. Left subcostal TAP block was performed using the method described by Hebbard with the M-Turbo((r)) ultrasound system and a linear probe placing immediately inferior and parallel to the costal margin. Using a 100 -mm long, 23 G short-bevel needle in-plane technique, 20 mL of 0.25% levobupivacaine was injected on the TAP. A sensory block from T7 to T11 was established and the satisfaction score was 7 - 8. CONCLUSIONS: Open gastrostomy was successfully performed under subcostal TAP block with small dose fentanyl supplementation. The subcostal TAP block is considered a useful anesthetic choice in surgery for high risk patients. PMID- 26478862 TI - Comparison of the Effects of Magnesium Sulfate and Remifentanil on Hemodynamic Responses During Tracheal Extubation After Laparotomy: A Randomized Double blinded Trial. AB - BACKGROUND: Because blood pressure and heart rate (HR) elevations during tracheal extubation are common, different medications have been studied to prevent such complications. OBJECTIVES: To compare magnesium sulfate, remifentanil, and placebo regarding mean arterial pressure (MAP) and HR changes during/after tracheal extubation, in patients who underwent laparotomy. MATERIALS AND METHODS: In this randomized double-blinded trial, 120 patients undergoing laparotomy were evenly divided into three groups, including remifentanil (1 mcg/kg), magnesium sulfate (50 mg/kg), or normal saline, as placebo. Hemodynamic responses (MAP and HR) were documented at different times (before operation, during medication administration, immediately before extubation, immediately after extubation, and also 3, 5, and 10 minutes after extubation). The double burst time (DBT) was determined using neuromuscular monitoring, as time interval, between administration of reverse medication and DBT of 100%. RESULTS: The HR was significantly lower, immediately after extubation and 3, 5, and 10 minutes after extubation, in both magnesium and remifentanil groups, compared to normal saline (P < 0.001). The MAP was also lower in magnesium and remifentanil groups, immediately after extubation and 3 minutes after extubation, in comparison to the normal saline group (P < 0.001). Mean (+/- SD) DBT 100% was significantly higher in magnesium group (30.2 +/- 15.3) vs. remifenatnil (13.6 +/- 6.8) and normal saline (13.5 +/- 8.2) groups (P < 0.001). CONCLUSIONS: Both remifentanil and magnesium had favorable outcomes in preventing HR and MAP elevation after tracheal extubation. However, remifentanil was associated with more rapid regaining of consciousness and reversal of muscular relaxation. PMID- 26478863 TI - Comparing the Duration of Spinal Anesthesia Induced With Bupivacaine and a Bupivacaince-Lidocaine Combination in Trans-Urethral Resection of the Prostate (TURP). AB - BACKGROUND: Spinal anesthesia is a safe anesthetic mode for transurethral prostate resection (TUPR). There are several studies assessing the effect of bupivacaine, lonely or accompanied by other drugs, on short duration operations. However, there is controversy regarding the exact combination. OBJECTIVES: The aim of the study was to compare the effects of spinal anesthesia with bupivacaine and low dose lidocaine with bupivacaine alone on postoperative pain in those undergoing transurethral resection of prostate (TURP). MATERIALS AND METHODS: This was a randomized clinical trial performed in Shiraz university of medical sciences during one year. Eighty men scheduled for TURP were randomly assigned to receive spinal anesthesia with 1.5 mL bupivacaine 0.6% and 0.6 mL Lidocaine 1% or spinal anesthesia with 1.5 mL bupivacaine 0.5% in combination with 0.6 mL normal saline. The primary endpoint was the time lag between induction of spinal anesthesia and reaching the highest spinal block level. We also recorded the duration of spinal block declining to L1 level, operation duration and the admission duration. RESULTS: Both study groups were comparable regarding the baseline characteristics. We did not find any difference between the two study groups regarding the duration of anesthetic block reaching the maximum level (P = 0.433) and duration of decreasing it to L1 (P = 0.189). The course of postoperative recovery and duration of hospital admission were also comparable between the groups (P = 0.661). CONCLUSIONS: Lidocaine does not have additive effects on duration and quality of spinal anesthesia with bupivacaine in those undergoing TURP. PMID- 26478864 TI - Caudal Anesthesia for Open Bladder Surgery in High-Risk Adolescent With Scoliosis and Neural Tube Defect. PMID- 26478865 TI - Effect of Trigger Sensitivity on Redistribution of Ventilation During Pressure Support Ventilation Detected by Electrical Impedance Tomography. AB - BACKGROUND: In supine position, pressure support ventilation causes a redistribution of ventilation towards the ventral regions of the lung. Theoretically, a less sensitive support trigger would cause the patient to breathe more actively, potentially attenuating the effect of positive pressure ventilation. OBJECTIVES: To quantify the effect of trigger setting, we assessed redistribution of ventilation during pressure support ventilation (PSV) using electrical impedance tomography (EIT). PATIENTS AND METHODS: With approval from the local ethics committee, six orthopedic patients were enrolled. All patients had general anesthesia with a laryngeal mask airway and a standardized anesthetic regimen (sufentanil, propofol and sevoflurane). Pressure support trigger settings varied between 2 and 15 L/minute and compared to unassisted spontaneous breathing. From EIT data, the center of ventilation (COV), the fraction of the total ventilation per region of interest (ROI) and intratidal gas distribution were calculated. RESULTS: At all trigger settings, pressure support ventilation caused a significant ventral shift of the center of ventilation compared with during spontaneous breathing, confirmed by the analysis by regions of interest. During spontaneous breathing, COV was not different from baseline values obtained before induction of anesthesia. During PSV, the intratidal regional gas distribution (ITV-analysis) revealed subtle changes during the early inspiratory phase not detected by the COV-analysis. CONCLUSIONS: Pressure support ventilation, but not spontaneous breathing, induces a significant redistribution of ventilation towards the ventral region. The sensitivity of the support trigger appears to influence the distribution of ventilation only during the early phase of inspiration. PMID- 26478866 TI - Heparinized and Saline Solutions in the Maintenance of Arterial and Central Venous Catheters After Cardiac Surgery. AB - BACKGROUND: Heparinized saline solution is used to prevent occlusion in the arterial catheters and central venous pressure monitoring catheters. Even at low dose, heparin administration can be associated with serious complications. Normal saline solution can maintain patency of arterial catheters and central venous pressure monitoring catheters. OBJECTIVES: The current study aimed to compare the efficacy of normal saline with that of heparinized one to maintain patency of arterial and central venous catheters after cardiac surgery. PATIENTS AND METHODS: In the current randomized controlled trial, 100 patients, with an age range of 18 - 65 years of valve and coronary artery surgery were studied in Rajaie heart center, Tehran, Iran. Patients were randomized to receive either heparinized saline (n = 50) or normal saline flush solutions (n = 50). In the study, arterial catheters and central venous pressure monitoring catheters were daily checked for any signs of occlusion in three postoperative days as primary end-point of the study. RESULTS: According to the information obtained from the study, four (8%) arterial catheters in the saline group (P value: 0.135) and three (6%) arterial catheters in the heparin group (P value = 0.097) were obstructed. Statistical analysis showed that the incidence of obstruction and changes in all other parameters between the two groups during the three-day follow-up was not significant (all P values > 0.05). CONCLUSIONS: It seems that there is no difference in the use of heparinized and normal saline solutions to prevent catheter occlusion of arterial and central venous pressure. PMID- 26478867 TI - Efficacy of Pregabalin in the Treatment of Radicular Pain: Results of a Controlled Trial. AB - BACKGROUND: Pregabalin is commonly used to treat patients with various neuropathic pain syndromes. OBJECTIVES: The purpose of the present study was to evaluate the efficacy of pregabalin in patients with lumbar or cervical radicular pain. PATIENTS AND METHODS: A prospective, randomized, double-blind trial was conducted in 39 patients with lumbar and cervical radicular pain, who received 3 weeks of either pregabalin (n = 10) or placebo (n = 9) treatment. Baseline pain and disability were evaluated before the treatment and were re-evaluated, along with overall patient satisfaction, after the 3 weeks of treatment. RESULTS: Data on 19 of the 39 patients recruited were available for analysis. No statistically significant differences in the pain, disability, and patient satisfaction scores were found between the groups. When the individual patient scores were assessed, the placebo treatment was found to be efficacious in 4 of the 9 patients and pregabalin was effective in 2 of the 10 patients, but the difference was not statistically significant (P = 0.350). CONCLUSIONS: The present data do not suggest that pregabalin is more efficacious than placebo in the treatment of lumbar and cervical radicular pain. However, the small sample size of this study may have affected the ability to detect such a difference. PMID- 26478869 TI - Effect of iron oxide nanoparticles coating type on the relationship between nanoparticles concentration and signal intensity in inversion recovery T1 weighted MRI. AB - BACKGROUND: Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are used as blood pool contrast agent for magnetic resonance angiography and perfusion imaging. Our aim in this study was to investigate the effect of the two coating types of iron oxide nanoparticles on the relationship between nanoparticles concentration and signal intensity (SI) in T1-weighted MR images. METHODS: Different concentrations of the polyethylene glycol (PEG), and carboxydextran-coated iron oxide nanoparticles were imaged using inversion recovery Turbo-FLASH (Turbo fast low-angle shot) pulse sequence with inversion times (TIs) of 300-900 ms (interval of 100 ms). The maximum non-linear and linear relationship between the corrected SI (after non-uniformity correction) and the concentration of the two coated nanoparticles were calculated in T1-weighted images. RESULTS: The maximum non-linear relationship between the corrected SI and the concentration of the PEG, and carboxydextran-coated nanoparticles were obtained at concentrations of 400 and 200 MUmol Fe/L at a TI of 900 ms, respectively. In addition, the maximum linear relationship between the corrected SI and the concentration of the PEG, and carboxydextran-coated nanoparticles (R2=0.99) appeared at 228.184 and 205.654 MUmolFe/L with a TI of 300 ms, respectively. CONCLUSION: The maximum non-linear corrected SI of the carboxydextran-coated nanoparticles was slightly higher than that of the PEG coated nanoparticles at similar TIs. However, the PEG-coated nanoparticles were better than the carboxydextran-coated nanoparticles as a T1 contrast agent for perfusion measurements. PMID- 26478870 TI - Therapeutic effects of Ventolin versus hypertonic saline 3% for acute bronchiolitis in children. AB - BACKGROUND: Complications of Ventolin as the most common drug used for bronchiolitis are widely known. The present study was conducted to determine the efficacy of hypertonic saline 3%, compared with Ventolin, for treatment of acute bronchiolitis in children. METHODS: This double-blinded clinical trial study was conducted in Hajar Hospital, Shahrekord, Iran, from 2011 to 2012. A total of 70 patients under the age of two years with bronchiolitis were divided into two groups of 35 each. Ventolin nebulizer and hypertonic saline 3% nebulizer three times per day were administered in the first (Ventolin) and second (Hypersaline) group, respectively. The length of recovery was compared between the two groups. The data were analyzed by SPSS software (version 22) using chi-square, t-test, paired t-test, and Mann-Whitney. RESULTS: The mean+/-SD length of recovery was 4.14+/-0.9 and 3.06+/-0.6 in the Ventolin and hypersaline groups, respectively. The mean duration of recovery was significantly lower in the hypersaline group (p<0.001). CONCLUSION: Hypertonic saline 3% nebulizer has more pleasant therapeutic effects on acute bronchiolitis than Ventolin. Therefore, use of hypertonic saline 3% nebulizer is recommended for the treatment of acute bronchiolitis in children under two years old. PMID- 26478868 TI - The TREM2-DAP12 signaling pathway in Nasu-Hakola disease: a molecular genetics perspective. AB - Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a rare recessively inherited disease that is associated with early dementia and bone cysts with fractures. Here, we review the genetic causes of PLOSL with loss-of-function mutations or deletions in one of two genes, TYROBP and TREM2, encoding for two proteins DNAX-activating protein 12 (DAP12) and triggering receptor expressed on myeloid cells-2 (TREM2). TREM2 and DAP12 form an immunoreceptor signaling complex that mediates myeloid cell, including microglia and osteoclasts, development, activation, and function. Functionally, TREM2-DAP12 mediates osteoclast multi-nucleation, migration, and resorption. In microglia, TREM2-DAP12 participates in recognition and apoptosis of neuronal debris and amyloid deposits. Review of the complex immunoregulatory roles of TREM2-DAP12 in the innate immune system, where it can both promote and inhibit pro-inflammatory responses, is given. Little is known about the function of TREM2-DAP12 in normal brain homeostasis or in pathological central nervous system diseases. Based on the state of the field, genetic testing now aids in diagnosis of PLOSL, but therapeutics and interventions are still under development. PMID- 26478871 TI - The effects of symbiotic therapy on anthropometric measures, body composition and blood pressure in patient with metabolic syndrome: a triple blind RCT. AB - BACKGROUND: Increase in prevalence of obesity and type 2 diabetes which are of the main risk factors of metabolic syndrome, is not only the result of changes in genetic, diet or physical activity, but also an imbalance of micro flora may play an important role. Therefore, alteration of micro flora using pre/probiotic is considered as a new strategy for treatment of metabolic disorders. METHODS: The current study is a triple blind randomized controlled trial. 46 patients from both sexes, who fulfilled inclusion criteria, randomly categorized into intervention or placebo group. The intervention and placebo groups consumed 2 probiotic capsules or 2 placebo capsules during 3 months, respectively. Both groups received a weight loss diet, according to their adjusted ideal body weight. Anthropometric, body composition, blood pressure and nutritional measurements were done in the beginning, at 6th week, and at the end of the study. T-test and paired-t test were used for statistical analysis. RESULTS: 40 patients completed the study. BMI, WC, HC, fat mass, lean mass and blood pressure were reduced in all participants (p< 0.05). Systolic blood pressure in symbiotic group was less than placebo group, significantly (p< 0.05). The trend of weight loss in symbiotic group continued at least for 12 weeks while it was stopped at week 6 in placebo group. CONCLUSION: Symbiotic supplement with the weight loss diet had synergistic effects on improvement in systolic blood pressure and anthropometric measurements. Based on our findings, symbiotic can postpone plateau phase of weight loss and it may prevent resistance to further weight loss. PMID- 26478872 TI - High crash areas resulting in injuries and deaths in Tehran traffic areas from november 2011 through february 2012: a geographic information system analysis. AB - BACKGROUND: Evaluation of intra-city roads in terms of environmental factors of motor vehicle injuries can help us to better identify these factors and the share of each of the factors in injuries. Therefore, this study was conducted to determine the high injury areas and the risk factors of motor vehicle crashes resulting in injury and death in Tehran, the capital city of Iran, from November 2011 through February 2012. METHODS: In this cross sectional study, the locations of the motor vehicle injuries resulting in injuries and deaths were obtained from police stations in Tehran. The coordinates of the injuries locations were extracted and entered into the Arc-GIS software to overlay the different layers of geographical data and extract the risk map. RESULTS: A total of 4257 motor vehicle injuries were evaluated in this study. Forty-two injuries (1%) resulted in death and 4215 injuries (99%) resulted in injury. The traffic districts 5 and 21 had the highest frequency of injuries resulting in death. The type of the motor vehicle resulting in injury or death was motorcycle in 2330 injuries (54.73%). CONCLUSION: The frequency of traffic injuries is more in the west and northwest areas of Tehran, and it is caused more by motorcycles in terms of traffic and motor injuries resulting in injury and death. It is useful to conduct more studies to better identify these factors considering their importance in traffic injuries. PMID- 26478873 TI - Remifentanil versus dexmedtomidine for posterior spinal fusion surgery. AB - BACKGROUND: Controlling the hemodynamic situation of patients who have spinal operation is of prime importance, and maintaining the heart rate and blood pressure in normal or low- normal levels in these patients can reduce their bleeding loss. One of the commonly used drugs for this purpose is remifentanil. Another sedative-hypnotic-analgesic drug, with acceptable effects is dexmedetomidine. The aim of this study was to compare the effect of dexmedetomidine with remifentanil in spinal operation. METHODS: In a double blind randomized clinical trial, using random sampling method, 60 patients with the age range of 15-65 years who were candidates for posterior spinal fusion operation were included. Induction of anesthesia was performed, and both groups received isoflurane 1% during the surgery. Remifentanil was injected via infusion pump in one group. The patients in the trial group received dexmedetomidine. As trial outcomes, heart rate and blood pressure were measured before, after induction and during the operation. Pain score, sedation score and the need to analgesic therapy were recorded in the recovery room and the ward. Independent sample t test and chi-square were used for statistical analysis. RESULTS: Dexmedetomidine had a significant lowering impact on intraoperative blood pressure and heart rate compared to remifentanil (p<0.001). The mean of sedation scores after extubation in patients who received dexmedetomidine was significantly higher than the sedation scores in patients who received remifentanil (p<0.001). The mean of post extubation and recovery pain score in patients taking remifentanil was significantly higher than patients taking dexmedetomidine (p<0.05). CONCLUSION: Dexmedetomidine in patients with spinal operation is associated with lower postoperative pain score and intraoperative bleeding. Hemodynamic effects are significantly better in patients received dexmedetomidine. PMID- 26478874 TI - Vestibular evoked myogenic potentials in patients with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune systemic disease. Most common autoimmune diseases are multisystem disorders that may also present with otological manifestations, and autoimmune inner ear disease accompanied by vestibular dysfunction. This study aimed to compare the vestibular function between RA patients and normal subjects using cervical vestibular evoked myogenic potentials (cVEMPs). METHODS: In this cross- sectional study, 25patients with RA (19 female and 6 male: mean (+/-SD) age, 40.00 (+/-7.92) years) and 20 healthy subjects (15 female and 5 male: mean (+/-SD) age, 35.35 (+/-10.48) years) underwent cVEMPs, using 500 Hz-tone bursts at 95 dB nHL intensity level. Data were analyzed using independent sample t-test through SPSS software v. 16. RESULTS: The mean peak latency of p13 was significantly higher in RA patients (p<0.001). The mean peak latency of n23 was significantly higher in patients in the left ear (p=0.03). Vestibular evoked myogenic potential (VEMP) responses were present in all (100%) of the participants. There were no significant differences in mean peak to peak amplitude and amplitude ratio between the two groups. CONCLUSION: According to the prolonged latency of VEMP responses in RA patients, lesions in the retrolabyrinthine, especially in the vestibulospinal tract are suspected. PMID- 26478875 TI - Ranking Iranian biomedical research centers according to H-variants (G, M, A, R) in Scopus and Web of Science. AB - BACKGROUND: We conducted a comprehensive bibliometrics analysis to calculate the H, G, M, A and R indicators for all Iranian biomedical research centers (IBRCs) from the output of ISI Web of Science (WoS) and Scopus between 1991 and 2010. We compared the research performance of the research centers according to these indicators. METHODS: This was a cross-sectional and descriptive-analytical study, conducted on 104 Iranian biomedical research centers between August and September 2011. We collected our data through Scopus and WoS. Pearson correlation coefficient between the scientometrics indicators was calculated using SPSS, version 16. RESULTS: The mean values of all indicators were higher in Scopus than in WoS. Drug Applied Research Center of Tabriz University of Medical Sciences had the highest number of publications in both WoS and Scopus databases. This research center along with Royan Institute received the highest number of citations in both Scopus and WoS, respectively. The highest correlation was seen between G and R (.998) in WoS and between G and R (.990) in Scopus. Furthermore, the highest overlap of the 10 top IBRCs was between G and H in WoS (100%) and between G-R (90%) and H-R (90%) in Scopus. CONCLUSION: Research centers affiliated to the top ranked Iranian medical universities obtained a better position with respect to the studied scientometrics indicators. All aforementioned indicators are important for ranking bibliometrics studies as they refer to different attributes of scientific output and citation aspects. PMID- 26478876 TI - Serum and saliva collagenase-3 (MMP-13) in patients with oral lichen planus and oral squamous cell carcinoma. AB - BACKGROUND: Oral lichen planus (OLP) has been classified as a pre-malignant condition. Matrix metalloproteinase-13 (MMP-13) or collagenase-3 may play a key role in cancer development. The aim of this study was to compare serum and saliva MMP-13 between patients with oral lichen planus (OLP) and oral squamous cell carcinoma (OSCC). METHODS: This cross sectional study was performed on 30 patients with OLP (8 reticular and 22 erosive forms) and 20 patients with OSCC (6 in low stage and 14 in advanced stage) who were selected randomly. The study was conducted at the Cancer Department, Clinic of Oral Medicine, Tehran University of Medical Sciences. The serum and saliva MMP-13 were assayed by ELISA method. Statistical analysis of the Student's t-test, ANOVA and Pearson correlation coefficient was performed. RESULTS: There were no significant differences in mean saliva and serum levels of MMP-13 between patients with OSCC and OLP and their subgroups. Serum MMP-13 correlated significantly with unstimulated (r = 0.307, p= 0.048), but not with stimulated, saliva MMP-13. CONCLUSION: Serum and saliva MMP 13 levels appear to be statistically similar in OLP and OSCC. PMID- 26478877 TI - Correlation between CRP and early failure of arteriovenous fistula (AVF). AB - BACKGROUND: Arteriovenous Fistula (AVF) is the ideal method of vascular access for patients on maintenance hemodialysis (HD). Therefore it is an important part of treatment in HD. There are several observations that indicate the role of inflammation in failure of AVF. The aim of this study was to evaluate the hematologic and inflammatory biomarkers in early AVF failure. METHODS: This case control study included 110 ESRD patients, whom were undergone AVF creation, divided in two groups. About 700 radius-cephalic AVF were created during these two years. We found 55 cases with AVF failure. In this study, we compared those 55 failures with 55 functional AVF which were selected using randomized sampling from the rest of patients according to age, gender, and AVF location. Levels of serum C-reactive protein (CRP) were checked in both groups to evaluate the relation between AVF failure and CRP level before surgery. RESULTS: The mean+/-SD age of the patients was 49.7+/-17.28 years. CRP was positive in 34 patients (61.8%) with unsuccessful fistula function, while only 4 (7.3%) of those with successful AVF had positive CRP and the rest had negative CRP. The difference between the two groups of patients was strongly significant (p<0.001). Statistically, there was not any significant difference between the average of age (p: 0.580) of patients in the control and experimental groups. However, the gender (p: 0.832) discrepancies was not meaningful between the groups. CONCLUSION: AVF thrombosis is one of the main complications after AVF creation. Therefore, it is recommended to check CRP before AVF surgery to prevent possible failure of the fistula function. PMID- 26478878 TI - Patient education process in teaching hospitals of Tehran University of Medical Sciences. AB - BACKGROUND: Patient education is widely recognized as a core component of nursing. Patient education can lead to quality outcomes including adherence, quality of life, patients' knowledge of their illness and self-management. This study aimed to clarify patient education process in teaching hospitals affiliated to Tehran University of Medical Sciences (TUMS) in Iran. METHODS: This cross sectional study was conducted in 2013. In this descriptive quantitative study, the sample covered 187 head nurses selected from ten teaching hospitals through convenience sampling. Data were collected with a questionnaire developed specifically for this study. The questionnaire measured patient education process in four dimensions: need assessment, planning, implementing and evaluating. RESULTS: The overall mean score of patient education was 3.326+/-0.0524. Among the four dimensions of the patient education process, planning was in the highest level (3.570+/-0.0591) and the lowest score belonged to the evaluation of patient education (2.840 +/-0.0628). CONCLUSION: Clarifying patient education steps, developing standardized framework and providing easily understandable tool-kit of the patient education program will improve the ability of nurses in delivering effective patient education in general and specialized hospitals. PMID- 26478879 TI - Measuring psychosocial exposures: validation of the Persian of the copenhagen psychosocial questionnaire (COPSOQ). AB - BACKGROUND: The effect of psychosocial work environment on personal and organizational aspects of employees is well-known; and it is of fundamental importance to have valid tools to evaluate them. This study aims to evaluate the reliability and validity of the Persian version of Copenhagen Psychosocial Questionnaire (COPSOQ). METHODS: The questionnaire was translated into Persian and then back translated into English by two translators separately. The wording of the final Persian version was established by comparing the translated versions with the original questionnaire. One hundred three health care workers completed the questionnaire. Chronbach's alpha was calculated, and factor analysis was performed. RESULTS: Factor analysis revealed acceptable validity for the five contexts of the questionnaire. Cronbach's alpha ranged from 0.73 to 0.82 in different contexts. CONCLUSION: This study revealed that the Persian version of COPSOQ is a reliable and valid instrument for measuring psychosocial factors at work. PMID- 26478880 TI - Clinical reasoning assessment through medical expertise theories: past, present and future directions. AB - Exploration into the concept of "medical expert" dates back to more than 50 years ago, yet yielding three leading theories in the area of clinical reasoning, namely, knowledge structure, hypotheticdeductive, and dual process. Each theory defines "medical expert" in a dissimilar way. Therefore, the methods of assessment through which the experts are identified have been changed during the time. In this paper, we tried to categorize and introduce some widely used tests for identification of experts within the framework of existing main theories. Implementation of the proposed categorization for providing future assessment tools is discussed. PMID- 26478881 TI - Treatment of knee osteoarthritis with platelet-rich plasma in comparison with transcutaneous electrical nerve stimulation plus exercise: a randomized clinical trial. AB - BACKGROUND: Osteoarthritis is a disabling musculoskeletal disease with no definite treatment. This study compared the effect of Platelet-rich plasma (PRP) and Transcutaneous Electrical Nerve Stimulation (TENS) plus exercise in the treatment of patients with knee joint osteoarthritis. METHODS: 54 eligible patients with knee osteoarthritis were randomly allocated into two groups. (IRCT2012110611382N) Group A (27 patients) received 2 injections of PRP (4 weeks apart) and group B (27 patients) received 10 sessions of TENS as well as exercise during the study period. Clinical outcome was evaluated using the Knee injury and Osteoarthritis Outcome Scores (KOOS) questionnaire before the treatment, 4 weeks, and 8 weeks after that the treatment. Pain was also assessed using a visual analog scale (VAS). Time to an intolerable knee pain during treadmill workout was also evaluated using an objective test. RESULTS: In the PRP group, the mean KOOS symptom score improved significantly from baseline to the end of study, while the change was not significant over this period for the group B. In both groups, significant reductions were observed in VAS scores from baseline till the end of study. The mean time to feel intolerable knee pain during treadmill work out of PRP group increased significantly from baseline to week 4, but no significant changes were found in this parameter over the time of study in the group B. CONCLUSION: Intraarticular injection of PRP is an effective, safe method for short-term treatment of patients with knee joint osteoarthritis. PMID- 26478882 TI - Tendency to breast reconstruction after breast mastectomy among Iranian women with breast cancer. AB - BACKGROUND: Women with the medical history of breast cancer constitute the biggest group of patients who survived cancer. Despite the high rate of mastectomy after breast cancer in Iran; only limited patients elect reconstruction surgery. The aim of our study was to evaluate the rate of tendency to breast reconstruction (BR) surgery among women with breast cancer who had mastectomy but not undergone reconstruction. METHODS: This cross sectional study was conducted in Mashhad, north east of Iran during 2013. A total of 108 patients with mastectomy due to breast cancer were selected through convenience sampling and completed the questionnaire. Demographic data collected and 21 items of questionnaire were compared between patients with and without tendency to BR. Data were analyzed using Chi square, t tests and logistic regression. RESULTS: In this study 62 (57.4%) patients had a tendency to BR and 46 (42.6%) had not. The mean (+/-SD) age of patients in first group was 43.3+/-8.03 and 49.6+/-9.9 in the second group (p<0.001). Frequency of agreement about impact of BR on appearance and beauty, mood, family living conditions and their opinion (p<0.001), lack of sufficient information (p=0.01), physician's opinion (p<0.001) and priority of cancer breast treatment (p=0.02) were significantly different between the two groups. CONCLUSION: More than half of the patients had a tendency to BR although they did not go under the surgery yet. Identification of factors that can increase the tendency and factors that help to change the intention to action are important and should be investigate in future research. PMID- 26478883 TI - Morphology of proximal tibia in Iranian population and its correlation with available prostheses. AB - BACKGROUND: Total knee arthroplasty is a complex procedure aiming to relieve pain and improve function. It is critical to select prosthesis that best cover the bone surfaces. Ethnicity may affect fitness of the components mainly designed for Caucasian populations. This study aimed to evaluate morphometric features of proximal tibia in Iranian population. METHODS: During 2013, 150 consecutive patients (96 males and 54 females) form orthopedics department of Rasoul-Akram hospital with knee CT scan were randomly enrolled. We entered cases with apparent normal extremity alignment and bone maturity. Cases with history of fracture or conditions affecting knee profile were excluded. Standard cuts were simulated on CT scan. Anteroposterior (AP), mediolateral (ML) and aspect ratio (ML/AP) were measured for general morphology. Medial and lateral AP distance of tibia and their distance to tibial center were measured for checking symmetry. RESULTS: Mean age was 43.0+/- 10.4 years (rang 11-80). Males showed significantly larger values in ML dimension and aspect ratio than females under a given AP value (p<0.001). However, the aspect ratio was suggestive of similar configuration of proximal tibia profiles among genders. Totally, close correlations were observed among simulated cuts and size-matched tibial components of the prostheses. However, better coverage was provided by some brands via designing interchangeable components for a given dimension. Medial and lateral condyles of tibia were almost symmetrical. CONCLUSION: Our findings indicated that some alterations in the shape of the components are needed to provide optimal coverage in Iranian population. We propose symmetrical configuration in designing tibial components as well. PMID- 26478884 TI - Labour economics and healthcare professional education. AB - Healthcare professional education is the undergraduate, postgraduate and continuing professional development for doctors, nurses and allied healthcare professionals. Labour economics is the relationship between workers and employers, and the resultant effect on employment and wages. Healthcare professional education ultimately produces a workforce, and that workforce is governed by the rules of labour economics like any other workforce. Despite all of these largely incontrovertible facts, there has been remarkably little interest in the relationship between healthcare professional education and labour economics. This short article attempts to redress this shortcoming by describing some of the factors that can affect healthcare professional education and labour economics, and aims to mention some of the methods in which these two disciplines can interact with each other. PMID- 26478885 TI - Household food security status in the Northeast of Iran: a cross-sectional study. AB - BACKGROUND: An important issue the world faces today is ensuring that households living in different countries have access to enough food to maintain a healthy life. Food insecurity is prevalent in both developed and developing countries. The objective of this study was to assess the household food security status and related factors among different rural districts of Neyshabur (A city in northeast of Iran). METHODS: Of 5000 selected rural households 4647 were studied in this cross-sectional study. A validated short questionnaire (with six questions) was used to measure food security. Chi-square test and logistic regression were used for data analysis through SPSS software. RESULTS: In total, 2747 households (59.1%) were identified as food secure. The highest prevalence of food security was observed in Central district (62.3%) and the lowest was in Miyanjolgeh district (52.9%). Backward multiple logistic regression revealed that car ownership, presence of chronic disease in household and household income (per month) were significantly associated with food security in all of surveyed districts (p< 0.05). CONCLUSION: According to results of this study, lower than 60% of Neyshabur rural households were food secure and economic variables were the most important factors. Therefore, a special attention should be paid to this health problem in these regions. PMID- 26478886 TI - Organochlorine pesticides residue in breast milk: a systematic review. AB - BACKGROUND: Chlorinated pesticides have been used in pest control for several decades in the world. These compounds are still applied in many regions, and their continuous usage has resulted in their bioaccumulation and residue in the food chain. These residues could transfer to food products and accumulate in fat tissues. Undoubtedly, the breast milk could be a significant biomarker for estimation of these residues in the human body. This study was conducted to review and compile the results of the studies undertaken in the world which surveyed the organochlorine pesticides residue in breast milk. METHODS: A total of 710 national and international articles and texts related to the focused subject were extracted from the virtual databases using the following key words: Chlorinated pesticides, residue and breast milk. Thirty articles published between 1980 and 2013 were selected and reviewed. RESULTS: The majority of the reviewed articles indicated the presence of two or more organochlorine pesticides in the collected samples of breast milk. Based on the reviewed studies, dichlorodiphenyltrichloroethane (DDT) had the highest level of concentration in the collected samples of breast milk. Moreover, there was a statistically significant positive correlation between mother's age, her multiparty and concentration of chlorinated pesticides in breast milk. CONCLUSION: The organochlorine pesticides are still applied in some developing countries including some regions of Iran. Thus, it seems essential to inform the community about the adverse effects of this class of pesticides; and most importantly the governments should also ban the use of such compounds. PMID- 26478887 TI - The association between air pollution and weather conditions with increase in the number of admissions of asthmatic patients in emergency wards: a case study in Kermanshah. AB - BACKGROUND: Industrialization and urbanization had a devastating impact on public health and caused an increase in health related morbidity and mortality. In fact, asthma is a chronic condition which is considered as one of the significant challenges of public health. In this study, we investigated the association of air pollution and weather conditions with excess emergency ward admissions of asthmatic patients in Kermanshah hospitals. METHODS: This was an ecological study. The total number of hospital admissions to emergency wards from all related and major hospitals of Kermanshah was collected from September 2008 through August 2009. In addition, data on air pollution as well as meteorological data were collected from the Environmental Protection Agency and Meteorological Organization of Kermanshah. To determine the association between the number of hospitalization due to asthma with those parameters, Poisson regression was used. RESULTS: The results of Poisson regression revealed a significant association between carbon monoxide, ozone, nitrogen dioxide and temperature with emergency room visits due to asthma in Kermanshah. No associations were found for sulfur dioxide or for particulate matter. CONCLUSION: This study provides further evidence for the significant effect of monoxide carbon on asthma; and it suggests that temperature may have a role in the exacerbation of asthma. However, due to the multi-factorial nature of asthma, other factors also play a major role in the development and exacerbation of this illness. PMID- 26478888 TI - Health literacy and its influencing factors in Iranian diabetic patients. AB - BACKGROUND: Health literacy is the ability to obtain, read, understand and use healthcare information to make appropriate health decisions and follow instructions for treatment. The aim of this study was to identify the effect of various factors on health literacy in patients with diabetes. METHODS: 407 patients with diabetes older than 15 years of age were identified from the Diabetes Clinic affiliated to the Institute of Endocrinology and Metabolism (IEM) of Iran University of Medical Sciences. We assessed patients' health literacy using the Persian version of Test of Functional Health Literacy in Adults (TOFHLA) questionnaire. RESULTS: Mean age of the patients was 55.8 +/- 11.3 years, and 61.7% the participants were female.. Overall, 18.2% of the patients had adequate health literacy skills, 11.8% had marginal and 70.0% inadequate health literacy skills. Male participants performed better than females (p< 0.01) and older patients had lower health literacy score than younger patients (p< 0.001). Furthermore, patients with higher educational and occupational levels had higher functional health literacy score than those with lower levels (p< 0.001). CONCLUSION: Health literacy score in Iranian patients with diabetes seems inadequate. Therefrom effective interventions should be designed and implemented for this group of patients to improve diabetes outcomes. PMID- 26478891 TI - Controlled Activation for Interrogation of the Electrophysiological Substrate. AB - Ectopic activation and conduction may give rise to arrhythmias when a diseased myocardial substrate exists. Electrophysiological mapping studies that record electrical properties of the heart in sinus rhythm may fail to uncover pro arrhythmic substrates that are triggered by ectopy. In this study we use simulation and experimental models of clinical, trackable, loop catheters to interrogate regions of myocardium by stimulating and recording with multiple activation patterns. Longitudinal and traverse conduction velocities of the tissue were acquired from the pacing protocol. Artifacts resulting from variable distance between the recording electrodes and pacing site were also detected and removed. This study demonstrates that the mapping of local tissue properties with variable activation patterns is feasible and can expose features of the electrophysiological substrate that can not be recovered during sinus conduction. PMID- 26478890 TI - Cervical Artery Dissection: A Review of the Epidemiology, Pathophysiology, Treatment, and Outcome. AB - CONTEXT: Cervical artery dissection (CAD) is a common cause of stroke in young adults. There is controversy over whether anticoagulation is superior to antiplatelet therapy in preventing stroke in patients with CAD, although meta analyses to date have not shown any difference between the two treatments. EVIDENCE ACQUISITION: We performed a PubMed search using each of the keywords: "Cervical artery dissection", "Dissection", "Carotid dissection", and "Vertebral dissection" between January 1st, 1990 and July 1st 2015. We identified evidence based peer-reviewed articles, including randomized trials, case series and reports, and retrospective reviews that encompass the epidemiology, clinical manifestations, pathophysiology, treatment, and outcome of cervical artery dissection. RESULTS: This paper highlights the mechanisms of cervical artery dissection and stroke in patients with dissection as well as the natural history and treatment. CONCLUSION: Given the relatively rare incidence of this disease, multicenter studies with collaborative effort among stroke centers worldwide should be considered to enroll patients with cervical artery dissection in a randomized trial comparing the two treatments. PMID- 26478892 TI - Long and Short Term Cumulative Structural Priming Effects. AB - We present six experiments that examine cumulative structural priming effects (i.e., structural priming effects that accumulate across many utterances). Of particular interest is whether (1) cumulative priming effects transfer across language production tasks and (2) the transfer of cumulative priming effects across tasks persists over the course of a week. Our data suggest that cumulative structural priming effects do transfer across language production tasks (e.g., from written stem completion to picture description, and from picture description to written stem completion), but only when both tasks are presented in the same experimental session. When cumulative priming effects are established in one task, and the second (changed) task is not presented until a week later, the cumulative priming effects are not observed. PMID- 26478893 TI - Designing and Interpreting Limiting Dilution Assays: General Principles and Applications to the Latent Reservoir for Human Immunodeficiency Virus-1. AB - Limiting dilution assays are widely used in infectious disease research. These assays are crucial for current human immunodeficiency virus (HIV)-1 cure research in particular. In this study, we offer new tools to help investigators design and analyze dilution assays based on their specific research needs. Limiting dilution assays are commonly used to measure the extent of infection, and in the context of HIV they represent an essential tool for studying latency and potential curative strategies. Yet standard assay designs may not discern whether an intervention reduces an already miniscule latent infection. This review addresses challenges arising in this setting and in the general use of dilution assays. We illustrate the major statistical method for estimating frequency of infectious units from assay results, and we offer an online tool for computing this estimate. We recommend a procedure for customizing assay design to achieve desired sensitivity and precision goals, subject to experimental constraints. We consider experiments in which no viral outgrowth is observed and explain how using alternatives to viral outgrowth may make measurement of HIV latency more efficient. Finally, we discuss how biological complications, such as probabilistic growth of small infections, alter interpretations of experimental results. PMID- 26478894 TI - Nemesis of neglected neurosarcoidosis. PMID- 26478889 TI - The Road Ahead to Cure Alzheimer's Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations. AB - Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Abeta) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Abeta1-42 (Abeta1-42), also expressed as Abeta1-42 : Abeta1-40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for "prodromal AD" and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2 deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication. PMID- 26478895 TI - Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease. AB - OBJECTIVE: People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (alpha-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated alpha-syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD-affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphe nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert. METHODS: High performance liquid chromatography and novel enzyme-linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 alpha-syn deposition) and six age-matched controls were tested. RESULTS: PD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups. INTERPRETATION: These results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced PD with dementia. PMID- 26478896 TI - Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy. AB - OBJECTIVE: To investigate anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Sera from 50 consecutive CIDP patients diagnosed in our clinic, 32 patients with multiple sclerosis, 40 patients with other neuropathies including 26 with Guillain-Barre syndrome (GBS)/Fisher syndrome, and 30 healthy controls were measured for anti-NF antibodies by flow cytometry using HEK293 cell lines stably expressing human NF155 or NF186. Four additional CIDP patients with anti-NF155 antibodies referred from other clinics were enrolled for clinical characterization. RESULTS: The positivity rate for anti-NF155 antibodies in CIDP patients was 18% (9/50), who all showed a predominance of IgG4 subclass. No other subjects were positive, except one GBS patient harboring IgG1 anti-NF155 antibodies. No anti-NF155 antibody carriers had anti-NF186 antibodies. Anti-NF155 antibody-positive CIDP patients had a significantly younger onset age, higher frequency of drop foot, gait disturbance, tremor and distal acquired demyelinating symmetric phenotype, greater cervical root diameter on magnetic resonance imaging neurography, higher cerebrospinal fluid protein levels, and longer distal and F-wave latencies than anti-NF155 antibody-negative patients. Marked symmetric hypertrophy of cervical and lumbosacral roots/plexuses was present in all anti-NF155 antibody-positive CIDP patients examined by neurography. Biopsied sural nerves from two patients with anti-NF155 antibodies demonstrated subperineurial edema and occasional paranodal demyelination, but no vasculitis, inflammatory cell infiltrates, or onion bulbs. Among anti-NF155 antibody-positive patients, treatment responders more frequently had daily oral corticosteroids and/or immunosuppressants in addition to intravenous immunoglobulins than nonresponders did. INTERPRETATION: Anti-NF155 antibodies occur in a subset of CIDP patients with distal-dominant involvement and symmetric nerve hypertrophy. PMID- 26478897 TI - Fine mapping of chromosome 15q25 implicates ZNF592 in neurosarcoidosis patients. AB - Neurosarcoidosis is a clinical subtype of sarcoidosis characterized by the presence of granulomas in the nervous system. Here, we report a highly significant association with a variant (rs75652600, P = 3.12 * 10(-8), odds ratios = 4.34) within a zinc finger gene, ZNF592, from an imputation-based fine mapping study of the chromosomal region 15q25 in African-Americans with neurosarcoidosis. We validate the association with ZNF592, a gene previously shown to cause cerebellar ataxia, in a cohort of European-Americans with neurosarcoidosis by uncovering low-frequency variants with a similar risk effect size (chr15:85309284, P = 0.0021, odds ratios = 5.36). PMID- 26478899 TI - Comment on: Short pulse width widens the therapeutic window of subthalamic neurostimulation. PMID- 26478898 TI - Dimethyl fumarate inhibits integrin alpha4 expression in multiple sclerosis models. AB - Dimethyl fumarate is an orally bioavailable compound for the treatment of multiple sclerosis and psoriasis. A mechanism involving nuclear factor erythroid 2-like 2 activation has been proposed to account for its efficacy in multiple sclerosis. Here, we report that dimethyl fumarate inhibits expression of integrin alpha4 on circulating lymphocytes in experimental autoimmune encephalomyelitis mice and also on activated human Jurkat T cells in a manner distinct from nuclear factor erythroid 2-like 2 activation. Our results offer an alternative mechanism for the efficacy of dimethyl fumarate in multiple sclerosis. PMID- 26478900 TI - Reply to comment on: Short pulse width widens the therapeutic window of subthalamic neurostimulation. PMID- 26478903 TI - Why Does Attention to Web Articles Fall With Time? AB - We analyze access statistics of 150 blog entries and news articles for periods of up to 3 years. Access rate falls as an inverse power of time passed since publication. The power law holds for periods of up to 1,000 days. The exponents are different for different blogs and are distributed between 0.6 and 3.2. We argue that the decay of attention to a web article is caused by the link to it first dropping down the list of links on the website's front page and then disappearing from the front page and its subsequent movement further into background. The other proposed explanations that use a decaying with time novelty factor, or some intricate theory of human dynamics, cannot explain all of the experimental observations. PMID- 26478901 TI - MINORITY STRESS, POSITIVE IDENTITY DEVELOPMENT, AND DEPRESSIVE SYMPTOMS: IMPLICATIONS FOR RESILIENCE AMONG SEXUAL MINORITY MALE YOUTH. AB - INTRODUCTION: Minority stress processes have been shown to have significant associations with negative mental health outcomes among sexual minority populations. Given that adversity may be experienced growing up as a sexual minority in heteronormative, if not heterosexist, environments, our research on resilience among sexual minority male youth proposes that positive identity development may buffer the effects of a range of minority stress processes. METHODS: An ethnically diverse sample of 200 sexual minority males ages 16-24 (mean age, 20.9 years) was recruited using mixed recruitment methods. We developed and tested two new measures: concealment stress during adolescence and sexual minority-related positive identity development. We then tested a path model that assessed the effects of minority stressors, positive identity development, and social support on major depressive symptoms. RESULTS: Experience of stigma was associated with internalized homophobia (beta=.138, p<.05) and major depressive symptoms (beta=1.076, OR=2.933, p<.001), and internalized homophobia partially mediated experience's effects on major depression (beta=.773, OR=2.167, p<.001). Concealment stress was associated with positive identity development (beta=.155, p<.05) and internalized homophobia (beta=.418, p<.001), and positive identity development partially mediated concealment stress's effects on internalized homophobia (beta=-.527, p<.001). Concealment stress demonstrated a direct effect on major depression (beta=1.400, OR=4.056, p<.001), and indirect paths to social support through positive identity development. CONCLUSIONS: With these results, we offer an exploratory model that empirically identifies significant paths among minority stress dimensions, positive identity development, and major depressive symptoms. This study helps further our understanding of minority stress, identity development, and resources of resilience among sexual minority male youth. PMID- 26478902 TI - Alcohol Versus Cannabinoids: A Review of Their Opposite Neuro-Immunomodulatory Effects and Future Therapeutic Potentials. AB - Due to the legalization of marijuana and the increased demand for cannabis and alcohol consumption, research efforts highlighting the biomedical consequences of the use of alcohol and cannabinoids are not only relevant to the substance abuse scientific field, but are also of public health interest. Moreover, an overview of the recent literature about alcohol and cannabinoids neuro-immunomodulatory effects highlighting their future therapeutic potentials will provide a significant contribution to science and medicine. Therefore, in the current review, we will first discuss briefly the prevalence of alcohol and marijuana abuse, followed by a discussion on the individual effects of alcohol and cannabinoids on the immune system; then, we will focus on the role of endocannabinoids on the alcohol-induced inflammatory effects. In addition, the review also incorporates cytokine array data obtained from human monocyte-derived dendritic cells, providing a different perspective on the alcohol and cannabinoid abuse divergent effects on cytokine production. The final section will highlight the therapeutic potential of cannabinoid receptors and the novel strategies to treat alcohol dependence as determined by in vitro, in vivo and clinical studies. PMID- 26478904 TI - Laboratory Activity for the Determination of Nicotine in Electronic Cigarette Liquids using Gas Chromatography-Mass Spectrometry. AB - In recent years the prevalence and popularity of electronic cigarettes (ECs) has increased noticeably and a large market for their refillable nicotine solutions (e-liquids) has also rapidly increased. These e-liquids contain nicotine, an addictive and potentially dangerous stimulant, but often the actual nicotine content differs significantly from manufacturers' labelling, due in part to lack of regulation for these products. A laboratory activity for undergraduate students was developed to directly test e-liquids for nicotine content using gas chromatography combined with mass spectrometry (GC-MS) as a means for teaching the instrumentation to undergraduate students using an authentic, real-world example. The activity introduces and/or re-emphasizes the theory and operation of GC-MS, standard/sample preparation, calibration curves, internal standards, selected ion monitoring mode of MS operation, and method validation. The laboratory experiment is designed for students enrolled in Quantitative Analysis courses (like Analytical Chemistry or Instrumental Analysis), but portions are also suitable for lower level chemistry courses or even those designed for allied health professionals or non-chemistry majors. Given the current popularity of ECs, this activity can provide the chemistry curriculum with a timely, real world, and contemporary application in which crucial course content is taught. Students can also benefit from the inherent discussion of ECs, regulations, and related social aspects of smoking and EC vaping - which can serve as a secondary learning outcome. PMID- 26478906 TI - Comparison of SIRT and SQS for Regularized Weighted Least Squares Image Reconstruction. AB - Tomographic image reconstruction is often formulated as a regularized weighted least squares (RWLS) problem optimized by iterative algorithms that are either inherently algebraic or derived from a statistical point of view. This paper compares a modified version of SIRT (Simultaneous Iterative Reconstruction Technique), which is of the former type, with a version of SQS (Separable Quadratic Surrogates), which is of the latter type. We show that the two algorithms minimize the same criterion function using similar forms of preconditioned gradient descent. We present near-optimal relaxation for both based on eigenvalue bounds and include a heuristic extension for use with ordered subsets. We provide empirical evidence that SIRT and SQS converge at the same rate for all intents and purposes. For context, we compare their performance with an implementation of preconditioned conjugate gradient. The illustrative application is X-ray CT of luggage for aviation security. PMID- 26478905 TI - Alcoholic Cardiomyopathy: Multigenic Changes Underlie Cardiovascular Dysfunction. AB - Alcoholism is the third leading cause of preventable death in the United States. Aside from promoting cardiomyopathies, chronic alcohol consumption is associated with an increased risk of dementia, the development of liver or pancreas failure, and cancers of the oral cavity and pharynx. Although a J-shaped curve for all cause mortality has been identified for average alcohol consumption, irregular heavy drinking also carries significantly greater risks for cardiovascular disease. Alcohol induced cardiovascular disease has a complex multigenic etiology. There is significant variation in the initial presentation of alcoholic cardiomyopathy with diastolic dysfunction possibly being the first indication. Ethanol exposure generates toxic metabolites, primarily acetaldehyde and ROS, which activate several cell signaling systems to alter cell function across many levels. Sudden cardiac death is a known occurrence of alcoholism that may be linked to an arrhythmogenic effect of alcohol. Microscopic and molecular examination of diseased hearts has demonstrated abnormal alterations to various cellular components, including the mitochondria and myofibrils. These studies have shown not only the direct impact on myocardial contractility but also disrupted metabolism that determines the long-term survival of the myocardium. Significant variations in the response to chronic alcohol consumption may be related to unique genotypes that modify the metabolic response to ethanol. Future studies to further characterize the role of different genotypes will help indentify those genotypes are more susceptible to chronic alcohol consumption. PMID- 26478907 TI - Trends in Multiple Tobacco Product Use, Among High School Students. AB - OBJECTIVE: The purpose of this study was to identify trends of tobacco use, among all students and current tobacco users, in a nationally representative sample of high school students from 1999 to 2013. METHODS: Trends in individual and concurrent use of cigarettes, cigars, and smokeless tobacco (SLT) products were tested using 8 repeated cross-sections of the YRBS between 1999 and 2013. Tests for effect modification of race/ethnicity and sex were conducted for each trend. RESULTS: Among all students, there were significant non-linear changes detected for the concurrent use of all 3 products, and the dual use of cigarettes and cigars. Girls significantly increased their use of SLT. Among users, significant changes were detected for each individual product and all combinations. Female users significantly increased their concurrent use of cigarettes and cigars and concurrent use of cigarettes and SLT. Male users significantly decreased their use of cigarettes and cigars. CONCLUSION: While the decrease in the youth prevalence of cigarette use is a public health success, there is concern about the increase in non-cigarette products, among tobacco users. These changes further drive increases in the concurrent use of tobacco products, adding to the potential health burden. PMID- 26478908 TI - Functional Integration of Adult-Born Hippocampal Neurons after Traumatic Brain Injury(1,2,3). AB - Traumatic brain injury (TBI) increases hippocampal neurogenesis, which may contribute to cognitive recovery after injury. However, it is unknown whether TBI induced adult-born neurons mature normally and functionally integrate into the hippocampal network. We assessed the generation, morphology, and synaptic integration of new hippocampal neurons after a controlled cortical impact (CCI) injury model of TBI. To label TBI-induced newborn neurons, we used 2-month-old POMC-EGFP mice, which transiently and specifically express EGFP in immature hippocampal neurons, and doublecortin-CreER(T2) transgenic mice crossed with Rosa26-CAG-tdTomato reporter mice, to permanently pulse-label a cohort of adult born hippocampal neurons. TBI increased the generation, outward migration, and dendritic complexity of neurons born during post-traumatic neurogenesis. Cells born after TBI had profound alterations in their dendritic structure, with increased dendritic branching proximal to the soma and widely splayed dendritic branches. These changes were apparent during early dendritic outgrowth and persisted as these cells matured. Whole-cell recordings from neurons generated during post-traumatic neurogenesis demonstrate that they are excitable and functionally integrate into the hippocampal circuit. However, despite their dramatic morphologic abnormalities, we found no differences in the rate of their electrophysiological maturation, or their overall degree of synaptic integration when compared to age-matched adult-born cells from sham mice. Our results suggest that cells born after TBI participate in information processing, and receive an apparently normal balance of excitatory and inhibitory inputs. However, TBI induced changes in their anatomic localization and dendritic projection patterns could result in maladaptive network properties. PMID- 26478909 TI - Organization of the Mammalian Locomotor CPG: Review of Computational Model and Circuit Architectures Based on Genetically Identified Spinal Interneurons(1,2,3). AB - The organization of neural circuits that form the locomotor central pattern generator (CPG) and provide flexor-extensor and left-right coordination of neuronal activity remains largely unknown. However, significant progress has been made in the molecular/genetic identification of several types of spinal interneurons, including V0 (V0D and V0V subtypes), V1, V2a, V2b, V3, and Shox2, among others. The possible functional roles of these interneurons can be suggested from changes in the locomotor pattern generated in mutant mice lacking particular neuron types. Computational modeling of spinal circuits may complement these studies by bringing together data from different experimental studies and proposing the possible connectivity of these interneurons that may define rhythm generation, flexor-extensor interactions on each side of the cord, and commissural interactions between left and right circuits. This review focuses on the analysis of potential architectures of spinal circuits that can reproduce recent results and suggest common explanations for a series of experimental data on genetically identified spinal interneurons, including the consequences of their genetic ablation, and provides important insights into the organization of the spinal CPG and neural control of locomotion. PMID- 26478911 TI - DREADD-Induced Silencing of the Medial Olfactory Tubercle Disrupts the Preference of Female Mice for Opposite-Sex Chemosignals(1,2,3). AB - Attraction to opposite-sex pheromones during rodent courtship involves a pathway that includes inputs to the medial amygdala (Me) from the main and accessory olfactory bulbs, and projections from the Me to nuclei in the medial hypothalamus that control reproduction. However, the consideration of circuitry that attributes hedonic properties to opposite-sex odors has been lacking. The medial olfactory tubercle (mOT) has been implicated in the reinforcing effects of natural stimuli and drugs of abuse. We performed a tract-tracing study wherein estrous female mice that had received injections of the retrograde tracer, cholera toxin B, into the mOT were exposed to volatile odors from soiled bedding. Both the anterior Me and ventral tegmental area sent direct projections to the mOT, of which a significant subset was selectively activated (expressed Fos protein) by testes-intact male (but not female) volatile odors from soiled bedding. Next, the inhibitory DREADD (designer receptors exclusively activated by designer drugs) receptor hM4Di was bilaterally expressed in the mOT of female mice. Urinary preferences were then assessed after intraperitoneal injection of either saline or clozapine-N-oxide (CNO), which binds to the hM4Di receptor to hyperpolarize infected neurons. After receiving CNO, estrous females lost their preference for male over female urinary odors, whereas the ability to discriminate these odors remained intact. Male odor preference returned after vehicle treatment in counterbalanced tests. There were no deficits in locomotor activity or preference for food odors when subject mice received CNO injections prior to testing. The mOT appears to be a critical segment in the pheromone reward pathway of female mice. PMID- 26478910 TI - Developing Extracellular Matrix Technology to Treat Retinal or Optic Nerve Injury(1,2,3). AB - Adult mammalian CNS neurons often degenerate after injury, leading to lost neurologic functions. In the visual system, retinal or optic nerve injury often leads to retinal ganglion cell axon degeneration and irreversible vision loss. CNS axon degeneration is increasingly linked to the innate immune response to injury, which leads to tissue-destructive inflammation and scarring. Extracellular matrix (ECM) technology can reduce inflammation, while increasing functional tissue remodeling, over scarring, in various tissues and organs, including the peripheral nervous system. However, applying ECM technology to CNS injuries has been limited and virtually unstudied in the visual system. Here we discuss advances in deriving fetal CNS-specific ECMs, like fetal porcine brain, retina, and optic nerve, and fetal non-CNS-specific ECMs, like fetal urinary bladder, and the potential for using tissue-specific ECMs to treat retinal or optic nerve injuries in two platforms. The first platform is an ECM hydrogel that can be administered as a retrobulbar, periocular, or even intraocular injection. The second platform is an ECM hydrogel and polymer "biohybrid" sheet that can be readily shaped and wrapped around a nerve. Both platforms can be tuned mechanically and biochemically to deliver factors like neurotrophins, immunotherapeutics, or stem cells. Since clinical CNS therapies often use general anti-inflammatory agents, which can reduce tissue-destructive inflammation but also suppress tissue-reparative immune system functions, tissue-specific, ECM based devices may fill an important need by providing naturally derived, biocompatible, and highly translatable platforms that can modulate the innate immune response to promote a positive functional outcome. PMID- 26478912 TI - CSF and Blood Levels of GFAP in Alexander Disease AB - Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region of GFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect the levels of GFAP in brain parenchyma, we have assayed GFAP levels in two body fluids in humans that are readily accessible as biopsy sites: CSF and blood. We find that GFAP levels are consistently elevated in the CSF of patients with Alexander disease, but only occasionally and modestly elevated in blood. These results provide the foundation for future studies that will explore whether GFAP levels can serve as a convenient means to monitor the progression of disease and the response to treatment. PMID- 26478913 TI - The Good and Bad Differentially Encoded within the Subthalamic Nucleus in Rats(1,2,3). AB - The subthalamic nucleus (STN) has only recently been added into the reward circuit. It has been shown to encode information regarding rewards (4% sucrose, 32% cocaine). To investigate the encoding of negative value, STN neurons were recorded in rats performing a task using discriminative stimuli predicting various rewards and especially during the replacement of a positive reinforcer (4% sucrose) by an aversive reinforcer (quinine). The results show that STN neurons encode information relative to both positive and aversive reinforcers via specialized subpopulations. The specialization is reset when the context is modified (change from a favorable context (4% vs 32% sucrose) to an unfavorable context (quinine vs 32% sucrose). An excitatory response to the cue light predicting the reward seems to be associated with the preferred situation, suggesting that STN plays a role in encoding the relative value of rewards. STN also seems to play a critical role in the encoding of execution error. Indeed, various subpopulations of neurons responding exclusively at early (i.e., "oops neurons") or at correct lever release were identified. The oops neurons respond mostly when the preferred reward (32% sucrose) is missed. Furthermore, STN neurons respond to reward omission, suggesting a role in reward prediction error. These properties of STN neurons strengthen its position in the reward circuit as a key cerebral structure through which reward-related processes are mediated. It is particularly important given the fact that STN is the target of surgical treatment for Parkinson's disease and obsessive compulsive disorders, and has been suggested for the treatment of addiction as well. PMID- 26478915 TI - Update on The Cancer Genome Atlas Project on Muscle-invasive Bladder Cancer. PMID- 26478914 TI - Layer-by-layer heparinization of decellularized liver matrices to reduce thrombogenicity of tissue engineered grafts. AB - BACKGROUND: Tissue-engineered liver grafts may offer a viable alternative to orthotopic liver transplantation and help overcome the donor organ shortage. Decellularized liver matrices (DLM) have a preserved vasculature and sustain hepatocellular function in culture, but graft survival after transplantation remains limited due to thrombogenicity of the matrix. AIM: To evaluate the effect of heparin immobilization on DLM thrombogenicity. METHODS: Heparin was immobilized on DLMs by means of layer-by-layer deposition. Grafts with 4 or 8 bilayers and 2 or 4 g/L of heparin were recellularized with primary rat hepatocytes and maintained in culture for 5 days. Hemocompatibility of the graft was assessed by ex vivo diluted whole-blood perfusion and heterotopic transplantation. RESULTS: Heparin was deposited throughout the matrix and the heparin content in the graft was higher with increasing number of bilayers and concentration of heparin. Recellularization and in vitro albumin and urea production were unaffected by heparinization. Resistance to blood flow during ex vivo perfusion was lower with increased heparinization and, macroscopically, no clots were visible in grafts with 8 bilayers. Following transplantation, flow through the graft was limited in all groups. Histological evidence of thrombosis was lower in heparinized DLMs, but transplantation of DLM grafts was not improved. CONCLUSIONS: Layer-by-layer deposition of heparin on a DLM is an effective method of immobilizing heparin throughout the graft and does not impede recellularization or hepatocellular function in vitro. Thrombogenicity during ex vivo blood perfusion was reduced in heparinized grafts and optimal with 8 bilayers, but transplantation remained unsuccessful with this method. RELEVANCE FOR PATIENTS: Tissue engineered liver grafts may offer a viable solution to dramatic shortages in donor organs. PMID- 26478916 TI - Community Pharmacy Use Patterns of Women with HIV and Women At Risk for HIV in the San Francisco Bay Area. AB - BACKGROUND: Community pharmacies play a key role in the care of patients when dispensing antiretroviral therapy. The primary objective of this study was to describe patterns of community pharmacy use of women enrolled in the San Francisco site of the Women's Interagency HIV Study (WIHS). The secondary objective was to determine whether the number of pharmacies a patient uses is associated with specific patient characteristics or virologic outcomes in HIV positive women. OBJECTIVES: The primary objective was to determine factors which were associated with using multiple dispensing pharmacies to obtain medications in a population of HIV+ and at-risk women. The secondary objective was to determine whether use of multiple pharmacies was associated with immunologic or virologic changes for the subset of HIV+ women. METHODS: A survey on community pharmacy use was distributed to San Francisco WIHS participants from 2004-2007. Poisson, linear, and logistic regression methods were used to determine associations between specific patient characteristics and use of multiple dispensing pharmacies and associations between multiple pharmacy use and CD4+ cell count or viral load changes. RESULTS: There was a trend towards an association between HIV status and use of multiple pharmacies (IRR=1.23; 95% CI 1.00-1.51, p =0.05). In multivariable analyses of HIV positive women, use of additional pharmacies (over the primary pharmacy) during the study period was not associated with statistically significant changes in CD4+ count or viral load. CONCLUSION: HIV positive participants may tend to use multiple pharmacies more frequently than their HIV negative counterparts, though this practice does not appear to be associated with poorer immunologic or virologic outcomes. Future studies should be conducted to determine whether different patient patterns of community pharmacy use affect HIV treatment outcomes. PMID- 26478918 TI - Evolution of a Structure-Searchable Database into a Prototype for a High-Fidelity SmartPhone App for 62 Common Pesticides Used in Delaware. AB - Synthetic pesticides are widely used in the modern world for human benefit. They are usually classified according to their intended pest target. In Delaware (DE), approximately 42 percent of the arable land is used for agriculture. In order to manage insectivorous and herbaceous pests (such as insects, weeds, nematodes, and rodents), pesticides are used profusely to biologically control the normal pest's life stage. In this undergraduate project, we first created a usable relational database containing 62 agricultural pesticides that are common in Delaware. Chemically pertinent quantitative and qualitative information was first stored in Bio-Rad's KnowItAll(r) Informatics System. Next, we extracted the data out of the KnowItAll(r) system and created additional sections on a Microsoft(r) Excel spreadsheet detailing pesticide use(s) and safety and handling information. Finally, in an effort to promote good agricultural practices, to increase efficiency in business decisions, and to make pesticide data globally accessible, we developed a mobile application for smartphones that displayed the pesticide database using Appery.ioTM; a cloud-based HyperText Markup Language (HTML5), jQuery Mobile and Hybrid Mobile app builder. PMID- 26478919 TI - A 3D Primary Vessel Reconstruction Framework with Serial Microscopy Images. AB - Three dimensional microscopy images present significant potential to enhance biomedical studies. This paper presents an automated method for quantitative analysis of 3D primary vessel structures with histology whole slide images. With registered microscopy images of liver tissue, we identify primary vessels with an improved variational level set framework at each 2D slide. We propose a Vessel Directed Fitting Energy (VDFE) to provide prior information on vessel wall probability in an energy minimization paradigm. We find the optimal vessel cross section associations along the image sequence with a two-stage procedure. Vessel mappings are first found between each pair of adjacent slides with a similarity function for four association cases. These bi-slide vessel components are further linked by Bayesian Maximum A Posteriori (MAP) estimation where the posterior probability is modeled as a Markov chain. The efficacy of the proposed method is demonstrated with 54 whole slide microscopy images of sequential sections from a human liver. PMID- 26478917 TI - The Evolution of Homeopathic Theory-Driven Research and the Methodological Toolbox. PMID- 26478920 TI - Polythiophene derivative on quartz resonators for miRNA capture and assay. AB - A novel approach for miRNA assay using a cationic polythiophene derivative, poly[3-(3'-N,N,N-triethylamino-1'-propyloxy)-4-methyl-2,5-thiophene hydrobromide] (PT), immobilized on a quartz resonator is proposed. The cationic PT enables capturing of all RNA sequences in the sample matrix via electrostatic interactions, resulting in the formation of PT-RNA duplex structures on quartz resonators. Biotinylated peptide nucleic acid (b-PNA) sequences are subsequently utilized for the RNA assay, upon monitoring the PT-RNA-b-PNA triplex formation. Signal amplification is achieved by anchoring avidin coated nanoparticles to b PNA in order to yield responses at clinically relevant concentration regimes. Unlike conventional nucleic acid assay methodologies that usually quantify a specific sequence of RNA, the proposed approach enables the assay of any RNA sequence in the sample matrix upon hybridization with a PNA sequence complementary to the RNA of interest. As an illustration, successful detection of mir21, (a miRNA sequence associated with lung cancer) is demonstrated with a limit of detection of 400 pM. Furthermore, precise quantification of mir21 in plasma samples is demonstrated without requiring PCR and sophisticated instrumentation. PMID- 26478921 TI - Detection of DNA methyltransferase activity using allosteric molecular beacons. AB - Abnormal DNA methylation patterns caused by altered DNA methyltransferase (MTase) activity are closely associated with cancer. Herein, using DNA adenine methylation methyltransferase (Dam MTase) as a model analyte, we designed an allosteric molecular beacon (aMB) for sensitive detection of Dam MTase activity. When the specific site in an aMB is methylated by Dam MTase, the probe can be cut by the restriction nuclease DpnI to release a fluorophore labeled aptamer specific for streptavidin (SA) which will bind to SA beads to generate highly fluorescent beads for easy signal readout by a microscope or flow cytometer. However, aMBs maintain a hairpin structure without the binding ability to SA beads in the absence of Dam MTase, leading to weakly fluorescent SA beads. Unlike the existing signal amplified assays, our method is simpler and more convenient. The high performance of the aptamer and the easy bead separation process make this probe superior to other methods for the detection of MTase in complex biological systems. Overall, the proposed method with a detection limit of 0.57 U mL(-1) for Dam MTase shows great potential for further applications in the detection of other MTases, screening of MTase inhibitors, and early diagnosis of cancer. PMID- 26478923 TI - Three-dimensional hierarchical Prussian blue composed of ultrathin nanosheets: enhanced hetero-catalytic and adsorption properties. AB - Three-dimensional hierarchical Prussian blue composed of ultrathin nanosheets was successfully synthesized by employing a self-aggregation and oriented attachment strategy. The unique structure highly increases the exposure of micropores and metal sites of Prussian blue to guests, thus significantly enhancing its hetero catalysis and adsorption properties compared to cubic and commercial counterparts. PMID- 26478922 TI - Folic acid conjugated magnetic iron oxide nanoparticles for nondestructive separation and detection of ovarian cancer cells from whole blood. AB - Because of the lack of early screening strategies, ovarian cancer is the most deadly cause of gynecologic malignancies. This paper describes an effective method for the separation and detection of ovarian cancer cells from female whole blood, using folic acid (FA) conjugated magnetic iron oxide nanoparticles (IO-FA nanoparticles). The IO nanoparticles were synthesized by thermal decomposition and then covalently conjugated with FA. The IO-FA nanoparticles were stably attached to the surface of ovarian cancer cells by coupling to the over-expressed folate receptor (FR), thereby making the cells magnetic. These "magnetic cells" were separated from the complex blood matrix without destruction under a magnetic field. The separation efficiency was as high as 61.3% when the abundance of spiked ovarian cancer SKOV3 cells was as low as 5 * 10(-5)%. We also successfully detected five (5) out of ten (10) metastatic ovarian cancer patients' whole blood. This study suggested the feasibility of early detecting of metastatic ovarian cancer cells, which may potentially improve the ovarian cancers patients' overall survival rate for clinical applications. PMID- 26478924 TI - Pd(OAc)2/S=PPh3 accelerated activation of gem-dichloroalkenes for the construction of 3-arylchromones. AB - The Pd-catalyzed regioselective intramolecular nucleophilic substitution of gem dichloroalkene derivatives with salicylaldehydes leading to the synthesis of 3 arylchromones has been developed. Pd(OAc)2/S=PPh3 could activate gem dichloroalkenes and undergo nucleophilic substitution by salicylaldehydes with the aid of a base. PMID- 26478925 TI - Direct production of naphthenes and paraffins from lignin. AB - The utilization of lignin as a fuel precursor has attracted attention, and a novel and facile process has been developed for one-pot conversion of lignin into cycloalkanes and alkanes with Ni catalysts under moderate conditions. This cascade hydrodeoxygenation approach may open the route to a new promising technique for direct liquefaction of lignin to hydrocarbons. PMID- 26478926 TI - Macromolecular cell surface engineering for accelerated and reversible cellular aggregation. AB - We report the synthesis of two simple copolymers that induce rapid cell aggregation within minutes in a fully reversible manner. The polymers can act as self-supporting "cellular glues" or as "drivers" of 3D cell spheroids/aggregates formation at minute concentrations. PMID- 26478927 TI - Coupled molecular motions driven by light or chemical inputs: spiropyran to merocyanine isomerisation followed by pseudorotaxane formation. AB - We have designed and prepared a new dual stimuli-responsive guest molecule containing a spiropyran fragment and a pyridinium moiety. Acid addition or UV light irradiation induces guest transformation to a merocyanine isomer, promoting the threading motion through a 24-crown-8 macrocycle and the formation of a [2]pseudorotaxane complex. PMID- 26478929 TI - Patterns in atrial fibrillation management and 'real-world' adherence to guidelines in the Balkan Region: an overview of the Balkan-atrial fibrillation survey. PMID- 26478930 TI - Digoxin mortality in heart failure and atrial fibrillation. PMID- 26478928 TI - Neuregulin 1 Prevents Phencyclidine-Induced Behavioral Impairments and Disruptions to GABAergic Signaling in Mice. AB - BACKGROUND: Substantial evidence from human post-mortem and genetic studies has linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic animal models and in vitro experiments have suggested that altered NRG1 signaling, rather than protein changes, contributes to the symptomatology of schizophrenia. However, little is known about the effect of NRG1 on schizophrenia-relevant behavior and neurotransmission (particularly GABAergic and glutamatergic) in adult animals. METHOD: To address this question, we treated adult mice with the extracellular signaling domain of NRG1 and assessed spontaneous locomotor activity and acoustic startle response, as well as extracellular GABA, glutamate, and glycine levels in the prefrontal cortex and hippocampus via microdialysis. Furthermore, we asked whether the effect of NRG1 would differ under schizophrenia-relevant impairments in mice and therefore co treated mice with NRG1 and phencyclidine (PCP) (3 mg/kg). RESULTS: Acute intraventricularly- or systemically-injected NRG1 did not affect spontaneous behavior, but prevented PCP induced hyperlocomotion and deficits of prepulse inhibition. NRG1 retrodialysis (10 nM) reduced extracellular glutamate and glycine levels in the prefrontal cortex and hippocampus, and prevented PCP induced increase in extracellular GABA levels in the hippocampus. CONCLUSION: With these results, we provide the first compelling in vivo evidence for the involvement of NRG1 signaling in schizophrenia-relevant behavior and neurotransmission in the adult nervous system, which highlight its treatment potential. Furthermore, the ability of NRG1 treatment to alter GABA, glutamate, and glycine levels in the presence of PCP also suggests that NRG1 signaling has the potential to alter disrupted neurotransmission in patients with schizophrenia. PMID- 26478931 TI - Cognitive impairment predicts worse outcome in heart failure. PMID- 26478932 TI - Depression associated with five-fold increased mortality risk in heart failure patients. PMID- 26478933 TI - Retraction notice to "Dual ACE-inhibition and angiotensin II AT1 receptor antagonism with curcumin attenuate maladaptive cardiac repair and improve ventricular systolic function after myocardial infarction in rat heart" [Eur.J.Pharmacol.January(2015)22-30]. PMID- 26478934 TI - Retraction notice to "Memantine enhances the inhibitory effects of naltrexone on ethanol consumption" [Eur.J.Pharmacol.584(2-3) (2008)352-356]. PMID- 26478935 TI - Science in court: Courage of conviction. PMID- 26478936 TI - Retraction notice to "Neoteric FT-IR investigation on the functional groups of phosphonium-based deep eutectic solvents" [Spectrochim. Acta Part A: Mol. Biomol. Spectrosc. 149 (2015) 588-591]. PMID- 26478937 TI - Jean-Jacques Lefrere in memoriam. PMID- 26478938 TI - Preface. Human Embryonic Stem Cell Protocols. PMID- 26478939 TI - Preface. G Protein-Coupled Receptors in Drug Discovery. PMID- 26478940 TI - Explaining the Persistence of Health Disparities: Social Stratification and the Efficiency-Equity Trade-off in the Kidney Transplantation System. AB - Why do health disparities persist when their previous mechanisms are eliminated? Fundamental-cause theorists argue that social position primarily improves health through two metamechanisms: better access to health information and technology. I argue that the general, cumulative, and embodied consequences of social stratification can produce another metamechanism: an efficiency-equity trade-off. A case in point is kidney transplantation, where the mechanisms previously thought to link race to outcomes--ability to pay and certain factors in the kidney allocation system--have been greatly reduced, yet large disparities persist. I show that these current disparities are rooted in factors that directly influence posttransplant success, placing efficiency and racial/ethnic equity at cross-purposes. PMID- 26478941 TI - Urbanization as Socioenvironmental Succession: The Case of Hazardous Industrial Site Accumulation. AB - This study rehabilitates concepts from classical human ecology and synthesizes them with contemporary urban and environmental sociology to advance a theory of urbanization as socioenvironmental succession. The theory illuminates how social and biophysical phenomena interact endogenously at the local level to situate urban land use patterns recursively and reciprocally in place. To demonstrate this theory we conduct a historical-comparative analysis of hazardous industrial site accumulation in four U.S. cities, using a relational database that was assembled for more than 11,000 facilities that operated during the past half century--most of which remain unacknowledged in government reports. Results show how three iterative processes--hazardous industrial churning, residential churning, and risk containment--intersect to produce successive socioenvironmental changes that are highly relevant to but often missed by research on urban growth machines, environmental inequality, and systemic risk. PMID- 26478942 TI - Metal Ion Complexes of N,N'-Bis(2-Pyridylmethyl)-trans-1,2-Diaminocyclohexane N,N'-Diacetic Acid, H2bpcd: Cis/Trans Isomerization Equilibria. AB - The synthesis of N,N'-bis(2-pyridylmethyl)-trans-1,2-diaminocyclohexane-N,N' diacetic acid (H2bpcd) and its complexation of Ga(III) and Co(III) are reported. H2bpcd and the metal-bpcd(2-) complexes, isolated as hexafluorophosphate salts, were characterized by elemental analysis, X-ray crystallography, IR spectroscopy, and (1)H and (13)C NMR spectroscopy. [Ga(bpcd)]PF6, [Ga(C22H26N4O4)]PF6, crystallized in the orthorhombic space group Ibca, with a = 13.8975(7) A, b = 15.0872(7) A, c = 22.2418(10) A, and Z = 8. Ga is coordinated in a distorted octahedral geometry provided by a N4O2 donor atom set with trans-monodentate acetate groups and cis-2-pyridylmethyl N atoms, i.e., the trans-O,O isomer. The diamagnetic [Co(bpcd)]PF6, [Co(C22H26N4O4)]PF6, also crystallized from solution in the Ibca space group as the trans-O,O isomer. The (1)H and (13)C assignments for H2bpcd and metal-bpcd(2-) complexes were made on the basis of 2D COSY and HSQC experiments, which were used to differentiate among three possible isomers, i.e., one cis (C1 symmetry) and two trans (C2 symmetry). NMR results indicate that the [Ga(bpcd)](+), [Co(bpcd)](+), and cis-O,O, cis-Npy,Npy-[Ga(bppd)](+) cations, where bppd(2-) stands for bis(2-pyridylmethyl)-1,3-diaminopropane diacetate, are present in solution as isomers with the same symmetry as observed in the solid state. The crystallographic data and the dramatic shift that occurs in the position of the cis/trans isomerization equilibria for the [Ga(bpad)](+) cations simply by increasing the number of bridging CH2 groups in the ligand's diamine backbone represent a unique opportunity to assess the accuracy of modern computational methods. The performance of several local density functionals using a pseudopotential-based SDD basis set was compared with the more rigorous HF and MP2 ab initio calculations. The SVWN5 and SV5LYP functionals provide significantly better Ga-O and Ga-N distances than the HF method or the nonlocal BLYP functional. However, to provide proper isomerization energies the pseudopotential-DFT calculations must be augmented by MP2 single-point energies and calculations of solvation free energies. PMID- 26478943 TI - Development of a face-to-face injunctive norms brief motivational intervention for college drinkers and preliminary outcomes. AB - Findings are presented from the first randomized clinical trial that compared changes in alcohol consumption and alcohol-related consequences among college student drinkers from baseline to follow-up across 4 conditions: (a) a new single component injunctive norms brief motivational intervention (IN-BMI) condition; (b) a single component descriptive norms brief motivational intervention (DN BMI); (c) a combined IN and DN brief motivational intervention (Combined-BMI); and (d) assessment-only control. DN-BMI focused on the juxtaposition of personal, perceived, and actual alcohol use by typical same-sex students at your university. IN-BMI focused on the juxtaposition of personal, perceived, and actual attitudes about alcohol-related consequences by the typical same-sex student at your university. Exploratory analyses assessed the effect of IN-BMI and DN-BMI on matched (e.g., the effect of DN-BMI on perceived DN) and mismatched norms (e.g., the effect of DN-BMI on perceived IN). IN-BMI resulted in greater decreases in alcohol use and consequences when delivered alone and in conjunction with DN-BMI compared with the control condition. Further, the Combined-BMI condition reported greater reductions in alcohol use but not consequences compared to the DN condition. Receiving IN-BMI either alone or in combination with DN-BMI produced greater changes in IN perceptions than were produced in the control group. Grounded in norms theory, this study examined how college student problem drinking is affected by both IN-BMI and DN-BMI alone and in combination. We conclude that IN-BMI alone or in combination with DN-BMI is able to modify alcohol use and reduce alcohol-related consequences. (PsycINFO Database Record PMID- 26478944 TI - Reciprocal relationships over time between descriptive norms and alcohol use in young adult sexual minority women. AB - Young adulthood, roughly ages 18-25, is a period of great risk for excessive consumption of alcohol, especially among sexual minority women (SMW). Despite the substantial literature examining the relationships between social norms and behavior in general, little attention has been given to the role of descriptive norms on the drinking behaviors of sexual minorities. The present study had 3 aims: to compare both typical woman descriptive norms and sexual minority specific descriptive normative perceptions among a sample of SMW, to examine reciprocal associations between sexual minority-specific descriptive norms and alcohol consumption over time, and to examine whether these reciprocal associations were moderated by sexual orientation (i.e., whether 1 identifies as lesbian or bisexual). A national sample of 1,057 lesbian and bisexual women between the ages of 18 and 25 was enrolled in this study. Participants completed an online survey at 4 time points that assessed the constructs of interest. Results indicated that SMW consistently perceived that SMW drank more than their nonsexual minority peers; that SMW-specific descriptive drinking norms and alcohol consumption influenced 1 another over time in a reciprocal, feed-forward fashion; and that these associations were not moderated by sexual orientation. These findings highlight the importance of considering SMW-specific norms as an important factor in predicting alcohol consumption in SMW. Results further support the development and testing of normative interventions for high-risk drinking among SMW. PMID- 26478945 TI - Management of drug resistantTB in patients with HIV co-infection. AB - INTRODUCTION: Multidrug-resistant and extensively drug-resistant tuberculosis (MDR- and XDR-TB) are major public health concerns worldwide. Their association with HIV/AIDS infection has contributed to the slowing down of TB incidence decline over the last two decades, therefore representing one of the most important barriers to reach TB elimination. AREAS COVERED: The aim of this manuscript is to critically review the recent scientific evidence on the management of drug-resistant TB (essentially MDR- and XDR-TB) in subjects coinfected with HIV, focusing on the two new recently-approved anti-TB drugs delamanid and bedaquiline. The medical search-engine PubMed was used, selecting the time-period January 2013 - February 2015, and using the following KEYWORDS: drug-resistant TB, multidrug resistant TB (or MDR-TB), extensively drug-resistant TB (or XDR-TB), delamanid and bedaquiline. EXPERT OPINION: The TB/HIV co-epidemic can be faced by implementing the 12 TB/HIV collaborative activities recommended by the World Health Organization. They are focused on the systematic screening of individuals to detect the Mycobacterium tuberculosis infection in HIV-positives, as well as HIV infection in TB patients in order to ensure a rapid initiation of the anti-retroviral therapy (ART). The clinical and public health management of HIV-positive individuals with MDR-TB is complex and expensive, given the cost of second line anti-TB drugs (including the new drugs, delamanid and bedaquiline) and ART. Political commitment and more investment to identify shorter, cheaper and effective anti-TB and HIV regimens as well as better diagnostics and, hopefully, a vaccine will contribute to boost the efforts to eliminate TB. PMID- 26478946 TI - Photochemical CO2 Reduction Catalyzed by Phenanthroline Extended Tetramesityl Porphyrin Complexes Linked with a Rhenium(I) Tricarbonyl Unit. AB - A series of heterodinuclear complexes (M-1-Re) based on a phenanthroline (phen) extended tetramesityl porphyrin ligand (H2-1) has been prepared. The phen moiety of this ligand selectively coordinates a Re(I) tricarbonyl chloride unit, whereas the metal in the porphyrin moiety has been varied: namely, Cu, Pd, Zn, Co, or Fe was used. These dinuclear complexes were fully characterized by standard analytical methods. Additionally, a crystal structure of Cu-1 Re.5.5(C7H8).0.5(C6H6) could be obtained, and extended time-resolved emission lifetime measurements were conducted. Furthermore, their ability to catalyze the photochemical reduction of CO2 to CO was investigated. Light-driven CO2 reduction experiments were performed in dimethylformamide (DMF) using triethylamine (TEA) as the sacrificial electron donor. The TONs (turnover numbers) of CO were determined and revealed a surprising catalytic activity that is obviously independent from the redox activity of the porphyrin metal. We have recently shown that the parent M-1 compounds are active photocatalysts, but the catalytic activity was dependent on the redox activity of the porphyrin metal. In the case of the new heterodinuclear complexes M-1-Re reported in this study, the catalytic active center seems to be the Re(I) moiety and not the porphyrin. Surprisingly, Zn-1-Re proved to be the most active compound in this series showing a TONCO of 13 after 24 h of illumination using a >375 nm cutoff filter while all other compounds showed minimal activity under this condition. PMID- 26478948 TI - Red blood cell membrane-facilitated release of nitrite-derived nitric oxide bioactivity. AB - The reduction of nitrite by deoxyhemoglobin to nitric oxide (NO) has been proposed as a mechanism for the transfer of NO bioactivity from the red blood cell (RBC) to the vasculature. This transfer can increase vascular dilatation. The major challenge to this hypothesis is the very efficient scavenging of NO by hemoglobin, which prevents the release of NO from RBCs. Previous studies indicate that the reaction of nitrite with deoxyhemoglobin produces two metastable intermediates involving nitrite bound to deoxyhemoglobin and a hybrid intermediate [Hb(II)NO(+) <-> Hb(III)NO] where the nitrite is reduced, but unavailable to react with hemoglobin. We have now shown how unique properties of these intermediates provide a pathway for the release of NO bioactivity from RBCs. The high membrane affinity of these intermediates (>100-fold greater than that of deoxyhemoglobin) places these intermediates on the membrane. Furthermore, membrane-induced conformational changes of the nitrite-reacted intermediates facilitate the release of NO from the hybrid intermediate and nitrite from the nitrite-bound intermediate. Increased membrane affinity, coupled with facilitated dissociation of NO and nitrite from the membrane-bound intermediates, provides the first realistic mechanism for the potential release of NO and nitrite from the RBC and their potential transfer to the vasculature. PMID- 26478947 TI - A Neuroprotective Sericin Hydrogel As an Effective Neuronal Cell Carrier for the Repair of Ischemic Stroke. AB - Ischemic stroke causes extensive cellular loss that impairs brain functions, resulting in severe disabilities. No effective treatments are currently available for brain tissue regeneration. The need to develop effective therapeutic approaches for treating stroke is compelling. A tissue engineering approach employing a hydrogel carrying both cells and neurotrophic cytokines to damaged regions is an encouraging alternative for neuronal repair. However, this approach is often challenged by low in vivo cell survival rate, and low encapsulation efficiency and loss of cytokines. To address these limitations, we propose to develop a biomaterial that can form a matrix capable of improving in vivo survival of transplanted cells and reducing in vivo loss of cytokines. Here, we report that using sericin, a natural protein from silk, we have fabricated a genipin-cross-linked sericin hydrogel (GSH) with porous structure and mild swelling ratio. The GSH supports the effective attachment and growth of neurons in vitro. Strikingly, our data reveal that sericin protein is intrinsically neurotrophic and neuroprotective, promoting axon extension and branching as well as preventing primary neurons from hypoxia-induced cell death. Notably, these functions are inherited by the GSH's degradation products, which might spare a need of incorporating costly cytokines. We further demonstrate that this neurotrophic effect is dependent on the Lkb1-Nuak1 pathway, while the neuroprotective effect is realized through regulating the Bcl-2/Bax protein ratio. Importantly, when transplanted in vivo, the GSH gives a high cell survival rate and allows the cells to continuously proliferate. Together, this work unmasks the neurotrophic and neuroprotective functions for sericin and provides strong evidence justifying the GSH's suitability as a potential neuronal cell delivery vehicle for ischemic stroke repair. PMID- 26478949 TI - Ultimate Limit of Light Extinction by Nanophotonic Structures. AB - Nanophotonic structures make it possible to precisely engineer the optical response at deep subwavelength scales. However, a fundamental understanding of the general performance limits remains a challenge. Here we use extensive electrodynamics simulations to demonstrate that the so-called f-sum rule sets a strict upper bound to the light extinction by nanostructures regardless their internal interactions and retardation effects. In particular, we show that the f sum rule applies to arbitrarily complex plasmonic metal structures that exhibit an extraordinary spectral sensitivity to size, shape, near-field coupling effects, and incident polarization. The results may be used for benchmarking light scattering and absorption efficiencies, thus imposing fundamental limits on solar light harvesting, biomedical photonics, and optical communications. PMID- 26478950 TI - Solvothermal Synthesis of Tetrahedrite: Speeding Up the Process of Thermoelectric Material Generation. AB - Derivatives of synthetic tetrahedrite, Cu12Sb4S13, are receiving increasing attention in the thermoelectric community due to their exploitation of plentiful, relatively nontoxic elements, combined with a thermoelectric performance that rivals that of PbTe-based compounds. However, traditional synthetic methods require weeks of annealing at high temperatures (450-600 degrees C) and periodic regrinding of the samples. Here we report a solvothermal method to produce tetrahedrite that requires only 1 day of heating at a relatively low temperature (155 degrees C). This allows preparation of multiple samples at once and is potentially scalable. The solvothermal material described herein demonstrates a dimensionless figure of merit (ZT) vs temperature curve comparable to that of solid-state tetrahedrite, achieving the same ZT of 0.63 at ~720 K. As with the materials from solid-state synthesis, products from this rapid solvothermal synthesis can be improved by mixing in a 1:1 molar ratio with the Zn-containing natural mineral, tennantite, to achieve 0.9 mol equiv of Zn. This leads to a 36% increase in ZT at ~720 K for solvothermal tetrahedrite, to 0.85. PMID- 26478952 TI - Surface 3D Micro Free Forms: Multifunctional Microstructured Mesoporous alpha Alumina by in Situ Slip Casting Using Excimer Laser Ablated Polycarbonate Molds. AB - Ceramic surface microstructuring is a rapidly growing field with a variety of applications in tribology, wetting, biology, and so on. However, there are limitations to large-area microstructuring and fabrication of three-dimensional (3D) micro free forms. Here, we present a route to obtain intricate surface structures through in situ slip casting using polydimethylsiloxane (PDMS) negative molds which are replicated from excimer laser ablated polycarbonate (PC) master molds. PC sheets are ablated with a nanosecond KrF (lambda = 248 nm) excimer laser mask projection system to obtain micron-scale 3D surface features over a large area of up to 3 m(2). Complex surface structures that include 3D free forms such as 3D topography of Switzerland, shallow structures such as diffractive optical elements (60 nm step) and conical micropillars have been obtained. The samples are defect-free produced with thicknesses of up to 10 mm and 120 mm diameter. The drying process of the slip cast alumina slurry takes place as a one-dimensional process, through surface evaporation and water permeation through the PDMS membrane. This allows homogeneous one-dimensional shrinkage during the drying process, independent of the sample's lateral dimensions. A linear mass diffusion model has been proposed to predict and explain the drying process of these ceramic colloidal suspensions. The calculated drying time is linearly proportional to the height of the slurry and the thickness of the negatively structured PDMS and is validated by the experimental results. An experimentally observed optimum Sylgard PDMS thickness range of ~400 MUm to 1 mm has achieved the best quality microstructured green compacts. Further, the model predicts that the drying time is independent of the microstructured areas and was validated using experimental observations carried out with microstructured areas of 300 mm(2), 1200 mm(2), and 120 cm(2). Therefore, in principle, the structures can be further replicated in areas up to 3 m(2) with the same drying time for the same slurry height. The surface structured ceramics display interesting wetting properties, for example, eicosane coated mesoporous microstructured alumina shows superhydrophobic behavior. Additionally, ceramic bulk samples could be further used as second-generation very hard and low-wear molds for further microfabrication. PMID- 26478951 TI - Pediatric Primary Care-Based Obesity Prevention for Parents of Preschool Children: A Pilot Study. AB - BACKGROUND: The Healthy Homes/Healthy Kids Preschool (HHHK-Preschool) pilot program is an obesity prevention intervention integrating pediatric care provider counseling and a phone-based program to prevent unhealthy weight gain among 2- to 4-year-old children at risk for obesity (BMI percentile between the 50th and 85th percentile and at least one overweight parent) or currently overweight (85th percentile <= BMI < 95th percentile). The aim of this randomized, controlled pilot study was to evaluate the feasibility, acceptability, and potential efficacy of the HHHK-Preschool intervention. METHODS: Sixty parent-child dyads recruited from pediatric primary care clinics were randomized to: (1) the Busy Bodies/Better Bites Obesity Prevention Arm or the (2) Healthy Tots/Safe Spots safety/injury prevention Contact Control Arm. Baseline and 6-month data were collected, including measured height and weight, accelerometry, previous day dietary recalls, and parent surveys. Intervention process data (e.g., call completion) were also collected. RESULTS: High intervention completion and satisfaction rates were observed. Although a statistically significant time by treatment interaction was not observed for BMI percentile or BMI z-score, post hoc examination of baseline weight status as a moderator of treatment outcome showed that the Busy Bodies/Better Bites obesity prevention intervention appeared to be effective among children who were in the overweight category at baseline relative to those who were categorized as at risk for obesity (p = 0.04). CONCLUSIONS: HHHK-Preschool pilot study results support the feasibility, acceptability, and potential efficacy in already overweight children of a pediatric primary care-based obesity prevention intervention integrating brief provider counseling and parent-targeted phone coaching. What's New: Implementing pediatric primary care-based obesity interventions is challenging. Previous interventions have primarily involved in-person sessions, a barrier to sustained parent involvement. HHHK-preschool pilot study results suggest that integrating brief provider counseling and parent-targeted phone coaching is a promising approach. PMID- 26478953 TI - Micronutrients (B, Co, Cu, Fe, Mn, Mo, and Zn) content in made tea (Camellia sinensis L.) and tea infusion with health prospect: A critical review. AB - Tea (Camellia sinensis L.) is a perennial acidophilic crop, and known to be a nonalcoholic stimulating beverage that is most widely consumed after water. The aim of this review paper is to provide a detailed documentation of selected micronutrient contents, viz. boron (B), cobalt (Co), copper (Cu), iron (Fe), manganese (Mn), molybdenum (Mo), and zinc (Zn) in made tea and tea infusion. Available data from the literature were used to calculate human health aspect associated with the consumption of tea infusion. A wide range of micronutrients reported in both made tea and tea infusion could be the major sources of micronutrients for human. The content of B, Co, Cu, Fe, Mn, Mo, and Zn in made tea are ranged from 3.04 to 58.44 MUg g-1, below detectable limit (BDL) to 122.4 MUg g-1, BDL to 602 MUg g-1, 0.275 to 13,040 MUg g-1, 0.004 to 15,866 MUg g-1, 0.04 to 570.80 MUg g-1 and 0.01 to 1120 MUg g-1, respectively. Only 3.2 MUg L-1 to 7.25 mg L-1, 0.01 MUg L-1 to 7 mg L-1, 3.80 MUg L-1 to 6.13 mg L-1, 135.59 MUg L-1 -11.05 mg L-1, 0.05 MUg L-1 to 1980.34 mg L-1, 0.012 to 3.78 MUg L-1, and 1.12 MUg L-1 to 2.32 MUg L-1 of B, Co, Cu, Fe, Mn, Mo, and Zn, respectively, are found in tea infusion which are lower than the prescribed limit of micronutrients in drinking water by World Health Organization. Furthermore, micronutrient contents in tea infusion depend on infusion procedure as well as on the instrument used for analysis. The proportion of micronutrients found in different tea types are 1.0-88.9% for B, 10-60% for Co, 2.0-97.8% for Cu, 67.8-89.9% for Fe, 71.0-87.4% for Mn, 13.3-34% for Mo, and 34.9-83% for Zn. From the results, it can also be concluded that consumption of three cups of tea infusion per day does not have any adverse effect on human health with respect to the referred micronutrients rather got beneficial effects to human. PMID- 26478954 TI - Promising Strategy To Improve Charge Separation in Organic Photovoltaics: Installing Permanent Dipoles in PCBM Analogues. AB - A multidisciplinary approach involving organic synthesis and theoretical chemistry was applied to investigate a promising strategy to improve charge separation in organic photovoltaics: installing permanent dipoles in fullerene derivatives. First, a PCBM analogue with a permanent dipole in the side chain (PCBDN) and its reference analogue without a permanent dipole (PCBBz) were successfully synthesized and characterized. Second, a multiscale modeling approach was applied to investigate if a PCBDN environment around a central donor acceptor complex indeed facilitates charge separation. Alignment of the embedding dipoles in response to charges present on the central donor-acceptor complex enhances charge separation. The good correspondence between experimentally and theoretically determined electronic and optical properties of PCBDN, PCBBz, and PCBM indicates that the theoretical analysis of the embedding effects of these molecules gives a reliable expectation for their influence on the charge separation process at a microscopic scale in a real device. This work suggests the following strategies to improve charge separation in organic photovoltaics: installing permanent dipoles in PCBM analogues and tuning the concentration of these molecules in an organic donor/acceptor blend. PMID- 26478955 TI - Giant Permittivity Polymer Nanocomposites Obtained by Curing a Direct Emulsion. AB - Near-percolated CNT-polymer composites are promising high-permittivity materials. The main challenge in the field consists of finding compromises that allow high permittivity and low losses in frequency ranges of interest. Using an emulsion approach and optimizing the size of the droplets and the curing procedure, we obtain unprecedented performances and measure giant permittivity larger than 20,000 at 100 Hz along with a conductivity below 10(-4) S/m. PMID- 26478956 TI - Optimization of exposure in panoramic radiography while maintaining image quality using adaptive filtering. AB - Objective The purpose of the present study was to investigate the potential of using advanced external adaptive image processing for maintaining image quality while reducing exposure in dental panoramic storage phosphor plate (SPP) radiography. Materials and methods Thirty-seven SPP radiographs of a skull phantom were acquired using a Scanora panoramic X-ray machine with various tube load, tube voltage, SPP sensitivity and filtration settings. The radiographs were processed using General Operator Processor (GOP) technology. Fifteen dentists, all within the dental radiology field, compared the structural image quality of each radiograph with a reference image on a 5-point rating scale in a visual grading characteristics (VGC) study. The reference image was acquired with the acquisition parameters commonly used in daily operation (70 kVp, 150 mAs and sensitivity class 200) and processed using the standard process parameters supplied by the modality vendor. Results All GOP-processed images with similar (or higher) dose as the reference image resulted in higher image quality than the reference. All GOP-processed images with similar image quality as the reference image were acquired at a lower dose than the reference. This indicates that the external image processing improved the image quality compared with the standard processing. Regarding acquisition parameters, no strong dependency of the image quality on the radiation quality was seen and the image quality was mainly affected by the dose. Conclusions The present study indicates that advanced external adaptive image processing may be beneficial in panoramic radiography for increasing the image quality of SPP radiographs or for reducing the exposure while maintaining image quality. PMID- 26478957 TI - Factors associated with hysterectomy among older women from Latin America and the Caribbean. AB - To identify factors associated with hysterectomy, data collected from 1999-2000 were assessed from seven cities of the Health, Well-Being and Aging in Latin America and the Caribbean Study on 6,549 women, aged 60 years and older. Hysterectomy prevalence ranged from 12.8% in Buenos Aires (Argentina) to 30.4% in Bridgetown (Barbados). The median age for having had a hysterectomy ranged from 45 to 50 years across the cities and was 47 years in the pooled sample. Ethnic differences in hysterectomy rates were partially explained by differences across cities. Factors significantly associated with lower odds for hysterectomy included older age, household crowding conditions, and having public/military or no health insurance, compared to having private health insurance. Women who had three or more children were less likely to have had a hysterectomy, a finding that differs from most previous studies. Socioeconomic position related to rates of hysterectomy in late life rather than hysterectomies earlier in life. However, the nature of these differences varied across birth cohorts. The findings suggested that adverse socioeconomic factors were most likely related to hysterectomy risk by affecting access to health care, whereas parity was most likely acting through an effect on decision-making processes. PMID- 26478958 TI - Event processing in the visual world: Projected motion paths during spoken sentence comprehension. AB - Motion events in language describe the movement of an entity to another location along a path. In 2 eye-tracking experiments, we found that comprehension of motion events involves the online construction of a spatial mental model that integrates language with the visual world. In Experiment 1, participants listened to sentences describing the movement of an agent to a goal while viewing visual scenes depicting the agent, goal, and empty space in between. Crucially, verbs suggested either upward (e.g., jump) or downward (e.g., crawl) paths. We found that in the rare event of fixating the empty space between the agent and goal, visual attention was biased upward or downward in line with the verb. In Experiment 2, visual scenes depicted a central obstruction, which imposed further constraints on the paths and increased the likelihood of fixating the empty space between the agent and goal. The results from this experiment corroborated and refined the previous findings. Specifically, eye-movement effects started immediately after hearing the verb and were in line with data from an additional mouse-tracking task that encouraged a more explicit spatial reenactment of the motion event. In revealing how event comprehension operates in the visual world, these findings suggest a mental simulation process whereby spatial details of motion events are mapped onto the world through visual attention. The strength and detectability of such effects in overt eye-movements is constrained by the visual world and the fact that perceivers rarely fixate regions of empty space. (PsycINFO Database Record PMID- 26478959 TI - Stimulus probability effects in absolute identification. AB - This study investigated the effect of stimulus presentation probability on accuracy and response times in an absolute identification task. Three schedules of presentation were used to investigate the interaction between presentation probability and stimulus position within the set. Data from individual participants indicated strong effects of presentation probability on both proportion correct and response times. The effects were moderated by the ubiquitous stimulus position effect. The accuracy and response time data were predicted by an exemplar-based model of perceptual cognition (Kent & Lamberts, 2005). The bow in discriminability was also attenuated when presentation probability for middle items was relatively high, an effect that will constrain future model development. The study provides evidence for item-specific learning in absolute identification. Implications for other theories of absolute identification are discussed. (PsycINFO Database Record PMID- 26478960 TI - Clinical outcome and gait analysis of a cat with bilateral slipped capital femoral epiphysis following bilateral ostectomy of the femoral head and neck. PMID- 26478962 TI - Broca's region and Visual Word Form Area activation differ during a predictive Stroop task. AB - Competing theories attempt to explain the function of Broca's area in single word processing. Studies have found the region to be more active during processing of pseudo words than real words and during infrequent words relative to frequent words and during Stroop (incongruent) color words compared to Non-Stroop (congruent) words. Two related theories explain these findings as reflecting either "cognitive control" processing in the face of conflicting input or a linguistic prediction error signal, based on a predictive coding approach. The latter implies that processing cost refers to violations of expectations based on the statistical distributions of input. In this fMRI experiment we attempted to disentangle single word processing cost originating from cognitive conflict and that stemming from predictive expectation violation. Participants (N = 49) responded to whether the words "GREEN" or "RED" were displayed in green or red (incongruent vs congruent colors). One of the colors, however, was presented three times as often as the other, making it possible to study both congruency and frequency effects independently. Auditory stimuli saying "GREEN" or "RED" had the same distribution, making it possible to study frequency effects across modalities. We found significant behavioral effects of both incongruency and frequency. A significant effect (p < .05 FWE) of incongruency was found in Broca's region, but no effect of frequency was observed and no interaction. Conjoined effects of incongruency and frequency were found in parietal regions as well as in the Visual Word Form Area (VWFA). No interaction between perceptual modality and frequency was found in VWFA suggesting that the region is not strictly visual. These findings speak against a strong version of the prediction error processing hypothesis in Broca's region. They support the idea that prediction error processes in the intermediate timeframe are allocated to more posterior parts of the brain. PMID- 26478961 TI - Investigating the functions of subregions within anterior hippocampus. AB - Previous functional MRI (fMRI) studies have associated anterior hippocampus with imagining and recalling scenes, imagining the future, recalling autobiographical memories and visual scene perception. We have observed that this typically involves the medial rather than the lateral portion of the anterior hippocampus. Here, we investigated which specific structures of the hippocampus underpin this observation. We had participants imagine novel scenes during fMRI scanning, as well as recall previously learned scenes from two different time periods (one week and 30 min prior to scanning), with analogous single object conditions as baselines. Using an extended segmentation protocol focussing on anterior hippocampus, we first investigated which substructures of the hippocampus respond to scenes, and found both imagination and recall of scenes to be associated with activity in presubiculum/parasubiculum, a region associated with spatial representation in rodents. Next, we compared imagining novel scenes to recall from one week or 30 min before scanning. We expected a strong response to imagining novel scenes and 1-week recall, as both involve constructing scene representations from elements stored across cortex. By contrast, we expected a weaker response to 30-min recall, as representations of these scenes had already been constructed but not yet consolidated. Both imagination and 1-week recall of scenes engaged anterior hippocampal structures (anterior subiculum and uncus respectively), indicating possible roles in scene construction. By contrast, 30 min recall of scenes elicited significantly less activation of anterior hippocampus but did engage posterior CA3. Together, these results elucidate the functions of different parts of the anterior hippocampus, a key brain area about which little is definitely known. PMID- 26478964 TI - Dynamic reorganization of functional brain networks during picture naming. AB - For efficient information processing during cognitive activity, functional brain networks have to rapidly and dynamically reorganize on a sub-second time scale. Tracking the spatiotemporal dynamics of large scale networks over this short time duration is a very challenging issue. Here, we tackle this problem by using dense electroencephalography (EEG) recorded during a picture naming task. We found that (i) the picture naming task can be divided into six brain network states (BNSs) characterized by significantly high synchronization of gamma (30-45 Hz) oscillations, (ii) fast transitions occur between these BNSs that last from 30 msec to 160 msec, (iii) based on the state of the art of the picture naming task, we consider that the spatial location of their nodes and edges, as well as the timing of transitions, indicate that each network can be associated with one or several specific function (from visual processing to articulation) and (iv) the comparison with previously-used approach aimed at localizing the sources showed that the network-based approach reveals networks that are more specific to the performed task. We speculate that the persistence of several brain regions in successive BNSs participates to fast and efficient information processing in the brain. PMID- 26478963 TI - The brain's dress code: How The Dress allows to decode the neuronal pathway of an optical illusion. AB - Optical illusions have broadened our understanding of the brain's role in visual perception. A modern day optical illusion emerged from a posted photo of a striped dress, which some perceived as white and gold and others as blue and black. Here we show, using functional magnetic resonance imaging (fMRI), that those who perceive The Dress as white/gold have higher activation in response to the image of The Dress in brain regions critically involved in higher cognition (frontal and parietal brain areas). These results are consistent with theories of top-down modulation and present a neural signature associated with the differences in perceiving The Dress as white/gold or blue/black. Furthermore the results support recent psychophysiological data on this phenomenon and provide a fundamental building block to study interindividual differences in visual processing. PMID- 26478965 TI - Quality of statistical reporting in developmental disability journals. AB - Null hypothesis significance testing (NHST) dominates quantitative data analysis, but its use is controversial and has been heavily criticized. The American Psychological Association has advocated the reporting of effect sizes (ES), confidence intervals (CIs), and statistical power analysis to complement NHST results to provide a more comprehensive understanding of research findings. The aim of this paper is to carry out a sample survey of statistical reporting practices in two journals with the highest h5-index scores in the areas of developmental disability and rehabilitation. Using a checklist that includes critical recommendations by American Psychological Association, we examined 100 randomly selected articles out of 456 articles reporting inferential statistics in the year 2013 in the Journal of Autism and Developmental Disorders (JADD) and Research in Developmental Disabilities (RDD). The results showed that for both journals, ES were reported only half the time (JADD 59.3%; RDD 55.87%). These findings are similar to psychology journals, but are in stark contrast to ES reporting in educational journals (73%). Furthermore, a priori power and sample size determination (JADD 10%; RDD 6%), along with reporting and interpreting precision measures (CI: JADD 13.33%; RDD 16.67%), were the least reported metrics in these journals, but not dissimilar to journals in other disciplines. To advance the science in developmental disability and rehabilitation and to bridge the research-to-practice divide, reforms in statistical reporting, such as providing supplemental measures to NHST, are clearly needed. PMID- 26478966 TI - Soft tissue and crestal bone changes around implants with platform-switched abutments placed nonsubmerged at subcrestal position: a 2-year clinical and radiographic evaluation. AB - PURPOSE: To evaluate crestal bone changes around implants with platform-switched abutments placed 1 mm subcrestally in a prospective clinical investigation. MATERIALS AND METHODS: Forty consecutive systemically healthy patients (mean age +/- standard deviation [SD], 55.2 +/- 8.7 years) with one or more missing teeth were consecutively treated with 1-mm subcrestally positioned, platform-switched, tapered, full treated implants restored with coded abutments. A total of 58 implants were placed. Final restorations were delivered 4 to 8 months after implant insertion. Digital standardized periapical radiographs using customized film holders were obtained at the time of implant insertion, and at 12 and 24 months after final prosthesis placement. Marginal peri-implant bone levels were measured at the mesial and distal surfaces of each implant using digital image software. RESULTS: All implants osseointegrated and were clinically stable at the 2-year follow-up. The cumulative survival rate was 100%. From implant insertion to the 2-year follow-up, the mean bone loss was 0.32 +/- 0.37 mm. No significant differences related to sex, implant site, and bone density were observed. The mean midbuccal and interproximal soft tissue margin positions were 1.13 +/- 0.5 mm and 1.15 +/- 0.6 mm coronal to the prosthetic finish line, respectively. CONCLUSION: There is limited clinical information regarding the amount of marginal bone loss around two-piece platform-switched implants placed at subcrestal positions. Results of this study suggest that platform switching and subcrestal location of the implant-abutment interface may be effective in reducing bone loss and in preserving esthetics around dental implants. PMID- 26478967 TI - Quality Assessment of Systematic Reviews on Oral Implants Placed Immediately into Fresh Extraction Sockets. AB - PURPOSE: During the last two decades, many clinical trials and systematic reviews (SRs) have evaluated the clinical outcomes of immediate implant placement and its effects on soft and hard tissue. Despite the increased popularity and knowledge of immediate implant placement, the evidence about its benefits is still not conclusive. The aim of this review was to assess the quality of published SRs with meta-analyses of immediate implant placement and provide an overview of the key findings. MATERIALS AND METHODS: Searches of MEDLINE, EMBASE, the Cochrane Library, and the Database of Abstracts of Reviews of Effects were performed to include SRs with meta-analysis of immediate implant placement. Two independent reviewers assessed the methodologic quality of SRs using A MeaSurement Tool to Assess Reviews (AMSTAR), the 2003 checklist of Glenny et al, and the Critical Appraisal Skills Program (CASP). RESULTS: A total of 742 articles were found; 5 were included. All included SRs were published after 2007. Implant survival rate was the most commonly reported outcome. There was insufficient information in the primary studies, and hence in the SRs, about other outcomes and any adverse events. However, the methodologic quality of the SRs was considered to be high. CONCLUSION: There is a general consensus among the included SRs that it is still premature to draw definite conclusions about the potential benefits of immediate implant placement because of the limited number of well-designed controlled clinical trials. Improvements in future SRs are still required and can be achieved by following established quality criteria, namely researching the unpublished literature and literature not in English and by reporting the quality assessment of primary studies and any sources of bias. PMID- 26478968 TI - Accuracy and reliability of cone beam computed tomographic measurements of the bone labial and palatal to the maxillary anterior teeth. AB - PURPOSE: The aim of this study was to measure the thickness of bone labial and palatal to maxillary anterior teeth on cone beam computed tomographic (CBCT) images and to compare these measurements with direct clinical measurements to determine the reliability and accuracy of CBCT. MATERIALS AND METHODS: Eighteen healthy subjects were randomly selected from among candidates for immediate implant placement in the anterior maxilla. After extraction, labial bone thickness was measured at 1, 4, and 8 mm from the bone crest. Palatal bone thickness was also measured at 1 and 4 mm from the bone crest. The same measurements were performed on presurgical CBCT images. The CBCT measurements were compared to the direct measurements, and their accuracy and reliability were assessed by Pearson correlation coefficients and intraclass correlation coefficients, respectively. RESULTS: The mean width of labial bone was 0.50 +/- 0.32 mm and 0.76 +/- 0.37 mm for direct and CBCT measurements, respectively. Average thickness of the palatal bone was 1.16 +/- 0.53 mm and 1.41 +/- 0.51 mm for direct and CBCT measurements, respectively. The mean absolute error and mean relative error of CBCT measurements compared to direct measurements were 0.28 +/- 0.29 mm and 0.60 +/- 0.84 mm, respectively. The Pearson correlation between CBCT and direct measurements was 0.795 (P < .001) and the intraclass correlation coefficient between direct and CBCT measurements was 0.840. The correlation between the measurement series increased significantly when the measured bone was more than 1 mm thick. CONCLUSION: CBCT measurements of labial bone mostly overestimated bone thickness. CBCT has relatively good accuracy and reliability for measurement of labial bone thickness when the alveolar bone is thicker than 1 mm. However, most subjects have labial bone thinner than 1 mm; therefore, CBCT could result in large errors in many patients. PMID- 26478969 TI - Three-Dimensional Finite Element Analysis of the Biomechanical Behaviors of Implants with Different Connections, Lengths, and Diameters Placed in the Maxillary Anterior Region. AB - PURPOSE: To evaluate the biomechanical behaviors of multiple implant-supported prostheses with different implant lengths, connections, locations, and restoration materials in the maxillary anterior region using three-dimensional finite element analysis. MATERIALS AND METHODS: A finite element model of a maxillary image was created from a tomography data bank. The simulations were executed in two types of models based on the treatment plan: (1) two implants with 4.0-mm diameters placed in the maxillary central incisors to simulate an implant-supported fixed prosthesis with four elements with a cantilever of both maxillary lateral incisors; (2) two implants with 3.75-mm diameters placed in the maxillary lateral incisors to simulate a conventional fixed prosthesis with four elements with pontics for maxillary central incisors. Subsequently, the models created were subdivided into eight subgroups according to implant length, connection type, and restoration material. A total static oblique load of 150 N was applied to the cingulum area of the palatal surfaces of the four incisors at an angle of 45 degrees to the long axis of the implant in the palatal-labial direction. Bone stresses were analyzed through maximum and minimum principal stresses and ductile material as implant, framework, and abutments were analyzed using von Mises stress criterion. RESULTS: Regardless of implant diameter and type of treatment, the 8.5-mm-long implants exhibited the lowest tensile and compressive stresses. Maximum and minimum principal stresses were identified in the cortical bone. The lowest von Mises equivalent stress values were identified in the metal-ceramic prostheses, with the exception of the cantilever prosthesis model with flat top connection. Conical cone implant models exhibited maximum von Mises equivalent stress in contact with the abutment. CONCLUSION: The lowest principal stresses in the peri-implant bone were observed in implants with conical cone connection and 8.5 mm in length. Also, in most cases, the models with metal-ceramic restorations exhibited better stress distributions. PMID- 26478971 TI - Key biomechanical characteristics of complete-arch fixed mandibular prostheses supported by three implants developed at P-I Branemark Institute, Bauru. AB - PURPOSE: To determine the range of vertical cantilever (VC), real cantilever (RC), and height of the imaginary triangle (h) formed by the bases of the three implant cylinders in full-arch mandibular prostheses supported by three implants. MATERIALS AND METHODS: The sample comprised 203 patients (147 women, 56 men; mean age, 58 years, range, 37 to 79 years) with full-arch mandibular rehabilitations. Their prostheses were measured in relation to implant placement to characterize numerical values for VC, force arm of the lever system (represented by the distal cantilever or RC), and resistance arm of the system (represented by the height of the imaginary triangle formed by the bases of the three implants). Data were tabulated and means and standard deviations calculated for all measurements. The range of each of the three measurements was then divided into quintiles for characterizing data distribution. RESULTS: The mean (standard deviation) values found were as follows: VC1 = 17.11 (3.39) mm; VC2 = 17.46 (2.89) mm; VC3 = 16.68 (3.16) mm; RC1 = 14.67 (3.90) mm; RC3 = 15.02 (4.15) mm; h = 8.27 (2.96) mm. CONCLUSION: VC ranged from 7.37 to 26.44 mm, RC ranged from 4.00 to 26.93 mm, and the height of the imaginary triangle formed by the bases of the three implant cylinders ranged from 0.37 to 15.33 mm. PMID- 26478970 TI - An Analysis of Frequency, Morphology, and Locations of Maxillary Sinus Septa Using Cone Beam Computed Tomography. AB - PURPOSE: To evaluate the frequency, morphology, and locations of maxillary sinus septa using cone beam computed tomographic (CBCT) imaging of the entire maxillary sinus and to analyze factors influencing the presence or absence of septa. MATERIALS AND METHODS: CBCT images of the maxilla taken during a 1-year study period (October 1, 2012, to September 30, 2013) were evaluated for the presence and type of septa as well as the health or pathology of the maxillary sinus. Differences in age, gender, type of dentition, septa location, and sinus pathology with regard to the incidence of sinus septa were analyzed statistically. RESULTS: The study included 294 maxillary sinuses in 212 patients (126 women and 86 men) with a mean age of 53.8 years. Sinus septa were present in 141 patients (66.5%) and in 166 of 294 sinuses (56.5%). The most common orientation of the septa was coronal (61.8%), 7.6% were oriented axially, and 3.6% were aligned sagittally. Most septa were located on the floor of the maxillary sinus (58.6%), commonly (60.7%) in the region of the first and second molars. The maxillary sinuses were diagnosed in 36.4% of cases as healthy and without thickening of the sinus membrane. Sex was a significant variable in the health of the maxillary sinus; 57.7% of the sinuses in women and 72.3% in men were diagnosed as pathologic. CONCLUSION: Septa are common anatomical structures and are most often found in the first or second molar region on the floor of the maxillary sinus. To prevent possible complications during sinus floor elevation procedures, a thorough three-dimensional radiographic examination of the sinus prior to surgery is recommended. PMID- 26478973 TI - Bilateral Cutaneous Fistula After the Placement of Zygomatic Implants. AB - Zygomatic implants are used to restore function in patients with highly edentulous atrophic maxillae, in which it is not possible to place conventional implants. The aim of this paper is to present a case of bilateral cutaneous fistula after placement of zygomatic implants and the treatment performed to resolve the condition, as well as to establish a hypothesis regarding the etiology of these lesions. Presented is a 59-year-old woman with an atrophic edentulous maxilla who received four zygomatic implants. At 8 months and 31 months after implant placement on the right and left sides, respectively, the patient developed inflammatory lesions in the lateral aspect of both orbits that evolved toward developing a fistula within weeks. The patient underwent surgery in both cases. Complications of zygomatic implants are relatively common but rarely involve the loss or removal of implants. In this case, the patient retained her implants, and several months after resection of both fistulae, the patient is asymptomatic without recurrence of the lesions. The probable cause of the occurrence of the fistula could be an accumulation of sinus mucosa remnants, periosteum, and bone particles at the malar level as a result of poor irrigation at the time of implant placement. PMID- 26478974 TI - Antimicrobial effectiveness of cetylpyridinium chloride and zinc chloride containing mouthrinses on bacteria of halitosis and peri-implant disease. AB - PURPOSE: To clarify the antimicrobial efficacy of zinc chloride (ZnCl2) and cetylpyridinium chloride (CPC) by testing their impact on the growth of seven bacterial strains known to be involved in the pathophysiology of both peri implant disease and halitosis-Staphylococcus aureus, Streptococcus mutans, Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, Treponema denticola, and Tannerella forsythia. MATERIALS AND METHODS: A time response growth curve was obtained. Commercial mouthrinses with CPC, ZnCl2, or both were added to the media in a final concentration of 0.25% CPC, 2.5% ZnCl2, and 2.5% ZnCl2 with 0.25% CPC. RESULTS: Both CPC and ZnCl2 effectively inhibited the growth of almost all bacterial strains tested except T denticola. ZnCl2 was generally more effective in suppressing bacterial growth than CPC. ZnCl2 with CPC showed the greatest inhibitory activities on almost all strains of bacterial growth except for P gingivalis and T denticola, followed by ZnCl2, then CPC, thus suggesting the possibility of a synergistic effect of the two agents. P gingivalis exhibited a different pattern because ZnCl2 showed the most significant inhibitory effect. CPC did not show growth inhibitory effects on T denticola, but ZnCl2 did. CONCLUSION: Zinc and CPC effectively inhibit bacterial growth that causes both halitosis and peri-implant disease. The effect is even more powerful when applied in combination. PMID- 26478975 TI - Changes in Sinus Membrane Thickness After Lateral Sinus Floor Elevation: A Radiographic Study. AB - PURPOSE: To radiographically monitor sinus membrane swelling after lateral sinus floor elevation surgery at short and long healing periods. MATERIALS AND METHODS: For 26 patients seeking posterior maxillary implant-supported reconstruction, 32 lateral sinus floor elevations were performed using Piezosurgery. Sinus membranes were grafted using synthetic calcium phosphate bone substitutes, and graft volume was measured in cubic centimeters for each case. Cone beam computed tomography (CBCT) examination was conducted preoperatively in all patients and for each grafted sinus at 1 day (n = 8), 2 days (n = 9), 3 days (n = 8), or 7 days (n = 7) after surgery. Control CBCT was then performed for all patients at 3, 6, and 12 months after surgery. Sinus membrane thickness was measured on cross-sectional CBCT images at nine standardized points per sinus, before lateral sinus floor elevation and at all postoperative examinations. RESULTS: Mean sinus membrane thickness was 0.73 mm before surgery, and 5 mm, 4.1 mm, 5.9 mm, and 7 mm, respectively, at 1, 2, 3, and 7 days after surgery. First week combined postoperative CBCT measurements of membrane thickness was 5.4 mm, then 1.3, 0.68, and 0.39 mm at 3, 6, and 12 months, respectively, after surgery. Membrane thickness significantly increased the first week after surgery and gradually decreased significantly at 3, 6, and 12 months in all groups (P < .001). First week postoperative measurements showed a significant increase in membrane thickness at 3 days compared with the 1- and 2-day results (P < .001) and at 7 days compared with all other time points (P < .001). Membrane thickness at 2 days did not change significantly compared with 1-day measurements. Larger graft volume was positively correlated with an increase in membrane thickness after surgery at all time points (n = 32; r = 0.527; P < .001). CONCLUSION: After lateral sinus floor elevation surgery, transient swelling of sinus membrane is observed. It reaches a peak value 7 days after surgery and completely resolves over months. This swelling is correlated to the extent of sinus floor elevation. PMID- 26478976 TI - The effect of implant thread design on stress distribution in anisotropic bone with different osseointegration conditions: a finite element analysis. AB - PURPOSE: Whereas bone is anisotropic, nearly all previous mechanical analyses of implants assumed bone as an isotropic material. Another means to simplify a simulation of the biomechanics of the implant-bone interface is the assumption of complete or no osseointegration; in clinical reality, an implant never achieves 100% contact with the surrounding bone. This study evaluated different thread profiles while not taking into account these two common simplifications. This study sought to (1) investigate the effects of various implant thread designs on stress distribution in the peri-implant bone, (2) appraise previous efforts in this area, and (3) find an optimum basic thread-form design. MATERIALS AND METHODS: Through finite element analysis, four different basic commercial thread form configurations for a solid screw-type implant were modeled: buttress, reverse buttress, V, and square. Bone was assumed to be transversely isotropic, and various degrees of osseointegration were simulated. RESULTS: Simulations showed that von Mises stresses were more distributed in the mesiodistal direction. Additionally, maximum stresses were concentrated at the cervical cortical bone region and the first thread. Moreover, in most of the models, von Mises stresses gradually increased in the supporting structure when the degree of osseointegration increased. CONCLUSION: The use of different thread designs and various osseointegration conditions did not affect the stress distribution patterns in the supporting bone. In this study, square threads showed the most favorable results according to the predicted values of von Mises equivalent stress, pressure, different shear stresses, and micromotion. PMID- 26478977 TI - Levels of osteoclastogenesis-related factors in the peri-implant crevicular fluid and clinical parameters of immediately loaded implants in patients with osteopenia: a short-term report. AB - PURPOSE: The aim of this prospective controlled study was to evaluate the influence of osteopenia on the levels of osteoclastogenesis-related factors in the peri-implant crevicular fluid (PICF) and on the clinical parameters of immediately loaded implants. MATERIALS AND METHODS: This study included 24 patients who received at least two implants in the mandible, with restorations delivered 48 hours after implant placement. Patients were divided into control (n = 11) and osteopenia (n = 13) groups. Seven days after implant placement (baseline) and 4 months after implant placement, PICF samples were obtained, and clinical parameters (Plaque Index, Gingival Index, bleeding on probing, suppuration, probing depths, clinical attachment levels) were measured. A commercially available enzyme-linked immunosorbent assay was used to analyze PICF samples for levels of soluble receptor activator of nuclear factor of kappaB ligand (sRANKL) and osteoprotegerin (OPG). At the 4-month follow-up visit, the implant-supported restorations were removed and periapical radiographs were acquired to evaluate bone loss around the implants. RESULTS: Eighty-eight immediately loaded implants were included in this study (38 in the control group, 50 in the osteopenia group). The RANKL and OPG levels, the RANKL/OPG ratio, and the clinical parameters were similar between the groups at both time points. However, the levels of these factors in PICF differed significantly between baseline and 4 months after surgery. CONCLUSION: Within the limitations of this short-term study, it can be concluded that osteopenia does not influence the PICF levels of osteoclastogenesis-related factors in immediately loaded implants after 4 months of loading. PMID- 26478978 TI - The Microbiologic Profile Associated with Peri-Implantitis in Humans: A Systematic Review. AB - PURPOSE: To qualitatively investigate the microbiologic profile in peri implantitis by systematically reviewing the published literature on peri-implant infection. MATERIALS AND METHODS: Searches of the US National Institutes of Health free digital archives of the biomedical and life sciences journal literature (PubMed) and The Cochrane Library of the Cochrane Collaboration (CENTRAL), as well as a hand search of other literature, were conducted to identify articles potentially relevant for the review. Randomized clinical trials, prospective cohort studies, longitudinal studies, case-control studies, and cross-sectional studies in humans reporting microbiologic findings in patients with diagnosed peri-implantitis were considered eligible for this review. Screening, data extraction, and quality assessment were conducted independently and in duplicate. RESULTS: Twenty-one articles were eligible for inclusion in this review. Early studies focused on the identification of target periopathogens, whereas more recent studies used advanced molecular techniques for comprehensive overview of the peri-implantitis-associated microbiome. In summary, the microbiologic profile in peri-implantitis (1) is complex and variable, (2) consists of gram-negative anaerobic periopathogens and opportunistic microorganisms in almost the same ratio, (3) is frequently associated with the Epstein-Barr virus and nonsaccharolytic anaerobic gram positive rods, (4) is not so strictly associated with Staphylococcus aureus, and (5) is different from that of periodontitis. A meta-analysis could not be performed because of the heterogeneity of the reviewed studies. CONCLUSION: Although a comparison of the published results was limited because of the inhomogeneity of the studies, it is clear that the microbiologic profile of peri implantitis consists of aggressive and resistant microorganisms and is distinct from that of periodontitis. It seems that the quantitative characteristics of the microflora cohabitants represent the key determinant of disease, rather than the qualitative composition, which is very similar in healthy and peri-implantitis states. PMID- 26478979 TI - Correlation of Fractal Dimension Values with Implant Insertion Torque and Resonance Frequency Values at Implant Recipient Sites. AB - PURPOSE: Fractal analysis is a mathematical method used to describe the internal architecture of complex structures such as trabecular bone. Fractal analysis of panoramic radiographs of implant recipient sites could help to predict the quality of the bone prior to implant placement. This study investigated the correlations between the fractal dimension values obtained from panoramic radiographs and the insertion torque and resonance frequency values of mandibular implants. MATERIALS AND METHODS: Thirty patients who received a total of 55 implants of the same brand, diameter, and length in the mandibular premolar and molar regions were included in the study. The same surgical procedures were applied to each patient, and the insertion torque and resonance frequency values were recorded for each implant at the time of placement. The radiographic fractal dimensions of the alveolar bone in the implant recipient area were calculated from preoperative panoramic radiographs using a box-counting algorithm. The insertion torque and resonance frequency values were compared with the fractal dimension values using the Spearman test. RESULTS: All implants were successful, and none were lost during the follow-up period. Linear correlations were observed between the fractal dimension and resonance frequency, between the fractal dimension and insertion torque, and between resonance frequency and insertion torque. CONCLUSION: These results suggest that the noninvasive measurement of the fractal dimension from panoramic radiographs might help to predict the bone quality, and thus the primary stability of dental implants, before implant surgery. PMID- 26478980 TI - Influence of reinforcement on strains within maxillary implant overdentures. AB - PURPOSE: The purpose of this study was to examine the influence of reinforcement of an embedded cast on the strains within maxillary implant overdentures. MATERIALS AND METHODS: A maxillary edentulous model with implants placed bilaterally in the canine positions, dome-shaped copings, and experimental overdentures was fabricated. Rosette-type strain gauges were attached in the canine positions and at three points along the midline of the polished surface of the denture and connected to the sensor interface controlled by a personal computer. Experimental dentures with five different reinforcements were tested: without reinforcement; with a cast cobalt-chrome reinforcement over the residual ridge and the tops of the copings; with the same reinforcement from first molar to first molar, over the residual ridge and the tops of the copings; with the same reinforcement over the residual ridge and the sides of the copings; and with the same reinforcement from first molar to first molar, over the residual ridge and the sides of the copings. A vertical occlusal load of 49 N was applied to the first premolar and then to the first molar, and the strains were measured and compared by analysis of variance. RESULTS: In both loading situations, significantly less strain was recorded in dentures with reinforcement than in those without reinforcement. When the first premolar was loaded on dentures with and without palatal reinforcement at the first premolars, the strains on the denture with reinforcement over the tops of the copings were significantly lower than on the denture with reinforcement over the sides of the copings at the canine position. CONCLUSION: Cast reinforcement over the residual ridge and the top of copings embedded in an acrylic base reduced the strain from occlusal stress on maxillary implant overdentures. PMID- 26478981 TI - Peroxisome proliferator-activated receptor gamma regulates bone remodeling after midpalatal suture expansion in mice. AB - PURPOSE: The effectiveness of rapid maxillary expansion is adversely affected by failure and relapse. It is important to identify key factors that increase new bone formation and improve bone remodeling of midpalatal sutures to improve the stability and effectiveness of this commonly used orthodontic procedure. Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in modulating osteogenesis and bone resorption in long bones. This study was designed to explore the function of PPARgamma in bone remodeling and tissue engineering of midpalatal sutures. MATERIALS AND METHODS: Pioglitazone, a PPARgamma agonist, and osteoclast PPARgamma knockout mice were used to explore the impact of PPARgamma activation and inactivation, respectively, on bone remodeling in a mouse model of midpalatal suture expansion (MSE). Histologic analysis including staining with hematoxylin-eosin, tartrate-resistant acid phosphatase, and alkaline phosphatase was used to evaluate tissue remodeling. Reverse-transcriptase quantitative polymerase chain reaction was used to measure gene expression. RESULTS: Pioglitazone decreased new bone formation after MSE. This was accompanied by an increased amount of osteoclasts and expression of genes promoting osteoclastogenesis, as well as a decreased amount of osteoblasts and expression of genes promoting osteoblastogenesis in midpalatal sutures. Conversely, osteoclast PPARgamma knockout mice increased new bone formation and decreased the amount of osteoclasts and expression of genes promoting osteoclastogenesis. CONCLUSION: In the process of bone remodeling after MSE, PPARgamma, particularly in osteoclasts, is an important regulator of osteoblast and osteoclast homeostasis and bone remodeling in midpalatal sutures. Blockade of PPARgamma might be an effective strategy to improve stability and decrease relapse in the practice of rapid maxillary expansion. PMID- 26478982 TI - The effect of pharmacogenetic profiling with a clinical decision support tool on healthcare resource utilization and estimated costs in the elderly exposed to polypharmacy. AB - OBJECTIVE: To compare healthcare resource utilization (HRU) and clinical decision making for elderly patients based on cytochrome P450 (CYP) pharmacogenetic testing and the use of a comprehensive medication management clinical decision support tool (CDST), to a cohort of similar non-tested patients. METHODS: An observational study compared a prospective cohort of patients >=65 years subjected to pharmacogenetic testing to a propensity score (PS) matched historical cohort of untested patients in a claims database. Patients had a prescribed medication or dose change of at least one of 61 oral drugs or combinations of >=3 drugs at enrollment. Four-month HRU outcomes examined included hospitalizations, emergency department (ED) and outpatient visits and provider acceptance of test recommendations. Costs were estimated using national data sources. RESULTS: There were 205 tested patients PS matched to 820 untested patients. Hospitalization rate was 9.8% in the tested group vs. 16.1% in the untested group (RR = 0.61, 95% CI = 0.39-0.95, p = 0.027), ED visit rate was 4.4% in the tested group vs. 15.4% in the untested group (RR = 0.29, 95% CI = 0.15 0.55, p = 0.0002) and outpatient visit rate was 71.7% in the tested group vs. 36.5% in the untested group (RR = 1.97, 95% CI = 1.74-2.23, p < 0.0001). The rate of overall HRU was 72.2% in the tested group vs. 49.0% in the untested group (RR = 1.47, 95% CI = 1.32-1.64, p < 0.0001). Potential cost savings were estimated at $218 (mean) in the tested group. The provider majority (95%) considered the test helpful and 46% followed CDST provided recommendations. CONCLUSION: Patients CYP DNA tested and treated according to the personalized prescribing system had a significant decrease in hospitalizations and emergency department visits, resulting in potential cost savings. Providers had a high satisfaction rate with the clinical utility of the system and followed recommendations when appropriate. PMID- 26478983 TI - Atomic-Level Sculpting of Crystalline Oxides: Toward Bulk Nanofabrication with Single Atomic Plane Precision. AB - The atomic-level sculpting of 3D crystalline oxide nanostructures from metastable amorphous films in a scanning transmission electron microscope (STEM) is demonstrated. Strontium titanate nanostructures grow epitaxially from the crystalline substrate following the beam path. This method can be used for fabricating crystalline structures as small as 1-2 nm and the process can be observed in situ with atomic resolution. The fabrication of arbitrary shape structures via control of the position and scan speed of the electron beam is further demonstrated. Combined with broad availability of the atomic resolved electron microscopy platforms, these observations suggest the feasibility of large scale implementation of bulk atomic-level fabrication as a new enabling tool of nanoscience and technology, providing a bottom-up, atomic-level complement to 3D printing. PMID- 26478984 TI - Long-term efficacy of Peg-Interferon/Ribavirin with and without Lamivudine therapy for HBeAg-positive hepatitis B and C dual infection. AB - BACKGROUND: The optimal therapeutic strategy for hepatitis B virus (HBV) e antigen (HBeAg)-seropositive and hepatitis C virus (HCV) dually infected patients remains unknown. We aimed to elucidate the effectiveness of peginterferon (Peg IFN)/ribavirin (RBV) with and without lamivudine (LAM) combination therapy in the clinical settings. PATIENTS AND METHODS: Nine patients seropositive for HBV surface antigen, HBeAg, antibodies to HCV and HCV RNA for >6 months were treated with Peg-IFN/RBV with (n = 5) and without (n = 4) a 12-month LAM add-on therapy at treatment week 12. The treatment duration of Peg-IFN/RBV was 24 weeks (HCV genotype 1 [HCV-1] with rapid virological response [RVR] or HCV-2) or 48 weeks (HCV-1 without RVR). Primary endpoints included HBeAg loss and HCV-sustained virological response (SVR). RESULTS: All of the nine patients had undetectable HCV RNA at treatment weeks 4 and 12 and end-of-Peg-IFN/RBV therapy. However, SVR was achieved in 100% of patients treated with triple therapy, compared with only 50% in those with Peg-IFN/RBV therapy (P = 0.167). The 3-year durability of HCV SVR was 100%. HBeAg loss and HBV DNA <2000 IU/mL at 6 months post-LAM treatment were found in 100% and 40% of patients treated with triple therapy, compared with none of the four patients with Peg-IFN/RBV therapy achieved any HBV responses. Of the five patients with triple therapy, four had persistent HBeAg loss during 3 year follow-up period; one developed HBeAg seroreversion 15 months after treatment. CONCLUSION: For HBeAg-positive HBV/HCV dually infected patients, Peg IFN/RBV was effective for HCV eradication. Add-on LAM might promote HBeAg loss in the clinical setting. PMID- 26478986 TI - A rhenium complex doped in a silica molecular sieve for molecular oxygen sensing: Construction and characterization. AB - This paper reported a diamine ligand and its Re(I) complex for potential application in oxygen sensing. The novelty of this diamine ligand localized at its increased conjugation chain which had a typical electron-withdrawing group of 1,3,4-oxadiazole. Electronic distribution of excited electrons and their lifetime were supposed to be increased, favoring oxygen sensing collision. This hypothesis was confirmed by single crystal analysis, theoretical calculation and photophysical measurement. It was found that this Re(I) complex had a long-lived emission peaking at 545 nm, favoring sensing application. By doping this complex into a silica matrix MCM-41, oxygen sensing performance and mechanism of the resulting composites were discussed in detail. Non-linear Stern-Volmer working curves were observed with maximum sensitivity of 5.54 and short response time of ~6 s. PMID- 26478987 TI - Needlestick Injuries in Agriculture Workers and Prevention Programs. AB - There are a variety of biologics, vaccines, antibiotics, and hormones used in animal agriculture. Depending upon the procedure or pharmaceutical used, accidental injections or product exposures can result in mild to severe injuries. Needlestick injury (NSI) prevention, research, and education for veterinarians and agriculture workers is limited. The objective of this study was to collect and review published case reports and case series/surveys on human needlestick exposure to veterinary biologics and to summarize needlestick prevention strategies for agricultural workers/veterinarians. A search was conducted of PubMed and Centre for Agriculture Bioscience International (CABI) databases. References were reviewed to identify additional articles. NSI among agricultural workers were primarily included in this review. Thirty articles were applicable to exposures in agricultural settings. Relevant literature consisted of case reports, survey/case series articles, prevention documents, and background articles. Fifty-nine case patients were identified. Most of these cases were associated with exposures to specific vaccines or veterinary products. Injury location was identified from 36 individuals: 24 (67%) NSI to the hands, 10 (28%) injuries to the legs, and 2 to other body locations. Of the 59 cases, 20 (34%) involved oil-adjuvant vaccines. Evidence of hospitalization was recorded for 30 case patients. The length of hospitalization was available from 11 case patients. Median length of hospitalization was 3 days (range: 1-4). Surgical intervention was reported in 25 case patients. Outcome information was available on 30 case patients. Fifteen made a complete recovery within 2 weeks of treatment, 14 had residual sequelae attributed to the injury, and there was 1 reported death. Of the 13 survey/case series articles: 2 focused on oil-adjuvant products, 1 on Brucellosis RB-51 vaccine, 3 on tilmicosin, 1 on Salmonella enteritidis vaccine, 1 on high-pressure injection, and 5 were nonspecific. NSI in agriculture workers and veterinarians can result in significant bodily injury and loss of work. There is a need for varied and comprehensive educational programs for agricultural workers and veterinarians to prevent NSI on livestock operations. PMID- 26478988 TI - Tailor-made rehabilitation approach using multiple types of hybrid assistive limb robots for acute stroke patients: A pilot study. AB - This article investigated the feasibility of a tailor-made neurorehabilitation approach using multiple types of hybrid assistive limb (HAL) robots for acute stroke patients. We investigated the clinical outcomes of patients who underwent rehabilitation using the HAL robots. The Brunnstrom stage, Barthel index (BI), and functional independence measure (FIM) were evaluated at baseline and when patients were transferred to a rehabilitation facility. Scores were compared between the multiple-robot rehabilitation and single-robot rehabilitation groups. Nine hemiplegic acute stroke patients (five men and four women; mean age 59.4 +/- 12.5 years; four hemorrhagic stroke and five ischemic stroke) underwent rehabilitation using multiple types of HAL robots for 19.4 +/- 12.5 days, and 14 patients (six men and eight women; mean age 63.2 +/- 13.9 years; nine hemorrhagic stroke and five ischemic stroke) underwent rehabilitation using a single type of HAL robot for 14.9 +/- 8.9 days. The multiple-robot rehabilitation group showed significantly better outcomes in the Brunnstrom stage of the upper extremity, BI, and FIM scores. To the best of the authors' knowledge, this is the first pilot study demonstrating the feasibility of rehabilitation using multiple exoskeleton robots. The tailor-made rehabilitation approach may be useful for the treatment of acute stroke. PMID- 26478989 TI - The peculiar economics of life-extending therapies: a review of costing methods in health economic evaluations in oncology. AB - Published literature lacks consensus, and most guidelines lack definitive recommendations as to whether cost-effectiveness analyses (CEAs) should include all "future" costs or distinguish between related and unrelated medical costs. This systematic review of oncology CEAs evaluated cost methods used and the impact on the cost-effectiveness of incorporating different cost categories, including costs due to study intervention, related medical costs of the treated condition, and unrelated medical costs. Of the 59 studies reviewed, none included medical costs unrelated to the treated condition and 14 studies (32%) excluded direct medical costs related to the condition but not the evaluated intervention. Recomputing ICERs using different cost categories altered overall cost effectiveness conclusions. The authors propose conventional CEA methods may implicitly penalize therapies that add "expensive" life years for chronically ill patients. Presenting ICERs computed with and without disease-attributable costs can help better convey how much the treatment itself contributes to overall costs. PMID- 26478985 TI - Has adult sleep duration declined over the last 50+ years? AB - The common assumption that population sleep duration has declined in the past few decades has not been supported by recent reviews, which have been limited to self reported data. The aim of this review was to assess whether there has been a reduction in objectively recorded sleep duration over the last 50+ years. The literature was searched for studies published from 1960 to 2013, which assessed objective sleep duration (total sleep time (TST)) in healthy normal-sleeping adults. The search found 168 studies that met inclusion criteria, with 257 data points representing 6052 individuals ages 18-88 y. Data were assessed by comparing the regression lines of age vs. TST in studies conducted between 1960 and 1989 vs. 1990-2013. Weighted regression analyses assessed the association of year of study with age-adjusted TST across all data points. Regression analyses also assessed the association of year of study with TST separately for 10-y age categories (e.g., ages 18-27 y), and separately for polysomnographic and actigraphic data, and for studies involving a fixed sleep schedule and participants' customary sleep schedules. Analyses revealed no significant association of sleep duration with study year. The results are consistent with recent reviews of subjective data, which have challenged the notion of a modern epidemic of insufficient sleep. PMID- 26478990 TI - A novel diagnostic method to detect truncated neurofibromin in neurofibromatosis 1. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition caused by dominant loss-of-function mutations of the tumor suppressor gene NF1 that encodes neurofibromin, a negative regulator of RAS activity. Mutation analysis of NF1 located at 17q11.2 has been hampered by the large size of the gene, the high rate of new mutations, the lack of mutational clustering, and the presence of several homologous loci. To date, about 80% of the reported NF1 mutations are predicted to result in protein truncation, but very few studies have correlated the causative NF1 mutation with its effect at the protein level. We evaluated a novel diagnostic method to detect truncated forms of neurofibromin in a large cohort of unrelated subjects suspected of having NF1, according to the NIH consensus criteria. Western blot analysis was carried out on protein extracts from patients' leukocytes to highlight the possible presence of altered neurofibromin as a result of mutations in NF1. Truncated neurofibromin was identified in 274/336 patients (81%), confirming the usefulness and reproducibility of the proposed diagnostic approach. Our methodology can be routinely applied in the diagnostic setting, thanks to its simplicity and reliability. Combined with molecular approaches, it may increase the accuracy and efficiency of NF1 genetic testing. We evaluated a novel diagnostic method to detect truncated forms of neurofibromin in patients fulfilling the clinical criteria for Neurofibromatosis 1. Western blot analysis identified truncated neurofibromin in 274/336 patients (81%). Our results indicate that the proposed technique is cheap and reliable, and could ideally be performed as a preliminary biochemical screening before molecular analysis of the NF1 gene. PMID- 26478991 TI - Tissue specific responses to cadmium-based quantum dots in the marine mussel Mytilus galloprovincialis. AB - In recent years, Cd-based quantum dots (QDs) have generated interest from the life sciences community due to their potential applications in nanomedicine, biology and electronics. However, these engineered nanomaterials can be released into the marine environment, where their environmental health hazards remain unclear. This study investigated the tissue-specific responses related to alterations in the antioxidant defense system induced by CdTe QDs, in comparison with its dissolved counterpart, using the marine mussel Mytilus galloprovincialis. Mussels were exposed to CdTe QDs and dissolved Cd for 14 days at 10 MUgCd L(-1) and biomarkers of oxidative stress [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (total, Se-independent and Se-dependent GPx) and glutathione-S-transferase (GST) activities] were analyzed along with Cd accumulation in the gills and digestive gland of mussels. Results show that both Cd forms changed mussels' antioxidant responses with distinct modes of action (MoA). There were tissue- and time-dependent differences in the biochemical responses to each Cd form, wherein QDs are more pro-oxidant when compared to dissolved Cd. The gills are the main tissue affected by QDs, with effects related to the increase of SOD, GST and GPx activities, while those of dissolved Cd was associated to the increase of CAT activity, Cd accumulation and exposure time. Digestive gland is a main tissue for accumulation of both Cd forms, but changes in antioxidant enzyme activities are smaller than in gills. A multivariate analysis revealed that the antioxidant patterns are tissue dependent, indicating nano-specific effects possibly associated to oxidative stress and changes in redox homeostasis. PMID- 26478993 TI - The functional architecture of skeletal compared to cardiac musculature: Myocyte orientation, lamellar unit morphology, and the helical ventricular myocardial band. AB - How the cardiomyocytes are aggregated within the heart walls remains contentious. We still do not fully understand how the end-to-end longitudinal myocytic chains are arranged, nor the true extent and shape of the lamellar units they aggregate to form. In this article, we show that an understanding of the complex arrangement of cardiac musculature requires knowledge of three-dimensional myocyte orientation (helical and intrusion angle), and appreciation of myocyte packing within the connective tissue matrix. We show how visualization and segmentation of high-resolution three-dimensional image data can accurately identify the morphology and orientation of the myocytic chains, and the lamellar units. Some maintain that the ventricles can be unwrapped in the form of a "helical ventricular myocardial band," that is, as a compartmentalized band with selective regional innervation and deformation, and a defined origin and insertion like most skeletal muscles. In contrast to the simpler interpretation of the helical ventricular myocardial band, we provide insight as to how the complex myocytic chains, the heterogeneous lamellar units, and connective tissue matrix form an interconnected meshwork, which facilitates the complex internal deformations of the ventricular wall. We highlight the dangers of disregarding the intruding cardiomyocytes. Preparation of the band destroys intruding myocytic chains, and thus disregards the functional implications of the antagonistic auxotonic forces they produce. We conclude that the ventricular myocardium is not analogous to skeletal muscle, but is a complex three-dimensional meshwork, with a heterogeneous branching lamellar architecture. PMID- 26478994 TI - Comments on, 'Extreme Variation of Nutritional Composition and Osmolality of Commercially Available Carbohydrate Energy Gels'. AB - No abstract available for this article. PMID- 26478992 TI - Prion protein as a mediator of synaptic transmission. AB - Neurodegenerative disorders are characterized by synaptic and neuronal dysfunction which precedes general neuronal loss and subsequent cognitive or behavioral anomalies. Although the exact early cellular signaling mechanisms involved in neurodegenerative diseases are largely unknown, a view is emerging that compromised synaptic function may underlie the initial steps in disease progression. Much recent research has been aimed at understanding these early underlying processes leading to dysfunctional synaptic signaling, as this knowledge could identify putative sites of interventions, which could potentially slow progression and delay onset of disease. We have recently reported that synaptic function in a Drosophila melanogaster model can be modulated by the presence of native mouse prion protein and this modulation is negatively affected by a mutation within the protein which is associated with the Gerstmann Straussler-Scheinker syndrome, a human form of prion disease. Indeed, wild-type prion protein facilitates synaptic release, whereas the mutated form induced diminished phenotypes. It is believed that together with the gain-of-function of neurotoxic misfolded prion signaling, the lack of prion protein contributes to the pathology in prion diseases. Therefore, our study investigated a potential endogenous role of prion protein in synaptic signaling, the lack of which could resemble a lack-of-function phenotype in prion disease. PMID- 26478996 TI - Pharmacotherapy for Neurodegenerative Diseases: Are We Approaching the Tipping Point? AB - Neurodegenerative diseases continue to represent major unmet medical and public health needs and will increasingly strain the healthcare system as people live longer due to medical advances in other diseases. Hopefully the emergence of increased understanding of the biology of these conditions coupled with novel clinical pharmacology tools, clinical trial designs, and regulatory innovation will allow the emergence of highly effective symptomatic and disease modifying pharmacotherapies. PMID- 26478999 TI - The Sense and Sensibility of SeENS in Sarajevo 2015: Building Bridges of Knowledge and Understanding. PMID- 26479001 TI - Temperature and Relative Humidity Inside Trailers During Finishing Pig Loading and Transport in Cold and Mild Weather. AB - The effect of bedding levels and trailer compartment on internal trailer temperature and relative humidity (RH) during loading and transport of finishing pigs was evaluated in cold and mild weather. Three levels of bedding were used in each experiment: 0.6 m3, 1.2 m3, and 2.4 m3. In mild weather, internal temperatures were lower when 1.2 m3 or 2.4 m3 of bedding were used during loading and transport compared to 0.6 m3 (P < 0.05). Internal trailer temperature increased in a quadratic fashion in the top front compartment when 1.2 m3 was used (P < 0.05), and in a linear fashion in the top rear compartment when 2.4 m3 were used in cold weather (P < 0.05). In mild weather, temperature increased linearly in the top front compartment with heavy bedding levels. Relative humidity increased in a linear fashion in the top front compartment with 0.6 m3, bottom front with 1.2 m3, and top front with 1.2 m3 in cold weather (P < 0.05). In general, temperature and RH increased as bedding levels increased in both cold and mild temperatures. Excess bedding can absorb more moisture, resulting in transport loss and decreased animal welfare. PMID- 26479002 TI - Tourists' Perceptions of the Free-Roaming Dog Population in Samoa. AB - A study was undertaken to establish how visiting tourists to Samoa perceived free roaming dogs (Canis familiaris) and their management, additionally some factors that influence their perceptions were assessed. Questionnaires were administered to 281 tourists across Samoa over 5 weeks. Free-roaming dogs were seen by 98.2% (n = 269/274) of respondents, with 64.9% (n = 137/211) reporting that their presence had a negative effect on overall holiday experience. Respondents staying in the Apia (capital city) area were more likely to consider dogs a problem (p < 0.0001), and there was a significant association between whether the respondent owned a dog and if they thought dogs were a nuisance in Samoa (p < 0.003). Forty four percent (20/89) of non-dog owners agreed that dogs were a nuisance compared to 22% (80/182) of dog owners. The majority felt that dogs required better control and management in Samoa (81%, n = 222) and that there were too many "stray" dogs (67.9%, n = 188). More respondents were negatively affected by the dogs' presence (64.9%, 137/211), and felt that the dogs made their holiday worse, than respondents that felt the dogs' presence improved their holiday experience (35.1%, 74/211). Most respondents stated that the dogs had a low impact (one to three; 68%, 187/275) on their stay in Samoa, whilst 24% (65/275) and 8% (23/275) stated they had a medium or high impact, respectively, on their stay. Respondents showed strong support for humane population management. Free-roaming dogs present a complex problem for Samoa and for its tourism industry in particular. The findings of this study further support the need for more discussion and action about the provision of veterinary services and population management for dogs in Samoa. It also provides information complementing an earlier study of the attitudes of local Samoans. PMID- 26479000 TI - Quantifying trophoblast migration: In vitro approaches to address in vivo situations. AB - When trophoblasts migrate and invade in vivo, they do so by interacting with a range of other cell types, extracellular matrix proteins, chemotactic factors and physical forces such as fluid shear stress. These factors combine to influence overall trophoblast migration and invasion into the decidua, which in turn determines the success of spiral artery remodelling, and pregnancy itself. Our understanding of these important but complex processes is limited by the simplified conditions in which we often study cell migration in vitro, and many discrepancies are observed between different in vitro models in the literature. On top of these experimental considerations, the migration of individual trophoblasts can vary widely. While time-lapse microscopy provides a wealth of information on trophoblast migration, manual tracking of individual cell migration is a time consuming task that ultimately restricts the numbers of cells quantified, and thus the ability to extract meaningful information from the data. However, the development of automated imaging algorithms is likely to aid our ability to accurately interpret trophoblast migration in vitro, and better allow us to relate these observations to in vivo scenarios. This commentary discusses the advantages and disadvantages of techniques commonly used to quantify trophoblast migration and invasion, both from a cell biology and a mathematical perspective, and examines how such techniques could be improved to help us relate trophoblast migration more accurately to in vivo function in the future. PMID- 26479003 TI - Leptospira spp. in Domestic Cats from Different Environments: Prevalence of Antibodies and Risk Factors Associated with the Seropositivity. AB - Leptospirosis is an emerging zoonotic disease of worldwide distribution. A cross sectional study was conducted in urban and rural environments in southern Chile (1) to detect domestic cats with serologic evidence of exposure to Leptospira spp.; (2) to determine the prevalence of anti-Leptospira antibodies; (3) to describe seroprevalences according to different characteristics of the animals, and (4) to identify risk factors associated with the seropositivity in the Microscopic Agglutination Test (MAT). Blood samples were taken from 124 owned cats. A frequentist and Bayesian approach were applied for prevalence estimation. The overall apparent prevalence of anti-Leptospira antibodies was 8.1% (95% Confident Interval = 3.9-4.3). With the Bayesian approach, the overall True Prevalence (TP) was 5.2% (95% Credibility Interval (CrI) = 0.6-12.4). The TP for urban cats was 1.8% (95% CrI = 0.1-7.2) and the TP for rural felines was 25.2% (95% CrI = 9.3-46.6). Cats that live in a place where agricultural activities are performed with water that flows in streams or backwater and cats that live in places near flooded areas had a higher risk of seropositivity in MAT. The exposure to Leptospira spp. in domestic cats of urban and rural origin in Southern Chile is a public health concern that requires an increased awareness and the implementation of preventive measures. PMID- 26479004 TI - Effect of Season, Transport Length, Deck Location, and Lairage Length on Pork Quality and Blood Cortisol Concentrations of Market Hogs. AB - The objective of this study was to investigate the effects of seasonal environment, transport conditions, and time in lairage on pork quality and serum cortisol concentrations. Market hogs were slaughtered during winter (n = 535), spring (n = 645), summer (n = 644), and fall (n = 488). Within season, hogs were randomly assigned to treatments in a 2 * 2 * 2 factorial arrangement, with 2 deck locations (top vs. bottom) and 2 transport and lairage durations (3 h vs. 6 h). Blood samples were collected at exsanguination for analysis of cortisol concentration. Loins were collected at 24 h postmortem for pork quality assessment. Season and deck did not have a main effect on cortisol concentrations or pork quality. Hogs transported 6 h had increased cortisol concentrations (103.0 vs. 95.5 ng/mL; P < 0.001) and decreased L* (52.49 vs. 52.69; P = 0.09), b* (6.28 vs. 6.36; P = 0.03), and hue angle (20.70 vs. 20.95; P = 0.03) compared to hogs transported 3 h. Hogs subjected to 6 h of lairage had increased 24-h pH (5.69 vs. 5.66; P = 0.005), a* (16.64 vs. 16.48; P < 0.0001), b* (6.42 vs. 6.22; P < 0.0001), saturation (17.85 vs. 17.64; P < 0.0001), and hue angle (21.01 vs. 20.65; P = 0.002) and decreased L* (52.49 vs. 52.69; P = 0.07) when compared to hogs subjected to 3 h of lairage. PMID- 26479005 TI - Effects of Transport at Weaning on the Behavior, Physiology and Performance of Pigs. AB - Transport of pigs to separate production facilities at the time of weaning is a common practice, primarily performed to reduce vertical transfer of disease and enhance production and overall farm efficiency. During transport, pigs are exposed to numerous stressors in conjunction with the stress experienced as a result of weaning. In this review, the behavioral and physiological response of pigs experiencing weaning and transport simultaneously will be described, including the effects of space allowance, season and transport duration. Based on the scientific literature, the gaps in the knowledge regarding potential welfare issues are discussed. Changes in behavior and physiology suggest that weaned pigs may experience stress due to transport. Space allowance, season and duration are aspects of transport that can have a marked impact on these responses. To date, the literature regarding the effects of transport on weaned pigs has primarily focused on the short term stress response and little is known about the effects of concurrent weaning and transport on other aspects of pig welfare including morbidity and mortality rates. Greater understanding of the short and long term consequences of transport on weaned pig welfare particularly in relation to factors such as trip duration, provision of feed and water, and best handling practices would benefit the swine industry. Furthermore, the development of guidelines and recommendations to enhance the short and long term welfare of weaned pigs in relation to transport are needed. PMID- 26479006 TI - Off-Stream Watering Systems and Partial Barriers as a Strategy to Maximize Cattle Production and Minimize Time Spent in the Riparian Area. AB - A study was conducted in 2009 at two locations in Manitoba (Killarney and Souris), Canada to determine the impact of off-stream waterers (OSW) with or without natural barriers on (i) amount of time cattle spent in the 10 m buffer created within the riparian area, referred to as the riparian polygon (RP), (ii) watering location (OSW or stream), and (iii) animal performance measured as weight gain. This study was divided into three 28-day periods over the grazing season. At each location, the pasture-which ranged from 21.0 ha to 39.2 ha in size-was divided into three treatments: no OSW nor barriers (1CONT), OSW with barriers along the stream bank to deter cattle from watering at the stream (2BARR), and OSW without barriers (3NOBARR). Cattle in 2BARR spent less time in the RP in Periods 1 (p = 0.0002), 2 (p = 0.1116), and 3 (p < 0.0001) at the Killarney site compared to cattle in 3NOBARR at the same site. Cattle in 2BARR at the Souris site spent more time in the RP in Period 1 (p < 0.0001) and less time in Period 2 (p = 0.0002) compared to cattle in 3NOBARR. Cattle did use the OSW, but not exclusively, as watering at the stream was still observed. The observed inconsistency in the effectiveness of the natural barriers on deterring cattle from the riparian area between periods and locations may be partly attributable to the environmental conditions present during this field trial as well as difference in pasture size and the ability of the established barriers to deter cattle from using the stream as a water source. Treatment had no significant effect (p > 0.05) on cow and calf weights averaged over the summer period. These results indicate that the presence of an OSW does not create significant differences in animal performance when used in extensive pasture scenarios such as those studied within the present study. Whereas the barriers did not consistently discourage watering at the stream, the results provide some indication of the efficacy of the OSW as well as the natural barriers on deterring cattle from the riparian area. PMID- 26479007 TI - Sex Differences in Physiological Acclimatization after Transfer in Wistar Rats. AB - Most laboratory animals used in research are vendor-bred and transferred to research facilities. Transfer procedures might have considerable and unintended effects on research results. In the present study we compared physiological and behavioral parameters before and after external and internal transfer, as well as between transferred and non-transferred Wistar rats. The impact of both external and internal transfer on body weight, plasma corticosterone levels, heart rate, blood pressure, and locomotor activity was studied in both male and female Wistar rats, taking into account the sex differences in stress responsivity. External transfer was found to decrease body weight, increase plasma corticosterone, increase activity, increase heart rate in female rats, but decrease heart rate in male rats. Parameters showed differences between the sexes and light phases. This study shows that acclimatization after transfer is sex-specific and researchers should take the sex into consideration when determining the acclimatization period. It is recommended to allow for acclimatization of at least 8 days in males and two weeks in females after external transfer and timely (2 days before starting experiments) transfer the animals internally to the testing room. PMID- 26479008 TI - Effects of Transfer from Breeding to Research Facility on the Welfare of Rats. AB - Transfer from the breeding facility to a research facility is a stressful event for laboratory animals. Heat stress has been reported to constitute one of the major concerns during transport of animals. This study measured ambient and body temperature, corticosterone and glucose levels, body weight, behavior and water and food intake before, during and after transfer in Wistar rats. Decreased body weight, water and food intake were observed on the day of transfer in rats. Environmental temperature strongly affected body temperature of rats and needs to be controlled. Male rats need to habituate for at least one week, females for two weeks after transfer. PMID- 26479009 TI - Ethical and Animal Welfare Considerations in Relation to Species Selection for Animal Experimentation. AB - Ethical principles governing the conduct of experiments with animals are reviewed, especially those relating to the choice of species. Legislation requires that the potential harm to animals arising from any procedure should be assessed in advance and justified in terms of its possible benefit to society. Potential harms may arise both from the procedures and the quality of the animals' lifetime experience. The conventional approach to species selection is to use animals with the "lowest degree of neurophysiological sensitivity". However; this concept should be applied with extreme caution in the light of new knowledge. The capacity to experience pain may be similar in mammals, birds and fish. The capacity to suffer from fear is governed more by sentience than cognitive ability, so it cannot be assumed that rodents or farm animals suffer less than dogs or primates. I suggest that it is unethical to base the choice of species for animal experimentation simply on the basis that it will cause less distress within society. A set of responsibilities is outlined for each category of moral agent. These include regulators, operators directly concerned with the conduct of scientific experiments and toxicology trials, veterinarians and animal care staff; and society at large. PMID- 26479010 TI - Loading and Unloading Weaned Pigs: Effects of Bedding Types, Ramp Angle, and Bedding Moisture. AB - The use of non-slip surfaces during loading and unloading of weaned pigs plays an important role in animal welfare and economics of the pork industry. Currently, the guidelines available only suggest the use of ramps below 20 degrees to load and unload pigs. Three ramp angles (0 degrees , 10 degrees or 20 degrees ), five bedding materials (nothing, sand, feed, wood shavings or wheat straw hay), two moistures (dry or wet bedding; >50% moisture) over two seasons (>23.9 degrees C summer, <23.9 degrees C winter) were assessed for slips/falls/vocalizations (n = 6,000 pig observations). "Score" was calculated by the sum of slips, falls, and vocalizations. With the exception of using feed as a bedding, all beddings provided some protection against elevated slips, falls, and vocalizations (P < 0.01). Providing bedding reduced (P < 0.05) scores regardless of whether the bedding was dry or wet. Scores increased as the slope increased (P < 0.01). Provision of bedding, other than feed, at slopes greater than zero, decreased slips, falls and vocalizations. The total time it took to load and unload pigs was affected by bedding type, ramp angle, and season (P < 0.05). Minimizing slips, falls, and vocalizations when loading and unloading pigs improved animal welfare. PMID- 26479011 TI - Rabbit Feces as Feed for Ruminants and as an Energy Source. AB - There are prospects for using novel feeds from various sources to provide ruminants with alternative sources of protein and energy such as by-products, and animal wastes. Rabbit feces are a concentrated source of fiber and could have commercial potential both as input biomass in anaerobic processes for biogas production, as well as a fibrous source for ruminal degradation. The aims of this work were to assess the potential as ruminant feeding and as biogas production of rabbit feces, in comparison with 12 crops. The chemical composition and the potential and experimental in vitro true digestibility (IVTD) and neutral detergent fiber digestibility (NDFD) of 148 feces samples were determined by using chemical methods, Daisy system digestibility and/or NIRS predictions. The average biomethane potential (BMP) was 286 +/- 10 lCH4/kg SV with -4% vs. the crops average. Milk forage unit (milk FU), IVTD and NDFD of feces were 0.54 +/- 0.06 milk FU/kg DM, 74% +/- 3% and 50% +/- 5%, respectively, with comparisons of 19%, -11% and -24% vs. the crops average. Reconstruction of the potential values based on the chemical constituents but using the crop partial least square model well agreed with the NIRS calibrations and cross-validation. In a global NIRS calibration of the feces and crops the relative predicted deviation for IVTD, NDFD and milk FU were 3.1, 2.9 and 2.6, respectively, and only 1.5 for BMP. Running the Daisy system for rabbit feces in rumen fluid gave some inconsistencies, weakened the functional relationships, and appeared not to be correlated with the potential values of IVTD and NDFD. Nevertheless, the energetic potential of feces appears to be similar to some conventional crops at different degrees of maturity. Thus we conclude that rabbit feces has potential value as a ruminant feed and for biogas production. PMID- 26479012 TI - Effects of Adding Corn Dried Distiller Grains with Solubles (DDGS) to the Dairy Cow Diet and Effects of Bedding in Dairy Cow Slurry on Fugitive Methane Emissions. AB - The specific objectives of this experiment were to investigate the effects of adding 10% or 30% corn dried distillers grains with solubles (DDGS) to the dairy cow diet and the effects of bedding type (wood shavings, straw or peat moss) in dairy slurry on fugitive CH4 emissions. The addition of DDGS10 to the dairy cow diet significantly increased (29%) the daily amount of fat excreted in slurry compared to the control diet. The inclusion of DDGS30 in the diet increased the daily amounts of excreted DM, volatile solids (VS), fat, neutral detergent fiber (NDF), acid detergent fiber (ADF) and hemicellulose by 18%, 18%, 70%, 30%, 15% and 53%, respectively, compared to the control diet. During the storage experiment, daily fugitive CH4 emissions showed a significant increase of 15% (p < 0.05) for the slurry resulting from the corn DDGS30 diet. The addition of wood shavings and straw did not have a significant effect on daily fugitive CH4 emissions relative to the control diet, whereas the addition of peat moss caused a significant increase of 27% (p < 0.05) in fugitive CH4 emissions. PMID- 26479013 TI - Thirst for knowledge: The effects of curiosity and interest on memory in younger and older adults. AB - Given age-related memory impairments, one's level of curiosity or interest could enhance memory for certain information. In the current study, younger and older adults read trivia questions, rated how curious they were to learn each answer, provided confidence and interest ratings, and judgments of learning after learning the answer. No age-related differences in memory were found. Analyses indicated that curiosity and interest contributed to the formation of judgments of learning. Additionally, interest had a unique increasing relationship with older, but not younger, adults' memory performance after a one-week delay. The results suggest that subjective interest may serve to enhance older adults' memory. PMID- 26479014 TI - The impact of red light running camera flashes on younger and older drivers' attention and oculomotor control. AB - Recent empirical evidence has suggested that the flashes associated with red light running cameras (RLRCs) distract younger drivers, pulling attention away from the roadway and delaying processing of safety-relevant events. Considering the perceptual and attentional declines that occur with age, older drivers may be especially susceptible to the distracting effects of RLRC flashes, particularly in situations in which the flash is more salient (a bright flash at night compared with the day). The current study examined how age and situational factors potentially influence attention capture by RLRC flashes using covert (cuing effects) and overt (eye movement) indices of capture. We manipulated the salience of the flash by varying its luminance and contrast with respect to the background of the driving scene (either day or night scenes). Results of 2 experiments suggest that simulated RLRC flashes capture observers' attention, but, surprisingly, no age differences in capture were observed. However, an analysis examining early and late eye movements revealed that older adults may have been strategically delaying their eye movements in order to avoid capture. Additionally, older adults took longer to disengage attention following capture, suggesting at least 1 age-related disadvantage in capture situations. Findings have theoretical implications for understanding age differences in attention capture, especially with respect to capture in real-world scenes, and inform future work that should examine how the distracting effects of RLRC flashes influence driver behavior. PMID- 26479015 TI - Online dating across the life span: Users' relationship goals. AB - Utilizing data from an eHarmony.com relationship questionnaire completed by new users (N = 5,434), this study identifies prioritized goals in new romantic relationships and whether importance of these goals differs by participants' age and gender. Overall, users valued interpersonal communication more than sex appeal. Older users rated sexual attraction as slightly less important than younger users did, but they still highly valued the goal. Women placed even greater emphasis on communication over sexual attraction compared to men. However, although men valued sexual attraction more than women at all ages, only the youngest women valued interpersonal communication more than young men. PMID- 26479016 TI - Do negative views of aging influence memory and auditory performance through self perceived abilities? AB - Memory and hearing are critical domains that interact during older adults' daily communication and social encounters. To develop a more comprehensive picture of how aging influences performance in these domains, the roles of social variables such as views of aging and self-perceived abilities need greater examination. The present study investigates the linkages between views of aging, self-perceived abilities, and performance within and across the domains of memory and hearing, connections that have never been examined together within the same sample of older adults. For both domains, 301 older adults completed measures of their views of aging, their self-perceived abilities and behavioral tests. Using structural equation modeling, we tested a hypothesized model in which older adults' negative views of aging predicted their performance in the domains of memory and hearing through negatively affecting their self-perceived abilities in those domains. Although this model achieved adequate fit, an alternative model in which hearing performance predicted self-perceived hearing also was supported. Both models indicate that hearing influences memory with respect to both behavioral and self-perception measures and that negative views of aging influence self-perceptions in both domains. These results highlight the importance of views of aging and self-perceptions of abilities within and across these domains. PMID- 26479017 TI - Effects of targeting disease and medication management interventions towards patients with COPD. AB - OBJECTIVE: Suboptimal adherence in chronic obstructive pulmonary disease (COPD) patients is associated with decreased clinical and economic outcomes. Intervention programs, targeted at patients with suboptimal adherence and exacerbations, offer opportunities for cost-effective COPD care. We have aimed to assess the effects of the Medication Monitoring and Optimization (MeMO) targeted COPD intervention. METHODS: Twenty community pharmacies participated in this 1 year real-world study with a pre-test/post-test design. Patients with a physician confirmed COPD diagnosis, oral corticosteroid use, suboptimal adherence and Clinical COPD Questionnaire (CCQ) score >=1 were selected by pharmacists. Pharmacy interventions included inhalation instruction, medication information and motivational interviewing regarding adherence and smoking cessation. Proposals for dose, medication and/or inhaler change and physical activity or diet recommendations were discussed with the general practitioner (GP), physiotherapist or dietician, when deemed relevant. Primary endpoint was the change in CCQ score. Secondary outcomes were adherence, exacerbations, healthcare utilization, quality of life (EQ-5D), modified Medical Research Council (mMRC) dyspnea score and cost-effectiveness. RESULTS: Interventions were performed in 88 patients (mean age: 69; 52% male; mean CCQ: 2.10). The most often performed interventions were inhalation instruction (89%), medication education (98%) and adherence counseling (58%). Respectively 9%, 45% and 16% were referred to GP, physiotherapist or dietician. After 1 year, mean CCQ decrement was 0.12 and 38% showed a clinically relevant improvement. There was a significant decrease in exacerbations (-0.82) per patient per year. Adherence, mMRC and EQ-5D hardly changed. Per patient, annual medication costs were ?26 higher, interventions cost ?33, but total healthcare costs were ?333 lower. The small sample size and lack of a control group were the main limitations. CONCLUSION: By specifically targeting COPD patients with potential room for improvement, the MeMO COPD program has the potential to be an effective and cost-saving method for preventing exacerbations. However, no effects on quality of life have been observed. Larger studies are therefore recommended. PMID- 26479018 TI - Biogeography of a defensive symbiosis. AB - Mutualistic microorganisms play important roles in nutrition, reproduction and defense of many insects, yet the factors contributing to their maintenance and dispersal remain unknown in most cases. Theory suggests that collaboration can be maintained by repeated interaction of the same partners (partner fidelity) or by selective discrimination against non-cooperative partners (partner choice). In the defensive mutualism between solitary beewolf wasps and their antibiotic producing Streptomyces bacteria, partner choice by host control of vertical symbiont transmission reinforces partner fidelity and has helped to maintain this highly specific association since it originated in the late Cretaceous. However, co-phylogenetic and biogeographic analyses suggest that there has also been considerable horizontal transmission of the symbionts. While the beewolves clearly have a paleotropic or palearctic origin, with later colonization of the nearctic and neotropics via Beringia and the Aves ridge, respectively, the bacteria show only weak geographical clustering, implying global dispersal or vicariance within the confines of an otherwise apparently exclusive symbiotic relationship. We discuss several hypotheses that may explain these patterns. Future studies investigating the occurrence of beewolf symbionts in the environment could yield broadly applicable insights into the relative impact of animal-vectored and free-living dispersal on the distribution of microorganisms in nature. PMID- 26479019 TI - A New Measure of the Perceived Influence of Sexually Explicit Online Media on the Sexual Behaviors of Men Who Have Sex With Men. AB - Men who have sex with men (MSM) frequently consume sexually explicit online media (SEOM), yet little is known about its influence on their sexual behaviors. We describe a sequence of four studies to develop and psychometrically validate a measure of the perceived influence of sexually explicit online media (PI-SEOM) on the sexual behaviors of MSM. Study 1 involved qualitative interviews (N = 28) and a quantitative survey (N = 100) to develop a preliminary measure. Using an Internet sample of MSM (N = 1,170), we assessed its factor structure and reliability in Studies 2 and 3 as well as convergent validity and associations with HIV-related sexual risk in Study 4. Based on findings the measure was divided into two subscales: influences on (1) self and (2) other MSM. Factor analyses confirmed a two-factor model for each subscale, measuring perceived influences on (a) general sexual scripts and (b) condomless sex scripts. Survey results indicated that the more men perceived SEOM influencing their own condomless sex scripts, the more likely they were to report engaging in sexual risk behaviors. The developed measure holds promise for assessing the influence of SEOM on the sexual behaviors of MSM and may prove useful for HIV-prevention research. PMID- 26479020 TI - Cellular and Mitochondrial Dual-Targeted Organic Dots with Aggregation-Induced Emission Characteristics for Image-Guided Photodynamic Therapy. AB - Targeted delivery of drugs toward mitochondria of specific cancer cells dramatically improves therapy efficiencies especially for photodynamic therapy (PDT), as reactive oxygen species (ROS) are short in lifetime and small in radius of action. Different from chemical modification, nanotechnology has been serving as a simple and nonchemical approach to deliver drugs to cells of interest or specific organelles, such as mitochondria, but there have been limited examples of dual-targeted delivery for both cells and mitochondria. Here, cellular and mitochondrial dual-targeted organic dots for image-guided PDT are reported based on a fluorogen with aggregation-induced emission (AIEgen) characteristics. The AIEgen possesses enhanced red fluorescence and efficient ROS production in aggregated states. The AIE dot surfaces are functionalized with folate and triphenylphosphine, which can selectively internalize into folate-receptor (FR) positive cancer cells, and subsequently accumulate at mitochondria. The direct ROS generation at mitochondria sites is found to depolarize mitochondrial membrane, affect cell migration, and lead to cell apoptosis and death with enhanced PDT effects as compared to ROS generated randomly in cytoplasm. This report demonstrates a simple and general nanocarrier approach for cellular and mitochondrial dual-targeted PDT, which opens new opportunities for dual-targeted delivery and therapy. PMID- 26479022 TI - Strength and Power Correlates of Throwing Velocity on Subelite Male Cricket Players. AB - Throwing velocity is an important aspect of fielding in cricket to affect run outs and reduce the opponent's run-scoring opportunities. Although a relationship between strength and/or power and throwing velocity has been well established in baseball, water polo, and European handball, it has not been adequately explored in cricket. Consequently, this study aimed to determine the relationship between measures of strength and/or power and throwing velocity in cricket players. Seventeen male cricket players (mean +/- SD; age, 21.1 +/- 1.6 years; height, 1.79 +/- 0.06 m; weight, 79.8 +/- 6.4 kg) from an elite athlete program were tested for maximal throwing velocity from the stretch position and after a 3 meter shuffle. They were also assessed for strength and power using a range of different measures. Throwing velocity from the stretch position (30.5 +/- 2.4 m.s) was significantly related to dominant leg lateral-to-medial jump (LMJ) distance (r = 0.71; p < 0.01), dominant shoulder internal rotation (IR) strength (r = 0.55; p <= 0.05), and dominant (r = 0.73; p < 0.01) and nondominant (r = 0.54; p <= 0.05) medicine ball rotation (MB Rot) throw velocity and medicine ball chest pass (MB CP) distance (r = 0.67; p < 0.01). A nonsignificant trend was observed for vertical jump (VJ) height (p = 0.06), whereas no significant relationships were observed for nondominant LMJ distance (p = 0.97), nondominant shoulder IR strength (p = 0.80), 1 repetition maximum (RM) squat strength (p = 0.57), 1RM bench press strength (p = 0.90), height (p = 0.33), or weight (p = 0.29). Multiple regression analysis revealed that dominant MB Rot and MB CP explained 66% of the variance. The results were similar for velocity after a shuffle step (31.8 +/- 2.1 m.s); however, VJ height reached statistical significance (r = 0.51; p <= 0.05). The multiple regression was also similar with MB Rot and MB CP explaining 70% of the variance. The cricketers in this study threw with greater velocity than elite junior and subelite senior cricketers but with lower velocities than elite senior cricketers and collegiate level and professional baseball players. This is the first study to demonstrate a link between strength and/or power and throwing velocity in cricket players and highlight the importance of power development as it relates to throwing velocity. Exercises that more closely simulated the speed (body weight jumps and medicine ball throws) or movement pattern (shoulder IR) of overhead throwing were greater predictors of throwing velocity. Strength and conditioning staff should assess and develop power to enhance throwing performance in cricket players. Exercises with greater movement and speed specificity to throwing should be used in preference over exercises that are slower and have less movement specificity to the throwing motion. Cricket players should engage in power training to bridge the gap in performance between them and baseball players. PMID- 26479021 TI - Longitudinal changes in mathematical abilities and white matter following paediatric mild traumatic brain injury. AB - PRIMARY OBJECTIVE: Paediatric traumatic brain injury (TBI) has been associated with acute and long-term mathematical difficulties. Little is known about the recovery of these impairments in children with mild TBI (mTBI) and their underlying pathophysiology, such as white matter abnormalities. RESEARCH DESIGN: A prospective longitudinal study followed the recovery of mathematical abilities and white matter in children with mTBI from the sub-acute (1 month post-injury) to chronic stage (6-8 months post-injury) of recovery. METHODS AND PROCEDURES: Twenty children with mTBI and 20 matched controls completed mathematics tests. Diffusion Tensor Imaging (DTI) metrics of white matter pathways corpus callosum (CC), superior and longitudinal fasciculi were examined with DTI-tractography. MAIN OUTCOMES AND RESULTS: Mathematical difficulties and white matter abnormalities in the CC observed shortly after the injury resolved after 6-8 months of recovery. Children with mTBI continued to show working memory deficits. Longitudinal DTI data suggest continued maturation of the CC in controls, but little maturation of the damaged CC in children with mTBI. CONCLUSIONS: Children with mTBI recovered in terms of mathematical abilities and white matter. These children continued to show working memory deficits, which might interfere with learning at school. PMID- 26479023 TI - Validity of Self-Reported Running Distance. AB - It is unclear whether there is a difference between subjective evaluation and objective global positioning systems (GPS) measurement of running distance. The purpose of this study was to investigate if such difference exists. A total of 100 participants (51% men; median age, 41.5; body mass, 78.1 kg +/-13.8 SD) completed a run of free choice, then subjectively reported the distance in kilometer (km). This information was subsequently compared with the distance derived from a nondifferential GPS watch using paired t-tests and Bland-Altman's 95% limits of agreement. No significant difference was found between the mean paired differences between subjective evaluations and GPS measurements (1.86%, 95% confidence interval = -1.53%; 5.25%, p = 0.96). The Bland-Altman 95% limits of agreement revealed considerable variation (lower limit = -28% and upper limit = 40%). Such variation exceeds the clinical error range of 10%. In conclusion, the mean running distance (km) is similar between self-reporting and GPS measurements. However, researchers should consider using GPS measurements in favor of subjective reporting of running distance because of considerable variation on an individual level. PMID- 26479024 TI - Effects of Cycling vs. Running Training on Endurance Performance in Preparation for Inline Speed Skating. AB - Winter weather conditions restrict regular sport-specific endurance training in inline speed skating. As a result, this study was designed to compare the effects of cycling and running training programs on inline speed skaters' endurance performance. Sixteen (8 men, 8 women) high-level athletes (mean +/- SD 24 +/- 8 years) were randomly assigned to 1 of 2 groups (running and cycling). Both groups trained twice a week for 8 weeks, one group on a treadmill and the other on a cycle ergometer. Training intensity and duration was individually calculated (maximal fat oxidation: ~52% of V[Combining Dot Above]O2peak: 500 kcal per session). Before and after the training intervention, all athletes performed an incremental specific (inline speed skating) and 1 nonspecific (cycling or running) step test according to the group affiliation. In addition to blood lactate concentration, oxygen uptake (V[Combining Dot Above]O2), ventilatory equivalent (VE/V[Combining Dot Above]O2), respiratory exchange ratio (RER), and heart rate were measured. The specific posttest revealed significantly increased absolute V[Combining Dot Above]O2peak values (2.9 +/- 0.4, 3.4 +/- 0.7, p = 0.01) and submaximal V[Combining Dot Above]O2 values (p <= 0.01). VE/V[Combining Dot Above]O2 and RER significantly decreased at maximal (46.6 +/- 6.6, 38.5 +/- 3.4, p = 0.005; 1.1 +/- 0.03, 1.0 +/- 0.04, p = 0.001) and submaximal intensities (p <= 0.04). None of the analysis revealed a significant group effect (p >= 0.15). The results indicate that both cycling vs. running exercise at ~52% of V[Combining Dot Above]O2peak had a positive effect on the athletes' endurance performance. The increased submaximal V[Combining Dot Above]O2 values indicate a reduction in athletes' inline speed skating technique. Therefore, athletes would benefit from a focus on technique training in the subsequent period. PMID- 26479025 TI - Harnessing structural darkness in the visible and infrared wavelengths for a new source of light. AB - Engineering broadband light absorbers is crucial to many applications, including energy-harvesting devices and optical interconnects. The performances of an ideal absorber are that of a black body, a dark material that absorbs radiation at all angles and polarizations. Despite advances in micrometre-thick films, the absorbers available to date are still far from an ideal black body. Here, we describe a disordered nanostructured material that shows an almost ideal black body absorption of 98-99% between 400 and 1,400 nm that is insensitive to the angle and polarization of the incident light. The material comprises nanoparticles composed of a nanorod with a nanosphere of 30 nm diameter attached. When diluted into liquids, a small concentration of nanoparticles absorbs on average 26% more than carbon nanotubes, the darkest material available to date. By pumping a dye optical amplifier with nanosecond pulses of ~100 mW power, we harness the structural darkness of the material and create a new type of light source, which generates monochromatic emission (~5 nm wide) without the need for any resonance. This is achieved through the dynamics of light condensation in which all absorbed electromagnetic energy spontaneously generates single-colour energy pulses. PMID- 26479026 TI - Placing molecules with Bohr radius resolution using DNA origami. AB - Molecular self-assembly with nucleic acids can be used to fabricate discrete objects with defined sizes and arbitrary shapes. It relies on building blocks that are commensurate to those of biological macromolecular machines and should therefore be capable of delivering the atomic-scale placement accuracy known today only from natural and designed proteins. However, research in the field has predominantly focused on producing increasingly large and complex, but more coarsely defined, objects and placing them in an orderly manner on solid substrates. So far, few objects afford a design accuracy better than 5 nm, and the subnanometre scale has been reached only within the unit cells of designed DNA crystals. Here, we report a molecular positioning device made from a hinged DNA origami object in which the angle between the two structural units can be controlled with adjuster helices. To test the positioning capabilities of the device, we used photophysical and crosslinking assays that report the coordinate of interest directly with atomic resolution. Using this combination of placement and analysis, we rationally adjusted the average distance between fluorescent molecules and reactive groups from 1.5 to 9 nm in 123 discrete displacement steps. The smallest displacement step possible was 0.04 nm, which is slightly less than the Bohr radius. The fluctuation amplitudes in the distance coordinate were also small (+/-0.5 nm), and within a factor of two to three of the amplitudes found in protein structures. PMID- 26479027 TI - Targeting the delivery of systemically administered haematopoietic stem/progenitor cells to the inflamed colon using hydrogen peroxide and platelet microparticle pre-treatment strategies. AB - Haematopoietic stem and progenitor cell (HSC) therapy may be promising for the treatment of inflammatory bowel disorders (IBDs). However, clinical success remains poor, partly explained by limited HSC recruitment following systemic delivery. The mechanisms governing HSC adhesion within inflamed colon, and whether this event can be enhanced, are not known. An immortalised HSC-like line (HPC7) was pre-treated with hydrogen peroxide (H2O2), activated platelet releasate enriched supernatant (PES) or platelet microparticles (PMPs). Subsequent adhesion was monitored using adhesion assays or in vivo ischaemia reperfusion (IR) and colitis injured mouse colon intravitally. Integrin clustering was determined confocally and cell morphology using scanning electron microscopy. Both injuries resulted in increased HPC7 adhesion within colonic mucosal microcirculation. H2O2 and PES significantly enhanced adhesion in vitro and in the colitis, but not IR injured, colon. PMPs had no effect on adhesion. PES and PMPs induced clustering of integrins on the HPC7 surface, but did not alter their expression. Adhesion to the colon is modulated by injury but only in colitis injury can this recruitment be enhanced. The enhanced adhesion induced by PES is likely through integrin distribution changes on the HPC7 surface. Improving local HSC presence in injured colon may result in better therapeutic efficacy for treatment of IBD. PMID- 26479028 TI - Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5 g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. AB - Linear aromatic N-tricyclic compounds with promising antiviral activity and minimal cytotoxicity were prepared and analyzed in the last years. Specifically, the pyrido[2,3-g]quinoxalinone nucleus was found endowed with high potency against several pathogenic RNA viruses as etiological agents of important veterinary and human pathologies. Following our research program on new antiviral agents we have designed, synthesized and assayed new series of imidazo[4,5 g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. Lead compounds 1-4 were further modified to enhance their antiviral activity and reduce their cytotoxicity. Thus, different substituents were introduced on N atom at position 1 or the O atom at position 2 of the leads; contextually, several groups were inserted on the nitrogen atom at position 7 of diaminoquinoline intermediates. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against RNA virus families containing single-stranded (either positive sense (ssRNA+) or negative-sense (ssRNA-)), and double-stranded genomes (dsRNA), and against two representatives of DNA virus families. Some derivatives emerged as potential leads for further development as antiviral agents against some viruses of public health significance, such as RSV, Reo, BVDV and HCV. Particularly, compounds 4, 11b, 11c, 13c, 15a, 18 and 21 resulted active against BVDV at concentrations ranging from 1.3 to 5 MUM. Compound 21 was also evaluated for its activity on the BVDV RdRp. Compound 4 was also tested as potential anti HCV compound in a subgenomic replication assay. Molecular simulation results provided a molecular rationale for the anti-BVDV activity of these compounds. PMID- 26479029 TI - Development of new highly potent imidazo[1,2-b]pyridazines targeting Toxoplasma gondii calcium-dependent protein kinase 1. AB - Using a structure-based design approach, we have developed a new series of imidazo[1,2-b]pyridazines, targeting the calcium-dependent protein kinase-1 (CDPK1) from Toxoplasma gondii. Twenty derivatives were thus synthesized. Structure-activity relationships and docking studies confirmed the binding mode of these inhibitors within the ATP binding pocket of TgCDPK1. Two lead compounds (16a and 16f) were then identified, which were able to block TgCDPK1 enzymatic activity at low nanomolar concentrations, with a good selectivity profile against a panel of mammalian kinases. The potential of these inhibitors was confirmed in vitro on T. gondii growth, with EC50 values of 100 nM and 70 nM, respectively. These best candidates also displayed low toxicity to mammalian cells and were selected for further in vivo investigations on murine model of acute toxoplasmosis. PMID- 26479030 TI - Design and studies of multiple mechanism of anti-Candida activity of a new potent Trp-rich peptide dendrimers. AB - PURPOSE: Eight peptide dendrimers were designed as structural mimics of natural cationic amphiphilic peptides with antifungal activity and evaluated for their anti-Candida potential against the wild type strains and mutants. METHODS: Dendrimer 14 containing four Trp residues and dodecyl tail and a slightly smaller dendrimer 9 decorated with four N-methylated Trp that displayed 100 and 99.7% of growth inhibition at 16 MUg/mL respectively, were selected for evaluation against the Candida albicans mutants with disabled biosynthesis of aspartic proteases responsible for host tissue colonization and morphogenesis during biofilm formation (sessile model). Flow cytometry method was employed to detect apoptotic cells with membrane alterations (phosphatidylserine translocation), and differentiation of apoptotic from necrotic cells was also performed. Simultaneous staining of cell surface phosphatidylserine with Annexin-V-Fluorescein and necrotic cells with propidium iodide was conducted. RESULTS: 14 at 16 MUg/mL caused C. albicans cells to undergo cellular apoptosis but its increasing concentrations induced necrosis. 14 influenced C. albicans biofilm viability as well as hyphal and cell wall morphology. Confocal microscopy and cell wall staining with calcofluor white revealed that in epithelial model the cell surface structure was perturbed at MIC of peptide dendrimer. It appears that tryptophan or 1-methyltryptophan groups displayed at the surface and positive charges hidden in the dendrimer tree along with hydrocarbon tail located at C-terminus are important for the anti-Candida activity since dendrimers containing tryptamine at C-terminus showed only a moderate activity. CONCLUSIONS: Our results suggest that membranolytic dendrimer 14, targeting cellular apoptotic pathway and impairing the cell wall formation in mature biofilm, may be a potential multifunctional antifungal lead compound for the control of C. albicans infections. PMID- 26479031 TI - Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity. AB - Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[h][1,6]naphthyridines, pyrrolo[3,2-c]quinolines, azepino[3,2 c]quinolines, and pyrano[3,2-c]quinolines through 2-4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei, T. cruzi, and Leishmania infantum, as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC50 values of 1.5 MUM, 6.1 MUM and 29.2 MUM against T. brucei, L. infantum and T. cruzi, respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC50 > 30 MUM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells. PMID- 26479032 TI - Structure of a eukaryotic SWEET transporter in a homotrimeric complex. AB - Eukaryotes rely on efficient distribution of energy and carbon skeletons between organs in the form of sugars. Glucose in animals and sucrose in plants serve as the dominant distribution forms. Cellular sugar uptake and release require vesicular and/or plasma membrane transport proteins. Humans and plants use proteins from three superfamilies for sugar translocation: the major facilitator superfamily (MFS), the sodium solute symporter family (SSF; only in the animal kingdom), and SWEETs. SWEETs carry mono- and disaccharides across vacuolar or plasma membranes. Plant SWEETs play key roles in sugar translocation between compartments, cells, and organs, notably in nectar secretion, phloem loading for long distance translocation, pollen nutrition, and seed filling. Plant SWEETs cause pathogen susceptibility possibly by sugar leakage from infected cells. The vacuolar Arabidopsis thaliana AtSWEET2 sequesters sugars in root vacuoles; loss of-function mutants show increased susceptibility to Pythium infection. Here we show that its orthologue, the vacuolar glucose transporter OsSWEET2b from rice (Oryza sativa), consists of an asymmetrical pair of triple-helix bundles, connected by an inversion linker transmembrane helix (TM4) to create the translocation pathway. Structural and biochemical analyses show OsSWEET2b in an apparent inward (cytosolic) open state forming homomeric trimers. TM4 tightly interacts with the first triple-helix bundle within a protomer and mediates key contacts among protomers. Structure-guided mutagenesis of the close paralogue SWEET1 from Arabidopsis identified key residues in substrate translocation and protomer crosstalk. Insights into the structure-function relationship of SWEETs are valuable for understanding the transport mechanism of eukaryotic SWEETs and may be useful for engineering sugar flux. PMID- 26479033 TI - The inner workings of the hydrazine synthase multiprotein complex. AB - Anaerobic ammonium oxidation (anammox) has a major role in the Earth's nitrogen cycle and is used in energy-efficient wastewater treatment. This bacterial process combines nitrite and ammonium to form dinitrogen (N2) gas, and has been estimated to synthesize up to 50% of the dinitrogen gas emitted into our atmosphere from the oceans. Strikingly, the anammox process relies on the highly unusual, extremely reactive intermediate hydrazine, a compound also used as a rocket fuel because of its high reducing power. So far, the enzymatic mechanism by which hydrazine is synthesized is unknown. Here we report the 2.7 A resolution crystal structure, as well as biophysical and spectroscopic studies, of a hydrazine synthase multiprotein complex isolated from the anammox organism Kuenenia stuttgartiensis. The structure shows an elongated dimer of heterotrimers, each of which has two unique c-type haem-containing active sites, as well as an interaction point for a redox partner. Furthermore, a system of tunnels connects these active sites. The crystal structure implies a two-step mechanism for hydrazine synthesis: a three-electron reduction of nitric oxide to hydroxylamine at the active site of the gamma-subunit and its subsequent condensation with ammonia, yielding hydrazine in the active centre of the alpha subunit. Our results provide the first, to our knowledge, detailed structural insight into the mechanism of biological hydrazine synthesis, which is of major significance for our understanding of the conversion of nitrogenous compounds in nature. PMID- 26479034 TI - Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract. AB - Enterococcus faecalis is both a common commensal of the human gastrointestinal tract and a leading cause of hospital-acquired infections. Systemic infections with multidrug-resistant enterococci occur subsequent to gastrointestinal colonization. Preventing colonization by multidrug-resistant E. faecalis could therefore be a valuable approach towards limiting infection. However, little is known about the mechanisms E. faecalis uses to colonize and compete for stable gastrointestinal niches. Pheromone-responsive conjugative plasmids encoding bacteriocins are common among enterococcal strains and could modulate niche competition among enterococci or between enterococci and the intestinal microbiota. We developed a model of colonization of the mouse gut with E. faecalis, without disrupting the microbiota, to evaluate the role of the conjugative plasmid pPD1 expressing bacteriocin 21 (ref. 4) in enterococcal colonization. Here we show that E. faecalis harbouring pPD1 replaces indigenous enterococci and outcompetes E. faecalis lacking pPD1. Furthermore, in the intestine, pPD1 is transferred to other E. faecalis strains by conjugation, enhancing their survival. Colonization with an E. faecalis strain carrying a conjugation-defective pPD1 mutant subsequently resulted in clearance of vancomycin-resistant enterococci, without plasmid transfer. Therefore, bacteriocin expression by commensal bacteria can influence niche competition in the gastrointestinal tract, and bacteriocins, delivered by commensals that occupy a precise intestinal bacterial niche, may be an effective therapeutic approach to specifically eliminate intestinal colonization by multidrug-resistant bacteria, without profound disruption of the indigenous microbiota. PMID- 26479037 TI - Impact of spiked concentrations of Cd, Pb, As and Zn in growth medium on elemental uptake of Nasturtium officinale (Watercress). AB - This study is aimed at investigating the impact of water quality on the uptake and distribution of three non-essential and toxic elements, namely, As, Cd and Pb in the watercress plant to assess for metal toxicity. The plant was hydroponically cultivated under greenhouse conditions, with the growth medium being spiked with varying concentrations of As, Cd and Pb. Plants that were harvested weekly for elemental analysis showed physiological and morphological symptoms of toxicity on exposure to high concentrations of Cd and Pb. Plants exposed to high concentrations of As did not survive and the threshold for As uptake in watercress was established at 5 ppm. Translocation factors were low in all cases as the toxic elements accumulated more in the roots of the plant than the edible leaves. The impact of Zn on the uptake of toxic elements was also evaluated and Zn was found to have an antagonistic effect on uptake of both Cd and Pb with no notable effect on uptake of As. The findings indicate that phytotoxicity or death of the watercress plant would prevent it from being a route of human exposure to high concentrations of As, Cd and Pb in the environment. PMID- 26479035 TI - Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. AB - The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients. PMID- 26479036 TI - Generation of human MHC (HLA-A11/DR1) transgenic mice for vaccine evaluation. AB - The rapid occurrence of emerging infectious diseases demonstrates an urgent need for a new preclinical experimental model that reliably replicates human immune responses. Here, a new homozygous humanized human leukocyte antigen (HLA)-A11/DR1 transgenic mouse (HLA-A11(+/+)/DR01(+/+)/H-2-beta2m(-/-)/IAbeta(-/-)) was generated by crossing HLA-A11 transgenic (Tg) mice with HLA-A2(+/+)/DR01(+/+)/H-2 beta2m(-/-)/IAbeta(-/-) mice. The HLA-A11-restricted immune response of this mouse model was then examined. HLA-A11 Tg mice expressing a chimeric major histocompatibility complex (MHC) molecule comprising the alpha1, alpha2, and beta2m domains of human HLA-A11 and the alpha3 transmembrane and cytoplasmic domains of murine H-2D(b) were generated. The correct integration of HLA-A11 and HLA-DR1 into the genome of the HLA-A11/DR1 Tg mice (which lacked the expression of endogenous H-2-I/II molecules) was then confirmed. Immunizing mice with a recombinant HBV vaccine or a recombinant HIV-1 protein resulted in the generation of IFN-gamma-producing cytotoxic T lymphocyte (CTL) and antigen-specific antibodies. The HLA-A11-restricted CTL response was directed at HLA immunodominant epitopes. These mice represent a versatile animal model for studying the immunogenicity of HLA CTL epitopes in the absence of a murine MHC response. The established animal model will also be useful for evaluating and optimizing T cell-based vaccines and for studying differences in antigen processing between mice and humans. PMID- 26479038 TI - Possible Common Aetiology behind Maternal Preeclampsia and Congenital Heart Defects in the Child: a Cardiovascular Diseases in Norway Project Study. AB - BACKGROUND: The aetiology of congenital heart defects (CHD) is mostly unknown, but maternal factors may modify the infant risk of CHD. We investigated the association between maternal preeclampsia and offspring risk of severe CHD in a nation-wide cohort study. METHODS: Information on all births registered in the Medical Birth Registry of Norway, 1994-2009, was completed with information on CHD diagnoses from national health registries and the Cardiovascular Diseases in Norway Project (CVDNOR). RESULTS: Among 914 703 singleton births without chromosomal abnormalities, 32 864 (3.6%) were born after a pregnancy with preeclampsia. The preeclampsia was diagnosed before the 34th week of pregnancy (early-onset preeclampsia) in 2618 (8.0% of preeclamptic pregnancies). CHDs were diagnosed in 10 691 infants; of these, 2473 had severe CHD. The risk of severe CHD was compared between births with and without maternal preeclampsia and estimated with binomial log-linear regression. When adjusting for year of birth, maternal age, parity, and pregestational diabetes, the risk ratio (RR) for severe CHD in offspring of mothers with any preeclampsia was 1.3 [95% confidence interval (CI) 1.1, 1.5], and in pregnancies with early-onset preeclampsia, the RR was 2.8 (95% CI 1.8, 4.4). The association between early-onset preeclampsia and specific types of severe CHD was stronger for atrioventricular septal defects (AVSD), with adjusted RR 13.5 (95% CI 6.8, 26.8). CONCLUSIONS: Early-onset preeclampsia was strongly associated with infant risk of severe CHD, specifically; the risk of AVSD was 15-fold higher if the mother was diagnosed with early-onset preeclampsia, suggesting common aetiological factors for early onset preeclampsia and erroneous fetal heart development. PMID- 26479039 TI - Engineering Rhodosporidium toruloides for increased lipid production. AB - Oleaginous yeast are promising organisms for the production of lipid-based chemicals and fuels from simple sugars. In this work, we explored Rhodosporidium toruloides for the production of lipid-based products. This oleaginous yeast natively produces lipids at high titers and can grow on glucose and xylose. As a first step, we sequenced the genomes of two strains, IFO0880, and IFO0559, and generated draft assemblies and annotations. We then used this information to engineer two R. toruloides strains for increased lipid production by over expressing the native acetyl-CoA carboxylase and diacylglycerol acyltransferase genes using Agrobacterium tumefaciens mediated transformation. Our best strain, derived from IFO0880, was able to produce 16.4 +/- 1.1 g/L lipid from 70 g/L glucose and 9.5 +/- 1.3 g/L lipid from 70 g/L xylose in shake-flask experiments. This work represents one of the first examples of metabolic engineering in R. toruloides and establishes this yeast as a new platform for production of fatty acid derived products. PMID- 26479040 TI - A Stretchable and Highly Sensitive Graphene-Based Fiber for Sensing Tensile Strain, Bending, and Torsion. AB - Wearable sensors are increasingly finding their way into applications of kinesthetic sensing, personal health monitoring, and smart prosthetics/robotics. A graphene-based composite fiber sensor with a "compression spring" structure is fabricated, featuring the ability of detecting multiple kinds of deformation. This fiber sensor is integrated into wearable sensors for monitoring human activities and intricate movements of robotics successfully. PMID- 26479041 TI - Effects of streptozotocin-induced type 1 maternal diabetes on PI3K/AKT signaling pathway in the hippocampus of rat neonates. AB - Diabetes in pregnancy impairs hippocampus development in offspring, leading to behavioral problems and learning deficits. Phosphatidylinositol 3-kinase/protein kinase B (PKB/Akt) signaling pathway plays a pivotal role in the regulation of neuronal proliferation, survival and death. The present study was designed to examine the effects of maternal diabetes on PKB/Akt expression and phosphorylation in the developing rat hippocampus. Wistar female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was killed at first postnatal day (P1). The hippocampal expression and phosphorylation level of PKB/Akt, one of the key molecules in PI3K/AKT signaling pathway, was evaluated using real-time polymerase chain reaction (PCR) and western blot analysis. We found a significant bilateral downregulation of AKT1 gene expression in the hippocampus of pups born to diabetic mothers (p < 0.05). Interestingly, our results revealed a marked upregulation of Akt1 gene in insulin treated group compared with other groups (p < 0.05). The western blot analysis also showed the reduction of phosphorylation level of all AKT isoforms in both diabetic and insulin-treated groups compared with control (p < 0.05). Moreover, the results showed a significant increase in phosphorylation level of AKT in insulin-treated group compared with the diabetic group. These results represent that diabetes during pregnancy strongly influences the regulation of PKB/AKT in the developing rat hippocampus. Furthermore, although the control of glycemia by insulin administration is not sufficient to prevent the alterations in PKB/Akt expression, it modulates the phosphorylation process, thus ultimately resulting in a situation comparable to that found in the normal condition. PMID- 26479042 TI - New insights into the functions of intersectin-1s. AB - Intersectin-1s (ITSN) is a ubiquitously expressed multifunctional protein known as a scaffold and regulator of the general endocytic machinery as well as a critical integrator of cellular signaling pathways. We showed recently that ITSN deficiency triggers a transforming growth factor beta (TGFbeta)/Alk5 signaling switch, from the canonical Smad 2/3 to the Erk1/2 MAPK pathway; moreover, endocytic impairment induced by ITSN deficiency enhances Alk5 ubiquitination and degradation and elicits TGFbeta-paracrine effects mediated by circulating microparticles, leading to endothelial cell survival and increased proliferation. The studies expand our understanding of how ITSN facilitates cross-regulation of signaling pathways and provide insights into the involvement of ITSN deficiency in human disease. PMID- 26479043 TI - TVT for the treatment of urodynamic stress incontinence: Efficacy and adverse effects at 13-year follow-up. AB - AIM: To assess long-term subjective, objective, and urodynamic outcomes of retropubic mid-urethral slings at 13-year follow-up. METHODS: This was a prospective observational study. Consecutive women with proven urodynamic stress incontinence were treated with standard retropubic tension free vaginal tape (TVT). Patients with mixed incontinence and/or anatomic evidence of pelvic organ prolapse were excluded. All the included patients underwent preoperative clinical and urodynamic evaluations. During follow-up examinations, women were assessed for subjective satisfaction and objective cure rates. The Cox model was used in order to investigate factors predicting the risk of recurrent stress urinary incontinence (SUI), over the study period. RESULTS: Overall, 55 patients were suitable for the analysis. At 13-year follow-up, 47 out of 55 (85.5%) patients declared themselves cured (p-for-trend 0.02) and 48 out of 58 (87.2%) were at least improved (p-for-trend 0.07). No significant deterioration of objective cure rates was observed over time (P = 0.29). At the time of the last evaluation, 50 out of 55 (90.9%) women were objectively cured; urodynamic evaluation confirmed this finding in 49 (89.1%) patients. Considering factors predictive of SUI recurrence, we observed that, via multivariate analysis, obesity (HR 7.2; P = 0.01) and maximum detrusor pressure during the voiding phase <=29 cmH2 O (HR 8.0; P = 0.01) were the only independent predictors of recurrent SUI. CONCLUSION: Our data confirmed that TVT is a highly effective and safe procedure also at 13-year follow-up. Interestingly, we observed a significant decrease of subjective satisfaction over time. Neurourol. Urodynam. 36:192-197, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26479046 TI - Scientific Collaboration in Chinese Nursing Research: A Social Network Analysis Study. AB - Collaboration has become very important in research and in technological progress. Coauthorship networks in different fields have been intensively studied as an important type of collaboration in recent years. Yet there are few published reports about collaboration in the field of nursing. This article aimed to reveal the status and identify the key features of collaboration in the field of nursing in China. Using data from the top 10 nursing journals in China from 2003 to 2013, we constructed a nursing scientific coauthorship network using social network analysis. We found that coauthorship was a common phenomenon in the Chinese nursing field. A coauthorship network with 228 subnetworks formed by 1428 nodes was constructed. The network was relatively loose, and most subnetworks were of small scales. Scholars from Shanghai and from military medical system were at the center of the Chinese nursing scientific coauthorship network. We identified the authors' positions and influences according to the research output and centralities of each author. We also analyzed the microstructure and the evolution over time of the maximum subnetwork. PMID- 26479044 TI - Role of AINTEGUMENTA-like gene NtANTL in the regulation of tobacco organ growth. AB - The Nicotiana tabacum AINTEGUMENTA-like gene (NtANTL), encoding one of AP2/ERF transcription factors, is a putative ortholog of the AtANT gene from Arabidopsis thaliana. In wild-type tobacco plants, the NtANTL gene was expressed in the actively dividing young flowers, shoot apices, and calluses, while the level of its mRNA increased considerably after treatment with exogenous 6 benzylaminopurine, indoleacetic acid and 24-epibrassinolide. We found a positive correlation among the expression levels of NtANTL, cyclin NtCYCD3;1 and cyclin dependent kinase NtCDKB1-1 genes, suggesting possible molecular links between AINTEGUMENTA and cell cycle regulators in tobacco plants. However, no correlation was observed between NtANTL, NtCYCD3;1 and NtCDKB1-1 expression levels in response to NaCl and ABA. These observations indicate that the transcription factor NtANTL was not involved in the regulation of the cellular response to salinity nor did it affect the expression of NtCYCD3;1 and NtCDKB1-1 when tobacco plants were exposed to salt stress and ABA. In addition, we generated transgenic tobacco plants with both up-regulated and down-regulated expression of the NtANTL gene. Constitutive expression of the NtANTL gene contributed to an increase in the size of leaves and corolla of transgenic plants. Transgenic plants with reduced expression of the NtANTL gene had smaller leaves, flowers and stems, but showed a compensatory increase in the cell size of leaves and flowers. The results show the significance of the NtANTL gene for the control of organ growth by both cell division and expansion in tobacco plants. PMID- 26479047 TI - Transient generalized glucocorticoid hypersensitivity. AB - BACKGROUND: Transient generalized glucocorticoid hypersensitivity is a rare disorder characterized by increased tissue sensitivity to glucocorticoids and compensatory hypo-activation of the hypothalamic-pituitary-adrenal axis. The condition itself and the underlying molecular mechanisms have not been elucidated. OBJECTIVE: To present the clinical manifestations, endocrinologic evaluation and transcriptomic profile in a patient with transient generalized glucocorticoid hypersensitivity. DESIGN AND RESULTS: A 9-year-old girl presented with an 8-month history of clinical manifestations suggestive of Cushing syndrome. Endocrinologic evaluation revealed undetectable 08:00 h ACTH (<1 pg/mL) and cortisol (0.025 MUg/dL) concentrations, which remained decreased throughout the 24-h period and did not respond to stimulation with ovine CRH. The disease gradually resolved spontaneously over the ensuing 3 months. Sequencing of the human glucocorticoid receptor gene revealed no mutations or polymorphisms. Western blot analysis in peripheral blood mononuclear cells revealed equal protein expression of hGRalpha of the patient in the disease and postresolution phases compared with a control subject. Transcriptomic analysis in peripheral blood mononuclear cells in the disease and postresolution phases identified 903 differentially expressed genes. Of these, 106 genes were up-regulated and 797 were down-regulated in the disease compared with the resolution phase. Bioinformatics analysis on the differentially expressed gene networks revealed Nuclear Factor-kappaB as the predominant transcription factor influencing the expression of the majority of differentially expressed genes. CONCLUSIONS: Our findings indicate that a transient postreceptor defect, or a virus- or bacterium encoded molecule, may have enhanced glucocorticoid signal transduction, leading to transient generalized glucocorticoid hypersensitivity and hypo-activation of the HPA axis. PMID- 26479048 TI - Development and validation of an Argentine set of facial expressions of emotion. AB - Pictures of facial expressions of emotion are used in a wide range of experiments. The last decade has seen an increase in the number of studies presenting local sets of emotion stimuli. However, only a few existing sets contain pictures of Latin Americans, despite the growing attention emotion research is receiving in this region. Here we present the development and validation of the Universidad Nacional de Cordoba, Expresiones de Emociones Faciales (UNCEEF), a Facial Action Coding System (FACS)-verified set of pictures of Argentineans expressing the six basic emotions, plus neutral expressions. FACS scores, recognition rates, Hu scores, and discrimination indices are reported. Evidence of convergent validity was obtained using the Pictures of Facial Affect in an Argentine sample. However, recognition accuracy was greater for UNCEEF. The importance of local sets of emotion pictures is discussed. PMID- 26479049 TI - [Immunogenetics of glomerulopathies]. AB - There are many evidences that the HLA genes are risk factors for kidney complex disease for the pathogenesis of which an abnormal response of the immune system is involved. In this review, we present the latest knowledge about the genetics of the HLA complex, the molecules encoded by the HLA genes, their polymorphism and the physiological role of the HLA system in the defense against infections. It then addresses the issue of the association between specific alleles of HLA and renal disorders. Many kidney diseases have been described associated with HLA. This review focuses on some examples of renal diseases, exploring in detail how certain HLA antigens are a risk factor for idiopathic membranous glomerulonephritis, Goodpasture's disease and vasculitis associated with the presence of ANCA. These diseases indeed offer a good example of how the presence of some variants of HLA class II genes in individuals who possess them promote the presentation of peptides derived from certain self proteins, able to initiate the autoimmune response. Immunogenetic study of many complex renal diseases can be useful for the understanding of their pathogenesis and the possible development of new therapies. PMID- 26479050 TI - [Introduction]. PMID- 26479051 TI - [Genetics of aHUS and transplant recurrence]. AB - Hemolytic uremic syndrome (HUS) is a rare disease with a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Several genetic and acquired abnormalities leading to abnormal activation of the alternative pathway of complement have been identified in patients with atypical HUS (aHUS). Studies over the past decade have shown that the risk of post transplant recurrence of aHUS depends on the underlying genetic abnormality. The risk is high in patients with mutations in genes (CFH, CFI, C3, CFB) encoding circulating complement proteins and regulators, while patients with mutations in membrane cofactor protein (MCP) and diacylglycerol kinase E (DGKE) generally show good transplant outcome. Recent data provided evidence about the efficacy of the anti-C5 monoclonal antibody Eculizumab in the prevention and treatment of post transplant aHUS recurrences. PMID- 26479052 TI - [Diagnosis of Alport syndrome]. AB - Diagnosis of Alport syndrome or Thin basement membrane disease is suggested first of all by the clinical picture, the presence of neurisensorial hypoacusia and/or ocular abnormalities, and the family history which should be as accurate as possible involving the largest number possible of family members to recognize the transmission modalities, i.e. X-linked or autosomal. Renal biopsy remains the main tool to confirm the diagnosis and requires electron microscopy observation and collagen IV alpha chains investigation on renal tissue by means of specific antibodies. Skin biopsy is a useful and less invasive tool in families with X linked Alport syndrome and can substitute renal biopsy in childhood as well as in patients with contraindication to renal biopsy. Confocal microscopy is mandatory to reduce the risk of false negative results in patients with segmental expression of alpha chains. Genetic analysis is at present indicated for studying subjects at risk for family planning or possible kidney donation but new techniques (Next Generation Sequencing) might increase their use in clinical practice. PMID- 26479053 TI - [Kidney Transplantation and inborn errors of metabolism]. AB - Inherited kidney diseases constitute at least 150 different disorders and they have an overall prevalence of about 6080 cases per 100,000 in Europe and in USA. At least 10% of adults and nearly all children who progress to renal-replacement therapy have an inherited kidney disease, representing the fifth most common cause of end-stage renal disease after diabetes, hypertension, glomerulonephritis, and pyelonephritis. These conditions include both structural and functional disorders, among which are counted diseases resulting from inborn errors of metabolism (IEM). Some inborn errors of metabolism primarily affect kidney and because of progress in renal replacement therapy, patients with inherited kidney disorders rarely die when their disease progresses and can live for many years. However, these patients often have compromised health with a poor quality of life. Renal transplantation offers a viable treatment option for those inborn errors of metabolism characterized by primary renal damage caused by dysfunction of a mutated protein, as in cystinuria. In this case, the indication to renal transplantation makes it possible to overcome the specific enzyme defect. However this option remains valid even when the genetic defect is expressed systemically and renal involvement is just one of the clinical manifestations of the disease, as in Anderson-Fabry disease, cystinosis, hereditary amyloidosis and primary hyperoxaluria. In these conditions, renal transplantation is combined with the liver (primary hyperoxaluria) or cardiac transplant (familial amyloidosis) improving the quality and life expectancy of patients. PMID- 26479054 TI - [Genetic approach to nephrolithiasis]. AB - Nephrolithiasis (NL) has high and increasing prevalence in western countries. Most renal stones contain calcium and/or uric acid and often occur as idiopathic stones, while seldom are caused by genetic disorders. Conversely, cystinuria, xantinuria, 2-8 dihydroxyadeninuria only occur in patients with mutations of corresponding genes. Inherited NL must be suspected in case of early onset, positive family history, severe recurrence rate, associated biochemical disorders, abnormal urinary sediment, renal insufficiency, involvement of other organs or apparatus. Pathophysiology is based on different mechanisms: electrolytic abnormalities, altered tubular transport, acid-base imbalances, cystic renal diseases. Sometimes NL is iatrogenic. Here we review some genetic NL, not only characterized by clinical relevance but also by the scientific interest in view of our better understanding of mechanisms of stone formation. Namely, Dents syndrome, calcium sensing receptor mutations, familial hypopomagnesiemic hypercalciuria (FHHNC), hypophosphatemic rickets (HHRH), renal tubular acidosis (dRTA), primary hyperoxaluria (PH), cystinuria, 2-8 dihydroxyadeninuria (2-8 DHA). We will briefly report on prevalence, genetics, pathophysiology, clinical aspects and treatment. The need for early diagnosis stems from the fact that, for most of these, selective treatment may be highly effective and can prevent progression to ESRD. Lastly, a better knowledge and understanding of genetic NL is a premise to study polymorphisms of candidate genes also in the setting of so-called idiopathic disease. PMID- 26479055 TI - [Genetic approach to hypertensive nephrosclerosis]. AB - Several epidemiological and experimental studies suggest an important role of genetic factors in the pathogenesis of hypertensive nephrosclerosis. However, identification of susceptibility genes is difficult. The association between apolipoprotein L1 gene (APOL1) variants and non-diabetic chronic kidney disease in African Americans has modified the approach to hypertensive glomerular sclerosis, as a member of a single disease spectrum: APOL1-associated FSGS. PMID- 26479056 TI - [Innate immunity and transplantation]. AB - Innate immunity is the first barrier against pathogen infection and has also the important function of activating the adaptive immunity. The receptors of innate immunity, such as toll-like receptors and other receptors, recognize as danger signals the molecular patterns of pathogens as well as those of endogenous molecules released by dying cells. The information is transmitted to adapter proteins that, through a chain of kinases that translate the signal to transcription factors regulating inflammatory genes. In the inflammatory milieu dendritic cells become mature, intercept the antigen and migrate to lymphoid organs where they present the antigen to naive T cells. Complement also exerts an important role of bridge between innate and adaptive immunity. In donor-deceased kidney transplantation, the innate immunity is triggered in the donor by brain death and is aggravated by the cold ischemia and even more by reperfusion. Once activated, innate immunity produces a local inflammatory environment leading to dendritic cell maturation and complement activation. Dendritic cells present the alloantigen to T cells and induce their differentiation towards effector Th1 and Th17 while inhibiting Th2 and T regulatory cells. A main goal of the current research in transplantation is to obtain an immunological tolerance. Experimental studies showed the possibility of inducing operative tolerance in murine models and even in primates with the infusion of regulatory dendritic cells. However, there are no data with this technique in clinical transplantation. PMID- 26479057 TI - [Kidney diseases associated with uromodulin (Tamm-Horsfall protein)]. AB - Uromodulin is the most abundant protein excreted in the urine under physiological conditions. It is exclusively expressed in the kidney by epithelial cells lining the thick ascending limb of Henles loop. It is mainly localized at the apical plasma membrane of tubular cells and released through a proteolytic cleavage. Although its function is still elusive it is proposed to have a protective role against urinary tract infection and kidney stone formation, in ion transport and in kidney innate immunity. Mutations in the gene UMOD encoding uromodulin lead to rare autosomal dominant diseases, collectively referred to as uromodulin associated kidney disease, that are characterized by progressive tubulo interstitial damage, impaired urinary concentrating ability, hyperuricemia, and progressive renal failure. Recently, genome-wide association studies identified uromodulin as a risk factor for chronic kidney disease and hypertension. Risk variants in the UMOD gene are common in all studied populations and are associated with higher expression and urinary level of the protein. PMID- 26479058 TI - [Podocytes: genetics and biology]. AB - Progresses in podocyte biology have been strictly connected with genetic advances; the identification of genes mutated in familial and sporadic forms of nephrotic syndrome has been followed by functional studies of the encoded proteins, revealing numerous properties of the cell. The molecules uncovered so far belong to three main categories: a) proteins located at the slit diaphragm, the intercellular junction which laterally connects podocyte processes and is responsible for selectivity of the glomerular filter, b) molecules involved in regulation of actin dynamics, which are essential for the maintenance of podocyte structure and function, and c) molecules belonging to intracellular organelles, such as mitochondria and lysosomes, which are central players in podocyte metabolism. Considering the key role of the podocyte in health and disease of the glomerular filter, better knowledge of this cell is a pre-requisite for developing targeted therapies of glomerular diseases. PMID- 26479059 TI - [Genetics of mesangial IgA nephropathy]. AB - IgA nephropathy is the most common form of primary glomerulonephritis, with a variable prevalence depending on the geographic area of examination. Marked differences in disease prevalence has suggested that genetics could play a role in the pathogenesis of the disease, indicating the existence of susceptibility genes detected with different frequencies in geographically separated populations. Moreover, familial forms of IgAN have been reported worldwide, in sibling pairs, families and extended pedigrees belonging to geographically isolated populations. In this article we describe recent discoveries in genetic studies on IgAN. If candidate-gene association studies require first survey on the pathogenesis of the disease, since the candidate loci are selected on the basis of information gathered from traditional biology, the linkage analysis consist in an alternative approach. Several susceptibility loci have been identified in pedigrees segregating for IgAN, but not the causative mutations of the disease. Further progress in the field of knowledge about the genetics of IgAN has recently been obtained by the application of genome-wide association studies (GWAS) in large cohorts of cases and controls of IgAN. GWAS have identified multiple susceptibility loci coding for genes involved in critical mechanisms for the development of IgAN and, accordingly, have shed new light on the biology of the disease, revealing unknown pathogenic pathways. The close connection between IgAN and many autoimmune diseases has been demonstrated. Moreover, these studies have made the correlation of genetic risk score of developing IgAN with the geo-epidemiological aspect of the disease possible. The goal of the integrated genomic approach will be to discover new potential therapeutic targets. PMID- 26479060 TI - [Familial Focal Segmental Glomerulosclerosis, a vademecum for clinical nephrologist]. AB - The new genomic technologies (Next Generation Sequencing, NGS) are opening a new era in Genomic Medicine. This simple guide gives a state-of-the-art description of the genes that cause Focal Segmental Glomerulosclerosis and nephrotic syndrome. PMID- 26479061 TI - [The ciliopathies--Polycystic Kidney Disease]. AB - The primary cilium is an organelle composed of microtubules that emerges from the cell surface. Its inappropriate structure or function leads to the onset of a series of disease conditions collectively defined as ciliopathies, a class of genetic disorders with a variety of manifestations in different organs. In the kidneys the ciliopathies manifest with renal cysts and propotype diseases are autosomal dominant and autosomal recessive polycystic kidney diseases (ADPKD and ARPKD, respectively) . ADPKD is one of the most frequent genetic disorders affecting 1: 500 to 1: 1000 at birth. It manifests primarily with the formation of cysts in both kidneys that increase in number and size during the life of an individual, eventually causing loss of renal function. ADPKD is caused by mutations in the genes PKD1 (85% of cases) or PKD2 (15% of cases), encoding for polycystin-1 (PC-1) and polycystin-2 (PC-2) respectively. The PC-1/PC-2 complex was found on the primary cilium and elsewhere. Here we summarize recent work from our and other labs suggesting that defective planar cell polarity and cellular shape might underly PKD and additional work suggesting that defective glucose metabolism is a feature of this disease. This is the summary of a presentation delivered during a recent meeting on the genetics of renal diseases. PMID- 26479062 TI - [Genetic Basis of Congenital Anomalies of the Kidney and Urinary Tract]. AB - Congenital anomalies of the kidney and urinary tract (CAKUT) occur have an incidence of about 1% and they are one of the most common birth defects. CAKUT is the most common cause of end stage renal disease in children, leading to high morbidity and mortality in these patients. Recent studies indicate a strong genetic component in the determination of CAKUT. The genetic architecture of these malformations involves both point mutations and structural variants. The recent improvement in next-generation sequencing technologies resulted in a boost on discovery of new genes involved in CAKUT. Results from micro-array study have demonstrated that rare structural variants are an important source of genetic variation in patients with CAKUT. Moreover, these structural variants have been proven to be associated with developmental disorders that develop later in life, especially neurodevelopment diseases, such as autism, schizophrenia, epilepsy, intellectual disability, and others. The easy pre-natal diagnosis of CAKUT by ultrasound and the possibility of a rapid molecular diagnosis in a significant fraction of patients, implicate the kidney and urinary tract as new possible sentinels for other diseases that develop later in life, bearing strong implications for personalized medicine. PMID- 26479063 TI - Dynapenic obesity and the risk of incident Type 2 diabetes: the English Longitudinal Study of Ageing. AB - AIM: Obesity is a well-established risk factor for developing Type 2 diabetes. Evidence suggests that sarcopenia, the age-related decline in muscle mass and strength, may exacerbate diabetes risk in obese individuals. The aim of this study was to determine the combined effect of obesity and low muscle strength, dynapenia, on the risk of incident Type 2 diabetes in older adults. METHODS: Participants were 5953 (1670 obese) men and women from the English Longitudinal Study of Ageing without known Type 2 diabetes at baseline and for whom handgrip strength, biochemical and other clinical data were collected. A diagnosis of Type 2 diabetes was recorded from self-reported physician diagnosis over 6 years. RESULTS: For each unit increase in grip strength, there was a reduction in diabetes risk (age-, sex- and BMI adjusted HR; 0.98; 95% CI 0.96-0.99). The risk of Type 2 diabetes was elevated in all obese participants, but was greatest in those with low handgrip strength (HR = 4.93, 95% CI 2.85, 8.53) compared with non obese individuals with high handgrip strength. Eleven per cent of the sample met the threshold for weakness (handgrip strength: men < 26 kg; women < 16 kg) that was associated with elevated Type 2 diabetes risk in obese (HR = 3.57, 95% CI 2.04, 6.24) but not in non-obese (HR = 0.86, 95% CI, 0.44, 1.68) compared with normal/non-obese participants. CONCLUSION: Dynapenic obesity, determined by high BMI and low handgrip strength, is associated with increased risk of incident Type 2 diabetes in older people. PMID- 26479065 TI - Inner Retinal Refractile Lesions in Type 1 Neurofibromatosis. PMID- 26479064 TI - Rubisco Activase Is Also a Multiple Responder to Abiotic Stresses in Rice. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase activase (RCA) is a nuclear gene that encodes a chloroplast protein that plays an important role in photosynthesis. Some reports have indicated that it may play a role in acclimation to different abiotic stresses. In this paper, we analyzed the stress responsive elements in the 2.0 kb 5'-upstream regions of the RCA gene promoter and the primary, secondary and tertiary structure of the protein. We identified some cis-elements of multiple stress-related components in the RCA promoter. Amino acid and evolution analyses showed that the RCA protein had conserved regions between different species; however, the size and type varied. The secondary structures, binding sites and tertiary structures of the RCA proteins were also different. This might reflect the differences in the transcription and translation levels of the two RCA isoforms during adaptation to different abiotic stresses. Although both the transcription and translation levels of RCA isoforms in the rice leaves increased under various stresses, the large isoform was increased more significantly in the chloroplast stroma and thylakoid. It can be concluded that RCA, especially RCAL, is also a multiple responder to abiotic stresses in rice, which provides new insights into RCA functions. PMID- 26479066 TI - Breast conservation versus mastectomy for patients with T3 primary tumors (>5 cm): A review of 5685 medicare patients. AB - BACKGROUND: Although breast conservation therapy (BCT) is standard for breast cancer treatment, patients with tumors measuring >5 cm have been excluded from clinical trials. Nevertheless, only a few small retrospective series to date have compared BCT with mastectomy for tumors measuring >5 cm. The current study was performed to determine whether survival is equivalent for BCT versus mastectomy using a large national data set. METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked cases were identified for patients aged >= 66 years undergoing breast conservation for invasive, noninflammatory, nonmetastatic breast cancer between 1992 and 2009. Propensity score-based adjustment was used to account for demographics and tumor and treatment factors. RESULTS: A total of 5685 patients with tumors measuring >5.0 cm underwent breast surgery, with 15.6% receiving BCT. Mean ages of the patients and tumor sizes were similar. Predictors of BCT included neoadjuvant chemotherapy and postoperative radiotherapy use, higher income, breast cancer as a first malignancy, and a higher Charlson Comorbidity Index. Predictors of mastectomy included younger age, nonductal histology, higher grade, numbers of lymph nodes examined and found to be positive, American Joint Committee on Cancer stage III disease, postoperative chemotherapy use, and residential region of the country. Adjusted overall and breast cancer-specific survival were not different between patients treated with BCT and mastectomy (hazard ratio, 0.934; 95% confidence interval, 0.791-1.103 [P = .419] for overall survival; and subdistribution hazard ratio, 1.042; 95% confidence interval, 0.793-1.369 [P = .769] for breast cancer-specific survival), with each improving over time. The median follow-up was 7.0 years. CONCLUSIONS: For Medicare patients with tumors measuring >5 cm, survival is similar between those treated with BCT and mastectomy as for patients with smaller primary tumors. Despite exclusion from randomized trials, BCT may remain an option for patients with larger tumors when deemed clinically and cosmetically amenable to surgical resection. PMID- 26479068 TI - Large-Scale Fabrication of Polymer Microcavities with Adjustable Openings and Surface Roughness Regulated by the Polarity of both Seed Surface and Monomers. AB - Polymer microcavities with adjustable openings and surface roughness are fabricated on a large scale via single-hole poly(glycidyl methacrylate) (PGMA) swelling seed particles. The size of openings of these microcavities can be adjusted by changing the amount of hydrophilic monomer, and the degree of surface roughness is easily regulated relying on the adjustment of the polarity of monomer. Furthermore, the morphology of PGMA/poly(styrene-methacrylic acid) (PGMA/P(S-MAA)) microparticles from microcavity to erythrocyte shape is controlled by the polarity of seed surface. From transmission electron microscopy images of PGMA/P(S-MAA) microparticles, a fresh polymer particle appears in the cavity. To confirm this phenomenon, thermal annealing process in dioxane/water solution is carried out. Considering the flexibility of polymers, the openings and closing of the prepared microparticles are regulated following the increase in volume ratio of dioxane/water. Ball-in-bowl-shaped PGMA/P(S-MAA) microparticles are further presented, which proves secondary nucleation of monomer in the polymerization stage. PMID- 26479067 TI - A Comparison Study of Canonical Correlation Analysis Based Methods for Detecting Steady-State Visual Evoked Potentials. AB - Canonical correlation analysis (CCA) has been widely used in the detection of the steady-state visual evoked potentials (SSVEPs) in brain-computer interfaces (BCIs). The standard CCA method, which uses sinusoidal signals as reference signals, was first proposed for SSVEP detection without calibration. However, the detection performance can be deteriorated by the interference from the spontaneous EEG activities. Recently, various extended methods have been developed to incorporate individual EEG calibration data in CCA to improve the detection performance. Although advantages of the extended CCA methods have been demonstrated in separate studies, a comprehensive comparison between these methods is still missing. This study performed a comparison of the existing CCA based SSVEP detection methods using a 12-class SSVEP dataset recorded from 10 subjects in a simulated online BCI experiment. Classification accuracy and information transfer rate (ITR) were used for performance evaluation. The results suggest that individual calibration data can significantly improve the detection performance. Furthermore, the results showed that the combination method based on the standard CCA and the individual template based CCA (IT-CCA) achieved the highest performance. PMID- 26479069 TI - Neurobehavioral foundation of environmental reactivity. AB - Sensitivity to environmental context has been of interest for many years, but the nature of individual differences in environmental sensitivity has become of particular focus over the past 2 decades. What is particularly uncertain are the neural variables and processes that mediate the effects of environment on developmental outcomes. Accordingly, we provide a neurobehavioral foundation of reactivity to the environment in several steps. First, the different patterns of environmental sensitivity are defined to identify the significant factors involved in the manifestation of these patterns. Second, we focus on neurobiological reactivity as the construct underlying variation in sensitivity to the environment by (a) providing an organizing threshold model of elicitation of neurobiology by environmental context; and (b) integrating the literature on 2 sets of neuromodulators in terms of each modulator's (a) contribution to neural and behavioral reactivity to stimulation, and (b) relation to emotional motivational systems (dopamine, opiates and oxytocin, corticotropin-releasing hormone) or the general modulation of those systems (serotonin, norepinephrine, and GABA). Discussion concludes with (a) a comprehensive neurobehavioral framework of environmental reactivity based on a combinatorial model of a supertrait, (b) methodological implications of the model, and (c) a developmental perspective on environmental reactivity. PMID- 26479070 TI - Does monitoring goal progress promote goal attainment? A meta-analysis of the experimental evidence. AB - Control theory and other frameworks for understanding self-regulation suggest that monitoring goal progress is a crucial process that intervenes between setting and attaining a goal, and helps to ensure that goals are translated into action. However, the impact of progress monitoring interventions on rates of behavioral performance and goal attainment has yet to be quantified. A systematic literature search identified 138 studies (N = 19,951) that randomly allocated participants to an intervention designed to promote monitoring of goal progress versus a control condition. All studies reported the effects of the treatment on (a) the frequency of progress monitoring and (b) subsequent goal attainment. A random effects model revealed that, on average, interventions were successful at increasing the frequency of monitoring goal progress (d+ = 1.98, 95% CI [1.71, 2.24]) and promoted goal attainment (d+ = 0.40, 95% CI [0.32, 0.48]). Furthermore, changes in the frequency of progress monitoring mediated the effect of the interventions on goal attainment. Moderation tests revealed that progress monitoring had larger effects on goal attainment when the outcomes were reported or made public, and when the information was physically recorded. Taken together, the findings suggest that monitoring goal progress is an effective self regulation strategy, and that interventions that increase the frequency of progress monitoring are likely to promote behavior change. PMID- 26479072 TI - Research Training in Psychiatry Residency: Strategies for Reform. PMID- 26479076 TI - Nickel Nanoparticle-Decorated Porous Carbons for Highly Active Catalytic Reduction of Organic Dyes and Sensitive Detection of Hg(II) Ions. AB - High surface area carbon porous materials (CPMs) synthesized by the direct template method via self-assembly of polymerized phloroglucinol-formaldehyde resol around a triblock copolymer template were used as supports for nickel nanoparticles (Ni NPs). The Ni/CPM materials fabricated through a microwave assisted heating procedure have been characterized by various analytical and spectroscopic techniques, such as X-ray diffraction, field emission transmission electron microscopy, vibrating sample magnetometry, gas physisorption/chemisorption, thermogravimetric analysis, and Raman, Fourier transform infrared, and X-ray photon spectroscopies. Results obtained from ultraviolet-visible (UV-vis) spectroscopy demonstrated that the supported Ni/CPM catalysts exhibit superior activity for catalytic reduction of organic dyes, such as methylene blue (MB) and rhodamine B (RhB). Further electrochemical measurements by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) also revealed that the Ni/CPM-modified electrodes showed excellent sensitivity (59.6 MUA MUM(-1) cm(-2)) and a relatively low detection limit (2.1 nM) toward the detection of Hg(II) ion. The system has also been successfully applied for the detection of mercuric ion in real sea fish samples. The Ni/CPM nanocomposite represents a robust, user-friendly, and highly effective system with prospective practical applications for catalytic reduction of organic dyes as well as trace level detection of heavy metals. PMID- 26479071 TI - High-Throughput Sequencing-The Key to Rapid Biodiversity Assessment of Marine Metazoa? AB - The applications of traditional morphological and molecular methods for species identification are greatly restricted by processing speed and on a regional or greater scale are generally considered unfeasible. In this context, high throughput sequencing, or metagenetics, has been proposed as an efficient tool to document biodiversity. Here we evaluated the effectiveness of 454 pyrosequencing in marine metazoan community analysis using the 18S rDNA: V1-V2 region. Multiplex pyrosequencing of the V1-V2 region was used to analyze two pooled samples of DNA, one comprising 118 and the other 37 morphologically identified species, and one natural sample taken directly from a North Sea zooplankton community. A DNA reference library comprising all species represented in the pooled samples was created by Sanger sequencing, and this was then used to determine the optimal similarity threshold for species delineation. The optimal threshold was found at 99% species similarity, with 85% identification success. Pyrosequencing was able to identify between fewer species: 67% and 78% of the species in the two pooled samples. Also, a large number of sequences for three species that were not included in the pooled samples were amplified by pyrosequencing, suggesting preferential amplification of some genotypes and the sensitivity of this approach to even low levels of contamination. Conversely, metagenetic analysis of the natural zooplankton sample identified many more species (particularly gelatinous zooplankton and meroplankton) than morphological analysis of a formalin-fixed sample from the same sampling site, suggesting an increased level of taxonomic resolution with pyrosequencing. The study demonstrated that, based on the V1-V2 region, 454 sequencing does not provide accurate species differentiation and reliable taxonomic classification, as it is required in most biodiversity monitoring. The analysis of artificially prepared samples indicated that species detection in pyrosequencing datasets is complicated by potential PCR-based biases and that the V1-V2 marker is poorly resolved for some taxa. PMID- 26479078 TI - Isolation of Uranyl Dicyanamide Complexes from N-Donor Ionic Liquids. AB - An ionic liquid (IL) approach for soft-donor f-element chemistry has been demonstrated by the isolation of several new uranyl dicyanamide complexes through reactions of UO2(NO3)2.6H2O with dicyanamide ([N(CN)2](-))-containing ILs. The [N(CN)2](-) ions are able to rapidly substitute uranium's O-donor ligands, as evidenced by single-crystal X-ray diffraction studies on two anhydrous adducts of UO2(NO3)2 with [N(CN)2](-) ILs as well as by IR and NMR spectroscopic studies on solutions of UO2(NO3)2 in these ILs. By contrast, the slow reaction of UO2(OAc)2.2H2O with a nitrile-functionalized imidazolium dicyanamide IL in solvent and the reaction of UO2(NO3)2.6H2O with NaN(CN)2 at elevated temperature resulted in irreversible hydrolysis. The reaction of UO2SO4 with [N(CN)2](-) ions in an acidified aqueous solution resulted in the crystallization of a [UO2](2+) complex with biuret, a N(CN)2](-) hydrolysis product. [N(CN)2](-) ions in the form of ILs react rapidly with [UO2](2+) at room temperature, allowing ligand substitution with [N(CN)2](-) to out-compete the slower hydrolysis reaction, enabling the isolation of uranyl dicyanamide complexes and challenging assumptions regarding the affinity of uranium for O-donors. PMID- 26479077 TI - Effect of health risk assessment and counselling on health behaviour and survival in older people: a pragmatic randomised trial. AB - BACKGROUND: Potentially avoidable risk factors continue to cause unnecessary disability and premature death in older people. Health risk assessment (HRA), a method successfully used in working-age populations, is a promising method for cost-effective health promotion and preventive care in older individuals, but the long-term effects of this approach are unknown. The objective of this study was to evaluate the effects of an innovative approach to HRA and counselling in older individuals for health behaviours, preventive care, and long-term survival. METHODS AND FINDINGS: This study was a pragmatic, single-centre randomised controlled clinical trial in community-dwelling individuals aged 65 y or older registered with one of 19 primary care physician (PCP) practices in a mixed rural and urban area in Switzerland. From November 2000 to January 2002, 874 participants were randomly allocated to the intervention and 1,410 to usual care. The intervention consisted of HRA based on self-administered questionnaires and individualised computer-generated feedback reports, combined with nurse and PCP counselling over a 2-y period. Primary outcomes were health behaviours and preventive care use at 2 y and all-cause mortality at 8 y. At baseline, participants in the intervention group had a mean +/- standard deviation of 6.9 +/- 3.7 risk factors (including unfavourable health behaviours, health and functional impairments, and social risk factors) and 4.3 +/- 1.8 deficits in recommended preventive care. At 2 y, favourable health behaviours and use of preventive care were more frequent in the intervention than in the control group (based on z-statistics from generalised estimating equation models). For example, 70% compared to 62% were physically active (odds ratio 1.43, 95% CI 1.16-1.77, p = 0.001), and 66% compared to 59% had influenza vaccinations in the past year (odds ratio 1.35, 95% CI 1.09-1.66, p = 0.005). At 8 y, based on an intention-to treat analysis, the estimated proportion alive was 77.9% in the intervention and 72.8% in the control group, for an absolute mortality difference of 4.9% (95% CI 1.3%-8.5%, p = 0.009; based on z-test for risk difference). The hazard ratio of death comparing intervention with control was 0.79 (95% CI 0.66-0.94, p = 0.009; based on Wald test from Cox regression model), and the number needed to receive the intervention to prevent one death was 21 (95% CI 12-79). The main limitations of the study include the single-site study design, the use of a brief self administered questionnaire for 2-y outcome data collection, the unavailability of other long-term outcome data (e.g., functional status, nursing home admissions), and the availability of long-term follow-up data on mortality for analysis only in 2014. CONCLUSIONS: This is the first trial to our knowledge demonstrating that a collaborative care model of HRA in community-dwelling older people not only results in better health behaviours and increased use of recommended preventive care interventions, but also improves survival. The intervention tested in our study may serve as a model of how to implement a relatively low-cost but effective programme of disease prevention and health promotion in older individuals. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number: ISRCTN 28458424. PMID- 26479079 TI - Glucocorticoid Receptor Mediates the Effect of High-Fat Diet on Mitochondrial Oxidative Phosphorylation in Mouse Liver. AB - Obesity is associated with hepatic mitochondrial dysfunction. The relationship between glucocorticoids (GCs) and obesity has also been demonstrated in several researches. Recent research showed that GCs can affect the mitochondrial function. However, the role of glucocorticoid receptor (GR) in obesity-induced mitochondrial dysfunction remains unclear. C57BL/6 male mice fed with a high-fat diet (HFD) for 7 weeks were used as a model. The mice were shown to be overweight, together with lower serum and hepatic corticosterone levels. The hepatic expressions of mitochondrial DNA (mtDNA)-encoded genes were lower in the HFD mice, same as the mtDNA copy number, ATP content, and COX enzyme activity. Both the translocation of GR (NR3C1) into mitochondria and the binding of GR to the mtDNA were lower in the liver of HFD mice. The PGC1alpha mRNA expression, protein content, and translocation into mitochondria were also found to be reduced, with the lower GR binding to the promoter region of PGC1alpha in the liver of HFD mice. GR, as a transcription factor, may take an important role in the regulation of mitochondrial oxidative phosphorylation in the HFD mice by interacting with PGC1alpha and controlling mtDNA expression. PMID- 26479080 TI - Recent development in 3D food printing. AB - Robots and software have been significantly improving our daily lives by rendering us much convenience. And 3D printing is a typical example, for it is going to usher in a new era of localized manufacturing that is actually based on digital fabrication by layer-by-layer deposition in three-dimensional space. In terms of food industry, the revolution that three-dimensional printing technologies is bringing to food manufacturing is convenience of low-cost customized fabrication and even precise nutrition control. This paper is aimed to give a brief introduction of recent development of food printing and material property of food ingredients that can be used to design the 3D food matrix and investigate the relationship between process parameters and resulting printed food properties in order to establish a food manufacturing process with this new food production approach. PMID- 26479081 TI - The Role of Routine Biopsy of the Lacrimal Sac During Dacryocystorhinostomy Surgery. AB - PURPOSE: To assess the role of routine histopathological evaluation of the lacrimal sac wall when performing dacryocystorhinostomy (DCR) surgery. METHODS: A retrospective review was conducted of the histology findings in lacrimal sac biopsies, taken routinely, in an external-approach DCR series. This is a single surgeon (RB), single pathologist (AG) consecutive series. The histopathology reports were reviewed and collated. Each patient's medical history and risk factors for malignancy were recorded. The surgeon documented any abnormal lacrimal sac appearance at the time of surgery. RESULTS: No patient in this series of 245, in whom 254 histology specimens were taken, recorded a significant pathological result that was not anticipated from pre-operative assessment, or from the appearance of the lacrimal sac intra-operatively. CONCLUSION: The reported recommendation for routine histopathological evaluation of the lacrimal sac wall when performing DCR surgery is not supported by this consecutive series. The authors recommend histopathological evaluation only in the setting of pre existing clinical suspicion of malignancy, or an abnormal intra-operative appearance of the lacrimal sac. PMID- 26479082 TI - Structure and Properties of Precursor/Successor Complex and Transition State of the FeCl(2+)/Fe(2+) Electron Self-Exchange Reaction via the Inner-Sphere Pathway. AB - The electron self-exchange reaction FeCl(OH2)5(2+) + Fe(OH2)6(2+) -> Fe(OH2)6(2+) + FeCl(OH2)5(2+), proceeding via the inner-sphere pathway, was investigated with quantum chemical methods. Geometry and vibrational frequencies of the precursor/successor complex, (H2O)5Fe(III)ClFe(II)(OH2)5(4+)/(H2O)5Fe(II)ClFe(III)(OH2)5(4+) (P/S), and the transition state, (H2O)5FeClFe(OH2)5(4+?) (TS), were computed with the LC-BOP functional and CPCM hydration. Bent and linear structures were computed for the TS and P/S. The electronic coupling matrix element (Hab) and the electronic energies were calculated with multistate extended general multiconfiguration quasi-degenerate second-order perturbation theory (XGMC-QDPT2) and spin-orbit configuration interaction (SO-CI). Since the Fe...Fe distance changes considerably along the electron transfer step, the transformation P -> TS -> S, equations based on the hypothesis of a fixed donor-acceptor distance cannot be applied. Hence, the rate constant for the electron transfer step (ket) was calculated as described previously (Rotzinger, F. P. Inorg. Chem. 2014, 53, 9923). ket is very fast, ~9.4 * 10(8)-6.6 * 10(9) s(-1) at 0 degrees C. The experimental rate constant of the title reaction (k) is much slower and controlled by the formation of the precursor complex. The substitution of a water ligand by FeCl(OH2)5(2+) at Fe(OH2)6(2+) is rate-determining. PMID- 26479083 TI - Modulation of sensitivity and resistance to multikinase inhibitors by microenvironmental platelet factors in HCC. AB - INTRODUCTION: Response of a tumor to chemotherapy or multikinase inhibitor therapy has been traditionally thought to be a reflection of the sum of the characteristics of both the drug and of the tumor cell resistance mechanisms. More recently, there has been a growing awareness of the role of non-tumor factors-both cellular and humoral-in the tumor microenvironment that can increase or decrease the tumor cellular responses to the therapy. This article focuses on platelet factors in clinical HCC and experimental evidence that they provide growth stimulants that can antagonize the growth inhibitory effects of therapy. AREAS COVERED: Review of the mechanisms of multikinase cancer growth inhibitors and of the role of platelets in providing growth factors that can antagonize their effects. EXPERT OPINION: These new ideas and data show that the response of a tumor to multikinase inhibitors or chemotherapy may be strongly influenced by microenvironmental factors. Conversely, antagonists to these environmental factors, such as EGFR inhibitors and IGF1-R inhibitors, might be expected to augment the anti-tumor effect of both chemotherapy and multikinase inhibitors. PMID- 26479085 TI - Observation of Plasmon Wave Packet Motions via Femtosecond Time-Resolved Near Field Imaging Techniques. AB - The generation and dynamics of plasmon wave packets in single gold nanorods were observed at a spatiotemporal scale of 100 nm and 10 fs via time-resolved near field optical microscopy. Following simultaneous excitation of two plasmon modes of a nanorod with an ultrashort near-field pulse, a decay and revival feature of the time-resolved signal was obtained, which reflected the reciprocating motion of the wave packet. The time-resolved near-field images were also indicative of the wave packet motion. At some period of time after the excitation, the spatial features of the two modes appeared alternately, showing motion of plasmonic wave crests along the rod. The wave packet propagation was clearly demonstrated from this observation with the aid of a simulation model. The present experimental scheme opens the door to coherent control of plasmon-induced optical fields in a nanometer spatial scale and femtosecond temporal scale. PMID- 26479084 TI - What we talk about when we talk about NICUs: infants' acuity and nurse staffing. AB - OBJECTIVE: Organizational features of neonatal intensive care influence the care of sick neonates. We estimated the acuity-adjusted nurse-to-patient ratio (NPR) in a national sample of Italian NICUs and factors influencing it. METHODS: Twelve monthly cross-sectional surveys were prospectively carried out in 63 NICUs. Number and acuity of infants, and number of nurses were recorded. Infants' acuity was assessed by Rogowki's 2013 and British Association for Perinatal Medicine 2001 classifications. RESULTS: We collected 702 reports regarding 11 082 infants. Non-intensive infants represented about 75% of NICU residents. Very preterm infants (<1501 g birth weight or <30 weeks gestation) represented 10.8% of admissions, but 44% of all infants surveyed. Average acuity-adjusted NPR was 0.31 (interquartile range 0.28-0.38); NPR depended on case-mix (proportion of intensive infants), size of the unit (larger units had a lower NPR) and was higher during morning shifts (+18%). Clustering on hospitals, reflecting shared components within each hospital, explained 47% of the variability of NPR. CONCLUSIONS: The majority of infants cared for in NICUs are not intensive. NPR is influenced by acuity of infants, size of units, shifts, but is largely due to other unobserved hospital-related organizational features. PMID- 26479086 TI - Solution-Processed Small-Molecule Bulk Heterojunctions: Leakage Currents and the Dewetting Issue for Inverted Solar Cells. AB - In organic photovoltaic (PV) devices based on solution-processed small molecules, we report here that the physicochemical properties of the substrate are critical for achieving high-performances organic solar cells. Three different substrates were tested: ITO coated with PEDOT: PSS, ZnO sol-gel, and ZnO nanoparticles. PV performances are found to be low when the ZnO nanoparticles layer is used. This performance loss is attributed to the formation of many dewetting points in the active layer, because of a relatively high roughness of the ZnO nanoparticles layer, compared to the other layers. We successfully circumvented this phenomenon by adding a small quantity of polystyrene (PS) in the active layer. The introduction of PS improves the quality of film forming and reduces the dark currents of solar cells. Using this method, high-efficiency devices were achieved, even in the case of substrates with higher roughness. PMID- 26479087 TI - Structure-Free Validation of Residual Dipolar Coupling and Paramagnetic Relaxation Enhancement Measurements of Disordered Proteins. AB - Residual dipolar couplings (RDCs) and paramagnetic relaxation enhancements (PREs) have emerged as valuable parameters for defining the structures and dynamics of disordered proteins by nuclear magnetic resonance (NMR) spectroscopy. Procedures for their measurement, however, may lead to conformational perturbations because of the presence of the alignment media necessary for recording RDCs, or of the paramagnetic groups that must be introduced for measuring PREs. We discuss here experimental methods for quantifying these effects by considering the case of the 40-residue isoform of the amyloid beta peptide (Abeta40), which is associated with Alzheimer's disease. By conducting RDC measurements over a range of concentrations of certain alignment media, we show that perturbations arising from transient binding of Abeta40 can be characterized, allowing appropriate corrections to be made. In addition, by using NMR experiments sensitive to long range interactions, we show that it is possible to identify relatively nonperturbing sites for attaching nitroxide radicals for PRE measurements. Thus, minimizing the conformational perturbations introduced by RDC and PRE measurements should facilitate their use for the rigorous determination of the conformational properties of disordered proteins. PMID- 26479088 TI - Drift from the Use of Hand-Held Knapsack Pesticide Sprayers in Boyaca (Colombian Andes). AB - Offsite pesticide losses in tropical mountainous regions have been little studied. One example is measuring pesticide drift soil deposition, which can support pesticide risk assessment for surface water, soil, bystanders, and off target plants and fauna. This is considered a serious gap, given the evidence of pesticide-related poisoning in those regions. Empirical data of drift deposition of a pesticide surrogate, Uranine tracer, within one of the highest potato producing regions in Colombia, characterized by small plots and mountain orography, is presented. High drift values encountered in this study reflect the actual spray conditions using hand-held knapsack sprayers. Comparison between measured and predicted drift values using three existing empirical equations showed important underestimation. However, after their optimization based on measured drift information, the equations showed a strong predictive power for this study area and the study conditions. The most suitable curve to assess mean relative drift was the IMAG calculator after optimization. PMID- 26479089 TI - Migrant Workers in Agriculture: A View from Thailand. AB - There has been a dramatic increase in the global movement of workers during the last few decades. As Thailand has developed rapidly over the past 20 years, it has attracted laborers (both authorized and unauthorized) from the neighboring countries of Myanmar, People's Democratic Republic of Lao (Lao PDR), and Cambodia. Given that agriculture has been Thailand's most important industry, its continued growth has been dependent on migrant workers. Both crop agriculture and animal-production agriculture have employed migrant labor. Migrants have been hired to plant, weed, fertilize, spray pesticides, and harvest crops such as rice, corn, sugar cane, and cassava. They have worked at rubber and coffee plantations, as well as in the production of ornamental crops. Also, migrants have labored on pig, beef, and duck farms. There have been numerous documented health problems among migrant workers, including acute diarrhea, malaria, and fever of unknown causes. Occupational illness and injury have been a significant concern, and there has been limited health and safety training. This article reviewed the demographic changes in Thailand, studied the agricultural crops and animal production that are dependent on migrant labor, discussed the health status and safety challenges pertaining to migrant workers in agriculture, and described several recommendations. Among the recommendations, the conclusions of this study have suggested that addressing the cost for health care and solutions to health care access for migrant labor are needed. PMID- 26479090 TI - Do Patients Want to Participate in Decisions About Their Own Medical Care? PMID- 26479091 TI - Placebo Effects and Informed Consent. AB - The concepts of placebos and placebo effects refer to extremely diverse phenomena. I recommend dissolving the concepts of placebos and placebo effects into loosely related groups of specific mechanisms, including (potentially among others) expectation-fulfillment, classical conditioning, and attentional-somatic feedback loops. If this approach is on the right track, it has three main implications for the ethics of informed consent. First, because of the expectation-fulfillment mechanism, the process of informing cannot be considered independently from the potential effects of treatment. Obtaining informed consent influences the effects of treatment. This provides support for the authorized concealment and authorized deception paradigms, and perhaps even for outright deceptive placebo use. Second, doctors may easily fail to consider the potential benefits of conditioning, leading them to misjudge the trade-off between beneficence and autonomy. Third, how attentional-somatic feedback loops play out depends not only on the content of the informing process but also on its framing. This suggests a role for libertarian paternalism in clinical practice. PMID- 26479092 TI - Placebos, Full Disclosure, and Trust: The Risks and Benefits of Disclosing Risks and Benefits. PMID- 26479093 TI - Placebo, Nocebo, Informed Consent, and Moral Technologies. PMID- 26479094 TI - Informed Consent: Hints From Placebo and Nocebo Research. PMID- 26479095 TI - Dealing With Placebo Effects: A Plea to Take Into Account Contextual Factors. PMID- 26479096 TI - Destigmatising the Placebo Effect. PMID- 26479097 TI - Authorized Concealment and Authorized Deception: Well-Intended Secrets Are Likely to Induce Nocebo Effects. PMID- 26479098 TI - Clinical Placebo Can Be Defined Positively: Implications for Informed Consent. PMID- 26479099 TI - Doctors, Patients, and Nudging in the Clinical Context--Four Views on Nudging and Informed Consent. AB - In an analysis of recent work on nudging we distinguish three positions on the relationship between nudging founded in libertarian paternalism and the protection of personal autonomy through informed consent. We argue that all three positions fail to provide adequate protection of personal autonomy in the clinical context. Acknowledging that nudging may be beneficial, we suggest a fourth position according to which nudging and informed consent are valuable in different domains of interaction. PMID- 26479100 TI - A Philosophical Misunderstanding at the Basis of Opposition to Nudging. PMID- 26479101 TI - On Nudging and Informed Consent. PMID- 26479102 TI - Evidence-Based Nudging: Best Practices in Informed Consent. PMID- 26479103 TI - In Defense of Nudge-Autonomy Compatibility. PMID- 26479104 TI - Are There Public Health Domains in "Domain-Specific" Health Nudging? PMID- 26479105 TI - When Aid Is a Good Thing: Trusting Relationships as Autonomy Support in Health Care Settings. PMID- 26479106 TI - Good Arguments, Wrong Target: Equivalence and the Compatibilist View. PMID- 26479107 TI - The Ethical Merits of Nudges in the Clinical Setting. PMID- 26479108 TI - Recontact and Recruitment of Young Adults Previously Enrolled in Neonatal Herpes Simplex Virus Research. PMID- 26479110 TI - A Knotty Problem of Intertwined Rights. PMID- 26479109 TI - Research Recruitment of Adult Survivors of Neonatal Infections: Is There a Role for Parental Consent? PMID- 26479111 TI - Consent Is the Cornerstone of Ethically Valid Research: Ethical Issues in Recontacting Subjects Who Enrolled in Research as a Minor. PMID- 26479112 TI - Is It Ethical to Enroll Cognitively Impaired Adults in Research That Is More Than Minimal Risk With No Prospect of Benefit? PMID- 26479113 TI - Inconsistent Approaches to Research Involving Cognitively Impaired Adults: Why the Broad View of Substituted Judgment Is Our Best Guide. PMID- 26479114 TI - Ethical and Regulatory Considerations Regarding Enrollment of Incompetent Adults in More Than Minimal Risk Research as Compared With Children. PMID- 26479115 TI - Acceptable Approaches to Enrolling Adults Who Cannot Consent in More Than Minimal Risk Research. PMID- 26479116 TI - Response to Open Peer Commentaries on "Placebo Effects and Informed Consent". PMID- 26479118 TI - Pd Nanoparticle Formation in Ionic Liquid Thin Films Monitored by in situ Vibrational Spectroscopy. AB - Ionic liquids (ILs) are flexible reaction media and solvents for the synthesis of metal nanoparticles (NPs). Here, we describe a new preparation method for metallic NPs in nanometer thick films of ultraclean ILs in an ultrahigh vacuum (UHV) environment. CO-covered Pd NPs are formed by simultaneous and by sequential physical vapor deposition (PVD) of the IL and the metal in the presence of low partial pressures of CO. The film thickness and the particle size can be controlled by the deposition parameters. We followed the formation of the NPs and their thermal behavior by time-resolved IR reflection absorption spectroscopy (TP IRAS) and by temperature-programmed IRAS (TR-IRAS). Codeposition of Pd and [C1C2Im][OTf] in CO at 100 K leads to the growth of homogeneous multilayer films of CO-covered Pd aggregates in an IL matrix. The size of these NPs can be controlled by the metal fraction in the co-deposit. With increasing metal fraction, the size of the Pd NPs also increases. At very low metal content, small Pd carbonyl-like species are formed, which bind CO in on-top geometry only. Upon annealing, the [OTf](-) anion coadsorbs at the NP surface and partially displaces CO. Co-adsorption of CO and IL is indicated by a strong red-shift of the CO stretching bands. While the weakly bound on-top CO is mainly replaced below the melting transition of the IL, coadsorbate shells with bridge-bonded CO and IL are stable well above the melting point. Larger three-dimensional Pd NPs can be prepared by PVD of Pd onto a solid [C1C2Im][OTf] film at 100 K. Upon annealing, on-top CO desorbs from these NPs below 200 K. Upon melting of the IL film, the CO covered Pd NPs immerse into the IL and again form a stable coadsorbate shell that consists of bridge-bonded CO and the IL. PMID- 26479119 TI - Thionine-Modified Poly(glycidyl methacrylate) Nanospheres as Labels of Antibodies for Biosensing Applications. AB - Monodisperse poly(glycidyl methacrylate) (PGMA) nanospheres were obtained by emulsifier-free emulsion polymerization and characterized by physicochemical methods. The effects of various reaction parameters on the particle properties were investigated. The particle size was controlled in the range of 350-420 nm. To introduce carboxyl groups, the PGMA nanospheres were hydrolyzed and oxidized with KMnO4. Subsequently, the enzyme horseradish peroxidase (HRP) and the electron mediator thionine were covalently attached to the PGMA nanospheres to obtain an antibody indicator suitable for enzyme-based electrochemical immunosensors. Combined HRP and thionine binding to the nanospheres had beneficial effects for the labeling efficiency and at the same time prevented the formation of soluble electron mediators. PMID- 26479120 TI - Comparison of health behaviors among women brothel workers to those of the general population of women in Denmark. AB - Previous research on behavioral risk factors for illness among sex workers has been limited and based on mixed, poorly defined groups of sex workers. The aim of the present study was to compare the health behaviors and weight of women brothel workers with women in the general population in Denmark. Logistic regression analyses were used to compare data from eighty-eight women working in brothels in 2010 with data from 3,225 women of similar age from the nationally representative Danish Health Survey 2010. Compared to Danish women, the prevalence of daily and heavy smoking was higher among brothel workers, but the prevalence of wanting to quit smoking was lower. The prevalence rates of exceeding the Danish high-risk level of alcohol consumption, binge drinking, and illicit drug use were higher among women brothel workers compared to Danish women. The prevalence of underweight was higher and overweight and obesity lower among brothel workers compared to Danish women. These differences were significant when adjusted for age and educational level. Few differences were noted regarding dietary habits and no differences regarding physical activity. Findings suggest the need for health-promotion initiatives, particularly for smoking, alcohol consumption, and drug use, targeted at women brothel workers. PMID- 26479121 TI - Analysis of waste management issues arising from a field study evaluating decontamination of a biological agent from a building. AB - The Bio-response Operational Testing and Evaluation (BOTE) Project was a cross government effort designed to operationally test and evaluate a response to a biological incident (release of Bacillus anthracis [Ba] spores, the causative agent for anthrax) from initial public health and law enforcement response through environmental remediation. The BOTE Project was designed to address site remediation after the release of a Ba simulant, Bacillus atrophaeus spp. globigii (Bg), within a facility, drawing upon recent advances in the biological sampling and decontamination areas. A key component of response to a biological contamination incident is the proper management of wastes and residues, which is woven throughout all response activities. Waste is generated throughout the response and includes items like sampling media packaging materials, discarded personal protective equipment, items removed from the facility either prior to or following decontamination, aqueous waste streams, and materials generated through the application of decontamination technologies. The amount of residual contaminating agent will impact the available disposal pathways and waste management costs. Waste management is an integral part of the decontamination process and should be included through "Pre-Incident" response planning. Overall, the pH-adjusted bleach decontamination process generated the most waste from the decontamination efforts, and fumigation with chlorine dioxide generated the least waste. A majority of the solid waste generated during pH-adjusted bleach decontamination was the nonporous surfaces that were removed, bagged, decontaminated ex situ, and treated as waste. The waste during the two fumigation rounds of the BOTE Project was associated mainly with sampling activities. Waste management activities may represent a significant contribution to the overall cost of the response/recovery operation. This paper addresses the waste management activities for the BOTE field test. IMPLICATIONS: Management of waste is a critical element of activities dealing with remediation of buildings and outdoor areas following a biological contamination incident. Waste management must be integrated into the overall remediation process, along with sampling, decontamination, resource management, and other important response elements, rather than being a stand-alone activity. The results presented in this paper will provide decision makers and emergency planners at the federal/state/tribal/local level information that can be used to integrate waste management into an overall systems approach to planning and response activities. PMID- 26479122 TI - Neuroproteomics and microRNAs studies in multiple sclerosis: transforming research and clinical knowledge in biomarker research. AB - Multiple sclerosis (MS) is a complex disease characterized by extensive phenotypic variability. Biomarkers to capture the different aspects of MS heterogeneity, and to help make a diagnosis and monitor disease progression, while providing insights into etiopathogenesis and response to treatment, are urgently needed. Omics technologies and research efforts with microRNAs have provide unparalleled opportunities for exploring altered protein profiles associated with molecular mechanisms of disease, substantially expanding the list of candidate biomarkers for MS. This review presents evidence from proteomic studies that have focused on identification of biomarkers released in biofluids as a result of the different pathophysiological processes of MS. Also discussed is the emerging role of miRNAs as complementary biomarkers related to cellular processes occurring in MS patients. Also provided is an overview of candidate biomarkers that have been proposed for elucidating pathophysiological processes and disease activity and for guiding clinical diagnosis and/or therapeutic interventions in MS. PMID- 26479123 TI - A Prospective, Multicentered Study to Assess Social Adjustment in Patients With an Intestinal Stoma in Turkey. AB - Patients with a stoma undergo physiological, psychological, and social adjustment to their new life situation. A descriptive, prospective study was conducted to assess adaptation among patients >18 years of age with a new temporary or permanent colostomy or ileostomy living in Turkey and receiving care at a participating stomatherapy unit. The study took place between September 1, 2011, and September 1, 2012. During hospitalization and following discharge, patients with a stoma received training and counseling according to their individual characteristics and their physiological, psychological, and social needs. Each participant completed the 19-item "Identification Form for Patients with a Stoma" at the beginning of the study to document sociodemographic and stoma characteristics. To assess adjustment to the stoma, The Ostomy Assessment Inventory (OAI-23) was administered 2 times - the first within 1 month and the second within 6 months after surgery or when a temporary stoma was closed (whichever came first). This instrument comprised 23 items regarding adaptation to the stoma using Likert-type response options (0-4 range). Total scores ranged from 10 to 92, with higher scores indicating better adjustment. The instruments were completed by stoma and wound care nurses during face-to-face interviews. Data were analyzed using the Kruskal-Wallis, Mann-Whitney, and Wilcoxon tests. Of the 135 participants, the majority (77, 57.0%) were male; 73 (54.1%) had a colostomy, and 106 (78.5%) had a temporary stoma. The primary reason for stoma creation was cancer (89, 65.9%). Mean total OAI-23 scores were 48.63 +/- 13.75 at the first administration and 50.59 +/- 13.89 for the second. In terms of sociodemographic factors, significant increases in mean scores from the first to the second survey time were noted among patients in the 50-69 age group, women, married persons, and unemployed persons (P less than 0.05). With regard to stoma characteristics, the OAI-23 scores of patients with planned stoma operations and persons with permanent stomas increased significantly (P less than 0.05) between assessments. Significant increases in OAI-23 scores also were noted among persons who did not receive information before the operation, patients whose stoma site was not marked, and patients who had experienced a complication (P less than 0.05). Postoperatively, it is important to consider sociodemographic and stoma characteristics as well as preoperative variables that may influence adaptation to stoma. Additional larger, multicentered studies with extended patient follow up are warranted. PMID- 26479124 TI - Use of a Dehydrated Amniotic Membrane Allograft on Lower Extremity Ulcers in Patients with Challenging Wounds: A Retrospective Case Series. AB - Lower extremity ulcers in patients with diabetes mellitus may take a long time to heal despite the use of advanced topical therapies. A retrospective review of cases was conducted to assess the use of a dehydrated amniotic membrane allograft (DAMA) in a convenience sample of 9 wounds in 8 patients (5 men, 3 women, average age 62 years [range 31-81 years]) with diabetes mellitus and/or vascular disease. Wound data and patient characteristics were abstracted from medical records. Descriptive statistics were used to summarize the data. In 5 of 9 wounds, DAMA was applied after a failure to demonstrate a 50% reduction in area after 4 weeks of treatment with advanced wound care, offloading, and compression as indicated. In 4 wounds, DAMA was applied 2-4 weeks after presentation because of concerns about existing patient risk factors for nonhealing. Wounds were present for an average of 11 weeks (range 1-35 weeks) before application of DAMA. Mean baseline wound area and volume were 3.11 cm2 (+/- 3.73) and 0.55 cm3 (+/- 0.58), respectively. All wounds healed in an average of 5.7 (+/- 2.9) weeks (range: 1-9 weeks) after a mean of 2.7 applications (+/- 1.7) (range 1-5 applications). No adverse events occurred. These observations suggest prospective, randomized, controlled clinical studies to compare the use of DAMA to other topical treatment modalities are warranted. PMID- 26479125 TI - Non-transfusion-dependent thalassemia and thalassemia intermedia: epidemiology, complications, and management. AB - OBJECTIVE: The non-transfusion-dependent thalassemias (NTDTs), including thalassemia intermedia (TI), hemoglobin E beta thalassemia, and hemoglobin H disease, have sometimes been regarded as less severe than their transfusion dependent variants; however, these disorders carry a substantial disease burden (e.g., splenomegaly, iron overload, skeletal effects, and cardiopulmonary disease). The aim of this review is to increase clinician awareness of the growing global problem of NTDT and TI, and discuss the current management strategies for these conditions. METHODS: Recent peer-reviewed articles (publication years 2000 through 2015) addressing the epidemiology, complications, management, and monitoring of NTDT were identified in the PubMed database and reviewed. RESULTS: The changing epidemiology of thalassemia constitutes a growing health problem. Increased clinician awareness is necessary for the appropriate diagnosis and management of patients with NTDT. CONCLUSIONS: Management of NTDT requires a comprehensive approach, beginning with screening and prenatal diagnosis, monitoring for iron overload and associated complications, and iron chelation therapy. Several novel strategies are in the early stages of investigation and may help increase treatment options in patients with NTDT. Importantly, ethnic or cultural barriers may exist within the affected populations and need to be considered in the management approach. PMID- 26479126 TI - Prevalence of mental health conditions after military blast exposure, their co occurrence, and their relation to mild traumatic brain injury. AB - PRIMARY OBJECTIVES: To measure common psychiatric conditions after military deployment with blast exposure and test relationships to post-concussion syndrome (PCS) symptoms and mild traumatic brain injury (mTBI) history. RESEARCH DESIGN: Cross-sectional. METHODS AND PROCEDURES: Service members or Veterans (n = 107) within 2 years of blast exposure underwent structured interviews for mTBI, post traumatic stress disorder (PTSD) and multiple mood and anxiety diagnoses. MAIN OUTCOMES AND RESULTS: MTBI history and active PTSD were both common, additionally 61% had at least one post-deployment mood or anxiety disorder episode. Psychiatric diagnoses had a high degree of comorbidity. Most dramatically, depression was 43-times (95% CI = 11-165) more likely if an individual had PTSD. PCS symptoms were greater in those with post-deployment PTSD or mood diagnosis. However, neither mTBI nor blast exposure history had an effect on the odds of having PTSD, mood or anxiety condition. CONCLUSIONS: These findings support that psychiatric conditions beyond PTSD are common after military combat deployment with blast exposure. They also highlight the non-specificity of post-concussion type symptoms. While some researchers have implicated mTBI history as a contributor to post-deployment mental health conditions, no clear association was found. This may partly be due to the more rigorous method of retrospective mTBI diagnosis determination. PMID- 26479127 TI - The multifaceted role of nitric oxide synthases in mitochondrial biogenesis and cell differentiation. AB - Nitric oxide (NO) is physiologically synthetized by a family of enzymes called NO synthases (NOSs). NO is a pleiotropic second messenger having a fundamental role in several cellular processes including cell differentiation. Being a high reactive molecule, NO must be synthetized in close proximity to the effector/target. For this reason, the subcellular localization of NOSs is tightly regulated by different post-translation mechanisms. Recently, in murine C2C12 myoblasts, we have demonstrated that mitochondrial biogenesis, an essential event for cell differentiation, can be effective only if the site of NO production is located at nuclear level, where NO favors the CREB-dependent expression of PGC 1alpha gene. The increase of NO flux in nuclei is elicited by the up-regulation and redistribution of neuronal NOS (nNOS) toward nuclei. Herein we show that an upregulation of endothelial NOS (eNOS) occurs during adipocyte differentiation in 3T3-L1 cells. However, differently to differentiating myocytes, a concomitant redistribution of eNOS toward nuclei was not detected. We also observed that, upon treatment with the NO synthesis inhibitor L-NAME, mitochondrial biogenesis as well as triglyceride accumulation that normally occurs during adipogenesis were not impeded. The absence of eNOS in nuclei together with the ineffectiveness of L-NAME suggest that, at least during 3T3-L1 differentiation, NO is not fundamental for the induction of mitochondrial biogenesis and adipogenesis. PMID- 26479128 TI - Member Perspectives on the Role of BDSM Communities. AB - Bondage-discipline/Dominance-submission/sadomasochism (BDSM) is an often misunderstood and misrepresented social phenomenon warranting further discourse and study. Community-based research that engages member perspective can assist in understanding socially marginalized experiences. The current study examined the role, meaning, and function of BDSM communities from the perspective of self identified members. Seven nominal group technique workshops were conducted representing a variety of practitioner experiences and identities. Workshops involved 48 participants and resulted in the generation of 133 unique terms describing the role of BDSM communities in their lives. Terms were coded using a five-step procedure involving both academic and community members. A total of 15 categories were identified and included domains such as acceptance, sexual expression, friendship, safety, and sharing of educational knowledge. Results underscore the multifaceted nature of the role of such communities. While results consisted of mostly positive features, participants also identified certain negative aspects, such as conflict among members. Results from the study provide a succinct, member-derived, structured inventory of the role of BDSM communities that can serve to validate and synthesize existing research, improve dissemination of community voice around BDSM, and inform future research. We conclude with a discussion of the study's implications for sex education, clinical practice, and community dissemination. PMID- 26479130 TI - Spectrum of Smoking-related Lung Diseases: Imaging Review and Update. AB - There is increased awareness of smoking-related lung diseases other than lung cancer and chronic obstructive pulmonary disease. Concurrently, there is general acceptance that there is difficulty in establishing a specific diagnosis of smoking-related interstitial lung disease (ILD), as many patients may not undergo biopsy to facilitate a specific histopathologic diagnosis. Cases that do proceed to biopsy may demonstrate multiple abnormalities, and histologic overlap between different disease processes may confound the picture. This review outlines the key aspects of smoking-related lung disease, including entities secondary to smoking-related lung inflammation such as respiratory bronchiolitis-ILD, desquamative idiopathic pneumonia, and pulmonary Langerhans cell histiocytosis, as well as chronic fibrosing lung diseases strongly associated with cigarette smoke including idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema, nonspecific interstitial pneumonia, and rheumatoid arthritis-ILD. The focus will be on incorporation of clinical findings, key pulmonary function testing parameters, high-resolution computer tomography (HRCT) findings, and pathologic correlates in refining the differential diagnosis and differentiating between the various entities. PMID- 26479131 TI - Multidisciplinary Approach to Hypersensitivity Pneumonitis. AB - Hypersensitivity pneumonitis (HP) may be a challenging diagnosis given the wide variability of its clinical, radiographic, and pathologic manifestations. A multidisciplinary approach to diagnosis is critical in maintaining a high specificity for HP. An in-depth knowledge of all 3 arms of the multidisciplinary approach helps clinicians, radiologists, and pathologists interpret their own findings in the context of the entire presentation. In some cases, the combination of clinical findings (ie, an identifiable exposure) and typical findings on high-resolution computed tomography is considered diagnostic of HP, and pathologic confirmation is not necessary. As many as 50% of patients do not have a clear exposure, however. These patients may be difficult to distinguish from idiopathic disorders. In these cases, high-resolution computed tomography and pathology are the primary data points that may suggest the correct diagnosis. The goal of this paper is to discuss recent advances in HP and to present the spectrum of clinical, radiographic, and pathologic findings. PMID- 26479129 TI - Carvedilol Suppresses Apoptosis and Ion Channel Remodelling of HL-1 Cardiac Myocytes Expressing E334K cMyBPC. AB - BACKGROUND: Besides its antiarrhythmic action, carvedilol has an activity to suppress cardiac tissue damage. However, it is unknown whether it has any effect on cellular apoptosis and ion channel remodelling. PURPOSE: To know whether carvedilol has any effect on apoptosis and ion channel remodeling of HL-1 cells expressing E334K MyBPC, and comparing it with bisoprolol. METHOD: We examined effects of carvedilol and bisoprolol on the levels of pro- and anti-apoptotic proteins and ion channels as well as apoptosis of HL-1 cells transfected with E334K MyBPC using Western blot and flow cytometry. RESULTS: Carvedilol decreased the protein levels of p53, Bax and cytochrome c and increased that of Bcl-2 in HL 1 cells expressing E334K MyBPC. Bisoprolol failed to affect the protein levels. Both carvedilol and bisoprolol increased the protein levels of Cav1.2 but not that of Nav1.5. Carvedilol was stronger than bisoprolol at decreasing the number of annexin-V positive cells in HL-1 cells expressing E334K MyBPC. CONCLUSION: Carvedilol suppressed apoptosis of HL-1 cells expressing E334K MyBPC through modification of pro- and anti-apoptotic proteins, whose was associated with an increase of Cav 1.2 protein expression. PMID- 26479133 TI - The Experience of Being a Guide Dog Puppy Raiser Volunteer: A Longitudinal Qualitative Collective Case Study. AB - There are no published studies that consider the experiences of guide dog puppy raisers. As these people are volunteers, their continued willingness to participate in the training of dogs for assisting the vision impaired and blind is essential for the viability of guide dog schools around the world. Using a qualitative, longitudinal methodology, data were collected from nine guide dog puppy raisers at four time points: before receiving the puppy, one week, then three months after the puppy arrived, and 13 months after the puppy arrived (at which time all puppies had left the raisers). Participants reported more challenges than benefits in raising the puppies. Volunteering to be a guide dog puppy raiser may not be the pleasant experience that is anticipated when community members first offer their services. Understanding what it is like to be a puppy raiser and working towards ways in which to address problems is essential, given that, without volunteers to train and care for puppies, vision impaired and blind people would not have access to guide dogs. PMID- 26479132 TI - A comparative evaluation of self-report and biological measures of cigarette use in nondaily smokers. AB - A large subset of individuals who smoke cigarettes do not smoke regularly, but the assessments used to collect data on cigarette consumption in nondaily smokers have not been rigorously evaluated. The current study examined several self report and biomarker approaches to the assessment of cigarette use in a sample of nondaily smokers (n = 176). Participants were randomly assigned to a daily monitoring condition (n = 89), requiring a daily report of the number of cigarettes smoked in the previous 24 hours, or a no monitoring condition (n = 87). Number of cigarettes smoked over the first 28 days of the study was assessed using 2 quantity frequency measures, a graduated frequency measure, and a timeline follow back (TLFB) interview at the Session 5 study visit. Hair nicotine (NIC), hair cotinine (COT), and expired-air carbon monoxide (CO) were collected from each participant. Total cigarettes reported via daily report were strongly correlated with all Session 5 measures of total cigarettes, but were most strongly associated with TLFB total cigarettes. Collapsed CO across 5 sessions was the biomarker most strongly correlated with daily report total cigarettes. The results support the use of daily report and TLFB methods of assessing cigarette use in nondaily smokers. Results also support the use of CO as appropriate biological markers of exposure in nondaily smokers, and point to some limitations in the use of hair biomarkers in this population. (PsycINFO Database Record PMID- 26479134 TI - Loading and Unloading Finishing Pigs: Effects of Bedding Types, Ramp Angle, and Bedding Moisture. AB - The use of non-slip surfaces during loading and unloading of finishing pigs plays an important role in animal welfare and economics of the pork industry. Currently, the guidelines available only suggest the use of ramps with a slope below 20 degrees to load and unload pigs. However, the total time it takes to load and unload animals and slips, falls, and vocalizations are a welfare concern. Three ramp angles (0, 10 or 20 degrees), five bedding materials (nothing, sand, feed, wood shavings or wheat straw hay), two moistures (dry or wet bedding, >50% moisture) over two seasons (>23.9 degrees C summer, <23.9 degrees C winter) were assessed for slips/falls/vocalizations (n = 2400 pig observations) and analyzed with a scoring system. The use of bedding during summer or winter played a role in the total time it took to load and unload the ramp (p < 0.05). Bedding, bedding moisture, season, and slope significantly interacted to impact the total time to load and unload finishing pigs (p < 0.05). Heart rate and the total time it took to load and unload the ramp increased as the slope of the ramp increased (p < 0.05). Heart rates were higher during the summer than winter, and summer heart rates increased as the slope increased (p < 0.05). The current study suggests that several factors should be considered in combination to identify the appropriate bedding for the specific occasion. PMID- 26479135 TI - Selecting a Conservation Surrogate Species for Small Fragmented Habitats Using Ecological Niche Modelling. AB - Flagship species are traditionally large, charismatic animals used to rally conservation efforts. Accepted flagship definitions suggest they need only fulfil a strategic role, unlike umbrella species that are used to shelter cohabitant taxa. The criteria used to select both flagship and umbrella species may not stand up in the face of dramatic forest loss, where remaining fragments may only contain species that do not suit either set of criteria. The Cinderella species concept covers aesthetically pleasing and overlooked species that fulfil the criteria of flagships or umbrellas. Such species are also more likely to occur in fragmented habitats. We tested Cinderella criteria on mammals in the fragmented forests of the Sri Lankan Wet Zone. We selected taxa that fulfilled both strategic and ecological roles. We created a shortlist of ten species, and from a survey of local perceptions highlighted two finalists. We tested these for umbrella characteristics against the original shortlist, utilizing Maximum Entropy (MaxEnt) modelling, and analysed distribution overlap using ArcGIS. The criteria highlighted Loris tardigradus tardigradus and Prionailurus viverrinus as finalists, with the former having highest flagship potential. We suggest Cinderella species can be effective conservation surrogates especially in habitats where traditional flagship species have been extirpated. PMID- 26479137 TI - Evaluating the Age-Dependent Potential for Protein Deposition in Naked Neck Meat Type Chicken. AB - The introduction of the naked neck gene (Na) into modern meat type chicken is known to be helpful in increasing the tolerance for a high ambient temperature (AT) by reducing the feather coverage which allows for a higher level of heat dissipation compared to normally feathered (na/na) birds. In addition, reduced feather coverage could affect requirements for sulfur containing amino acids. As a prerequisite for further modeling of individual amino acid requirements, the daily N maintenance requirement (NMR) and the threshold value of daily N retention (NRmaxT) were determined. This was carried out using graded dietary protein supply and exponential modeling between N intake (NI) and N excretion (NEX) or N deposition (ND), respectively. Studies with homozygous (Na/Na) and heterozygous (Na/na) naked neck meat type chicken utilized 144 birds of average weight (50% of each genotype and sex) within two N balance experiments during both the starter (days 10-20) and the grower period (days 25-35). Birds were randomly allotted to five diets with graded dietary protein supply but constant protein quality. The observed estimates depending on genotype, sex and age varied for NMR and NRmaxT from 224 to 395 and 2881 to 4049 mg N/BWkg(0.67)/day, respectively. PMID- 26479136 TI - Pet Food Palatability Evaluation: A Review of Standard Assay Techniques and Interpretation of Results with a Primary Focus on Limitations. AB - The pet food industry continues to grow steadily as a result of new innovative products. Quality control and product development tests for pet foods are typically conducted through palatability testing with dogs and cats. Palatability is the measure of intake of a food that indicates acceptance or the measure of preference of one food over another. Pet food palatability is most commonly measured using a single-bowl or a two-bowl assay. While these tests answer some questions about the animals' perception of the food, there are many limitations as well. This review addresses some of these limitations and indicates opportunities for future research. PMID- 26479138 TI - Modification of the Feline-AlityTM Assessment and the Ability to Predict Adopted Cats' Behaviors in Their New Homes. AB - It is estimated that 2.5 million cats enter animal shelters in the United States every year and as few as 20% leave the shelter alive. Of those adopted, the greatest risk to post-adoption human animal bond is unrealistic expectations set by the adopter. The ASPCA((r))'s Meet Your Match((r)) Feline-alityTM adoption program was developed to provide adopters with an accurate assessment of an adult cat's future behavior in the home. However, the original Feline-alityTM required a three-day hold time to collect cat behaviors on a data card, which was challenging for some shelters. This research involved creating a survey to determine in-home feline behavior post adoption and explored the predictive ability of the in-shelter assessment without the data card. Our results show that the original Feline-alityTM assessment and our modified version were predictive of feline behavior post adoption. Our modified version also decreased hold time for cats to one day. Shelters interested in increasing cat adoptions, decreasing length of stay and improving the adoption experience can now implement the modified version for future feline adoption success. PMID- 26479139 TI - Maintenance Energy Requirements of Double-Muscled Belgian Blue Beef Cows. AB - Sixty non-pregnant, non-lactating double-muscled Belgian Blue (DMBB) cows were used to estimate the energy required to maintain body weight (BW). They were fed one of three energy levels for 112 or 140 days, corresponding to approximately 100%, 80% or 70% of their total energy requirements. The relationship between daily energy intake and BW and daily BW change was developed using regression analysis. Maintenance energy requirements were estimated from the regression equation by setting BW gain to zero. Metabolizable and net energy for maintenance amounted to 0.569 +/- 0.001 and 0.332 +/- 0.001 MJ per kg BW(0.75)/d, respectively. Maintenance energy requirements were not dependent on energy level (p > 0.10). Parity affected maintenance energy requirements (p < 0.001), although the small numerical differences between parities may hardly be nutritionally relevant. Maintenance energy requirements of DMBB beef cows were close to the mean energy requirements of other beef genotypes reported in the literature. PMID- 26479140 TI - The Choice of Diet Affects the Oral Health of the Domestic Cat. AB - In this cross-sectional study, the gingivitis and the calculus indices of the teeth of N = 41 cats were used to model oral health as a dependent variable using a Poisson regression. The independent variables used were "quadrant", "teeth type", "age", and "diet". Teeth type (p < 0.001) and diet (p < 0.001) were found to be significant, however, age was not (p > 0.05). Interactions were all significant: age x teeth (p < 0.01), age * diet (p < 0.01), teeth * diet (p < 0.001), and teeth * age * diet (p < 0.001). The probability of poor oral health is lower in the incisors of young or adult cats, fed a dry diet in comparison to the cheek teeth of older cats fed a wet diet. Diet has a higher contribution to poor oral health than age. It is argued that cats' oral health may be promoted with an early age hygiene of the cheek teeth and with provision of abrasive dry food. PMID- 26479141 TI - The Effects of Fiber Inclusion on Pet Food Sensory Characteristics and Palatability. AB - The objectives of this study were to determine (a) the influence of fiber on the sensory characteristics of dry dog foods; (b) differences of coated and uncoated kibbles for aroma and flavor characteristics; (c) palatability of these dry dog foods; and (d) potential associations between palatability and sensory attributes. A total of eight fiber treatments were manufactured: a control (no fiber addition), guava fiber (3%, 6%, and 12%), sugar cane fiber (9%; large and small particle size), and wheat bran fiber (32%; large and small particle size). The results indicated significant effects of fibers on both flavor and texture properties of the samples. Bitter taste and iron and stale aftertaste were examples of flavor attributes that differed with treatment, with highest intensity observed for 12% guava fiber and small particle size sugar cane fiber treatments. Fracturability and initial crispness attributes were lowest for the sugar cane fiber treatments. Flavor of all treatments changed after coating with a palatant, increasing in toasted, brothy, and grainy attributes. The coating also had a masking effect on aroma attributes such as stale, flavor attributes such as iron and bitter taste, and appearance attributes such as porosity. Palatability testing results indicated that the control treatment was preferred over the sugar cane or the wheat bran treatment. The treatment with large sugarcane fiber particles was preferred over the treatment with small particles, while both of the wheat bran treatments were eaten at a similar level. Descriptive sensory analysis data, especially textural attributes, were useful in pinpointing the underlying characteristics and were considered to be reasons that may influence palatability of dog foods manufactured with inclusion of different fibers. PMID- 26479142 TI - Assessing Food Preferences in Dogs and Cats: A Review of the Current Methods. AB - Food is a major aspect of pet care; therefore, ensuring that pet foods are not only healthful but attractive to companion animals and their owners is essential. The petfood market remains active and requires ongoing evaluation of the adaptation and efficiency of the new products. Palatability-foods' characteristics enticing animals and leading them to consumption-is therefore a key element to look at. Based on the type of information needed, different pet populations (expert or naive) can be tested to access their preference and acceptance for different food products. Classical techniques are the one-bowl and two-bowl tests, but complementary (i.e., operant conditioning) and novel (i.e., exploratory behavior) approaches are available to gather more information on the evaluation of petfood palatability. PMID- 26479143 TI - A Critical Analysis of the British Horseracing Authority's Review of the Use of the Whip in Horseracing. AB - There is increasing controversy about the use of the whip as a performance aid in Thoroughbred horseracing and its impact on horse welfare. This paper offers a critical analysis of the British Horseracing Authority's (BHA) 2011 Report Responsible Regulation: A Review of the Use of the Whip in Horseracing. It examines the BHA's process of consultation and use of science and public opinion research through the application of current scientific literature and legal analysis. This analysis suggests that the BHA's findings on the welfare impact and justification for whip use are insufficiently defended by the report. These findings indicate that the report is an inadequate basis from which to draw any definitive conclusions on the impact of whips on racehorse welfare. Further review is needed, undertaken by an independent scientific body, to advance this debate. PMID- 26479144 TI - Rationale and design of a randomized controlled trial of allogeneic mesenchymal stem cells in patients with nonischemic cardiomyopathy. AB - AIMS: This article describes an ongoing study investigating the safety and efficacy of ischemia-tolerant mesenchymal stem cell (MSC) therapy in patients with nonischemic heart failure and dysfunctional viable myocardium without scarring. This study will follow principles of the previously described mechanistic translational-phase concept whereby the effect of the study agent on laboratory and imaging markers of cardiac structure and function will be tested in a small homogenous cohort with the goal to enhance the understanding of the effect of interventions on cardiac remodeling and performance. STUDY DESIGN: This single-blind, placebo-controlled, crossover, multicenter, randomized study will assess the safety, tolerability, and preliminary efficacy of a single intravenous (i.v.) dose of allogeneic ischemia-tolerant MSCs in individuals with heart failure of nonischemic cause, ejection fraction 40% or less, and dysfunctional viable myocardium who have been receiving guideline-directed medical therapy. Eligible patients will have no evidence of baseline replacement scarring on delayed-enhancement cardiac magnetic resonance (CMR). Approximately 20 patients will be randomized in a 1 : 1 ratio to receive an i.v. infusion of ischemia tolerant MSCs or placebo. At 90 days, the two groups will undergo crossover and received the alternative treatment. The primary endpoint is safety, as evaluated through at least 1-year post-MSC infusion. Additional efficacy endpoints will include measures of cardiac structure and function, as evaluated by serial cine CMR and transthoracic echocardiography at 90 and 180 days post-initial infusion. CONCLUSION: This pilot study will explore the safety and effects on cardiac structure and function of i.v. injection of ischemia-tolerant MSCs in a small homogenous cohort of nonischemic heart failure patients with reduced ejection fraction and absent replacement scarring on CMR. This study also represents a prospective mechanistic translational-phase study using baseline and serial CMR imaging in heart failure patients and serves as a potential model for design of future heart failure trials (ClinicalTrials.gov identifier: NCT02467387). PMID- 26479145 TI - Activity of nintedanib in germ cell tumors. AB - Germ cell tumors (GCTs) are the most frequent malignancy in male patients between 15 and 45 years of age. Cisplatin-based chemotherapy shows excellent cure rates, but patients with cisplatin-resistant GCTs have a poor prognosis. Nintedanib (BIBF 1120, Vargatef) inhibits the receptor classes vascular endothelial growth factor receptor, platelet derived growth factor receptor, and fibroblast growth factor receptor, and has shown activity against many tumors, as well as in idiopathic lung fibrosis and bleomycin-induced lung injury. Here, we investigated the antineoplastic and antiangiogenic properties of nintedanib in cisplatin resistant and cisplatin-sensitive GCT cells, both alone and in combination with classical cytotoxic agents such as cisplatin, etoposide, and bleomycin. The half maximal inhibitory concentration (IC50) of nintedanib was 4.5 +/- 0.43 MUmol/l, 3.1 +/- 0.45 MUmol/l, and 3.6 +/- 0.33 MUmol/l in cisplatin-sensitive NTERA2, 2102Ep, and NCCIT cells, whereas the IC50 doses of the cisplatin-resistant counterparts were 6.6 +/- 0.37 MUmol/l (NTERA2-R), 4.5 +/- 0.83 MUmol/l (2102Ep R), and 6.1 +/- 0.41 MUmol/l (NCCIT-R), respectively. Single treatment with nintedanib induced apoptosis and resulted in a sustained reduction in the capacity of colony formation in both cisplatin-sensitive and cisplatin-resistant GCT cells. Cell cycle analysis showed that nintedanib induced a strong G0/G1 phase arrest in all investigated cell lines. Combination treatment with cisplatin did not result in additive, synergistic, or antagonistic effects. The in-vivo activity was studied using the chorioallantoic membrane assay and indicated the antiangiogenic potency of nintedanib with markedly reduced microvessel density. Topical treatment of inoculated tumor plaques resulted in a significant reduction of the tumor size. This indicates that nintedanib might be a promising substance in the treatment of GCT. PMID- 26479146 TI - Getting to the root of plant iron uptake and cell-cell transport: Polarity matters! AB - Plasma membrane proteins play pivotal roles in mediating responses to endogenous and environmental cues. Regulation of membrane protein levels and establishment of polarity are fundamental for many cellular processes. In plants, IRON REGULATED TRANSPORTER 1 (IRT1) is the major root iron transporter but is also responsible for the absorption of other divalent metals such as manganese, zinc and cobalt. We recently uncovered that IRT1 is polarly localized to the outer plasma membrane domain of plant root epidermal cells upon depletion of its secondary metal substrates. The endosome-recruited FYVE1 protein interacts with IRT1 in the endocytic pathway and plays a crucial role in the establishment of IRT1 polarity, likely through its recycling to the cell surface. Our work sheds light on the mechanisms of radial transport of nutrients across the different cell types of plant roots toward the vascular tissues and raises interesting parallel with iron transport in mammals. PMID- 26479147 TI - Dynamic subnuclear relocalization of WRKY40, a potential new mechanism of ABA dependent transcription factor regulation. AB - The phytohormone ABA plays a major role during plant development, e.g. seed maturation and seed germination, and during adaptation to abiotic stresses like stomatal aperture regulation. The three closely related WRKY transcription factors WRKY18, WRKY40 and WRKY60 function in ABA signal transduction. We recently demonstrated that WRKY18 and WRKY40 but not WRKY60 localize to nuclear bodies in A. thaliana mesophyll protoplasts. WRKY40, a negative regulator of ABA dependent inhibition of seed germination, relocalizes from PNBs to the nucleoplasm in the presence of ABA in a dynamic and phosphorylation-dependent manner. We propose that subnuclear relocalization of WRKY40 might constitute a new regulatory mechanism of ABA-dependent modulation of transcription factor activity. PMID- 26479148 TI - Slow water transport in MgSO4 aerosol droplets at gel-forming relative humidities. AB - The effect of gel formation on the mass transfer of water during evaporation or condensation from MgSO4 droplets is studied using aerosol optical tweezers coupled with Raman spectroscopy. In particular, the kinetics of water transport during hydration and dehydration are followed for variable step changes in relative humidity and compared with previous measurements using different methodologies. Slow diffusion of water in the particle bulk is shown to limit water evaporation and condensation from the aerosol. Desorption of water continues over a long time at the very low RH region and this is validated with complementary studies made by FTIR-ATR and measurements of water adsorption isotherms. The observations can be rationalized when considering the possible phase transformation of the gel structure at very low RHs. Finally, the influence of the duration of the drying time (RH <= 10%) on the kinetics of condensation during hydration is investigated. Apparent diffusion coefficients of water molecules in the gel are obtained, showing little dependence on the water activity and droplet composition, and are consistent with the slow removal of water during drying from pores formed at the gel transition RH. PMID- 26479149 TI - Nanodiamond-Mediated Intercellular Transport of Proteins through Membrane Tunneling Nanotubes. AB - Recently discovered tunneling nanotubes (TNTs) are capable of creating intercellular communication pathways through which transport of proteins and other cytoplasmic components occurs. Intercellular transport is related to many diseases and nanotubes are potentially useful as drug-delivery channels for cancer therapy. Here, we apply fluorescent nanodiamond (FND) as a photostable tracker, as well as a protein carrier, to illustrate the transport events in TNTs of human cells. Proteins, including bovine serum albumin and green fluorescent protein, are first coated on 100-nm FNDs by physical adsorption and then single particle tracking of the bioconjugates in the transient membrane connections is carried out by fluorescence microscopy. Stop-and-go and to-and-fro motions mediated by molecular motors are found for the active transport of protein-loaded FNDs trapped in the endosomal vehicles of human embryonic kidney cells (HEK293T). Quantitative analysis of the heterotypical transport between HEK293T and SH-SY5Y neuroblastoma cells by flow cytometry confirm the formation of open-ended nanotubes between them, despite that their TNTs differ in structural components. Our results demonstrate the promising applications of this novel carbon-based nanomaterial for intercellular delivery of biomolecular cargo down to the single particle level. PMID- 26479150 TI - Effect of the co-culture of human bone marrow mesenchymal stromal cells with human umbilical vein endothelial cells in vitro. AB - Mesenchymal stem cells (MSCs) give origin to the marrow tromal environment that supports hematopoiesis. These cells present a wide range of differentiation potentials and a complex relationship with hematopoietic stem cells (HSCs) and endothelial cells. In addition to bone marrow (BM), MSCs can be obtained from other sites in the adult or the fetus. Recent studies have shown that cocultured endothelial cells and osteoblasts are mutually promotive in bone tissues repair. In this study, we observed the effects of coculture of endothelial cells and osteoblasts at different ratios on vasculogenesis and bone formation, and we found that angiogenic effect is more effective when endothelial cells are cocultured with osteoblasts at the ratio of 4:1, and osteogenic effect is more effective at the ratio of 1:4. It is concluded that the co-culture of human bone marrow mesenchymal stromal cells with human umbilical vein endothelial cells could be a promising culture system for bone tissue engineering applications. PMID- 26479151 TI - The spread of a novel behavior in wild chimpanzees: New insights into the ape cultural mind. AB - For years, the animal culture debate has been dominated by the puzzling absence of direct evidence for social transmission of behavioral innovations in the flagship species of animal culture, the common chimpanzee. Although social learning of novel behaviors has been documented in captivity, critics argue that these findings lack ecological validity and therefore may not be relevant for understanding the evolution of culture. For the wild, it is possible that group specific behavioral differences emerge because group members respond individually to unspecified environmental differences, rather than learning from each other. In a recent paper, we used social network analyses in wild chimpanzees (Pan troglodytes schweinfurthii) to provide direct evidence for social transmission of a behavioral innovation, moss-sponging, to extract water from a tree hole. Here, we discuss the implications of our findings and how our new methodological approach could help future studies of social learning and culture in wild apes. PMID- 26479152 TI - Successful maintenance on sulphonylurea therapy and low diabetes complication rates in a HNF1A-MODY cohort. AB - AIMS: HNF1A gene mutations are the most common cause of maturity-onset diabetes of the young (MODY) in the UK. Persons with HNF1A-MODY display sensitivity to sulphonylurea therapy; however, the long-term efficacy is not established. There is limited literature as to the prevalence of micro- and macrovascular complications in this unique cohort. The aim of this study was to determine the natural progression and clinical management of HNF1A-MODY diabetes in a dedicated MODY clinic. METHODS: Sixty patients with HNF1A-MODY and a cohort of 60 BMI-, age , ethnicity- and diabetes duration-matched patients with Type 1 diabetes mellitus participated in the study. All patients were phenotyped in detail. Clinical follow-up of the HNF1A-MODY cohort occurred on a bi-annual basis. RESULTS: Following a genetic diagnosis of MODY, the majority of the cohort treated with sulphonylurea therapy remained insulin independent at 84-month follow-up (80%). The HbA1c in the HNF1A-MODY group treated with sulphonylurea therapy alone improved significantly over the study period [from 49 (44-63) mmol/mol, 6.6 (6.2 7.9)% to 41 (31-50) mmol/mol, 5.9 (5-6.7)%; P = 0.003]. The rate of retinopathy was significantly lower than that noted in the Type 1 diabetes mellitus group (13.6 vs. 50%; P = 0.0001).There was also a lower rate of microalbuminuria and cardiovascular disease in the HNF1A-MODY group compared with the Type 1 diabetes mellitus group. CONCLUSIONS: This study demonstrates that the majority of patients with HNF1A-MODY can be maintained successfully on sulphonylurea therapy with good glycaemic control. We note a significantly lower rate of micro- and macrovascular complications than reported previously. The use of appropriate therapy at early stages of the disorder may decrease the incidence of complications. PMID- 26479153 TI - Expression profile of microRNA-200 family in cholangiocarcinoma arising from choledochal cyst. AB - BACKGROUND AND AIM: The risk of cholangiocarcinoma (cCC) arising from choledochal cyst (CC-CC) is imminent, if the latter not treated appropriately in time. Epithelial-to-mesenchymal transition (EMT) is considered a critical step for various solid cancers, which is regulated by the microRNA-200 (miR-200) family. The aim of this study was to assess the role of miR-200 family in the pathogenesis of CC-CC. METHODS: Sixteen patients with CC-CC were enrolled and 254 patients with conventional cCC served as clinicopathologic controls. Fifty-four cCC were selected to compare the miR-200 family expression and immunohistochemical characteristics. Gain-and loss-of-function studies of miR-200 family were conducted using the cCC cell lines. RESULTS: CC-CC were younger (P < 0.01), more female- predominated (P < 0.01), and rarely associated with lithiasis (P < 0.01) compared with those of cCC. miR-200 family was down-regulated in CC CC, while miR-200 family was paradoxically up-regulated in cCC (P < 0.01). CC-CC exhibited overt overexpression of mesenchymal markers including ZEB1, Twist, Snail, and vimentin as well an aberrant E-cadherin expression in comparison with cCC. In vitro migration assay showed that cCC cells bearing lower miR-200 s levels exhibited stronger migration ability. Invasive ability of cCC cells was increased after miR-200 s knockdown, accompanied by up-regulation of mesenchymal markers. CONCLUSIONS: CC-CC was characterized by distinct demographics, precipitating factors, and down-regulation of miR-200 family, compared with those of cCC. The pathogenesis of CC-CC might partly link to the silencing of miR-200 family, acting via ZEB1-directed EMT activation. PMID- 26479154 TI - Characterization of bacterial diversity in an atrazine degrading enrichment culture and degradation of atrazine, cyanuric acid and biuret in industrial wastewater. AB - An enrichment culture was used to study atrazine degradation in mineral salt medium (MSM) (T1), MSM+soil extract (1:1, v/v) (T2) and soil extract (T3). Results suggested that enrichment culture required soil extract to degrade atrazine, as after second sequential transfer only partial atrazine degradation was observed in T1 treatment while atrazine was completely degraded in T2 and T3 treatments even after fourth transfer. Culture independent polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) technique confirmed selective enrichment of genus Bacillus along with Pseudomonas and Burkholderia. Degradation of atrazine/metabolites in the industrial wastewater was studied at different initial concentrations of the contaminants [wastewater-water (v/v) ratio: T1, 1:9; T2, 2:8; T3, 3:7; T4, 5:5 and T5, undiluted effluent]. The initial concentrations of atrazine, cyanuric acid and biuret ranged between 5.32 and 53.92 ug mL(-1), 265.6 and 1805.2 ug mL(-1) and 1.85 and 16.12 ug mL(-1), respectively. The enrichment culture was able to completely degrade atrazine, cyanuric acid and biuret up to T4 treatment, while no appreciable degradation of contaminants was observed in the undiluted effluent (T5). Inability of enrichment culture to degrade atrazine/metabolites might be due to high concentrations of cyanuric acid. Therefore, a separate study on cyanuric acid degradation suggested: (i) no appreciable cyanuric acid degradation with accumulation of an unidentified metabolite in the medium where cyanuric acid was supplemented as the sole source of carbon and nitrogen; (ii) partial cyanuric acid degradation with accumulation of unidentified metabolite in the medium containing additional nitrogen source; and (iii) complete cyanuric acid degradation in the medium supplemented with an additional carbon source. This unidentified metabolite observed during cyanuric acid degradation and also detected in the enrichment culture inoculated wastewater samples, however, was degraded up to T4 treatments and was persistent in the T5 treatment. Probably, accumulation of this metabolite inhibited atrazine/cyanuric acid degradation by the enrichment culture in undiluted wastewater. PMID- 26479155 TI - Chemotherapy for Children With Medulloblastoma. PMID- 26479156 TI - Nurses and Women With Breast Cancer: No Time to Lose. PMID- 26479157 TI - The Crystal Hotel: A Microfluidic Approach to Biomimetic Crystallization. AB - A "crystal hotel" microfluidic device that allows crystal growth in confined volumes to be studied in situ is used to produce large calcite single crystals with predefined crystallographic orientation, microstructure, and shape by control of the detailed physical environment, flow, and surface chemistry. This general approach can be extended to form technologically important, nanopatterned single crystals. PMID- 26479158 TI - Risk of urinary retention after nerve-sparing surgery for deep infiltrating endometriosis: A systematic review and meta-analysis. AB - AIMS: Recently, nerve-sparing (NS) techniques have been incorporated in surgeries for deep infiltrating endometriosis (DIE) to prevent urinary complications. Our aim was to perform a systematic review and meta-analysis to assess the risk of urinary retention after NS surgery for DIE compared with classical (non-NS) techniques. METHODS: Following the MOOSE guidelines for systematic reviews of observational studies, data were collected from published research articles that compared NS techniques with non-NS techniques in DIE surgery, with regard to post operative urinary complications. INCLUSION CRITERIA: randomized clinical trials, intervention or observational (cohort and case-control) studies assessing women who underwent surgery for painful DIE. EXCLUSION CRITERIA: cancer surgery and women submitted to bladder or ureteral resections. The respective relative risks (RR) and 95% confidence intervals (CI) were extracted and a forest plot was generated to show individual and combined estimates. RESULTS: Preliminarily, 1,270 potentially relevant studies were identified from which four studies were selected. A meta-analysis was performed to assess the risk of urinary retention at discharge and 90 days after surgery. We found a common RR of 0.19 [95%CI: 0.03 1.17; (I2 = 50.20%; P = 0.09)] for need of self-catheterization at discharge in the NS group in relation to the conventional technique. Based on two studies, common RR for persistent urinary retention (after 90 days) was 0.16 [95%CI: 0.03 0.84]. CONCLUSIONS: Our results suggest significant advantages of the NS technique when considering the RR of persistent urinary retention. Controlled studies evaluating the best approach to manage the urinary tract after complex surgery for DIE are needed. Neurourol. Urodynam. 36:57-61, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26479159 TI - Enhanced suicidal erythrocyte death in acute cardiac failure. AB - BACKGROUND: A common complication of acute cardiac failure (AHF) is anaemia, which negatively influences the clinical outcome. Causes of anaemia include enhanced eryptosis, a suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation. Signalling triggering eryptosis include oxidative stress, increase of cytosolic Ca(2+) activity ([Ca(2+) ]i ) and ceramide. The present study explored whether AHF is associated with accelerated eryptosis. MATERIALS AND METHODS: Erythrocytes were drawn from healthy volunteers (n = 10) and patients hospitalized for AHF (n = 22). Phosphatidylserine exposure was estimated from annexin-V-binding, cell volume from forward scatter, [Ca(2+) ]i from Fluo3-fluorescence, ceramide abundance utilizing specific antibodies and reactive oxygen species (ROS) abundance from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, as determined by flow cytometry. RESULTS: In AHF-patients, haemoglobin concentration (11.5 +/- 0.5 g/dL), and haematocrit (35.6 +/- 1.2%) were significantly lower than haemoglobin concentration (14.1 +/- 0.4 g/dL), and haematocrit (40.1 +/- 1.0%) in healthy volunteers, even though reticulocyte number was significantly higher in AHF patients (2.3 +/- 0.3%) than in healthy volunteers (1.1 +/- 0.2%). The percentage of erythrocytes exposing phosphatidylserine was significantly higher in AHF patients (1.8 +/- 0.1%) than in healthy volunteers (1.2 +/- 0.2%). The forward scatter was significantly lower and the ROS abundance significantly larger in AHF patients than in healthy volunteers. In erythrocytes drawn from healthy volunteers, phosphatidylserine and ROS abundance was increased to significantly higher values following a 24 h treatment with plasma from AHF patients than with plasma from healthy volunteers. CONCLUSION: AHF leads to anaemia despite increased reticulocyte number and at least partially due to enhanced eryptosis. Underlying mechanisms include oxidative stress imposed by a plasma borne component. PMID- 26479160 TI - Macronutrient balancing affects patch departure by guerezas (Colobus guereza). AB - Foraging strategies are central in shaping social structure and grouping patterns in primates. We address Colobus guereza foraging strategies by investigating their patch departure decisions in relation to diet composition and nutrition. We examine whether guerezas are constrained in their intake of food in patches and thereby forage according to a fixed amount strategy that dictates patch departure. Additionally, we assess whether guereza employ a fixed time strategy or attempt to balance nutrients when foraging. We measured food patch occupancy time, intake rates, and analyzed foods for macronutrients, fiber, and condensed tannins. We determined that guerezas do not employ a fixed time foraging strategy; patch residence time varied widely between 1 and 290 min. They also did not depart patches or stop eating when they reached a specific intake of dry mass, macronutrients, or condensed tannins. However, guerezas maintained a macronutrient balance when feeding across patches, and the balance of protein to non-protein energy (fats and carbohydrates) in patches is the best indicator of time adult guerezas spent feeding in patches. Previous studies have shown that the protein-to-fiber ratio is important in predicting food selection for folivores and their biomass; however, we found that guerezas did not maximize protein and minimize fiber intake while foraging in patches, nor did they stay longer in patches with the highest ratio of protein to fiber concentrations. This study raises questions about the nutritional and social implications of patch depletion as a foraging strategy in folivorous monkeys where food limitation predicts competitive and social regimes. Am. J. Primatol. 79:e22495, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26479161 TI - Frequency and Severity of Pulmonary Hemorrhage in Patients Undergoing Percutaneous CT-guided Transthoracic Lung Biopsy: Single-Institution Experience of 1175 Cases. AB - PURPOSE: To evaluate the frequency and severity of pulmonary hemorrhage after transthoracic needle lung biopsy (TTLB) and assess possible factors associated with pulmonary hemorrhage. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. The requirement to obtain informed consent was waived. Records from 1113 patients who underwent 1175 TTLBs between January 2008 and April 2013 were retrospectively reviewed. Primary outcomes were pulmonary hemorrhage, documented hemoptysis, and bleeding complications necessitating intervention. Pulmonary hemorrhage was graded as follows: 0, none; 1, less than or equal to 2 cm around the needle; 2, more than 2 cm and sublobar; 3, at least lobar; and 4, hemothorax. Patient, technique, and lesion-related variables were evaluated as predictors of pulmonary hemorrhage. Patient-related variables included main pulmonary artery diameter (mPAD) at computed tomography (CT), pulmonary artery pressures at echocardiography and right-sided heart catheterization, medications, chronic lung disease, bleeding diathesis, and immunodeficiency. Technique- and lesion-related variables included needle gauge, number of passes, pleura-needle angle, lesion size and morphologic characteristics, and distance to pleura. Univariate analysis was performed with chi(2), Fisher exact, and Student t tests. RESULTS: Pulmonary hemorrhage occurred in 483 of the 1175 TTLBs (41.1%); hemoptysis was documented in 21 of the 1175 TTLBs (1.8%). Higher-grade hemorrhage (grade 2 or higher) occurred in 201 of the 1175 TTLBs (17.1%); five of the 1175 TTLBs (0.4%) necessitated hemorrhage-related admission. Higher-grade hemorrhage was more likely to occur with female sex (P = .001), older age (P = .003), emphysema (P = .004), coaxial technique (P = .025), nonsubpleural location (P < .001), lesion size of 3 cm or smaller (P < .001), and subsolid lesions (P = .028). Enlarged mPAD at CT (>=2.95 cm) was not significantly associated with higher-grade hemorrhage (P = .430). CONCLUSION: Pulmonary hemorrhage after TTLB is common but rarely requires intervention. An enlarged mPAD at CT may not be a risk factor for higher-grade hemorrhage. PMID- 26479162 TI - Comparative Analgesic Efficacy of Oxycodone/Acetaminophen Versus Hydrocodone/Acetaminophen for Short-term Pain Management in Adults Following ED Discharge. AB - OBJECTIVES: The objective was to test the hypothesis that oxycodone/acetaminophen provides superior analgesia to hydrocodone/acetaminophen for the treatment of acute extremity pain following emergency department (ED) discharge. METHODS: This was a prospective, randomized, double-blind clinical trial of nonelderly adult ED patients with acute musculoskeletal extremity pain, randomly allocated at discharge to receive oxycodone/acetaminophen (5 mg/325 mg) or hydrocodone/acetaminophen (5 mg/325 mg). The primary outcome was the between group difference in improvement in numerical rating scale (NRS) pain scores over a 2-hour period following the most recent ingestion of study drug, obtained during telephone contact 24 hours after ED discharge. Secondary outcomes included proportionate decrease in pain, comparative side-effect profiles, and patient satisfaction. RESULTS: A total of 240 patients were enrolled. The final sample consisted of 220 patients, 107 randomly allocated to oxycodone/acetaminophen and 113 to hydrocodone/acetaminophen. At 24 hours after ED discharge, the mean NRS pain scores prior to the most recent dose of outpatient pain medication were 7.8 and 7.9 in the oxycodone/acetaminophen and hydrocodone/acetaminophen groups, respectively. The mean decreases in pain scores over 2 hours were 4.4 NRS units in the oxycodone/acetaminophen group versus 4.0 NRS units in the hydrocodone/acetaminophen group, for a difference of 0.4 NRS units (95% confidence interval = -0.2 to 1.1 NRS units). Satisfaction with the analgesics was similar. CONCLUSIONS: This study design could not detect a clinically or statistically significant difference in analgesic efficacy between oxycodone/acetaminophen (5 mg/325 mg) and hydrocodone/acetaminophen (5 mg/325 mg) for treatment of acute musculoskeletal extremity pain in adults following ED discharge. Both opioids reduced pain scores by approximately 50%. PMID- 26479163 TI - Osseous Sarcoidosis Revealed by a Pathologic Fracture and Successfully Treated With Methotrexate and Prednisone. PMID- 26479164 TI - The necessity of clinicopathologic correlation: syphilis that could have been missed. PMID- 26479165 TI - Prediction of high naevus count in a healthy U.K. population to estimate melanoma risk. AB - BACKGROUND: Despite recent discoveries of germline and somatic mutations in melanoma, naevus count remains the most important risk factor for melanoma. Counting naevi on the whole body is time consuming. In order to identify patients at risk for melanoma, many studies have used naevus count on selected body sites as a proxy for total body naevus count (TBNC). OBJECTIVES: The main aim of this study was to assess the predictive value of naevus count on 17 different body sites in estimating TBNC in a large cohort of healthy U.K. Caucasian female subjects. Once the site with the best predictive value for TBNC was determined, a second aim was to estimate the cut-off values of naevus counts at this anatomical site that best predict the presence of 50 or 100 naevi, respectively. METHODS: The most predictive body site for TBNC was assessed in a cohort of healthy female twins. This finding was replicated on a control group from a U.K. case-control study and a prediction model was performed afterwards. The area under the receiver operating characteristics curve was used to evaluate the best cut-off for the prediction of having a TBNC of more than 50 or 100. RESULTS: There were 3694 female twins included. The TBNC showed a steady decline after the age of 30 years (P < 0.001). The most predictive sites for TBNC were the arms and legs: the adjusted correlation coefficients were 0.50 and 0.51 (P < 0.001) for the right and left arm, respectively, and 0.49 and 0.48 for the right and left legs, respectively (P < 0.001). The arm remained the most predictive site for TBNC when replicated in a control population including both sexes. In the twin study, women with more than 11 naevi on the right arm were approximately nine times more likely to have more than 100 naevi (odds ratio = 9.38, 95% confidence interval 6.71-13.11). CONCLUSIONS: The ability to estimate TBNC quickly by counting naevi on one arm could be a very useful tool in assessing melanoma risk in primary care. PMID- 26479166 TI - Adverse event surveillance in small animal anaesthesia: an intervention-based, voluntary reporting audit. AB - OBJECTIVE: To develop, test and refine an 'intervention-based' system for the surveillance of adverse events (AEs) during small animal anaesthesia. STUDY DESIGN: Prospective, voluntary reporting audit. ANIMALS: A total of 1386 consecutive small animal anaesthetics (including 972 dogs and 387 cats). METHODS: Adverse events were defined as undesirable perianaesthetic events requiring remedial intervention to prevent or limit patient morbidity. Using previous reports, 11 common AEs were selected and 'intervention-based' definitions were devised. A voluntary reporting audit was performed over 1 year at a university teaching hospital. Data on AEs were collected via paper checkbox forms completed after each anaesthetic and were assimilated using an electronic database. Interventions were performed entirely at the discretion of the attending anaesthetist. Comparisons between dogs and cats were made using Fisher's exact tests. RESULTS: Forms were completed for 1114 anaesthetics (a compliance of 80.4%), with 1001 AEs reported in 572 patients. The relative frequency of AEs reported were as follows: arousal or breakthrough pain (14.9%), hypoventilation (13.5%), hypotension (10.3%), arrhythmias (5.8%), hyperthermia/hypothermia (5.0%), airway complications (4.8%), recovery excitation (4.6%), aspiration risk (4.5%), desaturation (2.8%), hypertension (1.7%) and 'other' (3.7%). Canine anaesthetics (57.3%) were more likely to involve AEs than were feline anaesthetics (35.5%, p < 0.01). Escalation in postanaesthetic care was required in 20% of cases where an AE was reported (8% of anaesthetics overall). In 6% of cases (2% overall), this involved management in an intensive care unit. There were six intra-anaesthetic fatalities (0.43%) during this period. The tool was widely accepted, being considered quick and easy to complete, but several semantic, logistical and personnel factors were encountered. CONCLUSIONS AND CLINICAL RELEVANCE: Simple intervention-based surveillance tools can be easily integrated into small animal anaesthetic practice, providing a valuable evidence base for anaesthetists. A number of considerations must be addressed to ensure compliance and the quality of data collected. PMID- 26479168 TI - Effect of Meconium-Stained Amniotic Fluid on Perinatal Complications in Low-Risk Pregnancies at Term. AB - OBJECTIVE: This study aims to determine the impact of meconium-stained amniotic fluid (MSAF) in low-risk pregnancies at term on pregnancy outcome. STUDY DESIGN: A retrospective cohort study of women with MSAF during labor who delivered in a tertiary hospital at 37 to 41(+6) weeks of gestation (2007-2013). Exclusion criteria included: multiple gestations, noncephalic presentation, fetal structural/chromosomal anomalies, hypertensive disorders, diabetes, oligohydramnios, or small for gestational age. Pregnancy outcome of women with MSAF (N = 4,893) was compared with a control group of women without MSAF (N = 39,651). Neonatal respiratory morbidity was defined as the presence of any of the following: respiratory distress syndrome, transient tachypnea of the newborn, meconium aspiration syndrome, or need for ventilatory support. RESULTS: Overall, 10.9% of low-risk pregnancies at term were diagnosed with MSAF. Compared with the controls, women with MSAF had higher rates of nulliparity, gestational age at delivery >= 41 weeks, induction of labor, nonreassuring fetal heart rate, and operative deliveries. In multivariate analysis MSAF was associated with operative delivery (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.63-2.09; p < 0.001), cesarean section (OR, 1.48; 95% CI, 1.31-1.69; p < 0.001), respiratory morbidity (OR, 4.74; 95% CI, 3.87-5.82; p < 0.001), and increased risk for short term neonatal morbidity. CONCLUSIONS: MSAF is associated with a higher rate of adverse perinatal outcome even in low-risk pregnancies at term. PMID- 26479167 TI - Enhanced hydrolysis of lignocellulosic biomass: Bi-functional enzyme complexes expressed in Pichia pastoris improve bioethanol production from Miscanthus sinensis. AB - Lignocellulosic biomass is the most abundant utilizable natural resource. In the process of bioethanol production from lignocellulosic biomass, an efficient hydrolysis of cellulose and hemicellulose to release hexose and pentose is essential. We have developed a strain of Pichia pastoris that can produce ethanol via pentose and hexose using an assembly of enzyme complexes. The use of enzyme complexes is one of the strategies for effective lignocellulosic biomass hydrolysis. Xylanase XynB from Clostridium cellulovorans and a chimeric endoglucanase cCelE from Clostridium thermocellum were selected as enzyme subunits, and were bound to a recombinant scaffolding protein mini-CbpA from C. cellulovorans to assemble the enzyme complexes. These complexes efficiently degraded xylan and carboxymethylcellulose (CMC), producing approximately 1.18 and 1.07 g/L ethanol from each substrate, respectively, which is 2.3-fold and 2.7 fold higher than that of the free-enzyme expressing strain. Miscanthus sinensis was investigated as the lignocellulosic biomass for producing bioethanol, and 1.08 g/L ethanol was produced using our recombinant P. pastoris strain, which is approximately 1.9-fold higher than that of the wild-type strain. In future research, construction of enzyme complexes containing various hydrolysis enzymes could be used to develop biocatalysts that can completely degrade lignocellulosic biomass into valuable products such as biofuels. PMID- 26479169 TI - Early versus Late Feeding after Cesarean Delivery: A Randomized Controlled Trial. AB - OBJECTIVE: This study aims to evaluate whether early feeding after cesarean delivery (CD) shortens the time to pass flatus and bowel movement. METHODS: Women at term undergoing CD were randomly assigned to start oral intake either within 6 hours (early feeding) or after 12 hours (late feeding) from surgery completion. Women with preeclampsia, or requiring emergent CD, additional bowel surgery, or the use of general anesthesia were excluded. Our primary outcome was time of passing first flatus following surgery completion. Secondary outcomes included time of first bowel sounds, time of first bowel movement, nausea/vomiting, and length of maternal hospital stay (clinicaltrials.gov identifier NCT02396485). RESULTS: A total of 177 women were randomized to early (n = 85) or late feeding (n = 82). There was no loss to follow-up, and outcomes were available for all patients. There were no differences in baseline characteristics between the two groups. Early feeding resulted in shorter time to pass flatus (median [interquartile range], 715 [485-1,208] minutes vs. 1,300 [820-1,760] minutes; p < 0.001) and to have bowel sounds (232 [168-537.8] minutes vs. 554.5 [202-706] minutes; p = 0.001). Time to pass bowel movement was shorter in the early-feeding group, but did not reach significance. The groups did not differ in length of stay or in rates of nausea, vomiting, or ileus. CONCLUSION: In women undergoing CD, early oral intake is well tolerated and results in earlier return of bowel function. PMID- 26479171 TI - The Rising Burden of Preeclampsia in the United States Impacts Both Maternal and Child Health. AB - OBJECTIVE: Preeclampsia is one of the top six causes of maternal mortality in the United States (US) and is associated with considerable perinatal morbidity and mortality. Evidence suggests the US incidence of preeclampsia has increased dramatically over the past two decades. This study aims to compile, summarize, and critique the literature on the health and economic burden of preeclampsia and early-onset preeclampsia. STUDY DESIGN: We reviewed the literature for estimates of burden of preeclampsia and early-onset preeclampsia to both mother and child, summarized the evidence on economic and social burden, and highlighted current gaps in the literature. RESULTS: No recent studies comprehensively assess the costs and health consequences of preeclampsia or early-onset preeclampsia for both mother and child. Where it exists, the literature suggests preeclampsia and early-onset preeclampsia cause numerous adverse health consequences, but these conditions currently lack effective treatment. The need for preterm delivery from early-onset preeclampsia suggests its costs are substantial: very (28-31 weeks) and extremely (<28 weeks) preterm birth cost approximately 40 and 100 times a term pregnancy, respectively. CONCLUSION: Given the severity of outcomes from preeclampsia, further research on its health and economic consequences is essential to inform policy and resource allocation decisions in health care. PMID- 26479170 TI - Vaginal Microbiota in Pregnancy: Evaluation Based on Vaginal Flora, Birth Outcome, and Race. AB - OBJECTIVE: This study aims to evaluate vaginal microbiota differences by bacterial vaginosis (BV), birth timing, and race, and to estimate parameters to power future vaginal microbiome studies. METHODS: Previously, vaginal swabs were collected at 21 to 25 weeks (stored at -80 degrees C), and vaginal smears evaluated for BV (Nugent criteria). In a blinded fashion, 40 samples were selected, creating 8 equal-sized groups stratified by race (black/white), BV (present/absent), and birth timing (preterm/term). Samples were thawed, DNA extracted, and prepared. Polymerase chain reaction (PCR) with primers targeting the 16S rDNA V4 region was used to prepare an amplicon library. PCR products were sequenced and analyzed using quantitative insight into microbial ecology; taxonomy was assigned using ribosomal database program classifier (threshold 0.8) against the modified Greengenes database. RESULTS: After quality control, 97,720 sequences (mean) per sample, single-end 250 base-reads, were analyzed. BV samples had greater microbiota diversity (p < 0.05)-with BVAB1, Prevotella, and unclassified genus, Bifidobacteriaceae family (all p < 0.001) more abundant; there was minimal content of Gardnerella or Mobiluncus. Microbiota did not differ by race or birth timing, but there was an association between certain microbial clusters and preterm birth (p = 0.07). To evaluate this difference, 159 patients per group are needed. CONCLUSIONS: There are differences in the vaginal microbiota between patients with and without BV. Larger studies should assess the relationship between microbiota composition and preterm birth. PMID- 26479172 TI - Changes in liver acceptance patterns after implementation of share 35. PMID- 26479173 TI - Mothers' characteristics as predictors of adolescents' ethnic-racial identity: An examination of Mexican-origin teen mothers. AB - OBJECTIVE: The current longitudinal study examined Mexican-origin mothers' cultural characteristics and ethnic socialization efforts as predictors of their adolescent daughters' ethnic-racial identity (ERI) exploration, resolution, and affirmation. METHOD: Participants were 193 Mexican-origin adolescent mothers (M age = 16.78 years; SD = .98) and their mothers (M age = 41.24 years; SD = 7.11). RESULTS: Findings indicated that mothers' familism values and ERI exploration were positively associated with mother-reported ethnic socialization efforts 1 year later. Furthermore, mothers' ERI affirmation was a significant positive predictor of adolescents' ERI affirmation 2 years later, accounting for adolescents' ERI affirmation 1 year earlier. CONCLUSIONS: Discussion emphasizes the significance of ERI development among adolescent mothers who are negotiating the normative development of ERI and faced with their new role as parents and cultural socializers of their young children. (PsycINFO Database Record PMID- 26479174 TI - Determining Free-Radical Propagation Rate Coefficients with High-Frequency Lasers: Current Status and Future Perspectives. AB - Detailed knowledge of the polymerization mechanisms and kinetics of academically and industrially relevant monomers is mandatory for the precision synthesis of tailor-made polymers. The IUPAC-recommended pulsed-laser polymerization-size exclusion chromatography (PLP-SEC) approach is the method of choice for the determination of propagation rate coefficients and the associated Arrhenius parameters for free radical polymerization processes. With regard to specific monomer classes-such as acrylate-type monomers, which are very important from a materials point of view-high laser frequencies of up to 500 Hz are mandatory to prevent the formation of mid-chain radicals and the occurrence of chain-breaking events by chain transfer, if industrially relevant temperatures are to be reached and wide temperature ranges are to be explored (up to 70 degrees C). Herein the progress and state-of-the-art of high-frequency PLP-SEC with pulse repetition rates of 500 Hz is reported, with a critical collection of to-date investigated 500 Hz data as well as future perspectives for the field. PMID- 26479175 TI - Emerging targets in sarcoma: Rising to the challenge of RAS signaling in undifferentiated pleomorphic sarcoma. PMID- 26479181 TI - Colloidal Gold--Collagen Protein Core--Shell Nanoconjugate: One-Step Biomimetic Synthesis, Layer-by-Layer Assembled Film, and Controlled Cell Growth. AB - The biogenic synthesis of biomolecule-gold nanoconjugates is of key importance for a broad range of biomedical applications. In this work, a one-step, green, and condition-gentle strategy is presented to synthesize stable colloidal gold collagen core-shell nanoconjugates in an aqueous solution at room temperature, without use of any reducing agents and stabilizing agents. It is discovered that electrostatic binding between gold ions and collagen proteins and concomitant in situ reduction by hydroxyproline residues are critically responsible for the formation of the core-shell nanoconjugates. The film formed by layer-by-layer assembly of such colloidal gold-collagen nanoconjugates can notably improve the mechanical properties and promote cell adhesion, growth, and differentiation. Thus, the colloidal gold-collagen nanoconjugates synthesized by such a straightforward and clean manner, analogous to a biomineralization pathway, provide new alternatives for developing biologically based hybrid biomaterials toward a range of therapeutic and diagnostic applications. PMID- 26479182 TI - Modification of appetite by bread consumption: A systematic review of randomized controlled trials. AB - The inclusion of different ingredients or the use of different baking technologies may modify the satiety response to bread, and aid in the control of food intake. The aim of this study was to perform a systematic search of randomized clinical trials on the effect of bread consumption on appetite ratings in humans. The search equation was ("Bread"[MeSH]) AND ("Satiation"[MeSH] OR "Satiety response"[MeSH]), and the filter "clinical trials." As a result of this procedure, 37 publications were selected. The satiety response was considered as the primary outcome. The studies were classified as follows: breads differing in their flour composition, breads differing in ingredients other than flours, breads with added organic acids, or breads made using different baking technologies. In addition, we have revised the data related to the influence of bread on glycemic index, insulinemic index and postprandial gastrointestinal hormones responses. The inclusion of appropriate ingredients such as fiber, proteins, legumes, seaweeds and acids into breads and the use of specific technologies may result in the development of healthier breads that increase satiety and satiation, which may aid in the control of weight gain and benefit postprandial glycemia. However, more well-designed randomized control trials are required to reach final conclusions. PMID- 26479183 TI - Diastereoisomers of Ruthenium Dyes with Unsymmetric Ligands for DSC: Fundamental Chemistry and Photovoltaic Performance. AB - A new thiocyanic acid-free ruthenium sensitizer, CYC-B29, containing two unsymmetrical ancillary ligands, was synthesized, and its three diastereoisomers CYC-B29-CC, CYC-B29-TT, and CYC-B29-CT with significantly different optical, electronic, and electrochemical properties were carefully separated. CYC-B29-TT with the smallest size has the strongest absorption coefficient of the MLCT band, the shortest lambdamax, the lowest highest occupied molecular orbital level and the highest dye loading. Therefore, dye-sensitized solar cell based on CYC-B29-TT has the highest efficiency, which is two times higher than that of CYC-B29-CC sensitized device and 10% higher than that of N719-based cell. Time-dependent density functional theory-calculated transition bands for the three isomers are not identical, and only CYC-B29-TT has the calculated transition bands close to the experimental absorption profile. Although the calculated transition bands for CYC-B29-CC and CYC-B29-CT are not consistent with the experimental data, the ground-state vertical excitation energy with oscillator strength and electron density difference map data combining with the dye loading predict correctly the order of the photocurrent for the three isomers sensitized devices. PMID- 26479184 TI - Synthetic biology for microbial production of lipid-based biofuels. AB - The risks of maintaining current CO2 emission trends have led to interest in producing biofuels using engineered microbes. Microbial biofuels reduce emissions because CO2 produced by fuel combustion is offset by CO2 captured by growing biomass, which is later used as feedstock for biofuel fermentation. Hydrocarbons found in petroleum fuels share striking similarity with biological lipids. Here we review synthetic metabolic pathways based on fatty acid and isoprenoid metabolism to produce alkanes and other molecules suitable as biofuels. We further discuss engineering strategies to optimize engineered biosynthetic routes, as well as the potential of synthetic biology for sustainable manufacturing. PMID- 26479185 TI - Haemolacria: A Novel Approach to Lesion Localization. AB - PURPOSE: To report the use of punctal plugs as a new modality to assist in the localization of lesions providing symptomatic relief in patients with haemolacria during their workup. METHODS: Retrospective case series. RESULTS: One boy and one girl, ages 16 and 20, respectively, reported spontaneous bloody tearing. Workup included probing and irrigation of the nasolacrimal system, blood and coagulation profiles, blood typing, serum hormone levels, conjunctival biopsy, and imaging. All findings were normal and failed to suggest a cause in any of the cases. Punctal plugs were inserted into each patient's inferior punctum OS without complication. On initial follow-up visits, each patient reported cessation of bloody tears OS with continued bloody tears OD. Over time, both patients experienced complete cessation of haemolacria in both eyes. CONCLUSIONS: Haemolacria is a condition caused by a group of disorders that result in the production of tears that are partially composed of blood. The large majority of cases result in a specific diagnosis. Only rarely does workup result in undetermined etiology. The novel approach of utilizing punctal plugs in the management of haemolacria may not only provide symptomatic relief for lesions distal to and including the punctum, but also assists in anatomic localization in idiopathic cases. PMID- 26479187 TI - Childhood lead exposure and sexually transmitted infections: New evidence. AB - INTRODUCTION: The adverse health effects of lead exposure in children are well documented and include intellectual and behavioral maladies. Childhood lead exposure has also been linked to impulsive behaviors, which, in turn, are associated with a host of negative health outcomes including an increased risk for sexually transmitted infections (STI). The purpose of this study was to assess the association of lead exposure with STI rates across census tracts in St. Louis City, Missouri. METHODS: Incident cases of gonorrhea and chlamydia (GC) during 2011 were identified from the Missouri Department of Health and Senior Services and aggregated by census tract. We also geocoded the home address of 59,645 children >72 months in age who had blood lead level tests performed in St. Louis City from 1996 to 2007. Traditional regression and Bayesian spatial models were used to determine the relationship between GC and lead exposure while accounting for confounders (condom and alcohol availability, crime, and an index of concentrated disadvantage). RESULTS: Incident GC rates were found to cluster across census tracts (Moran's I=0.13, p=0.006). After accounting for confounders and their spatial dependence, a linear relationship existed between lead exposure and GC incidence across census tracts, with higher GC rates occurring in the northern part of St. Louis City CONCLUSIONS: At the census-tract level, higher lead exposure is associated with higher STI rates. Visualizing these patterns through maps may help deliver targeted interventions to reduce geographic disparities in GC rates. PMID- 26479188 TI - Structural & functional consequences of chronic psychosocial stress on the microbiome & host. AB - INTRODUCTION: Given the lasting impact of psychological distress on behavior, along with the role of the microbiome in neurobehavioral development, we sought to examine the relationship between the microbiota and stress-induced behavioral deficits. METHODS: Male C57BL/6 mice exposed to chronic social defeat were subjected to behavioral analysis and profiling of the intestinal microbiome. Mice were also analyzed for phenotypic and functional immune changes. A computational approach on 16S rRNA marker gene sequences was used to predict functional changes in the metagenome as a consequence of structural shifts in the microbiota. RESULTS: Chronic social defeat induced behavioral changes that were associated with reduced richness and diversity of the gut microbial community, along with distinct shifts at the level of operational taxonomic units (OTU) across phyla. The degree of deficits in social, but not exploratory behavior was correlated with group differences between the microbial community profile. In silico analysis predicted a shift in the functional profile of the microbiome: defeated mice exhibited reduced functional diversity and a lower prevalence of pathways involved in the synthesis and metabolism of neurotransmitter precursors and short chain fatty acids. Defeated mice also exhibited sustained alterations in dendritic cell activation, and transiently elevated levels of IL-10+ T regulatory cells that were suppressed over time. CONCLUSIONS: This study indicates that stress-induced disruptions in neurologic function are associated with altered immunoregulatory responses and complex OTU-level shifts in the microbiota. It is thus suggested that a dysbiotic state, along with specific changes in microbial markers, may predict the onset of adverse neurocognitive deficits commonly observed following exposure to severe stressors. The data also predict novel pathways that might underlie microbiota-mediated effects on brain and behavior, thus presenting targets for investigations into mechanisms and potential therapy. PMID- 26479186 TI - Leptin Matures Aspects of Lung Structure and Function in the Ovine Fetus. AB - In human and ovine fetuses, glucocorticoids stimulate leptin secretion, although the extent to which leptin mediates the maturational effects of glucocorticoids on pulmonary development is unclear. This study investigated the effects of leptin administration on indices of lung structure and function before birth. Chronically catheterized singleton sheep fetuses were infused iv for 5 days with either saline or recombinant ovine leptin (0.5 mg/kg . d leptin (LEP), 0.5 LEP or 1.0 mg/kg . d, 1.0 LEP) from 125 days of gestation (term ~145 d). Over the infusion, leptin administration increased plasma leptin, but not cortisol, concentrations. On the fifth day of infusion, 0.5 LEP reduced alveolar wall thickness and increased the volume at closing pressure of the pressure-volume deflation curve, interalveolar septal elastin content, secondary septal crest density, and the mRNA abundance of the leptin receptor (Ob-R) and surfactant protein (SP) B. Neither treatment influenced static lung compliance, maximal lung volume at 40 cmH2O, lung compartment volumes, alveolar surface area, pulmonary glycogen, protein content of the long form signaling Ob-Rb or phosphorylated signal transducers and activators of transcription-3, or mRNA levels of SP-A, C, or D, elastin, vascular endothelial growth factor-A, the vascular endothelial growth factor receptor 2, angiotensin-converting enzyme, peroxisome proliferator activated receptor gamma, or parathyroid hormone-related peptide. Leptin administration in the ovine fetus during late gestation promotes aspects of lung maturation, including up-regulation of SP-B. PMID- 26479189 TI - Better response to the SGLT2 inhibitor dapagliflozin in young adults with type 2 diabetes. AB - BACKGROUND AND AIM: A variation of the response to Sodium glucose co-transporter 2 (SGLT2) inhibitors with age has not been investigated in patients with diabetes. The aim of this study was to assess renal threshold of glucose (RTg) before and after administration of an SGLT2 inhibitor in young adult patients (<=40 years) and older adult patients (>40 years) with type 2 diabetes (T2DM). SUBJECTS AND METHODS: Twenty Japanese patients with T2DM were enrolled. Baseline data were obtained on the first day and dapagliflozin (5 mg) was administered at 6:00 on the second day. Glucose excursions were assessed by continuous glucose monitoring and urine samples were collected every hour during the daytime (7:00 to 15:00) on both days. RTg was estimated from the regression line of the scatter plot of the hourly mean glucose concentrations. RESULTS: After a single dose of dapagliflozin, RTg decreased from 121.5 to 6.1 mg/dl in the young adult group and from 151.0 mg/dl to -15.8 mg/dl in the older group. After dapagliflozin, the slope of the regression line was significantly steeper in the young adult group. CONCLUSION: Dapagliflozin was more effective in young patients because they showed a larger response of urinary glucose excretion. PMID- 26479190 TI - Effect of nitrogen doping on titanium carbonitride-derived adsorbents used for arsenic removal. AB - Arsenic in water and wastewater is considered to be a critical contaminant as it poses harmful health risks. In this regard, to meet the stringent regulation of arsenic in aqueous solutions, nitrogen doped carbon-based materials (CN) were prepared as adsorbents and tested for the removal of arsenic ion from aqueous solutions. Nitrogen-doped carbon (CNs) synthesized by chlorination exhibited well developed micro- and small meso-pores with uniform pore structures. The structure and characteristics of the adsorbents thus developed were confirmed by field emission scanning electron microscopy, transmission electron microscopy, Brunauer Emmett-Teller analysis, X-ray diffraction, X-ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy. Among the CNs developed, CN700 exhibited high adsorption capacity for arsenic (31.08 mg/g). The adsorption efficiency for arsenic ion was confirmed to be affected by pyrrolic nitrogen and micro-pores. These results suggest that CNs are useful adsorbents for the treatment of arsenic, and in particular, CN700 demonstrates potential for application as an adsorbent for the removal of anionic heavy metals from wastewater and sewage. PMID- 26479191 TI - DNA-free genome editing in plants with preassembled CRISPR-Cas9 ribonucleoproteins. AB - Editing plant genomes without introducing foreign DNA into cells may alleviate regulatory concerns related to genetically modified plants. We transfected preassembled complexes of purified Cas9 protein and guide RNA into plant protoplasts of Arabidopsis thaliana, tobacco, lettuce and rice and achieved targeted mutagenesis in regenerated plants at frequencies of up to 46%. The targeted sites contained germline-transmissible small insertions or deletions that are indistinguishable from naturally occurring genetic variation. PMID- 26479192 TI - Influence of the ionic liquid [C4mpy][Tf2N] on the structure of the miniprotein Trp-cage. AB - We examine the effect of the ionic liquid [C4mpy][Tf2N] on the structure of the miniprotein Trp-cage and contrast these results with the behavior of Trp-cage in water. We find the ionic liquid has a dramatic effect on Trp-cage, though many similarities with aqueous Trp-cage are observed. We assess Trp-cage folding by monitoring root mean square deviation from the crystallographic structure, radius of gyration, proline cis/trans isomerization state, protein secondary structure, amino acid contact formation and distance, and native and non-native contact formation. Starting from an unfolded configuration, Trp-cage folds in water at 298 K in less than 500 ns of simulation, but has very little mobility in the ionic liquid at the same temperature, which can be ascribed to the higher ionic liquid viscosity. At 365 K, the mobility of the ionic liquid is increased and initial stages of Trp-cage folding are observed, however Trp-cage does not reach the native folded state in 2 MUs of simulation in the ionic liquid. Therefore, in addition to conventional molecular dynamics, we also employ scaled molecular dynamics to expedite sampling, and we demonstrate that Trp-cage in the ionic liquid does closely approach the aqueous folded state. Interestingly, while the reduced mobility of the ionic liquid is found to restrict Trp-cage motion, the ionic liquid does facilitate proline cis/trans isomerization events that are not seen in our aqueous simulations. PMID- 26479193 TI - Polycystic ovary syndrome in globalizing India: An ecosocial perspective on an emerging lifestyle disease. AB - Polycystic ovary syndrome (PCOS) is an endocrine disorder linked to type II diabetes and the leading cause of female infertility worldwide. Despite being considered a "lifestyle" disease, PCOS has received scant attention in the social science literature. In India, media accounts citing prominent doctors have expressed concern that the syndrome affects a growing number of urban middle class Indian women. The general public, doctors, and afflicted women all attribute the condition to stress, lifestyle changes, "Westernization," modernization, and disrupted circadian rhythms. These factors are associated with changes in diets, gender roles, and aspirations since 1991, when the introduction of neoliberal reforms opened up the country to processes of globalization. Women with PCOS have come to be seen as living embodiments of the biosocial stresses associated with modern urban middle-class living, and discourse about PCOS serves as commentary indexing anxieties about social and political-economic shifts in the country. In this paper, based on ethnographic fieldwork in Mumbai, India, with 141 participants from 2012 to 2014, we point to local understanding of PCOS as corresponding to an ecosocial perspective that highlights the structural vulnerabilities of urban middle-class women. Whereas most research on structural vulnerabilities and health has centered on economically and otherwise disadvantaged groups, we use PCOS as a case study to draw attention to the rise of lifestyle disorders linked to the impact of globalization and the pressures of "modern" identities and aspirations among middle-class populations. PMID- 26479194 TI - Single-Band 2-nm-Line-Width Plasmon Resonance in a Strongly Coupled Au Nanorod. AB - This paper reports a dramatic reduction in plasmon resonance line width of a single Au nanorod by coupling it to a whispering gallery cavity of a silica microfiber. With fiber diameter below 6 MUm, strong coupling between the nanorod and the cavity occurs, leading to evident mode splitting and spectral narrowing. Using a 1.46-MUm-diameter microfiber, we obtained single-band 2-nm-line-width plasmon resonance in an Au nanorod around a 655-nm-wavelength, with a quality factor up to 330 and extinction ratio of 30 dB. Compared to an uncoupled Au nanorod, the strongly coupled nanorod offers a 30-fold enhancement in the peak intensity of plasmonic resonant scattering. PMID- 26479195 TI - Spot Spraying Reduces Herbicide Concentrations in Runoff. AB - Rainfall simulator trials were conducted on sugar cane paddocks across dry tropical and subtropical Queensland, Australia, to examine the potential for spot spraying to reduce herbicide losses in runoff. Recommended rates of the herbicides glyphosate, 2,4-D, fluoroxypyr, atrazine, and diuron were sprayed onto 0, 20, 40, 50, 70, or 100% of the area of runoff plots. Simulated rainfall was applied 2 days after spraying to induce runoff at one plant cane and three ratoon crop sites. Over 50% of all herbicides were transported in the dissolved phase of runoff, regardless of the herbicide's sediment-water partition coefficient. For most sites and herbicides, runoff herbicide concentrations decreased with decreasing spray coverage and with decreasing herbicide load in the soil and cane residues. Importantly, sites with higher infiltration prior to runoff and lower total runoff had lower runoff herbicide concentrations. PMID- 26479196 TI - Influence mechanism of low-dose ionizing radiation on Escherichia coli DH5alpha population based on plasma theory and system dynamics simulation. AB - It remains a mystery why the growth rate of bacteria is higher in low-dose ionizing radiation (LDIR) environment than that in normal environment. In this study, a hypothesis composed of environmental selection and competitive exclusion was firstly proposed from observed phenomena, experimental data and microbial ecology. Then a LDIR environment simulator (LDIRES) was built to cultivate a model organism of bacteria, Escherichia coli (E. coli) DH5alpha, the accurate response of bacterial population to ionizing radiation intensity variation was measured experimentally, and then the precise relative dosage of ionizing radiation E. coli DH5alpha population received was calculated by finite element analysis based on drift-diffusion equations of plasma. Finally, a highly valid mathematical model expressing the relationship between E. coli DH5alpha population and LDIR intensity was developed by system dynamics based on hypotheses, experimental data and microbial ecology. Both experiment and simulation results clearly showed that the E. coli DH5alpha individuals with greater specific growth rate and lower substrate consumption coefficient would adapt and survive in LDIR environment and those without such adaptability were finally eliminated under the combined effects of ionizing radiation selection and competitive exclusion. PMID- 26479197 TI - Stage-specific assembly events of the 6-MDa small-subunit processome initiate eukaryotic ribosome biogenesis. AB - Eukaryotic ribosome biogenesis involves a plethora of ribosome-assembly factors, and their temporal order of association with preribosomal RNA is largely unknown. By using Saccharomyces cerevisiae as a model organism, we developed a system that recapitulates and arrests ribosome assembly at early stages, thus providing in vivo snapshots of nascent preribosomal particles. Here we report the stage specific order in which 70 ribosome-assembly factors associate with preribosomal RNA domains, thereby forming the 6-MDa small-subunit processome. PMID- 26479199 TI - Control of magnetite primary particle size in aqueous dispersions of nanoclusters for high magnetic susceptibilities. AB - Aqueous dispersions of iron oxide nanoparticles with a high initial magnetic susceptibility (chii) are of interest as contrast agents in electromagnetic tomography. Nanoclusters composed of iron oxide primary particles were formed by co-precipitation of Fe(II) and Fe(III) chlorides at alkaline conditions and high temperature of 95 degrees C. Two-step addition of citrate was used to produce large primary particles and then stabilize the nanoclusters. The size of the primary particles was tuned from 5nm to 15nm by varying the citrate/iron precursor ratio during the normal phase hydrolysis reaction, while the second iteration of citrate stabilized the nanoclusters with hydrodynamic diameters of 30-75nm. The crystallinity of the iron oxide nanoparticles was promoted by annealing at 95 degrees C and systematically studied with Superconducting Quantum Interference Device (SQUID), Vibrating Sample Magnetometer (VSM), Transmission Electron Microscopy (TEM) and X-ray Diffraction (XRD). The dependence of chii was examined over a range of low volume fractions (0.005 18), and severe (AISI > 18). Additionally, comparing the 2 dynamic scores, AISI and Sartorius, AISI proved significantly faster than the Sartorius score (46.44 +/- 19.24 seconds vs 83.2 +/ 19.04 seconds; P =1.31 x 10-6). CONCLUSIONS: Being simple, fast, dynamic, and accurate, the AISI could represent the ideal measurement for HS severity in both real-life and clinical trial settings. PMID- 26479210 TI - A New Acid-oxidizing Solution: Assessment of Its Role on Methicillin-resistant Staphylococcus aureus (MRSA) Biofilm Morphological Changes. AB - OBJECTIVE: Biofilms represent a key challenge in the treatment of chronic wounds, as they are among the main reasons for delays in chronic wound healing. This in vitro study was aimed at evaluating the activity of a new acid-oxidizing solution (AOS) on biofilm formation. Acid-oxidizing solution contains free chlorine species with stabilized hypochlorous acid in high concentration (> 95%) and is characterized by acidic (pH less than 3) and super-oxidizing (Redox greater than 1000mV) features. MATERIALS AND METHODS: A 3-dimensional in vitro model of reconstructed human epidermis was used to compare the activity of AOS vs 2 reference products (RP) containing betaine and polyhexanide (RP1) and sodium hypochlorite and hypochlorous acid (RP2). Different approaches were used to assess the prevention and eradication of methicillin-resistant Staphyloccocus aureus biofilm by the study products. Xylitol and chlorhexidine were used as positive controls. The activity of the study products on the biofilm structure was evaluated analyzing the ultrastructural modification by scanning electron microscopy, while skin compatibility was assessed on noncolonized tissues measuring the metabolic activity of the cells. RESULTS: In all experiments, AOS showed to be active on the biofilm matrix, modifying its structure and allowing bacterial release from the matrix. In all experiments, no cytotoxicity was observed in the tissues treated with the product suggesting a good compatibility of AOS with skin tissues. Reference product 1 affected the biofilm, suggesting a disruption effect; RP2 was slightly less active than AOS in modifying the biofilm structure. CONCLUSION: Treatment with AOS affects biofilm by modifying its structure and therefore facilitating local bacteria accessibility to bactericidal agents, with consequent potential clinical benefits in the treatment of chronic wounds. PMID- 26479211 TI - Correlation Between Wound Temperature Obtained With an Infrared Camera and Clinical Wound Bed Score in Venous Leg Ulcers. AB - INTRODUCTION: The measurement of skin and wound bed temperature in chronic wounds may be a useful way to optimize the assessment and diagnosis of chronic wound infection. The aim of this clinical research trial was to correlate the wound bed score, validated by Falanga in 2006, to wound bed and perilesional skin temperature with an easy-to-use, handheld, noninvasive thermometer. MATERIALS AND METHODS: In this study, the authors recruited 18 patients affected by venous insufficiency and lower leg ulcers. A total of 24 chronic wound bed and perilesional skin ulcers were assessed using an infrared camera (FLIR T620 Thermal Imager, FLIR Systems Boston, MA). At the same visit, an operator blinded to the thermal image results made a wound bed score to make a clinical evaluation of the lesion. RESULTS: The wound bed temperature range after dressing removal was between 31 degrees C and 35 degrees C, and the perilesional skin temperature range was between 31 degrees C and 34 degrees C. The wound bed score range was between 5-14 (14 patients > 10; 11 patients <= 10). The study data showed an increasing relationship between the wound bed score and the wound bed temperature according to several studies that have demonstrated 33 degrees C is the critical temperature level required for normal cellular activity. The correlation between the wound bed score and the perilesional skin temperature is weaker compared to other measurements. CONCLUSION: The results obtained in this preliminary research suggest that this correlation is worth being further investigated with a larger dataset. PMID- 26479212 TI - Evidence Corner: Improving Outcomes of Colorectal Surgery. PMID- 26479213 TI - Editorial Message: The Psychology of Wound Healing. PMID- 26479214 TI - Geographic Variation in Outcome Benefits of Helicopter Transport for Trauma in the United States: A Retrospective Cohort Study. AB - OBJECTIVE: Evaluate the effect of US geographic region on outcomes of helicopter transport (HT) for trauma. BACKGROUND: HT is an integral component of trauma systems. Evidence suggests that HT is associated with improved outcomes; however, no studies examine the impact of geographic variation on outcomes for HT. METHODS: Retrospective cohort study of patients undergoing scene HT or ground transport in the National Trauma Databank (2009-2012). Subjects were divided by US census region. HT and ground transport subjects were propensity-score matched based on prehospital physiology and injury severity. Conditional logistic regression was used to evaluate the effect of HT on survival and discharge to home in each region. Region-level characteristics were assessed as potential explanatory factors. RESULTS: A total of 193,629 pairs were matched. HT was associated with increased odds of survival and discharge to home; however, the magnitude of these effects varied significantly across regions (P < 0.01). The South had the greatest survival benefit (odds ratio: 1.44; 95% confidence interval: 1.39-1.49, P < 0.01) and the Northeast had the greatest discharge to home benefit (odds ratio: 1.29; 95% confidence interval: 1.18-1.41, P < 0.01). A subset of region-level characteristics influenced the effect of HT on each outcome, including helicopter utilization, injury severity, trauma center and helicopter distribution, trauma center access, traffic congestion, and urbanicity (P < 0.05). CONCLUSIONS: Geographic region impacts the benefits of HT in trauma. Variations in resource allocation partially account for outcome differences. Policy makers should consider regional factors to better assess and allocate resources within trauma systems to optimize the role of HT. PMID- 26479216 TI - Incidence and causative agents of chemical eye injuries in Switzerland. AB - CONTEXT: Chemical eye injuries are ophthalmological emergencies with a high risk of secondary complications and severe visual loss. Only limited epidemiological data for such injuries are available for many countries. PATIENTS AND METHODS: We performed two independent studies. The cause of chemical eye injuries was assessed with a prospective questionnaire study. Questionnaires were sent to all ophthalmologists in Switzerland. A total of 163 patients (205 eyes) were included, between December 2012 and October 2014. Independent of the questionnaire study, the incidence of chemical eye injuries was assessed with a retrospective cohort study design using the database of the mandatory accident insurance. RESULTS: Ophthalmological questionnaires revealed that plaster/cement (20.5%), alkaline (12.2%) and acid (10.2%) solutions caused the highest number of chemical injuries. Only 2% of all injuries were classified as grade III and none as grade IV (Roper-Hall classification). The official toxicological information phone-hotline was contacted in 4.3% of cases. Using data from the accident insurance, an incidence of chemical eye injuries of about 50/100 000/year was found in the working population. CONCLUSION: Here, we present data on the involved agents of chemical eye injuries in Switzerland, and also the incidence of such injuries in the working population. This may also help to assess the need for further education programs and to improve and direct preventive measures. PMID- 26479215 TI - Examining the Psychometric Properties of the Sexual Excitation/Sexual Inhibition Inventory for Women (SESII-W) in a Sample of Lesbian and Bisexual Women. AB - The Sexual Excitation/Sexual Inhibition Inventory for Women (SESII-W) assesses propensities for sexual excitation (SE) and inhibition (SI). Previous research utilizing the SESII-W included samples comprised exclusively or almost entirely of heterosexual women. The purpose of this study was to examine the psychometric properties of the SESII-W and assess its relation to aspects of sexual function within a sample of lesbian and bisexual women. The sample included 974 self identified bisexual (n = 733) or lesbian/homosexual (n = 241) women who completed an online survey including items assessing women's sexual behaviors, feelings, and functioning, sociodemographics, and the SESII-W. The sample was split; exploratory factor analyses were conducted on the first half, yielding eight lower-order factors with two higher-order factors. Confirmatory factor analysis was conducted on the second half and suggested reasonable model fit. SI was positively correlated with sexual problems and negatively correlated with sexual pleasure; the correlations were significant but small. Hierarchical regression analyses were conducted to examine the relationships between SESII-W scores and sexual problems/sexual pleasure, controlling for age, relationship duration, and relationship status. Four lower-order factors predicted reports of sexual problems. Findings indicated the SESII-W has similar psychometric properties among sexual minority women as it does among heterosexual women. PMID- 26479217 TI - Readability of online patient resources for melanoma. AB - Medical information is often difficult for patients to understand. With specialized vocabulary and complex pathophysiology, even well-educated adults have trouble interpreting information about their healthcare. The average American adult reads at a seventh-grade level. In light of the inherent complexity of health information, the American Medical Association and National Institutes of Health have recommended that information for patients should be written at a sixth-grade level. The goal of this study was to evaluate the most commonly used online patient resources about melanoma in the context of these recommendations. A web search for 'melanoma' identified the 10 most-accessed websites. Location filters were disabled and sponsored results were excluded to avoid inadvertent search bias. All relevant, patient-directed articles were downloaded and formatted into plain text. Pictures, videos, links, advertisements, and references were removed. Readability analysis was carried out using 10 established tests, both overall and arranged by parent website for comparison. A total of 130 articles for melanoma information were identified. The overall mean reading grade level was 12.6. All sites exceeded the recommended sixth-grade level. Secondary analysis of articles grouped by website indicated a range of readability across sites from 9.9 (high school freshman) to 14.9 (university sophomore). Online patient resources for melanoma uniformly exceed the recommended reading level and may be too difficult for many Americans to understand. The range of readability among websites may indicate an opportunity for physicians to direct patients to more appropriate resources for their level of health literacy. PMID- 26479219 TI - A novel role of actomyosin bundles in ERK signaling. AB - Intracellular and extracellular mechanical environments have a significant impact on survival and proliferation of cells. While the extracellular signal-regulated kinase (ERK) subfamily of MAP kinases plays critical roles in regulations of these cellular behaviors, activation of ERK is affected by mechanical conditions of cells. We have recently found that ERK is activated on contractile actomyosin bundles. ERK activation on actomyosin bundles depends on tension in the bundles, which is generated by either myosin II activity of external forces. In this Addendum, we discuss a novel, potential role of actomyosin bundles in ERK signaling and mechanical regulation of cell survival and proliferation. PMID- 26479221 TI - The Controversial Case of Biperiden: From Prescription Drug to Drug of Abuse. PMID- 26479218 TI - Implications of age and conditional survival estimates for patients with melanoma. AB - Overall cancer incidence is decreasing, whereas melanoma cases are increasing. Conditional survival estimates offer a more accurate prognosis for patients the farther they are from time of diagnosis. The effect of age and stage on a melanoma patient's conditional survival estimate is unknown. Surveillance, Epidemiology, and End Results data were utilized to identify newly diagnosed cutaneous melanoma patients (N=95 041), from 1998 to 2005, with up to 12 years of follow-up. Estimates of disease-specific survival by stage and age were determined by Cox regression analysis and transformed to estimated conditional 5 year survival. Localized melanoma patients have an excellent 5-year survival at diagnosis and over subsequent years. For patients with localized and regional disease, an age effect is present for disease-specific mortality when comparing older patients (70-79 years) with younger patients (<30 years): hazard ratio (HR) for mortality 3.79 [95% confidence interval (CI) 3.01-4.84] and HR 2.36 (95% CI 1.93-2.91), respectively. No age effect difference is observed in disease specific survival for advanced disease: HR 1.14 (95% CI 0.87-1.53). Over time, conditional survival estimates improve for older patients with localized and regional disease. This improvement is not seen in distant disease, neither is the age gradient. Disease-specific mortality and conditional survival for patients with localized and regional melanomas are initially impacted by older age, with effects dissipating over time. Age does not affect survival in patients with advanced disease. Understanding the conditional 5-year disease-specific survival of melanoma based on age and stage can help patients and physicians, informing decision-making about treatment and surveillance. PMID- 26479220 TI - Pain Affects Clinical Patterns and Treatment Outcomes for Patients With Major Depressive Disorder Taking Fluoxetine. AB - The aim of the study was to determine whether baseline pain was associated with discernible clinical features and treatment outcomes for patients with major depressive disorder (MDD) receiving 6-week fluoxetine treatment. A total of 131 inpatients with acutely ill MDD were enrolled to receive 20 mg of fluoxetine daily for 6 weeks. Pain was measured by the Short-Form 36 body pain index. Symptom severity, functional impairment, and severity of adverse events were assessed at baseline and again at weeks 1 to 4 and 6 using the 17-item Hamilton Depression Rating Scale, Modified Work and Social Adjustment Scale, and Utvalg for Kliniske Undersogelser Side Effect Rating Scale, respectively. Simple linear regression was employed to examine the clinical variables significantly associated with pain. The generalized estimating equations method was used to analyze the influence of pain on the 17-item Hamilton Depression Rating Scale, Modified Work and Social Adjustment Scale, and Utvalg for Kliniske Undersogelser Side Effect Rating Scale over time. Of the 131 participants, 119 (90.8%) who completed baseline pain measurements and had at least 1 postbaseline assessment were included in the analysis. Patients experiencing greater pain were more likely to have more severe depression, to be at greater risk of suicide, to have functional impairment, to experience stressful life events, and to have poor treatment outcomes. These findings suggest that pain was significantly associated with multiple aspects of patients with MDD. Patients with MDD with higher levels of pain were clinically useful in predicting poor outcomes after acute fluoxetine treatment. PMID- 26479222 TI - Effect of Antipsychotic Dosing Regimen on Neurocognition in Schizophrenia. PMID- 26479224 TI - A Case of Frontotemporal Dementia Presenting With Treatment-Refractory Psychosis and Extreme Violence: Response to Combination of Clozapine, Medroxyprogesterone, and Sertraline. PMID- 26479223 TI - Efficacy of Tranylcypromine in Bipolar Depression: A Systematic Review. AB - OBJECTIVE: Currently, there is a paucity of treatment options with limited efficacy for bipolar depression. The monoamine oxidase inhibitor tranylcypromine might be an effective form of treatment. The current systematic review reassesses the efficacy and safety of tranylcypromine in bipolar depression. METHODS: For this systematic review comparing tranylcypromine with placebo or active comparators in bipolar depression, relevant randomized controlled trials were identified from systematic searches of PubMed, EMBASE, and Cochrane library databases. A manual search of the references of the included studies was also performed. RESULTS: Four studies with a total of 145 participants were identified. Response rates were higher in patients treated with tranylcypromine (60.0%-80.7%; overall response rate, 73.7%) compared with placebo, imipramine, and lamotrigine (the latter as add-on to a mood stabilizer) (12.9%-47.6%; overall response rate, 27.5%). The overall switch rate was 6.3% for patients treated with tranylcypromine and 18.4% for patients in the control group. CONCLUSIONS: This systematic review provides evidence for the efficacy and safety of tranylcypromine treatment in bipolar depression. Additional research is required to establish the efficacy of tranylcypromine as add-on to a mood stabilizer. PMID- 26479225 TI - Statistics Commentary Series: Commentary #12-One--Tailed and Two-Tailed Tests. PMID- 26479226 TI - Does the Naked Neck Meat Type Chicken Yield Lower Methionine Requirement Data? AB - Methionine (Met) requirement studies with homozygous (Na/Na) and heterozygous (Na/na) naked neck meat type chicken utilized 144 birds of average weight (50% each genotype and sex) within two N balance experiments involving both the starter (d10-20) and grower period (d25-35). The birds were randomly allotted to five experimental diets with graded protein supply and Met as the limiting amino acid. The proportion of native feed protein sources (soy protein concentrate, maize, wheat, fishmeal and wheat gluten) was kept constant to ensure a uniform protein quality in all diets. The Met requirement depending on genotype, sex, age period and growth performance (protein deposition) was estimated using a non linear modeling procedure of N utilization in monogastric animals. On average, 0.47% (Na/Na) and 0.45% (Na/na) dietary Met was established as adequate in the starter diet, as well as 0.37% (Na/Na) and 0.36% (Na/na) Met in the grower diet for both of the sexes. In conclusion, the Met requirement of the naked neck chicken is not significantly different from its normally-feathered counterparts. In addition, the low feather production was not reflected by reduced requirement for Met in naked neck birds. However, these conclusions are valid only at the given Met:Cys ratio (1:1) in the experimental diets. PMID- 26479227 TI - The Use of a Shelter Software (a) to Track Frequency and Selected Risk Factors for Feline Upper Respiratory Infection. AB - Objective-Feline upper respiratory infection (URI) is a common, multi-factorial infectious disease syndrome endemic to many animal shelters. Although a significant cause of morbidity and mortality in shelter cats, URI is seldom formally monitored in shelter cat populations. Without monitoring, effective control and prevention of this often endemic disease is difficult. We looked at an integrated case management software system (a) for animal care organizations, widely used in shelters across the United States. Shelter staff routinely enter information regarding individual animals and disease status, but do not commonly use the software system to track frequency of disease. The purpose of this study was to determine if the software system (a) can be used to track URI frequency and selected risk factors in a population, and to evaluate the quality and completeness of the data as currently collected in a shelter. Design (type of study)-Descriptive Survey. Animals (or Sample)-317 cats in an animal shelter. Procedures-Reports from the software system (a) containing data regarding daily inventory, daily intake, animal identification, location, age, vaccination status, URI diagnosis and URI duration were evaluated. The reports were compared to data collected manually by an observer (Ann Therese Kommedal) to assess discrepancies, completeness, timeliness, availability and accuracy. Data were collected 6 days a week over a 4 week period. Results-Comparisons between the software system (a) reports and manually collected reports showed that 93% of inventory reports were complete and of these 99% were accurate. Fifty-two percent of the vaccination reports were complete, of which 97% were accurate. The accuracy of the software system's age reports was 76%. Two-hundred and twenty three cats were assigned a positive or negative URI diagnosis by the observer. The predictive value of the URI status in the software system (a) was below 60% both for positive and negative URI diagnosis. Conclusions and Clinical Relevance data currently collected and entered into the software systems in the study shelter, was not useful for tracking URI frequency and risk factors, due to issues with both data quality and capture. However, the potential exists to increase the practicality and usefulness of this shelter software system to monitor URI and other diseases. Relevant data points, i.e., health status at intake and outcome, vaccination date and status, as well as age, should be made mandatory to facilitate more useful data collection and reporting. PMID- 26479229 TI - 2004 Methane and Nitrous Oxide Emissions from Manure Management in South Africa. AB - Manure management in livestock makes a significant contribution towards greenhouse gas emissions in the Agriculture; Forestry and Other Land Use category in South Africa. Methane and nitrous oxide emissions are prevalent in contrasting manure management systems; promoting anaerobic and aerobic conditions respectively. In this paper; both Tier 1 and modified Tier 2 approaches of the IPCC guidelines are utilized to estimate the emissions from South African livestock manure management. Activity data (animal population, animal weights, manure management systems, etc.) were sourced from various resources for estimation of both emissions factors and emissions of methane and nitrous oxide. The results show relatively high methane emissions factors from manure management for mature female dairy cattle (40.98 kg/year/animal), sows (25.23 kg/year/animal) and boars (25.23 kg/year/animal). Hence, contributions for pig farming and dairy cattle are the highest at 54.50 Gg and 32.01 Gg respectively, with total emissions of 134.97 Gg (3104 Gg CO2 Equivalent). Total nitrous oxide emissions are estimated at 7.10 Gg (2272 Gg CO2 Equivalent) and the three main contributors are commercial beef cattle; poultry and small-scale beef farming at 1.80 Gg; 1.72 Gg and 1.69 Gg respectively. Mitigation options from manure management must be taken with care due to divergent conducive requirements of methane and nitrous oxide emissions requirements. PMID- 26479228 TI - Challenges of Managing Animals in Disasters in the U.S. AB - Common to many of the repeated issues surrounding animals in disasters in the U.S. is a pre-existing weak animal health infrastructure that is under constant pressure resulting from pet overpopulation. Unless this root cause is addressed, communities remain vulnerable to similar issues with animals they and others have faced in past disasters. In the US the plight of animals in disasters is frequently viewed primarily as a response issue and frequently handled by groups that are not integrated with the affected community's emergency management. In contrast, animals, their owners, and communities would greatly benefit from integrating animal issues into an overall emergency management strategy for the community. There is no other factor contributing as much to human evacuation failure in disasters that is under the control of emergency management when a threat is imminent as pet ownership. Emergency managers can take advantage of the bond people have with their animals to instill appropriate behavior amongst pet owners in disasters. PMID- 26479230 TI - Behavioral Response of Invertebrates to Experimental Simulation of Pre-Seismic Chemical Changes. AB - Unusual behavior before earthquakes has been reported for millennia but no plausible mechanism has been identified. One possible way in which animals could be affected by pre-earthquake processes is via stress activated positive holes leading to the formation of hydrogen peroxide at the rock water interface. Aquatic and fossorial animals could be irritated by H2O2 and move down the concentration gradient. Here, we carry out avoidance tests with hydrogen peroxide in two model organisms; Daphnia pulex and earthworms. Daphnia were found to move away from increasing concentrations of H2O2 but earthworms appeared unaffected. It is possible that earthworm swarming behavior, reported frequently before earthquakes, is caused by electric field shifts or another unknown mechanism, whereas zooplankton may be affected by increasing levels of H2O2. PMID- 26479231 TI - The Efficiency of an Integrated Program Using Falconry to Deter Gulls from Landfills. AB - Gulls are commonly attracted to landfills, and managers are often required to implement cost-effective and socially accepted deterrence programs. Our objective was to evaluate the effectiveness of an intensive program that integrated the use of trained birds of prey, pyrotechnics, and playback of gull distress calls at a landfill located close to a large ring-billed gull (Larus delawarensis) colony near Montreal, Quebec, Canada. We used long-term survey data on bird use of the landfill, conducted behavioral observations of gulls during one season and tracked birds fitted with GPS data loggers. We also carried out observations at another landfill located farther from the colony, where less refuse was brought and where a limited culling program was conducted. The integrated program based on falconry resulted in a 98% decrease in the annual total number of gulls counted each day between 1995 and 2014. A separate study indicated that the local breeding population of ring-billed gulls increased and then declined during this period but remained relatively large. In 2010, there was an average (+/-SE) of 59 +/- 15 gulls/day using the site with falconry and only 0.4% +/- 0.2% of these birds were feeding. At the other site, there was an average of 347 +/- 55 gulls/day and 13% +/- 3% were feeding. Twenty-two gulls tracked from the colony made 41 trips towards the landfills: twenty-five percent of the trips that passed by the site with falconry resulted in a stopover that lasted 22 +/- 7 min compared to 85% at the other landfill lasting 63 +/- 15 min. We concluded that the integrated program using falconry, which we consider more socially acceptable than selective culling, was effective in reducing the number of gulls at the landfill. PMID- 26479232 TI - Characteristics of Trailer Thermal Environment during Commercial Swine Transport Managed under U.S. Industry Guidelines. AB - Transport is a critical factor in modern pork production and can seriously affect swine welfare. While previous research has explored thermal conditions during transport, the impact of extreme weather conditions on the trailer thermal environment under industry practices has not been well documented; and the critical factors impacting microclimate are not well understood. To assess the trailer microclimate during transport events, an instrumentation system was designed and installed at the central ceiling level, pig level and floor-level in each of six zones inside a commercial swine trailer. Transport environmental data from 34 monitoring trips (approximately 1-4 h in duration each) were collected from May, 2012, to February, 2013, with trailer management corresponding to the National Pork Board Transport Quality Assurance (TQA) guidelines in 31 of these trips. According to the TQA guidelines, for outdoor temperature ranging from 5 degrees C (40 degrees F) to 27 degrees C (80 degrees F), acceptable thermal conditions were observed based on the criteria that no more than 10% of the trip duration was above 35 degrees C (95 degrees F) or below 0 degrees C (32 degrees F). Recommended bedding, boarding and water application were sufficient in this range. Measurements support relaxing boarding guidelines for moderate outdoor conditions, as this did not result in less desirable conditions. Pigs experienced extended undesirable thermal conditions for outdoor temperatures above 27 degrees C (80 degrees F) or below 5 degrees C (40 degrees F), meriting a recommendation for further assessment of bedding, boarding and water application guidelines for extreme outdoor temperatures. An Emergency Livestock Weather Safety Index (LWSI) condition was observed inside the trailer when outdoor temperature exceeded 10 degrees C (50 degrees F); although the validity of LWSI to indicate heat stress for pigs during transport is not well established. Extreme pig surface temperatures in the rear and middle zones of the trailer were more frequently experienced than in the front zones, and the few observations of pigs dead or down upon arrival were noted in these zones. Observations indicate that arranging boarding placement may alter the ventilation patterns inside the trailer. PMID- 26479233 TI - The Use of Refuges by Communally Housed Cats. AB - The increase of domestic animals kept in shelters highlights the need to ensure animal welfare. Environmental enrichment can improve animal welfare in many ways, such as encouraging captive animals to use all the space available to them. The effects of physical environmental enrichment on the spatial distribution and behavioral repertoire of 35 neutered domestic cats housed communally were analyzed. The provision of boxes in the environment increases the use of available space by the cats. We suggest this improves the cats' welfare while in communally-housed rescue shelters. The frequencies of active and especially inactive behaviors also increased in the enriched condition. In a test with vertical environmental enrichment, the animals showed an increased length of stay in refuges located at a height of 0.5 m compared to those on the ground (0.0 m). However, the entry frequency was higher in refuges at 0.0 m. Both horizontal and vertical environmental enrichment increased the use of available space, demonstrating that box refuges as enrichment are effective in providing a refuge when at a height, or a place to explore at ground level. We suggest it enhances the welfare of cats in communally housed shelters. This information adds to the body of evidence relating to cat enrichment and can be useful in designing cat housing in veterinary clinics, research laboratories, shelters and domestic homes. PMID- 26479234 TI - The Mississippi State University College of Veterinary Medicine Shelter Program. AB - The shelter program at the Mississippi State University College of Veterinary Medicine provides veterinary students with extensive experience in shelter animal care including spay/neuter, basic wellness care, diagnostics, medical management, disease control, shelter management and biosecurity. Students spend five days at shelters in the junior year of the curriculum and two weeks working on mobile veterinary units in their senior year. The program helps meet accreditation standards of the American Veterinary Medical Association's Council on Education that require students to have hands-on experience and is in keeping with recommendations from the North American Veterinary Medical Education Consortium. The program responds, in part, to the challenge from the Pew Study on Future Directions for Veterinary Medicine that argued that veterinary students do not graduate with the level of knowledge and skills that is commensurate with the number of years of professional education. PMID- 26479236 TI - Determinants of Cat Choice and Outcomes for Adult Cats and Kittens Adopted from an Australian Animal Shelter. AB - The percentage of adult cats euthanized in animal shelters is greater than that of kittens because adult cats are less likely to be adopted. This study aimed to provide evidence to inform the design of strategies to encourage adult cat adoptions. One such strategy is to discount adoption prices, but there are concerns that this may result in poor adoption outcomes. We surveyed 382 cat adopters at the time of adoption, to assess potential determinants of adopters' cat age group choice (adult or kitten) and, for adult cat adopters, the price they are willing to pay. The same respondents were surveyed again 6-12 months after the adoption to compare outcomes between cat age groups and between adult cats in two price categories. Most adopters had benevolent motivations for adopting from the shelter and had put considerable thought into the adoption and requirements for responsible ownership. However, adult cat adopters were more likely to have been influenced by price than kitten adopters. Adoption outcomes were generally positive for both adult cats and kittens and for adult cats adopted at low prices. The latter finding alleviates concerns about the outcomes of "low-cost" adoptions in populations, such as the study population, and lends support for the use of "low-cost" adoptions as an option for attempting to increase adoption rates. In addition, the results provide information that can be used to inform future campaigns aimed at increasing the number of adult cat adoptions, particularly in devising marketing strategies for adult cats. PMID- 26479235 TI - Bleeding Diathesis in Fawn Hooded Rats-Possible Implications for Invasive Procedures and Refinement Strategies. AB - The Fawn hooded (FH) rat is commonly used in biomedical research. It is widely acknowledged that the FH rat has a bleeding disorder; leading to abundant bleedings. Although this bleeding disorder is investigated to model the storage pool defect; its impact on commonly performed invasive laboratory procedures has not yet been described. Our research group experienced clinically significant consequences of this bleeding disorder following invasive procedures (including intraperitoneal injections and neurocranial surgery) in the Rjlbm: FH stock. The clinical consequences of the surgical and anesthetic protocols applied; are described including the subsequent procedural refinements applied to minimize the impact of this disorder. It is strongly recommended to take the bleeding diathesis into account when performing invasive procedures in FH rats and to apply the suggested refinement of procedures. PMID- 26479237 TI - A Critical Look at Biomedical Journals' Policies on Animal Research by Use of a Novel Tool: The EXEMPLAR Scale. AB - Animal research is not only regulated by legislation but also by self-regulatory mechanisms within the scientific community, which include biomedical journals' policies on animal use. For editorial policies to meaningfully impact attitudes and practice, they must not only be put into effect by editors and reviewers, but also be set to high standards. We present a novel tool to classify journals' policies on animal use-the EXEMPLAR scale-as well as an analysis by this scale of 170 journals publishing studies on animal models of three human diseases: Amyotrophic Lateral Sclerosis, Type-1 Diabetes and Tuberculosis. Results show a much greater focus of editorial policies on regulatory compliance than on other domains, suggesting a transfer of journals' responsibilities to scientists, institutions and regulators. Scores were not found to vary with journals' impact factor, country of origin or antiquity, but were, however, significantly higher for open access journals, which may be a result of their greater exposure and consequent higher public scrutiny. PMID- 26479238 TI - Problems Associated with the Microchip Data of Stray Dogs and Cats Entering RSPCA Queensland Shelters. AB - A lack of published information documenting problems with the microchip data for the reclaiming of stray animals entering Australian shelters limits improvement of the current microchipping system. A retrospective study analysing admission data for stray, adult dogs (n = 7258) and cats (n = 6950) entering the Royal Society for the Prevention of Cruelty to Animals (RSPCA) Queensland between January 2012 and December 2013 was undertaken to determine the character and frequency of microchip data problems and their impact on outcome for the animal. Only 28% of dogs and 9% of cats were microchipped, and a substantial proportion (37%) had problems with their data, including being registered to a previous owner or organisation (47%), all phone numbers incorrect/disconnected (29%), and the microchip not registered (14%). A higher proportion of owners could be contacted when the microchip had no problems, compared to those with problems (dogs, 93% vs. 70%; cats, 75% vs. 41%). The proportion of animals reclaimed declined significantly between microchipped animals with no data problems, microchipped animals with data problems and non-microchipped animals-87%, 69%, and 37%, respectively, for dogs and 61%, 33%, and 5%, respectively, for cats. Strategies are needed to increase the accuracy of microchip data to facilitate the reclaiming of stray dogs and cats. PMID- 26479239 TI - Adaptation of Piglets Using Different Methods of Stress Prevention. AB - The purpose of this study was to evaluate the viability and growth rate of piglets after weaning, the content of lipids in the blood and liver, antioxidant activity (AOA) and lipid peroxidation (LPO) when various additives are used in feed. The experiments were performed on two crosses of piglets obtained from Large White breed sows and Landrace breed boars. Twenty to 28 animals were randomly assigned per group. The following additives were tested: the benzodiazepine phenazepam, the neuroleptic aminazine, vitamins E and C, and the extract Eleutherococcus senticosus (Araliaceae). Different doses and combinations of the additives against ultraviolet irradiation were used. The addition of these substances improved the growth rate and viability of piglets. AOA increased under the influence of all factors studied, especially with the addition of extract of Eleutherococcus in feed in combination with aminazine and UV-irradiation (p < 0.01). However, the addition of Eleutherococcus extract and aminazine intensified LPO (p < 0.01), but use of UV irradiation helped to decrease LPO values (p < 0.01). Feeding a mixture of additives per pig per day of 3 mL of Eleutherococcus extract, 80 mg of 25% tocopherol, and 500 mg of ascorbic acid increased survival rate, average daily gain, and live weight at the end of the experiment. Thus, the use of prophylactic antistress and sedative drugs during weaning helps AOA normalize LPO of red blood cells; enhance post weaning growth of the pigs by 4.8% to 24.6% and increases piglet survival rate by 5% to 5.1%. PMID- 26479240 TI - The Impacts of Climate Change Mitigation Strategies on Animal Welfare. AB - The objective of this review is to point out that the global dialog on reducing greenhouse gas emissions in animal agriculture has, thus far, not adequately considered animal welfare in proposed climate change mitigation strategies. Many suggested approaches for reducing emissions, most of which could generally be described as calls for the intensification of production, can have substantial effects on the animals. Given the growing world-wide awareness and concern for animal welfare, many of these approaches are not socially sustainable. This review identifies the main emission abatement strategies in the climate change literature that would negatively affect animal welfare and details the associated problems. Alternative strategies are also identified as possible solutions for animal welfare and climate change, and it is suggested that more attention be focused on these types of options when allocating resources, researching mitigation strategies, and making policy decisions on reducing emissions from animal agriculture. PMID- 26479241 TI - The First Shared Online Curriculum Resources for Veterinary Undergraduate Learning and Teaching in Animal Welfare and Ethics in Australia and New Zealand. AB - The need for undergraduate teaching of Animal Welfare and Ethics (AWE) in Australian and New Zealand veterinary courses reflects increasing community concerns and expectations about AWE; global pressures regarding food security and sustainability; the demands of veterinary accreditation; and fears that, unless students encounter AWE as part of their formal education, as veterinarians they will be relatively unaware of the discipline of animal welfare science. To address this need we are developing online resources to ensure Australian and New Zealand veterinary graduates have the knowledge, and the research, communication and critical reasoning skills, to fulfill the AWE role demanded of them by contemporary society. To prioritize development of these resources we assembled leaders in the field of AWE education from the eight veterinary schools in Australia and New Zealand and used modified deliberative polling. This paper describes the role of the poll in developing the first shared online curriculum resource for veterinary undergraduate learning and teaching in AWE in Australia and New Zealand. The learning and teaching strategies that ranked highest in the exercise were: scenario-based learning; a quality of animal life assessment tool; the so-called 'Human Continuum' discussion platform; and a negotiated curriculum. PMID- 26479242 TI - Effect of Provision of Feed and Water during Transport on the Welfare of Weaned Pigs. AB - Transportation is a complex stressor made up of factors including weaning itself and withdrawal from feed and water. Therefore, transportation has the potential to negatively impact the health and welfare of weaned pigs. Pigs were transported for 32 h and measures of performance, physiology, and behavior were taken to assess piglet welfare. Treatment groups included pigs not weaned or transported (CON), weaned pigs provided with feed and water (WEAN+), weaned pigs not provided with feed and water (WEAN-), weaned and transported pigs provided with feed and water (TRANS+), and weaned and transported pigs not provided with feed and water (TRANS-). Body weight loss was different among treatments (p < 0.01). CON pigs had a 6.5% +/- 0.45% gain in body weight after 32 h. WEAN+, WEAN-, TRANS+, and TRANS- groups all had a loss in body weight of 5.9% +/- 0.45%, 7.8% +/- 0.45%, 6.5% +/- 0.45% and 9.1% +/- 0.46%, respectively. The N:L was greater in all weaned pigs at 8 h compared to CON pigs (p < 0.01). WEAN- and transported pigs had significantly higher N:L than CON pigs from 8 h through 16 h, however, all treatment groups were similar to CON pigs after 16 h irrespective of provision of feed and water. Blood glucose levels were lower in transported and/or weaned pigs than CON pigs after 16 h irrespective of the provision of feed and water. TRANS+ females had higher creatine kinase (CK) levels than males (p < 0.05). After a 16 h transport period, TRANS- pigs had higher total plasma protein (TP) levels than all other treatment groups (p < 0.05). Significant changes in behavior were observed during and after transportation, which could also be indicative of stress. Overall, transportation and weaning had a negative effect on performance, physiology and behavior (both during and post-weaning) of pigs, especially when feed and water was not provided. Transporting pigs without feed and water for more than 24 h was a welfare concern as indicated by changes in body weight and physiology measures of stress. PMID- 26479243 TI - Epidemiology of Dog and Cat Abandonment in Spain (2008-2013). AB - Millions of pets are abandoned worldwide every year, which is an important animal welfare and financial problem. This paper was divided into three studies. Our first two studies were designed as a national survey of animal shelters to profile the population of stray dogs and cats, as well as to gather information on both relinquishment and adoption. The aim of our third study was to test the impact of identification on the recovery of dogs entering animal shelters. Studies one and two indicate that more than 100,000 dogs and more than 30,000 cats enter animal shelters annually in Spain. We observed a seasonal effect in the number of admissions in cats. Two-thirds of dogs and cats entering shelters were found as strays, while the rest were relinquished directly to the shelter. Most pets admitted to animal shelters were adult, non-purebred, and without a microchip, with the majority of dogs being medium sized. Adult dogs spent significantly more time in shelters than puppies. While most animals were either adopted or recovered by their owner, a considerable percentage remained at the shelter or was euthanized. The identification of dogs with a microchip increased by 3-fold the likelihood of them being returned to the owner. PMID- 26479244 TI - Dietary Mannoheptulose Increases Fasting Serum Glucagon Like Peptide-1 and Post Prandial Serum Ghrelin Concentrations in Adult Beagle Dogs. AB - There is a growing interest in the use of nutraceuticals for weight management in companion animals. The purpose of this study was to determine the effects of mannoheptulose (MH), a sugar in avocados that inhibits glycolysis, on energy metabolism in adult Beagle dogs. The study was a double-blind, randomized controlled trial where dogs were allocated to a control (CON, n = 10, 10.1 +/- 0.4 kg) or MH containing diet (168 mg/kg, n = 10, 10.3 +/- 0.4 kg). Blood was collected after an overnight fast and 1 h post-feeding (week 12) to determine serum satiety related hormones and biochemistry. Resting and post-prandial energy expenditure and respiratory quotient were determined by indirect calorimetry (weeks 4 and 8). Physical activity was measured using an accelerometer (weeks 3, 7, 11). Body composition was assessed using dual X-ray absorptiometry (week 12). MH significantly (p < 0.05) increased fasting serum glucagon-like peptide-1 and post-prandial serum ghrelin. MH tended (p < 0.1) to increase fasting serum gastric inhibitory peptide and decrease physical activity. Together, these findings suggest that dietary MH has the ability to promote satiation and lowers daily energy expenditure. PMID- 26479245 TI - Association Tests of Multiple Phenotypes: ATeMP. AB - Joint analysis of multiple phenotypes has gained growing attention in genome-wide association studies (GWASs), especially for the analysis of multiple intermediate phenotypes which measure the same underlying complex human disorder. One of the multivariate methods, MultiPhen (O' Reilly et al. 2012), employs the proportional odds model to regress a genotype on multiple phenotypes, hence ignoring the phenotypic distributions. Despite the flexibilities of MultiPhen, the properties and performance of MultiPhen are not well understood, especially when the phenotypic distributions are non-normal. In fact, it is well known in the statistical literature that the estimation is attenuated when the explanatory variables contain measurement errors. In this study, we first established an equivalence relationship between MultiPhen and the generalized Kendall tau association test, shedding light on why MultiPhen can perform well for joint association analysis of multiple phenotypes. Through the equivalence, we show that MultiPhen may lose power when the phenotypes are non-normal. To maintain the power, we propose two solutions (ATeMP-rn and ATeMP-or) to improve MultiPhen, and demonstrate their effectiveness through extensive simulation studies and a real case study from the Guangzhou Twin Eye Study. PMID- 26479246 TI - Activity Augmentation of Amphioxus Peptidoglycan Recognition Protein BbtPGRP3 via Fusion with a Chitin Binding Domain. AB - Peptidoglycan recognition proteins (PGRPs), which have been identified in most animals, are pattern recognition molecules that involve antimicrobial defense. Resulting from extraordinary expansion of innate immune genes, the amphioxus encodes many PGRPs of diverse functions. For instance, three isoforms of PGRP encoded by Branchiostoma belcheri tsingtauense, termed BbtPGRP1~3, are fused with a chitin binding domain (CBD) at the N-terminus. Here we report the 2.7 A crystal structure of BbtPGRP3, revealing an overall structure of an N-terminal hevein like CBD followed by a catalytic PGRP domain. Activity assays combined with site directed mutagenesis indicated that the individual PGRP domain exhibits amidase activity towards both DAP-type and Lys-type peptidoglycans (PGNs), the former of which is favored. The N-terminal CBD not only has the chitin-binding activity, but also enables BbtPGRP3 to gain a five-fold increase of amidase activity towards the Lys-type PGNs, leading to a significantly broadened substrate spectrum. Together, we propose that modular evolution via domain shuffling combined with gene horizontal transfer makes BbtPGRP1~3 novel PGRPs of augmented catalytic activity and broad recognition spectrum. PMID- 26479247 TI - Leukemia Inhibitory Factor (LIF) Inhibition during Mid-Gestation Impairs Trophoblast Invasion and Spiral Artery Remodelling during Pregnancy in Mice. AB - The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Trophoblast cell proliferation, migration and invasion into the endometrium are fundamental events in the initiation of placentation. Leukemia inhibitory factor (LIF) has been shown to promote trophoblast invasion in vitro, however its precise role in trophoblast invasion in vivo is unknown. We hypothesized that LIF would be required for normal trophoblast invasion and spiral artery remodeling in mice. Both LIF and its receptor (LIFRalpha) co-localized with cytokeratin-positive invasive endovascular extravillous trophoblasts (EVT) in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via administration of our unique LIFRalpha antagonist, PEGLA, resulted in abnormal trophoblast invasion and impaired spiral artery remodeling compared to PEG control. PEGLA-treated mouse decidual vessels were characterized by retention of alpha-smooth muscle actin (alphaSMA)-positive vascular smooth muscle cells (VSMCs), while PEG control decidual vessels were remodelled by cytokeratin-positive trophoblasts. LIF blockade did not alter F4/80 positive decidual macrophage numbers between treatment groups, but resulted in down-regulation of decidual transcript levels of monocyte chemoattractant protein 1 (MCP-1) and interleukin-10 (IL-10), which are important immune cell activation factors that promote spiral artery remodeling during pregnancy. Our data suggest that LIF plays an important role in trophoblast invasion in vivo and may facilitate trophoblast-decidual-immune cell cross talk to enable adequate spiral artery remodeling. PMID- 26479249 TI - [Abuse of power by psychiatrists--or why we should regularly take a good hard look in the mirror]. PMID- 26479248 TI - Paracetamol (acetaminophen) poisoning. AB - INTRODUCTION: Paracetamol directly causes around 150 deaths per year in UK. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments for acute paracetamol poisoning? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 127 studies. After deduplication and removal of conference abstracts, 64 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 46 studies and the further review of 18 full publications. Of the 18 full articles evaluated, one systematic review was updated and one RCT was added at this update. In addition, two systematic reviews and three RCTs not meeting our inclusion criteria were added to the Comment sections. We performed a GRADE evaluation for three PICO combinations. CONCLUSIONS: In this systematic overview we categorised the efficacy for six interventions, based on information about the effectiveness and safety of activated charcoal (single or multiple dose), gastric lavage, haemodialysis, liver transplant, methionine, and acetylcysteine. PMID- 26479250 TI - [Somatic screening in child and adolescent psychiatry: a descriptive pilot study]. AB - BACKGROUND: Somatic disorders occur more often in psychiatric patients than in the general population. Somatic symptoms can cause or increase psychiatric symptoms. Psychiatric symptoms and their treatment can have an effect on the physical state of the patient. A pilot study involving an adult outpatient population has demonstrated that 62% of the patients studied had new clinically relevant symptoms. So far, no other data are available relating to somatic screening in child and adolescent psychiatry. AIM: To assess whether somatic screening of children and adolescents newly referred to a department of child and adolescent psychiatry in the Netherlands gives added value to the diagnosis and treatment policy. METHOD: In a pilot study 43 newly referred patients aged between 6 and 18 were screened by means of somatic history, a physical examination and blood parameters. On this basis we could calculate the percentage of somatic symptoms and , where necessary, follow-up treatment could be applied. RESULTS: One or more clinically relevant disorders were found in almost 56% of the children and adolescents investigated. The disorders included dysmorphic anomalies, weight and height deviations, raised thyroid hormone levels, dyslipidaemia, anaemia and vitamin D and B12 deficiency. Advice about a healthy lifestyle was given to 44% of the patients. An antipsychotic medication in 25% of the patients was changed, in the case of 16% of the patients a family doctor was contacted about subsequent treatment and 19% of the patients were referred to a medical specialist. CONCLUSION: Although the results of the pilot study indicate that somatic screening does provide added value, more research is needed in order to optimise the screening procedure. PMID- 26479251 TI - [Dialectical behaviour theory in the Netherlands: implementation and consolidation]. AB - BACKGROUND: More and more evidence-based treatments for severe personality disorders are becoming available. Nevertheless, there are problems with the implementation of these treatments and it is proving difficult to keep the treatment programmes running. However, teams which offer dialectical behavior therapy (DBT) seem to survive. AIM: To find out which factors enable dbt teams to survive. METHOD: Twenty-five Dutch DBT teams received a questionnaire about factors that could be influencing the continuation of the DBT treatment programmes. The questionnaire consisted of 9 open questions, 2 multiple-choice questions and 26 closed questions. RESULTS: The results show that the continued existence of the treatment programmes is due largely to the commitment of both the team and its managers. They all feel embedded in the organisation as a whole, feel connected with one another and are supportive of the method. CONCLUSION: A well-functioning consultation team seems to be of crucial importance for the continued existence of the DBT programme. We believe that independent external supervision is essential to keep the dbt teams alert and aware of current trends and developments. PMID- 26479252 TI - [20 years dialectical behavior therapy in the Netherlands: who cares?]. PMID- 26479253 TI - [The delusion of world catastrophe. Is this classic symptom still relevant today?]. AB - BACKGROUND: The delusion of world catastrophe was conceptualised by classic authors such as Jaspers and Conrad as a specific expression of acute psychosis that deserved special attention in psychiatric diagnosis. We need to find out whether this approach is still relevant today. AIM: To provide an overview of the literature about the delusion of world catastrophe. METHOD: The literature was searched and historical literature was also consulted. RESULTS: A patient's delusion of world catastrophe often begins with a phase known as the 'Wahnstimmung' which may be accompanied by subtle positive disorders of perception. This is followed by frank psychosis, with hallucinations, formal thought disorders, and, in exceptional cases, can lead to suicidality and/or homicidality. Prevalence rates derived from populations of patients diagnosed with a schizophrenia spectrum disorder vary from 1% to 8%, with a single outlier of 63.5%. Wetzel was the first to conceptualise the delusion of world catastrophe as an attempt of the brain to make sense of a world on which it had lost its grip due to the psychotic process. The link Wetzel established between subtle disorders of perception and possible organic causes is still relevant today. CONCLUSION: Patients who are beginning to have delusions of world catastrophe deserve not only to get an early diagnosis of the neurobiological correlates of their perceptual disorders, but also to receive adequate treatment for their psychosis. PMID- 26479254 TI - [New generation behaviour therapy; new generation assessment measures; a review of currently available assessment measures]. AB - BACKGROUND: Acceptance and commitment therapy (ACT) is a relatively new form of behaviour therapy, which has relational frame theory as its theoretical foundation. Since ACT is not aimed primarily at reducing psychopathological symptoms, changes are likely to be needed in the nature and purpose of the assessment measures used. AIM: To provide an up-to-date overview of ACT-measures that are suitable for use with adults and that will assist Dutch-speaking clinicians and researchers. METHOD: We performed a systematic review of the literature. RESULTS: More than 50 ACT-related questionnaires were identified; of these, the AAQ-II was the most suitable for acceptance as an act component, the CFQ was the most appropriate for defusion and the SACS was the best for self as context; the FFMQ-SF was regarded as the best for contact with the present moment, the VLQ for values, the ELS for committed action and the FIT-60 for psychological flexibility. CONCLUSION: Clinicians and researchers with an interest in ACT have many measures at their disposal. Most of these are available free of charge and can also be used without payment. PMID- 26479255 TI - [Eating problems in individuals with autism spectrum disorder (ASD) but no intellectual impairment]. AB - BACKGROUND: Little is known about the co-occurrence--in individuals--of autism spectrum disorder (ASD) and eating disorders and eating problems. Consequently, clinicians do not have enough information about how to diagnose or treat the combination of ASD and eating problems. AIM: To discuss the scientific literature and clinical experiences relating to eating disorders and eating problems in people who have ASD but no intellectual impairment. METHOD: The scientific literature was searched by means of PubMed, Medline and PsycINFO, and clinical experiences were discussed. RESULTS: The combination of ASS and anorexia nervosa seems to be a strong predictor that the eating disorder will follow a chronic course. It is not clear how often bulimia nervosa occurs in persons with ASD. Eating problems in persons with ASD often seem to be related to sensory sensitivity, eating preferences and motor problems. So far, little is known about the treatment of eating disorders and eating problems in individuals with ASD. CONCLUSION: When diagnosing and treating eating disorders and eating problems in individuals with ASD, it is important to take information processing and behaviour characteristics of ASD into account. Further research is needed, particularly in order to cast more light on treatment possibilities. PMID- 26479256 TI - [Cushing's syndrome in a manic patient with a long-standing bipolar disorder: cause or coincidence?]. AB - Hypercortisolism is associated with mood disorders such as depression and bipolar disorder. A 75-year-old female patient who had been diagnosed with bipolar disorder forty years ago was admitted to our hospital with a severe, therapy resistant mania. Careful diagnostic considerations, resulted in the patient being diagnosed with Cushing's syndrome. Treatment with metyrapone led to a swift improvement of the patient's symptoms. Could Cushing's syndrome underlie this patient's psychiatric history? Or are two co-existing, intertwining causes responsible for the psychiatric symptoms? The case illustrates that even if a patient has a long history of psychiatric problems that have been plausibly diagnosed over time, clinicians and psychiatrists should always consider the possibility that there may be an underlying somatic cause for the patient's psychiatric symptoms. PMID- 26479257 TI - [Gradually increasing apathy and self-neglect in a 29-year-old man]. AB - A 29-year-old man presented with progressive behavioural changes, expressed mainly in the form of increasing of apathy and self-neglect. The initial differential diagnosis included a psychotic disorder, a mood disorder or a personality disorder. After a month of medication-free observation and uncertainty regarding the results of various diagnostic approaches, we decided to use MR-imaging; this revealed a frontal meningioma which had invaded the entire frontal lobe. Although patients with some types of somatic disorders frequently present with psychiatric symptoms, there are often indications (e.g. from history or physical examination) that in fact the symptoms are of organic origin. In this case report we discuss the indications that should lead clinicians and psychiatrists to consider the possibility of organic pathology when young adults present with only psychiatric symptoms. PMID- 26479258 TI - Functional Analysis and RNA Sequencing Indicate the Regulatory Role of Argonaute1 in Tomato Compound Leaf Development. AB - Regardless of whether a leaf is simple or compound, the mechanism underlying its development will give rise to a full comprehension of plant morphogenesis. The role of Argonaute1 (AGO1) in the development of simple leaves has been established, but its role in the development of compound leaves remains to be characterized. In this paper, a virus-induced gene silencing (VIGS) strategy was used to dramatically down-regulate the expression of AGO1 ortholog in tomatoes, a model plant for research into compound leaves. AGO1-silenced tomato compound leaves exhibited morphological defects of leaf adaxial-abaxial and trichome development. Analysis of global gene expression profiles indicated that the silencing of AGO1 in tomato compound leaf caused significant changes in the expression of several critical genes, including Auxin Response Factor 4 (ARF4) and Non-expressor of PR5 (NPR5), which were involved in adaxial-abaxial formation and IAA15 that was found to contribute to growth of trichomes as well as Gibberellic Acid Insensitive (GAI) which participated in hormone regulation. Collectively, these results shed light on the complicated mechanism by which AGO1 regulates compound leaf development. PMID- 26479259 TI - Error-related processing in adult males with elevated psychopathic traits. AB - Psychopathy is a serious personality disorder characterized by dysfunctional affective and behavioral symptoms. In incarcerated populations, elevated psychopathic traits have been linked to increased rates of violent recidivism. Cognitive processes related to error processing have been shown to differentiate individuals with high and low psychopathic traits and may contribute to poor decision making that increases the risk of recidivism. Error processing abnormalities related to psychopathy may be attributable to error-monitoring (error detection) or posterror processing (error evaluation). A recent 'bottleneck' theory predicts deficiencies in posterror processing in individuals with high psychopathic traits. In the current study, incarcerated males (n = 93) performed a Go/NoGo response inhibition task while event-related potentials (ERPs) were recorded. Classic time-domain windowed component and principal component analyses were used to measure error-monitoring (as measured with the error-related negativity [ERN/Ne]) and posterror processing (as measured with the error positivity [Pe]). Psychopathic traits were assessed using Hare's Psychopathy Checklist-Revised (PCL-R). PCL-R Total score, Factor 1 (interpersonal affective traits), and Facet 3 (lifestyle traits) scores were positively related to posterror processes (i.e., increased Pe amplitude) but unrelated to error monitoring processes (i.e., ERN/Ne). These results support the attentional bottleneck theory and further describe deficiencies related to elevated psychopathic traits that could be beneficial for new treatment strategies for psychopathy. PMID- 26479260 TI - On the role of a Lipid-Transfer Protein. Arabidopsis ltp3 mutant is compromised in germination and seedling growth. AB - Plant Lipid-Transfer Proteins (LTPs) exhibit the ability to reversibly bind/transport lipids in vitro. LTPs have been involved in diverse physiological processes but conclusive evidence on their role has only been presented for a few members, none of them related to seed physiology. Arabidopsis seeds rely on storage oil breakdown to supply carbon skeletons and energy for seedling growth. Here, Arabidopsis ltp3 mutant was analyzed for its ability to germinate and for seedling establishment. Ltp3 showed delayed germination and reduced germination frequency. Seedling growth appeared reduced in the mutant but this growth restriction was rescued by the addition of an exogenous carbon supply, suggesting a defective oil mobilization. Lipid breakdown analysis during seedling growth revealed a differential profile in the mutant compared to the wild type. The involvement of LTP3 in germination and seedling growth and its relationship with the lipid transfer ability of this protein is discussed. PMID- 26479261 TI - Desiccation tolerance in the streptophyte green alga Klebsormidium: The role of phytohormones. PMID- 26479262 TI - Ice-Templated Assembly Strategy to Construct 3D Boron Nitride Nanosheet Networks in Polymer Composites for Thermal Conductivity Improvement. AB - Owing to the growing heat removal issue of modern electronic devices, polymer composites with high thermal conductivity have drawn much attention in the past few years. However, a traditional method to enhance the thermal conductivity of the polymers by addition of inorganic fillers usually creates composite with not only limited thermal conductivity but also other detrimental effects due to large amount of fillers required. Here, novel polymer composites are reported by first constructing 3D boron nitride nanosheets (3D-BNNS) network using ice-templated approach and then infiltrating them with epoxy matrix. The obtained polymer composites exhibit a high thermal conductivity (2.85 W m(-1) K(-1)), a low thermal expansion coefficient (24-32 ppm K(-1)), and an increased glass transition temperature (T(g)) at relatively low BNNSs loading (9.29 vol%). These results demonstrate that this approach opens a new avenue for design and preparation of polymer composites with high thermal conductivity. The polymer composites are potentially useful in advanced electronic packaging techniques, namely, thermal interface materials, underfill materials, molding compounds, and organic substrates. PMID- 26479263 TI - Glycaemic behaviour during breastfeeding in women with Type 1 diabetes. AB - AIM: To describe glycaemia in both breastfeeding women and artificially feeding women with Type 1 diabetes, and the changes in glycaemia induced by suckling. METHODS: A blinded continuous glucose monitor was applied for up to 6 days in eight breastfeeding and eight artificially feeding women with Type 1 diabetes 2-4 months postpartum. Women recorded glucose levels, insulin dosages, oral intake and breastfeeding episodes. A standardized breakfast was consumed on 2 days. A third group (clinic controls) were identified from a historical database. RESULTS: Carbohydrate intake tended to be higher in breastfeeding than artificially feeding women (P = 0.09) despite similar insulin requirements. Compared with breastfeeding women, the high blood glucose index and standard deviation of glucose were higher in artificially feeding women (P = 0.02 and 0.06, respectively) and in the clinical control group (P = 0.02 and 0.05, respectively). The low blood glucose index and hypoglycaemia were similar. After suckling, the low blood glucose index increased compared with before (P < 0.01) and during (P < 0.01) suckling. Hypoglycaemia (blood glucose < 4.0 mmol/l) occurred within 3 h of suckling in 14% of suckling episodes, and was associated with time from last oral intake (P = 0.04) and last rapid-acting insulin (P = 0.03). After a standardized breakfast, the area under the glucose curve was positive. In breastfeeding women the area under the glucose curve was positive if suckling was avoided for 1 h after eating and negative if suckling occurred within 30 min of eating. CONCLUSIONS: Breastfeeding women with Type 1 diabetes had similar hypoglycaemia but lower glucose variability than artificially feeding women. Suckling reduced maternal glucose levels but did not cause hypoglycaemia in most episodes. PMID- 26479265 TI - Effects of low-dose light-emitting-diode therapy in combination with water bath for atopic dermatitis in NC/Nga mice. AB - BACKGROUND: Light-emitting diode (LED) phototherapy and water bath therapy have beneficial effect on atopic dermatitis (AD)-like skin disease. However, not all current treatments work well and alternative therapies are need. The contribution of combination therapy with low-dose 850 nm LED and water bath was investigated on dermatophagoides farina (Df)-induced dermatitis in NC/Nga mice. METHODS: Low dose LED (10, 15, and 20 J/cm(2) ) irradiation, water bath (36 +/- 1 degrees C) were administered separately and together to the Df-induced NC/Nga mice in acrylic jar once a day for 2 weeks. RESULTS: Combined therapy with low-dose LED therapy and water bath therapy significantly ameliorated the development of AD like skin lesions. These effects were correlated with the suppression of total IgE, NO, histamine, and Th2-mediated immune responses. Furthermore, combination therapy significantly reduced the infiltration of inflammatory cells and the induction of thymic stromal lymphopoietin (TSLP) in the skin lesions. The beneficial therapeutic effects of this combination therapy might regulate by the inhibition of various immunological responses including Th2-mediated immune responses, inflammatory mediators such as IgE, histamine, and NO, as well as inflammatory cells. CONCLUSIONS: The combination therapy of LED and water bath might be used as an efficacious, safe, and steroid-free alternative therapeutic strategy for the treatment of AD. PMID- 26479264 TI - Domestication footprints anchor genomic regions of agronomic importance in soybeans. AB - Present-day soybeans consist of elite cultivars and landraces (Glycine max, fully domesticated (FD)), annual wild type (Glycine soja, nondomesticated (ND)), and semi-wild type (semi-domesticated (SD)). FD soybean originated in China, although the details of its domestication history remain obscure. More than 500 diverse soybean accessions were sequenced using specific-locus amplified fragment sequencing (SLAF-seq) to address fundamental questions regarding soybean domestication. In total, 64,141 single nucleotide polymorphisms (SNPs) with minor allele frequencies (MAFs) > 0.05 were found among the 512 tested accessions. The results indicated that the SD group is not a hybrid between the FD and ND groups. The initial domestication region was pinpointed to central China (demarcated by the Great Wall to the north and the Qinling Mountains to the south). A total of 800 highly differentiated genetic regions and > 140 selective sweeps were identified, and these were three- and twofold more likely, respectively, to encompass a known quantitative trait locus (QTL) than the rest of the soybean genome. Forty-three potential quantitative trait nucleotides (QTNs; including 15 distinct traits) were identified by genome-wide association mapping. The results of the present study should be beneficial for soybean improvement and provide insight into the genetic architecture of traits of agronomic importance. PMID- 26479266 TI - Urinary incontinence in patients with cystic fibrosis. AB - OBJECTIVE: Owing to evolution in treatment, the average life expectancy of patients with cystic fibrosis (CF) has increased. This has been followed by an increase in urological complications such as urinary incontinence. As stress incontinence occurs during exercise, it may have a negative effect on the implementation of respiratory physiotherapy. The purpose of this study is to determine the prevalence of urinary incontinence and its effect on the quality of life and physiotherapy in a population with CF. MATERIALS AND METHODS: Questionnaires were used to determine the prevalence of incontinence in patients of the Cystic Fibrosis Clinic of the University Hospital in Brussels. Two different surveys were used, depending on the age of the patients (< 12 or >= 12 years). The different characteristics of incontinence were emphasized. RESULTS: Questionnaires were completed by 122 participants aged 6-59 years, showing an overall prevalence of 27% for urinary incontinence. Mainly adults reported urinary incontinence, with a prevalence of 11% in men and 68% in women aged 12 and above. The amount of urinary leakage was usually only a few drops and it was mainly triggered by coughing. Many of the participants had never mentioned this symptom to anyone. CONCLUSIONS: Doctors' and physical therapists' attention should be drawn to the fact that urinary incontinence is part of the complication spectrum of CF. A quarter of the study population refrained from coughing up phlegm and from physiotherapy. It is important to actively question and inform about this problem, to enable its detection and treatment. PMID- 26479267 TI - Estimating motor unit numbers from a CMAP scan. AB - INTRODUCTION: Compound muscle action potential (CMAP) scans are detailed stimulus response curves which provide information about motor unit properties in neuromuscular disorders. This study assessed a method of automatic motor unit number estimation (MUNE) from 5-min CMAP scans. METHODS: A preliminary model, derived from the variance and slope of the scan, is refined to fit the CMAP scan more closely. The method was tested by application to 60 simulated scans, generated from between 5 and 160 motor unit potentials. RESULTS: The fitting procedure took an average of 1.5 min on a standard personal computer. Small unit numbers (5-20) were on average correctly estimated, but large unit numbers (>40) were slightly underestimated. Overall, the absolute MUNE error averaged 6.9%. CONCLUSIONS: This new MUNE method takes all excitable motor units into account and provides realistic estimates of unit numbers over the range 5 to 160. Validation as a clinical tool awaits further study. Muscle Nerve 53: 889-896, 2016. PMID- 26479268 TI - Statics and Dynamics of Ferroelectric Domains in Diisopropylammonium Bromide. AB - An electrically written domain structure formed by a biased tip, and visualized in the piezoresponse force microscopy mode, shows stable charged domain walls in the organic ferroelectric diisopropylammonium chloride microcrystal. PMID- 26479269 TI - Remote calorimetric detection of urea via flow injection analysis. AB - The design and development of a calorimetric biosensing system enabling relatively high throughput sample analysis are reported. The calorimetric biosensor system consists of a thin (~20 MUm) micromachined Y-cut quartz crystal resonator (QCR) as a temperature sensor placed in close proximity to a fluidic chamber packed with an immobilized enzyme. Layer by layer enzyme immobilization of urease is demonstrated and its activity as a function of the number of layers, pH, and time has been evaluated. This configuration enables a sensing system where a transducer element is physically separated from the analyte solution of interest and is thereby free from fouling effects typically associated with biochemical reactions occuring on the sensor surface. The performance of this biosensing system is demonstrated by detection of 1-200 mM urea in phosphate buffer via a flow injection analysis (FIA) technique. Miniaturized fluidic systems were used to provide continuous flow through a reaction column. Under this configuration the biosensor has an ultimate resolution of less than 1 mM urea and showed a linear response between 0-50 mM. This work demonstrates a sensing modality in which the sensor itself is not fouled or contaminated by the solution of interest and the enzyme immobilized Kapton(r) fluidic reaction column can be used as a disposable cartridge. Such a system enables reuse and reliability for long term sampling measurements. Based on this concept a biosensing system is envisioned which can perform rapid measurements to detect biomarkers such as glucose, creatinine, cholesterol, urea and lactate in urine and blood continuously over extended periods of time. PMID- 26479270 TI - Experience-dependent plasticity of adult-born neuron connectivity. AB - In contrast to most areas of the adult brain, the dentate gyrus (DG) of the hippocampus is endowed with the capability to generate new neurons life-long. While recent evidence suggests that these adult-born neurons exert specialized functions in information processing compared to pre-existing DG granule neurons, to which extent the establishment of their evolving connectivity may be regulated by experience has been elusive. We recently demonstrated that environmental enrichment (EE) induces a surprising input-specific reorganization of the presynaptic connectivity of adult-born neurons, and that this form of structural plasticity appears to large degree confined to a defined period of few weeks shortly after their generation. Here, I briefly discuss how these findings may uncover a previously unknown layer of complexity in the processes regulating the synaptic integration of adult-born neurons and propose that their circuit incorporation within the pre-existing hippocampal network is not prefigured but rather modulated by specific experiences. PMID- 26479272 TI - Nocturnal behavior in captive giraffe (Giraffa camelopardalis)--A pilot study. AB - Captive giraffes (Giraffa camelopardalis) are known to perform oral and locomotor stereotypies. However, many studies do not consider the behavioral repertoire of these animals during the time when animals are confined to night quarters. At two zoological institutions, a total of six captive giraffes were observed via camera trap technology throughout six diurnal and nocturnal periods to record feeding, ruminating, and stereotypic behaviors. The effect of browse enrichment was assessed on alternate nights to determine how behaviors may be altered in the presence of natural forage. Results need to be interpreted with caution due to a high proportion of time when animals were out of camera range. For the observed time, stereotypical licking behavior was significantly higher at night compared to daytime at both facilities, while tongue play increased at the same time, but not significantly. The provision of browse enrichment during the night decreased the rate of tongue playing, but not significantly; however, browse did significantly reduce pacing behavior. Across treatments and institutions, observed oral stereotypies tended to correlate negatively with increased feeding behavior. Apart from a short-term effect of enrichment, this study indicates relevant differences in the frequencies of behaviors observed during the day and night, suggesting that assessing nocturnal behavior specifically may be important in many species. PMID- 26479271 TI - Endoscopic wire-guided papillectomy versus conventional papillectomy for ampullary tumors: A prospective comparative pilot study. AB - BACKGROUND AND AIM: A major concern about endoscopic snare papillectomy (ESP) is the risk of procedure-related pancreatitis. To maintain pancreatic duct access for stent placement after ESP, wire-guided ESP (WP) was introduced. The aim of the study was to compare post-procedure pancreatitis rates, the success rate of pancreatic stent insertion, and complete resection rates between WP and conventional ESP (CP) procedures. METHODS: This was a multi-center, prospective, randomized pilot study. Forty-five patients with ampullary tumors were randomly assigned to a WP group (n = 22) or a CP group (n = 23). In the WP group, a guidewire was placed in the pancreatic duct prior to ESP. A 5-Fr pancreatic stent was passed over the guidewire and placed across the pancreatic duct orifice. RESULTS: Complete resection was achieved in 20 patients (91%) in the WP group and 18 patients (78%) in the CP group (P = 0.414). A pancreatic stent was placed successfully in all patients in the WP group but in only 15 patients (65%) in the CP group (P = 0.004). Post-papillectomy pancreatitis occurred in four (18%) patients in the WP and three (13%) patients in the CP groups (P = 0.960). In the CP group, three of eight (37.5%) patients without stents developed pancreatitis compared with zero of 15 patients with stents (P = 0.032). CONCLUSIONS: The WP method is a useful technique used to insert a pancreatic stent after ESP, compared with CP. However, there was no significant difference in the post procedure pancreatitis or complete resection rates between the two methods. PMID- 26479273 TI - The Role of Cytokinin During Infection of Arabidopsis thaliana by the Cyst Nematode Heterodera schachtii. AB - Plant-parasitic cyst nematodes induce the formation of hypermetabolic feeding sites, termed syncytia, as their sole source of nutrients. The formation of the syncytium is orchestrated by the nematode, in part, by modulation of phytohormone responses, including cytokinin. In response to infection by the nematode Heterodera schachtii, cytokinin signaling is transiently induced at the site of infection and in the developing syncytium. Arabidopsis lines with reduced cytokinin sensitivity show reduced susceptibility to nematode infection, indicating that cytokinin signaling is required for optimal nematode development. Furthermore, lines with increased cytokinin sensitivity also exhibit reduced nematode susceptibility. To ascertain why cytokinin hypersensitivity reduces nematode parasitism, we examined the transcriptomes in wild type and a cytokinin hypersensitive type-A arr Arabidopsis mutant in response to H. schachtii infection. Genes involved in the response to biotic stress and defense response were elevated in the type-A arr mutant in the absence of nematodes and were hyperinduced following H. schachtii infection, which suggests that the Arabidopsis type-A arr mutants impede nematode development because they are primed to respond to pathogen infection. These results suggest that cytokinin signaling is required for optimal H. schachtii parasitism of Arabidopsis but that elevated cytokinin signaling triggers a heightened immune response to nematode infection. PMID- 26479274 TI - Education and Training Needs in the Radiation Sciences: Problems and Potential Solutions. AB - This article provides a summary of presentations focused on critical education and training issues in radiation oncology, radiobiology and medical physics from a workshop conducted as part of the 60th Annual Meeting of the Radiation Research Society held in Las Vegas, NV (September 21-24, 2014). Also included in this synopsis are pertinent comments and concerns raised by audience members, as well as recommendations for addressing ongoing and future challenges. PMID- 26479275 TI - Decernotinib: A Next-Generation Jakinib. PMID- 26479276 TI - Invited Review: Polycomb group genes in the regeneration of the healthy and pathological skeletal muscle. AB - The polycomb group (PcG) proteins are epigenetic repressors required during key developmental processes, such as maintenance of cell identity and stem cell differentiation. To exert their repressive function, PcG proteins assemble on chromatin into multiprotein complexes, known as polycomb repressive complex 1 and 2. In this review, we will focus on the role and mode of function of PcG proteins in the development and regeneration of the skeletal muscle, both in normal and pathological conditions and we will discuss the emerging concept of modulation of their expression to enhance the muscle-specific regenerative process for patient benefit. PMID- 26479277 TI - Preliminary investigation comparing a detomidine continuous rate infusion combined with either morphine or buprenorphine for standing sedation in horses. AB - OBJECTIVE: To compare sedative and analgesic properties of buprenorphine or morphine for standing procedures combined with a detomidine continuous rate infusion (CRI). STUDY DESIGN: Blinded, prospective, randomized clinical pilot study. ANIMALS: Ten horses presented for dental or sinus procedures. METHODS: Horses received 0.02 mg kg(-1) acepromazine intravenously (IV), followed 30 minutes later by detomidine 10 MUg kg(-1) IV. Five minutes later, buprenorphine 0.01 mg kg(-1) (n = 6) or morphine 0.1 mg kg(-1) (n = 4) was administered IV. Detomidine was administered by CRI (0.2 MUg kg(-1) minute(-1)) and adjusted to maintain appropriate sedation. Heart rate, respiratory frequency, gastrointestinal motility and rectal temperature were measured; pain, ataxia and sedation were scored. Sedation, pain scores and ataxia scores were analysed using a mixed linear model. Detomidine dose and procedure success scores were compared using Wilcoxon's rank sum test. Complications between groups were analysed using Fisher's exact test. RESULTS: Two horses had incomplete data. Weights and ages were not different between groups (p = 0.15 and p = 0.42, respectively). The dose rate for detomidine was not different between groups (0.33 +/- 0.02 MUg kg(-1) minute(-1) in the buprenorphine group and 0.33 +/- 0.05 MUg kg(-1) minute(-1), in the morphine group p = 0.89). Intraoperative visual analogue scale scores were greater after buprenorphine than morphine (mean +/- SD, buprenorphine 48 +/- 4, morphine 40 +/- 5, p = 0.0497). Procedure duration was not different between groups (buprenorphine 142 +/- 33, morphine 140 +/- 12 minutes). All horses treated with buprenorphine experienced complications compared with none in the morphine group (p = 0.0286). CONCLUSIONS AND CLINICAL RELEVANCE: At the doses used, buprenorphine produced greater sedation but more post-operative complications than morphine. However, Type I or Type II errors cannot be excluded and larger studies are required to confirm these findings. PMID- 26479278 TI - Pharmacoepidemiologic Methods for Studying the Health Effects of Drug-Drug Interactions. AB - A drug-drug interaction (DDI) occurs when one or more drugs affect the pharmacokinetics (the body's effect on the drug) and/or pharmacodynamics (the drug's effect on the body) of one or more other drugs. Pharmacoepidemiologic studies are the principal way of studying the health effects of potential DDIs. This article discusses aspects of pharmacoepidemiologic research designs that are particularly salient to the design and interpretation of pharmacoepidemiologic studies of DDIs. PMID- 26479279 TI - Functional analysis of mutual behavior in laboratory rats (Rattus norvegicus). AB - Three pairs of rats were trained to synchronize their lever pressing according to a mutual reinforcement contingency, in which alternating lever presses that fell within a 500-ms window were reinforced with food. In Experiment 1, rats worked in adjacent chambers separated by a transparent barrier, and the effects of the mutual reinforcement contingency were compared with those under yoked-control conditions that provided the same rate of food reinforcement but without the temporal coordination response requirement. In Experiment 2, coordinated behavior was compared with and without a barrier, and across different barrier types: transparent, opaque, wire mesh. In Experiment 3, the effects of social familiarity were assessed by switching partners, enabling a comparison of coordinated behavior with familiar and unfamiliar partners. The overall pattern of results shows that the coordinated behavior of 2 rats was (a) maintained by mutual reinforcement contingencies, (b) unrelated to the type or presence of a barrier separating the rats, and (c) sufficiently flexible to adjust to the presence and behavior of an unfamiliar partner. Taken as a whole, the study illustrates a promising approach to conceptualizing and analyzing behavioral mechanisms of mutual behavior, an important component of an integrated study of social behavior. PMID- 26479280 TI - Controlled Oxygenated Rewarming of Cold Stored Livers Prior to Transplantation: First Clinical Application of a New Concept. AB - BACKGROUND: Abrupt temperature shift from hypothermia to normothermia incurred on reperfusion of organ grafts has been delineated as a genuine factor contributing to reperfusion injury and graft dysfunction after transplantation. METHODS: In a first clinical series of 6 patients, cold-stored livers, all allocated by the rescue offer mechanism by Eurotransplant, were subjected to machine-assisted slow controlled oxygenated rewarming (COR) for 90 minutes before engrafting. A historical cohort of 106 patients basically similar in graft (all rescue offer organs) and recipient factors was used for comparison. RESULTS: The clinical benefit of COR was documented by a significant reduction by approximately 50% in peak serum transaminases after transplantation compared to untreated controls (AST 563.5 vs. 1204 U/L, P = 0.023). After 6 months graft survival was 100% in the COR group and 80.9% in the controls (P = 0.24). Respective patient survival was 100% and 84.7% (P = 0.28). Real-time assessment of glucose concentration in the perfusion solution correlated well with postoperative synthetic graft function (r = 0.78; P < 0.02). All treated recipients had normal liver function after a 6-month follow-up and are well and alive. CONCLUSIONS: This first clinical application suggests that controlled graft rewarming after cold storage is a feasible and safe method in clinical praxis and might become an adjunct in organ preservation. PMID- 26479282 TI - Nonalcoholic Steatohepatitis is the Most Rapidly Growing Indication for Simultaneous Liver Kidney Transplantation in the United States. AB - BACKGROUND: Frequency of liver transplantation (LT) is increasing in nonalcoholic steatohepatitis (NASH) with good post-transplant outcomes. Similar data on simultaneous liver kidney (SLK) transplants are limited. METHODS: United Network for Organ Sharing database (2002-2011) queried for deceased donor first LT for primary biliary cirrhosis, primary sclerosing cholangitis, or alcoholic cirrhosis (group I), NASH, and cryptogenic cirrhosis with body mass index greater than 30 (group II), and hepatitis C virus with and without alcohol, hepatitis B virus, and hepatocellular carcinoma (group III). RESULTS: Of 38 533 LT (9495, 3665, and 25 383 in groups I-III, respectively), about 5.6% (N = 2162) received SLK with 584 (6.2%), 320 (8.7%), and 1258 (5%) in groups I-III, respectively. The SLK performed for group II increased from 6.3% in 2002 to 2003 to 19.2% in 2010 to 2011. Similar trends remained unchanged in group I (26.1 to 26.6%) and decreased in group III (67.6 to 54.5%). Five-year outcomes were similar comparing group II versus group I for liver graft (78 vs 74%, P = 0.14) and patient survival (81 vs 76%, P = 0.07). In contrast, kidney graft outcome was worse for group II (70 vs 79%, P = 0.002). Risk of kidney graft loss was over 1.5-fold higher among group II SLK recipients compared to group I after controlling for recipient characteristics. Estimated glomerular filtration rate remained lower in group II compared with group I at various time points after SLK transplantation. CONCLUSIONS: The NASH is the most rapidly growing indication for SLK transplantation with poor renal outcomes. Studies are needed to examine mechanisms of these findings and develop strategies to improve renal outcomes in SLK recipients for NASH. PMID- 26479281 TI - Long-term Efficacy and Biocompatibility of Encapsulated Islet Transplantation With Chitosan-Coated Alginate Capsules in Mice and Canine Models of Diabetes. AB - BACKGROUND: Clinical application of encapsulated islet transplantation is hindered by low biocompatibility of capsules leading to pericapsular fibrosis and decreased islet viability. To improve biocompatibility, we designed a novel chitosan-coated alginate capsules and compared them to uncoated alginate capsules. METHODS: Alginate capsules were formed by crosslinking with BaCl2, then they were suspended in chitosan solution for 10 minutes at pH 4.5. Xenogeneic islet transplantation, using encapsulated porcine islets in 1,3 galactosyltransferase knockout mice, and allogeneic islet transplantation, using encapsulated canine islets in beagles, were performed without immunosuppressants. RESULTS: The chitosan-alginate capsules showed similar pore size, islet viability, and insulin secretory function compared to alginate capsules, in vitro. Xenogeneic transplantation of chitosan-alginate capsules demonstrated a trend toward superior graft survival (P = 0.07) with significantly less pericapsular fibrosis (cell adhesion score: 3.77 +/- 0.41 vs 8.08 +/- 0.05; P < 0.001) compared to that of alginate capsules up to 1 year after transplantation. Allogeneic transplantation of chitosan-alginate capsules normalized the blood glucose level up to 1 year with little evidence of pericapsular fibrotic overgrowth on graft explantation. CONCLUSIONS: The efficacy and biocompatibility of chitosan-alginate capsules were demonstrated in xenogeneic and allogeneic islet transplantations using small and large animal models of diabetes. This capsule might be a potential candidate applicable in the treatment of type 1 diabetes mellitus patients, and further studies in nonhuman primates are required. PMID- 26479283 TI - Estimation of Potential Deceased Organ Donors in Canada. AB - BACKGROUND: Development of strategies to increase deceased organ donation is dependent on timely, accurate information regarding the number of potential deceased organ donors. Our objective was to estimate the number of potential deceased organ donors in Canada. METHODS: This was a retrospective analysis of information captured from hospital separations in Canadian provinces with the exception of Quebec between 2005 and 2009. We studied individuals 70 years or younger who died in hospital. Our primary outcome measure was potential deceased organ donors (identified by the presence of diagnostic codes compatible with donation, the absence of contraindications to donation defined by Canadian Standards, and the use of mechanical ventilation). RESULTS: Among 335 793 hospital deaths, 8274 potential donors were identified. The study method was 81% sensitive and 93% specific for identification of potential donors, and overestimated potential donors by a factor of 1.6- to 2.1-fold when compared to information from chart audits. After accounting for this overestimation, there are conservatively 400 unrecognized potential deceased donors in Canada annually. CONCLUSIONS: These findings suggest there may be significant potential to increase deceased organ donations in Canada. Further studies to fully characterize the number of potential donors identified by the study method are needed. PMID- 26479284 TI - Warming Up--Not Only Essential for Athletes? PMID- 26479285 TI - Reassessing Preemptive Kidney Transplantation in the United States: Are We Making Progress? AB - BACKGROUND: Preemptive kidney transplantation (preKT) is associated with higher patient survival, improved quality of life, and lower costs. However, only a minority of patients receives preKT. The aim of this study was to examine changes over the past decade in rates of preKT, focusing on living donor kidney transplantation (LDKT) and specifically recipients who underwent kidney transplantation within 1 year of initiating dialysis. METHODS: Using United Network of Organ Sharing data, we examined retrospectively all kidney transplant candidates (n = 369 103) and recipients (n = 141 254) from 2003 to 2012 in the United States focusing on LDKT (n = 47 108). Predictors of preKT were examined, and patient and graft survival were compared for preKT, pretransplant dialysis less than 1 year, and pretransplant dialysis recipients of 1 year or longer. RESULTS: PreKT occurred in only 17% of recipients overall and 31% of LDKT recipients. Medicare patients (odds ratio [OR], 0.29; 95% confidence interval [95% CI], 0.28-0.31), diabetics (OR, 0.75; 95% CI, 0.69-0.80), and minorities (Hispanics OR, 0.62; 95% CI, 0.57-0.68 and African Americans OR, 0.58; 95% CI, 0.53-0.63) were less likely to receive preKT. Dialysis recipients for less than 1 year comprised 30% of nonpreemptive LDKT. Dialysis recipients of less than 1 year had similar patient survival to preKT (5 years: preKT, 94%; dialysis < 1 year, 94%; dialysis >= 1 year, 89%; P < 0.01), but decreased death-censored graft survival (5 years: preKT, 93%; dialysis < 1 year, 89%; and dialysis >= 1 year, 89%; P < 0.01). CONCLUSIONS: PreKT remains an unrealized goal for the majority of recipients. Medicare patients, diabetics, and minorities are less likely to receive preKT. Almost one third of nonpreemptive LDKT recipients were dialyzed for less than 1 year, highlighting an important target for improvement. PMID- 26479286 TI - The Challenge of Acute Antibody-Mediated Rejection in Kidney Transplantation. PMID- 26479287 TI - Cognitive Changes in Chronic Kidney Disease and After Transplantation. AB - Cognitive impairment is very common in chronic kidney disease (CKD) and is strongly associated with increased mortality. This review article will discuss the pathophysiology of cognitive impairment in CKD, as well as the effect of dialysis and transplantation on cognitive function. In CKD, uremic toxins, hyperparathyroidism and Klotho deficiency lead to chronic inflammation, endothelial dysfunction and vascular calcifications. This results in an increased burden of cerebrovascular disease in CKD patients, who consistently have more white matter hyperintensities, microbleeds, microinfarctions and cerebral atrophy on magnetic resonance imaging scans. Hemodialysis, although beneficial in terms of uremic toxin clearance, also contributes to cognitive decline by causing rapid fluid and osmotic shifts. Decreasing the dialysate temperature and increasing total dialysis time limits these shifts and helps maintain cognitive function in hemodialysis patients. For many patients, kidney transplantation is the preferred treatment modality, because it reverses the underlying mechanisms causing cognitive impairment in CKD. These positive effects have to be balanced against the possible neurotoxicity of infections and immunosuppressive medications, especially glucocorticosteroids and calcineurin inhibitors. A limited number of studies have addressed the overall effect of transplantation on cognitive function. These have mostly found an improvement after transplantation, but have a limited applicability to daily practice because they have only included relatively young patients. PMID- 26479289 TI - Acute Kidney Injury as a Complication of Cardiac Transplantation: Incidence, Risk Factors, and Impact on 1-year Mortality and Renal Function. AB - BACKGROUND: Although chronic deterioration in renal function is frequently seen after cardiac transplantation, which is partly explained by the use of calcineurin inhibitors, data on the consequences of acute kidney injury (AKI) after cardiac transplantation are scarce. In the current study, the incidence of AKI and its impact on mortality and renal function was evaluated. METHODS: Five hundred thirty-one cardiac transplant recipients (age >=18 years) were evaluated for the postoperative incidence of AKI defined by the Kidney Disease Improving Global Outcome criteria. Secondary outcomes were renal function and mortality during the first postoperative year. RESULTS: Overall, 405 (76%) recipients met the AKI criteria of which 211 (40%) had AKI stage I, 119 (22%) stage II, 75 (14%) stage III, and 25 patients (5%) required renal replacement therapy (RRT). One year mortality rates in patients without AKI, stages I, II, and III were 4.8%, 7.6%, 11.8%, and 14.7%, respectively (log-rank test for trend, P = 0.008). In patients that required RRT 1-year mortality was 28.2% (log-rank test P = 0.001). In multivariable analysis only AKI requiring RRT was an independent predictor of 1-year mortality (hazard ratio, 2.75; P = 0.03). Improvement in renal function, compared with baseline values, occurred in 27% of recipients 1 month after transplantation. This was less likely to occur after previous AKI (P <= 0.04). The AKI stages I to III were independently proportionally associated with a worse renal function 1 year after transplantation (P <= 0.01). CONCLUSIONS: Acute kidney injury is highly frequent after cardiac transplantation, and the stage of AKI is associated with increased mortality and impaired renal function in the first postoperative year. PMID- 26479288 TI - Outcomes of Kidney Transplantation from Circulatory Death Donors With Increased Terminal Creatinine Levels in Serum. AB - BACKGROUND: To alleviate chronic renal graft shortages in Japan, donation after circulatory death (DCD) is an increasingly used organ resource. Organs from DCD donors with progressively increased terminal creatinine (t-Cr) levels are frequently used, but the effects of this condition on kidney transplantation (KTx) remain unclear. METHODS: Between 1996 and 2013, 99 KTx from DCD donors were conducted in our department. Recipients were grouped according to the t-Cr (in mg/dL) of donors: group 1, t-Cr less than < 1.5; group 2, 1.5 <= t-Cr < 3.0; and group 3, t-Cr >= 3.0. We analyzed the long-term outcomes of KTx from DCD donors retrospectively in terms of donors' terminal renal function. RESULTS: The respective mean donor t-Cr in groups 1, 2, and 3 were 0.73 +/- 0.28, 2.02 +/- 0.40, and 6.69 +/- 3.68. The respective death-censored graft survival rates (%) in groups 1, 2, and 3 were 90.2, 96.2, and 86.7 at 1 year and 70.3, 86.2, and 73.4 at 10 years after transplantation. Group 1 exhibited lower incidence of delayed graft function than either group 2 or group 3 (80.5% vs 100% and 93.3%). Nevertheless, no significant difference was found between groups for several measures: Cr levels 1 month after KTx and lowest Cr levels throughout the observation period, prevalence of biopsy-proven acute rejection, and graft survival. Cox proportional hazard regression showed that donor age, cerebrovascular event, terminal urine output, and history of hypertension were significantly associated with graft survival. CONCLUSIONS: Results suggest that, under certain conditions, kidneys from DCD donors with progressively increased t Cr can be used safely with promising long-term outcomes. PMID- 26479290 TI - Phenolic compounds: Strong inhibitors derived from lignocellulosic hydrolysate for 2,3-butanediol production by Enterobacter aerogenes. AB - Lignocellulosic biomass are attractive feedstocks for 2,3-butanediol production due to their abundant supply and low price. During the hydrolysis of lignocellulosic biomass, various byproducts are formed and their effects on 2,3 butanediol production were not sufficiently studied compared to ethanol production. Therefore, the effects of compounds derived from lignocellulosic biomass (weak acids, furan derivatives and phenolics) on the cell growth, the 2,3 butanediol production and the enzymes activity involved in 2,3-butanediol production were evaluated using Enterobacter aerogenes ATCC 29007. The phenolic compounds showed the most toxic effects on cell growth, 2,3-butanediol production and enzyme activity, followed by furan derivatives and weak acids. The significant effects were not observed in the presence of acetic acid and formic acid. Also, feasibility of 2,3-butanediol production from lignocellulosic biomass was evaluated using Miscanthus as a feedstock. In the fermentation of Miscanthus hydrolysate, 11.00 g/L of 2,3-butanediol was obtained from 34.62 g/L of reducing sugar. However, 2,3-butanediol was not produced when the concentration of total phenolic compounds in the hydrolysate increased to more than 1.5 g/L. The present study provides useful information to develop strategies for biological production of 2,3-butanediol and to establish biorefinery for biochemicals from lignocellulosic biomass. PMID- 26479291 TI - RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas. AB - BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) constitutes the most common subtype of soft tissue sarcoma. However, UPS is clinically and molecularly poorly understood, in great extent due to its intrinsic phenotypic and cytogenetic complexity, which in turn results in the absence of specific prognostic or predictive biomarkers. The RAS/mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) pathways are considered to be 2 major mechanisms for sarcoma proliferation and survival and to the authors' knowledge their role in UPS remains unclear. The objective of the current study was to investigate whether the RAS/MAPK and PI3K/mTOR pathways are activated in UPS, and whether pathway activation is associated with outcome. METHODS: Records for patients diagnosed and treated for UPS in the study institution between 2000 and 2009 were reviewed. Phosphorylation status of 4E-binding protein (4E-BP1), eukaryotic translation initiation factor 4E (eIF-4E), S6-RP, and ERK 1/2, together with total forms of 4E-BP1 and eIF-4E, were assessed using immunohistochemistry in paraffin-embedded tumor tissue. Mutational analysis for KRAS; NRAS; BRAF; and phosphatidylinositol 4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) oncogenic mutations was performed as well. RESULTS: Critical lymph nodes within the RAS/MAPK and PI3K/mTOR pathways were found to be activated in >80% of UPS cases. Hyperactivation of the RAS/MAPK pathway, as assessed by expression of phosphorylated ERK 1/2, was found to independently predict a higher risk of disease recurrence and impaired overall survival. Only a KRAS A146V mutation was detected in 1 tumor. CONCLUSIONS: The RAS/MAPK and PI3K/mTOR pathways are activated in the majority of cases of UPS. The RAS/MAPK pathway distinguishes a subgroup of patients with localized UPS with a worse outcome. PMID- 26479292 TI - Feasibility and tolerability of self-insertion of a transnasal tube for esophagogastroduodenoscopy: a pilot study. PMID- 26479293 TI - Cold polypectomy for nonampullary duodenal adenoma. PMID- 26479294 TI - Laser lithotripsy with a standard endoscope through a hepaticoduodenostomy. PMID- 26479295 TI - Peroral endoscopic myotomy using the posterior approach in an 11-month-old girl with achalasia, severe malnutrition, and recurrent pneumonia. PMID- 26479296 TI - Transient gastric ischemia as a complication of cystotomy in endoscopic pancreatic pseudocyst drainage. PMID- 26479298 TI - Hole-making technique for the treatment for acute pancreatitis due to placement of a fully covered duodenal metallic stent. PMID- 26479297 TI - Effective endoscopic holmium laser lithotripsy in the treatment of a large impacted gallstone in the duodenum. PMID- 26479299 TI - Duodenal ulceration following gastroduodenal artery embolization with coils. PMID- 26479300 TI - Elastic band ligation for the removal of a colonic tubular adenoma in a diverticulum. PMID- 26479302 TI - Spontaneous tearing of a duodenal metallic stent: a rare adverse event. PMID- 26479301 TI - Eosinophilic granulomatosis with polyangiitis involving the small intestine: radiographic and endoscopic findings. PMID- 26479303 TI - Successful biliary drainage with peroral direct cholangioscopy in a patient with Roux-en-Y hepaticojejunostomy for congenital biliary dilatation. PMID- 26479304 TI - Interleukin 18 binding protein ameliorates ischemia/reperfusion-induced hepatic injury in mice. AB - Inflammation-associated oxidative stress contributes to hepatic ischemia/reperfusion injury (IRI). Detrimental inflammatory event cascades largely depend on activated Kupffer cells (KCs) and neutrophils, as well as proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin (IL) 18. The aim of our study was to evaluate the effects of IL 18 binding protein (IL 18Bp) in hepatic IRI of mice. Thirty C57BL/6 mice were allocated into 3 groups: sham operation, ischemia/reperfusion (I/R), and I/R with intravenous administration of IL 18Bp. Hepatic ischemia was induced for 30 minutes by Pringle's maneuver. After 120 minutes of reperfusion, mice were euthanized, and the liver and blood samples were collected for histological, immunohistochemical, molecular, and biochemical analyses. I/R injury induced the typical liver pathology and upregulated IL-18 expression in the liver of mice. Binding of IL 18 with IL 18Bp significantly reduced the histopathological indices of I/R liver injury and KC apoptosis. The I/R-induced increase of TNF-alpha, malondialdehyde, aspartate aminotransferase, and alanine aminotransferase levels was prevented in statistically significant levels because of the pretreatment with IL 18Bp. Likewise, blocking of IL 18 ablated the I/R-associated elevation of nuclear factor kappa B, c-Jun, myeloperoxidase, and IL 32 and the up-regulation of neutrophils and T-helper lymphocytes. Administration of IL 18Bp protects the mice liver from I/R injury by intervening in critical inflammation-associated pathways and KC apoptosis. PMID- 26479306 TI - Towards the identification of the allosteric Phe-binding site in phenylalanine hydroxylase. AB - The enzyme phenylalanine hydroxylase (PAH) is defective in the inherited disorder phenylketonuria. PAH, a tetrameric enzyme, is highly regulated and displays positive cooperativity for its substrate, Phe. Whether Phe binds to an allosteric site is a matter of debate, despite several studies worldwide. To address this issue, we generated a dimeric model for Phe-PAH interactions, by performing molecular docking combined with molecular dynamics simulations on human and rat wild-type sequences and also on a human G46S mutant. Our results suggest that the allosteric Phe-binding site lies at the dimeric interface between the regulatory and the catalytic domains of two adjacent subunits. The structural and dynamical features of the site were characterized in depth and described. Interestingly, our findings provide evidence for lower allosteric Phe-binding ability of the G46S mutant than the human wild-type enzyme. This also explains the disease causing nature of this mutant. PMID- 26479305 TI - Vitamin B12: a tunable, long wavelength, light-responsive platform for launching therapeutic agents. AB - Light-responsive agents offer the promise of targeted therapy, whose benefits include (i) prolonged action at the target site, (ii) overall reduced systemic dosage, (iii) reduced adverse effects, and (iv) localized delivery of multiple agents. Although photoactivated prodrugs have been reported, these species generally require short wavelengths (<450 nm) for activation. However, maximal tissue penetrance by light occurs within the "optical window of tissue" (600-900 nm), well beyond the wavelength range of most existing photocleavable functional groups. Furthermore, since multidrug therapy holds promise for the treatment of complex diseases, from cancer to neurological disorders, controlling the action of multiple drugs via wavelength modulation would take advantage of a property that is unique to light. However, discrimination between existing photoresponsive moieties has thus far proven to be limited. We have developed a vitamin B12/light facilitated strategy for controlling drug action using red, far-red, and NIR light. The technology is based on a light-triggered reaction displayed by a subset of B12 derivatives: alkyl-cob(III)alamins suffer photohomolysis of the C Co(III) bond. The C-Co(III) bond is weak (<30 kcal/mol), and therefore all wavelengths absorbed by the corrin ring (330-580 nm) induce photocleavage. In addition, by appending fluorophores to the corrin ring, long wavelength light (>600 nm) is readily captured and used to separate the Co-appended ligand (e.g., a drug) from B12. Consequently, it is now feasible to preassign the wavelength of homolysis by simply installing a fluorescent antenna with the desired photophysical properties. The wavelength malleability inherent within this strategy has been used to construct photoresponsive compounds that launch different drugs by simply modulating the wavelength of illumination. In addition, these phototherapeutics have been installed on the surface and interior of cells, such as erythrocytes or neural stem cells, and released upon expoure to the appropriate wavelength. We have shown that cytotoxic agents, such as doxorubicin, anti-inflammatories, such as dexamethasone, and anti- and pro-vascular agents are readily released from cellular vehicles as biologically active agents. We have also demonstrated that the concept of "optical window of tissue" phototherapeutics is not just limited to prodrugs. For example, stem cells have received considerable attention in the area of regenerative medicine. Hydrogels serve as scaffolds for stem cell growth and differentiation. We have shown that the formation of hydrogels can be triggered, in the presence of cells, using appropriately designed alkyl-cob(III)alamins and long wavelength light. The potential applications of phototherapeutics are broad and include drug delivery for a variety of indications, tissue engineering, and surgery. PMID- 26479307 TI - Phaseolus vulgaris lectins: A systematic review of characteristics and health implications. AB - Legume lectins are carbohydrate-binding proteins of non-immune origin. Significant amounts of lectins have been found in Phaseolus vulgaris beans as far back as in the last century; however, many questions about their potential biological roles still remain obscure. Studies have shown that lectins are anti nutritional factors that can cause intestinal disorders. Owing to their ability to act as toxic allergens and hemagglutinins, the Phaseolus vulgaris lectins are of grave concern for human health and safety. Nonetheless, their potential beneficial health effects, such as anti-cancer, anti-human immunodeficiency virus (anti-HIV), anti-microbial infection, preventing mucosal atrophy, reducing type 2 diabetes and obesity, promoting nutrients absorption and targeting drugs, are of immense interest. The significance of Phaseolus vulgaris lectins in biological researches and the potential biomedical applications have placed tremendous emphasis on the development of purification strategies to obtain the protein in pure and stable forms. These purification strategies entail considerations such as effects of proteolysis, heating, gamma radiation, and high-hydrostatic pressure that can have crucial outcomes in either eliminating or improving bioactivities of the lectins. Thus, up-to-date research findings of Phaseolus vulgaris lectins on different aspects such as anti-nutritional and health impacts, purification strategies and novel processing trends, are systematically reviewed. PMID- 26479308 TI - Cation-Poor Complex Metallic Alloys in Ba(Eu)-Au-Al(Ga) Systems: Identifying the Keys that Control Structural Arrangements and Atom Distributions at the Atomic Level. AB - Four complex intermetallic compounds BaAu(6+/-x)Ga(6+/-y) (x = 1, y = 0.9) (I), BaAu(6+/-x)Al(6+/-y) (x = 0.9, y = 0.6) (II), EuAu6.2Ga5.8 (III), and EuAu6.1Al5.9 (IV) have been synthesized, and their structures and homogeneity ranges have been determined by single crystal and powder X-ray diffraction. Whereas I and II originate from the NaZn13-type structure (cF104-112, Fm3c), III (tP52, P4/nbm) is derived from the tetragonal Ce2Ni17Si9-type, and IV (oP104, Pbcm) crystallizes in a new orthorhombic structure type. Both I and II feature formally anionic networks with completely mixed site occupation by Au and triel (Tr = Al, Ga) atoms, while a successive decrease of local symmetry from the parental structures of I and II to III and, ultimately, to IV correlates with increasing separation of Au and Tr on individual crystallographic sites. Density functional theory-based calculations were employed to determine the crystallographic site preferences of Au and the respective triel element to elucidate reasons for the atom distribution ("coloring scheme"). Chemical bonding analyses for two different "EuAu6Tr6" models reveal maximization of the number of heteroatomic Au-Tr bonds as the driving force for atom organization. The Fermi levels fall in broad pseudogaps for both models allowing some electronic flexibility. Spin-polarized band structure calculations on the "EuAu6Tr6" models hint to singlet ground states for europium and long-range magnetic coupling for both EuAu6.2Ga5.8 (III) and EuAu6.1Al5.9 (IV). This is substantiated by experimental evidence because both compounds show nearly identical magnetic behavior with ferromagnetic transitions at TC = 6 K and net magnetic moments of 7.35 MUB/f.u. at 2 K. The effective moments of 8.3 MUB/f.u., determined from Curie-Weiss fits, point to divalent oxidation states for europium in both III and IV. PMID- 26479309 TI - An evaluation of olfactory function in adults with gastro-esophageal reflux disease. AB - CONCLUSION: To the best of the authors' knowledge, this study is the first to evaluate the olfactory function of adult patients diagnosed with GERD. The results revealed that adults with GERD have diminished olfactory function. OBJECTIVE: This study aimed to evaluate the olfactory abilities of subjects using the 'Sniffin' Sticks' olfactory test. METHODS: A total of 35 men and women aged 18-60 years with a diagnosis of GERD and 45 healthy controls were included in the study. The Sniffin' Sticks olfactory test results of the two groups were compared, and the relationship between the study findings and the olfactory parameters was evaluated. RESULTS: The odor threshold (10.1; 9.5, p = 0.016), odor identification (9.6; 8.1, p < 0.001), and odor discrimination (10.7; 8.9, p < 0.001) of the GERD group were significantly lower than those of the control group. A statistically significant positive correlation was detected between the accompanying chronic pharyngitis, chronic sinusitis, and odor parameters. A significant correlation was not detected between the laryngeal findings and the olfactory parameters. PMID- 26479311 TI - VEGF-mediated cell survival in non-small-cell lung cancer: implications for epigenetic targeting of VEGF receptors as a therapeutic approach. AB - AIMS: To evaluate the potential therapeutic utility of histone deacetylase inhibitors (HDACi) in targeting VEGF receptors in non-small-cell lung cancer. MATERIALS & METHODS: Non-small-cell lung cancer cells were screened for the VEGF receptors at the mRNA and protein levels, while cellular responses to various HDACi were examined. RESULTS: Significant effects on the regulation of the VEGF receptors were observed in response to HDACi. These were associated with decreased secretion of VEGF, decreased cellular proliferation and increased apoptosis which could not be rescued by addition of exogenous recombinant VEGF. Direct remodeling of the VEGFR1 and VEGFR2 promoters was observed. In contrast, HDACi treatments resulted in significant downregulation of the Neuropilin receptors. CONCLUSION: Epigenetic targeting of the Neuropilin receptors may offer an effective treatment for lung cancer patients in the clinical setting. PMID- 26479312 TI - Diagnostic and prognostic epigenetic biomarkers in cancer. AB - Growing cancer incidence and mortality worldwide demands development of accurate biomarkers to perfect detection, diagnosis, prognostication and monitoring. Urologic (prostate, bladder, kidney), lung, breast and colorectal cancers are the most common and despite major advances in their characterization, this has seldom translated into biomarkers amenable for clinical practice. Epigenetic alterations are innovative cancer biomarkers owing to stability, frequency, reversibility and accessibility in body fluids, entailing great potential of assay development to assist in patient management. Several studies identified putative epigenetic cancer biomarkers, some of which have been commercialized. However, large multicenter validation studies are required to foster translation to the clinics. Herein we review the most promising epigenetic detection, diagnostic, prognostic and predictive biomarkers for the most common cancers. PMID- 26479310 TI - Epigenome-modifying tools in asthma. AB - Asthma is a chronic disease which causes recurrent breathlessness affecting 300 million people worldwide of whom 250,000 die annually. The epigenome is a set of heritable modifications and tags that affect the genome without changing the intrinsic DNA sequence. These marks include DNA methylation, modifications to histone proteins around which DNA is wrapped and expression of noncoding RNA. Alterations in all of these processes have been reported in patients with asthma. In some cases these differences are linked to disease severity and susceptibility and may account for the limited value of genetic studies in asthma. Animal models of asthma suggest that epigenetic modifications and processes are linked to asthma and may be tractable targets for therapeutic intervention. PMID- 26479313 TI - Catalytic Transformation of Lignin for the Production of Chemicals and Fuels. PMID- 26479314 TI - The use of antidepressants in bipolar disorder patients with depression. AB - INTRODUCTION: The proportion of time that bipolar patients experience depressive symptoms and clinical states, with associated psychosocial impairment and elevated risk of suicide, is significantly greater than the time spent in manic/hypomanic forms of bipolar disorders. Yet, manic states and symptoms have been the focus and interest of most clinical research over the past quarter century. Not a single antidepressant approved for treatment of major depressive disorder, as monotherapy, has received regulatory approval for treatment of bipolar depression as monotherapy, despite their common use in bipolar depression. AREAS COVERED: We reviewed randomized studies, particularly ones initially intended for registration purposes, and systematic treatment guidelines, in development of this guide to treatment decision and implementation of interventions for depression in bipolar disorders. EXPERT OPINION: The Expert Opinion section emphasizes strategies, not individual agents. The efficacious performance of mood stabilizers and second-generation antipsychotics as a component of the strategy is strongly supported by published studies. However, this section relies largely on secondary publications and our combined clinical experience, as few randomized, blinded studies have had, as their focus, the comparison of combined regimens for depression. This article summarizes the design features and results of studies dealing with depressive features and intervention strategies for bipolar disorders. The emphasis of the recommendations is on pragmatic treatment decisions that clinicians can make to enhance the probability of both short and long term benefits for patients. PMID- 26479315 TI - Deletion of murine Arv1 results in a lean phenotype with increased energy expenditure. AB - BACKGROUND: ACAT-related enzyme 2 required for viability 1 (ARV1) is a putative lipid transporter of the endoplasmic reticulum that is conserved across eukaryotic species. The ARV1 protein contains a conserved N-terminal cytosolic zinc ribbon motif known as the ARV1 homology domain, followed by multiple transmembrane regions anchoring it in the ER. Deletion of ARV1 in yeast results in defective sterol trafficking, aberrant lipid synthesis, ER stress, membrane disorganization and hypersensitivity to fatty acids (FAs). We sought to investigate the role of Arv1 in mammalian lipid metabolism. METHODS: Homologous recombination was used to disrupt the Arv1 gene in mice. Animals were examined for alterations in lipid and lipoprotein levels, body weight, body composition, glucose tolerance and energy expenditure. RESULTS: Global loss of Arv1 significantly decreased total cholesterol and high-density lipoprotein cholesterol levels in the plasma. Arv1 knockout mice exhibited a dramatic lean phenotype, with major reductions in white adipose tissue (WAT) mass and body weight on a chow diet. This loss of WAT is accompanied by improved glucose tolerance, higher adiponectin levels, increased energy expenditure and greater rates of whole-body FA oxidation. CONCLUSIONS: This work identifies Arv1 as an important player in mammalian lipid metabolism and whole-body energy homeostasis. PMID- 26479316 TI - NMR-based metabolic profiling in healthy individuals overfed different types of fat: links to changes in liver fat accumulation and lean tissue mass. AB - BACKGROUND: Overeating different dietary fatty acids influence the amount of liver fat stored during weight gain, however, the mechanisms responsible are unclear. We aimed to identify non-lipid metabolites that may differentiate between saturated (SFA) and polyunsaturated fatty acid (PUFA) overfeeding using a non-targeted metabolomic approach. We also investigated the possible relationships between plasma metabolites and body fat accumulation. METHODS: In a randomized study (LIPOGAIN study), n=39 healthy individuals were overfed with muffins containing SFA or PUFA. Plasma samples were precipitated with cold acetonitrile and analyzed by nuclear magnetic resonance (NMR) spectroscopy. Pattern recognition techniques were used to overview the data, identify variables contributing to group classification and to correlate metabolites with fat accumulation. RESULTS: We previously reported that SFA causes a greater accumulation of liver fat, visceral fat and total body fat, whereas lean tissue levels increases less compared with PUFA, despite comparable weight gain. In this study, lactate and acetate were identified as important contributors to group classification between SFA and PUFA (P<0.05). Furthermore, the fat depots (total body fat, visceral adipose tissue and liver fat) and lean tissue correlated (P(corr)>0.5) all with two or more metabolites (for example, branched amino acids, alanine, acetate and lactate). The metabolite composition differed in a manner that may indicate higher insulin sensitivity after a diet with PUFA compared with SFA, but this needs to be confirmed in future studies. CONCLUSION: A non-lipid metabolic profiling approach only identified a few metabolites that differentiated between SFA and PUFA overfeeding. Whether these metabolite changes are involved in depot-specific fat storage and increased lean tissue mass during overeating needs further investigation. PMID- 26479317 TI - A high-throughput platform for real-time analysis of membrane fission reactions reveals dynamin function. AB - Dynamin, the paradigmatic membrane fission catalyst, assembles as helical scaffolds that hydrolyse GTP to sever the tubular necks of clathrin-coated pits. Using a facile assay system of supported membrane tubes (SMrT) engineered to mimic the dimensions of necks of clathrin-coated pits, we monitor the dynamics of a dynamin-catalysed tube-severing reaction in real time using fluorescence microscopy. We find that GTP hydrolysis by an intact helical scaffold causes progressive constriction of the underlying membrane tube. On reaching a critical dimension of 7.3 nm in radius, the tube undergoes scission and concomitant splitting of the scaffold. In a constant GTP turnover scenario, scaffold assembly and GTP hydrolysis-induced tube constriction are kinetically inseparable events leading to tube-severing reactions occurring at timescales similar to the characteristic fission times seen in vivo. We anticipate SMrT templates to allow dynamic fluorescence-based detection of conformational changes occurring in self assembling proteins that remodel membranes. PMID- 26479318 TI - 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. AB - The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target. PMID- 26479319 TI - Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly. AB - Integrin receptor activation initiates the formation of integrin adhesion complexes (IACs) at the cell membrane that transduce adhesion-dependent signals to control a multitude of cellular functions. Proteomic analyses of isolated IACs have revealed an unanticipated molecular complexity; however, a global view of the consensus composition and dynamics of IACs is lacking. Here, we have integrated several IAC proteomes and generated a 2,412-protein integrin adhesome. Analysis of this data set reveals the functional diversity of proteins in IACs and establishes a consensus adhesome of 60 proteins. The consensus adhesome is likely to represent a core cell adhesion machinery, centred around four axes comprising ILK-PINCH-kindlin, FAK-paxillin, talin-vinculin and alpha-actinin zyxin-VASP, and includes underappreciated IAC components such as Rsu-1 and caldesmon. Proteomic quantification of IAC assembly and disassembly detailed the compositional dynamics of the core cell adhesion machinery. The definition of this consensus view of integrin adhesome components provides a resource for the research community. PMID- 26479321 TI - Synthesis of Biaryls via Benzylic C-C Bond Cleavage of Styrenes and Benzyl Alcohols. AB - A metal-free oxidative coupling of styrenes and benzyl alcohols with arenes has been developed for the synthesis of biaryls. The reaction features a conspicuous benzylic C-C bond cleavage of styrenes and benzyl alcohols. The reaction with both substrates proceeds through a common aldehydic intermediate formed through oxidative C-C bond cleavage of alkene and oxidation of benzyl alcohols. The reaction proceeds efficiently over a broad range of substrates with excellent functional group tolerance. PMID- 26479320 TI - Activator-inhibitor coupling between Rho signalling and actin assembly makes the cell cortex an excitable medium. AB - Animal cell cytokinesis results from patterned activation of the small GTPase Rho, which directs assembly of actomyosin in the equatorial cortex. Cytokinesis is restricted to a portion of the cell cycle following anaphase onset in which the cortex is responsive to signals from the spindle. We show that shortly after anaphase onset oocytes and embryonic cells of frogs and echinoderms exhibit cortical waves of Rho activity and F-actin polymerization. The waves are modulated by cyclin-dependent kinase 1 (Cdk1) activity and require the Rho GEF (guanine nucleotide exchange factor), Ect2. Surprisingly, during wave propagation, although Rho activity elicits F-actin assembly, F-actin subsequently inactivates Rho. Experimental and modelling results show that waves represent excitable dynamics of a reaction-diffusion system with Rho as the activator and F actin the inhibitor. We propose that cortical excitability explains fundamental features of cytokinesis including its cell cycle regulation. PMID- 26479322 TI - Assessing Interactions between Lipophilic and Hydrophilic Antioxidants in Food Emulsions. AB - Dietary lipids containing high concentrations of polyunsaturated fatty acids are considered to be beneficial to human health, yet their incorporation within formulated foods is complicated by their susceptibility to oxidation. Lipid oxidation in foods is inhibited through the incorporation of antioxidants, yet the list of antioxidants approved for food use is small, and consumers frequently demand foods without synthetic additives. As a consequence, food processors are now tasked with improving the efficacy of approved, "natural" (i.e., nonsynthetic) antioxidants; a rational strategy for doing so involves localizing the antioxidants at the interface where oxidation usually occurs and regenerating the consumed antioxidants after the oxidation event has occurred. The present study describes a procedure to evaluate antioxidant interactions in oil-in-water food emulsions, which is based on controlled oxidation reactions induced in the dispersed oil phase by the lipophilic radical generator, 2,2'-azobis(2,4 dimethylvaleronitrile). The extent of lipid oxidation is measured spectroscopically by following the loss of an oxidatively labile, lipophilic probe (methyl eleostearate), the synthesis of which is described here. Using this procedure, the ability of various aqueous phase solvated antioxidants (ascorbic acid, gallic acid, (-)-epicatechin, (-)-epigallocatechin-3-gallate) to regenerate lipid phase solvated alpha-tocopherol was evaluated. In all cases, the test compounds were able to inhibit oxidation reactions; however, these effects were not profoundly synergistic, and the maximum synergistic interaction observed was only ~ 3% using ascorbic acid. PMID- 26479323 TI - Sample tilt effects on atom column position determination in ABF-STEM imaging. AB - The determination of atom positions from atomically resolved transmission electron micrographs is fundamental for the analysis of crystal defects and strain. In recent years annular bright-field (ABF) imaging has become a popular imaging technique owing to its ability to map both light and heavy elements. Contrast formation in ABF is partially governed by the phase of the electron wave, which renders the technique more sensitive to the tilt of the electron beam with respect to the crystal zone axis than high-angle annular dark-field imaging. Here we show this sensitivity experimentally and use image simulations to quantify this effect. This is essential for error estimation in future quantitative ABF studies. PMID- 26479324 TI - Specific marker of feigned memory impairment: The activation of left superior frontal gyrus. AB - Faking memory impairment means normal people complain lots of memory problems without organic damage in forensic assessments. Using alternative forced-choice paradigm, containing digital or autobiographical information, previous neuroimaging studies have indicated that faking memory impairment could cause the activation in the prefrontal and parietal regions, and might involve a fronto parietal-subcortical circuit. However, it is still unclear whether different memory types have influence on faking or not. Since different memory types, such as long-term memory (LTM) and short-term memory (STM), were found supported by different brain areas, we hypothesized that feigned STM or LTM impairment had distinct neural activation mapping. Besides that, some common neural correlates may act as the general characteristic of feigned memory impairment. To verify this hypothesis, the functional magnetic resonance imaging (fMRI) combined with an alternative word forced-choice paradigm were used in this study. A total of 10 right-handed participants, in this study, had to perform both STW and LTM tasks respectively under answering correctly, answering randomly and feigned memory impairment conditions. Our results indicated that the activation of the left superior frontal gyrus and the left medial frontal gyrus was associated with feigned LTM impairment, whereas the left superior frontal gyrus, the left precuneus and the right anterior cingulate cortex (ACC) were highly activated while feigning STM impairment. Furthermore, an overlapping was found in the left superior frontal gyrus, and it suggested that the activity of the left superior frontal gyrus might be acting as a specific marker of feigned memory impairment. PMID- 26479326 TI - The levels of vitamin B12, folate and homocysteine in mothers and their babies with neural tube defects. AB - The aim of the present study was to determine the serum levels of vitamin B12, folate, and homocysteine (Hcy) in mothers and their babies, and to assess the association between these levels and neural tube defect (NTD). The study group included 92 baby-mother pairs, where the babies had NTD, and the control group included 102 pairs, where the babies had no NTD, from May 2012 to May 2015. Plasma vitamin B12, folate, and Hcy levels of the babies and mothers were measured, and compared with each other. NTD was diagnosed in 2.6% of our babies. The vitamin B12 levels in the mothers and the babies in the study group were determined as 166.2 +/- 63.7 pg/mL and 240.3 +/- 120.3 pg/mL, and in the control group as 1 9 0 +/- 80.2 pg/mL and 299.5 +/- 151.4 pg/mL, respectively. There was a significant difference between the two groups in terms of both the mothers' and the babies' vitamin B12 levels (p = 0.024 and p = 0.003, respectively). The plasma folate levels of the mothers in the study group (5.2 +/- 3 ng/mL) were significantly lower than control group (6.4 +/- 4.3 ng/mL, p = 0.032).The plasma Hcy level of the mothers in the study group (9.3 +/- 3.8 MUmol/L) was significantly higher than the control group (7 +/- 3.8 MUmol/L, p < 0.001). High plasma Hcy levels and low plasma folate and vitamin B12 levels are risk factors for NTD. Our results show that the risk for NTD can be decreased by fortification of mothers-to-be, particularly in rural areas with folate and vitamin B12 deficiency, which would lower the plasma Hcy level. PMID- 26479327 TI - Organochlorine Pesticides Exposure and Bladder Cancer: Evaluation from a Gene Environment Perspective in a Hospital-Based Case-Control Study in the Canary Islands (Spain). AB - The incidence of bladder cancer has increased significantly since the 1950s. Pesticide exposure has been linked with increasing bladder cancer incidence, although the evidence is inconclusive. However, most epidemiological studies did not evaluate the potential role played by the organochlorine pesticides, the most widely used pesticides in Western countries from the 1940s to the 1970s. Organochlorine pesticides were banned in the late 1970s because of their persistence in the environment and their carcinogenic and mutagenic effects. Organochlorine pesticides were employed in huge amounts in the Spanish archipelago of the Canary Islands; the authors, therefore, evaluated the role played by organochlorine pesticides exposure on bladder cancer. Serum levels of the most prevalent organochlorine pesticides used in the agriculture of these Islands (dichlorodiphenyltrichloroethane [p,p'-DDT], and its metabolites dichlorodiphenyldichloroethylene [p,p'-DDE] and dichlorodiphenyldichloroethane [p,p'-DDD], hexachlorobenzene, hexachlorocyclohexane isomers, aldrin, dieldrin, endrin, heptachlor, cis-chlordane, trans-chlordane, alpha- and beta-endosulfan, endosulfan sulfate, methoxychlor, and mirex) were measured in 140 bladder cancer cases and 206 controls. GST-M1 and GST-T1 gene polymorphisms were genotyped by polymerase chain reaction (PCR)-based methods. These results showed that serum levels of organochlorine pesticides did not increase bladder cancer risk. On the contrary, total burden of hexachlorocyclohexanes was found to be negatively associated to bladder cancer (odds ratio [OR] = 0.929, 95% confidence interval [CI]: 0.865-0.997; P = .041). This effect disappeared when the distribution of the gluthathione S-transferase polymorphisms was introduced in the statistical model. These results indicate that organochlorine pesticides are not a risk factor for bladder cancer. However, these findings provide additional evidence of gene-environment interactions for organochlorine pesticides and bladder cancer and reinforce the relevance of genes encoding xenobiotic-metabolizing enzymes in bladder cancer. PMID- 26479328 TI - Paper-Based Analytical Devices Relying on Visible-Light-Enhanced Glucose/Air Biofuel Cells. AB - A strategy that combines visible-light-enhanced biofuel cells (BFCs) and electrochemical immunosensor into paper-based analytical devices was proposed for sensitive detection of the carbohydrate antigen 15-3 (CA15-3). The gold nanoparticle modified paper electrode with large surface area and good conductibility was applied as an effective matrix for primary antibodies. The glucose dehydrogenase (GDH) modified gold-silver bimetallic nanoparticles were used as bioanodic biocatalyst and signal magnification label. Poly(terthiophene) (pTTh), a photoresponsive conducting polymer, served as catalyst in cathode for the reduction of oxygen upon illumination by visible light. In the bioanode, electrons were generated through the oxidation of glucose catalyzed by GDH. The amount of electrons is determined by the amount of GDH, which finally depended on the amount of CA15-3. In the cathode, electrons from the bioanode could combine with the generated holes in the HOMO energy level of cathode catalysts pTTh. Meanwhile, the high energy level photoexcited electrons were generated in the LUMO energy level and involved in the oxygen reduction reaction, finally resulting in an increasing current and a decreasing overpotential. According to the current signal, simple and efficient detection of CA15-3 was achieved. PMID- 26479325 TI - Comparison of three neurotropic viruses reveals differences in viral dissemination to the central nervous system. AB - Neurotropic viruses initiate infection in peripheral tissues prior to entry into the central nervous system (CNS). However, mechanisms of dissemination are not completely understood. We used genetically marked viruses to compare dissemination of poliovirus, yellow fever virus 17D (YFV-17D), and reovirus type 3 Dearing in mice from a hind limb intramuscular inoculation site to the sciatic nerve, spinal cord, and brain. While YFV-17D likely entered the CNS via blood, poliovirus and reovirus likely entered the CNS by transport through the sciatic nerve to the spinal cord. We found that dissemination was inefficient in adult immune-competent mice for all three viruses, particularly reovirus. Dissemination of all viruses was more efficient in immune-deficient mice. Although poliovirus and reovirus both accessed the CNS by transit through the sciatic nerve, stimulation of neuronal transport by muscle damage enhanced dissemination only of poliovirus. Our results suggest that these viruses access the CNS using different pathways. PMID- 26479329 TI - Implementing a routine outcome assessment procedure to evaluate the quality of assistive technology service delivery for children with physical or multiple disabilities: Perceived effectiveness, social cost, and user satisfaction. AB - There is a lack of evidence on the effects and quality of assistive technology service delivery (ATSD). This study presents a quasi-experimental 3-months follow up using a pre-test/post-test design aimed at evaluating outcomes of assistive technology (AT) interventions targeting children with physical and multiple disabilities. A secondary aim was to evaluate the feasibility of the follow-up assessment adopted in this study with a view to implement the procedure in routine clinical practice. Forty-five children aged 3-17 years were included. Parents were asked to complete the Individual Prioritised Problem Assessment (IPPA) for AT effectiveness; KWAZO (Kwaliteit van Zorg [Quality of Care]) and Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST) 2.0 for satisfaction with ATSD; Siva Cost Analysis Instrument (SCAI) for estimating the social cost of AT interventions. At follow-up, 25 children used the AT recommended. IPPA effect sizes ranged from 1.4 to 0.7, showing a large effect of AT interventions. Overall, parents were satisfied with ATSD, but Maintenance, Professional Services, and AT Delivery were rated not satisfactory. SCAI showed more resources spent for AT intervention compared to human assistance without technological supports. AT may be an effective intervention for children with disabilities. Issues concerning responsiveness and feasibility of the IPPA and the SCAI instruments are discussed with a view to inform routine clinical practice. PMID- 26479330 TI - Suppression of Low-Frequency Electronic Noise in Polymer Nanowire Field-Effect Transistors. AB - The authors report on the reduction of low-frequency noise in semiconductor polymer nanowires with respect to thin-films made of the same organic material. Flicker noise is experimentally investigated in polymer nanowires in the range of 10-10(5) Hz by means of field-effect transistor architectures. The noise in the devices is well described by the Hooge empirical model and exhibits an average Hooge constant, which describes the current power spectral density of fluctuations, suppressed by 1-2 orders of magnitude compared to thin-film devices. To explain the Hooge constant reduction, a resistor network model is developed, in which the organic semiconducting nanostructures or films are depicted through a two-dimensional network of resistors with a square-lattice structure, accounting for the different anisotropy and degree of structural disorder of the active nanowires and films. Results from modeling agree well with experimental findings. These results support enhanced structural order through size-confinement in organic nanostructures as effective route to improve the noise performance in polymer electronic devices. PMID- 26479331 TI - Structural Properties and Aggregation Behavior of 1-Hexyl-3-methylimidazolium Iodide in Aqueous Solutions. AB - The structural properties of 1-hexyl-3-methylimidazolium iodide ([C6mim]I)/water mixtures with molar ratios ranging from 1:1 to 1:200 have been investigated using molecular dynamics (MD) simulations with extended X-ray absorption fine structure (EXAFS) experimental data. The presence of a complex network of interactions among cations, anions, and water molecules has been highlighted from the MD simulations, even if water molecules have been found to interact preferentially with the I(-) anion. The EXAFS results show that, also for the 1:1 [C6mim]I/water mixture, the water molecules are placed next to the I(-) anion, and the I(-) hydration shell becomes more and more crowded with increasing water content. Tight ion pairs have been detected in the [C6mim]I/water mixtures with molar ratios from 1:1 to 1:12, while no ionic pairs were found in the most diluted solutions. The aggregation behavior has been determined from MD simulations with the aid of S(q) functions. For the most concentrated IL/water mixtures with molar ratios between 1:1 and 1:12 the existence of long-range structural correlations has been evidenced, even if the apolar chains are not completely segregated as expected for micelle-like structures. Conversely, for the 1:200 mixture, that is above the experimental critical aggregation concentration value, the alkyl chains are completely separated from each other. PMID- 26479332 TI - Tailor-Made Boronic Acid Functionalized Magnetic Nanoparticles with a Tunable Polymer Shell-Assisted for the Selective Enrichment of Glycoproteins/Glycopeptides. AB - Biomedical sciences, and in particular biomarker research, demand efficient glycoproteins enrichment platforms. In this work, we present a facile and time saving method to synthesize phenylboronic acid and copolymer multifunctionalized magnetic nanoparticles (NPs) using a distillation-precipitation polymerization (DPP) technique. The polymer shell is obtained through copolymerization of two monomers-affinity ligand 3-acrylaminophenylboronic acid (AAPBA) and a hydrophilic functional monomer. The resulting hydrophilic Fe3O4@P(AAPBA-co-monomer) NPs exhibit an enhanced binding capacity toward glycoproteins by an additional functional monomer complementary to the surface presentation of the target protein. The effects of monomer ratio of AAPBA to hydrophilic comonomers on the binding of glycoproteins are systematically investigated. The morphology, structure, and composition of all the synthesized microspheres are characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), and vibrating sample magnetometer (VSM). The hydrophilic Fe3O4@P(AAPBA-co monomer) microspheres show an excellent performance in the separation of glycoproteins with high binding capacity; And strong magnetic response allows them to be easily separated from solution in the presence of an external magnetic field. Moreover, both synthetic Fe3O4@P(AAPBA) and copolymeric NPs show good adsorption to glycoproteins in physiological conditions (pH 7.4). The Fe3O4@P(AAPBA-co-monomer) NPs are successfully utilized to selectively capture and identify the low-abundance glycopeptides from the tryptic digest of horseradish peroxidase (HRP). In addition, the selective isolation and enrichment of glycoproteins from the egg white samples at physiological condition is obtained by Fe3O4@P(AAPBA-co-monomer) NPs as adsorbents. PMID- 26479333 TI - Oxidative Stress, Cytotoxicity, and Genotoxicity Induced by Methyl Parathion in Human Gingival Fibroblasts: Protective Role of Epigallocatechin-3-Gallate. AB - Organophosphorous (OP) compounds are pesticides frequently released into the environment because of extensive use in agriculture. Among these, methyl parathion (mPT) recently received attention as a consequence of illegal use. The predominant route of human exposure to mPT is via inhalation, but inadvertent consumption of contaminated foods and water may also occur. The goal of this study was to investigate the in vitro effects of mPT on cells in the oral cavity and evaluate the potential protective role of epigallocathechin-3-gallate (EGCG) on these effects. Human gingival fibroblasts (HGF) were exposed to 10, 50, or 100 MU g/ml mPT for 24 h and assessed for oxidative stress, as evidenced by reactive generation of oxygen species (ROS), induction of apoptotic cell death, DNA damage (comet assay and cytochinesis-block micronucleus test), and nitric oxide (NO) production. The results showed that mPT produced significant oxidative stress, cytotoxicity, and genotoxicity and increased NO levels through stimulation of inducible NO synthase expression. Finally, data demonstrated that EGCG (10, 25, or 50 MU M) was able to inhibit the pesticide-induced effects on all parameters studied. Data indicate that cytotoxic and genotoxic effects may be associated with oxidative stress induced by mPT observed in HGF cultures and that EGCG plays a protective role via antioxidant activities. PMID- 26479334 TI - Physical Delivery of Macromolecules using High-Aspect Ratio Nanostructured Materials. AB - There is great need for the development of an efficient delivery method of macromolecules, including nucleic acids, proteins, and peptides, to cell cytoplasm without eliciting toxicity or changing cell behavior. High-aspect ratio nanomaterials have addressed many challenges present in conventional methods, such as cell membrane passage and endosomal degradation, and have shown the feasibility of efficient high-throughput macromolecule delivery with minimal perturbation of cells. This review describes the recent advances of in vitro and in vivo physical macromolecule delivery with high-aspect ratio nanostructured materials and summarizes the synthesis methods, material properties, relevant applications, and various potential directions. PMID- 26479336 TI - High-level mobility skills in children and adolescents with traumatic brain injury. AB - AIM: To evaluate the reliability, validity and responsiveness of the High-level Mobility Assessment Tool (HiMAT) in children and adolescents with traumatic brain injury (TBI) and to compare the mobility skills of children with TBI to those of healthy peers. METHOD: The mobility skills of 52 children with moderate and severe TBI (36 males; mean age = 12 years, range = 6-17) were assessed using the HiMAT and the Pediatric Evaluation of Disability Inventory (PEDI). Inter-rater reliability, re-test reliability and responsiveness of the HiMAT were evaluated in sub-groups by comparing results scored at several time-points. The HiMAT scores of children with TBI were compared with those of a healthy comparative cohort. RESULTS: The HiMAT demonstrated excellent inter-rater reliability (ICC = 0.93), re-test reliability (ICC = 0.98) and responsiveness to change (p = 0.002). The PEDI demonstrated a ceiling effect in mobility assessment of ambulant children with TBI. The HiMAT scores of children with TBI were lower than those of their healthy peers (p < 0.001). INTERPRETATION: The HiMAT is a reliable, valid and sensitive measure of high-level mobility skills following childhood TBI. The high-level mobility skills of children with TBI are less proficient than their peers. PMID- 26479337 TI - Surface Enhanced Raman Scattering Detection of Cancer Biomarkers with Bifunctional Nanocomposite Probes. AB - This report describes new findings of an investigation of a bifunctional nanocomposite probe for the detection of cancer biomarkers, demonstrating the viability of magnetic focusing and SERS detection in a microfluidic platform. The nanocomposite probe consists of a magnetic nickel-iron core and a gold shell. Upon bioconjugation, the nanoprobes are magnetically focused on a specific spot in a microfluidic channel, enabling an enrichment of "hot spots" for surface enhanced Raman scattering detection of the targeted carcinoembryonic antigen. The detection sensitivity, with a limit of detection of ~0.1 pM, is shown to scale with the magnetic focusing time and the nanoparticle size. The latter is also shown to exhibit an excellent agreement between the experimental data and the theoretical simulation. Implications of the findings to the development of rapid and sensitive microfluidic detection of cancer biomarkers are also discussed. PMID- 26479335 TI - Therapeutic targets for cholestatic liver injury. AB - INTRODUCTION: Cholestasis is a reduction in bile flow that occurs during numerous pathologies. Blockage of the biliary tracts results in hepatic accumulation of bile acids or their conjugate bile salts. The molecular mechanisms behind liver injury associated with cholestasis are extensively studied, but not well understood. Multiple models of obstructive cholestasis result in a significant inflammatory infiltrate at the sites of necrosis that characterize the injury. AREAS COVERED: This review will focus on direct bile acid toxicity during cholestasis, bile acid signaling processes and on the development and continuation of inflammation during cholestasis, with a focus on novel proposed molecular mediators of neutrophil recruitment. While significant progress has been made on these molecular mechanisms, a continued focus on how cholestasis and the innate immune system interact is necessary to discover targetable therapeutics that might protect the liver while leaving global immunity intact. EXPERT OPINION: While bile acid toxicity likely occurs in humans and other mammals when toxic bile acids accumulate, persistent inflammation is likely responsible for continued liver injury during obstructive cholestasis. Targeting molecular mediators of inflammation may help prevent liver injury during acute cholestasis both in murine models and human patients. PMID- 26479338 TI - Multi-modal signal acquisition using a synchronized wireless body sensor network in geriatric patients. AB - Wearable home-monitoring devices acquiring various biosignals such as the electrocardiogram, photoplethysmogram, electromyogram, respirational activity and movements have become popular in many fields of research, medical diagnostics and commercial applications. Especially ambulatory settings introduce still unsolved challenges to the development of sensor hardware and smart signal processing approaches. This work gives a detailed insight into a novel wireless body sensor network and addresses critical aspects such as signal quality, synchronicity among multiple devices as well as the system's overall capabilities and limitations in cardiovascular monitoring. An early sign of typical cardiovascular diseases is often shown by disturbed autonomic regulations such as orthostatic intolerance. In that context, blood pressure measurements play an important role to observe abnormalities like hypo- or hypertensions. Non-invasive and unobtrusive blood pressure monitoring still poses a significant challenge, promoting alternative approaches including pulse wave velocity considerations. In the scope of this work, the presented hardware is applied to demonstrate the continuous extraction of multi modal parameters like pulse arrival time within a preliminary clinical study. A Schellong test to diagnose orthostatic hypotension which is typically based on blood pressure cuff measurements has been conducted, serving as an application that might significantly benefit from novel multi-modal measurement principles. It is further shown that the system's synchronicity is as precise as 30 MUs and that the integrated analog preprocessing circuits and additional accelerometer data provide significant advantages in ambulatory measurement environments. PMID- 26479339 TI - The multifunctional lateral geniculate nucleus. AB - Providing the critical link between the retina and visual cortex, the well studied lateral geniculate nucleus (LGN) has stood out as a structure in search of a function exceeding the mundane 'relay'. For many mammals, it is structurally impressive: Exquisite lamination, sophisticated microcircuits, and blending of multiple inputs suggest some fundamental transform. This impression is bolstered by the fact that numerically, the retina accounts for a small fraction of its input. Despite such promise, the extent to which an LGN neuron separates itself from its retinal brethren has proven difficult to appreciate. Here, I argue that whereas retinogeniculate coupling is strong, what occurs in the LGN is judicious pruning of a retinal drive by nonretinal inputs. These nonretinal inputs reshape a receptive field that under the right conditions departs significantly from its retinal drive, even if transiently. I first review design features of the LGN and follow with evidence for 10 putative functions. Only two of these tend to surface in textbooks: parsing retinal axons by eye and functional group and gating by state. Among the remaining putative functions, implementation of the principle of graceful degradation and temporal decorrelation are at least as interesting but much less promoted. The retina solves formidable problems imposed by physics to yield multiple efficient and sensitive representations of the world. The LGN applies context, increasing content, and gates several of these representations. Even if the basic concentric receptive field remains, information transmitted for each LGN spike relative to each retinal spike is measurably increased. PMID- 26479340 TI - Evaluation of anti-inflammatory potential of the ethanolic extract of the Saussurea lappa root (costus) on adjuvant-induced monoarthritis in rats. AB - BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by polyarticular symmetrical arthritis. The prevalence of RA is consistent worldwide, affecting about 0.5%-1.0% of the population. The aim of this study was to investigate whether Saussurea lappa (costus) could ameliorate adjuvant arthritis (AA) in the rat for 21 days. METHODS: Animals were divided into eight groups (n=5/group). Group 1 acted as control, group 2 presented the AA rats (positive control), and groups 3, 4, and 5 were treated with different doses of S. lappa (200, 400, and 600 mg/kg, respectively), whereas groups 6, 7, and 8 were AA rats and orally administered with S. lappa (200, 400, and 600 mg/kg, respectively). The changes caused by chronic inflammation were evaluated through the measurement of ankle circumference (AC). Serum C-reactive protein (CRP), interleukins (IL-1beta and IL-6), tumor necrosis factor alpha (TNF-alpha), total oxidative capacity (TOC), and total antioxidant capacity (TAC) were determined. RESULTS: Saussurea lappa dose-dependently alleviated the severity of the disease based on the reduction in AC and on the clinical scores of the histological study. Histopathological examination proved that S. lappa decreased the infiltration of inflammatory cells and synovial hyperplasia as well as protected joint destruction. Saussurea lappa reduced the serum levels of CRP, TNF-alpha, IL 1beta, and IL-6, reduced the TOC, and improved the TAC as compared with AA rats. CONCLUSIONS: The S. lappa extract has potentially useful anti-arthritic activity as well as improves the immune and antioxidant responses of adjuvant-induced monoarthritis in rats. PMID- 26479341 TI - Melatonin and vitamin C exacerbate Cannabis sativa-induced testicular damage when administered separately but ameliorate it when combined in rats. AB - BACKGROUND: The mechanisms involved in the spermatotoxic effect of Cannabis sativa are inconclusive. The involvement of oxidative stress in male factor infertility has been well documented, and the antioxidative potential of melatonin and vitamin C in many oxidative stress conditions has been well reported. This study sought to investigate whether melatonin and vitamin C will ameliorate C. sativa-induced spermatotoxicity or not. METHODS: Fifty-five (55) male albino rats (250-300 g) were randomly divided in a blinded fashion into five oral treatment groups as follows: group I (control, n=5) received 1 mL/kg of 10% ethanol for 30 days; groups IIa, IIb, and IIc (n=5 each) received 2 mg/kg C. sativa for 20, 30, and 40 days, respectively; groups IIIa, IIIb, and IIIc (n=5 each) received a combination of 2 mg/kg C. sativa and 4 mg/kg melatonin for 20, 30, and 40 days, respectively; groups IVa, IVb, and IVc (n=5 each) received a combination of 2 mg/kg C. sativa and 1.25 g/kg vitamin C for 20, 30, and 40 days, respectively; group V (n=5) received a combination of 2 mg/kg C. sativa, 4 mg/kg melatonin, and 1.25 g/kg vitamin C for 30 days. RESULTS: Cannabis treatments reduced the Johnsen score, sperm count, motility, morphology, paired testicular/body weight ratio, and total antioxidant capacity, but increased lactate dehydrogenase activity. In addition, supplementation of cannabis-treated rats with either melatonin or vitamin C exacerbates the effect of cannabis on those parameters, whereas combination of melatonin and vitamin C reversed the trend to the level comparable to control. CONCLUSIONS: This study further showed the gonadotoxic effect of C. sativa, which could be mediated by oxidative stress. It also showed that melatonin and vitamin C exacerbate C. sativa-induced testicular damage when administered separately but ameliorate it when combined in rats. PMID- 26479342 TI - Chemical characterization, antioxidant and cytotoxic activities of the methanolic extract of Hymenocrater longiflorus grown in Iraq. AB - Hymenocrater longiflorus was collected from northern Iraq, and the chemical composition and antioxidant and cytotoxic activities of this plant were investigated. Ten compounds detected by HPLC-ESI/MS were identified as flavonoids and phenolic acids. The free radical scavenging activity of the 70% methanol extract was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The antioxidant activities of the extract may be attributed to its polyphenolic composition. The cytotoxicity of the plant extract against the osteosarcoma (U2OS) cell line was assessed with the 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay. The extract significantly reduced the viability of cells in a concentration- and time-dependent manner. Cells were arrested during the S-phase of the cell cycle, and DNA damage was revealed by antibodies against histone H2AX. The apoptotic features of cell shrinkage and decrease in cell size were also observed. Western blot analysis revealed cleavage of poly (ADP-ribose)-polymerase 1 (PARP-1), in addition to increases in the proteins p53, p21, and gamma-H2AX. Collectively, our findings demonstrate that the H. longiflorus extract is highly cytotoxic to U2OS cells, most likely due to its polyphenolic composition. PMID- 26479343 TI - A novel exonuclease (TaqMan) assay for rapid haptoglobin genotyping. AB - BACKGROUND: Haptoglobin is an acute-phase binding protein that scavenges free hemoglobin. The human haptoglobin gene (HP) is polymorphic with two main alleles, haptoglobin allele 1 (Hp1) and haptoglobin allele 2 (Hp2). The smaller Hp1 allele features no duplication and consists of four exons, whereas the larger Hp2 allele, containing a 1.7 kb duplication, consists of six exons, with the fifth and sixth being highly homologous to exons 3 and 4 of Hp1. METHODS: We designed an exonuclease (TaqMan) assay targeting single nucleotide differences between the homologous regions of Hp1 and Hp2. The assay contained one probe specifically binding to a site in intron 4 of Hp2, and another probe binding equally to intron 4 of Hp1 and intron 6 of Hp2. RESULTS: Measurement of post-PCR fluorescence allowed unambiguous discrimination of HP genotypes. Comparison with genotypes obtained by a method based upon allele-specific primers yielded fully corresponding results. CONCLUSIONS: The new HP genotyping method is fast, reliable, does not require real-time instruments and may be especially useful for high-throughput genotyping. PMID- 26479344 TI - Analysis of PMP22 duplication and deletion using a panel of six dinucleotide tandem repeats. AB - BACKGROUND: Charcot-Marie-Tooth type 1A (CMT1A) is the most common type of hereditary motor and sensory neuropathies (HMSN), caused by the duplication of the 17p11.2 region that includes the PMP22 gene. Reciprocal deletion of the same region is the main cause of hereditary neuropathy with liability to pressure palsies (HNPP). CMT1A accounts for approximately 50% of HMSN patients. Diagnostics of CMT1A and HNPP are based on quantitative analysis of the affected region or RFLP detection of breakage points. The aim of this study was to improve the sensitivity and efficiency of CMT1A and HNPP genetic diagnostics by introducing analysis of six STR markers (D17S261-D17S122-D17S839-D17S1358-D17S955 D17S921) spanning the duplicated region. METHODS: Forty-six CMT1A and seven HNPP patients, all genetically diagnosed by RFLP analysis, were tested for duplication or deletion using six STR markers. RESULTS: In all CMT1A and HNPP patients, microsatellite analysis comprising six STR markers confirmed the existence of a duplication or deletion. In 89% (41/46) CMT1A patients the confirmation was based on detecting three alleles on at least one locus. In the remaining 11% (5) CMT1A patients, duplication was also confirmed based on two peaks with clear dosage difference for at least two different markers. All HNPP patients (7/7) displayed only one allele for each analyzed locus. CONCLUSIONS: Microsatellite analysis using six selected STR loci showed a high level of sensitivity and specificity for genetic diagnostics of CMT1A and HNPP. The results here strongly suggest STR marker analysis as a method of choice in PMP22 duplication/deletion testing. PMID- 26479345 TI - The efficacy of an internet-based e-learning system using the CellaVision Competency Software for continuing professional development. PMID- 26479346 TI - Comparison of a 10- vs. 15-min centrifugation time for chemical and immunochemical assays and impact on turnaround time in a hospital laboratory. PMID- 26479347 TI - Preanalytical, analytical, gestational and pediatric aspects of the S100B immuno assays. AB - BACKGROUND: Traumatic brain injury management is a tricky issue in children and pregnant women (due to adverse effects of computer tomography). To facilitate management, we report the main analytical performances and reference ranges for blood tests for the well-established S100B biomarker in under-16 children on a DiaSorin(r) Liaison XL analyzer and in pregnant women on DiaSorin(r) Liaison XL and Roche Diagnostics(r) Cobas e411 analyzers. METHODS: Serum S100B concentrations were determined by chemiluminescent immunoassay on a DiaSorin(r) analyzer in a population of 409 healthy children aged 0-16 years and on DiaSorin(r)/Roche Diagnostics(r) instruments in a population of 50 pregnant women (one blood sample for each trimester). The analytical performances of both instruments and the influence of blood cells and skin pigmentation on the assay were also studied. RESULTS: For children, four age-groups emerged, i.e. 0-3 months (mean: 0.97 MUg/L; standard deviation (SD): 0.36; 95th percentile: 1.55), 4-9 months (mean: 0.58 MUg/L; SD: 0.30; 95th: 1.18), 10-24 months (mean: 0.31 MUg/L; SD: 0.12; 95th: 0.54) and 2-16 years (mean: 0.20 MUg/L; SD: 0.07; 95th: 0.32). For pregnant women, serum S100B concentrations were similar to defined ranges for adults and not significantly different between trimesters on DiaSorin(r) (p=0.652)/Roche Diagnostics(r) (p=0.877) analyzers. We also found S100B expression (protein, total mRNA) in lymphocytes, an influence of skin pigmentation, and good analytical performances for both instruments. CONCLUSIONS: Data provided here is useful for interpreting serum S100B test results, in terms of preanalytical conditions, analytical performances, pediatric and pregnancy' environment. PMID- 26479348 TI - The Italian External Quality Assessment (EQA) program on urinary sediment: results of the period 2012-2015. AB - BACKGROUND: Manual microscopy still represents the gold standard for urinary sediment (US) examination. We report the results obtained in the period 2012-2015 by the EQA Italian program on US, which today involves about 260 laboratories. METHODS: The program includes four surveys per year. In two surveys, participants are asked to supply identification and clinical association of US particles. In two other surveys, they are asked to supply the diagnosis of clinical cases, presented with images, some key laboratory findings and a short clinical history. Sixty-six images of US particles (21 cells, 2 lipids, 21 casts, 10 crystals, 3 microorganisms, 15 contaminants) and seven clinical cases were presented. RESULTS: The correct identification rate for each category of particles, in decreasing order, was: micro-organisms (mean+/-SD: 92.4%+/-4.5%), lipids (92.0%+/ 1.8%), casts (82.8%+/-8.8%), crystals (79.4%+/-29.8%), cells (77.3%+/-13.5%), and contaminants (70.9%+/-22.2%). For 13 particles, a correct clinical association was indicated by 91.5%+/-11.7% of participants, while it was 52.7% for particles associated with urinary tract infection. For clinical cases, due to a high rate of particles misidentification, only 44.3%+/-10.1% of participants achieved access to clinical diagnosis, which was then correctly indicated by 92.5%+/-5.3% of them. CONCLUSIONS: The results of the EQA program confirm that, while some US particles are well known in terms of identification, clinical association and clinical meaning, others particles still are not, and this represents an important reason to encourage EQA programs on US. PMID- 26479349 TI - Galectin-3, osteopontin and successful aging. AB - BACKGROUND: Individuals who reach exceptional longevity (100+ years of age) free of common chronic age diseases (i.e. 'dodgers') arguably represent the paradigm of successful aging in humans. As such, identification of potential biomarkers associated with this phenomenon is of medical interest. METHODS: We measured serum levels of galectin-3 and osteopontin, both of which have been shown to be linked with major chronic or aging-related disorders in younger populations, in centenarian 'dodgers' (n=81; 40 men; 100-104 years) and healthy controls (n=41; 24 men, 70-80 years). RESULTS: Both biomarkers showed significantly lower values (p<0.001) in the former (galectin-3: 2.4+/-1.7 vs. 4.8+/-2.8 ng/mL; osteopontin: 38.1+/-27.7 vs. 72.6+/-33.1 MUg/mL). Logistic regression analysis identified the combination of these two biomarkers as a significant predictor variable associated with successful aging regardless of sex (p<0.001). The area under the curve (AUC) classified the ability of galectin-3 and osteopontin to predict the likelihood of successful aging as 'fair' (AUC=0.75) and 'good' (AUC=0.80), respectively. Particularly, the combination of the two biomarkers showed good discriminatory power for successful aging (AUC=0.86), with sensitivity=83% and specificity=74%. CONCLUSIONS: Lower levels of both galectin-3 and osteopontin are associated with successful aging, representing potential biomarkers of this condition. Our cross-sectional data must be however approached with caution. Further research is necessary to replicate the present preliminary results in other cohorts and to identify the potential use of galectin-3 and osteopontin as potential targets (or at least predictors) in future personalized anti-aging therapies. PMID- 26479350 TI - Trefoil factor family peptides--friends or foes? AB - Trefoil factor family (TFF) peptides are a group of molecules bearing a characteristic three-loop trefoil domain. They are mainly secreted in mucous epithelia together with mucins but are also synthesized in the nervous system. For many years, TFF peptides were only known for their wound healing and protective function, e.g. in epithelial protection and restitution. However, experimental evidence has emerged supporting a pivotal role of TFF peptides in oncogenic transformation, tumorigenesis and metastasis. Deregulated expression of TFF peptides at the gene and protein level is obviously implicated in numerous cancers, and opposing functions as oncogenes and tumor suppressors have been described. With regard to the regulation of TFF expression, epigenetic mechanisms as well as the involvement of various miRNAs are new, promising aspects in the field of cancer research. This review will summarize current knowledge about the expression and regulation of TFF peptides and the involvement of TFF peptides in tumor biology and cancerogenesis. PMID- 26479351 TI - Developments and new vistas in the field of melanocortins. AB - Melanocortins play a fundamental role in several basic functions of the organism (sexual activity, feeding, inflammation and immune responses, pain sensitivity, response to stressful situations, motivation, attention, learning, and memory). Moreover, a large body of animal data, some of which were also confirmed in humans, unequivocally show that melanocortins also have impressive therapeutic effects in several pathological conditions that are the leading cause of mortality and disability worldwide (hemorrhagic, or anyway hypovolemic, shock; septic shock; respiratory arrest; cardiac arrest; ischemia- and ischemia/reperfusion-induced damage of the brain, heart, intestine, and other organs; traumatic injury of brain, spinal cord, and peripheral nerves; neuropathic pain; toxic neuropathies; gouty arthritis; etc.). Recent data obtained in animal models seem to moreover confirm previous hypotheses and preliminary data concerning the neurotrophic activity of melanocortins in neurodegenerative diseases, in particular Alzheimer's disease. Our aim was (i) to critically reconsider the established extrahormonal effects of melanocortins (on sexual activity, feeding, inflammation, tissue hypoperfusion, and traumatic damage of central and peripheral nervous system) at the light of recent findings, (ii) to review the most recent advancements, particularly on the effects of melanocortins in models of neurodegenerative diseases, (iii) to discuss the reasons that support the introduction into clinical practice of melanocortins as life-saving agents in shock conditions and that suggest to verify in clinical setting the impressive results steadily obtained with melanocortins in different animal models of tissue ischemia and ischemia/reperfusion, and finally, (iv) to mention the advisable developments, particularly in terms of selectivity of action and of effects. PMID- 26479353 TI - MDMA-induced angioedema treated with icatibant. PMID- 26479352 TI - CYP2D6 in Amerindians from Southern Mexico: low variability and higher frequency of functional alleles. AB - BACKGROUND: Several functional and nonfunctional CYP2D6 variants have been associated with interindividual and interethnic variability in pharmacological responses. The aim of this article was to study the diversity and the interpopulation relationships of CYP2D6 variants of south Native Mexicans to define predicted phenotypes. CONTENTS: A fully systematic review of CYP2D6 variants reported in Amerindian populations before 2015 was performed (NCBI, Google Scholar, and 1000 Genomes Project databases). Allele data were analyzed by methods such as heat map, dissimilarity matrix, dendogram, and principal component analysis using complete-linkage clustering method. Five original studies on CYP2D6 covering 13 Native Mexican populations were identified; three of these described CYP2D6 allele frequencies were in south Native Mexican populations. Overall, CYP2D6 allele variability is scarce in southern Native Mexican populations: besides the functional alleles *1 and *2 and the null variant *4, the other variants have frequencies <0.05. This implies that most of the southern Native Mexican populations may be considered CYP2D6 extended metabolizers. The statistical analyses tend to cluster the native communities by their geographical origin, but in a disperse pattern suggesting distinct subpopulation structures. CONCLUSIONS: CYP2D6 functional variants are prevalent in Native Mexicans, and they may be predicted as extended drug metabolizers. In addition, allele frequencies are related to the geographic distribution of the Amerindian groups and display important population stratification. PMID- 26479354 TI - Should Surgery for Hypospadias Be Performed Before An Age of Consent? AB - Hypospadias is a relatively common genital condition in which the urethral opening forms on the underside of the penis, as opposed to at the tip of the glans. Patients with hypospadias are typically referred for surgery during infancy or early childhood. Recent evidence, however, indicates that many individuals with hypospadias do not experience the functional or psychosocial difficulties commonly attributed to the condition, and that surgical intervention for hypospadias carries substantial risk of adverse outcomes. In this article, we review published outcomes data and conduct an in-depth analysis of the typical rationales for hypospadias surgery, taking into consideration both the potential benefits and harms of the procedure, as well as the existence of nonsurgical alternatives. We argue, first, that most childhood surgeries for hypospadias are performed for anticipated future problems concerning function and cosmesis, rather than extant physical and/or psychosocial problems that are adversely affecting the child's well-being. Second, we contend that the surgery can be safely performed after an age of consent without increasing the absolute risk of surgical complications to an ethically meaningful degree. We conclude, therefore, that surgery for hypospadias should be performed only if requested by the affected individual, under conditions of informed consent. PMID- 26479355 TI - Innovation in Nursing Education: What Outcomes? PMID- 26479356 TI - Interprofessional Education: Learning by Shadowing Other Providers. PMID- 26479357 TI - Teaching and Learning About Big Data: Start Small. PMID- 26479358 TI - Using a Nursing History Web Site With Today's Nursing Students. PMID- 26479359 TI - "Women Are Better Than Men"-Public Beliefs on Gender Differences and Other Aspects in Multitasking. AB - Reports in public media suggest the existence of a stereotype that women are better at multitasking than men. The present online survey aimed at supporting this incidental observation by empirical data. For this, 488 participants from various ethnic backgrounds (US, UK, Germany, the Netherlands, Turkey, and others) filled out a self-developed online-questionnaire. Results showed that overall more than 50% of the participants believed in gender differences in multitasking abilities. Of those who believed in gender differences, a majority of 80% believed that women were better at multitasking. The main reasons for this were believed to be an evolutionary advantage and more multitasking practice in women, mainly due to managing children and household and/or family and job. Findings were consistent across the different countries, thus supporting the existence of a widespread gender stereotype that women are better at multitasking than men. Further questionnaire results provided information about the participants' self rated own multitasking abilities, and how they conceived multitasking activities such as childcare, phoning while driving, and office work. PMID- 26479360 TI - On rivalry and goal pursuit: Shared competitive history, legacy concerns, and strategy selection. AB - Seven studies converge to show that prompting people to think about a rival versus a nonrival competitor causes them to view current competitions as more connected to past ones, to be more concerned with long-term legacy, and to pursue personal goals in a more eager, less cautious manner. These results are consistent with a social-cognitive view of rivalry that defines it as a competitive relational schema. A preliminary analysis revealed that people were more likely to appeal to past competitions to explain the importance of current rivalry than nonrivalry contests. Experiment 1 showed that people view rivalry versus nonrivalry competitions as more embedded in an ongoing competitive narrative and that this perception increases legacy concerns. The next 2 experiments used a causal chain approach to examine the possibility of legacy concerns acting as a mediator between rivalry and eagerness. Experiment 2a demonstrated that longer (vs. shorter) competitive histories are associated with increased legacy concerns. Experiment 2b manipulated legacy concerns and found that this shifted regulatory focus toward eagerness. Finally, 3 experiments tested the direct effect of thinking about a rival on eager strategy selection: Thinking about rivals (vs. nonrivals) led people to be more interested in offensive than defensive strategies (Experiment 3), to initiate rather than delay their goal pursuit (Experiment 4), and to rely on spontaneous rather than deliberative reasoning (Experiment 5). We suggest that rivalries affect how people view their goals and the strategies they use for pursuing them, and that these effects are at least partially attributable to the shared history between individuals and their rivals. PMID- 26479361 TI - Looking back to move forward: Nostalgia as a psychological resource for promoting relationship goals and overcoming relationship challenges. AB - Previous research has shown that nostalgia is a highly social emotion that provides a sense of social connectedness. In the present research, we tested a social motivational function of nostalgia. Specifically, across 7 studies we found converging evidence that nostalgia mobilizes social goals. In Study 1, nostalgia increased the importance people assigned to relationship goals and how optimistic they felt about achieving these goals. In Study 2, nostalgia increased intentions to pursue goals of connecting with friends. In Study 3, experimentally induced pessimism about achieving relationship goals instigated nostalgia. In Study 4, we found evidence that it is the interpersonal nature of nostalgia that is associated with striving to connect with others. Specifically, nostalgia about aspects of the past that were high in sociality was associated with intentions to interact with others, whereas nostalgia for aspects of the past that were low in sociality was not. In Study 5, nostalgic reflection increased friendship-approach goal striving relative to reflecting on ordinary social memories, but did not increase friendship-avoidant goal striving. Finally, in Studies 6 and 7, we found evidence that social-efficacy mediated the effect of nostalgia on striving to connect with others and striving to overcome interpersonal challenges. Together, these findings establish nostalgia as catalyst for social goal pursuit and growth. PMID- 26479362 TI - The nature of social dominance orientation: Theorizing and measuring preferences for intergroup inequality using the new SDO7 scale. AB - A new conceptualization and measurement of social dominance orientation individual differences in the preference for group based hierarchy and inequality is introduced. In contrast to previous measures of social dominance orientation that were designed to be unidimensional, the new measure (SDO7) embeds theoretically grounded subdimensions of SDO-SDO-Dominance (SDO-D) and SDO Egalitarianism (SDO-E). SDO-D constitutes a preference for systems of group-based dominance in which high status groups forcefully oppress lower status groups. SDO E constitutes a preference for systems of group-based inequality that are maintained by an interrelated network of subtle hierarchy-enhancing ideologies and social policies. Confirmatory factor and criterion validity analyses confirmed that SDO-D and SDO-E are theoretically distinct and dissociate in terms of the intergroup outcomes they best predict. For the first time, distinct personality and individual difference bases of SDO-D and SDO-E are outlined. We clarify the construct validity of SDO by strictly assessing a preference for dominance hierarchies in general, removing a possible confound relating to support for hierarchy benefitting the ingroup. Consistent with this, results show that among members of a disadvantaged ethnic minority group (African Americans), endorsement of SDO7 is inversely related to ingroup identity. We further demonstrate these effects using nationally representative samples of U.S. Blacks and Whites, documenting the generalizability of these findings. Finally, we introduce and validate a brief 4-item measure of each dimension. This article importantly extends our theoretical understanding of one of the most generative constructs in social psychology, and introduces powerful new tools for its measurement. PMID- 26479363 TI - Personality trait development at the end of life: Antecedents and correlates of mean-level trajectories. AB - Empirical evidence over the past 20 years has documented that key aspects of personality traits change during adulthood. However, it is essentially an open question whether and how traits change at the very end of life and what role health, cognitive performance, perceived control, and social factors play in those changes. To examine these questions, we applied growth models to 13-year longitudinal data obtained from now-deceased participants in the Berlin Aging Study (N = 463; age at baseline M = 85.9 years, SD = 8.4; 51% men). Results revealed that neuroticism, on average, increases (about 0.3 SD in the last 10 years) and that this increase becomes even steeper at the end of life. In contrast, extraversion and openness decline rather steadily at the end of life (about -0.5 SD in the last 10 years). Additionally, poor health manifested as a risk factor for declines in extraversion and openness late in life but not neuroticism. Similar to earlier phases of life, better cognitive performance related to more openness. More loneliness was associated with higher neuroticism, whereas more social activity was associated with higher levels of extraversion and openness. Intriguing additional insights indicated that more personal control was associated with higher levels of extraversion and openness, whereas the feeling that one's life is controlled by others was associated with higher neuroticism but also with higher openness closer to death. We discuss potential pathways by which health, cognitive performance, control, and social inclusion resources and risk factors affect personality development late in life. (PsycINFO Database Record PMID- 26479364 TI - Sentimental value and its influence on hedonic adaptation. AB - Sentimental value is a highly prevalent, yet largely understudied phenomenon. We introduce the construct of sentimental value and investigate how and why sentimental value influences hedonic adaptation. Across 7 studies, we examine the antecedents of sentimental value and demonstrate its effect on hedonic adaptation using both naturally occurring and experimentally manipulated items with sentimental value. We further test the underlying process linking sentimental value and hedonic adaptation by showing that whereas feature-related utility decreases for all items with time, sentimental value typically does not, and that sentimental value moderates the influence of the decrement in feature-related utility on hedonic adaptation. Moreover, this moderating effect of sentimental value is driven by a shift in focus from features of the item to the associations that item possess. We conclude with a discussion of related phenomena and implications for individuals. PMID- 26479365 TI - The motivation to express prejudice. AB - Contemporary prejudice research focuses primarily on people who are motivated to respond without prejudice and the ways in which unintentional bias can cause these people to act in a manner inconsistent with this motivation. However, some real-world phenomena (e.g., hate speech, hate crimes) and experimental findings (e.g., Plant & Devine, 2001, 2009) suggest that some prejudice is intentional. These phenomena and findings are difficult to explain solely from the motivations to respond without prejudice. We argue that some people are motivated to express prejudice, and we develop the Motivation to Express Prejudice Scale (MP) to measure this motivation. In 7 studies involving more than 6,000 participants, we demonstrate that, across scale versions targeted at Black people and gay men, the MP has good reliability and convergent, discriminant, and predictive validity. In normative climates that prohibit prejudice, the internal and external motivations to express prejudice are functionally nonindependent, but they become more independent when normative climates permit more prejudice toward a target group. People high in the motivation to express prejudice are relatively likely to resist pressure to support programs promoting intergroup contact and to vote for political candidates who support oppressive policies. The motivation to express prejudice predicted these outcomes even when controlling for attitudes and the motivations to respond without prejudice. This work encourages contemporary prejudice researchers to give greater consideration to the intentional aspects of negative intergroup behavior and to broaden the range of phenomena, target groups, and samples that they study. PMID- 26479366 TI - Emotion regulation and depressive symptoms: Close relationships as social context and influence. AB - Depression is associated with social dysfunction and maladaptive social environments, but mechanisms through which social relationships affect depressive psychopathology are unclear. We hypothesized that emotion regulation (ER) is such a mechanism, with outcomes of individuals' ER efforts sensitive to the social context, and individuals' ER strategy repertoire and use sensitive to social influence. In Study 1, a longitudinal study of community adults (N = 1,319), associations of individuals' ER strategies with depressive symptoms depended on social connectedness and romantic relationship status (social context hypothesis). Moreover, associations of social connectedness and relationship status with symptoms were accounted for by maladaptive ER concurrently and, for social connectedness, prospectively over 1 year (social influence hypothesis). Study 2a, using a national sample (N = 772), replicated and extended these findings with a broader array of ER strategies, and ruled out alternative explanations regarding social skills and psychological wellbeing. Among participants in romantic relationships (Study 2b; N = 558), intimacy and trust buffered associations of maladaptive ER strategies with symptoms (context), and maladaptive and adaptive ER mediated links between relationship variables and symptoms (influence). Findings suggest that close relationships-and variation in underlying relational processes within relationships-influence the ER strategies people use, and also affect whether individuals' own ER repertoires contribute to depression when deployed. Results elucidate core social mechanisms of ER in terms of both basic processes and depressive psychopathology, suggest ER is a channel through which social factors affect internal functioning and mental health, and inform relationship pathways for clinical intervention. PMID- 26479367 TI - Effects of a Multidisciplinary Approach to Improve Volume of Diagnostic Material in CT-Guided Lung Biopsies. AB - BACKGROUND: Recent publications have emphasized the importance of a multidisciplinary strategy for maximum conservation and utilization of lung biopsy material for advanced testing, which may determine therapy. This paper quantifies the effect of a multidisciplinary strategy implemented to optimize and increase tissue volume in CT-guided transthoracic needle core lung biopsies. The strategy was three-pronged: (1) once there was confidence diagnostic tissue had been obtained and if safe for the patient, additional biopsy passes were performed to further increase volume of biopsy material, (2) biopsy material was placed in multiple cassettes for processing, and (3) all tissue ribbons were conserved when cutting blocks in the histology laboratory. This study quantifies the effects of strategies #1 and #2. DESIGN: This retrospective analysis comparing CT-guided lung biopsies from 2007 and 2012 (before and after multidisciplinary approach implementation) was performed at a single institution. Patient medical records were reviewed and main variables analyzed include biopsy sample size, radiologist, number of blocks submitted, diagnosis, and complications. The biopsy sample size measured was considered to be directly proportional to tissue volume in the block. RESULTS: Biopsy sample size increased 2.5 fold with the average total biopsy sample size increasing from 1.0 cm (0.9 1.1 cm) in 2007 to 2.5 cm (2.3-2.8 cm) in 2012 (P<0.0001). The improvement was statistically significant for each individual radiologist. During the same time, the rate of pneumothorax requiring chest tube placement decreased from 15% to 7% (P = 0.065). No other major complications were identified. The proportion of tumor within the biopsy material was similar at 28% (23%-33%) and 35% (30%-40%) for 2007 and 2012, respectively. The number of cases with at least two blocks available for testing increased from 10.7% to 96.4% (P<0.0001). CONCLUSIONS: The effect of this multidisciplinary strategy to CT-guided lung biopsies was effective in significantly increasing tissue volume and number of blocks available for advanced diagnostic testing. PMID- 26479368 TI - Consistent Individual Behavioral Variation: The Difference between Temperament, Personality and Behavioral Syndromes. AB - Ethologists use a variety of terminology such as "personality", "temperament" and "behavioral syndromes" almost interchangeably to discuss the phenomenon of individuals within a population of animals consistently varying from one another in their behavioral responses to stimuli. This interchangeable usage of terminology has contributed to confusion within the field of animal behavior and limits the study of the phenomenon. Here we use a rapid, non-exhaustive and repeatable search strategy literature review to investigate where there were unique distinctions between these three terms and where there was an overlap in their usage. We identified three main areas of confusion in terminology: historical usage which is not updated; a lack of precision between different fields of study; and a lack of precision between different levels of variation. We propose a framework with which to understand and define the terms based on the levels of variation ethologists are interested in. Consistent individual animal behavioral variation relates to the different structures of variation of between individual/between-population and between and across contexts. By formalizing this framework we provide clarity between the three terms which can be easily defined and understood. PMID- 26479369 TI - Farm Management in Organic and Conventional Dairy Production Systems Based on Pasture in Southern Brazil and Its Consequences on Production and Milk Quality. AB - Pasture-based dairy production is used widely on family dairy farms in Southern Brazil. This study investigates conventional high input (C-HI), conventional low input (C-LI), and organic low input (O-LI) pasture-based systems and their effects on quantity and quality of the milk produced. We conducted technical site visits and interviews monthly over one year on 24 family farms (n = 8 per type). C-HI farms had the greatest total area (28.9 ha), greatest percentage of area with annual pasture (38.7%), largest number of lactating animals (26.2) and greatest milk yield per cow (22.8 kg.day(-1)). O-LI farms had the largest perennial pasture area (52.3%), with the greatest botanical richness during all seasons. Area of perennial pasture was positively correlated with number of species consumed by the animals (R2 = 0.74). Milk from O-LI farms had higher levels of fat and total solids only during the winter. Hygienic and microbiological quality of the milk was poor for all farms and need to be improved. C-HI farms had high milk yield related to high input, C-LI had intermediate characteristics and O-LI utilized a year round perennial pasture as a strategy to diminish the use of supplements in animal diets, which is an important aspect in ensuring production sustainability. PMID- 26479370 TI - Air Quality in Alternative Housing Systems May Have an Impact on Laying Hen Welfare. Part I-Dust. AB - The new legislation for laying hens in the European Union put a ban on conventional cages. Production systems must now provide the hens with access to a nest, a perch, and material for dust bathing. These requirements will improve the behavioral aspects of animal welfare. However, when hens are kept with access to litter, it is a concern that polluted air may become an increased threat to health and therefore also a welfare problem. This article reviews the literature regarding the health and welfare effects birds experience when exposed to barn dust. Dust is composed of inorganic and organic compounds, from the birds themselves as well as from feed, litter, and building materials. Dust may be a vector for microorganisms and toxins. In general, studies indicate that housing systems where laying hens have access to litter as aviaries and floor systems consistently have higher concentrations of suspended dust than caged hens with little (furnished cages) or no access to litter (conventional cages). The higher dust levels in aviaries and floor housing are also caused by increased bird activity in the non-cage systems. There are gaps in both the basic and applied knowledge of how birds react to dust and aerosol contaminants, i.e., what levels they find aversive and/or impair health. Nevertheless, high dust levels may compromise the health and welfare of both birds and their caretakers and the poor air quality often found in new poultry housing systems needs to be addressed. It is necessary to develop prophylactic measures and to refine the production systems in order to achieve the full welfare benefits of the cage ban. PMID- 26479372 TI - A High Percentage of Beef Bull Pictures in Semen Catalogues Have Feet and Lower Legs that Are Not Visible. AB - A total of 1379 beef bull pictures were surveyed to determine visibility of feet and legs from four American semen company websites. Five different breeds were represented: Angus, Red Angus, Hereford (polled and horned), Simmental, and Charolais. In addition to visibility, data on other variables were collected to establish frequencies and correlations. These included breed, color, material that obscured visibility, such as grass, picture taken at livestock show or outside, semen company, photographer, video, and age of bull. A foot and leg visibility score was given to each bull picture. Only 19.4% of the pictures had fully visible feet and legs. Both the hooves and dewclaws were hidden on 32.5% of the pictures. Correlation between bull's birthdate and the first four visibility scores was statistically significant (P < 0.0001). As age increased the feet and legs were more likely to be visible in the bull's picture. This may possibly be due to greater availability of both photo editing software and digital photography. One positive finding was that 6% of the bulls had a video of the bull walking which completely showed his feet and legs. PMID- 26479373 TI - Effects of Oxytocin Administration on the Response of Piglets to Weaning. AB - Weaning is often an abrupt and stressful process. We studied the effects of administering oxytocin, subcutaneously or intranasally, on the ability of pigs to cope with weaning. On a commercial farm 144, 30 day-old pigs from 24 litters were used. On the day of weaning, one male and one female in each litter were administered one of three treatments: intranasal oxytocin (24 International Unit), subcutaneous oxytocin (10 International Unit per kg of body weight), or handled as a control. The pigs were placed in one of eight weaner pens, split by sex and with an equal representation of treatments. Data included body weight and growth, physiology (neutrophil:lymphocyte ratio, plasma cortisol, C-reactive protein and Tumor Necrosis Factor-alpha concentrations), and behavior (feeding, drinking, social behavior). Both oxytocin treatments tended to result in higher levels of mild aggression within groups (p = 0.08), specifically between oxytocin administered and control pigs (subcutaneous to control p = 0.03; intranasal to control p = 0.10). Subcutaneously-administered pigs tended to frequent the feeder more often than intranasally-administered pigs (p < 0.10), with the latter having slightly lower body weight 38 days post-weaning (p = 0.03). However, acute oxytocin administration did not result in any noticeable physiological changes 4 or 28 h post-weaning. Hence, the use of a single administration of oxytocin prior to weaning in pigs is not recommended, at least not in the conditions studied here. PMID- 26479374 TI - A Critical Review of Horse-Related Risk: A Research Agenda for Safer Mounts, Riders and Equestrian Cultures. AB - While the importance of improving horse-related safety seems self-evident, no comprehensive study into understanding or reducing horse-related risk has been undertaken. In this paper, we discuss four dimensions of horse-related risk: the risk itself, the horse, the rider and the culture in which equestrian activities takes place. We identify how the ways in which risk is constructed in each dimension affects the applicability of four basic risk management options of avoidance, transference, mitigation and acceptance. We find the acceptance and avoidance of horse-related risk is generally high, most likely due to a common construction of horses as irrevocably unpredictable, fearful and dangerous. The transference of risk management is also high, especially in the use of protective technologies such as helmets. Of concern, the strategy least utilised is risk mitigation. We highlight the potential benefit in developing mitigation strategies directed at: (a) improving the predictability of horses (to and by humans), and (b) improving riders' competence in the physical skills that make them more resilient to injury and falls. We conclude with the presentation of a multidisciplinary agenda for research that could reduce accident, injury and death to horse-riders around the world. PMID- 26479371 TI - Digital Dermatitis in Dairy Cows: A Review of Risk Factors and Potential Sources of Between-Animal Variation in Susceptibility. AB - Digital dermatitis (DD) is a bacterial disease that primarily affects the skin on the heels of cattle. It is a major cause of lameness in dairy cows and a significant problem for the dairy industry in many countries, causing reduced animal welfare and economic loss. A wide range of infection levels has been found on infected farms, prompting investigations into both farm level and animal level risk factors for DD occurrence. There also appears to be individual variation between animals in susceptibility to the disease. The identification of factors affecting individual variation in susceptibility to DD might allow changes in breeding policies or herd management which could be used to reduce DD prevalence. Factors mentioned in the literature as possibly influencing individual variation in susceptibility to DD include physical factors such as hoof conformation and properties of the skin, physiological factors such as the efficacy of the immune response, and behavioural factors such as standing half in cubicles. Further work is required to determine the influence of these factors, identify the genetic basis of variation, clarify the level of heritability of DD susceptibility and to determine how this is correlated with production and health traits currently used in breeding programmes. PMID- 26479375 TI - Helmet Use Amongst Equestrians: Harnessing Social and Attitudinal Factors Revealed in Online Forums. AB - Equestrian activities pose significant head injury risks to participants. Yet, helmet use is not mandatory in Australia outside of selected competitions. Awareness of technical countermeasures and the dangers of equestrian activities has not resulted in widespread adoption of simple precautionary behaviors like helmet use. Until the use of helmets whilst riding horses is legislated in Australia, there is an urgent need to improve voluntary use. To design effective injury prevention interventions, the factors affecting helmet use must first be understood. To add to current understandings of these factors, we examined the ways horse riders discussed helmet use by analyzing 103 posts on two helmet use related threads from two different Australian equestrian forums. We found evidence of social influence on helmet use behaviors as well as three attitudes that contributed towards stated helmet use that we termed: "I Can Control Risk", "It Does Not Feel Right" and "Accidents Happen". Whilst we confirm barriers identified in previous literature, we also identify their ability to support helmet use. This suggests challenging but potentially useful complexity in the relationship between risk perception, protective knowledge, attitudes, decision making and behavior. Whilst this complexity is largely due to the involvement of interspecies relationships through which safety, risk and trust are distributed; our findings about harnessing the potential of barriers could be extended to other high risk activities. PMID- 26479376 TI - Inroads into Equestrian Safety: Rider-Reported Factors Contributing to Horse Related Accidents and Near Misses on Australian Roads. AB - Horse riding and horse-related interactions are inherently dangerous. When they occur on public roads, the risk profile of equestrian activities is complicated by interactions with other road users. Research has identified speed, proximity, visibility, conspicuity and mutual misunderstanding as factors contributing to accidents and near misses. However, little is known about their significance or incidence in Australia. To explore road safety issues amongst Australian equestrians, we conducted an online survey. More than half of all riders (52%) reported having experienced at least one accident or near miss in the 12 months prior to the survey. Whilst our findings confirm the factors identified overseas, we also identified issues around rider misunderstanding of road rules and driver misunderstanding of rider hand signals. Of particular concern, we also found reports of potentially dangerous rider-directed road rage. We identify several areas for potential safety intervention including (1) identifying equestrians as vulnerable road users and horses as sentient decision-making vehicles (2) harmonising laws regarding passing horses, (3) mandating personal protective equipment, (4) improving road signage, (5) comprehensive data collection, (6) developing mutual understanding amongst road-users, (7) safer road design and alternative riding spaces; and (8) increasing investment in horse-related safety initiatives. PMID- 26479377 TI - Inclusion of Oat in Feeding Can Increase the Potential Probiotic Bifidobacteria in Sow Milk. AB - The objectives of this study were to (i) investigate the impact of feeding oat on the population of bifidobacteria and (ii) evaluate their probiotic potential. In this study, we investigated the effects of supplementing sows' gestation and lactation feed with 15% oat (prebiotic source) on the levels of probiotic population in milk. We found that dietary inclusion of oat during lactation and gestation resulted in increased levels of bifidobacteria compared to lactobacilli in sow milk. Furthermore bifidobacteria within the sow milk samples were further evaluated for probiotic potential based on aggregating properties, and acid- and bile-tolerance after exposure to hydrochloric acid (pH 2.5) and bile salts (0%, 0.25%, 0.50%, 1.0% and 2.0%). All isolates survived under the condition of low pH and bile 2.0%. Autoaggregation ability ranged from 17.5% to 73%. These isolates also showed antimicrobial activity against E. coli O157:H7.Together our results suggest that inclusion of oat in feeding systems could have the potential to improve the intestinal health of piglets by increasing the population of bifidobacteria. PMID- 26479378 TI - An Insufferable Business: Ethics, Nonhuman Animals and Biomedical Experiments. AB - Each year millions of nonhuman animals suffer in biomedical experiments for human health benefits. Clinical ethics demand that nonhuman animals are used in the development of pharmaceuticals and vaccines. Nonhuman animals are also used for fundamental biomedical research. Biomedical research that uses nonhuman animals is big business but the financial gains are generally occluded. This paper explores how such research generates profits and gains for those associated with the industry. Research establishments, scientists, laboratories, companies that sell nonhuman animal subjects, that supply equipment for the research, and corporations that market the resulting products are among those that benefit financially. Given the complex articulation of ethical codes, enormous corporate profits that are secured and personal returns that are made, the accepted moral legitimacy of such experiments is compromised. In order to address this, within the confines of the moral orthodoxy, more could to be done to ensure transparency and to extricate the vested financial interests from the human health benefits. But such a determination would not address the fundamental issues that should be at the heart of human actions in respect of the nonhuman animals who are used in experiments. The paper concludes with such an address by calling for an end to the denigration of nonhuman animals as experimental subjects who can be used as commodities for profit-maximisation and as tools in experiments for human health benefits, and the implementation of a more inclusive ethic that is informed by universal concern about the suffering of and compassion for all oppressed beings. PMID- 26479379 TI - Predictions of Daily Milk and Fat Yields, Major Groups of Fatty Acids, and C18:1 cis-9 from Single Milking Data without a Milking Interval. AB - Reducing the frequency of milk recording would help reduce the costs of official milk recording. However, this approach could also negatively affect the accuracy of predicting daily yields. This problem has been investigated in numerous studies. In addition, published equations take into account milking intervals (MI), and these are often not available and/or are unreliable in practice. The first objective of this study was to propose models in which the MI was replaced by a combination of data easily recorded by dairy farmers. The second objective was to further investigate the fatty acids (FA) present in milk. Equations to predict daily yield from AM or PM data were based on a calibration database containing 79,971 records related to 51 traits [milk yield (expected AM, expected PM, and expected daily); fat content (expected AM, expected PM, and expected daily); fat yield (expected AM, expected PM, and expected daily; g/day); levels of seven different FAs or FA groups (expected AM, expected PM, and expected daily; g/dL milk), and the corresponding FA yields for these seven FA types/groups (expected AM, expected PM, and expected daily; g/day)]. These equations were validated using two distinct external datasets. The results obtained from the proposed models were compared to previously published results for models which included a MI effect. The corresponding correlation values ranged from 96.4% to 97.6% when the daily yields were estimated from the AM milkings and ranged from 96.9% to 98.3% when the daily yields were estimated from the PM milkings. The simplicity of these proposed models should facilitate their use by breeding and milk recording organizations. PMID- 26479380 TI - Influence of Soft or Hard Floors before and after First Calving on Dairy Heifer Locomotion, Claw and Leg Health. AB - Claw health, an important dairy cow welfare parameter, may be affected by early life foot/leg stresses. To investigate this, groups of pregnant heifers were allocated to deep straw bedding (Soft) or cubicles (Hard), both with scraped concrete feeding alleys. After the grazing season, they were re-housed in cubicle systems, half on slatted concrete (Hard) and half on slatted rubber (Soft) alleys. Claw measurements, contact area and pressure distribution claw/flooring, claw disorders and leg lesions were recorded at the start and end of each housing season. Locomotion and leg lesions were also scored monthly after calving. Prevalence of sole haemorrhages was higher among pregnant heifers in cubicles than in deep straw. After calving, first-calvers on Hard floors had higher odds for lameness (OR = 3.6; P < 0.01), sole haemorrhages/ulcers (OR = 2.2; P < 0.05), white-line haemorrhages (OR = 2.8; P < 0.01) and leg lesions (OR = 2.6; P < 0.02) than those on Soft floors. Lowest prevalence and severity of sole and white-line haemorrhages (non-significant) in first-calvers was found in those on Soft floors and reared on Hard floors and the highest prevalence and severity on those on Hard floors reared on Soft floors. Soft flooring after calving is of most importance for healthy feet and legs. PMID- 26479381 TI - Measuring Claw Conformation in Cattle: Assessing the Agreement between Manual and Digital Measurement. AB - Five measurements of claw conformation (toe angle, claw height, claw width, toe length and abaxial groove length) taken directly from the hoof were compared with the measurements taken from digital images of the same claws. Concordance correlation coefficients and limits-of-agreement analysis showed that, for four of the five measures (claw height, claw width, toe length and abaxial groove length), agreement was too poor for digital and manual measures to be used interchangeably. For all four of these measures, Liao's modified concordance correlation coefficient (mCCC) was <=0.4, indicating poor concordance despite Pearson's correlation being >0.6 in all cases. The worst concordance was seen for toe length (mCCC = 0.13). Limits-of-agreement analysis showed that, for all four measures, there was a large variation in the difference between the manual and digital methods, even when the effect of mean on difference was accounted for, with the 95% limits-of-agreement for the four measures being further away from the mean difference than 10% of the mean in all four cases. The only one of the five measures with an acceptable concordance between digital and manual measurement was toe angle (mCCC = 0.81). Nevertheless, the limits-of-agreement analysis showed that there was a systematic bias with, on average, the manual measure of toe angle, being 2.1 degrees smaller than the digital. The 95% limits of-agreement for toe angle were +/-3.4 degrees , probably at the upper limit of what is acceptable. However, the lack of data on the variability of individual measurements of claw conformation means that it is unclear how this variability compares to measurement of toe angle in the same animal using the same or a different manual technique. PMID- 26479382 TI - Physiologic Measures of Animal Stress during Transitional States of Consciousness. AB - Determination of the humaneness of methods used to produce unconsciousness in animals, whether for anesthesia, euthanasia, humane slaughter, or depopulation, relies on our ability to assess stress, pain, and consciousness within the contexts of method and application. Determining the subjective experience of animals during transitional states of consciousness, however, can be quite difficult; further, loss of consciousness with different agents or methods may occur at substantially different rates. Stress and distress may manifest behaviorally (e.g., overt escape behaviors, approach-avoidance preferences [aversion]) or physiologically (e.g., movement, vocalization, changes in electroencephalographic activity, heart rate, sympathetic nervous system [SNS] activity, hypothalamic-pituitary axis [HPA] activity), such that a one-size-fits all approach cannot be easily applied to evaluate methods or determine specific species applications. The purpose of this review is to discuss methods of evaluating stress in animals using physiologic methods, with emphasis on the transition between the conscious and unconscious states. PMID- 26479383 TI - Alterations of Innate Immunity Reactants in Transition Dairy Cows before Clinical Signs of Lameness. AB - The objectives of this study were to evaluate metabolic and innate immunity alterations in the blood of transition dairy cows before, during, and after diagnosis of lameness during periparturient period. Blood samples were collected from the coccygeal vain once per week before morning feeding from 100 multiparous Holstein dairy cows during -8, -4, disease diagnosis, and +4 weeks (wks) relative to parturition. Six healthy cows (CON) and six cows that showed clinical signs of lameness were selected for intensive serum analyses. Concentrations of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), haptoglobin (Hp), serum amyloid A (SAA), lipopolysaccharide binding protein (LBP), lactate, non-esterified fatty acids (NEFA), and beta-hydroxybutyrate (BHBA) were measured in serum by ELISA or colorimetric methods. Health status, DMI, rectal temperature, milk yield, and milk composition also were monitored for each cow during the whole experimental period. Results showed that cows affected by lameness had greater concentrations of lactate, IL-6, and SAA in the serum vs. CON cows. Concentrations of TNF tended to be greater in cows with lameness compared with CON. In addition, there was a health status (Hs) by time (week) interaction for IL-1, TNF, and Hp in lameness cows vs. CON ones. Enhanced serum concentrations of lactate, IL-6, and SAA at -8 and -4 wks before parturition were different in cows with lameness as compared with those of the CON group. The disease was also associated with lowered overall milk production and DMI as well as milk fat and fat-to-protein ratio. In conclusion, cows affected postpartum by lameness had alterations in several serum variables related to innate immunity and carbohydrate metabolism that give insights into the etiopathogenesis of the disease and might serve to monitor health status of transition dairy cows in the near future. PMID- 26479384 TI - Relationships between Circulating Urea Concentrations and Endometrial Function in Postpartum Dairy Cows. AB - Both high and low circulating urea concentrations, a product of protein metabolism, are associated with decreased fertility in dairy cows through poorly defined mechanisms. The rate of involution and the endometrial ability to mount an adequate innate immune response after calving are both critical for subsequent fertility. Study 1 used microarray analysis to identify genes whose endometrial expression 2 weeks postpartum correlated significantly with the mean plasma urea per cow, ranging from 3.2 to 6.6 mmol/L. The biological functions of 781 mapped genes were analysed using Ingenuity Pathway Analysis. These were predominantly associated with tissue turnover (e.g., BRINP1, FOXG1), immune function (e.g., IL17RB, CRISPLD2), inflammation (e.g., C3, SERPINF1, SERPINF2) and lipid metabolism (e.g., SCAP, ACBD5, SLC10A). Study 2 investigated the relationship between urea concentration and expression of 6 candidate genes (S100A8, HSP5A, IGF1R, IL17RB, BRINP1, CRISPLD2) in bovine endometrial cell culture. These were treated with 0, 2.5, 5.0 or 7.5 mmol/L urea, equivalent to low, medium and high circulating values with or without challenge by bacterial lipopolysaccharide (LPS). LPS increased S100A8 expression as expected but urea treatment had no effect on expression of any tested gene. Examination of the genes/pathways involved suggests that plasma urea levels may reflect variations in lipid metabolism. Our results suggest that it is the effects of lipid metabolism rather than the urea concentration which probably alter the rate of involution and innate immune response, in turn influencing subsequent fertility. PMID- 26479385 TI - RandAgiamoTM, a Pilot Project Increasing Adoptability of Shelter Dogs in the Umbria Region (Italy). AB - Current Italian legislation does not permit euthanasia of dogs, unless they are ill or dangerous. Despite good intentions and ethical benefits, this 'no-kill policy' has caused a progressive overpopulation of dogs in shelters, due to abandonment rates being higher than adoption rates. Shelter overcrowding has negative implications for dog welfare and increases public costs. The aim of this paper is to describe the pilot project "RandAgiamo" implemented in a rescue shelter in the Umbria Region and to evaluate its effectiveness on the rate of dog adoption using official data. RandAgiamo aimed to increase adult shelter dogs' adoptability by a standard training and socialization programme. It also promoted dogs' visibility by publicizing them through social media and participation in events. We analysed the official data of the Umbria regional health authorities regarding dog shelters of the Perugia province of the year 2014. In the RandAgiamo shelter, the dog adoption rate was 27.5% higher than that of dogs housed in other shelters located in the same geographical area (P < 0.001). The RandAgiamo project could be beneficial for the dogs' welfare, owner satisfaction, shelter management, and public perception of shelter dogs. However, staff were required to provide dog training and related activities. PMID- 26479386 TI - The Role of TCA Cycle Anaplerosis in Ketosis and Fatty Liver in Periparturient Dairy Cows. AB - The transition to lactation period in dairy cattle is characterized by metabolic challenges, negative energy balance, and adipose tissue mobilization. Metabolism of mobilized adipose tissue is part of the adaptive response to negative energy balance in dairy cattle; however, the capacity of the liver to completely oxidize nonesterified fatty acids may be limited and is reflective of oxaloacetate pool, the carbon carrier of the tricarboxylic acid cycle. Alternative metabolic fates of acetyl-CoA from nonesterified fatty acids include esterification to triacylglycerides and ketogenesis, and when excessive, these pathways lead to fatty liver and ketosis. Examination of the anaplerotic and cataplerotic pull of oxaloacetate by the tricarboxylic acid cycle and gluconeogenesis may provide insight into the balance of oxidation and esterification of acetyl-CoA within the liver of periparturient dairy cows. PMID- 26479387 TI - Evidence for a Role of Prolactin in Mediating Effects of Photoperiod during the Dry Period. AB - Photoperiod manipulation during the lactation cycle alters milk yield, with long days (LDPP) increasing yield in lactation and short days (SDPP) in the dry period improving subsequent yield. Circulating prolactin (PRL) is directly related to day length, with LDPP increasing and SDPP decreasing PRL, respectively. Two blocks of 24 multiparous Holstein cows were used during two consecutive years to test the hypothesis that the mammary response to SDPP is the result of decreased concentrations of PRL in the circulation relative to LDPP. Cows were randomly assigned to one of three treatment groups during the dry period: SDPP, LDPP, or SDPP+PRL. Cows were returned to ambient photoperiod at calving and milk yield and DMI recorded for 120 d and 42 d, respectively. Mammary biopsies were obtained to determine rates of [3H]-thymidine incorporation into DNA in vitro. Treatment of SDPP cows with PRL caused a rapid increase in systemic PRL that reached concentrations similar to cows under LDPP. The periparturient PRL surge was similar for LDPP and SDPP+PRL cows, but those groups had greater surge concentrations versus SDPP. Cows exposed to SDPP produced more milk than LDPP cows, and there was a trend for SDPP+PRL cows to produce more milk than LDPP cows. Milk production was inversely related to the periparturient PRL surge. There was a trend for a treatment effect on mammary cell proliferation with greater proliferation in mammary tissue of SDPP cows relative to LDPP or SDPP+PRL on day -20 relative to parturition. Replacement of PRL to cows on SDPP when dry resulted in milk yield intermediate to cows on SDPP or LDPP, supporting the concept of a link between dry period PRL and yield. PMID- 26479388 TI - "Chickens Are a Lot Smarter than I Originally Thought": Changes in Student Attitudes to Chickens Following a Chicken Training Class. AB - A practical class using clicker training of chickens to apply knowledge of how animals learn and practice skills in animal training was added to an undergraduate course. Since attitudes to animals are related to their perceived intelligence, surveys of student attitudes were completed pre- and post- the practical class, to determine if (1) the practical class changed students' attitudes to chickens and their ability to experience affective states, and (2) any changes were related to previous contact with chickens, training experience or gender. In the post- versus pre-surveys, students agreed more that chickens are easy to teach tricks to, are intelligent, and have individual personalities and disagreed more that they are difficult to train and are slow learners. Following the class, they were more likely to believe chickens experience boredom, frustration and happiness. Females rated the intelligence and ability to experience affective states in chickens more highly than males, although there were shifts in attitude in both genders. This study demonstrated shifts in attitudes following a practical class teaching clicker training in chickens. Similar practical classes may provide an effective method of teaching animal training skills and promoting more positive attitudes to animals. PMID- 26479389 TI - Lameness Detection in Dairy Cows: Part 1. How to Distinguish between Non-Lame and Lame Cows Based on Differences in Locomotion or Behavior. AB - Due to its detrimental effect on cow welfare, health and production, lameness in dairy cows has received quite a lot of attention in the last few decades-not only in terms of prevention and treatment of lameness but also in terms of detection, as early treatment might decrease the number of severely lame cows in the herds as well as decrease the direct and indirect costs associated with lameness cases. Generally, lame cows are detected by the herdsman, hoof trimmer or veterinarian based on abnormal locomotion, abnormal behavior or the presence of hoof lesions during routine trimming. In the scientific literature, several guidelines are proposed to detect lame cows based on visual interpretation of the locomotion of individual cows (i.e., locomotion scoring systems). Researchers and the industry have focused on automating such observations to support the farmer in finding the lame cows in their herds, but until now, such automated systems have rarely been used in commercial herds. This review starts with the description of normal locomotion of cows in order to define 'abnormal' locomotion caused by lameness. Cow locomotion (gait and posture) and behavioral features that change when a cow becomes lame are described and linked to the existing visual scoring systems. In addition, the lack of information of normal cow gait and a clear description of 'abnormal' gait are discussed. Finally, the different set-ups used during locomotion scoring and their influence on the resulting locomotion scores are evaluated. PMID- 26479390 TI - Lameness Detection in Dairy Cows: Part 2. Use of Sensors to Automatically Register Changes in Locomotion or Behavior. AB - Despite the research on opportunities to automatically measure lameness in cattle, lameness detection systems are not widely available commercially and are only used on a few dairy farms. However, farmers need to be aware of the lame cows in their herds in order treat them properly and in a timely fashion. Many papers have focused on the automated measurement of gait or behavioral cow characteristics related to lameness. In order for such automated measurements to be used in a detection system, algorithms to distinguish between non-lame and mildly or severely lame cows need to be developed and validated. Few studies have reached this latter stage of the development process. Also, comparison between the different approaches is impeded by the wide range of practical settings used to measure the gait or behavioral characteristic (e.g., measurements during normal farming routine or during experiments; cows guided or walking at their own speed) and by the different definitions of lame cows. In the majority of the publications, mildly lame cows are included in the non-lame cow group, which limits the possibility of also detecting early lameness cases. In this review, studies that used sensor technology to measure changes in gait or behavior of cows related to lameness are discussed together with practical considerations when conducting lameness research. In addition, other prerequisites for any lameness detection system on farms (e.g., need for early detection, real-time measurements) are discussed. PMID- 26479391 TI - Air Quality in Alternative Housing Systems may have an Impact on Laying Hen Welfare. Part II-Ammonia. AB - The EU ban on conventional barren cages for laying hens from 2012 has improved many aspects of laying hen welfare. The new housing systems allow for the expression of highly-motivated behaviors. However, the systems available for intensive large-scale egg production (e.g., aviaries, floor housing systems, furnished cages) may cause other welfare challenges. We have reviewed the literature regarding the health, behavior, production characteristics, and welfare of laying hens when exposed to ammonia in their housing environment. Concentrations of ammonia gas are commonly high in aviaries and floor housing systems in which manure is not regularly removed, whereas they are usually lower in furnished cages. High levels are found during the cold season when ventilation flow is often reduced. Ammonia is a pungent gas, and behavioral studies indicate chickens are averse to the gas. High concentrations of gaseous ammonia can have adverse health effects and, when very high, even influence production performance. The most profound effects seen are the occurrence of lesions in the respiratory tract and keratoconjunctivitis. There is also evidence that high ammonia concentrations predispose poultry to respiratory disease and secondary infections. We conclude that there are animal welfare challenges related to high ammonia levels, and that immediate actions are needed. Development of improved systems and management routines for manure removal and ventilation will be important for the reduction of ammonia levels and hence will contribute to safeguarding hen welfare. PMID- 26479392 TI - Workplace Injuries in Thoroughbred Racing: An Analysis of Insurance Payments and Injuries amongst Jockeys in Australia from 2002 to 2010. AB - BACKGROUND: There is no comprehensive study of the costs of horse-related workplace injuries to Australian Thoroughbred racing jockeys. OBJECTIVES: To analyse the characteristics of insurance payments and horse-related workplace injuries to Australian jockeys during Thoroughbred racing or training. METHODS: Insurance payments to Australian jockeys and apprentice jockeys as a result of claims for injury were reviewed. The cause and nature of injuries, and the breakdown of payments associated with claims were described. RESULTS: The incidence of claims was 2.1/1000 race rides, with an average cost of AUD 9 million/year. Race-day incidents were associated with 39% of claims, but 52% of the total cost. The mean cost of race-day incidents (AUD 33,756) was higher than non-race day incidents (AUD 20,338). Weekly benefits and medical expenses made up the majority of costs of claims. Fractures were the most common injury (29.5%), but head injuries resulting from a fall from a horse had the highest mean cost/claim (AUD 127,127). CONCLUSIONS: Costs of workplace injuries to the Australian Thoroughbred racing industry have been greatly underestimated because the focus has historically been on incidents that occur on race-days. These findings add to the evidence base for developing strategies to reduce injuries and their associated costs. PMID- 26479394 TI - Does Preeclampsia Reduce the Risk of Breast Cancer? PMID- 26479393 TI - Effects of Prepartum Dietary Energy Level and Nicotinic Acid Supplementation on Immunological, Hematological and Biochemical Parameters of Periparturient Dairy Cows Differing in Parity. AB - The periparturient period is critical according to health, productivity and profitability. As this period is fundamental for the success of the lactation period, the interest in improving periparturient health by dietary supplements increased in recent years. The present study investigated the effects of feeding nicotinic acid (NA) combined with varying dietary energy densities on immunological, hematological and biochemical parameters of periparturient cows differing in parity. Thirty-six multiparous and 20 primiparous dairy cows were enrolled in the study 42 days before expected parturition date until 100 days postpartum with the half of the cows being supplemented with 24 g of NA/d. After parturition a diet with 30% concentrate was fed to all cows which was followed by different concentrate escalation strategies. Dietary NA supplementation was ceased on day 24 postpartum. Dietary NA increased (P = 0.010) serum nicotinamide concentrations (mean of 3.35 +/- 1.65 ug/mL), whereas NA could not be detected. Present data emphasize that periparturient cows are faced with major physiological challenges and that both parity-groups have different prerequisites to adapt to those changes irrespective of NA supplementation. The overfeeding of energy to cows which were similar in body condition score had only minor effects on periparturient immune system function and the metabolism of those cows. PMID- 26479395 TI - Ligand-inducible dimeric antibody for selecting antibodies against a membrane protein based on mammalian cell proliferation. AB - A method for selecting antibodies against a membrane protein is important for attaining a variety of antibody-based diagnostics and therapies. In this study, we propose a novel system to select specific antibodies against a membrane protein based on mammalian cell proliferation as a readout. The system employs a chimeric membrane protein in which a target membrane protein of interest is fused to the intracellular signaling domain of a cytokine receptor. The chimeric membrane protein transduces a cell proliferation signal through dimerization when co-expressed with a specific single-chain Fv fused with a mutant of FK-binding protein 12 (scFv-Fk) that can be conditionally dimerized by a synthetic ligand AP20187. To demonstrate this system, ErbB2 and gp130 were chosen as the target membrane protein and cytokine receptor, respectively. Consequently, co-expression of the ErbB2/gp130 chimera and ErbB2-specific scFv-Fk rendered the cells proliferative in response to AP20187. The system also allowed selection of high affinity binders from a mixture composed of dominant low-affinity binders. This system may be extended to affinity maturation of scFvs by modulating AP20187 concentration in the selection process. PMID- 26479396 TI - Increased Rates of Mild Traumatic Brain Injury Among Older Adults in US Emergency Departments, 2009-2010. AB - OBJECTIVE: To estimate rates of emergency department (ED) visits for mild traumatic brain injury (TBI) among older adults. We defined possible mild TBI cases to assess underdiagnoses. DESIGN: Cross-sectional. SETTING: National sample of ED visits in 2009-2010 captured by the National Hospital Ambulatory Medical Care Survey. PARTICIPANTS: Aged 65 years and older. MEASUREMENTS: Mild TBI defined by International Classification of Diseases, Ninth Revision, Clinical Modification, codes (800.0x-801.9x, 803.xx, 804.xx, 850.xx-854.1x, 950.1x-950.3x, 959.01) and a Glasgow Coma Scale score of 14 or more or missing, excluding those admitted to the hospital. Possible mild TBI was defined similarly among those without mild TBI and with a fall or motor vehicle collision as cause of injury. We calculated rates of mild TBI and examined factors associated with a diagnosis of mild TBI. RESULTS: Rates of ED visits for mild TBI were 386 per 100 000 among those aged 65 to 74 years, 777 per 100 000 among those aged 75 to 84 years, and 1205 per 100 000 among those older than 84 years. Rates for women (706/100 000) were higher than for men (516/100 000). Compared with a possible mild TBI, a diagnosis of mild TBI was more likely in the West (odds ratio = 2.31; 95% confidence interval, 1.02-5.24) and less likely in the South/Midwest (odds ratio = 0.52; 95% confidence interval, 0.29-0.96) than in the Northeast. CONCLUSIONS: This study highlights an upward trend in rates of ED visits for mild TBI among older adults. PMID- 26479397 TI - Sports-Related Concussion Results in Differential Expression of Nuclear Factor kappaB Pathway Genes in Peripheral Blood During the Acute and Subacute Periods. AB - OBJECTIVE: To determine changes in global gene expression in peripheral leukocytes in the acute and subacute periods following a sports-related concussion in athletes. SETTING: Samples were collected at 2 universities in Rochester, New York. PARTICIPANTS: Fifteen contact sport athletes who experienced a sports-related concussion, and 16 nonconcussed teammates served as controls. DESIGN: Blood samples were collected at the start of the season (baseline), within 6 hours of injury (acute), and at 7 days (subacute) postinjury. Differential gene expression was measured using the GeneChip 3' in vitro transcription Expression kit and Affymetrix microarrays, and genes with fold difference of 2 or more were identified using Partek. MAIN MEASURES: Whole genome differential gene expression, and cognitive and balance measures to asses for clinical symptoms pre- and postinjury. RESULTS: In the concussed athletes, we observed 67 downregulated and 4 upregulated genes in the acute period and 63 downregulated and 2 upregulated genes in the subacute period compared with baseline. Of these, there were 28 genes from both time points involved in the inflammatory response. No significant differences in gene expression were detected in the control group. CONCLUSIONS: Our findings suggest that recovery from sports-related concussion relates to modulation of inflammation through cytokine and chemokine gene pathways, which can contribute to future development of personalized therapeutic agents. PMID- 26479398 TI - Pharmacotherapy for Depression Posttraumatic Brain Injury: A Meta-analysis. AB - OBJECTIVE: To examine the effectiveness of pharmacotherapy for the treatment of depression following traumatic brain injury (TBI). DESIGN: Systematic review and meta-analysis. Multiple electronic databases were searched to identify relevant studies examining effectiveness of pharmacotherapy for depression post-TBI. Clinical trials evaluating the use of pharmacotherapy in individuals with depression at baseline and using standardized assessments of depression were included. Data abstracted included sample size, antidepressant used, treatment timing/duration, method of assessment, and results pertaining to impact of treatment. Study quality was assessed using a modified Jadad scale. RESULTS: Nine studies met criteria for inclusion. Pooled analyses based on reported means (standard deviations) from repeated assessments of depression showed that, over time, antidepressant treatment was associated with a significant effect in favor of treatment (Hedges g = 1.169; 95% confidence interval, 0.849-1.489; P < .001). Similarly, when limited to placebo-controlled trials, treatment was associated with a significant reduction in symptoms (standardized mean difference = 0.84; 95% confidence interval, 0.314-1.366; P = .002). CONCLUSION: Pharmacotherapy after TBI may be associated with a reduction in depressive symptomatology. Given limitations within the available literature, further well-powered, placebo controlled trials should be conducted to confirm the effectiveness of antidepressant therapy in this population. PMID- 26479399 TI - The nuclear pore complex acts as a master switch for nuclear and cell differentiation. AB - Cell differentiation is associated with the functional differentiation of the nucleus, in which alteration of the expression profiles of transcription factors occurs to destine cell fate. Nuclear transport machineries, such as importin alpha, have also been reported as critical factors that induce cell differentiation. Using various fluorescence live cell imaging methods, including time-lapse imaging, FRAP analysis and live-cell imaging associated correlative light and electron microscopy (Live CLEM) of Tetrahymena, a unicellular ciliated protozoan, we have recently discovered that type switching of the NPC is the earliest detectable event of nuclear differentiation. Our studies suggest that this type switching of the NPC directs the fate of the nucleus to differentiate into either a macronucleus or a micronucleus. Our findings in this organism may provide new insights into the role of the NPC in controlling nuclear functions in general in eukaryotes, including controlling cell fate leading to cell differentiation in multicellular metazoa. PMID- 26479400 TI - French Experience with Buprenorphine : Do Physicians Follow the Guidelines? AB - Opiate dependence affects about 15,479,000 people worldwide. The effectiveness of opiate substitution treatments (OST) has been widely demonstrated. Buprenorphine plays a particular role in opiate dependence care provision in France. It is widely prescribed by physicians and national opiate substitution treatment guidelines have been available since 2004. In order to study the prescribing of buprenorphine, we used a questionnaire sent by email, to a large sample of physicians. These physicians were either in practice, or belonged to an addiction treatment network or a hospital. The main objective of this work was to measure the extent to which the theoretical, clinical attitude of physicians towards prescribing buprenorphine (BHD) complied with the statutory guidelines. We showed that the physicians we interviewed rarely took into account the guidelines regarding buprenorphine prescription. The actual prescribing of Buprenorphine differed from the guidelines. Only 42% of independent Family Physicians (FPs), working outside the national health care system, had prescribed buprenorphine as a first-time prescription and 40% of FPs do not follow up patients on buprenorphine. In terms of compliance with the guidelines, 55% of FPs gave theoretical answers that only partially complied with the guidelines. The variations in compliance with the guidelines was noted according to different variables and took into particular account whether the physician were affiliated to a network or in training. PMID- 26479401 TI - Endurance Cyclist Fluid Intake, Hydration Status, Thirst, and Thermal Sensations: Gender Differences. AB - This field investigation assessed differences (e.g., drinking behavior, hydration status, perceptual ratings) between female and male endurance cyclists who completed a 164-km event in a hot environment (35 degrees C mean dry bulb) to inform rehydration recommendations for athletes. Three years of data were pooled to create 2 groups of cyclists: women (n = 15) and men (n = 88). Women were significantly smaller (p < .001) than men in height (166 +/- 5 vs. 179 +/- 7 cm), body mass (64.6 +/- 7.3 vs. 86.4 +/- 12.3 kg), and body mass index (BMI; 23.3 +/- 1.8 vs. 26.9 +/- 3.4) and had lower preevent urinary indices of hydration status, but were similar to men in age (43 +/- 7 years vs. 44 +/- 9 years) and exercise time (7.77 +/- 1.24 hr vs. 7.23 +/- 1.75 hr). During the 164-km ride, women lost less body mass (-0.7 +/- 1.0 vs. -1.7 +/- 1.5 kg; -1.1 +/- 1.6% vs. -1.9 +/- 1.8% of body weight; p < .005) and consumed less fluid than men (4.80 +/- 1.28 L vs. 5.59 +/- 2.13 L; p < .005). Women consumed a similar volume of fluid as men, relative to body mass (milliliters/kilogram). To control for performance and anthropomorphic characteristics, 15 women were pair-matched with 15 men on the basis of exercise time on the course and BMI; urine-specific gravity, urine color, and body mass change (kilograms and percentage) were different (p < .05) in 4 of 6 comparisons. No gender differences were observed for ratings of thirst, thermal sensation, or perceived exertion. In conclusion, differences in relative fluid volume consumed and hydration indices suggest that professional sports medicine organizations should consider gender and individualized drinking plans when formulating pronouncements regarding rehydration during exercise. PMID- 26479402 TI - REDOX RESPONSIVE TRANSCRIPTION FACTOR1 is involved in age-dependent and systemic stress signaling. AB - REDOX RESPONSIVE TRANSCRIPTION FACTOR1 (RRTF1) regulates redox homeostasis under stress, however the mechanism is mainly unknown. In a recent publication, we analyzed rrtf1 knockout (ko) and RRTF1 overexpressor lines of Arabidopsis thaliana and showed that RRTF1 plays a crucial role in reactive oxygen species (ROS) production. Ko line produces less and overexpressor lines constitutively high levels of ROS under stress, and the amount of ROS increases with increase in stress and the RRTF1 level in the plant. The transcription factor also activates systemic ROS signaling under stress. (1) In this report, we show that RRTF1 exerts different roles in young and old leaves. While RRTF1 enhances defense responses to high light (HL) stress in young leaves, it induces senescence and chlorosis in older leaves. These findings suggest that RRTF1 and/or RRTF1 mediated ROS signaling induce stress responses in an age-dependent manner, and the age-dependent alteration in the RRTF1 function might be important for plants' acclimation to the stress environment. PMID- 26479403 TI - Dynamic buckling of actin within filopodia. AB - Filopodia are active tubular structures protruding from the cell surface which allow the cell to sense and interact with the surrounding environment through repetitive elongation-retraction cycles. The mechanical behavior of filopodia has been studied by measuring the traction forces exerted on external substrates.(1) These studies have revealed that internal actin flow can transduce a force across the cell surface through transmembrane linkers like integrins. In addition to the elongation-retraction behavior filopodia also exhibit a buckling and rotational behavior. Filopodial buckling in conjunction with rotation enables the cell to explore a much larger 3-dimensional space and allows for more complex, and possibly stronger, interactions with the external environment.(2) Here we focus on how bending of the filopodial actin dynamically correlates with pulling on an optically trapped microsphere which acts like an external substrate attached to the filopodial tip. There is a clear correlation between presence of actin near the tip and exertion of a traction force, thus demonstrating that the traction force is transduced along the actin shaft inside the filopodium. By extending a filopodium and holding it while measuring the cellular response, we also monitor and analyze the waiting times for the first buckle observed in the fluorescently labeled actin shaft. PMID- 26479404 TI - High Full-Electrode Basis Capacity Template-Free 3D Nanocomposite Secondary Battery Anodes. AB - A high full-electrode basis capacity secondary battery anode consisting of a template-free 3D nanostructured Fe3O4/C composite is presented. On a full electrode basis, the nanocomposite exhibits attractive electrochemical performance including a volumetric capacity of 1064 mAh cm(-3), which significantly exceeds both the practical (~300 mAh cm(-3)) and theoretical (837 mAh cm(-3)) capacity of a commercial graphite-based anode. PMID- 26479405 TI - Interactions among Collective Spectators Facilitate Eyeblink Synchronization. AB - Whereas the entrainment of movements and aspirations among audience members has been known as a basis of collective excitement in the theater, the role of the entrainment of cognitive processes among audience members is still unclear. In the current study, temporal patterns of the audience's attention were observed using eyeblink responses. To determine the effect of interactions among audience members on cognitive entrainment, as well as its direction (attractive or repulsive), the eyeblink synchronization of the following two groups were compared: (1) the experimental condition, where the audience members (seven frequent viewers and seven first-time viewers) viewed live performances in situ, and (2) the control condition, where the audience members (15 frequent viewers and 15 first-time viewers) viewed videotaped performances in individual experimental settings (results reported in previous study.) The results of this study demonstrated that the mean values of a measure of asynchrony (i.e., D interval) were much lower for the experimental condition than for the control condition. Frequent viewers had a moderate attractive effect that increased as the story progressed, while a strong attractive effect was observed throughout the story for first-time viewers. The attractive effect of interactions among a group of spectators was discussed from the viewpoint of cognitive and somatic entrainment in live performances. PMID- 26479407 TI - Ultrasound findings of carpal tunnel syndrome in a Hunter syndrome patient. AB - INTRODUCTION: Hunter syndrome (mucopolysaccharidosis II) is a rare genetic disorder. Carpal tunnel syndrome (CTS) is a common finding in these patients. METHODS: We report the ultrasound findings in a 40-year-old Hunter syndrome patient with severe CTS. RESULTS: Marked abnormalities of the median nerve were present proximal to the carpal tunnel with an unusual area of increased echogenicity between enlarged fascicles separating the area of maximal enlargement and the normal median nerve proximally. CONCLUSIONS: This case demonstrated unique ultrasound findings in a Hunter syndrome with CTS. Ultrasound also localized the median nerve lesion in the setting of end-stage median neuropathy and nonlocalizing electrophysiology. PMID- 26479406 TI - Evaluation of a Scenario in Which Estimates of Bioequivalence Are Biased and a Proposed Solution: tlast (Common). AB - In bioequivalence (BE) testing, it is the convention to identify tlast separately for each concentration-vs-time profile. Within-subject differences in tlast between treatments can arise when assay sensitivity is reached during washout, causing profiles to fall below the limit of quantitation (LOQ) at different sampling times. The resulting tlast difference may be systematic, due to true differences in exposure, and/or random, due to measurement noise. The conventional profile-specific tlast approach assumes that concentrations in the terminal phase are sufficiently low that use of different tlast values between treatments within a subject causes negligible bias in the AUC0-t geometric mean ratio (GMR). Here we investigate the validity of this assumption. Using concentration-vs-time data following oral inhalation of 50 MUg salmeterol as an example data set, we conducted simulations to evaluate whether use of different test/reference AUC timeframes arising from a systematic difference in exposure causes sufficient AUC0-t GMR bias to influence the determination of BE. To ensure that results would be relevant to BE testing, we considered only test/reference relative systemic exposures within the BE window (80.00%-125.00%). We show that use of conventional profile-specific tlast exaggerates true differences in systemic exposure; the resulting AUC0-t ratios are biased from true relative exposure by an amount large enough to impact the conclusion of BE. Thus, drugs whose concentrations fall below LOQ during washout may fail BE inappropriately using conventional methods. AUC0-t calculated over a common timeframe within each subject (tlast [common]) minimizes this bias and harmonizes the statistical analysis of BE. PMID- 26479408 TI - Translational regulation of the expression of the ubiquitin E3 ligase Nedd4-1 by mTORC1-dependent signaling. AB - We found recently that mTORC1 regulates the biosynthesis of the ubiquitin E3 ligase Nedd4-1, but not the close homolog Nedd4-2. This regulatory process plays a key role in promoting neurite growth in neurons of the mammalian central nervous system. The molecular mechanism underlying this rather specific regulation likely involves a pyrimidine-rich sequence stretch near the putative transcriptional start site within the 5' untranslated region of the Nedd4-1 mRNA, which may play a crucial role in directing the assembly of the protein translation machinery. We postulate that the Nedd4-1 mRNA is a major target of the local translation machinery within neurons that can be translated in a spatially and temporally controlled manner in response to various stimuli. Based on this model, neuronal Nedd4-1 may not only be involved in the regulation of neurite growth but also in axon guidance, spine formation, and synaptic plasticity. PMID- 26479410 TI - In vivo deformation of thin cartilage layers: Feasibility and applicability of T2* mapping. AB - The objectives of this study were as follows: (i) to assess segmentation consistency and scan precision of T2* mapping of human tibio-talar cartilage, and (ii) to monitor changes in T2* relaxation times of ankle cartilage immediately following a clinically relevant in vivo exercise and during recovery. Using multi echo gradient recalled echo sequences, averaged T2* values were calculated for tibio-talar cartilage layers in 10 healthy volunteers. Segmentation consistency and scan precision were determined from two repeated segmentations and two repeated acquisitions with repositioning, respectively. Subsequently, acute in vivo cartilage loading responses were monitored by calculating averaged tibio talar T2* values at rest, immediately after (i.e., deformation) and at 15 min (i.e., recovery) following a 30-repetition knee bending exercise. Precision errors attained 4-6% with excellent segmentation consistency point estimates (i.e., intra-rater ICC of 0.95) and acceptable limits of confidence. At deformation, T2* values were increased in both layers [+16.1 (10.7)%, p = 0.004 and +17.3 (15.3)%, p = 0.023, for the talus and tibia, respectively] whereas during recovery no significant changes could be established when comparing to baseline [talar cartilage: +5.2 (8.2)%, p = 0.26 and tibial cartilage: +6.6 (10.4)%, p = 0.23]. T2* mapping is a viable method to monitor deformational behavior in thin cartilage layers such as ankle cartilage. Longitudinal changes in T2* can be reliably appraised and require at least 4-6% differences to ascertain statistical significance. The ability to detect considerable change even after non-strenuous loading events, endorses T2* mapping as an innovative method to evaluate the effects of therapeutic exercise on thin cartilage layers. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:771-778, 2016. PMID- 26479411 TI - Novel Efficient Cell-Penetrating, Peptide-Mediated Strategy for Enhancing Telomerase Inhibitor Oligonucleotides. AB - At present, there are several therapeutic approaches for targeting telomerase in tumors. One in particular, currently undergoing clinical trials, is based on synthetic lipid-modified oligonucleotide antagonists aimed at inhibiting the ribonucleoprotein subunit of human telomerase. However, while enabling efficient uptake, the lipid modifications reduce the potency of the therapeutic oligonucleotides compared to nonmodified oligonucleotides. Moreover, lipid modification may increase oligonucleotide accumulation in the liver causing undesirable hepatotoxicity. Noncovalent complexation strategies for cell penetrating peptide (CPP)-mediated delivery present an option to circumvent the need for potency-reducing modifications, while allowing for a highly efficient uptake, and could significantly improve the efficiency of telomerase-targeting cancer therapeutics. Delivery of a nonlipidated locked nucleic acid/2'-O-methyl mixmer significantly inhibits the telomerase activity in treated HeLa cells. The inhibitory effect was further improved through addition of a CPP. Furthermore, calculated IC50-values for the oligonucleotide delivered by CPPs into HeLa cells are more than 20 times lower than telomerase inhibitor Imetelstat, currently undergoing clinical trials. These results emphasize the potential of CPP-mediated delivery of future pharmaceuticals and provide means by which to enhance an already promising therapeutic strategy for cancer treatment. PMID- 26479409 TI - Analysis of Multiple Families With Single Individuals Affected by Pseudohypoparathyroidism Type Ib (PHP1B) Reveals Only One Novel Maternally Inherited GNAS Deletion. AB - Proximal tubular resistance to parathyroid hormone (PTH) resulting in hypocalcemia and hyperphosphatemia are preeminent abnormalities in pseudohypoparathyroidism type Ib (PHP1B), but resistance toward other hormones as well as variable features of Albright's Hereditary Osteodystrophy (AHO) can occur also. Genomic DNA from PHP1B patients shows epigenetic changes at one or multiple differentially methylated regions (DMRs) within GNAS, the gene encoding Galphas and splice variants thereof. In the autosomal dominant disease variant, these methylation abnormalities are caused by deletions in STX16 or GNAS on the maternal allele. The molecular defect(s) leading to sporadic PHP1B (sporPHP1B) remains in most cases unknown and we therefore analyzed 60 sporPHP1B patients and available family members by microsatellite markers, single nucleotide polymorphisms (SNPs), multiplex ligation-dependent probe amplification (MLPA), and methylation-specific MLPA (MS-MLPA). All investigated cases revealed broad GNAS methylation changes, but no evidence for inheritance of two paternal chromosome 20q alleles. Some patients with partial epigenetic modifications in DNA from peripheral blood cells showed more complete GNAS methylation changes when testing their immortalized lymphoblastoid cells. Analysis of siblings and children of sporPHP1B patients provided no evidence for an abnormal mineral ion regulation and no changes in GNAS methylation. Only one patient revealed, based on MLPA and microsatellite analyses, evidence for an allelic loss, which resulted in the discovery of two adjacent, maternally inherited deletions (37,597 and 1427 bp, respectively) that remove the area between GNAS antisense exons 3 and 5, including exon NESP. Our findings thus emphasize that the region comprising antisense exons 3 and 4 is required for establishing all maternal GNAS methylation imprints. The genetic defect(s) leading in sporPHP1B to epigenetic GNAS changes and thus PTH-resistance remains unknown, but it seems unlikely that this disease variant is caused by heterozygous inherited or de novo mutations involving GNAS. PMID- 26479412 TI - Commentary on Some Recent Theses Relevant to Combating Aging: October 2015. PMID- 26479413 TI - Morphological spectrum of neovaginitis in autologous sigmoid transplant patients. AB - AIMS: Autologous intestinal grafts are used to (re)create a vagina in selected patients. The risk of diversion colitis is mentioned as a disadvantage, although its prevalence remains unclear. This study aimed to assess the histopathological characteristics of the sigmoid-derived neovaginal epithelial lining after diverting surgery and correlate these with clinical findings. METHODS AND RESULTS: Biopsy specimens were obtained from the epithelial lining of the sigmoid derived neovagina and remaining rectosigmoid as regular follow-up from 26 patients with a median age of 22 years (range 19-52) and median postoperative follow-up of 13 months (range 6-52). Medical history, neovaginal symptoms and sexual activity were documented. An experienced gastrointestinal histopathologist assessed the specimens using a descriptive item-score, comprising signs of chronic and active inflammation. Inflammatory changes were observed in 21 (80.7%) neovaginal and one (3.8%) rectosigmoid specimens. The neovaginal appearance was characterized by an increase of lymphoid aggregates and lymphoplasmacellular infiltrate. Other common features were the presence of polymorphonuclear neutrophils and Paneth cell metaplasia. Neovaginal discharge was correlated with the presence of inflammatory changes (P = 0.008, Spearman's rho = 0.506). DISCUSSION: Acute and chronic inflammation of the sigmoid-derived neovagina was commonly observed and consistent with a proposed diagnosis of diversion neovaginitis. Neovaginal discharge correlates with this histopathological entity. PMID- 26479415 TI - Why therapeutic drug monitoring is needed for monoclonal antibodies and how do we implement this? AB - Monoclonal antibodies (mAbs) have improved clinical outcomes for many therapeutic indications. However, extensive between-subject variability (BSV) contributes to therapeutic failures through suboptimal exposure. Therapeutic drug monitoring (TDM) is routinely implemented for inflammatory diseases; improving outcomes and reducing treatment costs. BSV can be more extensive with anticancer mAbs. Clearance BSV is associated with patient factors and disease burden, suggesting that TDM could benefit anticancer mAbs, as was seen with inflammatory disease, however, there are many hurdles. PMID- 26479414 TI - Association Between Initial Oral Therapy and Outcomes in Systemic Sclerosis Related Pulmonary Arterial Hypertension. AB - OBJECTIVE: To compare time to clinical worsening (TTCW) based on initial oral therapy for pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc)-related PAH. METHODS: Using data from the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry (a multicenter prospective observational study enrolling SSc patients with incident pulmonary hypertension), we selected patients with group 1 PAH (World Health Organization Clinical Classification system) who received initial therapy (for 6 months) with an endothelin receptor antagonist (ERA), a phosphodiesterase 5 (PDE5) inhibitor, or a combination of these 2 agents (ERA/PDE5 inhibitor). The main outcome was TTCW, defined as the first occurrence of death, PAH-related hospitalization, lung transplantation, initiation of parenteral prostacyclin treatment, or worsening symptoms. RESULTS: Ninety-eight patients (24 in the ERA group, 59 in the PDE5 inhibitor group, and 15 in the ERA/PDE5 inhibitor group) were included. No significant differences in the baseline characteristics of the patients were observed. TTCW was significantly worse in patients in the ERA group compared with those in the PDE5 inhibitor group or the ERA/PDE5 inhibitor group. Ten patients (41.6%) in the ERA group died during the 3-year observation period, compared with 4 patients (6.8%) in the PDE5 inhibitor group and 1 patient (6.7%) in the ERA/PDE5 inhibitor group. Baseline factors that were independently associated with a shorter TTCW were initial treatment with an ERA (hazard ratio [HR] 2.63 [P = 0.009]), lower diffusing capacity for carbon monoxide (HR 0.69 per 10% of predicted change [P = 0.04]), and higher pulmonary vascular resistance (HR 1.10 per Wood unit change [P = 0.007]). CONCLUSION: Compared with initial treatment with a PDE5 inhibitor or combination therapy with an ERA and a PDE5 inhibitor, initial therapy with an ERA in patients with SSc-related PAH was associated with significantly worse TTCW, even after adjustment for commonly accepted prognostic factors. Further study into the optimal initial oral therapy for patients with SSc-related PAH is needed. PMID- 26479417 TI - Understanding beta-mannanase from Streptomyces sp. CS147 and its potential application in lignocellulose based biorefining. AB - Hydrolytic enzymes such as cellulase and hemicellulase have been attracted in lignocellulose based biorefinery. Especially, mannanase has been a growing interest in industrial applications due to its importance in the bioconversion. In this study, an extracellular endo-beta-1,4-D-mannanase was produced by Streptomyces sp. CS147 (Mn147) and purified 8.5-fold with a 43.4% yield using Sephadex G-50 column. The characterization of Mn147 was performed, and the results were as follows: molecular weight of ~25 kDa with an optimum temperature of 50 degrees C and pH of 11.0. The effect of metal ions and various reagents on Mn147 was strongly activated by Ca(+2) but inhibited by Mg(+2) , Fe(+2) , hydrogen peroxide, EDTA and EGTA. Km and Vmax values of Mn147 were 0.13 mg/mL and 294 MUmol/min mg, respectively, when different concentrations (3.1 to 50 mg/mL) of locust bean gum galactomannan were used as substrate. In enzymatic hydrolysis of heterogeneous substrate (spent coffee grounds), Mn147 shows a similar conversion compared to commercial enzymes. In addition, lignocellulosic biomass can be hydrolyzed to oligosaccharides (reducing sugars), which can be further utilized for the production of biomaterials. These results showed that Mn147 is attractive in quest of potential bioindustrial applications. PMID- 26479419 TI - Haemangioma in an infant whose mother was receiving long-term propranolol treatment during pregnancy. PMID- 26479418 TI - Racial and ethnic socialization as moderators of racial discrimination and school adjustment of adopted and nonadopted Korean American adolescents. AB - This study investigated the roles of racial and ethnic socialization in the link between racial discrimination and school adjustment among a sample of 233 adopted Korean American adolescents from White adoptive families and 155 nonadopted Korean American adolescents from immigrant Korean families. Adopted Korean American adolescents reported lower levels of racial discrimination, racial socialization, and ethnic socialization than nonadopted Korean American adolescents. However, racial discrimination was negatively related to school belonging and school engagement, and ethnic socialization was positively related to school engagement for both groups. Racial socialization also had a curvilinear relationship with school engagement for both groups. A moderate level of racial socialization predicted positive school engagement, whereas low and high levels of racial socialization predicted negative school engagement. Finally, ethnic socialization moderated the link between racial discrimination and school belonging, which differed between groups. In particular, ethnic socialization exacerbated the relations between racial discrimination and school belonging for adopted Korean American adolescents, whereas ethnic socialization buffered this link for nonadopted Korean American adolescents. The findings illustrate the complex relationship between racial and ethnic socialization, racial discrimination, and school adjustment. PMID- 26479416 TI - Design and Implementation of the International Genetics and Translational Research in Transplantation Network. AB - BACKGROUND: Genetic association studies of transplantation outcomes have been hampered by small samples and highly complex multifactorial phenotypes, hindering investigations of the genetic architecture of a range of comorbidities which significantly impact graft and recipient life expectancy. We describe here the rationale and design of the International Genetics & Translational Research in Transplantation Network. The network comprises 22 studies to date, including 16494 transplant recipients and 11669 donors, of whom more than 5000 are of non European ancestry, all of whom have existing genomewide genotype data sets. METHODS: We describe the rich genetic and phenotypic information available in this consortium comprising heart, kidney, liver, and lung transplant cohorts. RESULTS: We demonstrate significant power in International Genetics & Translational Research in Transplantation Network to detect main effect association signals across regions such as the MHC region as well as genomewide for transplant outcomes that span all solid organs, such as graft survival, acute rejection, new onset of diabetes after transplantation, and for delayed graft function in kidney only. CONCLUSIONS: This consortium is designed and statistically powered to deliver pioneering insights into the genetic architecture of transplant-related outcomes across a range of different solid organ transplant studies. The study design allows a spectrum of analyses to be performed including recipient-only analyses, donor-recipient HLA mismatches with focus on loss-of-function variants and nonsynonymous single nucleotide polymorphisms. PMID- 26479420 TI - Evaluation of 122 advanced-stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies. AB - BACKGROUND: The authors hypothesized that comprehensive genomic profiling of advanced-stage cutaneous squamous cell carcinoma (cSCC) could identify genomic derived drug targets of therapy for patients with conventional therapy-resistant disease. METHODS: Comprehensive genomic profiling of 315 cancer genes was applied to 50 ng of DNA from 122 cSCC cases for the evaluation of all classes of genomic alterations (GAs). Clinically relevant genomic alterations (CRGAs) were defined as those identifying anticancer drugs on the market or in registered clinical trials. RESULTS: There were 21 women (17%) and 101 men (83%) with a median age of 64.9 years (range, 21-87 years). Eleven cSCC cases (9%) were histologic AJCC grade 1, 69 (57%) were grade 2, and 42 (34%) were grade 3. The primary cSCC was used for sequencing in 77 cases (63%). Metastatic lesions were sequenced in 37% of cases. There were 1120 total GAs identified (average of 9.2 GAs per tumor), with 100% of cases harboring at least 1 alteration. Of the 122 cSCCs, 107 (88%) harbored at least 1 CRGA (2.5 CRGAs per cSCC) includingNOTCH1 (43%); patched 1 (PTCH1) (11%); BRCA2 (10%); HRAS (8%); ataxia telangiectasia mutated (ATM) (7%); erb-B2 receptor tyrosine kinase 4 (ERBB4) (7%); neurofibromatosis type 1 (NF1) (7%); erb-B2 receptor tyrosine kinase 2 (ERBB2) (6%); phosphatidylinositol-4,5 bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (6%); cyclin D1 (CCND1) (6%); epidermal growth factor receptor (EGFR) (5%); and F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) (5%). CONCLUSIONS: In the current study, approximately 88% of patients with cSCC were found to harbor clinically relevant GAs that have the potential to guide the treatment of patients with advanced-stage tumors with targeted therapeutic agents. Cancer 2016;122:249-257. (c) 2015 American Cancer Society. PMID- 26479421 TI - Surgical Procedure Choice for Removing Hepatic Cysts of Echinococcus granulosus in Children. AB - Aim This study aims to evaluate the effectiveness of radical and conservative surgical procedures for removal of hydatid cysts in the liver of children. Methods A total of 112 pediatric patients had surgical treatment of hepatic cystic echinococcosis (CE) between January 2002 and December 2012 at the First Affiliated Hospital of Xinjiang Medical University were retrospectively evaluated. The patients were divided into two groups receiving either radical (n = 26) or conservative surgery (CS) (n = 86). Patient age, gender, symptoms, preoperative radiologic investigations, type of cyst, involvement of other organs, surgical procedure performed, postoperative complications, and mean hospital stay after surgery were recorded. Results The mean surgical procedure time for radical surgery (RS) was significantly longer than CS (126.4 +/- 37 vs. 90.4 +/- 22.9 minutes, p < 0.001], and the days for hospitalization showed no difference (11.0 +/- 2.1 vs. 11.5 +/- 3.1 days, p > 0.05]. Seven patients in the CS group had 20-300 mL of bile drainage 2-4 days post-operation and two patients developed a postoperative cavitary abscess; five patients in the RS group and one patient in the CS group developed a hydrothorax on the fifth day postoperatively. Follow-up of all patients showed that the majority had recovered well except for 3 cases who developed recurrences due to cysts ruptured accidently before surgery. There were no recurrences or biliary complications in the RS group. Conclusion CS is an effective method for liver CE cyst removal and RS is suitable for hepatic cysts in less risk position in pediatric patients. PMID- 26479423 TI - Pt/In2S3/CdS/Cu2ZnSnS4 Thin Film as an Efficient and Stable Photocathode for Water Reduction under Sunlight Radiation. AB - An electrodeposited Cu2ZnSnS4 (CZTS) compact thin film modified with an In2S3/CdS double layer and Pt deposits (Pt/In2S3/CdS/CZTS) was used as a photocathode for water splitting of hydrogen production under simulated sunlight (AM 1.5G) radiation. Compared to platinized electrodes based on a bare CZTS film (Pt/CZTS) and a CZTS film modified with a CdS single layer (Pt/CdS/CZTS), the Pt/In2S3/CdS/CZTS electrode exhibited a significantly high cathodic photocurrent. Moreover, the coverage of the In2S3 layer was found to be effective for stabilization against degradation induced by photocorrosion of the CdS layer. Bias-free water splitting with a power conversion efficiency of 0.28% was achieved by using a simple two-electrode cell consisting of the Pt/In2S3/CdS/CZTS photocathode and a BiVO4 photoanode. PMID- 26479422 TI - Intention to treat outcome of T1 hepatocellular carcinoma with the "wait and not ablate" approach until meeting T2 criteria for liver transplant listing. AB - Patients with T1 hepatocellular carcinoma (HCC; 1 lesion < 2 cm) are currently not eligible for priority listing for liver transplantation (LT). A common practice is to wait without locoregional therapy (LRT) until tumor growth occurs from T1 to T2 (1 lesion 2-5 cm or 2-3 lesions <= 3 cm) to be eligible for listing with Model for End-Stage Liver Disease exception. We aimed to evaluate the intention to treat outcome of the "wait and not ablate" approach for nonresection candidates with T1 HCC until tumor growth to T2. The study included 114 patients with T1 HCC 1.0-1.9 cm followed by serial imaging every 3 months. Two investigators performed independent imaging reviews to confirm the diagnosis. Median increase in total tumor diameter was 0.14 cm/month. Probabilities of progression from T1 to directly beyond T2 without LT listing were 4.4% at 6 months and 9.0% at both 12 and 24 months. The 1- and 3-year survival was 94.5% and 75.5%. In multivariate analysis, predictors of rapid tumor progression, defined as a > 1 cm increase in total tumor diameter over 3 months, included alcoholic liver disease (odds ratio [OR], 6.52; P = 0.02) and Hispanic race (OR, 3.86; P = 0.047), whereas hepatitis B appeared to be protective (OR, 0.09; P = 0.04). By competing risks regression, predictors of exclusion from LT (with or without listing for LT under T2) were alpha-fetoprotein (AFP) >= 500 ng/mL (HR, 12.69; 95% confidence interval, 2.8-57.0; P = 0.001) and rapid tumor progression (HR, 5.68; P < 0.001). In conclusion, the "wait and not ablate" approach until tumor growth from T1 to T2 before LT listing is associated with a <10% risk of tumor progression to directly beyond T2 criteria. However, patients with AFP >= 500 ng/mL and rapid tumor progression are at high risk for wait-list dropout and should receive early LRT. PMID- 26479424 TI - The relationships between content of heavy metals in soil and in strawberries. AB - The work was aimed at assessment of quality of strawberry based on the contents of heavy metals as well as the possible correlations between selected heavy metals in soil and strawberries. The results revealed that from all observed metals in soil determined in aqua regia only in the case of cadmium the maximum permissible limit in comparison with the limit resulting from the Law No. 220/2004 as well as threshold values proposed by European Commission (EC) (2006) has been exceeded. In our paper the values of cadmium in the soil representing 1.86 to 2.41 times higher values than limit valid in the Slovak Republic (0.7 mg/kg) and 2.6 to 3.38 times higher in comparison to EC (0.5 mg/kg). In our study in 1 M NH4NO3 the values of lead ranged from 0.125 to 0.205 mg/kg representing values exceeded the limit valid in Slovak Republic (0.1 mg/kg) about 0.037-0.105 mg/kg. Despite exceeded values of heavy metals in soil, no values above the limit directly in strawberries when compared to Food Codex of Slovak Republic as well as to Commission Regulation 1881/2006 were recorded. Among the varieties statistically significant differences (P < 0.05) in intake of heavy metals were found. PMID- 26479425 TI - Bulky N-Phosphino-Functionalized N-Heterocyclic Carbene Ligands: Synthesis, Ruthenium Coordination Chemistry, and Ruthenium Alkylidene Complexes for Olefin Metathesis. AB - Ruthenium chemistry and applications in catalytic olefin metathesis based on N phosphino-functionalized N-heterocyclic carbene ligands (NHCPs) are presented. Alkyl NHCP Ru coordination chemistry is described, and access to several potential synthetic precursors for ruthenium alkylidene complexes is outlined, incorporating both trimethylsilyl and phenyl alkylidenes. The Ru alkylidene complexes are evaluated as potential olefin metathesis catalysts and were shown to behave in a latent fashion. They displayed catalytic activity at elevated temperatures for both ring closing metathesis and ring opening metathesis polymerization. PMID- 26479426 TI - Audiologic evaluation of vestibular schwannoma and other cerebellopontine angle tumors. AB - CONCLUSION: Otologic accompanying symptoms, audiogram patterns, and hearing levels according to tumor size differed in patients with CPA tumors classified as VS and non-VS types. OBJECTIVES: The diagnosis of CPA tumors is often delayed. Late-diagnosed tumors can grow until they compress and damage vital structures. This study evaluated the otologic symptoms and results of audiologic tests in patients with vestibular schwannomas (VS) and other types of CPA tumors. METHODS: This study included 171 patients with otologic symptoms who were diagnosed with CPA tumors, including 116 with VS and 55 with other types of CPA tumors. Factors analyzed retrospectively included tumor type, size, and location and the results of audiometric examinations. RESULTS: The most common chief complaint in patients diagnosed with CPA tumors was asymmetrical hearing loss, with most frequent accompanying symptoms being tinnitus in patients with VS and dizziness in those with other types of CPA tumor. The most frequent patterns of hearing loss were the descending type in patients with VS and the flat type in patients with non-VS tumors (p < 0.05). Pure tone thresholds tended to increase more in patients with VS than non-VS tumors according to tumor size, and pure tone averages were significantly higher in patients with VS than non-VS tumors of 11-25 mm in size (p < 0.05). PMID- 26479427 TI - Compressive cyclic ratcheting and fatigue of synthetic, soft biomedical polymers in solution. AB - The use of soft, synthetic materials for the replacement of soft, load-bearing tissues has been largely unsuccessful due to a lack of materials with sufficient fatigue and wear properties, as well as a lack of fundamental understanding on the relationship between material structure and behavior under cyclic loads. In this study, we investigated the response of several soft, biomedical polymers to cyclic compressive stresses under aqueous conditions and utilized dynamic mechanical analysis and differential scanning calorimetry to evaluate the role of thermo-mechanical transitions on such behavior. Studied materials include: polycarbonate urethane, polydimethylsiloxane, four acrylate copolymers with systematically varied thermo-mechanical transitions, as well as bovine meniscal tissue for comparison. Materials showed compressive moduli between 2.3 and 1900MPa, with polycarbonate urethane (27.3MPa) matching closest to meniscal tissue (37.0MPa), and also demonstrated a variety of thermo-mechanical transition behaviors. Cyclic testing resulted in distinct fatigue-life curves, with failure defined as either classic fatigue fracture or a defined increased in maximum strain due to ratcheting. Our study found that polymers with sufficient dissipation mechanisms at the testing temperature, as evidenced by tan delta values, were generally tougher than those with less dissipation and exhibited ratcheting rather than fatigue fracture much like meniscal tissue. Strain recovery tests indicated that, for some toughened polymers, the residual strain following our cyclic loading protocol could be fully recovered. The similarity in ratcheting behavior, and lack of fatigue fracture, between the meniscal tissue and toughened polymers indicates that such polymers may have potential as artificial soft tissue. PMID- 26479428 TI - Effect of silanization of hydroxyapatite fillers on physical and mechanical properties of a bis-GMA based resin composite. AB - To evaluate the physical and mechanical properties of an experimental bis-GMA based resin composite incorporated with non-silanized and silanized nano hydroxyapatite (nHAP) fillers. Experimental bis-GMA based resin composites samples which were reinforced with nHAP fillers were prepared. Filler particles were surface treated with a silane coupling agent. Five test groups were prepared: 1. Unfilled, 2. Reinforced with 10wt% and 30wt% non-silanized nHAP fillers, and 3. Reinforced with 10wt% and 30wt% silanized nHAP fillers. The samples were subjected to tests in dry condition and in deionized water, aged at 37 degrees C for 30 days. Prepared silanized and non-silanized nHAP were analyzed with Fourier Transform Infrared (FTIR) Spectroscopy and X-ray Photoelectron Spectroscopy (XPS). The micro-hardness and water sorption were evaluated. Data were analyzed by one-way ANOVA (p<0.05). The samples were characterized by FTIR Spectroscopy, Thermogravimetric Analysis and Differential Scanning Calorimetry. The surface morphology of sample surfaces was examined by Scanning Electron Microscope (SEM). The results showed that the water sorption for nHAP fillers reinforced resins was significantly lower than unfilled resins. Surface hardness for resins reinforced with silane treated fillers was superior to unfilled and untreated fillers resins. The resin matrix loaded with 30wt% silanized-nHAP fillers would improve the physical and mechanical properties of a bis-GMA based resin. PMID- 26479429 TI - Flavonoids from Pronephrium megacuspe. AB - A chemical investigation of the whole plant of Pronephrium megacuspe (Bak.) Holtt. led to the isolation of four flavonoids, pronephrones A-D (1-4), which were firstly reported. The chemical structures of four compounds were established using spectroscopic methods. These isolates were further evaluated for cytotoxicity to ovarian cells of Spodoptera litura Fabricius. PMID- 26479430 TI - Glycerin esterification of scum derived free fatty acids for biodiesel production. AB - Scum is an oily waste stream of the wastewater treatment process that can be used to produce biodiesel. Combining acid hydrolysis and solvent extraction, a free fatty acid and acyl-glycerol rich product was produced. Free fatty acids (FFAs) present were converted to acyl-glycols via a high temperature (238 degrees C) glycerin esterification process known as glycerolysis. The inorganic catalysts zinc aluminum oxide and sodium sulfate were tested during glycerolysis to compare the reaction kinetics of converting FFA to acyl-glycerols. It was concluded that the zinc-based catalyst increased the reaction rate significantly, from a "k" value of 2.57 (uncatalyzed) to 5.63, completing the reaction in 60min, half the time it took the uncatalyzed reaction (120min). Sodium sulfate's presence however slowed the reaction, resulting in a "k" value of 1.45, completing the reaction in 180min. Use of the external catalyst Zn-Al2O3 showed the greatest catalytic potential, but also assumes additional costs. PMID- 26479431 TI - Enhancement of aerobic biodegradability potential of municipal waste activated sludge by ultrasonic aided bacterial disintegration. AB - An investigation was performed to study the influence of ultrasonic aided bacterial disintegration on the aerobic degradability of sludge. In first phase of the study, effective floc disruption was achieved at an ultrasonic specific energy input of 2.45kJ/kg TS with 44.5mg/L of Extracellular Polymeric Substance (EPS) release including 0.035U/mL and 0.025U/mL protease and amylase activity respectively. In second phase, experimental outcomes revealed bacterial disintegration of floc disrupted-sludge showing a maximum solubilization of about 23% and was observed to be superior to bacterially disintegrated (11%) and control (6%), respectively. The result of aerobic biodegradability of ultrasonic aided bacterially pretreated sludge showed volatile solids (VS) degradation of about 40.2%. The kinetic study of aerobic biodegradability through non linear regression modelling reveals that floc disrupted sludge showed better biodegradability with decay constant of about 0.19d(-1) relatively higher than the control (0.14d(-1)) and bacterially disintegrated (0.17d(-1)) sludges. PMID- 26479432 TI - Influence of an oxic settling anoxic system on biomass yield, protozoa and filamentous bacteria. AB - An oxic settling anoxic system coupled with an activated sludge process has been studied to reduce sewage sludge production. The reduction of sludge yield, excess sludge production and active biomass yield were 51.7%, 52.9% and 67.1%, respectively, compared with the control system. The oxic reactor of the oxic settling anoxic system, even with a lower active biomass concentration than the oxic reactor of control system, showed a higher metabolic activity in their active biomass. Diversity and crawling ciliates group have been shown as promising bioindicators of active biomass yield reduction. The identification of floc-forming bacteria in the control system suggested that oxic settling anoxic system will improve settling properties compared to a Conventional Activated Sludge process. PMID- 26479433 TI - Cervix removal at the time of hysterectomy: factors affecting patients' choice and effect on subsequent sexual function. AB - OBJECTIVES: To identify factors that influence the decision-making process on the type of hysterectomy (total or supracervical) and the impact of surgery of subsequent sexual function. STUDY DESIGN: A cross-sectional survey was undertaken on 212 women who underwent total laparoscopic hysterectomy (TLH) or laparoscopic supracervical hysterectomy (LSH) for benign conditions at the Division of Minimally Invasive Gynecology at Brigham and Women's Hospital in Boston, MA, USA. We analyzed the factors that patients considered in their decision-making process, their sexual function after surgery and their satisfaction with the surgery overall. Demographic and perioperative outcomes were also collected. RESULTS: A total of 115 women answered the survey, for a response rate of 54.24%. The patients who underwent LSH (n=54) and TLH (n=61) were overall similar in terms of baseline factors and perioperative outcomes. Patients reported that the physician was the main source of information regarding decision to remove or retain the cervix (79.13%). The physicians' recommendation was viewed as very or extremely important (83.68%) to the decision-making process, followed by concerns regarding their future sex life (51.09%). Almost half of the women reported that hysterectomy had no impact on sexual function. No statistically significant differences were seen between groups regarding satisfaction with sexual function (p=.822), impact on sexual function (p=.753) or recommendation of this surgery to other women (p=.505). CONCLUSION: Concerns about sexual health were important to women when considering the type of hysterectomy to undergo. Cervix removal or retention at the time of hysterectomy did not impact women's sexual function after mean follow-up of 15.2 months. PMID- 26479434 TI - Results from the International Consensus Conference on Myo-inositol and d-chiro inositol in Obstetrics and Gynecology: the link between metabolic syndrome and PCOS. AB - In recent years, interest has been focused to the study of the two major inositol stereoisomers: myo-inositol (MI) and d-chiro-inositol (DCI), because of their involvement, as second messengers of insulin, in several insulin-dependent processes, such as metabolic syndrome and polycystic ovary syndrome. Although these molecules have different functions, very often their roles have been confused, while the meaning of several observations still needs to be interpreted under a more rigorous physiological framework. With the aim of clarifying this issue, the 2013 International Consensus Conference on MI and DCI in Obstetrics and Gynecology identified opinion leaders in all fields related to this area of research. They examined seminal experimental papers and randomized clinical trials reporting the role and the use of inositol(s) in clinical practice. The main topics were the relation between inositol(s) and metabolic syndrome, polycystic ovary syndrome (with a focus on both metabolic and reproductive aspects), congenital anomalies, gestational diabetes. Clinical trials demonstrated that inositol(s) supplementation could fruitfully affect different pathophysiological aspects of disorders pertaining Obstetrics and Gynecology. The treatment of PCOS women as well as the prevention of GDM seem those clinical conditions which take more advantages from MI supplementation, when used at a dose of 2g twice/day. The clinical experience with MI is largely superior to the one with DCI. However, the existence of tissue-specific ratios, namely in the ovary, has prompted researchers to recently develop a treatment based on both molecules in the proportion of 40 (MI) to 1 (DCI). PMID- 26479435 TI - Romanian adolescents' knowledge and attitudes towards human papillomavirus infection and prophylactic vaccination. AB - OBJECTIVES: Since licensure of HPV vaccine in 2006, HPV vaccine coverage among Romanian adolescents remains worryingly low. The objectives of the study were to assess the knowledge and attitudes towards HPV infection and vaccination among Romanian adolescents and to explore the barriers to HPV vaccination with a view to developing strategies for expanding primary HPV infection prevention. STUDY DESIGN: This study was conducted in Bucharest between April and June 2015. A total of 524 adolescents aged 16-18 years old were recruited from the first two general highschools in Bucharest (according to the admission grade) and completed a self-administered questionnaire including demographics, HPV related and Papanicolau smear test knowledge. Odds ratio and 95% confidence intervals were used to identify the strength of association. Logistic regression analysis was used to identify the effect of demographic characteristics on the level of knowledge and HPV vaccination rate. Associations were considered statistically significant at p<0.05. RESULTS: Of the adolescents interviewed, a very small proportion had heard of HPV infection, HPV vaccine and Papanicolau smear test, that is, 20.22%, 67.92% and 22.9%, respectively. The overall vaccination rate for this group was 2.3%. The most common reason for not receiving the HPV vaccine was the lack of information (80.6%) followed by parents' concerns regarding safety (11%), fear of pain (5.59%) and not being sexually active (2.7%). However, 97.7% of the respondents declared interest in receiving more information about HPV. According to demographic characteristics, age at first sexual intercourse over 16 years old, monthly household income over one thousand euros and self-perceived good relationship with family members were statistically associated on a multivariate logistic regression analysis with a high HPV knowledge score and rate of vaccination. CONCLUSIONS: This study shows a low level of knowledge about HPV infection and prophylactic vaccination among Romanian adolescents which may be one of the most important factors for the alarmingly low HPV vaccination rate. We specifically call for HPV knowledge and awareness programs; the implication of health professionals, Romanian media and family members should be included as a centrepiece in the effort to inform this vulnerable population group. PMID- 26479436 TI - Power Doppler flow mapping and four-dimensional ultrasound for evaluating tubal patency compared with laparoscopy. AB - OBJECTIVES: To study the accuracy of four-dimensional (4D) ultrasound and power Doppler flow mapping in detecting tubal patency in women with sub-/infertility, and compare it with laparoscopy and chromopertubation. STUDY DESIGN: A prospective study. The study was performed in the outpatient clinic and infertility unit of a university hospital. The sonographic team and laparoscopic team were blinded to the results of each other. Women aged younger than 43 years seeking medical advice due to primary or secondary infertility and who planned to have a diagnostic laparoscopy performed, were recruited to the study after signing an informed consent. All of the recruited patients had power Doppler flow mapping and 4D hysterosalpingo-sonography by injecting sterile saline into the fallopian tubes 1 day before surgery. Registering Doppler signals, while using power Doppler, both at the tubal ostia and fimbrial end and the ability to demonstrate the course of the tube especially the isthmus and fimbrial end, while using 4D mode, was considered a patent tube. RESULTS: Out of 50 recruited patients, 33 women had bilateral patent tubes and five had unilateral patent tubes as shown by chromopertubation during diagnostic laparoscopy. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for two-dimensional power Doppler hysterosalpingography were 94.4%, 100%, 100%, 89.2%, and 96.2%, respectively and for 4D ultrasound were 70.4%, 100%, 100%, 70.4%, and 82.6%, respectively. CONCLUSIONS: Four-dimensional saline hysterosalpingography has acceptable accuracy in detecting tubal patency, but is surpassed by power Doppler saline hysterosalpingography. Power Doppler saline hysterosalpingography could be incorporated into the routine sub-/infertility workup. PMID- 26479437 TI - Systemic lupus erythematosus: review of synthetic drugs. AB - INTRODUCTION: Synthetic drugs are prescribed for nearly all patients with systemic lupus erythematosus (SLE), a multisystem autoimmune disease, to ameliorate symptoms and positively influence outcome. While only 2 biologic agents have been approved for the treatment of SLE, synthetic drugs are still the mainstay of therapy in SLE. The highly variable and unpredictable course of SLE poses a challenge for physicians as to what drug(s) should be prescribed for which patient. AREAS COVERED: Previous and recent studies have evaluated several synthetic drugs in the treatment of SLE. This article reviews currently available evidence for the efficacy and safety of synthetic drugs in SLE and discusses future treatment perspectives. EXPERT OPINION: Hydroxychloroquine should be considered an anchor drug in SLE because of the multiple beneficial effects of this agent. When patients present with persistent disease activity despite hydroxychloroquine therapy or need higher dosages and/or prolonged use of glucocorticoids (GCs), additional immunosuppressants should be promptly prescribed. Based on available evidence, azathioprine and mycophenolate mofetil are the drugs of first choice. Determination of a 'safe' GC dose for chronic daily use is of major importance and should be subject of further studies in large patient populations. PMID- 26479438 TI - MicroRNAs regulate the immunometabolic response to viral infection in the liver. AB - Immune regulation of cellular metabolism can be responsible for successful responses to invading pathogens. Viruses alter their hosts' cellular metabolism to facilitate infection. Conversely, the innate antiviral responses of mammalian cells target these metabolic pathways to restrict viral propagation. We identified miR-130b and miR-185 as hepatic microRNAs (miRNAs) whose expression is stimulated by 25-hydroxycholesterol (25-HC), an antiviral oxysterol secreted by interferon-stimulated macrophages and dendritic cells, during hepatitis C virus (HCV) infection. However, 25-HC only directly stimulated miR-185 expression, whereas HCV regulated miR-130b expression. Independently, miR-130b and miR-185 inhibited HCV infection. In particular, miR-185 significantly restricted host metabolic pathways crucial to the HCV life cycle. Interestingly, HCV infection decreased miR-185 and miR-130b levels to promote lipid accumulation and counteract 25-HC's antiviral effect. Furthermore, miR-185 can inhibit other viruses through the regulation of immunometabolic pathways. These data establish these microRNAs as a key link between innate defenses and metabolism in the liver. PMID- 26479440 TI - Chemical libraries: How dark is HTS dark matter? PMID- 26479439 TI - Mapping the energy landscape for second-stage folding of a single membrane protein. AB - Membrane proteins are designed to fold and function in a lipid membrane, yet folding experiments within a native membrane environment are challenging to design. Here we show that single-molecule forced unfolding experiments can be adapted to study helical membrane protein folding under native-like bicelle conditions. Applying force using magnetic tweezers, we find that a transmembrane helix protein, Escherichia coli rhomboid protease GlpG, unfolds in a highly cooperative manner, largely unraveling as one physical unit in response to mechanical tension above 25 pN. Considerable hysteresis is observed, with refolding occurring only at forces below 5 pN. Characterizing the energy landscape reveals only modest thermodynamic stability (DeltaG = 6.5 kBT) but a large unfolding barrier (21.3 kBT) that can maintain the protein in a folded state for long periods of time (t1/2 ~3.5 h). The observed energy landscape may have evolved to limit the existence of troublesome partially unfolded states and impart rigidity to the structure. PMID- 26479441 TI - Dark chemical matter as a promising starting point for drug lead discovery. AB - High-throughput screening (HTS) is an integral part of early drug discovery. Herein, we focused on those small molecules in a screening collection that have never shown biological activity despite having been exhaustively tested in HTS assays. These compounds are referred to as 'dark chemical matter' (DCM). We quantified DCM, validated it in quality control experiments, described its physicochemical properties and mapped it into chemical space. Through analysis of prospective reporter-gene assay, gene expression and yeast chemogenomics experiments, we evaluated the potential of DCM to show biological activity in future screens. We demonstrated that, despite the apparent lack of activity, occasionally these compounds can result in potent hits with unique activity and clean safety profiles, which makes them valuable starting points for lead optimization efforts. Among the identified DCM hits was a new antifungal chemotype with strong activity against the pathogen Cryptococcus neoformans but little activity at targets relevant to human safety. PMID- 26479442 TI - Polyketide synthase chimeras reveal key role of ketosynthase domain in chain branching. AB - Biosynthesis of rhizoxin in Burkholderia rhizoxinica affords an unusual polyketide synthase module with ketosynthase and branching domains that install the delta-lactone, conferring antimitotic activity. To investigate their functions in chain branching, we designed chimeric modules with structurally similar domains from a glutarimide-forming module and a dehydratase. Biochemical, kinetic and mutational analyses reveal a structural role of the accessory domains and multifarious catalytic actions of the ketosynthase. PMID- 26479443 TI - Epstein-Barr virus LMP1 induces focal adhesions and epithelial cell migration through effects on integrin-alpha5 and N-cadherin. AB - Epstein-Barr virus (EBV) is a gamma-herpesvirus associated with human epithelial and B-cell malignancies. The EBV latent membrane protein (LMP) 1 is expressed in nasopharyngeal carcinoma (NPC) and promotes oncogenic intracellular signaling mechanisms. LMP1 also promotes a pro-migratory phenotype through potential effects on cell surface proteins, as expression of LMP1 induces an epithelial mesenchymal transition (EMT) in epithelial cell lines. In this study, LMP1 was examined for potential effects on cadherin and integrin surface interactions, and assessed for biological effects on adhesion and motility to fibronectin. Expression of LMP1 in the non-tumorigenic epithelial cell line MCF10a induced an EMT-associated cadherin switch. The induced N-cadherin was ligated and localized to the cell surface as determined by triton-solubility and immunofluorescence assays. In addition, LMP1 induced the assembly of focal adhesions (FAs) with increased production of fibronectin in MCF10a and NP460hTERT-immortalized nasopharyngeal cells. Biochemical enrichment of fibronectin-associated proteins indicated that LMP1 selectively promoted the recruitment of integrin-alpha5 and Src family kinase proteins to FA complexes. Neutralizing antibodies to N-cadherin and integrin-alpha5, but not integrin-alphaV, blocked the adhesion and transwell motility of MCF10a cells to fibronectin induced by LMP1. LMP1-induced transwell motility was also decreased by Src inhibition with the PP2 kinase inhibitor and short hairpin RNAs. These studies reveal that LMP1 has multiple mechanisms to promote the adhesive and migratory properties of epithelial cells through induction of fibronectin and modulation of cell surface interactions involving integrin-alpha5 and N-cadherin, which may contribute to the metastatic potential of NPC. PMID- 26479444 TI - Nodes-and-connections RNAi knockdown screening: identification of a signaling molecule network involved in fulvestrant action and breast cancer prognosis. AB - Although RNA interference (RNAi) knockdown screening of cancer cell cultures is an effective approach to predict drug targets or therapeutic/prognostic biomarkers, interactions among identified targets often remain obscure. Here, we introduce the nodes-and-connections RNAi knockdown screening that generates a map of target interactions through systematic iterations of in silico prediction of targets and their experimental validation. An initial RNAi knockdown screening of MCF-7 human breast cancer cells targeting 6560 proteins identified four signaling molecules required for their fulvestrant-induced apoptosis. Signaling molecules physically or functionally interacting with these four primary node targets were computationally predicted and experimentally validated, resulting in identification of four second-generation nodes. Three rounds of further iterations of the prediction-validation cycle generated third, fourth and fifth generation of nodes, completing a 19-node interaction map that contained three predicted nodes but without experimental validation because of technical limitations. The interaction map involved all three members of the death associated protein kinases (DAPKs) as well as their upstream and downstream signaling molecules (calmodulins and myosin light chain kinases), suggesting that DAPKs play critical roles in the cytocidal action of fulvestrant. The in silico Kaplan-Meier analysis of previously reported human breast cancer cohorts demonstrated significant prognostic predictive power for five of the experimentally validated nodes and for three of the prediction-only nodes. Immunohistochemical studies on the expression of 10 nodal proteins in human breast cancer tissues not only supported their prognostic prediction power but also provided statistically significant evidence of their synchronized expression, implying functional interactions among these nodal proteins. Thus, the Nodes-and-Connections approach to RNAi knockdown screening yields biologically meaningful outcomes by taking advantage of the existing knowledge of the physical and functional interactions between the predicted target genes. The resulting interaction maps provide useful information on signaling pathways cooperatively involved in clinically important features of the malignant cells, such as drug resistance. PMID- 26479445 TI - Resonance light scattering determination of 6-mercaptopurine coupled with HPLC technique. AB - A simple, fast, costless, sensitive and selective method of resonance light scattering coupled with HPLC was established for the determination of 6 mercaptopurine in human urine sample. In a Britton-Robinson buffer solution of pH5.5, the formation of coordination complex between 6-mercaptopurine and metal palladium (II) led to enhance the RLS intensity of the system. The RLS signal was detected by fluorescence detector at lambda(ex)=lambda(em)=315 nm. The analytical parameters were provided by the coupled system, the linear of 6-mercaptopurine response from 0.0615 to 2.40 MUg L(-1) and the limit of detection (S/N=3) was 0.05 MUg L(-1). The presented method has been applied to determine 6 mercaptopurine in human urine samples which obtained satisfactory results. Moreover, the reaction mechanism and possible reasons for enhancement of RLS were fully discussed. PMID- 26479446 TI - Oxidative Cross-Coupling of sp(3)- and sp(2)-Hybridized C-H Bonds: Vanadium Catalyzed Aminomethylation of Imidazo[1,2-a]pyridines. AB - The vanadium-catalyzed oxidative coupling of substituted 2-arylimidiazo[1,2 a]pyridines to N-methylmorpholine oxide, which acts as both a coupling partner and an oxidant, has been achieved. This reaction was applied to various substituted imidiazo[1,2-a]pyridine and indole substrates, resulting in yields as high as 90%. Mechanistic investigations indicate that the reaction may proceed via a Mannich-type process. This work demonstrates how oxidative aminomethylation can be used as a useful method to introduce tertiary amines into heterocycles, thus providing an alternative method for conventional Mannich-type reactions. PMID- 26479447 TI - Physicochemical Properties and in Vitro Digestibility of Cooked Regular and Nondarkening Cranberry Beans (Phaseolus vulgaris L.) and Their Effects on Bioaccessibility, Phenolic Composition, and Antioxidant Activity. AB - Cranberry beans from regular (RR) and nondarkening (CND) genotypes were pressure cooked, and free, conjugated, and bound phenolics were analyzed. Simulated in vitro gastrointestinal digestion was used to assess the bioaccessibility of these phenolic fractions. Total phenolic content decreased after cooking and digestion, whereas individual phenolic compounds were affected differently. Cooking significantly increased the release of bound ferulic and sinapic acids and flavanols, whereas digestion released p-coumaric, ferulic, and sinapic acids in both genotypes, and p-hydroxybenzoic acid, epicatechin, and catechin in only RR. Bioaccessibility of phenolics in RR and CND was 8.75 and 14.69%, respectively. Difference in total phenolics was smaller after digestion, and enzymes potentially secreted by colonic bacteria released similar amounts of phenolic acids in both varieties. Resistant and slowly digestible starch contents showed no differences between RR and CND. These results suggest that the lower phenolic content in raw CND may not completely negate its impact on gut health. PMID- 26479448 TI - Editorial. PMID- 26479449 TI - Design of Microporous Material HUS-10 with Tunable Hydrophilicity, Molecular Sieving, and CO2 Adsorption Ability Derived from Interlayer Silylation of Layered Silicate HUS-2. AB - The attractive properties of zeolites, which make them suitable for numerous applications for the energy and chemical industries and for life sciences, are derived from their crystalline framework structures. Herein, we describe the rational synthesis of a microporous material, HUS-10, utilizing a layered silicate precursor, HUS-2, as a structural building unit. For the ordered micropores to be formed, interlayer pillars that supported the original silicate layer of HUS-2 were immobilized through the interlayer silylation of silanol groups with trichloromethylsilane and a subsequent dehydration-condensation reaction of the hydroxyl groups on the preintroduced tetrahedral units. An actual molecular sieving ability, enabling the adsorption of molecules smaller than ethane, was confirmed in the ordered micropores of HUS-10. The hydrophilic adsorption could also be controlled by changing the number of methyl and hydroxyl groups in the immobilized interlayer pillars. In addition, when the adsorption behaviors of CO2, CH4, and N2 on HUS-10 were compared to those on siliceous MFI and CDO zeolites with approximately the same pore diameter, the CO2 adsorption capacity of HUS-10 was comparable. Conversely, because of the adsorption inhibition of CH4 and N2, HUS-10 exhibited larger CO2/CH4 and CO2/N2 adsorption ratios relative to those of MFI and CDO zeolites. These results reveal that the unique microporous framework structure presented by the rational structural design using the layered silicate precursor HUS-2 has the potential to separate CO2 from gas mixtures. PMID- 26479450 TI - Acute renal failure in critically ill newborns increases the risk of death: a prospective observational study from India. AB - OBJECTIVE: To determine the incidence and risk factors of acute renal failure (ARF) in hospitalized critically ill neonates and analyze outcome of all neonates with renal failure in relation to risk factors. MATERIAL & METHODS: In this prospective observational study 815 infants were enrolled. Renal profile (blood urea and serum creatinine) was done after 12 h of life (or at the time of admission for outborn babies) and then every 12 hourly. Daily 24 h urine output was evaluated. RESULTS: Incidence of renal failure in critically ill neonates was 10.67%. Out of 87 ARF neonates 52 (60%) expired. Mortality in the renal failure group was significantly higher in comparison to control group (p < 0.01). Non oliguric renal failure was more common than oliguric renal failure, but mortality in the oliguric renal failure group was more. Neonatal sepsis was the most common cause of ARF. Eight neonates underwent peritoneal dialysis (PD) out of which there were seven neonatal deaths. CONCLUSION: Prognosis of neonates with ARF requiring PD was very poor. It can thus be concluded that the health care personal should do rapid diagnosis of ARF in neonates with potential risk factors and also goal at an early and effective treatment of these risk factors in neonates with ARF. PMID- 26479451 TI - Distribution and congener profiles of short-chain chlorinated paraffins in indoor/outdoor glass window surface films and their film-air partitioning in Beijing, China. AB - Short-chain chlorinated paraffins (SCCPs) are a group of n-alkanes with carbon chain length of 10-13. In this work, paired indoor/outdoor samples of organic films on window glass surfaces from urban buildings in Beijing, China, were collected to measure the concentrations and congener distributions of SCCPs. The total SCCP levels ranged from 337 ng/m(2) to 114 MUg/m(2), with total organic carbon (TOC) normalized concentrations of 365 MUg/m(2)-365 mg/m(2). Overall, the concentrations of SCCPs on the interior films were higher than the concentrations on the exterior films, suggesting an important indoor environmental exposure of SCCPs to the general public. A significant linear relationship was found between the SCCP concentrations and TOC, with a correlation coefficient of R = 0.34 (p < 0.01). A film-air partitioning model suggests that the indoor gas-phase SCCPs are related to their corresponding window film levels. PMID- 26479452 TI - Toxicity of TiO2 nanoparticle to denitrifying strain CFY1 and the impact on microbial community structures in activated sludge. AB - The antibacterial activity of titanium dioxide nanoparticles (TiO2 NPs) is well described, but little is known of their impact on specific microbial functions such as denitrification, nor on microbial community structure. In this study, a denitrifier (named as Pseudomonas stutzeri CFY1), which was isolated from the activated sludge and could remove up to 111.68 mg/L of NO3(-)-N under aerobic conditions, was utilized to evaluate the influences of TiO2 NPs on its nitrogen removal ability and associated gene expression under aerobic conditions. The variations of the bacterial diversity of activated sludge were also observed. The results showed that antibacterial activity increased with increasing concentrations of TiO2 NPs. Increased production of reactive oxygen species was responsible for TiO2 NPs toxicity. An up-regulation of denitrification genes was observed with increasing concentrations of TiO2 NPs under aerobic conditions. Accordingly, denitrification by P. stutzeri was accelerated when the concentration of TiO2 NPs was increased to 50 mg/L. However, the denitrification of CFY1 was inhibited at low concentrations of TiO2 NPs (5-25 mg/L), indicating that assimilatory and dissimilatory denitrification were synchronized in P. stutzeri CFY1; the latter process plays a major role in denitrification. Further study of the community using 454 pyrosequencing showed that after 7 days of exposure to 50 mg/L TiO2 NPs, the microbial composition of the activated sludge was significantly different and had a lower diversity compared to the controls. PMID- 26479453 TI - Vitellogenin expression in wild cyprinid Petroleuciscus esfahani as a biomarker of endocrine disruption along the Zayandeh Roud River, Iran. AB - Aquatic environments are the ultimate sink for most of anthropogenic pollutants. The Zayandeh Roud River is the most important river in the central Iranian Plateau, supplying water to a large population. In order to determine the potential occurrence and in vivo effects of Endocrine Disrupting Chemicals (EDCs) with estrogenic or anti-androgenic properties we analyzed the wild populations of an extensively distributed endemic fish species, Petroleuciscus esfahani. For this purpose, specimens were caught from two sites upstream and two sites downstream of the expected major anthropogenic pollution sources. P. esfahani full-length cDNAs for vitellogenin (vtg), with 4177 base pairs (bp) encoding a 1339 amino acids (aa), and for beta-actin (actb), with 1776 bp encoding a 375 aa, were amplified and cloned. Hepatic vtg mRNA expression levels were measured by quantitative real-time PCR. Condition factor, gonadosomatic index and sex ratio were calculated and compared with vtg expression. Gonad histology was performed to study the possible presence of intersex condition. Detection of vtg transcripts in male individuals from the two downstream sampling sites supports the hypothesis of exposure to EDCs in these regions. Higher vtg expression in male individuals, together with reduced gonad size and condition factor, in specimens from the site located downstream of the major steel mill plant suggest a major endocrine disruption in this area. PMID- 26479454 TI - Three-Dimensional Printing of Hollow-Struts-Packed Bioceramic Scaffolds for Bone Regeneration. AB - Three-dimensional printing technologies have shown distinct advantages to create porous scaffolds with designed macropores for application in bone tissue engineering. However, until now, 3D-printed bioceramic scaffolds only possessing a single type of macropore have been reported. Generally, those scaffolds with a single type of macropore have relatively low porosity and pore surfaces, limited delivery of oxygen and nutrition to surviving cells, and new bone tissue formation in the center of the scaffolds. Therefore, in this work, we present a useful and facile method for preparing hollow-struts-packed (HSP) bioceramic scaffolds with designed macropores and multioriented hollow channels via a modified coaxial 3D printing strategy. The prepared HSP scaffolds combined high porosity and surface area with impressive mechanical strength. The unique hollow struts structures of bioceramic scaffolds significantly improved cell attachment and proliferation and further promoted formation of new bone tissue in the center of the scaffolds, indicating that HSP ceramic scaffolds can be used for regeneration of large bone defects. In addition, the strategy can be used to prepare other HSP ceramic scaffolds, indicating a universal application for tissue engineering, mechanical engineering, catalysis, and environmental materials. PMID- 26479455 TI - Estimating the Prevalence of Heat-Related Symptoms and Sun Safety-Related Behavior among Latino Farmworkers in Eastern North Carolina. AB - In hot weather, thermal heat generated by the body, combined with environmental heat from the sun, can lead outdoor workers to experience heat-related stress, severe illness, or even death. The aims of this study were to estimate the prevalence of heat-related symptoms and potential risk factors associated with sun safety-related behavior among Latino farmworkers. Data from interviewer administered questionnaires were collected from a cross-sectional survey among farmworkers (N = 158) from August to September 2013. Data analysis assessed associations between work activities, sun safety behavior, and the prevalence of heat-related illness (HRI) symptoms among workers. Nearly two thirds (72%) of farmworkers experienced at least one HRI symptom and lacked proper cooling methods when working outdoors. Most workers reported wearing long-sleeved shirts (85%), long pants (98%), and baseball caps (93%). The prevalence of having one HRI symptom was 72% and 27% among workers having three or more HRI symptoms. The majority of farmworkers experience symptoms of HRI and are not provided with proper shade protection when working outdoors. Increased emphasis on administrative controls, particularly educating field supervisors and workers on how to avoid and recognize HRI, should be a priority. PMID- 26479456 TI - Evaluating pictogram prediction in a location-aware augmentative and alternative communication system. AB - This study compared the performance of two statistical location-aware pictogram prediction mechanisms, with an all-purpose (All) pictogram prediction mechanism, having no location knowledge. The All approach had a unique language model under all locations. One of the location-aware alternatives, the location-specific (Spec) approach, made use of specific language models for pictogram prediction in each location of interest. The other location-aware approach resulted from combining the Spec and the All approaches, and was designated the mixed approach (Mix). In this approach, the language models acquired knowledge from all locations, but a higher relevance was assigned to the vocabulary from the associated location. Results from simulations showed that the Mix and Spec approaches could only outperform the baseline in a statistically significant way if pictogram users reuse more than 50% and 75% of their sentences, respectively. Under low sentence reuse conditions there were no statistically significant differences between the location-aware approaches and the All approach. Under these conditions, the Mix approach performed better than the Spec approach in a statistically significant way. PMID- 26479457 TI - Binding of Short Cationic Peptides (KX)4K to Negatively Charged DPPG Monolayers: Competition between Electrostatic and Hydrophobic Interactions. AB - The influence of the peptide sequence on the binding of short cationic peptides composed of five lysines alternating with uncharged amino acids within the series (KX)4K to negatively charged monolayers of 1,2-dipalmitoyl-sn-glycero-3 phosphoglycerol (DPPG) was investigated by adsorption experiments in combination with epifluorescence microscopy. To evaluate the impact of electrostatic and hydrophobic contributions, different uncharged amino acids X with increasing hydrophobicity, where X = G (glycine), A (alanine), Abu (alpha-aminobutyric acid), V (valine), or L (leucine) were introduced into the peptide sequence to tune the peptide hydrophobicity. The adsorption kinetics of these peptides to a DPPG monolayer always showed two superimposed processes, one leading to an increase and another to a decrease of the surface pressure Pi. Thus, the plots of the change in Pi after peptide binding vs initial surface pressure of the monolayer showed an unusual behavior with maxima and negative changes in Pi at high initial Pi values. Epifluorescence microscopy confirmed that electrostatic binding of the peptides with a concomitant decrease in Pi leads to a condensation of the lipid monolayer and the formation of liquid-condensed (LC) domains even at Pi values where the monolayer is supposedly in the liquid-expanded (LE) state. An increase in hydrophobicity of the amino acid X was found to counteract the condensation and an increase in Pi upon peptide binding is observed at low Pi values, also concomitant with the formation of LC-domains. Compression of monolayers after peptide adsorption at low surface pressure for 4 h leads to a change of the isotherms compared to pure DPPG isotherms. The phase transition of DPPG from LE to LC state is smeared out or is shifted to higher surface pressure. Considerable changes in the shapes of LC-domains were observed after peptide binding. Growth of the LC-domains was hindered in most cases and regular domain patterns were formed. Binding of (KL)4K leads to a decrease in line tension and the formation of extended filaments protruding from initially circular domains. PMID- 26479458 TI - Pesticide Exposures and Body Mass Index (BMI) of Pesticide Applicators From the Agricultural Health Study. AB - Endocrine-disrupting chemicals, including pesticides, may be associated with weight gain. This is the first longitudinal study to examine a potential association between weight gain and pesticides using data on 8,365 male pesticide applicators from the Agricultural Health Study (AHS) cohort established in 1993. The relationship between total cumulative days of exposure to pesticide functional/chemical classes and to the four most frequently used individual pesticides was studied in relation to body mass index (BMI) at the time of 5-yr follow-up (beginning in 1998) with the length of the exposure period dating back to age 20 yr. Multiple regression, Spearman correlation, ordinal logistic regression, and logistic regression models all utilized a Bonferroni-adjusted p value, were adjusted for relevant covariates, and were stratified by state of residence (Iowa/North Carolina) and presence/absence of weight-related health conditions. Adjusted multiple regression yielded statistically significant positive parameter estimates for the study sample and Iowa subgroups with consistent findings for triazine herbicides and atrazine: Change in BMI per 100 cumulative pesticide exposure days ranged from 0.07 to 0.11 for triazine herbicides and from 0.10 to 0.19 for atrazine. Ordinal logistic regression compared normal weight with overweight and with obese using the zero exposure category as referent. Statistically significant adjusted odds ratios identified for the study sample and both state subgroups for the highest level of atrazine exposure ranged from 1.4 to 1.7. Further investigation is warranted to evaluate the associations identified here. PMID- 26479459 TI - Bifunctional Nitrogen-Doped Microporous Carbon Microspheres Derived from Poly(o methylaniline) for Oxygen Reduction and Supercapacitors. AB - Heteroatom-doped carbon materials have attracted significant attention because of their applications in oxygen reduction reaction (ORR) and supercapacitors. Here we demonstrate a facile poly(o-methylaniline)-derived fabrication of bifunctional microporous nitrogen-doped carbon microspheres (NCMSs) with high electrocatalytic activity and stability for ORR and energy storage in supercapacitors. At a pyrolysis temperature of 900 degrees C, the highly dispersed NCMSs present a high surface area (727.1 m(2) g(-1)), proper total content of doping N, and high concentration of quaternary N, which exhibit superior electrocatalytic activities for ORR to the commercial Pt/C catalysts, high specific capacitance (414 F g( 1)), and excellent durability, making them very promising for advanced energy conversion and storage. The presented conducting polymer-derived strategy may provide a new way for the fabrication of heteroatom-doped carbon materials for energy device applications. PMID- 26479460 TI - Letrozole versus clomiphene citrate in polycystic ovary syndrome: systematic review and meta-analysis. AB - The objective of the present systematic review and meta-analysis was to examine the literature and to identify the results of randomized controlled trials (RCTs) comparing the use of letrozole to clomiphene citrate (CC) for ovulation induction in patients with polycystic ovary syndrome (PCOS). An exhaustive electronic literature search was performed using the MEDLINE and EMBASE databases until October 2014. Seven prospective RCTs comparing the use of letrozole to CC in PCOS patients met the inclusion criteria. Overall, the seven included studies accounted for 1833 patients (906 in the letrozole group and 927 in the CC group) and for 4999 ovulation induction cycles (2455 in the letrozole group and 2544 in the CC group). Five of the included studies reported data on live birth rates. There was a statistically significant increase in the live birth and pregnancy rates in the letrozole group when compared to the CC group, with a relative risk (RR) = 1.55 (95% confidence interval (CI): 1.26-1.90; I(2) = 0%) and RR = 1.38 (95% CI: 1.05-1.83; I(2) = 61%), respectively. There were no differences in the multiple pregnancy, miscarriage and ovulation rates between the two groups. Our study found that letrozole is superior to CC when considering the live birth and pregnancy rates in patients with PCOS. PMID- 26479461 TI - Predictive value of hyperthermia and intracranial hypertension on neurological outcomes in patients with severe traumatic brain injury. AB - BACKGROUND: Intracranial hypertension (ICH) and hyperthermia are common after traumatic brain injury (TBI) and associated with worse neurological outcomes. This study sets out to determine the combined power of temperature and intracranial pressure (ICP) for predicting neurologic outcomes and prolonged length of stay (LOS) following severe TBI. METHODS: High resolution (every 6 seconds) temperature and ICP data were collected in adults with severe TBI from 2008-2010. Temperatures were plotted against concurrent ICP and divided based on breakpoints (Temperature: <36, 36-38.5 or >38.5 degrees C, ICP: <20, 20-30 or >30 mmHg). The percentage of time spent in each section, as well as several pooled unfavourable conditions (hyperthermia +/- ICH), were then evaluated for predictive value for ICU-LOS > 7 days and short-term (<6 months) vs. long-term (>6 months) dichotomized neurologic outcomes. RESULTS: Fifty patients were included for analysis with severe TBI. Evaluation of the area under the operating receiver curve (AUC) showed significant periods of fever and high ICP (<30 mmHg) had a strong association with poor long-term neurological outcomes (Day 3, AUC = 0.71, p = 0.04) and were higher than either condition alone. ICU-LOS > 7 days was increased when hyperthermia and/or ICH remained uncontrolled by Day 5 (AUC = 0.82, p = 0.02). SUMMARY: Hyperthermia combined with ICH were shown to be significant prognostic indicators of future poor neurologic outcomes in patients with severe traumatic brain injury. PMID- 26479462 TI - Structure-Correlation NMR Spectroscopy for Macromolecules Using Repeated Bidirectional Photoisomerization of Azobenzene. AB - Control over macromolecular structure offers bright potentials for manipulation of macromolecular functions. We here present structure-correlation NMR spectroscopy to analyze the correlation between polymorphic macromolecular structures driven by photoisomerization of azobenzene. The structural conversion of azobenzene was induced within the mixing time of a NOESY experiment using a colored light source, and the reverse structural conversion was induced during the relaxation delay using a light source of another color. The correlation spectrum between trans- and cis-azobenzene was then obtained. To maximize the efficiency of the bidirectional photoisomerization of azobenzene-containing macromolecules, we developed a novel light-irradiation NMR sample tube and method for irradiating target molecules in an NMR radio frequency (rf) coil. When this sample tube was used for photoisomerization of an azobenzene derivative at a concentration of 0.2 mM, data collection with reasonable sensitivity applicable to macromolecules was achieved. We performed isomerization of an azobenzene-cross linked peptide within the mixing time of a NOESY experiment that produced cross peaks between helix and random-coil forms of the peptide. Thus, these results indicate that macromolecular structure manipulation can be incorporated into an NMR pulse sequence using an azobenzene derivative and irradiation with light of two types of wavelengths, providing a new method for structural analysis of metastable states of macromolecules. PMID- 26479463 TI - Pulmonary Hypertension After Heart Transplantation in Patients Bridged with the Total Artificial Heart. AB - Pulmonary hypertension (PH) among heart transplant recipients is associated with an increased risk of mortality. Pulmonary hemodynamics improves after left ventricular assist device (LVAD) implantation; however, the impact of PH before total artificial heart (TAH) implantation on posttransplant hemodynamics and survival is unknown. This is a single center retrospective study aimed to evaluate the impact of TAH implantation on posttransplant hemodynamics and mortality in two groups stratified according to severity of PH: high (>=3 Woods units [WU]) and low (<3 WU) baseline pulmonary vascular resistance (PVR). Hemodynamic data were obtained from right heart catheterization performed at baseline (before TAH) and posttransplant at 1 and 12 months. Patients in the high PVR group (n = 12) experienced improvement in PVR (baseline = 4.31 +/- 0.7; 1 month = 1.69 +/- 0.7, p < 0.001; 12-month = 48 +/- 0.9, p < 0.001) and transpulmonary gradient (baseline = 15.8 +/- 3.3; 1-month = 11.57 +/- 5.0, p = 0.07; 12-month = 8.50 +/- 4.0, p = 0.008) after transplantation, reaching similar values as the low PVR group at 12 months. The filling pressures improved in the high PVR group after heart transplantation (HT), but remained elevated. There was no significant difference in survival between the two groups at 12 months follow up. Patients with high PVR who are bridged to transplant with TAH had improvement in PVR at 12 months after transplant, and the degree of PVR did not impact posttransplant survival. PMID- 26479464 TI - Incidence, Management, and Outcome of Suspected Continuous-Flow Left Ventricular Assist Device Thrombosis. AB - Left ventricular assist device (LVAD) thrombosis is associated with high morbidity and mortality because of device malfunction, embolic events, and hemolysis. There remains uncertainty as to whether immediate device exchange versus an initial trial of anticoagulant and antiplatelet therapy is most appropriate in hemodynamically stable patients. We conducted a retrospective analysis of all LVAD implantations at a single center between January 2009 and June 2013 with follow-up through December 2013. Suspected LVAD thrombosis occurred in 20% of patients (N = 25) over a median follow-up of 275 days. Medical therapy led to resolution of hemolysis, and discharge to home, in 15 of 25 (60%) cases; however, this strategy was associated with intracranial hemorrhage in 4 patients and readmission with recurrent thrombosis in 10 patients. The 30 day, 6 month, and 1 year freedom from suspected LVAD thrombosis was 96.5, 85.9, and 80.3% in HeartMate II devices and 100, 92.9, and 87.1% in HeartWare ventricular assist devices, respectively (p = 0.11). Although medical treatment with intravenous heparin, antiplatelet agents, antithrombotic agents, or thrombolytic therapy can lead to initial resolution of hemolysis, the risks of recurrence after transition to warfarin and adverse events are high. PMID- 26479465 TI - Surgical Considerations and Challenges for Bilateral Continuous-Flow Durable Device Implantation. AB - The concept of biventricular support with durable centrifugal pumps is evolving, and the surgical strategy and best practice guidelines for implantation of right sided devices are still unknown. We present optimal strategy for bilateral HeartWare continuous-flow ventricular assist device (HVAD) implantation in a series of four patients. Patients were implanted with the HVAD pumps simultaneously or sequentially. This report offers a perspective on surgical considerations such as right ventricular positioning, implications related to potential risks of obstruction from the tricuspid apparatus, the role if any of downsizing the outflow anastomosis, and considerations for speed adjustments. In this series, one patient died on support and three patients experienced pump thrombosis requiring device revision. All other patients survived until orthotopic heart transplantation, although one of these patients died from perioperative complications, 2 days posttransplantation. Surgical management of patients with medically refractory biventricular heart failure remains challenging and associated with a high incidence of pump thrombosis. Best practice guidelines from experts' consensus are still needed to address this challenging population. PMID- 26479466 TI - Early Results of Novel Bovine Pericardial Patch Using Comprehensive Anticalcification Procedure in a Swine Model. AB - We evaluated the short-term safety and effectiveness of our comprehensive anticalcification procedure in swine model. Our comprehensive anticalcification procedure consisted of four steps, including decellularization with sodium dodecyl sulfate and tritonX-100, space filler treatment with polyethylene glycol (PEG), glutaraldehyde cross-linking with organic solvent, and detoxification with glycine. We simultaneously implanted both the commercially available bovine pericardial patch (Supple Peri-Guard) and novel bovine pericardial patch processed by the comprehensive anticalcification procedure into the main pulmonary artery in seven pigs. Every pig underwent a cardiac angiography and was killed on the postoperative day 28. The extracted patches were stained with hematoxylin and eosin. All pigs survived for 4 weeks without any complication. Cardiac angiography showed the absence of leakage and structural problem. Neointimas were formed evenly without intimal hyperplasia. There were no significant differences in the degree of inflammation, necrosis, and calcification between the novel and commercially available patch (p = 0.450, p = 0.317, p = 0.999). Novel bovine pericardial patch using comprehensive anticalcification procedure was similar to existing cardiovascular patch in early surgical results in a swine model. The comprehensive anticalcification procedure could facilitate appropriate bioprosthetic properties of the bovine pericardium. PMID- 26479467 TI - Accuracy of the HVAD Pump Flow Estimation Algorithm. AB - Controller algorithms are an important feature for assessment of ventricular assist device performance. Flow estimation is one algorithm implemented in the HeartWare continuous-flow ventricular assist device pump system. This parameter estimates flow passing through the pump and is calculated using speed, current, and hematocrit. In vitro and in vivo studies were conducted to assess the algorithm accuracy. During in vitro testing, three pumps were tested in four water-glycerol solutions at 37 degrees C with viscosities equivalent to hematocrits of 20, 30, 40, and 50%. By using a linear regression model, a correlation coefficient of >0.94 was observed between measured and estimated flow for all conditions. In vivo studies (n = 9) were conducted in an ovine model where a reference flow probe was placed on the outflow graft and speed was adjusted from 1,800 to 4,000 revolutions per minute. During in vivo experiments, estimated pump flow (mean, minimum, and maximum) was compared with measured pump flow. The best-fit linear regression equation for the data is y = 0.96x + 0.54, r = 0.92. In addition, waveform fidelity was high (r > 0.96) in normal (i.e., nonsuction) cases where flow pulsatility was >2 L/min. The flow estimation algorithm demonstrated strong agreement with measured flow, both when analyzing average waveform magnitude and fidelity. PMID- 26479469 TI - Neural dynamics during repetitive visual stimulation. AB - OBJECTIVE: Steady-state visual evoked potentials (SSVEPs), the brain responses to repetitive visual stimulation (RVS), are widely utilized in neuroscience. Their high signal-to-noise ratio and ability to entrain oscillatory brain activity are beneficial for their applications in brain-computer interfaces, investigation of neural processes underlying brain rhythmic activity (steady-state topography) and probing the causal role of brain rhythms in cognition and emotion. This paper aims at analyzing the space and time EEG dynamics in response to RVS at the frequency of stimulation and ongoing rhythms in the delta, theta, alpha, beta, and gamma bands. APPROACH: We used electroencephalography (EEG) to study the oscillatory brain dynamics during RVS at 10 frequencies in the gamma band (40-60 Hz). We collected an extensive EEG data set from 32 participants and analyzed the RVS evoked and induced responses in the time-frequency domain. MAIN RESULTS: Stable SSVEP over parieto-occipital sites was observed at each of the fundamental frequencies and their harmonics and sub-harmonics. Both the strength and the spatial propagation of the SSVEP response seem sensitive to stimulus frequency. The SSVEP was more localized around the parieto-occipital sites for higher frequencies (>54 Hz) and spread to fronto-central locations for lower frequencies. We observed a strong negative correlation between stimulation frequency and relative power change at that frequency, the first harmonic and the sub-harmonic components over occipital sites. Interestingly, over parietal sites for sub-harmonics a positive correlation of relative power change and stimulation frequency was found. A number of distinct patterns in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz) and beta (15-30 Hz) bands were also observed. The transient response, from 0 to about 300 ms after stimulation onset, was accompanied by increase in delta and theta power over fronto-central and occipital sites, which returned to baseline after approx. 500 ms. During the steady-state response, we observed alpha band desynchronization over occipital sites and after 500 ms also over frontal sites, while neighboring areas synchronized. The power in beta band over occipital sites increased during the stimulation period, possibly caused by increase in power at sub-harmonic frequencies of stimulation. Gamma power was also enhanced by the stimulation. SIGNIFICANCE: These findings have direct implications on the use of RVS and SSVEPs for neural process investigation through steady-state topography, controlled entrainment of brain oscillations and BCIs. A deep understanding of SSVEP propagation in time and space and the link with ongoing brain rhythms is crucial for optimizing the typical SSVEP applications for studying, assisting, or augmenting human cognitive and sensorimotor function. PMID- 26479468 TI - The relationship between exposure to brand-specific alcohol advertising and brand specific consumption among underage drinkers--United States, 2011-2012. AB - BACKGROUND: Marketing is increasingly recognized as a potentially important contributor to youth drinking, yet few studies have examined the relationship between advertising exposure and alcohol consumption among underage youth at the brand level. OBJECTIVES: To examine the relationship between brand-specific exposure to alcohol advertising among underage youth and the consumption prevalence of each brand in a national sample of underage drinkers. METHODS: We analyzed the relationship between population-level exposure of underage youth ages 12-20 to brand-specific alcohol advertising in national magazines and television programs and the 30-day consumption prevalence--by brand--among a national sample of underage drinkers ages 13-20. Underage youth exposure to alcohol advertising by brand for each month in 2011, measured in gross rating points (GRPs, a standard measure of advertising exposure), was obtained from GfK MRI (a media consumer research company) and Nielsen for all measured national issues of magazines and all national television programs, respectively. The 30 day consumption prevalence for each brand was obtained from a national survey of 1031 underage drinkers conducted between December 2011 and May 2012. RESULTS: Underage youth were more than five times more likely to consume brands that advertise on national television and 36% more likely to consume brands that advertise in national magazines. The consumption prevalence of a brand increased by 36% for each 1.5 standard deviation (50 GRPs) increase in television adstock among underage youth and by 23% for each 1.5 standard deviation (10 GRPs) increase in magazine adstock. CONCLUSION: These findings suggest that alcohol advertising influences an important aspect of drinking behavior--brand choice- among youth who consume alcohol. PMID- 26479471 TI - Journal Club: Surgical Management of Trigeminal Neuralgia: Use and Cost Effectiveness From an Analysis of the Medicare Claims Database. PMID- 26479470 TI - CXCL4 mediates tumor regrowth after chemotherapy by suppression of antitumor immunity. AB - The recurrence of colorectal cancer after chemotherapy is the leading cause of its high mortality. We propose that elucidating the mechanisms of tumor regrowth after chemotherapy in tumor-bearing mice may provide new insights into tumor relapse in cancer patients. We firstly report the identification of a chemokine, CXCL4, that plays an important role in the molecular mechanism of cancer regrowth after chemotherapy. A syngenic transplantation tumor model was established with murine colon cancer CT26 cells and treated with 5-FU. Genome-wide gene expression analysis determined that CXCL4 was transiently upregulated in the tumor model. Systemic overexpression of CXCL4 accelerated cancer growth in vivo, but not in vitro. Conversely, the anti-CXCL4 monoclonal antibody (CXCL4-mab) retarded tumor regrowth after 5-FU treatment in immune-competent mice, but not nude mice. The CXCL4-mab treatment increased the local expression levels of IFN-gamma and Gran-b genes in the tumor-bed, and elevated the function of CTLs against CT26 cells. Thus, the colon cancer cells in responding to the cytotoxic stress of 5-FU produce a high level of CXCL4, which suppresses antitumor immunity to confer the residual cancer cells an advantage for regrowth after chemotherapy. Our findings provide a novel target for developing therapeutics aiming to increase antitumor immunity after chemotherapy. PMID- 26479472 TI - Response to Journal Club: Surgical Management of Trigeminal Neuralgia: Use and Cost-Effectiveness From an Analysis of the Medicare Claims Database. PMID- 26479475 TI - Probing viscoelastic response of soft material surfaces at the nanoscale. AB - We study the interaction between an AFM tip and a soft viscoelastic surface. Using a multifrequency method we measure the amplitude-dependence of the cantilever dynamic force quadratures, which clearly show the effect of finite relaxation time of the viscoelastic surface. A model is introduced which treats the tip and surface as a two-body dynamic problem with a nonlinear interaction depending on their separation. We find good agreement between simulations of this model and experimental data on polymer blend samples for a variety of materials and measurement conditions. PMID- 26479476 TI - Facility Delivery, Postnatal Care and Neonatal Deaths in India: Nationally Representative Case-Control Studies. AB - OBJECTIVE: Clinical studies demonstrate the efficacy of interventions to reduce neonatal deaths, but there are fewer studies of their real-life effectiveness. In India, women often seek facility delivery after complications arise, rather than to avoid complications. Our objective was to quantify the association of facility delivery and postnatal checkups with neonatal mortality while examining the "reverse causality" in which the mothers deliver at a health facility due to adverse perinatal events. METHODS: We conducted nationally representative case control studies of about 300,000 live births and 4,000 neonatal deaths to examine the effect of, place of delivery and postnatal checkup on neonatal mortality. We compared neonatal deaths to all live births and to a subset of live births reporting excessive bleeding or obstructed labour that were more comparable to cases in seeking care. FINDINGS: In the larger study of 2004-8 births, facility delivery without postnatal checkup was associated with an increased odds of neonatal death (Odds ratio = 2.5; 99% CI 2.2-2.9), especially for early versus late neonatal deaths. However, use of more comparable controls showed marked attenuation (Odds ratio = 0.5; 0.4-0.5). Facility delivery with postnatal checkup was associated with reduced odds of neonatal death. Excess risks were attenuated in the earlier study of 2001-4 births. CONCLUSION: The combined effect of facility deliveries with postnatal checks ups is substantially higher than just facility delivery alone. Evaluation of the real-life effectiveness of interventions to reduce child and maternal deaths need to consider reverse causality. If these associations are causal, facility delivery with postnatal check up could avoid about 1/3 of all neonatal deaths in India (~100,000/year). PMID- 26479477 TI - On-FarmWelfare Assessment Protocol for Adult Dairy Goats in Intensive Production Systems. AB - Within the European AWIN project, a protocol for assessing dairy goats' welfareon the farm was developed. Starting from a literature review, a prototype includinganimal-based indicators covering four welfare principles and 12 welfare criteria was set up.The prototype was tested in 60 farms for validity, reliability, and feasibility. After testing theprototype, a two-level assessment protocol was proposed in order to increase acceptabilityamong stakeholders. The first level offers a more general overview of the welfare status,based on group assessment of a few indicators (e.g., hair coat condition, latency to thefirst contact test, severe lameness, Qualitative Behavior Assessment), with no or minimalhandling of goats and short assessment time required. The second level starts if welfareAnimals 2015, 5 935problems are encountered in the first level and adds a comprehensive and detailed individualevaluation (e.g., Body Condition Score, udder asymmetry, overgrown claws), supported byan effective sampling strategy. The assessment can be carried out using the AWIN Goatapp. The app results in a clear visual output, which provides positive feedback on welfareconditions in comparison with a benchmark of a reference population. The protocol maybe a valuable tool for both veterinarians and technicians and a self assessment instrumentfor farmers. PMID- 26479478 TI - A Cross-Sectional Study of Horse-Related Injuries in Veterinary and Animal Science Students at an Australian University. AB - Specific estimates of the risk of horse-related injury (HRI) to university students enrolled in veterinary and animal sciences have not been reported. This study aimed to determine the risk of student HRI during their university education, the nature and management of such injuries. A retrospective questionnaire solicited demographic information, data on students' equine experience prior to and during their educational programs, and on HRI during their program of study. Of 260 respondents, 22 (8.5%) reported HRI (27 incidents). Including concurrent injuries the most commonly injured body parts were the foot or ankle (nine of 32 injures), the upper leg or knee (eight of 32), and hands (three of 32). Trampling and being kicked by a hind limb were each associated with 30.4% of HRI, and 13% with being bitten. Bruising (91.3% of respondents) and an open wound (17.4%) were most commonly described. No treatment occurred for 60.9% of incidents; professional medical treatment was not sought for the remainder. Most incidents (56.5%) occurred during program-related work experience placements. Although injury rates and severity were modest, a proactive approach to injury prevention and reporting is recommended for students required to handle horses as part of their education. Student accident and injury data should be monitored to ensure effective evaluation of risk-reduction initiatives. The risk and nature of university student horse-related injury (HRI) was studied. Of 260 students, 22 (8.5%) reported HRI (27 incidents). Including multiple injuries, reports described involvement of the foot or ankle (nine of 32 injures), upper leg or knee (eight of 32), and hands (three of 32). Trampling (30.4%) and being kicked (30.4%) accounted for most HRI. The injuries were usually bruising (91.3%) or an open wound (17.4%). Most (60.9%) injuries were untreated; professional medical treatment was not sought for the rest. Most incidents (56.5%) occurred during program-related off-campus work experiences. A proactive approach to injury prevention is recommended for students handling horses. PMID- 26479479 TI - Reducing Respiratory Health Risks to Horses and Workers: A Comparison of Two Stall Bedding Materials. AB - Stable air quality and the choice of bedding material are an important health issue both in horses and people working or visiting horse stables. Risks of impaired respiratory health are those that can especially be avoided by improving air quality in the stable. The choice of bedding material is particularly important in cold climate conditions; where horses are kept most of the day and year indoors throughout their life. This study examined the effect of two bedding materials; wood shavings and peat; on stable air quality and health of horses. Ammonia and dust levels were also measured to assess conditions in the stable. Ammonia was not detected or was at very low levels (<0.25 ppm) in the boxes in which peat was used as bedding; but its concentration was clearly higher (1.5-7.0 ppm) in stalls with wood shavings as bedding. Personal measurements of workers revealed quite high ammonia exposure (5.9 ppm8h) in the boxes in which wood shavings were used; but no exposure was Animals 2015, 5 966 observed in stalls bedded with peat. The respiratory symptoms in horses increased regardless of the bedding material at the beginning of the study. The health status of the horses in the peat bedding group returned to the initial level in the end of the trial but horses bedded with wood shavings continued to be symptomatic. The hooves of the horses with peat bedding had a better moisture content than those of the horses bedded with wood shavings. The results suggest that peat is a better bedding material for horses than wood shavings regarding the health of both horses and stable workers. PMID- 26479481 TI - Metabolic Profile and Inflammatory Responses in Dairy Cows with Left Displaced Abomasum Kept under Small-Scaled Farm Conditions. AB - Left displaced abomasum (LDA) is a severe metabolic disease of cattle with a strong negative impact on production efficiency of dairy farms. Metabolic and inflammatory alterations associated with this disease have been reported in earlier studies, conducted mostly in large dairy farms. This research aimed to: (1) evaluate metabolic and inflammatory responses in dairy cows affected by LDA in small-scaled dairy farms; and (2) establish an Animals 2015, 5 1022 association between lactation number and milk production with the outcome of metabolic variables. The cows with LDA had lower serum calcium (Ca), but greater concentrations of non-esterified fatty acids (NEFA) and beta-hydroxy-butyrate (BHBA), in particular when lactation number was >2. Cows with LDA showed elevated levels of aspartate aminotransferase, glutamate dehydrogenase, and serum amyloid A (SAA), regardless of lactation number. In addition, this study revealed strong associations between milk yield and the alteration of metabolic profile but not with inflammation in the sick cows. Results indicate metabolic alterations, liver damage, and inflammation in LDA cows kept under small-scale farm conditions. Furthermore, the data suggest exacerbation of metabolic profile and Ca metabolism but not of inflammation and liver health with increasing lactation number and milk yield in cows affected by LDA. PMID- 26479480 TI - Metabolic Disorders in the Transition Period Indicate that the Dairy Cows' Ability to Adapt is Overstressed. AB - Metabolic disorders are a key problem in the transition period of dairy cows and often appear before the onset of further health problems. They mainly derive from difficulties the animals have in adapting to changes and disturbances occurring both outside and inside the organisms and due to varying gaps between nutrient supply and demand. Adaptation is a functional and target-oriented process involving the whole organism and thus cannot be narrowed down to single factors. Most problems which challenge the organisms can be solved in a number of different ways. To understand the mechanisms of adaptation, the interconnectedness of variables and the nutrient flow within a metabolic network need to be considered. Metabolic disorders indicate an overstressed ability to balance input, partitioning and output variables. Dairy cows will more easily succeed in adapting and in avoiding dysfunctional processes in the transition period when the gap between nutrient and energy demands and their supply is restricted. Dairy farms vary widely in relation to the living conditions of the animals. The complexity of nutritional and metabolic processes Animals 2015, 5 979 and their large variations on various scales contradict any attempts to predict the outcome of animals' adaptation in a farm specific situation. Any attempts to reduce the prevalence of metabolic disorders and associated production diseases should rely on continuous and comprehensive monitoring with appropriate indicators on the farm level. Furthermore, low levels of disorders and diseases should be seen as a further significant goal which carries weight in addition to productivity goals. In the long run, low disease levels can only be expected when farmers realize that they can gain a competitive advantage over competitors with higher levels of disease. PMID- 26479482 TI - Predator Bounties in Western Canada Cause Animal Suffering and CompromiseWildlife Conservation Efforts. AB - Although predation bounty programs (rewards offered for capturing or killing an animal) ended more than 40 years ago in Canada, they were reintroduced in Alberta in 2007 by hunting, trapping, and farming organizations, municipalities and counties, and in 2009 in Saskatchewan, by municipal and provincial governments and the Saskatchewan Cattlemen's Association. Bounty hunters use inhumane and non selective killing methods such as shooting animals in non-vital regions, and killing neck snares and strychnine poisoning, which cause suffering and delayed deaths. They are unselective, and kill many non-target species, some of them at risk. Predator bounty programs have been found to be ineffective by wildlife professionals, and they use killing methods that cause needless suffering and jeopardize wildlife conservation programs. Our analysis therefore indicates that government agencies should not permit the implementation of bounty programs. Accordingly, they must develop conservation programs that will minimize wildlife human conflicts, prevent the unnecessary and inhumane killing of animals, and ensure the persistence of all wildlife species. PMID- 26479483 TI - How Can We Prevent School Avoidance and Behavior Problems in Preschool Children? PMID- 26479484 TI - Preventing Behavioral Disorders via Supporting Social and Emotional Competence at Preschool Age. AB - BACKGROUND: 13-18% of all preschool children have severe behavioral problems at least transiently, sometimes with long-term adverse consequences. In this study, the social training program "Lubo aus dem All! - Vorschulalter" (Lubo from Outer Space, Preschool Version) was evaluated in a kindergarten setting. METHODS: 15 kindergartens were randomly assigned to either an intervention group or a control group, in a 2:1 ratio. The intervention was designed to strengthen emotional knowledge and regulation, the ability to take another person's point of view, communication skills, and social problem solving. The control group continued with conventional kindergarten activities. The primary endpoint was improvement in social-cognitive problem solving strategies, as assessed with the Wally Social Skills and Problem Solving Game (Wally). Secondary endpoints were improvement in prosocial behavior and reduction in problematic behavior, as assessed with the Preschool Social Behavior Questionnaire (PSBQ) and the Caregiver-Teacher Report Form (C-TRF). Data were collected before and after the intervention and also 5 months later. Mixed models were calculated with random effects to take account of the cluster design and for adjustment for confounding variables. RESULTS: 221 children in kindergarten, aged 5-6 years, were included in the study. Randomization was unsuccessful: the children in the intervention group performed markedly worse on the tests carried out before the intervention. Five months after the end of the intervention, the social-cognitive problem solving strategies of the children in the intervention group had improved more than those of the children in the control group: the intergroup difference in improvement was 0.79 standard deviations of the Wally test (95% confidence interval [CI] 0.13 1.46). This effect was just as marked 5 months later (0.63, 95% CI 0.03-1.23). Prosocial behavior, as measured by the PSBQ, also improved more in the intervention group, with an intergroup difference of 0.37 standard deviations (95% CI 0.05-0.71). CONCLUSION: An age-appropriate program to prevent behavioral disorders among kindergarten children improved both the children's knowledge of prosocial problem solving strategies and their prosocial behavior. PMID- 26479485 TI - The Treatment of School Avoidance in Children and Adolescents With Psychiatric Illness. AB - BACKGROUND: 5-10% of schoolchildren in Germany are absent from school without an excuse more than five times per year. We investigate the effectiveness of manual based, multimodal cognitive behavioral therapy focusing on school-avoidant behavior and on the underlying mental disorders. METHODS: 112 school avoiders were recruited from an outpatient child and adolescent psychiatric clinic and adaptively randomized into two treatment groups. The first group received manual based multimodal treatment (MT), the second group treatment as usual (TAU) in the child and adolescent mental health care system. The primary outcome of the study was the percentage of classes attended in the five days prior to first measurement (before the intervention), as well as 6 and 12 months afterward. In each of these periods, school attendance was characterized as regular, partial, or none. Secondary outcomes were the severity of anxiety and depressive symptoms, self-efficacy, and quality of family life. RESULTS: In both treatment arms, the percentage of regular school attenders rose to about 60% in 6 months, regardless of the intervention (MT 60.6%, TAU 58.3%; odds ratio [OR] for changes over baseline 6.94, 95% confidence interval [CI] 3.98-12.12, p< 0.001; OR for MT versus TAU 1.05, 95% CI 0.58-1.90, p = 0.875). The improvement persisted 12 months after inclusion. CONCLUSION: In accordance with earlier studies, we found that manual-based multimodal treatment did not improve school avoidance to any greater extent than treatment as usual. Future studies should focus on the conditions for successful reintegration in school and on the differential indicators for outpatient versus inpatient treatment. PMID- 26479486 TI - Natural isotope correction of MS/MS measurements for metabolomics and (13)C fluxomics. AB - Fluxomics and metabolomics are crucial tools for metabolic engineering and biomedical analysis to determine the in vivo cellular state. Especially, the application of (13)C isotopes allows comprehensive insights into the functional operation of cellular metabolism. Compared to single MS, tandem mass spectrometry (MS/MS) provides more detailed and accurate measurements of the metabolite enrichment patterns (tandem mass isotopomers), increasing the accuracy of metabolite concentration measurements and metabolic flux estimation. MS-type data from isotope labeling experiments is biased by naturally occurring stable isotopes (C, H, N, O, etc.). In particular, GC-MS(/MS) requires derivatization for the usually non-volatile intracellular metabolites introducing additional natural isotopes leading to measurements that do not directly represent the carbon labeling distribution. To make full use of LC- and GC-MS/MS mass isotopomer measurements, the influence of natural isotopes has to be eliminated (corrected). Our correction approach is analyzed for the two most common applications; (13)C fluxomics and isotope dilution mass spectrometry (IDMS) based metabolomics. Natural isotopes can have an impact on the calculated flux distribution which strongly depends on the substrate labeling and the actual flux distribution. Second, we show that in IDMS based metabolomics natural isotopes lead to underestimated concentrations that can and should be corrected with a nonlinear calibration. Our simulations indicate that the correction for natural abundance in isotope based fluxomics and quantitative metabolomics is essential for correct data interpretation. PMID- 26479487 TI - Considering Eligibility for Studies of Deep Brain Stimulation for Treatment Resistant Depression: Insights From a Clinical Trial in Unipolar and Bipolar Depression. AB - BACKGROUND: While electroconvulsive therapy (ECT) is the most effective treatment for major depression (major depressive disorder [MDD]), deep brain stimulation (DBS) has shown efficacy in patients who have not received benefit from ECT. Studies of DBS are small, and a better understanding of which eligibility criteria lead to exclusion may help achieve a more appropriate balance between scientific rigor and generalizability in future trials. We assessed the rate and reasons for exclusion from a study of DBS for treatment-resistant MDD and bipolar type II (BPII) depression. METHODS: One thousand ninety-eight adults were screened for a study of DBS for MDD or BPII. Reasons for exclusion were documented. Descriptive statistics were calculated for each reason for exclusion for the entire sample as well as the self-reported MDD and BPII subgroups. RESULTS: Ninety-eight percent (98%) of patients screened were excluded. Exclusion due to lack of interest or inability to relocate to the study site was high (41%). Following this, primary reasons for exclusion were lack of prior ECT and presence of psychiatric/general medical comorbidity. Patients with MDD were more likely to be excluded because of inadequate ECT, whereas patients with BPII depression were more likely to be excluded for comorbid psychiatric diagnoses and not meeting minimum severity criteria. CONCLUSIONS: A surprisingly high number of potential participants were excluded because of lack of adequate ECT. This suggests that many patients self-identifying as "treatment resistant" have not truly exhausted available, evidence-based treatments. Overall exclusion rate was high, with key differences in exclusion reasons between the MDD and BPII subgroups. These findings can inform design of future clinical trials for treatment-resistant unipolar and bipolar depression.Clinicaltrials.gov Identifier: NCT00367003. PMID- 26479488 TI - The Efficacy of Electroconvulsive Therapy in a Perinatal Population: A Comparative Pilot Study. AB - OBJECTIVES: This study aims to investigate the effectiveness of electroconvulsive therapy (ECT) as a treatment for postnatal depression compared with a matched nonpostnatal population. A secondary aim is to compare the number of ECT treatments needed to treat in both groups. As the numbers in this study are small, this would act as a pilot study, allowing a power calculation to determine the numbers needed for a more definitive study. METHODS: Cases were identified from the local Scottish ECT Accreditation Network database. Twelve patients had received ECT and had complete data from all those admitted to the Glasgow Mother and Baby Unit since its opening. Each case was matched to 2 control subjects who had also received ECT and who were matched for age, sex, and severity of depressive symptoms. It was not possible to find 2 control subjects for each case, and 23 control subjects were allocated. Severity was matched using the Montgomery-Asberg Depression Rating Scale (MADRS), which is completed for all patients receiving ECT in Scotland, at the beginning and end of their course. As all control subjects were matched for initial severity of symptoms using MADRS, the change in MADRS score between both groups was compared. RESULTS: When comparing the mean change in MADRS scores between both groups, it was seen that the perinatal patients scores dropped by a mean of 10.09 points more than those of the control subjects (95% confidence interval for difference, -0.54 to 20.73, P = 0.062). No difference was seen between the groups when comparing the number of treatments (7.8 vs 8). CONCLUSIONS: Further research is required. PMID- 26479489 TI - Algal viruses hitchhiking on zooplankton across phytoplankton blooms. AB - Viruses infecting marine phytoplankton are key biogeochemical 'engines' of the oceans, regulating the dynamics of algal populations and the fate of their extensive blooms. In addition they are important ecological and evolutionary drivers of microbial diversification. Yet, little is known about mechanisms influencing viral dispersal in aquatic systems, enabling the rapid infection and demise of vast phytoplankton blooms. In a recent study we showed that migrating zooplankton as copepods that graze on marine phytoplankton can act as transmission vectors for algal viruses. We demonstrated that these grazers can concentrate virions through topical adsorption and by ingesting infected cells and then releasing back to the medium, via detachment or defecation, high viral titers that readily infect host populations. We proposed that this zooplankton driven process can potentially boost viral dispersal over wide oceanic scales and enhance bloom termination. Here, we highlight key results and further discuss the ecological and evolutionary consequences of our findings. PMID- 26479490 TI - Rapid Weight Loss Among Adolescents Participating In Competitive Judo. AB - Athletes competing in individual sports such as judo are categorized by weight. Before competitions, weight cutting is common. This cross-sectional study was designed to characterize and determine the prevalence of rapid weight loss (RWL) among adolescent judo competitors. Male athletes aged 12- to 17-years old (N = 108) were recruited from local judo teams. Each participant completed a validated questionnaire regarding RWL practices. Anthropometric measurements were also performed. Average age was 14.6 +/- 1.6 years and all participants were of normal body mass index (BMI). RWL was practiced by 80% of the athletes before competition, beginning at an average age of 12.5 +/- 2.2 years with the highest prevalence (~94%) in the oldest group of judoka (16-17.9 years). Precompetition weight loss duration was 8 +/- 5.4 days, with an average weight reduction of 1.5 +/- 1.1 kg. The number of weight loss efforts per athlete in the past season was 2.8 +/- 2.2. RWL was achieved by increased physical activity (82.6%), skipped meals (56.3%), or fasting at least once (47%). Two-thirds of the athletes indicated that their coaches were the most influential figure in their decision to lose weight before competition. RWL is highly prevalent in adolescent judo competitors. The methods used by these athletes can potentially lead to significant health risks including compromised nutritional status, diminished physical performance and impaired growth and development. It is of great importance to insure that those who guide young adults in weight loss for competitive sports have the knowledge and understanding to make safe recommendations and appropriate decisions regarding achieving specific weight goals. PMID- 26479491 TI - Entrapped Sediments as a Source of Phosphorus in Epilithic Cyanobacterial Proliferations in Low Nutrient Rivers. AB - Proliferations of the benthic mat-forming cyanobacteria Phormidium have been reported in rivers worldwide. Phormidium commonly produces natural toxins which pose a health risk to animal and humans. Recent field studies in New Zealand identified that sites with Phormidium proliferations consistently have low concentrations of water column dissolved reactive phosphorus (DRP). Unlike other river periphyton, Phormidium mats are thick and cohesive, with water and fine sediment trapped in a mucilaginous matrix. We hypothesized that daytime photosynthetic activity would elevate pH inside the mats, and/or night time respiration would reduce dissolved oxygen. Either condition could be sufficient to facilitate desorption of phosphates from sediment incorporated within mats, thus allowing Phormidium to utilize it for growth. Using microelectrodes, optodes and pulse amplitude modulation fluorometry we demonstrated that photosynthetic activity results in elevated pH (>9) during daytime, and that night-time respiration causes oxygen depletion (<4 mg L-1) within mats. Water trapped within the mucilaginous Phormidium mat matrix had on average 320-fold higher DRP concentrations than bulk river water and this, together with elevated concentrations of elements, including iron, suggest phosphorus release from entrapped sediment. Sequential extraction of phosphorus from trapped sediment was used to investigate the role of sediment at sites on the Mangatainoka River (New Zealand) with and without Phormidium proliferations. Deposition of fine sediment (<63 MUm) was significantly higher at the site with the most extensive proliferations and concentrations of biological available phosphorus were two- to four- fold higher. Collectively these results provide evidence that fine sediment can provide a source of phosphorus to support Phormidium growth and proliferation. PMID- 26479493 TI - Two-dimensional transition metal dichalcogenides as atomically thin semiconductors: opportunities and challenges. AB - The discovery of graphene has ignited intensive interest in two-dimensional layered materials (2DLMs). These 2DLMs represent a new class of nearly ideal 2D material systems for exploring fundamental chemistry and physics at the limit of single-atom thickness, and have the potential to open up totally new technological opportunities beyond the reach of existing materials. In general, there are a wide range of 2DLMs in which the atomic layers are weakly bonded together by van der Waals interactions and can be isolated into single or few layer nanosheets. The van der Waals interactions between neighboring atomic layers could allow much more flexible integration of distinct materials to nearly arbitrarily combine and control different properties at the atomic scale. The transition metal dichalcogenides (TMDs) (e.g., MoS2, WSe2) represent a large family of layered materials, many of which exhibit tunable band gaps that can undergo a transition from an indirect band gap in bulk crystals to a direct band gap in monolayer nanosheets. These 2D-TMDs have thus emerged as an exciting class of atomically thin semiconductors for a new generation of electronic and optoelectronic devices. Recent studies have shown exciting potential of these atomically thin semiconductors, including the demonstration of atomically thin transistors, a new design of vertical transistors, as well as new types of optoelectronic devices such as tunable photovoltaic devices and light emitting devices. In parallel, there have also been considerable efforts in developing diverse synthetic approaches for the rational growth of various forms of 2D materials with precisely controlled chemical composition, physical dimension, and heterostructure interface. Here we review the recent efforts, progress, opportunities and challenges in exploring the layered TMDs as a new class of atomically thin semiconductors. PMID- 26479492 TI - The Arabidopsis transcription factor NAI1 is required for enhancing the active histone mark but not for removing the repressive mark on PYK10, a seedling specific gene upon embryonic-to-postgerminative developmental phase transition. AB - We have recently shown that the expression onset of a seedling-specific gene, PYK10, occurs in a cell-by-cell manner upon the transition from the embryonic to the postgerminative phase and during embryogenesis in seed maturation regulator mutants such as lec1, and implicated epigenetic mechanisms in the process. Here, the role of the NAI1 transcription factor required for PYK10 expression in the developmental switching of PYK10 was investigated. The cell-by-cell onset of PYK10-EGFP in lec1 embryo was still observed in the nai1 background, but at greatly reduced levels. Decreases in the level of the repressive histone mark, H3K27 trimethylation observed upon the transition to the postgeminative phase normally occurred in nai1. However, concomitant increases in the level of the active mark, H3K4 trimethylation observed in wild type was significantly compromised in nai1. These results indicate that the switching of PYK10 upon developmental phase transition involves 2 separable steps of chromatin state change. PMID- 26479494 TI - Maintaining heterokaryosis in pseudo-homothallic fungi. AB - Among all the strategies displayed by fungi to reproduce and propagate, some species have adopted a peculiar behavior called pseudo-homothallism. Pseudo homothallic fungi are true heterothallics, i.e., they need 2 genetically compatible partners to mate, but they produce self-fertile mycelium in which the 2 different nuclei carrying the compatible mating types are present. This lifestyle not only enables the fungus to reproduce without finding a compatible partner, but also to cross with any mate it may encounter. However, to be fully functional, pseudo-homothallism requires maintaining heterokaryosis at every stage of the life cycle. We recently showed that neither the structure of the mating-type locus nor hybrid-enhancing effect due to the presence of the 2 mating types accounts for the maintenance of heterokaryosis in the pseudo-homothallic fungus P. anserina. In this addendum, we summarize the mechanisms creating heterokaryosis in P. anserina and 2 other well-known pseudo-homothallic fungi, Neurospora tetrasperma and Agaricus bisporus. We also discuss mechanisms potentially involved in maintaining heterokaryosis in these 3 species. PMID- 26479495 TI - Discrimination Power of Polynomial-Based Descriptors for Graphs by Using Functional Matrices. AB - In this paper, we study the discrimination power of graph measures that are based on graph-theoretical matrices. The paper generalizes the work of [M. Dehmer, M. Moosbrugger. Y. Shi, Encoding structural information uniquely with polynomial based descriptors by employing the Randic matrix, Applied Mathematics and Computation, 268(2015), 164-168]. We demonstrate that by using the new functional matrix approach, exhaustively generated graphs can be discriminated more uniquely than shown in the mentioned previous work. PMID- 26479496 TI - 3D Graphene-Infused Polyimide with Enhanced Electrothermal Performance for Long Term Flexible Space Applications. AB - Polyimides (PIs) have been praised for their high thermal stability, high modulus of elasticity and tensile strength, ease of fabrication, and moldability. They are currently the standard choice for both substrates for flexible electronics and space shielding, as they render high temperature and UV stability and toughness. However, their poor thermal conductivity and completely electrically insulating characteristics have caused other limitations, such as thermal management challenges for flexible high-power electronics and spacecraft electrostatic charging. In order to target these issues, a hybrid of PI with 3D graphene (3D-C), 3D-C/PI, is developed here. This composite renders extraordinary enhancements of thermal conductivity (one order of magnitude) and electrical conductivity (10 orders of magnitude). It withstands and keeps a stable performance throughout various bending and thermal cycles, as well as the oxidative and aggressive environment of ground-based, simulated space environments. This makes this new hybrid film a suitable material for flexible space applications. PMID- 26479497 TI - Application of a Stable Isotope Approach to Evaluate Impact of Changes in Manufacturing Parameters for an Immediate-Release Tablet. AB - There is continued emphasis from the various worldwide regulatory agencies to ensure that the pharmaceutical industry fully understands the products they are developing. This emphasis is seen via development of quality-by-design (QbD) publications and guidelines generated by the International Committee on Harmonization. The challenge to meet these expectations is primarily associated with the generation of in vivo data (eg, pharmacokinetic data) that is resource intensive. A technique reducing the resources needed to generate this in vivo data permits a more extensive application of QbD principles. This paper presents the application of stable isotopes in pharmacokinetic studies. The data show that the use of stable isotopes can significantly reduce the number of subjects required for a study. This reduction in subjects thus translates into a significant reduction in resources and time needed to generate the required in vivo data to support QbD. PMID- 26479498 TI - One gene but different proteins and diseases: the complexity of dystonin and bullous pemphigoid antigen 1. AB - Since the immunochemical identification of the bullous pemphigoid antigen 230 (BP230) as one of the major target autoantigens of bullous pemphigoid (BP) in 1981, our understanding of this protein has significantly increased. Cloning of its gene, development and characterization of animal models with engineered gene mutations or spontaneous mouse mutations have revealed an unexpected complexity of the gene encoding BP230. The latter, now called dystonin (DST), is composed of at least 100 exons and gives rise to three major isoforms, an epithelial, a neuronal and a muscular isoform, named BPAG1e (corresponding to the original BP230), BPAG1a and BPAG1b, respectively. The various BPAG1 isoforms play a key role in fundamental processes, such as cell adhesion, cytoskeleton organization, and cell migration. Genetic defects of BPAG1 isoforms are the culprits of epidermolysis bullosa and complex, devastating neurological diseases. In this review, we summarize recent advances of our knowledge about several BPAG1 isoforms, their role in various biological processes and in human diseases. PMID- 26479499 TI - Perinatal outcomes of fetal pleural effusion following thoracoamniotic shunting. AB - OBJECTIVE: The aim is to evaluate perinatal outcomes of fetal pleural effusion after thoracoamniotic shunting. METHODS: This was a retrospective study of 68 singleton pregnancies with massive fetal pleural effusion that underwent thoracoamniotic shunting between 1999 and 2012 at Asan Medical Center, Seoul, Korea. Through a review of medical records, we investigated perinatal outcomes according to the presence of fetal hydrops and identified prognostic factors by stepwise multivariate logistic regression analysis. RESULTS: Of the 68 pregnancies, three were lost to follow-up and two fetuses died in utero. The median gestational age at shunting was 28.3 weeks (range, 18.5-34.1 weeks). Of the 65 fetuses, 50 (76.9%) were hydropic, of which hydrops resolved following shunting in 29 fetuses (58.0%). Among the 63 live births, the median gestational age at delivery was 33.6 weeks (range, 26.2-40.0 weeks), with 36 fetuses (57.1%) delivered preterm. The overall survival rate was 75.4% (49/65), and in a subgroup analysis, the survival rate was highest for non-hydropic fetuses (14/15, 93.3%), followed by fetuses whose hydrops resolved (25/29, 86.2%) and remained after shunting (10/21, 47.6%). CONCLUSION: Thoracoamniotic shunting can be helpful for fetuses with massive pleural effusion. While fetal hydrops can occur in such cases, perinatal outcomes can be improved by successful shunting. PMID- 26479500 TI - Analysis of Attentional Bias towards Attractive and Unattractive Body Regions among Overweight Males and Females: An Eye-Movement Study. AB - BACKGROUND: Body image distortion is highly prevalent among overweight individuals. Whilst there is evidence that body-dissatisfied women and those suffering from disordered eating show a negative attentional bias towards their own unattractive body parts and others' attractive body parts, little is known about visual attention patterns in the area of obesity and with respect to males. Since eating disorders and obesity share common features in terms of distorted body image and body dissatisfaction, the aim of this study was to examine whether overweight men and women show a similar attentional bias. METHODS/DESIGN: We analyzed eye movements in 30 overweight individuals (18 females) and 28 normal weight individuals (16 females) with respect to the participants' own pictures as well as gender- and BMI-matched control pictures (front and back view). Additionally, we assessed body image and disordered eating using validated questionnaires. DISCUSSION: The overweight sample rated their own body as less attractive and showed a more disturbed body image. Contrary to our assumptions, they focused significantly longer on attractive compared to unattractive regions of both their own and the control body. For one's own body, this was more pronounced for women. A higher weight status and more frequent body checking predicted attentional bias towards attractive body parts. We found that overweight adults exhibit an unexpected and stable pattern of selective attention, with a distinctive focus on their own attractive body regions despite higher levels of body dissatisfaction. This positive attentional bias may either be an indicator of a more pronounced pattern of attentional avoidance or a self enhancing strategy. Further research is warranted to clarify these results. PMID- 26479501 TI - Eradication of osteosarcoma by fluorescence-guided surgery with tumor labeling by a killer-reporter adenovirus. AB - In a previous study, we developed fluorescence-guided surgery (FGS) for osteosarcoma using an orthotopic model with 143B human osteosarcoma cells expressing red fluorescent protein (RFP) implanted into the intramedullary cavity of the tibia in nude mice. The FGS-treated mice had a significantly higher disease-free survival (DFS) rate than the bright-light surgery (BLS). However, although FGS significantly reduced the recurrence of the primary tumor, it did not reduce lung metastasis. In the present study, we utilized the OBP-401 telomerase-dependent killer-reporter adenovirus, carrying green fluorescent protein (GFP), to label human osteosarcoma in situ in orthotopic mouse models. OBP-401-illuminated human osteosarcoma cell lines, 143B and MNNG/HOS cells in vitro and in vivo. OBP-401 tumor illumination enabled effective FGS of the 143B derived orthotopic mouse model of human osteosarcoma model as well as FGS eradication of residual cancer cells after BLS. OBP-401-assisted FGS significantly inhibited local recurrence and lung metastasis after surgery, thereby prolonging DFS and overall survival (OS), achieving a very important improvement of therapeutic outcomes over our previously reported FGS study. These therapeutic benefits of FGS were demonstrated using a clinically-viable methodology of direct labeling of human osteosarcoma in situ with the OBP-401 killer-reporter adenovirus in contrast with previous reports, which used genetically engineered labeled cells or antibody-based fluorescent labels for FGS. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:836-844, 2016. PMID- 26479502 TI - Carbohydrates, pollinators, and cycads. AB - Cycad biology, ecology, and horticulture decisions are not supported by adequate research, and experiments in cycad physiology in particular have been deficient. Our recent report on free sugar content in a range of cycad taxa and tissues sets the stage for developing continued carbohydrate research. Growth and development of cycad pollen, mediation of the herbivory traits of specialist pollinators, and support of expensive strobilus behavioral traits are areas of cycad pollination biology that would benefit from a greater understanding of the role of carbohydrate relations. PMID- 26479504 TI - 3'-hydroxy-epsilon,epsilon-caroten-3-one inhibits the differentiation of 3T3-L1 cells to adipocytes. AB - An oxidative metabolite of lutein, 3'-hydroxy-epsilon,epsilon-caroten-3-one, inhibited the differentiation of 3T3-L1 cells to adipocytes and the subsequent triacylglycerol production, but lutein did not. The alpha,beta-unsaturated carbonyl structure of 3'-hydroxy-epsilon,epsilon-caroten-3-one was considered to participate in the inhibitory effect, suggesting that this lutein metabolite has the potential to prevent metabolic syndrome. PMID- 26479505 TI - Bayesian Biostatistics 2014 - Satellite conference of the International Biometric Conference. PMID- 26479506 TI - Bayesian meta-analysis of test accuracy in the absence of a perfect reference test applied to bone scintigraphy for the diagnosis of complex regional pain syndrome. AB - There is conflicting evidence about the accuracy of bone scintigraphy (BS) for the diagnosis of complex regional pain syndrome 1 (CRPS 1). In a meta-analysis of diagnostic studies, the evaluation of test accuracy is impeded by the use of different imperfect reference tests. The aim of our study is to summarize sensitivity and specificity of BS for CRPS 1 and to identify factors to explain heterogeneity. We use a hierarchical Bayesian approach to model test accuracy and threshold, and we present different models accounting for the imperfect nature of the reference tests, and assuming conditional dependence between BS and the reference test results. Further, we include disease duration as explanatory variable in the model. The models are compared using summary ROC curves and the deviance information criterion (DIC). Our results show that those models which account for different imperfect reference tests with conditional dependence and inclusion of the covariate are the ones with the smallest DIC. The sensitivity of BS was 0.87 (95% credible interval 0.73-0.97) and the overall specificity was 0.87 (0.73-0.95) in the model with the smallest DIC, in which missing values of the covariate are imputed within the Bayesian framework. The estimated effect of duration of symptoms on the threshold parameter was 0.17 (-0.25 to 0.57). We demonstrate that the Bayesian models presented in this paper are useful to address typical problems occurring in meta-analysis of diagnostic studies, including conditional dependence between index test and reference test, as well as missing values in the study-specific covariates. PMID- 26479511 TI - Value of ultrasound with a single linear transducer to confirm correct positioning of central venous catheter in low body weight neonates. PMID- 26479510 TI - Postoperative shoulder pain after laparoscopic hysterectomy with deep neuromuscular blockade and low-pressure pneumoperitoneum: A randomised controlled trial. AB - BACKGROUND: Postoperative shoulder pain remains a significant problem after laparoscopy. Pneumoperitoneum with insufflation of carbon dioxide (CO2) is thought to be the most important cause. Reduction of pneumoperitoneum pressure may, however, compromise surgical visualisation. Recent studies indicate that the use of deep neuromuscular blockade (NMB) improves surgical conditions during a low-pressure pneumoperitoneum (8 mmHg). OBJECTIVE: The aim of this study was to investigate whether low-pressure pneumoperitoneum (8 mmHg) and deep NMB (posttetanic count 0 to 1) compared with standard-pressure pneumoperitoneum (12 mmHg) and moderate NMB (single bolus of rocuronium 0.3 mg kg with spontaneous recovery) would reduce the incidence of shoulder pain and improve recovery after laparoscopic hysterectomy. DESIGN: A randomised, controlled, double-blinded study. SETTING: Private hospital in Denmark. PARTICIPANTS: Ninety-nine patients. INTERVENTIONS: Randomisation to either deep NMB and 8 mmHg pneumoperitoneum (Group 8-Deep) or moderate NMB and 12 mmHg pneumoperitoneum (Group 12-Mod). Pain was assessed on a visual analogue scale (VAS) for 14 postoperative days. MAIN OUTCOME MEASURES: The primary endpoint was the incidence of shoulder pain during 14 postoperative days. Secondary endpoints included area under curve VAS scores for shoulder, abdominal, incisional and overall pain during 4 and 14 postoperative days; opioid consumption; incidence of nausea and vomiting; antiemetic consumption; time to recovery of activities of daily living; length of hospital stay; and duration of surgery. RESULTS: Shoulder pain occurred in 14 of 49 patients (28.6%) in Group 8-Deep compared with 30 of 50 (60%) patients in Group 12-Mod. Absolute risk reduction was 0.31 (95% confidence interval 0.12 to 0.48; P = 0.002). There were no differences in any secondary endpoints including area under the curve for VAS scores. CONCLUSION: Deep NMB and low-pressure pneumoperitoneum (8 mmHg) reduced the incidence of shoulder pain after laparoscopic hysterectomy in comparison to moderate NMB and standard-pressure pneumoperitoneum (12 mmHg). TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01722097. PMID- 26479512 TI - Efficacy of coaxial ventilation with a novel endotracheal catheter equipped with a functional cuff: A swine model study. AB - BACKGROUND: We have developed an endotracheal catheter with a functional cuff (ECFC) that inflates during inspiration and deflates during expiration. This catheter, together with a regular ICU ventilator, can provide coaxial ventilation. OBJECTIVE: The aim of this study was to determine the efficacy of ventilation in adult human-sized swine using an ECFC and a regular ICU ventilator. DESIGN: A prospective animal study. SETTING: Experimental, Trauma Transplant Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA. ANIMALS: Eight adult Yorkshire swine, weighing 45 to 50 kg, were studied. INTERVENTIONS: To create the ECFC, a 5 cm long latex cuff was placed over the distal side ports of either a 14 or 19-Fr gauge endotracheal catheter and a 1 cm long piece of plastic tube was inserted into the tip of the endotracheal catheter to create an internal resistance. The ECFC was placed into the trachea and the proximal end of the ECFC was connected to an ICU ventilator in pressure-control mode, with peak pressures set at either 25, 50 or 70 cmH2O. MAIN OUTCOME MEASURES: Tidal volume was calculated using plethysmography. RESULTS: During pressure control ventilation with the 14-Fr gauge ECFC at set inspiratory pressures of 25, 50 and 75 cmH2O, the tidal volumes generated were 209 +/- 36, 309 +/- 61 and 367 +/- 85 ml, respectively, and with the 19-Fr gauge ECFC these were 277 +/- 51, 442 +/- 91 and 538 +/- 123 ml, respectively. No complications were observed. CONCLUSION: An ECFC combined with a regular pressure-controlled ICU ventilator can produce adequate tidal volumes in adult human-sized swine. Our results establish the feasibility of ventilation with this new alternative technique. The safety and advantages of such a technique remain to be determined in humans. PMID- 26479513 TI - Anaesthesia and orphan disease: 22q11.2 microdeletion disorder (DiGeorge syndrome). PMID- 26479514 TI - Anaesthesia and orphan disease: primary autosomal recessive microcephaly-10 caused by a mutation in the ZNF335 gene. PMID- 26479515 TI - Anaesthesia and orphan disease: A septuagenarian patient with Segawa's dystonia. PMID- 26479516 TI - Using the C-MAC videolaryngoscope as a first-line device for out-of-hospital emergency intubation. PMID- 26479517 TI - A rare case of sevoflurane hypersensitivity. PMID- 26479519 TI - Improved growth and ethanol fermentation of Saccharomyces cerevisiae in the presence of acetic acid by overexpression of SET5 and PPR1. AB - To better understand the contribution of zinc-finger proteins to environmental stress tolerance, particularly inhibition from acetic acid, which is a potent inhibitor for cellulosic ethanol production by microbial fermentations, SET5 and PPR1 were overexpressed in Saccharomyces cerevisiae BY4741. With 5 g/L acetic acid addition, engineered strains BY4741/SET5 and BY4741/PPR1 showed improved growth and enhanced ethanol fermentation performance compared to that with the control strain. Similar results were also observed in ethanol production using corn stover hydrolysate. Further studies indicated that SET5 and PPR1 overexpression in S. cerevisiae significantly improved activities of antioxidant enzymes and ATP generation in the presence of acetic acid, and consequently decreased intracellular accumulation of reactive oxygen species (50.9 and 45.7%, respectively). These results revealed the novel functions of SET5 and PPR1 for the improvement of yeast acetic acid tolerance, and also implicated the involvement of these proteins in oxidative stress defense and energy metabolism in S. cerevisiae. This work also demonstrated that overexpression of SET5 and PPR1 would be a feasible strategy to increase cellulosic ethanol production efficiency. PMID- 26479520 TI - Carboxylate free MU-oxo bridged ferric wheel with a record exchange coupling. AB - A novel oxo-bridged, carboxylate free 'ferric wheel' was isolated with the molecular formula [FeIII8(MU-O)4(L(2-))8] (1). Magnetic susceptibility measurements suggest that the Fe(III) ions are coupled antiferromagnetically and magnetic data modelling yields J1 = -26.4 cm(-1), J2 = -170 cm(-1) which are rationalized by DFT calculation. The exchange value for of -170 cm(-1) (Fe-O(oxo) Fe) is the largest exchange value known compared to any homometallic or heterometallic wheel reported to date. PMID- 26479521 TI - Improving the Reliability of Optimal In-Feed Amino Acid Ratios Based on Individual Amino Acid Efficiency Data from N Balance Studies in Growing Chicken. AB - Three consecutive nitrogen balance experiments with fast-growing male broiler chickens (ROSS 308), both during starter and grower periods, were conducted to determine the ideal ratios of several indispensable amino acids relative to lysine. The control diets based on corn, wheat, fishmeal, field peas, wheat gluten and soybean oil were formulated by computer optimizing to meet the assumed ideal amino acid ratios and to fulfill both the energy and nutrient requirements of growing chicken. According to principles of the diet dilution technique, balanced control diets were diluted by wheat starch and refilled by crystalline amino acids and remaining feed ingredients, except the amino acid under study. The lysine, threonine, tryptophan, arginine, isoleucine and valine diluted diets resulted in significantly lower protein quality as compared to control diet, especially following increased dietary lysine supply (experiments II and III) and stronger amino acid dilution (experiment III). Accordingly, the limiting position of individual amino acids was confirmed, and the derived amino acid efficiency data were utilized to derive ideal amino acid ratios for the starter period: Lys (100): Thr (60): Trp (19): Arg (105): Ile (55): Val (63); and the grower period: Lys (100): Thr (62): Trp (17): Arg (105): Ile (65): Val (79). PMID- 26479522 TI - Livestock Production in the UK in the 21(st) Century: A Perfect Storm Averted? AB - There is a school of thought that future demand for meat and other farm animal products is unsustainable for several reasons, including greenhouse gas emissions, especially from ruminants; standards of farm animal health and welfare, especially when farm animals are kept intensively; efficiency of conversion by livestock of solar energy into (human) food, particularly by pigs and poultry; water availability and usage for all types of agricultural production, including livestock; and human health and consumption of meat, eggs and milk. Demand for meat is forecast to rise as a result of global population growth and increasing affluence. These issues buttress an impending perfect storm of food shortages, scarce water and insufficient energy, which is likely to coincide with global population reaching about 9 billion people in 2030 (pace Beddington). This paper examines global demand for animal products, the narrative of 'sustainable intensification' and the implications of each for the future of farm animal welfare. In the UK, we suggest that, though non-ruminant farming may become unsustainable, ruminant agriculture will continue to prosper because cows, sheep and goats utilize grass and other herbage that cannot be consumed directly by humans, especially on land that is unsuitable for other purposes. However, the demand for meat and other livestock-based food is often for pork, eggs and chicken from grain-fed pigs and poultry. The consequences of such a perfect storm are beginning to be incorporated in long-term business planning by retailers and others. Nevertheless, marketing sustainable animal produce will require considerable innovation and flair in public and private policies if marketing messages are to be optimized and consumer behaviour modified. PMID- 26479518 TI - Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting. AB - This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward. PMID- 26479524 TI - Impact of Selected Factors on the Occurrence of Contact Dermatitis in Turkeys on Commercial Farms in Germany. AB - In a long term research project in Germany the influence of husbandry on the health of fattening turkeys (Study 1) as well as the influence of practiced rearing conditions on the health of turkey poults (Study 2) was examined in 24 farms and at the meat processing plant. In all examined rearing farms, litter samples for the determination of litter moisture were taken. This paper summarizes the results obtained by our working group from 2007 until 2012. The results elucidate the universal problem of foot pad dermatitis (FPD). Nearly 100% of the observed turkeys showed a clinically apparent FPD at the meat processing plant. Furthermore, skin lesions of the breast, especially breast buttons were diagnosed, particularly at the slaughterhouse. FPD was detected in the first week of the rearing phase. Prevalence and degree showed a progressive development up to the age of 22-35 days, whereas 63.3% of the poults had foot pad alterations. As even mild alterations in the foot pad condition can be indicators for suboptimal design of the rearing environment, especially high litter moisture, it is important to focus on the early rearing phase. PMID- 26479523 TI - Towards a 'Good Life' for Farm Animals: Development of a Resource Tier Framework to Achieve Positive Welfare for Laying Hens. AB - The concept of a 'good life' recognises the distinction that an animal's quality of life is beyond that of a 'life worth living', representing a standard of welfare substantially higher than the legal minimum (FAWC, 2009). We propose that the opportunities required for a 'good life' could be used to structure resource tiers that lead to positive welfare and are compatible with higher welfare farm assurance schemes. Published evidence and expert opinion was used to define three tiers of resource provision (Welfare +, Welfare ++ and Welfare +++) above those stipulated in UK legislation and codes of practice, which should lead to positive welfare outcomes. In this paper we describe the principles underpinning the framework and the process of developing the resource tiers for laying hens. In doing so, we summarise expert opinion on resources required to achieve a 'good life' in laying hens and discuss the philosophical and practical challenges of developing the framework. We present the results of a pilot study to establish the validity, reliability and feasibility of the draft laying hen tiers on laying hen production systems. Finally, we propose a generic welfare assessment framework for farm animals and suggest directions for implementation, alongside outcome parameters, that can help define and promote a future 'good life' for farm animals. PMID- 26479525 TI - Emerging Profiles for Cultured Meat; Ethics through and as Design. AB - The development of cultured meat has gained urgency through the increasing problems associated with meat, but what it might become is still open in many respects. In existing debates, two main moral profiles can be distinguished. Vegetarians and vegans who embrace cultured meat emphasize how it could contribute to the diminishment of animal suffering and exploitation, while in a more mainstream profile cultured meat helps to keep meat eating sustainable and affordable. In this paper we argue that these profiles do not exhaust the options and that (gut) feelings as well as imagination are needed to explore possible future options. On the basis of workshops, we present a third moral profile, "the pig in the backyard". Here cultured meat is imagined as an element of a hybrid community of humans and animals that would allow for both the consumption of animal protein and meaningful relations with domestic (farm) animals. Experience in the workshops and elsewhere also illustrates that thinking about cultured meat inspires new thoughts on "normal" meat. In short, the idea of cultured meat opens up new search space in various ways. We suggest that ethics can take an active part in these searches, by fostering a process that integrates (gut) feelings, imagination and rational thought and that expands the range of our moral identities. PMID- 26479526 TI - Polymorphisms of the Dopamine D4 Receptor Gene in Stabled Horses are Related to Differences in Behavioral Response to Frustration. AB - In stabled horses, behavioral responses to frustration are often observed, especially around feeding time. These behavioral responses are a useful indicator of their welfare. In this study, we investigated the association between this behavioral indicator and DRD4 gene polymorphisms in stabled horses. Twenty one horses housed in two stables were used. The horses were observed for approximately 4 h around feeding over three or more days using focal-sampling and instantaneous-sampling. Horses were genotyped for the A-G substitution in the DRD4 gene. The effects of the A-G substitution (with or without the A allele in the DRD4 gene), the stables, and their interaction on the frequency of behavioral responses to frustration were analyzed using general linear models. The total time budget of behavioral responses to frustration was higher in horses without the A allele than in those with the A allele (P = 0.007). These results indicate that the A-G substitution of the DRD4 gene is related to frustration-related behavioral responses in stabled horses. Appropriate consideration should be made for the DRD4 gene polymorphism when the welfare of stabled horses is assessed, based on this behavioral indicator. PMID- 26479527 TI - Spatial and Temporal Habitat Use of an Asian Elephant in Sumatra. AB - Increasingly, habitat fragmentation caused by agricultural and human development has forced Sumatran elephants into relatively small areas, but there is little information on how elephants use these areas and thus, how habitats can be managed to sustain elephants in the future. Using a Global Positioning System (GPS) collar and a land cover map developed from TM imagery, we identified the habitats used by a wild adult female elephant (Elephas maximus sumatranus) in the Seblat Elephant Conservation Center, Bengkulu Province, Sumatra during 2007-2008. The marked elephant (and presumably her 40-60 herd mates) used a home range that contained more than expected medium canopy and open canopy land cover. Further, within the home range, closed canopy forests were used more during the day than at night. When elephants were in closed canopy forests they were most often near the forest edge vs. in the forest interior. Effective elephant conservation strategies in Sumatra need to focus on forest restoration of cleared areas and providing a forest matrix that includes various canopy types. PMID- 26479528 TI - An Attempt at Captive Breeding of the Endangered Newt Echinotriton andersoni, from the Central Ryukyus in Japan. AB - Anderson's crocodile newt (Echinotriton andersoni) is distributed in the Central Ryukyu Islands of southern Japan, but environmental degradation and illegal collection over the last several decades have devastated the local populations. It has therefore been listed as a class B1 endangered species in the IUCN Red List, indicating that it is at high risk of extinction in the wild. The species is also protected by law in both Okinawa and Kagoshima prefectures. An artificial insemination technique using hormonal injections could not be applied to the breeding of this species in the laboratory. In this study we naturally bred the species, and tested a laboratory farming technique using several male and female E. andersoni pairs collected from Okinawa, Amami, and Tokunoshima Islands and subsequently maintained in near-biotopic breeding cages. Among 378 eggs derived from 17 females, 319 (84.4%) became normal tailbud embryos, 274 (72.5%) hatched normally, 213 (56.3%) metamorphosed normally, and 141 (37.3%) became normal two month-old newts; in addition, 77 one- to three-year-old Tokunoshima newts and 32 Amami larvae are currently still growing normally. Over the last five breeding seasons, eggs were laid in-cage on slopes near the waterfront. Larvae were raised in nets maintained in a temperature-controlled water bath at 20 degrees C and fed live Tubifex. Metamorphosed newts were transferred to plastic containers containing wet sponges kept in a temperature-controlled incubator at 22.5 degrees C and fed a cricket diet to promote healthy growth. This is the first published report of successfully propagating an endangered species by using breeding cages in a laboratory setting for captive breeding. Our findings on the natural breeding and raising of larvae and adults are useful in breeding this endangered species and can be applied to the preservation of other similarly wild and endangered species such as E. chinhaiensis. PMID- 26479529 TI - Biological Anomalies around the 2009 L'Aquila Earthquake. AB - The April 6, 2009 L'Aquila earthquake was the strongest seismic event to occur in Italy over the last thirty years with a magnitude of M = 6.3. Around the time of the seismic swarm many instruments were operating in Central Italy, even if not dedicated to biological effects associated with the stress field variations, including seismicity. Testimonies were collected using a specific questionnaire immediately after the main shock, including data on earthquake lights, gas leaks, human diseases, and irregular animal behavior. The questionnaire was made up of a sequence of arguments, based upon past historical earthquake observations and compiled over seven months after the main shock. Data on animal behavior, before, during and after the main shocks, were analyzed in space/time distributions with respect to the epicenter area, evidencing the specific responses of different animals. Several instances of strange animal behavior were observed which could causally support the hypotheses that they were induced by the physical presence of gas, electric charges and electromagnetic waves in atmosphere. The aim of this study was to order the biological observations and thereby allow future work to determine whether these observations were influenced by geophysical parameters. PMID- 26479530 TI - Red Wolf (Canis rufus) Recovery: A Review with Suggestions for Future Research. AB - By the 1970s, government-supported eradication campaigns reduced red wolves to a remnant population of less than 100 individuals on the southern border of Texas and Louisiana. Restoration efforts in the region were deemed unpromising because of predator-control programs and hybridization with coyotes. The U.S. Fish and Wildlife Service (USFWS) removed the last remaining red wolves from the wild and placed them in a captive-breeding program. In 1980, the USFWS declared red wolves extinct in the wild. During 1987, the USFWS, through the Red Wolf Recovery Program, reintroduced red wolves into northeastern North Carolina. Although restoration efforts have established a population of approximately 70-80 red wolves in the wild, issues of hybridization with coyotes, inbreeding, and human caused mortality continue to hamper red wolf recovery. We explore these three challenges and, within each challenge, we illustrate how research can be used to resolve problems associated with red wolf-coyote interactions, effects of inbreeding, and demographic responses to human-caused mortality. We hope this illustrates the utility of research to advance restoration of red wolves. PMID- 26479531 TI - Uncertainty in Population Estimates for Endangered Animals and Improving the Recovery Process. AB - United States recovery plans contain biological information for a species listed under the Endangered Species Act and specify recovery criteria to provide basis for species recovery. The objective of our study was to evaluate whether recovery plans provide uncertainty (e.g., variance) with estimates of population size. We reviewed all finalized recovery plans for listed terrestrial vertebrate species to record the following data: (1) if a current population size was given, (2) if a measure of uncertainty or variance was associated with current estimates of population size and (3) if population size was stipulated for recovery. We found that 59% of completed recovery plans specified a current population size, 14.5% specified a variance for the current population size estimate and 43% specified population size as a recovery criterion. More recent recovery plans reported more estimates of current population size, uncertainty and population size as a recovery criterion. Also, bird and mammal recovery plans reported more estimates of population size and uncertainty compared to reptiles and amphibians. We suggest the use of calculating minimum detectable differences to improve confidence when delisting endangered animals and we identified incentives for individuals to get involved in recovery planning to improve access to quantitative data. PMID- 26479532 TI - Swooping in the Suburbs; Parental Defence of an Abundant Aggressive Urban Bird against Humans. AB - Masked Lapwings, Vanellus miles, often come into 'conflict' with humans, because they often breed in close proximity to humans and actively defend their ground nests through aggressive behaviour, which typically involves swooping. This study examined whether defensive responses differed when nesting birds were confronted with different human stimuli ('pedestrian alone' vs. 'person pushing a lawn mower' approaches to nests) and tested the effectiveness of a commonly used deterrent (mock eyes positioned on the top or back of a person's head) on the defensive response. Masked Lapwings did not swoop closer to a person with a lawn mower compared with a pedestrian, but flushed closer and remained closer to the nest in the presence of a lawn mower. The presence of eye stickers decreased (pedestrians) and increased (lawn mowers) swooping behaviour. Masked Lapwings can discriminate between different human activities and adjust their defensive behaviour accordingly. We also conclude that the use of eye stickers is an effective method to mitigate the human-lapwing 'conflict' in some, but not all, circumstances. PMID- 26479533 TI - The Supply Chain's Role in Improving Animal Welfare. AB - Supply chains are already incorporating citizen/consumer demands for improved animal welfare, especially through product differentiation and the associated segmentation of markets. Nonetheless, the ability of the chain to deliver high(er) levels and standards of animal welfare is subject to two critical conditions: (a) the innovative and adaptive capacity of the chain to respond to society's demands; (b) the extent to which consumers actually purchase animal friendly products. Despite a substantial literature reporting estimates of willingness to pay (WTP) for animal welfare, there is a belief that in practice people vote for substantially more and better animal welfare as citizens than they are willing to pay for as consumers. This citizen-consumer gap has significant consequences on the supply chain, although there is limited literature on the capacity and willingness of supply chains to deliver what the consumer wants and is willing to pay for. This paper outlines an economic analysis of supply chain delivery of improved standards for farm animal welfare in the EU and illustrates the possible consequences of improving animal welfare standards for the supply chain using a prototype belief network analysis. PMID- 26479534 TI - The Effect of Steps to Promote Higher Levels of Farm Animal Welfare across the EU. Societal versus Animal Scientists' Perceptions of Animal Welfare. AB - Information about animal welfare standards and initiatives from eight European countries was collected, grouped, and compared to EU welfare standards to detect those aspects beyond minimum welfare levels demanded by EU welfare legislation. Literature was reviewed to determine the scientific relevance of standards and initiatives, and those aspects going beyond minimum EU standards. Standards and initiatives were assessed to determine their strengths and weaknesses regarding animal welfare. Attitudes of stakeholders in the improvement of animal welfare were determined through a Policy Delphi exercise. Social perception of animal welfare, economic implications of upraising welfare levels, and differences between countries were considered. Literature review revealed that on-farm space allowance, climate control, and environmental enrichment are relevant for all animal categories. Experts' assessment revealed that on-farm prevention of thermal stress, air quality, and races and passageways' design were not sufficiently included. Stakeholders considered that housing conditions are particularly relevant regarding animal welfare, and that animal-based and farm level indicators are fundamental to monitor the progress of animal welfare. The most notable differences between what society offers and what farm animals are likely to need are related to transportation and space availability, with economic constraints being the most plausible explanation. PMID- 26479535 TI - The European Market for Animal-Friendly Products in a Societal Context. AB - This article takes a future focus on the direction in which social forces develop the market for animal-friendly products in Europe. On the basis of qualitative data gathered in the context of the European EconWelfare project, the differences across eight European countries are studied. The findings suggest that, given international trade barriers that prevent an improvement of animal welfare through legislation, many stakeholders believe that the market is the most viable direction to improve farm animal welfare. Economic productivity of the chain remains, however, an issue that on a fundamental level conflicts with the objective to improve animal welfare. With the help of a deeper conceptual understanding of willingness to pay for animal welfare, the paper finds that the European market for animal-friendly products is still largely fragmented and that the differences between European countries are considerable. A more animal friendly future that is achieved through the market will therefore need substantial policy attention from stakeholders in society. PMID- 26479536 TI - Behavior and Characteristics of Sap-Feeding North Island kaka (Nestor meridionalis septentrionalis) in Wellington, New Zealand. AB - The North Island kaka (Nestor meridionalis septentrionalis), a threatened New Zealand native parrot, was successfully reintroduced to an urban sanctuary in Wellington, New Zealand. Conflict has recently begun to emerge with Wellington City residents due to tree damage caused by kaka sap foraging. Little is known about sap foraging behavior of kaka, and this study aimed to gain a greater understanding of this behavior, and to test hypotheses that sap feeding is predominantly a female activity and that one technique, forming transverse gouges through bark, may be restricted to adult kaka. We used instantaneous scan sampling to record the behavior of kaka during 25 60-100 minute observation periods at Anderson Park, Wellington Botanic Garden, and during 13 opportunistic observations of sap feeding kaka in Wellington City. Forty-one observations of sap feeding were made of 21 individually-identified birds. Sap feeding birds were predominantly young and, based on estimated sex, females were no more likely to sap feed than males (exact binomial test p = 0.868). Twenty of the 21 identified sap feeding kaka utilized supplementary feeding stations at Zealandia-Karori Wildlife Sanctuary. Kaka were observed defending sap feeding sites from tui (Prosthemadera novaeseelandiae) and conspecifics. Sap appears to be an important resource for kaka across sexes and life stages, and provision of supplementary food is unlikely to reduce sap feeding and tree damage in Wellington City. PMID- 26479537 TI - Characteristics of a Canine Distemper Virus Outbreak in Dichato, Chile Following the February 2010 Earthquake. AB - Following the earthquake and tsunami disaster in Chile in February 2010, residents of Dichato reported high morbidity and mortality in dogs, descriptions of which resembled canine distemper virus (CDV). To assess the situation, free vaccine clinics were offered in April and May. Owner information, dog history and signalment were gathered; dogs received physical examinations and vaccines protecting against CDV, and other common canine pathogens. Blood was collected to screen for IgM antibodies to CDV. In total, 208 dogs received physical exams and vaccines were given to 177. IgM antibody titres to CDV were obtained for 104 dogs. Fifty-four dogs (51.9%) tested positive for CDV at the cut off titre of >1:50, but a total of 91.4% of dogs had a detectable titre >1:10. Most of the positive test results were in dogs less than 2 years of age; 33.5% had been previously vaccinated against CDV, and owners of 84 dogs (42.2%) reported clinical signs characteristic of CDV in their dogs following the disaster. The presence of endemic diseases in dog populations together with poor pre-disaster free-roaming dog management results in a potential for widespread negative effects following disasters. Creation of preparedness plans that include animal welfare, disease prevention and mitigation should be developed. PMID- 26479538 TI - Pre-Calving and Calving Management Practices in Dairy Herds with a History of High or Low Bovine Perinatal Mortality. AB - Bovine perinatal mortality is an increasing problem in dairy industries internationally. The objective of this study was to determine the risk factors associated with high and low herd-level calf mortality. Thirty herds with a history of either high (case) or low (control) calf mortality were recruited. A herd-level questionnaire was used to gather information on management practices likely to impact bovine perinatal mortality. The questionnaire was divided into four subsections dealing with pre-calving (breeding, diet and body condition score, endemic infectious diseases) and calving factors. Most of the significant differences between case and control herds were found in calving management. For example, in case herds, pregnant cattle were less likely to be moved to the calving unit two or more days and more likely to be moved less than 12 hours pre calving, they were also less likely to calve in group-calving facilities and their calves were more likely to receive intranasal or hypothermal resuscitation. These management procedures may cause social isolation and periparturient psychogenic uterine atony leading to dystocia, more weak calves requiring resuscitation and high perinatal calf mortality. The key finding is that calving, not pre-calving, management appears to be the most important area of concern in herds with high perinatal mortality. PMID- 26479539 TI - Searching for Animal Sentience: A Systematic Review of the Scientific Literature. AB - Knowledge of animal sentience is fundamental to many disciplines and imperative to the animal welfare movement. In this review, we examined what is being explored and discussed, regarding animal sentience, within the scientific literature. Rather than attempting to extract meaning from the many complex and abstract definitions of animal sentience, we searched over two decades of scientific literature using a peer-reviewed list of 174 keywords. The list consisted of human emotions, terminology associated with animal sentience, and traits often thought to be indicative of subjective states. We discovered that very little was actually being explored, and instead there was already much agreement about what animals can feel. Why then is there so much scepticism surrounding the science of animal sentience? Sentience refers to the subjective states of animals, and so is often thought to be impossible to measure objectively. However, when we consider that much of the research found to accept and utilise animal sentience is performed for the development of human drugs and treatment, it appears that measuring sentience is, after all, not quite as impossible as was previously thought. In this paper, we explored what has been published on animal sentience in the scientific literature and where the gaps in research lie. We drew conclusions on the implications for animal welfare science and argued for the importance of addressing these gaps in our knowledge. We found that there is a need for more research on positive emotional states in animals, and that there is still much to learn about taxa such as invertebrates. Such information will not only be useful in supporting and initiating legislative amendments but will help to increase understanding, and potentially positive actions and attitudes towards animals. PMID- 26479540 TI - Critical Analysis of Assessment Studies of the Animal Ethics Review Process. AB - In many countries the approval of animal research projects depends on the decisions of Animal Ethics Committees (AEC's), which review the projects. An animal ethics review is performed as part of the authorization process and therefore performed routinely, but comprehensive information about how well the review system works is not available. This paper reviews studies that assess the performance of animal ethics committees by using Donabedian's structure-process outcome model. The paper points out that it is well recognised that AECs differ in structure, in their decision-making methods, in the time they take to review proposals and that they also make inconsistent decisions. On the other hand, we know little about the quality of outcomes, and to what extent decisions have been incorporated into daily scientific activity, and we know almost nothing about how well AECs work from the animal protection point of view. In order to emphasise this viewpoint in the assessment of AECs, the paper provides an example of measures for outcome assessment. The animal suffering is considered as a potential measure for outcome assessment of the ethics review. Although this approach has limitations, outcome assessment would significantly increase our understanding of the performance of AECs. PMID- 26479541 TI - Understanding Vocalization Might Help to Assess Stressful Conditions in Piglets. AB - Assessing pigs' welfare is one of the most challenging subjects in intensive pig farming. Animal vocalization analysis is a noninvasive procedure and may be used as a tool for assessing animal welfare status. The objective of this research was to identify stress conditions in piglets reared in farrowing pens through their vocalization. Vocal signals were collected from 40 animals under the following situations: normal (baseline), feeling cold, in pain, and feeling hunger. A unidirectional microphone positioned about 15 cm from the animals' mouth was used for recording the acoustic signals. The microphone was connected to a digital recorder, where the signals were digitized at the 44,100 Hz frequency. The collected sounds were edited and analyzed. The J48 decision tree algorithm available at the Weka((r)) data mining software was used for stress classification. It was possible to categorize diverse conditions from the piglets' vocalization during the farrowing phase (pain, cold and hunger), with an accuracy rate of 81.12%. Results indicated that vocalization might be an effective welfare indicator, and it could be applied for assessing distress from pain, cold and hunger in farrowing piglets. PMID- 26479542 TI - Local Attitudes towards Bear Management after Illegal Feeding and Problem Bear Activity. AB - The "pot bears" received international media attention in 2010 after police discovered the intentional feeding of over 20 black bears during the investigation of an alleged marijuana-growing operation in Christina Lake, British Columbia, Canada. A two-phase random digit dialing survey of the community was conducted in 2011 to understand local perspectives on bear policy and management, before and after a summer of problem bear activity and government interventions. Of the 159 households surveyed in February 2011, most had neutral or positive attitudes towards bears in general, and supported the initial decision to feed the food-conditioned bears until the autumn hibernation. In contrast to wildlife experts however, most participants supported relocating the problem bears, or allowing them to remain in the area, ahead of killing; in part this arose from notions of fairness despite the acknowledged problems of relocation. Most locals were aware of the years of feeding but did not report it, evidently failing to see it as a serious form of harm, even after many bears had been killed. This underscores the importance of preventive action on wildlife feeding and the need to narrow the gap between public and expert opinion on the likely effects of relocation versus killing. PMID- 26479543 TI - Effects of Increased Vigilance for Locomotion Disorders on Lameness and Production in Dairy Cows. AB - The objective of this study was to determine the influence of weekly locomotion scoring and, thus, early detection and treatment of lame cows by a veterinarian on lameness prevalence, incidence, duration of lameness, fertility and milk yield on one dairy farm in Northern Germany. Cows were distributed to two groups. Cows in Group A (n = 99) with a locomotion score (LS) > 1 were examined and treated. In Group B (n = 99), it was solely in the hands of the farmer to detect lame cows and to decide which cows received treatment. Four weeks after the beginning of the experimental period, the prevalence of cows with LS = 1 was higher in Group A compared with Group B. Prevalence of lame cows (LS > 1) increased in Group B (47.6% in Week 2 to 84.0% in Week 40) and decreased in Group A from Week 2 to Week 40 (50% to 14.4%; P < 0.05). Within groups, the monthly lameness incidence did not differ. The average duration of lameness for newly lame cows was 3.7 weeks in Group A and 10.4 weeks in Group B (P < 0.001). There was no effect on fertility and incidence of puerperal disorders. The 100-day milk yield was calculated from cows having their first four Dairy Herd Improvement (DHI) test day results during the experimental period. The mean 100-day milk yield tended to be higher in Group A compared with Group B (3,386 kg vs. 3,359 kg; P = 0.084). PMID- 26479544 TI - The slow developmental time course of real-time spoken word recognition. AB - This study investigated the developmental time course of spoken word recognition in older children using eye tracking to assess how the real-time processing dynamics of word recognition change over development. We found that 9-year-olds were slower to activate the target words and showed more early competition from competitor words than 16-year-olds; however, both age groups ultimately fixated targets to the same degree. This contrasts with a prior study of adolescents with language impairment (McMurray, Samelson, Lee, & Tomblin, 2010) that showed a different pattern of real-time processes. These findings suggest that the dynamics of word recognition are still developing even at these late ages, and developmental changes may derive from different sources than individual differences in relative language ability. PMID- 26479545 TI - Peer effects on Head Start children's preschool competency. AB - The goals of this study were to investigate whether young children attending Head Start (N = 292; Mage = 4.3 years) selected peers based on their preschool competency and whether children's levels of preschool competency were influenced by their peers' levels of preschool competency. Children's peer interaction partners were intensively observed several times a week over 1 academic year. Social network analyses revealed that children selected peer interaction partners with similar levels of preschool competency and were influenced over time by their partners' levels of preschool competency. These effects held even after controlling for several child (e.g., sex and language) and family factors (e.g., financial strain and parent education). Implications for promoting preschool competency among Head Start children are discussed. (PsycINFO Database Record PMID- 26479546 TI - The better part of not knowing: Virtuous ignorance. AB - Suppose you are presented with 2 informants who have provided answers to the same question. One provides a precise and confident answer, and the other says that they do not know. If you were asked which of these 2 informants was more of an expert, intuitively you would select the informant who provided the certain answer over the ignorant informant. However, for cases in which precise information is practically or actually unknowable (e.g., the number of leaves on all the trees in the world), certainty and confidence indicate a lack of competence, while expressions of ignorance may indicate greater expertise. In 3 experiments, we investigated whether children and adults are able to use this "virtuous ignorance" as a cue to expertise. Experiment 1 found that adults and children older than 9 years selected confident informants for knowable information and ignorant informants for unknowable information. However, 5-6-year olds overwhelmingly favored the confident informant, even when such certainty was completely implausible. In Experiment 2 we replicated the results of Experiment 1 with a new set of items focused on predictions about the future, rather than numerical information. In Experiment 3, we demonstrated that 5-8-year-olds and adults are both able to distinguish between knowable and unknowable items when asked how difficult the information would be to acquire, but those same children failed to reject the precise and confident informant for unknowable items. We suggest that children have difficulty integrating information about the knowability of particular facts into their evaluations of expertise. (PsycINFO Database Record PMID- 26479547 TI - Understanding Chinese immigrant and European American mothers' expressions of warmth. AB - Maternal warmth, the quality of the affectional bond between mothers and their children, has been found to be consistently associated with children's positive developmental outcomes in Western cultures. However, researchers debate the potential differences in the cultural meanings of maternal warmth, particularly between Chinese and European American families. To address the lack of empirical research on this issue, the present study examined culturally derived perceptions and practices of maternal warmth through open-ended interviews with 70 Chinese immigrant and 70 European American mothers of preschoolers. Specifically, we compared mothers' perceived importance and degree of expression of warmth toward their children, and why and how they express warmth toward their children in the 2 cultural groups. Results showed that, although mothers perceived expressing warmth to be similarly important, European American mothers perceived expressing more warmth toward their children. Moreover, both cultural similarities and differences were found in why these 2 groups of mothers believed it was important to express warmth and the specific practices they used. Chinese immigrant mothers' responses were interpreted as reflecting a cultural emphasis on nurturance and instrumental support, whereas European American mothers' responses reflected the Western cultural focus on more direct and outward demonstrations of warmth. PMID- 26479548 TI - First-line treatment with paclitaxel for non-HIV-related Kaposi sarcoma: experience in 10 cases. PMID- 26479549 TI - Irisin in the Glucose Continuum. AB - AIM: Irisin, a novel myokine has been involved in the pathogenesis of type 2 diabetes (T2D) and metabolic syndrome. The aim of the current study was to investigate this association by comparing individuals from the whole spectrum of carbohydrate disturbances. METHOD: A total of 160 subjects participated in the study - 50 had normal glucose tolerance (NGT), 60 had prediabetes (PreDM), 50 had T2D. Subjects in the 3 groups were age, sex and BMI-matched. Standard OGTTs were performed for the distribution of patients in each group. Circulating serum irisin was measured by ELISA method. RESULTS: Mean age of the participants of the study was 48.8 (+/- 7.97) years. Circulating irisin levels were statistically different in the 3 study groups - highest in NGT - median 619 ng/ml (IQR=567), lower in PreDM - 314 ng/ml (IQR=577) and lowest in T2D - 228 ng/ml (IQR=200). In males, irisin correlated positively with BMI (r=0.475, p<0.001), negatively with fasting glucose (r=- 0.547, p<0.001) and negatively with hepatic enzymes: ALT (r= 0.281, p<0.05), AST (r=- 0.153, p>0.05), GGT (r=- 0.293, p<0.05). Similar correlations were observed in females. ROC analyses established irisin suitable for distinguishing T2D subjects from those without the condition (AUC=0.779, p<0.001) and insulin resistance (AUC=0.679, p=0.009), but not for MetS or dyslipidaemia. In a binary logistic regression model, after adjustment for confounders, irisin of <=658 ng/ml had an OR of 7.125 for T2D in females. CONCLUSION: Circulating irisin levels progressively decreased with the worsening of the glucose tolerance. Irisin correlated well with traditional biochemical and anthropometric parameters of metabolic health. PMID- 26479550 TI - The Skewness of Alpha Beta T Cell Receptors in Peripheral Blood of the Patients with Type 1 Diabetes. AB - AIM: To detect the skewness of TCR Valpha and TCR Vbeta of patients with type 1 diabetes (T1D). METHODS: The heparinized venous blood was collected from ten patients with T1D. The peripheral blood lymphocytes (PBL) were isolated and used to extract mRNA. Reverse amplyfication was performed for cDNA synthesis. The skewness of TCR Valpha and Vbeta was detected with real-time florescence quantitative polymerase chain reaction (RQ-PCR) and analyzed by DNA melting-curve analysis technique, respectively. RESULTS: Among the TCR Valpha genes, the skewness frequency rate (SFR) of Valpha22 was 30%; both of Valpha5 and Valpha24 were 20%; Valpha28 was the only restricted-clone gene with the SFR of 10%. In all the Vbeta genes, Vbeta7 and Vbeta17 were the the highest expression genes, and their SFRs were both 60%. Vbeta11 was near them with the SFR of 40%; the restricted clonal genes were Vbeta18 and Vbeta20, their SFRs were 10% and 20%, respectivley. CONCLUSION: There are skewd genes in TCR Valpha and TCR Vbeta, which are probably relative to the onset of T1D. PMID- 26479551 TI - Anticancer potential of dietary vitamin D and ascorbic acid: A review. AB - Cancers have been the leading cause of death worldwide and poor diet and physical inactivity are major risk factors in cancer-related deaths. Micronutrients such as vitamins and minerals appear to have preventive properties against cancer. One important mechanism by which dietary changes can exert preventive effects on cancer is via the modulation of micronutrient concentrations in target tissues. Many of these micronutrients are available in the form of dietary supplements, and the intake of these supplements is prevalent in various parts of the world. However, in most cases, it is not known which micronutrient (or combination of micronutrients) is best when it comes to lowering the risk of cancer. The present review illustrates the effect of vitamin D and ascorbic acid intake on preventing cancer. PMID- 26479552 TI - The clinical usefulness of the intraoperative detection of sentinel lymph node metastases by a rapid RT-PCR system in patients with gastric cancer. AB - BACKGROUND: The incidence of pathological lymph node metastases in patients with gastric cancer is 5% to 10%, which means that approximately 90% of patients with gastric cancer may undergo unnecessary lymphadenectomy. The precise intraoperative diagnosis of sentinel lymph node (SN) metastases is essential. The purpose of the current study was to verify the usefulness of a rapid reverse transcriptase-polymerase chain reaction (RT-PCR) system compared with hematoxylin and eosin staining for such diagnoses. METHODS: A total of 113 patients with clinical T1-T2 (cT1-T2) gastric cancer, including 73 patients with cT1cN0 disease with a tumor diameter <4 cm, were enrolled in the current study. SNs were identified by a radioisotope method. Carcinoembryonic antigen and cytokeratin 19 were used as markers for RT-PCR and the cutoff values were set using 1701 lymph nodes harvested from 157 patients with gastric cancer. RESULTS: SNs were detected in all 113 patients. Sensitivity and accuracy for detection by paraffin section were both 100% in patients with cT1 disease and were 60% and 90%, respectively, in patients with cT2 disease. The sensitivity of RT-PCR for the detection of pathological SN metastases was 92.3%. Furthermore, 11 patients had SN metastases detected only by RT-PCR, and these patients had frequent lymphatic invasion. Hematoxylin and eosin staining detected SN metastases in 6 of 73 patients with cT1cN0 gastric cancer; RT-PCR and frozen section detected SN metastases in 6 and 4 of these patients, respectively. Accordingly, the sensitivity of RT-PCR and frozen section for the detection of those pathological SN metastases were 100% and 66.6%, respectively. CONCLUSIONS: The rapid RT-PCR system appears to have clinical usefulness for the intraoperative detection of SN metastases in patients with gastric cancer. PMID- 26479553 TI - Non-Amyloid-beta Component of Human alpha-Synuclein Oligomers Induces Formation of New Abeta Oligomers: Insight into the Mechanisms That Link Parkinson's and Alzheimer's Diseases. AB - Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), of which their major component is the non-amyloid-beta component (NAC) of alpha synuclein (AS). Clinical studies have identified a link between PD and Alzheimer's disease (AD), but the question of why PD patients are at risk to develop various types of dementia, such as AD, is still elusive. In vivo studies have shown that Abeta can act as a seed for NAC/AS aggregation, promoting NAC/AS aggregation and thus contributing to the etiology of PD. However, the mechanisms by which NAC/AS oligomers interact with Abeta oligomers are still elusive. This work presents the interactions between NAC oligomers and Abeta oligomers at atomic resolution by applying extensive molecular dynamics simulations for an ensemble of cross-seeded NAC-Abeta(1-42) oligomers. The main conclusions of this study are as follows: first, the cross-seeded NAC-Abeta(1-42) oligomers represent polymorphic states, yet NAC oligomers prefer to interact with Abeta(1-42) oligomers to form double-layer over single-layer conformations due to electrostatic/hydrophobic interactions; second, among the single-layer conformations, the NAC oligomers induce formation of new beta-strands in Abeta(1 42) oligomers, thus leading to new Abeta oligomer structures; and third, NAC oligomers stabilize the cross-beta structure of Abeta oligomers, i.e., yielding compact Abeta fibril-like structures. PMID- 26479554 TI - INTRODUCTION: Return of Research Results: What About the Family? PMID- 26479556 TI - Preferences Regarding Return of Genomic Results to Relatives of Research Participants, Including after Participant Death: Empirical Results from a Cancer Biobank. AB - Data are lacking with regard to participants' perspectives on return of genetic research results to relatives, including after the participant's death. This paper reports descriptive results from 3,630 survey respondents: 464 participants in a pancreatic cancer biobank, 1,439 family registry participants, and 1,727 healthy individuals. Our findings indicate that most participants would feel obligated to share their results with blood relatives while alive and would want results to be shared with relatives after their death. PMID- 26479555 TI - Returning a Research Participant's Genomic Results to Relatives: Analysis and Recommendations. AB - Genomic research results and incidental findings with health implications for a research participant are of potential interest not only to the participant, but also to the participant's family. Yet investigators lack guidance on return of results to relatives, including after the participant's death. In this paper, a national working group offers consensus analysis and recommendations, including an ethical framework to guide investigators in managing this challenging issue, before and after the participant's death. PMID- 26479557 TI - Patients' Choices for Return of Exome Sequencing Results to Relatives in the Event of Their Death. AB - The informed consent process for genetic testing does not commonly address preferences regarding disclosure of results in the event of the patient's death. Adults being tested for familial colorectal cancer were asked whether they want their exome sequencing results disclosed to another person in the event of their death prior to receiving the results. Of 78 participants, 92% designated an individual and 8% declined to. Further research will help refine practices for informed consent. PMID- 26479558 TI - Mapping the Ethics of Translational Genomics: Situating Return of Results and Navigating the Research-Clinical Divide. AB - Both bioethics and law have governed human genomics by distinguishing research from clinical practice. Yet the rise of translational genomics now makes this traditional dichotomy inadequate. This paper pioneers a new approach to the ethics of translational genomics. It maps the full range of ethical approaches needed, proposes a "layered" approach to determining the ethics framework for projects combining research and clinical care, and clarifies the key role that return of results can play in advancing translation. PMID- 26479559 TI - Return of Genetic Research Results to Participants and Families: IRB Perspectives and Roles. AB - We surveyed IRB chairs' perspectives on offering individual genetic research results to participants and families, including family members of deceased participants, and the IRB's role in addressing these issues. Given a particular hypothetical scenario, respondents favored offering results to participants but not family members, giving choices at the time of initial consent, and honoring elicited choices. They felt IRBs should have authority regarding the process issues, but a more limited role in medical and scientific issues. PMID- 26479560 TI - Canadian Research Ethics Board Leadership Attitudes to the Return of Genetic Research Results to Individuals and Their Families. AB - Genomic research may uncover results that have direct actionable benefit to the individual. An emerging debate is the degree to which researchers may have responsibility to offer results to the biological relatives of the research participant. In a companion study to one carried out in the United States, we describe the attitudes of Canadian Research Ethics Board (REB) chairs to this issue and their opinions as to the role of the REB in developing related policy. PMID- 26479561 TI - Returning a Research Participant's Genomic Results to Relatives: Perspectives from Managers of Two Distinct Research Biobanks. AB - Research biobanks are heterogeneous and exist to manage diverse biosample types with the goal of facilitating and serving biomedical discovery. The perspectives of biobank managers are reviewed, and the perspectives of two biobank directors, one with experience in institutional biobanks and the other with national cooperative group banks, are presented. Most research biobanks are not designed, nor do they have the resources, to return research results and incidental findings to participants or their families. PMID- 26479562 TI - Pediatric Cancer Genetics Research and an Evolving Preventive Ethics Approach for Return of Results after Death of the Subject. AB - The return of genetic research results after death in the pediatric setting comes with unique complexities. Researchers must determine which results and through which processes results are returned. This paper discusses the experience over 15 years in pediatric cancer genetics research of returning research results after the death of a child and proposes a preventive ethics approach to protocol development in order to improve the quality of return of results in pediatric genomic settings. PMID- 26479563 TI - How Much Control Do Children and Adolescents Have over Genomic Testing, Parental Access to Their Results, and Parental Communication of Those Results to Others? AB - Adolescents may often have opinions about whether they want genetic and genomic testing in both the clinic and research and about who should have access to the results. This legal analysis demonstrates that the law provides very little protection to minors' wishes. PMID- 26479564 TI - A Family-Centered Model for Sharing Genetic Risk. AB - The successes of the Human Genome Project have ushered in a new era of genomic science. To effectively translate these discoveries, it will be critical to improve the communication of genetic risk within families. This will require a systematic approach that accounts for the nature of family relationships and sociocultural beliefs. This paper proposes the application of the Family Systems Illness Model, used in the setting of cancer care, to the evolving field of genomics. PMID- 26479566 TI - Return of Results from Research Using Newborn Screening Dried Blood Samples. AB - There may be compelling reasons to return to parents a limited subset of results from research conducted using residual newborn screening dried blood samples (DBS). This article explores the circumstances under which research results might be returned, as well as the mechanisms by which state newborn screening programs might facilitate the return of research results. The scope of any responsibility to return results of research conducted using DBS should be assessed in light of the potential impact on the primary mission of state newborn screening programs. PMID- 26479565 TI - Disclosing Secondary Findings from Pediatric Sequencing to Families: Considering the "Benefit to Families". AB - Secondary findings for adult-onset diseases in pediatric clinical sequencing can benefit parents or other family members. In the absence of data showing harm, it is ethically reasonable for parents to request such information, because in other types of medical decision-making, they are often given discretion unless their decisions clearly harm the child. Some parents might not want this information because it could distract them from focusing on the child's underlying condition that prompted sequencing. Collecting family impact data may improve future policy determinations. PMID- 26479567 TI - Considerations for Returning Research Results to Culturally Diverse Participants and Families of Decedents. AB - There has been considerable debate on which genomic research results to return to participants and when those results should be returned, but little attention to how those results should be returned, especially to minority and culturally diverse participants. This paper explores the cultural and ethical considerations around returning research results to participants and families of culturally diverse backgrounds, with a special focus on considerations when the research participant is deceased, and raises points for further discussion. PMID- 26479568 TI - International Policies on Sharing Genomic Research Results with Relatives: Approaches to Balancing Privacy with Access. AB - Returning genetic research results to relatives raises complex issues. In order to inform the U.S. debate, this paper analyzes international law and policies governing the sharing of genetic research results with relatives and identifies key themes and lessons. The laws and policies from other countries demonstrate a range of approaches to balancing individual privacy and autonomy with family access for health benefit, offering important lessons for further development of approaches in the United States. PMID- 26479569 TI - Certificates of Confidentiality: Protecting Human Subject Research Data in Law and Practice. AB - The federal Certificate of Confidentiality plays an important role in research on sensitive topics by authorizing researchers to refuse to disclose identifiable research data in response to subpoenas in any legal setting. However, there is little known about how effective Certificates are in practice. This article draws on our legal and empirical research on this topic to fill this information gap. It includes a description of the purpose of Certificates, their legislative and regulatory history, and a summary of the few reported and unreported cases that have dealt with Certificates. In addition, we outline other statutory confidentiality protections, compare them to the Certificate's protections, and analyze some of the vulnerabilities of a Certificate's protections. This analysis allows us to make specific recommendations for strengthening the protections afforded to research data. PMID- 26479570 TI - How Agencies Market Egg Donation on the Internet: A Qualitative Study. AB - We systematically examined the content of the websites of 46 agencies that buy and sell human eggs to understand how they market themselves to both donors and recipients. We found that these websites use marketing techniques that obscure the realities of egg donation, presenting egg donation as a mutually beneficial and fulfilling experience. Sites emphasize egg donors' emotional fulfillment (71.4%) and address recipients' anxieties by stressing the ability to find the perfect "fit" or "match" (56.5%), suiting recipients'"preferences"/"desires" (19.6%), and even designing/customizing a child (15.2%). Agencies attempt to create a sense of connection between the recipients and donors by reporting donors' personal characteristics - e.g., interests/hobbies (63%), traits (34.8%), mood/temperament (20%), and self-reported childhood behavior/memories (15%). Sites present donors as caring/generous (54.3%) and smart/successful/beautiful. These data, the first to examine several key aspects of egg donation agency websites, reveal critical aspects of how these companies communicate to prospective donors and recipients, raising several ethical concerns. Websites frame information in ways that may bias consumers, making emotional appeals that may distract from appropriate risk/benefit assessments and obscure the ethical challenges of egg donation. These data highlight needs for improved practices, adherence to guidelines, and consideration of enhanced guidelines or policy. PMID- 26479571 TI - Considering Actionability at the Participant's Research Setting Level for Anticipatable Incidental Findings from Clinical Research. AB - Determining what constitutes an anticipatable incidental finding (IF) from clinical research and defining whether, and when, this IF should be returned to the participant have been topics of discussion in the field of human subject protections for the last 10 years. It has been debated that implementing a comprehensive IF-approach that addresses both the responsibility of researchers to return IFs and the expectation of participants to receive them can be logistically challenging. IFs have been debated at different levels, such as the ethical reasoning for considering their disclosure or the need for planning for them during the development of the research study. Some authors have discussed the methods for re-contacting participants for disclosing IFs, as well as the relevance of considering the clinical importance of the IFs. Similarly, other authors have debated about when IFs should be disclosed to participants. However, no author has addressed how the "actionability" of the IFs should be considered, evaluated, or characterized at the participant's research setting level. This paper defines the concept of "Actionability at the Participant's Research Setting Level" (APRSL) for anticipatable IFs from clinical research, discusses some related ethical concepts to justify the APRSL concept, proposes a strategy to incorporate APRSL into the planning and management of IFs, and suggests a strategy for integrating APRSL at each local research setting. PMID- 26479572 TI - Funding the Costs of Disease Outbreaks Caused by Non-Vaccination. AB - While vaccination rates in the United States are high - generally over 90 percent - rates of exemptions have been going up, and preventable diseases coming back. Aside from their human cost and the financial cost of treatment imposed on those who become ill, outbreaks impose financial costs on an already burdened public health system, diverting resources from other areas. This article examines the financial costs of non-vaccination, showing how high they can be and what they include. It makes a case for requiring those who do not vaccinate to cover the costs of outbreak caused by their choice. Such recouping is justified because the choice not to vaccinate can easily be seen as negligent. But even if it is not, that choice involves imposing costs on others, and there are good reasons to require the actors to internalize those costs. The article proposes alternative statutory and regulatory schemes to cover the costs imposed on the public purse, focusing on no-fault mechanisms. We consider both ex ante mechanisms like a tax or a fee that will go into a no-fault fund to cover the costs and ex post mechanisms like a statutory authorization for recoupment of those costs by health officials. PMID- 26479573 TI - The Pediatrician's Dilemma: Refusing the Refusers of Infant Vaccines. AB - Dealing with the continuously increasing rates of families wanting to either significantly delay or completely postpone their infant's vaccines has created an alarmingly untenable dilemma for the general pediatricians dealing with these families on a daily basis. Pediatricians must decide whether to continue to provide substandard care by foregoing many or most of the infant's highly recommended protective vaccines, or whether to dismiss from the practice the family who refuses vaccines. Much has been written about why they should retain these families, but this paper will discuss some reasonable rationales as to why nearly 40% of pediatricians choose dismissal of these families. PMID- 26479574 TI - Physician Dismissal of Families Who Refuse Vaccination: An Ethical Assessment. AB - Thousands of U.S. parents choose to refuse or delay the administration of selected vaccines to their children each year, and some choose not to vaccinate their children at all. While most physicians continue to provide care to these families over time, using each visit as an opportunity to educate and encourage vaccination, an increasing number of physicians are choosing to dismiss these families from their practice unless they agree to vaccinate their children. This paper will examine this emerging trend along with the reasons given by those who advocate such an approach. I will argue that the strategy of refusing to allow families into a clinic unless they agree to vaccinate their children is misguided, and the arguments for doing so fail to stand up to close scrutiny. Such a strategy does not benefit the child or the health of the community, and may have a negative impact on both. Furthermore, some of the arguments in support of dismissal policies ignore the importance of professional obligation and appear to favor self-interest over the interest of the patient. PMID- 26479575 TI - Ethical Integrity in Health Care Organizations: Currents in Contemporary Bioethics. PMID- 26479577 TI - Longterm outcomes of auxiliary partial orthotopic liver transplantation in preadolescent children with fulminant hepatic failure. AB - By preserving part of the native liver, auxiliary partial orthotopic liver transplantation (APOLT) provides the advantage of potential immunosuppression (ISP) withdrawal if the native liver recovers but has had limited acceptance, especially in the United States, due to technical complications and low rates of native liver regeneration. No previous study has evaluated APOLT specifically for preadolescent children with fulminant hepatic failure (FHF). This population might benefit especially based on greater capacity for liver regeneration. Data from 13 preadolescent children who underwent APOLT were compared to 13 matched controls who underwent orthotopic liver transplantation (OLT) for FHF from 1996 to 2013. There were no significant differences in patient demographics or survival between the 2 groups. However, all surviving OLT recipients (10/13) remain on ISP, while all but 1 surviving APOLT recipient (12/13) showed native liver regeneration, and the first 10 recipients (76.9%) are currently off ISP with 2 additional patients currently weaning. In our experience, APOLT produced excellent survival and high rates of native liver regeneration in preadolescent children with FHF. This represents the largest series to date to report such outcomes. Liberating these children from lifelong ISP without the downside of increased surgical morbidity makes APOLT an attractive alternative. In conclusion, we therefore propose that, with the availability of technical expertise and with the technical modifications above, APOLT for FHF should be strongly considered for preteenage children with FHF. PMID- 26479578 TI - In-silico identification of inhibitors against mutated BCR-ABL protein of chronic myeloid leukemia: a virtual screening and molecular dynamics simulation study. AB - Aberrant and proliferative expression of the oncogene BCR-ABL in the bone marrow cells had been proven as the prime cause of chronic myeloid leukemia (CML). It has been established that tyrosine kinase domain of BCR-ABL protein is a potential therapeutic target for the treatment of CML. Imatinib is considered as a first-generation drug that can inhibit the enzymatic action by inhibiting the ATP binding with BCR-ABL protein. Later on, insensitivity of CML cells towards Imatinib has been observed may be due to mutation in tyrosine kinase domain of the ABL receptor. Subsequently, some other second-generation drugs have also been reported viz. Baustinib, Nilotinib, Dasatinib, Ponatinib, Bafetinib, etc., which can able to combat against mutated domain of ABL tyrosine kinase protein. By taking into account of bioavailability and resistance developed, there is an utmost need to find some more inhibitors for the mutated ABL tyrosine kinase protein. For virtual screening, a data-set has been generated by collecting the all available drug like natural compounds from ZINC and Drug Bank databases. Comparative docking analysis was also carried out on the active site of ABL tyrosine kinase receptor with reported reference inhibitors. Molecular dynamics simulation of the best screened interacting complex was done for 50 ns to validate the stability of the system. These selected inhibitors were further validated and analyzed through pharmacokinetics properties and series of ADMET parameters by in silico methods. Considering the above said parameters proposed molecules are concluded as potential leads for drug designing pipeline against CML. PMID- 26479579 TI - (1)H NMR chiral analysis of charged molecules via ion pairing with aluminum complexes. AB - Chiral analysis, such as determination of identity, concentration, and relative ratio of optically active (chiral) molecules, plays an indispensable role in contemporary synthetic, medicinal, and biological chemistry. Here, we describe the selective control of metal-centered chirality in an octahedral geometry to prepare negatively charged Al(III) complexes, which can be used as versatile (1)H NMR chiral solvating agents for both positively and negatively charged chiral molecules in polar or nonpolar solvents. During the formation of ion pairs between the Al(III) complexes and the chiral analytes such as amines and carboxylic acids, the metal-centered chirality in the Al complexes plays a crucial role in providing anisochronous chemical shifts to the (1)H NMR spectra. As a chiral solvating agent, Al(III) complexes display an unprecedentedly broad substrate scope, good solvent compatibility, and operational simplicity. PMID- 26479581 TI - Synthesis and Electrocatalytic Property of Diiron Hydride Complexes Derived from a Thiolate-Bridged Diiron Complex. AB - Interaction of a diiron thiolate-bridged complex, [Cp*Fe(MU-eta(2):eta(4) bdt)FeCp*] (1) (Cp* = eta(5)-C5Me5; bdt = benzene-1,2-dithiolate) with a proton gives an Fe(III)Fe(III) hydride bridged complex, [Cp*Fe(MU-bdt)(MU-H)FeCp*][BF4] (3[BF4]). According to in situ variable temperature (1)H NMR studies, the formation of 3[BF4] was evidenced to occur through a stepwise pathway: protonation occurring at an iron center to produce terminal hydride [Cp*Fe(MU bdt)(t-H)FeCp*][BF4] (2) and subsequent intramolecular isomerization to bridging hydride 3[BF4]. A one-electron reduction of 3[BF4] by CoCp2 affords a paramagnetic mixed-valent Fe(II)Fe(III) hydride complex, [Cp*Fe(MU-eta(2):eta(2) bdt)(MU-H)FeCp*] (4). Further, studies on protonation processes of diruthenium and iron-ruthenium analogues of 1, [Cp*M1(MU-bdt)M2Cp*] (M1 = M2 = Ru, 5; M1 = Fe, M2 = Ru, 8), provide experimental evidence for terminal hydride species at these bdt systems. Importantly, diiron or diruthenium hydride bridged complexes 3[BF4], 7[BF4] and iron-ruthenium heterodinuclear complex 8[PF6] can realize electrocatalytic hydrogen evolution. PMID- 26479580 TI - Coronary artery disease risk reduction in HIV-infected persons: a comparative analysis. AB - Despite an increased risk of coronary artery disease (CAD) in persons infected with human immunodeficiency virus (HIV), few data are available on primary prevention of CAD in this population. In this retrospective cohort study, HIV infected patients treated in an academic medical center HIV Specialty Clinic between 1996 and 2010 were matched by age, gender, and ethnicity to a cohort of presumed uninfected persons followed in an academic medical center Internal Medicine primary care clinic. We compared CAD primary prevention care practices between the two clinics, including use of aspirin, HMG-CoA reductase inhibitors ("statins"), and anti-hypertensive drugs. CAD risk between the two groups was assessed with 10-year Framingham CAD risk scores. In the comparative analysis, 890 HIV-infected persons were compared to 807 controls. Ten-year Framingham CAD Risk Scores were similar in the two groups (median, 3; interquartile range [IQR], 0-5). After adjusting for relevant risk factors, HIV-infected persons were less likely to be prescribed aspirin (odds ratio [OR] 0.53; 95% confidence interval [CI], 0.40-0.71), statins (OR, 0.70; 95% CI, 0.53-0.92), and anti-hypertensive drugs (OR, 0.63; 95% CI, 0.50-0.79) than persons in the control group. In summary, when compared to demographically similar uninfected persons, HIV infected persons treated in an HIV specialty clinic were less likely to be prescribed medications appropriate for CAD risk reduction. Improving primary preventative CAD care in HIV specialty clinic populations is an important step toward diminishing risk of heart disease in HIV-infected persons. PMID- 26479582 TI - Clinical characteristics and prognosis of low frequency sensorineural hearing loss without vertigo. AB - CONCLUSION: Factors prognostic of recovery from low frequency sensorineural hearing loss without vertigo are co-occurrence of tinnitus, PTA determined hearing level on the affected side before treatment initiation, and time from onset to treatment initiation. The rate of hearing recovery was higher in the oral steroid than in the intra-tympanic steroid and combined groups. OBJECTIVES: Although many studies have assessed acute sudden hearing loss, few have analyzed low-frequency hearing loss. Clinical characteristics of patients with hearing loss may vary by type of hearing loss. This study, therefore, analyzed the clinical characteristics, recovery rates, and factors associated with hearing recovery in patients with low-frequency sensorineural hearing loss unaccompanied by vertigo. METHOD: This study included 50 patients with severe low frequency hearing loss unaccompanied by vertigo and with normal tympanic membrane status who visited hospitals from July 2005 to May 2014 due to sudden tinnitus, ear fullness, or hearing loss. Of these patients, 29 were treated with oral steroids, eight with tympanic steroid injections, and 13 with both. Clinical and auditory characteristics before and after treatment, as well as treatment outcomes, were compared in these three groups. RESULTS: Age, sex, affected side, co-occurrence of ear fullness, and accompanying chronic diseases were similar in the three groups. All patients started on treatment within 10 days of hearing loss showed significant recovery, with complete recovery, unaccompanied by tinnitus, observed in 10 patients. Treatment outcomes were not affected by hearing thresholds on the unaffected side. Of the patients treated with both oral and intra-tympanic steroids, 39% showed complete recovery, and 77% showed audiometric improvement. The complete recovery rate was significantly higher in the oral steroid than in the other two groups (p = 0.029); and the audiometric improvement rate tended to be lower in the intra-tympanic steroid group than in the other groups. Cure rates, defined as complete disappearance of symptoms and normal findings on pure tone audiograms (PTA), in the oral, intra-tympanic, and combined steroid groups were 49%, 25%, and 23%, respectively. There were no significant differences among the three groups in cure, subjective improvement, and audiometric improvement rates. Factors prognostic of non-recovery of hearing included late treatment initiation (p = 0.044), accompanying tinnitus (p = 0.049), and higher hearing thresholds on the affected side before treatment initiation (p = 0.005). PMID- 26479583 TI - Social provocation modulates decision making and feedback processing: Examining the trajectory of development in adolescent participants. AB - Increasingly, research is turning to the ways in which social context impacts decision making and feedback processing in adolescents. The current study recorded electroencephalography to examine the trajectory of development across adolescence, with a focus on how social context impacts cognition and behaviour. To that end, younger (10-12 years) and older (14-16 years) adolescents played a modified Taylor Aggression Paradigm against two virtual opponents: a low-provoker and a high-provoker. During the task's decision phase (where participants select punishment for their opponent), we examined two event-related potentials: the N2 and the late positive potential (LPP). During the outcome phase (where participants experience win or loss feedback), we measured the feedback related negativity (FRN). Although N2 amplitudes did not vary with provocation, LPP amplitudes were enhanced under high provocation for the younger group, suggesting that emotional reactivity during the decision phase was heightened for early adolescents. During the outcome phase, the FRN was reduced following win outcomes under high provocation for both groups, suggesting that a highly provocative social opponent may influence the reward response. Collectively, the data argue that social context is an important factor modulating neural responses in adolescent behavioural and brain development. PMID- 26479584 TI - New C20-diterpenoid alkaloids from Aconitum vilmorrianum and structural revision of 2-O-acetylorochrine and orochrine. AB - Three new C20-diterpenoid alkaloids vilmorrianines E (1), F (2), and G (3) were isolated from the whole plants of Aconitum vilmorrianum, along with one artifact N-chloromethyl vilmorrianine E hydrochloride (4), as well as two known alkaloids hemsleyaconitines F (5) and G (6). The structures of 1-4 were established by HR ESI-MS, 1D-, 2D-NMR (HMQC, HMBC, and NOESY), and single-crystal X-ray diffraction analysis. In addition, the structures of naturally occurring 2-O-acetylorochrine (7) and orochrine (8) were revised to be the known alkaloids heterophylloidine (9) and deacetyl heterophylloidine (10), respectively, on the basis of consideration of transannular effect and chemical correlations. PMID- 26479585 TI - Enhanced visible light photocatalytic inactivation of Escherichia coli using silver nanoparticles as photocatalyst. AB - The silver nanoparticles (AgNPs) were green synthesized using Cirsium arvense plant extract as a reducing and stabilizing agent, with superior photo inactivation activity against Escherichia coli (E. coli). The synthesized AgNPs had crystalline structure and were characterized by UV-vis spectroscopy, XRD, HRTEM, SEM, EDX and FT-IR. The formation of nanoparticles was observed at different pH and different plant extract concentrations and it was found that at higher pH (pH>6) and at lower concentration (10 mL), the reducing and stabilizing efficiency of plant extract was increased. The synthesized AgNPs had small size (<15 nm) and spherical shape. The AgNPs were evaluated for antibacterial activity against E. coli. Before transferring it to antibacterial activity, it was placed under visible light for 120 min. The same experiment was performed in dark as a control medium. The photo irradiated AgNPs were observed to be more effective against E. coli. The results showed, that the diameter of zone of inhibition of visible light irradiated AgNPs against E. coli was 23 (+/-0.5)mm and in dark was 11 (+/-0.4)mm. PMID- 26479587 TI - Memory hierarchies map onto the hippocampal long axis in humans. AB - Memories, similar to the internal representation of space, can be recalled at different resolutions ranging from detailed events to more comprehensive, multi event narratives. Single-cell recordings in rodents have suggested that different spatial scales are represented as a gradient along the hippocampal axis. We found that a similar organization holds for human episodic memory: memory representations systematically vary in scale along the hippocampal long axis, which may enable the formation of mnemonic hierarchies. PMID- 26479589 TI - Neurons in the human amygdala encode face identity, but not gaze direction. AB - The amygdala is important for face processing, and direction of eye gaze is one of the most socially salient facial signals. Recording from over 200 neurons in the amygdala of neurosurgical patients, we found robust encoding of the identity of neutral-expression faces, but not of their direction of gaze. Processing of gaze direction may rely on a predominantly cortical network rather than the amygdala. PMID- 26479591 TI - Effect of waist diameter and twist on tapered asymmetrical dual-core fiber MZI filter. AB - A compact in-fiber Mach-Zehnder interferometer (MZI) filter fabricated from custom-designed asymmetrical dual-core fiber is numerically analyzed in detail and experimentally verified. The asymmetrical dual-core fiber has core diameters and a core pitch of 6.9, 6, and 19.9 MUm, respectively. The fiber tapering technique is introduced to fuse the originally uncoupled cores into strong coupling tapered regions. The length and diameter of the waist region have a close impact on the splitting ratio, which further affects the spectral properties of the MZI filter. The field evolution with varied waist parameters is characterized by the finite element method and beam propagation method. Repeatable comb filters with ~15 dB extinction ratio are successfully achieved under the guidance of simulated optimum conditions. The twist-induced circular birefringence gives rise to a retardance that causes the spectral shifts of the MZI filter. The theoretical and experimental results confirm that the relative wavelength shift is proportional to the retardance, which follows a sinc function in the limit of a large twist rate. PMID- 26479592 TI - Sensitivity modeling of binary optical receivers. AB - The sensitivity characteristics of optical receiver frontends for high-speed data communications depend on modulation format, detector type, and specific operational constraints. A general mathematical model of the receiver sensitivity that fits to analytical as well as measured data is required to compare different receiver implementations and assess the reliability of data links under varying received power as common in free-space optical communication links. In this paper, a new approach based on Q-factor modeling is presented, compared with analytical receiver models, and applied to a multitude of exemplary receiver implementations. A methodology is introduced to generally apply the model to ideal or practical binary optical receiver frontends. PMID- 26479590 TI - Reward expectation differentially modulates attentional behavior and activity in visual area V4. AB - Neural activity in visual area V4 is enhanced when attention is directed into neuronal receptive fields. However, the source of this enhancement is unclear, as most physiological studies have manipulated attention by changing the absolute reward associated with a particular location as well as its value relative to other locations. We trained monkeys to discriminate the orientation of two stimuli presented simultaneously in different hemifields while we independently varied the reward magnitude associated with correct discrimination at each location. Behavioral measures of attention were controlled by the relative value of each location. By contrast, neurons in V4 were consistently modulated by absolute reward value, exhibiting increased activity, increased gamma-band power and decreased trial-to-trial variability whenever receptive field locations were associated with large rewards. These data challenge the notion that the perceptual benefits of spatial attention rely on increased signal-to-noise in V4. Instead, these benefits likely derive from downstream selection mechanisms. PMID- 26479588 TI - Anchoring and synaptic stability of PSD-95 is driven by ephrin-B3. AB - Organization of signaling complexes at excitatory synapses by membrane-associated guanylate kinase (MAGUK) proteins regulates synapse development, plasticity, senescence and disease. Post-translational modification of MAGUK family proteins can drive their membrane localization, yet it is unclear how these intracellular proteins are targeted to sites of synaptic contact. Here we show using super resolution imaging, biochemical approaches and in vivo models that the trans synaptic organizing protein ephrin-B3 controls the synaptic localization and stability of PSD-95 and links these events to changes in neuronal activity via negative regulation of a newly identified mitogen-associated protein kinase (MAPK)-dependent phosphorylation site on ephrin-B3, Ser332. Unphosphorylated ephrin-B3 was enriched at synapses, and interacted directly with and stabilized PSD-95 at synapses. Activity-induced phosphorylation of Ser332 dispersed ephrin B3 from synapses, prevented the interaction with PSD-95 and enhanced the turnover of PSD-95. Thus, ephrin-B3 specifies the synaptic localization of PSD-95 and likely links the synaptic stability of PSD-95 to changes in neuronal activity. PMID- 26479593 TI - Tunable multiwavelength mode-locked Tm/Ho-doped fiber laser based on a nonlinear amplified loop mirror. AB - We propose and demonstrate a tunable multiwavelength mode-locked Tm/Ho-doped fiber laser based on a nonlinear amplified loop mirror (NALM). Without using polarization-maintaining fiber, only passive fibers with low birefringence were inserted into the NALM to help overcome mode competition and realize mode locking. The spacing between adjacent channels was measured to be ~6 nm. By adjusting the polarization controllers (PCs) to an appropriate position, self started mode-locking was achieved, which further overcame the mode competition in the fiber laser. A multiwavelength mode-locked fiber laser with at least three available channels were tunable in the widest range of 30 nm (from 1935 to 1965 nm) with a 3 dB channel bandwidth of ~1.6 nm. This multiwavelength mode-locked fiber laser is quite stable with the maximum peak fluctuation within 0.47 dB in long-term observations. PMID- 26479594 TI - Analysis of deformation of flexible hemispherical lens arrays based on soft elastomers. AB - In this paper, flexible hemispherical lens arrays based on soft elastomers were fabricated. Then, the effects of various geometric parameters on the deformation (i.e., hemispherical deformation and radial extension) of these lens arrays were investigated experimentally and were verified by finite element analysis. We focused on determining the relationship between the geometric parameters and the radius of curvature of the lens. We found that the height of the lens support post plays an important role in minimizing changes in the radius of curvature of the lens. The results of this research offer valuable design principles for flexible lens arrays, which can be used as an optical component of various flexible optoelectronic devices. PMID- 26479595 TI - Multi-trench fiber with four gaps for improved bend performance. AB - A modified multi-trench fiber (MTF) design with gaps to create leakage channels is proposed and investigated numerically using the scalar finite-difference beam propagation method algorithm. Great potential in single-mode operation, mode area enlargement, and resistance to bending is demonstrated. A high loss ratio (>50) between high-order modes and the fundamental mode is possible over a wide range of high-index ring thickness, gap width, and bending orientation. This reduces the required fabrication accuracy. We obtain an effective area of 920 MUm2 at a wavelength of 1050 nm and a 20 cm bend radius with a high loss ratio (>100). Our modified gap MTF can possibly be fabricated by drilling holes in an ordinary MTF and inserting rods into the holes. PMID- 26479596 TI - Mathematical modeling of surface roughness in magnetic abrasive finishing of BK7 optical glass. AB - Magnetic abrasive finishing (MAF) is one of the advanced machining processes efficiently used to finish hard-to-machine materials. Simulation and modeling of the process is of particular importance to understand the mechanics of material removal and consequently achieve a high-quality surface with a minimum of surface defects. Hence, in this paper, we performed a numerical-experimental study to mathematically model the surface roughness during the MAF of BK7 optical glass. For this purpose, the initial roughness profile was estimated using fast Fourier transform (FFT) and a Gaussian filter. We obtained the final surface profile based on the material removal mechanisms and the corresponding chipping depth values evaluated by finite element analysis. We then validated experimentally the simulation results in terms of the arithmetic average surface roughness (R(a ). The comparison between the obtained results demonstrates that the theoretical and experimental findings are in good agreement when predicting the parameters' effect on surface roughness behavior. PMID- 26479597 TI - Power-area method to precisely estimate laser linewidth from its frequency-noise spectrum. AB - We proposed a precise and simple method to estimate the laser linewidth from its frequency power spectral density, which is termed as power-area method (PAM). We applied this method to determine the full width at half-maximum (FWHM) of white frequency noise and flicker-frequency noise, and the error was less than 7%. Then we successfully estimated the FWHM of the beat note of delayed self homodyne/heterodyne interferometry with this method. Lastly we investigated the selection of loop gain and loop bandwidth using PAM to achieve a better result in linewidth compression with servo-loop control. PMID- 26479598 TI - Method for measuring the cone angle and the shape of the axicon simultaneously using computer-generated holograms. AB - An axicon is an optical element with rotational symmetry and cone shape, which is nowadays widely used in many fields of engineering, like laser beam shaping, imaging systems, optical testing, laser machining, etc. In this paper, we propose a new method to measure the cone angle and the shape of the axicon simultaneously by using a computer-generated hologram. This test is performed in a null-test configuration. PMID- 26479599 TI - Light-controllable linear dichroism in nematics. AB - We report a method to obtain a light-controllable dichroism. The main effect is achieved using spiropyran-doped (SP-doped) nematic liquid crystal mixtures. SP molecules exhibit a high solubility in the liquid crystal host, which can vary between 1% and 4% in weight, without destroying the liquid crystalline phase. Due to their elongated shape, SP molecules are oriented along the nematic liquid crystal director. The obtained linear dichroism was measured to be 1.08 with a dichroic ratio of 7.12. Further, a two-direction linear dichroism was obtained by adding a dichroic dye to the mixture. The angle between the two dichroic axes was found to be 11 degrees . Two-direction linear dichroism is also light controllable and can be switched back to one-direction dichroism. PMID- 26479601 TI - Phase-polarization parallax barriers for an autostereo/stereo/monoscopic display with full-screen resolution at each operation mode. AB - It is attractive to have a three-mode flat-panel 3D display capable of working in autostereoscopic, stereoscopic-with-passive-glasses, and monoscopic modes and providing full-screen resolution of images at each mode. The concept of autostereoscopic displays simultaneously reproducing two image elements in each display pixel based on information-dependent polarization coding and subsequent decoding was recently proposed. Such a concept allows full-screen resolution in each image view and flickerless 3D images to be observed even at a 60-Hz frame rate. The essential problem of such display implementation is to create the suitable structure of the phase-polarization parallax barrier (PPPB) capable of working properly at a variable polarization state of input light. This paper presents the results of theoretical research of an electrically switchable liquid crystal (LC) PPPB. The Jones matrix notation of the required performance function of the LC PPPB is found. The results of computer modeling of achromatic characteristics of suitable LC structures are discussed to determine the optimum structures for PPPB. The proposed layout of three-mode 3D display with LC PPPB allows it to go from autostereoscopic mode to "stereoscopic-with-passive-glasses" mode and backward by electrical switching the LC PPPB in combination with removing/inserting the output polaroid film. PMID- 26479600 TI - High-resolution moire interferometry for quantitative low-cost, real-time surface profilometry. AB - A two-dimensional optical profilometry system has been developed in which fringe projection and image processing methods allow for image acquisition and analysis at video frame rates with MUm-scale precision in an inexpensive portable device. The device presented can be used to interrogate any uniformly reflective surface, imaging an area of approximately 10 square centimeters and providing a real-time digital display of the surface's contours. The presented system has the ability to resolve surface features with a lateral resolution of <50 MUm and <15 MUm in height. PMID- 26479602 TI - Modeling and analysis of optical properties of a gold nanoring based on electric and magnetic dipoles. AB - The optical behavior of a plane-wave excited gold nanoring (NR), originated from localized surface plasmon resonance is modeled by two coupled electric- and magnetic-point dipoles. Considering the extinction cross-section spectrum, it is found that the electric-dipole effect is dominant in comparison with the magnetic dipole effect although the magnetic-dipole signature is observable in the near field response of the NR. In addition, the far-field electromagnetic radiation pattern of the NR verifies the corresponding radiation pattern of the point dipoles. The numerical simulation near-field results are in agreement with the proposed electric- and magnetic-dipole theory. PMID- 26479603 TI - Laser-induced breakdown spectroscopy technique for quantitative analysis of aqueous solution using matrix conversion based on plant fiber spunlaced nonwovens. AB - In the present work, laser-induced breakdown spectroscopy (LIBS) was applied to detect concentrations of chromium and nickel in aqueous solution in the form of matrix conversion using plant fiber spunlaced nonwovens as a solid-phase support, which can effectively avoid the inherent difficulties such as splashing, a quenching effect, and a shorter plasma lifetime during the liquid LIBS analysis. Drops of the sample solution were transferred to the plant fiber spunlaced nonwovens surface and uniformly diffused from the center to the whole area of the substrate. Owing to good hydrophilicity, the plant fiber spunlaced nonwovens can hold more of the liquid sample, and the surface of this material never wrinkles after being dried in a drying oven, which can effectively reduce the deviation during the LIBS analysis. In addition, the plant fiber spunlaced nonwovens used in the present work are relatively convenient and low cost. Also, the procedure of analysis was simple and fast, which are the unique features of LIBS technology. Therefore, this method has potential applications for practical and in situ analyses. To achieve sensitive elemental detection, the optimal delay time in this experiment was investigated. Under the optimized condition, the limits of detection for Cr and Ni are 0.7 and 5.7 MUg.mL(-1), respectively. The results obtained in the present study show that the matrix conversion method is a feasible option for analyzing heavy metals in aqueous solutions by LIBS technology. PMID- 26479604 TI - Compact linearly polarized ceramic laser made with anisotropic nanostructured thin films. AB - A novel method is proposed for the fabrication of polarizing laser mirrors for compact solid-state lasers using glancing angle deposition. Changing the inclination angle and the azimuthal orientation of the substrate during deposition allows one to create and control in-plane birefringence of a deposited thin film by changing its nanostructure. Principal refractive indices of tungsten trioxide films were determined for various deposition angles using transmission and reflection ellipsometry. High-reflectance contrast between orthogonal linear polarization directions was obtained using a single material without any additional processing steps. These birefringent films were the building blocks of a Bragg mirror that was tested as an output coupler of a (Yb0.1Y0.9)3Al5O12 ceramic laser in a laser-diode end-pumped configuration. Continuous-wave, linearly polarized, transverse single-mode laser emission was obtained at a wavelength of 1030 nm with a polarization extinction ratio higher than 973 (30 dB). PMID- 26479605 TI - Research on quantum efficiency for reflection-mode InGaAs photocathodes with thin emission layer. AB - In order to understand the photoemission mechanism of the reflection-mode InGaAs photocathode with a thin emission layer, the formula describing reflection-mode quantum efficiency is revised by solving the one-dimensional continuity equation, in which the electrons generated in the GaAs buffer layer are considered. Compared with the conventional formula, the revised formula is proved to be more suitable for the reflection-mode InGaAs photocathode with a thin emission layer. In experiment, the InGaAs sample goes through two-step surface preparation including a wet chemical cleaning process and a heat treatment process. Then the sample is activated by Cs/O and the experimental quantum efficiency curves are measured simultaneously every other hour. The measured results show that the shapes of the quantum efficiency curves degrade with time because of the contamination of residual gases in the vacuum system. All the quantum efficiency curves are well fitted by the revised formula. PMID- 26479606 TI - Analysis of mode-hop free tuning of folded cavity grating feedback lasers. AB - We analytically study an external cavity laser structure including a folded cavity. A steering mirror is utilized in the folded cavity to deflect the intracavity laser beam. A mode-hop free tuning range of ~400 GHz can be achieved by control of the steering mirror, and a fast tuning rate is expected because of the small mass of the steering mirror. This technique has potential for applications in spectroscopy for turbulent media, especially in the mid-infrared region. PMID- 26479607 TI - Nonblocking 3 * 3 polymer thermo-optic switch array based on total-internal reflection effect. AB - A nonblocking 3*3 polymer thermo-optic (TO) switch array based on the total internal-reflection (TIR) effect is demonstrated. The switch array consists of three 2*2 TIR TO switch elements with a total device length of 15.5 mm, and achieves nine switching states with no more than one switch element working. The fabricated 3*3 TO switch array shows excellent switching performance with low crosstalk for all switching states of less than -20 dB. The power consumption of each switch element is below 53 mW, and the switching rise time and fall time are ~450 and 550 MUs at 1550 nm wavelength, respectively. PMID- 26479608 TI - 1 GHz repetition rate femtosecond Yb:fiber laser for direct generation of carrier envelope offset frequency. AB - We report a mode-locked fiber laser working at a 1 GHz fundamental repetition rate. The laser delivers a 600 mW average power at a pump power of 1800 mW. The pulse spectrum bandwidth was 23 nm to support 64 fs near-transform-limited pulses. An octave-spanning supercontinuum from 590 to 1350 nm was generated in a tapered photonic crystal fiber solely with the mode-locked fiber-laser output, without amplifiers. A 30 dB f(ceo) beat signal was detected via f-to-2f interferometer. PMID- 26479610 TI - Analysis of thermo-optic effect-based refractive index dynamic modulation in microspherical resonator. AB - The thermo-optic effect has been utilized to modulate the refractive index dynamically within a whispering gallery mode resonator. Modulation with a large tuning range is mostly performed for mode locking and dynamic control of the optical path at a modulation frequency as low as several hertz, while high frequency modulation up to megahertz is mainly exploited in optical switching devices with small tuning range. Here, we introduce the response functions theoretically to describe the dynamic response of temperature changes in the mode volume and the resonator body, respectively. This result is verified experimentally in silica microspherical resonators. The dependence of the tuning range on the modulation frequency is achieved. This knowledge could pave the way toward more practical control of refractive index in microresonators. PMID- 26479609 TI - Stray light and tolerance analysis of an ultrathin waveguide display. AB - Waveguides are becoming increasingly popular in the field of near-eye display because of their low thickness and light weight. However, ghost stray light generated in the waveguide and the double-image problem caused by low parallelism precision seriously degrade the display quality. In this study, the causes of stray light are investigated, an effective solution is proposed, and a coupling in structure is designed to suppress stray light. The Monte Carlo tolerances on the parallelism errors based on the visual acuity for the two substrates and the partially reflective mirror array (PRMA) of the waveguide are implemented. Results show that the fabrication accuracy of the substrates and the PRMA should be controlled within 6'' and 9'', respectively. A 2.4 mm thick waveguide with stray light of less than 1% is designed. The field of view is 36 degrees in the pupil-expanding direction, and the diameter of the exit pupil is 11.6 mm at an eye relief of 20 mm. Finally, a proof-of-concept prototype is fabricated and demonstrated. PMID- 26479611 TI - Electromagnetic sunscreen model: design of experiments on particle specifications. AB - We report a numerical study on sunscreen design and optimization. Thanks to the combined use of electromagnetic modeling and design of experiments, we are able to screen the most relevant parameters of mineral filters and to optimize sunscreens. Several electromagnetic modeling methods are used depending on the type of particles, density of particles, etc. Both the sun protection factor (SPF) and the UVB/UVA ratio are considered. We show that the design of experiments' model should include interactions between materials and other parameters. We conclude that the material of the particles is a key parameter for the SPF and the UVB/UVA ratio. Among the materials considered, none is optimal for both. The SPF is also highly dependent on the size of the particles. PMID- 26479612 TI - Quantitative phase imaging applied to laser damage detection and analysis. AB - We investigate phase imaging as a measurement method for laser damage detection and analysis of laser-induced modification of optical materials. Experiments have been conducted with a wavefront sensor based on lateral shearing interferometry associated with a high-magnification optical microscope. The system has been used for the in-line observation of optical thin films and bulk samples, laser irradiated in two different conditions: 500 fs pulses at 343 and 1030 nm, and millisecond to second irradiation with a CO2 laser at 10.6 MUm. We investigate the measurement of the laser-induced damage threshold of optical material by detection and phase changes and show that the technique realizes high sensitivity with different optical path measurements lower than 1 nm. Additionally, the quantitative information on the refractive index or surface modification of the samples under test that is provided by the system has been compared to classical metrology instruments used for laser damage or laser ablation characterization (an atomic force microscope, a differential interference contrast microscope, and an optical surface profiler). An accurate in-line measurement of the morphology of laser-ablated sites, from few nanometers to hundred microns in depth, is shown. PMID- 26479613 TI - End-pumped temperature-dependent passively Q-switched lasers. AB - In this paper, we compare pulse parameters in two end-pumped passively Q-switched lasers by increasing the boundary temperature of the laser crystal. For the Nd:YAG/Cr:YAG laser, the pulse energy at 1 kHz increased from 12.4 to 21 MUJ when the boundary temperature increased from 20 degrees C to 120 degrees C, while the pulse width decreased by 1.2 times. For the Nd:YVO4 passively Q-switched laser using Cr:YAG as the saturable absorber, the pulse energy at 100 Hz increased from 5.45 to 24.5 MUJ when the boundary temperature increased from 26 degrees C to 113 degrees C, while the pulse width decreased by 2.4 times. An improved model based on the rate equations was introduced to analyze the large variation of pulse energy when heating the Nd:YVO4 crystal. PMID- 26479614 TI - Thin-film optoacoustic transducers for subcellular Brillouin oscillation imaging of individual biological cells. AB - At low frequencies ultrasound is a valuable tool to mechanically characterize and image biological tissues. There is much interest in using high-frequency ultrasound to investigate single cells. Mechanical characterization of vegetal and biological cells by measurement of Brillouin oscillations has been demonstrated using ultrasound in the GHz range. This paper presents a method to extend this technique from the previously reported single-point measurements and line scans into a high-resolution acoustic imaging tool. Our technique uses a three-layered metal-dielectric-metal film as a transducer to launch acoustic waves into the cell we want to study. The design of this transducer and measuring system is optimized to overcome the vulnerability of a cell to the exposure of laser light and heat without sacrificing the signal-to-noise ratio. The transducer substrate shields the cell from the laser radiation, efficiently generates acoustic waves, facilitates optical detection in transmission, and aids with heat dissipation away from the cell. This paper discusses the design of the transducers and instrumentation and presents Brillouin frequency images on phantom, fixed, and living cells. PMID- 26479615 TI - Investigation of micro-injection molding based on longitudinal ultrasonic vibration core. AB - An ultrasound-assisted micro-injection molding method is proposed to improve the rheological behavior of the polymer melt radically, and a micro-injection molding system based on a longitudinal ultrasonic vibration core is developed and employed in the micro-injection molding process of Fresnel lenses. The verification experiments show that the filling mold area of the polymer melt is increased by 6.08% to 19.12%, and the symmetric deviation of the Fresnel lens is improved 15.62% on average. This method improved the filling performance and replication quality of the polymer melt in the injection molding process effectively. PMID- 26479616 TI - THz wave in double-metal-film waveguides and the application of wavelength analysis. AB - We propose the double-metal-film waveguides for terahertz (THz) wave guiding. The loss and field features are analyzed. In the application of wavelength analysis, the formula of the wavelength has been derived, and it can be used to analyze the wavelength of the THz sources according to mode field distribution in the dielectric-substrate slab. The penetrating capability of the THz wave is also discussed for different structures. When there is more energy in the dielectric substrate slab, it will be better for wavelength analysis. PMID- 26479617 TI - Three dimensional polymer waveguide using hybrid lithography. AB - A three dimensional polymer waveguide with taper structure was demonstrated and fabricated by a reliable and effective hybrid lithography. The hybrid lithography consists of lithography to fabricate a polymer waveguide and gray scale lithography to fabricate a polymer taper structure. Laser ablation and shadow aluminum evaporation were designed for gray scale lithography. The length of the gray scale region ranging from 20 to 400 MUm could be controlled by the laser power, the ablation speed, and the aluminum thickness. The slope angle was determined by the length of the gray scale region and the thickness of the photoresist. The waveguide taper structure could be transferred to the lower layer by the etching method. The taper structure can be used for integration of the waveguide with different dimensions. PMID- 26479618 TI - Studies on dynamic motion compensation and positioning accuracy on star tracker. AB - Error from motion is the dominant restriction on the improvement of dynamic performance on a star tracker. As a remarkable motion error, the degree of nonuniformity of the star image velocity field on the detector is studied, and thus a general model for the moving star spot is built. To minimize velocity nonuniformity, a novel general method is proposed to derive the proper motion compensation and location accuracy in cases of both uniform velocity and acceleration. Using this method, a theoretic analysis on the accuracy of time delayed integration and similar techniques, which are thought of as state-of-the art approaches to reduce error from motion, is conducted. The simulations and experimental results validate the proposed method. Our method shows a more steady performance than the dynamic binning algorithm. The positional error could be neglected when the smear length is far less than 3.464 times the scale of star spot, which suggests accuracy can be maintained by changing frame-integration time inverse proportional to the velocity on the focal plane. It also shows that the acceleration effect must be compensated to achieve accuracy close to the Cramer-Rao lower bound. PMID- 26479619 TI - Low-timing-jitter high-power mode-locked 1063 nm Nd:GdVO4 master oscillator power amplifier. AB - A low-timing-jitter high-power semiconductor saturable absorber mirror mode locked picosecond (ps) 1063 nm Nd:GdVO4 master oscillator power amplifier is presented. Using a single-pass Nd:GdVO4 amplifier, an amplified laser with 21.5 W output power and 8.3 ps pulsewidth was achieved at 250 MHz repetition rate. Employing a servo control, an average RMS timing jitter of ~222 fs was realized. This laser can be used as a drive laser for photocathode injectors in free electron lasers. PMID- 26479620 TI - Approach for designing and developing high-precision integrative systems for strip flatness detection. AB - In this paper, we propose an approach for designing and developing high-precision integrative systems for strip flatness detection. Algorithms are developed for camera calibration, which are more accurate than the general method calculating all the camera parameters. On the basis of this method, a detection system is developed including an integrative device for easy calculation and repeated usage. On-site experiment results confirm that the proposed method works well under hostile environmental conditions in mills. PMID- 26479621 TI - Scattering phase function of a charged spherical particle. AB - We deduced the scattering phase function (SPF) of a charged spherical particle, which is significantly different from the SPF of an uncharged spherical sphere. The difference between the SPF of a charged spherical particle and the SPF of an uncharged spherical sphere is related to the surface conductivity, particle size parameter, frequency of the electromagnetic (EM) waves, and refractive index of the particle. The surface charges carried by the particle make the backward scattering of EM waves increase. Given the EM wave frequency and the refractive index, there is a threshold of surface conductivity for each particle size number, beyond which the SPF mainly depends on the surface conductivity. PMID- 26479622 TI - Efficient generation of Hermite-Gauss and Ince-Gauss beams through kinoform phase elements. AB - We discuss the generation of Hermite-Gauss and Ince-Gauss beams employing phase elements whose transmittances coincide with the phase modulations of such beams. A scaled version of the desired field appears, distorted by marginal optical noise, at the element's Fourier domain. The motivation to perform this study is that, in the context of the proposed approach, the desired beams are generated with the maximum possible efficiency. A disadvantage of the method is the distortion of the desired beams by the influence of several nondesired beam modes generated by the phase elements. We evaluate such distortion employing the root mean square deviation as a figure of merit. PMID- 26479623 TI - Determination of the refractive index of glucose-ethanol-water mixtures using spectroscopic refractometry near the critical angle. AB - A spectroscopic refractometer was used to investigate the dispersion curves of ethanol and D-glucose solutions in water near the critical angle; here, the reflectivity was measured using a white source. Dispersion curves were obtained in the 320-1000 nm wavelength range with a resolution better than 10(-4) for the refractive index, n. The differential refractive index is measured as a function of wavelength, and a simple expression is proposed to obtain the refractive index of the glucose-ethanol-water ternary system. Using this expression, combined with the experimental differential refractive index values, the concentrations of individual components can be calculated. PMID- 26479624 TI - Analysis of focused laser differential interferometry. AB - A computational method for predicting the output of a focused laser differential interferometer (FLDI) given an arbitrary density field is presented. The method is verified against analytical predictions and experimental data. The FLDI simulation software is applied to the problem of measuring Mack-mode wave packets in a hypervelocity boundary layer on a 5 degrees half-angle cone. The software is shown to complement experiments by providing the necessary information to allow quantitative density fluctuation magnitudes to be extracted from experimental measurements. PMID- 26479625 TI - Comparative study of Al(x)Ga(1-x)As/GaAs photocathodes with different aluminum concentrations by surface photovoltage spectroscopy. AB - The influence of aluminum concentration in an Al(x)Ga(1-x)As window layer on the performance of Al(x)Ga(1-x)As/GaAs photocathodes was investigated. Three types of transmission-mode photocathode materials with different aluminum concentrations were designed for the comparative research. The surface photovoltage technique was applied to prepare samples. After the Cs-O activation process, spectral response curves of Al(x)Ga(1-x)As/GaAs photocathodes were obtained. Comparative studies show that a higher aluminum composition in the window layer is beneficial to improve the response of Al(x)Ga(1-x)As/GaAs photocathodes in the shortwave region. The surface photovoltage calculation formula of photocathode materials was put forward and used to obtain key performance parameters of Al(x)Ga(1 x)As/GaAs photocathodes by fitting calculations. Through calculations, the Al(x)Ga(1-x)As/GaAs interface recombination velocity, the minority carrier diffusion length of the window layer, and the emission layer were deduced, and there is a positive correlation between the aluminum composition in the window layer and the Al(x)Ga(1-x)As/GaAs interface recombination velocity, which is negative with the performance of photocathodes. PMID- 26479626 TI - Proposed new approach to the design of universal logic gates using the electro optic effect in Mach-Zehnder interferometers. AB - Efficient application of the electro-optic effect in a lithium-niobate-based Mach Zehnder interferometer to construct universal gates has been demonstrated. The study is carried out by simulating the proposed device with the beam propagation method, and the results are verified using MATLAB. Various parameters influencing the performance of the device (such as speed, latency, and power consumption) also have been taken into account. PMID- 26479627 TI - Triple-image encryption based on phase-truncated Fresnel transform and basic vector operation. AB - A triple-image encryption method is proposed that is based on phase-truncated Fresnel transform (PTFT), basic vector composition, and XOR operation. In the encryption process, two random phase masks, with one each placed at the input plane and the transform plane, are generated by basic vector resolution operations over the first and the second plaintext images, and then a ciphered image in the input plane is fabricated by XOR encoding for the third plaintext image. When the cryptosystem is illuminated by an on-axis plane, assisted by PTFT, the ciphered image is finally encrypted into an amplitude-only noise-like image in the output plane. During decryption, possessing the correct private key, decryption keys, and the assistant geometrical parameter keys, and placing them at the corresponding correct positions, the original three plaintext images can be successfully decrypted by inverse PTFT, basic vector composition, and XOR decoding. Theoretical analysis and numerical simulations both verify the feasibility of the proposed method. PMID- 26479629 TI - Effects of graded band-gap structures on spectral response of AlGaAs/GaAs photocathodes. AB - The effects of AlGaAs/GaAs layer thickness and Al composition range on the spectral response and integral sensitivities of reflection-mode graded band-gap AlGaAs/GaAs photocathodes have been investigated and simulated. The experimental results demonstrate that the spectral response over the wavelength region of interest for graded band-gap photocathodes is greater than that for uniform band gap cathodes, and the increase in long-wavelength response is more pronounced. These results can be attributed to the built-in electric field in the graded band gap AlGaAs layer. We established a spectral response model of graded band-gap photocathodes based on the numerical solution of coupled Poisson and continuity equations. According to the model, we calculated the theoretical spectral response and sensitivities of graded band-gap cathodes, and found the optimum Al(x)Ga(1-x)As layer thicknesses are 6, 10, 16, and 22 MUm for the reflection mode cathodes with linearly graded Al composition x ranges of 0 to 0.1, 0.2, 0.3, and 0.4, respectively. PMID- 26479628 TI - NOMAD spectrometer on the ExoMars trace gas orbiter mission: part 1--design, manufacturing and testing of the infrared channels. AB - NOMAD is a spectrometer suite on board ESA's ExoMars trace gas orbiter due for launch in January 2016. NOMAD consists of two infrared channels and one ultraviolet and visible channel allowing the instrument to perform observations quasi-constantly, by taking nadir measurements at dayside and nightside, and during solar occultations. In this paper, the design, manufacturing, and testing of the two infrared channels are described. We focus upon the optical working principle in these channels, where an echelle grating, used as a diffractive element, is combined with an acousto-optical tunable filter, used as a diffraction order sorter. PMID- 26479630 TI - Cavity-enhanced Faraday rotation measurement with auto-balanced photodetection. AB - Optical cavity enhancement for a tiny Faraday rotation is demonstrated with auto balanced photodetection. This configuration is analyzed using the Jones matrix formalism. The resonant rotation signal is amplified, and thus, the angular sensitivity is improved. In the experiment, the air Faraday rotation is measured with an auto-balanced photoreceiver in single-pass and cavity geometries. The result shows that the measured Faraday rotation in the single-pass geometry is enhanced by a factor of 85 in the cavity geometry, and the sensitivity is improved to 7.54*10(-10) rad Hz(-1/2), which agrees well with the Jones matrix analysis. With this verification, we propose an AC magnetic sensor whose magnetic sensitivity is expected to achieve 10 pT Hz(-1/2). PMID- 26479631 TI - Monitoring techniques for the manufacture of tapered optical fibers. AB - The use of a range of optical techniques to monitor the process of fabricating optical fiber tapers is investigated. Thermal imaging was used to optimize the alignment of the optical system; the transmission spectrum of the fiber was monitored to confirm that the tapers had the required optical properties and the strain induced in the fiber during tapering was monitored using in-line optical fiber Bragg gratings. Tapers were fabricated with diameters down to 5 MUm and with waist lengths of 20 mm using single-mode SMF-28 fiber. PMID- 26479632 TI - Validation of ozone monitoring instrument ultraviolet index against ground-based UV index in Kampala, Uganda. AB - The Ozone Monitoring Instrument (OMI) overpass solar ultraviolet (UV) indices have been validated against the ground-based UV indices derived from Norwegian Institute for Air Research UV measurements in Kampala (0.31 degrees N, 32.58 degrees E, 1200 m), Uganda for the period between 2005 and 2014. An excessive use of old cars, which would imply a high loading of absorbing aerosols, could cause the OMI retrieval algorithm to overestimate the surface UV irradiances. The UV index values were found to follow a seasonal pattern with maximum values in March and October. Under all-sky conditions, the OMI retrieval algorithm was found to overestimate the UV index values with a mean bias of about 28%. When only days with radiation modification factor greater than or equal to 65%, 70%, 75%, and 80% were considered, the mean bias between ground-based and OMI overpass UV index values was reduced to 8%, 5%, 3%, and 1%, respectively. The overestimation of the UV index by the OMI retrieval algorithm was found to be mainly due to clouds and aerosols. PMID- 26479633 TI - Elasto-optic effect anisotropy in gallium phosphide crystals. AB - Elasto-optic coefficients of gallium phosphide (GaP) crystals were calculated on the basis of their piezo-optic and elastic coefficients. Surfaces of the spatial distribution of piezo- and elasto-optic effects in these crystals were built. The maxima of the surfaces of the elasto-optic effect and the geometries of acousto optic interaction that correspond to these maxima were found. Ratios that describe the rotation of optical indicatrix, depending on direction of the action of uniaxial pressure or deformation on cubic crystal, were recorded. It was shown that such rotations induced by mechanical stress do not exceed 1.5 degrees in GaP, but in some cubic crystals they can reach tens of degrees. PMID- 26479634 TI - Measurement of optical scattered power from laser-induced shallow pits on silica. AB - A model describing far-field scattered power and irradiance by a silica glass slab with a shallow-pitted exit surface is experimentally validated. The comparison to the model is performed using a precisely micromachined ensemble of ~11 MUm wide laser ablated shallow pits producing 1% of the incident beam scatter in a 10 mrad angle. A series of samples with damage initiations and laser induced shallow pits resulting from 351 nm, 5 ns pulsed laser cleaning of metal microparticles at different fluences between 2 J/cm2 and 11 J/cm2 are characterized as well and found in good agreement with model predictions. PMID- 26479635 TI - Statistics of the derivatives of complex signal derived from Riesz transform and its application to pseudo-Stokes vector correlation for speckle displacement measurement. AB - As an improvement of the well-known intensity correlation used in conventional electronic speckle photography, we have proposed a new technique, to the best of our knowledge, for displacement measurement referred to as pseudo-Stokes vector correlation (PSVC). To provide a theoretical background for the superiority of the proposed PSVC technique, we study the statistical properties of the spatial derivatives of the complex signal representation generated from the Riesz transform. Under the assumption of a Gaussian random process, a theoretical analysis for the pseudo Stokes vector correlation has been provided. Based on these results, we show mathematically that PSVC has a performance advantage over conventional intensity-based correlation technique. PMID- 26479636 TI - Quantitative phase microscopy via optimized inversion of the phase optical transfer function. AB - Although the field of quantitative phase imaging (QPI) has wide-ranging biomedical applicability, many QPI methods are not well-suited for such applications due to their reliance on coherent illumination and specialized hardware. By contrast, methods utilizing partially coherent illumination have the potential to promote the widespread adoption of QPI due to their compatibility with microscopy, which is ubiquitous in the biomedical community. Described herein is a new defocus-based reconstruction method that utilizes a small number of efficiently sampled micrographs to optimally invert the partially coherent phase optical transfer function under assumptions of weak absorption and slowly varying phase. Simulation results are provided that compare the performance of this method with similar algorithms and demonstrate compatibility with large phase objects. The accuracy of the method is validated experimentally using a microlens array as a test phase object. Lastly, time-lapse images of live adherent cells are obtained with an off-the-shelf microscope, thus demonstrating the new method's potential for extending QPI capability widely in the biomedical community. PMID- 26479637 TI - Free-form illumination of a refractive surface using multiple-faceted refractors. AB - We report a design method based on multiple-faceted refractors for free-form illumination of a refractive surface. The free-form surface is constructed as a set of primitive surface elements, which provide flexibility to satisfy the requirements of practical design problems. An extended light source can be considered, and a smooth free-form refractive surface can be established by adding feedback to the design process for a point source. Moreover, the performance can be improved by iterating this feedback process. Illumination systems with a point source and an extended source are designed and analyzed, resulting in uniform illuminance distribution, which demonstrates the validity of the method. PMID- 26479638 TI - Optical design of an LED motorcycle headlamp with compound reflectors and a toric lens. AB - An optical design for a new white LED motorcycle headlamp is presented. The motorcycle headlamp designed in this study comprises a white LED module, an elliptical reflector, a parabolic reflector, and a toric lens. The light emitted from the white LED module is located at the first focal point of the elliptical reflector and focuses on the second focal point. The second focal point of the elliptical reflector and the focal point of the parabolic reflector are confocal. We use nonsequential rays to improve the optical efficiency of the compound reflectors. The toric spherical lens allows the device to meet the Economic Commission of Europe, regulation no. 113 (ECE R113). Furthermore, good uniformity is obtained by using aspherical surface optimization of the same toric lens. The reflectivity of the reflector is 95%, and the transmittance of each lens surface is 98%. The average deviation of the high beam is 14.17%, and the optical efficiency is 66.45%. PMID- 26479639 TI - High temperature strain sensor based on a fiber Bragg grating and rhombus metal structure. AB - In this paper, a novel high temperature strain sensor based on a polyimide-coated fiber Bragg grating (FBG) and a rhombus metal structure is presented and experimentally demonstrated. By heating low softening point glass via a micro torch, the polyimide-coated FBG could be fixed into the rhombus metal structure. Consequently, when the rhombus structure is stretched and compressed, respectively, then the FBG will be subjected to a reverse state. Moreover, the strain sensitivity is controllable and enhanced by adjusting the dimension of the rhombus metal structure appropriately. The experiment was then carried out by using an equi-intensity cantilever beam and high temperature chamber, and the result showed that the proposed high temperature strain sensor could be used at the high temperature of 300 degrees C. A resolution of ~10 MUepsilon has been experimentally achieved. The average wavelength strain sensitivity at 300 degrees C is 1.821 and 1.814 pm/MUepsilon, for the compressed and stretched states, respectively. PMID- 26479640 TI - Least-squares fitting of Hartmann or Shack-Hartmann data with a circular array of sampling points. AB - A least-squares procedure to find the tilts, curvature, astigmatism, coma, and triangular astigmatism by means of measurements of the transverse aberrations using a Hartmann or Shack-Hartmann test is described. The sampling points are distributed in a ring centered on the pupil of the optical system. The properties and characteristics of rings with three, four, five, six, or more sampling points are analyzed with more detail and better mathematical analysis than in previous publications. PMID- 26479641 TI - Near-infrared imaging system for nondestructive inspection of micro-crack in wafer through dicing tape. AB - Detection of wafer/die crack after the wafer dicing process is important for yield rate control prior to packaging. The traditional approach of microscopic examination is done after the dies are stripped from the dicing tape, and further crack propagation could result from this pick-and-place process. An on-tape crack inspection technique is proposed in this paper so that the crack from the dicing process can be clearly identified. The issues of seeing through the silicon substrate and the scattering at the dicing tape have been resolved, respectively, using a near-infrared wavelength of 1100 nm for illumination and using a feeding index matching liquid for filling the rough surface of the tape. Both the illumination and imaging optics of the inspection system have been designed and simulated with a ray-tracing program, and the prototype demonstrates the ability of seeing through the silicon substrate and dicing tape as well as detecting micro-crack down to 1.25 MUm, whose resolution is sufficient for most applications of die crack inspection. PMID- 26479642 TI - Implementation of laser acupuncture with lifting-thrusting through the use of mechanically immobile components. AB - Lifting and thrusting constitute an important manipulation method in traditional Chinese acupuncture. Lifting and thrusting enables the implementation of various features, such as reinforcement and reduction, which enhance acupuncture effectiveness. Laser acupuncture stimulates acupoints through laser light, which is a noninvasive treatment, but can still achieve effects similar to those obtained from traditional acupuncture. Lifting and thrusting can be achieved by moving the laser focal point back and forth, thus concentrating the energy, as does the tip of the acupuncture needle when it is moved upward and downward in the acupoint. This article presents a novel optical design of a laser acupuncture device, in which a focus-tunable lens is used to move the position of the focused light in order to achieve the lifting and thrusting mechanism through programmable changes to the control current of the focus-tunable lens. The device employs an infrared laser with a wavelength of 808 nm and a maximum power of 150 mW. The focus-tunable lens used in this study had a diopter of -10 to +5. The results revealed that by controlling the lens diopter, the focused light can be moved from 4.5 to 9.5 cm. Therefore, the range of the lift and thrust for the laser acupuncture device was 5 cm. The area of the focal point was approximately 6*10(-3) mm2, which is comparable to that of the commonly used traditional acupuncture needle tip. Because the components are immobile, no additional space is required for the moving lens. Therefore, the size of the laser acupuncture head can be minimized, and the effectiveness of focus tuning can be improved. PMID- 26479643 TI - Image quality affected by diffraction of aperture structure arrangement in transparent active-matrix organic light-emitting diode displays. AB - Transparent display is one of the main technologies in next-generation displays, especially for augmented reality applications. An aperture structure is attached on each display pixel to partition them into transparent and black regions. However, diffraction blurs caused by the aperture structure typically degrade the transparent image when the light from a background object passes through finite aperture window. In this paper, the diffraction effect of an active-matrix organic light-emitting diode display (AMOLED) is studied. Several aperture structures have been proposed and implemented. Based on theoretical analysis and simulation, the appropriate aperture structure will effectively reduce the blur. The analysis data are also consistent with the experimental results. Compared with the various transparent aperture structure on AMOLED, diffraction width (zero energy position of diffraction pattern) of the optimize aperture structure can be reduced 63% and 31% in the x and y directions in CASE 3. Associated with a lenticular lens on the aperture structure, the improvement could reach to 77% and 54% of diffraction width in the x and y directions. Modulation transfer function and practical images are provided to evaluate the improvement of image blurs. PMID- 26479644 TI - Freeform lens design for light-emitting diode uniform illumination by using a method of source-target luminous intensity mapping. AB - We present a freeform lens for application to LED uniform illumination. This lens, which is designed with a method of simple source-target luminous intensity mapping, can produce irradiance uniformity of greater than 0.8 and optical efficiency above 90% with an arbitrary half-beam angle greater than 45 deg. Typically, as compared with a conventional source-target energy mapping method, this design method can achieve better optical performance of lenses for general LED lighting. When a non-Lambertian-type light source is employed, for example, the chip on board LED, the use of the method can result in a compact LED lens without losing the optical performances of high irradiance uniformity and high optical efficiency as yielded by lenses for Lambertian-type LED light sources. PMID- 26479645 TI - Design and assessment of a wide FOV and high-resolution optical tiled head mounted display. AB - It has always been a challenge to break the resolution/field-of-view (FOV) invariant to design a large FOV and high-resolution optical system, especially for a head-mounted display (HMD) system. In this study, a tiled HMD using two compact rotationally symmetrical eyepieces was designed and developed. Some issues on exit pupil and eye relief were analyzed in detail and taken into consideration during the design procedure. The overall optical system is compact with high performance. The system volume is smaller than 30 mm*35 mm*30 mm. Based on two 0.61 in. microdisplay devices, the overall tiled system demonstrates an FOV of 66 degrees (H)*32 degrees (V) with a 7.5 mm exit pupil diameter and a 15.7 mm eye relief. PMID- 26479646 TI - Solar concentrator with a toroidal relay module. AB - III-V multijunction solar cells require solar concentrators with a high concentration ratio to reduce per watt cost and to increase solar energy transforming efficiency. This paper discusses a novel solar concentrator design that features a high concentration ratio, high transfer efficiency, thin profile design, and a high solar acceptance angle. The optical design of the concentrator utilizes a toroidal relay module, which includes both the off-axis relay lens and field lens design in a single concentric toroidal lens shape. The optical design concept of the concentrator is discussed and the simulation results are shown. The given exemplary design has an aspect ratio of 0.24, a high averaged optical concentration ratio 1230*, a maximum efficiency of 76.8%, and the solar acceptance angle of +/-0.9 degrees . PMID- 26479647 TI - Freeform microstructure linear light emitter design for a natural light illumination system. AB - The major factors of an illuminative environment are a high rendering index and uniformity. The natural light illumination system (NLIS) is used to guide sunlight for indoor illumination. The NLIS consists of three subsystems: collecting, transmitting, and emitting. Nowadays, a variety of light emitters are available for different illuminative environments. This paper proposes a linear microstructure to diffuse parallel light for indoor illumination. To increase uniformity and promote the illuminative area, the light emitter includes two microstructures for the distribution of light. Finally, the proposed light emitter gives illuminance uniformity and efficiency of 0.55% and 74.18%, respectively. PMID- 26479648 TI - Innovative light collimator with afocal lens and total internal reflection lens for daylighting system. AB - This research presents a novel design of the collimator, which uses total internal reflection (TIR), convex, and concave lenses for the natural light illumination system (NLIS). The concept of the NLIS is to illuminate building interiors with natural light, which saves energy consumption. The TIR lens is used to collimate the light, and convex and concave lenses are used to converge the light to the required area. The results have shown that the efficiency in terms of achieving collimated light using the proposed collimator at the output of the light collector is better than that of a previous system without a collimator. PMID- 26479649 TI - Optical design of dental light with high performance and low power based on white LEDs. AB - This paper presents an optical design of a dental light that meets the regulation of ISO 9680. The designed light pattern on the target is an elliptical shape with uniform illumination. Moreover, the real module contains four optical modules, and is operated at 9 W and performs a maximum illuminance of 42,010 lx. In order to reduce the correlated color temperature (CCT) variation, we replace the original white light-emitting diode with a new one, which has an extremely low angular CCT derivation. Accordingly, the CCT variation is reduced to 232 K from 1323 K of the original module. PMID- 26479650 TI - Statistics-based reconstruction method with high random-error tolerance for integral imaging. AB - A three-dimensional (3D) digital reconstruction method for integral imaging with high random-error tolerance based on statistics is proposed. By statistically analyzing the points reconstructed by triangulation from all corresponding image points in an elemental images array, 3D reconstruction with high random-error tolerance could be realized. To simulate the impacts of random errors, random offsets with different error levels are added to a different number of elemental images in simulation and optical experiments. The results of simulation and optical experiments showed that the proposed statistic-based reconstruction method has relatively stable and better reconstruction accuracy than the conventional reconstruction method. It can be verified that the proposed method can effectively reduce the impacts of random errors on 3D reconstruction of integral imaging. This method is simple and very helpful to the development of integral imaging technology. PMID- 26479651 TI - Human vision model in relation to characteristics of shapes for the Mach band effect. AB - For human vision to recognize the contours of objects means that, as the contrast variation at the object's edges increases, so will the Mach band effect of human vision. This paper more deeply investigates the relationship between changes in the contours of an object and the Mach band effect of human vision. Based on lateral inhibition and the Mach band effect, we studied subjects' eyes as they watched images of different shapes under a fixed brightness at 34 cd/m2, with changes of contrast and spatial frequency. Three types of display were used: a television, a computer monitor, and a projector. For each display used, we conducted a separate experiment for each shape. Although the maximum values for the contrast sensitivity function curves of the displays were different, their variations were minimal. As the spatial frequency changed, the diminishing effect of the different lines also was minimal. However, as the shapes at the contour intersections were modified by the Mach band effect, a greater degree of variation occurred. In addition, as the spatial frequency at a contour intersection increased, the Mach band effect became lower, along with changes in the corresponding contrast sensitivity function curve. Our experimental results on the characteristics of human vision have led to what we believe is a new vision model based on tests with different shapes. This new model may be used for future development and implementation of an artificial vision system. PMID- 26479652 TI - Single-shot digital holography for fast measuring optical properties of fibers. AB - We propose a fast method for measuring optical properties, e.g., the refractive index profile and birefringence, of fibers. It is based on recovering the phase distribution of light refracted by a fiber sample at the recording plane from a single-shot digital hologram. During the recovering process, an optimized approach based on the spatial carrier frequency method was utilized. The proposed approach enhances affects that arise from the limited spatial extent of the bandpass filter associated with the implementation of the spatial carrier frequency method. In contrast to the low spatial resolution of off-axis digital holograms, the method ensures the best utilization of the camera support. From the recovered phase information, the optical path difference is measured; thus, the refractive index profile, the mean refractive index, and the birefringence of isotactic polypropylene (IPP) are determined. Experimental results are given for illustration. PMID- 26479653 TI - Double peak-induced distance error in short-time-Fourier-transform-Brillouin optical time domain reflectometers event detection and the recovery method. AB - The measured distance error caused by double peaks in the BOTDRs (Brillouin optical time domain reflectometers) system is a kind of Brillouin scattering spectrum (BSS) deformation, discussed and simulated for the first time in the paper, to the best of the authors' knowledge. Double peak, as a kind of Brillouin spectrum deformation, is important in the enhancement of spatial resolution, measurement accuracy, and crack detection. Due to the variances of the peak powers of the BSS along the fiber, the measured starting point of a step-shape frequency transition region is shifted and results in distance errors. Zero padded short-time-Fourier-transform (STFT) can restore the transition-induced double peaks in the asymmetric and deformed BSS, thus offering more accurate and quicker measurements than the conventional Lorentz-fitting method. The recovering method based on the double-peak detection and corresponding BSS deformation can be applied to calculate the real starting point, which can improve the distance accuracy of the STFT-based BOTDR system. PMID- 26479654 TI - Simulation of autofocus lens design for a cell phone camera with object distance from infinity to 9.754 mm. AB - This paper presents the simulation of an autofocus lens design with large depth of field for a cell phone camera. The object distance of the lens is from infinity to 9.754 mm. When the object distance is from infinity to 550 mm, the value of the modulation transfer function (MTF) is greater than 0.6 for the spatial frequency of 114 lp/mm, the optical distortion is less than 1.5%, and the relative illumination is greater than 67%. When the object distance is from 325 to 9.754 mm, the MTF values is greater than 0.4 for close-up shooting. The optical distortion is less than 1.454%, and the relative illumination is greater than 68.8%. PMID- 26479655 TI - Micro-lens array design on a flexible light-emitting diode package for indoor lighting. AB - An advanced, ultra-thin, flexible LED (FLED) package technique is first proposed in this study, where a polyimide substrate was used as the lead frame package material due to its physical stability in thermal processing. The experimental results showed that the thickness of the mockup sample measured by a vernier caliper was 260 MUm and 35% thinner than the Panasonic organic LED lighting panel announced on 4 March 2014 in Tokyo. Moreover, the flexible angle of the ultra thin LED package was 200.54 degrees when it surrounded a disk with a 1 cm radius. A design of a micro-lens array manufactured by silicone molding on the FLED is also proposed in this study. Finally, different types of micro-lenses were applied to different lighting regions to investigate their lighting effects. PMID- 26479656 TI - Optical analysis of miniature lenses with curved imaging surfaces. AB - Miniature cameras for consumer electronics and mobile phones have been, and continue to be, in fast development. The system level requirements, such as manufacturing cost, packaging, and sensor characteristics, impose unique challenges for optical designers. In this paper, we discuss the potential optical benefits of having a curved image surface rather than a flat one. We show that curved sensor technology allows for optically faster lens solutions. We discuss trade-offs of several relevant characteristics, such as packaging, chief ray angle, image quality, and tolerance sensitivity. A comparison of a benchmark flat field lens, and an evaluation design imaging on a curved surface and working at f/1.6, provides useful specific insights. For a given image quality, departing from a flat imaging surface does not allow significantly reducing the total length of a lens. PMID- 26479657 TI - Study of optical design of three-dimensional digital ophthalmoscopes. AB - This study primarily involves using optical zoom structures to design a three dimensional (3D) human-eye optical sensory system with infrared and visible light. According to experimental data on two-dimensional (2D) and 3D images, human-eye recognition of 3D images is substantially higher (approximately 13.182%) than that of 2D images. Thus, 3D images are more effective than 2D images when they are used at work or in high-recognition devices. In the optical system design, infrared and visible light wavebands were incorporated as light sources to perform simulations. The results can be used to facilitate the design of optical systems suitable for 3D digital ophthalmoscopes. PMID- 26479658 TI - Thin hollow light guide for high-efficiency planar illuminator. AB - Light guides have been widely used for transforming line sources into planar illuminators for lighting and display applications. Solid light guides provide good uniformity but still have the issues of heavy weight and material absorption, especially for large applications. Hollow light guides solve the problem of weight, but the uniformity is relatively poor or efficiency could be sacrificed for enhancing uniformity. In this paper, a hollow light guide with edge-lit LED sources has been proposed to simultaneously resolve the issues of weight, uniformity, and efficiency. The major approach is to modulate the LED luminous intensity profile by a ring of parabolic surface with continuously varied focal length. The modulated light emitting profile directly makes up sufficient uniformity on the planar surface, and extra components are not required. The prototype is a circular planar illuminator with a diameter of 178 mm and a weight of 240 g. The experiment shows an overall efficiency of 82.37%, with a uniformity of 83.7%. The weight of the whole module is 40% lighter than that of a solid light guide with the same size. PMID- 26479659 TI - Wavefront measurement made by an off-the-shelf laser-scanning pico projector. AB - Focal plane testing methods such as the Shack-Hartmann wavefront sensor and phase shifting deflectometry are valuable tools for optical testing. In this study, we propose a novel wavefront slope testing method that uses a scanning galvo laser, in which a single-mode Gaussian beam scans the pupils of the tested optics in the system. In addition, the ray aberration is reconstructed by the four-step phase shifting measurement by modulating the angular domain. The measured wavefront is verified by a Fizeau interferometer in terms of Zernike polynomials. PMID- 26479660 TI - Color multiplexing method to capture front and side images with a capsule endoscope. AB - This paper proposes a capsule endoscope (CE), based on color multiplexing, to simultaneously record front and side images. Only one lens associated with an X cube prism is employed to catch the front and side view profiles in the CE. Three color filters and polarizers are placed on three sides of an X-cube prism. When objects locate at one of the X-cube's three sides, front and side view profiles of different colors will be caught through the proposed lens and recorded at the color image sensor. The proposed color multiplexing CE (CMCE) is designed with a field of view of up to 210 deg and a 180 lp/mm resolution under f-number 2.8 and overall length 13.323 mm. A ray-tracing simulation in the CMCE with the color multiplexing mechanism verifies that the CMCE not only records the front and side view profiles at the same time, but also has great image quality at a small size. PMID- 26479661 TI - Investigation of remote-phosphor white light-emitting diodes with improved scattered photon extraction structure. AB - In this study, an improved scattered photon extraction (SPE) package structure with a reflection plate over the remote phosphor layer is presented. The important factors for the remote phosphor layer in the conventional and improved SPE package structures, including the phosphor layer thickness and phosphor concentration, are also studied. The simulation results show that the yellow-blue ratio (YBR) of the conventional and improved SPE package structure increases with the phosphor concentration when the phosphor layer is thin and that the YBR is saturated when the layer is thick. The experimental results show that for both conventional and improved SPE package structure, the correlated color temperature (CCT) decreases as the phosphor concentration increases. However, the YBR of the improved SPE package structure is higher than that of the conventional SPE package structure for a given phosphor layer thickness and phosphor concentration. That is, in the conventional SPE package structure, it is necessary to increase the phosphor concentration and then increase the absorption of blue light to obtain more yellow light. Hence, for the improved SPE package structure, less phosphor is required in the phosphor layer for achieving the chosen CCT. PMID- 26479662 TI - Precision distance measurement using a two-photon absorption process in a silicon avalanche photodiode with saw-tooth phase modulation. AB - We present a novel configuration of a precision laser distance measurement based on the two-photon absorption (TPA) photocurrent from a silicon avalanche photodiode (Si-APD). The proposed system uses saw-tooth phase modulation, known as serrodyne modulation, in order to shift the frequency of the reference light from that of the probe light. It suppresses the coherent interference noise between the probe and the reference. The serrodyne modulation also enables lock in detection of the TPA photocurrent. Furthermore, it contributes to the reduction of the system components. The precision measurement is experimentally demonstrated by measuring a fiber length difference of 2.6 m with a standard deviation of 27 MUm under constant temperature. The high-precision displacement measurement is also demonstrated by measuring the temperature-induced change in the optical path length difference of a fiber interferometer. PMID- 26479663 TI - Approach to analytically minimize the LCD moire by image-based particle swarm optimization. AB - In this paper, we proposed a methodology to optimize the parametric window of a liquid crystal display (LCD) system, whose visual performance was deteriorated by the pixel moire arising in between multiple periodic structures. Conventional analysis and minimization of moire patterns are limited by few parameters. With the proposed image-based particle swarm optimization (PSO), we enable a multivariable optimization at the same time. A series of experiments was conducted to validate the methodology. Due to its versatility, the proposed technique will certainly have a promising impact on the fast optimization in LCD design with more complex configuration. PMID- 26479664 TI - Experiment evaluation of speckle suppression efficiency of 2D quasi-spiral M sequence-based diffractive optical element. AB - The quasi-spiral 2D diffractive optical element (DOE) based on M-sequence of length N=15 is designed and manufactured. The speckle suppression efficiency by the DOE rotation is measured. The speckle suppression coefficients of 10.5, 6, and 4 are obtained for green, violet, and red laser beams, respectively. The results of numerical simulation and experimental data show that the quasi-spiral binary DOE structure can be as effective in speckle reduction as a periodic 2D DOE structure. The numerical simulation and experimental results show that the speckle suppression efficiency of the 2D DOE structure decreases approximately twice at the boundaries of the visible range. It is shown that a replacement of this structure with the bilateral 1D DOE allows obtaining the maximum speckle suppression efficiency in the entire visible range of light. PMID- 26479665 TI - Transverse image translation using an optical freeform single lens. AB - In this paper, we have proposed an approach that utilizes freeform optical surfaces to realize a novel optical function called transverse image translation, which acts as a basic geometrical transformation for images. Its purpose is to make the image of a given optical system move directionally with the designated distance by means of inserting and arranging some extra optical elements behind the given system. The structure of the given system, as well as its optical specifications, stays unchanged when performing the translation. As the translation is transverse, the image can only move transversely in the plane where the original image lies. A freeform single lens comprising two different freeform surfaces is designed for the given system as the only translation element. The image of the given system is expected to be successfully translated transversely as designed when the freeform lens is properly inserted. The design method and process of the freeform lens is presented briefly. Additionally, a design example is introduced to demonstrate the feasibility of our proposed approach for this new type of transverse image translation. PMID- 26479666 TI - Reconfigurable optofluidic switch for generation of optical pulse width modulation based on tunable reflective interface. AB - We present a numerical method for generation of optical pulse width modulation (PWM) based on tunable reflective interface by using a microfluidic droplet. We demonstrate a single layer, planar, optofluidic PWM switch that is driven by excited alternating microbubbles. The main parameters of generation of this PWM such as frequency and speed of switching can be controlled by the mass flow rates of input fluids, and the shape of plug or droplet. Advantages of this design are the reconfigurability in design and the easy control of the switching parameters. The validation of the proposed design is carried out by employing the finite element method (FEM) for the mechanical simulation and the finite-difference time domain (FDTD) for the optical simulation. PMID- 26479667 TI - Design of multisegmented freeform lens for LED fishing/working lamp with high efficiency. AB - A novel LED fishing/working light is proposed to enhance the lighting efficiency of a fishing boat. The study is focused on the freeform secondary lens design so as to create a lamp that attracts fish and sheds light on the deck for the crew's work. The experimental results show that the proposed multisegmented freeform lens can deliver the proposed aim, giving 3 times as much illuminating power as the traditional high-intensity discharge fishing lamp does with the same input of electrical power. PMID- 26479668 TI - Improving the color uniformity of multiple colored light-emitting diodes using a periodic microstructure surface. AB - This study looks at the performance of a periodic microstructure surface on multiple colored light-emitting diodes (LEDs). A periodic microstructure surface on the package was used to reshape the light from the different colored LED chips in the multiple colored LEDs, which decreased the color separation and color nonuniformity of the multiple colored LEDs. Experimental results show that the multiple colored LEDs with a periodic microstructure surface could achieve medium or high collimation as well as good color uniformity. Thus, this study provides a simple and cost-effective method to greatly improve the color uniformity of multiple colored LEDs with medium or high collimation. PMID- 26479669 TI - Conditions for having identical aberration behaviors of various thick lenses. AB - Two optical lenses with the same focal length but different lens thicknesses and principal plane locations can provide equivalent first-order optics on imagery if the marginal and chief ray heights and slope angles at their principal planes are equal, resulting in the same system magnification, object and image distances. In this paper, we will prove that if these lenses have the same primary aberrations (including Seidel aberrations, chromatic aberrations, and secondary spectrum) corresponding to the same marginal and chief rays then they must have the same new aberrations for any same new rays. This theorem is useful when designers would like to redesign a lens group in a system. The influence on the movements among lens groups, the special aberration properties of plane parallel plates, and afocal lens groups are also discussed. PMID- 26479670 TI - Dual-view angle backlight module design. AB - We propose a bilayer light guide plate (BLGP) with specially designed microstructures and two light source modules to achieve an adjustable viewing angle backlight for ecofriendly displays. The dual viewing angle backlight module has a thin, simple structure and a high optical efficiency. Comparison with the conventional edge-lit backlight module shows an improvement in the on-axis luminance of the narrow viewing angle mode of 4.3 times and a decrease in the half-luminance angle of 7 degrees in the horizontal direction. When using the wide viewing angle mode, there is an improvement in the on-axis luminance of 1.8 times and an improvement in the half-luminance angle of 54 degrees in the horizontal direction. The uniformity of illuminance can reach 80% in each mode. The backlight optical sheet number is reduced from 5 to 1. PMID- 26479671 TI - Aspherical lens design using hybrid neural-genetic algorithm of contact lenses. AB - The design of complex contact lenses involves numerous uncertain variables. How to help an optical designer to first design the optimal contact lens to reduce discomfort when wearing a pair of glasses is an essential design concern. This study examined the impact of aberrations on contact lenses to optimize a contact lens design for myopic and astigmatic eyes. In general, two aspherical surfaces can be assembled in an optical system to reduce the overall volume size. However, this design reduces the spherical aberration (SA) values at wide contact radii. The proposed optimization algorithm with optical design can be corrected to improve the SA value and, thus, reduce coma aberration (TCO) values and enhance the modulation transfer function (MTF). This means integrating a modified genetic algorithm (GA) with a neural network (NN) to optimize multiple-quality characteristics, namely the SA, TCO, and MTF, of contact lenses. When the proposed optional weight NN-GA is implemented, the weight values of the fitness function can be varied to adjust system performance. The method simplifies the selection of parameters in the optimization of optical systems. Compared with the traditional CODE V built-in optimal scheme, the proposed scheme is more flexible and intuitive to improve SA, TCO, and MTF values by 50.03%, 45.78%, and 24.7%, respectively. PMID- 26479672 TI - Optical and thermal design of light emitting diodes omnidirectional bulb. AB - The penetration of LED light bulbs into the lighting market is growing quickly in recent years due to significant increase of LED efficiency and reduction of cost. One major issue to be improved is the overall light bulb efficiency, which can fulfill "Energy Star for Lamps" while keeping sufficiently high efficiency. The efficiency issue results mainly from the high directionality of the LED sources and the corresponding solutions to make the emission more diverse. In this paper, a diffusion white reflection sheet (DWRS) with an array of holes is proposed as a high efficiency solution for modulating a light emission profile with SMD type LED source. The hole size is adjusted with fixed hole pitch to both maximize the efficiency and meet the omnidirectional specification. In addition, the concept of thermal plastic insertion molding metal is proposed for thermal management without fins for cooling. The prototype demonstrates the efficiency (Ef.) of 87.6% and LED pad temperature of 85 degrees C, which shows the feasibility as a total solution for high efficiency LED omnidirectional bulbs. PMID- 26479673 TI - Publishing supplementary material: editorial. AB - Editor-in-Chief Ron Driggers highlights the new supplemental material guidelines for OSA Journals. PMID- 26479674 TI - Optical design and testing: introduction. AB - Optical design and testing have numerous applications in industrial, military, consumer, and bio-medical settings. This issue features original research ranging from the optical design of image and nonimage optical stimuli for human perception, optics applications, bio-optics applications, displays, and solar energy systems to novel imaging modalities from deep UV to infrared spectral imaging, a systems perspective to imaging, as well as optical measurement. In addition, new concepts and trends for optics and further optical systems will be especially highlighted in this special issue. PMID- 26479675 TI - Scalable Synthesis of Human Ultralong Chain Ceramides. AB - Ceramides with ultralong chains (>=30 carbons), also known as acylceramides, play a critical role in the survival of mammals on dry land. An efficient and scalable synthesis of four major classes of ultralong human skin ceramides is reported. The key approach involves the use of a succinimidyl ester that acts as a protective group, helps overcome the extremely low solubility, and simultaneously activates the fatty acid for its clean and high-yielding attachment to a sphingoid base. PMID- 26479676 TI - ZINC 15--Ligand Discovery for Everyone. AB - Many questions about the biological activity and availability of small molecules remain inaccessible to investigators who could most benefit from their answers. To narrow the gap between chemoinformatics and biology, we have developed a suite of ligand annotation, purchasability, target, and biology association tools, incorporated into ZINC and meant for investigators who are not computer specialists. The new version contains over 120 million purchasable "drug-like" compounds--effectively all organic molecules that are for sale--a quarter of which are available for immediate delivery. ZINC connects purchasable compounds to high-value ones such as metabolites, drugs, natural products, and annotated compounds from the literature. Compounds may be accessed by the genes for which they are annotated as well as the major and minor target classes to which those genes belong. It offers new analysis tools that are easy for nonspecialists yet with few limitations for experts. ZINC retains its original 3D roots--all molecules are available in biologically relevant, ready-to-dock formats. ZINC is freely available at http://zinc15.docking.org. PMID- 26479677 TI - Community-based pedestrian safety training in virtual reality: A pragmatic trial. AB - Child pedestrian injuries are a leading cause of mortality and morbidity across the United States and the world. Repeated practice at the cognitive-perceptual task of crossing a street may lead to safer pedestrian behavior. Virtual reality offers a unique opportunity for repeated practice without the risk of actual injury. This study conducted a pre-post within-subjects trial of training children in pedestrian safety using a semi-mobile, semi-immersive virtual pedestrian environment placed at schools and community centers. Pedestrian safety skills among a group of 44 seven- and eight-year-old children were assessed in a laboratory, and then children completed six 15-minute training sessions in the virtual pedestrian environment at their school or community center following pragmatic trial strategies over the course of three weeks. Following training, pedestrian safety skills were re-assessed. Results indicate improvement in delay entering traffic following training. Safe crossings did not demonstrate change. Attention to traffic and time to contact with oncoming vehicles both decreased somewhat, perhaps an indication that training was incomplete and children were in the process of actively learning to be safer pedestrians. The findings suggest virtual reality environments placed in community centers hold promise for teaching children to be safer pedestrians, but future research is needed to determine the optimal training dosage. PMID- 26479678 TI - Bacterial Nanobioreactors--Directing Enzyme Packaging into Bacterial Outer Membrane Vesicles. AB - All bacteria shed outer membrane vesicles (OMVs) loaded with a diverse array of small molecules, proteins, and genetic cargo. In this study we sought to hijack the bacterial cell export pathway to simultaneously produce, package, and release an active enzyme, phosphotriesterase (PTE). To accomplish this goal the SpyCatcher/SpyTag (SC/ST) bioconjugation system was utilized to produce a PTE SpyCatcher (PTE-SC) fusion protein and a SpyTagged transmembrane porin protein (OmpA-ST), known to be abundant in OMVs. Under a range of physiological conditions the SpyTag and SpyCatcher domains interact with one another and form a covalent isopeptide bond driving packaging of PTE into forming OMVs. The PTE-SC loaded OMVs are characterized for size distribution, number of vesicles produced, cell viability, packaged PTE enzyme kinetics, OMV loading efficiency, and enzyme stability following iterative cycles of freezing and thawing. The PTE-loaded OMVs exhibit native-like enzyme kinetics when assayed with paraoxon as a substrate. PTE is often toxic to expression cultures and has a tendency to lose activity with improper handling. The coexpression of OmpA-ST with PTE-SC, however, greatly improved the overall PTE production levels by mitigating toxicity through exporting of the PTE-SC and greatly enhanced packaged enzyme stability against iterative cycles of freezing and thawing. PMID- 26479679 TI - Maternal complications associated with stillbirth delivery: A cross-sectional analysis. AB - This study sought to identify delivery complications associated with stillbirth labour and delivery. We conducted a retrospective chart review evaluating stillbirth demographics, pregnancy and maternal risk factors, and complications of labour and delivery. We performed bivariable analysis and multivariable logistic regression to evaluate factors associated with medical complications and variations by race. Our cohort included 543 mothers with stillbirth, of which two thirds were African-American. We noted high rates of shoulder dystocia, clinical chorioamnionitis, postpartum haemorrhage and retained placenta in women with stillbirths. Thirty-three women (6%) experienced at least one serious maternal complication. Complication rates did not vary by maternal race. Providers who perform obstetrical care should be alert to the high rate of maternal medical complications associated with labour and delivery of a stillbirth foetus. PMID- 26479680 TI - White Light-Activated Antimicrobial Paint using Crystal Violet. AB - Crystal violet (CV) was incorporated into acrylic latex to produce white-light activated antimicrobial paint (WLAAP). Measurement of the water contact angle of the WLAAP showed that the water contact angle increased with increasing CV concentration. In a leaching test over 120 h, the amount of CV that leached from the WLAAPs was close to the detection limit (<0.03%). The WLAAPs were used to coat samples of polyurethane, and these showed bactericidal activity against Escherichia coli, which is a key causative agent of healthcare-associated infections (HAIs). A reduction in the numbers of viable bacteria was observed on the painted coated polyurethane after 6 h in the dark, and the bactericidal activity increased with increasing CV concentration (P < 0.1). After 6 h of white light exposure, all of coated polyurethanes demonstrated a potent photobactericidal activity, and it was statistically confirmed that the WLAAP showed better activity in white light than in the dark (P < 0.05). At the highest CV concentration, the numbers of viable bacteria fell below the detection limit (<10(3) CFU/mL) after 6 h of white light exposure. The difference in antimicrobial activity between the materials in the light and dark was 0.48 log at CV 250 ppm, and it increased by 0.43 log at each increment of CV 250 ppm. The difference was the highest (>1.8 log) at the highest CV concentration (1000 ppm). These WLAAPs are promising candidates for use in healthcare facilities to reduce HAIs. PMID- 26479681 TI - Band Bending Inversion in Bi2Se3 Nanostructures. AB - Shubnikov-de Haas oscillations were studied under high magnetic field in Bi2Se3 nanostructures grown by chemical vapor transport, for different bulk carrier densities ranging from 3 * 10(19) cm(-3) to 6 * 10(17) cm(-3). The contribution of topological surface states to electrical transport can be identified and separated from bulk carriers and massive two-dimensional electron gas. Band bending is investigated, and a crossover from upward to downward band bending is found at low bulk density as a result of a competition between bulk and interface doping. These results highlight the need to control electrical doping both in the bulk and at interfaces in order to study only topological surface states. PMID- 26479682 TI - Effects of low-energy N(+)-beam implantation on root growth in Arabidopsis seedlings. AB - The effects of ion implantation on the morphology changes and biological responses of plants are dependent on implantation doses. Previous studies mainly focus on the application of ion-beam technology in genetic mutation. Our knowledge regarding the mechanism underlying the plant growth inhibition induced by ion implantation remains limited. In this study, we explore the responses of root growth to low-energy N(+)-beam implantation using implanted Arabidopsis seeds. Our results showed that the root and root tip length were obviously reduced by implantation with large doses of low-energy N(+) beam. The analysis of confocal images showed that ion implantation reduced the cell viability and cell division activity in root meristem. The production rate of superoxide radical (O2(*-)) and contents of hydrogen peroxide (H2O2) in roots under ion implantation were markedly higher than those of controls. Transcriptional expression analysis of selected genes revealed that Arabidopsis RBOH genes associated with reactive oxygen species (ROS) production were significantly up-regulated in roots in response to ion implantation. The activities of antioxidant enzymes were also induced by ion implantation. Moreover, ROS scavenging obviously enhanced cell viability and cell division in response to ion implantation and alleviated the root growth inhibition of the implanted seedlings. Our results suggest that the overproduction of ROS induced by ion implantation is involved in the inhibitory effect of low-energy ion beam on root growth by affecting the cell viability and cell division of root meristem in Arabidopsis seedlings. PMID- 26479683 TI - A Brief Report Describing the Union of Medical Training and Agricultural Health. AB - This brief report describes a mutually beneficial partnership forged to extend agricultural medicine training to physicians, nurses, veterinarians, public health workers, health care professionals, medical residents, and students. Agricultural Medicine: Occupational and Environmental Health for Rural Health Professionals originated at the University of Iowa, Iowa's Center for Agricultural Safety and Health, and the Great Plains Center for Agricultural Health. Through a National Institute for Occupational Safety and Health (NIOSH) funded Training Project Grant, The University of Texas Health Northeast worked with the University of Iowa and regional experts to adapt the agricultural medicine content for the southwestern United States. Further partnerships were developed with the Southwest Center for Agricultural Health, Injury Prevention and Education, The University of North Texas Health Science Center College of Osteopathic Medicine, and the Texas Rural Health Association to extend the reach of this training to other important stakeholders. Each of the collaborators offered unique resources to the coordination of the agricultural medicine course. Likewise, each organization benefited from extending regionally relevant agricultural medicine training to current and future health care providers. The long-term goal for the partnership is to train a broad array of health care providers with the basics of anticipation, recognition, diagnosis, treatment, and the prevention of occupational and environmental illnesses and injuries within rural and agricultural communities, customized to the Southwest Region. This brief descriptive report highlights the process by which strategic partners collaborated to conduct a regional agricultural medicine course, such that other organizations interested in offering a similar training might gain insight to best practices from our experience. PMID- 26479685 TI - Low-Friction Adsorbed Layers of a Triblock Copolymer Additive in Oil-Based Lubrication. AB - The tribological properties of the dilute solution of an ABA triblock copolymer, poly(11-acrylamidoundecanoic acid)-block-poly(stearyl methacrylate)-block-poly(11 acrylamidoundecanoic acid (A5S992A5), in poly(alpha-olefin) (PAO) confined between mica surfaces were investigated using the surface forces apparatus (SFA). Friction force was measured as a function of applied load and sliding velocity, and the film thickness and contact geometry during sliding were analyzed using the fringes of equal chromatic order (FECO) in the SFA. The results were contrasted with those of confined PAO films; the effects of the addition of A5S992A5 on the tribological properties were discussed. The thickness of the A5S992A5/PAO system varied with time after surface preparation and with repetitive sliding motions. The thickness was within the range from 40 to 70 nm 1 day after preparation (the Day1 film), and was about 20 nm on the following day (the Day2 film). The thickness of the confined PAO film was thinner than 1.4 nm, indicating that the A5S992A5/PAO system formed thick adsorbed layers on mica surfaces. The friction coefficient was about 0.03 to 0.04 for the Day1 film and well below 0.01 for the Day2 film, which were 1 or 2 orders of magnitude lower than the values for the confined PAO films. The time dependent changes of the adsorbed layer thickness and friction properties should be caused by the relatively low solubility of A5S992A5 in PAO. The detailed analysis of the contact geometry and friction behaviors implies that the particularly low friction of the Day2 film originates from the following factors: (i) shrinkage of the A5S992A5 molecules (mainly the poly(stearyl methacrylate) blocks) that leads to a viscoelastic properties of the adsorbed layers; and (ii) the intervening PAO layer between the adsorbed polymer layers that constitutes a high-fluidity sliding interface. Our results suggest that the block copolymer having relatively low solubility in a lubricant base oil is effective at forming low-friction adsorbed layers in oil-based lubrication. PMID- 26479684 TI - A novel mobile-cloud system for capturing and analyzing wheelchair maneuvering data: A pilot study. AB - The purpose of this pilot study was to provide a new approach for capturing and analyzing wheelchair maneuvering data, which are critical for evaluating wheelchair users' activity levels. We proposed a mobile-cloud (MC) system, which incorporated the emerging mobile and cloud computing technologies. The MC system employed smartphone sensors to collect wheelchair maneuvering data and transmit them to the cloud for storage and analysis. A k-nearest neighbor (KNN) machine learning algorithm was developed to mitigate the impact of sensor noise and recognize wheelchair maneuvering patterns. We conducted 30 trials in an indoor setting, where each trial contained 10 bouts (i.e., periods of continuous wheelchair movement). We also verified our approach in a different building. Different from existing approaches that require sensors to be attached to wheelchairs' wheels, we placed the smartphone into a smartphone holder attached to the wheelchair. Experimental results illustrate that our approach correctly identified all 300 bouts. Compared to existing approaches, our approach was easier to use while achieving similar accuracy in analyzing the accumulated movement time and maximum period of continuous movement (p > 0.8). Overall, the MC system provided a feasible way to ease the data collection process and generated accurate analysis results for evaluating activity levels. PMID- 26479686 TI - The effects of polycystic ovary syndrome on gestational diabetes mellitus. AB - The aim of this study was to explore the inter-relationship between polycystic ovary syndrome and gestational diabetes mellitus, and demonstrate maternal and fetal outcomes. This was a case-control study in 1360 pregnant women who received a diagnosis of gestational diabetes mellitus between 24 and 28 weeks of gestational age. Among all diagnosed with gestational diabetes mellitus, 150 pregnant women had received a polycystic ovary syndrome, and 160 women who did not have polycystic ovary syndrome were designated as controls. The incidence of pregnancy-induced hypertension was 26.3% and 12% in the case and control groups, respectively. Preeclampsia was seen at an incidence of 12% and 6% in case and in control groups, respectively. The difference in neonatal hypoglycemia between the two groups was statistically significant, with an incidence of 17% and 5% in the case and in control groups, respectively. This study demonstrated that the presence of polycystic ovary syndrome along with gestational diabetes mellitus increases the risk of pregnancy induced hypertension by 2.4 fold, preeclampsia by 2 fold and neonatal hypoglycemia by 3.2 fold, compared to gestational diabetes mellitus alone. PMID- 26479687 TI - Knee pain relief with genicular nerve blockage in two brain injured patients with heterotopic ossification. AB - BACKGROUND: Heterotopic ossification (HO) is the ectopic bone formation in non osseous tissues. This study aimed to present two patients with traumatic brain injury (TBI) who had HO in knee joint and pain relief after genicular nerve blockage. Case 1: A 14-year-old patient with TBI was admitted with bilateral knee pain and limited range of motion. Physical examination and x-ray graphics revealed calcification which was diagnosed as HO. Ultrasonography (US) guided genicular nerve blockage was performed to both knees with 2 ml lidocaine and 1 ml betamethasone. VAS of pain was decreased to 30 mm from 80 mm. At 6-month follow up, VAS of pain was still 30 mm. Case 2: A 29-year-old patient with TBI was admitted for rehabilitation. He had right knee pain and his pain was 80 mm according to VAS. Investigation revealed HO. US guided genicular nerve blockage was performed to the right knee and pain was decreased to 20 mm. DISCUSSION: US guided genicular nerve blockage can provide pain relief in HO and this technique may be effective and alternative for pain relief in patients with neurogenic knee HO to increase patient's compliance. PMID- 26479688 TI - CIDAR MoClo: Improved MoClo Assembly Standard and New E. coli Part Library Enable Rapid Combinatorial Design for Synthetic and Traditional Biology. AB - Multipart and modular DNA part libraries and assembly standards have become common tools in synthetic biology since the publication of the Gibson and Golden Gate assembly methods, yet no multipart modular library exists for use in bacterial systems. Building upon the existing MoClo assembly framework, we have developed a publicly available collection of modular DNA parts and enhanced MoClo protocols to enable rapid one-pot, multipart assembly, combinatorial design, and expression tuning in Escherichia coli. The Cross-disciplinary Integration of Design Automation Research lab (CIDAR) MoClo Library is openly available and contains promoters, ribosomal binding sites, coding sequence, terminators, vectors, and a set of fluorescent control plasmids. Optimized protocols reduce reaction time and cost by >80% from that of previously published protocols. PMID- 26479689 TI - Letters to the Editor: "I Have Read with Great Interest...". PMID- 26479690 TI - Payer Coverage: Myths and Truths. PMID- 26479691 TI - The Use of PRISM (Pictorial Representation of Illness and Self Measure) in Patients Affected by Chronic Cutaneous Ulcers. AB - OBJECTIVE: PRISM (Pictorial Representation of Illness and Self Measure) is a nonverbal visualization instrument. The authors chose to use this tool to avoid the limitation of the other tests for the assessment of quality of life by using interview methods that depend on the cognitive and cultural level of the patient. The aim of the study was to assess the impact on the quality of life of different types of chronic wounds using the PRISM test. SETTING: The PRISM test was administered by the same medical student to each patient visiting the dermatology department for a routine visit and medication. PARTICIPANTS: The PRISM test was administered to 77 patients with chronic cutaneous ulcers referred to the Dermatology Department of the Spedali Civili of Brescia, Italy. MATERIALS AND METHODS: The authors analyzed the "Self-llness-Separation"' (SIS) value, which resulted from the PRISM test, and related it to sex, age, and ulcer etiology. RESULTS: Considering all categories, the mean SIS was 9.58 cm; a different perception of the disease between the sexes was noted and also in the subgroups based on the ulcer's different etiology. In addition, the age of the affected patients influenced the SIS value. CONCLUSIONS: PRISM is an easy and sensitive instrument to record information about the patient's expectations and suffering in order to improve the overall physician-patient relationship. PMID- 26479692 TI - The Effect of Electrical Stimulation Combined with Foam Dressing on Ulcer Healing in Rats with Spinal Cord Injury. AB - OBJECTIVE: To evaluate the effect of electrical stimulation (ES) combined with foam dressing on wound healing in rats with spinal cord injury. METHODS: Complete spinal cord injury was induced in 49 male Sprague-Dawley rats at the T11-L1 level, after which a pressure ulcer was induced on the left thigh. The newly invented surface electrode, which was fitted with foam inside, was applied to the ulcers. Rats were divided into 2 groups as follows: the ES group, which received foam dressings and ES (2 Hz and 200-microsecond duration, 15 mA) for 4 times a day, 30 minutes each, for 3 weeks; and the control group, which received the foam dressings without ES. The ulcer area was measured by taking a photograph daily from day 0 to day 21. Histopathologic and immune-histochemical evaluations were performed on day 1 and days 7, 14, and 21. RESULTS: The area of the ulcers of the ES group was smaller than that of the control group after day 14 (P < .05). In the ES group, the vascularity was significantly greater on day 14 and more decreased on day 21 compared with day 7 than that in the control group (P < .05). In the ES group, the area of positive reaction to anti-alpha-SMA antibody was increased compared with the control group on days 7 and 14 and decreased on day 21 (P > .05). CONCLUSION: Electrical stimulation combined with foam dressing by means of newly invented surface electrodes facilitates and accelerates the wound healing process. PMID- 26479693 TI - Surgical Treatment of Pressure Ulcers with a Fibrin Sealant in Patients with Spinal Cord Injury: A Cost-Consequence Analysis. AB - BACKGROUND: A comparative study was performed to evaluate the effectiveness and costs of a fibrin sealant (Tissucol Duo [known as Tisseel in the United States], Baxter International, Deerfield, Illinois) to improve postoperative outcomes in patients with spinal cord injury undergoing surgical treatment for pressure ulcers (PrUs). METHODS: Between January and June 2011, 27 patients underwent surgical treatment for PrUs with the direct application of Tissucol Duo sprayed before closure. The costs and outcomes obtained in this cohort were compared with those obtained in a previous retrospective study where 71 patients underwent conventional surgery. RESULTS: Lower rates of hematoma-seroma were observed in the study group (3.7% vs 33.8%; P < .05). Drain removal occurred earlier (10 vs 15 days; P < .05), and the average drain volume was also lower (155 vs 360 mL; P < .05) for this group. The mean length of hospital stay was significantly lower in the study group and was the main contributing factor to the overall costs. CONCLUSIONS: The application of Tissucol Duo during surgical treatment of PrUs in patients with spinal cord injury has been shown to be effective in reducing postoperative complications and in shortening the duration of the hospital stay with a consequent savings in costs. PMID- 26479694 TI - Intervention with Formulated Collagen Gel for Chronic Heel Pressure Ulcers in Older Adults with Diabetes. AB - Chronic pressure ulcers (PrUs), ulcers that fail to progress through the expected phases of wound healing in a timely fashion, are not only a concern for the patients afflicted with them, but are also a significant burden for the long-term care facilities in which patients reside. The heel is the second most common location for PrUs. Morbidity and mortality rates for heel PrUs, particularly in the diabetic population, are alarming. Therefore, a consistently effective, cost conscious, and user-friendly topical treatment for heel ulcers would be welcomed by patients and clinicians. This article describes a marked and rapid improvement in wound granulation in 3 older adult patients following weekly treatment for 8 weeks of chronic (>=1-year duration) heel ulcers with an easy-to-use, cost effective, topical, formulated collagen gel. PMID- 26479695 TI - Differentiating a Pressure Ulcer from Acute Skin Failure in the Adult Critical Care Patient. AB - PURPOSE: The purpose of this learning activity is to provide information regarding the differentiation between pressure ulcers and acute skin failure (ASF) in critically ill patients. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to:1. Describe the purpose, methodology and impact of this research.2. Differentiate the pathophysiology of pressure ulcers and ASF.3. Identify risk factors and diagnostic criteria for ASF. ABSTRACT: To develop a statistical model to predict the development of acute skin failure in patients admitted to the intensive care unit (ICU) and to validate this model.Retrospective case-control, logistic regression modeling552 ICU patientsIntensive care unit patients with and without pressure ulcers (PrUs) were studied and compared on key variables sorted into the following categories: (1) disease status, (2) physical conditions, and (3) conditions of hospitalization.The variables, peripheral arterial disease (odds ratio [OR], 3.8; P = .002), mechanical ventilation greater than 72 hours (OR, 3.0; P < .001), respiratory failure (OR, 3.2; P < .001), liver failure (OR, 2.9; P = .04), and severe sepsis/septic shock (OR, 1.9; P = .02), were found to be statistically significant and independent predictors of acute skin failure in ICU patients. These variables created a predictor model for acute skin failure in the ICU.Lack of objective criteria to define acute skin failure presents a clinical conundrum for practitioners-the acknowledgment that skin failure exists, but no clear-cut diagnostic criteria in which to support its existence as a result of a paucity of empirical evidence. In certain populations, such as the critically ill patient, the phenomenon of acute skin failure may be occurring, and with the current level of evidence, these ulcers may be incorrectly identified as PrUs. Accurately distinguishing risk factors that lead to a PrU from factors that result in a lesion due to acute skin failure is crucial in the quest to provide evidence based practice to patients. PMID- 26479697 TI - The Strategic View of Meaningful Use: Part 2. PMID- 26479698 TI - Cut-off values for step count and TV viewing time as discriminators of hyperglycaemia in Brazilian children and adolescents. AB - BACKGROUND: The use of step count and TV viewing time to discriminate youngsters with hyperglycaemia is still a matter of debate. AIM: To establish cut-off values for step count and TV viewing time in children and adolescents using glycaemia as the reference criterion. SUBJECTS AND METHODS: A cross-sectional study was conducted on 1044 schoolchildren aged 6-18 years from Northeastern Brazil. Daily step counts were assessed with a pedometer over 1 week and TV viewing time by self-report. RESULTS: The area under the curve (AUC) ranged from 0.52-0.61 for step count and from 0.49-0.65 for TV viewing time. The daily step count with the highest discriminatory power for hyperglycaemia was 13 884 (sensitivity = 77.8; specificity = 51.8) for male children and 12 371 (sensitivity = 55.6; specificity = 55.5) and 11 292 (sensitivity = 57.7; specificity = 48.6) for female children and adolescents respectively. The cut-off for TV viewing time with the highest discriminatory capacity for hyperglycaemia was 3 hours/day (sensitivity = 57.7 77.8; specificity = 48.6-53.2). CONCLUSION: This study represents the first step for the development of criteria based on cardiometabolic risk factors for step count and TV viewing time in youngsters. However, the present cut-off values have limited practical application because of their poor accuracy and low sensitivity and specificity. PMID- 26479699 TI - The TZD insulin sensitizer clue provides a new route into diabetes drug discovery. AB - INTRODUCTION: Thiazolidinedione (TZD) insulin sensitizers have a pleotropic pharmacology including reduction of insulin resistance, a root cause of diabetes. Importantly, these agents also preserve pancreatic beta cell function. TZDs are not widely used, especially early on in disease progression when they might have the greatest benefit, because of side effects, principally volume expansion, weight gain, and increased bone reabsorption. Incomplete understanding of their mechanism of action has prevented the development of new agents. Recent studies suggest that these compounds modify mitochondrial metabolism and metabolic signals that coordinate downstream cell function. AREAS COVERED: The author provides a brief history of the development of the first generation insulin sensitizer TZDs, which coincided with the expansion of the concept of insulin resistance in disease. Furthermore, the article summarizes ideas as to how a newly identified mitochondrial target might explain the activity of new clinical candidates. EXPERT OPINION: Recognition of the pyruvate carrier complex as a mitochondrial target of the TZDs provides a new direction for discovery and development of anti-diabetic agents. Recent clinical studies have suggested that reduction of direct agonism of PPARgamma may prove to be useful therapeutically by reducing dose-limiting side effects. The study of the mechanism of insulin resistance produced by metabolic signals (metabolic inflammation) and the counterbalance of these signals by insulin sensitizers is likely to be useful in providing more target and discovery approaches to metabolic diseases. PMID- 26479700 TI - Evaluating the stage of change model to a cervical cancer screening intervention among Ohio Appalachian women. AB - Cervical cancer incidence and mortality rates are disproportionally high among women living in Appalachia Ohio. This study used the Transtheoretical Model to examine screening barriers before and after a lay health advisor (LHA) intervention (2005-2009) to increase cervical cancer screening rates. Ohio Appalachian women (n = 90) who were in need of a Pap test, based on risk appropriate guidelines, were randomized to a 10-month LHA intervention and received two in-person visits, two phone calls, and four mailed postcards targeted to the participant's stage of change. Findings revealed that 63% had forward stage movement 10 months after the intervention. The most frequently reported screening barriers were time constraints, forgetting to make an appointment, and cost. Women who reported the following barriers-doctor not recommending the test; being unable to afford the test; and being embarrassed, nervous, or afraid of getting a Pap test-were less likely to be in the action stage. Understanding the stages of change related to Pap testing and reported barriers among this underserved population may help inform researchers and clinicians of this population's readiness for change and how to set realistic intervention goals. PMID- 26479701 TI - The effects of chronic intracortical microstimulation on neural tissue and fine motor behavior. AB - OBJECTIVE: One approach to conveying sensory feedback in neuroprostheses is to electrically stimulate sensory neurons in the cortex. For this approach to be viable, it is critical that intracortical microstimulation (ICMS) causes minimal damage to the brain. Here, we investigate the effects of chronic ICMS on the neuronal tissue across a variety of stimulation regimes in non-human primates. We also examine each animal's ability to use their hand--the cortical representation of which is targeted by the ICMS--as a further assay of possible neuronal damage. APPROACH: We implanted electrode arrays in the primary somatosensory cortex of three Rhesus macaques and delivered ICMS four hours per day, five days per week, for six months. Multiple regimes of ICMS were delivered to investigate the effects of stimulation parameters on the tissue and behavior. Parameters included current amplitude (10-100 MUA), pulse train duration (1, 5 s), and duty cycle (1/1, 1/3). We then performed a range of histopathological assays on tissue near the tips of both stimulated and unstimulated electrodes to assess the effects of chronic ICMS on the tissue and their dependence on stimulation parameters. MAIN RESULTS: While the implantation and residence of the arrays in the cortical tissue did cause significant damage, chronic ICMS had no detectable additional effect; furthermore, the animals exhibited no impairments in fine motor control. SIGNIFICANCE: Chronic ICMS may be a viable means to convey sensory feedback in neuroprostheses as it does not cause significant damage to the stimulated tissue. PMID- 26479702 TI - Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms. AB - Childhood psychotic symptoms are associated with increased rates of schizophrenia, other psychiatric disorders, and suicide attempts in adulthood; thus, elucidating early risk indicators is crucial to target prevention efforts. There is considerable discordance for psychotic symptoms between monozygotic twins, indicating that child-specific non-genetic factors must be involved. Epigenetic processes may constitute one of these factors and have not yet been investigated in relation to childhood psychotic symptoms. Therefore, this study explored whether differences in DNA methylation at age 10 were associated with monozygotic twin discordance for psychotic symptoms at age 12. The Environmental Risk (E-Risk) Longitudinal Twin Study cohort of 2,232 children (1,116 twin pairs) was assessed for age-12 psychotic symptoms and 24 monozygotic twin pairs discordant for symptoms were identified for methylomic comparison. Children provided buccal samples at ages 5 and 10. DNA was bisulfite modified and DNA methylation was quantified using the Infinium HumanMethylation450 array. Differentially methylated positions (DMPs) associated with psychotic symptoms were subsequently tested in post-mortem prefrontal cortex tissue from adult schizophrenia patients and age-matched controls. Site-specific DNA methylation differences were observed at age 10 between monozygotic twins discordant for age 12 psychotic symptoms. Similar DMPs were not found at age 5. The top-ranked psychosis-associated DMP (cg23933044), located in the promoter of the C5ORF42 gene, was also hypomethylated in post-mortem prefrontal cortex brain tissue from schizophrenia patients compared to unaffected controls. These data tentatively suggest that epigenetic variation in peripheral tissue is associated with childhood psychotic symptoms and may indicate susceptibility to schizophrenia and other mental health problems. PMID- 26479704 TI - Ameliorating Spinal Cord Injury in an Animal Model With Mechanical Tissue Resuscitation. AB - BACKGROUND: Traumatic spinal cord injury (SCI) is a major worldwide cause of mortality and disability with limited treatment options. Previous research applying controlled negative pressure to traumatic brain injury in rat and swine models resulted in smaller injuries and more rapid recovery. OBJECTIVE: To examine the effects of the application of a controlled vacuum (mechanical tissue resuscitation [MTR]) to SCI in a rat model under several magnitudes of vacuum. METHODS: Controlled contusion SCIs were created in rats. Vacuums of -50 and -75 mm Hg were compared. Analysis included open-field locomotor performance, magnetic resonance imaging (in vivo T2, ex vivo diffusion tensor imaging and fiber tractography), and histological assessments. RESULTS: MTR treatment significantly improved the locomotor recovery from a Basso, Beattie, and Bresnahan score of 7.8 +/- 1.9 to 11.4 +/- 1.2 and 10.7 +/- 1.9 at -50- and -75-mm Hg pressures, respectively, 4 weeks after injury. Both pressures also reduced fluid accumulations > 10% by T2-imaging in SCI sites. The mean fiber number and mean fiber length were greater across injured sites after MTR treatment, especially with treatment with -50 mm Hg. Myelin volume was increased significantly by 60% in the group treated with -50 mm Hg. CONCLUSION: MTR of SCI in a rat model is effective in reducing edema in the injured cord, preserving myelin survival, and improving the rate and quantity of functional recovery. ABBREVIATIONS: BBB, Basso, Beattie, and BresnahanDTI, diffusion tensor imagingFA, fractional anisotropyMTR, mechanical tissue resuscitationMTR50, mechanical tissue resuscitation with 50-mm Hg subatmospheric pressureMTR75, mechanical tissue resuscitation with 75-mm Hg subatmospheric pressureROI, region of interestSCI, spinal cord injury. PMID- 26479703 TI - Upregulated KLK10 inhibits esophageal cancer proliferation and enhances cisplatin sensitivity in vitro. AB - The kallikrein-related peptidase 10 (KLK10) gene has tumor-suppressive function in various types of human cancer. However, previous studies showed that KLK10 also acts as an oncogene and is upregulated in gastrointestinal tumors. The role of KLK10 in human esophageal cancer (EC) remains unclear. In the present study, the expression of KLK10 in human esophageal and non-esophageal cancer tissues was investigated by immunohistochemistry. Quantitative RT-PCR and western blot analysis were utilized to detect KLK10 mRNA and protein expression in human esophageal cancer cell lines (TE-1 and Eca-109). Small interference RNA was utilized to specifically knockdown KLK10 expression in Eca-109 and TE-1 cells. Cell proliferation, cell cycle analysis as well as CDDP-dependent apoptosis were determined using a CCK-8 assay and flow cytometry. The results showed that, KLK10 was positive in 67 out of 83 (80.72%) human EC and positive in 3 out of 11 (27.27%) normal tissues (P=0.001). The present study indicated that KLK10 potentially plays a crucial role in Eca-109 cell growth. Additionally, the downregulation of KLK10 induced S-phase arrest and promoted cisplatin-induced apoptosis. The resutls of the present study suggested that KLK10 is a promising novel marker for the diagnostic and therapeutic target of esophageal cancer. PMID- 26479706 TI - Toward a formalized account of attitudes: The Causal Attitude Network (CAN) model. AB - This article introduces the Causal Attitude Network (CAN) model, which conceptualizes attitudes as networks consisting of evaluative reactions and interactions between these reactions. Relevant evaluative reactions include beliefs, feelings, and behaviors toward the attitude object. Interactions between these reactions arise through direct causal influences (e.g., the belief that snakes are dangerous causes fear of snakes) and mechanisms that support evaluative consistency between related contents of evaluative reactions (e.g., people tend to align their belief that snakes are useful with their belief that snakes help maintain ecological balance). In the CAN model, the structure of attitude networks conforms to a small-world structure: evaluative reactions that are similar to each other form tight clusters, which are connected by a sparser set of "shortcuts" between them. We argue that the CAN model provides a realistic formalized measurement model of attitudes and therefore fills a crucial gap in the attitude literature. Furthermore, the CAN model provides testable predictions for the structure of attitudes and how they develop, remain stable, and change over time. Attitude strength is conceptualized in terms of the connectivity of attitude networks and we show that this provides a parsimonious account of the differences between strong and weak attitudes. We discuss the CAN model in relation to possible extensions, implication for the assessment of attitudes, and possibilities for further study. PMID- 26479707 TI - Believing what we do not believe: Acquiescence to superstitious beliefs and other powerful intuitions. AB - Traditionally, research on superstition and magical thinking has focused on people's cognitive shortcomings, but superstitions are not limited to individuals with mental deficits. Even smart, educated, emotionally stable adults have superstitions that are not rational. Dual process models--such as the corrective model advocated by Kahneman and Frederick (2002, 2005), which suggests that System 1 generates intuitive answers that may or may not be corrected by System 2 -are useful for illustrating why superstitious thinking is widespread, why particular beliefs arise, and why they are maintained even though they are not true. However, to understand why superstitious beliefs are maintained even when people know they are not true requires that the model be refined. It must allow for the possibility that people can recognize--in the moment--that their belief does not make sense, but act on it nevertheless. People can detect an error, but choose not to correct it, a process I refer to as acquiescence. The first part of the article will use a dual process model to understand the psychology underlying magical thinking, highlighting features of System 1 that generate magical intuitions and features of the person or situation that prompt System 2 to correct them. The second part of the article will suggest that we can improve the model by decoupling the detection of errors from their correction and recognizing acquiescence as a possible System 2 response. I suggest that refining the theory will prove useful for understanding phenomena outside of the context of magical thinking. PMID- 26479708 TI - Comparison of rhBMP-2 versus Autogenous Iliac Crest Bone Graft for 2-Level Anterior Cervical Discectomy and Fusion for Cervical Spondylotic Myelopathy. AB - BACKGROUND: Few studies have examined the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) in 2-level anterior cervical discectomy and fusion (ACDF). The purpose of this study was to compare the outcomes in a series of patients with CSM treated with 2-level ACDF with or without rhBMP-2. MATERIAL AND METHODS: The retrospective study included a total of 146 patients with CSM. The rhBMP-2 group consisted of 73 patients who underwent 2-level ACDF with rhBMP 2. A total of 73 patients who also received 2-level ACDF with autogenous ICBG alone were included in the matched-pair ICBG group with a ratio of 1:1, based on age, sex, and BMI. All data, including fusion rate and time, VAS, JOA score, operative date, and complications, were assessed. RESULTS: With respect to the length of hospital stay, operative times, and blood loss, there were no significant difference between the 2 groups. However, the rhBMP-2 group presented a shorter fusion time (P<0.013) and higher fusion rate (P<0.036) than the ICBG group. In the rhBMP-2 group, 22% required additional treatment for complications compared to 18% of patients in the ICBG group, which showed no significant difference (P=0.543). CONCLUSIONS: The application of rhBMP-2 in 2-level ACDF showed higher fusion rates, shorter fusion time, and similar function outcomes compared to those who received ACDF with ICBG alone. PMID- 26479709 TI - Characterizing and predicting carboxylic acid reductase activity for diversifying bioaldehyde production. AB - Chemicals with aldehyde moieties are useful in the synthesis of polymerization reagents, pharmaceuticals, pesticides, flavors, and fragrances because of their high reactivity. However, chemical synthesis of aldehydes from carboxylic acids has unfavorable thermodynamics and limited specificity. Enzymatically catalyzed reductive bioaldehyde synthesis is an attractive route that overcomes unfavorable thermodynamics by ATP hydrolysis in ambient, aqueous conditions. Carboxylic acid reductases (Cars) are particularly attractive, as only one enzyme is required. We sought to increase the knowledge base of permitted substrates for four Cars. Additionally, the Lys2 enzyme family was found to be mechanistically the same as Cars and two isozymes were also tested. Our results show that Cars prefer molecules where the carboxylic acid is the only polar/charged group. Using this data and other published data, we develop a support vector classifier (SVC) for predicting Car reactivity and make predictions on all carboxylic acid metabolites in iAF1260 and Model SEED. PMID- 26479711 TI - High-Dose Probiotic Supplementation Containing Lactobacillus casei for 7 Days Does Not Enhance Salivary Antimicrobial Protein Responses to Exertional Heat Stress Compared With Placebo. AB - The study aimed to determine whether high-dose probiotic supplementation containing Lactobacillus casei (L. casei) for 7 consecutive days enhances salivary antimicrobial protein (S-AMP) responses to exertional-heat stress (EHS). Eight endurance-trained male volunteers (age 26 +/- 6 years, nude body mass 70.2 +/- 8.8 kg, height 1.75 +/- 0.05 m, VO2max 59 +/- 5 ml.kg-1.min-1 [M +/- SD]) completed a blinded randomized and counterbalanced crossover design. Oral supplementation of the probiotic beverage (PRO; L. casei . 1011 colony-forming units.day-1) or placebo (PLA) was consumed for 7 consecutive days before 2 hr running exercise at 60% VO2max in hot ambient conditions (34.0 degrees C and 32% RH). Body mass and unstimulated saliva and venous blood samples were collected at baseline (7 days before EHS), pre-EHS, post-EHS (1 hr, 2 hr, and 4 hr), and at 24 hr. Saliva samples were analyzed for salivary (S) IgA, alpha-amylase, lysozyme, and cortisol. Plasma samples were analyzed for plasma osmolality. Body mass and plasma osmolality did not differ between trials. Saliva flow rate remained relatively constant throughout the experimental design in PRO (overall M +/- SD = 601 +/- 284 MUl/min) and PLA (557 +/- 296 MUl/min). PRO did not induce significant changes in resting S-AMP responses compared with PLA (p > .05). Increases in S-IgA, S-alpha-amylase, and S-cortisol responses, but not S-lysozyme responses, were observed after EHS (p < .05). No main effects of trial or Time x Trial interaction were observed for S-AMP and S-cortisol responses. Supplementation of a probiotic beverage containing L. casei for 7 days before EHS does not provide any further oral-respiratory mucosal immune protection, with respect to S-AMP, over PLA. PMID- 26479710 TI - Pericytes are progenitors for coronary artery smooth muscle. AB - Epicardial cells on the heart's surface give rise to coronary artery smooth muscle cells (caSMCs) located deep in the myocardium. However, the differentiation steps between epicardial cells and caSMCs are unknown as are the final maturation signals at coronary arteries. Here, we use clonal analysis and lineage tracing to show that caSMCs derive from pericytes, mural cells associated with microvessels, and that these cells are present in adults. During development following the onset of blood flow, pericytes at arterial remodeling sites upregulate Notch3 while endothelial cells express Jagged-1. Deletion of Notch3 disrupts caSMC differentiation. Our data support a model wherein epicardial derived pericytes populate the entire coronary microvasculature, but differentiate into caSMCs at arterial remodeling zones in response to Notch signaling. Our data are the first demonstration that pericytes are progenitors for smooth muscle, and their presence in adult hearts reveals a new potential cell type for targeting during cardiovascular disease. PMID- 26479712 TI - Theoretical considerations for understanding a Purkinje cell timing mechanism. AB - In classical conditioning, cerebellar Purkinje cells learn an adaptively timed pause in spontaneous firing. This pause reaches its maximum near the end of the interstimulus interval. While it was thought that this timing was due to temporal patterns in the input signal and selective engagement of changes in synapse strength, we have shown Purkinje cells learn timed responses even when the conditional stimulus is delivered to its immediate afferents.(1) This shows that Purkinje cells have a cellular timing mechanism. The cellular models of intrinsic timing we are aware of are based on adapting the rise time of the concentration of a given ion. As an alternative, we here propose a selection mechanism in abstract terms for how a Purkinje cell could learn to respond at a particular time after an external trigger. PMID- 26479713 TI - A Graph Algorithmic Approach to Separate Direct from Indirect Neural Interactions. AB - Network graphs have become a popular tool to represent complex systems composed of many interacting subunits; especially in neuroscience, network graphs are increasingly used to represent and analyze functional interactions between multiple neural sources. Interactions are often reconstructed using pairwise bivariate analyses, overlooking the multivariate nature of interactions: it is neglected that investigating the effect of one source on a target necessitates to take all other sources as potential nuisance variables into account; also combinations of sources may act jointly on a given target. Bivariate analyses produce networks that may contain spurious interactions, which reduce the interpretability of the network and its graph metrics. A truly multivariate reconstruction, however, is computationally intractable because of the combinatorial explosion in the number of potential interactions. Thus, we have to resort to approximative methods to handle the intractability of multivariate interaction reconstruction, and thereby enable the use of networks in neuroscience. Here, we suggest such an approximative approach in the form of an algorithm that extends fast bivariate interaction reconstruction by identifying potentially spurious interactions post-hoc: the algorithm uses interaction delays reconstructed for directed bivariate interactions to tag potentially spurious edges on the basis of their timing signatures in the context of the surrounding network. Such tagged interactions may then be pruned, which produces a statistically conservative network approximation that is guaranteed to contain non-spurious interactions only. We describe the algorithm and present a reference implementation in MATLAB to test the algorithm's performance on simulated networks as well as networks derived from magnetoencephalographic data. We discuss the algorithm in relation to other approximative multivariate methods and highlight suitable application scenarios. Our approach is a tractable and data efficient way of reconstructing approximative networks of multivariate interactions. It is preferable if available data are limited or if fully multivariate approaches are computationally infeasible. PMID- 26479716 TI - Response to a letter to the Editor by Dr. David Egilman and Mr. John Schilling regarding the article by Donovan et al. (2011). PMID- 26479714 TI - Retention and splicing complex (RES) - the importance of cooperativity. AB - One of the great challenges to structural biologists lies in explaining the complexities of the spliceosome - a ribosome-sized molecular machine that is assembled in a step-wise manner and is responsible for pre-mRNA splicing. The spliceosome is both fascinating and difficult to work with, because of its dynamic nature. At each discrete step of splicing tens of proteins come and go orchestrating the functional transition through massive structural rearrangements. The retention and splicing complex (RES) is an important splicing factor interacting with pre-mRNA at the onset of the first transesterification reaction. RES is a specific splicing factor for a number of genes and is important for controlling pre-mRNA retention in the nucleus. RES is a 71 kDa heterotrimer composed of the 3 proteins Pml1p, Bud13p and Snu17p. We solved the 3 dimensional structure of the core of the RES complex as well as the 2 dimers, Snu17p-Bud13p and Snu17p-Pml1p. Further biophysical analysis revealed an astounding cooperativity that governs the assembly of this trimeric complex as well as its interaction with pre-mRNA. The more than 100-fold cooperativity originates from the progressive rigidification of Snu17p upon coupled binding-and folding of protein regions, which are disordered in the unbound state. Our work highlights the role of cooperativity in the spliceosome and poses new questions about the structure and assembly of the spliceosome. PMID- 26479715 TI - Potential impact of gene regulatory mechanisms on the evolution of multicellularity in the volvocine algae. AB - A fundamental question in biology is how multicellular organisms can arise from their single-celled precursors. The evolution of multicellularity requires the adoption of new traits in unicellular ancestors that allows the generation of form by, for example, increasing the size and developing new cell types. But what are the genetic, cellular and biochemical bases underlying the evolution of multicellularity? Recent advances in evolutionary developmental biology suggest that the regulation of gene expression by cis-regulatory factors, gene duplication and alternative splicing contribute to phenotypic evolution. These mechanisms enable different degrees of phenotypic divergence and complexity with variation in traits from genomes with similar gene contents. In addition, signaling pathways specific to cell types are developed to guarantee the modulation of cellular and developmental processes matched to the cell types as well as the maintenance of multicellularity. PMID- 26479717 TI - Population Pharmacokinetic Modeling After Repeated Administrations of RBP-6000, a New, Subcutaneously Injectable, Long-Acting, Sustained-Release Formulation of Buprenorphine, for the Treatment of Opioid Use Disorder. AB - RBP-6000 is a novel sustained-release formulation of buprenorphine for the treatment of opioid use disorder, which has been designed for once-monthly (28 days) subcutaneous (SC) injections. A population pharmacokinetic (PK) model was developed to describe the time course of buprenorphine plasma concentrations after repeated SC injections of RBP-6000 at 50 mg, 100 mg, 200 mg, or 300 mg in treatment-seeking opioid-dependent subjects previously on sublingual buprenorphine (Subutex((r)) ) treatment. The MU-opioid receptor occupancy was predicted using a previously developed PK/PD Emax model. The results of the population PK analysis jointly with the predicted level of MU-opioid receptor occupancy provided quantitative criteria for clinical dose selection for RBP 6000: the dose of 300 mg every 28 days seems appropriate for immediately achieving an effective exposure after the first SC injection and to maintain effective levels of exposure during chronic treatment. Furthermore, simulations conducted to evaluate the potential impact of a holiday in drug intake indicated that in the unexpected event of a 2-week holiday, levels of MU-opioid receptor occupancy remained consistently above 70% with no significant loss of drug efficacy. This analysis indicated that RBP-6000 has the potential for becoming an effective treatment for opioid-dependent subjects by addressing compliance issues associated with the current once-a-day treatments. PMID- 26479718 TI - Sensitivity of Hyperdense Basilar Artery Sign on Non-Enhanced Computed Tomography. AB - PURPOSE: The hyperdense basilar artery sign (HBAS) is an indicator of vessel occlusion on non contrast-enhanced computer tomography (NECT) in acute stroke patients. Since basilar artery occlusion (BAO) is associated with a high mortality and morbidity, its early detection is of great clinical value. We sought to analyze the influence of density measurement as well as a normalized ratio of Hounsfield unit/hematocrit (HU/Hct) ratio on the detection of BAO on NECT in patients with suspected BAO. MATERIALS AND METHODS: 102 patients with clinically suspected BAO were examined with NECT followed immediately by Multidetector computed tomography Angiography. Two observers independently analyzed the images regarding the presence or absence of HBAS on NECT and performed HU measurements in the basilar artery. Receiver operating characteristic curve analysis was performed to determine the optimal density threshold for BAO using attenuation measurements or HU/Hct ratio. RESULTS: Sensitivity of visual detection of the HBAS on NECT was relatively low 81% (95% CI, 54-95%) while specificity was high 91% (95%-CI, 82-96%). The highest sensitivity was achieved by the combination of visual assessment and additional quantitative attenuation measurements applying a cut-off value of 46.5 HU with 94% sensitivity and 81% specificity for BAO. A HU/Hct ratio >1.32 revealed sensitivity of 88% (95%-CI, 60-98%) and specificity of 84% (95%-CI, 74-90%). CONCLUSION: In patients with clinically suspected acute BAO the combination of visual assessment and additional attenuation measurement with a cut-off value of 46.5 HU is a reliable approach with high sensitivity in the detection of BAO on NECT. PMID- 26479721 TI - Charge-Transport Anisotropy in a Uniaxially Aligned Diketopyrrolopyrrole-Based Copolymer. AB - Aligned films of a semiconducting DPP-based copolymer exhibit highly anisotropic charge transport with a band-like temperature dependence along the alignment direction and hole mobilities of up to 6.7 cm(2) V(-1) s(-1) . X-ray diffraction measurements reveal an exceptional degree of in-plane alignment, high crystallinity, and a dominant face-on orientation of the polymer backbones. The surprising charge-transport properties are interpreted in a tie-chain model consistent with anisotropic activation energies. PMID- 26479722 TI - Intracoronary Delivery of Human Mesenchymal/Stromal Stem Cells: Insights from Coronary Microcirculation Invasive Assessment in a Swine Model. AB - BACKGROUND: Mesenchymal stem/stromal cells have unique properties favorable to their use in clinical practice and have been studied for cardiac repair. However, these cells are larger than coronary microvessels and there is controversy about the risk of embolization and microinfarctions, which could jeopardize the safety and efficacy of intracoronary route for their delivery. The index of microcirculatory resistance (IMR) is an invasive method for quantitatively assessing the coronary microcirculation status. OBJECTIVES: To examine heart microcirculation after intracoronary injection of mesenchymal stem/stromal cells with the index of microcirculatory resistance. METHODS: Healthy swine were randomized to receive by intracoronary route either 30x106 MSC or the same solution with no cells (1% human albumin/PBS) (placebo). Blinded operators took coronary pressure and flow measurements, prior to intracoronary infusion and at 5 and 30 minutes post-delivery. Coronary flow reserve (CFR) and the IMR were compared between groups. RESULTS: CFR and IMR were done with a variance within the 3 transit time measurements of 6% at rest and 11% at maximal hyperemia. After intracoronary infusion there were no significant differences in CFR. The IMR was significantly higher in MSC-injected animals (at 30 minutes, 14.2U vs. 8.8U, p = 0.02) and intragroup analysis showed a significant increase of 112% from baseline to 30 minutes after cell infusion, although no electrocardiographic changes or clinical deterioration were noted. CONCLUSION: Overall, this study provides definitive evidence of microcirculatory disruption upon intracoronary administration of mesenchymal stem/stromal cells, in a large animal model closely resembling human cardiac physiology, function and anatomy. PMID- 26479723 TI - Cyanobacterial composition and spatial distribution based on pyrosequencing data in the Gurbantunggut Desert, Northwestern China. AB - Cyanobacteria are the primary colonizers and form a dominant component of soil photosynthetic communities in biological soil crusts. They are crucial in improving soil environments, namely accumulating soil carbon and nitrogen. Many classical studies have examined cyanobacterial diversity in desert crusts, but relatively few comprehensive molecular surveys have been conducted. We used 454 pyrosequencing of 16S rRNA to investigate cyanobacterial composition and distribution on regional scales in the Gurbantunggut Desert. The relationship between cyanobacterial distribution and environmental factors was also explored. A total of 24,973 cyanobacteria partial 16S rRNA gene sequences were obtained, and 507OTUs were selected, as most OTUs had very few reads. Among these, 347 OTU sequences were of cyanobacteria origin, belonging to Oscillatoriales, Nostocales, Chroococcales, and uncultured cyanobacterium clone, respectively. Microcoleus vaginatus, Chroococcidiopsis spp. and M. steenstrupii were the dominant species in most areas of the Gurbantunggut Desert. Compared with other desert, the Gurbantunggut Desert differed in the prominence of Chroococcidiopsis spp. and lack of Pseudanabaenales. Species composition and abundance of cyanobacteria also showed distinct variations. Soil texture, precipitation, and nutrients and salt levels affected cyanobacterial distribution. Increased precipitation was helpful in improving cyanobacterial diversity. A higher content of coarse sand promoted the colonization and growth of Oscillatoriales and some phylotypes of Chroococcales. The fine-textured soil with higher nutrients and salts supported more varied populations of cyanobacteria, namely some heterocystous cyanobacteria. The results suggested that the Gurbantunggut Desert was rich in cyanobacteria and that precipitation was a primary regulating factor for cyanobacterial composition on a regional scale. PMID- 26479724 TI - Realistic analytical polyhedral MRI phantoms. AB - PURPOSE: Analytical phantoms have closed form Fourier transform expressions and are used to simulate MRI acquisitions. Existing three-dimensional (3D) analytical phantoms are unable to accurately model shapes of biomedical interest. The goal of this study was to demonstrate that polyhedral analytical phantoms have closed form Fourier transform expressions and can accurately represent 3D biomedical shapes. METHODS: The Fourier transform of a polyhedron was implemented and its accuracy in representing faceted and smooth surfaces was characterized. Realistic anthropomorphic polyhedral brain and torso phantoms were constructed and their use in simulated 3D and two-dimensional (2D) MRI acquisitions was described. RESULTS: Using polyhedra, the Fourier transform of faceted shapes can be computed to within machine precision. Smooth surfaces can be approximated with increasing accuracy by increasing the number of facets in the polyhedron; the additional accumulated numerical imprecision of the Fourier transform of polyhedra with many faces remained small. Simulations of 3D and 2D brain and 2D torso cine acquisitions produced realistic reconstructions free of high frequency edge aliasing compared with equivalent voxelized/rasterized phantoms. CONCLUSION: Analytical polyhedral phantoms are easy to construct and can accurately simulate shapes of biomedical interest. Magn Reson Med 76:663-678, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26479725 TI - The large-X effect in plants: increased species divergence and reduced gene flow on the Silene X-chromosome. AB - The disproportionately large involvement of the X-chromosome in the isolation of closely related species (the large-X effect) has been reported for many animals, where X-linked genes are mostly hemizygous in the heterogametic sex. The expression of deleterious recessive mutations is thought to drive the frequent involvement of the X-chromosome in hybrid sterility, as well as to reduce interspecific gene flow for X-linked genes. Here, we evaluate the role of the X chromosome in the speciation of two closely related plant species - the white and red campions (Silene latifolia and S. dioica) - that hybridize widely across Europe. The two species evolved separate sexes and sex chromosomes relatively recently (~10(7) years), and unlike most animal species, most X-linked genes have intact Y-linked homologs. We demonstrate that the X-linked genes show a very small and insignificant amount of interspecific gene flow, while gene flow involving autosomal loci is significant and sufficient to homogenize the gene pools of the two species. These findings are consistent with the hypothesis of the large-X effect in Silene and comprise the first report of this effect in plants. Nonhemizygosity of many X-linked genes in Silene males indicates that exposure of recessive mutations to selection may not be essential for the occurrence of the large-X effect. Several possible causes of the large-X effect in Silene are discussed. PMID- 26479726 TI - Type 2 Diabetes Biomarkers of Human Gut Microbiota Selected via Iterative Sure Independent Screening Method. AB - Type 2 diabetes, which is a complex metabolic disease influenced by genetic and environment, has become a worldwide problem. Previous published results focused on genetic components through genome-wide association studies that just interpret this disease to some extent. Recently, two research groups published metagenome wide association studies (MGWAS) result that found meta-biomarkers related with type 2 diabetes. However, One key problem of analyzing genomic data is that how to deal with the ultra-high dimensionality of features. From a statistical viewpoint it is challenging to filter true factors in high dimensional data. Various methods and techniques have been proposed on this issue, which can only achieve limited prediction performance and poor interpretability. New statistical procedure with higher performance and clear interpretability is appealing in analyzing high dimensional data. To address this problem, we apply an excellent statistical variable selection procedure called iterative sure independence screening to gene profiles that obtained from metagenome sequencing, and 48/24 meta-markers were selected in Chinese/European cohorts as predictors with 0.97/0.99 accuracy in AUC (area under the curve), which showed a better performance than other model selection methods, respectively. These results demonstrate the power and utility of data mining technologies within the large scale and ultra-high dimensional genomic-related dataset for diagnostic and predictive markers identifying. PMID- 26479729 TI - Society for Clinical Neuropsychology (American Psychological Association, Division 40) Annual Meeting Program Summary and Abstracts. PMID- 26479727 TI - Influence of Alluvial Morphology on Upscaled Hydraulic Conductivity. AB - The hydraulic conductivity of aquifers is a key parameter controlling the interactions between resource exploitation activities, such as unconventional gas production and natural groundwater systems. Furthermore, this parameter is often poorly constrained by typical data used for regional groundwater modeling and calibration studies performed as part of impact assessments. In this study, a systematic investigation is performed to understand the correspondence between the lithological descriptions of channel-type formation and the bulk effective hydraulic conductivities at a larger scale (Kxeff , Kyeff , and Kzeff in the direction of channel cross section, along the channel and in the vertical directions, respectively). This will inform decisions on what additional data gathering and modeling of the geological system can be performed to allow the critical bulk properties to be more accurately predicted. The systems studied are conceptualized as stacked meandering channels formed in an alluvial plain, and are represented as two facies. Such systems are often studied using very detailed numerical models. The main factors that may influence Kxeff , Kyeff , and Kzeff are the proportion of the facies representing connected channels, the aspect ratio of the channels, and the difference in hydraulic conductivity between facies. Our results show that in most cases, Kzeff is only weakly dependent on the orientations of channelized structures, with the main effects coming from channel aspect ratio and facies proportion. PMID- 26479731 TI - SH2B1 orchestrates signaling events to filopodium formation during neurite outgrowth. AB - Morphogenesis during development is fundamental to the differentiation of several cell types. As neurite outgrowth marks neuritogenesis, formation of filopodia precede the formation of dendrites and axons. While the structure of filopodia is well-known, the initiation of filopodia during neurite outgrowth is not clear. SH2B1 is known to promote neurite outgrowth of PC12 cells, hippocampal and cortical neurons. As a signaling adaptor protein, SH2B1 interacts with several neurotrophin receptors, and regulates signaling as well as gene expression. Our recent findings suggest that SH2B1 can be recruited to the plasma membrane and F actin fractions by IRSp53. IRSp53 bends plasma membrane and facilitates actin bundling to set the stage for filopodium formation. We further demonstrate that SH2B1-IRSp53 complexes enhance the formation of filopodia, dendrites and dendritic branches of hippocampal and cortical neurons. While the molecular mechanism underlying filopodium initiation is not clear, we propose that SH2B1 neurotrophin interacting sites may mark the putative sites of filopodium initiation. PMID- 26479732 TI - Advanced glycation end-product (AGE) induces apoptosis in human retinal ARPE-19 cells via promoting mitochondrial dysfunction and activating the Fas-FasL signaling. AB - Advanced glycation end-products (AGEs) are extremely accumulated in the retinal vascular and epithelial cells of diabetes mellitus (DM) patients, particularly with diabetic retinopathy (DR). To elucidate the pathogenesis of the AGE-induced toxicity to retinal epithelial cells, we investigated the role of Fas-Fas ligand (FasL) signaling and mitochondrial dysfunction in the AGE-induced apoptosis. Results demonstrated that the AGE-BSA- induced apoptosis of retinal ARPE-19 cells. And the AGE-BSA treatment caused mitochondrial dysfunction, via deregulating the B-cell lymphoma 2 (Bcl-2) signaling. Moreover, the Fas/FasL and its downstreamer Caspase 8 were promoted by the AGE-BSA treatment, and the exogenous alpha-Fas exacerbated the activation of Caspase 3/8. On the other side, the siRNA-mediated knockdown of Fas/FasL inhibited the AGE-BSA-induced apoptosis. Taken together, we confirmed the activation of Fas-FasL signaling and of mitochondrial dysfunction in the AGE-BSA-promoted apoptosis in retinal ARPE-19 cells, implying the important role of Fas-FasL signaling in the DR in DM. PMID- 26479733 TI - Clinical assessments of health status as a potential marker to identify patients who are too sick to undergo transplantation. PMID- 26479734 TI - Physiologic findings in children previously ventilator dependent at home due to bronchopulmonary dysplasia. AB - INTRODUCTION: Bronchopulmonary dysplasia (BPD) is the primary respiratory complication of premature birth. Some preterm newborns develop chronic respiratory failure, requiring home ventilator support. While physiologic measures have been described for prematurely born children, little is known about spirometric indices in patients with severe BPD who were previously ventilator dependent at home. METHODS: We retrospectively reviewed medical charts of patients with severe BPD who were ventilator dependent at home. We excluded patients with other comorbidities that could contribute to the severity of BPD. Spirometry was performed when the patient was able to follow commands. RESULTS: Between 1984 and 2012, within our severe BPD cohort who previously required home ventilator support, 19 patients were able to perform reproducible spirometry meeting ATS/ERS acceptability criteria. Ten (52.6%) were females, 13 (68.4%) were Caucasians. Mean age at liberation from ventilation was 2.4 years (C.I. 2.0, 2.9) and at decannulation was 3.5 years (C.I. 2.9, 4.0); median age at first reproducible spirometry measurement was 6.6 years (IQR: 4.9, 8.3). Spirometry results revealed significant airway obstruction, as demonstrated by Z-scores values of -1.5 (C.I. -2.5, -0.4) for FVC, -2.7 (C.I. -3.3, -1.9) for FEV1 , and 3.6 (C.I. -4.3, -2.9) for FEF25-75 . More so, serial spirometric measurements' slopes revealed that the airway obstruction remained static over time (FEV1 slope: -0.07, P-value: 0.2624; FVC slope: -0.01, P-value: 0.9064; and FEF25-75 : 0.0, P-value: 0.8532). CONCLUSIONS: Extreme prematurity associated with severe BPD requiring home ventilator support carries significant risks of morbidity. These patients had substantially diminished respiratory function reflecting airflow abnormalities that remained static over time. PMID- 26479735 TI - Evaluation of screening and brief intervention for hazardous alcohol use integrated into clinical practice in an inner-city Emergency Department. AB - INTRODUCTION: In small studies, Screening, Brief Intervention and Referral to Treatment (SBIRT) in Emergency Departments (EDs) is effective in reducing hazardous alcohol use. OBJECTIVE: To examine the effectiveness of SBIRT at an inner-city ED in routine clinical practice. METHODS: Of the 41 900 consecutive ED patients aged 18 years and older, 22 537 (53.8%) were screened using the Alcohol Use Disorders Identification Test (AUDIT-C). Patients with positive AUDIT-C scores (men>=5 and women>=4) received educational leaflets. Brief interventions were performed by ED personnel trained in motivational interviewing. At 3 months, patients were contacted by telephone and recent drinking pattern was assessed. RESULTS: Out of 22 537 patients, 2209 (9.8%) had an elevated AUDIT-C score. Male sex, alcohol-related reason for ED visit, alcohol or other intoxication at ED visit, head injury, stomach or intestinal bleeding and wounds were significant predictors of hazardous alcohol use in both univariate and multivariate analysis (all P<0.001). Out of 2209 patients, 894 (40.5%) AUDIT-C-positive patients received an intervention: of these 894 patients, 70% received educational material and 30% received motivational intervention and educational material. In the subset of patients available for follow-up, 34.9% either reduced or stopped alcohol use. CONCLUSION: Our study shows that in a large inner-city ED, SBIRT can be implemented in daily care. Screening uncovered large numbers of patients with hazardous alcohol use and identified several risk factors. Moreover, screening and intervention appeared to be effective in reducing alcohol intake. PMID- 26479736 TI - Reverse triage: more than just another method. AB - Reverse triage is a way to rapidly create inpatient surge capacity by identifying hospitalized patients who do not require major medical assistance for at least 96 h and who only have a small risk for serious complications resulting from early discharge. Electronic searches were conducted in the MEDLINE, TRIP, Cochrane Library, CINAHL, EMBASE, Web of Science, and SCOPUS databases to identify relevant publications published from 2004 to 2014. The reference lists of all relevant articles were screened for additional relevant studies that might have been missed in the primary searches. There will always be small individual differences in the reverse triage decision process, influencing the potential effect on surge capacity, but at most, 10-20% of hospital total bed capacity can be made available within a few hours. Reverse triage could be a response to Emergency Department (ED) crowding, as it gives priority to ED patients with urgent needs over inpatients who can be discharged with little to no health risks. The early discharge of inpatients entails negative consequences. They often return to the ED for further assessment, treatment, and even readmission. When time to a medical referral or bed is less than 4-6 h, 100 additional lives per annum are predicted to be potentially saved. The results of our systematic review identified only a small number of publications addressing reverse triage, indicating that reverse triage and surge capacity are relatively new subjects of research within the medical field. Not all research questions could be fully answered. PMID- 26479737 TI - Length of stay in emergency department and cerebral intravenous thrombolysis in community hospitals. AB - OBJECTIVES: Current guidelines for the early management of patients with acute ischemic stroke recommend completion of an evaluation within 60 min of the patient's arrival at the emergency department (ED) because prolongation of ED length of stay (LOS) may reduce the efficacy of acute stroke treatment. AIM: To evaluate the LOS in EDs at the community-based Polish stroke centers, to determine logistic, social, epidemiological, and clinical factors responsible for its prolongation, and to assess the association between increased LOS and the implementation of cerebral intravenous (IV) thrombolysis. MATERIALS AND METHODS: This study carried out an evaluation of the medical records of 8398 patients with stroke and transient ischemic attack who consecutively reported to the Pomeranian Stroke Registry from 2010 to 2012. RESULTS: The median ED LOS in the studied cohort was 97 (44-196) min and was prolonged (>60 min) in 63.1% of patients. Prolongation of ED LOS contributed to a low (4.9%) IV thrombolysis rate. Functional status at discharge was worse in patients with prolonged versus nonprolonged LOS [modified Rankin scale: 2 (0-3) vs. 1 (0-3) points; P<0.001]. Multivariate analysis showed that onset-to-door time more than 270 min or unknown time of symptoms onset, referral to ED in urban areas, living alone, presence of diabetes, motor, sensory, visual, and gait deficits at stroke onset, and NIHSS score on admission contributed toward prolongation of ED LOS. CONCLUSION: A prolonged ED LOS, because of ineffective prehospital logistics, ED urban location, patients' risk factors, and cohabitation profile and stroke symptoms and severity, commonly exists among patients with stroke and transient ischemic attack and contributes toward a low rate of IV thrombolysis in Polish community hospitals. PMID- 26479738 TI - Acute urinary retention and the difficult catheterization: current emergency management. AB - Acute urinary retention (AUR) is a common presentation to emergency departments. This article updates the reader on the appropriate management, investigations and guidelines for AUR. It looks at the mechanism of normal micturition and describes the theories of AUR. It outlines urethral catheterization techniques for difficult cases, reviews suprapubic catheterization procedures and describes the management of AUR in polytrauma. Although emergency management is by bladder drainage, key points in the history and examination may expose significant, latent pathologies. PMID- 26479739 TI - Time delay to surgery for appendicitis: no difference between surgical assessment unit and emergency department. AB - BACKGROUND: In Denmark, emergency departments (EDs) are replacing acute surgical and medical units. The aim of this study was to compare the trajectory of patients undergoing surgery on the suspicion of appendicitis in a surgical assessment unit (SAU) and EDs with an observation unit, respectively. The primary outcome measure was the time from hospital arrival-to-decision for surgery. MATERIALS AND METHODS: A comparative retrospective study with a cross-sectional design and a before-and-after design was carried out during January 2011 to December 2012 at a SAU and an ED at a university hospital (U-SAU and U-ED) and at an ED at a regional hospital (R-ED). Data included time of arrival, decision for surgery, surgery and discharge, and number of blood tests. RESULTS: In total, 250 patients were included. Time to decision for surgery was 4.50, 4.95, and 4.63 h (P=0.58) in the U-SAU, R-ED, and U-ED, respectively. Time from decision for surgery to start of surgery was 4.60, 3.29, and 4.12 h in the U-SAU, R-ED, and U ED, respectively. The difference was significant between the U-SAU and R-ED (P=0.05) and between R-ED and U-ED (P=0.03). Time from surgery to discharge from the hospital was 17.88, 19.28, and 15.13 h in the U-SAU, R-ED, and U-ED, respectively. The difference was significant between the EDs (P=0.02). Significantly more blood tests were performed in the EDs than in the U-SAU. CONCLUSION: The introduction of EDs with observation units did not influence time to decision for surgery, but more blood tests were performed. PMID- 26479740 TI - Optimal timing for performing percutaneous transhepatic gallbladder drainage and subsequent cholecystectomy for better management of acute cholecystitis. AB - BACKGROUND: We aimed to clarify the appropriate timing for performing percutaneous transhepatic gallbladder drainage (PTGBD) and cholecystectomy, and the effect of PTGBD on surgical difficulty in acute cholecystitis patients. METHODS: We retrospectively examined 46 patients who underwent laparoscopic cholecystectomy (LC) after PTGBD for acute cholecystitis. We evaluated the duration from acute cholecystitis onset to PTGBD and the appropriate interval from PTGBD to elective LC. Intraoperative blood loss, operating time, rate of conversion to open surgery, and rate of severe adhesion were the objective and subjective measures. RESULTS: Based on the cut-off value calculated using the Youden index, the group with a duration from acute cholecystitis onset to PTGBD of <=73.5 h had a significantly shorter operating time (127.5 min vs. 180.0 min, P = 0.007), lower rate of severe adhesion (3/20 vs. 14/26, P = 0.007), and lower rate of conversion to open surgery (2/20 vs. 13/26, P = 0.004); moreover, the interval from PTGBD to elective LC did not significantly differ between these groups. CONCLUSION: The most important predictor of successful LC following PTGBD for acute cholecystitis was a duration from acute cholecystitis onset to PTGBD of <=73.5 h. Hence, PTGBD should be performed immediately in cases where early cholecystectomy is not indicated. PMID- 26479741 TI - Scholarly Activity Program Requirements: The Review Committee-Emergency Medicine (RC-EM) Perspective. PMID- 26479742 TI - Resveratrol, sirtuins, and viruses. AB - Resveratrol is a natural phenolic product found in some plants in response to stress and has been linked to the many health benefits of red wine. Over the past several decades, a great deal of research has identified diverse biological roles associated with resveratrol, including anti-oxidant, anti-proliferation, anti inflammation, anti-cancer, anti-fungal, and antiviral activities. Such biological activities of resveratrol are likely mediated through multiple cellular targets or pathways, such as sirtuins, a family of NAD(+)-dependent deacetylases. In this treatise, the literatures focusing on the roles of resveratrol and sirtuins in modulating infections by a broad-spectrum of viruses are reviewed, with an emphasis on its potential antiviral mechanisms. A working model about the effects of resveratrol on virus infection is proposed to stimulate further researches on this exciting topic. PMID- 26479743 TI - Correction: Synthesis and crystal structure of a new hexagonal perovskite 7H Ba7Li1.75Mn3.5O15.75 with Mn(4+)/Mn(5+) charge distribution. PMID- 26479745 TI - Peer Review: We Can't Do Without You. PMID- 26479744 TI - Novel 1-Phenyl-3-hydroxy-4-pyridinone Derivatives as Multifunctional Agents for the Therapy of Alzheimer's Disease. AB - A series of novel 1-phenyl-3-hydroxy-4-pyridinone derivatives were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy through incorporation of 3-hydroxy-4-pyridinone moiety from deferiprone into the scaffold of H3 receptor antagonists. Most of these new compounds displayed designed quadruple functions, H3 receptor antagonism, Abeta aggregation inhibition, metal ion chelation, and radical scavenging. Especially, the most promising compound 5c displayed nanomolar IC50 values in H3 receptor antagonism with high selectivity, efficient capability to interrupt the formation of Abeta(1 42) fibrils, good copper and iron chelating properties, and more potent 2,2' azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) radical cation (ABTS(*+)) scavenging activity than Trolox. Further biological evaluation revealed that it did not show obvious cytotoxicity and hERG potassium channel inhibition at micromolar concentration. In addition, compound 5c demonstrated suitable pharmacokinetic properties and acceptable blood-brain barrier (BBB) permeability in vivo. All these results indicate that compound 5c is a potential multifunctional candidate for AD therapy. PMID- 26479746 TI - Frog Swarms: Earthquake Precursors or False Alarms? AB - In short-term earthquake risk forecasting, the avoidance of false alarms is of utmost importance to preclude the possibility of unnecessary panic among populations in seismic hazard areas. Unusual animal behaviour prior to earthquakes has been reported for millennia but has rarely been scientifically documented. Recently large migrations or unusual behaviour of amphibians have been linked to large earthquakes, and media reports of large frog and toad migrations in areas of high seismic risk such as Greece and China have led to fears of a subsequent large earthquake. However, at certain times of year large migrations are part of the normal behavioural repertoire of amphibians. News reports of "frog swarms" from 1850 to the present day were examined for evidence that this behaviour is a precursor to large earthquakes. It was found that only two of 28 reported frog swarms preceded large earthquakes (Sichuan province, China in 2008 and 2010). All of the reported mass migrations of amphibians occurred in late spring, summer and autumn and appeared to relate to small juvenile anurans (frogs and toads). It was concluded that most reported "frog swarms" are actually normal behaviour, probably caused by juvenile animals migrating away from their breeding pond, after a fruitful reproductive season. As amphibian populations undergo large fluctuations in numbers from year to year, this phenomenon will not occur on a yearly basis but will depend on successful reproduction, which is related to numerous climatic and geophysical factors. Hence, most large swarms of amphibians, particularly those involving very small frogs and occurring in late spring or summer, are not unusual and should not be considered earthquake precursors. In addition, it is likely that reports of several mass migration of small toads prior to the Great Sichuan Earthquake in 2008 were not linked to the subsequent M = 7.9 event (some occurred at a great distance from the epicentre), and were probably co-incidence. Statistical analysis of the data indicated frog swarms are unlikely to be connected with earthquakes. Reports of unusual behaviour giving rise to earthquake fears should be interpreted with caution, and consultation with experts in the field of earthquake biology is advised. PMID- 26479747 TI - A Framework to Evaluate Wildlife Feeding in Research, Wildlife Management, Tourism and Recreation. AB - Feeding of wildlife occurs in the context of research, wildlife management, tourism and in opportunistic ways. A review of examples shows that although feeding is often motivated by good intentions, it can lead to problems of public safety and conservation and be detrimental to the welfare of the animals. Examples from British Columbia illustrate the problems (nuisance animal activity, public safety risk) and consequences (culling, translocation) that often arise from uncontrolled feeding. Three features of wildlife feeding can be distinguished: the feasibility of control, the effects on conservation and the effects on animal welfare. An evaluative framework incorporating these three features was applied to examples of feeding from the literature. The cases of feeding for research and management purposes were generally found to be acceptable, while cases of feeding for tourism or opportunistic feeding were generally unacceptable. The framework should allow managers and policy-makers to distinguish acceptable from unacceptable forms of wildlife feeding as a basis for policy, public education and enforcement. Many harmful forms of wildlife feeding seem unlikely to change until they come to be seen as socially unacceptable. PMID- 26479748 TI - Should Dogs and Cats be Given as Gifts? AB - Policies that state dogs and cats should not be adopted as gifts are prevalent at animal welfare organizations, despite the fact that this belief is unfounded. Denying adopters who intend to give the animals as gifts may unnecessarily impede the overarching goal of increasing the rate of live-releases of dogs and cats from our nations' shelter system. The results of this brief survey show that receiving a dog or cat as a gift was neither significantly associated with impact on self-perceived love/attachment, nor was it associated with whether or not respondents still had the dog or cat in the home. The results from this survey add to a growing body of literature that suggests there is no increased risk of relinquishment for dogs and cats received as a gift. PMID- 26479749 TI - Stakeholder Perceptions of Threatened Species and Their Management on Urban Beaches. AB - We surveyed 579 recreationists regarding management of the threatened, beach dwelling Hooded Plover Thinornis rubricollis. We postulated that: (1) lower awareness of the species and higher 'inconvenience' of management would engender less favourable perceptions of conservation and management; and (2) that frequency of beach use and dog ownership may mediate perceptions and levels of awareness and inconvenience. Overall, inconvenience was low while awareness and support for plover conservation were high. Education and awareness strategies were considered less effective than regulations; exclusion and regulations were considered less desirable than on-ground protective measures. Awareness, frequency of beach use and dog walking did not influence the perceived effectiveness of different managements. More frequent beach users had greater awareness of the species and their plight but reported greater inconvenience associated with management. Respondents with high awareness rated the severity of human-related threats higher; low awareness was associated with more inconvenience associated with on-ground protection, and exclusion and regulations. Dog walkers reported more inconvenience associated with exclusions and regulations than non-dog walkers. Dog walkers who used the beach infrequently rated threats significantly higher than frequent beach users. Conservation and education strategies could usefully be tailored to beach users' level of use and pet ownership. PMID- 26479750 TI - Animal Health and Welfare Issues Facing Organic Production Systems. AB - The demand for organically-grown produce is increasing worldwide, with one of the drivers being an expectation among consumers that animals have been farmed to a high standard of animal welfare. This review evaluates whether this expectation is in fact being met, by describing the current level of science-based knowledge of animal health and welfare in organic systems. The primary welfare risk in organic production systems appears to be related to animal health. Organic farms use a combination of management practices, alternative and complementary remedies and convenional medicines to manage the health of their animals and in many cases these are at least as effective as management practices employed by non-organic producers. However, in contrast to non-organic systems, there is still a lack of scientifically evaluated, organically acceptable therapeutic treatments that organic animal producers can use when current management practices are not sufficient to maintain the health of their animals. The development of such treatments are necessary to assure consumers that organic animal-based food and fibre has not only been produced with minimal or no chemical input, but under high standards of animal welfare. PMID- 26479752 TI - Do Formal Inspections Ensure that British Zoos Meet and Improve on Minimum Animal Welfare Standards? AB - We analysed two consecutive inspection reports for each of 136 British zoos made by government-appointed inspectors between 2005 and 2011 to assess how well British zoos were complying with minimum animal welfare standards; median interval between inspections was 1,107 days. There was no conclusive evidence for overall improvements in the levels of compliance by British zoos. Having the same zoo inspector at both inspections affected the outcome of an inspection; animal welfare criteria were more likely to be assessed as unchanged if the same inspector was present on both inspections. This, and erratic decisions as to whether a criterion applied to a particular zoo, suggest inconsistency in assessments between inspectors. Zoos that were members of a professional association (BIAZA) did not differ significantly from non-members in the overall number of criteria assessed as substandard at the second inspection but were more likely to meet the standards on both inspections and less likely to have criteria remaining substandard. Lack of consistency between inspectors, and the high proportion of zoos failing to meet minimum animal welfare standards nearly thirty years after the Zoo Licensing Act came into force, suggest that the current system of licensing and inspection is not meeting key objectives and requires revision. PMID- 26479751 TI - Why Do So Many Calves Die on Modern Dairy Farms and What Can We Do about Calf Welfare in the Future? AB - Poor bovine neonatal survival rates are an international animal welfare issue. The key modifiable risk factors associated with such loss are age at first calving in primiparae, calf breed, gender and gestation length and calving management. The primary causes of mortality in the perinatal period are calving problems, in particular dystocia, defined as both difficult and abnormal calvings. Calf loss rates are rising on modern dairy farms in many countries internationally. High calf loss rates are often not recognised at national or at farm-level; recording needs to be improved. Improving bovine neonatal survival requires re-prioritization of this issue. Stakeholders need to be made cognisant of this prioritization. Actions to effect change need to occur at both national and farm-levels. National-level actions need firstly to address raising awareness of the issue. Farm-level actions need to focus on identifiable problem farms through targeted surveillance. Application of existing knowledge to alter modifiable risk factors is the key to improving calf welfare in the future. Research also has a role to play in filling knowledge gaps in particular about the 'unexplained stillbirth'. PMID- 26479753 TI - Challenges Encountered During the Veterinary Disaster Response: An Example from Chile. AB - Large-scale disasters have immeasurable effects on human and animal communities. Evaluating and reporting on the response successes and difficulties encountered serves to improve existing preparedness documents and provide support to those in the process of developing plans. Although the majority of disasters occur in low and middle income nations, less than 1% of the disaster literature originates from these countries. This report describes a response to a disease outbreak in domestic dogs in Dichato, Chile following the 2010 earthquake/tsunami. With no national plan coordinating the companion animal response, there was a chaotic approach among animal welfare organizations towards rescue, diagnosis, treatment and record-keeping. Similar to the medical response following the 1985 earthquake near Santiago, we experienced problems within our own teams in maintenance of data integrity and protocol compliance. Loss of infrastructure added complications with transportation, communications and acquisition of supplies. Similar challenges likely occur in most disasters, but can be reduced through pro active planning at national and local levels. There is sufficient information to support the human and animal welfare benefits of including companion animals in national planning, and lessons learned through this and other experiences can assist planners in the development of comprehensive and locally relevant contingency plans. PMID- 26479754 TI - Policing Farm Animal Welfare in Federated Nations: The Problem of Dual Federalism in Canada and the USA. AB - In recent European animal welfare statutes, human actions injurious to animals are new "offences" articulated as an injury to societal norms in addition to property damage. A crime is foremost a violation of a community moral standard. Violating a societal norm puts society out of balance and justice is served when that balance is returned. Criminal law normally requires the presence of mens rea, or evil intent, a particular state of mind; however, dereliction of duties towards animals (or children) is usually described as being of varying levels of negligence but, rarely can be so egregious that it constitutes criminal societal injury. In instrumental justice, the "public goods" delivered by criminal law are commonly classified as retribution, incapacitation and general deterrence. Prevention is a small, if present, outcome of criminal justice. Quazi-criminal law intends to establish certain expected (moral) standards of human behavior where by statute, the obligations of one party to another are clearly articulated as strict liability. Although largely moral in nature, this class of laws focuses on achieving compliance, thereby resulting in prevention. For example, protecting the environment from degradation is a benefit to society; punishing non compliance, as is the application of criminal law, will not prevent the injury. This paper will provide evidence that the integrated meat complex of Canada and the USA is not in a good position to make changes to implement a credible farm animal protection system. PMID- 26479756 TI - Wildlife Warning Signs: Public Assessment of Components, Placement and Designs to Optimise Driver Response. AB - Wildlife warning signs are the most commonly used and widespread form of road impact mitigation, aimed at reducing the incidence of wildlife-vehicle collisions. Evidence of the effectiveness of currently used signs is rare and often indicates minimal change in driver behaviour. Improving the design of these signs to increase the likelihood of appropriate driver response has the potential to reduce the incidence of wildlife-vehicle collisions. This study aimed to examine and assess the opinions of drivers on wildlife warning sign designs through a public opinion survey. Three currently used sign designs and five alternative sign designs were compared in the survey. A total of 134 drivers were surveyed. The presence of temporal specifications and an updated count of road killed animals on wildlife warning signs were assessed, as well as the position of the sign. Drivers' responses to the eight signs were scaled separately at three speed limits and participants indicated the sign to which they were most likely to respond. Three signs consistently ranked high. The messages conveyed by these signs and their prominent features were explored. Animal-activated and vehicle speed-activated signs were ranked very highly by participants. Extensive field trials of various sign designs are needed to further this research into optimizing wildlife warning sign designs. PMID- 26479755 TI - Influence of Different Housing Systems on Distribution, Function and Mitogen Response of Leukocytes in Pregnant Sows. AB - In pig production, pregnant sows are either housed in individual crates or in groups, the latter being mandatory in the EU since 2013. The consequences of different housing conditions on the immune system are however poorly investigated, although immunological alterations may have severe consequences for the animal's health, performance, and welfare. This study assessed measures of blood celluar immunity with special emphasis on T cells in pregnant German Landrace sows either housed in individual crates or in a social group. Blood samples were taken at four samplings pre partum to evaluate numbers of lymphocyte subpopulations, mitogen-induced lymphocyte proliferation and cytokine-producing T cells. Plasma cortisol concentrations were evaluated as an indicator of stress. We found lower blood lymphocyte numbers (p < 0.01) in individually housed as opposed to group-housed sows, an effect due to lower numbers of cytotoxic T cells, naive TH cells, and CD8+ gd-T cells. Individually housed sows showed higher cortisol concentrations (p < 0.01), whereas lymphocyte functionality did not differ between sows of both housing systems. Possible implications and underlying mechanisms for the endocrine and immunological differences are discussed. We favor the hypothesis that differences in the stressfulness of the environment contributed to the effects, with crate-housing being a more stressful environment-at least under conditions of this study. PMID- 26479757 TI - Practical Physical and Behavioral Measures to Assess the Socialization Spectrum of Cats in a Shelter-Like Setting during a Three Day Period. AB - Animal welfare organizations routinely accept large numbers of cats with unknown histories, and whose backgrounds vary from well-socialized pets to cats that have had little or no contact with humans. Agencies are challenged with making the determination of socialization level in a highly stressful environment where cats are often too frightened to show typical behaviors. A variety of structured behavioral assessments were conducted in a shelter-like environment, from intake through a three day holding period, on cats from the full range of socialization as reported by their caregivers. Our results show that certain behaviors such as rubbing, playing, chirping, having the tail up or being at the front of the cage were found to be unique to More Socialized cats. While not all more socialized cats showed these behaviors, cats that did were socialized. Assessing the cats throughout the three day period was beneficial in eliciting key behaviors from shyer and more frightened cats. These results will be used in future work to develop an assessment tool to identify the socialization status of cats as a standardized guide for transparent and reliable disposition decisions and higher live release rates for cats in animal shelters. PMID- 26479758 TI - Reliability and Validity of a Survey of Cat Caregivers on Their Cats' Socialization Level in the Cat's Normal Environment. AB - Stray cats routinely enter animal welfare organizations each year and shelters are challenged with determining the level of human socialization these cats may possess as quickly as possible. However, there is currently no standard process to guide this determination. This study describes the development and validation of a caregiver survey designed to be filled out by a cat's caregiver so it accurately describes a cat's personality, background, and full range of behavior with people when in its normal environment. The results from this survey provided the basis for a socialization score that ranged from unsocialized to well socialized with people. The quality of the survey was evaluated based on inter rater and test-retest reliability and internal consistency and estimates of construct and criterion validity. In general, our results showed moderate to high levels of inter-rater (median of 0.803, range 0.211-0.957) and test-retest agreement (median 0.92, range 0.211-0.999). Cronbach's alpha showed high internal consistency (0.962). Estimates of validity did not highlight any major shortcomings. This survey will be used to develop and validate an effective assessment process that accurately differentiates cats by their socialization levels towards humans based on direct observation of cats' behavior in an animal shelter. PMID- 26479759 TI - Physical and Behavioral Measures that Predict Cats' Socialization in an Animal Shelter Environment during a Three Day Period. AB - Animal welfare organizations typically take in cats with unknown levels of socialization towards humans, ranging from unsocialized cats well-socialized but lost pets. Agencies typically determine the socialization status and disposition options of cats within three days, when even a well-socialized pet may be too frightened of the unfamiliar surroundings to display its typical behavior. This is the third part of a three-phase project to develop and evaluate a reliable and valid tool to predict cats' socialization levels. We recruited cats from the full spectrum of socialization and, using information from the cats' caregivers regarding typical behavior toward familiar and unfamiliar people, assigned each cat to a Socialization Category. This information was compared to the cats' behavior during three days of structured assessments conducted in a shelter-like setting. The results of logistic regression modeling generated two models using assessments from the mornings of the second and third day, focusing on predicting shyer or more aloof but socialized cats. Using the coefficients from each of these models, two sets of points were calculated which were useful in differentiating More and Less Socialized cats. In combination with key socialized behaviors, these points were able to fairly accurately identify More and Less Socialized cats. PMID- 26479760 TI - Ventricular Catheter Systems with Subcutaneous Reservoirs (Ommaya Reservoirs) in Pediatric Patients with Brain Tumors: Infections and Other Complications. AB - OBJECTIVE: This study aims to describe complications related to ventricular catheter systems with subcutaneous reservoirs (VCSR) (such as Ommaya reservoirs) in pediatric patients with brain tumors. METHODS: Retrospective analysis of consecutive patients with a total of 31 VCSR treated at the Children's University Hospital of Zurich, Switzerland. RESULTS: A total of 20 patients with a median age of 3.3 years at VCSR implantation received 31 VCSR. Overall, 19 complications in 11 patients were recorded: 7 patients had a VCSR-related infection with coagulase-negative staphylococci, 4 of these probably as a surgical complication and 3 probably related to VCSR use. Systemic perioperative prophylaxis was administered in 22 cases, and intraventricular vancomycin and gentamicin were given in 8 cases (none of which subsequently developed an infection). Other complications included wound dehiscence, catheter malplacement, and leakage of cerebrospinal fluid. Overall, 17 VCSR were explanted due to complications. CONCLUSION: Infections were the most frequent VCSR-related complication. In our own institution, the high rate of complications led to the definition of a bundle of measures as a standard operating procedure for VCSR placement and use. Prospective studies in larger patient collectives are warranted to better identify risk factors and evaluate preventive measures such as the administration of perioperative antibiotics and the use of antimicrobial coating of catheters. PMID- 26479761 TI - A Multinational Survey on Actual Diagnostics and Treatment of Subacute Sclerosing Panencephalitis. AB - Subacute sclerosing panencephalitis (SSPE) is a chronic infection of the central nervous system caused by the measles virus (MV). Its prevalence remains high in resource poor countries and is likely to increase in the Northern Europe as vaccination rates decrease. Clinical knowledge of this devastating condition, however, is limited. We therefore conducted this multinational survey summarizing experience obtained from more than 500 patients treated by 24 physicians in seven countries. SSPE should be considered in all patients presenting with otherwise unexplained acquired neurological symptoms. In most patients, the diagnosis will be established by the combination of typical clinical symptoms (characteristic repetitive myoclonic jerks), a strong intrathecal synthesis of antibodies to MV and typical electroencephalogram findings (Radermecker complexes). Whereas the therapeutic use of different antiviral (amantadine, ribavirin) and immunomodulatory drugs (isoprinosine, interferons) and of immunoglobulins has been reported repeatedly, optimum application regimen of these drugs has not been established. This is partly due to the absence of common diagnostic and clinical standards focusing on neurological and psychosocial aspects. Carbamazepine, levetiracetam, and clobazam are the drugs most frequently used to control myoclonic jerks. We have established a consensus on essential laboratory and clinical parameters that should facilitate collaborative studies. Those are urgently needed to improve outcome. PMID- 26479763 TI - Prenatal Magnetic Resonance Imaging of Atypical Partial Rhombencephalosynapsis with Involvement of the Anterior Vermis: Two Case Reports. AB - Rhombencephalosynapsis is a hindbrain malformation characterized by complete or partial absence of the cerebellar vermis, with varying degrees of midline continuity of cerebellar hemispheres, dentate nuclei, and in some patients of the superior cerebellar peduncles. Partial rhombencephalosynapsis usually consists of a segmental deficiency of posterior vermis. Although prenatal diagnosis of rhombencephalosynapsis is feasible by ultrasound and magnetic resonance imaging both, partial rhombencephalosynapsis might be difficult to detect, especially at an early gestational age. We report two fetal cases of atypical partial rhombencephalosynapsis, with deficiency of anterior vermis, detected by prenatal magnetic resonance imaging at 21st and 23rd week of gestation, respectively. PMID- 26479762 TI - Low Serum Level alpha-Synuclein and Tau Protein in Autism Spectrum Disorder Compared to Controls. AB - alpha-Synuclein (alpha-syn) and tau proteins are thought to be related with the synaptic loss and cell death underlying several important neurodegenerative diseases. The aim of our study was to investigate serum alpha-syn and tau levels in autism. Serum levels of alpha-syn and tau were measured, and autism spectrum disorder (ASD) severity was assessed at admission using the Childhood Autism Rating Scale (CARS) total score. The mean CARS score of the autism group on admission was 47.91 points (SD: 5.97). The results indicated that the mean serum alpha-syn and serum tau levels were significantly (p < 0.001) lower in children with ASD as compared with normal cases (33.01 +/- 20.78 and 55.19 +/- 15.34 ng/mL and 241.23 +/- 290.5 and 509.78 +/- 269.25 ng/mL, respectively). There was a significant positive correlation between serum alpha-syn levels and serum levels of tau identified by Pearson correlation analysis (r = 0.922, n = 28, p < 0.001). Synaptic abnormality in autism may result from microglial activity. Furthermore, alpha-syn and tau aggregation may lead to synaptic dysfunction, and this may contribute to either neuronal or synaptic dysfunction or neurodegeneration. Our preliminary study suggests that low levels of serum alpha-syn and tau may be implicated in the relationship between synaptic activity and autism. PMID- 26479764 TI - Clinical, Electrodiagnostic, and Genetic Features of Tangier Disease in an Adolescent Girl with Presentation of Peripheral Neuropathy. AB - Tangier disease (TD) is a rare, autosomal recessive inherited disorder caused by a mutation in the adenosine triphosphate-binding cassette transporter 1 (ABCA1) gene, which results in a decrease in plasma high-density lipoprotein (HDL) levels. Peripheral neuropathy can be seen in approximately 50% of patients with TD, which usually occurs after the age of 15 years, and is characterized by relapsing-remitting mono- or polyneuropathy or syringomyelia-like neuropathy. Herein, we report a 16-year-old female patient who was initially diagnosed with peripheral neuropathy at the age of 13 years. Whole exome sequencing was performed, and a nonsense mutation (p.Arg1817X) in ABCA1 was identified. The patient was investigated for systemic findings of TD after the genetic diagnosis was made, and low (< 5 mg/dL) levels of HDL cholesterol were detected by lipid electrophoresis. Other family members were reexamined after the diagnosis of the proband, and asymptomatic sister of the proband was diagnosed with TD. We would like to emphasize that TD should be considered in the differential diagnosis of pediatric patients presenting with peripheral neuropathy; furthermore detection of HDL levels by lipid electrophoresis is a simple but indicative diagnostic test. PMID- 26479765 TI - X-Linked Hereditary Motor Sensory Neuropathy Type 1 (CMTX1) in a Three-Generation Gelao Chinese Family. AB - In this report, we describe a three-generation family (the Gelao nationality, a minority ethnic group from Guizhou Province in the southwest China) with one affected member with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) in each generation. The three affected members carrying the R164W mutation in the Cx32 gene had different clinical symptoms. The proband, a 13-year-old boy presented recurrent episodes of transient central nervous system symptoms and concomitant transient diffuse white matter lesions on magnetic resonance imaging. His grandfather had the peripheral neurological presentations with later onset in the fourth decade, characterized by slowly progressive weakness of the distal muscles, atrophy, and foot deformities. But no sensory loss was observed. The proband's 38-year-old mother denied any neurological symptoms. The examination was normal except for pes cavus and diminished deep tendon reflexes in her lower limbs bilaterally. Genetic sequencing revealed the proband and his grandfather had a hemizygous mutation (p.164R > W) of CJB1 gene, and his mother had R164W heterozygous mutation. Our three cases denied symptoms of sensory disturbances, the sensory examination including touch, pin prick, and temperature sensation showed no obvious abnormalities. Thus, further investigation is needed to improve our understanding of the Cx32 protein function in the nervous system. PMID- 26479766 TI - Age-Dependent Seroprevalence of JCV Antibody in Children. AB - Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system infection, caused by the John Cunningham virus (JCV). PML may occur during treatment with immunosuppressive agents or monoclonal antibodies such as natalizumab. The JCV seroprevalence increases with age with a seropositivity of 60% in the adult human population. In this study, we analyzed sera from 109 pediatric multiple sclerosis (MS) patients (mean age 14 years) as well as sera from 162 patients with a wide range of suspected neurologic disorders (mean age 6.3 years). Our results showed a considerably lower seroprevalence for JCV in our pediatric cohort with 33.3% and equal distribution in both subgroups, compared with reported seropositivity in adult population. This could result in a lower risk for drug-induced PML in pediatric patients compared with adult patients and can influence the indication for natalizumab therapy in pediatric MS patients. PMID- 26479768 TI - Unmasking mycosis fungoides/Sezary syndrome from preceding or co-existing benign inflammatory dermatoses requiring systemic therapies: patients frequently present with advanced disease and have an aggressive clinical course. PMID- 26479767 TI - Social factors in informal cancer caregivers: The interrelationships among social stressors, relationship quality, and family functioning in the CanCORS data set. AB - BACKGROUND: Social and family factors can influence the health outcomes and quality of life of informal caregivers. Little is known about the distribution and correlates of such factors for caregivers of cancer patients. This study sought to fill this gap with data from the Cancer Care Outcomes Research and Surveillance consortium. METHODS: Lung and colorectal cancer patients nominated an informal caregiver to participate in a caregiving survey. Caregivers reported their sociodemographic and caregiving characteristics, social stress, relationship quality with the patient, and family functioning. Descriptive statistics and Pearson correlations were used to assess the distribution of caregivers' social factors. Multivariable linear regressions assessed the independent correlates of each social factor. RESULTS: Most caregivers reported low to moderate levels of social stress and good relationship quality and family functioning. In multivariable analyses, older age was associated with less social stress and better family functioning but worse relationship quality, with effect sizes (Cohen's d) up to 0.40 (P < .05). Caring for a female patient was associated with less social stress and better relationship quality but worse family functioning (effect sizes <= 0.16, P < .05). Few caregiving characteristics were associated with social stress, whereas several were significant independent correlates of relationship quality. Finally, social factors were important independent correlates of one another. CONCLUSIONS: The results indicate the importance of personal and caregiving-related characteristics and the broader family context to social factors. Future work is needed to better understand these pathways and assess whether interventions targeting social factors can improve health or quality-of-life outcomes for informal cancer caregivers. Cancer 2016;122:278-286. (c) 2015 American Cancer Society. PMID- 26479769 TI - Biological activity of Stevia rebaudiana Bertoni and their relationship to health. AB - The leaves of Stevia rebaudiana Bertoni has nutrients and phytochemicals, which make it an adequate source for the extraction and production of functional food ingredients. Preclinical and clinical studies suggest therapeutic and pharmacological applications for stevia and their extracts because they are not toxic and exhibit several biological activities. This review presents the biological activity of Stevia rebaudiana Bertoni and their relationship to antidiabetic, anticariogenic, antioxidant, hypotensive, antihypertensive, antimicrobial, anti-inflammatory and antitumor activities. Consumption and adverse effects were also reviewed. PMID- 26479770 TI - It's all in the anticipation: How perception of threat is enhanced in anxiety. AB - The importance of top-down factors such as goals and expectations is well established in both visual perception and anxiety. However, researchers have attributed the perceptual prioritization of threatening stimuli in anxiety to bottom-up, automatic processing of these stimuli while neglecting the role of prestimulus, top-down factors. Furthermore, different kinds of anxiety (dispositional versus induced) impact cognitive functions differently, suggesting that top-down factors may have distinct effects on threat perception. In the present study, we examined whether prestimulus representations of threatening stimuli facilitate perception differently, depending on induced and trait anxiety. Two groups of participants completed a cued discrimination task using threatening or neutral cues to identify subsequently presented fearful and neutral faces, degraded to each participant's perceptual threshold. In Group 1, threat of shock induced anxiety (n = 22; 12 men), whereas in Group 2, no anxiety was induced (n = 29; 7 men). The impact of induced anxiety on perception interacted with trait anxiety. Following fear cues, higher trait anxiety was associated with improved perceptual sensitivity and faster reaction time under threat of shock, and worse perceptual sensitivity and slower reaction time in absence of shock. The present findings represent an important advance in the literature because they elucidate the role of previously ignored top-down factors in threat perception for individuals with varying levels of anxiety and highlight the distinct impact that different types of anxiety have on the perception of threatening stimuli. Furthermore, these findings underline the importance of including top-down factors in future conceptualizations of perceptual bias toward threat in anxiety. PMID- 26479771 TI - Distracted by pleasure: Effects of positive versus negative valence on emotional capture under load. AB - We report 3 experiments examining the effects of positive versus negative valence and perceptual load in determining attention capture by irrelevant emotional distractors. Participants performed a letter search task searching for 1 of 2 target letters (X or N) in conditions of either low perceptual load (circular nontarget letters) or high perceptual load (angular nontarget letters that are similar to the target letters). On 25% of the trials an irrelevant emotional distractor was presented at the display center and participants were instructed to ignore it. The distractor stimulus was either positive or negative and was selected from 3 different classes: IAPS pictures of erotica or mutilated bodies (Experiment 1), happy or angry faces (Experiment 2), and faces associated with gain or loss in a prior value-learning phase involving a betting game (Experiment 3). The results showed a consistent pattern of interaction of load and valence across the 3 experiments. Irrelevant emotional distractors produced interference effects on search reaction time (RT) in conditions of low load, with no difference between negative and positive valence. High perceptual load, however, consistently reduced interference from the negative-valence distractors, but had no effect on the positive-valence distractors. As these results were consistently found across 3 different categories of emotional distractors, they suggest the general conclusion that attentional capture by irrelevant emotional distractors depends on both their valence and the level of perceptual load in the task and highlight the special status of distractors associated with pleasure. PMID- 26479772 TI - Emotional and organizational supports for preschoolers' emotion regulation: Relations with school adjustment. AB - Preschool teachers, like parents, support children in ways that promote the regulation capacities that drive school adjustment, especially for children struggling to succeed in the classroom. The purpose of this study was to explore the emotionally and organizationally supportive classroom processes that contribute to the development of children's emotion regulation and executive control. Emotion regulation and executive control were assessed in 312 3-, 4- and 5-year-old children. The 44 teachers of these children completed questionnaires asking about 3 components of children's school adjustment: Positive/Engaged, Independent/Motivated, and Prosocial/Connected. Observations of classroom emotional and organizational supports were conducted. Results of multilevel models indicated emotion regulation was significantly associated with the Positive/Engaged school adjustment component, but only when teachers' emotional and organizational supports were taken into account. Children with lower levels of emotion regulation, who were also in less supportive classrooms, had the lowest scores on the Positive/Engaged component. Children's executive control was associated with the Independent/Motivated and Prosocial/Connected components independently of teacher effects. In general, moderate support was found for the notion that teachers' supports can be particularly helpful for children struggling to regulate their emotions to be better adjusted to school. Children's emotionally salient classroom behaviors, and teachers' emotion scaffolding, are discussed. PMID- 26479773 TI - Variation in normal mood state influences sensitivity to dynamic changes in emotional expression. AB - Normal social functioning depends on the ability to efficiently and accurately detect when someone's facial expression changes to convey positive or negative emotion. While observer mood state has been shown to influence emotion recognition, how variations in normal mood might influence sensitivity to the dynamic emergence of expressions has not yet been addressed. To investigate this, we modified an existing face-morphing paradigm in which a central face gradually changes from neutral to expressive (angry, sad, happy, surprised). Our sample comprised healthy young adults, and current mood state was measured using the PANAS-X. Participants pressed a key as soon as they (1) noticed a physical change in expression (perceptual sensitivity-novel task element), and (2) could clearly conceptualize which expression was emerging (conceptual sensitivity). A final unspeeded response required participants to explicitly label the expression as a measure of recognition accuracy. We measured the percentage morph (expression intensity) at which a perceptual and conceptual change was detected, where greater intensity equates to poorer sensitivity. Increased positive mood reduced perceptual and conceptual sensitivity to angry and sad expressions only (a mood incongruency effect). Of particular interest, increased negative mood decreased conceptual sensitivity for all expressions, but had limited impact on perceptual sensitivity. Thus, heightened negative mood is particularly detrimental for effectively decoding someone else's mood change. This may reflect greater introspection and consumption of attentional resources directed toward the negative self, leaving fewer resources to process emotional signals conveyed by others. This could have important consequences for human social interaction. PMID- 26479774 TI - Intensity Modulation: A Novel Approach to Percept Control in Spinal Cord Stimulation. AB - OBJECTIVE: Spinal cord stimulation (SCS) can be effective for neuropathic pain, but clinical benefit is sometimes inadequate or is offset by stimulation-induced side-effects, and response can be inconsistent among patients. Intensity modulated stimulation (IMS) is an alternative to tonic stimulation (TS) that involves continuous variation of stimulation intensity in a sinusoidal pattern between two different values, sequentially activating distinct axonal populations to produce an effect that resembles natural physiological signals. The purpose of this study is to evaluate the effect of IMS on the clinical effect of SCS. METHODS: Seven patients undergoing a percutaneous SCS trial for postlaminectomy syndrome were enrolled. Thresholds for perception, pain relief, and discomfort were measured and used to create patient-specific models of axonal activation and charge delivery for both TS and IMS. All participants underwent three two-min periods of blinded stimulation using TS, IMS, and placebo, and were asked to describe the effect on quality of the sensory percept and pain relief. RESULTS: All participants perceived IMS differently from placebo, and five noted significant differences from TS that resulted in a more comfortable sensation. TS was described as electric and tingling, whereas IMS was described as producing a focal area of deep pressure with a sense of motion away from that focus. The anatomic location of coverage was similar between the two forms of stimulation, although one participant reported better lower back coverage with IMS. Computer modeling revealed that, compared with TS, IMS involved 36.4% less charge delivery and produced 78.7% less suprathreshold axonal activation. CONCLUSIONS: IMS for SCS is feasible, produces a more comfortable percept than conventional TS, and appears to provide a similar degree of pain relief with significantly lower energy requirements. Further studies are necessary to determine whether this represents an effective alternative to tonic SCS for treatment of neuropathic pain. PMID- 26479775 TI - Light-induced cation exchange for copper sulfide based CO2 reduction. AB - Copper(I)-based catalysts, such as Cu2S, are considered to be very promising materials for photocatalytic CO2 reduction. A common synthesis route for Cu2S via cation exchange from CdS nanocrystals requires Cu(I) precursors, organic solvents, and neutral atmosphere, but these conditions are not compatible with in situ applications in photocatalysis. Here we propose a novel cation exchange reaction that takes advantage of the reducing potential of photoexcited electrons in the conduction band of CdS and proceeds with Cu(II) precursors in an aqueous environment and under aerobic conditions. We show that the synthesized Cu2S photocatalyst can be efficiently used for the reduction of CO2 to carbon monoxide and methane, achieving formation rates of 3.02 and 0.13 MUmol h(-1) g(-1), respectively, and suppressing competing water reduction. The process opens new pathways for the preparation of new efficient photocatalysts from readily available nanostructured templates. PMID- 26479776 TI - Peptidomics for Studying Limited Proteolysis. AB - Limited proteolysis is a pivotal mechanism regulating protein functions. Identifying physiologically or pathophysiologically relevant cleavage sites helps to develop molecular tools that can be used for diagnostics or therapeutics. During proteolysis of secretory and membrane proteins, part of the cleaved protein is liberated and destined to undergo degradation but should retain original cleavage sites created by proteolytic enzymes. We profiled endogenous peptides accumulated for 4 h in media conditioned by primary cultured rat cardiac fibroblasts. A total of 3916 redundant peptide sequences from 94 secretory proteins and membrane proteins served to identify limited cleavage sites, both annotated and unannotated, for signal peptide or propeptide removal, peptide hormone processing, ectodomain shedding, and regulated intramembrane proteolysis. Incorrectly predicted signal cleavage sites are found in typical proteins such as extracellular matrix proteins and the peptide hormone precursor adrenomedullin ADM. The revealed signal peptide cleavage site for ADM was experimentally verified by identifying the major molecular form of flanking proadrenomedullin N terminal peptide. We suggest that profiling of endogenous peptides, like transcriptome sequence reads, makes sense in regular cells such as fibroblasts and that peptidomics provides insight into proteolysis-regulated protein functions. PMID- 26479777 TI - Fear of falling and its predictors among community-living older adults in Korea. AB - OBJECTIVES: To explore the prevalence and predicting factors of fear of falling (FOF) among community-living older adults in Korea. METHODS: Secondary data analysis of the 2011 Korean National Elderly Living Conditions and Welfare Desire Survey was used. Logistic regression analysis was conducted to examine the predictors of FOF. RESULTS: In total, 75.6% of older adults with normal cognition have FOF. Factors associated with an increased risk of FOF in older adults are previous experience with falling (OR = 3.734, 95% CI = 2.996-4.655), limitations in the performance of exercise involving lower extremities (OR = 2.428, 95% CI = 2.063-2.858), being female (OR = 2.335, 95% CI = 2.023-2.694), having more than three chronic diseases (OR = 1.994, 95% CI = 1.625-2.446), limitations in instrumental activities of daily living (IADLs) (OR = 1.745, 95% CI = 1.230 2.477), limitations in the performance of exercise involving upper extremities (OR = 1.646, 95% CI = 1.357-1.997), living without a spouse (OR = 1.626, 95% CI = 1.357-1.948), having poor self-rated health (OR = 1.571, 95% CI = 1.356-1.821), limitations in muscle strength (OR = 1.455, 95% CI = 1.150-1.841), age (>=75 years) (OR = 1.320, 95% CI = 1.150-1.516), lower levels of education (0-6 years) (OR = 1.231, 95% CI = 1.075-1.409), and life satisfaction (OR = 1.104, 95% CI = 1.065-1.114). CONCLUSION: A multidimensional construct of general characteristics, physical, and psychosocial variables act as risk factors for FOF. Preventive intervention should be developed to decrease the FOF among Korean older adults. PMID- 26479778 TI - Structural Difference in Superconductive and Nonsuperconductive Bi-S Planes within Bi4O4Bi2S4 Blocks. AB - The relationship between the structure and superconductivity of Bi4O4S3 powders synthesized by heating under ambient and high pressures was investigated using synchrotron X-ray diffraction, Raman spectroscopy, and transmission electron microscopy (TEM) observation. The Bi4O4S3 powders synthesized under ambient pressure exhibited a strong superconductivity (diamagnetic) signal and zero resistivity below ~4.5 K, while the Bi4O4S3 powder synthesized by the high pressure method exhibited a low-intensity signal down to 2 K. Further annealing of the latter Bi4O4S3 powder under ambient pressure led to the development of a strong signal and zero resistivity. The crystal structures of all Bi4O4S3 phases consisted of Bi4O4Bi2S4 blocks including a Bi-S layer and anion(s) sandwiched between Bi4O4Bi2S4 blocks, but minor structural differences were detected. A comparison of the structures of the superconductive and nonsuperconductive Bi4O4S3 samples suggested that the superconductive Bi4O4S3 phases had slightly smaller lattice parameters. The average structures of the superconductive Bi4O4S3 phases were characterized by a slightly shorter and less bent Bi-S plane. Raman spectroscopy detected vibration of the S-O bonds, which can be attributed to sandwiched anion(s) such as SO4(2-). TEM observation showed stacking faults in the superconductive Bi4O4S3 phases, which indicated local fluctuation of the average structures. The observed superconductivity of Bi4O4S3 was discussed based on impurity phases, enhanced hybridization of the px and py orbitals of the Bi-S plane within Bi4O4Bi2S4 blocks, local fluctuation of the average structures, compositional deviation related to suspicious anion(s) sandwiched between Bi4O4Bi2S4 blocks, and the possibility of suppression of the charge-density-wave state by enriched carrier concentrations. PMID- 26479779 TI - Long-term follow-up of individuals undergoing sex reassignment surgery: Psychiatric morbidity and mortality. AB - BACKGROUND: There is a lack of long-term register-based follow-up studies of sex reassigned individuals concerning mortality and psychiatric morbidity. Accordingly, the present study investigated both mortality and psychiatric morbidity using a sample of individuals with transsexualism which comprised 98% (n = 104) of all individuals in Denmark. AIMS: (1) To investigate psychiatric morbidity before and after sex reassignment surgery (SRS) among Danish individuals who underwent SRS during the period of 1978-2010. (2) To investigate mortality among Danish individuals who underwent SRS during the period of 1978 2010. METHOD: Psychiatric morbidity and mortality were identified by data from the Danish Psychiatric Central Research Register and the Cause of Death Register through a retrospective register study of 104 sex-reassigned individuals. RESULTS: Overall, 27.9% of the sample were registered with psychiatric morbidity before SRS and 22.1% after SRS (p = not significant). A total of 6.7% of the sample were registered with psychiatric morbidity both before and after SRS. Significantly more psychiatric diagnoses were found before SRS for those assigned as female at birth. Ten individuals were registered as deceased post-SRS with an average age of death of 53.5 years. CONCLUSIONS: No significant difference in psychiatric morbidity or mortality was found between male to female and female to male (FtM) save for the total number of psychiatric diagnoses where FtM held a significantly higher number of psychiatric diagnoses overall. Despite the over representation of psychiatric diagnoses both pre- and post-SRS the study found that only a relatively limited number of individuals had received diagnoses both prior to and after SRS. This suggests that generally SRS may reduce psychological morbidity for some individuals while increasing it for others. PMID- 26479780 TI - Biofouling on polymeric heat exchanger surfaces with E. coli and native biofilms. AB - The biofouling affinity of different polymeric surfaces (polypropylene, polysulfone, polyethylene terephthalate, and polyether ether ketone) in comparison to stainless steel (SS) was studied for the model bacterium Escherichia coli K12 DSM 498 and native biofilms originating from Rhine water. The biofilm mass deposited on the polymer surfaces was minimized by several magnitudes compared to SS. The cell count and the accumulated biomass of E. coli on the polymer surfaces showed an opposing linear trend. The promising low biofilm formation on the polymers is attributed to the combination of inherent surface properties (roughness, surface energy and hydrophobicity) when compared to SS. The fouling characteristics of E. coli biofilms show good conformity with the more complex native biofilms investigated. The results can be utilized for the development of new polymer heat exchangers when using untreated river water as coolant or for other processes needing antifouling materials. PMID- 26479781 TI - Cyst decreased in size post maxillary sinus floor augmentation surgery in diabetic patient: A case report. AB - INTRODUCTION: Whether mucosal cyst of maxillary sinus is contraindication for sinus floor augmentation surgery has been a controversial hot spot for years. PRESENTATION OF CASE: This case aims to present the surgical procedure of sinus floor augmentation surgery with cyst (18.72mm*24.61mm) in diabetic patient. And 6 months later, the cyst decreased in size. The authors elevated the sinus floor and cyst simultaneously. The surgery was carried out successfully without sinus membrane perforation and the alveolar ridge gained about 8mm height. Six months later, the cyst decreased in size and osseointegration was observed. DISCUSSION: Interdisciplinary cooperation is encouraged to diagnose benign mucosal cyst. The isolation between sinus lumen and the grafted sub-sinus space is important. Graft contamination or dispersion into the sinus lumen should be avoided. The integrity of the sinus membrane and use of antibiotics are very important to prevent the occurrence of postoperative sinus infection CONCLUSION: The authors conclude that sinus augmentation surgery could be done with mucosal cyst in diabetic patient. PMID- 26479782 TI - Efficacy and surgical procedures of preoperative splenic artery embolization for laparoscopic splenectomy of a massive splenomegaly: A case report. AB - Here, we describe the case of a 58-year-old woman diagnosed with massive splenomegaly with a malignant lymphoma that had a maximum diameter of 24cm. Splenectomy was indicated because of thrombocytopenia and abdominal distention. Therefore, a balloon catheter was inserted preoperatively through the splenic artery for embolization and continuous infusion to reduce the spleen volume. It enabled easy handling of the spleen and minimized bleeding. The volume of the spleen was estimated at 1896g through the skin incision, as measured by volumetric computed tomography; thus, laparoscopy seemed difficult. However, the surgery was successfully performed only with laparoscopic surgery, and the volume of the resected spleen was 1020g. This preoperative preparation is an effective alternative to laparoscopic removal of a huge splenomegaly. PMID- 26479783 TI - Pseudo subclavian steal syndrome: Case report. AB - INTRODUCTION: Vertebrobasilar insufficiency (VBI) is a condition that results from restricted blood flow to the posterior portions of the brain, which are primarily served by the vertebral and basilar arteries. It is the most common cause of vertigo in the elderly and is usually accompanied by impaired vision and sensation. Congenital abnormalities, atherosclerosis, stroke and/or trauma may all lead to decreased vertebrobasilar circulation. A syndrome called Subclavian Steal Syndrome (SSS), which manifests with similar neurological symptoms but with a different pathophysiology, may also cause VBI. CASE PRESENTATION: A middle-aged female presented with gradual onset fainting and vertigo attacks. Cardiac, auditory and autonomic etiologies were investigated and excluded. Clinical findings and presentation were highly suggestive of subclavian steal. However, subsequent CT angiography showed normal subclavian arteries. Instead, findings included a persistent right trigeminal artery (PTA), stenosis of the right proximal internal carotid artery, atresis of the left vertebral artery and distal segment of right vertebral artery, congenitally compromised changes in vertebral circulation (bilateral absence of the posterior communicating arteries (PCOMs)) and an absent anterograde vertebrobasilar circulation. Symptoms resolved after carotid endarterectomy. DISCUSSION: Due to the absence of a normally developed posterior circulation, the PTA was the main source of blood supply for the patient. Development of recent artheromatous changes in the right internal carotid artery, however, resulted in decreased blood through PTA, further compromising posterior circulation. This resulted in vertebrobasilar insufficiency, and manifested in symptomology similar to SSS. CONCLUSIONS: This clinical encounter illustrates the relative contribution of anatomical and vasoocclusive factors in closely mimicking symptoms of subclavian steal syndrome. PMID- 26479784 TI - Correction to Manganese-Cycling Microbial Communities Inside Deep-Sea Manganese Nodules. PMID- 26479785 TI - KMnO4-Fe(II) pretreatment to enhance Microcystis aeruginosa removal by aluminum coagulation: Does it work after long distance transportation? AB - KMnO4-Fe(II) pretreatment was proposed to enhance Microcystis aeruginosa (M. aeruginosa) removal by aluminum (Al) coagulation in drinking water treatment plants (DWTPs) in our previous study. This study aims to optimize this process and evaluate the feasibility of using the process at water sources, which are usually far away from DWTPs. The optimum molar ratio of KMnO4 to Fe(II) [Formula: see text] is observed to be 1:3 with respect to algae removal and residual manganese (Mn) control. As indicated from flow cytometer analysis, KMnO4 at <20 MUM promisingly maintains cell integrity, with damaged cell ratios of below 10%. KMnO4 at 30 and 60 MUM damages M. aeruginosa cells more significantly and the damaged cell ratios increase to 21% and 34% after 480 min. The intracellular organic matter (IOM) release can be controlled by the subsequent introduction of Fe(II) to quench residual KMnO4. KMnO4-Fe(II) pretreatment at the KMnO4 dose of 10 MUM dramatically enhances the algae removal by over 70% compared to that by Al coagulation, even if KMnO4 and Fe(II) are introduced 480 min prior to the addition of Al2(SO4)3. The Al doses can be reduced by more than half to achieve the same algae removal. Furthermore, the deposition of the tiny Fe-Mn precipitates formed rarely occurs, as indicated by a settleability evaluation prior to Al addition. The KMnO4-Fe(II) process can be sequentially dosed at intake points in water sources to achieve moderate inactivation of algae cells and to enhance algae removal in DWTPs thereafter. PMID- 26479786 TI - Dihydrocodeine: safety concerns. AB - Dihydrocodeine (DHC) is a semi-synthetic analogue of codeine, which was formed by the hydrogenation of the double tie in the main chain of the codeine molecule - instead of a double bond between carbons 7 and 8 DHC possesses a single bond. DHC is used as an analgesic and antitussive agent and for the management of dyspnea and opioid addiction. Limited data is available on the potency of DHC to other opioids. The analgesic effect of DHC is similar to codeine and approximately twice as potent as tramadol for an oral route. In contrast to codeine and tramadol, DHC analgesia seem to be irrespective of CYP2D6 activity due to parent compound analgesic effects, multiple metabolic pathways and limited role of dihydromorphine in DHC analgesia. As the drug is commonly available appropriate titration and dosing and knowledge of its metabolism and possible adverse effects are important for safe prescription of DHC. PMID- 26479787 TI - Translational Research and Plasma Proteomic in Cancer. AB - Proteomics is a recent field of research in molecular biology that can help in the fight against cancer through the search for biomarkers that can detect this disease in the early stages of its development. Proteomic is a speedily growing technology, also thanks to the development of even more sensitive and fast mass spectrometry analysis. Although this technique is the most widespread for the discovery of new cancer biomarkers, it still suffers of a poor sensitivity and insufficient reproducibility, essentially due to the tumor heterogeneity. Common technical shortcomings include limitations in the sensitivity of detecting low abundant biomarkers and possible systematic biases in the observed data. Current research attempts are trying to develop high-resolution proteomic instrumentation for high-throughput monitoring of protein changes that occur in cancer. In this review, we describe the basic features of the proteomic tools which have proven to be useful in cancer research, showing their advantages and disadvantages. The application of these proteomic tools could provide early biomarkers detection in various cancer types and could improve the understanding the mechanisms of tumor growth and dissemination. PMID- 26479790 TI - Multisegment oven scheme for Gouy phase shift compensation in second-harmonic generation. AB - We present a theoretical model that describes a multisegment oven configuration to compensate for the Gouy phase shift in the tight focusing regime. The model is provided to obtain maximum efficiency of the second-harmonic wave. Numerical simulations are performed based on the experimental setup employing an MgO:sPPLT nonlinear crystal. It is shown by the simulation that the three-segment oven is potentially capable of reaching the highest efficiency by canceling the effect of Gouy phase when the temperature of each segment is so optimized that the phase matching condition is re-established. It is found that by using a multisegment oven scheme with optimized temperature, the highest attainable second-harmonic generation (SHG) efficiency exceeds about 4.4% at a confocal parameter of 3.32. Moreover, it is shown that for long crystals with large confocal parameter, the only way to attain the maximum efficiency is by using multisegment ovens. The results indicate that when the number of segments is changed from one to nine, the confocal parameter can be varied from 3.90 to 5.85. In the candidate three segment oven, by applying active control on the temperature of each segment, for a certain combination of segment lengths, ~4% improvement in the SHG efficiency is achieved. This results in a relatively large increase in the acceptance temperature bandwidth of the crystal of up to 2 times, reflecting a comparatively large enhancement in the second-harmonic power stability and efficiency. PMID- 26479791 TI - Spatial light modulator phase mask implementation of wavefront encoded 3D computational-optical microscopy. AB - Spatial light modulator (SLM) implementation of wavefront encoding enables various types of engineered point-spread functions (PSFs), including the generalized-cubic and squared-cubic phase mask wavefront encoded (WFE) PSFs, shown to reduce the impact of sample-induced spherical aberration in fluorescence microscopy. This investigation validates dynamic experimental parameter variation of these WFE-PSFs. We find that particular design parameter bounds exist, within which the divergence of computed and experimental WFE-PSFs is of the same order of magnitude as that of computed and experimental conventional PSFs, such that model-based approaches for solving the inverse imaging problem can be applied to a wide range of SLM-WFE systems. Interferometric measurements were obtained to evaluate the SLM implementation of the numeric mask. Agreement between experiment and theory in terms of a wrapped phase, 0-2pi, validates the phase mask implementation and allows characterization of the SLM response. These measurements substantiate experimental practice of computational-optical microscope imaging with an SLM-engineered PSF. PMID- 26479789 TI - The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation. AB - Deregulation of the TH17 subset of helper T cells is closely linked with immunological disorders and inflammatory diseases. However, the mechanism by which TH17 cells are regulated remains elusive. Here we found that the phosphatase DUSP2 (PAC1) negatively regulated the development of TH17 cells. DUSP2 was directly associated with the signal transducer and transcription activator STAT3 and attenuated its activity through dephosphorylation of STAT3 at Tyr705 and Ser727. DUSP2-deficient mice exhibited severe susceptibility to experimental colitis, with enhanced differentiation of TH17 cells and secretion of proinflammatory cytokines. In clinical patients with ulcerative colitis, DUSP2 was downregulated by DNA methylation and was not induced during T cell activation. Our data demonstrate that DUSP2 is a true STAT3 phosphatase that modulates the development of TH17 cells in the autoimmune response and inflammation. PMID- 26479792 TI - Single-pulse laser ablation threshold of borosilicate, fused silica, sapphire, and soda-lime glass for pulse widths of 500 fs, 10 ps, 20 ns. AB - In this work, we report a comparative study of the laser ablation threshold of borosilicate, fused silica, sapphire, and soda-lime glass as a function of the pulse width and for IR laser wavelengths. We determine the ablation threshold for three different pulse durations: tau=500 fs, 10 ps, and 20 ns. Experiments have been performed using a single laser pulse per shot in an ambient (air) environment. The results show a significant difference, of two orders of magnitude, between the group of ablation thresholds obtained for femtosecond, picosecond, and nanosecond pulses. This difference is reduced to 1 order of magnitude in the soda-lime substrate with tin impurities, pointing out the importance of the incubation effect. The morphology of the marks generated over the different glass materials by one single pulse of different pulse durations has been analyzed using a scanning electron microscope (FESEM ULTRA Plus). Our results are important for practical purposes, providing the ablation threshold data of four commonly used substrates at three different pulse durations in the infrared regime (1030-1064 nm) and complete data for increasing the understanding of the differences in the mechanism's leading ablation in the nanosecond, picosecond, and femtosecond regimes. PMID- 26479788 TI - PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection. AB - Enhancing the response to interferon could offer an immunological advantage to the host. In support of this concept, we used a modified form of the transcription factor STAT1 to achieve hyper-responsiveness to interferon without toxicity and markedly improve antiviral function in transgenic mice and transduced human cells. We found that the improvement depended on expression of a PARP9-DTX3L complex with distinct domains for interaction with STAT1 and for activity as an E3 ubiquitin ligase that acted on host histone H2BJ to promote interferon-stimulated gene expression and on viral 3C proteases to degrade these proteases via the immunoproteasome. Thus, PARP9-DTX3L acted on host and pathogen to achieve a double layer of immunity within a safe reserve in the interferon signaling pathway. PMID- 26479793 TI - Analysis of defect mode in a one-dimensional symmetric double-negative photonic crystal containing magnetized cold plasma defect. AB - In this paper, the characteristic matrix method is employed to theoretically investigate properties of the defect mode in a 1D lossy symmetric defective photonic crystal containing two magnetized cold plasma defect layers. The considered photonic crystal is made of double-negative and double-positive materials. The defect mode, as a function of the magnetic field and the electron density, will be investigated in three different structures. The results show that the defect mode frequency can be tuned by variations of the magnetic field and the electron density as well. Due to the polarization-dependent magnetized cold plasma, the shift trend in the defect mode is shown to also rely on the polarization. The proposed structures could provide another alternative for the design of narrowband filters at microwave. PMID- 26479794 TI - Impact of laser-contaminant interaction on the performance of the protective capping layer of 1 omega high-reflection mirror coatings. AB - High dielectric constant multilayer coatings are commonly used on high-reflection mirrors for high-peak-power laser systems because of their high laser-damage resistance. However, surface contaminants often lead to damage upon laser exposure, thus limiting the mirror's lifetime and performance. One plausible approach to improve the overall mirror resistance against laser damage, including that induced by laser-contaminant coupling, is to coat the multilayers with a thin protective capping (absentee) layer on top of the multilayer coatings. An understanding of the underlying mechanism by which laser-particle interaction leads to capping layer damage is important for the rational design and selection of capping materials of high-reflection multilayer coatings. In this paper, we examine the responses of two candidate capping layer materials, made of SiO2 and Al2O3, over silica-hafnia multilayer coatings. These are exposed to a single oblique shot of a 1053 nm laser beam (fluence ~10 J/cm2, pulse length 14 ns), in the presence of Ti particles on the surface. We find that the two capping layers show markedly different responses to the laser-particle interaction. The Al2O3 cap layer exhibits severe damage, with the capping layer becoming completely delaminated at the particle locations. The SiO2 capping layer, on the other hand, is only mildly modified by a shallow depression. Combining the observations with optical modeling and thermal/mechanical calculations, we argue that a high-temperature thermal field from plasma generated by the laser-particle interaction above a critical fluence is responsible for the surface modification of each capping layer. The great difference in damage behavior is mainly attributed to the large disparity in the thermal expansion coefficient of the two capping materials, with that of Al2O3 layer being about 15 times greater than that of SiO2. PMID- 26479795 TI - GaN-based metamaterial terahertz bandpass filter design: tunability and ultra broad passband attainment. AB - Engineering metamaterial-based devices such as terahertz bandpass filters (BPFs) play a definitive role in advancement of terahertz technology. In this article, we propose a design procedure to obtain a considerably broadband terahertz BPF at a normal incidence; it shows promising filtering characteristics, including a wide passband of ~1.34 THz at a central frequency of 1.17 THz, a flat top in a broad band, and high transmission, compared to previous reports. Then, exploiting the voltage-dependent carrier density control in an AlGaN/GaN heterostructure with a Schottky gate configuration, we investigate the tuning of the transmission properties in a narrow-band terahertz filter. A combination of the ultra-wide, flat-top BPF in series with the tunable, narrow band filter designed in the current study offers the ability to tune the desired resonance frequency along with high out-of-band rejection and the suppression of unwanted resonances in a large spectral range. The proposed structure exhibits a frequency tunability of 103 GHz for a voltage change between -8 and 2 V, and a transmission amplitude change of ~0.51. This scheme may open up a route for the improved design of terahertz filters and modulators. PMID- 26479796 TI - Sparse representations for online-learning-based hyperspectral image compression. AB - Sparse models provide data representations in the fewest possible number of nonzero elements. This inherent characteristic enables sparse models to be utilized for data compression purposes. Hyperspectral data is large in size. In this paper, a framework for sparsity-based hyperspectral image compression methods using online learning is proposed. There are various sparse optimization models. A comparative analysis of sparse representations in terms of their hyperspectral image compression performance is presented. For this purpose, online-learning-based hyperspectral image compression methods are proposed using four different sparse representations. Results indicate that, independent of the sparsity models, online-learning-based hyperspectral data compression schemes yield the best compression performances for data rates of 0.1 and 0.3 bits per sample, compared to other state-of-the-art hyperspectral data compression techniques, in terms of image quality measured as average peak signal-to-noise ratio. PMID- 26479797 TI - Fast frame scanning camera system for light-sheet microscopy. AB - In the interest of improving the temporal resolution for light-sheet microscopy, we designed a fast frame scanning camera system that incorporated a galvanometer scanning mirror into the imaging path of a home-built light-sheet microscope. This system transformed a temporal image sequence to a spatial one so that multiple images could be acquired during one exposure period. The improvement factor of the frame rate was dependent on the number of sub-images that could be tiled on the sensor without overlapping each other and was therefore a trade-off with the image size. As a demonstration, we achieved 960 frames/s (fps) on a CCD camera that was originally capable of recording images at only 30 fps (full frame). This allowed us to observe millisecond or sub-millisecond events with ordinary CCD cameras. PMID- 26479798 TI - Microstructure core photonic crystal fiber for gas sensing applications. AB - In this paper, a highly sensitive gas sensor based on the microstructure core and cladding photonic crystal fiber (PCF) is presented over the wavelength range from 1.3 to 2.2 MUm, which is advantageous for sensor fabrication. The guiding properties of the proposed structure are dependent on geometrical parameters and wavelengths, which are numerically investigated by using a finite element method (FEM). Introducing the microstructure core makes it possible to obtain higher relative sensitivity and achieves low confinement loss. Moreover, it can be shown that increasing the diameter of the air holes in the microstructure core and decreasing the size of hole to hole space (pitch), the relative sensitivity is enhanced. In addition, the confinement loss is reduced by increasing the value of the diameter of the air holes in the cladding. Simulation results reveal that for the optimum design of the proposed PCF it is possible to obtain the highest relative sensitivity of about 42.27% at the wavelength lambda=1.33 MUm for the absorption line of methane (CH4) and hydrogen fluoride (HF) gases. In this case, the confinement loss of the fiber is 4.78345*10-6 dB/m. PMID- 26479799 TI - Two-channel algorithm for single-shot, high-resolution measurement of optical wavefronts using two image sensors. AB - We propose a two-channel holographic diversity interferometer (2ch-HDI) system for single-shot and highly accurate measurements of complex amplitude fields with a simple optical setup. In this method, two phase-shifted interference patterns are generated, without requiring a phase-shifting device, by entering a circularly polarized reference beam into a polarizing beam splitter, and the resulting patterns are captured simultaneously using two image sensors. However, differences in the intensity distributions of the two image sensors may lead to serious measurement errors. Thus, we also develop a two-channel algorithm optimized for the 2ch-HDI to compensate for these differences. Simulation results show that this algorithm can compensate for such differences in the intensity distributions in the two image sensors. Experimental results confirm that the combination of the 2ch-HDI and the calculation algorithm significantly enhances measurement accuracy. PMID- 26479800 TI - Analytical model for CO(2) laser ablation of fused quartz. AB - This paper reports the development of an analytical model, with supporting experimental data, which quite accurately describes the key features of CO2 laser ablation of fused silica glass. The quantitative model of nonexplosive, evaporative material removal is shown to match the experimental data very well, to the extent that it can be used as a tool for ablative measurements of absorption coefficient and vaporization energy. The experimental results indicated that a minimum of 12 MJ kg-1 is required to fully vaporize fused quartz initially held at room temperature, which is in good agreement with the prediction of the model supplied with input data available in the literature. An optimal window for the machining of fused quartz was revealed in terms of pulse duration 20-80 MUs and CO2 laser wavelength optimized for maximum absorption coefficient. Material removal rates of 0.33 MUm per J cm-2 allow for a high-precision depth control with modest laser stability. The model may also be used as a parameter selection guide for CO2 laser ablation of fused silica or other materials of similar thermophysical properties. PMID- 26479801 TI - Diamagnetic tellurite glass and fiber based magneto-optical current transducer. AB - Diamagnetic TeO2-ZnO-Na2O glasses and fibers were fabricated and characterized for magneto-optical current-sensor applications. Two prototypes based on the obtained glass and fibers were constructed. An analysis of the distribution of the magnetic field flux inside the conductor was performed. Hardware and developed software were constructed for the acquisition of weak output signals induced by a low current. The good sensitivities of the fiber magneto-optical current transducer and the bulk magneto-optical current transducer are due to the high Verdet constant and homemade signal-acquisition hardware. PMID- 26479802 TI - Estimation of measurement uncertainty caused by surface gradient for a white light interferometer. AB - Although the scanning white light interferometer can provide measurement results with subnanometer resolution, the measurement accuracy is far from perfect. The surface roughness and surface gradient have significant influence on the measurement uncertainty since the corresponding height differences within a single CCD pixel cannot be resolved. This paper presents an uncertainty estimation method for estimating the measurement uncertainty due to the surface gradient of the workpiece. The method is developed based on the mathematical expression of an uncertainty estimation model which is derived and verified through a series of experiments. The results show that there is a notable similarity between the predicted uncertainty from the uncertainty estimation model and the experimental measurement uncertainty, which demonstrates the effectiveness of the method. With the establishment of the proposed uncertainty estimation method, the uncertainty associated with the measurement result can be determined conveniently. PMID- 26479803 TI - Automatic parameter estimation based on the degree of texture overlapping in accurate cost-aggregation stereo matching for three-dimensional video display. AB - Stereo matching plays a significant role in three-dimensional (3D) display applications. The estimation of the regularization parameter, which strikes a balance between the spatial distance and color difference, is essential for successfully solving ill-posed image-matching problems. Based on the cost filtering algorithm, a degree of texture overlapping is designed to simultaneously estimate the optimal regularization parameter and achieve accurate matching results. The experimental results demonstrate that the proposed model can estimate the smoothing parameter well, and the accuracy is comparable to other methods with manual adjustment. The application of the presented stereo matching method in the 32-view 3D display is demonstrated. PMID- 26479804 TI - Spectropolarimetric detection using photoelastic modulators and acousto-optic tunable filter. AB - This paper proposes a spectropolarimetric detection method based on three photoelastic modulators (3PEMs) and an acousto-optic tunable filter (AOTF). Operating the 3PEMs at slightly resonant frequencies (omega1,omega2,omega3) generates a different frequency signal that modulates the polarized component of the incident light at a low-frequency (0, 2omega1-2omega3, omega2 omega3). The frequency of the low-frequency modulation component is two to three orders of magnitude lower than the resonant frequency of any of the 3PEMs so the general area array detector can realize the detection. I, Q, and U of the incident light's Stokes parameters can be obtained in only one detection by extracting the low-frequency component from the detector's signals, and then combining it with an AOTF to finally realize the spectropolarimetric imaging detection. The paper introduces the basic principle, preliminarily verifies feasibility through a corresponding numerical simulation and experiment, and makes an error analysis on the polarization detection results according to factors of difference frequency and phase delay amplitude. The theory has potential application value to spectropolarimetric technology. PMID- 26479805 TI - Photonic jets produced by dielectric micro cuboids. AB - The formation of photonic jets produced by dielectric micro cuboids is reported. The spatial electromagnetic field has been numerically analyzed on the basis of the finite-difference time-domain calculation. The characteristics of photonic jets, such as propagation length and location, can be drastically changed by controlling the cuboid dimensions. Visually three morphological types of photonic jets are introduced for classification. Combining key parameters of photonic jets, the quality criterion is used to describe the jet quality. The super resolution imaging of the dielectric micro cuboid can be expected from the long focal length and small beam waist. The simulation results show that it can be of interest for several potential applications, such as subdiffraction resolution optical microlenses, ultradirectional optical antennae, and nanolithography based on the micro cuboid. PMID- 26479806 TI - Facility for assessing spectral normal emittance of solid materials at high temperature. AB - Spectral emittance is a key topic in the study of new compositions, depositions, and mechanical machining of materials for solar absorption and for renewable energies in general. The present work reports on the realization and testing of a new experimental facility for the measurement of directional spectral emittance in the range of 2.5-20 MUm. Our setup provides emittance spectral information in a completely controlled environment at medium-high temperatures up to 1200 K. We describe the layout and first tests on the device, comparing the results obtained for hafnium carbide and tantalum diboride ultrarefractory ceramic samples to previous quasi-monochromatic measurements carried out in the PROMES-CNRS (PROcedes, Materiaux et Energie Solaire- Centre National de la Recherche Scientifique, France) solar furnace, obtaining a good agreement. Finally, to assess the reliability of the widely used approach of estimating the spectral emittance from room-temperature reflectance spectrum, we compared the calculation in the 2.5-17 MUm spectral range to the experimental high-temperature spectral emittance, obtaining that the spectral trend of calculated and measured curves is similar but the calculated emittance underestimates the measured value. PMID- 26479807 TI - Differential resistance of GaN-based laser diodes with and without polarization effect. AB - In this paper, we used numerical calculation and simulation to investigate the differential resistance of GaN-based laser diodes (LDs) with and without polarization effect. We confirmed the existence of a kink at the vicinity of threshold current in the differential resistance curve of GaN-based LDs and found that the kink polarity can be reversed dependent on the polarization effect. The serial parasitic diodes should be included in the theoretical analysis of the equivalent circuit of the LD devices. We determined that the superposition effects of the n-side, active, and p-side regions of the LDs caused the kink and its polarity. We also found that the differential resistance before and after the threshold was dominated by the p-side region and its gradual reduction is related to an electron overflow into p-side. Finally, we studied the effects of cavity facet reflectivity on the kink. PMID- 26479808 TI - Fiber-optic ammonia sensor using Ag/SnO(2) thin films: optimization of thickness of SnO(2) film using electric field distribution and reaction factor. AB - A highly sensitive ammonia gas sensor exploiting the gas sensing characteristics of tin oxide (SnO2) has been reported. The methodology of the sensor is based on the phenomenon of surface plasmon resonance (SPR) with a fiber-optic probe consisting of coatings of silver as a plasmonic material and SnO2 as the sensing layer. The sensing principle relies on the change in refractive index of SnO2 upon its reaction with ammonia gas. The capability of the sensor has been tested for a 10 to 100 ppm concentration range of ammonia gas. To enhance the sensitivity, probes with different thicknesses of SnO2 have been fabricated and characterized for ammonia sensing. It has been found that at a particular thickness the sensitivity is highest. The reason for the highest sensitivity at a particular thickness has been evinced theoretically. The electromagnetic field distribution for the multilayer structure of the probe reveals the enhancement of the evanescent field at the tin oxide-ammonia gas interface, which in turn manifests the highest shift in resonance wavelength at a particular thickness. The selectivity of the probe has been tested for various gases, and it has been found to be most accurate for the sensing of ammonia. A sensor utilizing optical fiber, the SPR technique, and metal oxide as sensing element combines the advantages of a miniaturized probe, online monitoring, and remote sensing on one hand and stability, high sensitivity and selectivity, ruggedness, and low cost on the other. PMID- 26479809 TI - Experimental demonstration of single-mode fiber coupling over relatively strong turbulence with adaptive optics. AB - High-speed free-space optical communication systems using fiber-optic components can greatly improve the stability of the system and simplify the structure. However, propagation through atmospheric turbulence degrades the spatial coherence of the signal beam and limits the single-mode fiber (SMF) coupling efficiency. In this paper, we analyze the influence of the atmospheric turbulence on the SMF coupling efficiency over various turbulences. The results show that the SMF coupling efficiency drops from 81% without phase distortion to 10% when phase root mean square value equals 0.3lambda. The simulations of SMF coupling with adaptive optics (AO) indicate that it is inevitable to compensate the high order aberrations for SMF coupling over relatively strong turbulence. The SMF coupling efficiency experiments, using an AO system with a 137-element deformable mirror and a Hartmann-Shack wavefront sensor, obtain average coupling efficiency increasing from 1.3% in open loop to 46.1% in closed loop under a relatively strong turbulence, D/r0=15.1. PMID- 26479810 TI - Europium-doped SiAlON and borosilicate glass composites for white light-emitting diode. AB - The oxynitride phosphor Ca-alpha-SiAlON:Eu2+ has a high thermal tolerance. In this study, we prepared sodium borosilicate glass [4Na2O 56B2O3-40SiO2, mol. %], and examined its ability to host Ca-alpha-SiAlON:Eu2+ phosphor powder. We successfully used a melting method to fabricate glass-SiAlON phosphor composites, which can emit yellow light when irradiated with blue light (with a wavelength of 450 nm). The chromaticity of the composites, which was estimated from photoluminescence spectra, changed from blue to yellow with increasing SiAlON concentration and sample thickness. A 3 mm thick composite with 4 mass% SiAlON and a 2 mm thick composite with 5 mass% SiAlON generated near-white light. The quantum efficiency of the composites did not depend on the SiAlON concentration and was similar to that of the phosphor powder. The PL intensity decreased with increasing temperature, but the decrease was similar to that for SiAlON powder. PMID- 26479811 TI - Measurements for displacement and deformation at high temperature by using edge detection of digital image. AB - In this work, we propose a structural deformation measuring method based on structural feature processing (straight line/edge detection) of the recorded digital images for specimens subjected to a high-temperature environment. Both radiation light and oxidation at high temperatures challenge the optics-based measurements. The images of a rectangular piece of copper specimen are obtained by using a bandpass filtering method at high temperatures, then all the edges are detected by using an edge detection operator, and then a Hough transform is conducted to search the straight edges for the calculation of deformation. Especially, due to the severe oxidation, a special seed strategy is adopted to reduce the oxidation effect and obtain an accurate result. For validation, the structural thermal deformation and the values of coefficients of thermal expansion for the copper specimen are measured and compared with data in the literature. The results reveal that the proposed method is accurate to measure the deformation of the structures at high temperatures. PMID- 26479812 TI - Photonic band gap structure for a ferroelectric photonic crystal at microwave frequencies. AB - In this work, the photonic band gap (PBG) structure in a one-dimensional ferroelectric photonic crystal (PC) is theoretically investigated. We consider a PC, air/(AB)N/air, in which layer A is a dielectric of MgO and layer B is taken to be a ferroelectric of Ba0.55Sr0.45TiO3 (BSTO). With an extremely high value in the dielectric constant in BSTO, the calculated photonic band structure at microwave frequencies exhibits some interesting features that are significantly different from those in a usual dielectric-dielectric PC. First, the photonic transmission band consists of multiple and nearly discrete transmission peaks. Second, the calculated bandwidth of the PBG is nearly unchanged as the angle of incidence varies in the TE wave. The bandwidth will slightly reduce for the TM mode. Thus, a wide omnidirectional PBG can be obtained. Additionally, the effect of the thickness of the ferroelectric layer on the PBG is much more pronounced compared to the dielectric layer thickness. That is, the increase of ferroelectric thickness can significantly decrease the PBG bandwidth. PMID- 26479813 TI - Computational structured illumination. AB - We propose a computational structured illumination method for flexible object observation and measurement, which is a gradual extension of computational imaging. In the method, the impulse responses of illumination (IRIs) are observed in advance, and then the optical reflection for an arbitrary illumination pattern is generated by the superposition of the impulse responses. As a benefit of the method, illumination patterns can be easily designed and adjusted for different purposes without physical experiments after the IRI observation, and the desired information can be reconstructed with the same process as that used in conventional-structure illumination methods. A high-precision optical setup does not have to be maintained physically because it is virtualized in a computer. We experimentally demonstrated three-dimensional shape measurement and signal separation between direct- and internal-reflection components using the proposed method. PMID- 26479814 TI - Homodyne chiral polarimetry for measuring thermo-optic refractive index variations. AB - Novel reflection-type homodyne chiral polarimetry is proposed for measuring the refractive index variations of a transparent plate under thermal impact. The experimental results show it is a simple and useful method for providing accurate measurements of refractive index variations. The measurement can reach a resolution of 7*10-5. PMID- 26479815 TI - Spatiotemporal evolution of a cosine-modulated stationary field and Kerr frequency comb generation in a microresonator. AB - Based on the normalized spatiotemporal Lugiato-Lefever equation, the evolutions of cosine-modulated stationary fields relating to the generation of single-free spectral range (FSR) or multi-FSR Kerr frequency combs in a microresonator with anomalous dispersion are studied numerically. The research results show that a single-FSR comb arises when a dissipative soliton pulse or multiple nonequidistant soliton pulses form in the cavity. Compared with the smooth and regular spectral structure of a single soliton pulse, the comb corresponding to the uneven distribution of multiple soliton pulses exhibits a complex and irregular profile. When the stable intracavity field consists of a "roll" Turing pattern or N(N>1) evenly distributed soliton pulses separated by 2pi/N, multi-FSR combs can be generated. In the case of the "roll" Turing pattern solution, it is found that third-order dispersion could modify the comb mode spacing and decrease the intensity of high-order comb modes. For the situation of multiple soliton pulse generation, the simulation results indicate that both the number and locations of the soliton pulses can be actively controlled through the careful selection of modulation frequency. In addition, for the selected cosine-modulated initial field profile, only those modes with the mode numbers being equal to an integer multiple of N can be greatly amplified by the parametric gain during propagation in the microresonator. This process eventually leads to the formation of a N-FSR frequency comb. PMID- 26479816 TI - Implementation and performance of an in-line incomplete Stokes polarimeter based on a single biaxial crystal. AB - Due to the increasing interest of polarimetric information in numerous applications, different Stokes polarimeter designs are provided in the literature for the measure of light beam polarization. Recently, the concept of polarimeters based on the conical refraction (CR) phenomenon, occurring in biaxial crystals, was proposed. CR polarimeters are snapshot polarimeters that allow controlling the volume of data redundancy without an increase in the acquisition time. We present the implementation, calibration, and analysis of an incomplete CR polarimeter optimized for the measure of linear polarizations. A simpler and cheaper experimental configuration is achieved, if compared with other polarimeters proposed in the literature. The suitability of the polarimeter is experimentally demonstrated and some of its benefits, such as its performance in low-intensity conditions, are discussed. PMID- 26479817 TI - Shock-tube measurements of excited oxygen atoms using cavity-enhanced absorption spectroscopy. AB - We report the use of cavity-enhanced absorption spectroscopy (CEAS) using two distributed feedback diode lasers near 777.2 and 844.6 nm for sensitive, time resolved, in situ measurements of excited-state populations of atomic oxygen in a shock tube. Here, a 1% O2/Ar mixture was shock-heated to 5400-8000 K behind reflected shock waves. The combined use of a low-finesse cavity, fast wavelength scanning of the lasers, and an off-axis alignment enabled measurements with 10 MUs time response and low cavity noise. The CEAS absorption gain factors of 104 and 142 for the P35<-S520 (777.2 nm) and P0,1,23< S310 (844.6 nm) atomic oxygen transitions, respectively, significantly improved the detection sensitivity over conventional single-pass measurements. This work demonstrates the potential of using CEAS to improve shock-tube studies of nonequilibrium electronic-excitation processes at high temperatures. PMID- 26479818 TI - 355-nm high spectral resolution airborne lidar LNG: system description and first results. AB - A high spectral resolution (HSR) measurement capability in the ultraviolet has been added to the 3-wavelength-2-polarization-backscatter lidar LNG (lidar aerosols nouvelle generation) and tested during several flights. The system includes a Mach-Zehnder interferometer (MZI) as a spectral discriminator and does not require any frequency locking between the emitter and the interferometer. Results obtained during test flights show that the backscatter and extinction coefficients at 355 nm can be measured with a relative precision of 10% for 60 m and 240 m vertical resolution, respectively, in aerosol layers of 10-6 m-1 sr-1 backscatter coefficient with a 30-km horizontal resolution. The same relative precision is obtained in cirrus clouds of a 2*10-5 m-1 sr-1 backscatter coefficient for the same vertical resolution and a horizontal resolution reduced to 5 km. The capacity of the system to perform wind velocity measurements is also demonstrated with precisions in the range of 1 to 2 ms-1. Particle-to-total backscatter ratio and line-of-sight speed measurements have been performed on ground echoes; averaged data show biases less than 1% and 0.15 ms-1, respectively. PMID- 26479819 TI - Lamb wave acousto-optic modulator in ZnO/MgO multiple quantum wells and comparison with classical modulator. AB - An analysis of a ZnO/MgO multiple quantum well (MQW) acousto-optic modulator with Lamb waves is performed. With the MQW thickness in the range of 0.2 times the Lamb wavelength, the only observed Lamb modes are the lowest-order symmetric S0 and antisymmetric A0 modes. These modes induce strain and electric field components which influence the absorption coefficient of the modulator by the associated variation of the excitonic energies of MQW. The optical absorption coefficient spectra of the modulator as a function of the Lamb waves' power is presented. The Lamb-wave-based modulator gives a better absorption coefficient than the Rayleigh-wave-based one. An analysis of a classical acousto-optic modulator is also performed for comparison of performance. PMID- 26479820 TI - Ray tracing method in arbitrarily shaped radial graded-index waveguide. AB - A ray tracing algorithm for an arbitrarily shaped axially symmetric graded index waveguide was proposed. This was achieved by considering the center of the waveguide (optical axis) as a set of discrete points. The refractive index depends on the distance of the ray position from the optical axis. This distance was approximated as the shortest distance between the ray position and a point in the set. Using this algorithm, ray tracing could be performed, regardless of the waveguide configuration. In this study, a precise explanation of the algorithm is given and the errors are evaluated. A technique to reduce computing time is also included. PMID- 26479821 TI - Tunable passively harmonic mode-locked Yb-doped fiber laser with Lyot-Sagnac filter. AB - A novel passively harmonic mode-locked dissipative soliton Yb-doped fiber laser with all normal dispersion is proposed and experimentally demonstrated based on a semiconductor saturable absorption mirror and tunable Lyot-Sagnac filter. By only tuning the bandwidth of the filter at fixed pump power, the repetition rate of 9.87 to 167.8 MHz (corresponding to 17th-order harmonic) is obtained. This is the highest repetition rate and harmonic order for a passively harmonic mode-locked dissipative soliton Yb-doped fiber laser with all-normal dispersion to the best of our knowledge. The signal-to-noise ratio and super-mode suppression ratio for all harmonic orders are higher than 65 and 35 dB, respectively, which shows the high stability of the fiber laser. PMID- 26479822 TI - Passively Q-switched Nd:YAG/Cr(4+):YAG bonded crystal microchip laser operating at 1112 nm and its application for second-harmonic generation. AB - A passively Q-switched Nd:YAG/Cr4+:YAG microchip laser operating at 1112 nm is demonstrated. Under a pump power of 5.5 W, a maximum average output power of 623 mW was obtained with T=6% output coupler, corresponding to an optical-to-optical conversion efficiency of 11.3% and a slope efficiency of 19.5%. The minimum pulse width was 2.8 ns, the pulse energy and peak power were 39.3 MUJ and 14 kW, respectively. Additionally, based on the 1112 nm laser, a 230 mW 556 nm green-yellow laser was achieved within an LBO crystal. PMID- 26479823 TI - Alignment of sources and detectors on breast surface for noncontact diffuse correlation tomography of breast tumors. AB - Noncontact diffuse correlation tomography (ncDCT) is an emerging technology for 3D imaging of deep tissue blood flow distribution without distorting hemodynamic properties. To adapt the ncDCT for imaging in vivo breast tumors, we designed a motorized ncDCT probe to scan over the breast surface. A computer-aided design (CAD)-based approach was proposed to create solid volume mesh from arbitrary breast surface obtained by a commercial 3D camera. The sources and detectors of ncDCT were aligned on the breast surface through ray tracing to mimic the ncDCT scanning with CAD software. The generated breast volume mesh along with the boundary data of ncDCT at the aligned source and detector pairs were used for finite-element-method-based flow image reconstruction. We evaluated the accuracy of source alignments on mannequin and human breasts; largest alignment errors were less than 10% in both tangential and radial directions of scanning. The impact of alignment errors (assigned 10%) on the tumor reconstruction was estimated using computer simulations. The deviations of simulated tumor location and blood flow contrast resulted from the alignment errors were 0.77 mm (less than the node distance of 1 mm) and 1%, respectively, which result in minor impact on flow image reconstruction. Finally, a case study on a human breast tumor was conducted and a tumor-to-normal flow contrast was reconstructed, demonstrating the feasibility of ncDCT in clinical application. PMID- 26479824 TI - Present and past: Can writing abilities in school children be associated with their auditory discrimination capacities in infancy? AB - Literacy acquisition is highly associated with auditory processing abilities, such as auditory discrimination. The event-related potential Mismatch Response (MMR) is an indicator for cortical auditory discrimination abilities and it has been found to be reduced in individuals with reading and writing impairments and also in infants at risk for these impairments. The goal of the present study was to analyze the relationship between auditory speech discrimination in infancy and writing abilities at school age within subjects, and to determine when auditory speech discrimination differences, relevant for later writing abilities, start to develop. We analyzed the MMR registered in response to natural syllables in German children with and without writing problems at two points during development, that is, at school age and at infancy, namely at age 1 month and 5 months. We observed MMR related auditory discrimination differences between infants with and without later writing problems, starting to develop at age 5 months-an age when infants begin to establish language-specific phoneme representations. At school age, these children with and without writing problems also showed auditory discrimination differences, reflected in the MMR, confirming a relationship between writing and auditory speech processing skills. Thus, writing problems at school age are, at least, partly grounded in auditory discrimination problems developing already during the first months of life. PMID- 26479825 TI - Effectiveness of cognitive-behaviour therapy for hoarding disorder in people with mild intellectual disabilities. AB - Evaluations of cognitive behavioural interventions for hoarding for those with intellectual disabilities (ID) have not been previously attempted. This investigation therefore examined the acceptability and effectiveness of cognitive behavioural therapy (CBT) in a sample of N=14 adults with mild ID. All participants had hoarding as their primary problem and received twelve individual CBT sessions, all conducted via domiciliary visits. The primary outcome measure was an environmental measure (Clutter Image Rating Scale), which was scored at baseline, end of treatment and at six-month follow-up. Acceptability of CBT was measured via the treatment refusal and dropout rate. Secondary self-report outcomes included measures of hoarding, depression and anxiety. Results demonstrate that hoarding significantly reduced following treatment on both self report and environmental assessment. No participants refused or dropped out of treatment and that there was no evidence of relapse over the follow-up period. No adverse treatment incidences were reported. This open trial suggests that CBT may be a safe and effective intervention for hoarding difficulties in people with ID, but that the evidence base in this population needs urgent and detailed attention. PMID- 26479826 TI - An Effective Method for the Construction of Esters Using Cs2CO3 as Oxygen Source. AB - An effective method for the construction of esters from acyl chloride and halohydrocarbon using Cs2CO3 as an oxygen source was achieved for the first time. The methodology has a wide scope of substrates and can be scaled up. The study of a preliminary reaction mechanism demonstrated that the O in the products comes from Cs2CO3 and this esterification proceeds through a free radical reaction. It was also found that CO2 can also be used in this esterification reaction as an oxygen source. PMID- 26479827 TI - N3 and BNN: Two New Similarity Based Classification Methods in Comparison with Other Classifiers. AB - Two novel classification methods, called N3 (N-nearest neighbors) and BNN (binned nearest neighbors), are proposed. Both methods are inspired by the principles of the K-nearest neighbors (KNN) method, being both based on object pairwise similarities. Their performance was evaluated in comparison with nine well-known classification methods. In order to obtain reliable statistics, several comparisons were performed using 32 different literature data sets, which differ for number of objects, variables and classes. Results highlighted that N3 on average behaves as the most efficient classification method with similar performance to support vector machine based on radial basis function kernel (SVM/RBF). The method BNN showed on average higher performance than the classical K-nearest neighbors method. PMID- 26479828 TI - Dropout in looking time studies: The role of infants' temperament and cognitive developmental status. AB - Dropout of infants in looking time studies sometimes occurs at high rates, raising concerns that the representativeness of the final sample might be reduced in comparison to the originally obtained sample. The current study investigated which infant characteristics play a role in dropout. Infants were presented with a preferential looking task at 6 and 9 months of age. At 9 months of age, an additional habituation task and a subsequent novelty preference task were conducted. In addition, temperament was assessed via the Infant Behavior Questionnaire - Revised (IBQ-R, Gartstein & Rothbart, 2003), and cognitive developmental status was assessed via the Cognitive Scale of the Bayley Scale of Infant and Toddler Development (BSID-III, Bayley, 2006). Dropout was positively related to the IBQ-R temperament scales Distress to Limitations and Approach, and negatively related to the scales Falling Reactivity and Cuddliness. The representativeness of the final sample regarding situation-specific temperament dimensions is affected by dropout. Dropout was not related to cognitive developmental status as measured via the BSID-III, habituation speed and novelty preference. Dropout at 6 months of age was associated with dropout at 9 months of age. We concluded that in looking time studies, the representativeness of the final sample regarding performance-relevant temperament dimensions or cognitive developmental status is not affected by dropout. PMID- 26479829 TI - Dietary exposure to cadmium and risk of breast cancer in postmenopausal women: A systematic review and meta-analysis. AB - BACKGROUND: With tobacco smoking, diet is the main source of cadmium (Cd) exposure in the general population. The carcinogenic and estrogenic activities of Cd make it a contaminant of potential concern for hormone-dependent cancers including breast cancer. Postmenopausal women represent the most appropriate population to investigate the possible impact of exogenous factors with potential estrogenic activity on breast cancer as, after menopause, their estrogenic influence is predominant. OBJECTIVES: We systematically reviewed available studies on the association between dietary exposure to Cd and breast cancer focusing on postmenopausal women. A meta-analysis combining the risk estimators was performed and potential sources of between studies heterogeneity were traced. METHODS: Studies were searched from MEDLINE through 31 January 2015 and from the reference lists of relevant publications. Six eligible studies published between 2012 and 2014 were identified and relative risk estimates were extracted. Meta rate ratio estimates (mRR) were calculated according to fixed and random-effect models. Meta-analyses were performed on the whole set of data and separate analyses were conducted after stratification for study design, geographic location, use of hormone replacement therapy (HRT), tumor estrogen receptor status (ER+ or ER-), progesterone receptor status (PGR+ or PGR-), body mass index (BMI), smoker status, zinc or iron intake. RESULTS: No statistically significant increased risk of breast cancer was observed when all studies were combined (mRR=1.03; 95% confidence interval [CI]: 0.89-1.19). Several sources of heterogeneity and inconsistency were identified, including smoker status, HRT use, BMI, zinc and iron intake. Inconsistency was also strongly reduced when only considering ER-, PGR-, tumors subgroups from USA and from Japan. The risks were, however, not substantially modified after stratifications. No evidence of publication bias was found. CONCLUSION: The present study does not provide support for the hypothesis that dietary exposure to Cd increases the risk of breast cancer in postmenopausal women. Misclassification in dietary Cd assessment in primary studies could have biased the results towards a finding of no association. PMID- 26479830 TI - Impact of climate change on human infectious diseases: Empirical evidence and human adaptation. AB - Climate change refers to long-term shifts in weather conditions and patterns of extreme weather events. It may lead to changes in health threat to human beings, multiplying existing health problems. This review examines the scientific evidences on the impact of climate change on human infectious diseases. It identifies research progress and gaps on how human society may respond to, adapt to, and prepare for the related changes. Based on a survey of related publications between 1990 and 2015, the terms used for literature selection reflect three aspects--the components of infectious diseases, climate variables, and selected infectious diseases. Humans' vulnerability to the potential health impacts by climate change is evident in literature. As an active agent, human beings may control the related health effects that may be effectively controlled through adopting proactive measures, including better understanding of the climate change patterns and of the compound disease-specific health effects, and effective allocation of technologies and resources to promote healthy lifestyles and public awareness. The following adaptation measures are recommended: 1) to go beyond empirical observations of the association between climate change and infectious diseases and develop more scientific explanations, 2) to improve the prediction of spatial-temporal process of climate change and the associated shifts in infectious diseases at various spatial and temporal scales, and 3) to establish locally effective early warning systems for the health effects of predicated climate change. PMID- 26479831 TI - A review of organic UV-filters in wastewater treatment plants. AB - UV-filters are a group of compounds which have been massively used in the past years due to the recent concerns with sunburns, premature skin ageing and the risk of developing skin cancer, related to sun exposure. At the moment, these compounds have been identified by the scientific community as emerging pollutants, due to their persistence in the environment, potential to accumulate in biota and potential threat as endocrine disruptors. At some point, the majority of sunscreens will find their way into wastewater (due to bathing and washing activities) and because wastewater treatment plants (WWTPs) are not able to remove and/or degrade them, consequently they find their way into rivers, lakes and ocean, so it is not surprising that UV-filters are found in the environment. Therefore, wastewater treatment plants should be the focus of the scientific community aiming to better understand the fate of the UV-filters and develop new technologies to remove them from wastewater and sludge. This review, aims to provide the current state of the art in the occurrence and fate of UV filters in wastewater treatment plants and how the technologies that are being used are successfully removing these compounds from both wastewater and sludge. PMID- 26479832 TI - Biomimetic chimeric peptide-tethered hydrogels for human mesenchymal stem cell delivery. AB - Here, we report a chimeric peptide-tethered fibrin hydrogel scaffold for delivery of human mesenchymal stem cells (hMSC). Osteopontin-derived peptide (OP) was used as an hMSC-tethering moiety. OP showed hMSC adhesion properties and enhanced hMSC proliferation. A natural fibrin-binding protein-derived peptide (FBP) was tested for its ability to tether hMSC to the fibrin gel matrix. FBP loading on fibrin gels was 8.2-fold higher than that of a scrambled peptide (scFBP). FBP-loaded fibrin gels were retained at injection sites longer than scFBP-loaded fibrin gels, showing a 15.9-fold higher photon intensity of fluorescent FBP-grafted fibrin gels than fluorescent scFBP-loaded fibrin gels 48 h after injection. On the basis of the fibrin gel-binding properties of FBP and the hMSC-binding and proliferation-supporting properties of OP, we constructed chimeric peptides containing FBP and OP linked with a spacer (FBPsOP). Four days after transplantation, the survival of hMSC in FBPsOP-grafted fibrin gels was 3.9-fold higher than hMSC in fibrin gels alone. Our results suggest the potential of FBPsOP-grafted fibrin gels as a bioactive delivery system for enhanced survival of stem cells. PMID- 26479833 TI - Solution-Processed Self-Assembled Nanodielectrics on Template-Stripped Metal Substrates. AB - The coupling of hybrid organic-inorganic gate dielectrics with emergent unconventional semiconductors has yielded transistor devices exhibiting record setting transport properties. However, extensive electronic transport measurements on these high-capacitance systems are often convoluted with the electronic response of the semiconducting silicon substrate. In this report, we demonstrate the growth of solution-processed zirconia self-assembled nanodielectrics (Zr-SAND) on template-stripped aluminum substrates. The resulting Zr-SAND on Al structures leverage the ultrasmooth (r.m.s. roughness <0.4 nm), chemically uniform nature of template-stripped metal substrates to demonstrate the same exceptional electronic uniformity (capacitance ~700 nF cm(-2), leakage current <1 MUA cm(-2) at -2 MV cm(-1)) and multilayer growth of Zr-SAND on Si, while exhibiting superior temperature and voltage capacitance responses. These results are important to conduct detailed transport measurements in emergent transistor technologies featuring SAND as well as for future applications in integrated circuits or flexible electronics. PMID- 26479834 TI - The contribution of tumour-derived exosomes to the hallmarks of cancer. AB - Exosomes are small, biologically active extracellular vesicles and over the last decade, both stromal and tumour-derived exosomes (TDE) have been implicated in cancer onset, progression and metastases. Cancer is a complex disease that is underpinned by several "cancer hallmarks", originally described by Hanahan and Weinberg in 2000 and then revised in 2011. The hallmarks of cancer comprise six biological capabilities, along with two emerging hallmarks and two enabling characteristics that facilitate tumour growth and metastatic dissemination. Ample evidence supports a clear role for TDE in four of the original biological hallmarks (sustaining proliferative signalling, resisting cell death, inducing angiogenesis and activating invasion and metastases). A less-defined role exists for TDE in evading growth suppressors, and currently, there is no evidence to suggest a role for TDE in enabling replicative immortality. TDE are intimately involved in the newly defined hallmarks of cancer and enabling characteristics, most evidently in immune inhibition and tumour-promoting inflammation, which ultimately enable escape from immune destruction and tumour progression. Herein, we discuss the role of TDE in the context of the hallmarks and enabling characteristics of cancer as defined by Hanahan and Weinberg. PMID- 26479835 TI - Thermo- and pH-Responsive Copolymers Bearing Cholic Acid and Oligo(ethylene glycol) Pendants: Self-Assembly and pH-Controlled Release. AB - A family of block and random copolymers of norbornene derivatives bearing cholic acid and oligo(ethylene glycol) pendants were prepared in the presence of Grubbs' catalyst. The phase transition temperature of the copolymers in aqueous solutions may be tuned by the variation of comonomer ratios and pH values. Both types of copolymers formed micellar nanostructures with a hydrophilic poly(ethylene glycol) shell and a hydrophobic core containing cholic acid residues. The micellar size increased gradually with increasing pH due to the deprotonation of the carboxylic acid groups. These micelles were capable of encapsulating hydrophobic compounds such as Nile Red (NR). A higher hydrophobicity/hydrophilicity ratio in both copolymers resulted in a higher loading capacity for NR. With similar molecular weights and monomer compositions, the block copolymers showed a higher loading capacity for NR than the random copolymers. The NR-loaded micelles exhibited a pH-triggered release behavior. At pH 7.4 within 96 h, the micelles formed by the block and random of copolymers released 56 and 97% NR, respectively. Therefore, these micelles may have promise for use as therapeutic nanocarriers in drug delivery systems. PMID- 26479836 TI - Fractional Quantum Hall States in Bilayer Graphene Probed by Transconductance Fluctuations. AB - We have investigated fractional quantum Hall (QH) states in Bernal-stacked bilayer graphene using transconductance fluctuation measurements. A variety of odd-denominator fractional QH states with nuQH -> nuQH + 2 symmetry, as previously reported, are observed. However, surprising is that also particle-hole symmetric states are clearly resolved in the same measurement set. We attribute their emergence to the reversal of orbital states in the octet level scheme induced by a strong local charge imbalance, which can be captured by the transconductance fluctuations. Also the even-denominator fractional QH state at filling -1/2 is observed. However, contrary to a previous study on a suspended graphene layer [ Ki et al. Nano Lett. 2014, 14 , 2135 ], the particle-hole symmetric state at filling 1/2 is detected as well. These observations suggest that the stability of both odd and even denominator fractional QH states is very sensitive to local transverse electric fields in bilayer graphene. PMID- 26479837 TI - A model for effective planning of SME support services. AB - This paper presents a model for effective planning of support services for small and medium-sized enterprises (SMEs). The idea is to scrutinize and measure the suitability of support services in order to give recommendations for the improvement of a support planning process. We examined the applied support services and matched them with the problems and needs of SMEs, based on the survey conducted in 2013 on a sample of 336 SMEs in Serbia. We defined and analysed the five research questions that refer to support services, their consistency with the SMEs' problems and needs, and the relation between the given support and SMEs' success. The survey results have shown a statistically significant connection between them. Based on this result, we proposed an eight phase model as a method for the improvement of support service planning for SMEs. This model helps SMEs to plan better their requirements in terms of support; government and administration bodies at all levels and organizations that provide support services to understand better SMEs' problems and needs for support. PMID- 26479838 TI - A comparative study of virtual hand prosthesis control using an inductive tongue control system. AB - This study compares the time required to activate a grasp or function of a hand prosthesis when using an electromyogram (EMG) based control scheme and when using a control scheme combining EMG and control signals from an inductive tongue control system (ITCS). Using a cross-over study design, 10 able-bodied subjects used a computer model of a hand and completed simulated grasping exercises. The time required to activate grasps was recorded and analyzed for both control schemes. End session mean activation times (ATs; seconds) for the EMG control scheme grasps 1 -5 were 0.80, 1.51, 1.95, 2.93, and 3.42; for the ITCS control scheme grasps 1 -5 they were 1.19, 1.89, 1.75, 2.26, and 1.80. Mean AT for grasps 1 and 2 was statistically significant in favor of the EMG control scheme (p = 0.030; p = 0.004). For grasp 3 no statistical significance occurred, and for grasps 4 and 5 there was a statistical significance in favour of the ITCS control scheme (p = 0.048; p = 0.004). Based on the amount of training and the achieved level of performance, it is concluded that the proposed ITCS control scheme can be used as a means of enhancing prosthesis control. PMID- 26479839 TI - The Dialectic of Chaos and Control in the Experience of Therapists Who Work With Sexually Abused Children. AB - The aim of this study is to contribute to the understanding the interaction between the emotionally destructive intensity of the trauma and forces that foster growth in therapists who treat sexually abused children. Data were collected through in-depth semistructured interviews with 14 experienced social workers. Content analysis reveals two emotional poles. At one pole, the dominant experiences are anxiety, turmoil, and intrusion that disrupted the order in the interviewee's secure world. At the opposing pole, the dominant experiences are positive, such as hope and faith. These formed the basis of empowering meaning construction that engendered a sense of control, enabling the therapists to trust the value of intervention with sexually abused children. The discussion uses a dialectical perspective to examine how interaction between these two poles enhances our understanding of the emotional and existential threats inherent in working with children who have experienced sexual abuse and on the potential for positive change. PMID- 26479840 TI - Self-Assembly of Charged Nanoparticles by an Autocatalytic Reaction Front. AB - In this work we present that aggregation of charged and pH sensitive nanoparticles can be spatiotemporally controlled by an autonomous way using the chlorite-tetrathionate autocatalytic front, where the front regulates the electrostatic interaction between nanoparticles due to protonation of the capping (carboxylate-terminated) ligand. We found that the aggregation and sedimentation of nanoparticles in liquid phase with the effect of reversible binding of the autocatalyst (H(+)) play important roles in changing the front stability (mixing length) and the velocity of the front in both cases when the fronts propagate upward and downward. Calculation of interparticle interactions (electrostatic and van der Waals) with the measurement of front velocity revealed that the aggregation process occurs fast (within a few seconds) at the front position. PMID- 26479841 TI - Diagnosis of a Family with the Novel -alpha(21.9) Thalassemia Deletion. AB - The Qinzhou alpha-thalassemia (alpha-thal) or -alpha(21.9) deletion was first described at the Qinzhou Maternal and Child Health Care Hospital, Qinzhou, Guangxi, People's Republic of China (PRC) in 2013. The molecular biological mechanism by which this allele leads to alpha-thal involves the deletion of a 21.9 kb DNA fragment of the alpha-globin gene cluster (NG_000006.1), designated as -alpha(21.9). During routine screening, a new family with -alpha(21.9) was found by the research group. This is the first time that an adult patient with the -alpha(21.9)/alphaalpha genotype and a 6-month-old baby with the alpha(21.9)/- -(SEA) (Southeast Asian) genotype were detected in one family. The discovery of this family demonstrates that there is a certain risk for the Qinzhou alpha-thal deletion in the southern regions of Guangxi Province, PRC. The detection of the adult patient with the -alpha(21.9)/alphaalpha genotype and the analysis of hematological data are important supplements for -alpha(21.9) research. Additionally, Hb Bart's (gamma4) and Hb H (beta4) were detected in the 6-month-old, confirming that the baby with the -alpha(21.9)/- -(SEA) genotype also carries Hb H disease. The analysis of this family verifies that the alpha(21.9) deletion is an alpha(+)-thal allele. PMID- 26479843 TI - Occupational Accidents with Agricultural Machinery in Austria. AB - The number of recognized accidents with fatalities during agricultural and forestry work, despite better technology and coordinated prevention and trainings, is still very high in Austria. The accident scenarios in which people are injured are very different on farms. The common causes of accidents in agriculture and forestry are the loss of control of machine, means of transport or handling equipment, hand-held tool, and object or animal, followed by slipping, stumbling and falling, breakage, bursting, splitting, slipping, fall, and collapse of material agent. In the literature, a number of studies of general (machine- and animal-related accidents) and specific (machine-related accidents) agricultural and forestry accident situations can be found that refer to different databases. From the database Data of the Austrian Workers Compensation Board (AUVA) about occupational accidents with different agricultural machinery over the period 2008-2010 in Austria, main characteristics of the accident, the victim, and the employer as well as variables on causes and circumstances by frequency and contexts of parameters were statistically analyzed by employing the chi-square test and odds ratio. The aim of the study was to determine the information content and quality of the European Statistics on Accidents at Work (ESAW) variables to evaluate safety gaps and risks as well as the accidental man machine interaction. PMID- 26479844 TI - Circadian variation in murine hepatotoxicity to the antituberculosis agent "Isoniazide". AB - The circadian time is an important process affecting both pharmacokinetics and pharmacodynamics of drugs. Consequently, the desired and/or undesired effects vary according to the time of drug administration in the 24 h scale. This study investigates whether the toxicity in liver as well as oxidative stress varies according to the circadian dosing-time of isoniazid (INH) in mice. A potentially toxic INH dose (120 mg/kg) was injected by i.p. route to different groups of animals at three different circadian times: 1, 9, and 17 Zeitgeber time (ZT). INH administration at 1 ZT resulted in a maximum hepatotoxicity assessed by the significant increase in both serum transaminase (ALAT: alanine aminotransferase) and (ASAT: aspartate aminotransferase) and antioxidant enzyme activities (catalase: CAT and superoxide dismutase: SOD). The highest malondialdehyde (MDA) level indicating an induction of lipid peroxidation resulting in oxidative damage was also observed at 1 ZT. Liver histopathology from INH groups at 9 ZT and at 1 ZT showed moderate to severe cytoplasma vacuolation, hepatocyte hypertrophy, ballooning, and necrosis. The circadian variation in INH toxicity may help realize a chronotherapy protocol in humans based on the selection of the best time associated to optimal tolerance or least side effects. PMID- 26479845 TI - Theoretical Study of the Pyridine-Helium van der Waals Complexes. AB - In this study we evaluate a high-level ab initio ground-state intermolecular potential-energy surface for the pyridine-He van der Waals complex, using the CCSD(T) method and Dunning's augmented correlation consistent polarized valence double-zeta basis set extended with a set of 3s3p2d1f1g midbond functions. The potential is characterized by two symmetric global minima of -93.2 cm(-1) that correspond to geometries where the distance between the helium atom and the pyridine center of mass is 3.105 A and the angle with respect to the pyridine c rotational axis is 3.9 degrees . Six local minima can be observed for geometries with the helium atom in the plane cotaining the pyridine molecule. To further analyze the nature of the intermolecular interactions in the complex, we use symmetry-adapted perturbation theory (SAPT). Additional consideration of the pyridine-He2 complex provides a better insight into many-body nonadditive contributions to intermolecular interactions in systems with more helium atoms. PMID- 26479846 TI - Preparation and in vitro evaluation of Methotrexate-loaded magnetic nanoparticles modified with biocompatible copolymers. AB - Superparamagnetic iron oxide nanoparticles (SPION) are attractive materials that have been widely used in medicine for drug delivery, diagnostic imaging and therapeutic applications. In our study, SPION and the anticancer drug, Methotrexate, were encapsulated into polycaprolactone-polyethylene glycol (PCL PEG) nanoparticles for local treatment. The magnetic properties conferred by SPION could help to maintain the nanoparticles in the joint with an external magnet. The drug encapsulation efficiency achieved for Fe3O4 magnetic nanoparticles modified with PCL-PEG copolymer was 92.36%. There is potential for use of these nanoparticles for biomedical application. PMID- 26479848 TI - A Community-Based Home Visitation Program's Impact on Birth Outcomes. AB - BACKGROUND: MOMS Orange County is a coordinated home visitation program in which trained paraprofessional home visitors work under the close supervision of registered nurses. This model was developed to address health disparities in birth outcomes in a Hispanic community in Orange County, CA. PURPOSE: The primary objective was to test the impact of MOMS Orange County on birth outcomes. The second objective was to examine the breadth of prenatal health education topics as a mediator of the relationship between home visits and birth outcomes. METHODS: A retrospective cohort design was used. Paraprofessional home visitors collected prenatal and postnatal data during home visits. Only those whose birth outcomes were obtained were included in the analysis (N = 2,027 participants). Regression models were conducted to test the associations between prenatal home visits and birth outcomes, adjusting for 10 covariates. RESULTS: Number of prenatal home visits predicted higher birthweight and greater gestational age at birth. Breadth of health education topics partially mediated the associations between home visits and birthweight. The same mediation was revealed with gestational age at birth. CLINICAL IMPLICATIONS: The MOMS Orange County prenatal home visitation program may be a promising approach to decrease adverse birth outcomes in disadvantaged communities. Rigorously designed studies are needed to further test this model. PMID- 26479850 TI - Dynamics of histone H3 acetylation in the nucleosome core during mouse pre implantation development. AB - In mammals, the time period that follows fertilization is characterized by extensive chromatin remodeling, which enables epigenetic reprogramming of the gametes. Major changes in chromatin structure persist until the time of implantation, when the embryo develops into a blastocyst, which comprises the inner cell mass and the trophectoderm. Changes in DNA methylation, histone variant incorporation, and covalent modifications of the histones tails have been intensively studied during pre-implantation development. However, modifications within the core of the nucleosomes have not been systematically analyzed. Here, we report the first characterization and temporal analysis of 3 key acetylated residues in the core of the histone H3: H3K64ac, H3K122ac, and H3K56ac, all located at structurally important positions close to the DNA. We found that all 3 acetylations occur during pre-implantation development, but with different temporal kinetics. Globally, H3K64ac and H3K56ac were detected throughout cleavage stages, while H3K122ac was only weakly detectable during this time. Our work contributes to the understanding of the contribution of histone modifications in the core of the nucleosome to the "marking" of the newly established embryonic chromatin and unveils new modification pathways potentially involved in epigenetic reprogramming. PMID- 26479849 TI - Effects of the phencyclidine model of schizophrenia and nicotine on total and categorized ultrasonic vocalizations in rats. AB - Patients with schizophrenia smoke cigarettes at a higher rate than the general population. We hypothesized that a factor in this comorbidity is sensitivity to the reinforcing and reinforcement-enhancement effects of nicotine. Phencyclidine (PCP) was used to model behavioral changes resembling negative symptoms of schizophrenia in rats. Ultrasonic vocalizations (USVs) in rats have been used to measure emotional states, with 50 kHz USVs indicating positive states and 22 kHz USVs indicating negative states. Total and categorized numbers of 22 and 50 kHz USVs and USVs during a visual stimulus (e.g. a potential measure of reinforcement enhancement) were examined in rats following injection of PCP (2.0 mg/kg) and/or nicotine (0.2 or 0.4 mg/kg) daily for 7 days. PCP was then discontinued and all rats received nicotine (0.2 and 0.4 mg/kg) and PCP (2.0 mg/kg) on three challenge days. PCP acutely decreased 50 kHz vocalizations, whereas repeated nicotine potentiated rates of vocalizations, with similar patterns during light presentations. Rats in the PCP and nicotine combination groups made more 50 kHz vocalizations compared with rats in the control groups on challenge days. We conclude that PCP may produce a reward deficit, which is shown by decreased 50 kHz USVs, and behaviors post-PCP exposure may best model the comorbidity between schizophrenia and nicotine. PMID- 26479851 TI - Postpartum depression and its psychosocial correlates: A longitudinal study among a group of women in Turkey. AB - The postpartum period is a window of risk for psychological disturbances and particularly for depressive symptoms. This study explored the relationships between postpartum depression and prepartum depressive symptoms, marital adjustment, support from family, previous depressive symptomology, and pregnancy planning. A total of 128 women who were receiving prenatal care at a state hospital in Istanbul, Turkey, and who were in the last trimester of their pregnancy participated in the first phase of the study. Of these, eighty-seven women also participated in the second phase, during the 3-6 month postpartum period. The results indicated that depressed mood in the last trimester of pregnancy, family support, care and support from spouse, previous depression history, and unplanned pregnancy were significant risk factors for postpartum depressive symptoms; significant differences were found for study variables as a function of women's scores on the Edinburgh Postnatal Depression Scale in pregnancy and in the postpartum period. The recommendation is made to use screening tools, like the Edinburgh Postnatal Depression Scale, in the course of routine prenatal care, and to refer women with Edinburgh Postnatal Depression Scale scores above the cutoff score for further clinical examination. PMID- 26479852 TI - Perceived school climate across the transition from elementary to middle school. AB - The implications of the transition from elementary to middle school are of major concern for educators and researchers worldwide. Previous studies have yielded ambiguous findings; some have indicated negative outcomes of school transition, whereas others have demonstrated null or even positive effects. The aim of the current research was to explore the impact of school transition on students' perceived educational climate while distinguishing between transition effects and age-related effects by comparing students who transitioned to middle schools at the end of the sixth grade versus those who did not. The research included 2 complementary studies. Study 1 was based on a large-scale national survey in Israel (N = 71,739) that compared students from fifth to eighth grades using a cross-sectional design, in which the students completed a survey once in the middle of the school year. Study 2 followed a sample of 415 students across 2 years including 4 waves of survey completion, at the beginning and the end of 2 consecutive school years, during which 55% of the students experienced a transition and 45% remained in elementary school. In both studies, the students completed self-report surveys assessing the perceived school climate. Both multilevel and nonlinear growth-curve analyses consistently indicated that the students who transitioned reported positive perceptions of the school climate before the transition that declined more quickly and become equal to or lower than those of the nontransitioning students. Teachers should apply practices that enhance students' sense of support, specifically following school transitions. (PsycINFO Database Record PMID- 26479853 TI - An HCG-rich microenvironment contributes to ovarian cancer cell differentiation into endothelioid cells in a three-dimensional culture system. AB - We investigated the expression of human chorionic gonadotropin (HCG) and its effects on vasculogenic mimicry (VM) formation in ovarian cancer cells under normoxic and hypoxic conditions in three-dimensional matrices preconditioned by an endothelial-trophoblast cell co-culture system. The co-culture model was established using human umbilical vein endothelial cells (HUVECs) and HTR-8 trophoblast cells in a three-dimensional culture system. The co-cultured cells were removed with NH4OH, and ovarian cancer cells were implanted into the preconditioned matrix. VM was identified morphologically and by detecting vascular markers expressed by cancer cells. The specificity of the effects of exogenous HCG in the microenvironment was assessed by inhibition with a neutralizing anti-HCG antibody. HCG siRNA was used to knock down endogenous HCG expression in OVCAR-3 ovarian cancer cells. HTR-8 cells 'fingerprinted' HUVECs to form capillary-like tube structures in co-cultures. In the preconditioned HCG rich microenvironment, the number of vessel-like network structures formed by HCG receptor-positive OVCAR-3 cells and the expression levels of CD31, VEGF and factor VIII were significantly increased. The preconditioned HCG-rich microenvironment significantly increased the expression of hypoxia inducible factor-1alpha (HIF-1alpha) and VM formation in OVCAR-3 cells under hypoxic conditions. Treatment with a neutralizing anti-HCG antibody but not HCG siRNA significantly inhibited the formation of vessel-like network structures. HCG in the microenvironment contributes to OVCAR-3 differentiation into endothelioid cells in three-dimensional matrices preconditioned with an endothelial trophoblast cell co-culture system. HCG may synergistically enhance hypoxia induced vascular markers and HIF-1alpha expression. These findings would provide perspectives on new therapeutic targets for ovarian cancer. PMID- 26479854 TI - Robotic rectal cancer surgery: literature review and perspective. AB - Surgical treatment of patients with rectal cancer is challenging. The concept of robotic surgery is attractive and has earned considerable interest after its successful implementation in the fields of urology and gynecology. Recently, robotic surgery for rectal cancer with total mesorectal excision (TME) has also obtained an increasing amount of attention in the colorectal field. In this review, we introduce the commonly performed methods of robotic rectal surgery and discuss results to date and future perspectives. PMID- 26479855 TI - Production in Pichia pastoris of protein-based polymers with small heterodimer forming blocks. AB - Some combinations of leucine zipper peptides are capable of forming alpha-helical heterodimeric coiled coils with very high affinity. These can be used as physical cross-linkers in the design of protein-based polymers that form supramolecular structures, for example hydrogels, upon mixing solutions containing the complementary blocks. Such two-component physical networks are of interest for many applications in biomedicine, pharmaceutics, and diagnostics. This article describes the efficient secretory production of A and B type leucine zipper peptides fused to protein-based polymers in Pichia pastoris. By adjusting the fermentation conditions, we were able to significantly reduce undesirable proteolytic degradation. The formation of A-B heterodimers in mixtures of the purified products was confirmed by size exclusion chromatography. Our results demonstrate that protein-based polymers incorporating functional heterodimer forming blocks can be produced with P. pastoris in sufficient quantities for use in future supramolecular self-assembly studies and in various applications. PMID- 26479856 TI - High-Intensity Interval Training and Isocaloric Moderate-Intensity Continuous Training Result in Similar Improvements in Body Composition and Fitness in Obese Individuals. AB - This study aimed to determine the effects of 12 weeks of isocaloric programs of high-intensity intermittent training (HIIT) or moderate-intensity continuous training (MICT) or a short-duration HIIT (1/2HIIT) inducing only half the energy deficit on a cycle ergometer, on body weight and composition, cardiovascular fitness, resting metabolism rate (RMR), respiratory exchange ratio (RER), nonexercise physical activity (PA) levels and fasting and postprandial insulin response in sedentary obese individuals. Forty-six sedentary obese individuals (30 women), with a mean BMI of 33.3 +/- 2.9 kg/m2 and a mean age of 34.4 +/- 8.8 years were randomly assigned to one of the three training groups: HIIT (n = 16), MICT (n = 14) or 1/2HIIT (n = 16) and exercise was performed 3 times/week for 12 weeks. Overall, there was a significant reduction in body weight, waist (p < .001) and hip (p < .01) circumference,, trunk and leg fat mass (FM; p < .01) and an increase in trunk and leg fat free mass (FFM; p < .01) and cardiovascular fitness (VO2max in ml/kg/min; p < .001) with exercise. However, no significant differences were observed between groups. There was no significant change in RMR, RER, nonexercise PA levels, fasting insulin or insulin sensitivity with exercise or between groups. There was a tendency for a reduction in AUC insulin with exercise (p = .069), but no differences between groups. These results indicate that isocaloric training protocols of HIIT or MICT (or 1/2HIIT inducing only half the energy deficit) exert similar metabolic and cardiovascular improvements in sedentary obese individuals. PMID- 26479857 TI - Pre-Travel Medical Preparation of Business and Occupational Travelers: An Analysis of the Global TravEpiNet Consortium, 2009 to 2012. AB - OBJECTIVES: The aim of the study was to understand more about pre-travel preparations and itineraries of business and occupational travelers. METHODS: De identified data from 18 Global TravEpiNet clinics from January 2009 to December 2012 were analyzed. RESULTS: Of 23,534 travelers, 61% were non-occupational and 39% occupational. Business travelers were more likely to be men, had short times to departure and shorter trip durations, and commonly refused influenza, meningococcal, and hepatitis B vaccines. Most business travelers indicated that employers suggested the pre-travel health consultation, whereas non-occupational travelers sought consultations because of travel health concerns. CONCLUSIONS: Sub-groups of occupational travelers have characteristic profiles, with business travelers being particularly distinct. Employers play a role in encouraging business travelers to seek pre-travel consultations. Such consultations, even if scheduled immediately before travel, can identify vaccination gaps and increase coverage. PMID- 26479858 TI - Vesicular control of fusion pore expansion. AB - Exocytic post-fusion events play an important role determining the composition and quantity of cellular secretion. In particular, Ca(2+)-dependent regulation of fusion pore dilation/closure is a key regulator for fine-tuning vesicle content secretion. This requires a tight temporal and spatial integration of vesicle fusion with the PM, Ca(2+) signals and translation of the Ca(2+) signal into fusion pore dilation via auxiliary factors. Yet, it is still mostly elusive how this is achieved in slow and non-excitable secretory cells, where initial Ca(2+) signals triggering fusions will abate before onset of the post-fusion phase. New results suggest, that the vesicles themselves provide the necessary itinerary to sense and link vesicle fusion to generation of local Ca(2+) signals and fusion pore expansion. PMID- 26479859 TI - How can clinicians detect and treat autism early? Methodological trends of technology use in research. AB - We reviewed original research papers that used quantifiable technology to detect early autism spectrum disorder (ASD) and identified 376 studies from 34 countries from 1965 to 2013. Publications have increased significantly since 2000, with most coming from the USA. Electroencephalogram, magnetic resonance imaging and eye tracking were the most frequently used technologies. CONCLUSION: The use of quantifiable technology to detect early ASD has increased in recent decades, but has had limited impact on early detection and treatment. Further scientific developments are anticipated, and we hope that they will increasingly be used in clinical practice for early ASD screening, diagnosis and intervention. PMID- 26479860 TI - Evolutionarily conserved exon definition interactions with U11 snRNP mediate alternative splicing regulation on U11-48K and U11/U12-65K genes. AB - Many splicing regulators bind to their own pre-mRNAs to induce alternative splicing that leads to formation of unstable mRNA isoforms. This provides an autoregulatory feedback mechanism that regulates the cellular homeostasis of these factors. We have described such an autoregulatory mechanism for two core protein components, U11-48K and U11/U12-65K, of the U12-dependent spliceosome. This regulatory system uses an atypical splicing enhancer element termed USSE (U11 snRNP-binding splicing enhancer), which contains two U12-type consensus 5' splice sites (5'ss). Evolutionary analysis of the USSE element from a large number of animal and plant species indicate that USSE sequence must be located 25 50 nt downstream from the target 3' splice site (3'ss). Together with functional evidence showing a loss of USSE activity when this distance is reduced and a requirement for RS-domain of U11-35K protein for 3'ss activation, our data suggests that U11 snRNP bound to USSE uses exon definition interactions for regulating alternative splicing. However, unlike standard exon definition where the 5'ss bound by U1 or U11 will be subsequently activated for splicing, the USSE element functions similarly as an exonic splicing enhancer and is involved only in upstream splice site activation but does not function as a splicing donor. Additionally, our evolutionary and functional data suggests that the function of the 5'ss duplication within the USSE elements is to allow binding of two U11/U12 di-snRNPs that stabilize each others' binding through putative mutual interactions. PMID- 26479861 TI - Can we understand how developmental stress enhances performance under future threat with the Yerkes-Dodson law? AB - Recently we have shown that adult rats exposed to chronic stress during adolescence increase foraging performance in high-threat conditions by 43% compared to rats reared without stress. Our findings suggest that stress during adolescence can prepare rats to better function under future threat, which supports hypotheses describing an adaptive role for the long-term consequences of early stress (e.g. the thrifty phenotype and maternal mismatch hypotheses). These hypotheses often predict that early stress will impair performance in low-threat conditions later in life. However, we did not find any difference in performance under low-threat conditions between adolescent-stressed and unstressed adult animals. To understand why stress during adolescence may affect performance in high-threat but not in low-threat conditions, we discuss our findings in the framework of the Yerkes-Dodson law, a key precept of psychology that has been used for over a century to describe how stress affects performance. PMID- 26479862 TI - Morphological Changes within the Rat Lateral Ventricle after the Administration of Proteasome Inhibitors. AB - The broad variety of substances that inhibit the action of the ubiquitin proteasome system (UPS)-known as proteasome inhibitors-have been used extensively in previous studies, and they are currently frequently proposed as a novel form of cancer treatment and as a protective factor in intracerebral hemorrhage treatment. The experimental data on the safest route of proteasome inhibitor administration, their associated side effects, and the possible ways of minimizing these effects have recently become a very important topic. The aim of our present study was to determine the effects of administering of MG-132, lactacystin and epoxomicin, compounds belonging to three different classes of proteasome inhibitors, on the ependymal walls of the lateral ventricle. Observations were made 2 and 8 weeks after the intraventricular administration of the studied substances dissolved in dimethyl sulfoxide (DMSO) into the lateral ventricle of adult Wistar rats. Qualitative and quantitative analysis of brain sections stained with histochemical and inmmunofluorescence techniques showed that the administration of proteasome inhibitors caused a partial occlusion of the injected ventricle in all of the studied animals. The occlusion was due to ependymal cells damage and subsequent ependymal discontinuity, which caused direct contact between the striatum and the lateral nuclei of the septum, mononuclear cell infiltration and the formation of a glial scar between these structures (with the activation of astroglia, microglia and oligodendroglia). Morphologically, the ubiquitin-positive aggregates corresponded to aggresomes, indicating impaired activity of the UPS and the accumulation and aggregation of ubiquitinated proteins that coincided with the occurrence of glial scars. The most significant changes were observed in the wall covering the striatum in animals that were administered epoxomicin, and milder changes were observed in animals administered lactacystin and MG-132. Interestingly, DMSO administration also caused damage to some of the ependymal cells, but the aggresome-like structures were not formed. Our results indicate that all of the studied classes of proteasome inhibitors are detrimental to ependymal cells to some extent, and may cause severe changes in the ventricular system. The safety implications of their usage in therapeutic strategies to attenuate intracerebral hemorrhagic injury and in brain cancer treatment will require further studies. PMID- 26479864 TI - Hemoglobin-Based Nanoarchitectonic Assemblies as Oxygen Carriers. AB - Safe and effective artificial oxygen carriers are the subject of great interest due to the problems of traditional blood transfusion and enormous demand in clinical use. In view of its unique oxygen-transport ability and normal metabolic pathways, hemoglobin is regarded as an ideal oxygen-carrying unit. With advances in nano-biotechnology, hemoglobin assemblies as artificial oxygen carriers achieve great development. Here, recent progress on hemoglobin-based oxygen carriers is highlighted in view of two aspects: acellular hemoglobin-based oxygen carriers and cellular hemoglobin-based oxygen carriers. These novel oxygen carriers exhibit advantages over traditional carriers and will greatly promote research on reliable and feasible oxygen carriers. PMID- 26479863 TI - Domestic animals as models for biomedical research. AB - Domestic animals are unique models for biomedical research due to their long history (thousands of years) of strong phenotypic selection. This process has enriched for novel mutations that have contributed to phenotype evolution in domestic animals. The characterization of such mutations provides insights in gene function and biological mechanisms. This review summarizes genetic dissection of about 50 genetic variants affecting pigmentation, behaviour, metabolic regulation, and the pattern of locomotion. The variants are controlled by mutations in about 30 different genes, and for 10 of these our group was the first to report an association between the gene and a phenotype. Almost half of the reported mutations occur in non-coding sequences, suggesting that this is the most common type of polymorphism underlying phenotypic variation since this is a biased list where the proportion of coding mutations are inflated as they are easier to find. The review documents that structural changes (duplications, deletions, and inversions) have contributed significantly to the evolution of phenotypic diversity in domestic animals. Finally, we describe five examples of evolution of alleles, which means that alleles have evolved by the accumulation of several consecutive mutations affecting the function of the same gene. PMID- 26479865 TI - Editor-in-Chief editorial and introduction to 'Metabolomics and biomarkers' special issue. PMID- 26479866 TI - Free-breathing slice-interleaved myocardial T2 mapping with slice-selective T2 magnetization preparation. AB - PURPOSE: To develop and evaluate a free-breathing slice-interleaved T2 mapping sequence by proposing a new slice-selective T2 magnetization preparation (T2 prep) sequence that allows interleaved data acquisition for different slices in subsequent heartbeats. METHODS: We developed a slice-selective T2 prep for myocardial T2 mapping by adding slice-selective gradients to a conventional single-slice T2 prep sequence. In this sequence, five slices are acquired during five consecutive heartbeats, each using a slice-selective T2 prep. The scheme was repeated four times using different T2 prep echo times. We compared the performance of the proposed slice-interleaved T2 mapping sequence and the conventional single-slice T2 mapping sequence in term of accuracy, precision, and reproducibility using phantom experiments and in vivo imaging in 10 healthy subjects. We also evaluated the feasibility of the proposed sequence in 28 patients with cardiovascular disease, and the quality of the maps was scored subjectively. Furthermore, we investigated the impact of through-plane motion by comparing T2 measurements acquired during end-systole versus mid-diastole. RESULTS: T2 measurements using a slice-interleaved T2 mapping sequence were correlated with a spin echo (r(2) = 0.88) and single-slice T2 mapping sequence (r(2) = 0.98). The mean myocardial T2 values were correlated between slice interleaved (48 ms) and single-slice (51 ms) T2 mapping sequences. Subjective scores of T2 map quality were good to excellent in 81% of the maps in patients. There was no difference in T2 measurements between end-systole versus mid diastole. CONCLUSIONS: The proposed free-breathing slice-interleaved T2 mapping sequence allows T2 measurements of five left ventricular slices in 20 heartbeats with similar reproducibility and precision as the single-slice T2 mapping sequence but with a four-fold reduction in acquisition time. Magn Reson Med 76:555-565, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26479867 TI - Next-generation monitoring of aquatic biodiversity using environmental DNA metabarcoding. AB - Global biodiversity in freshwater and the oceans is declining at high rates. Reliable tools for assessing and monitoring aquatic biodiversity, especially for rare and secretive species, are important for efficient and timely management. Recent advances in DNA sequencing have provided a new tool for species detection from DNA present in the environment. In this study, we tested whether an environmental DNA (eDNA) metabarcoding approach, using water samples, can be used for addressing significant questions in ecology and conservation. Two key aquatic vertebrate groups were targeted: amphibians and bony fish. The reliability of this method was cautiously validated in silico, in vitro and in situ. When compared with traditional surveys or historical data, eDNA metabarcoding showed a much better detection probability overall. For amphibians, the detection probability with eDNA metabarcoding was 0.97 (CI = 0.90-0.99) vs. 0.58 (CI = 0.50 0.63) for traditional surveys. For fish, in 89% of the studied sites, the number of taxa detected using the eDNA metabarcoding approach was higher or identical to the number detected using traditional methods. We argue that the proposed DNA based approach has the potential to become the next-generation tool for ecological studies and standardized biodiversity monitoring in a wide range of aquatic ecosystems. PMID- 26479869 TI - Tracing microbiota changes in yamahai-moto, the traditional Japanese sake starter. AB - Sake is made from steamed rice, malted rice, and water. Sake production begins with the preparation of a small-scale starter (moto); the quality of moto significantly influences the flavor and richness of sake. In the traditional starter, yamahai-moto, the growth of naturally occurring lactic acid bacteria represses the putrefactive micro-organisms, whereas in the modern starter, sokujo moto, this is achieved by adding lactic acid. In this study, the successive change in bacterial flora of yamahai-moto was analyzed by pyrosequencing 16S ribosomal RNA genes. Lactobacillus was dominant throughout the process (93-98%). Nitrate-reducing bacteria that have been generally assumed to be the first colonizers of yamahai-moto were scarcely found in the early stage, but Lactobacillus acidipiscis dominated. Lactobacillus sakei drastically increased in the middle stage. This is the first report, though one case study, to show how the early stage microbiota in Japanese yamahai-moto is varyingly controlled without nitrate-reducing bacteria using next-generation sequencing. PMID- 26479868 TI - Non-Hematopoietic beta-Arrestin1 Confers Protection Against Experimental Colitis. AB - beta-Arrestins are multifunctional scaffolding proteins that modulate G protein coupled receptor (GPCR)-dependent and -independent cell signaling pathways in various types of cells. We recently demonstrated that beta-arrestin1 (beta-arr1) deficiency strikingly attenuates dextran sodium sulfate (DSS)-induced colitis in mice. Since DSS-induced colitis is in part dependent on gut epithelial injury, we examined the role of beta-arr1 in intestinal epithelial cells (IECs) using a colon epithelial cell line, SW480 cells. Surprisingly, we found that knockdown of beta-arr1 in SW480 cells enhanced epithelial cell death via a caspase-3-dependent process. To understand the in vivo relevance and potential cell type-specific role of beta-arr1 in colitis development, we generated bone marrow chimeras with beta-arr1 deficiency in either the hematopoietic or non-hematopoietic compartment. Reconstituted chimeric mice were then subjected to DSS-induced colitis. Similar to our previous findings, beta-arr1 deficiency in the hematopoietic compartment protected mice from DSS-induced colitis. However, consistent with the role of beta-arr1 in epithelial apoptosis in vitro, non hematopoietic beta-arr1 deficiency led to an exacerbated colitis phenotype. To further understand signaling mechanisms, we examined the effect of beta-arr1 on TNF-alpha-mediated NFkappaB and MAPK pathways. Our results demonstrate that beta arr1 has a critical role in modulating ERK, JNK and p38 MAPK pathways mediated by TNF-alpha in IECs. Together, our results show that beta-arr1-dependent signaling in hematopoietic and non-hematopoietic cells differentially regulates colitis pathogenesis and further demonstrates that beta-arr1 in epithelial cells inhibits TNF-alpha-induced cell death pathways. PMID- 26479871 TI - Correction: Structural Synaptic Plasticity Has High Memory Capacity and Can Explain Graded Amnesia, Catastrophic Forgetting, and the Spacing Effect. PMID- 26479870 TI - Malva sylvestris Inhibits Inflammatory Response in Oral Human Cells. An In Vitro Infection Model. AB - The aim of this study was to investigate the in vitro anti-inflammatory activity of Malva sylvestris extract (MSE) and fractions in a co-culture model of cells infected by Aggregatibacter actinomycetemcomitans. In addition, we evaluated the phytochemical content in the extract and fractions of M. sylvestris and demonstrated that polyphenols were the most frequent group in all samples studied. An in vitro dual-chamber model to mimic the periodontal structure was developed using a monolayer of epithelial keratinocytes (OBA-9) and a subepithelial layer of fibroblasts (HGF-1). The invasive periodontopathogen A. actinomycetemcomitans (D7S-1) was applied to migrate through the cell layers and induce the synthesis of immune factors and cytokines in the host cells. In an attempt to analyze the antimicrobial properties of MSE and fractions, a susceptibility test was carried out. The extract (MIC 175 MUg/mL, MBC 500MUg/mL) and chloroform fraction (MIC 150 MUg/mL, MBC 250 MUg/mL) were found to have inhibitory activity. The extract and all fractions were assessed using a cytotoxicity test and results showed that concentrations under 100 MUg/mL did not significantly reduce cell viability compared to the control group (p > 0.05, viability > 90%). In order to analyze the inflammatory response, transcriptional factors and cytokines were quantified in the supernatant released from the cells. The chloroform fraction was the most effective in reducing the bacterial colonization (p< 0.05) and controlling inflammatory mediators, and promoted the down-regulation of genes including IL-1beta, IL-6, IL-10, CD14, PTGS, MMP-1 and FOS as well as the reduction of the IL-1beta, IL-6, IL-8 and GM-CSF protein levels (p< 0.05). Malva sylvestris and its chloroform fraction minimized the A. actinomycetemcomitans infection and inflammation processes in oral human cells by a putative pathway that involves important cytokines and receptors. Therefore, this natural product may be considered as a successful dual anti-inflammatory antimicrobial candidate. PMID- 26479872 TI - mVps45 knockdown selectively modulates VAMP expression in 3T3-L1 adipocytes. AB - Insulin stimulates the delivery of glucose transporter-4 (GLUT4)-containing vesicles to the surface of adipocytes. Depletion of the Sec1/Munc18 protein mVps45 significantly abrogates insulin-stimulated glucose transport and GLUT4 translocation. Here we show that depletion of mVps45 selectively reduced expression of VAMPs 2 and 4, but not other VAMP isoforms. Although we did not observe direct interaction of mVps45 with any VAMP isoform; we found that the cognate binding partner of mVps45, Syntaxin 16 associates with VAMPs 2, 4, 7 and 8 in vitro. Co-immunoprecipitation experiments in 3T3-L1 adipocytes revealed an interaction between Syntaxin 16 and only VAMP4. We suggest GLUT4 trafficking is controlled by the coordinated expression of mVps45/Syntaxin 16/VAMP4, and that depletion of mVps45 regulates VAMP2 levels indirectly, perhaps via reduced trafficking into specialized subcellular compartments. PMID- 26479873 TI - Determinants of Socioeconomic Inequalities in Traumatic Dental Injuries among Urban Indian Adolescents. AB - OBJECTIVES: To assess socioeconomic inequalities in traumatic dental injuries (TDIs) in adolescents in New Delhi and examine the role of material, psychosocial and behavioural factors in explaining these inequalities. METHODS: We conducted a cross sectional study of 1386 adolescents aged between 12-15 years residing in three diverse areas of New Delhi. A non-invasive clinical examination was used to estimate the prevalence of TDIs, and an interviewer-administered questionnaire was used to gather relevant behavioural and socio-demographic data. Multiple logistic regression models were used to assess the association between area based socioeconomic position and TDIs. RESULTS: The overall prevalence of TDIs was 10.9%. Social inequalities in the prevalence of TDIs were observed across the adolescent population according to their area of residence. Socio-economic group differences in the prevalence of TDIs remained statistically significant after adjusting for demographic factors, material resources, social capital, social support and health affecting behaviours (OR 3.36, 95% CI 1.75-6.46 and OR 3.99, 95% CI 1.86-8.56 for adolescents from resettlement areas and urban slums respectively in comparison to middle class adolescents). Different psychosocial, material and socio-demographic variables did not attenuate the estimates for the relationship between area socioeconomic position and TDIs. CONCLUSION: Area of residence was a strong predictor of TDIs in adolescents with a higher prevalence in more deprived areas. Social inequalities in TDIs were not explained by psychosocial and behavioural variables. Health promoting policies aimed at improving the physical environment in which adolescents reside might be instrumental in reducing the prevalence of TDIs and associated inequalities. PMID- 26479874 TI - Biological variation of thromboelastrography variables in 10 clinically healthy horses. AB - OBJECTIVE: To assess the utility of population-based reference intervals (PRIs) for interpreting thromboelastography (TEG) variables in horses using biological variation data. DESIGN: Prospective cohort biologic variation study conducted over a 5-week period. SETTING: Veterinary teaching hospital and research facility. ANIMALS: Ten clinically healthy horses randomly selected from a veterinary school research and teaching herd. INTERVENTIONS: Horse health was determined using physical examination, CBC, and biochemical and coagulation profiles prior to the start of the study. Subsequently, once weekly blood sampling for TEG testing was performed for 5 weeks. MEASUREMENTS AND MAIN RESULTS: The 4 TEG variables reaction time (R), clot formation time (K), angle, and maximum amplitude (MA) were measured, and coefficient of variation representing within- and between-horse biological variation (CVi and CVg , respectively) and coefficient of variation representing analytical variation (CVa ) were calculated using a nested ANOVA after removing outlier data. The CVi , CVg , and CVa for R were 26.8%, 5.2%, and 5.9%; for K were 31.0%, 0.0%, and 5.9%; for angle were 9.4%, 6.2%, and 21.7%; and for MA were 3.4%, 4.1%, and 4.4%, respectively. Index of individuality (IOI) was then calculated for each variable using the formula {( CVi2 + CVa2/CVg2)}1/2. IOI for R was 5.3, for angle was 3.8, and for MA was 1.4; IOI was not assessed for K. CONCLUSIONS: PRIs are appropriate for TEG variables, R, angle, and MA when interpreting results from individual horses based on calculated IOI values equal to or greater than 1.4. PRIs are likely appropriate when interpreting K, but IOI could not be calculated for this variable. PMID- 26479875 TI - Protecting against ischaemic stroke in rats by heat shock protein 20-mediated exercise. AB - BACKGROUND: Exercise preconditioning (EP(+) ) has been widely accepted as a being of safe and effective preventive measure for stroke. The purpose of this study was to investigate whether EP(+) improves outcomes of ischaemic stroke by promoting neuronal and glial expression of heat shock protein (HSP) 20. MATERIALS AND METHODS: Adult male Sprague-Dawley rats (288 in number) were used to investigate the contribution of HSP20-containing neurons and HSP20-containing glial cells in the exercise-mediated neuroprotection in the stroke condition using middle cerebral artery occlusion. RESULTS: Exercise preconditioning, in addition to increasing the numbers of both the HSP20-containg neurons (88 +/- 8 vs. 43 +/- 4; n = 8 each group; P < 0.05) and the HSP20-containg astrocytes (102 +/- 10 vs. 56 +/- 5; n = 8; P < 0.05) significantly attenuated stroke-induced brain infarct (140 +/- 9 vs. 341 +/- 20 mm(3) ; n = 8 per group; P < 0.01), neuronal apoptosis (20 +/- 5 vs. 87 +/- 7; n = 8 per group; n = 8; P < 0.01), glial apoptosis (29 +/- 5 vs. 101 +/- 4; n = 8; P < 0.01), and neurological deficits (6.6 +/- 0.3 vs. 11.7 +/- 0.8; n = 8 per group; P < 0.01). Reducing the numbers of both HSP20-containing neurons and HSP20-contaiing glia by intracerebral injection of pSUPER small interfering RNAiota expressing HSP20 significantly reversed the beneficial effects of EP(+) in attenuating stroke induced cerebral infarct, neuronal and glial apoptosis, and neurological deficits. CONCLUSIONS: The numbers of both the HSP20-containing neurons and the HSP20-containing glia inversely correlated with the outcomes of ischaemic stroke. In addition, preischaemic treadmill exercise improves outcomes of ischaemic stroke by increasing the numbers of both the HSP20-containing neurons and the HSP20-containing glia. PMID- 26479877 TI - Sholom Wacholder, 1955-2015. PMID- 26479876 TI - Growth and Mortality Outcomes for Different Antiretroviral Therapy Initiation Criteria in Children Ages 1-5 Years: A Causal Modeling Analysis. AB - BACKGROUND: There is limited evidence regarding the optimal timing of initiating antiretroviral therapy (ART) in children. We conducted a causal modeling analysis in children ages 1-5 years from the International Epidemiologic Databases to Evaluate AIDS West/Southern-Africa collaboration to determine growth and mortality differences related to different CD4-based treatment initiation criteria, age groups, and regions. METHODS: ART-naive children of ages 12-59 months at enrollment with at least one visit before ART initiation and one follow up visit were included. We estimated 3-year growth and cumulative mortality from the start of follow-up for different CD4 criteria using g-computation. RESULTS: About one quarter of the 5,826 included children was from West Africa (24.6%).The median (first; third quartile) CD4% at the first visit was 16% (11%; 23%), the median weight-for-age z-scores and height-for-age z-scores were -1.5 (-2.7; -0.6) and -2.5 (-3.5; -1.5), respectively. Estimated cumulative mortality was higher overall, and growth was slower, when initiating ART at lower CD4 thresholds. After 3 years of follow-up, the estimated mortality difference between starting ART routinely irrespective of CD4 count and starting ART if either CD4 count <750 cells/mm3 or CD4% <25% was 0.2% (95% CI = -0.2%; 0.3%), and the difference in the mean height-for-age z-scores of those who survived was -0.02 (95% CI = -0.04; 0.01). Younger children ages 1-2 and children in West Africa had worse outcomes. CONCLUSIONS: Our results demonstrate that earlier treatment initiation yields overall better growth and mortality outcomes, although we could not show any differences in outcomes between immediate ART and delaying until CD4 count/% falls below 750/25%. PMID- 26479878 TI - A Simple Technique for Accurate Transfer of Secondary Copings in a Tooth Supported Telescopic Prosthesis. AB - Residual ridge resorption is a rapid, progressive, irreversible, and inevitable process of bone resorption. Long-standing teeth and implants have been shown to have maintained the bone around them without resorption. Thus, overdenture therapy has been proven to be beneficial in situations where few remaining teeth are present. In addition to the various advantages seen with tooth-supported telescopic overdentures, a few shortcomings can also be expected, including unseating of the overdenture, increased bulk of the prosthesis, secondary caries, etc. The precise transfer of the secondary telescopic copings to maintain the spatial relationship, without any micromovement, remains the most critical step in ensuring the success of the tooth-supported telescopic prosthesis. Thus, a simple and innovative technique of splinting the secondary copings was devised to prevent distortion and micromovement and maintain its spatial relationship. PMID- 26479879 TI - Morphological Changes in Skin Glands During Development in Rhinella Arenarum (Anura: Bufonidae). AB - Avoiding predation is critical to survival of animals; chemical defenses represent a common strategy among amphibians. In this study, we examined histologically the morphology of skin glands and types of secretions related to chemical skin defense during ontogeny of Rhinella arenarum. Prior to metamorphic climax the epidermis contains typical bufonid giant cells producing a mucous substance supposedly involved in triggering a flight reaction of the tadpole school. An apical layer of alcianophilic mucus covers the epidermis, which could produce the unpleasant taste of bufonid tadpoles. Giant cells disappear by onset of metamorphic climax, when multicellular glands start developing, but the apical mucous layer remains. By the end of climax, neither the granular glands of the dorsum nor the parotoid regions are completely developed. Conversely, by the end of metamorphosis the mucous glands are partially developed and secrete mucus. Adults have at least three types of granular glands, which we designate type A (acidophilic), type B (basophilic) and ventral (mucous). Polymorphic granular glands distribute differently in the body: dorsal granular glands between warts and in the periphery of parotoids contain protein; granular glands of big warts and in the central region of parotoids contain catecholamines, lipids, and glycoconjugates, whereas ventral granular glands produce acidic glycoconjugates. Mucous glands produce both mucus and proteins. Results suggest that in early juveniles the chemical skin defense mechanisms are not functional. Topographical differences in adult skin secretions suggest that granular glands from the big warts in the skin produce similar toxins to the parotoid glands. PMID- 26479880 TI - Molecular insight into the viral biology and clinical features of trichodysplasia spinulosa. AB - Trichodysplasia spinulosa (TS) is a disfiguring skin disease that occurs most frequently in patients receiving immunosuppressive therapies, and is thus frequently associated with organ transplantation. TS is characterized clinically by folliculocentric papular eruption, keratin spine formation and development of leonine face; and histologically by expansion of the inner root sheath epithelium and high expression of the proliferative marker Ki-67. Recent discovery of the TS associated polyomavirus (TSPyV) and emerging studies demonstrating the role of TSPyV tumour antigens in cell proliferation pathways have opened a new corridor for research on TS. In this brief review, we summarize the clinical and histological features of TS and evaluate the current options for therapy. Furthermore, we address the viral aetiology of the disease and explore the mechanisms by which TSPyV may influence TS development and progression. As reports of TS continue to rise, clinician recognition of TS, as well as accompanying research on its underlying pathogenesis and therapeutic options, is becoming increasingly important. It is our hope that heightened clinical suspicion for TS will increase rates of diagnosis and will galvanize both molecular and clinical interest in this disease. PMID- 26479881 TI - Effectiveness of Gel Repellents on Feral Pigeons. AB - Millions of feral pigeons (Columba livia) live in close association with the human population in our cities. They pose serious health risks to humans and lead to high economic loss due to damage caused to buildings. Consequently, house owners and city authorities are not willing to allow pigeons on their buildings. While various avian repellents are regularly introduced onto the market, scientific proof of efficacy is lacking. This study aimed at testing the effectiveness of two avian gel repellents and additionally examined their application from animal welfare standpoint. The gels used an alleged tactile or visual aversion of the birds, reinforced by additional sensory cues. We mounted experimental shelves with the installed repellents in a pigeon loft and observed the behavior of free-living feral pigeons towards the systems. Both gels showed a restricted, transient repellent effect, but failed to prove the claimed complete effectiveness. Additionally, the gels' adhesive effect remains doubtful in view of animal welfare because gluing of plumage presents a risk to feral pigeons and also to other non-target birds. This study infers that both gels lack the promised complete efficacy, conflict with animal welfare concerns and are therefore not suitable for feral pigeon management in urban areas. PMID- 26479882 TI - Conscientious Objection to Harmful Animal Use within Veterinary and Other Biomedical Education. AB - Laboratory classes in which animals are seriously harmed or killed, or which use cadavers or body parts from ethically debatable sources, are controversial within veterinary and other biomedical curricula. Along with the development of more humane teaching methods, this has increasingly led to objections to participation in harmful animal use. Such cases raise a host of issues of importance to universities, including those pertaining to curricular design and course accreditation, and compliance with applicable animal welfare and antidiscrimination legislation. Accordingly, after detailed investigation, some universities have implemented formal policies to guide faculty responses to such cases, and to ensure that decisions are consistent and defensible from legal and other policy perspectives. However, many other institutions have not yet done so, instead dealing with such cases on an ad hoc basis as they arise. Among other undesirable outcomes this can lead to insufficient student and faculty preparation, suboptimal and inconsistent responses, and greater likelihood of legal challenge. Accordingly, this paper provides pertinent information about the evolution of conscientious objection policies within Australian veterinary schools, and about the jurisprudential bases for conscientious objection within Australia and the USA. It concludes with recommendations for the development and implementation of policy within this arena. PMID- 26479883 TI - Dogs' Body Language Relevant to Learning Achievement. AB - The facial expressions and body postures of dogs can give helpful information about their moods and emotional states. People can more effectively obedience train their dogs if we can identify the mannerisms associated with learning in dogs. The aim of this study was to clarify the dog's body language during operant conditioning to predict achievement in the test that followed by measuring the duration of behaviors. Forty-six untrained dogs (17 males and 26 females) of various breeds were used. Each session consisted of 5 minutes of training with a treat reward followed by 3 minutes of rest and finally an operant conditioning test that consisted of 20 "hand motion" cues. The operant tests were conducted a total of nine times over three consecutive days, and the success numbers were counted. The duration of the dog's behavior, focusing on the dog's eyes, mouth, ears, tail and tail-wagging, was recorded during the operant conditioning sessions before the test. Particular behaviors, including wide-eyes, closed mouth, erect ears, and forward and high tail carriage, without wagging or with short and quick wagging, related to high achievement results. It is concluded that dogs' body language during operant conditioning was related to their success rate. PMID- 26479884 TI - Characteristics of Loads of Cattle Stopping for Feed, Water and Rest during Long Distance Transport in Canada. AB - This study is the first comprehensive examination of long-haul cattle being transported across Canada and off-loaded for feed, water and rest. A total of 129 truckloads were observed at one of two commercial rest stations near Thunder Bay, Ontario. Data collected included information regarding the truck driver, the trailer, the trip, the animals and animal handling. The majority of the loads stopping were feeder calves (60.94%) while 21.09% were weaned calves, and the remaining 14.84% were market weight cattle. The truck loads surveyed were in transit for, on average, 28.2 +/- 5.0 hours before stopping and cattle were rested for an average of 11.2 +/- 2.8 hours. These data suggest that loads stopping at the rest station were adhering to the regulations stated in the Health of Animals Act, which outline a maximum of 48 hours in transit before a mandatory stop of at least 5 hours for feed, water and rest. There was a large amount of variability around how well recommendations, such as stocking density were followed. Further research is required to assess how well cattle are coping with long-distance transport under current regulations and industry practices. PMID- 26479885 TI - Effect of Corn Dried Distiller Grains with Solubles (DDGS) in Dairy Cow Diets on Manure Bioenergy Production Potential. AB - The main objective of this study was to obtain scientifically sound data on the bioenergy potential of dairy manures from cows fed different levels of corn dried distillers grains with solubles (DDGS). Three diets differing in corn DDGS content were formulated: 0% corn DDGS (DDGS0; control diet), 10% corn DDGS (DDGS10) and 30% corn DDGS (DDGS30). Bioenergy production was determined in psychrophilic (25 +/- 1 degrees C) sequencing batch reactors (SBRs) fed 3 g COD L(-1).day(-1) during a two-week feeding period followed by a two-week react period. Compared to the control diet, adding DDGS10 and DDGS30 to the dairy cow diet increased the daily amount of fat excreted in slurry by 29% and 70%, respectively. The addition of DDGS30 increased the cows' daily production of fresh feces and slurry by 15% and 11%, respectively. Furthermore, the incorporation of DDGS30 in the diet increased the daily amounts of dry matter (DM), volatile solids (VS), neutral detergent fiber (NDF), acid detergent fiber (ADF) and hemicellulose by 18%, 18%, 30%, 15% and 53%, respectively, compared to the control diet. While the addition of DDGS did not significantly affect the specific CH4 production per kg VS compared to the control diet, DDGS30 increased the per cow daily CH4 production by 14% compared to the control diet. PMID- 26479886 TI - Social Networks and Welfare in Future Animal Management. AB - It may become advantageous to keep human-managed animals in the social network groups to which they have adapted. Data concerning the social networks of farm animal species and their ancestors are scarce but essential to establishing the importance of a natural social network for farmed animal species. Social Network Analysis (SNA) facilitates the characterization of social networking at group, subgroup and individual levels. SNA is currently used for modeling the social behavior and management of wild animals and social welfare of zoo animals. It has been recognized for use with farm animals but has yet to be applied for management purposes. Currently, the main focus is on cattle, because in large groups (poultry), recording of individuals is expensive and the existence of social networks is uncertain due to on-farm restrictions. However, in many cases, a stable social network might be important to individual animal fitness, survival and welfare. For instance, when laying hens are not too densely housed, simple networks may be established. We describe here small social networks in horses, brown bears, laying hens and veal calves to illustrate the importance of measuring social networks among animals managed by humans. Emphasis is placed on the automatic measurement of identity, location, nearest neighbors and nearest neighbor distance for management purposes. It is concluded that social networks are important to the welfare of human-managed animal species and that welfare management based on automatic recordings will become available in the near future. PMID- 26479887 TI - Environmental and Anthropogenic Impacts on Avifaunal Assemblages in an Urban Parkland, 1976 to 2007. AB - Urban environments are unique, rapidly changing habitats in which almost half of the world's human population resides. The effects of urbanisation, such as habitat (vegetation) removal, pollution and modification of natural areas, commonly cause biodiversity loss. Long-term ecological monitoring of urban environments is vital to determine the composition and long-term trends of faunal communities. This paper provides a detailed view of long-term changes in avifaunal assemblages of the Adelaide City parklands and discusses the anthropogenic and environmental factors that contributed to the changes between 1976 and 2007. The Adelaide City parklands (ACP) comprise 760 ha of land surrounding Adelaide's central business district. Naturalist Robert Whatmough completed a 32-year survey of the ACP to determine the structure of the urban bird community residing there. Annual species richness and the abundance of birds in March and September months were analysed. Linear regression analysis was applied to species richness and abundance data of each assemblage. Resident parkland birds demonstrated significant declines in abundance. Native and introduced species also exhibited long-term declines in species richness and abundance throughout the 32-year period. Cycles of varying time periods indicated fluctuations in avian biodiversity demonstrating the need for future monitoring and statistical analyses on bird communities in the Adelaide City parklands. PMID- 26479888 TI - Interaction between gut immunity and polysaccharides. AB - The human gut is colonized with a vast and diverse microbial ecosystem, and these bacteria play fundamental roles in the well being of our bodies. Gut-associated lymphoid tissues, the largest mucosal immune system, should never be overlooked for their profound effect in maintaining the host immunity. Therefore, we discussed the relationship between gut immunity and host health, primarily from two aspects: the homeostasis of gut microbiota, and the function of gut associated lymphoid tissues. Polysaccharides, widely concerned as bioactive macromolecules in recent centuries, have been proved to benefit the intestinal health. Dietary polysaccharides can improve the ratio of probiotics, regulate the intestinal microenvironment like decreasing the gut pH, and stimulate the macrophages or lymphocytes in gut tissues to fight against diseases like cancer. Based on various experimental and clinical evidence, the impacts of dietary polysaccharides on intestinal health are summarized, in order to reveal the possible immunomodulatory mechanisms of polysaccharides. PMID- 26479889 TI - Conditional survival in patients with chronic myeloid leukemia in chronic phase in the era of tyrosine kinase inhibitors. AB - BACKGROUND: Tyrosine kinase inhibitors (TKIs) significantly improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). Conditional probability provides survival information in patients who have already survived for a specific period of time after treatment. METHODS: Cumulative response and survival data from 6 consecutive frontline TKI clinical trials were analyzed. Conditional probability was calculated for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS) according to depth of response within 1 year of the initiation of TKIs, including complete cytogenetic response, major molecular response, and molecular response with a 4-log or 4.5-log reduction. RESULTS: A total of 483 patients with a median follow-up of 99.4 months from the initiation of treatment with TKIs were analyzed. Conditional probabilities of FFS, TFS, EFS, and OS for 1 additional year for patients alive after 12 months of therapy ranged from 92.0% to 99.1%, 98.5% to 100%, 96.2% to 99.6%, and 96.8% to 99.7%, respectively. Conditional FFS for 1 additional year did not improve with a deeper response each year. Conditional probabilities of TFS, EFS, and OS for 1 additional year were maintained at >95% during the period. CONCLUSIONS: In the era of TKIs, patients with chronic myeloid leukemia in chronic phase who survived for a certain number of years maintained excellent clinical outcomes in each age group. Cancer 2016;122:238-248. (c) 2015 American Cancer Society. PMID- 26479890 TI - Erythropoietin concentration in acute kidney injury is associated with insulin like growth factor-binding protein-1. AB - AIM: Erythropoietin (EPO) production is stimulated by hypoxia in the kidney. Ischaemic injury plays a crucial role in the pathogenesis of acute kidney injury (AKI). However, EPO concentrations in critically ill patients complicated with AKI have not been evaluated sufficiently. This study was conducted to clarify the factors associated with plasma EPO concentrations in AKI. METHODS: This study prospectively enrolled 98 critically ill adult patients treated at the adult mixed ICU. Plasma EPO, insulin-like growth factor-binding protein-1 (IGFBP-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-6 (IL-6) and urinary N-acetyl-beta-D-glucosaminidase (NAG) were measured on ICU admission. RESULTS: Acute kidney injury occurred in 42 (42.9%) patients. Significantly higher plasma EPO in the AKI group was detected than in the non-AKI group (16.13 (9.87-28.47) mIU/mL versus 27.81 (10.16-106.02) mIU/mL, P < 0.05). Plasma IGFBP-1 in the AKI group was also significantly higher than in the non-AKI group (19 208 (8820-50 780) pg/mL versus 63 199 (25 289-147 489) pg/mL, P < 0.05). Plasma EPO concentration was negatively correlated with haemoglobin in the non-AKI group with statistical significance, but not in the AKI group. Multiple logistic regression analysis revealed that plasma EPO in the AKI group was associated significantly with plasma IGFBP-1 and complication of diabetes mellitus, but not the haemoglobin concentration, partial pressure of arterial oxygen (PaO2 ), and IL-6. CONCLUSIONS: Not low arterial oxygen tension, haemoglobin concentration, and inflammation evaluated by IL-6 but plasma IGFBP-1 was significantly associated with plasma EPO concentration in AKI, suggesting an unknown mechanism related to systemic stress conditions for EPO regulation in AKI. PMID- 26479891 TI - Structure Sensitivity of the Oxygen Evolution Reaction Catalyzed by Cobalt(II,III) Oxide. AB - Quantum chemical calculations and simulated kinetics were used to examine the structure sensitivity of the oxygen evolution reaction on several surface terminations of Co3O4. Active sites consisting of two adjacent Co(IV) cations connected by bridging oxos were identified on both the (001) and (311) surfaces. Formation of the O-O bond proceeds on these sites by nucleophilic attack of water on a bridging oxo. It was found that the relative turnover frequencies for the different sites are highly dependent on the overpotential, with the dual-Co site on the (311) surface being most active at medium overpotentials (0.46-0.77 V), where O-O bond formation by water addition is rate limiting. A similar dual-Co site on the (001) surface is most active at low overpotentials (<0.46 V), where O2 release is rate limiting, and a single-Co site on the (110) surface is most active at overpotentials that are high enough (>0.77 V) to form a significant concentration of highly reactive terminal Co(V)?O species. Two overpotential dependent Sabatier relationships were identified based on the Bronsted basicity and redox potential of the active site, explaining the change in the active site with overpotential. The (311) dual-Co site that is most active in the medium overpotential range is consistent with recent experimental observations suggesting that a defect site is responsible for the observed oxygen evolution activity and that a modest concentration of superoxo intermediates is present on the surface. Importantly, we find that it is essential to consider the kinetics of the water addition and O2 release steps rather than only the thermodynamics. PMID- 26479892 TI - Definitions in hemophilia: resolved and unresolved issues. AB - Definitions of clinical events and end points of care are important for disease characterization as well as documentation of outcomes in clinical practice and trials. Until recently, the only definitions in hemophilia that were provided through an international scientific organization related to disease severity and levels of inhibitors. Recently, the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis, through its Factor VIII and IX subcommittee, published consensus definitions for several other aspects of hemophilia management, including classification of disease severity; inhibitors; bleeding (and rebleeding) into muscles and joints; target joints; different forms of factor replacement therapy; and response to therapy for joint bleeding and surgical hemostasis. These definitions should help to bring greater uniformity in the documentation of critical clinical events and laboratory data that are reported both from clinical trials as well as real-world practice. This article describes these definitions in greater detail than the SSC short report and also addresses some of the unresolved issues. Wide dissemination of these concepts and definitions and their acceptance by relevant leading scientific societies, drug regulators, industry, and patient organizations will go a long way in ensuring their acceptance and use globally. PMID- 26479893 TI - Imaging evaluation of hemophilia: musculoskeletal approach. AB - Imaging assessment is an important tool to evaluate clinical joint outcomes of hemophilia. Arthropathic changes have traditionally been evaluated by plain radiography and more recently by ultrasound and magnetic resonance imaging (MRI). Early arthropathic changes can be identified by modern imaging techniques such as T2 mapping MRI of cartilage even before clinical symptoms become apparent. Cross sectional imaging modalities such as CT, ultrasonography, and MRI are useful in assessing bleeding-related musculoskeletal complications such as pseudotumors that still exist in some parts of the world. This article provides an overview of imaging of hemophilic arthropathy, and discusses the role and scope of individual imaging modalities currently in use in clinical practice, as well as of promising techniques that require further investigation in the immediate future. PMID- 26479894 TI - Meeting Report: 18th International Meeting of the Danubian League against Thrombosis and Haemorrhagic Disorders. PMID- 26479895 TI - Assessment of clotting factor concentrates--pivotal studies and long-term requirements. AB - Assessment of quality in terms of safety and efficacy of clotting factor concentrates (CFCs) is very important for all new therapeutic products. In rare diseases this is often complicated due to small number of trial participants. In hemophilia, an extra complication is the large impact previous treatments have on both the risk on inhibitors and the overall response to bleedings. For new CFCs, safety needs to be evaluated against inhibitor risk whereas efficacy is primarily judged against the most common clinical manifestations of the disease, namely, bleeding into joints and muscles. In this article the challenges are described for hemophilia that recruits patients globally. Recommendations of ISTH are discussed; these propose to substitute the single-arm prelicensure study with a two-stage approach, which considers epidemic and endemic incidence rate, and might increase the feasibility of studying multiple new products in populations with rare disease without compromising the assessment of product safety and efficacy. We also suggest that the annual bleeding rate (ABR) is an unreliable predictor of efficacy. The response to treatment highly depends on the current disease status of every patient participating in a clinical trial. The phenotype of patients with hemophilia is highly influenced by previous treatment history. Patients with severe hemophilia of the same age can demonstrate a different response to treatment. PMID- 26479896 TI - Emotional health across the transition to first and second unions among emerging adults. AB - The link between romantic relationships and emotional health has been extensively examined and suggests that marriage provides more emotional health benefits than cohabiting or dating relationships. However, the contemporary context of intimate relationships has changed and these associations warrant reexamination among emerging adults in the 2000s. We examined the change in emotional health across the entrance into first and second unions, including cohabiting unions, direct marriage (marriage without premarital cohabitation), and marriage preceded by cohabitation. Using the National Longitudinal Survey of Youth, 1997, a nationally representative panel study of youth born between 1980 and 1984 in the United States, pooled fixed-effects regression models indicated that entrance into first cohabiting unions and direct marriages, and all second unions, were significantly associated with reduced emotional distress. Gender differences were found for first unions only; for men, only direct marriage was associated with an emotional health benefit, while both direct marriage and cohabitation benefited women's emotional health. PMID- 26479897 TI - Quantitative analysis of pesticide residues in vegetables and fruits by liquid chromatography quadrupole time-of-flight mass spectrometry. AB - The applicability of liquid chromatography coupled to hybrid quadrupole time-of flight mass spectrometry (LC-QTOF-MS) for the quantitative analysis of pesticide residues in vegetables and fruits was demonstrated. The LC-QTOF-MS parameters, such as cone voltage, capillary voltage, collision energy and mass extraction window, were carefully optimised for the analysis of pesticide residues. The LC QTOF-MS method was validated for 149 pesticides in four vegetables and fruits, i.e. apple, potato, cabbage and spinach, at a spiking level of 0.01 mg kg(-1). The samples were prepared according to the Japanese official multi-residue method with a modification to the column clean-up procedure. Of the 149 pesticides, recoveries in the range of 70-120% were achieved for 147 pesticides in apple, 145 in potato, 141 in cabbage and 131 in spinach, with intra-day precisions (RSDs) of < 25% and inter-day precisions (RSDs) of < 30%, which are within the acceptable range given in the Japanese method validation guideline. Matrix effects were negligible for the majority of the target pesticides. Except for spiroxamine in spinach, no interfering peaks were observed in the blank samples. The target pesticides, except those with low sensitivity, achieved calibration curves with satisfactory linearity, with correlation coefficients (r) greater than 0.995 in the concentration range of 0.002-0.1 MUg ml(-1). Furthermore, the majority of the target pesticides provided more than one fragment ion or isotope ion that could be used for confirmation. The overall results suggest that LC-QTOF-MS is a powerful tool for the quantification of pesticide residues in vegetables and fruits at the level of 0.01 mg kg(-1). PMID- 26479898 TI - Sulfasalazine-induced renal injury in rats and the protective role of thiol reductants. AB - Sulfasalazine is widely used for inflammatory-mediated disorders in human. Renal damage is a serious adverse effect accompanied sulfasalazine administration. No specific therapeutic option is available against this complication so far. Oxidative stress seems to play a role in sulfasalazine-induced renal injury. Current investigation was designed to evaluate the effect of N-acetyl cysteine (NAC) and dithiothreitol (DTT) as thiol reductants against sulfasalazine-induced renal injury in rats. Oral administration of sulfasalazine (600 mg/kg for 14 consecutive days) caused renal injury as judged by increase in serum level of creatinine and blood urea nitrogen. Furthermore, the level of reactive oxygen species and lipid peroxidation were raised in kidney tissue after sulfasalazine administration. Additionally, it was also found that renal glutathione reservoirs were significantly depleted in sulfasalazine-treated animals. Histopathological examination of kidney endorsed organ injury in drug-treated rats. Daily intraperitoneal administration of NAC (250 and 500 mg/kg/day) and/or DTT (15 and 30 mg/kg/day) effectively alleviated renal damage induced by sulfasalazine. Data suggested that thiol reductants could serve as potential protective agents with therapeutic capabilities against sulfasalazine adverse effect toward kidney. PMID- 26479899 TI - Syntheses, Structural Characterization, and Catalytic Properties of Di- and Trinickel Polyoxometalates. AB - The syntheses, structural characterization, and catalytic properties of two different nickel-containing polyoxometalates (POMs) are presented. The dinickel containing sandwich-type POM [Ni2(P2W15O56)2](20-) (Ni2) exhibits an unusual alphaalphaalphaalpha geometry. The trinickel-containing Wells-Dawson POM [Ni3(OH)3(H2O)3P2W16O59](9-) (Ni3) shows a unique structure where the [alpha P2W15O56](12-) ligand is capped by a triangular Ni3O13 unit and a WO6 octahedron. Ni3 shows a high catalytic activity for visible-light-driven hydrogen evolution, while the activity for Ni2 is minimal. An analysis of the structures of multinickel-containing POMs and their hydrogen evolution activity is given. PMID- 26479900 TI - Two nematicidal furocoumarins from Ficus carica L. leaves and their physiological effects on pine wood nematode (Bursaphelenchus xylophilus). AB - The ethanol extract of the Ficus carica L. leaves was tested to show strong nematicidal activity against pine wood nematode (PWN), Bursaphelenchus xylophilus, causing 90.93% corrected mortality within 72 h at 1.0 mg/mL. From the ethyl acetate soluble fraction of the F. carica L. leaves extract, the main nematicidal constituents were obtained by bioassay-guided isolation and identified as linear furocoumarins bergapten (1) and psoralen (2) by mass and NMR spectral data analysis. Bergapten and psoralen had significant nematicidal activity against PWN with the LC50 values of 97.08 aKSnd 115.03 MU g/mL within 72 h, respectively. The two furocoumarins could inhibit the activities of amylase, cellulase and acetylcholinesterase (AchE) from PWN. The morphologies of PWNs changed much after they were treated by bergapten and psoralen. The physiological effects of bergapten and psoralen on PWN might provide helpful clues to elucidate their nematicidal mechanisms. PMID- 26479901 TI - Novel Vaccine Candidates against Brucella melitensis Identified through Reverse Vaccinology Approach. AB - Global health therapeutics is a rapidly emerging facet of postgenomics medicine. In this connection, Brucella melitensis is an intracellular bacterium that causes the zoonotic infectious disease, brucellosis. Presently, no licensed vaccines are available for human brucellosis. Here, we report the identification of potential vaccine candidates against B. melitensis using a reverse vaccinology approach. Based on a systematic screening of exoproteome and secretome of B. melitensis 16 M, we identified eight proteins as potential vaccine candidates, including LPS assembly protein LptD, a polysaccharide export protein, a cell surface protein, heme transporter BhuA, flagellin FliC, 7-alpha-hydroxysteroid dehydrogenase, immunoglobulin-binding protein EIBE, and hemagglutinin. Among these, the roles of BhuA and hemagglutinin in the virulence of Brucella are essential to establish infection. Roles of other proteins in the virulence are yet to be studied. Prediction of protein-protein interactions revealed that these proteins can interact with other proteins involved in virulence, secretion system, metabolism, and transport. From these eight potential vaccine candidates, we predicted three surface exposed novel antigenic epitopes that can induce both B-cell and T-cell immune responses. These peptides can be used for the development of either exclusive peptide vaccines or multi-component vaccines against human brucellosis. Reverse vaccinology is an important strategy for discovery of novel global health therapeutics. PMID- 26479902 TI - Control processes through the suppression of the automatic response activation triggered by task-irrelevant information in the Simon-type tasks. AB - The congruency sequence effect, one of the indices of cognitive control, refers to a smaller congruency effect after an incongruent than congruent trial. Although the effect has been found across a variety of conflict tasks, there is not yet agreement on the underlying mechanism. The present study investigated the mechanism underlying cognitive control by using a cross-task paradigm. In Experiments 1, 2, and 3, participants performed a modified Simon task and a spatial Stroop task alternately in a trial-by-trial manner. The task-irrelevant dimension of the two tasks was perceptually and conceptually identical in Experiment 1, whereas it was perceptually different but conceptually identical in Experiment 2. The response sets for both tasks were different in Experiment 3. In Experiment 4, participants performed two Simon tasks with different task-relevant dimensions. In all experiments in which the task-irrelevant dimension and response mode were shared, significant congruency sequence effects were found between the two different congruencies, indicating that Simon-type conflicts were resolved by a control mechanism, which is specific to an abstract task-irrelevant stimulus spatial dimension. PMID- 26479903 TI - Effect of Pressure on Valence and Structural Properties of YbFe2Ge2 Heavy Fermion Compound--A Combined Inelastic X-ray Spectroscopy, X-ray Diffraction, and Theoretical Investigation. AB - The crystal structure and the Yb valence of the YbFe2Ge2 heavy fermion compound was measured at room temperature and under high pressures using high-pressure powder X-ray diffraction and X-ray absorption spectroscopy via both partial fluorescence yield and resonant inelastic X-ray emission techniques. The measurements are complemented by first-principles density functional theoretical calculations using the self-interaction corrected local spin density approximation investigating in particular the magnetic structure and the Yb valence. While the ThCr2Si2-type tetragonal (I4/mmm) structure is stable up to 53 GPa, the X-ray emission results show an increase of the Yb valence from v = 2.72(2) at ambient pressure to v = 2.93(3) at ~9 GPa, where at low temperature a pressure-induced quantum critical state was reported. PMID- 26479904 TI - Optimizing clinical outcomes of transcatheter aortic valve implantation patients with comorbidities. AB - Transcatheter aortic valve implantation (TAVI) has revolutionized the management of high-risk or inoperable patients presenting with symptomatic severe aortic stenosis (AS). There are several factors to consider to optimize patient outcomes from TAVI. Before TAVI, patient selection is key and an understanding the effects of common comorbidities on outcomes after TAVI is critical. Some comorbidities share common risk factors with AS (e.g. coronary artery disease), others are directly or indirectly caused or exacerbated by severe AS (e.g. atrial fibrillation, pulmonary hypertension, mitral regurgitation, tricuspid regurgitation and right ventricular dysfunction), whereas others are not directly related to severe AS (e.g. chronic kidney disease and chronic lung disease). Choice of transcatheter heart valve prosthesis, vascular access route and mode of anesthesia are important considerations during TAVI. New onset conduction disturbances and arrhythmias remain a vexing issue after TAVI. The aim of the present review is to provide an overview of these issues. PMID- 26479905 TI - Polymerase chain reaction-free detection of hepatitis B virus DNA using a nanostructured impedance biosensor. AB - A polymerase chain reaction (PCR)-free technique for the effective detection of genomic length hepatitis B virus (HBV) DNA is described in this study. The honeycomb-like barrier layer of an anodic aluminum oxide (AAO) film having a uniform nanohemisphere array was used as the substrate of the sensing electrode. A 30-nm gold film was sputtered onto the AAO barrier layer surface as the electrode, followed by electrochemical deposition of gold nanoparticles (GNPs) on the hemisphere surface. A specially designed single-strand 96-mer gene fragment of the target genomic DNA of HBV based on the genome sequences of HBV was immobilized on the nanostructured electrode as the capture probe. Target HBV DNA obtained from clinical samples was hybridized to the sensing probes. Detection results illustrate two dynamic linear ranges, 10(2)-10(3) and 10(3)-10(5.1) copies/mL, having R(2) values of 0.801 and 0.996 could be obtained, respectively. The detection limit of the proposed sending scheme was measured to be 111 copies/mL. The total of 45 target samples, including 20 samples with HBV concentration being lower than 10(2) copies/mL and 25 samples with HBV concentration being in the range of 10(3)-10(5.1) copies/mL, were used for real test. The concentration of these 45 HBV DNA samples was measured by the COBAS Ampliprep system. Comparing the measured results of the COBAS Ampliprep and our system, it was illustrated that the HBV DNA concentrations measured by the proposed method in this study had a high linear correlation with the COBAS Ampliprep, having R(2) values of 0.983. The proposed sensing scheme is highly feasible for future clinical applications. PMID- 26479906 TI - A G-pentaplex-based assay for Cs(+) ions in aqueous solution using a luminescent Ir(III) complex. AB - A series of 5 randomly designed in-house cyclometalated Ir(III) complexes were examined for their application in G-pentaplex probes and the "proof-of-principle" concept in G-pentaplex-based Cs(+) ions detection. The G-pentaplex-forming sequence (DNA1, 5'-T(iG)4T-3', where iG=isoguanine) is present in single strand DNA form ab initio, however, the addition of Cs(+) ions lead to formation of the intermolecular G-pentaplex structure which is identified by the novel Ir(III) complex 1 afterward and produce an enhanced luminescence signal for Cs(+) ions monitoring. To the best of our knowledge, this is the first G-pentaplex probe and also the first G-pentaplex-based label-free detection platform for Cs(+) ions reported in the literature. The monitoring of spiked Cs(+) ions in natural water samples demonstrates the potential application and technical sound of this "proof of-principle" concept sensing platform. PMID- 26479907 TI - Productivity and carbon footprint of perennial grass-forage legume intercropping strategies with high or low nitrogen fertilizer input. AB - A three-season field experiment was established and repeated twice with spring barley used as cover crop for different perennial grass-legume intercrops followed by a full year pasture cropping and winter wheat after sward incorporation. Two fertilization regimes were applied with plots fertilized with either a high or a low rate of mineral nitrogen (N) fertilizer. Life cycle assessment (LCA) was used to evaluate the carbon footprint (global warming potential) of the grassland management including measured nitrous oxide (N2O) emissions after sward incorporation. Without applying any mineral N fertilizer, the forage legume pure stand, especially red clover, was able to produce about 15 t above ground dry matter ha(-1) year(-1) saving around 325 kg mineral Nfertilizer ha(-1) compared to the cocksfoot and tall fescue grass treatments. The pure stand ryegrass yielded around 3t DM more than red clover in the high fertilizer treatment. Nitrous oxide emissions were highest in the treatments containing legumes. The LCA showed that the low input N systems had markedly lower carbon footprint values than crops from the high N input system with the pure stand legumes without N fertilization having the lowest carbon footprint. Thus, a reduction in N fertilizer application rates in the low input systems offsets increased N2O emissions after forage legume treatments compared to grass plots due to the N fertilizer production-related emissions. When including the subsequent wheat yield in the total aboveground production across the three season rotation, the pure stand red clover without N application and pure stand ryegrass treatments with the highest N input equalled. The present study illustrate how leguminous biological nitrogen fixation (BNF) represents an important low impact renewable N source without reducing crop yields and thereby farmers earnings. PMID- 26479908 TI - Concentrations and potential health risks of methyl tertiary-butyl ether (MTBE) in air and drinking water from Nanning, South China. AB - Levels of methyl tertiary-butyl ether (MTBE) in occupational air, ambient air, and drinking water in Nanning, South China, were investigated, and then their potential health risks to occupational workers and the general public were evaluated. Results show that the MTBE concentration in occupational air from 13 service stations was significantly higher than that in ambient air from residential areas (p<0.0001); both are far lower than the threshold limit value time weighted average of MTBE regulated in the United States (US). The drinking water samples from household taps yielded detectable MTBE in the range of 0.04 0.33 MUg/L, which is below the US drinking water standard of 20-40 MUg/L. The non carcinogenic risk of MTBE from air inhalation may be negligible because the calculated hazard quotient was less than 1. The mean MTBE lifetime cancer risk was within the acceptable limit of 1 * 10(-6) to 1 * 10(-4), but the lifetime cancer risk of refueling workers in the urban service station at the 95th percentile slightly exceeded the maximum acceptable carcinogen risk (1 * 10(-4)), indicating the potential carcinogenic health effects on the population highly exposed to MTBE in this region. The hazard index and carcinogenic risk of MTBE in drinking water were significantly lower than the safe limit of US Environmental Protection Agency, suggesting that drinking water unlikely poses significant health risks to the residents in Nanning. PMID- 26479909 TI - Temporal trends of persistent organic pollutants in dated sediment cores: Chemical fingerprinting of the anthropogenic impacts in the Seine River basin, Paris. AB - Persistent organic pollutants (POPs) were extensively produced and used throughout the last century. In the early 1980s, a rising concern on the environmental impact of these chemicals has led to the establishment of regulations and changes of use including bans. Long term monitoring of the environmental impacts of these emissions and regulations is a challenge because regular monitoring was not mandatory at the beginning of the first emissions. Moreover, the analytical methods have been strongly improved over the decades. To overcome the lack of monitoring and accurate data, sediment cores are powerful tools to construct contamination records. In this study, a high resolution record was constructed for four POPs families (13 polycyclic aromatic hydrocarbons (PAHs), 15 polychlorinated biphenyls (PCBs), 3 alkylphenols (APs) and 8 polybromodiphenyl ethers (PBDEs)) to establish their historical trends in a long term urbanized and industrialized environment: the Seine River basin, France. These specific families were selected because they had different sources, uses and histories. The results showed concentrations up to 90 mg/kg for ?PAHs, 2.3mg/kg for ?PCB, 1.2mg/kg for ?APs and 0.06 mg/kg for ?PBDE. The vertical distribution profiles were different from one family to another and presented a good correlation with uses (e.g. transition from coal to natural gas for PAHs), and regulation implementation (e.g., AP ban after "OSPAR Convention" in 1992). The study of compounds distribution provided original information on sources, e.g. temporal variations in PAH uses. This study demonstrates the usefulness and accuracy of sedimentary archives in floodplain to assess the fate of POPs through time in continental hydrosystems. These first results give a comprehensive overview of the contamination in the Seine River basin downstream of Paris Megacity. They were in good agreement with previous studies dedicated to European areas and highlighted specificities of this basin that were not reported before. PMID- 26479910 TI - Microbial responses to polycyclic aromatic hydrocarbon contamination in temporary river sediments: Experimental insights. AB - Temporary rivers are characterized by dry-wet phases and represent an important water resource in semi-arid regions worldwide. The fate and effect of contaminants have not been firmly established in temporary rivers such as in other aquatic environments. In this study, we assessed the effects of sediment amendment with Polycyclic Aromatic Hydrocarbons (PAHs) on benthic microbial communities. Experimental microcosms containing natural (Control) and amended sediments (2 and 20 mg PAHs kg(-1) were incubated for 28 days. The PAH concentrations in sediments were monitored weekly together with microbial community structural (biomass and phylogenetic composition by TGGE and CARD-FISH) and functional parameters (ATP concentration, community respiration rate, bacterial carbon production rate, extracellular enzyme activities). The concentration of the PAH isomers did not change significantly with the exception of phenanthrene. No changes were observed in the TGGE profiles, whereas the occurrence of Alpha- and Beta-Proteobacteria was significantly affected by the treatments. In the amended sediments, the rates of carbon production were stimulated together with aminopeptidase enzyme activity. The community respiration rates showed values significantly lower than the Control after 1 day from the amendment then recovering the Control values during the incubation. A negative trend between the respiration rates and ATP concentration was observed only in the amended sediments. This result indicates a potential toxic effect on the oxidative phosphorylation processes. The impoverishment of the energetic resources that follows the PAH impact may act as a domino on the flux of energy from prokaryotes to the upper level of the trophic chain, with the potential to alter the temporary river functioning. PMID- 26479911 TI - Exploring the potential of novel biomixtures and Lentinula edodes fungus for the degradation of selected pesticides. Evaluation for use in biobed systems. AB - An approach to reduce the contamination of water sources with pesticides is the use of biopurificaction systems. The active core of these systems is the biomixture. The composition of biomixtures depends on the availability of local agro-industrial wastes and design should be adapted to every region. In Portugal, cork processing is generally regarded as environmentally friendly and would be interesting to find applications for its industry residues. In this work the potential use of different substrates in biomixtures, as cork (CBX); cork and straw, coat pine and LECA (Light Expanded Clay Aggregates), was tested on the degradation of terbuthylazine, difenoconazole, diflufenican and pendimethalin pesticides. Bioaugmentation strategies using the white-rot fungus Lentinula edodes inoculated into the CBX, was also assessed. The results obtained from this study clearly demonstrated the relevance of using natural biosorbents as cork residues to increase the capacity of pesticide dissipation in biomixtures for establishing biobeds. Furthermore, higher degradation of all the pesticides was achieved by use of bioaugmented biomixtures. Indeed, the biomixtures inoculated with L. edodes EL1 were able to mineralize the selected xenobiotics, revelling that these white-rot fungi might be a suitable fungus for being used as inoculum sources in on-farm sustainable biopurification system, in order to increase its degradation efficiency. After 120 days, maximum degradation of terbuthylazine, difenoconazole, diflufenican and pendimethalin, of bioaugmented CBX, was 89.9%, 75.0%, 65.0% and 99.4%, respectively.. The dominant metabolic route of terbuthylazine in biomixtures inoculated with L. edodes EL1 proceeded mainly via hydroxylation, towards production of terbuthylazine-hydroxy-2 metabolite. Finally, sorption process to cork by pesticides proved to be a reversible process, working cork as a mitigating factor reducing the toxicity to microorganisms in the biomixture, especially in the early stages. PMID- 26479912 TI - Spatial and temporal variability of river periphyton below a hypereutrophic lake and a series of dams. AB - Klamath River is described as an "upside-down" river due to its origins from the hypereutrophic Upper Klamath Lake (UKL) and hydrology that is heavily regulated by upstream dams. Understanding the lake and reservoir effects on benthic communities in the river can inform important aspects of its water quality dynamics. Periphyton samples were collected in May-November from 2004, 2006-2013 at nine long-term monitoring sites along 306 river km below UKL and a series of dams (n=299). Cluster analysis of periphyton assemblages identified three statistically different periphyton groups (denoted Groups 1-3). Group 1 occurred primarily in the upstream reach for June-October and had a higher percentage of sestonic species, including the cyanobacteria Aphanizomenon flos-aquae and Microcystis aeruginosa, consistent with the presence of upstream reservoirs. Group 2 had the highest relative biomass of diatoms and lowest relative biomass of cyanobacteria. Sites in the lower reach of the Klamath River fell into Group 2 in May-June and transitioning into Group 3 for July-October. Group 3 was dominated by nitrogen (N)-fixing species, including three diatoms (Epithemia sorex, Epithemia turgida, and Rhopalodia gibba) with cyanobacterial endosymbionts and the cyanobacterium Calothrix sp. Periphyton assemblages were strongly associated with temporal variations in flow conditions (e.g., decreasing flow from spring to fall) and spatial gradients in nutrient concentrations (e.g., decreasing from upstream to downstream). The inverse longitudinal relationship between periphyton biomass and nutrients may be explained by the ability of benthic N-fixers (Group 3) to overcome N limitation. Overall results showed a strong inverse relationship between the relative biomass of N-fixers and nitrogen concentrations and flow. This long-term dataset provides valuable insight into Klamath River's seasonal and longitudinal patterns of benthic algal communities and associated environmental variables. Our findings can inform river management decisions such as reducing upstream nutrient loads, setting flow regimes, and potential dam removals. PMID- 26479913 TI - Utility of Bayesian networks in QMRA-based evaluation of risk reduction options for recycled water. AB - BACKGROUND: Quantitative microbial risk assessment (QMRA), the current method of choice for evaluating human health risks associated with disease-causing microorganisms, is often constrained by issues such as availability of required data, and inability to incorporate the multitude of factors influencing risk. Bayesian networks (BNs), with their ability to handle data paucity, combine quantitative and qualitative information including expert opinions, and ability to offer a systems approach to characterisation of complexity, are increasingly recognised as a powerful, flexible tool that overcomes these limitations. OBJECTIVES: We present a QMRA expressed as a Bayesian network (BN) in a wastewater reuse context, with the objective of demonstrating the utility of the BN method in health risk assessments, particularly for evaluating a range of exposure and risk mitigation scenarios. As a case study, we examine the risk of norovirus infection associated with wastewater-irrigated lettuce. METHODS: A Bayesian network was developed following a QMRA approach, using published data, and reviewed by domain experts using a participatory process. DISCUSSION: Employment of a BN facilitated rapid scenario evaluations, risk minimisation, and predictive comparisons. The BN supported exploration of conditions required for optimal outcomes, as well as investigation of the effect on the reporting nodes of changes in 'upstream' conditions. A significant finding was the indication that if maximum post-treatment risk mitigation measures were implemented, there was a high probability (0.84) of a low risk of infection regardless of fluctuations in other variables, including norovirus concentration in treated wastewater. CONCLUSION: BNs are useful in situations where insufficient empirical data exist to satisfy QMRA requirements and they are exceptionally suited to the integration of risk assessment and risk management in the QMRA context. They allow a comprehensive visual appraisal of major influences in exposure pathways, and rapid interactive risk assessment in multifaceted water reuse scenarios. PMID- 26479914 TI - Air pollution monitoring using emission inventories combined with the moss bag approach. AB - Inventory of emission sources and biomonitoring with moss transplants are two different methods to evaluate air pollution. In this study, for the first time, both these approaches were simultaneously applied in five municipalities in Campania (southern Italy), deserving attention for health-oriented interventions as part of a National Interest Priority Site. The pollutants covered by the inventory were CO, NOx, particulate matter (PM10), volatile organic compounds (VOCs), and some heavy metals (As, Cd, Cr, Cu, Hg, Ni, Pb, Se, and Zn). The biomonitoring survey was based on the use of the devitalized moss Hypnum cupressiforme transplanted into bags, following a harmonized protocol. The exposure covered 40 agricultural and urban/residential sites, with half of them located in proximity to roads. The pollutants monitored were Al, As, Cd, Cr, Cu, Fe, Hg, Ni, Pb, Se, and Zn, as well as total polycyclic aromatic hydrocarbons (PAHs) only in five sites. Using the emission inventory approach, high emission loads were detected for all the major air pollutants and the following heavy metals: Cr, Cu, Ni, Pb and Zn, over the entire study area. Arsenic, Pb, and Zn were the elements most accumulated by moss. Total PAH postexposure contents were higher than the preexposure values (~20-50% of initial value). Moss uptakes did not differ substantially among municipalities or within exposure sites. In the five municipalities, a similar spatial pattern was evidenced for Pb by emission inventory and moss accumulation. Both approaches indicated the same most polluted municipality, suggesting their combined use as a valuable resource to reveal contaminants that are not routinely monitored. PMID- 26479915 TI - Impact of human interventions on nutrient biogeochemistry in the Pamba River, Kerala, India. AB - Anthropogenic inputs nowadays are the major source of nutrients to the coastal area. While a wealth of data exists from high latitude regions, little is known on the amount and composition of nutrient fluxes from densely populated tropical catchments. The South Indian Pamba River is a prime example in this respect because of its manifold human interventions such as the Sabarimala pilgrimage, the largest pilgrim centre in the world and agricultural practices. In order (i) to identify direct cause-effect relationships, (ii) to quantify land use specific nutrient inputs and (iii) to assess the respective impacts water was sampled along the river course during the pre monsoon, south west monsoon and north east monsoon periods in 2010 to 2012. Sampling segments were chosen according to prevailing land use. A socioeconomic survey on agricultural practices was conducted to collect information on the type, time and quantity of fertilizer application. Our results indicate (i) little human activities in the forest segment resulted in a low nutrient yield; (ii) pilgrim activities led to high ammonium and phosphate yields in the temple segment; (iii) specific fertilizer management resulted in moderate and maximum nitrate yields in the respective agriculture segments. Annual NPK fertilizer inputs to the catchment were 95 kg ha(-1) yr(-1).The average yield for the Pamba River catchment amounted to 3.5 kg ha(-1) yr(-1) of DIN and 0.2 kg ha(-1) yr(-1) of phosphate-P. As opposing predictions for densely-populated regions the N and P yields of the Pamba River are moderate to low on a global scale. It highlights the need for land use specific quantitative estimates from tropical regions in order to improve the global database and local water quality management. PMID- 26479916 TI - Comparative study of the effect of pharmaceutical additives on the elimination of antibiotic activity during the treatment of oxacillin in water by the photo Fenton, TiO2-photocatalysis and electrochemical processes. AB - Synthetic pharmaceutical effluents loaded with the beta-lactam antibiotic oxacillin were treated using advanced oxidation processes (the photo-Fenton system and TiO2 photocatalysis) and chloride mediated electrochemical oxidation (with Ti/IrO2 anodes). Combinations of the antibiotic with excipients (mannitol or tartaric acid), an active ingredient (calcium carbonate, i.e. bicarbonate ions due to the pH) and a cleaning agent (sodium lauryl ether sulfate) were considered. Additionally, urban wastewater that had undergone biological treatment was doped with oxacillin and treated with the tested systems. The evolution of antimicrobial activity was monitored as a parameter of processes efficiency. Although the two advanced oxidation processes (AOPs) differ only in the way they produce OH, marked differences were observed between them. There were also differences between the AOPs and the electrochemical system. Interestingly, each additive had a different effect on each treatment. For water loaded with mannitol, electrochemical treatment was the most suitable option because the additive did not significantly affect the efficiency of the system. Due to the formation of a complex with Fe(3+), tartaric acid accelerated the elimination of antibiotic activity during the photo-Fenton process. For TiO2 photocatalysis, the presence of bicarbonate ions contributed to antibiotic activity elimination through the possible formation of carbonate and bicarbonate radicals. Sodium lauryl ether sulfate negatively affected all of the processes. However, due to the higher selectivity of HOCl compared with OH, electrochemical oxidation showed the least inhibited efficiency. For the urban wastewater doped with oxacillin, TiO2 photocatalysis was the most efficient process. These results will help select the most suitable technology for the treatment of water polluted with beta-lactam antibiotics. PMID- 26479917 TI - Biotransformation of pharmaceuticals under nitrification, nitratation and heterotrophic conditions. AB - The effect of nitrification, nitratation and heterotrophic conditions on the biotransformation of several pharmaceuticals in a highly enriched nitrifying activated sludge was evaluated in this study by selective activation of ammonia oxidizing bacteria (AOB), nitrite oxidizing bacteria (NOB) and heterotrophic bacteria. Nitrifiers displayed a noticeable capacity to process ibuprofen due to hydroxylation by ammonia monooxygenase (AMO) to produce 2-hydroxy-ibuprofen. Naproxen was also biotransformed under nitrifying conditions. On the other hand, heterotrophic bacteria present in the nitrifying activated sludge (NAS) biotransformed sulfamethoxazole. In contrast, both nitrifying and heterotrophic activities were ineffective against diclofenac, diazepam, carbamazepine and trimethoprim. Similar biotransformation rates of erythromycin, roxithromycin and fluoxetine were observed under all conditions tested. Overall, results from this study give more evidence on the role of the different microbial communities present in activated sludge reactors on the biological removal of pharmaceuticals. PMID- 26479918 TI - Seasonal dynamics and long-term trend of hypoxia in the coastal zone of Emilia Romagna (NW Adriatic Sea, Italy). AB - Long-term series of meteorological, hydrological and oceanographic data were compared with hypoxia occurrence, in order to define characteristics and trends of this phenomenon in the Emilia Romagna Coastal Zone (ERCZ) in 1977-2008. During this period, hypoxia was recorded at all sampling stations, up to 20 km offshore. In winter, spring and late autumn, hypoxia appearance was matched to significant positive anomalies of air and surface seawater temperatures (up to +3.6 degrees C), whereas this effect was less pronounced in August-October. Hypoxia generally occurred with scarce precipitation (0-2 dm(3)m(2)d(-1)) and low wind velocity (0 2 ms(-1)), suggesting the importance of stable meteo-marine conditions for the onset of this phenomenon. Nevertheless, wind direction emerged as an indicator of hydrodynamic seasonal changes in the area and is thus a hypoxia regulator. In winter, spring and autumn, hypoxia was favored by large increases of biomass induced by river freshets. In contrast, summer hypoxia occurred during periods of low runoff, suggesting that pronounced stratification and weak circulation of coastal waters were more important in this season. Since the 1990s, a shift from widespread summer hypoxia to local hypoxia irregularly distributed across the year has occurred. This process was concomitant to long-term increases of air temperature (+0.14 degrees C yr(-1)), wind speed (+0.03 ms(-1) yr(-1)) and salinity (+0.09 yr(-1)), and decreases of Po River flow (-0.54 km(3) yr(-1)), oxygen saturation (-0.2% yr(-1)) and PO4(3-) (-0.004 MUmol P L(-1) yr(-1)) and NH4(+) (-0.04 MUmol N L(-1) yr(-1)) concentrations in surface coastal waters. Despite that several of these changes suggest an ERCZ trophic level positive reduction, similar to that reported for the N Adriatic, the concomitant climate warming might further exacerbate hypoxia in particularly shallow shelf locations. Therefore, in order to avoid hypoxia development a further mitigation of anthropogenic pressure is still needed in the area. PMID- 26479919 TI - Weekly variability of precipitation induced by anthropogenic aerosols: A case study in Korea in summer 2004. AB - We examine the effect of anthropogenic aerosols on the weekly variability of precipitation in Korea in summer 2004 by using Weather Research and Forecasting (WRF) and Community Multiscale Air Quality (CMAQ) models. We conduct two WRF simulations including a baseline simulation with empirically based cloud condensation nuclei (CCN) number concentrations and a sensitivity simulation with our implementation to account for the effect of aerosols on CCN number concentrations. The first simulation underestimates observed precipitation amounts, particularly in northeastern coastal areas of Korea, whereas the latter shows higher precipitation amounts that are in better agreement with the observations. In addition, the sensitivity model with the aerosol effects reproduces the observed weekly variability, particularly for precipitation frequency with a high R at 0.85, showing 20% increase of precipitation events during the weekend than those during weekdays. We find that the aerosol effect results in higher CCN number concentrations during the weekdays and a three-fold increase of the cloud water mixing ratio through enhanced condensation. As a result, the amount of warm rain is generally suppressed because of the low auto conversion process from cloud water to rain water under high aerosol conditions. The inefficient conversion, however, leads to higher vertical development of clouds in the mid-atmosphere with stronger updrafts in the sensitivity model, which increases by 21% cold-phase hydrometeors including ice, snow, and graupel relative to the baseline model and ultimately results in higher precipitation amounts in summer. PMID- 26479920 TI - Distribution and ecological risk of organic pollutants in the sediments and seafood of Yangtze Estuary and Hangzhou Bay, East China Sea. AB - A wide variety of persistent organic pollutants (POPs) in the surface marine sediments and seafood from four geographic areas of the East China Sea were investigated. The POP concentrations were analyzed and their possible ecotoxicological risks assessed. The total concentrations of hexachlorocyclohexanes (HCHs), dichlorodiphenyltrichloroethanes (DDTs), polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs) in the sediments were found to be ND-22.40, ND-5.10, 32.10-171.70, and 0.60-63.00 ng/g dry weight (dw), respectively. Low-chlorinated biphenyl congeners and HCHs were predominantly found at the Hangzhou Bay and Yangtze River areas. The sediment ecotoxicological risk was assessed, indicating the toxic effect of PCBs and DDTs on benthic organisms. In marine organisms of economic importance, the concentration of total PAHs, PCBs, and organochlorine pesticides (OCPs) ranged from 43.20 to 291.20, 2.60 to 96.20, and 12.70 to 235.20 MUg/kg dw, respectively. The bioaccumulation in marine organisms did not pose a significant health risk to consumers. As indicated by the POP residues in both marine sediments and organisms, POPs were persistent over time, posing a long-term risk to the local ecosystem and human health via the food chain. PMID- 26479921 TI - Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment, the presence of which can promote both cancer induction and growth. Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY323). This alternative p38 activation pathway is required for pro-inflammatory cytokine production. Here we show in human PDAC that a high percentage of infiltrating pY323(+) T cells was associated with large numbers of tumor necrosis factor (TNF)-alpha- and interleukin (IL)-17 producing CD4(+) tumor-infiltrating lymphocytes (TILs) and aggressive disease. The growth of mouse pancreatic tumors was inhibited by genetic ablation of the alternative p38 pathway, and transfer of wild-type CD4(+) T cells, but not those lacking the alternative pathway, enhanced tumor growth in T cell-deficient mice. Notably, a plasma membrane-permeable peptide derived from GADD45-alpha, the naturally occurring inhibitor of p38 pY323(+) (ref. 7), reduced CD4(+) TIL production of TNF-alpha, IL-17A, IL-10 and secondary cytokines, halted growth of implanted tumors and inhibited progression of spontaneous KRAS-driven adenocarcinoma in mice. Thus, TCR-mediated activation of CD4(+) TILs results in alternative p38 activation and production of protumorigenic factors and can be targeted for therapeutic benefit. PMID- 26479922 TI - Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma. AB - The skin harbors a variety of resident leukocyte subsets that must be tightly regulated to maintain immune homeostasis. Hair follicles are unique structures in the skin that contribute to skin dendritic cell homeostasis through chemokine production. We demonstrate that CD4(+) and CD8(+) skin-resident memory T cells (TRM cells), which are responsible for long-term skin immunity, reside predominantly within the hair follicle epithelium of the unperturbed epidermis. TRM cell tropism for the epidermis and follicles is herein termed epidermotropism. Hair follicle expression of IL-15 was required for CD8(+) TRM cells, and IL-7 for CD8(+) and CD4(+) TRM cells, to exert epidermotropism. A lack of either cytokine in the skin led to impaired hapten-induced contact hypersensitivity responses. In a model of cutaneous T cell lymphoma, epidermotropic CD4(+) TRM lymphoma cell localization depended on the presence of hair follicle-derived IL-7. These findings implicate hair follicle-derived cytokines as regulators of malignant and non-malignant TRM cell tissue residence, and they suggest that the cytokines may be targeted therapeutically in inflammatory skin diseases and lymphoma. PMID- 26479923 TI - High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. AB - Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ~1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 * 1 * 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses. PMID- 26479926 TI - Depolarizing differential Mueller matrix of homogeneous media under Gaussian fluctuation hypothesis. AB - In this paper, we address the issue of the existence of a solution of depolarizing differential Mueller matrix for a homogeneous medium. Such a medium is characterized by linear changes of its differential optical properties with z the thickness of the medium. We show that, under a short correlation distance assumption, it is possible to derive such linear solution, and we clarify this solution in the particular case where the random fluctuation processes associated to the optical properties are Gaussian white noise-like. A solution to the problem of noncommutativity of a previously proposed model [J. Opt. Soc. Am.30, 2196 (2013)JOSAAH0030-394110.1364/JOSAA.30.002196] is given by assuming a random permutation of the order of the layers and by averaging all the differential matrices resulting from these permutations. It is shown that the underlying assumption in this case is exactly the Gaussian white noise assumption. Finally, a recently proposed approach [Opt. Lett.39, 4470 (2014)OPLEDP0146 959210.1364/OL.39.004470] for analysis of the statistical properties related to changes in optical properties is revisited, and the experimental conditions of application of these results are specified. PMID- 26479924 TI - Cardiac RKIP induces a beneficial beta-adrenoceptor-dependent positive inotropy. AB - In heart failure therapy, it is generally assumed that attempts to produce a long term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well tolerated, persistent increase in cardiac contractility that is mediated by the beta1-adrenoceptor (beta1AR). This result is unexpected, as beta1AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the beta2AR subtype. Analogously, RKIP deficiency exaggerates pressure overload induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy. PMID- 26479927 TI - Fourier method for modeling slanted lamellar gratings of arbitrary end-surface shapes in conical mounting. AB - An efficient modal method for numerically modeling slanted lamellar gratings of isotropic dielectric or metallic media in conical mounting is presented. No restrictions are imposed on the slant angle and the length of the lamellae. The end surface of the lamellae can be arbitrary, subject to certain restrictions. An oblique coordinate system that is adapted to the slanted lamella sidewalls allows the most efficient way of representing and manipulating the electromagnetic fields. A translational coordinate system that is based on the oblique Cartesian coordinate system adapts to the end-surface profile of the lamellae, so that the latter can be handled simply and easily. Moreover, two matrix eigenvalue problems of size 2N * 2N, one for each fundamental polarization of the electromagnetic fields in the periodic lamellar structure, where N is the matrix truncation number, are derived to replace the 4N * 4N eigenvalue problem that has been used in the literature. The core idea leading to this success is the polarization decomposition of the electromagnetic fields inside the periodic lamellar region when the fields are expressed in the oblique translational coordinate system. PMID- 26479928 TI - Snapshot colored compressive spectral imager. AB - Traditional spectral imaging approaches require sensing all the voxels of a scene. Colored mosaic FPA detector-based architectures can acquire sets of the scene's spectral components, but the number of spectral planes depends directly on the number of available filters used on the FPA, which leads to reduced spatiospectral resolutions. Instead of sensing all the voxels of the scene, compressive spectral imaging (CSI) captures coded and dispersed projections of the spatiospectral source. This approach mitigates the resolution issues by exploiting optical phenomena in lenses and other elements, which, in turn, compromise the portability of the devices. This paper presents a compact snapshot colored compressive spectral imager (SCCSI) that exploits the benefits of the colored mosaic FPA detectors and the compression capabilities of CSI sensing techniques. The proposed optical architecture has no moving parts and can capture the spatiospectral information of a scene in a single snapshot by using a dispersive element and a color-patterned detector. The optical and the mathematical models of SCCSI are presented along with a testbed implementation of the system. Simulations and real experiments show the accuracy of SCCSI and compare the reconstructions with those of similar CSI optical architectures, such as the CASSI and SSCSI systems, resulting in improvements of up to 6 dB and 1 dB of PSNR, respectively. PMID- 26479925 TI - Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. AB - Mechanical allodynia, induced by normally innocuous low-threshold mechanical stimulation, represents a cardinal feature of neuropathic pain. Blockade or ablation of high-threshold, small-diameter unmyelinated group C nerve fibers (C fibers) has limited effects on mechanical allodynia. Although large, myelinated group A fibers, in particular Abeta-fibers, have previously been implicated in mechanical allodynia, an A-fiber-selective pharmacological blocker is still lacking. Here we report a new method for targeted silencing of A-fibers in neuropathic pain. We found that Toll-like receptor 5 (TLR5) is co-expressed with neurofilament-200 in large-diameter A-fiber neurons in the dorsal root ganglion (DRG). Activation of TLR5 with its ligand flagellin results in neuronal entry of the membrane-impermeable lidocaine derivative QX-314, leading to TLR5-dependent blockade of sodium currents, predominantly in A-fiber neurons of mouse DRGs. Intraplantar co-application of flagellin and QX-314 (flagellin/QX-314) dose dependently suppresses mechanical allodynia after chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that co-application of flagellin/QX-314 selectively suppressed Abeta-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated Abeta-fiber blockade, but not capsaicin-mediated C-fiber blockade, also reduced chemotherapy-induced ongoing pain without impairing motor function. Finally, flagellin/QX-314 co-application suppressed sodium currents in large-diameter human DRG neurons. Thus, our findings provide a new tool for targeted silencing of Abeta-fibers and neuropathic pain treatment. PMID- 26479929 TI - Effect of induced transverse chromatic aberration on peripheral vision. AB - Transverse chromatic aberration (TCA) is one of the largest optical errors affecting the peripheral image quality in the human eye. However, the effect of chromatic aberrations on our peripheral vision is largely unknown. This study investigates the effect of prism-induced horizontal TCA on vision, in the central as well as in the 20 degrees nasal visual field, for four subjects. Additionally, the magnitude of induced TCA (in minutes of arc) was measured subjectively in the fovea with a Vernier alignment method. During all measurements, the monochromatic optical errors of the eye were compensated for by adaptive optics. The average reduction in foveal grating resolution was about 0.032 +/- 0.005 logMAR/arcmin of TCA (mean +/- std). For peripheral grating detection, the reduction was 0.057 +/- 0.012 logMAR/arcmin. This means that the prismatic effect of highly dispersive spectacles may reduce the ability to detect objects in the peripheral visual field. PMID- 26479930 TI - Cancelable face verification using optical encryption and authentication. AB - In a cancelable biometric system, each instance of enrollment is distorted by a transform function, and the output should not be retransformed to the original data. This paper presents a new cancelable face verification system in the encrypted domain. Encrypted facial images are generated by a double random phase encoding (DRPE) algorithm using two keys (RPM1 and RPM2). To make the system noninvertible, a photon counting (PC) method is utilized, which requires a photon distribution mask for information reduction. Verification of sparse images that are not recognizable by direct visual inspection is performed by unconstrained minimum average correlation energy filter. In the proposed method, encryption keys (RPM1, RPM2, and PDM) are used in the sender side, and the receiver needs only encrypted images and correlation filters. In this manner, the system preserves privacy if correlation filters are obtained by an adversary. Performance of PC-DRPE verification system is evaluated under illumination variation, pose changes, and facial expression. Experimental results show that utilizing encrypted images not only increases security concerns but also enhances verification performance. This improvement can be attributed to the fact that, in the proposed system, the face verification problem is converted to key verification tasks. PMID- 26479931 TI - Modal analysis of a multilayer dielectric microsphere in a free-space ambient medium. AB - An analysis of the eigenmodes associated with a dielectric sphere embedded within one or more spherical layers of varying permittivity is presented. A matrix formulation is applied to the general multilayer problem, and the solution is validated by comparison to the complex transcendental equations derived for the homogeneous dielectric spherical resonator and a single-layer spherical dielectric resonator. Although only lossless cases are considered for simplicity, the formulation presented is applicable to resonators (with loss or gain) via the replacement of real permittivities with complex permittivities. The matrix formulation presented for the multilayer dielectric sphere follows a previously published development with the inclusion of some significant corrections. A Wronskian filter effective index approximation is developed for the estimation of Bessel functions of large order (expanding the functionality of the models to evaluation of whispering gallery modes), which is easily integrated into the presented models. Numerical simulations are generated utilizing MATLAB to solve for the complex roots of the characteristic equation, amplitude reflection coefficient, surface impedance of the dielectric layers, Q-factor, and field patterns for both TE and TM modes. Results are presented for single-layer and multilayer spherical geometries and compared to previously published results. PMID- 26479932 TI - Propagation of time-truncated Airy-type pulses in media with quadratic and cubic dispersion. AB - In this paper, we describe analytically the propagation of Airy-type pulses truncated by a finite-time aperture when second- and third-order dispersion effects are considered. The mathematical method presented here, which is based on the superposition of exponentially truncated Airy pulses, is very effective and allows us to avoid the use of time-consuming numerical simulations. We analyze the behavior of the time-truncated ideal Airy pulse and also the interesting case of a time-truncated Airy pulse with a "defect" in its initial profile, which reveals the self-healing property of this kind of pulse solution. PMID- 26479933 TI - Analysis of 2-D dielectric-waveguide-coupled optical ring resonators using a transmission-line formulation. AB - A rigorous and fast method for a Fourier-based analysis of 2-D dielectric waveguide-coupled optical ring resonators (ORRs) is presented. As a first step, the structure under investigation is periodically repeated along a specific direction. The resulting periodic structure is then analyzed using a transmission line formulation (TLF). For a sufficiently long period, the solutions of the resulting periodic structure converge with those of the actual structure. As will be demonstrated, the simulation time for the analysis of a sample ORR of high index contrast at a single frequency point amounts to a few seconds without remarkable computing resources. Our results are in close agreement with those of the pseudospectral time-domain (PSTD). PMID- 26479934 TI - Orbital angular momentum of superposition of identical shifted vortex beams. AB - We have formulated and proven the following theorem: the superposition of an arbitrary number of arbitrarily off-axis, identical nonparaxial optical vortex beams of arbitrary radially symmetric shape, integer topological charge n, and arbitrary real weight coefficients has the normalized orbital angular momentum (OAM) equal to that of individual constituent identical beams. This theorem enables generating vortex laser beams with different (not necessarily radially symmetric) intensity profiles but identical OAM. Superpositions of Bessel, Hankel Bessel, Bessel-Gaussian, and Laguerre-Gaussian beams with the same OAM are discussed. PMID- 26479935 TI - Group multiple-image encoding and watermarking using coupled logistic maps and gyrator wavelet transform. AB - A novel method of group multiple-image encoding and watermarking using coupled logistic maps and gyrator wavelet transform is presented. The proposed method employs three different groups of multiple images. The color images of each group are individually segregated into R, G, and B channels. Each channel is first permutated by using a sequence of chaotic pairs generated with a system of two symmetrically coupled identical logistic maps and then gyrator transformed. The gyrator spectrum of each channel is multiplied together and then modulated by a random phase function to obtain a corresponding multiplex channel. The encoded multiplex image is restituted through a concatenation of R, G, and B multiplex channels. The phase and amplitude functions of the first, second, and third groups of encoded multiplex images are generated. The host image is a single level 2D discrete wavelet transformed to decompose into LL, HL, LH, and HH subbands. HL, LH, and HH subbands are then replaced with phase functions of the first, second, and third groups, respectively. Finally, the resultant image is an inverse single-level 2D discrete wavelet transformed to construct a watermarked image. The three groups of multiple images are protected not only by the encryption algorithm but also visually by the host image. Thus, a high level of security can be achieved. Each group includes group decryption keys, and each image of the group comprises individual decryption keys beside parameters of coupled logistic maps and gyrator transform. As a result, the key space is very large. The decryption system can be realized by using an optoelectronic device. The numerical simulation results confirm the validity and security of the proposed scheme. PMID- 26479936 TI - Lifetime estimation of moving subcellular objects in frequency-domain fluorescence lifetime imaging microscopy. AB - Fluorescence lifetime is usually defined as the average nanosecond-scale delay between excitation and emission of fluorescence. It has been established that lifetime measurements yield numerous indications on cellular processes such as interprotein and intraprotein mechanisms through fluorescent tagging and Forster resonance energy transfer. In this area, frequency-domain fluorescence lifetime imaging microscopy is particularly appropriate to probe a sample noninvasively and quantify these interactions in living cells. The aim is then to measure the fluorescence lifetime in the sample at each location in space from fluorescence variations observed in a temporal sequence of images obtained by phase modulation of the detection signal. This leads to a sensitivity of lifetime determination to other sources of fluorescence variations such as intracellular motion. In this paper, we propose a robust statistical method for lifetime estimation for both background and small moving structures with a focus on intracellular vesicle trafficking. PMID- 26479937 TI - Wavefront aberration function in terms of R. V. Shack's vector product and Zernike polynomial vectors. AB - Previous papers have shown how, for rotationally symmetric optical imaging systems, nodes in the field dependence of the wavefront aberration function develop when a rotationally symmetric optical surface within an imaging optical system is decentered and/or tilted. In this paper, we show how Shack's vector product (SVP) can be used to express the wavefront aberration function and to define vectors in terms of the Zernike polynomials. The wavefront aberration function is then expressed in terms of the Zernike vectors. It is further shown that SVP fits within the framework of two-dimensional geometric algebra (GA). Within the GA framework, an equation for the third-order node locations for the binodal astigmatism term that emerge in the presence of tilts and decenters is then demonstrated. A computer model of a three-mirror telescope system is used to demonstrate the validity of the mathematical development. PMID- 26479938 TI - General Rytov approximation. AB - We examine how the Rytov approximation describing log-amplitude and phase fluctuations of a wave propagating through weak uniform turbulence can be generalized to the case of turbulence with a large-scale nonuniform component. We show how the large-scale refractive index field creates Fermat rays using the path integral formulation for paraxial propagation. We then show how the second order derivatives of the Fermat ray action affect the Rytov approximation, and we discuss how a numerical algorithm would model the general Rytov approximation. PMID- 26479939 TI - Second-order axial color of thin lenses in air. AB - In present research, the influence of higher-order aberrations on the correction of secondary axial color is under investigation. Analytical solutions have so far been restricted to special cases and simple optical systems. Common theories require the tracing of rays of different wavelengths. Such numerical approaches do not support the comprehension of the underlying physical effects. In this paper, a formula for second-order axial color contributions is derived which is based on paraxial ray data for the reference wavelength only. Therefore, it allows the determination of second-order axial color in early paraxial design stages without further numerical ray trace. For systems of thin lenses in air, three second-order effects are identified and discussed using simple examples. A quantitative comparison with intrinsic secondary axial color is given. PMID- 26479940 TI - Finite-difference time-domain analysis for the dynamics and diffraction of exciton-polaritons. AB - We adopted a finite-difference time-domain (FDTD) scheme to simulate the dynamics and diffraction of exciton-polaritons, governed by the coupling of polarization waves with electromagnetic waves. The polarization wave, an approximate solution to the Schrodinger's equation at low frequencies, essentially captures the exciton behavior. Numerical stability of the scheme is analyzed and simple examples are provided to prove its validity. The system considered is both temporally and spatially dispersive, for which the FDTD analysis has attracted less attention in the literature. Here, we demonstrate that the FDTD scheme could be useful for studying the optical response of the exciton-polariton and its dynamics. The diffraction of a polariton wave from a polaritonic grating is also considered, and many sharp resonances are found, which manifest the interference effect of polariton waves. This illustrates that the measurement of transmittance or reflectance near polariton resonance can reveal subwavelength features in semiconductors, which are sensitive to polariton scattering. PMID- 26479941 TI - Tuning the locality of filtering with a spatially weighted implementation of random spray Retinex. AB - The human color sensation depends on the spatial distribution of the colors in the viewed scene. This principle is at the basis of the random spray Retinex (RSR) algorithm. In this work, we modify RSR by integrating its approach with a method to weight and tune the locality of spatial image information. This modification allows for spatial control of the local effect of RSR on image color filtering. We study the performances of this spatially weighted version of RSR on a public image dataset by analyzing and comparing several image features of the output image and its local properties. PMID- 26479942 TI - Detection and estimation of liquid flow through a pipe in a tissue-like object with ultrasound-assisted diffuse correlation spectroscopy. AB - Using coherent light interrogating a turbid object perturbed by a focused ultrasound (US) beam, we demonstrate localized measurement of dynamics in the focal region, termed the region-of-interest (ROI), from the decay of the modulation in intensity autocorrelation of light. When the ROI contains a pipe flow, the decay is shown to be sensitive to the average flow velocity from which the mean-squared displacement (MSD) of the scattering centers in the flow can be estimated. While the MSD estimated is seen to be an order of magnitude higher than that obtainable through the usual diffusing wave spectroscopy (DWS) without the US, it is seen to be more accurate as verified by the volume flow estimated from it. It is further observed that, whereas the MSD from the localized measurement grows with time as tau(alpha) with alpha~1.65, without using the US, alpha is seen to be much less. Moreover, with the local measurement, this super diffusive nature of the pipe flow is seen to persist longer, i.e., over a wider range of initial tau, than with the unassisted DWS. The reason for the super diffusivity of flow, i.e., alpha<2, in the ROI is the presence of a fluctuating (thermodynamically nonequilibrium) component in the dynamics induced by the US forcing. Beyond this initial range, both methods measure MSDs that rise linearly with time, indicating that ballistic and near-ballistic photons hardly capture anything beyond the background Brownian motion. PMID- 26479943 TI - Blob parameter selection for image representation. AB - A technique for optimizing parameters for image representation using blob basis functions is presented and demonstrated. The exact choice of the basis functions significantly influences the quality of the image representation. It has been previously established that using spherically symmetric volume elements (blobs) as basis functions, instead of the more traditional voxels, yields superior representations of real objects, provided that the parameters that occur in the definition of the family of blobs are appropriately tuned. The technique presented in this paper makes use of an extra degree of freedom, which has been previously ignored, in the blob parameter space. The efficacy of the resulting parameters is illustrated. PMID- 26479944 TI - Supported Palladium Nanoparticle-Catalyzed Carboxylation of Aryl Halides, Alkenylsilanes, and Organoboronic Acids Employing Oxalic Acid as the C1 Source. AB - Polystyrene-supported palladium(0) (Pd@PS) nanoparticles as a heterogeneous catalyst have been developed for caboxylation of aryl halides, alkenylsilanes, and organoboronic acids to produce the corresponding carboxylic acids with minor quantities of corresponding aldehydes using bench-stable and inexpensive oxalic acid as the C1 source under focused microwave irradiation. The close vicinity of oxalic acid to Pd@PS maintained through ionic bonding helped to produce CO2 over the catalytic surface that concurrently participated in the carboxylation reaction. PMID- 26479945 TI - Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors. AB - Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing. PMID- 26479946 TI - Morphology of three Litonotus species (Ciliophora: Pleurostomatida) from China seas, with brief notes on their SSU rDNA-based phylogeny. AB - The morphology and ciliary pattern of three brackish pleurostomatid ciliates, Litonotus gracilis spec. nov., L. tropicus spec. nov., and L. duplostriatus, were investigated. Litonotus gracilis differs from its congeners by body size (200 400*15-40MUm in vivo), body shape (slenderly spindle-shaped, long neck), the number of somatic kineties (6-7 left and 11-17 right somatic kineties), long bar shaped extrusomes arranged along oral slit, tiny cortical granules arranged like honeycomb, one subterminally located contractile vacuole and, usually, four macronuclear nodules. Litonotus tropicus is characterized by four contractile vacuoles dorsally located, 8-11 right and four or five left somatic kineties. Litonotus duplostriatus is lanceolate-shaped, with 11-14 right and five or six left somatic kineties, one subterminally located contractile vacuole, fusiform shaped extrusomes distributed along oral slit. Litonotus dragescoiPan et al., 2013 is not a valid name, it still be named as Litonotus fasciolatus (basionym Loxophyllum fasciolatusDragesco, 1966). Molecular phylogenetic analyses based on SSU rDNA sequence data indicate that neither the family Litonotidae nor the genus Litonotus is monophyletic, and L. gracilis has a closer relationship with the genus Kentrophyllum than with other Litonotus species. PMID- 26479947 TI - Correlates, causes, and consequences of fat talk: A review. AB - Fat talk is a term used to describe self-disparaging remarks made to other people about one's weight or body. Fat talk has been both causally and correlationally linked to a number of negative body image-related variables including low body esteem, body dissatisfaction, drive for thinness, body-related cognitive distortions, and perceived sociocultural pressure to be thin. As such, body image researchers and clinicians would benefit from increased awareness of the current literature concerning fat talk. A narrative synthesis approach is used to summarize all research containing the keywords fat talk, body talk, or weight talk that was published from 1994 to 2014 inclusive. The measures used to study fat talk, outcomes and correlates associated with fat talk, theories that may help explain these findings, and the purpose served by fat talk are reviewed and discussed. In addition, directions for future research on fat talk, including intervention strategies, are examined. PMID- 26479948 TI - Modeling the chelation of As(III) in lewisite by dithiols using density functional theory and solvent-assisted proton exchange. AB - Dithiols such as British anti-lewisite (BAL, rac-2,3-dimercaptopropanol) are an important class of antidotes for the blister agent lewisite (trans-2 chlorovinyldichloroarsine) and, more generally, are chelating agents for arsenic and other toxic metals. The reaction of the vicinal thiols of BAL with lewisite through the chelation of the As(III) center has been modeled using density functional theory (DFT) and solvent-assisted proton exchange (SAPE), a microsolvation method that uses a network of water molecules to mimic the role of bulk solvent in models of aqueous phase chemical reactions. The small activation barriers for the stepwise SN2-type nucleophilic attack of BAL on lewisite (0.7 4.9kcal/mol) are consistent with the favorable leaving group properties of the chloride and the affinity of As(III) for soft sulfur nucleophiles. Small, but insignificant, differences in activation barriers were found for the initial attack of the primary versus secondary thiol of BAL and the R vs S enantiomer. An examination of the relative stability of various dithiol-lewisite complexes shows that ethanedithiols like BAL form the most favorable chelation complexes because the angles formed in five-membered ring are most consistent with the hybridization of As(III). More obtuse S-As-S angles are required for larger chelate rings, but internal As?N or As?O interactions can enhance the stability of moderate-sized rings. The low barriers for lewisite detoxification by BAL and the greater stability of the chelation complexes of small dithiols are consistent with the rapid reversal of toxicity demonstrated in previously reported animal models. PMID- 26479949 TI - Click Synthesis of Hydrophilic Maltose-Functionalized Iron Oxide Magnetic Nanoparticles Based on Dopamine Anchors for Highly Selective Enrichment of Glycopeptides. AB - The development of methods to isolate and enrich low-abundance glycopeptides from biological samples is crucial to glycoproteomics. Herein, we present an easy and one-step surface modification strategy to prepare hydrophilic maltose functionalized Fe3O4 nanoparticles (NPs). First, based on the chelation of the catechol ligand with iron atoms, azido-terminated dopamine (DA) derivative was assembled on the surface of magnetic Fe3O4 nanoparticles by sonication. Second, the hydrophilic maltose-functionalized Fe3O4 (Fe3O4-DA-Maltose) NPs were obtained via copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry). The morphology, structure, and composition of Fe3O4-DA-Maltose NPs were investigated by Fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), X-ray powder diffraction (XRD), X-ray photoelectron spectrometer (XPS), and vibrating sample magnetometer (VSM). Meanwhile, hydrophilicity of the obtained NPs was evaluated by water contact angle measurement. The hydrophilic Fe3O4-DA-Maltose NPs were applied in isolation and enrichment of glycopeptides from horseradish peroxidase (HRP), immunoglobulin (IgG) digests. The MALDI-TOF mass spectrometric analysis indicated that the novel NPs exhibited high detection sensitivity in enrichment from HRP digests at concentration as low as 0.05 ng MUL(-1), a large binding capacity up to 43 mg g( 1), and good recovery for glycopeptides enrichment (85-110%). Moreover, the Fe3O4 DA-Maltose NPs were applied to enrich glycopeptides from human renal mesangial cells (HRMC) for identification of N-glycosylation sites. Finally, we identified 115 different N-linked glycopeptides, representing 93 gene products and 124 glycosylation sites in HRMC. PMID- 26479950 TI - Role of vitamin D in cytotoxic T lymphocyte immunity to pathogens and cancer. AB - The discovery of vitamin D receptor (VDR) expression in immune cells has opened up a new area of research into immunoregulation by vitamin D, a niche that is distinct from its classical role in skeletal health. Today, about three decades since this discovery, numerous cellular and molecular targets of vitamin D in the immune system have been delineated. Moreover, strong clinical associations between vitamin D status and the incidence/severity of many immune-regulated disorders (e.g. infectious diseases, cancers and autoimmunity) have prompted the idea of using vitamin D supplementation to manipulate disease outcome. While much is known about the effects of vitamin D on innate immune responses and helper T (T(H)) cell immunity, there has been relatively limited progress on the frontier of cytotoxic T lymphocyte (CTL) immunity--an arm of host cellular adaptive immunity that is crucial for the control of such intracellular pathogens as human immunodeficiency virus (HIV), tuberculosis (TB), malaria, and hepatitis C virus (HCV). In this review, we discuss the strong historical and clinical link between vitamin D and infectious diseases that involves cytotoxic T lymphocyte (CTL) immunity, present our current understanding as well as critical knowledge gaps in the realm of vitamin D regulation of host CTL responses, and highlight potential regulatory connections between vitamin D and effector and memory CD8 T cell differentiation events during infections. PMID- 26479951 TI - Ultrasensitive NO2 Sensor Based on Ohmic Metal-Semiconductor Interfaces of Electrolytically Exfoliated Graphene/Flame-Spray-Made SnO2 Nanoparticles Composite Operating at Low Temperatures. AB - In this work, flame-spray-made undoped SnO2 nanoparticles were loaded with 0.1-5 wt % electrolytically exfoliated graphene and systematically studied for NO2 sensing at low working temperatures. Characterizations by X-ray diffraction, transmission/scanning electron microscopy, and Raman and X-ray photoelectron spectroscopy indicated that high-quality multilayer graphene sheets with low oxygen content were widely distributed within spheriodal nanoparticles having polycrystalline tetragonal SnO2 phase. The 10-20 MUm thick sensing films fabricated by spin coating on Au/Al2O3 substrates were tested toward NO2 at operating temperatures ranging from 25 to 350 degrees C in dry air. Gas-sensing results showed that the optimal graphene loading level of 0.5 wt % provided an ultrahigh response of 26,342 toward 5 ppm of NO2 with a short response time of 13 s and good recovery stabilization at a low optimal operating temperature of 150 degrees C. In addition, the optimal sensor also displayed high sensor response and relatively short response time of 171 and 7 min toward 5 ppm of NO2 at room temperature (25 degrees C). Furthermore, the sensors displayed very high NO2 selectivity against H2S, NH3, C2H5OH, H2, and H2O. Detailed mechanisms for the drastic NO2 response enhancement by graphene were proposed on the basis of the formation of graphene-undoped SnO2 ohmic metal-semiconductor junctions and accessible interfaces of graphene-SnO2 nanoparticles. Therefore, the electrolytically exfoliated graphene-loaded FSP-made SnO2 sensor is a highly promising candidate for fast, sensitive, and selective detection of NO2 at low operating temperatures. PMID- 26479952 TI - Nanoscale Electromechanics To Measure Thermal Conductivity, Expansion, and Interfacial Losses. AB - We study the effect of localized Joule heating on the mechanical properties of doubly clamped nanowires under tensile stress. Local heating results in systematic variation of the resonant frequency; these frequency changes result from thermal stresses that depend on temperature dependent thermal conductivity and expansion coefficient. The change in sign of the linear expansion coefficient of InAs is reflected in the resonant response of the system near a bath temperature of 20 K. Using finite element simulations to model the experimentally observed frequency shifts, we show that the thermal conductivity of a nanowire can be approximated in the 10-60 K temperature range by the empirical form kappa = bT W/mK, where the value of b for a nanowire was found to be b = 0.035 W/mK(2), significantly lower than bulk values. Also, local heating allows us to independently vary the temperature of the nanowire relative to the clamping points pinned to the bath temperature. We suggest a loss mechanism (dissipation ~10(-4)-10(-5)) originating from the interfacial clamping losses between the metal and the semiconductor nanostructure. PMID- 26479953 TI - The text telephone as an empowering technology in the daily lives of deaf people A qualitative study. AB - Text-telephone technology (TTY) has been used for communication between deaf people since 1964. There is a gap in the scientific knowledge about the influence this may have had especially in relation to effective participation in society as well as the feeling of capability, confidence and collective meaningfulness. The aim of the present paper is, first, to disentangle the different aspects of TTY as an empowering artifact; and, second, to explore the role of TTY in their lives. To provide a framework for the empirical analysis, the paper draws on Empowerment Theory: personal control, a proactive approach to life, and a critical awareness of one's socio-political environment. Twenty-four people aged 16-64 with Swedish Sign Language (SSL) as their first language were interviewed. The findings indicate that the introduction of the TTY was of great importance for self-esteem, equality and independence. The findings show that feelings of empowerment are closely linked to language use and contextually driven, and it is in interaction between deaf and hearing that such feelings arise (or not). The results indicate the need for further research into Deaf people's use of other means of interacting, using modern technique for example in social digital media and interactive platforms. PMID- 26479954 TI - Considerations on exercise stress testing: A personal experience of grey zones. PMID- 26479955 TI - Endomyocardial Biopsy in acute cardiogenic shock: Diagnosis of pheochromocytoma. PMID- 26479956 TI - A new approach: Left atrial appendage occlusion, as an alternative to anticoagulant, to treat patient who suffered of atrial fibrillation, acute coronary syndrome and clopidogrel resistance. PMID- 26479957 TI - Closure access leading venous advanced gain new ability: A new technique to overcome implantable device venous occlusion. PMID- 26479958 TI - Inadvertent implantation of a pacemaker lead in the left ventricle: A new challenge in cardiology. PMID- 26479959 TI - Clinical epidemiology of heart failure with preserved ejection fraction (HFpEF) in comparatively young hospitalized patients. AB - BACKGROUND: While heart failure with preserved ejection fraction (HFpEF) is primarily a disease of old age, risk factors that contribute to HFpEF are not limited to older patients. The objectives of this population-based observational study were to describe the clinical epidemiology of HFpEF in younger (<65 years) as compared with older (>=65 years) patients hospitalized with acute decompensated heart failure. METHODS AND RESULTS: We reviewed the medical records of residents of central Massachusetts hospitalized with HFpEF at all 11 greater Worcester (MA) medical centers during the 5 study years of 1995, 2000, 2002, 2004, and 2006. Among the 2398 patients hospitalized with confirmed HFpEF, 357 (14.9%) were <65 years old. Younger patients were more likely to be male, non Caucasian, obese, and to have a history of diabetes and chronic kidney disease than older patients with HFpEF. Younger patients hospitalized with HFpEF were less likely to have received commonly prescribed cardiac medications, had a longer hospital stay, and experienced significantly lower post-discharge death rates than older hospitalized patients. CONCLUSION: While HFpEF is predominantly a disease of old age, data from longitudinal studies remain needed to identify risk factors in younger individuals that may predispose them to the development of HFpEF. PMID- 26479960 TI - Disclosure and Psychological Well-Being of Sexually Abused Adolescents in Hong Kong. AB - The role of disclosure on psychological well-being of adolescents with child sexual abuse experience was investigated in a subsample of 74 disclosers among 800 adolescents recruited in the community in Hong Kong. The results supported that CSA experiences have differential impact on adolescents' psychological well being. Family characteristics of the disclosers accounted for only a small amount of the variance in an array of psychological well-being measures. CSA characteristics were robust predictors of disclosers' sexual eroticism and externalizing behavioral symptoms. Disclosers' cognitive appraisal of CSA experience and quality of parental attachment were strong predictors of their self-esteem and internalizing behavioral problems. After controlling for the aforementioned factors, negative disclosure experience still significantly predicted lower self-esteem, higher sexual anxiety, more internalizing behavior, and more severe post-traumatic stress disorder responses. Research to understand the factors that generate negative disclosure experiences is needed for developing effective intervention strategies to mitigate the negative consequences of disclosure. PMID- 26479961 TI - Lanthanide-Dipicolinic Acid Coordination Driven Micelles with Enhanced Stability and Tunable Function. AB - Lanthanide-incorporated polymer micelles have been prepared driven by the lanthanide-dipicolinic acid (Ln-DPA) coordination. The terdentate DPA ligand is grafted to the PVP block of a diblock copolymer poly(4-vinylpyridine)-b poly(ethylene oxide) (P4VP48-b-PEO193). Upon addition of Eu(III) ions to a solution of the DPA16-g-P4VP48-b-PEO193 block copolymer, intermolecular cross links form and the ligand-carrying blocks assemble, leading to the formation of micelles, stabilized by the hydrophilic PEO blocks. The DPA exhibits a dual function in this study. First, the chelate group strongly coordinates to Eu(III) in a three to one ratio, and leads to high stability of the formed micelles, as proven by light scattering and luminescence spectroscopy. Second, DPA acts as an antenna that transfers energy to the Eu(III) ion and dramatically enhances the luminescence emission. The Eu(III) emission is moreover most sensitive for local environment and allows to shine light on the internal structure of this class of self-assembled 36 nm size soft nanoparticles. With the same strategy gadolinium(III) can be incorporated providing micelles which show enhanced magnetic relaxation rates. Micelles capping a mixture of Eu(III) and Gd(III) show both enhanced luminescence emission and magnetic relaxation rates, and the functions can be tuned by regulating the mixing ratio of Eu(III) and Gd(III), showing great potential for developing multimodal imaging agents for diagnostic as well as therapeutic applications. PMID- 26479962 TI - Understanding the Origins of Ischemia and Reperfusion. PMID- 26479963 TI - Advances in Ischemia and Reperfusion. PMID- 26479965 TI - Nuclear Bound States of Molecular Hydrogen Physisorbed on Graphene: An Effective Two-Dimensional Model. AB - The interaction potential of molecular hydrogen physisorbed on a graphene sheet is evaluated using the ab initio-based periodic dlDF+Das scheme and its accuracy is assessed by comparing the nuclear bound-state energies supported by the H2(D2/HD)/graphite potentials with the experimental energies. The periodic dlDF+Das treatment uses DFT-based symmetry-adapted perturbation theory on surface cluster models to extract the dispersion contribution to the interaction whereas periodic dispersionless density functional (dlDF) calculations are performed to determine the dispersion-free counterpart. It is shown that the H2/graphene interaction is effectively two-dimensional (2D), with the distance from the molecule center-of-mass to the surface plane and the angle between the diatomic axis and the surface normal as the relevant degrees of freedom. The global potential minimum is found at the orthogonal orientation of the molecule with respect to the surface plane, with an equilibrium distance of 3.17 A and a binding energy of -51.9 meV. The comparison of the binding energies shows an important improvement of our approach over the vdW-corrected DFT schemes when we are dealing with the very weak H2/surface interaction. Next, the 2D nuclear bound state energies are calculated numerically. As a cross-validation of the interaction potential, the bound states are also determined for molecular hydrogen on the graphite surface (represented as an assembly of graphene sheets). With the largest absolute deviation being 1.7 meV, the theoretical and experimental energy levels compare very favorably. PMID- 26479964 TI - The Feasibility of Using Electronic Health Records to Describe Demographic and Clinical Indicators of Migrant and Seasonal Farmworkers. AB - Few extensive, national clinical databases exist on the health of migrant and seasonal farmworkers (MSFWs). Electronic health records (EHRs) are increasingly utilized by Federally Qualified Health Centers (FQHCs) and have the potential to improve clinical care and complement current surveillance and epidemiologic studies of underserved working populations, such as MSFWs. The aim of this feasibility study was to describe the demographics and baseline clinical indicators of patients at an FQHC by MSFW status. The authors described 2012 patient demographics, social history, medical indicators, and diagnoses by MSFW status from the de-identified EHR database of a large, multisite Colorado Migrant Health Center (MHC). Included in the study were 41,817 patients from 2012: 553 (1.3%) MSFWs, 20,665 (49.4%) non-MSFWs, and 20,599 (49.3%) who had no information in the MSFW field. MSFWs were more often male, married, employed, Hispanic, and Spanish-speaking compared with non-MSFWs. The most frequent diagnoses for all patients were hypertension, overweight/obesity, lipid disorder, type 2 diabetes, or a back disorder. Although there were significant missing values, this feasibility study was able to analyze medical data in a timely manner and show that Meaningful Use requirements can improve the usability of EHR data for epidemiologic research of MSFWs and other patients at FQHCs. The results of this study were consistent with current literature available for MSFWs. By reaching this vulnerable working population, EHRs may be a key data source for occupational injury and illness surveillance and research. PMID- 26479966 TI - Immobilized laccase-based biosensor for the detection of disubstituted methyl and methoxy phenols - application of Box-Behnken design with response surface methodology for modeling and optimization of performance parameters. AB - An amperometric principle-based biosensor, employing immobilized laccase enzyme from Trametes versicolor, was developed for the detection of disubstituted methyl and methoxy phenols. Three immobilization methods such as entrapment, cross linking, and co-cross-linking, with bovine serum albumin (BSA) on nylon membrane have been compared. Among tested methods of immobilization, co-cross-linking method with BSA was superior to the other methods in terms of; sensitivity, limit of detection, response time, and operating stability. The increased sensitivity of the probe optimization of concentrations of laccase, BSA and glutaraldehyde can be achieved by, employing the Box-Behnken design of experiment. PMID- 26479967 TI - (18)F-Based Pretargeted PET Imaging Based on Bioorthogonal Diels-Alder Click Chemistry. AB - A first-of-its-kind (18)F pretargeted PET imaging approach based on the bioorthogonal inverse electron demand Diels-Alder (IEDDA) reaction between tetrazine (Tz) and trans-cyclooctene (TCO) is presented. As proof-of-principle, a TCO-bearing immunoconjugate of the anti-CA19.9 antibody 5B1 and an Al[(18)F]NOTA labeled tetrazine radioligand were harnessed for the visualization of CA19.9 expressing BxPC3 pancreatic cancer xenografts. Biodistribution and (18)F-PET imaging data clearly demonstrate that this methodology effectively delineates tumor mass with activity concentrations up to 6.4 %ID/g at 4 h after injection of the radioligand. PMID- 26479969 TI - Paclitaxel-coated balloon plus bare-metal stent for de-novo coronary artery disease: final 5-year results of a randomized prospective multicenter trial. AB - BACKGROUND: The PERfECT Stent Study compared paclitaxel-coated balloon (PCB) angioplasty plus bare-metal stent (BMS) implantation with BMS alone in de-novo lesions in native coronary artery disease. Angiographic follow-up after 6 months showed the superiority of the additional PCB. We evaluated a potential late catch up phenomenon with the use of PCB. METHODS AND RESULTS: In the prospective, multicenter, single-blind, randomized PERfECT Stent trial, 120 patients were assigned to either PCB angioplasty plus BMS implantation or BMS alone. For BMS, the endothelial progenitor cell capturing stent was used. Dual antiplatelet therapy was recommended for 3 months. The clinical endpoint for 5-year follow-up was a composite of cardiac death, myocardial infarction attributed to the target vessel, or target lesion revascularization. The follow-up rate after 5 years was 97%. Baseline and procedural characteristics did not differ. At the 5-year follow up, clinically driven target lesion revascularization was 23.2% in the BMS group versus 15% with PCB plus BMS (P=0.26). The clinical endpoint (major adverse cardiac event) was 30.4% with BMS and with 23.5% lower with PCB plus BMS. No definite or probable stent thrombosis was found in either group with a dual antiplatelet therapy for 3 months for the total period. CONCLUSION: PCB angioplasty plus BMS was superior to BMS alone for the treatment of de-novo lesions. The combined clinical endpoint was lower with PCB plus BMS at 6 months and remained lower after 5 years. There was no late catch-up phenomenon (http://www.clinicaltrials.gov; NCT 00732953). PMID- 26479968 TI - Advances in intravesical therapy for urinary tract disorders. AB - INTRODUCTION: Intravesical therapy is a valuable option in the clinical management of urinary tract disorders such as interstitial cystitis/ painful bladder syndrome (IC/PBS) and refractory overactive bladder. This review will cover the latest advances in this field using polymer and liposomes as delivery platform for drugs, protein and nucleic acids. AREAS COVERED: This review summarizes the significance of intravesical therapy for lower urinary tract disorders. The recent advancement of liposomes as a drug delivery platform for botulinum toxin, tacrolimus and small interfering RNA is discussed. The importance of polymers forming indwelling devices and hydrogels are also discussed, where all preparations improved efficacy parameters in rodent models. Clinical experience of treating IC/PBS with indwelling devices and liposomes are summarized and preclinical evidence about the downregulation of target gene expression in rodent bladder with liposomes complexed with siRNA is also reviewed. EXPERT OPINION: There have been several advances in the field of intravesical therapy for improving clinical outcomes. One of the most promising research avenues is the repurposing of drugs, given previously by other routes of administration, such as tacrolimus. Intravesical therapy also opens up novel therapeutic targets with improved efficacy and safety for underactive bladder. PMID- 26479970 TI - CRISPR/Cas mutagenesis of soybean and Medicago truncatula using a new web-tool and a modified Cas9 enzyme. AB - The CRISPR/Cas9 system is rapidly becoming the reagent of choice for targeted mutagenesis and gene editing in crop species. There are currently intense research efforts in the crop sciences to identify efficient CRISPR/Cas9 platforms to carry out targeted mutagenesis and gene editing projects. These efforts typically result in the incremental tweaking of various platform components including the identification of crop-specific promoters and terminators for optimal expression of the Cas9 enzyme and identification of promoters for expression of the CRISPR guide RNA. In this report, we demonstrate the development of an online web tool for fast identification of CRISPR/Cas9 target loci within soybean gene models, and generic DNA sequences. The web-tool described in this work can quickly identify a high number of potential CRISPR/Cas9 target sites, including restriction enzyme sites that can facilitate the detection of new mutations. In conjunction with the web tool, a soybean codon optimized CRISPR/Cas9 platform was designed to direct double-stranded breaks to the targeted loci in hairy root transformed cells. The modified Cas9 enzyme was shown to successfully mutate target genes in somatic cells of 2 legume species, soybean and Medicago truncatula. These new tools may help facilitate targeted mutagenesis in legume and other plant species. PMID- 26479971 TI - Physical activity level of postmenopausal women in Nigeria: Association with self rated health status, overall obesity, and abdominal obesity. AB - Regular physical activity (PA) has been shown to have many health benefits in various populations, including postmenopausal women (n = 310). Self-rated health has been positively associated with PA. This cross-sectional survey of postmenopausal women in Nigeria was conducted from April to September 2012 to investigate associations among PA level, self-rated health, overall obesity (body mass index [BMI]), and abdominal obesity (waist-height ratio, waist-hip ratio, and waist circumference). The International Physical Activity Questionnaire was used to classify PA. Chi-square and logistic regression were used for analyses with level of significance set at .05. Participants were aged 53.0 +/- 4.2 years; moderate to vigorous PA was reported by 188 (60.0%), while 26 (8.4%) self-rated their health as poor/fair, and 242 (78.1%) were either predominantly overweight or obese when classified according to BMI. Participants with fair/poor self-rated health had less odds of involvement in moderate to vigorous PA. Obese postmenopausal women had greater odds of reporting lower PA. PA was positively related to self-rated health, which was negatively associated with overall obesity but not abdominal obesity. Measures to control obesity among postmenopausal women are essential in view of its direct association with poor self-rated health and low PA in this group of women. PMID- 26479972 TI - Cystatin C: A Marker for Inflammation and Renal Function Among HIV-infected Children and Adolescents. AB - BACKGROUND: Renal disease is a leading cause of morbidity in HIV-infected adults in the highly active antiretroviral therapy (HAART) era. Cystatin C has been proposed as a more sensitive marker of renal function, but it may be affected by ongoing inflammation. We aimed to study the cystatin C levels in a cohort of HIV infected pediatric patients at 3 Spanish centers. METHODS: This is a multicenter cross-sectional observational study. Renal function was assessed by means of first morning urine protein/creatinine and albumin/creatinine ratios and creatinine-estimated glomerular filtration rates (GFRs), together with the following inflammation markers: cystatin C, reactive C protein, beta-2 microglobulin and 25(OH)-vitamin D levels. A control group of healthy children and adolescents was used. RESULTS: Eighty-three patients (51 females, median age: 13.3 years; 32 males, median age: 13.6 years) and 44 controls (24 females, median age: 12.2 years; 20 males, median age: 10.9 years) were included. Among the former, mean CD4 cell count was 860/mm, 29(35%) patients had a previous AIDS diagnosis, 73(88%) were on HAART and HIV viremia was undetectable in 61(73%). No differences in cystatin C levels were observed between the 2 groups. In HIV infected patients, cystatin C levels correlated with GFR (r = -0.27; P = 0.01), age at first HAART (r = -0.21; P = 0.05), and beta-2-microglobulin (r = 0.569; P < 0.01). In multivariate analysis, lower GFR (P = 0.014) and higher beta-2 microglobulin levels (P = 0.001) remained as independent risk factors for higher cystatin C values. CONCLUSIONS: Cystatin C values were associated with GFR and beta-2-microglobulin. Cystatin C may be useful as a marker of renal function in HIV-infected pediatric patients, independently of ongoing inflammation or viremia. PMID- 26479973 TI - Immunogenicity and Safety of a 3- and 4-dose Vaccination Series of a Meningococcal ACWY Conjugate Vaccine in Infants: Results of a Phase 3b, Randomized, Open-label Trial. AB - BACKGROUND: The quadrivalent meningococcal glycoconjugate vaccine MenACWY-CRM is licensed for children from 2 months of age as a 4-dose series. This study assessed the immunogenicity of a 3-dose MenACWY-CRM vaccination series in infants, compared with the 4-dose series, and evaluated the impact of MenACWY-CRM concomitant administration on immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13). METHODS: Overall, 751 healthy infants (age: 55-89 days) were randomized to receive 3 or 4 doses of MenACWY-CRM (2/4/12 or 2/4/6/12 months of age, respectively) with PCV13 + routine vaccinations (ACWY3 and ACWY4 groups, respectively) or PCV13 + routine vaccinations only (routine group). Immunological noninferiority of the 3-dose versus 4-dose MenACWY-CRM vaccination series was evaluated at 13 months of age for serogroups CWY; noninferiority of immune responses to PCV13 serotypes for concomitant administration of MenACWY-CRM and PCV13 was evaluated at 7 and 13 months of age. RESULTS: At 13 months, 88% 100% of subjects in groups ACWY3 and ACWY4 achieved seroprotective bactericidal antibody titers against serogroups ACWY; noninferiority criteria for the 3-dose versus 4-dose MenACWY-CRM vaccination series were met. At 7 months, noninferiority criteria were met for all PCV13 serotypes except for serotypes 3 and 5 (group ACWY3) and 19A (group ACWY4). At 13 months, noninferiority criteria were met for all PCV13 serotypes for both ACWY groups. CONCLUSIONS: After completion of either MenACWY-CRM vaccination series, most subjects achieved seroprotective titers against serogroups ACWY, with the 3-dose series being noninferior to the 4-dose series for serogroups CWY, and no interference with immune responses against PCV13 serotypes was observed (NCT01214837). PMID- 26479974 TI - The use of uncertainty forecasts in complex decision tasks and various weather conditions. AB - Recent research on weather-related decision-making suggests that the inclusion of numeric uncertainty estimates in weather forecasts improves decision quality over single value forecasts or specific advice. However, it is unclear if the benefit of uncertainty estimates extends to more complex decision tasks, presumably requiring greater cognitive effort, or to tasks in which the decision is clear cut, perhaps making the additional uncertainty information unnecessary. In the present research, participants completed a task in which they used single value weather forecasts, either alone, with freeze probabilities, advice, or both, to decide whether to apply salt to roads in winter to prevent icing or to withhold salt and risk a penalty. Participants completed either a simple binary choice version of the task or a complex version with 3 response options and accompanying rules for application. Some participants were shown forecasts near the freezing point, such that the need for salt was ambiguous, whereas other participants were shown forecasts well below the freezing point. Results suggest that participants with uncertainty estimates did better overall, and neither the task complexity nor the coldness of the forecasts reduced that advantage. However, unexpectedly colder forecasts lead to poorer decisions and an advantage for specific advice. PMID- 26479975 TI - The pathogenesis of pulmonary hypertension--an update. AB - Elevation of the mean pulmonary arterial pressure to >=25 mm Hg within the low pressure system of the pulmonary circulation is defined as pulmonary hypertension. Pulmonary hypertension may be the consequence of various clinical and pathophysiological entities. Many of these conditions, however, result in a final common pathway of pathogenesis. This pathway is characterised by the triad of excessive vasoconstriction, microthrombosis and remodelling of pulmonary arteries. Remodelling is arguably the most important factor: its complex pathogenesis is not completely understood and no specific treatment directly targets vascular remodelling. This article aims to review the current understanding of the pathogenesis of pulmonary hypertension and to give insights in future developments in this evolving field. PMID- 26479976 TI - Inactivation of nitrate reductase alters metabolic branching of carbohydrate fermentation in the cyanobacterium Synechococcus sp. strain PCC 7002. AB - To produce cellular energy, cyanobacteria reduce nitrate as the preferred pathway over proton reduction (H2 evolution) by catabolizing glycogen under dark anaerobic conditions. This competition lowers H2 production by consuming a large fraction of the reducing equivalents (NADPH and NADH). To eliminate this competition, we constructed a knockout mutant of nitrate reductase, encoded by narB, in Synechococcus sp. PCC 7002. As expected, DeltanarB was able to take up intracellular nitrate but was unable to reduce it to nitrite or ammonia, and was unable to grow photoautotrophically on nitrate. During photoautotrophic growth on urea, DeltanarB significantly redirects biomass accumulation into glycogen at the expense of protein accumulation. During subsequent dark fermentation, metabolite concentrations--both the adenylate cellular energy charge (~ATP) and the redox poise (NAD(P)H/NAD(P))--were independent of nitrate availability in DeltanarB, in contrast to the wild type (WT) control. The DeltanarB strain diverted more reducing equivalents from glycogen catabolism into reduced products, mainly H2 and d-lactate, by 6-fold (2.8% yield) and 2-fold (82.3% yield), respectively, than WT. Continuous removal of H2 from the fermentation medium (milking) further boosted net H2 production by 7-fold in DeltanarB, at the expense of less excreted lactate, resulting in a 49-fold combined increase in the net H2 evolution rate during 2 days of fermentation compared to the WT. The absence of nitrate reductase eliminated the inductive effect of nitrate addition on rerouting carbohydrate catabolism from glycolysis to the oxidative pentose phosphate (OPP) pathway, indicating that intracellular redox poise and not nitrate itself acts as the control switch for carbon flux branching between pathways. PMID- 26479977 TI - Pulmonary hypertension associated with bronchiolitis obliterans after hematopoietic stem cell transplantation. PMID- 26479978 TI - Haploidentical hematopoietic stem cell transplantation for nonresponders to immunosuppressive therapy against acquired severe aplastic anemia. PMID- 26479979 TI - Pericardial effusion post transplantation predicts inferior overall survival following allo-hematopoietic stem cell transplant. PMID- 26479980 TI - Autologous hematopoietic stem cell transplantation in light chain amyloidosis (AL) with renal involvement. PMID- 26479981 TI - Characteristics and outcomes of aplastic anemia in HIV patients: a brief report from the severe aplastic anemia working party of the European Society of Blood and Bone Marrow Transplantation. PMID- 26479982 TI - The use of basiliximab-infliximab combination for the treatment of severe gastrointestinal acute GvHD. AB - After allogeneic stem cell transplant, severe grade III-IV gastrointestinal (GI) acute GvHD is associated with significant morbidity and mortality, and generally results in poor outcomes. Salvage therapy for patients who fail steroid therapy is not well defined in the literature. In the current retrospective study, we reviewed our experience with the combination of basiliximab and infliximab in 21 patients with severe, grade III-IV GI acute GvHD of whom 16 met the definition for steroid-refractory disease. The overall response rate was 76%, with 43% CR at a median time of 21 days after beginning treatment. The survival at 1 year was 24%, with most deaths due to complications from GvHD and recurrence of primary disease. All five of the long-term survivors have chronic GvHD. On the basis of a review of the literature, this regimen does not seem to be significantly more effective than other strategies for severe GI GvHD and seems to be worse than the results reported for basiliximab alone. Future studies of single-agent basiliximab and newer agents are required. PMID- 26479983 TI - Case Study: Nutritional and Lifestyle Support to Reduce Infection Incidence in an International-Standard Premier League Soccer Player. AB - Professional soccer players are exposed to large amounts of physiological and psychological stress, which can increase infection risk and threaten availability for training and competition. Accordingly, it is important for practitioners to implement strategies that support player well-being and prevent illness. This case study demonstrates how a scientifically supported and practically applicable nutrition and lifestyle strategy can reduce infection incidence in an illness prone professional soccer player. In the 3 months before the intervention, the player had 3 upper-respiratory tract infections (URTIs) and subsequently missed 3 competitive matches and 2 weeks' training. He routinely commenced morning training sessions in the fasted state and was estimated to be in a large daily energy deficit. Throughout the 12-week intervention, the amount, composition, and timing of energy intake was altered, quercetin and vitamin D were supplemented, and the player was provided with a daily sleep and hygiene protocol. There was a positive increase in serum vitamin D 25(OH) concentration from baseline to Week 12 (53 n.mol-1 to 120 n.mol-1) and salivary immunoglobulin-A (98 mg.dl-1 to 135 mg.dl-1), as well as a decline in the number of URTI symptoms (1.8 +/- 2.0 vs. 0.25 +/- 0.5 for Weeks 0-4 and Weeks 8-12, respectively). More important, he maintained availability for all training and matches over the 12-week period. We offer this case study as a real-world applied example for other players and practitioners seeking to deploy nutrition and lifestyle strategies to reduce risk of illness and maximize player availability. PMID- 26479984 TI - Accelerated Unilateral Radiographic Huntingtonian Changes Following Neoadjuvant Chemotherapy for a Nongerminomatous Germ Cell Tumor Leading to Identification of Occult Disease in the Dorsal Striatum. AB - Basal ganglia nongerminomatous germ cell tumors comprise 10% to 15% of germ cell tumor and have substantial morbidity at the time of local failure. In this submitted image we present a case where neoadjuvant chemotherapy unmasked a unilateral caudate head loss consistent with Huntingtonian changes. Careful review of the patient's imaging identified disease within the dorsal striatum that was not previously identified at the time of diagnosis. Review of the diffusion tensor fractional anisotropy imaging identified progressive white matter likely secondary to the occult disease within the dorsal striatum. Although this patient was asymptomatic and had no signs of a movement disorder, similar findings have been noted to be a prelude to such findings several months later. The occult disease was incorporated into the patient's radiotherapy planning target volume as oversight of these changes would have led to a marginal miss and potential early disease relapse. PMID- 26479985 TI - G6PC3 Deficiency: Primary Immune Deficiency Beyond Just Neutropenia. AB - Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency was recently defined as a new severe congenital neutropenia subgroup remarkable with congenital heart defects, urogenital malformations, endocrine abnormalities, and prominent superficial veins. Here, we report 3 patients with G6PC3 deficiency presenting with recurrent diarrhea, failure to thrive, and sinopulmonary infections leading to bronchiectasis. In patient I and II, a combined immune deficiency was suspected due to early-onset disease with lymphopenia, neutropenia, and thrombocytopenia, along with variable reductions in lymphocyte subpopulations and favorable response to intravenous gamma-globulin therapy. Apart from neutropenia, all 3 patients had intermittent thrombocytopenia, anemia, and lymphopenia. All patients had failure to thrive and some of the classic syndromic features of G6PC3 deficiency, including cardiac abnormalities and visibility of superficial veins in all, endocrinologic problems in PI and PIII, and urogenital abnormalities in PII. Our experience suggests that a diagnosis of congenital neutropenia due to G6PC3 may not be as straightforward in such patients with combined lymphopenia and thrombocytopenia. A high index of suspicion and the other syndromic features of G6PC3 were clues to diagnosis. Screening of all combined immune deficiencies with neutropenia may help to uncover the whole spectra of G6PC3 deficiency. PMID- 26479986 TI - Chronic Neutropenia in Childhood: Experience From a Single Center. AB - Chronic neutropenia (CN) is defined as neutropenia that persists for >3 months; it is caused by a heterogeneous group of diseases in children. The aim of the present study was to evaluate the significance and clinical manifestations of CN in children at a single children's hospital. Between October 2004 and April 2014, CN patient data were evaluated retrospectively. Thirty-one patients were assessed in this study. Thirteen of them (41.9%) were younger than 12 months of age at initial diagnosis. There was no difference in the absolute number of neutrophils at diagnosis between the children aged younger than 12 months and those aged 12 months and older at CN onset. Twenty-two of the patients (70.9%) were diagnosed during treatment for acute infections. A total of 11 patients (35.5%) were hospitalized because of recurrent infections. Most of the recurrent infections occurred in the lungs (81.8%). Congenital neutropenia (CoN) was identified in 14 patients (45.1%). Eight of 14 patients (57.1%) required granulocyte-colony stimulating factor treatment, and none of them experienced adverse effects from this treatment. Fifteen patients (48.3%) were diagnosed with idiopathic neutropenia. Comparison between the idiopathic and CoN groups revealed no differences in age, the absolute number of neutrophils, or the presence of infection at diagnosis; however, differences were detected in sex and the rate of spontaneous recovery from neutropenia. Ten of the patients (32.2%) experienced spontaneous recovery from neutropenia during a follow-up period of 7 to 52 months. In current study, we found a higher CoN ratio in the CN patients compared with previous reports, which may be due to the high rate of consanguineous marriages in our country. However, the finding of CN requires several laboratory investigations, prolonged follow-up, and advanced molecular analysis, and its etiology can remain idiopathic. PMID- 26479987 TI - Pathologic Risk Factors in Pediatric and Adolescent Patients With Clinical Stage I Testicular Stromal Tumors. AB - BACKGROUND: Testicular stromal tumors (TSTs) are rare. In adult men with TSTs, various pathologic risk factors have been identified in patients with clinically localized disease that increase the risk of occult metastatic disease (OMD). We systematically reviewed existing literature to analyze the impact of these risk factors on OMD in prepubertal (0 to 12 y) and postpubertal (13 to 21 y) patients. METHODS: A literature search was conducted using the combination of terms: "testicular stromal tumors," "testicular leydig cell tumors," "testicular sertoli tumors," "testicular interstitial tumors," "testicular granulosa tumor," and "testicular sex cord tumors." Studies of patients 0 to 21 years with clinical stage I TSTs were included. RESULTS: A total of 100 patients from 31 publications were included with a median age at diagnosis of 5.7 years (range, 1.2 mo to 21 y). Seventy-nine patients were 12 years and below (median 7.2 mo) and 21 patients were 13 to 21 years (median 16 y). No patients in either group were identified to have OMD at retroperitoneal lymph node dissection or during follow-up surveillance (median follow-up 45.6 y; range, 4 to 360 mo). 99% of those 12 years and below versus 95% of those above 12 years had 0 to 1 pathologic risk factors, and 1% versus 5% had 2+ pathologic risk factors (P=0.38). CONCLUSIONS: Clinical stage I TSTs in adolescent, postpubertal patients appear to behave in a benign manner with few pathologic risk factors, similar to prepubertal patients. Given the low risk of relapse in this population, low-impact surveillance strategies are paramount. Prospective study of these patients is needed, and entry into a tumor registry such as the International Ovarian and Testicular Stromal Tumor Registry is important to learning more about this rare disease. PMID- 26479988 TI - Secondary Hemophagocytic Lymphohistiocytosis in a Patient With Favorable Histology Wilms Tumor. AB - Secondary hemophagocytic lymphohistiocytosis (HLH) is most commonly associated with malignancy, infection, or an underlying autoimmune disorder. Malignancy associated hemophagocytic syndrome is responsible for most secondary HLH cases, but it has not been well described in children. We present a case of a 4-year-old female with favorable histology of Wilms tumor who developed secondary HLH after unsuccessful resection of the tumor and initiation of chemotherapy. PMID- 26479989 TI - Tissue Expander Placement to Prevent the Adverse Intestinal Effects of Radiotherapy in Malignant Pelvic Tumors. AB - We herein report the findings of 3 patients with primary Ewing sarcoma in a pelvic lesion who underwent the placement of a tissue expander (TE) before radiation therapy to prevent the adverse effects of radiotherapy. The simulation study showed that the TE drastically reduced volume of the intestine that was irradiated at all dose levels. All patients could receive the scheduled dose of radiotherapy without any acute and late complications such as diarrhea, melena, the dislodging of the TE, infection, or the formation of fistulae. In the 4-year (minimum) observation period, we did not observe intestinal complications in any of our patients. TE placement is considered to be a safe and effective method for preventing the adverse effects of radiotherapy in pediatric malignant pelvic tumors. PMID- 26479990 TI - Use of Vandetanib in Metastatic Medullary Carcinoma of Thyroid in a Pediatric Patient With Multiple Endocrine Neoplasia 2B. AB - We describe a child with advanced, metastatic, inoperable medullary carcinoma of thyroid associated with multiple endocrine neoplasia 2B and rearranged during transfection mutation with a positive response to vandetanib treatment. He responded well with a fall in calcitonin levels and a reduction in size of the thyroid malignancy, lymph nodes, and pulmonary metastases. He has been on vandetanib for 4 years with good clinical and biochemical response. Vandetanib has a role in the treatment of patients including children with inoperable locally advanced and metastatic medullary carcinoma of thyroid. More information is needed on its use in children and long-term outcome. PMID- 26479991 TI - Severe G6PD Deficiency Due to a New Missense Mutation in an Infant of Northern European Descent. AB - We report a term male infant born to parents of Danish descent, who on the second day of life developed jaundice peaking at 67 hours and decreasing on applied double-sided phototherapy. In the weeks following, the infant showed signs of ongoing hemolysis. Laboratory tests showed very low glucose-6-phosphate dehydrogenase (G6PD) enzymatic activity, and sequencing of the G6PD gene revealed a previously uncharacterized missense mutation c. 592 C>A (Arg198Ser). Oral DNA from the infant had the same G6PD mutation, suggesting a spontaneous maternal germline mutation as the mutation was not observed in leukocytes from the mother. PMID- 26479992 TI - Comparing the Quality of Life of Patients With Hemophilia and Juvenile Idiopathic Arthritis in Which Chronic Arthropathy Is a Common Complication. AB - INTRODUCTION: Hemophilia is a genetic disorder in which recurrent joint bleeding causes arthropathy. Inflammation and degeneration play roles in the pathogenesis of hemophilic arthropathy. Patients with juvenile idiopathic arthritis (JIA) experience a similar inflammatory degenerative joint disease. A comparison of different patients with common pathogenetic features may identify unique features helpful in terms of the follow-up. AIM: We compared the quality of life (QoL) of patients with hemophilia and JIA, and healthy controls, using a generic QoL scale, Kidscreen and Disabkids Questionnaires (KINDL). Differences among groups were evaluated in terms of sociodemographic characteristics and clinical parameters affecting the QoL. METHODS: We included 33 hemophilia patients, 19 JIA patients, and 32 healthy individuals aged 4 to 18 years. Sociodemographic characteristics (the age, the maternal educational status, the place of residence, the size of the household, the household income, divorced parents) were noted, and the KINDL was administered to all participants. Clinical parameters associated with arthropathy (the functional independence score [FISH], the hemophilia joint health score [HJHS], the arthropathic joint count, and the painful joint count) were documented. Differences in frequencies and medians among the groups were evaluated using the chi, the Mann-Whitney U, and the Kruskal-Wallis tests. RESULTS: All KINDL dimensions were above 50, reflecting "good conditions" in the 2 patient groups. No difference between patients with hemophilia and JIA was evident in terms of the clinical parameters of FISH, the HJHS, or the arthropathic or painful joint counts (P>0.05). Sociodemographically, only the frequency of literate mothers was lower in patients with hemophilia than in those with JIA and healthy controls (P=0.03). Patients with JIA scored more higher on the KINDL dimension of chronic illness than those with hemophilia (P=0.02). The FISH score correlated with the total QoL score in both patients with hemophilia and JIA (r=0.39, P=0.03 and r=0.48, P=0.04, respectively). CONCLUSIONS: Although no difference was evident between the patient groups in terms of clinical parameters associated with arthropathy, JIA patients coped better with illness than those with hemophilia. JIA patients had a higher proportion of literate mothers than hemophilia patients; this may affect a patient's ability to cope with issues relating to chronic illness. Implementation of an educational program for mothers of hemophilia patients, during follow-up, may improve the patient's QoL. Also, hemophilia patients should be assisted to improve their QoL in the dimensions of self-esteem and schooling. Lastly, the evaluation of functional disability by FISH in hemophilia patients is important because the FISH score correlated with the total QoL score, as revealed by KINDL. In JIA patients also, functional disabilities caused by arthropathy affected the QoL. PMID- 26479993 TI - Fatigue in Children With Sickle Cell Disease: Association With Neurocognitive and Social-Emotional Functioning and Quality of Life. AB - Children with sickle cell disease (SCD) report fatigue in addition to acute and chronic pain, which can decrease overall health-related quality of life (HRQL). The primary objective of the current study was to investigate the relationship between fatigue and HRQL. Given limited prior research, secondary objectives included investigation of associations between fatigue and functional outcomes, including child neurocognitive and social-emotional functioning. Children aged 8 to 16 years (N=32) and a caregiver completed measures of fatigue, HRQL, pain, and neurocognitive and social-emotional functioning. Controlling for pain and number of SCD-related hospitalizations, hierarchical linear regression models were used to determine the impact of child-reported and parent-reported fatigue on child HRQL. Correlational analyses were used to explore the relationship between fatigue and additional child outcomes. Data indicated that children with SCD experience clinically relevant levels of fatigue, which independently predicts lower HRQL. Fatigue was also associated with lower working memory, executive functioning, and higher levels of internalizing symptoms. Given its observed impact on HRQL and relationship to functional outcomes, fatigue may be an important target of clinical, home, or school interventions. This practice may attenuate the burden of fatigue in these patients, and in turn, help improve the quality of life of children living with SCD. PMID- 26479994 TI - Health-related Quality of Life in Infants With Sickle Cell Disease. AB - Using historical cohorts of healthy, acutely ill, and chronically ill infants for comparison, we sought to determine whether infants with sickle cell disease (SCD) have impaired health-related quality of life (HRQL). We conducted a cross sectional study at 2 sites: the Medical College of Wisconsin/Children's of Wisconsin and the University of Alabama School of Medicine/Children's of Alabama. Parents of 90 infants with SCD completed the PedsQL Infant Module corresponding to their infant's age (1 to 12 mo or 13 to 24 mo) during a regular clinic visit. At 1 to 12 months, infants with SCD displayed lower Physical HRQL than healthy infants, but better HRQL than chronically ill infants. By 13 to 24 months, infants with SCD had worse HRQL in all areas than healthy infants and worse Physical and Total HRQL than acutely ill infants. Compared with chronically ill infants in this age group, infants with SCD had similar Physical HRQL and better Psychosocial and Total HRQL. By 13 to 24 months, a greater proportion of infants with SCD had impaired Physical and Total HRQL compared with infants aged 1 to 12 months. All differences were significant at the (P<0.05) level. Impaired HRQL can be detected in infants with SCD. PMID- 26479995 TI - Effect of Malnutrition at Diagnosis on Clinical Outcomes of Children With Acute Lymphoblastic Leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Although studies have shown that malnutrition can negatively affect treatment outcome, results are controversial. This retrospective study aims at determining the prevalence of malnutrition and its association with treatment outcome among children with ALL treated at the Children's Cancer Institute in Lebanon. A total of 103 patients diagnosed with ALL between April 2002 and May 2010 were enrolled. Anthropometric data were collected from medical records upon diagnosis, at 3 and 6 months, and at the end of treatment. Body mass index was calculated for children 2 years of age and older, whereas weight-for-height ratio was used for patients below 2 years. Patients were considered underweight, stunted, or wasted if their Z-scores were <-2 SD. The prevalence of malnourished children was 25.2% at diagnosis and remained almost the same at the end of treatment. The odds of having a poor outcome (death and relapse) was higher among malnourished children and more so among stunted children with an odds ratios=2.15; 95% confidence interval, 0.5-8.3 and odds ratio=2.63; 95% confidence interval, 0.6-11.5, respectively. Although there was a trend showing worse outcomes in malnourished children with ALL at diagnosis when compared with well-nourished children larger studies using additional tools like arm anthropometry need to be conducted to prove the association. PMID- 26479996 TI - Which Variables Are Useful for Predicting Severe Infection in Children With Febrile Neutropenia? AB - To distinguish children with chemotherapy-induced febrile neutropenia (FN) at low risk of severe infection, the variables that are significant risk factors must be identified. Our objective was to identify them by applying evidence-based standards. This retrospective 2-center cohort study included all episodes of chemotherapy-induced FN in children in 2005 and 2006. The medical history, clinical, and laboratory data available at admission were collected. Severe infection was defined by bacteremia, a positive culture of a normally sterile body fluid, invasive fungal infection, or localized infection at high risk of extension. Univariate analysis identified potential predictive variables. A generalized mixed model was used to determine the adjusted variables that predict severe infection. We analyzed 372 FN episodes. Severe infections occurred in 16.1% of them. Variables predictive of severe infection at admission were: disease with high risk of prolonged neutropenia (adjusted odds ratio [aOR]=2.5), blood cancer (aOR=1.9), fever >=38.5 degrees C (aOR=3.7), and C-reactive protein level >=90 mg/L (aOR=4.5). Now that we have identified these variables significantly associated with the risk of severe infection, they must be validated prospectively before combining the best predictive variables in a decision rule that can be used to distinguish children at low risk. PMID- 26479997 TI - Left Ventricular Metastasis in Neuroblastoma: A Case Report. AB - Neuroblastoma is the most common extracranial solid tumor in children. Most common sites of metastases from neuroblastoma are bone marrow, bone and lymph nodes, however cardiac metastasis is rarely seen. Metastatic cardiac tumors are 20 to 40 times more common than primary cardiac tumors. Mechanism of cardiac metastasis can be hematogenous, lymphatogenous, and direct extension/infiltration of tumor cells. Usually right heart metastasis is seen. Left ventricular metastatic tumor has never been reported with neuroblastoma. PMID- 26479998 TI - New ribosomes for new memories? AB - Widely thought to be a housekeeping process, the regulation and synthesis of rRNA emerges as a potentially central mechanism for the maintenance of synaptic plasticity and memory. We have recently shown that an essential component of late phase synaptic plasticity is rRNA biosynthesis - the rate-limiting step in the production of new ribosomes. We hypothesize that a particular population of ribosomes is generated upon learning-associated neural activity to alter the rate of synthesis of plasticity factors at tagged synapses that will support the maintenance of synaptic plasticity and memory. PMID- 26479999 TI - Associations between amount of smoking and alcohol intake and risk of colorectal neoplasm. AB - BACKGROUND AND AIM: Although smoking and alcohol has been linked to an increased risk of colorectal neoplasm (CRN), large-scale studies to identify dose-dependent relationship between amount of smoking and alcohol consumption and risk of CRN are rare. We aimed to investigate the risk for CRN according to the amount of smoking and alcohol intake in a large sample of Korean adults. METHODS: A cross sectional study was performed on 31,714 examinees aged >=30 years undergoing their first colonoscopy as part of routine preventive health care between 2010 and 2011. Never smokers were compared with six groups of smokers according to smoking amount, and individuals with alcohol intake of <= 6.25 g ethanol per day were compared with three groups according to alcohol amount. RESULTS: In adjusted models, the risk of overall CRN increased with increasing amount of smoking (P for trend < 0.001). The adjusted odds ratios for overall CRN comparing never smokers with six smoker groups according to smoking amount (<=2.50, 2.51-5.60, 5.61-9.00, 9.01-13.00, 13.01-19.50, and >=19.51 pack-years) were 1.02, 1.19, 1.35, 1.53, 1.63, and 2.03, respectively. In addition, the risk of both non advanced and advanced CRN increased with increasing amount of smoking (both P for trend < 0.001). However, the amount of alcohol consumption was not correlated with the risk of CRN. CONCLUSIONS: The prevalence of CRN was associated with increasing amount of smoking in a dose-response manner, whereas it was not associated with the amount of alcohol consumption. Our study suggests that smoking amount as well as smoking status should be considered for CRN risk stratification. PMID- 26480001 TI - Promoting the confluence of tropical cyclone research. AB - Contributions of biologists to tropical cyclone research may improve by integrating concepts from other disciplines. Employing accumulated cyclone energy into protocols may foster greater integration of ecology and meteorology research. Considering experienced ecosystems as antifragile instead of just resilient may improve cross-referencing among ecological and social scientists. Quantifying ecosystem capital as distinct from ecosystem services may improve integration of tropical cyclone ecology research into the expansive global climate change research community. PMID- 26480003 TI - AVMA's advocacy efforts protect, promote, and advance your interests. PMID- 26480004 TI - IT DOESN'T HAVE TO HUR+. PMID- 26480000 TI - Identification of linc-NeD125, a novel long non coding RNA that hosts miR-125b-1 and negatively controls proliferation of human neuroblastoma cells. AB - The human genome contains some thousands of long non coding RNAs (lncRNAs). Many of these transcripts are presently considered crucial regulators of gene expression and functionally implicated in developmental processes in Eukaryotes. Notably, despite a huge number of lncRNAs are expressed in the Central Nervous System (CNS), only a few of them have been characterized in terms of molecular structure, gene expression regulation and function. In the present study, we identify linc-NeD125 as a novel cytoplasmic, neuronal-induced long intergenic non coding RNA (lincRNA). Linc-NeD125 represents the host gene for miR-125b-1, a microRNA with an established role as negative regulator of human neuroblastoma cell proliferation. Here, we demonstrate that these two overlapping non coding RNAs are coordinately induced during in vitro neuronal differentiation, and that their expression is regulated by different mechanisms. While the production of miR-125b-1 relies on transcriptional regulation, linc-NeD125 is controlled at the post-transcriptional level, through modulation of its stability. We also demonstrate that linc-NeD125 functions independently of the hosted microRNA, by reducing cell proliferation and activating the antiapoptotic factor BCL-2. PMID- 26480005 TI - An honest look at common stressors in the profession. PMID- 26480006 TI - What Is Your Diagnosis? Congenital intrapulmonary bronchogenic cyst. PMID- 26480007 TI - What Is Your Diagnosis? Acute, severe trauma resulting in multiple fractures and complete luxation of the thoracic vertebral column. PMID- 26480008 TI - What Is Your Neurologic Diagnosis? Astrocytoma affecting the pontine region of the brainstem. PMID- 26480009 TI - ECG of the Month. Atrioventricular dissociation arrhythmia. PMID- 26480010 TI - Pathology in Practice. Acute to subacute multifocal to coalescing necrosis of the myocardium. PMID- 26480011 TI - Usefulness of whole blood, plasma, peritoneal fluid, and peritoneal fluid supernatant glucose concentrations obtained by a veterinary point-of-care glucometer to identify septic peritonitis in dogs with peritoneal effusion. AB - OBJECTIVE: To evaluate the usefulness of a veterinary point-of-care glucometer for identification of septic peritonitis in dogs with peritoneal effusion (PE). DESIGN: Prospective clinical evaluation. ANIMALS: 39 dogs with PE. PROCEDURES: Blood and peritoneal fluid convenience samples were collected concurrently in all dogs at the time of initial evaluation. A veterinary point-of-care glucometer was used to measure glucose concentration in heparinized whole blood, plasma, peritoneal fluid, and peritoneal fluid supernatant samples. Seventeen dogs had confirmed septic peritonitis, and 22 dogs had nonseptic PE. Sensitivity, specificity, positive and negative predictive values, and accuracy of identification of dogs with septic peritonitis were calculated for glucose concentration differences for whole blood versus peritoneal fluid (WB-PF), plasma versus peritoneal fluid (P-PF), and plasma versus peritoneal fluid supernatant (P PFS). RESULTS: With a cutoff of > 20 mg/dL, the glucose concentration difference for WB-PF was an insensitive indicator of septic peritonitis (sensitivity, 41.2%; specificity, 100%). In comparison, the glucose concentration differences for P-PF and P-PFS had a higher sensitivity for septic peritonitis (88.2% and 82.4%, respectively) but a lower specificity (80% and 77.8%, respectively). With a glucose concentration difference cutoff of >= 38 mg/dL, specificity, positive predictive value, and accuracy of P-PF and P-PFS improved. CONCLUSIONS AND CLINICAL RELEVANCE: Determination of the glucose concentration difference for WB PF with the veterinary point-of-care glucometer was not useful in identifying all dogs with septic peritonitis. A glucose concentration difference of >= 38 mg/dL for P-PF or P-PFS, however, supported an accurate diagnosis of septic peritonitis in dogs with PE. PMID- 26480012 TI - Efficacy of endotracheal tube disinfection strategies for elimination of Streptococcus zooepidemicus and Bordetella bronchiseptica. AB - OBJECTIVE: To evaluate the efficacy of various endotracheal tube disinfection strategies for elimination of Streptococcus zooepidemicus and Bordetella bronchiseptica. DESIGN: Experimental in vitro study. SAMPLE: 12 sterile endotracheal tubes. PROCEDURES: Endotracheal tubes were inoculated with S zooepidemicus or B bronchiseptica and subjected to 1 of 5 treatments (spraying with accelerated hydrogen peroxide solution [AHP] or soaking in one of the following: AHP, 0.5% chlorhexidine gluconate solution [CHG], 0.3% triclosan containing soap solution, or tap water) or left untreated (controls). After 5 minutes, tubes were rinsed with water and swabbed for direct and enrichment culture. Culture results were scored semiquantitatively. Each isolate was tested separately (10 endotracheal tubes/isolate/treatment). RESULTS: No growth was identified by direct culture of any samples collected from CHG-treated endotracheal tubes, whereas S zooepidemicus and B bronchiseptica were each identified from 1 of 10 tubes sprayed or soaked with AHP and from all tubes (10/10 each) treated by other methods or used as controls. The CHG and AHP treatments resulted in significantly lower median growth scores after direct culture than did other treatments. After enrichment culture, samples from CHG treated tubes had significantly lower growth scores than samples from AHP-treated tubes, which had significantly lower scores than samples from other treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: High-level disinfection (ie, elimination of all vegetative bacterial growth) was not achieved with any treatment tested. Although optimal approaches are not known, processing of endotracheal tubes with CHG or AHP appears to be the best approach when sterilization is not feasible. PMID- 26480013 TI - Use of a caudoventral-craniodorsal oblique radiographic view made at 45 degrees to the frontal plane to evaluate the pectoral girdle in raptors. AB - OBJECTIVE: To evaluate use of a caudoventral-craniodorsal oblique radiographic view made at 45 degrees to the frontal plane (H view) for assessment of the pectoral (thoracic) girdle in raptors. DESIGN: Retrospective cross-sectional analysis. ANIMALS: 24 raptors suspected to have a fracture of the thoracic girdle. PROCEDURES: Standard ventrodorsal and H views were obtained for all birds. Radiographs were evaluated twice by a radiologist blinded to the final diagnosis, with each view first evaluated independently and views then evaluated in combination. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, with results of surgery or necropsy used as the gold standard. RESULTS: 9 birds had thoracic girdle fractures; fractures were correctly identified in 8 of these 9 birds on the ventrodorsal view alone, 7 of these 9 birds on the H view alone, and all 9 birds on the 2 views in combination. Fifteen birds did not have thoracic girdle fractures; radiographs were correctly classified in 12 of these 15 birds when the ventrodorsal view was evaluated alone, all 15 birds when the H view was evaluated alone, and 14 of these 15 birds when the 2 views were evaluated in combination. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that the H view or the addition of the H view to the VD view could be useful in raptors suspected to have fractures of the thoracic girdle. Agreement with the gold standard (ie, fracture present or absent) was higher with the H view and combination of views than with the ventrodorsal view alone. PMID- 26480014 TI - Outcome of full-thickness skin grafts used to close skin defects involving the distal aspects of the limbs in cats and dogs: 52 cases (2005-2012). AB - OBJECTIVE: To describe the outcome of full-thickness skin grafts used to close skin defects involving the distal aspects of the limbs in cats and dogs and identify factors associated with outcome. DESIGN: Retrospective case series. ANIMALS: 20 cats and 32 dogs with a skin defect involving the distal aspect of a limb that received 58 full-thickness skin grafts between 2005 and 2012. PROCEDURES: Data regarding patient signalment, location and cause of the skin defect, surgical and anesthetic duration, and postoperative bandaging protocol were obtained from the medical records. Graft outcome was assessed by interpreting descriptions in the records; skin viability over >= 75% of the graft area between 7 and 14 days after surgery was considered a successful outcome. RESULTS: For 4 of the 58 grafts, graft outcome could not be determined from the medical record. For the remaining grafts, success rate was significantly higher for grafts placed in cats (17/22 [77%]) than in dogs (12/32 [38%]). The overall complication rate was 50%; complications included skin graft failure, donor site dehiscence, and bandage-induced sloughing of skin adjacent to the graft recipient site. In addition to species, anatomic location of the skin defect was identified as a prognostic indicator of graft outcome. CONCLUSIONS AND CLINICAL RELEVANCE: Full-thickness skin grafting had a higher success rate in cats than in dogs. Skin grafts applied to the antebrachium, compared with other locations on the distal aspects of the limbs, were associated with a poorer prognosis. PMID- 26480015 TI - Establishment of reference values for various coagulation tests in healthy Florida manatees (Trichechus manatus latirostris) and evaluation of coagulation in debilitated manatees during rehabilitation. AB - OBJECTIVE: To establish reference ranges for coagulation parameters in healthy Florida manatees (Trichechus manatus latirostris) and compare results with those for debilitated manatees undergoing treatment at a rehabilitation facility. DESIGN: Prospective study. ANIMALS: 29 healthy manatees and 45 debilitated manatees with various diseases. PROCEDURES: Manatees considered healthy on the basis of results of physical examination, CBC, and serum biochemical analysis underwent coagulation testing including measurement of prothrombin time, partial thromboplastin time, D-dimer concentration, platelet count, and fibrinogen concentration to establish reference ranges. For comparison, a group of manatees undergoing rehabilitation was also tested, and the results were compared. Thromboelastography was also performed on some animals. RESULTS: Values for D dimer concentration were significantly higher in debilitated versus healthy animals. There was no significant difference for prothrombin time, partial thromboplastin time, platelet count, or fibrinogen concentration between groups. Thromboelastography was performed on 8 healthy animals. CONCLUSIONS AND CLINICAL RELEVANCE: Reference ranges were established for various tests of coagulation that may assist clinicians during the initial evaluation and rehabilitation of Florida manatees. Future research to evaluate the effect of specific disease processes on the coagulation cascade is recommended. PMID- 26480017 TI - Wettability Contrast Gravure Printing. AB - Silicon gravure patterns are engineered to have cells that are wettable and lands that are not wettable by aqueous inks. This strategy allows excess ink on the lands to be removed without using a doctor blade. Using an aqueous silica ink, continuous lines as narrow as 1.2 MUm with 1.5 MUm space are gravure printed. PMID- 26480018 TI - Simultaneous detection of fluquinconazole and flusilazole in lettuce using gas chromatography with a nitrogen phosphorus detector: decline patterns at two different locations. AB - Method validations in addition to decline patterns of fluquinconazole and flusilazole in lettuce grown under greenhouse conditions at two different locations were investigated. Following the application of fluquinconazole and flusilazole at a dose rate of 20 mL/20 L water, lettuce samples were collected randomly for up to 7 days post-application, and simultaneously extracted with acetone, purified through solid-phase extraction, analyzed via gas chromatography with a nitrogen phosphorus detector, and confirmed through gas chromatography mass spectrometry. The linearity was excellent, with determination coefficients (R(2) ) between 0.9999 and 1.0. The method was validated in triplicate at two different spiking levels (0.2 and 1.0 mg/kg) with satisfactory recoveries between 75.7 and 97.9% and relative standard deviations of <9. The limit of quantification was 0.01 mg/kg. Both analytes declined very quickly, as can be seen from the short half-life time of <4 days. Statistical analysis revealed significant differences between residues at different days of sampling, except at 7 days post-application (triple application). At that point, the decline patterns of fluquinconazole and flusilazole were independent of application rate, location, temperature and humidity. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26480019 TI - Dielectric waveguides for ultrahigh field magnetic resonance imaging. AB - PURPOSE: The design of RF coils for MRI transmit becomes increasingly challenging at high frequencies required for MRI at 7T and above. Our goal is to show a proof of principle of a new type of transmit coil for higher field strengths. METHOD: We demonstrate an alternative transmit coil design based on dielectric waveguide principles which transfers energy via evanescent wave coupling. The operating principles and conditions are explored by simulations. The waveguide is applied for in vivo imaging at 7T. RESULTS: The waveguide can be an efficient transmit coil when four conditions are fulfilled: (1) the waveguide should be operated just above the cutoff frequency of the lowest order transverse electric mode, (2) the waveguide should not operate at a frequency where the wavelength fits an integer number of times in the waveguide length and standing wave patterns become very prominent, (3) for homogeneous excitation, the waveguide should be bent around the object, and (4) there should be an air gap between the waveguide and the object. CONCLUSIONS: By choosing the dielectric and the dimensions adequately, the dielectric waveguide couples the magnetic field efficiently into the body. The waveguide can be redesigned for higher frequencies by simple adaptations and may be a promising transmit alternative. Magn Reson Med 76:1314 1324, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26480020 TI - Towards the rationalization of catalytic activity values by means of local hyper softness on the catalytic site: a criticism about the use of net electric charges. AB - By means of the Spin-Polarized Conceptual Density Functional Theory (SP-CDFT), three 2,6-bis(imino)pyridine catalysts based on iron(II), used for polymerization of ethylene, were studied. The catalysts differed by the substituent group, bearing either -H, -NO2 or -OCH3. To date, catalytic activity, a purely experimental parameter measuring the mass of polyethylene produced per millimole of iron per time and pressure unit at a fixed temperature, has not been explained in terms of local hyper-softness. The latter is a purely theoretical parameter designed for quantifying electronic effects; it is measured using the metal atom responsible for the coordination process with the monomer (ethylene). Because steric effects are not relevant in these kinds of catalysts and only electronic effects drive the catalytic process, an interesting link is found between catalytic activity and the local hyper-softness condensed on the iron atom by means of four functionals (B3LYP, BP86, B97D, and VSXC). This work demonstrates that the use of local hyper-softness, predicted by the SP-CDFT, is a suitable parameter for explaining order relationships among catalytic activity values, thus quantifying the electronic influence of the substituent group inducing this difference; the use of only net electric charges does not lead to clear conclusions. This finding can aid in estimating catalytic activities leading to a more rational design of new catalysts via computational chemistry. PMID- 26480021 TI - Angelman syndrome: A review highlighting musculoskeletal and anatomical aberrations. AB - Angelman's syndrome (AS) is a genetic neurodevelopment disorder. The cause is a known abnormality involving the maternal inherited ubiquitin-protein ligase (UBE3A) gene. Clinical characteristics universal to the disorder are well documented in the literature and include developmental delay, seizures, ataxia, altered tone, severely impaired speech and intellect, as well as an overall happy demeanor, frequent bouts of laughter, and hypermotoric behavior. Associated with this disorder are several musculoskeletal aberrations. To date, a review of case studies reporting on these musculoskeletal changes has not been carried out. Thus, the purpose of this paper was to provide an overview of the musculoskeletal changes present in individuals with AS. In our review of 21 case reports from 1965-2013, the most consistently reported anatomical changes were of the craniofacial region. These include microcephaly, brachycephaly, a palpable occipital groove, prognathism, and wide spaced teeth. Other musculoskeletal abnormalities less frequently reported in the literature include scoliosis, excessive lumbar lordosis, and pes planus. Given that the majority of the case reports reviewed was of young children, the possibility of underreporting musculoskeletal changes which may manifest in the later years of life may be present. Early diagnosis and interventions to minimize secondary complications are crucial to maintain quality of life. An overall multidisciplinary approach is emphasized to maximize developmental potential for these individuals. Future prospective studies that follow patients into adulthood are needed to better understand the prevalence and development of secondary musculoskeletal changes, which in turn can inform intervention techniques and preventative measures. Clin. Anat. 29:561-567, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26480022 TI - Fractionation of Poly(butyl methacrylate) by Molecular Topology Using Multidetector Thermal Field-Flow Fractionation. AB - Thermal field-flow fractionation (ThFFF) is an interesting alternative to column based fractionation being able to address different molecular parameters including size and composition. Until today it has not been shown to be able to fractionate polymers of similar molar masses and chemical compositions by molecular topology. The present study demonstrates that poly(butyl methacrylates) with identical molar masses can be fractionated by ThFFF according to the topology of the butyl group. The influence of the solvent polarity on the thermal diffusion behavior of these polymers is presented and it is shown to have a significant influence on the fractionation of poly(n-butyl methacrylate) and poly(t-butyl methacrylate). Fractionation improves with increasing solvent polarity and solvent polarity may have a greater influence on fractionation than solvent viscosity. It is found that the thermal diffusion coefficient, D(T), as well as the hydrodynamic diameter, D(h), exhibit increasing trends with increasing solvent polarity. The solvent quality has a significant influence on the fractionation. It is found that cyclohexane, being a theta solvent for poly(t butyl methacrylate) but not for poly(n-butyl methacrylate), significantly improves the fractionation of the samples by decreasing the diffusion rate of the former but not the latter. PMID- 26480023 TI - Designed Amino Acid Feed in Improvement of Production and Quality Targets of a Therapeutic Monoclonal Antibody. AB - Cell culture feeds optimization is a critical step in process development of pharmaceutical recombinant protein production. Amino acids are the basic supplements of mammalian cell culture feeds with known effect on their growth promotion and productivity. In this study, we reported the implementation of the Plackett-Burman (PB) multifactorial design to screen the effects of amino acids on the growth promotion and productivity of a Chinese hamster ovary DG-44 (CHO DG44) cell line producing bevacizumab. After this screening, the amino acid combinations were optimized by the response surface methodology (RSM) to determine the most effective concentration in feeds. Through this strategy, the final monoclonal antibody (mAb) titre was enhanced by 70%, compared to the control group. For this particular cell line, aspartic acid, glutamic acid, arginine and glycine had the highest positive effects on the final mAb titre. Simultaneously, the impact of the designed amino acid feed on some critical quality attributes of bevacizumab was examined in the group with highest productivity. The product was analysed for N-glycan profiles, charge variant distribution, and low molecular weight forms. The results showed that the target product quality has been improved using this feeding strategy. It was shown how this strategy could significantly diminish the time and number of experiments in identifying the most effective amino acids and related concentrations in target product enhancement. This model could be successfully applied to other components of culture media and feeds. PMID- 26480024 TI - Effect of Docosahexaenoic Acid on Cell Cycle Pathways in Breast Cell Lines With Different Transformation Degree. AB - n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), abundant in fish, have been shown to affect development and progression of some types of cancer, including breast cancer. The aim of our study was to further analyze and clarify the effects of these nutrients on the molecular mechanisms underlying breast cancer. Following treatments with DHA we examined cell viability, death, cell cycle, and some molecular effects in breast cell lines with different transformation, phenotypic, and biochemical characteristics (MCF-10A, MCF-7, SK-BR-3, ZR-75-1). These investigations showed that DHA is able to affect cell viability, proliferation, and cell cycle progression in a different way in each assayed breast cell line. The activation of ERK1/2 and STAT3 pathways and the expression and/or activation of molecules involved in cell cycle regulation such as p21(Waf1/Cip1) and p53, are very differently regulated by DHA treatments in each cell model. DHA selectively: (i) arrests non tumoral MCF-10A breast cells in G0 /G1 cycle phase, activating p21(Waf1/Cip1) , and p53, (ii) induces to death highly transformed breast cells SK-BR-3, reducing ERK1/2 and STAT3 phosphorylation and (iii) only slightly affects each analyzed process in MCF-7 breast cell line with transformation degree lower than SK-BR-3 cells. These findings suggest a more relevant inhibitory role of DHA within early development and late progression of breast cancer cell transformation and a variable effect in the other phases, depending on individual molecular properties and degree of malignancy of each clinical case. PMID- 26480025 TI - Identification of the zebrafish red nucleus using Wheat Germ Agglutinin transneuronal tracing. AB - The red nucleus is located in the rostral midbrain of the vertebrate brain and controls motor coordination during locomotion. It receives input from the cerebellum and sends its output to the spinal cord. The presence of the red nucleus is well established in tetrapods, and its existence has also been suggested in teleosts but its presence and position has still been under discussion. By using wheat germ agglutinin (WGA) as a genetically encoded anterograde tracer, we recently identified contralateral projections from the cerebellum to a putative red nucleus in the zebrafish midbrain tegmentum. In this report we further revealed red nucleus derived from this contralateral afferent from the cerebellum using WGA and contralateral projections to the hindbrain spinal cord junction site using DiI-mediated retrograde tracing. Thus the structure that we have identified by anterograde and retrograde tracing fulfills the anatomical demands for the red nucleus: the location in the midbrain tegmentum, contralateral afferent from the cerebellum (cerebello-ruber projection) and contralateral efferent to the spinal cord (rubro-spinal projection). PMID- 26480026 TI - The sensory system: More than just a window to the external world. AB - While the traditional importance of the sensory system lies in its ability to perceive external information about the world, emerging discoveries suggest that sensory perception has a greater impact on health and longevity than was previously appreciated. These effects are conserved across species. In this mini review, we discuss the specific sensory cues that have been identified to significantly impact organismal physiology and lifespan. Ongoing work in the aging field has begun to identify the downstream molecules that mediate the broad effects of sensory signals. Candidates include FOXO, neuropeptide F (NPF), adipokinetic hormone (AKH), dopamine, serotonin, and octopamine. We then discuss the many implications that arise from our current understanding of the effects of sensory perception on health and longevity. PMID- 26480027 TI - Different definition of microvascular angina. AB - We sometimes encounter patients with microvascular angina (MVA), a disease characterized by anginal pain without abnormal coronary arteriographic findings or coronary spasm. More than 40 years have passed since MVA was first confirmed. The terms 'syndrome X', 'cardiac syndrome X' and 'microvascular dysfunction' have also been used to describe conditions similar to MVA, but all with slightly different definitions. The cause of MVA seems almost certain to be organic and functional abnormalities of the small arteries of the heart. Patients with MVA are likely to suffer from endothelial dysfunction and other microvascular abnormalities of both the coronary and peripheral arteries. The major treatment of MVA has been medication, most often calcium channel blockers. The prognosis of MVA is generally excellent, although symptoms remain in many studies. Some MVA patients with accompanying hypertensive heart disease have gone on to develop progressive left ventricular dysfunction, with poor prognosis. The different definitions applied to the terms used to describe this condition, what we refer to here as MVA, can confound issues involved in diagnosis, prognosis and proper treatment. Therefore, it is extremely important to distinguish primary MVA without underlying heart disease from secondary MVA to explore the disease mechanism and examine the clinical characteristics. It is more than 40 years since Likoff first confirmed this disease; therefore, all researchers know that strict diagnostic criteria for MVA should be immediately established. PMID- 26480029 TI - Effect of Different Surface Treatments on Porcelain-Resin Bond Strength. AB - PURPOSE: The aim of this study was to evaluate the effects of various surface treatments on the surface structure and shear bond strength (SBS) of different ceramics. MATERIALS AND METHODS: A total of 192 disk-shaped cores were prepared using two all-ceramic systems, of which 168 were submitted to SBS tests, and 24 were investigated by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The ceramics used were IPS Empress e.max (EX) lithium glass ceramic and Vita In-Ceram Zirconia glass-infiltrated zirconia (ICZ). The specimens were randomly divided into seven groups (n = 12) on the basis of the surface treatment used: control; SB-sandblasting with 50 MUm Al2 O3 particles; CJ chairside silica coating with 30 MUm SiO2 particles and silanization (Clearfil Porcelain Bond Activator); HF-etching in 5% hydrofluoric acid and silanization; ER-etching with an Er:YAG laser (10 W); ND-Nd:YAG laser etching (0.8 W); and FS etching with a femtosecond laser (860 mW). A luting cement (Clearfil Esthetic) was photopolymerized on each treated ceramic disk. After subjecting the specimens to thermocycling (1000 cycles, 5 degrees C to 55 degrees C), SBS tests were performed using a universal testing machine. The data were analyzed with two-way ANOVA and Tukey's tests using a significance limit of 5%. RESULTS: Among the EX ceramics, the CJ (29.10 MPa) and HF (26.07 MPa) specimens had statistically higher SBS values. For the ICZ ceramics, the highest value (28.08 MPa) was obtained for the CJ specimens. CONCLUSIONS: Silanization after coating with silica improves the bond strengths of both EX and ICZ specimens, while HF etching is favorable only for the EX specimens. PMID- 26480028 TI - Synaptic Efficacy as a Function of Ionotropic Receptor Distribution: A Computational Study. AB - Glutamatergic synapses are the most prevalent functional elements of information processing in the brain. Changes in pre-synaptic activity and in the function of various post-synaptic elements contribute to generate a large variety of synaptic responses. Previous studies have explored postsynaptic factors responsible for regulating synaptic strength variations, but have given far less importance to synaptic geometry, and more specifically to the subcellular distribution of ionotropic receptors. We analyzed the functional effects resulting from changing the subsynaptic localization of ionotropic receptors by using a hippocampal synaptic computational framework. The present study was performed using the EONS (Elementary Objects of the Nervous System) synaptic modeling platform, which was specifically developed to explore the roles of subsynaptic elements as well as their interactions, and that of synaptic geometry. More specifically, we determined the effects of changing the localization of ionotropic receptors relative to the presynaptic glutamate release site, on synaptic efficacy and its variations following single pulse and paired-pulse stimulation protocols. The results indicate that changes in synaptic geometry do have consequences on synaptic efficacy and its dynamics. PMID- 26480030 TI - Ancient Human Bone Microstructure in Medieval England: Comparisons between Two Socio-Economic Groups. AB - Understanding the links between bone microstructure and human lifestyle is critical for clinical and anthropological research into skeletal growth and adaptation. The present study is the first to report correspondence between socio economic status and variation in bone microstructure in ancient humans. Products of femoral cortical remodeling were assessed using histological methods in a large human medieval sample (N = 450) which represented two distinct socio economic groups. Osteonal parameters were recorded in posterior midshaft femoral sections from adult males (N = 233) and females (N = 217). Using univariate and multivariate statistics, intact, fragmentary, and osteon population densities, Haversian canal area and diameter, and osteon area were compared between the two groups, accounting for sex, age, and estimated femoral robusticity. The size of osteons and their Haversian canals, as well as osteon density, varied significantly between the socio-economic groups, although minor inconsistencies were observed in females. Variation in microstructure was consistent with historical textual evidence that describes differences in mechanical loading and nutrition between the two groups. Results demonstrate that aspects of ancient human lifestyle can be inferred from bone microstructure. PMID- 26480031 TI - Sentinel lymph node biopsy in Merkel cell carcinoma: a 15-year institutional experience and statistical analysis of 721 reported cases. AB - Merkel cell carcinoma (MCC) is a rare aggressive cutaneous neuroendocrine malignancy that frequently metastasizes to the regional lymphatic basin. Pathological assessment of regional lymph nodes with sentinel lymph node biopsy (SLNB) in patients without clinical involvement has permitted more accurate staging and more appropriate management. Nonetheless, concerns have been raised regarding the accuracy of this technique and its prognostic implications. We conducted a review of previously published data analysing the positive and false negative rates of SLNB in MCC. A search of the Medline and Embase databases to April 2015 identified 36 published studies between 1997 and 2015 comprising 692 patients. With the addition of 29 patients treated at our own institution, we conducted an analysis of 721 patients. Among this cumulative cohort, SLNBs were performed from 736 regional sites with 29.6% recorded as positive. Regional metastasis occurred in 45 cases following a negative SLNB, for a false negative rate of 17.1%. Adjuvant regional radiotherapy in the setting of a negative SLNB did not affect regional recurrence (P = 0.31), providing credence to emerging evidence that regional therapy can be safely omitted in the setting of a negative SLNB. Distant relapse was noted far more frequently following a positive rather than negative SLNB (17.6% vs. 7.3%, P < 0.001). PMID- 26480032 TI - Sterilization by Cooling in Isochoric Conditions: The Case of Escherichia coli. AB - High hydrostatic pressure (HHP) affects the structure, metabolism and survival of micro-organisms including bacteria. For this reason HHP is a promising treatment in the food industry. The aim of this work is to evaluate the effect of high pressure, under isochoric cooling conditions, on Escherichia coli, where such high pressure develops due to the fact water cannot expand. We combine survival curves obtained by spectrophotometry and images of atomic force microscopy in this study. Our results show that cooling at -20 and -30 degrees C leads to a partial destruction of a Escherichia coli population. However, cooling at -15 degrees C causes a total extermination of bacteria. This intriguing result is explained by the phase diagram of water. In the first case, the simultaneous formation of ice III and ice Ih crystals provides a safe environment for bacteria. In the second case (-15 degrees C) Escherichia coli remains in a metastable and amorphous free-of-crystals liquid subjected to high pressure. Our work is the first experimental study carried out to inactivate Escherichia coli under isochoric cooling conditions. Unlike HHP, which is based on the application of an external load to augment the pressure, this technique only requires cooling. The method could be used for annihilation of other Escherichia coli strains and perhaps other micro-organisms. PMID- 26480033 TI - Unusual Animal Behavior Preceding the 2011 Earthquake off the Pacific Coast of Tohoku, Japan: A Way to Predict the Approach of Large Earthquakes. AB - Unusual animal behaviors (UABs) have been observed before large earthquakes (EQs), however, their mechanisms are unclear. While information on UABs has been gathered after many EQs, few studies have focused on the ratio of emerged UABs or specific behaviors prior to EQs. On 11 March 2011, an EQ (Mw 9.0) occurred in Japan, which took about twenty thousand lives together with missing and killed persons. We surveyed UABs of pets preceding this EQ using a questionnaire. Additionally, we explored whether dairy cow milk yields varied before this EQ in particular locations. In the results, 236 of 1,259 dog owners and 115 of 703 cat owners observed UABs in their pets, with restless behavior being the most prominent change in both species. Most UABs occurred within one day of the EQ. The UABs showed a precursory relationship with epicentral distance. Interestingly, cow milk yields in a milking facility within 340 km of the epicenter decreased significantly about one week before the EQ. However, cows in facilities farther away showed no significant decreases. Since both the pets' behavior and the dairy cows' milk yields were affected prior to the EQ, with careful observation they could contribute to EQ predictions. PMID- 26480034 TI - Potential of Biological Processes to Eliminate Antibiotics in Livestock Manure: An Overview. AB - Degrading antibiotics discharged in the livestock manure in a well-controlled bioprocess contributes to a more sustainable and environment-friendly livestock breeding. Although most antibiotics remain stable during manure storage, anaerobic digestion can degrade and remove them to various extents depending on the concentration and class of antibiotic, bioreactor operating conditions, type of feedstock and inoculum sources. Generally, antibiotics are degraded during composting > anaerobic digestion > manure storage > soil. Manure matrix variation influences extraction, quantification, and degradation of antibiotics, but it has not been well investigated. Fractioning of manure-laden antibiotics into liquid and solid phases and its effects on their anaerobic degradation and the contribution of abiotic (physical and chemical) versus biotic degradation mechanisms need to be quantified for various manures, antibiotics types, reactor designs and temperature of operations. More research is required to determine the kinetics of antibiotics' metabolites degradation during anaerobic digestion. Further investigations are required to assess the degradation of antibiotics during psychrophilic anaerobic digestion. PMID- 26480035 TI - Establishing Sprinkling Requirements on Trailers Transporting Market Weight Pigs in Warm and Hot Weather. AB - This study was conducted July of 2012 in Iowa, in WARM (<26.7 degrees C) and HOT (>=26.7 degrees C) weather. Four sprinkling methods were compared, with one treatment being randomly assigned to each load: control- no sprinkling (not applied in HOT weather), pigs only, bedding only, or pigs and bedding. Experiment 1 used 51 loads in WARM- and 86 loads in HOT weather to determine sprinkling effects on pig measures (surface temperature, vocalizations, slips and falls, and stress signs). Experiment 2 used 82 loads in WARM- and 54 loads in HOT weather to determine the sprinkling effects on transport losses (non-ambulatory, dead, and total transport losses). Experiment 1 found that, in WARM weather, there were no differences between sprinkling treatments for surface temperature, vocalizations, or slips and falls (p >= 0.18). However, stress signs were 2% greater when sprinkling pigs- or bedding only- compared to control (p = 0.03). Experiment 2 found that, in WARM and HOT weather, sprinkling did not affect non-ambulatory, dead, or total transport losses (p >= 0.18). Although the current study did not find any observed sprinkling effects for pig measures or transport losses it is extremely important to note that the inference space of this study is relatively small, so further studies should be conducted to see if these results are applicable to other geographical regions and seasons. PMID- 26480036 TI - The Effect of Age, Stocking Density and Flooring during Transport on Welfare of Young Dairy Calves in Australia. AB - Transport of young ('bobby') calves for slaughter is a contentious welfare issue for some sectors of the Australian community. Factors of age, stocking density and flooring need further research to develop appropriate welfare standards for transport of bobby calves. The objective of this study was to identify the space allowance requirements for transport of bobby calves and to understand factors such as age and flooring that minimise risks to calf welfare during transport. Animals aged 3-, 5- and 10-day old were transported for 12 h in a custom-made cattle truck fitted with 9 pens, with movable mesh divisions. Each pen contained 4 calves, with space allowances of 0.2, 0.3 and 0.5 m2 per calf and flooring of solid metal, mesh or straw bedding. A total of 432 male dairy calves were transported in 12 trips during the 2-year study. Behavioural measurements included lying during transport, and lying and drinking for 12 h after transport during recovery. Blood samples were taken prior to transport, immediately after transport and 12 h after transport. Blood samples were analysed for metabolic state (glucose, beta-hydroxy-butyrate (BOHB)), hydration (packed cell volume (PCV)) and exhaustion/bruising (creatine kinase (CK) activity). It was found that several measures were affected by age, which indicates that the physiology and in particular lying behaviour of 3-day old calves is fundamentally different from that of older calves. It is unclear how this affects their ability to cope with the stressors of transport. Space affected the posture changes and CK activity during and after transport and it is concluded that space allowance should be at least 0.3 m2 per calf for calves of average size, while CK activity suggested that providing more space to 0.5 m2 per calf may provide even greater benefits. Straw bedding is of clear benefit to calves during transport, to the extent that it may even reduce some of the negative effects of reduced space on lying behaviour. PMID- 26480037 TI - Welfare of Pigs Being Transported over Long Distances Using a Pot-Belly Trailer during Winter and Summer. AB - A total of 2,145 pigs were transported for 8 h in summer (six trips) and winter (five trips) using a pot-belly trailer accommodating pigs in four locations (upper deck or UD, bottom-nose or BN, middle deck or MD and bottom deck or BD). Heart rate of pigs during loading and transportation and lactate and creatine kinase (CK) concentrations in exsanguination blood were measured. Meat quality was evaluated in the Longissimus thoracis (LT), Semimembranosus (SM) and Adductor (AD) muscles. During summer, pigs loaded in the UD and MD had higher (P < 0.05) heart rate at loading compared to those located in the BD and BN. Blood lactate and CK concentrations were higher (P < 0.001) in winter than in summer. Lactate concentration was higher (P = 0.01) in the blood of pigs transported in the BN. Pigs transported in the BN had higher pHu values in the LT, SM and AD muscles (P = 0.02, P < 0.001 and P = 0.002, respectively) and lower (P = 0.002) drip loss values in the SM muscle. This study confirms that some locations within the PB trailer have a negative impact on the welfare of pigs at loading and during transport with more pronounced effects in the winter due to the additive effect of cold stress. PMID- 26480038 TI - No Pet or Their Person Left Behind: Increasing the Disaster Resilience of Vulnerable Groups through Animal Attachment, Activities and Networks. AB - Increased vulnerability to natural disasters has been associated with particular groups in the community. This includes those who are considered de facto vulnerable (children, older people, those with disabilities etc.) and those who own pets (not to mention pets themselves). The potential for reconfiguring pet ownership from a risk factor to a protective factor for natural disaster survival has been recently proposed. But how might this resilience-building proposition apply to vulnerable members of the community who own pets or other animals? This article addresses this important question by synthesizing information about what makes particular groups vulnerable, the challenges to increasing their resilience and how animals figure in their lives. Despite different vulnerabilities, animals were found to be important to the disaster resilience of seven vulnerable groups in Australia. Animal attachment and animal-related activities and networks are identified as underexplored devices for disseminating or 'piggybacking' disaster related information and engaging vulnerable people in resilience building behaviors (in addition to including animals in disaster planning initiatives in general). Animals may provide the kind of innovative approach required to overcome the challenges in accessing and engaging vulnerable groups. As the survival of humans and animals are so often intertwined, the benefits of increasing the resilience of vulnerable communities through animal attachment is twofold: human and animal lives can be saved together. PMID- 26480039 TI - Establishing Bedding Requirements during Transport and Monitoring Skin Temperature during Cold and Mild Seasons after Transport for Finishing Pigs. AB - The broad aim of this study was to determine whether bedding level in the transport trailer influenced pig performance and welfare. Specifically, the objective was to define the bedding requirements of pigs during transportation in commercial settings during cold and mild weather. Animals (n = 112,078 pigs on 572 trailers) used were raised in commercial finishing sites and transported in trailers to commercial processing plants. Dead on arrival (DOA), non-ambulatory (NA), and total dead and down (D&D) data were collected and skin surface temperatures of the pigs were measured by infrared thermography. Data were collected during winter (Experiment 1) and fall/spring (Experiment 2). Total D&D percent showed no interaction between bedding level and outside air temperature in any experiments. Average skin surface temperature during unloading increased with outside air temperature linearly in both experiments (P < 0.01). In conclusion, over-use of bedding may be economically inefficient. Pig skin surface temperature could be a useful measure of pig welfare during or after transport. PMID- 26480040 TI - The Effects of Cooking Process and Meat Inclusion on Pet Food Flavor and Texture Characteristics. AB - The pet food industry is an important portion of the food and feed industries in the US. The objectives of this study were (1) to determine cooking method (baking or extrusion), meat inclusion (0 or 20%), and extrusion thermal to mechanical energy ratios (low, medium, and high) effects on sensory and volatile properties of pet foods, and (2) to determine associations among sensory and volatile characteristics of baked and extruded pet foods. Descriptive sensory analysis and gas chromatography-mass spectrometry were used to analyze the pet food samples. It was found that baked samples were lighter in color (2.0-2.6 baked vs. 3.5-4.3 extruded, color intensity scale 0-15), and had lower levels of attributes that indicated rancidity (i.e., fishy flavor; 0.3-0.6 baked, 0.6-1.5 extruded, scale 0 15), whereas extruded pet foods were more cohesive in mass, more friable, hard, and crisp, but less powdery than baked samples. Fresh meat inclusion tended to decrease bitterness and increase fishy flavor and cohesiveness of pet foods. High thermal to mechanical energy ratio during extrusion resulted in less musty and more porous kibbles. The main volatile compounds included aldehydes, such as hexanal and heptanal, ketones, and alcohols. Extruded samples did not contain methylpyrazine, while baked samples did not contain 2-butyl furan. Future studies should consider evaluating the relationship between sensory results and animal palatability for these types of foods. PMID- 26480041 TI - Hopping Down the Main Street: Eastern Grey Kangaroos at Home in an Urban Matrix. AB - Most urban mammals are small. However, one of the largest marsupials, the Eastern Grey Kangaroo Macropus giganteus, occurs in some urban areas. In 2007, we embarked on a longitudinal study of this species in the seaside town of Anglesea in southern Victoria, Australia. We have captured and tagged 360 individuals to date, fitting each adult with a collar displaying its name. We have monitored survival, reproduction and movements by resighting, recapture and radio-tracking, augmented by citizen science reports of collared individuals. Kangaroos occurred throughout the town, but the golf course formed the nucleus of this urban population. The course supported a high density of kangaroos (2-5/ha), and approximately half of them were tagged. Total counts of kangaroos on the golf course were highest in summer, at the peak of the mating season, and lowest in winter, when many males but not females left the course. Almost all tagged adult females were sedentary, using only part of the golf course and adjacent native vegetation and residential blocks. In contrast, during the non-mating season (autumn and winter), many tagged adult males ranged widely across the town in a mix of native vegetation remnants, recreation reserves, vacant blocks, commercial properties and residential gardens. Annual fecundity of tagged females was generally high (>=70%), but survival of tagged juveniles was low (54%). We could not determine the cause of death of most juveniles. Vehicles were the major (47%) cause of mortality of tagged adults. Road-kills were concentrated (74%) in autumn and winter, and were heavily male biased: half of all tagged males died on roads compared with only 20% of tagged females. We predict that this novel and potent mortality factor will have profound, long-term impacts on the demography and behavior of the urban kangaroo population at Anglesea. PMID- 26480042 TI - Cows Come Down from the Mountains before the (Mw = 6.1) Earthquake Colfiorito in September 1997; A Single Case Study. AB - The September-October 1997 seismic sequence in the Umbria-Marche regions of Central Italy has been one of the stronger seismic events to occur in Italy over the last thirty years, with a maximum magnitude of Mw = 6.1. Over the last three years, a collection of evidence was carried out regarding non-seismic phenomena, by interviewing local residents using a questionnaire. One particular observation of anomalous animal behaviour, confirmed by many witnesses, concerned a herd of cows, which descended from a mountain close to the streets of a village near the epicentre, a few days before the main shock. Testimonies were collected using a specific questionnaire including data on earthquake lights, spring variations, human diseases, and irregular animal behaviour. The questionnaire was compiled after the L'Aquila earthquake in 2009, and was based upon past historical earthquake observations. A possible explanation for the cows' behavior-local air ionization caused by stress-activated positive holes-is discussed. PMID- 26480043 TI - Consumer Acceptance of Dry Dog Food Variations. AB - The objectives of this study were to compare the acceptance of different dry dog food products by consumers, determine consumer clusters for acceptance, and identify the characteristics of dog food that drive consumer acceptance. Eight dry dog food samples available in the US market were evaluated by pet owners. In this study, consumers evaluated overall liking, aroma, and appearance liking of the products. Consumers were also asked to predict their purchase intent, their dog's liking, and cost of the samples. The results indicated that appearance of the sample, especially the color, influenced pet owner's overall liking more than the aroma of the product. Overall liking clusters were not related to income, age, gender, or education, indicating that general consumer demographics do not appear to play a main role in individual consumer acceptance of dog food products. PMID- 26480044 TI - Comparison of Performance, Meat Lipids and Oxidative Status of Pigs from Commercial Breed and Organic Crossbreed. AB - The aim of this research was to determine the effect of rearing systems for pig production, as concerns performance, meat lipid content, the fatty acid profile, histidinic antioxidants, coenzyme Q10, and TBARs. One hundred pigs were assigned to one of three treatments: intensively reared commercial hybrid pig (I), free range commercial hybrid pig (FR) or organically reared crossbred pig (O), according to organic EU Regulations. I pigs showed the best productive performance, but FR and O increased: C20:1n9, Delta9-desaturase (C18) and thioesterase indices in meat. Lipid, dipeptides and CoQ10 appeared correlated to glycolytic and oxidative metabolic pathways. We can conclude that all studied parameters were influenced by the rearing system used, and that differences were particularly evident in the O system, which produced leaner meat with higher oxidative stability. In this respect, the organic pig rearing system promotes and enhances biodiversity, environmental sustainability and food quality. PMID- 26480045 TI - Refining Housing, Husbandry and Care for Animals Used in Studies Involving Biotelemetry. AB - Biotelemetry can contribute towards reducing animal numbers and suffering in disciplines including physiology, pharmacology and behavioural research. However, the technique can also cause harm to animals, making biotelemetry a 'refinement that needs refining'. Current welfare issues relating to the housing and husbandry of animals used in biotelemetry studies are single vs. group housing, provision of environmental enrichment, long term laboratory housing and use of telemetered data to help assess welfare. Animals may be singly housed because more than one device transmits on the same wavelength; due to concerns regarding damage to surgical sites; because they are wearing exteriorised jackets; or if monitoring systems can only record from individually housed animals. Much of this can be overcome by thoughtful experimental design and surgery refinements. Similarly, if biotelemetry studies preclude certain enrichment items, husbandry refinement protocols can be adapted to permit some environmental stimulation. Nevertheless, long-term laboratory housing raises welfare concerns and maximum durations should be defined. Telemetered data can be used to help assess welfare, helping to determine endpoints and refine future studies. The above measures will help to improve data quality as well as welfare, because experimental confounds due to physiological and psychological stress will be minimised. PMID- 26480046 TI - Health and Welfare in Dutch Organic Laying Hens. AB - From 2007-2008, data on animal health and welfare and farm management during rearing and laying periods were collected from 49 flocks of organic laying hens in the Netherlands. Our aim was to investigate how organic egg farms performed in terms of animal health and welfare and which farm factors affected this performance. The flocks in our study were kept on farms with 34 to 25,000 hens (average 9,300 hens). Seventy-one percent of the flocks consisted of 'silver hybrids': white hens that lay brown eggs. Fifty-five percent of the flocks were kept in floor-based housing and 45% of the flocks in aviaries. No relation was found between the amount of time spent outdoors during the laying period and mortality at 60 weeks. Flocks that used their outdoor run more intensively had better feather scores. In 40% of the flocks there was mortality caused by predators. The average feed intake was 129 g/day at 30 weeks and 133 g/day at 60 weeks of age. The average percentage of mislaid eggs decreased from three at 30 weeks to two at 60 weeks. The average mortality was 7.8% at 60 weeks. Twenty-five percent of the flocks were not treated for worms in their first 50 weeks. Flubenol((c)) was applied to the flocks that were treated. Ten percent of the flocks followed Flubenol((c)) instructions for use and were wormed five or more times. The other 65% percent were treated irregularly between one and four times. Sixty-eight percent of the flocks showed little or no feather damage, 24% showed moderate damage and 8% showed severe damage. The feather score was better if the hens used the free-range area more intensely, the laying percentage at 60 weeks was higher, and if they were allowed to go outside sooner after arrival on the laying farm. In 69% of the flocks, hens had peck wounds in the vent area: on average this was 18% of the hens. Keel bone deformations were found in all flocks, on average in 21% of the birds. In 78% of the flocks, an average of 13% of the hens had foot-sole wounds, mostly a small crust. Combs were darker in flocks that used the range area more intensively. More fearful flocks had lighter combs. We conclude that organic farms are potentially more animal friendly than other poultry systems based on the animal welfare benefits of the free range areas. However, we also observed mortality rates, internal parasites, keel bone deformities, and foot sole lesions on organic farms that were comparable to or worse than in other husbandry systems. It is unclear whether these 'remaining' problems can be attributed to housing or if they are the result of keeping high productive genotypes in an artificial environment. Organic farms use the same high productive genotypes as other husbandry systems. PMID- 26480047 TI - Non-Destructive and rapid evaluation of staple foods quality by using spectroscopic techniques: A review. AB - Staple foods, including cereals, legumes, and root/tuber crops, dominate the daily diet of humans by providing valuable proteins, starch, oils, minerals, and vitamins. Quality evaluation of staple foods is primarily carried out on sensory (e.g. external defect, color), adulteration (e.g. species, origin), chemical (e.g. starch, proteins), mycotoxin (e.g. Fusarium toxin, aflatoxin), parasitic infection (e.g. weevil, beetle), and internal physiological (e.g. hollow heart, black heart) aspects. Conventional methods for the quality assessment of staple foods are always laborious, destructive, and time-consuming. Requirements for online monitoring of staple foods have been proposed to encourage the development of rapid, reagentless, and noninvasive techniques. Spectroscopic techniques, such as visible-infrared spectroscopy, Raman spectroscopy, nuclear magnetic resonance spectroscopy, and spectral imaging, have been introduced as promising analytical tools and applied for the quality evaluation of staple foods. This review summarizes the recent applications and progress of such spectroscopic techniques in determining various qualities of staple foods. Besides, challenges and future trends of these spectroscopic techniques are also presented. PMID- 26480048 TI - Does skin cancer screening save lives? A detailed analysis of mortality time trends in Schleswig-Holstein and Germany. AB - BACKGROUND: After a pilot study on skin cancer screening was performed between 2003 and 2004 in Schleswig-Holstein, Germany, the country implemented what to the authors' knowledge is the first nationwide skin cancer screening program in the world in 2008. The objective of the current study was to provide details regarding mortality trends in Schleswig-Holstein and Germany in relation to the screening. METHODS: Annual age-standardized mortality rates for skin melanoma (using the 10th Revision of the International Statistical Classification of Diseases and Related Health Problems [ICD-10] code C43) and malignant neoplasms of ill-defined, secondary, and unspecified sites (ICD-10 code C76-C80) were analyzed. The European Standard population was used for age standardization. A bias analysis was performed to estimate the number of skin melanoma deaths that may have been incorrectly counted as ICD-10 code C76-C80 when the skin melanoma mortality declined in Schleswig-Holstein. RESULTS: The observed mortality decline in Schleswig-Holstein 5 years after the pilot study was accompanied by a considerable increase in the number of deaths due to malignant neoplasms of ill defined, secondary, and unspecified sites (ICD-10 code C76-C80) that is not explainable by an increase in the incidence of these neoplasms. Incorrect assignment of 8 to 35 and 12 to 23 skin melanoma deaths per year among men and women, respectively, as ICD-10 code C76-C80 during 2007 through 2010 could explain the transient skin melanoma mortality decline observed in Schleswig Holstein. Five years after implementation of the program, the nationwide skin melanoma mortality increased (age-standardized rate change of +0.4 per 100,000 person-years [95% confidence interval, 0.2-0.6] in men and +0.1 per 100,000 person-years [95% confidence interval, -0.1 to 0.2] in women). CONCLUSIONS: Although the current analyses raise doubts that the skin cancer screening program in Germany can reduce the skin cancer mortality rate, the authors do not believe the program should be immediately stopped. Further in-depth evaluations are required. Cancer 2016;122:432-437. (c) 2015 American Cancer Society. PMID- 26480049 TI - Tuning the Electromechanical Properties of Single DNA Molecular Junctions. AB - Understanding the interplay between the electrical and mechanical properties of DNA molecules is important for the design and characterization of molecular electronic devices, as well as understanding the role of charge transport in biological functions. However, to date, force-induced melting has limited our ability to investigate the response of DNA molecular conductance to stretching. Here we present a new molecule-electrode linker based on a hairpin-like design, which prevents force-induced melting at the end of single DNA molecules during stretching by stretching both strands of the duplex evenly. We find that the new linker group gives larger conductance than previously measured DNA-electrode linkers, which attach to the end of one strand of the duplex. In addition to changing the conductance the new linker also stabilizes the molecule during stretching, increasing the length a single DNA molecule can be stretched before an abrupt decrease in conductance. Fitting these electromechanical properties to a spring model, we show that distortion is more evenly distributed across the single DNA molecule during stretching, and thus the electromechanical effects of the pi-pi coupling between neighboring bases is measured. PMID- 26480050 TI - [Not Available]. PMID- 26480051 TI - Caliber of the common bile duct: effect of cholecystectomy and other factors in a ultrasonographic study of 8534 patients. AB - OBJECTIVE: The objective of the present study was to analyze the effects of different factors impacting the caliber of the common bile duct (CBD) and a comparison of maximum extrahepatic bile duct caliber in patients with and without a history of cholecystectomy. MATERIAL AND METHODS: A retrospective data analysis was undertaken of 8534 patients (4480 females; 4054 males; average age: 59.2+/ 18.0 years) with sonographic documentation of bile duct caliber. Maximum intra- and extrahepatic bile duct diameters were studied. The normal maximum diameter of the extrahepatic bile duct was defined as 7 mm. In patients who had undergone prior cholecystectomy, a maximum bile duct diameter<10 mm was considered normal. RESULTS: The average maximum diameter of the CBD amounted to 5.3+/-3.0 mm for the overall collective. In patients who had undergone prior cholecystectomy, maximum CBD diameters in the normal range (<7 mm) were documented in 55%, while larger diameters (>7 mm) were observed in 45%. In the collective of patients without prior cholecystectomy, CBD diameters in the normal range (<7 mm) were found in 81%, with larger diameters observed in only 18.4% of patients. In both subgroups, there was a significant association between age and bile duct diameter (for those with prior cholecystectomy, p=0.0003; without prior cholecystectomy, p<0.0001). No statistically significant influence on CBD diameter was observed for either prior cholecystectomy (p=0.2116) or time interval since cholecystectomy (p=0.3537). Females, both with and without a history of prior cholecystectomy, showed a 1.4-1.5-fold higher risk of exhibiting a CBD diameter>7 mm (for those with prior cholecystectomy, p=0.0485; without prior cholecystectomy, p<0.001). CONCLUSIONS: Our data show a positive correlation between age and CBD diameter. There was no statistically significant relationship between CBD diameter and prior cholecystectomy, postoperative interval and BMI. PMID- 26480052 TI - [Evaluation of endoscopic live case demonstrations--the patient's and participant's perspective]. AB - INTRODUCTION: Benefits and ethics of live demonstrations of endoscopic interventions as part of educational meetings are controversial. Of particular importance is the acceptance and satisfaction of patients treated and the opinion of the participants of the courses. METHODS: A validated questionnaire was sent to all patients who were treated in live demonstrations at the Dusseldorf International Endoscopy Symposium (DIES) in the years 2008-2014. In addition, all participants completed evaluation forms of the same events were evaluated in order to determine the benefits of live performances. The assessments were carried out with evaluations 1-6 (1=very good, 6=very poor). RESULTS: Of 174 patients, 76 written questionnaires were returned, of which 70 were evaluable (40.2%). The rate of satisfaction with the course of treatment and stay in the endoscopy department was 80.8%. The vast majority of patients (84.1%) did not feel that a wrong treatment option was chosen, and only a few (6.7%) questioned the expertise of the treating physician. 83% of respondents felt also at the nurses in good hands. For three-quarters of patients surveyed (74.3%), the quality of life has improved as a result of the measures in the live demonstrations. Of 10,004 participants of the symposia, 6770 evaluation forms were filled out. Mean scores of below 2 were rated for questions about the quality of patient care from a medical and ethical point of view as well as for questions about the learning effect through live demonstrations compared to canned videos. CONCLUSION: The vast majority of patients treated within live demonstrations as part of the DIES is satisfied with the course, treatment and patient care and outcomes. Congress participants assess the educational value of the live broadcasts as well as patient care in medical and ethical terms as good to very good. PMID- 26480053 TI - Quantitative perfusion analysis in pancreatic contrast enhanced ultrasound (DCE US): a promising tool for the differentiation between autoimmune pancreatitis and pancreatic cancer. AB - In the work-up of focal pancreatic lesions autoimmune pancreatitis (AIP) is a rare differential diagnosis to pancreatic cancer (PC) with similar clinical constellations. The aim of our study was to compare differences between proven AIP and PC using transabdominal dynamic contrast enhanced ultrasound (DCE-US). Therefore we recorded 3-minute-clips of CEUS examinations and analyzed perfusion parameters with VueBox(r)-quantification software. To obtain DCE-US Parameters, Regions-of-Interest were selected within the lesions and the surrounding pancreas parenchyma, serving as reference tissue. We compared 3 patients with AIP (mean age: 58 years; lesion mean size: 40 mm) to 17 patients with PC (mean age: 68 years; lesion mean size: 35.9 mm). Significant differences between PC and parenchyma could be found in the following parameters: Peak-Enhancement (PE), Wash-in-and-Wash-out-AUC, Wash-in Perfusion-Index. PE of AIP was comparable to normal parenchyma. The relation of PE between parenchyma and lesion (DeltaPE) AIP and PC was significantly different [AIP: 0.21 (+/-0.06); PC: 0.81 (+/-0.1); p<0.01]. PE of neoplastic lesions was significantly lower as AIP and normal parenchyma (p<0.01). Therefore perfusion analysis in DCE-US can help to differentiate hypovascular PC from AIP presenting nearly isovascular time intensity curves. Diagnostic accuracy of DCE-US in this setting has to be validated in future prospective studies in comparison to CT and MRI. PMID- 26480054 TI - ["Giant" fibrovascular esophageal polyp]. AB - Fibrovascular polyps are rare mesenchymal tumors that arise mainly in the cricopharyngeal portion of the esophagus. They may protrude distally to become "giant" pedunculated lesions filling almost the entire esophageal lumen. Histologically they contain varying amounts of adipose, fibrous and vascular tissues and belong to spindle cell lipomas according to the classification of soft tissue tumors. Immediate resection of these benign lesions is warranted as they may be regurgitated and cause asphyxia. These lesions are usually treated by open surgery (left cervicotomy) or, less invasively, by peroral endoscopic surgery. Polyp removal by flexible endoscopy has been described but may be hazardous if its stalk is broad-based. In this report the case of a 73-year-old male with dysphagia is described in whom a "giant" fibrovascular polyp was diagnosed endoscopically and promptly removed surgically by the peroral route. At control endoscopy 14 months later, the asymptomatic patient was free of polyp recurrence. PMID- 26480055 TI - [Morbus Behcet or inflammatory bowel disease--a diagnostic and therapeutic dilemma]. AB - We present the case of a 43-year old caucasian male suffering from a condition initially diagnosed as colitis ulcerosa. For 2 years Azathioprine and anti-TNF alpha antibodies were used for treatment without convincing benefit but with serious adverse events. After the first occurrence of complex accompanying symptoms like oral and scrotal ulcerations, arthritis and scratch-induced skin lesions the differential diagnosis of a Morbus Adamantiades-Behcet with intestinal evolvement was considered. After introduction of a parenteral Ciclosporin medication, which was later switched to Tacrolimus and Azathioprin, a remission could be achieved that lasted for several months. When a drug-induced acute kidney injury occurred, the regime was changed to Golimumab and a delayed but significant improvement was achieved. To separate Morbus Adamantiades-Behcet from inflammatory bowel disease is of some difficulty, demands interdisciplinary cooperation and is the basis for a successful therapy. PMID- 26480056 TI - [Guidelines for gastroenteropancreatic neuroendocrine tumors--what is new? What should be incorporated in daily therapeutic decisions?]. AB - Neuroendocrine neoplasias are seldom, but increasing. This holds true for the incidence but even more for the prevalence, since patients are able to live with their disease for quite a long time. The European Neuroendocrine Tumor Society (ENETS) as well as other societies (NANETS: North American Neuroendocrine Tumor Society; NCCN: National Comprehensive Cancer Network; ESMO: European Society of Medical Oncology) have published diagnostic and therapeutic guidelines that we present in this review. We aim to summarize those actual guidelines in a practice based diagnostic and therapeutic algorithm, but also wish to point to open questions that have to be discussed in a multidisciplinary approach. PMID- 26480057 TI - [From bench to bedside--predictor of response to an anti-TNF-therapy in patients with Crohn's disease during confocal laser endomicroscopy]. PMID- 26480059 TI - Performance analysis of the retractable dome for the Chinese Large Telescope. AB - In order to quantitatively assess the influence of the retractable dome on the observational performance of the 4-m Chinese Large Telescope (CLT), an integrated analysis method based on computational fluid dynamics (CFD) and sub-harmonic phase screen is proposed in this paper. The pressure, the temperature, and the speed of air surrounding the retractable dome are attained by CFD simulations, and then the fluctuation of refractive index of air is calculated. Based on sub harmonic phase screen algorithm, three kinds of performance evaluation parameters are presented: irradiance, phase of the target, and Full Width Half Maximum (FWHM). The wind tunnel tests (WT) with a 1:120 scaled model of the retractable dome for the CLT are conducted to verify the calculated precision of the CFD. The results show that the fluctuation of air refractive index surrounding the CLT is mainly caused by the inhomogeneous distribution of temperature and speed, and with the help of pier's height the impact of inhomogeneous air temperature from the ground layer on the fluctuation of air refractive index can be effectively decreased. Furthermore, the lower of the air speed is, the better performance of the retractable dome will be, and when the speed of air is less than 5m/s, the dome seeing induced by the retractable dome on the observational wave front is less than 0.13 arcsec. PMID- 26480060 TI - Compendium of natural hyperbolic materials. AB - Artificially structured hyperbolic metamaterials (HMMs) - uniaxial materials with opposite signs of permittivity for ordinary and extraordinary waves - are one of the most attractive classes of metamaterials. Their existing in nature counterpart natural (homogeneous) hyperbolic materials (NHMs) has several advantages but has not yet been analyzed extensively. Here, based on literature available data on permittivity as a function of wavelength, we review materials with naturally occurring anisotropy of permittivity in specific wavelength ranges. We suggest the best choice of materials that may act as NHMs depending on the wavelength, strength of the dielectric anisotropy (SDA), and losses. PMID- 26480061 TI - Phase unwrapping with a virtual Hartmann-Shack wavefront sensor. AB - The use of a spatial light modulator for implementing a digital phase-shifting (PS) point diffraction interferometer (PDI) allows tunability in fringe spacing and in achieving PS without the need for mechanically moving parts. However, a small amount of detector or scatter noise could affect the accuracy of wavefront sensing. Here, a novel method of wavefront reconstruction incorporating a virtual Hartmann-Shack (HS) wavefront sensor is proposed that allows easy tuning of several wavefront sensor parameters. The proposed method was tested and compared with a Fourier unwrapping method implemented on a digital PS PDI. The rewrapping of the Fourier reconstructed wavefronts resulted in phase maps that matched well the original wrapped phase and the performance was found to be more stable and accurate than conventional methods. Through simulation studies, the superiority of the proposed virtual HS phase unwrapping method is shown in comparison with the Fourier unwrapping method in the presence of noise. Further, combining the two methods could improve accuracy when the signal-to-noise ratio is sufficiently high. PMID- 26480062 TI - Accurate calculation of computer-generated holograms using angular-spectrum layer oriented method. AB - Fast calculation and correct depth cue are crucial issues in the calculation of computer-generated hologram (CGH) for high quality three-dimensional (3-D) display. An angular-spectrum based algorithm for layer-oriented CGH is proposed. Angular spectra from each layer are synthesized as a layer-corresponded sub hologram based on the fast Fourier transform without paraxial approximation. The proposed method can avoid the huge computational cost of the point-oriented method and yield accurate predictions of the whole diffracted field compared with other layer-oriented methods. CGHs of versatile formats of 3-D digital scenes, including computed tomography and 3-D digital models, are demonstrated with precise depth performance and advanced image quality. PMID- 26480063 TI - Effect of spectral sampling on the temporal coherence analysis of a broadband source in a SFG interferometer. AB - In the frame of sum frequency generation of a broadband infrared source, we aim to enlarge the converted bandwidth by using a pump frequency comb while keeping a high conversion efficiency. The nonlinear effects are simultaneously induced in the same nonlinear medium. In this paper, we investigate the spectral filtering effect on the temporal coherence behavior with a Mach-Zehnder interferometer using two pump lines. We show that joined effects of quasi-phase matching and spectral sampling lead to an original coherence behavior. PMID- 26480058 TI - Computational Systems Biology of Psoriasis: Are We Ready for the Age of Omics and Systems Biomarkers? AB - Computational biology and 'omics' systems sciences are greatly impacting research on common diseases such as cancer. By contrast, dermatology covering an array of skin diseases with high prevalence in society, has received relatively less attention from 'omics' and computational biosciences. We are focusing on psoriasis, a common and debilitating autoimmune disease involving skin and joints. Using computational systems biology and reconstruction, topological, modular, and a novel correlational analyses (based on fold changes) of biological and transcriptional regulatory networks, we analyzed and integrated data from a total of twelve studies from the Gene Expression Omnibus (sample size = 534). Samples represented a comprehensive continuum from lesional and nonlesional skin, as well as bone marrow and dermal mesenchymal stem cells. We identified and propose here a JAK/STAT signaling pathway significant for psoriasis. Importantly, cytokines, interferon-stimulated genes, antimicrobial peptides, among other proteins, were involved in intrinsic parts of the proposed pathway. Several biomarker and therapeutic candidates such as SUB1 are discussed for future experimental studies. The integrative systems biology approach presented here illustrates a comprehensive perspective on the molecular basis of psoriasis. This also attests to the promise of systems biology research in skin diseases, with psoriasis as a systemic component. The present study reports, to the best of our knowledge, the largest set of microarray datasets on psoriasis, to offer new insights into the disease mechanisms with a proposal of a disease pathway. We call for greater computational systems biology research and analyses in dermatology and skin diseases in general. PMID- 26480064 TI - Supercontinuum generation in silicon waveguides relying on wave-breaking. AB - Four-wave-mixing processes enabled during optical wave-breaking (OWB) are exploited in this paper for supercontinuum generation. Unlike conventional approaches based on OWB, phase-matching is achieved here for these nonlinear interactions, and, consequently, new frequency production becomes more efficient. We take advantage of this kind of pulse propagation to obtain numerically a coherent octave-spanning mid-infrared supercontinuum generation in a silicon waveguide pumping at telecom wavelengths in the normal dispersion regime. This scheme shows a feasible path to overcome limits imposed by two-photon absorption on spectral broadening in silicon waveguides. PMID- 26480065 TI - Laser frequency noise induced error in resonant fiber optic gyro due to an intermodulation effect. AB - For the first time, a significant noise source in the resonant fiber optic gyroscope (RFOG) called intermodulation induced error is proposed and deeply analyzed in this paper. The intermodulation error is produced by the laser frequency noise at even multiples of the modulation frequency due to an intermodulation effect, which will seriously limit the random noise performance of the RFOG. Experiments are designed and conducted to verify and measure the intermodulation induced error in the RFOG. The experimental results confirm the existence of intermodulation error, and fit well with the theory. As for the design of the RFOG, light sources with a narrow intrinsic linewidth and a high modulation frequency are preferable to achieve a high rotation-rate sensitivity. PMID- 26480066 TI - Extreme ultraviolet proximity lithography for fast, flexible and parallel fabrication of infrared antennas. AB - We present a method for fabrication of large arrays of nano-antennas using extreme-ultraviolet (EUV) illumination. A discharge-produced plasma source generating EUV radiation around 10.88 nm wavelength is used for the illumination of a photoresist via a mask in a proximity printing setup. The method of metallic nanoantennas fabrication utilizes a bilayer photoresist and employs a lift-off process. The impact of Fresnel-diffraction of EUV light in the mask on a shape of the nanostructures has been investigated. It is shown how by the use of the same rectangular apertures in the transmission mask, antennas of various shapes can be fabricated. Using Fourier transform infrared spectroscopy, spectra of antennas reflectivity were measured and compared to FDTD simulations demonstrating good agreement. PMID- 26480067 TI - Radiative properties of diffractively-coupled optical nano-antennas with helical geometry. AB - In this paper, using the rigorous Surface Integral Equation (SIE) method, we study light scattering by Au nano-helices with geometrical dimensions comparable to the wavelength of visible light and we demonstrate that they behave as highly directional nano-antennas with largely controllable radiation and polarization characteristics in the optical regime. In particular, we systematically investigate the radiation properties of helical nano-antennas with realistic Au dispersion parameters in the visible spectral range, and we establish general design rules that enable the engineering of directional scattering with elliptical or circular polarization. Given the realistic material and geometric parameters used in this work, our findings provide novel opportunities for the engineering of chiral sensors, filters, and components for nano-scale antennas with unprecedented beam forming and polarization capabilities. PMID- 26480068 TI - Grating-assisted silicon-on-insulator racetrack resonator reflector. AB - We experimentally demonstrate a grating-assisted silicon-on-insulator (SOI) racetrack resonator reflector with a reflect port suppression of 10.3 dB and no free spectral range. We use contra-directional grating couplers within the coupling regions of the racetrack resonator to enable suppression of all but one of the peaks within the reflect port spectrum as well as all but one of the notches within the through port spectrum. PMID- 26480069 TI - Fade-resistant photochromic reactions in a self-healable polymer. AB - Molecular diffusion in a polymer matrix was studied to prevent degradation of photochromic reactions during repeated coloration-decoloration processes. Photochromic diarylethene was dispersed in polydimethylsiloxane (cured polymer), since it promoted exchange of damaged and fresh molecules owing to high diffusivity. The diffusion coefficient was evaluated by measuring a distribution of dye molecules that were colored within a narrow laser beam path. Temporal change of the distribution fitted well to theoretical curves that were drawn according to the 2-D solutions of Fick's equation. The experimental results indicated a fifteen-fold enhancement of the diffusion coefficient (0.0015 mm(2)/s) when the polymer was swollen with toluene. Fading of this photochromic polymer was examined by repeating alternative irradiation of violet and green laser beams. Although a non-swollen polymer faded seriously within 1,000 photochromic cycles, a swollen polymer exhibited an excellent photochromic function even after 30,000 cycles. PMID- 26480070 TI - Extreme ultraviolet Talbot interference lithography. AB - Periodic nanopatterns can be generated using lithography based on the Talbot effect or optical interference. However, these techniques have restrictions that limit their performance. High resolution Talbot lithography is limited by the very small depth of focus and the demanding requirements in the fabrication of the master mask. Interference lithography, with large DOF and high resolution, is limited to simple periodic patterns. This paper describes a hybrid extreme ultraviolet lithography approach that combines Talbot lithography and interference lithography to render an interference pattern with a lattice determined by a Talbot image. As a result, the method enables filling the arbitrary shaped cells produced by the Talbot image with interference patterns. Detailed modeling, system design and experimental results using a tabletop EUV laser are presented. PMID- 26480071 TI - Microwave photonic filter with multiple independently tunable passbands based on a broadband optical source. AB - In this paper, a novel microwave photonic filter (MPF) with multiple independently tunable passbands is proposed. A broadband optical source (BOS) is employed and split by a 1:N coupler into several branches. One branch is directed to a phase modulator which is modulated by a radio frequency signal and the other branches are delayed by optical delay lines (ODLs), respectively. All of these branches are combined by another 1:N coupler and sent to a dispersion compensation fiber which is used to introduce group delay dispersion to the optical signal. At a photodetector, each time-delayed broadband lightwave beating with the sidebands produced by the phase modulator forms a passband of the MPF. By tuning the delay of each broadband lightwave, the center frequency of the passband can be independently tuned. An MPF with two independently tunable passbands is experimentally demonstrated. The two passbands can be tuned from DC to 30 GHz with a 3-dB bandwidth of about 250 MHz. The stability and dynamic range of the MPF are also evaluated. By employing more branches delayed by ODLs, more passbands can be generated. PMID- 26480072 TI - Characterization of a swept external cavity quantum cascade laser for rapid broadband spectroscopy and sensing. AB - The performance of a rapidly swept external cavity quantum cascade laser (ECQCL) system combined with an open-path Herriott cell was evaluated for time-resolved measurements of chemical species with broad and narrow absorption spectra. A spectral window spanning 1278 - 1390 cm(-1) was acquired at a 200 Hz acquisition rate, corresponding to a tuning rate of 2x10(4) cm(-1)/s, with a spectral resolution of 0.2 cm(-1). The capability of the ECQCL to measure < 100 ppbv changes in nitrous oxide (N(2)O) and 1,1,1,2-tetrafluoroethane (F134A) concentrations on millisecond timescales was demonstrated in simulated plume studies with releases near the open-path Herriott cell. Absorbance spectra measured using the ECQCL system exhibited noise-equivalent absorption coefficients of 5x10(-9) cm(-1)Hz(-1/2). For a spectrum acquisition time of 5 ms, noise-equivalent concentrations (NEC) for N(2)O and F134A were measured to be 70 and 16 ppbv respectively, which improved to sub-ppbv levels with averaging to 100 s. Noise equivalent column densities of 0.64 and 0.25 ppmv * m in 1 sec are estimated for N(2)O and F134A. PMID- 26480073 TI - Effects of Raman pump power distribution on output spectrum in a multi-wavelength BRFL. AB - This paper aims to investigate changes in multi-wavelength Brillouin-Raman fiber laser (MBRFL) spectra characteristics that are influenced by variation of Raman pump power distribution along the two fiber-entry points. This is carried out by incorporating a Raman pump source with a set of couplers with various ratios. In this arrangement, the optimization of pumping ratio is properly carried out to achieve high number of lasing lines with 20 GHz spacing which yield the highest peak power discrepancy between odd- and even-order lasing lines and an excellent Stokes optical signal-to-noise ratio (S-OSNR). Employment of 50/50 coupler offers 212 flat amplitude channels with an average 27.5 dB S-OSNR and -10 dBm Stokes peak power when the Brillouin pump wavelength is set at 1543 nm. Achievements such flat and wide bandwidth MBRFL spectrum with 20 GHz spacing and excellent S OSNR utilizing just a single pump source is significant in terms of simplicity and flexibility. PMID- 26480074 TI - Multiwavelength ultrafast LiNbO(3) Raman laser. AB - We present a multiwavelength ultrafast Raman laser based on lithium niobate which uses polariton scattering in combination with Raman scattering to selectively generate new wavelengths from a nanojoule-scale picosecond pump laser. Pumped by a 1064 nm pump laser, the system generates 1123 nm by stimulated polariton scattering (SPS) and 1140 nm by stimulated Raman scattering (SRS). Cascading of these intracavity fields generates 1155 nm and 1174 nm, as well as generating THz output. PMID- 26480075 TI - Optical fibers with gradient index nanostructured core. AB - We present a new approach for the development of structured optical fibers. It is shown that fibers having an effective gradient index profile with designed refractive index distribution can be developed with internal nanostructuring of the core composed of two glasses. As proof-of-concept, fibers made of two soft glasses with a parabolic gradient index profile are developed. Energy-dispersive X-ray spectroscopy reveals a possibility of selective diffusion of individual chemical ingredients among the sub-wavelength components of the nanostructure. This hints a postulate that core nanostructuring also changes material dispersion of the glasses in the core, potentially opening up unique dispersion shaping possibilities. PMID- 26480076 TI - Probability of the moire effect in barrier and lenticular autostereoscopic 3D displays. AB - The probability of the moire effect in LCD displays is estimated as a function of angle based on the experimental data; a theoretical function (node spacing) is proposed basing on the distance between nodes. Both functions are close to each other. The connection between the probability of the moire effect and the Thomae's function is also found. The function proposed in this paper can be used in the minimization of the moire effect in visual displays, especially in autostereoscopic 3D displays. PMID- 26480077 TI - Experimental demonstration of low-complexity fiber chromatic dispersion mitigation for reduced guard-interval OFDM coherent optical communication systems based on digital spectrum sub-band multiplexing. AB - We experimentally demonstrate a novel digital signal processing (DSP) structure for reduced guard-interval (RGI) OFDM coherent optical systems. The proposed concept is based on digitally slicing optical channel bandwidth into multiple spectrally disjoint sub-bands which are then processed in parallel. Each low bandwidth sub-band has a smaller delay-spread compared to a full-band signal. This enables compensation of both chromatic dispersion (CD) and polarization mode dispersion using a simple timing and one-tap-per-symbol frequency domain equalizer with a small cyclic prefix overhead. In terms of the DSP architecture, this allows for a highly efficient parallelization of DSP tasks performed over the received signal samples by deploying multiple processors running at a lower clock rate. It should be noted that this parallelization is performed in the frequency domain and it allows for flexible optical transceiver schemes. In addition, the resulting optical receiver is simplified due to the removal of the CD compensation equalizer compared to conventional RGI-OFDM systems. In this paper we experimentally demonstrate digital sub-banding of optical bandwidth. We test the system performance for different modulation formats (QPSK, 16QAM and 32QAM) over various transmission distances and optical launch powers using a 1.5% CP overhead in all scenarios. We also compare the proposed RGI-OFDM architecture performance against common single carrier modulation formats. At the same total data rate and signal bandwidth both systems have similar performance and transmission reach whereas the proposed method allows for a significant reduction of computational complexity due to removal of CD pre/post compensation equalizer. PMID- 26480078 TI - Visible-pulse generation in gain crystal of near-infrared femtosecond optical parametric oscillator. AB - An optical parametric oscillator (OPO) based on magnesium-oxide-doped periodically poled lithium niobate (MgO:PPLN) is demonstrated to deliver visible femtosecond pulses, which were created through the intra-cavity nonlinear interactions within the PPLN itself. The signal from the OPO produces femtosecond pulses in the near-infrared region tunable from 1050 to 1600 nm. Visible femtosecond pulses in the range of 522-800 nm and those of 455-540 nm, respectively, were generated via second-harmonic generation (SHG) of signal photons and through sum-frequency generation (SFG) of pump and signal photons. Maximum output efficiencies of 9.2% at 614 nm and 8.0% at 522 nm for the SHG and SFG are attained, respectively, where the efficient visible pulse generation relies on the quasi-phase matching with the aid of the higher-order grating momentum. PMID- 26480079 TI - Beam wandering of femtosecond laser filament in air. AB - The spatial wandering of a femtosecond laser filament caused by the filament heating effect in air has been studied. An empirical formula has also been derived from the classical Karman turbulence model, which determines quantitatively the displacement of the beam center as a function of the propagation distance and the effective turbulence structure constant. After fitting the experimental data with this formula, the effective turbulence structure constant has been estimated for a single filament generated in laboratory environment. With this result, one may be able to estimate quantitatively the displacement of a filament over long distance propagation and interpret the practical performance of the experiments assisted by femtosecond laser filamentation, such as remote air lasing, pulse compression, high order harmonic generation (HHG), etc. PMID- 26480080 TI - Comprehensive model for studying noise induced by self-homodyne detection of backward Rayleigh scattering in optical fibers. AB - Backward Rayleigh scattering in optical fibers due to the fluctuations that are "frozen-in" to the fiber during the manufacturing process may limit the performance of optical sensors and bidirectional coherent optical communication systems. In this manuscript we describe a comprehensive model for studying intensity noise induced by spontaneous Rayleigh backscattering in optical systems that are based on self-homodyne detection. Our model includes amplitude and frequency noise of the laser source, random distribution of the scatterers along the fiber, and phase noise induced in fibers due to thermal and mechanical fluctuations. The model shows that at frequencies above about 10 kHz the noise spectrum is determined by the laser white frequency noise. The laser flicker frequency noise becomes the dominant effect at lower frequencies. The noise amplitude depends on the laser polarization. A very good agreement between theory and experiment is obtained for fibers with a length between 500 m to 100 km and for a laser with a linewidth below 5 kHz. PMID- 26480081 TI - Athermal silicon ring resonators clad with titanium dioxide for 1.3um wavelength operation. AB - We investigate the athermal characteristics of silicon waveguides clad with TiO(2) designed for 1.3 um wavelength operation. Using CMOS-compatible fabrication processes, we realize and experimentally demonstrate silicon photonic ring resonators with resonant wavelengths that vary by less than 6 pm/ degrees C at 1.3 um. The measured ring resonance wavelengths across the 20-50 degrees C temperature range show nearly complete cancellation of the first-order thermo optical effects and exhibit second-order thermo-optical effects expected from the combination of TiO(2) and Si. PMID- 26480082 TI - Multicore optical fiber Y-splitter. AB - In future high capacity multicore optical fiber (MCF) networks, signal-processing devices should be able to manipulate data without sacrificing network capacity or MCFs advantages. Thus, it is crucial to have high performance novel devices that can be connected directly to MCFs without conversion to conventional single-core fibers. In this work, a novel Y-splitter for multicore optical fibers is proposed and numerically demonstrated for the first time. The splitter can directly split the power of input MCF cores by 50/50 splitting-ratio into two output MCFs cores. The splitter principle of operation mainly depends on novel double-hump graded index (DHGI) profile that can space-division split (SDS) optical power by half. Both finite-difference-time-domain and eigenmode-expansion simulations are performed to design, verify, and characterize performance of Y-splitter. It shows wideband operation over the S, C, L, U-bands with polarization insensitivity. It also demonstrates high performance with reasonable insertion-loss, in addition to very low excess-loss and return-loss. Moreover, the splitter shows good performance tolerance to both MCF and design parameters variations. PMID- 26480083 TI - Developing high-power hybrid resonant gain-switched thulium fiber lasers. AB - In this paper, we propose hybrid-pumped resonant gain-switched thulium fiber lasers to realize high-average-power and high-pulse-energy 2-MUm laser emissions. Based on numerical simulation, laser dynamics (pulse peak power, pulse energy, pulse duration, etc.) of this kind of laser system are investigated in detail. By taking advantages of the 793 nm continuous wave pump and the 1900 nm pulsed pump, performance of the laser emission can be significantly improved, with the highest average power of 28 W, peak power of 3.5 kW, pulse energy of 281 MUJ, and narrowest pulse duration of 92 ns, all of which can be further optimized through designing the cavity parameters and the pumping circumstance. Compared with the pump pulses, two times improvement in pulse energy and average power has been achieved. This hybrid resonant gain-switched system has an all-fiber configuration and high efficiency (low heat load), and can be steadily extended into the cladding pump scheme, thus paving a new way to realize high power (>100 W average power) and high pulse energy (>1 mJ) 2 MUm thulium fiber lasers. PMID- 26480084 TI - High-sensitivity liquid refractive-index sensor based on a Mach-Zehnder interferometer with a double-slot hybrid plasmonic waveguide. AB - A Mach-Zehnder Interferometer (MZI) liquid sensor, employing ultra-compact double slot hybrid plasmonic (DSHP) waveguide as active sensing arm, is developed. Numerical results show that extremely large optical confinement factor of the tested analytes (as high as 88%) can be obtained by DSHP waveguide with optimized geometrical parameters, which is larger than both, conventional SOI waveguides and plasmonic slot waveguides with same widths. As for MZI sensor with 40MUm long DSHP active sensing area, the sensitivity can reach as high value as 1061nm/RIU (refractive index unit). The total loss, excluding the coupling loss of the grating coupler, is around 4.5dB. PMID- 26480085 TI - Bandwidth improvement for germanium photodetector using wire bonding technology. AB - We demonstrate an ultrahigh speed germanium photodetector by introducing gold wires into the discrete ground electrodes with standard wire bonding technology. To engineer the parasitic parameter, the physical dimension of the gold wire used for wire bonding is specially designed with an inductance of about 450 pH. Simulation and experimental results show that the bandwidth of the photodetector can be effectively extended from less than 30 GHz to over 60 GHz. PMID- 26480086 TI - Manipulation of metallic nanoparticle with evanescent vortex Bessel beam. AB - In this work, we propose a novel strategy to optically trap and manipulate metallic nanoparticles using evanescent vortex Bessel beam (EVBB). A versatile method is presented to generate evanescent Bessel beam with tunable optical angular momentum by focusing a radially polarized vortex beam onto a one dimensional photonics band gap structure. The behavior of a metallic nanoparticle in the EVBB is numerically studied. We show that such particle can be stably trapped near the surface. The orbital angular momentum drives the metallic nanoparticle to orbit around the beam axis, and the direction of the orbital motion is controlled by the handedness of the helical phase front. The technique demonstrated in this work may open up new avenues for optical manipulation, and the non-contact tunable orbiting dynamics of the trapped particle may find important applications in higher resolution imaging techniques. PMID- 26480087 TI - Spherical space Bessel-Legendre-Fourier localized modes solver for electromagnetic waves. AB - Maxwell's vector wave equations are solved for dielectric configurations that match the symmetry of a spherical computational domain. The electric or magnetic field components and the inverse of the dielectric profile are series expansion defined using basis functions composed of the lowest order spherical Bessel function, polar angle single index dependant Legendre polynomials and azimuthal complex exponential (BLF). The series expressions and non-traditional form of the basis functions result in an eigenvalue matrix formulation of Maxwell's equations that are relatively compact and accurately solvable on a desktop PC. The BLF matrix returns the frequencies and field profiles for steady states modes. The key steps leading to the matrix populating expressions are provided. The validity of the numerical technique is confirmed by comparing the results of computations to those published using complementary techniques. PMID- 26480088 TI - Cloak based on the angle dependent constitutive parameters tensors. AB - The transformation optics cloak was proposed for the medium with the angle dependent tensors of permittivity and permeability consisted of the right-handed and left-handed metamaterial media. The cloaking effect was numerically simulated using finite element method in the terahertz frequency range for different wave sources. The impact of cloaking medium thickness on the invisibility effect was demonstrated. PMID- 26480089 TI - Scalable two- and three-dimensional optical labels generated by 128-port encoder/decoder for optical packet switching. AB - This paper deals with massive number of optical code (OC) label generation and recognition for scalable optical packet switching (OPS) networks. In order to expand the system scalability of code label processing, we develop a record port count 128 x 128 optical encoder/decoder (E/D) and propose a novel three dimensional (3-D) optical label combining code label with wavelength and polarization. In the experiment, we conduct a proof-of-concept demonstration of 4 code x 2-wavelength x 2-polarization and validate that the 3-D labeling scheme can consequently increase the available number of code label up to more than 1,000 labels. Real-time labeling performance using a field programmable gate array (FPGA)-based processor and crosstalk influence at an optical switch are also experimentally evaluated. PMID- 26480090 TI - Cyclostationarity-based joint monitoring of symbol-rate, frequency offset, CD and OSNR for Nyquist WDM superchannels. AB - Software-defined transceivers can be reconfigured based on demand and existing channel impairments, and as such, monitoring of both signal and channel parameters is necessary. We demonstrate a novel joint estimation method suitable for spectrally efficient Nyquist wavelength-division multiplexing (WDM), based on the cyclostationary property of linearly modulated signals, exploited both in the frequency and time domains. Using a Nyquist superchannel composed of three 10 GBaud channels, we experimentally demonstrate the simultaneous monitoring of symbol-rate with 100% accuracy, roll-off, frequency offset (FO), chromatic dispersion (CD) and optical signal-to-noise ratio (OSNR) with root-mean-square errors (RMSE) of 20%, 4 MHz, 200 ps/nm and 1.5 dB respectively, when the roll-off factor is larger than 0.06 for DP-QPSK and 0.3 for DP-16QAM. PMID- 26480091 TI - Omnidirectional diffraction control with rotational topological defects. AB - We present a new scheme for the directional diffraction management of light with incompatible transformation optics. By introducing the concept of disclinations into transformation optics, we demonstrate that the rotational incompatible mapping violates the integrability condition of the coordinate transformation and gives rise to the non-vanishing Frank vector. It is revealed that such special coordinate transformations can produce rotational topological defects in physical space, which magnifies or compresses the diffraction of light beams propagating in arbitrary directions. We verify our theoretical analysis by numerical simulations of the light scattering from a cylinder of a generic disclination medium. PMID- 26480092 TI - Thin waveplate lenses of switchable focal length--new generation in optics. AB - We present new lenses - waveplate lenses created in liquid crystal and liquid crystal polymer materials. Using an electrically-switchable liquid-crystal half wave retarder we realized switching between focused and defocused beams by the waveplate lens. A combination of two such lenses allowed the collimation of a laser beam as well as the change of focal length of optical system. PMID- 26480093 TI - Flexible calibration method for microscopic structured light system using telecentric lens. AB - This research presents a novel method to calibrate a microscopic structured light system using a camera with a telecentric lens. The pin-hole projector calibration follows the standard pin-hole camera calibration procedures. With the calibrated projector, the 3D coordinates of those feature points used for projector calibration are then estimated through iterative Levenberg-Marquardt optimization. Those 3D feature points are further used to calibrate the camera with a telecentric lens. We will describe the mathematical model of a telecentric lens, and demonstrate that the proposed calibration framework can achieve very high accuracy: approximately 10 MUm with a volume of approximately 10(H) mm * 8(W) mm * 5(D) mm. PMID- 26480094 TI - Fragmentation-aware service provisioning for advance reservation multicast in SD EONs. AB - In this paper, we study the service provisioning schemes for dynamic advance reservation (AR) multicast requests in elastic optical networks (EONs). We first propose several algorithms that can handle the service scheduling and routing and spectrum assignment (RSA) of AR multicast requests jointly, including an integrated two-dimensional fragmentation-aware RSA (2D-FMA) that can alleviate the 2D fragmentation caused by light-tree provisioning. Then, we leverage the idea of software-defined EONs (SD-EONs) that utilizes OpenFlow (OF) in the control plane to demonstrate and evaluate the proposed algorithms. Specifically, we build an SD-EON control plane testbed, implement the algorithms in it, and perform control plane experiments on dynamic AR multicast provisioning. The results indicate that 2D-FMA achieves the best blocking performance and provides the shortest average setup delay. PMID- 26480095 TI - Acousto-optic coupling in phoxonic crystal nanobeam cavities with plasmonic behavior. AB - Acousto-optic (AO) coupling in a two-layer GaAs/Ag heterogeneous phoxonic crystal nanobeam cavity with plasmonic behavior is studied numerically. Because of the Ag metal layer, the cavity structure hybridizes photons and surface plasmons, squeezing the optical energy into small regions near the GaAs/Ag interface; the phononic cavity modes can be simultaneously tailored to highly match the photonic cavity modes at reduced regions in the cavity. Consequently, AO coupling is enhanced at near-infrared wavelengths. Boosting of the interface effect by the acoustic displacement field mainly contributes to the AO coupling enhancement. The simultaneous small photonic mode volume and high spatial matching of photonic and phononic cavity modes enhance the photonic resonance wavelength shift by one order of magnitude. This study enables applications of strong AO or photon-phonon interaction in subwavelength nano-structures. PMID- 26480096 TI - Linear and nonlinear characterization of low-stress high-confinement silicon-rich nitride waveguides. AB - In this paper we introduce a low-stress silicon enriched nitride platform that has potential for nonlinear and highly integrated optics. The manufacturing process of this platform is CMOS compatible and the increased silicon content allows tensile stress reduction and crack free layer growth of 700 nm. Additional benefits of the silicon enriched nitride is a measured nonlinear Kerr coefficient n(2) of 1.4.10(-18) m(2)/W (5 times higher than stoichiometric silicon nitride) and a refractive index of 2.1 at 1550 nm that enables high optical field confinement allowing high intensity nonlinear optics and light guidance even with small bending radii. We analyze the waveguide loss (~1 dB/cm) in a spectrally resolved fashion and include scattering loss simulations based on waveguide surface roughness measurements. Detailed simulations show the possibility for fine dispersion and nonlinear engineering. In nonlinear experiments we present continuous-wave wavelength conversion and demonstrate that the material does not show nonlinear absorption effects. Finally, we demonstrate microfabrication of resonators with high Q-factors (~10(5)). PMID- 26480097 TI - Adaptive electrowetting lens-prism element. AB - An adaptive electrowetting-based element with focusing and steering capability has been demonstrated in a monolithic design. Curvature and tip-tilt variation have been demonstrated using low voltages. A steering range of up to 4.3 degrees and lens tuning of 18 diopters have been measured at 30 V DC and 21 V DC, respectively. PMID- 26480098 TI - Transmission spectra of sausage-like microresonators. AB - We experimentally develop a sausage-like microresonator (SLM) by making two microtapers on a single-mode fiber, and study whispering-gallery modes (WGMs) in SLMs with different lengths. The transmission spectra from 1530 nm to 1550 nm of several SLMs are presented and SLMs with different lengths are shown to have different transmission features. The maximal Q factor observed in the SLMs is 3.8 * 10(7). For comparison, the transmission spectrum of a fiber cylinder microresonator is given and the maximal Q factor achieved in the fiber microcylinder resonator is 1.7 * 10(7). The strain tuning of the SLM is also demonstrated. PMID- 26480099 TI - Self-assembled dielectric microsphere array enhanced Raman scattering for large area and ultra-long working distance confocal detection. AB - Here we report enhanced confocal Raman detection with large-area and ultra-long working distance by capping dielectric microsphere array. Microspheres have been found to provide three channels for Raman scattering enhancement, including localized photonic nanojets, directional antenna effects, and whispering-gallery modes. The maximum enhancement ratio of Raman intensity is up to 14.6 using 4.94 MUm-diameter polystyrene (PS) microspheres. Investigation on the directional antenna effect of microsphere reveals that the microsphere array confines electromagnetic (EM) waves to a narrow distribution with small divergent angles, by which the signal-to-noise ratio is retained and the offset of focal plane position from sample surface can be up to +/- 7.5 mm. The present work reduces the requirement of focusing in confocal Raman detection and hence makes the large area detection possible via rapid mapping. It opens up a simple approach for high sensitivity Raman detection of 3D-structured surface. PMID- 26480100 TI - Submicro-pillars and holes from the depth-wise Talbot images of a conical phase mask. AB - We construct two-dimensional arrays of submicro-pillars and holes from the depth wise Talbot images of a conical phase mask in a photoactive layer prepared on a quartz substrate. In contrast to the conventional Talbot lithography employing only one image in the photoactive layer, two images of the phase mask are produced in a depth-wise manner such that the pillar patterns are in the primary image plane while the hole patterns in the secondary image plane according to the penetration depth of the exposure energy. The conical symmetry plays a critical role in producing the covariant patterns of the phase mask in the photoactive layer through the suppression of higher orders of diffraction. Our two image-type approach is simple and versatile for producing different kinds of periodic structures for photonic applications and surface engineering on a micrometer-to nanometer scale. PMID- 26480101 TI - Parallel determination of absolute distances to multiple targets by time-of flight measurement using femtosecond light pulses. AB - Distances to multiple targets are measured simultaneously using a single femtosecond pulse laser split through a diffractive optical element. Pulse arrival from each target is detected by means of balanced cross-correlation of second harmonics generated using a PPKTP crystal. Time-of-flight of each returning pulse is counted by dual-comb interferometry with 0.01 ps timing resolution at a 2 kHz update rate. This multi-target ranging capability is demonstrated by performing multi-degree of freedom (m-DOF) sensing of a rigid body motion simulating a satellite operating in orbit. This method is applicable to diverse terrestrial and space applications requiring concurrent multiple distance measurements with high precision. PMID- 26480102 TI - 160 W 800 fs Yb:YAG single crystal fiber amplifier without CPA. AB - We demonstrate a compact and simple two-stage Yb:YAG single crystal fiber amplifier which delivers 160 W average power, 800 fs pulses without chirped pulse amplification. This is the highest average power of femtosecond laser based on SCF. Additionally, we demonstrate the highest small signal gain of 32.5 dB from the SCF in the first stage and the highest extraction efficiency of 42% in the second stage. The excellent performance of the second stage was obtained using the bidirectional pumping scheme, which is applied to SCF for the first time. PMID- 26480103 TI - Raman-scattering-assistant broadband noise-like pulse generation in all-normal dispersion fiber lasers. AB - We report on the observation of both stable dissipative solitons and noise-like pulses with the presence of strong Raman scattering in a relatively short all normal-dispersion Yb-doped fiber laser. We show that Raman scattering can be filtered out by intracavity filter. Furthermore, by appropriate intracavity polarization control, the Raman effect can be utilized to generate broadband noise-like pulses (NLPs) with bandwidth up to 61.4 nm. To the best of our knowledge, this is the broadest NLP achieved in all-normal-dispersion fiber lasers. PMID- 26480104 TI - 293 W, GHz narrow-linewidth, polarization maintaining nanosecond fiber amplifier with SBS suppression employing simultaneous phase and intensity modulation. AB - We present a new method of SBS suppression in fiber amplifier system by employing simultaneously phase and intensity modulation. In this way, a GHz narrow linewidth polarization-maintaining (PM) all-fiber pulsed laser is obtained based on a master oscillator power amplifier (MOPA) configuration. The pulsed seed is generated from a single-frequency continuous wave (CW) laser at 1064 nm by simultaneous modulation using an electro-optic intensity modulator (EOIM) and an electro-optic phase modulator (EOPM). Theoretical model is built and simulation framework has been established to estimate the SBS threshold of the pulsed amplifier system before and after modulation. In experiment, in order to suppress SBS effectively, the pulse width is set to be 4 ns and the phase modulation voltage is set to be 5 V. After amplifying by the amplifier chain, a ~3.5 ns pulsed laser with average/peak power of 293 W/3.9 kW is obtained at intensity repetition rate of 20 MHz and phase repetition rate of 100MHz, showing good agreement with simulation results. The linewidth of the output laser is ~4.5 GHz, the M(2) factor at maximal output power is measured to be ~1.1 and the slope efficiency is ~86%.This method provides some references to suppress the SBS in narrow linewidth pulsed amplifier systems. PMID- 26480105 TI - Experimental research of a chain of diode pumped rubidium amplifiers. AB - In this paper, we have set up a diode pumped rubidium MOPA system with a chain of two amplifiers. The experimental results show an amplified laser power of 26W with amplification factor of 16.3 and power extraction efficiency of 53% for a single amplifier, and an amplified laser power of 11W with amplification factor of 7.9 and power extraction efficiency of 26% for a chain of two amplifiers. The reason for lower performance of cascade amplification is mainly due to the limited total pump power, which will be not sufficient for efficient pumping when assigned from a single amplifier into two amplifiers. The situation could be well improved by increasing the seed laser power as well as the pump power for each amplifier to realize high efficient saturated amplification. Such MOPA configuration has the potential for scaling high beam quality alkali laser into high powers. PMID- 26480106 TI - Metal-dielectric-metal resonators with deep subwavelength dielectric layers increase the near-field SEIRA enhancement. AB - Plasmonic nanostructures presenting either structural asymmetry or metal dielectric-metal (M-D-M) architecture are commonly used structures to increase the quality factor and the near-field confinement in plasmonic materials. This characteristic can be leveraged for example to increase the sensitivity of IR spectroscopy, via the surface enhanced IR absorption (SEIRA) effect. In this work, we combine structural asymmetry with the M-D-M architecture to realize Ag Ag(2)O-Ag asymmetric ring resonators where two Ag layers sandwich a native silver oxide (Ag(2)O) layer. Their IR response is compared with the one of fully metallic (Ag) resonators of the same size and shape. The photothermal induced resonance technique (PTIR) is used to obtain near-field SEIRA absorption maps and spectra with nanoscale resolution. Although the native Ag(2)O layer is only 1 nm to 2 nm thick, it increases the quality factor of the resonators' dark-mode by ~27% and the SEIRA enhancement by ~44% with respect to entirely Ag structures. PMID- 26480107 TI - Spatio-temporal modeling and optimization of a deformable-grating compressor for short high-energy laser pulses. AB - Monolithic large-scale diffraction gratings are desired to improve the performance of high-energy laser systems and scale them to higher energy, but the surface deformation of these diffraction gratings induce spatio-temporal coupling that is detrimental to the focusability and compressibility of the output pulse. A new deformable-grating-based pulse compressor architecture with optimized actuator positions has been designed to correct the spatial and temporal aberrations induced by grating wavefront errors. An integrated optical model has been built to analyze the effect of grating wavefront errors on the spatio temporal performance of a compressor based on four deformable gratings. A 1.5 meter deformable grating has been optimized using an integrated finite-element analysis and genetic-optimization model, leading to spatio-temporal performance similar to the baseline design with ideal gratings. PMID- 26480108 TI - Toward a nonlinearity model for a heterodyne interferometer: not based on double frequency mixing. AB - Residual periodic errors detected in picometer-level heterodyne interferometers cannot be explained by the model based on double-frequency mixing. A new model is established and proposed in this paper for analysis of these errors. The multi order Doppler frequency shift ghost beams from measurement beam itself are involved in final interference leading to multi-order periodic errors, whether or not frequency-mixing originating from the two incident beams occurs. For model validation, a novel setup free from double-frequency mixing is constructed. The analyzed measurement signal shows that phase mixing of measurement beam itself can lead to multi-order periodic errors ranging from tens of picometers to one nanometer. PMID- 26480109 TI - Enhancing the humidity response time of polymer optical fiber Bragg grating by using laser micromachining. AB - The humidity sensors constructed from polymer optical fiber Bragg gratings (POFBG) respond to the water content change in the fiber induced by varying environmental condition. The water content change is a diffusion process. Therefore the response time of the POFBG sensor strongly depends on the geometry and size of the fiber. In this work we investigate the use of laser micromachining of D-shaped and slotted structures to improve the response time of polymer fiber grating based humidity sensors. A significant improvement in the response time has been achieved in laser micromachined D-shaped POFBG humidity sensors. The slotted geometry allows water rapid access to the core region but this does not of itself improve response time due to the slow expansion of the bulk of the cladding. We show that by straining the slotted sensor, the expansion component can be removed resulting in the response time being determined only by the more rapid, water induced change in core refractive index. In this way the response time is reduced by a factor of 2.5. PMID- 26480110 TI - Large viewing angle three-dimensional display with smooth motion parallax and accurate depth cues. AB - A three-dimensional (3D) display with smooth motion parallax and large viewing angle is demonstrated, which is based on a microlens array and a coded two dimensional (2D) image on a 50 inch liquid crystal device (LCD) panel with the resolution of 3840 * 2160. Combining with accurate depth cues expressing, the flipping images of the traditional integral imaging (II) are eliminated, and smooth motion parallax can be achieved. The image on the LCD panel is coded as an elemental image packed repeatedly, and the depth cue is determined by the repeated period of elemental image. To construct the 3D image with complex depth structure, the varying period of elemental image is required. Here, the detailed principle and coding method are presented. The shape and the texture of a target 3D image are designed by a structure image and an elemental image, respectively. In the experiment, two groups of structure images and their corresponding elemental images are utilized to construct a 3D scene with a football in a green net. The constructed 3D image exhibits obviously enhanced 3D perception and smooth motion parallax. The viewing angle is 60 degrees , which is much larger than that of the traditional II. PMID- 26480111 TI - Laser-induced periodic surface structures on titanium upon single- and two-color femtosecond double-pulse irradiation. AB - Single- and two-color double-fs-pulse experiments were performed on titanium to study the dynamics of the formation of laser-induced periodic surface structures (LIPSS). A Mach-Zehnder inter-ferometer generated polarization controlled (parallel or cross-polarized) double-pulse sequences in two configurations - either at 800 nm only, or at 400 and 800 nm wavelengths. The inter-pulse delays of the individual 50-fs pulses ranged up to some tens of picoseconds. Multiple of these single- or two-color double-fs-pulse sequences were collinearly focused by a spherical mirror to the sample surface. In both experimental configurations, the peak fluence of each individual pulse was kept below its respective ablation threshold and only the joint action of both pulses lead to the formation of LIPSS. Their resulting characteristics were analyzed by scanning electron microscopy and the periods were quantified by Fourier analyses. The LIPSS periods along with the orientation allow a clear identification of the pulse which dominates the energy coupling to the material. A plasmonic model successfully explains the delay-dependence of the LIPSS on titanium and confirms the importance of the ultrafast energy deposition stage for LIPSS formation. PMID- 26480112 TI - All-fiber 10 MHz acousto-optic modulator of a fiber Bragg grating at 1060 nm wavelength. AB - Acousto-optic modulation of a 1 cm fiber Bragg grating at 10.9 MHz frequency and 1065 nm wavelength is demonstrated for the first time. A special modulator design is employed to acoustically induce a dynamic radial long period grating which couples power of the fundamental mode to the higher-order modes supported by the Bragg grating. A modulated reflection band with a depth of 16 dB and 320 pm bandwidth has been achieved. The results indicate a higher modulation frequency compared to previous studies using flexural acoustic waves. In addition, the reduction of the grating length and the modulator size points to compact and faster acousto-optic modulators. PMID- 26480113 TI - Highly stabilized optical frequency comb interferometer with a long fiber-based reference path towards arbitrary distance measurement. AB - An optical frequency comb interferometer with a 342-m-long fiber-based optical reference path was developed. The long fiber-based reference path was stabilized to 10(-12)-order stability by using a fiber noise cancellation technique, and small temperature changes on the millikelvin order were detected by measuring an interferometric phase signal. Pulse number differences of 30 and 61 between the measurement and reference paths were determined precisely, with slight tuning of the 53.4 MHz repetition frequency. Moreover, with pulse number difference of 61, a 6.4-m-wide scanning for the relative pulse position is possible only by 1 MHz repetition frequency tuning, which makes pulses overlapped for arbitrary distance. Such wide-range high-precision delay length scanning can be used to measure arbitrary distances by using a highly stabilized long fiber-based reference path. PMID- 26480114 TI - Time-gated digital optical frequency domain reflectometry with 1.6-m spatial resolution over entire 110-km range. AB - A novel time-gated digital optical frequency domain reflectometry (TGD-OFDR) technique with high spatial resolution over long measurement range is proposed and experimentally demonstrated. To solve the contradictory between the tuning rate of lightwave frequency, which determines the spatial resolution, and the measurable distance range in traditional OFDR, our proposed scheme sweeps the frequency of probe beam only within a time window, while the local reference remains a frequency-stable continuous lightwave. The frequency-to-distance mapping is digitally realized with equivalent references in data domain. In demonstrational experiments, a 1.6-m spatial resolution is obtained over an entire 110-km long fiber link, proving that the phase noises of the laser source as well as environmental perturbations are well suppressed. Meanwhile, the dynamic range was 26 dB with an average of only 373 measurements. The proposed reflectometry provides a simple-structure and high-performance solution for the applications where both high spatial resolution and long distance range are required. PMID- 26480115 TI - Accelerating fDOT image reconstruction based on path-history fluorescence Monte Carlo model by using three-level parallel architecture. AB - The excessive time required by fluorescence diffuse optical tomography (fDOT) image reconstruction based on path-history fluorescence Monte Carlo model is its primary limiting factor. Herein, we present a method that accelerates fDOT image reconstruction. We employ three-level parallel architecture including multiple nodes in cluster, multiple cores in central processing unit (CPU), and multiple streaming multiprocessors in graphics processing unit (GPU). Different GPU memories are selectively used, the data-writing time is effectively eliminated, and the data transport per iteration is minimized. Simulation experiments demonstrated that this method can utilize general-purpose computing platforms to efficiently implement and accelerate fDOT image reconstruction, thus providing a practical means of using path-history-based fluorescence Monte Carlo model for fDOT imaging. PMID- 26480116 TI - Quantum discord protection from amplitude damping decoherence. AB - Entanglement is known to be an essential resource for many quantum information processes. However, it is now known that some quantum features may be acheived with quantum discord, a generalized measure of quantum correlation. In this paper, we study how quantum discord, or more specifically, the measures of entropic discord and geometric discord are affected by the influence of amplitude damping decoherence. We also show that a protocol deploying weak measurement and quantum measurement reversal can effectively protect quantum discord from amplitude damping decoherence, enabling to distribute quantum correlation between two remote parties in a noisy environment. PMID- 26480117 TI - Generation of dark solitons in erbium-doped fiber lasers based Sb(2)Te(3) saturable absorbers. AB - Dark solitons, which have better stability in the presence of noise, have potential applications in optical communication and ultrafast optics. In this paper, the dark soliton formation in erbium-doped fiber lasers based Sb(2)Te(3) saturable absorber (SA) is first experimentally demonstrated. The Sb(2)Te(3) SA is fabricated by using the pulsed laser deposition method. The generated dark solitons are centered at the wavelength of 1530 nm and repetition rate of 94 MHz. Analytic solutions for dark solitons are also obtained theoretically. PMID- 26480118 TI - Design of a dynamic dual-foveated imaging system. AB - A new kind of dynamic dual-foveated imaging system in the infrared band is designed and optimized in this paper. Dual-foveated imaging refers to the variation in spatial resolution at the two selected fields across the image. Such variable resolution imaging system is suitable for a variety of applications including monitoring, recognition, and remote operation of unmanned aerial vehicle. In this system, a transmissive spatial light modulator (SLM) is used as an active optical element which is located near the image plane instead of pupil plane creatively in order to divide the two selected fields. PMID- 26480119 TI - Electrically controllable Fresnel lens in 90 degrees twisted nematic liquid crystals. AB - This study presents a theoretical analysis and experimental demonstration of an electrically controllable Fresnel lens in a 90 degrees twisted nematic liquid crystal cell. The cell gap was chosen to satisfy the Gooch-Tarry conditions, and therefore, the polarization rotation effect was valid regardless of the incident polarization direction. The polarization sensitivity of the diffraction efficiency of the 90 degrees twisted nematic Fresnel lens was dependent on the applied voltage regime. Theoretical calculations effectively explain the experimental results. PMID- 26480120 TI - Estimation of bulk optical properties of turbid media from hyperspectral scatter imaging measurements: metamodeling approach. AB - In many research areas and application domains, the bulk optical properties of biological materials are of great interest. Unfortunately, these properties cannot be obtained easily for complex turbid media. In this study, a metamodeling approach has been proposed and applied for the fast and accurate estimation of the bulk optical properties from contactless and non-destructive hyperspectral scatter imaging (HSI) measurements. A set of liquid optical phantoms, based on intralipid, methylene blue and water, were prepared and the Vis/NIR bulk optical properties were characterized with a double integrating sphere and unscattered transmittance setup. Accordingly, the phantoms were measured with the HSI technique and metamodels were constructed, relating the Vis/NIR reflectance images to the reference bulk optical properties of the samples. The independent inverse validation showed good prediction performance for the absorption coefficient and the reduced scattering coefficient, with R(2)(p) values of 0.980 and 0.998, and RMSE(P) values of 0.032 cm(-1) and 0.197 cm(-1) respectively. The results clearly support the potential of this approach for fast and accurate estimation of the bulk optical properties of turbid media from contactless HSI measurements. PMID- 26480121 TI - Plane wave scattering from a plasmonic nanowire-film system with the inclusion of non-local effects. AB - In this paper we present a theoretical analysis of the electromagnetic response of a plasmonic nanowire-film system. The analytical solution accounts for both the dispersive as well as non-local nature of the plasmonic media. The physical structure comprises of a plasmonic nanowire made of a plasmonic metal such as gold or silver placed over a plasmonic film of the same material. Such a nanostructure exhibits a spectrum that is extremely sensitive to various geometric parameters such as spacer thickness and nanowire radius, which makes it favorable for various sensing applications. The non-locality of the plasmonic medium, which can be captured using the hydrodynamic model, significantly affects the resonant wavelength of this system for structures of small dimensions (~ less than 5 nm gap between the nanowire and the film). We present an analytical method that can be used to predict the effect of non-locality on the resonances of the system. To validate the analytical method, we also report a comparison of our analytical solution with a numerical Finite Difference Time Domain analysis (FDTD) of the same structure with the plasmonic medium being treated as local in nature. PMID- 26480122 TI - Visible light communication using mobile-phone camera with data rate higher than frame rate. AB - Complementary Metal-Oxide-Semiconductor (CMOS) image sensors are widely used in mobile-phone and cameras. Hence, it is attractive if these image sensors can be used as the visible light communication (VLC) receivers (Rxs). However, using these CMOS image sensors are challenging. In this work, we propose and demonstrate a VLC link using mobile-phone camera with data rate higher than frame rate of the CMOS image sensor. We first discuss and analyze the features of using CMOS image sensor as VLC Rx, including the rolling shutter effect, overlapping of exposure time of each row of pixels, frame-to-frame processing time gap, and also the image sensor "blooming" effect. Then, we describe the procedure of synchronization and demodulation. This includes file format conversion, grayscale conversion, column matrix selection avoiding blooming, polynomial fitting for threshold location. Finally, the evaluation of bit-error-rate (BER) is performed satisfying the forward error correction (FEC) limit. PMID- 26480123 TI - Thin-film Pancharatnam lens with low f-number and high quality. AB - We have made an ultra-thin (~2.26 um) f/2.1 lens based on the Pancharatnam phase effect using the polarization holography alignment technique. This lens exhibits a continuous phase profile, high efficiency (>97%), and is switchable from having a positive focal length to a negative one by changing the handedness of input circularly polarized light. We analyzed its optical performance and simulated it as a gradient index lens for further comparison, and to discuss its bandwidth limitation. The conditions required for improving the performance and its low cost fabrication method is discussed. Because of the nature of Pancharatnam devices and the demonstrated fabrication method, these results are applicable to a wide size range. PMID- 26480125 TI - Design optical antenna and fiber coupling system based on the vector theory of reflection and refraction. AB - A Cassegrain antenna system and an optical fiber coupling system which consists of a plano-concave lens and a plano-convex lens are designed based on the vector theory of reflection and refraction, so as to improve the transmission performance of the optical antenna and fiber coupling system. Three-dimensional ray tracing simulation are performed and results of the optical aberrations calculation and the experimental test show that the aberrations caused by on axial defocusing, off-axial defocusing and deflection of receiving antenna can be well corrected by the optical fiber coupling system. PMID- 26480124 TI - Low-visibility patterning of transparent conductive silver-nanowire films. AB - A partial etching mechanism is proposed to meet the requirement for low visibility patterning of silver nanowire (AgNW)-based transparent conductive electrodes (TCEs) by reducing the difference in optical properties between conductive and nonconductive regions of the pattern. Using the finite difference time domain (FDTD) method, etched geometries that provide the smallest difference in transmittance after etching are theoretically determined. A sodium hypochlorite-based etchant capable that allows the etched geometry to be varied by controlling the pH is used to create a low-visibility pattern with a transmittance and haze difference of 0.07 and 0.04%, respectively. To the best of our knowledge, this is the first time that a partial etching mechanism such as this has been studied in relation to AgNW-based TCEs. PMID- 26480126 TI - Static/dynamic strain sensing applications by monitoring the correlation peak from optical wideband chaos. AB - We present a new sensing demodulation approach by monitoring the amplitude changes of correlation peak through using optical wideband chaos. For the static strain sensing, the reflection intensity of optical wideband chaos can be modulated by the strain induced wavelength spacing between the wavelength division multiplexing (WDM) device and the sensing grating. Thus, the relative amplitude change (RAC) of correlation peak is mainly determined by the change of chaotic reflection intensity. For the dynamic strain sensing, the reflection intensity of optical wideband chaos can be modulated by the fast fluctuant evanescent wave on a section of no-core fiber (NCF). Thus, the response from correlation peak's RAC is mainly according to the dynamic strain frequency. The experimental measurements show that a high strain sensing sensitivity of 7.04*10 3 RAC/MUepsilon is achieved within the measurement range of 900 MUepsilon during the static strain test. While in the dynamic test, the demodulation can detect the vibration frequency of 6 kHz located at 6 km long. This demodulation method can simultaneously achieve static/dynamic sensing and precisely locating the fiber break point with the high accuracy of several centimeters, making it very easy for network maintenance. PMID- 26480127 TI - Direct superresolution for realistic image reconstruction. AB - Traditional superresolution techniques employ optimizers, priors, and regularizers to deliver stable, appealing restorations even though deviating from the real, ground-truth scene. We have developed a non-regularized superresolution algorithm that directly solves a fully-characterized multi-shift imaging reconstruction problem to achieve realistic restorations without being penalized by improper assumptions made in the inverse problem. An adaptive frequency-based filtering scheme is introduced to upper bound the reconstruction errors while still producing more fine details as compared with previous methods when inaccurate shift estimation, noise, and blurring scenarios are considered. PMID- 26480128 TI - Sub-100 fs pulses from an all-polarization maintaining Yb-fiber oscillator with an anomalous dispersion higher-order-mode fiber. AB - We present an Yb-fiber oscillator with an all-polarization-maintaining cavity with a higher-order-mode fiber for dispersion compensation. The polarization maintaining higher order mode fiber introduces not only negative second order dispersion but also negative third order dispersion in the cavity, in contrast to dispersion compensation schemes used in previous demonstrations of all polarization maintaining Yb-fiber oscillators. The performance of the saturable absorber mirror modelocked oscillator, that employs a free space scheme for coupling onto the saturable absorber mirror and output coupling, was investigated for different settings of the intracavity dispersion. When the cavity is operated with close to zero net dispersion, highly stable 0.5-nJ pulses externally compressed to sub-100-fs are generated. These are to our knowledge the shortest pulses generated from an all-polarization-maintaining Yb-fiber oscillator. The spectral phase of the output pulses is well behaved and can be compensated such that wing-free Fourier transform limited pulses can be obtained. Further reduction of the net intracavity third order dispersion will allow generating broader output spectra and consequently shorter pulses, without sacrificing pulse fidelity. PMID- 26480129 TI - Polarimetric dehazing method for dense haze removal based on distribution analysis of angle of polarization. AB - Many dehazing methods have proven to be effective in removing haze out of the hazy image, but few of them are adaptive in handling the dense haze. In this paper, based on the angle of polarization (AOP) distribution analysis we propose a kind of polarimetric dehazing method, which is verified to be capable of enhancing the contrast and the range of visibility of images taken in dense haze substantially. It is found that the estimating precision of the intensity of airlight is a key factor which determines the dehazing quality, and fortunately our method involves a high precision estimation inherently. In the experiments a good dehazing performance is demonstrated, especially for dense haze removal. We find that the visibility can be enhanced at least 74%. Besides, the method can be used not only in dense haze but also in severe sea fog. PMID- 26480130 TI - Graphene-assisted nonlinear optical device for four-wave mixing based tunable wavelength conversion of QPSK signal. AB - We fabricate a nonlinear optical device based on a fiber pigtail cross-section coated with a single-layer graphene grown by chemical vapor deposition (CVD) method. Using such graphene-assisted nonlinear optical device, we experimentally demonstrate tunable wavelength conversion of a 10 Gbaud quadrature phase-shift keying (QPSK) signal by exploiting degenerate four-wave mixing (FWM) progress in graphene. We study the conversion efficiency as functions of the pump power and pump wavelength and evaluate the bit-error rate (BER) performance. The observed optical signal-to-noise ratio (OSNR) penalties for tunable QPSK wavelength conversion are less than 2.2 dB at a BER of 1 * 10(-3). PMID- 26480131 TI - Design, fabrication and characterization of an AWG at 4.5 um. AB - In this paper, we present the design, the fabrication and the characterization of an Arrayed Waveguide Grating (AWG) based on a SiGe graded index waveguide platform, operating at 4.5 um. These devices were specifically designed to work together with an array of Distributed Feedback Bragg Quantum Cascade Lasers (DFB QCL) emitting at different wavelengths. The AWG enables to combine the different light sources into a single output and the design adopted allows to maximize transmission over the entire spectral range defined by the array of DFB-QCLs. PMID- 26480132 TI - Binary prefix for sampling frequency offset estimation in dispersive optical transmissions. AB - We propose and experimentally demonstrate a method for sampling frequency offset (SFO) estimation in optical communication systems based on periodically inserted identical binary prefix. Different from conventional cyclic prefix, binary prefix provides not only high tolerance to chromatic dispersion in dispersive fiber transmission, but also the ability to estimate SFO by simple receiver-side digital signal processing. Moreover, this binary prefix based scheme is generally applicable to any advanced modulation formats. A proof-of-concept experiment is conducted to quantify the accuracy and tolerance of the scheme in estimating SFO. It is found that over a wide SFO range up to 341 ppm, the estimation error is kept under 20 ppb and signals are recovered with the same quality as with zero offset sampling. The experimental results also confirm that this method is tolerant to link signal-to-noise ratio loss and dispersion, showing no additional penalty after transmission over a 40-km standard single-mode fiber at 1550 nm. PMID- 26480133 TI - Modeling and compensation of transmitter nonlinearity in coherent optical OFDM. AB - We present a comprehensive study of nonlinear distortions from an optical OFDM transmitter. Nonlinearities are introduced by the combination of effects from the digital-to-analog converter (DAC), electrical power amplifier (PA) and optical modulator in the presence of high peak-to-average power ratio (PAPR). We introduce parameters to quantify the transmitter nonlinearity. High input backoff avoids OFDM signal compression from the PA, but incurs high penalties in power efficiency. At low input backoff, common PAPR reduction techniques are not effective in suppressing the PA nonlinear distortion. A bit error distribution investigation shows a technique combining nonlinear predistortion with PAPR mitigation could achieve good power efficiency by allowing low input backoff. We use training symbols to extract the transmitter nonlinear function. We show that piecewise linear interpolation (PLI) leads to an accurate transmitter nonlinearity characterization. We derive a semi-analytical solution for bit error rate (BER) that validates the PLI approximation accurately captures transmitter nonlinearity. The inverse of the PLI estimate of the nonlinear function is used as a predistorter to suppress transmitter nonlinearity. We investigate performance of the proposed scheme by Monte Carlo simulations. Our simulations show that when DAC resolution is more than 4 bits, BER below forward error correction limit of 3.8 * 10(-3) can be achieved by using predistortion with very low input power backoff for electrical PA and optical modulator. PMID- 26480134 TI - Modal wavefront estimation from its slopes by numerical orthogonal transformation method over general shaped aperture. AB - Wavefront estimation from the slope-based sensing metrologies zis important in modern optical testing. A numerical orthogonal transformation method is proposed for deriving the numerical orthogonal gradient polynomials as numerical orthogonal basis functions for directly fitting the measured slope data and then converting to the wavefront in a straightforward way in the modal approach. The presented method can be employed in the wavefront estimation from its slopes over the general shaped aperture. Moreover, the numerical orthogonal transformation method could be applied to the wavefront estimation from its slope measurements over the dynamic varying aperture. The performance of the numerical orthogonal transformation method is discussed, demonstrated and verified by the examples. They indicate that the presented method is valid, accurate and easily implemented for wavefront estimation from its slopes. PMID- 26480135 TI - Simultaneous generation of multiple orbital angular momentum (OAM) modes using a single phase-only element. AB - Based on the conventional iterative algorithm, we present a pattern search assisted iterative (PSI) algorithm to simultaneously generate multiple orbital angular momentum (OAM) modes using a single phase-only element. The PSI algorithm shows a favorable operation performance for generating 100 randomly spaced OAM modes and 50 evenly spaced OAM modes with high diffraction efficiency (>93%), low relative root-mean-square error (R-RMSE) and low standard deviation. Moreover, we can also manipulate the relative power distribution of the generated OAM modes simply by setting the initial weight coefficients in the PSI algorithm. PMID- 26480136 TI - 300-MHz-repetition-rate, all-fiber, femtosecond laser mode-locked by planar lightwave circuit-based saturable absorber. AB - We show the implementation of fiber-pigtailed, evanescent-field-interacting, single-walled carbon nanotube (CNT)-based saturable absorbers (SAs) using standard planar lightwave circuit (PLC) fabrication processes. The implemented PLC-CNT-SA device is employed to realize self-starting, high-repetition-rate, all fiber ring oscillators at telecommunication wavelength. We demonstrate all-fiber Er ring lasers operating at 303-MHz (soliton regime) and 274-MHz (stretched-pulse regime) repetition-rates. The 303-MHz (274-MHz) laser centered at 1555 nm (1550 nm) provides 7.5 nm (19 nm) spectral bandwidth. After extra-cavity amplilfication, the amplified pulse train of the 303-MHz (274-MHz) laser delivers 209 fs (178 fs) pulses. To our knowledge, this corresponds to the highest repetition-rates achieved for femtosecond lasers employing evanescent-field interacting SAs. The demonstrated SA fabrication method, which is based on well established PLC processes, also shows a potential way for mass-producible and lower-cost waveguide-type SA devices suitable for all-fiber and waveguide lasers. PMID- 26480137 TI - Out-of-plane actuation with a sub-micron initial gap for reconfigurable terahertz micro-electro-mechanical systems metamaterials. AB - We propose a reconfigurable terahertz (THz) metamaterial that can control the transmittance by out-of-plane actuation with changing the sub-micron gap distance between electrically coupled metamaterial elements. By using the out-of-plane actuation, it was possible to avoid contact between the coupled metamaterial elements across the small initial gap during the adjustment of the gap size. THz spectroscopy was performed during actuation, and the transmission dip frequency was confirmed to be tunable from 0.82 to 0.92 THz for one linear polarization state and from 0.80 to 0.91 THz for the other linear polarization; the two polarizations were orthogonal. The proposed approach will contribute to the development of tunable metamaterials based on structural deformations. PMID- 26480138 TI - Soliton-dark pulse pair formation in birefringent cavity fiber lasers through cross phase coupling. AB - We report on the experimental observation of soliton-dark pulse pair formation in a birefringent cavity fiber laser. Temporal cavity solitons are formed in one polarization mode of the cavity. It is observed that associated with each of the cavity solitons a dark pulse is induced on the CW background of the orthogonal polarization mode. We show that the dark pulse formation is a result of the incoherent cross polarization coupling between the soliton and the CW beam and has a mechanism similar to that of the polarization domain formation observed in the fiber lasers. PMID- 26480139 TI - RF frequency sextupling via an optical two-tone signal generated from two modulation lightwaves from one Mach-Zehnder optical modulator. AB - An optical two-tone (OTT) signal is generated with a wide frequency separation, based on the suppression of +/- 1st-order optical sidebands without using optical band-rejection filtering. By combining two orthogonally polarized lightwaves modulated with different modulation indices, each optical sideband constituting the combined lightwave has a different polarization. Some of these optical sidebands can be suppressed using a polarizer. By using a single Mach-Zehnder optical modulator to achieve two optical modulations, an OTT signal with a 60-GHz frequency-separation was successfully generated with 32-dB suppression of undesired +/- 1st-order optical sidebands. An rf signal was also obtained from the OTT signal. PMID- 26480140 TI - Low-loss and high-Q Ta(2)O(5) based micro-ring resonator with inverse taper structure. AB - A low-loss and high-Q Ta(2)O(5) based micro-ring resonator is presented. The micro-ring resonator and channel waveguide with core area of the 700 by 400 nm(2) were fabricated on amorphous Ta(2)O(5) thin films prepared by reactive sputtering at 300 degrees C and post annealing at 650 degrees C for 3 hours. The Ta(2)O(5) micro-ring resonator with a diameter of 200 MUm was coupled to the channel waveguide with a coupled Q up to 38,000 at a 0.9 MUm coupling gap. By fitting the transmission spectrum of the resonator, the extracted loss coefficient inside the ring cavity and transmission coefficient of TE mode were 8.1dB/cm and 0.9923, leading to the estimated unloaded Q of higher than 44,000. In addition, based on the cut-back method, the propagation loss and the coupling loss of Ta(2)O(5) channel waveguide with an inverse taper were 1.5dB/cm and 3.2 dB, respectively. The proposed Ta(2)O(5) technology offers an unique alternative for fabricating high performance guided wave devices, and may well lead to novel applications in photonic integrated circuits. PMID- 26480141 TI - Efficient coupling of double-metal terahertz quantum cascade lasers to flexible dielectric-lined hollow metallic waveguides. AB - The growth in terahertz frequency applications utilising the quantum cascade laser is hampered by a lack of targeted power delivery solutions over large distances (>100 mm). Here we demonstrate the efficient coupling of double-metal quantum cascade lasers into flexible polystyrene lined hollow metallic waveguides via the use of a hollow copper waveguide integrated into the laser mounting block. Our approach exhibits low divergence, Gaussian-like emission, which is robust to misalignment error, at distances > 550 mm, with a coupling efficiency from the hollow copper waveguide into the flexible waveguide > 90%. We also demonstrate the ability to nitrogen purge the flexible waveguide, increasing the power transmission by up to 20% at 2.85 THz, which paves the way for future fibre based terahertz sensing and spectroscopy applications. PMID- 26480142 TI - Numerical analysis of fast saturable absorber mode-locked Yb(3+) lasers under large modulation depth. AB - Numerical analysis of fast saturable absorber mode-locked Yb(3+)-doped solid state lasers is reported. The analysis includes a special case in which the spectral bandwidth of the short pulse is larger than the fluorescence bandwidth of the gain material. The relationship between the available shortest pulse duration and modulation depth for a standard bulk and thin disk laser geometries with several gain materials are shown. The characteristic phenomena observed in our previous Kerr-lens mode-locked laser experiments were reproduced in the simulation. PMID- 26480143 TI - Optical parametric oscillator based on degenerate four-wave mixing in suspended core tellurite microstructured optical fiber. AB - We report on a suspended core tellurite microstructured optical fiber (TMOF) based optical parametric oscillator (OPO). The intracavity gain is provided by the degenerate four-wave mixing (DFWM) occurred in a 1.5-m-long TMOF synchronously pumped by a mode-locked picosecond erbium-doped fiber laser. The oscillated signal can be generated from 1606 nm to 1743.5 nm, and the idler can be emited from 1526.8 nm to 1395 nm by adjusting the pump wavelength from 1565.4 nm to 1551 nm. A total intenal conversion efficiency of -17.2 dB has been achieved. PMID- 26480144 TI - Ultra efficient silicon nitride grating coupler with bottom grating reflector. AB - We theoretically propose a silicon nitride (Si(3)N(4)) grating coupler (GC) with both ultrahigh efficiency and simplified fabrication processes. Instead of using a bottom distributed Bragg reflector (DBR) or metal reflector, a bottom Si grating reflector (GR) with comparable reflectivity is utilized to improve the coupling efficiency. The fully etched Si GR is designed based on an industrially standard silicon-on-insulator (SOI) wafer with 220 nm top Si layer. By properly adjusting the trench width and period length of the Si GR, a high reflectivity over 90% is obtained. The Si(3)N(4) GC is optimized based on a common 400 nm Si(3)N(4) layer sitting on the Si GR with a SiO(2) separation layer. With an appropriate distance between the Si(3)N(4) GC and bottom Si GR, a low coupling loss of -1.47 dB is theoretically obtained using uniform GC structure. A further record ultralow loss of -0.88 dB is predicted by apodizing the Si(3)N(4) GC. The specific fabrication processes and tolerance are also investigated. Compared with DBR, the bottom Si GR can be easily fabricated by single step of patterning and etching, simplifying the fabrication processes. PMID- 26480145 TI - Switching in multicore fibers using flexural acoustic waves. AB - We propose an in-line wavelength selective core switch for multicore fiber (MCF) transmission systems, based on the acousto-optic effect. A theoretical model addressing the interaction between flexural acoustic waves and the optical signal in MCFs is developed. We show that an optical signal propagating in a particular core can be switched to any other core or distributed over all the cores. By tuning the acoustic wave amplitude, we can adjust the amount of optical power transferred between the cores. PMID- 26480146 TI - Photonic nanojets in Fresnel zone scattering from non-spherical dielectric particles. AB - We experimentally and numerically study near-field and far-field visible light scattering from lithographically defined micron scale dielectric particles. We demonstrate field confinement and elongated intensity features known as photonic nanojets in the Fresnel zone. An experimental setup is introduced which allows simultaneous mapping of the angular properties of the scattering in the Fresnel zone and far-field regions. Precise control over the shape, size and position of the scatterers, allows direction control of the near-field intensity distribution. Intensity features with 1/3 the divergence of free space Gaussian beams of similar waist are experimentally observed. Additionally the direction and polarization of the incident light can be used to switch on and off intensity hot spots in the near-field. Together these parameters allow a previously un obtainable level of control over the intensity distribution in the near-field, compared to spherically and cylindrically symmetric scattering particles. PMID- 26480147 TI - Carrier-induced fast wavelength switching in tunable V-cavity laser with quantum well intermixed tuning section. AB - We report on the fast wavelength switching in V-cavity laser (VCL) with quantum well intermixed tuning section. The laser wavelength can be switched between 32 channels at 100 GHz spacing using a single electrode control. The fabrication process involves a quantum well intermixing (QWI) process using KrF laser irradiation and rapid thermal annealing (RTA). The tuning current is less than 40 mA, much lower than previously demonstrated tunable VCL based on electro-thermal optic effect. The wavelength switching is also faster by three orders of magnitude. The dynamic switching characteristics between two channels with different numbers of intermediate channels are investigated. It shows that the switching time is about 1 ns between adjacent channels and increases up to 12 ns with increasing number of intermediate channels. PMID- 26480148 TI - Electro-optic directed XOR logic circuits based on parallel-cascaded micro-ring resonators. AB - We report an electro-optic photonic integrated circuit which can perform the exclusive (XOR) logic operation based on two silicon parallel-cascaded microring resonators (MRRs) fabricated on the silicon-on-insulator (SOI) platform. PIN diodes embedded around MRRs are employed to achieve the carrier injection modulation. Two electrical pulse sequences regarded as two operands of operations are applied to PIN diodes to modulate two MRRs through the free carrier dispersion effect. The final operation result of two operands is output at the Output port in the form of light. The scattering matrix method is employed to establish numerical model of the device, and numerical simulator SG-framework is used to simulate the electrical characteristics of the PIN diodes. XOR operation with the speed of 100Mbps is demonstrated successfully. PMID- 26480149 TI - Directional solidification, thermo-mechanical and optical properties of (Mg(x)Ca(1-x))(3)Al(2)Si(3)O(12) glasses doped with Nd(3+) ions. AB - In this work glass rods of (Mg(x)Ca(1-x))(3)Al(2)Si(3)O(12) (x = 0, 0.5 and 1) doped with 1 wt% Nd(2)O(3) were produced by the laser floating zone technique. Thermo-mechanical and spectroscopic properties have been evaluated. The three glass samples present good thermo-mechanical properties, with similar hardness, toughness and glass transition temperatures. The spectroscopic characterization shows spectral shifts in absorption and emission spectra. These spectral shifts together with Judd-Ofelt intensity parameters and ionic packing ratio have been used to investigate the local structure surrounding the Nd(3+) ions and the covalency of the Nd-O bond. All obtained results agree and confirm the higher covalency of the Nd-O bond in the Ca(3)Al(2)Si(3)O(12) glass. PMID- 26480150 TI - Unidirectional hybrid silicon ring laser with an intracavity S-bend. AB - We demonstrate a hybrid silicon ring laser with an internal amplifying S-bend that couples a fraction of the counter-clockwise circulating light into the the clockwise direction. The device supported single-mode, unidirectional laser oscillation at certain bias conditions. A spatial field distribution model is derived to describe the unidirectional operation. A unidirectional clockwise laser output with a suppression ratio up to 18.6 dB over the counter-clockwise mode was achieved. PMID- 26480151 TI - Real-time compensation of the refractive index of air in distance measurement. AB - A two-color scheme of heterodyne laser interferometer is devised for distance measurements with the capability of real-time compensation of the refractive index of the ambient air. A fundamental wavelength of 1555 nm and its second harmonic wavelength of 777.5 nm are generated, with stabilization to the frequency comb of a femtosecond laser, to provide fractional stability of the order of 3.0 * 10(-12) at 1 s averaging. Achieved uncertainty is of the order of 10(-8) in measuring distances of 2.5 m without sensing the refractive index of air in adverse environmental conditions. PMID- 26480152 TI - Three-dimensional fiber probe based on orthogonal micro focal-length collimation for the measurement of micro parts. AB - A 3-dimensional fiber probe based on orthogonal micro focal-length collimation (MFL-collimation) is proposed for the measurement of micro parts with high aspect ratios. The probe consists of a fiber stylus which acts as a micro focal-length cylindrical lens (MFLC-lens) of the two orthogonal MFL-collimation optical paths and a probe tip fixed on the free end of the fiber stylus for touching the workpiece. The fiber stylus will deflect (deflection mode) or buckle (buckling mode) under contacts, and the deflection or buckling of the fiber stylus will cause corresponding shifts of the fringe images of the two orthogonal MFL collimation optical paths. Therefore, the 3-dimensional displacements of the probe tip are transformed into the centroid position shifts of the zero-order fringe images. Experimental results indicate that the fiber probe has a measuring capability in 3-dimensional tactility, and a radial and axial resolution of 5 nm and 3 nm can be obtained respectively. The probe is easily applied in the measurement of micro parts because of its high resolution, low cost, high measurable aspect ratio, low probing forces and capability in three-dimensional tactility. PMID- 26480153 TI - High-resolution extended source optical coherence tomography. AB - High resolution optical coherence tomography (OCT) is capable of providing detailed tissue microstructures that are critical for disease diagnosis, yet its sensitivity is usually degraded since the system key components are typically not working at their respective center wavelengths. We developed a novel imaging system that achieves enhanced sensitivity without axial resolution degradation by the use of a spectrally encoded extended source (SEES) technique; it allows larger sample power without exceeding the maximum permissible exposure (MPE). In this study, we demonstrate a high-resolution extended source (HRES) OCT system, which is capable of providing a transverse resolution of 4.4 um and an axial resolution of 2.1 um in air with the SEES technique. We first theoretically show a sensitivity advantage of 6-dB of the HRES-OCT over that of its point source counterpart using numerical simulations, and then experimentally validate the applicability of the SEES technique to high-resolution OCT (HR-OCT) by comparing the HRES-OCT with an equivalent point-source system. In the HRES-OCT system, a dispersive prism was placed in the infinity space of the sample arm optics to spectrally extend the visual angle (angular subtense) of the light source to 10.3 mrad. This extended source allowed ~4 times larger MPE than its point source counterpart, which results in an enhancement of ~6 dB in sensitivity. Specifically, to solve the unbalanced dispersion between the sample and the reference arm optics, we proposed easy and efficient methods for system calibration and dispersion correction, respectively. With a maximum scanning speed reaching up to 60K A-lines/s, we further conducted imaging experiments with HRES-OCT using the human fingertip in vivo and the swine eye tissues ex vivo. Results demonstrate that the HRES-OCT is able to achieve significantly larger penetration depth than its conventional point source OCT counterpart. PMID- 26480154 TI - Influence of energy pooling and ionization on physical features of a diode-pumped alkali laser. AB - In recent years, a diode-pumped alkali laser (DPAL) has become one of the most hopeful candidates to achieve the high power performance. A series of models have been established to analyze the DPAL's kinetic process and most of them were based on the algorithms in which only the ideal 3-level system was considered. In this paper, we developed a systematic model by taking into account the influence of excitation of neutral alkali atoms to even-higher levels and their ionization on the physical features of a static DPAL. The procedures of heat transfer and laser kinetics were combined together in our theoretical model. By using such a theme, the continuous temperature and number density distribution have been evaluated in the transverse section of a cesium vapor cell. The calculated results indicate that both energy pooling and ionization play important roles during the lasing process. The conclusions might deepen the understanding of the kinetic mechanism of a DPAL. PMID- 26480155 TI - Tunable photonic nanojet formed by generalized Luneburg lens. AB - Nanojet has been emerging as an interesting topic in variety photonics applications. In this paper, inspired by the properties of generalized Luneburg lens (GLLs), a two-dimensional photonic nanojet system has been developed, which focal distance can be tuned by engineering the refractive index profile of GLLs. Simulation and analysis results show that the maximum light intensity, transverse and longitudinal dimensions of the photonic nanojet are dependent on the focal distance of the GLLs, thereby, by simply varying the focal distance, it is possible to obtain localized photon fluxes with different power characteristics and spatial dimensions. This can be of interest for many promising applications, such as high-resolution optical detection, optical manipulation, technology of direct-write nano-patterning and nano-lithography. PMID- 26480156 TI - Spin-selected focusing and imaging based on metasurface lens. AB - Spin of light provides a route to control photons. Spin-based optical devices which can manipulate photons with different spin states are imperative. Here we experimentally demonstrated a spin-selected metasurface lens based on the spin orbit interaction originated from the Pancharatnam-Berry (PB) phase. The optimized PB phase enables the light with different spin states to be focused on two separated points in the preset plane. Furthermore, the metasurface lens can perform the spin-selected imaging according to the polarization of the illuminating light. Such a spin-based device capacitates a lot of advanced applications for spin-controlled photonics in quantum information processing and communication based on the spin and orbit angular momentum. PMID- 26480157 TI - Single-section quantum well mode-locked laser for 400 Gb/s SSB-OFDM transmission. AB - Successful use of a single-section quantum well (QW) passively mode-locked laser (MLL) as a comb source for optical interconnects is demonstrated for the first time. Sixteen comb lines spaced by 37.6 GHz are modulated using 25 Gb/s compatible single sideband orthogonal frequency division multiplexed (SSB-OFDM) signals and transmitted over 50 km of standard single-mode fiber with bit error ratio below the 7% forward error correction limit. The system performance, analyzed on the basis of the relative intensity noise of the device, reveal the suitability of single-section QW MLLs as inexpensive comb sources for inter- and intra-data center communication scenarios. PMID- 26480158 TI - Low crosstalk Bragg grating/Mach-Zehnder interferometer optical add-drop multiplexer in silicon photonics. AB - We characterize the interferometric crosstalk and system performance of two optical add-drop multiplexer (OADM) designs based on Bragg grating/Mach-Zehnder interferometers implemented in silicon-on-insulator. Both OADM designs exhibit low crosstalk and negligible crosstalk-induced power penalties over their 3 dB bandwidths. The devices are tolerant to wavelength drift and misalignment between the transmitter and OADM; moreover, their designs can be optimized further to enable high performance operation in WDM systems. PMID- 26480159 TI - Acousto-optical detection of hidden objects via speckle based imaging. AB - Optical detection of objects hidden behind opaque screening layers is a challenging problem. We demonstrate an optically detected echographic-like method that combines collimated acoustic and laser beams. The acoustic waves cross the screening layers, and their back-reflection from the hidden objects is detected through the analysis of a dynamic laser speckle pattern created at the outer surface of the screening layer. Real-time remote detection of moving targets 15 meters away, with a few mm resolution is demonstrated using a very sensitive camera detection scheme. PMID- 26480160 TI - Einstein-Podolsky-Rosen paradox in single pairs of images. AB - Spatially entangled twin photons provide a test of the Einstein-Podolsky-Rosen (EPR) paradox in its original form of position (image plane) versus impulsion (Fourier plane). We show that recording a single pair of images in each plane is sufficient to safely demonstrate an EPR paradox. On each pair of images, we have retrieved the fluctuations by subtracting the fitted deterministic intensity shape and then have obtained an intercorrelation peak with a sufficient signal to noise ratio to safely distinguish this peak from random fluctuations. A 95% confidence interval has been determined, confirming a high degree of paradox whatever the considered single pairs. Last, we have verified that the value of the variance of the difference between twin images is always below the quantum (poissonian) limit, in order to ensure the particle character of the demonstration. Our demonstration shows that a single image pattern can reveal the quantum and non-local behavior of light. PMID- 26480161 TI - 28 Gb/s direct modulation heterogeneously integrated C-band InP/SOI DFB laser. AB - We demonstrate direct modulation of a heterogeneously integrated C-band DFB laser on SOI at 28 Gb/s with a 2 dB extinction ratio. This is the highest direct modulation bitrate so far reported for a membrane laser coupled to an SOI waveguide. The laser operates single mode with 6 mW output power at 100 mA bias current. The 3 dB modulation bandwidth is 15 GHz. Transmission experiments using a 2 km non zero dispersion shifted single mode fiber were performed at 28 Gb/s bitrate using a 2(7)-1 NRZ-PRBS pattern resulting in a 1 dB power penalty. PMID- 26480162 TI - Optical characterisation of plasmonic nanostructures on planar substrates using second-harmonic generation. AB - Off-normal, polarization dependent second-harmonic generation (SHG) measurements were performed ex situ on plasmonic nanostructures grown by self-assembly on nanopatterned templates. These exploratory studies of Ag nanoparticle (NP) arrays show that the sensitivity of SHG to the local fields, which are modified by the NP size, shape and distribution, makes it a promising fixed wavelength characterization technique that avoids the complexity of spectroscopic SHG. The off-normal geometry provides access to the out-of-plane SH response, which is typically an order-of-magnitude larger than the in-surface-plane response measured using normal incidence, for example in SHG microscopy. By choosing the plane of incidence orthogonal to the NP array direction, it was shown that the p polarized SH response, as a function of input polarization, is very sensitive to NP morphology, with a change of 20% in the aspect ratio of the NPs producing a variation of a factor of 30 in the easily measureable ratio of the p-polarized SH field strength for s- and p-polarized input. The results show that such a fixed geometry could be used for the in situ characterization of anisotropic nanostructure morphology during growth by self-assembly, which could be particularly useful in situations where rotating the sample may be neither desirable nor easily accomplished. PMID- 26480163 TI - Kilowatt-level near-diffraction-limited and linear-polarized Ytterbium-Raman hybrid nonlinear amplifier based on polarization selection loss mechanism. AB - Ytterbium-Raman cascaded oscillators with linearly polarized output are designed and achieved based on polarization selection loss (PSL) mechanism for the first time. The 1120 nm laser cavity is designed with fully non polarization-maintained (NPM) fiber Bragg gratings (FBGs) and NPM active fiber while the 1080 nm laser cavity is designed based on polarization-maintained (PM) FBGs and PM active fiber. By using PSL mechanism in 1080 nm cavity, even with fully NPM 1120 nm cavity, both linear-polarized 1120 nm and 1080 nm lasers are achieved in the output port of the cascaded oscillators. Based on the new designed cascaded seeds, a high power polarization-maintained Yb-Raman hybrid nonlinear amplifier is established for further power scaling of the 1120 nm laser. In the nonlinear amplifier, only 21-meter-long active fiber and 1.5-meter-long passive fiber is used for power transferring from 1080 nm to 1120 nm. Output power of 1181 W is achieved at central wavelength of 1120 nm with the M(2) factor of <1.2 and polarization-extinction ratio (PER) of 18.2 dB. As far as we known, the output power of this all fiber format is the highest one in 1120 nm with linear polarization. This type of high power Yb-Raman nonlinear amplifier design with linear polarization can be further extended to Yb-Raman amplifying the wavelength range of 1100-1200 nm. PMID- 26480164 TI - De-noising and retrieving algorithm of Mie lidar data based on the particle filter and the Fernald method. AB - The signal-to-noise ratio (SNR) of an atmospheric lidar decreases rapidly as range increases, so that maintaining high accuracy when retrieving lidar data at the far end is difficult. To avoid this problem, many de-noising algorithms have been developed; in particular, an effective de-noising algorithm has been proposed to simultaneously retrieve lidar data and obtain a de-noised signal by combining the ensemble Kalman filter (EnKF) and the Fernald method. This algorithm enhances the retrieval accuracy and effective measure range of a lidar based on the Fernald method, but sometimes leads to a shift (bias) in the near range as a result of the over-smoothing caused by the EnKF. This study proposes a new scheme that avoids this phenomenon using a particle filter (PF) instead of the EnKF in the de-noising algorithm. Synthetic experiments show that the PF performs better than the EnKF and Fernald methods. The root mean square error of PF are 52.55% and 38.14% of that of the Fernald and EnKF methods, and PF increases the SNR by 44.36% and 11.57% of that of the Fernald and EnKF methods, respectively. For experiments with real signals, the relative bias of the EnKF is 5.72%, which is reduced to 2.15% by the PF in the near range. Furthermore, the suppression impact on the random noise in the far range is also made significant via the PF. An extensive application of the PF method can be useful in determining the local and global properties of aerosols. PMID- 26480165 TI - Spectral estimation optical coherence tomography for axial super-resolution. AB - The depth reflectivity profile of Fourier domain optical coherence tomography (FD OCT) is estimated from the inverse Fourier transform of the spectral interference signals (interferograms). As a result, the axial resolution is fundamentally limited by the coherence length of the light source. We demonstrate that using the autoregressive spectral estimation technique instead of the inverse Fourier transform, to analyze the spectral interferograms can improve the axial resolution. We name this method spectral estimation OCT (SE-OCT). SE-OCT breaks the coherence length limitation and improves the axial resolution by a factor of up to 4.7 compared with FD-OCT. Furthermore, SE-OCT provides complete sidelobe suppression in the depth point-spread function, further improving the image quality. We demonstrate that these technical advances enables clear identification of corneal endothelium anatomical details ex vivo that cannot be identified using the corresponding FD-OCT. Given that SE-OCT can be implemented in the FD-OCT devices without any hardware changes, the new capabilities provided by SE-OCT are likely to offer immediate improvements to the diagnosis and management of diseases based on OCT imaging. PMID- 26480166 TI - Oxide mediated spectral shifting in aluminum resonant optical antennas. AB - As a key feature among metals showing good plasmonic behavior, aluminum extends the spectrum of achievable plasmon resonances of optical antennas into the deep ultraviolet. Due to degradation, a native oxide layer gives rise to a metal core/oxide-shell nanoparticle and influences the spectral resonance peak position. In this work, we examine the role of the underlying processes by applying numerical nanoantenna models that are experimentally not feasible. Finite-difference time-domain simulations are carried out for a large variety of elongated single-arm and two-arm gap nanoantennas. In a detailed analysis, which takes into account the varying surface-to-volume ratio, we show that the overall spectral shift toward longer wavelengths is mainly driven by the higher index surrounding material rather than by the decrease of the initial aluminum volume. In addition, we demonstrate experimentally that this shifting can be minimized by an all-inert fabrication and subsequent proof-of-concept encapsulation. PMID- 26480167 TI - Enhanced second-harmonic generation from magnetic resonance in AlGaAs nanoantennas. AB - We designed AlGaAs-on-aluminium-oxide all-dielectric nanoantennas with magnetic dipole resonance at near-infrared wavelengths. These devices, shaped as cylinders of 400nm height and different radii, offer a few crucial advantages with respect to the silicon-on-insulator platform for operation around 1.55MUm wavelength: absence of two-photon absorption, high chi((2)) nonlinearity, and the perspective of a monolithic integration with a laser. We analyzed volume chi((2)) nonlinear effects associated to a magnetic dipole resonance in these nanoantennas, and we predict second-harmonic generation exceeding 10(-3) efficiency with 1GW/cm(2) of pump intensity. PMID- 26480168 TI - Optical bidirectional beacon based visible light communications. AB - In an indoor bidirectional visible light communications (VLC), a line-of-sight (LOS) transmission plays a major role in obtaining adequate performance of a VLC system. Signals are often obstructed in the LOS transmission path, causing an effect called optical shadowing. In the absence of LOS, the performance of the VLC system degrades significantly and, in particular, at uplink transmission this degradation becomes severe due to design constraints and limited power at uplink devices. In this paper, a novel concept and design of an optical bidirectional beacon (OBB) is presented as an efficient model to counter the performance degradation in a non-line-of-sight (NLOS) VLC system. OBB is an independent operating bidirectional transceiver unit installed on walls, composed of red, green, and blue (RGB) light emitting diodes (LEDs), photodetectors (PDs) and color filters. OBB improves the coverage area in the form of providing additional or alternate paths for transmission and enhances the performance of the VLC system in terms of bit error rate (BER). To verify the effectiveness of the proposed system, simulations were carried out under optical shadowing conditions at various locations in an indoor environment. The simulation results and analysis show that the implementation of OBB improves the performance of the VLC system significantly, especially when the LOS bidirectional transmission paths are completely or partially obstructed. PMID- 26480169 TI - Evidence of near-infrared partial photonic bandgap in polymeric rod-connected diamond structures. AB - We present the simulation, fabrication, and optical characterization of low-index polymeric rod-connected diamond (RCD) structures. Such complex three-dimensional photonic crystal structures are created via direct laser writing by two-photon polymerization. To our knowledge, this is the first measurement at near-infrared wavelengths, showing partial photonic bandgaps for this structure. We characterize structures in transmission and reflection using angular resolved Fourier image spectroscopy to visualize the band structure. Comparison of the numerical simulations of such structures with the experimentally measured data show good agreement for both P- and S-polarizations. PMID- 26480170 TI - Talbot interferometry with curved quasi-periodic gratings: towards large field of view X-ray phase-contrast imaging. AB - X-ray phase-contrast imaging based on grating interferometry has become a common method due to its superior contrast in biological soft tissue imaging. The high sensitivity relies on the high-aspect ratio structures of the planar gratings, which prohibit the large field of view applications with a diverging X-ray source. Curved gratings allow a high X-ray flux for a wider angular range, but the interference fringes are only visible within ~10 degrees range due to the geometrical mismatch with the commonly used flat array detectors. In this paper, we propose a design using a curved quasi-periodic grating for large field of view imaging with a flat detector array. Our scheme is numerically verified in the X ray regime and experimentally verified in the visible optical regime. The interference fringe pattern is observed over 25 degrees , with less than 10% of decrease in visibility in our experiments. PMID- 26480171 TI - Generalized Poincare sphere. AB - We present a generalized Poincare sphere (G sphere) and generalized Stokes parameters (G parameters), as a geometric representation, which unifies the descriptors of a variety of vector fields. Unlike the standard Poincare sphere, the radial dimension in the G sphere is not used to describe the partially polarized field. The G sphere is constructed by extending the basic Jones vector bases to the general vector bases with the continuously changeable ellipticity (spin angular momentum, SAM) and the higher dimensional orbital angular momentum (OAM). The north and south poles of different spherical shells in the G sphere represent the pair of different orthogonal vector basis with different ellipticity (SAM) and the opposite OAM. The higher-order Poincare spheres are just the two special spherical shells of the G sphere. We present a quite flexible scheme, which can generate all the vector fields described in the G sphere. PMID- 26480172 TI - Midinfrared frequency comb from self-stable degenerate GaAs optical parametric oscillator. AB - We pump a degenerate frequency-divide-by-two optical parametric oscillator (OPO) based on orientation-patterned GaAs with a stable Tm frequency comb at 2 micrometer wavelength and measure the OPO comb offset frequency and linewidth. We show frequency division by two with sub-Hz relative linewidth of the comb teeth. The OPO thermally self-stabilizes and oscillates for nearly an hour without any active control. PMID- 26480173 TI - Optimal pulse penetration in Lorentz-Model dielectrics using the Sommerfeld and Brillouin precursors. AB - Under proper initial conditions, the interrelated effects of phase and attenuation dispersion in ultrawideband pulse propagation modify the input pulse into precursor fields. Because of their minimal decay in a given dispersive medium, precursor-type pulses possess optimal penetration into that material at the frequency-chirped Lambert-Beer's law limit, making them ideally suited for remote sensing and medical imaging. PMID- 26480174 TI - Femtosecond laser direct writing of large-area two-dimensional metallic photonic crystal structures on tungsten surfaces. AB - Metallic photonic crystals (MPCs) and metamaterials operating in the visible spectrum are required for high-temperature nanophotonics, but they are often difficult to construct. This study demonstrates a new approach to directly write two-dimensional (2D) MPCs on tungsten surfaces through the cylindrical focusing of two collinear femtosecond laser beams with certain temporal delays and orthogonal linear polarizations. Results are physically attributed to the laser induced transient crossed temperature grating patterns and tempo-spatial thermal correlations. Optical properties of the fabricated MPCs are characterized. Such a simple and efficient technique can be used to fabricate large-area, 2D microstructures on metal surfaces for potential applications. PMID- 26480175 TI - Power limits and a figure of merit for stimulated Brillouin scattering in the presence of third and fifth order loss. AB - We derive a set of design guidelines and a figure of merit to aid the engineering process of on-chip waveguides for strong Stimulated Brillouin Scattering (SBS). To this end, we examine the impact of several types of loss on the total amplification of the Stokes wave that can be achieved via SBS. We account for linear loss and nonlinear loss of third order (two-photon absorption, 2PA) and fifth order, most notably 2PA-induced free carrier absorption (FCA). From this, we derive an upper bound for the output power of continuous-wave Brillouin-lasers and show that the optimal operating conditions and maximal realisable Stokes amplification of any given waveguide structure are determined by a dimensionless parameter F involving the SBS-gain and all loss parameters. We provide simple expressions for optimal pump power, waveguide length and realisable amplification and demonstrate their utility in two example systems. Notably, we find that 2PA induced FCA is a serious limitation to SBS in silicon and germanium for wavelengths shorter than 2200nm and 3600nm, respectively. In contrast, three photon absorption is of no practical significance. PMID- 26480176 TI - Laser ablation- and plasma etching-based patterning of graphene on silicon-on insulator waveguides. AB - We present a new approach to remove monolayer graphene transferred on top of a silicon-on-insulator (SOI) photonic integrated chip. Femtosecond laser ablation is used for the first time to remove graphene from SOI waveguides, whereas oxygen plasma etching through a metal mask is employed to peel off graphene from the grating couplers attached to the waveguides. We show by means of Raman spectroscopy and atomic force microscopy that the removal of graphene is successful with minimal damage to the underlying SOI waveguides. Finally, we employ both removal techniques to measure the contribution of graphene to the loss of grating-coupled graphene-covered SOI waveguides using the cut-back method. PMID- 26480177 TI - Investigations on ring-shaped pumping distributions for the generation of beams with radial polarization in an Yb:YAG thin-disk laser. AB - We present experimental investigations on the generation of radially polarized laser beams excited by a ring-shaped pump intensity distribution in combination with polarizing grating waveguide mirrors in an Yb:YAG thin-disk laser resonator. Hollow optical fiber components were implemented in the pump beam path to transform the commonly used flattop pumping distribution into a ring-shaped distribution. The investigation was focused on finding the optimum mode overlap between the ring-shaped pump spot and the excited first order Laguerre-Gaussian (LG(01)) doughnut mode. The power, efficiency and polarization state of the emitted laser beam as well as the thermal behavior of the disk was compared to that obtained with a standard flattop pumping distribution. A maximum output power of 107 W with a high optical efficiency of 41.2% was achieved by implementing a 300 mm long specially manufactured hollow fiber into the pump beam path. Additionally it was found that at a pump power of 280 W the maximum temperature increase is about 21% below the one observed with standard homogeneous pumping. PMID- 26480178 TI - Electro- and photosensitive azopolymer for alignment of liquid crystals. AB - We report an electro- and photosensitive metal containing polymer material for alignment of liquid crystals (LCs). Irradiation with polarized light and/or application of dc-field result in an anisotropy of the polymer and formation of an easy orientation axes of a LC on the polymer surface. The light-induced anisotropy of the polymer and the LC anchoring on the polymer surface can be controlled by the low dc-field at room temperature. PMID- 26480179 TI - Modeling third harmonic generation from layered materials using nonlinear optical matrices: erratum. AB - We present corrected versions of Equations (11), (13), and (14) where typos were made. PMID- 26480180 TI - Quantitative phase retrieval with arbitrary pupil and illumination. AB - We present a general algorithm for combining measurements taken under various illumination and imaging conditions to quantitatively extract the amplitude and phase of an object wave. The algorithm uses the weak object transfer function, which incorporates arbitrary pupil functions and partially coherent illumination. The approach is extended beyond the weak object regime using an iterative algorithm. We demonstrate the method on measurements of Extreme Ultraviolet Lithography (EUV) multilayer mask defects taken in an EUV zone plate microscope with both a standard zone plate lens and a zone plate implementing Zernike phase contrast. PMID- 26480181 TI - Ultrafast laser inscription of volume phase gratings with low refractive index modulation and self-images of high visibility. AB - Ultrafast laser inscription of volume phase gratings with low index contrast and self-images with visibility of 0.96 is demonstrated. It is also demonstrated that phase differences of pi/2 for visible light are achievable with only one layer of structures induced in bulk borosilicate glass by direct laser writing. The fabrication method avoids the stitching of several layers of structures and significantly reduces the time of process. The increment of visibility with the induced phase difference is proved and results are compared with the expected for planar phase gratings. PMID- 26480182 TI - Terahertz balanced self-heterodyne spectrometer with SNR-limited phase measurement sensitivity. AB - Photonics-based frequency-domain terahertz (THz) wave measurement systems have received significant attention in both scientific and industrial fields due to their high-frequency resolution. Highly sensitive phase-measurement systems have been desired in the chemical, material, and biomedical sciences to facilitate microanalysis of materials. Here, we demonstrate a balanced self-heterodyne technique that, for the first time, simultaneously offers wide frequency tunability of more than 2.5 THz and high phase sensitivity, which is limited only by the signal-to-noise ratio (SNR) of the amplitude measurement. Using free running lasers for THz wave generation and detection, the experimentally achieved minimum detectable optical path length change was 400+/-50 nm at 2 THz for a SNR of 37.7 +/- 0.7 dB, even though the theoretically expected SNR-limited value was 310 +/- 20 nm. The phase measurement sensitivity of our system is almost one order of magnitude better than that of the conventional systems in which limitations arise from phase instabilities in the optical components and/or laser linewidth. PMID- 26480183 TI - Scalable micromesh-digital spatial light modulators. AB - Digital spatial light modulators (SLMs) with small pitch comparable to the wavelength of illuminating light and large physical dimension comparable to consumer displays are highly demanding for realizing realistic digital holography but are impractical due to various technical issues. Previously we proposed the way to overcome these hurdles by scalable SLM-micromesh (MUM) heterostructures utilizing large scale consumer displays and passive binary amplitude MUMs (AMs). However, a few drawbacks with these heterostructures are identified such as their low power efficiency due to the blocking of light beam diffracted from the SLM by the opaque part of the AM and the brightest zeroth order diffraction beam causing the lower power efficiency at higher diffraction orders. Thus in this paper, we employed scalable binary phase micromeshes (PMs) instead of AMs in the scalable heterostructures. This is able to minimize the power loss and to diminish the zeroth order diffraction beam simultaneously without requiring any time consuming steps. As a result, this allows full utilization of large scale consumer displays for scalable digital holography by employing scalable SLM-MUM heterostructures with negligible power loss. PMID- 26480184 TI - Real-mode depth-fused display with viewer tracking. AB - A real-mode depth-fused display is proposed by employing an integral imaging method in the depth-fused display system with viewer tracking. By giving depth fusing effect between a transparent display and a floated planar two-dimensional image generated by the real-mode integral imaging method, a three-dimensional image is generated in front of the display plane unlike conventional depth-fused displays. The viewing angle of the system is expanded with a viewer tracking method. In addition, dynamic vertical and horizontal motion parallax can be given according to the tracked position of the viewer. As the depth-fusing effect is not dependent on the viewing distance, accommodation cue and motion parallax are provided for a wide range of viewing position. We demonstrate the feasibility of our proposed method by experimental system. PMID- 26480185 TI - Q-switched fiber laser based on transition metal dichalcogenides MoS(2), MoSe(2), WS(2), and WSe(2). AB - In this paper, we report 4 different saturable absorbers based on 4 transition metal dichalcogenides (MoS(2), MoSe(2), WS(2), WSe(2)) and utilize them to Q switch a ring-cavity fiber laser with identical cavity configuration. It is found that MoSe(2) exhibits highest modulation depth with similar preparation process among four saturable absorbers. Q-switching operation performance is compared from the aspects of RF spectrum, optical spectrum, repetition rate and pulse duration. WS(2) Q-switched fiber laser generates the most stable pulse trains compared to other 3 fiber lasers. These results demonstrate the feasibility of TMDs to Q-switch fiber laser effectively and provide a meaningful reference for further research in nonlinear fiber optics with these TMDs materials. PMID- 26480186 TI - Impact of Kerr nonlinearity on the whispering gallery modes of a microsphere. AB - To describe the temporal evolution of the mode amplitude of a spherical microcavity, a nonlinear equation is developed by considering loss and Kerr nonlinear effect as perturbations. In order to study the impact of Kerr nonlinearity, the tensor components of chi((3)) in spherical coordinates are calculated. To describe the impact of Kerr nonlinearity, effective mode volume and effective nonlinear coefficient are defined. We found that the resonant modes undergo a negative frequency shift proportional to the injected energy, consistant with the reported experimental observations. PMID- 26480187 TI - Efficient speckle-suppressed white light source by micro-vibrated and color mixing techniques for lighting applications. AB - In this paper, we have demonstrated an efficient speckle-suppressed white light source generation when a blue laser diode illuminates on a micro-vibrated phosphor paper. Both micro-vibrated and color-mixing techniques are used in this system. With only micro-vibrated technique, the speckle contrast can be reduced from about 50% to 7.4% for the scattering blue image for a 16-ms integration time. Together with color-mixing technique, mixing speckle contrast is defined for laser diode pumped phosphor and almost speckle-free result is achieved. For color temperature lower than 5000 K, almost speckle-free mixed white can be obtained even without vibration technique. PMID- 26480188 TI - Blind modulation format identification for digital coherent receivers. AB - In this paper, a simple novel digital modulation format identification (MFI) scheme for coherent optical systems is proposed. The scheme is based on the evaluation of the peak-to-average-power ratio (PAPR) of the incoming data samples after analog-to-digital conversion (ADC), chromatic dispersion (CD) and polarization mode demultiplexing (PMD) compensation at the receiver (Rx). Since at a particular optical-signal-to-noise ratio (OSNR) value different modulation formats have distinct PAPR values, it is possible to identify them. The proposed scheme and the results are analyzed both experimentally and through numerical simulations. The results demonstrate successful identification among four modulation formats (MF) commonly used in digital coherent systems. PMID- 26480189 TI - An ultra-compact multiplexed holographic microscope using a multiple-pinhole aperture. AB - In this paper, we present a low-cost and ultra-compact holographic microscope with multiple imaging areas. Instead of a dual-pinhole aperture as presented in our previous work, a multi-pinhole aperture is employed to filter the light source and to generate a reference wave as well as multiple object waves. The reference wave and the object waves interfere at the digital sensor and form multiplexed off-axis holograms without any lenses, splitters or combiners. The optimal number of object waves is determined which does not only fit our system but also brings some inspiration for traditional multiplexed off-axis holography. Our new system is tested to be able to retrieve quantitative phase images along with the amplitude images of multiple imaging areas at the same time with a lateral resolution of ~ 2.2um and an accuracy of the optical path of tens of nanometers. PMID- 26480190 TI - Comparative analysis of opto-electronic performance of aluminium and silver nano porous and nano-wired layers. AB - The comparison of optical and electronic properties between squarely and hexagonally arranged nano-porous layers and uniformly arranged nano-wired layers of aluminium and silver was presented. The nano-wired configuration exhibit 20 and 10% higher average transmittance in visible wavelength range in comparison to square and hexagonal nano-porous designs, respectively. The insignificant difference of the transmittance for aluminium and silver nano-porous and nano wired layers is observed, when interpore/interwire distance is larger than wavelengths of incoming light. This difference becomes considerable at the interpore/interwire distance less than wavelengths of incoming light: silver nano porous and nano-wired layers possess up to 27% higher transmittance in comparison to aluminium layers. PMID- 26480191 TI - Excitable laser processing network node in hybrid silicon: analysis and simulation. AB - The combination of ultrafast laser dynamics and dense on-chip multiwavelength networking could potentially address new domains of real-time signal processing that require both speed and complexity. We present a physically realistic optoelectronic simulation model of a circuit for dynamical laser neural networks and verify its behavior. We describe the physics, dynamics, and parasitics of one network node, which includes a bank of filters, a photodetector, and excitable laser. This unconventional circuit exhibits both cascadability and fan-in, critical properties for the large-scale networking of information processors based on laser excitability. In addition, it can be instantiated on a photonic integrated circuit platform and requires no off-chip optical I/O. Our proposed processing system could find use in emerging applications, including cognitive radio and low-latency control. PMID- 26480192 TI - Mid-infrared optical frequency combs based on difference frequency generation for molecular spectroscopy. AB - Mid-infrared femtosecond optical frequency combs were produced by difference frequency generation of the spectral components of a near-infrared comb in a 3-mm long MgO:PPLN crystal. We observe strong pump depletion and 9.3 dB parametric gain in the 1.5 MUm signal, which yields powers above 500 mW (3 MUW/mode) in the idler with spectra covering 2.8 MUm to 3.5 MUm. Potential for broadband, high resolution molecular spectroscopy is demonstrated by absorption spectra and interferograms obtained by heterodyning two combs. PMID- 26480193 TI - Double-field-of-view, quasi-common-path interferometer using Fourier domain multiplexing. AB - We present a quasi-common-path interferometer with a double field of view (FOV). The laser beam of an imaging system is separated into three parts using three mirrors; the first and second beams are used to image two different areas of a sample, while the third beam functions as a reference beam. The reference beam is prepared by making clear area in a sample and projecting it on an image sensor. A double FOV is obtained by Fourier domain multiplexing, whereby two interferometric images corresponding to two different areas of a sample are modulated with two different spatial carrier frequencies. The feasibility of this technique is experimentally demonstrated by imaging two different areas of a test target with a single image sensor. PMID- 26480194 TI - 2 MUm wavelength range InP-based type-II quantum well photodiodes heterogeneously integrated on silicon photonic integrated circuits. AB - The heterogeneous integration of InP-based type-II quantum well photodiodes on silicon photonic integrated circuits for the 2 um wavelength range is presented. A responsivity of 1.2 A/W at a wavelength of 2.32 um and 0.6 A/W at 2.4 um wavelength is demonstrated. The photodiodes have a dark current of 12 nA at -0.5 V at room temperature. The absorbing active region of the integrated photodiodes consists of six periods of a "W"-shaped quantum well, also allowing for laser integration on the same platform. PMID- 26480195 TI - Iterative signal separation based multiple phase estimation in digital holographic interferometry. AB - We propose a new method for signal separation from a multicomponent interference field recorded in a digital holographic interferometry setup. The setup consisting of multiple object illuminating beams results in an interference field containing multiple signal components. The proposed method utilizes an amplitude discrimination criteria established by setting different intensities to the object illuminating beams in order to separate the signal components iteratively. The signal separation is performed in a small block of the interference field at a time. The augmentation of the block matrix with its own rows and columns is performed which has an effect of noise subspace inflation. This operation offers an improved noise robustness to the signal separation capability of the proposed method. The simulation and experimental results are provided to substantiate the applicability of the proposed method in multidimensional deformation measurement. PMID- 26480196 TI - Efficient matrix approach to optical wave propagation and Linear Canonical Transforms. AB - The Fresnel diffraction integral form of optical wave propagation and the more general Linear Canonical Transforms (LCT) are cast into a matrix transformation form. Taking advantage of recent efficient matrix multiply algorithms, this approach promises an efficient computational and analytical tool that is competitive with FFT based methods but offers better behavior in terms of aliasing, transparent boundary condition, and flexibility in number of sampling points and computational window sizes of the input and output planes being independent. This flexibility makes the method significantly faster than FFT based propagators when only a single point, as in Strehl metrics, or a limited number of points, as in power-in-the-bucket metrics, are needed in the output observation plane. PMID- 26480197 TI - Ultra-wide-range measurements of thin-film filter optical density over the visible and near-infrared spectrum. AB - We present the improved structure and operating principle of a spectrophotometric mean that allows us for the recording of the transmittance of a thin-film filter over an ultra-wide range of optical densities (from 0 to 11) between 400 and 1000 nm. The operation of this apparatus is based on the combined use of a high power supercontinuum laser source, a tunable volume hologram filter, a standard monochromator and a scientific grade CCD camera. The experimentally recorded noise floor is in good accordance with the optical density values given by the theoretical approach. A demonstration of the sensitivity gain provided by this new set-up with respect to standard spectrophotometric means is performed via the characterization of various types of filters (band-pass, long-pass, short-pass, and notch). PMID- 26480198 TI - Attometer resolution spectral analysis based on polarization pulling assisted Brillouin scattering merged with heterodyne detection. AB - Spectral analysis is essential for measuring and monitoring advanced optical communication systems and the characterization of active and passive devices like amplifiers, filters and especially frequency combs. Conventional devices have a limited resolution or tuning range. Therefore, the true spectral shape of the signal remains hidden. In this work, a small part of the signal under test is preselected with help of the polarization pulling effect of stimulated Brillouin scattering where all unwanted spectral components are suppressed. Subsequently, this part is analyzed more deeply through heterodyne detection. Thereby, the local oscillator is generated from a narrow linewidth fiber laser which acts also as pump wave for Brillouin scattering. By scanning the pump wave together with the local oscillator through the signal spectrum, the whole signal is measured. The method is tunable over a broad wavelength range, is not affected by unwanted mixing products and utilizes a conventional narrow bandwidth photo diode. First proof of concept experiments show the measurement of the power spectral density function with a resolution in the attometer or lower kilohertz range at 1550 nm. PMID- 26480199 TI - Moderators of the effects of indicated group and bibliotherapy cognitive behavioral depression prevention programs on adolescents' depressive symptoms and depressive disorder onset. AB - We investigated factors hypothesized to moderate the effects of cognitive behavioral group-based (CB group) and bibliotherapy depression prevention programs. Using data from two trials (N = 631) wherein adolescents (M age = 15.5, 62% female, 61% Caucasian) with depressive symptoms were randomized into CB group, CB bibliotherapy, or an educational brochure control condition, we evaluated the moderating effects of individual, demographic, and environmental factors on depressive symptom reductions and major depressive disorder (MDD) onset over 2-year follow-up. CB group and bibliotherapy participants had lower depressive symptoms than controls at posttest but these effects did not persist. No MDD prevention effects were present in the merged data. Relative to controls, elevated depressive symptoms and motivation to reduce depression amplified posttest depressive symptom reduction for CB group, and elevated baseline symptoms amplified posttest symptom reduction effects of CB bibliotherapy. Conversely, elevated substance use mitigated the effectiveness of CB group relative to controls on MDD onset over follow-up. Findings suggest that both CB prevention programs are more beneficial for youth with at least moderate depressive symptoms, and that CB group is more effective for youth motivated to reduce their symptoms. Results also imply that substance use reduces the effectiveness of CB group-based depression prevention. PMID- 26480200 TI - Electrolytically generated acid functional water inhibits NF-kappaB activity by attenuating nuclear-cytoplasmic shuttling of p65 and p50 subunits. AB - BACKGROUND: Human beta-defensin 2 (hBD2) gene expression is dependent on nuclear factor kappa B (NF-kappaB) activity. We have previously demonstrated that electrolytically generated acid functional water (FW) induces the expression of hBD2 in the human oral squamous cell carcinoma (OSCC) cell line Ca9-22. However, the induction was not dependent on NF-kappaB activity; in fact, FW inhibited NF kappaB activity. Therefore, we hypothesized that FW might reduce spontaneous interleukin 8 (IL-8) secretion by Ca9-22 cells, which is heavily dependent on NF kappaB activity. This study aimed at demonstrating the inhibitory effect of FW on NF-kappaB activity. METHODS: Ca9-22 cells were incubated with FW, and spontaneous IL-8 secretion was observed by enzyme-linked immunosorbent assay. Luciferase assay was performed using the 5'-untranslated region of the IL-8 gene. The steps of NF-kappaB activation blocked by FW were evaluated by localization of the NF kappaB subunits p65 and p50 by immunofluorescence staining. Western blotting was further performed to confirm the changes in NF-kappaB subunit localization. RESULTS: The Ca9-22 cells spontaneously secreted IL-8, which was rapidly and drastically inhibited by FW treatment. The luciferase assay demonstrated the inhibitory action of FW, which was diminished by deletion of the NF-kappaB binding site from this construct. FW treatment altered the distribution of both the p65 and p50 subunits. P65, which was localized in the nucleus during the resting state, moved to the cytoplasm after FW treatment, whereas, p50, localized in the cytoplasm during the resting state, moved to the nucleus subsequent to FW treatment. CONCLUSIONS: The results from this study indicate that FW might inhibit spontaneous IL-8 secretion by redistribution of the NF-kappaB subunits within the cells. PMID- 26480201 TI - Glial-endothelial crosstalk regulates blood-brain barrier function. AB - The blood-brain barrier (BBB) is comprised of unique endothelial cells (ECs) that regulate the delicate central nervous system (CNS) microenvironment. During development, vasculature sprouts from the perivascular neural plexus and penetrates the CNS parenchyma. Recent studies indicate that these nascent vessels rely on radial glia (RG)-secreted factors for guidance and barrier induction. This early association also sustains astrocyte development, allowing for a tight interaction between these mature glia and ECs. The astrocyte-EC interface is crucial to BBB function and is substantially modified during pathology. Understanding the relationship between astrocytes and ECs lays the groundwork for advancing protective therapies that target neuroinflammatory disorders. PMID- 26480202 TI - Perturbation of the transcriptome: implications of the innate immune system in Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disease with broad impact. Although Abeta and tau have been proposed as the key molecules in the disease mechanism, comprehensive understanding of AD pathogenesis requires a systemic view at the genomic level. From studies on the brain transcriptome of AD, we have gradually realized the contribution of the immune system to AD development. Recent explorations on the blood transcriptome of AD patients have revealed robust immune activation in the peripheral blood. The combination of transcriptome studies and other types of studies has further elucidated the roles of specific immune pathways in distinct cell types during AD development and highlighted the critical contributions from immune genes such as TREM2. PMID- 26480203 TI - Topochemical Oxidation of Perovskite KCoF3 to a K2PtCl6 Structure-Type Oxyfluoride. AB - Oxyfluoride, K2CoOF4 with K2PtCl6 structure, has been stabilized from a perovskite-based KCoF3 complex by a simple oxidative anion insertion topochemical reaction. Similar structural transformations have been observed for Ni- and Mn containing systems. The generation of such unusual compounds, by soft chemical methods, strengthens the efforts toward materials discovery. PMID- 26480204 TI - Hoofbeats From the Currituck Outer Banks: A Study of the Corolla Wild Horse Fund Adoption Program. AB - Research on the adoption and relinquishment of horses, both domestic and wild, remains limited. As a result, little is known about adopters, their adopted horses, and their adoption experience. This study surveyed and interviewed 17 adopters of Colonial Spanish mustangs through the Corolla Wild Horse Fund (CWHF). Together, they adopted 22 horses of varying ages and genders from 2002 to 2012. The participants, who had a range of previous experience with and knowledge of horses, were generally very satisfied with their horses and their adoption experience. Being able to adopt a gentled/trained mustang and receiving support from the CWHF during the adoption process played key roles in adoption success. Additionally, participants' strong desire to preserve a perceived endangered species or national treasure appeared to be a major reason for adopting a Colonial Spanish mustang and served as motivation for making the adoption successful. The results of the study provide insights into ways to improve the number and success of adoptions through other equine programs, especially the Bureau of Land Management's wild horse and burro program. PMID- 26480205 TI - Telephone-administered psychotherapy in combination with antidepressant medication for the acute treatment of major depressive disorder. AB - BACKGROUND: Telephone-administered psychotherapies (T-P) provided as an adjunct to antidepressant medication may improve response rates in major depressive disorder (MDD). The goal of this study was to compare telephone-administered social rhythm therapy (T-SRT) and telephone-administered intensive clinical management (T-ICM) as adjuncts to antidepressant medication for MDD. A secondary goal was to compare T-P with Treatment as Usual (TAU) as adjunctive treatment to medication for MDD. METHODS: 221 adult out-patients with MDD, currently depressed, were randomly assigned to 8 sessions of weekly T-SRT (n=110) or T-ICM (n=111), administered as an adjunct to agomelatine. Both psychotherapies were administered entirely by telephone, by trained psychologists who were blind to other aspects of treatment. The 221 patients were a posteriori matched with 221 depressed outpatients receiving TAU (controls). The primary outcome measure was the percentage of responders at 8 weeks post-treatment. RESULTS: No significant differences were found between T-SRT and T-ICM. But T-P was associated with higher response rates (65.4% vs 54.8%, p=0.02) and a trend toward higher remission rates (33.2% vs 25.1%; p=0.06) compared to TAU. LIMITATIONS: Short term study. CONCLUSIONS: This study is the first assessing the short-term effects of an add-on, brief, telephone-administered psychotherapy in depressed patients treated with antidepressant medication. Eight sessions of weekly telephone delivered psychotherapy as an adjunct to antidepressant medication resulted in improved response rates relative to medication alone. PMID- 26480206 TI - Longitudinal relationship between Personal and Social Performance (PSP) and anxiety symptoms in schizophrenia. AB - BACKGROUND: We aimed to examine the longitudinal relationship between the personal and social functioning and anxiety symptoms in patients with schizophrenia. For this purpose, we confirmed the validity of the anxiety subscale of the Symptom-Checklist-90-Revised (SCL-90-R) and then applied the latent growth modeling method for longitudinal causal relationships. METHODS: Five hundred and seventy-eight patients diagnosed with schizophrenia were evaluated and 369 patients were included in the study at baseline. After conducting Rasch model analyses for the validation of the anxiety subscale in the SCL-90-R, we applied latent growth model to determine the causal relationship between the PSP and the anxiety symptoms. RESULTS: The validity of the anxiety subscale of the SCL-90-R was confirmed based on the Rasch rating model, where the criteria for Infit, Outfit, item difficulty, and point-measure correlations were satisfied. The results from the latent growth model showed that the intercept and slope (rate of change) of the PSP negatively predicted the slope of anxiety symptoms along the longitudinal trajectory. Together with previous studies examining the predictive role of anxiety symptoms on quality of life, our longitudinal findings lend evidence for bidirectional effects between quality of life and anxiety symptoms. The transactional nature of the relationship between anxiety symptoms and quality of life warrant further investigation using a longitudinal cross-lagged design. CONCLUSION: The anxiety subscale of the SCL-90 R may be utilized by clinicians and researcher to make inferences about quality of life in addition to assessing anxiety symptoms in patients with schizophrenia. PMID- 26480207 TI - Relationship between cardiac vagal activity and mood congruent memory bias in major depression. AB - BACKGROUND: Previous studies suggest that autonomic reactivity during encoding of emotional information could modulate the neural processes mediating mood congruent memory. In this study, we use a point-process model to determine dynamic autonomic tone in response to negative emotions and its influence on long term memory of major depressed subjects. METHODS: Forty-eight patients with major depression and 48 healthy controls were randomly assigned to either neutral or emotionally arousing audiovisual stimuli. An adaptive point-process algorithm was applied to compute instantaneous estimates of the spectral components of heart rate variability [Low frequency (LF), 0.04-0.15 Hz; High frequency (HF), 0.15-0.4 Hz]. Three days later subjects were submitted to a recall test. RESULTS: A significant increase in HF power was observed in depressed subjects in response to the emotionally arousing stimulus (p=0.03). The results of a multivariate analysis revealed that the HF power during the emotional segment of the stimulus was independently associated with the score of the recall test in depressed subjects, after adjusting for age, gender and educational level (Coef. 0.003, 95%CI, 0.0009-0.005, p=0.008). LIMITATIONS: These results could only be interpreted as responses to elicitation of specific negative emotions, the relationship between HF changes and encoding/recall of positive stimuli should be further examined. CONCLUSIONS: Alterations on parasympathetic response to emotion are involved in the mood-congruent cognitive bias observed in major depression. These findings are clinically relevant because it could constitute the mechanism by which depressed patients maintain maladaptive patterns of negative information processing that trigger and sustain depressed mood. PMID- 26480208 TI - The specificity of the familial aggregation of early-onset bipolar disorder: A controlled 10-year follow-up study of offspring of parents with mood disorders. AB - BACKGROUND: Two major sources of heterogeneity of mood disorders that have been demonstrated in clinical, family and genetic studies are the mood disorder subtype (i.e. bipolar (BPD) and major depressive disorder (MDD)) and age of onset of mood episodes. Using a prospective high-risk study design, our aims were to test the specificity of the parent-child transmission of BPD and MDD and to establish the risk of psychopathology in offspring in function of the age of onset of the parental disorder. METHODS: Clinical information was collected on 208 probands (n=81 with BPD, n=64 with MDD, n=63 medical controls) as well as their 202 spouses and 372 children aged 6-17 years at study entry. Parents and children were directly interviewed every 3 years (mean duration of follow-up=10.6 years). Parental age of onset was dichotomized at age 21. RESULTS: Offspring of parents with early onset BPD entailed a higher risk of BPD HR=7.9(1.8-34.6) and substance use disorders HR=5.0(1.1-21.9) than those with later onset and controls. Depressive disorders were not significantly increased in offspring regardless of parental mood disorder subtype or age of onset. LIMITATIONS: Limited sample size, age of onset in probands was obtained retrospectively, age of onset in co-parents was not adequately documented, and a quarter of the children had no direct interview. CONCLUSIONS: Our results provide support for the independence of familial aggregation of BPD from MDD and the heterogeneity of BPD based on patterns of onset. Future studies should further investigate correlates of early versus later onset BPD. PMID- 26480209 TI - Comparative neurocognitive effects of lithium and anticonvulsants in long-term stable bipolar patients. AB - BACKGROUND: The aim of choosing a mood-stabilizing drug (lithium or anticonvulsants) or a combination of them with minimal neurocognitive effects is to stimulate the development of criteria for a therapeutic adequacy, particularly in Bipolar Disorder (BD) patients who are clinically stabilized. METHOD: Three groups of BD patients were established according to their treatment: (i) lithium monotherapy (n=29); (ii) lithium together with one or more anticonvulsants (n=28); and (iii) one or more anticonvulsants (n=16). A group of healthy controls served as the control (n=25). The following tests were applied: Wechsler Adult Intelligence Scale, Trail Making Test, Wechsler Memory Scale, Rey Complex Figure Test, Stroop color-word test, Wisconsin Card Sorting Test, Tower of Hanoi, Frontal Assessment Battery, and Reading the Mind in the Eyes Test. RESULTS: Relative to healthy controls, BD patients showed the following: (i) those on lithium monotherapy, but not other BD groups, had preserved short-term auditory memory, long-term memory, and attention; (ii) those who took only anticonvulsants showed worse findings in short-term visual memory, working memory, and several executive functions; and (iii) all BD patients showed worse performance in processing speed, resistance to interference, and emotion recognition. LIMITATIONS: Medication alone cannot explain why all BD patients showed common cognitive deficits despite different pharmacological treatment. CONCLUSION: The impairment on some executive functions and emotion recognition is an inherent trait in BD patients, regardless of their pharmacological treatment. However, while memory, attention, and most of the executive functions are preserved in long-term stable BD patients, these cognitive functions are impaired in those who take anticonvulsants. PMID- 26480210 TI - The association between blood lead level and clinical mental disorders in fifty thousand lead-exposed male workers. AB - BACKGROUND: While there has been research into the relationship between blood lead (BPb) level and mental disorders, there have been few investigations that use clinically diagnosed mental disorders in the adult population with a retrospective cohort study design. Hence, our study investigated the association between BPb level and risk of clinically diagnosed mental disorders. METHODS: The data of male workers exposed to lead (Pb; n=54,788) were collected from annual Pb associated medical check-ups from 2000 to 2004 in Korea. The workers' hospital admission histories due to mental disorders (International Classification of Diseases, 10th revision, F00-F99) were used to identify clinically diagnosed mental disorders. After merging the data, the hazard ratio (HR) with a 95% confidence interval (95% CI) was calculated by survival analysis using the Cox proportional hazards model according to the quartile level of BPb (1st quartile<4.10 MUg/dl, 2nd quartile<6.04 MUg/dl, 3rd quartile<10.00 MUg/dl, and 4th quartile>=10 MUg/dl). RESULTS: In a total of 54,788 workers, there were 223 admission cases of mental disorders (F00-F99) during the follow-up period. The HR (95% CI) of total mental and behavioral disorders (F00-F99) was 1.63 (1.12-2.39) in the 4th quartile group compared to the HR of the 1st quartile group after adjusting for age. The HR (95% CI) of the 4th quartile group was 2.59 (1.15-5.82) for mood (affective) disorders (F30-F39). LIMITATION: The hospital admission data, not outpatient data, were used for current study while almost affective disorder treated at outpatient clinic level. CONCLUSION: Our study highlighted that Pb exposure can cause clinical mental disorders that require hospital admission in adult male workers. Our relatively large sample size strengthens the evidence of the association between BPb level and risk of clinically diagnosed mental disorders. PMID- 26480211 TI - Associations between depression and specific childhood experiences of abuse and neglect: A meta-analysis. AB - BACKGROUND: Research documents a strong relationship between childhood maltreatment and depression. However, only few studies have examined the specific effects of various types of childhood abuse/neglect on depression. This meta analysis estimated the associations between depression and different types of childhood maltreatment (antipathy, neglect, physical abuse, sexual abuse, and psychological abuse) assessed with the same measure, the Childhood Experience of Care and Abuse (CECA) interview. METHOD: A systematic search in scientific databases included use of CECA interview and strict clinical assessment for major depression as criteria. Our meta-analysis utilized Cohen's d and relied on a random-effects model. RESULTS: The literature search yielded 12 primary studies (reduced from 44), with a total of 4372 participants and 34 coefficients. Separate meta-analyses for each type of maltreatment revealed that psychological abuse and neglect were most strongly associated with the outcome of depression. Sexual abuse, although significant, was less strongly related. Furthermore, the effects of specific types of childhood maltreatment differed across adult and adolescent samples. LIMITATIONS: Our strict criteria for selecting the primary studies resulted in a small numbers of available studies. It restricted the analyses for various potential moderators. CONCLUSION: This meta-analysis addressed the differential effects of type of childhood maltreatment on major depression, partially explaining between-study variance. The findings clearly highlight the potential impact of the more "silent" types of childhood maltreatment (other than physical and sexual abuse) on the development of depression. PMID- 26480212 TI - Discriminant validity and gender differences in DSM-5 posttraumatic stress disorder symptoms. AB - BACKGROUND: The posttraumatic stress disorder (PTSD) literature is replete with investigations of factor structure, however, few empirical studies have examined discriminant validity and the moderating role of gender on factor structure and symptom expression. This study aimed to address these gaps. METHODS: An online, population-based study of 3175 Australian adults was conducted. This study analyzed data from 642 participants who reported a traumatic event. Overall, 10.2% (13.4% females, 7.6% males) met diagnostic criteria for current PTSD. RESULTS: Confirmatory factor analyses indicated that eight factor models provided excellent fit to the data. The DSM-5 model, anhedonia and hybrid models provided strong fit to the data, based on statistical fit indices and parsimony. The models' factors were significantly associated with a number of external correlates. Factor structure was gender invariant for the three models, albeit significant latent mean-level differences were apparent in relation to the intrusion/re-experiencing and alterations in arousal and reactivity factors. Bonferroni-adjusted Wald chi-square tests indicated significant gender differences in four DSM-5 PTSD symptoms: females reported significantly higher rates of negative beliefs, diminished interest, restricted affect and sleep disturbance symptoms compared to men. LIMITATIONS: Response rate to the survey was low. However, the number of respondents who completed the survey was high and population weights were employed to account for self-selection biases and aid generalizability. CONCLUSIONS: The findings provide support for the DSM-5, anhedonia and hybrid models compared to alternative models based on DSM-5 symptoms. Discriminant validity analyses indicated similar patterns of significant associations with the transdiagnostic factors, potentially suggesting that all the PTSD factors are related to non-specific distress. Further research investigating how gender influences PTSD symptom expression is warranted, including possible gender differences in symptom item interpretation. PMID- 26480213 TI - Diagnostic accuracy of the Patient Health Questionnaire-9 for assessment of depression in type II diabetes mellitus and/or coronary heart disease in primary care. AB - BACKGROUND: Depression is common among type 2 diabetes mellitus (DM2)/coronary heart disease (CHD) patients and is associated with adverse health effects. A promising strategy to reduce burden of disease is to identify patients at risk for depression in order to offer indicated prevention. This study aims to assess the diagnostic accuracy of the Patient Health Questionnaire-9 (PHQ-9) to be used as a tool to identify high risk patients. METHODS: In this cross-sectional study, 586 consecutive DM2/CHD patients aged >18 were recruited through 23 general practices. PHQ-9 outcomes were compared to the Mini International Neuropsychiatric Interview (MINI), which was considered the reference standard. Diagnostic accuracy was evaluated for minor and major depression, comparing both sum- and algorithm based PHQ-9 scores. RESULTS: For minor depression, the optimal cut-off score was 8 (sensitivity 71%, specificity 71% and an AUC of 0.74). For major depression, the optimal cut-off score was 10 resulting in a sensitivity of 84%, a specificity of 82%, and an AUC of 0.88. The positive predictive value of the PHQ-9 algorithm for diagnosing minor and major depression was 25% and 33%, respectively. LIMITATIONS: Two main limitations apply. MINI Interviewers were not blinded for PHQ-9 scores and less than 10% of all invited patients could be included in the analyses. This could have resulted in biased outcomes. CONCLUSIONS: The PHQ-9 sum score performs well in identifying patients at high risk of minor and major depression. However, the PHQ-9 showed suboptimal results for diagnostic purposes. Therefore, it is recommended to combine the use of the PHQ-9 with further diagnostics to identify depression. PMID- 26480214 TI - Panic disorder and agoraphobia: A direct comparison of their multivariate comorbidity patterns. AB - BACKGROUND: Scientific debate has long surrounded whether agoraphobia is a severe consequence of panic disorder or a frequently comorbid diagnosis. Multivariate comorbidity investigations typically treat these diagnoses as fungible in structural models, assuming both are manifestations of the fear-subfactor in the internalizing-externalizing model. No studies have directly compared these disorders' multivariate associations, which could clarify their conceptualization in classification and comorbidity research. METHODS: In a nationally representative sample (N=43,093), we examined the multivariate comorbidity of panic disorder (1) without agoraphobia, (2) with agoraphobia, and (3) regardless of agoraphobia; and (4) agoraphobia without panic. We conducted exploratory and confirmatory factor analyses of these and 10 other lifetime DSM-IV diagnoses in a nationally representative sample (N=43,093). RESULTS: Differing bivariate and multivariate relations were found. Panic disorder without agoraphobia was largely a distress disorder, related to emotional disorders. Agoraphobia without panic was largely a fear disorder, related to phobias. When considered jointly, concomitant agoraphobia and panic was a fear disorder, and when panic was assessed without regard to agoraphobia (some individuals had agoraphobia while others did not) it was a mixed distress and fear disorder. LIMITATIONS: Diagnoses were obtained from comprehensively trained lay interviewers, not clinicians and analyses used DSM-IV diagnoses (rather than DSM-5). CONCLUSIONS: These findings support the conceptualization of agoraphobia as a distinct diagnostic entity and the independent classification of both disorders in DSM-5, suggesting future multivariate comorbidity studies should not assume various panic/agoraphobia diagnoses are invariably fear disorders. PMID- 26480215 TI - The role of fathers' psychopathology in the intergenerational transmission of captivity trauma: A twenty three-year longitudinal study. AB - BACKGROUND: The aversive impact of combat and parents' combat-induced posttraumatic stress disorder (PTSD) on young children has been examined in a few studies. However, the long-term toll of war captivity on the secondary traumatization (ST) of adult offspring remains unknown. This study aimed to assess the longitudinal associations between former prisoners of war (ex-POWs), PTSD, depressive symptoms and their adult offsprings ST. METHOD: A sample of 134 Israeli father-child dyads (80 ex-POWs dyads and a comparison group of 44 veterans'dyads) completed self-report measures. The fathers participated in three waves of measurements following the Yom Kippur War (T1: 1991, T2: 2003, and T3: 2008), while the offspring took part in T4 (2013). RESULTS: Offspring of ex-POWs with PTSD at T3 reported more ST symptoms than offspring of ex-POWs without PTSD and controls. Ex-POWs' PTSD hyper-arousal symptom cluster at T3 was positively related to offsprings ST avoidance symptom cluster. Offspring of ex-POWs with chronic and delayed PTSD trajectories reported more ST symptoms than offspring of ex-POWS and controls with resilient trajectories. Ex-POWs' PTSD and depression symptoms at T1, T2 and T3 mediated the link between war captivity (groups) and offsprings ST in T4. LIMITATIONS: The use of self-report measures that did not cover the entire span of 40 years since the war, might may bias the results. CONCLUSIONS: The intergenerational transmission of captivity related trauma following the Yom Kippur War was exemplified. ST symptoms among ex-POWs' adult offspring are closely related to their father' PTSD and related depressive symptom comorbidity. PMID- 26480216 TI - Overexpression of GRbeta in colonic mucosal cell line partly reflects altered gene expression in colonic mucosa of patients with inflammatory bowel disease. AB - The glucocorticoid receptor (GR) plays a crucial role in inflammatory responses. GR has several isoforms, of which the most deeply studied are the GRalpha and GRbeta. Recently it has been suggested that in addition to its negative dominant effect on GRalpha, the GRbeta may have a GRalpha-independent transcriptional activity. The GRbeta isoform was found to be frequently overexpressed in various autoimmune diseases, including inflammatory bowel disease (IBD). In this study, we wished to test whether the gene expression profile found in a GRbeta overexpressing intestinal cell line (Caco-2GRbeta) might mimic the gene expression alterations found in patients with IBD. Whole genome microarray analysis was performed in both normal and GRbeta overexpressing Caco-2 cell lines with and without dexamethasone treatment. IBD-related genes were identified from a meta-analysis of 245 microarrays available in online microarray deposits performed on intestinal mucosa samples from patients with IBD and healthy individuals. The differentially expressed genes were further studied using in silico pathway analysis. Overexpression of GRbeta altered a large proportion of genes that were not regulated by dexamethasone suggesting that GRbeta may have a GRalpha-independent role in the regulation of gene expression. About 10% of genes differentially expressed in colonic mucosa samples from IBD patients compared to normal subjects were also detected in Caco-2 GRbeta intestinal cell line. Common genes are involved in cell adhesion and cell proliferation. Overexpression of GRbeta in intestinal cells may affect appropriate mucosal repair and intact barrier function. The proposed novel role of GRbeta in intestinal epithelium warrants further studies. PMID- 26480217 TI - Bidirectional associations between perceived parental support for violent and nonviolent responses and early adolescent aggressive and effective nonviolent behaviors. AB - The current study examined bidirectional relations between early adolescents' perceptions of parental support for violent and nonviolent responses to conflict and their aggressive and effective nonviolent behaviors six months later. Data was collected across the sixth and seventh grades for 520 adolescents at three middle schools in the southeastern United States. At baseline, participants were ages 10-14 (M = 11.29). Longitudinal path models showed that perceived parental support for violent responses was negatively associated with effective nonviolent behaviors and positively associated with aggressive behaviors across sixth and seventh grades. Across seventh grade, reciprocal negative relations were found between perceived parental support of nonviolent responses and aggressive behaviors. Effective nonviolent behaviors were positively associated with perceived parental support for nonviolent responses. Study implications include the importance of adolescent perceptions of parental support of violent and nonviolent responses in influencing early adolescents' effective nonviolent and aggressive behavior. PMID- 26480218 TI - From anatomy to function: diagnosis of atherosclerotic renal artery stenosis. AB - Atherosclerotic renal artery stenosis (ARAS) affects 7% of the over 65 s and will be increasingly common with an ageing population. ARAS obstructs normal renal perfusion with adverse renal and cardiovascular consequences. Drug therapy is directed at reducing atherosclerotic risk. Two recent major trials of revascularization for ARAS showed that clinical outcomes were not improved beyond those offered by optimal drug therapy in most patients. This reflects experimental data showing that restoration of blood flow alone may not attenuate a cascade of tissue injury. A shift from anatomic to functional imaging of ARAS coupled to novel therapies might improve clinical outcomes in selected patients. This review outlines the case for separately assessing hemodynamic significance of arterial stenosis and functional reserve of renal parenchymal tissue. The authors consider current and emerging diagnostic techniques for ARAS and their potential to allow individualized and functionally directed treatments. PMID- 26480219 TI - Peculiar Magnetoelectric Coupling in BaTiO3:Fe113 ppm Nanoscopic Segregations. AB - We report polycrystalline BaTiO3 with cooperative magnetization behavior associated with the scarce presence of about 113 atomic ppm of Fe ions, clearly displaying magnetoelectric coupling with significant changes in magnetization (up to DeltaM/M ~ 32%) at the ferroelectric transitions. We find that Fe ions are segregated mostly at the interfaces between grain boundaries and an Fe-rich phase, forming a self-composite with high magnetoelectric coupling above room temperature. We compare our results with ab initio calculations and other experimental results found in the literature, proposing mechanisms that could be behind the magnetoelectric coupling within the ferroelectric matrix. These findings open the way for further strategies to optimize interfacial magnetoelectric couplings. PMID- 26480220 TI - Psychotropic medication in pregnancy: The cost-benefit ratio revised. PMID- 26480221 TI - Pharmacological agents under research for the maintenance treatment in bipolar disorder. AB - The treatment of bipolar disorder is a current challenge for clinicians and despite progress in psychopharmacology, options remain limited and results are often unsatisfactory. Current research focuses on finding new pharmaceutical agents for all phases of bipolar disorder, i.e. mania, bipolar depression and maintenance. Particularly, relapse prevention and longterm stabilization is a major therapeutic target. Combination treatment and polypharmacy are the most common choices concerning relapse prevention. Furthermore, during maintenance phase patients often experience residual mood symptoms, cognitive deficits and functional decline, which altogether illustrate the inadequate effectiveness of existing treatments and the need for new, targeted, effective and safe treatments for bipolar disorder. This review focuses on active agents for maintenance treatment in bipolar disorder investigated during the last 5 years. The compounds under investigation have been tried or tested either as monotherapy or as an add on treatment in clinical trials that have progressed up to phase 3 or in preclinical models of bipolar disorder. While awaiting the completion of many ongoing studies, the results so far indicate that paliperidone and pregabalin may have a position in the maintenance treatment of bipolar disorder. Additionally, dextromethorphan, which acts primarily as a NMDA antagonist, may be an interesting compound for further study. However, results on memantine, another NMDA antagonist, were not encouraging. The effects of omega-3 fatty acids and cytidine were not superior to placebo, although they both have neurotrophic and neuroprotective properties. Eslicarbazepine, which has antiepileptic action, provided some evidence of efficacy as monotherapy. Regarding preclinical studies in experimental models, the pharmacological agents under investigation seem to follow the neurobiological pathways related to mechanism of action of lithium, which is still the "golden standard" for preventing recurrence in bipolar disorder. Major therapeutic targets are synthetic glucose kinase 3 (GSK-3) and the path of phosphoinositol (IMP), both probably involved in the action of lithium. Furthermore, the role of circadian rhythms maintenance is being studied in preclinical and clinical trials investigating the efficacy and safety of compounds CK-01 and ramelteon, respectively. Research also focuses on pharmacological agents based on epigenetic changes and gene expression modulation, as the inhibitor of histone deacetylase (HDAC). Of note, the development of valid and reliable experimental models for bipolar disorder, which currently remains quite controversial, will contribute to the understanding of the pathogenic mechanisms and the development of new effective treatments. Improving methodology aspects of clinical trials, such as diagnosis, clinical heterogeneity, monitoring time, gender differences and comorbidities, may promote research. Current studies seem promising for the development of novel pharmacological agents in the near future, although there are methodological limitations in the search for the maintenance treatment in bipolar disorder. New therapeutic targets include not only the already known mechanisms of action, but also novel pathophysiological pathways, probably implicated in bipolar disorder. PMID- 26480222 TI - Mental health services commissioning and provision: Lessons from the UK? AB - The commissioning and provision of healthcare, including mental health services, must be consistent with ethical principles - which can be summarised as being "fair", irrespective of the method chosen to deliver care. They must also provide value to both patients and society in general. Value may be defined as the ratio of patient health outcomes to the cost of service across the whole care pathway. Particularly in difficult times, it is essential to keep an open mind as to how this might be best achieved. National and regional policies will necessarily vary as they reflect diverse local histories, cultures, needs and preferences. As systems of commissioning and delivering mental health care vary from country to country, there is the opportunity to learn from others. In the future international comparisons may help identify policies and systems that can work across nations and regions. However a persistent problem is the lack of clear evidence over cost and quality delivered by different local or national models. The best informed economists, when asked about the international evidence do not provide clear answers, stating that it depends how you measure cost and quality, the national governance model and the level of resources. The UK has a centrally managed system funded by general taxation, known as the National Health Service (NHS). Since 2010, the UK's new Coalition* government has responded by further reforming the system of purchasing and providing NHS services - aiming to strengthen choice and competition between providers on the basis of quality and outcomes as well as price. Although the present coalition government's intention is to maintain a tax-funded system, free at the point of delivery, introducing market-style purchasing and provider-side reforms to encompass all of these bring new risks, whilst not pursuing reforms of a system in crisis is also seen to carry risks. Competition might bring efficiency, but may weaken cooperation between providers, and transparency too. On the other hand, it is hard to implement necessary governance and control without worsening bureaucracy and inefficiency. The pursuit of market efficiencies has been particularly contentious in mental health care, where many professionals are defensive about the risks to vulnerable patients and to traditional ways of professional working. Developments and debates in the UK may be instructive for others. We conclude this paper with a set of questions that may help inform debate and evaluation of mental health services internationally. PMID- 26480223 TI - NICE recommendations for psychotherapy in depression: Of limited clinical utility. AB - In 2009/10 NICE partially updated its guidelines on the treatment and management of depression in adults. Due to methodological shortcomings the recommendations for psychotherapy must be treated with caution. Despite recognising the heterogeneous and comorbid nature of depression, and the limitations of depression as a unitary diagnostic category, NICE treats depression as if it were a unitary entity differentiated only by severity. The guidance ignores important aetiological factors such as trauma, loss and maltreatment, personality and interpersonal difficulties. It excludes the largest naturalistic studies on clinical populations treated in the National Health Service on the grounds that they are observational studies conducted in heterogeneous groups with mixed neurotic disorders. It unquestioningly accepts that the "brand" of psychotherapy has construct validity, and ignores psychotherapy process research indicating significant commonalities, and overlap, between treatment modalities and evidence that individual practitioner effects are larger than the differences between treatment modalities. It fails to consider patient differences and preferences, which are known to influence uptake, completion and response. It takes an exclusively short-term perspective on a chronic relapsing disorder. It does not consider the evidence for longer-term treatments. It is of special concern that NICE misrepresents the findings of its own systematic review by implying that CBT and IPT are superior treatments. NICE's systematic review actually found no evidence of superiority between CBT, IPT, psychodynamic psychotherapy, or counselling. Based on the exclusion of much clinically relevant research demonstrating the effectiveness of psychodynamic psychotherapy and counselling many commentators have alleged a bias towards CBT in the guidance. With regard to service delivery NICE proposes the replacement of psychiatric assessment and individualised treatment plans, with an unproven stepped-care model. These clinical and theoretical limitations, perceived bias in the selection of studies, neglect of patient differences, preferences and values, misrepresentation of results of the systematic review, and the proposal for an unproven service delivery model together seriously undermine the validity of the guidance. The guidance, lacking validity is of questionable use, it undermines patient autonomy, professional expertise and, ultimately, patient welfare. PMID- 26480224 TI - Mental health and sexual activity according to ancient Greek physicians. AB - The ancient Greek physicians have not failed in their studies to indicate the beneficial role of sexual activity in human health. They acknowledged that sex helps to maintain mental balance. Very interesting is their observation that sex may help mental patients to recover. Nevertheless they stressed emphatically that sex is beneficial only when there is a measure in it, so they believed that sexual abstinence or excessive sexual activity affect negatively the mental and physical health of man. Ancient Greek physicians reached this conclusion by empirical observation. They tried to justify the mental imbalance, as the potential physical problems, which probably will be listed today in the psychosomatic manifestations, of people with long-term sexual abstinence or hyperactivity, based on the theory of humors which was the main methodological tool of ancient Greek medicine. Their fundamental idea was that the four humors of the body (blood, phlegm, yellow and black bile) should be in balance. Therefore they believed that the loss and the exchange of bodily fluids during sex help body's humors to maintain their equilibrium which in turn will form the basis for the physical and mental health. Although in ancient medical texts the irrationality presented by people in the aforementioned conditions was not attributed in any of the major mental illnesses recognized in antiquity, as mania, melancholy and phrenitis, our belief is that their behavior is more suited to the characteristics of melancholy, while according to modern medicine it should be classified in the depressive disorders. We have come to this conclusion, because common characteristics of people who either did not have sexual life or was overactive, was sadness, lack of interest and hope, as well as paranoid thinking that can reach up to suicide. Regarding the psychosomatic problems, which could occur in these people, they were determined by the ancient Greek physicians in the following; continuous headaches and heaviness, dilatancy, pain, dysuria and fever. But all these symptoms would disappear when the man gained a measure sexual activity, as was categorically stated by Galen. It is striking that these ideas were maintained over time, starting already from the authors of the Hippocratic Corpus, from which the distinguished work De virginum morbis, refers indeed to women who reached the point of suicide due to the absence sexual life, hanging themselves or falling into wells and eventually passing to the works of Rufus of Ephesus, Soranus of Ephesus and Galen. PMID- 26480225 TI - Validity of the Greek Eating Disorder Examination Questionnaire 6.0 (EDE-Q-6.0) among Greek adolescents. AB - The aim of this study is to examine the validity of the Greek version of the Eating Disorder Examination Questionnaire 6.0 (EDE-Q-6.0) in a sample of adolescent pupils. EDE-Q is a self- report instrument that assesses attitudes and behaviors related to Eating Disorders (EDs). A two-stage identification protocol has been applied to the 16 schools that agreed to participate in the present study. Initially, 2058 adolescents, in class under the supervision of one research assistant and one teacher, completed a Questionnaire on socio demographic data, the Greek EDE-Q-6.0 and the Greek Eating Attitudes Test (EAT 26) while their weight and height were measured. Six-hundred and twenty six participants, who had scores on EAT-26>=20 and/or were underweight or overweight, were considered as "possible-cases" while the remaining 1432 pupils of the sample were thought as "non-possible cases". At the second stage, parents of 66 of the participants identified as possible-cases as well as parents of 72 participants from 358 controls randomly selected from the sample of "non-possible cases" agreed that their children would be examined by means of Best Estimate Diagnostic Procedure. Participants meeting DSM-IV-TR Eating Disorders criteria were identified. Receiver Operating Characteristics (ROC) analysis was applied to reveal EDE-Q's criterion validity. The kappa statistic test was used as measure of agreement between categorical variables at EDE-Q and at interview (the presence of objective binge eating episode, of self-induced vomiting, the use of laxatives and of excessive exercise). The Discriminant and Convergent validity were assessed using the non-parametric Mann-Whitney U test and by means of the Spearman's correlation coefficient, respectively. Nineteen cases of EDs were identified [one case of Anorexia Nervosa (AN), 13 cases of Eating Disorder Not Otherwise Specified (EDNOS), 5 cases of Binge Eating Disorder (BED)]. At the cut off point of 2.6125 on the EDE-Q's global scale the instrument screens with a sensitivity (Se) of 89.5% and a specificity (Sp) of 73.1%, a Positive Predictive Value (PPV) of 34.7% and a Negative Predictive Value (NPV) of 97.8% The same analyses for both sexes revealed a cut-off point of 2.612 for females and of 3.125 for males on the global EDE-Q-6.0 score (Se=84.62%, Sp=73.33% for females and Se=83.33%, Sp= 84.09% for males), yielding a PPV and a NPV of 35.5% and of 96.5% for females and 41.7% and 97.4% for males, respectively. A very low agreement level, between EDE-Q and interview, was observed regarding the presence of objective bulimic episodes (OBEs) [k=0.191 (SE=0.057)] and the unhealthy weight control behaviors [k=0.295 (SE=0.073)]. Positive correlations were found between EAT-26 and EDE-Q-6.0 for both global scale and subscales (rho=0.50-0.57). The results suggest that EDE-Q-6.0, when using its global score, appears to be a proper screening tool for assessing the core psychopathology of eating disorders in community samples in two-stage screening studies since it distinguishes very well the cases from the non-cases. However, the assessment of the presence and frequency of pathological behaviours which characterize EDs appears to be problematic since adolescents, especially the younger ones, misunderstood terms like large amount of food and loss of control or misinterpret the motivation for excessive exercise. Therefore, marked discrepancies were observed between pathological behaviors self-reported at questionnaire and those detected at interview. We may assume that giving participants more information regarding the definition of these concepts may increase the accuracy with which the participants report these behaviors. PMID- 26480226 TI - Inter-rater reliability of the Greek version of CAARMS among two groups of mental health professionals. AB - There is increasing interest within the Greek psychiatric community in the early detection and prevention of psychotic disorders. To support this, there is a need for a valid and reliable tool to identify young people that may be at risk of developing a psychotic disorder. Our team has previously translated the Comprehensive Assessment of At-Risk Mental States (CAARMS). The validity of the CAARMS was ensured by the procedure of translation and the aim of the current study was to estimate the interrater reliability of the CAARMS Greek translation among residents in psychiatry and specialized mental health professionals. 43 mental health workers (27 residents in psychiatry and 16 specialized mental health professionals (i.e. 11 psychiatrists and 5 psychologist) participated in two seminars that covered theoretical information about the ultra high risk concept and training in the CAARMS. During the seminars, 10 vignettes with psychiatric history cases were presented, including healthy, ultra high risk and first episode psychosis. The mean correlated percentage of agreement with the correct answers regarding diagnosis of the presented history cases among all our subjects was 81.42, among specialized mental health professionals 77.88, and among residents 84.46. Intraclass correlation co-efficients were 0.994 for specialized mental health professionals and 0.997 for residents. The translated Greek version of CAARMS presents a satisfying interrater reliability when used by both residents and specialized mental health professionals. Residents declare even higher intraclass correlation co-efficients and mean correlated percentage of agreement than specialized mental health professionals, which indicate that residents are capable of using the CAARMS in early intervention units. PMID- 26480227 TI - Fast diffusion of water nanodroplets on graphene. AB - Diffusion across surfaces generally involves motion on a vibrating but otherwise stationary substrate. Here, using molecular dynamics, we show that a layered material such as graphene opens up a new mechanism for surface diffusion whereby adsorbates are carried by propagating ripples in a motion similar to surfing. For water nanodroplets, we demonstrate that the mechanism leads to exceedingly fast diffusion that is 2-3 orders of magnitude faster than the self-diffusion of water molecules in liquid water. We also reveal the underlying principles that regulate this new mechanism for diffusion and show how it also applies to adsorbates other than water, thus opening up the prospect of achieving fast and controllable motion of adsorbates across material surfaces more generally. PMID- 26480228 TI - Deep blue phosphorescent organic light-emitting diodes with very high brightness and efficiency. AB - The combination of both very high brightness and deep blue emission from phosphorescent organic light-emitting diodes (PHOLED) is required for both display and lighting applications, yet so far has not been reported. A source of this difficulty is the absence of electron/exciton blocking layers (EBL) that are compatible with the high triplet energy of the deep blue dopant and the high frontier orbital energies of hosts needed to transport charge. Here, we show that N-heterocyclic carbene (NHC) Ir(III) complexes can serve as both deep blue emitters and efficient hole-conducting EBLs. The NHC EBLs enable very high brightness (>7,800 cd m(-2)) operation, while achieving deep blue emission with colour coordinates of [0.16, 0.09], suitable for most demanding display applications. We find that both the facial and the meridional isomers of the dopant have high efficiencies that arise from the unusual properties of the NHC ligand-that is, the complexes possess a strong metal-ligand bond that destabilizes the non-radiative metal-centred ligand-field states. Our results represent an advance in blue-emitting PHOLED architectures and materials combinations that meet the requirements of many critical illumination applications. PMID- 26480229 TI - A high-specific-strength and corrosion-resistant magnesium alloy. AB - Ultra-lightweight alloys with high strength, ductility and corrosion resistance are desirable for applications in the automotive, aerospace, defence, biomedical, sporting and electronic goods sectors. Ductility and corrosion resistance are generally inversely correlated with strength, making it difficult to optimize all three simultaneously. Here we design an ultralow density (1.4 g cm(-3)) Mg-Li based alloy that is strong, ductile, and more corrosion resistant than Mg-based alloys reported so far. The alloy is Li-rich and a solute nanostructure within a body-centred cubic matrix is achieved by a series of extrusion, heat-treatment and rolling processes. Corrosion resistance from the environment is believed to occur by a uniform lithium carbonate film in which surface coverage is much greater than in traditional hexagonal close-packed Mg-based alloys, explaining the superior corrosion resistance of the alloy. PMID- 26480230 TI - Magnesium alloys: Ready for the road. PMID- 26480231 TI - Design principles for maximizing photovoltage in metal-oxide-protected water splitting photoanodes. AB - Metal oxide protection layers for photoanodes may enable the development of large scale solar fuel and solar chemical synthesis, but the poor photovoltages often reported so far will severely limit their performance. Here we report a novel observation of photovoltage loss associated with a charge extraction barrier imposed by the protection layer, and, by eliminating it, achieve photovoltages as high as 630 mV, the maximum reported so far for water-splitting silicon photoanodes. The loss mechanism is systematically probed in metal-insulator semiconductor Schottky junction cells compared to buried junction p(+)n cells, revealing the need to maintain a characteristic hole density at the semiconductor/insulator interface. A leaky-capacitor model related to the dielectric properties of the protective oxide explains this loss, achieving excellent agreement with the data. From these findings, we formulate design principles for simultaneous optimization of built-in field, interface quality, and hole extraction to maximize the photovoltage of oxide-protected water splitting anodes. PMID- 26480232 TI - Characteristics of on-road driving by persons with central vision loss: Learning to drive with a bioptic telescope. AB - There is limited research on the driving performance and safety of bioptic drivers and even less regarding the driving skills that are most challenging for those learning to drive with bioptic telescopes. This research consisted of case studies of five trainee bioptic drivers whose driving skills were compared with those of a group of licensed bioptic drivers (n = 23) while they drove along city, suburban, and controlled-access highways in an instrumented dual-brake vehicle. A certified driver rehabilitation specialist was positioned in the front passenger seat to monitor safety and two backseat evaluators independently rated driving using a standardized scoring system. Other aspects of performance were assessed through vehicle instrumentation and video recordings. Results demonstrate that while sign recognition, lane keeping, steering steadiness, gap judgments, and speed choices were significantly worse in trainees, some driving behaviors and skills, including pedestrian detection and traffic light recognition were not significantly different from those of the licensed drivers. These data provide useful insights into the skill challenges encountered by a small sample of trainee bioptic drivers which, while not generalizable because of the small sample size, provide valuable insights beyond that of previous studies and can be used as a basis to guide training strategies. PMID- 26480233 TI - A Pentacoordinate Mn(II) Precatalyst That Exhibits Notable Aldehyde and Ketone Hydrosilylation Turnover Frequencies. AB - Heating (THF)2MnCl2 in the presence of the pyridine-substituted bis(imino)pyridine ligand, (PyEt)PDI, allowed preparation of the respective dihalide complex, ((PyEt)PDI)MnCl2. Reduction of this precursor using excess Na/Hg resulted in deprotonation of the chelate methyl groups to yield the bis(enamide)tris(pyridine)-supported product, (kappa(5)-N,N,N,N,N-(PyEt)PDEA)Mn. This complex was characterized by single-crystal X-ray diffraction and found to possess an intermediate-spin (S = (3)/2) Mn(II) center by the Evans method and electron paramagnetic resonance spectroscopy. Furthermore, (kappa(5)-N,N,N,N,N (PyEt)PDEA)Mn was determined to be an effective precatalyst for the hydrosilylation of aldehydes and ketones, exhibiting turnover frequencies of up to 2475 min(-1) when employed under solvent-free conditions. This optimization allowed for isolation of the respective alcohols and, in two cases, the partially reacted silyl ethers, PhSiH(OR)2 [R = Cy and CH(Me)((n)Bu)]. The aldehyde hydrosilylation activity observed for (kappa(5)-N,N,N,N,N-(PyEt)PDEA)Mn renders it one of the most efficient first-row transition metal catalysts for this transformation reported to date. PMID- 26480235 TI - Catalytic Dynamics and Oxygen Diffusion in Doped PrBaCo2O(5.5+delta) Thin Films. AB - The Sr and Fe codoped double perovskites PrBaCo2O5.5+delta (PrBCO) thin films of Pr(Ba0.5Sr0.5)(Co1.5Fe0.5)O5.5+delta (PBSCFO) were epitaxially grown for chemical catalytic studies. The resistance behavior of PBSCFO epitaxial films was monitored under the switching flow of reducing and oxidizing gases as a function of the gas flow time, t, using an electrical conductivity relaxation (ECR) experimental setup. The R(t) vs t relationships determined at various temperatures show the occurrence of two oxidation processes, Co(2+)/Co(3+) <-> Co(3+) and Co(3+) <-> Co(3+)/Co(4+). Mathematical fitting of the observed R(t) vs t relationships was carried out using Fick's second law for one-dimensional diffusion of charge carriers to derive the diffusivity D(T) and tau(T) for the two processes at various temperatures, T. The D(T) vs T relationships were analyzed in terms of the Arrhenius relationship to find the activation energies Ea for each process. Oscillations in the dR(t)/dt plots, observed under oxidation reactions, were discussed in terms of a layer-by-layer oxygen vacancy exchange diffusion mechanism. Our work suggests that thin films of LnBCO (Ln = lanthanide) with their A and B sites doped as in PBSCFO are excellent candidates for the development of low or intermediate temperature energy conversion devices and gas sensor applications. PMID- 26480234 TI - Emotion in bipolar I disorder: Implications for functional and symptom outcomes. AB - Despite the centrality of emotion disturbance in neurobiological models of bipolar disorder, the behavioral literature has not yet clearly identified the most central aspects of emotion disturbance in bipolar disorder. Toward this aim, we gathered a battery of emotion-related measures in 67 persons diagnosed with bipolar I disorder as assessed with the SCID and a well-matched control group of 58 persons without a history of mood disorders. Those with bipolar disorder were interviewed monthly until they achieved remission, and then tested on emotion measures. A subset of 36 participants with bipolar disorder completed symptom severity interviews at 12-month follow-up. Factor analyses indicated 4 emotion factor scores: Negative Emotion, Positive Emotion, Reappraisal, and Suppression. Bivariate analyses suggested that bipolar disorder was tied to a host of emotion disturbances, but multivariate analyses suggested that bipolar disorder was particularly tied to elevations of Negative Emotion. High Negative Emotion, low Positive Emotion, and high Suppression were conjointly related to lower functioning. Reappraisal predicted declines in depression over time for those with bipolar disorder. Findings highlight the importance of considering the overall profile of emotion disturbance in bipolar disorder. Emotion and emotion regulation appear central to a broad range of outcomes in bipolar disorder. PMID- 26480237 TI - Strain-Induced Spatial and Spectral Isolation of Quantum Emitters in Mono- and Bilayer WSe2. AB - Two-dimensional transition metal dichalcogenide semiconductors are intriguing hosts for quantum light sources due to their unique optoelectronic properties. Here, we report that strain gradients, either unintentionally induced or generated by substrate patterning, result in spatially and spectrally isolated quantum emitters in mono- and bilayer WSe2. By correlating localized excitons with localized strain variations, we show that the quantum emitter emission energy can be red-tuned up to a remarkable ~170 meV. We probe the fine-structure, magneto-optics, and second-order coherence of a strained emitter. These results raise the prospect of strain-engineering quantum emitter properties and deterministically creating arrays of quantum emitters in two-dimensional semiconductors. PMID- 26480236 TI - Tailoring Oxygen Sensitivity with Halide Substitution in Difluoroboron Dibenzoylmethane Polylactide Materials. AB - The dual-emissive properties of solid-state difluoroboron beta-diketonate poly(lactic acid) (BF2bdkPLA) materials have been utilized for biological oxygen sensing. In this work, BF2dbm(X)PLA materials were synthesized, where X = H, F, Cl, Br, and I. The effects of changing the halide substituent and PLA polymer chain length on the optical properties in dilute CH2Cl2 solutions and solid-state polymer films were studied. These luminescent materials show fluorescence, phosphorescence, and lifetime tunability on the basis of molecular weight, as well as lifetime modulation via the halide substituent. Short BF2dbm(Br)PLA (6.0 kDa) and both short and long BF2dbm(I)PLA polymers (6.0 or 20.3 kDa) have fluorescence and intense phosphorescence ideal for ratiometric oxygen sensing. The lighter halide-dye polymers with hydrogen, fluorine, and chlorine substitution have longer phosphorescence lifetimes and can be utilized as ultrasensitive oxygen sensors. Photostability was also analyzed for the polymer films. PMID- 26480238 TI - Effect of Donor-Acceptor Coupling on TICT Dynamics in the Excited States of Two Dimethylamine Substituted Chalcones. AB - Significant effect of coupling between the electron donor and acceptor groups in intramolecular charge transfer (ICT) dynamics has been demonstrated by comparing the photophysical properties of two isomeric N,N-dimethylaminochalcone derivatives (namely, DMAC-A and DMAC-B). In the case of the DMAC-B molecule, the distance between the donor (N,N-dimethylaniline or DMA) and the acceptor (carbonyl) groups is larger by one ethylene unit as compared to that in the case of DMAC-A. The excited singlet (S1) states of both the isomers have strong ICT character but their photophysical properties are remarkably different. In polar solvents, fluorescence quantum yields (and the lifetimes of the S1 state) of DMAC A are more than 2 orders of magnitude lower (and shorter) than those of DMAC-B. Remarkable differences in the photophysical properties of these two isomers arise due to occurrence of the ultrafast twisting of the DMA group (or the TICT process) during the course of deactivation of the S1 state of the DMAC-A molecule, but not in the case of DMAC-B. In the later case, because of the presence of a large energy barrier along the twisting coordinate(s), TICT is not a feasible process, and hence, the S1 state of DMAC-B has the planar ICT structure. In the DMAC-A molecule, the strength of coupling between the donor and acceptor groups is relatively stronger because of a shorter distance between these groups. Femtosecond transient absorption spectroscopic measurements and DFT/TDDFT calculations have been adopted to establish the above aspects of the relaxation dynamics of the S1 states of these two isomeric chalcones. PMID- 26480239 TI - The impact of blood ethanol concentration on the classification of head injury severity in traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) is classified into mild, moderate and severe, based on the Glasgow Coma Score (GCS). However, TBI patients are often influenced by ethanol, which in itself can attenuate the level of consciousness. This study investigated the effect of ethanol on the GCS group classification in TBI patients. METHODS: The Oslo University Hospital trauma database was searched for all patients admitted with a head injury where the blood ethanol concentration (BEC) had been measured (n = 1004). The effect of BEC on GCS groups was analysed using multivariate ordinal logistic regression. RESULTS: This study identified 546, 142 and 316 patients in the mild, moderate and severe groups, respectively. Increasing BEC by 1 g kg(-1) and pre-hospital intubation had OR = 1.34 and 16.34 for being in a more severe GCS group, respectively. Increasing head abbreviated injury scale (head-AIS) was significantly associated with being in a more severe GCS group. The modelled probability of detecting a head-AIS of 4 or 5 in a patient with BEC of 2.0 g kg(-1) was 20%, 38% and 65% in the mild, moderate and severe groups, respectively. CONCLUSIONS: Increasing BEC was associated with increasing odds of being in a more severe GCS group. However, because the modelled probability of significant brain injury was high in patients with high levels of BEC, a reduced level of consciousness in intoxicated patients mandates further radiological investigations. PMID- 26480240 TI - Review of vorapaxar for the prevention of atherothrombotic events. AB - INTRODUCTION: Atherosclerosis is frequently caused by clot blockage of the coronary or peripheral arteries, and may lead to myocardial infarction (MI) or peripheral arterial disease (PAD). Despite advancements in management of atherosclerosis, mortality and ischemic rates remain high. Vorapaxar is a protease activated receptor-1 (PAR-1) antagonist, and prevents thrombin activation of PAR-1 receptors on platelets. AREAS COVERED: Vorapaxar was studied in 2 landmark trials in patients with acute coronary syndrome (ACS) and in those with history of atherosclerosis. For patients with ACS, vorapaxar did not significantly reduce rates of the primary efficacy outcome as compared to placebo. For patients with a history of atherosclerosis, vorapaxar significantly reduced rates of primacy outcome. However, in both landmark trials, vorapaxar significantly increased risks of bleeding, and significantly increases risks of intracranial hemorrhage in patients with a history of stroke. Vorapaxar was approved in 2014 in the US for patients with a history of MI or PAD, and in the European Union for patients with a history of MI. EXPERT OPINION: Use of vorapaxar may be limited due to its high potential for causing bleeding. Efficacy of vorapaxar in addition to aspirin and prasugrel or ticagrelor for the management of ACS should be studied in the future. PMID- 26480241 TI - Epidemiology of Musculoskeletal Symptoms Among Milkers and Dairy Farm Characteristics in Sweden and Germany. AB - International studies have shown that musculoskeletal symptoms (MSS) and disorders (MSD) are common among dairy farm milkers. Although dairy production is diverse, it has so far not been possible to explain the high risk by production parameters. Two national studies carried out under similar conditions were the incentive to merge the data and increase the sample size. The Standardized Nordic Questionnaire was used to assess MSS prevalence among 92 Swedish and 116 German male and female milkers. Eighty-four percent and 85% of the Swedish and German milkers reported MSS in at least one body part. Highest prevalence was reported in the lower back, shoulder, and neck. Females showed a significantly higher risk of MSS. Apart from that, small significant influence of MSS was found for other risk factors. These findings indicate that technical and organizational modifications of the work place design in milking parlors are needed. PMID- 26480242 TI - Demographic and Motivation Differences Among Online Sex Offenders by Type of Offense: An Exploration of Routine Activities Theories. AB - This article presents an analysis of the relationship between online sexual offenders' demographic background and characteristics indicative of motivation and offense type. Specifically, we investigate whether these characteristics can distinguish different online sexual offender groups from one another as well as inform routine activity theorists on what potentially motivates perpetrators. Using multinomial logistic regression, this study found that online sexual offenders' demographic backgrounds and characteristics indicative of motivation do vary by offense types. Two important implications of this study are that the term "online sexual offender" encompasses different types of offenders, including some who do not align with mainstream media's characterization of "predators," and that the potential offender within routine activity theory can be the focus of empirical investigation rather than taken as a given in research. PMID- 26480243 TI - Studies on the Adhesive Property of Snail Adhesive Mucus. AB - Many gastropod molluscs are known to secrete mucus which allow these animals to adhere to a substrate while foraging over it. While the mucus is known to provide strong adhesion to both dry and wet surfaces, including both horizontal and vertical ones, no systematic study has been carried out to understand the strength of such adhesion under different conditions. We report here results from preliminary studies on adhesion characteristics of the mucus of a snail found in eastern India, Macrochlamys indica. When perturbed, the snail was found to secrete its adhesive mucus, which was collected and subjected to regular adhesion tests. The hydrated mucus was used as such, and also as mixed with buffer of different pH. These experiments suggest that the mucus was slightly alkaline, and showed the maximum adhesion strength of 9 kPa when present in an alkaline buffer. Preliminary studies indicate that adhesive force is related to the ability of the mucus to incorporate water. In alkaline condition, the gel like mass that it forms, incorporate water from a wet surface and enable strong adhesion. PMID- 26480244 TI - An additional role for the Bronsted acid-base catalysts of mandelate racemase in transition state stabilization. AB - Mandelate racemase (MR) catalyzes the interconversion of the enantiomers of mandelate and serves as a paradigm for understanding the enzyme-catalyzed abstraction of an alpha-proton from a carbon acid substrate with a high pKa. The enzyme utilizes a two-base mechanism with Lys 166 and His 297 acting as Bronsted acid and base catalysts, respectively, in the R -> S reaction direction. In the S -> R reaction direction, their roles are reversed. Using isothermal titration calorimetry (ITC), MR is shown to bind the intermediate/transition state (TS) analogue inhibitor benzohydroxamate (BzH) in an entropy-driven process with a value of DeltaCp equal to -358 +/- 3 cal mol(-1) K(-1), consistent with an increased number of hydrophobic interactions. However, MR binds BzH with an affinity that is ~2 orders of magnitude greater than that predicted solely on the basis of hydrophobic interactions [St. Maurice, M., and Bearne, S. L. (2004) Biochemistry 43, 2524], suggesting that additional specific interactions contribute to binding. To test the hypothesis that cation-pi/NH-pi interactions between the side chains of Lys 166 and His 297 and the aromatic ring and/or the hydroxamate/hydroximate moiety of BzH contribute to the binding of BzH, site directed mutagenesis was used to generate the MR variants K166M, K166C, H297N, and K166M/H297N and their binding affinity for various ligands determined using ITC. Comparison of the binding affinities of these MR variants with the intermediate/TS analogues BzH and cyclohexanecarbohydroxamate revealed that cation-pi/NH-pi interactions between His 297 and the hydroxamate/hydroximate moiety and the phenyl ring of BzH contribute approximately 0.26 and 0.91 kcal/mol to binding, respectively, while interactions with Lys 166 contribute approximately 1.74 and 1.74 kcal/mol, respectively. Similarly, comparison of the binding affinities of these mutants with substrate analogues revealed that Lys 166 contributes >2.93 kcal/mol to the binding of (R)-atrolactate, and His 297 contributes 2.46 kcal/mol to the binding of (S)-atrolactate. These results are consistent with Lys 166 and His 297 playing dual roles in catalysis: they act as Bronsted acid-base catalysts, and they stabilize both the enolate moiety and phenyl ring of the altered substrate in the TS. PMID- 26480245 TI - The revised Stress Measurement of Female Marriage Immigrants in Korea: Evaluation of the psychometric properties. AB - The twenty-one item Stress Measurement of Female Marriage Immigrants (SMFMI) was developed to assess stress of female marriage immigrants in Korea. This study reports the psychometric properties of a revised SMFMI (SMFMI-R) for application with female marriage immigrants to Korea who were raising children. Participants were 190 female marriage immigrants from China, Vietnam, the Philippines, and other Asian countries, who were recruited using convenience sampling between November 2013 and December 2013. Survey questionnaires were translated into study participants' native languages (Chinese, Vietnamese, and English). Principal component analysis yielded nineteen items in four factors (family, parenting, cultural, and economic stress), explaining 63.5% of the variance, which was slightly better than the original scale. Confirmatory factor analysis indicated adequate fit for the four-factor model. Based on classic test theory and item response theory, strong support was provided for item discrimination, item difficulty, and internal consistency (Cronbach's alpha = 0.923). SMFMI-R scores were negatively associated with Korean proficiency and subjective economic status. The SMFMI-R is a valid, reliable, and comprehensive measure of stress for female marriage immigrants and can provide useful information to develop intervention programs for those who may be at risk for emotional stress. PMID- 26480246 TI - Predicting high levels of multitasking reduces between-tasks interactions. AB - The simultaneous handling of 2 tasks requires shielding of the prioritized primary task (T1) from interference caused by the secondary task (T2) processing. Such interactions between tasks (e.g., between-task interference, or crosstalk) depend on the similarity of both tasks and are especially pronounced when both tasks overlap strongly in time. In the present study we investigated whether between-tasks interference can be reduced when specific items do not predict the level of interference but instead the degree of temporal proximity between both tasks. We implemented an item-specific proportion manipulation of temporal task overlap (stimulus onset asynchrony [SOA]). Selected stimuli of T1 predicted high temporal task overlap (short SOAs) in 80% of trials, whereas other stimuli of T1 predicted low temporal task overlap (long SOAs) in 80% of trials. Results showed that the predictive value of T1 stimuli determined the adjustment of T1 shielding. That is, interference from the secondary task was significantly reduced for items predicting high temporal task overlap compared to items predicting low temporal task overlap. It is important to note that task shielding was not initiated by predicting the actual conflict level (i.e., whether T1 and T2 required compatible/incompatible responses) between tasks but by specific items predicting conditions in which 2 tasks are likely to interact (i.e., short vs. long SOA). These findings offer new insights into the specificity of contextual bottom-up regulations of cognitive control. PMID- 26480247 TI - Cultural similarities and differences in perceiving and recognizing facial expressions of basic emotions. AB - The ability to recognize facial expressions of basic emotions is often considered a universal human ability. However, recent studies have suggested that this commonality has been overestimated and that people from different cultures use different facial signals to represent expressions (Jack, Blais, Scheepers, Schyns, & Caldara, 2009; Jack, Caldara, & Schyns, 2012). We investigated this possibility by examining similarities and differences in the perception and categorization of facial expressions between Chinese and white British participants using whole-face and partial-face images. Our results showed no cultural difference in the patterns of perceptual similarity of expressions from whole-face images. When categorizing the same expressions, however, both British and Chinese participants were slightly more accurate with whole-face images of their own ethnic group. To further investigate potential strategy differences, we repeated the perceptual similarity and categorization tasks with presentation of only the upper or lower half of each face. Again, the perceptual similarity of facial expressions was similar between Chinese and British participants for both the upper and lower face regions. However, participants were slightly better at categorizing facial expressions of their own ethnic group for the lower face regions, indicating that the way in which culture shapes the categorization of facial expressions is largely driven by differences in information decoding from this part of the face. PMID- 26480249 TI - When do humans spontaneously adopt another's visuospatial perspective? AB - Perspective-taking is a key component of social interactions. However, there is an ongoing controversy about whether, when and how instances of spontaneous visuospatial perspective-taking occur. The aim of this study was to investigate the underlying factors as well as boundary conditions that characterize the spontaneous adoption of another person's visuospatial perspective (VSP) during social interactions. We used a novel paradigm, in which a participant and a confederate performed a simple stimulus-response (SR) compatibility task sitting at a 90 degrees angle to each other. In this set-up, participants would show a spatial compatibility effect only if they adopted the confederate's VSP. In a series of 5 experiments we found that participants reliably adopted the VSP of the confederate, as long as he was perceived as an intentionally acting agent. Our results therefore show that humans are able to spontaneously adopt the differing VSP of another agent and that there is a tight link between perspective taking and performing actions together. The results suggest that spontaneous VSP taking can effectively facilitate and speed up spatial alignment processes accruing from dynamic interactions in multiagent environments. PMID- 26480250 TI - The role of spatial frequency in expert object recognition. AB - Novices recognize objects at the basic-category level (e.g., dog, chair, and bird) at which identification is based on the global form of the objects (Rosch, Mervis, Gray, Johnson, & Boyes-Braem, 1976). In contrast, experts recognize objects within their domain of expertise at the subordinate level (e.g., Sparrow or Finch) for which the internal object information may play an important role in identification (Tanaka & Taylor, 1991). To investigate whether expert recognition relies on internal object information, we band-pass filtered bird images over a range of spatial frequencies (SF) and then masked the filtered image to preserve its global form. In Experiment 1, bird experts categorized common birds at the family level (e.g., Robin or Sparrow) more quickly and more accurately than novices. Both experts and novices were more accurate when bird images contained the internal information represented by a middle range of SFs, and this finding was characterized by a quadratic function in which accuracy decreased toward each end of the SF spectrum. However, the experts, but not the novices, showed a similar quadratic relationship between response times and SF range. In Experiment 2, experts categorized Warblers and Finches at the more specific, species level (e.g., Wilson's Warbler or House Finch). Recognition was again fastest and most accurate for images filtered in the middle range of SFs. Collectively, these results indicate that a midrange of SFs contain crucial information for subordinate recognition, and that extensive perceptual experience can influence the efficiency with which this information is utilized. (PsycINFO Database Record PMID- 26480248 TI - Sound segregation via embedded repetition is robust to inattention. AB - The segregation of sound sources from the mixture of sounds that enters the ear is a core capacity of human hearing, but the extent to which this process is dependent on attention remains unclear. This study investigated the effect of attention on the ability to segregate sounds via repetition. We utilized a dual task design in which stimuli to be segregated were presented along with stimuli for a "decoy" task that required continuous monitoring. The task to assess segregation presented a target sound 10 times in a row, each time concurrent with a different distractor sound. McDermott, Wrobleski, and Oxenham (2011) demonstrated that repetition causes the target sound to be segregated from the distractors. Segregation was queried by asking listeners whether a subsequent probe sound was identical to the target. A control task presented similar stimuli but probed discrimination without engaging segregation processes. We present results from 3 different decoy tasks: a visual multiple object tracking task, a rapid serial visual presentation (RSVP) digit encoding task, and a demanding auditory monitoring task. Load was manipulated by using high- and low-demand versions of each decoy task. The data provide converging evidence of a small effect of attention that is nonspecific, in that it affected the segregation and control tasks to a similar extent. In all cases, segregation performance remained high despite the presence of a concurrent, objectively demanding decoy task. The results suggest that repetition-based segregation is robust to inattention. PMID- 26480251 TI - Genome-scale metabolic model of Pichia pastoris with native and humanized glycosylation of recombinant proteins. AB - Pichia pastoris is used for commercial production of human therapeutic proteins, and genome-scale models of P. pastoris metabolism have been generated in the past to study the metabolism and associated protein production by this yeast. A major challenge with clinical usage of recombinant proteins produced by P. pastoris is the difference in N-glycosylation of proteins produced by humans and this yeast. However, through metabolic engineering, a P. pastoris strain capable of producing humanized N-glycosylated proteins was constructed. The current genome-scale models of P. pastoris do not address native nor humanized N-glycosylation, and we therefore developed ihGlycopastoris, an extension to the iLC915 model with both native and humanized N-glycosylation for recombinant protein production, but also an estimation of N-glycosylation of P. pastoris native proteins. This new model gives a better prediction of protein yield, demonstrates the effect of the different types of N-glycosylation of protein yield, and can be used to predict potential targets for strain improvement. The model represents a step towards a more complete description of protein production in P. pastoris, which is required for using these models to understand and optimize protein production processes. PMID- 26480252 TI - [Protein-energy wasting and nutritional supplementation in chronic hemodialysis]. AB - Protein Energy Wasting (PEW) is a pathological condition characterized by a progressive reduction of protein and energy stores. PEW has a high prevalence among patients with CKD/ESRD (Chronic Kidney Disease/End Stage Renal Disease) and is closely associated with adverse clinical outcomes and increased rate of hospitalization, complications and mortality. The multifactorial pathogenesis of PEW is complex. A key role is played both by the reduced intake of nutrients and the condition of hypercatabolism/reduced anabolism typical of renal patients. The approach to prevent or treat PEW has several milestones such as reduction of potential risk factors, improvement in lifestyle and correction of any factor related to dialysis. It also needs a periodic assessment of nutritional status by using biochemical markers, body and muscle mass variables, nutritional scores and instrumental methods, aiming for an early diagnosis. In case of reduced protein and energy intake, the administration of nutrients during dialysis, or the use of oral supplements specific for renal patients are the first nutritional interventions recommended. In fact, oral nutritional supplementation represents the most effective nutritional approach to PEW prevention and treatment. It is simple and safe and it has a positive impact on quality of life and survival of haemodialysis patients. In the case of failure of oral supplementation, nutritional support should be enhanced by using intradialytic parenteral nutrition (IDPN). If the patient has difficulty in swallowing or IDPN is insufficient, total enteral nutrition should be considered. PMID- 26480253 TI - [Anti-diabetics and chronic kidney disease]. AB - Diabetes mellitus (DM) is the most important non-communicable disease after hypertension. Prevalence of type 2 DM has progressively increased over the last decades. In Italy, 11.8% of the general adult population can be identified as diabetic. The major complication of DM is diabetic nephropathy (DM-CKD), which develops in approximately one-third of diabetics. Achieving optimal glycemic control is the first therapeutic goal in the management of DM-CKD. In recent years, new antidiabetic drugs have been marketed (GLP1 analogues, DPP-4 inhibitors, SGLT-2 inhibitors) to ameliorate glycemia in patients nave or treated by means of traditional agents, such as sulfonylureas, metformin, glinides, insulin. However, use of these drugs in DM-CKD should be evaluated carefully, mainly because of the higher risk of hypoglycemia that requires dosing adjustments. Metformin still represents an adequate choice if proper dose adjustments are made on the basis of renal function. Sulfonylureas with limited renal clearance, i.e., gliquidone, glipizide and gliclazide are an alternative to metformin and more effective than repaglinide on glycemic control. Other antidiabetic agents with potential nephroprotective effects, namely DPP-4 inhibitors, incretin analogues and SGLT-2 inhibitors, may allow nephroprotective effects independent of glycemic control. Insulin remains the cornerstone of therapy when oral therapy is no longer effective. PMID- 26480254 TI - [Which genetic testing in renal disease]. AB - Clinical genetics plays a central role in the diagnostic practice, mainly due to both the hereditary and non-hereditary genetic component, which characterizes most of the diseases. This branch of medicine has been characterized by a rapid technological growth since 2003, when the entire human genome was sequenced. We need to consider the reduction in terms of both time and costs that the gene sequencing has gone through. Before, 13 years and about three billion dollars were needed, now it takes only a few weeks and about ten thousand dollars to sequence the entire human genome. The applicability of clinical genetics in nephrology is due to the fact that many kidney diseases are characterized by genetic mutations (e.g., von-Hippel Lindau syndrome, MYH9 related disorders, Fabry's syndrome, Liddle's and Bartter's Syndrome, and others). Clinical genetics plays, therefore, a crucial role since many of these diseases are often not properly diagnosed. In this review, we examine the new technologies that are available to the nephrologist for the molecular diagnosis of renal diseases. PMID- 26480256 TI - [Lactic acidosis, acute renal failure and heart failure during treatment with metformin: what do we know?]. AB - Metformin is a common medication used for the treatment of type 2 diabetes, especially in obese subjects. Clinical studies show that, in addition to the lowering effect of blood glucose, metformin reduces cardiovascular risk, does not induce weight gain and additionally, provides a unique safety strategy and efficacy in patients with diabetes and heart disease. However, this treatment is not without risks. The most feared metabolic complication is lactic acidosis that often occurs with complex and severe clinical symptoms and is associated with a high mortality risk. We detail our experience, during one year, regarding four patients with diabetes treated with metformin who developed such acute renal failure and lactic acidosis as to require hemodialysis treatment. The patients selected had previous normal renal function but a history of serious cardiovascular disease (hypertensive cardiomiopathy, ischemic revascularized and/or dilated, chronic obstructive arterial disease). We observed in all four of our patients an onset of non-related symptoms (fever, fatigue, vomiting and gastrointestinal disorders), a rapid deterioration in renal function, anuria and very high levels of lactic acid. In two patients we found acute pancreatitis. In addition to rehydration therapy, hemodialysis was started instantly with progressive rebalancing of the biohumoral status, effective recovery of spontaneous diuresis and improvement of the clinical status in three patients. Unfortunately, we had a failure during the initial hours of ward admittance, with an important clinical situation complicated by acute cardiac ischemia, abnormal heart rhythm, ending in death. Our experience provides us with elements to reflect on. Lactic acidosis is a serious metabolic disorder because it is associated with a high mortality risk. So a rapid diagnosis and a complete recognition of all the fundamental elements are important for its management. Starting hemodialysis early and prolonged treatment can solve complicated clinical status, correct acidosis and restore kidney function in patients with serious comorbidity. PMID- 26480255 TI - ["Getting to zero infections" in hemodialysis]. AB - INTRODUCTION: We describe two measures adopted in hemodialysis outpatient population in order to reduce Central Venous Catheter (CVC) related infections. The first is a nurse staff training in the field project and the second deals with the employment of chlorhexidine-impregnated dressing devices. These actions were performed after high infection rates were observed through a dedicated register. MATERIALS AND METHODS: In the limited assistance dialysis center, direct observation (12/2012-02/2013) quantified the gap between the observed and expected health care behaviour. Training needs were defined and a 40 hours nurse staff training in the field was performed on two occasions. In the hospital dialysis center, we introduced alcoholic 2% chlorhexidine solution and chlorhexidine-impregnated dressing devices to the exit site (CHG-Tegaderm and BioPatch). Infections (cumulatively bacteremia/sepsis/skin exit/subcutaneous tunnel) were monitored continuously. RESULTS: Infection rates at the two locations were progressively reduced, reaching a value of zero at the limited assistance center. Nurse staff training in the field produced: two patient reports and three CVC management protocols, Italian language translation of the "The 5 moments of dialysis" WHO poster, alcoholic 2% chlorhexidine adoption to exit-site medication and improvement of environment cleaning/sanitation actions. CONCLUSIONS: Our experience shows that continuously monitoring infection rates represents the first step for timely corrective action. The continuous updating of health personnel, codified prevention measures and an ongoing commitment to raise awareness in a routine practice, allows us to obtain the goal of "getting to zero infections". The staff training produced equal or superior results compared to the isolated use of new chlorhexidine-impregnated dressing devices. PMID- 26480257 TI - [Analysis of clinical Risk and adoption of shared procedures: experience of nephrology and dialysis unit of ASL BA]. AB - Currently, English scientific literature is lacking in studies showing that medical assistance may be delivered without errors. Since two years ago, the department of nephrology and urology of ASL BA has been establishing a process of clinical risk management.Starting with the reporting of a single error, a related database was subsequently developed, in order to validate technical and organizational procedures that would be of common use in the daily clinical practice.With regard to error reporting, the system of incident reporting was adopted: that is a structured collection of significant events for the safety of patients with a specific form for reporting to be filled out by health professionals. Reports have been collected, coded and analysed. Finally measures were adopted to reduce the recurrence of the error.This first phase consisted on writing the procedures in order to create structured diagnostic-therapeutic protocols. In 18 months of observation adopting the incident reporting form, 48 errors have been reported: 52% due to adverse events; 12.5% to adverse reactions; 31.2% near misses and 2% to sentinel events. In 35.4 % of cases the error occurred in the administration or prescription of drug therapies, in 18.7% of cases it occurred in the organizational stage, in 12.5% it was a surgical error, in 18.7% of cases the error was due to incorrect asepsis, in 8.3% of cases it occurred during the medical examination and finally in 8.3% during dialysis. An analysis of the error database resulted in the choice of more urgent procedures. It is our view that only the observation of procedures can ensure the achievement of a high quality with improved clinical outcomes, reduction of complications, elimination of inappropriate interventions and increased patient satisfaction. PMID- 26480258 TI - [Periorbital purpura: a pathognomonic but late sign of AL amyloidosis]. AB - INTRODUCTION: AL amyloidosis is the most common type of systemic amyloidosis and is caused by the deposition of an amyloidogenic protein composed of immunoglobulin light chains produced by a clonal population of plasma cells. CASE REPORT: We report the case of a 77-year-old woman with arterial hypotension, peripheral edema and renal failure. Electrocardiogram reveals low voltage on peripheral leads. Echocardiogram shows normal values for left ventricle size with increased wall thickness and cardiac wall reflectance with ground glass appearance. Serum immunofixation electrophoresis (IFE) is negative while urine IFE detects type monoclonal light chains. Abdominal Fat Pad biopsy is positive for Congo red with typical apple green birefringence after polarization under optical microscopy (OM) while ultrastructural analysis does not show presence of amyloid deposition. Two months later, the patient undergoes further worsening of general clinical condition and development of purpura in the periorbital area, at the base of the neck and in the anterior chest wall. DISCUSSION: This clinical case presents classic signs of AL amyloidosis, such as cardiac and renal involvement with the presence of a urine monoclonal component. Periorbital purpura is a pathognomonic sign of AL amyloidosis but it appears late. Final diagnosis is "AL amyloidosis with prevalent cardiac, renal and soft tissue involvement". PMID- 26480259 TI - [Kidney toxicity's "HAART" therapy]. AB - Human immunodeficiency virus (HIV) and antiretroviral therapy can damage the kidney. Highly active antiretroviral therapy (HAART) generally improves the renal function as it reduces the viral replication, although the renal function may be reduced by certain antiretroviral drugs. HAART causes acute tubular necrosis, acute interstitial nephritis, calculi, Fanconi Syndrome, crystal nephropathy, elevated lipid levels as well as calcium and phosphorus alteration. The physician must estimate renal function before and during antiretroviral therapy, especially when HIV-infected patients have some risk factors for renal damage such as high blood pressure or hepatitis B or C infections. PMID- 26480260 TI - [Untitled]. PMID- 26480261 TI - [Clinical experience with ferric carboxymaltose in non-dialysis chronic kidney disease]. AB - BACKGROUND: Patients with non-dialysis-dependent chronic kidney disease (ND-CKD) often show anemia and iron deficiency despite oral iron supplementation caused by poor iron absorption, intolerance and non-compliance. METHODS: We prospectively followed seven adult patients with ND-CKD (eGFR <60 ml/min/1.73m2), anemia (Hb<11 g/dl or treatment with ESA), iron deficiency (TSAT<20% and/or ferritin<100 ng/mL) and intolerant or non-responders to oral iron supplementation. Patients received ferric carboxymaltose (FCM) (single dose of 500 mg iv) eventually followed by further doses if iron deficiency persisted. Hemoglobin, ferritin, TSAT and ESA doses were recorded at baseline and after 2, 4, 8, 12, 16, 20 and 24 weeks. RESULTS: After 2 weeks of FCM, ferritin increased from 5348 to 222154 ng/mL (P<0.05) and remained steady thereafter. The increase of TSAT from baseline (115%) was more gradual being significant from week 4 (198%) up to week 24 (2412%). During the study, patients received on average 2.31.0 injections of FCM, to the amount of 1143440 mg. Hb levels remained stable throughout the study, despite a significant reduction of ESA dosage (from 3426 g/week at baseline to 1116 and 1710 g/week, after 4 and 24 weeks, respectively). On average, the ESA dose saving was 2024 g/week. Even considering the higher cost of FCM, ESA dose reduction allowed shortening overall costs by 673/patient during the 24 weeks of study. CONCLUSION: In ND-CKD patients, FCM is effective in correcting iron deficiency and associated with stable Hb levels and significant decrease of ESA dosage. This allows a marked reduction of costs for anemia correction. PMID- 26480262 TI - [The prevention of corruption]. AB - The escalation of the crisis between society and administration had a negative impact on public administration, as highlighted by criminal acts (bribery, extortion, abuse of power). Other consequences of this crisis have been the bad administration phenomena, such as delays in carrying out the practices, lack of attention to people's questions and failure to comply with working hours. These phenomena culminate in treating people without due respect and necessary kindness. In this context, the so-called applied ethics has developed, consisting of the construction of rules for moral behaviour, adapted to particular fields as well as to the public. PMID- 26480263 TI - Muscle stimulation in elderly patients with CKD and sarcopenia. AB - OBJECTIVES: Aim of our study was to assess the potential effects of high-tone external muscle stimulation (HTEMS) on improvement of endothelial dysfunction (ED) and kidney damage in elderly patients with chronic kidney disease (CKD), sarcopenia and/or serious physical disability with a high Multidisciplinary Prognostic Index (MPI). METHODS: We enrolled 12 consecutive CKD patients with MPI > 0,66 from January 1st, 2008 to December 31st, 2014. Six patients underwent a 2 hours HTEMS during the first day (group A) and the other six patients (group B) underwent a sham experiment with HTEMS without power supply. After 24 hours, patients of group A were shifted to group B and vice-versa. Nitrite/nitrate (NOx), endotheline-1 (ET-1) and urine creatinine concentration were measured in all patients. RESULTS: During HTEMS urine amount increased by 22% (p=0.049), so did urine creatinine that increased by 40%, (p=0.034) and creatinine clearance that increased by 26% (p=0.041). There was no statistical difference in urine nitrogen (that raised by 11%, p=0.526), urine sodium (that reduced by 42%, p=0.121) and urine potassium levels (p=0,491). At the same time, NOx changed from 44.15.1 to 38.45.3 M/L after 1 hour, to 36.44.8 M/L after 2 hours, to 41.15.7 M/L after 3 hours and to 46,95.0 M/L after 4 hours (p=0.008) during HTEMS, while it did not vary during the sham section of the experiment, respectively 43.66.1 M/L , 436.4 M/L, 42.85.5 M/L, 434.7 M/L, and 42.85.8 M/L (p=0.992). CONCLUSION: Our study showed that HTEMS may improve microcirculation and, through this mechanism, may reduce kidney damage in elderly patients with CKD and severe muscle atrophy. PMID- 26480264 TI - [Divest and reallocate: a successful combination to save the public health]. PMID- 26480265 TI - [Chronic kidney disease: fertility and sexuality]. PMID- 26480266 TI - [Prescription unsuitability and dialysis]. PMID- 26480267 TI - Case Study: The Role of Milk in a Dietary Strategy to Increase Muscle Mass and Improve Recovery in an Elite Sprint Kayaker. AB - Flatwater kayaking requires upper-body muscle strength and a lean body composition. This case study describes a nutrition intervention with a 19-year old male elite sprint kayaker to increase muscle mass and improve recovery posttraining. Before the intervention, average daily energy intake was 13.6 +/- 2.5 MJ (M +/- SD; protein, 1.8 g/kg; carbohydrate, 3.6 g/kg), and the athlete was unable to eat sufficient food to meet the energy demands of training. During the 18-month intervention period, the athlete's daily energy intake increased to 22.1 +/- 3.8 MJ (protein, 3.2 g/kg; carbohydrate, 7.7 g/kg) by including milk-based drinks pre- and posttraining and before bed and an additional carbohydrate-based snack midmorning. This simple dietary intervention, along with a structured strength and conditioning program, resulted in an increase of 10 kg body mass with minimal change in body fat percentage. Adequate vitamin D status was maintained without the need for supplementation during the intervention period. In addition, the athlete reported the milk-based drinks and carbohydrate snacks were easy to consume, and no adverse side effects were experienced. This was the first time the athlete was able to maintain weight during intensive phases of the training cycle. PMID- 26480269 TI - [Executive functions and psychopathology: Current status]. AB - The aim of this review is to bring clinicians closer to the current discussion about the complex concept of Executive Functions in mental disorders that the DSM includes in axis 1, such as Bipolar Disorder, Depression, Social Phobia, Obsessive Compulsive Disorder and Generalized Anxiety Disorder. The present controversies about the definitions of Executive Functions are exposed as well as the importance of its study. The article also presents the idea that patients with these disorders suffer alterations in their Executive Functions and as the knowledge in this area is fragmented and contradictory, it is important to continue its study. Finally, the review concludes that not only it is necessary to define the neuropsychological profile in different disorders but also to work together with the clinicians to build a common place of study and discussion. PMID- 26480268 TI - Proteomic analysis of acidocalcisomes of Trypanosoma brucei uncovers their role in phosphate metabolism, cation homeostasis, and calcium signaling. AB - Trypanosoma brucei, the causative agent of African trypanosomiasis, is a unicellular parasite that possesses lysosome-related organelles known as acidocalcisomes. These organelles have been found from bacteria to human cells, and are characterized by their acidic nature and high calcium and polyphosphate (polyP) content. Our proteomic analysis of acidocalcisomes of T. brucei procyclic stages, together with in situ epitope-tagging and immunofluorescence assays with specific antibodies against selected proteins, established the presence of 2 H(+) pumps, a vacuolar H(+)-ATPase and a vacuolar H(+)-pyrophosphatase, that acidify the organelles as well as of a number of transporters and channels involved in phosphate metabolism, cation uptake and calcium signaling. Together with recent work in other organisms, these results provide direct evidence that acidocalcisomes are especially adapted to accumulate polyP bound to cations and for calcium signaling. PMID- 26480270 TI - [Prescription patterns in the treatment of schizophrenia]. AB - OBJECTIVE: The aim of this study was to determine prescribing patterns for the pharmacological treatment of schizophrenia in a sample of Argentinean psychiatrists and to compare some results with those obtained in a previous survey done on a similar population. METHODS: A self-administered survey was conducted among psychiatrists who attended a conference of psychopharmacology held in August 2012 in Buenos Aires city. Answers were analyzed descriptively and some of them were compared with results of another survey done in 2006 in a psychiatry conference. RESULTS: Ninety six percent of the surveyed psychiatrists considered that every schizophrenic patient with an acute episode must be pharmacologically treated. For the acute and chronic treatment of positive symptoms most psychiatrists chose risperidone, haloperidol, olanzapine and quetiapine. In contrast, for the chronic treatment of negative symptomatology, physicians preferred risperidone, aripiprazole, olanzapine, quetiapine and clozapine. An increased choice of quetiapine and aripiprazole was observed between this survey and the previous one. Sixty four percent of respondents reported using antipsychotic combination, similar as assessed in the previous survey. Most preferred to maintain pharmacological treatment during the pregnancy, although changing the antipsychotic to haloperidol. Ninety eight percent stated that they use some kind of psychotherapy in the treatment. CONCLUSION: In the pharmacological treatment of schizophrenia, similarities between reported clinical practice and current treatment guidelines were observed. There were no significant differences in the prescription patterns referred by psychiatrists between 2006 and 2012. PMID- 26480271 TI - [Proposal of initial psychotherapeutic and psychopharmacological approach in patients with diagnose of five different subtypes of Borderline Personality Disorder]. AB - The evidence shows that borderline personality disorder (BPD) is the most frequently diagnosed personality disorder. However, the diagnostic criteria are very heterogeneous, suggesting that very different patients may be included within a single construct. Despite its severity, there are no standardized treatments for this group of patients. We find the same problem in the Acute Mental Health Services. The numerous proposals that have been put forward are unclear and have not reached a final consensus. According to Oldham's classification, BPD can be divided into the following subtypes: Affective, Impulsive, Aggressive, Empty and Dependent. In this paper, we propose a psychotherapeutic initial approach from the Dialectical Behavioral Therapy (DBT) perspective and an initial psychopharmacological approach for each subtype of BPD. PMID- 26480272 TI - ['Third generation' psychotherapies]. PMID- 26480273 TI - [Acceptance and Commitment Therapy (ACT): Behaviorism, mindfulness and values]. AB - Over the last decades a series of psychological treatments labeled 'Third Generation Therapies' have been developed. Acceptance and Commitment Therapy (ACT) is a third generation therapy that essentially seeks to promote the acceptance of private events in opposition to their modification or change, with the aim of promoting cognitive flexibility. Thus, it is intended that the subject be permitted to choose their behavior consistent with personal values. The current work aims to provide overview specific to the contextual conditions that promoted the emergence of ACT, the underlying philosophy and theory, and the particularities of the intervention model. PMID- 26480274 TI - [Functional Analytic Psychotherapy: Approaches and scope of behavior therapy based on changes in the therapeutic context]. AB - Functional Analytic Psychotherapy (FAP) is a therapeutic approach developed in 'third wave therapies' context. FAP is characterized by use therapeutic relationship and the behaviors emit into it to improve clients daily life functioning. This therapeutic model is supported in behavior analysis principles and contextual functionalism philosophy. FAP proposes that clients behavior in session are functional equivalent with those out of session; therefore, when therapists respond to clients behaviors in session contingently, they promote and increase improvements in the natural setting. This article poses main features of FAP, its philosophical roots, achievements and research challenges to establish FAP as an independent treatment based on the evidence. PMID- 26480275 TI - [Mindfulness-Based Cognitive Therapy (MBCT) and the 'Third Wave' of Cognitive Bahavioral Therapies (CBT)]. AB - The paper presents the reasons that led to the incorporation of mindfulness as part of a cognitive therapy approach to the prevention of relapse of recurrent depressive disorders. It describes the context in which models focused on the contents of cognition gave way to models focused on cognitive processes. We highlight the problems encountered by the standard cognitive model when trying to account for the cognitive vulnerability of individuals who, having experienced a depressive episode, are in remission. We briefly describe the theoretical foundations of Mindfulness-Based Cognitive Therapy and its therapeutic approach. PMID- 26480276 TI - [Dialectical-Behavior Therapy: A possible treatment for patients with severe disorders]. AB - Clinical work with patient suffering complex or multiple problems represents one of the biggest challenges for mental health professionals. The third wave of cognitive behavioral therapies emphasizes the context and function of psychological events more so than their validity, frequency, or form, while incorporating processes of acceptance and mindfulness. The current work aims to provide a description of one type of these therapies, Dialectical Behavioral Therapy (DBT), which was developed by Dr. Marsha M. Linehan. In the 80's DBT's efficacy was investigated among women diagnosed with borderline personality disorder, while later extending the model to be used for other disorders. Specifically, the orientation of DBT, the central dialectic component between acceptance and change, validation procedures, and changes are explained. Moreover, the biosocial theory of the etiology and maintenance of behavioral problems are considered. Lastly, the targeted problems specific to when they occurred and their components for treatment are explained in stages. PMID- 26480277 TI - [Christofried Jakob: The arrival of the science of brain to the Modern Argentina (1899-1956)]. PMID- 26480278 TI - [The man without brain. Biopathological studies about dysgenesis of central nervous system in the man]. PMID- 26480279 TI - [Anthropology of curses]. AB - The symbolic order offers a great number of opportunities for understanding man's greatest fears. Based on Levi-Strauss' original concept, we can study the symbolic efficacy of curses and enrich it with the most recent contributions of neuroscience, philosophy, and the anthropology of consciousness. This is a report of qualitative research traversed by the methods of phenomenology and symbolic hermeneutics on a rarely addressed subject of unique significance to cultural psychiatry. We have worked on the empirical data of some classic religious curses of great historical value, but we have also inquired into the phenomenon of secular excommunication. Finally, we have interpreted the symbols used in curses and the areas of the psyche that they succeed in mobilizing. We suggest that the primary core of curses is dogma, without which their symbolic efficacy would not be possible. PMID- 26480281 TI - Epiplakin is a Paraneoplastic Pemphigus Autoantigen and Related to Bronchiolitis Obliterans in Japanese Patients. AB - All plakin family proteins are known to be autoantigens in paraneoplastic pemphigus (PNP). In this study, we first examined whether PNP sera also react with epiplakin, another plakin protein, by various immunological methods using 48 Japanese PNP sera. Immunofluorescence confirmed that cultured keratinocytes expressed epiplakin. Epiplakin was detected by 72.9% of PNP sera by immunoprecipitation-immunoblotting with KU-8 cell extract, but not by immunoblotting of either normal human epidermal extract or KU-8 cell extract. Epiplakin was essentially not detected by 95 disease and normal control sera. Statistical analyses of various clinical and immunological findings revealed significant correlation of the presence of anti-epiplakin antibodies with both bronchiolitis obliterans and mortality. No epiplakin-negative PNP case developed bronchiolitis obliterans. However, although 29.4% of European PNP patients had bronchiolitis obliterans, significant correlation with anti-epiplakin autoantibodies was not observed. In further studies for lung, immunofluorescence showed the presence of epiplakin in normal human lung, particularly respiratory bronchiole, immunoprecipitation-immunoblotting showed that PNP sera reacted with epiplakin in cultured lung cells, and mice injected with polyclonal antibody specific to epiplakin histopathologically showed abnormal changes in small airway epithelia. These results indicated that epiplakin is one of major PNP autoantigens and is related to PNP-related bronchiolitis obliterans.Journal of Investigative Dermatology accepted article preview online, 19 October 2015. doi:10.1038/jid.2015.408. PMID- 26480282 TI - Factors Driving Local Health Departments' Partnerships With Other Organizations in Maternal and Child Health, Communicable Disease Prevention, and Chronic Disease Control. AB - OBJECTIVES: To describe levels of partnership between local health departments (LHDs) and other community organizations in maternal and child health (MCH), communicable disease prevention, and chronic disease control and to assess LHD organizational characteristics and community factors that contribute to partnerships. DATA SOURCES: Data were drawn from the National Association of County & City Health Officials' 2013 National Profile Study (Profile Study) and the Area Health Resources File. LHDs that received module 1 of the Profile Study were asked to describe the level of partnership in MCH, communicable disease prevention, and chronic disease control. Levels of partnership included "not involved," "networking," "coordinating," "cooperating," and "collaborating," with "collaborating" as the highest level of partnership. Covariates included both LHD organizational and community factors. Data analyses were conducted using Stata 13 SVY procedures to account for the Profile Study's survey design. RESULTS: About 82%, 92%, and 80% of LHDs partnered with other organizations in MCH, communicable disease prevention, and chronic disease control programs, respectively. LHDs having a public health physician on staff were more likely to partner in chronic disease control programs (adjusted odds ratio [AOR] = 2.33; 95% confidence interval [CI], 1.03-5.25). Larger per capita expenditure was also associated with partnerships in MCH (AOR = 2.43; 95% CI, 1.22-4.86) and chronic disease prevention programs (AOR = 1.76; 95% CI, 1.09-2.86). Completion of a community health assessment was associated with partnership in MCH (AOR = 7.26; 95% CI, 2.90-18.18), and chronic disease prevention (AOR = 5.10; 95% CI, 2.28-11.39). CONCLUSION: About 1 in 5 LHDs did not have any partnerships in chronic disease control. LHD partnerships should be promoted to improve care coordination and utilization of limited health care resources. Factors that might promote LHDs' partnerships include having a public health physician on staff, higher per capita expenditure, and completion of a community health assessment. Community context likely influences types and levels of partnerships. A better understanding of these contextual factors may lead to more complete and effective LHD partnerships. PMID- 26480283 TI - Delivering Partner Services to Reduce Transmission and Promote Linkage to Care: Process Outcomes Varied for Chlamydial Infection, Gonorrhea, HIV, and Syphilis Cases. AB - CONTEXT: Partner services for HIV and sexually transmitted diseases, a public health intervention activity recommended by the Centers for Disease Control and Prevention, includes counseling, partner notification, linkage to care, and referral to other services. OBJECTIVE: A time study of partner services case investigations documented differences in times to process HIV/sexually transmitted disease cases. SETTING: Cases were from 9 local and regional sites in New York. PARTICIPANTS: Fifty-two partner services disease investigators documented 542 randomly selected cases (271 chlamydial infections, 162 gonorrhea, 48 HIV, and 61 syphilis cases) assigned between June and September 2014. Cases were the unit of the analysis and represented 6.9% of all partner services investigations in 2014. DESIGN: Cases were selected via stratified random sampling of infections assigned to staff. For each case, disease investigators completed a standard time study form to document the time spent on specific tasks and other outcomes. Kruskal-Wallis tests for continuous variables and chi tests for categorical variables assessed variation in outcomes across infection type. MAIN OUTCOME MEASURES: Outcomes included minutes spent on specific tasks (such as medical provider and index case outreach, travel, and partner notification), days the case remained open, disposition codes, and number of partners reached. RESULTS: Case processing times varied, with HIV and syphilis tasks taking more minutes (P < .001) and cases staying open for more days (P < .001). Partners were notified in 33% of cases overall, with more notifications in syphilis (44%). Most time (median = 77%) was spent on index cases and 2% (median) on partner notification, with a wide range across cases. CONCLUSIONS: Given their chronic resource constraints, public health agencies must identify efficient methods to allocate resources, including which infections to prioritize. Documenting how workers allocate time across cases is essential to improving the effectiveness and efficiency of this program and generating the data to model return on investment. PMID- 26480284 TI - Increased Risk of Atrial Fibrillation After Treatment for Differentiated Thyroid Carcinoma. AB - BACKGROUND: Patients with differentiated thyroid carcinoma (DTC) have a favorable prognosis after treatment with thyroidectomy, radioiodine, and TSH suppression. However, treatment is associated with long-term cardiovascular toxicity. The aim of this study was to evaluate whether there is an increased risk of atrial fibrillation (AF) in DTC patients and whether AF occurrence is related to DTC treatment. PATIENTS AND METHODS: Incident AF was compared between 518 DTC patients and 1563 matched controls. A cumulative incidence curve was plotted, and competing risk regression analyses with adjustment for all-cause mortality were performed. Within the DTC cohort, associations between time-varying DTC treatment variables and incident AF were analyzed. RESULTS: For both cohorts, the mean age was 48.6 years (75% of subjects were women). The AF incidence rate was 6.2/1000 person-years for DTC patients and 2.7/1000 person-years for controls. DTC patients had a 2.25-fold (95% confidence interval [CI], 1.40-3.63) and 2.47-fold (95% CI, 1.55-3.95) increased AF risk in crude and fully adjusted analyses, respectively. Within the DTC cohort, the TSH level (which was suppressed in 85.7% of patients) was not associated with AF, whereas a higher cumulative radioiodine dose slightly increased AF risk: subdistribution hazard ratio, 1.04 (95% CI, 1.01 1.08) per 50 mCi (1.85 GBq) increase, after adjustment. CONCLUSION: Patients with DTC have an increased AF risk, independent from established AF risk factors. We could not demonstrate a relation between TSH and AF, whereas a higher cumulative radioiodine dose was associated with a slightly increased AF risk. Electrocardiogram screening for AF may be warranted during follow-up of DTC patients to allow early diagnosis and treatment of AF and to prevent its complications. PMID- 26480285 TI - No Association Between Transient Hypothyroxinemia of Prematurity and Neurodevelopmental Outcome in Young Adulthood. AB - CONTEXT: Transient hypothyroxinemia of prematurity (THoP) has been associated with neurodevelopmental impairment in infancy and childhood. It is not known whether these relations persist into adulthood. OBJECTIVE: The objective was to examine whether there is an effect of THoP on intelligence quotient (IQ) score and motor functioning at a young adult age. DESIGN: This study was part of the 19 year follow-up of the Project On Preterm and Small-for-gestational-age birth (POPS) cohort, which included infants born very preterm (ie, <32 wk) and/or with a very low birth weight (ie, <1500 g). SETTING: This was a multicenter study. PATIENTS: There were 398 19-year-old participants of the POPS cohort, of whom 120 had THoP. EXPOSURE: T4 concentrations were obtained through the national neonatal screening program for congenital hypothyroidism. THoP was defined as a total T4 concentration < -3 SD of the daily mean (approximately 60 nmol/L). MAIN OUTCOME MEASURES: Main outcome measures were IQ and motor functioning, measured with the digital Multicultural Capacities Test-Intermediate Level and a revised version of Touwen's examination of minor neurological dysfunction, respectively. RESULTS: THoP was not associated with IQ score (mean difference, 0 [95% confidence interval, -3.8 to 3.8] points) or motor function (mean difference, 0.6 [95% confidence interval, -1.3 to 2.5] points) after adjustment for demographic and perinatal characteristics. CONCLUSIONS: No associations between THoP and neurodevelopmental outcome at age 19 years were found. PMID- 26480286 TI - Circulating Microvesicles Regulate Treg and Th17 Differentiation in Human Autoimmune Thyroid Disorders. AB - BACKGROUND: Microvesicles (MVs) are emerging as important contributors to the development of inflammatory and autoimmune diseases. MVs can mediate immune modulation carrying genetic information, including microRNAs that can be transferred between cells. DESIGN: We determined the plasma levels of annexin-V+ MVs derived from different immune cells and platelets in patients with autoimmune thyroid diseases (AITDs) and in healthy controls. T lymphocyte polarization assays were performed in the presence of MVs to evaluate their effect in T regulatory and T helper 17 cells differentiation. microRNA content into plasma MVs and their corresponding mRNA targets were evaluated by RT-PCR. RESULTS: The percentage of platelet-derived MVs (CD41a+) was significantly increased in plasma samples from AITD patients compared with healthy controls. In contrast, patients with AITD showed a lower percentage of leukocyte and endothelial cell-derived MVs compared with controls. In addition, functional assays showed that MVs from AITD patients inhibited the in vitro differentiation of Foxp3+ T regulatory cells (11.35% vs 4.40%, P = .01) and induced the expression of interferon-gamma by CD4+ lymphocytes (10.91% vs 13.99%, P = .01) as well as the differentiation of T helper 17 pathogenic (IL-17+interferon-gamma+) cells (1.98% vs 5.13%, P = .03). Furthermore, in AITD patients, whereas miR-146a and miR-155 were increased in circulating MVs, their targets IL-8 and SMAD4 were decreased in peripheral blood mononuclear cells. CONCLUSIONS: Our data indicate that circulating MVs seem to have a relevant role in the modulation of the inflammatory response observed in AITD. PMID- 26480287 TI - Application of imaging fusion combining contrast-enhanced ultrasound and magnetic resonance imaging in detection of hepatic cellular carcinomas undetectable by conventional ultrasound. AB - BACKGROUND AND AIM: The aim of this study is to explore the value of volume navigation image fusion-assisted contrast-enhanced ultrasound (CEUS) in detection for radiofrequency ablation guidance of hepatocellular carcinomas (HCCs), which were undetectable on conventional ultrasound. METHODS: From May 2012 to May 2014, 41 patients with 49 HCCs were included in this study. All lesions were detected by dynamic magnetic resonance imaging (MRI) and planned for radiofrequency ablation but were undetectable on conventional ultrasound. After a bolus injection of 2.4 ml SonoVue(r) (Bracco, Italy), LOGIQ E9 ultrasound system with volume navigation system (version R1.0.5, GE Healthcare, Milwaukee, WI, USA) was used to fuse CEUS and MRI images. The fusion time, fusion success rate, lesion enhancement pattern, and detection rate were analyzed. RESULTS: Image fusions were conducted successfully in 49 HCCs, the technical success rate was 100%. The average fusion time was (9.2 +/- 2.1) min (6-12 min). The mean diameter of HCCs was 25.2 +/- 5.3 mm (mean +/- SD), and mean depth was 41.8 +/- 17.2 mm. The detection rate of HCCs using CEUS/MRI imaging fusion (95.9%, 47/49) was significantly higher than CEUS (42.9%, 21/49) (P < 0.05). For small HCCs (diameter, 1-2 cm), the detection rate using imaging fusion (96.9%, 32/33) was also significantly higher than CEUS (18.2%, 6/33) (P < 0.01). All HCCs displayed a rapid wash-in pattern in the arterial phase of CEUS. CONCLUSIONS: Imaging fusion combining CEUS and MRI is a promising technique to improve the detection, precise localization, and accurate diagnosis of undetectable HCCs on conventional ultrasound, especially small and atypical HCCs. PMID- 26480289 TI - Visible-Light Modulation on Lattice Dielectric Responses of a Piezo-Phototronic Soft Material. AB - In situ synchrotron X-ray diffraction is used to investigate a three-way piezo phototronic soft material. This new system is composed of a semi-crystalline poly(vinylidene fluoride-co-trifluoroethylene) piezoelectric polymer and titanium oxide nanoparticles. Under light illumination, photon-induced piezoelectric responses are nearly two times higher at both the lattice-structure and the macroscopic level than under conditions without light illumination. A mechanistic model is proposed. PMID- 26480290 TI - An Observational Study of 2,248 Patients Presenting With Headache, Suggestive of Subarachnoid Hemorrhage, Who Received Lumbar Punctures Following Normal Computed Tomography of the Head. AB - OBJECTIVES: The objective was to determine the incidence of subarachnoid hemorrhage (SAH) diagnosed by lumbar puncture (LP) when the head computed tomography (CT) was reported as demonstrating no subarachnoid blood. METHODS: Data were obtained on patients who received LP to diagnose or exclude SAH attending six hospitals over 5 years. Subsequent investigations and outcomes were reviewed in all patients with LPs that did not exclude SAH. RESULTS: A total of 2,248 patients were included. A total of 1,898 LPs were suitable for biochemical analysis, of which 92 (4.8%) were positive for blood, suggesting SAH; 1,507 (79.4%) were negative; and 299 (15.6%) were inconclusive. Of the 92 patients with positive cerebrospinal fluid analysis, eight patients (0.4%) had aneurysms on further imaging, and one had a carotid cavernous fistula. CONCLUSIONS: In patients presenting to the emergency department with acute severe headache, LP to diagnose or exclude SAH after negative head CT has a very low diagnostic yield, due to low prevalence of the disease and uninterpretable or inconclusive samples. A clinical decision rule may improve diagnostic yield by selecting patients requiring further evaluation with LP following nondiagnostic or normal noncontrast CT brain imaging. PMID- 26480288 TI - Viral activation of stress-regulated Rho-GTPase signaling pathway disrupts sites of mRNA degradation to influence cellular gene expression. AB - Viruses are useful tools that often reveal previously unrecognized levels of control within a cell. By studying the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), we discovered a new signaling axis in endothelial cells (ECs) that links actin cytoskeleton dynamics to post-transcriptional control of gene expression. Translational repression and rapid decay of mRNAs containing AU-rich elements (AREs) occurs in cytoplasmic RNA granules known as processing bodies (PBs). Rho-GTPase activity influences PB dynamics but mechanistic details remain obscure. We have previously shown that the KSHV Kaposin B protein blocks the degradation of ARE-mRNAs that encode potent cytokines and angiogenic factors, at least in part by preventing PB formation. Moreover, Kaposin B is sufficient to cause marked alterations in endothelial cell physiology including the formation of long parallel actin stress fibers and accelerated migration and angiogenic phenotypes. All of these phenotypes depend on Kaposin B-mediated activation of a non-canonical signaling pathway comprising the stress-inducible kinase MK2, hsp27, p115RhoGEF and RhoA. Accelerated endothelial cell migration and angiogenesis depends on the subsequent activation of the RhoA-dependent kinase ROCK, but PB disruption is ROCK-independent. In this Commentary, we discuss implications of the activation of this signaling axis, and propose mechanistic links between RhoA activation and PB dynamics. PMID- 26480291 TI - Improved accuracy and precision of tracer kinetic parameters by joint fitting to variable flip angle and dynamic contrast enhanced MRI data. AB - PURPOSE: To improve the accuracy and precision of tracer kinetic model parameter estimates for use in dynamic contrast enhanced (DCE) MRI studies of solid tumors. THEORY: Quantitative DCE-MRI requires an estimate of precontrast T1 , which is obtained prior to fitting a tracer kinetic model. As T1 mapping and tracer kinetic signal models are both a function of precontrast T1 it was hypothesized that its joint estimation would improve the accuracy and precision of both precontrast T1 and tracer kinetic model parameters. METHODS: Accuracy and/or precision of two-compartment exchange model (2CXM) parameters were evaluated for standard and joint fitting methods in well-controlled synthetic data and for 36 bladder cancer patients. Methods were compared under a number of experimental conditions. RESULTS: In synthetic data, joint estimation led to statistically significant improvements in the accuracy of estimated parameters in 30 of 42 conditions (improvements between 1.8% and 49%). Reduced accuracy was observed in 7 of the remaining 12 conditions. Significant improvements in precision were observed in 35 of 42 conditions (between 4.7% and 50%). In clinical data, significant improvements in precision were observed in 18 of 21 conditions (between 4.6% and 38%). CONCLUSION: Accuracy and precision of DCE-MRI parameter estimates are improved when signal models are fit jointly rather than sequentially. Magn Reson Med 76:1270-1281, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26480293 TI - Quantum theory of concerted electronic and nuclear fluxes associated with adiabatic intramolecular processes. AB - An elementary molecular process can be characterized by the flow of particles (i.e., electrons and nuclei) that compose the system. The flow, in turn, is quantitatively described by the flux (i.e., the time-sequence of maps of the rate of flow of particles though specified surfaces of observation) or, in more detail, by the flux density. The quantum theory of concerted electronic and nuclear fluxes (CENFs) associated with electronically adiabatic intramolecular processes is presented. In particular, it is emphasized how the electronic continuity equation can be employed to circumvent the failure of the Born Oppenheimer approximation, which always predicts a vanishing electronic flux density (EFD). It is also shown that all CENFs accompanying coherent tunnelling between equivalent "reactant" and "product" configurations of isolated molecules are synchronous. The theory is applied to three systems of increasing complexity. The first application is to vibrating, aligned H2(+)((2)Sigmag(+)), or vibrating and dissociating H2(+)((2)Sigmag(+), J = 0, M = 0). The EFD maps manifest a rich and surprising structure in this simplest of systems; for example, they show that the EFD is not necessarily synchronous with the nuclear flux density and can alternate in direction several times over the length of the molecule. The second application is to coherent tunnelling isomerization in the model inorganic system B4, in which all CENFs are synchronous. The contributions of core and valence electrons to the EFD are separately computed and it is found that core electrons flow with the nuclei, whereas the valence electrons flow obliquely to the core electrons in distinctive patterns. The third application is to the Cope rearrangement of semibullvalene, which also involves coherent tunnelling. An especially interesting discovery is that the so-called "pericyclic" electrons do not behave in the manner typically portrayed by the traditional Lewis structures with appended arrows. Indeed, it is found that only about 3 pericyclic electrons flow, in contrast to the 6 predicted by the Lewis picture. It is remarkable that the time scales of these three processes vary by 18 orders of magnitude: femtoseconds (H2(+)((2)Sigmag(+))); picoseconds (B4); kilosceconds (semibullvalene). It is emphasized that results presented herein are appearing in the literature for the first time. PMID- 26480292 TI - Childhood Respiratory Morbidity after Late Preterm and Early Term Delivery: a Study of Medicaid Patients in South Carolina. AB - BACKGROUND: There is a growing body of research documenting an increased risk of neonatal morbidity for late preterm infants (LPI, 34(0/7) weeks to 36(6/7) weeks) and early term infants (ETI, 37(0/7) weeks to 38(6/7) weeks) compared with term infants (TI, 39(0/7) to 41(6/7) ); however, there has been little research on outcomes beyond the first year of life. In this study, we examined respiratory outcomes of LPI and ETI in early childhood. METHODS: South Carolina Medicaid claims data for maternal delivery and infant birth hospitalisations were linked to vital records data for the years 2000 through 2003. Medicaid claims for all infants were then followed until their fifth birthday or until a break in their eligibility. Infants born between 34(0/7) and 41(6/7) weeks were eligible. Infants with congenital anomaly, birthweight below 500 g or above 6000 g, and multiple births were excluded. We fit Cox proportional hazard models from which adjusted hazard ratio (HR) and 95% confidence interval (CI) were derived. RESULTS: A total of 3476 LPI, 12 398 ETI, and 25 975 term infants were included. Both LPI and ETI were associated with an increased risk for asthma (LPI: HR 1.24, 95% CI 1.10, 1.40; ETI: HR 1.12, 95% CI 1.06, 1.19), and bronchitis (LPI: HR 1.15, 95% CI 1.00, 1.34; ETI: HR 1.13, 95% CI 1.05, 1.2) at 3 to 5 years of age. CONCLUSIONS: Late preterm infants and early term infants are at increased risk for asthma and bronchitis. PMID- 26480295 TI - Pentafluorophenyl Ester-based Polymersomes as Nanosized Drug-Delivery Vehicles. AB - In this work, activated ester chemistry is employed to synthesize biocompatible and readily functionalizable polymersomes. Via aminolysis of pentafluorophenyl methacrylate-based precursor polymers, an N-(2-hydroxypropyl) methacrylamide (HPMA)-analog hydrophilic block is obtained. The precursor polymers can be versatile functionalized by simple addition of suitable primary amines during aminolysis as demonstrated using a fluorescent dye. Vesicle formation is proven by cryoTEM and light scattering. High encapsulation efficiencies for hydrophilic cargo like siRNA are achieved using dual centrifugation and safe encapsulation is demonstrated by gel electrophoresis. In vitro studies reveal low cytotoxicity and no protein adsorption-induced aggregation in human blood serum occurs, making the vesicles interesting candidates as nanosized drug carriers. PMID- 26480294 TI - Usefulness of Multi-Parametric MRI for the Investigation of Posterior Cortical Atrophy. AB - BACKGROUND: Posterior Cortical Atrophy (PCA) is a neurodegenerative disease characterized by a progressive decline in selective cognitive functions anatomically referred to occipital, parietal and temporal brain regions, whose diagnosis is rather challenging for clinicians. The aim of this study was to assess, using quantitative Magnetic Resonance Imaging techniques, the pattern of regional grey matter loss and metabolism in individuals with PCA to improve pathophysiological comprehension and diagnostic confidence. METHODS: We enrolled 5 patients with PCA and 5 matched controls who all underwent magnetic resonance imaging (MRI) and spectroscopy (MRS). Patients also underwent neuropsychological and cerebrospinal fluid (CSF) assessments. MRI data were used for unbiased assessment of regional grey matter loss in PCA patients compared to controls. MRS data were obtained from a set of brain regions, including the occipital lobe and the centrum semiovale bilaterally, and the posterior and anterior cingulate. RESULTS: VBM analysis documented the presence of focal brain atrophy in the occipital lobes and in the posterior parietal and temporal lobes bilaterally but more pronounced on the right hemisphere. MRS revealed, in the occipital lobes and in the posterior cingulate cortex of PCA patients, reduced levels of N-Acetyl Aspartate (NAA, a marker of neurodegeneration) and increased levels of Myo Inositol (Ins, a glial marker), with no hemispheric lateralization. CONCLUSION: The bilateral but asymmetric pattern of regional grey matter loss is consistent with patients' clinical and neuropsychological features and with previous literature. The MRS findings reveal different stages of neurodegeneration (neuronal loss; gliosis), which coexist and likely precede the occurrence of brain tissue loss, and might represent early biomarkers. In conclusion, this study indicates the potential usefulness of a multi-parametric MRI approach for an early diagnosis and staging of patients with PCA. PMID- 26480296 TI - Ligament of the head of femur: A comprehensive review of its anatomy, embryology, and potential function. AB - The functional significance of the ligament of the head of femur (LHF), or ligamentum teres has often been debated. Having gained recent attention in clinical practice, it is suggested to partly provide some mechanical stability to the hip joint. However, the anatomy of this ligament is not well studied. This paper systematically reviews the anatomy of the LHF with the aim of exploring our current understanding of this structure and identifying any gaps in knowledge regarding its morphology and function. A systematic search of Medline, Embase, ProQuest, Web of Science, and Scopus databases was undertaken and relevant data extracted, analyzed. A total of 69 references were obtained, that included 53 full text articles, three published abstracts, and 13 textbooks. Many publications related to clinical studies (n = 11) rather than gross anatomy (n = 7), with one report on variation of the LHF. Considerable inconsistency in the naming and description of the LHF morphology was observed. Variable attachment sites were reported except for the acetabular notch, transverse acetabular ligament, and the femoral fovea. Presence and patency of the ligamental arteries supplying the head of the femur and their exact location were variably described and were often incomplete. The LHF is believed to be taught in extreme hip adduction, but there is little evidence to support this. In conclusions, further investigation of the anatomy of the LHF is recommended, particularly to clarify its mechanical role, innervation, and vascular contribution to the developing and adult femur, so to better inform clinical practice. PMID- 26480297 TI - Modulation of 17beta-Estradiol Signaling on Cellular Proliferation by Caveolin-2. AB - The sex hormone 17beta-estradiol (E2) exerts pleiotropic effects by binding to the ligand-activated transcription factor estrogen receptor alpha (ERalpha). The E2:ERalpha complex regulates several physiological processes, including cell survival and proliferation, through transcriptional effects (i.e., estrogen responsive element [ERE]-based gene transcription) and non-transcriptional membrane-initiated effects (i.e., the activation of extra-nuclear signaling cascades), which derive from the activation of the pool of ERalpha that is localized to plasma membrane caveolae. Caveolae are omega-shaped membrane sub domains that are composed of scaffold proteins named caveolins (i.e., caveolin-1, caveolin-2, and caveolin-3). Although caveolin-3 is exclusively expressed in muscles, caveolin-1 and caveolin-2 are co-expressed in all human tissues. From a functional point of view, caveolin-2 can operate both dependently on and independently of caveolin-1, which is the main coat component of caveolae. Interestingly, while a functional interplay between caveolin-1 and ERalpha has been reported in the control of E2-induced physiological effects, the role of caveolin-2 in E2:ERalpha signaling within the cell remains poorly understood. This study shows that siRNA-mediated caveolin-2 depletion in breast ductal carcinoma cells (MCF-7) reduces E2-induced ERalpha phosphorylation at serine residue 118 (S118), controls intracellular receptor levels, precludes ERalpha mediated extra-nuclear activation of signaling pathways, reduces ERalpha transcriptional activity, and prevents cellular proliferation. Meanwhile, the impact of caveolin-1 depletion on ERalpha signaling in MCF-7 cells is shown to be similar to that elicited by siRNA-mediated caveolin-2 depletion. Altogether, these data demonstrate that caveolin-2 expression is necessary for the control of E2-dependent cellular proliferation. PMID- 26480298 TI - Cytosolically expressed PrP GPI-signal peptide interacts with mitochondria. AB - We previously reported that PrP GPI-anchor signal peptide (GPI-SP) is specifically degraded by the proteasome. Additionally, we showed that the point mutation P238S, responsible for a genetic form of prion diseases, while not affecting the GPI-anchoring process, results in the accumulation of PrP GPI-SP, suggesting the possibility that PrP GPI-anchor signal peptide could play a role in neurodegenerative prion diseases. We now show that PrP GPI-SP, when expressed as a cytosolic peptide, is able to localize to the mitochondria and to induce mitochondrial fragmentation and vacuolarization, followed by loss in mitochondrial membrane potential, ultimately resulting in apoptosis. Our results identify the GPI-SP of PrP as a novel candidate responsible for the impairment in mitochondrial function involved in the synaptic pathology observed in prion diseases, establishing a link between PrP GPI-SP accumulation and neuronal death. PMID- 26480300 TI - Sympathetic activation in cardiovascular disease: evidence, clinical impact and therapeutic implications. AB - BACKGROUND: The sympathetic nervous exerts a key role in cardiovascular homeostasis control by regulating cardiac output, systemic vascular resistance, heart rate and blood pressure. MATERIALS AND METHODS: Data collected during the past 30 years have unequivocally shown that in a considerable number of cardiovascular as well as noncardiovascular disease there is a marked activation of the sympathetic nervous system which exerts in the long-term period unfavourable haemodynamic, metabolic, cardiovascular and renal effects. RESULTS: This paper will review the current knowledge on the alterations in sympathetic function described in cardiovascular disease, with particular focus on hypertension, heart failure and myocardial infarction. CONCLUSIONS: The consequences of the phoenomenon will be discussed together with its therapeutic implications. This will be done by examining the impact of nonpharmacological as well as pharmacological interventions on sympathetic cardiovascular drive. The effects of new invasive approaches, such as carotid baroreceptor stimulation as well as renal nerves ablation, will be also briefly discussed. PMID- 26480299 TI - Whole-exome Sequence Analysis Implicates Rare Il17REL Variants in Familial and Sporadic Inflammatory Bowel Disease. AB - BACKGROUND: Rare variants (<1%) likely contribute significantly to risk for common diseases such as inflammatory bowel disease (IBD) in specific patient subsets, such as those with high familiality. They are, however, extraordinarily challenging to identify. METHODS: To discover candidate rare variants associated with IBD, we performed whole-exome sequencing on 6 members of a pediatric-onset IBD family with multiple affected individuals. To determine whether the variants discovered in this family are also associated with nonfamilial IBD, we investigated their influence on disease in 2 large case-control (CC) series. RESULTS: We identified 2 rare variants, rs142430606 and rs200958270, both in the established IBD-susceptibility gene IL17REL, carried by all 4 affected family members and their obligate carrier parents. We then demonstrated that both variants are associated with sporadic ulcerative colitis (UC) in 2 independent data sets. For UC in CC 1: rs142430606 (odds ratio [OR] = 2.99, Padj = 0.028; minor allele frequency [MAF]cases = 0.0063, MAFcontrols = 0.0021); rs200958270 (OR = 2.61, Padj = 0.082; MAFcases = 0.0045, MAFcontrols = 0.0017). For UC in CC 2: rs142430606 (OR = 1.94, P = 0.0056; MAFcases = 0.0071, MAFcontrols = 0.0045); rs200958270 (OR = 2.08, P = 0.0028; MAFcases = 0.0071, MAFcontrols = 0.0042). CONCLUSIONS: We discover in a family and replicate in 2 CC data sets 2 rare susceptibility variants for IBD, both in IL17REL. Our results illustrate that whole-exome sequencing performed on disease-enriched families to guide association testing can be an efficient strategy for the discovery of rare disease-associated variants. We speculate that rare variants identified in families and confirmed in the general population may be important modifiers of disease risk for patients with a family history, and that genetic testing of these variants may be warranted in this patient subset. PMID- 26480301 TI - Lipid disequilibrium in biological membranes, a possible pathway to neurodegeneration. AB - We recently reported that knocking down the enzyme phosphatidylserine decarboxylase, which synthesizes the phospholipid phosphatidylethanolamine (PE) in mitochondria, perturbs the homeostasis of the human Parkinson disease (PD) protein alpha-synuclein (expressed in yeast or worms). In yeast, low PE in the psd1Delta deletion mutant induces alpha-synuclein to enter cytoplasmic foci, the level of this protein increases 3-fold compared to wild-type cells, and the mutant cells are severely sick. The metabolite ethanolamine protects both yeast and worms from the deleterious synergistic effects of low mitochondrial PE and alpha-synuclein. Here we highlight a Drosophila mutant called easily shocked thought to be a model of epilepsy-that cannot use ethanolamine to synthesize PE. We also highlight recently identified mutated genes associated with defective lipid metabolism in PD and epilepsy patients. We propose that disruptions in lipid homeostasis (synthesis and degradation) may be responsible for some cases of PD and epilepsy. PMID- 26480302 TI - E-learning, dual-task, and cognitive load: The anatomy of a failed experiment. AB - The rising popularity of commercial anatomy e-learning tools has been sustained, in part, due to increased annual enrollment and a reduction in laboratory hours across educational institutions. While e-learning tools continue to gain popularity, the research methodologies used to investigate their impact on learning remain imprecise. As new user interfaces are introduced, it is critical to understand how functionality can influence the load placed on a student's memory resources, also known as cognitive load. To study cognitive load, a dual task paradigm wherein a learner performs two tasks simultaneously is often used, however, its application within educational research remains uncommon. Using previous paradigms as a guide, a dual-task methodology was developed to assess the cognitive load imposed by two commercial anatomical e-learning tools. Results indicate that the standard dual-task paradigm, as described in the literature, is insensitive to the cognitive load disparities across e-learning tool interfaces. Confounding variables included automation of responses, task performance tradeoff, and poor understanding of primary task cognitive load requirements, leading to unreliable quantitative results. By modifying the secondary task from a basic visual response to a more cognitively demanding task, such as a modified Stroop test, the automation of secondary task responses can be reduced. Furthermore, by recording baseline measures for the primary task as well as the secondary task, it is possible for task performance tradeoff to be detected. Lastly, it is imperative that the cognitive load of the primary task be designed such that it does not overwhelm the individual's ability to learn new material. PMID- 26480303 TI - Liver injury-on-a-chip: microfluidic co-cultures with integrated biosensors for monitoring liver cell signaling during injury. AB - Tissue injury triggers complex communication between cells via secreted signaling molecules such as cytokines and growth factors. Discerning when and where these signals begin and how they propagate over time is very challenging with existing cell culture and analysis tools. The goal of this study was to develop new tools in the form of microfluidic co-cultures with integrated biosensors for local and continuous monitoring of secreted signals. Specifically, we focused on how alcohol injury affects TGF-beta signaling between two liver cell types, hepatocytes and stellate cells. Activation of stellate cells happens early during liver injury and is at the center of liver fibrosis. We demonstrated that alcohol injury to microfluidic co-cultures caused significantly higher levels of stellate cell activation compared to conditioned media and transwell injury experiments. This highlighted the advantage of the microfluidic co-culture: placement of two cell types in close proximity to ensure high local concentrations of injury promoting secreted signals. Next, we developed a microsystem consisting of five chambers, two for co-culturing hepatocytes with stellate cells and three additional chambers containing miniature aptamer-modified electrodes for monitoring secreted TGF-beta. Importantly, the walls separating microfluidic chambers were actuatable; they could be raised or lowered to create different configurations of the device. The use of reconfigurable microfluidics and miniature biosensors revealed that alcohol injury causes hepatocytes to secrete TGF-beta molecules, which diffuse over to neighboring stellate cells and trigger production of additional TGF-beta from stellate cells. Our results lend credence to the emerging view of hepatocytes as active participants of liver injury. Broadly speaking, our microsystem makes it possible to monitor paracrine crosstalk between two cell types communicating via the same signaling molecule (e.g. TGF-beta). PMID- 26480304 TI - Skincare products containing low concentrations of formaldehyde detected by the chromotropic acid method cannot be safely used in formaldehyde-allergic patients. AB - BACKGROUND: Formaldehyde is a well-known contact sensitizer. Formaldehyde releasers are widely used preservatives in skincare products. It has been found that formaldehyde at concentrations allowed by the European Cosmetics Directive can cause allergic contact dermatitis. However, we still lack information on whether formaldehyde at low concentrations affects dermatitis in formaldehyde allergic individuals. OBJECTIVES: To study the effects of low concentrations of formaldehyde on irritant contact dermatitis in formaldehyde-allergic individuals. METHODS: Fifteen formaldehyde-allergic individuals and a control group of 12 individuals without contact allergy to formaldehyde and formaldehyde releasers were included in the study. The individuals performed the repeated open application test (ROAT) during 4 weeks with four different moisturizers releasing formaldehyde in concentrations that had been determined as > 40, 20-40, 2.5-10 and 0 p.p.m. by the chromotropic acid (CA) spot test. Dimethyloldimethylhydantoin was used as a formaldehyde releaser in the moisturizers. The ROAT was performed on areas of experimentally induced sodium lauryl sulfate dermatitis. The study was double blind, controlled and randomized. RESULTS: Nine of the 15 formaldehyde allergic individuals had reappearance or worsening of dermatitis on the areas that were treated with moisturizers containing formaldehyde. No such reactions were observed in the control group (P < 0.001) or for the moisturizers without formaldehyde in the formaldehyde-allergic individuals (P < 0.001). CONCLUSIONS: Our results demonstrate that the low concentrations of formaldehyde often found in skincare products by the CA method are sufficient to worsen an existing dermatitis in formaldehyde-allergic individuals. PMID- 26480305 TI - Summary of the 2nd International Symposium on Arthrogryposis, St. Petersburg, Russia, September 17-19, 2014. PMID- 26480306 TI - Resolution of refractory hypotension and anuria in a premature newborn with loss of-function of ACE. PMID- 26480307 TI - Mutation spectrum of COL1A1 and COL1A2 genes in Indian patients with osteogenesis imperfecta. PMID- 26480310 TI - Informed consent required for federally funded studies on bloodspots. PMID- 26480311 TI - Research sheds light on gene expression differences in 22q11.2 deletion syndrome. PMID- 26480313 TI - Does Further Education in Adulthood Improve Physical and Mental Health among Australian Women? A Longitudinal Study. AB - OBJECTIVE: We analyzed whether further education in young adult and mid-life [adult educational mobility] influences physical functioning and depressive symptoms in women. METHODS: 14247 women born 1973-78 (younger cohort) and 13715 women born 1946-51 (mid-aged cohort) from the Australian Longitudinal Study on Women's Health were followed for 14-16 years. Measures were the Short-Form 36 Health Survey physical functioning subscale (SF-36 PF) and Centre for Epidemiologic Studies 10-item Depression Scale (CESD-10). Linear mixed modelling, accounting for time varying covariates, assessed the influence of further education on physical functioning and depressive symptoms over time. Sensitivity analysis to assess the impact of missing data was conducted using multiple imputation. RESULTS: Compared to younger women with a pre-existing high level of education, women gaining further education (up to age 39 years) from low levels had lower SF-36 PF scores (poorer physical functioning) (fully adjusted beta estimates (95%CIs) -1.52 (-2.59, -0.44)) while those gaining further education from middle to high levels showed equivalent SF-36 PF scores (-0.08 (-0.61, 0.44)). A similar pattern was shown for CESD-10 scores (0.78 (0.29, 1.25); -0.02 (-0.26, 0.21), respectively) where higher scores represented more depressive symptoms. For mid-age women, further education from a middle to high level resulted in equivalent SF-36 PF scores (-0.61 (-1.93,0.71)) but higher CESD-10 scores (0.49 (0.11, 0.86)), compared to highly educated women. CONCLUSION: Women who delay further education until they are aged between their 40s and 60s can improve or maintain their physical functioning but may have missed the critical time to minimise depressive symptomatology. Public health policy should focus on encouraging women to upgrade their educational qualifications earlier in life in order to potentially offset the negative associations between their initial lower socio-economic position class of origin and their mental health. PMID- 26480314 TI - Public Attitudes toward Animal Research: A Review. AB - The exploration of public attitudes toward animal research is important given recent developments in animal research (e.g., increasing creation and use of genetically modified animals, and plans for progress in areas such as personalized medicine), and the shifting relationship between science and society (i.e., a move toward the democratization of science). As such, public engagement on issues related to animal research, including exploration of public attitudes, provides a means of achieving socially acceptable scientific practice and oversight through an understanding of societal values and concerns. Numerous studies have been conducted to explore public attitudes toward animal use, and more specifically the use of animals in research. This paper reviews relevant literature using three categories of influential factors: personal and cultural characteristics, animal characteristics, and research characteristics. A critique is given of survey style methods used to collect data on public attitudes, and recommendations are given on how best to address current gaps in public attitudes literature. PMID- 26480315 TI - Large Dog Relinquishment to Two Municipal Facilities in New York City and Washington, D.C.: Identifying Targets for Intervention. AB - While the overall trend in euthanasia has been decreasing nationally, large dogs are at a higher risk of euthanasia than other sized dogs in most animal shelters in the United States. We hypothesized one way to increase the lives saved with respect to these large dogs is to keep them home when possible. In order to develop solutions to decrease relinquishment, a survey was developed to learn more about the reasons owners relinquish large dogs. The survey was administered to owners relinquishing their dogs at two large municipal facilities, one in New York City and one in Washington, D.C. There were 157 responses between the two facilities. We found both significant similarities and differences between respondents and their dogs from the two cities. We identified opportunities to potentially support future relinquishers and found that targets for interventions are likely different in each community. PMID- 26480316 TI - Emerging and Re-Emerging Zoonoses of Dogs and Cats. AB - Since the middle of the 20th century, pets are more frequently considered as "family members" within households. However, cats and dogs still can be a source of human infection by various zoonotic pathogens. Among emerging or re-emerging zoonoses, viral diseases, such as rabies (mainly from dog pet trade or travel abroad), but also feline cowpox and newly recognized noroviruses or rotaviruses or influenza viruses can sicken our pets and be transmitted to humans. Bacterial zoonoses include bacteria transmitted by bites or scratches, such as pasteurellosis or cat scratch disease, leading to severe clinical manifestations in people because of their age or immune status and also because of our closeness, not to say intimacy, with our pets. Cutaneous contamination with methicillin-resistant Staphylococcus aureus, Leptospira spp., and/or aerosolization of bacteria causing tuberculosis or kennel cough are also emerging/re-emerging pathogens that can be transmitted by our pets, as well as gastro-intestinal pathogens such as Salmonella or Campylobacter. Parasitic and fungal pathogens, such as echinococcosis, leishmaniasis, onchocercosis, or sporotrichosis, are also re-emerging or emerging pet related zoonoses. Common sense and good personal and pet hygiene are the key elements to prevent such a risk of zoonotic infection. PMID- 26480317 TI - A Prototype Tool to Enable Farmers to Measure and Improve the Welfare Performance of the Farm Animal Enterprise: The Unified Field Index. AB - Schemes for the assessment of farm animal welfare and assurance of welfare standards have proliferated in recent years. An acknowledged short-coming has been the lack of impact of these schemes on the welfare standards achieved on farm due in part to sociological factors concerning their implementation. Here we propose the concept of welfare performance based on a broad set of performance attributes of an enterprise and describe a tool based on risk assessment and benchmarking methods for measuring and managing welfare performance. The tool termed the Unified Field Index is presented in a general form comprising three modules addressing animal, resource, and management factors. Domains within these modules accommodate the principle conceptual perspectives for welfare assessment: biological functioning; emotional states; and naturalness. Pan-enterprise analysis in any livestock sector could be used to benchmark welfare performance of individual enterprises and also provide statistics of welfare performance for the livestock sector. An advantage of this concept of welfare performance is its use of continuous scales of measurement rather than traditional pass/fail measures. Through the feedback provided via benchmarking, the tool should help farmers better engage in on-going improvement of farm practices that affect animal welfare. PMID- 26480318 TI - Productive and Economic Responses in Grazing Dairy Cows to Grain Supplementation on Family Farms in the South of Brazil. AB - Pasture-based dairy production has been a major source of income for most family farms in the south of Brazil. Increasing milk prices have spurred an increase in grain supplementation, which has been poorly implemented, resulting in low levels of efficiency. To evaluate the consequences of supplementation on milk production and composition, grazing behavior and economic return, the widely used grain management system (CC-commercial concentrate, containing 21% CP, offered at 1 kg per 3.7 L of milk) was compared with an energy supplement (GC-ground corn, with 9.5% CP, offered at 0.4% of live weight). Ten Holstein cows were paired into two groups, and subjected to the two treatments in a crossover design. The cows remained in the same grazing group, and the grain supplement was offered individually at milking time and consumed completely. Each experimental period lasted 14 days, with 10 days for diet adaptation and four days for data collection; individual milk production and samples were collected to determine levels of fat, protein, lactose, carotenoids, vitamin A and N-urea. Grazing behavior was observed (scans every 5 min) in the first 4 h after the morning milking, and chemical composition of hand plucked samples of forage were measured. The cost of the supplement and profitability per treatment were calculated. Cows supplemented with GC consumed herbage with higher crude protein (CP: 16.23 vs. 14.62%; p < 0.05), had higher biting rate (44.21 vs. 39.54 bites/min; p < 0.03) and grazing time (22.20 vs. 20.55 scans; p < 0.05) than when receiving CC. There were no differences in milk composition between treatments (p > 0.05). However, higher concentrations of beta-carotene and total carotenoids were detected in the milk of cows at 70-164 days of lactation, compared to <70 days of lactation (p < 0.05). Milk production was higher (13.19 vs. 11.59 kg/day; p < 0.05) when cows consumed CC, but resulted in lower profitability compared to GC (US$ 4.39 vs. US$ 4.83/cow per day). Our results show that higher productivity does not necessarily improve profitability. Cows receiving supplement with lower levels of protein were able to adjust their grazing behavior to meet their protein needs and this level of diet modification did not alter milk composition. PMID- 26480319 TI - Establishing Bedding Requirements on Trailers Transporting Market Weight Pigs in Warm Weather. AB - During warm weather, incorrect bedding levels on a trailer transporting market weight pigs may result in heat stress, fatigue, and death. Two experiments were conducted in June and July of 2011; Experiment 1 used 80 loads (n = 13,887 pigs) to determine the effects of two bedding levels (3 (68.1 kg) or 6 bags (136.2 kg) of wood shavings/trailer [each bag contained 22.7 kg, 0.2 m3]) on pig measures (surface temperature, vocalizations, slips and falls, and stress signs). Experiment 2 used 131 loads (n = 22,917 pigs) to determine the effects of bedding (3 vs. 6 bags) on transport losses (dead, sum of dead- and euthanized- on arrival; non-ambulatory, sum of fatigued and injured; total transport losses sum of dead and non-ambulatory). Bedding did not affect surface temperature, vocalizations, or slips and falls (p = 0.58, p = 0.50, and p = 0.28, respectively). However, pigs transported on 6 bags/trailer had 1.5% more stress signs than pigs transported on 3 bags/trailer (p < 0.01). No differences were observed between bedding levels for non-ambulatory, dead, or total transport losses (p = 0.10, p = 0.67, and p = 0.34, respectively). Within the context of these experiments, bedding level did not result in deleterious effects on pig measures or transport losses. However, using more bedding may result in higher costs to the industry. Therefore, 3 bags of bedding/trailer may be used when transporting market weight pigs during warm weather in the Midwestern U.S. PMID- 26480320 TI - Pain Management for Animals Used in Science: Views of Scientists and Veterinarians in Canada. AB - To explore the challenges and opportunities for pain management for animals used in research an interview study with 9 veterinarians, 3 veterinarian-scientists and 9 scientists, all engaged in animal-based studies in Canada, was carried out. Our broader aim was to contribute to further discussion of how pain can be minimized for animals used in science. Diverse views were identified regarding the ease of recognizing when animals are in pain and whether animals hide pain. Evidence of inconsistencies in pain management across laboratories, institutions and species were also identified. Clarification of the interactions between scientific objectives and pain management are needed, as well as a stronger evidence base for pain management approaches. Detailed examination of pain management for individual invasive animal models may be useful, and may support the development of model-specific pain management protocols. PMID- 26480321 TI - Establishing Trailer Ventilation (Boarding) Requirements for Finishing Pigs during Transport. AB - Specifically, this study aimed to establish the effects on mortality and morbidity of boarding levels (amount of side-wall trailer ventilation) for finishing pigs in mild weather (8.80 +/- 0.30 degrees C, 71.70% +/- 1.12% humidity). Pigs from commercial finishing sites were transported in 302 pot bellied trailers to commercial processing plants. Measures collected at the processing plant were rates of dead on arrival (DOA), non-ambulatory, non-injured (NANI), non-ambulatory, injured (NAI), and total dead and down (D&D). Boarding levels (% that side walls were closed off with inserted boards) were divided into 3 bins: low, medium, and high, and outside temperature was divided into 4 bins <5 degrees C, 5.10-10 degrees C, and 10.10-15 degrees C and >15 degrees C. Average rates of DOA, NANI, NAI, and D&D were approximately 0.30%, 0.12%, 0.04%, and 0.46%, respectively. The D&D was highest when boarding level was low with temperatures <5 degrees C (p < 0.05). However, variations in boarding level (medium and high boarding) in the temperature range of 5.10 degrees C to 23.30 degrees C did not affect pig losses. PMID- 26480322 TI - Effect of Transport Distance and Season on Some Defects of Fresh Hams Destined for DPO Production. AB - Pre-slaughter handling is related to defects in fresh hams that result in exclusion from the DPO Parma chain, including hematomas, lacerations, microhaemorrhages and veining. To determine the effects of transport conditions on hams, we collected data on defects in 901,990 trimmed fresh hams from heavy pigs provided by 3,650 batches from slaughterhouse during 2012 and 2013. For all batches, transport distance (1-276 km) season and year of delivery were considered. A decrease of all defect occurrences was observed for increasing distance up to 170 km (P < 0.05). Above 170 km, however, all defects frequencies increased (P < 0.05). Season showed an effect on the incidence of defects, with an increasing of hematomas and lacerations in winter and autumn respectively (P < 0.05) and the highest percentage of veining and hemorrhages in spring (P < 0.05). Summer had the lowest incidence of defects on fresh hams. We concluded that the incidence of the examined defects and the subsequent rejection for DPO Parma ham production is lower in fresh hams transported 38-170 km during the summer. PMID- 26480323 TI - The Effects of Using a Ramp and Elevator to Load and Unload Trailers on the Behavior and Physiology of Piglets. AB - Transport is an inevitable process in the modern U.S. swine industry. The loading process is a novel and potentially stressful experience. This study uses behavior, heart rate and leukocyte counts to compare stress one hour before, during and after loading via ramp or elevator. Piglets were held in a home pen (control (CON)), walked up and down an aisle (handled (HAN)), or walked to a truck and loaded via elevator (ELE) or ramp (RAM). Sitting, feeding and blood parameters did not show a significant treatment by time effect (p > 0.05). Standing behavior did not differ between CON and HAN piglets nor between RAM and ELE piglets (p > 0.05); however, CON and HAN piglets stood more than RAM and ELE piglets during treatment (p < 0.05). After treatment, drinking behavior was increased in RAM piglets (p < 0.05). The heart rate of ELE piglets decreased 6.3% after treatment; whereas the heart rate of RAM piglets remained elevated 2.4% (p < 0.05). In terms of heart rate, loading by elevator appears to be less stressful than loading by ramp. PMID- 26480324 TI - Park Rangers' Behaviors and Their Effects on Tourists and Tibetan Macaques (Macaca thibetana) at Mt. Huangshan, China. AB - Previous studies have reported the negative impacts of tourism on nonhuman primates (NHPs) and tourists and advocated the improvement of tourism management, yet what constitutes good quality management remains unclear. We explored whether rates of macaque aggression and self-directed behaviors (SDBs) differed under the supervision of two park ranger teams at the Valley of the Wild Monkeys (VWM) in Mt. Huangshan, Anhui Province, China. The two ranger teams provisioned and managed a group of macaques on an alternating monthly basis. Monkey, tourist and ranger behaviors were collected from August 16-September 30, 2012. Macaque aggression and SDB rates did not differ significantly under the management of the two teams. Overall, there was little intervention in tourist-macaque interactions by park rangers, and even when rangers discouraged tourists' undesirable behaviors, tourist interactions with monkeys persisted. Furthermore, only one or sometimes two park rangers managed monkeys and tourists, and rangers established dominance over the monkeys to control them. In order to effectively manage tourists and monkeys by a single park ranger, we recommend that rangers: (1) prohibit tourists from feeding; (2) move around the viewing platform more frequently; and (3) limit the number of tourists each visiting session. PMID- 26480325 TI - A Reproductive Management Program for an Urban Population of Eastern Grey Kangaroos (Macropus giganteus). AB - Traditionally, culling has been the expedient, most common, and in many cases, the only tool used to control free-ranging kangaroo populations. We applied a reproductive control program to a population of eastern grey kangaroos confined to a golf course in South East Queensland. The program aimed to reduce fecundity sufficiently for the population to decrease over time so that overgrazing of the fairways and the frequency of human-animal conflict situations were minimised. In 2003, 92% of the female kangaroos above 5 kg bodyweight were implanted with the GnRH agonist deslorelin after darting with a dissociative anaesthetic. In 2007, 86% of the females above 5 kg were implanted with deslorelin and also 87% of the males above 5 kg were sterilised by either orchidectomy or vasectomy. In 2005, 2008 and 2009, the population was censused to assess the effect of each treatment. The 2003 deslorelin program resulted in effective zero population growth for approximately 2.5 years. The combined deslorelin-surgery program in 2007 reduced the birth rate from 0.3 to 0.06%/year for 16 months, resulting in a 27% population reduction by November 2009. The results were consistent with implants conferring contraception to 100% of implanted females for at least 12 months. The iatrogenic mortality rates for each program were 10.5% and 4.9%, respectively, with 50% of all mortalities due to darting-related injuries, exertional myopathy/hyperthermia or recovery misadventure. The short term sexual and agonistic behaviour of the males was assessed for the 2007 program: no significant changes were seen in adult males given the vasectomy procedure, while sexual behaviours' were decreased in adult males given the orchidectomy procedure. It is concluded that female reproduction was effectively controlled by implantation with deslorrelin and male reproductive behaviour was reduced by orchidectomy, which together achieved population control. PMID- 26480327 TI - 50 Years Ago ... PMID- 26480330 TI - Copper-Catalyzed Formation of alpha-Alkoxycycloalkenones from N-Tosylhydrazones. AB - The combination of 20 mol % of copper iodide and lithium tert-butoxide triggers the formation of a broad range of substituted, functionalized alpha-alkoxy 2H naphthalenones from readily available N-tosylhydrazones. The data suggests that this transformation occurs through cycloaddition of a copper carbenoid with an ester, followed by a Lewis acid-catalyzed [1,2] alkyl shift of the in situ generated alkoxyepoxide intermediate. PMID- 26480329 TI - Divergent Reactivity of Rhodium(I) Carbenes Derived from Indole Annulations. AB - Rhodium(I) carbenes were generated from propargylic alcohol derivatives as the result of a dehydrative indole annulation. Depending on the choice of the electron-withdrawing group on the aniline nitrogen nucleophile, either a cyclopropanation product or dimerization product was obtained chemoselectively. Intramolecular hydroamidation occurred for the same type of propargylic alcohol derivatives when other transition-metal catalysts were employed. PMID- 26480326 TI - Initiation of universal tumor screening for Lynch syndrome in colorectal cancer patients as a model for the implementation of genetic information into clinical oncology practice. AB - BACKGROUND: Lynch syndrome confers a hereditary predisposition to colorectal and other cancers. Universal tumor screening (UTS) for Lynch syndrome is recommended by several professional societies, but the implementation can be complex. This article describes the evaluation, process development, and initiation of Lynch syndrome UTS at a tertiary referral cancer center. METHODS: A multidisciplinary team developed the new process design. Issues in 5 themes were noted: timing, funding, second-opinion patients, result processing, and the role of genetics providers. A committee approach was used to examine each issue for process improvement development. RESULTS: The issues related to testing were addressed individually for the successful implementation of UTS at the institutional level. In the conventional-care period, 9 of 30 cases (30%) received Lynch syndrome screening, and 4 cases were referred to medical genetics. During the 6 months following the implementation of UTS, 32 of 44 patients (73%) received Lynch syndrome screening. The 13 unscreened patients all had identified reasons for nonscreening (eg, financial limitations). Ten patients were referred to medical genetics, which identified no new cases of Lynch syndrome, but a low-risk adenomatous polyposis coli (APC) variant was detected in 1 individual. CONCLUSIONS: The implementation of effective Lynch syndrome UTS can feasibly alter practice at the institutional level. This experience with the assessment and management of issues relevant to the successful implementation of a new clinical care paradigm based on emerging technology has implications for the uptake of advances across molecular oncology into clinical practice, and this is highly relevant in the current era of rapidly evolving genomic technology. PMID- 26480331 TI - Radical Formation in the Gas-Phase Ozonolysis of Deprotonated Cysteine. AB - Although the deleterious effects of ozone on the human respiratory system are well-known, many of the precise chemical mechanisms that both cause damage and afford protection in the pulmonary epithelial lining fluid are poorly understood. As a key first step to elucidating the intrinsic reactivity of ozone with proteins, its reactions with deprotonated cysteine [Cys-H](-) are examined in the gas phase. Reaction proceeds at near the collision limit to give a rich set of products including 1) sequential oxygen atom abstraction reactions to yield cysteine sulfenate, sulfinate and sulfonate anions, and significantly 2) sulfenate radical anions formed by ejection of a hydroperoxy radical. The free radical pathway occurs only when both thiol and carboxylate moieties are available, implicating electron-transfer as a key step in this reaction. This novel and facile reaction is also observed in small cys-containing peptides indicating a possible role for this chemistry in protein ozonolysis. PMID- 26480332 TI - Synthesis and Thermal Behavior of a Fused, Tricyclic 1,2,3,4-Tetrazine Ring System. AB - This study presents the synthesis and characterization of a fused, tricyclic 1,2,3,4-tetrazine ring system. The molecule is synthesized in a three-step process from 5,5'-dinitro-bis,1,2,4-triazole via a di-N-amino compound. Oxidation to form the azo-coupled fused tricyclic 1,2,3,4-tetrazine is achieved using tert butyl hypochlorite as the oxidant. The di-N-amino compound and the desired fused tricyclic 1,2,3,4-triazine display interesting thermal behavior and are predicted to be high-performance energetic materials. PMID- 26480333 TI - Reversible Photoswitching of a Spin-Crossover Molecular Complex in the Solid State at Room Temperature. AB - Spin-crossover metal complexes are highly promising magnetic molecular switches for prospective molecule-based devices. The spin-crossover molecular photoswitches developed so far operate either at very low temperatures or in the liquid phase, which hinders practical applications. Herein, we present a molecular spin-crossover iron(II) complex that can be switched between paramagnetic high-spin and diamagnetic low-spin states with light at room temperature in the solid state. The reversible photoswitching is induced by alternating irradiation with ultraviolet and visible light and proceeds at the molecular level. PMID- 26480334 TI - A Low-Valent Iron Imido Heterocubane Cluster: Reversible Electron Transfer and Catalysis of Selective C-C Couplings. AB - Enzymes and cofactors with iron-sulfur heterocubane core structures, [Fe4 S4 ], are often found in nature as electron transfer reagents in fundamental catalytic transformations. An artificial heterocubane with a [Fe4 N4 ] core is reported that can reversibly store up to four electrons at very negative potentials. The neutral [Fe4 N4 ] and the singly reduced low-valent [Fe4 N4 ](-) heterocubanes were isolated and fully characterized. The low-valent species bears one unpaired electron, which is localized predominantly at one iron center in the electronic ground state but fluctuates with increasing temperatures. The electrons stored or released by the [Fe4 N4 ]/[Fe4 N4 ](-) redox couple can be used in reductive or oxidative C?C couplings and even allow catalytic one-pot reactions, which show a remarkably enhanced selectivity in the presence of the [Fe4 N4 ] heterocubanes. PMID- 26480335 TI - Towards Structural-Functional Mimics of Acetylene Hydratase: Reversible Activation of Acetylene using a Biomimetic Tungsten Complex. AB - The synthesis and characterization of a biomimetic system that can reversibly bind acetylene (ethyne) is reported. The system has been designed to mimic catalytic intermediates of the tungstoenzyme acetylene hydratase. The thiophenyloxazoline ligand S-Phoz (2-(4',4'-dimethyloxazolin-2'-yl)thiophenolate) is used to generate a bioinspired donor environment around the W center, facilitating the stabilization of W-acetylene adducts. The featured complexes [W(C2 H2 )(CO)(S-Phoz)2 ] (2) and [WO(C2 H2 )(S-Phoz)2 ] (3) are extremely rare from a synthetic and structural point of view as very little is known about W-C2 H2 adducts. Upon exposure to visible light, 3 can release C2 H2 from its coordination sphere to yield the 14-electron species [WO(S-Phoz)2 ] (4). Under light-exclusion 4 re-activates C2 H2 making this the first fully characterized system for the reversible activation of acetylene. PMID- 26480336 TI - A Photonic Crystal Protein Hydrogel Sensor for Candida albicans. AB - We report two-dimensional (2D) photonic crystal (PC) sensing materials that selectively detect Candida albicans (C. albicans). These sensors utilize Concanavalin A (Con A) protein hydrogels with a 2D PC embedded on the Con A protein hydrogel surface, that multivalently and selectively bind to mannan on the C. albicans cell surface to form crosslinks. The resulting crosslinks shrink the Con A protein hydrogel, reduce the 2D PC particle spacing, and blue-shift the light diffracted from the PC. The diffraction shifts can be visually monitored, measured with a spectrometer, or determined from the Debye diffraction ring diameter. Our unoptimized hydrogel sensor has a detection limit of around 32 CFU/mL for C. albicans. This sensor distinguishes between C. albicans and those microbes devoid of cell-surface mannan such as the gram-negative bacterium E. coli. This sensor provides a proof-of-concept for utilizing recognition between lectins and microbial cell surface carbohydrates to detect microorganisms in aqueous environments. PMID- 26480337 TI - Rhodium(III)-Catalyzed Amidation of Unactivated C(sp(3) )-H Bonds. AB - Nitrogenation by direct functionalization of C-H bonds represents an important strategy for constructing C-N bonds. Rhodium(III)-catalyzed direct amidation of unactivated C(sp(3) )-H bonds is rare, especially under mild reaction conditions. Herein, a broad scope of C(sp(3) )-H bonds are amidated under rhodium catalysis in high efficiency using 3-substituted 1,4,2-dioxazol-5-ones as the amide source. The protocol broadens the scope of rhodium(III)-catalyzed C(sp(3) )-H activation chemistry, and is applicable to the late-stage functionalization of natural products. PMID- 26480338 TI - Highly Efficient Near-Infrared Delayed Fluorescence Organic Light Emitting Diodes Using a Phenanthrene-Based Charge-Transfer Compound. AB - Significant efforts have been made to develop high-efficiency organic light emitting diodes (OLEDs) employing thermally activated delayed fluorescence (TADF) emitters with blue, green, yellow, and orange-red colors. However, efficient TADF materials with colors ranging from red, to deep-red, to near-infrared (NIR) have been rarely reported owing to the difficulty in molecular design. Herein, we report the first NIR TADF molecule TPA-DCPP (TPA=triphenylamine; DCPP=2,3 dicyanopyrazino phenanthrene) which has a small singlet-triplet splitting (DeltaEST ) of 0.13 eV. Its nondoped OLED device exhibits a maximum external quantum efficiency (EQE) of 2.1 % with a Commission International de L'Eclairage (CIE) coordinate of (0.70, 0.29). Moreover, an extremely high EQE of nearly 10 % with an emission band at lambda=668 nm has been achieved in the doped device, which is comparable to the most-efficient deep-red/NIR phosphorescent OLEDs with similar electroluminescent spectra. PMID- 26480339 TI - Formation of Frustrated Lewis Pairs in Ptx -Loaded Zeolite NaY. AB - The formation of a frustrated Lewis pair consisting of sodium hydride (Na(+) H(-) ) and a framework-bound hydroxy proton O(H(+) ) is reported upon H2 treatment of zeolite NaY loaded with Pt nanoparticles (Ptx /NaY). Frustrated Lewis pair formation was confirmed using in situ neutron diffraction and spectroscopic measurements. The activity of the intrazeolite NaH as a size-selective catalyst was verified by the efficient esterification of acetaldehyde (a small aldehyde) to form the corresponding ester ethyl acetate, whereas esterification of the larger molecule benzaldehyde was unsuccessful. The frustrated Lewis pair (consisting of Na(+) H(-) and O(H(+) )) generated within zeolite NaY may be a useful catalyst for various catalytic reactions which require both H(-) and H(+) ions, such as catalytic hydrogenation or dehydrogenation of organic compounds and activation of small molecules. PMID- 26480341 TI - Synthesis and Stereochemical Assignment of Crypto-Optically Active (2) H6 Neopentane. AB - The determination of the absolute configuration of chiral molecules is at the heart of asymmetric synthesis. Here we probe the spectroscopic limits for chiral discrimination with NMR spectroscopy in chiral aligned media and with vibrational circular dichroism spectroscopy of the sixfold-deuterated chiral neopentane. The study of this compound presents formidable challenges since its stereogenicity is only due to small mass differences. For this purpose, we selectively prepared both enantiomers of (2) H6 -1 through a concise synthesis utilizing multifunctional intermediates. While NMR spectroscopy in chiral aligned media could be used to characterize the precursors to (2) H6 -1, the final assignment could only be accomplished with VCD spectroscopy, despite the fleetingly small dichroic properties of 1. Both enantiomers were assigned by matching the VCD spectra with those computed with density functional theory. PMID- 26480343 TI - Computer-Navigated Total Knee Arthroplasty Utilization. AB - Computer-navigated total knee arthroplasty (CN-TKA) has been used to improve component alignment, though the evidence is currently mixed on whether there are clinically significant differences in long-term outcomes. Given the established increased costs and operative time, we hypothesized that the utilization rate of CN-TKA would be decreasing relative to standard TKA in the Medicare population given the current health care economic environment. We queried 1,914,514 primary TKAs performed in the entire Medicare database from 2005 to 2012. Current Procedural Terminology (CPT) and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were used to identify and separate CN-TKAs. Utilization of TKA was compared by year, gender, and region. Average change in cases per year and compound annual growth rate (CAGR) were used to evaluate trends in utilization of the procedure. We identified 30,773 CN-TKAs performed over this time period. There was an increase in utilization of CN-TKA per year from 984 to 5,352 (average = 572/year, R (2) = 0.85, CAGR = 23.58%) from 2005 to 2012. In contrast, there was a slight decrease in overall TKA utilization from 264,345 to 230,654 (average = 4297/year, R (2) = 0.74, CAGR = - 1.69%). When comparing proportion of CN-TKA to all TKAs, there was an increase from 0.37 to 2.32% (average 0.26%/year, R (2) = 0.88, CAGR = 25.70%). CN-TKA growth in males and females was comparable at 24.42 and 23.11%, respectively. The South region had the highest growth rate at 28.76%, whereas the Midwest had the lowest growth rate at 15.51%. The Midwest was the only region that peaked (2008) with a slow decline in utilization until 2012. Despite increased costs with unclear clinical benefit, CN-TKA is increasing in utilization among Medicare patients. Reasons could include patient preference, advertising, proper of coding the procedure, and increased publicly available information about arthroplasty options. PMID- 26480340 TI - Rhodium(II) Proximity-Labeling Identifies a Novel Target Site on STAT3 for Inhibitors with Potent Anti-Leukemia Activity. AB - Nearly 40 % of children with acute myeloid leukemia (AML) suffer relapse arising from chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). Herein, rhodium(II) catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML. PMID- 26480344 TI - Implant Size Availability Affects Reproduction of Distal Femoral Anatomy. AB - A total knee arthroplasty system offers more distal femoral implant anterior posterior (AP) sizes than its predecessor. The purpose of this study is to investigate the impact of increased size availability on an implant system's ability to reproduce the AP dimension of the native distal femur. We measured 200 cadaveric femora with the AP-sizing guides of Zimmer (Warsaw, IN) NexGen (8 sizes) and Zimmer Persona (12 sizes) total knee arthroplasty systems. We defined "size deviation" as the difference in the AP dimension between the anatomic size of the native femur and the closest implant size. We defined satisfactory reproduction of distal femoral dimensions as < 1 mm difference between the implant and native femur size. The NexGen system was associated with a mean 0.46 mm greater implant size deviation than Persona (p < 0.001). When using a 1 mm size deviation as a cutoff for satisfactory replication of the native distal femoral anatomy, 85/200 specimens (42.5%) were a poor fit by NexGen, but a satisfactory fit by Persona. Only 1/200 specimens (0.5%) was a poor fit by Persona, but a satisfactory fit by NexGen (p < 0.001). The novel knee system with 12 versus 8 sizes reproduces the AP dimension of the native distal femur more closely than its predecessor. Further study is needed to determine the clinical impact of these differences. PMID- 26480345 TI - Surgical Approaches to Posterolateral Tibial Plateau Fractures. AB - Tibial plateau fractures involving the posterolateral articular surface present a unique challenge to treating surgeons due to the complex anatomy of the region. The posterolateral corner complex and the proximity of the common peroneal nerve restrict both the exposure of the joint surface and the ability to distract across the joint using a varus force. Further, injury to the soft tissue envelope may prevent use of the optimal surgical incision. For these reasons, a thorough understanding of the anatomy and available approaches is essential when treating these fractures. Approach selection should be based on fracture pattern, the surrounding soft tissue envelope, and the patient's clinical conditions; concomitant injuries and overall health status must be accounted for. In this article, we highlight five surgical approaches that can be utilized to improve visualization and access to the posterolateral tibial plateau. These include three separate osteotomies performed through an anterolateral approach: lateral femoral epicondyle osteotomy, fibular head resection osteotomy, and a novel digastric fibular osteotomy. In addition, we will discuss a posterolateral approach and a direct posterior approach. PMID- 26480346 TI - Staged Fixation of Tibial Plateau Fractures: Strategies for the Posterior Approach. AB - A critical assessment of radiographic and clinical outcomes after complex articular fractures of the proximal tibia demonstrates several aspects worthy of reevaluation and potential modification. These include a refined understanding of fracture pathoanatomy, injury classification, operative exposure, surgical timing, and preferred fixation constructs in addition to implant design modifications. Evolving trends include increasing appreciation of the importance of the fracture morphology in the axial plane and the role that the fracture pattern has on the choice of surgical approach. This focused review will highlight the attributes and limitations of classification schemes (both conventional and contemporary) as well as the role that posterior surgical approaches performed in the prone position may offer in select clinical scenarios. The merits of staged fixation (prone followed by supine patient positioning), its technique, indications, and potential liabilities are described and case examples offered. PMID- 26480347 TI - Posterolateral Reconstruction of the Knee: Two-Tailed Surgical Techniques. AB - Reconstruction of the posterolateral corner of the knee using two-tailed techniques involved grafts originating from the femur and inserting on the proximal tibia and fibular head. This method reconstructs the fibular collateral ligament, popliteofibular ligament, and popliteus tendon using anatomically placed grafts. This article describes the history, anatomy, indications, and authors' preferred technique for a two-tailed posterolateral corner reconstruction. In addition, biomechanical and clinical outcomes of this technique will be compared. PMID- 26480350 TI - InGaP/GaAs heterojunction phototransistors transferred to a Si substrate by metal wafer bonding combined with epitaxial lift-off. AB - We report fabrication and optical characteristics of an InGaP/GaAs heterojunction phototransistor (HPT) transferred to a Si substrate by a metal wafer bonding (MWB) and epitaxial lift-off (ELO) process at room temperature. An intermediate Pt/Au double layer between the HPT layer and Si provided a very smooth surface by which to achieve the MWB, and excellent durability against the acid solution during the ELO process. These processes were observed using scanning electron microscope (SEM) and atomic force microscopy (AFM). While the results on a low temperature photoluminescence (LTPL) signal and high resolution x-ray diffraction (HRXRD) rocking curve of the bonded device film implied a defect-free bonding, a very low collector dark current of the fabricated HPT was observed. The optical performance of a bonded InGaP/GaAs HPT on Si, operating at 635 nm wavelength is also investigated. PMID- 26480349 TI - Effect of anxiety on behavioural pattern separation in humans. AB - Behavioural pattern separation (BPS), the ability to distinguish among similar stimuli based on subtle physical differences, has been used to study the mechanism underlying stimulus generalisation. Fear overgeneralisation is often observed in individuals with posttraumatic stress disorder and other anxiety disorders. However, the relationship between anxiety and BPS remains unclear. The purpose of this study was to determine the effect of anxiety (threat of shock) on BPS, which was assessed across separate encoding and retrieval sessions. Images were encoded/retrieved during blocks of threat or safety in a 2 * 2 factorial design. During retrieval, participants indicated whether images were new, old, or altered. Better accuracy was observed for altered images encoded during periods of threat compared to safety, but only if those images were also retrieved during periods of safety. These results suggest that overgeneralisation in anxiety may be due to altered pattern separation. PMID- 26480351 TI - Tuning of resonance spacing over whole free spectral range based on Autler-Townes splitting in a single microring resonator. AB - In this paper, a single microring resonator structure formed by incorporating a reflectivity-tunable loop mirror is demonstrated for the tuning of resonance spacing. Autler-Townes splitting in the resonator is utilized to tune the spacing between two adjacent resonances by controlling the strength of coupling between the two counter-propagating degenerate modes in the microring resonator. A theoretical model based on the transfer matrix method is built to analyze the device. The theoretical analysis indicates that the resonance spacing can be tuned from zero to one free spectral range (FSR). In experiment, by integrating metallic microheater, the tuning of resonance spacing in the range of the whole FSR (1.17 nm) is achieved within 9.82 mW heating power dissipation. The device has potential for applications in reconfigurable optical filtering and microwave photonics. PMID- 26480348 TI - Increased Transcript Complexity in Genes Associated with Chronic Obstructive Pulmonary Disease. AB - Genome-wide association studies aim to correlate genotype with phenotype. Many common diseases including Type II diabetes, Alzheimer's, Parkinson's and Chronic Obstructive Pulmonary Disease (COPD) are complex genetic traits with hundreds of different loci that are associated with varied disease risk. Identifying common features in the genes associated with each disease remains a challenge. Furthermore, the role of post-transcriptional regulation, and in particular alternative splicing, is still poorly understood in most multigenic diseases. We therefore compiled comprehensive lists of genes associated with Type II diabetes, Alzheimer's, Parkinson's and COPD in an attempt to identify common features of their corresponding mRNA transcripts within each gene set. The SERPINA1 gene is a well-recognized genetic risk factor of COPD and it produces 11 transcript variants, which is exceptional for a human gene. This led us to hypothesize that other genes associated with COPD, and complex disorders in general, are highly transcriptionally diverse. We found that COPD-associated genes have a statistically significant enrichment in transcript complexity stemming from a disproportionately high level of alternative splicing, however, Type II Diabetes, Alzheimer's and Parkinson's disease genes were not significantly enriched. We also identified a subset of transcriptionally complex COPD-associated genes (~40%) that are differentially expressed between mild, moderate and severe COPD. Although the genes associated with other lung diseases are not extensively documented, we found preliminary data that idiopathic pulmonary disease genes, but not cystic fibrosis modulators, are also more transcriptionally complex. Interestingly, complex COPD transcripts are more often the product of alternative acceptor site usage. To verify the biological importance of these alternative transcripts, we used RNA-sequencing analyses to determine that COPD-associated genes are frequently expressed in lung and liver tissues and are regulated in a tissue-specific manner. Additionally, many complex COPD-associated genes are spliced differently between COPD and non-COPD patients. Our analysis therefore suggests that post-transcriptional regulation, particularly alternative splicing, is an important feature specific to COPD disease etiology that warrants further investigation. PMID- 26480352 TI - Design of flexible multi-mode fiber endoscope. AB - Multi-mode fiber (MMF) endoscopes are extremely thin and have higher spatial resolution than conventional endoscopes; however, all current MMF endoscope designs require either that the MMF remain rigid during insertion and imaging or that the orientation of the MMF be known. This limits their possible medical applications. We describe an MMF endoscope design that allows the MMF to be arbitrarily bent as it is maneuvered to the target site prior to imaging. This is achieved by the addition of a partial reflector to the distal end of the MMF, which allows measurement of the mode coupling in the MMF using the reflected light arriving at the proximal end of the MMF. This measurement can be performed while the distal end of the endoscope is not directly accessible, as when the endoscope is being maneuvered. We simulate imaging through such a flexible MMF endoscope, where the MMF is step-index with 1588 spatial modes, and obtain an image even after the mode coupling matrix of the MMF is altered randomly, corresponding to an unknown bending of the MMF. PMID- 26480353 TI - Sparse nonlinear inverse imaging for shot count reduction in inverse lithography. AB - Inverse lithography technique (ILT) is significant to reduce the feature size of ArF optical lithography due to its strong ability to overcome the optical proximity effect. A critical issue for inverse lithography is the complex curvilinear patterns produced, which are very costly to write due to the large number of shots needed with the current variable shape beam (VSB) writers. In this paper, we devise an inverse lithography method to reduce the shot count by incorporating a model-based fracturing (MBF) in the optimization. The MBF is formulated as a sparse nonlinear inverse imaging problem based on representing the mask as a linear combination of shots followed by a threshold function. The problem is approached with a Gauss-Newton algorithm, which is adapted to promote sparsity of the solution, corresponding to the reduction of the shot count. Simulations of inverse lithography are performed on several test cases, and results demonstrate reduced shot count of the resulting mask. PMID- 26480354 TI - Effects of high-repetition-rate femtosecond laser micromachining on the physical and chemical properties of polylactide (PLA). AB - The effects of femtosecond laser ablation, with 115 fs pulses at 1040 nm wavelength and 57 MHz repetition-rate, on the physical and chemical properties of polylactide (PLA) were studied in air and in water. The surface of the PLA sample ablated by high-repetition-rate femtosecond laser was analysed using field emission scanning electron microscopy, infrared spectroscopy, raman spectroscopy, as well as X-ray photoelectron spectroscopy. Compared with the experiments in the air at ambient temperature, melting resolidification was negligible for the experiments conducted under water. Neither in air nor under water did oxidation and crystallization process take place in the laser ablated surface. In addition, the intensity of some oxygen related peaks increased for water experiments, probably due to the hydrolysis. Meantime, the chemical shift to higher energies appeared in C1s XPS spectrum of laser processing in water. Interestingly, a large amount of defects were observed after laser processing in air, while no significant change was shown under water experiments. This indicates that thermal and mechanical effects by high-repetition-rate femtosecond laser ablation in water are quite limited, which could be even ignored. PMID- 26480355 TI - Slot waveguide ring resonators coated by an atomic layer deposited organic/inorganic nanolaminate. AB - In this study, slot waveguide ring resonators patterned on a silicon-on-insulator (SOI) wafer and coated with an atomic layer deposited nanolaminate consisting of alternating layers of tantalum pentoxide and polyimide were fabricated and characterized. To the best of our knowledge, this is the first demonstration of atomic layer deposition (ALD) of organic materials in waveguiding applications. In our nanolaminate ring resonators, the optical power is not only confined in the narrow central air slot but also in several parallel sub-10 nm wide vertical polyimide slots. This indicates that the mode profiles in the silicon slot waveguide can be accurately tuned by the ALD method. Our results show that ALD of organic and inorganic materials can be combined with conventional silicon waveguide fabrication techniques to create slot waveguide ring resonators with varying mode profiles. This can potentially open new possibilities for various photonic applications, such as optical sensing and all-optical signal processing. PMID- 26480356 TI - All-optical 4x10 Gbps NAND gate using single mode Fabry-Perot laser diode. AB - We demonstrate all-optical 4x10 Gbps NAND gate with an individual input data rate of 10 Gbps using single mode Fabry-Perot laser diode. The proposed scheme is based on the principle of multi-input injection locking. All-optical NAND gate is one of the universal logic gates which can be used for realizing all other logic gates for optical communication and networks. The output performance of the proposed all-optical multi-input NAND gate is verified with output spectrum domain results, waveforms, rising-falling time, and eye diagram measurement at 10 Gbps input. The ON/OFF contrast ratio of 41 dB is measured at the spectrum domain output when all four input beams are logic high. In all other combinations of four inputs, maximum ON/OFF contrast ratio of 1.5 dB ON/OFF is measured. Clear output waveform, output eye diagram with an extinction ratio of about 11 dB, and rising-falling time of about 35 ps are obtained. The BER measurement is carried out and we found the power penalty of about 1.7 dB at BER of 10(-9). PMID- 26480358 TI - Photoacoustic tomography from weak and noisy signals by using a pulse decomposition algorithm in the time-domain. AB - Photoacoustic tomography is a promising and rapidly developed methodology of biomedical imaging. It confronts an increasing urgent problem to reconstruct the image from weak and noisy photoacoustic signals, owing to its high benefit in extending the imaging depth and decreasing the dose of laser exposure. Based on the time-domain characteristics of photoacoustic signals, a pulse decomposition algorithm is proposed to reconstruct a photoacoustic image from signals with low signal-to-noise ratio. In this method, a photoacoustic signal is decomposed as the weighted summation of a set of pulses in the time-domain. Images are reconstructed from the weight factors, which are directly related to the optical absorption coefficient. Both simulation and experiment are conducted to test the performance of the method. Numerical simulations show that when the signal-to noise ratio is -4 dB, the proposed method decreases the reconstruction error to about 17%, in comparison with the conventional back-projection method. Moreover, it can produce acceptable images even when the signal-to-noise ratio is decreased to -10 dB. Experiments show that, when the laser influence level is low, the proposed method achieves a relatively clean image of a hair phantom with some well preserved pattern details. The proposed method demonstrates imaging potential of photoacoustic tomography in expanding applications. PMID- 26480357 TI - High-sensitivity DNA biosensor based on optical fiber taper interferometer coated with conjugated polymer tentacle. AB - A sensitive bio-probe to in situ detect unlabeled single-stranded DNA targets based on optical microfiber taper interferometer coated by a high ordered pore arrays conjugated polymer has been presented. The polymer coating serves as tentacles to catch single-stranded DNA molecules by pi-pi conjugated interaction and varies the surface refractive index of the optical microfiber. The microfiber taper interferometer translates the refractive index information into wavelength shift of the interference fringe. The sensor exhibits DNA concentration sensitivity of 2.393 nm/log M and the lowest detection ability of 10(-10) M or even lower. PMID- 26480359 TI - Focus modulation of cylindrical vector beams by using 1D photonic crystal lens with negative refraction effect. AB - Sub-wavelength focusing of cylindrical vector beams (CVBs) has attracted great attention due to the specific physical effects and the applications in many areas. More powerful, flexible and effective ways to modulate the focus transversally and also longitudinally are always being pursued. In this paper, cylindrically symmetric lens composed of negative-index one-dimensional photonic crystal is proposed to make a breakthrough. By revealing the relationship between focal length and the exit surface shape of the lens, a quite simple and effective principle of designing the lens structure is presented to realize specific focus modulation. Plano-concave lenses are parameterized to modulate the focal length and the number of focuses. An axicon constructed by one-dimensional photonic crystal is proposed for the first time to obtain a large depth of focus and an optical needle focal field with almost a theoretical minimum FWHM of 0.362lambda is achieved under radially polarized incident light. Because of the almost identical negative refractive index for TE and TM polarization states, all the modulation methods can be applied for any arbitrary polarized CVBs. This work offers a promising methodology for designing negative-index lenses in related application areas. PMID- 26480360 TI - Color image generation for screen-scanning holographic display. AB - Horizontally scanning holography using a microelectromechanical system spatial light modulator (MEMS-SLM) can provide reconstructed images with an enlarged screen size and an increased viewing zone angle. Herein, we propose techniques to enable color image generation for a screen-scanning display system employing a single MEMS-SLM. Higher-order diffraction components generated by the MEMS-SLM for R, G, and B laser lights were coupled by providing proper illumination angles on the MEMS-SLM for each color. An error diffusion technique to binarize the hologram patterns was developed, in which the error diffusion directions were determined for each color. Color reconstructed images with a screen size of 6.2 in. and a viewing zone angle of 10.2 degrees were generated at a frame rate of 30 Hz. PMID- 26480362 TI - In-line femtosecond common-path interferometer in reflection mode. AB - An innovative method to perform femtosecond time-resolved interferometry in reflection mode is proposed. The experiment consists in the combined use of a pump-probe setup and of a fully passive in-line femtosecond common-path interferometer. The originality of this interferometer relies on the use of a single birefringent crystal first to generate a pair of phase-locked pulses and second to recombine them to interfere. As predicted by analytical modeling, this interferometer measures the temporal derivative of the ultrafast changes of the complex optical reflection coefficient of the sample. Working conditions are illustrated through picosecond opto-acoustic experiments on a thin film. PMID- 26480361 TI - Digital micromirror device-based laser-illumination Fourier ptychographic microscopy. AB - We report a novel approach to Fourier ptychographic microscopy (FPM) by using a digital micromirror device (DMD) and a coherent laser source (532 nm) for generating spatially modulated sample illumination. Previously demonstrated FPM systems are all based on partially-coherent illumination, which offers limited throughput due to insufficient brightness. Our FPM employs a high power coherent laser source to enable shot-noise limited high-speed imaging. For the first time, a digital micromirror device (DMD), imaged onto the back focal plane of the illumination objective, is used to generate spatially modulated sample illumination field for ptychography. By coding the on/off states of the micromirrors, the illumination plane wave angle can be varied at speeds more than 4 kHz. A set of intensity images, resulting from different oblique illuminations, are used to numerically reconstruct one high-resolution image without obvious laser speckle. Experiments were conducted using a USAF resolution target and a fiber sample, demonstrating high-resolution imaging capability of our system. We envision that our approach, if combined with a coded-aperture compressive-sensing algorithm, will further improve the imaging speed in DMD-based FPM systems. PMID- 26480363 TI - Mid-wave infrared metasurface microlensed focal plane array for optical crosstalk suppression. AB - Spatial crosstalk is one of the fundamental drawbacks of diminishing pixel size in mid-wave infrared focal plane arrays (IR-FPAs). We proposed an IR-FPA using the concept of optical phase discontinuities for substantial optical crosstalk suppression. This IR-FPA consists of asymmetrically tailored V-shaped optical antennas. Full-wave simulations confirmed major improvements in narrowing the intensity distribution of incident light beam by over 30-folds and concentrating these distributions in the central pixel of IR-FPA by achieving optical crosstalks of <1%. PMID- 26480364 TI - Light coupling with a nonlinear prism. AB - We propose the use of a prism with nonlinear optical properties to improve the prism-coupling method. The principle is based on the inscription of an adapted waveguide inside this prism by beam self-trapping to enhance the coupling efficiency and stability. The experimental demonstration is realized with a prism diced from a LiNbO3 wafer to couple light into a resonator. PMID- 26480365 TI - Phase-shifted Bragg gratings for Bloch surface waves. AB - An analogue of phase-shifted Bragg grating (PSBG) for Bloch surface waves (BSW) propagating along the interface between a one-dimensional photonic crystal and a homogeneous medium is proposed. The studied structure consists of a set of dielectric ridges located on the photonic crystal surface, the height of which is chosen so that they encode the required distribution of the effective refractive index. Rigorous simulation results of the surface wave diffraction on the proposed structure are compared with the plane wave diffraction on a conventional phase-shifted Bragg grating. The simulation results demonstrate the possibility of using the proposed analogue of PSBG for temporal differentiation of picosecond BSW pulses. The obtained results can find application in the design of the prospective on-chip systems for all-optical analog computing. PMID- 26480366 TI - Comparison of phase modulation schemes for coherently combined fiber amplifiers. AB - Optical linewidth broadening through both white noise (WNS) and pseudo-random binary sequence (PBRS) phase modulation are effective techniques for suppressing stimulated Brillouin scattering (SBS) in high- power fiber amplifiers. However, detailed studies comparing both coherent beam combining and SBS suppression of these phase modulation schemes have not been reported. In this study, a passive fiber cutback experiment is performed comparing the SBS threshold enhancement factor of a PRBS and WNS broadened seed as a function of linewidth and fiber length. Particularly, assuming an optimal PRBS pattern is chosen, pseudo-random modulation provides superior SBS suppression than WNS for a given fiber length and signal linewidth. Furthermore, two WNS and PRBS modulated 150 W fiber lasers are coherently combined to measure and compare the combining efficiency, beam quality, and coherence as a function of optical path length difference. Notably, the discrete spectral density of PRBS modulation provides a re-coherence effect where the lasers periodically come back into phase. Overall, this may reduce path length matching complexity in coherently combined fiber laser systems. PMID- 26480367 TI - Resolution-improved in situ DNA hybridization detection based on microwave photonic interrogation. AB - In situ bio-sensing system based on microwave photonics filter (MPF) interrogation method with improved resolution is proposed and experimentally demonstrated. A microfiber Bragg grating (mFBG) is used as sensing probe for DNA hybridization detection. Different from the traditional wavelength monitoring technique, we use the frequency interrogation scheme for resolution-improved bio sensing detection. Experimental results show that the frequency shift of MPF notch presents a linear response to the surrounding refractive index (SRI) change over the range of 1.33 to 1.38, with a SRI resolution up to 2.6 * 10(-5) RIU, which has been increased for almost two orders of magnitude compared with the traditional fundamental mode monitoring technique (~3.6 * 10(-3) RIU). Due to the high Q value (about 27), the whole process of DNA hybridization can be in situ monitored. The proposed MPF-based bio-sensing system provides a new interrogation method over the frequency domain with improved sensing resolution and rapid interrogation rate for biochemical and environmental measurement. PMID- 26480368 TI - Measurement of particle motion in optical tweezers embedded in a Sagnac interferometer. AB - We have constructed a counterpropagating optical tweezers setup embedded in a Sagnac interferometer in order to increase the sensitivity of position tracking for particles in the geometrical optics regime. Enhanced position determination using a Sagnac interferometer has previously been described theoretically by Taylor et al. [Journal of Optics 13, 044014 (2011)] for Rayleigh-regime particles trapped in an antinode of a standing wave. We have extended their theory to a case of arbitrarily-sized particles trapped with orthogonally-polarized counter propagating beams. The working distance of the setup was sufficiently long to optically induce particle oscillations orthogonally to the axis of the tweezers with an auxiliary laser beam. Using these oscillations as a reference, we have experimentally shown that Sagnac-enhanced back focal plane interferometry is capable of providing an improvement of more than 5 times in the signal-to background ratio, corresponding to a more than 30-fold improvement of the signal to-noise ratio. The experimental results obtained are consistent with our theoretical predictions. In the experimental setup, we used a method of optical levitator-assisted liquid droplet delivery in air based on commercial inkjet technology, with a novel method to precisely control the size of droplets. PMID- 26480369 TI - Tailoring the dispersion behavior of optical nanowires with intercore-cladding lithium niobate thin film. AB - The dispersion properties of silica and silicon subwavelength-diameter wires with intercore-cladding uniaxial dielectric lithium niobate thin film has been studied numerically in detail. The waveguide dispersion shifts centered around 1550-nm wavelength have been investigated. It shows that the dispersion of optical nanowires with intercore-cladding lithium niobate thin film is highly sensitive to fiber geometry. Moreover, with applied electric field, considerable dispersion shifts without changing its geometric structure can be obtained. Our work may provide an inroad for developing miniaturized functional optoelectronic devices. PMID- 26480370 TI - Active integral imaging system based on multiple structured light method. AB - In this paper, we simplify the equipments for integral imaging (II) pickup and implement an active II system based on multiple structured light (MSL) method. In the active II system, the complete three-dimensional (3D) shape of the 3D scene can be reconstructed, and the tunable parallaxes can be generated without occlusions. Therefore, the high-quality 3D images can be displayed efficiently by the II. We also use the Compute Unified Device Architecture implementing the processing algorithms in graphics processing unit. The experimental results demonstrate the effectiveness of the MSL method for the II pickup and the acceleration for the elemental image array generation. Especially, the proposed method is suitable for the real scene with high precision. PMID- 26480371 TI - Phase-only synthesis of ultrafast stretched square pulses. AB - We report the generation of square temporal-shape pulses with no loss of spectral bandwidth, using an analytic expression for the spectral phase modulation dependent only on the input spectrum and stretching factor. We demonstrate numerically and experimentally conversion of 40fs pulses into 150 times longer flat top pulses with sharp on and off fronts. Applications in pulse amplification and free electron lasers are considered. PMID- 26480372 TI - Plasma temperature clamping in filamentation laser induced breakdown spectroscopy. AB - Ultrafast laser filament induced breakdown spectroscopy is a very promising method for remote material detection. We present characteristics of plasmas generated in a metal target by laser filaments in air. Our measurements show that the temperature of the ablation plasma is clamped along the filament channel due to intensity clamping in a filament. Nevertheless, significant changes in radiation intensity are noticeable, and this is essentially due to variation in the number density of emitting atoms. The present results also explain the near absence of ion emission but strong atomic neutral emission from plumes produced during fs LIBS in air. PMID- 26480373 TI - Application of a broadly tunable SG-DBR QCL for multi-species trace gas spectroscopy. AB - Feasibility of using a mid-Infrared tunable sampled-grating distributed Bragg reflectors quantum cascade laser for high resolution multicomponent trace gas spectroscopy is demonstrated. By controlling the driving currents to the front and back sections of the laser, we were able to tune a pulsed 4.55 um laser over a frequency range a of 30 cm(-1) with high resolution, accuracy and repeatability. The laser was applied to absorption spectroscopy of ambient and reduced pressure (150 Torr) air in a 205 meters multi-pass Herriott cell, and by using standard LSQ fitting to a spectral database of these trace gases (HITRAN), the concentrations of nitrous oxide, carbon monoxide, and water vapor were retrieved. PMID- 26480374 TI - Optimized calibration strategy for high order adaptive optics systems in closed loop: the slope-oriented Hadamard actuation. AB - The accurate calibration of the interaction matrix affects the performance of an adaptive optics system. In the case of high-order systems, when the number of mirror modes is worth a few thousands, the calibration strategy is critical to reach the maximum interaction matrix quality in the minimum time. This is all the more true for the future European Extremely Large Telescope. Here, we propose a novel calibration scheme, the Slope-Oriented Hadamard strategy. We then build a tractable interaction matrix quality criterion, and show that our method tends to optimize it. We demonstrate that for a given level of quality, the calibration time needed using the Slope-Oriented Hadamard method is seven times less than with a classical Hadamard scheme. These analytic and simulation results are confirmed experimentally on the SPHERE XAO system (SAXO). PMID- 26480375 TI - Improved carrier injection in GaN-based VCSEL via AlGaN/GaN multiple quantum barrier electron blocking layer. AB - In this report, the improved lasing performance of the III-nitride based vertical cavity surface-emitting laser (VCSEL) has been demonstrated by replacing the bulk AlGaN electron blocking layer (EBL) in the conventional VCSEL structure with an AlGaN/GaN multiple quantum barrier (MQB) EBL. The output power can be enhanced up to three times from 0.3 mW to 0.9 mW. In addition, the threshold current density of the fabricated device with the MQB-EBL was reduced from 12 kA/cm2 (9.5 mA) to 10.6 kA/cm2 (8.5 mA) compared with the use of the bulk AlGaN EBL. Theoretical calculation results suggest that the improved carrier injection efficiency can be mainly attributed to the partial release of the strain and the effect of quantum interference by using the MQB structure, hence increasing the effective barrier height of the conduction band. PMID- 26480376 TI - Active metasurface terahertz deflector with phase discontinuities. AB - Metasurfaces provide great flexibility in tailoring light beams and reveal unprecedented prospects on novel functional components. However, techniques to dynamically control and manipulate the properties of metasurfaces are lagging behind. Here, for the first time to our knowledge, we present an active wave deflector made from a metasurface with phase discontinuities. The active metasurface is capable of delivering efficient real-time control and amplitude manipulation of broadband anomalous diffraction in the terahertz regime. The device consists of complementary C-shape split-ring resonator elements fabricated on a doped semiconductor substrate. Due to the Schottky diode effect formed by the hybrid metal-semiconductor, the real-time conductivity of the doped semiconductor substrate is modified by applying an external voltage bias, thereby effectively manipulating the intensity of the anomalous deflected terahertz wave. A modulation depth of up to 46% was achieved, while the characteristics of broadband frequency responses and constant deflected angles were well maintained during the modulation process. The modulation speed of diffraction amplitude reaches several kilohertz, limited by the capacitance and resistance of the depletion region. The scheme proposed here opens up a novel approach to develop tunable metasurfaces. PMID- 26480377 TI - High fidelity digital inline holographic method for 3D flow measurements. AB - Among all the 3D optical flow diagnostic techniques, digital inline holographic particle tracking velocimetry (DIH-PTV) provides the highest spatial resolution with low cost, simple and compact optical setups. Despite these advantages, DIH PTV suffers from major limitations including poor longitudinal resolution, human intervention (i.e. requirement for manually determined tuning parameters during tracer field reconstruction and extraction), limited tracer concentration, and expensive computations. These limitations prevent this technique from being widely used for high resolution 3D flow measurements. In this study, we present a novel holographic particle extraction method with the goal of overcoming all the major limitations of DIH-PTV. The proposed method consists of multiple steps involving 3D deconvolution, automatic signal-to-noise ratio enhancement and thresholding, and inverse iterative particle extraction. The entire method is implemented using GPU-based algorithm to increase the computational speed significantly. Validated with synthetic particle holograms, the proposed method can achieve particle extraction rate above 95% with fake particles less than 3% and maximum position error below 1.6 particle diameter for holograms with particle concentration above 3000 particles/mm3. The applicability of the proposed method for DIH-PTV has been further validated using the experiment of laminar flow in a microchannel and the synthetic tracer flow fields generated using a DNS turbulent channel flow database. Such improvements will substantially enhance the implementation of DIH-PTV for 3D flow measurements and enable the potential commercialization of this technique. PMID- 26480378 TI - Broadband high reflectivity in subwavelength-grating slab waveguides. AB - We computationally study a subwavelength dielectric grating structure, show that slab waveguide modes can be used to obtain broadband high reflectivity, and analyze how slab waveguide modes influence reflection. A structure showing interference between Fabry-Perot modes, slab waveguide modes, and waveguide array modes is designed with ultra-broadband high reflectivity. Owing to the coupling of guided modes, the region with reflectivity R > 0.99 has an ultra-high bandwidth (Deltaf / f > 30%). The incident-angle region with R > 0.99 extends over a range greater than 40 degrees . Moreover, an asymmetric waveguide structure with a semiconductor substrate is studied. PMID- 26480379 TI - Electro-optical co-simulation for integrated CMOS photonic circuits with VerilogA. AB - We present a Cadence toolkit library written in VerilogA for simulation of electro-optical systems. We have identified and described a set of fundamental photonic components at the physical level such that characteristics of composite devices (e.g. ring modulators) are created organically - by simple instantiation of fundamental primitives. Both the amplitude and phase of optical signals as well as optical-electrical interactions are simulated. We show that the results match other simulations and analytic solutions that have previously been compared to theory for both simple devices, such as ring resonators, and more complicated devices and systems such as single-sideband modulators, WDM links and Pound Drever Hall Locking loops. We also illustrate the capability of such toolkit for co-simulation with electronic circuits, which is a key enabler of the electro optic system development and verification. PMID- 26480380 TI - Terahertz transmission and sensing properties of microstructured PMMA tube waveguide. AB - A terahertz (THz) tube waveguide with grating structure has been designed, fabricated and characterized as a microstructure waveguide sensor. The resonance and polarization properties of this microstructured tube have been experimentally and theoretically investigated, which indicates that the grating etched on the tube surface has a remarkable modulation effect on the tube resonance and polarization dependence for THz waves. Moreover, a real-time quantitative sensing has been realized based on this tube waveguide in the THz time-domain spectroscopy system. Compared with the bare tube without grating, the grating structure strongly enhances the interaction between THz evanescent field on the tube surface and analytes, improving the sensitivity. This microstructured PMMA THz tube reveals a high sensitivity of 50GHz/MUl and precision of larger than 0.125MUl with a good linear relationship for THz sensing applications. PMID- 26480381 TI - High bandwidth, high responsivity waveguide-coupled germanium p-i-n photodiode. AB - A novel waveguide-coupled germanium p-i-n photodiode is demonstrated which combines high responsivity with very high -3 dB bandwidth at a medium dark current. Bandwidth values are 40 GHz at zero bias and more than 70 GHz at -1 V. Responsivity at 1.55 um wavelength ranges from 0.84 A/W at zero bias to 1 A/W at 1 V. Room temperature dark current density at -1 V is about 1 A/cm2. The high responsivity mainly results from the use of a new, low-loss contact scheme, which moreover also reduces the negative effect of photo carrier diffusion on bandwidth. PMID- 26480382 TI - Two-dimensional tomographic terahertz imaging by homodyne self-mixing. AB - We realize a compact two-dimensional tomographic terahertz imaging experiment involving only one photoconductive antenna (PCA) simultaneously serving as a transmitter and receiver of the terahertz radiation. A hollow-core Teflon cylinder filled with alpha-Lactose monohydrate powder is studied at two terahertz frequencies, far away and at a specific absorption line of the powder. This sample is placed between the antenna and a chopper wheel, which serves as back reflector of the terahertz radiation into the PCA. Amplitude and phase information of the continuous-wave (CW) terahertz radiation are extracted from the measured homodyne self-mixing (HSM) signal after interaction with the cylinder. The influence of refraction is studied by modeling the set-up utilizing ZEMAX and is discussed by means of the measured 1D projections. The tomographic reconstruction by using the Simultaneous Algebraic Reconstruction Technique (SART) allows to identify both object geometry and alpha-Lactose filling. PMID- 26480383 TI - Switchable quarter-wave plate with graphene based metamaterial for broadband terahertz wave manipulation. AB - Graphene is a good candidate material in designing tunable terahertz devices due to its tunability of sheet conductivity. In this paper, we propose a scheme to design switchable quarter-wave plate for terahertz wave that is composed of graphene based grating and metallic grating structures. The proposed active device can dynamically switch the transmission wave among left-handed, right handed circular polarization and linear polarization states by electrically controlling the Fermi energy of the graphene grating. The device is analyzed with grating circular polarizer theory and its performance is investigated through full wave simulations on practically realizable geometry. The proposed quarter wave plate having a subwavelength thickness demonstrates a wide angle of incidence tolerance, and a broad bandwidth operation. This device concept offers a further step in developing tunable polarizers and polarization switchers, which may be applied in practical terahertz image and communication systems. PMID- 26480384 TI - Suppression of WDM four-wave mixing crosstalk in fibre optic parametric amplifier using Raman-assisted pumping. AB - We perform an extensive numerical analysis of Raman-Assisted Fibre Optical Parametric Amplifiers (RA-FOPA) in the context of WDM QPSK signal amplification. A detailed comparison of the conventional FOPA and RA-FOPA is reported and the important advantages offered by the Raman pumping are clarified. We assess the impact of pump power ratios, channel count, and highly nonlinear fibre (HNLF) length on crosstalk levels at different amplifier gains. We show that for a fixed 200 m HNLF length, maximum crosstalk can be reduced by up to 7 dB when amplifying 10x58Gb/s QPSK signals at 20 dB net-gain using a Raman pump of 37 dBm and parametric pump of 28.5 dBm in comparison to a standard single-pump FOPA using 33.4 dBm pump power. It is shown that a significant reduction in four-wave mixing crosstalk is also obtained by reducing the highly nonlinear fibre interaction length. The trend is shown to be generally valid for different net-gain conditions and channel grid size. Crosstalk levels are additionally shown to strongly depend on the Raman/parametric pump power ratio, with a reduction in crosstalk seen for increased Raman pump power contribution. PMID- 26480385 TI - Temperature dependence of spin photocurrent spectra induced by Rashba- and Dresselhaus-type circular photogalvanic effect at inter-band excitation in InGaAs/AlGaAs quantum wells. AB - Spin photocurrent spectra induced by Rashba- and Dresselhaus-type circular photogalvanic effect (CPGE) at inter-band excitation have been experimentally investigated in InGaAs/AlGaAs quantum wells at a temperature range of 80 to 290 K. It is found that, the sign of Rashba-type current reverses at low temperatures, while that of Dresselhaus-type remains unchanged. The temperature dependence of ratio of Rashba and Dresselhaus spin-orbit coupling parameters, increasing from -6.7 to 17.9, is obtained, and the possible reasons are discussed. We also develop a model to extract the Rashba-type effective electric field at different temperatures. It is demonstrated that excitonic effect will significantly influence the Rashba-type CPGE, while it has little effect on Dresselhaus-type CPGE. PMID- 26480386 TI - Chip-based silica microspheres for cavity optomechanics. AB - We have experimentally realized on-chip silica microspheres that feature excellent thermal coupling to the silicon wafer. The chip-based microspheres significantly reduce laser-induced heating and correspondingly exhibit much lower threshold optical power for heating-induced optical bistability. We also show that the chip-based microspheres have optical and especially optomechanical properties that are similar to those of traditional fiber-stem-attached silica microspheres, making the chip-based microspheres suitable for optomechanical studies in a vacuum environment. PMID- 26480387 TI - Modal analysis and efficient coupling of TE01 mode in small-core THz Bragg fibers. AB - We report a design of low-loss THz Bragg fibers with a core size on the order of wavelength that operates near the cutoff frequency of its TE01 mode. We also propose a broadband Y-type mode converter based on branched rectangular metallic waveguides to facilitate coupling between the TE01 mode of the Bragg fiber and the TEM mode in free space with 60% efficiency. Our fiber holds strong promise to facilitate beam-wave interaction in gyrotron for high-efficiency THz generation. PMID- 26480388 TI - InAsP quantum dot lasers grown by MOVPE. AB - We report on InAsP quantum dot lasers grown by MOVPE for 730-780 nm wavelength emission and compare performance with InP dot samples grown under similar conditions and with similar structures. 1-4 mm long, uncoated facet InAsP dot lasers emit between 760 and 775 nm and 2 mm long lasers with uncoated facets have threshold current density of 260 Acm(-2), compared with 150 Acm(-2) for InP quantum dot samples, which emit at shorter wavelengths, 715-725 nm. Pulsed lasing is demonstrated for InAsP dots up to 380 K with up to 200 mW output power. Measured absorption spectra indicate the addition of Arsenic to the dots has shifted the available transitions to longer wavelengths but also results in a much larger degree of spectral broadening. These spectra and transmission electron microscopy images indicate that the InAsP dots have a much larger degree of inhomogeneous broadening due to dot size variation, both from layer to layer and within a layer. PMID- 26480389 TI - Femtosecond solid-state laser based on tungsten disulfide saturable absorber. AB - A new kind of WS2 film was designed, which was composed of few-layer WS2 nanosheets. The nanosheets spread evenly over the SiO2 substrate. By applying the samples into a solid-state laser cavity, excellent mode-locking (ML) performance was obtained. The pulse repetition rate was 86.7 MHz with a pulse width of 736 fs. The results indicate that WS2 material have prosperous application future in solid-state lasers. PMID- 26480390 TI - Improving performance of channel equalization in RSOA-based WDM-PON by QR decomposition. AB - In reflective semiconductor optical amplifier (RSOA)-based wavelength division multiplexed passive optical network (WDM-PON), the bit rate is limited by low modulation bandwidth of RSOAs. To overcome the limitation, we apply QR decomposition in channel equalizer (QR-CE) to achieve successive interference cancellation (SIC) for discrete Fourier transform spreading orthogonal frequency division multiplexing (DFT-S OFDM) signal. Using an RSOA with a 3-dB modulation bandwidth of only ~800 MHz, we experimentally demonstrate a 15.5-Gb/s over 20-km SSMF DFT-S OFDM transmission with QR-CE. The experimental results show that DFTS OFDM with QR-CE attains much better BER performance than DFTS-OFDM and OFDM with conventional channel equalizers. The impacts of several parameters on QR-CE are investigated. It is found that 2 sub-bands in one OFDM symbol and 1 pilot in each sub-band are sufficient to achieve optimal performance and maintain the high spectral efficiency. PMID- 26480391 TI - Towards highly efficient and highly transparent OLEDs: advanced considerations for emission zone coupled with capping layer design. AB - Strategies to achieve efficient transparent organic light-emitting diodes (TrOLEDs) are presented. The emission zone position is carefully adjusted by monitoring the optical phase change upon reflection from the top electrode, which is significant when the thickness of the capping layer changes. With the proposed design strategy, external quantum efficiency and transmittance values as high as 15% and 80% are demonstrated simultaneously. The effect of surface plasmon polariton (SPP) loss from thin metal electrodes is also taken into account to correctly describe the full scaling behavior of the efficiency of TrOLEDs over key optical design parameters. PMID- 26480392 TI - Flexible generation of coherent rectangular pulse from an ultrafast fiber laser based on dispersive Fourier transformation technique. AB - We propose a new solution to flexibly generate the coherent rectangular pulse from an ultrafast fiber laser based on the dispersive Fourier transformation (DFT) technique. The rectangular dissipative soliton (DS) spectra emitted from a net-normal dispersion mode-locked fiber laser is mapped into a time-domain coherent rectangular waveform through the DFT technique. The rectangular pulse can be broadened flexibly with the adjustments of the pump power. The coherence and shot-to-shot fluctuations of the achieved rectangular pulses are further verified by the Mach-Zehnder interference experiment and the recorded single-shot pulse train, respectively. The results demonstrate that the combination of DS mode-locked laser and DFT technique might be indeed an effective and flexible way to achieve highly coherent rectangular pulses. PMID- 26480393 TI - 240-GHz continuously frequency-tuneable Nd:YVO4/LBO laser with two intra-cavity locked etalons. AB - This work reports for the first time on study of a single-frequency Nd:YVO4 laser with intra-cavity frequency doubling, in which quasi-continuous frequency tuning over an ultra-broad range is implemented with two intra-cavity locked etalons and automatic stitching between ranges of smooth scanning of the laser's output frequency. The proposed and demonstrated method allowed to continuously tune the output frequency of the studied 1.5-W Nd:YVO4/LBO laser over a record-breaking broad range of 240 GHz at 532 nm. PMID- 26480394 TI - Dynamical measurement of refractive index distribution using digital holographic interferometry based on total internal reflection. AB - We present a method for dynamically measuring the refractive index distribution in a large range based on the combination of digital holographic interferometry and total internal reflection. A series of holograms, carrying the index information of mixed liquids adhered on a total reflection prism surface, are recorded with CCD during the diffusion process. Phase shift differences of the reflected light are reconstructed exploiting the principle of double-exposure holographic interferometry. According to the relationship between the reflection phase shift difference and the liquid index, two dimensional index distributions can be directly figured out, assuming that the index of air near the prism surface is constant. The proposed method can also be applied to measure the index of solid media and monitor the index variation during some chemical reaction processes. PMID- 26480395 TI - Non-orthogonal optical multicarrier access based on filter bank and SCMA. AB - This paper proposes a novel non-orthogonal optical multicarrier access system based on filter bank and sparse code multiple access (SCMA). It offers released frequency offset and better spectral efficiency for multicarrier access. An experiment of 73.68 Gb/s filter bank-based multicarrier (FBMC) SCMA system with 60 km single mode fiber link is performed to demonstrate the feasibility. The comparison between fast Fourier transform (FFT) based multicarrier and the proposed scheme is also investigated in the experiment. PMID- 26480396 TI - Polarization-selective dynamically tunable multispectral Fano resonances: decomposing of subgroup plasmonic resonances. AB - We analyze the design of near infrared all-optical controllable and dynamically tunable multispectral Fano resonances based on subgroup decomposition of plasmonic resonances in hybrid nanoslits antenna plasmonic system. The theoretical investigation complemented with numerical simulations show that the Fano resonance lines shape can be tailored efficiently and continuously with the nanoslits geometry and the variation of the polarization states of the incident light. The subgroup decomposition of the spectral profile and the modification of plasmonic resonances lineshape that leads to the Fano-type profile of transmission is investigated and revealed. The separate contribution from individual spectral of single-slit array subgroup is attributed to the resulting overall multispectral Fano lineshape of the proposed T-shaped slits array at their corresponding spectral peaks zone. The polarization-selective tunability of the multispectral Fano resonances in the planar hybrid plasmonic system creates new avenues for designing multi-channel multi-wavelength tunable Fano effect. PMID- 26480397 TI - Scalable software-defined optical networking with high-performance routing and wavelength assignment algorithms. AB - The feasibility of software-defined optical networking (SDON) for a practical application critically depends on scalability of centralized control performance. The paper, highly scalable routing and wavelength assignment (RWA) algorithms are investigated on an OpenFlow-based SDON testbed for proof-of-concept demonstration. Efficient RWA algorithms are proposed to achieve high performance in achieving network capacity with reduced computation cost, which is a significant attribute in a scalable centralized-control SDON. The proposed heuristic RWA algorithms differ in the orders of request processes and in the procedures of routing table updates. Combined in a shortest-path-based routing algorithm, a hottest-request-first processing policy that considers demand intensity and end-to-end distance information offers both the highest throughput of networks and acceptable computation scalability. We further investigate trade off relationship between network throughput and computation complexity in routing table update procedure by a simulation study. PMID- 26480398 TI - Broadband plasmon-induced transparency in terahertz metamaterials via constructive interference of electric and magnetic couplings. AB - Plasmon-induced transparency (PIT) is a result of destructive interference of different plasmonic resonators. Due to the extreme dispersion within the narrow transparency window, PIT metamaterials are utilized to realize slow light and nonlinear effect. However, other applications such as broadband filtering more desire a broad transmission frequency band at the PIT resonance. In this paper, a broadband PIT effect is demonstrated theoretically in a planar terahertz metamaterial, consisting of a U-shaped ring (USR) supporting electric and magnetic dipole modes as the bright resonator and a cut wire pair (CWP) possessing planar electric quadrupole and magnetic dipole modes as the dark resonator. The dark resonant modes of the CWP can be excited simultaneously via near-field by both the electric and magnetic dipole modes of the USR. When the electric as well as magnetic excitation pathways constructively interact with each other, the enhanced near-field coupling between bright and dark resonators gives rise to an ultra-broad transparency window across a frequency range greater than 0.61 THz in the transmittance spectrum. PMID- 26480399 TI - Kinetic behavior of light emission in cholesteric liquid crystal lasers: An experimental study. AB - Some dynamical aspects of fluorescence and lasing have been studied in a dye doped cholesteric liquid crystal by measuring the response of the material to nanosecond optical pumping. It has been found that as the pumping energy is increased the fluorescence pulse duration decreases, reaching a minimum at the lasing threshold. Above the threshold the temporal profiles are irregular and consist of a set of narrow pulses whose measured duration is limited by the detector risetime (1 ns). The results are interpreted in terms of a recently proposed model [JETP, 118, 822 (2014)] that makes use of rate equations to account for the laser generation in cholesteric liquid crystals. The prediction of such equations for an experimental configuration appropriate for fluorescence lifetime measurements is analyzed. PMID- 26480400 TI - Generalized analytical model based on harmonic coupling for hybrid plasmonic modes: comparison with numerical and experimental results. AB - Metal nanoparticle arrays have proved useful for different applications due to their ability to enhance electromagnetic fields within a few tens of nanometers. This field enhancement results from the excitation of various plasmonic modes at certain resonance frequencies. In this article, we have studied an array of metallic nanocylinders placed on a thin metallic film. A simple analytical model is proposed to explain the existence of the different types of modes that can be excited in such a structure. Owing to the cylinder array, the structure can support localized surface plasmon (LSP) modes. The LSP mode couples to the propagating surface plasmon (PSP) mode of the thin film to give rise to the hybrid lattice plasmon (HLP) mode and anti-crossing phenomenon. Due to the periodicity of the array, the Bragg modes (BM) are also excited in the structure. We have calculated analytically the resonance frequencies of the BM, LSP and the corresponding HLP, and have verified the calculations by rigorous numerical methods. Experimental results obtained in the Kretschmann configuration also validate the proposed analytical model. The dependency of the resonance frequencies of these modes on the structural parameters such as cylinder diameter, height and the periodicity of the array is shown. Such a detailed study can offer insights on the physical phenomenon that governs the excitation of various plasmonic modes in the system. It is also useful to optimize the structure as per required for the different applications, where such types of structures are used. PMID- 26480401 TI - Efficiency of evanescent excitation and collection of spontaneous Raman scattering near high index contrast channel waveguides. AB - We develop and experimentally verify a theoretical model for the total efficiency eta0 of evanescent excitation and subsequent collection of spontaneous Raman signals by the fundamental quasi-TE and quasi-TM modes of a generic photonic channel waveguide. Single-mode silicon nitride (Si3N4) slot and strip waveguides of different dimensions are used in the experimental study. Our theoretical model is validated by the correspondence between the experimental and theoretical absolute values within the experimental errors. We extend our theoretical model to silicon-on-insulator (SOI) and titanium dioxide (TiO2) channel waveguides and study eta0 as a function of index contrast, polarization of the mode and the geometry of the waveguides. We report nearly 2.5 (4 and 5) times larger eta0 for the fundamental quasi-TM mode when compared to eta0 for the fundamental quasi-TE mode of a typical Si3N4 (TiO2 and SOI) strip waveguide. eta0 for the fundamental quasi-TE mode of a typical Si3N4, (TiO2 and SOI) slot waveguide is about 7 (22 and 90) times larger when compared to eta0 for the fundamental quasi-TE mode of a strip waveguide of the similar dimensions. We attribute the observed enhancement to the higher electric field discontinuity present in high index contrast waveguides. PMID- 26480402 TI - 2-LP mode few-mode fiber amplifier employing ring-core erbium-doped fiber. AB - A fiber amplifier supporting 2 LP modes that employs a ring-core erbium-doped fiber (RC-EDF) is investigated to reduce differential modal gain (DMG). The inner and outer radii of the ring-core of the RC-EDF are clarified for 2-LP mode operation of the amplifier, and are optimized to reduce the DMG. It is shown that using the overlap integral between the erbium-doped core area and the signal power mode distribution is a good way to optimize the inner and outer radii of the ring-core of the RC-EDF and thus minimize the DMG. A fabricated RC-EDF and a constructed 2-LP mode EDFA are described and a small DMG of around 1 dB is realized for LP01, LP11 and LP21 pumping. PMID- 26480403 TI - Signal-noise interaction in nonlinear optical fibers: a hydrodynamic approach. AB - We present a new perturbative approach to the study of signal-noise interactions in nonlinear optical fibers. The approach is based on the hydrodynamic formulation of the nonlinear Schrodinger equation that governs the propagation of light in the fiber. Our method is discussed in general and is developed in more details for some special cases, namely the small-dispersion regime, the continuous-wave (CW) signal and the solitonic pulse. The accuracy of the approach is numerically tested in the CW case. PMID- 26480404 TI - Improved polarization dependent loss tolerance for polarization multiplexed coherent optical systems by polarization pairwise coding. AB - Polarization dependent loss (PDL) causes imbalanced optical signal to noise ratio (OSNR) of the two polarizations, thus remains one of the major bottlenecks for next-generation polarization-division-multiplexed (PDM) coherent optical transmission systems. In this paper, we investigate Pairwise Coding for adaptive PDL mitigation in PDM coherent optical systems. By pre-coding across two polarizations, the PDL-induced performance degradation can be largely mitigated without any coding overhead. We present details of the coding and de-coding design, and also derive the analytical symbol/bit error rate of the Polarization Pairwise Coding scheme, which can be used to predict the performance gain as well as for optimal rotation angle calculation. Simulation results verify that Pairwise Coding achieves substantial system performance gains over a wide range of PDL values. Compared with other digital coding techniques, Polarization Pairwise Coding shows improved performance than Walsh-Hadamard transform since it maximizes the coordinate diversity; and also Pairwise Coding is computationally much simpler to decode compared with the Golden and Silver Codes, therefore is practical for current 100-Gb/s and future 400-Gb/s and 1-Tb/s digital coherent transceivers. PMID- 26480405 TI - Spectral division amplification of a 40 nm bandwidth in a multicore Yb doped fiber and femtosecond pulse synthesis with in-fiber delay line. AB - A compact multicore ytterbium doped fiber amplifier has been implemented according to the spectral division scheme. It was shown that it allows amplification of pulses with about 40 nm wide spectrum. Compensation of the different spectral bands delay through bending and twist of the multicore ribbon fiber followed by appropriate setting of their phase permitted the synthesis of pulses close to 100 fs duration. PMID- 26480406 TI - Perturbative solution for terahertz two-wire metallic waveguides with different radii. AB - We introduce the technique of perturbation of boundary condition to the problem of terahertz two-wire metallic waveguides with different radii. Based on the quasi-TEM analytical mode fields derived by use of Mobius transformation, a concise expression for the complex effective index is obtained analytically. The expression is in good agreement with the simulation result. Further, the dispersion and attenuation are obtained from the expression. In addition, we find a zero value point of the group velocity dispersion around 1.268 THz. The results show that the technique of perturbation of boundary condition is helpful in the analysis and design of terahertz metal waveguide. PMID- 26480407 TI - Color filters based on a nanoporous Al-AAO resonator featuring structure tolerant color saturation. AB - Reflection type subtractive tri-color filters, enabling metal-thickness tolerant high color saturation, were proposed and demonstrated capitalizing on a nanoporous metal-dielectric-metal (MDM) resonant structure, which comprises a cavity made of self-assembled nanoporous anodic aluminum oxide (AAO), sandwiched between an Al film of the same nanoporous configuration and a highly reflective aluminum (Al) substrate. For the proposed filter, the output color was easily determined by controlling the resonance wavelength via the thickness of the porous AAO cavity. In particular, the spectral response was deemed to exhibit a near-zero resonant dip, thereby achieving enhanced color saturation, which was stably maintained irrespective of the thickness of the porous Al film, due to its reduced effective refractive index. In order to manufacture the proposed color filters on a large scale, a porous Al film of hexagonal lattice configuration was integrated with an identically porous self-assembled AAO layer, which has been grown on an Al substrate. For the realized tri-color filters for cyan, magenta, and yellow (CMY), having a 15-nm Al film, near-zero reflection dips were observed to be centered at the wavelengths of 436, 500, and 600 nm, respectively. The resulting enhanced color saturation was stably maintained even though the variations were as large as 10 nm in the metal thickness. PMID- 26480409 TI - Analyzing the temperature sensitivity of Fabry-Perot sensor using multilayer graphene diaphragm. AB - A miniature Fabry-Perot interferometric sensor with an ultra-high temperature sensitivity was constructed by using an approximate 8-layer graphene diaphragm. The extremely thin diaphragm was transferred onto the endface of a ferrule with an inner diameter of 125 MUm, and van der Waals interactions between the graphene diaphragm and its substrate created a low finesse Fabry-Perot interferometer with a cavity length of 42.86 MUm. Temperature testing demonstrated a temperature induced cavity length change of 352 nm/ degrees C with a good linearity in the range of 20-60 degrees C. The result conformed well to the proposed analytical models relating to thermal expansion of trapped gas, thermal-optical property of graphene diaphragm and deflection behavior of bulged graphene blister. However, the ultra-thin diaphragm exhibited a small deflection deformation characteristic due to the applied higher loads. PMID- 26480408 TI - Enhanced resolution in a multimode fiber imaging system. AB - Multimode fibers have recently been demonstrated to be a promising candidate for ultrathin and high resolution endoscopy. However, this method does not offer depth discrimination for fluorescence imaging and the numerical aperture of the fiber limits its resolution. In this paper we demonstrate optical sectioning and enhanced resolution using saturated excitation and temporal modulation. Using a continuous wave laser excitation, we demonstrate improved resolution in all three dimensions and increased image contrast by rejecting out of focus light. PMID- 26480410 TI - Sub-90 fs a stretched-pulse mode-locked fiber laser based on a graphene saturable absorber. AB - In this paper a stretched-pulse, mode-locked Er-doped fiber laser based on graphene saturable absorber (SA) is presented. A 60 layer graphene/polymer composite was used as a SA. The all-fiber dispersion managed laser resonator with the repetition frequency of 21.15 MHz allows for Gaussian pulses generation with the full width at half maximum (FWHM) of 48 nm. The generated chirped pulses were compressed outside the cavity to the 88 fs using a piece of standard single mode fiber. The average output power and pulse energy were of 1.5 mW and 71 pJ, respectively. PMID- 26480411 TI - WS2 saturable absorber for dissipative soliton mode locking at 1.06 and 1.55 um. AB - Transition-metal dichalcogenides, such as tungsten disulfide (WS2) and molybdenium disulfide (MoS2), are highly anisotropic layered materials and have attracted growing interest from basic research to practical applications due to their exotic physical property that may complement graphene and other semiconductor materials. WS2 nanosheets are found to exhibit broadband nonlinear saturable absorption property, and saturable absorbers (SAs) are fabricated by depositing WS2 nanosheets on side-polished fibers. Attributing to the weak evanescent field and long interaction length, the WS2 nanosheets are not exposed to large optical intensity, which allows the SA to work at the high-power regime. The SAs are used to mode lock erbium- and ytterbium-doped fiber lasers with normal dispersion, producing trains of dissipative soliton at 1.55 and 1.06 um respectively. Simulations show that the bandgap of WS2 nanosheets decreases from 1.18 to 0.02 and 0.65 eV by introducing W and S defects respectively, which may contribute to the broadband saturable absorption property of the WS2. PMID- 26480412 TI - Influence of pre-annealing on the thermal regeneration of fiber Bragg gratings in standard optical fibers. AB - A detailed study of the dynamics during thermal regeneration of fiber Bragg gratings, written in hydrogen-loaded standard single-mode fibers using a ns pulsed 213 nm UV laser, is reported. Isothermal pre-annealing performed in the range 85 degrees C to 1100 degrees C, with subsequent grating regeneration at 1100 degrees C, resulted in a maximum refractive index modulation, Deltan(m) ~1.4?10(-4), for gratings pre-annealed near 900 degrees C while a minimum value of Deltan(m) ~2?10(-5) was achieved irrespective of pre-annealing temperature. This optimum denote an inflection point between opposing thermally triggered processes, which we ascribe to the reaction-diffusion mechanism of molecular water and hydroxyl species in silica. The results shed new light on the mechanisms underlying thermal grating regeneration in optical fibers. PMID- 26480413 TI - Organic photo sensors for multi-angle light scattering characterization of particle systems. AB - Organic Photo Sensor (OPS) technology allows printing on conformable plastic-like substrates complex-shaped, arbitrarily-sized and pre-aligned photosensitive elements. This article reports, to the best of our knowledge, the first investigation to implement this emerging technology for Multi-Angle Light Scattering (MALS) characterization of nano- and microparticle suspensions. Monte Carlo and Lorenz-Mie theory calculations as well as preliminary experimental results on latex suspensions clearly demonstrate the potential of the proposed approach. PMID- 26480414 TI - Perspective projection model for prism-based stereovision. AB - A perspective projection model for prism-based stereovision was presented in this paper. The prism was considered as a single optical lens. By analyzing each plane individually and then combining them together, an affine transformation matrix which can express the relationship between an object point and its image was derived. Next, the perspective projection model between object point and its image was established. The methods for model parameter calibration, distortion correction and 3D reconstruction were also provided. The proposed method was based on optical geometry and could be used in a multi-ocular prism. Experimental results are presented to demonstrate the reliability and accuracy of our method which could be used in morphological measurement with high precision. PMID- 26480415 TI - Pattern recognition cytometry for label-free cell classification by 2D light scattering measurements. AB - We develop a pattern recognition cytometric technique for label-free cell classification. Two dimensional (2D) light scattering patterns from single cells and cell aggregates are obtained with a static cytometer. Good performance of the cytometric setup is verified by comparing yeast cell experimental results with theoretical simulations. Adaptive boosting (AdaBoost) method (a machine learning algorithm) is adopted for the analysis of the 2D light scattering patterns. It is shown that aggregates of three yeast cells can be well differentiated from aggregates of four yeast cells by this pattern recognition cytometric technique. We demonstrate that the pattern recognition cytometry can perform label-free classification of normal cervical cells and HeLa cells with a high accuracy rate. PMID- 26480416 TI - Achromatic polarization manipulation by dispersion management of anisotropic meta mirror with dual-metasurface. AB - A dual-metasurface-based reflective device ("meta-mirror") has been proposed for broadband polarization manipulation, which is composed of orthogonal metallic cut wire arrays separated from a grounded plane with different distances. The reflective phases of orthogonally linearly-polarized components can be independently adjusted by changing the dimensions of the cut-wire pairs. Benefiting from the fully released dispersion management ability in both dimensions, achromatic (i.e., ultra-broadband) polarization manipulation can be achieved. The suggested approach has been numerically verified in both microwave and optical band. Moreover, experimental characterization in microwave regime has demonstrated the broadband polarization manipulation ability within 5 - 30 GHz. The underlying physical mechanism of dispersion engineering was explained in general equivalent circuit theory and transmission line model. PMID- 26480417 TI - Sufficient condition for producing photonic band gaps in one-dimensional optical waveguide networks. AB - In this paper, we investigate the influences of the mode, number, and sequence of unit cell on the production of photonic band gaps (PBGs) in one-dimensional (1D) optical waveguide networks (OWNs) and find that the sufficient condition for producing PBG is related to the mode and number of unit cell, but the sequence of unit cell does not affect the production of PBGs. Only when a 1D OWN contains enough evanescent-mode unit cells can it produce PBGs. Otherwise, no matter how the sequence of unit cell is, the 1D OWN can not produce any PBG. It may deepen people's knowledge on the mechanism of the production of PBGs in 1D OWNs and may be useful for the designing of PBG materials/devices. On the other hand, according to the classification method of 1D lattices in solid state physics, we classify the unit cells of OWNs as two types: the simple and complex unit cells. This classification method may be useful for investigating OWNs strictly, deeply, and taxonomically. PMID- 26480418 TI - Sidemode suppression for coupled optoelectronic oscillator by optical pulse power feedforward. AB - Multiple sidemodes have been observed in a coupled optoelectronic oscillator (COEO) when the contained actively mode-locked fiber ring laser employs erbium doped fiber (EDF). We propose that such sidemodes can be suppressed significantly by an optical pulse power feedforward scheme, through which the mode-locked optical pulse is reversely intensity-modulated by itself, resulting in a fast power limiting. Experimentally we show that sidemodes are suppressed as much as 40 dB in a 10-GHz COEO. The additional noise induced by the power feedforward technique is analyzed numerically. We show that for a COEO with a typical cavity length, the feedforward contribution to final single-side band (SSB) noise is minor and neglectable. PMID- 26480419 TI - Laser induced periodic surface structuring on Si by temporal shaped femtosecond pulses. AB - We investigated the effect of temporal shaped femtosecond pulses on silicon laser micromachining. By using sinusoidal spectral phases, pulse trains composed of sub pulses with distinct temporal separations were generated and applied to the silicon surface to produce Laser Induced Periodic Surface Structures (LIPSS). The LIPSS obtained with different sub-pulse separation were analyzed by comparing the intensity of the two-dimensional fast Fourier Transform (2D-FFT) of the AFM images of the ripples (LIPSS). It was observed that LIPSS amplitude is more emphasized for the pulse train with sub-pulses separation of 128 fs, even when compared with the Fourier transform limited pulse. By estimating the carrier density achieved at the end of each pulse train, we have been able to interpret our results with the Sipe-Drude model, that predicts that LIPSS efficacy is higher for a specific induced carrier density. Hence, our results indicate that temporal shaping of the excitation pulse, performed by spectral phase modulation, can be explored in fs-laser microstructuring. PMID- 26480420 TI - Radiation build-up in laminar and turbulent regimes in quasi-CW Raman fiber laser. AB - We study the radiation build-up in laminar and turbulent generation regimes in quasi-CW Raman fiber laser. We found the resulted spectral shape and generation type is defined by the total spectral broadening/narrowing balance over laser cavity round-trip, which is substantially different in different regimes starting from first round-trips of the radiation build-up. In turbulent regime, the steady state is reached only after a few round-trips, while in the laminar regime the laser approaches the equilibrium spectrum shape asymptotically. PMID- 26480421 TI - Cladding-like waveguide structure in Nd:YAG crystal fabricated by multiple ion irradiation for enhanced waveguide lasing. AB - We report on a cladding-like waveguide structure in Nd:YAG crystal fabricated by the multiple carbon ion beam irradiation. After the designed multiple irradiation process, the cladding-like waveguide with triple refractive-index layers were constructed in the region near the surface of the crystal. With such a structure, the waveguiding core was compressed and refractive index profile was modified, resulting in a higher light intensity than that of the single ion-beam-irradiated monolayer waveguide. The waveguide lasing at wavelength of 1064 nm was achieved with enhanced performance in the cladding-like structures with both planar and ridge configurations by the optical pump at 810 nm. PMID- 26480422 TI - Research on the standards of indicators associated with maintain time in bidirectional beam tracking in inter-satellites optical communication links. AB - We report on a novel technology for high-speed inter-satellites optical communication by bidirectional beam tracking. By establishing the relation between the compensation effect and the parameters of response time and overshoot situation, the stability can be well compensated simply by the control system. Thus the relation between compensation effect and maintain time can be predicted from ground tests, and the certain evaluation standard could be established to meet the requirements of system. The other critical factors, such as signal-to noise ratio and pointing angle error, have also been considered to improve the stability. The general approach can provide us a powerful path to overcome the performance limitation of bidirectional beam tracking, which can be expected to be widely applied in Free Space optics communications in future. PMID- 26480423 TI - Polarizer-free liquid crystal display with double microlens array layers and polarization-controlling liquid crystal layer. AB - We propose a polarizer-free liquid crystal display (LCD) consisting of two microlens array (MLA) layers, a twisted nematic (TN) LC layer, and two light blocking masks. By changing the polarization state, focal length of the LCD can be controlled. Since two light-blocking masks have a circular stop pattern and a complementary open pattern, entire gray-scale spectrum may be realized by controlling the intensity of light passing through masks. Ultimately, fast response time characteristics could be achieved due to the alignment of LC molecules on the flat MLA surface. PMID- 26480424 TI - Quantitative sectioning and noise analysis for structured illumination microscopy: erratum. AB - We correct an error in the original manuscript, where an unrecognized assumption was made about the relationship between the out-of-focus light and the in-focus light. We summarize the condition under which the assumption may still hold, and mention alternative methods researchers can use to obtain accurate quantitative sectioning. PMID- 26480425 TI - Axial range of conjugate adaptive optics in two-photon microscopy: erratum. AB - We correct an omission from the Acknowledgments section of our manuscript. PMID- 26480426 TI - Fast Hadamard transforms for compressive sensing of joint systems: measurement of a 3.2 million-dimensional bi-photon probability distribution. AB - We demonstrate how to efficiently implement extremely high-dimensional compressive imaging of a bi-photon probability distribution. Our method uses fast Hadamard-transform Kronecker-based compressive sensing to acquire the joint space distribution. We list, in detail, the operations necessary to enable fast transform-based matrix-vector operations in the joint space to reconstruct a 16.8 million-dimensional image in less than 10 minutes. Within a subspace of that image exists a 3.2 million-dimensional bi-photon probability distribution. In addition, we demonstrate how the marginal distributions can aid in the accuracy of joint space distribution reconstructions. PMID- 26480427 TI - Localized optical manipulation in optical ring resonators. AB - We propose a tunable optical trapping system for nanoparticles based on generating standing wave by coupling two coherent beams into a ring resonator in opposite directions, respectively. The distributions of the mode field excited in three types of the ring-resonators-based trapping systems (microring, microdisk and slot ring) and the corresponding optical forces on the nanoparticles are calculated numerically. By the stability analysis in all directions, the smallest size of the particles could be stably trapped under the Brownian motion in the microring resonator is 61.2 nm when the input power is 10 mW, and the azimuthal orientations of the trapped particles are depended on the phase difference between the two input beams. On the other hand, the appearance of high order radial modes in the microdisk resonator enables a tunable radial trapping. To improve the trapping capability for the smaller particles, we utilize the slot ring resonator to make full use of the optical power and the trapping size could be minimized to ~29 nm when the input power is also set as 10 mW. PMID- 26480428 TI - Single-channel stereoscopic video imaging modality based on transparent rotating deflector. AB - In this study, we developed a single-channel stereoscopic video imaging modality based on a transparent rotating deflector (TRD). Sequential two-dimensional (2D) left and right images were obtained through the TRD synchronized with a camera, and the components of the imaging modality were controlled by a microcontroller unit. The imaging modality was characterized by evaluating the stereoscopic video image generation, rotation of the TRD, heat generation by the stepping motor, and image quality and its stability in terms of the structural similarity index. The degree of depth perception was estimated and subjective analysis was performed to evaluate the depth perception improvement. The results show that the single channel stereoscopic video imaging modality may: 1) overcome some limitations of conventional stereoscopic video imaging modalities; 2) be a potential economical compact stereoscopic imaging modality if the system components can be miniaturized; 3) be easily integrated into current 2D optical imaging modalities to produce a stereoscopic image; and 4) be applied to various medical and industrial fields. PMID- 26480429 TI - Single mode thermal emission. AB - We report on the properties of a thermal emitter which radiates into a single mode waveguide. We show that the maximal power of thermal radiation into a propagating single mode is limited only by the temperature of the thermal emitter and does not depend on other parameters of the waveguide. Furthermore, we show that the power of the thermal emitter cannot be increased by resonant coupling. For a given temperature, the enhancement of the total emitted power is only possible if the number of excited modes is increased. Either a narrowband or a broadband thermal excitation of the mode is possible, depending on the properties of the emitter. We finally discuss an example system, namely a thermal source for silicon photonics. PMID- 26480430 TI - Highly spectrum-selective ultraviolet photodetector based on p-NiO/n-IGZO thin film heterojunction structure. AB - Ultraviolet photodetector with p-n heterojunction is fabricated by magnetron sputtering deposition of n-type indium gallium zinc oxide (n-IGZO) and p-type nickel oxide (p-NiO) thin films on ITO glass. The performance of the photodetector is largely affected by the conductivity of the p-NiO thin film, which can be controlled by varying the oxygen partial pressure during the deposition of the p-NiO thin film. A highly spectrum-selective ultraviolet photodetector has been achieved with the p-NiO layer with a high conductivity. The results can be explained in terms of the "optically-filtering" function of the NiO layer. PMID- 26480431 TI - Optimal distribution of integration time for intensity measurements in Stokes polarimetry. AB - We consider the typical Stokes polarimetry system, which performs four intensity measurements to estimate a Stokes vector. We show that if the total integration time of intensity measurements is fixed, the variance of the Stokes vector estimator depends on the distribution of the integration time at four intensity measurements. Therefore, by optimizing the distribution of integration time, the variance of the Stokes vector estimator can be decreased. In this paper, we obtain the closed-form solution of the optimal distribution of integration time by employing Lagrange multiplier method. According to the theoretical analysis and real-world experiment, it is shown that the total variance of the Stokes vector estimator can be significantly decreased about 40% in the case discussed in this paper. The method proposed in this paper can effectively decrease the measurement variance and thus statistically improves the measurement accuracy of the polarimetric system. PMID- 26480432 TI - Magnetically driven second-harmonic generation with phase matching in MnWO4. AB - Phase matching is known to enhance the nonlinear optical response in materials with a non-centrosymmetric crystallographic or electronic structure. In contrast, phase-matched frequency doubling driven by non-centrosymmetric magnetism that induces acentricity in otherwise centrosymmetric structures has not been reported yet. In our study we demonstrate the emergence of magnetically driven second harmonic generation (SHG) with phase matching in MnWO4. The phase-matched wavelength for SHG can be tuned continuously between 450 nm to 630 nm with the conversion efficiency being determined by the refractive indices and their dispersion. Our findings reveal a new strategy towards magnetism-based conversion materials and a route for controlling the nonlinear signal yield by acting primarily on the material's spin degree of freedom rather than employing its electronic or structural properties. PMID- 26480433 TI - Depolarized guided acoustic wave Brillouin scattering in hollow-core photonic crystal fibers. AB - By performing quantum-noise-limited optical heterodyne detection, we observe polarization noise in light after propagation through a hollow-core photonic crystal fiber (PCF). We compare the noise spectrum to the one of a standard fiber and find an increase of noise even though the light is mainly transmitted in air in a hollow-core PCF. Combined with our simulation of the acoustic vibrational modes in the hollow-core PCF, we are offering an explanation for the polarization noise with a variation of guided acoustic wave Brillouin scattering (GAWBS). Here, instead of modulating the strain in the fiber core as in a solid core fiber, the acoustic vibrations in hollow-core PCF influence the effective refractive index by modulating the geometry of the photonic crystal structure. This induces polarization noise in the light guided by the photonic crystal structure. PMID- 26480434 TI - Linearity improvement of high-speed avalanche photodiodes using thin depleted absorber operating with higher order modulation format. AB - We present an avalanche photodiode (APD) with high-speed, high-responsivity and high-linearity operation to cope with higher order modulation format, such as pulse-amplitude modulation (PAM). A hybrid absorber configuration with thin depleted region which we newly employed successfully eliminates the space charge effect in the APD while maintaining high responsivity and operating speed. The fabricated APD shows an improved optical-input-electrical-output linearity for an optical input power over -8 dBm, and an optical receiver with this APD achieves both an error-free operation with a KP4 FEC and a high sensitivity of -17 dBm against a 28-Gbaud PAM4 signal. PMID- 26480435 TI - Differentiation of morphotic elements in human blood using optical coherence tomography and a microfluidic setup. AB - We demonstrate a novel optical method for the detection and differentiation between erythrocytes and leukocytes that uses amplitude and phase information provided by optical coherence tomography (OCT). Biological cells can introduce significant phase modulation with substantial scattering anisotropy and dominant forward-scattered light. Such physical properties may favor the use of a trans illumination imaging technique. However, an epi-illumination mode may be more practical and robust in many applications. This study describes a new way of measuring the phase modulation introduced by flowing microobjects. The novel part of this invention is that it uses the backscattered signal from the substrate located below the flowing/moving objects. The identification of cells is based on phase-sensitive OCT signals. To differentiate single cells, a custom-designed microfluidic device with a highly scattering substrate is introduced. The microchannels are molded in polydimethylsiloxane (PDMS) mixed with titanium dioxide (TiO2) to ensure high scattering properties. The statistical parameters of the measured signal depend on the cells' features, such as their size, shape, and internal structure. PMID- 26480436 TI - Mode selection in square resonator microlasers for widely tunable single mode lasing. AB - Mode selection in square resonator semiconductor microlasers is demonstrated by adjusting the width of the output waveguide coupled to the midpoint of one side. The simulation and experimental results reveal that widely tunable single mode lasing can be realized in square resonator microlasers. Through adjusting the width of the output waveguide, the mode interval of the high-Q modes can reach four times of the longitudinal mode interval. Therefore, mode hopping can be efficiently avoided and the lasing wavelength can be tuned continuously by tuning the injection current. For a 17.8-MUm-side-length square microlaser with a 1.4 MUm-width output waveguide, mode-hopping-free single-mode operation is achieved with a continuous tuning range of 9.2 nm. As a result, the control of the lasing mode is realized for the square microlasers. PMID- 26480437 TI - Generation of high-quality parabolic pulses with optimized duration and energy by use of dispersive frequency-to-time mapping. AB - We propose and demonstrate a novel linear-optics method for high-fidelity parabolic pulse generation with durations ranging from the picosecond to the sub nanosecond range. This method is based on dispersion-induced frequency-to-time mapping combined with spectral shaping in order to overcome constraints of previous linear shaping approaches. Temporal waveform distortions associated with the need to satisfy a far-field condition are eliminated by use of a virtual time lens process, which is directly implemented in the linear spectral shaping stage. Using this approach, the generated parabolic pulses are able to maintain most energy spectrum available from the input pulse frequency bandwidth, regardless of the target pulse duration, which is not anymore limited by the finest spectral resolution of the optical pulse spectrum shaper. High-quality parabolic pulses, with durations from 25ps to 400ps and output powers exceeding 4dBm before amplification, have been experimentally synthesized from a picosecond mode-locked optical source using a commercial optical pulse shaper with a frequency resolution >10GHz. In particular, we report the synthesis of full-duty cycle parabolic pulses that match up almost exactly with an ideal fitting over the entire pulse period. PMID- 26480438 TI - Direct observation of optical near field in nanophotonics devices at the nanoscale using Scanning Thermal Microscopy. AB - In recent years, following the miniaturization and integration of passive and active nanophotonic devices, thermal characterization of such devices at the nanoscale is becoming a task of crucial importance. The Scanning Thermal Microscopy (SThM) is a natural candidate for performing this task. However, it turns out that the SThM capability to precisely map the temperature of a photonic sample in the presence of light interacting with the sample is limited. This is because of the significant absorption of light by the SThM probe. As a result, the temperature of the SThM probe increases and a significant electrical signal which is directly proportional to the light intensity is obtained. As such, instead of measuring the temperature of the sample, one may directly measure the light intensity profile. While this is certainly a limitation in the context of thermal characterization of nanophotonic devices, this very property provides a new opportunity for optical near field characterization. In this paper we demonstrate numerically and experimentally the optical near field measurements of nanophotonic devices using a SThM probe. The system is characterized using several sets of samples with different properties and various wavelengths of operation. Our measurements indicate that the light absorption by the probe can be even larger than the light induced heat generation in the sample. The frequency response of the SThM system is characterized and the 3 dB frequency response was found to be ~1.5 kHz. The simplicity of the SThM system which eliminates the need for complex optical measurement setups together with its broadband wavelength of operation makes this approach an attractive alternative to the more conventional aperture and apertureless NSOM approaches. Finally, referring to its original role in characterizing thermal effects at the nanoscale, we propose an approach for characterizing the temperature profile of nanophotonic devices which are heated by light absorption within the device. This is achieved by spatially separating between the optical near field distribution and the SThM probe, taking advantage of the broader temperature profile as compared to the more localized light profile. PMID- 26480439 TI - Analysis of the polarization rotation effect in the inversely tapered spot size converter. AB - Inversely tapered spot size converter (SSC) is widely used to connect silicon waveguide with fiber in silicon photonics. However, the tapered structure may cause polarization rotation and further generate interference fluctuation in the transmission spectrum even of a straight waveguide. We analyzed the light propagation in a straight waveguide with SSC at the both ends with coupling matrix and transmission matrix methods. The analysis results matched with the phenomena we observed in the transmission spectrum. Combining the analysis with the measurement results, we calculated the polarization rotation efficiency of the SSC in different samples and analyzed the origin of the polarization rotation effect. Finally, we discussed the influence of the effect to the DP-QPSK signal and proposed several methods to release the impact. PMID- 26480440 TI - Intense 2.89 MUm emission from Dy3+/Yb3+-codoped PbF2 crystal by 970 nm laser diode pumping. AB - A novel Dy(3+)/Yb(3+) co-doped PbF2 mid-IR laser crystal was successfully grown using the vertical Bridgman method. Efficient emission at around 3 MUm from the crystal was observed under excitation of a conventional 970 nm laser diode (LD). The energy transfer efficiency from Yb(3+) to Dy(3+) in Dy(3+)/Yb(3+):PbF2 crystal is as high as (97.7+/-0.3)%. It is also found that the Dy(3+)/Yb(3+):PbF2 crystal possesses long fluorescence lifetime (15.4+/-0.2) ms, high quantum efficiency (95.0+/-0.3)%, and large emission cross section (1.37+/-0.11)*10(-20) cm2 corresponding to the stimulated emission of Dy(3+):(6)H(13/2)->(6)H(15/2) transition. Additionally, the phonon energy of the crystal was analyzed by the Raman spectrum. These results indicate that Dy(3+)/Yb(3+):PbF2 crystal may become a promising material for 3 MUm solid state lasers under a conventional 970 nm LD pump. PMID- 26480441 TI - Second and third harmonic waves excited by focused Gaussian beams. AB - Harmonic generation by tightly-focused Gaussian beams is finding important applications, primarily in nonlinear microscopy. It is often naively assumed that the nonlinear signal is generated predominantly in the focal region. However, the intensity of Gaussian-excited electromagnetic harmonic waves is sensitive to the excitation geometry and to the phase matching condition, and may depend on quite an extended region of the material away from the focal plane. Here we solve analytically the amplitude integral for second harmonic and third harmonic waves and study the generated harmonic intensities vs. focal-plane position within the material. We find that maximum intensity for positive wave-vector mismatch values, for both second harmonic and third harmonic waves, is achieved when the fundamental Gaussian is focused few Rayleigh lengths beyond the front surface. Harmonic-generation theory predicts strong intensity oscillations with thickness if the material is very thin. We reproduced these intensity oscillations in glass slabs pumped at 1550nm. From the oscillations of the 517nm third-harmonic waves with slab thickness we estimate the wave-vector mismatch in a Soda-lime glass as Deltak(H)= -0.249MUm(-1). PMID- 26480442 TI - Self-heterodyne interference spectroscopy using a comb generated by pseudo-random modulation. AB - We present an original instrument designed to accomplish high-speed spectroscopy of individual optical lines based on a frequency comb generated by pseudo-random phase modulation of a continuous-wave (CW) laser. This approach delivers efficient usage of the laser power as well as independent control over the spectral point spacing, bandwidth and central wavelength of the comb. The comb is mixed with a local oscillator generated from the same CW laser frequency-shifted by an acousto-optic modulator, enabling a self-heterodyne detection scheme. The current configuration offers a calibrated spectrum every 1.12 us. We demonstrate the capabilities of the spectrometer by producing averaged, as well as time resolved, spectra of the D1 transition of cesium with a 9.8-MHz point spacing, a 50-kHz resolution and a span of more than 3 GHz. The spectra obtained after 1 ms of averaging are fitted with complex Voigt profiles that return parameters in good agreement with expected values. PMID- 26480443 TI - High angular accuracy manufacture method of micro v-grooves based on tool alignment by on-machine measurement. AB - Micro v-groove has found wide applications in optical areas as one of the most important structures. However, its performance is significantly affected by its angular geometry accuracy. The diamond cutting has been commonly used as the fabrication method of micro v-groove, but it is still difficult to guarantee the cutting tool angle, which is limited by the measurement accuracy in the manufacture and mounting of the diamond tool. A cutting tool alignment method based on the on-machine measurement is proposed to improve the fabricated quality of the v-groove angle. An on-machine probe is employed to scan the v-groove geometrical deviation precisely. The system errors model, data processing algorithm and tool alignment methods are analyzed in details. Experimental results show that the measurement standard deviation within 0.01 degrees can be achieved. Retro-reflection mirrors are fabricated and measured finally by the proposed method for verification. PMID- 26480444 TI - OSOAA: a vector radiative transfer model of coupled atmosphere-ocean system for a rough sea surface application to the estimates of the directional variations of the water leaving reflectance to better process multi-angular satellite sensors data over the ocean. AB - In this study, we present a radiative transfer model, so-called OSOAA, that is able to predict the radiance and degree of polarization within the coupled atmosphere-ocean system in the presence of a rough sea surface. The OSOAA model solves the radiative transfer equation using the successive orders of scattering method. Comparisons with another operational radiative transfer model showed a satisfactory agreement within 0.8%. The OSOAA model has been designed with a graphical user interface to make it user friendly for the community. The radiance and degree of polarization are provided at any level, from the top of atmosphere to the ocean bottom. An application of the OSOAA model is carried out to quantify the directional variations of the water leaving reflectance and degree of polarization for phytoplankton and mineral-like dominated waters. The difference between the water leaving reflectance at a given geometry and that obtained for the nadir direction could reach 40%, thus questioning the Lambertian assumption of the sea surface that is used by inverse satellite algorithms dedicated to multi-angular sensors. It is shown as well that the directional features of the water leaving reflectance are weakly dependent on wind speed. The quantification of the directional variations of the water leaving reflectance obtained in this study should help to correctly exploit the satellite data that will be acquired by the current or forthcoming multi-angular satellite sensors. PMID- 26480445 TI - Mechanism and elimination of bending effect in femtosecond laser deep-hole drilling. AB - In this work, a comprehensive study of the bending effect, which remains one of the most critical challenges during deep-hole drilling, was conducted. The experimental statistics indicate that polarization is not the main factor in bending, but the deviation of the hole tends to be perpendicular to the polarization direction. Also, the dynamic ablated material/plasma was studied. Straight microholes were obtained by extending the interval between laser pulses to avoid dynamic ablated material existing in the millisecond time domain. Therefore, we speculated that the disturbance of the laser beam at the dynamic ablated aerosol, which have not sufficiently dispersed in the millisecond domain, is the main mechanism of bending. However, to more efficiently reduce the disturbance factor, a rough vacuum environment was applied; and the bending effect was also eliminated. The critical pressure for eliminating bending was about 2 * 10(4) Pa that is about one order of magnitude lower than the atmosphere. The fabricated high-quality microhole arrays without bending show that the proposed drilling method is convenient and efficient with high repeatability and controllability. PMID- 26480446 TI - Cellular dye lasers: lasing thresholds and sensing in a planar resonator. AB - Biological cell lasers are promising novel building blocks of future biocompatible optical systems and offer new approaches to cellular sensing and cytometry in a microfluidic setting. Here, we demonstrate a simple method for providing optical gain by using a variety of standard fluorescent dyes. The dye gain medium can be located inside or outside a cell, or in both, which gives flexibility in experimental design and makes the method applicable to all cell types. Due to the higher refractive index of the cytoplasm compared to the surrounding medium, a cell acts as a convex lens in a planar Fabry-Perot cavity. Its effect on the stability of the laser cavity is analyzed and utilized to suppress lasing outside cells. The resonance modes depend on the shape and internal structure of the cell. As proof of concept, we show how the laser output modes are affected by the osmotic pressure. PMID- 26480447 TI - Robust metamodel-based inverse estimation of bulk optical properties of turbid media from spatially resolved diffuse reflectance measurements. AB - Estimation of the bulk optical properties of turbid samples from spatially resolved reflectance measurements remains challenging, as the relation between the bulk optical properties and the acquired spatially resolved reflectance profiles is influenced by wavelength-dependent properties of the measurement system. The resulting measurement noise is apparent in the estimation of the bulk optical properties. In this study, a constrained inverse metamodeling approach is proposed to overcome these problems. First, a metamodel has been trained on a set of intralipid phantoms covering a wide range of optical properties to link the acquired spatially resolved reflectance profiles to the respective combinations of bulk optical properties (absorption coefficient and reduced scattering coefficient). In this metamodel, the wavelength (500 - 1700 nm) is considered as a third input parameter for the model to account for the wavelength dependent effects introduced by the measurement system. Secondly, a smoothness constraint on the reduced scattering coefficient spectra was implemented in the iterative inverse estimation procedure to robustify it against measurement noise and increase the reliability of the obtained bulk absorption and reduced scattering coefficient spectra. As the estimated values in some regions may be more reliable than others, the difference between simulated and measured values as a function of the evaluated absorption and scattering coefficients was combined in a 2D cost function. This cost function was used as a weight in the fitting procedure to find the parameters of the u(s)' function giving the lowest cost over all the wavelengths together. In accordance with previous research, an exponential function was considered to represent the u(s)' spectra of intralipid phantoms. The fitting procedure also provides an absorption coefficient spectrum which is in accordance with the measurements and the estimated parameters of the exponential function. This robust inverse estimation algorithm was validated on an independent set of intralipid(r) phantoms and its performance was also compared to that of a classical single-wavelength inverse estimation algorithm. While its performance in estimating u(a) was comparable (R2 of 0.844 vs. 0.862), it resulted in a large improvement in the estimation of u(s)' (R2 of 0.987 vs. 0.681). The change in performance is more apparent in the improvement of RMSE of u(s)', which decreases from 10.36 cm(-1) to 2.10 cm(-1). The SRS profiles change more sensitively as a function of u(a). As a result, there is a large range of u(s)' and a small range of ua resulting in a good fit between measurement and simulation. The robust inverse estimator incorporates information over the different wavelengths, to increase the accuracy of u(s)'estimations and robustify the estimation process. PMID- 26480448 TI - Numerical calculation of phase-matching properties in photonic crystal fibers with three and four zero-dispersion wavelengths. AB - Photonic crystal fibers with three and four zero-dispersion wavelengths are presented through special design of the structural parameters, in which the closing to zero and ultra-flattened dispersion can be obtained. The unique phase matching properties of the fibers with three and four zero-dispersion wavelengths are analyzed. Variation of the phase-matching wavelengths with the pump wavelengths, pump powers, dispersion properties, and fiber structural parameters is analyzed. The presence of three and four zero-dispersion wavelengths can realize wavelength conversion of optical soliton between two anomalous dispersion regions, generate six phase-matching sidebands through four-wave mixing and create more new photon pairs, which can be used for the study of supercontinuum generation, optical switches and quantum optics. PMID- 26480449 TI - Orthogonal polynomials describing polarization aberration for rotationally symmetric optical systems. AB - Optical lithography has approached a regime of high numerical aperture and wide field, where the impact of polarization aberration on imaging quality turns to be serious. Most of the existing studies focused on the distribution rule of polarization aberration on the pupil, and little attention had been paid to the field. In this paper, a new orthonormal set of polynomials is established to describe the polarization aberration of rotationally symmetric optical systems. The polynomials can simultaneously reveal the distribution rules of polarization aberration on the exit pupil and the field. Two examples are given to verify the polynomials. PMID- 26480450 TI - Signal phase regeneration through multiple wave coherent addition enabled by hybrid optical phase squeezer. AB - A newly proposed concept, which is called hybrid optical phase squeezer (HOPS), achieves multi-level optical phase quantization through coherent addition of two (dual-wave scheme) or three (triple-wave scheme) optical waves exploiting optical parametric processes and electro-optic modulation. The triple-wave scheme enables signal phase regeneration free from phase-to-amplitude noise transfer, which is inevitable in the dual-wave scheme. By using HOPS in the dual-wave scheme, 3-fold phase-noise reduction was achieved for 24-Gb/s QPSK signals with a slight increase of amplitude noise. On the other hand, HOPS in the triple-wave scheme allowed phase regeneration of 12-Gb/s BPSK signal with a suppression of phase-to amplitude noise transfer. PMID- 26480451 TI - Arbitrary-detuning asynchronous optical sampling with amplified laser systems. AB - We demonstrate that Arbitrary-Detuning ASynchronous OPtical Sampling (AD-ASOPS) makes possible multiscale pump-probe spectroscopy with time delays spanning from picosecond to millisecond. The implementation on pre-existing femtosecond amplifiers seeded by independent free-running oscillators is shown to be straightforward. The accuracy of the method is determined by comparison with spectral interferometry, providing a distribution with a standard deviation ranging from 0.31 to 1.7 ps depending on experimental conditions and on the method used to compute the AD-ASOPS delays. PMID- 26480452 TI - Fabrication of a microresonator-fiber assembly maintaining a high-quality factor by CO2 laser welding. AB - We demonstrate fabrication of a microtoroid resonator of a high-quality (high-Q) factor using femtosecond laser three-dimensional (3D) micromachining. A fiber taper is reliably assembled to the microtoroid using CO2 laser welding. Specifically, we achieve a high-Q-factor of 2.12 * 10(6) in the microresonator fiber assembly by optimizing the contact position between the fiber taper and the microtoroid. PMID- 26480453 TI - Focused terahertz waves generated by a phase velocity gradient in a parallel plate waveguide. AB - We demonstrate the focusing of a free-space THz beam emerging from a leaky parallel-plate waveguide (PPWG). Focusing is accomplished by grading the launch angle of the leaky wave using a PPWG with gradient plate separation. Inside the PPWG, the phase velocity of the guided TE1 mode exceeds the vacuum light speed, allowing the wave to leak into free space from a slit cut along the top plate. Since the leaky wave angle changes as the plate separation decreases, the beam divergence can be controlled by grading the plate separation along the propagation axis. We experimentally demonstrate focusing of the leaky wave at a selected location at frequencies of 100 GHz and 170 GHz, and compare our measurements with numerical simulations. The proposed concept can be valuable for implementing a flat and wide-aperture beam-former for THz communications systems. PMID- 26480454 TI - Subduing surface recombination for continuous-wave operation of photonic crystal nanolasers integrated on Silicon waveguides. AB - Detrimental surface recombination of carriers in InP-based photonic crystal nanobeams containing quantum wells is reduced by employing chemical treatment followed by silica encapsulation. Carrier lifetime is shown to recover to 2.63ns close to the bulk value. This enables us to obtain optically pumped room temperature continuous-wave nanolasers at 1.55um integrated onto Silicon on insulator waveguide platform with a threshold of 8uW. PMID- 26480455 TI - Optical side scattering radiometry for high resolution, wide dynamic range longitudinal assessment of optical fibers. AB - Current optical reflectometric techniques used to characterize optical fibers have to trade-off longitudinal range with spatial resolution and therefore struggle to provide simultaneously wide dynamic range (>20dB) and high resolution (<10cm). In this work, we develop and present a technique we refer to as Optical Side Scattering Radiometry (OSSR) capable of resolving discrete and distributed scattering properties of fibers along their length with up to 60dB dynamic range and 5cm spatial resolution. Our setup is first validated on a standard single mode telecoms fiber. Then we apply it to a record-length 11km hollow core photonic band-gap fiber (HC-PBGF) the characterization requirements of which lie far beyond the capability of standard optical reflectometric instruments. We next demonstrate use of the technique to investigate and explain the unusually high loss observed in another HC-PBGF and finally demonstrate its flexibility by measuring a HC-PBGF operating at a wavelength of 2um. In all of these examples, good agreement between the OSSR measurements and other well-established (but more limited) characterization methods, i.e. cutback loss and OTDR, was obtained. PMID- 26480456 TI - Dynamic intensity normalization using eigen flat fields in X-ray imaging. AB - In X-ray imaging, it is common practice to normalize the acquired projection data with averaged flat fields taken prior to the scan. Unfortunately, due to source instabilities, vibrating beamline components such as the monochromator, time varying detector properties, or other confounding factors, flat fields are often far from stationary, resulting in significant systematic errors in intensity normalization. In this work, a simple and efficient method is proposed to account for dynamically varying flat fields. Through principal component analysis of a set of flat fields, eigen flat fields are computed. A linear combination of the most important eigen flat fields is then used to individually normalize each X ray projection. Experiments show that the proposed dynamic flat field correction leads to a substantial reduction of systematic errors in projection intensity normalization compared to conventional flat field correction. PMID- 26480457 TI - Diffraction properties of multilayer Laue lenses with an aperture of 102 um and WSi2/Al bilayers. AB - We report on the characterization of a multilayer Laue lens (MLL) with large acceptance, made of a novel WSi2/Al bilayer system. Fabrication of multilayers with large deposition thickness is required to obtain MLL structures with sufficient apertures capable of accepting the full lateral coherence length of x rays at typical nanofocusing beamlines. To date, the total deposition thickness has been limited by stress-buildup in the multilayer. We were able to grow WSi2/Al with low grown-in stress, and asses the degree of stress reduction. X-ray diffraction experiments were conducted at beamline 1-BM at the Advanced Photon Source. We used monochromatic x-rays with a photon energy of 12 keV and a bandwidth of DeltaE/E=5.4.10(-4). The MLL was grown with parallel layer interfaces, and was designed to have a large focal length of 9.6 mm. The mounted lens was 2.7 mm in width. We found and quantified kinks and bending of sections of the MLL. Sections with bending were found to partly have a systematic progression in the interface angles. We observed kinking in some, but not all, areas. The measurements are compared with dynamic diffraction calculations made with Coupled Wave Theory. Data are plotted showing the diffraction efficiency as a function of the external tilting angle of the entire mounted lens. This way of plotting the data was found to provide an overview into the diffraction properties of the whole lens, and enabled the following layer tilt analyses. PMID- 26480458 TI - Analytical investigation of optical vortices emitted from a collectively polarized dipole array. AB - Many approaches for producing optical vortices have been developed both for fundamental interests of science and for engineering applications. In particular, the approach with direct excitation of several emitters has a potential to control the topological charges with a control of the source conditions without any modifications of structures of the system. In this paper, we investigate the propagation properties of the optical vortices emitted from a collectively polarized electric dipole array as a simple model of the several emitters. Using an analytical approach based on the Jacobi-Anger expansion, we derive a relationship between the topological charge of the optical vortices and the source conditions of the emitter, and clarify and report our new finding; there exists an intrinsic split of the singular points in the electric field due to the spin-orbit interaction of the dipole fields. PMID- 26480459 TI - Additive mode-locked resembling pulses in a Tm-doped fiber laser with a hybrid cavity configuration. AB - We report on the generation of modulated spikes distributed across a mode-locked pulse profile, which is termed as "additive mode-locked resembling (AMLR)", in a Tm-doped fiber laser with a hybrid cavity configuration based on nonlinear polarization rotation (NPR) technique. The hybrid cavity configuration is composed of a ring cavity containing a micro Fabry-Perot (F-P) cavity. The F-P cavity is used to take the cavity-trip frequency (CTF) modulation on the mode locked pulses for forming AMLR pulses. We observe AMLR pulses with uniform and chirped modulation depths, as well as uniform and nonuniform spike separations, respectively. Numerical simulations confirm the experimental observations and show that the filtering effect of the F-P cavity is the main mechanism for taking CTF modulation on mode-locked pulses to generate AMLR pulses. PMID- 26480460 TI - Two-photon imaging of a magneto-fluorescent indicator for 3D optical magnetometry. AB - We developed an optical method to visualize the three-dimensional distribution of magnetic field strength around magnetic microstructures. We show that the two photon-excited fluorescence of a chained donor-bridge-acceptor compound, phenanthrene-(CH2)12-O-(CH2)2-N,N-dimethylaniline, is sensitive to ambient magnetic field strength. A test structure is immersed in a solution of the magneto-fluorescent indicator and a custom two-photon microscope maps the fluorescence of this compound. The decay kinetics of the electronic excited state provide a measure of magnetic field that is insensitive to photobleaching, indicator concentration, or local variations in optical excitation or collection efficiency. PMID- 26480461 TI - Iterative optimum frequency combination method for high efficiency phase imaging of absorptive objects based on phase transfer function. AB - In this work, an optimum frequency combination (OFC) method is proposed to reconstruct high quality phase information of the complex light field, which is really valuable for many objects such as optical elements and cells. It is shown that the difference image between two symmetrical separated, larger defocused planes contains a lot of lower frequency components of the phase distribution and the higher frequency components can be easily observed in the difference image between two nearly focused planes. Based on the phase transfer function (PTF), our method combines different frequency components with high Signal-to-Noise Ratio (SNR) together to estimate a more accurate frequency spectrum of the object's phase distribution without any complicated linear or nonlinear regression. Then, we can directly reconstruct a high-quality phase map through inverse Fourier transform. What's more, in order to compensate the phase discrepancy resulted from strong absorption in the intensity, an iterative compensation algorithm is proposed. Both the simulation and experimental results demonstrate that our iterative OFC (IOFC) method can give a computationally efficient and noise-robust phase reconstruction for absorptive phase objects with higher accuracy and fewer defocus planes. PMID- 26480462 TI - Spectral-domain optical coherence tomography with dual-balanced detection for auto-correlation artifacts reduction. AB - We developed a spectral domain optical coherence tomography (SD-OCT) to reduce auto-correlation artifacts (AC) using dual-balanced detection (DBD). AC were composed of the interference signals between different sample tissue depths, and shown up as artifacts in OCT images. This system employed a free-space Michelson interferometer, at the refraction plane of whose beam splitter, the light reflected experienced a pi/2 phase shift with respect to the light transmitted. Then two phase-opposed interferometric spectra sharing the same spectrometer optics were obtained simultaneously using two lines of a three-line CCD. This new design was of lower cost compared to the dual spectrometer design reported previously. DBD enabled this SD-OCT to achieve two-fold increase in the interested signal amplitude inherently, and obtain a SNR increase of ~2.9 dB experimentally. To demonstrate the feasibility and performance of this SD-OCT system with DBD, we conducted an imaging experiment using a glass plate to obtain the optimal spectral matching between dual-balanced spectrometer channels. As a result, this SD-OCT achieved AC reduction up to about 9 dB and direct current (DC) term suppression up to about 30 dB by cancelling the identical components between dual-balanced spectrometer channels. The efficacy of AC reduction and DC suppression was validated by imaging the polymer coating of a drug-eluting stent and fresh swine corneal tissue ex vivo. The quality of DBD optimized images was significantly improved with regard to the single-channel images. PMID- 26480463 TI - Real-time optical wireless transmissions of digital TV signals using white InGaN LEDs grown with an asymmetric quantum barrier. AB - The feasibility of using InGaN LEDs grown with asymmetric barrier layer (ABL) as transmitters in visible light communications is investigated experimentally. Compared with normal LEDs, the improvement in the spontaneous emission rate due to enhanced carrier localization and better uniformity of carrier distribution in ABL-containing MQWs leads to the fabricated LEDs can exhibit a 32.6% (@ 350 mA) increase in emission intensity and a 10.5% increase in modulation bandwidth. After eliminating the slow-responding phosphorescent components emitting from the phosphor-converted white LEDs, an open eye-diagram at 180 Mb/s is demonstrated over a distance of 100 cm in directed line-of-sight optical links. With the use of proposed LEDs, real-time transmissions of digital TV signals over a moderate distance (~100 cm) in free space is shown to be available in a 150 Mbit/s white LED-based optical link with conventional on-off keying modulation. PMID- 26480464 TI - Measurement of depth-resolved thermal deformation distribution using phase contrast spectral optical coherence tomography. AB - An updated B-scan method is proposed for measuring the evolution of thermal deformation fields in polymers. In order to measure the distributions of out-of plane deformation and normal strain field, phase-contrast spectral optical coherence tomography (PC-SOCT) was performed with the depth range and resolution of 4.3 mm and 10.7 MUm, respectively, as thermal loads were applied to three different multilayer samples. The relation between temperature and material refractive index was predetermined before the measurement. After accounting for the refractive index, the thermal deformation fields in the polymer were obtained. The measured thermal expansion coefficient of silicone sealant was approximately equal to its reference value. This method allows correctly assessing the mechanical properties in semitransparent polymers. PMID- 26480465 TI - Cascaded random distributed-feedback Raman fiber laser assisted by Fresnel reflection. AB - We propose a new type of cascaded random distributed- feedback Raman fiber laser (RD-RFL), with the linear output at the second-order Stokes wavelength. The guideline about building such a RD-RFL with particular output power and conversion efficiency is presented based on numerical study. We also experimentally instantiate the principle, and confirm the effectiveness of the scheme on lasing generation. Moreover, the added Fresnel reflection feature maintains the simplicity and flexibility of the RD-RFL. PMID- 26480466 TI - Adaptive mode control of a few-mode fiber by real-time mode decomposition. AB - A novel approach to adaptively control the beam profile in a few-mode fiber is experimentally demonstrated. We stress the fiber through an electric-controlled polarization controller, whose driven voltage depends on the current and target modal content difference obtained with the real-time mode decomposition. We have achieved selective excitations of LP01 and LP11 modes, as well as significant improvement of the beam quality factor, which may play crucial roles for high power fiber lasers, fiber based telecommunication systems and other fundamental researches and applications. PMID- 26480467 TI - High-power, high-repetition-rate performance characteristics of beta-BaB2O4 for single-pass picosecond ultraviolet generation at 266 nm. AB - We report a systematic study on the performance characteristics of a high-power, high-repetition-rate, picosecond ultraviolet (UV) source at 266 nm based on beta BaB2O4 (BBO). The source, based on single-pass fourth harmonic generation (FHG) of a compact Yb-fiber laser in a two-crystal spatial walk-off compensation scheme, generates up to 2.9 W of average power at 266 nm at a pulse repetition rate of ~80 MHz with a single-pass FHG efficiency of 35% from the green to UV. Detrimental issues such as thermal effects have been studied and confirmed by performing relevant measurements. Angular and temperature acceptance bandwidths in BBO for FHG to 266 nm are experimentally determined, indicating that the effective interaction length is limited by spatial walk-off and thermal gradients under high-power operation. The origin of dynamic color center formation due to two-photon absorption in BBO is investigated by measurements of intensity dependent transmission at 266 nm. Using a suitable theoretical model, two-photon absorption coefficients as well as the color center densities have been estimated at different temperatures. The measurements show that the two-photon absorption coefficient in BBO at 266 nm is ~3.5 times lower at 200 degrees C compared to that at room temperature. The long-term power stability as well as beam pointing stability is analyzed at different output power levels and focusing conditions. Using cylindrical optics, we have circularized the generated elliptic UV beam to a circularity of >90%. To our knowledge, this is the first time such high average powers and temperature-dependent two-photon absorption measurements at 266 nm are reported at repetition rates as high as ~80 MHz. PMID- 26480468 TI - Avoiding the requirement for pre-existing optical contact during picosecond laser glass-to-glass welding: erratum. AB - The results presented in Fig. 8 were incorrect; the growth in the weld structure presented was due to the laser taking 3 ms to reach full power. Here we present a corrected version of the figure and associated discussion. It should be noted that this affects only the exact number of pulses required to form the weld structure and some of the low pulse number observations. This does not therefore affect the theory presented in the paper. In addition Fig. 9 and Fig. 10 were reversed in the published version. The correct figures are presented below. PMID- 26480469 TI - The feasibility and acceptability of a brief Acceptance and Commitment Therapy (ACT) group intervention for people with psychosis: The 'ACT for life' study. AB - BACKGROUND AND OBJECTIVES: Acceptance and Commitment Therapy (ACT) is a contextual cognitive-behavioural approach with a developing evidence base for clinical and cost-effectiveness as an individually-delivered intervention to promote recovery from psychosis. ACT also lends itself to brief group delivery, potentially increasing access to therapy without inflating costs. This study examined, for the first time, the feasibility and acceptability of ACT groups for people with psychosis (G-ACTp). METHODS: Participants were recruited from community psychosis teams. Ratings of user satisfaction, and pre-post change in self-rated functioning (primary outcome), mood (secondary outcome) and ACT processes were all completed with an independent assessor. Of 89 people recruited, 83 completed pre measures, 69 started the four-week G-ACTp intervention, and 65 completed post measures. RESULTS: Independently assessed acceptability and satisfaction were high. Functioning (Coeff. = -2.4, z = -2.9, p = 0.004; 95% CI: -4.0 to -0.8; within subject effect size (ES) d = 0.4) and mood (Coeff. = -2.3, z = -3.5, p = 0.001; 95% CI: -3.5 to -1.0; d = 0.4) improved from baseline to follow-up. Commensurate changes in targeted ACT processes were consistent with the underlying model. LIMITATIONS: The uncontrolled, pre-post design precluded blinded assessments, and may have inflated effect sizes. Participants may have improved as a result of other factors, and findings require replication in a randomized controlled trial (RCT). CONCLUSIONS: This preliminary study showed that brief group ACT interventions for people with psychosis are feasible and acceptable. Uncontrolled, pre-post assessments suggest small clinical improvements, and changes in psychological processes consistent with an ACT model. Replication in an RCT is required, before implementation can be recommended. PMID- 26480470 TI - Linking chlorophyll biosynthesis to a dynamic plastoquinone pool. AB - Chlorophylls are essential cofactors in photosynthesis. All steps in the chlorophyll pathway are well characterized except for the cyclase reaction in which the fifth ring of the chlorophyll molecule is formed during conversion of Mg-protoporphyrin IX monomethyl ester into Protochlorophyllide. The only subunit of the cyclase identified so far, is AcsF (Xantha-l in barley and Chl27 in Arabidopsis). This subunit contains a typical consensus di-iron-binding sequence and belongs to a subgroup of di-iron proteins, such as the plastid terminal oxidase (PTOX) in the chloroplast and the alternative oxidase (AOX) found in mitochondria. In order to complete the catalytic cycle, the irons of these proteins need to be reduced from Fe(3+) to Fe(2+) and either a reductase or another form of reductant is required. It has been reported that the alternative oxidase (AOX) and the plastid terminal oxidase (PTOX) utilize the di-iron center to oxidise ubiquinol and plastoquinol, respectively. In this paper, we have used a specific inhibitor of di-iron proteins as well as Arabidopsis and barley mutants affected in regulation of photosynthetic electron flow, to show that the cyclase step indeed is directly coupled to the plastoquinone pool. Thus, plastoquinol might act as an electron donor for the cyclase reaction and thereby fulfil the role of a cyclase reductase. That would provide a functional connection between the redox status of the thylakoids and the biosynthesis of chlorophyll. PMID- 26480471 TI - Gd-AAZTA-MADEC, an improved blood pool agent for DCE-MRI studies on mice on 1 T scanners. AB - A novel MRI blood-pool contrast agent (Gd-AAZTA-MADEC) has been compared with established blood pool agents for tumor contrast enhanced images and angiography. Synthesis, relaxometric properties, albumin binding affinity and pharmacokinetic profiles are reported. For in vivo studies, angiographic images and tumor contrast enhanced images were acquired on mice with benchtop 1T-MRI scanners and compared with MS-325, B22956/1 and B25716/1. The design of this contrast agent involved the elongation of the spacer between the targeting deoxycholic acid moiety and the Gd-AAZTA imaging reporting unit that drastically changed either the binding affinity to albumin (KA(HSA) = 8.3 * 10(5) M(-1)) and the hydration state of the Gd ion (q = 2) in comparison to the recently reported B25716/1. The very markedly high binding affinity towards mouse and human serum albumins resulted in peculiar pharmacokinetics and relaxometric properties. The NMRD profiles clearly indicated that maximum efficiency is attainable at magnetic field strength of 1 T. In vivo studies showed high enhancement of the vasculature and a prolonged accumulation inside tumor. The herein reported pre-clinical imaging studies show that a great benefit arises from the combination of a benchtop MRI scanner operating at 1 T and the albumin-binding Gd-AAZTA-MADEC complex, for pursuing enhanced angiography and improved characterization of tumor vascular microenvironment. PMID- 26480472 TI - Horizontal gene transfer from macrophages to ischemic muscles upon delivery of naked DNA with Pluronic block copolymers. AB - Intramuscular administration of plasmid DNA (pDNA) with non-ionic Pluronic block copolymers increases gene expression in injected muscles and lymphoid organs. We studied the role of immune cells in muscle transfection upon inflammation. Local inflammation in murine hind limb ischemia model (MHLIM) drastically increased DNA, RNA and expressed protein levels in ischemic muscles injected with pDNA/Pluronic. The systemic inflammation (MHLIM or peritonitis) also increased expression of pDNA/Pluronic in the muscles. When pDNA/Pluronic was injected in ischemic muscles the reporter gene, Green Fluorescent Protein (GFP) co-localized with desmin(+) muscle fibers and CD11b(+) macrophages (MOs), suggesting transfection of MOs along with the muscle cells. P85 enhanced (~ 4 orders) transfection of MOs with pDNA in vitro. Moreover, adoptively transferred MOs were shown to pass the transgene to inflamed muscle cells in MHLIM. Using a co-culture of myotubes (MTs) and transfected MOs expressing a reporter gene under constitutive (cmv-luciferase) or muscle specific (desmin-luciferase) promoter we demonstrated that P85 enhances horizontal gene transfer from MO to MTs. Therefore, MOs can play an important role in muscle transfection with pDNA/Pluronic during inflammation, with both inflammation and Pluronic contributing to the increased gene expression. pDNA/Pluronic has potential for therapeutic gene delivery in muscle pathologies that involve inflammation. PMID- 26480473 TI - DNA-binding-domain fusions enhance the targeting range and precision of Cas9. AB - The CRISPR-Cas9 system is commonly used in biomedical research; however, the precision of Cas9 is suboptimal for applications that involve editing a large population of cells (for example, gene therapy). Variations on the standard Cas9 system have yielded improvements in the precision of targeted DNA cleavage, but they often restrict the range of targetable sequences. It remains unclear whether these variants can limit lesions to a single site in the human genome over a large cohort of treated cells. Here we show that by fusing a programmable DNA binding domain (pDBD) to Cas9 and attenuating Cas9's inherent DNA-binding affinity, we were able to produce a Cas9-pDBD chimera with dramatically improved precision and an increased targeting range. Because the specificity and affinity of this framework can be easily tuned, Cas9-pDBDs provide a flexible system that can be tailored to achieve extremely precise genome editing at nearly any genomic locus. PMID- 26480474 TI - Continuously tunable nucleic acid hybridization probes. AB - In silico-designed nucleic acid probes and primers often do not achieve favorable specificity and sensitivity tradeoffs on the first try, and iterative empirical sequence-based optimization is needed, particularly in multiplexed assays. We present a novel, on-the-fly method of tuning probe affinity and selectivity by adjusting the stoichiometry of auxiliary species, which allows for independent and decoupled adjustment of the hybridization yield for different probes in multiplexed assays. Using this method, we achieved near-continuous tuning of probe effective free energy. To demonstrate our approach, we enforced uniform capture efficiency of 31 DNA molecules (GC content, 0-100%), maximized the signal difference for 11 pairs of single-nucleotide variants and performed tunable hybrid capture of mRNA from total RNA. Using the Nanostring nCounter platform, we applied stoichiometric tuning to simultaneously adjust yields for a 24-plex assay, and we show multiplexed quantitation of RNA sequences and variants from formalin-fixed, paraffin-embedded samples. PMID- 26480477 TI - The Interconnectedness of Diet Choice and Distance Running: Results of the Research Understanding the NutritioN of Endurance Runners (RUNNER) Study. AB - This study examined differences in diet, particularly vegetarian and vegan, among ultramarathon and other long distance runners. Participants who had completed a half- (HALF), full- (FULL), or ultramarathon (ULTRA) in the past 12 months were recruited to complete an online survey assessing current diet, reason for diet, and other dietary behaviors. A total of 422 participants completed the survey (n=125 ULTRA, n=152 FULL, n=145 HALF). More ULTRA participants were men (63%) (vs. FULL (37%) and HALF (23%)) and ULTRA participants reported significantly more years of running (16.2 +/- 13.6) than FULL (12.1 +/- 11.1, P<0.05) or HALF (10.6 +/- 11.6, P<0.05). Body Mass Index (self-reported height/weight) was significantly higher in HALF (24.3 +/- 4.4 kg/m2) vs. FULL (23.1 +/- 3.2 kg/m2, P<0.05). ULTRA runners were almost twice as likely to report following a vegan/vegetarian diet than HALF and FULL marathoners combined (B=1.94, 95% CI=1.08, 3.48) and reported following their current diet longer (13.7+/-15.3 years) than HALF participants (8.6+/-12.1 years, P=0.01). ULTRA participants more commonly cited environmental concerns whereas HALF and FULL participants cited weight loss or maintenance as a reason for following their current diet. There was no difference in diet quality between ULTRA and other runners but vegan and vegetarian runners had higher diet quality scores than non-vegetarian runners (P<0.001). The findings point to an interconnectedness between long distance running, diet, and diet choice and can help guide nutrition, exercise, and psychology professionals who are working with distance runners. PMID- 26480476 TI - Risk factors to develop autonomic dysreflexia during urodynamic examinations in patients with spinal cord injury. AB - AIMS: The risk factors for developing autonomic dysreflexia (AD) during urodynamic (UD) examination in patients with spinal cord injury (SCI) above Th6 still remain unclear. The main goal of our study is to investigate the risk factors that could be associated with AD in these particular patients. DESIGN: Cross sectional survey. SUBJECT AND METHODS: The study was carried out in 83 patients with SCI above Th6 who were submitted to our center for a UD examination. AD was defined as a rise in systolic blood pressure above 15 mm Hg with a pulse rate below 60 beats per minute. RESULTS: The prevalence rate of AD among our patients was 54%. Univariate analysis of our study showed the following risk factors: patient's age, SCI completeness, traumatic etiology, indwelling catheter, presence of chills or sweating, anticholinergic treatment, maximum detrusor voiding pressure, detrusor pressure at maximum flow rate, detrusor external sphincter dyssynergia, and bladder outlet obstruction. Using multivariate logistic regression, we found that there are only two independent risk factors: patient's age equal to or above 45 years of age (OR = 10.995) and maximum detrusor voiding pressure equal to or above 31 cm H2 O (OR = 3.879). CONCLUSIONS: According to our results, the patient's age and maximum detrusor voiding pressure should be considered at the time of performing a UD examination in order to prevent the sudden onset of AD in patients with SCI above Th6. Neurourol. Urodynam. 36:171-175, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26480475 TI - Tissue matrix arrays for high-throughput screening and systems analysis of cell function. AB - Cell and protein arrays have demonstrated remarkable utility in the high throughput evaluation of biological responses; however, they lack the complexity of native tissue and organs. Here we spotted tissue extracellular matrix (ECM) particles as two-dimensional (2D) arrays or incorporated them with cells to generate three-dimensional (3D) cell-matrix microtissue arrays. We then investigated the responses of human stem, cancer and immune cells to tissue ECM arrays originating from 11 different tissues. We validated the 2D and 3D arrays as representative of the in vivo microenvironment by means of quantitative analysis of tissue-specific cellular responses, including matrix production, adhesion and proliferation, and morphological changes after culture. The biological outputs correlated with tissue proteomics, and network analysis identified several proteins linked to cell function. Our methodology enables broad screening of ECMs to connect tissue-specific composition with biological activity, providing a new resource for biomaterials research and further understanding of regeneration and disease mechanisms. PMID- 26480478 TI - Transferable Measurements of Heredity in Models of the Origins of Life. AB - We propose a metric which can be used to compute the amount of heritable variation enabled by a given dynamical system. A distribution of selection pressures is used such that each pressure selects a particular fixed point via competitive exclusion in order to determine the corresponding distribution of potential fixed points in the population dynamics. This metric accurately detects the number of species present in artificially prepared test systems, and furthermore can correctly determine the number of heritable sets in clustered transition matrix models in which there are no clearly defined genomes. Finally, we apply our metric to the GARD model and show that it accurately reproduces prior measurements of the model's heritability. PMID- 26480479 TI - Initial fungal effector production is mediated by early endosome motility. AB - Fungal plant pathogenicity is facilitated by effector proteins that are specifically expressed during infection and are responsible for suppressing plant defense mechanisms. Recent studies have elucidated the detailed molecular mechanisms of effector action throughout fungal infection. However, little is known about the trafficking and secretion of effectors in fungal hyphae during the initial stage of infection. Using state-of-the-art microscopy we have demonstrated that early endosome (EE) motility is required for effector production during fungal infection. Moreover, the MAPK Crk1 has been shown to travel on EEs and to function as a negative regulator of effector expression, suggesting that motile EEs are involved in signal transduction. Here I further discuss possible mechanisms whereby EE motility regulates effector expression in the initial stages of infection. PMID- 26480482 TI - [Septic Shock: Innate Molecular Genetic Mechanisms of the Development of Generalized Inflammation]. AB - The capacity for immune surveilance and protection against genetically alien agents is a basic property of multicellular organisms, and increasing significance in realizing this, capacity is assigned to mechanisms of innate immunity. The data accumulated to date show that many components of these mechanisms have a very wide spectrum of biological functions and play essential roles at different stages of ontogeny. An illustrative example is the signal system activated by tumor necrosis factor alpha (TNFalpha), which is responsible for the inflammation process. Analysis of its structural organization has shown that signaling mechanisms initiating inflammation largely overlap with mechanisms of programmed cell death. This is why hypersecretion of TNFalpha may lead to systemic inflammatory reation, or septic shok, and, hence, have a fatal outcome. Although studies on the TNFalpha-dependent mechanism have long history, many aspects of its regulation remain obscure. In particular, this concerns the nature of interspecific differences in the sensitivity of mammals to TNFalpha action and the ability of TNFalpha to activate oppositely directed cell programs depending on cell type or ambient conditions. The numerous data obtained in studies on different experimental systems need generalization and critical analysis. This review is an attempt at such an analysis. Its scope is concentrated on modern views on the divergence of TNFalpha-induced signal at the level of intracellular receptor-associated proteins. A description is given to potential "molecular triggers" responsible for switching between the main TNFalpha-dependent signaling pathways: inflammation, apoptosis, and necroptosis. The contribution of necroptosis (genetically programmed necrotic cell death) to the development of systemic inflammation and the lethal effect of TNFalpha are described. Consideration is also given to various lines of mice possessing natural resistance or sensitivity to TNFalpha, which hold much promise as models for deciphering the molecular genetic bases of the regulation of innate immune reactions and other TNFalpha-dependent processes. PMID- 26480481 TI - [Extrathymic Differentiation of alphabetaT Lymphocytes]. AB - Extrathymic differentiation is an alternative way of alphabetaT lymphocyte development. In normal conditions it is expressed slightly and limited mainly to the liver and intestinal mucous. However, it increases significantly with age, as well as in certain physiological and pathological conditions, buying more widespread. In the review, the phenotypical and functional features of extrathymic T lymphocytes have been considered in detail depending on their localization and a way of the process activation. The mechanisms of such differentiation induction have been analyzed. Special attention is paid to the biological significance of extrathymic alphabetaT cell development. PMID- 26480480 TI - Disrupted Renal Mitochondrial Homeostasis after Liver Transplantation in Rats. AB - BACKGROUND: Suppressed mitochondrial biogenesis (MB) contributes to acute kidney injury (AKI) after many insults. AKI occurs frequently after liver transplantation (LT) and increases mortality. This study investigated whether disrupted mitochondrial homeostasis plays a role in AKI after LT. METHODS: Livers were explanted from Lewis rats and implanted after 18 h cold storage. Kidney and blood were collected 18 h after LT. RESULTS: In the kidney, oxidative phosphorylation (OXPHOS) proteins ATP synthase-beta and NADH dehydrogenase-3 decreased 44% and 81%, respectively, with marked reduction in associated mRNAs. Renal PGC-1alpha, the major regulator of MB, decreased 57% with lower mRNA and increased acetylation, indicating inhibited synthesis and suppressed activation. Mitochondrial transcription factor-A, which controls mtDNA replication and transcription, protein and mRNA decreased 66% and 68%, respectively, which was associated with 64% decreases in mtDNA. Mitochondrial fission proteins Drp-1 and Fis-1 and mitochondrial fusion protein mitofusin-1 all decreased markedly. In contrast, PTEN-induced putative kinase 1 and microtubule-associated protein 1A/1B light chain 3 increased markedly after LT, indicating enhanced mitophagy. Concurrently, 18- and 13-fold increases in neutrophil gelatinase-associated lipocalin and cleaved caspase-3 occurred in renal tissue. Both serum creatinine and blood urea nitrogen increased >2 fold. Mild to moderate histological changes were observed in the kidney, including loss of brush border, vacuolization of tubular cells in the cortex, cast formation and necrosis in some proximal tubular cells. Finally, myeloperoxidase and ED-1 also increased, indicating inflammation. CONCLUSION: Suppression of MB, inhibition of mitochondrial fission/fusion and enhancement of mitophagy occur in the kidneys of recipients of liver grafts after long cold storage, which may contribute to the occurrence of AKI and increased mortality after LT. PMID- 26480483 TI - [Life Forms of Lampreys (Petromyzontidae) as a Manifestation of Intraspecific Diversity of Ontogenesis]. AB - Some lamprey genera include the forms that have significantly different life cycles (the most well-known are the "anadromous" and "resident," or the "parasitic" and "nonparasitic" forms). The analysis of data on the genetic characteristics of these forms shows that, in some cases, the nonparasitic lampreys independently derived from the parasitic ones in different aqueous systems. These data, together with the results of morphological analysis as well as data on the distribution, ecology, hybridization, and observations ofjoint spawning of parasitic and nonparasitic forms show that these forms belong to the same species (except the resident forms that were isolated long ago). PMID- 26480484 TI - [Morphogenesis of Human Fetal Thymus during Weeks 22-27 of Development]. AB - Distinctive features of human fetal thymus morphogenesis in early ontogeny in the case of uncomplicated pregnancy have been characterized. A steady increase of thymus dimensions and weight occurred concomitantly to differentiation of morphofunctional zones within the organ. Cell differentiation in the subcapsular and inner cortical zones of the thymus lobes was manifested as changes in parameters of expression of T-lymphocyte antigens CD1, CD2, and CD3 and ultrastructural features of reticuloepithelial cells (REC) type I and II forming a microenvironment for lymphocytes. RECs of the medullar zone formed a glomerular syncytium with desmosomal interepithelial contacts by week 22 of fetal development. Small lymphocytes predominated among thymocytes (66%). Hassall's corpuscles, the structural correlates of morphological and functional maturity, predominated in the fetal thymuses during developmental weeks 25-27. PMID- 26480485 TI - [In vitro Regeneration from Bulbous Scales of Fritillaria sonnikovae, an Endemic Species]. AB - Features of in vitro regeneration of Fritillaria sonnikovae from bulb scales were studied. The initiation of shoot formation was obtained on a nutrient medium BDS, supplemented with 5 uM 6-benzylaminopurine and 2 uM alpha-naphthaleneacetic acid. Optimization of propagation stage was carried out using obtained microbulbs as explants. High regenerative response of explants and shoot multiplication rate were observed on both media supplemented with growth regulators (up to 47% and 4.2 +/- 0.6 pcs./explant, respectively) and hormone-free medium (48% and 4.1 +/- 0.2 shoots per explant, respectively). It has been established that the ad- dition of growth regulators on the stage of cultivation does not cause increased morphogenic response but contributes to the accelerated initiation and development of microbulbs. Morphological and histological analysis revealed the dynamics of the formation of shoots de novo. In vitro development of F. sonnikovae follows the path of direct organogenesis from the epidermal tissue of the explant. PMID- 26480486 TI - [Early Stages of Skull Embryogenesis in the Grass Snake, Natrix natrix (Serpentes, Colubridae)]. AB - Studies of previous authors on snake skull embryogenesis have been performed on embryos obtained from eggs after oviposition. The aim of this study was to investigate the initial stages of chondrocranium development in Grass-snake Natrixnatrix Linnaeus, 1758, embryos before oviposition. Natrix natrix embryos at early developmental stages (24-27 according to the table of normal development by D. Zehr (1962)) were obtained by means of caesarean section. At developmental stages 25-27, previously undescribed structures were found in the region of future skull formation. These structures exist during one or two stages and then disappear. Therefore, we call them "temporary structures." The assumption about the nature of these structures is based on their topography and comparison with the structures of developing or fully formed chondrocranium in other vertebrates. It is hypothesized that the temporary structures in Natrix natrix chondrocranium are vestiges ofprimary chondrocranium of ancestral vertebrate forms, and they indicate the existence of several variants in the formation of chondrocranium in the historical vertebrates.' development. PMID- 26480487 TI - [Morphometry in Development of Red Deer's Adrenal Glands]. AB - Histological structures and morphometric and some histochemical indicators of elk's adrenal gland development as subspecies of red deer in prenatal and postnatal ontogenies stages was studied. It was found that the growth of the fetus adrenal glands weight and the thickness of the structures adrenal glands fragments continue throughout the prenatal period of ontogeny. The cells of androgenic zone with single wandering sympathogoniae are differentiated in the adrenal glands in the second month of development. The androgenic and definite zone and the adrenal medulla are differentiated by the third month of development. At the 4 months, adrenal gland cortex zona glomerulosa and zona fasciculate-reticularis are differentiated; zona reticularis is differentiated only by the seventh month. By the eighth month, the structure of adrenal glands corresponds to the adrenal glands of a newborn. Full structural formation of the adrenal glands takes place in young animals by age 1.5. Obvious structural changes were not found late in the postnatal stages of development. PMID- 26480488 TI - Are You an Asset or a Liability in Your Committee? PMID- 26480489 TI - Preceptorship and Mentoring: Are They the Same Thing? PMID- 26480490 TI - TeamSTEPPS: A Path to High Functioning Teams. PMID- 26480491 TI - Five Proven Strategies for Goal Achievement. PMID- 26480492 TI - Facing the Reality of Today's Candidate-Driven Market in Nursing and Nurse Leadership. PMID- 26480494 TI - Job Seekers Etiquette 101: Why You Should Always Send a Thank You Letter After Your Interview. PMID- 26480493 TI - What Can I Do With A BSN? PMID- 26480495 TI - Creating a Nursing Portfolio. PMID- 26480496 TI - I Have a Job Interview! Oh My ... I Have a Job Interview--Now What? PMID- 26480497 TI - Letter from the Dean. PMID- 26480498 TI - Dr. Seizaburo Sakamoto, Former HSDM Faculty Member, Donates More Than $536,000 to HSDM. PMID- 26480500 TI - Dr. Leonard B. Kaban. PMID- 26480502 TI - HSDM Develops Collaborations in Asia. PMID- 26480501 TI - Dr. Shanele Williams. PMID- 26480503 TI - Remembering Dr. Gerald Shklar. PMID- 26480504 TI - Letter from the Dean. PMID- 26480505 TI - HSDM Launches an Initiative to Integrate Oral Health and Primary Care after Successful Leadership Forum. PMID- 26480506 TI - Remembering Deah, Yusor and Razan. PMID- 26480507 TI - Senior Dental Leaders Program. PMID- 26480508 TI - Update from Rwanda: Year Three. PMID- 26480509 TI - Five Questions for Dr. Brian Swann: Working to Increase the Capacity of Healthcare on a Global Level. PMID- 26480510 TI - From the Dean. PMID- 26480511 TI - Case Completion Curriculum Shines. PMID- 26480512 TI - Oral Health Care for Elders in Bolivia. PMID- 26480513 TI - Report from Rwanda. PMID- 26480514 TI - Harvard School of Dental Medicine: Reflections of a Graduate from a 70-Year Perspective. PMID- 26480515 TI - From the Dean. PMID- 26480516 TI - Alumnus Conducts Public Health Work in the Cook Islands. PMID- 26480517 TI - HSDM Works with Wampanoag Tribe. PMID- 26480518 TI - Shared Visits Offer Benefits for Patient and Provider. PMID- 26480519 TI - Building Bridges to Peace. PMID- 26480520 TI - From the Dean. PMID- 26480521 TI - Addressing Childhood Caries Through Education. PMID- 26480522 TI - Care for Indigent Rural Patients in Vermont. PMID- 26480523 TI - My Experience at Red Logan. PMID- 26480525 TI - Providing Oral Health Care in Ecuador. PMID- 26480524 TI - A Summer of Service. PMID- 26480527 TI - HSDM Creates Osteoarthritis Initiative. PMID- 26480526 TI - HSDM at the United Nations: Toward Global Health Equity. PMID- 26480528 TI - From the Dean. PMID- 26480529 TI - Frank Bliss Established a Legacy--and Received a Lifetime Income. PMID- 26480530 TI - Major HSDM Supporters Douglas and Eltress Dick Step Up Again. PMID- 26480531 TI - Ed Morin, DMD60, Longtime Donor. PMID- 26480532 TI - Marjorie Jeffcoat, DMD76, PD78: Researcher and Teacher. PMID- 26480533 TI - The HSDM Public Health Initiative. PMID- 26480534 TI - Collaborating on Oral Health Access and Education in Rwanda. PMID- 26480535 TI - New Drugs from Old Remedies. PMID- 26480536 TI - From the Dean. PMID- 26480537 TI - Heejoon Sun, DMD88, MPH88. PMID- 26480538 TI - Rochelle Lindner, DMD82, and Gary Lindner, DMSc83, PD83. PMID- 26480541 TI - Give Kids a Smile 2013. PMID- 26480539 TI - Martin Nweeia Studies an Enigma. PMID- 26480542 TI - Women in Dentistry CE Course. PMID- 26480543 TI - HSDM Students Receive Major Grant. PMID- 26480544 TI - [Clinical observation on obesity and hyperlipidemia of yang deficiency of spleen and kidney syn- drome in female patients treated with warm acupuncture combined with auricular acupuncture]. AB - OBJECTIVE: To compare the differences of clinical effects in female patients with obesity and hyperlipidemia of yang deficiency of spleen and kidney syndrome between warm acupuncture combined with auricular acupuncture and simple warm acupuncture. METHODS: One hundred and thirty patients were randomly divided into an observation group and a control group, 65 cases in each one. In the control group, acupuncture was used at Pishu (BL 20), Zhongwan(CV 12), Shenshu(BL 23), Zhongji(CV 3), Guanyuan(CV 4), Mingmen(GV 4), Taibai(SP 3), Fenglong(ST 40), etc.; warm acupuncture was applied at Pishu(BL 20), Zhongwan(CV 12), Shenshu(BL 23) and Zhongji(CV 3); the treatment was required once every two days and for 3 months continuously. In the observation group, based on the treatment in the control group, thumbtack intradermal needles were embedded at auricular points, including pi(CO13), shen(CO10), pangguang(CO9), sanjiao(CO17), neifenmi(CO18), neishengzhiqi(TF2), etc. Obesity indices [body mass(W), obesity degree(A), body mass index(BMI), body fat percentage(F%)] blood lipid indices [serum total cholesterol(TC), triglyceride(TG), low density lipoprotein(LDL-C), high density lipoprotein(HDL-C)] and clinical efficacy were observed before and after treatment in the two groups. Results After treatment in the two groups, the obesity indices of W, A, BMI, F% and the blood lipid levels of TC, TG, LDL-C were obviously decreased compared with those before treatment (all P<0. 01) and the HDL-C levels were apparently increased than those before treatment (both P<0. 01). After treatment, the improvement of TC and HDL-C in the observation group was superior to that in the control group (both P<0. 01). The difference was not statistically significant in the aspect of improving every obesity index between two groups (all P>. 05). The comprehensive total effective rate of the observation group was 95.4% (62/65), which was better than 84. 6% (55/65) of the control group (P<0. 001). CONCLUSION: Warm acupuncture combined with auricular acupuncture and simple warm acupuncture can both benignly adjust abnormal lipid metabolism of obesity patients with hyperlipidemia, and warm acupuncture combined with auricular acupuncture are superior to simple warm acupuncture treatment on antiobesity action and improving the TC and HDL-C levels. PMID- 26480545 TI - [Impacts on fine movement of upper extremity with flaccid paralysis in stroke treated with acupuncture combined with motor imagery]. AB - OBJECTIVE: To explore the impacts on the fine movement of upper extremity with flaccid paralysis in stroke treated with acupuncture and motor imagery. METHODS: Sixty-two cases of flaccid paralysis of upper extremity in stroke were randomized into an observation group (30 cases) and a control group (32 cases). In the control group, the conventional western medication and the passive movement of the extremity were applied. Additionally, the penetrating needling technique was used at the head points [penetrating needling from Baihui (GV 20) to Taiyang (EX HN 5)] and the local affected extremity [penetrating needling from Jianyu (LI 15) to Binao (LI1 14), from Quchi (LI 11) to Shaohai (HT 3), from Waiguan (TE 5) to Neiguan (PC 6), etc]. The needles were retained for 30 min. In the observation group, on the basic treatment as the control group, during the needle retaining, the motor imagery therapy was supplemented. The treatment was given once a day, 5 treatments a week, for 4 weeks totally in the either group. The scores in the action research arm test (ARAT) and the modified Fugl-Meyer assessment (FMA) were recorded at the moment of enrollment, in 2 and 4 weeks of treatment, in the 6th and 8th weeks, as well as after 90 days separately. RESULTS: (1) ARAT score: since the 2nd week, ARAT scores in the observation group were all improved significantly as compared with those in the control group at the each time points (all P<0. 05). In the observation group, the scores were improved significantly in the pair comparison at the time points (all P<0. 05). In the control group, the score in the 2nd week was not different significantly as compared with that before treatment (P>0. 05), but the scores at the rest time points were improved significantly in the pair comparison (all P<0. 05); (2) FMA score: in the 2nd week and on the 90th day, FMA score in the observation group was higher significantly than those in the control group (both P < 0. 05). In the observation group, the scores were all improved significantly in the pair comparison at the time points (all P<0. 05). In the control group, except that in comparison between the 90th day and the 8th week (P>0. 05), the results were all P<0. 05 at the rest time points. CONCLUSION: The early intervention of the combined therapy of acupuncture and motor imagery effectively promotes the recovery of the coordination function and the fine movement of upper extremity, especially the improvements of the fine movement in stroke at flaccid paralysis stage. The efficacy is better than the single acupuncture treatment. PMID- 26480546 TI - [Impact on serum 5-HT and TH1/TH2 in patients of depressive disorder at acute stage treated with acupuncture and western medication]. AB - OBJECTIVE: To compare the difference in depression relief in the treatment of depressive disorder at the acute stage between the combined therapy of acupuncture and 5-HT (5-hydroxytryptamine) selective serotonini reuptake inhibitors (SSRIs) and the single application of SSRIs and explore the impact on the imbalance of 5-HT and TH1/TH2. METHODS: Ninety cases of depressive disorder at the acute stage were randomized into a combined therapy group and a medication group, 45 cases in each one. In the medication group, SSRIs were prescribed forl oral administration, once or twice a day, continuously for 4 weeks. In the combined therapy group, on the basis of treatment as the medication group, acupuncture was combined. The main acupoints were Baihui (GV 20), Yintang (GV 29), Shenting (GV 24), Fengchi (GB 20), Dazhui (GV 14) and Sishencong (EX-HN 1), once every two. days, continuously for 4 weeks. Before treatment, and after the 1st, 2nd and 4th weeks of treatment, the Hamilton depression scale (HAMD) was used to evaluate the depression severity. Separately, before and after the 4 weeks of treatment, the levels of serum 5-HT, interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), interleukin-4 (IL-4) and interleukin-10 (IL-10) were determined and compared with those in 45 cases of the healthy group. RESULTS: HAMD score was reduced in the 1st, 2nd and 4th weeks of treatment as compared with that before treatment in the combined therapy group (all P<0 01). HAMD score was reduced in the 2nd and 4th weeks of treatment as compared with that before treatment in the medication group (all P<0. 01). HAMD scores in the combined therapy group were lower than those in the medication group in the 1st, 2nd and 4th weeks of treatment (all P< 0. 01). Before treatment, in the combined therapy group and the medication group, the levels of serum 5-HT, IL-4 and IL-10 were all lower than those in the healthy group (all P<0. 01); the levels of IL-1beta and IL-6 were higher than those in the healthy group (all P<0. 01). In the combined therapy group and the medication group, the levels of 5-HT, IL-4 and IL-10 in 4 weeks of treatment were all increased as compared with those before treatment (all P<0. 01), and the levels of IL-1beta and IL-6 were lower than those before treatment (all P<0. 01). In the combined therapy group, the levels of IL-1beta and IL-6 in 4 weeks of treatment were lower than those in the medication group, and the levels of 5-HT, IL-4 and IL-10 were higher than those in the medication group (P<0. 01, P< 0. 05). CONCLUSION: The combined therapy of acupuncture and SSRIs achieves much quicker and more effective re-' sult for relieving depression in the patients of depressive disorder as compared with simple oral administration of' SSRIs, and much more contributes to adjust the imbalance of serum 5-HT and TH1/TH2. PMID- 26480548 TI - [Expressions of neurotransmitters in patients of insomnia differentiated as liver stagnation transforming into fire treated with acupuncture]. AB - OBJECTIVE: To compare the difference in the efficacy between acupuncture and oral administration of trazodone and the expressions of neurotransmitters in patients of insomnia differentiated as liver stagnation transforming into fire. METHODS: Seventy patients of insomnia differentiated as liver stagnation transforming into fire were randomized into an observation group and a control group, 35 cases in each one. In the observation group, acupuncture therapy was adopted at Shenmen (HT 7), Baihui (GV 20), Yintang (GV 29), Hegu (LI 4), Taichong (LR 3), etc. The needles were retained for 20 min each time. The treatment was given once a day, the treatment of 2 weeks made one session. In the control group, trazodone, 100 mg, oral administration, once a day, the treatment of 2 weeks made one session. Two sessions were required in the two groups. The scores in Pittsburgh sleep quality index (PSQI) and Asberg rating scale for side effects (SERS), the levels of neurotransmitters such as 5-hydroxy tryptamine (5-HT) and norepinephrine (NE) and the expressions of protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) in peripheral blood were observed before and after treatment in the two groups. RESULTS: PSQI score and SERS score after treatment were all decreased compared with those in both groups before treatment (both P<0. 05). After treatment, PSQI score and SERS score in the observation group were lower apparently than those in the control group (both P<0. 05). After treatment NE content and PKC level were decreased; 5-HT content and BDNF mRNA were increased compared with those in both groups before treatment (all P<0. 05). NE content and PKC level in the observation group were lower apparently than those in the control group (both P<0. 05). The serum 5-HT content and BDNF mRNA expression in the observation group were higher than those in the control group separately (both P<0. 05). CONCLUSION: Acupuncture therapy improves the sleeping quality of patients of insomnia differentiated as liver stagnation transforming into fire, and reduces serum NE level and increases 5-HT content and BDNF expression, which achieves the better efficacy as compared with the oral administration of trazodone. It is one of the effective approaches to the treatment of insomnia differentiated as liver stagnation transforming into fire. PMID- 26480547 TI - [Senile insomnia treated with integrated acupuncture and medication therapy: a randomized controlled trial]. AB - OBJECTIVE: To compare the efficacy difference in the treatment of senile insomnia among western, medication, acupuncture and the integrated therapy of acupuncture and western medication. METHODS: Ninety-eight patients of senile insomnia were randomized into a western medication group (30 cases), an acupuncture group (35 cases) and an integrated acupuncture and medication group (35 cases). In the western medication group, estazolam 1mg was prescribed, taken 30 min before going to bed, oryzanol 20 mg, oral administration, three times a day, for 4 weeks totally. In the acupuncture group, the simple acupuncture therapy was applied at Shenmen (HT 7), Sanyinjiao (SP 6), Anmian (Extra), Baihui (GV 20) and Sishencong (EX-HN 1), as well as the supplementary points selected according to the differentiation. The acupuncture treatment was given once a day, 5 treatments a week, for 4 weeks totally. In the integrated acupuncture and medication group, the western medication was combined with acupuncture. The dosage and usage of western medication were same as those in the western medication group; and acupoints in acupuncture treatment were same as those in the acupuncture group. The treatment lasted for 4 weeks in the three groups. Pittsburgh sleep quality index (PSQI) and clinical efficacy were observed before treatment, after 4 weeks' treatment and in 4 weeks after discontinuity of treatment in the three groups. RESULTS: Four weeks after treatment, the clinical curative rates were 3. 3% (1/30), 21. 2% (7/33) and 25. 7% (9/35) in the western medication group, the acupuncture group and the integrated acupuncture and medicines group separately. The total effective rates were 70. 0%(21/30), 93. 9%(31/33) and 97. 1%(34/35) in the three groups separately. The curative rates and the total effective rates in the integrated acupuncture and medication group and the acupuncture group were higher than those in the western medication group separately (all, P<0. 01). PSQI scores after 4 Weeks' treatment were all improved as compared with those before treatment in the three groups (all P<0. 05). PSQI score in either the integrated acupuncture and medication group or the acupuncture group was lower than that in the western medication group, indicating the significant difference (both P< 0. 05). Four weeks after discontinuity of treatment, the efficacy was stable in the acupuncture group and the integrated acupuncture and medication group. PSQI score did not change as compared with that in the 4th week of treatment. The score in the western medication group ran back, close to that before treatment (P>0. 05). During the treatment, a few patients had dry mouth in the western medication group. The adverse reactions were not discovered in the other two groups. CONCLUSION: The integrated therapy of acupuncture and medication achieves the quick efficacy on senile insomnia and rapidly relieves the symptoms, with quite high clinical curative rate and total effective rate obtained. The long-term efficacy is better than that of western medication. The integrated therapy is the first option among the three therapeutic programs. PMID- 26480549 TI - [Clinical observation of peripheral facial palsy treated with electro-acupuncture based on surface electromyography]. AB - OBJECTIVE: To observe the difference in the clinical efficacy on peripheral facial palsy between electro-acupuncture (EA) assisted with surface electromyography (sEMG) and conventional EA. METHODS: Sixty cases of peripheral facial palsy were randomized into an observation group and a control group, 30 cases in each one. EA was applied during the first 15 days of sickness in the two groups, at Xiaguan (ST 7), Jiache (ST 6), Dicang (ST 4), Yangbai (GB 14), Taiyang (EX-HN 5), Quanliao (SI 18) and Hegu (LI 4), once a day. In the observation, group, 15 days after sickness, according to the situation in sEMG, on the basis of the acupoints in the previous treatment, the corresponding acupoints were reselected for EA. In the control group, the conventional EA was kept on. The treatment was given once every two days till the 35th day of sickness. Separately, on the 5th, 15th and 35th days of sickness, according to the detection of sEMG in the patients of two groups, the means ratios of: root mean square (RMS) of musculi buccinators, orbicularis oris, frontalis and nasalis on the healthy and affected sides were recorded and analyzed. RESULTS: The differences of ratio in RMS of musculi buccinators, orbicularis oris, frontalis and nasalis on the healthy and affected sides were significant statistically in comparison between the, 15th day and the 5th day, and between the 35th day and the 15th day of sickness within each group (all P<0. 01). The differences of ratio in RMS of the muscles on the healthy and affected sides were significant statistically on the 15th and 35th days between the two groups (all P<0. 05). CONCLUSION: EA assisted with sEMG achieves the significant efficacy on peripheral facial palsy, better than the conventional EA. PMID- 26480550 TI - [Burning mouth syndrome]. PMID- 26480551 TI - [Clinical observation of dysantonomia treated with transcutaneous electrical stimulation at Renying (ST 9) combined with stellate ganglion block]. AB - OBJECTIVE: To compare the clinical efficacy difference in dysantonomia between transcutaneous electrical stimulation at Renying(ST 9) combined with stellate ganglion block(SGB) and simple SGB. METHODS: Sixty patients in accord with the diagnostic criteria of dysantonomia were randomly divided into two groups,30 cases in each group. In the observation group,transcutaneous electrical stimulation at Renying(ST 9) combined with SGB were adopted; in the control group,simple SGB was applied. In the two groups, treatment was used three times a week,and nine treatments were considered as one course. There was an interval of one week between courses,and two courses were treated. Total seven weeks were required. Scores were evaluated according to subjective symptoms before treatment,one month and three months after treatment in the two groups. RESULTS: The scores of subjective symptoms were not statistically different before treatment in the two groups(P>0. 05). The scores of subjective symptoms one month and three months after treatment were all lower than those before treatment(all P< 0. 01), and subjective symptoms scores in the observation group were lower than those in the control group(both P<0. 01). CONCLUSION: Transcutaneous electrical stimulation at Renying(ST 9) combined with SGB could obviously enhance the clinical effects for dysantonomia, and the control and improvement for clinical symptoms are apparently superior to simple SGB. PMID- 26480552 TI - [Case of infertility]. PMID- 26480553 TI - [Clinical research of chronic pelvic cavity pain syndrome treated with acupoint catgut embedding therapy]. AB - OBJECTIVE: To explore the clinical efficacy of acupoint catgut embedding therapy on chronic pelvic cavity pain syndrome differentiated as kidney deficiency and stagnation of damp heat, and explore the impacts on plasma P substance (SP), plasma beta-endorphin (beta-EP). METHODS: One hundred and eighty cases were randomly divided into a catgut embedding group (90 cases) and a western medication group (90 cases). In the western medication group, tamsulosin capsules 0. 2 mg were prescribed for oral administration, once a day; indometacin sustained release tablets, 25 mg, three times a day. Totally, the oral administration for 8 weeks was required. In the catgut embedding group, the acupoint catgut embedding therapy was applied to Qugu (CV 2), Shenshu (BL 23), Zhibian (BL 54), Huiyin (CV 1) and Sanyinjiao (SP 6), once every two weeks; the treatment of 4 weeks made one session, and two sessions were required. Before and after treatment, TCM symptom score, NIH-CPSI (the National Institute of Health Chronic Prostatitis Symptom Index) score, lecithin body numbers in prostatic fluid, score in SAS (self-rating anxiety scale), score in SDS (self-rating depression scale), the levels of SP and beta-EP, etc. were observed in the two groups, and the clinical efficacy was assessed in the two groups. RESULTS: (1) Ten cases were dropped in either group. The total effective rate was 91. 25% (73/80) in the catgut embedding group, higher than 78. 75% (63/80) in the western medication group (P<0. 05). (2) After treatment, TCM symptom score, total score in NIH-CPSI, pain score and the scores in SAS and SDS were all reduced as compared with those before treatment in the two groups (all P<0. 05). After treatment, TCM symptom score, total score and pain score in NIH-CPSI, and the scores in SAS and SDS in the catgut embedding group were both lower than those in the western medication group (all P<0. 05). (3) After treatment, the lecithin body numbers were both increased as compared with those before treatment in the two groups (both P<0. 05), and the result in the catgut embedding group was higher than that in the western medication group (P<0. 05). (4)After treatment, the SP level was lower than that before treatment in the two groups (both P<0. 05); the level of p-EP was increased as compared with that before treatment (both P<0. 05). The SP level in the catgut embedding group was lower than that in the western medication group (P<0. 05); the level of beta-EP was higher than that in the western medication group (P<0. 05). CONCLUSION: The acupoint catgut embedding therapy apparently relieves the clinical symptoms of chronic pelvic cavity pain syndrome differentiated as kidney deficiency and stagnation of damp heat as well as the condition of anxiety and depression, increases lecithin body numbers in prostatic fluid and beta-EP level and reduces SP level. PMID- 26480554 TI - [Finger pressing and garlic-partition moxibustion for 12 cases of chronic appendicitis]. PMID- 26480555 TI - [Clinical observation on therapeutic effect of myopia in children treated with abdominal acupuncture]. AB - OBJECTIVE: To observe the clinical effects of myopia in children treated with abdominal acupuncture. METHODS: Ninety children with myopia were randomly divided into an abdominal acupuncture group (45 cases with 90 ill eyes) and an auricular point group(45 cases with 90 ill eyes). In the abdominal acupuncture group, Zhongwan (CV 12), Shangqu(KI 17), Xiawan(CV 10), Tianshu(ST 25), Qihai(CV 6), Guanyuan(CV 4) were treated with tapping method. The needles were not retained and down to the lower in accordance with the order from Zhongwan (CV 12) to Guanyuan(CV 4) for 5 min,and the erubescence skin without blood was proper. In the auricular point group, vaccaria seeds were pasted at gan(CO12), shen(CO10),pi(CO13), wei(CO4), yan(LO5), pingjianqian(TG2i), pingjianhou(ATli) and zhen(AT3); one ear was chosen every time and the other ear the second time with pressing of patient's own for 5 min every day. The treatment was given twice a week and 10 treatments were considered as one course in the two groups. The changes of the visual levels in visual chart before treatment, 20 min after the first treatment, after 5 weeks' and 3 months' treatment were compared between the two groups,and the clinicall efficacy was compared between the two groups as well. RESULTS: (1) The visual levels in visual chart were improved in the abdominal acupuncture group and auricular point group, and the effects 20 min after the first treatment, after 5 weeks' and 3 months' treatment in the abdominal acupuncture group were superior to those in the auricular point group(4. 78+/-0. 16 vs 4. 69+/-0. 22, P<0. 01; 4. 85+/-0. 16 vs 4. 79+/-0. 21, P<0. 05; 4. 89+/-0. 13 vs 4. 71+/-0. 25, P<0. 01). (2)The effective rates 20 min after the first treatment, after 5 weeks' and 3 months' treatment in the abdominal acupuncture group were better than those in the auricular point group[31. 4% (27/86) vs 0% (0/82). 81.4%(70/86) vs 60. 0%(49/82); 88. 4%(76/86) vs 51. 2%(42/82), all P<0. 01]. CONCLUSION: Abdominal acupuncture for improving the visual levels of myopia in children is superior to auricular point sticking. PMID- 26480556 TI - [Catgut injection therapy for 26 cases of ankylosing spondylitis]. PMID- 26480557 TI - [Bone-length measurement at low back and its application]. AB - By reviewing some acupuncture literature regarding the settings of bone-length measurement at low back, it was found out that ancient and modern descriptions were not consistent. In China current acupuncture textbook, it was mostly described as "the horizontal distance between inner borders of two scapulas was 6 cun". However, after analysis, it was believed that this setting was not reasonable in the clinical application of acupuncture, and it was agreed with the opinion that "midpoint of inner borders of two scapulas when scapulas are in abduction position" should be taken as bone-length measurement of low back. Besides, a self-made bone-length scale was applied to locate acupoint at low back, which could provide references for its standardized application manipulation. PMID- 26480558 TI - [Clinical experience of postoperative complications]. PMID- 26480559 TI - [Effects of electroacupuncture on cochlea morphology and expression of aquaporins in guinea pigs with endolymphatic hydrops]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) on cochlea morphology and expression of aquaporin 1 (AQP1) in guinea pigs with endolymphatic hydrops, so as to explore the possible mechanism of EA on endolymphatic hydrops. METHODS: Forty guinea pigs were randomly divided into a blank group, a model group, a medication group and an EA group, 10 guinea pigs in each one. Model of endolymphatic hydrops was established by using intraperitoneal injection of aldosterone. Guinea pigs in the blank group and model group were treated with identical immobilization as EA group but no treatment was given; guinea pigs in the medication group were treated with intragastric administration of hydrochlorothiazide at a dose of 5 mg/kg, once a day for consecutive 10 days; guinea pigs in the EA group were treated with' EA at "Baihui" (GV 20) and "Tinggong"(SI 19), once a day for consecutive 10 days. The serum ionic concentration in each group was tested by turbidimetric method; hematoxylin-eosin staining was used to measure the severity of cochlea hydrops; immunohistochemical method was used to observe the expression of AQP1 in the cochlea. RESULTS: (1) There was no endolymphatic hydrops in the blank group, moderate-severe endolymphatic hydrops in the model group and slight endolymphatic hydrops in the EA group and medication group. (2) The concentration of K+ and Ca2+ in the EA group was higher than that in the model group and medication group (all P<0. 01); the concentration of Na+ was lower than that in the model group (P< 0. 01) but higher than that in the medication group (P<0. 01); the concentration of Cl- was higher than that in the medication group (P<0. 01), but not significantly different from the model group (P>0. 05). (3) The ratio of expression area of AQP1 in the model group was lower than that in the blank group (P<0. 01); the ratio of expression area of AQP1 in the EA group was higher than that in the model group (P<0. 01), and lower than that in the medication group without significant difference (P>0. 05). CONCLUSION: EA could relieve the endolymphatic hydrops in guinea pigs; the mechanism is likely to be related with up-regulating the expression of AQP1 in cochlea and ion concentration might be an important factor involved. PMID- 26480560 TI - [Neurological protection effects of "paraplegia-triple-needling method" on rats with incomplete spinal cord injury]. AB - OBJECTIVE: To observe the neurological protection effects of "paraplegia-triple needling method" on rats with incomplete spinal cord injury (SCI), so as to make a preliminary exploration on its mechanism. METHODS: A total of 45 SD rats were randomly divided into a paraplegia-triple-needling method group (group A), a regular acupuncture group (group B) and a model group (group C), 15 rats in each one. The rats model of incomplete spinal cord injury was established by modified Allen's method. The acupoints of governor vessel and back-shu points next to the vertebras of upper end and lower end of injured segment as well as motor points in key muscle of lower extremities were treated with acupuncture in the group A; the acupoints of governor vessel and back-shu points next to the vertebras of upper end and lower end of injured segment as well as "Huantiao" (GB 30), "Housanli" (ST 36), "Yanglingquan" (GB 34) and "Genduan"(Extra) were treated with acupuncture in the group B; rats in the group C received no treatment after model establishment but grabbing and immobilization. The needles were retained for 15 min in the group A and group B, once a day for 14 times. 1 d, 7 d and 14 d after model establishment, Basso Beattie Bresnahan (BBB) scores were observed in each group; the morphologic change of injured spinal cord and expression of positive cells of calcitonin gene-related peptide (CGRP) were observed. Results (1) One day after SCI, there was no significant difference of BBB scores among three groups (P> 0. 05); 7 days and 14 days after SCI, BBB scores in the group A and group B were significantly superior to those in the group C (all P<0. 05), and the BBB scores in the group A were superior to those in the group B ( both P<0. 05). (2) There was expression of CGRP positive cells in all three groups, and that in the group A and group B was significantly higher than that in group C (both P<0. 05); 14 days after treatment, the expression in the group A was higher than that in the group B (P<0. 05). CONCLUSION: The "paraplegia-triple-needling method" could obviously! improve the motor function of rats with SCI, especially the expression of neuroprotective factor CGRP, which is likely to be one of the mechanisms of neurological protection effect. PMID- 26480561 TI - [Acupuncture at cervical Jiaji (EX-B 2) points for 60 cases of ocular hypertension]. PMID- 26480562 TI - [Acupoints selecting and medication rules analysis based on data mining technique for bronchial asthma treated with acupoint application]. AB - Clinical literature of bronchial asthma treated with acupoints application from January 2000 to March 2014 in modern periodicals databases was retrieved through computer. With cluster analysis and frequency analysis methods of data mining, acupoints selecting and medication rules of bronchial asthma treated with acupoints application were analyzed. Total 38 articles were included eventually, including 25 acupoints and 42 medicines. The results indicate that on acupoints selecting, Feishu (BL 13) is used as the main acupoint and 3 groups of bladder meridian and conception vessel acupoints are applied alternately and on medicines, Baijiezi (Brassica alba Boiss), Xixin (Radix et Rhizoma Asari), Gansui (Radix Kansui), Yanhusuo (Corydalis) and Mahuang (Radix et Rhizonma Ephedrae) are primarily adopted, epispastic medicines being the main medicines; medicines mostly belong to lung meridian, main medicines being unchanged mostly with Shengjiang as guiding drug. PMID- 26480563 TI - [Yuan-source points and luo-connecting points combination with western medication for 30 cases of post-stroke anxiety disorder]. PMID- 26480564 TI - [Academic thoughts of "pushing meridians to treat viscera diseases" in LIU' s infantile tuina in Xiangxi area]. AB - As one of the most important schools of Chinese infantile tuina, the main academic thoughts of LIU's infantile tuina in Xiangxi area ware "pushing the meridians". In clinical treatment; he focuses on zang-fu syndrome differentiation and meridians tropism treatment, and based on the generation-inhibition of five elements as well as the infantile physiological and pathological characteristics, the "pushing meridians to treat viscera diseases" was gradually developed, which has enriched the academic connotation and performed a better guide for clinical pediatric treatment. PMID- 26480565 TI - [Professor SONG Nanchang's experience for treatment of peripheral facial paralysis]. AB - Professor SONG Nanchang's clinical experience and characteristics for treatment of peripheral facial paralysis are introduced. In clinical treatment, professor SONG has adopted staging treatment strategy, and performed acupuncture stimulation with different levels. He attaches great importance to the acupoint selection on distal limbs. For the treatment on the face, he takes temperature as necessity; he inherits from famous Chinese doctor ZONG Ruilin's acupuncture technique of slow-twisting and gentle-pressing. Meanwhile, he excels in combination, of different therapies, using acupuncture, moxibustion, electroacupuncture, auricular point sticking, Chinese herbal medicine, etc. according to individual condition and disease stages. He also emphasizes on psychological counseling and daily life care to achieve rehabilitation within the shortest time. PMID- 26480566 TI - [Professor ZHENG Kuishan's experience in the clinical treatment of bi syndrome with acupuncture and moxibustion]. AB - Professor ZHENG Kuishan has been engaged in the education and clinical practice of acupuncture and moxibustion for over 60 years. Professor ZHENG is strict in scholarly research and exquisite in medical techniques and he is good at treatment of bi syndrome induced by invasion of wind, cold and damp with warming and, promoting therapy. He emphasizes on syndrome differentiation and acupoint combination and selects the accurate manipulations. Not only are the symptoms relieved apparently, but also the body state is improved. As a result, the primary and secondary are treated simultaneously. In the paper, professor ZHENG's experience is introduced in the treatment of bi syndrome in the aspects of theory, method, formula, acupoint and technique. And his clinical therapeutic approaches have been deeply analyzed. PMID- 26480567 TI - [Bloodletting at sifeng (EX-UE 10) point for 49 cases of psoriasis vulgaris]. PMID- 26480569 TI - [Electric-heat needling for 56 cases of cervical spondylosis with the neck type]. PMID- 26480568 TI - [Analysis and discussion on current condition of acupuncture clinical research registration]. AB - To introduce the international registration condition of acupuncture clinical research. With the examples of World Health Organization International Clinical Trials Registry Platform and the U. S. National Institutes of Health Clinical Registration Platform, the registration method and current condition of acupuncture clinical trials in international clinical trials registration platform were analyzed. The results indicate that the number of acupuncture clinical trials registration is gradually increased and the registration number from China is on the rise as well. But most domestic acupuncture clinical researches haven't been registered arid the researchers' valuing degree for clinical trials registration and methodology research needs to be improved. PMID- 26480570 TI - [Correlation between positive reaction point of auricular points and stroke]. AB - OBJECTIVE: To explore the auricular point specificity of the electric determination in stroke so as to provide the evidence for the objective study on the auricular point diagnosis in stroke. METHODS: Thirty patients of stroke were selected in an observation group; 30 patients of non-stroke internal medicine disorder were in a control group A; 30 persons of healthy examination were in a control group B. In the observation group.and the control group A, beside the conventional treatment, acupuncture was applied to all the cases. In the observation group, Jianyu (LI 15), Quchi (LI 11), Shousanili (LI 10), Hegu (LI 4), Waiguan (TE 5), Liangqiu (ST 34), Zusanli (ST 36), Sanyinjiao (SP 6) and Taichong (LR 3) were selected on the affected side. In the control group A, Yin tang (GV 29), Baihui (GV 20), Sishencong (EX-HN 1), Fengfu (GV 16), Dazhui (GV 14), Fengchi (GB 20), Tianzhu (BL 10), Jiaji (EX-B 2) C4-C7 were selected. Acupuncture was given once a day in the two groups. The; treatment of one week made one session, and continuously 2 sessions were required. In the control group B, the convention physical examination was provided without any medication and acupuncture involved. The CLRH-A auricular point detector was used to detect the entire auricular point area in the subjects and the positive reaction sites of auricular points in the subjects of each group before and after treatment separately. The auricular point positive detecting score and positive point frequency were observed in the subjects. RESULTS: Before treatment, the auricular points detecting score in the observation group was obviously higher than that in the control group A and control group B (both P<0. 05). The difference in the score between the control groups was not significant in' comparison (P>0. 05). In two weeks of treatment, the auricular points detecting score in the observation group was reduced apparently (P<0. 05). The difference was not significant before and after treatment in either the control grolip A or the control group B (both P>0.05). In the observation group, the first 15 points with high frequencies of positive reaction were naogan (AT3,4i), pizhixia (AT4), e (AT1), xin (CO15), gan (CO12), nie (AT2), zhen (AT3), shen (CO10), jiaogan (AH6a), pi (CO13) shenmen (TF4), wei (CO4), neifenmi (CO18), shenshangxian (TG2p) and erjian (HX6,7i). The differences were significant in the frequencies of positive reaction at 9 auricular points as compared with the control group A and the control group B respectively, named naogan (AT3,4i), pizhixia (AT4), e (AT1), xin (CO15), gan (CO12), nie (AT2), zhen (AT3), shen (CO10) and jiaogan (AH6a) (all P <0. 05). CONCLUSION: The pathological degree of positive reaction about auricular points in stroke patients is higher than those in the patients of non-stroke internal medicine disease and the healthy people. It is verified that the auricular diagnostic method is specific in stroke. naogan (AT3,4i), pizhixia (AT4), e (AT1), xin (C15), gan (GO12), nie (AT2), zhen (AT3), shen (CO10) and jiaogan (AH6a) are correlative with stroke. PMID- 26480571 TI - [Analysis on the requirements for clinical trial protocol writing of external treatment of TCM such as tuina]. AB - According to Standard Protocol Items: Recommendations for Interventional Trials, Consolidated Standard of Reporting Trials 2010 Statement (CONSORT), CONSORT Extension for Non-Pharmacologic Treatment Interventions (CONSORT for NPT) and Good Clinical Practice, the detailed requirements for protocol writing, reporting, and practicing of clinical trial were classified and summarized in this article. By combining the practical situation of clinical trial of external treatment of TCM such as tuina, the requirernents for clinical trial protocol writing of external treatment of TCM were analyzed and acquired which could improve the quality of clinical trial protocol of external treatment of TCM, thus to provide references for standardized execution of TMC clinical trial and reports of research results. PMID- 26480572 TI - [Discussion of the reasons why Shimen(CV 5) is called Dantian]. PMID- 26480573 TI - [Original meaning of mai and its academic evolution]. AB - Mai is the important concept in TCM and this term has been found in the early classic work of TCM. With the development and perfection of TCM theory, the original meaning of mai is "blood vessels entirely distrusted in the body". In five dynasties, the meaning of it was supplemented as "distribution of qi and blood in five zang and six fu organs to the four extremities", in which, not only blood but also qi has been included. With the constant understanding on mai, qi and blood, the unique concept of meridian and collateral is gradually generated. In terms of the modern study on the original meaning of mai and the academic evolution of meridian and collateral, it is discovered that qi is predominated and distributed in meridian and collateral as compared with blood. It is very significant to study the original meaning and academic evolution of mai, as well as the origin of the concept of meridian and collateral and to provide the reference support for the terminology standardization and basic study. PMID- 26480574 TI - [Application of Jiao Xue on men's diseases]. PMID- 26480575 TI - [Clinical rules for acupoint selection and prescription composition in treatment of polycystic ovary syndrome with acupuncture]. AB - OBJECTIVE: To summarize and analyze rules for acupoint selection and prescription composition in clinical literature regarding acupuncture for polycystic ovary syndrome (PCOS). METHODS: CHKD, VIP and Wan-fang databases were retrieved. The clinical literature data included in the study was collected. The descriptive statistical analysis was conducted on the main acupoints, main meridians of main acupoints, distribution of main acupoints, application of special points and rules for acupoint composition. RESULTS: Fifty-two articles were included, involving 55 main acupoints with a total frequency of 375. The most frequent acupoints of acupuncture for PCOS were Sanyinjiao (SP 6), Guanyuan (CV 4), Zigong (EX-CA 1), Zhongji (CV 3) and Qihai (CV 6). The meridians of main acupoitns were conception vessel, spleen meridian of foot-taiyin and stomach meridian of foot yangming. The main acupoints were distributed in the lower abdomen, lower limbs and back. In the special points, the use of front-mu points, five-shu points and back-shu points was more frequent. The prescription was usually consisted of 5 to 7 acupoints, (6. 9 +/- 3. 6) acupoints in average. CONCLUSION: In the modern treatment of acupuncture for PCOS, Sanyinjiao (SP 6), Guanyuan (CV 4), Zigong (EX CA 1), Zhongii (CV 3) and Qihai (CV 6) are most used. With the theories of meridian and zang-fu as essential references, the acupoint selection is based on disease differentiation and meridian circulation. Additionally, the methods for selecting the adjacent points and the distant points are adopted. PMID- 26480576 TI - [Study on Chinese Acup-Mox Medicine by YAO Tianmin]. AB - The characteristics and academic thoughts of Chinese Acup-Mox Medicine written by YAO Tianmin during the Republic of China was studied and analyzed in this paper. The academic thoughts of this book were confluence of Chinese and western knowledge, respecting for classics culture but not stubborn, using western science and medicine without worshiping it. The main characteristics were the scientific meridian-acupoint theory, extensive acupoint selection, "qie" method of acupuncture, high recommendation on medicated thread and ironing moxibustion, reinforcing and reducing based on the meridian direction in infantile massage, using acupuncture and cream formula for surgical treatment, and creating his own acupuncture codes. PMID- 26480577 TI - [Analysis on acupoint characteristics of medical records in Zhenjiu Dacheng]. AB - Twenty-nine medical records of acupuncture and moxibustion at the end of volume in Zhenjiu Dacheng are precious clinical examples. The characteristics of selecting acupoints are less and ingenious with precious matching on the basis of syndrome differentiation and examining pathogenesis detailedly, according to meridians with diseases locations recognized clearly, keeping adopting acupoints on regular meridians combined with extra points and making good use of specific points, and attaching importance to acquired essence with protecting spleen and stomach. Valuable experience is provided for physicians of later generations to treat diseases. PMID- 26480578 TI - [A literature review on acupuncture and moxibustion for prevention and treatment of lung cancer in SCI iournals (2003-2013)]. AB - To explore the status of acupuncture and moxibustion for prevention and treatment of lung cancer in current years; literature regarding acupuncture and moxibustion for prevention and treatment of lung cancer between 2003 and 2013 from SCI journals was retrieved and analyzed. As a result, 20 papers were included, which were published in 17 journals including Journal of Clinical Oncology, Chest, Respirology and Lung Cancer, etc. Of them, 3 papers discussed the effects of acupuncture on progressing of lung cancer; 4 articles confirmed that acupuncture could reduce myelosuppression and digestive tract reactions induced by radiotherapy and chemotherapy; 6 papers showed that acupuncture could relieve pain or fatigue of lung cancer; 3 papers indicated that acupuncture could palliate dyspnea in lung cancer patients. It is concluded by domestic and overseas researches that acupuncture and moxibustion are effective and safe for symptoms of lung cancer, which is worthy of further study. PMID- 26480579 TI - A Message from the New Editor. PMID- 26480581 TI - ODA Cares: Calvary Baptist Dental Clinic. PMID- 26480582 TI - ODA New Member Spotlight: David Taylor Evans, DMD, Oklahoma City, OK. PMID- 26480580 TI - The Spirit of Oklahoma Dentistry. PMID- 26480583 TI - 7 Steps to Prevent a Data Breach. PMID- 26480586 TI - Mathew, 1975-2015. PMID- 26480584 TI - Fluoridation is OK! PMID- 26480585 TI - Preventing Prescription Opioid Misuse, Abuse and Overdose in Dentistry. PMID- 26480587 TI - The Google Guarantee: Too Good To Be True? PMID- 26480588 TI - An Interview with the President-Elect: Dr. L King Scott. PMID- 26480589 TI - Regulatory Affairs and You. PMID- 26480590 TI - Mammography Rotations for All Students. PMID- 26480591 TI - Beyond Biopsy: The Cost Benefits of ShearWave Elastography for Liver Diagnosis. PMID- 26480592 TI - Imaging Clinical Decision Support: The Time is Now. AB - Organizations need to be ready for the imaging workflow changes related to the legislative mandates of P.L. 113-93 (Protecting Access to Medicare Act of 2014). They also need to have a good understanding of what's required to meet these mandates. There has been only one large scale study to determine the possible value of imaging CDS. Beginning in 2009, CMS initiated the Medicare Imaging Demonstration (MID) project--its subsequent evaluation is very instructive. The use of imaging CDS will be required for submitting claims to CMS as of January 1, 2017. This means a mechanism that the Secretary of HHS has approved must be used and the results from that imaging CDS must be included on the claim submitted by the imaging facility. PMID- 26480593 TI - Humility. PMID- 26480594 TI - Implementing Protocols to Improve Patient Safety in the Medical Imaging Department. AB - Patient safety is a focal point in healthcare because of recent changes issued by CMS. Hospital reimbursement rates have fallen, and these reimbursement rates are governed by CMS mandates regarding patient safety procedures. Reimbursement changes are reflected in the National Patient Safety Goals (NPSGs) administered annually by The Joint Commission. Medical imaging departments have multiple areas of patient safety concerns including effective handoff communication, proper patient identification, and safe medication/contrast administration. This literature review examines those areas of patient safety within the medical imaging department and reveals the need for continued protocol and policy changes to keep patients safe. PMID- 26480595 TI - Mid-Year Check-Up: 2015. AB - There are always opportunities to improve processes within radiology. As radiology professionals, we pride ourselves on our willingness to adapt and improve in our realm of influence (personally and professionally). Don't neglect the opportunity to lend your interest and skills to the coding and billing areas that really can have a significant impact for your department and facility. PMID- 26480596 TI - ICD-10 Traumatic Fractures. PMID- 26480597 TI - The Imaging Administrator's Guide to XR-29. AB - It is important for an imaging administrator to know a few things about XR 29, the new radiation standard for CT: what the standard means, how to assess existing CT equipment for compliance, and what will be lost in the case of noncompliance. On January 1, 2016 Medicare will pay 5% less for diagnostic CT scans performed on non-compliant CT equipment. In 2017, this reduction will soar to a 15% reduction in reimbursement Understanding what the XR-29 standard is and how to assess existing equipment will help protect the organization's bottom line, but it will also help keep patient radiation exposure to the lowest practical levels. PMID- 26480598 TI - From X-Ray School to the C-Suite. PMID- 26480599 TI - Cross-Trained Radiologic Technologists: A Survey. AB - Cross-training technologists would help increase department efficiency from a labor viewpoint, while also helping to increase the job stability and marketability of staff members. A survey of radiology managers was conducted to determine views on hiring preferences of radiologic technologists with a focus on multi-modality training. The current trend for hiring radiologic technologists sees an increase in demand for multi-modality and cross-trained employees. Employees who are content with their single modality training should be encouraged to cross-train and certify in an additional area. Radiology managers should also help to create opportunities and incentivize those who are currently interested in doing so. PMID- 26480600 TI - End of Useful Life. PMID- 26480601 TI - Holistic & Integrative Nursing: Understanding our Roots. PMID- 26480602 TI - MINDFUL EATING: Body, Mind, and Oxytocin. PMID- 26480604 TI - Whole Foods Feed Our Cellular Health. PMID- 26480603 TI - Peas pass the carrots: Introducing Plant-based Nutrition in Primary Care. PMID- 26480605 TI - ENZYMES: The Foundations of Life and Health! PMID- 26480606 TI - Psychosocial factors and heart disease: My Father's Journey. PMID- 26480607 TI - Healing Nutrition: One Woman's Journey. PMID- 26480608 TI - [EXCELLENCE IN QUALITY, SERVICE AND RESEARCH]. AB - Meir Medical Center was founded in 1956 as a hospital for patients with tuberculosis and lung disease. In 1962 its status was changed to a general hospital. Since 1971 it has been academically affiliated with the Tel Aviv University. Presently, Meir is a leading institution with regards to medical leadership. The strategic goals of the Meir Medical Center have been defined as excellence in care quality, service and research. In terms of scientific activity, the institutional Research Authority has been involved in strengthening the scientific community. This has been achieved through various initiatives including research grants, annual scientific meetings, development of infrastructure as well as a long term strategy for the promotion of academic research. Here we outline major recent progress in the implementation of quality control indices and improved patient experience. Furthermore, this issue of Harefuah highlights the hospital's multifaceted accomplishments in the clinical and academic fields. PMID- 26480612 TI - [REPORTING CRITICAL LAB RESULTS, A CHALLENGE FOR THE LAB AND THE PHYSICIAN - A SUMMARY OF FOUR YEARS OF EXPERIENCE IN MEIR MEDICAL CENTER LABORATORIES]. AB - INTRODUCTION: Critical laboratory results require prompt reporting to the attending physician, as they may indicate that a patient is in a life-threatening condition. Although this important subject has been covered in many publications, it needs more attention from our healthcare organizations, which have no official policy on the subject. Matching expectations between the doctor and the laboratory needs to be better defined. PURPOSE: The aim of this work was to inform the community of doctors and laboratories about the multiple problems concerning the reporting of critical laboratory results, to create a platform for exchanging views and ideas, and to build an extensive infrastructure for developing a unified plan to address this important issue. METHODS: We present the results of four years of experience of reporting critical laboratory values at the Meir Medical Center Laboratories. The idea leading this work was to present the relatively low rate of critical results reported by the laboratories in 2010, sharing the problems discovered while investigating the situation in depth, and presenting the solutions that enabled us to obtain the desired results within four years. RESULTS: Gradual implementation of these improvements resulted in critical value reporting increasing from 55% in 2010 to 95% currently. CONCLUSION: We suggest a model for improving critical laboratory values reporting based on our 4-year experience, which emphasizes: (1) The importance of selecting proper tests and values for critical results; (2) The significance of using technology and computerized measures to support the process; and (3) Developing quick procedures for monitoring and controlling the process. PMID- 26480613 TI - [LAPAROSCOPIC APPROACH AND SURGICAL CONSIDERATIONS IN RESECTION OF A LARGE EPIPHRENIC ESOPHAGEAL DIVERTICULUM]. AB - Epiphrenic diverticulum of the esophagus is an uncommon finding. Small diverticula are usually asymptomatic in nature. Large diverticula may present with dysphagia, chest or upper abdominal discomfort, vomiting, irritating cough or halitosis. There are a few different surgical approaches to epiphrenic diverticulum resection. It can be performed with an abdominal or a thoracic approach and in an open or a laparoscopic manner. In this case report we present a 70 years old male patient with a giant epiphrenic diverticulum and dysphagia. The patient was operated upon via a laparoscopic abdominal approach with intra operative endoscopic assistance and underwent a diverticulum resection. We present a review of the different kinds of esophageal diverticula, the mechanism of their formation, and the surgical considerations associated with choosing the appropriate surgical approach. PMID- 26480614 TI - [MENTORING PROGRAM - ANOTHER FACET OF RESIDENT EDUCATION]. AB - Medical residents are exposed to physical and emotional pressure and are required to cope with numerous demands during long working hours. Often, the intense workload leads to neglect of possible difficulties and professional and personal growth and empowerment. The Mentoring Program provides each resident with an attending physician mentor to help him or her adjust to the residency and to cope with its demands. The mentor guides the resident in career development and provides support in the event of difficulties. Attending physicians received professional guidance in the objectives and meaning of mentorship and were teamed with residents. The residents completed questionnaires regarding satisfaction and self-confidence before and a year after the mentoring program was established. The program significantly increased their feelings of support, confidence and satisfaction. As the program continued, the mentors' role in guiding the residents was expanded. The Mentoring Program has become an integral part of departmental teaching and team communication. It seems that the mentors, the residents and the department, all benefit from the program. PMID- 26480610 TI - [THE EFFECT OF PLACENTAL SOLUBLE FACTORS AND STEROID HORMONES ON OVARIAN CANCER PHENOTYPE]. AB - Estrogen is involved in ovarian cancer etiology. Crosstalk exists between estrogen and progesterone ending with the inhibition of estrogen effects. While estrogen induces ovarian cancer cell proliferation, progesterone protects women from ovarian cancer. The placenta facilitates estrogen and progesterone production. Moreover, during pregnancy epithelial ovarian cancer is more common than in young non-pregnant women and borderline ovarian tumors exhibit aggressive behavior These data suggest that pregnancy changes ovarian cancer characteristics. AIM: Analyzing the effect of placental soluble factors and estrogen+progesterone [E+P, in placental supernatant level) on epithelial ovarian cancer cell phenotype. METHODS: Ovarian epithelial cancer cells (OVCAR-3, SKOV-3) were exposed to 1) supernatants collected from first trimester human placental explant culture; 2) E+P in levels equivalent to those measured in the placental supernatants. As a control OVCAR-3 and SKOV-3 were exposed to their supernatants or to the hormones solvent. Then we tested ovarian cancer cells proliferation, death, cell-cycle and migration. RESULTS: Placental supernatants facilitated cancer cells migration and SKOV-3 proliferation. E+P facilitated SKOV-3 migration and elevated OVCAR-3 cell-number and apoptotic rate. CONCLUSION: Placental soluble factors and E+P affect ovarian cancer cells phenotype. Discussion: The elevated aggressiveness observed following exposure of ovarian cancer cells to placental supernatant and to E+P may contribute to the special phenomena observed in ovarian cancer during pregnancy. During pregnancy, ovarian cancer is usually discovered at an early stage, which improves patients' prognosis. Nevertheless, our results suggest that physicians should closely follow ovarian tumors during pregnancy as they might be affected by pregnancy-related factors. PMID- 26480611 TI - [INTERNATIONAL NORMALIZED RATIO VALUES AND HEMORRHAGE IN HOSPITALIZED PATIENTS STARTING WARFARIN THERPY: AN OBSERVATIONAL STUDY]. AB - INTRODUCTION: Vitamin K antagonist (VKA) therapy is challenging because of the narrow therapeutic range, and the influence of numerous factors on the international normalized ratio (INR). During the beginning of warfarin treatment, INR must be assessed regularly in order to optimize treatment and minimize the risk for hemorrhage. In this study we examined the laboratory and clinical outcomes of a cohort of hospitalized patients starting warfarin treatment. AIMS: To document the rate of patients with supra-therapeutic INR values and the rate of major hemorrhage, during the first month after starting warfarin. METHODS: A prospective observational study of all patients admitted to Meir Medical Center starting warfarin treatment during a 3-month period. Baseline demographics, clinical data, warfarin dose, INR levels and bleeding events were documented. Patients were followed for 30 days after starting treatment with warfarin. RESULTS: Fifty-seven patients who started VKA therapy were identified during the study period. The mean age was 71.2+/-13.1 years. Atrial fibrillation was the indication for treatment in 63.2% of patients, deep vein thrombosis in 19.3%, pulmonary embolus in 10.5% and other indications in 7% of patients. In the first 30 days of treatment, 60% of the patients had at least one INR value of >3. Of these patients, half had an INR of above 5. The number of concomitant medications were associated with INR values of >3. Arab patients tended to have a higher INR. Of note, there were 5 cases (8.8%) of major hemorrhage, which occurred with INR values ranging from 3.29 to >10, 4 of these patients were treated concomitantly with Aspirin. CONCLUSIONS: In this cohort of hospitalized patients starting warfarin therapy, excessive INR values were commonly encountered. There was a significant incidence of major hemorrhage among the patients. Further studies to define risk factors for elevated INR values and hemorrhage in hospitalized patients are needed. PMID- 26480609 TI - [ENDOSCOPIC ULTRASOUND EXAMINATION IN ELDERLY LUNG PATIENTS: OUR EXPERIENCE AT MEIR MEDICAL CENTER]. AB - INTRODUCTION: The endobronchial ultrasound (EBUS) examination is the prime choice in patients with unexplained mediastinal lymphadenopathy. We summarize our experience at Meir Medical Center with EBUS in the elderly (over 75 years of age) patients with lung cancer including indications, benefits and risks factors. METHODS: The study included 20 patients over the age of 75, 13 men and 7 women. The average age was 81 +/- 5 years. Indications included 11 patients with lung cancer and nine patients with mediastinal lymphadenopathy. Sixteen patients (80%] were diagnosed by the EBUS. Three patients needed a further diagnostic procedure. There was test accuracy in 18 of 20 patients (90%). Side effects included: One patient developed severe cough and another patient developed hypoxemia without the need for respiration, no bleeding was observed and there were no decreases in blood pressure. There was no arrhythmia or other complications. All patients were released on the examination day. CONCLUSIONS: The efficacy and safety of EBUS in the elderly are similar to the conditions for the general population. There were no significant complications observed including bleeding or arrhythmias. PMID- 26480615 TI - [NON-CLONAL MAST CELL ACTIVATION SYNDROME: DESCRIPTION OF SERIES OF PATIENTS, DIAGNOSTIC CRITERIA AND TREATMENT]. AB - A non-clonal mast cell activation syndrome is a newly emerged diagnosis. It shares the clinical features of anaphylaxis and mastocytosis despite having distinct mast cell biology. In this,paper we describe a series of patients representing the spectrum of non-clonal mast cell activation syndrome (nc-MCAS). We highlight the clinical manifestations of nc-MCAS as well as the diagnostic criteria and treatment options. PMID- 26480616 TI - [LUNG CANCER TREATMENT IN 2015: ADVANCES AND FUTURE OUTLOOK]. AB - Every third cancer death in Israel is due to lung cancer. Still, 80% of the lung cancer cases are related to tobacco smoking; and therefore, more must be done for primary prevention, screening for lung cancer among risk cohort and against the tobacco industry. In the last decade, significant progress in the molecular understanding of this disease brought to a marked improvement in the overall survival and in the quality of life of these patients. The treatment paradigm is shifting from "one treatment fits all" regimens to personalized treatment strategies that allow patients to be treated with a variety of novel drugs that prolong their survival and maintain their quality of life. The latest revolutionary concept of immunotherapy in lung cancer is emerging and promises further hope to this population PMID- 26480617 TI - [THE INVOLVEMENT OF THYROID HORMONES IN CANCER]. AB - The possible association between thyroid hormones and cancer has been reported over the years in pre-clinical and clinical studies. These studies suggest that high levels of hormones induce cancer cell proliferation while low levels slow disease progress. A context in which to interpret such findings is the recent description of a plasma membrane receptor for the thyroid hormone on cancer cells and dividing tumor-associated endothelial cells. PMID- 26480618 TI - [UPDATE ON CATARACT EXTRACTION SURGERY AND INTRA-OCULAR LENS IMPLANTATION]. AB - Cataract extraction and intra-ocular lens (IOL) implantation is one of the most prevalent surgical interventions worldwide. In Israel more than 50,000 procedures were performed in 2013. The progress in cataract surgery is dual, including the surgical technique of the crystalline lens removal along with developments in IOL structure and optic characteristics. This review focuses on new techniques in cataract surgery and modern types of IOLs for implantation. PMID- 26480619 TI - [THE CURRENT APPROACH TO ADVANCED LUNG CANCER]. AB - Non-small cell lung cancer (NSCLC) is a subtype of lung cancer and accounts for approximately 80% of lung cancer cases. For several years, chemotherapy treatment was the only optional treatment. The combination of two drugs - based on the platinum group, was the first line therapy. However the prognosis for patients with metastatic stage lung cancer is poor with a median survival time of 9-12 months. Recent studies of molecular biology in lung cancer have expanded our understanding of the processes involved in cancer. Subsequently developed targeted drugs operate on cancer cell mechanisms, such as antibodies and kinase inhibitors. However, the majority of patients with metastatic lung cancer still do not benefit from clinical therapy. One reason for this is the development of drug resistance. Today, the major focus is on the development of a personal pharmacological approach - targeted therapy. Progress has been made in the understanding of molecular biomarkers in the cell, due to the execution of many studies that incorporate the new treatments for these patients. PMID- 26480620 TI - [BILE DUCT PROBLEMS - ENDOSCOPIC SOLUTIONS]. AB - Patients with symptomatic bile duct stones are at increased risk for complications, which can be life-threatening. In the last four decades, with the development of endoscopic retrograde cholangiopancreatography (ERCP) and biliary sphincterotomy, endoscopic treatment has almost totally replaced surgical treatment of bile duct stones. In addition, a variety of benign and malignant conditions such as iatrogenic strictures (post cholecystectomy/post liver transplant), PSC, papillary adenoma or malignant tumors of bile duct or pancreas, are now amenable to endoscopic treatment. In the early years, ERCP served as a diagnostic and therapeutic tool With the development of non-invasive imaging alternatives, ERCP became a purely therapeutic procedure. However, in recent years, advanced technologies have restored diagnostic abilities to FRCP. PMID- 26480621 TI - [THE EFFECT OF PREGNANCY ON BREAST CANCER]. AB - Cancer and pregnancy coincide in about one in 1,000 pregnancies. One of the most common malignancies associated with pregnancy is breast cancer. Women with pregnancy-associated breast cancer (PABC) have a higher likelihood of being diagnosed with metastatic disease and estrogen receptor (ER) negative tumors than do non-pregnant women. Controversies exist regarding the effect of pregnancy on breast cancer prognosis. Some researchers suggest that pregnancy does not affect breast cancer prognosis, whereas others claim the opposite. Although PABC is usually discovered in an advanced stage, breast cancer metastasis on the placenta is a rare event. During cancer progression, the surrounding microenvironment co evolves into an activated state through continuous communication with the malignant cells, thereby promoting tumor growth. The effect of pregnancy and placental environment on breast cancer biology is the issue of this review. Placental and cancer cells implantation processes share similar molecular pathways. This suggests that placental factors may affect breast cancer cells biology. Previously, we analyzed the effect of first trimester human placenta on breast cancer cells. Breast cancer cells were co-cultured with placental explants during their implantation on matrigel substrate. We found that the placenta reduced ER expression on the cancer cells and induced their migration and invasion abilities. As a result of it, breast cancer cells migrated away from the placental implantation sites. Hormonal pathways were involved in these phenomena. These results may explain the high incidence of metastases during pregnancy in on the one hand and the rarity of metastases on the placenta on the other hand. PMID- 26480623 TI - Implants Today Section Debut. PMID- 26480622 TI - [THE CURRENT APPROACH TO METASTATIC RENAL CELL CARCINOMA]. AB - Renal cell carcinona is the most common kidney tumor. In Israel more than 600 cases are diagnosed annually. Risk factors for renal cell carcinoma include obesity, smoking, hypertension, and diabetes; 20-30% of the patients are diagnosed with metastatic disease, and 70-80% of patients are diagnosed with an early non-metastatic tumor. The treatment of an early non-metastatic tumor is resection. At present, the role of adjuvant systemic therapy has not been established; 20-40% of the patients operated on for an early tumor will suffer from metastatic disease recurrence. The lungs are the most common site of metastases. Renal cell carcinoma is relatively refractory to chemotherapy and radiation. In the last decade, an improved understanding of the biology of the tumor, led to the development of biologic therapies targeting specific molecular mechanisms involved in the process of the disease, and a significant expansion of treatment horizon in these patients. The biologic therapies for metastatic renal cell carcinoma belong to two main groups: angiogenesis inhibitors (VEGF-R inhibitors like sunitinib, sorafenib, pazopanib and axitinib), and inhibitors of the mTOR protein (everolimus and temsirolimus). These biologic therapies led to a significant improvement in the patients' survival. Nonetheless, these therapies are associated with a unique profile of side effects like hypertension, mucositis, and hand-foot syndrome with VEGF-R inhibitors therapy, and non infectious pneumonitis with mTOR inhibitors therapy. The present review will focus on the modern approach to metastatic renal cell carcinoma. PMID- 26480624 TI - Conflict of Interest Revisited: Law Versus Ethics. PMID- 26480625 TI - Rella Christensen, PhD, discusses the newest in zirconia restorations and how zirconia is changing. PMID- 26480626 TI - A Review of E-Cigarettes and Related Health Issues. PMID- 26480627 TI - Marrying Clinical Techniques and Teamwork. PMID- 26480628 TI - Future Trends in Implant Dentistry. PMID- 26480629 TI - Latest Trends in Implant Dentistry. PMID- 26480630 TI - The Immediate Smile: Fixed Provisionalization Using Digital Technology. PMID- 26480631 TI - Metal-Based Restoration Replacement: Using Lithium Disilicate for Aesthetics and Strength. PMID- 26480632 TI - Endodontic Shaping Procedures: The Past, Present, and Near Future. PMID- 26480633 TI - Optimizing Your Shade-Matching Success: Tips, Tools, and Clinical Techniques. PMID- 26480635 TI - Where Do We Grow From Here? PMID- 26480634 TI - Diastema Closure: A Restorative Design and Treatment Challenge. PMID- 26480636 TI - Optimal Dental Therapy for Obstructive Sleep Apnea. PMID- 26480637 TI - Taken to the woodshed...again. PMID- 26480638 TI - How politics might unravel Medicaid expansion. PMID- 26480639 TI - Preparing For the future: Advanced care planning for the patient with ESRD. PMID- 26480641 TI - Trends in nephrology practice. AB - The analysis of this benchmarking data tells us several things. Nephrology practices are more complex. Physicians are generating more RVUs for less money and a greater percentage of income is coming from things other than direct patient care. Practices have responded partly by becoming larger and looking for revenue stream diversification. The ability to predict the financial future from the historical data is problematic. We know from the most recent survey that a significant number of nephrology practices are already participating in accountable care organizations, shared savings programs, and even risk sharing contracts. We know that the incentive for participation in government quality reporting programs and meaningful use is transitioning from the carrot to the stick and that reductions in reimbursement will be applied to those who are unsuccessful. In order to take on the challenges and complexity that the future holds, successful nephrology practices will likely be larger, more sophisticated and tightly aligned with all stakeholders in the pursuit to provide high quality, low cost care to patients with kidney disease. PMID- 26480640 TI - HIPAA enforcement issues and dialysis providers. PMID- 26480643 TI - Monitoring and surveillance of the hemodialysis vascular access. AB - The physical exam, the clinical assessment, along with the surveillance tool we use has provided us the ability to identify access problems or potential problems. Abnormal surveillance data is always correlated with physical exam and clinical findings to determine the need for intervention. Monitoring and surveillance of vascular access are an integral part of the care of the hemodialysis patient. There are different techniques and methods available for identifying access dysfunction. Despite multiple studies that have been performed, there is still no consensus as to the best methodology to use. Physical exam and clinical evaluation remain key in detecting access problems. This along with a surveillance method chosen by the clinic can provide early identification of stenosis allowing for timely intervention of access dysfunction. PMID- 26480642 TI - Dialysis technicians' perception of certification. AB - The Nephrology Nursing Certification Commission initiated this research project to study the viewpoint of dialysis technicians regarding the value of certification. A national convenience sample was obtained using both paper-and pencil and online forms of the survey instrument. Demographic characteristics were obtained concerning age, race, ethnicity, education, and future employment planning. Technicians' primary work settings, the roles they fill, and the types of certification they hold are described. Incentives offered by employers are considered to explore how they contribute to job satisfaction. Understanding the perceptions of technicians regarding the benefits of certification and the limitations of workplace incentives should enable employers to improve their recruitment and retention programs. Information obtained may offer a baseline for future observations of the characteristics of these significant and essential contributors to the nephrology workforce. PMID- 26480644 TI - Access options for dialysis patients: A surgeon's view. PMID- 26480646 TI - The great salt debate: What is best for ESRD patients? PMID- 26480645 TI - Statement on nephrologists, other physicians, surgeons, and advanced practitioners with regard to compliance with infection control standards. PMID- 26480647 TI - [Effect of CD86 Gene Modified Recipient Dendritic Cell on Mix Cultured Donor derived Islet with Recipient-derived Lymphocyte in vitro]. AB - OBJECTIVE: To investigate the effect of CD86 gene modified recipient dendritic cell (DC) on mix cultured donor-derived islet with recipient-derived lymphocyte in vitro. METHODS: DCs were separated from bone marrow of BALB/c mice and identified by flow cytometry. Chemically synthesized CD86 siRNA was transferred into DC. Donor islets were separated from the pancreas of SD rats. Acridine orange (AO)/Propidium iodide (PI) staining was conducted to assess the viability of islets. Lymphocytes were collected from the spleen of SD rats and then co cultured with CD86 gene modified recipient DCs. CD86 gene modified recipient DC, donor-derived islet (400 IEQ) and recipient-derived lymphocyte (1 x 10(6)) were mix cultured in vitro. Four groups were set: blank group (islets of SD rat only), control 1 group (islets of SD rat with splenic lymphocyte of BALB/c mice) , control 2 group (islets of SD rat, splenic lymphocyte of BALB/c mice with normal recipient DC) and experimental group (islets of rat, splenic lymphocyte of BALB/c mice with CD86 gene modified recipient DC). After 3 days culture, the cellular morphology of culture was observed with light inverted microscope. The levels of IL-2, IL-4, IL-10 and IFN-gamma in the culture supernatant were tested, and islets viability was assessed by AO/PI staining. GSIS was conducted and stimulation index (SD was calculated. RESULTS: Typical DC morphology was found from the collected cells. The positive rates of CD1lc, CD80 and CD86 protein expression on DCs were 86.26% +/- 9.73%, 72.64% +/- 8.55% and 77.18% +/- 10.23%, respectively. The positive rate of CD86 protein expression on DCs after transfection was 23.64% +/- 5.25%. The viability of islets was over 95%. After 3 days culture, the level of IL-10 increased significantly and the levels of IL-2 and INF-gamma decreased significantly in experimental group (vs. control 1 and control 2 groups, P < 0.05). The level of IL-4 was similar in control 1, control 2 and experimental groups, but the proliferation rate of lymphocyte in the experimental group was the lowest one, the viability of islets in the experimental group was the best and the SI was the highest. The levels of IL-2, IL-4, IL-10 and IFN-gamma in the experimental group were higher than those in the blank group. CONCLUSION: CD86 gene modified recipient DC loaded with donor derived antigen could protect the islet function in vitro to some extent. PMID- 26480648 TI - [Effect of Recombinant Super-compound Interferon (rSIFN-co) on Proliferation and Apoptosis of Human Pulmonary Adenocarcinoma Cell A549]. AB - OBJECTIVE: To investigate the effect of recombinant super-compound interferon (rSIFN-co) on the proliferation and apoptosis of pulmonary adenocarcinoma cell line A549. METHODS: Screening tests were conducted to determine the concentrations of rSIFN-co that have a significant impact on A549 and the optimal concentration and duration for the test of rSIFN-co combined with Cisplatin. A549 cells were treated with rSIFN-co, Infergen, rSIFN- co+ Cisplatin, Infergen + Cisplatin, and Cisplatin, respectively, and compared with those cultured in normal medium. The viable A549 cells from Day 1 to Day 7 were detected by MTT assay. Cell apoptosis was detected by flow cytometry (FCM). Apoptosis-associated proteins, Fas and Bcl-2 were detected by immunofluoroscence at 48 h. RESULTS: Effective concentrations of rSIFN-co ranged from 1 to 64 ug/mL, and a minimal of 2 ug/mL Cisplatin was needed. The optimal test condition was set at 5 ug/mL rSIFN co combined with 2 ug/mL Cisplatin for a duration of 48 h. rSIFN-co demonstrated a stronger inhibiting effect on cell proliferation than Infergen. The inhibiting efficiency of rSIFN-co+Cisplatin was also stronger than that of Infergen+Cisplatin. Apoptosis of A549 cells induced by rSIFN-co was also more significant than that of Infergen (P = 0.000). Cells treated with rSIFN- co+ Cisplatin has a higher apoptosis rate than those treated with rSIFN-co (P = 0.004) or Cisplatin (P = 0.023). rSIFN-co increased the expression of Fas and decreased the expression of Bcl-2. Cells treated with rSIFN-co showed lower fluoroscence intensity of Bcl-2 than those treated with Infergen (P < 0.05). CONCLUSION: rSIFN-co inhibits the proliferation of A549 and its effect is stronger than that of Infergen. Cisplatin can further enhance the inhibiting effect of rSIFN-co. The inhibiting efficiency may be associated with the expression of apoptosis-related genes. PMID- 26480649 TI - [The Involvement of CRMP-2 on Axonal and Dendrictic Injury after Hypoxic-Ischemic Brain Injury in Neonatal Rat]. AB - OBJECTIVE: To investigate the activity of collapsin response mediator protein 2 (CRMP-2) and its possible regulation for axonal and dendrictic injury under hypoxia-ischemia (HI). METHODS: Postnatal day 10 SD rats were suffered the right common carotid artery ligation and 8% mixture of oxygen and nitrogen hypoxia 2.5 h to produce HI model. The expression of total and phosphorylated CRMP-2 and amyloid precursor protein (APP) were detected by Western blot after HI. After pretreatment of protein kinase B (Akt) inhibitor, wortmannin or LY294002, western blot and immunohistochemistry were applied to detect the expression of total and phosphorylated of CRMP-2 at 4 h and 24 h after HI. At 72 h after HI, APP was detected by Western blot and immunohistochemistry, axonal and dendrictic injury was determined by electron microscope. RESULTS: Total CRMP-2 was not obviously changed after HI, compared with that of sham controls. However, the phosphorylated CRMP-2 (p-CRMP-2) protein transiently increased at 0.5 h, started to decrease at 2 h, remained at a low level at the rest of the time points, compared with that of sham controls. APP protein started to increase at 2 h, remained at a high level at 4, 8, 24 h, and then progressively increased at 48 and 72 h. In wortmannin and LY294002 group, CRMP-2 protein was not obviously changed at 4 h and 24 h after HI. However, p-CRMP-2 increased at 4 h and 24 h. At 72 h, wortmannin pretreatment increased APP expression, leading to more severe ultrastructure failure of axon and dendrite. CONCLUSION: As a downstream effector of Akt pathway, CRMP-2 is involved in axonal and dendritic injury regulation after HI in neonatal rat. PMID- 26480650 TI - [Effect of GABA(B) Receptor Signal to Corticosterone-induced Neuron Apoptosis]. AB - OBJECTIVE: To investigate whether corticosterone results in neuron apoptosis through regulating gamma-aminobutyric acid (GABA) receptor. METHODS: In vivo: the hyperglycemic rat model with applying chronic restraint stress to healthy male SD rats (3 months) was established, after paraffin embedding the brain was sliced, and the level of neuron apoptosis was tested by detecting active Caspase-3 with immune-histochemical staining and TUNEL. The level of corticosterone in serum was detected by using ELISA. In vitro: the level of active Caspase-3 in NG108-15 cells (neuroblastoma and glioma cell line) after treated with corticosterone (10( 7) mol/L) was detected with Western blot. In NG108-15 cells recombinanted with GABA(B2) receptor, after administrating separately with the GABA(B) agonist baclofen (100 umol/L) and antagonist CGP35348 (100 umol/L), the level of active Caspase-3 under the effect of corticosterone (10(-7) mol/L) was detected. RESULTS: Active Caspase-3 positive apoptotic cells and TUNEL-positive cells were detected in solitary nucleus of hyperglycemia rat induced by chronic restraint stress, and the level of serum corticosterone had recovered after an initial ascent. NG108-15 cells could express GABA(B1) receptor endogenously, and the expression of active Caspase-3 increased after corticosterone treatment (P < 0.05). In NG108-15 cells transfected with GABA(B2) receptor subunits, baclofen could reduce the effect of corticosterone- induced active Caspase-3 upexpression, while CGP35348 enhanced this effect (P < 0.05). CONCLUSION: Corticosterone may lead to abnormal neuron excitability and neuron apoptosis by means of inhibiting GABA receptor B. PMID- 26480651 TI - [Effects of Minocycline on the Neuronal Plasticity in Rats after Focal Cerebral Ischemia Reperfusion Injury]. AB - OBJECTIVE: To observe the effects of minocycline on morphology and the expression of synaptophysin in cortical tissues of rats after cerebral ischemia reperfusion injury. METHODS: 36 male SD rats were randomly divided into 3 groups: sham group, model group [ischemia reperfusion (I/R)] and minocycline (Min) group (treated with minocycline for 14 d, 3 mg/kg, 2 times/d ). Middle cerebral artery occlusion (MCAO) was used to established as focal cerebral I/R model. At 14 d after I/R. Neurological functional recovery was evaluated using the staircase test, the cell morphology in cortex was evaluated by HE staining, the neurite growth was observed by immunostaining with anti-microtubule-associated protein-2 (MAP-2) antibody, the expression of synaptophysin in pei-infarct region was tested by Western blot. RESULTS: In the sham group, the rats did not show any neurological deficits. The neurons in the cortex were arranged in neat rows and the morphology were normal, the MAP-2 positive neurons showed longer neuronal processes than the model group. Compared to the model group, minocycline significantly improved forelimb motor function, increased the expression of synaptophysin and the number of MAP-2-positive cells in peri-infarct region (P < 0.05). CONCLUSION: Minocycline could improve the neurite regrowth and the expression of synaptophysin of neuron in ischemic cortex, promote neurological functional recovery of rats after MCAO, which is related to regulate the neuronal plasticity. PMID- 26480652 TI - [Effect of Risperidone on BDNF-TrkB Signaling Pathway in Rat Brain]. AB - OBJECTIVE: To investigate the effect of risperidone on the expression of brain derived neurotrophic factor (BDNF) and its receptors, tyrosine kinase receptor (TrkB) and P75 neurotrophin receptor (P75NTR) in rat brain. METHODS: Sixteen SD rats were divided into two groups (n = 8 for each group). The rats in experimental group were treated with risperidone [0.25 mg/(kg . d)] for 14 d, while the control group was given placebo. Total RNA sample in prefrontal cortex, temporal cortex and hippocampus was extracted, and the expression of BDNF, TrkB and P75NTR mRNA were determined by quantitative real-time PCR. RESULTS: The treatment of risperidone significantly up-regulated the expressions of BDNF and TrkB in prefrontal cortex, temporal cortex and hippocampus, while the expression of P75NTR was not significantly changed. CONCLUSION: Risperidone upregulated BDNF TrkB signaling, but not BDNF-P75NTR signaling, which may be helpful for the further pharmacological study of risperidone. PMID- 26480653 TI - [B Cell Activating Transcription Factor Regulates Acute Airway Inflammation in Asthmatic Mice]. AB - OBJECTIVE: To investigate the regulatory effect of B cell activating transcription factor (BATF) on acute airway inflammation and its association with retinoic acid orphan nuclear receptors gammat (RORyt) in asthmatic mice. METHODS: 24 female BALB/c mice were randomly and equally divided into three groups (n 8): normal saline (NS) treated, asthma (AS) control and dexamethasone (DEX) treated. AS mice were sensitized and challenged with OVA to establish murine asthma model. Histological changes in lung tissues of the mice were observed by HE staining. Numbers of white blood cell (WBC), polymorphonuclear leukocyte (PMN) and eosinophils (EOS) in the bronchoalveolar lavage fluid (BALF) of the mice were counted. The concentration of interleukin-17 (IL-17) in BALF was measured by ELISA. Quantitative real-time PCR (RT-PCR) was performed to assess the mRNA expressions of BATF, IL-17 and RORgammat in the lung tissues. RESULTS: The HE staining showed a higher level of inflammatory cell infiltration around the bronchi of AS mice compared with those treated with NS, predominantly in the forms of EOS, PMN and lymphocytes. The AS and DEX treated mice had higher levels of EOS, PMN, WBC and mRNA expressions of BATF, IL-17 and RORgammat in BALF than those treated with NS (P < 0.05). DEX reduced the levels of EOS, PMN, WBC and IL 17 in BALF significantly (P < 0.05). The mRNA expression of BATF in lung tissues of mice was positively correlated with the expression of IL-17, RORgammat and the counts of WBC,EOS and PMN in BALF (P < 0.05). CONCLUSION: Asthmatic mice have increased expressions of BATF, IL-17 and RORgammat in bronchial and lung tissues. BATF can, through regulating the secretion of Th17 cells, readjust the airway inflammatory. The regulatory function may take effect through synergy with RORgammat . PMID- 26480654 TI - [Effect of HIF-1alpha Gene Silence on Biological Characteristics of Human Colon Cancer Cells SW480]. AB - OBJECTIVE: To investigate changes in proliferation and apoptosis of human colon cancer SW480 cells after silencing hypoxia inducible factor-lalpha (HIF-1alpha) expression. METHODS: siRNA interference technology was performed to silence the expression of HIF-1alpha using lipofectamine mediation to transfect siRNA into human colon cancer SW480 cells. The siRNA interfered SW480 cells were compared with a negative control group, an empty vector group, and a blank control group. Real-time PCR and Western blot were used to measure the expressions of HIF-lalpha protein and mRNA. MTT and flow cytometry (FCM) were used to evaluate the apoptosis and proliferation of SW480 cells. RESULTS: The interfered SW480 cells had a higher level of silence of HIF-lalpha mRNA (> 80%) compared with those of in the three control groups (P < 0.05). Higher levels of apoptosis and lower levels of proliferation were detected in the interfered cells compared with those in the control groups (P < 0.01). CONCLUSION: HIF-lalpha silencing promotes apoptosis and inhibits the proliferation of SW480 cells in vitro. PMID- 26480658 TI - [Changes of the Expression of Brain Derived Neurotrophic Factors in Rats Trachea Induced by Acrolein Exposure]. AB - OBJECTIVE: To investigate expressional changes of brain derived neurotrophic factor (BDNF) in the trachea of rats with acrolein inhalation. METHODS: Twenty two SD rats were divided into 2 groups: the rats in experimental group were subjected to acrolein inhalation for the induce of trachea inflammatory injury, while the rats with saline (NS) inhalation were as control. All the rats were sacrificed in 1,3,6 weeks after acrolein (n = 11 at each time point) or saline inhalation (n = 11 at each time point), the samples of trachea epithelium were harvested. The immunohistochemistry and in situ hybridization was performed to detect the location of BDNF protein and mRNA in trachea. The expression of BDNF mRNA in the trachea tissues were determined by RT-PCR. RESULTS: There are positive cells in epithelium of trachea for BDNF protein and mRNA, with cytoplasm staining. The expression of BDNF mRNA in the trachea was increased at 1 week after acrolein inhalation (P < 0.05, vs. control group), then decreased along with the time and reached to the same level as control group at 3 weeks, then last to 6 weeks (P > 0.05). CONCLUSION: The inflammatory injury in trachea induced by acrolein exposure could be associated with the increased expression of BDNF. BDNF may be one of the crucial inflammatory factors in the process of inflammatory reaction in trachea with acrolein stimulation. PMID- 26480657 TI - [Expression of Tcf-4, MMP7 and Survivin in Colorectal Cancer and Its Clinical Significance]. AB - OBJECTIVE: To explore the clinical and pathological significance and correlations among the xpressions of Tcf-4, MMP7 and survivin in colorectal cancer. METHODS: The expressions of Tcf-4, MMP7 and survivin mRNA in tumor tissues and adjacent normal mucosa from 50 colorectal cancer patients were detected by reverse transcription PCR (RT-PCR). The expressed proteins of Tcf-4, MMP7 and survivin were measured using mmunohistochemistry staining technique (Elivision) in 100 colorectal cancer samples and 60 normal mucosa tissue samples. We analyzed the correlations between those measurements and their associations with clinical and pathological characteristics. RESULTS: Positive expressions of Tcf-4, MMP7 and survivin mRNA were found in both cancer and adjacent mucosa tissues, despite a higher level of expression in the cancer tissues (P < 0.01). Expressed proteins were detected in cancer tissues of 69.00% (69/100) of those with a positive Tcf-4 expression, 77.00% (77/100) of those with a positive MMP7 expression, and 65.00% (65/100) of those with a positive survivin expression. Compared with cancer tissues, lower levels of protein expression were found in normal mucosa tissues [16.67% (10/60) for Tcf-4, 13.33% (8/60) for MMP7 and 15.00% (9/60) for survivin, P < 0.01]. The expressions of Tcf-4, MMP7 and survivin were all associated with lymphatic metastasis and Dukes staging (P < 0.05). MMP7 expression was associated with depth of tumor invasion (P < 0.05). Survivin expression was associated with tumor differentiation. The Spearman rank correlation analyses showed that protein expressions in colorectal cancer tissues in those with a positive Tcf-4 were correlated with those with a positive MMP7 (r = 0.302) and those with a positive survivin (r = 0.279) (P < 0.01), but not in those with a positive MMP7 and those with a positive survivin (r = 0.097, P > 0.05). CONCLUSION: The expression levels of Tcf-4, MMP7 and survivin are high in colorectal cancer, all being linked to lymph node metastasis and Dukes stages of patients. This suggests that they may be involved in the occurrence, development, malignant growth and clinical progression of colorectal cancer. PMID- 26480659 TI - [Study of Pregnancy Exposure to PFOS on Reproductive Toxicities and Mechanism in Male Offspring Rats]. AB - OBJECTIVE: To explore the effects of testosterone synthesis in adult leydig cell (ALC) of male rats exposed by perfluorooctane sulfonate (PFOS) during pregnancy. METHODS: At gestations 12 day, the pregnant rats were exposed to PFOS (5 mg/kg, PFOS group) or 0.5% Tween (control group) by gavage, once a day for 8 consecutive days. On postnatal day (PND) 70, several indexes of male offspring rats were measured including body mass, testicular coefficient, sperm count, serum testosterone concentration. The mRNA levels of ALC associated with testosterone synthesis were detected by real-time quantitative RT-PCR. RESULTS: The result showed that sperm count and serum testosterone concentration decreased in male offspring rats of PFOS group (P < 0.05), and body mass was significantly lower (P < 0.001). The expression of steroidogenic acute regulatory factor (Star), scavenger receptor class B type 1 (Scarb1), Cyp11a1 (coding gene of cytochrome P450 side chain cleavage) and Hsd17b3 (coding gene of 17beta-hydroxysteroid dehydrogenase) were down regulated (P < 0.05), no significant statistical difference was observed on the mRNA level of insulin-like growth factor-1 (Igf1) and insulin-like factor 3 (Insl3). CONCLUSION: Gestational exposure to PFOS can inhibit the mRNA levels associated with testosterone synthesis, and decrease the ability of testosterone synthesis in ALC of male offspring rats. PMID- 26480655 TI - [Infiltrated T Cells Induce the Accumulation of Myeloid-derived Suppressor Cells in Tumor Microenvironment]. AB - OBJECTIVE: To determine the role of infiltrated T cells in the accumulation of myeloid-derived suppressor cells (MDSCs) in tumor microenvironment. METHODS: T cell-deficient nude mice models were established using BALB/c mice. Growth of tumors was compared between those with and without adoptive transfer of T cells. Pathological changes of the tumors were examined with HE histological analysis. The levels of MDSCs were detected with flow cytometry (FACS). RESULTS: Tumor growth was promoted in T-cell-deficient nude mice, which was accompanied with lower levels of MDSCs compared with BALB/c mice (P < 0.05). T cell transfer increased the level of MDSCs significantly (P < 0.05). T cells depletion decreased the level of MDSCs (P < 0.05). CONCLUSION: Infiltrated T cells induce the accumulation of MDSCs in tumor microenvironment, and influence tumor growth. PMID- 26480656 TI - [Study of Mechanism of Esophageal Cancer Development through MKK6 Over-expression Regulated SIRTI Expression Level]. AB - OBJECTIVE: To observe the influence of silent information regulator of transcription 1 (SIRT1) level by regulation of MKK6 over-expression in esophageal cancer cell Eca109, and then to explore the relationship between p38-MAPK-SIRT1 axis and progressing of esophageal cancer. METHODS: MKK6 over-expression vector was successfully constructed firstly. Then the divided Eca109 cells were treated according to four groups: empty vector group, MKK6 over-xpression group (MKK6 group), MKK6-SIRT1 ShRNA group, MKK6-RES group. The expression of MKK6 and endogenous SIRT1 were tested by Western blot; cell proliferation capability was detected by MTT method; cell invasion force was observed by transwell method; and cell apoptosis was detected with flow cytometry. RESULTS: pcDNA3.1 (+)/myc-His A MKK6 over-expression vector was constructed successfully and proved by sequencing. MKK6's over-expressing could reduce the expression of endogenous SIRT1. The viability of Eca109 cells was decreased. The increasing of invasion and apoptosis was observed. CONCLUSION: There might be the p38-MAPK-SIRT1 regulation axis in Eca109 cells and affecting on a series of physiological characteristics of Eca109 cells. PMID- 26480660 TI - [Study on Microbial Diversity of Peri-implantitis Subgingival by High-throughput Sequencing]. AB - OBJECTIVE: To study microbial diversity of peri-implantitis subgingival with high throughput sequencing, and investigate microbiological etiology of peri implantitis. METHODS: Subgingival plaques were sampled from the patients with peri-implantitis (D group) and non-peri-implantitis subjects (N group). The microbiological diversity of the subgingival plaques was detected by sequencing V4 region of 16S rRNA with Illumina Miseq platform. The diversity of the community structure was analyzed using Mothur software. RESULTS: A total of 156 507 gene sequences were detected in nine samples and 4 402 operational taxonomic units (OTUs) were found. Selenomonas, Pseudomonas, and Fusobacterium were dominant bacteria in D group, while Fusobacterium, Veillonella and Streptococcus were dominant bacteria in N group. Differences between peri-implantitis and non peri-implantitis bacterial communities were observed at all phylogenetic levels by LEfSe, which was also found in PcoA test. CONCLUSION: The occurrence of peri implantitis is not only related to periodontitis pathogenic microbe, but also related with the changes of oral microbial community structure. Treponema, Herbaspirillum, Butyricimonas and Phaeobacte may be closely related to the occurrence and development of peri-implantitis. PMID- 26480661 TI - [HCV Genotype Distribution in Southwest China and Its Influence on Patients' Response to Pegylated-interferon alpha-2a Plus Ribavirin Therapy]. AB - OBJECTIVE: To study the distribution of hepatitis C virus (HCV) genotype in Sichuan population and to investigate the effects of HCV genotypes on the viral response of hepatitis C patients treated with pegylated interferon alpha-2a plus ribavirin as well as the relationship between HCV genotype and the severity of disease. METHODS: 189 patients with HCV infection were enrolled. The level of serum HCV-RNA at various points during the treatment was measured while HCV genotypes and baseline serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) were detected. RESULTS: The genotype of HCV in Sichuan population is dominated by genotype-1 (which accounting for 79.89%), while the other genotypes accounting for 20.11%. Patients with genotype-1 infection have lower end-oftreatment virological response (ETVR) rates and early virological response (EVR) compared with non-genotype-1 patients (P< 0 . 5). But the disease associated indexes between these two groups have no significant differences. CCONCLUSION: he distribution of the HCV genotypes in Sichuan population has certain regularity, dominated by HCV genotype-1 infection. We confirmed that HCV genotype can be a predictive factor of the virological response of the standard antiviral treatment. PMID- 26480662 TI - [Association Between SNP rs6007897 of CELSR1 and Acute Ischemic Stroke in Western China Han Population: a Case-control Study]. AB - OBJECTIVE: To investigate the relationship between single nucleotide polymorphism (SNP) rs6007897 of CELSR1 and acute ischemic stroke in Western China Han population. METHODS: All subjects (759 acute ischemic stroke patients and 786 controls) were genotyped using ligation detection reaction (LDR). We analyzed the differences between SNP rs6007897 genotypes and allele frequencies between two groups. RESULTS: Two genotypes (AA, AG) of rs6007897 were found in both stroke and control group. There was no statistically significance between two groups about genotype and allele frequency. After adjusting for risk factors, we found there was no significant association between rs6007897 and ischemic stroke CP = 0.797, odds ratio (OR) = 0.886, 95% confidence interval (CI) = 0.352-2.227). CONCLUSION: SNP rs6007897 of CELSR1 was not significantly associated with ischemic stroke in Western China Han population. PMID- 26480663 TI - [Cross-sectional Study on the Relationship among Syndrome of TCM, BODE Index and Qulity of Life, in Patients with COPD at Stable Phase]. AB - OBJECTIVE: To study the syndrome of traditional Chinese medicine (TCM) and relevant indexes of conventional Western medicine for patients with chronic obstructive pulmonary disease (COPD) at stable phase, and further explore the trend of change of the deficiency syndrome of TCM, and the correlation of each syndrome with the BODE index (body mass index, airflow obstruction, dyspnea, and exercise capacity index) and quality of life. METHODS: 300 cases with COPD which were in line with the standard were differentiated to 5 groups (60 cases for each group) by the symptoms. which were Lung Qi deficiency (Group A), Lung and Spleen Qi deficiency (Group B), Lung and Kidney Qi deficiency (Group C), Lung, Spleen and Kidney Qi deficiency (Group D), and deficiency of both Qi and Yin (Group E). Some basic details about the patients were recorded, such as body mass and height. Also BODE index and COPD assessment test were conducted. And then the differences of the indexes among groups, the relationship between the BODE index and the COPD assessment test (CAT) score were analyzed. RESULTS: Comparison in 5 groups, the body mass index (BMD and forced expiratory volume in 1 s to forced vital capacity ratio (FEV1%) of Group A was the highest, the 6-min walk distance (6MWD) of Group A was the longest, but the degree of dyspnea, BODE index and CAT score of patients in Group A were the lowest (P < 0.05) No statistical significance of above index and score between Group D and E was observed (P > 0.05). In Group D and E, the BMI and FEV1% was the lowest, 6MWD was the shortest, and the degree of dyspnea of patients was the highest (P < 0.05). A positive correlation between BODE index and CAT score observed (r = 0.883, P < 0.05). CONCLUSION: With the progress of COPD, disease from single viscera gradually accumulated to multiple viscera, from Group A --> Group B/Group C --> Group D, with the gradually increasing of BODE index and CAT score. PMID- 26480664 TI - [Effects of GLP-1 Agonist Exenatide on Cardiac Diastolic Function and Vascular Endothelial Function in Diabetic Patients]. AB - OBJECTIVE: To study the protective effect of glucagon-like peptide-1 (GLP-1) on the left ventricular diastolic function and endothelial function in patients with type 2 diabetes. METHODS: 27 patients with type 2 diabetes were randomly divided into two groups: GLP-1 treated group and insulin treated group. Patients in the GLP-1 group were given GLP-1 analogue and metformin hydrochloride. Patients in the insulin group were given insulin and metformin hydrochloride. The outcomes of treatments were measured by fasting plasma glucose (FBG) fasting lipid profile, glycosylated hemoglobin (HbA1c), blood pressure and general clinical features. High resolution Doppler ultrasound was performed to detect mitral early diastolic rapid filling (E-wave), atrial contraction late filling (A-wave), E/A ratio, early diastolic mitral annular velocity (e), late diastolic mitral annular velocity (a), e/a ratio, endothelium-dependent vasodilatation (EDV) mediated by brachial arterial blood flow, and endothelium-independent vasodilatation (EIV) mediated by nitroglycerin. RESULTS: The levels of FBG and HbA1c decreased significantly in both groups after treatments (P < 0.05). Patients in the GLP-1 group showed improved e, e/a ratio, and E/e ratio after treatments (P < 0.05), but no significant changed in E, A, and E/A ratio (P > 0.05). By contrast, patients in the insulin group showed no significant changes in e, a, E, A, E/A ratio, e/a ratio and E/e ratio after treatments (P > 0.05). EDV increased significantly after treatments in both groups (P < 0.05). A higher level of post treatment EDV was found in patients in the GLP-1 group compared with those in the insulin group. No significant changes in EIV were found in both groups. CONCLUSION: GLP-1 may be able to mitigate the left ventricular diastolic dysfunction and improve endothelial function of patients with type 2 diabetes. Our findings suggest that GLP-1 has the potential to prevent or delay cardiovascular complications in patients with type 2 diabetes. Further studies are needed. PMID- 26480665 TI - [Real-time Three-dimensional Dobutamine Stress Echocardiography for the Evaluation of Ischemic Mitral Regurgitation]. AB - OBJECTIVE: To evaluate mitral regurgitation (MR) and left ventricular myocardial function in the patients with ischemic mitral regurgitation (IMR) by real-time three-dimensional dobutamine stress echocardiography (RT3D-DSE). METHODS: Seventy two consecutive in-patients with myocardial infarction and MR were enrolled in the study during 2006-2012. Each patient underwent RT3D-DSE examination before treatment. Three-dimensional (3D) heart full-volume data and 3D MR were obtained at baseline and each stress state. Quantitative parameters including: left ventricular end-diastolic/systolic volume (LVEDV/LVESV), left ventricular ejection fraction (LVEF) , left ventricular diastolic /systolic mass (LVMd/s). The time to the point of minimal regional systolic volume (Tmsv) was measured from the time volume curves of 17 segments, the standard deviation (Tmsv-SD) and maximal difference (Tmsv-Dif) of Tmsv were calculated. Excursion max (Emax), excursion SD (Esd), vena contarcta area (VCA) also were measured. RESULTS: 94.4% patients reached dobutamine (Dob) at 30 ug/(kg . min), 69.4% patients completed Dob 40 ug/(kg . min), only 38.9% patients completed Dob at 50 ug/(kg . min). At different stress state, VCA decreased significantly, and the decrement was up to the largest at 30 ug/(kg . min). 2D-LVEF, 3D-LVEF increased gradually, but decreased at 50 ug/(kg . min). 2D-LVESV and LVMd decreased, but increased at 50 ug/(kg . min). Tmsv-16/12/6 SD%, Tmsv-16/12/6 Dif% decreased, but increased at 50 ug/(kg . min). Eave and Esd increased, but decreased at 40-50 ug/(kg . min). Compared each with the baseline, LV remodeling parameters and VCA were statistically significant. CONCLUSION: IMR patients showed a biphasic response during RT3D-DSE. The decrease of VCA is associated with an improvement of LV remodeling and synchronization when Dob <= 40 ug/(kg . min). PMID- 26480667 TI - [Reliability and Validity of the Jefferson Scale of Physician Empathy in Chinese Medical Students]. AB - OBJECTIVE: To access the reliability and validity of the student version of Jefferson Scale of Physician Empathy (JSPE-S). METHODS: The JSPE-S was translated into Chinese using back-translation procedures and administered to 358 Chinese medical students at Sichuan University. The reliability was evaluated with Split half reliability and internal consistency. The validity was analyzed using discriminate validity, convergent validity and structure validity. RESULTS: The JSPE-S had a split-half reliability coefficient of 0.853 and Cronbach alpha of 0.861. The convergent test achieved 95.0% success rate. The discriminant test achieved 95.0% success rate. Three factors were extracted, with a cumulative variance contribution of 50.87%. The estimated factor loading ranged from 0.485 to 0.834, with factor variance ranging from 1.736 to 4.625. CONCLUSION: The Chinese JSPE-S has satisfactory reliability and validity in medical students. PMID- 26480666 TI - [Estimating Left Ventricular Diastolic Function through Simultaneous Measurement of T E-e' using Dual-Doppler]. AB - OBJECTIVE: Time interval between the onset of E and e' (T E-e') was applied as a non-invasive index for estimating left ventricular diastolic function. The T E-e' was measured simultaneously using dual- Doppler. METHODS: Dual-Doppler method was established, which allowed simultaneous recording and display of E and e', thus facilitating the measuring of T E-e'. Seventy-eight patients with suspected coronary artery disease, class II or above NYHA heart function, and >= 50% left ventricle ejection fraction (LVEF) were recruited. The patients were given conventional echocardiography and dual-Doppler echocardiography. Left ventricle end diastolic pressure (LVEDP) of the patients was measured during left heart catheterization. The patients were divided into diastolic dysfunction group (n = 48) and control group (n = 30) according to their LVEDP. RESULTS: The patients with diastolic dysfunction had higher T E-e' [(24.1 +/- 31.4) ms vs. the controls (8.1 +/- 23.3) ms, P = 0.019]. Significant linear correlation was found between T E-e' and LVEDP (r = 0.424, P < 0.001). The receiver operating characteristic (ROC) curve showed a sensitivity of 56.3% and a specificity of 76.7% for T E-e' detecting elevated LVEDP. T E-e' estimated by dual-Doppler had better inter observer reliability (limit of agreement: -28. 0-27. 3 ms) compared with the conventional method (limit of agreement: -37.7-34.9 ms). CONCLUSION: Simultaneous T E-e' estimated by dual-Doppler has improved reliability, which is correlated with LVEDP. Patients with diastolic dysfunction have greater T E-e'. PMID- 26480672 TI - [Identifying Factors Associated with Visits to Doctors using a Multilevel Zero inflated Poisson Model]. AB - OBJECTIVE: To determine factors influencing patient visits to doctors using a multilevel zero-inflated Poisson model with count data with excessive zero. METHODS: The data in relation to rural health services collected in Sichuan Province as part of the Fifth National Health Service Survey (2013) were used in this study. A multilevel random intercept zero-inflated Poisson model was established to identify factors associated with visits to doctors in two weeks. RESULTS: The logistic regression showed that gender, age and presence of chronic diseases were the main factors associated with the likelihood of visiting doctors in two weeks. The Poisson regression revealed that travel time to the nearest medical facility, ethnicity, marital status and educational attainment were associated with numbers of visits to doctors in two weeks. CONCLUSION: Rural residents with a high level of education, unmarried, and living close to medical facility are more likely to visit doctors than others. The multilevel zero inflated Poisson model can be used for analyzing data with zero extra. PMID- 26480668 TI - [Characteristics and Functional Status of Victims with Fractured Injury in Lushan Earthquake]. AB - OBJECTIVE: To analyze the functional limitations and characteristics of victims with fractured injury in Lushan Earthquake. METHODS: A total of 113 patients admitted to the hospital from April 20th to 30th 2013 for treatment of fractured injury in Lushan Earthquake were recruited for this study. They were evaluated by the department of rehabilitation medicine in West China Hospital using a questionnaire. RESULTS: The most common cause of injury was falling (39.82%). Vertebral fractures (26.55%) was the most common type of injury. Most injure was light (80.53%), but incidence of complications was high (89.37%). Motor functional limitations included restricted range of motion (97.35%), balance functional limitation (89.38%) and decreased muscle force (87.61%). Limited cardiopulmonary function and limited circular function occurred in about 19.47% of patients. About 76. 11% patients had restricted activities of daily living capacities, predominantly in bathing (96.46%), stair climbing (86.73%), and walking (78.76%). Pain symptoms were common (97.35%), with 4-6 in visual analogue scale (VAS) values accounting for 40.71% of those reporting pains. Limited psychological function, professional function and social function was reported by 46.02%, 99.12% and 100% patients, respectively. CONCLUSION: Fractured injury of Lushan earthquake victims has its own characteristics. Increased attention should be paid to the restoration of psychological function, professional function and social function. PMID- 26480671 TI - [A Novel All-arthroscopic PCL Tibial Inlay Reconstruction]. AB - OBJECTIVE: To design new apparatus and develop relative surgical procedures for all-arthroscopic tibial inlay PCL reconstruction. METHODS: The new apparatus consisting of three main components for total arthroscopic tibial inlay were designed and manufactured, and the relative surgical procedures were experimented on 6 cadaveric knees. RESULTS: The apparatus for tibial sloting including three components was designed and manufactured successfully, which could be used easily. The surgical procedures were proved to be feasible, which could be performed within a short time (mean, 78.5 min). The graft fixation was proved to be firm enough by mechanical tests. Image examination (X ray, CT and MRI) confirmed that the location of implants was appropriate. CONCLUSION: The newly designed apparatus and surgical procedures for all-arthroscopic tibial inlay seems feasible and useful. PMID- 26480669 TI - [Influence Factors on Serum Thyroid Hormone Level in Healthy People]. AB - OBJECTIVE: To explore the influences of age, gender and season on serum thyroid stimulating hormone level and thyroid hormone level in healthy people. METHODS: There were 2 564 healthy volunteers enrolled in this study, whom were divided into different groups according to gender, age and the season. The levels of serum TSH, T3, T4, FT3, FT4 were measured and the data were statistically analyzed. RESULTS: The level of serum TSH in both young and middle-age groups of female was higher than that in the same age groups of male. The serum levels of T3, FT3, FT4 in both young and middle-age groups of female were lower than those in the same age groups of male (P < 0.05). In female, the serum level of TSH was increasing with age. However, the serum levels of FT3, FT4 had the opposite tendency. The level of serum FT3 in young group was higher than that in elderly group of, but T4 were lower. Lower levels of TSH, T3, FT4 were found in summer instead of winter (P < 0.05) and there was no significant difference of FT3 between that two seasons. The levels of serum TSH, T3, T4 and FT4 were correlated with seasons (r = 0.079, 0.092,-0.137, 0.140). CONCLUSION: The levels of serum TSH and thyroid hormones are influenced by age, gender and seasons, which needs to be considered for the diagnosis of thyroid diseases and evaluation of thyroid function. PMID- 26480670 TI - [Rapid Detection of Adenovirus in Fecal Samples by Capillary Electrophoresis laser Induced Fluorescence and Microchip Capillary Electrophoresis-laser Induced Fluorescence]. AB - OBJECTIVE: To establish a rapid and sensitive method based on polymerase chain reaction (PCR) combined with capillary electrophoresis-laser induced fluorescence (CE-LIF) and microchip capillary electrophoresis-laser induced fluorescence (MCE LIF) for detecting adenoviruses in fecal samples. METHODS: The DNA of adenovirus in fecal samples were extracted by the commercial kits and the conserved region of hexon gene was selected as the target gene and amplified by PCR reaction. After labeling highly sensitive nucleic acid fluorescent dye SYBR Gold and SYBR Orange respectively, PCR amplification products were separated by CE and MCE under the optimized condition and detected by LIF detector. RESULTS: PCR amplification products could be detected within 9 min by CE-LIF and 6 min by MCE LIF under the optimized separation condition. The sequenced PCR product showed good specificity in comparison with the prototype sequences from NCBI. The intraday and inter-day relative standard deviation (RSD) of the size (bp) of the target DNA was in the range of 1.14%-1.34% and 1.27%- 2.76%, respectively, for CE LIF, and 1.18%-1.48% and 2.85%-4.06%, respectively, for MCE-LIF. The detection limits was 2.33 x 10(2) copies/mL for CE-LIF and 2.33 x 10(3) copies/mL for MCE LIF. The two proposed methods were applied to detect fecal samples, both showing high accuracy. CONCLUSION: The two proposed methods of PCR-CE-LIF and PCR-MCE-LIF can detect adenovirus in fecal samples rapidly, sensitively and specifically. PMID- 26480673 TI - [Correlation Between Serological Indices and Liver Histological Pathology in Patients with HBV Infection]. AB - OBJECTIVE: To analyze the correlation between serological indices and liver histological pathology in the patients with hepatitis B virus ( HBV) infection. METHODS: This study enrolled 301 patients with HBV infection. All of them received liver biopsy, serum biochemical examination, including alanineamino transferase (ALT), aspart ateaminotransferase (AST), albumin (ALB), globulin (GLB ), HBV DNA test and HBV genotype detection. RESULTS: ALT, AST and AST/ALT in G2/G(3+4) group were significantly higher than those in group G0/G1 (P < 0.05), and all showed positive correlation with liver inflammation (r = 0.487, 0.648, 0.509, P < 0.05). GLB in S2/S(3+4) group was significantly higher than that in group S0/S1 (P < 0.05), which had positive correlation with liver fibrosis (r = 0.674, P < 0.05). ALB/GLB (A/G) in S2/S(3+4) group was significantly lower than that in group S0/S1 (P < 0.05), it had negative correlation with liver fibrosis(r = -0.500, P < 0.05). The inflammation and fibrosis level in patients with C genotype was higher than that of B genotype (chi2 = 11.460, 12.729, P < 0.05). CONCLUSION: ALT, AST and AST/ALT show better diagnostic value in liver inflammation. GLB and A/G show better diagnostic value in liver fibrosis. The progress of this disease is relatively faster in the patients with C genotype HBV infection. PMID- 26480674 TI - [Proximal Aorta Reconstruction for Type A Aortic Dissection Patients without Intimal Tear in Aortic Arch: the Early and Mid-outcomes]. AB - OBJECTIVE: To evaluate the early and mid-outcomes of proximal aorta reconstruction for type A aortic dissection (AAD) patients without intimal tear in aortic arch, and assess the safety and efficacy of this surgical strategy. METHODS: From January 2010 to February 2013, there were 23 AAD patients without intimal tear in the aortic arch received proximal aorta reconstruction surgery. Clinical data of these patients were analyzed retrospectively, the mean age was (48.04 +/- 12.37) years old (21-73 yr.). Twelve cases were acute aortic dissection, the others were chronic dissection. Bentall surgery was performed for 13 cases, Cabrol surgery for 2 cases, Wheat surgery for 1 case, ascending aorta replacement and aortic valve repair was employed for 1 patient, simple ascending aorta replacement for 6 cases. The patients received follow-up every 3 to 6 months after the surgery. RESULTS: The duration of CPB time was (182.83 +/- 36.98) min, cardiac arrest time was (111.87 +/- 18.82) min, circulatory arrest time was (24.22 +/- 6.38) min. The complications were lung infection (4 cases, 17.4%), tracheotomy (2 cases), peritoneal dialysis (1 case), 2 cases suffered transient neurological dysfunction. None stroke, paralysis, and permanent neurological dysfunction occurred. All the patients were discharged. Mean time of follow-up was (38.35 +/- 11.95) months (18-56 months). All patients were alive and return to normal life, the proportion of false lumen closure was 65.22% (15 cases). None patients need secondary surgery. CONCLUSION: Proximal aorta reconstruction is safe and effective for AAD patient without intimal tear in aortic arch, the operation strategy can be used individually. PMID- 26480676 TI - [Background and trigger factors for neuroimmunological diseases]. PMID- 26480675 TI - [History and future perspective of the research on neuroimmunological diseases]. PMID- 26480683 TI - [Animal models for multiple sclerosis]. PMID- 26480682 TI - [Microglia in neuroimmunological disorders]. PMID- 26480679 TI - [Neuroimmunological disorders and antibody-mediated immunity]. PMID- 26480678 TI - [Cell-mediated immunity in neuroimmunological disorders]. PMID- 26480677 TI - [Innate immunity and neuroimmune disease]. PMID- 26480680 TI - [Breakdown of BBB and BNB in neuroimmunological diseases]. PMID- 26480684 TI - [Animal model of neuromyelitis optica]. PMID- 26480681 TI - [Neural stem cells in autoimmune neurological diseases]. PMID- 26480685 TI - [An animal model of Guillain-Barre syndrome]. PMID- 26480686 TI - [Animal models of myasthenia gravis]. PMID- 26480689 TI - [Epidemiology of multiple sclerosis]. PMID- 26480693 TI - [Blood and cerebrospinal fluid test in multiple sclerosis]. PMID- 26480687 TI - [Animal model of polymyositis/dermatomyositis]. PMID- 26480688 TI - [Changes of epidemiological and clinical features and disease concept in multiple sclerosis]. PMID- 26480691 TI - [Symptoms and neurological findings in patients with multiple sclerosis]. PMID- 26480690 TI - [Clinical course and prognosis of multiple sclerosis]. PMID- 26480692 TI - [Neuropathology of multiple sclerosis]. PMID- 26480694 TI - [MR imaging of multiple sclerosis]. PMID- 26480699 TI - [Plasmapheresis in acute phase of multiple sclerosis]. PMID- 26480697 TI - [How to use Japanese guidelines for the treatment of multiple sclerosis]. PMID- 26480700 TI - [Interferon beta]. PMID- 26480695 TI - [Electrophysiological examination of multiple sclerosis]. PMID- 26480696 TI - [Diagnostic criteria to patients with multiple sclerosis and clinically isolated syndrome]. PMID- 26480698 TI - [Corticosteroid treatment]. PMID- 26480701 TI - [Fingolimod]. PMID- 26480707 TI - [Pediatric multiple sclerosis]. PMID- 26480702 TI - [Immunosuppressive treatments]. PMID- 26480708 TI - [QoL in MS and guide for patients' education]. PMID- 26480711 TI - [Neuromyelitis optica and anti-aquaporin 4 antibody]. PMID- 26480709 TI - [Current and historical concept of neuromyelitis optica]. PMID- 26480706 TI - [Treatment for multiple sclerosis in patients with collagen diseases]. PMID- 26480703 TI - [Natalizumab]. PMID- 26480710 TI - [Epidemiology of neuromyelitis optica]. PMID- 26480705 TI - [Symptomatic therapy in multiple sclerosis]. PMID- 26480712 TI - [Symptoms and clinical manifestations in neuromyelitis optica]. PMID- 26480704 TI - [Emerging new disease--modifying therapies for multiple sclerosis]. PMID- 26480714 TI - [Differntial diagnosis of neuromyelitis optica]. PMID- 26480717 TI - [Therapeutic development for neuromyelitis optica]. PMID- 26480716 TI - [Treatment and prognosis of neuromyelitis optica(NMO)]. PMID- 26480713 TI - [MRI and CSF features in neuromyelitis optica]. PMID- 26480718 TI - [Acute disseminated encephalomyelitis (ADEM)]. PMID- 26480715 TI - [NMO spectrum disorder]. PMID- 26480720 TI - [Balo's disease (concentric sclerosis)]. PMID- 26480719 TI - [Autoimmune central nervous system disorders associated with streptococcal infection and anti-basal ganglia antibodies]. PMID- 26480721 TI - [Atopic myelitis]. PMID- 26480722 TI - [Acute transverse myelitis]. PMID- 26480723 TI - [Concepts and epidemiology of combined central and peripheral demyelination]. PMID- 26480724 TI - [Anti-neurofascin antibody in combined central and peripheral demyelination]. PMID- 26480725 TI - [Pathology, diagnosis, and treatment of combined central and peripheral demyelination]. PMID- 26480726 TI - [Anti-glycolipid antibodies in Guillain-Barre syndrome and Fisher syndrome]. PMID- 26480727 TI - [Epidemiology, symptoms and neurological signs in Guillain-Barre syndrome]. PMID- 26480728 TI - [Guillain-Barre syndrome: Clinical examination, diagnosis, and differential diagnosis]. PMID- 26480729 TI - [Treatment and prognosis of Guillain-Barre syndrome]. PMID- 26480730 TI - [Fisher's syndrome]. PMID- 26480732 TI - [Epidemiology and clinical symptoms of CIDP]. PMID- 26480731 TI - [Keypoints of the guideline for management of Guillain -Barre syndrome and Fisher syndrome, 2013]. PMID- 26480733 TI - [Clinical, electrophysiological, and differential diagnosis of CIDP]. PMID- 26480734 TI - [Chronic inflammatory demyelinating polyradiculoneuropathy(CIDP): Treatment and prognosis]. PMID- 26480735 TI - [Practice guideline for CIDP and MMN 2013]. PMID- 26480736 TI - [Epidemiology, symptoms, and pathogenesis of MMN]. PMID- 26480737 TI - [Diagnosis of multifocal motor neuropathy]. PMID- 26480738 TI - [Treatment and prognosis of multifocal motor neuropathy]. PMID- 26480739 TI - [Neuropathy associated with IgM monoclonal gammopathy with anti-myelin-associated glycoprotein (MAG) antibody]. PMID- 26480740 TI - [Crow-Fukase (POEMS) syndrome]. PMID- 26480741 TI - [Acute autonomic and sensory neuropathy]. PMID- 26480742 TI - [(Autoimmune autonomic ganglionopathy: AAG)]. PMID- 26480743 TI - [The role of autoantibodies in myasthenia gravis]. PMID- 26480744 TI - [Myasthenia gravis: epidemiology and prognosis]. PMID- 26480745 TI - [Clinical features and associated conditions of myasthenia gravis]. PMID- 26480746 TI - [Diagnosis, differential diagnosis and laboratory examinations in myasthenia gravis]. PMID- 26480747 TI - [The new clinical guidelines: basic policy against generalized MG]. PMID- 26480748 TI - [Clinical feature of late-onset myasthenia gravis]. PMID- 26480749 TI - [Cholinesterase inhibitors]. PMID- 26480750 TI - [Oral immunotherapy]. PMID- 26480751 TI - [Intravenous immunoglobulin in myasthenia gravis]. PMID- 26480752 TI - [Plasmapheresis in treatment of myasthenia gravis]. PMID- 26480753 TI - [Thymectomy]. PMID- 26480754 TI - [Biological agents treatment for myasthenia gravis]. PMID- 26480755 TI - [Clinical characteristics and managements of juvenile myasthenia gravis]. PMID- 26480756 TI - [Quality of life and advice for lifestyle in myasthenia gravis]. PMID- 26480757 TI - [HTLV-1-associated myelopathy(HAM)]. PMID- 26480758 TI - [Autoantibodies in myositis]. PMID- 26480759 TI - [Polymyositis]. PMID- 26480760 TI - [Dermatomyositis]. PMID- 26480761 TI - [Sporadic inclusion body myositis]. PMID- 26480762 TI - [Necrotizing myopathy]. PMID- 26480763 TI - [Autoimmune encephalitis/encephalopathy: An introduction]. PMID- 26480764 TI - [Hashimoto's encephalopathy]. PMID- 26480765 TI - [Anti -NMDA receptor encephalitis]. PMID- 26480766 TI - [Anti-VGKC complex antibody associated limbic encephalitis]. PMID- 26480767 TI - [Rasmussen syndrome (encephalitis)]. PMID- 26480768 TI - [NMDA receptor encephalitis]. PMID- 26480769 TI - [Autoimmune cerebellar ataxia]. PMID- 26480770 TI - [Bickerstaff brainstem encephalitis]. PMID- 26480771 TI - [Neuropsychiatric systemic lupus erythematosus]. PMID- 26480772 TI - [Rheumatoid arthritis]. PMID- 26480773 TI - [Muscle involvement in systemic sclerosis]. PMID- 26480774 TI - [Mixed connective tissue disease (MCTD)]. PMID- 26480775 TI - [Sjogren's syndrome (sicca syndrome)]. PMID- 26480776 TI - [Neuro-Behcet's disease]. PMID- 26480777 TI - [Neuro-Sweet disease]. PMID- 26480778 TI - [Sarcoidosis]. PMID- 26480779 TI - [Vasculitis: neurological aspects]. PMID- 26480780 TI - [Central nervous system vasculitis]. PMID- 26480781 TI - [Antiphospholipid syndrome]. PMID- 26480782 TI - [Polymyalgia rheumatica]. PMID- 26480783 TI - [Susac syndrome]. PMID- 26480784 TI - [Celiac disease]. PMID- 26480785 TI - [Whipple disease]. PMID- 26480786 TI - [Paraneoplastic neurological syndrome]. PMID- 26480787 TI - [Paraneoplastic encephalomyelitis]. PMID- 26480788 TI - [Paraneoplastic limbic encephalitis]. PMID- 26480789 TI - [Paraneoplastic cerebellar degeneration (PCD)]. PMID- 26480790 TI - [Paraneoplastic brainstem encephalitis]. PMID- 26480791 TI - [Paraneoplastic opsoclonus-myoclonus syndrome (POMS)]. PMID- 26480792 TI - [Paraneoplastic retinopathy]. PMID- 26480793 TI - [Paraneoplastic motor neuron disease]. PMID- 26480794 TI - [Paraneoplastic neuropathy]. PMID- 26480795 TI - [Paraneoplastic myositis]. PMID- 26480796 TI - [Lambert-Eaton myasthenic syndrome (LEMS)]. PMID- 26480797 TI - [Isaacs syndrome]. PMID- 26480798 TI - [Morvan's syndrome (Morvan's fibrillary chorea)]. PMID- 26480799 TI - [Stiff-person syndrome]. PMID- 26480800 TI - [Semaphorin 4 in multiple sclerosis]. PMID- 26480801 TI - [Tumefactive multiple sclerosis and connexin]. PMID- 26480802 TI - [NLRP3 inflammasome and multiple sclerosis/EAE]. PMID- 26480803 TI - [Anti-myelin oligodendrocyte glycoprotein (MOG) antibody]. PMID- 26480805 TI - [Remyelination strategy for multiple sclerosis]. PMID- 26480804 TI - [Multiple sclerosis and microRNA]. PMID- 26480806 TI - [Future issues of the multiple sclerosis treatment from a medical economic viewpoint]. PMID- 26480807 TI - [Molecular targeted therapy and progressive multifocal leukoencephalopathy]. PMID- 26480808 TI - [The patients with pregnancy of the neuroimmunological diseases: the management and treatment]. PMID- 26480809 TI - A prospective randomized study comparing transnasal and peroral 5-mm ultrathin endoscopy. PMID- 26480810 TI - Pre-treatment protoporphyrin IX concentration in actinic keratosis lesions may be a predictive biomarker of response to aminolevulinic-acid based photodynamic therapy. AB - BACKGROUND: Although aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) photodynamic therapy (PDT) is an effective FDA-approved therapy for actinic keratosis (AK), a substantial fraction of patients (up to 25%) do not respond to treatment. This study examined the feasibility of using pre-treatment measurements of PpIX concentration in AK lesions to predict response of ALA-PpIX PDT. METHODS: A non-invasive fiber-optic fluorescence spectroscopy system was used to measure PpIX concentration in patients undergoing standard-of-care ALA PDT for AK. All patients provided assessments of pain at the time of treatment (n=70), and a subset reported pain and erythema 48-76 h after treatment (n=13). RESULTS: PpIX concentration was significantly higher in lesions of patients reporting high levels of pain (VAS score >=5) immediately after treatment vs. patients reporting pain scores below VAS=5 (p<0.022) (n=70). However, pain was not an exclusive indicator of PpIX concentration as many patients with low PpIX concentration reported high pain. In a subpopulation of patients surveyed in the days after treatment (n=13), PpIX concentration measured on the day of treatment was uncorrelated with pain-reported immediately after treatment (r=0.17, p<0.57), but positive correlations were found between PpIX concentration and patient reported pain (r=0.55, p<0.051) and erythema (r=0.58, p<0.039) in the 48-72 h following treatment. CONCLUSIONS: These data suggest that in vivo optical measurements of PpIX concentration acquired before light delivery may be an objective predictor of response to ALA-PpIX PDT. Identification of non-responding patients on the day of treatment could facilitate the use of interventions that may improve outcomes. PMID- 26480811 TI - Excessive eccentric exercise leads to transitory hypothalamic inflammation, which may contribute to the low body weight gain and food intake in overtrained mice. AB - Low body weight gain and food intake are related to exhaustive training and overtraining; however, the molecular mechanisms responsible for these alterations remain unknown. The main aim of this study was to evaluate the effects of running overtraining (OT) protocols performed downhill, uphill and without inclination on the inflammatory pathway in the mouse hypothalamus. The rodents were randomized into the control (C), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up) and overtrained by running without inclination (OTR) groups. The body weights and food intake were recorded daily. The incremental load, exhaustive, rotarod and grip force tests were used to measure performance. At 36 h after the grip force test was performed at the end of OT protocols (i.e., week eight) and/or after a 2-week total recovery period (i.e., week 10), the hypothalamus and gastrocnemius were extracted for immunoblotting analysis. In addition, the serum was used to determine cytokine and leptin concentrations. From week 0 to week 8, the OTR/down group exhibited decreased body weight and food intake, and the OTR/up group increased their food intake. At week 10, the OTR/down group exhibited increased body weight, while the OTR group decreased their food intake. The OTR/down group exhibited increased IL-1beta, IL-6, TNF alpha, pSAPK/JNK and SOCS3 levels at week eight. The OTR/down, OTR/up and OTR groups exhibited increased IL-10 levels at week 10. The OTR/up group displayed increased pJAK2 levels at week eight. While the OTR/down group exhibited increased IL-1beta levels, the OTR/down and OTR/up groups exhibited increased IL 6 and TNF-alpha levels, but decreased IL-10 levels in the gastrocnemius at week eight. The three OT protocols increased the IL-1beta and IL-6 levels, but only the OTR/down and OTR/up groups had increased TNF-alpha levels in serum at week eight. The serum leptin levels were lower for the OTR group compared with the CT group at week eight. In conclusion, the OTR/down protocol induced transitory hypothalamic inflammation with concomitant reductions in the body weight and food intake. After the 2-week total recovery period, the OTR/down group had reversed the hypothalamic inflammation, with the concomitant normalization of the body weight and food intake. PMID- 26480812 TI - Alcohol and high fat induced chronic pancreatitis: TRPV4 antagonist reduces hypersensitivity. AB - The pathogenesis of pain in chronic pancreatitis is poorly understood, and its treatment can be a major clinical challenge. Surgical and other invasive methods have variable outcomes that can be unsatisfactory. Therefore, there is a great need for further discovery of the pathogenesis of pancreatitis pain and new therapeutic targets. Human and animal studies indicate a critical role for oxidative stress and activation of transient receptor potential (TRP) cation channel subfamily members TRPV1 and TRPA1 on pancreatic nociceptors in sensitization mechanisms that result in pain. However, the in vivo role of transient receptor potential cation channel subfamily V member 4 (TRPV4) in chronic pancreatitis needs further evaluation. The present study characterized a rat alcohol/high fat diet (AHF)-induced chronic pancreatitis model with hypersensitivity, fibrotic pathology, and fat vacuolization consistent with the clinical syndrome. The rats with AHF-induced pancreatitis develop referred visceral pain-like behaviors, i.e. decreased hindpaw mechanical thresholds and shortened abdominal and hindpaw withdrawal latency to heat. In this study, oxidative stress was characterized as well as the role of TRPV4 in chronic visceral hypersensitivity. Lipid peroxidase and oxidative stress were indicated by increased plasma thiobarbituric acid reactive substances (TBARS) and diminished pancreatic manganese superoxide dismutase (MnSOD). The secondary sensitization associated with AHF-induced pancreatitis was effectively alleviated by the TRPV4 antagonist, HC 067047. Similarity of the results to those with the peripherally restricted MU-opiate receptor agonist, loperamide, suggested TRPV4 channel activated peripheral sensitization. This study using a reliable model that provides pre-clinical correlates of human chronic pancreatitis provides further evidence that TRPV4 channel is a potential therapeutic target for treatment of pancreatitis pain. PMID- 26480814 TI - The C-terminal binding protein (CTBP-1) regulates dorsal SMD axonal morphology in Caenorhabditis elegans. AB - C-terminal binding proteins (CtBPs) are transcriptional co-repressors which cooperate with a variety of transcription factors to repress gene expression. Caenorhabditis elegans CTBP-1 expression has been observed in the nervous system and hypodermis. In C. elegans, CTBP-1 regulates several processes including Acute Functional Tolerance to ethanol and functions in the nervous system to modulate both lifespan and expression of a lipase gene called lips-7. Incorrect structure and/or function of the nervous system can lead to behavioral changes. Here, we demonstrate reduced exploration behavior in ctbp-1 mutants. Our examination of a subset of neurons involved in regulating locomotion revealed that the axonal morphology of dorsal SMD (SMDD) neurons is altered in ctbp-1 mutants at the fourth larval (L4) stage. Expressing CTBP-1 under the control of the endogenous ctbp-1 promoter rescued both the exploration behavior phenotype and defective SMDD axon structure in ctbp-1 mutants at the L4 stage. Interestingly, the pre synaptic marker RAB-3 was found to localize to the mispositioned portion of SMDD axons in a ctbp-1 mutant. Further analysis of SMDD axonal morphology at days 1, 3 and 5 of adulthood revealed that the number of ctbp-1 mutants showing an SMDD axonal morphology defect increases in early adulthood and the observed defect appears to be qualitatively more severe. CTBP-1 is prominently expressed in the nervous system with weak expression detected in the hypodermis. Surprisingly, solely expressing CTBP-1a in the nervous system or hypodermis did not restore correct SMDD axonal structure in a ctbp-1 mutant. Our results demonstrate a role for CTBP-1 in exploration behavior and the regulation of SMDD axonal morphology in C. elegans. PMID- 26480813 TI - Impact of chronic morphine on delta opioid receptor-expressing neurons in the mouse hippocampus. AB - Delta opioid (DOP) receptors participate to the control of chronic pain and emotional responses. Recent data also identified their implication in spatial memory and drug-context associations pointing to a critical role of hippocampal delta receptors. To better appreciate the impact of repeated drug exposure on their modulatory activity, we used fluorescent knock-in mice that express a functional delta receptor fused at its carboxy-terminus with the green fluorescent protein in place of the native receptor. We then tested the impact of chronic morphine treatment on the density and distribution of delta receptor expressing cells in the hippocampus. A decrease in delta receptor-positive cell density was observed in the CA1, CA3 and dentate gyrus without alteration of the distribution across the different GABAergic populations that mainly express delta receptors. This effect partly persisted after four weeks of morphine abstinence. In addition, we observed increased DOP receptor expression at the cell surface compared to saline-treated animals. In the hippocampus, chronic morphine administration thus induces DOP receptor cellular redistribution and durably decreases delta receptor-expressing cell density. Such modifications are likely to alter hippocampal physiology, and to contribute to long-term cognitive deficits. PMID- 26480815 TI - Peripheral nerve injury induces aquaporin-4 expression and astrocytic enlargement in spinal cord. AB - Aquaporin-4 (AQP4), a water channel protein, is expressed mainly in the perivascular end-feet of astrocytes in the brain and spinal cord. Dysregulation of AQP4 is critically associated with abnormal water transport in the astrocytes. We aimed to examine whether peripheral nerve injury (PNI) could induce the changes of AQP4 expression and astrocytic morphology in the spinal cord. Two different PNI models [partial sciatic nerve transection (PST) and chronic constriction injury (CCI)] were established on the left sciatic nerve in Sprague Dawley rats, which decreased the pain withdrawal threshold in the ipsilateral hind paws. Both PNI models were associated with a persistent up-regulation of AQP4 in the ipsilateral dorsal horn at the lower lumbar region over 3 weeks, despite an absence of direct injury to the spinal cord. Three-dimensional reconstruction of astrocytes was made and morphometric analysis was done. Up regulation of AQP4 was accompanied by a significant increase in the length and volume of astrocytic processes and the number of branch points. The most prominent changes were present in the distal processes of the astrocytes and the changes were maintained throughout the whole experimental period. Extravasation of systemically administered tracers Evans Blue and sodium fluorescein was not seen in both models. Taken together, PNI was associated with a long-lasting AQP4 up-regulation and enlargement of astrocytic processes in the spinal cord in rats, both of which were not related to the disruption of blood-spinal cord barrier. The findings could provide novel insights on the understanding of pathophysiology of spinal cords after PNI. PMID- 26480816 TI - Baicalin decreases SGK1 expression in the hippocampus and reverses depressive like behaviors induced by corticosterone. AB - The present study was to investigate whether baicalin can prevent repeated exogenous corticosterone injection-induced depressive-like behaviors and explore its possible mechanisms. After a 21-day treatment with baicalin (10 and 20 mg/kg), sucrose preference in the sucrose preference test (SPT) and immobility time in forced swimming test (FST) were observed, serum corticosterone levels and brain-derived neurotrophic factor (BDNF) contents in the hippocampus were examined by enzyme-linked immunosorbent assay (ELISA). In addition, quantitative real-time polymerase chain reaction (qPCR) and western blot were used to detect the mRNA and protein expression in the hippocampus. The results showed that 21 day cortiscosterone injections caused depressive-like behaviors in mice, including the reduced sucrose preference and increased duration of immobility. Baicalin reversed these behavioral changes described above and restored serum corticosterone levels. Additionally, baicalin up-regulated the mRNA and protein expression of glucocorticoid receptor (GR) and BDNF, accompanied with the down regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1) in the hippocampus. Moreover, baicalin significantly increased the protein expression of 11beta-hydroxysteroid dehydrogenase-2 (11beta-HSD2) in the hippocampus. The present results confirmed the antidepressant-like effects of baicalin in a mice model of depression induced by corticosterone and suggested that its mechanism was possibly involved in reducing serum corticosterone and thereby increasing BDNF in the hippocampus. PMID- 26480817 TI - Antenatal pelvic floor biometry is related to levator ani muscle injury. AB - OBJECTIVE: To evaluate the relationship between antenatal pelvic floor biometry and levator ani muscle (LAM) injury in Chinese women. METHODS: Three-dimensional transperineal ultrasound was performed in nulliparous Chinese women with a singleton pregnancy at 9-12 weeks, 26-28 weeks and 36-38 weeks of gestation and again at 12 months after delivery. Hiatal anteroposterior (AP) diameter, transverse diameter and area were measured on the antenatal ultrasound volumes obtained at rest, on Valsalva maneuver and during pelvic floor muscle contraction (PFMC). LAM injury was evaluated using ultrasound volumes obtained during PFMC at 12 months after delivery. RESULTS: In total, 328 women completed the study. At 12 months after delivery, 38 (14.8% of those who delivered vaginally) women had LAM injury; 28 were unilateral (14 right- and 14 left-sided) and 10 were bilateral. In all three trimesters there was smaller hiatal AP diameter and hiatal area in women with LAM injury when compared with women without injury. On multivariable analysis of the three factors, hiatal AP diameter at rest, hiatal area at rest and operative vaginal delivery, only hiatal AP diameter at rest in all three trimesters was an independent factor of LAM injury. A larger hiatal AP diameter at rest in the first, second and third trimesters reduced the likelihood of LAM injury with odds ratios of 0.21, 0.15 and 0.21, respectively. CONCLUSIONS: A smaller antenatal hiatal AP diameter at rest is a risk factor for LAM injury. The hiatal AP diameter is relatively simple to measure and the error in measurement is relatively small. A prospective study to confirm this relationship and to explore whether this measurement, performed in the midsagittal plane, is repeatable should be performed. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26480818 TI - The human complement inhibitor Sushi Domain-Containing Protein 4 (SUSD4) expression in tumor cells and infiltrating T cells is associated with better prognosis of breast cancer patients. AB - BACKGROUND: The human Sushi Domain-Containing Protein 4 (SUSD4) was recently shown to function as a novel inhibitor of the complement system, but its role in tumor progression is unknown. METHODS: Using immunohistochemistry and quantitative PCR, we investigated SUSD4 expression in breast cancer tissue samples from two cohorts. The effect of SUSD4 expression on cell migration and invasion was studied in vitro using two human breast cancer cell lines overexpressing SUSD4. RESULTS: Tissue stainings revealed that both tumor cells and tumor-infiltrating cells expressed SUSD4. The highest SUSD4 expression was detected in differentiated tumors with decreased rate of metastasis, and SUSD4 expression was associated with improved survival of the patients. Moreover, forced SUSD4 expression in human breast cancer cells attenuated their migratory and invasive traits in culture. SUSD4 expression also inhibited colony formation of human breast cancer cells cultured on carcinoma-associated fibroblasts. Furthermore, large numbers of SUSD4-expressing T cells in the tumor stroma associated with better overall survival of the breast cancer patients. CONCLUSION: Our findings indicate that SUSD4 expression in both breast cancer cells and T cells infiltrating the tumor-associated stroma is useful to predict better prognosis of breast cancer patients. PMID- 26480819 TI - Challenges to translating new media interventions in community practice: a sexual health SMS program case study. AB - Issue addressed Herein we discuss translational challenges for new media interventions, using the Sexual Health & Youth (SHY) short message service (SMS) project to illustrate particular challenges relating to recruitment and evaluation. Methods Following the delivery of an SMS sexual health program, available documents (progress reports, communications with project staff, ethics submissions and reporting) were analysed thematically to elucidate the barriers to recruitment, implementation and evaluation. Results Despite being framed by evidence-based research, the project had little impact on the intended population. Only 119 of an expected 5100 young people (2%) enrolled to receive SMS messages. Program documents highlighted the difficulty of recruiting participants for new media interventions. Key issues identified in recruitment included under-resourcing, delays waiting to receive ethics approval and challenges of school-based recruitment. Conclusion The minimal impact of the SHY program illustrates the need for improved research translation in the field of new media interventions. It is important that recruitment procedures align with the convenience and appeal of mobile phone-based interventions. So what? New media research is not always easily translated into community settings. Large scale recruitment requires adequate resourcing and careful planning, even for low cost mobile interventions. Stronger formative research, documentation and use of partnerships are essential for successful implementation. Researchers must also consider translation in planning and disseminating their work. PMID- 26480821 TI - Phenethyl isothiocyanate, by virtue of its antioxidant activity, inhibits invasiveness and metastatic potential of breast cancer cells: HIF-1alpha as a putative target. AB - Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a crucial role in facilitating tumor progression and metastasis. Reducing the levels of HIF-1alpha might therefore be an important anticancer strategy. This could be achieved by understanding the key cellular events involved in HIF-1alpha activation. Present study explored the effect of phenethyl isothiocyanate (PEITC), a natural isothiocyanate, found in cruciferous vegetables on the expression of HIF-1alpha and HSP90 in breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231) under both normoxia and hypoxia. This study established the possible role of ROS in the up regulation of these markers in breast cancer cells. PEITC-induced nuclear accumulation of Nrf2, increased the activities of several antioxidant enzymes, and thus reduced the ROS burden of the tumor cells by acting as an indirect antioxidant. This resulted in the down-regulation of HSP90 and thereby HIF-1alpha expression. HSP90 was also found to be involved in the regulation of HIF-1alpha. A probable link between down-regulation of HIF-1alpha with reduction of ROS by PEITC through induction of Nrf2 was determined. Finally, our study demonstrated that modulation of HIF-1alpha by PEITC retarded adhesion, aggregation, migration and invasion of the breast cancer cells, thereby showing anti-metastatic effect. Activities of MMPs (2 & 9) and expression of VEGF were also altered by PEITC. PMID- 26480820 TI - The kinase inhibitor D11 induces caspase-mediated cell death in cancer cells resistant to chemotherapeutic treatment. AB - BACKGROUND: Multi-drug resistance and predisposition to metastasize are major clinical problems in cancer treatment. Malignant primary brain tumor and pancreatic cancer are two well-known examples of malignant tumors resistant to conventional therapies where aberrant EGFR-mediated and NF-kappaB signal transduction pathways are likely to play an important role. We have recently identified 1,3-Dichloro-6-[(E)-((4-methoxyphenyl)imino)methyl] diben-zo(b,d) furan-2,7-diol (D11) as a potent and selective inhibitor of CK2 a serine/threonine protein kinase that modulates the aforementioned signaling cascades. METHODS: Human cancer cell lines (glioblastoma and pancreatic adenocarcinoma) resistant to conventional chemotherapeutic agents were incubated with increasing concentrations of D11 for variable amounts of time. Cell viability, cell death and effects on major signal transduction pathways deregulated in cancer cells were analyzed by ELISA, FACS and Western blot-based assays, respectively. Moreover, effects on cell migration and in cell protein protein association were investigated by wound-healing and in situ proximity ligation assays, respectively. RESULTS: We show here, that D11 treatment leads to i) significant caspase-mediated apoptotic cell death, ii) down-regulation of EGFR expression and iii) inhibition of NF-kappaB transcriptional activity. Furthermore, cell exposure to D11 results in impaired cell migration and correlates with reduced expression of the ion co-transporter and cell volume regulator Na(+)-K(+)-2Cl(-) (NKCC1). CONCLUSIONS: Data reported here underline the therapeutic potential of D11 with respect to certain types of cancer that carry aberrant intracellular signaling cascades and/or exhibit sustained cell migration and suggest a new therapeutic strategy against chemotherapy resistance. PMID- 26480822 TI - Experimentally induced cartilage degeneration treated by pulsed electromagnetic field stimulation; an in vitro study on bovine cartilage. AB - BACKGROUND: Osteoarthritis (OA) is the final result of progressive alterations to articular cartilage structure, composition and cellularity, followed by an increase in the concentration of pro-inflammatory cytokines in joint synovial fluid. Even though the effect of pulsed electromagnetic field (PEMF) stimulation in counteracting OA progression and inflammation is of increasing interest, because of its anabolic and anti-inflammatory properties, the present study aimed to improve the knowledge on cartilage extracellular matrix (ECM) and chondrocyte changes related to the exposure of PEMF, from a histological and histomorphometric point of view. METHODS: An in vitro OA model was realized, culturing bovine cartilage explants with a high dose of interleukin 1beta (IL1beta, 50 ng/ml) at different experimental times (24 h, and 7 and 21 days). The effects of PEMFs (75 Hz, 1.5 mT) were evaluated in cartilage explants treated with IL1beta or not (control), in terms of cartilage structure, cellularity and proteoglycans, glycosaminoglycans, collagen II and transforming growth factor beta1 synthesis by using histology, histomorphometry and immunohistochemistry. RESULTS: Making a comparison with control cartilage, IL1beta-treated explants showed a decrease in cartilage matrix, structure and cellularity parameters. PEMFs were able to counteract the progression of OA acting on both cartilage cellularity and ECM in cartilage previously treated with IL1beta. Normal distribution (Kolmogroc-Smirnov test) and homoscedasticity (Levene test) of data were verified, then, the non-parametric Kruskal Wallis test followed by Mann Whiteny U test for pairwise comparisons were performed. The p-value was adjusted according to the Dunn-Sidak correction. CONCLUSIONS: These results, obtained by culturing and treating cartilage explants from two different joints, confirmed that PEMF stimulation can be used as adjuvant therapy to preserve cartilage from detrimental effects of high inflammatory cytokine levels during OA. PMID- 26480824 TI - Current Assessment of Reciprocation in Endodontic Preparation: A Comprehensive Review--Part II: Properties and Effectiveness. AB - INTRODUCTION: Many reciprocating file systems (RFs) have recently been introduced. This article reviews the properties, effectiveness, and clinical outcomes of the RFs. METHODS: A PubMed electronic search was conducted by using appropriate key words to identify investigations on RFs. After retrieving the full-text relevant articles, the cross citations were also identified. RESULTS: This review summarizes the mechanical properties, shaping ability, preservation of the root canal anatomy, shaping time, cleaning effectiveness, microcrack formation, bacterial reduction, extrusion of debris, and removal of root canal filling materials of RFs. CONCLUSIONS: The favorable results of RFs indicate their potential application as viable alternatives to rotary file systems, yet no filing system is able to entirely prepare the dentin of canals, totally eliminate sessile and planktonic microorganisms, or remove the filling material completely from the root canal system. PMID- 26480823 TI - Integrated metabolic modelling reveals cell-type specific epigenetic control points of the macrophage metabolic network. AB - BACKGROUND: The reconstruction of context-specific metabolic models from easily and reliably measurable features such as transcriptomics data will be increasingly important in research and medicine. Current reconstruction methods suffer from high computational effort and arbitrary threshold setting. Moreover, understanding the underlying epigenetic regulation might allow the identification of putative intervention points within metabolic networks. Genes under high regulatory load from multiple enhancers or super-enhancers are known key genes for disease and cell identity. However, their role in regulation of metabolism and their placement within the metabolic networks has not been studied. METHODS: Here we present FASTCORMICS, a fast and robust workflow for the creation of high quality metabolic models from transcriptomics data. FASTCORMICS is devoid of arbitrary parameter settings and due to its low computational demand allows cross validation assays. Applying FASTCORMICS, we have generated models for 63 primary human cell types from microarray data, revealing significant differences in their metabolic networks. RESULTS: To understand the cell type-specific regulation of the alternative metabolic pathways we built multiple models during differentiation of primary human monocytes to macrophages and performed ChIP-Seq experiments for histone H3 K27 acetylation (H3K27ac) to map the active enhancers in macrophages. Focusing on the metabolic genes under high regulatory load from multiple enhancers or super-enhancers, we found these genes to show the most cell type-restricted and abundant expression profiles within their respective pathways. Importantly, the high regulatory load genes are associated to reactions enriched for transport reactions and other pathway entry points, suggesting that they are critical regulatory control points for cell type-specific metabolism. CONCLUSIONS: By integrating metabolic modelling and epigenomic analysis we have identified high regulatory load as a common feature of metabolic genes at pathway entry points such as transporters within the macrophage metabolic network. Analysis of these control points through further integration of metabolic and gene regulatory networks in various contexts could be beneficial in multiple fields from identification of disease intervention strategies to cellular reprogramming. PMID- 26480825 TI - Luteinizing hormone receptors are expressed in rat myenteric neurons and mediate neuronal loss. AB - BACKGROUND: Clinical observations have suggested repeated gonadotropin-releasing hormone (GnRH) exposure to cause intestinal dysfunction and loss of enteric neurons. This has been further studied and confirmed in a rat in vivo model involving iterated GnRH treatments. Mechanisms behind are enigmatic since no GnRH receptors are found to be expressed in enteric neurons neither in man nor rat. Both species, however, harbor substantial subpopulations of luteinizing hormone (LH) receptor-immunoreactive myenteric neurons which suggests that intestinal GnRH-induced neuropathy may be mediated by LH release. AIMS: To reveal if exposures of GnRH or LH to rat myenteric neurons in vitro cause neuronal loss. METHODS: Primary cultured adult rat myenteric neurons were exposed to single or repeated treatments of the GnRH analog buserelin or the LH analog lutrotropin alpha, and neuronal survival was determined by cell counting. Possible presence of GnRH- or LH receptor -immunoreactive neurons was determined by immunocytochemistry. RESULTS: Exposure to the LH, but not the GnRH, analog caused significantly reduced neuronal survival. LH, but not GnRH, receptors were found to be expressed on cultured myenteric neurons. CONCLUSION: Myenteric neurons express LH receptors in vitro and LH exposure causes reduced neuronal survival. This suggests that GnRH-induced enteric neuropathy in vivo is mediated by way of LH release and activation of enteric neuronal LH receptors. PMID- 26480827 TI - Functional genomics: A novel CRISPR-Cas system for easier genome editing? PMID- 26480826 TI - Epigenetics: Fatherly histone influences. PMID- 26480828 TI - Achiral Dye/Surfactant Heteroaggregates for Chiral Sensing of Phosphocholines. AB - An investigation, based on absorption and circular dichroism spectroscopy, was carried out on assemblies formed in water upon the interaction of heteroaggregates, composed of dyes (Congo Red or Evans Blue) and cetyltrimethylammonium bromide (CTAB), with four enantiopure phopshocholines (DMPC, DPPC, DOPC, and POPC) characterized by the same polar head and different hydrophobic tails. The results show that the nature of the lipid as well as the concentration ratios influence sensitively the absorption and chiroptical properties of the supramolecular structure. Intriguingly, the transfer of chirality from the lipid to the assembly may be triggered or not, depending on the nature of the lipid hydrophobic chain. These findings confirm the fundamental role of hydrophobic interactions in the transcription of chirality from molecules to complex architectures. PMID- 26480829 TI - Landscape-Based Biology. PMID- 26480830 TI - Minimizing Penile Implant Infection: A Literature Review of Patient and Surgical Factors. AB - Inflatable penile prosthesis (IPP) is an effective treatment for erectile dysfunction in patients' refractory to oral or injectable treatment. While the rate of infection has decreased over the past decade, it is still the most feared complication of IPP placement. Here, we assemble possible patient and surgical factors attributing to the risk of infection. Studies have been gathered addressing each of these factors, and an Oxford Level of Evidence is assigned to each recommendation based on strength of the study. The goal of this review is to inform surgeons of possible risks in order to further reduce the risk of infection and thus increase success of IPP placement. PMID- 26480831 TI - Whole body creatine and protein kinetics in healthy men and women: effects of creatine and amino acid supplementation. AB - Creatine kinetics were measured in young healthy subjects, eight males and seven females, age 20-30 years, after an overnight fast on creatine-free diet. Whole body turnover of glycine and its appearance in creatine was quantified using [1 (13)C] glycine and the rate of protein turnover was quantified using L-ring [(2)H5] phenylalanine. The creatine pool size was estimated by the dilution of a bolus [C(2)H3] creatine. Studies were repeated following a five days supplement creatine 21 g.day(-1) and following supplement amino acids 14.3 g day(-1). Creatine caused a ten-fold increase in the plasma concentration of creatine and a 50 % decrease in the concentration of guanidinoacetic acid. Plasma amino acids profile showed a significant decrease in glycine, glutamine, and taurine and a significant increase in citrulline, valine, lysine, and cysteine. There was a significant decrease in the rate of appearance of glycine, suggesting a decrease in de-novo synthesis (p = 0.006). The fractional and absolute rate of synthesis of creatine was significantly decreased by supplemental creatine. Amino acid supplement had no impact on any of the parameters. This is the first detailed analysis of creatine kinetics and the effects of creatine supplement in healthy young men and women. These methods can be applied for the analysis of creatine kinetics in different physiological states. PMID- 26480832 TI - A prolonged maturational time course in brain development for cortical processing of temporal modulations. PMID- 26480833 TI - Quantitative sleep EEG and polysomnographic predictors of driving simulator performance in obstructive sleep apnea. AB - OBJECTIVES: To improve identification of obstructive sleep apnea (OSA) patients at risk of driving impairment, this study explored predictors of driving performance impairment in untreated OSA patients using clinical PSG metrics, sleepiness questionnaires and quantitative EEG markers from routine sleep studies. METHODS: Seventy-six OSA patients completed sleepiness questionnaires and driving simulator tests in the evening of their diagnostic sleep study. All sleep EEGs were subjected to quantitative power spectral analysis. Correlation and multivariate linear regression were used to identify the strongest predictors of driving simulator performance. RESULTS: Absolute EEG spectral power across all frequencies (0.5-32 Hz) throughout the entire sleep period and separately in REM and NREM sleep, (r range 0.239-0.473, all p<0.05), as well as sleep onset latency (r=0.273, p<0.017) positively correlated with driving simulator steering deviation. Regression models revealed that amongst clinical and qEEG variables, the significant predictors of worse steering deviation were greater total EEG power during NREM and REM sleep, greater beta EEG power in NREM and greater delta EEG power in REM (range of variance explained 5-17%, t range 2.29-4.0, all p<0.05) and sleep onset latency (range of variance explained 4-9%, t range 2.15 2.5, all p<0.05). CONCLUSIONS: In OSA patients, increased EEG power, especially in the faster frequency (beta) range during NREM sleep and slower frequency (delta) range in REM sleep were associated with worse driving performance, while no relationships were observed with clinical metrics e.g. apnea, arousal or oxygen indices. SIGNIFICANCE: Quantitative EEG analysis in OSA may provide useful markers of driving impairment risk. Future studies are necessary to confirm these findings and assess the clinical significance of quantitative EEG as predictors of driving impairment in OSA. PMID- 26480834 TI - EEG entropy measures indicate decrease of cortical information processing in Disorders of Consciousness. AB - OBJECTIVE: Clinical assessments that rely on behavioral responses to differentiate Disorders of Consciousness are at times inapt because of some patients' motor disabilities. To objectify patients' conditions of reduced consciousness the present study evaluated the use of electroencephalography to measure residual brain activity. METHODS: We analyzed entropy values of 18 scalp EEG channels of 15 severely brain-damaged patients with clinically diagnosed Minimally-Conscious-State (MCS) or Unresponsive-Wakefulness-Syndrome (UWS) and compared the results to a sample of 24 control subjects. Permutation entropy (PeEn) and symbolic transfer entropy (STEn), reflecting information processes in the EEG, were calculated for all subjects. Participants were tested on a modified active own-name paradigm to identify correlates of active instruction following. RESULTS: PeEn showed reduced local information content in the EEG in patients, that was most pronounced in UWS. STEn analysis revealed altered directed information flow in the EEG of patients, indicating impaired feed-backward connectivity. Responses to auditory stimulation yielded differences in entropy measures, indicating reduced information processing in MCS and UWS. CONCLUSIONS: Local EEG information content and information flow are affected in Disorders of Consciousness. This suggests local cortical information capacity and feedback information transfer as neural correlates of consciousness. SIGNIFICANCE: The utilized EEG entropy analyses were able to relate to patient groups with different Disorders of Consciousness. PMID- 26480835 TI - Metabolic responses to dietary protein/carbohydrate ratios in zebra sea bream (Diplodus cervinus, Lowe, 1838) juveniles. AB - This study aims to evaluate the effect of diets with different protein to carbohydrate ratios (P:C) on the omnivorous zebra sea bream (Diplodus cervinus) juveniles growth performance, feed efficiency, N excretion and metabolic response of intermediary metabolism enzymes. Four isoenergetic and isolipidic diets were formulated to contain increasing protein levels (25, 35, 45 and 55%) at the expense of carbohydrates (43, 32, 21 and 9%): diets P25C43, P35C32, P45C21 and P55C9. Growth performance, feed efficiency (FE), N intake [(g kg(-1) average body weight (ABW) day(-1))], N retention (g kg(-1) ABW day(-1)) and energy retention (kJ kg(-1) ABW day(-1)) increased with the increase of P:C ratio. The best growth performance and FE were achieved with diet P45C21. Ammonia excretion (mg NH4-N kg(-1) ABW day(-1)) increased as dietary protein level increased. Alanine aminotransferase and glutamate dehydrogenase activities increased with the increase of dietary P:C ratio. The opposite was observed for malic enzyme activity. Aspartate aminotransferase, hexokinase, glucokinase, fructose-1, 6 bisphosphatase and fatty acid synthetase activities were unaffected by dietary treatments. Response of key amino acid catabolic enzymes and N excretion levels to dietary P:C ratio supports the metabolic adaptability of this species to dietary protein inclusion levels. Overall, zebra sea bream seems capable of better utilize dietary protein rather than dietary carbohydrates as energy source which may be an obstacle for using more economically diets and thus for reducing environmental N loads in semi-intensive aquaculture of this species. PMID- 26480836 TI - Memory strength versus memory variability in visual change detection. AB - Observers made change-detection judgments for colored squares in a paradigm that manipulated the retention interval, the magnitude of change, and objective change probability. The probability of change judgments increased across the retention interval for "same" and "small-change" test items but stayed the same or decreased for "large-change" and "far" test items. A variety of formal models were fitted to the individual-subject data. The modeling results provided evidence that, beyond changes in visual-memory precision, there were decreases in memory strength of individual study items across the retention interval. In addition, the modeling results provided evidence of a zero-information, absence of-memory state that required guessing. The data were not sufficiently strong to sharply distinguish whether the losses in memory strength across the retention interval were continuous in nature or all-or-none. The authors argue that the construct of memory strength as distinct from memory variability is an important component of the nature of forgetting from visual working memory. PMID- 26480837 TI - How do healthcare workers judge pain in older palliative care patients with delirium near the end of life? AB - OBJECTIVE: Pain and delirium are commonly reported in older people with advanced cancer. However, assessing pain in this population is challenging, and there is currently no validated assessment tool for this task. The present retrospective cohort study was conducted to understand how healthcare workers (HCWs; nurses and physicians) determine that older cancer patients with delirium are in pain. METHOD: We reviewed the medical records of consecutive palliative care inpatients, 65 years of age and above (N = 113), in order to identify patient based cues used by HCWs to make pain judgments and to examine how the cues differ by delirium subtype and outcome. RESULTS: We found that HCWs routinely make judgments about pain in older patients with delirium using a repertoire of strategies that includes patient self-report and observations of spontaneous and evoked behavior. Using these strategies, HCWs judged pain to be highly prevalent in this inpatient palliative care setting. SIGNIFICANCE OF RESULTS: These novel findings will inform the development of valid and reliable tools to assess pain in older cancer patients with delirium. PMID- 26480838 TI - The potential of virtual reality-based training to enhance the functional autonomy of Alzheimer's disease patients in cooking activities: A single case study. AB - Impairments in performing activities of daily living occur early in the course of Alzheimer's disease (AD). There is a great need to develop non-pharmacological therapeutic interventions likely to reduce dependency in everyday activities in AD patients. This study investigated whether it was possible to increase autonomy in these patients in cooking activities using interventions based on errorless learning, vanishing-cue, and virtual reality techniques. We recruited a 79-year old woman who met NINCDS-ADRDA criteria for probable AD. She was trained in four cooking tasks for four days per task, one hour per day, in virtual and in real conditions. Outcome measures included subjective data concerning the therapeutic intervention and the experience of virtual reality, repeated assessments of training activities, neuropsychological scores, and self-esteem and quality of life measures. The results indicated that our patient could relearn some cooking activities using virtual reality techniques. Transfer to real life was also observed. Improvement of the task performance remained stable over time. This case report supports the value of a non-immersive virtual kitchen to help people with AD to relearn cooking activities. PMID- 26480839 TI - Different Complexation Behavior of P-Functionalized Ferrocene Derivatives Towards SnCl2 , SnCl4 and SnPh2 Cl2 : Auto-ionization and Redox-Type Reactions. AB - The novel phosphonyl-substituted ferrocene derivatives [Fe(eta(5) -Cp)(eta(5) -C5 H3 {P(O)(O-iPr)2 }2 -1,2)] (Fc(1,2) ) and [Fe{eta(5) -C5 H4 P(O)(O-iPr)2 }2 ] (Fc(1,1') ) react with SnCl2 , SnCl4 , and SnPh2 Cl2 , giving the corresponding complexes [(Fc(1,2) )2 SnCl][SnCl3 ] (1), [{(Fc(1,1') )SnCl2 }n ] (2), [(Fc(1,1') )SnCl4 ] (3), [{(Fc(1,1') )SnPh2 Cl2 }n ] (4), and [(Fc(1,2) )SnCl4 ] (5), respectively. The compounds are characterized by elemental analyses, (1) H, (13) C, (31) P, (119) Sn NMR and IR spectroscopy, (31) P and (119) Sn CP-MAS NMR spectroscopy, cyclovoltammetry, electrospray ionization mass spectrometry, and single-crystal as well as powder X-ray diffraction analyses. The experimental work is accompanied by DFT calculations, which help to shed light on the origin for the different reaction behavior of Fc(1,1') and Fc(1,2) towards tin(II) chloride. PMID- 26480840 TI - Adaptive changes in spatiotemporal gait characteristics in women during pregnancy. AB - Spatiotemporal gait cycle characteristics were assessed at early (P1), and late (P2) pregnancy, as well as at 2 months (PP1) and 6 months (PP2) postpartum. A substantial decrease in walking speed was observed throughout the pregnancy, with the slowest speed (1+/-0.2m/s) being during the third trimester. Walking at slower velocity resulted in complex adaptive adjustments to their spatiotemporal gait pattern, including a shorter step length and an increased duration of both their stance and double-support phases. Duration of the swing phase remained the least susceptible to changes. Habitual walking velocity (1.13+/-0.2m/s) and the optimal gait pattern were fully recovered 6 months after childbirth. Documented here adaptive changes in the preferred gait pattern seem to result mainly from the altered body anthropometry leading to temporary balance impairments. All the observed changes within stride cycle aimed to improve gait safety by focusing on its dynamic stability. The pregnant women preferred to walk at a slower velocity which allowed them to spend more time in double-support compared with their habitual pattern. Such changes provided pregnant women with a safer and more tentative ambulation that reduced the single-support period and, hence, the possibility of instability. As pregnancy progressed a significant increase in stance width and a decrease in step length was observed. Both factors allow also for gait stability improvement. PMID- 26480841 TI - Late development of cue integration is linked to sensory fusion in cortex. AB - Adults optimize perceptual judgements by integrating different types of sensory information [1, 2]. This engages specialized neural circuits that fuse signals from the same [3-5] or different [6] modalities. Whereas young children can use sensory cues independently, adult-like precision gains from cue combination only emerge around ages 10 to 11 years [7-9]. Why does it take so long to make best use of sensory information? Existing data cannot distinguish whether this (1) reflects surprisingly late changes in sensory processing (sensory integration mechanisms in the brain are still developing) or (2) depends on post-perceptual changes (integration in sensory cortex is adult-like, but higher-level decision processes do not access the information) [10]. We tested visual depth cue integration in the developing brain to distinguish these possibilities. We presented children aged 6-12 years with displays depicting depth from binocular disparity and relative motion and made measurements using psychophysics, retinotopic mapping, and pattern classification fMRI. Older children (>10.5 years) showed clear evidence for sensory fusion in V3B, a visual area thought to integrate depth cues in the adult brain [3-5]. By contrast, in younger children (<10.5 years), there was no evidence for sensory fusion in any visual area. This significant age difference was paired with a shift in perceptual performance around ages 10 to 11 years and could not be explained by motion artifacts, visual attention, or signal quality differences. Thus, whereas many basic visual processes mature early in childhood [11, 12], the brain circuits that fuse cues take a very long time to develop. PMID- 26480842 TI - Natural sleep and its seasonal variations in three pre-industrial societies. AB - How did humans sleep before the modern era? Because the tools to measure sleep under natural conditions were developed long after the invention of the electric devices suspected of delaying and reducing sleep, we investigated sleep in three preindustrial societies [1-3]. We find that all three show similar sleep organization, suggesting that they express core human sleep patterns, most likely characteristic of pre-modern era Homo sapiens. Sleep periods, the times from onset to offset, averaged 6.9-8.5 hr, with sleep durations of 5.7-7.1 hr, amounts near the low end of those industrial societies [4-7]. There was a difference of nearly 1 hr between summer and winter sleep. Daily variation in sleep duration was strongly linked to time of onset, rather than offset. None of these groups began sleep near sunset, onset occurring, on average, 3.3 hr after sunset. Awakening was usually before sunrise. The sleep period consistently occurred during the nighttime period of falling environmental temperature, was not interrupted by extended periods of waking, and terminated, with vasoconstriction, near the nadir of daily ambient temperature. The daily cycle of temperature change, largely eliminated from modern sleep environments, may be a potent natural regulator of sleep. Light exposure was maximal in the morning and greatly decreased at noon, indicating that all three groups seek shade at midday and that light activation of the suprachiasmatic nucleus is maximal in the morning. Napping occurred on <7% of days in winter and <22% of days in summer. Mimicking aspects of the natural environment might be effective in treating certain modern sleep disorders. PMID- 26480843 TI - Caffeinated forage tricks honeybees into increasing foraging and recruitment behaviors. AB - In pollination, plants provide food reward to pollinators who in turn enhance plant reproduction by transferring pollen, making the relationship largely cooperative; however, because the interests of plants and pollinators do not always align, there exists the potential for conflict, where it may benefit both to cheat the other [1, 2]. Plants may even resort to chemistry: caffeine, a naturally occurring, bitter-tasting, pharmacologically active secondary compound whose main purpose is to detract herbivores, is also found in lower concentrations in the nectar of some plants, even though nectar, unlike leaves, is made to be consumed by pollinators. [corrected]. A recent laboratory study showed that caffeine may lead to efficient and effective foraging by aiding honeybee memory of a learned olfactory association [4], suggesting that caffeine may enhance bee reward perception. However, without field data, the wider ecological significance of caffeinated nectar remains difficult to interpret. Here we demonstrate in the field that caffeine generates significant individual- and colony-level effects in free-flying worker honeybees. Compared to a control, a sucrose solution with field-realistic doses of caffeine caused honeybees to significantly increase their foraging frequency, waggle dancing probability and frequency, and persistency and specificity to the forage location, resulting in a quadrupling of colony-level recruitment. An agent-based model also demonstrates how caffeine-enhanced foraging may reduce honey storage. Overall, caffeine causes bees to overestimate forage quality, tempting the colony into sub-optimal foraging strategies, which makes the relationship between pollinator and plant less mutualistic and more exploitative. VIDEO ABSTRACT. PMID- 26480844 TI - Asterless Reduction during Spermiogenesis Is Regulated by Plk4 and Is Essential for Zygote Development in Drosophila. AB - Centrosome reduction is the decrease in centrosomal components during spermatid differentiation (spermiogenesis). It is one of several dramatic subcellular reorganizations that lead to spermatozoa formation common to a wide range of animals. However, the mechanism underlying centrosome reduction is unknown and its functions are unclear. Here, we show that in Drosophila melanogaster spermiogenesis, the quantity of centrosomal proteins is dramatically reduced; for example, Asterless (Asl) is reduced ~500-fold and is barely detected in spermatozoa. Asl reduction is regulated through a subset of its domains by the master regulator of centriole duplication Plk4 and by the ubiquitin ligase that targets Plk4 for degradation: Slimb. When Asl reduction is attenuated by Asl overexpression, plk4 mutations, Plk4 RNAi, or Slimb overexpression, Asl levels are higher in spermatozoa, resulting in embryos with reduced viability. Significantly, overexpressing Plk4 and Asl simultaneously, or combining plk4 and slimb mutations, balances their opposing effects on Asl reduction, restoring seemingly normal fertility. This suggests that increased Asl levels cause the observed reduced fertility and not other pleotropic effects. Attenuation of Asl reduction also causes delayed development and a failure to form astral microtubules in the zygote. Together, we provide the first insight into a molecular mechanism that regulates centrosome reduction and the first direct evidence that centrosome reduction is essential for post-fertilization development. PMID- 26480846 TI - Ecological Momentary Assessment of the Association Between Exposure to Alcohol Advertising and Early Adolescents' Beliefs About Alcohol. AB - PURPOSE: To evaluate the momentary association between exposure to alcohol advertising and middle-school students' beliefs about alcohol in real-world settings and to explore racial/ethnic differences in this association. METHODS: Middle-school students (N = 588) carried handheld data collection devices for 14 days, recording their exposures to all forms of alcohol advertising during the assessment period. Students also responded to three investigator-initiated control prompts (programmed to occur randomly) on each day of the assessment period. After each exposure to advertising and at each control prompt, students reported their beliefs about alcohol. Mixed-effects regression models compared students' beliefs about alcohol between moments of exposure to alcohol advertising and control prompts. RESULTS: Students perceived the typical person their age who drinks alcohol (prototype perceptions) more favorably and perceived alcohol use as more normative at times of exposure to alcohol advertising than at times of nonexposure (i.e., at control prompts). Exposure to alcohol advertising was not associated with shifts in the perceived norms of black and Hispanic students, however, and the association between exposure and prototype perceptions was stronger among non-Hispanic students than among Hispanic students. CONCLUSIONS: Exposure to alcohol advertising is associated with acute shifts in adolescents' perceptions of the typical person that drinks alcohol and the normativeness of drinking. These associations are both statistically and substantively meaningful. PMID- 26480847 TI - Theory of Planned Behavior in School-Based Adolescent Problem Gambling Prevention: A Conceptual Framework. AB - Given its serious implications for psychological and socio-emotional health, the prevention of problem gambling among adolescents is increasingly acknowledged as an area requiring attention. The theory of planned behavior (TPB) is a well established model of behavior change that has been studied in the development and evaluation of primary preventive interventions aimed at modifying cognitions and behavior. However, the utility of the TPB has yet to be explored as a framework for the development of adolescent problem gambling prevention initiatives. This paper first examines the existing empirical literature addressing the effectiveness of school-based primary prevention programs for adolescent gambling. Given the limitations of existing programs, we then present a conceptual framework for the integration of the TPB in the development of effective problem gambling preventive interventions. The paper describes the TPB, demonstrates how the framework has been applied to gambling behavior, and reviews the strengths and limitations of the model for the design of primary prevention initiatives targeting adolescent risk and addictive behaviors, including adolescent gambling. PMID- 26480845 TI - The host immune response to gastrointestinal nematode infection in sheep. AB - Gastrointestinal nematode infection represents a major threat to the health, welfare and productivity of sheep populations worldwide. Infected lambs have a reduced ability to absorb nutrients from the gastrointestinal tract, resulting in morbidity and occasional mortality. The current chemo-dominant approach to nematode control is considered unsustainable due to the increasing incidence of anthelmintic resistance. In addition, there is growing consumer demand for food products from animals not subjected to chemical treatment. Future mechanisms of nematode control must rely on alternative, sustainable strategies such as vaccination or selective breeding of resistant animals. Such strategies take advantage of the host's natural immune response to nematodes. The ability to resist gastrointestinal nematode infection is considered to be dependent on the development of a protective acquired immune response, although the precise immune mechanisms involved in initiating this process remain to be fully elucidated. In this study, current knowledge on the innate and acquired host immune response to gastrointestinal nematode infection in sheep and the development of immunity is reviewed. PMID- 26480848 TI - Early Postoperative Chemotherapy After Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Isolated Peritoneal Carcinomatosis of Colon Cancer: A Multicenter Study. AB - PURPOSE: The prognosis of peritoneal carcinomatosis (PC) from colorectal cancer has been improved with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). However, benefits of postoperative chemotherapy (CT) are unclear. METHODS: This retrospective, multicenter study included 231 patients treated by CRS and HIPEC for isolated PC of colon cancer in four expert's centers. Overall survival (OS), progression-free survival (PFS), and peritoneal recurrence-free survival (PRFS) were compared between patients with adjuvant CT (started within 3 months after surgery) and patients with surveillance only. RESULTS: After exclusion of 10 patients for early postoperative death (4%), 221 patients were included (CT group: n = 151; surveillance group: n = 70). Main postoperative CT regimens (median of 6 cycles) were Folfox (28%), Folfiri bevacizumab (24.5%), Folfiri (16%), and Folfiri cetuximab (12.5%). The median OS after surgery was 43.3 months with no difference between CT and surveillance groups. In multivariate analysis, a low peritoneal cancer index (p < 0.0001) and a long delay between diagnosis of CP and HIPEC (p = 0.001) were associated with increased OS. The median PFS and PRFS were 12.4 and 17 months, respectively. At 1 year, more patients were without progression (p = 0.001) or PC recurrence (0.0004) in the CT group, but with prolonged follow-up this difference was no longer significant. CONCLUSIONS: Early postoperative CT does not improve OS after CRS and HIPEC for colon carcinomatosis. However, a transient effect on PFS and PRFS was observed. A subgroup of patients who may benefit more from CT remain to be defined. PMID- 26480849 TI - Role of Adjuvant Radiotherapy in Locally Advanced Colonic Carcinoma in the Modern Chemotherapy Era. AB - BACKGROUND: The role of adjuvant radiation therapy (RT) in the treatment of resected, locally advanced colon cancer is unclear. One randomized controlled trial (Intergroup-0130) addressed this question but failed to meet its accrual goals. Since this trial, few attempts have been made to reassess the role of RT in this clinical setting. METHODS: Sixty-two patients with non-metastatic, American Joint Committee on Cancer 7th edition stage T4 colonic adenocarcinoma were treated at our institution between 2000 and 2013. All underwent curative intent surgery. Sixteen patients underwent resection only, 33 patients received adjuvant chemotherapy (ChT), and 13 patients received adjuvant chemoradiation therapy (CRT). RESULTS: Patients receiving adjuvant CRT were more likely to have T4b (vs. T4a) disease and were more likely to undergo R1 or R2 resection compared with those receiving adjuvant ChT alone. Despite this, multivariate analysis demonstrated that treatment with adjuvant CRT (vs. adjuvant ChT) enhanced locoregional control and disease-free survival (hazard ratio 0.044 and 0.145, respectively; p < 0.05). CONCLUSIONS: Adjuvant RT for T4 colon cancers may be appropriate in select patients, specifically those with T4b lesions and/or residual disease following resection. PMID- 26480850 TI - Open Versus Laparoscopic Adrenalectomy for Adrenocortical Carcinoma: A Meta analysis of Surgical and Oncological Outcomes. AB - PURPOSE: This study was designed to determine the role of laparoscopic adrenalectomy (LA) in the surgical management of adrenocortical carcinoma (ACC). METHODS: A systematic literature review was performed on January 2, 2015 using PubMed. Article selection proceeded according to PRISMA criteria. Studies comparing open adrenalectomy (OA) to LA for ACC and including at least 10 cases per each surgical approach were included. Odds ratio (OR) was used for all binary variables, and weight mean difference (WMD) was used for the continuous parameters. Pooled estimates were calculated with the fixed-effect model, if no significant heterogeneity was identified; alternatively, the random-effect model was used when significant heterogeneity was detected. Main demographics, surgical outcomes, and oncological outcomes were analyzed. RESULTS: Nine studies published between 2010 and 2014 were deemed eligible and included in the analysis, all of them being retrospective case-control studies. Overall, they included 240 LA and 557 OA cases. Tumors treated with laparoscopy were significantly smaller in size (WMD -3.41 cm; confidence interval [CI] -4.91, -1.91; p < 0.001), and a higher proportion of them (80.8 %) more at a localized (I-II) stage compared with open surgery (67.7 %) (odds ratio [OR] 2.8; CI 1.8, 4.2; p < 0.001). Hospitalization time was in favor of laparoscopy, with a WMD of -2.5 days (CI -3.3, -1.7; p < 0.001). There was no difference in the overall recurrence rate between LA and OA (relative risk [RR] 1.09; CI 0.83, 1.43; p = 0.53), whereas development of peritoneal carcinomatosis was higher for LA (RR 2.39; CI 1.41, 4.04; p = 0.001). No difference could be found for time to recurrence (WMD -8.2 months; CI -18.2, 1.7; p = 0.11), as well as for cancer specific mortality (OR 0.68; CI 0.44, 1.05; p = 0.08). CONCLUSIONS: OA should still be considered the standard surgical management of ACC. LA can offer a shorter hospital stay and possibly a faster recovery. Therefore, this minimally invasive approach can certainly play a role in this setting, but it should be only offered in carefully selected cases to avoid jeopardizing the oncological outcome. PMID- 26480851 TI - Muscle synergies underlying control of taking a step during support surface translation. AB - PURPOSE: We investigated the muscle activation patterns and the center of pressure (COP) displacement in stepping behavior to determine the relations between anticipatory synergy adjustments (ASAs) and anticipatory postural adjustments (APAs) during support surface translation. METHODS: Surface muscle activity of eleven leg and trunk muscles was analyzed to identify sets of four muscle modes (M-modes). Linear combination of M-modes and their relationship to changes in the COP shift in the anterior-posterior (AP) direction were then determined. Uncontrolled manifold (UCM) analysis was performed to determine variance components in the M-mode space and indices of M-mode synergy stabilizing the COP shift. RESULTS: Prior to the step initiation, synergies stabilizing COP were seen in both conditions. The synergy index started to drop before a change in the averaged activation levels across trials in postural muscles. The magnitude of synergy index was significantly larger under the perturbation condition. CONCLUSIONS: Results of the study have revealed that the central nervous system is able to prepare multi-muscle synergies when a step is performed during support surface translation. Prior to APAs, ASAs reduce stability of COPAP coordinate that is to be adjusted during the APAs. These findings may help get closer to understanding of physiological mechanism of postural preparation to external perturbation. PMID- 26480852 TI - Halogenated Phenazines that Potently Eradicate Biofilms, MRSA Persister Cells in Non-Biofilm Cultures, and Mycobacterium tuberculosis. AB - Conventional antibiotics are ineffective against non-replicating bacteria (for example, bacteria within biofilms). We report a series of halogenated phenazines (HP), inspired by marine antibiotic 1, that targets persistent bacteria. HP 14 demonstrated the most potent biofilm eradication activities to date against MRSA, MRSE, and VRE biofilms (MBEC = 0.2-12.5 MUM), as well as the effective killing of MRSA persister cells in non-biofilm cultures. Frontline MRSA treatments, vancomycin and daptomycin, were unable to eradicate MRSA biofilms or non-biofilm persisters alongside 14. HP 13 displayed potent antibacterial activity against slow-growing M. tuberculosis (MIC = 3.13 MUM), the leading cause of death by bacterial infection around the world. HP analogues effectively target persistent bacteria through a mechanism that is non-toxic to mammalian cells and could have a significant impact on treatments for chronic bacterial infections. PMID- 26480853 TI - Elderly men with moderate and intense training lifestyle present sustained higher antibody responses to influenza vaccine. AB - We aimed to verify whether different levels of training performed regularly and voluntarily for many years could have an impact on one of the main issues of immunosenescence: the poor response to vaccines. We recruited 61 healthy elderly men (65-85 years old), 23 with a moderate training (MT) lifestyle (for 17.0 +/- 3.2 years), 22 with an intense training (IT) lifestyle (for 25.9 +/- 3.4 years), and 16 without a training lifestyle (NT). Fitness was evaluated through the IPAQ and VO2max consumption. The participants were evaluated regarding cognitive aspects, nutritional status, depression, and quality of life. Antibody titers were determined by hemagglutination inhibition assay prior to influenza vaccination and at 6 weeks and 6 months post-vaccination. Strains used were B, H3N2, and H1N1. Our groups were matched for most characteristics, except for those directly influenced by their lifestyles, such as BMI, VO2max, and MET. In general, MT and IT elderly men showed significantly higher antibody titers to the three vaccine strains post-vaccination than NT elderly men. There were also higher titers against B and H1N1 strains in the trained groups before vaccination. Additionally, there were higher proportions of seroprotected (titers >=1:40) individuals in the pooled trained groups both at 6 weeks (B and H3N2, p < 0.05) and 6 months (H1N1, p < 0.05; B, p = 0.07). There were no significant differences between the MT and IT groups. Either a moderate or an intense training is associated with stronger and longstanding antibody responses to the influenza vaccine, resulting in higher percentages of seroprotected individuals. PMID- 26480854 TI - Charge versus Energy Transfer Effects in High-Performance Perylene Diimide Photovoltaic Blend Films. AB - Perylene diimide (PDI)-based organic photovoltaic devices can potentially deliver high power conversion efficiency values provided the photon energy absorbed is utilized efficiently in charge transfer (CT) reactions instead of being consumed in nonradiative energy transfer (ET) steps. Hitherto, it remains unclear whether ET or CT primarily drives the photoluminescence (PL) quenching of the PDI excimer state in PDI-based blend films. Here, we affirm the key role of the thermally assisted PDI excimer diffusion and subsequent CT reaction in the process of PDI excimer PL deactivation. For our study we perform PL quenching experiments in the model PDI-based composite made of poly[4,8-bis(5-(2-ethylhexyl)thiophen-2 yl)benzo[1,2-b;4,5-b']dithiophene-2,6-diyl-alt-(4-(2-ethylhexanoyl)-thieno[3,4 b]thiophene)-2-6-diyl] (PBDTTT-CT) polymeric donor mixed with the N,N'-bis(1 ethylpropyl)-perylene-3,4,9,10-tetracarboxylic diimide (PDI) acceptor. Despite the strong spectral overlap between the PDI excimer PL emission and UV-vis absorption of PBDTTT-CT, two main observations indicate that no significant ET component operates in the overall PL quenching: the PL intensity of the PDI excimer (i) increases with decreasing temperature and (ii) remains unaffected even in the presence of 10 wt % content of the PBDTTT-CT quencher. Temperature dependent wide-angle X-ray scattering experiments further indicate that nonradiative resonance ET is highly improbable due to the large size of PDI domains. The dominance of the CT over the ET process is verified by the high performance of devices with an optimum composition of 30:70 PBDTTT-CT:PDI. By adding 0.4 vol % of 1,8-diiodooctane we verify the plasticization of the polymer side chains that balances the charge transport properties of the PBDTTT-CT:PDI composite and results in additional improvement in the device efficiency. The temperature-dependent spectral width of the PDI excimer PL band suggests the presence of energetic disorder in the PDI excimer excited state manifold. PMID- 26480855 TI - Prevalence of hemoglobin S trait among blood donors: a cross-sectional study. AB - BACKGROUND: Sickle cell trait (SCT) or Hemoglobin S (HbS) trait which is due to inheritance of an abnormal hemoglobin (Hb) gene from one parent and a normal gene from the other has been known to be common among people of African descent. Individuals with SCT may find themselves in the blood donor population without knowing their 'carrier' status and this may have severe consequences on their health as well as that of a recipient, particularly if they happen to be a sickle cell disease patient. The aim of the study was to determine the prevalence of HbS trait among blood donors. RESULTS: This cross-sectional study employed convenience sampling method to recruit subjects. A total of 150 prospective and healthy blood donors comprising 138 males and 12 females were involved in the study. Two (2) ml of venous blood was collected from each donor into K(3)EDTA tubes and analyzed using the sodium metabisulphite slide test and cellulose acetate Hb electrophoresis at alkaline pH (8.6) for Hb genotypes. Statistical Package for Social Sciences version 20.0 (SPSS 20.0) and Chi square were used to analyse the data obtained. Out of the 150 blood donors, 133 (88.7 %) tested negative for sickling (131 were genotype AA and 2 were AC) and 17 (11.3 %) tested positive for sickling, all of whom were genotype AS. CONCLUSION: The results of the study showed the existence of SCT among the blood donor population sampled. Taking blood from such people can harm their health as well as that of the recipient if they happen to be sickle cell disease (SCD) patients. It is therefore recommended that blood donors as well as donated blood units should be screened for SCT to avoid causing any harm to both the donor and recipient. PMID- 26480856 TI - My older patient with cancer reports falls: What should I do? AB - Falling is one of the major geriatric syndromes, with a multi-factorial pathogenesis due to age-related changes, pathological conditions and environmental hazards. Such a multi-factorial syndrome needs a standardized approach aimed at identifying risk factors. A comprehensive loco-motor, gait and standing balance, cardiovascular and neurological assessment, as well as a drugs regimens review, should be part of the routinely approach. Modification of environmental hazards, exercise training, behavioral and pharmacological treatment of specific diseases which can be the leading cause of falls, should all be part of an individualized intervention. Particular attention should be paid in the evaluation of unexplained falls, which can mask hypotensive or arrhythmic syncope. PMID- 26480857 TI - Simple reaction time in 8-9-year old children environmentally exposed to PCBs. AB - Simple reaction time (SRT) has been studied in children exposed to polychlorinated biphenyls (PCBs), with variable results. In the current work we examined SRT in 146 boys and 161 girls, aged 8.53 +/- 0.65 years (mean +/- SD), exposed to PCBs in the environment of eastern Slovakia. We divided the children into tertiles with regard to increasing PCB serum concentration. The mean +/- SEM serum concentration of the sum of 15 PCB congeners was 191.15 +/- 5.39, 419.23 +/ 8.47, and 1315.12 +/- 92.57 ng/g lipids in children of the first, second, and third tertiles, respectively. We created probability distribution plots for each child from their multiple trials of the SRT testing. We fitted response time distributions from all valid trials with the ex-Gaussian function, a convolution of a normal and an additional exponential function, providing estimates of three independent parameters MU, sigma, and tau. MU is the mean of the normal component, sigma is the standard deviation of the normal component, and tau is the mean of the exponential component. Group response time distributions were calculated using the Vincent averaging technique. A Q-Q plot comparing probability distribution of the first vs. third tertile indicated that deviation of the quantiles of the latter tertile from those of the former begins at the 40th percentile and does not show a positive acceleration. This was confirmed in comparison of the ex-Gaussian parameters of these two tertiles adjusted for sex, age, Raven IQ of the child, mother's and father's education, behavior at home and school, and BMI: the results showed that the parameters MU and tau significantly (p <= 0.05) increased with PCB exposure. Similar increases of the ex-Gaussian parameter tau in children suffering from ADHD have been previously reported and interpreted as intermittent attentional lapses, but were not seen in our cohort. Our study has confirmed that environmental exposure of children to PCBs is associated with prolongation of simple reaction time reflecting impairment of cognitive functions. PMID- 26480859 TI - Combining Systemic Therapies with Radiation in Non small Cell Lung Cancer. AB - Radiotherapy has been the mainstay of treatment of stage III nonsmall cell lung cancer patients. In the early 90s, combined treatment with chemotherapy was introduced. In 1995, a meta-analysis showed improved treatment outcome of the sequential use of cisplatin-based chemotherapy and radiotherapy compared to radiotherapy alone. Subsequent randomized studies and two meta-analyses demonstrated that concurrent radiochemotherapy is superior (local control and overall survival) to sequential usage of both method. However, several questions remain unanswered concerning the optimal chemotherapy regimen and radiotherapy doses and techniques in terms of treatment outcome and toxicity profile. Targeted therapies represent a new class of drugs, which interfere with specific molecular targets (typically proteins) playing critical roles in tumor growth and progression. Some combinations appear to be too toxic, such as the vascular epithelial growth factor antibody bevacizumab. The feasibility of adding the epidermal growth factor receptor inhibitor cetuximab has been recently reported for nonsmall cell lung cancer patients. Strategies to incorporate safely novel antiangiogenic agents into combined- modality therapy in lung cancer are needed. Hopefully, rapid development of molecular oncology will contribute to better patient selection to particular strategies and to treatment optimization. Increasing radiotherapy doses applied according to up -to -date techniques and combinations with new biologicals might lead to further treatment improvements. PMID- 26480858 TI - Lactational exposure of mice to low levels of non-dioxin-like polychlorinated biphenyls increases susceptibility to neuronal stress at a mature age. AB - Lactational exposure to low levels of the sum of the six indicator polychlorinated biphenyls (Sigma6 NDL-PCBs, 10ng/kg/day) is known to lead to persistent anxious behavior in young and adult offspring mice at postnatal days 40 and 160, respectively. At more advanced life stages, we evaluated the effects on the mouse brain of neuronal stress induced by the synaptotoxic amyloid-beta (Abeta) peptide. Perinatal exposure of lactating mice to Sigma6 NDL-PCBs did not affect short-term memory performances of their offspring male mice aged 14 months as compared to control PCB-naive mice. However, following intracerebroventricular injection of soluble Abeta oligomers, significant impairments in long-term memory were detected in the mice that had been lactationally treated with Sigma6 NDL PCBs. In addition, immunoblot analyses of the synaptosomal fraction of hippocampal tissues from treated mice revealed a lower expression of the synaptic proteins synaptophysin and PSD-95. Though preliminary, our findings suggest for the first time that early exposure to low levels of NDL-PCBs induce late neuronal vulnerability to amyloid stress. Additional experiments are needed to confirm whether early environmental influences are involved in the etiology of brain aging and cognitive decline. PMID- 26480860 TI - [Methods of Assesing Quality of Life in Women with Breast Cancer - Overview and Basic Characteristics]. AB - BACKGROUND: For the assessment of health -related quality of life (HRQOL) in women with diagnosis of breast carcinoma, patient-eported outcome measures are reported that allow subjective assessment of quality of life related to health status and satisfaction with treatment and medical care. However, their research use is still limited by the low availability of reliable and valid tools tested on samples of specific populations with malignant disease. AIM: The aim of the article is to provide review and short description of available instruments related to HRQOL of patients with a history of treatment for breast cancer with evidence of validation in the breast cancer population. RESULTS: In this review 15 validated patientreported outcome measures are presented specifically relating to HRQOL in women with breast carcinoma. CONCLUSION: Most of the presented measures are suitable in research and clinical trials but not for individual use in clinical practice. Most of the specific measures for assessing HRQOL in patients with breast cancer are not yet available in Czech language and Czech cultural environment adapted versions. Research versions of some of these measures are available in Czech, but these methods have not yet been validated in the Czech Republic. Lack of available tools for use in our conditions means significant limiting factor for research as well as for clinical practice in the Czech Republic. On the other hand, it also offers great scope for validation studies. PMID- 26480861 TI - [The Relevance of MicroRNAs in Glioblastoma Stem Cells]. AB - Glioblastoma multiforme is the most common intracranial malignity of astrocyte origin in adults. Despite complex therapy consisting of maximal surgical resection, adjuvant concomitant chemoradiotherapy with temozolomide followed by temozolomide in monotherapy, the median of survival ranges between 12 and 15 months from dia-gnosis. This infaust prognosis is very often caused by both impossibility of achieving of sufficient radical surgical resection and tumor resistance to adjuvant therapy, which relates to the presence of glioblastoma stem cells. Similarly to normal stem cells, glioblastoma stem cells are capable of self -renewal, differentiation, and unlimited slow proliferation. Their resistance to conventional therapy is also due to higher expressions of DNA repair enzymes, antiapoptotic factors and multidrug transporters. Therefore, targeting these unique properties could be a novel promising therapeutic approach leading to more effective therapy and better prognosis of glioblastoma multiforme patients. One of the approaches how to successfully regulate above -mentioned properties is targeted regulation of microRNAs (miRNAs). These small noncoding RNA molecules posttranscriptionally regulate expression of more than 2/ 3 of all human genes that are also involved in stem cell associated signaling pathways. Moreover, deregulated expression of some miRNAs has been observed in many cancers, including glioblastoma multiforme. PMID- 26480862 TI - [Surgical Treatment of Lung Metastases of Colorectal Carcinoma - Survival and Prognostic Factors]. AB - BACKROUND: Colorectal carcinoma has the third highest incidence of all tumor diseases in the world. In the long term, Slovak republic is among countries with highest occurrence of this disease. About 25% of patients have distant metastases at the time of diagnosis, and about 50% of patients progress. The first possibility of colorectal carcinoma lung metastases treatment is metastasectomy which may have a curative character. MATERIALS AND METHODS: In this paper, the authors retrospectively evaluated 50 patients who had undergone surgical treatment to establish the diagnosis of colorectal carcinoma lung metastases at the Clinic of thoracic surgery of JLF UK and UH Martin between 2003 and 2014. RESULTS: Altogether, 27 men and 23 women were operated (average age: 62 and 61 years). 52% of patients had solitary metastasis.We chose thoracotomy as a surgical access for majority of the surgeries (76%), and the most common type of surgical procedure was a wedge resection (74%). 3-year survival of patients after complete metastasectomy was 55.5%, and 5-year survival was 31.8% with a median survival of 42 months. We did not record any statistically significant influence of number of metastases (p = 0.3297) and length of disease-free interval (p = 0.4423) on the long-term survival, but we confirmed a significant difference of survival in different prognostic groups according to the International registry of lung metastases (p = 0.049). CONCLUSION: A surgical removal of colorectal carcinoma lung metastases in selected patients is an important curative modality that might prolongsurvival, improve the prognosis and at the same time have minimum complications. The results show that the strongest predicative indicator of prognosis is incorporation of the patients to the prognostic groups determined by the International Registry of Lung Metastases. PMID- 26480863 TI - Utilization of Prognostic Indexes for Patients with Brain Metastases in Daily Radiotherapy Routine - is the Complexity and Intricacy Still an Issue? AB - BACKGROUND: Many prognostic indexes are available for patients with brain metastases in order to estimate remaining lifetime before selection of appropriate treatment including palliative radiotherapy. Their routine utilization is often deprecated for their complexity. We developed a practical tool based on widely available spreadsheet editors for facilitation of daily clinical use of selected indexes (RPA, GPA and WBRT 30) and evaluated its usage for retrospective single institutional survival analysis of patients irradiated for brain metastases. PATIENTS AND METHODS: Spreadsheet platform was prepared and adjusted for automatic calculation of selected prognostic indexes after input of the relevant parameters. The consecutive series of newly diagnosed patients referred during 2011 to the palliative brain radiotherapy were analyzed, and real calculated survival parameters of individual subgroups of RPA, GPA and WBRT 30 were compared with estimated ones. Correlation of radiotherapy technique and estimated survival at the time of treatment indication was evaluated. RESULTS: Total of 121 patients (61% with multiple metastases) were irradiated with the majority undergoing whole brain radiotherapy. Median overall survival from the time of radiotherapy indication was 3.13 months. Non balanced distribution into individual scoring systems subgroups was observed with 8 (7%), 89 (73%) and 24 (20%) patients assigned to RPA 1, 2 and 3 subgroup, 3 (3%), 9 (7%), 57 (47%) and 52 (43%) patients assigned to GPA 3.5- 4, GPA 3.0, GPA 1.5- 2.5 and GPA 0- 1.0 subgroup and 10 (8%), 88 (73%) and 23 (19%) patients assigned to WBRT 30 subgroup D, B and A. Entire differences in overall survival between subgroups are significant among all three scoring systems. CONCLUSION: Routine calculation of available prognostic indexes is useful in decision making regarding the best radiotherapy of brain metastases, and their calculation is greatly facilitated by properly prepared widely available spreadsheet tools. PMID- 26480864 TI - [Assessment of Heavy/ Light Chain Pairs of Immunoglobulin (Hevylite assay) - Benefit for Stratification of Multiple Myeloma?]. AB - BACKGROUND: The aim of the study was the comparison of two novel stratification models in multiple myeloma (MM), ie. according to Avet- Loiseau (A L) and according to Ludwig (L), based on the HLC r index (ratio of serum levels of involved- HLC/ uninvolved HLC, ie. HLC kappa/ HLC lambda assessed using ie. nephelometric/turbidimetric technique using specific polyclonal antibodies on a Binding Site SPA(PLUS)) technique) and beta(2) microglobulin (beta(2) M) with selected prognostic factors (PF) of MM and staging systems according to Durie- Salmon (D S) and International Staging System (ISS). PATIENTS AND METHODS: In a cohort of 132 patients (94 with IgG and 38 with IgA type of MM) at the time of dia-gnosis, we assessed HLC r, select-ed PF and D S, ISS, A L and L stratification systems. RESULTS: Unlike in IgA isotype, in IgG isotype we found a significant relationship of HLC r to stratification according to D S and ISS with the difference between A and B substages according to D S (p = 0.049) and between ISS stages 1 vs. 3 (p = 0.001). In the IgG group, there was highly significant relationship of the depth of Hb and albumin decrease and beta(2) M increase to the results of stratification according to ISS, A L and L model (p < 0.0001), increase of LDH in the ISS system and A L, and creatinine according to ISS and L but not the relationship of the stages according to any of the stratification systems to the values of FLC r (ratio of serum free light chains kappa/ lambda of immunoglobulin), thrombocytes and Ca. In the IgA type, there was a significant relationship of the depth of the decrease of Hb, thrombocytes, albumin and increase of beta(2) M to the results of stratification according to ISS, A L and L and increase of creatinine in the case of ISS, but not of the values of FLC r, Ca and LDH in the case of any of the stratification systems. The degree of correlation of selected PF, especially of Hb, albumin and beta(2) M, event. of thrombocytes, LDH and creatinine to the stages according to ISS and to stage 1-3 according to A L and L model was in IgG vs IgA isotype significantly different (p < 0.0001- 0.030). Staging system according to ISS had proportional distribution of stages 1- 3, whereas in the A L model prevailed in IgA and IgG isotype risk category 2, ie. intermediate-risk (47.3 and 44.7%) and in the L model prevailed risk category 3, ie. high-risk (41.5 and 52.6%) with low count of category 1, ie. low- risk category (23.4 and 10.5%). McNemar- Bowker test of symmetry showed in both types of MM the highest concordance between the stratification according to D S and L in category 3, ie. high-risk (31.9 vs. 28.9%) with overall accord only in 53.2 and 42.1% and with significant shift in the case of IgG isotype only (p = 0.036). In IgG and IgA isotype there was an overall concordance in the distribution of categories 1- 3 according to ISS vs. A L (62.4 and 63.2%) but with significant shift of the stratification (p = 0.002 and 0.028). In the case of IgG and IgA isotype there was a close relationship between the models A L and L (64.5 and 81.6%) with significant stratification shift (p < 0.0001 and 0.030). CONCLUSION: The new stratification models for MM according to A L and L are easily practically applicable, with close relationship to principal PF but they need separate assessment of IgG and IgA isotypes of MM. The choice of optimal model for routine practice needs a validation study aimed at progression free survival and overall survival. PMID- 26480865 TI - Forbidden to Drive - a New Chemotherapy Side Effect. AB - BACKGROUND: Capecitabine is an oral antineoplastic agent classified as a pyrimidin analogue. It is widely used in different types of cancers. Unfortunately, it does not come without a cost, as the drug may have adverse effects - largely diarrhea, but also hand -foot syndrome and loss of fingerprints in extreme cases. CASE: We report a case of a 47-year-old male, which had been diagnosed with metastatic rectal cancer and received capecitabine, developing a severe hand foot syndrome which led him to lose his fingerprints in spite of complete resolution of the syndrome after stoppage of the drug. CONCLUSION: This case highlights a rare condition that, even though not precisely a disease per se, may hinder patients quality of life and must be recognised by the treating physician as an treatment related side effect. PMID- 26480866 TI - Lung cancer survival in Germany: A population-based analysis of 132,612 lung cancer patients. AB - OBJECTIVES: Lung cancer is the most common cancer-related death worldwide. In Germany it accounts for 25% of cancer deaths in men, and 14% in women. The aim of this study is to provide an overview of 5-year relative survival by sex, age, histology, and tumour stage in Germany representing a population of 26.7 million people. MATERIALS AND METHODS: The study is based on a pooled German dataset including data from 12 population-based cancer registries covering around one third of the German population. A total of 132,612 patients diagnosed with lung cancer from 2002 to 2010 were included in the analysis. Survival estimates for the time period 2007-2010 were calculated using period analysis. Differences in survival between sexes were tested for statistical significance by model-based period analysis (poisson regression model). The relative excess risk (RER) of death (women vs. men) was extracted from the model with the p value for the difference in RER. RESULTS: The overall age adjusted 5-year relative survival was 15.5% (standard error (SE) 0.2) for men and 20.3% (SE 0.3) in women. Survival differed markedly according to age (men: <60 years 18.5% vs. 80+ years 8.4% and women 23.7% vs. 10.6%, respectively), histology (largest difference between histological groups: men 25.7 and women 44.4% points) and stage (men: UICC Ia 62.9%, vs. UICC IV 4.6% and women 75.2% vs. 7.0%, respectively). Our study showed survival advantages for women compared to men, most notably in younger aged patients (RER 0.83, p<0.0001), patients with adenocarcinoma (RER 0.80, p<0.0001), and patients with lower stage cancer (RER 0.62, p<0.0001). CONCLUSIONS: This study presents up-to-date survival estimates for lung cancer in Germany. Compared to other European countries survival was relatively high. Women showed higher survival than men independent of age, histology and stage. The reasons for the survival differences require further clarification. PMID- 26480867 TI - An overview on fluid resuscitation and resuscitation endpoints in burns: Past, present and future. Part 1 - historical background, resuscitation fluid and adjunctive treatment. AB - An improved understanding of burn shock pathophysiology and subsequent development of fluid resuscitation strategies has led to dramatic outcome improvements in burn care during the 20th century. While organ hypoperfusion caused by inadequate resuscitation has become rare in clinical practice, there is growing concern that increased morbidity and mortality related to over resuscitation is occurring more frequently in burn care. In order to reduce complications related to this concept of "fluid creep", such as respiratory failure and compartment syndromes, efforts should be made to resuscitate with the least amount of fluid in order to provide adequate organ perfusion. In this first part of a concise review, historic and current evidence regarding the available fluids is discussed, as well as some adjunctive treatments modulating the inflammatory response. In the second part, special reference will be made to the role of abdominal hypertension in burn care and the endpoints used to guide fluid resuscitation will be discussed. Finally, as urine output has been recognized as a poor resuscitation target, a resuscitation protocol is suggested in part two which includes new targets and endpoints that can be obtained with modern, less invasive hemodynamic monitoring devices. PMID- 26480868 TI - An overview on fluid resuscitation and resuscitation endpoints in burns: Past, present and future. Part 2 - avoiding complications by using the right endpoints with a new personalized protocolized approach. AB - While organ hypoperfusion caused by inadequate resuscitation has become rare in clinical practice due to the better understanding of burn shock pathophysiology, there is growing concern that increased morbidity and mortality related to over resuscitation induced by late 20th century resuscitation strategies based on urine output, is occurring more frequently in burn care. In order to reduce complications related to this concept of "fluid creep", such as respiratory failure and compartment syndromes, efforts should be made to resuscitate with the least amount of fluid to provide adequate organ perfusion. In this second part of a concise review, the different targets and endpoints used to guide fluid resuscitation are discussed. Special reference is made to the role of intra abdominal hypertension in burn care and adjunctive treatments modulating the inflammatory response. Finally, as urine output has been recognized as a poor resuscitation target, a new personalized stepwise resuscitation protocol is suggested which includes targets and endpoints that can be obtained with modern, less invasive hemodynamic monitoring devices like transpulmonary thermodilution. PMID- 26480869 TI - Striatal NELF-mediated RNA polymerase II stalling controls L-dopa induced dyskinesia. AB - Long-term l-3,4-dihydroxyphenylalanine (L-Dopa) treatment in Parkinson's disease leads to involuntary movements called dyskinesia, notably through an overexpression of immediate-early genes (IEG). Their rapid transcription involves the stalling of RNA polymerase II on IEG promoters, a mechanism that critically depends on the presence of the negative elongation factor (NELF) protein complex. We here down-regulated the key NELF-E subunit using lentiviral vector delivery of a short hairpin RNA in the striatum of 6-hydroxydopamine lesioned rats. Such NELF E reduced expression significantly attenuated the development of abnormal involuntary movements in response to chronic L-Dopa treatment. Effectiveness of silencing was demonstrated by the significant decrease in striatal ?FosB, ARC and Zif268 IEG expression. Repression of NELF-mediating RNA polymerase II stalling thus achieves both antidyskinetic and potentiation of antiparkinsonian L-Dopa effect, highlighting the role of transcriptional events in dyskinesia establishment, acute dyskinetic manifestation and in the therapeutic response to L-Dopa. PMID- 26480870 TI - Anthropometry, muscular strength and aerobic capacity up to 5 years after pediatric burns. AB - OBJECTIVE: Physical functioning is of major importance after burns in many areas of life, in both the short and the long term. This cross-sectional study aimed to describe anthropometry, muscular strength and aerobic capacity in children and adolescents between 0.5-5 years after burns over 10% TBSA. PROCEDURES: Assessments took place in a mobile exercise lab. Demographics, burn characteristics and anthropometrics were recorded. Muscular strength in six muscle groups was measured using hand-held dynamometry and aerobic capacity was measured with a graded cardiopulmonary exercise test. Subjects' scores were compared with Dutch age- and gender-matched norm values and converted to Z scores. RESULTS: The assessments were completed by 24 subjects with pediatric burns ranging from 10 to 41% TBSA and time after burn from 1 to 5 years (58.3% male; 6-18 years). On group level, no significant differences between the subjects' scores and norm values were found. No trends were seen indicating an effect of extent of burn or time after burn. Individually, eight subjects (33.3%), mostly aged 6 or 7, showed significantly low performance on at least one variable: seven for strength, one for aerobic capacity and one for both. CONCLUSION: Anthropometry, muscular strength and aerobic capacity are adequate in the majority of Dutch children and adolescents 1-5 years after 10-41% TBSA burns. PMID- 26480872 TI - Structured data quality reports to improve EHR data quality. AB - OBJECTIVE: To examine whether a structured data quality report (SDQR) and feedback sessions with practice principals and managers improve the quality of routinely collected data in EHRs. METHODS: The intervention was conducted in four general practices participating in the Fairfield neighborhood electronic Practice Based Research Network (ePBRN). Data were extracted from their clinical information systems and summarised as a SDQR to guide feedback to practice principals and managers at 0, 4, 8 and 12 months. Data quality (DQ) metrics included completeness, correctness, consistency and duplication of patient records. Information on data recording practices, data quality improvement, and utility of SDQRs was collected at the feedback sessions at the practices. The main outcome measure was change in the recording of clinical information and level of meeting Royal Australian College of General Practice (RACGP) targets. RESULTS: Birth date was 100% and gender 99% complete at baseline and maintained. DQ of all variables measured improved significantly (p<0.01) over 12 months, but was not sufficient to comply with RACGP standards. Improvement was greatest with allergies. There was no significant change in duplicate records. CONCLUSIONS: SDQRs and feedback sessions support general practitioners and practice managers to focus on improving the recording of patient information. However, improved practice DQ, was not sufficient to meet RACGP targets. Randomised controlled studies are required to evaluate strategies to improve data quality and any associated improved safety and quality of care. PMID- 26480873 TI - Teaching Neuroimages: Cerebral Fat Embolism After Cemented Hip Replacement. PMID- 26480874 TI - ? AB - There is an ongoing discussion about reimbursement of stent-angioplasty for the treatment of intracranial stenoses in Germany. The discussion was initiated by the statutory health insurance companies after publication of the SAMMPRIS study results, which were in favor for medical management compared to stent-angioplasty with the Wingspan(r) stent system. A report (Rapid report N14-01) mainly based on SAMMPRIS was written by the German Institute for Quality and Efficiency in Health Care (IQWiG) and serves as a basis for the decision-making process. This report was previously commented by the medical societies involved. Limitations of the SAMMPRIS trial and vital indications for intracranial stenting were outlined in this comment (acute vessel occlusion, hemodynamic impairment, recurrent symptoms under medical treatment).Currently also emergency stent procedures are a matter of debate. In this context a second IQWiG report was commissioned (GA 15 - 02) addressing the results of the VISSIT trial, the transferability of the results of the first report to emergency treatments and the practice of emergency intracranial stent treatment in Germany6. Regarding transferability of results the main conclusion was that there was no evidence that the results of the studies analyzed for the first report (mainly SAMMPRIS) could not be transferred to emergency treatments. From a medical professional and scientific standpoint it is inacceptable to compare outcomes of a secondary prophylactic treatment with emergency procedures. The analysis of emergency treatments in Germany based on retrospective case series with a cumulative number of 31 patients. Since most emergency procedures are performed in a clinical context and are not necessarily subject to scientific evaluation, this does not reflect current practice in Germany.The first part of this statement briefly outlines the design of SAMMPRIS and VISSIT and the interpretation of the trial results from a professional perspective. The current state of discussion regarding reimbursement of intracranial stenting is summarized. The second section contains a detailed comment on the current IQWiG report GA15-02 "Stents for the treatment of intracranial artery stenosis: VISSIT study and acute treatment in Germany". PMID- 26480871 TI - Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia. AB - BACKGROUND: Synaptic dysfunction is a key event in pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) where synapse loss pathologically correlates with cognitive decline and dementia. Although evidence suggests that aberrant protein production and aggregation are the causative factors in familial subsets of such diseases, drugs singularly targeting these hallmark proteins, such as amyloid-beta, have failed in late stage clinical trials. Therefore, to provide a successful disease-modifying compound and address synaptic dysfunction and memory loss in AD and mixed pathology dementia, we repurposed a clinically proven drug, CMZ, with neuroprotective and anti inflammatory properties via addition of nitric oxide (NO) and cGMP signaling property. RESULTS: The novel compound, NMZ, was shown to retain the GABAA potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. NMZ reversed amnestic blockade of acetylcholine receptors by scopolamine as well as NMDA receptor blockade by a benzodiazepine and a NO synthase inhibitor in the step-through passive avoidance (STPA) test of learning and working memory. A PK/PD relationship was developed based on STPA analysis coupled with pharmacokinetic measures of drug levels in the brain: at 1 nM concentration in brain and plasma, NMZ was able to restore memory consolidation in mice. CONCLUSION: Our findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia. PMID- 26480875 TI - Challenges in randomized controlled trials and emerging multiple sclerosis therapeutics. AB - The remarkable global development of disease-modifying therapies (DMTs) specific for multiple sclerosis (MS) has significantly reduced the frequency of relapse, slowed the progression of disability, and improved the quality of life in patients with MS. With increasing numbers of approved DMTs, neurologists in North America and Europe are able to present multiple treatment options to their patients to achieve a better therapeutic outcome, and in many cases, no evidence of disease activity. MS patients have improved accessibility to various DMTs at no or minimal out-of-pocket cost. The ethical guidelines defined by the Edinburgh revision of the Declaration of Helsinki strongly discourage the use of placebo control groups in modern MS clinical trials. The use of an active comparator control group increases the number of participants in each group that is essential to achieve statistical significance, thus further increasing the difficulty of completing randomized controlled trials (RCTs) for the development of new MS therapies. There is evidence of a high prevalence of MS and a large number of patients in Asia. The belief of the existence of Asian types of MS that are distinct from Western types, and regulatory policies are among the reasons why DMTs are limited in most Asian countries. Lack of access to approved DMTs provides a good opportunity for clinical trials that are designed for the development of new MS therapies. Recently, data from RCTs have demonstrated excellent recruitment of participants and the completion of multi-nation and single-nation MS trials within this region. Recent studies using the McDonald MS diagnostic criteria carefully excluded patients with neuromyelitis optica (NMO) and NMO spectrum disorder, and demonstrated that patients with MS in Asia have clinical characteristics and treatment responses similar to those in Western countries. PMID- 26480876 TI - Cortico-centric effects of general anesthetics on cerebrocortical evoked potentials. AB - Despite their ubiquitous use for rendering patients unconscious for surgery, our understanding of how general anesthetics cause hypnosis remains rudimentary at best. Recent years have seen increased interest in "top-down" cortico-centric theories of anesthetic action. The aim of this study was to explore this by investigating direct cortical effects of anesthetics on cerebrocortical evoked potentials in isolated mouse brain slices. Evoked potentials were elicited in cortical layer IV by electrical stimulation of the underlying white matter. The effects of three anesthetics (ketamine, etomidate, and isoflurane) on the amplitude, latency, and slope of short-latency evoked potentials were quantified. The N2/P3/N4 potentials-which represent the early cortical response-were enhanced by etomidate (increased P3-N4 slope, P <0.01), maintained by ketamine, and reduced by isoflurane (lower N2/P3 amplitude, P <0.01). These effects closely resemble those seen in vivo for the same drugs and point to a cortical mechanism independent of effects on subcortical structures such as the thalamus. PMID- 26480877 TI - Neer Award 2015: A randomized, prospective evaluation on the effectiveness of tranexamic acid in reducing blood loss after total shoulder arthroplasty. AB - BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic agent that has been shown to significantly reduce blood loss and transfusion requirements after total knee and hip arthroplasty. The purpose of this study was to evaluate the effect of TXA on postoperative blood loss after shoulder arthroplasty. METHODS: A total of 111 patients (62 women; average age, 67 years) who underwent shoulder arthroplasty were prospectively randomized in double-blinded fashion to receive either 100 mL of normal saline or 100 mL of normal saline with 2 g TXA by topical application into the wound at the completion of the case. All patients received a postoperative drain. Drain output representing postoperative blood loss, transfusion requirements, and change in hemoglobin level were recorded. All postoperative complications were noted. RESULTS: The average blood loss recorded after surgery was 170 mL in the placebo group and 108 mL in the TXA group (P = .017). The average change in hemoglobin level was 2.6 g/dL in the placebo group and 1.7 g/dL in the TXA group (P < .001). There were no transfusion requirements or postoperative complications noted in either group. DISCUSSION: In this cohort of patients, those treated with TXA experienced a significantly lower amount of postoperative blood loss and a significantly smaller change in hemoglobin level compared with those treated with placebo. Further work is required to determine the effectiveness and clinical significance of TXA in reducing transfusion requirements in shoulder arthroplasty and, more specifically, shoulder arthroplasty performed for complicated patients or for trauma and fracture patients. PMID- 26480878 TI - The efficacy of celecoxib in preventing heterotopic ossification recurrence after open arthrolysis for post-traumatic elbow stiffness in adults. AB - BACKGROUND: Heterotopic ossification (HO) recurrence after joint surgery is always a disturbing problem for patients and surgeons. Our study was performed to assess the efficacy and safety of celecoxib in preventing the recurrence of HO after open arthrolysis for post-traumatic elbow stiffness. METHODS: We retrospectively studied 152 patients with stiff elbows caused by post-traumatic HO. After surgery, 77 patients received celecoxib (200 mg once daily) for 28 days, whereas 75 did not. Radiographic evaluation was performed at 3, 6, and 9 months postoperatively. Univariate and multivariate analyses were performed to determine which factors affected HO recurrence. RESULTS: HO was both more common and more severe in the no-celecoxib group than in the celecoxib group at 3, 6, and 9 months after surgery. A significant difference was observed between the 2 groups in terms of postoperative extension (P = .030), flexion (P = .008), and pronation (P = .005); however, no significant difference in postoperative supination was noted (P = .622). Logistic regression analysis showed that taking celecoxib was the protective factor for HO recurrence, whereas overweight (body mass index > 25) and male gender were the risk factors. CONCLUSIONS: A short course of celecoxib aids in the prevention of HO recurrence after open arthrolysis for elbow stiffness in adults and could be an effective and safe option. PMID- 26480879 TI - Is minimally invasive plating osteosynthesis for humeral shaft fracture advantageous compared with the conventional open technique? AB - BACKGROUND: The minimally invasive plate osteosynthesis (MIPO) technique has been described and used effectively in humeral shaft fractures. However, the postoperative deformity resulting from malreduction with the minimally invasive technique has not received adequate attention. The purpose of this study was to evaluate the postoperative malrotation and the functional results of the MIPO technique and conventional plating in open reduction and internal fixation after humeral shaft fracture. METHODS: A prospective cohort research was performed; 53 cases of humeral shaft fractures in a level I trauma center were included and allocated into group I for open reduction and internal fixation or group II for MIPO. Computed tomography was used to measure the postoperative malrotation. The status of the union, functional scoring, and muscle strength were recorded at 12 months after surgery. RESULTS: Both groups exhibited satisfactory union results and final shoulder function scoring. Shoulder girdle musculature of both groups exhibited considerable strength loss with no obvious intergroup discrepancy, with greater internal rotation strength loss compared with external rotation. A significantly increased incidence of postoperative malrotation >20 degrees was observed in the MIPO group (40.9% vs. 0%; P < .01). A linear correlation between postoperative malrotation and range of rotation loss was observed. CONCLUSIONS: The MIPO technique might be advantageous as a cosmetic consideration; however, it did not improve postoperative function and strength restoration results more than the open technique. Moreover, MIPO was associated with greater postoperative malrotation, which was considered to be correlated with subsequent long-term shoulder degeneration. PMID- 26480880 TI - Short-term clinical results of arthroscopic osteochondral fixation for elbow osteochondritis dissecans in teenaged baseball players. AB - BACKGROUND: Reports regarding arthroscopic fixation of the osteochondral fragments for elbow osteochondritis dissecans (OCD) are few. This study assessed the clinical outcomes of arthroscopic fixation of unstable osteochondral fragments by using absorbable pins over a postoperative period of at least 1 year. METHODS: The patients were 13 adolescent baseball players with a mean age of 14 years (range, 12-16 years) who underwent OCD of primary lesions at International Cartilage Repair Society grades III and IV. The patients were evaluated by using validated outcome measures at a mean follow-up period of 24 months (range, 12-50 months). RESULTS: The mean (standard deviation) score in the disability/symptom section of the Disabilities of the Arm, Shoulder, and Hand improved from 12.4 (6.0) before the surgery to 0.5 (1.2) after the surgery, and the sports section improved from 74.5 (25.4) to 1.4 (5.2). The mean (standard deviation) extension improved from -11 degrees (10.8) to -2 degrees (3.9; P < .001). The mean (SD) flexion improved from 129 degrees (11.6) to 137 degrees (5.6; P = .040). All patients were able to resume playing baseball, and 9 (69%) resumed playing at the same position as before their injuries. CONCLUSIONS: The clinical results of arthroscopic osteochondral fragment fixation in the teenaged baseball players with elbow OCD, albeit obtained over only a short period, were favorable. This arthroscopic treatment enables repair of lesions and is considered appropriate for unstable OCD during the adolescent growth spurt. PMID- 26480881 TI - Elbow arthrodesis for post-traumatic sequelae: surgical tactics using the Ilizarov frame. AB - BACKGROUND: Surgical arthrodesis of the elbow joint is frequently unsuccessful and rarely performed. It is the purpose of this article to evaluate tactics and different constructs to achieve elbow arthrodesis (EA) using the Ilizarov apparatus in patients with post-traumatic nonreconstructable elbow sequelae. METHODS: A consecutive series of 4 patients were treated between 2009 and 2013 (3 men and 1 woman; mean age, 46.7 [35-75] years). Two patients had late complications in total elbow replacement and developed nonunion after condylar fractures of the distal humerus. There were 3 ulnohumeral arthrodeses and 1 radiohumeral arthrodesis. The hybrid advanced Ilizarov technique was used in all cases. RESULTS: Complete union was obtained in 3 EAs (75%) without additional surgery at an average of 23 weeks. Fusion angles ranged from 90 degrees to 120 degrees . One patient required amputation above the elbow because of persistent infection and chronic pain after attempted reconstruction with distraction osteogenesis for infected total elbow replacement with humeral bone loss. The average length of follow-up after EA was 33 months (range, 18-60 months). At final follow-up, the median score of the shortened Disabilities of the Arm, Shoulder, and Hand questionnaire was 42.4 (27.3-52.2). Three patients returned to their working activities. CONCLUSIONS: EA is not a common orthopedic procedure. Despite its difficulties and need of specific training, the Ilizarov technique provides a reproducible and reliable way of achieving solid fusion with the desired angle. Advantages include infection control, early mobilization, accurate application, convertibility and versatility compared with a monolateral fixator, and improved union rate. PMID- 26480882 TI - Regarding "Surgical treatment of displaced middle-third clavicular fractures: a prospective, randomized trial in a working compensation population". PMID- 26480883 TI - Response to Letter to the Editor regarding "Surgical treatment of displaced middle-third clavicular fractures: a prospective, randomized trial in a working compensation population". PMID- 26480884 TI - Diarrhea and Weight Loss in a 67-Year-Old Man. PMID- 26480885 TI - Perianal Fistula, Weight Loss, and Skin Rash: Good Job Making the Diagnosis. PMID- 26480886 TI - Slow Growing Abdominal Mass Over 10 Years. PMID- 26480887 TI - Evaluation and Validation of the Detection of soluble Triggering Receptor Expressed on Myeloid Cells 1 by Enzyme-linked immunosorbent Assay. AB - Triggering receptor expressed on myeloid cells (TREM)-1 plays an important role in innate immune responses and is upregulated under infectious as well as non infectious conditions. In addition, a soluble TREM-1 variant (sTREM-1) is detectable in sera or bronchoalveolar-lavage fluids from patients. Currently, various studies are difficult to compare, since the methods of detection by enzyme-linked immunosorbent assays (ELISA) vary among different research groups. In this study, we compared three different s-TREM-1 specific ELISAs and identified individual assay characteristics finding notable differences in sTREM 1 concentrations in part depending on the employed buffers. Investigating potential confounding factors for sTREM-1 detection, serum heat-inactivation (HI) showed improved recovery compared to non-HI (NHI) serum, reproducible by addition of complement and re-heat-inactivation. Hence we identified complement as a heat sensitive confounder in some sTREM-1 ELISAs. We conclude that it is difficult to directly compare data of several studies, in particular if different ELISAs are engaged. Immunoassays for research use only are in general hampered by lack of standardization. Further standardization is needed until sTREM-1 ELISA is capable for better reproducibility of studies and clinical application. PMID- 26480888 TI - [Inhaled treatments: Choice of devices, systemic absorption of inhaled drugs and bitter taste receptors in the respiratory tract]. AB - Inhaled drugs are now routinely prescribed in daily medical practice. Recent topics about these treatments have been developed during the fourth annual meeting of the Groupe de travail aerosoltherapie (GAT) of the French-speaking respiratory society (Societe de pneumologie de langue francaise). This article focuses mainly upon the choice of devices, systemic absorption of inhaled drugs and bitter taste receptors in the respiratory tract, a potential new target for drug development. PMID- 26480889 TI - Eliminating the phrase "elective abortion": why language matters. AB - The phrase "elective abortion" is often used to describe induced abortions performed for reasons other than a direct, immediate threat to maternal physical health. We argue that the term "elective abortion" is variably defined, misrepresents the complexity and multiplicity of indications for abortion and perpetuates stigma. In practice, restricting access to abortion at the legal, regulatory or institutional level based on subjective perceptions of patient need constrains health care providers' ability to act according to their best clinical judgments and limits patient access to care. The phrase "elective abortion" should be eliminated from scientific and medical discourse to prevent further damage to the public understanding of the variety of indications for which women require expeditious and equitable access to induced abortion. PMID- 26480890 TI - Women's experiences with doula support during first-trimester surgical abortion: a qualitative study. AB - OBJECTIVE: To explore how doula support influences women's experiences with first trimester surgical abortion. STUDY DESIGN: We conducted semistructured interviews with women given the option to receive doula support during first-trimester surgical abortion in a clinic that uses local anesthesia and does not routinely allow support people to be present during procedures. Dimensions explored included (a) reasons women did or did not choose doula support; (b) key aspects of the doula interaction; and (c) future directions for doula support in abortion care. Interviews were transcribed, and computer-assisted content analysis was performed; salient themes are presented. RESULTS: Thirty women were interviewed: 19 received and 11 did not receive doula support. Reasons to accept doula support included (a) wanting companionship during the procedure and (b) being concerned about the procedure. Reasons to decline doula support included (a) a sense of stoicism and desiring privacy or (b) not wanting to add emotion to this event. Women who received doula support universally reported positive experiences with the verbal and physical techniques used by doulas during the procedure, and most women who declined doula support subsequently regretted not having a doula. Many women endorsed additional roles for doulas in abortion care, including addressing informational and emotional needs before and after the procedure. CONCLUSION: Women receiving first-trimester surgical abortion in this setting value doula support at the time of the procedure. This intervention has the potential to be further developed to help women address pre- and postabortion informational and emotional needs. IMPLICATIONS: In a setting that does not allow family or friends to be present during the abortion procedure, women highly valued the presence of trained abortion doulas. This study speaks to the importance of providing support to women during abortion care. Developing a volunteer doula service is one approach to addressing this need, especially in clinics that otherwise do not permit support people in the procedure room or for women who do not have a support person and desire one. PMID- 26480892 TI - InSAR analysis of surface deformation over permafrost to estimate active layer thickness based on one-dimensional heat transfer model of soils. AB - This paper presents a novel method to estimate active layer thickness (ALT) over permafrost based on InSAR (Interferometric Synthetic Aperture Radar) observation and the heat transfer model of soils. The time lags between the periodic feature of InSAR-observed surface deformation over permafrost and the meteorologically recorded temperatures are assumed to be the time intervals that the temperature maximum to diffuse from the ground surface downward to the bottom of the active layer. By exploiting the time lags and the one-dimensional heat transfer model of soils, we estimate the ALTs. Using the frozen soil region in southern Qinghai Tibet Plateau (QTP) as examples, we provided a conceptual demonstration of the estimation of the InSAR pixel-wise ALTs. In the case study, the ALTs are ranging from 1.02 to 3.14 m and with an average of 1.95 m. The results are compatible with those sparse ALT observations/estimations by traditional methods, while with extraordinary high spatial resolution at pixel level (~40 meter). The presented method is simple, and can potentially be used for deriving high-resolution ALTs in other remote areas similar to QTP, where only sparse observations are available now. PMID- 26480893 TI - Optimizing the lifetimes of phenoxonium cations derived from vitamin E via structural modifications. AB - Systematic synthesis of a number of new phenolic compounds with structures similar to vitamin E led to the identification of several sterically hindered compounds that when electrochemically oxidised in acetonitrile in a -2e(-)/-H(+) process formed phenoxonium diamagnetic cations that were resistant to hydrolysis reactions. The reactivity of the phenoxonium ions was ascertained by performing cyclic voltammetric scans during the addition of carefully controlled quantities of water into acetonitrile solutions, with the data modelled using digital simulation techniques. PMID- 26480891 TI - The cell competition-based high-throughput screening identifies small compounds that promote the elimination of RasV12-transformed cells from epithelia. AB - Recent studies have revealed that cell competition can occur between normal and transformed epithelial cells; normal epithelial cells recognize the presence of the neighboring transformed cells and actively eliminate them from epithelial tissues. Here, we have established a brand-new high-throughput screening platform that targets cell competition. By using this platform, we have identified Rebeccamycin as a hit compound that specifically promotes elimination of RasV12 transformed cells from the epithelium, though after longer treatment it shows substantial cytotoxic effect against normal epithelial cells. Among several Rebeccamycin-derivative compounds, we have found that VC1-8 has least cytotoxicity against normal cells but shows the comparable effect on the elimination of transformed cells. This cell competition-promoting activity of VC1 8 is observed both in vitro and ex vivo. These data demonstrate that the cell competition-based screening is a promising tool for the establishment of a novel type of cancer preventive medicine. PMID- 26480894 TI - Effect of Bacillus subtilis CGMCC 1.1086 on the growth performance and intestinal microbiota of broilers. AB - AIMS: Probiotics have been proved to be the most preferred and effective alternative to antibiotics as growth promoter and pathogens inhibitor in poultry industry. In this study Bacillus subtilis CGMCC 1.1086 as a probiotic bacterium was administered in diet and its effects on both the growth performance and the caecal microbiota of broilers were evaluated. METHODS AND RESULTS: A total of 240 male Arbor Acres (AA) broilers were randomly allocated into two treatment groups of basal diet without any addition of probiotics and basal diet containing B. subtilis CGMCC 1.1086. The body weight of broilers was measured individually at 32, 39 and 46 days of bird age. Furthermore, MiSeq high-throughput sequencing analysis of 16S rRNA was used to investigate the bacterial community structure in the caeca of broilers. The results indicated that broilers receiving diet supplemented with B. subtilis CGMCC 1.1086 showed 27.7% higher daily weight gain than those of control during 2 weeks. The feed conversion ratio (FCR) of B. subtilis CGMCC 1.1086 group was also improved by 10.3%. In the caeca of broilers fed with B. subtilis CGMCC 1.1086, the relative abundance of Alistipes, Odoribacter, Ruminococcus, Blautia and Desulfovibrio were higher, while the potential pathogens such as Staphylococcus and Escherichia-Shigella were lower than those of control. CONCLUSIONS: The probiotic B. subtilis CGMCC 1.1086 can effectively improve the growth performance and FCR of broilers via the beneficial modulation of caecal microbiota. SIGNIFICANCE AND IMPACT OF THE STUDY: The effect of B. subtilis on growth performance of broilers was evaluated and the relationship between growth and caecal microbiota was revealed. The results of this study help to promote application of probiotics in poultry industry. PMID- 26480895 TI - The salt-sensitive structure and zinc inhibition of Borrelia burgdorferi protease BbHtrA. AB - HtrA serine proteases are highly conserved and essential ATP-independent proteases with chaperone activity. Bacteria express a variable number of HtrA homologues that contribute to the virulence and pathogenicity of bacterial pathogens. Lyme disease spirochetes possess a single HtrA protease homologue, Borrelia burgdorferi HtrA (BbHtrA). Previous studies established that, like the human orthologue HtrA1, BbHtrA is proteolytically active against numerous extracellular proteins in vitro. In this study, we utilized size exclusion chromatography and blue native polyacrylamide gel electrophoresis (BN-PAGE) to demonstrate BbHtrA oligomeric structures that were substrate independent and salt sensitive. Examination of the influence of transition metals on the activity of BbHtrA revealed that this protease is inhibited by Zn(2+) > Cu(2+) > Mn(2+). Extending this analysis to two other HtrA proteases, E. coli DegP and HtrA1, revealed that all three HtrA proteases were reversibly inhibited by ZnCl2 at all micro molar concentrations examined. Commercial inhibitors for HtrA proteases are not available and physiologic HtrA inhibitors are unknown. Our observation of conserved zinc inhibition of HtrA proteases will facilitate structural and functional studies of additional members of this important class of proteases. PMID- 26480896 TI - The relationship between C-reactive protein rs3091244 polymorphism and ankylosing spondylitis. AB - AIMS: Previous studies have shown that C-reactive protein (CRP) gene polymorphism can be related to inflammatory changes. The present study aimed to examine the association between CRP gene polymorphism and clinical and laboratory findings in ankylosing spondylitis (AS) patients. MATERIALS AND METHODS: A total of 80 patients, 40 with AS and 40 controls, were included in the study. Diagnosis of AS was made according to Assessment in AS International Working Group criteria. Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index and Bath Ankylosing Spondylitis Radiology Index scores were evaluated. CRP gene C, A and T alleles were evaluated and were determined using the analysis of melting curves after real time polymerase chain reaction. The odds ratios were calculated for all alleles and haploids of the CRP gene. We investigated the relationship between the CRP polymorphism and clinical and laboratory findings. RESULTS: A, C, T allele frequencies in the control group were 15%, 57.5% and 27.5%. The allele frequencies in the AS group were 38%, 68.8% and 26.2%. While C and T allele frequencies were shown to be similar in the two groups, A allele frequency was higher in the AS group compared to the control group. The CC wild allele was 42.5% in the control group and 47.5% in the AS group (P = 1.0). Odds ratios for the C allele were 1.6, for the CC haploid 1.2 and for the CT haploid 3.7. Chest expansion and finger-to-ground distance was better in the CRP gene polymorphism group compared to the no polymorphism group. CONCLUSION: The presence of the CRP gene CC wild haploid and C allele in patients may indicate an increased risk for AS. PMID- 26480897 TI - Kruppel-like factor 5 promotes apoptosis triggered by tumor necrosis factor alpha in LNCaP prostate cancer cells via up-regulation of mitogen-activated protein kinase kinase 7. AB - OBJECTIVES: Kruppel-like factor 5 (KLF5) modulates multiple cell processes in different cancers. It is frequently deleted and inactivated in prostate cancer and may exert a tumor suppressor function. However, how KLF5 inhibits the progression of prostate cancer is still not clear. In the present study, we identified how KLF5 and tumor necrosis factor alpha (TNFalpha) pathway, which can induce apoptosis in cancer, regulate each other in LNCaP prostate cancer cells. MATERIAL AND METHODS: The expression of messenger RNA and protein was detected by real-time polymerase chain reaction assay and western blot analysis, respectively. To identify whether KLF5 regulates the activity of TNFalpha downstream pathway, we constructed a stable KLF5 knockdown or KLF5 overexpressing cell line with lentivirus-containing short hairpin RNA targeting KLF5 or full length KLF5 in LNCaP cells. Cell apoptosis was determined through flow cytometry assay. In addition, the regulation of KLF5 on target gene transcription was detected by reporter luciferase activity assay, and the binding of KLF5 on target promoter was detected through oligonucleotides pull-down analysis. RESULTS: We found that TNFalpha induced the expression of KLF5 at both messenger RNA and protein levels; moreover, TNFalpha up-regulated KLF5 through TNF receptor 1 but not through TNF receptor 2 in LNCaP cells. Knockdown of KLF5 decreased apoptosis induced by TNFalpha, whereas cell apoptosis was increased by KLF5 overexpression. Consistently, expression of cleaved PARP and caspase-3 induced by TNFalpha was decreased by KLF5 knockdown, whereas it was increased by overexpressed KLF5. JNK activity is essential for the apoptosis induced by TNFalpha. We found that knockdown of KLF5 not only decreased the phosphorylation of JNK induced by TNFalpha, but also down-regulated the transcription of mitogen-activated protein kinase kinase 7 (MKK7), an upstream kinase of JNK, by binding to the MKK7 promoter. CONCLUSIONS: Our results indicate that KLF5 is an essential transcription regulator of MKK7 kinase and promotes the apoptosis induced by TNFalpha in LNCaP cells. Loss of KLF5 in prostate cancer may decrease cell response to TNFalpha-inducing apoptosis and facilitate cancer initiation and progression; moreover, KLF5 could be a potential molecular marker for predicting the effect of high-dose TNFalpha on tumor growth inhibition in prostate cancer. PMID- 26480898 TI - Age-related variation and predictors of long-term quality of life in germ cell tumor survivors. AB - PURPOSE: To compare long-term health-related quality of life (QoL) in germ cell tumor survivors (GCTS) and age-adjusted men and to identify predictors of variation in long-term QoL in GCTS. METHODS: We used the Short-Form Health Survey to measure QoL in a cross-sectional sample of 164 survivors of germ cell tumors from Hamburg, Germany. QoL was compared with age-adjusted German norm data. Sociodemographic and medical data from questionnaires and medical records were used to find predictors of QoL. RESULTS: On average, patients were 44.4 years old (standard deviation = 9.6 y) and average time since first germ cell tumor diagnosis was 11.6 years (standard deviation = 7.3 y). We found significantly lower mental component scores in GCTS when compared with norm data (Hedges g = 0.44, P<0.001). An exploratory analysis by age group showed the largest difference in mental QoL in survivors aged 31 to 40 years (Hedges g =-0.67). Linear regression analysis revealed age (beta =-0.46, P<0.001), marital status (beta = 0.20, P = 0.024), advanced secondary qualifications (beta =-0.25, P = 0.001), time since diagnosis (beta = 0.17, P = 0.031), and tumor stage (beta = 0.17, P = 0.024) as statistically significant predictors of the physical component score, accounting for 22% of the variance. Statistically significant predictors of the mental component score were higher secondary qualifications (beta = 0.17, P = 0.033) and unemployment (beta =-0.21, P = 0.009), accounting for 6% of the variance. CONCLUSIONS: Survivors of germ cell tumors can expect an overall long-term QoL similar to that of other men of their age. PMID- 26480899 TI - In vitro evaluation of the effects of anti-fungals, benzodiazepines and non steroidal anti-inflammatory drugs on the glucuronidation of 19-norandrosterone: implications on doping control analysis. AB - We have studied whether the phase II metabolism of 19-norandrosterone, the most representative metabolite of 19-nortestosterone (nandrolone), can be altered in the presence of other drugs that are not presently included on the Prohibited List of the World Anti-Doping Agency. In detail, we have evaluated the effect of non-prohibited drugs belonging to the classes of anti-fungals, benzodiazepines, and non-steroidal anti-inflammatory drugs on the glucuronidation of 19 norandrosterone. In vitro assays based on the use of either pooled human liver microsomes or specific recombinant isoforms of uridine diphosphoglucuronosyl transferase were designed and performed to monitor the formation of 19 norandrosterone glucuronide from 19-norandrosterone. Determination of 19 norandrosterone (free and conjugated fraction) was performed by gas chromatography - mass spectrometry after sample pretreatment consisting of an enzymatic hydrolysis (performed only for the conjugated fraction), liquid/liquid extraction with tert-butylmethyl ether, and derivatization to form the trimethylsilyl derivative. In parallel, a method based on reversed-phase liquid chromatography coupled to tandem mass spectrometry in positive electrospray ionization with acquisition in selected reaction monitoring mode was also developed to identify the non-prohibited drugs considered in this study. Incubation experiments have preliminarily shown that the glucuronidation of 19 norandrosterone is principally carried out by UGT2B7 (39%) and UGT2B17 (31%). Inhibition studies have shown that the yield of the glucuronidation reaction is reduced in the presence of the anti-fungals itraconazole, ketoconazole, and miconazole, of the benzodiazepine triazolam and of the non-steroidal anti inflammatory drugs diclofenac and ibuprofen, while no alteration was recorded in the presence of all other compounds considered in this study. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26480900 TI - Herpes viruses and human papilloma virus in nasal polyposis and controls. AB - INTRODUCTION: Chronic rhinosinusitis with nasal polyps is a multifactorial disease entity with an unclear pathogenesis. Contradictory data exist in the literature on the potential implication of viral elements in adult patients with chronic rhinosinusitis. OBJECTIVE: To compare the prevalence of human herpes viruses (1-6) and Human Papilloma Virus in adult patients with chronic rhinosinusitis with nasal polyps and healthy controls. METHODS: Viral DNA presence was evaluated by real-time polymerase chain reaction application to nasal polyps specimens from 91 chronic rhinosinusitis with nasal polyps patients and nasal turbinate mucosa from 38 healthy controls. RESULTS: Epstein-Barr virus positivity was higher in nasal polyps (24/91; 26.4%) versus controls (4/38; 10.5%), but the difference did not reach significance (p=0.06). Human herpes virus-6 positivity was lower in nasal polyps (13/91; 14.29%) versus controls (10/38; 26.32%, p=0.13). In chronic rhinosinusitis with nasal polyps group, 1 sample was herpes simplex virus-1-positive (1/91; 1.1%), and another was cytomegalovirus-positive (1/91; 1.1%), versus none in controls. No sample was positive for herpes simplex virus-2, varicella-zoster virus, high-risk-human papilloma viruses (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) and low-risk human papilloma viruses (6, 11). CONCLUSION: Differences in Epstein-Barr virus and human herpes virus-6 positivity among patients with chronic rhinosinusitis with nasal polyps and healthy controls are not statistically significant, weakening the likelihood of their implication in chronic rhinosinusitis with nasal polyps pathogenesis. PMID- 26480901 TI - Long-latency auditory evoked potentials with verbal and nonverbal stimuli. AB - INTRODUCTION: Long-latency auditory evoked potentials represent the cortical activity related to attention, memory, and auditory discrimination skills. Acoustic signal processing occurs differently between verbal and nonverbal stimuli, influencing the latency and amplitude patterns. OBJECTIVE: To describe the latencies of the cortical potentials P1, N1, P2, N2, and P3, as well as P3 amplitude, with different speech stimuli and tone bursts, and to classify them in the presence and absence of these data. METHODS: A total of 30 subjects with normal hearing were assessed, aged 18-32 years old, matched by gender. Nonverbal stimuli were used (tone burst; 1000Hz - frequent and 4000Hz - rare); and verbal (/ba/ - frequent; /ga/, /da/, and /di/ - rare). RESULTS: Considering the component N2 for tone burst, the lowest latency found was 217.45ms for the BA/DI stimulus; the highest latency found was 256.5ms. For the P3 component, the shortest latency with tone burst stimuli was 298.7 with BA/GA stimuli, the highest, was 340ms. For the P3 amplitude, there was no statistically significant difference among the different stimuli. For latencies of components P1, N1, P2, N2, P3, there were no statistical differences among them, regardless of the stimuli used. CONCLUSION: There was a difference in the latency of potentials N2 and P3 among the stimuli employed but no difference was observed for the P3 amplitude. PMID- 26480902 TI - Investigation of neutrophil-to-lymphocyte ratio and mean platelet volume in sudden hearing loss. AB - INTRODUCTION: Several theories attempt to explain the pathophysiology of sudden hearing loss. OBJECTIVE: The objective of this study was to investigate the possible role of inflammation and atherothrombosis in sudden hearing loss patients through the neutrophil-to-lymphocyte ratio and mean platelet volume. METHODS: Study design - retrospective cross-sectional historical cohort. This study was conducted on two groups: one with 59 individuals diagnosed with sudden hearing loss, and other with 59 healthy individuals with the same characteristics of gender and age distribution, neutrophil-to-lymphocyte ratio and mean platelet volume levels were measured in patients diagnosed with sudden hearing loss as well as in the control group, and it was verified whether these results interfered for a better or worse prognosis with treatment of sudden deafness. RESULTS: Neutrophil-to-lymphocyte ratio levels are much higher in patients diagnosed with sudden hearing loss compared to the control group. Similarly, mean levels of neutrophil-to-lymphocyte ratio are higher in non-recovered versus recovered patients (p=0.001). However, we could not find a correlation with mean platelet volume levels (p>0.05). CONCLUSION: Neutrophil-to-lymphocyte ratio is a quick and reliable indicator regarding diagnosis and prognosis of sudden hearing loss; on the other hand, mean platelet volume may be considered a less important indicator in this aspect. PMID- 26480903 TI - Newborn physiological responses to noise in the neonatal unit. AB - INTRODUCTION: The incorporation of technologies in the care of infants has contributed to increased survival; however, this has turned neonatal unit into a noisy environment. OBJECTIVE: To evaluate the physiological and functional effects resulting from the exposure to noise on low-weight newborns in incubators in a neonatal unit. METHODS: Prospective, observational, quantitative, exploratory, descriptive study. The adopted statistical method included tables of frequency, descriptive statistics, and Student's t-test, with a 0.05 level of significance. As data collection tools, the environmental noise and the noise inside of the incubator were evaluated, and the Assessment of Preterm Infant Behavior scale was used to assess premature newborn behavior and projected specifically to document the neurobehavioral functioning of preterm infants. The data collection occurred from September of 2012 to April of 2013; 61 low-weight newborns admitted in the neonatal unit and in incubators were observed. RESULTS: Significant differences in the variables heart rate and oxygen saturation were noted when newborns were exposed to noise. CONCLUSION: Low-weight neonates in incubators present physiological alterations when facing discomfort caused by environmental noise in neonatal units. PMID- 26480904 TI - Effects of vibrotactile vestibular substitution on vestibular rehabilitation - preliminary study. AB - INTRODUCTION: Some patients with severe impairment of body balance do not obtain adequate improvement from vestibular rehabilitation (VR). OBJECTIVE: To evaluate the effectiveness of VertiguardTM biofeedback equipment as a sensory substitution (SS) of the vestibular system in patients who did not obtain sufficient improvement from VR. METHODS: This was a randomized prospective clinical study. Thirteen patients without satisfactory response to conventional VR were randomized into a study group (SG), which received the vibrotactile stimulus from VertiguardTM for ten days, and a control group (CG), which used equipment without the stimulus. For pre- and post-treatment assessment, the Sensory Organization Test (SOT) protocol of the Computerized Dynamic Posturography (CDP) and two scales of balance self-perception, Activities-specific Balance Confidence (ABC) and Dizziness Handicap Inventory (DHI), were used. RESULTS: After treatment, only the SG showed statistically significant improvement in C5 (p=0.007) and C6 (p=0.01). On the ABC scale, there was a significant difference in the SG (p=0.04). The DHI showed a significant difference in CG and SG with regard to the physical aspect, and only in the SG for the functional aspect (p=0.04). CONCLUSION: The present findings show that sensory substitution using the vibrotactile stimulus of the VertiguardTM system helped with the integration of neural networks involved in maintaining posture, improving the strategies used in the recovery of body balance. PMID- 26480905 TI - Inverted papilloma originating from the left ethmoid sinus invading the nasal cavity bilaterally via the frontal sinus septum. PMID- 26480906 TI - Pulsatile tinnitus related to progestin from intrauterine device. PMID- 26480907 TI - High frequency hearing thresholds and product distortion otoacoustic emissions in cystic fibrosis patients. AB - INTRODUCTION: The treatment of patients with cystic fibrosis involves the use of ototoxic drugs, mainly aminoglycoside antibiotics. Due to the use of these drugs, fibrocystic patients are at risk of developing hearing loss. OBJECTIVE: To evaluate the hearing of patients with cystic fibrosis by High Frequency Audiometry and Distortion Product Otoacoustic Emissions. METHODS: Cross-sectional study. The study group consisted of 39 patients (7-20 years of age) with cystic fibrosis and a control group of 36 individuals in the same age group without otologic complaints, with normal audiometric thresholds and type A tympanometric curves. High Frequency Audiometry and Distortion Product Otoacoustic Emissions tests were conducted. RESULTS: The study group had significantly higher thresholds at 250, 1000, 8000, 9000, 10,000, 12,500, and 16,000Hz (p=0.004) as well as higher prevalence of otoacoustic emission alterations at 1000 and 6000Hz (p=0.001), with significantly lower amplitudes at 1000, 1400, and 6000Hz. There was a significant association between alterations in hearing thresholds in High Frequency Audiometry with the number of courses of aminoglycosides administered (p=0.005). Eighty-three percent of patients who completed more than ten courses of aminoglycosides had hearing loss in High Frequency Audiometry. CONCLUSION: A significant number of patients with cystic fibrosis who received repeated courses of aminoglycosides showed alterations in High Frequency Audiometry and Distortion Product Otoacoustic Emissions. The implementation of ten or more aminoglycoside cycles was associated with alterations in High Frequency Audiometry. PMID- 26480908 TI - Translation and cross-cultural adaptation into Brazilian Portuguese of the Vanderbilt Head and Neck Symptom Survey version 2.0 (VHNSS 2.0) for the assessment of oral symptoms in head and neck cancer patients submitted to radiotherapy. AB - INTRODUCTION: Patients submitted to radiotherapy for the treatment of head and neck cancer have several symptoms, predominantly oral. The Vanderbilt Head and Neck Symptom Survey version 2.0 is an American tool developed to evaluate oral symptoms in head and neck cancer patients submitted to radiotherapy. OBJECTIVE: The aim of the present study was to translate the Vanderbilt Head and Neck Symptom Survey version 2.0 into Brazilian Portuguese and cross-culturally adapt this tool for subsequent validation and application in Brazil. METHODS: A method used for the translation and cultural adaptation of tools, which included independent translations, synthesis of the translations, back-translations, expert committee, and pre-test, was used. The pre-test was performed with 37 head and neck cancer patients, who were divided into four groups, to assess the relevance and understanding of the assessed items. Data were submitted to descriptive statistical analysis. RESULTS: The overall mean of the content validity index was 0.79 for semantic and idiomatic equivalence, and it was higher than 0.8 for cultural and conceptual equivalence. The cognitive interview showed that patients were able to paraphrase the items, and considered them relevant and easily understood. CONCLUSION: The tool was translated and cross-culturally adapted to be used in Brazil. The authors believe this translation is suited for validation. PMID- 26480909 TI - Extracranial neurogenic tumors of the head and neck. AB - INTRODUCTION: Peripheric nerve tumors typically derive from Schwann cells of the peripheral nerve sheet. Since these tumors are uncommon, they should be considered in preoperative differential diagnosis. OBJECTIVE: To report the experience of a tertiary care department. METHODS: Forty-two patients with head and neck peripheral neurogenic tumors were retrospectively analyzed and evaluated from 1977 to 2013. The preoperative diagnosis was confirmed by biopsy or imaging study. RESULTS: The mean age was 41.7 and 15 patients (36%) were male. The mean size was 5.5cm and 26 (61%) were located laterally in the neck. Most tumors (39.9%) presented as an asymptomatic neck mass. Most (39.9%) were resected through a neck approach. Cranial nerves were the commonest site of origin. CONCLUSIONS: Extracranial neurogenic tumors presented with a mean size of 5.5cm, were located laterally in the neck, normally had their origin from cranial nerves, and their resection approach is cervical. PMID- 26480911 TI - Pathogen surveillance in wild bottlenose dolphins Tursiops truncatus. AB - The number and prevalence of diseases is rapidly increasing in the marine ecosystem. Although there is an increase in the number of marine diseases observed world-wide, current understanding of the pathogens associated with marine mammals is limited. An important need exists to develop and apply platforms for rapid detection and characterization of pathogenic agents to assess, prevent and respond to disease outbreaks. In this study, a broad-spectrum molecular detection technology capable of detecting all sequenced microbial organisms, the Lawrence Livermore Microbial Detection Array, was used to assess the microbial agents that could be associated with wild Atlantic dolphins. Blowhole, gastric, and fecal samples from 8 bottlenose dolphins were collected in Charleston, SC, as part of the dolphin assessment effort. The array detected various microbial agents from the dolphin samples. Clostridium perfringens was most prevalent in the samples surveyed using the microarray. This pathogen was also detected using microbiological culture techniques. Additionally, Campylobacter sp., Staphylococcus sp., Erwinia amylovora, Helicobacter pylori, and Frankia sp. were also detected in more than one dolphin using the microarray, but not in culture. This study provides the first survey of pathogens associated with 3 tissue types in dolphins using a broad-spectrum microbial detection microarray and expands insight on the microbial community profile in dolphins. PMID- 26480912 TI - First isolation of a rhabdovirus from perch Perca fluviatilis in Switzerland. AB - Perca fluviatilis is a fish species of increasing interest to the Swiss fish farming industry. In recent years, recirculation systems have been specifically set up to increase production. In one of these farms, abnormal spiral swimming associated with elevated mortalities occurred in repeated batches of imported perch shortly after stocking on several occasions. No bacterial or parasitic etiology was detected, but a virus grown in bluegill fry (BF-2) cells was identified as perch rhabdovirus. Subsequent investigations of other samples suggested a viral tropism for the central nervous system (CNS). Phylogenetic analysis of the partial N and entire G gene sequences positioned this isolate in genogroup C of the species Perch rhabdovirus, with high nucleotide and amino acid (aa) sequence identities with the DK5533 strain isolated in Denmark in 1989. Comparative studies using other closely related isolates allowed the distinction of 2 serological patterns among perch rhabdoviruses and the identification of a proline substitution by a serine in position 147 of the glycoprotein potentially involved in antigenic differentiation. Even if perch imported onto the farm tested negative by virus isolation prior to transport, they may have been the origin of this outbreak since CNS tissue was not included in the samples that were analyzed. Another possibility might be a sub-clinical infection with a viral load in resident fish too low to be detected. This study reports the first isolation of a perch rhabdovirus in Switzerland, and emphasizes the necessity of optimizing diagnostic tools that facilitate better control of the risks associated with fish translocation. PMID- 26480913 TI - Molecular confirmation of infectious spleen and kidney necrosis virus (ISKNV) in farmed and imported ornamental fish in Australia. AB - Viruses of the genus Megalocytivirus have not been detected in wild populations of fish in Australia but circulate in imported ornamental fish. In 2012, detection of a megalocytivirus in healthy platys Xiphophorus maculatus was reported from a farm in Australia during surveillance testing as part of a research project undertaken at the University of Sydney. Confirmatory testing of the original samples at the AAHL Fish Diseases Laboratory verified the presence of an infectious spleen and kidney necrosis virus (ISKNV)-like virus. Additional sampling at the positive farm confirmed the persistence of the virus in the platys, with 39 of 265 (14.7%) samples testing positive. Comparison of 3 separate gene regions of the virus with those of ISKNV confirmed the detection of a virus indistinguishable from ISKNV. Subsequently, ISKNV was also detected in a range of imported ornamental fish from several countries between 2013 and 2014, by screening with real-time PCR and confirmation by conventional PCR and sequence analysis. Accordingly, the current importation of live ornamental fish acts as a potential perpetual source for the establishment of ISKNV viruses within Australia. The testing of the farmed and imported ornamental fish verified the utility of the probe-based real-time PCR assay for screening of ornamental fish for Megalocytivirus. PMID- 26480914 TI - Immune responses of flounder Paralichthys olivaceus vaccinated by immersion of formalin-inactivated Edwardsiella tarda following hyperosmotic treatment. AB - The aim of the present study was to evaluate the effects of hyperosmotic immersion (HI) vaccination and determine the optimum hyperosmotic salinity for flounder Paralichthys olivaceus by investigating its immune responses following vaccination. Flounder were immersed in 1 of 3 hyperosmotic solutions at 50, 60 and 700/00 salinity, then transferred into 300/00 salinity normal seawater containing formalin-inactivated Edwardsiella tarda for vaccination (3 HI groups), or were immersed in normal seawater as direct immersion (DI group). The results showed that the percentages of surface membrane immunoglobulin-positive (sIg+) cells in peripheral blood leukocytes and spleen leukocytes induced by HI were significantly higher than that with DI (p < 0.05), and the 500/00 salinity group showed the strongest response among the HI groups, which reached peaks at Week 4. ELISA assay showed that the specific serum antibodies gradually increased after vaccination and reached peak at Day 32, and the fish treated with HI showed stronger antibody responses; among the HI groups, a significantly higher specific antibody level was detected in the 500/00 salinity group at Day 32 (p < 0.05). Similarly, the fish treated with HI showed higher specific mucosal antibody levels compared to the DI group, and the mucosal antibody showed a faster response, with peak time arriving 1 wk earlier than for the serum antibody. The relative percent survival (RPS) of flounder treated with HI at 50, 60 and 700/00 salinities were 79, 71 and 57% respectively, while this was 43% in the DI group. These results demonstrated that HI, especially the 500/00 salinity, could efficiently enhance the immune response of flounder and show higher RPS. This has significant value for immunological prevention of edwardsiellosis in flounder. PMID- 26480915 TI - Explained and unexplained tissue loss in corals from the Tropical Eastern Pacific. AB - Coral reefs rival rainforest in biodiversity, but are declining in part because of disease. Tissue loss lesions, a manifestation of disease, are present in dominant Pocillopora along the Pacific coast of Mexico. We characterized tissue loss in 7 species of Pocillopora from 9 locations (44 sites) spanning southern to northern Mexico. Corals were identified to species, and tissue loss lesions were photographed and classified as those explainable by predation and those that were unexplained. A focal predation study was done concurrently at 3 locations to confirm origin of explained lesions. Of 1054 cases of tissue loss in 7 species of corals, 84% were associated with predation (fish, snails, or seastar) and the remainder were unexplained. Types of tissue loss were not related to coral density; however there was significant geographic heterogeneity in type of lesion; one site in particular (Cabo Pulmo) had the highest prevalence of predator-induced tissue loss (mainly pufferfish predation). Crown-of-thorns starfish, pufferfish, and snails were the most common predators and preferred P. verrucosa, P. meandrina, and P. capitata, respectively. Of the 9 locations, 4 had unexplained tissue loss with prevalence ranging from 1 to 3% with no species predilection. Unexplained tissue loss was similar to white syndrome (WS) in morphology, indicating additional study is necessary to clarify the cause(s) of the lesions and the potential impacts to dominant corals along the Pacific coast of Mexico. PMID- 26480916 TI - Proteomic profiling of healthy and diseased hybrid soft corals Sinularia maxima * S. polydactyla. AB - Emerging diseases of marine invertebrates have been implicated as one of the major causes of the continuing decline in coral reefs worldwide. To date, most of the focus on marine diseases has been aimed at hard (scleractinian) corals, which are the main reef builders worldwide. However, soft (alcyonacean) corals are also essential components of tropical reefs, representing food, habitat and the 'glue' that consolidates reefs, and they are subject to the same stressors as hard corals. Sinularia maxima and S. polydactyla are the dominant soft corals on the shallow reefs of Guam, where they hybridize. In addition to both parent species, the hybrid soft coral population in Guam is particularly affected by Sinularia tissue loss disease. Using label-free shotgun proteomics, we identified differences in protein expression between healthy and diseased colonies of the hybrid S. maxima * S. polydactyla. This study provided qualitative and quantitative data on specific proteins that were differentially expressed under the stress of disease. In particular, metabolic proteins were down-regulated, whereas proteins related to stress and to symbiont photosynthesis were up regulated in the diseased soft corals. These results indicate that soft corals are responding to pathogenesis at the level of the proteome, and that this label free approach can be used to identify and quantify protein biomarkers of sub lethal stress in studies of marine disease. PMID- 26480917 TI - Cellulose is not degraded in the tunic of the edible ascidian Halocynthia roretzi contracting soft tunic syndrome. AB - Soft tunic syndrome is a fatal disease in the edible ascidian Halocynthia roretzi, causing serious damage to ascidian aquaculture in Korea and Japan. In diseased individuals, the tunic, an integumentary extracellular matrix of ascidians, softens and eventually tears. This is an infectious disease caused by the kinetoplastid flagellate Azumiobodo hoyamushi. However, the mechanism of tunic softening remains unknown. Because cellulose fibrils are the main component of the tunic, we compared the contents and structures of cellulose in healthy and diseased tunics by means of biochemical quantification and X-ray diffractometry. Unexpectedly, the cellulose contents and structures of cellulose microfibrils were almost the same regardless of the presence or absence of the disease. Therefore, it is unlikely that thinning of the microfibrils occurred in the softened tunic, because digestion should have resulted in decreases in crystallinity index and crystallite size. Moreover, cellulase was not detected in pure cultures of A. hoyamushi in biochemical and expressed sequence tag analyses. These results indicate that cellulose degradation does not occur in the softened tunic. PMID- 26480918 TI - Herpesvirus-like respiratory infection in African penguins Spheniscus demersus admitted to a rehabilitation centre. AB - Rehabilitation is an important strategy for the conservation of the Endangered African penguin Spheniscus demersus, and disease has been raised as a concern in the management of the species, both in the wild and in rehabilitation centres. We report 8 cases of herpesvirus-like respiratory infection in African penguin chicks undergoing rehabilitation between 2010 and 2013 at a facility in Cape Town, South Africa. Infection was confirmed through the identification of viral inclusions in the tracheal epithelium and demonstration of particles consistent with herpesvirus by electron microscopy, whereas virus isolation in eggs, serology and PCR testing failed to detect the virus. Only penguin chicks were affected; they were in poor body condition, and in 2 cases infection occurred prior to admission to the rehabilitation centre. The role played by the herpesvirus-like infection in the overall respiratory disease syndrome is uncertain, due to identification of lesions in only a small proportion of the chicks as well as to the occurrence of other concurrent pathological processes. Further studies are advised to characterise the specific virus involved through the development of sensitive diagnostic methods and to clarify the epidemiology and significance of these infections in wild African penguins. PMID- 26480919 TI - Identification, molecular and phylogenetic analysis of poxvirus in skin lesions of southern right whale. AB - Poxvirus skin disease has been reported in several species of cetaceans, principally in odontocetes, and a single report in mysticetes. Southern right whales Eubalaena australis in Peninsula Valdes, Argentina, show a variety of skin lesions of unknown etiology, and the number of these lesions has increased in recent years. Samples from dead whales were taken in order to establish the etiology of these lesions. One calf and one adult presented ring-type lesions, characterized by a circumscribed and slightly raised area of skin. Lesions were histologically characterized by the presence of microvesicles and vacuolated cells in the stratum spinosum, along with hyperplasia of the stratum corneum and eosinophilic inclusion bodies in the cytoplasm of the epithelial cells. Transmission electron microscopy showed aggregations of virions with typical poxvirus morphology. PCR of cetacean poxvirus (CPV) DNA polymerase, DNA topoisomerase I and parapoxvirus DNA polymerase gene fragments was done, and confirmed the presence of poxvirus in one sample. Phylogenetic analysis showed that the detected poxvirus belongs to the CPV-2 group. This is the first confirmed report of poxvirus in southern right whales in Argentina. PMID- 26480922 TI - Healthcare utilization and costs associated with tyrosine kinase inhibitor switching in patients with chronic myeloid leukemia. AB - Differences in healthcare utilization and costs were examined in chronic myeloid leukemia (CML) patients experiencing first-, second- and third-line tyrosine kinase inhibitor (TKI) therapy. Three CML cohorts were identified from the Truven Health MarketScan(r) database: No-Switch Cohort (NSc) = did not switch from first line; One-Switch Cohort (OSc) = switched from first- to second-line only; Two Switch Cohort (TSc) = switched to second- and then third-line. A total of 3510 patients were identified (mean = 54%; age = 55.8 years). NSc comprised 81% of the sample, OSc comprised 15% and 4% were in the TSc. First-line utilization/costs were significantly higher in the OSc/TSc compared to the NSc. Second-line hospital/outpatient visits and costs were higher in TSc compared to OSc. TSc experienced a significant cost increase from first- to second-line ($4226.46), twice that of OSc ($2488.03). TKI switching is associated with a substantial increase in healthcare utilization and costs, particularly for patients who switch twice. PMID- 26480920 TI - Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat. AB - BACKGROUND: To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT); visceral adipose tissue (VAT); total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR). SUBJECTS AND METHODS: Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT-BMI) or without (TRAIT) adjustment for body mass index (BMI), and cohort-specific results were combined via a fixed effects meta analysis. A total of 2513 subjects of European descent were available for the discovery phase. For replication, 2171 European Americans and 772 African Americans were available. RESULTS: A total of 52 single-nucleotide polymorphisms (SNPs) encompassing 7 loci showed suggestive evidence of association (P<1.0 * 10( 6)) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; P=1.10 * 10(-7)), an association that was replicated (P=0.02). For the BMI adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT-BMI (rs10506943; P=2.42 * 10(-7)). Our sex-specific analyses identified one genome-wide significant (P<5.0 * 10(-8)) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (P=3.97 * 10(-8) to 1.13 * 10(-8)). The THNSL2 gene previously associated with VAT in women was also replicated (P=0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively. CONCLUSIONS: Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women. PMID- 26480923 TI - Spinal cord involvement in Behcet's disease. AB - BACKGROUND: Spinal cord involvement in Behcet's disease is not well studied. OBJECTIVE: To evaluate the clinical, laboratory and magnetic resonance imaging characteristics of spinal cord involvement in Behcet's disease. METHODS: We retrospectively reviewed 10 spinal cord involvements in seven patients with Behcet's disease. RESULTS: The median age of onset for spinal cord involvement was 32 (23-45 years). Two patients showed a secondary progressive course. Cerebrospinal fluid findings revealed mild to moderate pleocytosis and/or elevated protein levels. In eight spinal cord involvements, the lesion was longer than three vertebrae. Serum anti-aquaporin-4 antibody was negative in all four patients tested. CONCLUSIONS: Longitudinally extensive transverse myelitis is a characteristic manifestation of spinal cord involvement in Behcet's disease. PMID- 26480924 TI - Prevalence of neuropathic pain in early multiple sclerosis. AB - BACKGROUND: Pain is considered a frequent symptom in multiple sclerosis. Neuropathic pain is the type of pain most closely related to the pathology of multiple sclerosis and its prevalence estimates vary largely. OBJECTIVE: We prospectively assessed the prevalence of neuropathic pain in patients with early multiple sclerosis and investigated the association of neuropathic pain with other clinical parameters. METHODS: A total of 377 outpatients with multiple sclerosis at an early disease stage were included in this prospective study. Mean disease duration was 4.2 years, mean Expanded Disability Status Scale (EDSS) score was 1.6, 96.8% of patients were classified as having relapsing-remitting multiple sclerosis. Neuropathic pain was assessed using the PainDETECT questionnaire (PDQ). Depression, fatigue and cognition were assessed using the Beck Depression Inventory (BDI), the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Paced Auditory Serial Addition Test. RESULTS: PDQ scores indicative of neuropathic pain were found in 4.2% of patients. Regression analysis revealed EDSS, BDI and FMSC scores as strongest predictors of PDQ scores. CONCLUSIONS: Neuropathic pain appears to be less frequent in early multiple sclerosis than expected and is significantly associated with disability, depression and fatigue. The assessment and therapy of pain in multiple sclerosis should thus take into account neuropsychiatric symptoms already at early disease stages. PMID- 26480926 TI - Impact of Maximum Allowable Cost on CO2 Storage Capacity in Saline Formations. AB - Injecting CO2 into deep saline formations represents an important component of many greenhouse-gas-reduction strategies for the future. A number of authors have posed concern over the thousands of injection wells likely to be needed. However, a more important criterion than the number of wells is whether the total cost of storing the CO2 is market-bearable. Previous studies have sought to determine the number of injection wells required to achieve a specified storage target. Here an alternative methodology is presented whereby we specify a maximum allowable cost (MAC) per ton of CO2 stored, a priori, and determine the corresponding potential operational storage capacity. The methodology takes advantage of an analytical solution for pressure build-up during CO2 injection into a cylindrical saline formation, accounting for two-phase flow, brine evaporation, and salt precipitation around the injection well. The methodology is applied to 375 saline formations from the U.K. Continental Shelf. Parameter uncertainty is propagated using Monte Carlo simulation with 10 000 realizations for each formation. The results show that MAC affects both the magnitude and spatial distribution of potential operational storage capacity on a national scale. Different storage prospects can appear more or less attractive depending on the MAC scenario considered. It is also shown that, under high well-injection rate scenarios with relatively low cost, there is adequate operational storage capacity for the equivalent of 40 years of U.K. CO2 emissions. PMID- 26480921 TI - Physical Activity Is Associated with Attention Capacity in Adolescents. AB - OBJECTIVE: To assess the relationships among physical activity, measured objectively, and attention capacity in European adolescents. STUDY DESIGN: The study included 273 adolescents, aged 12.5-17.5 years, who participated in the Healthy Lifestyle in Europe by Nutrition in Adolescence Study. Participants wore a uniaxial accelerometer for 7 days to measure physical activity. The d2 Test of Attention was administered to assess attention capacity. Multivariate analyses were used to study the association of attention capacity with each measure of physical activity. Receiver operating characteristic analysis was performed to determine thresholds that best discriminate between low and good attention capacity. RESULTS: After controlling for potential confounding variables (age, sex, body mass index, parental educational level, fat mass, aerobic fitness, and center), adolescents' attention capacity test performances were significantly and positively associated with longer time spent in moderate or moderate-to-vigorous physical activity (MVPA) in free-living conditions (P < .05). Receiver operating characteristic curve analyses revealed that the physical activity thresholds that best discriminated between low/good attention capacities were >=41 min.day(-1) for moderate, >=12 min.day(-1) for vigorous, and >=58 min.day(-1) for MVPA. CONCLUSION: These findings suggest that promoting MVPA may be have a beneficial effect on attention capacity, an important component of cognition, in adolescents. PMID- 26480925 TI - Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia. AB - Bilirubin-induced neurologic dysfunction (BIND) and kernicterus has been used to describe moderate to severe neurologic dysfunction observed in children exposed to excessive levels of total serum bilirubin (TSB) during the neonatal period. Here we use a new mouse model that targets deletion of the Ugt1 locus and the Ugt1a1 gene in liver to promote hyperbilirubinemia-induced seizures and central nervous system toxicity. The accumulation of TSB in these mice leads to diffuse yellow coloration of brain tissue and a marked cerebellar hypoplasia that we characterize as kernicterus. Histologic studies of brain tissue demonstrate that the onset of severe neonatal hyperbilirubinemia, characterized by seizures, leads to alterations in myelination and glia reactivity. Kernicterus presents as axonopathy with myelination deficits at different brain regions, including pons, medulla oblongata, and cerebellum. The excessive accumulation of TSB in the early neonatal period (5 days after birth) promotes activation of the myelin basic protein (Mbp) gene with an accelerated loss of MBP that correlates with a lack of myelin sheath formation. These changes were accompanied by increased astroglial and microglial reactivity, possibly as a response to myelination injury. Interestingly, cerebellum was the area most affected, with greater myelination impairment and glia burden, and showing a marked loss of Purkinje cells and reduced arborization of the remaining ones. Thus, kernicterus in this model displays not only axonal damage but also myelination deficits and glial activation in different brain regions that are usually related to the neurologic sequelae observed after severe hyperbilirubinemia. PMID- 26480927 TI - The dollars and sense of economic incentives to modify HIV-related behaviours. PMID- 26480928 TI - ST-Segment Elevation and Fractionated Electrograms in Brugada Syndrome Patients Arise From the Same Structurally Abnormal Subepicardial RVOT Area but Have a Different Mechanism. AB - BACKGROUND: Brugada syndrome (BrS) is characterized by a typical ECG pattern. We aimed to determine the pathophysiologic basis of the ST-segment in the BrS-ECG with data from various epicardial and endocardial right ventricular activation mapping procedures in 6 BrS patients and in 5 non-BrS controls. METHODS AND RESULTS: In 7 patients (2 BrS and 5 controls) with atrial fibrillation, an epicardial 8*6 electrode grid (interelectrode distance 1 mm) was placed epicardially on the right ventricular outflow tract (RVOT) before video-assisted thoracoscopic surgical pulmonary vein isolation. In 2 other BrS patients, endocardial, epicardial RV (CARTO), and body surface mapping was performed. In 2 additional BrS patients, we performed decremental preexcitation of the RVOT before endocardial RV mapping. During video-assisted thoracoscopic surgical pulmonary vein isolation and CARTO mapping, BrS patients (n=4) showed greater activation delay and more fractionated electrograms in the RVOT region than controls. Ajmaline administration increased the region with fractionated electrograms, as well as ST-segment elevation. Preexcitation of the RVOT (n=2) resulted in ECGs that supported the current-to-load mismatch hypothesis for ST segment elevation. Body surface mapping showed that the area with ST-segment elevation anatomically correlated with the area of fractionated electrograms and activation delay at the RVOT epicardium. CONCLUSIONS: ST-segment elevation and epicardial fractionation/conduction delay in BrS patients are most likely related to the same structural subepicardial abnormalities, but the mechanism is different. ST-segment elevation may be caused by current-to-load mismatch, whereas fractionated electrograms and conduction delay are expected to be caused by discontinuous conduction in the same area with abnormal myocardium. PMID- 26480929 TI - Decrement Evoked Potential Mapping: Basis of a Mechanistic Strategy for Ventricular Tachycardia Ablation. AB - BACKGROUND: Substrate-based mapping for ventricular tachycardia (VT) ablation is hampered by its inability to determine critical sites of the VT circuit. We hypothesized that those potentials, which delay with a decremental extrastimulus (decrement evoked potentials or DEEPs), are more likely to colocalize with the diastolic pathways of VT circuits. METHODS AND RESULTS: DEEPs were identified in intraoperative left ventricular maps from 6 patients with ischemic cardiomyopathy (total 9 VTs) and were compared with late potential (LP) and activation maps of the diastolic pathway for each VT. Mathematical modeling was also used to further validate and elucidate the mechanisms of DEEP mapping. All patients demonstrated regions of DEEPs and LPs. The mean endocardial surface area of these potentials was 18+/-4% and 21+/-6%, respectively (P=0.13). The mean sensitivity for identifying the diastolic pathway in VT was 50+/-23% for DEEPs and 36+/-32% for LPs (P=0.31). The mean specificity was 43+/-23% versus 20+/-8% for DEEP and LP mapping, respectively (P=0.031). The electrograms that displayed the greatest decrement in each case had a sensitivity and specificity for the VT isthmus of 29+/-10% and 95+/-1%, respectively. Mathematical modeling studies recapitulated DEEPs at the VT isthmus and demonstrated their role in VT initiation with a critical degree of decrement. CONCLUSIONS: In this preliminary study, DEEP mapping was more specific than LP mapping for identifying the critical targets of VT ablation. The mechanism of DEEPs relates to conduction velocity restitution magnified by zigzag conduction within scar channels. PMID- 26480930 TI - Long-Term Natural History of Adult Wolff-Parkinson-White Syndrome Patients Treated With and Without Catheter Ablation. AB - BACKGROUND: There are a paucity of data about the long-term natural history of adult Wolff-Parkinson-White syndrome (WPW) patients in regard to risk of mortality and atrial fibrillation. We sought to describe the long-term outcomes of WPW patients and ascertain the impact of ablation on the natural history. METHODS AND RESULTS: Three groups of patients were studied: 2 WPW populations (ablation: 872, no ablation: 1461) and a 1:5 control population (n=11 175). Long term mortality and atrial fibrillation rates were determined. The average follow up for the WPW group was 7.9+/-5.9 (median: 6.9) years and was similar between the ablation and nonablation groups. Death rates were similar between the WPW group versus the control group (hazard ratio, 0.96; 95% confidence interval, 0.83 1.11; P=0.56). Nonablated WPW patients had a higher long-term death risk compared with ablated WPW patients (hazard ratio, 2.10; 95% confidence interval: 1.50 20.93; P<0.0001). Incident atrial fibrillation risk was higher in the WPW group compared with the control population (hazard ratio, 1.55; 95% confidence interval, 1.29-1.87; P<0.0001). Nonablated WPW patients had lower risk than ablated patients (hazard ratio, 0.39; 95% confidence interval, 0.28-0.53; P<0.0001). CONCLUSIONS: Long-term mortality rates in WPW patients are low and similar to an age-matched and gender-matched control population. WPW patients that underwent the multifactorial process of ablation had a lower mortality compared to nonablated WPW patients. Atrial fibrillation rates are high long term, and ablation does not reduce this risk. PMID- 26480931 TI - High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. AB - This study compared the efficacy and safety of high-dose dexamethasone (HD-DXM) and conventional prednisone (PDN) on the largest cohort to date as first-line strategies for newly diagnosed adult primary immune thrombocytopenia (ITP). Patients enrolled were randomized to receive DXM 40 mg/d for 4 days (n = 95, nonresponders received an additional 4-day course of DXM) or prednisone 1.0 mg/kg daily for 4 weeks and then tapered (n = 97). One or 2 courses of HD-DXM resulted in a higher incidence of overall initial response (82.1% vs 67.4%, P = .044) and complete response (50.5% vs 26.8%, P = .001) compared with prednisone. Time to response was shorter in the HD-DXM arm (P < .001), and a baseline bleeding score >=8 was associated with a decreased likelihood of initial response. Sustained response was achieved by 40.0% of patients in the HD-DXM arm and 41.2% in the PDN arm (P = .884). Initial complete response was a positive indicator of sustained response, whereas presence of antiplatelet autoantibodies was a negative indicator. HD-DXM was generally tolerated better. We concluded that HD-DXM could be a preferred corticosteroid strategy for first-line management of adult primary ITP. This study is registered at www.clinicaltrials.gov as #NCT01356511. PMID- 26480932 TI - Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells. AB - Autologous hematopoietic stem cell transplantation (HSCT) is increasingly considered for patients with severe autoimmune diseases whose prognosis is poor with standard treatments. Regulatory T cells (Tregs) are thought to be important for disease remission after HSCT. However, eliciting the role of donor and host Tregs in autologous HSCT is not possible in humans due to the autologous nature of the intervention. Therefore, we investigated their role during immune reconstitution and re-establishment of immune tolerance and their therapeutic potential following congenic bone marrow transplantation (BMT) in a proteoglycan induced arthritis (PGIA) mouse model. In addition, we determined Treg T-cell receptor (TCR) CDR3 diversity before and after HSCT in patients with juvenile idiopathic arthritis and juvenile dermatomyositis. In the PGIA BMT model, after an initial predominance of host Tregs, graft-derived Tregs started dominating and displayed a more stable phenotype with better suppressive capacity. Patient samples revealed a striking lack of diversity of the Treg repertoire before HSCT. This ameliorated after HSCT, confirming reset of the Treg compartment following HSCT. In the mouse model, a therapeutic approach was initiated by infusing extra Foxp3(GFP+) Tregs during BMT. Infusion of Foxp3(GFP+) Tregs did not elicit additional clinical improvement but conversely delayed reconstitution of the graft-derived T-cell compartment. These data indicate that HSCT-mediated amelioration of autoimmune disease involves renewal of the Treg pool. In addition, infusion of extra Tregs during BMT results in a delayed reconstitution of T-cell compartments. Therefore, Treg therapy may hamper development of long term tolerance and should be approached with caution in the clinical autologous setting. PMID- 26480933 TI - Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. AB - This long-term follow-up analysis evaluated overall survival (OS) and relapse free survival (RFS) in a phase 2 study of the bispecific T-cell engager antibody construct blinatumomab in 36 adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). In the primary analysis, 25 (69%) patients with relapsed/refractory ALL achieved complete remission with full (CR) or partial (CRh) hematologic recovery of peripheral blood counts within the first 2 cycles. Twenty-five patients (69%) had a minimal residual disease (MRD) response (<10(-4) blasts), including 22 CR/CRh responders, 2 patients with hypocellular bone marrow, and 1 patient with normocellular bone marrow but low peripheral counts. Ten of the 36 patients (28%) were long-term survivors (OS >=30 months). Median OS was 13.0 months (median follow-up, 32.6 months). MRD response was associated with significantly longer OS (Mantel-Byar P = .009). All 10 long-term survivors had an MRD response. Median RFS was 8.8 months (median follow-up, 28.9 months). A plateau for RFS was reached after ~18 months. Six of the 10 long-term survivors remained relapse-free, including 4 who received allogeneic stem cell transplantation (allo-SCT) as consolidation for blinatumomab and 2 who received 3 additional cycles of blinatumomab instead of allo-SCT. Three long-term survivors had neurologic events or cytokine release syndrome, resulting in temporary blinatumomab discontinuation; all restarted blinatumomab successfully. Long-term survivors had more pronounced T-cell expansion than patients with OS <30 months. PMID- 26480935 TI - A novel approach to promote motivation to change in the treatment of anorexia nervosa using visualisation and imagery. PMID- 26480934 TI - Antipsychotic medication side effect assessment tools: A systematic review. AB - OBJECTIVE: The aim of this systematic review was to critically appraise the psychometric properties of antipsychotic medication side effect assessment tools. METHODS: Systematic searches were undertaken in PubMed, CINAHL and CENTRAL from inception to October 2014. Studies were included if they detailed the evaluation of psychometric properties of antipsychotic medication side effect assessment tools in mental health populations. Studies were excluded if they examined the use of antipsychotic medication side effect assessment tools in non-mental health populations, including people suffering from dementia, Parkinsonism and Alzheimer's. Narrative reviews and studies published in any language other than English were also excluded. RESULTS: Content validity was appropriately established for only one of the tools, reliability was inappropriately evaluated for all but one tool, and the assessment of responsiveness was not acceptable for any tool. CONCLUSION: Further psychometric studies are warranted to consolidate the psychometric properties of the included antipsychotic medication side effect assessment tools before any of these tools can be confidently recommended for either research or clinical purposes. PMID- 26480936 TI - Deep brain stimulation in depression. PMID- 26480937 TI - Comorbid bipolar disorder and obsessive-compulsive disorder in children and adolescents: Treatment implications. PMID- 26480938 TI - HOPE-trial: hemiarthroplasty compared to total hip arthroplasty for displaced femoral neck fractures in the elderly-elderly, a randomized controlled trial. AB - BACKGROUND: A femoral neck fracture (FNF) is a common cause of suffering and premature death in the elderly population. Optimizing the treatment for improved outcome and a reduced need for secondary surgery is important both for the patient and the society. The choice of primary total or hemiarthroplasty in patients over eighty years are controversial. We hypothesized that total hip arthroplasty has an equal or better outcome in patient-reported outcome compared with hemiarthroplasty. METHODS/DESIGN: A prospective, randomized, single-blinded trial will be conducted. We will include 120 patients, 80 years of age and over with an acute (<36 h) displaced femoral neck fracture. The patients will be randomized in a 1:1 ratio to either total hip arthroplasty or hemiarthroplasty. The primary endpoints are Harris hip Score and EQ-5D. Secondary endpoints include pain measured with visual analogue scale, surgical time, reoperations, complications and radiological measurement of erosion in patients operated with hemiarthroplasty. Follow-up will be performed postoperatively after three months, 1, 2, 4 and 10 years. DISCUSSION: To our knowledge, this is the first randomized controlled trial comparing total hip arthroplasty and hemiarthroplasty for displaced femoral neck fracture in patients age 80 years and over. TRIAL REGISTRATION: Clinicaltrial.gov: NCT02246335. PMID- 26480940 TI - Preservation of fertility and subsequent childbirth after methotrexate treatment of placenta percreta: a case report. AB - INTRODUCTION: Placenta percreta is associated with maternal morbidity and mortality. A hysterectomy is often needed to control the bleeding in such cases. However, it has been advocated that placenta percreta be managed conservatively to avoid massive pelvic bleeding and to preserve the patient's fertility. Here, we present a case of placenta percreta diagnosed by magnetic resonance imaging, and treated with systemic administration of methotrexate. CASE PRESENTATION: A 27 year-old nulliparous Japanese woman at 39 gestational weeks had an uncomplicated vaginal delivery of a 3244-g infant. However, her placenta was not delivered, and we could not remove it manually. Contrast-enhanced magnetic resonance imaging indicated deep myometrial invasion by placental tissue and the whole placenta was strongly enhanced. Seven days post-partum, her serum human chorionic gonadotropin level was 12,656IU/L. Our patient hoped to preserve her uterus for a future pregnancy. She therefore received 13 courses of methotrexate (50mg/week, intravenous injection). Her serum human chorionic gonadotropin level was undetectable 97 days after the first methotrexate injection. At 117 days post partum, she had a labor-like pain every three minutes and delivered the placenta. Our patient regained normal menses and at follow-up remained in good health. Two years later, she delivered a healthy daughter. CONCLUSION: We should try to detect placenta percreta in high-risk patients by any means. For low-risk patients, we should give a diagnosis swiftly and control any intrauterine infection and massive bleeding. PMID- 26480941 TI - Accuracy of an HRP-2/panLDH rapid diagnostic test to detect peripheral and placental Plasmodium falciparum infection in Papua New Guinean women with anaemia or suspected malaria. AB - BACKGROUND: The diagnosis of malaria during pregnancy is complicated by placental sequestration, asymptomatic infection, and low-density peripheral parasitaemia. Where intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine is threatened by drug resistance, or is inappropriate due to low transmission, intermittent screening and treatment (ISTp) with rapid diagnostic tests for malaria (RDT) could be a valuable alternative. Therefore, the accuracy of RDTs to detect peripheral and placental infection was assessed in a declining transmission setting in Papua New Guinea (PNG). METHODS: The performance of a combination RDT detecting histidine-rich protein-2 (HRP-2) and Plasmodium lactate dehydrogenase (pLDH), and light microscopy (LM), to diagnose peripheral Plasmodium falciparum and Plasmodium vivax infections during pregnancy, were assessed using quantitative real-time PCR (qPCR) as the reference standard. Participants in a malaria prevention trial in PNG with a haemoglobin <=90 g/L, or symptoms suggestive of malaria, were tested. Ability of RDT and LM to detect active placental infection on histology was evaluated in some participants. RESULTS: Among 876 women, 1162 RDTs were undertaken (anaemia: 854 [73.5 %], suspected malaria: 308 [26.5 %]). qPCR detected peripheral infection during 190 RDT episodes (165 P. falciparum, 19 P. vivax, 6 mixed infections). Overall, RDT detected peripheral P. falciparum infection with 45.6 % sensitivity (95 % CI 38.0 53.4), a specificity of 96.4 % (95.0-97.4), a positive predictive value of 68.4 % (59.1-76.8), and a negative predictive value of 91.1 % (89.2-92.8). RDT performance to detect P. falciparum was inferior to LM, more so amongst anaemic women (18.6 vs 45.3 % sensitivity, Liddell's exact test, P < 0.001) compared to symptomatic women (72.9 vs 82.4 % sensitivity, P = 0.077). RDT and LM missed 88.0 % (22/25) and 76.0 % (19/25) of P. vivax infections, respectively. In a subset of women tested at delivery and who had placental histology (n = 158) active placental infection was present in 19.6 %: all three peripheral blood infection detection methods (RDT, LM, qPCR) missed >50 % of these infections. CONCLUSIONS: In PNG, HRP-2/pLDH RDTs may be useful to diagnose peripheral P. falciparum infections in symptomatic pregnant women. However, they are not sufficiently sensitive for use in intermittent screening amongst asymptomatic (anaemic) women. These findings have implications for the management of malaria in pregnancy. The adverse impact of infections undetected by RDT or LM on pregnancy outcomes needs further evaluation. PMID- 26480942 TI - The role of communication in breast cancer screening: a qualitative study with Australian experts. AB - BACKGROUND: One well-accepted strategy for optimising outcomes in mammographic breast cancer screening is to improve communication with women about screening. It is not always clear, however, what it is that communication should be expected to achieve, and why or how this is so. We investigated Australian experts' opinions on breast screening communication. Our research questions were: 1 What are the views of Australian experts about communicating with consumers on breast screening? 2 How do experts reason about this topic? METHODS: We used a qualitative methodology, interviewing 33 breast screening experts across Australia with recognisable influence in the Australian mammographic breast cancer screening setting. We used purposive and theoretical sampling to identify experts from different professional roles (including clinicians, program managers, policy makers, advocates and researchers) with a range of opinions about communication in breast screening. RESULTS: Experts discussed the topic of communication with consumers by focusing on two main questions: how strongly to guide consumers' breast cancer screening choices, and what to communicate about overdiagnosis. Each expert adopted one of three approaches to consumer communication depending on their views about these topics. We labelled these approaches: Be screened; Be screened and here's why; Screening is available please consider whether it's right for you. There was a similar level of support for all three approaches. Experts' reasoning was grounded in how they conceived of and prioritised their underlying values including: delivering benefits, avoiding harms, delivering more benefits than harms, respecting autonomy and transparency. CONCLUSIONS: There is disagreement between experts regarding communication with breast screening consumers. Our study provides some insights into this persisting lack of consensus, highlighting the different meanings that experts give to values, and different ways that values are prioritised. We suggest that explicit discussion about ethical values might help to focus thinking, clarify concepts and promote consensus in policy around communication with consumers. More specifically, we suggest that decision-makers who are considering policy on screening communication should begin with identifying and agreeing on the specific values to be prioritised and use this to guide them in establishing what the communication aims will be and which communication strategy will achieve those aims. PMID- 26480943 TI - A comprehensive mapping of the structure and gene organisation in the sheep MHC class I region. AB - BACKGROUND: The major histocompatibility complex (MHC) is a chromosomal region that regulates immune responsiveness in vertebrates. This region is one of the most important for disease resistance because it has been associated with resistance or susceptibility to a wide variety of diseases and because the MHC often accounts for more of the variance than other loci. Selective breeding for disease resistance is becoming increasingly common in livestock industries, and it is important to determine how this will influence MHC polymorphism and resistance to diseases that are not targeted for selection. However, in sheep the order and sequence of the protein coding genes is controversial. Yet this information is needed to determine precisely how the MHC influences resistance and susceptibility to disease. METHODS: CHORI bacterial artificial chromosomes (BACs) known to contain sequences from the sheep MHC class I region were sub cloned, and the clones partially sequenced. The resulting sequences were analysed and re-assembled to identify gene content and organisation within each BAC. The low resolution MHC class I physical map was then compared to the cattle reference genome, the Chinese Merino sheep MHC map published by Gao, et al. (2010) and the recently available sheep reference genome. RESULTS: Immune related class I genes are clustered into 3 blocks; beta, kappa and a novel block not previously identified in other organisms. The revised map is more similar to Bovidae maps than the previous sheep maps and also includes several genes previously not annotated in the Chinese Merino BAC assembly and others not currently annotated in the sheep reference chromosome 20. In particular, the organisation of nonclassical MHC class I genes is similar to that present in the cattle MHC. Sequence analysis and prediction of amino acid sequences of MHC class I classical and nonclassical genes was performed and it was observed that the map contained one classical and eight nonclassical genes together with three possible pseudogenes. CONCLUSIONS: The comprehensive physical map of the sheep MHC class I region enhances our understanding of the genetic architecture of the class I MHC region in sheep and will facilitate future studies of MHC function. PMID- 26480944 TI - The frequency of osteolytic bone metastasis is determined by conditions of the soil, not the number of seeds; evidence from in vivo models of breast and prostate cancer. AB - BACKGROUND: While both preclinical and clinical studies suggest that the frequency of growing skeletal metastases is elevated in individuals with higher bone turnover, it is unclear whether this is a result of increased numbers of tumour cells arriving in active sites or of higher numbers of tumour cells being induced to divide by the bone micro-environment. Here we have investigated how the differences in bone turnover affect seeding of tumour cells and/or development of overt osteolytic bone metastasis using in vivo models of hormone independent breast and prostate cancer. METHODS: Cohorts of 6 (young) and 16 (mature)-week old BALB/c nude mice were culled 1, 7 and 21 days after received intracardiac injection of luciferase expressing human prostate (PC3) or breast cancer (MDA-MB-231) cell lines labelled with a fluorescent cell membrane dye (Vybrant DiD). The presence of growing bone metastases was determined by bioluminescence using an in vivo imaging system (IVIS) and followed by anatomical confirmation of tumour metastatic sites post mortem, while the presence of individual fluorescently labelled tumour cells was evaluated using two-photon microscopy ex vivo. The bone remodelling activities were compared between young and mature naive mice (both male and female) using micro-CT analysis, ELISA and bone histomorphometry. RESULTS: Both prostate and breast cancer cells generated higher numbers of overt skeletal lesions in young mice (~80%) than in mature mice (~20%). Although mature mice presented with fewer overt bone metastases, the number of tumour cells arriving/colonizing in the tibias was comparable between young and mature animals. Young naive mice had lower bone volume but higher bone formation and resorption activities compared to mature animals. CONCLUSIONS: Our studies suggest that higher frequencies of growing osteolytic skeletal metastases in these models are linked to increased bone turnover and not to the initial number of tumour cells entering the bone microenvironment. PMID- 26480945 TI - Messenger RNA exchange between scions and rootstocks in grafted grapevines. AB - BACKGROUND: Grafting has been widely practiced for centuries in the propagation and production of many vegetable and fruit species. However, the underlying molecular and genetic mechanisms for how the graft partners interact with each other to produce a successful graft remain largely unknown. We hypothesized that genome-wide mRNA exchanges, which were recently documented in grafted model plant species, are a general phenomenon widely present in grafted plants, including those in vegetable and fruit species, and have specific genotype- and environment dependent characteristics modulating plant performance. METHODS: Using diagnostic SNPs derived from high throughput genome sequencing, we identified and characterized the patterns of genome-wide mRNA exchanges across graft junctions in grafted grapevines grown in the in vitro and field conditions. RESULTS: We identified more than 3000 genes transporting mRNAs across graft junctions. These genes were involved in diverse biological processes and those involved in basic cellular, biosynthetic, catabolic, and metabolic activities, as well as responses to stress and signal transduction, were highly enriched. Field-grown mature grafts had much fewer genes transmitting mRNAs than the in vitro young grafts (987 vs. 2679). These mobile mRNAs could move directionally or bi-directionally between scions and rootstocks. The mRNA transmission rates of these genes were generally low, with 65% or more having transmission rates lower than 0.01. Furthermore, genotypes, graft combinations and growth environments had impact on the directions of mRNA movement as well as the numbers and species of mRNAs being exchanged. Moreover, we found evidence for the presences of both passive and selective mechanisms underlying long distance mRNA trafficking in grafted grapevines. CONCLUSIONS: We extended the studies of mRNA exchanges in model species to grapevines and demonstrated that genomic-scale mRNA exchange across graft junctions occurred in grapevines in a passive or genotype and environment dependent manner. PMID- 26480946 TI - Age trajectories of everyday cognition in African American and White older adults under prompted and unprompted conditions. AB - We investigated how race and verbal prompting interacted with age to predict age trajectories on a performance-based measure of everyday cognition. African American (n = 727) and White (n = 2052) older adults from the ACTIVE clinical trial were given the Observed Tasks of Daily Living (OTDL; a performance-based measure of medication management/finances/telephone use) at baseline and 1-, 2-, 3-, 5-, and 10-year follow-ups. When participants said "I don't know" or did not respond, they received a standardised verbal prompt, which served only as a cue to initiate the first step. At each occasion, unprompted (sum of items correct without prompting) and prompted (sum of correct prompted and unprompted items) scores were derived for each participant. Mixed effects models for change were used to determine the age trajectories of OTDL performance by race. When not prompted, African Americans demonstrated more rapid decline in OTDL performance than Whites, especially after age 80. When prompted, both groups had improved performance and evinced shallower decline, although African Americans continued to demonstrate a slightly more rapid decline. Simple prompting attenuated age related changes of African Americans and Whites on a measure of everyday cognition. Prompting may be especially helpful for older African Americans. PMID- 26480947 TI - Ranibizumab versus bevacizumab for the treatment of idiopathic choroidal neovascularization: 2-Year results. AB - PURPOSE: To compare the efficacy and safety of bevacizumab vs ranibizumab for the treatment of idiopathic choroidal neovascularization (ICNV). METHODS: This retrospective study included 60 eyes of 60 patients with ICNV who underwent intravitreal injection of bevacizumab (1.25 mg/0.05 mL, n = 30 eyes) or ranibizumab (0.5 mg/0.05 mL, n = 30 eyes). Multiple treatments were based on complete ophthalmologic investigation including slit-lamp biomicroscopy, fundus examination, fundus fluorescein angiography (FFA), optical coherence tomography (OCT), and best-corrected visual acuity (BCVA). The BCVA, central retinal thickness (CRT), intraocular pressure (IOP), FFA results, and complications were compared between the 2 groups during the 2-year follow-up. RESULTS: Visual acuity was significantly better at 1, 3, 6, 12, and 24 months after treatment (p<0.01), with no significant difference in visual acuity between the bevacizumab and ranibizumab groups. In both groups of patients, the CRT after treatment was significantly less than before. At 12 and 24 months, the CRT in the ranibizumab group was significantly less than in the bevacizumab group (p<0.05). The FFA examination showed that CNV was reduced after intravitreal injection of either drug, with no significant difference in IOP between the 2 groups. No ophthalmologic or systemic complications occurred. CONCLUSIONS: Bevacizumab and ranibizumab are effective and safe in the treatment of ICNV, with similar effects in improving visual acuity and reducing retinal edema. The long-term efficacy of ranibizumab is superior to bevacizumab in reducing CRT. PMID- 26480948 TI - Reasons for visits to an emergency center and hemostatic alterations in patients with recurrent spontaneous subconjunctival hemorrhage. AB - PURPOSE: To evaluate causes of visits to the Eye Emergency Department, determine the prevalence of subconjunctival hemorrhage (SCH), and assess the role of hemostatic abnormalities among patients with spontaneous recurrent SCH (SRSCH). METHODS: In a prospective study conducted over 2 years, hemostatic function was studied in a subgroup of 105 consecutive patients (39 male) with SRSCH free of systemic risk factors and in 53 age- and sex-matched healthy controls (HC) (24 male). RESULTS: A total of 10,090 patients (mean age 57.2 +/- 16.7 years, range 0 94, median 58.4) were evaluated. A total of 39.3% had ocular trauma, 34.9% inflammatory ocular surface disorder, 5.7% floaters, 3.3% visual symptoms of neurologic origin, 1.6% uveitis, 1.5% ocular hypertension, 0.8% retinal tear or detachment, 0.7% retinal vascular disease, and 0.5% other causes. A total of 1.6% of the patients were hospitalized. A total of 11.7% of patients had SCH: in 86.7% it was spontaneous, in 13.3% consequent to trauma or to ocular surface disorders. A total of 105 patients had SRSCH, and the prevalence of hemostatic abnormalities among them was not different from HC. Type I von Willebrand disease was diagnosed in 1 patient with SCH and in none of the HC (chi2 = 0.13, p = 0.72). CONCLUSIONS: Most patients had ocular infection or trauma and were treated on an outpatient basis; SCH was the third cause of access. The large majority of SCH were unprovoked, and the prevalence of hemostatic alterations in patients with SRSCH and no systemic causes was not different from the general population. Hemostatic screening or second level blood clotting tests were of no use in these patients. PMID- 26480949 TI - Thioredoxin interacting protein expression in the urinary sediment associates with renal function decline in type 1 diabetes. AB - AIMS: Thioredoxin interacting protein (TXNIP), an inhibitor of antioxidant thioredoxin (Trx), is upregulated by hyperglycemia and implicated in pathogenesis of diabetes complications. We evaluated mRNA expressions of genes encoding TXNIP and Trx (TXN) in urinary sediment and peripheral blood mononuclear cells (PBMC) of type 1 diabetes (T1D) patients with different degrees of chronic complications. METHODS: qPCR was employed to quantify target genes in urinary sediment (n = 55) and PBMC (n = 161) from patients sorted by presence or absence of diabetic nephropathy (DN), retinopathy, peripheral and cardiovascular neuropathy; 26 healthy controls and 13 patients presenting non-diabetic nephropathy (focal and segmental glomerulosclerosis, FSGS) were also included. RESULTS: Regarding the urinary sediment, TXNIP (but not TXN) expression was higher in T1D (p = 0.0023) and FSGS (p = 0.0027) patients versus controls. Expressions of TXNIP and TXN were higher, respectively, in T1D patients with versus without DN (p = 0.032) and in those with estimated glomerular filtration rate (eGFR) < 60 versus >=60 mL/min/1.73 m(2) (p = 0.008). eGFR negatively correlated with TXNIP (p = 0.04, r = -0.28) and TXN (p = 0.04, r = -0.30) expressions. T1D patients who lost >=5 mL/min/1.73 m(2) yearly of eGFR presented higher basal TXNIP expression than those who lost <5 mL/min/1.73 m(2) yearly after median follow-up of 24 months. TXNIP (p < 0.0001) and TXN (p = 0.002) expressions in PBMC of T1D patients were significantly higher than in controls but no differences were observed between patients with or without chronic complications. CONCLUSIONS: TXNIP and TXN are upregulated in urinary sediment of T1D patients with diabetic kidney disease (DKD), but only TXNIP expression is associated with magnitude of eGFR decline. PMID- 26480950 TI - Cornelia de Lange syndrome: specific features for prenatal diagnosis. PMID- 26480951 TI - Downfall of the current antibody correlates of influenza vaccine response in yearly vaccinated subjects: Toward qualitative rather than quantitative assays. AB - Response to seasonal influenza vaccination is currently evaluated by antibody correlates that estimate vaccine seroconversion as well as immune protection. These correlates rely on the general dogmas surrounding seasonal influenza vaccination; that is, that vaccine-induced antibodies would exclusively generate immunity to influenza vaccine strains and that protective immunity would wane before the next season. Here, we summarize recently reported data on immunity to seasonal influenza in healthy individuals and rediscuss results on yearly vaccinated pediatric immunocompromised patients that together highlight the need for revision of the current correlates of vaccine response to shift from quantitative to qualitative measurements. PMID- 26480952 TI - TaGS5-3A, a grain size gene selected during wheat improvement for larger kernel and yield. AB - Grain size is a dominant component of grain weight in cereals. Earlier studies have shown that OsGS5 plays a major role in regulating both grain size and weight in rice via promotion of cell division. In this study, we isolated TaGS5 homoeologues in wheat and mapped them on chromosomes 3A, 3B and 3D. Temporal and spatial expression analysis showed that TaGS5 homoeologues were preferentially expressed in young spikes and developing grains. Two alleles of TaGS5-3A, TaGS5 3A-T and TaGS5-3A-G were identified in wheat accessions, and a functional marker was developed to discriminate them. Association analysis revealed that TaGS5-3A-T was significantly correlated with larger grain size and higher thousand kernel weight. Biochemical assays showed that TaGS5-3A-T possesses a higher enzymatic activity than TaGS5-3A-G. Transgenic rice lines overexpressing TaGS5-3A-T also exhibited larger grain size and higher thousand kernel weight than TaGS5-3A-G lines, and the transcript levels of cell cycle-related genes in TaGS5-3A-T lines were higher than those in TaGS5-3A-G lines. Furthermore, systematic evolution analysis in diploid, tetraploid and hexaploid wheat showed that TaGS5-3A underwent strong artificial selection during wheat polyploidization events and the frequency changes of two alleles demonstrated that TaGS5-3A-T was favoured in global modern wheat cultivars. These results suggest that TaGS5-3A is a positive regulator of grain size and its favoured allele TaGS5-3A-T exhibits a larger potential application in wheat high-yield breeding. PMID- 26480953 TI - Enantioselective Addition of a 2-Alkoxycarbonyl-1,3-dithiane to Imines Catalyzed by a Bis(guanidino)iminophosphorane Organosuperbase. AB - A chiral bis(guanidino)iminophosphorane catalyzes enantioselective addition reactions of a 1,3-dithiane derivative as a pronucleophile. The chiral uncharged organosuperbase facilitates the addition of benzyloxycarbonyl-1,3-dithiane to aromatic N-Boc-protected imines to provide optically active alpha-amino-1,3 dithiane derivatives, which are valuable versatile building blocks in organic synthesis. PMID- 26480954 TI - The challenge of using experimental infectivity data in risk assessment for Ebola virus: why ecology may be important. AB - Analysis of published data shows that experimental passaging of Zaire ebolavirus (EBOV) in guinea pigs changes the risk of infection per plaque-forming unit (PFU), increasing infectivity to some species while decreasing infectivity to others. Thus, a PFU of monkey-adapted EBOV is 10(7) -fold more lethal to mice than a PFU adapted to guinea pigs. The first conclusion is that the infectivity of EBOV to humans may depend on the identity of the donor species itself and, on the basis of limited epidemiological data, the question is raised as to whether bat-adapted EBOV is less infectious to humans than nonhuman primate (NHP)-adapted EBOV. Wildlife species such as bats, duikers and NHPs are naturally infected by EBOV through different species giving rise to EBOV with different wildlife species-passage histories (heritages). Based on the ecology of these wildlife species, three broad 'types' of EBOV-infected bushmeat are postulated reflecting differences in the number of passages within a given species, and hence the degree of adaptation of the EBOV present. The second conclusion is that the prior species-transmission chain may affect the infectivity to humans per PFU for EBOV from individuals of the same species. This is supported by the finding that the related Marburg marburgvirus requires ten passages in mice to fully adapt. It is even possible that the evolutionary trajectory of EBOV could vary in individuals of the same species giving rise to variants which are more or less virulent to humans and that the probability of a given trajectory is related to the heritage. Overall the ecology of the donor species (e.g. dog or bushmeat species) at the level of the individual animal itself may determine the risk of infection per PFU to humans reflecting the heritage of the virus and may contribute to the sporadic nature of EBOV outbreaks. PMID- 26480955 TI - An ion-pairing, reversed-phase liquid chromatography method to assess the cross contamination of cancer chemotherapy infusions prepared in a dual-operator aseptic isolator. AB - Cytotoxics are usually prepared in a centralized pharmacy unit in a controlled hospital environment. Despite the rigorous operating procedures used for such preparations, contamination is theoretically possible - for example due to vial switches. Therefore products ought to be checked in order to determine whether quality control measures are adequate. Numerous strategies have been applied locally to ensure the safety of both patients and operators but the efficacy of these methodologies has not previously been examined. The aim of this study was to develop an analytical method sensitive enough to detect traces of anti-cancer drugs, in order to evaluate cross-contamination between infusions prepared in a dual-operator isolator in the dedicated pharmacy unit. We developed a high performance liquid chromatography (HPLC) method with ultraviolet (UV) detection to identify and quantify the following seven drugs: 5-Fluorouracil, Cytarabine, Gemcitabine, Irinotecan, Doxorubicin, Epirubicin, and Daunorubicin. We assessed the levels of cross-contamination in 20 random preparations. We achieved separation of the seven drugs in less than 28 min, with a lower limit of quantification capable of detecting cross-contamination. An assessment of 20 preparations revealed no cross-contamination. We developed a reproducible and sensitive HPLC method which could be a potentially useful tool for use in practice. We checked the level of cross-contamination in anti-cancer drug infusions and confirmed that the process in current use was safe. This study is the first to assess cross-contamination in anti-cancer preparations. This work is the first step in an extensive programme of quality control, whose aim is to ensure the safety of both patients and operators. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY FINDINGS: Development of a reproducible and sensitive HPLC method capable of detecting seven anticancer drugs. This method could be used alongside MS detection, to check for biological contamination of nursing and pharmacy staff with anticancer drugs. No cross-contamination was detected in cancer chemotherapy infusions prepared in a dual-operator aseptic isolator. PMID- 26480956 TI - Effects of amino acid starvation on RelA diffusive behavior in live Escherichia coli. AB - During amino acid starvation, bacterial cells rapidly synthesize the nucleotides (p)ppGpp, causing a massive re-programming of the transcriptional profile known as the stringent response. The (p)ppGpp synthase RelA is activated by ribosomes harboring an uncharged tRNA at the A site. It is unclear whether synthesis occurs while RelA is bound to the ribosome or free in the cytoplasm. We present a study of three Escherichia coli strains, each expressing a different RelA-fluorescent protein (RelA-FP) construct: RelA-YFP, RelA-mEos2 and RelA-Dendra2. Single molecule localization and tracking studies were carried out under normal growth conditions and during amino acid starvation. Study of three labeling schemes enabled us to assess potential problems with FP labeling of RelA. The diffusive trajectories and axial spatial distributions indicate that amino acid starvation induces net binding of all three RelA-FP constructs to 70S ribosomes. The data are most consistent with a model in which RelA synthesizes (p)ppGpp while bound to the 70S ribosome. We suggest a 'short hopping time' model of RelA activity during starvation. Our results contradict an earlier study of RelA-Dendra2 diffusion that inferred off-ribosome synthesis of (p)ppGpp. The reasons for the discrepancy remain unclear. PMID- 26480957 TI - Association of tocilizumab treatment with changes in measures of regional left ventricular function in rheumatoid arthritis, as assessed by cardiac magnetic resonance imaging. AB - OBJECTIVE: The goal of this study was to determine whether the powerful anti inflammatory effect of anti-interleukin-6 with tocilizumab (TCZ) might lead to a reduction in left ventricular (LV) dysfunction in patients with rheumatoid arthritis (RA). METHODS: Consecutive RA patients with active disease and healthy control subjects without a clinical diagnosis of cardiovascular disease were enrolled. The RA patients each had inadequate clinical response to non-biologic disease-modifying anti-rheumatic drugs and were prescribed TCZ therapy. All subjects underwent baseline evaluation of LV function, as measured by cardiac magnetic resonance imaging (CMRI). Peak systolic regional radial strain (Err, %) was calculated by feature tracking of cine CMRI. After baseline (BL) CMRI measurements, treatment with TCZ was initiated, and patients were followed for 52 weeks. We compared peak Err of RA patients at BL and at 52 weeks. RESULTS: Thirteen RA patients (mean age 52.6 +/- 5.4 years) were assessed at BL and at 52 weeks, and these patients were compared with 10 non-RA controls (mean age 55.7 +/ 4.6 years). Disease Activity Score of 28 joints - erythrocyte sedimentation rate and Simple Disease Activity Index were significantly lower in RA patients at 52 weeks than at BL. Mean peak Err at BL in RA patients was significantly lower than in normal subjects (P = 0.03). Mean peak Err was significantly higher at 52 weeks than at BL (P = 0.028) in RA patients. CONCLUSION: We showed that TCZ was associated with left ventricular dysfunction in RA patients which correlated with a reduction in RA disease activity. PMID- 26480958 TI - Language Experience Affects Grouping of Musical Instrument Sounds. AB - Language experience clearly affects the perception of speech, but little is known about whether these differences in perception extend to non-speech sounds. In this study, we investigated rhythmic perception of non-linguistic sounds in speakers of French and German using a grouping task, in which complexity (variability in sounds, presence of pauses) was manipulated. In this task, participants grouped sequences of auditory chimeras formed from musical instruments. These chimeras mimic the complexity of speech without being speech. We found that, while showing the same overall grouping preferences, the German speakers showed stronger biases than the French speakers in grouping complex sequences. Sound variability reduced all participants' biases, resulting in the French group showing no grouping preference for the most variable sequences, though this reduction was attenuated by musical experience. In sum, this study demonstrates that linguistic experience, musical experience, and complexity affect rhythmic grouping of non-linguistic sounds and suggests that experience with acoustic cues in a meaningful context (language or music) is necessary for developing a robust grouping preference that survives acoustic variability. PMID- 26480959 TI - Induction of neurite outgrowth in 3D hydrogel-based environments. AB - The ability of peripheral nervous system (PNS) axons to regenerate and re innervate their targets after an injury has been widely recognized. However, despite the considerable advances made in microsurgical techniques, complete functional recovery is rarely achieved, especially for severe peripheral nerve injuries (PNIs). Therefore, alternative therapies that can successfully repair peripheral nerves are still essential. In recent years the use of biodegradable hydrogels enriched with growth-supporting and guidance cues, cell transplantation, and biomolecular therapies have been explored for the treatment of PNIs. Bearing this in mind, the aim of this study was to assess whether Gly Arg-Gly-Asp-Ser synthetic peptide (GRGDS)-modified gellan gum (GG) based hydrogels could foster an amenable environment for neurite/axonal growth. Additionally, strategies to further improve the rate of neurite outgrowth were also tested, namely the use of adipose tissue derived stem cells (ASCs), as well as the glial derived neurotrophic factor (GDNF). In order to increase its stability and enhance its bioactivity, the GDNF was conjugated covalently to iron oxide nanoparticles (IONPs). The impact of hydrogel modification as well as the effect of the GDNF-IONPs on ASC behavior was also screened. The results revealed that the GRGDS-GG hydrogel was able to support dorsal root ganglia (DRG)-based neurite outgrowth, which was not observed for non-modified hydrogels. Moreover, the modified hydrogels were also able to support ASCs attachment. In contrast, the presence of the GDNF-IONPs had no positive or negative impact on ASC behavior. Further experiments revealed that the presence of ASCs in the hydrogel improved axonal growth. On the other hand, GDNF-IONPs alone or combined with ASCs significantly increased neurite outgrowth from DRGs, suggesting a beneficial role of the proposed strategy for future applications in PNI regenerative medicine. PMID- 26480960 TI - Suberythemal Sun Exposures at Swedish Schools Depend on Sky Views of the Outdoor Environments - Possible Implications for Pupils' Health. AB - More scheduled outdoor stay is increasingly advocated for school children. This study measured 2(nd) , 5(th) and 8(th) graders' erythemal UV-exposure in September, March and May at four Swedish schools. We related those exposures, as fractions of total available ambient radiation, to the schools outdoor environments differing in amount of shade, vegetation, and peripheral city-scape quantified as percentage of free sky view calculated from fish-eye photographs. Exposures correlated with the sky views (with exceptions in May) and were suberythemal. The exposures were also below the threshold limit of the International Commission on Non-Ionizing Radiation Protection (ICNIRP) for hazard evaluation of UVR but were potentially enough for adequate vitamin D formation according to a cited model calculation - as illustrated in the results and discussed. The school environments, typical in southern and middle Sweden, offer enough shade to protect children from overexposure during seasons with potentially harmful solar UV radiation. Pupils' outdoor stay may be extended during September and March. In May extended outdoor stay of the youngest pupils requires a more UVR-protective environment. PMID- 26480961 TI - Development of chitosan-pullulan composite nanoparticles for nasal delivery of vaccines: optimisation and cellular studies. AB - Nasal immunisation with nanoparticles has already shown promising results. In this study, nanoparticle composites carrying BSA for nasal vaccination prepared using electrostatic interaction process between polycation N-trimethyl chitosan chloride (TMC), chitosan glutamate (CG), chitosan chloride (CCl) and polyanion carboxymethyl pullulan (CMP). A mass ratio of 2:1 for TMC-CMP combination produced stable nanocarriers. For CCl-CMP and CG-CMP formulations needed a mass ratio of 3:1. Loading efficiency was >90% for all formulations. Nanoparticles' size ranged from 207 to 603 nm. The surface charge of the complexes varied between +14 and +33 mV. SDS-PAGE integrity of the model antigen was also demonstrated. MTT studies showed that nanoparticle composites were less toxic to Calu-3 cells than the particles of cationic polymers alone. FITC-BSA loaded nanoparticles efficiently taken up by J774A.1 macrophages as confirmed by confocal microscopy highlighting the potential of these novel nanoparticulate carriers' use for nasal vaccination. PMID- 26480962 TI - Development of chitosan-pullulan composite nanoparticles for nasal delivery of vaccines: in vivo studies. AB - Here, we aimed at developing chitosan/pullulan composite nanoparticles and testing their potential as novel systems for the nasal delivery of diphtheria toxoid (DT). All the chitosan derivatives [N-trimethyl (TMC), chloride and glutamate] and carboxymethyl pullulan (CMP) were synthesised and antigen-loaded composites were prepared by polyion complexation of chitosan and pullulan derivatives (particle size: 239-405 nm; surface charge: +18 and +27 mV). Their immunological effects after intranasal administration to mice were compared to intramuscular route. Composite nanoparticles induced higher levels of IgG responses than particles formed with chitosan derivative and antigen. Nasally administered TMC-pullulan composites showed higher DT serum IgG titre when compared with the other composites. Co-encapsulation of CpG ODN within TMC-CMP-DT nanoparticles resulted in a balanced Th1/Th2 response. TMC/pullulan composite nanoparticles also induced highest cytokine levels compared to those of chitosan salts. These findings demonstrated that TMC-CMP-DT composite nanoparticles are promising delivery system for nasal vaccination. PMID- 26480964 TI - SELEX: How It Happened and Where It will Go. PMID- 26480963 TI - Preparation and detection of calcium alginate/bone powder hybrid microbeads for in vitro culture of ADSCs. AB - Calcium alginate microbeads have been widely used in tissue engineering application, due to their excellent biocompatibility, biodegradability, enhanced mechanical strength and toughness. Bone powder containing abundant hydroxylapatite, type I collagen and growth factors such as BMP2 and BMP4, possesses good osteoinductive activity. Herein, a hybrid calcium alginate/bone powder microbead was therefore prepared. Afterwards, different seeding density of adipose-derived stem cells (ADSCs) in these hybrid microbeads was discussed systematically for further in vitro expansion. Optimised microbeads suitable for in vitro expansion and differentiation of ADSCs were prepared using the droplet method under overall considering suitable concentrations of calcium alginate and calcium chloride as well as the density of bone powder through an orthogonal experiment. The results showed that the concentration of sodium alginate had the most influence on inside mass transfer and mechanical strength of the hybrid microbeads, secondly the calcium chloride, then the density of bone powder. The hybrid microbeads could be optimally performed while the concentrations of sodium alginate and calcium chloride were 2.5% and 4.5%, as well as 5.0 mg/mL bone powder, respectively. Live/Dead assay showed that the expanded ADSCs differentiated well with an initial embedding density of 5 * 10(6) cells/mL. PMID- 26480965 TI - Is There a Role for Publication Consultants and How Should Their Contribution be Recognized? AB - When a scientific paper, dissertation or thesis is published the author(s) have a duty to report who has contributed to the work. This recognition can take several forms such as authorship, relevant acknowledgments and by citing previous work. There is a growing industry where publication consultants will work with authors, research groups or even institutions to help get their work published, or help submit their dissertation/thesis. This help can range from proof reading, data collection, analysis (including statistics), helping with the literature review and identifying suitable journals/conferences. In this opinion article we question whether these external services are required, given that institutions should provide this support and that experienced researchers should be qualified to carry out these activities. If these services are used, we argue that their use should at least be made transparent either by the consultant being an author on the paper, or by being acknowledged on the paper, dissertation or thesis. We also argue that publication consultants should provide an annual return that details the papers, dissertations and thesis that they have consulted on. PMID- 26480968 TI - The Eye of the Beholder. PMID- 26480967 TI - Diabetes Mellitus Care Provided by Nurse Practitioners vs Primary Care Physicians. AB - OBJECTIVES: To compare processes and cost of care of older adults with diabetes mellitus cared for by nurse practitioners (NPs) with processes and cost of those cared for by primary care physicians (PCPs). DESIGN: Retrospective cohort study. SETTING: Primary care in communities. PARTICIPANTS: Individuals with a diagnosis of diabetes mellitus in 2009 who received all their primary care from NPs or PCPs were selected from a national sample of Medicare beneficiaries (N = 64,354). MEASUREMENTS: Propensity score matching within each state was used to compare these two cohorts with regard to rate of eye examinations, low-density lipoprotein cholesterol (LDL-C) and glycosylated hemoglobin (HbA1C) testing, nephropathy monitoring, specialist consultation, and Medicare costs. The two groups were also compared regarding medication adherence and use of statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (for individuals with a diagnosis of hypertension), and potentially inappropriate medications (PIMs). RESULTS: Nurse practitioners and PCPs had similar rates of LDL-C testing (odds ratio (OR) = 1.01, 95% confidence interval (CI) = 0.94-1.09) and nephropathy monitoring (OR = 1.05, 95% CI = 0.98-1.03), but NPs had lower rates of eye examinations (OR = 0.89, 95% CI = 0.84-0.93) and HbA1C testing (OR = 0.88, 95% CI = 0.79-0.98). NPs were more likely to have consulted cardiologists (OR = 1.29, 95% CI = 1.21-1.37), endocrinologists (OR = 1.64, 95% CI = 1.48 1.82), and nephrologists (OR = 1.90, 95% CI = 1.67-2.17) and more likely to have prescribed PIMs (OR = 1.07, 95% CI = 1.01-1.12). There was no statistically significant difference in adjusted Medicare spending between the two groups (P = .56). CONCLUSION: Nurse practitioners were similar to PCPs or slightly lower in their rates of diabetes mellitus guideline-concordant care. NPs used specialist consultations more often but had similar overall costs of care to PCPs. PMID- 26480969 TI - Dietary Glycemic Index and Glycemic Load Are Positively Associated with Risk of Developing Metabolic Syndrome in Middle-Aged and Elderly Adults. AB - OBJECTIVES: To evaluate how glycemic index (GI) and glycemic load (GL) are associated with the metabolic syndrome (MetS) and its features in middle-aged and elderly adults at high cardiovascular risk. DESIGN: Prospective, longitudinal, population-based cohort. SETTING: PREvencion con DIeta MEDiterranea study. PARTICIPANTS: Men and women (N = 6,606) divided into three age groups (<65, 65 74, >=75). MEASUREMENTS: Energy and nutrient intake was evaluated using a validated 137-item food frequency questionnaire. MetS and its features were defined in accordance with the criteria of the American Heart Association and National Heart, Lung, and Blood Institute. RESULTS: A positive association was observed between GI and MetS prevalence in the youngest and middle age groups for participants without diabetes mellitus, but no relationship was found for those with diabetes mellitus. During the median follow-up of 4.8 years, higher GI and GL were related to greater risk of MetS in the middle age group, independent of the presence of diabetes mellitus. Changes in dietary GI were associated with risk of developing the high fasting glucose component of the MetS in the oldest age category, and changes in dietary GL were associated with risk of developing abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, and high blood pressure in the youngest age category. CONCLUSION: Dietary GI and GL have a potential role in the development of MetS and associated clinical features, with particular age-dependent considerations. PMID- 26480970 TI - Increase in Disability Prevalence Before Hip Fracture. AB - OBJECTIVES: To establish the prevalence and correlates of disability during the 2 years before hip fracture. DESIGN: Data from participants who experienced hip fracture in the Health and Retirement Study (HRS) with hip fracture identified using linked Medicare claims. Each participant was interviewed at varying time points in the 2 years before hip fracture. Disability was defined as self-report of the need for assistance in any activity of daily living (walking across the room, eating, bathing, dressing, using the toilet, transferring). Based on the timing between interview and hip fracture, prevalence of disability was calculated in the cohort as a whole over the 2 years before hip fracture and in subgroups defined according to demographic and clinical characteristics. SETTING: The HRS is a nationally representative longitudinal study (1992-2010). PARTICIPANTS: HRS participants aged >=65 with hip fracture (mean age at fracture 84, 77% female). RESULTS: The adjusted prevalence of disability was 20% (95% confidence interval (CI) = 14-25%) 2 years before hip fracture, with little change until approximately 10 months before fracture, when it started to rise, reaching 44% (95% CI = 33-55%) in the month before hip fracture. The prevalence of disability was highest in the last month before fracture for persons aged 85 and older (53%) and for those with dementia (60%). CONCLUSION: Care models for hip fracture need to consider not only the acute medical and surgical needs, but also the high level of need for supportive care and caregiver assistance that chronically disabled individuals require. PMID- 26480971 TI - Intervention to Reduce Ventilator-Associated Pneumonia in Individuals on Long Term Ventilation by Introducing a Customized Bundle. AB - OBJECTIVES: To evaluate the effectiveness of a modified bundle of preventative measures to decrease ventilator-associated pneumonia (VAP) in chronically ventilated long-term care facility (LTCF) residents. DESIGN: Cohort before-and after study. SETTING: Geriatric hospital ward. PARTICIPANTS: LTCF residents on long-term ventilation. INTERVENTION: The modified bundle included hand hygiene before patient care, elevation of the head of the bed to more than 30 degrees for individuals who are supine, chlorhexidine oral care at the beginning of each nursing shift, keeping tracheostomy cannula balloon pressure at 20 to 30 cm H2 O, and measuring nasogastric food remnants before every meal for individuals fed through a nasogastric tube. MEASUREMENTS: Number of VAP episodes was determined prospectively, and rates were calculated as episodes per 1,000 ventilation days. RESULTS: VAP rate decreased from 5.97 before the intervention to 2.34 after the intervention (P < .001). The use of broad-spectrum antibiotics decreased from 1,788 defined daily doses before the intervention to 1,093 after (P = .04). CONCLUSION: A modified bundle successfully decreased VAP rates in chronically ventilated elderly LTCF residents. PMID- 26480972 TI - Self-Reported Hearing Loss, Hearing Aids, and Cognitive Decline in Elderly Adults: A 25-Year Study. AB - OBJECTIVES: To investigate the association between hearing loss, hearing aid use, and cognitive decline. DESIGN: Prospective population-based study. SETTING: Data gathered from the Personnes Agees QUID study, a cohort study begun in 1989-90. PARTICIPANTS: Individuals aged 65 and older (N = 3,670). MEASUREMENTS: At baseline, hearing loss was determined using a questionnaire assessing self perceived hearing loss; 137 subjects reported major hearing loss, 1,139 reported moderate problems (difficulty following the conversation when several persons talk at the same time or in a noisy background), and 2,394 reported no hearing trouble. Cognitive decline was measured using the Mini-Mental State Examination (MMSE), administered at follow-up visits over 25 years. RESULTS: Self-reported hearing loss was significantly associated with lower baseline MMSE score (beta = 0.69, P < .001) and greater decline during the 25-year follow-up period (beta = 0.04, P = .01) independent of age, sex, and education. A difference in the rate of change in MMSE score over the 25-year follow-up was observed between participants with hearing loss not using hearing aids and controls (beta = -0.06, P < .001). In contrast, subjects with hearing loss using a hearing aid had no difference in cognitive decline (beta = 0.07, P = .08) from controls. CONCLUSION: Self-reported hearing loss is associated with accelerated cognitive decline in older adults; hearing aid use attenuates such decline. PMID- 26480973 TI - Preparedness for End of Life-a Survey of Jerusalem District Nursing Homes. AB - OBJECTIVES: To evaluate the quality of end-of-life (EOL) care in nursing homes. DESIGN: Survey and semistructured interviews. SETTING: Jerusalem district nursing homes. PARTICIPANTS: Staff members of 28 long-term care and skilled nursing facilities in the Jerusalem area in Israel of various ethnic, religious, and administrative affiliations (N = 207). MEASUREMENTS: Qualitative analysis of semistructured interviews and statistical analysis of questionnaires. RESULTS: Most staff members reported that EOL preferences were unknown for more than 90% of residents and that fewer than 10% had a healthcare proxy. Most staff members recalled conducting fewer than five EOL conversations over the past year with residents or family members and could recall fewer than five cases in which a resident was allowed to die in the nursing home. According to staff opinions the prevalence of tube feeding was estimated at greater than 10%, initiated because of aspiration, malnutrition, and understaffing, often against family's preferences. More than 25% of staff members believed that pain management was inadequate. Knowledge about management of chronic pain was poor in half of nurses and nearly one-third of physicians. Most staff would rather not receive the treatments they administered to residents. CONCLUSION: Nursing homes in Jerusalem lack competency for quality EOL care, and there are multiple psychological, training, and policy challenges to improvement. PMID- 26480974 TI - Concordance Between Anticholinergic Burden Scales. AB - OBJECTIVES: To evaluate concordance of five commonly used anticholinergic scales. DESIGN: Cross-sectional secondary analysis. SETTING: Pittsburgh, Pennsylvania, and Memphis, Tennessee. PARTICIPANTS: Community-dwelling adults aged 70 to 79 with baseline medication data from the Health, Aging, and Body Composition Study (N = 3,055). MEASUREMENTS: Any anticholinergic use, weighted scores, and total standardized daily dosage were calculated using five anticholinergic measures (Anticholinergic Cognitive Burden (ACB) Scale, Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), Drug Burden Index anticholinergic component (DBI-ACh), and Summated Anticholinergic Medications Scale (SAMS)). Concordance was evaluated using kappa statistics and Spearman rank correlations. RESULTS: Any anticholinergic use in rank order was 51% for the ACB, 43% for the ADS, 29% for the DBI-ACh, 23% for the ARS, and 16% for the SAMS. Kappa statistics for all pairwise use comparisons ranged from 0.33 to 0.68. Similarly, concordance as measured using weighted kappa statistics ranged from 0.54 to 0.70 for the three scales not incorporating dosage (ADS, ARS, ACB). Spearman rank correlation between the DBI-ACh and SAMS was 0.50. CONCLUSION: Only low to moderate concordance was found between the five anticholinergic scales. Future research is needed to examine how these differences in measurement affect their predictive validity with respect to clinically relevant outcomes, such as cognitive impairment. PMID- 26480975 TI - Recognition and Management of Hypertension in Older Persons: Focus on African Americans. AB - Hypertension is the most commonly diagnosed condition in persons aged 60 and older and is the single most important risk factor for cardiovascular disease (ischemic heart disease, heart failure, and stroke), kidney disease, and dementia. More than half of individuals with hypertension in the United States are aged 60 and older. Hypertension disproportionately affects African Americans, with all age groups, including elderly adults, having a higher burden of hypertension-related complications than other U.S. POPULATIONS: Multiple clinical trials have demonstrated the beneficial effects of blood pressure (BP) reduction on cardiovascular morbidity and mortality, with most of the evidence in individuals aged 60 and older. Several guidelines have recently been published on the specific management of hypertension in individuals aged 60 and older, including in high-risk groups such as African Americans. Most recommend careful evaluation, thiazide diuretics and calcium-channel blockers for initial drug therapy in most African Americans, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in those with chronic kidney disease or heart failure. Among the areas of controversy is the recommended target BP in African Americans aged 60 and older. A recent U.S. guideline recommended raising the systolic BP target from less than 140 mmHg to less than 150 mmHg in this population. This article will review the evidence and current guideline recommendations for hypertension treatment in older African Americans, including the rationale for continuing to recommend a SBP target of less than 140 mmHg in this population. PMID- 26480976 TI - The Highs and Lows of Blood Pressure Targets in Elderly Adults and Other High Risk Populations. PMID- 26480978 TI - Assessing Care of Vulnerable Elders to the Rescue. PMID- 26480977 TI - Effect of Physician Delegation to Other Healthcare Providers on the Quality of Care for Geriatric Conditions. AB - The quality of care of older adults in the United States has been consistently shown to be inadequate. This gap between recommended and actual care provides an opportunity to improve the value of health care for older adults. Prior work from the Assessing Care of Vulnerable Elders (ACOVE) investigators first defined, and then sought to improve, clinical practice for common geriatric conditions. A critical component of the ACOVE intervention for practice improvement was an emphasis on the delegation of specific care processes, but the independent effect of delegation on the quality of care has not been evaluated. This study analyzed the pooled results of prior ACOVE projects from 1998 to 2010. Totaled, these studies included 4,776 individuals aged 65 and older of mixed demographic backgrounds and 16,204 ACOVE quality indicators (QIs) for three geriatric conditions: falls, urinary incontinence, and dementia. In unadjusted analyses, QI pass probabilities were 0.36 for physician-performed tasks, 0.55 for nurse practitioner (NP)-, physician assistant (PA)-, and registered nurse (RN) performed tasks; and 0.61 for medical assistant- and licensed vocational nurse performed tasks. In multiply adjusted models, the independent pass-probability effect of delegation to NPs, PAs, and RNs was 1.37 (P = .05). These findings suggest that delegation of selected tasks to nonphysician healthcare providers is associated with higher quality of care for these geriatric conditions in community practices and supports the value of interdisciplinary team management for common outpatient conditions in older adults. PMID- 26480979 TI - Participation of Medical Students in Discharge Tasks: A Needs Assessment. PMID- 26480980 TI - Early Commencement of Oral Intake and Physical Function are Associated with Early Hospital Discharge with Oral Intake in Hospitalized Elderly Individuals with Pneumonia. PMID- 26480982 TI - Deep Brain Stimulation Ameliorates Postural Hypotension in Parkinson's Disease. PMID- 26480981 TI - Levodopa Does Not Worsen Gastric Emptying in Parkinson's Disease. PMID- 26480983 TI - Acupuncture for Gait Disturbance in Parkinson's Disease: Immediate Effects of Acupuncture Treatment. PMID- 26480984 TI - Does Age Influence Treatment and Oncological Outcomes in Individuals with Sporadic Colorectal Cancer? PMID- 26480985 TI - Effectiveness of a Cardiovascular Evaluation and Intervention in Older Fallers: A Pilot Study. PMID- 26480986 TI - Views of Primary Care Physicians and Home Care Nurses on the Causes of Readmission of Older Adults. PMID- 26480987 TI - Circulating Levels of Advanced Glycation End Products in Diabetes Mellitus Related Dementia. PMID- 26480988 TI - Inappropriate Proton Pump Inhibitor Prescription in Elderly Adults: As Usual As Dangerous. PMID- 26480990 TI - Anemia, Physical Function, and Mortality in Long-Lived Individuals Aged 95 and Older: A Population-Based Study. PMID- 26480989 TI - Use of Vitamin K Antagonists and Brain Volumetry in Older Adults: Preliminary Results From the GAIT Study. PMID- 26480991 TI - Antihypertensive Treatment After Ischemic Stroke in Elderly Adults: Beware of Nocturnal Hypotension Episodes. PMID- 26480992 TI - Conservative Management of Intentional Massive Dabigatran Overdose. PMID- 26480993 TI - Low-Dose Sip Feeding in Individuals with Malnutrition-Effects on the Nutritional Parameters. PMID- 26480994 TI - Effects of Weighted Tai Chi on Leg Strength of Older Adults. PMID- 26480995 TI - Potential Effect of Coding Differences on Comparisons of Rural and Urban Outcomes. PMID- 26480996 TI - Timing Is Critical in Determining the Association Between Delirium and S100 Calcium-Binding Protein B. PMID- 26480997 TI - Older Adult Openness to Physician Questioning About Firearms. PMID- 26480998 TI - Differences in Medicare Billing of Internal Medicine Physicians According to Sex. PMID- 26480999 TI - Older Dutch People's Self-Reported Advance Euthanasia Directive Completion Before and After the Enactment of the Euthanasia Law: A Time Trend Study (1998-2011). PMID- 26481000 TI - Don't Let the BEDBUGS Bite: An Overlooked Cause of Rash in an Older Adult. PMID- 26481001 TI - Hypervitaminosis B12 As an Additional Prognostic Indicator in Elderly Adults with a Neoplastic Disease: Report of a Case and Review of the Literature. PMID- 26481002 TI - Bisphosphonate-Related Osteonecrosis of the Jaw in an 80-Year-Old Woman with Diabetes Mellitus: Case Report. PMID- 26481003 TI - The Program of All-Inclusive Care for the Elderly Model: Lessons for the Medicare Medicaid Coordination Office. PMID- 26481006 TI - Suppression and Working Memory in Auditory Comprehension of L2 Narratives: Evidence from Cross-Modal Priming. AB - Using a cross-modal priming task, the present study explores whether Chinese English bilinguals process goal related information during auditory comprehension of English narratives like native speakers. Results indicate that English native speakers adopted both mechanisms of suppression and enhancement to modulate the activation of goals and keep track of the "causal path" in narrative events and that L1 speakers with higher working memory (WM) capacity are more skilled at attenuating interference. L2 speakers, however, experienced the phenomenon of "facilitation-without-inhibition." Their difficulty in suppressing irrelevant information was related to their performance in the test of working memory capacity. For the L2 group with greater working memory capacity, the effects of both enhancement and suppression were found. These findings are discussed in light of a landscape model of L2 text comprehension which highlights the need for WM to be incorporated into comprehensive models of L2 processing as well as theories of SLA. PMID- 26481005 TI - Downregulation of hepatic betaine:homocysteine methyltransferase (BHMT) expression in taurine-deficient mice is reversed by taurine supplementation in vivo. AB - The cysteine dioxygenase (Cdo1)-null and the cysteine sulfinic acid decarboxylase (Csad)-null mouse are not able to synthesize hypotaurine/taurine by the cysteine/cysteine sulfinate pathway and have very low tissue taurine levels. These mice provide excellent models for studying the effects of taurine on biological processes. Using these mouse models, we identified betaine:homocysteine methyltransferase (BHMT) as a protein whose in vivo expression is robustly regulated by taurine. BHMT levels are low in liver of both Cdo1-null and Csad-null mice, but are restored to wild-type levels by dietary taurine supplementation. A lack of BHMT activity was indicated by an increase in the hepatic betaine level. In contrast to observations in liver of Cdo1-null and Csad-null mice, BHMT was not affected by taurine supplementation of primary hepatocytes from these mice. Likewise, CSAD abundance was not affected by taurine supplementation of primary hepatocytes, although it was robustly upregulated in liver of Cdo1-null and Csad-null mice and lowered to wild-type levels by dietary taurine supplementation. The mechanism by which taurine status affects hepatic CSAD and BHMT expression appears to be complex and to require factors outside of hepatocytes. Within the liver, mRNA abundance for both CSAD and BHMT was upregulated in parallel with protein levels, indicating regulation of BHMT and CSAD mRNA synthesis or degradation. PMID- 26481007 TI - Microsatellite-based genetic diversity patterns in disjunct populations of a rare orchid. AB - We investigated the patterns of genetic diversity and structure in seven disjunct populations of a rare North American orchid, Cypripedium kentuckiense by including populations that represented the periphery and the center of the its range. Eight nuclear and two chloroplast microsatellites were used. Genetic diversity was low across the sampled populations of C. kentuckiense based on both nuclear (average An = 4.0, Ho = 0.436, He = 0.448) and cpDNA microsatellites (average An = 1.57, Nh = 1.57 and H = 0.133). The number of private alleles ranged from one to four per population with a total of 17 private alleles detected at five nuclear microsatellites. One private allele at one cpDNA microsatellite was also observed. Although the absolute values for nuclear microsatellite based population differentiation were low (Fst = 0.075; phiPT = 0.24), they were statistically significant. Pairwise Fst values ranged from 0.038 to 0.123 and each comparison was significant. We also detected isolation by distance with nDNA microsatellites based on the Mantel test (r(2) = 0.209, P = 0.05). STRUCTURE analysis and the neighbor joining trees grouped the populations similarly whereby the geographically proximal populations were genetically similar. Our data indicate that the species is genetically depauperate but the diversity is distributed more or less equally across its range. Population differentiation and isolation by distance were detectable, which indicates that genetic isolation is beginning to manifest itself across the range in this rare species. PMID- 26481008 TI - The role of the transformer gene in sex determination and reproduction in the tephritid fruit fly, Bactrocera dorsalis (Hendel). AB - Transformer (tra) is a switch gene in the somatic sex-determination hierarchy that regulates sexual dimorphism based on RNA splicing in many insects. In tephritids, a Y-linked male determining gene (M) controls sex in the sex determination pathway. Here, homologues of Drosophila tra and transformer-2 (tra 2) genes were isolated and characterized in Bactrocera dorsalis (Hendel), one of the most destructive agricultural insect pests in many Asian countries. Two male specific and one female-specific isoforms of B. dorsalis transformer (Bdtra) were identified. The presence of multiple TRA/TRA-2 binding sites in Bdtra suggests that the TRA/TRA-2 proteins are splicing regulators promoting and maintaining, epigenetically, female sex determination by a tra positive feedback loop in XX individuals during development. The expression patterns of female-specific Bdtra transcripts during early embryogenesis shows that a peak appears at 15 h after egg laying. Using dsRNA to knock-down Bdtra expression in the embryo and adult stages, we showed that sexual formation is determined early in the embryo stage and that parental RNAi does not lead to the production of all male progeny as in Tribolium castaneum. RNAi results from adult abdominal dsRNA injections show that Bdtra has a positive influence on female yolk protein gene (Bdyp1) expression and fecundity. PMID- 26481010 TI - Strategy for enhancing the therapeutic efficacy of histone deacetylase inhibitor dacinostat: the novel paradigm to tackle monotonous cancer chemoresistance. AB - Histone deacetylases (HDACs) regulate gene expression by creating the closed state of chromatin via histone hypoacetylation. Histone acetylation deregulation caused by aberrant expression of classical HDACs leads to imprecise gene regulation culminating in various diseases including cancer. Histone deacetylase inhibitors (HDACi), the small-molecules modulating the biological function of HDACs have shown promising results in inducing cell cycle arrest, differentiation and apoptosis in tumour models. HDACi do not show desired cytotoxic effect when used in monotherapy due to triggering of various resistance mechanisms in cancer cells emphasizing the desperate need of novel strategies that can be used to overcome such challenges. The present article provides intricate details about the novel HDACi dacinostat (LAQ-824) against multiple myeloma and acute myeloid leukaemia. The distinct molecular mechanisms modulated by dacinostat in exerting cytotoxic effect against the defined malignancies have also been detailed. The article also explains the strategy that can be used to circumvent the conventional therapy resistant cases and for enhancing the therapeutic efficacy of dacinostat for effective anticancer therapy. PMID- 26481009 TI - Protein kinase OsSAPK8 functions as an essential activator of S-type anion channel OsSLAC1, which is nitrate-selective in rice. AB - MAIN CONCLUSION: OsSAPK8 is an essential activator of OsSLAC1 by phosphorylation, and OsSLAC1 is a nitrate-selective anion channel. S-type anion channel AtSLAC1 and protein kinase AtOST1 have been well-characterized as two core components of ABA signaling cascade in Arabidopsis guard cells, and AtOST1 functions as a main upstream activator of AtSLAC1 for drought stress- and ABA-induced stomata closure. However, the identity of the ortholog of AtOST1 in rice, the main activator of OsSLAC1, is still unknown. Here, we report that protein kinase OsSAPK8 interacts with and activates OsSLAC1 mainly by phosphorylating serine 129 (S129) of OsSLAC1, and this phosphorylating site corresponds to the specific phosphorylating site serine 120 (S120) of AtSLAC1 for AtOST1. Additionally, we found that OsSLAC1 is a nitrate-selective anion channel without obvious permeability to chloride, malate, and sulfate, and the expression of OsSLAC1 in Arabidopsis slac1-3 (atslac1-3) mutant successfully rescued the hypersensitive phenotype of this mutant to drought stress. Together, this research suggests that OsSAPK8 is a counterpart of AtOST1 for the activation of OsSLAC1, which is a nitrate-selective anion channel. PMID- 26481012 TI - Longitudinal tumor hypoxia imaging with [(18)F]FAZA-PET provides early prediction of nanoliposomal irinotecan (nal-IRI) treatment activity. AB - BACKGROUND: Non-invasive measurement of tumor hypoxia has demonstrated potential for the evaluation of disease progression, as well as prediction and assessment of treatment outcome. [(18)F]fluoroazomycin arabinoside (FAZA) positron emission tomography (PET) has been identified as a robust method for quantification of hypoxia both preclinically and clinically. The goal of this investigation was to evaluate the feasibility and value of repeated FAZA-PET imaging to quantify hypoxia in tumors that received multi-dose chemotherapy. METHODS: FAZA-PET imaging was conducted over a 21-day period in a mouse xenograft model of HT-29 human colorectal carcinoma, following multi-dose chemotherapy treatment with irinotecan (CPT-11) or nanoliposomal irinotecan (nal-IRI, MM-398). RESULTS: Tumors treated with 10 mg/kg nal-IRI maintained significantly lower levels of hypoxia and smaller hypoxic fractions compared to tumors that received 50 mg/kg CPT-11. Specifically, differences in FAZA uptake were detectable 9 days before any significant differences in tumor volume were observed between the treatment groups. CONCLUSIONS: These findings highlight the potential use of FAZA-PET as an early marker of treatment response following multi-dose chemotherapy. PMID- 26481011 TI - Purple potato (Solanum tuberosum L.) anthocyanins attenuate alcohol-induced hepatic injury by enhancing antioxidant defense. AB - Alcoholic liver disease (ALD) is a serious and challenging health issue. In the past decade, natural components possessing hepatoprotective properties have gained more attention for ALD intervention. In this study, the phytochemical components of anthocyanins from purple potato were assessed using UPLC-MS/MS, and the hepatoprotective effects of purple potato anthocyanins (PPAs) were investigated in the ALD mouse model. Serum and liver biochemical parameters were determined, along with histopathological changes in liver tissue. In addition, the major contributors to alcohol-induced oxidative stress were assessed. The results indicated that the levels of aspartate transaminase and alanine transaminase were lower in the serum of the PPA-treated group than the alcohol treated group. PPAs significantly inhibited the reduction of total cholesterol and triglycerides. Higher levels of superoxide dismutase and reduced glutathione enzymes as well as a reduction in the formation of malondialdehyde occurred in mice fed with PPAs. In addition, PPAs protected against increased alcohol-induced levels and activity of cytochrome P450 2E1 (CYP2E1), which demonstrates the effects of PPAs against alcohol-induced oxidative stress and liver injury. This study suggests that PPAs could be an effective therapeutic agent in alcohol induced liver injuries by inhibiting CYP2E1 expression and thereby strengthening antioxidant defenses. PMID- 26481013 TI - [Party and designer drugs : From ecstasy and crystal meth to angel's trumpet]. AB - BACKGROUND: The growing abuse of party and designer drugs increases the number of emergency cases related to drug consumption. OBJECTIVES: Presentation of the scenario as well as the diagnostic and therapeutic principles of emergency management and characterization of the most frequently abused drugs and its effects. MATERIALS AND METHODS: Evaluation of drug statistics, and work-up and discussion of expert publications and recommendations. RESULTS: In 2014, there were 1032 drug-related deaths, which is 3 % more incidents than in 2013. However, there is a drastically and steadily increasing consumption of newer enhancing drugs such as crystal meth. Throughout Europe, there are about 1500 designer drugs that are disguised as so-called spice mixtures or bath salts. In addition to stimulating substances, hallucinogenic and sedative drugs are also consumed. Common nonspecific symptoms of emergency drug overdose are psychosis, impaired consciousness, seizures, and disorders of various internal organs. Based on the clinical presentation, different neurotransmitter syndromes can be distinguished and the drug etiology can be diagnosed and proven by laboratory assays. Therapy includes symptom-oriented measures. CONCLUSIONS: Knowledge of different party and designer drugs and their complications enables prompt emergency management. PMID- 26481014 TI - [Investing in knowledge]. PMID- 26481015 TI - [DNA fragments synthesized by polymerase alpha shape our genome]. PMID- 26481016 TI - [Macrophage migration inhibitory factor: a key cytokine for endometriosis]. PMID- 26481017 TI - [Viagra(r) makes Plasmodium stiff: a novel way to block malaria transmission?]. PMID- 26481018 TI - [Altruism in the retina: sticks feed cones]. PMID- 26481019 TI - [Retinal prostheses: high-resolution photovoltaic implants]. PMID- 26481020 TI - [Immunosuppression by Treg can be decreased with anti-GARP antibodies]. PMID- 26481021 TI - [PRAF2, an endoplasmic reticulum gatekeeper, controls the cell-surface export of the GABA(B) receptor in neurons]. PMID- 26481022 TI - [Co-activation of AMPK and mTORC1: a therapeutic application of synthetic lethality in acute myeloid leukemia]. PMID- 26481023 TI - [Molecular pathogenesis of peripheral T-cell lymphoma (1): angioimmunoblastic T cell lymphoma, peripheral T-cell lymphoma, not otherwise specified and anaplastic large cell lymphoma]. AB - Peripheral T-cell lymphomas (PTCL) belong to the group of non-Hodgkin lymphoma and particularly that of mature T/NK cells lymphoproliferative neoplasms. The 2008 WHO classification describes different PTCL entities with varying prevalence. With the exception of the histological subtype "ALK positive anaplastic large cell lymphoma", PTCL are characterized by a poor prognosis. The mechanisms underlying the pathogenesis of these lymphomas are not yet fully understood, but development of genomic high-throughput analysis techniques now allows to extensively identify the molecular abnormalities present in tumor cells. This review aims to summarize the current knowledge and recent advances about the molecular events occurring at the origin or during the natural history of main entities of PTCL. It will be published in two parts : the first is focused on the three more frequent entities, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified, and anaplastic large cell lymphoma. The second (which will appear in the november issue) will describe other subtypes less frequent and of poor prognosis : extranodal NK/T-cell lymphoma, nasal type, adult T-cell leukemia/lymphoma, and enteropathy-associated T-cell lymphoma. T or NK cell lymphoproliferative disorders with leukemic presentation, primary cutaneous T-cell lymphoma and very rare subtypes of PTCL whose prevalence is less than 5% (hepatosplenic T-cell lymphoma and subcutaneous panniculitis-like T cell lymphoma) will not be discussed herein. PMID- 26481024 TI - [Prader-Willi syndrome in 2015]. AB - Prader-Willi syndrome is a neurodevelopmental disorder caused by the lack of expression of imprinted genes of the chromosomal region 15q11-q12. Diagnosis can now be made in the first months of life, allowing a precise description of the natural history of the disease. Of interest, nutritional phases appear to be more complex than those initially reported, starting with a severe hypotonia with deficit of suckling and failure to thrive in neonates, and subsequently switching to excessive weight gain with morbid obesity due to hyperphagia and deficit of satiety. The phenotype also includes endocrine dysfunction, intellectual disability, learning deficits, behavioural troubles with impaired social skills and psychiatric features. Multidisciplinary care has been strongly improved by the rare disease programme launched in France in 2004 and the Obesity programme in 2011 in link with the patient association. New therapeutic perspectives have arisen from knowledge of the pathophysiology of PWS. PMID- 26481025 TI - [Complete hydatidiform mole]. AB - "The battle of the sexes begins in the zygote" W. Reik and J. Walter. Complete hydatidiform mole (CHM) is a pathology of the placenta with androgenetic diploid origin (chromosomes only from paternal origin). Placental villi present an abnormal hyperproliferation and hydropic degeneration associated with the absence of embryo. Three mechanisms can be envisaged at its origin: (1) destruction/expulsion of the female pronucleus at the time of fertilization by one or two spermatozoa, the former being followed by an endoreplication of the male pronucleus (homozygous mole), (2) a triploid zygote (fertilization by two spermatozoa) leading to a haploid and a diploid clones. The diploid clone may produce a normal fetus while the haploid clone, after endoreplication, generates a complete hydatidiform mole, (3) a nutritional defect during the differentiation of the oocytes of the female embryo that will affect the integrity and maturity of her oocytes during her adult life and lead to hydatidiform mole. In countries with a poor medical health care system, moles can be invasive or, in rare cases, lead to gestational choriocarcinomas. PMID- 26481026 TI - [Punish or cherish: p53, metabolism and tumor suppression]. AB - The p53 gene is essential for tumor suppression, but how it does so remains unclear. Upon genotoxic or oncogenic stresses, increased p53 activity induces transient cell cycle arrest, senescence or apoptosis, the three cornerstones of the so-called triumvirate. Accordingly, it has long been thought that p53 suppresses tumorigenesis by somehow counteracting cell proliferation or survival. However, several recently described genetically modified mice indicate that p53 can suppress tumorigenesis without triggering these three responses. Rather, as an important mechanism for tumor suppression, these mutant mice point to the ability of p53 to prevent the Warburg effect, that is to dampen glycolysis and foster mitochondrial respiration. Interestingly, these metabolic functions of p53 rely, in part, on its "unstressed" (basal) expression, a feature shared by its mechanistically linked anti-oxydant function. Together, these "conservative" activities of p53 may prevent tumor initiation by promoting and maintaining a normal oxidative metabolism and hence underly the "daily" tumor suppression by p53 in most cells. Conversely, destructive activities elicited by high p53 levels and leading to senescence or apoptosis provide a shield against partially or overtly transformed cells. This last situation, although relatively infrequent throughout life, is usual in experimental settings, which could explain the disproportionally high number of data implicating the triumvirate in tumor suppression by p53. PMID- 26481027 TI - [Molecular determinants of pathological cardiac remodeling: the examples of Epac and Carabin]. AB - Physical exercise or hypertension requires that the heart increases its hemodynamic work. However, this adaptation is based on distinct cardiac remodelling according to the physiological or pathological origin of the stress. As shown here with two examples, understanding the molecular events leading to cardiac remodeling may offer new opportunities for the development of therapies for heart failure. The recently described Epac1 protein is an effector of the second messenger cAMP. Following a pathological stress, the cAMP-binding protein Epac1 induces cardiac hypertrophy and fibrosis as well as alteration of calcium cycling suggesting that Epac1 pharmacological inhibition may be of therapeutic value. Furthermore, the protein carabin is an important regulator of several effectors of pathological cardiac remodelling. Experimental manipulation of carabin expression profoundly alters the development of heart failure. PMID- 26481028 TI - [Randomness and cell fate]. AB - Thermal fluctuations at the molecular scale cause random fluctuations of gene expression, which, in association with differentiation circuits, can lead to phenotypic diversification in cell populations. In this synthesis article, we detail the mechanisms that generate this diversification and illustrate their consequences in various organisms. In bacteria, random phenotypic diversification allows to anticipate environmental changes that are otherwise unpredictable, in particular during metabolic transitions and stress responses, for example inducing a transient form of antibiotic resistance. In multi-cellular organisms, similar mechanisms allow the maintenance of healthy tissues, such as intestinal crypts, epidermis and retina, but also seem to play a role in establishment and renewal of tumoral heterogeneity. PMID- 26481029 TI - [Targeting and role of alpha4beta7 integrin in the pathophysiology of IBD and HIV infection]. AB - Integrins are a large family of heterodimeric cell adhesion molecules that are key regulators in multiple biological functions. They orchestrate cell-cell and cell-extracellular matrix (ECM) adhesive interactions from embryonic development to mature tissue function, and are thus involved in cell migration, proliferation, differentiation, and survival. As such, they are also involved in human diseases, such as thrombotic diseases, inflammation, cancer, fibrosis and infectious diseases. Integrins are exciting pharmacological targets because they are exposed on the cell surface. Indeed, several compounds have been developed that block integrins function, and five have been approved as therapeutic drugs for use in clinic. This review will detail the role of alpha4beta7, an integrin of particular relevance for mucosal diseases such as IBD (inflammatory bowel disease) and also, as reported more recently, HIV infection. PMID- 26481030 TI - [Brain-computer interfaces, Locked-In syndrome, and disorders of consciousness]. AB - Detecting signs of consciousness in patients with severe brain injury constitutes a real challenge for clinicians. The current gold standard in clinical diagnosis is the behavioral scale relying on motor abilities, which are often impaired or nonexistent in these patients. In this context, brain-computer interfaces (BCIs) could offer a potential complementary tool to detect signs of consciousness whilst bypassing the usual motor pathway. In addition to complementing behavioral assessments and potentially reducing error rate, BCIs could also serve as a communication tool for paralyzed but conscious patients, e.g., suffering from Locked-In Syndrome. In this paper, we report on recent work conducted by the Coma Science Group on BCI technology, aiming to optimize diagnosis and communication in patients with disorders of consciousness and Locked-In syndrome. PMID- 26481031 TI - [Potential of the zebrafish model to study congenital muscular dystrophies]. AB - In order to better understand the complexity of congenital muscular dystrophies (CMD) and develop new strategies to cure them, it is important to establish new disease models. Due to its numerous helpful attributes, the zebrafish has recently become a very powerful animal model for the study of CMD. For some CMD, this vertebrate model is phenotypically closer to human pathology than the murine model. Over the last few years, researchers have developed innovative techniques to screen rapidly and on a large scale for muscle defects in zebrafish. Furthermore, new genome editing techniques in zebrafish make possible the identification of new disease models. In this review, the major attributes of zebrafish for CMD studies are discussed and the principal models of CMD in zebrafish are highlighted. PMID- 26481032 TI - [What do we know of the construction of French and American thoughts on the issue of drugs? From parallelism of beginnings until the turning point during the Thirties]. AB - This article traces the major milestones in the development of French and American thought on the issue of drugs and drug addiction, between the second half of the nineteenth century and the end of the twentieth century. The historical perspective highlights the relative parallelism of concerns and conceptualizations until the years 1920-1930. Beyond, a real turning point of American thought is observed, which will develop original ways of thinking and action. These original ways will have no equivalents in French thought. PMID- 26481033 TI - [Sequencing babies?]. AB - An extension of newborn screening to genome sequencing is now feasible but raises a number of scientific, organisational and ethical issues. This is being explored in discussions and in several funded trials, in order to maximize benefits and avoid some identified risks. As some companies are already offering such a service, this is quite an urgent matter. PMID- 26481034 TI - Frequency, intensity, and correlates of spiritual pain in advanced cancer patients assessed in a supportive/palliative care clinic. AB - OBJECTIVE: Regular assessments of spiritual distress/spiritual pain among patients in a supportive/palliative care clinic (SCPC) are limited or unavailable. We modified the Edmonton Symptom Assessment Scale (ESAS) by adding spiritual pain (SP) to the scale (0 = best, 10 = worst) to determine the frequency, intensity, and correlates of self-reported SP (>=1/10) (pain deep in your soul/being that is not physical) among these advanced cancer patients. METHOD: We reviewed 292 consecutive consults of advanced cancer patients (ACPs) who were evaluated at our SCPC between October of 2012 and January of 2013. Symptoms were assessed using the new instrument (termed the ESAS-FS). RESULTS: The median age of patients was 61 (range = 22-92). Some 53% were male; 189 (65%) were white, 45 (15%) African American, and 34 (12%) Hispanic. Some 123 of 282 (44%) of ACPs had SP (mean (95% CI) = 4(3.5-4.4). Advanced cancer patients with SP had worse pain [mean (95% CI) = 5.3(4.8, 5.8) vs. 4.5(4.0, 5.0)] (p = 0.02); depression [4.2(3.7, 4.7) vs. 2.1(1.7, 2.6), p < 0.0001]; anxiety [4.2(3.6, 4.7) vs. 2.5(2.0, 3.0), p < 0.0001]; drowsiness [4.2(3.7, 4.7) vs. 2.8(2.3, 3.2), p < 0.0001]; well-being [5.4(4.9, 5.8) vs. 4.5(4.1, 4.9), p = 0.0136]; and financial distress (FD) [4.4(3.9, 5.0) vs. 2.2(1.8, 2.7), p < 0.0001]. Spiritual pain correlated (Spearman) with depression (r = 0.45, p < 0.0001), anxiety (r = 0.34, p < 0.0001), drowsiness (r = 0.26, p < 0.0001), and FD (r = 0.44, p < 0.0001). Multivariate analysis showed an association with FD [OR (95% Wald CI) = 1.204(1.104-1.313), p < 0.0001] and depression [1.218(1.110-1.336), p < 0.0001]. The odds that patients who had SP at baseline would also have SP at follow-up were 182% higher (OR = 2.82) than for patients who were SP-negative at baseline (p = 0.0029). SP at follow-up correlated with depression (r = 0.35, p < 0.0001), anxiety (r = 0.25, p = 0.001), well-being (r = 0.27, p = 0.0006), nausea (r = 0.29, p = 0.0002), and financial distress (r = 0.42, p < 0.0001). SIGNIFICANCE OF RESULTS: Spiritual pain, which is correlated with physical and psychological distress, was reported in more than 40% of ACPs. Employment of the ESAS-FS allows ACPs with SP to be identified and evaluated in an SCPC. More research is needed. PMID- 26481035 TI - Roles of the Lateral Habenula and Anterior Cingulate Cortex in Negative Outcome Monitoring and Behavioral Adjustment in Nonhuman Primates. AB - Animals monitor the outcome of their choice and adjust subsequent choice behavior using the outcome information. Together with the anterior cingulate cortex (ACC), the lateral habenula (LHb) has recently attracted attention for its crucial role in monitoring negative outcome. To investigate their contributions to subsequent behavioral adjustment, we recorded single-unit activity from the LHb and ACC in monkeys performing a reversal learning task. The monkey was required to shift a previous choice to the alternative if the choice had been repeatedly unrewarded in past trials. We found that ACC neurons stored outcome information from several past trials, whereas LHb neurons detected the ongoing negative outcome with shorter latencies. ACC neurons, but not LHb neurons, signaled a behavioral shift in the next trial. Our findings suggest that, although both the LHb and the ACC represent signals associated with negative outcome, these structures contribute to subsequent behavioral adjustment in different ways. PMID- 26481036 TI - A National Network of Neurotechnology Centers for the BRAIN Initiative. AB - We propose the creation of a national network of neurotechnology centers to enhance and accelerate the BRAIN Initiative and optimally leverage the effort and creativity of individual laboratories involved in it. As "brain observatories," these centers could provide the critical interdisciplinary environment both for realizing ambitious and complex technologies and for providing individual investigators with access to them. PMID- 26481037 TI - Hebbian and Homeostatic Plasticity Mechanisms in Regular Spiking and Intrinsic Bursting Cells of Cortical Layer 5. AB - Layer 5 contains the major projection neurons of the neocortex and is composed of two major cell types: regular spiking (RS) cells, which have cortico-cortical projections, and intrinsic bursting cells (IB), which have subcortical projections. Little is known about the plasticity processes and specifically the molecular mechanisms by which these two cell classes develop and maintain their unique integrative properties. In this study, we find that RS and IB cells show fundementally different experience-dependent plasticity processes and integrate Hebbian and homeostatic components of plasticity differently. Both RS and IB cells showed TNFalpha-dependent homeostatic plasticity in response to sensory deprivation, but IB cells were capable of a much faster synaptic depression and homeostatic rebound than RS cells. Only IB cells showed input-specific potentiation that depended on CaMKII autophosphorylation. Our findings demonstrate that plasticity mechanisms are not uniform within the neocortex, even within a cortical layer, but are specialized within subcircuits. PMID- 26481038 TI - A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cgamma1 Prevents Epilepsy Induced by Status Epilepticus. AB - The BDNF receptor tyrosine kinase, TrkB, underlies nervous system function in both health and disease. Excessive activation of TrkB caused by status epilepticus promotes development of temporal lobe epilepsy (TLE), revealing TrkB as a therapeutic target for prevention of TLE. To circumvent undesirable consequences of global inhibition of TrkB signaling, we implemented a novel strategy aimed at selective inhibition of the TrkB-activated signaling pathway responsible for TLE. Our studies of a mouse model reveal that phospholipase Cgamma1 (PLCgamma1) is the dominant signaling effector by which excessive activation of TrkB promotes epilepsy. We designed a novel peptide (pY816) that uncouples TrkB from PLCgamma1. Treatment with pY816 following status epilepticus inhibited TLE and prevented anxiety-like disorder yet preserved neuroprotective effects of endogenous TrkB signaling. We provide proof-of-concept evidence for a novel strategy targeting receptor tyrosine signaling and identify a therapeutic with promise for prevention of TLE caused by status epilepticus in humans. PMID- 26481039 TI - Malignancy risk in Australian rheumatoid arthritis patients treated with anti tumour necrosis factor therapy: analysis of the Australian Rheumatology Association Database (ARAD) prospective cohort study. AB - BACKGROUND: Malignancy risk with tumour necrosis factor inhibitor (TNFi) therapy remains unclear. Our primary aim was to assess malignancy risk with TNFi therapy in a cohort of Australian patients with rheumatoid arthritis (RA). We also assessed risk in a biologic-naive group. METHODS: Demographic data of all RA patients enrolled in the Australian Rheumatology Association Database before 25 October 2010 were matched to national cancer records in July 2010 (linkage complete to 2007). Verified self-reported malignancies occurring between 1 January 2008 and 25 October 2010 were also included in the analysis. Standardised incidence ratios (SIRs) were used to compare malignancy incidence in biologic naive and TNFi-exposed ARAD participants to the general population using site-, age- and sex-specific rates by calendar year. Rate ratios (RRs) were used to compare malignancy incidence in TNFi-exposed participants to biologic-naive RA patients, and a composite RA cohort that included pre-TNFi person years, both adjusted for age, gender, smoking, methotrexate use and prior malignancy. RESULTS: Forty-four malignancies were reported after 5752 person-years in the TNFi-exposed group (N = 2145) and 32 malignancies were reported after 1682 person years in the biologic-naive group (N = 803). No overall increased risk of malignancy in TNFi-treated RA patients was found when compared with the general population or with biologic-naive RA patients. Compared to the biologic naive group, without the inclusion of pre-TNFi years in the comparator group, the relative risk of female breast cancer was reduced in TNFi-treated patients (RR 0.17 (95 % CI 0.03 to 0.95)). It was no longer significant when adding pre-TNFi years in the comparator group. The risk of melanoma was increased for both biologic naive and TNFi-treated patients when compared with the general population (SIR 2.72 (95 % CI 1.13 to 6.53) and SIR 2.03 (95 % CI 1.09 to 3.78) respectively). The relative risk of melanoma was not increased in the TNFi exposed group compared with biologic naive patients (RR 0.54, 95 % CI 0.12, 2.40). Inclusion of pre-TNFi person years in the comparator group did not change these results. CONCLUSIONS: Malignancy incidence was low in this RA cohort and biologic exposure did not increase the risk of malignancy. Melanoma risk was increased in both TNFi-treated and biologic-naive RA patients compared with the general population suggesting that RA status, and possibly methotrexate exposure, may be responsible. PMID- 26481040 TI - Long-term survival in low-grade endometrial stromal sarcoma with childbirth and multidisciplinary treatment: a case report. AB - INTRODUCTION: Low-grade endometrial stromal sarcoma is very rare and difficult to diagnose in the early stage. A standard treatment has not been established. In this case report of a patient with long-term survival, we describe an effective treatment for advanced low-grade endometrial stromal sarcoma. CASE PRESENTATION: A 24-year-old Japanese woman who presented with prolonged menstruation was diagnosed with leiomyoma on the basis of a specimen resected transvaginally. She underwent ten resections in 10 years without a malignancy diagnosis. During this period, she gave birth. At age 34 years, she visited our hospital, complaining of lower abdominal pain. A 10cm tumor was detected behind her uterus. The disease was diagnosed as an advanced malignant ovarian tumor before surgery. A laparotomy was performed, with many remnants left in the abdominal cavity. The final diagnosis was advanced low-grade endometrial stromal sarcoma. After 12 cycles of gemcitabine and docetaxel combination chemotherapy, the tumor disappeared completely. A retrospective pathological review of the specimens resected transvaginally showed that the tumors included low-grade endometrial stromal sarcoma elements. When the patient was age 42 years, the sarcoma recurred. It was detected around the right diaphragm and liver. Despite administration of gemcitabine and docetaxel, ascites and pleural effusion accumulated. Administration of medroxyprogesterone acetate, leuprorelin acetate, and anastrozole gradually reduced the ascites and pleural effusion. In addition to the three hormone drugs, 18 cycles of paclitaxel and carboplatin were administered. The patient recovered from her critically ill state and is currently alive with reduced tumor at age 45 years. CONCLUSIONS: Our patient with low-grade endometrial stromal sarcoma whose disease began in her youth gave birth and experienced long-term survival with surgery, chemotherapy, and hormone therapy. PMID- 26481041 TI - Growth inhibitory effect of an injectable hyaluronic acid-tyramine hydrogels incorporating human natural interferon-alpha and sorafenib on renal cell carcinoma cells. AB - Immunotherapy including interferon-alpha (IFN-alpha) is one of the treatment options for metastatic renal cell carcinoma (mRCC) patients. Despite clinical benefits for the selected patients, IFN-alpha therapy has some problems, such as poor tolerability and dose-limiting adverse effects. In addition, the frequent injections reduce a patient's quality of life and compliance. Recently, an injectable and biodegradable hydrogel system to prolong drug release is reported. In this study, we investigated the anticancer effect of IFN-alpha (Sumiferon(r)) incorporated hyaluronic acid-tyramine (HA-Tyr) hydrogels in human RCC-xenografted in nude mice. We also evaluated the synergistic efficacy of IFN-alpha incorporated HA-Tyr hydrogels+sorafenib in this model. IFN-alpha-incorporated HA Tyr hydrogels+sorafenib most effectively inhibited tumor growth on human RCC cells xenografted in nude mice. In addition, IFN-alpha-incorporated HA-Tyr hydrogels+sorafenib inhibited the proliferation of tumor in nude mice by inducing apoptosis and the suppression of angiogenesis. Our results suggest a possibility that HA-Tyr hydrogel drug delivery system prolongs the biological half-life of natural human IFN-alpha and enhances its anticancer effects on human RCC cells. STATEMENT OF SIGNIFICANCE: The scope of this study is to provide an alternative approach to improve the anticancer efficacy in renal cell carcinoma (RCC) treatment by using hyaluronic acid-tyramine (HA-Tyr) hydrogel drug delivery system. We investigated the anticancer effect of natural interferon-alpha (IFN alpha)-incorporated HA-Tyr hydrogels in RCC cells. We also evaluated the synergistic efficacy of natural human IFN-alpha-incorporated HA-Tyr hydrogels+sorafenib. We demonstrated that HA-Tyr hydrogel system is able to release natural human IFN-alpha in sustained manner and enhances its anticancer effects on human RCC cells. In addition, we suggested that IFN-alpha-incorporated HA-Tyr hydrogels+sorafenib exhibited most effectively anticancer effects. Hence, we believe that this approach could be applied to treatment with RCC in the future. PMID- 26481043 TI - Editorial. PMID- 26481042 TI - Endothelial sprouting and network formation in collagen- and fibrin-based modular microbeads. AB - A modular tissue engineering approach may have advantages over current therapies in providing rapid and sustained revascularization of ischemic tissue. In this study, modular protein microbeads were prepared from pure fibrin (FIB) and collagen-fibrin composites (COL-FIB) using a simple water-in-oil emulsification technique. Human endothelial cells and fibroblasts were embedded directly in the microbead matrix. The resulting microbeads were generally spheroidal with a diameter of 100-200MUm. Cell viability was high (75-80% viable) in microbeads, but was marginally lower than in bulk hydrogels of corresponding composition (85 90% viable). Cell proliferation was significantly greater in COL-FIB microbeads after two weeks in culture, compared to pure FIB microbeads. Upon embedding of microbeads in a surrounding fibrin hydrogel, endothelial cell networks formed inside the microbead matrix and extended into the surrounding matrix. The number of vessel segments, average segment length, and number of branch points was higher in FIB samples, compared to COL-FIB samples, resulting in significantly longer total vessel networks. Anastomosis of vessel networks from adjacent microbeads was also observed. These studies demonstrate that primitive vessel networks can be formed by modular protein microbeads containing embedded endothelial cells and fibroblasts. Such microbeads may find utility as prevascularized tissue modules that can be delivered minimally invasively as a therapy to restore blood flow to ischemic tissues. STATEMENT OF SIGNIFICANCE: Vascularization is critically important for tissue engineering and regenerative medicine, and materials that support and/or promote neovascularization are of value both for translational applications and for mechanistic studies and discovery-based research. Therefore, we fabricated small modular microbeads formulated from pure fibrin (FIB) and collagen-fibrin (COL-FIB) containing endothelial cells and supportive fibroblasts. We explored how cells encapsulated within these materials form microvessel-like networks both within and outside of the microbeads when embedded in larger 3D matrices. FIB microbeads were found to initiate more extensive sprouting into the surrounding ECM in vitro. These results represent an important step towards our goal of developing injectable biomaterial modules containing preformed vascular units that can rapidly restore vascularization to an ischemic tissue in vivo. PMID- 26481045 TI - [Pitfalls for renogram interpretation in pediatric urology]. AB - Renograms are currently used for functional assessment by pediatric urologists. The aim of the present work was to focus on the potential pitfalls concerning renography. Potential confounding factors are described in reference to concrete cases. The main types of pitfalls concern venous or urinary catheters and background area definition. Protocols and renogram interpretation are critiqued in a bibliographic review. We propose a technical update and original data on the potential pitfalls in renography interpretation. Multidisciplinary discussion between nuclear medicine, pediatrics and pediatric surgery departments is required before drawing conclusions. PMID- 26481044 TI - Nampt is required for long-term depression and the function of GluN2B subunit containing NMDA receptors. AB - Nicotinamide adenine dinucleotide (NAD(+)) is an essential coenzyme/cosubstrate for many biological processes in cellular metabolism. The rate-limiting step in the major pathway of mammalian NAD(+) biosynthesis is mediated by nicotinamide phosphoribosyltransferase (Nampt). Previously, we showed that mice lacking Nampt in forebrain excitatory neurons (CamKIIalphaNampt(-/-) mice) exhibited hyperactivity, impaired learning and memory, and reduced anxiety-like behaviors. However, it remained unclear if these functional effects were accompanied by synaptic changes. Here, we show that CamKIIalphaNampt(-/-) mice have impaired induction of long-term depression (LTD) in the Schaffer collateral pathway, but normal induction of long-term potentiation (LTP), at postnatal day 30. Pharmacological assessments demonstrated that CamKIIalphaNampt(-/-) mice also display dysfunction of synaptic GluN2B (NR2B)-containing N-methyl-d-aspartate receptors (NMDARs) prior to changes in NMDAR subunit expression. These results support a novel, important role for Nampt-mediated NAD(+) biosynthesis in LTD and in the function of GluN2B-containing NMDARs. PMID- 26481046 TI - Lentiviral vector-mediated transduction of goat undifferentiated spermatogonia. AB - Recent studies show that spermatogonial stem cells (SSCs) are able to colonize and form mature spermatozoa following transplantation into germ cell depleted testes of recipient males. Therefore, efficient ways for enrichment and gene transfer into SSCs provides a powerful tool for production of transgenic animals. In order to adapt the technique to goats, three issues were addressed: (i) enrichment of the undifferentiated spermatogonia including SSCs using magnetic activated cell sorting (MACS), (ii) lentiviral vector-mediated transduction of an enhanced green fluorescent protein (EGFP) transgene into enriched cells, and (iii) transplantation of transduced undifferentiated spermatogonia into the germ cell depleted testes of immune-suppressed mice to assess for migration and colony formation ability. Enriched cells were transduced by lentiviral vectors and subsequently analyzed for expression of THY1, PLZF, VASA, UCHL1 and BCL6B genes. Cells were also analyzed for GFP and PLZF by flow cytometry. Enriched transduced cells were transplanted into germ cell depleted mice testis. Quantitative analysis of transcripts revealed that MACS-enrichment significantly increased the expression of SSC-characteristic genes THY1, PLZF, VASA, UCHL1 and BCL6B compared to non-enriched population (P<=0.05). EGFP transduction did not affect the expression levels of SSC-characteristic genes. Flow cytometry revealed that 72% of transduced-enriched cells were positive for EGFP. Finally, transduced-enriched goat SSCs could colonize within the cells into the seminiferous tubules of germ cell depleted recipient mice at higher frequency than non-enriched cells. The results indicated that enrichment of goat undifferentiated spermatogonia by magnetic-activated cell sorting for THY1 antibody combined with lentiviral vector mediated transduction has the potential to be used for production of transgenic goats. PMID- 26481047 TI - Timed artificial insemination in blocks: A new alternative to improve fertility in lactating beef cows. AB - The aim of this study was to evaluate whether changing the interval from CIDR removal to timed artificial insemination (TAI) according to the diameter of the preovulatory follicle (POF) would improve pregnancy per AI in cows. In Study 1, a retrospective analysis of TAI experiments (n=96 cows) was performed to characterize the time of ovulation according to the diameter of the dominant follicle. It was observed that cows with a larger POF had ovulations earlier than cows with smaller POF, according to the equation: y=0.72x(2)-26.74x+264.54 (R(2)=0.63; P<0.001). In Study 2, lactating Nelore cows (n=412) were subjected to an EB-CIDR based TAI protocol. On the morning of Day 10 (time of TAI), cows were randomized into Control (n=209) and Block (n=203) groups; (1) Cows in the Control Group were TAI 48 h after CIDR removal (08:00 am on Day 10), and; (2) Cows in the block group were inseminated once at one of the following time points, according to the diameter of the POF on Day 10: B0 (POF>=15mm, TAI 0 h after convetional TAI), B1 (POF 13-14.9 mm, TAI 6h later), B2 (POF 10.1-12.9 mm, TAI 24h later) and B3 (POF<=10mm, TAI 30 h later). The cows of the Block Group had greater pregnancy rates per AI than the Control Group (129/203, 63.5% when compared with 102/209, 48.8%, respectively; P<0.01). In conclusion, results of the present study demonstrate that adjusting the timing of TAI according to the diameter of the POF can be an effective practice for improving fertility of cows in TAI protocols. PMID- 26481048 TI - Common and distinct neural mechanisms of the fundamental dimensions of social cognition. AB - In the present study, we used a valence classification task to investigate the common and distinct neural basis of the two fundamental dimensions of social cognition (agency and communion) using functional magnetic resonance imaging (fMRI). The results showed that several brain areas associated with mentalizing, along with the inferior parietal gyrus in the mirror system, showed overlap in response to both agentic and communal words. These findings suggest that both content categories are related to the neural basis of social cognition; further, several areas in the default mode network (DMN) showed similar deactivations between agency and communion, reflecting task-induced deactivation (TID). In terms of distinct activations, the findings indicated greater deactivations for communal than agentic content in the ventral anterior cingulate (vACC) and medial orbitofrontal cortex (mOFC). Communion also showed greater activation in some visual areas compared to agentic content, including occipital gyrus, lingual gyrus, and fusiform gyrus. These activations may reflect greater allocation of attentional resources to visual areas when processing communal content, or inhibition of cognitive activity irrelevant to task performance. If so, this suggests greater attention and engagement with communion-related content. The present research thus suggests common and differential activations for agency- versus communion-related content. PMID- 26481049 TI - Hederagenin, a major component of Clematis mandshurica Ruprecht root, attenuates inflammatory responses in RAW 264.7 cells and in mice. AB - Clematis mandshurica Ruprecht root has been used in Asia as a traditional anti inflammatory, analgesic, and antitumor agent. Its main active component is hederagenin, a naturally occurring triterpene, and in this study, we examined the anti-inflammatory effects of hederagenin in lipopolysaccharide-stimulated RAW 264.7 cells using an enzyme-linked immunosorbent assay, Western blot, and RT-PCR. In addition, its effects on acute inflammation in vivo were observed using a carrageenan-induced mouse hind paw edema assay. Furthermore, the changes on the histopathology and histomorphometry of hind paw skins were examined using carrageenan-treated mice. Treatment with hederagenin (10, 30 and 100MUM) resulted in inhibited levels of protein expression of lipopolysaccharide-stimulated iNOS, COX-2, and NF-kappaB as well as production of NO, PGE2, TNF-alpha, IL-1beta, and IL-6 induced by lipopolysaccharide. Consistent with these results, hederagenin also dose-dependently reduced the lipopolysaccharide-induced mRNA levels of iNOS and COX-2, and of the above-mentioned cytokines. Interestingly, results of the carrageenan-induced mouse hind paw edema assay showed an anti-edema effect of hederagenin. Furthermore, hederagenin (30mg/kg) inhibited the carrageenan-induced increases in skin thicknesses, infiltrated inflammatory cells, and mast cell degranulation. These results suggest that hederagenin may possess anti inflammatory activities. PMID- 26481051 TI - PLK4 trans-Autoactivation Controls Centriole Biogenesis in Space. AB - Centrioles are essential for cilia and centrosome assembly. In centriole containing cells, centrioles always form juxtaposed to pre-existing ones, motivating a century-old debate on centriole biogenesis control. Here, we show that trans-autoactivation of Polo-like kinase 4 (PLK4), the trigger of centriole biogenesis, is a critical event in the spatial control of that process. We demonstrate that centrioles promote PLK4 activation through its recruitment and local accumulation. Though centriole removal reduces the proportion of active PLK4, this is rescued by concentrating PLK4 to the peroxisome lumen. Moreover, while mild overexpression of PLK4 only triggers centriole amplification at the existing centriole, higher PLK4 levels trigger both centriolar and cytoplasmatic (de novo) biogenesis. Hence, centrioles promote their assembly locally and disfavor de novo synthesis. Similar mechanisms enforcing the local concentration and/or activity of other centriole components are likely to contribute to the spatial control of centriole biogenesis under physiological conditions. PMID- 26481050 TI - Establishment of Par-Polarized Cortical Domains via Phosphoregulated Membrane Motifs. AB - The Par polarity complex creates mutually exclusive cortical domains in diverse animal cells. Activity of the atypical protein kinase C (aPKC) is a key output of the Par complex as phosphorylation removes substrates from the Par domain. Here, we investigate how diverse, apparently unrelated Par substrates couple phosphorylation to cortical displacement. Each protein contains a basic and hydrophobic (BH) motif that interacts directly with phospholipids and also overlaps with aPKC phosphorylation sites. Phosphorylation alters the electrostatic character of the sequence, inhibiting interaction with phospholipids and the cell cortex. We searched for overlapping BH and aPKC phosphorylation site motifs (i.e., putative phosphoregulated BH motifs) in several animal proteomes. Candidate proteins with strong PRBH signals associated with the cell cortex but were displaced into the cytoplasm by aPKC. These findings demonstrate a potentially general mechanism for exclusion of proteins from the Par cortical domain in polarized cells. PMID- 26481052 TI - Taking Aim at Moving Targets in Computational Cell Migration. AB - Cell migration is central to the development and maintenance of multicellular organisms. Fundamental understanding of cell migration can, for example, direct novel therapeutic strategies to control invasive tumor cells. However, the study of cell migration yields an overabundance of experimental data that require demanding processing and analysis for results extraction. Computational methods and tools have therefore become essential in the quantification and modeling of cell migration data. We review computational approaches for the key tasks in the quantification of in vitro cell migration: image pre-processing, motion estimation and feature extraction. Moreover, we summarize the current state-of the-art for in silico modeling of cell migration. Finally, we provide a list of available software tools for cell migration to assist researchers in choosing the most appropriate solution for their needs. PMID- 26481053 TI - Chondromyxoid fibroma invasion of the transverse-sigmoid sinus junction causing posterior fossa hemorrhage. AB - We report a 50-year-old woman with a chondromyxoid fibroma of the occipital bone, who presented with a cerebellar hemorrhage due to invasion of the adjacent sinus. Chondromyxoid fibromas are benign cartilaginous tumors. However, this case represents the first example, to our knowledge, of a chondromyxoid fibroma invading the transverse-sigmoid junction, resulting in intracranial hemorrhage. Our report highlights that the location of an intracranial chondromyxoid fibroma is an important factor in guiding surgical management. PMID- 26481054 TI - Innovation and hard work: The 2015 George E. Palade Medal Award Lecture. AB - The George E Palade Medal is the highest honor awarded by the International Association of Pancreatology and is given to an individual who has made outstanding contributions to the understanding of the pancreas and pancreatic diseases. Professor David C Whitcomb, University of Pittsburgh, is the 2015 recipient. The Palade Lecture, presented in Shanghai, China on August 28, 2015, included 5 personal stories that provide perspective from a life-time of achievement: "My life in a nutshell"; "Two old ladies"; "7777"; "I helped put a man on the moon"; and "Rugby". Together, the stories provide encouragement to a younger generation, struggling to find their way as physicians and scientists who are working on pancreatic or other diseases in a challenging world. PMID- 26481056 TI - A systematic review of filler agents for aesthetic treatment of HIV facial lipoatrophy (FLA). AB - HIV facial lipoatrophy (FLA) is characterized by facial volume loss. HIV FLA affects the facial contours of the cheeks, temples, and orbits, and is associated with social stigma. Although new highly active antiretroviral therapy medications are associated with less severe FLA, the prevalence of HIV FLA among treated individuals exceeds 50%. The goal of our systematic review is to examine published clinical studies involving the use of filler agents for aesthetic treatment of HIV FLA and to provide evidence-based recommendations based on published efficacy and safety data. A systematic review of the published literature was performed on July 1, 2015, on filler agents for aesthetic treatment of HIV FLA. Based on published studies, poly-L-lactic acid is the only filler agent with grade of recommendation: B. Other reviewed filler agents received grade of recommendation: C or D. Poly-L-lactic acid may be best for treatment over temples and cheeks, whereas calcium hydroxylapatite, with a Food and Drug Administration indication of subdermal implantation, may be best used deeply over bone for focal enhancement. Additional long-term randomized controlled trials are necessary to elucidate the advantages and disadvantages of fillers that have different biophysical properties, in conjunction with cost effectiveness analysis, for treatment of HIV FLA. PMID- 26481055 TI - Fulminant lymphocytic myocarditis associated with orbital myositis and diaphragmatic paralysis. AB - Although the clinical presentation of myocarditis is very diverse, ranging from mild dyspnea to hemodynamic collapse, myocarditis accompanied with extracardiac myositis is extremely rare. We report a single case of fulminant myocarditis associated with orbital myositis and diaphragmatic paralysis in a 40-year-old man, which was successfully managed by immunosuppressive therapy with steroid. PMID- 26481057 TI - Factors related to outcome of early and delayed prosthetic joint infections. PMID- 26481058 TI - Evidence-based practice and barriers to compliance: Face bow transfer. AB - PURPOSE: To recapitulate a 2003 study inquiring of US dental schools whether they teach the face bow transfer by means of a survey in order to determine if compliance with clinical evidence has improved. METHODS: The same 54 dental schools surveyed in 2003 were asked the same question regarding whether they teach the use of the face bow transfer in the complete denture curriculum. RESULTS: Teaching of the face bow transfer has increased in prevalence from 84% of surveyed schools in 2003 to 93.75% of surveyed schools in 2015. CONCLUSIONS: This finding is especially interesting in light of the fact that there is no compelling evidence supporting the use of the face bow transfer with regard to improving patient outcomes. With respect to the continued unjustified teaching of the face bow transfer, some possible reasons for non-compliance with best available evidence are presented using the medical literature for reference. PMID- 26481059 TI - A conservative approach to retrieve a fractured abutment screw - Case report. AB - INTRODUCTION: Regarding implant-supported prostheses, the most reported types of complications are related to loosening or fracturing of abutment or prosthesis screws. This case report shows a series of procedures that allowed a conservative solution for a fractured screw. It avoided removing the implant and also allowed the same prosthesis to be used after guided-drilling the fractured screw and re tapping the implant internal threads. The same prosthesis was replaced immediately after the procedure. PATIENT: A 67-year-old male patient, who had a fractured abutment screw of the lower left first molar implant. The patient decided for the conservative treatment option and an attempt was made to remove the fractured screw. DISCUSSION: Parafunctional habits can generate excessive occlusal forces, which are risk factors associated with loosening and fracturing implant screws and even the fixtures themselves. This case report focus on the probable causes, difficulties and risks associated with this procedure and it also discusses the alternative approaches. CONCLUSION: The purposed treatment allowed a time and money saving resolution for fractured abutment screws. PMID- 26481060 TI - Prognostic value of lymphocyte-to-monocyte ratio in patients with solid tumors: A systematic review and meta-analysis. AB - BACKGROUND: The immune system plays an important role in cancer pathogenesis. A low lymphocyte-to-monocyte ratio (LMR), as a simple biomarker of host immune system, has been suggested to be related to poor prognosis in various cancers. We performed a systematic review and meta-analysis to quantify the prognostic value of LMR on clinical outcomes in non-hematologic solid tumors. PATIENTS AND METHODS: We searched PubMed and the ASCO online database of meeting abstracts up to July 2015 for relevant studies. We included studies assessing the prognostic impact of pre-treatment LMR on clinical outcomes in patients with non-hematologic solid tumors. The primary outcome was overall survival (OS) and the secondary outcomes were cancer-specific survival (CSS) and disease-free survival (DFS). The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated. RESULTS: A total of 11,197 patients from 29 studies were included. LMR lower than the cut-off was associated with poor OS (HR, 1.73; 95% CI, 1.55-1.93; P<0.001), CCS (HR, 1.56; 95% CI, 1.27-1.91; P<0.001) and DFS (HR, 1.56; 95% CI, 1.31-1.86; P<0.001). The effect of LMR on OS was observed in among various tumor types and across disease stages. The median cut-off value for LMR was 3.0 (range=2.0-5.3). Subgroup analysis according to cut-off value (<3.0, 3.0 to <4.0, 4.0 to <5.0, and ?5.0) showed a significant prognostic value of LMR on OS in all subgroups. CONCLUSIONS: A low pre-treatment LMR seems to represent an unfavorable and robust prognostic factor for clinical outcomes in patients with non-hematologic malignancies. FUNDING: None. PMID- 26481061 TI - Mitochondrial pharmacology: A need in modern biomedicine. PMID- 26481062 TI - Intraocular pressure evaluation in healthy eyes and diseased ones using contact and non contact devices. AB - PURPOSE: To analyze and compare intraocular pressure (IOP) values measured in healthy subjects (HS), keratoconus (KC) patients and patients that underwent myopic photorefractive keratectomy (REF), using Goldmann applanation tonometry (GAT), dynamic contour tonometry (DCT), ocular response analyzer (ORA) and Corvis ST (CST). METHODS: The study included 76 eyes of 76HS, 15 eyes of 15 KC patients and 18 eyes of 18 subjects that underwent REF. Each participant underwent a complete ophthalmic evaluation, IOP measurement with GAT, DCT, ORA and CST. RESULTS: HS showed a mean GAT value of 15.62+/-2.33 mm Hg, a mean DCT value of 17.44+/-2.51 mm Hg, a mean ORA value of 15.99+/-3.58 mm Hg and a mean CST value of 17.24+/-3.44 mm Hg. KC showed a mean GAT value of 15.07+/-1.83 mm Hg, a mean DCT value of 17.01+/-1.96 mm Hg, a mean ORA value of 13.58+/-2.99 mm Hg and a mean CST value of 14.37+/-1.89 mm Hg. REF showed a mean GAT value of 14.06+/-1.51 mm Hg, a mean DCT value of 15.12+/-2.34 mm Hg, a mean ORA value of 16.85+/-2.4 mm Hg and a mean CST value of 15.57+/-1.77 mm Hg. CONCLUSION: Our data suggest that ORA and GAT could be used interchangeably in HS; GAT, ORA and CST could be used interchangeably in KC patients and that GAT provides lower IOP values compared to the other devices in eyes previously submitted to myopic PRK. PMID- 26481063 TI - Functional integrity of rostral regions of the immature brainstem is impaired in babies born extremely preterm. AB - OBJECTIVE: Babies born extremely preterm are predisposed to brain damage. We test the hypothesis that functional integrity of the auditory brainstem, particularly the rostral regions, is impaired in extremely preterm babies. METHODS: We recruited 68 babies who were born at 23-27 weeks of gestation. At term date, these babies were studied by recording and analysing maximum length sequence brainstem auditory evoked response (MLS BAER) with click rates 91-910/s. Detailed data analysis was performed in 65 babies from whom reliable MLS BAER measurements were obtained. RESULTS: Compared with normal term controls, the extremely preterm babies showed a significant increase in wave V latency, and I-V interval at all rates 91-910/s (p<0.01-0.001). Of two small intervals, I-III interval showed no apparent abnormality, but III-V interval was significantly increased at all rates, which was supported by a significant increase in III-V/I-III interval ratio (all p<0.001). These abnormalities were more significant at higher than at lower rates. The slopes of wave V latency-, I-V interval- and particularly III-V interval-rate functions were all increased. The same was true for the slope of III-V/I-III interval ratio-rate function. CONCLUSIONS: MLS BAER variables that mainly reflect central neural conduction in the extremely preterm babies were abnormally increased. The most important abnormality was a significant increase in III-V interval and its click rate-dependent change. The abnormalities tended to be more significant than those previously reported in late and very preterm babies. SIGNIFICANCE: Babies born extremely preterm have a major impairment or maturational delay in functional integrity of the rostral regions of the immature brainstem, which is more significant than in less preterm babies. PMID- 26481064 TI - The small GTPase Rap1 is a modulator of Hedgehog signaling. AB - During development, the evolutionarily conserved Hedgehog (Hh) morphogen provides instructional cues that influence cell fate, cell affinity and tissue morphogenesis. To do so, the Hh signaling cascade must coordinate its activity with other morphogenetic signals. This can occur through engagement of or response to effectors that do not typically function as core Hh pathway components. Given the ability of small G proteins of the Ras family to impact cell survival, differentiation, growth and adhesion, we wanted to determine whether Hh and Ras signaling might intersect during development. We performed genetic modifier tests in Drosophila to examine the ability of select Ras family members to influence Hh signal output, and identified Rap1 as a positive modulator of Hh pathway activity. Our results suggest that Rap1 is activated to its GTP-bound form in response to Hh ligand, and that the GTPase exchange factor C3G likely contributes to this activation. The Rap1 effector Canoe (Cno) also impacts Hh signal output, suggesting that a C3G-Rap1-Cno axis intersects the Hh pathway during tissue morphogenesis. PMID- 26481066 TI - Obturator prostheses versus free tissue transfers: A systematic review of the optimal approach to improving the quality of life for patients with maxillary defects. AB - STATEMENT OF PROBLEM: Patient perspectives on the treatment options for maxillary defects, which include free tissue transfers or obturator prostheses, may help eliminate current uncertainty as to the best choice of treatment plan. PURPOSE: The purpose of this systematic review was to evaluate the quality of life (QoL) of patients with maxillary defects who had undergone restoration with obturator prostheses and/or free tissue transfers. MATERIAL AND METHODS: A systematic search of Medline/PubMed and Web of Science databases for articles published before April 2015 was performed by 2 independent reviewers. A manual search of articles published from January 2005 to March 2015 was also conducted. Studies published in English that evaluated the QoL in patients with head and neck cancers were included. The Cohen kappa method was used to calculate inter reviewer agreement. RESULTS: Ten studies were included. The University of Washington Head and Neck Questionnaire (UW-QOL) was most commonly used to measure QoL. The majority of maxillary defects were Class IIa-b. Two studies reported that the global QoL for patients with obturator prostheses is equivalent to or even better than that of other chronic disease populations. One study revealed no significant difference in QoL when the 2 treatment options were compared. CONCLUSIONS: The limited data indicate that the QoL of patients treated with obturator prostheses and that of patients free of tumors is similar. Well designed clinical studies are necessary to draw definitive conclusions about how obturator prostheses compare with free tissue transfers in terms of affecting patient QoL. PMID- 26481065 TI - Endoglin is required in Pax3-derived cells for embryonic blood vessel formation. AB - Mutations in endoglin, a TGFbeta/BMP coreceptor, are causal for hereditary hemorrhagic telangiectasia (HHT). Endoglin-null (Eng-/-) mouse embryos die at embryonic day (E)10.5-11.5 due to defects in angiogenesis. In part, this is due to an absence of vascular smooth muscle cell differentiation and vessel investment. Prior studies from our lab and others have shown the importance of endoglin expression in embryonic development in both endothelial cells and neural crest stem cells. These studies support the hypothesis that endoglin may play cell-autonomous roles in endothelial and vascular smooth muscle cell precursors. However, the requirement for endoglin in vascular cell precursors remains poorly defined. Our objective was to specifically delete endoglin in neural crest- and somite-derived Pax3-positive vascular precursors to understand the impact on somite progenitor cell contribution to embryonic vascular development. Pax3Cre mice were crossed with Eng+/- mice to obtain compound mutant Pax3(Cre/+);Eng+/- mice. These mice were then crossed with homozygous endoglin LoxP-mutated (Eng(LoxP/LoxP)) mice to conditionally delete the endoglin gene in specific lineages that contribute to endothelial and smooth muscle constituents of developing embryonic vessels. Pax3(Cre/+);Eng(LoxP/)(-) mice showed a variety of vascular defects at E10.5, and none of these mice survived past E12.5. Embryos analyzed at E10.5 showed malformations suggestive of misdirection of the intersomitic vessels. The dorsal aorta showed significant dilation with associated vascular smooth muscle cells exhibiting disorganization and enhanced expression of smooth muscle differentiation proteins, including smooth muscle actin. These results demonstrate a requirement for endoglin in descendants of Pax3-expressing vascular cell precursors, and thus provides new insight into the cellular basis underlying adult vascular diseases such as HHT. PMID- 26481067 TI - Is there still a need for prophylactic intra-abdominal drainage in elective major gastro-intestinal surgery? AB - Prophylactic drainage of the abdominal cavity after gastro-intestinal surgery is widely used. The rationale is that intra-abdominal drainage enhances early detection of complications (gastro-intestinal leakage, hemorrhage, bile leak), prevents collection of fluid or pus, reduces morbidity and mortality, and decreases the duration of hospital stay. However, dogmatic attitudes favoring systematic drain placement should be questioned. The aim of this review was to evaluate the evidence supporting systematic use of prophylactic abdominal drainage following gastrectomy, pancreatectomy, liver resection, and rectal resection. Based on this review of the literature: (i) there was no evidence in favor of intra-peritoneal drainage following total or sub-total gastrectomy with respect to morbidity-mortality, nor was it helpful in the diagnosis or management of leakage, however the level of evidence is low, (ii) following pancreatic resection, data are conflicting but, overall, suggest that the absence of drainage is prejudicial, and support the notion that short-term drainage is better than long-term drainage, (iii) after liver resection without hepatico intestinal anastomosis, high level evidence supports that there is no need for abdominal drainage, and (iv) following rectal resection, data are insufficient to establish recommendations. However, results from the French multicenter randomized controlled trial GRECCAR5 (NCT01269567) should provide new evidence this coming year. Accumulating data support that systematic drainage of the abdominal cavity in digestive surgery is a non-beneficial and obsolete practice, except following pancreatectomy where the consensus appears to indicate the usefulness of short-term drainage. While the level of evidence is high for liver resections, new randomized controlled trials are awaited regarding gastric, pancreatic and rectal surgery. PMID- 26481068 TI - Answer to the recent article by Blot C et al. "Conservative surgical management of persistent leak after sleeve gastrectomy by Roux-en-Y gastro-jejunostomy to the fistulous orifice". PMID- 26481069 TI - Clinicopathological features and outcomes in patients undergoing radical resection for early gastric cancer with signet ring cell histology. AB - BACKGROUND: The signet ring cell histology is regarded as an independent predictor of poor prognosis in advanced gastric adenocarcinomas, but its biologic behavior in early gastric cancer remains highly controversial. OBJECTIVE: Our objective was to compare the clinicopathological features and outcomes in patients undergoing curative resection between SRCs and non-SRCs histologic types of early gastric cancer. METHODS: Clinicopathologic features and the overall survival rates of 334 patients with early gastric cancer undergoing D2 curative resection from January 1994 to December 2008 were retrospectively reviewed and compared according to the histologic type. RESULTS: Clinicopathologic features were comparable between two groups, except age, ulcer findings and the presence of lymph node metastasis. The incidence of recurrence for SRCs group was significantly lower than that for non-SRCs group (10.4% vs. 19.6%; P<0.05). The overall 5-year survival rate was 88.6% in all cases. The overall survival rate of patients in SRCs group was significantly better than that of patients in non-SRCs group (5-year survival, 93.9% vs. 85.8%; P=0.027). Multivariable analysis revealed that SRCs subtype, lymphovascular invasion, and lymph node metastasis were independent prognostic factors. CONCLUSION: Our analysis revealed that the biological behavior of SRCs was different from other undifferentiated cancer histologic subtypes in early stage. Early gastric cancer with signet ring cell histology had low incidence of lymph node metastasis and a relatively favorable prognosis. PMID- 26481070 TI - Alternative Solution for Bilateral Common Iliac Aneurysm in a Patient With Left External Iliac Artery Occlusion. PMID- 26481071 TI - Lipoprotein subfraction oxidation in acute exercise and ageing. AB - Exercise and ageing can independently increase free radical production that may enhance the susceptibility of LDL to oxidation and create a more atherogenic LDL particle. This investigation was designed to examine exercise and ageing on the susceptibility of LDL subfractions to oxidation. Eleven aged (55 +/- 4 years) and twelve young (21 +/- 2 years) participants completed a progressive exercise test to exhaustion and within one week performed a 1 h bout of moderate intensity (65% VO(2max)) exercise. Blood was assayed for metabolites associated with lipid composition (total cholesterol, free cholesterol, triglycerides) and lipoprotein susceptibility to oxidation. Exercise increased small density (sdLDL) oxidation, independently of age (p < 0.05). However, sdLDL oxidation further increased 24 h post exercise in the aged group (p < 0.05). With regards to the changes in lipid components within LDL, free and total cholesterol and triglycerides in large buoyant (lbLDL) were all elevated 24 h post exercise in aged compared with young (p < 0.05 for all comparisons). There was a decrease in triglycerides in medium density (mdLDL) 24 h post exercise in the aged group (p < 0.05). The lipid composition of sdLDL, VLDL, HDL(2), HDL(3) and serum lipid hydroperoxides remained unchanged as a function of exercise and ageing (p > 0.05). Although regular exercise training is known to be protective against cardiovascular disease (CVD) onset, our data demonstrates that acute exercise can increase sdLDL oxidative susceptibility, and this is independent of age and regardless of a change in LDL lipid composition. However, age seems to be a determining factor with regards the susceptibility of sdLDL to oxidation 24 h following exercise. PMID- 26481072 TI - [In Process Citation]. AB - OBJECTIVE: The significance of surgery in elderly patients with lung cancer is debated. The age is a predisposing risk factor for developing cancer thereby the possibilities of surgical procedure is increasing in the elderly patients. To clarify the benefit of surgery in patients with lung cancer aged 70 years and over we reviewed our cohort of 206 patients. METHODS: Data of elderly patients out of 4022 lung cancer cases were analysed. 124 patients with lung tumours presented symptomatically and imaging suggested the presence of lung malignancies in 82 patients. 155 tumours were located peripherally, while 51 were central. All patients underwent detailed lung function test and cardiovascular examinations prior to surgery; significant comorbidities were optimised, too. RESULTS: One patient's data was lost during follow-up. In 122 cases lobectomy was the choice of surgery, 49 patients underwent atypical resection, 16 had pneumonectomies, and 18 explorations were performed. Postoperative mortality rate was 1%. Histology revealed adenocarcinoma in 121 patients, squamous cell carcinoma in 73 patients, small cell carcinoma nine and large cell carcinoma three patients. As far as postoperative staging 100 patients had stage I, 54 had stage II, 38 had stage III (III/a: 34, III/b: 4) and 13 had stage IV disease. 5-year survival was 40%. Survival by histology was 40% for adenocarcinoma and 45% for squamous cell carcinoma at five years. Survival rate for patients with stage I was 58% (st I/a: 75%), with stage II 29%, with stage III 14% (st III/a: 17%), with stage IV no five-year survivor was observed. Lymph node involvement was significantly associated with outcome (5-year survival rate in N0 was 49% in N2: 8%). CONCLUSIONS: Our results confirmed an acceptable perioperative risk and benefit of surgery for elderly patients with lung cancer. The age alone is not a contraindication for lung resection with meticulous patient's selection and active postoperative rehabilitation. More patients had adenocarcinoma than squamous cell carcinoma, similarly to all patients. In the elderly patients limited parenchymal resection is an acceptable alternative. Surgery offers good outcome in early stage disease, but surgery should not be the choice of treatment for advanced cancers (st III/b and st IV especially N2). PMID- 26481073 TI - [In Process Citation]. AB - INTRODUCTION: The number of patients operated on with endometriosis increases, the urological organ and the bowels are involved in 10-40% of the cases in addition to the gynaecological organs. PATIENTS AND METHODS: Sigmoideoscopy detected bowel endometriosis in 224 patients from 383 patients with endometriosis, and 127 patients were operated on from 14.07.2009 to 13.01.2014 at the 1st Gynaecological Department of Semmelweis University, Budapest, Hungary. All the operation was made by the same gynaecologist and surgeon team. RESULTS: Segment resection of the bowel was performed in 120 patients, local resection in two patients and shaving in another two cases. The involved part of the bowels were the rectum at 46 patients, rectosigmoid in 68, sigmoid bowel in 30, coecum in 4, appendix in 2 and the small intestine in 2 patients. Bladder resection was carried out in 9 patients, ureter resection in two patients and ureterolysis in 26 cases were done due to infiltration of the urological organs. The laparoscopic operation needed to be converted on one single occasion due to bleeding from the epigastric artery, and a laparoscopic suture of the anastomosis was applied for bleeding in another patient. The specimen was extracted transvaginally in 16 patients and transanally in 13 patients. Anastomotic leakage was detected in two patients and rectovaginal fistula in four patients. All reoperations (creation and closing of the stoma) were done laparoscopically. CONCLUSIONS: The treatment of the bowel endometriosis is suggested with segment resection by multidisciplinary team, where the invasivity can be decreased by transanal specimen extraction. PMID- 26481074 TI - [Not Available]. AB - Among patients undergoing radical cystectomy for muscle-invasive bladder cancer, local and distant recurrence is the main reason for cancer-related deaths. In case of adrenal location of metachronous metastases, the standard treatment consists on cisplatin-based systemic chemotherapy. While surgical removal of metastasis remains controversial approach, more and more data support such treatment as effective and safe. We report two cases of patients submitted to laparoscopic adrenalectomy as a sole treatment mode due to metachronous metastases of bladder cancer. No adjuvant systemic therapy was implemented. After a follow-up of 12 months patients remain disease free. This report is another voice in the on-going debate on the role of surgical treatment of patients with metastatic bladder cancer. PMID- 26481075 TI - [In Process Citation]. AB - Due to the climate change zoonoses, dirofilariasis in particular is spreading. Hence, it is likely that we will encounter with this problem more frequently in the future Our intention with this case presentation is to draw attention to the increasing number of nematodes that cause differential diagnostic problems. The patient underwent surgery with suspicion of pulmonary malignancy suggested by a peripheral rounded opacity in imaging, but histological examination revealed dirofilariasis. PMID- 26481077 TI - [In Process Citation]. PMID- 26481076 TI - [In Process Citation]. PMID- 26481079 TI - The Underestimated Belly Factor: Waist Circumference Is Linked to Significant Morbidity Following Isolated Coronary Artery Bypass Grafting. AB - BACKGROUND: Waist circumference (WC) and body mass index (BMI) are clinically used to assess adiposity. The aim of the present study was to evaluate the association of WC with postoperative morbidity and mortality in patients who underwent isolated coronary artery bypass grafting (CABG) in relation to patients' BMI category. METHODS: We analyzed the associations of WC and BMI with short-term postoperative outcomes in a cohort of 7446 patients who underwent isolated CABG. We performed univariate and adjusted analyses on main postoperative outcomes after CABG for WC and BMI. RESULTS: Adverse events researched included postoperative mortality, intensive care unit and hospital length of stay, cardiovascular and cerebrovascular events, respiratory complications, infectious, hemostasis complications, and renal complications. WC was independently associated with all postoperative outcomes except prolonged intubation and mortality. Overall, patients in the upper WC quartile in each BMI category were at increased risk of adverse events compared with patients in the lower 3 WC quartiles, with a maximal incremental risk of 1.91 (95% confidence interval, 1.23-2.95) among patients with a BMI >= 35. This association was observed for men and women, across all overweight and obesity categories. Neither WC nor BMI was associated with short-term postoperative mortality. CONCLUSIONS: In our large cohort of patients who underwent isolated CABG, WC was significantly associated with clinical adverse events, independently of BMI. These findings provide further evidence on the added value of measuring WC as a simple and easy to measure anthropometric marker to refine risk assessment beyond BMI among patients who undergo CABG. PMID- 26481078 TI - Differences in Vessel Healing Between Sirolimus- and Everolimus-Eluting Stent Implantation for Bifurcation Lesions: The J-REVERSE Optical Coherence Tomography Substudy. AB - BACKGROUND: We aimed to clarify the differences in vessel healing after stenting of bifurcation lesions using sirolimus-eluting stents (SESs) or everolimus eluting stents (EESs). METHODS: Japanese Registry Study in Comparison Between Everolimus-Eluting Stent and Sirolimus-Eluting Stent for the Bifurcation Lesion (J-REVERSE) is a prospective multicentre registry of 303 bifurcation lesions that were treated with provisional SES or EES with or without final kissing inflation. The first 115 lesions at selected study sites were predefined for inclusion in the optical coherence tomography (OCT) substudy, and 9-month follow-up OCT was conducted in 64 lesions (SES, n = 18; EES, n = 46). In addition to standard OCT parameters, stent eccentricity index (SEI; minimum divided by the maximum stent diameter), neointimal unevenness score (NUS; maximum neointimal thickness in the cross-section [CS] divided by the average neointimal thickness [NIT] of the same CS; uniformity of the neointima suppression) were averaged for each segment (proximal, bifurcation, and distal segments). RESULTS: Overall, the average stent and luminal area, NIT, and frequency of uncovered struts were similar. The frequency of malapposed struts and SEI were significantly lower in the EES group than in the SES group. The EES group had a significantly smaller NUS in the proximal and distal segments. CONCLUSIONS: EESs offer homogeneous vessel healing with less malapposition in the treatment of bifurcation lesions. PMID- 26481080 TI - Left Ventricular Dilatation Assessed on the Lateral Chest Radiograph: The Classic Hoffman and Rigler Sign Falls Short in a Modern-Day Population. AB - BACKGROUND: The classic Hoffman and Rigler (H&R) sign, originally described in 1965, suggests that left ventricular (LV) dilatation is present if the left ventricle extends more than 18 mm posterior to the inferior vena cava at a level 2 cm above their crossing on a lateral chest radiograph. This sign is still widely used by radiologists but has not been well evaluated against modern methods of noninvasive assessment. This study investigated the sensitivity and specificity of the H&R sign in a modern population. METHODS: A sample of 145 patients with LV dilatation based on current echocardiographic criteria was matched for age and sex with 145 patients without LV dilatation. Patients were required to have undergone a lateral chest radiograph in the 3 months before or after undergoing echocardiography; the H&R sign and the cardiothoracic index were assessed on the radiograph independently by 2 blinded physicians. RESULTS: Using the threshold value of 18 mm, sensitivity, specificity, and positive and negative likelihood ratios of the H&R sign were 54.9%, 59.2%, 1.34, and 0.76, respectively (area under the curve [AUC], 0.58). In comparison, the cardiothoracic index provided better prediction of LV dilatation (sensitivity, 87.9%; specificity, 47.5%; AUC, 0.72). CONCLUSIONS: The H&R sign is a poor marker of LV enlargement when compared with echocardiography and should not be used as a radiologic index of LV enlargement. PMID- 26481081 TI - Refractory Hypoxemia After Laparoscopic Nissen Fundoplication. AB - Postoperative hypoxemia can result from a variety of causes. We describe a case of platypnea-orthodeoxia caused by shunting across a patent foramen ovale in a 72 year-old woman immediately after a laparoscopic Nissen fundoplication procedure. This was diagnosed by echocardiography and treated successfully with percutaneous device closure. An intracardiac shunt should always be considered as a potential cause of refractory postoperative hypoxemia after procedures on the thorax and upper abdomen. PMID- 26481082 TI - Heart Failure, Iron Deficiency, and Supplementation: Where Do We Stand? PMID- 26481084 TI - Transcatheter Aortic Valve Implantation: Current and Evolving Indications. AB - Transcatheter Aortic Valve Implantation (TAVI) was initially developed to treat aortic stenosis in patients with high risk for surgical intervention. With great initial adoption of the technology and improvements in device design and procedural success TAVI is increasingly being performed in broader populations for diverse indications. This paper is a concise review of the evolving and expanding use of TAVI in the current era. PMID- 26481083 TI - Novel Approaches in Primary Cardiovascular Disease Prevention: The HOPE-3 Trial Rationale, Design, and Participants' Baseline Characteristics. AB - BACKGROUND: Cholesterol and blood pressure (BP) can be effectively and safely lowered with statin drugs and BP-lowering drugs, reducing major cardiovascular (CV) events by 20%-30% within 5 years in high-risk individuals. However, there are limited data in lower-risk populations. The Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial is evaluating whether cholesterol lowering with a statin drug, BP lowering with low doses of 2 antihypertensive agents, and their combination safely reduce major CV events in individuals at intermediate risk who have had no previous vascular events and have average cholesterol and BP levels. METHODS: A total of 12,705 women 65 years or older and men 55 years or older with at least 1 CV risk factor, no known CV disease, and without any clear indication or contraindication to the study drugs were randomized to rosuvastatin 10 mg/d or placebo and to candesartan/hydrochlorothiazide 16/12.5 mg/d or placebo (2 * 2 factorial design) and will be followed for a mean of 5.8 years. The coprimary study outcomes are the composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke and the composite of CV death, nonfatal MI, nonfatal stroke, resuscitated cardiac arrest, heart failure, and arterial revascularization. RESULTS: Participants were recruited from 21 countries in North America, South America, Europe, Asia, and Australia. Mean age at randomization was 66 years and 46% were women. CONCLUSIONS: The HOPE-3 trial will provide new information on cholesterol and BP lowering in intermediate-risk populations with average cholesterol and BP levels and is expected to inform approaches to primary prevention worldwide (HOPE-3 ClinicalTrials.gov NCT00468923). PMID- 26481085 TI - Cardiopulmonary Bypass Increases Plasma Glial Fibrillary Acidic Protein Only in First Stage Palliation of Hypoplastic Left Heart Syndrome. AB - BACKGROUND: Univentricular congenital heart defects require open-heart surgery soon after birth, and are associated with risk of brain injury and poor neurologic outcome. METHODS: This is a prospective, observational study on children undergoing cardiac surgery. Plasma glial fibrillary acidic protein (GFAP), as an early marker of brain injury, was measured by ELISA at the end of anaesthesia induction, initiation of cardiopulmonary bypass (CPB), the end of cooling, the end of rewarming, the end of CPB, and after protamine administration. We recorded clinical and surgical parameters to assess which CPB phase and clinical parameters were associated with a GFAP increase. RESULTS: We studied 13 children less than 50 months of age: 8 underwent Norwood or Damus-Kaye Stansel palliation (group 1) and 5 underwent Fontan procedure (group 2). A GFAP increase was only observed in group 1, with the highest median value at the end of rewarming. No quantifiable levels of GFAP were measured at pre-bypass and the start of CPB stages in all patients. End of cooling and CPB-end GFAP, GFAP maximum value, and GFAP area under the curve all correlated with the CPB time spent at a cerebral regional saturation < 45% (P = 0.021, 0.028, 0.007, 0.021, respectively). CONCLUSIONS: Children with univentricular heart defects exhibit a CPB plasma-GFAP increase only after stage 1 palliation. The maximum GFAP increase occurred at the end of rewarming. Further studies are needed to identify which clinical or surgical parameter(s) could reflect a GFAP increase during surgery for congenital heart defects, and whether GFAP levels correlate with the neurologic outcome. PMID- 26481086 TI - Obstructive Sleep Apnea and Cardiovascular Risk. PMID- 26481087 TI - Arch to Descending Aorta Extra-anatomic Aortic Repair for Thoracic Stent Graft Infection. AB - We report a case of a pedunculated mass of the aortic isthmus. The patient was treated with bilateral carotid-subclavian bypass and a stent graft to cover the thrombus within the distal arch. The postoperative course was complicated by a stent graft infection. The patient underwent graft explantation with aortic continuity using extra-anatomic bypass from the aortic arch to the distal descending aorta. PMID- 26481088 TI - A Pilot Study on the Utility of Serum Metabolomics in Neuroblastoma Patients and Xenograft Models. AB - BACKGROUND: Improved prediction of neuroblastoma (NB) behavior is needed to detect treatment-refractory disease and may allow further reduction in therapy for some patients. In this regard, serum metabolomic analysis has proven utility in several cancer types. We hypothesize that serum metabolomic analysis will correlate with risk-group classification for patients with NB, and sensitively detect NB in murine xenograft models. PROCEDURE: A pilot study was done on Children's Oncology Group (COG) tumor bank sera from 10 patients (five high-, five low-risk). An institutional pilot study was carried out on five patients comparing sera obtained during active versus minimal disease (complete response/very good partial response; CR/VGPR). XENOGRAFT: Flank tumors were established in Nu/Nu mice by injection of NB cell lines (IMR-32, SH-EP, SK-N-AS). Serum for comparison was drawn pre-injection, at 1 week after injection when there was no visible tumor, and again once tumors were grossly visible. Comparisons were also made between tumor bearing mouse serum and supernatants from NB cell lines. METABOLOMIC ANALYSIS: Samples were analyzed by nuclear magnetic resonance and/or gas chromatography-mass spectrometry. Multivariate data analysis was conducted using SIMCA-P (Umetrics). RESULTS: Serum metabolomic analysis differentiated high- and low-risk patients as well as active disease from CR/VGPR. Differences were in nitrogen, amino acid, and carbohydrate metabolism, as well as ketosis. The serum metabolomic signature in murine xenograft models sensitively detected NB cells and correlated with disease burden. Similar metabolic changes attributable to NB were noted in both human and murine serum. CONCLUSIONS: Serum metabolomic analysis can distinguish several characteristics of NB. A larger analysis of COG banked sera is warranted. PMID- 26481090 TI - Prevention of pre-eclampsia by low-molecular-weight heparin in addition to aspirin: a meta-analysis. AB - OBJECTIVE: To estimate the impact of adding low-molecular-weight heparin (LMWH) or unfractionated heparin to low-dose aspirin started <= 16 weeks' gestation on the prevalence of pre-eclampsia (PE) and the delivery of a small-for-gestational age (SGA) neonate. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed by searching the medical databases PubMed, EMBASE, Web of Science and Cochrane Central. Pregnant women randomized to receive LMWH or unfractionated heparin in addition to low-dose aspirin were compared with those who received low-dose aspirin alone. Outcome measures were PE, severe PE, early-onset PE and SGA. Pooled relative risks (RRs) with 95% CI were calculated using a random-effects model. RESULTS: Eight RCTs met the inclusion criteria; the indication for recruitment was previous recurrent miscarriage in five studies (three included women with thrombophilia) and a history of severe or early-onset PE in three studies (including women with thrombophilia in one). LMWH was administered in seven studies and unfractionated heparin in one. In women with a history of PE, treatment with LMWH and aspirin, compared with aspirin alone, was associated with a significant reduction in development of PE (three trials (n = 379); RR, 0.54 (95% CI, 0.31-0.92); P = 0.03) and in delivery of SGA neonates (two trials (n = 363); RR, 0.54 (95% CI, 0.32-0.91); P = 0.02). These outcomes were not significantly reduced in women with recurrent miscarriage who received LMWH and aspirin, compared with aspirin alone. The small number of studies precluded sensitivity analyses and the evaluation of publication biases. Blinding to the allocation treatment was absent in all RCTs. CONCLUSIONS: Based on limited evidence, the addition of LMWH to low-dose aspirin could reduce the prevalence of PE and SGA in women with a history of PE. This observation should be the basis of a well-conducted future trial rather than a recommendation for immediate clinical application. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26481089 TI - Spatially extensive microbial biogeography of the Indian Ocean provides insights into the unique community structure of a pristine coral atoll. AB - Microorganisms act both as drivers and indicators of perturbations in the marine environment. In an effort to establish baselines to predict the response of marine habitats to environmental change, here we report a broad survey of microbial diversity across the Indian Ocean, including the first microbial samples collected in the pristine lagoon of Salomon Islands, Chagos Archipelago. This was the first large-scale ecogenomic survey aboard a private yacht employing a 'citizen oceanography' approach and tools and protocols easily adapted to ocean going sailboats. Our data highlighted biogeographic patterns in microbial community composition across the Indian Ocean. Samples from within the Salomon Islands lagoon contained a community which was different even from adjacent samples despite constant water exchange, driven by the dominance of the photosynthetic cyanobacterium Synechococcus. In the lagoon, Synechococcus was also responsible for driving shifts in the metatranscriptional profiles. Enrichment of transcripts related to photosynthesis and nutrient cycling indicated bottom-up controls of community structure. However a five-fold increase in viral transcripts within the lagoon during the day, suggested a concomitant top-down control by bacteriophages. Indeed, genome recruitment against Synechococcus reference genomes suggested a role of viruses in providing the ecological filter for determining the beta-diversity patterns in this system. PMID- 26481091 TI - Random Plant Viral Variants Attain Temporal Advantages During Systemic Infections and in Turn Resist other Variants of the Same Virus. AB - Infection of plants with viruses containing multiple variants frequently leads to dominance by a few random variants in the systemically infected leaves (SLs), for which a plausible explanation is lacking. We show here that SL dominance by a given viral variant is adequately explained by its fortuitous lead in systemic spread, coupled with its resistance to superinfection by other variants. We analyzed the fate of a multi-variant turnip crinkle virus (TCV) population in Arabidopsis and N. benthamiana plants. Both wild-type and RNA silencing-defective plants displayed a similar pattern of random dominance by a few variant genotypes, thus discounting a prominent role for RNA silencing. When introduced to plants sequentially as two subpopulations, a twelve-hour head-start was sufficient for the first set to dominate. Finally, SLs of TCV-infected plants became highly resistant to secondary invasions of another TCV variant. We propose that random distribution of variant foci on inoculated leaves allows different variants to lead systemic movement in different plants. The leading variants then colonize large areas of SLs, and resist the superinfection of lagging variants in the same areas. In conclusion, superinfection resistance is the primary driver of random enrichment of viral variants in systemically infected plants. PMID- 26481092 TI - A Multistate Model Predicting Mortality, Length of Stay, and Readmission for Surgical Patients. AB - OBJECTIVE: Simultaneously evaluate postoperative mortality, length of stay (LOS), and readmission. DATA SOURCE: National Surgical Quality Improvement Program (NSQIP). DESIGN: Retrospective cohort. METHODS: Data from elective general surgical patients were obtained from the 2012 NSQIP Participant Use File. For each postoperative day, each patient's state was classified as index hospitalization, discharged home, discharged to long-term care (LTC), readmitted, or dead. Transition rates were estimated using exponential regression, assuming constant rates for specified time periods. These estimates were combined into a multistate model, simulated results of which were compared to observed outcomes. FINDINGS: Age, comorbidities, more complex procedures, and longer index LOS were associated with lower rates of discharge home and higher rates of death, discharge to LTC, and readmission. The longer patients had been discharged, the less likely they were to die or be readmitted. The model predicted 30-day mortality 0.38 percent (95 percent CI: 0.36-0.41), index LOS 2.85 days (95 percent CI: 2.83-2.86), LTC discharge 2.76 percent (95 percent CI: 2.69-2.82), and readmissions 5.53 percent (95 percent CI: 5.43-5.62); observed values were 0.39 percent, 2.82 days, 2.87 percent, and 5.70 percent, respectively. CONCLUSIONS: Multistate models can simultaneously predict postoperative mortality, LOS, discharge destination, and readmissions, which allows multidimensional comparison of surgical outcomes. PMID- 26481096 TI - Repair: Mobilizing stem cells. PMID- 26481098 TI - The neural bases of emotion regulation. AB - Emotions are powerful determinants of behaviour, thought and experience, and they may be regulated in various ways. Neuroimaging studies have implicated several brain regions in emotion regulation, including the ventral anterior cingulate and ventromedial prefrontal cortices, as well as the lateral prefrontal and parietal cortices. Drawing on computational approaches to value-based decision-making and reinforcement learning, we propose a unifying conceptual framework for understanding the neural bases of diverse forms of emotion regulation. PMID- 26481099 TI - Sulfur-Limonene Polysulfide: A Material Synthesized Entirely from Industrial By Products and Its Use in Removing Toxic Metals from Water and Soil. AB - A polysulfide material was synthesized by the direct reaction of sulfur and d limonene, by-products of the petroleum and citrus industries, respectively. The resulting material was processed into functional coatings or molded into solid devices for the removal of palladium and mercury salts from water and soil. The binding of mercury(II) to the sulfur-limonene polysulfide resulted in a color change. These properties motivate application in next-generation environmental remediation and mercury sensing. PMID- 26481100 TI - Genome editing of CXCR4 by CRISPR/cas9 confers cells resistant to HIV-1 infection. AB - Genome editing via CRISPR/Cas9 has become an efficient and reliable way to make precise, targeted changes to the genome of living cells. CXCR4 is a co-receptor for the human immunodeficiency virus type 1 (HIV-1) infection and has been considered as an important therapeutic target for AIDS. CXCR4 mediates viral entry into human CD4(+) cells by binding to envelope protein, gp120. Here, we show that human CXCR4 gene is efficiently disrupted by CRISPR/Cas9-mediated genome editing, leading to HIV-1 resistance of human primary CD4(+) T cells. We also show that the Cas9-mediated ablation of CXCR4 demonstrated high specificity and negligible off-target effects without affecting cell division and propagation. The precise and efficient genome editing of CXCR4 will provide a new strategy for therapeutic application against HIV-1 infection. PMID- 26481101 TI - The effects of high-intensity interval training on glucose regulation and insulin resistance: a meta-analysis. AB - The aim of this meta-analysis was to quantify the effects of high-intensity interval training (HIIT) on markers of glucose regulation and insulin resistance compared with control conditions (CON) or continuous training (CT). Databases were searched for HIIT interventions based upon the inclusion criteria: training >=2 weeks, adult participants and outcome measurements that included insulin resistance, fasting glucose, HbA1c or fasting insulin. Dual interventions and participants with type 1 diabetes were excluded. Fifty studies were included. There was a reduction in insulin resistance following HIIT compared with both CON and CT (HIIT vs. CON: standardized mean difference [SMD] = -0.49, confidence intervals [CIs] -0.87 to -0.12, P = 0.009; CT: SMD = -0.35, -0.68 to -0.02, P = 0.036). Compared with CON, HbA1c decreased by 0.19% (-0.36 to -0.03, P = 0.021) and body weight decreased by 1.3 kg (-1.9 to -0.7, P < 0.001). There were no statistically significant differences between groups in other outcomes overall. However, participants at risk of or with type 2 diabetes experienced reductions in fasting glucose (-0.92 mmol L(-1), -1.22 to -0.62, P < 0.001) compared with CON. HIIT appears effective at improving metabolic health, particularly in those at risk of or with type 2 diabetes. Larger randomized controlled trials of longer duration than those included in this meta-analysis are required to confirm these results. PMID- 26481102 TI - Monitoring 2-phenylethanamine and 2-(3-hydroxyphenyl)acetamide sulfate in doping controls. AB - 2-Phenylethanamine (phenethylamine, PEA) represents the core structure of numerous drugs with stimulant-like properties and is explicitly featured as so called specified substance on the World Anti-Doping Agency (WADA) Prohibited List. Due to its natural occurrence in humans as well as its presence in dietary products, studies concerning the ability of test methods to differentiate between an illicit intake and the renal elimination of endogenously produced PEA were indicated. Following the addition of PEA to the Prohibited List in January 2015, retrospective evaluation of routine doping control data of 10 190 urine samples generated by combined gas chromatography-mass spectrometry and nitrogen phosphorus-specific detection (GC-MS/NPD) was performed. Signals for PEA at approximate concentrations > 500 ng/mL were observed in 31 cases (0.3%), which were subjected to a validated isotope-dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) test method for accurate quantification of the target analyte. Further, using elimination study urine samples collected after a single oral administration of 250 mg of PEA hydrochloride to two healthy male volunteers, two tentatively identified metabolites of PEA were observed and evaluated concerning their utility as discriminative markers for PEA intake. The ID-LC-MS/MS approach was extended to allow for the simultaneous detection of PEA and 2-(3-hydroxyphenyl)acetamide sulfate (M1), and concentration ratios of M1 and PEA were calculated for elimination study urine samples and a total of 205 doping control urine samples that returned findings for PEA at estimated concentrations of 50-2500 ng/mL. Urine samples of the elimination study with PEA yielded concentration ratios of M1/PEA up to values of 9.4. Notably, the urinary concentration of PEA did increase with the intake of PEA only to a modest extent, suggesting a comprehensive metabolism of the orally administered substance. Conversely, doping control urine samples with elevated (>50 ng/mL) amounts of PEA returned quantifiable concentrations of M1 only in 3 cases, which yielded maximum ratios of M1/PEA of 0.9, indicating an origin of PEA other than an orally ingested drug formulation. Consequently, the consideration of analyte abundance ratios (e.g. M1/PEA) is suggested as a means to identify the use of PEA by athletes, but further studies to support potential decisive criteria are warranted. PMID- 26481103 TI - Antibacterial efficacy of 405, 460 and 520 nm light emitting diodes on Lactobacillus plantarum, Staphylococcus aureus and Vibrio parahaemolyticus. AB - AIMS: Little information is available on a direct comparison of the antibacterial efficacy of light emitting diode (LEDs) of different peak wavelengths. Thus, the objective of this study was to evaluate the effect of LEDs of three different wavelengths on bacterial inactivation. METHODS AND RESULTS: Lactobacillus plantarum, Staphylococcus aureus and Vibrio parahaemolyticus were illuminated with 405, 460 and 520 nm LEDs at 4, 10 and 25 degrees C respectively. Inactivation curves were plotted and fitted using Gompertz Model. Illumination with 405 and 460 nm LED produced significant inactivation (P < 0.05) in the population of V. parahaemolyticus (>4 log) while Lact. plantarum and Staph. aureus showed relatively less susceptibility to the LED illumination. The 520 nm LED produced negligible inactivation. CONCLUSIONS: The 405 and 460 nm LEDs proved more effective in inactivating the selected foodborne bacteria in this study compared to 520 nm LED. The 405 nm LED showed the greatest antibacterial effect at the same level of energy dose. SIGNIFICANCE AND IMPACT OF THE STUDY: The results in this study demonstrated the antibacterial efficacy of 405 nm LED on Lact. plantarum and V. parahaemolyticus, suggesting its potential for use in food industry for the control of these micro-organisms. PMID- 26481104 TI - Diacerein reduces joint damage, pain behavior and inhibits transient receptor potential vanilloid 1, matrix metalloproteinase and glial cells in rat spinal cord. AB - AIM: To investigate the antinociceptive, antiedematogenic and chondroprotective effects of diacerein (DIA) in a model of joint inflammation induced by complete Freund's adjuvant (CFA), as well as to investigate the involvement of metalloproteinase (MMP)-9, transient receptor potential vanilloid 1 (TRPV1) and glial cells in DIA's action mechanism. METHODS: Complete Freund's adjuvant was injected into the knee joint of male rats. We observed mechanical and cold hypersensitivity, vocalization and spontaneous pain-related behaviors, as well as edema of the knee. Tissue samples of the knee were stained with Cason's technique and the thickness of the condilus cartilage was measured. Immunohistochemical analysis was performed on the spinal cord using anti-GFAP (glial fibrillary acidic protein), anti-MMP and anti-TRPV1 antibodies. Sections of the dorsal horns of the spinal cord were captured and an optical density was obtained. RESULTS: Complete Freund's adjuvant induced mechanical and thermal hypersensitivity, as well as joint edema and changes in the synovial membrane and cartilage. DIA (30 mg/kg, orally, daily) significantly inhibited mechanical (58 +/- 10-87 +/- 3%) and thermal (66 +/- 12-87 +/- 8%) hypersensitivity, vocalization (83 +/- 5-41 +/- 11%), spontaneous pain score, joint swelling (60 +/- 6-40 +/- 9%), as well as the histological changes induced by CFA. In addition, DIA inhibited astrocyte activation, and prevented the increase of MMP-9 and TRPV1 expression in the spinal cord of the animals subjected to CFA injections. CONCLUSIONS: In short, this study shows that DIA reduces joint damage and hypersensitivity associated with inflammation induced by CFA through the inhibition of astroglial activation and decreases the expression of TRPV1 and MMP-9 in the rat spinal cord. PMID- 26481105 TI - Temperature control in critically ill patients with a novel esophageal cooling device: a case series. AB - BACKGROUND: Mild hypothermia and fever control have been shown to improve neurological outcomes post cardiac arrest. Common methods to induce hypothermia include body surface cooling and intravascular cooling; however, a new approach using an esophageal cooling catheter has recently become available. METHODS: We report the first three cases of temperature control using an esophageal cooling device (ECD). The ECD was placed in a similar fashion to orogastric tubes. Temperature reduction was achieved by connecting the ECD to a commercially available external heat exchange unit (Blanketrol Hyperthermia - Hypothermia System). RESULTS: The first patient, a 54 year-old woman (86 kg) was admitted after resuscitation from an out-of-hospital non-shockable cardiac arrest. Shortly after admission, she mounted a fever peaking at 38.3 degrees C despite administration of cold intravenous saline and application of cooling blankets. ECD utilization resulted in a temperature reduction to 35.7 degrees C over a period of 4 h. She subsequently recovered and was discharged home at day 23. The second patient, a 59 year-old man (73 kg), was admitted after successful resuscitation from a protracted out-of hospital cardiac arrest. His initial temperature was 35 degrees C, but slowly increased to 35.8 degrees C despite applying a cooling blanket and ice packs. The ECD was inserted and a temperature reduction to 34.8 degrees C was achieved within 3 h. The patient expired on day 3. The third patient, a 47 year-old man (95 kg) presented with a refractory fever secondary to necrotizing pneumonia in the postoperative period after coronary artery bypass grafting. His fever persisted despite empiric antibiotics, antipyretics, cooling blankets, and ice packs. ECD insertion resulted in a decrease in temperature from 39.5 to 36.5 degrees C in less than 5 h. He eventually made a favorable recovery and was discharged home after 59 days. In all 3 patients, device placement occurred in under 3 min and ease-of-use was reported as excellent by nursing staff and physicians. CONCLUSIONS: The esophageal cooling device was found to be an effective temperature control modality in this small case series of critically ill patients. Preliminary data presented in this report needs to be confirmed in large randomized controlled trials comparing its efficacy and safety to standard temperature control modalities. PMID- 26481106 TI - Feasibility and cost of using mobile phones for capturing drug safety information in peri-urban settlement in Ghana: a prospective cohort study of patients with uncomplicated malaria. AB - BACKGROUND: The growing need to capture data on health and health events using faster and efficient means to enable prompt evidence-based decision-making is making the use of mobile phones for health an alternative means to capture anti malarial drug safety data. This paper examined the feasibility and cost of using mobile phones vis-a-vis home visit to monitor adverse events (AEs) related to artemisinin-based combination therapy (ACT) for treatment of uncomplicated malaria in peri-urban Ghana. METHODS: A prospective, observational, cohort study conducted on 4270 patients prescribed ACT in 21 health facilities. The patients were actively followed by telephone or home visit to document AEs associated with anti-malarial drugs. Call duration and travel distances of each visit were recorded. Pre-paid call cards and fuel for motorbike travels were used to determine cost of conducting both follow-ups. Ms-Excel 2010 and STATA 11.2 were used for analysis. RESULTS: Of the 4270 patients recruited, 4124 (96.6 %) were successfully followed up and analyzed. Of these, 1126/4124 (27.3 %) were children under 5 years. Most 3790/4124 (91.9 %) follow-ups were done within 7 days of ACT intake. Overall, follow up by phone (2671/4124-64.8 %) was almost two times the number done by home visits (1453/4124-35.2 %). Duration of telephone calls ranged from 38 s to 53 min, costing between GHc0.26 (0.20USD) and GHc41.70 (27.USD). On the average, the calls lasted 3 min 51 s (SD = 3 min, 21 s) costing GHc2.70 (0.77USD). Distance travelled for home visit ranged from 0.65 to 62 km costing GHc0.29 (0.20USD) and GHc279.00 (79.70USD). Thirty-two per cent (1128/4124) of patients reported AEs. In total, 1831 AE were reported, 1016/1831(55.5 %) by telephone and 815/1831 (44.5 %) by home visits. Events such as nausea, dizziness, diarrhoea, and vomiting were commonly reported. CONCLUSION: Majority of patients was successfully followed up by telephone and reported the most AEs. The cost of telephone interviewing was almost two times less than the cost of home visit. Telephone follow up should be considered for monitoring drug adverse events in low resource settings. PMID- 26481107 TI - Relapsing pneumonitis due to two distinct inhibitors of the MAPK/ERK pathway: report of a case. AB - BACKGROUND: BRAF and MEK are component of the MAPK/ERK pathway and inhibitors of these proteins have significantly improved the outcome of metastatic melanoma. We report for the first time two sequential episodes of pneumonitis presumably induced by trametinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor) in a 50 year-old man. CASE PRESENTATION: While receiving trametinib for a metastatic melanoma, the patient developed non-febrile acute respiratory failure in the context of bilateral ground-glass opacities and sub pleural reticulations on high resolution computed tomography. An excess of lymphocytes was found in the bronchoalveolar lavage fluid. Outcome was favorable after simple drug discontinuation. He subsequently developed a similar clinical-imaging picture 6 months into vemurafenib. A transthoracic lung biopsy disclosed interstitial lymphocytic infiltrate, poorly-formed granulomas with multinucleated giant cells and scattered eosinophils. Outcome was again favorable after simple drug discontinuation. CONCLUSION: These two episodes in the same patient suggest that MAPK/ERK inhibitors may cause interstitial lung disease and may exert cross toxicity. This side effect is of particular interest for physicians in charge of patients with melanoma but this drug family is currently under development for several other solid tumors. PMID- 26481108 TI - Leishmania donovani-specific Ub-related modifier-1: an early endosome-associated ubiquitin-like conjugation in Leishmania donovani. AB - Protein modification by ubiquitin (Ub) and Ub-like molecules (Ubls) is a diverse biological process that regulates the activity of the target proteins. Systematic studies of Ubls in trypanosomatids like Leishmania, the causative organism of potentially fatal visceral leishmaniasis, would yield a better understanding of the disease pathogenesis and identify novel therapeutic targets. The present study is the first to characterize Leishmania donovani-specific Ub-related modifier-1 (LdUrm1) and the associated conjugation pathway. Based on homology modeling, LdUrm1 was found to possess a beta-grasp fold and a C-terminal di glycine motif unique to Ub/Ubls, essential for its conjugation to the target proteins. We identified LdUba4 as the E1 enzyme for LdUrm1 and demonstrated its energy-dependent enzymatic activity. LdUrm1 was immunolocalized anteriorly near the flagellar reservoir, while LdUba4 was cytoplasmic, both in promastigotes and axenic amastigotes. Expression of nonconjugatable LdUrm1 in L. donovani resulted in depleted parasite growth suggesting its role in the pathogenesis. By mass spectrometry, we identified Rab5, a known mediator of early endosome regulated hemoglobin endocytosis in Leishmania, as a target of LdUrm1. Our data suggest that LdUrm1 conjugation pathway may have a role in early endosome-mediated heme uptake in Leishmania that may be explored as a drug target. PMID- 26481109 TI - Middle latency auditory-evoked potential index monitoring of cerebral function to predict functional outcome after emergency craniotomy in patients with brain damage. AB - BACKGROUND: At present, no satisfactory reports on the monitoring of cerebral function to predict functional outcomes after brain damage such as traumatic brain injury (TBI) and stroke. The middle latency auditory-evoked potential index (MLAEPi) monitor (aepEX plus(r), Audiomex, UK) is a mobile MLAEP monitor measuring the degree of consciousness that is represented by numerical values. Hence, we hypothesized that MLAEPi predicts neurological outcome after emergency craniotomy among patients with disturbance of consciousness (DOC), which was caused by brain damage. METHODS: The afore-mentioned patients who underwent emergency craniotomy within 12 h of brain damage and were subsequently monitored using MLAEPi were enrolled in this study. DOC was defined as an initial Glasgow Coma Scale score < 8. MLAEPi was measured for 14 days after craniotomy. Neurological outcome was evaluated before discharge using a cerebral performance category (CPC) score and classified into three groups: favorable outcome group for a CPC score of 1 or 2, unfavorable outcome group for a score of 3 or 4, and brain dead (BD) group for a score of 5. RESULTS: Thirty-two patients were included in this study (17 with TBIs and 15 with acute stroke). Regarding outcome, 10 patients had a favorable outcome, 15 had an unfavorable outcome, and 7 were pronounced BD. MLAEPi was observed to be significantly higher on day 5 than that observed immediately after craniotomy in cases of favorable or unfavorable outcome (63 +/- 3.5 vs. 36 +/- 2.5 in favorable outcome; 63 +/- 3.5 vs. 34 +/- 1.8 in unfavorable outcome). MLAEPi was significantly lower in BD patients than in those with a favorable or unfavorable outcome on day 3 (24 +/- 4.2 in BD vs. 52 +/- 5.2 and 45 +/- 2.7 in favorable and unfavorable outcome, respectively) and after day 4. MLAEPi was significantly higher in patients with a favorable outcome than in those with a favorable or unfavorable outcome after day 6 (68 +/- 2.3 in favorable outcome vs. 48 +/- 2.3 in unfavorable outcome). CONCLUSION: We believe that MLAEPi satisfactorily denotes cerebral function and predicts outcomes after emergency craniotomy in patients with DOC, which was caused by acute brain damage. PMID- 26481110 TI - Investigation of regions impacting inbreeding depression and their association with the additive genetic effect for United States and Australia Jersey dairy cattle. AB - BACKGROUND: Variation in environment, management practices, nutrition or selection objectives has led to a variety of different choices being made in the use of genetic material between countries. Differences in genome-level homozygosity between countries may give rise to regions that result in inbreeding depression to differ. The objective of this study was to characterize regions that have an impact on a runs of homozygosity (ROH) metric and estimate their association with the additive genetic effect of milk (MY), fat (FY) and protein yield (PY) and calving interval (CI) using Australia (AU) and United States (US) Jersey cows. METHODS: Genotyped cows with phenotypes on MY, FY and PY (n = 6751 US; n = 3974 AU) and CI (n = 5816 US; n = 3905 AU) were used in a two-stage analysis. A ROH statistic (ROH4Mb), which counts the frequency of a SNP being in a ROH of at least 4 Mb was calculated across the genome. In the first stage, residuals were obtained from a model that accounted for the portion explained by the estimated breeding value. In the second stage, these residuals were regressed on ROH4Mb using a single marker regression model and a gradient boosted machine (GBM) algorithm. The relationship between the additive and ROH4Mb of a region was characterized based on the (co)variance of 500 kb estimated genomic breeding values derived from a Bayesian LASSO analysis. Phenotypes to determine ROH4Mb and additive effects were residuals from the two-stage approach and yield deviations, respectively. RESULTS: Associations between yield traits and ROH4Mb were found for regions on BTA13, BTA23 and BTA25 for the US population and BTA3, BTA7, BTA17 for the AU population. Only one association (BTA7) was found for CI and ROH4Mb for the US population. Multiple potential epistatic interactions were characterized based on the GBM analysis. Lastly, the covariance sign between ROH4Mb and additive SNP effect of a region was heterogeneous across the genome. CONCLUSION: We identified multiple genomic regions associated with ROH4Mb in US and AU Jersey females. The covariance of regions impacting ROH4Mb and the additive genetic effect were positive and negative, which provides evidence that the homozygosity effect is location dependent. PMID- 26481111 TI - Perception of Sentence Stress in Speech Correlates With the Temporal Unpredictability of Prosodic Features. AB - Numerous studies have examined the acoustic correlates of sentential stress and its underlying linguistic functionality. However, the mechanism that connects stress cues to the listener's attentional processing has remained unclear. Also, the learnability versus innateness of stress perception has not been widely discussed. In this work, we introduce a novel perspective to the study of sentential stress and put forward the hypothesis that perceived sentence stress in speech is related to the unpredictability of prosodic features, thereby capturing the attention of the listener. As predictability is based on the statistical structure of the speech input, the hypothesis also suggests that stress perception is a result of general statistical learning mechanisms. To study this idea, computational simulations are performed where temporal prosodic trajectories are modeled with an n-gram model. Probabilities of the feature trajectories are subsequently evaluated on a set of novel utterances and compared to human perception of stress. The results show that the low-probability regions of F0 and energy trajectories are strongly correlated with stress perception, giving support to the idea that attention and unpredictability of sensory stimulus are mutually connected. PMID- 26481113 TI - A new iron calcium phosphate material to improve the osteoconductive properties of a biodegradable ceramic: a study in rabbit calvaria. AB - beta-tricalcium phosphate (beta-TCP) is an osteoconductive and biodegradable material used in bone regeneration procedures, while iron has been suggested as a tool to improve the biological performance of calcium phosphate-based materials. However, the mechanisms of interaction between these materials and human cells are not fully understood. In order to clarify this relationship, we have studied the iron role in beta-TCP ceramics. Iron-containing beta-TCPs were prepared by replacing CaCO3 with C6H5FeO7 at different molar ratios. X-ray diffraction analysis indicated the occurrence of beta-TCP as the sole phase in the pure beta TCP and iron-containing ceramics. The incorporation of iron ions in the beta-TCP lattice decreased the specific surface area as the pore size was shifted toward meso- and/or macropores. Furthermore, the human osteoblastlike cell line MG-63 was cultured onto the ceramics to determine cell proliferation and viability, and it was observed that the iron-beta-TCP ceramics have better cytocompatibility than pure beta-TCP. Finally, in vivo assays were performed using rabbit calvaria as a bone model. The scaffolds were implanted for 8 and 12 weeks in the defects created in the skullcap with pure beta-TCP as the control. The in vivo behavior, in terms of new bone formed, degradation, and residual graft material were investigated using sequential histological evaluations and histomorphometric analysis. The in vivo implantation of the ceramics showed enhanced bone tissue formation and scaffold degradation for iron-beta-TCPs. Thus, iron appears to be a useful tool to enhance the osteoconductive properties of calcium phosphate ceramics. PMID- 26481112 TI - Photobiological Origins of the Field of Genomic Maintenance. AB - Although sunlight is essential for life on earth, the ultraviolet (UV) wavelengths in its spectrum constitute a major threat to life. Various cellular responses have evolved to deal with the damage inflicted in DNA by UV, and the study of these responses in model systems has spawned the burgeoning field of DNA repair. Although we now know of many types of deleterious alterations in DNA, the approaches for studying them and the early mechanistic insights have come in large part from pioneering research on the processing of UV-induced bipyrimidine photoproducts in bacteria. It is also notable that UV was one of the first DNA damaging agents for which exposure was directly linked to cancer; the sun sensitive syndrome, xeroderma pigmentosum, was the first example of a cancer prone hereditary disease involving a defect in DNA repair. We provide a short history of advances in the broad field of genomic maintenance as they have emerged from research in photochemistry and photobiology. PMID- 26481114 TI - Infant feeding practices and childhood diet at Apollonia Pontica: Isotopic and dental evidence. AB - OBJECTIVE: This study analyzes deciduous dental pathology and stable isotopes to investigate the relationship between diet, feeding practices, and oral health in a subadult skeletal sample from the Greek colonial site of Apollonia Pontica, Bulgaria (mid-5th to mid-3rd Centuries BC). METHODS: Stable carbon and nitrogen isotope analysis was conducted on 74 bone collagen samples, and the deciduous dentitions of 85 individuals aged 8.5 months to 11 years were examined for evidence of caries, calculus, antemortem tooth loss, abscesses, and occlusal tooth wear. RESULTS: delta(13) C and delta(15) N values of the collagen samples indicate that weaning began between the ages of 6 months and 1 year, and was complete for most individuals by the age of 3. The isotopic data are consistent with a mixed diet of primarily terrestrial C3 resources. The dental pathology data indicate that complementary foods provided to young children had an impact on their oral health early on. Four outliers exhibited elevated delta(15) N values compared with the adult female range and lower levels of tooth wear than other members of their age groups. Possible explanations include prolonged breastfeeding, the consumption of diets elevated in (15) N, and physiological/nutritional stress. CONCLUSIONS: The deciduous dental data correlate well with the isotopic data and are consistent with later textual sources regarding the timing and duration of weaning, and the composition of complementary foods. The results of this research demonstrate the value of combining isotopic and dental evidence to investigate the dietary practices of infants and young children and the impact of these practices on oral health. PMID- 26481115 TI - Stereoselective recognition of the Ac-Glu-Tyr-OH dipeptide by pseudopeptidic cages. AB - Pseudopeptidic molecular cages are appealing receptors since they can display different polar and non-polar interaction sites in a modular framework and a controlled disposition. Inspired by previous host-guest knowledge, two pseudopeptidic molecular cages based on serine and threonine (CySer and CyThr, respectively) were designed and synthesized as hosts for the binding of the four possible stereoisomers of the Ac-Glu-Tyr-OH dipeptide, a target sequence of tyrosine kinases. The careful NMR titration experiments in aqueous acetonitrile allowed the determination of the binding constants and reflected a difference in the stability of the corresponding diastereomeric host-guest complexes. The CySer cage proved to be slightly more efficient than the CyThr counterpart, although both showed similar stereoselectivity trends: LL > DD >= LD > DL. This stereoselective binding was retained in the gas phase, as shown by ESI-MS competition experiments using the enantiomer-labelled method (EL), as well as CID experiments. Thus, the MS-determined discriminations follow the same trends observed by NMR, suggesting that the stereoselectivity observed for these systems must be mainly dictated by the polar host-guest interactions. Despite the stereoselective binding of short peptide sequences in competitive media being a challenging issue in supramolecular chemistry, our results demonstrate the power of pseudopeptidic cages in molecular recognition with foreseen implications in chemical biology. PMID- 26481116 TI - Positional Relationship Between the Pulmonary Venous Confluence-Vertical Vein and Atria in Infracardiac Total Anomalous Pulmonary Venous Connection. AB - To explore the positional relationship between the pulmonary venous confluence venous vein (PVC-VV) and both the atria in infracardiac total anomalous pulmonary venous connection (iTAPVC), using two-dimensional (2D) computerized tomography (CT) reconstruction. Through the 2D reconstruction of enhanced cardiac CT images of patients with iTAPVC, the projection of PVC-VV on coronal axial images was acquired and its location on the bilateral atrial splice was analyzed. Sagittal axial reconstruction was used to identify which atrium had a precise anterior posterior positional relationship with PVC-VV. The type of iTAPVC, where the projection of PVC-VV was lying on the left atrium, and the left atrium had a precise anterior-posterior positional relationship with PVC-VV, was classified as the left atrial type. If the projection of PVC-VV was lying on the right atrium and the right atrium had a precise anterior-posterior positional relationship with PVC-VV, it was classified as the right atrial type. Finally, if the projection of PVC-VV was lying in the middle of the bilateral atria, and both the atria had precise anterior-posterior positional relationship with PVC-VV, it was referred to as the bilateral atrial type. Upon analysis of the 22 enhanced cardiac CT images, 6 were the left atrial type (27.27 %), 9 were right atrial type (40.91 %), while 7 were of the bilateral atrial type (31.82 %). The positional relationship between PVC-VV and the bilateral atria are variable, and iTAPVC classification using 2D CT reconstruction is an invaluable tool in designing the surgical approaches in iTAPVC. PMID- 26481117 TI - Characterization of Cardiac Troponin Elevation in the Setting of Pediatric Supraventricular Tachycardia. AB - Cardiac troponin (cTn) is currently considered the gold standard biomarker for detection of myocardial necrosis. Patients with supraventricular tachycardia (SVT) often present with symptoms resulting in cTn assessment; however, there are no data on the results of such testing in childhood. We hypothesized that cTn elevation would be common in the pediatric SVT population and would portend a benign prognosis. A retrospective review of all pediatric patients (<=21 years) presenting with SVT was performed. Clinical and electrocardiographic variables from the emergency department (ED) presentation were reviewed and clinical outcomes during subsequent follow-up assessed. Of 128 patients seen in the ED for SVT, cTn was assessed in 48 (38 %). Of patients with cTn assessment, 14 (29 %) patients demonstrated cTn elevation. Univariate predictors of cTn elevation included presentation with respiratory or gastrointestinal symptoms (50 vs 12 % and 42 vs 9 %; p = 0.008 and p = 0.01, respectively), lower mean arterial blood pressure (73 vs 85 mm Hg, p = 0.009), higher age-adjusted tachycardia rate (z score 9.3 vs 7.2, p < 0.001), and longer tachycardia duration (4.2 vs 1.0 h, p = 0.02). Multivariate logistic regression confirmed the association of age-adjusted tachycardia rate (odds ratio [OR] 3.8 per heart rate z score, confidence interval [CI] 1.9-11.8, p = 0.003) and duration (OR 1.5 per hour, CI 1.1-2.5, p = 0.03). Clinical outcome was excellent with no adverse sequelae during a median of 2.9 years of follow-up. Cardiac Tn elevation is common in the pediatric population presenting with SVT. Episode severity, characterized by respiratory or gastrointestinal symptoms, lower mean blood pressure, and increased tachycardia rate and duration are predictive. Clinical follow-up is favorable. PMID- 26481118 TI - Arrhythmias in Adult Congenital Patients With Bodily Isomerism. AB - There are an increasing number of adults with congenital heart disease, some of whom have bodily isomerism. Bodily isomerism or heterotaxy is a unique clinical entity associated with congenital malformations of the heart which further increases the risk for future cardiovascular complications. We aimed to investigate the frequency of arrhythmias in adults with bodily isomerism. We utilized the 2012 iteration of the Nationwide Inpatient Sample to identify adult inpatient admissions associated with arrhythmias in patients with isomerism. Data regarding demographics, comorbidities, and various procedures were collected and compared between those with and without isomerism. A total of 6,907,109 admissions were analyzed with a total of 861 being associated isomerism. The frequency of arrhythmias was greater in those with isomerism (20.8 vs. 15.4 %). Those with isomerism were also more five times more likely to undergo invasive electrophysiology studies. Length and cost of hospitalization for patients with arrhythmias also tended to be greater in those with isomerism. Mortality did not differ between the two groups. Arrhythmias are more prevalent in those with isomerism, with a majority of arrhythmias in isomerism being atrial. Those with isomerism and arrhythmias also tended to have greater length and cost of hospitalization. PMID- 26481120 TI - A 1-bp deletion in Fgf5 causes male-dominant long hair in the Syrian hamster. AB - Hair length in mammals is generally regulated by the hair cycle, and its disruption leads to abnormal hair morphogenesis in several species. FGF5, one of the hair cycle regulators, has a role in inducing catagen, and that mutation causes abnormal hair length in both sexes in humans, mice, dogs, and cats. Male dominant long-haired coat (MALC) is an inbred strain of Syrian hamster exhibiting spontaneous long hair in males. After castration, MALC exhibited significantly shorter hair than the control individuals, but testosterone administration to castrated MALC showed reversion to the original phenotype. Moreover, flutamide administration led to MALC phenotype repression. Histological analysis revealed that hair follicle regression was shown in the wild-type 4 weeks after depilation, but that of MALC remained in the anagen phase. We detected a c.546delG of Fgf5 in MALC (Fgf5malc) that might lead to truncation resulting from a frame shift in FGF5 (p.Arg184GlyfsX6). Additionally, homozygous Fgf5malc was only detected in long-haired (Slc:Syrian*MALC)F2 and (J-2-Nn*MALC)F2 progenies, and all homozygous wild and heterozygous Fgf5malc individuals showed normal hair length. Thus, Fgf5malc leads to male-dominant long hair via a prolonged anagen phase which is affected by testosterone in hamsters. To our knowledge, this report is the first to present the sexual dimorphism of hair length caused by the Fgf5 mutation. PMID- 26481122 TI - Does Early versus Delayed Spanning External Fixation Impact Complication Rates for High-energy Tibial Plateau and Plafond Fractures? AB - BACKGROUND: High-energy tibial plateau and tibial plafond fractures have a high complication rate and are frequently treated with a staged approach of spanning external fixation followed by definitive internal fixation after resolution of soft tissue swelling. A theoretical advantage to early spanning external fixation is that earlier fracture stabilization could prevent further soft tissue damage and potentially reduce the occurrence of subsequent infection. However, the relative urgency of applying the external fixator after injury is unknown, and whether delay in this intervention is correlated to subsequent treatment complications has not been examined. QUESTIONS/PURPOSES: Is delay of more than 12 hours to spanning external fixation of high-energy tibial plateau and plafond fractures associated with increased (1) infection risk; (2) compartment syndrome risk; and (3) time to definitive fixation, length of hospitalization, or risk of secondary surgeries? We further stratified our results based on injury site: plateau and plafond. In practical clinical terms, many of these high-energy C type articular fractures will arrive at the regional trauma center in the evening and this investigation attempted to explore if these injuries need to be placed in temporizing fixators that evening or if they may be safely addressed in a dedicated trauma room the next morning. METHODS: We performed a retrospective review of all patients at a Level I university trauma center with high-energy tibial plateau and plafond fractures who underwent staged treatment with a spanning external fixation followed by subsequent definitive internal fixation between 2006 and 2012. Patients who received a fixator within 12 hours of recorded injury time were classified as early external fixation; those who received a fixator greater than 12 hours from injury were classified as delayed external fixation. There were 80 patients (42 plateaus and 38 plafonds) in the early external fixation cohort and 79 patients (45 plateaus and 34 plafonds) in the delayed external fixation cohort. Deep infection rate was 13% in plateau fractures and 18% in plafond fractures. Rates of infection, compartment syndrome, secondary surgeries, time to definitive fixation, and length of hospitalization were recorded. RESULTS: Controlling for differences in open fracture severity between groups, there was no difference in infection for plafond (early fixation: 12 of 38 [32%]; delayed fixation: seven of 34 [21%]; adjusted relative risk = 1.39 [95% confidence interval {CI}, 0.45-4.31], p = 0.573) and plateau (early fixation: eight of 42 [19%]; delayed fixation: nine of 45 [20%]; adjusted relative risk: 0.93 [95% CI, 0.31-2.78], p = 0.861) groups. For compartment syndrome risk, there was no difference between early and delayed groups for plateau fractures (early fixation: six of 42 [14%]; delayed fixation: three of 45 [7%]; relative risk = 0.47 [0.12-1.75], p = 0.304) and plafond fractures (early fixation: two of 38 [5%]; delayed fixation: three of 34 [9%]; relative risk = 1.67 [0.30-9.44], p = 0.662). There was no difference for length of hospitalization for early (9 +/- 7 days) versus delayed fixation (9 +/- 6 days) (mean difference = 0.24 [95% CI, -2.9 to 3.4], p = 0.878) for patients with plafond fracture. Similarly, there was no difference in length of hospitalization for early (10 +/- 6 days) versus delayed fixation (8 +/- 4 days) (mean difference = 1.6 [95% CI, -3.9 to 0.7], p = 0.170) for patients with plateau fracture. Time to definitive fixation for plateau fractures in the early external fixation group was 8 +/- 6 days compared with 11 +/- 7 days for the delayed external fixation group (mean difference = 2.9 [95% CI, 0.13-5.7], p = 0.040); there was no difference in time to definitive fixation for early (12 +/- 7 days) versus delayed (12 +/- 6 days) for patients with plafond fractures (mean difference = 0.39 [95% CI, -2.7 to 3.4], p = 0.801). There was no difference in risk of secondary surgeries between early external fixation (21 of 38 [55%]) and delayed external fixation (13 if 34 [38%]) for plafond fractures (adjusted relative risk = 0.69 [95% CI, 0.41-1.16], p = 0.165) and no difference between early fixation (24 of 42 [57%]) and delayed fixation (26 of 45 [58%]) for plateau fractures (adjusted relative risk = 1.0 [95% CI, 0.70-1.45], p = 1.00). CONCLUSIONS: We were unable to detect a difference in infection, compartment syndrome, secondary procedures, or length of hospitalization for patients who undergo early versus delayed external fixation for high-energy tibial plateau or plafond fractures. This may affect decisions for resource use at trauma centers such as whether high energy periarticular lower extremity fractures need to be spanned on the evening of presentation or whether this procedure may wait until the morning trauma room. Given the high complication rate of these injuries and clinical relevance of this question, this may also need to be examined in a prospective manner. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26481123 TI - Gendered Innovations in Orthopaedic Science: Sex, Lies, and Stereotype: In Praise of the Systematic Review. PMID- 26481124 TI - Comparison of tip apex distance and cut-out complications between helical blades and lag screws in intertrochanteric fractures among the elderly: a meta-analysis. AB - PURPOSE: To investigate whether helical blade implant systems have advantages in terms of tip apex distance (TAD) and cut-out rate in comparison to conventional lag screws for intertrochanteric fractures in a geriatric population. Methods: Relevant articles were sourced from the MEDLINE, Embase, Ovid and Cochrane Library databases from inception through March 2015. All randomized controlled trials (RCTs) comparing outcomes between helical blade and lag screw implant systems were selected. Mean TAD values and reported cut-out complications were noted. Each author independently assessed the relevance of the enrolled studies and the quality of the extracted data. Data were analyzed using R software. RESULTS: Ten studies including 1831 patients were eligible for this review, seven of which were included in a combined analysis of dichotomous outcomes and five in a combined analysis of continuous outcomes. The results revealed that, compared with lag screw implantations, the use of helical blades led to a lower rate of cut-out complications (95 % CI: 0.28-0.96, P = 0.036). Patients who experienced cut-out complications had a significantly greater tip apex distance (95 % CI: 0.68-1.34, P < 0.001). However, the actual tip apex distances were similar between the screw group and blade group (95 % CI: -0.44-0.79, P = 0.58). CONCLUSIONS: No difference in TAD values was found between blades and screws. In addition, the cut-out risk in the blade-design group was lower than that of the screw group. Therefore, TAD is not an accurate predictor of cut-out risk. PMID- 26481125 TI - Timing of referral to inpatient palliative care services for advanced cancer patients and earlier referral predictors in mainland China. AB - OBJECTIVE: Routine early integration of palliative care with advanced cancer management is not yet a part of standard practice in many countries, including mainland China. Whether patients in China suffering from advanced cancer are referred to palliative care services in a timely manner remains unclear. We sought to investigate the timing of palliative care referral of Chinese cancer patients at our center and its predictors. METHOD: Retrospective medical data including demographic characteristics and referral information were collected for analysis. A total of 759 patients referred to our palliative care unit (PCU) from January of 2007 to December of 2013 were included in the final analysis. RESULTS: The mean age of the 759 patients included in the study was 62.89 years (range 61.95-63.82). Some 369 patients (48.6%) were male and 559 (73.6%) Shanghainese (indigenous). Lung cancer (17.9%) was the most common diagnosis. The time interval since enrollment into the PCU until a patient's death (length of stay, LOS) was calculated. A longer LOS indicated earlier referral to inpatient PC services. The median LOS was 21 days (CI 95% = 19.79-22.21). Multivariate analysis showed that whether or not the patient was indigenous (p = 0.002) and younger than 65 (p = 0.031) were independent factors for a longer LOS. Such other characteristics as gender and primary cancer type bore no relationship to LOS. SIGNIFICANCE OF RESULTS: Our findings demonstrate that Chinese cancer patients are referred relatively late in the course of their disease to inpatient palliative care services. To overcome the barriers to early integration of palliative care into a patient's treatment plan, accurate information about palliative care must be provided to both oncologists and patients via comprehensive and systematic educational programs. PMID- 26481126 TI - Initial Host Response to Bacteria in the Murine Lung Differs Between Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pneumoniae. AB - Phagocytosis of bacteria is an important process during early host defence. It has been directly observed only ex vivo or in vitro. Here, we report on the observation of phagocytosis under in vivo conditions by using intravital microscopy in the murine lung. Suspensions of fluorescently labelled Streptococcus pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa cells were each instilled intratracheally to anaesthetized mice. After thoracotomy, the alveolar surface was observed for 30 min. Alveolar phagocytes exhibiting ingested bacteria could be detected and counted. The highest numbers were found after the infection with P. aeruginosa. By using intravital microscopy, cellular host defence could be observed in living mice lungs. The initial phagocytic reaction crucially depends on the species of applied bacteria invading the lung. PMID- 26481129 TI - Diversification of four human HOX gene clusters by step-wise evolution rather than ancient whole-genome duplications. AB - HOX genes encode transcriptional factors that play a pivotal role in specifying regional identity in nearly every bilateral animal. The birth of HOX gene cluster and its subsequent evolution, either in regulation or function, underlie the evolution of many bilaterian features and hence to the evolutionary radiation of this group. Despite of this importance, evolution of HOX cluster in vertebrates remains largely obscure because the phylogenetic history of these genes is poorly resolved. This has led to the controversy about whether four HOX clusters in human originated through two rounds (2R) of whole-genome duplications or instead evolved by small-scale events early in vertebrate evolution. Recently, the large scale phylogenetic analysis of triplicate and quadruplicate paralogous regions residing on human HOX-bearing chromosomes provided an unprecedented insight into events that shaped vertebrate genome early in their history. Based on these data and comparative genomic analysis of fruit fly, red floor beetle, and human, this study infers the genic content of minimal HOX locus in the Urbilaterian and reconstructs its duplication history. It appears that four HOX clusters of humans are not remnants of polyploidy events in vertebrate ancestry. Rather, current evidence suggests that one-to-four transition in HOX cluster number occurred by three-step sequential process involving regional duplication events. Therefore, it is concluded that the evolutionary origin of vertebrate novelties, including the complexity of their body, is the consequence of small-scale genetic changes at widely different times over their history. PMID- 26481128 TI - Genetic and functional characterization of an extracellular modular GH6 endo-beta 1,4-glucanase from an earthworm symbiont, Cellulosimicrobium funkei HY-13. AB - The gene (1608-bp) encoding a GH6 endo-beta-1,4-glucanase (CelL) from the earthworm-symbiotic bacterium Cellulosimicrobium funkei HY-13 was cloned from its whole genome sequence, expressed recombinantly, and biochemically characterized. CelL (56.0 kDa) is a modular enzyme consisting of an N-terminal catalytic GH6 domain (from Val57 to Pro396), which is 71 % identical to a GH6 protein (accession no.: WP_034662937) from Cellulomonas sp. KRMCY2, together with a C terminal CBM 2 domain (from Cys429 to Cys532). The highest catalytic activity of CelL toward carboxymethylcellulose (CMC) was observed at 50 degrees C and pH 5.0, and was relatively stable at a broad pH range of 4.0-10.0. The enzyme was capable of efficiently hydrolyzing the cellulosic polymers in the order of barley beta-1,3-1,4-D-glucan > CMC > lichenan > Avicel > konjac glucomannan. However, cellobiose, cellotriose, p-nitrophenyl derivatives of mono- and disaccharides, or structurally unrelated carbohydrate polymers including beta-1,3-D-glucan, beta 1,4-D-galactomannan, and beta-1,4-D-xylan were not susceptible to CelL. The enzymatic hydrolysis of cellopentaose resulted in the production of a mixture of 68.6 % cellobiose and 31.4 % cellotriose but barley beta-1,3-1,4-D-glucan was 100 % degraded to cellotriose by CelL. The enzyme strongly bound to Avicel, ivory nut mannan, and chitin but showed relatively weak binding affinity to lichenan, lignin, or poly(3-hydroxybutyrate) granules. PMID- 26481130 TI - Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells. AB - Promiscuous expression of a plethora of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential for central tolerance. This promiscuous gene expression (pGE) is characterized by inclusion of a broad range of TRAs and by its mosaic expression patterns, i.e. each antigen is only expressed in 1-3% of mTECs. It is currently unclear to which extent random and/or deterministic mechanisms are involved in the regulation of pGE. In order to address this issue, we deconstructed the transcriptional heterogeneity in mTEC to minor subsets expressing a particular TRA. We identified six delineable co expression groups in mouse mTECs. These co-expression groups displayed a variable degree of mutual overlap and mapped to different stages of mTEC development. Co expressed genes showed chromosomal preference and clustered within delimited genomic regions. Moreover, co-expression groups in mice and humans selected by a pair of orthologous genes preferentially co-expressed sets of orthologous genes attesting to the species conservation of pGE between mouse and human. Furthermore, co-expressed genes were enriched for specific transcription factor binding motifs concomitant with up-regulation of the corresponding transcription factors, implicating additional factors in the regulation of pGE besides the Autoimmune Regulator (Aire). Thus promiscuous transcription of self-antigens in mTECs entails a highly coordinated process, which is evolutionary strictly conserved between species. PMID- 26481131 TI - Episodic-like memory trace in awake replay of hippocampal place cell activity sequences. AB - Episodic memory retrieval of events at a specific place and time is effective for future planning. Sequential reactivation of the hippocampal place cells along familiar paths while the animal pauses is well suited to such a memory retrieval process. It is, however, unknown whether this awake replay represents events occurring along the path. Using a subtask switching protocol in which the animal experienced three subtasks as 'what' information in a maze, I here show that the replay represents a trial type, consisting of path and subtask, in terms of neuronal firing timings and rates. The actual trial type to be rewarded could only be reliably predicted from replays that occurred at the decision point. This trial-type representation implies that not only 'where and when' but also 'what' information is contained in the replay. This result supports the view that awake replay is an episodic-like memory retrieval process. PMID- 26481133 TI - Four pestalpolyols from a mycoparasite Pestalotipsis sp. PG52. AB - A mycoparasite PG52 isolated from aeciospore piles of Aecidium pourthiaea was identified as Pestalotipsis sp. The chemical constituents of Pestalotipsis sp. PG52 were investigated. Four novel polyketides, named pestalpolyols E-H (1-4), were isolated from solid fermentations of Pestalotiopsis sp. PG52. Their structures were elucidated by interpretation of extensive spectroscopic methods, including 1D and 2D NMR, HR-MS experiments; and the absolute configuration of 1 was confirmed by single-crystal X-ray diffraction analysis using the anomalous scattering of Cu Kalpha radiation. Compounds 2-4 showed cytotoxic activities against human tumor cell lines. PMID- 26481132 TI - Cryptotanshinone and wogonin up-regulate eNOS in vascular endothelial cells via ERalpha and down-regulate iNOS in LPS stimulated vascular smooth muscle cells via ERbeta. AB - Phytoestrogens were widely used as natural alternatives to estrogen for treating cardiovascular diseases. They have been reported to have cardioprotective and anti-inflammatory response, but the mechanisms remain unclear. In this study, we found cryptotanshinone and wogonin exhibited phytoestrogenic property in an estrogen-responsive reporter assay. In EA.hy926 cells, treatment of cryptotanshinone and wogonin led to significant increase in NO production levels, which were inhibited by co-incubation of estrogen receptor (ER)alpha antagonist methyl-piperidino-pyrazole (MPP). The expression of endothelial NO synthase (eNOS) and ERalpha were up-regulated with the same treatment, indicating they stimulate NO and eNOS expression via ERalpha-dependent pathway in endothelial cells. While in lipopolysaccharide activated vascular smooth muscle cell line A7r5, cryptotanshinone and wogonin exerted anti-inflammatory effects by inhibiting NO and inducible NO synthase expression via ERbeta-dependent pathway. The reduction of NO synthesis was not affected by MPP, and was abrogated by ERbeta antagonist R,R-tetrahydrochrysene. Our findings provide the potential molecular mechanism of cryptotanshinone and wogonin as phytoestrogens for their cardioprotective effects, which exerted regulatory effects on NO synthesis through differential regulation of estrogen receptors. It can be employed as a basis for evaluating the beneficial effects of phytoestrogens in the treatment of patients at risk of cardiovascular disease. PMID- 26481134 TI - Membrane immunoglobulin expressed by retroviral vector gene transfer mimics partial function of the B-cell receptor in vivo. AB - Activation of B-cells is initiated by the ligation of B-cell receptors by its cognate antigen, inducing a series of signal cascades. Understanding the molecular mechanisms of these important events is a crucial goal for immunologists. Chimeric B cell receptors provide a powerful tool for analysis of B-cell signal function. However, this method can only be used in tool cells, but cannot be used for in vivo study. Here, we constructed a retroviral vector to encode both heavy chains and light chains of a membrane immunoglobulin, and expressed them in primary B-cells using retroviral gene transfer. Our results demonstrate that the membrane immunoglobulin expressed by retroviral vectors transfer can initiate B-cell receptor-mediated signaling, resulting in the phosphorylation of Syk and Erk1/2 proteins. The results showed that B-cells expressing membrane immunoglobulin can make proliferative responses to cognate antigen both in vitro and in vivo. Therefore, we provide a methodology for rapidly analyzing the downstream signals of B-cell receptors both in vitro and in vivo, which could expedite the identification of proteins involved in B-cell function. PMID- 26481135 TI - The discovery of artemisinin and the Nobel Prize in Physiology or Medicine. PMID- 26481136 TI - "Ductal adenocarcinoma in annular pancreas": Is it really an annular pancreas with pancreatic cancer? PMID- 26481137 TI - Three new alkaloids and three new phenolic glycosides from Liparis odorata. AB - Three new alkaloids, liparis alkaloid A (1), B (2), C (3), and three new phenolic glycosides, liparis glycoside H (4), I (5), J (6), together with three known phenolic glycosides (7-9) were isolated from the whole plant of Liparis odorata. Their structures were characterized on the basis of extensive 1D-, 2D-NMR and HR ESI-MS experiments. In addition, compounds 1-3 revealed hypolipidemic effects in the in vitro bioassays, and the ability to inhibit LPS-induced NO production of these isolated phenolic glycosides (4-9) was also evaluated. PMID- 26481138 TI - Flavonol dimers from callus cultures of Dysosma versipellis and their in vitro neuraminidase inhibitory activities. AB - A chemical investigation of callus cultures of Dysosma versipellis led to the isolation of five new flavonol dimers, dysoverines A-E (1-5), together with 12 known compounds (6-17). The structures of new compounds were determined by the extensive spectroscopic data analyses. The biosynthetic pathway of the new compounds was proposed to involve O-methylation, prenylation, and Diels-Alder cycloaddition, which successively occurred in cultured plant cells. Compounds 1 17 exhibited in vitro neuraminidase inhibitory activities with the IC50 values of 31.0-93.9MUM. PMID- 26481139 TI - Undetected human papillomavirus DNA and uterine cervical carcinoma: Association with cancer recurrence. AB - BACKGROUND: The time course of human papillomavirus (HPV) DNA clearance was studied in patients with carcinoma of the cervix during follow-up after primary radical radiotherapy (RT). This study investigated the relationship between timing of HPV clearance and RT effectiveness. PATIENTS AND METHODS: A total of 71 consecutive patients who were treated for cervical cancer with primary radical radiotherapy and high-dose rate intracavitary brachytherapy with or without chemotherapy were enrolled in the study. Samples for HPV DNA examination were taken before (1) treatment, (2) every brachytherapy, and (3) every follow-up examination. The times when HPV DNA was undetected were analyzed for association with recurrence-free survival. RESULTS: HPV DNA was not detected in 13 patients (18 %) before RT. Of the 58 patients with HPV DNA detected before treatment, HPV DNA was not detected in 34 % during treatment and in 66 % after the treatment. Within 6 months after RT, HPV DNA was detected in 0 % of all patients. The patients were followed up for a median period of 43 months (range 7-70 months). In all, 20 patients were found to develop recurrence. The 3-year cumulative disease-free survival (DFS) rate was 71 ?} 5.4 % for all 71 patients. In multivariate analysis, DFS was significantly associated with HPV (detected vs. not detected) with a hazard ratio of 0.07 (95 % confidence interval 0.008-0.6, p = 0.009). CONCLUSION: In this study, patients in whom HPV was not detected had the worst prognosis. Six months after RT, HPV DNA was detected in 0 % of the patients. Patients in whom HPV DNA could not be detected before treatment need careful follow-up for recurrence and may be considered for additional, or alternative treatment. PMID- 26481140 TI - Information extraction from multi-institutional radiology reports. AB - OBJECTIVES: The radiology report is the most important source of clinical imaging information. It documents critical information about the patient's health and the radiologist's interpretation of medical findings. It also communicates information to the referring physicians and records that information for future clinical and research use. Although efforts to structure some radiology report information through predefined templates are beginning to bear fruit, a large portion of radiology report information is entered in free text. The free text format is a major obstacle for rapid extraction and subsequent use of information by clinicians, researchers, and healthcare information systems. This difficulty is due to the ambiguity and subtlety of natural language, complexity of described images, and variations among different radiologists and healthcare organizations. As a result, radiology reports are used only once by the clinician who ordered the study and rarely are used again for research and data mining. In this work, machine learning techniques and a large multi-institutional radiology report repository are used to extract the semantics of the radiology report and overcome the barriers to the re-use of radiology report information in clinical research and other healthcare applications. MATERIAL AND METHODS: We describe a machine learning system to annotate radiology reports and extract report contents according to an information model. This information model covers the majority of clinically significant contents in radiology reports and is applicable to a wide variety of radiology study types. Our automated approach uses discriminative sequence classifiers for named-entity recognition to extract and organize clinically significant terms and phrases consistent with the information model. We evaluated our information extraction system on 150 radiology reports from three major healthcare organizations and compared its results to a commonly used non-machine learning information extraction method. We also evaluated the generalizability of our approach across different organizations by training and testing our system on data from different organizations. RESULTS: Our results show the efficacy of our machine learning approach in extracting the information model's elements (10-fold cross-validation average performance: precision: 87%, recall: 84%, F1 score: 85%) and its superiority and generalizability compared to the common non-machine learning approach (p-value<0.05). CONCLUSIONS: Our machine learning information extraction approach provides an effective automatic method to annotate and extract clinically significant information from a large collection of free text radiology reports. This information extraction system can help clinicians better understand the radiology reports and prioritize their review process. In addition, the extracted information can be used by researchers to link radiology reports to information from other data sources such as electronic health records and the patient's genome. Extracted information also can facilitate disease surveillance, real-time clinical decision support for the radiologist, and content-based image retrieval. PMID- 26481141 TI - In-office magnetic resonance imaging (MRI) equipment ownership and MRI volume among medicare patients in orthopedic practices. AB - BACKGROUND: Concerns have been raised about physician ownership of onsite advanced imaging equipment as allowed under Stark laws by the in-office ancillary service exception (IOASE). METHODS: A web-based survey of orthopedic practices in the United States was used to assign a first date of onsite MRI capacity acquisition (if any) to specific orthopedic practices. Medicare claims data for 2006-2010 was obtained for providers in orthopedic practices acquiring onsite MRI capacity and in matched orthopedic practices without an onsite MRI over the same period of time. Multivariate regression was used to estimate the change in provider Medicare MRI volume one year before and one year after the onsite MRI acquisition year for providers in MRI practices compared to providers in propensity-score matched non-MRI practices. RESULTS: In all of the MRI volume change models estimated, the association between onsite MRI acquisition and the change in provider Medicare MRI volume (one-year post-onsite-MRI-acquisition less one year pre-acquisition) was consistently small and not statistically significant. This lack of association was robust to changes in model specification in terms of types of MRI exams considered, specific covariates included in the multivariate model, or the process used to confirm individual provider affiliation with study practices in study years. CONCLUSIONS: Our analysis of Medicare claims data provides no empirical support for the proposition that acquisition of onsite MRI capacity within an orthopedic surgery practice induces an increase in the rate of MRI use for Medicare patients among practice providers, relative to physicians in practices without MRI capacity over the same time period. PMID- 26481142 TI - Reply to the Letter to the Editor: A rebuttal: FSFI questionnaire does not assess female sexual function, by V. Puppo and G. Puppo: Sexual function: From pulp fiction to evidence-based screening. PMID- 26481143 TI - A novel cold-adapted type I pullulanase of Paenibacillus polymyxa Nws-pp2: in vivo functional expression and biochemical characterization of glucans hydrolyzates analysis. AB - BACKGROUND: Pullulanase is an important debranching enzyme and has been widely utilized to hydrolyse the alpha-1,6 glucosidic linkages in starch/sugar industry. Selecting new bacterial strains or improving bacterial strains is a prerequisite and effective solution in industrial applications. Although many pullulanase genes have been cloned and sequenced, there is no report of P. polymyxa type I pullulanase gene or the recombinant strain. Meanwhile most of the type I pullulanase investigated exhibit thermophilic or mesophilic properties. There are just few reports of cold-adapted pullulanases, which have optimum activity at moderate temperature and exhibit rather high catalytic activity at cold. Previously, six strains showing distinct pullulan degradation ability were isolated using enrichment procedures. As containing novel bacterium resource and significant pullulanase activity, strain Nws-pp2 was selected for in-depth study. METHODS: In this study, a type I pullulanase gene (pulN) was obtained from the strain P. polymyxa Nws-pp2 by degenerate primers. Through optimization of induced conditions, the recombinant PulN achieved functional soluble expression by low temperature induction. The enzyme characterizations including the enzyme activity/stability, optimum temperature, optimum pH and substrate specificity were also described through protein purification. RESULTS: The pullulanase gene (named pulN), encoding a novel cold-adapted type I pullulanase (named PulN), was obtained from isolated strain Paenibacillus polymyxa Nws-pp2. The gene had an open reading frame of 2532-bp and was functionally expressed in Escherichia coli through optimization of induced conditions. The level of functional PulN-like protein reached the maximum after induction for 16 h at 20 degrees C and reached about 0.34 mg/ml (about 20 % of total protein) with an activity of 6.49 U/ml. The purified recombinant enzyme with an apparent molecular mass of about 96 kDa was able to attack specifically the alpha-1,6 linkages in pullulan to generate maltotriose as the major product. The purified PulN showed optimal activity at pH 6.0 and 35 degrees C, and retained more than 40 % of the maximum activity at 10 degrees C (showing cold-adapted). The pullulanase activity was significantly enhanced by Co(2+) and Mn(2+), meanwhile Cu(2+) and SDS inhibited pullulanase activity completely. The Km and Vmax values of purified PulN were 15.25 mg/ml and 20.1 U/mg, respectively. The PulN hydrolyzed pullulan, amylopectin, starch, and glycogen, but not amylose. Substrate specificity and products analysis proved that the purified pullulanase from Paenibacillus polymyxa Nws-pp2 belong to a type I pullulanase. CONCLUSIONS: This report of the novel type I pullulanase in Paenibacillus polymyxa would contribute to pullulanase research from Paenibacillus spp. significantly. Also, the cold-adapted pullulanase produced in recombinant strain shows the potential application. PMID- 26481145 TI - Correlates of concurrency among young people in Carletonville, South Africa. AB - There is still a considerable debate about whether socioeconomic or cultural factors underpin the high prevalence of sexual partner concurrency in parts of Southern and Eastern Africa. We analyzed the patterning and correlates of concurrency in a population-based sample of 1182 sexually active 14-24 year olds in Carletonville, South Africa. Potential demographic, socioeconomic and attitudinal risk factors were assessed via a questionnaire. The association between risk factors and respondent reported concurrency were assessed using multivariate logistic regression. Separate models were run for men and women. Point-concurrency rates at the time of the survey and 6 months prior to the survey were similarly high--19.3 (95% confidence interval, CI 14.2-18.5%) and 16.2% (CI 14.1-18.4%), respectively. Multivariate logistic regression revealed that for men and women, concurrency was not associated with socioeconomic deprivation but was associated with a number of sexual partners, being married and having a partner who was thought to have an additional partner. Female concurrents were more likely to use alcohol, have an older partner and have difficulties negotiating condom usage and refusing sex with their partners. Male concurrents were less likely to use a condom regularly and less likely to wear a condom when their partner asked them to. The strong relationship between respondent and partner concurrency appears to depend on contemporary concurrency, as opposed to the behavior of previous partners. If high concurrency rates are in part driven by positive feedback loops of partner and respondent concurrency, then norm change involving the rejection of concurrents could be self-amplifying leading to a rapid decline of concurrency. PMID- 26481144 TI - Differential ability of MSCs isolated from placenta and cord as feeders for supporting ex vivo expansion of umbilical cord blood derived CD34(+) cells. AB - INTRODUCTION: Ex vivo expansion of umbilical cord blood (UCB) is attempted to increase cell numbers to overcome the limitation of cell dose. Presently, suspension cultures or feeder mediated co-cultures are performed for expansion of hematopoietic stem cells (HSCs). Mesenchymal stem cells (MSCs) have proved to be efficient feeders for the maintenance of HSCs. Here, we have established MSCs HSCs co-culture system with MSCs isolated from less invasive and ethically acceptable sources like umbilical cord tissue (C-MSCs) and placenta (P-MSCs). MSCs derived from these tissues are often compared with bone marrow derived MSCs (BM-MSCs) which are considered as a gold standard. However, so far none of the studies have directly compared C-MSCs with P-MSCs as feeders for ex vivo expansion of HSCs. Thus, we for the first time performed a systematic comparison of hematopoietic supportive capability of C and P-MSCs using paired samples. METHODS: UCB-derived CD34(+) cells were isolated and co-cultured on irradiated C and P-MSCs for 10 days. C-MSCs and P-MSCs were isolated from the same donor. The cultures comprised of serum-free medium supplemented with 25 ng/ml each of SCF, TPO, Flt-3 L and IL-6. After 10 days cells were collected and analyzed for phenotype and functionality. RESULTS: C-MSCs and P-MSCs were found to be morphologically and phenotypically similar but exhibited differential ability to support ex vivo hematopoiesis. Cells expanded on P-MSCs showed higher percentage of primitive cells (CD34(+)CD38(-)), CFU (Colony forming unit) content and LTC-IC (Long term culture initiating cells) ability. CD34(+) cells expanded on P-MSCs also exhibited better in vitro adhesion to fibronectin and migration towards SDF 1alpha and enhanced NOD/SCID repopulation ability, as compared to those grown on C-MSCs. P-MSCs were found to be closer to BM-MSCs in their ability to expand HSCs. P-MSCs supported expansion of functionally superior HSCs by virtue of reduction in apoptosis of primitive HSCs, higher Wnt and Notch activity, HGF secretion and cell-cell contact. On the other hand, C-MSCs facilitated expansion of progenitors (CD34(+)CD38(+)) and differentiated (CD34(-)CD38(+)) cells by secretion of IL1-alpha, beta, MCP-2, 3 and MIP-3alpha. CONCLUSIONS: P-MSCs were found to be better feeders for ex vivo maintenance of primitive HSCs with higher engraftment potential than the cells expanded with C-MSCs as feeders. PMID- 26481146 TI - Twins with incurable progressive disease can be taken off life support, High Court rules. PMID- 26481147 TI - A LIN28B-RAN-AURKA Signaling Network Promotes Neuroblastoma Tumorigenesis. AB - A more complete understanding of aberrant oncogenic signaling in neuroblastoma, a malignancy of the developing sympathetic nervous system, is paramount to improving patient outcomes. Recently, we identified LIN28B as an oncogenic driver in high-risk neuroblastoma. Here, we identify the oncogene RAN as a LIN28B target and show regional gain of chromosome 12q24 as an additional somatic alteration resulting in increased RAN expression. We show that LIN28B influences RAN expression by promoting RAN Binding Protein 2 expression and by directly binding RAN mRNA. Further, we demonstrate a convergence of LIN28B and RAN signaling on Aurora kinase A activity. Collectively, these findings demonstrate that LIN28B RAN-AURKA signaling drives neuroblastoma oncogenesis, suggesting that this pathway may be amenable to therapeutic targeting. PMID- 26481150 TI - Discovery of pyridine-based agrochemicals by using Intermediate Derivatization Methods. AB - Pyridine-based compounds have been playing a crucial role as agrochemicals or pesticides including fungicides, insecticides/acaricides and herbicides, etc. Since most of the agrochemicals listed in the Pesticide Manual were discovered through screening programs that relied on trial-and-error testing and new agrochemical discovery is not benefiting as much from the in silico new chemical compound identification/discovery techniques used in pharmaceutical research, it has become more important to find new methods to enhance the efficiency of discovering novel lead compounds in the agrochemical field to shorten the time of research phases in order to meet changing market requirements. In this review, we selected 18 representative known agrochemicals containing a pyridine moiety and extrapolate their discovery from the perspective of Intermediate Derivatization Methods in the hope that this approach will have greater appeal to researchers engaged in the discovery of agrochemicals and/or pharmaceuticals. PMID- 26481148 TI - Erythropoietin Stimulates Tumor Growth via EphB4. AB - While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo's effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we identified EphB4 as an Epo receptor that triggers downstream signaling via STAT3 and promotes rhEpo-induced tumor growth and progression. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression and further provide clinically significant dimension to the biology of erythropoietin. PMID- 26481149 TI - A roadmap to improve the quality of atrial fibrillation management: proceedings from the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference. AB - At least 30 million people worldwide carry a diagnosis of atrial fibrillation (AF), and many more suffer from undiagnosed, subclinical, or 'silent' AF. Atrial fibrillation-related cardiovascular mortality and morbidity, including cardiovascular deaths, heart failure, stroke, and hospitalizations, remain unacceptably high, even when evidence-based therapies such as anticoagulation and rate control are used. Furthermore, it is still necessary to define how best to prevent AF, largely due to a lack of clinical measures that would allow identification of treatable causes of AF in any given patient. Hence, there are important unmet clinical and research needs in the evaluation and management of AF patients. The ensuing needs and opportunities for improving the quality of AF care were discussed during the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference in Nice, France, on 22 and 23 January 2015. Here, we report the outcome of this conference, with a focus on (i) learning from our 'neighbours' to improve AF care, (ii) patient-centred approaches to AF management, (iii) structured care of AF patients, (iv) improving the quality of AF treatment, and (v) personalization of AF management. This report ends with a list of priorities for research in AF patients. PMID- 26481151 TI - Stereospecific inhibition of nitric oxide production in macrophage cells by flavanonols: Synthesis and the structure-activity relationship. AB - To explore the structure-activity relationships on the inhibitory activity of flavanonols against nitric oxide (NO) production in inflammatory cells, we synthesized 19 flavanonols which shared a common 3,5,7-trihydroxychroman scaffold. A range of substitutions was included in the B ring in order to investigate the structure-activity relationship. We also succeeded in isolating stereoisomers from 16 of the flavanonols using chiral column chromatography. The inhibitory effects of these compounds on NO production were examined in RAW 264.7 cells (a murine macrophage-like cell line), which were activated by lipopolysaccharide (LPS). We only observed inhibitory activity against NO production in (2R,3R) stereoisomers, while the inhibitory activities of (2S,3S) stereoisomers were significantly weaker. We also evaluated the free radical scavenging potential of the flavanonols using 1,1-diphenyl-2-picrylhydrazyl (DPPH). Each stereoisomer indicated the equivalent DPPH scavenging potential as expected. The radical scavenging activity was not correlated with the inhibitory activity against NO. The inhibition of NO production by flavanonols is stereospecific and cannot simply be explained by their radical scavenging activity. We propose the possible existence of a 'target' molecule for flavanonols which is involved in the production and/or regulation of NO in RAW 264.7 cells. PMID- 26481153 TI - The outcome of H. influenzae and S. pneumoniae inter-species interactions depends on pH, nutrient availability and growth phase. AB - Haemophilus influenzae and Streptococcus pneumoniae exist together as common commensals of the healthy human nasopharynx, but both are important aetiological agents of different diseases, including the paediatric disease otitis media. It was recently shown that the formation of a multispecies biofilm of H. influenzae and S. pneumoniae is the cause of chronic forms of otitis media. However, the interactions between the two species are not clearly defined. Using a defined and kinetic analysis, our study has shown that while co-existence of the two species occurs, S. pneumoniae is also able to convert H. influenzae to a non-culturable state. We determined that this process was dependent on growth phase and pH. To analyse the H. influenzae/S. pneumoniae interactions in more depth, we investigated the growth and transcriptional profile in a pH-defined batch culture model, as well as in a growth phase independent flow cell system. Transcriptomics has shown that there are changes in gene expression in each of the species when grown in co-culture, intriguingly inducing the S. pneumoniae bacteriocin transport genes, and phage-associated genes in both species. Importantly, we have shown vast changes in gene expression in a group of S. pneumoniae metabolic genes, including those encoding lactose utilisation, glycerol utilisation and sugar transport proteins; we have shown that the expression of these genes depends not only on the presence of H. influenzae, but also on the growth system utilised. PMID- 26481152 TI - Isolation, semisynthesis, covalent docking and transforming growth factor beta activated kinase 1 (TAK1)-inhibitory activities of (5Z)-7-oxozeaenol analogues. AB - (5Z)-7-Oxozeanol and related analogues were isolated and screened to explore their activity as TAK1 inhibitors. Seven analogues were synthesized and more than a score of natural products isolated that examined the role that different areas of the molecule contribute to TAK1 inhibition. A novel nonaromatic difluoro derivative was synthesized that had similar potency compared to the lead. This is the first example of a nonaromatic compound in this class to have TAK1 inhibition. Covalent docking for the isolated and synthesized analogues was carried out and found a strong correlation between the observed activities and the calculated binding. PMID- 26481154 TI - Effect of glycemic and lipid achievements on clinical outcomes type 2 diabetic, Chinese patients with stable coronary artery disease. AB - AIMS: To describe the effect of glycemic and lipid achievements and their joint roles in future major adverse cardiovascular events (MACEs) prediction. METHODS: One thousand two hundred sixty consecutive, type 2 diabetic patients with stable coronary artery disease (CAD) were identified, they were followed up a median of 24.07months. RESULTS: At baseline, 85.4% of patients with blood pressure less than 140/90mmHg, while only a minority of patients met guideline-recommended hemoglobin A1C (HbA1C) (44.2%), low-density lipoprotein cholesterol (LDL-C) (24.7%), non high-density lipoprotein cholesterol (NHDL-C) (36.3%), or apolipoprotein B (apoB) levels (38.6%). After follow-up, patients achieving either glycemic or lipid goals experienced a lower rate of future events (HbA1C 35.4%, LDL-C 19.3%, NHDL-C 30.4%, apoB 26.7%). Dual-goal achievements of HbA1C and lipids showed the lowest event risk (adjusted relative risk, RR: HbA1C, 0.92 vs. LDL-C 0.75 vs. dual 0.27; HbA1C, 0.86 vs. NHDL-C 0.59 vs. dual 0.44; HbA1C, 0.74 vs. apoB 0.64 vs. dual 0.55). Patients with suboptimal goals (LDL-C 1.8 2.5mmol/L, NHDL-C 2.5-3.4mmol/L, or apoB 0.8-1.0g/L) were at risk when compared to those with guideline-recommended goals. CONCLUSIONS: Dual-achievement of glycemic and lipid goals based on a relative well-controlled condition of blood pressure conferred a better prognosis in type 2 diabetic patients with CAD. PMID- 26481157 TI - On the origins of autism: The Quantitative Threshold Exposure hypothesis. AB - The Quantitative Threshold Exposure (QTE) hypothesis is a multifactorial threshold model that accounts for the cumulative effects of risk factor exposure in both the causation of autism spectrum disorder (ASD) and its dramatic increase over the past 30 years. The QTE hypothesis proposes that ASD is triggered by the cumulative effects of high-level exposure to endogenous and environmental factors that act as antigens to impair normal immune system (IS) and associated central nervous system (CNS) functions during critical developmental stages. The quantitative threshold parameters that comprise a cumulative risk for the development of ASD are identified by the assessment of documented epidemiological factors that, in sum, determine the likelihood that ASD will occur as a result of their effects on critically integrated IS and CNS pathways active during prenatal, neo-natal and early childhood brain maturation. The model proposes an explanation for the relationship between critical developmental stages of brain/immune system development in conjunction with the quantitative effects of genetic and environmental risk factors that may interface with these critical developmental windows. This model may be useful even when the individual contributions of specific risk factors cannot be quantified, as it proposes that the combined quantitative level of exposure to risk factors for ASD rather than exposure to any one risk factor per se defines threshold occurrence rates. PMID- 26481156 TI - Analyzing HT-SELEX data with the Galaxy Project tools--A web based bioinformatics platform for biomedical research. AB - The development of DNA and RNA aptamers for research as well as diagnostic and therapeutic applications is a rapidly growing field. In the past decade, the process of identifying aptamers has been revolutionized with the advent of high throughput sequencing (HTS). However, bioinformatics tools that enable the average molecular biologist to analyze these large datasets and expedite the identification of candidate aptamer sequences have been lagging behind the HTS revolution. The Galaxy Project was developed in order to efficiently analyze genome, exome, and transcriptome HTS data, and we have now applied these tools to aptamer HTS data. The Galaxy Project's public webserver is an open source collection of bioinformatics tools that are powerful, flexible, dynamic, and user friendly. The online nature of the Galaxy webserver and its graphical interface allow users to analyze HTS data without compiling code or installing multiple programs. Herein we describe how tools within the Galaxy webserver can be adapted to pre-process, compile, filter and analyze aptamer HTS data from multiple rounds of selection. PMID- 26481155 TI - Parkinson's disease proteins: Novel mitochondrial targets for cardioprotection. AB - Ischemic heart disease (IHD) is the leading cause of death and disability worldwide. Therefore, novel therapeutic targets for protecting the heart against acute ischemia/reperfusion injury (IRI) are required to attenuate cardiomyocyte death, preserve myocardial function, and prevent the onset of heart failure. In this regard, a specific group of mitochondrial proteins, which have been linked to familial forms of Parkinson's disease (PD), may provide novel therapeutic targets for cardioprotection. In dopaminergic neurons of the substantia nigra, these PD proteins, which include Parkin, PINK1, DJ-1, LRRK2, and alpha-synuclein, play essential roles in preventing cell death-through maintaining normal mitochondrial function, protecting against oxidative stress, mediating mitophagy, and preventing apoptosis. These rare familial forms of PD may therefore provide important insights into the pathophysiology underlying mitochondrial dysfunction and the development of PD. Interestingly, these PD proteins are also present in the heart, but their role in myocardial health and disease is not clear. In this article, we review the role of these PD proteins in the heart and explore their potential as novel mitochondrial targets for cardioprotection. PMID- 26481158 TI - Possible role of mechanical force in regulating regeneration of the vascularized fat flap inside a tissue engineering chamber. AB - In plastic and reconstructive surgery, adipose tissue is widely used as effective filler for tissue defects. Strategies for treating soft tissue deficiency, which include free adipose tissue grafts, use of hyaluronic acid, collagen injections, and implantation of synthetic materials, have several clinical limitations. With the aim of overcoming these limitations, researchers have recently utilized tissue engineering chambers to produce large volumes of engineered vascularized fat tissue. However, the process of growing fat tissue in a chamber is still relatively limited, and can result in unpredictable or dissatisfactory final tissue volumes. Therefore, detailed understanding of the process is both necessary and urgent. Many studies have shown that mechanical force can change the function of cells via mechanotransduction. Here, we hypothesized that, besides the inflammatory response, one of the key factors to control the regeneration of vascularized fat flap inside a tissue engineering chamber might be the balance of mechanical forces. To test our hypothesis, we intend to change the balance of forces by means of measures in order to make the equilibrium point in favor of the direction of regeneration. If those measures proved to be feasible, they could be applied in clinical practice to engineer vascularized adipose tissue of predictable size and shape, which would in turn help in the advancement of tissue engineering. PMID- 26481159 TI - Adaptation of a mixed culture of acidophiles for a tank biooxidation of refractory gold concentrates containing a high concentration of arsenic. AB - We adapted a mixed culture of acidophiles to high arsenic concentrations to confirm the possibility of achieving more than 70% biooxidation of refractory gold concentrates containing high arsenic (As) concentration. The biooxidation process was applied to refractory gold concentrates containing approximately 139.67 g/kg of total As in a stirred tank reactor using an adapted mixed culture of Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans. The percentage of the biooxidation process was analyzed based on the total As removal efficiency. The As removal was monitored by inductively coupled plasma (ICP) analysis, conducted every 24 h. The results obtained with the adapted culture were compared with the percentage of biooxidation obtained with a non-adapted mixed culture of A. ferrooxidans and A. thiooxidans, and with their respective pure cultures. The percentages of biooxidation obtained during 358 h of reaction were 72.20%, 38.20%, 27.70%, and 11.45% for adapted culture, non-adapted culture, and pure cultures of A. thiooxidans and A. ferrooxidans, respectively. The adapted culture showed a peak maximum percentage of biooxidation of 77% at 120 h of reaction, confirming that it is possible to obtain biooxidation percentages over 70% in gold concentrates containing high As concentrations. PMID- 26481160 TI - Screening of natural yeast isolates under the effects of stresses associated with second-generation biofuel production. AB - Robust microorganisms are required for sustainable second-generation biofuel production. We evaluated the growth and fermentation performance of six natural isolates that were derived from grape wine and medicinal herbs using a wide range of carbon sources, rice and wheat straw hydrolysates as well as stress conditions associated with second-generation ethanol production. Sequence analysis of the 5.8S internal transcribed spacer (ITS) and species-specific PCR amplification of the HO gene region assigned the natural isolates to Saccharomyces cerevisiae. Restriction fragment length polymorphism (RFLP) analysis of the mitochondrial DNA revealed that natural yeast isolates are genetically closer to the laboratory strain BY4741 than to the CEN.PK strains. Dextrose fermentation by a natural isolate, MTCC4780, under semi-anaerobic conditions produced maximum ethanol yields of 0.44 g/g and 0.39 g/g, respectively, with and without the stresses encountered during lignocellulosic ethanol fermentation. However, MTCC4780 produced ethanol yields of 0.48 g/g, 0.42 g/g and 0.45 g/g, respectively, with glucose, rice and wheat straw enzymatic hydrolysate fermentation in a bioreactor. The isolates MTCC4781 and MTCC4796 showed higher growth and fermentation performance than did MTCC4780 in the presence of elevated temperature and pre treatment inhibitors. Taken together, the MTCC4780, MTCC4781 and MTCC4796 strains have the potential to serve as a platform for lignocellulosic ethanol production under stresses associated with second-generation biofuel production. PMID- 26481161 TI - Production of raw starch-degrading enzyme by Aspergillus sp. and its use in conversion of inedible wild cassava flour to bioethanol. AB - The major bottlenecks in achieving competitive bioethanol fuel are the high cost of feedstock, energy and enzymes employed in pretreatment prior to fermentation. Lignocellulosic biomass has been proposed as an alternative feedstock, but because of its complexity, economic viability is yet to be realized. Therefore, research around non-conventional feedstocks and deployment of bioconversion approaches that downsize the cost of energy and enzymes is justified. In this study, a non-conventional feedstock, inedible wild cassava was used for bioethanol production. Bioconversion of raw starch from the wild cassava to bioethanol at low temperature was investigated using both a co-culture of Aspergillus sp. and Saccharomyces cerevisiae, and a monoculture of the later with enzyme preparation from the former. A newly isolated strain of Aspergillus sp. MZA-3 produced raw starch-degrading enzyme which displayed highest activity of 3.3 U/mL towards raw starch from wild cassava at 50 degrees C, pH 5.5. A co culture of MZA-3 and S. cerevisiae; and a monoculture of S. cerevisiae and MZA-3 enzyme (both supplemented with glucoamylase) resulted into bioethanol yield (percentage of the theoretical yield) of 91 and 95 at efficiency (percentage) of 84 and 96, respectively. Direct bioconversion of raw starch to bioethanol was achieved at 30 degrees C through the co-culture approach. This could be attractive since it may significantly downsize energy expenses. PMID- 26481162 TI - Left Ventricular Thrombus Formation After ST-Segment-Elevation Myocardial Infarction: Insights From a Cardiac Magnetic Resonance Multicenter Study. AB - BACKGROUND: Data on left ventricular (LV) thrombus formation after primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction (STEMI) are scarce. The aims of this study were to assess the (1) incidence of LV thrombi using cardiac magnetic resonance in a multicenter cohort of STEMI patients and (2) prognostic relevance of LV thrombi at 1-year follow-up. METHODS AND RESULTS: In total, 738 STEMI patients reperfused by primary angioplasty were enrolled in 8 centers. Cardiac magnetic resonance was completed within 1 week after infarction. Central core laboratory-masked analyses for the presence of LV thrombi were performed. The primary clinical end point was the occurrence of major adverse cardiac events within 1 year. LV thrombi were detected in 26 patients (3.5%) in the overall cohort and in 7.1% in anterior STEMI patients. The presence of thrombi was associated with larger infarcts (P<0.001), less myocardial salvage (P<0.01), impaired LV ejection fraction (P<0.001), and more pronounced late microvascular obstruction (P=0.002). The presence of thrombi was independently associated with the incidence of major adverse cardiac events at 12 months (hazard ratio, 2.73; 95% confidence interval, 1.11-6.73; P=0.03). CONCLUSIONS: In this multicenter cohort of patients with STEMI, thrombus prevalence assessed by cardiac magnetic resonance was 3.5% and associated with decreased myocardial salvage, larger infarcts, and more pronounced reperfusion injury. Importantly, LV thrombus was independently associated with major adverse cardiac events at 1-year follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00712101. PMID- 26481163 TI - Thrombosis and Prognosis Following ST-Elevation Myocardial Infarction: Left Ventricular Thrombus Assessment by Cardiac Magnetic Resonance. PMID- 26481164 TI - Chronic sodium salicylate administration enhances population spike long-term potentiation following a combination of theta frequency primed-burst stimulation and the transient application of pentylenetetrazol in rat CA1 hippocampal neurons. AB - The effect of chronic administration of sodium salicylate (NaSal) on the excitability and synaptic plasticity of the rodent hippocampus was investigated. Repeated systemic treatment with NaSal reliably induced tolerance to the anti nociceptive effect of NaSal (one i.p. injection per day for 6 consecutive days). Following chronic NaSal or vehicle treatment, a series of electrophysiological experiments on acute hippocampal slices (focusing on the CA1 circuitry) were tested whether tolerance to NaSal would augment pentylenetetrazol (PTZ)-induced long-term potentiation (LTP) and /or epileptic activity, and whether the augmentation was the same after priming activity with a natural stimulus pattern prior to PTZ. We noted an altered synaptic input-to-spike transformation, such that neuronal firing increased after a given synaptic drive. Population spike-LTP (PS-LTP) was increased in the NaSal-tolerant animals, but only when it was induced via a combination of electrical stimulation (theta pattern primed-burst stimulation) and the transient application of PTZ. Identifying and understanding these changes in neuronal excitability and synaptic plasticity following chronic salicylate treatment could prove useful in the clinical diagnosis or treatment of chronic aspirin-induced, or even idiopathic, seizure activity. PMID- 26481165 TI - Coumaglutide, a novel long-acting GLP-1 analog, inhibits beta-cell apoptosis in vitro and invokes sustained glycemic control in vivo. AB - Glucagon-like peptide-1 (GLP-1) is a potential candidate for the treatment of type 2 diabetes. However, native GLP-1 is not suitable for therapy of diabetes due to its short half-life (t1/2=2 min). Our recent discovery of the novel long acting GLP-1 analog, coumaglutide, elicits favorable hypoglycemic effects. The present study was aimed at determining the protection effect of beta-cell from apoptosis and in vivo pharmacologic properties of coumaglutide in diabetic mice. To determine the protective effect of coumaglutide on INS-1 cell viability and apoptosis, cells were exposed to 1 MUM streptozotocin (STZ) and coumaglutide for 24 h. Moreover, STZ-induced diabetic mice were treated daily with coumaglutide for 20 days and a range of pharmacologic parameters, including hemoglobin A1c (HbA1C), intraperitoneal glucose tolerance, food intake and body weight were assessed before and after the treatment. As with other glucagon-like peptide-1 receptor agonizts, coumaglutide was able to protect beta-cell from apoptosis in vitro and induce a durable restoration of glycemic control (normalization of both HbA1C and improvement of intraperitoneal glucose tolerance) in diabetic mice. It can be concluded that coumaglutide retains native GLP-1 activities and thus may serve as a promising hypoglycemic drug candidate. PMID- 26481166 TI - Inhibition of calcineurin/NFAT pathway plays an essential role in renoprotective effect of tropisetron in early stage of diabetic nephropathy. AB - Recent studies have shown that calcineurin plays a central role in hypertrophy and extracellular matrix (ECM) accumulation in glomeruli at the early stages of diabetic nephropathy. Tropisetron is an effective antiemetic drug which also can potently inhibit calcineurin. The aim of this study was to investigate whether tropisetron can prevent glomerular hypertrophy and ECM expansion in early diabetic nephropathy. Streptozotocin (STZ)-induced diabetic rats were treated with tropisetron and cyclosporine A, a pharmacological calcineurin inhibitor, and the renal function and the expression of calcineurin and fibronectin were then assessed as well as nuclear localization of nuclear factor of activated T-cell c1 (NFATc1). 2 weeks after diabetes induction, all STZ-treated rats showed hyperglycemia, polyuria, body weight loss and renal dysfunction, as evidenced by increased glomerular filtration rate (GFR), along with a marked pathological changes in kidney. Calcineurin expression was increased in association with increased nuclear localization of the calcineurin substrate NFATc1 and fibronectin expression in glomeruli of diabetic rats. In parallel, the diabetic glomeruli became hypertrophic with an increase in kidney weight. Tropisetron, as potent as cyclosporine A, significantly ameliorated the early nephropathy symptoms, potentially through suppression of calcineurin expression, nuclear localization of NFATc1 and accumulation of fibronectin, and thereby reduced hypertrophy in glomeruli of diabetic rats. In conclusion, our results showed that tropisetron could ameliorate kidney injury in the early stage of diabetic nephropathy in rats. The renoprotective effects of tropisetron can be attributed, at least in part, to the suppression of diabetes-induced increases in calcineurin expression in kidney tissue. PMID- 26481167 TI - Sporadic hereditary motor and sensory neuropathies: Advances in the diagnosis using next generation sequencing technology. AB - Hereditary motor and sensory neuropathies (HMSN) are genetically heterogeneous disorders affecting peripheral motor and sensory functions. Many different pathogenic variants in several genes involved in the demyelinating, the axonal and the intermediate HMSN forms have been identified, for which all inheritance patterns have been described. The mutation screening currently available is based on Sanger sequencing and is time-consuming and relatively expensive due to the high number of genes involved and to the absence of mutational hot spots. To overcome these limitations, we have designed a custom panel for simultaneous sequencing of 28 HMSN-related genes. We have applied this panel to three representative patients with variable HMSN phenotype and uncertain diagnostic classifications. Using our NGS platform we rapidly identified three already described pathogenic heterozygous variants in MFN2, MPZ and DNM2 genes. Here we show that our pre-custom platform allows a fast, specific and low-cost diagnosis in sporadic HMSN cases. This prompt diagnosis is useful for providing a well timed treatment, establishing a recurrence risk and preventing further investigations poorly tolerated by patients and expensive for the health system. Importantly, our study illustrates the utility and successful application of NGS to mutation screening of a Mendelian disorder with extreme locus heterogeneity. PMID- 26481168 TI - Spinobulbar muscular atrophy (Kennedy's disease): A rare diagnosis in the Greek population. PMID- 26481169 TI - Dietary transition difficulties in preterm infants: critical literature review. AB - OBJECTIVE: To analyze the scientific literature on dietary changes in preterm children during the first years of life. DATA SOURCE: The PubMed database was used for article selection. The texts were analyzed according to their objectives, research design, and research group characteristics. The following were selected to comprise the criteria: (1) publications in the period from 1996 to 2014; (2) participation of infants and children from birth to 10 years of age; (3) development of oral motor skills necessary for feeding; (4) development of the feeding process; and (5) feeding difficulties during childhood. SUMMARY OF THE FINDINGS: There were 282 studies identified, of which 17 were used in the review, and five more articles were identified through the reference list of selected articles, totaling 22 references. CONCLUSION: Very low birth weight preterm newborns are more likely to have feeding problems in early postnatal stages and during childhood when compared with full-term infants. Monitoring the feeding of these infants after hospital discharge is strictly recommended in an early intervention program aiming at better development of feeding skills. PMID- 26481171 TI - Sex differences in hospital length of stay in children and adults hospitalized for asthma exacerbation. PMID- 26481170 TI - Family responses to a child with schizophrenia: An Indonesian experience. AB - Indonesian culture puts a high value on family bonding. Therefore, support and encouragement for each family member is high that any problems are the responsibility of the whole family. This paper explores the implications of the phenomena whether is a schizophrenic child in the family affected the parental relationship in Indonesian family and trying to find out the implication of parental relationship on medication adherence. This was a cross-sectional study which involved 180 parents of children with schizophrenia and parents with aged matched non-schizophrenic children as a control group; consisting of 45 parents of children with schizophrenia and 135 parents of non-schizophrenic children. The parental relationship was examined by using the Indonesian version of Family Adaptability and Cohesion Evaluation Scale IV (Indonesian version of FACES IV). Our study revealed that 75.6% parents of children with schizophrenia experienced a healthy parental relationship compared to 94.80% in the parents of non schizophrenic children group. The most prevalent of unhealthy relationship among parents of children with schizophrenia was chaotic disengagement. Parental adherence to give medication for their child with schizophrenia was better if they had a healthy parental relationship. In conclusion, a small number of Indonesian parents with schizophrenic children experienced an unhealthy parental relationship. Therefore, psycho-education and supportive psychotherapy still needed to facilitate those families to express their emotion adapt and cope. PMID- 26481172 TI - Differential Response to Risperidone in Schizophrenia Patients by KCNH2 Genotype and Drug Metabolizer Status. AB - OBJECTIVE: Antipsychotic drugs target dopamine and serotonin receptors as well as Kv11.1 potassium channels encoded by KCNH2. Variable patient responses and a wide range of side effects, however, limit their efficacy. Slow metabolizer status and gene variants in KCNH2 associated with increased expression of Kv11.1-3.1, an alternatively spliced isoform of Kv11.1, are correlated with improved responses to antipsychotic medications. Here, the authors test the hypothesis that these effects may be influenced by differential drug binding to Kv11.1 channel isoforms. METHOD: Drug block of Kv11.1 isoforms was tested in cellular electrophysiology assays. The effects of drug metabolism and KCNH2 genotypes on clinical responses were assessed in patients enrolled in the multicenter Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). RESULTS: Risperidone caused greater in vitro block of the alternatively spliced Kv11.1-3.1 isoform than full-length Kv11.1-1A channels, whereas its metabolite paliperidone and other atypical antipsychotics have similar potencies for the two isoforms. In the CATIE study (N=362), patients with genotypes associated with increased Kv11.1-3.1 expression (N=52) showed a better treatment response to risperidone compared with other drugs, but this association was dependent on metabolism status. Patients with KCNH2 risk genotypes and slow metabolizer status (approximately 7% of patients) showed marked improvement in symptoms when treated with risperidone compared with patients with fast metabolizer status or without the KCNH2 risk genotypes. CONCLUSIONS: These data support the hypothesis that Kv11.1 channels play a role in the therapeutic action of antipsychotic drugs, particularly risperidone, and further highlight the promise of optimizing response with genotype-guided therapy for schizophrenia patients. PMID- 26481173 TI - The Sequential Integration of Pharmacotherapy and Psychotherapy in the Treatment of Major Depressive Disorder: A Meta-Analysis of the Sequential Model and a Critical Review of the Literature. AB - OBJECTIVE: A number of randomized controlled trials in major depressive disorder have employed a sequential model, which consists of the use of pharmacotherapy in the acute phase and of psychotherapy in its residual phase. The aim of this review was to provide an updated meta-analysis of the efficacy of this approach in reducing the risk of relapse in major depressive disorder and to place these findings in the larger context of treatment selection. METHOD: Keyword searches were conducted in MEDLINE, EMBASE, PsycINFO, and Cochrane Library from inception of each database through October 2014. Randomized controlled trials examining the efficacy of the administration of psychotherapy after successful response to acute-phase pharmacotherapy in the treatment of adults with major depressive disorder were considered for inclusion in the meta-analysis. RESULTS: Thirteen high-quality studies with 728 patients in a sequential treatment arm and 682 in a control treatment arm were included. All studies involved cognitive-behavioral therapy (CBT). The pooled risk ratio for relapse/recurrence was 0.781 (95% confidence interval [CI]=0.671-0.909; number needed to treat=8), according to the random-effects model, suggesting a relative advantage in preventing relapse/recurrence compared with control conditions. A significant effect of CBT during continuation of antidepressant drugs compared with antidepressants alone or treatment as usual (risk ratio: 0.811; 95% CI=0.685-0.961; number needed to treat=10) was found. Patients randomly assigned to CBT who had antidepressants tapered and discontinued were significantly less likely to experience relapse/recurrence compared with those assigned to either clinical management or continuation of antidepressant medication (risk ratio: 0.674; 95% CI=0.482-0.943; number needed to treat=5). CONCLUSIONS: The sequential integration of CBT and pharmacotherapy is a viable strategy for preventing relapse in major depressive disorder. The current indications for the application of psychotherapy in major depressive disorder are discussed, with special reference to its integration with pharmacotherapy. PMID- 26481175 TI - RAISE-ing Our Expectations for First-Episode Psychosis. PMID- 26481174 TI - Comprehensive Versus Usual Community Care for First-Episode Psychosis: 2-Year Outcomes From the NIMH RAISE Early Treatment Program. AB - OBJECTIVE: The primary aim of this study was to compare the impact of NAVIGATE, a comprehensive, multidisciplinary, team-based treatment approach for first-episode psychosis designed for implementation in the U.S. health care system, with community care on quality of life. METHOD: Thirty-four clinics in 21 states were randomly assigned to NAVIGATE or community care. Diagnosis, duration of untreated psychosis, and clinical outcomes were assessed via live, two-way video by remote, centralized raters masked to study design and treatment. Participants (mean age, 23) with schizophrenia and related disorders and <=6 months of antipsychotic treatment (N=404) were enrolled and followed for >=2 years. The primary outcome was the total score of the Heinrichs-Carpenter Quality of Life Scale, a measure that includes sense of purpose, motivation, emotional and social interactions, role functioning, and engagement in regular activities. RESULTS: The 223 recipients of NAVIGATE remained in treatment longer, experienced greater improvement in quality of life and psychopathology, and experienced greater involvement in work and school compared with 181 participants in community care. The median duration of untreated psychosis was 74 weeks. NAVIGATE participants with duration of untreated psychosis of <74 weeks had greater improvement in quality of life and psychopathology compared with those with longer duration of untreated psychosis and those in community care. Rates of hospitalization were relatively low compared with other first-episode psychosis clinical trials and did not differ between groups. CONCLUSIONS: Comprehensive care for first-episode psychosis can be implemented in U.S. community clinics and improves functional and clinical outcomes. Effects are more pronounced for those with shorter duration of untreated psychosis. PMID- 26481176 TI - Letter to the Editor. PMID- 26481177 TI - Suppression of Tinnitus in Chinese Patients Receiving Regular Cochlear Implant Programming. AB - OBJECTIVE: To assess the clinical effect of cochlear implant programming on tinnitus. METHODS: Tinnitus patients (n = 234) were divided into 3 groups: (1) preoperative tinnitus (n = 108), (2) postoperative tinnitus occurring before implant switch-on at week 4 (n = 88), and (3) tinnitus occurring more than 1 year postoperatively (n = 44). Patients in each group were randomly allocated into a programming subgroup that received programming for 12 weeks postoperatively or after tinnitus occurrence or a control subgroup. Impedance testing and the Tinnitus Handicap Inventory (THI) were performed preoperatively and at 4, 6, 8, and 12 weeks postoperatively (groups 1 and 2) or after tinnitus occurrence (group 3). Comparisons were performed using t tests and chi-square tests. RESULTS: Impedance was significantly lower in the programming subgroup than in the control subgroup in groups 1 and 2 at 8 and 12 weeks and in group 3 at 12 weeks. The THI scores decreased in both programming and control subgroups in all groups. However, this decrease was pronounced in the programming subgroup, whereas in the control subgroup, it occurred slowly over time. CONCLUSION: Cochlear implant programming decreases impedance and improves tinnitus symptoms. PMID- 26481178 TI - Treatment and Survival Trends in Glottic Carcinoma in Situ and Stage I Cancer From 1988 to 2012. AB - OBJECTIVE: To identify trends in treatment and survival for patients with stage I glottic cancer and glottic carcinoma in situ (CIS). METHODS: The 18-registry SEER data were analyzed for CIS and stage I glottic cancer. Treatment variables and observed and relative survival were assessed separately for stage I and glottic CIS. RESULTS: Among 14 025 cases of stage I glottic cancer identified from 1988 to 2012, radiation was the most common treatment for all eras. An increase in surgical treatment occurred with a decline in combination therapy. There were 3169 cases of glottic CIS, with surgery the most common initial treatment but with radiotherapy increasing across the years. Relative survival was similar for treatment type and era of diagnosis. Among the 3738 patients with glottic CIS, 5.4% went on to develop invasive glottic carcinoma of any stage, with invasive cancer more common in patients treated by surgery alone compared to radiation or surgery with radiation. CONCLUSIONS: Despite changes in treatment modalities for CIS and stage I glottic cancer, there have not been significant changes in survival for CIS, with slightly improved survival for treatment with surgery alone. Patients treated with surgery alone had an increased rate of subsequent invasive cancer. PMID- 26481179 TI - Giant right coronary aneurysm untreatable by percutaneous intervention. PMID- 26481180 TI - Rare presentation of ruptured syphilitic aortic aneurysm with pseudoaneurysm. AB - We report the interesting case of a rare form of presentation of rupture of the ascending aorta with formation of a pseudoaneurysm, diagnosed following the development of a large mass on the surface of the chest over a period of about eight months. Serological tests were positive for syphilis. Echocardiography and computed tomography angiography were essential to confirm the diagnosis and therapeutic management. Cardiovascular syphilis is a rare entity since the discovery of penicillin. Rupture of an aortic aneurysm with formation of a pseudoaneurysm is a potentially fatal complication. The postoperative period was uneventful and the patient was discharged from hospital within days of surgery. PMID- 26481181 TI - Comment on "Cost-effectiveness of rivaroxaban for stroke prevention in atrial fibrillation in the Portuguese setting". PMID- 26481182 TI - Portuguese Society of Cardiothoracic and Vascular Surgery/Portuguese Society of Cardiology recommendations for waiting times for cardiac surgery. AB - Appointed jointly by the Portuguese Society of Cardiothoracic and Vascular Surgery (SPCCTV) and the Portuguese Society of Cardiology (SPC), the Working Group on Waiting Times for Cardiac Surgery was established with the aim of developing practical recommendations for clinically acceptable waiting times for the three critical phases of the care of adults with heart disease who require surgery or other cardiological intervention: cardiology appointments; the diagnostic process; and invasive treatment. Cardiac surgery has specific characteristics that are not comparable to other surgical specialties. It is important to reduce maximum waiting times and to increase the efficacy of systems for patient monitoring and tracking. The information in this document is mainly based on available clinical information. The methodology used to establish the criteria was based on studies on the natural history of heart disease, clinical studies comparing medical treatment with intervention, retrospective and prospective analyses of patients on waiting lists, and the opinions of experts and working groups. Following the first step, represented by publication of this document, the SPCCTV and SPC, as the bodies best suited to oversee this process, are committed to working together to define operational strategies that will reconcile the clinical evidence with the actual situation and with available resources. PMID- 26481183 TI - Preserved High Probability of Overall Survival with Significant Reduction of Chemotherapy for Myeloid Leukemia in Down Syndrome: A Nationwide Prospective Study in Japan. AB - BACKGROUND: On the basis of results of previous Japanese trials for myeloid leukemia in Down syndrome (ML-DS), the efficacy of risk-oriented therapy was evaluated in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D05 study. PROCEDURE: All patients received induction chemotherapy that consisted of pirarubicin, intermediate-dose cytarabine, and etoposide. Patients who achieved complete remission (CR) after initial induction therapy were stratified to the standard risk (SR) group and received four courses of reduced-dose intensification therapy. Patients who did not achieve CR were stratified to the high risk (HR) group and received intensified therapy that consisted of continuous or high-dose cytarabine. RESULTS: A total of 72 patients were eligible and evaluated. One patient died of sepsis during initial induction therapy. Sixty nine patients were stratified to SR and two patients to HR. No therapy-related deaths were observed during intensification therapy. The 3-year event-free and overall survival rates were 83.3% +/- 4.4% and 87.5% +/- 3.9%, respectively. Age at diagnosis less than 2 years was a significant favorable prognostic factor for risk of relapse (P = 0.009). CONCLUSIONS: The attempt of risk-oriented prospective study for ML-DS was unsuccessful, but despite the dose reduction of chemotherapeutic agents, the overall outcome was good, and further dose reduction might be possible for specific subgroups. PMID- 26481184 TI - Caerulomycin A inhibits Th2 cell activity: a possible role in the management of asthma. AB - We have recently demonstrated that Caerulomycin A induces regulatory T cells differentiation by suppressing Th1 cells activity. The role of regulatory T cells is well established in suppressing the function of Th2 cells. Th2 cells are known to inflict the induction of the activation of asthma. Consequently, in the present study, we monitored the influence of Caerulomycin A in inhibiting the activity of Th2 cells and its impact in recuperating asthma symptoms. Interestingly, we observed that Caerulomycin A significantly suppressed the differentiation of Th2 cells, as evidenced by downregulation in the GATA-3 expression. Further, decline in the levels of IL-4, IL-5 and IL-13 cytokines and IgE was noted in the animals suffering from asthma. Furthermore, we noticed substantial suppression in the inflammatory response and number of eosinophils in the lungs. In essence, this study signifies an important therapeutic role of Caerulomycin A in asthma. PMID- 26481185 TI - A case of Epstein-Barr encephalitis with some curiosities. AB - We present the magnetic resonance imaging findings of an eight-year-old boy with Epstein-Barr virus (EBV) encephalitis, with special attention to lesion neuroanatomic distribution, diffusion-weighted images, and proton magnetic resonance spectroscopy (MRS). T2 and FLAIR-weighted images showed bilateral and symmetric basal nuclei lesions, with diffusion facilitation. MRS of the lesions demonstrated elevated lactate/lipid and excitatory neurotransmitters. The purpose of this report is to alert to this imagiologic pattern of EBV infection, and in particular to the fact that facilitated diffusion does occur on EBV encephalitis. PMID- 26481186 TI - The gently pull-back technique for neck bypass in treatment of wide-necked internal carotid artery aneurysms: A report of three cases and review of the literature. AB - Neck bypass failure in endovascular treatment of wide-necked internal carotid artery (ICA) aneurysms may adversely affect the technical success of the procedure. We used the gently pull-back technique to bypass the aneurysm neck and access the distal parent artery during endovascular treatment in patients with wide-necked ICA aneurysms. In this technique, a loop was made in the aneurysm and the distal parent artery was reached by using a small diameter microguidewire and a microcatheter. After providing reliable distal access, the microguidewire was removed and the whole system which consists of the microcatheter was gently pulled back. Finally the microcatheter was straightened and the aneurysm neck was passed. After crossing the aneurysm neck, a flow-diverting stent treatment and stent-assisted coiling were performed in three cases with wide-necked ICA aneurysm. The gently pull-back technique is a simple and effective method which requires no extra intravascular device and helps to bypass the aneurysm neck through a small diameter microguidewire and a microcatheter. This technique may be useful for neck aneurysm bypass in endovascular treatment of wide-necked ICA aneurysms. PMID- 26481187 TI - Utility of diffusion tensor imaging parameters for diagnosis of hemimegalencephaly. AB - BACKGROUND: Hemimegalencephaly is a rare hamartomatous entity characterised by enlargement of all or part of the cerebral hemisphere ipsilaterally with cortical dysgenesis, large lateral ventricle and white matter hypertrophy with or without advanced myelination. Although conventional magnetic resonance imaging (MRI) is useful for detecting these diagnostic features, hemimegalencephaly is not always easily distinguished from other entities, especially when hemimegalencephaly shows blurring between the grey and white matter. Diffusion tensor imaging (DTI) is a functional MRI technique commonly used to assess the integrity of white matter. The usefulness of DTI in assessing hemimegalencephaly has not been fully elucidated. In this study, we clarified the characteristics of hemimegalencephaly with regard to DTI and its parameters including fractional anisotropy and apparent diffusion coefficient. METHODS: Three patients with hemimegalencephaly underwent MRI including DTI. We first visually compared fractional anisotropy mapping and conventional MRI. Next, we quantitatively measured the fractional anisotropy and apparent diffusion coefficient values in the subcortical white matter of the hemisphere with hemimegalencephaly and corresponding normal appearing contralateral regions and analysed the values using the Mann-Whitney U test. RESULTS: On fractional anisotropy mapping, we could clearly distinguish the junction of grey and white matter and observed thicker white matter in the hemisphere with hemimegalencephaly, which was unclear on conventional MRI. The white matter in the hemisphere with hemimegalencephaly showed significantly higher fractional anisotropy (P<0.0001) and lower apparent diffusion coefficient (P=0.0022) values than the normal contralateral side. CONCLUSION: DTI parameters showed salient hemimegalencephaly features and could be useful in its assessment. PMID- 26481188 TI - Blocking autophagy enhances meloxicam lethality to hepatocellular carcinoma by promotion of endoplasmic reticulum stress. AB - OBJECTIVES: Meloxicam, a selective cyclooxygenase-2 (COX-2) inhibitor, has been demonstrated to exert anti-tumour effects against various malignancies. However, up to now, mechanisms involved in meloxicam anti-hepatocellular carcinoma effects have remained unclear. MATERIALS AND METHODS: Cell viability and apoptosis were assessed by CCK-8 and flow cytometry. Endoplasmic reticulum (ER) stress and autophagy-associated molecules were analysed by western blotting and immunofluorescence assay. GRP78 and Atg5 knock-down by siRNA or chemical inhibition was used to investigate cytotoxic effects of meloxicam treatment on HCC cells. RESULTS: We found that meloxicam led to apoptosis and autophagy in HepG2 and Bel-7402 cells via a mechanism that involved ER stress. Up-regulation of GRP78 signalling pathway from meloxicam-induced ER stress was critical for activation of autophagy. Furthermore, autophagy activation attenuated ER stress related cell death. Blocking autophagy by 3-methyladenine (3-MA) or Atg5 siRNA knock-down enhanced meloxicam lethality for HCC by activation of ER stress related apoptosis. In addition, GRP78 seemed to lead to autophagic activation via the AMPK-mTOR signalling pathway. Blocking AMPK with a chemical inhibitor inhibited autophagy suggesting that meloxicam-regulated autophagy requires activation of AMPK. CONCLUSIONS: Our results revealed that both ER stress and autophagy were involved in cell death evoked by meloxicam in HCC cells. This inhibition of autophagy to enhance meloxicam lethality, suggests a novel therapeutic strategy against HCC. PMID- 26481189 TI - Light-induced cell damage in live-cell super-resolution microscopy. AB - Super-resolution microscopy can unravel previously hidden details of cellular structures but requires high irradiation intensities to use the limited photon budget efficiently. Such high photon densities are likely to induce cellular damage in live-cell experiments. We applied single-molecule localization microscopy conditions and tested the influence of irradiation intensity, illumination-mode, wavelength, light-dose, temperature and fluorescence labeling on the survival probability of different cell lines 20-24 hours after irradiation. In addition, we measured the microtubule growth speed after irradiation. The photo-sensitivity is dramatically increased at lower irradiation wavelength. We observed fixation, plasma membrane permeabilization and cytoskeleton destruction upon irradiation with shorter wavelengths. While cells stand light intensities of ~1 kW cm(-2) at 640 nm for several minutes, the maximum dose at 405 nm is only ~50 J cm(-2), emphasizing red fluorophores for live-cell localization microscopy. We also present strategies to minimize phototoxic factors and maximize the cells ability to cope with higher irradiation intensities. PMID- 26481191 TI - Glomerular disease: Protective role of TGR5 activation. PMID- 26481190 TI - Hospital Readmission Rates in U.S. States: Are Readmissions Higher Where More Patients with Multiple Chronic Conditions Cluster? AB - RESEARCH OBJECTIVE: This study examines small area variations in readmission rates to assess whether higher readmission rate in an area is associated with higher clusters of patients with multiple chronic conditions. STUDY DESIGN: The study uses hospital discharge data of adult (18+) patients in 6 U.S. states for 2009 from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, linked to contextual and provider data from Health Resources and Services Administration. A multivariate cross sectional design at primary care service area (PCSA) level is used. PRINCIPAL FINDINGS: Adjusting for area characteristics, the readmission rates were significantly higher in PCSAs having higher proportions of patients with 2-3 chronic conditions and those with 4+ chronic conditions, compared with areas with a higher concentration of patients with 0-1 chronic conditions. CONCLUSIONS: Using small area analysis, the study shows that areas with higher concentration of patients with increased comorbid conditions are more likely to have higher readmission rates. PMID- 26481192 TI - Developmental biology: Nephrogenesis in kidney organoids derived from human pluripotent stem cells. PMID- 26481194 TI - Enantioselective Total Syntheses of (-)-Rhazinilam, (-)-Leucomidine B, and (+) Leuconodine F. AB - A divergent total synthesis of three structurally distinct natural products from imine 9 was accomplished through an approach featuring: 1) a Pd-catalyzed decarboxylative cross-coupling, and 2) heteroannulation of 9 with bromoacetaldehyde and oxalyl chloride to give tetrahydroindolizine 6 and dioxopyrrole 7, respectively. The former was converted into (-)-rhazinilam, while the latter was converted into (-)-leucomidine B and (+)-leuconodine F. A substrate-directed highly diastereoselective reduction of a sterically unbiased double bond by using a homogeneous palladium catalyst was developed. A self induced diastereomeric anisochronism (SIDA) phenomenon was observed for leucomidine B. PMID- 26481193 TI - European S3-Guidelines on the systemic treatment of psoriasis vulgaris--Update 2015--Short version--EDF in cooperation with EADV and IPC. PMID- 26481195 TI - Interaction of Cx43 with Hsc70 regulates G1/S transition through CDK inhibitor p27. AB - Connexin 43 (Cx43) functions as a cell growth suppressor. We have demonstrated that Cx43 interacts with heat shock cognate protein 70 (Hsc70) for regulating cell proliferation. Hsc70 interacts with CDK inhibitor p27, which regulates the assembly and subcellular localization of cyclin D1-CDK4-p27 complex. However, the involvement of p27 with Cx43-mediated cell cycle suppression is still poorly understood. Here, we report that nuclear accumulation of p27 is reduced by overexpression of Cx43, and that this reduction is restored by co-overexpression with Hsc70. We found that Cx43 competes with p27 for binding to Hsc70, and as a result, decreases the level of Hsc70 in cyclin D1-CDK4-p27 complex, leading to prevention of the nuclear translocation of the complex and the G1/S transition. Collectively, our findings suggest that, in Cx43 up-regulation, which is most likely an emergency measure, Cx43-Hsc70 interaction regulates cell cycle G1/S progression through a novel mechanism by which Cx43-Hsc70 interaction prevents the nuclear accumulation of p27 through controlling the nuclear translocation of cyclin D1-CDK4-p27 complex. PMID- 26481196 TI - Student conceptions about the DNA structure within a hierarchical organizational level: Improvement by experiment- and computer-based outreach learning. AB - As non-scientific conceptions interfere with learning processes, teachers need both, to know about them and to address them in their classrooms. For our study, based on 182 eleventh graders, we analyzed the level of conceptual understanding by implementing the "draw and write" technique during a computer-supported gene technology module. To give participants the hierarchical organizational level which they have to draw, was a specific feature of our study. We introduced two objective category systems for analyzing drawings and inscriptions. Our results indicated a long- as well as a short-term increase in the level of conceptual understanding and in the number of drawn elements and their grades concerning the DNA structure. Consequently, we regard the "draw and write" technique as a tool for a teacher to get to know students' alternative conceptions. Furthermore, our study points the modification potential of hands-on and computer-supported learning modules. PMID- 26481198 TI - Role of vitamin D supplementation in improving disease activity in rheumatoid arthritis: An exploratory study. AB - AIM: The aim of this exploratory study is to estimate the relationship between vitamin D (vit D) deficiency and active rheumatoid arthritis (RA), and the role of supplementation in improving disease activity. METHOD: A randomized recruitment, consent screening, open-label interventional study was conducted in patients who fulfilled American College of Rheumatology/European League Against Rheumatism 2010 criteria for diagnosing RA and on stable disease-modifying anti rheumatic drugs (DMARDs) for 3 months. Serum vit D levels and Disease Activity Score of 28 joints/C-reactive protein (DAS28-CRP) disease activity status were estimated at the first visit. Subjects with low vit D levels and DAS28-CRP > 2.6 were supplemented with vit D for 12 weeks, and were assessed for improvement in disease activity and serum vit D levels. RESULTS: One hundred and fifty RA patients of mean age 49 +/- 12.1 years, mean duration of illness 78 +/- 63 months, and on treatment with DMARDs for 44 +/- 39 months were recruited for the study. Of these, 73 (49%) subjects were found to have DAS28-CRP > 2.6 and serum vit D below 20 ng/mL. The patients received vit D supplement of 60 000 IU/week for 6 weeks, followed by 60 000 IU/month for a total duration of 3 months. Disease activity and vit D status were assessed for 59 (80.8%) patients who reported at the end of 12 weeks of treatment. Mean DAS28-CRP of these patients showed a statistically significant improvement from 3.68 +/- 0.93 at baseline to 3.08 +/- 1.11 after supplementation (P = 0.002). Serum vit D levels improved from 10.05 +/- 5.18 to 57.21 +/- 24.77 ng/mL (P < 0.001) during the period. CONCLUSION: Supplementation of vit D in RA patients with persisting disease activity and vit D deficiency contributed to significant improvement in disease activity within a short duration. PMID- 26481197 TI - The fructanolytic abilities of the rumen bacterium Butyrivibrio fibrisolvens strain 3071. AB - AIMS: To determine if Butyrivibrio fibrisolvens strain 3071 is able to use fructose polymers for growth and to identify the enzymes involved in their digestion. METHODS AND RESULTS: Strain 3071 utilized 97, 89, 85 and 60% of sucrose, timothy grass fructan, inulin oligosaccharides and inulin, respectively, in the growth medium. A cell extract from timothy grass fructan-grown bacteria was used for identification of fructanolytic enzymes by anion exchange chromatography, gel filtration, zymography and thin-layer chromatography. The bacterium synthesizes a specific endolevanase and a nonspecific beta fructofuranosidase. Both enzymes occurred in two forms differing in molecular weight. The beta-fructofuranosidase was not able to digest long-chain inulin or timothy grass fructan, but degraded inulin oligosaccharides and sucrose. Addition of 1,4-dithioerythritol to an enzyme solution did not affect the activity of endolevanase(s), but increased the ability of beta-fructofuranosidase to digest sucrose. The digestion of timothy grass fructan by endolevanase(s) was described by Michaelis-Menten kinetics in which Km = 2.82 g l(-1) and Vmax = 4.01 MUmoles reducing sugar equivalents * mg(-1) * min(-1) . CONCLUSION: Strain 3071 synthesizes enzymes enabling it to use grass fructans for growth. SIGNIFICANCE AND IMPACT OF THE STUDY: Butyrivibrio fibrisolvens strain 3071 can be considered a member of the rumen fructanolytic guild. PMID- 26481199 TI - Atomic force microscopy reveals a dual collagen-binding activity for the staphylococcal surface protein SdrF. AB - Staphylococcus epidermidis causes nosocomial infections by colonizing and forming biofilms on indwelling medical devices. This process involves specific interactions between cell wall-anchored (CWA) proteins and host proteins adsorbed onto the biomaterial. Here, we have explored the molecular forces by which the S. epidermidis CWA protein serine-aspartate repeat protein F (SdrF) binds to type I collagen, by means of advanced atomic force microscopy (AFM) techniques. Using single-cell force spectroscopy, we found that SdrF mediates bacterial adhesion to collagen-coated substrates through both weak and strong bonds. Single-molecule force spectroscopy demonstrated that these bonds involve the A and B regions of SdrF, thus revealing that the protein is capable of dual ligand-binding activity. Both weak and strong bonds showed high dissociation rates, indicating they are much less stable than those formed by the well-characterized 'dock, lock and latch' mechanism. Collectively, our results show that CWA proteins can bind to ligands by novel mechanisms. We anticipate that AFM will greatly contribute to the identification of novel binding partners and binding mechanisms in staphylococcal CWA proteins. PMID- 26481200 TI - Burden of Proof in Bioethics. AB - A common strategy in bioethics is to posit a prima facie case in favour of one policy, and to then claim that the burden of proof (that this policy should be rejected) falls on those with opposing views. If the burden of proof is not met, it is claimed, then the policy in question should be accepted. This article illustrates, and critically evaluates, examples of this strategy in debates about the sale of organs by living donors, human enhancement, and the precautionary principle. We highlight general problems with this style of argument, and particular problems with its use in specific cases. We conclude that the burden ultimately falls on decision-makers (i.e. policy-makers) to choose the policy supported by the best reasons. PMID- 26481201 TI - The Ethics of Introducing GMOs into sub-Saharan Africa: Considerations from the sub-Saharan African Theory of Ubuntu. AB - A growing number of countries in sub-Saharan Africa are considering legalizing the growth of genetically modified organisms (GMOs). Furthermore, several projects are underway to develop transgenic crops tailored to the region. Given the contentious nature of GMOs and prevalent anti-GMO sentiments in Africa, a robust ethical analysis examining the concerns arising from the development, adoption, and regulation of GMOs in sub-Saharan Africa is warranted. To date, ethical analyses of GMOs in the global context have drawn predominantly on Western philosophy, dealing with Africa primarily on a material level. Yet, a growing number of scholars are articulating and engaging with ethical theories that draw upon sub-Saharan African value systems. One such theory, Ubuntu, is a well-studied sub-Saharan African communitarian morality. I propose that a robust ethical analysis of Africa's agricultural future necessitates engaging with African moral theory. I articulate how Ubuntu may lead to a novel and constructive understanding of the ethical considerations for introducing GMOs into sub-Saharan Africa. However, rather than reaching a definitive prescription, which would require significant engagement with local communities, I consider some of Ubuntu's broader implications for conceptualizing risk and engaging with local communities when evaluating GMOs. I conclude by reflecting on the implications of using local moral theory in bioethics by considering how one might negotiate between universalism and particularism in the global context. Rather than advocating for a form of ethical relativism, I suggest that local moral theories shed light on salient ethical considerations that are otherwise overlooked. PMID- 26481202 TI - Reexamining Healthcare Justice in the Light of Empirical Data. AB - This article discusses the notion of justice from a capabilities approach. We undertake an empirical analysis of the concepts of justice held by healthcare personnel, gleaned from a qualitative analysis of interviews on the subject of ethical dilemmas in everyday practice. The article states that Justice undoubtedly presents a work in progress, which implicates the link between justice as capability and human dignity. We empirically found a contrast between the views of justice based on the patient's own perceptions and those based on the perceptions of healthcare personnel. We establish the kind of actions, communication skills and justice required to build a stronger relationship between patients and healthcare professionals, which would improve prognosis, treatment efficiency and therapeutic adhesion. PMID- 26481203 TI - Ideas of Perfection and the Ethics of Human Enhancement. AB - Whatever ethical stance one takes in the debate regarding the ethics of human enhancement, one or more reference points are required to assess its morality. Some have suggested looking at the bioethical notions of safety, justice, and/or autonomy to find such reference points. Others, arguing that those notions are limited with respect to assessing the morality of human enhancement, have turned to human nature, human authenticity, or human dignity as reference points, thereby introducing some perfectionist assumptions into the debate. In this article, we ask which perfectionist assumptions should be used in this debate. After a critique of views that are problematic, we take a positive approach, suggesting some perfectionist elements that can lend guidance to the practice of human enhancement, based on the work of Martha Nussbaum's Capability Approach. We suggest that the central capabilities can be used to define the human aspect of human enhancement and thereby allow a moral evaluation of enhancement interventions. These central capabilities can be maximized harmoniously to postulate what an ideal human would look like. Ultimately, the aim of this article is twofold. First, it seeks to make explicit the perfectionist assumptions found in the debate and eliminate those that are problematic. Second, the paper clarifies an element that is often neglected in the debate about human enhancement, the view of the ideal human towards which human enhancement should strive. Here, we suggest that some central capabilities that are essential for an ideal human being can be maximized harmoniously and can therefore serve as possible reference points to guide human enhancement. PMID- 26481204 TI - Mitochondrial Replacement: Ethics and Identity. AB - Mitochondrial replacement techniques (MRTs) have the potential to allow prospective parents who are at risk of passing on debilitating or even life threatening mitochondrial disorders to have healthy children to whom they are genetically related. Ethical concerns have however been raised about these techniques. This article focuses on one aspect of the ethical debate, the question of whether there is any moral difference between the two types of MRT proposed: Pronuclear Transfer (PNT) and Maternal Spindle Transfer (MST). It examines how questions of identity impact on the ethical evaluation of each technique and argues that there is an important difference between the two. PNT, it is argued, is a form of therapy based on embryo modification while MST is, instead, an instance of selective reproduction. The article's main ethical conclusion is that, in some circumstances, there is a stronger obligation to use PNT than MST. PMID- 26481205 TI - The Ethics of Fertility Preservation for Paediatric Cancer Patients: From Offer to Rebuttable Presumption. AB - Given advances in the science of fertility preservation and the link between fertility choices and wellbeing, it is time to reframe our ethical thinking around fertility preservation procedures for children and young people with cancer. The current framing of fertility preservation as a possible offer may no longer be universally appropriate. There is an increasingly pressing need to discuss the ethics of failing to preserve fertility, particularly for patient groups for whom established techniques exist. I argue that the starting point for deliberating about a particular patient should be a rebuttable presumption that fertility preservation ought to be attempted. Consideration of the harms applicable to that specific patient may then override this presumption. I outline the benefits of attempting fertility preservation; these justify a presumption in favour of the treatment. I then discuss the potential harms associated with fertility preservation procedures, which may justify failing to attempt fertility preservation in an individual patient's particular case. Moving from a framework of offer to one of rebuttable presumption in favour of fertility preservation would have significant implications for medical practice, healthcare organizations and the state. PMID- 26481206 TI - Food Culture, Preferences and Ethics in Dysphagia Management. AB - Adults with dysphagia experience difficulties swallowing food and fluids with potentially harmful health and psychosocial consequences. Speech pathologists who manage patients with dysphagia are frequently required to address ethical issues when patients' food culture and/ or preferences are inconsistent with recommended diets. These issues incorporate complex links between food, identity and social participation. A composite case has been developed to reflect ethical issues identified by practising speech pathologists for the purposes of illustrating ethical concerns in dysphagia management. The case examines a speech pathologist's role in supporting patient autonomy when patients and carers express different goals and values. The case presents a 68-year-old man of Australian/Italian heritage with severe swallowing impairment and strong values attached to food preferences. The case is examined through application of the dysphagia algorithm, a tool for shared decision-making when patients refuse dietary modifications. Case analysis revealed the benefits and challenges of shared decision-making processes in dysphagia management. Four health professional skills and attributes were identified as synonymous with shared decision making: communication, imagination, courage and reflection. PMID- 26481207 TI - Real-time Responsiveness for Ethics Oversight During Disaster Research. AB - Disaster research has grown in scope and frequency. Research in the wake of disasters and during humanitarian crises--particularly in resource-poor settings- is likely to raise profound and unique ethical challenges for local communities, crisis responders, researchers, and research ethics committees (RECs). Given the ethical challenges, many have questioned how best to provide research ethics review and oversight. We contribute to the conversation concerning how best to ensure appropriate ethical oversight in disaster research and argue that ethical disaster research requires of researchers and RECs a particular sort of ongoing, critical engagement which may not be warranted in less exceptional research. We present two cases that typify the concerns disaster researchers and RECs may confront, and elaborate upon what this ongoing engagement might look like--how it might be conceptualized and utilized--using the concept of real-time responsiveness (RTR). The central aim of RTR, understood here as both an ethical ideal and practice, is to lessen the potential for research conducted in the wake of disasters to create, perpetuate, or exacerbate vulnerabilities and contribute to injustices suffered by disaster-affected populations. Well cultivated and deployed, we believe that RTR may enhance the moral capacities of researchers and REC members, and RECs as institutions where moral agency is nurtured and sustained. PMID- 26481211 TI - In this Issue: A Snapshot of World Bioethics and an Invitation. PMID- 26481208 TI - Morally Relevant Similarities and Differences Between Children and Dementia Patients as Research Subjects: Representation in Legal Documents and Ethical Guidelines. AB - Children and adults with dementia are vulnerable populations. Both groups are also relatively seldom included in biomedical research. However, including them in clinical trials is necessary, since both groups are in need of scientific innovation and new therapies. Their dependence and limited decision-making capacities increase their vulnerability, necessitating extra precautions when including them in clinical trials. Beside these similarities there are also many differences between the groups. The most obvious one is that children have an entire life ahead of them and will become persons with certain ideals and preferences, while adults with dementia have lived a life in which they have expressed their ideals and preferences. Some of the available research guidelines recognize these differences, setting one list of specific requirements for groups of incapacitated adults and another list for children. Other documents, however, do not differentiate and only set requirements for subjects unable to consent as a single category of subjects. In this article we analyse to what extent the similarities and differences between the two groups are represented in legal documents and ethical guidelines. The article presents an overview and an analysis of the requirements for doing research with children and dementia patients. We conclude with suggestions about how to better incorporate the morally relevant aspects of these two groups in legislation and ethical guidelines. PMID- 26481212 TI - Chirality- and pH-Controlled Supramolecular Isomerism in Cobalt Phosphonates and Its Impact on the Magnetic Behavior. AB - Two pairs of enantiomeric compounds with formulas (S)- or (R)-Co3 (ppap)2 (4,4' bpy)2 (H2 O)2 ?4 H2 O [(S)-1 or (R)-1], (S)- or (R)-Co3 (ppap)2 (4,4'-bpy)2 (H2 O)2 ?3 H2 O [(S)- or (R)-2), and related racemic compound Co3 (ppap)2 (4,4'-bpy)2 (H2 O)2 ?4 H2 O (rac-3; 4,4'-bpy=4,4'-bipyridine, H3 ppap=3-phenyl-2 [(phosphonomethyl)amino]propanoic acid) are reported. Compounds 1 and rac-3 show identical three-dimensional framework structures, whereas compounds 2 have two dimensional layer structures. Compounds 1 and 2 are catenation isomers, formation of which is controlled solely by the pH of the reaction mixtures, whereas the formation of isomeric compounds 1 and rac-3 is controlled purely by the chirality of the phosphonate ligand. The magnetic properties of fully dehydrated (S)-1, (S) 2, and rac-3 are highly dependent on both structure and chirality. PMID- 26481213 TI - Augmentation index is associated with coronary revascularization in patients with high Framingham risk scores: a hospital-based observational study. AB - BACKGROUND: This study analyzed PWAs in patients with high Framingham risk scores to determine whether PWA is predictive of coronary artery disease (CAD) severity and percutaneous coronary intervention (PCI) treatment. METHODS: In total, 310 patients were screened due to suspected CAD; 78 were excluded due to PCI history (32), atrial fibrillation (11), or acute myocardial infarction (35). The augmentation index (AIx) was analyzed immediately before coronary angiography. PCI was performed in 73 (31.5 %) patients. RESULTS: The mean AIx, adjusted by heart rate (AIx@75) was different for each clinical diagnosis in the PCI group (stable angina, 30.6 +/- 7.7 %; silent ischemia, 30.2 +/- 8.6 %; unstable angina, 38.5 +/- 8.5 %; p = 0.026). The 10-year estimate of CVD risk, based on the Framingham heart score, was 25.3 +/- 6.5 % and the mean AIx@75 was 31.6 +/- 8.5 % in the PCI group, significantly higher than in the non-PCI group (18.8 +/- 10.2 %, p < 0.001; 27.2 +/- 9.0 %, p = 0.006, respectively). An inverse correlation was observed between the minimal luminal area and AIx@75 (rho = -0.559, p = 0.010, n = 20). In ROC curve analysis of multivariate logistic regression model, higher HDL, medication of hypertension, and higher body mass index were associated with non-PCI and higher AIx@75 was associated with PCI (area under the curve, 0.764; 95 % CI: 0.701 to 0.819, z = 8.005; p <0.001). CONCLUSIONS: The AIx@75 seemed to reflect the clinical severity of CAD and was associated with PCI in patients with a high Framingham risk score. PMID- 26481214 TI - High adherence to malaria treatment: promising results of an adherence study in South Kivu, Democratic Republic of the Congo. AB - BACKGROUND: In resource-poor settings, treatment adherence is a major determinant of response to anti-malarial drugs as most are taken at home without medical supervision. Evidence on adherence to artemisinin-based combination therapy (ACT) is limited. The study aimed to measure adherence and identify reasons for non adherence to a 3-day, fixed-dose combination (FDC) of artesunate-amodiaquine (ASAQ), the first-line treatment for uncomplicated malaria in the Medecins Sans Frontieres project in the Shabunda Health Zone, South Kivu, Democratic Republic of Congo, a highly malarious and conflict-affected area. METHODS: The study took place in the health centres/outpatient departments of the Shabunda general hospital, the quarter Mbangayo, and participant households. Patients prescribed FDC ASAQ were visited at home on the day after their regimen finished and asked to complete an adherence questionnaire. Patients/caretakers were also interviewed when exiting the outpatient department to understand their attitude towards FDC ASAQ and assess the quality of the prescribing process. RESULTS: 148 patients/caretakers completed the adherence questionnaire: 11.5 % (17/148, 95 % CI 7-17) had >=1 tablet left at the time of the home visit and were defined as certainly non-adherent; 13.5 % (20/148, 95 % CI 8-19) were probably non-adherent; thus total non-adherence was 25.0 % (37/148, 95 % CI 18-32). 75 % (111/148, 95 % CI 68-82) were defined as probably adherent. In exit interviews, 87.5 % (105/120) knew they had malaria or could name the correct signs/symptoms. 89 % (107/120) could identify FDC ASAQ as anti-malarials among all tablets given and correctly repeat the intake instructions given at the outpatient department. CONCLUSIONS: This is the first study to assess adherence to an FDC of ACT under real treatment conditions in a context of high instability. High quality prescribing of anti malarials at health centre level and patient adherence to the correct intake of ACT were possible in this setting. Adherence to treatment regimen requires careful and constant monitoring which might be better guaranteed at health centre rather than community level. It could, nevertheless, be a precondition to the successful introduction of home- or community based management of malaria. PMID- 26481216 TI - Novel In Vitro Antioxidant and Photoprotection Capacity of Plants from High Altitude Ecosystems of Colombia. AB - Currently, plants have gained widespread interest as a source of natural sunscreen. Specifically, plants from high altitude ecosystems are exposed to high UVR levels; therefore, they must produce an adaptive chemical response. The aim of this study was to evaluate the photo-protection and antioxidant capacity in vitro of nine plants from high altitude ecosystems in Antioquia, Colombia (Sphagnum meridense, Calamagrostis effusa, Lycopodiella alopecuroides, Morella parvifolia, Baccharis antioquensis, Pentacalia pulchella, Castilleja fissifolia, Hesperomeles ferruginea and Hypericum juniperinum). B. antioquensis and P. pulchella extracts showed the best results over a broad spectrum UVA-UVB with antioxidant capacity in vitro. However, B. antioquensis extracts presented the highest absorption coefficient in UVB-UVA range among plants under study. Furthermore, the gel formulation containing the crude extract of B. antioquensis showed significant values of UVAPF, UVA/UVB ratio, critical wavelength (lambdac ) and SPF (3, 0.78 380 nm and 4.73 +/- 0.26; respectively), indicating interesting photostability and antiradical capacities. All of these properties could be improve in order to satisfy the requirements for broad-spectrum UVB/UVA protection. Finally, P. pulchella and B. antioquensis extracts could be a potential source of a new natural sunscreen compounds with photostable and antiradical properties. PMID- 26481215 TI - Feasibility study of docetaxel plus bevacizumab as first line therapy for elderly patients with advanced non-small-cell lung cancer: Thoracic Oncology Research Group (TORG) 1014. AB - BACKGROUND: Docetaxel monotherapy is one of the standard treatments for non-small cell lung cancer in elderly patients. The addition of bevacizumab to docetaxel seems promising; however, the feasibility of this combination has not been investigated in such patients. METHODS: Patients with advanced non-squamous non small-cell lung cancer aged 70 years or older who had not previously received cytotoxic chemotherapy were enrolled. Patients in the Level 0 cohort received docetaxel 60 mg/m(2) and bevacizumab 15 mg/kg, whereas those in the Level-1 cohort received docetaxel 50 mg/m(2) and bevacizumab 15 mg/kg. Chemotherapy was repeated 3 weekly for six cycles. The primary endpoint was toxicity and the secondary endpoints were response rate, progression-free survival, overall survival, and proportion of patients who underwent three or more cycles of chemotherapy. RESULTS: Twenty-one patients were enrolled from December 2010 to September 2012 at six institutes. Of the nine patients enrolled in Level 0, two experienced dose-limiting toxicity (febrile neutropenia and prolonged Grade 4 neutropenia in one patient, and Grade 3 infection in another patient) during the first cycle. Enrollment to the Level 0 cohort was terminated because two patients developed Grade 4 sepsis during later cycles. The remaining 12 patients were enrolled in the Level-1 cohort, in which two dose-limiting toxicities (prolonged Grade 4 neutropenia and Grade 3 increased aminotransferase level) were observed. No patient in the Level-1 cohort experienced Grade 4 nonhematologic toxicity. Grade 4 neutropenia occurred in 89 % of Level 0 patients and 50 % of Level-1 patients. The proportion of patients who experienced Grade 3/4 infection, febrile neutropenia or sepsis was 44 % in the Level 0 cohort, and 8 % in the Level-1 cohort. The overall response rate to chemotherapy and progression-free survival were 29 % (95 % CI, 11-52 %) and 5.9 months (95 % CI, 3.6-9.1 months), respectively. Efficacy outcomes did not differ significantly between the cohorts. CONCLUSIONS: Toxicities were tolerable in level-1 cohort. The recommended dose of combination chemotherapy with docetaxel and bevacizumab for elderly patients was determined as 50 mg/m(2) of docetaxel and 15 mg/kg of bevacizumab and toxicities were tolerable. Further studies are warranted. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004240 . PMID- 26481217 TI - Synthesis and mechanical evaluation of Sr-doped calcium-zirconium-silicate (baghdadite) and its impact on osteoblast cell proliferation and ALP activity. AB - For the first time the successful preparation of Sr doped baghdadite (Ca3-x Sr x ZrSi2O9 x = 0.1 and 0.75) is shown. Sr-doped as well as pure baghdadite are prepared via a versatile solid-state synthesis and conventional sintering at 1400 degrees C. XRD measurements and crystal structure refinements reveal that a substitution of Ca atoms with Sr and a high purity (>99%) is achieved. The physical, mechanical, and biological properties of these novel bioceramics are presented in relation to the dopant concentration. Incorporating Sr into the baghdadite crystal caused only minor changes to the grain size and the mechanical properties. The characteristic strength ranges from 145 to 168 MPa and a Weibull modulus of 4.9 to 9.2 is observed. Other mechanical properties like fracture toughness and hardness vary from 1.23 +/- 0.07 MPam(0.5) to 1.31 +/- 0.12 MPam(0.5) and 7.3 +/- 0.6 GPa to 8.0 +/- 0.7 GPa, respectively. The in vitro cellular response of human osteoblasts showed an increase in the cell proliferation and a significantly higher alkaline phosphatase (ALP) activity with an increase in the Sr content. From the improved biological properties and the suitable mechanical performance we conclude that this material is a highly promising candidate for bone replacement material and bioactive implant coatings. PMID- 26481218 TI - Improved and sustained triage skills in firemen after a short training intervention. AB - BACKGROUND: A previous study has shown no measurable improvement in triage accuracy among physicians attending the Advanced Trauma Life Support (ATLS) course and suggests a curriculum revision regarding triage. Other studies have indicated that cooperative learning helps students acquire knowledge. OBJECTIVE: The present study was designed to evaluate the effectiveness of trauma cards in triage training for firemen. METHODS: Eighty-six firemen were randomly assigned into two groups: the trauma card group and the direct instruction group. Both groups received the same 30-min PowerPoint lecture on how to perform triage according to the Sort Assess Lifesaving interventions Treatment and transport (SALT) Mass Casualty Triage Algorithm. In the trauma card group, the participants were divided into groups of 3-5 and instructed to triage 10 trauma victims according to the descriptions on the trauma cards. In the direct instruction group, written forms about the same 10 victims were used and discussed as a continuation of the PowerPoint lecture. Total training time was 60 min for both groups. A test was distributed before and after the educational intervention to measure the individual triage skills. The same test was applied again 6 months later. RESULTS: There was a significant improvement in triage skills directly after the intervention and this was sustained 6 months later. No significant difference in triage skills was seen between the trauma card group and the direct instruction group. Previous experience of multi-casualty incidents, years in service, level of education or age did not have any measurable effects on triage accuracy. CONCLUSIONS: One hour of triage training with the SALT Mass Casualty Triage Algorithm was enough to significantly improve triage accuracy in both groups of firemen with sustained skills 6 months later. Further studies on the first assessment on scene versus patient outcome are necessary to provide evidence that this training can improve casualty outcome. The efficacy and validity of trauma cards for disaster management training need to be tested in future studies. PMID- 26481220 TI - Spectators Control Selectivity in Surface Chemistry: Acrolein Partial Hydrogenation Over Pd. AB - We present a mechanistic study on selective hydrogenation of acrolein over model Pd surfaces--both single crystal Pd(111) and Pd nanoparticles supported on a model oxide support. We show for the first time that selective hydrogenation of the C?O bond in acrolein to form an unsaturated alcohol is possible over Pd(111) with nearly 100% selectivity. However, this process requires a very distinct modification of the Pd(111) surface with an overlayer of oxopropyl spectator species that are formed from acrolein during the initial stages of reaction and turn the metal surface selective toward propenol formation. By applying pulsed multimolecular beam experiments and in situ infrared reflection-absorption spectroscopy, we identified the chemical nature of the spectator and the reactive surface intermediate (propenoxy species) and experimentally followed the simultaneous evolution of the reactive intermediate on the surface and formation of the product in the gas phase. PMID- 26481219 TI - Characterizing Benzo[a]pyrene-induced lacZ mutation spectrum in transgenic mice using next-generation sequencing. AB - BACKGROUND: The transgenic rodent mutation reporter assay provides an efficient approach to identify mutagenic agents in vivo. A major advantage of this assay is that mutant reporter transgenes can be sequenced to provide information on the mode of action of a mutagen and to identify clonally expanded mutations. However, conventional DNA sequence analysis is laborious and expensive for long transgenes, such as lacZ (3096 bp), and is not normally implemented in routine screening. METHODS: We developed a high-throughput next-generation sequencing (NGS) approach to simultaneously sequence large numbers of barcoded mutant lacZ transgenes from different animals. We collected 3872 mutants derived from the bone marrow DNA of six MutaTMMouse males exposed to the well-established mutagen benzo[a]pyrene (BaP) and six solvent-exposed controls. Mutants within animal samples were pooled, barcoded, and then sequenced using NGS. RESULTS: We identified 1652 mutant sequences from 1006 independent mutations that underwent clonal expansion. This deep sequencing analysis of mutation spectrum demonstrated that BaP causes primarily guanine transversions (e.g. G:C -> T:A), which is highly consistent with previous studies employing Sanger sequencing. Furthermore, we identified novel mutational hotspots in the lacZ transgene that were previously uncharacterized by Sanger sequencing. Deep sequencing also allowed for an unprecedented ability to correct for clonal expansion events, improving the sensitivity of the mutation reporter assay by 50 %. CONCLUSION: These results demonstrate that the high-throughput nature and reduced costs offered by NGS provide a sensitive and fast approach for elucidating and comparing mutagenic mechanisms of various agents among tissues and enabling improved evaluation of genotoxins. PMID- 26481221 TI - Comparison of Immune Profiles in Fetal Hearts with Idiopathic Dilated Cardiomyopathy, Maternal Autoimmune-Associated Dilated Cardiomyopathy and the Normal Fetus. AB - The etiology of idiopathic dilated cardiomyopathy (iDCM) remains unknown. Immune therapies have improved outcome in fetuses with DCM born to mothers with autoimmune disease (aDCM). The purpose of this retrospective study was to compare the myocardial B and T cell profiles in fetuses and neonates with idiopathic DCM (iDCM) versus autoimmune-mediated DCM (aDCM) and to describe the normal cell maturation within the human fetal myocardium. Of 60 fetal autopsy cases identified from institutional databases, 10 had aDCM (18-38 weeks), 12 iDCM (19 37 weeks) and 38 had normal hearts (11-40 weeks). Paraffin-embedded myocardium sections were stained for all lymphocyte (CD45), B cells (CD20, CD79a), T cells (CD3, CD4, CD7, CD8) and monocyte (CD68) surface markers. Two independent, blinded cell counts were performed. Normal hearts expressed all B and T cell markers in a bimodal fashion, with peaks at 22 and 37 weeks of gestation. The aDCM cohort was most distinct from normal hearts, with less overall T cell markers [EST -9.1 (2.6) cells/mm(2), p = 0.001], CD4 [EST -2.0 (0.6), p = 0.001], CD3 [EST -3.9 (1.0), p < 0.001], CD7 [EST -3.0 (1.1), p = 0.01] overall B cell markers [EST -4.9 (1.8), p = 0.01] and CD79a counts [EST -2.3 (0.9), p = 0.01]. The iDCM group had less overall B cell markers [EST -4.0 (1.8), p = 0.03] and CD79a [EST -1.7 (0.9), p = 0.05], but no difference in T cell markers. Autoimmune mediated DCM fetuses have less B and T cell markers, whereas iDCM fetuses have less B cell markers compared with normal fetal hearts. The fetal immune system may play a role in the normal development of the heart and evolution of dilated cardiomyopathy. PMID- 26481222 TI - White-Coat and Reverse White-Coat Effects Correlate with 24-h Pulse Pressure and Systolic Blood Pressure Variability in Children and Young Adults. AB - Masked hypertension (MH) and white-coat hypertension (WCH) are associated with organ damage. In the present study, we examined the correlation between the magnitude of white-coat effect (WCE) or reverse WCE (RWCE) and 24-h pulse pressure (PP), an indicator of target organ damage and arterial stiffness, in children and young adults. We also examined the relationship of WCE or RWCE and blood pressure (BP) variability, another predictor of clinical outcomes. One hundred and ninety-eight subjects were studied. According to the office BP and ambulatory BP, they were divided into normotension, WCH, MH, and hypertension. The magnitude of WCE or RWCE, along with male gender and 24-h systolic BP, was the determinant of 24-h PP. In subjects with 24-h PP >= 61 mmHg, the magnitude of WCE or RWCE, age, male ratio, height, weight, BMI, the percentage of secondary hypertension, that of MH, office systolic BP, and 24-h systolic BP were significantly greater. There was a progressive increase in 24-h PP from normotension, WCH, MH, to hypertension. BP variability in subjects with MH was numerically highest in both systolic and diastolic. Diastolic BP variability of WCH, MH, and hypertension was significantly higher than that of normotension. Finally, the magnitude of WCE or RWCE in systolic showed a significant correlation with systolic BP variability. In conclusion, the magnitude of WCE or RWCE correlates with 24-h PP and systolic BP variability, which may suggest increased arterial stiffness in WCH and MH. PMID- 26481223 TI - Cardioplegia Dose Effect on Immediate Postoperative Alterations in Coronary Artery Flow Velocities After Congenital Cardiac Surgery. AB - Abnormalities in coronary artery (CA) flow detected by echocardiography are increasingly used to guide clinical decisions in patient management. Increased CA flow has been seen postoperatively in congenital cardiac surgery. This study sought to determine immediate postoperative changes in left anterior descending (LAD) CA flow velocities, and to investigate possible factors associated with these changes. CA flow in the proximal LAD was sampled with pulsed-wave Doppler during trans-esophageal echocardiography imaging in the immediate preoperative and postoperative studies in 46 subjects. The peak velocity, velocity time integral (VTI), VTI corrected for heart rate (VTIc), and VTI rate pressure product (VTIrpp) were determined. The percent change in each measure between the preoperative and postoperative study was calculated and compared to age, body surface area (BSA), cardiopulmonary bypass time, cross-clamp time, and number of cardioplegia (CP) doses. The pH, oxygen saturation, temperature, and hemoglobin concentration (Hb) were compared for those with and without increased flow characteristics. There was an overall increase in LAD flow parameters in subjects who underwent congenital cardiac surgery. There was a significant and positive correlation of percent change in VTI, VTIc, and VTIrrp with number of CP doses and lower Hb. We propose that this phenomenon is likely of multifactorial origin, involving autoregulatory mechanism disturbance. The imaging and measurement of LAD flow velocities are feasible, reliable, and is positively correlated with number of CP doses. Interpretation of postoperative LAD flow velocities should be made in the context of intraoperative events since heart rate, blood pressure, and Hb concentration also influence CA flow parameters. PMID- 26481225 TI - High-level construal benefits, meaning making, and posttraumatic growth in cancer patients. AB - OBJECTIVE: The present study sought to explore the role of meaning making and high-level construal in the relationship between meaning discrepancy and posttraumatic growth among Chinese cancer patients. METHOD: The participants were 193 individuals diagnosed with cancer. Meaning discrepancy, meaning making, high level construal in meaning making, and posttraumatic growth were measured. Bootstrapping and structural equation modeling were performed to test the mediation effects of high-level construal on the meaning-making process. RESULTS: Mediation analysis revealed that perceived discrepancies were associated with individuals' meaning-making efforts. Meaning-making efforts prompted participants to adopt a high-level construal orientation, which in turn enhanced posttraumatic growth. SIGNIFICANCE OF RESULTS: Our study empirically tested construal level theory in a population suffering from severe chronic trauma. The results demonstrate the important role of high-level construal in the meaning-making process of cancer patients, suggesting a specific effective strategy to foster posttraumatic growth. It seems encouraging to indicate that adopting such high level construal may be included as part of psychological interventions for cancer patients. PMID- 26481224 TI - Isolated Mitral Cleft in Trisomy 21: An Initially 'Silent' Lesion. AB - Congenital cardiac anomalies are common in trisomy 21, and transthoracic echocardiogram within the first month of life is recommended. While a cleft mitral valve associated with atrioventricular septal defect has been well defined in this population, the prevalence of isolated mitral valve cleft has not been previously reported. The aim of our study was to define the occurrence of isolated mitral cleft in the first echocardiogram of patients with trisomy 21. This retrospective chart review examined echocardiographic data on all Trisomy 21 patients <1 year of age obtained during January 1, 2010, to May 1, 2014, at our institution. Images were reviewed by one of the authors with no knowledge of the official diagnosis. In addition to evaluation for isolated mitral valve cleft, data obtained included presence of additional congenital heart defects and need for surgical intervention. A total of 184 patients (median age 5 days) were identified. Isolated mitral cleft was identified in 12 patients (6.5 %). Four were diagnosed retrospectively (33 %). Only one had mitral regurgitation on initial echocardiogram. Seven required surgery for closure of ventricular septal defects. Isolated mitral cleft is present in an important number of neonates with Trisomy 21. Mitral regurgitation is often absent in the neonatal period and should not be used as a reliable indicator of absence of valve abnormality. Careful attention should be directed toward the mitral valve during the first echocardiogram to exclude an isolated cleft, which can lead to progressive mitral regurgitation. PMID- 26481226 TI - Endorectal multiparametric 3-tesla magnetic resonance imaging associated with systematic cognitive biopsies does not increase prostate cancer detection rate: a randomized prospective trial. AB - PURPOSE: To investigate prostate cancer (PC) detection rate, employing endorectal multiparametric 3-tesla magnetic resonance imaging (MRI) driving subsequent cognitive systematic prostatic biopsy (CSPB) versus a homogenous group of patients who did not undergo endorectal MRI. MATERIALS AND METHODS: A series of patients with a first negative biopsy were enrolled in the study. Patients were randomized into two groups: Group A: patients underwent MRI and subsequent CSPB; Group B: patients that did not undergo MRI. Each patient underwent a 13-core sampling. Patients from Group A had four cores more for each MRI suspected lesion. The cancer detection rate was calculated for each group with regard to possible matches or mismatches between MRI evidence and pathological reports. RESULTS: Two hundred consecutive patients were investigated. Fifty out of 200 (25 %) patients had a diagnosis of PC, 24 in Group A and 26 in Group B. In Group A, 67 patients (67 %) were positive for suspected lesions at the MRI. The mismatch between MRI findings and the CSPB outcome was 61 % with an MRI-driven detection rate of 15 %. Group B detection rate was 26 % with no significant differences versus Group A (P = NS). Patient discomfort was higher in Group A (82 %). The accuracy of CSPB was 41 % with a positive predictive value of 22.3 %. This rate is lower in high-grade cancers (11.9 %). The cost-effectiveness was higher in Group A. CONCLUSIONS: Prostate cancer detection rate does not improve by CSPB. The accuracy of CSPB was lower in high-grade PC, and a higher cost was found with CSPB. PMID- 26481227 TI - Additional elastography-targeted biopsy improves the agreement between biopsy Gleason grade and Gleason grade at radical prostatectomy. AB - PURPOSE: To assess whether real-time elastography-targeted biopsy (RTE-bx) may help to correctly assign Gleason grade at radical prostatectomy (RP) and to compare discriminant properties of systematic biopsy alone (sbx) versus combination with RTE-bx (comb-bx) to distinguish between postoperatively favorable (Gleason 3 + 3, pT2, Nx/0) and postoperatively unfavorable (Gleason >=4 + 4) prostate cancer (PCa) at RP. PATIENTS AND METHODS: Overall, 259 patients diagnosed with PCa at systematic biopsy in combination with RTE-bx underwent RP between 2008 and 2011. Gleason Score derived from sbx versus comb-bx was compared to the gold-standard RP, and discriminant properties were assessed. Specificity gains were examined for sbx versus comb-bx when the endpoint consisted of postoperatively favorable PCa at RP. Sensitivity gains were examined, when analyses focused on postoperatively unfavorable PCa. RESULTS: Comb-bx resulted in higher correct overall Gleason assignment (68.3 vs. 56.7 %, p = 0.008) than sbx. Similarly, lower rates of undergrading (21.2 vs. 36.3 %, p < 0.001) were recorded. Specificity gains with comb-bx were 10 % (92 vs. 82 %, p = 0.004) for postoperatively favorable PCa. Comb-bx resulted in 31 % sensitivity gains relative to sbx (94 vs. 63 %, p = 0.03), when postoperatively unfavorable PCa was the endpoint. CONCLUSION: The agreement between biopsy and pathology Gleason Score was significantly higher for comb-bx than sbx. Additionally, comb-bx reduced the rate of false positives in the diagnosis of favorable PCa. Rates of correctly classified unfavorable PCa at RP were also higher for comb-bx. Those data indicate that comb-bx is useful in clinical practice. PMID- 26481228 TI - Erratum to: Nonclassically Secreted Proteins as Possible Antigens for Vaccine Development: A Reverse Vaccinology Approach. PMID- 26481229 TI - Study of metabolic profile of Rhizopus oryzae to enhance fumaric acid production under low pH condition. AB - Ensuring a suitable pH is a major problem in industrial organic acid fermentation. To circumvent this problem, we used a metabolic profiling approach to analyze metabolite changes in Rhizopus oryzae under different pH conditions. A correlation between fumaric acid production and intracellular metabolic characteristics of R. oryzae was revealed by principal component analysis. The results showed that to help cell survival in the presence of low pH, R. oryzae altered amino acid and fatty acid metabolism and promoted sugar or sugar alcohol synthesis, corresponding with a suppressing of energy metabolism, phenylalanine, and tyrosine synthesis and finally resulting in the low performance of fumaric acid production. Based on this observation, 1 % linoleic acid was added to the culture medium in pH 3.0 to decrease the carbon demand for cell survival, and the fumaric acid titer was enhanced by 39.7 % compared with the control (pH 3.0 without linoleic acid addition), reaching 18.3 g/L after 84 h of fermentation. These findings provide new insights into the mechanism by which R. oryzae responds to acidic stress and would be helpful for the development of efficient strategies for fumaric acid production at low pH. PMID- 26481230 TI - Comparative Characterization of Aroma Volatiles and Related Gene Expression Analysis at Vegetative and Mature Stages in Basmati and Non-Basmati Rice (Oryza sativa L.) Cultivars. AB - Aroma volatiles in Basmati-370, Ambemohar-157 (non-basmati scented), and IR-64 (non-scented) rice cultivars were qualitatively and quantitatively analyzed at vegetative and maturity stages to study their differential accumulation using headspace solid-phase microextraction, followed by gas chromatography mass spectrometry (HS-SPME-GCMS) with selected ion monitoring (SIM) approach. In addition, expression analysis of major aroma volatile 2-acetyl-1-pyrroline (2AP) related genes, betaine aldehyde dehydrogenase 2 (badh2) and Delta(1)-pyrolline-5 carboxylic acid synthetase (P5CS), were studied by real-time PCR. Maximum number of volatiles recorded at vegetative (72-58) than at mature stage (54-39). Twenty new compounds (12 in scented and 8 in both) were reported in rice. N-containing aromatic compounds were major distinguishing class separating scented from non scented. Among quantified 26 volatiles, 14 odor-active compounds distinguished vegetative and mature stage. Limit of detection (LOD) and limit of quantification (LOQ) for 2AP was 0.001 mg/kg of 2AP and 0.01 g of rice, respectively. 2AP accumulation in mature grains was found three times more than in leaves of scented rice. Positive correlation of 2AP with 2-pentylfuran, 6-methyl-5-hepten-2 one, and (E)-2-nonenal suggests their major role as aroma contributors. The badh2 expression was inversely and P5CS expression was positively correlated with 2AP accumulation in scented over non-scented cultivar. PMID- 26481231 TI - Detection of Asp371, Phe375, and Tyr376 Influence on GD-95-10 Lipase Using Alanine Scanning Mutagenesis. AB - GD-95-10 and GD-95-20 lipases are modified GD-95 lipase variants, which lack 10 and 20 C-terminal amino acids, respectively. Previous analysis showed that GD-95 10 lipase has higher activity than GD-95 lipase, while GD-95-20 lipase almost completely loses its activity. Analysis in silico suggested three conservative amino acids at region between 369 and 378 amino acids which can be relevant to the activity of GD-95-10 lipase. These amino acids have direct contacts with residues involved in substrate binding, stabilization of the serine loop or form oxyanion hole. In this work, the role of Asp371, Phe375, and Tyr376 on activity, functionality, and structure of GD-95-10 lipase was analyzed by Ala scanning mutagenesis. We showed that even a single mutation can impact the main structure and activity of Geobacillus lipases. Our experiments provide new knowledge about lipases from thermophilic Geobacillus bacteria and are important for protein engineering and synthetic biology. These enzymes and their engineering can be basis for future biocatalysts applied in production of biofuel or other industrial esters. PMID- 26481232 TI - A Review on the Genetics of Aliphatic and Aromatic Hydrocarbon Degradation. AB - Because of the high diversity of hydrocarbons, degradation of each class of these compounds is activated by a specific enzyme. However, most of other downstream enzymes necessary for complete degradation of hydrocarbons maybe common between different hydrocarbons. The genes encoding proteins for degradation of hydrocarbons, including the proteins required for the uptake of these molecules, the specific enzyme used for the initial activation of the molecules and other necessary degrading enzymes are usually arranged as an operon. Although the corresponding genes in many phylogenetic groups of microbial species show different levels of diversity in terms of the gene sequence, the organisation of the genes in the genome or on plasmids and the activation mode (inductive or constitutive), some organisms show identical hydrocarbon-degrading genes, probably as a result of horizontal gene transfer between microorganisms. PMID- 26481233 TI - The caverno-apical triangle: anatomic-pathological considerations and pictorial review. AB - BACKGROUND: The caverno-apical triangle (CAT) is defined from the components that define its contours: the cavernous sinus and the orbital apex. A wide range of pathologies arise from the space between the cavernous sinus and the orbital apex. OBJECT: To better define radiologically this critical anatomic landmark and establish an organized approach for image analysis to help generate focused differential diagnoses and accurately characterize lesions found on imaging. CONCLUSION: We have identified common imaging characteristics of frequently encountered lesions and divided them into specific categories to facilitate creation of logical and focused differential diagnoses. PMID- 26481234 TI - Transdentinal cytotoxicity of resin-based luting cements to pulp cells. AB - OBJECTIVES: The aim of this study was to evaluate the transdentinal cytotoxicity of components released from different resin-based luting cements to cultured MDPC 23 odontoblast-like cells and human dental pulp cells (HDPCs). MATERIALS AND METHODS: Artificial pulp chamber (APC)/dentin disc sets were distributed into four groups according to the materials tested (n = 10), as follows: G1, control (no treatment); G2, resin-modified glass-ionomer cement (RelyX Luting 2); G3, self-adhesive resin cement (RelyX U200); and G4, conventional resin cement (RelyX ARC). The materials were applied to the occlusal surfaces (facing up) of the dentin discs adapted to the APCs. The pulpal surfaces of the discs were maintained in contact with culture medium. Then, an aliquot of 400 MUL from the extract (culture medium + resin-based components that diffused through dentin) of each luting cement was applied for 24 h to HDPCs or MDPC-23 cells previously seeded in wells of 24-well plates. Cell viability analysis was performed by the MTT assay (1-way ANOVA/Tukey test; alpha = 5 %). RESULTS: For MDPC-23 cells, RelyX ARC (G4) and RelyX Luting 2 (G2) caused greater reduction in cell viability compared with the negative control group (P < 0.05). Only the HDPCs exposed to RelyX ARC (G4) extract showed a tendency toward viability decrease (9.3 %); however, the values were statistically similar to those of the control group (G1) (P > 0.05). CONCLUSIONS: In accordance with the safe limits of ISO 10993-5:1999 (E) recommendations, all resin-based luting cements evaluated in this study can be considered as non-toxic to pulp cells. CLINICAL RELEVANCE: Cytotoxicity of resin-based luting cements is material-dependent, and the different protocols for the application of these dental materials to dentin may interfere with their cytotoxicity. PMID- 26481236 TI - BEND3 is involved in the human-specific repression of calreticulin: Implication for the evolution of higher brain functions in human. AB - Recent emerging evidence indicates that changes in gene expression levels are linked to human evolution. We have previously reported a human-specific nucleotide in the promoter sequence of the calreticulin (CALR) gene at position 220C, which is the site of action of valproic acid. Reversion of this nucleotide to the ancestral A-allele has been detected in patients with degrees of deficit in higher brain cognitive functions. This mutation has since been reported in the 1000 genomes database at an approximate frequency of <0.0004 in humans (rs138452745). In the study reported here, we present update on the status of rs138452745 across evolution, based on the Ensembl and NCBI databases. The DNA pulldown assay was also used to identify the proteins binding to the C- and A alleles, using two cell lines, SK-N-BE and HeLa. Consistent with our previous findings, the C-allele is human-specific, and the A-allele is the rule across all other species (N=38). This nucleotide resides in a block of 12-nucleotides that is strictly conserved across evolution. The DNA pulldown experiments revealed that in both SK-N-BE and HeLa cells, the transcription repressor BEN domain containing 3 (BEND3) binds to the human-specific C-allele, whereas the nuclear factor I (NFI) family members, NF1A, B, C, and X, specifically bind to the ancestral A-allele. This binding pattern is consistent with a previously reported decreased promoter activity of the C-allele vs. the A-allele. We propose that there is a link between binding of BEND3 to the CALR rs138452745 C-allele and removal of NFI binding site from this nucleotide, and the evolution of human specific higher brain functions. To our knowledge, CALR rs138452745 is the first instance of enormous nucleotide conservation across evolution, except in the human species. PMID- 26481235 TI - Local, systemic, demographic, and health-related factors influencing pathogenic yeast spectrum and antifungal drug administration frequency in oral candidiasis: a retrospective study. AB - OBJECTIVES: In order to identify oral candidiasis patients being at risk of carrying potentially drug-resistant Candida, the aim of the study was to detect local, systemic, demographic, and health-related factors influencing (I) yeast spectrum composition and (II) antifungal administration frequency. Additionally, the aim was to investigate (III) species shift occurrence. MATERIALS AND METHODS: Data from 798 patients (496 females, 302 males; mean age 59.7) with oral candidiasis diagnosed based on positive clinical and microbial findings (species identification and CFU count) between 2006 and 2011 were retrospectively analyzed using Pearson's chi(2) test and regression analysis. RESULTS: Among 958 isolates, Candida albicans was the most frequently detected (76.8 %). Also, species intrinsically resistant to azoles were frequently isolated (15.8 and 17.7 % of isolates and patients). (I) Infections only caused by C. albicans were significantly associated with the use of inhalation steroids (p = 0.001) and antibiotics (p = 0.04), super-infection of lichen planus (p = 0.002), and the absence of removable dentures (p < 0.001). (II) Anti-mycotics were significantly more frequently administered in patients using inhalation steroids (p = 0.001), suffering from asthma/COPD, or smoking heavily (p = 0.003) and if C. albicans and non-albicans species were detected together (p = 0.001). (III) Pathogen composition did not change over time within the examined period (p = 0.239). CONCLUSIONS: Different variables enhance the presence of certain Candida and the antifungal prescription frequency. No species shift was evident. CLINICAL RELEVANCE: The major pathogen in oral candidiasis remains C. albicans. Nevertheless, therapeutic problems may be caused by the frequent presence of species intrinsically resistant to azoles, especially in patients wearing dentures. PMID- 26481237 TI - Sequence variation of Bemisia tabaci Chemosensory Protein 2 in cryptic species B and Q: New DNA markers for whitefly recognition. AB - Bemisia tabaci Gennadius biotypes B and Q are two of the most important worldwide agricultural insect pests. Genomic sequences of Type-2 B. tabaci chemosensory protein (BtabCSP2) were cloned and sequenced in B and Q biotypes, revealing key biotype-specific variations in the intron sequence. A Q260 sequence was found specifically in Q-BtabCSP2 and Cucumis melo LN692399, suggesting ancestral horizontal transfer of gene between the insect and the plant through bacteria. A cleaved amplified polymorphic sequences (CAPS) method was then developed to differentiate B and Q based on the sequence variation in exon of BtabCSP2 gene. The performances of CSP2-based CAPS for whitefly recognition were assessed using B. tabaci field collections from Shandong Province (P.R. China). Our SacII based CAPS method led to the same result compared to mitochondrial cytochrome oxidase based CAPS method in the field collections. We therefore propose an explanation for CSP origin and a new rapid simple molecular method based on genomic DNA and chemosensory gene to differentiate accurately the B and Q whiteflies of the Bemisia complex around the world. PMID- 26481238 TI - A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population. AB - The mutation spectrum for the phenylalanine hydroxylase (PAH) gene was investigated in a cohort of 84 hyperphenylalaninemia (HPA) patients from Romania identified through newborn screening or neurometabolic investigations. Differential diagnosis identified 81 patients with classic PAH deficiency while 3 had tetrahydropterin-cofactor deficiency and/or remained uncertain due to insufficient specimen. PAH-genetic analysis included a combination of Sanger sequencing of exons and exon-intron boundaries, MLPA and NGS with genomic DNA, and cDNA analysis from immortalized lymphoblasts. A diagnostic efficiency of 99.4% was achieved, as for one allele (out of a total of 162 alleles) no mutation could be identified. The most prevalent mutation was p.Arg408Trp which was found in ~ 38% of all PKU alleles. Three novel mutations were identified, including the two missense mutations p.Gln226Lys and p.Tyr268Cys that were both disease causing by prediction algorithms, and the large genomic deletion EX6del7831 (c.509 + 4140_706 + 510del7831) that resulted in skipping of exon 6 based on PAH-cDNA analysis in immortalized lymphocytes. The genomic deletion was present in a heterozygous state in 12 patients, i.e. in ~ 8% of all the analyzed PKU alleles, and might have originated from a Romanian founder. PMID- 26481239 TI - Prevalence and phylogenetic analysis of Babesia spp. in Ixodes ricinus and Ixodes persulcatus ticks in Latvia. AB - Babesia spp. are tick-borne protozoan parasites that have been reported in many European countries and are considered to be emerging pathogens. Several Babesia spp. have been identified in ticks in Latvia. Recently, canine babesiosis cases were diagnosed for the first time in Latvia; therefore, continued studies on the prevalence and occurrence of new species are warranted. In the present study, questing tick samples collected in 2005-2007 were screened for the presence of Babesia spp.; in total, 432 Ixodes ricinus and 693 Ixodes persulcatus ticks were analyzed. Babesia spp. were detected in 1.4% of the I. ricinus ticks and in 1.9% of I. persulcatus ticks. Sequencing revealed that ixodid ticks in Latvia contained Babesia microti, Babesia capreoli, and Babesia venatorum. Babesia microti was the most prevalent species, accounting for 58% of all positive samples; moreover, two distinct B. microti genotypes were identified. Phylogenetic analysis of the full-length 18S rRNA gene of two B. capreoli/B. divergens isolates indicated a closer relationship to the B. capreoli clade than B. divergens. This is the first report of B. venatorum in I. persulcatus ticks in Latvia. Our results suggest that both I. ricinus and I. persulcatus ticks play important roles in the epidemiology of these zoonotic pathogens in Latvia. PMID- 26481240 TI - Revealing the functional structure of a new PLA2 K49 from Bothriopsis taeniata snake venom employing automatic "de novo" sequencing using CID/HCD/ETD MS/MS analyses. AB - Snake venoms are composed of approximately 90% of proteins with several pharmacological activities having high potential in research as biological tools. One of the most abundant compounds is phospholipases A2 (PLA2), which are the most studied venom protein due to their wide pharmacological activity. Using a combination of chromatographic steps, a new PLA2 K49 was isolated and purified from the whole venom of the Bothriopsis taeniata and submitted to analyses mass spectrometry. An automatic "de novo" sequencing of this new PLA2 K49 denominated Btt-TX was performed using Peaks Studio 6 for analysis of the spectra. Additionally, a triplex approach CID/HCD/ETD has been performed, to generate higher coverage of the sequence of the protein. Structural studies correlating biological activities were made associating specific Btt-TX regions and myotoxic activity. Lysine acetylation was performed to better understand the mechanism of membrane interaction, identifying the extreme importance of the highly hydrophobic amino acids L, P and F for disruption of the membrane. Our myotoxical studies show a possible membrane disruption mechanism by Creatine Kinase release without a noticeable muscle damage, that probably occurred without phospholipid hydrolyses, but with a probable penetration of the hydrophobic amino acids present in the C-terminal region of the protein. PMID- 26481241 TI - The extended, dynamic mitochondrial reticulum in skeletal muscle and the creatine kinase (CK)/phosphocreatine (PCr) shuttle are working hand in hand for optimal energy provision. PMID- 26481242 TI - Correction. PMID- 26481243 TI - IgG4-related disease: A relatively new concept for clinicians. AB - IgG4-related disease (IgG4-RD) is a recently recognized chronic fibrotic inflammation, which can affect almost every organ, and may come to clinical attention first due to visible organ swelling or organ dysfunction, or is identified incidentally by imaging and specific biopsy. The disorder has an allergic background and is immune-mediated. Up-regulated responses of T helper 2 and T regulatory cells and their cytokines play a major role in disease progression. About 30-50% of patients are atopic or have mild eosinophilia. IgG4 RD predominantly affects middle-aged male patients. The cornerstones of diagnosis of the disease are compatible clinical features and typical histopathology. Swelling of salivary and lacrimal glands, lymphadenopathy, and type 1 autoimmune pancreatitis (AIP) are the most common manifestations of the disease. However, other tissues and organs, such as retroperitoneum, lung, kidney, aorta, upper airways, thyroid gland, meninges, heart, mesenterium and skin may be involved. Typical histopathology is lymphoplasmacytic infiltration abundant in IgG4 positive plasma cells, storiform-type fibrosis, and obliterative phlebitis. Elevated serum IgG4 concentration supports the diagnosis. Characteristic imaging features such as a "capsule-like rim" surrounding the pancreatic lesions is highly specific to type 1 AIP. 18F-fluorodeoxyglucose positron emission tomography/computed tomography enables mapping the sites of inflammation, permits evaluation of the extent of the disease, helps in guiding biopsy decision, and may be used in monitoring response to treatment. Glucocorticoids alone or in combination with B-cell depletion with rituximab induces prompt clinical response to IgG4-RD. This article reviews the current understanding, different clinical manifestations, and approaches to diagnosis and treatment of IgG4-RD. PMID- 26481244 TI - A methodology for comprehensive breast cancer Ki67 labeling index with intra tumor heterogeneity appraisal based on hexagonal tiling of digital image analysis data. AB - Digital image analysis (DIA) enables higher accuracy, reproducibility, and capacity to enumerate cell populations by immunohistochemistry; however, the most unique benefits may be obtained by evaluating the spatial distribution and intra tissue variance of markers. The proliferative activity of breast cancer tissue, estimated by the Ki67 labeling index (Ki67 LI), is a prognostic and predictive biomarker requiring robust measurement methodologies. We performed DIA on whole slide images (WSI) of 302 surgically removed Ki67-stained breast cancer specimens; the tumour classifier algorithm was used to automatically detect tumour tissue but was not trained to distinguish between invasive and non invasive carcinoma cells. The WSI DIA-generated data were subsampled by hexagonal tiling (HexT). Distribution and texture parameters were compared to conventional WSI DIA and pathology report data. Factor analysis of the data set, including total numbers of tumor cells, the Ki67 LI and Ki67 distribution, and texture indicators, extracted 4 factors, identified as entropy, proliferation, bimodality, and cellularity. The factor scores were further utilized in cluster analysis, outlining subcategories of heterogeneous tumors with predominant entropy, bimodality, or both at different levels of proliferative activity. The methodology also allowed the visualization of Ki67 LI heterogeneity in tumors and the automated detection and quantitative evaluation of Ki67 hotspots, based on the upper quintile of the HexT data, conceptualized as the "Pareto hotspot". We conclude that systematic subsampling of DIA-generated data into HexT enables comprehensive Ki67 LI analysis that reflects aspects of intra-tumor heterogeneity and may serve as a methodology to improve digital immunohistochemistry in general. PMID- 26481246 TI - Communication skills in diagnostic pathology. AB - Communication is an essential element of good medical practice also in pathology. In contrast to technical or diagnostic skills, communication skills are not easy to define, teach, or assess. Rules almost do not exist. In this paper, which has a rather personal character and cannot be taken as a set of guidelines, important aspects of communication in pathology are explored. This includes what should be communicated to the pathologist on the pathology request form, communication between pathologists during internal (interpathologist) consultation, communication around frozen section diagnoses, modalities of communication of a final diagnosis, with whom and how critical and unexpected findings should be communicated, (in-)adequate routes of communication for pathology diagnoses, who will (or might) receive pathology reports, and what should be communicated and how in case of an error or a technical problem. An earlier more formal description of what the responsibilities are of a pathologist as communicator and as collaborator in a medical team is added in separate tables. The intention of the paper is to stimulate reflection and discussion rather than to formulate strict rules. PMID- 26481245 TI - The heterogeneity of follicular lymphomas: from early development to transformation. AB - Follicular lymphoma (FL) is a lymphoma composed of germinal center B cells, i.e., centroblasts and centrocytes, that almost always show at least a focal follicular growth pattern. Most cases have a characteristic CD5-, CD10+, BCL6+, and BCL2+ immunophenotype, and 85 % of cases exhibit the hallmark translocation t(14;18)(q32;q21) involving BCL2 and IGH. Although the typical clinicopathological findings of FL are well recognized, cases with unusual clinical, morphologic, immunophenotypic, and genetic features may pose problems in diagnosis and nomenclature. In the slide workshop organized by the European Association for Haematopathology (EAHP) and the Society for Hematopathology (SH) held in Istanbul, Turkey, unusual variants of FL were discussed based on the submitted cases, including early lesions, localized extranodal presentation, uncommon immunophenotype, rare genetic alterations, diffuse variant, and marginal zone differentiation. Interesting features such as blastoid morphology and unusual progression forms were presented, aiming to understand the genetic basis of transformation. In this report, novel findings and diagnostic challenges emerging from the submitted cases will be highlighted, and new terminologies for some of these lesions are proposed. PMID- 26481247 TI - Cerebellar Control on Prefrontal-Motor Connectivity During Movement Inhibition. AB - Converging evidence suggests a crucial role of right inferior frontal gyrus (r IFG) and right pre-supplementary motor area (r-preSMA) in movement inhibition control. The present work was aimed to investigate how the effective connectivity between these prefrontal areas and the primary motor cortex could change depending on the activity of the cerebellar cortex. Paired transcranial magnetic stimulation (TMS) was delivered in healthy subjects over the r-IFG/left primary motor area (l-M1) and over r-preSMA/l-M1 before (100 ms after the fixation cross onset) and 50, 75, 100, 125, and 150 ms after the presentation of a Go/NoGo visual cue establishing the specific time course and the causal interactions of these regions in relation to l-M1 as measured by motor evoked potentials (MEPs). The same paired-pulse protocol was applied following sham or real cerebellar continuous theta burst stimulation (cTBS). Following sham cTBS, for NoGo trials only, MEPs collected showed the expected pattern of activation for both r-IFG-l M1 and r-preSMA-l-M1 connectivity, characterized by peaks of increased and decreased MEP amplitude regularly repeated every 50 ms. Following cerebellar cTBS, this pattern of activation related to NoGo trials was modified selectively for the r-IFG-M1 but not for r-preSMA-M1 connection. A common monitoring action of r-IFG and r-preSMA in inhibitory control was confirmed. The effects of cerebellar cTBS showed a specific interaction between cerebellum and r-IFG activity during the inhibitory process. PMID- 26481248 TI - Harness the power of endogenous neural stem cells by biomaterials to treat spinal cord injury. PMID- 26481249 TI - Primary orbital yolk sac tumor: report of a case and review of literature. AB - Germ cell tumor can affect extragonadal sites. Teratoma is a well-recognized extragonadal tumor in the orbit. Primary yolk sac tumor (YST) or endodermal sinus tumor of orbit is rare and only few cases have been reported in the literature. Its clinical presentation may mimic many common pediatric orbital conditions, and delay in diagnosis affects ocular morbidity and mortality. In the past orbital YST has been treated with multimodal therapy including surgery, systemic chemotherapy, and radiotherapy. Herein we describe a case of primary orbital YST and reviewed the literature for similar cases. The review aims to describe the clinical presentation, imaging features, histopathological characteristics, and management of orbital YST. PMID- 26481250 TI - Evaluation of hematological markers in minor head trauma in the emergency room. AB - INTRODUCTION: A rule exists regarding the use of computed tomography (CT) for patients presenting to the emergency department with head trauma and a Glasgow coma score (GCS) of 15; however, it can be difficult to make this decision due to overcrowded emergency rooms or exaggerated patients complaints. We evaluated patients who presented to the emergency room with minor head trauma, and we aimed to investigate the relationship between brain pathology on CT and hematological markers in order to find markers that help us identify brain pathology in patients with a GCS of 15. METHODS: This retrospective study included 100 patients with pathologies present on their CT scans and a control group consisting of 100 patients with a normal CT. All data obtained from this study were recorded and evaluated using "Statistical Package for Social Sciences for Windows 20" program. Parametric tests (independent samples test) were used with normally distributed data, while non-parametric tests (Mann-Whitney U test) were used with non-normally distributed data. A p <= 0.05 was considered significant. FINDING: When we divided the cases into two groups based on the presence of pathologies on CT scan, we determined that there were significant differences between the groups in terms of white blood cell (WBC), hemoglobin (Hb), mean platelet volume (MPV), neutrophil (neu), troponin T, neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR). When differentiating the patients that had brain pathologies on CT scan from patients that had normal CT scans, the troponin T cut-off value of 6.16 lead to 90 % specificity, and setting the NLR cut-off value at 4.29 resulted in a specificity of 90 %. CONCLUSION: MPV, NLR, and troponin T can be used as parameters that indicate brain pathologies on CT scans of patients presenting to the emergency department with isolated minor head trauma and GCS of 15 when the necessity of a CT scan is otherwise unclear. PMID- 26481251 TI - Diagnostic value of MRI features of sacroiliitis in juvenile spondyloarthritis. AB - AIM: To determine the diagnostic utility of magnetic resonance imaging (MRI) features of sacroiliitis in juvenile spondyloarthritis (JSpA). MATERIALS AND METHODS: This was a prospective study of 80 paediatric patients who underwent MRI of the sacroiliac joints that were clinically suspected to have sacroiliitis. The prevalence of MRI features of active and structural lesions of sacroiliitis was recorded. Patients were classified according to the International League of Association for Rheumatology criteria. The MRI findings were compared to the final clinical diagnosis. RESULTS: Sacroiliitis was seen in 25/80 (31%) patients. MRI showed active inflammation in 23 patients (29%): synovial enhancement (28%), high short tau inversion recovery (STIR)-signal in the joint space (29%), bone marrow oedema (BMO; 20%), and capsulitis (8%). Structural changes were present in 14 patients (18%): erosion (14%), fat infiltration (13%), sclerosis (8%), and ankylosis (1%). Of all MRI features, ankylosis (100%), capsulitis (98%), BMO (96%), and erosion (96%) had the highest specificity for JSpA; global diagnostic impression (55%) and synovial enhancement (52%) were the MRI features with the highest sensitivity. The likelihood ratios (LR+) for diagnosis of JSpA were high for BMO (10.5), capsulitis (7.5), global diagnostic impression (6.9), and erosions (6.75), but greater for BMO concomitant with synovial enhancement (LR+ 19.5) and for erosion concomitant with BMO (LR+ 12) or synovial enhancement (LR+ 13.5). CONCLUSION: There are multiple features of active inflammation and structural damage visible at MRI of the sacroiliac joints that can provide a specific diagnosis of JSpA when present in children with suspected sacroiliitis. Synovial enhancement is the MRI feature with the highest sensitivity for JSpA. If BMO is seen concomitant with synovial enhancement or erosion, the diagnosis of JSpA is very likely. Ankylosis, capsulitis, bone marrow oedema, and erosion all have a high specificity for JSpA. Absence of MRI findings of sacroiliitis does not exclude the diagnosis of JSpA. PMID- 26481252 TI - Editorial - All Change. PMID- 26481253 TI - Dual treatment of acute HCV infection in HIV co-infection: influence of HCV genotype upon treatment outcome. AB - PURPOSE: With DAAs still only being licensed for chronic HCV infection, the ongoing epidemic of acute hepatitis C (AHC) infection among MSM highlights the need to identify factors allowing for optimal HCV treatment outcome. METHODS: 303 HIV-infected patients from 4 European countries with diagnosed acute HCV infection were treated early with pegylated interferon (pegIFN) and ribavirin (RBV) (n = 273) or pegylated interferon alone (n = 30). RESULTS: All patients were male, median age was 39 years. Main routes of transmission were MSM (95%) and IVDU (3%). 69% of patients were infected with HCV GT 1, 4.3% with GT 2, 10.6% with GT 3, 16.1% with GT 4. Overall SVR rate was 69.3% (210/303). RVR (p <= 0.001), 48-w treatment duration (p <= 0.001) and GT 2/3 (p = 0.024) were significantly associated with SVR. SVR rates were significantly higher in HCV GT 2/3 receiving pegIFN and RBV (33/35) when compared with pegIFN mono-therapy (6/10) (94% vs. 60 % respectively; p = 0.016). In multivariate analysis, pegIFN/RBV combination therapy (p = 0.017) and rapid virological response (RVR) (p = 0.022) were significantly associated with SVR in HCV GT 2/3. In HCV GT 1/4, RVR (p <= 0.001) and 48-w treatment duration (p <= 0.001) were significantly associated with SVR. CONCLUSIONS: Treatment of AHC GT 2 and 3 infections with pegIFN/RBV is associated with higher SVR rates suggesting different cure rates depending on HCV genotype similar to the genotype effects seen previously in chronic HCV under pegIFN/RBV. With pegIFN/RBV still being the gold standard of AHC treatment and in light of cost issues around DAAs and very limited licensed interferon-free DAA treatment options for chronic HCV GT 3 infection AHC GT 3 patients might benefit most from early interferon-containing treatment. PMID- 26481254 TI - Agenesis of internal carotid artery associated with isolated growth hormone deficiency: a case report and literature review. AB - BACKGROUND: Agenesis of the internal carotid artery (ICA) is a rare congenital abnormality, sporadically reported to be associated with a combined congenital hypopituitarism. Nevertheless, only a few cases have been extensively described, and none of these have been characterized by an isolated growth hormone (GH) deficiency. CASE PRESENTATION: Here, we describe a 17-year old boy referred to our hospital for fatigue, decreased muscle strength and severe headache reported after the cessation of rhGH treatment for a GH deficiency diagnosed at the age of 2 years and 3 months. Magnetic resonance imaging (MRI) showed an adenohypophyseal hypoplasia with a lack of posterior pituitary hyperintensity, whereas MRI angiography indicated the absence of a normal flow void in the left ICA. Endocrinological tests confirmed the GH deficiency (GH peak after growth-hormone releasing hormone (GHRH) + arginine: 2.42 ng/mL) with a very low IGF-I value (31 ng/mL) and normal function of other pituitary axes. CONCLUSION: To the best of our knowledge this is the first confirmed case of an isolated GH deficiency in a patient with ICA agenesis. The presence of an isolated pituitary deficit is unlike to be considered only as an effect of hemodynamic mechanism, suggesting a role for genetic factor(s) as a common cause of these two rare birth defects. Further studies could clarify this issue and the underlying mechanisms to better understand the etiopathogenetic characteristics of this disorder. PMID- 26481255 TI - Cancer classification in the genomic era: five contemporary problems. AB - Classification is an everyday instinct as well as a full-fledged scientific discipline. Throughout the history of medicine, disease classification is central to how we develop knowledge, make diagnosis, and assign treatment. Here, we discuss the classification of cancer and the process of categorizing cancer subtypes based on their observed clinical and biological features. Traditionally, cancer nomenclature is primarily based on organ location, e.g., "lung cancer" designates a tumor originating in lung structures. Within each organ-specific major type, finer subgroups can be defined based on patient age, cell type, histological grades, and sometimes molecular markers, e.g., hormonal receptor status in breast cancer or microsatellite instability in colorectal cancer. In the past 15+ years, high-throughput technologies have generated rich new data regarding somatic variations in DNA, RNA, protein, or epigenomic features for many cancers. These data, collected for increasingly large tumor cohorts, have provided not only new insights into the biological diversity of human cancers but also exciting opportunities to discover previously unrecognized cancer subtypes. Meanwhile, the unprecedented volume and complexity of these data pose significant challenges for biostatisticians, cancer biologists, and clinicians alike. Here, we review five related issues that represent contemporary problems in cancer taxonomy and interpretation. (1) How many cancer subtypes are there? (2) How can we evaluate the robustness of a new classification system? (3) How are classification systems affected by intratumor heterogeneity and tumor evolution? (4) How should we interpret cancer subtypes? (5) Can multiple classification systems co-exist? While related issues have existed for a long time, we will focus on those aspects that have been magnified by the recent influx of complex multi-omics data. Exploration of these problems is essential for data-driven refinement of cancer classification and the successful application of these concepts in precision medicine. PMID- 26481256 TI - Alterations in walking knee joint stiffness in individuals with knee osteoarthritis and self-reported knee instability. AB - Increased walking knee joint stiffness has been reported in patients with knee osteoarthritis (OA) as a compensatory strategy to improve knee joint stability. However, presence of episodic self-reported knee instability in a large subgroup of patients with knee OA may be a sign of inadequate walking knee joint stiffness. The objective of this work was to evaluate the differences in walking knee joint stiffness in patients with knee OA with and without self-reported instability and examine the relationship between walking knee joint stiffness with quadriceps strength, knee joint laxity, and varus knee malalignment. Overground biomechanical data at a self-selected gait velocity was collected for 35 individuals with knee OA without self-reported instability (stable group) and 17 individuals with knee OA and episodic self-reported instability (unstable group). Knee joint stiffness was calculated during the weight-acceptance phase of gait as the change in the external knee joint moment divided by the change in the knee flexion angle. The unstable group walked with lower knee joint stiffness (p=0.01), mainly due to smaller heel-contact knee flexion angles (p<0.01) and greater knee flexion excursions (p<0.01) compared to their knee stable counterparts. No significant relationships were observed between walking knee joint stiffness and quadriceps strength, knee joint laxity or varus knee malalignment. Reduced walking knee joint stiffness appears to be associated with episodic knee instability and independent of quadriceps muscle weakness, knee joint laxity or varus malalignment. Further investigations of the temporal relationship between self-reported knee joint instability and walking knee joint stiffness are warranted. PMID- 26481257 TI - A comparison of variability in spatiotemporal gait parameters between treadmill and overground walking conditions. AB - Motorized treadmills are commonly used in biomechanical and clinical studies of human walking. Whether treadmill walking induces identical motor responses to overground walking, however, is equivocal. The purpose of this study was to examine differences in the spatiotemporal gait parameters of the lower extremities and trunk during treadmill and overground walking using comparison of mean and variability values. Twenty healthy participants (age 23.8+/-1.2 years) walked for 6min on a treadmill and overground while wearing APDM 6 Opal inertial monitors. Stride length, stride time, stride velocity, cadence, stance phase percentage, and peak sagittal and frontal plane trunk velocities were measured. Mean values were calculated for each parameter as well as estimates of short- (SD1) and long-term variability (SD2) using Poincare analyses. The mean, SD1, and SD2 values were compared between overground and treadmill walking conditions with paired t-tests (alpha=0.05) and with effect size estimates using Cohen's d statistic. Mean values for each of the gait parameters were statistically equivalent between treadmill and overground walking (p>0.05). The SD1 and SD2 values representing short- and long-term variability were considerably reduced (p<0.05) on the treadmill as compared to overground walking. This demonstrates the importance of consideration of gait variability when using treadmills for research or clinical purposes. Treadmill training may induce invariant gait patterns, posing difficulty in translating locomotor skills gained on a treadmill to overground walking conditions. PMID- 26481258 TI - Contributors of stiff knee gait pattern for able bodies: Hip and knee velocity reduction and tiptoe gait. AB - Stiff-knee gait (SKG) is commonly encountered in clinic; many other gait abnormalities are seen together with this pathology. Simulation studies revealed that diminished knee flexion (KF) velocity and increased knee extension moments are strongly related with SKG. This study aimed to determine whether tiptoe walking and hip-knee flexion velocity reduction causes SKG pattern in healthy participants. METHODS: Fourteen able-bodied adults' (Av. age: 23.0+/-2.4) heel toe (N), tiptoe (T), and walking with 5% body weight on both shanks (W) were analyzed using 3D gait analysis by controlling cadence (90step/min). Repeated measures analysis of variance was used followed by Bonferroni correction (p<0.05). RESULTS: Walking velocity and cadence were similar for all conditions (p>0.1). Maximum hip flexion velocity was reduced (15%) significantly as well as the KF velocity (10%) in the W condition. The peak knee flexion (PKF) (8.3% for T, 8.6% for W) and total knee range (10.9% for T, 13% for W) were reduced for both conditions (p<0.05). The knee range in early swing and the duration between toe-off and PKF were reduced only in the weighted-leg condition (p<0.05). CONCLUSIONS: Slow hip and knee flexion diminished all SKG parameters except timing of PKF. Tiptoe gait itself generated a borderline SKG pattern by reducing the PKF and total knee range. By considering that tiptoe gait and SKG commonly seen together, some of the SKG contributors can be treated by normalizing the ankle motion in the stance and increasing the hip-knee flexion velocity by rigorously planned muscle lengthening procedures and effective strengthening exercises. PMID- 26481259 TI - Association of serum VEGF with clinical response to anti-TNFalpha therapy for Crohn's disease. AB - Down-regulation of immune-mediated angiogenesis seems to be an important mechanism in anti-tumor necrosis factor alpha (anti-TNFalpha) therapy for Crohn's disease (CD). However, it remains to be established whether the baseline pro angiogenic activity as reflected by the level of vascular endothelial growth factor (VEGF) could be of predictive value for successful clinical outcome of such treatment. Here, the levels of serum VEGF and other crucial angiogenesis regulating peptides were assessed before and after induction anti-TNFalpha therapy in CD patients, and in age- and sex-matched healthy controls. Clinical, endoscopic, and biochemical activity of CD was estimated in parallel. CD patients were divided into two subgroups, depending on baseline VEGF levels: a "low-VEGF" subgroup with VEGF levels similar to those detected in healthy people, and a "high-VEGF" subgroup with VEGF levels significantly increased. VEGF levels were found to significantly correlate with CD clinical activity. Compared to the "low VEGF" subgroup, the reduction in CD clinical activity as assessed by Crohn's Disease Activity Index was significantly greater in "high-VEGF" patients both in absolute numbers, and as a percentage of pre-treatment values. Accordingly, the fraction of patients who did not respond adequately to treatment was significantly greater in the "low-VEGF" group. These data indicate that VEGF may serve as an additional marker of CD activity and that baseline VEGF levels can be helpful in predicting the efficacy of anti-TNFalpha therapy. PMID- 26481260 TI - Interleukin-15 enhances the expansion and function of natural killer T cells from adult peripheral and umbilical cord blood. AB - Invariant natural killer T cells (iNKT cells) are innate-like non-conventional T cells restricted by the CD1d molecule that are unique in their ability to play a pivotal role in immune regulation. Deficient iNKT function has been reported in patients receiving umbilical cord blood (UCB) transplantation. We sought to determine the effect of interleukin (IL)-15 on alpha-galactosylceramide (alpha GalCer)-expanded iNKT cell function from UCB and adult peripheral blood (APB) mononuclear cells (MNCs). Fresh APB and UCB MNCs were cultured with IL-15 (50 ng/ml) in the presence or absence of alpha-GalCer (100 ng/ml) for 10 days. Cells were harvested for examination of cell yield, apoptosis, cytokine production and cytotoxic function of Valpha24(+)/Vbeta11(+) iNKT cells. We observed that alpha GalCer-expanded APB and UCB iNKT cells and such expansion was further enhanced with IL-15. The percentage of CD3(+)CD56(+) NKT-like cells in both APB and UCB MNCs was increased with IL-15 but not with alpha-GalCer. Apoptosis of UCB iNKT cells was ameliorated by IL-15. Although APB and UCB iNKT cells secreted lower IFN-gamma, it could be enhanced with IL-15. The expression of perforin in APB iNKT cells can also be enhanced with IL-15. UCB Valpha24(+)Vbeta11(+) iNKT cells further augmented K562 cytotoxicity mediated by IL-15. Taken together, these results demonstrated the relative functional deficiencies of alpha-GalCer induced UCB iNKT cells, which can be ameliorated by IL-15. Our findings suggest a therapeutic benefit of IL-15 immunotherapy during the post-UCB transplant period when iNKT function remains poor. PMID- 26481261 TI - An investigation into the exercise behaviours of regionally based Australian pregnant women. AB - OBJECTIVES: Regular exercise during pregnancy is a recommended prenatal care strategy with short and long-term health benefits to mother and child. Unfortunately, most pregnant women are insufficiently active to obtain health benefits and there is evidence that activity levels decrease overall during pregnancy. Physical activity among regionally based women is lower than that of urban-based women within Australia. However, little is currently known about exercise behaviours of regionally based Australian pregnant women. To successfully promote exercise among regionally based pregnant women, a greater understanding of exercise behaviours must first be explored. This study investigated exercise behaviours in a sample of regionally based Australian pregnant women. DESIGN: Regionally based Australian pregnant women (n=142) completed a modified version of the Godin Leisure-Time Exercise Questionnaire examining exercise behaviours before and during pregnancy. METHODS: Women self reported their exercise behaviours, including exercise frequency, intensity, time and type, before and during pregnancy. RESULTS: Chi-square analysis revealed significantly less (chi(2)=31.66, p<0.05) women participated in exercise during pregnancy (61%) compared to before pregnancy (87%). During pregnancy, respondents exercised at a significantly lower frequency (chi(2)=111.63, p<0.05), intensity (chi(2)=67.41, p<0.05), shorter time/duration (chi(2)=114.33, p<0.05), and significantly less (chi(2)=8.55, p<0.05) women (8%) are meeting 'exercise during pregnancy' guidelines compared to women before pregnancy (49%) meeting physical activity guidelines. CONCLUSIONS: Exercise during pregnancy decreases to levels significantly lower than what is currently recommended. Public health initiatives that promote exercise among Australian pregnant women should aim to increase frequency, intensity, time and type of exercise to be undertaken during pregnancy. PMID- 26481262 TI - School's out ... now what? Objective estimates of afterschool sedentary time and physical activity from childhood to adolescence. AB - OBJECTIVES: To describe the change in afterschool levels of sedentary time and physical activity from childhood to adolescence. DESIGN: Longitudinal. METHODS: 375 youth (50% boys) from the Study of Early Child Care and Youth Development (United States) provided accelerometer data at 9 (2000/01) and 15 yrs (2006/07). Average time spent in sedentary, light, moderate, vigorous, and moderate-to vigorous physical activity (MVPA; minh(-1)) was reported across the afterschool period (15:00-22:00) and separately across whole days. Mean comparisons were conducted to report between- and within-group differences in afterschool data. Analysis of covariance was used to determine the effect of sex, ethnicity, and baseline body mass index (BMI) on the 6-yr change in afterschool sedentary time and MVPA before and after adjusting for covariates (baseline afterschool sedentary/MVPA time, change in non-afterschool sedentary/MVPA time, difference in afterschool wear time, and socioeconomic status). RESULTS: From 9 to 15 yrs, sedentary time increased and activity decreased during the afterschool period. After covariate adjustment, the decline in afterschool MVPA was significantly greater among girls, compared to boys (B coefficient (95%CI)=-0.94 (-1.47, 0.40)), and among overweight/obese youth, compared to youth with normal BMI values (B coefficient (95%CI)=-0.65 (-1.22, -0.08)). CONCLUSIONS: During the transition from childhood to adolescence, afterschool activity (minh(-1)) decreases while sedentary time increases. Programs are needed throughout this period that promote the maintenance of activity or encourage additional activity with age. PMID- 26481263 TI - Quantitative Analysis of the Degree of Frontal Rotation Required to Anatomically Align the First Metatarsal Phalangeal Joint During Modified Tarsal-Metatarsal Arthrodesis Without Capsular Balancing. AB - The data from 35 consecutive patients with hallux valgus undergoing triplane arthrodesis at the first tarsal metatarsal joint were studied to determine the amount of first metatarsal frontal plane rotation (supination) needed to anatomically align the first metatarsal phalangeal joint on an anterior posterior radiograph without soft tissue balancing at the first metatarsal phalangeal joint. Radiographs were measured both pre- and postoperatively to assess the 1-2 intermetatarsal angle, hallux abductus angle, and tibial sesamoid position (TSP). The mean amount of varus (supination) rotation performed during correction was 22.1 degrees +/- 5.2 degrees and the mean amount of intermetatarsal angle reduction achieved after completion of the procedure was 6.9 degrees +/- 3.0 degrees . The TSP changed by a mean of 3.3 degrees +/- 1.2 degrees . A series of univariate linear regression analyses was performed to analyze the relationship between the frontal plane rotation of the first metatarsal performed during the operation and the preoperative intermetatarsal angle, hallux abductus angle, and TSP. Greater preoperative TSP scores were associated with greater intraoperative varus (supination) rotation required for joint alignment. Direct observation of the alignment changes at the first metatarsal phalangeal joint after metatarsal rotation without distal procedures strengthened the notion that the frontal plane rotational position plays an important role in the bunion deformity. PMID- 26481264 TI - Big Questions for "Big Data". PMID- 26481265 TI - The Use of Ophthalmic Ultrasonography to Identify Retinal Injuries Associated With Abusive Head Trauma. AB - Abusive head trauma includes any nonaccidental injury inflicted to a child's head and body. It is often characterized by, but not limited to, the repetitive acceleration-deceleration forces with or without blunt head impact. It has a mortality rate of 30%, and 80% of survivors experience permanent neurologic damage. In this case series, we hypothesize that bedside ultrasonography can be useful in the identification of retinal injuries that are consistent with abusive head trauma. Ocular manifestations of abusive head trauma are identified by dilated ophthalmic examination showing retinal hemorrhages that are too numerous to count, multilayered, and extending to the periphery. Traumatic retinoschisis, splitting of the retinal layers with or without blood accumulating in the intervening space, is exclusive for abusive head trauma in infants without a history of significant cerebral crush injury. Direct visualization of intraocular structures is difficult when the eyelids are swollen shut or when dilatation must be delayed. We present a series of 11 patients with brain injuries who underwent ophthalmic point-of-care ultrasonography that revealed traumatic retinoschisis on average 60 hours earlier than direct ophthalmic visualization. Dilated ophthalmic examinations and autopsy reports confirmed retinoschisis and other forms of retinal hemorrhages that were too numerous to count, multilayered, and extending to the periphery in all 11 patients. One patient did not have a dilated ophthalmic examination; however, traumatic retinoschisis and retinal hemorrhages were confirmed on autopsy. Ocular point-of-care ultrasonography is a promising tool to investigate abusive head trauma through the identification of traumatic retinoschisis and retinal hemorrhages when pupillary dilatation and direct ophthalmic examination is delayed. PMID- 26481266 TI - In vivo and in vitro analyses of alpha-galactosylceramide uptake by conventional dendritic cell subsets using its fluorescence-labeled derivative. AB - Conventional dendritic cells (cDCs) present alpha-galactosylceramide (alphaGC) to invariant natural killer T (iNKT) cells through CD1d. Among cDC subsets, CD8(+) DCs efficiently induce IFN-gamma production in iNKT cells. Using fluorescence labeled alphaGC, we showed that CD8(+) DCs incorporated larger amounts of alphaGC and kept it intact longer than CD8(-) DCs. Histological analyses revealed that Langerin(+)CD8(+) DCs in the splenic marginal zone, which was the unique equipment to capture blood-borne antigens, preferably incorporated alphaGC, and the depletion of Langerin(+) cells decreased IFN-gamma and IL-12 production in response to alphaGC. Furthermore, splenic Langerin(+)CD8(+) DCs expressed more membrane-bound CXCL16, which possibly anchored iNKT cells in the marginal zone, than CD8(-) DCs. Collectively, it is suggested that the cellular properties and localization of CD8(+) DCs are important for stimulation of iNKT cells by alphaGC. PMID- 26481267 TI - Cognitive Load in Mastoidectomy Skills Training: Virtual Reality Simulation and Traditional Dissection Compared. AB - OBJECTIVE: The cognitive load (CL) theoretical framework suggests that working memory is limited, which has implications for learning and skills acquisition. Complex learning situations such as surgical skills training can potentially induce a cognitive overload, inhibiting learning. This study aims to compare CL in traditional cadaveric dissection training and virtual reality (VR) simulation training of mastoidectomy. DESIGN: A prospective, crossover study. Participants performed cadaveric dissection before VR simulation of the procedure or vice versa. CL was estimated by secondary-task reaction time testing at baseline and during the procedure in both training modalities. SETTING: The national Danish temporal bone course. PARTICIPANTS: A total of 40 novice otorhinolaryngology residents. RESULTS: Reaction time was increased by 20% in VR simulation training and 55% in cadaveric dissection training of mastoidectomy compared with baseline measurements. Traditional dissection training increased CL significantly more than VR simulation training (p < 0.001). CONCLUSIONS: VR simulation training imposed a lower CL than traditional cadaveric dissection training of mastoidectomy. Learning complex surgical skills can be a challenge for the novice and mastoidectomy skills training could potentially be optimized by employing VR simulation training first because of the lower CL. Traditional dissection training could then be used to supplement skills training after basic competencies have been acquired in the VR simulation. PMID- 26481269 TI - Non-residents with unpaid NHS bills can be reported to Home Office, Court of Appeal rules. PMID- 26481268 TI - A Disease-Specific Hybrid Rotation Increases Opportunities for Deliberate Practice. AB - IMPORTANCE: Incorporating deliberate practice (DP) into residency curricula may optimize education. DP includes educationally protected time, continuous expert feedback, and a focus on a limited number of technical skills. It is strongly associated with mastery level learning. OBJECTIVE: Determine if a multidisciplinary breast rotation (MDB) increases DP opportunities. DESIGN: Beginning in 2010, interns completed the 4-week MDB. Three days a week were spent in surgery and surgical clinic. Half-days were in breast radiology, pathology, medical oncology, and didactics. The MDB was retrospectively compared with a traditional community rotation (TCR) and a university surgical oncology service (USOS) using rotation feedback and resident operative volume. Data are presented as mean +/- standard deviation. SETTING: Oregon Health and Science University in Portland, Oregon; an academic tertiary care general surgery residency program. PARTICIPANTS: General surgery residents at Oregon Health and Science University participating in either the MDB, TCR or USOS. RESULTS: A total of 31 interns rated the opportunity to perform procedures significantly higher for MDB than TCR or USOS (4.6 +/- 0.6 vs 4.2 +/- 0.9 and 4.1 +/- 1.0, p < 0.05). MDB was rated higher than TCR on quality of faculty teaching and educational materials (4.5 +/- 0.7 vs 4.1 +/- 0.9 and 4.0 +/- 1.2 vs 3.5 +/- 1.0, p < 0.05). Interns operated more on the MDB than on the USOS and were more focused on breast resections, lymph node dissections, and port placements than on the traditional surgical rotation or USOS. CONCLUSIONS: The MDB incorporates multidisciplinary care into a unique, disease-specific, and educationally focused rotation. It is highly rated and affords a greater opportunity for DP than either the USOS or TCR. DP is strongly associated with mastery learning and this novel rotation structure could maximize intern education in the era of limited work hours. PMID- 26481270 TI - Positive Youth Development and Contraceptive Use Consistency. AB - INTRODUCTION: Understanding protective factors associated with adolescent contraceptive use can guide strategies to prevent unprotected sex and its consequences. The current study investigated associations between a set of protective factors, specifically indicators of positive youth development, and consistency of contraceptive use. METHOD: This cross-sectional study examined relationships between positive youth development indicators and consistency of contraceptive use among sexually active adolescent girls at elevated risk for pregnancy. Multivariate models assessed whether measures of individual attributes, social attachments, and social norms were associated with consistent condom and hormonal contraceptive use. RESULTS: Adolescents with higher self esteem and greater family connectedness reported more consistent hormonal contraceptive use. Two factors, stress management skills and perceived peer prosocial norms, were protective for consistent condom use. In contrast, steady partnership status was associated with less consistent condom use. DISCUSSION: Findings suggest that interventions targeting protective factors may influence adolescents' contraceptive use, in addition to promoting their healthy development. PMID- 26481271 TI - Trichloroacetic acid treatment as a tricky way for rapid purification of 1N/4R tau protein. AB - Tau protein consists of six different isoforms and each one has particular physiological roles. In order to analyze the specific function of each single isoforms, large quantity of highly purified tau isoforms is essential. Many studies have been done to purify tau isoforms by heat treatment, followed by perchloric acid and glycerol precipitation. We found out that 1N/4R tau is soluble in glycerol, that is why mentioned methods do not work for purifying this isoform. In this study, large amounts of active and highly purified (97%) 1N/4R tau protein has been prepared by utilization of trichloroacetic acid as precipitating agent. PMID- 26481272 TI - Efficient expression and purification of biologically active human cystatin proteins. AB - Cystatins are reversible cysteine protease inhibitor proteins. They are known to play important roles in controlling cathepsins, neurodegenerative disease, and in immune system regulation. Production of recombinant cystatin proteins is important for biochemical and function characterization. In this study, we cloned and expressed human stefin A, stefin B and cystatin C in Escherichia coli. Human stefin A, stefin B and cystatin C were purified from soluble fraction. For cystatin C, we used various chaperone plasmids to make cystatin C soluble, as it is reported to localize in inclusion bodies. Trigger factor, GroES-GroEL, DnaK DnaJ-GrpE chaperones lead to the presence of cystatin C in the soluble fraction. Immobilized metal affinity chromatography, glutathione sepharose and anion exchange chromatography techniques were employed for efficient purification of these proteins. Their biological activities were tested by inhibition assays against cathepsin L and H3 protease. PMID- 26481273 TI - Expression and purification of histone H3 proteins containing multiple sites of lysine acetylation using nonsense suppression. AB - Lysine acetylation is a common post-translational modification, which is especially prevalent in histone proteins in chromatin. A number of strategies exist for generating histone proteins containing lysine acetylation, but an especially attractive approach is to genetically encode acetyl-lysine residues using nonsense suppression. This strategy has been successfully applied to single sites of histone acetylation. However, because histone acetylation can often occur at multiple sites simultaneously, we were interested in determining whether this approach could be extended. Here we show that we can express histone H3 proteins that incorporate up to four sites of lysine acetylation on the histone tail. Because the amount of expressed multi-acetylated histone is reduced relative to the wild type, a purification strategy involving affinity purification and ion exchange chromatography was optimized. This expression and purification strategy ultimately generates H3 histone uniformly acetylated at the desired position at levels and purity sufficient to assemble histone octamers. Histone octamers containing four sites of lysine acetylation were assembled into mononucleosomes and enzymatic assays confirmed that this acetylation largely blocks further acetylation by the yeast SAGA acetyltransferase complex. PMID- 26481274 TI - Epstein-Barr virus infection is equally distributed across the invasive ductal and invasive lobular forms of breast cancer. AB - The role of Epstein-Barr virus (EBV) in the pathogenesis of breast cancer is still unclear, although a growing body of evidence supports a link. The aim of this study was to investigate if EBV infection was more prevalent in invasive ductal carcinoma or invasive lobular carcinoma. An immunohistochemical marker for EBV (Epstein-Barr virus nuclear antigen 1 (EBNA1) clone E1-2.5) was applied to a tissue micro array section. The tissue micro array contained 80 cases of invasive ductal carcinoma, and 80 cases of invasive lobular carcinoma. Each case was scored as positive or negative for nuclear expression of EBNA1 in tumor cells using standard light microscopy. EBNA1 staining was evident in the tumor cells of 63 cases (39.4% of tumor cases). By tumor type (ductal/lobular) EBV infection was noted in 34 (42.5%) cases of invasive ductal carcinoma and 29 (36.2%) cases of invasive lobular carcinoma, this difference was not found to be significant (P=0.518). This study indicates that EBV infection is equally distributed across the ductal and lobular tumor types. PMID- 26481275 TI - Modelling characteristics to predict Legionella contamination risk - Surveillance of drinking water plumbing systems and identification of risk areas. AB - For the surveillance of drinking water plumbing systems (DWPS) and the identification of risk factors, there is a need for an early estimation of the risk of Legionella contamination within a building, using efficient and assessable parameters to estimate hazards and to prioritize risks. The precision, accuracy and effectiveness of ways of estimating the risk of higher Legionella numbers (temperature, stagnation, pipe materials, etc.) have only rarely been empirically assessed in practice, although there is a broad consensus about the impact of these risk factors. We collected n = 807 drinking water samples from 9 buildings which had had Legionella spp. occurrences of >100 CFU/100mL within the last 12 months, and tested for Legionella spp., L. pneumophila, HPC 20 degrees C and 36 degrees C (culture-based). Each building was sampled for 6 months under standard operating conditions in the DWPS. We discovered high variability (up to 4 log(10) steps) in the presence of Legionella spp. (CFU/100 mL) within all buildings over a half year period as well as over the course of a day. Occurrences were significantly correlated with temperature, pipe length measures, and stagnation. Logistic regression modelling revealed three parameters (temperature after flushing until no significant changes in temperatures can be obtained, stagnation (low withdrawal, qualitatively assessed), pipe length proportion) to be the best predictors of Legionella contamination (>100 CFU/100 mL) at single outlets (precision = 66.7%; accuracy = 72.1%; F(0.5) score = 0.59). PMID- 26481276 TI - Optimising the diagnosis of narcolepsy: looking deeper into sleep studies. PMID- 26481277 TI - Differentially expressed microRNAs in kidney biopsies from various subtypes of nephrotic children. AB - BACKGROUND: Our previous study showed a set of increased miRNAs in serum or urine from nephrotic syndrome children. In this study, we investigated the renal expression of these miRNAs in nephrotic children and explored their role in pathogenesis and as potential indicators to differentiate subtypes of kidney diseases. METHODS: We enrolled 52 children with six different subtypes of nephropathy, and 8 normal kidney tissues were used as controls. RT-qPCR was used to quantify the expression of miR-191, miR-151-3p, miR-150, miR-30a-5p and miR 19b in renal tissues. RESULTS: miR-191 and miR-151-3p exhibited significantly higher and lower intrarenal expression in all six subtypes of kidney diseases compared to controls. miR-19b was upregulated in three subtypes, and miR-30a-5p and miR-150 were downregulated in two and four subtypes, respectively. The intrarenal expression of miR-150 was significantly different between minimal change disease (MCD) and some other subtypes. The renal levels of these miRNAs correlated significantly with some renal functions and immune parameters. Bioinformatics showed that some target genes of these miRNAs were associated with immune and renal pathological changes. CONCLUSIONS: These five miRNAs may be involved in the pathogenesis of nephropathy in children. miR-150 is a potential typing indictor to differentiate MCD from other nephropathy subtypes. PMID- 26481279 TI - Pulmonary vein stenosis: Severity and location predict survival after surgical repair. AB - OBJECTIVES: Pulmonary vein characteristics that influence survival after repair of stenosis have not been defined. We sought to develop a predictive model relating postrepair survival to preoperative pulmonary vein characteristics on computed tomography and magnetic resonance imaging. METHODS: Patients who underwent pulmonary vein stenosis repair (1990-2012) with preoperative computed tomography and magnetic resonance imaging were reviewed. We measured pulmonary vein short and long cross-sectional diameters at the left atrial junction (downstream), vein bifurcation (upstream), and narrowest point, and calculated the total cross-sectional area indexed for body surface area. The relationship between pulmonary vein dimensions and survival was related via risk-adjusted parametric hazard analyses. RESULTS: Of 145 patients who underwent surgical repair, 31 had preoperative computed tomography and magnetic resonance imaging and were analyzed. Surgical repairs were sutureless (n = 30) or pericardial patch reconstruction (n = 1). Mean follow-up was 4.28 +/- 4.2 years. In-hospital mortality was 9.7%; unadjusted survival was 75% +/- 7%, 69% +/- 8%, and 64% +/- 7% at 1, 3, and 5 years, respectively. Median downstream total cross-sectional area indexed for body surface area was 163 mm(2)/m(2), upstream total cross sectional area indexed for body surface area was 263 mm(2)/m(2), and total cross sectional area indexed for body surface area at maximal stenosis, localized at the left atrial junction in approximately two thirds of patients, was 163 mm(2)/m(2). Smaller upstream total cross-sectional area indexed for body surface area (P = .030) and greater number of stenotic pulmonary veins (P = .0069) were associated with increased early (<1 year) risk of death. Smaller downstream total cross-sectional area indexed for body surface area tended to be associated with a late risk of death (P = .059). CONCLUSIONS: Smaller upstream or downstream total cross-sectional area indexed for body surface area negatively influenced survival. Early survival seemed especially poor for patients with a greater number of stenotic veins and upstream pulmonary vein involvement. The total cross sectional area indexed for body surface area measurements can help to inform prognosis and stratify patients for enrollment in clinical trials of agents directed at pulmonary vein pathology. PMID- 26481280 TI - Septal myectomy for patients with hypertrophic cardiomyopathy: A new paradigm. PMID- 26481278 TI - Rapamycin prevents bronchiolitis obliterans through increasing infiltration of regulatory B cells in a murine tracheal transplantation model. AB - OBJECTIVE: B lymphocytes are generally considered to be activators of the immune response; however, recent findings have shown that a subtype of B lymphocytes, regulatory B lymphocytes, play a role in attenuating the immune response. Bronchiolitis obliterans remains the major limitation to modern-day lung transplantation. The role of regulatory B lymphocytes in bronchiolitis obliterans has not been elucidated. We hypothesized that regulatory B lymphocytes play a role in the attenuation of bronchiolitis obliterans. METHODS: We performed a standard heterotopic tracheal transplant model. Tracheas from Balb/c mice were transplanted into C57BL/6 recipients. Rapamycin treatment and dimethyl sulfoxide control groups were each treated for the first 14 days after the transplant. Tracheas were collected on days 7, 14, and 28 post-transplantation. Luminal obliteration was evaluated by hematoxylin-eosin staining and Picrosirius red staining. Immune cell infiltration and characteristics, and secretion of interleukin-10 and transforming growth factor-beta1 were accessed by immunohistochemistry. Cytokines and transforming growth factor-beta1 were measured using the Luminex assay (Bio-Rad, Hercules, Calif). RESULTS: The results revealed that intraperitoneal injection of rapamycin for 14 days after tracheal transplantation significantly reduced luminal obliteration on day 28 when compared with the dimethyl sulfoxide control group (97.78% +/- 3.63% vs 3.02% +/- 2.14%, P < .001). Rapamycin treatment markedly induced regulatory B lymphocytes (B220(+)IgM(+)IgG(-)IL-10(+)TGF-beta1(+)) cells when compared with dimethyl sulfoxide controls. Rapamycin treatment inhibited interleukin-1beta, 6, 13, and 17 on days 7 and 14. Rapamycin also greatly increased interleukin-10 and transforming growth factor-beta1 production in B cells and regulatory T lymphocytes infiltration on day 28. CONCLUSIONS: Mammalian target of rapamycin inhibition decreases the development of bronchiolitis obliterans via inhibition of proinflammatory cytokines and increasing regulatory B lymphocytes cell infiltration, which subsequently produces anti-inflammatory cytokines and upregulates regulatory T lymphocyte cells. PMID- 26481281 TI - Discussion. PMID- 26481282 TI - Toll-like receptor 4 inhibition attenuates ischemia-reperfusion injury in rats: Will it work in human beings? PMID- 26481283 TI - Discussion. PMID- 26481284 TI - Primary Prevention of Sudden Death in Patients With Valvular Cardiomyopathy. AB - INTRODUCTION AND OBJECTIVES: Few data exist on the outcomes of valvular cardiomyopathy patients referred for defibrillator implantation for primary prevention. The aim of the present study was to describe the outcomes of this cardiomyopathy subgroup. METHODS: This multicenter retrospective study included consecutive patients referred for defibrillator implantation to 15 Spanish centers in 2010 and 2011, and to 3 centers after 1 January 2008. RESULTS: Of 1174 patients, 73 (6.2%) had valvular cardiomyopathy. These patients had worse functional class, wider QRS, and a history of atrial fibrillation vs patients with ischemic (n=659; 56.1%) or dilated (n=442; 37.6%) cardiomyopathy. During a follow-up of 38.1 +/- 21.3 months, 197 patients (16.7%) died, without significant differences among the groups (19.2% in the valvular cardiomyopathy group, 15.8% in the ischemic cardiomyopathy group, and 17.9% in the dilated cardiomyopathy group; P=.2); 136 died of cardiovascular causes (11.6%), without significant differences among the groups (12.3%, 10.5%, and 13.1%, respectively; P=.1). Although there were no differences in the proportion of appropriate defibrillator interventions (13.7%, 17.9%, and 18.8%; P=.4), there was a difference in inappropriate interventions (8.2%, 7.1%, and 12.0%, respectively; P=.03). CONCLUSIONS: All-cause and cardiovascular mortality in patients with valvular cardiomyopathy were similar to those in other patients referred for defibrillator implantation. They also had similar rates of appropriate interventions. These data suggest that defibrillator implantation in this patient group confers a similar benefit to that obtained by patients with ischemic or dilated cardiomyopathy. PMID- 26481285 TI - Culture-negative Endocarditis: Mycoplasma hominis Infection. PMID- 26481286 TI - The Descending Septal Artery: Description of This Infrequent Coronary Anatomical Variant in Three Different Clinical Scenarios. PMID- 26481287 TI - Broad-band UVB versus paint PUVA for palmoplantar psoriasis treatment. AB - BACKGROUND: Plaque-type palmoplantar psoriasis (PPTP) is a chronic recalcitrant dermatosis with treatment modalities ranging through topical, phototherapy or systemic. Phototherapy options include various forms of ultraviolet B (UVB) and ultraviolet A with prior psoralen sensitization (PUVA). Currently, few comparative studies have been reported. PURPOSE: To compare Broad-Band UVB (BB UVB) versus paint PUVA (p-PUVA) in regard to efficacy and safety in the treatment of PPTP. METHODS: A retrospective non-randomized cohort study comprised of all the patients with PPTP treated in our phototherapy centre during 2010-2012, either with BB-UVB or p-PUVA. RESULTS: Among the 248 patients included in this study, 122 received BB-UVB and 126 followed p-PUVA treatment. About 36 (30%) and 53 (42%) had complete remission, 29 (24%) and 59 (47%) responded partially and 57 (47%) and 14 (11%) patients did not improve with BB-UVB and p-PUVA, respectively. The odds ratio for remission (p-PUVA: BB-UVB) was 7.9. Duration of remission was 21.9 +/- 1.34 months for p-PUVA and 16.75 +/- 1.83 months for BB-UVB. CONCLUSION: Both BB-UVB and p-PUVA are good therapeutic options for PPTP. P-PUVA emerges as the superior treatment modality, yielding a better and more extended response. BB UVB represents a feasible alternative in patients with milder disease or possible contraindications for p-PUVA. PMID- 26481288 TI - Electromyographic, mechanomyographic, and metabolic responses during cycle ergometry at a constant rating of perceived exertion. AB - Ten subjects performed four 8-min rides (65%-80% peak oxygen consumption) to determine the physical working capacity at the OMNI rating of perceived exertion (RPE) threshold (PWCOMNI). Polynomial regression analyses were used to examine the patterns of responses for surface electromyographic (EMG) amplitude (EMG AMP), EMG mean power frequency (EMG MPF), mechanomyographic (MMG) AMP, and MMG MPF of the vastus lateralis as well as oxygen consumption rate, respiratory exchange ratio (RER), and power output (PO) were examined during a 1-h ride on a cycle ergometer at a constant RPE that corresponded to the PWCOMNI. EMG AMP and MMG MPF tracked the decreases in oxygen consumption rate, RER, and PO, while EMG MPF and MMG AMP tracked RPE. The decreases in EMG AMP and MMG MPF were likely attributable to decreases in motor unit (MU) recruitment and firing rate, while the lack of change in MMG AMP may have resulted from a balance between MU de recruitment as PO decreased, and an increase in the ability of activated fibers to oscillate. The current findings suggested that during submaximal cycle ergometry at a constant RPE, MU de-recruitment and mechanical changes within the muscle may influence the perception of effort via feedback from group III and IV afferents. PMID- 26481289 TI - Muscle sympathetic activity in resting and exercising humans with and without heart failure. AB - The sympathetic nervous system is critical for coordinating the cardiovascular response to various types of physical exercise. In a number of disease states, including human heart failure with reduced ejection fraction (HFrEF), this regulation can be disturbed and adversely affect outcome. The purpose of this review is to describe sympathetic activity at rest and during exercise in both healthy humans and those with HFrEF and outline factors, which influence these responses. We focus predominately on studies that report direct measurements of efferent sympathetic nerve traffic to skeletal muscle (muscle sympathetic nerve activity; MSNA) using intraneural microneurographic recordings. Differences in MSNA discharge between subjects with and without HFrEF both at rest and during exercise and the influence of exercise training on the sympathetic response to exercise will be discussed. In contrast to healthy controls, MSNA increases during mild to moderate dynamic exercise in the presence of HFrEF. This increase may contribute to the exercise intolerance characteristic of HFrEF by limiting muscle blood flow and may be attenuated by exercise training. Future investigations are needed to clarify the neural afferent mechanisms that contribute to efferent sympathetic activation at rest and during exercise in HFrEF. PMID- 26481290 TI - How to Regenerate and Protect Desert Riparian Populus euphratica Forest in Arid Areas. AB - We found that the most suitable flooding disturbance model for regenerating Populus euphratica forest was two to three times per year with a duration of 15 20 days and an intensity of 25-30 m(3)/s. The flooding should take place during the seed emergence to young tree growth stages, and should be based on flooding experiments and data from vegetation quadrats and ecological water conveyance. Furthermore, we found that tree-ring width index for P. euphratica declined as the groundwater depth increased, and ascertained that the minimum groundwater depths for young trees, near-mature trees, mature trees and over-mature trees were 4.0 m, 5.0-5.4 m, 6.9 m and 7.8 m, respectively. These were derived from a quantitative relationship model between groundwater depth and tree-ring width index. The range for ecological water conveyance volume was 311-320 million m(3) in the lower reaches of the Tarim River. This study not only provides a technical basis for sustainable ecological water conveyance in the Tarim River Basin, but also offers a theoretical guide and scientific information that could be used in similar areas to regenerate and protect Populus euphratica around the world. PMID- 26481291 TI - Tissue engineering of nanosilver-embedded peripheral nerve scaffold to repair nerve defects under contamination conditions. AB - INTRODUCTION: We employed a nanosilver-collagen scaffold and tested its effects on inhibiting bacteria and facilitating nerve regeneration. METHODS: Based on our previous research, we prepared bionic scaffolds with different concentrations of nanosilver and examined their internal structures by scanning electron microscopy and energy dispersive spectroscopy. We implanted these scaffolds or autologous nerve grafts into rats to repair a 10-mm injury of the sciatic nerve. RESULTS: The 2 mg/ml group showed a >10 mm bacterial inhibition zone in all 3 types of bacterial culture dishes. At day 60 postsurgery, the 2 mg/ml group also showed the highest amplitude of evoked potential (AMP) and nerve conduction velocity (NCV). The regenerating nerves in the 2 mg/ml group were denser and more mature, and with thicker and well-arrayed myelin sheath. CONCLUSIONS: These results demonstrate that nanosilver scaffolds (2 mg/ml group) were effective in inhibiting bacteria both in vitro and in vivo, and reduced the contamination caused immune responses, which in turn promoted nerve regeneration and functional recovery. PMID- 26481292 TI - Injury-induced inflammation and inadequate HSP expression in mesothelial cells upon repeat exposure to dual-chamber bag peritoneal dialysis fluids. AB - PURPOSE: Peritoneal dialysis fluids (PDFs) may induce inadequate heat-shock protein (HSP) expression and injury-related inflammation in exposed mesothelial cells. The aim of this study was to relate cellular injury to these cellular responses in mesothelial cells following repeated exposure to 3 commercial PDFs with different biocompatibility profiles. METHODS: Primary cultures of human peritoneal mesothelial cells (HPMC) were exposed to a 1:2 mixture of cell culture medium and CAPD2 (single-chamber bag PDF; Fresenius, Bad Homburg, Germany), Physioneal (dual-chamber bag PDF; Baxter, Deerfield, IL, USA) or Balance (dual chamber bag PDF, Fresenius) for up to 10 days exposure time (4 dwells). Supernatant was analyzed for LDH, IL-6, and IL-8, cells for HSP-72 expression, and protein content. RESULTS: PDF exposure resulted in a biphasic pattern of cell damage switching from an earlier phase with increased injury by single-chamber PDF to a delayed phase with increased susceptibility to dual-chamber PDF. Sterile inflammation was related to LDH release over time and could be reproduced by exposure to necrotic cellular material. PDF exposure resulted in low HSP-72 expression in all tested PDFs. CONCLUSIONS: Exposure to single-chamber as well as to dual-chamber bag PDFs induce increased vulnerability of mesothelial cells to repeated exposure of the same solution. These effects were delayed with dual chamber PDFs. Injury-induced inflammation and impaired HSP expression upon PDF exposure might initiate a vicious cycle with progredient mesothelial cell damage upon repeated PDF exposure. Certainly, interventional studies and translation of these results into the in vivo system is needed. PMID- 26481293 TI - Comparing changes in plasma and skin autofluorescence in low-flux versus high flux hemodialysis. AB - BACKGROUND: Tissue advanced glycation end products (AGE) are increased in hemodialysis (HD) patients, especially those with cardiovascular complications. Skin autofluorescence (skin-AF) can noninvasively estimate the accumulation of AGE in tissue. The aim was to clarify whether HD using a high-flux (HF) dialyzer favors plasma-or skin-AF removal compared to low-flux (LF) dialysis. MATERIAL AND METHODS: 28 patients were treated with either an HF-HD or LF-HD but otherwise unchanged conditions in a cross-over design. A glucose containing dialysate was used. Skin-AF was measured noninvasively with an AGE reader before and after HD. Fluorescence (370 nm/465 nm) of plasma (p-AF) was determined as total and nonprotein-bound fractions. Correction for hemoconcentrations were made using the change in serum albumin.Paired and nonpaired statistical analyses were used. RESULTS: Skin-AF was unchanged after LF- and HF-dialysis. Total, free, and protein- bound p-AF was reduced after a single LF-HD by 21%, 28%, and 17%, respectively (P<.001). After HF HD total and free p-AF was reduced by 5% and 15%, respectively (P<.001), while protein bound values were unchanged. The LF-HD resulted in a more pronounced reduction of p-AF than did HF HD (P<.001). Serum albumin correlated inversely with p-AF in HF-HD. CONCLUSIONS: In the dialysis settings used there was no significant change in skin AF after dialysis, with LF or with HF dialysis. Although only limited reduction in plasma fluorescence was observed, this was more pronounced when performing LF dialysis. These data are not in overwhelming support of the use of HF dialysis in the setting used in this study. PMID- 26481294 TI - Protein array identification of protein markers for serodiagnosis of Mycobacterium tuberculosis infection. AB - The lack of effective and accurate diagnostic tools contributes to the high prevalence of tuberculosis (TB) worldwide. The current serodiagnostics for TB are inadequate mainly due to lack of TB-specific antigens with highly accurate diagnosis. In the current study, we aimed to identify novel diagnostic antigens using glutathione S-transferase (GST)-fusion protein technique. We determined the reactivity of these recombinant proteins arrayed in solution and on GSH immobilized microplates with TB patient sera. Of 409 TB proteins produced, ninety two yielded seropositive reactions, fourteen including eight novel proteins showed strong immunoreactivity. Further, six were selected and constructed as a multiple-antigen combination set through analysis of various combinations. A comparative study of the multiple-antigen combination set and a commercially available kit revealed that the combination set showed 66.3% (95% CI 60.5-71.8) sensitivity, which was significantly higher than that of the commercial kit [31.6% (95% CI 26.3-37.3)]. The specificity of both methods was similar at 89.6% (95% CI 83.3-95.4) and 90.6% (95% CI 83.0-95.6), respectively. This study provides a set of novel diagnostic protein markers with great potential for the development of novel diagnostic tools for active TB. PMID- 26481295 TI - Risk indicators for tooth loss in Kiriri Adult Indians: a cross-sectional study. AB - BACKGROUND: The aim of this cross-sectional study was to evaluate the risk indicators of tooth loss in adult Kiriri Indians from Brazil. METHODS: A representative sample of 225 Indians (>= 19 years of age) was assessed. Interviews using a structured written questionnaire were performed to collect data on demographics and socio-economic status, and health-related data. Probing depth, the distance between the cement-enamel junction and the free gingival margin, and decayed, missing or filled teeth were evaluated. Bivariate and logistic models were used to assess associations between tooth loss and age, sex, income, education, diabetic status, smoking habits, dental caries, severe periodontitis, plaque index and previous dental visit. RESULTS: Eighty per cent of subjects had lost one tooth or more, and 20% had lost eight teeth or more. Mean (+/- standard deviation) tooth loss was 5.09 (+/- 5.83) teeth. After adjustment for covariates, loss of one tooth or more was associated with older age [>= 35 years; odds ratio (OR) = 4.06, 95% confidence interval (95% CI): 1.38 11.94, P = 0.01], severe periodontitis (OR = 3.35, 95% CI: 0.99-11.24, P = 0.05), higher dental caries (OR = 3.24, 95% CI: 1.35-7.78, P = 0.01) and previous dental visit (OR = 23.32, 95% CI: 5.75-94.63, P < 0.001). CONCLUSION: Tooth loss is highly prevalent in Kiriri Indians. Older age, severe periodontitis, higher caries index and previous dental visit were associated with tooth loss. Prevention and treatment programmes, targeting high-risk groups, are required to promote the oral health of the population. PMID- 26481296 TI - Brain health and shared risk factors for dementia and stroke. AB - Impaired brain health encompasses a range of clinical outcomes, including stroke, dementia, vascular cognitive impairment, cognitive ageing, and vascular functional impairment. Conditions associated with poor brain health represent leading causes of global morbidity and mortality, with projected increases in public health burden as the population ages. Many vascular risk factors are shared predictors for poor brain health. Moreover, subclinical brain MRI markers of vascular damage are risk factors shared between stroke and dementia, and can be used for risk stratification and early intervention. The broad concept of brain health has resulted in a conceptual shift from vascular risk factors to determinants of brain health. Global campaigns to reduce cardiovascular diseases by targeting modifiable risk factors are necessary and will have a broad impact on brain health. Research is needed on the distinct and overlapping aetiologies of brain health conditions, and to define MRI markers to help clinicians identify patients who will benefit from aggressive prevention measures. PMID- 26481297 TI - Motor neuron disease: Human endogenous retrovirus-K activation is implicated in amyotrophic lateral sclerosis. PMID- 26481298 TI - Decade in review-stroke: progress in acute ischaemic stroke treatment and prevention. PMID- 26481299 TI - Increased levels of IL-17 in tear fluid of moderate-to-severe psoriatic patients is reduced by adalimumab therapy. PMID- 26481301 TI - Site-Specific Zwitterionic Polymer Conjugates of a Protein Have Long Plasma Circulation. AB - Many proteins suffer from suboptimal pharmacokinetics (PK) that limit their utility as drugs. The efficient synthesis of polymer conjugates of protein drugs with tunable PK to optimize their in vivo efficacy is hence critical. We report here the first study of the in vivo behavior of a site-specific conjugate of a zwitterionic polymer and a protein. To synthesize the conjugate, we first installed an initiator for atom-transfer radical polymerization (ATRP) at the N terminus of myoglobin (Mb-N-Br). Subsequently, in situ ATRP was carried out in aqueous buffer to grow an amine-functionalized polymer from Mb-N-Br. The cationic polymer was further derivatized to two zwitterionic polymers by treating the amine groups of the cationic polymer with iodoacetic acid to obtain poly(carboxybetaine methacrylate) with a one-carbon spacer (PCBMA; C1 ), and sequentially with 3-iodopropionic acid and iodoacetic acid to obtain PCBMA(mix) with a mixture of C1 and C2 spacers. The Mb-N-PCBMA polymer conjugates had a longer in vivo plasma half-life than a PEG-like comb polymer conjugate of similar molecular weights (MW). The structure of the zwitterion plays a role in controlling the in vivo behavior of the conjugate, as the PCBMA conjugate with a C1 spacer had significantly longer plasma circulation than the conjugate with a mixture of C1 and C2 spacers. PMID- 26481302 TI - Sirt6 depletion causes spindle defects and chromosome misalignment during meiosis of mouse oocyte. AB - Sirt6, a member of the sirtuin family of NAD-dependent protein deacetylases, has been implicated in multiple biological processes. However, the roles of Sirt6 in meiosis have not been addressed. In the present study, by employing knockdown analysis in mouse oocytes, we evaluated the effects of Sirt6 on meiotic apparatus. We found that specific depletion of Sirt6 results in disruption of spindle morphology and chromosome alignment in oocytes. Consistent with this observation, incidence of aneuploidy is also markedly increased in Sirt6-depleted oocytes. Furthermore, confocal scanning showed that kinetochore-microtubule interaction, an important mechanism controlling chromosome segregation, is severely impaired in metaphase oocytes following Sirt6 knockdown. Unexpectedly, we discovered that Sirt6 modulates the acetylation status of histone H4K16 as their knockdown specifically induces the hyperacetylation of H4K16 in oocytes, which may be associated with the defective phenotypes described above via altering kinetochore function. Altogether, our data reveal a novel function of Sirt6 during oocyte meiosis and indicate a pathway regulating meiotic apparatus. PMID- 26481303 TI - Evaluation of guideline-adherent treatment in cluster headache. AB - BACKGROUND: Several treatment guidelines exist for cluster headache. However, it is not yet known how many cluster headache patients are treated according to these guidelines. METHODS: We enrolled 434 cluster headache patients with confirmed diagnosis referred to two tertiary pain centers. The history of treatment was registered and analyzed according to the treatment guidelines of the European Federation of Neurological Societies. RESULTS: Regarding acute attack treatment, 62.1% of the episodic and 71.0% of the chronic cluster headache patients were treated according to the guidelines. The efficacy rate was above 92% in both groups. Regarding prophylactic treatment, 31.3% of the episodic and 50.9% of the chronic cluster headache patients were treated according to the guidelines. The efficacy rate was 92.8% for episodic and 70.9% for chronic cluster headache. CONCLUSION: The rate of guideline-adherent treatment in cluster headache is about 70% for acute treatment and about 35% for prophylactic treatment. The efficacy of this treatment is significantly higher than the efficacy of non-guideline-adherent treatment. PMID- 26481304 TI - Trigeminal neuralgia (part I): Revisiting the clinical phenotype. AB - AIMS: We conducted a cross-sectional study to re-examine the clinical profile of patients with a clinical diagnosis of classical trigeminal neuralgia (CTN). METHODS: Inclusion criteria consisted of the International Headache Society's published classification of CTN. For the specific purposes of the study, features such as autonomic signs, persistent background pain, attack durations of >2 minutes and reports of pain-related awakening were included. The demographic and clinical phenotype of each patient were carefully recorded for analysis. RESULTS: The study cohort consisted of 81 patients and based on reported attack duration these were divided into short (<= 2 minutes, n = 61) and long (> 2 minutes, n = 20) groups for further analysis. The group with short attack duration neatly fit most of the criteria for CTN while the long attack group presents a more challenging diagnosis. There were no significant differences in pain severity, quality and location between the short and long attack groups. The frequency of persistent background pain was significantly higher in the long (70%) compared to the short attack group (29.5%, p = 0.001). There were significantly more reports of pain-related awakenings in the long (55%) than in the short attack groups (29.5%, p = 0.04). There were no significant differences in the frequency of autonomic signs between the short (21.3%) and long attack groups (40%, p = 0.1). In the short attack group, the presence of autonomic signs was significantly associated with longer disease duration, increased pain-related awakenings, and a reduced prognosis. CONCLUSION: There are clear diagnostic criteria for CTN but often patients present with features, such as long pain attacks, that challenge such accepted criteria. In our cohort the clinical phenotype of trigeminal, neuralgiform pain with or without autonomic signs and background pain was observed across both short and long attack groups and the clinical implications of this are discussed. PMID- 26481305 TI - The Multivalent Adhesion Molecule SSO1327 plays a key role in Shigella sonnei pathogenesis. AB - Shigella sonnei is a bacterial pathogen and causative agent of bacillary dysentery. It deploys a type III secretion system to inject effector proteins into host epithelial cells and macrophages, an essential step for tissue invasion and immune evasion. Although the arsenal of bacterial effectors and their cellular targets have been studied extensively, little is known about the prerequisites for deployment of type III secreted proteins during infection. Here, we describe a novel S. sonnei adhesin, SSO1327 which is a multivalent adhesion molecule (MAM) required for invasion of epithelial cells and macrophages and for infection in vivo. The S. sonnei MAM mediates intimate attachment to host cells, which is required for efficient translocation of type III effectors into host cells. SSO1327 is non-redundant to IcsA; its activity is independent of type III secretion. In contrast to the up-regulation of IcsA-dependent and independent attachment and invasion by deoxycholate in Shigella flexneri, deoxycholate negatively regulates IcsA and MAM in S. sonnei resulting in reduction in attachment and invasion and virulence attenuation in vivo. A strain deficient for SSO1327 is avirulent in vivo, but still elicits a host immune response. PMID- 26481306 TI - Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle. AB - Skeletal muscle mitochondrial content and oxidative capacity are important determinants of muscle function and whole-body health. Mitochondrial content and function are enhanced by endurance exercise and impaired in states or diseases where muscle function is compromised, such as myopathies, muscular dystrophies, neuromuscular diseases, and age-related muscle atrophy. Hence, elucidating the mechanisms that control muscle mitochondrial content and oxidative function can provide new insights into states and diseases that affect muscle health. In past studies, we identified Perm1 (PPARGC1- and ESRR-induced regulator, muscle 1) as a gene induced by endurance exercise in skeletal muscle, and regulating mitochondrial oxidative function in cultured myotubes. The capacity of Perm1 to regulate muscle mitochondrial content and function in vivo is not yet known. In this study, we use adeno-associated viral (AAV) vectors to increase Perm1 expression in skeletal muscles of 4-wk-old mice. Compared to control vector, AAV1 Perm1 leads to significant increases in mitochondrial content and oxidative capacity (by 40-80%). Moreover, AAV1-Perm1-transduced muscles show increased capillary density and resistance to fatigue (by 33 and 31%, respectively), without prominent changes in fiber-type composition. These findings suggest that Perm1 selectively regulates mitochondrial biogenesis and oxidative function, and implicate Perm1 in muscle adaptations that also occur in response to endurance exercise. PMID- 26481307 TI - An agonist antibody that blocks autoimmunity by inducing anti-inflammatory macrophages. AB - We have devised a method of using intracellular combinatorial libraries to select antibodies that control cell fates. Many agonist antibodies have been selected with this method, and the process appears to be limited only by the availability of a phenotypic selection system. We demonstrate the utility of this approach to discover agonist antibodies that engage an unanticipated target and regulate macrophage polarization by selective induction of anti-inflammatory M2 macrophages. This antibody was used therapeutically to block autoimmunity in a classic mouse model of spontaneous systemic lupus erythematosus. PMID- 26481308 TI - Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions. AB - Autonomic dysfunction is a characteristic of cardiac disease and decreased vagal activity is observed in heart failure. Rodent cardiomyocytes produce de novo ACh, which is critical in maintaining cardiac homeostasis. We report that this nonneuronal cholinergic system is also found in human cardiomyocytes, which expressed choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT). Furthermore, VAChT expression was increased 3- and 1.5-fold at the mRNA and protein level, respectively, in ventricular tissue from patients with heart failure, suggesting increased ACh secretion in disease. We used mice with genetic deletion of cardiomyocyte-specific VAChT or ChAT and mice overexpressing VAChT to test the functional significance of cholinergic signaling. Mice deficient for VAChT displayed an 8% decrease in fractional shortening and 13% decrease in ejection fraction compared with angiotensin II (Ang II)-treated control animals, suggesting enhanced ventricular dysfunction and pathologic remodeling in response to Ang II. Similar results were observed in ChAT-deficient mice. Conversely, no decline in ventricular function was observed in Ang II-treated VAChT overexpressors. Furthermore, the fibrotic area was significantly greater (P < 0.05) in Ang II-treated VAChT-deficient mice (3.61 +/- 0.64%) compared with wild-type animals (2.24 +/- 0.11%). In contrast, VAChT overexpressing mice did not display an increase in collagen deposition. Our results provide new insight into cholinergic regulation of cardiac function, suggesting that a compensatory increase in cardiomyocyte VAChT levels may help offset cardiac remodeling in heart failure. PMID- 26481309 TI - Survival protein anoctamin-6 controls multiple platelet responses including phospholipid scrambling, swelling, and protein cleavage. AB - Scott syndrome is a rare bleeding disorder, characterized by altered Ca(2+) dependent platelet signaling with defective phosphatidylserine (PS) exposure and microparticle formation, and is linked to mutations in the ANO6 gene, encoding anoctamin (Ano)6. We investigated how the complex platelet phenotype of this syndrome is linked to defective expression of Anos or other ion channels. Mice were generated with heterozygous of homozygous deficiency in Ano6, Ano1, or Ca(2+)-dependent KCa3.1 Gardos channel. Platelets from these mice were extensively analyzed on molecular functions and compared with platelets from a patient with Scott syndrome. Deficiency in Ano1 or Gardos channel did not reduce platelet responses compared with control mice (P > 0.1). In 2 mouse strains, deficiency in Ano6 resulted in reduced viability with increased bleeding time to 28.6 min (control 6.4 min, P < 0.05). Platelets from the surviving Ano6-deficient mice resembled platelets from patients with Scott syndrome in: 1) normal collagen induced aggregate formation (P > 0.05) with reduced PS exposure (-65 to 90%); 2) lowered Ca(2+)-dependent swelling (-80%) and membrane blebbing (-90%); 3) reduced calpain-dependent protein cleavage (-60%); and 4) moderately affected apoptosis dependent PS exposure. In conclusion, mouse deficiency of Ano6 but not of other channels affects viability and phenocopies the complex changes in platelets from hemostatically impaired patients with Scott syndrome. PMID- 26481310 TI - DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH. AB - Bone minerals are acquired during growth and are key determinants of adult skeletal health. During puberty, the serum levels of growth hormone (GH) and its downstream effector IGF-1 increase and play critical roles in bone acquisition. The goal of the current study was to determine how bone cells integrate signals from the GH/IGF-1 to enhance skeletal mineralization and strength during pubertal growth. Osteocytes, the most abundant bone cells, were shown to orchestrate bone modeling during growth. We used dentin matrix protein (Dmp)-1-mediated Ghr knockout (DMP-GHRKO) mice to address the role of the GH/IGF axis in osteocytes. We found that DMP-GHRKO did not affect linear growth but compromised overall bone accrual. DMP-GHRKO mice exhibited reduced serum inorganic phosphate and parathyroid hormone (PTH) levels and decreased bone formation indices and were associated with an impaired response to intermittent PTH treatment. Using an osteocyte-like cell line along with in vivo studies, we found that PTH sensitized the response of bone to GH by increasing Janus kinase-2 and IGF-1R protein levels. We concluded that endogenously secreted PTH and GHR signaling in bone are necessary to establish radial bone growth and optimize mineral acquisition during growth. PMID- 26481311 TI - Galectin-4 interacts with the drug transporter human concentrative nucleoside transporter 3 to regulate its function. AB - The intracellular N-terminal domain of the nucleoside and drug transporter human concentrative nucleoside transporter (hCNT)3 was used as bait in a glutathione S transferase pull-down approach, to identify hCNT3 protein partners, using human colon homogenates as a prey source. Galectin (Gal)-4 was identified as a potential hCNT3 partner in the colon. The biochemical validation of the Gal-4 hCNT3 interaction was verified by targeted pull-down assays and coimmunoprecipitation experiments in HT-29 cells, which endogenously express hCNT3 and Gal-4. Furthermore, Gal-4 was shown to colocalize with hCNT3 in HT-29 cells. The biologic significance of this interaction was obtained from experiments in which Gal-4 was knocked down, showing that this protein is a regulator of hCNT3 trafficking and retention at the cell membrane, reducing its plasma membrane location by 70%. Conversely, the addition of Gal-4 increased hCNT3 location at the plasma membrane by 77%, thereby demonstrating that this lectin modulates hCNT3 function in colonic cells. The integrity of this partnership may be clinically relevant, because hCNT3 may be responsible for the translocation of thiopurines, such as 6-mercaptopurine, a front-line treatment in inflammatory bowel disease. The expression of Gal-4 and hCNT3 proteins is not impaired in inflamed colon from patients with Crohn's disease, thereby anticipating the integrity of this system for drug targeting. PMID- 26481312 TI - Inclusion of gametocyte parameters in anti-malarial drug efficacy studies: filling a neglected gap needed for malaria elimination. AB - Standard anti-malarial drug efficacy and drug resistance assessments neglect the gametocyte parameters in their protocols. With the spread of drug resistance and the absence of clinically proven vaccines, the use of gametocytocidal drugs or drug combinations with transmission-blocking activity is a high priority for malaria control and elimination. However, the limited repertoire of gametocytocidal drugs and induction of gametocytogenesis after treatment with certain anti-malarial drugs necessitate both regular monitoring of gametocytocidal activities of anti-malarial drugs in clinical use and the effectiveness of candidate gametocytocidal agents. Therefore, updating current protocols of anti-malarial drug efficacy is needed to reflect the effects of anti malarial drugs or drug combinations on gametocyte carriage and gametocyte density along with asexual parasite density. Developing protocols of anti-malarial drug efficacy that include gametocyte parameters related to both microscopic and submicroscopic gametocytaemias is important if drugs or drug combinations are to be strategically used in transmission-blocking interventions in the context of malaria elimination. The present piece of opinion highlights the challenges in gametocyte detection and follow-up and discuss the need for including the gametocyte parameter in anti-malarial efficacy studies. PMID- 26481313 TI - The HgF2 Ionic Switch: A Triumph of Electrostatics against Relativistic Odds. AB - A remarkable transition in the chemical bonding in (HgF2)n clusters as a function of n is identified and characterized. HgF2 is a fascinating material. Certain significant consequences of relativistic effects on the structure of the HgF2 molecule, dimer, and trimer disappear in the extended solid. Relativistic effects in Hg ensure that HgX2 molecules (X=F, Cl, Br, and I) are linear, rigid, and form weakly bound dimers and trimers held together by weak electrostatic and van der Waals-type forces (unlike ZnX2 and CdX2 systems in which the intermonomer contacts are strong polar covalent bonds). For HgF2, the location and nature of an apparent transition from weak interactions in the smallest (HgF2)n clusters to ionic bonding in the (fluorite) HgF2 extended solid has remained a mystery. Computational evidence obtained at the M06-2X, B97D3, and MP2 levels of theory and reported herein indicate that polar covalent bonding in (HgF2)n begins as early as n=5. For n=2 through to n=13, the transition or switch from weak (primarily dipole-dipole-type) intermonomer interactions to a preference for polar covalent bonding occurs within the range 520, PSM, and N1 patients. The area under curve (AUC) for CAPRA in predicting BCR was 0.713 at 2 years, 0.692 at 3 years, and 0.641 at 5 years. Increasing CAPRA score was associated with an increased risk of BCR (HR = 1.33, P < 0.001). CONCLUSIONS: pT3b prostate cancer is a heterogeneous disease commonly associated with several high-risk features. Stratifying men with SVI by prognostic features (i.e., Gleason, PSA, node status, surgical margin status) and using these features to augment the CAPRA score will improve identification of those at higher risk for BCR that should be strongly considered for adjuvant XRT. PMID- 26481327 TI - Preparing for (valenced) action: The role of differential effort in the orthogonalized go/no-go task. AB - Associating reward to task performance has been shown to benefit scores of cognitive functions. Importantly, this typically entails associating reward to the execution of a response, hence intertwining action-related processes with motivational ones. However, recently, preparatory action requirements (go/no-go) and outcome valence (reward/punishment) were elegantly separated using a cued orthogonalized go/no-go task. Functional magnetic resonance imaging results from this task showed that typical areas of the "reward network," like the dopaminergic midbrain and the striatum, predominantly encode action rather than valence, displaying enhanced activity when preparing for action (go) compared to inaction (no-go). In the current study, we used ERPs to probe for differences in preparatory state related to cognitive effort in this task, which has similarly been linked to reward-network activity. Importantly, the contingent negative variation, which is linked to effortful cognitive preparation processes during cue-target intervals, was clearly observed in go trials but not in no-go trials. Moreover, target-locked ERP results (N1 and P3) suggested that attention to the target was enhanced when an action had to be performed (go trials), and typical inhibition-related ERP components were not observed in no-go trials, suggesting a lack of active response inhibition. Finally, feedback-related P3 results could suggest that correct feedback was valued more in motivated go trials, again implying that more effort was required to correctly perform the task. Together, these results indicate that the anticipation of action compared to inaction simultaneously entails differences in mental effort, highlighting the need for further dissociation of these concepts. PMID- 26481328 TI - Solving 21st Century Problems in Biological Inorganic Chemistry Using Synthetic Models. PMID- 26481329 TI - Taking a Nanoscale "Look" at Chemical Reactions on Surfaces. PMID- 26481330 TI - Managing Community Resilience to Climate Extremes, Rapid Unsustainable Urbanization, Emergencies of Scarcity, and Biodiversity Crises by Use of a Disaster Risk Reduction Bank. AB - Earth's climate is changing and national and international decision-makers are recognizing that global health security requires urgent attention and a significant investment to protect the future. In most locations, current data are inadequate to conduct a full assessment of the direct and indirect health impacts of climate change. All states require this information to evaluate community level resilience to climate extremes and climate change. A model that is being used successfully in the United Kingdom, Australia, and New Zealand is recommended to generate rapid information to assist decision-makers in the event of a disaster. The model overcomes barriers to success inherent in the traditional ''top-down'' approach to managing crises and recognizes the capacity of capable citizens and community organizers to facilitate response and recovery if provided the opportunity and resources. Local information is a prerequisite for strategic and tactical statewide planning. Time and resources are required to analyze risks within each community and what is required to prevent (mitigate), prepare, respond, recover (rehabilitate), anticipate, and assess any threatening events. Specific requirements at all levels from state to community must emphasize community roles by focusing on how best to maintain, respond, and recover public health protections and the infrastructure necessary for health security. PMID- 26481331 TI - Particle jumps in structural glasses. AB - Particles in structural glasses rattle around temporary equilibrium positions, that seldom change through a process which is much faster than the relaxation time, known as particle jump. Since the relaxation of the system is due to the accumulation of many such jumps, it could be possible to connect the single particle short time motion to the macroscopic relaxation by understanding the features of the jump dynamics. Here we review recent results in this research direction, clarifying the features of particle jumps that have been understood and those that are still under investigation, and examining the role of particle jumps in different theories of the glass transition. PMID- 26481332 TI - Lipid-soluble nutrient status of healthy Omani school children before and after intervention with oily fish meal or re-esterified triacylglycerol fish oil. AB - OBJECTIVES: Over the past two decades, the Omani diet has changed considerably to resemble a high calorie and a low nutrient density Western diet. We investigated the fat soluble nutrient status of children before and after intervention with fish diet or fish oil. METHODS: Children ages 9 and 10 y (n = 314) were recruited from three randomly selected schools. The schools were assigned to a fish, fish oil, or control group and the children were given a lightly grilled oily fish, a re-esterified triacylglycerol fish oil capsule, or no fish for 12 wk. RESULTS: Plasma vitamin A, beta carotene, vitamin E concentrations, and vitamin E/total lipid ratio at baseline were 2.7 +/- 0.85 MUmol/L, 0.68 +/- 0.48 MUmol/L, 21.1 +/ 4.8 MUmol/L, and 5.0 +/- 0.81 MUmol/mmol, respectively, and none of the children were deficient. They were severely deficient (<27.5 nmol/L; 10.5% boys and 28.5% girls), deficient (27.5-44.9 nmol/L; 47.6% boys and 49.4% girls) or insufficient (50-74.9 nmol/L; 34.6% boys and 21.5% girls) in vitamin D; only 7.3% boys and 0.6% girls had optimal status (>=75 nmol/L). Parathyroid hormone (5.0 +/- 1.7 versus 5.8 +/- 2.1 pmol/L; P < 0.0001) and alkaline phosphatase (225.2 +/- 66.6 versus 247.8 +/- 73.7 U/L; P < 0.01) levels were lower in boys. Postintervention, the fish oil (54.1 +/- 17.5 nmol/L; P < 0.001) and fish (49.2 +/- 17.4 nmol/L; P < 0.05) groups had elevated levels of vitamin D compared with the controls (42.3 +/- 17.5 nmol/L). CONCLUSIONS: Vitamin D deficiency is prevalent in Omani school children, but it can be mitigated with omega-3 fatty acid supplementation. Vitamin D plays a crucial role in skeletal and extraskeletal systems. Hence, there is a need for a child-focused program of food fortification and outdoor activities to alleviate the problem. PMID- 26481333 TI - The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase. AB - Chronic obstructive pulmonary disease (COPD) is the leading cause of cigarette smoke-related death worldwide. Acrolein, a crucial reactive electrophile found in cigarette smoke mimics many of the toxic effects of cigarette smoke-exposure in the lung. In macrophages, cigarette smoke is known to hinder histone deacetylases (HDACs), glucocorticoid-regulated enzymes that play an important role in the pathogenesis of glucocorticoid resistant inflammation, a common feature of COPD. Thus, we hypothesize that acrolein plays a role in COPD-associated glucocorticoid resistance. To examine the role of acrolein on glucocorticoid resistance, U937 monocytes, differentiated with PMA to macrophage-like cells were treated with acrolein for 0.5h followed by stimulation with hydrocortisone for 8h, or treated simultaneously with LPS and hydrocortisone for 8h without acrolein. GSH and nuclear HDAC activity were measured, or gene expression was analyzed by qPCR. Acrolein-mediated TNFalpha gene expression was not suppressed by hydrocortisone whereas LPS-induced TNFalpha expression was suppressed. Acrolein also significantly inhibited nuclear HDAC activity in macrophage-like cells. Incubation of recombinant HDAC2 with acrolein led to the formation of an HDAC2 acrolein adduct identified by mass spectrometry. Therefore, these results suggest that acrolein-induced inflammatory gene expression is resistant to suppression by the endogenous glucocorticoid, hydrocortisone. PMID- 26481334 TI - Comparison of image quality and radiation dose between an image-intensifier system and a newer-generation flat-panel detector system - technical phantom measurements and evaluation of clinical imaging in children. AB - BACKGROUND: Many image-intensifier fluoroscopy systems have been replaced by flat panel detectors in recent years. OBJECTIVE: To compare the level of contrast, image resolution and radiation dose between an image-intensifier and a newer generation flat-panel detector system in a pediatric radiology unit. MATERIALS AND METHODS: We compared two systems - a conventional image intensifier and a newer-generation flat-panel system. We measured image quality and radiation dose using a technical phantom. Additionally, we retrospectively compared age-matched fluoroscopic pediatric voiding cystourethrography (n = 15) and upper gastrointestinal investigations (n = 25). RESULTS: In phantom studies image contrast was equal while image resolution was higher and mean radiation dose lower using the flat-panel system (P < 0.0001). In pediatric investigations, mean dose area product was significantly reduced on the flat-panel system for upper gastrointestinal investigation (45 +/- 38 MUGy*m2 vs. 11 +/- 9 MUGy*m2; P < 0.0001) and for voiding cystourethrography (18 +/- 20 MUGy*m2 vs. 10 +/- 12 MUGy*m2; P = 0.04). CONCLUSION: The newer flat-panel system performs at lower dose levels with equal to better image quality and therefore seems to be the more suitable technique for pediatric fluoroscopy in comparison to image-intensifier systems. PMID- 26481335 TI - Inter-radiologist agreement for CT scoring of pediatric splenic injuries and effect on an established clinical practice guideline. AB - BACKGROUND: The American Pediatric Surgical Association (APSA) advocates for the use of a clinical practice guideline to direct management of hemodynamically stable pediatric spleen injuries. The clinical practice guideline is based on the CT score of the spleen injury according to the American Association for the Surgery of Trauma (AAST) CT scoring system. OBJECTIVE: To determine the potential effect of radiologist agreement for CT scoring of pediatric spleen injuries on an established APSA clinical practice guideline. MATERIALS AND METHODS: We retrospectively analyzed blunt splenic injuries occurring in children from January 2007 to January 2012 at a single level 1 trauma center (n = 90). Abdominal CT exams performed at clinical presentation were reviewed by four radiologists who documented the following: (1) splenic injury grade (AAST system), (2) arterial extravasation and (3) pseudoaneurysm. Inter-rater agreement for AAST injury grade was assessed using the multi-rater Fleiss kappa and Kendall coefficient of concordance. Inter-rater agreement was assessed using weighted (AAST injury grade) or prevalence-adjusted bias-adjusted (binary measures) kappa statistics; 95% confidence intervals were calculated. We evaluated the hypothetical effect of radiologist disagreement on an established APSA clinical practice guideline. RESULTS: Inter-rater agreement was good for absolute AAST injury grade (kappa: 0.64 [0.59-0.69]) and excellent for relative AAST injury grade (Kendall w: 0.90). All radiologists agreed on the AAST grade in 52% of cases. Based on an established clinical practice guideline, radiologist disagreement could have changed the decision for intensive care management in 11% (10/90) of children, changed the length of hospital stay in 44% (40/90), and changed the time to return to normal activity in 44% (40/90). CONCLUSION: Radiologist agreement when assigning splenic AAST injury grades is less than perfect, and disagreements have the potential to change management in a substantial number of pediatric patients. PMID- 26481336 TI - Right L4/L5 Extreme-Lateral Interbody Fusion for Adult Degenerative Scoliosis: When the Black Swan Is Too Real.... PMID- 26481337 TI - The Role of Serial Oxidative Stress Levels in Acute Traumatic Brain Injury and as Predictors of Outcome. AB - BACKGROUND: Oxidative stress is thought to participate in the pathobiology of secondary brain injury after acute traumatic brain injury (TBI). This study posits that oxidative stress levels in acute TBI are predictive of outcome. METHODS: Two hundred and twenty-nine blood samples from 88 patients admitted within 24 hours after TBI were obtained on admission and on days 4 and 7. Serial plasma oxidative level and antioxidant were examined in 88 patients with acute TBI and 27 control individuals. RESULTS: Compared with controls, patients with TBI had significantly increased serum glutathione (GSH) levels on presentation and significantly decreased erythrocyte superoxide dismutase levels. Outcome was assessed on discharge using the Glasgow Outcome Scale. Serum GSH and erythrocyte superoxide dismutase levels were significantly higher in the good outcome group than in the poor outcome group on day 1 (P = 0.008 and P = 0.026, respectively). In the logistic regression analysis, only motor deficits and GSH levels on presentation were independently associated with outcome. A GSH cutoff value of 1.106 MUmol/L on presentation was associated with good outcome in patients with acute TBI. CONCLUSIONS: Quantifying biomarkers of oxidative stress and antioxidant status of serum correlate with trauma severity and may be used to predict outcomes after TBI. Higher serum GSH levels on admission are associated with better outcome. PMID- 26481338 TI - Use of General Anesthesia for Emergent Large Vessel Occlusion Patients. PMID- 26481339 TI - New Reversal Agents for Oral Anticoagulants on the Horizon. PMID- 26481341 TI - [In Process Citation]. PMID- 26481340 TI - Role of Rho Kinase and Fasudil on Synaptic Plasticity in Multiple Sclerosis. AB - In addition to myelin loss and oligodendrocyte injury, axonal damage is a major cause of irreversible neurological disability in multiple sclerosis (MS). A series of studies have demonstrated that Rho kinase (ROCK) is involved in synaptic plasticity of neurons. Here, we found that ROCK activity in MS serum was elevated compared with serum from healthy controls. In experimental autoimmune encephalomyelitis (EAE), ROCK activity was also increased in serum, spleen, brain and spinal cord. Neuron injury with scratch and TNF-alpha stimulation induced the up-regulation of ROCK activity. When serum of MS patients was co-cultured with mouse cortical neurons in vitro, MS serum caused neurite shortening and reduction of cell viability, while the addition of Fasudil partially restored synaptic morphology of neurons, revealing that MS sera inhibited neurite outgrowth and synapse formation. The expression of synaptophysin was decreased in MS serum neurons, and elevated in the presence of Fasudil. In contrast, the expression of phosphorylated collapsin response mediator protein-2 (CRMP-2) was elevated in MS serum-neurons and decreased in the presence of Fasudil. However, the addition of anti-ROCK I/II mixed antibodies in MS serum partially declined ROCK activity, but did not improve neurite outgrowth of neurons, revealing that Fasudil should prevent synaptic damage possibly through inhibiting intracellular ROCK activation mediated with MS serum. Our results indicate that axonal loss in MS may be related to increased ROCK activity. Fasudil could promote synaptogenesis and thus may contribute to preventing irreversible neurological disability associated with MS. PMID- 26481342 TI - [Comparison of hang-back recession and conventional recession for correction of exotropia]. AB - BACKGROUND AND OBJECTIVE: Weakening of the lateral rectus muscle to correct exotropia can be achieved by using a conventional or a hang-back recession. This study was conducted to compare the results of these techniques and to analyze the dose-response curve and complication rates. STUDY DESIGN AND METHODS: Patients who underwent a lateral rectus muscle recession for exotropia were included in this retrospective study. The recession was performed conventionally with direct scleral fixation at the desired point or with a hang-back recession, each combined with a plication of the ipsilateral medial rectus muscle. The study analyzed ocular alignment and motility preoperatively as well as 1 day and 3 months postoperatively. Intraoperative and postoperative complications were compared. RESULTS: A total of 50 patients (age 4-75 years) met the inclusion criteria for this study. A conventional recession of the lateral rectus muscle was performed in 30 patients and a hang-back recession in 20. Preoperative ocular alignment with distance fixation was - 33.8 +/- 14.4 prism diopters (PD) in the conventional group and - 30.6 +/- 11.8 PD (mean +/- standard deviation) in the hang-back group (where negative values constitute exotropia and positive values are esotropia). Preoperative ocular alignment with near fixation was - 40 +/- 15.2 PD and - 36 +/- 14.7 PD for conventional and hang-back recession, respectively. Ocular alignment with distance fixation 3 months postoperatively was - 10 +/- 14.1 PD in the conventional group and - 11.1 +/- 13.2 PD in the hang back group and with near fixation it was - 15.4 +/- 13.9 PD and - 11.5 +/- 13.9 PD, respectively. In the conventional group 1 mm of combined surgery corrected 2.03 +/- 0.88 PD (- 0.31-4.15 PD/mm) of exotropia with distance fixation and 2.13 +/- 0.87 PD (0.89-3.85 PD/mm) with near fixation. In the hang-back group, it corrected 1.83 +/- 0.89 PD (0.42-2.95 PD/mm) and 2.32 +/- 1.25 PD (0.17-4.76 PD/mm), respectively. Differences between groups were not statistically significant. Intraoperative complications, such as scleral perforation were not observed. Postoperative complications, particularly slipped or lost muscles or induced vertical strabismus were not documented in either group. CONCLUSION: The hang-back recession is an effective and safe alternative to conventional recession of the lateral rectus muscle for exotropia. Larger studies with longer follow-up would be desirable to prospectively compare these two techniques. PMID- 26481343 TI - The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis. AB - BACKGROUND: It is believed that Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are useful biomarkers for the diagnosis of various types of interstitial lung diseases, including hypersensitivity pneumonitis (HP). The clinical features of chronic HP are similar to those of idiopathic interstitial pneumonias, especially idiopathic pulmonary fibrosis (IPF). OBJECTIVE: We sought to clarify the usefulness of serum KL-6 and SP-D for the diagnosis and management of chronic HP. METHODS: We examined serum KL-6 and SP-D levels and retrospectively evaluated the clinical parameters of acute HP (n = 35), chronic HP (n = 57), IPF (n = 54), collagen vascular disease-associated interstitial pneumonia (CVD-IP) (n = 67), and sarcoidosis (n = 47). We analyzed the relations between the two biomarkers and clinical data in chronic HP. RESULTS: Serum KL-6 and SP-D levels in acute HP (2710 U/ml and 338 ng/ml, median) and chronic HP (1500 U/ml and 264 ng/ml, median) were significantly higher than in IPF, CVD-IP, and sarcoidosis. The area under the curve (AUC) values for serum KL-6 and SP-D between chronic HP and IPF were 0.771 and 0.729, respectively. Serum KL-6 levels in chronic HP were significantly higher during episodes of acute exacerbation than 1 month before acute exacerbation. The serum KL-6 levels had correlations with serum SP-D and the percentage of lymphocytes in bronchoalveolar lavage fluid. CONCLUSIONS: Serum KL-6 and SP-D levels are useful for the diagnosis and management of chronic HP. PMID- 26481344 TI - Anxiety in childhood across the globe: findings from meta-regression analyses of the past 15 years (1998-2013). PMID- 26481345 TI - Biological control of Tetranychus urticae by Phytoseiulus macropilis and Macrolophus pygmaeus in tomato greenhouses. AB - Biological control against phytophagous arthropods has been widely used under greenhouse conditions. Its success is dependent on a number of factors related to the abiotic conditions and to the interactions between pests and biological control agents. In particular, when multiple predator species are introduced to suppress one pest, competitive interactions might occur, including intraguild predation (IGP). In tomato crops, the spider mite Tetranychus urticae Koch is a very problematic phytophagous mite and its control is not yet satisfactory. In 2012 and 2013, the ability of a potential new predatory mite Phytoseiulus macropilis (Banks) was assessed, alone and in the presence of Macrolophus pygmaeus Rambur. Macrolophus pygmaeus is a polyphagous mirid supposed to predate on P. macropilis. Both years, under greenhouse conditions, the effectiveness of the two predators was compared between the following treatments: T. urticae, T. urticae + P. macropilis, T. urticae + M. pygmaeus, and T. urticae + P. macropilis + M. pygmaeus. The number of arthropods per tomato plant over time indicated that P. macropilis well-controlled the population of T. urticae, whereas M. pygmaeus had a very limited impact. Furthermore, there was no evidence of IGP between the two predators but in the presence of M. pygmaeus, P. macropilis tended to have a more clumped spatial distribution. Further studies should clarify the number and location of inoculation points to optimize the control of T. urticae by P. macropilis. PMID- 26481346 TI - Procedure for the systematic orientation of digitised cranial models. Design and validation. AB - Comparison of bony pieces requires that they are oriented systematically to ensure that homologous regions are compared. Few orientation methods are highly accurate; this is particularly true for methods applied to three-dimensional models obtained by surface scanning, a technique whose special features make it a powerful tool in forensic contexts. The aim of this study was to develop and evaluate a systematic, assisted orientation method for aligning three-dimensional cranial models relative to the Frankfurt Plane, which would be produce accurate orientations independent of operator and anthropological expertise. The study sample comprised four crania of known age and sex. All the crania were scanned and reconstructed using an Eva ArtecTM portable 3D surface scanner and subsequently, the position of certain characteristic landmarks were determined by three different operators using the Rhinoceros 3D surface modelling software. Intra-observer analysis showed a tendency for orientation to be more accurate when using the assisted method than when using conventional manual orientation. Inter-observer analysis showed that experienced evaluators achieve results at least as accurate if not more accurate using the assisted method than those obtained using manual orientation; while inexperienced evaluators achieved more accurate orientation using the assisted method. The method tested is a an innovative system capable of providing very precise, systematic and automatised spatial orientations of virtual cranial models relative to standardised anatomical planes independent of the operator and operator experience. PMID- 26481347 TI - Age estimation by dental developmental stages in children and adolescents in Iceland. AB - Studies have shown that it is necessary to create a database for dental maturity for every population and compare it to others. The present study is the first one for dental development in the Icelandic population the age range being 4-24 years. It will help in forensic dental age estimation and will also help dentists, physicians, anthropologists, archaeologists and other professionals who rely on developmental age assessment in children and adolescents. In this present retrospective cross-sectional study, dental maturity was determined in 1100 Icelandic children and adolescents from orthopantomograms (OPGs). The first 100 were used for a pilot study and the remaining 1000 for the main study. A total of 23 subjects were excluded. The sample consisted of 508 girls and 469 boys from the age of 4-24 years and a dental developmental scoring system was used as a standard for determination of dental maturity stages. A total of 200 OPGs were studied both on the left and right side and the remaining on the right side. Dental maturity was established for all teeth and both genders, when the sample permitted, from the beginning of crown formation to the root apex closure. The Cronbach's Alpha reliability test showed high reliability, R=0.982. Girls in Iceland reach dental maturity root completed (stage 10, Rc) at 17.81 years of age for the maxillary and at 18.47 years for the mandibular teeth. Boys reach dental maturity root completed (stage 10, Rc) at 18.00 years of age in the maxilla and 17.63 in the mandible. There was no significant difference between left and right side (r=0.95-1.00) and there was no gender difference, except in root formation in maxillary and mandibular canines where girls reached root completed earlier than boys. A reliable database has been established in Iceland for tooth development in the age range of 4-24 years, which is compatible with international studies. These results will help forensic odontologists and other professionals to estimate with high accuracy both age and dental maturity in Icelandic children and adolescents. PMID- 26481348 TI - Epitope-tagged yeast strains reveal promoter driven changes to 3'-end formation and convergent antisense-transcription from common 3' UTRs. AB - Epitope-tagging by homologous recombination is ubiquitously used to study gene expression, protein localization and function in yeast. This is generally thought to insulate the regulation of gene expression to that mediated by the promoter and coding regions because native 3' UTR are replaced. Here we show that the 3' UTRs, CYC1 and ADH1, contain cryptic promoters that generate abundant convergent antisense-transcription in Saccharomyces cerevisiae. Moreover we show that aberrant, truncating 3' -end formation is often associated with regulated transcription in TAP-tagged strains. Importantly, the steady-state level of both 3' -truncated and antisense transcription products is locus dependent. Using TAP and GFP-tagged strains we show that the transcriptional state of the gene-of interest induces changes to 3' -end formation by alternative polyadenylation and antisense transcription from a universal 3' UTR. This means that these 3' UTRs contains plastic features that can be molded to reflect the regulatory architecture of the locus rather than bringing their own regulatory paradigm to the gene-fusions as would be expected. Our work holds a cautionary note for studies utilizing tagged strains for quantitative biology, but also provides a new model for the study of promoter driven rewiring of 3' -end formation and regulatory non-coding transcription. PMID- 26481349 TI - CRISPR-CAS9 D10A nickase target-specific fluorescent labeling of double strand DNA for whole genome mapping and structural variation analysis. AB - We have developed a new, sequence-specific DNA labeling strategy that will dramatically improve DNA mapping in complex and structurally variant genomic regions, as well as facilitate high-throughput automated whole-genome mapping. The method uses the Cas9 D10A protein, which contains a nuclease disabling mutation in one of the two nuclease domains of Cas9, to create a guide RNA directed DNA nick in the context of an in vitro-assembled CRISPR-CAS9-DNA complex. Fluorescent nucleotides are then incorporated adjacent to the nicking site with a DNA polymerase to label the guide RNA-determined target sequences. This labeling strategy is very powerful in targeting repetitive sequences as well as in barcoding genomic regions and structural variants not amenable to current labeling methods that rely on uneven distributions of restriction site motifs in the DNA. Importantly, it renders the labeled double-stranded DNA available in long intact stretches for high-throughput analysis in nanochannel arrays as well as for lower throughput targeted analysis of labeled DNA regions using alternative methods for stretching and imaging the labeled long DNA molecules. Thus, this method will dramatically improve both automated high-throughput genome wide mapping as well as targeted analyses of complex regions containing repetitive and structurally variant DNA. PMID- 26481350 TI - The SIDER database of drugs and side effects. AB - Unwanted side effects of drugs are a burden on patients and a severe impediment in the development of new drugs. At the same time, adverse drug reactions (ADRs) recorded during clinical trials are an important source of human phenotypic data. It is therefore essential to combine data on drugs, targets and side effects into a more complete picture of the therapeutic mechanism of actions of drugs and the ways in which they cause adverse reactions. To this end, we have created the SIDER ('Side Effect Resource', http://sideeffects.embl.de) database of drugs and ADRs. The current release, SIDER 4, contains data on 1430 drugs, 5880 ADRs and 140 064 drug-ADR pairs, which is an increase of 40% compared to the previous version. For more fine-grained analyses, we extracted the frequency with which side effects occur from the package inserts. This information is available for 39% of drug-ADR pairs, 19% of which can be compared to the frequency under placebo treatment. SIDER furthermore contains a data set of drug indications, extracted from the package inserts using Natural Language Processing. These drug indications are used to reduce the rate of false positives by identifying medical terms that do not correspond to ADRs. PMID- 26481351 TI - Expression Atlas update--an integrated database of gene and protein expression in humans, animals and plants. AB - Expression Atlas (http://www.ebi.ac.uk/gxa) provides information about gene and protein expression in animal and plant samples of different cell types, organism parts, developmental stages, diseases and other conditions. It consists of selected microarray and RNA-sequencing studies from ArrayExpress, which have been manually curated, annotated with ontology terms, checked for high quality and processed using standardised analysis methods. Since the last update, Atlas has grown seven-fold (1572 studies as of August 2015), and incorporates baseline expression profiles of tissues from Human Protein Atlas, GTEx and FANTOM5, and of cancer cell lines from ENCODE, CCLE and Genentech projects. Plant studies constitute a quarter of Atlas data. For genes of interest, the user can view baseline expression in tissues, and differential expression for biologically meaningful pairwise comparisons-estimated using consistent methodology across all of Atlas. Our first proteomics study in human tissues is now displayed alongside transcriptomics data in the same tissues. Novel analyses and visualisations include: 'enrichment' in each differential comparison of GO terms, Reactome, Plant Reactome pathways and InterPro domains; hierarchical clustering (by baseline expression) of most variable genes and experimental conditions; and, for a given gene-condition, distribution of baseline expression across biological replicates. PMID- 26481352 TI - DIDA: A curated and annotated digenic diseases database. AB - DIDA (DIgenic diseases DAtabase) is a novel database that provides for the first time detailed information on genes and associated genetic variants involved in digenic diseases, the simplest form of oligogenic inheritance. The database is accessible via http://dida.ibsquare.be and currently includes 213 digenic combinations involved in 44 different digenic diseases. These combinations are composed of 364 distinct variants, which are distributed over 136 distinct genes. The web interface provides browsing and search functionalities, as well as documentation and help pages, general database statistics and references to the original publications from which the data have been collected. The possibility to submit novel digenic data to DIDA is also provided. Creating this new repository was essential as current databases do not allow one to retrieve detailed records regarding digenic combinations. Genes, variants, diseases and digenic combinations in DIDA are annotated with manually curated information and information mined from other online resources. Next to providing a unique resource for the development of new analysis methods, DIDA gives clinical and molecular geneticists a tool to find the most comprehensive information on the digenic nature of their diseases of interest. PMID- 26481353 TI - ECMDB 2.0: A richer resource for understanding the biochemistry of E. coli. AB - ECMDB or the Escherichia coli Metabolome Database (http://www.ecmdb.ca) is a comprehensive database containing detailed information about the genome and metabolome of E. coli (K-12). First released in 2012, the ECMDB has undergone substantial expansion and many modifications over the past 4 years. This manuscript describes the most recent version of ECMDB (ECMDB 2.0). In particular, it provides a comprehensive update of the database that was previously described in the 2013 NAR Database Issue and details many of the additions and improvements made to the ECMDB over that time. Some of the most important or significant enhancements include a 13-fold increase in the number of metabolic pathway diagrams (from 125 to 1650), a 3-fold increase in the number of compounds linked to pathways (from 1058 to 3280), the addition of dozens of operon/metabolite signalling pathways, a 44% increase in the number of compounds in the database (from 2610 to 3760), a 7-fold increase in the number of compounds with NMR or MS spectra (from 412 to 3261) and a massive increase in the number of external links to other E. coli or chemical resources. These additions, along with many other enhancements aimed at improving the ease or speed of querying, searching and viewing the data within ECMDB should greatly facilitate the understanding of not only the metabolism of E. coli, but also allow the in-depth exploration of its extensive metabolic networks, its many signalling pathways and its essential biochemistry. PMID- 26481354 TI - Synthesis and cell-free cloning of DNA libraries using programmable microfluidics. AB - Microfluidics may revolutionize our ability to write synthetic DNA by addressing several fundamental limitations associated with generating novel genetic constructs. Here we report the first de novo synthesis and cell-free cloning of custom DNA libraries in sub-microliter reaction droplets using programmable digital microfluidics. Specifically, we developed Programmable Order Polymerization (POP), Microfluidic Combinatorial Assembly of DNA (M-CAD) and Microfluidic In-vitro Cloning (MIC) and applied them to de novo synthesis, combinatorial assembly and cell-free cloning of genes, respectively. Proof-of concept for these methods was demonstrated by programming an autonomous microfluidic system to construct and clone libraries of yeast ribosome binding sites and bacterial Azurine, which were then retrieved in individual droplets and validated. The ability to rapidly and robustly generate designer DNA molecules in an autonomous manner should have wide application in biological research and development. PMID- 26481355 TI - Mechanism of aromatic amine carcinogen bypass by the Y-family polymerase, Dpo4. AB - Bulky DNA damage inhibits DNA synthesis by replicative polymerases and often requires the action of error prone bypass polymerases. The exact mechanism governing adduct-induced mutagenesis and its dependence on the DNA sequence context remains unclear. In this work, we characterize Dpo4 binding conformations and activity with DNA templates modified with the carcinogenic DNA adducts, 2 aminofluoene (AF) or N-acetyl-2-aminofluorene (AAF), using single-molecule FRET (smFRET) analysis and DNA synthesis extension assays. We find that in the absence of dNTPs, both adducts alter polymerase binding as measured by smFRET, but the addition of dNTPs induces the formation of a ternary complex having what appears to be a conformation similar to the one observed with an unmodified DNA template. We also observe that the misincorporation pathways for each adduct present significant differences: while an AF adduct induces a structure consistent with the previously observed primer-template looped structure, its acetylated counterpart uses a different mechanism, one consistent with a dNTP-stabilized misalignment mechanism. PMID- 26481356 TI - Lnc2Cancer: a manually curated database of experimentally supported lncRNAs associated with various human cancers. AB - Lnc2Cancer (http://www.bio-bigdata.net/lnc2cancer) is a manually curated database of cancer-associated long non-coding RNAs (lncRNAs) with experimental support that aims to provide a high-quality and integrated resource for exploring lncRNA deregulation in various human cancers. LncRNAs represent a large category of functional RNA molecules that play a significant role in human cancers. A curated collection and summary of deregulated lncRNAs in cancer is essential to thoroughly understand the mechanisms and functions of lncRNAs. Here, we developed the Lnc2Cancer database, which contains 1057 manually curated associations between 531 lncRNAs and 86 human cancers. Each association includes lncRNA and cancer name, the lncRNA expression pattern, experimental techniques, a brief functional description, the original reference and additional annotation information. Lnc2Cancer provides a user-friendly interface to conveniently browse, retrieve and download data. Lnc2Cancer also offers a submission page for researchers to submit newly validated lncRNA-cancer associations. With the rapidly increasing interest in lncRNAs, Lnc2Cancer will significantly improve our understanding of lncRNA deregulation in cancer and has the potential to be a timely and valuable resource. PMID- 26481357 TI - WikiPathways: capturing the full diversity of pathway knowledge. AB - WikiPathways (http://www.wikipathways.org) is an open, collaborative platform for capturing and disseminating models of biological pathways for data visualization and analysis. Since our last NAR update, 4 years ago, WikiPathways has experienced massive growth in content, which continues to be contributed by hundreds of individuals each year. New aspects of the diversity and depth of the collected pathways are described from the perspective of researchers interested in using pathway information in their studies. We provide updates on extensions and services to support pathway analysis and visualization via popular standalone tools, i.e. PathVisio and Cytoscape, web applications and common programming environments. We introduce the Quick Edit feature for pathway authors and curators, in addition to new means of publishing pathways and maintaining custom pathway collections to serve specific research topics and communities. In addition to the latest milestones in our pathway collection and curation effort, we also highlight the latest means to access the content as publishable figures, as standard data files, and as linked data, including bulk and programmatic access. PMID- 26481358 TI - ZFP57 recognizes multiple and closely spaced sequence motif variants to maintain repressive epigenetic marks in mouse embryonic stem cells. AB - Imprinting Control Regions (ICRs) need to maintain their parental allele-specific DNA methylation during early embryogenesis despite genome-wide demethylation and subsequent de novo methylation. ZFP57 and KAP1 are both required for maintaining the repressive DNA methylation and H3-lysine-9-trimethylation (H3K9me3) at ICRs. In vitro, ZFP57 binds a specific hexanucleotide motif that is enriched at its genomic binding sites. We now demonstrate in mouse embryonic stem cells (ESCs) that SNPs disrupting closely-spaced hexanucleotide motifs are associated with lack of ZFP57 binding and H3K9me3 enrichment. Through a transgenic approach in mouse ESCs, we further demonstrate that an ICR fragment containing three ZFP57 motif sequences recapitulates the original methylated or unmethylated status when integrated into the genome at an ectopic position. Mutation of Zfp57 or the hexanucleotide motifs led to loss of ZFP57 binding and DNA methylation of the transgene. Finally, we identified a sequence variant of the hexanucleotide motif that interacts with ZFP57 both in vivo and in vitro. The presence of multiple and closely located copies of ZFP57 motif variants emerges as a distinct characteristic that is required for the faithful maintenance of repressive epigenetic marks at ICRs and other ZFP57 binding sites. PMID- 26481359 TI - Human telomerase reverse transcriptase binds to a pre-organized hTR in vivo exposing its template. AB - Telomerase is a specialized reverse transcriptase that is responsible for telomere length maintenance. As in other organisms, the minimal components required for an active human telomerase are the template-providing telomerase RNA (hTR) and the enzymatic entity telomerase reverse transcriptase (hTERT). Here, we explored the structure of hTR and the hTERT-induced conformational changes within hTR in living cells. By employing an in vivo DMS chemical probing technique, we showed that the pseudoknot and associated triple helical scaffold form stably in vivo independently of hTERT. In fact, the dimethyl-sulfate (DMS) modification pattern suggests that hTR alone is capable of adopting a conformation that is suited to interact with hTERT. However, in the absence of hTERT the template region of hTR is only weakly accessible to DMS-modifications. The predominant change after binding of hTERT to hTR is the exposure of the template region. PMID- 26481360 TI - Secondary structure encodes a cooperative tertiary folding funnel in the Azoarcus ribozyme. AB - A requirement for specific RNA folding is that the free-energy landscape discriminate against non-native folds. While tertiary interactions are critical for stabilizing the native fold, they are relatively non-specific, suggesting additional mechanisms contribute to tertiary folding specificity. In this study, we use coarse-grained molecular dynamics simulations to explore how secondary structure shapes the tertiary free-energy landscape of the Azoarcus ribozyme. We show that steric and connectivity constraints posed by secondary structure strongly limit the accessible conformational space of the ribozyme, and that these so-called topological constraints in turn pose strong free-energy penalties on forming different tertiary contacts. Notably, native A-minor and base-triple interactions form with low conformational free energy, while non-native tetraloop/tetraloop-receptor interactions are penalized by high conformational free energies. Topological constraints also give rise to strong cooperativity between distal tertiary interactions, quantitatively matching prior experimental measurements. The specificity of the folding landscape is further enhanced as tertiary contacts place additional constraints on the conformational space, progressively funneling the molecule to the native state. These results indicate that secondary structure assists the ribozyme in navigating the otherwise rugged tertiary folding landscape, and further emphasize topological constraints as a key force in RNA folding. PMID- 26481361 TI - Bovine Genome Database: new tools for gleaning function from the Bos taurus genome. AB - We report an update of the Bovine Genome Database (BGD) (http://BovineGenome.org). The goal of BGD is to support bovine genomics research by providing genome annotation and data mining tools. We have developed new genome and annotation browsers using JBrowse and WebApollo for two Bos taurus genome assemblies, the reference genome assembly (UMD3.1.1) and the alternate genome assembly (Btau_4.6.1). Annotation tools have been customized to highlight priority genes for annotation, and to aid annotators in selecting gene evidence tracks from 91 tissue specific RNAseq datasets. We have also developed BovineMine, based on the InterMine data warehousing system, to integrate the bovine genome, annotation, QTL, SNP and expression data with external sources of orthology, gene ontology, gene interaction and pathway information. BovineMine provides powerful query building tools, as well as customized query templates, and allows users to analyze and download genome-wide datasets. With BovineMine, bovine researchers can use orthology to leverage the curated gene pathways of model organisms, such as human, mouse and rat. BovineMine will be especially useful for gene ontology and pathway analyses in conjunction with GWAS and QTL studies. PMID- 26481362 TI - BindingDB in 2015: A public database for medicinal chemistry, computational chemistry and systems pharmacology. AB - BindingDB, www.bindingdb.org, is a publicly accessible database of experimental protein-small molecule interaction data. Its collection of over a million data entries derives primarily from scientific articles and, increasingly, US patents. BindingDB provides many ways to browse and search for data of interest, including an advanced search tool, which can cross searches of multiple query types, including text, chemical structure, protein sequence and numerical affinities. The PDB and PubMed provide links to data in BindingDB, and vice versa; and BindingDB provides links to pathway information, the ZINC catalog of available compounds, and other resources. The BindingDB website offers specialized tools that take advantage of its large data collection, including ones to generate hypotheses for the protein targets bound by a bioactive compound, and for the compounds bound by a new protein of known sequence; and virtual compound screening by maximal chemical similarity, binary kernel discrimination, and support vector machine methods. Specialized data sets are also available, such as binding data for hundreds of congeneric series of ligands, drawn from BindingDB and organized for use in validating drug design methods. BindingDB offers several forms of programmatic access, and comes with extensive background material and documentation. Here, we provide the first update of BindingDB since 2007, focusing on new and unique features and highlighting directions of importance to the field as a whole. PMID- 26481363 TI - DNA-binding proteins from marine bacteria expand the known sequence diversity of TALE-like repeats. AB - Transcription Activator-Like Effectors (TALEs) of Xanthomonas bacteria are programmable DNA binding proteins with unprecedented target specificity. Comparative studies into TALE repeat structure and function are hindered by the limited sequence variation among TALE repeats. More sequence-diverse TALE-like proteins are known from Ralstonia solanacearum (RipTALs) and Burkholderia rhizoxinica (Bats), but RipTAL and Bat repeats are conserved with those of TALEs around the DNA-binding residue. We study two novel marine-organism TALE-like proteins (MOrTL1 and MOrTL2), the first to date of non-terrestrial origin. We have assessed their DNA-binding properties and modelled repeat structures. We found that repeats from these proteins mediate sequence specific DNA binding conforming to the TALE code, despite low sequence similarity to TALE repeats, and with novel residues around the BSR. However, MOrTL1 repeats show greater sequence discriminating power than MOrTL2 repeats. Sequence alignments show that there are only three residues conserved between repeats of all TALE-like proteins including the two new additions. This conserved motif could prove useful as an identifier for future TALE-likes. Additionally, comparing MOrTL repeats with those of other TALE-likes suggests a common evolutionary origin for the TALEs, RipTALs and Bats. PMID- 26481364 TI - Factors Associated with Travel Time and Distance to Access Hospital Care Among Infants with Spina Bifida. AB - OBJECTIVES: Using geographic information systems (GIS), we examined travel time and distance to access hospital care for infants with spina bifida (SB). METHODS: This study was a statewide, population-based analysis of Florida-born children with SB, 1998-2007, identified by the Florida Birth Defects Registry and linked to hospitalizations. We geocoded maternal residence at delivery and identified hospital locations for infants (<1 year). Using 2007 Florida Department of Transportation road data, we calculated one-way mean travel time and distance to access hospital care. We used Poisson regression to examine selected factors associated with travel time and distance [<=30 vs. >30 min/miles (reference)], including presence of hydrocephalus and SB type [isolated (no other major birth defect) versus non-isolated SB]. RESULTS: For 612 infants, one-way mean (median) travel time was 45.1 (25.9) min. Infants with both non-isolated SB and hydrocephalus traveled longest to access hospitals (mean 60.8 min/48.5 miles; median 34.2 min/26.9 miles). In adjusted results, infants with non-isolated SB and whose mothers had a rural residence were less likely to travel <=30 min to hospitals. Infants born to mothers in minority racial/ethnic groups were more likely to travel <=30 min. CONCLUSIONS: Birth defects registry data and GIS-based methods can be used to evaluate geographic accessibility to hospital care for infants with birth defects. Results can help to identify geographic barriers to accessing hospital care, such as travel time and distance, and inform opportunities to improve access to care for infants with SB or other special needs. PMID- 26481365 TI - Forum on the functioning of ethical committees: The nature of the problem. PMID- 26481366 TI - Role of Chemoradiotherapy in Elderly Patients With Limited-Stage Small-Cell Lung Cancer. AB - PURPOSE: To investigate outcomes for elderly patients treated with chemotherapy (CT) alone versus chemoradiotherapy (CRT) in the modern era by using a large national database. PATIENTS AND METHODS: Elderly patients (age >= 70 years) with limited-stage small-cell lung cancer clinical stage I to III who received CT or CRT were identified in the National Cancer Data Base between 2003 and 2011. Hierarchical mixed-effects logistic regression with clustering by reporting facility was performed to identify factors associated with treatment selection. Overall survival (OS) of patients receiving CT versus CRT was compared by using the log-rank test, Cox proportional hazards regression, and propensity score matching. RESULTS: A total of 8,637 patients were identified, among whom 3,775 (43.7%) received CT and 4,862 (56.3%) received CRT. The odds of receiving CRT decreased with increasing age, clinical stage III disease, female sex, and the presence of medical comorbidities (all P < .01). Use of CRT was associated with increased OS compared with CT on univariable and multivariable analysis (median OS, 15.6 v 9.3 months; 3-year OS, 22.0% v 6.3%; log-rank P < .001; Cox P < .001). Propensity score matching identified a matched cohort of 6,856 patients and confirmed a survival benefit associated with CRT (hazard ratio, 0.52; 95% CI, 0.50 to 0.55; P < .001). Subset analysis of CRT treatment sequence showed that patients alive 4 months after diagnosis derived a survival benefit with concurrent CRT over sequential CRT (median OS, 17.0 v 15.4 months; log-rank P = .01). CONCLUSION: In elderly patients with limited-stage small-cell lung cancer, modern CRT appears to confer an additional OS advantage beyond that achieved with CT alone in a large population-based cohort. Our findings suggest that CRT should be the preferred strategy in elderly patients who are expected to tolerate the toxicities of the combined approach. PMID- 26481367 TI - Improving structural development in oncology: transformation of theoretical health care standards and knowledge into a practical approach -- 2nd European Roundtable Meeting (ERTM), May 8, 2015, Berlin, Germany. AB - PURPOSE: It is widely accepted that National Cancer Control Plans (NCCPs) are essential to improve cancer care. They often describe the structural requirements such as cancer centers, clinical cancer registries and quality control. During the 2nd European roundtable meeting, the implementation processes were analyzed and discussed. RESULTS: Communication strategies between cancer registries and cancer centers need to be developed. Analyses and discussion of collected data have to be performed by multidisciplinary teams. This has to be followed by appropriate actions to improve quality of care. It is essential to describe the clinical procedures, organizational processes and communication between individuals and professional teams. The patients' perspectives have to be included in the development of cancer care networks. The patients' feedback on cancer care is a routine quality indicator. CONCLUSION: NCCPs that include the description of structural requirements are important. In addition, it is essential to develop cancer care networks including multidisciplinary organizational processes to guarantee high quality. These have to consider patients preferences. PMID- 26481369 TI - The Journey of International Fellows: Have you been to America? PMID- 26481370 TI - Quantifying predictive accuracy in survival models. AB - For time-to-event outcomes in medical research, survival models are the most appropriate to use. Unlike logistic regression models, quantifying the predictive accuracy of these models is not a trivial task. We present the classes of concordance (C) statistics and R 2 statistics often used to assess the predictive ability of these models. The discussion focuses on Harrell's C, Kent and O'Quigley's R 2, and Royston and Sauerbrei's R 2. We present similarities and differences between the statistics, discuss the software options from the most widely used statistical analysis packages, and give a practical example using the Worcester Heart Attack Study dataset. PMID- 26481372 TI - Current natural products with antihypertensive activity. AB - Natural products have been an important source of new drugs, which also played a dominant role in the discovery and research of new drugs for the treatment of hypertension. This review article reviews the recent progress in the research and development of natural lead compounds with antihypertensive activity, including alkaloids, diterpenes, coumarins, flavonoids, and peptides. We summarized their structures, sources, as well as the antihypertensive mechanisms. These information provides instructive reference for the following structural modifications and optimization. PMID- 26481373 TI - Modulation of signal transduction pathways by natural compounds in cancer. AB - Cancer is generally regarded as the result of abnormal growth of cells. According to World Health Organization, cancer is the leading cause of mortality worldwide. Mother nature provides a large source of bioactive compounds with excellent therapeutic efficacy. Numerous phytochemicals from nature have been investigated for anticancer properties. In this review article, we discuss several natural compounds, which have shown anti-cancer activity. Natural compounds induce cell cycle arrest, activate intrinsic and extrinsic apoptosis pathways, generate Reactive Oxygen Species (ROS), and down-regulate activated signaling pathways, resulting in inhibition of cell proliferation, progression and metastasis of cancer. Several preclinical studies have suggested that natural compounds can also increase the sensitivity of resistant cancers to available chemotherapy agents. Furthermore, combining FDA approved anti-cancer drugs with natural compounds results in improved efficacy. On the basis of these exciting outcomes of natural compounds against several cancer types, several agents have already advanced to clinical trials. In conclusion, preclinical results and clinical outcomes against cancer suggest promising anticancer efficacy of agents from natural sources. PMID- 26481374 TI - Sheng-Mai-San attenuates contractile dysfunction and structural damage induced by chronic intermittent hypoxia in mice. AB - Sheng-Mai-San (SMS), a well-known Chinese medicinal plant formula, is widely used for the treatment of cardiac diseases characterized by deficiency of Qi and Yin syndrome. A mouse chronic intermittent hypoxia (CIH) model was established to mimic the primary clinical features of deficiency of Qi and Yin syndrome. Mice experienced CIH for 28 days (nadir 7% to peak 8% oxygen, 20 min per day), resulting in left ventricle (LV) dysfunction and structure abnormalities. After administration of SMS (0.55, 1.1, and 5.5 g.kg(-1).d(-1)) for four weeks, improved cardiac function was observed, as indicated by the increase in the ejection fraction from the LV on echocardiography. SMS also preserved the structural integrity of the LV against eccentric hypotrophy, tissue vacuolization, and mitochondrial injury as measured by histology, electron microscopy, and ultrasound assessments. Mechanistically, the antioxidant effects of SMS were demonstrated; SMS was able to suppress mitochondrial apoptosis as indicated by the reduction of several pro-apoptotic factors (Bax, cytochrome c, and cleaved caspase-3) and up-regulation of the anti-apoptosis factor Bcl-2. In conclusion, these results demonstrate that SMS treatment can protect the structure and function of the LV and that the protective effects of this formula are associated with the regulation of the mitochondrial apoptosis pathway. PMID- 26481375 TI - Drug-target networks for Tanshinone IIA identified by data mining. AB - Tanshinone IIA is a pharmacologically active compound isolated from Danshen (Salvia miltiorrhiza), a traditional Chinese herbal medicine for the management of cardiac diseases and other disorders. But its underlying molecular mechanisms of action are still unclear. The present investigation utilized a data mining approach based on network pharmacology to uncover the potential protein targets of Tanshinone IIA. Network pharmacology, an integrated multidisciplinary study, incorporates systems biology, network analysis, connectivity, redundancy, and pleiotropy, providing powerful new tools and insights into elucidating the fine details of drug-target interactions. In the present study, two separate drug target networks for Tanshinone IIA were constructed using the Agilent Literature Search (ALS) and STITCH (search tool for interactions of chemicals) methods. Analysis of the ALS-constructed network revealed a target network with a scale free topology and five top nodes (protein targets) corresponding to Fos, Jun, Src, phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and mitogen-activated protein kinase kinase 1 (MAP2K1), whereas analysis of the STITCH-constructed network revealed three top nodes corresponding to cytochrome P450 3A4 (CYP3A4), cytochrome P450 A1 (CYP1A1), and nuclear factor kappa B1 (NFkappaB1). The discrepancies were probably due to the differences in the divergent computer mining tools and databases employed by the two methods. However, it is conceivable that all eight proteins mediate important biological functions of Tanshinone IIA, contributing to its overall drug-target network. In conclusion, the current results may assist in developing a comprehensive understanding of the molecular mechanisms and signaling pathways of in a simple, compact, and visual manner. PMID- 26481371 TI - Novelty Seeking and Drug Addiction in Humans and Animals: From Behavior to Molecules. AB - Global treatment of drug addiction costs society billions of dollars annually, but current psychopharmacological therapies have not been successful at desired rates. The increasing number of individuals suffering from substance abuse has turned attention to what makes some people more vulnerable to drug addiction than others. One personality trait that stands out as a contributing factor is novelty seeking. Novelty seeking, affected by both genetic and environmental factors, is defined as the tendency to desire novel stimuli and environments. It can be measured in humans through questionnaires and in rodents using behavioral tasks. On the behavioral level, both human and rodent studies demonstrate that high novelty seeking can predict the initiation of drug use and a transition to compulsive drug use and create a propensity to relapse. These predictions are valid for several drugs of abuse, such as alcohol, nicotine, cocaine, amphetamine, and opiates. On the molecular level, both novelty seeking and addiction are modulated by the central reward system in the brain. Dopamine is the primary neurotransmitter involved in the overlapping neural substrates of both parameters. In sum, the novelty-seeking trait can be valuable for predicting individual vulnerability to drug addiction and for generating successful treatment for patients with substance abuse disorders. PMID- 26481376 TI - Pleurotus nebrodensis polysaccharide (PN-S) enhances the immunity of immunosuppressed mice. AB - In the present study, the effects of Pleurotus nebrodensis polysaccharide (PN-S) on the immune functions of immunosuppressed mice were determined. The immunosuppressed mouse model was established by treating the mice with cyclophosphamide (40 mg/kg/2d, CY) through intraperitoneal injection. The results showed that PN-S administration significantly reversed the CY-induced weight loss, increased the thymic and splenic indices, and promoted proliferation of T lymphocyte, B lymphocyte, and macrophages. PN-S also enhanced the activity of natural killer cells and increased the immunoglobulin M (IgM) and immunoglobulin G (IgG) levels in the serum. In addition, PN-S treatment significantly increased the phagocytic activity of mouse peritoneal macrophages. PN-S also increased the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (INF-gamma), and nitric oxide (NOS) in splenocytes. qRT-PCR results also indicated that PN-S increased the mRNA expression of IL-6, TNF alpha, INF-gamma, and nitric oxide synthase (iNOS) in the splenocytes. These results suggest that PN-S treatment enhances the immune function of immunosuppressed mice. This study may provide a basis for the application of this fungus in adjacent immunopotentiating therapy against cancer and in the treatment of chemotherapy-induced immunosuppression. PMID- 26481377 TI - Protective effects of Rabdosia japonica var. glaucocalyx extract on lipopolysaccharide-induced acute lung injury in mice. AB - The present study was designed to evaluate the protective effects of ethanol extracts of Rabdosia japonica var. glaucocalyx (Maxim.) Hara (RJ) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible underlying mechanisms of action. The mice were orally administrated with RJ extract (16, 32 or 64 mg(kg(-1)) daily for consecutive7 days before LPS challenge. The ung specimens and the bronchoalveolar lavage fluid (BALF) were collected for histopathological examinations and biochemical analyses. Pretreatment with RJ significantly enhanced superoxide dismutase (SOD) activity and reduced the wet-to-dry weight (W/D) ratio, the levels of nitric oxide (NO) and protein leakage, and myeloperoxidase (MPO) activity in mice with ALI, in a dose-dependent manner. RJ reduced complement deposition and significantly attenuated LPS-induced ALI by reducing productions of inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta). The results demonstrated that RJ may attenuate LPS induced ALI via reducing the production of pro-inflammatory mediators, and reducing complement deposition and radicals. PMID- 26481379 TI - Identification and characterization of two new xanthones from Cudrania fruticosa. AB - The present study was designed to investigate the chemical constituents of the roots of Cudrania fruticosa Wight. Compounds were isolated by various column chromatographic methods including silica gel, polyamide, sephadex LH-20, and semi preparative HPLC. Their structures were elucidated by a combination of 1D and 2D NMR techniques, mass spectrometry, and chemical methods. Two new xanthones, Cudraxanthone T and U (1-2), along with four known compounds (3-6) were isolated from the roots of Cudrania fruticosa Wight. PMID- 26481378 TI - Therapeutic effects of Qishen Yiqi Dropping Pill on myocardial injury induced by chronic hypoxia in rats. AB - The present study was designed to determine the effects of a traditional Chinese medicine, called Qishen Yiqi Dropping Pill on chronic hypoxia-induced myocardial injury. To establish a rat chronic hypoxia model to be used in the evaluation of the therapeutic effects of the Qishen Yiqi Dropping Pill, Sprague-Dawley (SD) rats were randomly divided into three groups: the control, model, and treatment groups (n = 10 per group). The animals were housed in a plexiglass container. The control animals were under normal oxygen concentration and the model and treatment groups were exposed to air and nitrogen for 5 weeks. The rats in the treatment group were orally administered the Qishen Yiqi Dropping pill (35 mg.kg( 1).d(-1)) for 5 weeks. After the treatment, the cardiac function and morphology were analyzed, and the expression levels of hypoxia-inducible factor 1alpha (HIF 1alpha) were determined using Western blotting. Our results indicated that the cardiac function was impaired, cell apoptosis was enhanced, and HIF-1alpha expression was up-regulated in the model group, compared to the control group. These changes were ameliorated by the treatment with the Qishen Yiqi Dropping Pill. In conclusion, Qishen Yiqi Dropping pill can ameliorate myocardial injury induced by chronic hypoxia, improve cardiac function, and decrease myocardial cell apoptosis, which may provide a basis for its clinical use for the treatment of chronic cardiovascular diseases. PMID- 26481380 TI - Analgesic effects and structural elucidation of two new flavone C-glycosides from Artemisa sacrorum. AB - The present study was designed to isolate and characterize the analgesic compounds of Artemisa sacrorum Ledeb. The EtOAc crude extracts from the aerial parts of Artemisa sacrorum Ledeb were separated by chromatography and the structures of new compounds were elucidated based on spectral analyses. Analgesic activities of the isolated compounds were assessed in rats with hot plate test and paw pressure assay. Two new flavone C-glycosides, named as Sacroroside A and B (Compounds 1 and 2) were isolated from the EtOAc crude extract of the aerial parts ofArtemisa sacrorum Ledeb. They showed significant analgesic effects. In conclusion, Compounds 1 and 2 are new natural products, which show significant analgesic effects in a dose-dependent manner. PMID- 26481381 TI - A high-performance liquid chromatography with circular dichroism detector for determination of stereochemistry of 6, 9-oxygen bridge dibenzocyclooctadiene lignans from kadsura coccinea. AB - The stereochemistry of two 6, 9-oxygen bridge dibenzocyclooctadiene lignans from Kadsura coccinea, are difficult to separate and very unstable. The present study was designed to develop a high-performance liquid chromatography using circular dichroism detection for the analysis of the stereochemistry. A new 6, 9-oxygen bridge dibenzocyclooctadiene lignans named Kadsulignan Q was firstly found with an S-biphenyl configuration. The other compound was identified as Kadsulignan L with an R- biphenyl configuration. In order to obtain kinetic data on their reversible interconversion, the stability was measured at different deuterated solvents such as deuterated methanol, deuterated chloroform and deuterated dimethylsulfoxide. The lignans were more unstable and converted more easily in deuterated methanol than in deuterated chloroform and deuterated dimethylsulfoxide. PMID- 26481382 TI - Glycosylation and sulfation of emodin by Gliocladium deliquescens NRRL 1086. AB - The present study was designed to explore the substrate scope and biocatalytic capability of Gliocladium deliquescens NRRL 1086 on phenolic natural products. Emodin was subjected to the fermentation culture of Gliocladium deliquescens NRRL 1086 according to the standard two-stage protocol. The biotransformation process was monitored by HPLC-DAD-MS, the main product was isolated by column chromatography, and the structure was elucidated on the basis of NMR spectroscopy. Emodin could be fully metabolized by Gliocladium deliquescens NRRL 1086, resulting in high yield of emodin 6-O-beta-D-glucopyranoside and small amount of sulfated product. In conclusion, our results may provide a convenient method to prepare emodin 6-O-beta-D-glucopyranoside and the microbe catalyzed glucosylation/sulfation will give an inspiration to pharmacokinetic model studies in vitro. PMID- 26481383 TI - Preoperative ICD risk score variables predict 30-day readmission after implantable cardioverter defibrillator implantation in patients with heart failure. AB - OBJECTIVE: To determine if preoperative ICD Risk Score for Adverse Outcome (ICD RSAO) would predict need for hospital 30-day readmission. BACKGROUND: Pre analysis of National Cardiovascular Data Registry ICD database identified preoperative predictors of adverse outcomes associated with ICD implantation. METHODS: Logistic regression, descriptive statistics and Chi-square were used to examine the relationship between ICD-RSAO and 30-day readmission after ICD implantation. RESULTS: BUN >30, history of lung disease, NYHA Class IV and device implant during inpatient stay were predicative of 30-day readmission (P = 0.001; 95% CI = 0.58-0.79). Patients with a combination of two or more of four variables were more likely to be readmitted (Hosmer-Lemeshow (chi(2) = 3.44, P = 0.49), c statistic = 0.71, and Nagelkerke R(2) = 0.15). CONCLUSION: Patients who have elevated BUN's, NYHA Class IV, chronic lung disease and ICD implantation during a concomitant hospital admission are at increased risk for readmission and need early follow up. PMID- 26481384 TI - Factors associated with excessive bleeding after cardiac surgery: A prospective cohort study. AB - OBJECTIVE: To identify factors associated with excessive bleeding (ExB) after cardiac surgery in adults. BACKGROUND: Excessive bleeding after cardiac surgery must be anticipated for implementation of timely interventions. METHODS: A prospective cohort study with 323 adults requiring open-chest cardiac surgery. Potential factors associated with ExB were investigated through univariate analysis and logistic regression. The accuracy of the relationship between the independent variables and the outcome was depicted through the receiver-operating characteristic (ROC) curve. RESULTS: The factors associated with ExB included gender, body mass index (BMI), preoperative platelet count, intraoperative heparin doses and intraoperative platelet transfusion. The ROC curve cut-off points were 26.35 for the BMI; 214,000 for the preoperative platelet count, and 6.25 for intraoperative heparin dose. This model had an accuracy = 77.3%, a sensitivity = 81%, and a specificity = 62%. CONCLUSIONS: Male gender, BMI, preoperative platelet count, dose of intraoperative heparin >312.5 mg without subsequent platelet transfusion, are factors associated with ExB. PMID- 26481385 TI - Catalysts for Change: The Role of Small Business Funders in the Creation and Dissemination of Innovation. AB - A gap exists between the expanding space of technological innovations to aid those affected by autism spectrum disorders, and the actual impact of those technologies on daily lives. This gap can be addressed through a very practical path of commercialization. However, the path from a technological innovation to a commercially viable product is fraught with challenges. These challenges can be mitigated through small business funding agencies, which are, more and more, catalyzing the dissemination of innovation by fostering social entrepreneurship through capital support and venture philanthropy. This letter describes the differences and nature of these agencies, and their importance in facilitating the translational and real-world impact of technological and scientific discoveries. PMID- 26481386 TI - Parental Awareness of Sexual Experience in Adolescent Boys With Autism Spectrum Disorder. AB - Parent report and adolescent self-report data on lifetime sexual experience in adolescents with ASD were compared in 43 parent-adolescent dyads. Parents tended to underestimate the lifetime sexual experience of their sons, particularly solo sexual experiences such as masturbation and experience with orgasm. Parental underestimation and unawareness of adolescents' sexual experience may influence communication and education about sex and sexuality in families. These findings have implications for the interpretation of earlier research, based on parent and caregiver reports, on sexuality in adolescents with ASD. PMID- 26481387 TI - Brief Report: Burden of Care in Mothers of Children with Autism Spectrum Disorder or Intellectual Disability. AB - Compared to other mothers, mothers of children with autism spectrum disorder (ASD) or intellectual disability (ID) have higher rates of treatment episodes for psychiatric disorders. We aimed to estimate the maternal burden of care by comparing the length of hospitalisations for psychiatric disorders and the treatment rates for psychiatric disorders after the birth in mothers of children with ASD/ID and no psychiatric history to that of other mothers with no psychiatric history. Mothers of children with ID of known cause (not Down syndrome) and mothers of children ASD without ID emerged as particularly vulnerable. Mothers of children with Down syndrome were resilient. The development of specialised organisations to provide support to mothers of children with ID of known cause (not Down syndrome) and mothers of children with ASD without ID could assist them to maintain their mental health. PMID- 26481388 TI - [Telephone enquiries on the topic of malignant hyperthermia: Evaluation of the content and subsequent diagnostic results at the MH Center Leipzig]. AB - BACKGROUND: Malignant hyperthermia (MH) is an autosomal dominant metabolic myopathy. The in vitro contracture test (IVCT) is still considered to be the gold standard for diagnosing a disposition for MH. However, advances in genetic testing for MH disposition have supplemented or even replaced the invasive procedure of the IVCT. Information about MH can be obtained by either contacting the hotline for MH as a nationwide 24 h/7 days a week service or one of the regional MH centers. METHODS: The protocols of telephone conversations concerning MH at the MH Center University Leipzig were retrospectively analyzed. Data were collected from January 2011 to March 2015. Additionally, the results of the IVCT and genetic testing evolving from the counseling interviews were examined. RESULTS: A total of 205 telephone calls were documented during the period in question and an IVCT was performed as a consequence of 112 of the telephone calls. The IVCT resulted in 27 individuals being identified as MH susceptible which was subsequently diagnosed in 15 individuals with known familial MH disposition and 12 individuals were identified as new index patients. In 24 individuals a total of 13 different mutations were detected and of these 4 mutations were causative concerning MH. Of the 205 telephone calls 131 were private and 74 of medical professional origin. Among the private enquiries MH disposition within the family was a frequent reason for contacting the MH Center (61.8%). Conversations relating to MH-like symptoms during general anesthesia were carried out with 35.1% of medical doctors and with 22.9% of private callers. Advice about neuromuscular symptoms of unknown genesis was given to 15.3% of private individuals and to 24.3% of medical doctors. Overall MH topics were discussed with 23% (N = 17) of the medical profession and approximately half of these were anesthesiologists (N = 8). Not a single call was documented for the treatment of a suspected MH crisis. CONCLUSION: Private individuals and families affected by a MH disposition often showed good compliance with respect to counseling and diagnostics for MH and contacted the MH center more often than medical doctors. A more comprehensive cooperation with the medical profession is preferable and necessary to obtain a systematic and broad synopsis of characteristic and uncharacteristic signs and symptoms of MH. The telephone conversations analyzed as well as the diagnostic results (IVCT and genetic testing) underline that MH disposition is still a current and relevant topic. PMID- 26481389 TI - [Advantages and disadvantages of different methods for the implementation and the support of standard operating procedures: From PDF files to an app- and webbased SOP management system]. AB - BACKGROUND: The quality assurance of care and patient safety, with increasing cost pressure and performance levels is of major importance in the high-risk and high cost area of the operating room (OR). Standard operating procedures (SOP) are an established tool for structuring and standardization of the clinical treatment pathways and show multiple benefits for quality assurance and process optimization. OBJECTIVES: An internal project was initiated in the department of anesthesiology and a continuous improvement process was carried out to build up a comprehensive SOP library. MATERIAL AND METHODS: In the first step the spectrum of procedures in anesthesiology was transferred to PDF-based SOPs. The further development to an app-based SOP library (Aesculapp) was due to the high resource expenditure for the administration and maintenance of the large PDF-based SOP collection and to deficits in the mobile availability. The next developmental stage, the SOP healthcare information assistant (SOPHIA) included a simplified and advanced update feature, an archive feature previously missing and notably the possibility to share the SOP library with other departments including the option to adapt each SOP to the individual situation. A survey of the personnel showed that the app-based allocation of SOPs (Aesculapp, SOPHIA) had a higher acceptance than the PDF-based developmental stage SOP form. CONCLUSION: The SOP management system SOPHIA combines the benefits of the forerunner version Aesculapp with improved options for intradepartmental maintenance and administration of the SOPs and the possibility of an export and editing function for interinstitutional exchange of SOPs. PMID- 26481390 TI - [Prevention of catheter-associated urinary tract infections: established and new aspects for the clinical routine : Revised recommendations on "prevention and control of catheter-associated urinary tract infections" of the commission for hospital hygiene and infection prevention at the Robert Koch Institute]. AB - Catheter-associated urinary tract infections (CAUTI) are one of the most common healthcare-associated infections (HAI) in Germany and are of particular relevance for intensive and standard care units. The revised guidelines of the commission for hospital hygiene and infection prevention (KRINKO) provide an update on prevention of CAUTI. The guidelines consider and evaluate the new literature published after the initial publication in 1999. The KRINKO recommendations should be implemented to protect patients from such infections, especially as CAUTIs are one of the most preventable types of HAI. In this respect tailor-made infection prevention bundles seem to be most effective and continuous infection surveillance procedures are of particular importance. Thus, a comparison with the reference data provided by the (German) National Reference Center for surveillance of nosocomial infections is possible. This article explains the recommendations for prevention measures included in the new KRINKO guidelines. PMID- 26481391 TI - [Intubating laryngeal tube suction disposable: Initial clinical experiences with a novel device for endotracheal intubation]. AB - BACKGROUND: According to the recent guidelines supraglottic airways, such as laryngeal tubes are recommended to ensure oxygenation in patients with unexpected difficult airways. The novel Intubating Laryngeal Tube Suction Disposable (iLTS D) is a modified laryngeal tube designed for secondary tracheal intubation. This pilot study evaluated the use of the iLTS-D in clinical practice with respect to practicality and efficacy. METHODS: In this study the airways of 30 consecutive adult patients with no evidence of a difficult airway undergoing elective ear, nose and throat (ENT) surgery were managed with the iLTS-D. After induction of anesthesia the iLTS-D was placed in position and checked for correct ventilation. Following muscle relaxation, endotracheal intubation through the iLTS-D was performed under continuous visualization using a flexible bronchoscope. Finally, the iLTS-D was removed leaving the endotracheal tube in place. Data were collected anonymously as part of a quality assurance program. Publication of the data was approved by the institutional review board. RESULTS: Initial iLTS-D placement took a median of 17 s (range 12-90 s) and provided sufficient ventilation in all patients; however, the position of the iLTS-D needed to be adjusted in four patients. Endotracheal intubation through the iLTS-D was achieved in 29 out of 30 patients at the first attempt (n = 23) or after 2 attempts (n = 6) and the median time required for intubation was 32 s (range 18 187 s). In five patients no laryngeal structures could initially be identified by bronchoscopy. Blind endotracheal intubation through the iLTS-D was performed in two cases and in two other patients the endotracheal tube was also blindly advanced but into the esophagus. After removal of the endotracheal tube and repositioning of the iLTS-D, successful tracheal intubation was subsequently achieved under bronchoscopic vision. The procedure was aborted and uneventful conventional intubation using direct laryngoscopy was carried out in one patient. The median time for removal of the iLTS-D after successful intubation was 20 s (range 15-80 s). Minor blood stains on the iLTS-D were observed in three patients. With one exception, all problems and adverse events occurred during the first 10 patients. CONCLUSION: This first clinical study demonstrated that in patients with apparently normal airways and in the hands of users without previous experience, the iLTS-D allowed sufficient ventilation in all patients and had a high success rate for subsequent endotracheal intubation. The results are, however, preliminary until confirmed by further studies, particularly in patients with difficult airways. PMID- 26481392 TI - [Ultrasound-guided retrograde emergency intubation : Life-saving management of a bleeding airway emergency with unclear anatomical situation]. AB - The technique of ultrasound-guided retrograde intubation is a less invasive procedure for airway management especially in an emergency situation with massive bleeding. This article describes a case of postoperative neck bleeding into the pharynx and neck leading to significant anatomical impairment combined with laryngeal obstruction that was successfully managed using this technique in a modified way. Anatomically non-palpable from a superficial approach, conventional cricotomy and awake tracheotomy were not possible and attempts of fiber optic intubation failed; therefore, ultrasound-guided tracheal puncture was used to advance a conventional central line guidewire towards and out of the mouth and to install orotracheal intubation via a Cook airway catheter cut in half which was advanced over the wire. All airway material remained in place in order to secure the airway until permanent tracheostomy was established along the wire entrance. Sufficient ventilation was possible with the Cook catheter and wire still in the tube. No hypoxic episodes occurred and the patient achieved full recovery. PMID- 26481393 TI - A radiopaque polymer hydrogel used as a fiducial marker in gynecologic-cancer patients receiving brachytherapy. AB - PURPOSE: We assessed a novel Food and Drug Administration-approved hydrogel, synthesized as absorbable iodinated particles, in gynecologic-cancer patients undergoing computed tomography (CT) or magnetic resonance (MR) based brachytherapy after external beam radiation. METHODS AND MATERIALS: Nineteen patients underwent CT-guided (n = 13) or MR-guided (n = 6) brachytherapy for gynecologic cancers. Seventy-seven hydrogel injections were placed. The hydrogel material was injected into gross residual disease and/or key anatomic landmarks in amounts ranging from 0.1 to 0.4 mL. The visibility of the tracer was scored on CT and on MR images using a 5-point scoring scale. A Cohen's kappa statistic was calculated to assess interobserver agreement. To assess the unadjusted effects of baseline parameters on hydrogel visibility, we modeled visibility using a linear mixed-effect model. RESULTS: Injections were without complication. The kappa statistic was 0.77 (95% confidence interval [CI], 0.68-0.87). The volume of hydrogel injected was significantly associated with visibility on both CT (p = 0.032) and magnetic resonance imaging (p = 0.016). We analyzed visibility by location, controlling for amount. A 0.1-cc increase in volume injected was associated with increases of 0.54 (95% CI = 0.05-1.03) in the CT visibility score and 0.83 (95% CI = 0.17-1.49) in the MR visibility score. Injection of 0.4 cc or more was required for unequivocal visibility on CT or MR. No statistically significant correlation was found between tumor type, tumor location, or anatomical location of injection and visibility on either CT or magnetic resonance imaging. CONCLUSIONS: In this first report of an injectable radiopaque hydrogel, targets were visualized to assist with three-dimensional-based brachytherapy in gynecologic malignancies. This marker has potential for several applications, is easy to inject and visualize, and caused no acute complications. PMID- 26481395 TI - ? PMID- 26481394 TI - 'Becoming a Physician'-medical students get acquainted with disadvantaged populations, and practise sensitive and effective communication. AB - BACKGROUND: The three-year pre-medical programme 'Becoming a Physician' focuses on different aspects of medical professionalism. Objectives are to increase awareness and sensitivity to disadvantaged populations, and practise sensitive effective communication skills. METHODS: The curriculum includes: (1) Visits to treatment centres for people with special needs, mental illnesses, substance abuse issues, physically or sexually abused, and prisoners. Students tour the facility, hold discussions with residents, and discuss ethical professional interrelations to the medical world. Students then write 'reflective diaries' summarizing their thoughts and emotions. (2) Participation in a communication course that focuses on learning by practising patient-oriented communication. Qualitative data were collected from three sources: reflective diaries, students' course evaluations, and interviews with the students' tutors. RESULTS: Data indicated that the students were very satisfied with the programme. They indicated an increase in awareness of the special needs of diverse populations, and in the sense of efficacy for conducting interviews tailored to patients' needs. Tutors reported a sense of 'personal growth' following their role as mentors. REFLECTIONS: Interactions of medical students with diverse populations, when accompanied by appropriate feedback mechanisms and strengthening of communication skills, can improve awareness and sensitivity to patients' special needs. This could help students become more sensitive and thoughtful physicians. PMID- 26481396 TI - Foundation years: a time of reflection. PMID- 26481397 TI - Pneumopericardium Due to Mediastinum Metastatic Lymph Nodes. AB - Pneumopericardium is rare. We report a case of unresectable oropharyngeal cancer with mediastinum metastatic lymph nodes, which lead to left main bronchus fistula and pneumopericardium. PMID- 26481398 TI - Relationships between Anticoagulation, Risk Scores and Adverse Outcomes in Dialysis Patients with Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the commonest cardiac arrhythmia including in end-stage renal failure patients, but controversy remains whether these patients benefit from anticoagulation. We reviewed the characteristics, management and outcomes of end-stage renal failure patients on dialysis with AF. METHODS: All patients started on dialysis at Middlemore Hospital between January 2000 and December 2008 who had AF were studied. Data regarding demographics, co morbidities, renal disease, AF and embolic, bleeding and/or mortality events were recorded. RESULTS: There were 141 out of 774(18.2%) dialysis patients with AF followed-up for 4.4+/-2.5 years, and 41.8%(59) were on warfarin. Incidence of all embolic events, ischaemic stroke, all bleeding and intracranial bleed were 4.1, 3.1, 9.6 and 0.82/100 person years respectively. Warfarin anticoagulation was associated with increased risk of intracranial bleed (hazards ratio=11.1, P=0.038), but not total embolic, bleeding events or mortality during follow-up (P=0.317-0.980). All three scores (CHADS2, CHA2DS2-VASc and HAS-BLED) could detect all embolic events (c=0.808-0.838), but not bleeding events (c=0.459 0.498). CONCLUSIONS: Anticoagulation with warfarin didn't significantly reduce embolism or mortality in dialysis patients with AF, but increased the risk of intracranial bleeds. Convention risk scores predict embolic but not bleeding events in these patients. PMID- 26481399 TI - Modification of Simplified Pulmonary Embolism Severity Index and its Prognostic Value in Patients with Acute Pulmonary Embolism. AB - BACKGROUND: Various risk stratification systems have been used to predict the clinical outcome of patients with pulmonary embolism (PE). In this study we present a modification of the simplified Pulmonary Embolism Severity Index (S PESI) score and evaluate its accuracy in predicting the outcome of these patients. MATERIALS AND METHODS: Patients older than 18 years with documented PE were enrolled in this study. S-PESI was calculated in all patients. We added electrocardiographic evidence of right ventricular strain as a new criteria and replaced the O2 saturation of <90% in S-PESI score with PaO2 /PaCO2 ratio obtained from the arterial blood gas analysis as two newly modified criteria to define a modified form of S-PESI system (modified s-PESI). Patients were followed for about one year in outpatient clinics. Any deaths attributable to PE or for unknown reasons were considered as PE related. We defined Major Adverse Cardio Pulmonary Events (MACPE) as sum of one-year mortality, need for thrombolysis and mechanical ventilation during index hospitalisation. RESULTS: Among 300 enrolled patients, in-hospital mortality occurred in 38 (12.7%) and one-year mortality in 73 (24.3%) patients. Considering a cut-off point of 3, modified s-PESI score had a lower sensitivity (49.3% vs. 89%) and higher specificity (79.4% vs. 37.7%) than S-PESI to predict one-year mortality. Area Under Curve (AUC) to predict MACPE was significantly higher for modified s-PESI (0.692 vs 0.730, P=0.012). CONCLUSION: The modified s-PESI is superior to S-PESI in predicting one-year outcome in patients with PE and can be used for more accurate risk stratification of these patients. PMID- 26481400 TI - UK quality statements on end of life care in dementia: a systematic review of research evidence. AB - BACKGROUND: Globally, the number of people who die with dementia is increasing. The importance of a palliative approach in the care of people with dementia is recognised and there are national polices to enhance current care. In the UK implementation of these polices is promoted by the National Institute for Health and Care Excellence (NICE) Dementia Quality Standards (QS). Since publication of the QS new care interventions have been developed. AIM: To explore critically the current international research evidence on effect available to inform NICE Dementia QS relevant to end of life (EOL) care. DESIGN: We used systematic review methods to seek the research evidence for three statements within the Dementia QS. These are those that recommend: (1) a case management approach, (2) discussing and consideration of making a statement about future care (SFC) and (3) a palliative care assessment (PCA). We included evaluative studies of relevant interventions that used a comparative design, such as trials and cohort studies, and measured EOL care outcomes for persons dying with moderate to severe dementia. Our primary outcome of interest was whether the intervention led to a measurable impact on wellbeing for the person with dementia and their family. We assessed included studies for quality using a scale by Higginson and colleagues (2002) for assessment of quality of studies in palliative care, and two authors undertook key review processes. Data sources included Cinahl, Embase, and PsychINFO from 2001 to August 2014. Our search strategy included free text and medical subject headings relevant to population and recommended care. RESULTS: We found seven studies evaluating a care intervention; four assessed SFC, three PCA. None assessed case management. Studies were of weak design; all used retrospective data and relied on others for precise record keeping and for accurate recall of events. There was limited overlap in outcome measurements. Overall reported benefits were mixed. CONCLUSIONS: Quality statements relevant to EOL care are useful to advance practice however they have a limited evidence base. High quality empirical work is needed to establish that the recommendations in these statements are best practice. PMID- 26481401 TI - Face and content validity of a virtual-reality simulator for myringotomy with tube placement. AB - BACKGROUND: Myringotomy with tube insertion can be challenging for junior Otolaryngology residents as it is one of the first microscopic procedures they encounter. The Western myringotomy simulator was developed to allow trainees to practice microscope positioning, myringotomy, and tube placement. This virtual reality simulator is viewed in stereoscopic 3D, and a haptic device is used to manipulate the digital ear model and surgical tools. OBJECTIVE: To assess the face and content validity of the Western myringotomy simulator. METHODS: The myringotomy simulator was integrated with new modules to allow speculum placement, manipulation of an operative microscope, and insertion of the ventilation tube through a deformable tympanic membrane. A questionnaire was developed in consultation with instructing surgeons. Fourteen face validity questions focused on the anatomy of the ear, simulation of the operative microscope, appearance and movement of the surgical instruments, deformation and cutting of the eardrum, and myringotomy tube insertion. Six content validity questions focused on training potential on surgical tasks such as speculum placement, microscope positioning, tool navigation, ear anatomy, myringotomy creation and tube insertion. A total of 12 participants from the Department of Otolaryngology-Head and Neck Surgery were recruited for the study. Prior to completing the questionnaire, participants were oriented to the simulator and given unlimited time to practice until they were comfortable with all of its aspects. RESULTS: Responses to 12 of the 14 questions on face validity were predominantly positive. One issue of concern was with contact modeling related to tube insertion into the eardrum, and the second was with the movement of the blade and forceps. The former could be resolved by using a higher resolution digital model for the eardrum to improve contact localization. The latter could be resolved by using a higher fidelity haptic device. With regard to content validity, 64% of the responses were positive, 21% were neutral, and 15% were negative. CONCLUSIONS: The Western myringotomy simulator appears to have sufficient face and content validity. Further development with automated metrics and skills transference testing is planned. PMID- 26481402 TI - Error significance but not error expectancy predicts error-related negativities for different error types. AB - Violations of outcome expectancies have been proposed to account for error related brain activity in the medial prefrontal cortex. The present study investigated whether early error monitoring processes are sensitive only to the expectancy of errors, or whether these processes also evaluate the significance of errors. To this end, we considered the error-related negativity (Ne/ERN), an electrophysiological marker of early error monitoring, in a modified flanker task in which errors could occur because participants responded to the flankers instead of the target (flanker error) or because a response unrelated to the stimulus was given (nonflanker error). By manipulating the onset of the flankers relative to the target, we manipulated two variables: the probability (and thus the expectancy) of flanker errors and the proportion of significant attention errors among each error type. Contrary to the predictions of outcome expectancy accounts, we found that the Ne/ERN was larger for flanker errors than for nonflanker errors only in the condition in which flanker errors were particularly frequent. Consistent with the error significance account, however, Ne/ERN amplitude mirrored the estimated proportion of significant attention errors as estimated by multinomial modeling. These results provide support for the idea that early performance monitoring as reflected by the Ne/ERN involves an evaluation of error significance. PMID- 26481403 TI - Association of APOE with tau-tangle pathology with and without beta-amyloid. AB - This study tested the hypothesis that the association of apolipoprotein E (APOE) with paired helical filament tau (PHF-tau) tangle pathology differs in brains with and without beta-amyloid. Participants were 1056 autopsied individuals from 2 clinical-pathologic cohort studies of aging and Alzheimer's disease (AD), the Religious Orders Study, and the Rush Memory and Aging Project. Neuropathologic measures were obtained using immunohistochemistry targeting beta-amyloid and PHF tau tangles in 8 brain regions. Linear regression was used to compare the relation of APOE epsilon4 and epsilon2 to PHF-tau-tangle density in persons with beta-amyloid relative to persons without beta-amyloid. We found an interaction between APOE epsilon4 carriers and presence of beta-amyloid (beta = -0.968, p = 0.013) such that the association of APOE epsilon4 with PHF-tau tangles was much stronger in brains with beta-amyloid. Stratified analysis shows that the association of APOE epsilon4 with PHF-tau tangles was considerably stronger among those with beta-amyloid (beta = 0.757, p = 1.1 * 10(-15)) compared to those without beta-amyloid which was not significant (beta = -0.201, p = 0.424). Separately, APOE epsilon2 was associated with fewer tangles in brains with beta amyloid (beta = -0.425, p = 7.6 * 10(-4)) compared to those without beta-amyloid which was not significant (beta = -0.102, p = 0.506). Thus, the presence of APOE epsilon4 and epsilon2 alleles was not associated with PHF-tau tangles in the absence of beta-amyloid. The data provide additional evidence that PHF-tau tangles in the absence of beta-amyloid may reflect a pathologic process distinct from Alzheimer's disease. PMID- 26481404 TI - Effect of mitochondrial cofactors and antioxidants supplementation on cognition in the aged canine. AB - A growing body of research has focused on modifiable risk factors for prevention and attenuation of cognitive decline in aging. This has led to an unprecedented interest in the relationship between diet and cognitive function. Several preclinical and epidemiologic studies suggest that dietary intervention can be used to improve cognitive function but randomized controlled trials are increasingly failing to replicate these findings. Here, we use a canine model of aging to evaluate the effects of specific components of diet supplementation which contain both antioxidants and a combination of mitochondrial cofactors (lipoic acid [LA] and acetyl-l-carnitine) on a battery of cognitive functions. Our data suggest that supplementation with mitochondrial cofactors, but not LA or antioxidant alone, selectively improve long-term recall in aged canines. Furthermore, we found evidence that LA alone could have cognitive impairing effects. These results contrast to those of a previous longitudinal study in aged canine. Our data demonstrate that one reason for this difference may be the nutritional status of animals at baseline for the 2 studies. Overall, this study suggests that social, cognitive, and physical activity together with optimal dietary intake (rather than diet alone) promotes successful brain aging. PMID- 26481406 TI - Changes in Femoral Version During Implantation of Anatomic Stems: Implications on Stem Design. AB - BACKGROUND: Component positioning in total hip arthroplasty (THA) is among the primary indicators for longevity and success. Acetabular component positioning has been discussed in literature at length; however, femoral component positioning is also important as it contributes to combined anteversion. METHODS: In this study, we examined the changes in femoral anteversion after the implantation of anatomic stem ABG II. A cadaveric study, a computed tomography based computer modeling study, and a clinical study using a navigation system were conducted to document these changes. RESULTS: These studies demonstrated that the anatomic stem ABG II increased the postimplantation femoral version by approximately 7 degrees . The postimplantation versions followed a bimodal distribution. The computed tomography and navigation data also highlighted that the patient population may roughly be divided into 2 groups: the first group that needs anteverted stem and the second group that needs little or no anteversion in the stem to recreate the desired version and offset. CONCLUSION: Based upon our data, we propose a new anatomic stem design that is offered in 2 version angles of 0 degrees and 7 degrees to help create the desired version and offset. PMID- 26481405 TI - Impact of proton pump inhibitor treatment on gastrointestinal bleeding associated with non-steroidal anti-inflammatory drug use among post-myocardial infarction patients taking antithrombotics: nationwide study. AB - STUDY QUESTION: What is the effect of proton pump inhibitors (PPIs) on the risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with non-steroidal anti-inflammatory drugs (NSAIDs)? METHODS: This was a nationwide cohort study based on linked administrative registry data from all hospitals in Denmark between 1997 and 2011. The study included patients aged 30 years and over admitted with a first myocardial infarction who survived at least 30 days after discharge. The association between PPIs and risk of gastrointestinal bleeding according to NSAID plus antithrombotic therapy was estimated using adjusted time dependent Cox regression models. STUDY ANSWER AND LIMITATIONS: The use of PPIs was independently associated with decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with NSAIDs. Of 82,955 post myocardial infarction patients (mean age 67.4 years, 64% (n=53,070) men), all of whom were taking single or dual antithrombotic therapy, 42.5% (n=35,233) filled at least one prescription for NSAIDs and 45.5% (n=37,771) received PPIs. Over a mean follow-up of 5.1 years, 3229 gastrointestinal bleeds occurred. The crude incidence rates of bleeding (events/100 person years) on NSAID plus antithrombotic therapy were 1.8 for patients taking PPIs and 2.1 for those not taking PPIs. The adjusted risk of bleeding was lower with PPI use (hazard ratio 0.72, 95% confidence interval 0.54 to 0.95) regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used. The main limitation of the study is its observational non-randomised design. The results suggest that PPI treatment probably has a beneficial effect regardless of underlying gastrointestinal risk and that when NSAIDs cannot be avoided in post-myocardial infarction patients, physicians might prescribe a PPI as well. The study does not clarify whether PPIs might be safely omitted in specific subgroups of patients with a low risk of gastrointestinal bleeding. WHAT THIS STUDY ADDS: In post myocardial infarction patients, bleeding complications have been associated with both antithrombotic and NSAID treatment. Concurrent use of PPIs was independently associated with a decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and NSAID, regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used. FUNDING, COMPETING INTERESTS, DATA SHARING: AMSO has received a grant from the Danish Council of Independent Research (grant 12-132760). GHG is supported by an unrestricted research scholarship from the Novo Nordisk Foundation. PMID- 26481407 TI - A Comparison of 2 Tibial Inserts of Different Constraint for Cruciate-Retaining Primary Total Knee Arthroplasty: An Additional Tool for Balancing the Posterior Cruciate Ligament. AB - BACKGROUND: Frequently, a normal posterior-cruciate ligament (PCL) is removed at the surgeon's discretion, converting the normal 4-ligament knee to a 2-ligament knee, thus eliminating the need to balance all 4 ligaments. The development of modular tibial components has led to the availability of differing polyethylene inserts that permit adjustment to the flexion gap independent of the extension gap, permitting PCL balancing not previously available. The purpose of this study is to analyze a specific cruciate-retaining (CR) prosthesis which has 2 polyethylene inserts intended for CR knee use. METHODS: Between February 2004 and February 2013, the senior author (R.H.E.) has performed 930 total knee arthroplasties using the CR flat insert and 424 knees using the CR lipped insert. The inserts were selected during surgery, based on the assessed tension and function of the PCL. The patients were followed up as part of a prospective total joint program with the Knee Society clinical scoring, range of motion, complications, revisions, preoperative coronal deformity, gender, body mass index, and status of the anterior-cruciate ligament intraoperatively. RESULTS: The average Knee Score was 92.4 for the flat group and 92.1 for the lipped group. Average knee flexion was 116.2 degrees for the flat group and 114.4 degrees for the lipped group (P=.2). Average knee extension (flexion deformity) was 2.1 degrees for the flat group and 0.9 degrees for the lipped group CONCLUSION: The results reported here show that clinical outcomes and survivorship were no different for either insert option, leading to indirect evidence that appropriate soft tissue balance had been achieved. PMID- 26481408 TI - Direct Cost and Complications Associated With Total Joint Arthroplasty in Patients With Preoperative Anxiety and Depression. AB - INTRODUCTION: The outcome of total joint arthroplasty (TJA) may be affected by numerous factors including the mental health status of patients and the presence of psychological disorders Therefore, the present study was designed and conducted to determine the impact of concomitant psychiatric disorders on the hospitalization charges and complications in patients with preoperative depression or anxiety undergoing TJA. MATERIALS AND METHODS: International Classification of Diseases, Ninth Revision, codes were used to identify perioperative complications in patients with and without concomitant diagnosis of depression or anxiety who underwent TJA at our institution during 2009. Hospitalization charges and complications were compared for patients with and without depression or anxiety undergoing TJA. RESULTS: Respectively, 12.7% and 6.4% of knee and the hip arthroplasty patients had concomitant depression or anxiety. In the knee but not the hip group, the charge was $3420 higher in patients with depression/anxiety (P < .001). Anxiety and depression and higher American Society of Anesthesiologists score were independent predictors of complications. DISCUSSION: Depression or anxiety was a predictor of increased complications after TJA. Therefore, patients with depression or anxiety undergoing TJA need to be counselled appropriately, and all efforts need to be invested to minimize complications and the added cost in these patients. PMID- 26481409 TI - Surgeons' Leadership Styles and Team Behavior in the Operating Room. AB - BACKGROUND: The importance of leadership is recognized in surgery, but the specific impact of leadership style on team behavior is not well understood. In other industries, leadership is a well-characterized construct. One dominant theory proposes that transactional (task-focused) leaders achieve minimum standards and transformational (team-oriented) leaders inspire performance beyond expectations. STUDY DESIGN: We videorecorded 5 surgeons performing complex operations. Each surgeon was scored on the Multifactor Leadership Questionnaire, a validated method for scoring transformational and transactional leadership style, by an organizational psychologist and a surgeon researcher. Independent coders assessed surgeons' leadership behaviors according to the Surgical Leadership Inventory and team behaviors (information sharing, cooperative, and voice behaviors). All coders were blinded. Leadership style (Multifactor Leadership Questionnaire) was correlated with surgeon behavior (Surgical Leadership Inventory) and team behavior using Poisson regression, controlling for time and the total number of behaviors, respectively. RESULTS: All surgeons scored similarly on transactional leadership (range 2.38 to 2.69), but varied more widely on transformational leadership (range 1.98 to 3.60). Each 1-point increase in transformational score corresponded to 3 times more information sharing behaviors (p < 0.0001) and 5.4 times more voice behaviors (p = 0.0005) among the team. With each 1-point increase in transformational score, leaders displayed 10 times more supportive behaviors (p < 0.0001) and displayed poor behaviors 12.5 times less frequently (p < 0.0001). Excerpts of representative dialogue are included for illustration. CONCLUSIONS: We provide a framework for evaluating surgeons' leadership and its impact on team performance in the operating room. As in other fields, our data suggest that transformational leadership is associated with improved team behavior. Surgeon leadership development, therefore, has the potential to improve the efficiency and safety of operative care. PMID- 26481410 TI - Twenty-year dynamics of hypertension in Iranian adults: age, period, and cohort analysis. AB - Hypertension is a well-known health problem all over the world. Many studies have assessed its prevalence and associated risk factors, but all were cross-sectional and did not evaluate the trend of hypertension through all three different temporal dimensions including age, period, and cohort. So, we aimed to assess the 20-year dynamics of hypertension via the age-period-cohort model. Data from 74,155 subjects aged 25-60 years gathered through five national health surveys (1990-91, 1999, 2003, 2007, and 2011) were used in this study. The age-period cohort effect on hypertension was analyzed using the intrinsic estimator model. The prevalence of hypertension increased with age for both genders except for males in 2003 and 2011 periods with drops of 3.5% for ages 55-60 and 8.1% for ages 50-60, respectively. As for the period effect, the prevalence of hypertension was almost constant in all age groups for both genders from 1990 1999. The cohort-based prevalence of hypertension showed a declining trend in all cohorts for females except for 2011 in birth cohort of 1950-1955 which remains stationary. The trend of prevalence for males also follows a decreasing trend except for periods of 2003, 2007, and 2011; birth cohorts of 1945-1949, 1975 1980, and 1950-1960 increase by 3.5%, 1.9%, and 8.1%, respectively. The age effect on the prevalence of hypertension showed an almost monotonic increasing trend. The period effect increased the total prevalence of hypertension from 1992 to 1997. The cohort effect also showed a monotonic decrease in hypertension prevalence except for a few discrepancies. PMID- 26481411 TI - Association of serum cotinine levels and the parameters of vascular structure and function in never-smoking adults. AB - Passive smoking is now recognized to be associated with early arterial damage. The aim of this study was to assess the relationship between secondhand smoke (SHS) exposure, measured objectively by serum cotinine level, and the parameters used to assess vascular structure and function among never smokers in North China. From January 2008 to August 2008, 652 adults aged 20-70 years were enrolled. Brachial-ankle pulse wave velocity (baPWV), ankle-brachial index, and carotid intima-media thickness measurements were performed in all patients. All participants were required to respond to an interviewer-led questionnaire including medical histories and demographic data and to receive blood tests on biochemical indicators. We found that in nonsmokers, higher levels of serum cotinine were positively associated with higher baPWV and brachial pulse pressure after adjusting for heart rate, body mass index, and other confounders. Tests for linear trends for this association were statistically significant. In contrast, no association was present with ankle-brachial index and carotid intima-media thickness. In never smokers, higher SHS exposure measured objectively by serum cotinine levels was found to be associated with brachial pulse pressure and baPWV after adjusting for confounders. PMID- 26481412 TI - Metal release from contaminated coastal sediments under changing pH conditions: Implications for metal mobilization in acidified oceans. AB - To investigate the impacts and processes of CO2-induced acidification on metal mobilization, laboratory-scale experiments were performed, simulating the scenarios where carbon dioxide was injected into sediment-seawater layers inside non-pressurized chambers. Coastal sediments were sampled from two sites with different contamination levels and subjected to pre-determined pH conditions. Sediment samples and overlying water were collected for metal analysis after 10 days. The results indicated that CO2-induced ocean acidification would provoke increased metal mobilization causing adverse side-effects on water quality. The mobility of metals from sediment to the overlying seawater was correlated with the reduction in pH. Results of sequential extractions of sediments illustrated that exchangeable metal forms were the dominant source of mobile metals. Collectively, our data revealed that high metal concentrations in overlying seawater released from contaminated sediments under acidic conditions may strengthen the existing contamination gradients in Maluan Bay and represent a potential risk to ecosystem health in coastal environments. PMID- 26481413 TI - Accumulation and distribution of trace metals within soils and the austral cordgrass Spartina densiflora in a Patagonian salt marsh. AB - Concentrations of Cd, Cu, Fe, Pb, and Zn were determined in soils and in below- and above-ground structures of Spartina densiflora in a Patagonian salt marsh (San Antonio, Rio Negro, Argentina). Also, the relationship between trace metal concentrations in soils and plants was investigated to improve our knowledge regarding the ability of this plant species to take up and accumulate trace metals from the soil. Our results indicate that, within the studied salt marsh, soil trace metal concentrations follow a decreasing concentration gradient toward the sea. They show moderate pollution and a potentially negative biological effect in one site of the salt marsh. While below-ground structures reflect the soil metal concentration pattern, this is not so evident in above-ground concentrations. Also, S. densiflora is able to absorb a limited amount of metals present in the soil, the soil bioaccumulation factor being lower in sites where soil metal concentration is higher. PMID- 26481414 TI - Heavy metal levels in dune sands from Matanzas urban resorts and Varadero beach (Cuba): Assessment of contamination and ecological risks. AB - Concentrations of chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn) and lead (Pb) in dune sands from six urban and suburban Matanzas (Cuba) resorts and Varadero beach were estimated by X-ray fluorescence analysis. Ranges of metal contents in dune sands show a strong variation across the studied locations (in mg/kg(-1)): 20-2964 for Cr, 17-183 for Ni, 17-51 for Cu, 18-88 for Zn and 5-29 for Pb. The values of contamination factors and contamination degrees how that two of the studied Matanzas's resorts (Judio and Chirry) are strongly polluted. The comparison with Sediment Quality Guidelines shows that dune sands from Judio resort represent a serious risk for humans, due to polluted Cr and Ni levels, while sands from the rest of the studied resorts, including Varadero beach, do not represent any risk for public use. PMID- 26481415 TI - Xeno-immunosuppressive properties of human decidual stromal cells in mouse models of alloreactivity in vitro and in vivo. AB - BACKGROUND AIMS: Human decidual stromal cells (hDSCs) may cure acute graft-versus host disease (GVHD) in humans. We evaluated immunosuppression by xenogenic hDSCs in mice, both in vitro and in vivo. METHODS: hDSCs inhibited mouse lymphocyte proliferation in allo- and xeno-stimulation assays in mixed lymphocyte culture (MLC) and after mitogenic stimulation. The immunosuppressive effect of hDSCs was dose-dependent and strain-independent. Trans-well experiments showed that hDSCs needed cell-to-cell contact to be immunosuppressive. In a GVHD model, Balb/c mice were transplanted with bone marrow and splenocytes from C57BL/6 a donor. Varying doses of hDSCs (10(5)-10(6) per mouse) were infused at different time points. Recipient mice showed lower GVHD scores than untreated mice, but they did not have consistently improved survival. Histopathological investigation of liver, gastrointestinal tract and skin of animals with GVHD did not show any significant improvement from hDSC infusion. RESULTS: hDSCs were transduced with immunosuppressive genes including those encoding interleukin-10, prostaglandin-E2 receptor, indoleamine dioxygenase, interferon-gamma and programmed death ligand 1. Transduced and untransduced hDSCs showed similar effects in vitro and in vivo. At a dose of 10(6)hDSCs per mouse, the majority of recipients died of embolism. CONCLUSIONS: hDSCs inhibit allo-reactivity, xeno-reactivity and mitogen-induced stimulation in mouse lymphocytes. Although the GVHD score was reduced by hDSC infusion, survival and GVHD histopathology were not improved. One reason for failure was fatal embolism. PMID- 26481417 TI - Lactate and its many faces. AB - BACKGROUND: Lactate is traditionally seen as a marker of ischemia and a waste product of anaerobic glycolysis. In the last thirty years a more beneficial side of lactate as an alternative 'glucose sparing' fuel has been demonstrated. However, the translation of these growing insights to clinical practice seems to appear with great delay. METHODS: A review of the literature was performed, focusing on glucose and lactate in relation to cerebral energy metabolism, in the context of four typical clinical situations, namely (transient states of) low glucose availability for the brain due to hypoglycemia, combined with high blood lactate concentrations; permanent neuroglycopenia; lactic acidosis in mitochondrial disorders; and ischemic as well as traumatic brain injury. RESULTS: Lactate is thought to be an alternative fuel in the brain of patients with glucose transporter type 1 deficiency syndrome and glycogen storage disease, and it has been demonstrated that lactate might have a protective role in ischemic and traumatic brain injury. CONCLUSION: Lactate has an apparently largely ignored, but potential beneficial role in the clinical management of several neurologic disorders. PMID- 26481416 TI - Gemcitabine-releasing mesenchymal stromal cells inhibit in vitro proliferation of human pancreatic carcinoma cells. AB - BACKGROUND AIMS: Pancreatic cancer (pCa) is a tumor characterized by a fibrotic state and associated with a poor prognosis. The observation that mesenchymal stromal cells (MSCs) migrate toward inflammatory micro-environments and engraft into tumor stroma after systemic administration suggested new therapeutic approaches with the use of engineered MSCs to deliver and produce anti-cancer molecules directly within the tumor. Previously, we demonstrated that without any genetic modifications, MSCs are able to deliver anti-cancer drugs. MSCs loaded with paclitaxel by exposure to high concentrations release the drug both in vitro and in vivo, inhibiting tumor proliferation. On the basis of these observations, we evaluated the ability of MSCs (from bone marrow and pancreas) to uptake and release gemcitabine (GCB), a drug widely used in pCa treatment. METHODS: MSCs were primed by 24-h exposure to 2000 ng/mL of GCB. The anti-tumor potential of primed MSCs was then investigated by in vitro anti-proliferation assays with the use of CFPAC-1, a pancreatic tumor cell line sensitive to GCB. The uptake/release ability was confirmed by means of high-performance liquid chromatography analysis. A cell-cycle study and secretome evaluation were also conducted to better understand the characteristics of primed MSCs. RESULTS: GCB-releasing MSCs inhibit the growth of a human pCa cell line in vitro. CONCLUSIONS: The use of MSCs as a "trojan horse" can open the way to a new pCa therapeutic approach; GCB loaded MSCs that integrate into the tumor mass could deliver much higher concentrations of the drug in situ than can be achieved by intravenous injection. PMID- 26481418 TI - Morphometric structural diversity of a natural armor assembly investigated by 2D continuum strain analysis. AB - Many armored fish scale assemblies use geometric heterogeneity of subunits as a design parameter to provide tailored biomechanical flexibility while maintaining protection from external penetrative threats. This study analyzes the spatially varying shape of individual ganoid scales as a structural element in a biological system, the exoskeleton of the armored fish Polypterus senegalus (bichir). X-ray microcomputed tomography is used to generate digital 3D reconstructions of the mineralized scales. Landmark-based geometric morphometrics is used to measure the geometric variation among scales and to define a set of geometric parameters to describe shape variation. A formalism using continuum mechanical strain analysis is developed to quantify the spatial geometry change of the scales and illustrate the mechanisms of shape morphing between scales. Five scale geometry variants are defined (average, anterior, tail, ventral, and pectoral fin) and their functional implications are discussed in terms of the interscale mobility mechanisms that enable flexibility within the exoskeleton. The results suggest that shape variation in materials design, inspired by structural biological materials, can allow for tunable behavior in flexible composites made of segmented scale assemblies to achieve enhanced user mobility, custom fit, and flexibility around joints for a variety of protective applications. PMID- 26481419 TI - Structural insights into the mechanism of Escherichia coli YmdB: A 2'-O-acetyl ADP-ribose deacetylase. AB - The Escherichia coli protein YmdB belongs to the macrodomain protein family, which can bind ADP-ribose (ADPr) and its derivatives. Recently, YmdB was reported to be capable of deacetylating O-acetyl-ADP-ribose (OAADPr) to yield ADPr and free acetate. To study the substrate specificity and catalytic mechanism, the crystal structures of E. coli YmdB in complex with ADPr, double mutant N25AD35A complexed with 2'-OAADPr, and Y126A/ADPr complex were solved at 1.8A, 2.8A and 3.0A resolution, respectively. Structural and biochemical studies reveal that YmdB has substrate specificity against 2'-OAADPr. The conserved residues Asn25 and Asp35 are crucial for catalytic activity, and an active water molecule is proposed as the nucleophile to attack the acetyl group of 2'-OAADPr. Our findings indicate that the conserved phenyl group of Tyr126 plays a crucial role in catalytic activity by stabilizing the right orientation of distal ribose and that Gly32 may be important for activity by interacting with the acetyl group of 2' OAADPr. Based on these observations, a model of YmdB in complex with 2'-OAADPr was made to illustrate the proposed catalytic mechanism of YmdB. PMID- 26481420 TI - Comparative epigenetic influence of autologous versus fetal bovine serum on mesenchymal stem cells through in vitro osteogenic and adipogenic differentiation. AB - Mesenchymal stem cells (MSCs) derived from bone marrow (BM) represents a useful source of adult stem cells for cell therapy and tissue engineering. MSCs are present at a low frequency in the BM; therefore expansion is necessary before performing clinical studies. Fetal bovine serum (FBS) as a nutritional supplement for in vitro culture of MSCs is a suitable additive for human cell culture, but not regarding subsequent use of these cells for clinical treatment of human patients due to the risk of viral and prion transmission as well as xenogeneic immune responses after transplantation. Recently, autologous serum (AS) has been as a supplement to replace FBS in culture medium. We compared the effect of FBS versus AS on the histone modification pattern of MSCs through in vitro osteogenesis and adipogenesis. Differentiation of stem cells under various serum conditions to a committed state involves global changes in epigenetic patterns that are critically determined by chromatin modifications. Chromatin immunoprecipitation (ChIP) coupled with real-time PCR showed significant changes in the acetylation and methylation patterns in lysine 9 (Lys9) of histone H3 on the regulatory regions of stemness (Nanog, Sox2, Rex1), osteogenic (Runx2, Oc, Sp7) and adipogenic (Ppar-gamma, Lpl, adiponectin) marker genes in undifferentiated MSCs, FBS and AS. All epigenetic changes occurred in a serum dependent manner which resulted in higher expression level of stemness genes in undifferentiated MSCs compared to differentiated MSCs and increased expression levels of osteogenic genes in AS compared to FBS. Adipogenic genes showed greater expression in FBS compared to AS. These findings have demonstrated the epigenetic influence of serum culture conditions on differentiation potential of MSCs, which suggest that AS is possibly more efficient serum for osteogenic differentiation of MSCs in cell therapy purposes. PMID- 26481422 TI - Role of P2 * 7 receptor in the differentiation of bone marrow stromal cells into osteoblasts and adipocytes. AB - Imbalance in osteogenesis and adipogenesis of bone marrow stromal cells is a crucial pathological process of osteoporosis. P2 * 7-deficient mice were previously shown to exhibit an osteopenic phenotype and abnormal fat distribution, leading us to hypothesize that P2 * 7R activation was involved in the differentiation of BMSCs. Consequently, we investigated the effect of P2 * 7R activation on osteogenic and adipogenic differentiation of BMSCs in vitro, and established an ovariectomized (OVX) osteoporosis model to test P2 * 7R activation on adipocytes formation, trabecular and cortical bone parameters in vivo. Our results showed that activation of P2 * 7R by BzATP resulted in increase in the gene expression of osteoblastic markers, the activity of alkaline phosphatase and bone mineralization, and decrease in the gene expression of adipogenic markers and the number of adipocytes generated by BMSCs. MicroCT analysis showed that BzATP treatment ameliorated the micro-architecture of trabecular bones in OVX mice, while cortical bone parameters were unaffected. H&E staining analysis showed that was increase in the volume of trabecular bone and number of trabecular bone, and decrease in bone marrow adipocytes in BzATP-treated OVX mice compared with OVX mice. Also, activation of P2 * 7R transduced to ERK1/2 and JNK signaling pathways. This transduction was prevented by BBG, U0126, and SP600125. U0126 and SP600125 prevented BzATP-induced up-regulation of osteogenic-related genes expression and down-regulation of adipogenic-related genes expression. These data suggest that BzATP activates the differentiation of BMSCs into osteoblasts but not adipocytes by stimulating ERK1/2 and JNK signaling pathways in a P2 * 7R-dependent way. PMID- 26481421 TI - Regulation of fibrin-mediated tumor cell adhesion to the endothelium using anti thrombin aptamer. AB - Molecular intervention during transient stages of various metastatic pathways may lead to development of promising therapeutic technologies. One of such involves soluble fibrin (sFn) that has been implicated as a cross-linker between circulating blood or tumor cells and endothelial cell receptors, promoting cell arrest on the endothelium during circulation. sFn generation is a result of thrombin-mediated fibrinogen (Fg) cleavage due to either vascular injuries or a tumor microenvironment. For cancer therapy, thrombin-mediated conversions of Fg to sFn thus serve as potential intervention points to decrease circulating tumor cell adhesion to the endothelium and subsequent metastatic events. The purpose of this work was to investigate the function of an anti-thrombin oligonucleotide aptamer in reducing tumor cell arrest. Both molecular and cellular interactions were examined to demonstrate the binding and inhibitory effects of anti-thrombin aptamer. The results show that the aptamer is capable of inhibiting thrombin mediated Fg conversion, thereby reducing sFn-mediated tumor cell adhesion in a concentration-dependent manner. Notably, the aptamer is able to bind thrombin under dynamic flow conditions and reduce tumor cell adhesive events at various physiological shear rates. This study further indicates that oligonucleotide aptamers hold great promise as therapeutic regulators of tumor cell adhesion, and consequently, metastatic activity. PMID- 26481423 TI - Putting the MeaT into TeaM Training: Development, Delivery, and Evaluation of a Surgical Team-Training Workshop. AB - BACKGROUND: Despite importance to patient care, team training is infrequently used in surgical education. To address this, a workshop was developed by the Association for Surgical Education Simulation Committee to teach team training using high-fidelity patient simulators and the American College of Surgeons Association of Program Directors in Surgery team-training curriculum. METHODS: Workshops were conducted at 3 national meetings. Participants completed preworkshop and postworkshop questionnaires to define experience, confidence in using simulation, intention to implement, as well as workshop content quality. The course consisted of (A) a didactic review of Preparation, Implementation, and Debriefing and (B) facilitated small group simulation sessions followed by debriefings. RESULTS: Of 78 participants, 51 completed the workshops. Overall, 65% indicated that residents at their institutions used patient simulation, but only 33% used the American College of Surgeons-the Association of Program Directors in Surgery team-training modules. The workshop increased confidence to implement simulation team training (3.4 +/- 1.3 vs 4.5 +/- 0.9). Quality and importance were rated highly (5.4 +/- 00.6, highest score = 6). CONCLUSIONS: Preparation for simulation-based team training is possible in this workshop setting, although the effect on actual implementation remains to be determined. PMID- 26481424 TI - Novel Educational Module for Subclavian Central Venous Catheter Insertion Using Real-Time Ultrasound Guidance. AB - OBJECTIVE: Given increasing evidence supporting a real-time ultrasound (US) guided approach for subclavian vein (SCV) central venous catheter (CVC) insertion as compared with the traditional landmark approach, we sought to develop a standardized curriculum to offer healthcare providers a means to attain increased competency and confidence in US-guided SCV CVC insertion. DESIGN: Retrospective review of prospectively collected data. SETTING: Single institution's American College of Surgeons Level 1 Accredited Education Institute within an academic tertiary care center. SUBJECTS: A total of 77 residents and midlevel providers working in our surgical intensive care unit. INTERVENTIONS: Providers participated in a tiered educational module designed to teach safe US-guided SCV CVC insertion. The education consisted of a multimedia didactic presentation and a hands-on simulation session, including US anatomy on live subjects and anatomical model-based SCV CVC insertion. MEASUREMENTS AND MAIN RESULTS: Assessment of the effect of education included a written examination and confidence survey, administered pre- and postintervention, and videotaped simulation session graded by blinded expert evaluators. Of the 77 participants, 70 participants completed a posttest with a median 5-point increase in score compared with that of the pretest score (p < 0.0001). Confidence ratings based on a 5-point Likert scale demonstrated an increase in confidence in SCV CVC insertion (p < 0.0001), using the landmark approach (p < 0.0001), using US-guided approach (p < 0.0001), and in use of US to image the SCV (p < 0.0001). Postgraduate year-1 residents had lower mean global rating score (p = 0.010) than any other participants. CONCLUSIONS: This comprehensive hands-on teaching module based curriculum enhanced learner knowledge of and confidence in US-guided SCV CVC insertion. This module can be implemented in simulation centers for teaching safe and successful SCV CVC insertion. PMID- 26481425 TI - Hirsch Index Value and Variability Related to General Surgery in a UK Deanery. AB - OBJECTIVES: The Hirsch Index (h-index) is often used to assess research impact, and on average a social science senior lecturer will have an h-index of 2.29, yet its validity within the context of UK General Surgery (GS) is unknown. The aim of this study was to calculate the h-indices of a cohort of GS consultants in a UK Deanery to assess its relative validity. DESIGN: Individual h-indices and total publication (TP) counts were obtained for GS consultants via the Scopus and Web of Science (WoS) Internet search engines. Assessment of construct validity and reliability of these 2 measures of the h-index was undertaken. SETTING: All hospitals in a single UK National Health Service Deanery were included (14 general hospitals). PARTICIPANTS: All 136 GS consultants from the Deanery were included. RESULTS: Median h-index (Scopus) was 5 (0-52) and TP 15 (0-369), and strong correlation was found between h-index and TP (rho = 0.932, p < 0.001), with the intraclass correlation between Scopus and WoS h-index also significant (intraclass correlation coefficient = 0.973 [95% CI: 0.962-0.981], p < 0.001). Academic GS consultants had higher h-indices than nonacademic University Hospital and District General Hospital consultants (Scopus 12 vs 7 vs 4 [p < 0.001] and WoS 10.5 vs 7 vs 4 [p < 0.001]). h-Index was >2.29 in 57.4% of consultants. No subspecialty differences were apparent in median h-indices (p = 0.792) and TP (p = 0.903). CONCLUSIONS: h-Index is a valid GS research productivity metric with over half of consultants performing at levels equivalent to social science Senior Lecturers. PMID- 26481426 TI - ["English" language in medicine]. PMID- 26481427 TI - IL-4 Protects the Mitochondria Against TNFalpha and IFNgamma Induced Insult During Clearance of Infection with Citrobacter rodentium and Escherichia coli. AB - Citrobacter rodentium is a murine pathogen that serves as a model for enteropathogenic Escherichia coli. C. rodentium infection reduced the quantity and activity of mitochondrial respiratory complexes I and IV, as well as phosphorylation capacity, mitochondrial transmembrane potential and ATP generation at day 10, 14 and 19 post infection. Cytokine mRNA quantification showed increased levels of IFNgamma, TNFalpha, IL-4, IL-6, and IL-12 during infection. The effects of adding these cytokines, C. rodentium and E. coli were hence elucidated using an in vitro colonic mucosa. Both infection and TNFalpha, individually and combined with IFNgamma, decreased complex I and IV enzyme levels and mitochondrial function. However, IL-4 reversed these effects, and IL-6 protected against loss of complex IV. Both in vivo and in vitro, the dysfunction appeared caused by nitric oxide-generation, and was alleviated by an antioxidant targeting mitochondria. IFNgamma -/- mice, containing a similar pathogen burden but higher IL-4 and IL-6, displayed no loss of any of the four complexes. Thus, the cytokine environment appears to be a more important determinant of mitochondrial function than direct actions of the pathogen. As IFNgamma and TNFalpha levels increase during clearance of infection, the concomitant increase in IL-4 and IL-6 protects mitochondrial function. PMID- 26481428 TI - Hemocompatibility evaluation in vitro of methoxy polyethyleneglycol polycaprolactone copolymer solutions. AB - Amphiphilic block copolymer methoxy polyethyleneglycol-polycaprolactone (mPEG PCL) has attracted interest in the biomedical field, due to its water solubility and biodegradability. Nevertheless, the blood safety of mPEG-PCL copolymers has not been investigated in detail. Because mPEG-PCL copolymers introduced in vivo would inevitably interact with blood tissue, an investigation of possible interactions of mPEG-PCL with key blood components is crucial. We studied the effects of two mPEG-PCL copolymer solutions on blood coagulation, the morphology and lysis of human red blood cells (RBCs), the structure of plasma fibrinogen, complement activation, and platelet aggregation. We found that higher concentrations of the mPEG-PCL copolymers impaired blood clotting, and the copolymers had little impact on the morphology or lysis of RBCs. From the spectroscopy results, the copolymers affected the local microstructure of fibrinogen. The copolymers significantly activated the complement system in a concentration-dependent way. At higher concentrations, the copolymers impaired platelet aggregation, which may have been mediated by an inhibition of the arachidonic acid pathway. These findings provide important information that may be useful for the molecular design and biomedical applications of mPEG-PCL copolymers. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 802 812, 2016. PMID- 26481429 TI - Redox-Dependent HMGB1 Isoforms as Pivotal Co-Ordinators of Drug-Induced Liver Injury: Mechanistic Biomarkers and Therapeutic Targets. AB - SIGNIFICANCE: High-mobility group box 1 (HMGB1) is a critical protein in the coordination of the inflammatory response in drug-induced liver injury (DILI). HMGB1 is released from necrotic hepatocytes and activated immune cells. The extracellular function of HMGB1 is dependent upon redox modification of cysteine residues that control chemoattractant and cytokine-inducing properties. Existing biomarkers of DILI such as alanine aminotransferase (ALT) have limitations such as lack of sensitivity and tissue specificity that can adversely affect clinical intervention. RECENT ADVANCES: HMGB1 isoforms have been shown to be more sensitive biomarkers than ALT for predicting DILI development and the requirement for liver transplant following acetaminophen (APAP) overdose. Hepatocyte-specific conditional knockout of HMGB1 has demonstrated the pivotal role of HMGB1 in DILI and liver disease. Tandem mass spectrometry (MS/MS) enables the characterization and quantification of different mechanism-dependent post-translationally modified isoforms of HMGB1. CRITICAL ISSUES: HMGB1 shows great promise as a biomarker of DILI. However, current diagnostic assays are either too time-consuming to be clinically applicable (MS/MS) or are unable to distinguish between different redox and acetyl isoforms of HMGB1 (ELISA). Additionally, HMGB1 is not liver specific, so while it outperforms ALT (also not liver specific) as a biomarker for the prediction of DILI development, it should be used in a biomarker panel along with liver-specific markers such as miR-122. FUTURE DIRECTIONS: A point-of care test for HMGB1 and the development of redox and acetyl isoform-targeting antibodies will advance clinical utility. Work is ongoing to validate baseline levels of circulating HMGB1 in healthy volunteers. PMID- 26481432 TI - Rheumatoid arthritis: Hitting the brakes on ectopic lymphoid structure formation. PMID- 26481431 TI - Transcriptome sequencing of a thalloid bryophyte; Dumortiera hirsuta (Sw) Nees: assembly, annotation, and marker discovery. AB - Bryophytes are the first land plants but are scarcely studied at the molecular level. Here, we report transcriptome sequencing and functional annotation of Dumortiera hirsuta, as a representative bryophyte. Approximately 0.5 million reads with ~195 Mb data were generated by sequencing of mRNA using 454 pyrosequencer. De novo assembly of reads yielded 85,240 unigenes (12,439 contigs and 72,801 singletons). BlastX search at NCBI-NR database showed similarity of 33,662 unigenes with 10-(10) e-value. A total of 23,685 unigenes were annotated at TAIR10 protein database. The annotated unigenes were further classified using the Gene Ontology. Analysis at Kyoto Encyclopedia of Genes and Genomes pathway database identified 95 pathways with significant scores, among which metabolic and biosynthesis of secondary metabolite were the major ones. Phenylpropanoid pathway was elucidated and selected genes were characterized by real time qPCR. We identified 447 transcription factors belonging to 41 families and 1594 eSSRs in 1479 unigenes. D. hirsuta unigenes showed homology across the taxa from algae to angiosperm indicating their role as the connecting link between aquatic and terrestrial plants. This could be a valuable genomic resource for molecular and evolutionary studies. Further, it sheds light for the isolation and characterization of new genes with unique functions. PMID- 26481430 TI - 1,3-propanediol binds deep inside the channel to inhibit water permeation through aquaporins. AB - Aquaporins and aquaglyceroporins (AQPs) are membrane channel proteins responsible for transport of water and for transport of glycerol in addition to water across the cell membrane, respectively. They are expressed throughout the human body and also in other forms of life. Inhibitors of human AQPs have been sought for therapeutic treatment for various medical conditions including hypertension, refractory edema, neurotoxic brain edema, and so forth. Conducting all-atom molecular dynamics simulations, we computed the binding affinity of acetazolamide to human AQP4 that agrees closely with in vitro experiments. Using this validated computational method, we found that 1,3-propanediol (PDO) binds deep inside the AQP4 channel to inhibit that particular aquaporin efficaciously. Furthermore, we used the same method to compute the affinities of PDO binding to four other AQPs and one aquaglyceroporin whose atomic coordinates are available from the protein data bank (PDB). For bovine AQP1, human AQP2, AQP4, AQP5, and Plasmodium falciparum PfAQP whose structures were resolved with high resolution, we obtained definitive predictions on the PDO dissociation constant. For human AQP1 whose PDB coordinates are less accurate, we estimated the dissociation constant with a rather large error bar. Taking into account the fact that PDO is generally recognized as safe by the US FDA, we predict that PDO can be an effective diuretic which directly modulates water flow through the protein channels. It should be free from the serious side effects associated with other diuretics that change the hydro-homeostasis indirectly by altering the osmotic gradients. PMID- 26481433 TI - Clinical guidelines: Best practices and uncertainties in the management of PMR. PMID- 26481435 TI - Connective tissue diseases: Functional MRI in SLE-the current state. PMID- 26481434 TI - Vitamin D in rheumatoid arthritis-towards clinical application. AB - In addition to its well-documented involvement in mineral homeostasis, vitamin D seems to have broad effects on human health that go beyond the skeletal system. Prominent among these so-called nonclassical effects of vitamin D are its immunomodulatory properties. In vitro studies have shown anti-inflammatory effects of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D. In addition, epidemiological analysis of patients with established inflammatory disease identified associations between vitamin D deficiency (low serum concentrations of inactive 25-hydroxyvitamin D, abbreviated to 25(OH)D) and inflammatory conditions, including rheumatoid arthritis (RA). The association of vitamin D deficiency with RA severity supports the hypothesis of a role for vitamin D in the initiation or progression of the disease, or possibly both. However, whether 25(OH)D status is a cause or consequence of RA is still incompletely understood and requires further analysis in prospective vitamin D supplementation trials. The characterization of factors that promote the transition from preclinical to clinical phases of RA has become a major focus of research, with the aim to facilitate earlier diagnosis and treatment, and improve therapeutic outcomes. In this Review, we aim to describe the current knowledge of vitamin D and the immune system specifically in RA, and discuss the potential benefits that vitamin D might have on slowing RA progression. PMID- 26481436 TI - Decade in review-clinical rheumatology: 10 years of therapeutic advances in the rheumatic diseases. PMID- 26481437 TI - Osteoarthritis: Autophagy prevents age-related OA. PMID- 26481438 TI - Vasculitis syndromes: PR3 on apoptotic cells promotes inflammation in GPA. PMID- 26481439 TI - Pupil diameter, working distance and illumination during habitual tasks. Implications for simultaneous vision contact lenses for presbyopia. AB - PURPOSE: To determine working distance, pupil diameter and illumination in real life conditions in a sample of presbyopic participants performing habitual tasks. METHODS: A total of 59 presbyopic subjects (aged between 45 and 63 years) with different occupational backgrounds participated in the study. Participants were first interviewed regarding their habitual tasks with the aid of an ad hoc questionnaire, following which in-office photopic and mesopic pupil diameter was determined. Pupil diameter was also evaluated while participants conducted each of the self-reported habitual tasks by taking a photograph, which was later submitted to image analysis. In addition, working distance was determined with a measuring tape and the illumination that reached the pupil during each of the different tasks was measured, in lux, with a light meter. RESULTS: The four most common habitual tasks were computer use, reading, sewing and sports. A high intersubject variability was found in pupil diameter, working distance and illumination conditions while conducting the same task. Statistically significant differences were found between the in-office measured photopic and mesopic pupil diameters and those obtained while participants were conducting their habitual tasks in real life conditions (all p<0.001). CONCLUSIONS: Potential multifocal contact lens users may present with different ages, different jobs or hobbies and different preferences regarding lighting conditions and working distances. This results in different pupil size, even within the same task. This information may be critical when selecting a particular lens design and add power. Eye care practitioners are therefore advised to assess pupil diameter in real life conditions. PMID- 26481440 TI - MicroRNAs in the pathogenesis of renal cell carcinoma and their diagnostic and prognostic utility as cancer biomarkers. AB - PURPOSE: To provide information about the role of microRNAs in the pathogenesis of renal cell carcinoma (RCC) and their diagnostic and prognostic utility as cancer biomarkers. METHODS: A literature search was performed in the PubMed and Web of Science databases using the keywords "renal cancer/renal cell carcinoma/kidney cancer" and "miR*/miRNA*/microRNA*". Articles dealing with the role of miRNAs in the pathogenesis of RCC, diagnostic miRNAs and prognostic miRNAs were separated. RESULTS: MiRNAs act both as oncogenes and tumor suppressors. They regulate apoptosis, cell growth, migration, invasion, proliferation, colony formation and angiogenesis through target proteins involved in several signaling pathways, and they are involved in key pathogenetic mechanisms such as hypoxia (HIF/VHL dependent) and epithelial-to-mesenchymal transition. Differentially expressed miRNAs can discriminate either tumor tissue from healthy renal tissue or different RCC subtypes. Circulating miRNAs are promissing as diagnostic biomarkers of RCC. Information about urinary miRNAs associated with RCC is sparse. Detection of a relapse is another implication of diagnostic miRNAs. The expression profiles of several miRNAs correlate with the prognosis of RCC patients. Comparison between primary tumor tissue and metastasis may help identify high-risk primary tumors. Finally, response to target therapy can be estimated thanks to differences in miRNA expression in tissue and serum of therapy-resistant versus therapy-sensitive patients. CONCLUSIONS: Our understanding of the role of microRNAs in RCC pathogenesis has been increasing dramatically. Identification and validation of their gene targets may have direct impact on developing microRNA-based anticancer therapy. Several microRNAs can serve as diagnostic and prognostic biomarkers. PMID- 26481441 TI - p16 cutoff in head and neck squamous cell carcinoma: correlation between tumor and patient characteristics and outcome. AB - BACKGROUND: p16 has been indicated as a suitable surrogate biomarker of HPV infection. The prognosis of p16-positive oropharynx tumors (OTs) of squamous cell carcinoma (SCC) histology is better than that of p16-negative tumors. METHODS: We analyzed 209 samples of head and neck SCC to establish a predictive cutoff for p16 and determine the role of p16 positivity in OTs versus non-OTs. We compared the outcomes of tumors harboring any percentage of p16-positive cells (>=1%) with those of p16-negative OTs. We then considered 3 cutoffs (10%, 50% and 70% positive cells) to evaluate the outcome of OTs/non-OTs with similar p16 expression and p16-positive versus p16-negative tumors stratified by patient age. RESULTS: p16-negative tumors among OTs and non-OTs were 29% and 49%, respectively (p = 0.0054). The cumulative distribution showed that the positive values were located around 2 focus points: 2% and 96%. Subgroup analysis showed that only OTs occurred in young patients (aged <65 years) and that there was a >=70% gain in survival in cases with p16-positive cells. CONCLUSIONS: p16 positivity influences outcome only in young patients and OTs (p = 0.048). PMID- 26481442 TI - SA-VA Difference with Extended Utility-More to Consider. PMID- 26481443 TI - The N-cadherin cytoplasmic domain confers anchorage-independent growth and the loss of contact inhibition. AB - Tumor growth is characterized by anchorage independence and the loss of contact inhibition. Previously, we showed that either a red fluorescent protein (DsRed) tagged N-cadherin or E-cadherin cytoplasmic domain (DNCT or DECT) could function as a dominant negative inhibitor by blocking the cell surface localization of endogenous E-cadherin and inducing cell dissociation. Here, we show that expression of DNCT abrogated contact inhibition of proliferation and conferred anchorage-independent growth. DNCT expression induced the relocation of the tumor suppressor Merlin from the cell surface to intracellular compartments. Although DNCT expression induced redistribution of TAZ from the cytoplasm to the nucleus, YAP/TAZ signaling was not activated. An E-cadherin-alpha-catenin chimera that functions as a beta-catenin-independent cell adhesion molecule restored contact inhibition and anchorage-dependency of growth. Addition of the SV40 large T antigen nuclear localization signal reversed the effects of DNCT expression, indicating that DNCT functioned outside of the nucleus. PMID- 26481444 TI - The N-acetylglucosamine catabolic gene cluster in Trichoderma reesei is controlled by the Ndt80-like transcription factor RON1. AB - Chitin is an important structural constituent of fungal cell walls composed of N acetylglucosamine (GlcNAc) monosaccharides, but catabolism of GlcNAc has not been studied in filamentous fungi so far. In the yeast Candida albicans, the genes encoding the three enzymes responsible for stepwise conversion of GlcNAc to fructose-6-phosphate are clustered. In this work, we analysed GlcNAc catabolism in ascomycete filamentous fungi and found that the respective genes are also clustered in these fungi. In contrast to C. albicans, the cluster often contains a gene for an Ndt80-like transcription factor, which we named RON1 (regulator of N-acetylglucosamine catabolism 1). Further, a gene for a glycoside hydrolase 3 protein related to bacterial N-acetylglucosaminidases can be found in the GlcNAc gene cluster in filamentous fungi. Functional analysis in Trichoderma reesei showed that the transcription factor RON1 is a key activator of the GlcNAc gene cluster and essential for GlcNAc catabolism. Furthermore, we present an evolutionary analysis of Ndt80-like proteins in Ascomycota. All GlcNAc cluster genes, as well as the GlcNAc transporter gene ngt1, and an additional transcriptional regulator gene, csp2, encoding the homolog of Neurospora crassa CSP2/GRHL, were functionally characterised by gene expression analysis and phenotypic characterisation of knockout strains in T. reesei. PMID- 26481446 TI - A Superior Na3 V2 (PO4 )3 -Based Nanocomposite Enhanced by Both N-Doped Coating Carbon and Graphene as the Cathode for Sodium-Ion Batteries. AB - A superior Na3 V2 (PO4 )3 -based nanocomposite (NVP/C/rGO) has been successfully developed by a facile carbothermal reduction method using one most-common chelator, disodium ethylenediamintetraacetate [Na2 (C10 H16 N2 O8 )], as both sodium and nitrogen-doped carbon sources for the first time. 2D-reduced graphene oxide (rGO) nanosheets are also employed as highly conductive additives to facilitate the electrical conductivity and limit the growth of NVP nanoparticles. When used as the cathode material for sodium-ion batteries, the NVP/C/rGO nanocomposite exhibits the highest discharge capacity, the best high-rate capabilities and prolonged cycling life compared to the pristine NVP and single carbon-modified NVP/C. Specifically, the 0.1 C discharge capacity delivered by the NVP/C/rGO is 116.8 mAh g(-1) , which is obviously higher than 106 and 112.3 mAh g(-1) for the NVP/C and pristine NVP respectively; it can still deliver a specific capacity of about 80 mAh g(-1) even at a high rate up to 30 C; and its capacity decay is as low as 0.0355 % per cycle when cycled at 0.2 C. Furthermore, the electrochemical impedance spectroscopy was also implemented to compare the electrode kinetics of all three NVP-based cathodes including the apparent Na diffusion coefficients and charge-transfer resistances. PMID- 26481445 TI - The utility of the apolipoprotein A1 remnant ratio in predicting incidence coronary heart disease in a primary prevention cohort: The Jackson Heart Study. AB - BACKGROUND: Dyslipidemia plays a significant role in the progression of cardiovascular disease. The apolipoprotein (apo) A1 remnant ratio (apo A1/VLDL3-C + IDL-C) has recently been shown to be a strong predictor of death/myocardial infarction risk among women >50 years undergoing angiography. However, whether this ratio is associated with coronary heart disease risk among other populations is unknown. We evaluated the apo A1 remnant ratio and its components for coronary heart disease incidence. DESIGN: Observational. METHODS: Participants (N = 4722) of the Jackson Heart Study were evaluated. Baseline clinical characteristics and lipoprotein subfractions (Vertical Auto Profile method) were collected. Cox hazard regression analysis, adjusted by standard cardiovascular risk factors, was utilized to determine associations of lipoproteins with coronary heart disease. RESULTS: Those with new-onset coronary heart disease were older, diabetic, smokers, had less education, used more lipid-lowering medication, and had a more atherogenic lipoprotein profile. After adjustment, the apo A1 remnant ratio (hazard ratio = 0.67 per 1-SD, p = 0.002) was strongly associated with coronary heart disease incidence. This association appears to be driven by the IDL-C denominator (hazard ratio = 1.23 per 1-SD, p = 0.007). Remnants (hazard ratio = 1.21 per 1-SD, p = 0.017), but not apo A1 (hazard ratio = 0.85 per 1-SD, p = 0.121) or VLDL3-C (hazard ratio = 1.13 per 1-SD, p = 0.120) were associated with coronary heart disease. Standard lipids were not associated with coronary heart disease incidence. CONCLUSION: We found the apo A1 remnant ratio to be strongly associated with coronary heart disease. This ratio appears to better stratify risk than standard lipids, apo A1, and remnants among a primary prevention cohort of African Americans. Its utility requires further study as a lipoprotein management target for risk reduction. PMID- 26481447 TI - Application of analyzer based X-ray imaging technique for detection of ultrasound induced cavitation bubbles from a physical therapy unit. AB - BACKGROUND: The observation of ultrasound generated cavitation bubbles deep in tissue is very difficult. The development of an imaging method capable of investigating cavitation bubbles in tissue would improve the efficiency and application of ultrasound in the clinic. Among the previous imaging modalities capable of detecting cavitation bubbles in vivo, the acoustic detection technique has the positive aspect of in vivo application. However the size of the initial cavitation bubble and the amplitude of the ultrasound that produced the cavitation bubbles, affect the timing and amplitude of the cavitation bubbles' emissions. METHODS: The spatial distribution of cavitation bubbles, driven by 0.8835 MHz therapeutic ultrasound system at output power of 14 Watt, was studied in water using a synchrotron X-ray imaging technique, Analyzer Based Imaging (ABI). The cavitation bubble distribution was investigated by repeated application of the ultrasound and imaging the water tank. The spatial frequency of the cavitation bubble pattern was evaluated by Fourier analysis. Acoustic cavitation was imaged at four different locations through the acoustic beam in water at a fixed power level. The pattern of cavitation bubbles in water was detected by synchrotron X-ray ABI. RESULTS: The spatial distribution of cavitation bubbles driven by the therapeutic ultrasound system was observed using ABI X-ray imaging technique. It was observed that the cavitation bubbles appeared in a periodic pattern. The calculated distance between intervals revealed that the distance of frequent cavitation lines (intervals) is one-half of the acoustic wave length consistent with standing waves. CONCLUSION: This set of experiments demonstrates the utility of synchrotron ABI for visualizing cavitation bubbles formed in water by clinical ultrasound systems working at high frequency and output powers as low as a therapeutic system. PMID- 26481448 TI - Assessing the association between occupancy and outcome in critically Ill hospitalized patients with sepsis. AB - BACKGROUND: Sepsis has a high prevalence, mortality-rate and cost. Sepsis patients usually enter the hospital through the Emergency Department (ED). Process or structural issues related to care may affect outcome. METHODS: Multi centered retrospective observational cohort study using administrative databases to identify adult patients (> = 18 years) with sepsis and severe sepsis admitted to Alberta Health Services Calgary zone adult multisystem intensive care units (ICU) through the ED between January 1, 2006 and September 30, 2009. We examined the association between ICU occupancy and hospital outcome. We explored other associations of hospital outcome including the effect of ED wait time, admission from ED during weekdays versus weekends and ED admission during the day versus at night. RESULTS: One thousand and seven hundred seventy patients were admitted to hospital via ED, 1036 (58.5 %) with sepsis and 734 (41.5 %) with severe sepsis. In patients with sepsis, ICU occupancy > 90 % was associated with an increase in hospital mortality even after adjusting for age, sex, triage level, Charlson index, time of first ED physician assessment and ICU admission. No differences in hospital mortality were found for patients who waited more than 7 h, were admitted during the day versus night or weekdays versus weekends. CONCLUSIONS: In patients with sepsis admitted via the ED, increased ICU occupancy was associated with higher in-hospital mortality. PMID- 26481449 TI - Privileging Naturals Over Strivers: The Costs of the Naturalness Bias. AB - A preference for "naturals" over "strivers" in performance judgments was investigated to test whether the effect is generalizable across domains, as well as to ascertain any costs imposed on decision quality by favoring naturals. Despite being presented with entrepreneurs equal in achievement, participants judged the natural and his business proposal to be superior to the striver and his proposal on multiple dimensions of performance and success (Study 1a and Study 1b). These findings were extended in Study 2, which quantified the costs of the naturalness bias using conjoint analysis to measure specific decision tradeoffs. Together, these three studies show that people tend to pass over better-qualified individuals in favor of apparent naturals. PMID- 26481450 TI - Taking Race Off the Table: Agenda Setting and Support for Color-Blind Public Policy. AB - Whites are theorized to support color-blind policies as an act of racial agenda setting-an attempt to defend the existing hierarchy by excluding race from public and institutional discourse. The present analysis leverages work distinguishing between two forms of social dominance orientation (SDO): passive opposition to equality (SDO-E) and active desire for dominance (SDO-D). We hypothesized that agenda setting, as a subtle hierarchy-maintenance strategy, would be uniquely tied to high levels of SDO-E. When made to believe that the hierarchy was under threat, Whites high in SDO-E increased their endorsement of color-blind policy (Study 1), particularly when the racial hierarchy was framed as ingroup advantage (Study 2), and became less willing to include race as a topic in a hypothetical presidential debate (Study 3). Across studies, Whites high in SDO-D showed no affinity for agenda setting as a hierarchy-maintenance strategy. PMID- 26481451 TI - Genome-wide mapping reveals single-origin chromosome replication in Leishmania, a eukaryotic microbe. AB - BACKGROUND: DNA replication initiates on defined genome sites, termed origins. Origin usage appears to follow common rules in the eukaryotic organisms examined to date: all chromosomes are replicated from multiple origins, which display variations in firing efficiency and are selected from a larger pool of potential origins. To ask if these features of DNA replication are true of all eukaryotes, we describe genome-wide origin mapping in the parasite Leishmania. RESULTS: Origin mapping in Leishmania suggests a striking divergence in origin usage relative to characterized eukaryotes, since each chromosome appears to be replicated from a single origin. By comparing two species of Leishmania, we find evidence that such origin singularity is maintained in the face of chromosome fusion or fission events during evolution. Mapping Leishmania origins suggests that all origins fire with equal efficiency, and that the genomic sites occupied by origins differ from related non-origins sites. Finally, we provide evidence that origin location in Leishmania displays striking conservation with Trypanosoma brucei, despite the latter parasite replicating its chromosomes from multiple, variable strength origins. CONCLUSIONS: The demonstration of chromosome replication for a single origin in Leishmania, a microbial eukaryote, has implications for the evolution of origin multiplicity and associated controls, and may explain the pervasive aneuploidy that characterizes Leishmania chromosome architecture. PMID- 26481453 TI - Allogeneic hand transplantation and rehabilitation of hand function: a 10-year follow-up study. AB - The purpose of this study is to present the long-term outcomes of allogenic hand transplantations performed at our centre. Between January 2001 and October 2002, five allogeneic limb transplantations were performed in three patients (two bilateral forearm and one left hand transplantation). Donors and recipients were matched for blood types (ABO/Rh) and had at least two human leukocyte antigen (HLA) matches. A comprehensive rehabilitation plan integrating preoperative, intraoperative and postoperative management was developed for each patient. After 10 years, all transplantations were performed successfully without complications. As of 2014, all grafts were viable. The transplanted hands showed palmate morphology, perceived superficial pain and tactile sensations, and the static two point discrimination ranged from 2.5 to 4.0 mm. Chronic rejection at 4 years after surgery reduced hand function in case 2. Grip strength ranged from 3 kg (case 2) to 16-18 kg (case 1) to 41-43 kg for case 3. Lifting strength ranged from 3 kg (case 2) to 21-23 kg (case 1) to 47-51 kg for case 3. They lead a completely independent life. In summary, hand function following allogeneic limb transplantation allows the ability to perform tasks of daily living. PMID- 26481452 TI - The adherence paradox: guideline deviations contribute to the increased 5-year survival of breast cancer patients. AB - BACKGROUND: In German breast cancer care, the S1-guidelines of the 1990s were substituted by national S3-guidelines in 2003. The application of guidelines became mandatory for certified breast cancer centers. The aim of the study was to assess guideline adherence according to time intervals and its impact on survival. METHODS: Women with primary breast cancer treated in three rural hospitals of one German geographical district were included. A cohort study design encompassed women from 1996-97 (N = 389) and from 2003-04 (N = 488). Quality indicators were defined along inpatient therapy sequences for each time interval and distinguished as guideline-adherent and guideline-divergent medical decisions. Based on all of the quality indicators, a binary overall adherence index was defined and served as a group indicator in multivariate Cox-regression models. A corrected group analysis estimated adjusted 5-year survival curves. RESULTS: From a total of 877 patients, 743 (85 %) and 504 (58 %) were included to assess 104 developed quality indicators and the resuming binary overall adherence index. The latter significantly increased from 13-15 % (1996-97) up to 33-35 % (2003-04). Within each time interval, no significant survival differences of guideline-adherent and -divergent treated patients were detected. Across time intervals and within the group of guideline-adherent treated patients only, survival increased but did not significantly differ between time intervals. Across time intervals and within the group of guideline-divergent treated patients only, survival increased and significantly differed between time intervals. CONCLUSIONS: Infrastructural efforts contributed to the increase of process quality of the examined certified breast cancer center. Paradoxically, a systematic impact on 5-year survival has been observed for patients treated divergently from the guideline recommendations. This is an indicator for the appropriate application of guidelines. A maximization of guideline-based decisions instead of the ubiquitous demand of guideline adherence maximization is advocated. PMID- 26481455 TI - Simple route for nano-hydroxyapatite properties expansion. AB - Simple surface modification of nano-hydroxyapatite, through acid-basic reactions, allows expanding the properties of this material. Introduction of organic groups such as hydrophobic alkyl chains, carboxylic acid, and amide or amine basic groups on the hydroxyapatite surface systematically change the polarity, surface area, and reactivity of hydroxyapatite without modifying its phase. Physical and chemical properties of the new derivative particles were analyzed. The biocompatibility of modified Nano-Hap on Raw 264.7 cells was also assessed. PMID- 26481456 TI - Use of fine-needle aspirate calcitonin to detect medullary thyroid carcinoma: A systematic review. AB - BACKGROUND: The measurement of calcitonin in washout fluids of thyroid nodule aspirate (FNA-calcitonin) has been reported as accurate to detect medullary thyroid carcinoma (MTC). The results from these studies have been promising and the most updated version of ATA guidelines quoted for the first time that "FNA findings that are inconclusive or suggestive of MTC should have calcitonin measured in the FNA washout fluid." Here we aimed to systematically review published data on this topic to provide more robust estimates. RESEARCH DESIGN AND METHODS: A comprehensive computer literature search of the medical databases was conducted by searching for the terms "calcitonin" AND "washout." The search was updated until April 2015. RESULTS: Twelve relevant studies, published between 2007 and 2014, were found. Overall, 413 thyroid nodules or neck lymph nodes underwent FNA-calcitonin, 95 were MTC lesions and 93 (97.9%) of these were correctly detected by this measurement regardless of their cytologic report. CONCLUSIONS: The present study shows that the above ATA recommendation is well supported. Almost all MTC lesions are correctly detected by FNA-calcitonin and this technique should be used to avoid false negative or inconclusive results from cytology. The routine determination of serum calcitonin in patients undergoing FNA should improve the selection of patients at risk for MTC, guiding the use of FNA-calcitonin in the same FNA sample and providing useful information to the cytopathologist for the morphological assessment and the application of tailored ancillary tests. PMID- 26481454 TI - Alkaline phosphatase predicts response in polycystic liver disease during somatostatin analogue therapy: a pooled analysis. AB - BACKGROUND & AIMS: Somatostatin analogues reduce liver volumes in polycystic liver disease. However, patients show considerable variability in treatment responses. Our aim was to identify specific patient, disease or treatment characteristics that predict response in polycystic liver disease during somatostatin analogue therapy. METHODS: We pooled the individual patient data of four trials that evaluated long-acting somatostatin analogues (120 mg lanreotide or 40 mg octreotide) for 6-12 months in polycystic liver disease patients. We performed uni- and multivariate linear regression analysis with preselected patient, disease and drug variables to identify independent predictors of response, defined as per cent change in liver or kidney volume (in ADPKD subgroup). All analyses were adjusted for baseline liver volume and centre. RESULTS: We included 153 polycystic liver disease patients (86% female, median liver volume 4974 ml) from three international centres, all treated with octreotide (n = 70) or lanreotide (n = 83). Mean reduction in liver volume was 4.4% (range -31.6 to +9.4%). Multivariate linear regression revealed that elevated baseline alkaline phosphatase was associated with increased liver volume reduction during therapy (-2.7%, 95% CI -5.1 to -0.2%, P = 0.04), independently of baseline liver volume. Somatostatin analogue type, underlying diagnosis and eGFR did not affect response. In our ADPKD subpopulation (n = 100), elevated alkaline phosphatase predicted liver volume reduction (-3.2%, P = 0.03) but did not predict kidney volume reduction (+0.1%, P = 0.97). Total gastro-intestinal symptom severity decreased with therapy in a subgroup analysis (n = 95; P < 0.001). CONCLUSION: Alkaline phosphatase is a liver-specific, independent predictor of response in polycystic liver disease during somatostatin analogue therapy. PMID- 26481457 TI - An outbreak of multiple norovirus strains on a cruise ship in China, 2014. AB - AIMS: To determine the cause of an outbreak of acute gastroenteritis that occurred on a cruise ship sailing along the Yangzi River from Chongqing to Nanjing, China. METHODS AND RESULTS: Noroviruses were identified by reverse transcription-PCR (RT-PCR) in rectal swabs from 34 of 54 subjects tested (63.0%). Sequencing and genotyping showed that noroviruses of up to seven different genotypes circulated in this outbreak: noroviruses GI.1, GI.2, GI.3, GI.4, GI.8, GI.9 and an uncommon strain GII.17. Common genotypes were not identified in this event. None of the food or water samples were tested positive for noroviruses. CONCLUSIONS: We suspected that it was a point-source infection due to contaminated water or food harvested from contaminated water, taking account of the co-existence of diverse norovirus genotypes. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, we presented the molecular investigation of a norovirus outbreak on a cruise in China. We revealed that the outbreak was caused by several different norovirus genotypes and analysed the possible source of infection as well, thus facilitating the evaluation of epidemiological issues regarding noroviruses in this area. PMID- 26481458 TI - Satellite RNA pathogens of plants: impacts and origins-an RNA silencing perspective. AB - Viral satellite RNAs (satRNAs) are among the smallest RNA pathogens in plants. They have little or no protein-coding capacity but can have a major impact on the host plants through trilateral interactions with helper viruses and host plants. Studies around the 1980s revealed much of what we know about satRNAs: they can affect helper virus accumulation, modulate helper virus-induced disease symptoms, and induce their own symptoms with the assistance of helper viruses which depend on specific nucleotide sequences of their genome and host species. The molecular basis of these satRNA-caused impacts and the origin of satRNAs have yet to be fully understood and revealed, but recent understanding of the antiviral RNA silencing pathways and advancement in RNA and DNA sequencing technologies have provided new avenues and opportunities to examine these unanswered questions. These RNA silencing-based studies have revealed the existence of cross silencing between some satRNAs and helper viruses, the downregulation of helper virus encoded suppressor (VSR) of RNA silencing or inhibition/enhancement of VSR activity by satRNAs, the silencing of host-encoded genes by satRNA-derived small interfering RNA (siRNAs), and the presence of satRNA-like small RNAs in uninfected host plants. These findings have provided alternative RNA silencing based models to explain the pathogenicity and origin of satRNAs. WIREs RNA 2016, 7:5-16. doi: 10.1002/wrna.1311 For further resources related to this article, please visit the WIREs website. PMID- 26481459 TI - Electrophysiological signatures of the race model in human primary motor cortex. AB - For 30 years, the independent race model has been used to account for the attempt to reactively inhibit on-going responses in the stop-signal task (reactive behavioral inhibition). The success of the race model derives in part by assuming that motor response activation speed is not different on inhibition trials compared to trials where inhibition is not required. To date, neurophysiological evidence supporting this assumption (context independence) has been limited, especially in human participants. In this study, we used EEG to investigate stop signal task performance in human participants, focusing on lateralized readiness potentials (LRPs) to examine context independence in human primary motor cortex (M1). The current results provided support for the context independence assumption, and further showed that successful inhibition was largely contingent upon the timing of response activation in M1 relative to stop-signal onset. These data afford a valuable insight into how stop-signal response inhibition is effected in the human brain. PMID- 26481460 TI - Global identification and analysis of long non-coding RNAs in diploid strawberry Fragaria vesca during flower and fruit development. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) are a new class of regulatory molecules with roles in diverse biological processes. While much effort has been invested in the analysis of lncRNAs from established plant models Arabidopsis, maize, and rice, almost nothing is known about lncRNAs from fruit crops, including those in the Rosaceae family. RESULTS: Here, we present a genome-scale identification and characterization of lncRNAs from a diploid strawberry, Fragaria vesca, based on rich RNA-seq datasets from 35 different flower and fruit tissues. 5,884 Fve-lncRNAs derived from 3,862 loci were identified. These lncRNAs were carefully cataloged based on expression level and whether or not they contain repetitive sequences or generate small RNAs. About one fourth of them are termed high-confidence lncRNAs (hc-lncRNAs) because they are expressed at a level of FPKM higher than 2 and produce neither small RNAs nor contain repetitive sequence. To identify regulatory interactions between lncRNAs and their potential protein-coding (PC) gene targets, pairs of lncRNAs and PC genes with positively or negatively correlated expression trends were identified based on their expression; these pairs may be candidates of cis- or trans-acting lncRNAs and their targets. Finally, blast searches within plant species indicate that lncRNAs are not well conserved. CONCLUSIONS: Our study identifies a large number of tissue-specifically expressed lncRNAs in F. vesca, thereby highlighting their potential contributions to strawberry flower and fruit development and paving the way for future functional studies. PMID- 26481461 TI - The mechanism of lowering cholesterol absorption by calcium studied by using an in vitro digestion model. AB - Studies in humans show that a calcium-enriched diet leads to lower cholesterol in blood serum. This phenomenon is usually explained in the literature with a reduced cholesterol absorption in the small intestine. Our study aims to clarify the effect of calcium on the solubilisation of cholesterol and fatty acid in the dietary mixed micelles (DMM), viz. on the bioaccessibility of these lipophilic substances in the gut. We use an in vitro digestion model which mimics very closely the intestinal pH-profile and the composition of the intestinal fluids. We quantified the effects of Ca(2+) concentration on the lipid solubilization for fats and oils with different saturated/unsaturated fatty acid (FA) contents. We found that the increase of calcium significantly decreases the solubilization of cholesterol, FA and MG. Most importantly, we observe a clear positive correlation between the amounts of solubilized cholesterol, on one side, and solubilized free fatty acids and monoglycerides, on the other side. The main conclusion is that Ca(2+) ions strongly affect the bioaccessibility of both cholesterol and saturated FA. Therefore, calcium may decrease the serum cholesterol via two complementary mechanisms: (1) fatty acid precipitation by calcium ions reduces the solubilisation capacity of the DMM, thus decreasing the levels of solubilised (bioaccessible) cholesterol; (2) the observed strong decrease of the bioaccessible saturated FA, in its own turn, may suppress the cholesterol synthesis in the liver. PMID- 26481462 TI - Clioquinol Improves Cognitive, Motor Function, and Microanatomy of the Alpha Synuclein hA53T Transgenic Mice. AB - The abnormal accumulation of alpha-synuclein (alpha-syn) has been linked to a number of neurodegenerative disorders, the most noteworthy of which is Parkinson's disease. Alpha-synuclein itself is not toxic and fulfills various physiological roles in the central nervous system. However, specific types of aggregates have been shown to be toxic, and metals have been linked to the assembly of these toxic aggregates. In this paper, we have characterized a transgenic mouse that overexpresses the A53T mutation of human alpha-syn, specifically assessing cognition, motor performance, and subtle anatomical markers that have all been observed in synucleinopathies in humans. We hypothesized that treatment with the moderate-affinity metal chelator, clioquinol (CQ), would reduce the interaction between metals and alpha-syn to subsequently improve the phenotype of the A53T animal model. We showed that CQ prevents an iron-synuclein interaction, the formation of urea-soluble alpha-syn aggregates, alpha-syn-related substantia nigra pars compacta cell loss, reduction in dendritic spine density of hippocampal and caudate putamen medium spiny neurons, and the decline in motor and cognitive function. In conclusion, our data suggests that CQ is capable of mitigating the pathological metal/alpha-syn interactions, suggesting that the modulation of metal ions warrants further study as a therapeutic approach for the synucleinopathies. PMID- 26481463 TI - One-post patterning of multiple protein gradients using a low-cost flash foam stamp. AB - Printing of versatile chemical and biological inks for protein and cell patterning was achieved using a simple and cost-effective flash foam stamp (FFS). The grey-scale mask fabricated stamp can generate multiple protein gradients with one-post stamping. Due to the importance of spatially controlled protein patterns in both biology and tissue engineering, this straightforward and reliable tool is an accessible solution for resource-limited laboratories conducting molecular patterning experiments. PMID- 26481464 TI - Robustness of quantitative hypoxia PET image analysis for predicting local tumor control. AB - BACKGROUND: Previous studies suggested the maximum tumor to background ratio (TBRmax) in FMISO PET images as a potentially predictive parameter for local control after radio-chemotherapy (CRT) in head and neck squamous cell carcinomas (HNSCC). However, different TBRmax thresholds for stratification were reported, implying that a common threshold cannot readily be used among different institutions without the risk of reducing prediction accuracy. Therefore, this study investigated the robustness of using a common pre-defined TBRmax, simulating a multicenter clinical trial. MATERIAL AND METHODS: FMISO PET/CT was performed four hours post-injection in 22 patients with advanced HNSCC in a phase II FMISO dose escalation study. PET background regions of interest (ROIs) were manually defined in deep neck muscles. TBRmax was calculated as the mean of the highest-valued voxels within the high risk RT planning target volume. Its predictive power with respect to local control was tested, classifying patients using median TBRmax as threshold. The influence of systematically varying quantification between institutions was studied in silico by applying offsets of +/- 10% and +/- 20% to the TBRmax of all patients, while the threshold remained constant. The effect was analyzed using a receiver operating characteristic (ROC). True positive and false positive rates (TPR/FPR) as well as positive and negative predictive values (PPV/NPV) were evaluated. RESULTS: For the reference condition without an offset the median TBRmax was 2.0 (1.4-3.5). Patients were classified using this threshold and TPR = 0.7, FPR = 0.4, PPV = 0.5 and NPV = 0.8 were observed. Accuracy declined with increasing offsets. Negative offsets of 10% and -20% resulted in TPR = 0.43 and 0.14, FPR = 0.20 and 0.13, PPV = 0.50 and 0.33 and NPV = 0.75 and 0.68, respectively. Positive offsets of + 10% and + 20% resulted in TPR = 1.00 and 1.00, FPR = 0.53 and 0.67, PPV = 0.47 and 0.41 and NPV = 1.00 and 1.00, respectively. CONCLUSIONS: Using a common pre-defined TBRmax threshold in multicenter trials requires careful standardization and harmonization of all steps from patient preparation to image analysis. Our results indicate that TBRmax should deviate less than 10% from reference conditions (absolute value in this dataset +/- 0.2). This conclusion likely applies to all low contrast nitroimidazole hypoxia PET tracers. PMID- 26481465 TI - Evaluation of miR-21 and miR-375 as prognostic biomarkers in esophageal cancer. AB - BACKGROUND: MicroRNAs (miRNAs) have been associated with prognosis in esophageal cancer, suggesting a role for miRNAs to help guide treatment decisions. Especially, miR-21 and miR-375 have been investigated as prognostic biomarkers. The aim of this study was to evaluate the prognostic potential of miR-21 and miR 375 in primary esophageal squamous cell carcinomas (ESCC) and esophagogastric adenocarcinomas (EAC). MATERIAL AND METHODS: Pre-therapeutic tumor specimens from 195 patients with loco-regional esophageal cancer treated with neoadjuvant or definitive chemoradiotherapy or perioperative chemotherapy were analyzed. Expression levels of miR-21 and miR-375 were quantified using Affymetrix GeneChip miRNA 1.0 Array. The Cox proportional hazards model was used to assess the correlation of miR-21 and miR-375 with disease-specific survival (DSS) and overall survival (OS). Forest plots were performed to evaluate the prognostic impact of miR-21 and miR-375 in the present study and previously published reports. RESULTS: In ESCC, patients with miR-21 expression levels above median showed a trend towards poorer DSS and OS. When dividing miR-21 expression by tertiles, high levels of miR-21 significantly correlated with shortened DSS [HR 1.76 (95% CI 1.05-2.97) but not OS. Similarly for EAC, a significant association between miR-21 expression above median and DSS was observed [HR 3.37 (95% CI 1.41 8.05)], in addition to a trend towards poorer OS for patients with miR-21 expression above median. Multivariate analyses identified miR-21 as an independent prognostic marker for DSS in EAC [HR 3.52 (95% CI 1.06-11.69)]. High miR-375 was not correlated with improved prognosis in either histology. However, Forest plots demonstrated that both miR-21 and miR-375 were of prognostic impact in ESCC. CONCLUSION: In this study, miR-21 was identified as an independent prognostic biomarker for DSS in patients with EAC whereas miR-21 failed to show independent prognostic significance in ESCC. High miR-375 was not associated with enhanced survival in either histology. PMID- 26481466 TI - Youth Resilience Corps: An Innovative Model to Engage Youth in Building Disaster Resilience. AB - OBJECTIVE: Despite the growing awareness that youth are not just passive victims of disaster but can contribute to a community's disaster resilience, there have been limited efforts to formally engage youth in strengthening community resilience. The purpose of this brief report was to describe the development of a Youth Resilience Corps, or YRC (ie, a set of tools to engage young people in youth-led community resilience activities) and the findings from a small-scale pilot test. METHODS: The YRC was developed with input from a range of government and nongovernmental stakeholders. We conducted a pilot test with youth in Washington, DC, during summer 2014. Semi-structured focus groups with staff and youth surveys were used to obtain feedback on the YRC tools and to assess what participants learned. RESULTS: Focus groups and youth surveys suggested that the youth understood resilience concepts, and that most youth enjoyed and learned from the components. CONCLUSIONS: The YRC represent an important first step toward engaging youth in building disaster resilience, rather than just focusing on this group as a vulnerable population in need of special attention. PMID- 26481467 TI - Influence of hot isostatic pressing on ZrO2-CaO dental ceramics properties. AB - Different hot isostatic pressing conditions were used to obtain zirconia ceramics, in order to assess the influence of HIP on phase transformation, compressive strength, Young's modulus and density. First, CaO stabilized zirconia powder was synthesized through sol-gel method, using zirconium propoxide, calcium isopropoxide and 2-metoxiethanol as precursors, then HIP treatment was applied to obtain final dense ceramics. Ceramics were morphologically and structurally characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). Density measurements, compressive strength and Young's modulus tests were also performed in order to evaluate the effect of HIP treatment. The zirconia powders heat treated at 500 degrees C for 2h showed a pure cubic phase with average particle dimension about 70nm. The samples that were hot isostatic pressed presented a mixture of monoclinic-tetragonal or monoclinic-cubic phases, while for pre-sintered samples, cubic zirconia was the single crystalline form. Final dense ceramics were obtained after HIP treatment, with relative density values higher than 94%. ZrO2-CaO ceramics presented high compressive strength, with values in the range of 500-708.9MPa and elastic behavior with Young's modulus between 1739MPa and 4372MPa. Finally zirconia ceramics were tested for biocompatibility allowing the normal development of MG63 cells in vitro. PMID- 26481468 TI - Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing. AB - The aim of this work was to explore the feasibility of using fused deposition modelling (FDM) 3D printing (3DP) technology with hot melt extrusion (HME) and fluid bed coating to fabricate modified-release budesonide dosage forms. Budesonide was sucessfully loaded into polyvinyl alcohol filaments using HME. The filaments were engineered into capsule-shaped tablets (caplets) containing 9mg budesonide using a FDM 3D printer; the caplets were then overcoated with a layer of enteric polymer. The final printed formulation was tested in a dynamic dissolution bicarbonate buffer system, and two commercial budesonide products, Cortiment(r) (Uceris(r)) and Entocort(r), were also investigated for comparison. Budesonide release from the Entocort(r) formulation was rapid in conditions of the upper small intestine while release from the Cortiment(r) product was more delayed and very slow. In contrast, the new 3D printed caplet formulation started to release in the mid-small intestine but release then continued in a sustained manner throughout the distal intestine and colon. This work has demonstrated the potential of combining FDM 3DP with established pharmaceutical processes, including HME and film coating, to fabricate modified release oral dosage forms. PMID- 26481469 TI - Thermoanalytical and Fourier transform infrared spectral curve-fitting techniques used to investigate the amorphous indomethacin formation and its physical stability in Indomethacin-Soluplus(r) solid dispersions. AB - The amorphous form of a drug has higher water solubility and faster dissolution rate than its crystalline form. However, the amorphous form is less thermodynamically stable and may recrystallize during manufacturing and storage. Maintaining the amorphous state of drug in a solid dosage form is extremely important to ensure product quality. The purpose of this study was to quantitatively determine the amount of amorphous indomethacin (INDO) formed in the Soluplus(r) solid dispersions using thermoanalytical and Fourier transform infrared (FTIR) spectral curve-fitting techniques. The INDO/Soluplus(r) solid dispersions with various weight ratios of both components were prepared by air drying and heat-drying processes. A predominate IR peak at 1683cm(-1) for amorphous INDO was selected as a marker for monitoring the solid state of INDO in the INDO/Soluplus(r) solid dispersions. The physical stability of amorphous INDO in the INDO/Soluplus(r) solid dispersions prepared by both drying processes was also studied under accelerated conditions. A typical endothermic peak at 161 degrees C for gamma-form of INDO (gamma-INDO) disappeared from all the differential scanning calorimetry (DSC) curves of INDO/Soluplus(r) solid dispersions, suggesting the amorphization of INDO caused by Soluplus(r) after drying. In addition, two unique IR peaks at 1682 (1681) and 1593 (1591)cm(-1) corresponded to the amorphous form of INDO were observed in the FTIR spectra of all the INDO/Soluplus(r) solid dispersions. The quantitative amounts of amorphous INDO formed in all the INDO/Soluplus(r) solid dispersions were increased with the increase of gamma-INDO loaded into the INDO/Soluplus(r) solid dispersions by applying curve-fitting technique. However, the intermolecular hydrogen bonding interaction between Soluplus(r) and INDO were only observed in the samples prepared by heat-drying process, due to a marked spectral shift from 1636 to 1628cm(-1) in the INDO/Soluplus(r) solid dispersions. The INDO/Soluplus(r) solid dispersions prepared by both drying processes could keep the amorphous state of INDO in the INDO/Soluplus(r) solid dispersions at the accelerated storage condition. PMID- 26481470 TI - Incremental prognostic value of high-sensitive C-reactive protein in patients undergoing coronary computed tomography angiography. AB - BACKGROUND: This study was performed to investigate whether combined use of high sensitivity C-reactive protein (hs-CRP) levels and coronary computed tomography angiography (CCTA) results have additional prognostic value for predicting cardiovascular events in patients with suspected coronary artery disease (CAD). METHODS: A total of 445 patients (61.6+/-9.3 years and 62.9% men) with suspected CAD who underwent both CCTA and hs-CRP measurement within one month were evaluated. Information on cardiovascular events, including cardiac death, non fatal myocardial infarction, unstable angina and late (>=six months after CCTA) coronary revascularization was assessed. RESULTS: One hundred and eighty-five patients (41.6%) had obstructive CAD on CCTA (stenosis >=50%). Both high hs-CRP (>=2.25mg/L) and obstructive CAD were the independent predictors of cardiovascular events. Kaplan-Meier analysis showed that event rates were significantly different according to the presence of obstructive CAD and hs-CRP levels. Addition of hs-CRP levels to combined information of clinical factors and CCTA results further increased the predictive power for cardiovascular events (global chi-square ratio, from 13.51 to 19.14, p=0.022). Event risks were approximately 21.0-fold higher in the highest-risk group with both obstructive CAD and high hs-CRP levels than in the lowest-risk group with both insignificant CAD and low hs-CRP levels (p=0.007). CONCLUSIONS: Combined use of hs-CRP levels and CCTA results provided a significant improvement in prognostic power for cardiovascular events in patients with suspected CAD. hs-CRP measurement may be a simple and useful method for determining risk stratification and treatment strategy in patients undergoing CCTA. PMID- 26481471 TI - Transport of membrane-bound mineral particles in blood vessels during chicken embryonic bone development. AB - During bone formation in embryos, large amounts of calcium and phosphate are taken up and transported to the site where solid mineral is first deposited. The initial mineral forms in vesicles inside osteoblasts and is deposited as a highly disordered calcium phosphate phase. The mineral is then translocated to the extracellular space where it penetrates the collagen matrix and crystallizes. To date little is known about the transport mechanisms of calcium and phosphate in the vascular system, especially when high transport rates are needed and the concentrations of these ions in the blood serum may exceed the solubility product of the mineral phase. Here we used a rapidly growing biological model, the chick embryo, to study the bone mineralization pathway taking advantage of the fact that large amounts of bone mineral constituents are transported. Cryo scanning electron microscopy together with cryo energy dispersive X-ray spectroscopy and focused-ion beam imaging in the serial surface view mode surprisingly reveal the presence of abundant vesicles containing small mineral particles in the lumen of the blood vessels. Morphologically similar vesicles are also found in the cells associated with bone formation. This observation directly implicates the vascular system in solid mineral distribution, as opposed to the transport of ions in solution. Mineral particle transport inside vesicles implies that far larger amounts of the bone mineral constituents can be transported through the vasculature, without the danger of ectopic precipitation. This introduces a new stage into the bone mineral formation pathway, with the first mineral being formed far from the bone itself. PMID- 26481473 TI - Leisure-time physical activity and risk of type 2 diabetes: a meta-analysis of prospective cohort studies. AB - Published articles reported controversial results about the association between leisure-time physical activity (LTPA) and risk of type 2 diabetes. A meta analysis of prospective cohort studies was conducted to explore the effect of LTPA on the incidence of type 2 diabetes. PubMed and Embase databases were searched from its inception to June 13, 2014. Fixed or random effects models were used to calculate the pooled effect sizes based on between-study heterogeneity that was examined by the Q test and I (2) statistic. A total of eight studies, including 296,395 participants and 10,815 incident cases, were included in this study. Both high-level LTPA [high vs. low: hazard ratio (HR) 0.69, 95 % confidence interval (CI) 0.61-0.78] and moderate-level LTPA (moderate vs. low: HR 0.79, 95 % CI 0.70-0.89) were associated with decreased incidence of type 2 diabetes. In conclusion, LTPA was significantly associated with decreased risk of diabetes; high-level LTPA is more beneficial in decreasing the incidence of type 2 diabetes than moderate-level LTPA. PMID- 26481474 TI - Pre-training levels of testosterone and sex hormone-binding globulin are not correlated with training adaptations in fat mass and insulin sensitivity in healthy young men. PMID- 26481472 TI - Lipid dynamics in boar sperm studied by advanced fluorescence imaging techniques. AB - The (re)organization of membrane components is of special importance to prepare mammalian sperm to fertilization. Establishing suitable methods to examine physico-chemical membrane parameters is of high interest. We characterized the behavior of fluorescent (NBD) analogs of sphingomyelin (SM), phosphatidylserine (PS), and cholesterol (Ch) in the acrosomal and postacrosomal macrodomain of boar sperm. Due to their specific transverse membrane distribution, a leaflet-specific investigation of membrane properties is possible. The behavior of lipid analogs in boar sperm was investigated by fluorescence lifetime imaging microscopy (FLIM), fluorescence recovery after photobleaching (FRAP), and fluorescence correlation spectroscopy (FCS). The results were compared with regard to the different temporal and spatial resolution of the methods. For the first time, fluorescence lifetimes of lipid analogs were determined in sperm cell membrane and found to be in a range characteristic for the liquid-disordered phase in artificial lipid membranes. FLIM analyses further indicate a more fluid microenvironment of NBD-Ch and NBD-PS in the postacrosomal compared to the acrosomal region. The concept of a more fluid cytoplasmic leaflet is supported by lower fluorescence lifetime and higher average D values (FCS) for NBD-PS in both head compartments. Whereas FLIM analyses did not indicate coexisting distinct liquid-ordered and -disordered domains in any of the head regions, comparisons between FRAP and FCS measurements suggest the incorporation of NBD-SM as well as NBD-PS in postacrosomal subpopulations with different diffusion velocity. The analog-specific results indicate that the lipid analogs used are suitable to report on the various physicochemical properties of different microenvironments. PMID- 26481475 TI - A piecewise lookup table for calculating nonbonded pairwise atomic interactions. AB - A critical challenge for molecular dynamics simulations of chemical or biological systems is to improve the calculation efficiency while retaining sufficient accuracy. The main bottleneck in improving the efficiency is the evaluation of nonbonded pairwise interactions. We propose a new piecewise lookup table method for rapid and accurate calculation of interatomic nonbonded pairwise interactions. The piecewise lookup table allows nonuniform assignment of table nodes according to the slope of the potential function and the pair interaction distribution. The proposed method assigns the nodes more reasonably than in general lookup tables, and thus improves the accuracy while requiring fewer nodes. To obtain the same level of accuracy, our piecewise lookup table accelerates the calculation via the efficient usage of cache memory. This new method is straightforward to implement and should be broadly applicable. Graphical Abstract Illustration of piecewise lookup table method. PMID- 26481476 TI - SCD1 mediates the influence of exogenous saturated and monounsaturated fatty acids in adipocytes: Effects on cellular stress, inflammatory markers and fatty acid elongation. AB - Palmitate (PA), stearate (SA), palmitoleate (PMA) and oleate (OA) are among the most abundant fatty acids (FAs) in adipose tissue (AT). These FAs differentially regulate AT inflammation by altering adipocyte signalling pathways and the secretion of proinflammatory cytokines. Intracellular levels of these FAs are controlled, in part, by stearoyl-CoA desaturase 1 (SCD1). Therefore, SCD1 may have an important role mediating FA-regulation of adipocyte inflammation. Given this, we hypothesized that the influence of PA, SA, PMA and OA on inflammation and cellular stress, as well as FA metabolism, would be exacerbated with reduced SCD1 activity. Real-time RT-PCR, immunoassays, gas chromatography and western blotting were used to examine the expression and secretion of common inflammatory markers, as well as FA profiles and markers of cellular stress, in 3T3-L1 adipocytes. FA treatments differentially affected inflammatory markers and FA profiles in SCD1-inhibited adipocytes. Specifically, SA significantly increased the expression of Ccl5 (5.3-fold) and Mcp-1 (3.2-fold), and the secretion of IL-6 (17.8-fold) and MCP-1 (4.0-fold) in SCD1-inhibited adipocytes compared to controls. The proinflammatory effects observed with SA are particularly notable given that SCD1-inhibited adipocytes increased elongation of PA to SA, as determined using U-(13)C-PA. The effects of PA, PMA and OA were not as substantial as those of SA, although PA did significantly increase Ccl5 (2.7 fold) and Mcp-1 (1.2-fold) expression in SCD1-inhibited adipocytes. None of the FAs altered markers of cellular stress. Collectively, these results emphasize the differential effects of individual FAs and highlight how SCD1 influences their regulation of adipocyte inflammation. PMID- 26481477 TI - Membrane-bound heat shock proteins facilitate the uptake of dying cells and cross presentation of cellular antigen. AB - Heat shock proteins (HSPs) were originally identified as stress-responsive proteins and serve as molecular chaperones in different intracellular compartments. Translocation of HSPs to the cell surface and release of HSPs into the extracellular space have been observed during the apoptotic process and in response to a variety of cellular stress. Here, we report that UV irradiation and cisplatin treatment rapidly induce the expression of membrane-bound Hsp60, Hsp70, and Hsp90 upstream the phosphatidylserine exposure. Membrane-bound Hsp60, Hsp70 and Hsp90 could promote the release of IL-6 and IL-1beta as well as DC maturation by the evaluation of CD80 and CD86 expression. On the other hand, Hsp60, Hsp70 and Hsp90 on cells could facilitate the uptake of dying cells by bone marrow derived dendritic cells. Lectin-like oxidized LDL receptor-1 (LOX-1), as a common receptor for Hsp60, Hsp70, and Hsp90, is response for their recognition and mediates the uptake of dying cells. Furthermore, membrane-bound Hsp60, Hsp70 and Hsp90 could promote the cross-presentation of OVA antigen from E.G7 cells and inhibition of the uptake of dying cells by LOX-1 decreases the cross-presentation of cellular antigen. Therefore, the rapid exposure of HSPs on dying cells at the early stage allows for the recognition by and confers an activation signal to the immune system. PMID- 26481478 TI - Effect of vasoactive peptides in Tetrahymena: chemotactic activities of adrenomedullin, proadrenomedullin N-terminal 20 peptide (PAMP) and calcitonin gene-related peptide (CGRP). AB - Adrenomedullin (AMD), proadrenomedullin N-terminal 20 peptide (PAMP) and calcitonin gene-related peptide (CGRP) were studied for chemotaxis, chemotactic selection and G-actin/F-actin transition in Tetrahymena. The aim of the experiments was to study the effects of two different peptides encoded by the same gene compared to a peptide related to one of the two, but encoded by a different gene, at a low level of phylogeny. The positive, chemotactic effect of ADM and the strong negative, chemorepellent effect of PAMP suggest that in Tetrahymena, the two peptides elicit their chemotactic effects via different signalling mechanisms. The complexity of swimming behaviour modulated by the three peptides underlines that chemotaxis, chemokinesis and some characteristics of migratory behaviour (velocity, tortuosity) are working as a sub-population level complex functional unit. Chemotactic responsiveness to ADM and CGRP is short-term, in contrast to PAMP, which as a chemorepellent ligand, has the ability to select sub-populations with negative chemotactic responsiveness. The different effects of ADM and PAMP on the polymerization of actin networks show that the microtubular structure of cilia is more essential to chemotactic response than are transitions of the actin network. The results draw attention to the characteristic effects of vasoactive peptides at this low level of phylogeny. PMID- 26481479 TI - Up-regulation of liver Pcsk9 gene expression as a possible cause of hypercholesterolemia in experimental chronic renal failure. AB - Dyslipidemia commonly present in patients with chronic kidney disease (CKD) has been recently linked to increased proprotein convertase subtilisin/kexin type 9 (PCSK9) serum concentration. We tested a hypothesis that increased liver PCSK9 biosynthesis could be partially responsible for the elevated circulating PCSK9 level, and subsequently contribute to hypercholesterolemia observed in subjects with CKD. Rat model of chronic renal failure (CRF) was used in the study. Animals underwent a 5/6 nephrectomy or a sham operation. Liver expression of Pcsk9, sterol regulatory element-binding transcription factor 2 (Srebf-2), and beta actin were quantified by real-time RT-PCR. Liver protein levels of PCSK9, LDL receptor (LDL-R), and SREBF-2 were analyzed using Western blotting. Serum PCSK9 concentration was estimated by immunoassay. Rats with an experimental CRF as compared to pair-fed and control ones were characterized by: (a) an up-regulation of liver Pcsk9 and Srebf-2 genes expression with parallel increase of serum PCSK9 concentration; (b) a decrease in liver LDL-R protein level, and (c) an increase of serum total and LDL-cholesterol concentrations. We also found significant correlations between serum creatinine and liver PCSK9 mRNA levels (r = 0.88, p < 0.001) and between serum creatinine and circulating PCSK9 levels (r = 0.73, p < 0.001). The results suggest that a rat model of CRF is associated with an increased liver Pcsk9 gene expression. The coordinated up-regulation of Pcsk9 and Srebf-2 genes expression suggests that SREBF-2 may play a key role in regulation of Pcsk9 gene expression, circulating PCSK9 level, and hypercholesterolemia in experimental CRF. PMID- 26481480 TI - Pancreatic ductal adenocarcinoma and chronic mass-forming pancreatitis: Differentiation with dual-energy MDCT in spectral imaging mode. AB - OBJECTIVE: To investigate the value of dual-energy MDCT in spectral imaging in the differential diagnosis of chronic mass-forming chronic pancreatitis (CMFP) and pancreatic ductal adenocarcinoma (PDAC) during the arterial phase (AP) and the pancreatic parenchymal phase (PP). MATERIALS AND METHODS: Thirty five consecutive patients with CMFP (n=15) or PDAC (n=20) underwent dual-energy MDCT in spectral imaging during AP and PP. Iodine concentrations were derived from iodine-based material-decomposition CT images and normalized to the iodine concentration in the aorta. The difference in iodine concentration between the AP and PP, contrast-to-noise ratio (CNR) and the slope K of the spectrum curve were calculated. RESULTS: Normalized iodine concentrations (NICs) in patients with CMFP differed significantly from those in patients with PDAC during two double phases (mean NIC, 0.26+/-0.04 mg/mL vs. 0.53+/-0.02 mg/mL, p=0.0001; 0.07+/-0.02 mg/mL vs. 0.28+/-0.04 mg/mL, p=0.0002, respectively). There were significant differences in the value of the slope K of the spectrum curve in two groups during AP and PP (K(CMFP)=3.27+/-0.70 vs. K(PDAC)=1.35+/-0.41, P=0.001, and K(CMFP)=3.70+/-0.17 vs. K(PDAC)=2.16+/-0.70, p=0.003, respectively). CNRs at low energy levels (40-70 keV) were higher than those at high energy levels (80-40 keV). CONCLUSION: Individual patient CNR-optimized energy level images and the NIC can be used to improve the sensitivity and the specificity for differentiating CMFP from PDAC by use of dual-energy MDCT in spectral imaging with fast tube voltage switching. PMID- 26481481 TI - Comparison of fat-saturated T2-weighted and contrast-enhanced fat-saturated T1 weighted sequences in MR imaging of sacroiliac joints in diagnosing active sacroiliitis. AB - OBJECTIVES: To compare fat-saturated T2-weighted (FST2W) with contrast-enhanced fat-saturated T1-weighted (cFST1W) pulse sequences in magnetic resonance (MR) imaging of sacroiliac joints in diagnosis of active sacroiliitis associated with axial spondyloarthropathies. MATERIALS AND METHODS: MR examinations of 147 adult patients suspected for sacroiliitis were retrospectively analyzed. Signs of active inflammation, bone marrow edema/osteitis, capsulitis, enthesitis, and synovitis were noted both on FST2W and cFST1W images. Diagnosis of active sacroiliitis was made according to the Assessment in SpondyloArthritis international Society (ASAS) definition. RESULTS: Sixty three patients were diagnosed as having active sacroiliitis based on both FST2W images showing bone marrow edema and cFST1W images showing osteitis. All areas with osteitis seen on cFST1W images were also noted as having bone marrow edema on FST2W images while FST2W images revealed 4 additional areas of active bone marrow changes. Qualitative and quantitative analyses also revealed that FST2W images were superior in showing active bone marrow lesions, the hallmark of active sacroiliitis, while cFST1W images helped detecting enthesitis and/or capsulitis and were necessary for detecting synovitis. CONCLUSION: Although cFST1W images help detecting enthesitis and/or capsulitis and are necessary for detecting synovitis, FST2W sequence is superior in detecting active bone marrow lesions and therefore more valuable in diagnosing active sacroiliitis associated with axial spondyloarthropathies based on ASAS criteria. PMID- 26481482 TI - Pulmonary perfusion imaging: Qualitative comparison of TCIR MRI and SPECT/CT in porcine lung. AB - OBJECTIVES: To validate the anatomical accuracy, homogeneity and sensitivity of two-compartment modeled inversion recovery (TCIR) magnetic resonance imaging (MRI) in a multimodal animal experiment as a non-invasive alternative to standard functional imaging techniques. METHODS: Seven pigs were studied on a 1.5 T whole body MR scanner and SPECT/CT. The specimens were intubated and maintained in general anesthesia throughout the experiment. TCIR maps of the fractional pulmonary blood volume were compared to dynamic contrast enhanced MRI and SPECT/CT via a region of interest (ROI) based reader study. A comprehensive statistical analysis was performed on the coefficient of variation to evaluate homogeneity properties. Sensitivity was assessed by detecting gravitation dependent perfusion variation and delineation of pathological areas. RESULTS: The fPBV-maps of all examined specimens indicate a superior homogeneity in the computed values (p<1.3*10(-4)). The sensitivity of the TCIR maps to a gravitation effect on the blood distribution was verified and a similar anteroposterior signal and count dependency was observed in DCE MRI and SPECT. Bland-Altman analysis showed no significant intra- or inter-observer difference within the ROI reader study (p>0.06). CONCLUSION: Superior information content, significantly higher homogeneity and similar sensitivity of TCIR when compared to DCE and SPECT/CT demonstrated the feasibility of TCIR MRI as an alternative contrast agent-free, non-invasive functional lung imaging approach. PMID- 26481483 TI - Incidence and therapeutic frequency of extrahepatic collateral arteries in transcatheter arterial chemoembolization of hepatocellular carcinoma: Experience from 182 patients with survival time more than 3 years. AB - PURPOSE: To retrospectively evaluate the incidence of each extrahepatic collateral artery (EHCA) supplying to hepatocellular carcinoma (HCC) in sessions of transcatheter arterial chemoembolization (TACE) and its therapeutic frequency. MATERIALS AND METHODS: Between February 2002 and May 2008, 182 patients with HCC underwent TACE and survived more than 3 years. For TACE procedure, angiographic evaluation of all suspected EHCAs that could supply the tumor were performed. The incidence of EHCAs in TACE sessions and therapeutic frequency were analyzed. Correlations between the number of collaterals and the number of TACE sessions were investigated. RESULTS: 162 patients showed 647 EHCAs supplying tumors in a total of 795 sessions of TACE. The initially confirmed EHCAs in TACE sessions were the right inferior phrenic artery (RIPA, n=150), left inferior phrenic artery (LIPA, n=8), right internal mammary artery (RIMA, n=4), right adrenal artery (RAA, n=2) and left gastric artery (LGA, n=5), respectively. The incidences of EHCAs were 51.1%, 68.1%, 50.0%, 50.0%, 42.3%, 34.6%, 29.1%, 19.8%, 6.6%, 3.3% and 0.6% from 1 to 11 session of TACE, respectively. The RIPA was accounted for 62.5% of EHCAs and other EHCAs often occurred after the attenuation of RIPA. There were correlations between the number of TACE sessions and either the sum number of collaterals (r=-0.961; p<0.001), the number of RIPA(r=-0.948; p<0.001) or the number of LGA(r=-0.670; p=0.024). The mean therapeutic frequencies of TACE were 2.6, 1.5, 1.6, 1.3, 1.5, 1.2, 3.3, 1.1, 1.0 and 7.0 times for the RIPA, LIPA, RIMA, left internal mammary artery (LIMA), omental artery (OMA), LGA, right intercostal artery (RICA), RAA, right renal capsular artery (RRCA) and colic artery (COA), respectively. CONCLUSIONS: The RIPA angiography should be routinely performed in TACE procedure. EHCAs should be searched during the sessions of TACE in the following order: RIPA, RIMA, LIPA and other collaterals of lower incidence. PMID- 26481484 TI - A review of direct-acting antivirals for the treatment of hepatitis C in patients with advanced chronic kidney disease. AB - Historically, standard treatment of hepatitis C virus (HCV) infection in patients with renal impairment has been limited by low cure rates and poor tolerability. The introduction of direct-acting antivirals (DAAs) has revolutionized the treatment of HCV with impressive cure rates >90% and low rates of adverse events. Despite these major advancements, treatment of patients with HCV and advanced chronic kidney disease (CKD) is a major challenge due to the lack of efficacy and safety data in this patient population. The purpose of this review is to summarize the available data for efficacy and safety of the following DAAs in treating HCV patients with advanced Stage 4 and 5 CKD: simeprevir, sofosbuvir, ledipasvir, ombitasvir, paritaprevir, dasabuvir, grazoprevir, elbasvir and daclatasvir. PMID- 26481485 TI - Synthesis and characterization of fast-swelling porous superabsorbent hydrogel based on starch as a hemostatic agent. AB - The body can't control massive bleeding without treatment. Different hemostatic agents have been prepared recently, but most of them are ineffective in severe bleeding and expensive or cause safety concerns. In this study, in order to achieve fast control of bleeding, we synthesized and characterized fast-swelling porous superabsorbent hydrogel (FSPSH) and investigated its use as a hemostatic agent. The FSPSH was prepared by grafting acrylic acid and acrylamide onto starch through free-radical polymerization in aqueous solution. The FSPSH was characterized by Fourier transform infrared, X-ray diffraction, field emission scanning electron microscope, and thermogravimetric analysis. Then, temporal swelling behavior and coagulation time experiments were used to predict the in vivo behavior of the FSPSH. The hemocompatibility of synthesized FSPSH was evaluated by hemolysis test and blood cells function. In vivo study using femoral artery injury in rat demonstrated the FSPSH's ability to aid in rapid hemostasis. Furthermore, monitoring the rat on first and seventh day after femoral artery injury also showed no harmful effect. This study indicates that FSPSH adsorbs fluid and swells, thus forms a physical barrier to blood loss. FSPSH, moreover, as hemostat is simple to use, lightweight, stable, and harmless. PMID- 26481486 TI - Trichinella spiralis infection changes immune response in mice performed abdominal heterotopic cardiac transplantation and prolongs cardiac allograft survival time. AB - Allograft rejection has been an obstacle for long-term survival of patients for many years. Current strategies for transplant rejection are not as optimal as we expected, especially for long-term treatments. Trichinella spiralis, a nematode parasitized in mammalian muscle and as an invader, maintains harmonious with host in the long term by evading host immune attack. To determine whether T. spiralis infection impacts on allograft rejection, we performed mice cardiac allograft transplantation model by using BALB/c (H-2(b)) mice as donors and C57BL/6 (H 2(b)) mice orally infected with 300 muscle larvae for 28 days as recipients. Graft survival was monitored by daily palpation of the abdomen; histologic change was observed by H&E stain; and CD4(+), CD8(+), CD4(+)IFN-gamma(+), and CD4(+)IL 17(+) T cells and regulatory T cells were examined with the use of flow cytometry. Serum cytokine levels were measured by Luminex. Finally, we found that mean survival time of cardiac allografts in T. spiralis group was 23.40 +/- 1.99 days, while the vehicle control group was 10.60 +/- 0.75 days. Furthermore, we observed alleviated histological changes in the heart allograft, decreased corresponding CD8(+) T cells, suppressed Th1 and Th17 responses, and increased regulatory T cell frequency in a murine cardiac transplantation model at day 7 post-transplantation in experimental group. These data suggest that T. spiralis infection resulted in prolonged allograft survival following murine cardiac transplantation, with suppressed Th1/Th17 responses and augmented regulatory T cells. PMID- 26481487 TI - Comparative analysis of spermatids of Rhipicephalus sanguineus sensu lato (Ixodidae) and Ornithodoros rostratus ticks (Argasidae): morphophysiology aimed at systematics. AB - The phylogenetic relationships among tick species (Acari: Ixodida) have been revisited by several researchers over the last decades. Two subfamilies, Rhipicephalinae (Ixodidae) and Ornithodorinae (Argasidae), deserve special attention. The male reproductive system morphology, as well as the ultrastructure of the germ cells, may provide important information for phylogeny and systematics of metazoan groups, with spermatozoa exhibiting characters that can be used for this purpose. With that information in mind, this study aimed at evaluating, through a comparative analysis, the morphology of the male reproductive systems and germ cells of ticks species Rhipicephalus sanguineus and Ornithodoros rostratus. In order to do that, histology and scanning electron microscopy techniques were used. The results have shown that despite the similarities in the general morphology of the male reproductive system among studied Ixodida so far, there are morphological differences among the species studied herein, mainly the U-shaped testis (ancestral character) in O. rostratus and the pair testes (derived character) in R. sanguineus, and the general morphology of germ cells (spermatids V). Besides that, the morphological changes observed during the spermiogenesis appear to be different between the species studied here, probably characterizing the two families considered. The data generated in this study showed the importance of comparative internal morphology studies, mainly in regard to spermatology, despite the morphological data obtained herein not being enough to product a cladogram (sperm cladistics), it was already possible to observe clear differences among families Argasidae and Ixodidae in regard to the organization of their male reproductive systems and concerning the external morphology of spermatids. Data yet to be obtained through transmission electron microscopy techniques will allow the application of spermiocladistics and spermiotaxonomy as tools for tick systematics. PMID- 26481488 TI - Pentatrichomonas hominis: prevalence and molecular characterization in humans, dogs, and monkeys in Northern China. AB - Pentatrichomonas hominis is an anaerobic amitochondrial flagellated protist that primarily colonizes the large intestines of a number of species, including cats, dogs, nonhuman primates, and humans. The prevalence of this parasite in dogs, monkeys, and humans is, however, poorly understood. In this study, a total of 362 fecal samples including 252 dogs, 60 monkeys, and 50 humans from northern China were collected for an epidemiological survey of P. hominis infection.The average prevalence of P. hominis infection determined by nested PCR was 27.38% (69/252), 4.00% (2/50), and 46.67% (28/60) in dogs, humans, and monkeys, respectively. The prevalence was significantly higher in 6-month-old dogs (41.53%) and children (7.69%) than in older dogs (14.39%) and adults (0%) (P < 0.05). Sequencing of amplicons revealed that four variable positions separated sequences into three types, called CC1-3. CC1 was the most prevalent in the study population. This study determined that P. hominis infection is common in dogs, monkeys, and humans, especially in children and young dogs. Given the infection prevalence, P. hominis may pose a risk of zoonotic and anthroponotic transmission. PMID- 26481490 TI - Survey for Toxoplasma gondii by PCR detection in meat for human consumption in Colombia. AB - The overall risk for toxoplasmosis in meat produced in Colombia is unknown. We analyzed by PCR assay meat samples for human consumption in two types of plants in Colombia: 120 samples from class I plants (60 samples from chicken, 30 from swine and 30 from beef) and 60 from class II plants (30 samples from beef and 30 from swine). Presence of Toxoplasma DNA was established by targeted B1 nested PCR assay. We detected 79 (43%) samples that were positive by B1 nested PCR (33 from chicken, 22 from beef, and 24 from pork). No differences were found by region or species. Eleven positive samples were confirmed by sequencing of the B1 repeated region. Some polymorphisms were detected without relation with clonal groups nor meat species. Food animals are highly exposed to Toxoplasma in Colombia. Detailed studies are needed to establish the reasons for differences in Toxoplasma prevalence between farms, regarding practices of animal food production. PMID- 26481489 TI - Cross-resistance of Leishmania infantum isolates to nitric oxide from patients refractory to antimony treatment, and greater tolerance to antileishmanial responses by macrophages. AB - Visceral leishmaniasis is a life-threatening disease characterized by intense parasitism of the spleen, liver, and bone marrow. Antimonials have served as front-line antileishmanial therapeutics for decades, but the increasing failure rates under antimonial treatment have challenged the continued use of these drugs. Pentavalent antimonials are known to reinforce the killing mechanisms of macrophages, although the associated mechanism remains unclear. Here, for the first time, we determined whether Leishmania infantum strains isolated from patients refractory to antimony treatment (relapse cases) were cross-resistant to antimonials, liposomal amphotericin B, and/or nitric oxide, and also whether these strains modulate macrophage infection. We selected four clinical isolates from relapse cases and two clinical isolates from antimony-responsive patients (control group) for the present study. The L. infantum promastigotes from all four relapse cases were resistant to trivalent antimonial treatment and nitric oxide, while only one isolate was resistant to liposomal amphotericin B. We evaluated whether the resistant strains from relapse cases showed enhanced infectivity and amastigote survival in macrophages, or macrophage-killing mechanisms in macrophages activated by lipopolysaccharide plus interferon gamma. Infection indexes calculated using macrophages infected with isolates from relapse were higher than those observed with control strains that were stimulated independently. Macrophage infection was higher with L. infantum isolates from relapse cases and correlated with enhanced interleukin 1-beta production but showed similar nitrite production. Our results demonstrate that L. infantum field isolates from relapse cases were resistant to antimonials and nitric oxide and that these parasites stimulated inflammatory cytokines and were resistant to macrophage-killing mechanisms, factors that may contribute to disease severity. PMID- 26481492 TI - Bacteria-induced hatching of Trichuris muris eggs occurs without direct contact between eggs and bacteria. AB - Using three isolates of the murine parasitic nematode Trichuris muris, E, E/J (the E isolate maintained in Japan), and S, I have previously demonstrated that when the embryonated eggs of the E/J and E isolates are incubated with the intestinal bacteria Escherichia coli and Staphylococcus aureus, they are induced to hatch in vitro. However, the eggs of the S isolate are unresponsive to these bacteria. In the present study, I investigated whether direct contact between the embryonated eggs of the E/J and E isolates and bacteria is required to induce their hatching. To do so, a new co-culture system for eggs and bacteria (E. coli or S. aureus) was developed to block any direct contact between the eggs and the bacteria. In the hatching experiment using the new system, when direct contact between the eggs and bacteria was completely prevented, the eggs still hatched. However, the peak levels of hatching without direct contact were about 20 % lower than those with direct contact, and peak hatching occurred later without direct contact. This evidence suggests that hatching occurs without direct contact between the eggs and bacteria, and that unidentified material derived from active bacteria induces the hatching of embryonated eggs of the E/J and E isolates of T. muris in vitro. PMID- 26481491 TI - Increase number of mitochondrion-like organelle in symptomatic Blastocystis subtype 3 due to metronidazole treatment. AB - Blastocystis sp., an intestinal organism is known to cause diarrhea with metronidazole regarded as the first line of treatment despite reports of its resistance. The conflicting reports of variation in drug treatment have been ascribed to subtype differences. The present study evaluated in vitro responses due to metronidazole on ST3 isolated from three symptomatic and asymptomatic patients, respectively. Symptomatic isolates were obtained from clinical patients who showed symptoms such as diarrhea and abdominal bloating. Asymptomatic isolates from a stool survey carried out in a rural area. These patients had no other pathogens other than Blastocystis. Ultrastructural studies using transmission electron microscopy (TEM) and scanning electron microscopy (SEM) revealed drug-treated ST3 from symptomatic patients were irregular and amoebic with surface showing high-convoluted folding when treated with metronidazole. These organisms had higher number of mitochondrion-like organelle (MLO) with prominent cristae. However, the drug-treated ST3 from asymptomatic persons remained spherical in shape. Asymptomatic ST3 showed increase in the size of its central body with the MLO located at the periphery. PMID- 26481493 TI - Trends in Prescribing Oral Anticoagulants in Canada, 2008-2014. AB - PURPOSE: The non-vitamin K antagonist oral anticoagulants (NOACs), dabigatran, rivaroxaban, and apixaban, provide several advantages over vitamin K antagonists, such as warfarin. Little is known about the trends of prescribing OACs in Canada. In this study we analyzed changes in prescription volumes for OAC drugs since the introduction of the NOACs in Canada overall, by province and by physician specialty. METHODS: Canadian prescription volumes for warfarin, dabigatran, rivaroxaban, and apixaban from January 2008 to June 2014 were obtained from the Canadian Compuscript Audit of IMS Health Canada Inc and were analyzed by physician specialty at the national and provincial levels. Total prescriptions by indication were calculated based on data from the Canadian Disease and Therapeutic Index for all OAC indications and for each commonly prescribed dose of dabigatran (75, 110, and 150 mg), rivaroxaban (10, 15, and 20 mg), and apixaban (2.5 and 5 mg). FINDINGS: The overall number of OAC prescriptions in Canada has increased annually since 2008. With the availability of the NOACs, the proportion of total OAC prescriptions attributable to warfarin has steadily decreased, from 99% in 2010 to 67% by June 2014, and the absolute number of warfarin prescriptions has been decreasing since February 2011. The greatest decline in proportionate warfarin prescriptions was in Ontario. In general, the increase of NOAC prescriptions coincided with the introduction of provinces' reimbursement of NOAC prescription costs. The proportion of total OAC prescriptions represented by the NOACs varied by specialty, with the greatest proportionate prescribing found among orthopedic surgeons, cardiologists, and neurologists. IMPLICATIONS: Since their approval, the NOACs have represented a growing share of total OAC prescriptions in Canada. This trend is expected to continue because the NOACs are given preference over warfarin in guidelines on stroke prevention in patients with atrial fibrillation, because of growing physician experience, and due to the emergence of potential new indications. An understanding of the current prescribing patterns will help to encourage knowledge translation and possibly influence policy/reimbursement strategies. PMID- 26481494 TI - "Clinical approach to fibromyalgia: Synthesis of Evidence-based recommendations, a systematic review". AB - OBJECTIVES: Efforts have been made to standardise evidence-based practice, but clinical practice guidelines do not always follow strict development methods. The objective of this review is to identify the current guidelines, analyse the variability of its recommendations and make a synthesis for clinical practice. MATERIAL AND METHODS: A systematic review of clinical practice guidelines was made in electronic databases and guidelines databases; using "fibromyalgia" AND ["guideline" OR "Clinical Practice guideline"] as terms, from January for 2003 to July of 2013. Guidelines were selected according to the following criteria: a) aimed to fibromyalgia treatment in adults; b) based on scientific evidence, systematically searched; c) evidence levels and strength of recommendation included; d) written in English or Spanish. RESULTS: From 249 initial results, six guides fulfilled the inclusion criteria. Clinical practice guidelines analysed in this review show great variability both in the presence and level of evidence and in the strength of recommendation of many treatments. Physical exercise and cognitive-behavioural therapy are first-line treatments, showing high level of evidence. Amitriptyline, used for short periods of time for pain control, is the pharmacologic treatment with the most solid evidence. The multimodal approach reported better results than the isolated application of any treatment. CONCLUSIONS: Final recommendations in this review identify optimal treatments, facilitating the translation of evidence into practice and enabling more efficient and effective quality care. PMID- 26481495 TI - Understanding poor health behaviours as predictors of different types of hospital admission in older people: findings from the Hertfordshire Cohort Study. AB - BACKGROUND: Rates of hospital admission are increasing, particularly among older people. Poor health behaviours cluster but their combined impact on risk of hospital admission among older people in the UK is unknown. METHODS: 2997 community-dwelling men and women (aged 59-73) participated in the Hertfordshire Cohort Study (HCS). We scored (from 0 to 4) number of poor health behaviours engaged in at baseline (1998-2004) out of: current smoking, high weekly alcohol, low customary physical activity and poor diet. We linked HCS with Hospital Episode Statistics and mortality data to 31/03/2010 and analysed associations between the score and risk of different types of hospital admission: any; elective; emergency; long stay (>7 days); 30-day readmission (any, or emergency). RESULTS: 32%, 40%, 20% and 7% of men engaged in 0, 1, 2 and 3/4 poor health behaviours; corresponding percentages for women 51%, 38%, 9%, 2%. 75% of men (69% women) experienced at least one hospital admission. Among men and women, increased number of poor health behaviours was strongly associated (p<0.01) with greater risk of long stay and emergency admissions, and 30-day emergency readmissions. Hazard ratios (HRs) for emergency admission for 3/4 poor health behaviours in comparison with none were: men, 1.37 (95% CI 1.11 to 1.69); women, 1.84 (95% CI 1.22 to 2.77). Associations were unaltered by adjustment for age, body mass index and comorbidity. CONCLUSIONS: Clustered poor health behaviours are associated with increased risk of hospital admission among older people in the UK. Lifecourse interventions to reduce number of poor health behaviours could have substantial beneficial impact on health and use of healthcare in later life. PMID- 26481496 TI - Development of evidence-based clinical algorithms for prescription of exercise based cardiac rehabilitation. AB - BACKGROUND: Guideline adherence with respect to exercise-based cardiac rehabilitation (CR) is hampered by a large variety of complex guidelines and position statements, and the fact that these documents are not specifically designed for healthcare professionals prescribing exercise-based CR programs. This study aimed to develop clinical algorithms that can be used in clinical practice for prescription and evaluation of exercise-based CR in patients with coronary artery disease (CAD) and chronic heart failure (CHF). METHODS: The clinical algorithms were developed using a systematic approach containing four steps. First, all recent Dutch and European cardiac rehabilitation guidelines and position statements were reviewed and prioritised. Second, training goals requiring a differentiated training approach were selected. Third, documents were reviewed on variables to set training intensity, modalities, volume and intensity and evaluation instruments. Finally, the algorithms were constructed. RESULTS: Three Dutch guidelines and three European position statements were reviewed. Based on these documents, five training goals were selected and subsequently five algorithms for CAD patients and five for CHF patients were developed. CONCLUSIONS: This study presents evidence-based clinical algorithms for exercise based CR in patients with CAD and CHF according to their training goals. These algorithms may serve to improve guideline adherence and the effectiveness of exercise-based CR. PMID- 26481497 TI - Estimating Tumor Growth Rates In Vivo. AB - In this paper, we develop methods for inferring tumor growth rates from the observation of tumor volumes at two time points. We fit power law, exponential, Gompertz, and Spratt's generalized logistic model to five data sets. Though the data sets are small and there are biases due to the way the samples were ascertained, there is a clear sign of exponential growth for the breast and liver cancers, and a 2/3's power law (surface growth) for the two neurological cancers. PMID- 26481498 TI - Emerging Roles of Disordered Sequences in RNA-Binding Proteins. AB - RNA-binding proteins (RBPs) maintain RNA metabolism homeostasis in the cell by regulating temporal, spatial, and functional dynamics of RNAs. RBPs achieve RNA binding not only through classical structured RNA-binding domains but also with sequences that are intrinsically disordered and often of low amino acid complexity. RBP-RNA interactions form ribonucleoprotein (RNP) complexes and emerging evidence indicates that RNPs form higher structures or lattices, promoting territories of phase transitions. Herein, we discuss the role of disordered sequences in RBPs, their function in RNPs and protein networks, as well as their regulation by post-translational modifications and how RBP deregulation leads to disease. PMID- 26481499 TI - Dynamics-Driven Allostery in Protein Kinases. AB - Protein kinases have very dynamic structures and their functionality strongly depends on their dynamic state. Active kinases reveal a dynamic pattern with residues clustering into semirigid communities that move in MUs-ms timescale. Previously detected hydrophobic spines serve as connectors between communities. Communities do not follow the traditional subdomain structure of the kinase core or its secondary structure elements. Instead they are organized around main functional units. Integration of the communities depends on the assembly of the hydrophobic spine and phosphorylation of the activation loop. Single mutations can significantly disrupt the dynamic infrastructure and thereby interfere with long-distance allosteric signaling that propagates throughout the whole molecule. Dynamics is proposed to be the underlying mechanism for allosteric regulation in protein kinases. PMID- 26481500 TI - Chemistry and Biology of Self-Cleaving Ribozymes. AB - Self-cleaving ribozymes were discovered 30 years ago, but their biological distribution and catalytic mechanisms are only beginning to be defined. Each ribozyme family is defined by a distinct structure, with unique active sites accelerating the same transesterification reaction across the families. Biochemical studies show that general acid-base catalysis is the most common mechanism of self-cleavage, but metal ions and metabolites can be used as cofactors. Ribozymes have been discovered in highly diverse genomic contexts throughout nature, from viroids to vertebrates. Their biological roles include self-scission during rolling-circle replication of RNA genomes, co transcriptional processing of retrotransposons, and metabolite-dependent gene expression regulation in bacteria. Other examples, including highly conserved mammalian ribozymes, suggest that many new biological roles are yet to be discovered. PMID- 26481501 TI - Why more is less and less is more when it comes to ovarian stimulation. AB - PURPOSE: The purpose of the present study is to describe the possible mechanisms which may explain the apparent paradox of "less is more." Mild ovarian stimulation for in vitro fertilization (IVF) minimizes ovarian hyperstimulation syndrome (OHSS) and multiple gestations without compromising the pregnancy rate (PR). METHODS: The pertinent English literature (PubMed) addressing mild stimulation for IVF/assisted reproductive technology (ART) and publications addressing "mild" or "soft" controlled ovarian stimulation (COS) vs conventional COS for IVF, OHSS, natural cycle IVF, and IVF outcome in association with COS was searched. RESULTS: Four possible mechanisms can be put forward to explain the apparent paradox of "less is more." (1) In the natural or mild stimulation cycles, the healthiest follicles are selected by the principle of "quality for quantity"; (2) high estradiol (E2) in the late follicular phase significantly correlated with higher rates of small for gestational age (SGA) and low-birth weight (LBW) neonates; (3) anti-Mullerian hormone (AMH), LH, testosterone, and E(2) are significantly higher in natural cycle (NC)-IVF than in stimulated IVF follicles, suggesting an alteration of the follicular metabolism in stimulated cycles; and (4) supraphysiological E(2) may increase the growth hormone-binding protein (GH-BP) bio-neutralizing GH and diminishing the resultant insulin-like growth factor (IGF) levels, necessary for optimal synergism with follicle stimulating hormone (FSH). CONCLUSIONS: It is suggested to aim at the retrieval of around eight to ten eggs. Mild stimulation should be the common practice for IVF. In cases where more than ten ova are retrieved or high E(2) levels are reached, either intentionally or unintentionally, "freeze-all policy" should be considered and embryo transfer (ET) done in a subsequent natural cycle. PMID- 26481502 TI - Effect of follicle-stimulating hormone receptor Asn680Ser polymorphism on the outcomes of controlled ovarian hyperstimulation: an updated meta-analysis of 16 cohort studies. AB - PURPOSE: The purpose of this study is to evaluate the influence of follicle stimulating hormone receptor (FSHR) Asn680Ser polymorphism on the ovarian response to exogenous follicle-stimulating hormone (FSH) and clinical outcomes in women undergoing controlled ovarian hyperstimulation (COH). METHODS: A database search was conducted to identify the eligible studies that investigated the effect of FSHR Asn680Ser polymorphism on ovarian response and clinical outcomes. A pooled analysis was performed with the odds ratio (OR) or weighted mean difference (WMD) and their respective 95 % confidence interval (CI) by the STATA software with random effects model. RESULTS: Sixteen cohort studies comprising a total of 4287 subjects were included. The number of retrieved oocytes was significantly fewer in subjects with the SS genotype at position 680, compared to subjects with the NN or NS genotype (WMD = -1.36, 95 % CI = -1.85 to -0.87). Lack of association was detected between the genotypes (SS genotype vs. NN or NS genotype) and clinical outcomes such as exogenous FSH dose (WMD = 98.96 IU, 95 % CI = -22.33 to 220.24), poor response (OR = 1.08, 95 % CI = 0.71-1.64), ovarian hyperstimulation syndrome (OHSS) (OR = 1.58, 95 % CI = 0.41-6.07), and clinical pregnancy rate (OR = 1.10, 95 % CI = 0.86-1.40). However, poor ovarian response and number of retrieved oocytes were significantly influenced by the Asn680Ser polymorphism in the Asian subjects. In addition, no publication bias was detected. CONCLUSION: FSHR Asn680Ser polymorphism might be a significant biomarker for predicting the number of retrieved oocytes and poor response, especially in Asian subjects. Other outcomes such as exogenous FSH dose, OHSS, and pregnancy rate were not influenced by FSHR Asn680Ser polymorphism. PMID- 26481503 TI - Predictors of functional limitation trajectories after injury in a nationally representative U.S. older adult population. AB - PURPOSE: Studies examining postinjury functional status have demonstrated that individuals with severe injuries often do not return to baseline levels of physical functioning. We sought to investigate the impact injuries have on changes in physical functioning across the life course of older adults. The study's objectives were to (1) identify trajectories of long-term functional limitations after injury in the older adult population to better characterize the recovery process and (2) predict which individuals are most at risk for poor functional trajectories after injury. METHODS: A retrospective cohort study was conducted using six waves of data from the Health and Retirement Study, which surveys Americans older than 50 years every two years. A group-based trajectory model was used to identify trajectories of functional limitations in injured participants. Using multivariate regression, we identified significant predictors of each trajectory. RESULTS: Five distinct trajectories were identified: Trajectory 1--consistently low functional limitations scores (18.9%), Trajectory 2--increase in functional limitations after injury followed by a gradual, incomplete recovery (46.3%), Trajectory 3--increase in functional limitations followed by further decline in functioning (10.5%), Trajectory 4--increase in functional limitations after injury followed by a gradual, complete recovery (13.4%), and Trajectory 5--consistently high functional limitations scores (10.8%). Gender, multiple health conditions, and insurance status predicted trajectory membership. CONCLUSIONS: Functional limitations after injury follow distinct trajectories that can be predicted by baseline individual characteristics. PMID- 26481504 TI - Medical consultations about fertility preservation with haematological patients of childbearing age: A qualitative study. AB - PURPOSE: Oncological treatments can cause serious long-term consequences, including effects on patients' fertility. Communication about possible fertility impairment is essential for cancer patients who want to have children. When oncologists initiate this discussion in a timely manner, patients can be referred to fertility specialists and avail themselves of fertility preservation methods. The oncologist plays a key role in this context. METHODS: 30 cancer patients of childbearing age (21-43 years) took part in semi-structured interviews between March 2011 and April 2012 about fertility and their desire to have children. Interview transcripts were thematically analyzed. RESULTS: Physician-patient consultations broached the issue as a central theme in almost all patients. A few consultations were patient initiated, and the majority took place before the beginning of treatment. Almost half of the patients were satisfied with their consultations and were referred to a fertility specialist. The ideal setting for these conversations is in the presence of the patient's partner, in a private space, before the beginning of treatment. CONCLUSIONS: All patients should be informed about the possibility of their fertility being impaired due to treatments, even if they have not explicitly expressed wanting children. The oncologist is the first and most important contact for the patient and, hence, should bring up the issue of family planning and fertility. An interdisciplinary communication and collaboration between oncologists and fertility specialists can improve patient care. PMID- 26481506 TI - Defining Extended Spectrum beta-Lactamases: Implications of Minimum Inhibitory Concentration-Based Screening Versus Clavulanate Confirmation Testing. AB - INTRODUCTION: While the Clinical and Laboratory Standards Institute (CLSI) recommends against routine screening for extended spectrum beta-lactamases (ESBLs), knowledge of these data can provide valuable insights regarding epidemiology and drug therapy decisions. The purpose of this study was to compare the impact of minimum inhibitory concentration (MIC)-based screening versus phenotypic confirmatory testing of ESBLs on the susceptibility profile of selected antimicrobials. METHODS: Broth microdilution MICs were determined for various antimicrobial agents against a collection contemporary clinical Escherichia coli and Klebsiella pneumoniae isolates. Isolates identified as ESBL positive by MIC screening were then subjected to confirmatory phenotypic testing. Percent susceptibility was based on CLSI or United States Food and Drug Administration breakpoints. RESULTS: Four-hundred and forty-two (18%) isolates screened positive for ESBL production. Of these, 274 (62%) were confirmed positive for ESBL production; 28 (10%) were also carbapenem non-susceptible. We found an under-prediction of activity for ceftolozane/tazobactam (C/T), ertapenem (ETP), meropenem (MEM), and piperacillin/tazobactam (TZP) when considering only the screen-positive testing. CONCLUSION: For agents with potential activity against ESBLs such as C/T, TZP, ETP, and MEM, reduced susceptibility was noted when only considering the MIC screen-positive test. Although phenotypic screening selects for resistant organisms, inclusion of other genotypes besides ESBL (i.e., AmpC, carbapenemase) may falsely under-predict the potency against some ESBL producers and may limit applicability of surveillance data to geographic areas not plagued with carbapenemase producers. FUNDING: Cubist Pharmaceuticals. PMID- 26481505 TI - Coordinate regulation of microenvironmental stimuli and role of methylation in bone metastasis from breast carcinoma. AB - The pathogenesis of bone metastasis is unclear, and much focus in metastatic biology and therapy relays on epigenetic alterations. Since DNA-methyltransferase blockade with 5-aza-2'-deoxycytidine (dAza) counteracts tumour growth, here we utilized dAza to clarify whether molecular events undergoing epigenetic control were critical for bone metastatization. In particular, we investigated the patterns of secreted-protein acidic and rich in cysteine (SPARC) and of Endothelin 1, affected by DNA methyltransferases in tumours, with the hypothesis that in bone metastasis a coordinate function of SPARC and Endothelin 1, if any occurs, was orchestrated by DNA methylation. To this purpose, we prepared a xenograft model with the clone 1833, derived from human-MDA-MB231 cells, and dAza administration slowed-down metastasis outgrowth. This seemed consequent to the reductions of SPARC and Endothelin 1 at invasive front and in the bone marrow, mostly due to loss of Twist. In the metastasis bulk Snail, partly reduced by dAza, might sustain Endothelin 1-SPARC cooperativity. Both SPARC and Endothelin 1 underwent post-translational control by miRNAs, a molecular mechanism that might explain the in vivo data. Ectopic miR29a reduced SPARC expression also under long term dAza exposure, while Endothelin 1 down-regulation occurred in the presence of endogenous-miR98 expression. Notably, dAza effects differed depending on in vivo and in vitro conditions. In 1833 cells exposed to 30-days dAza, SPARC protein level was practically unaffected, while Endothelin 1 induction depended on the 3'-UTR functionality. The blockade of methyltransferases leading to SPARC reduction in vivo, might represent a promising strategy to hamper early steps of the metastatic process affecting the osteogenic niche. PMID- 26481507 TI - Periarrest intestinal bacterial translocation and resuscitation outcome. AB - During the periarrest period, intestinal ischemia may result in barrier dysfunction and bacterial translocation, which has clear mechanistic links to inflammation and cascade stimulation, especially in patients who are treated with therapeutic hypothermia. Despite optimal management, periarrest bacterial translocation may worsen the outcome of cardiac arrest victims. PMID- 26481509 TI - Respiratory Disease: An Update for Radiologists. PMID- 26481508 TI - XingNaoJing, prescription of traditional Chinese medicine, prevents autophagy in experimental stroke by repressing p53-DRAM pathway. AB - BACKGROUND: Xingnaojing (XNJ), a well known prescription in traditional Chinese medicine, has been used for treatment of stroke in China. However, the effects and mechanisms of XNJ on autophagy are not clear. Here, we used the cell models of autophagy induced by serum-free condition and ischemia stroke in rats to further investigate whether the p53-DRAM pathway is involved in the effects of XNJ on autophagy. METHODS: We used the cell model of autophagy induced by serum free condition and the rat model of ischemia caused by a middle cerebral artery occlusion (MCAO). The effects of XNJ on p53 transcriptional activity of PC12 cells were evaluated by the luciferase activity assay. The mRNA levels and the expression of p53 and its target autophagy gene DRAM (damage-regulated autophagy modulator) were analyzed respectively by Quantitative-RTPCR and Western blot assay. The activation of autophagy was detected by the levels of autophagy markers, microtubule associated protein light chain 3 (LC3) and p62 by Immunofluorescence and Western blot. p53 inhibitor was used to determine whether p53 is responsible for the effects of XNJ on preventing autophagy. RESULTS: The assay for luciferase activity of p53 promoter indicated that XNJ inhibited p53 transcriptional activity. XNJ reduced the expression of p53 and its target autophagy gene DRAM (damage-regulated autophagy modulator) in serum-free condition PC12 cells and the cortex in MCAO rats. XNJ reduced autophagy of PC12 cells induced by serum-free condition and the cortex in MCAO rats. Furthermore, suppression of p53 by p53 inhibitor significantly reduced the effects of XNJ on the autophagy of PC12 cells in serum-free condition. CONCLUSION: XNJ prevents autophagy in experimental stroke by repressing p53/DRAM pathway. Our findings are therefore of considerable therapeutic significance and provide the novel and potential application of XNJ for the treatment of brain diseases. PMID- 26481510 TI - Understanding and Enhancing the Pediatric Radiology Patient's Experience. PMID- 26481511 TI - Long-term survival trends of gastric cancer patients between 1972 and 2011 in Qidong. AB - BACKGROUND: There have been few reports on long-term survival of gastric cancer patients. This study analyzed the survival data of gastric cancer patients obtained from the population-based Qidong Cancer Registry between 1972 and 2011, providing a basis for evaluation of gastric cancer treatment and prognosis. METHODS: The cumulative observed survival rate and relative survival rate of gastric cancer patients were calculated using Hakulinen's method via the SURV3.01 software, which was developed by the Finnish Cancer Registry. The date of the last follow-up for the survival status of the 15,401 registered cases was April 30, 2012. RESULTS: The 1-, 5-, 10-, 20-, and 30-year observed survival rates were 33.82%, 14.18%, 10.35%, 6.63%, and 4.19%, respectively, and the 1-, 5-, 10-, 20-, and 30-year relative survival rates were 35.43%, 18.13%, 17.50%, 21.96%, and 32.84%, respectively. For males, the corresponding observed survival rates were 34.50%, 14.40%, 10.42%, 6.46%, and 4.05%, and the corresponding relative survival rates were 36.23%, 18.67%, 18.28%, 23.73%, and 38.61%. For females, the corresponding observed survival rates were 32.62%, 13.80%, 10.22%, 6.95%, and 4.46%, and the corresponding relative survival rates were 34.03%, 17.21%, 16.28%, 19.70%, and 26.78%. Significant differences in relative survival rates were observed between sexes (P = 0.003). For the 15-34, 35-44, 45-54, 55-64, 65-74, and 75+ age groups, the 5-year relative survival rates were 16.13%, 21.77%, 18.63%, 12.61%, 7.99%, and 2.94%, respectively, and the 10-year relative survival rates were 16.49%, 22.83%, 20.50%, 15.97%, 15.88%, and 15.73%, respectively. Remarkable improvement could be observed for the 5-, 10-, and 15-year relative survival rates in Qidong beginning in the 1980s. CONCLUSION: The survival outcome of registered gastric cancer cases in Qidong showed gradual progress over the past two decades. PMID- 26481512 TI - Unstable coronary plaque characteristics are associated with high-sensitivity cardiac troponin T and N-terminal Pro-Brain Natriuretic Peptide. AB - BACKGROUND: Unstable plaque characteristics on coronary CT angiography (CTA), serum high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) concentrations are associated with cardiovascular events. OBJECTIVE: To investigate the association between coronary CTA defined quantifiable plaque characteristics, hs-cTnT and NT-proBNP. METHODS: 81 consecutive stable chest pain patients with an intermediate-to-high risk were analyzed. Coronary CTA was performed using a 64-slice multidetector-row CT scanner. Total coronary plaque volume, calcified volume, non-calcified volume, plaque burden, remodeling index (RI) and number of plaques were measured using dedicated software. A total plaque score ("Sum plaque score") incorporating total plaque volume, RI, plaque burden and number of plaques was defined. Hs-cTnT and NT-proBNP concentrations were measured in serum samples before coronary CTA. RESULTS: Univariate regression analysis demonstrated significant associations of hs-cTnT and NT-proBNP with total plaque volume (r hs-cTnT = .256; r NT-proBNP = .270), calcified volume (r hs-cTnT = .344; r NT-proBNP = .344), RI (r hs-cTnT = .335; r NT-proBNP = .342) and number of plaques (r hs-cTnT = .355; r NT-proBNP = .301) (all P values <= .021). Non-calcified plaque volume showed no association with hs-cTnT and NT-proBNP (r hs-cTnT = .050; r NT-proBNP = .087; P value = .660 and P value = .442). The "Sum plaque score" showed the highest correlation compared to other plaque parameters (r hs-cTnT = .362; r NT-proBNP = .409; P value = .001 and P value <= .001). CONCLUSION: Our data suggest that coronary plaque morphology parameters, derived by dedicated software, are associated with serum hs-cTnT and NT-proBNP concentrations. PMID- 26481513 TI - The effect of exercise on skeletal muscle glucose uptake in type 2 diabetes: An epigenetic perspective. AB - Changes in eating habits and sedentary lifestyle are main contributors to type 2 diabetes (T2D) development, and studies suggest that epigenetic modifications are involved with the growing incidence of this disease. Regular exercise modulates many intracellular pathways improving insulin resistance and glucose uptake in skeletal muscle, both early abnormalities of T2D. Mitochondria dysfunction and decreased expression of glucose transporter (GLUT4) were identified as main factors of insulin resistance. Moreover, it has been suggested that skeletal muscle of T2D subjects have a different pattern of epigenetic marks on the promoter of GLUT4 and PGC1, main regulator of mitochondrial function, compared with nondiabetic individuals. Recent studies have proposed that regular exercise could improve glucose uptake by the attenuation of such epigenetic modification induced at GLUT4, PGC1 and its downstream regulators; however, the exact mechanism is still to be understood. Herein we review the known epigenetic modifications on GLUT4 and mitochondrial proteins that lead to impairment of skeletal muscle glucose uptake and T2D development, and the effect of physical exercise at these modifications. PMID- 26481514 TI - Gluteus medius coactivation response in field hockey players with and without low back pain. AB - OBJECTIVES: To examine the effect of prolonged standing on gluteus medius coactivation and to observe whether the changes in gluteus medius coactivation over time were related to the development of low back pain in elite female field hockey players. DESIGN: Prospective cohort design. METHODS: Participants were 39 elite female field hockey players (14 with a history of low back pain). Before the prolonged stand, maximal hip abduction strength, side bridge hold endurance and hip abduction range of motion were measured bilaterally. Surface electromyography was collected from the gluteus medius for coactivation analysis during a prolonged stand for 70 min. Low back pain was rated every 10 min on a visual analogue scale. RESULTS: Fourteen of 39 participants developed low back pain. The Time effect was significant for gluteus medius coactivation response (p = 0.003) and visual analogue scale score (p < 0.001). There were no significant group * time interactions. Yet athletes who developed pain had higher coactivation for the majority of the stand task. CONCLUSIONS: While female field hockey players have high agonist-antagonist coactivation patterns during prolonged standing, stand task is a useful tool to predict low back pain occurrence in players with and without history of pain. PMID- 26481515 TI - A rash starting on the palms and soles. PMID- 26481516 TI - Effects of repeated handling and air exposure on the immune response and the disease resistance of gibel carp (Carassius auratus gibelio) over winter. AB - High mortalities and suppressed immune functions of farmed fish over winter are the universal problems in aquaculture. It is necessary to improve the immune response and disease resistance in the overwintering fish. A recent study suggested that repeated handling increased innate immune mechanisms and disease resistance in Senegalese sole. Therefore, the present study evaluated the hypothesis that appropriate repeated handling could compromise the immune depression and increase the disease resistance in gibel carp over winter. The experiment was executed in field net cages (2 m * 2 m * 2 m) from Dec. 4, 2012 to Apr. 2, 2013. Three cages with 50 fish per cage were randomly designed as the control group and did not receive any interfere over winter. The other three cages received repeated handling with an air exposure for 5 min every week during the experiment. Fish were not fed over winter. At the end of the trial, fish were challenged with Aeromonas hydrophila at a dose of 1.5 * 10(8) CFU ml(-1). The results showed that no significant difference of final body weight was found between groups. The spleen and kidney somatic index increased in the control fish after bacterial challenge and showed a rising trend but not a statistical change in repeated handled fish. Plasma cortisol levels significantly increased in the control fish at 6 h post bacterial challenge and then declined. However, repeated handled fish did not show any significant change in plasma cortisol levels after challenge. The reduced inducement of heat shock protein 70 (HSP70) expressions by repeated handling was found in gibel carp post bacterial challenge. After overwintering, the repeated handled fish exhibited increased catalase (CAT) and superoxide dismutase (SOD) activities. Enhanced plasma CAT activities and reduced plasma malondialdehyde (MDA) contents were found in repeated handled fish over time against invading bacteria. Up-regulation of myeloid differentiation primary response gene 88 (MyD88) and interleukin 11 (IL11) was observed in repeated handled fish over time after bacterial challenge. The overexpression of IL11 was significantly reduced by repeated handling against invading bacteria compared to the control group. The present results implied that a MyD88-dependent signaling pathway was involved in the innate immune responses of gibel carp by repeated handling over winter against invading bacteria. PMID- 26481517 TI - Viral and bacterial septicaemic infections modulate the expression of PACAP splicing variants and VIP/PACAP receptors in brown trout immune organs. AB - Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and PACAP-Related Peptide (PRP) are structurally similar peptides encoded in the same transcripts. Their transcription has been detected not only in the brain but also in a wide range of peripheral tissues, even including organs of the immune system. PACAP exerts pleiotropic activities through G-protein coupled membrane receptors: the PACAP-specific PAC-1 and the VPAC-1 and VPAC-2 receptors that exhibit similar affinities for the Vasoactive Intestinal Peptide (VIP) and PACAP. Recent findings added PACAP and its receptors to the growing list of mediators that allow cross talk between the nervous, endocrine and immune systems in fish. In this study the expression of genes encoding for PACAP and PRP, as well as VIP/PACAP receptors was studied in laboratory-reared brown trout (Salmo trutta) after septicaemic infections. Respectively Viral Haemorrhagic Septicaemia Virus (VHSV-Ia) or the Gram-negative bacterium Yersinia ruckeri (ser. O1 - biot. 2) were used in infection challenges. Kidney and spleen, the teleost main lymphopoietic organs, were sampled during the first two weeks post-infection. RT-qPCR analysis assessed specific pathogens burden and gene expression levels. PACAP and PRP transcription in each organ was positively correlated to the respective pathogen burden, assessed targeting the VHSV-glycoprotein or Y. ruckeri 16S rRNA. Results showed as the transcription of PACAP splicing variants and VIP/PACAP receptors is modulated in these organs during an acute viral and bacterial septicaemic infections in brown trout. These gene expression results provide clues as to how the PACAP system is modulated in fish, confirming an involvement during active immune responses elicited by both viral and bacterial aetiological agents. However, further experimental evidence is still required to fully elucidate and characterize the role of PACAP and PRP for an efficient immune response against pathogens. PMID- 26481518 TI - Recombinant Saccharomyces cerevisiae serves as novel carrier for oral DNA vaccines in Carassius auratus. AB - Oral delivery of DNA vaccines represents a promising vaccinating method for fish. Recombinant yeast has been proved to be a safe carrier for delivering antigen proteins and DNAs to some species in vivo. However, whether recombinant yeast can be used to deliver functional DNAs for vaccination to fish is still unknown. In this study, red crucian carp (Carassius auratus) was orally administrated with recombinant Saccharomyces cerevisiae harboring CMV-EGFP expression cassette. On day 5 post the first vaccination, EGFP expression in the hindgut was detected under fluorescence microscope. To further study whether the delivered gene could induce specific immune responses, the model antigen ovalbumin (OVA) was used as immunogen, and oral administrations were conducted with recombinant S. cerevisiae harboring pCMV-OVA mammalian gene expression cassette as gene delivery or pADH1 OVA yeast gene expression cassette as protein delivery. Each administration was performed with three different doses, and the OVA-specific serum antibody was detected in all the experimental groups by western blotting and enzyme-linked immunosorbent assay (ELISA). ELISA assay also revealed that pCMV-OVA group with lower dose (pCMV-OVA-L) and pADH1-OVA group with moderate dose (pADH1-OVA-M) triggered relatively stronger antibody response than the other two doses. Moreover, the antibody level induced by pCMV-OVA-L group was significantly higher than pADH1-OVA-M group at the same serum dilutions. All the results suggested that recombinant yeast can be used as a potential carrier for oral DNA vaccines and would help to develop more practical strategies to control infectious diseases in aquaculture. PMID- 26481519 TI - Identification and characterization of a mitochondrial unfolded protein response transcription factor ATFS-1 in Litopenaeus vannamei. AB - A mitochondrial specific stress response termed mitochondrial unfolded protein response (UPR(mt)) is activated in responding to disturbance of protein homeostasis in mitochondria. The activating transcription factor associated with stress-1 (designated as ATFS-1) is the key regulator of UPR(mt). To investigating the roles of ATFS-1 (LvATFS-1) in Litopenaeus vannamei mitochondrial stress remission and immunity, it's full length cDNA was cloned. The open reading frame of LvATFS-1 was 1, 557 bp in length, deducing to a 268 amino acids protein. LvATFS-1 was highly expressed in muscle, hemocytes and eyestalk. Subcellular location assays showed that N-terminal of LvATFS-1 contained a mitochondrial targeting sequence, which could directed the fused EGFP located to mitochondria. And the C-terminal of LvATFS-1, which had a nuclear localization signal, expressed in nucleus. The in vitro experiments verified that LvATFS-1 could reduced the level of intracellular reactive oxygen species (ROS). And results of real-time RT-PCR indicated that LvATFS-1 might scavenge excess ROS via ROS eliminating genes regulation. Reporter gene assays showed that LvATFS-1 could upregulated the expression of the antimicrobial peptide genes in Drosophila Schneider 2 cells. Results of real-time RT-PCR showed that Vibrio alginolyticus or white spot syndrome virus (WSSV) infection induced the expression of LvATFS-1. And knocked-down LvATFS-1 by RNAi resulted in a higher cumulative mortality of L. vannamei upon V. alginolyticus or WSSV infection. These results suggested that LvATFS-1 not only rolled in mitochondrial specific stress responding, but also important for L. vannamei immunologic defence. PMID- 26481521 TI - Inhibition of voltage-gated Na+ channels by hinokiol in neuronal cells. AB - BACKGROUND: Hinokiol is a naturally occurring diterpenoid compound isolated from plants such as Taiwania cryptomerioides. Anti-oxidation, anti-cancer, and anti inflammation effects of this compound have been reported. It is not yet known if hinokiol affects neurons or neuronal ion channel activities. We reported here that hinokiol inhibited voltage-gated Na(+) channels (VGSC) in neuronal cells and we characterized the mechanisms of block. METHODS: The effects of hinokiol on Na(+) channels were examined using the voltage-clamp (whole-cell mode) technique. RESULTS: VGSC was blocked by hinokiol in a concentration-dependent and state dependent manner in neuroblastoma N2A cells: IC(50) are 11.3 and 37.4MUM in holding potentials of -70 and -100 mV, respectively. In the presence of hinokiol there was a 13-mV left shift in steady-state inactivation curves; however, activation gating was not altered. VGSC inhibition by hinokiol did not require channel opening and was thus considered to be closed-channel block. In the presence of hinokiol, since the degree of block did not enhance with stimulation frequency, block by hinokiol thus did not exhibit use-dependence. Recovery from channel inactivation was not significantly affected in the presence of hinokiol. In addition, hinokiol also inhibited VGSC of differentiated neuronal NG108-15 cells and rat hippocampal CA1 neurons. CONCLUSION: Our results therefore suggest hinokiol inhibited VGSC in a closed-channel block manner and such inhibition involved intensification of channel inactivation. PMID- 26481520 TI - Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons. AB - We have recently demonstrated that reactive glial cells can be directly reprogrammed into functional neurons by a single neural transcription factor, NeuroD1. Here we report that a combination of small molecules can also reprogram human astrocytes in culture into fully functional neurons. We demonstrate that sequential exposure of human astrocytes to a cocktail of nine small molecules that inhibit glial but activate neuronal signaling pathways can successfully reprogram astrocytes into neurons in 8-10 days. This chemical reprogramming is mediated through epigenetic regulation and involves transcriptional activation of NEUROD1 and NEUROGENIN2. The human astrocyte-converted neurons can survive for >5 months in culture and form functional synaptic networks with synchronous burst activities. The chemically reprogrammed human neurons can also survive for >1 month in the mouse brain in vivo and integrate into local circuits. Our study opens a new avenue using chemical compounds to reprogram reactive glial cells into functional neurons. PMID- 26481522 TI - Molecular identification of P2X receptors in vascular smooth muscle cells from rat anterior, posterior, and basilar arteries. AB - BACKGROUND: Purinergic P2X receptors in vascular smooth muscle cells (VSMCs) play an important role in physiological stimulatory responses to the extracellularly released ATP. The aim of this work was to identify molecular P2X receptor subunits in VSMCs isolated from rat anterior, posterior and basilar arteries using a number of contemporary laboratory techniques. METHODS: P2X mediated ionic currents were recorded using amphotericin B perforated patch clamp method. Gene expression analysis was performed using RT-PCR in manually collected VSMCs. The expression of proteins was confirmed by fluorescent immunocytochemistry. RESULTS: Under voltage clamp conditions VSMCs stimulated by application of 10 MUmol/l selective P2X receptor agonist alphabeta-meATP, the biphasic currents consisting of rapidly rising rapidly desensitizing and slowly desensitizing components were observed in freshly isolated myocytes from all three arteries. Using RT-PCR, the expression of genes encoding only P2X1 and P2X4 receptor subunits was detected in preparations from all three arteries. The expression of corresponding P2X1 and P2X4 receptor subunit proteins was confirmed in isolated VSMCs. CONCLUSIONS: Our work therefore identified that in major arteries of rat cerebral circulation VSMCs express only P2X1 and P2X4 receptors subunits. We can propose that these P2X receptor subunits participate in functional P2X receptor structures mediating ATP-evoked stimulatory responses in cerebral vascular myocytes in vivo. PMID- 26481523 TI - Protective effect of gallic acid against bleomycin-induced pulmonary fibrosis in rats. AB - BACKGROUND: Bleomycin (BLM), a chemotherapeutic agent is indicated in the management of some types of cancers. This drug produces a dose-dependent pulmonary fibrosis (PF) in most patients as well as experimental animals through oxidative injury. This study aimed to investigate the effect of gallic acid (GA), a polyphenolic compound, against PF-induce by BLM in rats. MATERIALS AND METHODS: The rats were given GA orally at doses (50, 100, and 200 mg/kg/day) for 7 consecutive days before the administration of single intratracheal (it) instillation of BLM at 7.5 IU/kg. GA doses were continued for 21 days after BLM exposure. The regulatory effects of GA on BLM-induced pulmonary toxicity were determined by assaying oxidative stress biomarkers, lung and serum cytokine levels, and by histopathological examination of lung tissue. RESULTS: The results showed that intratracheal BLM administration significantly increased the inflammatory or fibrotic changes, collagen content, levels of malondialdehyde (MDA), and pro-inflammatory cytokines such as TNF-alpha and IL1beta in lung. Also, it significantly decreased non-enzymatic (total thiol) and enzymatic (glutathione peroxidase (GPx)) antioxidant contents in the rats' lung tissue. However, oral administration of GA reversed all of these biochemical indices as well as histopathological alterations induced by BLM. CONCLUSION: Results of the present study demonstrate that GA, by its antioxidant properties, attenuates oxidative damage and fibrosis induced by BLM. Thus, an effective supplement with GA as an adjuvant therapy may be a very promising compound in reducing the side effects of BLM. PMID- 26481524 TI - Targeting aberrant cancer metabolism - The role of sirtuins. AB - Cancer cells, as opposed to normal cells, generate energy by increasing aerobic glycolysis, which is a phenomenon called "the Warburg effect". An altered energy metabolism supporting continuous cell growth and proliferation was pointed to as the new "hallmark" of cancer cells. Several hypotheses have been proposed to explain the maintenance of this seemingly wasteful catabolic state. The epigenetic mechanisms which depend on the covalent modifications of both DNA and histones have recently emerged as important players in the regulation of glucose metabolism. The sirtuin family of histone deacetylases has emerged as important regulators of diverse physiological and pathological events, including cancer metabolism. Sirtuins 1-7 (SIRT1-7) belong to class III of histone deacetylase enzymes which are dependent on NAD(+) for activity. It was recently demonstrated that SIRT6 is a tumor suppressor that modulates aerobic glycolysis by repressing HIF1 transcription. Members of this family of enzymes are considered promising pharmaceutical targets for cancer treatment. This review highlights the major functions of sirtuins in relation to cancer metabolism and the possibilities of their activation and inhibition by small molecule drugs. PMID- 26481525 TI - In vitro studies of antifibrotic and cytoprotective effects elicited by proto berberine alkaloids in human dermal fibroblasts. AB - BACKGROUND: The pathogenic mechanisms of skin fibrosis are still not completely understood, unlike the profibrotic role played by inflammatory cytokines and transforming growth factor-beta1 (TGF-beta1). Few antifibrotic drugs are available. Nevertheless, folk medicine suggests numerous treatments of fibrotic conditions. Based on information from folk medicine and literature, the hypothesis was made that proto-berberine alkaloids could act as antifibrotic and cytoprotective agents. METHODS: The effects of berberine, dihydroberberine, canadine, stylopine, and coptisine were investigated on an in vitro model of fibrosis purposely set up. The study is based on the use of human dermal fibroblasts (HDF). The ability of the proto-berberine alkaloids investigated to modulate mitochondrial dehydrogenase activity, cell proliferation, collagen production, and inflammatory cytokine (IL-1beta and IL-6) production was tested on HDF cells grown under standard growth conditions, in the presence of 100 MUM H(2)O(2), simulating oxidative stress conditions, and in the presence of 34 ng/ml TGF-beta1, simulating fibrotic conditions. Antiradical activity was assayed as well, as it could contribute to cytoprotection. RESULTS: Each alkaloid tested showed peculiar effects on HDF. In particular, all of the alkaloids tested, with the exception of coptisine, inhibited TGF-beta1-induced collagen production. CONCLUSIONS: Due to its irritant effects and the lack of desired properties, coptisine has low exploitation potentialities. The other proto-berberine alkaloids investigated resulted all endowed with activities for which they can be exploited as antifibrotic and cytoprotective agents. Stylopine globally proved to be the most promising compound, being endowed with revitalizing, anti inflammatory, antifibrotic and wound-healing promoting activities, and showing no toxic effects. PMID- 26481526 TI - Naringenin protects cardiac hypercholesterolemia-induced oxidative stress and subsequent necroptosis in rats. AB - BACKGROUND: In earlier studies, the supplementation of the natural compound Naringenin (NGEN), improved the liver oxidative and inflammatory status, which indicates its direct effect via inhibition of the nuclear factor kappaB pathway on high cholesterol-induced hepatic damages. In this regard, the present study highlights the mechanisms associated with the protective efficacy of NGEN in the heart tissue of hypercholesterolemic diet rats. RESULTS: The animals exposed to a high cholesterol diet (HCD) for 90 days exhibited a significant increase in the levels of serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities, nitric oxide (NO) levels, protein and lipid oxidative markers and cardiac lipids profile. Moreover, hypercholesterolemia decreased the levels of enzymatic and non enzymatic antioxidants associated with mitochondrial dysfunctions as proved by the decrease in the mitochondrial complexes in comparison to controls. Importantly, cholesterol-feeding significantly increased myocardial reactive oxygen species (ROS) and nuclear DNA damage and led to the activation of gene expression of the tumor necrosis factor-alpha (TNF-alpha) and receptor interacting protein kinase 3 (RIP3) mRNA that contributed to the elucidation of cholesterol-induced necroptosis, a recently described type of programmed necrosis, in the cardiac tissue. CONCLUSIONS: Our results show that the co administration of NGEN (50 mg/kg/bw) in HCD rats improved all the altered parameters and provided insight into a possible molecular mechanism underlying NGEN suppression of necroptosis pathway in the heart. PMID- 26481527 TI - Current approach for detection of sub-clinical left ventricular dysfunction associated with chemotherapy. AB - The article describes the current knowledge concerning approaches for detection of sub-clinical left ventricular dysfunction associated with chemotherapy. The authors focused on the problem of defining cardiotoxicity as well as diagnostic methods, which may be useful in predicting the occurrence of such complications. Currently, cardiac biomarkers measurement (troponin, NT-proBNP), tissue Doppler based strain imaging and peak systolic longitudinal strain rate are most useful for detection of early myocardial changes during therapy, whereas speckle tracking echocardiography (STE) and peak systolic global longitudinal strain (GLS) appear to be the best measure. The problem of cardiotoxicity requires close cooperation between oncologists and cardiologists, particularly in light of the growing number of cancer cases. PMID- 26481528 TI - A ground state of PPARgamma activity and expression is required for appropriate neural differentiation of hESCs. AB - BACKGROUND: Several evidences indicate stimulation of peroxisome proliferator activated receptor gamma (PPARg), promotes neuronal differentiation. This study was conducted to testify the prominence of PPARgamma during neural differentiation of human embryonic stem cells (hESCs). METHODS: PPARgamma expression level was assessed during neural differentiation of hESCs. Meanwhile, the level of endogenous miRNAs, which could be engaged in regulation of PPARgamma expression, was measured. Next, natural and synthetic components of PPARgamma agonists and antagonist were implemented on neural progenitor formation during neural differentiation of hESCs. RESULTS: Data showed an increasing wave of PPARgamma expression level when human neural progenitors (NPs) were formed upon retinoic acid treatment. Interestingly, there was no significant difference in the amount of PPARgamma proteins during the differentiation of hESCs that is inconsistent with what we observed for RNA level. Our results indicated that miRNAs are not involved in the regulation of PPARgamma expression, while proteasome-mediated degradation may to some degree be involved in this process. Among numerous treatments, PPARgamma inactivation during NPs formation significantly decreased expression of NP markers. CONCLUSIONS: We conclude that a ground state of PPARgamma activity is required for NP formation of hESCs during early neural differentiation. However, high expression and activity of PPARgamma could not enhance the required neural differentiation, whereas the PPARgamma inactivation could negatively influence NP formation from hESCs by antagonist. PMID- 26481529 TI - Knockdown of AKT3 and PI3KCA by RNA interference changes the expression of the genes that are related to apoptosis and autophagy in T98G glioblastoma multiforme cells. AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant and invasive human brain tumor and it is characterized by a poor prognosis and short survival time. The PI3K/AKT/PTEN signaling pathway plays a crucial role in GBM development and it is connected with the regulation of apoptosis and autophagy. Akt is involved in various aspects of cancer cell biology such as cell survival, in addition to both apoptosis and autophagy. The current study was undertaken to examine the effect of the siRNAs that target AKT3 and PI3KCA genes on the apoptosis and autophagy of T98G cells. METHODS: T98G cells were transfected with AKT3 and/or PI3KCA siRNAs. Alterations in the mRNA expression of apoptosis- and autophagy-related genes were analyzed using QRT-PCR. LC3IIA protein-positive cells were identified using flow cytometry with specific antibodies. RESULTS: Our findings demonstrate for the first time that the siRNAs that target AKT3 and PI3KCA change the expression of the genes that are related to apoptosis and autophagy and change the expression of the LC3IIA protein in T98G cells. CONCLUSIONS: Thus, there is a high probability that the knockdown of these genes induces apoptosis and autophagy in T98G cells, but further studies are necessary in order to clarify and check whether autophagy induction is a positive phenomenon for the treatment of GBM. PMID- 26481530 TI - Valproic acid (VPA) reduces sensorimotor gating deficits and HDAC2 overexpression in the MAM animal model of schizophrenia. AB - BACKGROUND: Evidence indicates that the disruption of epigenetic processes might play an important role in the development of schizophrenia symptoms. The present study investigated the role of histone acetylation in the development of sensorimotor gating deficits in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17. METHODS: Valproic acid (VPA), an inhibitor of class I histone deacetylases, was administered (250 mg/kg, twice a day for 7 consecutive days) in early adolescence (23rd-29th day) or early adulthood (63rd-69th day) to rats. The effect of VPA treatment on the sensorimotor gating deficits induced by prenatal MAM administration was analyzed in adult rats at postnatal day 70 (P70). In addition, the effects of VPA administration (at the same doses) on MAM-induced changes in the levels of histone H3 acetylation at lysine 9 (H3K9ac) and histone deacetylase 2 (HDAC2) in the medial prefrontal cortex (mPFC) were determined at P70 using Western blot. RESULTS: VPA administration in either adolescence or early adulthood prevented the sensorimotor gating deficits induced by MAM. However, VPA administration in early adolescence or early adulthood did not alter H3K9ac levels induced by MAM. In contrast, VPA administration in either adolescence or adulthood prevented the increase in HDAC2 level evoked by MAM. CONCLUSIONS: Prenatal MAM administration impaired histone acetylation in the mPFC, which might be involved in the development of some of the neurobehavioral deficits (i.e., sensorimotor gating deficits) associated with schizophrenia. Blockade of HDAC2 might prevent the disruption of sensorimotor gating in adulthood. PMID- 26481531 TI - Decrease of interleukin (IL)17A gene expression in leucocytes and in the amount of IL-17A protein in CD4+ T cells in children with Down Syndrome. AB - BACKGROUND: Down Syndrome is by far the most common and best known chromosomal disorder in humans. It expresses multiple systemic complications with both structural and functional defects as part of the clinical manifestation. The mechanisms of immune changes occurring in Down Syndrome are complex and include an extra gene copy of chromosome 21 and secondary dysregulation of numerous intercellular interactions. Recent studies suggest a role of interleukin 17A (IL 17A), a pro-inflammatory cytokine located on 6p12 chromosome, in the pathogenesis of inflammatory and autoimmune diseases. We aimed to analyze IL17A gene expression in peripheral white cells and IL-17A intracellular expression on CD4+ T-cells. METHODS: The research was carried out on a group of 58 children aged 6 12 years including a group of 30 children with Down Syndrome (simple trisomy of chromosome 21 only) and a reference group of 28 healthy children. We evaluated gene IL17A expression using real-time PCR and intracellular IL-17A analyzed by flow cytometry. RESULTS: We found significantly decreased gene expression in white cells and significantly decreased expression of IL-17A levels on CD4+ T cells in Down Syndrome. CONCLUSIONS: Our data indicate that decreased IL-17A expression may play a significant role in the etiology of infections in Down Syndrome. Moreover, we demonstrated that in Down Syndrome the other gene located outside the extra chromosome 21 is also affected. PMID- 26481532 TI - Up-regulation of the GPR39 Zn2+-sensing receptor and CREB/BDNF/TrkB pathway after chronic but not acute antidepressant treatment in the frontal cortex of zinc deficient mice. AB - BACKGROUND: The GPR39-Zn(2+)-sensing receptor seems to be involved in the pathophysiology of depression. GPR39 knockout animals show depressive- and anxiety-like behavior. Chronic treatment with selective antidepressants (ADs) up regulates GPR39. OBJECTIVE AND METHODS: In the present study we investigated whether acute or chronic treatment with imipramine, escitalopram, reboxetine and bupropion would cause changes in CREB, BDNF, TrkB and GPR39-Zn(2+) receptor proteins (measured by Western Blot) in the frontal cortex of mice fed with a low zinc diet. RESULTS: The administration of acute antidepressants induced diverse effects in the proteins that were examined (namely, GPR39 down-regulation and a reduction in CREB protein after administration of all ADs; a decrease in BDNF after administration of imipramine and escitalopram; an increase in BDNF after administration of reboxetine; no change in BDNF following administration of bupropion; and a decrease in TrkB following the administration of all ADs except bupropion). On the other hand, chronic treatment (which is required for depression relief) with all antidepressants increased the levels of all these proteins. CONCLUSIONS: The present study for the first time demonstrates the up regulation of GPR39 (and CREB, BDNF, and TrkB) protein when induced by chronic treatment with antidepressants (with different pharmacological profiles) in a zinc-deficiency model in mice. These data further indicate that the GPR39 receptor may be an important target in the antidepressant response. PMID- 26481533 TI - Interactions between an antidepressant reboxetine and four classic antiepileptic drugs in the mouse model of myoclonic seizures. AB - BACKGROUND: The incidence rate of depression among patients with epilepsy is relatively high. The basis of proper therapy is knowledge of drug interactions, which may enable to maximize therapeutic effects and minimize undesired effects of the combined treatment. The purpose of this study was to evaluate the influence of reboxetine, a selective norepinephrine reuptake inhibitor, on the seizure threshold and anticonvulsant effects of four classic antiepileptic drugs: valproate, phenobarbital, ethosuximide, and clonazepam. Moreover, we assessed the adverse effects of reboxetine and combinations of reboxetine with antiepileptic drugs on motor coordination and long-term memory. METHODS: The subcutaneous pentylenetetrazole (PTZ) test in mice was used to determine effects of anticonvulsant activity of antiepileptic drugs and reboxetine. Undesired effects of either reboxetine or and its combinations with antiepileptics were evaluated in the chimney test (motor coordination) and the step-through passive-avoidance task (long-term memory). RESULTS: Analysis of obtained results revealed that reboxetine given at doses of 10 and 15 mg/kg doses exhibits anticonvulsant activity expressed by increasing the median convulsive dose (CD(50)) for pentylenetetrazole (p < 0.01). However, the antidepressant did not affect the anticonvulsant action of antiepileptic drugs studied in this seizure model. Moreover, no adverse reactions were found after administration of reboxetine alone or in combinations. CONCLUSION: If further research confirms the obtained results, reboxetine may be categorized as an antidepressant which can be safely administered to epileptic patients treated with valproate, phenobarbital, ethosuximide or clonazepam. PMID- 26481534 TI - Icariin regulates PRMT/ADMA/DDAH pathway to improve endothelial function. AB - BACKGROUND: Oxidative stress may affect PRMT/ADMA/DDAH (protein arginine methyltransferases/asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase) pathway to impair endothelial dysfunction. The present study was carried out to test the effect of icariin on endothelial function and the mechanisms responsible for this. METHODS: Eighty mice at 12 weeks of age were separated randomly into four groups (n = 20): C57BL/6J control, untreated apolipoprotein E-deficient (ApoE(-/-)), two groups of icariin-treated (10 or 30 mg/kg body wt/day, intragastrically) ApoE(-/-). Primary human umbilical vein endothelial cells (HUVECs) were randomly divided into 7 groups: control group, vehicle of icariin (10 MUmol/L) group, icariin (10 MUmol/L) group, lysophosphatidylcholine (LPC) (10 MUg/mL) group, LPC plus icariin (1 MUmol/L) group, LPC plus icariin (3 MUmol/L) group, and LPC plus icariin (10 MUmol/L) group. RESULTS: In ApoE(-/-) mice and primary HUVECs, icariin treatment decreased reactive oxygen species production, PRMT I expression, ADMA level, half-maximum effective concentration of ApoE(-/-) mice aortic rings. Icariin increased DDAH II expression, DDAH activity, maximal relaxation value and endothelium-dependent vasorelaxation in aortic rings from ApoE(-/-) mice (p < 0.05 or p < 0.01). CONCLUSIONS: The present results suggest that icariin regulates PRMT/ADMA/DDAH pathway to improve endothelial function. PMID- 26481535 TI - The effect of GABA transporter 1 (GAT1) inhibitor, tiagabine, on scopolamine induced memory impairments in mice. AB - BACKGROUND: GABAergic neurotransmission is involved in long-term potentiation, a neurophysiological basis for learning and memory. On the other hand, GABA enhancing drugs may impair memory and learning in humans and animals. The present study aims at investigating the effect of GAT1 inhibitor tiagabine on memory and learning. METHODS: Albino Swiss (CD-1) and C57BL/6J mice were used in the passive avoidance (PA), Morris water maze (MWM) and radial arm water maze (RAWM) tasks. Scopolamine (1mg/kg ip) was applied to induce cognitive deficits. RESULTS: In the retention trial of PA scopolamine reduced step-through latency as compared to vehicle-treated mice, and pretreatment with tiagabine did not have any influence on this effect. In MWM the results obtained for vehicle-treated mice, scopolamine treated group and combined scopolamine+tiagabine-treated mice revealed variable learning abilities in these groups. Tiagabine did not impair learning in the acquisition trial. In RAWM on day 1 scopolamine-treated group made nearly two fold more errors than vehicle-treated mice and mice that received combined scopolamine and tiagabine. Learning abilities in the latter group were similar to those of vehicle-treated mice in the corresponding trial block on day 1, except for the last trial block, during which tiagabine+scopolamine-injected mice made more errors than control mice and the scopolamine-treated group. In all groups a complete reversal of memory deficits was observed in the last trial block of day 2. CONCLUSIONS: The lack of negative influence of tiagabine on cognitive functions in animals with scopolamine-induced memory impairments may be relevant for patients treated with this drug. PMID- 26481536 TI - Antiarrhythmic activity of new 2-methoxyphenylpiperazine xanthone derivatives after ischemia/reperfusion in rats. AB - BACKGROUND: We have previously shown significant prophylactic and therapeutic antiarrhythmic activity in adrenaline-induced arrhythmia, as well as alpha1 adrenolytic properties of new derivatives of xanthone. Herein, we investigated their antiarrhythmic activity in the model of ischemia/reperfusion in isolated hearts. Furthermore, we assessed antioxidant activity in biochemical studies. METHODS: Antiarrhythmic activity in the model of ischemia/reperfusion in isolated perfused hearts was performed according to the Langendorff technique. Antioxidant activity was measured by lipid peroxidation level in tissue homogenate and in the FRAP assay. RESULTS: All studied compounds (MH-94, MH-99 and MH-105) showed significant antiarrhythmic activity in the model of ventricular arrhythmias associated with coronary artery occlusion and reperfusion. However, they did not demonstrate antioxidant effect, probably, because of the lack of free hydroxyl group(s) at a key position in the xanthone scaffold. CONCLUSIONS: The present study provides evidences for antiarrhythmic activity of some 2 methoxyphenylpiperazine derivatives of xanthone. PMID- 26481537 TI - Chelidonine, a principal isoquinoline alkaloid of Chelidonium majus, attenuates eosinophilic airway inflammation by suppressing IL-4 and eotaxin-2 expression in asthmatic mice. AB - BACKGROUND: Chelidonine, a major bioactive, isoquinoline alkaloid ingredient in Chelidonium majus, exhibits anti-inflammatory and other pharmacological properties. However, its molecular mechanisms in asthma remain unclear. In this work we investigated chelidonine's effect and mechanism in airway inflammation in a mouse model of allergic asthma. METHODS: The mice were sensitized to ovalbumin followed by aerosol allergen challenges and determination of chelidonine's effect on enhanced pause (Penh), pulmonary eosinophilic infiltration, eotaxin-2, interleukin-4 (IL-4), IL-13, OVA-specific IgE production, and several transcription factors. RESULT: Chelidonine strongly suppressed airway eosinophilia, expression of eotaxin-2, IL-4, and IL-13 cytokine production in bronchoalveolar lavage fluid (BALF). It also attenuated lung IL-17, and eotaxin-2 mRNA expression levels. Moreover, it suppressed eotaxin-2 and IL-17 production in accordance with up- and downregulation of forkhead box p3 (Foxp3), and signal transducer and activator of transcription (STAT6) expression, respectively. CONCLUSIONS: Chelidonine has profound inhibitory effects on airway inflammation and this effect is caused by suppression of IL-4, eotaxin-2, and OVA-specific IgE production through the STAT6 and Foxp3 pathways. So chelidonine can improve allergic asthma in mice and be a novel anti-asthma therapeutic. PMID- 26481538 TI - Inhibition of human cytochrome P450 isoenzymes by a phenothiazine neuroleptic levomepromazine: An in vitro study. AB - BACKGROUND: Inhibition of cytochrome P450 (CYP) isoenzymes is the most common cause of harmful drug-drug interactions. The present study was aimed at examining the inhibitory effect of the phenothiazine neuroleptic levomepromazine on main CYP isoenzymes in human liver. METHODS: The experiment was performed in vitro using the human cDNA-expressed CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (Supersomes). CYP isoenzyme activities were determined using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6) and testosterone 6beta-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of levomepromazine (1-50 MUM). The concentrations of CYP-specific substrates and their metabolites formed by CYP isoenzymes were measured by HPLC with UV or fluorimetric detection. RESULTS: Levomepromazine potently inhibited CYP2D6 (K(i) = 6 MUM) in a competitive manner. Moreover, the neuroleptic moderately diminished the activity of CYP1A2 (K(i) = 47 MUM) and CYP3A4 (K(i) = 34 MUM) via a mixed mechanism. On the other hand, levomepromazine did not affect the activities of CYP2C9 and CYP2C19. CONCLUSION: The inhibition of CYP1A2, CYP2D6 and CYP3A4 by levomepromazine, demonstrated in vitro in the present study, should also be observed in vivo (especially the CYP2D6 inhibition by levomepromazine), since the calculated K(i) values are below or close to the presumed concentration range for levomepromazine in the liver in vivo. Therefore pharmacokinetic interactions involving levomepromazine and CYP2D6, CYP1A2 or CYP3A4 substrates are likely to occur in patients during co-administration of the above-mentioned substrates/drugs. PMID- 26481539 TI - The effect of combined treatment with risperidone and antidepressants on the MK 801-induced deficits in the social interaction test in rats. AB - BACKGROUND: Several clinical reports have suggested that augmentation of atypical antipsychotics' activity by antidepressants may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. METHODS: The aim of the present study was to investigate the effect of antidepressant mirtazapine or escitalopram and risperidone (an atypical antipsychotic), given separately or jointly, on the MK-801-induced deficits in the social interaction test in rats. Antidepressants and risperidone were given 60 and 30 min before the test, respectively. The social interaction of male Wistar rats was measured for 10 min, starting 4 h after MK-801 (0.1 mg/kg) administration. RESULTS: In the social interaction test, MK-801-induced deficits in the parameters studied, i.e. the number of episodes and the time of interactions. Risperidone at a higher dose (0.1 mg/kg) reversed that effect. Co-treatment with an ineffective dose of risperidone (0.01 mg/kg) and mirtazapine (2.5 or 5 mg/kg) or escitalopram only at a dose of 5 mg/kg (but not 2.5 and 10 mg/kg) abolished the deficits evoked by MK 801. CONCLUSION: The obtained results suggest that especially mirtazapine, and to a smaller degree escitalopram may enhance the antipsychotic-like effect of risperidone in the animal test modeling some negative symptoms of schizophrenia. PMID- 26481540 TI - Effect of a kynurenic acid analog on home-cage activity and body temperature in rats. AB - BACKGROUND: N-(2-N,N-Dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (SzR-72) is a kynurenic acid (KYNA) amide analog that displays neuroprotective action. Whereas its brain penetration ability and its solubility limit the therapeutic use of KYNA: the corresponding properties of the analog exceed those of the parent compound. Although SzR-72 has been extensively studied, its exact mechanism of action has not yet been fully clarified. As KYNA induces hypothermia in laboratory rodents, it may be hypothesized that SzR-72 may have a similar effect. This would be of major importance, since the hypothermia generated by external cooling is neuroprotective, thus a putative hypothermic effect of SzR-72 could contribute to its neuroprotective action. METHODS: The effects of SzR-72 on the body temperature and home-cage activity of rats were studied by using a telemetry system. In order to follow the longitudinal changes in the effects of the compound, subchronic drug administration was applied. RESULTS: The initial administration of the compound induced substantial hypothermia and reduced the home-cage activity. During the 5 days of SzR-72 administration, partial tolerance developed to the hypothermic effect, while the inhibition of home-cage activity detected after the acute administration was completely tolerated. CONCLUSIONS: On the basis of these results, it cannot be excluded that the hypothermic effect of SzR-72 contributes to its neuroprotective action. PMID- 26481541 TI - Thalidomide can promote erythropoiesis by induction of STAT5 and repression of external pathway of apoptosis resulting in increased expression of GATA-1 transcription factor. AB - BACKGROUND: Thalidomide was shown to stimulate erythropoiesis and increase hemoglobin level in multiple myeloma patients, but way of such activity remains unclear. The aim of the study was to investigate the mechanisms of thalidomide stimulating effect on erythroid differentiation. METHODS: Hematopoietic stem cells were isolated from bone marrow aspirates taken from myeloma patients and cultured with or without thalidomide. Then the generation of erythroid cells and the expression of STAT5, GATA-1, GATA-2, selected caspases and Bcl-2 family proteins in erythroid cells were assessed using flow cytometry and real-time PCR. RESULTS: The generation of erythroblasts was higher in thalidomide than in control cultures (63.9% vs. 55.8%, p < 0.001). The expression of caspase 3 (cytometry 947.3 vs. 1021.0, p = 0.025; PCR 12.9 vs. 16.3, p = 0.025) and caspase 8 (cytometry 1050.8 vs. 1168.5, p = 0.033; PCR 16.2 vs. 17.8, p = 0.004) was significantly lower in thalidomide than in control cultures. The expression of STAT5 (cytometry 331.5 vs. 276.1, p = 0.015; PCR 24.3 vs. 21.1, p = 0.003) and GATA-1 (cytometry 259.7 vs. 232.0, p = 0.027; PCR 18.9 vs. 16.5, p = 0.003) was higher in thalidomide than in control cultures. CONCLUSION: Our results suggest that thalidomide enhances expression of STAT5 in response of erythroid cells to erythropoietin and as a result of caspase 3 suppression. Moreover it may exert inhibitory effect on an external pathway of caspases activation with consequent decreased degradation of GATA-1 transcription factor by downstream caspases. PMID- 26481542 TI - Selective ablation of glucocorticoid receptors in the noradrenergic system affects evening corticosterone levels in a sex-dependent manner. AB - BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis, which is involved in the release of corticosterone in response to stress, exhibits large circadian variations in its activity that can also be regulated by the noradrenergic system, thereby contributing to the pathophysiology of depression. We have recently shown that mice in which glucocorticoid receptors (GR) are selectively ablated in the noradrenergic system (GR(DBHCre) mice) exhibit sex-dependent phenotype alterations, manifested as increased anxiety- and depressive-like behaviors in female but not male mutants. METHODS: In this study, we investigated the regulation of circadian HPA axis activity in GR(DBHCre) transgenic mice by measuring plasma corticosterone levels. RESULTS: We found that evening plasma corticosterone increase was profoundly higher in females than males, and this diversification was further augmented in mutant GR(DBHCre) mice. CONCLUSIONS: Our results provide evidence of the involvement of the noradrenergic system in the regulation of the sexually dimorphic circadian activity of the HPA axis. PMID- 26481543 TI - Psychotropic drugs and personality changes: A case of lithium. AB - BACKGROUND: The effect of psychopharmacological treatment on personality has been mostly studied with antidepressant drugs. Previously, we demonstrated an association between long-term lithium response and affective temperaments measured by the Temperament Scale of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A), and schizotypic traits, measured by the Oxford Liverpool Inventory of Feelings and Experiences (O-LIFE). Therefore, we were interested whether long-term lithium treatment per se may influence personality traits measured by these scales. METHODS: The study was performed on 40 patients with bipolar mood disorder (16 male, 24 female) with a mean age of 46 +/- 10 years, either hospitalized or attending the outpatient clinic, Department of Adult Psychiatry, Poznan University of Medical Sciences. Among them, twenty patients (8 male, 12 female) have received lithium for 10-33 years, and twenty (8 male, 12 female) have never been exposed to lithium and have been given other mood-stabilizing drugs. Each patient, had the assessment made by the TEMPS-A and O-LIFE, during euthymic state. RESULTS: Patients on long-term lithium treatment were significantly older and had longer duration of bipolar illness compared with non-lithium patients. Lithium-treated patients obtained significantly lower scores of cyclothymic and irritable temperaments on the TEMPS-A, and of unusual experiences, cognitive disorganization and impulsive nonconformity on the O-LIFE. CONCLUSIONS: It is hypothesized that the differences in personality, revealed by the TEMPS-A and O-LIFE scales, are related to the long-term treatment with lithium. The decrease in cyclothymic temperament and in cognitive disorganization trait were previously shown to be associated with the therapeutic effect of lithium. PMID- 26481544 TI - Effects of neuroleptics administration on adult neurogenesis in the rat hypothalamus. AB - BACKGROUND: Among many factors influencing adult neurogenesis, pharmacological modulation has been broadly studied. It is proven that neuroleptics positively affect new neuron formation in canonical neurogenic sites - subgranular zone of the hippocampal dentate gyrus and subventricular zone of the lateral ventricles. Latest findings suggest that adult neurogenesis also occurs in several additional regions like the hypothalamus, amygdala, neocortex and striatum. As the hypothalamus is considered an important target of neuroleptics, a hypothesis can be made that these substances are able to modulate local neural proliferation. METHODS: Experiments were performed on adult male rats injected for 28 days or 1 day by three neuroleptics: olanzapine, chlorpromazine and haloperidol. Immunohistochemistry was used to determine expression of proliferation marker (Ki 67) and the marker of neuroblasts - doublecortin (DCX) - which may inform about drug influence on adult neurogenesis at the level of the hypothalamus. RESULTS: It was shown that a single injection of antipsychotics causes significant decrease in hypothalamic DCX expression, but after chronic treatment with chlorpromazine, but not olanzapine, there is an increase in the number of newly formed neuroblasts. Haloperidol has the opposite effect - its long-term administration decreases the number of DCX-positive cells. Cell proliferation levels (Ki-67 expression) increase after long-term drug administration, whereas their single doses do not have any modulatory effect on proliferation potential. CONCLUSIONS: Our results throw a new light on the neuroleptics mechanism of action. They also support the potential role of antipsychotics as a factor that can modulate hypothalamic neurogenesis with putative clinical applications. PMID- 26481545 TI - Piroxicam, a traditional non-steroidal anti-inflammatory drug (NSAID) causes apoptosis by ROS mediated Akt activation. AB - BACKGROUND: Piroxicam (Px) belongs to the oxicam group of the non-steroidal anti inflammatory drugs (NSAIDs) and have been shown to exert chemopreventive and chemotherapeutic effects in animal models and cultured animal cells. However, little is known about the mode of action of Px and its cellular targets. METHODS: We explored the role of Px, in triggering apoptosis and examined the involvement of upstream cellular mechanisms in apoptosis induction by Px. RESULTS AND DISCUSSION: Our studies with human breast cancer cells MCF-7 show that Px induces reactive oxygen species (ROS) generation along with apoptotic cell death. ROS release lead to Akt activation. On evaluation it became evident that ROS mediated apoptosis induction was due to Akt activation (hyper phosphorylation). Silencing the expression of Akt using siRNA and a specific Akt inhibitor, triciribine further confirmed the findings. However Px failed to cause ROS generation, cell death or Akt phosphorylation in another human breast cancer cells MDA-MB-231 which is estrogen receptor negative and more aggressive compared to MCF-7 cells. This suggests that Px has cell type specific effects. Thus we revealed for the first time that Px can induce apoptosis by ROS mediated Akt hyperphosphorylation/activation. PMID- 26481546 TI - Propranolol combined with dopamine has a synergistic action in intensifying and prolonging cutaneous analgesia in rats. AB - BACKGROUND: The purpose of the experiment was to assess interactions of dopamine with propranolol as an infiltrative anesthetic. METHODS: After injecting the rats with four doses of drugs subcutaneously, the cutaneous analgesic effect of propranolol was compared with dopamine through the blockade of cutaneous trunci muscle reflex (CTMR) in response to local skin pinprick. Drug-drug interactions were examined via an isobolographic analysis. RESULTS: We demonstrated that the action of propranolol and dopamine was dose dependent to skin infiltrative analgesia. On the ED(50) (50% effective dose) basis, the rank of drug potency was propranolol (11.3 [10.6-12.2]MUmol) > dopamine (195 [188-205]MUmol) (p < 0.001). At the equi-anesthetic doses (ED(25), ED(50), ED(75)), the block duration caused by dopamine was equal to that caused by propranolol. Coadministration of dopamine and propranolol exhibited a synergistic effect on infiltrative cutaneous analgesia. CONCLUSIONS: The preclinical data showed that dopamine produced a lesser potency but a comparable duration of cutaneous analgesia compared to propranolol. Adding dopamine to propranolol potentiated and prolonged propranolol's cutaneous analgesic effect. PMID- 26481547 TI - Stability of erythrocyte membrane and overall hemostasis potential - A biocompatibility study of mebrofenin and other iminodiacetic acid derivatives. AB - BACKGROUND: Intravenous injection seems to be the most convenient way of administering drugs and contrast agents, which makes components of the blood the first and usually unwanted target of their action. Binding of intravenously administered compounds to erythrocytes, blood platelets and vascular wall may have serious clinical implications. The aim of this study was to examine the influence of four iminodiacetic acid derivatives, potential ligands for gadolinium complexation, on the process of coagulation and fibrinolysis, activity of thrombin and hemolysis. METHODS: Kinetic parameters of coagulation and fibrinolysis process were determined during an optical CL-test based on measurement of transmittance alterations. Thrombin (0.5 IU/mL) and t-PA (240 ng/mL) were used to obtain a clotting and lysis curve. The activity of thrombin was determined with a chromogenic substrate S-2238. Hemolysis was examined spectrophotometrically and expressed as a percentage of released hemoglobin. RESULTS: Exposure to iminodiacetic acid derivatives resulted in a significant increase in the overall potential of clotting and lysis (CLAUC), as well as with the significant changes in the key parameters of these processes (thrombin time, initial plasma clotting velocity, clot stabilization time). Furthermore, iminodiacetic acid derivatives caused a significant decrease in the amidolytic activity of thrombin and enhanced hemolysis in a concentration-dependent manner. CONCLUSION: Despite their influence on the process of coagulation and fibrinolysis, amidolytic activity of thrombin and hemolysis, iminodiacetic acid derivatives should be generally considered safe as the significant effects were observed mostly at 4 MUmol/mL, which is about 10-fold higher than the theoretical plasma concentration of these compounds. PMID- 26481548 TI - Antidiabetic drugs and risk of cancer. AB - Antidiabetic drugs are an important group of medications used worldwide. They differ from each other in the mechanisms of lowering blood glucose as well as in adverse effects that may affect the course of the treatment and its efficacy. In recent years, new drugs have been discovered in order to improve the maintenance of proper blood glucose level and to reduce unwanted effects of these drugs. Their growing administration is related to the increasing incidence of diabetes observed in all countries in the world. Epidemiological data indicate that diabetes increases the risk of cancer, as well as the risk of death linked with neoplasms. It is still unknown whether this is an effect of antidiabetic drugs or just the effect of diabetes itself. In recent years there have been numerous investigations and meta-analyzes, based on both comparative and cohort studies trying to establish the relationship between antidiabetic pharmacotherapy and the incidence and mortality due to cancer. According to their findings, most of antidiabetic drugs increase the risk of cancer while only few of them show antitumor properties. Different mechanisms of action of glucose-lowering drugs may be responsible for these effects. However, most of the published studies concerning the influence of these drugs on cancer incidence were designed with some limitations and differed from each other in the approach. In this review, we discuss the association between antidiabetic drugs used in monotherapy or polytherapy and cancer risk, and consider potential mechanisms responsible for the observed effects. PMID- 26481549 TI - Serum concentrations of chemokines (CCL-5 and CXCL-12), chemokine receptors (CCR 5 and CXCR-4), and IL-6 in patients with posttraumatic stress disorder and avoidant personality disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) can be perceived as a psychoneuroimmunological disorder in which cytokines affecting the neurochemical and neuroendocrine functions of the body play an important role. Among cytokines, chemokines participating in activation of the inflammatory response are considered to be crucial. METHOD: 220 men and women were enrolled in the study. 180 of them constituted the study group. The studied groups consisted of: 60 patients with a diagnosed avoidant personality disorders (APD), 60 patients with a diagnosed APD and with PTSD and of 60 patients with PTSD but without a APD. There were 30 women and 30 men in each group of 60 subjects. The control group consisted of 40 healthy individuals. The plasma levels of chemokines and their receptors (CCL-5, CXCR-5, CXCL-12 and CXCR-4), as well as IL-6, were assessed by ELISA. RESULTS: There was an increase in the CXCL-12 and CCL-5 levels in women and men with the PTSD versus the control group. Also, increased levels of IL-6 and the receptors CXCR-4, CCR-5 were observed in women and men with PTSD. The levels of CXCL-12 and CCL-5 chemokines, as well as CCR-5 and CXCR4 receptors were higher in women than in men. The results of this study indicate a need for assessment of the CCL-5 and CXCL-12 chemokine levels, as they are likely markers of PTSD. CONCLUSIONS: Measurement of the concentrations of chemokines, chemokine receptors and IL-6 in women and men with PTSD along with concomittant APD may be useful for early detection of mental disorders. PMID- 26481551 TI - A pterostilbene derivative suppresses osteoclastogenesis by regulating RANKL mediated NFkappaB and MAPK signaling in RAW264.7 cells. AB - BACKGROUND: A dysfunctional osteoclast activity is often the cause of bone destructive diseases, such as osteoporosis, periodontitis, erosive arthritis, and cancer. The NFkappaB ligand (RANKL) has been identified as a major mediator of bone resorption. Agents that suppress RANKL signaling have the potential to inhibit bone resorption or osteoclastogenesis. The present study aimed to determine the effect of a pterostilbene derivative (PTERC-T) for suppressing RANKL or tumor cells-induced osteoclastogenesis in RAW264.7 murine macrophages. METHODS: Cytotoxicity was measured by MTT assay and inhibitory effect on osteoclastogenesis was analyzed by counting the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and measuring the expression levels of the osteoclast-specific genes. The reactive oxygen species (ROS) generation was detected by FACS. Further, signaling pathways were analyzed by immunofluorescence and immunoblot analyses. RESULTS: PTERC-T suppressed the differentiation of monocytes to osteoclasts in a dose and time-dependent manner. The expression of osteoclast marker genes like TRAP, cathepsin K (CTSK), matrix metalloproteinase 9 (MMP9) and transcription factors c-Fos, and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) were also diminished by PTERC-T. PTERC-T scavenged intracellular ROS generation within osteoclast precursors during RANKL stimulated osteoclastogenesis. Mechanistically, PTERC-T abrogated the phosphorylation of MAPKs (ERK and JNK) and inhibited RANKL-induced activation of NFkappaB by suppressing IkappaBalpha phosphorylation and preventing NFkappaB/p65 nuclear translocation. CONCLUSIONS: This study thus identifies PTERC-T as an inhibitor of osteoclast formation and provides evidence for its role in preventing osteoporosis and other bone related disorders. However, further studies are needed to establish its efficacy in vivo. PMID- 26481552 TI - Modulation of Kv2.1 channels inactivation by curcumin. AB - BACKGROUND: The aim of the present study was to assess the effects of curcumin on the voltage-dependent Kv2.1 potassium channel. METHODS: The whole-cell patch clamp technique was used to explore the regulation of Kv2.1 channels expressed in HEK293 cells by curcumin. RESULTS: Curcumin reduced the Kv2.1 currents; the inhibition occurred with a slow time course and was partially reversible. Curcumin did not alter the kinetics and voltage dependence of activation; however, the kinetics of open- and closed-state inactivation was accelerated by curcumin along with a hyperpolarizing shift in the voltage dependence of inactivation. Curcumin inhibition of Kv2.1 current was not use-dependent. CONCLUSIONS: Overall, our data suggest that curcumin inhibits Kv2.1 channels by modulating the inactivation gating, which would be expected to impact cellular physiology. PMID- 26481550 TI - Impact of morin-5'-sulfonic acid sodium salt on cyclophosphamide-induced gastrointestinal toxicity in rats. AB - BACKGROUND: The aim of this study was to evaluate the effect of morin-5'-sulfonic acid sodium salt (NaMSA) on cyclophosphamide-induced gastrointestinal changes in rats. METHODS: Rats received intragastrically 0.9% saline (group C), cyclophosphamide (15 mg/kg) (group CX), NaMSA (100 mg/kg) (group M) or cyclophosphamide (15 mg/kg) with NaMSA (100 mg/kg) (group M-CX), respectively, for 10 days. RESULTS: No histological lesions were observed in the liver and the large intestine in the control group and group receiving NaMSA. In the cyclophosphamide-treated group, a generalized blurred trabecular structure, hepatocyte apoptosis, focal and diffuse necrosis were noticed in the liver and atypia of epithelial cells or adenoma were noticed in the large intestine. In the group receiving both cyclophosphamide and NaMSA, hepatocyte apoptosis in the liver was observed less frequently. Histological examination of the small intestine revealed: low-grade dysplasia adenoma in the C, M, CX and M-CX group (in 44%, 0%, 100%, and 55.6% of specimens, respectively) with adenocarcinoma in 55.6% of specimens in the cyclophosphamide-receiving group only. Adenoma with high-grade dysplasia was observed in the control and NaMSA-receiving group with a similar frequency (22%). In addition to the histological evaluation, blood cell count parameters, as well as total protein concentration, blood glucose level, amylase, ALT, AST and GGTP activities were evaluated. Cyclophosphamide impaired weight gain, decreased blood cell count parameters and total protein concentration, and increased the GGTP activity. Those changes were not reversed by NaMSA. CONCLUSIONS: Summing up, NaMSA may protect against some cyclophosphamide-induced histological abnormalities in the gastrointestinal tract, including intestinal neoplasia in rats. PMID- 26481554 TI - Dorsal Fracture-Dislocations of the Proximal Interphalangeal Joint. PMID- 26481553 TI - Internalization of bevacizumab by retinal endothelial cells and its intracellular fate: Evidence for an involvement of the neonatal Fc receptor. AB - Bevacizumab is one of the VEGF-binding proteins that are established in clinical practice to treat various ocular diseases. In view of therapeutic long-term application, potential accumulation of the antibody in retinal cells gave reason for safety concerns. Internalization of considerable amounts of bevacizumab by retinal endothelial (REC) and pigment epithelial cells has been observed which may affect their important functions. Therefore we investigated the transport and intracellular localization of bevacizumab in immortalized bovine REC (iBREC) in detail, considering possible roles of vesicles and receptors mediating uptake and intracellular transport. By performing transcytosis assays with iBREC monolayers cultivated on porous membrane inserts, we demonstrated that bevacizumab was transported efficiently through a tight monolayer from the lower to the upper chamber or vice versa. When added to the lower chamber in excess, the internalized antibody was transported through the cells, but it was also recycled to be set free at the same side of the cell into a bevacizumab-free environment. The rates of both processes strongly depended on the concentration of fetal bovine serum (FBS) in the environment. This observation is important because in vivo REC might be exposed to varying amounts of serum, e.g. in patients with macular edema. FBS also affected the intracellular localization of bevacizumab as shown by analyses of subcellular fractions and direct immunofluorescence staining. When iBREC were cultivated in low-serum medium, most of the antibody was found in the fraction of cytoskeleton proteins and spots of high intensity of bevacizumab-specific staining close to the nuclei were observed. Cultivation in medium with FBS resulted in internalized bevacizumab predominately found in the membrane/organelle fraction in addition to its weaker association with proteins from the cytoskeleton and uniform staining of the cell. Bevacizumab-specific staining close to the cytoskeleton proteins alpha-tubulin or vimentin was also observed. Accumulation and association of the antibody with the cytoskeleton induced by serum reduction could be reversed by subsequent FBS addition. In uptake and transport of bevacizumab vesicles and binding to a receptor seems to be involved: Internalization was strongly temperature-dependent which ruled out paracellular passage and a fraction of the internalized bevacizumab was associated with early endosomes. Protein A inhibited transcytosis and affected intracellular localization suggesting a key role of the neonatal Fc receptor (FcRn). Interestingly, FcRn expression was decreased when iBREC were cultivated without FBS. Our results suggest this pathway of bevacizumab uptake and transition through iBREC: Independent of serum, bevacizumab is taken up through a nonspecific mechanism. The subsequent sorting into transport vesicles depends on the presence of serum as regulator of FcRn expression. Without sufficient amounts of the receptor being expressed, a likely obstructed exocytosis results in intracellular accumulation and an increased association with cytoskeleton proteins. Interaction of substantial amounts of bevacizumab with the cytoskeleton may be the reason for under these conditions suppressed migration of iBREC. If long-term therapies by intravitreal injection lead to accumulation of bevacizumab in REC in vivo and potentially harmful consequences, will have to be revealed by future investigations. PMID- 26481555 TI - The Origin and Meaning of "Intercalated Segment". PMID- 26481556 TI - Dissatisfaction After First Dorsal Compartment Release for de Quervain Tendinopathy. PMID- 26481557 TI - Visualizing chemical states and defects induced magnetism of graphene oxide by spatially-resolved-X-ray microscopy and spectroscopy. AB - This investigation studies the various magnetic behaviors of graphene oxide (GO) and reduced graphene oxides (rGOs) and elucidates the relationship between the chemical states that involve defects therein and their magnetic behaviors in GO sheets. Magnetic hysteresis loop reveals that the GO is ferromagnetic whereas photo-thermal moderately reduced graphene oxide (M-rGO) and heavily reduced graphene oxide (H-rGO) gradually become paramagnetic behavior at room temperature. Scanning transmission X-ray microscopy and corresponding X-ray absorption near-edge structure spectroscopy were utilized to investigate thoroughly the variation of the C 2p(pi*) states that are bound with oxygen containing and hydroxyl groups, as well as the C 2p(sigma*)-derived states in flat and wrinkle regions to clarify the relationship between the spatially resolved chemical states and the magnetism of GO, M-rGO and H-rGO. The results of X-ray magnetic circular dichroism further support the finding that C 2p(sigma*) derived states are the main origin of the magnetism of GO. Based on experimental results and first-principles calculations, the variation in magnetic behavior from GO to M-rGO and to H-rGO is interpreted, and the origin of ferromagnetism is identified as the C 2p(sigma*)-derived states that involve defects/vacancies rather than the C 2p(pi*) states that are bound with oxygen-containing and hydroxyl groups on GO sheets. PMID- 26481558 TI - Drug diffusion, integration, and stability of nanoengineered drug-releasing implants in bone ex-vivo. AB - To treat skeletal conditions such as bone infections, osteoporotic fractures, and osteosarcoma, it would be ideal to introduce drugs directly to the affected site. Localized drug delivery from the bone implants is a promising alternative to systemic drug administration. In this study we investigated electrochemically nanoengineered Ti wire implants with titania nanotubes (TNTs), as minimally invasive drug-releasing implants for the delivery of drugs directly into the bone tissue. Since trabecular bone in vivo contains a highly interconnected bone marrow, we sought to determine the influence of marrow on drug release and diffusion. Electrochemical anodization of Ti wires (length 10 mm) was performed to create an oxide layer with TNTs on the surface, followed by loading with a fluorescent model drug, Rhodamine B (RhB). Cores of bovine trabecular bone were generated from the sternum of a young steer, and were processed to have an intact bone marrow, or the marrow was removed. RhB-loaded TNTs/Ti wires were inserted into the bone cores, which were then cultured ex vivo using the ZetOSTM bioreactor system to maintain bone viability. Release and diffusion of RhB inside the bone was monitored using fluorescence imaging and different patterns of drug transport in the presence or absence of marrow were observed. Scanning electron microscopy of the implants after retrieval from bone cores confirmed survival of the TNTs structures. Histological investigation showed the presence of bone cells adherent on the implants. This study shows a potential of Ti drug-releasing implants based on TNTs technology towards localized bone therapy. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 714-725, 2016. PMID- 26481559 TI - Molecular subclasses of hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition. AB - A recent gene expression classification of hepatocellular carcinoma (HCC) includes a poor survival subclass termed S2 representing about one-third of all HCC in clinical series. S2 cells express E-cadherin and c-myc and secrete AFP. As the expression of fibroblast growth factor receptors (FGFRs) differs between S2 and non-S2 HCC, this study investigated whether molecular subclasses of HCC predict sensitivity to FGFR inhibition. S2 cell lines were significantly more sensitive (p < 0.001) to the FGFR inhibitors BGJ398 and AZD4547. BGJ398 decreased MAPK signaling in S2 but not in non-S2 cell lines. All cell lines expressed FGFR1 and FGFR2, but only S2 cell lines expressed FGFR3 and FGFR4. FGFR4 siRNA decreased proliferation by 44% or more in all five S2 cell lines (p < 0.05 for each cell line), a significantly greater decrease than seen with knockdown of FGFR1-3 with siRNA transfection. FGFR4 knockdown decreased MAPK signaling in S2 cell lines, but little effect was seen with knockdown of FGFR1-3. In conclusion, the S2 molecular subclass of HCC is sensitive to FGFR inhibition. FGFR4-MAPK signaling plays an important role in driving proliferation of a molecular subclass of HCC. This classification system may help to identify those patients who are most likely to benefit from inhibition of this pathway. PMID- 26481560 TI - Morphological Variability and Distinct Protein Profiles of Cultured and Endosymbiotic Symbiodinium cells Isolated from Exaiptasia pulchella. AB - Symbiodinium is a dinoflagellate that plays an important role in the physiology of the symbiotic relationships of Cnidarians such as corals and sea anemones. However, it is very difficult to cultivate free-living dinoflagellates after being isolated from the host, as they are very sensitive to environmental changes. How these symbiont cells are supported by the host tissue is still unclear. This study investigated the characteristics of Symbiodinium cells, particularly with respect to the morphological variability and distinct protein profiles of both cultured and endosymbiotic Symbiodinium which were freshly isolated from Exaiptasia pulchella. The response of the cellular morphology of freshly isolated Symbiodinium cells kept under a 12 h L:12 h D cycle to different temperatures was measured. Cellular proliferation was investigated by measuring the growth pattern of Symbiodinium cells, the results of which indicated that the growth was significantly reduced in response to the extreme temperatures. Proteomic analysis of freshly isolated Symbiodinium cells revealed twelve novel proteins that putatively included transcription translation factors, photosystem proteins, and proteins associated with energy and lipid metabolism, as well as defense response. The results of this study will bring more understandings to the mechanisms governing the endosymbiotic relationship between the cnidarians and dinoflagellates. PMID- 26481561 TI - Production of soluble and active microbial transglutaminase in Escherichia coli for site-specific antibody drug conjugation. AB - Applications of microbial transglutaminase (mTGase) produced from Streptomyces mobarensis (S. mobarensis) were recently extended from food to pharmaceutical industry. To use mTGase for clinical applications, like generation of site specific antibody drug conjugates, it would be beneficial to manufacture mTGase in Escherichia coli (E. coli). To date, attempts to express recombinant soluble and active S. mobarensis mTGase have been largely unsuccessful. mTGase from S. mobarensis is naturally expressed as proenzyme and stepwise proteolytically processed into its active mature form outside of the bacterial cell. The pro domain is essential for correct folding of mTGase as well as for inhibiting activity of mTGase inside the cell. Here, we report a genetically modified mTGase that has full activity and can be expressed at high yields in the cytoplasm of E. coli. To achieve this we performed an alanine-scan of the mTGase pro-domain and identified mutants that maintain its chaperone function but destabilize the cleaved pro-domain/mTGase interaction in a temperature dependent fashion. This allows proper folding of mTGase and keeps the enzyme inactive during expression at 20 degrees C, but results in full activity when shifted to 37 degrees C due to loosen domain interactions. The insertion of the 3C protease cleavage site together with pro-domain alanine mutants Tyr14, Ile24, or Asn25 facilitate high yields (30-75 mg/L), and produced an enzyme with activity identical to wild type mTGase from S. mobarensis. Site-specific antibody drug conjugates made with the E .coli produced mTGase demonstrated identical potency in an in vitro cell assay to those made with mTGase from S. mobarensis. PMID- 26481562 TI - Understanding the Healthy Immigrant Effect and Cardiovascular Disease: Looking to Big Data and Beyond. PMID- 26481564 TI - The 2013 American Heart Association/American College of Cardiology/The Obesity Society Guideline for the Management of Overweight and Obesity in Adults: What Is New About Diet, Drugs, and Surgery for Obesity? PMID- 26481563 TI - Value-Based Insurance Design: Aligning Incentives to Improve Cardiovascular Care. PMID- 26481566 TI - Prenatal Diagnosis and Management of Berry Syndrome, a Rare Conotruncal Anatomy. PMID- 26481567 TI - When a Thrombus Is Life-Saving. PMID- 26481568 TI - Letter by Hayward Regarding Article, "Hyperlipidemia in Early Adulthood Increases Long-Term Risk of Coronary Heart Disease". PMID- 26481569 TI - Response to Letter Regarding Article, "Hyperlipidemia in Early Adulthood Increases Long-Term Risk of Coronary Heart Disease". PMID- 26481570 TI - Letter by Edwards et al Regarding Article, "Coronary Microvascular Rarefaction and Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction". PMID- 26481571 TI - Letter by Campbell Regarding Article, "Coronary Microvascular Rarefaction and Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction". PMID- 26481572 TI - Response to Letters Regarding Article, "Coronary Microvascular Rarefaction and Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction". PMID- 26481573 TI - Kidney cancer: RNA activation in RCC: p21 and miR-1236 are a promising pair. PMID- 26481574 TI - Gender differences in incidence and outcomes of urothelial and kidney cancer. PMID- 26481575 TI - A step-wise approach to sperm retrieval in men with neurogenic anejaculation. AB - Normal fertility is dependent on intravaginal delivery of semen through ejaculation. This process is highly dependent on an intact ejaculatory reflex arc, which can be disrupted through any type of trauma or disease causing damage to the CNS and/or peripheral nerves. Neurogenic anejaculation is most commonly associated with spinal cord injury. This aetiology is especially relevant because most men with spinal cord injuries are injured at reproductive age. Assisted ejaculation in the form of penile vibratory stimulation is the first choice for sperm retrieval in such patients because it is noninvasive and inexpensive. In patients in whom vibratory stimulation fails, electroejaculation is almost always successful. When both methods of assisted ejaculation are unsuccessful, sperm retrieval by aspiration from either the vas deferens or the epididymis, or by testicular biopsy or surgery are reasonable options. In such cases the most inexpensive and least invasive methods should be considered first. The obtained semen can be used for intravaginal or intrauterine insemination or in vitro fertilization with or without intracytoplasmic sperm injection. PMID- 26481577 TI - Botox injections are effective for Fowler's syndrome. PMID- 26481576 TI - Imaging and evaluation of patients with high-risk prostate cancer. AB - Approximately 15% of men with newly diagnosed prostate cancer have high-risk disease. Imaging is critically important for the diagnosis and staging of these patients, and also for the selection of management. While established prostate cancer staging guidelines have increased the appropriate use of imaging, underuse for high-risk prostate cancer remains substantial. Several factors affect the utility of initial diagnostic imaging, including the variable definition of high risk prostate cancer, variable guideline recommendations, poor accuracy of existing imaging tests, and the difficulty in validating imaging findings. Conventional imaging modalities, including CT and radionuclide bone scan, have been employed for local and metastatic staging, but their performance characteristics have generally been poor. Emerging modalities including multiparametricMRI, positron emission tomography (PET)-CT, and PET-MRI have shown increased diagnostic accuracy and could improve accuracy in staging patients with high-risk prostate cancer. PMID- 26481578 TI - [Dietary habits of a sample of patients with schizophrenia]. PMID- 26481579 TI - The reasons for the failure of the primary arteriovenous fistula surgery in patients with end-stage renal disease. AB - PURPOSE: To analyze the reasons for the failure of the primary arteriovenous fistula surgery and explore preventive measures. METHODS: A total of 819 patients with end-stage renal disease were enrolled in the study. Autologous arteriovenous fistula surgery was performed on all patients. Their clinical data of hemoglobin (HB), albumin (ALB), cholesterol (CHOL), parathyroid hormone (PTH), blood glucose and blood pressure were collected before surgery, while the diameters of the radial artery and cephalic vein were measured by ultrasound. RESULTS: The operations in 742 patients were successful, but failed in 77 cases (accounting for 7.07%). The failure group was significantly older (61.3 +/- 13.4 years) than the successful group (45.6 +/- 11.2 years). The ratio of diabetes 36 (46.8%) and hypertension 20 (26.0%) was significantly higher in the failure group than in the successful group, respectively 235 (31.7%) and 145 (19.5%). The patients with blood pressure below 120/70 mm Hg had a higher risk of failed surgery (36.4%) than those with blood pressure above 120/70 mm Hg (9.16%). The cephalic vein and radial artery diameter were significantly smaller in the failure group (1.35 +/- 0.64 mm, 2.13 +/- 0.81 mm) than in the successful group (1.98 +/- 0.47 mm, 2.47 +/- 0.74 mm); [corrected] the PTH levels in the failure group were significantly higher (782.39 +/- 423.85) than in the successful group (378.83 +/- 352.21). CONCLUSIONS: The autogenous arteriovenous fistula surgery failure highly correlated with the patient's age, blood pressure, the primary disease and the vessel diameter. In addition, the PTH levels had a certain correlation with the failure of the fistula surgery. PMID- 26481580 TI - SA-VA Difference with Extended Utility--More to Consider. PMID- 26481581 TI - Revealing hidden depression in older people: a qualitative study within a randomised controlled trial. AB - BACKGROUND: The prevalence of depressive symptoms in older people may be as high as 20 %. Depression in older people is associated with loss, loneliness and physical co-morbidities; it is known to be under-diagnosed and under-treated. Older people may find it difficult to speak to their GPs about low mood, and GPs may avoid identifying depression due to limited consultation time and referral options for older patients. METHODS: A nested qualitative study in a randomised controlled trial for older people with moderate to severe depression: the CASPER Plus Trial (Collaborative Care for Screen Positive Elders). We interviewed GPs, case managers (CM) and patient participants to explore perspectives and experiences of delivering and receiving a psychosocial intervention, developed specifically for older adults in primary care, within a collaborative care framework. Transcripts were analysed thematically using principles of constant comparison. RESULTS: Thirty three interviews were conducted and, across the three data-sets, four main themes were identified: revealing hidden depression, reducing the 'blind spots', opportunity to talk outside the primary care consultation and 'moving on' from depression. CONCLUSIONS: Depression in older people is commonly hidden, and may coexist with physical conditions that are prioritised by both patients and GPs. Being invited to participate in a trial about depression may allow older people to disclose their feelings, name the problem, and seek help. Offering older people an opportunity to talk outside the primary care consultation is valued by patients and GPs. A psychosocial intervention delivered by a case manager in the primary care setting may fill the gap in the care of older people with depression. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45842879 . PMID- 26481582 TI - The influence of storage and heat treatment on a magnesium-based implant material: an in vitro and in vivo study. AB - BACKGROUND: Magnesium alloys are recommended as a potential material for osteosynthesis. It is known that storage-induced property modifications can occur in materials like aluminum. Thus the aim of this study was to analyze the influence of storage durations of up to 48 weeks on the biomechanical, structural, and degradation properties of the degradable magnesium alloy LAE442. METHODS: Extruded implants (n = 104; O 2.5 mm * 25 mm) were investigated after storage periods of 0, 12, 24, and 48 weeks in three different sub-studies: (I) immediately after the respective storage duration and after an additional (II) 56 days of in vitro corrosion in simulated body fluid (SFB), and (III) 48 weeks in vivo corrosion in a rabbit model, respectively. In addition, the influence of a T5-heat treatment (206 degrees C for 15 h in an argon atmosphere) was tested (n = 26; 0 week of storage). Evaluation was performed by three-point bending, scanning electron microscopy, radiography, u-computed tomography, evaluation of the mean grain size, and contrast analysis of precipitations (such as aluminum or lithium). RESULTS: The heat treatment induced a significant reduction in initial stability, and enhanced the corrosion resistance. In vivo experiments showed a good biocompatibility for all implants. During the storage of up to 48 weeks, no significant changes occurred in the implant properties. CONCLUSIONS: LAE442 implants can be safely used after up to 48 weeks of storage. PMID- 26481583 TI - Repetitive Transcranial Magnetic Stimulation Changes Cerebral Oxygenation on the Left Dorsolateral Prefrontal Cortex in Bulimia Nervosa: A Near-Infrared Spectroscopy Pilot Study. AB - Previous studies showed that food craving in eating disorders can be weakened with high-frequency repetitive transcranial magnetic stimulation (rTMS) on the left dorsolateral prefrontal cortex (DLPFC). The aims of this study were to assess cerebral oxygenation change induced with rTMS and to assess the short-term impact of rTMS on food craving and other bulimic symptoms in patients with bulimia nervosa (BN). Eight women diagnosed with BN according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria participated in this study. We measured haemoglobin concentration changes in the DLPFC with near-infrared spectroscopy during cognitive tasks measuring self regulatory control in response to food photo stimuli, both at baseline and after a single session of rTMS. Subjective ratings for food cravings demonstrated significant reduction. A significant decrease in cerebral oxygenation of the left DLPFC was also observed after a single session of rTMS. Measurement with NIRS after rTMS intervention may be applicable for discussing the mechanisms underlying rTMS modulation in patients with BN. PMID- 26481586 TI - Can Authoritarianism Lead to Greater Liking of Out-Groups? The Intriguing Case of Singapore. PMID- 26481584 TI - The utility of transposon mutagenesis for cancer studies in the era of genome editing. AB - The use of transposons as insertional mutagens to identify cancer genes in mice has generated a wealth of information over the past decade. Here, we discuss recent major advances in transposon-mediated insertional mutagenesis screens and compare this technology with other screening strategies. PMID- 26481587 TI - New Route to Stabilize Ruthenium Nanoparticles with Non-Isolable Chiral N Heterocyclic Carbenes. AB - Ru nanoparticles (RuNPs) stabilized by non-isolable chiral N-heterocyclic carbenes (NHCs), namely SIDPhNp ((4S,5S)-1,3-di(naphthalen-1-yl)-4,5 diphenylimidazolidine) and SIPhOH ((S)-3-((1S,2R)-2-hydroxy-1,2-diphenylethyl)-1 ((R)-2-hydroxy-1,2-diphenylethyl)-4,5-dihydro-3H-imidazoline), have been synthesized through a new procedure that does not require isolation of the free carbenes. The obtained RuNPs have been characterized by state-of-the-art techniques and their surface chemistry has been investigated by FTIR and solid state MAS NMR upon the coordination of CO, which indicated the presence of free and reactive Ru sites. Their catalytic activity has been tested in various hydrogenation reactions involving competition between different sites, whereby interesting differences in selectivity were observed, but no enantioselectivity. PMID- 26481585 TI - A case-control study of sporadic retinoblastoma in relation to maternal health conditions and reproductive factors: a report from the Children's Oncology group. AB - BACKGROUND: The early age at retinoblastoma occurrence, the most common eye malignancy in childhood, suggests that perinatal factors may contribute to its etiology. METHODS: In a large multicenter study of non-familial retinoblastoma, we conducted structured interviews with the parents of 280 cases and 146 controls to elicit information on health during the perinatal period. We used unconditional logistic regression to assess associations between retinoblastoma and parental fertility treatment, birth control use in the year prior to pregnancy, maternal health conditions and the use of prescription medications during pregnancy, and whether mothers breastfed the index child. RESULTS: Bilateral retinoblastoma was related to maternal underweight (body mass index <18.5) prior to pregnancy [Odds Ratio (OR) = 4.5, 95 % confidence interval (CI) 1.0, 20]. With regards to unilateral retinoblastoma, we observed a negative association with the use of condoms in the year prior to pregnancy (OR = 0.4, CI 0.2, 0.9), and a trend towards a positive association with maternal diabetes (OR = 2.2, CI 0.8, 6.6). CONCLUSIONS: Results from our study suggest a role for several maternal health and reproductive factors. Given that there are few epidemiologic studies of retinoblastoma, our results require replication in studies which utilize medical record review. PMID- 26481588 TI - Fine mapping of QTL and genomic prediction using allele-specific expression SNPs demonstrates that the complex trait of genetic resistance to Marek's disease is predominantly determined by transcriptional regulation. AB - BACKGROUND: Marek's disease (MD) is a lymphoproliferative disease of poultry induced by Marek's disease virus (MDV), a highly oncogenic alphaherpesvirus. Identifying the underlying genes conferring MD genetic resistance is desired for more efficacious control measures including genomic selection, which requires accurately identified genetic markers throughout the chicken genome. METHODS: Hypothesizing that variants located in transcriptional regulatory regions are the main mechanism underlying this complex trait, a genome-wide association study was conducted by genotyping a ~1,000 bird MD resource population derived from experimental inbred layers with SNPs containing 1,824 previously identified allele-specific expression (ASE) SNPs in response to MDV infection as well as 3,097 random SNPs equally spaced throughout the chicken genome. Based on the calculated associations, genomic predictions were determined for 200 roosters and selected sires had their progeny tested for Marek's disease incidence. RESULTS: Our analyses indicate that these ASE SNPs account for more than 83 % of the genetic variance and exhibit nearly all the highest associations. To validate these findings, 200 roosters had their genetic merit predicted from the ASE SNPs only, and the top 30 and bottom 30 ranked roosters were reciprocally mated to random hens. The resulting progeny showed that after only one generation of bidirectional selection, there was a 22 % difference in MD incidence and this approach gave a 125 % increase in accuracy compared to current pedigree-based estimates. CONCLUSIONS: We conclude that variation in transcriptional regulation is the major driving cause for genetic resistance to MD, and ASE SNPs identify the underlying genes and are sufficiently linked to the causative polymorphisms that they can be used for accurate genomic prediction as well as help define the underlying molecular basis. Furthermore, this approach should be applicable to other complex traits. PMID- 26481589 TI - Curvilinear shapes and the snake detection hypothesis: An ERP study. AB - Consistent with the snake detection hypothesis, previous ERP studies have established a larger early posterior negativity (EPN) in response to pictures depicting snakes than to pictures depicting other creatures. Here, we examined to what extent the curvilinear shape of the snake's body drives the larger EPN. To this end, we employed pictures of threatening and nonthreatening species with or without typical curvature. Participants watched a random rapid serial visual presentation of snake, worm, spider, and beetle pictures. The EPN was scored as the mean activity (225-300 ms after picture onset) at occipital and parieto occipital electrodes. Across electrodes, the EPN was significantly larger for snake pictures than for spider, worm, and beetle pictures, and for spider and worm pictures than for beetle pictures. The results suggest that curvilinear body shapes may partly drive the enhanced EPN. However, the unique cortical response to snakes is not fully explained by this mechanism, and is most probably also determined by other threat-relevant cues. PMID- 26481590 TI - Aconitum Alkaloid Poisoning Because of Contamination of Herbs by Aconite Roots. AB - Aconitum alkaloid poisoning can occur after drinking decoction and soup made from non-toxic herbs contaminated by aconite roots. In the present review, the main objective is to describe the clinical features, investigations and possible sources of contamination. A combination of neurological, gastrointestinal and cardiovascular signs and symptoms was seen. Ventricular tachyarrhythmias could occur in 18% of subjects. Yunaconitine and crassicauline A, mainly found in certain aconite roots from Southwest China, are most commonly involved. Herbal residues and unused herbs should first be inspected for gross contamination. On site inspection at the retailer should exclude accidental mix-up or cross contamination when handling aconite roots. Samples of prescribed herbs are examined for gross contamination and analysed for the presence of Aconitum alkaloids. Samples of the implicated herb are also collected from the wholesaler for investigation. If post-import contamination is unlikely, the regulatory authorities of the exporting countries should be notified for follow-up actions. It is a challenging task to work out how non-toxic herbs become contaminated by aconite roots. The source control with good agricultural and collection practices and quality assurance must be enhanced. PMID- 26481591 TI - One-year results of the ICON (Ionic versus non-ionic Contrast to Obviate worsening Nephropathy after angioplasty in chronic renal failure patients) Study. AB - BACKGROUND: Long-term clinical outcomes after exposure to non-ionic iso-osmolar contrast medium (IOCM) or ionic low-osmolar CM (LOCM) in patients with chronic kidney disease (CKD) undergoing coronary angiography are unclear. METHODS: The ICON trial was a prospective, double-blinded, multicentre study that randomly assigned 146 patients with CKD undergoing coronary angiography with or without percutaneous coronary intervention to the non-ionic IOCM Iodixanol or the ionic LOCM Ioxaglate. We report the 1-year clinical outcomes. RESULTS: After randomization, baseline and procedural characteristics were well-matched between the two groups. At 1 year, three deaths (4.1%) occurred in the ioxaglate and nine deaths in the iodixanol group (13.6%, P = 0.07). The cardiac death rate at 1 year was 2.7% in the ioxaglate group and 9.1% in the iodixanol group (P = 0.07). There were no significant differences in the rates of myocardial infarction (1.4% vs. 1.5%; P = 1.00) and repeated revascularization (6.8% vs. 9.1%; P = 0.75). CONCLUSIONS: The use of ionic LOCM ioxaglate was associated with a numerically lower mortality at 1 year as compared to iodixanol in patients who underwent cardiac catheterization. Future studies evaluating long-term safety following exposure to different types of CM are warranted. PMID- 26481592 TI - Periodontal tissue regeneration with PRP incorporated gelatin hydrogel sponges. AB - Gelatin hydrogels have been designed and prepared for the controlled release of the transforming growth factor (TGF-b1) and the platelet-derived growth factor (PDGF-BB). PRP (Platelet rich plasma) contains many growth factors including the PDGF and TGF-b1. The objective of this study was to evaluate the regeneration of periodontal tissue following the controlled release of growth factors in PRP. For the periodontal ligament cells and osteoblast, PRP of different concentrations was added. The assessment of DNA, mitochondrial activity and ALP activity were measured. To evaluate the TGF-beta1 release from PRP incorporated gelatin sponge, amounts of TGF-beta1 in each supernatant sample were determined by the ELISA. Transplantation experiments to prepare a bone defect in a rat alveolar bone were an implanted gelatin sponge incorporated with different concentration PRP. In DNA assay and MTT assay, after the addition of PRP to the periodontal ligament cells and osteoblast, the cell count and mitochondrial activity had increased the most in the group with the addition of 5 * PRP. In the ALP assay, after the addition of PRP to the periodontal ligament cells, the cell activity had increased the most in the group with the addition of 3 * PRP. In the transplantation, the size of the bone regenerated in the defect with 3 * PRP incorporated gelatin sponge was larger than that of the other group. PMID- 26481593 TI - TROP-2 expression in papillary thyroid carcinoma: Potential Diagnostic Utility. AB - TROP-2 is a type I transmembrane glycoprotein which is over-expressed in various malignancies, and is related to epithelial cell adhesion molecule (EpCAM), also called TROP-1, gp40, and KSA. In this study, we evaluated TROP-2 expression in papillary thyroid carcinoma (PTC) and compared it to other thyroid neoplastic and non-neoplastic lesions. Immunohistochemical (IHC) evaluation for TROP-2 was performed on 137 thyroid fine needle aspiration (FNA) cell blocks (CB) which included classic PTC (64), follicular variant PTC (FVPTC) (10), anaplastic thyroid carcinoma (AC) (2), medullary carcinoma (MC) (8), follicular neoplasms (FN) (8), Hurthle cell neoplasms (HCN) (9), follicular lesion of uncertain significance (FLUS) (12), and benign thyroid nodule (BTN) (24). IHC for TROP-2 expression was also performed on 331 BTN and malignant tumor tissue sections in tissue microarray (TMA). Membranous staining in >5% of tumor cells was considered positive. TROP-2 stained 61 of 64 PTC CB, 7 of 10 FVPTC CB, and 9 of 12 FLUS CB. All other cases were negative for TROP-2. TROP-2 showed a sensitivity of 95.31% and specificity of 89% for classic PTC in FNA CB. In TMA samples, TROP-2 stained 54 of 60 classic PTC cases and hence showed a high sensitivity and specificity. All BTN in CB and TMA were negative. We conclude that TROP-2 is a highly sensitive and specific IHC marker for identifying classic PTC. TROP-2 may play an important role in diagnosing classic PTC, especially in equivocal cases. This study also identifies a strong role for TROP-2 in separating PTC from BTN. PMID- 26481595 TI - Malleable (Semi-Rigid) Penile Prosthesis (MPP). PMID- 26481596 TI - Why We Should Stop Confusing Hypoactive Sexual Desire Disorder with Low Sexual Desire/Interest Syndrome. PMID- 26481597 TI - Prenatal Hypoxia Ischemia Increases Male Rat Sexual Behavior. AB - INTRODUCTION: Research consistently indicates an association between prenatal hypoxia-ischemia (HI) and mortality and chronic neurological diseases in newborns. HI can cause permanent effects, including mental retardation, motor impairment, learning disabilities, epilepsy, and cerebral palsy. Moreover, little is known about the relationship between HI and sexual behavior. AIMS: The aims of this study are to examine whether HI is associated with changes in sexual behavior. METHODS: HI was induced by clamping the uterine arteries of pregnant rats. The arteries were clamped for 45 minutes on the 18th day of gestation (HI group). Shams received laparotomy and anesthesia only. Pups were born at term. At 90 days of age, sexual behavior was evaluated. Statistical analysis was performed using two-way analysis of variance and post hoc Bonferonni correction. MAIN OUTCOME MEASURES: The main outcome measures of sexual response were standard sexual behavior, homosexual behavior, and sexual attempt on nonreceptive females. RESULTS: The stimulatory effect of HI on male rat sexual behavior has been shown in various experimental models; these animals showed reduced mount, intromission and ejaculation latencies; increased copulatory efficiency; and homosexual mounting. Additionally, there was an increase in fighting in trying to mount an unreceptive female. CONCLUSION: Our results indicate that HI had a long-term effect on sexual behavior despite exhibiting motor skill impairment. Accordingly, injuries during the fetal period may cause behavioral problems in adulthood. PMID- 26481598 TI - Bias in Evaluating Erectile Function in Lifelong Premature Ejaculation Patients with the International Index of Erectile Function-5. AB - INTRODUCTION: Lifelong premature ejaculation (LPE) is the most important ejaculating dysfunction. Relatively little is known about erectile function in this population. AIMS: We attempted to evaluate the erectile function of patients with LPE using the International Index of Erectile Function-5 (IIEF-5) to determine if it is sufficiently reliable and accurate to make such an assessment. METHODS: A total of 406 patients with LPE were enrolled in our study. The participants voluntarily answered the Premature Ejaculation Diagnostic Tool (PEDT) and IIEF-5 questionnaires and underwent a full history evaluation and clinical examination by doctors. Their answers were converted into data analyzed by a statistic software. MAIN OUTCOME MEASURES: The patients were diagnosed with LPE based on the diagnostic criteria and PEDT scores. The intravaginal ejaculation latency time was recorded according to patient self-reports. The IIEF 5 was used to evaluate their erectile function. Thorough history and clinical examination helped doctors make more correct diagnoses of erectile dysfunction (ED). RESULTS: Of the 406 patients, 70 (17.24%) patients had ED, as confirmed by doctors. IIEF-5 was accurate for the assessment of the erectile function of LPE patients when the cutoff was decreased to 15.5. Question 5 (1.34 +/- 0.53) was the main reason for the drop in the total IIEF-5 score. Questions 1 and 5 shared low consistency with the other three IIEF-5 items, thus they lowered the reliability of the IIEF-5 scores. These questions created a confounding bias that decreased the diagnostic threshold of IIEF-5. However, they could not be removed from the IIEF-5 because they did not reduce its diagnostic accuracy in patients with LPE. CONCLUSIONS: Bias from questions 1 and 5 lowered the reliability of the IIEF-5 scores; however, it did not reduce the diagnostic accuracy of the IIEF-5. The recommendation is to edit questions 1 and 5 when they are applied to populations with LPE. PMID- 26481599 TI - Editorial Comment on "Bias in Evaluating Erectile Function in Lifelong Premature Ejaculation Patients with the International Index of Erectile Function-5": Failure to Generalize Does Not Equal Instrument Bias. PMID- 26481600 TI - Vaginoplasty in Male-to-Female Transsexual Surgery: A Training Concept Incorporating Dissection Room Experience to Optimize Functional and Cosmetic Results. AB - INTRODUCTION: Learning a new technique, even for an established surgeon, requires a learning curve; however, in transsexual surgery especially, there is a lack of professional and public tolerance for suboptimal aesthetic and functional results due to a learning curve. AIMS: In this context, we have tried to build a learning concept for vaginoplasty that includes four steps: (i) formal identification of the surgical steps in order to provide both measure of surgical process and measures of outcomes; (ii) training on cadavers with expert assistance; (iii) performing the live surgery with assistance from expert; and (iv) performing the surgery alone. Herein, we emphasize the second step of our learning concept. MATERIAL AND METHODS: Between September 2013 and December 2013, 15 cadavers were operated on by an established surgeon learning vaginoplasty under assistance from two expert practitioners. Mean global time and mean time necessary to perform each step of the operation were recorded by the experts. Intraoperative complications were systematically registered. The final depth and diameter of the neaovaginal cavity were precisely measured. For each cadaver, the aesthetic results were assessed by one of the experts. RESULTS: Mean total operating time was 179 +/- 34 minutes and decreased from 262 minutes for the first training attempt to 141 minutes for the last one. Intraoperative expert correction included modification of the scrotal triangular flap design and change of position of the urethra: This happened during the first training. No lesion of the urethra or of the anus occurred. The two experts judged the outcomes as excellent in seven cases, very good in four cases, good in two cases, and fair in two cases. CONCLUSION: Despite the numerous reports on vaginoplasty in the literature, there is a real lack of published information on the learning curve of this operation. We make the hypothesis that introducing a learning concept with assistance from expert practitioners at the beginning of the surgeon's experience can optimize both the duration of his learning curve and reduce the risk of major complications. PMID- 26481601 TI - Re: What is a Good Looking Penis? How Women Rate the Penile Appearance of Men with Surgically Corrected Hypospadias, J Sex Med 2015;12:1737-457. PMID- 26481602 TI - Response and Rebuttal to the Letter to the Editor "Re: What is a Good Looking Penis? How Women Rate the Penile Appearance of Men with Surgically Corrected Hypospadias". PMID- 26481603 TI - Electric Double-Layer Effects Induce Separation of Aqueous Metal Ions. AB - Metal ion separation is crucial to environmental decontamination, chromatography, and metal recovery and recycling. Theoretical studies have suggested that the ion distributions in the electric double-layer (EDL) region depend on the nature of the ions and the characteristics of the charged electrode surface. We believe that rational design of the electrode material and device structure will enable EDL-based devices to be utilized in the separation of aqueous metal ions. On the basis of this concept, we fabricate an EDL separation (EDLS) device based on sandwich-structured N-functionalized graphene sheets (CN-GS) for selective separation of aqueous toxic heavy metal ions. We demonstrate that the EDLS enables randomly distributed soluble ions to form a coordination-driven layer and electrostatic-driven layer in the interfacial region of the CN-GS/solution. Through tuning the surface potential of the CN-GS, the effective separation of heavy metal ions (coordination-driven layer) from alkali or alkaline earth metal ions (electrostatic-driven layer) can be achieved. PMID- 26481604 TI - Ultrafast electronic state conversion at room temperature utilizing hidden state in cuprate ladder system. AB - Photo-control of material properties on femto- (10(-15)) and pico- (10(-12)) second timescales at room temperature has been a long-sought goal of materials science. Here we demonstrate a unique ultrafast conversion between the metallic and insulating state and the emergence of a hidden insulating state by tuning the carrier coherence in a wide temperature range in the two-leg ladder superconductor Sr(14-x)Ca(x)Cu24O41 through femtosecond time-resolved reflection spectroscopy. We also propose a theoretical scenario that can explain the experimental results. The calculations indicate that the holes injected by the ultrashort light reduce the coherence among the inherent hole pairs and result in suppression of conductivity, which is opposite to the conventional photocarrier doping mechanism. By using trains of ultrashort laser pulses, we successively tune the carrier coherence to within 1 picosecond. Control of hole-pair coherence is shown to be a realistic strategy for tuning the electronic state on ultrafast timescales at room temperature. PMID- 26481605 TI - Characteristics of traditional Chinese medicine use in patients with rheumatoid arthritis in Taiwan: A nationwide population-based study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Large-scale study of traditional Chinese medicine (TCM) usage among patients with rheumatoid arthritis (RA) is lacking. The aim of this study is to evaluate the TCM usage among RA patients in Taiwan. MATERIALS AND METHODS: We examined the "registry for catastrophic illness patient dataset" of the National Health Insurance Research Database (NHIRD; n=23 million people) in Taiwan. Patients (n=25,263) newly diagnosed as RA in 2001-2009 were included and then followed-up until the end of 2011. Based on the medical utilization, they were further categorized into TCM users (n= 6891; 27.3%) and non-TCM users (n=18,372; 72.7%). The demographic data and core prescription patterns of the TCM users were analyzed. RESULTS: Compared to non-TCM user, TCM users were younger (mean age: 49.6 versus 54.0 years), had a higher female/male ratio (82.7%/17.3% versus 74.1%/25.9%), resided in more urbanized area. Herbal remedies were the most commonly used therapeutic approach (76.4%), followed by combining acupuncture (21.1%). The frequency of outpatient visits in TCM users was higher across all disease categories except circulatory system. The most commonly prescribed formula and herb was Shang-Jong-Shiah-Tong-Yong-Tong-Feng-Wan and Rhizoma Corydalis, respectively. The analysis of core pattern revealed that Dang Gui-Nian-Tong-Tang, Shu-Jing-Huo-Xie-Tang, Gui-Zhi-Shao-Yao-Zhi-Mu-Tang, Myrrha and Olibanum, were among the most frequently used combinations. RA patients who had anxiety and depression, allergic rhinitis, osteoporosis, menstrual disorder, and menopausal syndrome were prone to have more TCM visits compared to non-TCM users. CONCLUSIONS: Our population-based study revealed the high prevalence and specific usage patterns of TCM in the RA patients in Taiwan. The information could be used for further pharmacological investigation and clinical trials. PMID- 26481606 TI - The protective effects of Ribes diacanthum Pall on cisplatin-induced nephrotoxicity in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ribes diacanthum Pall. (Saxifragaceae), a Mongolian folk medicinal plant, was used to treat urinary system diseases. The present work aims to investigate the protective effects of Ribes diacanthum Pall (RDP) against cisplatin-induced nephrotoxicity. METHODS: The renal injury was modeled by intraperitoneal injection of cisplatin for 5 consecutive days (5 mg/kg). Nephroprotection of RDP was investigated by oral administration of RDP aqueous extract at a daily dose of 40 mg/kg for 14 consecutive days, starting 7 days prior to cisplatin administration. RESULTS: We demonstrated that pretreatment with RDP aqueous extract protected the mice from death induced by cisplatin administration. RDP treatment also significantly reduced blood urea nitrogen (BUN) and serum creatinine (Cr) levels observed in cisplatin administrated mice. Histopathological analysis demonstrated that RDP administration protected cisplatin-induced renal tubular cell apoptosis. Further western blotting analysis revealed that RDP significantly reversed cisplatin increased expression levels of cleaved-Caspase-3, Bax and cisplatin-decreased expression level of Bcl-2 in renal tissue. Finally, RDP markedly enhanced enzyme activities of reduced superoxide dismutase (SOD), Heme oxygenase 1 (HO-1) and catalase (CAT), suppressed lipid peroxidation as well as reactive oxygen species (ROS) production. CONCLUSION: We concluded that RDP displayed nephroprotective effects against cisplatin-induced renal tubular cell apoptosis, possibly associated with both enhanced antioxidase activity and suppressed ROS generation. Given the major nephrotoxicity of cisplatin cancer chemotherapy, RDP might be a potential candidate for neoadjuvant chemotherapy. PMID- 26481608 TI - Annickia affinis and A. chlorantha (Enantia chlorantha)--A review of two closely related medicinal plants from tropical Africa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Annickia affinis (Exell) Versteegh & Sosef, closely related to A. chlorantha Setten & P.J.Maas (both species also referred to as Enantia chlorantha Oliv.), from the Annonaceae family, are multi-purpose medicinal plants used widely across tropical Africa. The two Annickia species are morphologically distinct from each other and have different distribution patterns, but are frequently confused. Furthermore, the name Enantia chlorantha is an illegitimate name, but is still used today. MATERIALS AND METHODS: A review of the literature was undertaken and an in-depth analysis of previous research and future prospectives are considered. While a myriad of publications cite the species "Enantia chlorantha", this is not the case for A. affinis and A. chlorantha, and no reviews are available for any of the species to date. Consequently, a summary of their ethnobotany, phytochemistry and biological properties is presented here (for the period 1933 - November 2014) in order to substantiate their traditional importance as medicines for rural people in Africa. RESULTS: To this effect, these species seem to be the preferred traditional treatments for malaria in tropical Africa, an area suffering heavily under the malaria pandemic. Their chemical composition is dominated particularly by various isoquinoline alkaloids, as well as by acetogenins and sesquiterpenes, which have been isolated from the bark and leaves. All three of these classes of compounds have been reported to exhibit noteworthy biological activity. CONCLUSIONS: Due to their widespread use, especially of the bark, these species have already been categorized as threatened with extinction. Consequently this study further aims to identify areas where more research needs to be conducted involving these important species, and also to suggest possible means of increasing the biological activities of their extracts as a way to conserve the species. PMID- 26481607 TI - Medicinal and local food plants in the south of Alava (Basque Country, Spain). AB - ETHNOBOTANICAL RELEVANCE: Medicinal and food plants in the Basque Country are an integral part of a fast changing culture. With a distinct tradition and language, this region of Europe provides an important example demonstrating the changing role of local and traditional knowledge in industrial countries. As other Mediterranean regions it preserves a rich heritage of using plants as medicine and food, offering a unique opportunity for studying the medicine food interface in an ethnopharmacological context. Therefore, the key goal of this study has been to contribute to an understanding of local and traditional plant usage, to evaluate their uses as food and medicine as well as to critically assess the role of these plants in the south of the Basque Country contributing to an understanding of how foods and medicines are used. METHODS: A mixed methods approach, including participant observation; open and semi structured interviews was used. Ethnobotanical field work included 183 people, ages ranged from 24 to 98 years old with a majority being between 70 and 80 years old (mean age 71) from 31 towns of three different regions. The basic interview was a one-to-one meeting, which often included field walking and collection of samples as directed by the informants. 700 voucher specimens (most of them with duplicates) were collected for the data obtained. Using SPSS version 20 the gathered information was processed and the replies of the different informants were subsequently organised in variables like medicine and food plants, part of the plants used, forms of preparations, zones preferred for collecting these plants. The data were analysed based on the frequency of records. This type of approach allows us to understand the way the informant's categorize the species, and how these categories are distributed along the sample. In order to analyse the data three main categories of use were distinguished: Medicine (M), Food (F) and an intermediate Health-Food (H-F). The three categories were divided in 27 subcategories (common uses). RESULTS AND DISCUSSION: The informants recognise and use a total of 184 species from 49 families. During interviews, 5658 individual use-reports were collected relating to three use-categories - as medicines, food and health-food. The two main groups with almost the same number of species each are health-food (75 species) and (locally gathered) food only (73), with medicinal uses only (36) being the smallest group. This highlights the important overlap between food and medicines. Overall, three core families were identified (based on the number of use reports and in the number of species): Asteraceae (25 species), Lamiaceae and Rosaceae (24 each). The most frequently reported species are Jasonia glutinosa, Chamaemelum nobile, Prunus spinosa and Quercus ilex subsp. ballota. The most important general use-subcategories are as raw vegetables (27.43% of the use-reports and including 81 species), infusions (14.74%/42) and gastrointestinal (12.53%/42). Conceptually foods and medicines are clearly distinguished but the intermediate group of health foods is more ambiguous. CONCLUSION: Food and medicinal uses of plants are culturally closely linked. A wide range of plants are known and many still used. The analysis shows that the Basques use a wide range of species which are typical for Western European cultures. In comparison to other studies in the Mediterranean countries there are many similarities in the uses of different families, species of plants and their use and preparations. Some of these plants are key Mediterranean species, often used for a multitude of uses as food and medicine. PMID- 26481609 TI - Metal-carbonyl organometallic polymers, PFpP, as resists for high-resolution positive and negative electron beam lithography. AB - Metal-containing resists for electron beam lithography (EBL) are attracting attention owing to their high dry etching resistance and possibility for directly patterning metal-containing nanostructures. The newly developed organometallic metal carbonyl polymers, PFpP, can function as EBL resists with strong etching resistance. One significant feature of the PFpP resist is its high resolution. Line arrays with line-widths as narrow as 17 nm have been created. The resist can also be used in positive tone. PMID- 26481610 TI - Arcobacter butzleri isolates exhibit pathogenic potential in intestinal epithelial cell models. AB - AIMS: The pathogenic potential of Arcobacter butzleri isolates on human (HT 29/B6) and porcine epithelial (IPEC-J2) cells was investigated by in vitro assays. METHODS AND RESULTS: Five of six A. butzleri isolates were able to adhere and invade HT-29/B6 cells while only four isolates adhered and two invaded IPEC J2 cells. Two non- or poorly invasive A. butzleri isolates were highly cytotoxic to differentiated HT-29/B6 cells but none to IPEC-J2 cells as determined by WST assays. Epithelial integrity of cell monolayers, monitored by measurement of the transepithelial electrical resistance (TER), was decreased by all A. butzleri isolates in HT-29/B6 and IPEC-J2 cells to 30-15% and 90-50% respectively. CONCLUSION: The A. butzleri strain-specific pathomechanisms observed with the human colon cell line HT-29/B6, like adhesion, invasion and cytotoxicity might all contribute to epithelial barrier dysfunction, which could explain a leak-flux type of diarrhoea in humans. In contrast, porcine cells seem to be less susceptible to A. butzleri. SIGNIFICANCE AND IMPACT OF THE STUDY: Arcobacter butzleri has enteric pathogenic potential, characterized by defined interactions with human epithelial cells and strain-specific pathomechanisms. PMID- 26481613 TI - Contribution of myosin II activity to cell spreading dynamics. AB - Myosin II activity and actin polymerization at the leading edge of the cell are known to be essential sources of cellular stress. However, a quantitative account of their separate contributions is still lacking; so is the influence of the coupling between the two phenomena on cell spreading dynamics. We present a simple analytic elastic theory of cell spreading dynamics that quantitatively demonstrates how actin polymerization and myosin activity cooperate in the generation of cellular stress during spreading. Consistent with experiments, myosin activity is assumed to polarize in response to the stresses generated during spreading. The characteristic response time and the overall spreading time are predicted to determine different evolution profiles of cell spreading dynamics. These include, a (regular) monotonic increase of cell projected area with time, a non-monotonic (overshooting) profile with a maximum, and damped oscillatory modes. In addition, two populations of myosin II motors are distinguished based on their location in the lamella; those located above the major adhesion zone at the cell periphery are shown to facilitate spreading whereas those in deeper regions of the lamella are shown to oppose spreading. We demonstrate that the attenuation of myosin activity in the two regions may result in reciprocal effects on spreading. These findings provide important new insight into the function of myosin II motors in the course of spreading. PMID- 26481612 TI - The immune system in Duchenne muscular dystrophy: Friend or foe. AB - Duchenne muscular dystrophy (DMD) is a genetic disease caused by mutations in the X-linked dystrophin gene, resulting in reduced or absent protein production, subsequently leading to the structural instability of the dystroglycan complex (DGC), muscle degeneration, and early death in males. Thus, current treatments have been targeting the genetic defect either by bypassing the mutation through exon skipping or replacing the defective gene through gene therapy and stem cell approaches. However, what has been an underappreciated mediator of muscle pathology and, ultimately, of muscle degeneration and fibrotic replacement, is the prominent inflammatory response. Of potentially critical importance, however, is the fact that the elements mediating the inflammatory response also play an essential role in tissue repair. In this opinion piece, we highlight the detrimental and supportive immune parameters that occur as a consequence of the genetic disorder and discuss how changes to immunity can potentially ameliorate the disease intensity and be employed in conjunction with efforts to correct the genetic disorder. PMID- 26481611 TI - Neutralizing antibodies against West Nile virus identified directly from human B cells by single-cell analysis and next generation sequencing. AB - West Nile virus (WNV) infection is an emerging mosquito-borne disease that can lead to severe neurological illness and currently has no available treatment or vaccine. Using microengraving, an integrated single-cell analysis method, we analyzed a cohort of subjects infected with WNV - recently infected and post convalescent subjects - and efficiently identified four novel WNV neutralizing antibodies. We also assessed the humoral response to WNV on a single-cell and repertoire level by integrating next generation sequencing (NGS) into our analysis. The results from single-cell analysis indicate persistence of WNV specific memory B cells and antibody-secreting cells in post-convalescent subjects. These cells exhibited class-switched antibody isotypes. Furthermore, the results suggest that the antibody response itself does not predict the clinical severity of the disease (asymptomatic or symptomatic). Using the nucleotide coding sequences for WNV-specific antibodies derived from single cells, we revealed the ontogeny of expanded WNV-specific clones in the repertoires of recently infected subjects through NGS and bioinformatic analysis. This analysis also indicated that the humoral response to WNV did not depend on an anamnestic response, due to an unlikely previous exposure to the virus. The innovative and integrative approach presented here to analyze the evolution of neutralizing antibodies from natural infection on a single-cell and repertoire level can also be applied to vaccine studies, and could potentially aid the development of therapeutic antibodies and our basic understanding of other infectious diseases. PMID- 26481614 TI - Association study of functional polymorphisms in interleukins and interleukin receptors genes: IL1A, IL1B, IL1RN, IL6, IL6R, IL10, IL10RA and TGFB1 in schizophrenia in Polish population. AB - Schizophrenia has been associated with a large range of autoimmune diseases, with a history of any autoimmune disease being associated with a 45% increase in risk for the illness. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. In particular, increases or imbalance in cytokine before birth or during the early stages of life may affect neurodevelopment and produce vulnerability to the disease. A total of 27 polymorphisms of IL1N gene: rs1800587, rs17561; IL1B gene: rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627; IL1RN gene: rs419598, rs315952, rs9005, rs4251961; IL6 gene: rs1800795, rs1800797; IL6R gene: rs4537545, rs4845617, rs2228145, IL10 gene: rs1800896, rs1800871, rs1800872, rs1800890, rs6676671; IL10RA gene: rs2229113, rs3135932; TGF1B gene: rs1800469, rs1800470; each selected on the basis of molecular evidence for functionality, were investigated in this study. Analysis was performed on a group of 621 patients with diagnosis of schizophrenia and 531 healthy controls in Polish population. An association of rs4848306 in IL1B gene, rs4251961 in IL1RN gene, rs2228145 and rs4537545 in IL6R with schizophrenia have been observed. rs6676671 in IL10 was associated with early age of onset. Strong linkage disequilibrium was observed between analyzed polymorphisms in each gene, except of IL10RA. We observed that haplotypes composed of rs4537545 and rs2228145 in IL6R gene were associated with schizophrenia. Analyses with family history of schizophrenia, other psychiatric disorders and alcohol abuse/dependence did not show any positive findings. Further studies on larger groups along with correlation with circulating protein levels are needed. PMID- 26481616 TI - Survival analysis of the use of first and second generation antipsychotics among patients suffering schizophrenia: A nationwide population-based cohort study. AB - BACKGROUND: Few studies have investigated the relationship between the use of different generations of antipsychotics and mortality with contradictory results. The aim of this study is to compare mortality among patients suffering schizophrenia taking different generations of antipsychotics in a nationwide population-based cohort study in Taiwan. METHODS: A total of 812 patients suffering newly diagnosed schizophrenia under monotherapy of second generation antipsychotics (SGAs) comprised the group of cases. The matched controls were under monotherapy of first generation antipsychotics (FGAs). Each case was matched individually with their initial antipsychotics prescription calendar year and month, gender, and age. Cox regression analyses were applied to estimate survival time, adjusting for gender, age, residence, insurance premium, Charlson comorbidity index, hospital admission days, and hospital admission times. An analysis including the number of antipsychotic prescriptions, a proxy indicator of adherence, into the fully adjusted model to reveal the effect of adherence on survival of patients served as a sensitivity analysis. RESULTS: Subjects receiving SGAs had lower admission times and inpatient days, more antipsychotic prescriptions, and longer follow-up time than FGAs. Compared with the FGAs group, the adjusted hazard ratio of mortality was 0.58 (95% confidence interval =0.34 0.96, p=.034) for SGAs group. After controlling for the number of antipsychotic prescriptions, the difference in mortality between antipsychotic generations was non-significant. CONCLUSIONS: The results of this study suggest that SGAs were better than FGAs in mortality among patients suffering schizophrenia. The difference in mortality can be explained by the better medication adherence of SGAs. PMID- 26481615 TI - Pursuit eye movements as an intermediate phenotype across psychotic disorders: Evidence from the B-SNIP study. AB - Smooth pursuit eye tracking deficits are a promising intermediate phenotype for schizophrenia and possibly for psychotic disorders more broadly. The Bipolar Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium investigated the severity and familiality of different pursuit parameters across psychotic disorders. Probands with schizophrenia (N=265), schizoaffective disorder (N=178), psychotic bipolar disorder (N=231), their first-degree relatives (N=306, N=217, N=273, respectively) and healthy controls (N=305) performed pursuit tracking tasks designed to evaluate sensorimotor and cognitive/predictive aspects of pursuit. Probands from all diagnostic groups were impaired on all pursuit measures of interest compared to controls (p<0.001). Schizophrenia probands were more impaired than other proband groups on both early pursuit gain and predictive gain. Relatives with and without enhanced psychosis spectrum personality traits were impaired on initial eye acceleration, the most direct sensorimotor pursuit measure, but not on pursuit gain measures. This suggests that alterations in early sensorimotor function may track susceptibility to psychosis even in the absence of psychosis related personality traits. There were no differences in pursuit measures between relatives of the three proband groups. Familiality estimates of pursuit deficits indicate that early pursuit gain was more familial than predictive gain, which has been the most widely used measure in previous family studies of psychotic disorders. Thus, while disease-related factors may induce significant impairments of pursuit gain, especially in schizophrenia, the pattern of deficits in relatives and their familiality estimates suggest that alterations in sensorimotor function at pursuit onset may indicate increased susceptibility across psychotic disorders. PMID- 26481617 TI - Development of a new measure for assessing insight: Psychometric properties of the insight orientation scale (IOS). AB - INTRODUCTION: Given the centrality of insight in promoting change, the relevance of measures for assessing this construct has become increasingly clear. This paper describes a new self-report measure for assessing some of the characteristics of insight, the insight orientation scale (IOS). AIMS: In study 1, we evaluated the factor structure and the reliability of the scale. In study 2, we analyzed the concurrent and discriminant validity of the scale in patients with different clinical diagnoses. METHODS: In study 1 participants were 600 individuals (41.1% male, 58.9% female) with a mean age of 33.95 years (SD = 13.04). In study 2 participants were 136 individuals divided into the following groups: 1) schizophrenia spectrum and other psychotic disorders (n = 26); 2) substance-related disorders (n = 55); 3) depressive disorders (n = 27); and 4) personality disorders (n = 28). INSTRUMENTS: Instruments are the insight orientation scale (IOS) and the Beck cognitive insight scale. RESULTS: The goodness-of-fit indices showed a satisfactory fit of a one factor model. We found also a good internal consistency (alpha = .77). CONCLUSIONS: These findings support the dimensionality of the IOS and suggest that it may be useful as an assessment tool for use in guiding psychotherapy. PMID- 26481618 TI - Regulation of cellulase expression, sporulation, and morphogenesis by velvet family proteins in Trichoderma reesei. AB - Homologs of the velvet protein family are encoded by the ve1, vel2, and vel3 genes in Trichoderma reesei. To test their regulatory functions, the velvet protein-coding genes were disrupted, generating Deltave1, Deltavel2, and Deltavel3 strains. The phenotypic features of these strains were examined to identify their functions in morphogenesis, sporulation, and cellulase expression. The three velvet-deficient strains produced more hyphal branches, indicating that velvet family proteins participate in the morphogenesis in T. reesei. Deletion of ve1 and vel3 did not affect biomass accumulation, while deletion of vel2 led to a significantly hampered growth when cellulose was used as the sole carbon source in the medium. The deletion of either ve1 or vel2 led to the sharp decrease of sporulation as well as a global downregulation of cellulase-coding genes. In contrast, although the expression of cellulase-coding genes of the ?vel3 strain was downregulated in the dark, their expression in light condition was unaffected. Sporulation was hampered in the ?vel3 strain. These results suggest that Ve1 and Vel2 play major roles, whereas Vel3 plays a minor role in sporulation, morphogenesis, and cellulase expression. PMID- 26481619 TI - Identification of catalytically important residues of the carotenoid 1,2 hydratases from Rubrivivax gelatinosus and Thiocapsa roseopersicina. AB - Carotenoid 1,2-hydratases (CrtC) catalyze the selective addition of water to an isolated carbon-carbon double bond. Although their involvement in the carotenoid biosynthetic pathway is well understood, little is known about the mechanism by which these hydratases transform carotenoids such as lycopene into the corresponding hydroxyl compounds. Key residues were identified at positions His239, Trp241, Tyr266, and Asp268 in CrtC from Rubrivivax gelatinosus (and corresponding positions in Thiocapsa roseopersicina). Alanine mutants at these positions were found to be completely inactive, suggesting their direct involvement in the catalytic reaction. Our resulting mechanistic hypothesis is in analogy with the recently studied class of terpenoid cyclase enzymes containing a highly acidic aspartic residue in their active site. We propose that a similar aspartic acid residue, which is conserved through all putative CrtCs, is involved in initial protonation of the double bond in lycopene. PMID- 26481620 TI - Antifungal activities of three different Lactobacillus species and their production of antifungal carboxylic acids in wheat sourdough. AB - This study was undertaken to assess the antifungal performance of three different Lactobacillus species.Experiments were conducted in vitro and in situ to extend the shelf life of wheat bread. Standard sourdough analyses were performed characterising acidity and carbohydrate levels. Overall, the strains showed good inhibition in vitro against the indicator mould Fusarium culmorum TMW4.2043. Sourdough bread fermented with Lactobacillus amylovorus DSM19280 performed best in the in situ shelf life experiment. An average shelf life extension of six more mould-free days was reached when compared to the non-acidified control bread. A range of antifungal-active acids like 3-phenyllactic acid, 4-hydroxyphenyllactic acid and 2-hydroxyisocaproic acid in quantities between 0.1 and 360 mg/kg were present in the freeze-dried sourdoughs. Their concentration differed greatly amongst the species.However, a higher concentration of these compounds could not completely justify the growth inhibition of environmental moulds. In particular, although Lb. reuteri R29 produced the highest total concentration of these active compounds in the sourdough, its addition to bread did not result in a longest shelf life. Nevertheless, when the artificial compounds were spiked into a chemically acidified dough, it succeeded in a longer shelf life (+25 %) than achieved only by acidifying the dough. This provides evidence of their contribution to the antifungal activity and their synergy in concentration levels far below their single minimal inhibition concentrations under acidic conditions. PMID- 26481621 TI - Immobilization of biogenic Pd(0) in anaerobic granular sludge for the biotransformation of recalcitrant halogenated pollutants in UASB reactors. AB - The capacity of anaerobic granular sludge to reduce Pd(II), using ethanol as electron donor, in an upflow anaerobic sludge blanket (UASB) reactor was demonstrated. Results confirmed complete reduction of Pd(II) and immobilization as Pd(0) in the granular sludge. The Pd-enriched sludge was further evaluated regarding biotransformation of two recalcitrant halogenated pollutants: 3-chloro nitrobenzene (3-CNB) and iopromide (IOP) in batch and continuous operation in UASB reactors. The superior removal capacity of the Pd-enriched biomass when compared with the control (not exposed to Pd) was demonstrated in both cases. Results revealed 80 % of IOP removal efficiency after 100 h of incubation in batch experiments performed with Pd-enriched biomass whereas only 28 % of removal efficiency was achieved in incubations with biomass lacking Pd. The UASB reactor operated with the Pd-enriched biomass achieved 81 +/- 9.5 % removal efficiency of IOP and only 61 +/- 8.3 % occurred in the control reactor lacking Pd. Regarding 3 CNB, it was demonstrated that biogenic Pd(0) promoted both nitro-reduction and dehalogenation resulting in the complete conversion of 3-CNB to aniline while in the control experiment only nitro-reduction was documented. The complete biotransformation pathway of both contaminants was proposed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis evidencing a higher degree of nitro-reduction and dehalogenation of both contaminants in the experiments with Pd-enriched anaerobic sludge as compared with the control. A biotechnological process is proposed to recover Pd(II) from industrial streams and to immobilize it in anaerobic granular sludge. The Pd-enriched biomass is also proposed as a biocatalyst to achieve the biotransformation of recalcitrant compounds in UASB reactors. PMID- 26481623 TI - Transcriptome analysis of Cronobacter sakazakii ATCC BAA-894 after interaction with human intestinal epithelial cell line HCT-8. AB - Cronobacter spp. are opportunistic pathogens that are responsible for infections including severe meningitis, septicemia, and necrotizing enterocolitis in neonates and infants. To date, questions still remain regarding the mechanisms of pathogenicity and virulence determinants for each bacterial strain. In this study, we established an in vitro model for Cronobacter sakazakii ATCC BAA-894 infection of HCT-8 human colorectal epithelial cells. The transcriptome profile of C. sakazakii ATCC BAA-894 after interaction with HCT-8 cells was determined using high-throughput whole-transcriptome sequencing (RNA sequencing (RNA-seq)). Gene expression profiles indicated that 139 genes were upregulated and 72 genes were downregulated in the adherent C. sakazakii ATCC BAA-894 strain on HCT-8 cells compared to the cultured bacteria in the cell-free medium. Expressions of some flagella genes and virulence factors involved in adherence were upregulated. High osmolarity and osmotic stress-associated genes were highly upregulated, as well as genes responsible for the synthesis of lipopolysaccharides and outer membrane proteins, iron acquisition systems, and glycerol and glycerophospholipid metabolism. In sum, our study provides further insight into the mechanisms underlying C. sakazakii pathogenesis in the human gastrointestinal tract. PMID- 26481624 TI - Modeling the fate of antibiotic resistance genes and class 1 integrons during thermophilic anaerobic digestion of municipal wastewater solids. AB - This study investigated the use of thermophilic anaerobic digestion for removing antibiotic resistance genes (ARGs) from residual municipal wastewater solids. Four laboratory-scale anaerobic digesters were operated in 8-day batch cycles at temperatures of 40, 56, 60, and 63 degrees C. Two tetracycline resistance genes (tet(W) and tet(X)), a fluoroquinolone resistance gene (qnrA), the integrase gene of class 1 integrons (intI1), 16S rRNA genes of all Bacteria, and 16S rRNA genes of methanogens were quantified using real-time quantitative PCR. ARG and intI1 quantities decreased at all temperatures and were described well by a modified form of the Collins-Selleck disinfection kinetic model. The magnitudes of Collins Selleck kinetic parameters were significantly greater at thermophilic temperatures compared to 40 degrees C, but few statistically significant differences were observed among these parameters for the thermophilic anaerobic digesters. This model allows for the direct comparison of different operating conditions (e.g., temperature) on anaerobic digestion performance in mitigating the quantity of ARGs in wastewater solids and could be used to design full-scale anaerobic digesters to specifically treat for ARGs as a "pollutant" of concern. PMID- 26481622 TI - Carboxydotrophic growth of Geobacter sulfurreducens. AB - This study shows that Geobacter sulfurreducens grows on carbon monoxide (CO) as electron donor with fumarate as electron acceptor. Geobacter sulfurreducens was tolerant to high CO levels, with up to 150 kPa in the headspace tested. During growth, hydrogen was detected in very slight amounts (~5 Pa). In assays with cell free extract of cells grown with CO and fumarate, production of hydrogen from CO was not observed, and hydrogenase activity with benzyl viologen as electron acceptor was very low. Taken together, this suggested that CO is not utilized via hydrogen as intermediate. In the presence of CO, reduction of NADP(+) was observed at a rate comparable to CO oxidation coupled to fumarate reduction in vivo. The G. sulfurreducens genome contains a single putative carbon monoxide dehydrogenase-encoding gene. The gene is part of a predicted operon also comprising a putative Fe-S cluster-binding subunit (CooF) and a FAD-NAD(P) oxidoreductase and is preceded by a putative CO-sensing transcription factor. This cluster may be involved in a novel pathway for CO oxidation, but further studies are necessary to ascertain this. Similar gene clusters are present in several other species belonging to the Deltaproteobacteria and Firmicutes, for which CO utilization is currently not known. PMID- 26481625 TI - A newly discovered arabinoxylan-specific arabinofuranohydrolase. Synergistic action with xylanases from different glycosyl hydrolase families. AB - Arabinofuranosidase Abf43A from Bacillussp. BP-7 i s a newly discovered arabinoxylan arabinofuranohydrolase (AXH). It is a modular enzyme comprised of a GH43 catalytic domain and a carbohydrate-binding module of family CBM6. Recombinant Abf43A showed high activity on arabinoxylans, being rye arabinoxylan the preferred substrate on which the purified enzyme exhibited a Km of 10.6 +/- 3.3 mg/ml and a Vmax of 29.2 +/- 3.4 U/mg. Thin-layer chromatography analysis of hydrolysis products showed arabinose as the only sugar released by the enzyme from its substrates. The GH43 and CBM6 modules of the enzyme were individually cloned and expressed in Escherichia coli. While the isolated catalytic GH43 module did not show hydrolytic activity, the purified CBM6 bound to soluble arabinoxylan in affinity gel electrophoresis analysis. Evaluation of cooperative activity of arabinofuranosidase Abf43A with xylanases from families GH10, GH11, andGH30, (Xyn10A, Xyn11E, and Xyn30D from Paenibacillus barcinonensis) on arabinoxylan depolymerization revealed that the studied enzyme showed synergism with Xyn11E, a 2.54-fold increase in the amount of sugars released. On the contrary, Abf43A did not show synergism with the xylanases of families GH10 or GH30 evaluated. The enzyme characterized contributes to understanding the role of this class of enzymes in the catalytic depolymerization of arabinoxylans and their potential for the production of valuable xylooligosaccharides from these abundant plant polymers. PMID- 26481626 TI - Laboratory-scale bioaugmentation relieves acetate accumulation and stimulates methane production in stalled anaerobic digesters. AB - An imbalance between acidogenic and methanogenic organisms during anaerobic digestion can result in increased accumulation of volatile fatty acids, decreased reactor pH, and inhibition of methane-producing Archaea. Most commonly the result of organic input overload or poor inoculum selection, these microbiological and biochemical changes severely hamper reactor performance, and there are a few tools available to facilitate reactor recovery. A small, stable consortium capable of catabolizing acetate and producing methane was propagated in vitro and evaluated as a potential bioaugmentation tool for stimulating methanogenesis in acidified reactors. Replicate laboratory-scale batch digesters were seeded with a combination of bioethanol stillage waste and a dairy manure inoculum previously observed to result in high volatile fatty acid accumulation and reactor failure. Experimental reactors were then amended with the acetoclastic consortium, and control reactors were amended with sterile culture media. Within 7 days, bioaugmented reactors had significantly reduced acetate accumulation and the proportion of methane in the biogas increased from 0.2 +/- 0 to 74.4 +/- 9.9 % while control reactors showed no significant reduction in acetate accumulation or increase in methane production. Organisms from the consortium were enumerated using specific quantitative PCR assays to evaluate their growth in the experimental reactors. While the abundance of hydrogenotrophic microorganisms remained stable during the recovery period, an acetoclastic methanogen phylogenetically similar to Methanosarcina sp. increased more than 100-fold and is hypothesized to be the primary contributor to reactor recovery. Genomic sequencing of this organism revealed genes related to the production of methane from acetate, hydrogen, and methanol. PMID- 26481627 TI - Enhancement of antioxidant ability of Bombyx mori silk fibroins by enzymatic coupling of catechin. AB - Enzymatic modification of Bombyx mori silk fibroin was carried out by using (+) catechin, aiming at improving the antioxidant ability of the fibroin-based materials.The actions of tyrosinase on catechin were evaluated by using spectrophotometry, LC-MS, and Fourier transform infrared spectroscopy (FTIR). epsilon-Polylysine (epsilon-PLL) was used to investigate the possibility of the covalent reaction between catechin and the primary amine compound. The properties of the fibroin membranes before and after grafting of catechin were compared. The results revealed that catechin was oxidized into reactive o-quinones and subsequently formed catechin derivatives.Meanwhile, catechin could be efficiently grafted onto epsilon-PLL and led to a decrease in the amount of primary amine groups. 1H-NMR analysis verified the occurrence of the tyrosinase-catalyzed coupling of catechin onto the surface of silk fibroins. Improved antioxidant activity and better durability were obtained for the silk fibroin membrane based on catechin/tyrosinase treatment. Thermal behavior and biocompatibility for the catechin-grafted fibroin membranes did not noticeably change as compared to that of the untreated sample. The present work provided a novel method for preparation of the fibroin-based materials for biomedical applications. PMID- 26481628 TI - The Complementary Role of Transcription Factors in the Accurate Diagnosis of Clinically Nonfunctioning Pituitary Adenomas. AB - Clinically nonfunctioning pituitary adenomas (NFAs) may be hormonally inactive tumors of differentiated cells, mainly not only gonadotroph adenomas (GAs) but also silent corticotroph adenomas (SCAs) and other differentiated silent adenomas. Recently, the use of transcription factors has been recommended to confirm cytodiffererentiation of these neoplasms. Our objective was to assess the clinical significance of the new classification system using transcription factors. Five hundred sixteen consecutive NFAs were studied retrospectively. They were initially classified based on hormone immunohistochemistry as follows: 119 hormone-negative adenomas (23.1 %), 300 GAs (58.1 %), 51 SCAs (9.9 %), and 46 other silent adenomas. The 119 hormone-negative adenomas were further evaluated for expression of transcription factors including steroidogenic factor-1 (SF-1), estrogen receptor-alpha (ERalpha), pituitary-specific transcription factor 1 (Pit 1), and t-box transcription factor (Tpit). One hundred thirteen of 119 (95 %) hormone-negative adenomas showed mutually exclusive lineage-specific differentiation as gonadotrophs (SF-1 positive), corticotrophs (Tpit positive), or somatotrophs/mammosomatotrophs/lactotrophs/thyrotrophs (Pit-1 positive) in 79 cases (66.4 %), 32 cases (26.9 %), and 2 cases, respectively. The 32 ACTH negative and Tpit-positive adenomas had higher pro-opiomelanocortin mRNA expression levels compared with GAs (P = 0.0001) on quantitative real-time PCR. They showed a female preponderance (P < 0.0001) and were more frequently giant adenomas (P = 0.0028) associated with marked cavernous sinus invasion (P < 0.0001) compared with GAs. These clinical features were identical to those of the 51 ACTH-positive SCAs. Our results justify the complementary role of transcription factors in the precise classification of NFAs that can more accurately characterize biological behavior. Our data suggest that more than one quarter of hormone-negative adenomas are SCAs that share distinct clinicopathological features with ACTH-expressing SCAs. PMID- 26481629 TI - A Novel Somatic Deletion Mutation of ATP2B3 in Aldosterone-Producing Adenoma. AB - Aldosterone-producing adenoma (APA) is a form of primary aldosteronism (PA). Recent studies suggested that somatic mutations in the KCNJ5, ATP1A1, ATP2B3, and CACNA1D genes are involved in the pathogenesis of APA. We report a case of a 62 year-old man diagnosed as PA with left adrenal mass. He underwent adrenalectomy for treatment. We identified a novel somatic deletion mutation in ATP2B3 in the adrenal tumor: c.1269_1274delTGTGCT which spans three codons (423-425) resulting in p.Val424_Leu425del. Immunohistochemical analysis revealed strong expression of aldosterone synthase (CYP11B2) in the tumor tissue, which is consistent with APA. Here, we identified a novel somatic deletion mutation in ATP2B3, which results in the amino acid sequences increasing intracellular calcium concentrations as reported previously, leading to increased aldosterone synthase (CYP11B2) expression and following excess aldosterone production in the APA cells. The novel ATP2B3 mutation detected in our case supports the pathogenic significance of the locus spanning the codon 424-426 of ATP2B3. PMID- 26481630 TI - Hashimoto's Thyroiditis Does Not Affect Ultrasonographical, Cytological, and Histopathological Features in Patients with Papillary Thyroid Carcinoma. AB - The association between papillary thyroid carcinoma (PTC) and Hashimoto's thyroiditis (HT) is controversial. In this study, we aimed to compare preoperative thyroid functions, ultrasonography (US) features, fine-needle aspiration biopsy (FNAB) results, and histopathological characteristics of PTC in patients with and without HT. Data of 919 PTC patients were reviewed retrospectively. The diagnosis of HT was based on histopathological examination and patients were grouped as HT and non-HT. There were 1321 PTC lesions in 919 patients among which 317 (34.5 %) had coexistent HT. There were no significant differences in nodule volume, longitudinal diameter, texture, echogenicity, marginal regularity, presence of microcalcification and hypoechoic halo, and peripheral vascularization in patients with and without HT (p > 0.05, for all parameters). Macrocalcification was observed more frequently in the non-HT group (p = 0.021). FNAB results were similar in the two groups (p = 0.105). Distribution of variants, capsule invasion, vascular invasion, and extrathyroidal extension were observed with similar rates in the HT and non-HT groups. Lymph node metastasis was significantly higher in patients without HT (p = 0.012). Of the carcinomas, 66.1 % (n = 874) were papillary thyroid microcarcinoma (PTMC). Tumor size was lower in PTMC lesions coexistent with HT (p = 0.026). We observed lower rates of capsule invasion, extrathyroidal extension, and lymph node metastases in PTMC with HT compared to without HT (p = 0.007, p = 0.003, and p = 0.015, respectively). This study showed that US features, FNAB results, and histopathological findings of PTC lesions are not influenced by the presence of HT. However, PTMC seems to be related with less aggressive histopathological behavior in HT. PMID- 26481631 TI - Activity of ceftaroline and comparators against pathogens isolated from skin and soft tissue infections in Latin America - results of AWARE surveillance 2012. AB - As part of the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program in 2012 the in vitro activity of ceftaroline and relevant comparator antimicrobials was evaluated in six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico and Venezuela) against pathogens isolated from patients with hospital associated skin and soft tissue infections (SSTIs). The study documented that ceftaroline was highly active (MIC90 0.25mg/L/% susceptible 100%) against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus (MIC90 2mg/L/% susceptible 83.3%) and beta-hemolytic streptococci (MIC90 0.008-0.015mg/L/% susceptible 100%). The activity of ceftaroline against selected species of Enterobacteriaceae was dependent upon the presence or absence of extended-spectrum beta-lactamases (ESBLs). Against ESBL screen-negative Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca the MIC90 and percent susceptible for ceftaroline were (0.5mg/L/94.1%), (0.5mg/L/99.0%) and (0.5mg/L/91.5%), respectively. Ceftaroline demonstrated potent activity against a recent collection of pathogens associated with SSTI in six Latin American countries in 2012. PMID- 26481632 TI - Plasmodium falciparum and hepatitis B virus infection in Nigerian urban population. PMID- 26481633 TI - Nitrincola nitratireducens sp. nov. isolated from a haloalkaline crater lake. AB - The novel, cream coloured, Gram-negative-staining, rod-shaped, motile bacteria, designated strains AK23(T) and AK28, were isolated from sediment samples collected from Lonar Lake, Buldhana district, India. The predominant fatty acids were C18:1omega7c, C16:0, C10:0 3OH and C16:1omega7c and/or iso-C15:0 2OH (summed feature 3). Polar lipid content of strains AK23(T) and AK28 were found to be phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphotidylserine (PS), one unidentified phospholipid (PL) and two unidentified lipids (L1 and L2). The 16S rRNA gene sequence analysis indicated strains AK23(T) and AK28 as the members of the genus Nitrincola and closely related to the type strain Nitrincola lacisaponensis with pair-wise sequence similarity of 97.67% and 97.62% respectively. DNA-DNA hybridization between strain AK23(T) and AK28 showed a relatedness of 91%. Genome of strains AK23(T) and N. lacisaponensis DSM 16316(T) were sequenced. A comparative genomics approach was used to study strains AK23(T), N. lacisaponensis DSM 16316(T) and five other phylogenetic neighbours. The genome size of N. lacisaponensis DSM 16316(T) was found to be 614,784bp smaller than that of the strain AK23(T). This variation could be due to multiple reasons, gene uptake, evolution, mutation, genome reduction phenomenon and draft nature of sequencing. Based on data from the current polyphasic study, strains AK23(T) and AK28 are proposed as novel species of the genus Nitrincola, for which the name Nitrincola nitratireducens sp. nov. is proposed. The type strain of N. nitratireducens is AK23(T) (=JCM 18788(T)=MTCC 11628(T)). PMID- 26481634 TI - Von Willebrand factor is reversibly decreased during torpor in 13-lined ground squirrels. AB - During torpor in a hibernating mammal, decreased blood flow increases the risk of blood clots such as deep vein thrombi (DVT). In other animal models platelets, neutrophils, monocytes and von Willebrand factor (VWF) have been found in DVT. Previous research has shown that hibernating mammals decrease their levels of platelets and clotting factors VIII (FVIII) and IX (FIX), increasing both bleeding time and activated partial thromboplastin time. In this study, FVIII, FIX and VWF activities and mRNA levels were measured in torpid and non hibernating ground squirrels (Ictidomys tridecemlineatus). Here, we show that VWF high molecular weight multimers, collagen-binding activity, lung mRNA and promoter activity decrease during torpor. The VWF multimers reappear in plasma within 2 h of arousal in the spring. Similarly, FIX activity and liver mRNA both dropped threefold during torpor. In contrast, FVIII liver mRNA levels increased twofold while its activity dropped threefold, consistent with a post transcriptional decrease in FVIII stability in the plasma due to decreased VWF levels. Finally, both neutrophils and monocytes are decreased eightfold during torpor which could slow the formation of DVT. In addition to providing insight in how blood clotting can be regulated to allow mammals to survive in extreme environments, hibernating ground squirrels provide an interesting model for studying. PMID- 26481635 TI - Thermal drying of the solid fraction from biogas digestate: Effects of acidification, temperature and ventilation on nitrogen content. AB - Drying of solids produced from digestate is prone to N losses through NH3 volatilisation. The applicability of acidification as an NH3 emission mitigation technique during the drying of solids from digestate was assessed in a drying experiment. Operating conditions comprised four drying temperatures (70-160 degrees C), two air ventilation rates (natural, 420ml/min) and three pH levels (9.2, 6.5 and 5.5) of the solids, modified by the addition of concentrated sulphuric acid. Acidification of the solids from digestate significantly decreased the NH3 emission during drying, irrespective of the drying conditions. A parallel decrease in the organic nitrogen content and an increase in the ammonium content of the solids was observed after acidification of the solids. It was confirmed that acidification before thermal concentration of solids from digestate, minimised NH3 losses under a wide range of drying conditions. PMID- 26481636 TI - The effect of bioleaching on sewage sludge pyrolysis. AB - The effects of bioleaching on sewage sludge pyrolysis were studied. Sewage sludge was treated by bioleaching with solid concentrations of 6% (w/v), 8% (w/v), 10% (w/v). Results showed that bioleaching treatment could modify the physicochemical properties of sewage sludge and enhance the metals removal. The optimum removal efficiencies of heavy metals were achieved with solid concentration of 6% (w/v) bioleaching treatment: Cu, 73.08%; Zn, 78.67%; Pb, 24.65%; Cd, 79.46%. The characterization results of thermogravimetric analysis (TGA) showed that the bioleached sewage sludge with a 6% (w/v) solid concentration treatment was the easiest to decompose. Pyrolytic experiments of bioleached sewage sludge were performed in a laboratory-scale fixed bed reactor. Results indicated that bioleaching treatment greatly influenced the product yields and gas composition. PMID- 26481637 TI - Management of landfill leachate: The legacy of European Union Directives. AB - Landfill leachate is the product of water that has percolated through waste deposits and contains various pollutants, which necessitate effective treatment before it can be released into the environment. In the last 30years, there have been significant changes in landfill management practices in response to European Union (EU) Directives, which have led to changes in leachate composition, volumes produced and treatability. In this study, historic landfill data, combined with leachate characterisation data, were used to determine the impacts of EU Directives on landfill leachate management, composition and treatability. Inhibitory compounds including ammonium (NH4-N), cyanide, chromium, nickel and zinc, were present in young leachate at levels that may inhibit ammonium oxidising bacteria, while arsenic, copper and silver were present in young and intermediate age leachate at concentrations above inhibitory thresholds. In addition, the results of this study show that while young landfills produce less than 50% of total leachate by volume in the Republic of Ireland, they account for 70% of total annual leachate chemical oxygen demand (COD) load and approximately 80% of total 5-day biochemical oxygen demand (BOD5) and NH4-N loads. These results show that there has been a decrease in the volume of leachate produced per tonne of waste landfilled since enactment of the Landfill Directive, with a trend towards increased leachate strength (particularly COD and BOD5) during the initial five years of landfill operation. These changes may be attributed to changes in landfill management practices following the implementation of the Landfill Directive. However, this study did not demonstrate the impact of decreasing inputs of biodegradable municipal waste on leachate composition. Increasingly stringent wastewater treatment plant (WWTP) emission limit values represent a significant threat to the sustainability of co-treatment of leachate with municipal wastewater. In addition, the seasonal variation in leachate production poses a risk to effective co-treatment in municipal WWTPs, as periods of high leachate production coincide with periods of maximum hydraulic loading in WWTPs. PMID- 26481638 TI - Common Influencing Factors Are No Evidence of Association: A Comment on Callander, Newman, and Holt (2015). PMID- 26481639 TI - The concept of "the inflamed brain" in acute liver failure: mechanisms and new therapeutic opportunities. AB - The presence and severity of a systemic inflammatory response is a major predictor of brain edema and encephalopathy in acute liver failure (ALF) and polymorphisms of the gene coding for the proinflammatory cytokine TNF-alpha are known to influence the clinical outcome in ALF. Recent reports provide robust evidence for a role of neuroinflammation(inflammation of the brain per se) in ALF with the cardinal features of neuroinflammation including activation of microglial cells and increased production in situ of pro-inflammatory cytokines such as TNF-alpha and interleukins IL-1beta and IL-6. Multiple liver-brain signalling pathways have been proposed to explain the phenomenon of neuroinflammation in liver failure and these include direct effects of systemically-derived cytokines, recruitment of monocytes relating to microglial activation as well as effects of liver failure-derived toxins and altered permeability of the blood-brain barrier. Synergistic mechanisms involving ammonia and cytokines have been proposed. Currently-available strategies aimed at lowering of blood ammonia such as lactulose, probiotics and rifaximin have the potential to dampen systemic inflammation as does the anti-oxidant N-acetyl cysteine, mild hypothermia and albumin dialysis. Experimental studies demonstrate that deletion of genes coding for TNF-alpha or IL-1 leads to attenuation of the CNS consequences of ALF and administration of the TNF-alpha receptor antagonist etanercept has comparable beneficial effects in experimental ALF. Together, these findings confirm a major role for central neuroinflammatory mechanisms in general and mechanisms involving TNF-alpha in particular in the pathogenesis of the cerebral consequences of ALF and open the door to novel therapeutic interventions in this often fatal disorder. PMID- 26481640 TI - Apolipoprotein E genotyping and questionnaire-based assessment of lifestyle risk factors in dyslipidemic patients with a family history of Alzheimer's disease: test development for clinical application. AB - The cholesterol-raising properties of the apolipoprotein E (APOE) epsilon-4 (epsilon-4) allele has been validated in the South African population. Mounting evidence supports the added value of APOE genotyping for the evaluation of cardiovascular risk in dyslipidemic patients beyond its established role in the diagnosis of late-onset Alzheimer's disease (AD). The aim of this study was to determine the potential benefits of combining AD family history with questionnaire-based lifestyle assessment to facilitate the clinical interpretation of APOE genotyping results. A total of 580 unrelated South African individuals prospectively enrolled in a chronic disease screening program incorporating a genetic component (2010-2015) was selected for inclusion in this study based on the presence (75) or absence (505) of AD family history. Biochemical assessment of their lipid profiles was performed according to standard laboratory protocols. All study participants were genotyped for the APOE epsilon-2/epsilon-3/epsilon-4 alleles using allele-specific TaqMan real-time polymerase chain reaction technology. In patients without a family history of AD, APOE genotype modified the relationship between alcohol intake and body mass index (p = 0.026), with a significant positive correlation noted between these parameters being limited to epsilon-4 allele carriers. APOE genotype also modified the association between alcohol intake and total serum cholesterol in patients with a positive family history of AD (p = 0.026). We demonstrated the benefits of a questionnaire-based approach for assessment of lifestyle risk factors to facilitate clinical interpretation of APOE genotyping results for targeted intervention in a genetic subgroup of dyslipidemic patients at increased risk for AD. PMID- 26481642 TI - Development of the Diabetes Technology Society Blood Glucose Monitor System Surveillance Protocol. AB - BACKGROUND: Inaccurate blood glucsoe monitoring systems (BGMSs) can lead to adverse health effects. The Diabetes Technology Society (DTS) Surveillance Program for cleared BGMSs is intended to protect people with diabetes from inaccurate, unreliable BGMS products that are currently on the market in the United States. The Surveillance Program will provide an independent assessment of the analytical performance of cleared BGMSs. METHODS: The DTS BGMS Surveillance Program Steering Committee included experts in glucose monitoring, surveillance testing, and regulatory science. Over one year, the committee engaged in meetings and teleconferences aiming to describe how to conduct BGMS surveillance studies in a scientifically sound manner that is in compliance with good clinical practice and all relevant regulations. RESULTS: A clinical surveillance protocol was created that contains performance targets and analytical accuracy-testing studies with marketed BGMS products conducted by qualified clinical and laboratory sites. This protocol entitled "Protocol for the Diabetes Technology Society Blood Glucose Monitor System Surveillance Program" is attached as supplementary material. CONCLUSION: This program is needed because currently once a BGMS product has been cleared for use by the FDA, no systematic postmarket Surveillance Program exists that can monitor analytical performance and detect potential problems. This protocol will allow identification of inaccurate and unreliable BGMSs currently available on the US market. The DTS Surveillance Program will provide BGMS manufacturers a benchmark to understand the postmarket analytical performance of their products. Furthermore, patients, health care professionals, payers, and regulatory agencies will be able to use the results of the study to make informed decisions to, respectively, select, prescribe, finance, and regulate BGMSs on the market. PMID- 26481641 TI - Physical Activity Capture Technology With Potential for Incorporation Into Closed Loop Control for Type 1 Diabetes. AB - Physical activity is an important determinant of glucose variability in type 1 diabetes (T1D). It has been incorporated as a nonglucose input into closed-loop control (CLC) protocols for T1D during the last 4 years mainly by 3 research groups in single center based controlled clinical trials involving a maximum of 18 subjects in any 1 study. Although physical activity data capture may have clinical benefit in patients with T1D by impacting cardiovascular fitness and optimal body weight achievement and maintenance, limited number of such studies have been conducted to date. Clinical trial registries provide information about a single small sample size 2 center prospective study incorporating physical activity data input to modulate closed-loop control in T1D that are seeking to build on prior studies. We expect an increase in such studies especially since the NIH has expanded support of this type of research with additional grants starting in the second half of 2015. Studies (1) involving patients with other disorders that have lasted 12 weeks or longer and tracked physical activity and (2) including both aerobic and resistance activity may offer insights about the user experience and device optimization even as single input CLC heads into real world clinical trials over the next few years and nonglucose input is introduced as the next advance. PMID- 26481643 TI - The Glucose Measurement Industry and Hemoglobin A1c: An Opportunity for Creative Destruction. AB - The MyStar Extra self-monitoring blood glucose (SMBG) system provides moving estimates of the patient's hemoglobin A1c (HbA1c). There is a treasure trove of highly accurate glucose data available from highly accurate SMBG, CGM and FGM along with highly accurate HPLC HbA1c. If Nathan's criteria are used to select subjects whose glucoses can be correlated to the HbA1c, then algorithms can be developed for robustly transforming glucose into HbA1c. These algorithms can then be implemented in any SMBG or with the CGM and FGM software. This calculated HbA1c would even be accurate with Nathan's excluded population thus reducing the use of fructosamine and glycated protein. Finally, the developer of these new algorithms is advised to use a specific approach for testing her algorithm. PMID- 26481644 TI - Identification of Main Factors Explaining Glucose Dynamics During and Immediately After Moderate Exercise in Patients With Type 1 Diabetes. AB - BACKGROUND: Physical activity is recommended for patients with type 1 diabetes (T1D). However, without proper management, it can lead to higher risk for hypoglycemia and impaired glycemic control. In this work, we identify the main factors explaining the blood glucose dynamics during exercise in T1D. We then propose a prediction model to quantify the glycemic drop induced by a mild to moderate physical activity. METHODS: A meta-data analysis was conducted over 59 T1D patients from 4 different studies in the United States and France (37 men and 22 women; 47 adults; weight, 71.4 +/- 10.6 kg; age, 42 +/- 10 years; 12 adolescents: weight, 60.7 +/- 12.5 kg; age, 14.0 +/- 1.4 years). All participants had physical activity between 3 and 5 pm at a mild to moderate intensity for approximately 30 to 45 min. A multiple linear regression analysis was applied to the data to identify the main parameters explaining the glucose dynamics during such physical activity. RESULTS: The blood glucose at the beginning of exercise ([Formula: see text]), the ratio of insulin on board over total daily insulin ([Formula: see text]) and the age as a categorical variable (1 for adult, 0 for adolescents) were significant factors involved in glucose evolution at exercise (all P < .05). The multiple linear regression model has an R-squared of .6. CONCLUSIONS: The main factors explaining glucose dynamics in the presence of mild to-moderate exercise in T1D have been identified. The clinical parameters are formally quantified using real data collected during clinical trials. The multiple linear regression model used to predict blood glucose during exercise can be applied in closed-loop control algorithms developed for artificial pancreas. PMID- 26481645 TI - Identification of microRNA-like RNAs from Curvularia lunata associated with maize leaf spot by bioinformation analysis and deep sequencing. AB - Deep sequencing of small RNAs is a useful tool to identify novel small RNAs that may be involved in fungal growth and pathogenesis. In this study, we used HiSeq deep sequencing to identify 747,487 unique small RNAs from Curvularia lunata. Among these small RNAs were 1012 microRNA-like RNAs (milRNAs), which are similar to other known microRNAs, and 48 potential novel milRNAs without homologs in other organisms have been identified using the miRBase(c) database. We used quantitative PCR to analyze the expression of four of these milRNAs from C. lunata at different developmental stages. The analysis revealed several changes associated with germinating conidia and mycelial growth, suggesting that these milRNAs may play a role in pathogen infection and mycelial growth. A total of 8334 target mRNAs for the 1012 milRNAs that were identified, and 256 target mRNAs for the 48 novel milRNAs were predicted by computational analysis. These target mRNAs of milRNAs were also performed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. To our knowledge, this study is the first report of C. lunata's milRNA profiles. This information will provide a better understanding of pathogen development and infection mechanism. PMID- 26481646 TI - Unrevealed mosaicism in the next-generation sequencing era. AB - Mosaicism refers to the presence in an individual of normal and abnormal cells that are genotypically distinct and are derived from a single zygote. The incidence of mosaicism events in the human body is underestimated as the genotypes in the mosaic ratio, especially in the low-grade mosaicism, stay unrevealed. This review summarizes various research outcomes and diagnostic questions in relation to different types of mosaicism. The impact of both tested biological material and applied method on the mosaicism detection rate is especially highlighted. As next-generation sequencing technologies constitute a promising methodological solution in mosaicism detection in the coming years, revisions in current diagnostic protocols are necessary to increase the detection rate of the unrevealed mosaicism events. Since mosaicism identification is a complex process, numerous examples of multistep mosaicism investigations are presented and discussed. PMID- 26481647 TI - Societal Implications of Health Insurance Coverage for Medically Necessary Services in the U.S. Transgender Population: A Cost-Effectiveness Analysis. AB - BACKGROUND: Recently, the Massachusetts Group Insurance Commission (GIC) prioritized research on the implications of a clause expressly prohibiting the denial of health insurance coverage for transgender-related services. These medically necessary services include primary and preventive care as well as transitional therapy. OBJECTIVE: To analyze the cost-effectiveness of insurance coverage for medically necessary transgender-related services. DESIGN: Markov model with 5- and 10-year time horizons from a U.S. societal perspective, discounted at 3% (USD 2013). Data on outcomes were abstracted from the 2011 National Transgender Discrimination Survey (NTDS). PATIENTS: U.S. transgender population starting before transitional therapy. INTERVENTIONS: No health benefits compared to health insurance coverage for medically necessary services. This coverage can lead to hormone replacement therapy, sex reassignment surgery, or both. MAIN MEASURES: Cost per quality-adjusted life year (QALY) for successful transition or negative outcomes (e.g. HIV, depression, suicidality, drug abuse, mortality) dependent on insurance coverage or no health benefit at a willingness to-pay threshold of $100,000/QALY. Budget impact interpreted as the U.S. per member-per-month cost. KEY RESULTS: Compared to no health benefits for transgender patients ($23,619; 6.49 QALYs), insurance coverage for medically necessary services came at a greater cost and effectiveness ($31,816; 7.37 QALYs), with an incremental cost-effectiveness ratio (ICER) of $9314/QALY. The budget impact of this coverage is approximately $0.016 per member per month. Although the cost for transitions is $10,000-22,000 and the cost of provider coverage is $2175/year, these additional expenses hold good value for reducing the risk of negative endpoints--HIV, depression, suicidality, and drug abuse. Results were robust to uncertainty. The probabilistic sensitivity analysis showed that provider coverage was cost-effective in 85% of simulations. CONCLUSIONS: Health insurance coverage for the U.S. transgender population is affordable and cost-effective, and has a low budget impact on U.S. society. Organizations such as the GIC should consider these results when examining policies regarding coverage exclusions. PMID- 26481648 TI - Molecular simulation assisted identification of Ca(2+) binding residues in TMEM16A. AB - Calcium-activated chloride channels (CaCCs) play vital roles in a variety of physiological processes. Transmembrane protein 16A (TMEM16A) has been confirmed as the molecular counterpart of CaCCs which greatly pushes the molecular insights of CaCCs forward. However, the detailed mechanism of Ca(2+) binding and activating the channel is still obscure. Here, we utilized a combination of computational and electrophysiological approaches to discern the molecular mechanism by which Ca(2+) regulates the gating of TMEM16A channels. The simulation results show that the first intracellular loop serves as a Ca(2+) binding site including D439, E444 and E447. The experimental results indicate that a novel residue, E447, plays key role in Ca(2+) binding. Compared with WT TMEM16A, E447Y produces a 30-fold increase in EC50 of Ca(2+) activation and leads to a 100-fold increase in Ca(2+) concentrations that is needed to fully activate the channel. The following steered molecular dynamic (SMD) simulation data suggests that the mutations at 447 reduce the Ca(2+) dissociation energy. Our results indicated that both the electrical property and the size of the side chain at residue 447 have significant effects on Ca(2+) dependent gating of TMEM16A. PMID- 26481649 TI - The statistics of virtual screening and lead optimization. AB - Analytic formulae are used to estimate the error for two virtual screening metrics, enrichment factor and area under the ROC curve. These analytic error estimates are then compared to bootstrapping error estimates, and shown to have excellent agreement with respect to area under the ROC curve and good agreement with respect to enrichment factor. The major advantage of the analytic formulae is that they are trivial to calculate and depend only on the number of actives and inactives and the measured value of the metric, information commonly reported in papers. In contrast to this, the bootstrapping method requires the individual compound scores. Methods for converting the error, which is calculated as a variance, into more familiar error bars are also discussed. PMID- 26481650 TI - Associations of Dispositional Mindfulness with Obesity and Central Adiposity: the New England Family Study. AB - PURPOSE: To evaluate whether dispositional mindfulness (defined as the ability to attend nonjudgmentally to one's own physical and mental processes) is associated with obesity and central adiposity. METHODS: Study participants (n = 394) were from the New England Family Study, a prospective birth cohort, with median age 47 years. Dispositional mindfulness was assessed using the Mindful Attention Awareness Scale (MAAS). Central adiposity was assessed using dual-energy X-ray absorptiometry (DXA) scans with primary outcomes android fat mass and android/gynoid ratio. Obesity was defined as body mass index >=30 kg/m(2). RESULTS: Multivariable-adjusted regression analyses demonstrated that participants with low vs. high MAAS scores were more likely to be obese (prevalence ratio for obesity = 1.34 (95 % confidence limit (CL): 1.02, 1.77)), adjusted for age, gender, race/ethnicity, birth weight, childhood socioeconomic status, and childhood intelligence. Furthermore, participants with low vs. high MAAS level had a 448 (95 % CL 39, 857) g higher android fat mass and a 0.056 (95 % CL 0.003, 0.110) greater android/gynoid fat mass ratio. Prospective analyses demonstrated that participants who were not obese in childhood and became obese in adulthood (n = 154) had -0.21 (95 % CL -0.41, -0.01; p = 0.04) lower MAAS scores than participants who were not obese in childhood or adulthood (n = 203). CONCLUSIONS: Dispositional mindfulness may be inversely associated with obesity and adiposity. Replication studies are needed to adequately establish whether low dispositional mindfulness is a risk factor for obesity and adiposity. PMID- 26481651 TI - Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: An Update. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life threatening mucocutaneous reactions, predominantly drug induced. The mortality rates for SJS and TEN are as high as 30 %, and short- and long-term morbidities are very common. SJS/TEN is one of the few dermatological diseases that constitute a true medical emergency. Early recognition and prompt and appropriate management can be lifesaving. In recent years, our understanding of the pathogenesis, clinical presentation, and management of SJS/TEN has improved. Nevertheless, in 2015, there are still no internationally accepted management guidelines. This review summarizes up-to-date insights on SJS/TEN and describes a protocol for assessment and treatment. We hope these suggested guidelines serve as a practical clinical tool in the management of SJS/TEN. The classic manifestation of SJS/TEN consists of initial "flu-like" symptoms (malaise, fever, anorexia) in the prodromal phase, followed by cutaneous and mucous membrane (ocular, oral, and genital) inflammation and pain, and other systemic involvement. Symptoms usually begin 4-28 days after the onset of drug intake. Treatment is multidisciplinary and includes identification and withdrawal of the culprit drug, transfer to a specialist unit, supportive care, medical treatment, communication, and provision of appropriate information and emotional support. PMID- 26481652 TI - Extraction optimization of medicinally important metabolites from Datura innoxia Mill.: an in vitro biological and phytochemical investigation. AB - BACKGROUND: The present study aims to probe the impact of polarity dependent extraction efficiency variation on pharmacological spectrum of Datura innoxia Mill. in order to reconnoiter its underexplored therapeutic potential. METHODS: A range of solvent extracts was subjected to phytochemical and biological assays to find the most proficient solvent system and plant part for each type of bioactivity. Total phenolic and flavonoid contents were determined colorimetrically and specific polyphenols were quantified by HPLC-DAD analysis. The samples were biologically evaluated by employing multimode antioxidant, cytotoxic, protein kinase inhibition and antimicrobial assays. RESULTS: Among all the solvents used, maximum percent extract recovery (33.28 %) was obtained in aqueous leaf extract. The highest amount of gallic acid equivalent phenolic and quercetin equivalent flavonoid content was obtained in the distilled water and ethyl acetate-ethanol extracts of leaf i.e., 29.91 +/- 0.12 and 15.68 +/- 0.18 mg/g dry weight (DW) respectively. Reverse phase HPLC-DAD based quantification revealed the presence of significant amounts of catechin, caffiec acid, apigenin and rutin ranging from 0.16 to 5.41 mg/g DW. Highest DPPH radical scavenging activity (IC50 = 16.14 MUg/ml) was displayed by the ethyl acetate-acetone stem extract. Maximum total antioxidant capacity and reducing power potential were recorded in the aqueous leaf and ethyl acetate stem extracts i.e., 46.98 +/- 0.24 and 15.35 +/- 0.61 mg ascorbic acid equivalent/g DW respectively. Cytotoxicity against brine shrimps categorized 25 % of the leaf, 16 % of the stem and 8.3 % of the fruit extracts as highly potent (LC50 <= 100 MUg/ml). Significant cytotoxicity against human leukemia (THP-1) cell line was exhibited by the chloroform and n-hexane fruit extracts with IC50 4.52 and 3.49 MUg/ml respectively. Ethyl acetate and methanol-chloroform extracts of leaf and stem exhibited conspicuous protein kinase inhibitory activity against Streptomyces 85E strain with 22 mm bald phenotype. A noteworthy antimicrobial activity was exhibited by leaf extracts against Micrococcus luteus and n-hexane fruit extract against Aspergillus niger (MIC 3.70 and 12.5 MUg/ml respectively). CONCLUSION: Multiple solvent system is a crucial variable to retrieve pharmacological potential of medicinal plants and D. innoxia can be envisaged as a novel source of natural antioxidants, antimicrobials and anticancer compounds. PMID- 26481653 TI - [Violence and health. Symptoms, consequences and treatment of victimized patients]. AB - BACKGROUND: Violence has many faces and often results in a variety of consequences. Some studies indicated different types of violence and health consequences in men and women. However, it is still unclear whether this is reflected in clinical context, for example in a patient sample of a German university hospital. OBJECTIVES: The primary goal of the present study was to analyze associations of violence with health, gender and social, economic, job related, psychological and physical consequences. In addition, the effects of psychological treatment were examined. MATERIALS AND METHODS: One line of research refers to the survey of more than 5000 patients of the university hospital Aachen, evaluating violence experience and several health complaints anonymously. Another line of research deals with detailed interviews with victims of violence and their experienced consequences. A final data source stems from the evaluation of psychological counseling of patients with prior experience of violence. Changes in subjectively perceived depressive symptoms and acceptance of the treatment are evaluated. RESULTS AND CONCLUSIONS: Experience of violence increases the risk for several health problems, especially the experience of multiple types of violence. The interviews showed that more than 60% of the victims had a clinical diagnosis--independent of sex. The risk for a clinical diagnosis increased with multiple violence experiences during childhood. Patients with a clinical diagnosis indicated more subjective consequences of violence, and consequences of violence were more pronounced in patients that experienced multiple types of violence. The good acceptance as well as the effects on symptomatology and other relevant therapeutic variables provides a first indication for a successful treatment of victims of violence in a clinical context. PMID- 26481654 TI - [Bright light therapy in seasonal bipolar depressions]. AB - INTRODUCTION: Bipolar disorders (BD) are frequent mood disorders associated with a poor prognosis mainly due to a high relapse rate. Depressive relapses may follow a seasonal cyclicality, and bright-light therapy (BLT) has been established as the treatment of choice for seasonal affective disorder (SAD). The use of BLT for seasonal unipolar depression is well known, but the scientific literature is much poorer on the management of seasonal depressive episodes in BD. In addition, some specificities related to BD must be taken into account. METHODS: We conducted a comprehensive review using Medline and Google Scholar databases up to August 2014 using the following keywords combination: "bipolar disorder" and "light therapy" or "phototherapy". Papers were included in the review if (a) they were published in an English or French-language peer-reviewed journal; (b) the study enrolled patients with BD and SAD; and (c) the diagnosis was made according to the DSM or ICD criteria. RESULTS: BLT was considered among the first-line treatments for SAD with a size effect similar to antidepressants. Most of the studies did not distinguish between patients with unipolar and bipolar disorders. However, it has been demonstrated that the most significant risk of BLT in patients with BD is the mood shift. Thus, the most important therapeutic adaptation corresponds to the use of an effective mood stabilizer, as with any antidepressant. Another therapeutic adaptation in first intention is that the times of exposure to light should be shifted from morning to midday. This review also includes therapeutic guidelines regarding the management of BLT in seasonal bipolar depressive episodes. DISCUSSION: There are very few specific data on seasonal bipolar depressive episodes. This literature review has highlighted that BLT should be handled as a regular antidepressant treatment in patients suffering from seasonal bipolar depressive episodes. PMID- 26481655 TI - Hypoxia Inhibits De Novo Vascular Assembly of Adipose-Derived Stromal/Stem Cell Populations, but Promotes Growth of Preformed Vessels. AB - Vascularization is critical for cell survival within tissue-engineered grafts. Adipose-derived stromal/stem cells (ASCs) are widely used in tissue engineering applications as they are a clinically relevant source of stem cells and endothelial progenitor cells. ASCs have previously been shown to self-assemble into pericyte-stabilized vascular networks in normoxic (20% O2) cultures. This capacity for de novo vascular assembly may accelerate graft vascularization in vivo rather than relying solely on angiogenic ingrowth. However, oxygen depletion within large cell-seeded grafts will be rapid, and it is unclear how this worsening hypoxic environment will impact the vascular assembly of the transplanted cells. The objectives of this study were to determine whether ASC derived vessels could grow in hypoxia and to assess whether the vessel maturity (i.e., individual cells vs. preformed vessels) influenced this hypoxic response. Utilizing an in vitro vascularization model, ASCs were encapsulated within fibrin gels and cultured in vitro for up to 6 days in either normoxia (20% O2) or hypoxia (0.2% or 2% O2). In a subsequent experiment, vessels were allowed to preform in normoxia for 6 days before an additional 6 days of either normoxia or hypoxia. Viability, vessel growth, pericyte coverage, proliferation, metabolism, and angiogenic factor expression were assessed for each experimental approach. Vessel growth was dramatically inhibited in both moderate and severe hypoxia (47% and 11% total vessel length vs. normoxia, respectively), despite maintaining high cell viability and upregulating endogenous expression of vascular endothelial growth factor in hypoxia. Bromodeoxyuridine labeling indicated significantly reduced proliferation of endothelial cells in hypoxia. In contrast, when vascular networks were allowed to preform for 6 days in normoxia, vessels not only survived but also continued to grow more in hypoxia than those maintained in normoxia. These findings demonstrate that vascular assembly and growth are tightly regulated by oxygen tension and may be differentially affected by hypoxic conditions based on the maturity of the vessels. Understanding this relationship is critical to developing effective approaches to engineer viable tissue engineered grafts in vivo. PMID- 26481657 TI - Novel, potent, selective and cellular active ABC type PTP1B inhibitors containing (methanesulfonyl-phenyl-amino)-acetic acid methyl ester phosphotyrosine mimetic. AB - Protein tyrosine phosphatase 1B (PTP1B) which plays an important role in the negative regulation of insulin and leptin pathway has emerged as a novel promising therapeutic target for the treatment of type 2 diabetes mellitus and obesity. Upon careful study, a series of novel scaffold and simple synthesis method inhibitors were discovered based on the analysis of X-ray crystal structures of PTP1B/inhibitor complexes and docking simulations. Among them, compound P7 exhibited high inhibitory activity (IC50=222 nM) with moderate selectivity (8-fold) over T-cell PTPase (TCPTP) through interacting with the A, B and C binding sites of PTP1B enzyme. Further studies on cellular activities revealed that compound P7 could enhance insulin-mediated IRbeta phosphorylation and insulin-stimulated glucose uptake. PMID- 26481656 TI - Carotid Anatomy Does Not Predict the Risk of New Ischaemic Brain Lesions on Diffusion-Weighted Imaging after Carotid Artery Stenting in the ICSS-MRI Substudy. AB - INTRODUCTION: The International Carotid Stenting Study (ICSS, ISRCTN25337470) randomized patients with recently symptomatic carotid artery stenosis > 50% to carotid artery stenting (CAS) or endarterectomy. CAS increased the risk of new brain lesions visible on diffusion-weighted magnetic resonance imaging (DWI-MRI) more than endarterectomy in the ICSS-MRI Substudy. The predictors of new post stenting DWI lesions were assessed in these patients. METHODS: ICSS-MRI Substudy patients allocated to CAS were studied. Baseline or pre-stenting catheter angiograms were rated to determine carotid anatomy. Baseline patient demographics and the influence of plaque length, plaque morphology, internal carotid angulation, and external or common carotid atheroma were examined in negative binomial regression models. RESULTS: A total of 115 patients (70% male, average age 70.4) were included; 50.4% had at least one new DWI-MRI-positive lesion following CAS. Independent risk factors increasing the number of new lesions were a left-sided stenosis (incidence risk ratio [IRR] 1.59, 95% CI 1.04-2.44, p = .03), age (IRR 2.10 per 10-year increase in age, 95% CI 1.61-2.74, p < .01), male sex (IRR 2.83, 95% CI 1.72-4.67, p < .01), hypertension (IRR 2.04, 95% CI 1.25 3.33, p < .01) and absence of cardiac failure (IRR 6.58, 95% CI 1.23-35.07, p = .03). None of the carotid anatomical features significantly influenced the number of post-procedure lesions. CONCLUSION: Carotid anatomy seen on pre-stenting catheter angiography did not predict of the number of ischaemic brain lesions following CAS. PMID- 26481658 TI - Synthesis of fucosylated lacto-N-tetraose using whole-cell biotransformation. AB - Fucosylated oligosaccharides present a predominant group of free oligosaccharides found in human milk. Here, a microbial conversion of lactose, D-glucose and L fucose to fucosylated lacto-N-tetraose by growing Escherichia coli cultures is presented. The recombinant expression of genes encoding for the beta1,3-N acetylglucosaminyltransferase (LgtA) and the beta1,3-galactosyltransferase (WbgO) enables the whole-cell biotransformation of lactose to lacto-N-tetraose. By the additional expression of a recombinant GDP-L-fucose salvage pathway together with a bacterial fucosyltransferase, lacto-N-tetraose is further converted into the respective fucosylated compounds. The expression of a gene encoding the alpha1,2 fucosyltransferase (FutC) in the lacto-N-tetraose producing E. coli strain led to the formation of lacto-N-fucopentaose I, whereas the expression of a gene encoding the alpha1,4-fucosyltransferase (FucT14) mainly led to the conversion of lacto-N-tetraose to lacto-N-difucohexaose II. PMID- 26481659 TI - New macrocyclic analogs of the natural histone deacetylase inhibitor FK228; design, synthesis and preliminary biological evaluation. AB - Among the natural histone deacetylase inhibitors (HDACi), the bicyclic depsipeptide macrolactone FK228 stands out for its unique chemical structure and mechanism of action. In order to expand the chemical diversity, exploiting the FK228 peculiar structure, we have synthesized a collection of 24 simplified novel analogs. A first series consists of bicyclic macrolactones, where the carboxy terminus of the natural compound was substituted by peptidomimetic aminomethylphenylacetic acid derivatives. These analogs, 7a-i, showed submicromolar cytotoxic activity, even though very low inhibitory activity against HDAC enzymes, suggesting that most probably they behave with a mechanism different from the natural compound. One of the most active members in the group, 7g, was evaluated in vivo and exhibited significant antitumor activity. This evidence supports that the activity is unrelated to HDAC inhibition and these compounds represent a novel series of promising active agents. Another analog series consists of monocyclic macrolactones, 9a-c and 10a-d which lack the disulfide bridge and bear the protected sulfur on the linear external chain; they showed similar cytotoxic activities compared to the natural compound, but proved to be very sensitive to the nature of the sulfur protection. In fact, when the sulfur was protected by an 1-octanoyl residue, like in 9b, the product displayed a one digit nanomolar activity. The results provide evidence that our approach may be followed to develop novel series of FK228 analogs. PMID- 26481660 TI - Folate and vitamin B12 status and dietary intake of anaemic adolescent schoolgirls in the delta region of Myanmar. AB - The aim of the present study was to assess the prevalence of deficiency of folate and vitamin B12 and, simultaneously, the nutrient intake adequacy of folate, vitamin B12, iron, vitamin A, vitamin C, vitamin B6 and calcium in 391 adolescent anaemic (Hb<120 g/l) schoolgirls living in the delta region of Myanmar (Burma). Dietary intakes were assessed using a 3 d estimated food record. The distribution of observed intakes calculated from the food records were adjusted for usual intakes, and the prevalence of inadequacy was estimated using the estimated average requirement cut-point method. Median (first, third quartile) serum folate and vitamin B12 concentrations were 6.5 (4.6, 8.5) nmol/l and 612.8 (443.2, 795.2) pmol/l, respectively. The prevalence of folate deficiency defined as <6.8 nmol/l was 54 %; however, vitamin B12 deficiency defined as <148 pmol/l was negligible (<1 %). The prevalence of inadequate intake of folate was high (100 %) as was the prevalence of inadequate intakes of vitamin A, vitamin C, vitamin B6 and calcium, ranging from 60 to 100 %. Red meat or poultry was rarely consumed, but fish was consumed on a daily basis. Green leafy vegetables were also consumed frequently but consumption of dairy products was uncommon. Folate deficiency was high, and the prevalence of inadequate intake of folate among other key micronutrients was relatively common in this sample of anaemic adolescent schoolgirls. Appropriate strategies such as food fortification and dietary diversification are needed to improve the micronutrient status of these young women to ensure optimal health and future reproductive success. PMID- 26481661 TI - Implementing and expanding HIV testing in immigrant populations in Europe: Comparing guideline's recommendations and expert's opinions. AB - Immigrant populations, especially those from endemic countries, living in the European Union (EU) suffer a disproportionate burden of HIV, delayed diagnosis and poorer access to antiretroviral treatment. While International Organisations are developing recommendations aimed at increasing the uptake of HIV testing, the feasibility and real outcomes of these measures remain unexplored. The aim of this review was, firstly to identify the recommendations of the main International Organisations (IO) on HIV testing in immigrants. Secondly, to describe the challenges for implementing and expanding HIV testing and counselling interventions targeting immigrants by interviewing key informants. The importance of HIV testing in immigrants is discussed, along with the appropriateness of universal HIV testing approaches vs most at risk targeted approaches. Also addressed is, pre- and post-HIV test counselling characteristics and community initiatives suitable to reach this population and, finally the legal issues regarding access to treatment for illegal immigrants. PMID- 26481662 TI - [Prevalence of human inmunodeficiency virus and hepatitis C virus markers in forensic autopsy cases in Barcelona and Lleida]. PMID- 26481665 TI - Epidermal burn at a PEG site. PMID- 26481663 TI - PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth. AB - Phosphoenolpyruvate carboxykinase (PEPCK) is well known for its role in gluconeogenesis. However, PEPCK is also a key regulator of TCA cycle flux. The TCA cycle integrates glucose, amino acid, and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. We show here an unexpected role for PEPCK in promoting cancer cell proliferation in vitro and in vivo by increasing glucose and glutamine utilization toward anabolic metabolism. Unexpectedly, PEPCK also increased the synthesis of ribose from non-carbohydrate sources, such as glutamine, a phenomenon not previously described. Finally, we show that the effects of PEPCK on glucose metabolism and cell proliferation are in part mediated via activation of mTORC1. Taken together, these data demonstrate a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation. PMID- 26481664 TI - Anionic Phospholipids Stabilize RecA Filament Bundles in Escherichia coli. AB - We characterize the interaction of RecA with membranes in vivo and in vitro and demonstrate that RecA binds tightly to the anionic phospholipids cardiolipin (CL) and phosphatidylglycerol (PG). Using computational models, we identify two regions of RecA that interact with PG and CL: (1) the N-terminal helix and (2) loop L2. Mutating these regions decreased the affinity of RecA to PG and CL in vitro. Using 3D super-resolution microscopy, we demonstrate that depleting Escherichia coli PG and CL altered the localization of RecA foci and hindered the formation of RecA filament bundles. Consequently, E. coli cells lacking aPLs fail to initiate a robust SOS response after DNA damage, indicating that the membrane acts as a scaffold for nucleating the formation of RecA filament bundles and plays an important role in the SOS response. PMID- 26481666 TI - Comparison of Hypoalgesic Effects of Neural Stretching vs Neural Gliding: A Randomized Controlled Trial. AB - OBJECTIVE: The purpose of this study was to evaluate the immediate mechanical hypoalgesic effect of neural mobilization in asymptomatic subjects. We also compared neural gliding vs neural stretching to see which produced greater hypoalgesic effects in asymptomatic subjects. METHODS: Forty-five asymptomatic subjects (20 men and 25 women; mean +/- SD age, 20.8 +/- 2.83 years) were randomly allocated into 3 groups: the neural glide group, the neural stretch group, and the placebo group. Each subject received 1 treatment session. Outcome measures included bilateral pressure pain threshold measured at the trigeminal, cervical, and tibialis anterior points, assessed pre-treatment and immediately post-treatment by a blinded assessor. Three-way repeated-measures analysis of variance was used to evaluate changes in pressure pain threshold, with group (experimental or control) as the between-subjects variable and time (pre-, post treatment) or side (dominant, nondominant) as the within-subjects variable. RESULTS: Group differences were identified between neural mobilization groups and the placebo group. Changes occurred in all of the pressure pain threshold measures for neural gliding, and in all but the trigeminal point for neural stretch. No changes in the pressure pain threshold measures occurred in the placebo group. CONCLUSIONS: This research provides new experimental evidence that neural mobilization produces an immediate widespread hypoalgesic effect vs placebo but neural gliding produces hypoalgesic effects in more body sites than neural stretching. PMID- 26481667 TI - TNFRs and Control of Chronic LCMV Infection: Implications for Therapy. AB - The control of persistent viral infections requires the immune system to limit the spread of the virus while avoiding immunopathology. Recent studies have revealed that members of the tumor necrosis factor receptor (TNFR) superfamily play unique and pivotal roles in control of chronic lymphocytic choriomeningitis virus (LCMV) infection and in some settings can tip the balance between immune control and immune pathology. We review these findings and discuss how our understanding of the role of TNFRs in the immune response to chronic LCMV infection may shed light on what happens during HIV infection in humans. We discuss preclinical models of TNF/TNFR family-targeted immunotherapy of chronic LCMV infection and evaluate which TNFRs present the most promising targets for immune intervention. PMID- 26481669 TI - Genome editing by natural genetic transformation in Streptococcus mutans. AB - Classical mutagenesis strategies using selective markers linked to designed mutations are powerful and widely applicable tools for targeted mutagenesis via natural genetic transformation in bacteria and archaea. However, the markers that confer power are also potentially problematic as they can be cumbersome, risk phenotypic effects of the inserted genes, and accumulate as unwanted genes during successive mutagenesis cycles. Alternative mutagenesis strategies use temporary plasmid or cassette insertions and can in principle achieve equally flexible mutation designs, but design of suitable counter-selected markers can be complex. All these drawbacks are eased by use of direct genome editing. Here we describe a strategy for directly editing the genome of S. mutans, which is applied to the widely studied reference strain UA159 (ATCC 700610) and has the advantage of extreme simplicity, requiring construction of only one synthetic donor amplicon and a single transformation step, followed by a simple PCR screen among a few dozen clones to identify the desired mutant. The donor amplicon carries the mutant sequence and extensive flanking segments of homology, which ensure efficient and precise integration by the recombination machinery specific to competent cells. The recipients are highly competent cells, in a state achieved by treatment with a synthetic competence pheromone. PMID- 26481668 TI - Leptin Deficiency Shifts Mast Cells toward Anti-Inflammatory Actions and Protects Mice from Obesity and Diabetes by Polarizing M2 Macrophages. AB - Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue (WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro- and anti-inflammatory cytokines, but do not affect T cell differentiation. Rampant body weight gain in ob/ob mice, a strain that lacks leptin, associates with reduced MC content in WAT. In ob/ob mice, genetic depletion of MCs exacerbates obesity and diabetes, and repopulation of ex vivo expanded ob/ob MCs ameliorates these diseases. PMID- 26481670 TI - Modulation of Hippocampal Activity by Vagus Nerve Stimulation in Freely Moving Rats. AB - BACKGROUND: Vagus Nerve Stimulation (VNS) has seizure-suppressing effects but the underlying mechanism is not fully understood. To further elucidate the mechanisms underlying VNS-induced seizure suppression at a neurophysiological level, the present study examined effects of VNS on hippocampal excitability using dentate gyrus evoked potentials (EPs) and hippocampal electroencephalography (EEG). METHODS: Male Sprague-Dawley rats were implanted with a VNS electrode around the left vagus nerve. A bipolar stimulation electrode was implanted in the left perforant path and a bipolar recording electrode was implanted in the left dentate gyrus for EEG and dentate field EP recording. Following recovery, VNS was applied in freely moving animals, using a duty cycle of 7 s on/18 s off, 30 Hz frequency, 250 us pulse width, and an intensity of either 0 (SHAM), 25 uA or 1000 uA, while continuously monitoring EEG and dentate field EPs. RESULTS: VNS at 1000 uA modulated dentate field EPs by decreasing the field excitatory post-synaptic potential (fEPSP) slope and increasing the latency and amplitude of the population spike. It additionally influenced hippocampal EEG by slowing theta rhythm from 7 Hz to 5 Hz and reducing theta peak and gamma band power. No effects were observed in the SHAM or 25 uA VNS conditions. CONCLUSION: VNS modulated hippocampal excitability of freely moving rats in a complex way. It decreased synaptic efficacy, reflected by decreased fEPSP slope and EEG power, but it simultaneously facilitated dentate granule cell discharge indicating depolarization of dentate granule cells. PMID- 26481671 TI - Mapping entrained brain oscillations during transcranial alternating current stimulation (tACS). AB - Transcranial alternating current stimulation (tACS), a non-invasive and well tolerated form of electric brain stimulation, can influence perception, memory, as well as motor and cognitive function. While the exact underlying neurophysiological mechanisms are unknown, the effects of tACS are mainly attributed to frequency-specific entrainment of endogenous brain oscillations in brain areas close to the stimulation electrodes, and modulation of spike timing dependent plasticity reflected in gamma band oscillatory responses. tACS-related electromagnetic stimulator artifacts, however, impede investigation of these neurophysiological mechanisms. Here we introduce a novel approach combining amplitude-modulated tACS during whole-head magnetoencephalography (MEG) allowing for artifact-free source reconstruction and precise mapping of entrained brain oscillations underneath the stimulator electrodes. Using this approach, we show that reliable reconstruction of neuromagnetic low- and high-frequency oscillations including high gamma band activity in stimulated cortical areas is feasible opening a new window to unveil the mechanisms underlying the effects of stimulation protocols that entrain brain oscillatory activity. PMID- 26481672 TI - An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging. AB - In this paper we describe a method for retrospective estimation and correction of eddy current (EC)-induced distortions and subject movement in diffusion imaging. In addition a susceptibility-induced field can be supplied and will be incorporated into the calculations in a way that accurately reflects that the two fields (susceptibility- and EC-induced) behave differently in the presence of subject movement. The method is based on registering the individual volumes to a model free prediction of what each volume should look like, thereby enabling its use on high b-value data where the contrast is vastly different in different volumes. In addition we show that the linear EC-model commonly used is insufficient for the data used in the present paper (high spatial and angular resolution data acquired with Stejskal-Tanner gradients on a 3T Siemens Verio, a 3T Siemens Connectome Skyra or a 7T Siemens Magnetome scanner) and that a higher order model performs significantly better. The method is already in extensive practical use and is used by four major projects (the WU-UMinn HCP, the MGH HCP, the UK Biobank and the Whitehall studies) to correct for distortions and subject movement. PMID- 26481673 TI - Decoding the direction of imagined visual motion using 7T ultra-high field fMRI. AB - There is a long-standing debate about the neurocognitive implementation of mental imagery. One form of mental imagery is the imagery of visual motion, which is of interest due to its naturalistic and dynamic character. However, so far only the mere occurrence rather than the specific content of motion imagery was shown to be detectable. In the current study, the application of multi-voxel pattern analysis to high-resolution functional data of 12 subjects acquired with ultra high field 7T functional magnetic resonance imaging allowed us to show that imagery of visual motion can indeed activate the earliest levels of the visual hierarchy, but the extent thereof varies highly between subjects. Our approach enabled classification not only of complex imagery, but also of its actual contents, in that the direction of imagined motion out of four options was successfully identified in two thirds of the subjects and with accuracies of up to 91.3% in individual subjects. A searchlight analysis confirmed the local origin of decodable information in striate and extra-striate cortex. These high accuracy findings not only shed new light on a central question in vision science on the constituents of mental imagery, but also show for the first time that the specific sub-categorical content of visual motion imagery is reliably decodable from brain imaging data on a single-subject level. PMID- 26481674 TI - fMRI neurofeedback of amygdala response to aversive stimuli enhances prefrontal limbic brain connectivity. AB - Down-regulation of the amygdala with real-time fMRI neurofeedback (rtfMRI NF) potentially allows targeting brain circuits of emotion processing and may involve prefrontal-limbic networks underlying effective emotion regulation. Little research has been dedicated to the effect of rtfMRI NF on the functional connectivity of the amygdala and connectivity patterns in amygdala down regulation with neurofeedback have not been addressed yet. Using psychophysiological interaction analysis of fMRI data, we present evidence that voluntary amygdala down-regulation by rtfMRI NF while viewing aversive pictures was associated with increased connectivity of the right amygdala with the ventromedial prefrontal cortex (vmPFC) in healthy subjects (N=16). In contrast, a control group (N=16) receiving sham feedback did not alter amygdala connectivity (Group*Condition t-contrast: p<.05 at cluster-level). Task-dependent increases in amygdala-vmPFC connectivity were predicted by picture arousal (beta=.59, p<.05). A dynamic causal modeling analysis with Bayesian model selection aimed at further characterizing the underlying causal structure and favored a bottom-up model assuming predominant information flow from the amygdala to the vmPFC (xp=.90). The results were complemented by the observation of task-dependent alterations in functional connectivity of the vmPFC with the visual cortex and the ventrolateral PFC in the experimental group (Condition t-contrast: p<.05 at cluster-level). Taken together, the results underscore the potential of amygdala fMRI neurofeedback to influence functional connectivity in key networks of emotion processing and regulation. This may be beneficial for patients suffering from severe emotion dysregulation by improving neural self-regulation. PMID- 26481675 TI - Differential aging of cerebral white matter in middle-aged and older adults: A seven-year follow-up. AB - The few extant reports of longitudinal white matter (WM) changes in healthy aging, using diffusion tensor imaging (DTI), reveal substantial differences in change across brain regions and DTI indices. According to the "last-in-first-out" hypothesis of brain aging late-developing WM tracts may be particularly vulnerable to advanced age. To test this hypothesis we compared age-related changes in association, commissural and projection WM fiber regions using a skeletonized, region of interest DTI approach. Using linear mixed effect models, we evaluated the influences of age and vascular risk at baseline on seven-year changes in three indices of WM integrity and organization (axial diffusivity, AD, radial diffusivity, RD, and fractional anisotropy, FA) in healthy middle-aged and older adults (mean age=65.4, SD=9.0years). Association fibers showed the most pronounced declines over time. Advanced age was associated with greater longitudinal changes in RD and FA, independent of fiber type. Furthermore, older age was associated with longitudinal RD increases in late-developing, but not early-developing projection fibers. These findings demonstrate the increased vulnerability of later developing WM regions and support the "last-in-first-out" hypothesis of brain aging. PMID- 26481676 TI - MAOA-VNTR polymorphism modulates context-dependent dopamine release and aggressive behavior in males. AB - A recent [(18)F]FDOPA-PET study reports negative correlations between dopamine synthesis rates and aggressive behavior. Since dopamine is among the substrates for monoamine oxidase A (MAOA), this investigation examines whether functional allelic variants of the MAOA tandem repeat (VNTR) promotor polymorphism, which is known to modulate aggressive behavior, influences dopamine release and aggression in response to violent visual stimuli. We selected from a genetic prescreening sample, strictly case-matched groups of 2*12 healthy male subjects with VNTRs predictive of high (MAOA-High) and low (MAOA-Low) MAOA expression. Subjects underwent pairs of PET sessions (dopamine D2/3 ligand [(18)F]DMFP) while viewing a movie of neutral content, versus violent content. Directly afterwards, aggressive behavior was assessed by the Point Subtraction Aggression Paradigm (PSAP). Finally, PET data of 23 participants and behavioral data of 22 participants were analyzed due to post hoc exclusion criteria. In the genetic prescreening sample MAOA-Low carriers had significantly increased scores on the Buss-Perry Aggression Questionnaire. In the PET-study-group, aggressive behavior under the emotional neutral condition was significantly higher in the MAOA-Low group. Interestingly, the two MAOA-groups showed inverse dopaminergic and behavioral reactions to the violent movie: The MAOA-High group showed higher dopamine release and increased aggression after the violent movie; MAOA-Low subjects showed decreases in aggressive behavior and no consistent dopamine release. These results indicate a possible impact of the MAOA-promotor polymorphism on the neurobiological modulation of aggressive behavior. However, the data do not support approaches stating that MAOA-Low fosters aggression by a simple pro-dopaminergic mechanism. PMID- 26481677 TI - Tractography atlas-based spatial statistics: Statistical analysis of diffusion tensor image along fiber pathways. AB - The quantitative analysis of diffusion tensor image (DTI) data has attracted increasing attention in recent decades for studying white matter (WM) integrity and development. Among the current DTI analysis methods, tract-based spatial statistics (TBSS), as a pioneering approach for the voxelwise analysis of DTI data, has gained a lot of popularity due to its user-friendly framework. However, in recent years, the reliability and interpretability of TBSS have been challenged by several works, and several improvements over the original TBSS pipeline have been suggested. In this paper, we propose a new DTI statistical analysis method, named tractography atlas-based spatial statistics (TABSS). It doesn't rely on the accurate alignment of fractional anisotropy (FA) images for population analysis and gets rid of the skeletonization procedures of TBSS, which have been indicated as the major sources of error. Furthermore, TABSS improves the interpretability of results by directly reporting the resulting statistics on WM tracts, waiving the need of a WM atlas in the interpretation of the results. The feasibility of TABSS was evaluated in an example study to show age-related FA alternation pattern of healthy human brain. Through this preliminary study, it is validated that TABSS can provide detailed statistical results in a comprehensive and easy-to-understand way. PMID- 26481679 TI - Matched signal detection on graphs: Theory and application to brain imaging data classification. AB - Motivated by recent progress in signal processing on graphs, we have developed a matched signal detection (MSD) theory for signals with intrinsic structures described by weighted graphs. First, we regard graph Laplacian eigenvalues as frequencies of graph-signals and assume that the signal is in a subspace spanned by the first few graph Laplacian eigenvectors associated with lower eigenvalues. The conventional matched subspace detector can be applied to this case. Furthermore, we study signals that may not merely live in a subspace. Concretely, we consider signals with bounded variation on graphs and more general signals that are randomly drawn from a prior distribution. For bounded variation signals, the test is a weighted energy detector. For the random signals, the test statistic is the difference of signal variations on associated graphs, if a degenerate Gaussian distribution specified by the graph Laplacian is adopted. We evaluate the effectiveness of the MSD on graphs both with simulated and real data sets. Specifically, we apply MSD to the brain imaging data classification problem of Alzheimer's disease (AD) based on two independent data sets: 1) positron emission tomography data with Pittsburgh compound-B tracer of 30 AD and 40 normal control (NC) subjects, and 2) resting-state functional magnetic resonance imaging (R-fMRI) data of 30 early mild cognitive impairment and 20 NC subjects. Our results demonstrate that the MSD approach is able to outperform the traditional methods and help detect AD at an early stage, probably due to the success of exploiting the manifold structure of the data. PMID- 26481678 TI - How the brain learns how few are "many": An fMRI study of the flexibility of quantifier semantics. AB - Previous work has shown that the meaning of a quantifier such as "many" or "few" depends in part on quantity. However, the meaning of a quantifier may vary depending on the context, e.g. in the case of common entities such as "many ants" (perhaps several thousands) compared to endangered species such as "many pandas" (perhaps a dozen). In a recent study (Heim et al., 2015 Front. Psychol.) we demonstrated that the relative meaning of "many" and "few" may be changed experimentally. In a truth value judgment task, displays with 40% of circles in a named color initially had a low probability of being labeled "many". After a training phase, the likelihood of acceptance 40% as "many" increased. Moreover, the semantic learning effect also generalized to the related quantifier "few" which had not been mentioned in the training phase. Thus, fewer 40% arrays were considered "few." In the present study, we tested the hypothesis that this semantic adaptation effect was supported by cytoarchitectonic Brodmann area (BA) 45 in Broca's region which may contribute to semantic evaluation in the context of language and quantification. In an event-related fMRI study, 17 healthy volunteers performed the same paradigm as in the previous behavioral study. We found a relative signal increase when comparing the critical, trained proportion to untrained proportions. This specific effect was found in left BA 45 for the trained quantifier "many", and in left BA 44 for both quantifiers, reflecting the semantic adjustment for the untrained but related quantifier "few." These findings demonstrate the neural basis for processing the flexible meaning of a quantifier, and illustrate the neuroanatomical structures that contribute to variable meanings that can be associated with a word when used in different contexts. PMID- 26481680 TI - [Indicated preterm birth in a type 3 maternity ward: Evaluation of practices]. AB - The purpose of this study was to evaluate the proportion of indicated preterm births among all preterm births in a type 3 maternity ward; to assess practices in terms of mode of delivery in such cases; and to analyse the observed outcomes for such deliveries. MATERIALS AND METHODS: A retrospective study was conducted in the obstetrics department of the regional university hospital of Tours (type 3 maternity ward) over a 22-month period. Women with an indicated preterm birth between 22 and 37 weeks of gestation, for whom vaginal delivery was possible, were included in the study. For every woman, the choice of mode of delivery (caesarean before labour or induction of labour) as well as maternal, obstetrical and neonatal factors were recorded. RESULTS: From January 2012 to October 2013, 539 deliveries were preterm among which 42.5% were indicated preterm births. Out of 114 women for whom vaginal delivery was possible, 33.3% had a caesarean before labour and 66.7% had an induction of labour. The choice of mode of delivery is influenced by various factors such as local conditions, gestational age and type of obstetrical pathologies. Moreover, birth weight and Apgar score are significantly lower and the hospitalisation rate of newborns is significantly higher in the "caesarean before labour" group. CONCLUSION: Indicated preterm births represent almost half of preterm births in the maternity ward. A third of these indicated preterm births were caesareans before labour. Due to the neonatal morbidity resulting from indicated preterm birth, it is essential to regularly reassess indications of indicated preterm birth. PMID- 26481681 TI - [Assessment of shoulder dystocia related knowledge among French obstetrics and gynecology residents]. AB - OBJECTIVE: To study the related knowledge of French residents in obstetrics concerning maneuvers for shoulder dystocia (SD). MATERIALS AND METHODS: Multicenter descriptive transversal study conducted from June to September 2014. Data collection was performed through questionnaires sent by email to French resident in obstetrics. RESULTS: Among the 1080 questionnaires sent, 366 responses were obtained with a response rate of 33.9%. One hundred and forty three residents (39.1%) were in the first part of their training (<=5th semester) and 60.9% (n=223) were in the second part of their training. Theoretical training on the SD was provided to 88.2% of resident (n=323). In total, 38.8% (n=142) obtained their French degree in mechanical and technical obstetric and among them 77.5% (n=110) had the opportunity to train on simulators and dummies. Concerning their practical experiences, 31.5% (n=45) residents <=5th semester reported having experienced SD during their residency vs 58.3% (n=130) amongst oldest residents (P<0.001). In the second part of residency, 40% of residents (n=89) expressed to feel able to manage shoulder dystocia. Only 19.1% (n=70) were satisfied with their residency training program vs 39.1% (n=143) who were unsatisfied. CONCLUSION: Our study showed that less than one resident out of two (40%) felt able to perform maneuvers for SD in the second part of residency. We think that simulation activities should be mandatory for residency training programs in Obstetrics and Gynecology, which have to develop dependable measures to assess resident competencies to execute practical maneuvers for clinical emergencies in obstetrics. PMID- 26481682 TI - [Prescribed and dispensed in the third trimester of pregnancy drugs: What practices and risks?]. AB - OBJECTIVE: The aim of the study was to describe the prescribing of drugs to pregnant women during the third trimester of pregnancy. PATIENTS AND METHODS: The retrospective analysis is interested by pregnant women from August 2009 to April 2011, living in Franche-Comte. The used data are recorded in the database of the French Health Insurance Service. Drugs prescribing were analyzed and classified according to three categories: drugs that are contraindicated, not recommended drugs and drugs that are used. This classification is based on two databases: the Summaries of Product Characteristics of Vidal 2010 and data from the National Security Agency of Medicines. The potential exposure of patients was pointed out. RESULTS: On 15,027 patients, 80% had a prescription. Six percent of prescriptions containing drugs not recommended and 1% drugs that contraindicated. Therapeutic classes identified are analgesics, anti-infective drugs and medicines supplementing with vitamins and minerals. Contraindicated drugs (10%) are NSAIDs, rubella vaccine, cyclins and ACE inhibitors and ARBs. Approximately 2.7% of women were potentially exposed to these drugs. DISCUSSION AND CONCLUSION: Despite the recommendations of the ANSM, some drugs that are contraindicated are prescribed for pregnant women in their third trimester of pregnancy. In the absence of studies, the decision must be made on a case by case basis by assessing the risk benefit ratio. Particular care is to bring about the drugs taken in self medication. Information and advice are key steps to avoid incidents. PMID- 26481684 TI - Oct1 and OCA-B are selectively required for CD4 memory T cell function. AB - Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ~50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory. PMID- 26481685 TI - TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. AB - Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis. PMID- 26481687 TI - Auditory P3a and P3b neural generators in schizophrenia: An adaptive sLORETA P300 localization approach. AB - The present study investigates the neural substrates underlying cognitive processing in schizophrenia (Sz) patients. To this end, an auditory 3-stimulus oddball paradigm was used to identify P3a and P3b components, elicited by rare distractor and rare-target tones, respectively. Event-related potentials (ERP) were recorded from 31 Sz patients and 38 healthy controls. The P3a and P3b brain source generators were identified by time-averaging of low-resolution brain electromagnetic tomography (LORETA) current density images. In contrast with the commonly used fixed window of interest (WOI), we proposed to apply an adaptive WOI, which takes into account subjects' P300 latency variability. Our results showed different P3a and P3b source activation patterns in both groups. P3b sources included frontal, parietal and limbic lobes, whereas P3a response generators were localized over bilateral frontal and superior temporal regions. These areas have been related to the discrimination of auditory stimulus and to the inhibition (P3a) or the initiation (P3b) of motor response in a cognitive task. In addition, differences in source localization between Sz and control groups were observed. Sz patients showed lower P3b source activity in bilateral frontal structures and the cingulate. P3a generators were less widespread for Sz patients than for controls in right superior, medial and middle frontal gyrus. Our findings suggest that target and distractor processing involves distinct attentional subsystems, both being altered in Sz. Hence, the study of neuroelectric brain information can provide further insights to understand cognitive processes and underlying mechanisms in Sz. PMID- 26481686 TI - Qualitative changes in human gamma-secretase underlie familial Alzheimer's disease. AB - Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed gamma-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall gamma-secretase activity levels, and therefore, loss of overall (endopeptidase) gamma-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (gamma secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like gamma secretase activity with gamma-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase-like gamma-secretase activities. However and interestingly, a few SAD patient samples display gamma-secretase dysfunction, suggesting that gamma-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-beta (Abeta) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Abeta products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations. PMID- 26481688 TI - The proteome quest to understand biology and disease (HUPO 2014). PMID- 26481689 TI - A Plasmonic Spanner for Metal Particle Manipulation. AB - Typically, metal particles are difficult to manipulate with conventional optical vortex (OV) tweezers, because of their strong absorption and scattering. However, it has been shown that the vortex field of surface plasmonic polaritons, called plasmonic vortex (PV), is capable of stable trapping and dynamic rotation of metal particles, especially those of mesoscopic and Mie size. To uncover the different physical mechanisms of OV and PV tweezers, we investigated the force distribution and trapping potential of metal particles. In OV tweezers the stronger scattering force causes a positive potential barrier that repels particles, whereas in PV tweezers the dominant gradient force contributes to a negative potential well, resulting in stably trapped particles. Compared with OV, the orbital angular momentum of PV produces an azimuthal scattering force that rotates the trapped particles with more precise radius and position. Our results demonstrate that PV tweezers are superior in manipulation of metal particles. PMID- 26481690 TI - Budget impact model of a 5-grass sublingual immunotherapy tablet for the treatment of grass pollen-induced allergic rhinitis. AB - OBJECTIVE: Allergic rhinitis (AR) is a chronic disease with a substantial clinical and economic burden. This study estimated the potential budget impact (BI) associated with market entry of Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract Tablet for Sublingual Use ('5-grass SLIT tablet') for patients aged 10-65 with grass pollen induced AR. METHODS: A budget impact model was constructed to estimate the potential BI from a US payer perspective. The model calculated pharmacy, medical, and total (pharmacy + medical) costs per-member-per-month (PMPM) with and without market entry of the 5-grass SLIT tablet, considering a 3-year time horizon. The target population was determined using an epidemiological approach and existing literature. The treatment market shares without 5-grass SLIT tablet entry were derived from an analysis of de-identified insurance claims data. Pharmacy costs and medical utilization rates and costs were obtained from the claims data analysis and existing literature. One-way sensitivities were conducted for key model inputs. RESULTS: Using an illustrative example of a hypothetical health plan with one million members, the estimated target population of AR patients aged 10-65 was 26,320. On a PMPM basis, pharmacy costs increased by $0.36, $0.44, and $0.51, while total costs (after medical cost offsets) increased by $0.15, $0.18, and $0.22 in the first, second, and third years following entry of the 5 grass SLIT tablet, respectively. Results were most sensitive to changes in the compliance rate, treatment duration, and price. The BI will vary from the base case example when alternative, payer-specific inputs are used. CONCLUSIONS: Using base case inputs, use of the 5-grass SLIT tablet to treat grass pollen-induced AR increased the pharmacy budget for a hypothetical third-party payer. Higher pharmacy costs were partially offset by lower medical budget due to reduced resource use compared with existing treatments. PMID- 26481691 TI - All enamel is not created equal:Supports from a novel FAM83H mutation. PMID- 26481693 TI - The role of the galU gene of uropathogenic Escherichia coli in modulating macrophage TNF-alpha response. AB - Uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections (UTI). These bacteria are equipped with an arsenal of virulence factors, such as siderophores and adhesins enabling UPECs to sufficiently colonize the urinary tract of humans and animals. Such virulence factors manipulate and impair the recognition of UPECs by the host's innate immune system. Among those, factors like the TIR domain containing proteins in E. coli (TcpC) have been described to interfere with the Toll-like receptor 4 signaling cascade. Nevertheless, some UPECs such as strain UTI89 lack TcpC, but also manipulate the innate immune response. By a random mutant-library approach we identified the galU gene of strain UTI89 to be responsible for a reduced immune response of macrophages. Consequently, we created a site directed knockout mutant of the galU gene in strain UTI89. This mutant caused a significantly increased cytokine response when co-incubated with J774A.1 macrophages. This phenotype could be recomplemented in trans by insertion of a galU-expressing plasmid. No differences in the viability of macrophages co-incubated with either the wild type (WT) or the DeltagalU mutant strain could be observed. Nor could any growth impairment be detected in the DeltagalU mutant compared to WT strain. Hence, the increased cytokine response was not due to differences in the bacterial cytotoxicity or bacterial counts in the assay. Our results also demonstrated a reduction of intracellular counts of UTI89DeltagalU in the infection model. We were able to show a loss of the O-polysaccharide side chain of the DeltagalU mutant LPS. A comparable LPS structure could be generated by the deletion of the waaL gene in the UTI89. This also caused an impaired immune modulation. In contrast, purified LPS was not sufficient to impair cytokine release of macrophages. Moreover, no differences could be detected by applying bacteria inactivated with heat or formalin treatment. From this, we assume that the aberration of the LPS structure caused by the knockout of the galU gene is an important but not the exclusive cause for the loss of UPEC's immune modulating properties. PMID- 26481692 TI - The endocrine-immune network during taeniosis by Taenia solium: The role of the pituitary gland. AB - It is well known that sex hormones play an important role during Taenia solium infection; however, to our knowledge no studies exist concerning the immune response following complete or lobe-specific removal of the pituitary gland during T. solium infection. Thus, the aim of this work was to analyze in hamsters, the effects of lack of pituitary hormones on the duodenal immune response, and their impact on T. solium establishment and development. Thus, in order to achieve this goal, we perform anterior pituitary lobectomy (AL, n = 9), neurointermediate pituitary lobectomy (NIL, n = 9) and total hypophysectomy (HYPOX, n = 8), and related to the gut establishment and growth of T. solium, hematoxylin-eosin staining of duodenal tissue and immunofluorescence of duodenal cytokine expression and compared these results to the control intact (n = 8) and control infected group (n = 8). Our results indicate that 15 days post-infection, HYPOX reduces the number and size of intestinally recovered T. solium adults. Using semiquantitative immunofluorescent laser confocal microscopy, we observed that the mean intensity of duodenal IFN-gamma and IL-12 Th1 cytokines was mildly expressed in the infected controls, in contrast with the high level of expression of these cytokines in the NIL infected hamsters. Likewise, the duodenum of HYPOX animals showed an increase in the expression of Th2 cytokines IL-5 and IL-6, when compared to control hamsters. Histological analysis of duodenal mucosa from HYPOX hamsters revealed an exacerbated inflammatory infiltrate located along the lamina propria and related to the presence of the parasite. We conclude that lobe specific pituitary hormones affect differentially the T. solium development and the gut immune response. PMID- 26481694 TI - Faith (F) and presence moment (O) in analytic processes: an example of a narcissistic disorder. AB - Based on Freud's remark that a neurosis can not be slain in absentia, the thesis is established that presence moments constitute the central points in the analytic process. The interpenetrative dynamics between analyst and analysand creates an analytical field, in which a pre-conception is formed. This pre conception meets the self-revealing psychic world of the patient. This realization is a moment of presence (O) and the analytic third is determined. In this moment, the presence of psychic reality is irrefutable present and can be called by name. The name, which is seen as a presentational symbol, is a creation of the analytic couple, but has its source in the genetic roots of the patient. The presentational arises from the presence, which can then become the representation. F is central in this process and is part of the analytic couple. Based on detailed case material of a narcissistic disorder it is shown that a dynamic that impresses at first narcissistic, can be understood from a different point of view as a struggle for the analytical attitude and belief (F). PMID- 26481695 TI - Radiographic quantifications of joint space narrowing progression by computer based approach using temporal subtraction in rheumatoid wrist. AB - OBJECTIVE: To investigate the validity of a computer-based method using temporal subtraction in carpal joints of patients with rheumatoid arthritis (RA), which can detect the difference in joint space between two images with the joint space difference index (JSDI). METHODS: The study consisted of 43 patients with RA (39 females and 4 males) who underwent radiography at baseline and at 1-year follow up. The joint space narrowing (JSN) of carpal joints on bilateral hand radiographs was assessed by our computer-based method, using the Sharp/van der Heijde method as the standard of reference. We compared the JSDI of joints with JSN progression in the follow-up period with that of those without JSN progression. In addition, we examined whether there is a significant difference in JSDI in terms of laterality or topology of the joint. RESULTS: The JSDI of joints with JSN progression was significantly higher than that of those without JSN progression (Mann-Whitney U test, p < 0.001). There was no statistically significant difference in the JSDI between the left and right carpal joints, which was analysed for five different joints altogether and each joint separately (Mann-Whitney U test, p > 0.05). There was statistically significant difference in JSDI among different joints (Kruskal-Wallis test, p = 0.003). CONCLUSION: These results suggest that our computer-based method may be useful to recognize the JSN progression on radiographs of rheumatoid wrists. ADVANCES IN KNOWLEDGE: The computer-based temporal subtraction method can detect the JSN progression in the wrist, which is the single most commonly involved site in RA. PMID- 26481696 TI - Evaluation of 39 medical implants at 7.0 T. AB - OBJECTIVE: With increased signal to noise ratios, 7.0-T MRI has the potential to contribute unique information regarding anatomy and pathophysiology of a disease. However, concerns for the safety of subjects with metallic medical implants have hindered advancement in this field. The purpose of the present research was to evaluate the MRI safety for 39 commonly used medical implants at 7.0 T. METHODS: Selected metallic implants were tested for magnetic field interactions, radiofrequency-induced heating and artefacts using standardized testing techniques. RESULTS: 5 of the 39 implants tested may be unsafe for subjects undergoing MRI at 7.0 T. CONCLUSION: Implants were deemed either "MR Conditional" or "MR Unsafe" for the 7.0-T MRI environment. Further research is needed to expand the existing database categorizing implants that are acceptable for patients referred for MRI examinations at 7.0 T. ADVANCES IN KNOWLEDGE: Lack of MRI testing for common metallic medical implants limits the translational potential of 7.0-T MRI. For safety reasons, patients with metallic implants are not allowed to undergo a 7.0-T MRI scan, precluding part of the population that can benefit from the detailed resolution of ultra-high-field MRIs. This investigation provides necessary MRI testing of common medical implants at 7.0 T. PMID- 26481698 TI - Nurses' attitudes and spontaneous adverse drug reaction reporting: a case-control study in Portugal. AB - AIM: To identify the attitudes and knowledge associated with adverse drug reactions (ADR) under-reporting by nurses. BACKGROUND: The voluntary reporting system is fundamental for expediting the detection of ADR during post-marketing surveillance. METHODS: We performed a case-control study. A self-administered questionnaire was sent by mail to 1325 nurses. The knowledge and attitudes related to ADR under-reporting were primarily based on Inman's seven deadly sins. RESULTS: The overall response rate was 34.2%. Nurses working in primary care were 12-fold more likely to report an ADR. A change of attitude increased the probability of ADR reporting for:'The belief that the one case an individual nurse might see could not contribute to medical knowledge'; 'I do not know how the information reported is used by the system'; 'I would be more likely to report if the method was easier'; 'I think the most correct way to report is to inform the doctor' and 'I do not have time to think about the involvement of the drug in ADRs'. CONCLUSIONS: Our study shows that the beliefs of nurses, such as 'one single report would not make any difference' and 'the pharmacovigilance system is very complex', act as a barrier to ADR reporting. IMPLICATIONS FOR NURSING MANAGEMENT: It is important to clarify the ADR reporting procedure and increase the nurses reporting rate. PMID- 26481697 TI - Systems assessment of intercalated combination of chemotherapy and EGFR TKIs versus chemotherapy or EGFR TKIs alone in advanced NSCLC patients. AB - Both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied for the treatment of non-small cell lung cancer (NSCLC), but the efficacy of these two treatments in combination is not yet clear. Thus, we sought to evaluate the efficacy of the intercalated combination of these two treatments in NSCLC. The PubMed database, EMBASE, Cochrane Controlled Trials Register, and Chinese Biomedical Database were systematically searched by two researchers for randomized clinical trials (RCTs) that examined the intercalated combination of chemotherapy and EGFR TKIs in NSCLC. Ten studies involving 1,660 patients were included in this systematic review. The statistical results showed that the intercalated combination of chemotherapy and EGFR TKIs significantly improved overall survival (OS) (hazard ratio (HR) = 0.83, 95% confidence interval (CI): 0.70-0.98), progression-free survival (PFS) (HR = 0.65, 95% CI: 0.51-0.84), and the objective response rate (ORR) (risk ratio (RR) = 1.90, 95% CI: 1.22-2.98) compared to chemotherapy alone. Similarly, compared to EGFR TKIs monotherapy, the intercalated combination of chemotherapy and EGFR TKIs seemed superior to EGFR TKIs alone in terms of PFS, ORR and DCR (PFS: HR = 0.75, 95% CI: 0.62-0.91, ORR: RR = 1.49, 95% CI: 1.12-2.00 and DCR: RR = 1.33, 95% CI: 1.15-1.54) in advanced NSCLC therapy. PMID- 26481699 TI - Blood metabolic response to a long-term wheelchair rugby training. AB - STUDY DESIGN: A cross-sectional study with comparison group. OBJECTIVES: To evaluate the effects of long-term wheelchair rugby (WR) training on lipid profile, blood antioxidant status and the brain-derived neurotrophic factor (BDNF) level. SETTING: Academy of Physical Education, Katowice, Poland. METHODS: Thirty-two males with chronic cervical spinal cord injury (SCI) assigned into the physically active 'low-point' (LP, n=15) or 'high-point' (HP, n=8) WR players groups and the sedentary manual wheelchair users (SED, n=9) participated in this study. Fasting blood samples were collected at rest for assessment of activities of antioxidant enzymes, concentrations of reduced glutathione, uric acid, malondialdehyde (MDA), lipid profile measures and BDNF. RESULTS: No significant differences were found in anthropometric measures and serum lipid profile indices, although a slight tendency toward higher high-density lipoprotein cholesterol level was evidenced in WR players. Significantly lower serum malondialdehyde (MDA) and significantly higher levels of the overall enzymatic antioxidant potential index (EAP) in WR players, compared with SED, may reflect some WR training-induced increase in the blood's antioxidant capacity. There was also a slight tendency toward higher serum BDNF level in WR players compared with the SED group and a significant positive association between years of WR training and the BDNF level. CONCLUSION: A voluntary participation in a long-term WR training program has several health promoting outcomes for individuals with chronic SCI. Among the most important are enhancement of the blood antioxidant defense capacity evidenced by lower MDA and higher EAP levels, as well as WR training-induced activation of BDNF signaling. PMID- 26481701 TI - Establishing standard hospital performance measures for cervical spinal trauma: a Nationwide In-patient Sample study. AB - STUDY DESIGN: A retrospective national administrative database study. OBJECTIVE: Patient safety indicators (PSIs) and hospital-acquired conditions (HACs) are metrics for quality of health care and are linked to reimbursement. The prevalence of PSIs/HACs may impact access to health care for certain conditions. We estimated the national occurrence rates of PSIs/HACs among cervical trauma patients and identified patient factors that correlate with their occurrence. SETTING: United States of America. METHODS: We queried Nationwide In-patient Sample database (NIS) hospitalizations (2002-2010) for diagnoses of cervical fracture with and without spinal cord injury (SCI). The incidence of each PSI/HAC was determined by ICD-9 (International Classification of Disease, 9th Revision) codes. Multivariate analysis was used to identify the correlation between specific variables and the probability of each indicator. RESULTS: There were 52,377 hospitalizations for cervical fracture in the NIS (without SCI, n = 41,708; with SCI, n = 10,669). Among those without SCI, there were 5374 (12.9%) reported PSIs and 117 (0.3%) HACs. Leading adverse events were postoperative respiratory failure (8.45%), pulmonary embolism (1.70%) and pressure ulcer (1.12%). Among those with SCI, there were 6600 (61.9%) PSIs and 143 (1.3%) HACs. Leading adverse events were postoperative respiratory failure (39.2%), pressure ulcer (7.78%), sepsis (5.71%), deep venous thrombosis (3.81%) and PE (1.70%). Adverse events were associated with several factors, including age, gender, Comorbidity Score and Injury Severity Score. Those with ? 1 PSI/HAC had significantly longer lengths of stay (P < 0.0001) and higher hospital costs (P < 0.0001) and mortality (P < 0.0001) compared with patients without events. CONCLUSIONS: These results estimate baseline national rates of PSIs/HACs in patients with cervical spine trauma. These data may be used to gauge individual institutional quality of care in comparison with national data. PMID- 26481700 TI - Focal adhesion kinase signaling is decreased 56 days following spinal cord injury in rat gastrocnemius. AB - STUDY DESIGN: Descriptive study. OBJECTIVES: The goal of this study was to determine the effects of spinal cord injury (SCI) on aspects of the focal adhesion kinase (FAK) signaling pathway 56 days post injury in rat gastrocnemius. SETTING: This study was conducted in Bronx, NY, USA. METHODS: Three-month-old male Wistar rats were exposed to either a sham surgery (n=10) or complete T4 spinal cord transection (n=10). Rats were killed 56 days following surgery and the muscle was collected. Following homogenization, proteins of the FAK pathway were analyzed by western immunoblotting or reverse transcription-qPCR. In addition, cellular markers for proteins that target the degradation of FAK were investigated. RESULTS: SCI resulted in significantly lower levels of total and phosphorylated FAK, cSrc and p70S6k, and a trend for increased FRNK protein expression. SCI did not change levels of the alpha7 or beta1 integrin subunits, total or phosphorylated ERK1/2, phosphorylated Akt and TSC2 or total p70S6k. SCI resulted in a greater expression of total Akt. mRNA expression of FAK and the alpha7 or beta1 integrins remained unchanged between sham and SCI groups. Caspase 3/7 activity and Trim72 mRNA and protein expression remained unchanged following SCI. CONCLUSION: SCI results in diminished FAK signaling and is independent of ERK1/2 and Akt. SCI has no effect on mRNA levels for genes encoding components of the focal adhesion 56 days after injury. PMID- 26481702 TI - Feasibility of an online well-being intervention for people with spinal cord injury: a pilot study. AB - STUDY DESIGN: Pre-test and post-test designs with 14 participants. Measurements were taken at baseline (T1), immediately after the intervention (T2) and at 3 month follow-up (T3). OBJECTIVES: Psyfit is an online self-help program designed to enhance well-being in persons with depressed mood. We examined the feasibility of Psyfit in people with spinal cord injury (SCI). SETTING: Community, the Netherlands. METHODS: Participants chose two of the six Psyfit modules. The researcher maintained telephone contact with the participants. Feasibility was inferred from the completion rate of the modules and feedback from the participants. Outcome measures were the Mental Health Inventory-5, the Center for Epidemiological Studies Depression scale and the Warwick-Edinburgh Mental Well Being Scale. RESULTS: Overall, 75% of the first module and 39% of the second module were completed. Seven participants were considered as study completers and were included in the evaluation. They evaluated Psyfit as a useful program and helpful for persons with SCI. Several technical problems were reported that mainly concerned browser compatibility. An increase in mental health and nonsignificant change of well-being were found at the end of the intervention period, but these were not maintained at follow-up. CONCLUSION: Psyfit seems a potentially feasible program. However, adaptation to the SCI population and further study with a controlled design and utilizing a larger sample size are necessary before it can be recommended as part of SCI rehabilitation. PMID- 26481703 TI - Mortality benefit of statin use in traumatic spinal cord injury: a retrospective analysis. AB - STUDY DESIGN: An observational study based on retrospective review of the medical charts and death records of 163 individuals with traumatic spinal cord injuries (SCI). OBJECTIVES: To determine whether HMG coA Reductase Inhibitor ('statin') use in a cohort of patients with traumatic SCI reduced overall and cause-specific mortality. SETTING: An outpatient clinic designated for veterans with SCI at the Oklahoma City Veterans Administration Hospital. METHODS: Review and analysis of the medical records of 163 veterans with traumatic SCI cared for between the years 2000 and 2014. Data collected included statin use, duration of statin use and intensity of statin therapy, as well as cause-specific mortality. RESULTS: Seventy five participants had taken statins for an average of 5.7 +/- 3.7 years, and had greater cardiovascular risk burdens than those who had not taken statins (n = 88). Statin use was associated with a reduced risk of death. The mortality rate for those patients on statins was 33.8-49.9 per 1000 person-years, depending on assumptions made regarding residual effects of statin use. Under most assumptions this was significantly lower than the mortality rate seen in those not on statins (47.4-66.8 deaths per 1000 person-years). Within the statin group, neither duration nor average intensity of statin therapy affected mortality. CONCLUSION: Statin use among a cohort of veterans with traumatic SCI reduced all cause mortality. This retrospective study ought to spur further investigations into the potential benefits of statin use among people with chronic SCI, and begin a discussion as to whether individuals with injuries should routinely be offered statin therapy. PMID- 26481704 TI - EGb761 improves histological and functional recovery in rats with acute spinal cord contusion injury. AB - STUDY DESIGN: This is an experimental study. OBJECTIVES: The objective of this study was to evaluate the neuroprotective effects of Ginkgo biloba extract 761 (EGb761) on histological features of injured sites and on functional performance of rats subjected to standardized spinal cord injury (SCI). SETTING: This study was conducted in Xian, Shaanxi, China. METHODS: Thirty female Sprague-Dawley rats were randomly divided into three groups: sham-operated, saline-treated control and EGb761-treated. The Basso, Beattie, Bresnahan Locomotor Rating Score (BBB score) was calculated and footprint analysis was performed to evaluate the functional performance of the rats in each group. Hematoxylin and eosin (HE) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase-3 staining were performed to evaluate the necrosis area and apoptotic cells at the injured site in each group. RESULTS: At 14, but not 1, 3 and 7, days post injury (DPI), rats in the EGb761-treated group exhibited significantly better BBB scores compared with the saline-treated control group (P<0.05). The EGb761-treated group also showed increased stride length, decreased stride width and reduced toe dragging at 14 DPI (P<0.05). Analysis of HE staining revealed that the EGb761-treated group had reduced necrosis at the injury site compared with the saline-treated control group (P<0.05). Analysis of TUNEL and caspase-3 staining demonstrated that cell apoptosis was increased at 1-14 DPI, peaking at 24-h post injury in the gray matter, and 7 DPI in the white matter. At 7 DPI, the quantity of apoptotic cells was significantly decreased in the EGb761-treated group. CONCLUSION: EGb761 administration during the acute phase after SCI significantly reduced secondary injury-induced tissue necrosis and cell apoptosis and improved functional performance in rats. PMID- 26481705 TI - Validation of the Italian version of the Spinal Cord Independence Measure (SCIM III) Self-Report. AB - STUDY DESIGN: Cross-sectional validation study. OBJECTIVES: To validate the Italian version of the Spinal Cord Independence Measure Self-Report (SCIM SR). SETTING: Two spinal cord injury (SCI) rehabilitation facilities in Italy. METHODS: The SCIM III comprises items on 19 daily tasks, grouped into three subscales: 'Self-care,' 'Respiration and sphincter management' and 'Mobility'. The total SCIM score ranges between 0 and 100. The Italian self-reported version (SCIM SR) was translated from the German tool. We studied 116 patients on their first hospitalization for rehabilitation after an SCI. At the time of discharge, patients were evaluated by the rehabilitation team using the SCIM III and self assessed their independence with regard to activities of daily living using the SCIM SR. Pearson's correlation, Bland-Altman method, and stratified and regression analyses were used to examine the differences between evaluations. RESULTS: On the basis of Pearson's correlation, there was good agreement between the data from the SCIM III and SCIM SR (r=0.918 for 'Self-care,' 0.806 for 'Respiration and sphincter management,' 0.906 for 'Mobility' and 0.934 for total scores). By Bland-Altman analysis, patients rated their functioning nearly the same as professionals-the mean difference between SCIM III and SCIM SR scores was approximately 0 for all subscales and total scores. The stratified and regression analyses failed to identify any specific factor that was associated with differences between SCIM III and SCIM SR scores. CONCLUSIONS: These results support the validity of the Italian version of the SCIM SR, which can facilitate longer-term evaluations of the independence of individuals with SCIs. PMID- 26481706 TI - Active Living Leaders Training Program for adults with spinal cord injury: a pilot study. AB - STUDY DESIGN: Quasi-experimental pre-post design with 6-month follow-up. OBJECTIVES: Active Living Leaders Training Program (ALLTP) equips individuals with knowledge and skills to encourage those with spinal cord injury (SCI) to increase their leisure-time physical activity (LTPA). The purpose of this pilot study was to, first, (i) evaluate participants' perceptions of the relevance/usefulness of ALLTP material/presentation, (ii) examine changes in participants' self-efficacy to promote LTPA, (iii) identify program components associated with greater self-efficacy and, second, measure participants' use of ALLTP skills and resources over the subsequent 6 months. SETTING: Canada. METHODS: Six SCI fitness trainers and six adults with SCI completed the three sections of ALLTP and, after each section, provided feedback. Six months later, participants' use of resources and skills was assessed. Means, standard deviations, repeated measures analysis of variance and Pearson's correlations were computed. RESULTS: Relevance/usefulness of the program was rated favorably. Self-efficacy to speak about and encourage LTPA remained high throughout the ALLTP and was positively correlated with the relevance/usefulness of program content and presentation. At follow-up, participants had discussed LTPA with an average of seven people with disabilities and reported using at least one skill and resource from the ALLTP during those discussions. CONCLUSIONS: Users had positive perceptions of ALLTP and reported using the training to promote LTPA to others with disabilities. Participant feedback has been used to improve ALLTP. ALLTP can now be used to train people with SCI and SCI fitness trainers to promote LTPA to others with disabilities. PMID- 26481707 TI - Lipofilling (fat grafting) in the secondary prevention of ischial tuberosity and pelvic pressure ulcers. AB - STUDY DESIGN: Retrospective study. OBJECTIVES: Lipofilling was proposed to adult chronic spinal cord injury patients with history of ischial tuberosity pressure ulcers surgery, at risk of recurrence of pressure ulcers due to unsatisfactory adipose tissue thickness. SETTING: Fondation Hopale, Berck, France. METHODS: The three staged (Coleman) procedure for fat grafting consisted of water-jet assisted liposuction (Harvest-Jet), decantation, and reinjection of the autologous fat in three-dimensional plan. RESULTS: Ten consecutive patients (eight paraplegics and two tetraplegics) benefited from bilateral ischial lipofilling, with additional lipofilling of the sacrum (three patients) and the trochanters (two patients). All patients attended the seating clinic with pressure mapping before and after lipofilling for appropriate cushion prescription. Mean follow-up time was 16 months (4-24 months). Complications were limited to stage I (two patients) and stage II (one patient) pressure ulcers, due to negligence. Excellent results with minimal fat wasting (between 10% and 25%) underneath the ischial tuberosity were seen in eight patients, with significant improvement of adipose tissue thickness. Total fat waste was seen in two patients, one of whom following dramatic weight loss. Results were always good in the sacrum and trochanteric areas. Lipofilling allowed longer sitting times (three patients), improved skin quality (nine patients), improved quality of life (six patients), 'a better feeling of positioning in their wheelchair' (four patients), and decrease in pelvic pain (three patients). DISCUSSION AND CONCLUSION: Pelvic lipofilling is safe, cost effective, and can now be considered in the primary prevention of pelvic pressure ulcers in patients with insufficient adipose tissue. PMID- 26481708 TI - Development of the International Spinal Cord Injury Activities and Participation Basic Data Set. AB - STUDY DESIGN: Consensus decision-making process. OBJECTIVES: The objective of this study was to develop an International Spinal Cord Injury (SCI) Activities and Participation (A&P) Basic Data Set. SETTING: International working group. METHODS: A committee of experts was established to select and define A&P data elements to be included in this data set. A draft data set was developed and posted on the International Spinal Cord Society (ISCoS) and American Spinal Injury Association websites and was also disseminated among appropriate organizations for review. Suggested revisions were considered, and a final version of the A&P Data Set was completed. RESULTS: Consensus was reached to define A&P and to incorporate both performance and satisfaction ratings. Items that were considered core to each A&P domain were selected from two existing questionnaires. Four items measuring activities were selected from the Spinal Cord Independence Measure III to provide basic data on task execution in activities of daily living. Eight items were selected from the Craig Handicap Assessment and Reporting Technique to provide basic data on the frequency of participation. An additional rating of satisfaction on a three-point scale for each item completes the total of 24 A&P variables. CONCLUSION: Collection of the International SCI A&P Basic Data Set variables in all future research on SCI outcomes is advised to facilitate comparison of results across published studies from around the world. Additional standardised instruments to assess activities of daily living or participation can be administered, depending on the purpose of a particular study. PMID- 26481709 TI - Clinical and demographic profile of traumatic spinal cord injury: a Mexican hospital-based study. AB - STUDY DESIGN: Review of clinical data. OBJECTIVES: The objective of this study was to describe the clinical and demographical profile of patients with traumatic spinal cord injury (TSCI) admitted to a single center. SETTING: Unidad de Medicina Fisica y Rehabilitacion Centro, Mexico. PARTICIPANTS: Patients with TSCI attending rehabilitation for the first time. INTERVENTION: Not applicable. MAIN MEASUREMENTS: Age, gender, educational level, occupational activity, causes of injury, level of injury, neurological level, injury severity and category were recorded. RESULTS: Four hundred and sixty-four clinical files of patients with TSCI were collected. The mean age was 37.9 +/- 15.9 years; 78.2% (363/464) were male, basic educational level predominated in 63.6% (296/464) and 73.1% (339/464) were employed. A fall was the main mechanism of the injury in 41.6% (193/464), replacing automobile accidents from the first place. The mean age of persons who suffered falls was 44 +/- 16 years. Injuries sustained by younger persons were due to violence (28.4 +/- 10.1 years) and the cause of injury associated with male gender was violence. Thoracic level was most often affected (in 56.7%, 263/464) and neurological level C4 in 13.4% (62/464). In regard to the extent of the injury, lesions classified as American Spinal Injury Association A predominated (56.2%, 261/464) as with complete paraplegia in 43.3% (201/464). CONCLUSIONS: The mean age of our patients was 37 years. Men are affected in a higher proportion. Our population has <9 years of study. Physical labor was the usual pre-injury activity. The main mechanism of injury was falls. Thoracic spine was the most affected. PMID- 26481710 TI - Prevalence of secondary medical complications and risk factors for pressure ulcers after traumatic spinal cord injury during acute care in South Africa. AB - STUDY DESIGN: Prospective, population-based cohort study. OBJECTIVES: To determine the prevalence of selected complications following traumatic spinal cord injury during acute care and to identify the risk factors for pressure ulcers. SETTING: The only tertiary academic (Groote Schuur) hospital in the catchment region providing specialised acute care. METHODS: A descriptive, observational study of an inception cohort. Secondary complications were predefined and consisted of pressure ulcers, pulmonary complications (pneumonia and atelectasis), urinary tract infections, autonomic dysreflexia, deep vein thrombosis, pulmonary embolism, postural hypotension, neuropathic pain and spasticity. Possible risk factors for pressure ulcers included variables concerning demographic and injury characteristics and complications. Both univariate and multivariate logistic regression analyses were used. RESULTS: Data of 141 patients (97%) were analysed. In total, 71 (50.3%) patients had one or more complication. The most common was pressure ulcers (n=42; 29.8%), followed by pulmonary complications (n=33; 23.4%) and urinary tract infections (n=24; 17%). Significant risk factors were gun-shot injury, motor completeness (American Spinal Injury Association Impairment Scale (AIS) A?B), vertebral injury, no spinal surgery, pulmonary complications, urinary tract infection and level of consciousness. In the final multivariate model that correctly predicted 81.6% of subjects, motor completeness and vertebral injury remained significant independent factors, whereas having a urinary tract infection was associated with an increased risk (odds ratio: 2.86), but not significant at the 5% level. CONCLUSION: Pressure ulcers and pulmonary complications were prevalent during specialised acute phase. The occurrence of pressure ulcers, despite protocols in place, is worrisome. To prevent pressure ulcers, special attention seems necessary for persons with motor complete lesions and those with vertebral injuries. PMID- 26481711 TI - Locomotor improvement of spinal cord-injured rats through treadmill training by forced plantar placement of hind paws. AB - STUDY DESIGN: Experimental training model of rats with spinal cord injury (SCI). SETTING: Osaka, JapanObjective:To investigate the effect of forced treadmill training by plantar placement (PP), as compared with dorsal placement (DP), of the dorsal paws on the locomotor behaviors of spinal cord-injured rats. METHODS: The spinal cord was contusion-injured at the thoracic level. Rats were divided into three groups: forced training involving stepping by PP and DP and non-forced training/assistance (nT). Training began 1 week after injury and was conducted for 4 weeks. Locomotor behaviors were estimated using Basso-Beattie-Bresnahan (BBB) scores, dorsiflexion of the hind paws and footprints of the hind paws. Histological and immunohistochemical examinations of the spinal cord lesions were conducted after 4 weeks of training. RESULTS: The values, respectively, of PP, DP and nT groups at 4 weeks of training were as follows: BBB scores were 15.6+/-0.8, 7.7+/-1.3 and 10.3+/-0.4. The paw dorsiflexion angles were 34.1+/-5.2, 16.4+/-2.4 and 23.6+/-3.0 degrees, respectively. The stride angles were 5.1+/-0.9, 13.7+/ 4.9 and 17.8+/-4.0 degrees for the left paws. Cavity volumes were 10.3+/-2.1, 31.0+/-2.0 and 28.2+/-4.9%. In addition to cavities, there were astrocyte-devoid areas containing some loose tissues, through which many axons extended longitudinally. CONCLUSIONS: The BBB score, dorsiflexion angle and stride angle were consistently improved in the PP group. Cavity formation was more reduced, and many axons extended through coarse tissues formed in astrocyte-devoid areas at the lesion in the PP group. Forced training by PP of the hind paws promoted the behavioral and histological improvement of rats with SCI. PMID- 26481712 TI - Effects of tacrolimus and erythropoietin in experimental spinal cord lesion in rats: functional and histological evaluation. AB - STUDY DESIGN: Experimental study with rats. OBJECTIVE: To evaluate functional and histological effects of tacrolimus (FK 506) and erythropoietin (EPO) after experimental spinal cord contusion injury (SCI). SETTING: Brazil. METHODS: Wistar rats (n=60) were submitted to SCI with the NYU Impactor system. The control group received saline; the EPO group received EPO; the group EPO+FK 506 received EPO associated with tacrolimus and the group FK 506 received tacrolimus only. The Sham group underwent SCI, but did not receive any drug. Locomotor function was evaluated after SCI by BBB (Basso, Beattie and Bresnahan) weekly and by the motor evoked potential test in 42 days. The spinal cord was histologically evaluated. RESULTS: There was a significant difference between treated and the control groups from the seventh day on for BBB scores, with no difference between the groups EPO and EPO+FK 506 by the end of the study. There were significant differences between groups for necrosis and bleeding, but not for hiperemia, degeneration and cellular infiltrate. Axon neuron count was different between all groups (P=0.001), between EPO+FK 506 and FK 506 (P=0.011) and between EPO+FK 506 and Sham (P=0.002). Amplitude was significantly different between all groups except between control and sham. For latency, there was no difference. CONCLUSIONS: This study did not reveal significant differences in the recovery of locomotor function, or in the histological and electrophysiological analysis in animals treated with EPO and tacrolimus after thoracic SCI. PMID- 26481714 TI - Ventricular Overdrive Pacing: Beyond V-A-V and V-A-A-V. PMID- 26481713 TI - Quality of websites with patient information about spinal cord injury in Spanish. AB - STUDY DESIGN: Descriptive, cross-sectional analysis of websites with information on spinal cord injury (SCI) in Spanish. OBJECTIVE: To assess the quality, readability and presence of quality labels on web pages with information about SCI in Spanish. SETTING: The Internet. METHODS: An Internet search was conducted on Google with the keywords 'lesion medular' (spinal cord injury), 'paraplejia' (paraplegia) and 'tetraplejia' (tetraplegia). The first 50 results of each search were included. The quality of websites was assessed with the LIDA tool while the readability was assessed with the Flesch-Szigriszt index and the INFLESZ scale. We also checked the presence of any quality label. RESULTS: After excluding duplicated and irrelevant results, 33 websites were analysed. Only four of them had a quality label. The mean score of the LIDA tool was 61.12% (medium quality), and the worst results were those referring to the reliability of the information. The readability of the web pages was somewhat difficult, with a mean of 48.22 in the Flesch-Szigriszt index. Only eight of the websites showed normal readability. We observed no differences in either the quality or the readability of the websites according to their origin or the presence of quality labels. CONCLUSIONS: The websites analysed present a medium quality. Mainly, they should improve the reliability of their contents and their readability, including more quality labels. For SCI information in Spanish to be understandable and to provide valuable content, websites analysed in our study need to improve the quality parameters. PMID- 26481715 TI - Narrow band imaging and bladder cancer: when and how. AB - Narrow band imaging (NBI) is an optical enhancement technology for endoscopy. NBI works filtering the standard white light in two bandwidths of illumination of 415 nm, blue, and 540 nm, green. As a result, capillaries on mucosal surface appear brown and veins in connective subepithelial layer cyan, enhancing the contrast among epithelial, subepithelial tissue and its vascularisation. Given that it is a filter, it is safe, does not need any kind of instillation and the vision modality can be switched from NBI to white light and vice versa without any limitations of time. NBI-assisted cystoscopy increases the detection rate of urothelial lesions and enhances visibility of tumour margins with respect to standard white light modality, although it does not need a particular learning curve. NBI exploration of the bladder should be avoided during active bleeding because the light absorption would be excessive impeding an optimal vision. Moreover, it should always be employed in combination with standard white light modality to avoid an excess of false-positive findings, particularly during or immediately after topic treatments. It can be used in office to anticipate bladder recurrences and in the operating theatre to perform a complete tumour resection. As a matter of fact, it is able to reduce the recurrence rate and ameliorate bladder cancer management by identifying high-grade cancerous tissue, especially Cis, undetected by the standard white light modality. PMID- 26481718 TI - Clinical pitfalls in diagnosis of nonmuscle-invasive bladder cancer. AB - Current global economic crisis imposes healthcare system to reduce unnecessary investigations and increase early detection of tumors, to decrease the costs of an advanced disease. Several diagnostic pitfalls may occur dealing with bladder cancer (BC), particularly in nonmuscle-invasive (NMIBC) one. Hematuria, the commonest sign in NMIBC, is often underestimated. Urinary cytology is highly specific for high-grade tumors, but has a low sensitivity for low-grade BC, is operator dependent, and not always obtainable in clinical practice. Numerous urinary tests are available to ameliorate the accuracy of cytology, but none of them is routinly used in urological practice. Ultrasound could hardly detect a small bladder tumor, especially if located in the bladder neck or in the anterior wall. Computed tomography (CT) is widely adopted as an alternative to conventional urography, but its usefulness in patients with hematuria is still debated. MRI has a higher accuracy than CT for staging BC and evaluate the bladder-wall invasion. A negative cystoscopy cannot exclude Tis and should be accompanied by urinary cytology in patients with suspected Tis or high-risk NMIBC; however, new techniques such as narrow band imaging (NBI) and photodynamic (PDD) increase the detection rate of BC and flat lesions. Nearly half of all diagnostic resections present omission of muscle in the specimen or its mention in the pathology report, which is associated with an increased mortality. An adequate muscle sampling during endoscopic resection is mandatory, particularly in patients with high-grade disease. Recognition of pitfalls in diagnosis and management of BC represents the first step for a correct approach. PMID- 26481720 TI - NBI: results review. AB - The narrow band imaging (NBI) is a new technology introduced to complement the traditional endoscopy in order to enhance the detection of nonmuscle-invasive bladder cancer and, consequently, to improve the management of the disease. In this review, we considered the most important studies about the use of NBI in the diagnosis and treatment of bladder cancer. Current results demonstrate a greater sensitivity in the diagnosis of bladder cancer and especially a better negative predictive value of cystoscopy enhanced by NBI technology than white light standard cystoscopy. Similarly, improving the performance of endoscopic resection, this new technology would have a positive therapeutic impact in order to decrease residual tumors and relapses. The validation of the results and diffusion of NBI in clinical practice may provide new perspectives in the management of nonmuscle-invasive bladder cancer. PMID- 26481721 TI - The occult urothelial cancer. AB - Transitional cell carcinoma (TCC) is the tumor that most frequently affects the urinary tract. The most common location is in the bladder; the diagnosis, as the follow-up, is based on urine cytology, endoscopic, and radiological examinations. Urinary cytology is an important non invasive tool used in the diagnosis and follow-up of patients with TCC. A positive urine cytology result is highly predictive of the presence of TCC, even in the presence of normal cystoscopy, because malignant cells may appear in the urine long time before any cystoscopically visible lesion becomes apparent. The presence of a positive urinary cytology, in the absence of clinical or endoscopic evidence of a TCC, can identify an occult urothelial cancer, located in any site of the urinary tract (upper urinary tract, bladder, prostatic urethra). Most of the urothelial tumors of the renal pelvis and ureters are diagnosed by radiological examinations, but we can observe a high rate of false negatives. In order to improve the diagnostic role of urinary cytology and other conventional examinations, numerous molecular markers have been identified; however, the real clinical application remains unclear. Photodynamic diagnosis and narrow band imaging (NBI) cystoscopy increase the diagnostic accuracy of endoscopic examinations in the presence of lesions not easily detectable. The aim of this review is to analyze the current diagnostic standards in the presence of occult urothelial cancer. PMID- 26481722 TI - Field-Induced Slow Magnetic Relaxation in a Mononuclear Manganese(III)-Porphyrin Complex. AB - We report on a novel manganese(III)-porphyrin complex with the formula [Mn(III) (TPP)(3,5-Me2 pyNO)2 ]ClO4 ?CH3 CN (2; 3,5-Me2 pyNO=3,5-dimethylpyridine N-oxide, H2 TPP=5,10,15,20-tetraphenylporphyrin), in which the Mn(III) ion is six coordinate with two monodentate 3,5-Me2 pyNO molecules and a tetradentate TPP ligand to build a tetragonally elongated octahedral geometry. The environment in 2 is responsible for the large and negative axial zero-field splitting (D=-3.8 cm(-1) ), low rhombicity (E/|D|=0.04) of the high-spin Mn(III) ion, and, ultimately, for the observation of slow magnetic-relaxation effects (Ea =15.5 cm( 1) at H=1000 G) in this rare example of a manganese-based single-ion magnet (SIM). Structural, magnetic, and electronic characterizations were carried out by means of single-crystal diffraction studies, variable-temperature direct- and alternating-current measurements and high-frequency and -field EPR spectroscopic analysis followed by quantum-chemical calculations. Slow magnetic-relaxation effects were also observed in the already known analogous compound [Mn(III) (TPP)Cl] (1; Ea =10.5 cm(-1) at H=1000 G). The results obtained for 1 and 2 are compared and discussed herein. PMID- 26481723 TI - Costs and consequences: Hepatitis C seroprevalence in the military and its impact on potential screening strategies. AB - Knowledge of the contemporary epidemiology of hepatitis C viral (HCV) infection among military personnel can inform potential Department of Defense screening policy. HCV infection status at the time of accession and following deployment was determined by evaluating reposed serum from 10,000 service members recently deployed to combat operations in Iraq and Afghanistan in the period 2007-2010. A cost model was developed from the perspective of the Department of Defense for a military applicant screening program. Return on investment was based on comparison between screening program costs and potential treatment costs avoided. The prevalence of HCV antibody-positive and chronic HCV infection at accession among younger recently deployed military personnel born after 1965 was 0.98/1000 (95% confidence interval 0.45-1.85) and 0.43/1000 (95% confidence interval 0.12 1.11), respectively. Among these, service-related incidence was low; 64% of infections were present at the time of accession. With no screening, the cost to the Department of Defense of treating the estimated 93 cases of chronic HCV cases from a single year's accession cohort was $9.3 million. Screening with the HCV antibody test followed by the nucleic acid test for confirmation yielded a net annual savings and a $3.1 million dollar advantage over not screening. CONCLUSIONS: Applicant screening will reduce chronic HCV infection in the force, result in a small system costs savings, and decrease the threat of transfusion transmitted HCV infection in the battlefield blood supply and may lead to earlier diagnosis and linkage to care; initiation of an applicant screening program will require ongoing evaluation that considers changes in the treatment cost and practice landscape, screening options, and the epidemiology of HCV in the applicant/accession and overall force populations. PMID- 26481724 TI - A nonparametric spatial scan statistic for continuous data. AB - BACKGROUND: Spatial scan statistics are widely used for spatial cluster detection, and several parametric models exist. For continuous data, a normal based scan statistic can be used. However, the performance of the model has not been fully evaluated for non-normal data. METHODS: We propose a nonparametric spatial scan statistic based on the Wilcoxon rank-sum test statistic and compared the performance of the method with parametric models via a simulation study under various scenarios. RESULTS: The nonparametric method outperforms the normal-based scan statistic in terms of power and accuracy in almost all cases under consideration in the simulation study. CONCLUSION: The proposed nonparametric spatial scan statistic is therefore an excellent alternative to the normal model for continuous data and is especially useful for data following skewed or heavy tailed distributions. PMID- 26481726 TI - Paresthesia-Free High-Density Spinal Cord Stimulation for Postlaminectomy Syndrome in a Prescreened Population: A Prospective Case Series. AB - OBJECTIVE: Spinal cord stimulation (SCS) traditionally is thought to require paresthesia, but there is evidence that paresthesia-free stimulation using high density (HD) parameters might also be effective. The purpose of this study is to evaluate relative effectiveness of conventional, subthreshold HD, and sham stimulation on pain intensity and quality of life. METHODS: Fifteen patients with response to conventional stimulation (60 Hz/350 MUsec) were screened with a one week trial of subthreshold HD (1200 Hz/200 MUsec/amplitude 90% paresthesia threshold) and enrolled if there was at least 50% reduction on visual analog scale (VAS) for pain. Subjects were randomized into two groups and treated with four two-week periods of conventional, subthreshold HD, and sham stimulation in a randomized crossover design. RESULTS: Four of 15 patients responded to subthreshold HD stimulation. Mean VAS during conventional, subthreshold HD, and sham stimulation was 5.32 +/- 0.63, 2.29 +/- 0.41, and 6.31 +/- 1.22, respectively. There was a significant difference in pain scores during the blinded crossover study of subthreshold HD vs. sham stimulation (p < 0.05, Student's t-test). Post hoc analysis revealed that subjects reported significantly greater attention to pain during conventional stimulation compared with subthreshold HD stimulation (p < 0.05, Student's t-test). All subjects reported a positive impression of change for subthreshold HD stimulation compared with conventional stimulation, and there was a trend toward greater likelihood for response to subthreshold HD stimulation in comparison with sham stimulation (p = 0.07, Fisher's exact test). At the end of the trial, all subjects elected to continue to receive subthreshold HD stimulation rather than conventional stimulation. CONCLUSIONS: Paresthesia are not necessary for pain relief using commercially available SCS devices, and may actually increase attention to pain. Subthreshold HD SCS represents a viable alternative to conventional stimulation among patients who are confirmed to have a clinical response to it. PMID- 26481725 TI - Prevalence of inflammatory bowel disease among coeliac disease patients in a Hungarian coeliac centre. AB - BACKGROUND: Celiac disease, Crohn disease and ulcerative colitis are inflammatory disorders of the gastrointestinal tract with some common genetic, immunological and environmental factors involved in their pathogenesis. Several research shown that patients with celiac disease have increased risk of developing inflammatory bowel disease when compared with that of the general population. The aim of this study is to determine the prevalence of inflammatory bowel disease in our celiac patient cohort over a 15-year-long study period. METHODS: To diagnose celiac disease, serological tests were used, and duodenal biopsy samples were taken to determine the degree of mucosal injury. To set up the diagnosis of inflammatory bowel disease, clinical parameters, imaging techniques, colonoscopy histology were applied. DEXA for measuring bone mineral density was performed on every patient. RESULTS: In our material, 8/245 (3,2 %) coeliac disease patients presented inflammatory bowel disease (four males, mean age 37, range 22-67), 6/8 Crohn's disease, and 2/8 ulcerative colitis. In 7/8 patients the diagnosis of coeliac disease was made first and inflammatory bowel disease was identified during follow-up. The average time period during the set-up of the two diagnosis was 10,7 years. Coeliac disease serology was positive in all cases. The distribution of histology results according to Marsh classification: 1/8 M1, 2/8 M2, 3/8 M3a, 2/8 M3b. The distribution according to the Montreal classification: 4/6 Crohn's disease patients are B1, 2/6 Crohn's disease patients are B2, 2/2 ulcerative colitis patients are S2. Normal bone mineral density was detected in 2/8 case, osteopenia in 4/8 and osteoporosis in 2/8 patients. CONCLUSIONS: Within our cohort of patients with coeliac disease, inflammatory bowel disease was significantly more common (3,2 %) than in the general population. PMID- 26481727 TI - Contrast-enhanced ultrasound of embolic consolidations in patients with pulmonary embolism: A pilot study. AB - PURPOSE: To analyze and describe the contrast-enhanced ultrasound (CEUS) patterns of peripheral lung lesions in patients with pulmonary embolism (PE) confirmed on CT angiography or lung scintigraphy. METHODS: CEUS had been performed on 35 patients with peripheral lung lesions detected on gray-scale imaging and confirmed as PE. The following data were evaluated retrospectively: (1) accumulation of contrast medium (absent or present), (2) differentiation between pulmonary arterial (PA) and bronchial arterial blood supply, and (3) contrast enhancement pattern (absent/nonhomogeneous or homogeneous). A CEUS pattern of absent or nonhomogeneous enhancement was suspicious (ie, typical) of embolic consolidations (EC), whereas a pattern of homogeneous PA enhancement was considered to be atypical of EC. RESULTS: Peripheral lesions showed a CEUS pattern suspicious of EC in 80% of the patients, with no enhancement in 40% and nonhomogeneous enhancement in another 40%. A CEUS pattern of homogeneous PA enhancement, atypical of EC, was identified in the remaining 20% of the patients. Pulmonary lesions larger than 1 cm showed vascularization more often than smaller lesions did (p < 0.001). CONCLUSIONS: Peripheral lung lesions in patients with confirmed PE show a CEUS pattern of absent or nonhomogeneous contrast enhancement for suspicious EC. Further prospective studies are required to verify the diagnostic accuracy of CEUS for EC. PMID- 26481728 TI - Retinal hemorrhages following fingolimod treatment for multiple sclerosis; a case report. AB - BACKGROUND: Fingolimod is the first oral agent used for treatment of relapsing remitting multiple sclerosis. Macular edema, but not retinal hemorrhage, is a well-known adverse effect of fingolimod treatment. To the best of our knowledge, this is the first case report of extensive retinal hemorrhages following fingolimod treatment. CASE PRESENTATION: A 31-year-old male with relapsing remitting multiple sclerosis developed macular edema and retinal hemorrhages in his left eye, 1 month after starting fingolimod treatment; treatment was then discontinued. The hemorrhages were flame-shaped, and were extensive along retinal arteries and veins. The hemorrhages started to decrease at 4 weeks and disappeared completely at 24 weeks after cessation of fingolimod treatment. CONCLUSIONS: Occurrence of retinal hemorrhage warrants careful follow-up for multiple sclerosis patients treated with fingolimod. PMID- 26481729 TI - Mitral valve repair after annuloplasty ring dehiscence using MitraClip. AB - Dehiscence of a surgical mitral annuloplasty ring for repair of functional mitral regurgitation (MR) is an infrequently reported complication that often manifests as recurrent MR and heart failure. Re-do mitral valve surgery to correct ring dehiscence may not be feasible for patients at high risk of operative mortality or serious morbidity. We report two cases of mitral annular ring dehiscence and severe mitral regurgitation in patients at prohibitive risk for re-do mitral valve surgery who were successfully treated with MitraClip. (c) 2015 Wiley Periodicals, Inc. PMID- 26481730 TI - Uncritical and unbalanced coverage of synthetic biology in the Nordic press. AB - Synthetic biology will probably have a high impact on a variety of fields, such as healthcare, environment, biofuels, agriculture, and so on. A driving theme in European research policy is the importance of maintaining public legitimacy and support. Media can influence public attitudes and are therefore an important object of study. Through qualitative content analysis, this study investigates the press coverage of synthetic biology in the major Nordic countries between 2009 and 2014. The press coverage was found to be event-driven and there were striking similarities between countries when it comes to framing, language use, and treated themes. Reporters showed a marked dependence on their sources, mainly scientists and stakeholders, who thus drives the media agenda. The media portrayal was very positive, with an optimistic look at future benefits and very little discussion of possible risks. PMID- 26481732 TI - Lucky China: Efficient Prevention from Middle East Respiratory Syndrome and its Beyond. PMID- 26481731 TI - De novo transcriptome analysis of Medicago falcata reveals novel insights about the mechanisms underlying abiotic stress-responsive pathway. AB - BACKGROUND: The entire world is facing a deteriorating environment. Understanding the mechanisms underlying plant responses to external abiotic stresses is important for breeding stress-tolerant crops and herbages. Phytohormones play critical regulatory roles in plants in the response to external and internal cues to regulate growth and development. Medicago falcata is one of the stress tolerant candidate leguminous species and is able to fix atmospheric nitrogen. This ability allows leguminous plants to grow in nitrogen deficient soils. METHODS: We performed Illumina sequencing of cDNA prepared from abiotic stress treated M. falcata. Sequencedreads were assembled to provide a transcriptome resource. Transcripts were annotated using BLASTsearches against the NCBI non redundant database and gene ontology definitions were assigned. Acomparison among the three abiotic stress treated samples was carried out. The expression of transcriptswas confirmed with qRT-PCR. RESULTS: We present an abiotic stress responsive M. falcata transcriptome using next-generation sequencing data from samples grown under standard, dehydration, high salinity, and cold conditions. We combined reads from all samples and de novo assembled 98,515 transcripts to build the M. falcata gene index. A comprehensive analysis of the transcriptome revealed abiotic stress-responsive mechanisms underlying the metabolism and core signalling components of major phytohormones. We identified nod factor signalling pathways during early symbiotic nodulation that are modified by abiotic stresses. Additionally, a global comparison of homology between the M. falcata and M. truncatula transcriptomes, along with five other leguminous species, revealed a high level of global sequence conservation within the family. CONCLUSIONS: M. falcata is shown to be a model candidate for studying abiotic stress-responsive mechanisms in legumes. This global gene expression analysis provides new insights into the biochemical and molecular mechanisms involved in the acclimation to abiotic stresses. Our data provides many gene candidates that might be used for herbage and crop breeding. Additionally, FalcataBase ( http://bioinformatics.cau.edu.cn/falcata/ ) was built for storing these data. PMID- 26481733 TI - Clinical and Radiological Profile of Acute Fibrinous and Organizing Pneumonia: A Retrospective Study. AB - BACKGROUND: Acute fibrinous and organizing pneumonia (AFOP) is a unique pathological entity with intra-alveolar fibrin in the form of "fibrin balls" and organizing pneumonia. It was divided into rare idiopathic interstitial pneumonia according to the classification notified by American Thoracic Society/European Respiratory Society in 2013. As a rare pathological entity, it is still not well known and recognized by clinicians. We reviewed the clinical features of 20 patients with AFOP diagnosed in a teaching hospital. METHODS: The medical records of 20 patients with biopsy-proven diagnosis of AFOP were retrospectively reviewed. The patients' symptoms, duration of the disease, comorbidities, clinical laboratory data, pulmonary function testing, radiographic studies, and the response to treatment were extracted and analyzed. RESULTS: Fever was the most common symptom and was manifested in 90% of AFOP patients. For clinical laboratory findings, systematic inflammatory indicators, including C-reactive protein and erythrocyte sedimentation rate, were significantly higher than normal in AFOP patients. In accordance with this increased indicators, injured liver functions were common in AFOP patients. Inversely, AFOP patients had worse clinical conditions including anemia and hypoalbuminemia. For pulmonary function testing, AFOP patients showed the pattern of restrictive mixed with obstructive ventilation dysfunction. For high-resolution computerized tomography (HRCT) findings, the most common pattern for AFOP patients was lobar consolidation which was very similar to pneumonia. However, unlike pneumonia, AFOP patients responded well to glucocorticoids. CONCLUSION: Patients with AFOP manifest as acute inflammatory-like clinical laboratory parameters and lobar consolidation on HRCT, but respond well to steroid. PMID- 26481734 TI - Healthcare-associated Pneumonia: Clinical Features and Retrospective Analysis Over 10 Years. AB - BACKGROUND: Healthcare-associated pneumonia (HCAP) is associated with drug resistant pathogens and high mortality, and there is no clear evidence that this is due to inappropriate antibiotic therapy. This study was to elucidate the clinical features, pathogens, therapy, and outcomes of HCAP, and to clarify the risk factors for drug-resistant pathogens and prognosis. METHODS: Retrospective observational study among hospitalized patients with HCAP over 10 years. The primary outcome was 30-day all-cause hospital mortality after admission. Demographics (age, gender, clinical features, and comorbidities), dates of admission, discharge and/or death, hospitalization costs, microbiological results, chest imaging studies, and CURB-65 were analyzed. Antibiotics, admission to Intensive Care Unit (ICU), mechanical ventilation, and pneumonia prognosis were recorded. Patients were dichotomized based on CURB-65 (low- vs. high-risk). RESULTS: Among 612 patients (mean age of 70.7 years), 88.4% had at least one comorbidity. Commonly detected pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, and coagulase-negative staphylococci. Initial monotherapy with beta-lactam antibiotics was the most common initial therapy (50%). Mean age, length of stay, hospitalization expenses, ICU admission, mechanical ventilation use, malignancies, and detection rate for P. aeruginosa, and Staphylococcus aureus were higher in the high-risk group compared with the low-risk group. CURB 65 >=3, malignancies, and mechanical ventilation were associated with an increased mortality. Logistic regression analysis showed that cerebrovascular diseases and being bedridden were independent risk factors for HCAP. CONCLUSION: Initial treatment of HCAP with broad-spectrum antibiotics could be an appropriate approach. CURB-65 >=3, malignancies, and mechanical ventilation may result in an increased mortality. PMID- 26481735 TI - Whole Lung Lavage Treatment of Chinese Patients with Autoimmune Pulmonary Alveolar Proteinosis: A Retrospective Long-term Follow-up Study. AB - BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare lung disease, the most common type of which is autoimmune PAP. The gold standard therapy for PAP is whole lung lavage (WLL). Few studies have reported the optimal technique with which to evaluate the response to WLL. In this study, we aimed to identify parameters with which to assess the need for repeat WLL during a long-term 8-year follow-up. METHODS: We conducted a retrospective analysis of 120 patients with autoimmune PAP with 80 of whom underwent WLL. Physiologic, serologic, and radiologic features of the patients were analyzed during an 8-year follow-up after the first WLL treatment. RESULTS: Of the 40 patients without any intervention, 39 patients either achieved remission or remained stable and only one died of pulmonary infection. Of the 56 patients who underwent WLL for 1 time, 55 remained free from a second WLL and 1 patient died of cancer. Twenty-four required additional treatments after their first WLL. The baseline PaO 2 (P = 0.000), PA-aO 2 (P = 0.000), shunt fraction rate (P = 0.001), percent of predicted normal diffusing capacity of the lung for carbon monoxide (DLCO%Pred) (P = 0.016), 6-min walk test (P = 0.013), carcinoembryonic antigen (CEA) (P = 0.007), and neuron-specific enolase (NSE) (P = 0.003) showed significant differences among the three groups. The need for a second WLL was significantly associated with PaO 2 (P = 0.000), CEA (P = 0.050) , the 6-minute walk test (P = 0.026), and DLCO%Pred (P = 0.041). The DLCO%Pred on admission with a cut-off value of 42.1% (P = 0.001) may help to distinguish whether patients with PAP require a second WLL. CONCLUSIONS: WLL is the optimal treatment method for PAP and provides remarkable improvements for affected patients. The DLCO%Pred on admission with a cut-off value of 42.1% may distinguish whether patients with PAP require a second WLL. PMID- 26481736 TI - Endobronchial Ultrasound Elastography for Diagnosing Mediastinal and Hilar Lymph Nodes. AB - BACKGROUND: Pathophysiological processes, such as malignancy, can lead to the formation of stiffer tissue in lung cancers. Endobronchial ultrasound (EBUS) elastography is a novel technique for measuring tissue stiffness during EBUS guided transbronchial needle aspiration (EBUS-TBNA). The current study was conducted to investigate the diagnostic value of EBUS elastography for mediastinal and hilar lymph node metastasis in lung cancers. METHODS: From January 2014 to January 2015, 40 patients suspected of lung cancer were enrolled, and a total of 68 lymph nodes were evaluated by EBUS-TBNA. EBUS-guided elastography of lymph nodes was performed prior to EBUS-TBNA. Standard EBUS characteristics were also described. Pathological determination of malignant or benign lymph nodes was used as the gold standard for this study. If EBUS-TBNA did not result in a formal pathological diagnosis of malignancy, patients were referred for a surgical procedure. Comparisons of elastography and standard EBUS characteristics were made between benign and malignant lymph nodes. RESULTS: Elastography grading scores and strain ratios showed significant differences between benign and malignant lymph nodes (P = 0.000). The elastography strain ratio was more sensitive and specific for determining malignant lymph nodes than elastography grading score or standard EBUS criteria. The receiver operating characteristic curve for the elastography strain ratio showed an area under the curve of 0.933. The best cut-off point of the strain ratio for differentiating malignant from benign lymph nodes was 32.07. The elastography strain ratio had a sensitivity of 88.1%, the specificity of 80.8%, positive predictive value of 88.1%, and negative predictive value of 80.8% for distinguishing malignant from benign nodes. The overall accuracy of elastography strain ratio was 85.3%. The strain ratio of malignant and benign lymph nodes positively correlated with the elastography grading score (r = 0.561, P = 0.000). CONCLUSIONS: EBUS elastography can be effectively used to predict mediastinal and hilar lymph node metastases in lung cancer. This noninvasive technique may thus complement standard EBUS and help guide EBUS-TBNA procedures. PMID- 26481737 TI - Parainfluenza Virus Types 1, 2, and 3 in Pediatric Patients with Acute Respiratory Infections in Beijing During 2004 to 2012. AB - BACKGROUND: Although human parainfluenza virus (HPIV) has been determined as an important viral cause of acute respiratory infections (ARIs) in infants and young children, data on long-term investigation are still lacking to disclose the infection pattern of HPIV in China. METHODS: Nasopharyngeal aspirates were collected from 25,773 hospitalized pediatric patients with ARIs from January 2004 through December 2012 for respiratory virus screen by direct immuno-fluorescence assay. RESULTS: Out of these specimens, 1675 (6.50%, 1675/25,773) showed HPIV positive, including 261 (1.01%, 261/25,773) for HPIV1, 28 (0.11%, 28/25,773) for HPIV2, and 1388 (5.39%, 1388/25,773) for HPIV3, 2 of the samples were positive for both HPIV1 and HPIV3, and 36 were co-detected with other viruses. The positive rates of HPIVs were higher in those younger than 3 years old. HPIV3 was detected from all age groups, predominantly from patients under 3 years of age, and the highest frequency was found in those 6 months to 1-year old (352/4077, 8.63%). HPIV3 was the dominant type in each of the years detected between May and July. HPIV1 showed a peak in every odd year, mainly in August or September. HPIV was detected most frequently from patients with upper respiratory infection (12.49%, 157/1257), followed by bronchitis (11.13%, 176/2479), asthma (9.31%, 43/462), bronchiolitis (5.91%, 150/2536), pneumonia (6.06%, 1034/17,068), and those with underlying diseases (1.0%, 15/1506). HPIV3 is the dominant type in these six disease groups referred above, especially in the asthma group. CONCLUSIONS: HPIV is one of the important viral causes of ARIs in infants and young children in Beijing based on the data from the hospitalized children covering a 9-year term. HPIV3 is the predominant type in all these years and in most of the disease groups. HPIVs with different types show different seasonality. PMID- 26481738 TI - A Matched Comparison Study of Uniportal Versus Triportal Thoracoscopic Lobectomy and Sublobectomy for Early-stage Nonsmall Cell Lung Cancer. AB - BACKGROUND: Both uniportal and triportal thoracoscopic lobectomy and sublobectomy are feasible for early-stage non-small cell lung cancer (NSCLC). The aim of this study was to compare the perioperative outcomes of uniportal and triportal thoracoscopic lobectomy and sublobectomy for early-stage NSCLC. METHODS: A total of 405 patients with lung lesions underwent thoracoscopic lobectomy or sublobectomy through a uniportal or triportal procedure in approximately 7-month period (From November 2014 to May 2015). A propensity-matched analysis, incorporating preoperative variables, was used to compare the short-term outcomes of patients who received uniportal or triportal thoracoscopic lobectomy and sublobectomy. RESULTS: Fifty-eight patients underwent uniportal and 347 patients underwent triportal pulmonary resection. The conversion rate for uniportal and triportal procedure was 3.4% (2/58) and 2.3% (8/347), respectively. The complication rate for uniportal and triportal procedure was 10.3% and 9.5%, respectively. There was no perioperative death in either group. Most patients had early-stage NSCLC in both groups (uniportal: 45/47, 96%; triportal: 313/343, 91%). Propensity score-matching analysis demonstrated no significant differences in operation time, intraoperative blood loss, numbers of dissected lymph nodes, number of stations of lymph node dissected, duration of chest tube, and complication rate between uniportal and triportal group for early-stage NSCLC. However, the duration of postoperative hospitalization was longer in the uniportal group (6.83 +/- 4.17 vs. 5.42 +/- 1.86 d, P = 0.036) compared with the triportal group. CONCLUSIONS: Uniportal thoracoscopic lobectomy and sublobectomy is safe and feasible, with comparable short-term outcomes with triportal thoracoscopic pulmonary resection. Uniportal lobectomy and sublobectomy lead to similar cure rate as triportal lobectomy and sublobectomy for early NSCLC. PMID- 26481739 TI - Intravaginal Misoprostol for Cervical Ripening and Labor Induction in Nulliparous Women: A Double-blinded, Prospective Randomized Controlled Study. AB - BACKGROUND: In China, no multicenter double-blinded prospective randomized controlled study on labor induction has been conducted till now. This study is to evaluate the efficacy and safety of intravaginal accurate 25-MUg misoprostol tablets for cervical ripening and labor induction in term pregnancy in nulliparous women. METHODS: This was a double-blinded, prospective randomized controlled study including nulliparous women from 6 university hospitals across China. Subjects were randomized into misoprostol or placebo group with the sample size ratio set to 7:2. Intravaginal 25-MUg misoprostol or placebo was applied at an interval of 4 h (repeated up to 3 times) for labor induction. Primary outcome measures were the incidence of cumulative Bishop score increases >=3 within 12 h or vaginal delivery within 24 h. Safety assessments included the incidences of maternal morbidity and adverse fetal/neonatal outcomes. RESULTS: A total of 173 women for misoprostol group and 49 women for placebo were analyzed. The incidence of cumulative Bishop score increases >=3 within 12 h or vaginal delivery within 24 h was higher in the misoprostol group than in the placebo (64.2% vs. 22.5%, relative risk [RR]: 2.9, 95% confidence interval [CI]: 1.4-6.0). The incidence of onset of labor within 24 h was significantly higher in the misoprostol group than in the placebo group (48.0% vs. 18.4%, RR: 2.6, 95% CI: 1.2-5.7); and the induction-onset of labor interval was significantly shorter in the misoprostol group (P = 0.0003). However, there were no significant differences in the median process time of vaginal labor (6.4 vs. 6.8 h; P = 0.695), incidence (39.3% vs. 49.0%, RR: 0.8, 95% CI: 0.4-1.5) and indications (P = 0.683) of cesarean section deliveries, and frequencies of maternal, fetal/neonatal adverse events between the groups. CONCLUSION: Intravaginal misoprostol 25 MUg every 4 h is efficacious and safe in labor induction and cervical ripening. PMID- 26481740 TI - Mortality and Morbidity of Extremely Low Birth Weight Infants in the Mainland of China: A Multi-center Study. AB - BACKGROUND: With the progress of perinatal medicine and neonatal technology, more and more extremely low birth weight (ELBW) survived all over the world. This study was designed to investigate the short-term outcomes of ELBW infants during their Neonatal Intensive Care Unit (NICU) stay in the mainland of China. METHODS: All infants admitted to 26 NICUs with a birth weight (BW) < l000 g were included between January l, 2011 and December 31, 2011. All the data were collected retrospectively from clinical records by a prospectively designed questionnaire. The data collected from each NICU transmitted to the main institution where the results were aggregated and analyzed. Categorical variables were performed with Pearson Chi-square test. Binary Logistic regression analysis was used to detect risk factors. RESULTS: A total of 258 ELBW infants were admitted to 26 NICUs, of whom the mean gestational age (GA) was 28.1 +/- 2.2 weeks, and the mean BW was 868 +/- 97 g. The overall survival rate at discharge was 50.0%. Despite aggressive treatment 60 infants (23.3%) died and another 69 infants (26.7%) died after medical care withdrawal. Furthermore, the survival rate was significantly higher in coastal areas than inland areas (53.6% vs. 35.3%, P = 0.019). BW < 750 g and GA < 28 weeks were the largest risk factors, and being small for gestational age was a protective factor related to mortality. Respiratory distress syndrome was the most common complication. The incidence of patent ductus arteriosus, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, retinopathy of prematurity was 26.2%, 33.7%, 6.7%, 48.1%, and 41.4%, respectively. Ventilator associated pneumonia was the most common hospital acquired infection during hospitalization. CONCLUSIONS: Our study was the first survey that revealed the present status of ELBW infants in the mainland of China. The mortality and morbidity of ELBW infants remained high as compared to other developed countries. PMID- 26481741 TI - Does Early Postsurgical Temozolomide Plus Concomitant Radiochemotherapy Regimen Have Any Benefit in Newly-diagnosed Glioblastoma Patients? A Multi-center, Randomized, Parallel, Open-label, Phase II Clinical Trial. AB - BACKGROUND: The radiochemotherapy regimen concomitantly employing temozolomide (TMZ) chemotherapy and radiotherapy (RT) 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma (GBM). However, its median overall survival (OS) is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen. METHODS: A randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide (early TMZ group) or standard concomitant radiochemotherapy regimen (control group). Overall response was assessed based on objective tumor assessments, administration of corticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event (AE), and neurological condition were measured for 24 months of follow-up. The primary efficacy endpoint of this study was overall survival (OS). The secondary endpoint was progression free survival (PFS). RESULTS: The median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group (log-rank test P = 0.021). In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively (P < 0.05). The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group (log-rank test P = 0.695). AEs occurred in 29 (55.8%) and 31(73.8%) patients respectively in early and control groups, including nausea (15.4% vs. 33.3%), vomiting (7.7% vs. 28.6%), fever (7.7% vs. 11.9%), and headache (3.8% vs. 23.8%). Only 30.8% and 33.3% were drug related, respectively. CONCLUSIONS: Addition of TMZ chemotherapy in the early break of the standard concomitant radiochemotherapy regimen was well tolerated and significantly improved the OS of the GBM patients, compared with standard concomitant radiochemotherapy regimen. However, a larger randomized trial is warranted to verify these results. PMID- 26481742 TI - Expression of Transcription Factor FOXO3a is Decreased in Patients with Ulcerative Colitis. AB - BACKGROUND: Ulcerative colitis (UC) is associated with differential expression of genes involved in inflammation and tissue remodeling, including FOXO3a, which encodes a transcription factor known to promote inflammation in several tissues. However, FOXO3a expression in tissues affected by UC has not been examined. This study investigated the effects of FOXO3a on UC pathogenesis. METHODS: FOXO3a expression, in 23 patients with UC and in HT29 cells treated with tumor necrosis factor-alpha (TNF-alpha) for various durations, was detected by quantitative real time polymerase chain reaction and Western blotting analysis. Enzyme-linked immunosorbent assay was used to quantify interleukin (IL)-8 expression in FOXO3a silenced HT29 cells treated with TNF-alpha for various durations. RESULTS: The messenger RNA and protein expression of FOXO3a were significantly lower in UC tissues than those in normal subjects (P < 0.01). TNF-alpha treatment for 0, 0.5, 1, 6, and 24 h induced FOXO3 degradation in HT29 cells. FOXO3a silencing increased IL-8 levels in HT29 cells treated with TNF-alpha for 6 h (P < 0.05). CONCLUSION: FOXO3a may play an important role in the intestinal inflammation of patients with UC. PMID- 26481743 TI - Aortic Artery and Cardiac Valve Calcification are Associated with Mortality in Chinese Hemodialysis Patients: A 3.5 Years Follow-up. AB - BACKGROUND: This study was to investigate the relationship among aortic artery calcification (AAC), cardiac valve calcification (CVC), and mortality in maintenance hemodialysis (MHD) patients. METHODS: All MHD patients in Shanghai Ruijin Hospital in July 2011 were included. To follow up for 42 months, clinical data, predialysis blood tests, echocardiography, and lateral lumbar X-ray plain radiography results were collected. Plasma FGF23 level was measured using a C terminal assay. RESULTS: Totally, 110 MHD patients were involved in this study. Of which, 64 (58.2%) patients were male, the mean age was 55.2 +/- 1.4 years old, and the median dialysis duration was 29.85 (3.0-225.5) months. About 25.5% of the 110 MHD patients had CVC from echocardiography while 61.8% of the patients had visible calcification of aorta from lateral lumbar X-ray plain radiography. After 42 months follow-up, 25 (22.7%) patients died. Kaplan-Meier analysis showed that patients with AAC or CVC had a significant greater number of all-cause and cardiovascular deaths than those without. In multivariate analyses, the presence of AAC was a significant factor associated with all-cause mortality (hazard ratio [HR]: 3.149, P = 0.025) in addition to lower albumin level and lower 25-hydroxy Vitamin D (25(OH)D) level. The presence of CVC was a significant factor associated with cardiovascular mortality (HR: 3.800, P = 0.029) in addition to lower albumin level and lower 25(OH)D level. CONCLUSION: Lateral lumbar X-ray plain radiography and echocardiography are simple methods to detect AAC and CVC in dialysis patients. The presence of AAC and CVC was independently associated with mortality in MHD patients. Regular follow-up by X-ray and echocardiography could be a useful method to stratify mortality risk in MHD patients. PMID- 26481744 TI - Aneuploidy in Early Miscarriage and its Related Factors. AB - BACKGROUND: Genetic factors are the main cause of early miscarriage. This study aimed to investigate aneuploidy in spontaneous abortion by fluorescence in situ hybridization (FISH) using probes for 13, 16, 18, 21, 22, X and Y chromosomes. METHODS: A total of 840 chorionic samples from spontaneous abortion were collected and examined by FISH. We analyzed the incidence and type of abnormal cases and sex ratio in the samples. We also analyzed the relationship between the rate of aneuploidy and parental age, the rate of aneuploidy between recurrent abortion and sporadic abortion, the difference in incidence of aneuploidy between samples from previous artificial abortion and those from no previous induced abortion. RESULTS: A total of 832 samples were finally analyzed. 368 (44.23%) were abnormal, in which 84.24% (310/368) were aneuploidies and 15.76% (58/368) were polyploidies. The first was trisomy 16 (121/310), followed by trisomy 22, and X monosomy. There was no significant difference in the rate of aneuploidy in the advanced maternal age group (>= 35 years old) and young maternal age group (<35 years old). However, the rate of trisomy 22 and the total rate of trisomies 21, 13, and 18 (the number of trisomy 21 plus trisomy 13 and trisomy 18 together) showed significantly different in two groups. We found no skewed sex ratio. There was no significant difference in the rate of aneuploidy between recurrent miscarriage and sporadic abortion or between the samples from previous artificial abortion and those from no previous artificial abortion. CONCLUSIONS: Aneuploidy is a principal factor of miscarriage and total parental age is a risk factor. There is no skewed sex ratio in spontaneous abortion. There is also no difference in the rate of aneuploidy between recurrent abortion and sporadic abortion or between previous artificial abortion and no previous induced abortion. PMID- 26481745 TI - Analysis of Renal Artery Stenosis in Patients with Heart Failure: A RASHEF Study. AB - BACKGROUND: Previous data are controversial about the association of renal artery stenosis (RAS) with clinical outcome in patients with heart failure. Definition of RAS in previous studies might not be appropriate. By definition of RAS with renal duplex sonography, we investigated the association of RAS with clinical outcome in patients with heart failure. METHODS: In this retrospective study, we identified 164 patients with heart failure (New York Heart Association classification >=II; left ventricular ejection fraction <50%) who had received renal duplex sonography during hospital stay. RAS was defined as renal-aortic ratio >=3.5 or a peak systolic velocity >=200 cm/s (or both), or occlusion of the renal artery. Categorical data of patients were compared using the Chi-square test or Fisher's exact test. Cox proportional hazards regression modeling technique was used to investigate the prognostic significance of possible predictors. RESULTS: Finally, 143 patients were enrolled. Median follow-up time was 32 months (1-53 months). Twenty-two patients were diagnosed as RAS by renal duplex sonography, including 13 unilateral RAS (3 left RAS, 10 right RAS) and 9 bilateral RAS. There were more all-cause mortality and cardiovascular death in patients with RAS than patients without RAS. By multivariate analysis, RAS was a significant predictor for all-cause death and cardiovascular death (hazard ratio [HR] = 4.155, 95% confidence interval [CI]: 1.546-11.164, P = 0.005; and HR = 3.483, 95% CI: 1.200-10.104, P = 0.022, respectively). As for composite endpoint events, including death, nonfatal myocardial infarction, ischemic stroke or intracranial hemorrhage, rehospitalization for cardiac failure, and renal replacement therapy, only angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was significant predictor. RAS was not a significant predictor for composite endpoint events. CONCLUSIONS: Our data suggested that RAS is associated with a poorer clinical outcome in patients with heart failure. PMID- 26481746 TI - Single-fiber Electromyography in the Extensor Digitorum Communis for the Predictive Prognosis of Ocular Myasthenia Gravis: A Retrospective Study of 102 Cases. AB - BACKGROUND: Single-fiber electromyography (SFEMG) abnormality in the extensor digitorum communis (EDC) was reported in ocular myasthenia gravis (OMG), which indicated subclinical involvement beyond extraocular muscles in OMG patients. The relationship between the abnormal findings of SFEMG in EDC and the probability for OMG to develop generalized myasthenia gravis (GMG) is unknown. This retrospective study aimed to determine the predictive value of abnormality of SFEMG in EDC of OMG patients. METHODS: One-hundred and two OMG patients underwent standard clinical diagnosis process and SFEMG test in EDC muscle when diagnosed and were clinically followed up for 5 years. The SFEMG data were compared between different clinical groups according to thymus status, onset age, and different outcome of OMG developing. Chances of progressing to GMG were compared between two different groups according to SFEMG and repetitive nerve stimulation (RNS) results, acetylcholine receptor antibody (AchRAb) titer, thymus status, and onset age. RESULTS: Abnormal SFEMG results were observed in 84 (82.4%) patients. The mean jitter, percentage of jitter >55 MUs (%), and blocking were higher in OMG patients than in healthy volunteers. There were no statistical differences in jitter analysis between thymoma group and non-thymoma group (P = 0.65), or between the later OMG group and the later GMG group (P = 0.31), including mean jitter, percentage of jitter >55 MUs (%), and blocking. Elderly group (>=45 years old) had a higher mean jitter than younger group (t = 2.235, P = 0.028). Total 55 OMG developed GMG, including 47 in abnormal SFEMG group while 8 in normal SFEMG group. There was no statistical difference in the conversion rates between the two groups (chi2 = 0.790, P = 0.140). RNS abnormality, AchRab titer, or onset age had no correlation with OMG prognosis (P = 0.150, 0.070, 0.120, respectively) while thymoma did (chi2 = 0.510, P = 0.020). CONCLUSION: SFEMG test in the EDC showed high abnormality in OMG, suggesting subclinical involvement other than extraocular muscles. Nevertheless, the abnormal jitter analysis did not predict the prognosis of OMG according to clinical follow-up. PMID- 26481747 TI - Process of Hypertrophic Scar Formation: Expression of Eukaryotic Initiation Factor 6. AB - BACKGROUND: Hypertrophic scar is one of the most common complications and often causes the disfigurement or deformity in burn or trauma patients. Therapeutic methods on hypertrophic scar treatment have limitations due to the poor understanding of mechanisms of hypertrophic scar formation. To throw light on the molecular mechanism of hypertrophic scar formation will definitely improve the outcome of the treatment. This study aimed to illustrate the negative role of eukaryotic initiation factor 6 (eIF6) in the process of human hypertrophic scar formation, and provide a possible indicator of hypertrophic scar treatment and a potential target molecule for hypertrophic scar. METHODS: In the present study, we investigated the protein expression of eIF6 in the human hypertrophic scar of different periods by immunohistochemistry and Western blot analysis. RESULTS: In the hypertrophic scar tissue, eIF6 expression was significantly decreased and absent in the basal layer of epidermis in the early period, and increased slowly and began to appear in the basal layer of epidermis by the scar formation time. CONCLUSIONS: This study confirmed that eIF6 expression was significantly related to the development of hypertrophic scar, and the eIF6 may be a target molecule for hypertrophic scar control or could be an indicator of the outcomes for other treatment modalities. PMID- 26481748 TI - Distribution of Major Pathogens from Sputum and Bronchoalveolar Lavage Fluid in Patients with Noncystic Fibrosis Bronchiectasis: A Systematic Review. AB - OBJECTIVE: Noncystic fibrosis (non-CF) bronchiectasis remains as a common health problem in Asia. Pathogens' distribution in airways of patients with non-CF bronchiectasis is important for doctors to make right decision. DATA SOURCES: We performed this systematic review on the English language literatures from 1966 to July 2014, using various search terms included "pathogens" or "bacteria" or "microbiology" and "bronchiectasis" or "non-cystic fibrosis bronchiectasis" or "non-CF bronchiectasis" or "NCFB." STUDY SELECTION: We included studies of patients with the confirmed non-CF bronchiectasis for which culture methods were required to sputum or bronchoalveolar lavage fluid (BALF). Weighted mean isolation rates for Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Stapylococcus aureus, Moxarella catarrhails were compared according to different methodology. RESULTS: The total mean bacterial culture positive rates were 63%. For studies using sputum samples, the mean positive culture rates were 74%. For studies using BALF alone or BALF and sputum, it was 48%. The distributions of main bacterial strains were 29% for H. influenzae, 28% for P. aeruginosa, 11% for S. pneumoniae, 12% for S. aureus, and 8% for M. catarrhails with methodology of sputum. Meanwhile, the bacterial distributions were 37% for H. influenzae, 8% for P. aeruginosa, 14% for S. pneumoniae, 5% for S. aureus, and 10% for M. catarrhails with methodology of BALF alone or BALF and sputum. Analysis of the effect of different methodology on the isolation rates revealed some statistically significant differences. CONCLUSIONS: H. influenzae accounted for the highest percentage in different methodology. Our results suggested that the total positive culture rates and the proportion of P. aeruginosa from sputum and BALF specimens had significant differences, which can be used in further appropriate recommendations for the treatment of non-CF bronchiectasis. PMID- 26481749 TI - Asthma and Obstructive Sleep Apnea. AB - OBJECTIVE: To get a comprehensive understanding about the relationship between obstructive sleep apnea (OSA) and asthma by reviewing the epidemiology, pathophysiology, and clinical manifestation and then summarizing the latest progress on diagnosis and treatment. DATA SOURCES: Articles referred in this review were mainly collected from a comprehensive search of the PubMed published in English from 1990 to 2015 with the terms "OSA" and "asthma" as the main keywords. Highly regarded older publications were also included. STUDY SELECTION: Information about the features of the two diseases in common, the pathophysiologic association between them and their current treatments from the literature search were identified, retrieved, and summarized. RESULTS: Both OSA and asthma are very prevalent conditions. The incidences of them have kept on rising in recent years. Asthma is often accompanied by snoring and apnea, and OSA often combines with asthma, as well. They have many predisposing and aggravating factors in common. Possible shared direct mechanistic links between them include mechanical effects, intermittent hypoxia, nerve reflex, inflammation, leptin, etc. Indirect mechanistic links include medication, nose diseases, smoking, obesity, and gastroesophageal reflux disease. Since OSA presents many similar features with nocturnal asthma, some scholars termed them as a sole syndrome - "alternative overlap syndrome," and proved that asthma symptoms in those patients could be improved through the treatment of continuous positive airway pressure. CONCLUSIONS: OSA and asthma are closely associated in pathogenesis, symptoms, and therapies. With the growing awareness of the relationship between them, we should raise our vigilance on the coexistence of OSA in those difficult-to-control asthmatic patients. Further studies are still needed to guide the clinical works. PMID- 26481751 TI - Tuberculosis of Lymph Node Combined with Pulmonary Mucormycosis. PMID- 26481750 TI - Intestinal Microbiota Metabolism and Atherosclerosis. AB - OBJECTIVE: This review aimed to summarize the relationship between intestinal microbiota metabolism and cardiovascular disease (CVD) and to propose a novel CVD therapeutic target. DATA SOURCES: This study was based on data obtained from PubMed and EMBASE up to June 30, 2015. Articles were selected using the following search terms: "Intestinal microbiota", "trimethylamine N-oxide (TMAO)", "trimethylamine (TMA)", "cardiovascular", and "atherosclerosis". STUDY SELECTION: Studies were eligible if they present information on intestinal microbiota metabolism and atherosclerosis. Studies on TMA-containing nutrients were also included. RESULTS: A new CVD risk factor, TMAO, was recently identified. It has been observed that several TMA-containing compounds may be catabolized by specific intestinal microbiota, resulting in TMA release. TMA is subsequently converted to TMAO in the liver. Several preliminary studies have linked TMAO to CVD, particularly atherosclerosis; however, the details of this relationship remain unclear. CONCLUSIONS: Intestinal microbiota metabolism is associated with atherosclerosis and may represent a promising therapeutic target with respect to CVD management. PMID- 26481752 TI - Polycythemia, Ablepsia, and Obesity Hypoventilation Syndrome: A Case Report. PMID- 26481753 TI - Folding Sutures Following Tourniquet Binding as a Conservative Surgical Approach for Placenta Previa Combined with Morbidly Adherent Placenta. PMID- 26481754 TI - Acute Bilateral Optic Neuritis in Active Ankylosing Spondylitis. PMID- 26481755 TI - Fungal Keratitis Associated with Viral Keratitis. PMID- 26481756 TI - Multiple Ecchordosis Physaliphora: A Challenging Diagnosis. PMID- 26481757 TI - A Rare Novel Copy Number Variation of Xp22.33-p11.22 Duplication is Associated with Congenital Heart Defects. PMID- 26481758 TI - Repair of Large Diaphragmatic Defect Using Artificial Patch in Hydatid Disease. PMID- 26481759 TI - Kaposi's Varicelliform Eruption During Long-term Treatment of Rosacea with 0.03% Tacrolimus Ointment. PMID- 26481760 TI - Sudden Thrombosis in Coronary Artery Bypass Grafting Surgery. PMID- 26481761 TI - Stevens-Johnson Syndrome and Hypothermia Associated with Anti-tuberculosis Medication in a Patient with Heart Failure. PMID- 26481762 TI - Scalp Avulsion Combined with Unusual Severe Open Craniocerebral Avulsion Injury. PMID- 26481763 TI - Apheresis for babesiosis: Therapeutic parasite reduction or removal of harmful toxins or both? AB - Babesiosis is a potentially life-threatening illness caused by intraerythrocytic protozoan parasites of the genus Babesia that are transmitted most commonly by Ixodes ticks, and rarely from blood transfusion or congenitally. Clinical presentations of babesiosis include asymptomatic infection, mild to moderate disease, or severe disease. Antibiotics such as atovaquone plus azithromycin or clindamycin and quinine can be used effectively to treat this disease in most cases, however in high risk populations, the mortality rate can be as high as 20% despite therapy. Therapeutic exchange transfusion has been used in severe babesiosis and is of apparent therapeutic benefit. It is not entirely clear through what mechanism therapeutic exchange transfusion may help patients. Data suggests that in addition to parasite load reduction, it is possible that therapeutic exchange transfusion removes toxins generated by babesia infection. There are many remaining questions that need to be addressed regarding exchange transfusion for babesiosis. J. Clin. Apheresis 31:454-458, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26481764 TI - Potential biomarkers for the early detection of acute kidney injury after percutaneous nephrolithotripsy. AB - This study aims to investigate the role of urinary biomarkers in the determination of the potential risks of renal parenchymal tubular damage in adult patients who underwent percutaneous nephrolithotomy (PNL) with the indication of renal stone. A randomized and prospective controlled study was performed between June and December 2013. We enrolled 29 consecutive patients with renal calculi > 2 cm and who underwent PNL, as well as 47 healthy control subjects. Urine samples, including 2 h before surgery, 2 and 24 h after surgery were collected from the patient group. Freshly voided urine samples were collected from the control group. Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-glucosaminidase (NAG), and liver-type fatty acid binding protein (LFABP) levels were measured from these urine samples. The mean KIM-1/Cr value that measured 24 h after the operation was statistically significant, higher than its preoperative (preop) level (p = 0.045). A significant difference was detected between the mean preop and postoperative (postop) 24 h NAG/Cr values (p < 0.001). Also, postop 24 h NGAL/Cr levels were statistically significant, higher than its preop levels (p = 0.013). According to the comparison of preop and postop levels, an increase in LFABP/Cr values secondary to surgical intervention was observed without any statistically significant difference. Besides the LFABP/Cr levels do not change after percutaneous kidney surgery, KIM-1/Cr, NAG/Cr, and NGAL/Cr levels increase postop period, especially at 24 h. Further studies with a larger series and repeated measurements should be performed to clarify if they can be used to demonstrate renal damage after percutaneous surgery or not. PMID- 26481765 TI - Do patients discussed at a lung cancer multidisciplinary team meeting receive guideline-recommended treatment? AB - AIM: Clinical guidelines provide evidence-based management recommendations to guide practice. This study aimed to evaluate whether patients discussed at a lung cancer multidisciplinary team meeting received guideline-recommended treatment and determine reasons for not receiving guideline-recommended treatment. METHODS: All new lung cancer patients discussed at the Liverpool/Macarthur lung cancer multidisciplinary team meeting between 1 December 2005 and 31 December 2010 were included. Guideline-recommended treatment was assigned according to pathology, stage and ECOG (Eastern Co-operative Oncology Group) performance status as per the 2004 Australian Lung Cancer Guidelines. This was compared with actual treatment received to determine adherence to guidelines. For those patients who did not receive guideline-recommended treatment, the medical record was reviewed to determine the reason(s) for this. Survival was compared between those who did and did not receive guideline-recommended treatment. RESULTS: 808 new patients were discussed at the multidisciplinary team meeting. Guideline-recommended treatment could not be assigned in 2% of patients due to missing data. 435 patients (54%) received guideline-recommended treatment, and 356 (44%) did not. The most common reasons for not receiving guideline-recommended treatment were a decline in ECOG performance status (24%), large tumor volume precluding radical radiotherapy (17%), comorbidities (15%) and patient preference (13%). Patients less than 70 years who received guideline-recommended treatment had improved survival compared with those who did not. CONCLUSIONS: A significant proportion of lung cancer patients did not receive guideline-recommended treatment due to legitimate reasons. Alternative guidelines are needed for patients not suitable for current best practice. Treatment according to guidelines was a predictor for survival. PMID- 26481766 TI - High-Quality Graphene Ribbons Prepared from Graphene Oxide Hydrogels and Their Application for Strain Sensors. AB - Reduced graphene oxide (rGO) ribbons with arbitrary lengths were prepared by dry spinning of the hydrogels of graphene oxide (GO) formed via thermal annealing GO dispersions, and followed by chemical reduction. These rGO ribbons are flexible, having ultrahigh tensile strengths of 582 +/- 17 MPa, ultrahigh fracture energies of 18.29 +/- 2.47 MJ m(-3), high conductivities of 662 +/- 41 S cm(-1), and an extremely large breakdown current density of about 11,500 A cm(-2). Strain sensors based on the meshes of these ribbons showed sensitive recoverable responses to different tensile strains with excellent cycling stability, promising for the applications in wearable devices. PMID- 26481767 TI - Electromechanical oscillations in bilayer graphene. AB - Nanoelectromechanical systems constitute a class of devices lying at the interface between fundamental research and technological applications. Realizing nanoelectromechanical devices based on novel materials such as graphene allows studying their mechanical and electromechanical characteristics at the nanoscale and addressing fundamental questions such as electron-phonon interaction and bandgap engineering. In this work, we realize electromechanical devices using single and bilayer graphene and probe the interplay between their mechanical and electrical properties. We show that the deflection of monolayer graphene nanoribbons results in a linear increase in their electrical resistance. Surprisingly, we observe oscillations in the electromechanical response of bilayer graphene. The proposed theoretical model suggests that these oscillations arise from quantum mechanical interference in the transition region induced by sliding of individual graphene layers with respect to each other. Our work shows that bilayer graphene conceals unexpectedly rich and novel physics with promising potential in applications based on nanoelectromechanical systems. PMID- 26481768 TI - Phospholipid fatty acid composition linking larval-density to lifespan of adult Drosophila melanogaster. AB - Pre-adult density-associated alterations in the composition of storage lipids may affect the cell membrane fatty acid profile (mainly phospholipids), membrane integrity, and cell function. The present study evaluated the impact of pre-adult density conditions, sex, and the selection regime on the composition of phospholipid fatty acids and lifespan of Drosophila melanogaster. The phospholipid profile of adult flies developed under larval crowding contained a higher proportion of polyunsaturated fatty acids, lower proportion of monounsaturated fatty acids, and greater risk of peroxidation. There was also a negative correlation between the peroxidation index (PI) and longevity. The longevity-selected females showed a lower PI compared with control lines under both densities. The present results indicate that pre-adult density may play a significant role in the lifespan of adult flies by altering the composition of phospholipids and shaping cell membrane bilayers with different susceptibilities to peroxidation. PMID- 26481770 TI - Sequential renal and bone marrow transplants in a child with Fanconi anemia. AB - FA is an autosomal recessive disorder characterized by small stature and renal abnormalities. FA can lead to progressive bone marrow failure, myelodysplastic syndrome, or acute leukemia. Using a multidisciplinary team approach, we managed a 3-yr-old boy with FA who simultaneously developed renal and hematopoietic failure. Because renal function was insufficient to support the conditioning regimen for HCT, we performed a deceased donor renal transplant in December 2012 prior to HCT with the known risk of graft-versus-graft rejection of the donor kidney. Seven months later he underwent allogeneic HCT. He obtained myeloid engraftment on day +11 and peripheral blood chimerism demonstrated all donor by day +21. He developed asymptomatic CMV reactivation and despite antirejection medications, mild skin graft-versus-host disease. He has maintained excellent renal function and remains transfusion independent with full hematopoietic recovery. He has not experienced any renal rejection episodes nor developed donor specific antibodies toward his renal donor. Peripheral blood chimerism remains completely HCT donor. He is clinically well, now greater than two and a half yr after renal transplant and two yr after HCT. The continuing close collaboration between the Pediatric Nephrology and Bone Marrow Transplant teams is a major factor in this successful outcome. PMID- 26481769 TI - Leucine supplementation improves regeneration of skeletal muscles from old rats. AB - The decreased regenerative capacity of old skeletal muscles involves disrupted turnover of proteins. This study investigated whether leucine supplementation in old rats could improve muscle regenerative capacity. Young and old male Wistar rats were supplemented with leucine; then, the muscles were cryolesioned and examined after 3 and 10 days. Leucine supplementation attenuated the decrease in the expression of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and eukaryotic translation initiation factor 4E (eIF4E) in young and old muscles on day 3 post-injury and promoted an increase in the cross-sectional area of regenerating myofibers from both young and old soleus muscles on day 10 post injury. This supplementation decreased the levels of ubiquitinated proteins and increased the proteasome activity in young regenerating muscles, but the opposite effect was observed in old regenerating muscles. Moreover, leucine decreased the inflammation area and induced an increase in the number of proliferating satellite cells in both young and old muscles. Our results suggest that leucine supplementation improves the regeneration of skeletal muscles from old rats, through the preservation of certain biological responses upon leucine supplementation. Such responses comprise the decrease in the inflammation area, increase in the number of proliferating satellite cells and size of regenerating myofibers, combined with the modulation of components of the phosphoinositide 3 kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and ubiquitin-proteasome system. PMID- 26481771 TI - A local redox cycling-based electrochemical chip device with nanocavities for multi-electrochemical evaluation of embryoid bodies. AB - An electrochemical device, which consists of electrode arrays, nanocavities, and microwells, was developed for multi-electrochemical detection with high sensitivity. A local redox cycling-based electrochemical (LRC-EC) system was used for multi-electrochemical detection and signal amplification. The LRC-EC system consists of n(2) sensors with only 2n bonding pads for external connection. The nanocavities fabricated in the sensor microwells enable significant improvement of the signal amplification compared with the previous devices we have developed. The present device was successfully applied for evaluation of embryoid bodies (EBs) from embryonic stem (ES) cells via electrochemical measurements of alkaline phosphatase (ALP) activity in the EBs. In addition, the EBs were successfully trapped in the sensor microwells of the device using dielectrophoresis (DEP) manipulation, which led to high-throughput cell analysis. This device is considered to be useful for multi-electrochemical detection and imaging for bioassays including cell analysis. PMID- 26481773 TI - Human iPS cell models of Jervell and Lange-Nielsen syndrome. AB - Recessive mutations in the ion channel-encoding KCNQ1 gene may cause Jervell and Lange-Nielsen syndrome (JLNS), a fatal cardiac disease leading to arrhythmia and sudden cardiac death in young patients. Mutations in KCNQ1 may also cause a milder and dominantly inherited form of the disease, long QT syndrome 1 (LQT1). However, why some mutations cause LQT1 and others cause JLNS can often not be understood a priori. In a recent study,(1) we have generated human induced pluripotent stem cell (hiPSC) models of JLNS. Our work mechanistically revealed how distinct classes of JLNS-causing genetic lesions, namely, missense and splice site mutations, may promote the typical severe features of the disease at the cellular level. Interestingly, the JLNS models also displayed highly sensitive responses to pro-arrhythmic stresses. We hence propose JLNS hiPSCs as a powerful system for evaluating both phenotype-correcting as well as cardiotoxicity-causing drug effects. PMID- 26481772 TI - Comparing a Video and Text Version of a Web-Based Computer-Tailored Intervention for Obesity Prevention: A Randomized Controlled Trial. AB - BACKGROUND: Web-based computer-tailored interventions often suffer from small effect sizes and high drop-out rates, particularly among people with a low level of education. Using videos as a delivery format can possibly improve the effects and attractiveness of these interventions OBJECTIVE: The main aim of this study was to examine the effects of a video and text version of a Web-based computer tailored obesity prevention intervention on dietary intake, physical activity, and body mass index (BMI) among Dutch adults. A second study aim was to examine differences in appreciation between the video and text version. The final study aim was to examine possible differences in intervention effects and appreciation per educational level. METHODS: A three-armed randomized controlled trial was conducted with a baseline and 6 months follow-up measurement. The intervention consisted of six sessions, lasting about 15 minutes each. In the video version, the core tailored information was provided by means of videos. In the text version, the same tailored information was provided in text format. Outcome variables were self-reported and included BMI, physical activity, energy intake, and appreciation of the intervention. Multiple imputation was used to replace missing values. The effect analyses were carried out with multiple linear regression analyses and adjusted for confounders. The process evaluation data were analyzed with independent samples t tests. RESULTS: The baseline questionnaire was completed by 1419 participants and the 6 months follow-up measurement by 1015 participants (71.53%). No significant interaction effects of educational level were found on any of the outcome variables. Compared to the control condition, the video version resulted in lower BMI (B=-0.25, P=.049) and lower average daily energy intake from energy-dense food products (B=-175.58, P<.001), while the text version had an effect only on energy intake (B=-163.05, P=.001). No effects on physical activity were found. Moreover, the video version was rated significantly better than the text version on feelings of relatedness (P=.041), usefulness (P=.047), and grade given to the intervention (P=.018). CONCLUSIONS: The video version of the Web-based computer-tailored obesity prevention intervention was the most effective intervention and most appreciated. Future research needs to examine if the effects are maintained in the long term and how the intervention can be optimized. CLINICALTRIAL: Netherlands Trial Register: NTR3501; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3501 (Archived by WebCite at http://www.webcitation.org/6cBKIMaW1). PMID- 26481774 TI - Universal contact-line dynamics at the nanoscale. AB - The relaxation dynamics of the contact angle between a viscous liquid and a smooth substrate is studied at the nanoscale. Through atomic force microscopy measurements of polystyrene nanostripes we simultaneously monitor both the temporal evolution of the liquid-air interface and the position of the contact line. The initial configuration exhibits high curvature gradients and a non equilibrium contact angle that drive liquid flow. Both these conditions are relaxed to achieve the final state, leading to three successive regimes in time: (i) stationary contact line levelling; (ii) receding contact line dewetting; (iii) collapse of the two fronts. For the first regime, we reveal the existence of a self-similar evolution of the liquid interface, which is in excellent agreement with numerical calculations from a lubrication model. For different liquid viscosities and film thicknesses we provide evidence for a transition to dewetting featuring a universal critical contact angle and dimensionless time. PMID- 26481775 TI - Robotic Mitral Valve Repair for Simple and Complex Degenerative Disease: Midterm Clinical and Echocardiographic Quality Outcomes. AB - BACKGROUND: Severe primary (degenerative) mitral regurgitation (MR) is repaired with durable results when simple single-scallop disease is addressed. The midterm quality outcomes of minimally invasive repair for complex disease are unknown, however. METHODS AND RESULTS: From January 2008 to January 2015, 487 patients (56+/-11 years, 360 men, ejection fraction 65+/-6%, 98.8% complete follow-up) underwent robotic mitral valve repair for severe nonischemic degenerative MR. Simple pathology was addressed in 289 of 487 (59%) patients, and complex repair (all others) was performed in 198 of 487 (41%). Four patients died during follow up with a 5-year survival rate 99.5% (99.4% simple; 99.5% complex; hazard ratio, 0.48; 95% confidence interval, 0.05-4.59); and New York Heart Association functional class I/II was documented in 97.9% (477/487). Eight patients had recurrence of moderate-to-severe MR (4 simple, 4 complex), with a 5-year freedom from MR of 94.6% (96.2% simple; 92.7%, complex; P=0.67; hazard ratio, 1.36; 95% confidence interval, 0.34-5.43). Seven patients (2 simple, 5 complex), underwent mitral reoperation, with a 5-year freedom from reoperation of 97.7% (99.1% simple; 95.7% complex; P=0.13; hazard ratio, 3.35; 95% confidence interval, 0.65 17.32). CONCLUSIONS: At a large tertiary care referral center, midterm quality outcomes after robotic correction of degenerative MR are excellent, with very high survival, infrequent complications, and a low likelihood of MR recurrence, regardless of mitral valve repair complexity. Awareness of these improvements in outcome is important to inform contemporary decisions regarding high-quality alternatives to conventional and percutaneous mitral repair. PMID- 26481776 TI - Robotic Mitral Valve Repair for Degenerative Mitral Valve Regurgitation: Is It for Everyone? PMID- 26481777 TI - Ongoing Evolution of Outcomes Analysis for Pediatric and Congenital Cardiac Catheterization. PMID- 26481778 TI - Adjusting for Risk Associated With Pediatric and Congenital Cardiac Catheterization: A Report From the NCDR IMPACT Registry. AB - BACKGROUND: As US health care increasingly focuses on outcomes as a means for quantifying quality, there is a growing demand for risk models that can account for the variability of patients treated at different hospitals so that equitable comparisons between institutions can be made. We sought to apply aspects of prior risk-standardization methodology to begin development of a risk-standardization tool for the National Cardiovascular Data Registry (NCDR) IMPACT (Improving Pediatric and Adult Congenital Treatment) Registry. METHODS AND RESULTS: Using IMPACT, we identified all patients undergoing diagnostic or interventional cardiac catheterization between January 2011 and March 2013. Multivariable hierarchical logistic regression was used to identify patient and procedural characteristics predictive of experiencing a major adverse event after cardiac catheterization. A total of 19,608 cardiac catheterizations were performed between January 2011 and March 2013. Among all cases, a major adverse event occurred in 378 of all cases (1.9%). After multivariable adjustment, 8 variables were identified as critical for risk standardization: patient age, renal insufficiency, single-ventricle physiology, procedure-type risk group, low systemic saturation, low mixed venous saturation, elevated systemic ventricular end-diastolic pressure, and elevated main pulmonary artery pressures. The model had good discrimination (C statistic, 0.70), confirmed by bootstrap validation (validation C statistic, 0.69). CONCLUSIONS: Using prior risk-standardization efforts as a foundation, we developed and internally validated a model to predict the occurrence of a major adverse event after cardiac catheterization for congenital heart disease. Future efforts should be directed toward further refinement of the model variables within this large, multicenter data set. PMID- 26481779 TI - Genetic analysis of Xp22.3 micro-deletions in seventeen families segregating isolated form of X-linked ichthyosis. PMID- 26481780 TI - Ligand-activated PPARdelta upregulates alpha-smooth muscle actin expression in human dermal fibroblasts: A potential role for PPARdelta in wound healing. AB - BACKGROUND: The phenotypic changes that accompany differentiation of resident fibroblasts into myofibroblasts are important aspects of the wound healing process. Recent studies showed that peroxisome proliferator-activated receptor (PPAR) delta plays a critical role in wound healing. OBJECTIVE: To determine whether the nuclear receptor PPARdelta can modulate the differentiation of human dermal fibroblasts (HDFs) into myofibroblasts. METHODS: These studies were undertaken in primary HDFs using Western blot analyses, small interfering (si)RNA mediated gene silencing, reporter gene assays, chromatin immunoprecipitation (ChIP), migration assays, collagen gel contraction assays, and real-time PCR. RESULTS: Activation of PPARdelta by GW501516, a specific ligand of PPARdelta, specifically upregulated the myofibroblast marker alpha-smooth muscle actin (alpha-SMA) in a time- and concentration-dependent manner. This induction was significantly inhibited by the presence of siRNA against PPARdelta, indicating that PPARdelta is involved in myofibroblast transdifferentiation of HDFs. Ligand activated PPARdelta increased alpha-SMA promoter activity in a dual mode by directly binding a direct repeat-1 (DR1) site in the alpha-SMA promoter, and by inducing expression of transforming growth factor (TGF)-beta, whose downstream effector Smad3 interacts with a Smad-binding element (SBE) in another region of the promoter. Mutations in these cis-elements totally abrogated transcriptional activation of the alpha-SMA gene by the PPARdelta ligand; thus both sites represent novel types of PPARdelta response elements. GW501516-activated PPARdelta also increased the migration and contractile properties of HDFs, as demonstrated by Transwell and collagen lattice contraction assays, respectively. In addition, PPARdelta-mediated upregulation of alpha-SMA was correlated with elevated expression of myofibroblast markers such as collagen I and fibronectin, with a concomitant reduction in expression of the epithelial marker E-cadherin. CONCLUSION: PPARdelta plays pivotal roles in wound healing by promoting fibroblast-to-myofibroblast differentiation via TGF-beta/Smad3 signaling. PMID- 26481781 TI - Kounis Syndrome Caused by Chronic Autoimmune Urticaria: A Case Report. AB - BACKGROUND: Coincidental occurrence of acute coronary syndrome with symptoms associated with an allergic reaction is called Kounis syndrome (KS). Although KS has been recognized for several years and has been reported in many documents, KS induced by chronic autoimmune urticaria (CAU), to the authors' knowledge, has not been reported. CASE REPORT: The patient was a 31-year-old woman who suffered from chronic urticaria for nearly 3 years. Her urticaria became more serious 1 week before this visit and was accompanied by repeated attacks of cardiac symptoms. Autologous serum skin test and serum anti-high affinity immunoglobulin E receptor antibody test were positive for CAU. Her coronary artery pathological changes were confirmed by electrocardiogram (ECG), cardiac troponin T (cTnT) value, and angiocardiography. The patient was diagnosed with KS. After being treated with cetirizine, glucocorticoids, and azathioprine, the patient did not relapse during the first year of follow-up. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: When seeing a patient with intermittent exacerbations of chronic urticaria accompanied by repeated attacks of cardiac symptoms, emergency physicians should consider the diagnosis of KS. It is important to monitor changes in the ECG and cTnT value. Angiocardiography is necessary to eliminate myocardial infarction or unstable angina. Second-generation antihistamines and glucocorticoids are effective in the treatment of CAU and also alleviate coronary spasm. Another important consideration for the emergency physician is the fact that some first generation antihistamines have the side effect of ventricular tachycardia or fibrillation, so it is better not to use these drugs to treat urticaria if KS is suspected. PMID- 26481782 TI - Diagnosis of an Arteriovenous (AV) Graft Pseudoaneurysm by Bedside Ultrasound in the Emergency Department. PMID- 26481783 TI - New paleoradiological investigations of ancient human remains from North West Lombardy archaeological excavations. AB - OBJECTIVE: Since its birth in 1895, radiology has been used to study ancient mummies. The purpose of this article is to present paleoradiological investigations conducted on several medieval human remains in Varese province. Anthropological (generic identification) and paleopathological analyses were carried out with the support of diagnostic imaging (X-ray and CT scans). MATERIALS AND METHODS: Human remains were discovered during excavations of medieval archaeological sites in northwest Lombardy. Classical physical anthropological methods were used for the macroscopic identification of the human remains. X-ray and CT scans were performed on the same scanner (16-layer Hitachi Eclos 16 X-ray equipment). Results Radiological analysis permitted investigating (1) the sex, (2) age of death, (3) type of trauma, (4) therapeutic interventions and (5) osteomas in ancient human remains. In particular, X-ray and CT examinations showed dimorphic facial traits on the mummified skull, and the same radiological approaches allowed determining the age at death from a mummified lower limb. CT analyses allow investigating different types of traumatic lesions in skulls and postcranial skeleton portions and reconstructing the gait and functional outcomes of a fractured femur. Moreover, one case of possible Gardner's syndrome (GS) was postulated from observing multiple osteomas in an ancient skull. CONCLUSION: Among the medical tests available to the clinician, radiology is the most appropriate first-line procedure for a diagnostic approach to ancient human remains because it can be performed without causing any significant damage to the specimen. PMID- 26481784 TI - Bone graft substitute prepared with the patient's blood. Technical tip. AB - Bone grafts are widely used during surgery in many fields in order to repair bone defects. During surgery, it is very common that small particles of bone graft scatter around the soft tissue. Every fragment has to be picked up and reinserted into the desired area. The aim of this work is to show a useful technical tip in order to avoid bone graft scattered in an undesired area. The bone graft particles are mixed with patient blood forming a gel-like mass containing all fragments together. This technical tip avoids time loss in picking up all fragments that scattered around soft tissue during surgery. PMID- 26481785 TI - Evolution of perceived footwear comfort over a prolonged running session. AB - BACKGROUND: The purpose of this study was to investigate the subjective perception of overall footwear comfort over a prolonged running session. METHODS: Ten runners performed two similar sessions consisting of a 13-km trail run (5 laps of 2.6 km) as fast as possible. The overall footwear comfort was evaluated before running and at the end of each lap with a 150-mm visual analogic scale, as well as speed, heart rate and rate of perceived exertion. RESULTS: The results showed that both overall footwear comfort and speed decreased consistently during the run session, and significantly after 44 min of running (i.e. the 3rd lap). It could be hypothesized that the deterioration of overall footwear comfort was explained by mechanical and energetical parameter changes with time and/or fatigue occurring at the whole body, foot and footwear levels. CONCLUSION: These results justify the use of a prolonged running test for running footwear comfort evaluation. PMID- 26481786 TI - Talar head fracture: A case report, systematic review and suggested algorithm of treatment. AB - INTRODUCTION: Talar head fractures are uncommon. This rarity contributes to the lack of structure and clarity in its management. The purpose of this systematic review is to analyse the published literature on management of these injuries and suggest a treatment plan that was followed in our case. METHODS: A search of Medline, EMBASE, AMED and Google Scholar was performed on 1st September 2014. Any article reporting case(s) of talar head fractures were included and studies of other anatomical types of talar fractures, stress fractures or paediatric cases were excluded. The paucity of data precluded data synthesis and instead a narrative synthesis was performed. RESULTS: Of 45 studies identified, five publications with seven case reports met the inclusion criteria. One occurred secondary to snowboarding, one wakeboarding, one inversion injury whilst walking and one gymnastic injury. Two patients were managed operatively and two non surgically with one requiring surgery for a symptomatic mal-union. CONCLUSION: Talar head fractures are rare and high quality literature regarding management of these injuries is lacking. A suggested algorithm for treatment is proposed, but further robust studies are required to substantiate this approach. PMID- 26481788 TI - Intratendinous ganglion cyst of the extensor digitorum longus tendon: A case report. AB - INTRODUCTION: Ganglion cysts are benign lesions, common in the hand and wrist. Intratendinous ganglion, however, are rare. We present the first reported case of an intratendinous ganglion cyst in an extensor digitorum longus (EDL) tendon of the foot. CASE REPORT: A 35-year old presented with a left-sided painful dorsolateral foot swelling. Ultrasound suggested a ganglion cyst in proximity to the EDL tendon of the 5th toe. Two distinct swellings were identified on surgical exploration, including a 6*1cm ganglion lying within the EDL tendon substance that had resulted in tendon splitting. The lesions were excised and EDL tendon repaired. Histological analysis confirmed that both lesions were ganglion cysts. Post-operative recovery was uneventful. DISCUSSION: Intratendinous ganglion cysts are rare lesions that pose a unique set of diagnostic and treatment challenges. Unlike conventional ganglion, their diagnosis may not be possible until surgical exploration. They have been reported to increase the risk of spontaneous tendon rupture. As such, a lower operative threshold should be applied to prevent their progression. A high index of suspicion should be applied to any ganglion reported radiologically to be in close contact with tendons. If diagnosed upon surgical exploration, it is essential that the operating surgeon is prepared to appropriately modify the procedure to involve primary tendon repair, tendon transfer or tenodesis. PMID- 26481787 TI - Jones fracture of the fifth metatarsal: Is operative intervention justified? A systematic review of the literature and meta-analysis of results. AB - BACKGROUND: This study assesses the outcomes of surgical vs. conservative management in the treatment of the Jones fracture. MATERIALS AND METHODS: A systematic review using four databases from their inception until September 2014 was undertaken. Six studies were found evaluating operative therapy compared to conservative treatment. RESULTS: Six relevant studies were included, with a total of 237 patients. Of these, 51% were treated non-operatively, and 49% had surgical intervention. Those in the non-operative group were found to have a significantly higher odds ratio (OR) of fracture non-union (OR 5.74, 95% confidence interval (CI) 2.65-12.40, P<0.001). Studies also reported a prolonged healing time and a longer time to return to sports. Of the trials with time to union as an outcome measure, 3 of 4 trials found favourable results in the operative cohort. CONCLUSIONS: Surgical intervention is recommended for patients presenting with a Jones fracture as it is found to result in a lesser non-union rate and an improved time to union. PMID- 26481789 TI - Fatal diphenidol poisoning: a case report and a retrospective study of 16 cases. AB - Diphenidol hydrochloride (DPN), a nonphenothiazinic antiemetic agent used primarily in patients with Meniere disease and labyrinthopathies to treat vomiting and vertigo, is considered to be a relatively safe drug. Since it was first approved in the United States in 1967, this drug has been widely used in Latin America and Asia and has contributed to sporadic suicidal and accidental poisonings in mainland China and Taiwan. However, its toxic or lethal concentration ranges have not yet been determined. We report a case of a 23-year old female who suffered from DPN poisoning that resulted in death. At autopsy, there were no typical pathological findings, except for cerebral edema with high acetylcholinesterase expression. Postmortem analysis of DPN revealed 45 ug/ml in heart blood, 39 ug/ml in femoral vein blood, 141 ug/g in the liver, and 53 mg in the gastric contents. These concentrations indicated that the cause of death was DPN poisoning. The circumstances indicated that the manner of death was suicide. We also present a retrospective study, in which we review and summarize the literature from 1998 to 2014 and describe 16 cases of poisoning, including information from autopsy reports and postmortem drug concentrations. In forensic practice, drug residues at the scene, patients with convulsions and disturbance of consciousness, and rapidly occurring deaths, should draw attention to the possibility of this drug. Toxicological analysis and the exclusion of other diseases may ultimately be used to confirm DPN poisoning. PMID- 26481790 TI - Helicopter induced propeller injuries. PMID- 26481791 TI - Effects of arterial blood flow on walls of the abdominal aorta: distributions of wall shear stress and oscillatory shear index determined by phase-contrast magnetic resonance imaging. AB - Although abdominal aortic aneurysms (AAAs) occur mostly inferior to the renal artery, the mechanism of the development of AAA in relation to its specific location is not yet clearly understood. The objective of this study was to evaluate the hypothesis that even healthy volunteers may manifest specific flow characteristics of blood flow and alter wall shear or oscillatory shear stress in the areas where AAAs commonly develop. Eight healthy male volunteers were enrolled in this prospective study, aged from 24 to 27. Phase-contrast magnetic resonance imaging (MRI) was performed with electrocardiographic triggering. Flow sensitive four-dimensional MR imaging of the abdominal aorta, with three directional velocity encoding, including simple morphological image acquisition, was performed. Information on specific locations on the aortic wall was applied to the flow encodes to calculate wall shear stress (WSS) and oscillatory shear index (OSI). While time-framed WSS showed the highest peak of 1.14 +/- 0.25 Pa in the juxtaposition of the renal artery, the WSS plateaued to 0.61 Pa at the anterior wall of the abdominal aorta. The OSI peaked distal to the renal arteries at the posterior wall of the abdominal aorta of 0.249 +/- 0.148, and was constantly elevated in the whole abdominal aorta at more than 0.14. All subjects were found to have elevated OSI in regions where AAAs commonly occur. These findings indicate that areas of constant peaked oscillatory shear stress in the infra-renal aorta may be one of the factors that lead to morphological changes over time, even in healthy individuals. PMID- 26481794 TI - Population variation affects interactions between two California salt marsh plant species more than precipitation. AB - Species that occur along broad environmental gradients often vary in phenotypic traits that make them better adapted to local conditions. Variation in species interactions across gradients could therefore be due to either phenotypic differences among populations or environmental conditions that shift the balance between competition and facilitation. To understand how the environment (precipitation) and variation among populations affect species interactions, we conducted a common garden experiment using two common salt marsh plant species, Salicornia pacifica and Jaumea carnosa, from six salt marshes along the California coast encompassing a large precipitation gradient. Plants were grown alone or with an individual of the opposite species from the same site and exposed to one of three precipitation regimes. J. carnosa was negatively affected in the presence of S. pacifica, while S. pacifica was facilitated by J. carnosa. The strength of these interactions varied by site of origin but not by precipitation treatment. These results suggest that phenotypic variation among populations can affect interaction strength more than environment, despite a threefold difference in precipitation. Geographic intraspecific variation may therefore play an important role in determining the strength of interactions in communities. PMID- 26481792 TI - Differences in Adolescent Physical Fitness: A Multivariate Approach and Meta analysis. AB - Physical fitness can be defined as a set of components that determine exercise ability and influence performance in sports. This study investigates the genetic and environmental influences on individual differences in explosive leg strength (vertical jump), handgrip strength, balance, and flexibility (sit-and-reach) in 227 healthy monozygotic and dizygotic twin pairs and 38 of their singleton siblings (mean age 17.2 +/- 1.2). Heritability estimates were 49% (95% CI 35-60%) for vertical jump, 59% (95% CI 46-69%) for handgrip strength, 38% (95% CI 22-52%) for balance, and 77% (95% CI 69-83%) for flexibility. In addition, a meta analysis was performed on all twin studies in children, adolescents and young adults reporting heritability estimates for these phenotypes. Fifteen studies, including results from our own study, were meta-analyzed by computing the weighted average heritability. This showed that genetic factors explained most of the variance in vertical jump (62%; 95% CI 47-77%, N = 874), handgrip strength (63%; 95% CI 47-73%, N = 4516) and flexibility (50%; 95% CI 38-61%, N = 1130) in children and young adults. For balance this was 35% (95% CI 19-51%, N = 978). Finally, multivariate modeling showed that the phenotypic correlations between the phenotypes in current study (0.07 < r < 0.27) were mostly driven by genetic factors. It is concluded that genetic factors contribute significantly to the variance in muscle strength, flexibility and balance; factors that may play a key role in the individual differences in adolescent exercise ability and sports performance. PMID- 26481795 TI - Herbivory and dominance shifts among exotic and congeneric native plant species during plant community establishment. AB - Invasive exotic plant species often have fewer natural enemies and suffer less damage from herbivores in their new range than genetically or functionally related species that are native to that area. Although we might expect that having fewer enemies would promote the invasiveness of the introduced exotic plant species due to reduced enemy exposure, few studies have actually analyzed the ecological consequences of this situation in the field. Here, we examined how exposure to aboveground herbivores influences shifts in dominance among exotic and phylogenetically related native plant species in a riparian ecosystem during early establishment of invaded communities. We planted ten plant communities each consisting of three individuals of each of six exotic plant species as well as six phylogenetically related natives. Exotic plant species were selected based on a rapid recent increase in regional abundance, the presence of a congeneric native species, and their co-occurrence in the riparian ecosystem. All plant communities were covered by tents with insect mesh. Five tents were open on the leeward side to allow herbivory. The other five tents were completely closed in order to exclude insects and vertebrates. Herbivory reduced aboveground biomass by half and influenced which of the plant species dominated the establishing communities. Exposure to herbivory did not reduce the total biomass of natives more than that of exotics, so aboveground herbivory did not selectively enhance exotics during this early stage of plant community development. Effects of herbivores on plant biomass depended on plant species or genus but not on plant status (i.e., exotic vs native). Thus, aboveground herbivory did not promote the dominance of exotic plant species during early establishment of the phylogenetically balanced plant communities. PMID- 26481796 TI - Quantitative Methodologies Reveal a Diversity of Nutrition, Infection/Illness, and Psychosocial Stressors During Pregnancy and Lactation in Rural Mam-Mayan Mother-Infant Dyads From the Western Highlands of Guatemala. AB - BACKGROUND: The nature and severity of 3 categories of maternal stressors (nutritional, infectious, and psychosocial) that may impact maternal health and early infant growth are not often considered together. OBJECTIVES: To describe quantitative methodologies; assess construct validity of questionnaires; report variability in sociodemographic, obstetric, nutritional, infectious, and psychosocial characteristics; and compare characteristics between pregnancy and lactation and between study cohorts of Mam-Mayan mother-infant dyads. METHODS: Grounded in participatory action research and a socioecological framework, this observational study enrolled a longitudinal cohort of 155 women, followed during pregnancy (6-9 months), early (0-6 weeks), and later (4-6 months) postpartum, and 2 cross-sectional cohorts (60 early and 56 later postpartum). Household and social factors; obstetric history; nutritional, infectious, and psychosocial stressors; and infant characteristics were explored. RESULTS: Diet diversity (3.4 +/- 1.3) and adult food security (38%) were low. Urinary and gastrointestinal infections were rare (<5%), whereas experience of local idioms of distress was frequent (20%-50%). Participants reported low maternal autonomy (81%), high paternal support (70%), small social support networks (2.7 +/- 1.3 individuals), and high trust in family (88%) and community-based institutions (61%-65%) but low trust in government services (6%). Domestic violence was commonly reported (22%). Infant stunting was common (36% early postpartum and 43% later postpartum) despite frequent antenatal care visits (7.5 +/- 3.8). Participant engagement with the research team did not influence study outcomes based on comparisons between longitudinal and cross-sectional cohorts. CONCLUSIONS: The variability in sociodemographic, nutritional, and psychosocial variables, will allow exploration of factors that promote resilience or increase vulnerability of the mother-infant dyad. PMID- 26481797 TI - Exploring Life Satisfaction Among Older Adults in Dakar. AB - Studies on correlates of subjective well-being of older adults are virtually non existent in sub-Saharan Africa. Yet, understanding and improving the well-being of older adults should be a focal point of research and policy directed at this fast growing population. The aim of this study was to assess the links between socio-demographic factors, economic conditions, health, social relations, and the life satisfaction of older adults in Dakar. To this end, a survey was conducted on a sample of 500 dwellers of the Senegalese capital, aged 50 to 100, using the quota method for greater representativeness. Results revealed that with advancing age older adults expressed greater life satisfaction, and that older women were more satisfied than older men. As well, economic conditions were a main predictor of life satisfaction, along with good social relations. In contrast to findings with Western populations, neither self-rated health nor physical disabilities were associated with aging adults' life satisfaction. Findings suggest a number of avenues for future research. PMID- 26481799 TI - Why 'Optimal' Payment for Healthcare Providers Can Never be Optimal Under Community Rating. AB - This article extends the existing literature on optimal provider payment by accounting for consumer heterogeneity in preferences for health insurance and healthcare. This heterogeneity breaks down the separation of the relationship between providers and the health insurer and the relationship between consumers and the insurer. Both experimental and market evidence for a high degree of heterogeneity are presented. Given heterogeneity, a uniform policy fails to effectively control moral hazard, while incentives for risk selection created by community rating cannot be neutralized through risk adjustment. Consumer heterogeneity spills over into relationships with providers, such that a uniform contract with providers also cannot be optimal. The decisive condition for ensuring optimality of provider payment is to replace community rating (which violates the principle of marginal cost pricing) with risk rating of contributions combined with subsidization targeted at high risks with low incomes. PMID- 26481798 TI - Protective action of the phyllanthin against carbon tetrachloride-induced hepatocyte damage in Cyprinus carpio. AB - The present study was to investigate the protective effect and possible mechanism of phyllanthin against carbon tetrachloride (CCl4)-induced hepatocyte damage in carp. Phyllanthin (5, 10, and 15 MUg/ml) was added to carp primary hepatocytes before (pre-treatment) and after (post-treatment) incubation of the hepatocytes in medium containing CCl4 at 8 mM; supernatant and cell were collected for the analyses of cell viability, biochemical parameters, and gene expression. The results showed that phyllanthin at the concentration of 15 MUg/ml significantly suppressed the elevation of glutamate pyruvate transaminase (GPT), glutamate oxalate transaminase (GOT), lactate dehydrogenase (LDH), and malondialdehyde (MDA), and the reduction of cell viability, superoxide dismutase (SOD) activity, cytochrome P450 1a (CYP1A), and cytochrome P450 3a (CYP3A) messenger RNA (mRNA) levels expect LDH in the post-treatment. The levels of GPT, GOT, and CYP1A mRNA were also effectively restored in the pretreatment with phyllanthin (10 MUg/ml). Overall, our results suggested that phyllanthin may be used as a hepatoprotective agent to prevent liver diseases in fish. PMID- 26481801 TI - [Erratum to: Soft tissue plastic surgery for complications in the skull region]. PMID- 26481800 TI - Protective effect of Suxiao jiuxin pill, a traditional Chinese medicine, against acute myocardial ischemia in dogs. AB - BACKGROUND: The purpose of this study was to investigate the effect of Suxiao Jiuxin Pill (SX), a traditional Chinese medicine, on acute myocardial ischemia induced by coronary occlusion in anesthetized dogs. METHODS: Acute myocardial ischemia model was established by ligating the left anterior descending artery to reduce flow by 90 %. Adult mongrel dogs were randomly divided into six groups: model, SX high dose, SX middle dose, SX low dose, Isosorbide dinitrate (ISD) and Sham groups. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate (HR), mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular dP/dt, coronary blood flow (CBF), myocardial blood flow (MBF), coronary vascular resistance (CVR), and epicardial electrocardiogram (EECG). After administration with SX, changes in hemodynamics were recorded. Serum enzymes and blood gas analysis were also detected. RESULTS: SX has a dose-dependent effect on the reduction of infarct size. Besides, SX exerted a notable inhibition on the elevation of serum creatine kinase MB (CK MB), lactate dehydrogenase (LDH), malondialdehyde (MDA), and elevation in the superoxide dismutase (SOD) activity. SX also showed a capacity to recover myocardial function by significantly reducing MAP, CVR, LVSP, left ventricular systolic pressure (LVEDP), systolic blood pressure (SBP), diastolic blood pressure (SDP), and increasing CBF and myocardial blood flow (MBF). In addition, SX high dose group markedly reduced total mV of ST segment elevation (Sigma-ST), total number of sites with this degree of ST segment elevation (N-ST) and oxygen extraction ratio (O2 Extr). CONCLUSION: SX can improve hemodynamic and myocardial oxygen metabolism, reduce the degree and scope of myocardial ischemia, and hence exert notable anti-anginal ischaemic effect. PMID- 26481802 TI - Laboratory guidelines for the diagnosis and follow-up of patients with monoclonal gammopathies. AB - We present guidelines from the Immunochemistry group of the Spanish Society for Immunology that are designed to provide a practical tool for the diagnosis and follow-up of monoclonal gammopathies. We review the clinical and analytical features of various monoclonal gammopathies, international consensus guidelines and techniques used to detect and follow-up monoclonal components. PMID- 26481803 TI - A case of cardiogenic shock with preserved ejection function. PMID- 26481805 TI - Cabozantinib and nivolumab for renal cell carcinoma. PMID- 26481806 TI - 21-gene assay identifies patients who can avoid chemotherapy. PMID- 26481807 TI - Preoperative MRI in breast cancer. PMID- 26481808 TI - Radiotherapy in the elderly and frail with glioblastoma. PMID- 26481809 TI - Effect of passengers' active head tilt and opening/closure of eyes on motion sickness in lateral acceleration environment of cars. AB - This study examined the effect of passengers' active head-tilt and eyes-open/eyes closed conditions on the severity of motion sickness in the lateral acceleration environment of cars. In the centrifugal head-tilt condition, participants intentionally tilted their heads towards the centrifugal force, whereas in the centripetal head-tilt condition, the participants tilted their heads against the centrifugal acceleration. The eyes-open and eyes-closed cases were investigated for each head-tilt condition. In the experimental runs, the sickness rating in the centripetal head-tilt condition was significantly lower than that in the centrifugal head-tilt condition. Moreover, the sickness rating in the eyes-open condition was significantly lower than that in the eyes-closed condition. The results suggest that an active head-tilt motion against the centrifugal acceleration reduces the severity of motion sickness both in the eyes-open and eyes-closed conditions. They also demonstrate that the eyes-open condition significantly reduces the motion sickness even when the head-tilt strategy is used. Practitioner Summary: Little is known about the effect of head-tilt strategies on motion sickness. This study investigated the effects of head-tilt direction and eyes-open/eyes-closed conditions on motion sickness during slalom automobile driving. Passengers' active head tilt towards the centripetal direction and the eyes-open condition greatly reduce the severity of motion sickness. PMID- 26481810 TI - [Acquired A hemophilia and lymphoproliferative diseases: A literature review]. AB - Acquired A haemophilia is a rare but severe autoimmune disease. It is caused by autoantibodies against the coagulation factor VIII. These autoantibodies could have different consequences: no effect, inhibition of factor VIII or factor VIII activity hydrolyzing. In about half of the cases, no cause is associated with the disorder [idiopathic acquired A haemophilia]. But in remaining 50% of the patients, some circumstances could be associated with acquired hemophilia: post partum, autoimmune disorders, cancer and sometimes malignant blood disorders. The objective of this article was to review the literature about acquired A hemophilia associated with lymphoproliferative diseases. PMID- 26481811 TI - No effect of modest selenium supplementation on insulin resistance in UK pregnant women, as assessed by plasma adiponectin concentration. AB - Concern has been expressed recently that Se may increase the risk of type 2 diabetes, but this has not been tested in a randomised-controlled trial (RCT) in pregnant women. We took advantage of having stored plasma samples from the Se in Pregnancy Intervention (SPRINT) RCT of Se supplementation in pregnancy to test the effect of Se supplementation on a marker of insulin resistance in UK pregnant women. Because our blood samples were not fasted, we measured plasma adiponectin concentration, a recognised marker of insulin resistance that gives valid measurements in non-fasted samples, as diurnal variability is minor and there is no noticeable effect of food intake. In SPRINT, 230 primiparous UK women were randomised to treatment with Se (60 MUg/d) or placebo from 12 weeks of gestation until delivery. We hypothesised that supplementation with Se at a nutritional level would not exacerbate the fall in adiponectin concentration that occurs in normal pregnancy, indicating the lack of an adverse effect on insulin resistance. Indeed, there was no significant difference between the two groups in the change in adiponectin from 12 to 35 weeks (P=0.938), nor when the analysis was restricted to the bottom or top quartiles of baseline whole-blood Se (P=0.515 and 0.858, respectively). Cross-sectionally, adiponectin concentration was not associated with any parameter of Se status, either at 12 or 35 weeks. It is reassuring that a nutritional dose of Se had no adverse effect on the concentration of adiponectin, a biomarker of insulin resistance, in pregnant women of modest Se status. PMID- 26481812 TI - Insights into Collagen Uptake by C-type Mannose Receptors from the Crystal Structure of Endo180 Domains 1-4. AB - The C-type mannose receptor and its homolog Endo180 (or uPARAP, for urokinase plasminogen activator receptor-associated protein) mediate the endocytic uptake of collagen by macrophages and fibroblasts. This process is required for normal tissue remodeling, but also facilitates the growth and dissemination of tumors. We have determined the crystal structure at 2.5 A resolution of the N-terminal region of Endo180, consisting of a ricin-like domain, a fibronectin type II (FN2) domain, and two C-type lectin (CTL) domains. The L-shaped arrangement of these domains creates a shallow trench spanning the FN2 and CTL1 domains, which was shown by mutagenesis to bind triple-helical and denatured collagen. Small-angle X ray scattering showed that the L-shaped structure is maintained in solution at neutral and acidic pH, irrespective of calcium ion loading. Collagen binding was equally unaffected by acidic pH, suggesting that collagen release in endosomes is not regulated by changes within the Endo180 N-terminal region. PMID- 26481813 TI - Structure and Sequence Analyses of Clustered Protocadherins Reveal Antiparallel Interactions that Mediate Homophilic Specificity. AB - Clustered protocadherin (Pcdh) proteins mediate dendritic self-avoidance in neurons via specific homophilic interactions in their extracellular cadherin (EC) domains. We determined crystal structures of EC1-EC3, containing the homophilic specificity-determining region, of two mouse clustered Pcdh isoforms (PcdhgammaA1 and PcdhgammaC3) to investigate the nature of the homophilic interaction. Within the crystal lattices, we observe antiparallel interfaces consistent with a role in trans cell-cell contact. Antiparallel dimerization is supported by evolutionary correlations. Two interfaces, located primarily on EC2-EC3, involve distinctive clustered Pcdh structure and sequence motifs, lack predicted glycosylation sites, and contain residues highly conserved in orthologs but not paralogs, pointing toward their biological significance as homophilic interaction interfaces. These two interfaces are similar yet distinct, reflecting a possible difference in interaction architecture between clustered Pcdh subfamilies. These structures initiate a molecular understanding of clustered Pcdh assemblies that are required to produce functional neuronal networks. PMID- 26481814 TI - Molecular Mechanism of Dopamine Transport by Human Dopamine Transporter. AB - Dopamine transporters (DATs) control neurotransmitter dopamine (DA) homeostasis by reuptake of excess DA, assisted by sodium and chloride ions. The recent resolution of DAT structure (dDAT) from Drosophila permits us for the first time to directly view the sequence of events involved in DA reuptake in human DAT (hDAT) using homology modeling and full-atomic microseconds accelerated simulations. Major observations are spontaneous closure of extracellular gates prompted by DA binding; stabilization of a holo-occluded intermediate; disruption of N82-N353 hydrogen bond and exposure to intracellular (IC) water triggered by Na2 dislocation; redistribution of a network of salt bridges at the IC surface in the inward-facing state; concerted tilting of IC-exposed helices to enable the release of Na(+) and Cl(-) ions; and DA release after protonation of D79. The observed time-resolved interactions confirm the conserved dynamics of LeuT-fold family, while providing insights into the mechanistic role of specific residues in hDAT. PMID- 26481815 TI - Multiple RF classifier for the hippocampus segmentation: Method and validation on EADC-ADNI Harmonized Hippocampal Protocol. AB - The hippocampus has a key role in a number of neurodegenerative diseases, such as Alzheimer's Disease. Here we present a novel method for the automated segmentation of the hippocampus from structural magnetic resonance images (MRI), based on a combination of multiple classifiers. The method is validated on a cohort of 50 T1 MRI scans, comprehending healthy control, mild cognitive impairment, and Alzheimer's Disease subjects. The preliminary release of the EADC ADNI Harmonized Protocol training labels is used as gold standard. The fully automated pipeline consists of a registration using an affine transformation, the extraction of a local bounding box, and the classification of each voxel in two classes (background and hippocampus). The classification is performed slice-by slice along each of the three orthogonal directions of the 3D-MRI using a Random Forest (RF) classifier, followed by a fusion of the three full segmentations. Dice coefficients obtained by multiple RF (0.87 +/- 0.03) are larger than those obtained by a single monolithic RF applied to the entire bounding box, and are comparable to state-of-the-art. A test on an external cohort of 50 T1 MRI scans shows that the presented method is robust and reliable. Additionally, a comparison of local changes in the morphology of the hippocampi between the three subject groups is performed. Our work showed that a multiple classification approach can be implemented for the segmentation for the measurement of volume and shape changes of the hippocampus with diagnostic purposes. PMID- 26481816 TI - Dental cone beam CT: A review. AB - For the maxillofacial region, there are various indications that cannot be interpreted from 2D images and will benefit from multiplanar viewing. Dental cone beam CT (CBCT) utilises a cone- or pyramid-shaped X-ray beam using mostly flat panel detectors for 3D image reconstruction with high spatial resolution. The vast increase in availability and amount of these CBCT devices offers many clinical benefits, and their ongoing development has potential to bring various new clinical applications for medical imaging. Additionally, there is also a need for high quality research and education. European guidelines promote the use of a medical physics expert for advice on radiation protection, patient dose optimisation, and equipment testing. In this review article, we perform a comparison of technical equipment based on manufacturer data, including scanner specific X-ray spectra, and describe issues concerning CBCT image reconstruction and image quality, and also address radiation dose issues, dosimetry, and optimisation. We also discuss clinical needs and what type of education users should have in order to operate CBCT systems safely. We will also take a look into the future and discuss the issues that still need to be solved. PMID- 26481817 TI - Pitfalls in the Use of Stereoacuity in the Diagnosis of Nonorganic Visual Loss. AB - PURPOSE: The Titmus Stereotest (Stereo Optical Co., Inc., Chicago, IL) has been used to estimate visual acuity (VA) in the evaluation of nonorganic visual loss. Previous predictions were derived from optical degradation of VA in normal subjects and may not account for the variability seen in patients with neuro ophthalmic pathologies included in the differential diagnosis of nonorganic visual loss. The purpose of this study was to evaluate the relationship between Titmus stereoacuity and minimal VA based on a real-world testing environment. DESIGN: Cross-sectional observational study. PARTICIPANTS: All patients treated at the authors' neuro-ophthalmology service between April 25, 2014, and July 31, 2014. METHODS: All subjects underwent routine neuro-ophthalmic examination, including Titmus stereoacuity measurements. A compound Bayesian logit-lognormal model accounting for heteroscedasticity was used to determine 95% and 99% prediction intervals of the worse eye's near VA based on stereoacuity. Logarithm of the minimum angle of resolution VA and log stereoacuity were analyzed. MAIN OUTCOME MEASURES: Titmus stereoacuity and worse eye VA. RESULTS: Of 561 patients, 364 subjects 11 to 91 years of age were included. Titmus stereoacuity was associated positively with VA: 9 circles correct (40 seconds of arc) indicated VA of at least 20/40 with 95% confidence and VA of at least 20/79 with 99% confidence; 6 circles correct (80 seconds of arc) indicated VA of at least 20/62 and 20/180, respectively; and 4 circles correct (140 seconds of arc) indicated VA of at least 20/110 and 20/570, respectively. CONCLUSIONS: When fully accounting for individual variation and the full spectrum of neuro-ophthalmic diseases affecting VA, stereoacuity remains associated with VA, but previous commonly used VA estimates based on stereoacuity overestimated VA. Our results more accurately predict minimum VA from Titmus stereoacuity and should be used preferentially when evaluating patients with suspected nonorganic visual loss. We demonstrated that Titmus stereoacuity cannot definitively establish normal VA, and therefore can suggest, but not fully establish, the diagnosis of nonorganic visual loss. PMID- 26481818 TI - Expression of Vascular Endothelial Growth Factor Receptors in Benign Vascular Lesions of the Orbit: A Case Series. AB - PURPOSE: Vascular lesions of the orbit, although not malignant, can cause morbidity because of their location near critical structures in the orbit. For the same reason, they can be challenging to remove surgically. Anti-vascular endothelial growth factor (VEGF) drugs are increasingly being used to treat diseases with prominent angiogenesis. Our study aimed to determine to what extent VEGF receptors and their subtypes are expressed on selected vascular lesions of the orbit. DESIGN: Retrospective case series of all orbital vascular lesions removed by one of the authors (JAG) at the Mayo Clinic. PARTICIPANTS: A total of 52 patients who underwent removal of vascular orbital lesions. METHODS: The pathology specimens from the patients were retrieved, their pathologic diagnosis was confirmed, demographic and clinical information were gathered, and sections from vascular tumors were stained with vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor type 1 (VEGFR1), vascular endothelial growth factor receptor type 2 (VEGFR2), and vascular endothelial growth factor receptor type 3 (VEGFR3). MAIN OUTCOME MEASURES: The existence and pattern of staining with VEGF and its subtypes on these lesions. RESULTS: There were 28 specimens of venous malformations, 4 capillary hemangiomas, 7 lymphatic malformations, and 6 lymphaticovenous malformations. All samples stained with VEGF, 55% stained with VEGFR1, 98% stained with VEGFR2, and 96% stained with VEGFR3. Most (94%) of the VEGFR2 staining was diffuse. CONCLUSIONS: Most orbital vascular lesions express VEGF receptors, which may suggest a future target for nonsurgical treatment. PMID- 26481820 TI - Descemet Stripping Endothelial Keratoplasty for Fuchs' Endothelial Corneal Dystrophy: Five-Year Results of a Prospective Study. AB - PURPOSE: To determine 5-year outcomes of Descemet stripping endothelial keratoplasty (DSEK) for Fuchs' endothelial corneal dystrophy (FECD). DESIGN: Prospective cohort study. PARTICIPANTS: Fifty-two eyes of 45 subjects with FECD undergoing primary DSEK. METHODS: Subjects were examined before and at fixed intervals through 60 months after DSEK. At each visit, graft survival was determined by slit-lamp examination; best spectacle-corrected visual acuity (BSCVA) was measured using the electronic Early Treatment Diabetic Retinopathy Study (ETDRS) protocol; total anterior corneal higher-order aberrations (HOAs) were derived from corneal topography; and corneal backscatter, corneal thickness, and endothelial cell density were measured from confocal microscopy images. Corneal thickness also was measured by ultrasonic pachymetry. Changes after DSEK were analyzed using generalized estimating equation models. MAIN OUTCOME MEASURES: Best-corrected visual acuity, HOAs, endothelial cell loss, corneal thickness, and corneal backscatter. RESULTS: Complete 60-month follow-up was possible in 34 eyes. Mean BSCVA+/-standard deviation improved from 0.45+/-0.19 logarithm of the minimum angle of resolution (logMAR) (Snellen equivalent, 20/56) before DSEK to 0.09+/-0.13 logMAR (Snellen equivalent, 20/25) at 5 years (P < 0.001). Between 1 and 5 years, BSCVA improved by 0.06 logMAR (or 3 ETDRS letters; 95% confidence interval, 0.05-0.07 logMAR) per year (P < 0.001), and 56% of eyes were 0.1 logMAR (20/25) or better at 5 years. Graft thickness (approximately 155 MUm) and corneal thickness (approximately 700 MUm) did not change after surgery. Anterior corneal HOAs and backscatter decreased between 1 and 5 years (P <= 0.002). Six grafts failed, of which 4 were primary (iatrogenic); mean endothelial cell loss+/-standard deviation was 55+/-15% at 5 years. CONCLUSIONS: Between 1 and 5 years after DSEK, BSCVA continues to improve such that at 5 years, more than half of eyes see better than 20/25 with a mean total corneal thickness of 700 MUm. Improvement in vision is accompanied by continued reduction in corneal haze and aberrations, suggesting ongoing remodeling of the cornea after restoration of endothelial function. PMID- 26481819 TI - Ultrahigh-Speed, Swept-Source Optical Coherence Tomography Angiography in Nonexudative Age-Related Macular Degeneration with Geographic Atrophy. AB - PURPOSE: To investigate ultrahigh-speed, swept-source optical coherence tomography (SSOCT) angiography for visualizing vascular changes in eyes with nonexudative age-related macular degeneration (AMD) with geographic atrophy (GA). DESIGN: Observational, prospective, cross-sectional study. PARTICIPANTS: A total of 63 eyes from 32 normal subjects and 12 eyes from 7 patients with nonexudative AMD with GA. METHODS: A 1050-nm, 400-kHz A-scan rate SSOCT system was used to perform volumetric optical coherence tomography angiography (OCTA) of the retinal and choriocapillaris (CC) vasculatures in normal subjects and patients with nonexudative AMD with GA. Optical coherence tomography angiography using variable interscan time analysis (VISTA) was performed to assess CC alteration and differentiate varying degrees of CC flow impairment. MAIN OUTCOME MEASURES: Qualitative comparison of retinal and CC vasculatures in normal subjects versus those in patients with a clinical diagnosis of nonexudative AMD with GA. RESULTS: In all 12 eyes with GA, OCTA showed pronounced CC flow impairment within the region of GA. In 10 of the 12 eyes with GA, OCTA with VISTA showed milder CC flow impairment extending beyond the margin of GA. Of the 5 eyes exhibiting foveal sparing GA, OCTA showed CC flow within the region of foveal sparing in 4 of the eyes. CONCLUSIONS: The ability of ultrahigh-speed, swept-source OCTA to noninvasively visualize alterations in the retinal and CC vasculatures makes it a promising tool for assessing nonexudative AMD with GA. Optical coherence tomography angiography using VISTA can distinguish varying degrees of CC alteration and flow impairment and may be useful for elucidating disease pathogenesis, progression, and response to therapy. PMID- 26481822 TI - Report questions FDA approval of controversial anticoagulant. PMID- 26481821 TI - Predictive Value of Retinal Morphology for Visual Acuity Outcomes of Different Ranibizumab Treatment Regimens for Neovascular AMD. AB - PURPOSE: To establish the predictive value of defined retinal morphologic parameters on visual outcomes and re-treatment needs in patients with neovascular age-related macular degeneration (nAMD) receiving ranibizumab treatment. DESIGN: Post hoc analysis of a prospective, 12-month, multicenter, phase IIIb trial. PARTICIPANTS: Three hundred fifty-three treatment-naive patients with nAMD. METHODS: Available data from 319 treatment-naive patients receiving ranibizumab 0.3 mg monthly (frequent regimen; n = 102) or ranibizumab 0.3 or 0.5 mg quarterly (pooled 0.3/0.5 mg = infrequent regimen; n = 217) were analyzed to assess the correlations between baseline retinal morphologic parameters and best-corrected visual acuity (BCVA) change (structure-function correlations). The BCVA was measured at monthly visits. Optical coherence tomography scans were acquired monthly for quantitative measures of the central retinal thickness and qualitative assessment of retinal morphologic features. Assessed morphologic parameters included intraretinal cystoid fluid (IRC), subretinal fluid (SRF), pigment epithelial detachment, and vitreomacular interface configuration classification comprising vitreomacular adhesion and posterior vitreous detachment (PVD). An analysis of covariance was conducted to evaluate the impact of retinal morphologic features on BCVA change at month 12. MAIN OUTCOME MEASURES: Change in BCVA from baseline to month 12 compared between frequent and infrequent treatment arms. RESULTS: Relevant predictive factors for BCVA change at month 12 were baseline SRF (P = 0.05), PVD (P = 0.03), IRC (P = 0.05), treatment frequency (P < 0.01), and BCVA (P < 0.01). The presence of both SRF and PVD at baseline was associated with similar BCVA gains regardless of treatment frequency (mean difference in BCVA gains at month 12 of +2.6 letters in favor of infrequent treatment). Subretinal fluid was present in 71% of patients, and PVD was present in 64% of patients. CONCLUSIONS: In patients with both SRF and PVD at baseline, similar BCVA outcomes were observed regardless of treatment frequency. These patients may require less frequent treatments compared with patients without SRF, without PVD, or without either who may require more frequent injections for maintenance of vision. This finding may have implications in clinical practice by helping to tailor an individualized re-treatment interval in nAMD patients. PMID- 26481823 TI - Yttrium-90 Infusion: Incidence and Outcome of Delivery System Occlusions during 885 Deliveries. AB - PURPOSE: To evaluate the incidence, cause, and management of delivery system occlusions during yttrium-90 (90Y) microsphere infusions and to identify techniques to prevent occlusions. MATERIALS AND METHODS: A retrospective review was conducted of 885 consecutive radioembolization deliveries during 820 procedures (some with multiple deliveries) in 503 patients (mean age, 65 y; 293 male) performed between June 2001 and July 2013 at a single academic tertiary care hospital. Occlusions were reported prospectively, and procedural details were reviewed. Statistical analysis assessed associations between catheter occlusions and patient and procedural characteristics. RESULTS: Of 885 90Y microsphere deliveries, 11 resulted in occlusion (1.2%). Five occlusions were associated with contained leakage of radioactive material, and one was associated with a spill. Treatment was completed in the same day in 10 patients; repeat catheterization was required in five patients. One patient returned 1 week later to complete treatment. Occlusions were more frequent with deliveries of resin (11/492; 2.2%) versus glass (0/393; 0%) microspheres (P = .002). Occlusions were more likely to occur within the proximal portion of the delivery apparatus (P = .002). There was no significant relationship with any patient characteristics, and there was no improvement with operator experience. The most common cause of occlusion was resin microsphere delivery device failure. CONCLUSIONS: (90)Y microsphere delivery device occlusion is uncommon but does occur with resin microspheres. Understanding causes and how to troubleshoot can limit the incidence and detrimental effects. PMID- 26481824 TI - Recurrent Bleeding, Survival, and Longitudinal Pulmonary Function following Bronchial Artery Embolization for Hemoptysis in a U.S. Adult Population. AB - PURPOSE: To report outcomes of bronchial artery embolization (BAE) for hemoptysis, including recurrent bleeding, survival, and longitudinal pulmonary function. MATERIALS AND METHODS: A prospective database identified 69 patients who underwent 97 BAE procedures (n = 1-7 per patient) at a tertiary academic medical center over a period of 11 years. Technical and clinical success were determined. Recurrent bleeding and survival were compared by etiology of lung disease. Rates of change in pulmonary function (forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]) were measured and compared before and after index BAE by linear regression in 17 patients. RESULTS: The technical success rate of BAE was 90%. Clinical success rates at 24 hours and 30 days were 82% and 68%, respectively. Thirty percent of patients had recurrent bleeding that required bronchoscopy (7%) or additional embolization (23%). Median time to recurrent bleeding was 29 days among the 13 patients with sarcoidosis, compared with 293 days among patients without sarcoidosis (P = .0013). The hazard ratio for death in patients with sarcoidosis compared with those without sarcoidosis was 4 (95% confidence interval, 2.6-14.6). Analyzing all instances of pulmonary function tests, slopes of decline in FEV1 and FVC were significantly different (FEV1, P = .0048; FVC, P < .0001) before and after index BAE, with an improvement after BAE (FEV1, 0.8%/y; FVC, 1%/y) and a decrease before BAE (FEV1, -1.6%/y; FVC, -1.4%/y). CONCLUSIONS: BAE is an effective therapy for hemoptysis, but patients with sarcoidosis are at significant risk of recurrent bleeding and death compared with patients with other lung diseases. BAE does not accelerate deterioration in lung function. PMID- 26481825 TI - Cassane diterpenoids from the roots of Caesalpinia decapetala var. japonica and structure revision of caesaljapin. AB - Two cassane-type furanoditerpenoids, designated caesalacetal and caesalpinetate, and a norditerpenoid designated caesalpinone were isolated from the roots of Caesalpinia decapetala var. japonica along with seven known diterpenoids. Structures were elucidated by interpretation of their spectroscopic data, and the absolute structure of caesalacetal was confirmed by X-ray crystallographic analysis. Furthermore, the structure of a previously reported furanoditerpenoid, caesaljapin, was revised as its C-4 epimer on the basis of detailed NMR spectroscopic data as well as X-ray crystallographic analysis. PMID- 26481827 TI - Emerging Approaches to GPCR Ligand Screening for Drug Discovery. AB - The superfamily of G-protein-coupled receptors (GPCRs) represents the largest class of cell surface receptors and, thus, a prominent family of drug targets. Recently, there has been significant progress in determination of GPCR crystal structures. The structure-based ligand discovery of GPCRs is emerging as a powerful path to drug development. Sensor surface-immobilized GPCRs can identify direct receptor-ligand interactions of a range of chemical libraries. This type of screening shows great promise as an alternative strategy for ligand discovery. Here, we summarize the most recent developments of structure- and sensor-based GPCR ligand discovery. We also highlight certain areas where GPCRs harbor great potential for the development of novel therapeutics, emphasizing the strategic approaches that may yield significant breakthroughs. PMID- 26481826 TI - Pharmacy workforce to prevent and manage non-communicable diseases in developing nations: The case of Nepal. AB - Non-communicable diseases (NCDs, e.g. cardiovascular diseases, cancer, chronic respiratory diseases and diabetes mellitus) are the main causes of mortality and morbidity in developing countries, including Nepal. Nearly half of the deaths in Nepal are caused by NCDs. Nepal lacks adequate human resources to prevent and manage NCDs, but the skills and expertise of pharmacists in Nepal are underused. There is evidence from many countries that pharmacists can contribute substantially to the prevention and management NCD. We aim to describe the opportunities and challenges for pharmacists to prevent and manage NCDs in Nepal. Pharmacists can contribute by screening and monitoring NCDs; counseling on lifestyle; providing medication therapy management services; promoting public health; and providing other pharmaceutical services. Challenges to the implementation of some of these activities in the current context include inadequate training of pharmacists in NCD prevention and management, the cost of pharmaceutical services to patients and government, and the existing health care service delivery model. There is a need for health services research to determine how pharmacists can be best used to prevent and manage NCDs in Nepal. PMID- 26481828 TI - Bile Acid-Activated Receptors, Intestinal Microbiota, and the Treatment of Metabolic Disorders. AB - The composition of the bile acid pool is a function of the microbial metabolism of bile acids in the intestine. Perturbations of the microbiota shape the bile acid pool and modulate the activity of bile acid-activated receptors (BARs) even beyond the gastrointestinal tract, triggering various metabolic axes and altering host metabolism. Bile acids, in turn, can also regulate the composition of the gut microbiome at the highest taxonomic levels. Primary bile acids from the host are preferential ligands for the farnesoid X receptor (FXR), while secondary bile acids from the microbiota are ligands for G-protein-coupled bile acid receptor 1 (GPBAR1). In this review, we examine the role of bile acid signaling in the regulation of intestinal microbiota and how changes in bile acid composition affect human metabolism. Bile acids may offer novel therapeutic modalities in inflammation, obesity, and diabetes. PMID- 26481829 TI - Evaluation of various techniques for microalgal biomass quantification. AB - Biomass concentration is one of the most important parameters in the biotechnology processes. Its measurement relies on the physical, chemical or biological properties of the cells. Several techniques were applied in this work to measure the cell concentration of four microalgae: Botryococcussp., Botryococcusbraunii, Chlorella vulgaris, and Ettlia sp. The experiments were performed using samples taken from a chemostat for each strain to provide microalgal cell suspensions in a stable physiological state and concentration. The dry cell weight (DCW) was used as the reference method for the evaluation of other methods. The two commercial sensors used to determine optical density and dielectric permittivity showed a broad effective measurement range up to more than 20gl(-1). A Red-Green-Blue model analysis of microalgal digital images in combination with Fourier equation significantly extended the measurements range up to 6gl(-1). Cell count using a flow cytometer showed a broad range of linearity to DCW in washed samples, but other counting methods using hemocytometer and microscopic automated count were limited. Finally, the oxygen production rate, representing the photosynthetic activity, showed a linear regression with DCW at cell concentrations lower than 1gl(-1). PMID- 26481831 TI - Insect cell entrapment, growth and recovering using a single-use fixed-bed bioreactor. Scaling up and recombinant protein production. AB - Insect cells are largely used for industrial production of vaccines, viral vectors and recombinant proteins as well as in research and development as an important tool for biology and bioprocess studies. They grow in suspension and are semi-adherent cells. Among the cell culture systems enabling scalable bioprocess the single-use fixed-bed iCELLis((r)) bioreactors offer great advantages. We have established the conditions for Drosophila melanogaster Schneider 2 (S2) and Spodoptera frugiperda (Sf9) cells entrapment into the fixed bed, cell growth and recover from the fixed-bed once high cell densities were attained. Our established protocol allowed these cells, at a cell seeding of 2*1E5 cells/microfiber carriers (MC) (3.5*1E6cells/mL; 1.7*1E4cells/cm(2)), to grow inside a 4m(2)/200mL fixed-bed attaining a concentration of 5.3*1E6 cells/MC (9.5*1E7cells/mL; 4.7*1E5 cells/cm(2)) for S2 cells or 4.6*1E6 cells/MC (8*1E7cells/mL; 4.1*1E5cells/cm(2)) for Sf9 cells. By washing the fixed-bed, entrapped cells could then be recovered from the fixed-bed at a high rate (>85%) with high viability (>95%) by increasing the agitation to 1200/1500rpm. Although the cell yields in the fixed-bed bioreactor were comparable to those obtained in a stirred tank (respectively, 1.3*1E10 and 2.5*1E10 total cells), S2 cells stably transfected with a cDNA coding for the rabies virus glycoprotein (RVGP) showed a 30% higher preserved rRVGP production (2.5+/-0.1 and 1.9+/-0.1MUg/1E7 cells), as evidenced by a conformational ELISA evaluation. These findings demonstrate not only the possibility to entrap, cultivate to high densities and recover insect cells using a single-use fixed-bed bioreactor, but also that this system provides suitable physiological conditions for the entrapped cells to produce a cell membrane associated recombinant protein with higher specific biological activity as compared to classical suspension cell cultures. PMID- 26481830 TI - Glucosylation of aroma chemicals and hydroxy fatty acids. AB - To explore the utility of glycosyltransferases as novel biocatalysts, we isolated the glycosyltransferase genes CaUGT2 and SbUGTA1 from Catharanthus roseus and Starmerella bombicola, respectively and heterologously expressed them in Escherichia coli. The purified recombinant proteins were assayed with a variety of small molecule substrates. Carvacrol and its phenol isomer thymol are efficiently glucosylated by CaUGT2. The Vmax/Km ratios show that CaUGT2 exhibits the highest specificity towards carvacrol, followed by thymol, geraniol, eugenol, vanillin, menthol, and tyrosol. In contrast, SbUGTA1 accepts omega-hydroxy fatty acids and 1-alkanols as substrates. The Vmax/Km ratios indicate that SbUGTA1 exhibits the highest specificity towards 16-hydroxy palmitic acid, followed by octanol, decanol, and hexadecanol. In biotransformation experiments 23, 88 and 99% of octanol, 16-hydroxy palmitic acid, and decanol, respectively is converted into the corresponding beta-glucosides by E. coli cells expressing SbUGTA1 whereas those cells expressing CaUGT2 glucosylate 18, 61, 77 and 97% of applied eugenol, thymol, vanillin, and carvacrol, respectively. To optimize the biotransformation rate, the effects of the concentration of IPTG, glucose, and substrate on the production of glucosides were tested. Taken together, this procedure is a simple operation, environmentally friendly, and is useful for the preparation of glycosides as additives for food and cosmetics. PMID- 26481832 TI - Identification of genetic risk for pancreatic adenocarcinoma. AB - Recent consortium guidelines support research-based screening for those at high risk of pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)). Genetic testing plays an important role in the establishment of high-risk PDAC research clinics by delineating those individuals who would benefit from screening protocols. We retrospectively examined patients referred for PDAC-related genetic testing from January 2009 to June 2014. Patients were referred for a personal and/or family history of PDAC or a questioned diagnosis of hereditary pancreatitis (HP). Of the 75 referred patients, 36 underwent testing, of which 11 (31%) were mutation-positive. In total, 36% of patients with chronic pancreatitis carried a mutation, 11% of patients with a family history of PDAC carried a mutation, and 20% of patients with a personal history of PDAC carried a mutation. The most common barrier to testing was lack of insurance coverage. Genetic testing yields a suitable number of mutation-positive individuals who may benefit from increased screening. Subjects with possible HP yielded the highest positive rate. Individuals with idiopathic pancreatitis, onset of pancreatitis before the age of 30 years, and those with a family history of PDAC should be considered for testing. Sub-optimal insurance coverage remains a major deterrent to obtaining testing. PMID- 26481833 TI - Comparison of culture-dependent and independent approaches to characterize fecal bifidobacteria and lactobacilli. AB - Different culture-dependent and independent methods were applied to investigate the population of bifidobacteria and lactobacilli in the feces of five healthy subjects. Bacteria were isolated on MRS, a complex medium supporting growth of lactobacilli and bifidobacteria, and on three selective media for bifidobacteria and two for lactobacilli. Taxonomic characterization of the isolates was carried out by RAPD-PCR and partial 16S sequencing. The selectivity of genus-specific media was also investigated by challenging colonies from MRS plates to grow onto each medium. In parallel, a quantitative and qualitative description of bifidobacteria and lactic acid bacteria was obtained by FISH, qPCR, TRFLP, and 16S rRNA gene sequencing. Bifidobacteria did not fail to grow on their specific media and were easily isolated and enumerated, showing comparable quantitative data among culture-dependent and -independent techniques. The Bifidobacterium species identified on plates and those extracted from TRFLP and 16S rRNA gene sequencing were mostly overlapping. Selective media for lactobacilli gave unsuitable results, being too stringent or too permissive. The quantification of lactobacilli through selective plates, qPCR, FISH, and 16S rRNA gene sequencing gave unreliable results. Therefore, unlike bifidobacteria, intestinal lactobacilli are still problematic in terms of quantification and accurate profiling at level of species and possibly of strains by both culture-dependent and culture-independent techniques. PMID- 26481835 TI - [Neonatal circumcision with local anesthesia. Results of a standardized protocol]. AB - INTRODUCTION: Neonatal circumcision is a common procedure in the US and other countries, with low rates of complications in trained hands. However, it has recently been incorporated into the clinical environment in Chile. Our goal was to establish a local standardised protocol for neonatal circumcision under local anaesthesia, and evaluate the results and possible complications. PATIENTS AND METHOD: A standardised prospective protocol was used on patients who underwent neonatal circumcision. The inclusion criteria were: children <60days and <5kg. The surgical technique used was topical local anaesthesia and penile block, attrition of redundant prepuce and mucosa with Mogen(r) clamp, and section with scalpel. The protocol was used and evaluated from November 2005 to October 2014 by a paediatric surgeon and/or paediatric urologist trained in the technique. Complications and conditions until final discharge were analysed. RESULTS: The protocol was applied to 108 patients over a 9year period. The mean age at procedure was 9days (1-52). One patient (0.9%) had immediate bleeding, requiring further surgery. All patients were discharged from further medical checks at 1 month, without any other complications. The reason for the procedure was by parental request in 100% of the cases, and always for sociocultural reasons. CONCLUSION: Neonatal circumcision under local anaesthesia is a simple procedure, and has excellent results in selected patients, and with no major complications. With proper training, and adapting the initial protocol, it can be performed on an outpatient basis, without putting the neonates through the risks of general anaesthesia. PMID- 26481834 TI - Polymicrobial infection alter inflammatory microRNA in rat salivary glands during periodontal disease. AB - Periodontal disease initiated by subgingival pathogens is linked with diminished secretion of saliva, and implies pathogenic bacteria dissemination to or affects secondary sites such as the salivary glands. MicroRNAs activated in response to bacteria may modulate immune responses against pathogens. Therefore, Sprague Dawley rats were infected by oral lavage consisting of polymicrobial inocula, namely Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, or sham-infected for 12 weeks (n = 6). We quantified inflammatory miRNA expression levels of miRNA-132, miR-146a, and miR-155 at secondary sites to the primary infection of the gingiva, including submandibular salivary glands, lacrimal glands, and pancreas. The presence of bacteria was detected in situ at secondary sites. Infected rat gingiva showed increased relative expression of miR 155. In contrast, miRNA-155 expression was decreased in submandibular salivary glands, along with positive identification of P. gingivalis in 2/6 and T. denticola in 1/6 rat salivary glands. Furthermore, miRNA-132 and miRNA-146a were significantly decreased in the pancreas of infected rats. This study is the first to show primary periodontal infections can alter miRNA profiles in secondary sites such as the salivary gland and pancreas. Whether these alterations contribute to pathologies of salivary glands in Sjogren's syndrome or of pancreas in diabetes warrants further investigation. PMID- 26481836 TI - Sirolimus for Refractory Autoimmune Hemolytic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report and Literature Review of the Treatment of Post-Transplant Autoimmune Hemolytic Anemia. AB - Autoimmune hemolytic anemia (AIHA) may occur after any type of allogeneic hematopoietic stem cell transplantation (HCT), even ABO-matched transplantation. It tends to be refractory to standard corticosteroid treatment and requires multiple transfusions. Though, there is no consensus regarding the optimal treatment for post-transplant severe AIHA. We present a pediatric patient with refractory AIHA after umbilical cord blood transplantation. She developed severe AIHA at 3months after transplantation and was unresponsive to multiple treatment modalities, including corticosteroids, intravenous immunoglobulin, plasma exchange and rituximab, resulting in persistent transfusion dependency. Sirolimus, a mammalian target of rapamycin inhibitor, was started on day 67 after the onset of AIHA, and this patient was successfully rescued without any complications. Sirolimus induces apoptosis in autoreactive lymphocytes, increases regulatory T cells and has been reported to have a positive effect on AIHA following solid organ transplantation (SOT). We reviewed the literature regarding post-transplant AIHA in the PubMed database and evaluated the treatment outcome of sirolimus in AIHA after SOT. PMID- 26481837 TI - Treatment Outcomes in CML Patients Treated With Tyrosine Kinase Inhibitors at a Tertiary Teaching Hospital in South Africa. AB - BACKGROUND: Chronic myeloid leukemia (CML) has become one of the most treatable hematologic neoplasms since the advent of the tyrosine kinase inhibitors (TKIs), but it was not known if similar treatment outcomes could be achieved in a resource-limited country. We tested the hypothesis that, despite challenges to access to second-generation TKIs, excellent responses could be replicated in the setting of limited resources. PATIENTS AND METHODS: Records of 58 patients with newly diagnosed CML in the chronic phase treated with TKIs at a tertiary teaching hospital in Cape Town, South Africa between 2003 and 2012 were reviewed and assessed according to European LeukemiaNet (ELN) criteria. RESULTS: After a median follow-up of 60.5 months, progression-free survival at 60 and 96 months was 79.98% and 68.4%, respectively. Overall survival at 60 and 96 months was 92.9% and 83.6%, respectively. Progression to blast phase at 60 months was associated with poorer survival (P = .0002) but progression to accelerated phase was not (P = .1456). Attainment of a complete cytogenetic response at 12 months (P = .28) or major molecular response at 18 months (P = .268) did not have prognostic significance. CONCLUSION: Despite delays in achievement of the target responses defined according to ELN criteria, the use of imatinib mesylate as a first-line treatment can still result in treatment outcomes comparable with those in developed countries. These data suggest opportunities for improvement and success might be even greater with uninterrupted access to second-generation or newer TKIs. PMID- 26481838 TI - Viability, Remodeling, and CABG: Another STICH in the Shroud of Observation-Based Paradigm? PMID- 26481839 TI - Low-Gradient Aortic Stenosis: Are We Getting Closer to Solving a Diagnostic and Therapeutic Dilemma? PMID- 26481840 TI - Coronary MR Imaging: Moving From Lumenography to Plaque Assessment. PMID- 26481841 TI - Conceptual New Biomechanical Approaches to Identify Coronary Plaques at Risk of Disruption. PMID- 26481842 TI - Radiation Exposure in Medical Imaging: Is the Message Out or Just Being Ignored? PMID- 26481843 TI - Predictors of Plaque Rupture Within Nonculprit Fibroatheromas in Patients With Acute Coronary Syndromes: The PROSPECT Study. AB - OBJECTIVES: The study sought to examine the relative importance of lesion location versus vessel area and plaque burden in predicting plaque rupture within nonculprit fibroatheromas (FAs) in patients with acute coronary syndromes. BACKGROUND: Previous studies have demonstrated that plaque rupture is associated with larger vessel area and greater plaque burden clustering in the proximal segments of coronary arteries. METHODS: In the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study 3-vessel grayscale and radiofrequency-intravascular ultrasound was performed after successful percutaneous coronary intervention in 697 patients with acute coronary syndromes. Untreated nonculprit lesion FAs were classified as proximal (<20 mm), mid (20 to 40 mm), and distal (>40 mm) according to the distance from the ostium to the maximum necrotic core site. RESULTS: Overall, 74 ruptured FAs and 2,396 nonruptured FAs were identified in nonculprit vessels. The majority of FAs (73.6%) were located within 40 mm of the ostium, and the vessel area and plaque burden progressively decreased from proximal to distal FA location (both p < 0.001). In a multivariate logistic regression model, independent predictors for plaque rupture included the distance from the ostium to the maximum necrotic core site per millimeter (odds ratio [OR]: 0.86; 95% confidence interval [CI]: 0.76 to 0.98; p = 0.02), plaque burden per 10% (OR: 2.05; 95% CI: 1.63 to 2.58; p < 0.0001), vessel area per mm(2) (OR: 1.14; 95% CI: 1.11 to 1.17; p < 0.0001), calcium (OR: 0.09; 95% CI: 0.05 to 0.18; p < 0.0001), and right coronary artery location (OR: 2.16; 95% CI: 1.25 to 3.27; p = 0.006). By receiver-operating characteristic analysis, vessel area correlated with plaque rupture stronger than either plaque burden (p < 0.001) or location (p < 0.001). CONCLUSIONS: Large vessel area, plaque burden, proximal location, right coronary artery location, and lack of calcium were associated with FA plaque rupture. The present study suggests that among these variables, vessel area may be the strongest predictor of plaque rupture among non-left main coronary arteries. ( PROSPECT: An Imaging Study in Patients With Unstable Atherosclerotic Lesions [PROSPECT]; NCT00180466). PMID- 26481844 TI - A Bigger Artery Is Not Better: Predicting Coronary Plaque Rupture. PMID- 26481845 TI - Multimodality Imaging in the Context of Transcatheter Mitral Valve Replacement: Establishing Consensus Among Modalities and Disciplines. AB - Transcatheter mitral valve implantation (TMVI) represents a promising approach to treating mitral valve regurgitation in patients at increased risk of perioperative mortality. Similar to transcatheter aortic valve replacement (TAVR), TMVI relies on pre- and periprocedural noninvasive imaging. Although these imaging modalities, namely echocardiography, computed tomography, and fluoroscopy, are well established in TAVR, TMVI has entirely different requirements. Approaches and nomenclature need to be standardized given the multiple disciplines involved. Herein we provide an overview of anatomical principles and definitions, a methodology for anatomical quantification, and perioperative guidance. PMID- 26481846 TI - Noninvasive Fractional Flow Reserve Derived From Coronary CT Angiography: Clinical Data and Scientific Principles. AB - Fractional flow reserve derived from coronary computed tomography angiography enables noninvasive assessment of the hemodynamic significance of coronary artery lesions and coupling of the anatomic severity of a coronary stenosis with its physiological effects. Since its initial demonstration of feasibility of use in humans in 2011, a significant body of clinical evidence has developed to evaluate the diagnostic performance of coronary computed tomography angiography-derived fractional flow reserve compared with an invasive fractional flow reserve reference standard. The purpose of this paper was to describe the scientific principles and to review the clinical data of this technology recently approved by the U.S. Food and Drug Administration. PMID- 26481847 TI - Mechanisms of Mitral Valve Dysfunction Following Mitral Valve Repair for Degenerative Disease. PMID- 26481848 TI - Presence of Ischemia by FFR Without Significant Anatomic Stenosis Is Likely due to Concomitant Diffuse Disease and Not due to Impaired Vasodilation From Pharmacological Stress. PMID- 26481849 TI - Reply: Presence of Ischemia by FFR Without Significant Anatomic Stenosis Is Likely due to Concomitant Diffuse Disease and Not due to Impaired Vasodilation From Pharmacological Stress. PMID- 26481850 TI - Myocardial Viability and Remodeling: Does Size Matter? PMID- 26481851 TI - Aorta-Iliac Bypass in Thoracoabdominal Aortic Aneurysm Repair in Young Chinese Patients. AB - BACKGROUND: Many surgical methods of thoracoabdominal aortic aneurysm repair (TAAAR) have been introduced over the past several decades, with varying degrees of success. We developed an aorta-iliac bypass technique to treat thoracoabdominal aortic aneurysm (TAAA) in young Chinese patients. The aim of this study is to evaluate the results of this technique intraoperatively and postoperatively. METHODS: From June 2014 to March 2015, 28 patients underwent TAAAR using aorta-iliac bypass technique. A four-branched tetrafurcate graft was used. Two branches of the graft are sutured to bilateral common iliac arteries in an end-to-side fashion. The trunk of the graft was sutured to the proximal descending aorta in an end-to-end fashion. Then aorta-iliac bypass was established, and the lower extremities, viscera organ and spinal cord (SC) obtained perfusion from proximal descending aorta via the bypass graft. The thoracic and abdominal aorta were clamped in a staged fashion. The patent segmental arteries (SAs), and visceral arteries (coeliac trunk, superior mesenteric arteries, and renal arteries) were reattached sequentially. Evoked potential (EP) monitoring was adopted to assess the SC ischaemia throughout the procedure. The postoperative outcomes and follow-up results of this technique were evaluated. RESULTS: There was no in-hospital mortality. Complications included acute kidney dysfunction and pulmonary haemorrhage in one case (3.6%) each. The SAs were reattached in all cases. The EP wave disappeared after proximal descending aorta was clamped, and gradually recovered after the patent SAs reattached. The median follow-up after operation was eight months (range, 1 10 months). There was no delayed neurologic deficit or late death. CONCLUSIONS: Thoracoabdominal aortic aneurysm repair using aorta-iliac bypass may be a simple and safe choice for young Chinese patients with thoracoabdominal aortic aneurysms. PMID- 26481852 TI - Elevation of neuron specific enolase and brain iron deposition on susceptibility weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood: Additional case report and review of the literature. AB - Beta-propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), is a subtype of neurodegeneration with brain iron accumulation (NBIA). BPAN is caused by mutations in an X-linked gene WDR45 that is involved in autophagy. BPAN is characterized by developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. Brain magnetic resonance imaging (MRI) shows iron deposition in the bilateral globus pallidus (GP) and substantia nigra (SN). Clinical manifestations and laboratory findings in early childhood are limited. We report a 3-year-old girl with BPAN who presented with severe developmental delay and characteristic facial features. In addition to chronic elevation of serum aspartate transaminase, lactate dehydrogenase, creatine kinase, and soluble interleukin-2 receptor, she had persistent elevation of neuron specific enolase (NSE) in serum and cerebrospinal fluid. MRI using susceptibility-weighted imaging (SWI) demonstrated iron accumulation in the GP and SN bilaterally. Targeted next generation sequencing identified a de novo splice-site mutation, c.831-1G>C in WDR45, which resulted in aberrant splicing evidenced by reverse transcriptase PCR. Persistent elevation of NSE and iron deposition on SWI may provide clues for diagnosis of BPAN in early childhood. PMID- 26481853 TI - Cavity enhanced atomic magnetometry. AB - Atom sensing based on Faraday rotation is an indispensable method for precision measurements, universally suitable for both hot and cold atomic systems. Here we demonstrate an all-optical magnetometer where the optical cell for Faraday rotation spectroscopy is augmented with a low finesse cavity. Unlike in previous experiments, where specifically designed multipass cells had been employed, our scheme allows to use conventional, spherical vapour cells. Spherical shaped cells have the advantage that they can be effectively coated inside with a spin relaxation suppressing layer providing long spin coherence times without addition of a buffer gas. Cavity enhancement shows in an increase in optical polarization rotation and sensitivity compared to single-pass configurations. PMID- 26481854 TI - Activity of SHIP, Which Prevents Expression of Interleukin 1beta, Is Reduced in Patients With Crohn's Disease. AB - BACKGROUND & AIMS: Crohn's disease (CD) is associated with a dysregulated immune response to commensal micro-organisms in the intestine. Mice deficient in inositol polyphosphate 5'-phosphatase D (INPP5D, also known as SHIP) develop intestinal inflammation resembling that of patients with CD. SHIP is a negative regulator of PI3Kp110alpha activity. We investigated mechanisms of intestinal inflammation in Inpp5d(-/-) mice (SHIP-null mice), and SHIP levels and activity in intestinal tissues of subjects with CD. METHODS: We collected intestines from SHIP-null mice, as well as Inpp5d(+/+) mice (controls), and measured levels of cytokines of the interleukin 1 (IL1) family (IL1alpha, IL1beta, IL1ra, and IL6) by enzyme-linked immunosorbent assay. Macrophages were isolated from lamina propria cells of mice, IL1beta production was measured, and mechanisms of increased IL1beta production were investigated. Macrophages were incubated with pan-phosphatidylinositol 3-kinase inhibitors or PI3Kp110alpha-specific inhibitors. Some mice were given an antagonist of the IL1 receptor; macrophages were depleted from ilea of mice using clodronate-containing liposomes. We obtained ileal biopsies from sites of inflammation and peripheral blood mononuclear cells (PBMCs) from treatment-naive subjects with CD or without CD (controls), and measured SHIP levels and activity. PBMCs were incubated with lipopolysaccharide and adenosine triphosphate, and levels of IL1beta production were measured. RESULTS: Inflamed intestinal tissues and intestinal macrophages from SHIP-null mice produced higher levels of IL1B and IL18 than intestinal tissues from control mice. We found PI3Kp110alpha to be required for macrophage transcription of Il1b. Macrophage depletion or injection of an IL1 receptor antagonist reduced ileal inflammation in SHIP-null mice. Inflamed ileal tissues and PBMCs from patients with CD had lower levels of SHIP protein than controls (P < .0001 and P < .0002, respectively). There was an inverse correlation between levels of SHIP activity in PBMCs and induction of IL1beta production by lipopolysaccharide and adenosine triphosphate (R(2) = .88). CONCLUSIONS: Macrophages from SHIP-deficient mice have increased PI3Kp110alpha-mediated transcription of Il1b, which contributes to spontaneous ileal inflammation. SHIP levels and activity are lower in intestinal tissues and peripheral blood samples from patients with CD than controls. There is an inverse correlation between SHIP activity and induction of IL1beta production by lipopolysaccharide and adenosine triphosphate in PBMCs. Strategies to reduce IL1B might be developed to treat patients with CD found to have low SHIP activity. PMID- 26481856 TI - Seeing and being seen: Shame in the clinical situation. AB - Shame may prevent the patient from emerging from a psychic retreat. As begins to do so he confronts two fears, first of seeing the object more clearly and second of being seen become prominent. Seeing leads to deeper and more distressing feelings connected with guilt and depression as the damage done to good objects is recognized. However it cannot be faced if shame leads to a demand for immediate relief. Shame is a prominent feature of the analytic situation and recognizing this may help the analyst to support his patients to tolerate the discomfort of being seen so that the conflicts about seeing can be worked through. Two clinical examples are briefly discussed. In the first feelings of inferiority lessened as they were analysed and allowed appreciative and depressive feelings to emerge. In the second embarrassment was associated with progress that the patient felt he had made but was embarrassed to admit. It is argued that the analysis of shame in the analytic situation is necessary so that being seen can be tolerated and allow the conflicts over seeing to be worked through. PMID- 26481855 TI - Differences in Alimentary Glucose Absorption and Intestinal Disposal of Blood Glucose After Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy. AB - BACKGROUND & AIMS: Bariatric procedures, such as Roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG), are the most effective approaches to resolve type 2 diabetes in obese individuals. Alimentary glucose absorption and intestinal disposal of blood glucose have not been directly compared between individuals or animals that underwent RYGB vs VSG. We evaluated in rats and humans how the gut epithelium adapts after surgery and the consequences on alimentary glucose absorption and intestinal disposal of blood glucose. METHODS: Obese male rats underwent RYGB, VSG, or sham (control) operations. We collected intestine segments from all rats; we performed histologic analyses and measured levels of messenger RNAs encoding the sugar transporters SGLT1, GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5. Glucose transport and consumption were assayed using ex vivo jejunal loops. Histologic analyses were also performed on Roux limb sections from patients who underwent RYGB 1-5 years after surgery. Roux limb glucose consumption was assayed after surgery by positron emission and computed tomography imaging. RESULTS: In rats and humans that underwent RYGB, the Roux limb became hyperplasic, with an increased number of incretin-producing cells compared with the corresponding jejunal segment of controls. Furthermore, expression of sugar transporters and hypoxia-related genes increased and the nonintestinal glucose transporter GLUT1 appeared at the basolateral membrane of enterocytes. Ingested and circulating glucose was trapped within the intestinal epithelial cells of rats and humans that underwent RYGB. By contrast, there was no hyperplasia of the intestine after VSG, but the intestinal absorption of alimentary glucose was reduced and density of endocrine cells secreting glucagon like peptide-1 increased. CONCLUSIONS: The intestine adapts differently to RYGB vs VSG. RYGB increases intestinal glucose disposal and VSG delays glucose absorption; both contribute to observed improvements in glycemia. PMID- 26481858 TI - Dental calculus evidence of Tai Forest Chimpanzee plant consumption and life history transitions. AB - Dental calculus (calcified dental plaque) is a source of multiple types of data on life history. Recent research has targeted the plant microremains preserved in this mineralised deposit as a source of dietary and health information for recent and past populations. However, it is unclear to what extent we can interpret behaviour from microremains. Few studies to date have directly compared the microremain record from dental calculus to dietary records, and none with long term observation dietary records, thus limiting how we can interpret diet, food acquisition and behaviour. Here we present a high-resolution analysis of calculus microremains from wild chimpanzees (Pan troglodytes verus) of Tai National Park, Cote d'Ivoire. We test microremain assemblages against more than two decades of field behavioural observations to establish the ability of calculus to capture the composition of diet. Our results show that some microremain classes accumulate as long-lived dietary markers. Phytolith abundance in calculus can reflect the proportions of plants in the diet, yet this pattern is not true for starches. We also report microremains can record information about other dietary behaviours, such as the age of weaning and learned food processing techniques like nut-cracking. PMID- 26481859 TI - The Dichotic Right Ear Advantage Does not Change with Transcranial Direct Current Stimulation (tDCS). PMID- 26481857 TI - Histidine provides long-term neuroprotection after cerebral ischemia through promoting astrocyte migration. AB - The formation of glial scar impedes the neurogenesis and neural functional recovery following cerebral ischemia. Histamine showed neuroprotection at early stage after cerebral ischemia, however, its long-term effect, especially on glial scar formation, hasn't been characterized. With various administration regimens constructed for histidine, a precursor of histamine, we found that histidine treatment at a high dose at early stage and a low dose at late stage demonstrated the most remarkable long-term neuroprotection with decreased infarct volume and improved neurological function. Notably, this treatment regimen also robustly reduced the glial scar area and facilitated the astrocyte migration towards the infarct core. In wound-healing assay and transwell test, histamine significantly promoted astrocyte migration. H2 receptor antagonists reversed the promotion of astrocyte migration and the neuroprotection provided by histidine. Moreover, histamine upregulated the GTP-bound small GTPase Rac1, while a Rac1 inhibitor, NSC23766, abrogated the neuroprotection of histidine and its promotion of astrocyte migration. Our data indicated that a dose/stage-dependent histidine treatment, mediated by H2 receptor, promoted astrocyte migration towards the infarct core, which benefited long-term post-cerebral ischemia neurological recovery. Therefore, targeting histaminergic system may be an effective therapeutic strategy for long-term cerebral ischemia injury through its actions on astrocytes. PMID- 26481860 TI - Analysis of youtube as a source of information for peripheral neuropathy. AB - INTRODUCTION: YouTube is an important resource for patients. No study has evaluated the information on peripheral neuropathy disseminated by YouTube videos. In this study, our aim was to perform a systematic review of information on YouTube regarding peripheral neuropathy. METHODS: The Web site (www.youtube.com) was searched between September 19 and 21, 2014, for the terms "neuropathy," "peripheral neuropathy," "diabetic neuropathy," "neuropathy causes," and "neuropathy treatment." RESULTS: Two hundred videos met the inclusion criteria. Healthcare professionals accounted for almost half of the treatment videos (41 of 92; 44.6%), and most came from chiropractors (18 of 41; 43.9%). Alternative medicine was cited most frequently among the treatment discussions (54 of 145, 37.2%), followed by devices (38 of 145, 26.2%), and pharmacological treatments (23 of 145, 15.9%). CONCLUSIONS: Approximately half of the treatment options discussed in the videos were not evidence-based. Caution should be exercised when YouTube videos are used as a patient resource. PMID- 26481861 TI - Long-term survival in a patient with head and neck paraganglioma treated with tailored modalities for 20 years: a case report. AB - AIMS AND BACKGROUND: Primary paragangliomas of nasal cavity and paranasal sinus are rare conditions that could show aggressive behavior with local recurrence and metastasis development. The diagnosis of malignancy is challenging because there are no available histopathologic criteria. In these cases, the prognosis is usually poor. METHODS: We report a case of a woman with malignant paranasal sinus paragangliomas. RESULTS: The patient was treated with several surgical approaches, radiotherapy, and medical therapy for different recurrences. CONCLUSIONS: Despite the malignant behavior of the disease, this patient is still alive many years after first diagnosis. PMID- 26481862 TI - A neuro-oncologic challenge: the case of a large, aggressive, malignant meningioma of the skull base with paranasal sinus involvement. AB - BACKGROUND: Malignant meningiomas, rare tumors that account for approximately 1% 3% of all meningioma, have high recurrence, morbidity, and mortality rate and a particularly poor outcome. Surgical excision followed by adjuvant radiotherapy is the current approach for the treatment of these tumors. METHODS: In the case reported, the disease, characterized by a high proliferative index (Ki67 60% 70%), was treated with endoscopic surgery limited to the extracranial portion; then the patient underwent radiotherapy, on the residual tumor volume, to a total dose of 66 Gy delivered in 33 fractions (2 Gy/fraction) by helical intensity modulated radiation therapy with image-guided radiotherapy daily checks (tomotherapy). RESULTS: Two and a half years after the treatment, the patient is alive and a partial response is maintained. The patient is healthy overall with grade I fatigue and grade II hearing loss as late toxicity (Common Terminology Criteria for Adverse Events 4.1). CONCLUSIONS: Within a multidisciplinary approach, new radiotherapy techniques confirm their effectiveness and reliability for the treatment of malignant meningioma. PMID- 26481864 TI - When curing a pediatric tumor is not enough: the case of a psychiatric disorder in a woman surviving osteosarcoma. AB - AIMS AND BACKGROUND: We describe the case of a woman cured of osteosarcoma who took part in a mono-institutional study using different questionnaires to assess pediatric cancer survivors' quality of life and behavioral features 12 years after completing her cancer treatment. RESULTS: The high levels of psychological distress and psychopathologic symptoms revealed by this patient prompted us to offer her specific and prolonged support at our institution, since she refused to seek the help of other psychiatric services. The woman revealed a dysfunctional social and family setting and a borderline personality disorder. She was hospitalized after attempting suicide. No psychological distress had previously come to light during her long follow-up for cancer. CONCLUSIONS: Cancer survivors are at risk of psychological and behavioral problems, so they should be followed up over time. Questionnaires and standard scales are important, but not enough: the physician-patient relationship is crucial to bring out a patient's psychological issues and needs. This means that dedicated resources should be made available, whenever possible. PMID- 26481863 TI - NMDA receptor encephalitis with cancer of unknown primary origin. AB - PURPOSE: N-methyl-D-aspartate receptor (NMDAR) encephalitis may present as a paraneoplastic syndrome in young women and is often associated with ovarian teratoma. METHODS: We report 2 male cases of NMDAR encephalitis presenting with metastatic cancer of unknown primary origin. RESULTS: Both patients showed cognitive dysfunction as well as other neurological symptoms, slow waves on EEG, and NMDAR antibodies in sera and CSF. Symptoms were effectively treated by pulse steroid and intravenous immunoglobulin treatment. The patients developed metastatic small cell neuroendocrine carcinoma of the parotid gland and inguinal metastatic squamous cell cancer shortly after their neurological episodes. Follow up PET studies showed small cell lung cancer in the first patient while no primary origin could be found in the second patient. CONLUSIONS: Our cases imply that NMDAR encephalitis may present with metastatic cancers that display slow progression rates and occur after encephalitis attacks. PMID- 26481865 TI - Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy? AB - Malignant pleural mesothelioma is a rare cancer with a cause-effect relationship to asbestos exposure. The prognosis is poor and chemotherapy seems the best treatment option. In the last two decades a deeper understanding of mesothelioma carcinogenesis and invasiveness mechanisms has prompted research efforts to test new agents in patients with malignant pleural mesothelioma, but the results have been modest. Attractive preclinical data disappointed in subsequent experimental phases. Other promising agents failed to improve patient outcomes due to high toxicity. Interesting suggestions have come from preliminary data on immunotherapy. Several trials are ongoing and the results are eagerly awaited. The aim of this review is to discuss the most recent news on systemic therapy for advanced malignant pleural mesothelioma. PMID- 26481866 TI - Hepatosplenic T-cell lymphoma with coexistent hepatitis B infection: a rare clinicopathologic entity. AB - BACKGROUND: Hepatosplenic T-cell lymphoma (HSTL) is a rare extranodal and systemic lymphoma derived from cytotoxic T cells usually of gammadelta T cell receptor type. It is characterized by primary extranodal disease with typical sinusoidal infiltration of liver, spleen, and bone marrow by medium-sized lymphoid cells. CASE REPORT: A 29-year-old man, with no significant prior medical history, presented with fever and massive splenomegaly. A diagnosis of HSTL was established by histologic examination and immunohistochemistry. Staging workup demonstrated bone marrow involvement by lymphoma. In addition, the patient was found to have hepatitis B infection. The association of these 2 entities has been described rarely. CONCLUSIONS: Hepatosplenic T-cell lymphoma is a distinct T cell lymphoma associated with an aggressive clinical course, a poor response to conventional treatment, and an exceedingly high mortality rate. An association of HSTL with hepatitis B as seen in the present case is exceedingly rare, with few cases reported in the literature. PMID- 26481867 TI - Selective Heterogeneous C-H Activation/Halogenation Reactions Catalyzed by Pd@MOF Nanocomposites. AB - A directed heterogeneous C-H activation/halogenation reaction catalyzed by readily synthesized Pd@MOF nanocatalysts was developed. The heterogeneous Pd catalysts used were a novel and environmentally benign Fe-based metal-organic framework (MOF)(Pd@MIL-88B-NH2(Fe)) and the previously developed Pd@MIL-101 NH2(Cr). Very high conversions and selectivities were achieved under very mild reaction conditions and in short reaction times. A wide variety of directing groups, halogen sources, and substitution patterns were well tolerated, and valuable polyhalogenated compounds were synthesized in a controlled manner. The synthesis of the Pd-functionalized Fe-based MOF and the recyclability of the two catalysts are also presented. PMID- 26481868 TI - Up-regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis. AB - Epigenetic deregulation plays an important role in liver carcinogenesis. Using transcriptome sequencing, we examined the expression of 591 epigenetic regulators in hepatitis B-associated human hepatocellular carcinoma (HCC). We found that aberrant expression of epigenetic regulators was a common event in HCC. We further identified SETDB1 (SET domain, bifurcated 1), an H3K9-specific histone methyltransferase, as the most significantly up-regulated epigenetic regulator in human HCCs. Up-regulation of SETDB1 was significantly associated with HCC disease progression, cancer aggressiveness, and poorer prognosis of HCC patients. Functionally, we showed that knockdown of SETDB1 reduced HCC cell proliferation in vitro and suppressed orthotopic tumorigenicity in vivo. Inactivation of SETDB1 also impeded HCC cell migration and abolished lung metastasis in nude mice. Interestingly, SETDB1 protein was consistently up-regulated in all metastatic foci found in different organs, suggesting that SETDB1 was essential for HCC metastatic progression. Mechanistically, we showed that the frequent up regulation of SETDB1 in human HCC was attributed to the recurrent SETDB1 gene copy gain at chromosome 1q21. In addition, hyperactivation of specificity protein 1 transcription factor in HCC enhanced SETDB1 expression at the transcriptional level. Furthermore, we identified miR-29 as a negative regulator of SETDB1. Down regulation of miR-29 expression in human HCC contributed to SETDB1 up-regulation by relieving its post-transcriptional regulation. CONCLUSION: SETDB1 is an oncogene that is frequently up-regulated in human HCCs; the multiplicity of SETDB1 activating mechanisms at the chromosomal, transcriptional, and posttranscriptional levels together facilitates SETDB1 up-regulation in human HCC. PMID- 26481869 TI - Simple renal cyst and renal dysfunction: A pilot study using dimercaptosuccinic acid renal Scan. AB - AIM: Little is known about the association between renal cyst and renal dysfunction. We evaluated the deterioration of renal function in patients with unilateral, large, simple renal cysts. METHODS: Fifty patients with unilateral, simple renal cysts measuring >= 4 cm (cyst group) and 50 kidney donors (control group) were enrolled. Dimercaptosuccinic acid (DMSA) renal scans were performed to calculate split renal function. The differences between split renal function were calculated and compared. Clinical factors affecting decreased renal function in the cyst group were assessed. RESULTS: The mean age of the patients in the cyst group was higher than the control group (59.1 vs 39.2 years; P = 0.001). Patients with renal cysts tended to be diagnosed with hypertension (P = 0.001), However, the two groups did not significantly differ in terms of the other characteristics. The median cyst size was 7.2 cm (range, 4.5-14.2), and 31 of the 50 patients (60.2%) in the cyst group demonstrated decreased renal function in the cystic kidney units (median: 5.8%; range, 0.2-33). Although there were no differences in split renal function (50.1% vs 49.9%; P = 0.629) in the control group, the relative renal function of the cystic kidney units were significantly lower than the contralateral kidney units in the cyst group (48.3% vs 51.7%; P = 0.001). The decrease in relative renal function (>8%) in the cystic kidney units was associated with a higher serum uric acid levels and higher RENAL complexity (P = 0.035 and P = 0.007, respectively). CONCLUSION: A significant proportion of unilateral, large, simple renal cysts are associated with decreased relative renal function on DMSA renal scans. PMID- 26481870 TI - A 3-arm randomized controlled trial on the effects of dance movement intervention and exercises on elderly with early dementia. AB - BACKGROUND: Dementia is characterized by a progressive decline and deterioration of brain regions such as memory, spatial navigation and language, along with disturbances in daily functioning. Non-pharmacological interventions that offer a holistic approach by targeting cognitive functioning, prognosis and the psychological and social effects of dementia require rigorous investigation. The well-established benefits of physical activity for cognitive functioning and psychological support in dementia have been observed with dance-movement intervention. There is substantial evidence that dance-movement interventions provide emotional and social advantages. Thus, a randomized controlled trial (RCT) is planned to investigate the positive effects of a dance movement intervention, compared with mild physical exercise, on the physical and psychological well-being of elderly Chinese individuals with early dementia. METHODS/DESIGN: A 3-arm RCT with waitlist control design will be used in this study. Two hundred and one elderly participants with very mild to mild dementia will be screened and randomized into the following groups: (i) dance movement based intervention, (ii) stretching and exercise intervention and (iii) no intervention waitlist-control group. The two intervention groups will receive a 1 h intervention, twice a week, for 12 weeks. The participants will be assessed four times over the course of 12 months: baseline before randomization, post intervention (3 months), 6 months from baseline and 12 months from baseline. The primary outcomes will be compared between assessment points and between groups on neuropsychiatric symptoms, psychosocial well-being and cognitive and daily functioning. Secondary outcomes will assess the changes in salivary cortisol levels and their relationships with the primary outcome measures. DISCUSSION: This study will provide substantial evidence of the efficacy of a dance-movement based intervention in slowing down dementia progression, due to its ability to act as a buffer against decline and improve areas affected by dementia. We also anticipate an association between cortisol levels and the outcome measures. The further development of this intervention into a structural program may be warranted for early psychosocial support among elderly populations. TRIAL REGISTRATION: The trial has been registered in the Chinese Clinical Trial Registry ( ChiCTR-IOR-15006541 ). PMID- 26481871 TI - Prestenting for prevention of melody valve stent fractures: A systematic review and meta-analysis. AB - INTRODUCTION: The role of right ventricular outflow tract (RVOT) prestenting in the prevention of Melody valve stent fractures (SFs) is not well defined. We aimed to perform a systematic review and meta-analysis comparing the incidence of SF in Melody valve transcatheter pulmonary implants with and without prestenting. METHODS: PubMed, EMBASE, and Cochrane Central were searched for studies that reported the incidence of SF in Melody valve transcatheter pulmonary implants stratified by the presence or absence of RVOT prestenting. Subgroup analyses were performed for (1) SF associated with a loss of stent integrity and (2) SF requiring reintervention. RESULTS: Five studies and 360 patients were included, of whom 207 (57.5%) received prestenting. Follow-up ranged from 15 to 30 months. SF were significantly reduced in the prestenting group (16.7%) when compared to no prestenting (33.5%) (odds-ratio [OR] 0.39; 95%CI 0.22-0.69). Patients who received prestenting also had a lower incidence of (1) SF associated with loss of stent integrity (OR 0.16; 95%CI 0.05-0.48) and (2) SF requiring reintervention (OR 0.15; 95%CI 0.02-0.91). CONCLUSION: Our findings suggest that stenting of the RVOT prior to Melody valve implantation is associated with a reduction in the incidence of SF and fracture-related reinterventions. PMID- 26481872 TI - A Metal-free Approach to 3-Aryl-3-hydroxy-2-oxindoles by Treatment of 3-Acyloxy-2 oxindoles with Diaryliodonium Salts. AB - A mild, metal-free approach has been realized for the facile construction of highly valuable 3-(hetero)aryl-3-hydroxy-2-oxindoles. Direct arylations of 3 acyloxy-2-oxindoles with diaryliodonium salts as arylation reagents are implemented in the presence of K2 CO3 at room temperature without using an organometallic promoter to deliver an array of 3-(hetero)aryl-3-hydroxy-2 oxindoles in good yields. PMID- 26481875 TI - Do we have the resources and right ecosystem to channel the Indian work force to accelerate research and innovation? PMID- 26481874 TI - Central retinal artery occlusion associated with persistent truncus arteriosus and single atrium: a case report. AB - BACKGROUND: Central retinal artery occlusion (CRAO) is an ocular emergency and most of the cases present with painless sudden persistent loss of vision in the range of counting fingers to perception of light. The presentation of CRAO is associated with a variety of medical conditions. We report a rare case of CRAO associated with persistent truncus arteriosus (PTA) and single atrium in a female patient. CASE PRESENTATION: A 23-year-old woman was admitted due to sudden painless visual loss in the left eye. On examination visual acuity of light perception was noted in the left eye with a left relative afferent pupillary defect. Fundoscopic examination revealed retinal ischemic whitening, constriction of the arteriole and venule with segmentation and typical "cherry-red spot" suggesting CRAO. The patient was treated with ocular massage and anterior chamber paracentesis. She was commenced on 150 mg of aspirin and also received hyperbaric oxygen therapy. An echocardiogram revealed PTA and single atrium. A diagnosis of CRAO associated with PTA and single atrium was made. CONCLUSION: The ophthalmologist should enquire about congenital and acquired cardiac abnormalities in patients with CRAO and consider such abnormalities to be possible sources of emboli. PMID- 26481876 TI - Self-reporting of improper data interpretation. PMID- 26481873 TI - The Patient Remote Intervention and Symptom Management System (PRISMS) - a Telehealth- mediated intervention enabling real-time monitoring of chemotherapy side-effects in patients with haematological malignancies: study protocol for a randomised controlled trial. AB - BACKGROUND: Outpatient chemotherapy is a core treatment for haematological malignancies; however, its toxicities frequently lead to distressing/potentially life-threatening side-effects (neutropenia/infection, nausea/vomiting, mucositis, constipation/diarrhoea, fatigue). Early detection/management of side-effects is vital to improve patient outcomes, decrease morbidity and limit lengthy/costly hospital admissions. The ability to capture patient-reported health data in real time, is regarded as the 'gold-standard' to allow rapid clinical decision making/intervention. This paper presents the protocol for a Phase 3 multi-site randomised controlled trial evaluating a novel nurse-led Telehealth intervention for remote monitoring/management of chemotherapy side-effects in Australian haematological cancer patients. METHODS/DESIGN: Two hundred and twenty-two patients will be recruited from two hospitals. Eligibility criteria include: diagnosis of chronic lymphocytic leukaemia/Hodgkin's/non-Hodgkin's lymphoma; aged >= 18 years; receiving >= 2 cycles chemotherapy. Patients will be randomised 1:1 to either the control or intervention arm with stratification by diagnosis, chemotherapy toxicity (high versus low), receipt of previous chemotherapy and hospital. Patients allocated to the control arm will receive 'Usual Care' whilst those allocated to the intervention will receive the intervention in addition to 'Usual Care'. Intervention patients will be provided with a computer tablet and software prompting twice-daily completion of physical/emotional scales for up to four chemotherapy cycles. Should patient data exceed pre-determined limits an Email alert is delivered to the treatment team, prompting nurses to view patient data, and contact the patient to provide clinical intervention. In addition, six scheduled nursing interventions will be completed to educate/support patients in use of the software. Patient outcomes will be measured cyclically (midpoint and end of cycles) via pen-and-paper self-report alongside review of the patient medical record. The primary outcome is burden due to nausea, mucositis, constipation and fatigue. Secondary outcomes include: burden due to vomiting and diarrhoea; psychological distress; ability to self-manage health; level of cancer information/support needs and; utilisation of health services. Analyses will be intention-to-treat. A cost-effectiveness analysis is planned. DISCUSSION: This trial is the first in the world to test a remote monitoring/management intervention for adult haematological cancer patients receiving chemotherapy. Future use of such interventions have the potential to improve patient outcomes/safety and decrease health care costs by enabling early detection/clinical intervention. TRIAL REGISTRATION: ACTRN12614000516684 . Date registered: 12 March 2014 (registered retrospectively). PMID- 26481877 TI - Defensins in periodontal health. AB - Defensins are abundant and widely distributed peptides in human and animal tissues that are involved in host defence. Defensins not only have the ability to strengthen the innate immune system but can also enhance the adaptive immune system by chemotaxis of monocytes, T-lymphocytes, dendritic cells and mast cells to the infection site. Defensins also improves the capacity of macrophage phagocytosis. A greater understanding of how these peptides act in the healthy, gingivitis and periodontitis conditions would definitely open new opportunities for identification, prevention and treatment of periodontal diseases. This discussion focuses on recent studies about biological function of defensins in human diseases and animal models. PMID- 26481878 TI - Prevalence of carotid artery calcifications detected on panoramic radiographs and confirmed by Doppler ultrasonography: Their relationship with systemic conditions. AB - CONTEXT: Atherosclerosis affects large and medium caliber arteries by forming calcific atheromas, precursors of cerebral vascular disease. Diabetes mellitus, obesity, and hypertension are considered as risk factors of atherosclerosis. Panoramic radiographs can display images suggestive of carotid artery calcifications (CACs). AIMS: To investigate the prevalence of images suggestive of CAC in panoramic radiographs of the jaws (PRJs) and confirm them by Doppler ultrasonography. To evaluate their anatomic locations and relationships between systemic conditions (diabetes, hypertension, and obesity) and the presence of unilateral or bilateral CAC detected on PRJ or by Doppler ultrasonography. MATERIALS AND METHODS: Of the 723 routinely performed PRJ in patients over 40 years at the Radiology Center in Sao Luis, Maranhao, Brazil, 21 PRJ containing images suggestive of CAC were selected in this cross-sectional study. The findings from the PRJ were confirmed by Doppler sonography. RESULTS: Images suggestive of CAC was detected in 21 (2.9%) of the PRJ evaluated, consisting of 11 (52.4%) hypertensive, 7 (33.3%) diabetics, and 9 (42.9%) obese. There was a higher prevalence of hypertensive patients in the unilateral CAC group (100%) and bilateral CAC (60%) compared to patients without CAC (25%). CONCLUSIONS: CACs can be detected in PRJs, and are more frequent in common carotid arteries. No significant associations were detected between the presence of unilateral or bilateral CAC in PRJ and hypertension, diabetes, or obesity. PMID- 26481879 TI - Age-related - oral manifestations and co-morbidities in human immunodeficiency virus-infected/acquired immune deficiency syndrome adults in Hyderabad, India. AB - BACKGROUND: The objective of the study was to clinically evaluate age-related - oral manifestations and co-morbidities in different age groups of human immunodeficiency virus-infected/acquired immune deficiency syndrome adults. MATERIALS AND METHODS: A cross-sectional study was conducted among 200 adult patients aged above 20 years at infectious diseases units, medical wards and ART centre of Gandhi Medical Hospital, Hyderabad. Oral manifestations were diagnosed according to the presumptive criteria of EC-Clearinghouse Classification, and clinical data were retrieved from patient's medical records. Chi-square test was used for statistical analysis. RESULTS: Men (72%) in the young age group of 21-30 years were commonly affected. Heterosexual mode of transmission was most common in all the age groups, and the overall distribution were statistically significant (P < 0.05). Most common oral findings seen in 21-30 years of age were depapillation (90%), hyperpigmentation (70% and 72%) in 31-40 and 41-50 years old and linear gingival erythema (68%) in above 50 years of age group. The various co morbidities included the recurrent bacterial and skin infections (64% and 62% respectively) in the younger age group. Renal and cardiac diseases with pulmonary tuberculosis (74%) were commonly observed in middle-aged and elders. CONCLUSIONS: The underlying oral manifestations and co-morbidities could become very important variables that must be taken into account in determining treatment efficacy or health policy. PMID- 26481880 TI - Increased overjet is a risk factor for dental trauma in preschool children. AB - CONTEXT: Traumatic dental injury and malocclusion constitute a public health problem due to their high prevalence. Preventing or detecting such conditions, in any population, is of paramount importance. AIM: Assessing the association of anterior occlusal characteristics and dental trauma in preschool children. SETTINGS AND DESIGN: A cross-sectional study was carried out with 2-6-year-old randomly selected by a sample calculation, resulting in 606 subjects MATERIALS AND METHODS: A questionnaire to collect information about the sample (age, gender, and race) was sent to the children's parents. Two trained and calibrated examiners (Kappa 0.80) evaluated dental trauma according to criteria established by the World Health Organization. The following anterior occlusal characteristics were evaluated: Normal occlusion, anterior open bite, anterior crossbite, increased overjet (categorized as >=3 mm), and increased overbite (categorized as >=3 mm). STATISTICAL ANALYSIS USED: The variables associations were assessed (odds ratio, Chi-square test, and logistic regression, P < 0.05) using statistical software (SPSS, version 16.0). RESULTS: Dental trauma was observed in 20.8% and malocclusion in 48.6% of the children. There is an association between malocclusion and dental trauma (P = 0.01). Children with malocclusion have a 64% higher chance of suffering dental trauma. Increased overjet was the type of malocclusion related to a higher rate of tooth fracture (P < 0.01). Subjects with this type of malocclusion suffered tooth fractures three times more often than subjects with other malocclusion types. CONCLUSIONS: There was association of dental trauma and malocclusion. Increased overjet was the most common malocclusion related to dental trauma. Preventive strategies are needed to reduce the rate of anterior malocclusion and, consequently, dental trauma in preschool children. PMID- 26481881 TI - Evaluation of normal range of mouth opening using three finger index: South India perspective study. AB - AIMS: The frequency, with which restricted mouth opening is encountered in the clinical practice, makes it essential to establish what constitutes the normal range. This study was undertaken to evaluate the normal range of mouth opening in adult population in south India. SETTINGS AND DESIGN: randomized clinical study conducted on dentate adult patients to evaluate the normal range of mouth openin. MATERIALS AND METHODS: 500 healthy patients aged between 18-59 were randomly selected and divided into four groups according to their age ranges. The maximum inter-incisal distance and width of right and left three fingers at the first distal inter-phalanges were measured using vernier calipers. STATISTICAL ANALYSIS USED: ANOVA test, student t test and pearsons correlation test. RESULTS: The mean value and range of maximum mouth opening of 50.3 mm +/- 6.26 mm for males and 49.9 mm +/- 6.74 mm for females was recorded. These values were significant and correlated with the width of three fingers. It was found that the greatest mean maximum mouth opening was recorded in youngest age group and lowest was recorded in older age group in both genders. CONCLUSIONS: The mean mouth opening value decreases with age and is lesser in females as compared to males of same age. This study demonstrated that individuals in all the four groups were able to vertically align their right and left three fingers between the upper and lower central incisors upto the first distal interphalangeal folds thus suggesting that, width of three fingers can be used as 'tool' to distinguish 'normal' from 'restricted' mouth opening. PMID- 26481882 TI - Comparative evaluation of hydroxyapatite and nano-bioglass in two forms of conventional micro- and nano-particles in repairing bone defects (an animal study). AB - CONTEXT: Many synthetic bone materials have been introduced for repairing bone defects. AIM: The aim of this study is to comparatively evaluate the efficacy of nano-hydroxyapatite (HA) and nano-bioglass bone materials with their traditional micro counterparts in repairing bone defects. MATERIALS AND METHODS: In this prospective animal study, four healthy dogs were included. First to fourth premolars were extracted in each quadrant and five cavities in each quadrant were created using trephine. Sixteen cavities in each dog were filled by HA, nano-HA, bioglass, and nano-bioglass and four defects were left as the control group. All defects were covered by a nonrestorable membrane. Dogs were sacrificed after 15, 30, 45, and 60 days sequentially. All 20 samples were extracted by trephine #8 with a sufficient amount of surrounding bone. All specimens were investigated under an optical microscope and the percentage of total regenerated bone, lamellar, and woven bone were evaluated. STATISTICAL ANALYSIS USED: Data analysis was carried out by SPSS Software ver. 15 and Mann-Whitney U-test (alpha =0.05). RESULTS: After 15 days, the bone formation percentage showed a significant difference between HA and nano-HA and between HA and bioglass (P < 0.001). The nano-HA group showed the highest rate of bone formation after 15 days. Nano bioglass and bioglass and nano-HA and nano-bioglass groups represented a significant difference and nano-bioglass showed the highest rate of bone formation after 30 days (P = 0.01). After 45 days, the bone formation percentage showed a significant difference between nano-bioglass and bioglass and between nano-HA and nano-bioglass groups (P = 0.01). CONCLUSIONS: Nano-HA and nano bioglass biomaterials showed promising results when compared to conventional micro-particles in the repair of bone defects. PMID- 26481883 TI - Flapless versus open flap techniques of implant placement: A 15-month follow-up study. AB - AIM: To evaluate and compare the effect of flapless and "open flap" techniques of implant placement on crestal bone height (CBH) around implants. MATERIALS AND METHODS: This prospective study comprised of 32 implants placed in 16 subjects with a bilateral missing mandibular first molar. In each subject, one implant was placed with "flapless" and other using "open flap" technique. Radiographic assessment of CBH was carried out using standardized intraoral periapical radiograph of the site at baseline, 3 months, 9 months and 15 months after implant placement. STATISTICAL ANALYSIS: Data were analyzed using STATA 11.0 statistical software. To determine the changes in CBH from baseline, at 3-, 9-, and 15-month, repeated measures analysis of variance followed by post-hoc Bonferroni was used for each of the two techniques for mesial and distal aspects separately. For both techniques, changes in CBH from baseline to 15 months were compared using an independent t-test with a confidence interval of 95%. RESULTS: For "flapless" technique, there was no statistically significant (P > 0.05) reduction of CBH in initial 9 months but was significant for the 9-15 months period while for "open flap" technique, statistically significant (P < 0.05) reduction was observed up to 15 months. Comparison of both techniques showed significantly lesser reduction with "flapless" than "open flap" technique. The overall average crestal bone loss was 0.046 +/- 0.008 mm on mesial aspect, 0.043 +/- 0.012 mm on distal aspect with "flapless" technique and 1.48 +/- 0.085 mm on mesial aspect, 1.42 +/- 0.077 on distal aspect "open flap" technique. CONCLUSIONS: Both techniques showed a reduction in CBH with time but the flapless technique showed a lesser reduction. Therefore, the flapless technique can be considered as a better treatment approach for placement of implants, especially where adequate width and height of available bone are present. PMID- 26481884 TI - Effects of clinical use and sterilization on surface topography and surface roughness of three commonly used types of orthodontic archwires. AB - AIM: To evaluate the changes in surface topography and roughness of stainless steel (SS), nickel-titanium and beta-titanium (beta-Ti) archwires after clinical use and sterilization. SETTINGS AND DESIGN: Thirty wires each of SS, nitinol, and beta-Ti (3M Unitek) were tested in as received, as received and autoclaved, and clinically retrieved then autoclaved conditions. MATERIALS AND METHODS: A sterilization protocol of 134 degrees C for 18 min was performed using an autoclave. Surface topography of specimens from each subgroup was examined using an environmental scanning electron microscope (ESEM model Quanta 200, The Netherlands) at *100, *1000, and *2500 magnifications. Surface roughness was measured using arithmetic mean roughness (Ra) values obtained from optical profilometric scanning (Taylor Hobson, Leicester, UK). STATISTICAL ANALYSIS: Data were analyzed by one-way analysis of variance and Tukey's post-hoc procedures. RESULTS: Scanning electron microscope images revealed an increase in surface irregularities in SS and nitinol wires after clinical use. There was a significant increase in Ra values of SS orthodontic wires after intra-oral exposure (P = 0.0002). CONCLUSION: Surface roughness of SS wires increased significantly after clinical use. Autoclave sterilization did not affect considerably on surface characteristics of any archwire. PMID- 26481885 TI - The clinical efficacy of laser assisted modified Widman flap: A randomized split mouth clinical trial. AB - OBJECTIVE: The objective of the study was to compare the clinical efficacy of use of a diode laser (DL) (810 nm) as an adjunct to modified Widman flap (MWF) surgery to that of MWF alone. MATERIALS AND METHODS: Twenty-five patients between the ages of 20 and 50 years with generalized chronic periodontitis were selected for the study. Control sites (Group A) were randomly selected to receive an MWF, and the contralateral test sites (Group B) received MWF in conjunction with low level laser therapy. The energy density of 4 J/cm2 was applied to the gingival surface after periodontal treatment. The study tooth/site was treated along with any additional teeth in the quadrant in which the site was located if needed. Randomization was done using a coin flip. The DL was used to de-epithelialize the inner part of the periodontal flap and photo-biostimulate the surgical area. Plaque index (PI), papillary bleeding index (PBI), probing depth (PD), and clinical attachment level (CAL) scores were recorded at baseline and at 6 and 9 months. STATISTICAL ANALYSIS: Data were expressed as the mean +/- standard deviation. Statistical analyzes were performed using paired Student's t-testfor intragroup comparisons and unpaired Student's t-test for intergroup comparisons. RESULTS: No significant difference was observed in PI scores between the two groups at baseline, 6 and 9 months. PBI scores were significantly lower in Group B versus Group A at 6 months (P < 0.01). However, no significant difference was observed between the two groups in PBI scores at the end of 9 months. PD reduction in Group B versus Group A was statistically significant at the end of 9 months (P < 0.01). Gains in CAL were significantly greater in Group B versus Group A at 6 and 9 months. CONCLUSION: The use of an 810 nm DL provided additional benefits to MWF surgery in terms of clinical parameters. PMID- 26481886 TI - Comparison of shear bond strength of self-etching fluoride releasing adhesives with and without pumice prophylaxis. AB - CONTEXT: Despite the advances in orthodontic material and treatment mechanics, the placement of fixed appliances increases the risk of enamel demineralization. The development of fluoride release adhesives has attracted considerable interests because the combined use of antimicrobials and fluoride enhances the cariostatic effect. AIM: To compare the shear bond strength (SBS) of fluoride release adhesives with established orthodontic adhesives and assess failure mode using adhesive remnant index (ARI). SETTINGS AND DESIGN: The present study included 80 maxillary premolars which were randomly divided into four groups (n = 20) and were further subdivided into two subgroups A - Pumice prophylaxis (PP) and subgroup B - No PP (n = 10). MATERIALS AND METHODS: Stainless steel brackets were bonded with Transbond XT, Transbond plus (TP) color change adhesive, Light Bond, and Clearfil protect bond. After debonding, the ARI was used to assess the mode of bracket failure. STATISTICAL ANALYSIS: The data were analyzed using two way analysis of variance, Post-hoc Tukey Honest significant differences test, and Chi-square test. RESULTS: The mean SBS of Group 4 was comparably higher regardless of PP. Brackets bonded with TP showed a comparable SBS to conventional Transbond XT. The ARI scores were predominately 2. CONCLUSIONS: Fluoride releasing adhesives combined with antibacterial monomer can play a vital role in reducing white spot lesions by enhancing the cariostatic effect especially in noncompliant?medically compromised patients. PMID- 26481887 TI - Mandibular canine index: A reliable predictor for gender identification using study cast in Indian population. AB - CONTEXT: Various methods are used for gender identification in anthropologic and forensic investigations. The canine tooth is widely used for gender determination because of its sexual dimorphism and durability in the oral cavity. Mandibular canine index (MCI) is one of the most reliable and valid predictor for gender identification. AIM: To assess the reliability of MCI in gender determination in Indian population. SETTINGS AND DESIGN: This was an experimental study involving the preparation of plaster models of 100 individuals residing in Udaipur, Rajasthan, India. Of these 45 were males and 55 were females. Both sexes were in the age group of 20-30 years. Study casts were prepared for all individuals and the measurements of mandibular canine teeth were taken. The MCI was calculated using standardized equation. In addition, the percentage of sexual dimorphism was calculated. STATISTICAL ANALYSIS USED: Independent sample t-test was used. P < 0.05 was considered statistically significant. RESULTS: There was a significant difference (P < 0.05) observed between inter-canine distance, right and left canine width and right and left MCI between males and females. Sexual dimorphism is more on left permanent mandibular canine teeth than right permanent mandibular canine teeth. The overall percentage of accuracy observed was 85.5%. CONCLUSIONS: Study findings reveal that MCI can be used a reliable predictor for gender determination in Indian population and can form the basis of anthropologic and forensic investigations. PMID- 26481888 TI - Rehabilitation of weakened premolars with a new polyfiber post and adhesive materials. AB - BACKGROUND: Polyfiber posts used inside the root canal can help to restore the fracture resistance of weakened premolars. AIM: To assess the fracture resistance of endodontically treated premolars restored with different techniques, including the new polyfiber post (Spirapost). MATERIALS AND METHODS: One hundred superior premolars were distributed into 10 groups (n = 10): Sound teeth (G1-positive control) and experimental (G2 to G10), which received MODP cavities and canal treatment. Groups were restored as follows: G2 - unrestored (negative control); G3 - microhybrid resin (MR); G4 - flowable resin (FR) + (MR); G5 - glass fiber post (Reforpost) + MR; G6 - Reforpost + FR + MR; G7 - polyethylene fiber (Ribbond) + MR; G8 - Ribbond + FR + MR; G9 - polyfiber post (Spirapost) + MR and G10 - Spirapost + FR + MR. After 24 h, the specimens were loaded until fracture. Data were analyzed by ANOVA and Tukey's test (P < 0.05). RESULTS: Premolars restored with Spirapost (G9 and G10) provided the highest fracture strength (P < 0.05), similar to sound teeth (G1), regardless of the composite resin. Intermediate values were achieved by G3, G4, G5, G6, G7, and G8, which were similar (P > 0.05) and different from the others (P < 0.05). Inferior values were found in G2 (P < 0.05). CONCLUSION: Fracture resistance of premolars with MODP cavities and endodontic access was recovered with the direct rehabilitation with Spirapost, regardless of the type of composite resin. PMID- 26481889 TI - Quantitative evaluation of apical extrusion of intracanal bacteria using rotary ProTaper, K3XF, twisted and hand K-file system: An ex vivo study. AB - AIMS: The aim of this study was to evaluate the number of intracanal bacteria extruded apically during root canal preparation using rotary ProTaper, K3XF, twisted, and hand K-file system. SUBJECTS AND METHODS: Seventy extracted single rooted human mandibular premolar teeth were used. Access cavities were prepared and the teeth were mounted in glass vials. Root canals were then contaminated with a pure culture of Enterococcus faecalis (ATCC 29212) and incubated at 37 degrees C for 24 h. The contaminated roots were divided into four experimental groups of 15 teeth each and one control group of 10 teeth. Group 1: ProTaper; Group 2: K3XF; Group 3: Twisted file; Group 4: Hand K-file; Group 5: Control group. Bacteria extruded from the apical foramen during instrumentation were collected into vials. The microbiological samples were incubated in culture media for 24 h. Colonies of bacteria were counted and the results were given as number of colony-forming units (CFU)/ml. STATISTICAL ANALYSIS USED: The obtained data were analyzed using the Kruskal-Wallis one-way analysis of variance and Mann Whitney U-tests. RESULTS: There was a significant difference between the rotary and hand instrumentation system related to the apically extruded intracanal bacteria. CONCLUSIONS: Both the rotary and hand instrumentation systems extruded intracanal bacteria through the apical foramen. K3XF file system showed least bacterial extrusion amongst all instrumentation groups. PMID- 26481890 TI - Bond efficacy of recycled orthodontic brackets: A comparative in vitro evaluation of two methods. AB - CONTEXT: Recycling of orthodontic brackets in developing orthodontic economies is an extremely common procedure. Bonding protocols and reliability of these brackets is, however, questionable, and still the subject of research. AIMS: The aim was to evaluate and compare the shear bond strength of brackets recycled with sandblasting and silicoating. MATERIALS AND METHODS: Ninety extracted human premolars were bonded with 0.022" SS brackets (American Orthodontics, Sheboygan USA) and then debonded. The debonded brackets were divided into three groups of 30 each. Group I: Sandblasting with 50-MUm aluminum oxide (control group) Group II: Sandblasting with 50-MUm aluminum oxide followed by metal primer application Group III: Silicoating with 30-MUm Cojet sand followed by silane application and rebonded with Transbond XT. The sandblasted brackets and silicoated brackets were viewed under the scanning electron microscope, immediately after surface conditioning before rebonding. The shear bond strength with each group was tested. STATISTICAL ANALYSIS USED: One-way analysis of variance, post-hoc Scheffe multiple comparison tests. RESULTS: The results showed that sandblasting created more irregularities and deeper erosions while silica coating created superficial irregularities and shallow erosions. PMID- 26481891 TI - Effect of sodium hypochlorite as dentinal pretreatment on bonding strength of adhesive systems. AB - AIM: This study aimed to evaluate the effect of sodium hypochlorite (NaOCl) pretreatment on bond strength of adhesive systems to different dentin regions. MATERIALS AND METHODS: Forty human molars were randomly assigned according to different adhesive systems (Adper Single Bond 2; Clearfil SE Bond; Adper SE Plus; G-Bond), pretreatments (control and NaOCl - deproteinization) and dentin regions (proximal, superficial occlusal [SO] and deep occlusal [DO]), n = 5. Cylindrical cavities were performed at the proximal and occlusal surfaces of each sample. For deproteinization, 10% NaOCl was applied on conditioned dentin for 60 s before the adhesive systems application. Two occlusal and one proximal slice were obtained from each sample and submitted to the push-out test. The mode of fracture was analyzed. The data were subjected to three-way ANOVA and Tukey test (P < 0.05). RESULTS: There was statistically significant difference between the adhesive systems (P < 0.01) and dentin regions (P < 0.01); however, the pretreatment did not significantly affect the bond strength values (P > 0.05). The bond strength values were higher for the proximal surface, followed by SO and later by DO, being influenced by the adhesive system. The two-step self-etch adhesive systems presented the highest bond strength results. CONCLUSION: The deproteinization pretreatment showed similar bonding effectiveness to the conventional adhesive technique. The dentin region plays a rule on the bond strength values. PMID- 26481892 TI - Immediate implant in single rooted teeth - Study on primary stability and bone formation. AB - BACKGROUND: Dental implants (DI) are emerging as an alternative to dentures. Immediate placement of DI for esthetic concern has been always in demand. This is a retrospective analysis of the success rate of immediately placed DI in freshly extracted single-rooted tooth socket, by clinical, radiographical, soft and hard tissue changes in a follow-up period of 1 year. MATERIALS AND METHODS: Retrospective analysis of all cases of immediate DI placed in the single rooted socket was performed. Cases were selected based on previously established inclusion and exclusion criteria. Age, gender, tooth, jaw, cause of impending tooth loss, tooth diameter along the cervical margin, the width of keratinized gingiva (WKG), and radiographic measures were performed for up to a year. Descriptive statistics and comparison of means were presented. P < 0.05 was taken as significant. RESULTS: Of the 324 immediate DI placed in 207 patients during the study period, 61 fulfilled the criteria. There were 49.2% males 31.15% had dental caries, 61% involving maxilla. The mean age of patients was 34.82 +/- 7.97 years. Mean extraction socket diameter was 4.6 +/- 1.78 mm. From complete stability of DI, the WKG decreased from baseline to 3 months period and regained at 12-month follow-up. The difference was statistically significant (P = 0.01). The same trend was noticed in the distance of the mesial and distal papilla as measured in the probe (P = 0.075). Radiographical changes also reflected a similar trend. DISCUSSION: The success of DI, in terms of clinical and radiographical parameters, in an immediate DI placed in a single rooted fresh extracted socket, gives adequate clinical results. PMID- 26481893 TI - Review of research designs and statistical methods employed in dental postgraduate dissertations. AB - CONTEXT: There is a need to evaluate the quality of postgraduate dissertations of dentistry submitted to university in the light of the international standards of reporting. AIMS: We conducted the review with an objective to document the use of sampling methods, measurement standardization, blinding, methods to eliminate bias, appropriate use of statistical tests, appropriate use of data presentation in postgraduate dental research and suggest and recommend modifications. SETTINGS AND DESIGN: The public access database of the dissertations from Rajiv Gandhi University of Health Sciences was reviewed. SUBJECTS AND METHODS: Three hundred and thirty-three eligible dissertations underwent preliminary evaluation followed by detailed evaluation of 10% of randomly selected dissertations. The dissertations were assessed based on international reporting guidelines such as strengthening the reporting of observational studies in epidemiology (STROBE), consolidated standards of reporting trials (CONSORT), and other scholarly resources. STATISTICAL ANALYSIS USED: The data were compiled using MS Excel and SPSS 10.0. Numbers and percentages were used for describing the data. RESULTS: The "in vitro" studies were the most common type of research (39%), followed by observational (32%) and experimental studies (29%). The disciplines conservative dentistry (92%) and prosthodontics (75%) reported high numbers of in vitro research. Disciplines oral surgery (80%) and periodontics (67%) had conducted experimental studies as a major share of their research. Lacunae in the studies included observational studies not following random sampling (70%), experimental studies not following random allocation (75%), not mentioning about blinding, confounding variables and calibrations in measurements, misrepresenting the data by inappropriate data presentation, errors in reporting probability values and not reporting confidence intervals. Few studies showed grossly inappropriate choice of statistical tests and many studies needed additional tests. CONCLUSIONS: Overall observations indicated the need to comply with standard guidelines of reporting research. PMID- 26481894 TI - Preformed stainless steel crown in special conditions in adults: Two case reports. AB - Stainless steel crowns (SSC) are extensively used in child patients. They are mainly used following the pulp therapy in deciduous teeth. They are also used in multi-surface restoration, as an abutment in space maintainers, correction of anterior tooth cross bite, restoration of hypoplasic teeth, etc. In permanent teeth, they are mainly used as interim restorations following root canal treatment in first molars prior to the eruption of permanent second molars. The main advantage of SSC is its limited chair side time, durability and ease of placement. Patients with conditions such as pregnancy and old age who cannot tolerate multiple and long appointments can greatly benefit from the use of SSC. Though SSC can be used by other dental specialties very effectively, its use seems to be limited to pediatric dentistry. Presented here are few adult cases in which SSC is given with good success. PMID- 26481895 TI - Scope of photodynamic therapy in periodontics. AB - Periodontal disease results from inflammation of the supporting structure of the teeth and in response to chronic infection caused by various periodontopathic bacteria. The mechanical removal of this biofilm and adjunctive use of antibacterial disinfectants and antibiotics have been the conventional methods of periodontal therapy. However, the removal of plaque and the reduction in the number of infectious organisms can be impaired in sites with difficult access. Photodynamic therapy (PDT) is a powerful laser-initiated photochemical reaction, involving the use of a photoactive dye (photosensitizer) activated by light of a specific wavelength in the presence of oxygen. Application of PDT in periodontics such as pocket debridement, gingivitis, and aggressive periodontitis continue to evolve into a mature clinical treatment modality and is considered as a promising novel approach for eradicating pathogenic bacteria in periodontitis. PMID- 26481896 TI - A word of caution on the new scam on authorship. PMID- 26481897 TI - Mechanical insights of oxythiamine compound as potent inhibitor for human transketolase-like protein 1 (TKTL1 protein). AB - Transketolase is a connecting link between glycolytic and pentose phosphate pathway, which is considered as the rate-limiting step due to synthesis of large number of ATP molecule and it can be proposed as a plausible target facilitating the growth of cancerous cells suggesting its potential role in cancer. Oxythiamine, an antimetabolite has been proved to be an efficient anticancerous compound in vitro, but its structural elucidation of the inhibitory mechanism has not yet been done against the human transketolase-like 1 protein (TKTL1). The three-dimensional (3D) structure of TKTL1 protein was modeled and subjected for refinement, stability and validation. Based on the reported homologs of transketolase (TKT), the active site residues His46, Ser49, Ser52, Ser53, Ile56, Leu82, Lys84, Leu123, Ser125, Glu128, Asp154, His160, Thr216 and Lys218 were identified and considered for molecular-modeling studies. Docking studies reveal the H-bond interactions with residues Ser49 and Lys218 that could play a major role in the activity of TKTL1. Molecular dynamics (MD) simulation study was performed to reveal the comparative stability of both native and complex forms of TKTL1. MD trajectory at 30 ns, confirm the role of active site residues Ser49, Lys84, Glu128, His160 and Lys218 in suppressing the activity of TKTL1. Glu128 is observed to be the most important residue for deprotonation state of the aminopyrimidine moiety and preferred to be the site of inhibitory action. Thus, the proposed mechanism of inhibition through in silico studies would pave the way for structure-oriented drug designing against cancer. PMID- 26481898 TI - Reverse second dorsal metacarpal artery vascularized bone flap for index distal bone loss: A case report. AB - Fingertip trauma with resultant bony loss is optimally reconstructed with an autologous bone substitute, offering a unique opportunity for use of a local vascularized bone graft. The second dorsal metacarpal artery is well-described for use in soft tissue and bony reconstruction, with recent cadaveric studies suggesting a reverse-flow second dorsal metacarpal artery bone flap could reach defects in the distal phalanx. The aim of the current report is to illustrate the use of this technique in reconstructing the distal digit in a traumatized index finger with bony loss of the middle third of the distal phalanx. A 49-year-old man presented with a traumatic circular saw injury to his left index finger, with the unique finding of distal phalanx bony loss to the middle third of this bone, with no associated disruption of palmar or dorsal structures. Reconstructive goals were solely that of bony reconstruction, with no soft tissue coverage required. A reverse SDMA vascularized bone flap was successfully used for reconstruction, with the vascularized bone flap mobilized on its reverse SDMA pedicle and pivoted at the level of the distal anastomoses between the palmar and dorsal metacarpal arteries. There was uncomplicated donor and recipient site closures, and good functional outcomes with the ability to retain full distal interphalangeal joint motion and force on distal pinch grip. This case shows that the reverse second dorsal metacarpal artery vascularized bone flap may be undertaken to reconstruct bony loss in the distal phalanx. PMID- 26481899 TI - Transmission of the PabI family of restriction DNA glycosylase genes: mobility and long-term inheritance. AB - BACKGROUND: R.PabI is an exceptional restriction enzyme that functions as a DNA glycosylase. The enzyme excises an unmethylated base from its recognition sequence to generate apurinic/apyrimidinic (AP) sites, and also displays AP lyase activity, cleaving the DNA backbone at the AP site to generate the 3'-phospho alpha, beta-unsaturated aldehyde end in addition to the 5'-phosphate end. The resulting ends are difficult to religate with DNA ligase. The enzyme was originally isolated in Pyrococcus, a hyperthermophilic archaeon, and additional homologs subsequently identified in the epsilon class of the Gram-negative bacterial phylum Proteobacteria, such as Helicobacter pylori. RESULTS: Systematic analysis of R.PabI homologs and their neighboring genes in sequenced genomes revealed co-occurrence of R.PabI with M.PabI homolog methyltransferase genes. R.PabI and M.PabI homolog genes are occasionally found at corresponding (orthologous) loci in different species, such as Helicobacter pylori, Helicobacter acinonychis and Helicobacter cetorum, indicating long-term maintenance of the gene pair. One R.PabI and M.PabI homolog gene pair is observed immediately after the GMP synthase gene in both Campylobacter and Helicobacter, representing orthologs beyond genera. The mobility of the PabI family of restriction-modification (RM) system between genomes is evident upon comparison of genomes of sibling strains/species. Analysis of R.PabI and M.PabI homologs in H. pylori revealed an insertion of integrative and conjugative elements (ICE), and replacement with a gene of unknown function that may specify a membrane associated toxin (hrgC). In view of the similarity of HrgC with toxins in type I toxin-antitoxin systems, we addressed the biological significance of this substitution. Our data indicate that replacement with hrgC occurred in the common ancestor of hspAmerind and hspEAsia. Subsequently, H. pylori with and without hrgC were intermixed at this locus, leading to complex distribution of hrgC in East Asia and the Americas. In Malaysia, hrgC was horizontally transferred from hspEAsia to hpAsia2 strains. CONCLUSIONS: The PabI family of RM system behaves as a mobile, selfish genetic element, similar to the other families of Type II RM systems. Our analysis additionally revealed some cases of long-term inheritance. The distribution of the hrgC gene replacing the PabI family in the subpopulations of H. pylori, hspAmerind, hspEAsia and hpAsia2, corresponds to the two human migration events, one from East Asia to Americas and the other from China to Malaysia. PMID- 26481900 TI - Effects of Long-Term Erythropoiesis-Stimulating Agents on Iron Metabolism in Patients on Hemodialysis. AB - Continuous erythropoietin receptor activator (CERA) and darbepoetin-alpha (DA) might differently affect iron metabolism and erythropoiesis in patients on hemodialysis (HD). This prospective study examined a cohort of patients on HD who had received either intravenous CERA every 2 or 4 weeks (N = 25) or DA once each week (N = 47). Blood was sampled before HD sessions on days 0, 2, 4, 7 and 14, and on days 0, 3, 5, 7 and 14 from patients who were injected with ESA at the beginning and end of the dialysis week, respectively. Changes in factors indicating erythropoiesis and biomarkers of iron metabolism were examined. Hemoglobin levels were maintained in the target range between 10.0 and 11.0 g/dL and ferritin levels at baseline and during the study period were similar between the DA and CERA groups. Levels of hepcidin 25 decreased from days 2-3 to day 5 and returned to the baseline at day 7 in the DA group, whereas those and transferrin saturation were serially suppressed from days 2-3 to day 14 in the CERA group. Levels of soluble transferrin receptor and reticulocyte counts were significantly elevated from days 4-5 to day 14 by CERA. Both DA and CERA stabilized erythropoiesis, but CERA might mobilize iron from body stores more effectively than DA in patients on HD. PMID- 26481901 TI - An Optically Driven Bistable Janus Rotor with Patterned Metal Coatings. AB - Bistable rotation is realized for a gold-coated Janus colloidal particle in an infrared optical trap. The metal coating on the Janus particles are patterned by sputtering gold on a monolayer of closely packed polystyrene particles. The Janus particle is observed to stably rotate in an optical trap. Both the direction and the rate of rotation can be experimentally controlled. Numerical calculations reveal that the bistable rotation is the result of spontaneous symmetry breaking induced by the uneven curvature of the coating patterns on the Janus sphere. Our results thus provide a simple method to construct large quantities of fully functional rotary motors for nano- or microdevices. PMID- 26481902 TI - High-temperature superconductivity in space-charge regions of lanthanum cuprate induced by two-dimensional doping. AB - The exploitation of interface effects turned out to be a powerful tool for generating exciting material properties. Such properties include magnetism, electronic and ionic transport and even superconductivity. Here, instead of using conventional homogeneous doping to enhance the hole concentration in lanthanum cuprate and achieve superconductivity, we replace single LaO planes with SrO dopant planes using atomic-layer-by-layer molecular beam epitaxy (two-dimensional doping). Electron spectroscopy and microscopy, conductivity measurements and zinc tomography reveal such negatively charged interfaces to induce layer-dependent superconductivity (Tc up to 35 K) in the space-charge zone at the side of the planes facing the substrate, where the strontium (Sr) profile is abrupt. Owing to the growth conditions, the other side exhibits instead a Sr redistribution resulting in superconductivity due to conventional doping. The present study represents a successful example of two-dimensional doping of superconducting oxide systems and demonstrates its power in this field. PMID- 26481904 TI - Quantification of mass fat fraction in fish using water-fat separation MRI. AB - Selection of fish with appropriate fat content and anatomic distribution is searched in fish industry. This necessitates fast and accurate measurements of mass fat fraction maps on a large number of fish. The objective of this work is to assess the relevance of MRI water-fat separation for this purpose. For the separation of the water and fat images we rely on a single T2(*) and a multiple peak fat spectrum model, the parameters of which are estimated using the "Varpro" method. The difference of proton density between fat and water and the lack of the signal from the macromolecules are taken into account to convert the obtained proton density fat fraction into mass fat fraction. We used 0.23T NMR to validate the method on 30 salmon steaks. The fat fraction values were in the range of 5% to 25%. Very good accordance was found between 1.5T MRI and NMR although MRI slightly overestimated the mass fat fraction. The R(2) of the linear regression was equal to 0.96 (P<10(-5)), the slope to 1.12 (CI.95=0.03). These results demonstrate that a good accuracy can be achieved. We also show that high throughput can be achieved since the measurements do not depend on the position and we conclude that, for example, it is feasible to quantify the mass fat fraction in fish steaks within about one minute per sample. PMID- 26481903 TI - Wavelet-based clustering of resting state MRI data in the rat. AB - While functional connectivity has typically been calculated over the entire length of the scan (5-10min), interest has been growing in dynamic analysis methods that can detect changes in connectivity on the order of cognitive processes (seconds). Previous work with sliding window correlation has shown that changes in functional connectivity can be observed on these time scales in the awake human and in anesthetized animals. This exciting advance creates a need for improved approaches to characterize dynamic functional networks in the brain. Previous studies were performed using sliding window analysis on regions of interest defined based on anatomy or obtained from traditional steady-state analysis methods. The parcellation of the brain may therefore be suboptimal, and the characteristics of the time-varying connectivity between regions are dependent upon the length of the sliding window chosen. This manuscript describes an algorithm based on wavelet decomposition that allows data-driven clustering of voxels into functional regions based on temporal and spectral properties. Previous work has shown that different networks have characteristic frequency fingerprints, and the use of wavelets ensures that both the frequency and the timing of the BOLD fluctuations are considered during the clustering process. The method was applied to resting state data acquired from anesthetized rats, and the resulting clusters agreed well with known anatomical areas. Clusters were highly reproducible across subjects. Wavelet cross-correlation values between clusters from a single scan were significantly higher than the values from randomly matched clusters that shared no temporal information, indicating that wavelet based analysis is sensitive to the relationship between areas. PMID- 26481907 TI - Resting state connectivity in alcohol dependent patients and the effect of repetitive transcranial magnetic stimulation. AB - Alcohol dependence is thought to result from an overactive neural motivation system and a deficient cognitive control system, and rebalancing these systems may mitigate excessive alcohol use. This study examines the differences in functional connectivity of the fronto-parietal cognitive control network (FPn) and the motivational network (striatum and orbitofrontal cortex) between alcohol dependent patients (ADPs) and healthy controls (HCs), and the effect of repetitive transcranial magnetic stimulation (rTMS) on these networks. This randomized controlled trial included 38 ADPs and 37 HCs, matched on age, gender and education. Participants were randomly assigned to sham or right dorsolateral prefrontal cortex (dlPFC) stimulation with rTMS. A 3T resting state functional Magnetic Resonance Imaging (fMRI) scan was acquired before and after active or sham 10Hz rTMS. Group differences of within and between network connectivity and the effect of rTMS on network connectivity was assessed using independent component analysis. Results showed higher connectivity within the left FPn (p=0.012) and the left fronto-striatal motivational network (p=0.03) in ADPs versus HCs, and a further increase in connectivity within the left FPn after active stimulation in ADPs. ADPs also showed higher connectivity between the left and the right FPns (p=0.025), and this higher connectivity was related to fewer alcohol related problems (r=0.30, p=0.06). The results show higher within and between network connectivity in ADPs and a further increase in fronto-parietal connectivity after right dlPFC rTMS in ADPs, suggesting that frontal rTMS may have a beneficial influence on cognitive control and may result in lower relapse rates. PMID- 26481905 TI - Endocytosis of Ligand-Activated Sphingosine 1-Phosphate Receptor 1 Mediated by the Clathrin-Pathway. AB - The sphingosine 1-phosphate receptor 1 (S1PR1) is one of five G protein-coupled receptors activated by the lipid sphingosine 1-phosphate (S1P). Stimulation of S1PR1 by binding S1P or the synthetic agonist FTY720P results in rapid desensitization, associated in part with depletion of receptor from the cell surface. We report here combining spinning disc confocal fluorescence microscopy and flow cytometry to show that rapid internalization of activated S1PR1 relies on a functional clathrin-mediated endocytic pathway. Uptake of activated S1PR1 was strongly inhibited in cells disrupted in their clathrin-mediated endocytosis by depleting clathrin or AP-2 or by treating cells with dynasore-OH. The uptake of activated S1P1R was strongly inhibited in cells lacking both beta-arrestin 1 and beta-arrestin 2, indicating that activated S1PR1 follows the canonical route of endocytosis for G-protein coupled receptor's (GPCR)'s. PMID- 26481906 TI - Prescription Tablets in the Digital Age: A Cross-Sectional Study Exploring Patient and Physician Attitudes Toward the Use of Tablets for Clinic-Based Personalized Health Care Information Exchange. AB - BACKGROUND: To reduce the cost of health care while increasing efficiency and quality, health systems are seeking innovative means to engage and empower patients. Improved use of information technology and electronic health record (EHR) infrastructure is essential, and required for "meaningful use" as mandated by the federal government. Providing personalized health information using tablets at the point of care could enhance the clinical experience and enable efficient collection of patient reported outcome measures to guide clinical decision making. OBJECTIVE: The aim of this study is to explore patient and provider attitudes and interest in a proposed clinic-based tablet system for personal health information exchange. To provide a context to understand patients' use of tablets during their clinic visit, we also examine patients' current activities and time spent in the waiting room, and their use of health information resources. METHODS: Surveys were administered to 84 patients in the waiting room of a community health center affiliated with Massachusetts General Hospital (MGH) in Boston, MA. This survey included a vignette and illustration describing a proposed tablet-based system in which the patient, upon sign in at the clinic, receives a tablet loaded with personalized information tailored to their specific medical conditions and preferences. Patients were queried about their interest in such a system in comparison to traditional forms of patient education as well as their current health information seeking behaviors and activities and time spent in the waiting room. Interviews with five MGH affiliated health care providers were conducted to assess their opinions regarding the proposed tablet system. RESULTS: The majority (>60%) of patients were "very" or "extremely" interested in the proposed tablet system and thought it would improve their knowledge about their medical condition (60%), assist them in making healthy choices (57%), and help them to feel more comfortable talking with their provider (55%). Patients thought the system would be more motivating, informative, and engaging than traditional printed health education materials. The tablet system was not considered more effective than face-to-face interaction with providers, though 44% thought it would improve their relationship with their physician. Overall, 91% of respondents were willing to learn how to use a tablet and 75% reported being "very" or "extremely" confident they could use one. Four of the five providers believed that the proposed tablet system would improve clinical workflow and patient education. Patients and providers were concerned about privacy and security of data collected using the tablets. CONCLUSIONS: Both patients and providers were highly amenable to integrating tablets into the clinical experience, and tablets may be useful in improving patients' health knowledge, the collection of patient reported outcome measures, and improved patient-provider communication. Further research into operationalizing such systems and their validation is necessary before integration into standard clinical practice. PMID- 26481908 TI - Contribution of genes and unique environment to cross-sectional and longitudinal measures of subcortical volumes in bipolar disorder. AB - The influence of genes and environment on the association between bipolar disorder (BD) and volumes of subcortical brain regions involved in emotion processing has rarely been studied. Furthermore, as far as we know, longitudinal twin studies of subcortical brain volume change in BD have not been carried out at all. In this study, we focused on the genetic and environmental contributions to cross-sectional and longitudinal measures of subcortical brain volumes in BD. A total of 99 twins from monozygotic and dizygotic pairs concordant or discordant for BD and 129 twins from monozygotic and dizygotic healthy control pairs underwent magnetic resonance imaging at baseline. Longitudinal assessment was carried out in 48 twins from monozygotic and dizygotic patient pairs and 52 twins from monozygotic and dizygotic control pairs. Subcortical volume measures were obtained with Freesurfer software and analyzed with structural equation modeling software OpenMx. At baseline, BD was phenotypically and genetically associated with smaller volumes of the thalamus, putamen and nucleus accumbens. BD was not associated with subcortical brain volume change over time in any of the examined regions. Heritability of subcortical volumes at baseline was high, whereas subcortical volume change had low heritability. Genes contributing to BD showed overlap with those associated with smaller volumes of the thalamus, putamen and nucleus accumbens at baseline. Further evaluation of genetic contributions to abnormalities in subcortical brain regions assumed to be involved in emotion processing is recommended. PMID- 26481909 TI - Exploration of the nature of a unique natural polymer-based thermosensitive hydrogel. AB - The chitosan (CS)/beta-glycerol phosphate (GP) system is a heat induced gelling system with a promising potential application, such as an injectable biomedical material. Unlike most thermosensitive gelling systems, the CS/GP system is only partially reversible. That is once the hydrogel is fully matured, it only softens but cannot go back to its initial liquid state when cooled down. Here, we perform both the small and large amplitude oscillatory shear (SAOS and LAOS) tests on the fully matured CS/GP hydrogel samples at a variety of temperatures within the cooling process. The purpose of such tests is to investigate the structural change of the hydrogel network and thus to understand the possible gelation mechanism of this unique thermosensitive hydrogel. From the LAOS results and the further analysis with the Chebyshev expansion method, it shows that the CS/GP hydrogel is composed of a colloidal network dominated by hydrophobic interactions at high temperature, and gradually turns into a flexible network dominated by hydrogen bonding when the temperature goes down. Therefore, we may conclude that LOAS is a powerful tool to study the nonlinear behaviour of a polymer system that is closely related to its structure, and as a practical example, we achieve a clearer vision on the gelation mechanism of the unique CS/GP thermosensitive hydrogel on the basis of considerable previous studies and assumptions in this laboratory and other research groups. PMID- 26481910 TI - Relevance of graph literacy in the development of patient-centered communication tools. AB - OBJECTIVE: To determine the literacy skill sets of patients in the context of graphical interpretation of interactive dashboards. METHODS: We assessed literacy characteristics of prostate cancer patients and assessed comprehension of quality of life dashboards. Health literacy, numeracy and graph literacy were assessed with validated tools. We divided patients into low vs. high numeracy and graph literacy. We report descriptive statistics on literacy, dashboard comprehension, and relationships between groups. We used correlation and multiple linear regressions to examine factors associated with dashboard comprehension. RESULTS: Despite high health literacy in educated patients (78% college educated), there was variation in numeracy and graph literacy. Numeracy and graph literacy scores were correlated (r=0.37). In those with low literacy, graph literacy scores most strongly correlated with dashboard comprehension (r=0.59-0.90). On multivariate analysis, graph literacy was independently associated with dashboard comprehension, adjusting for age, education, and numeracy level. CONCLUSIONS: Even among higher educated patients; variation in the ability to comprehend graphs exists. PRACTICE IMPLICATIONS: Clinicians must be aware of these differential proficiencies when counseling patients. Tools for patient-centered communication that employ visual displays need to account for literacy capabilities to ensure that patients can effectively engage these resources. PMID- 26481911 TI - Chemical constituents from Hericium erinaceus and their ability to stimulate NGF mediated neurite outgrowth on PC12 cells. AB - One new meroterpenoid, named hericenone K (11), along with 10 known compounds (1 10), ergosterol peroxide (1), cerevisterol (2), 3beta,5alpha,9alpha-trihydroxy ergosta-7,22-dien-6-one (3), inoterpene A (4), astradoric acid C (5), betulin (6), oleanolic acid (7), ursolic acid (8), hemisceramide (9), and 3,4-dihydro-5 methoxy-2-methyl-2-(4'-methyl-2'-oxo-3'-pentenyl)-9(7H)-oxo-2H-furo[3,4 h]benzopyran (10), was isolated from the fruiting bodies of the mushroom Hericium erinaceus. Their structures were characterized on the basis of spectroscopic methods, as well as through comparison with previously reported data. Compounds 3 6, 8, and 9 were isolated from Hericium species for the first time. Compounds 10 and 11 was suggested to be racemic by the CD spectrum data and specific rotations, which ware resolved by chiral HPLC into respective enantiomers. Compounds 1-3, (+/-)-10, (-)-10 and (+)-10 in the presence of NGF (20 ng/mL) exerted a significant increase in neurite-bearing cells. PMID- 26481912 TI - Erratum to: Impact of PET/CT image reconstruction methods and liver uptake normalization strategies on quantitative image analysis. PMID- 26481914 TI - Immunology and cartilage regeneration. AB - The intrinsic regenerative capacity of avascular cartilage is limited. Cartilage injuries result in chronic, non-healing lesions requiring surgical management. Frequently, these surgical techniques make use of allogeneic cells and tissues. This review discusses the immune status of these materials. Cartilage allografts, often used in orthopedic and plastic surgeries, have rarely provoked a significant immune response. In whole cartilage transplants, the dense matrix produced by chondrocytes inhibits lymphocyte migration, preventing immune detection rendering them "antigen sequestered." It is unclear whether isolated chondrocytes are immune-privileged; chondrocytes express immune inhibitory B7 molecules, indicating that they have some ability to modulate immune reactions. Allogeneic cartilage grafts often involve a bony portion often retaining immunogenic cells and proteins-to facilitate good surgical attachment and concern that this may enhance inflammation and immune rejection. However, studies of failed cartilage grafts have not found immune responses to be a contributing factor. Meniscus allografts, which also retain a bony portion, raise similar concerns as cartilage allografts. Despite this, the plugs improved patient outcomes, indicating that the immunological effects were not clinically significant. Finally, allogeneic mesenchymal stromal cells (MSCs) also are being investigated as a treatment for cartilage damage. MSCs have been demonstrated to have unique immunomodulatory properties including their ability to reduce immune cell infiltration and to modulate inflammation. In summary, the immunogenic properties of cartilage vary with the type of allograft used: Cartilage allografts demonstrate active immune-suppressive mechanisms as evidenced by lack of allograft rejection, while MSC allografts appear to be safe for transplantation. PMID- 26481915 TI - Heart-focused anxiety in patients with chronic heart failure before implantation of an implantable cardioverter defibrillator: baseline findings of the Anxiety CHF Study. AB - AIMS: We analysed heart-focused anxiety (HFA) and its predictors in patients with heart failure before implantation of an implantable cardioverter defibrillator (ICD). Herein, we report the baseline data of the Anxiety-CHF Study which investigates HFA before and after ICD implantation. METHODS AND RESULTS: HFA, general anxiety and depression, perceived quality of life (QoL) and type D personality were measured with validated psychological instruments. Clinical parameters such as severity of heart failure measured by NYHA class and left ventricular ejection fraction (EF) were determined. One hundred and ten patients were interrogated before ICD implantation (70 % male, mean age = 60.5 +/- 14.9 years, mean EF = 31 % +/- 9 %, 91 % NYHA II-III, 92 % primary prevention). HFA was present in 53 patients (48.6 %); 37 participants (33.9 %) showed increased levels of general anxiety and 33 patients (30.3 %) showed increased levels of depression with clinical significant levels in 16 subjects (14.7 %) for general anxiety and 13 subjects (11.9 %) for depression. Poor QoL was reported in 30 patients (27.5 %). HFA was correlated with QoL, general anxiety, depression, type D personality, myocardial infarction (MI), and systolic blood pressure. QoL, general anxiety and former MI were significant predictors of HFA (R (2) = 0.453). CONCLUSION: Heart-focused anxiety is highly prevalent in heart failure patients prior to ICD implantation. Measures of disease severity such as EF or NYHA class do not predict HFA, neither does Type D personality. HFA is predicted by a history of MI and psychological parameters such as general anxiety and impaired QoL. CLINICALTRIALS. GOV IDENTIFIER: NCT02226770. PMID- 26481913 TI - Lupus brain fog: a biologic perspective on cognitive impairment, depression, and fatigue in systemic lupus erythematosus. AB - Cognitive disturbances, mood disorders and fatigue are common in SLE patients with substantial adverse effects on function and quality of life. Attribution of these clinical findings to immune-mediated disturbances associated with SLE remains difficult and has compromised research efforts in these areas. Improved understanding of the role of the immune system in neurologic processes essential for cognition including synaptic plasticity, long term potentiation and adult neurogenesis suggests multiple potential mechanisms for altered central nervous system function associated with a chronic inflammatory illness such as SLE. This review will focus on the biology of cognition and neuroinflammation in normal circumstances and potential biologic mechanisms for cognitive impairment, depression and fatigue attributable to SLE. PMID- 26481916 TI - Three-dimensional electroanatomic voltage mapping to guide biopsy sampling in unexplained cardiomyopathies: a proof-of-principle case series. PMID- 26481917 TI - Management of central giant cell granuloma of the jaws with intralesional steroid injection and review of the literature. AB - PURPOSE: We report the results of the intralesional steroid injections for the management of central giant cell granuloma (CGCG) of the jaws. METHODS: Seven CGCGs were treated with intralesional injection of corticosteroids. To accomplish this, 3.5 mL of triamcinolone and 3.5 mL of 0.5 % marcaine with 1/200,000 epinephrine (total 7 mL) were mixed. An adequate amount of steroid was injected into different areas of the lesion. This procedure was repeated on a weekly basis for 6 weeks. RESULTS: Clinical and radiological examination showed complete resolution and ossification of the lesions in four patients. Partial recovery was achieved in two patients. One patient did not respond to the treatment and underwent surgical curettage. CONCLUSIONS: We suggest that intralesional steroid injection is safe and effective for the treatment of CGCG, especially in non aggressive lesions. PMID- 26481918 TI - Role of propranolol in ulcerated haemangioma of head and neck: a prospective comparative study. AB - PURPOSE: Infantile haemangiomas comprise the majority of vascular anomalies and are considered the predominant vascular tumour type 1. We performed this prospective study to evaluate the therapeutic response and propranolol tolerance in infants with ulcerated infantile haemangioma of head and neck region. METHODS: Sixty-four patients with ulcerated infantile haemangiomas (IHs) of head and neck region, without any prior treatment and with age older than 1 month, were included in the study, after informed consent was obtained, and were randomly divided into groups A and B. Group A patients were given oral propranolol at a dose of 2 mg/kg per day in three divided doses as outpatients. Group B patients were given oral ibuprofen at a dose of 10 mg/kg 8-hourly and paracetamol at dose of 16.2 mg/kg 8-hourly. Documentation of gender, age, haemangioma location, duration of ulceration and pain was measured on the second and fifth day after commencement of treatment in both groups using the Children's Hospital of Eastern Ontario Pain Scale. RESULTS: There was no difference in pain score between the two groups (P value 0.074). Mean duration of healing of ulceration in group A was 17.93 +/- 2.22 days and in group B was 27.71 +/- 2.33 days (P value <0.001). In group A, out of 28 patients, 8 (28.5 %) were complete responders, 16 (57.1 %) were partial responders and 4 (14.2 %) were non-responders. CONCLUSION: Propranolol is a valuable therapeutic alternative for treatment of ulcerated haemangiomas and effectively reduces pain. PMID- 26481919 TI - Effect of temperature on replicative aging of the budding yeast Saccharomyces cerevisiae. AB - The use of the budding yeast Saccharomyces cerevisiae in gerontological studies was based on the assumption that the reproduction limit of a single cell (replicative aging) is a consequence of accumulation of a hypothetical universal "senescence factor" within the mother cell. However, some evidence suggests that molecules or structures proposed as the "aging factor", such as rDNA circles, oxidatively damaged proteins (with carbonyl groups) or mitochondria, have little effect on replicative lifespan of yeast cells. Our results also suggest that protein aggregates associated with Hsp104, treated as a marker of yeast aging, do not seem to affect the numeric value of replicative lifespan of yeast. What these results indicate, however, is the need for finding a different way of expressing age and longevity of yeast cells instead of the commonly used number of daughters produced over units of time, as in the case of other organisms. In this paper, we show that the temperature has a stronger influence on the time of life (the total lifespan) than on the reproductive potential of yeast cells. PMID- 26481921 TI - Biodiesel production potential of mixed microalgal culture grown in domestic wastewater. AB - In this study, a mixed microalgal culture grown in secondarily treated domestic wastewater effluent was investigated for biodiesel production using in situ transesterification method with conventional heating. The total lipid content of the mixed culture was found as 26.2% +/- 0.6 by weight of dry biomass, and 74% of the lipids were contributed by total glycerides. In situ transesterification with conventional heating process under acidic conditions produced higher biodiesel yield with chloroform as the co-solvent (82.1% +/- 3.9) compared to hexane (55.3% +/- 3.9) under the same reaction conditions. The gas chromatography analysis showed that FAME composition was mainly composed of palmitic, palmitoleic, stearic, oleic, linoleic and linolenic acid methyl esters., and thus the mixed microalgal culture fed by domestic wastewaters has had comparable biodiesel conversion yields and FAME composition to mono-culture and pure cultures fed by synthetic culture media. Hence, this study showed that secondarily treated domestic wastewater could potentially be a suitable and sustainable medium for microalgae grown to be used as biodiesel feedstock. PMID- 26481920 TI - Essential Oils for Treatment for Onychomycosis: A Mini-Review. AB - Onychomycosis are fungal infections affecting finger and toenails mainly caused by dermatophyte fungi and some Candida species. Low cure rates and frequent recurrence, development of a fungal resistance front to various antimicrobial agents topical and systemic, and an ineffective topical treatment make onychomycosis difficult to treat. Essential oils are excellent candidates for the topical treatment for onychomycosis because the development of resistance by fungi is rare, and the presence of side effects is low. They are composed of a complex variety of compounds, mainly terpenes, with low molecular weight, which may easily penetrate into the nail plate, finding the fungi elements. The complex mixture confers a broad antifungal spectrum of action, through interaction with biological membranes, interference in radical and enzymatic reaction of fungi cells. Essential oils may become the source of new therapeutic molecules, and the use of an essential oil incorporated into a topical formulation is an interesting, safe, and effective alternative for the treatment for onychomycosis. However, studies are needed to evaluate the efficacy of essential oils in the treatment for onychomycosis in vivo. This mini-review aims to present the potential use of essential oils for the treatment for onychomycosis, focusing on the last decade. PMID- 26481923 TI - How precise are precision injections and how can we improve? PMID- 26481922 TI - Development of a two-step process for production of 3-hydroxypropionic acid from glycerol using Klebsiella pneumoniae and Gluconobacter oxydans. AB - In this work, a two-step process was developed for the production of 3 hydroxypropionic acid from glycerol. In the first step, glycerol was converted to 1,3-propanediol by Klebsiella pneumonia. In the second step, the 1,3-propanediol was converted into 3-hydroxypropionic acid by Gluconobacter oxydans. In a 7.0 L bioreactor, the whole process took 54 h, consumed 480 g glycerol and produced 242 g 3-hydroxypropionic acid. The conversion rate of glycerol to 3-hydroxypropionic acid was 50.4 % (g g(-1)). The final concentration of 3-hydroxypropionic acid arrived 60.5 g L(-1). The process was effective for 3-HP production from glycerol and it might provide a new approach to the biosynthesis of 3-HP from a cheap starting material. Moreover, in this paper, it was first reported that the by product of 3-hydroxypropionic acid production from 1,3-propandeiol was acrylic acid. PMID- 26481924 TI - Using radiological markers for Kirschner wire fixation of phalangeal fractures. PMID- 26481925 TI - Near-infrared fluorescent swallow test for detection of the alimentary tract anastomotic leakage. PMID- 26481926 TI - Are overweight and obese patients who receive autologous free-flap breast reconstruction satisfied with their postoperative outcome? A single-centre study. AB - INTRODUCTION: Obese and overweight patients represent a challenging surgical group for autologous free-flap breast reconstruction. There is a paucity of information regarding post-operative patient-reported satisfaction in this increasingly prevalent cohort. This retrospective study aimed to determine using BREAST-Q patient-reported satisfaction amongst normal, overweight and obese patients receiving autologous free-flap breast reconstruction. METHODS: BREAST-Q (post-reconstruction) module was sent to 174 autologous breast free flap reconstruction patients between 2001 and 2012. Clinical data were collated for patients who returned questionnaires. Post-operative complications and satisfaction scores were compared between normal versus overweight and obese patients. RESULTS: A total of 101 patients (normal body mass index (BMI) = 27; overweight BMI = 48 and obese BMI = 25) completed BREAST-Q (response rate 66%). Obese and overweight patients are significantly more likely to develop major (44.8% and 31.1% vs. 29.6%) and minor (34.4% and 20% vs. 7.4%) complications in comparison to normal BMI patients (p < 0.02). Overweight and obese patients demonstrated similar levels of satisfaction compared with normal patients with the shape of their reconstructed breasts (73.2 and 72.1 vs. 71.2; p > 0.05) and overall surgical outcome (75.8 and 78.9 vs. 75.4; p > 0.05). CONCLUSIONS: Patient post-operative satisfaction is gaining increasing relevance in assessing the outcomes from autologous breast reconstruction. Overweight and obese women benefit from autologous breast reconstruction, despite being at increased risk of post-operative complications, and eventually achieve comparable levels of post operative satisfaction. This should be reflected in pre-operative counselling. PMID- 26481927 TI - CHAPAS-3 fills the gap. PMID- 26481929 TI - Picturing the torment of cluster headache. PMID- 26481930 TI - Evidence-based guideline summary: Evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. PMID- 26481928 TI - Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. AB - BACKGROUND: WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz. METHODS: In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2-4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957. FINDINGS: Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2.3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2.6 years vs 6.2 years in ART experienced). 917 grade 2-4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0.63; zidovudine vs stavudine: hazard ratio [HR] 0.99 [95% CI 0.75-1.29]; abacavir vs stavudine: HR 0.88 [0.67-1.15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0.58); most ART experienced children maintained suppression (p=1.00). INTERPRETATION: All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favours abacavir for African children, supporting WHO 2013 guidelines. FUNDING: European Developing Countries Clinical Trials Partnership. PMID- 26481931 TI - Neuropsychological outcome after deep brain stimulation for Parkinson disease. PMID- 26481932 TI - Clinical Reasoning: A 58-year-old man with right facial numbness. PMID- 26481933 TI - Teaching NeuroImages: Dyke-Davidoff-Masson in Sturge-Weber syndrome. PMID- 26481934 TI - Is allopurinol use associated with an excess risk of osteoporotic fracture? A National Prescription Registry study. AB - Using a Danish Register cohort of 86,039 adult new allopurinol users and propensity score matched controls, we found that gout requiring allopurinol prescription was associated with an increased fracture risk. PURPOSE: Gout, an acute inflammatory arthritis, is common and associated with elevated serum urate, obesity and high alcohol consumption. The mainstay of therapy is the urate lowering agent, allopurinol. Here, we report the relationship between allopurinol prescription and fracture in a large registry population. METHODS: We established a Danish Register cohort of 86,039 adult cases (new allopurinol users) and 86,039 age, sex and propensity score matched controls (not exposed to allopurinol or with a gout diagnosis), with no diagnosis of malignancy in the year prior. RESULTS: We found a modest adjusted effect of allopurinol prescription on major osteoporotic fractures (hazard ratio (HR) 1.09, 95 % confidence interval (CI) 1.05-1.14, p = 0.04) and on hip fractures (HR 1.07, 95 % CI 1.11-1.14, p < 0.001), robust to adjustment for confounding factors (age, sex, comorbidity, medication use). Associations were stronger in men than women, and among incident allopurinol users whose gout diagnosis had been confirmed by at least one hospital contact. Prespecified subanalyses by filled dose of allopurinol (mg/day in first year of prescription) showed increased hip and major fracture risk in women in the highest allopurinol dose grouping only, while a less strong dose effect was evident for fracture rates in men. CONCLUSION: Gouty arthritis requiring allopurinol is associated with an excess risk of major or hip fracture, with an allopurinol dose effect evident in women such that women taking the highest doses of allopurinol--suggestive of more severe disease--were at increased risk relative to women taking lower doses. PMID- 26481936 TI - Potential strategies for preventing chronic postoperative pain: a practical approach: Continuing Professional Development. AB - PURPOSE: This manuscript proposes pharmacological strategies that might decrease persistent postsurgical pain (PPSP). These recommendations are based on a review of current publications available in the literature. PRINCIPAL FINDINGS: Persistent postsurgical pain has been defined by the International Association for the Study of Pain as clinical discomfort that lasts more than two months after surgery. Recent reviews reported that 10-50% of patients develop chronic pain after surgery, 2-10% with disabling chronic pain at six months. Preventive interventions should target all types of surgery, but specific attention should be placed on surgical insults that carry a high risk of pain chronicization. Regional anesthesia (RA) should be used whenever feasible, and a continuous perineural/epidural local anesthetic infusion is preferred over a single-shot technique. The RA should be initiated prior to the surgical incision and then continued for at least 24-72 hr after the surgery. Perioperative opioids should be used for nociceptive stimuli not managed by the RA. An intravenous infusion of ketamine, an N-methyl-D-aspartate receptor (NMDA) antagonist, might be added for a further decrease in neuronal sensitization, especially when the procedure is extensive or when RA is not feasible or contraindicated. A multimodal approach is always suggested. The literature still does not strongly support the use of gabapentinoids for PPSP prevention; however, they might be maintained in patients who use them preoperatively. CONCLUSIONS: A winning strategy to reduce the incidence of PPSP may well involve performing minimally invasive surgery, providing adequate perioperative analgesia based on RA, and using a multimodal approach with NMDA antagonists. PMID- 26481938 TI - Perioperative management of patients with obstructive sleep apnea: a survey of Canadian anesthesiologists. AB - INTRODUCTION: Obstructive sleep apnea (OSA) may increase the incidence of postoperative complications when undiagnosed. The purpose of this study was to evaluate the perspectives of Canadian anesthesiologists regarding the perioperative management of patients with diagnosed or suspected OSA. METHODS: This study was conducted as a survey of Canadian anesthesiologists using a self administered scenario-based questionnaire. We initially mailed the survey questionnaire and then mailed it again to non-respondents six weeks later. Subsequently, we e-mailed the online version of our survey to active members of the Canadian Anesthesiologists' Society. RESULTS: The response rates were 35% and 26% for the postal and online modes of administration, respectively. About 50% of the respondents relied on clinical suspicion rather than on a systematic screening to identify patients who may have undiagnosed OSA preoperatively. Forty seven percent of all respondents either did not know of any institutional policy to guide their perioperative management of patients with OSA or reported an absence of an institutional policy. Fifteen percent of the respondents would discharge diagnosed OSA inpatients with compliant use of continuous positive airway pressure (CPAP) to the ward without monitoring. Nevertheless, a more conservative approach was observed for CPAP non-compliant inpatients. We indeed observed that more than 40% of respondents would send an ambulatory OSA patient home, while another 60% would favour hospital admission. CONCLUSIONS: The majority of anesthesiologists continue to rely on clinical suspicion alone to identify OSA. Moreover, the lack of institutional policy is concerning. A concerted effort to develop an evidence-based guideline may be the next step to assist institutions. PMID- 26481939 TI - Mismanagement of obstructive sleep apnea may result in finding these patients dead in bed. PMID- 26481940 TI - FDA Draft Guidance on the Naming of Biosimilars. PMID- 26481941 TI - Selective Phosphodiesterase Inhibitors for Psoriasis: Focus on Apremilast. AB - Phosphodiesterase (PDE) 4 participates in regulating the inflammatory response by degrading cyclic adenosine 3'5'-monophosphate (cAMP), a key second messenger. Inhibition of PDE4 increases the intracellular cAMP level, which in turn results in a reduction in inflammatory mediators and an increase in anti-inflammatory mediators. Immune-modulating effects of PDE4 inhibitors have been investigated in a number of inflammatory conditions, such as asthma, atopic dermatitis, chronic obstructive pulmonary disease, Behcet's disease, psoriasis, and psoriatic arthritis. Apremilast, a selective PDE4 inhibitor, has been shown to block the production of pro-inflammatory cytokines (interferon-gamma, tumor necrosis factor alpha, interleukin [IL]-12, IL-17, and IL-23), which are the key players in the pathogenesis of psoriasis. Increased intracellular cAMP levels result in a range of anti-inflammatory effects on numerous cell lines. A decrease in proinflammatory activity has been shown to result in a reduced psoriasiform response in preclinical in vivo models of psoriasis, and reduction of biologic activity in a pilot study in humans. The efficacy and safety of apremilast in the treatment of psoriasis have been demonstrated in phase II and III clinical trials. Apremilast demonstrated efficacy in reducing the severity of moderate to severe plaque psoriasis. Treatment with apremilast was well tolerated, with generally mild gastrointestinal complaints, which occurred early in the course of the treatment and resolved over time, and there was no requirement for laboratory test monitoring. These results make apremilast an attractive therapeutic option for plaque psoriasis. PMID- 26481942 TI - Lessons Learned Designing and Using an Online Discussion Forum for Care Coordinators in Primary Care. AB - While an increasing number of researchers are using online discussion forums for qualitative research, few authors have documented their experiences and lessons learned to demonstrate this method's viability and validity in health services research. We comprehensively describe our experiences, from start to finish, of designing and using an asynchronous online discussion forum for collecting and analyzing information elicited from care coordinators in Patient-Centered Medical Homes across the United States. Our lessons learned from each phase, including planning, designing, implementing, using, and ending this private online discussion forum, provide some recommendations for other health services researchers considering this method. An asynchronous online discussion forum is a feasible, efficient, and effective method to conduct a qualitative study, particularly when subjects are health professionals. PMID- 26481943 TI - Stepping Back and Listening: Staff Experiences of Using a Coaching Approach in an Acute Rehabilitation Ward for Older Adults. AB - Previous research has highlighted that acute care provision can lead to a loss of confidence, control, and independent functioning in older adult patients. In addition, it is recognized that interactions between patients and health care staff are central to the prevention of functional decline in patients. In this study, we aimed to affect the staff-patient relationship by implementing a coaching intervention in an older adult acute care setting. Here, we report on staff experiences of this coaching approach. Data were collected from 16 members of staff via semi-structured interviews, which were analyzed using thematic analysis. Four themes were identified: Putting a Label on It, Stepping Back and Listening, Identifying the Opportunities, and Working as Team. Our findings show that a coaching approach can be successful in getting staff to reconsider their interactions with patients and to focus on strategies that foster the independence and autonomy of older adult patients. PMID- 26481944 TI - Toward an Understanding of the Poor Health Status of Indigenous Australian Men. AB - The purpose of this study was to investigate perceptions of health and health behaviors among Indigenous Australian men. Using a participatory action research (PAR) framework, we conducted two focus groups and 40 individual semi-structured interviews with men between the ages of 18 and 35 years in each of three locations across Australia. We used the health beliefs model to provide a framework for the analyses. Participants recognized that their Indigenous status placed them in a vulnerable position with regard to health, and that there might be serious consequences of failing to follow a good diet and engage in appropriate exercise. However, they delineated a number of barriers to engaging in such health behaviors. These perceived barriers require addressing at a range of policy levels within government, with a focus on social structures and institutionalized discrimination, as well as unemployment, poverty, dispossession, and cultural oppression. PMID- 26481945 TI - Communication and Culture in the Surgical Intensive Care Unit: Boundary Production and the Improvement of Patient Care. AB - This ethnography explores communication around critically ill surgical patients in three surgical intensive care units (ICUs) in Canada. A boundary framework is used to articulate how surgeons', intensivists', and nurses' communication practices shape and are shaped by their respective disciplinary perspectives and experiences. Through 50 hours of observations and 43 interviews, these health care providers are found to engage in seven communication behaviors that either mitigate or magnify three contested symbolic boundaries: expertise, patient ownership, and decisional authority. Where these boundaries are successfully mitigated, experiences of collaborative, high-quality patient care are produced; by contrast, boundary magnification produces conflict and perceptions of unsafe patient care. Findings reveal that high quality and safe patient care are produced through complex social and cultural interactions among surgeons, intensivists, and nurses that are also expressions of knowledge and power. This enhances our understanding of why current quality improvement efforts targeting communication may be ineffective. PMID- 26481946 TI - The aqueous extract of Albizia adianthifolia leaves attenuates 6-hydroxydopamine induced anxiety, depression and oxidative stress in rat amygdala. AB - BACKGROUND: While the Albizia adianthifolia (Schumach.) W. Wright (Fabaceae) is a traditional herb largely used in the African traditional medicine as analgesic, purgative, antiinflammatory, antioxidant, antimicrobial, memory-enhancer, anxiolytic and antidepressant drug, there are no scientific data that clarify the anxiolytic and antidepressant-like effects in 6-hydroxydopamine (6-OHDA)-lesioned animal model of Parkinson's disease. This study was undertaken in order to identify the effects of aqueous extract of A. adianthifolia leaves on 6 hydroxydopamine-induced anxiety, depression and oxidative stress in the rat amygdala. METHODS: The effect of the aqueous extract of A. adianthifolia leaves (150 and 300 mg/kg, orally, daily, for 21 days) on anxiety and depression was assessed using elevated plus-maze and forced swimming tests, as animal models of anxiety and depression. Also, the antioxidant activity in the rat amygdala was assessed using assessed using superoxide dismutase, glutathione peroxidase and catalase specific activities, the total content of the reduced glutathione, protein carbonyl and malondialdehyde levels. Statistical analyses were performed using by one-way analysis of variance (ANOVA). Significant differences were determined by Tukey's post hoc test. F values for which p < 0.05 were regarded as statistically significant. Pearson's correlation coefficient and regression analysis were used in order to evaluate the connection between behavioral measures, the antioxidant defence and lipid peroxidation. RESULTS: 6-OHDA lesioned rats exhibited the following: decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. Administration of the aqueous extract significantly exhibited anxiolytic- and antidepressant-like effects and also antioxidant potential in the rat amygdala. CONCLUSIONS: Our results suggest that the aqueous extract ameliorates 6-OHDA-induced anxiety and depression by attenuation of the oxidative stress in the rat amygdala. These pieces of evidence accentuate its use in traditional medicine. PMID- 26481947 TI - Tentative nil per os leads to poor outcomes in older adults with aspiration pneumonia. AB - BACKGROUND & AIMS: Patients with aspiration pneumonia (AP) may experience swallowing function declines during treatment, necessitating artificial feeding methods. Proper AP treatment contributes to maintaining activities of daily living. The aim was to assess the effect of tentative nil per os (NPO) status on the recovery of AP patients and declines in their swallowing abilities. METHODS: In this retrospective cohort study, 331 patients with AP having oral food intake in premorbid status were included after exclusions for reasons such as vomiting or respiratory insufficiency. We divided subjects into 2 groups: an early oral intake (EOI) group and a tentative NPO group according to the directions by the attending doctors at admission. We created a population model related to groupings from all subjects, which was a homoscedastic model without statistical differences by the inverse probability of treatment weighted (IPTW) method and compared outcomes between the groups. RESULTS: In the IPTW model, tentative NPO status resulted in poorer nutritional intake every day for 1 week from the date of admission (p < 0.05), a significantly longer treatment duration (50% treatment length: NPO group, 13 days [95% confidence interval (CI), 12.04-13.96] and EOI group, 8 days [95% CI, 7.69-8.31 [log-rank test, p < 0.001]) and greater decline in swallowing ability over the course of treatment (p < 0.001). CONCLUSIONS: Tentative NPO status with AP at hospital admission resulted in adverse effects on patients, including prolonged treatment duration and declines in swallowing ability. Avoiding unnecessary NPO might be another method to treat AP and contribute to the patient's outcomes in addition to medication administration. PMID- 26481948 TI - Should significant weight loss mandated to be "unintentional" for resulting in and regarded as malnutrition? PMID- 26481949 TI - Nut consumption is associated with better nutrient intakes: results from the 2008/09 New Zealand Adult Nutrition Survey. AB - A limited number of studies have examined associations between nut consumption and nutrient intakes or diet quality. None has investigated these associations in the Southern Hemisphere. The purpose of this study was to examine associations between nut consumption and nutrient intakes among adult New Zealanders. Data from the 24-h recalls of 4721 participants from the cross-sectional 2008/09 New Zealand Adult Nutrition Survey (2008/09 NZANS) were used to determine whole nut intake and total nut intake from all sources as well as nutrient intakes. Regression models, both unadjusted and adjusted for potential confounders, were used to estimate differences in nutrient intakes between those consuming and those not consuming nuts. From adjusted models, compared with non-whole nut consumers, whole nut consumers had higher intakes of energy and percentage of energy from total fat, MUFA and PUFA, whereas percentage of energy from SFA and carbohydrate was lower (all P<=0.025). After the additional adjustment for energy intake, whole nut consumers had higher intakes of dietary fibre, vitamin E, folate, Cu, Mg, K, P and Zn (all P<=0.044), whereas cholesterol and vitamin B12 intakes were significantly lower (both P<=0.013). Total nut consumption was associated with similar nutrient profiles as observed in whole nut consumers, albeit less pronounced. Nut consumption was associated with better nutrient profiles, especially a lower intake of SFA and higher intakes of unsaturated fats and a number of vitamins and minerals that could collectively reduce the risk for chronic disease, in particular for CVD. PMID- 26481950 TI - Anticancer treatment and fertility: Effect of therapeutic modalities on reproductive system and functions. AB - The significant improvement of cancer treatments entailed a longer life in cancer survivors and raised expectations for higher quality of life with minimized long term toxicity. Infertility and gonadal dysfunction are adverse effects of anticancer therapy or may be related to specific tumors. In female cancer survivors, premature ovarian failure is common after antineoplastic treatments resulting in infertility and other morbidities related to oestrogen deficiency such as osteoporosis. In male cancer survivors, infertility and persistent a zoospermia is a more common long-term adverse effect than hypogonadism because germ cells are more sensitive to chemotherapy and radiotherapy than leydig cells. Gonadal toxicity and compromise of reproductive functions will be more efficiently prevented and treated if addressed before treatment initiation. This review focuses on these issues in young cancer survivors of childbearing age, where methods of protecting or restoring endocrine function and fertility need to be considered. PMID- 26481951 TI - Exploring miRNA based approaches in cancer diagnostics and therapeutics. AB - MicroRNAs (miRNAs), a highly conserved class of tissue specific, small non protein coding RNAs maintain cell homeostasis by negative gene regulation. Proper controlling of miRNA expression is required for a balanced physiological environment, as these small molecules influence almost every genetic pathway from cell cycle checkpoint, cell proliferation to apoptosis, with a wide range of target genes. Deregulation in miRNAs expression correlates with various cancers by acting as tumor suppressors and oncogenes. Although promising therapies exist to control tumor development and progression, there is a lack of efficient diagnostic and therapeutic approaches for delineating various types of cancer. The molecularly different tumors can be differentiated by specific miRNA profiling as their phenotypic signatures, which can hence be exploited to surmount the diagnostic and therapeutic challenges. Present review discusses the involvement of miRNAs in oncogenesis with the analysis of patented research available on miRNAs. PMID- 26481952 TI - Second-line treatment in inoperable pancreatic adenocarcinoma: A systematic review and synthesis of all clinical trials. AB - There remains uncertainty regarding the optimal second-line chemotherapy in advanced pancreatic ductal adenocarcinoma (PDAC). The current recommendation of 5 fluorouracil and oxaliplatin may not be relevant in current practice, as FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) has become a more popular first line therapy in fit patients. The majority of studies in this setting are single-arm Phase II trials with significant heterogeneity of patient populations, treatments and outcomes. In this review, we sought to systematically review and synthesise all prospective data available for the second-line treatment of advanced PDAC. PMID- 26481953 TI - Combination or single-agent chemotherapy as adjuvant treatment of gastric cancer: A systematic review and meta-analysis of published trials. AB - BACKGROUND: Chemotherapy is standard care in resected gastric cancer (GC). Despite the evidence that combination chemotherapy (CT) increases overall survival (OS) as compared to single agent therapy in metastatic disease, no study proved this benefit in the adjuvant setting. We performed a systematic review and meta-analysis based on trial data on the role of combination over single agent CT as adjuvant treatment of GC. METHODS: MEDLINE/PubMed and Cochrane Library were searched for randomized phase III trials that compared combination vs. single agent CT in patients treated with radical surgery for non-metastatic GC. Data extraction was conducted according to the PRISMA statement. Statistical analyses were conducted to calculate the summary hazard ratio (HR) for OS and disease free survival (DFS) and 95% Confidence Intervals (CIs) by using random-effects or fixed effects models based on the heterogeneity of included studies. A subgroup analysis was performed in patients treated with D2 lymphadenectomy. RESULTS: A total of 3572 patients were available for this analysis, 1857 received D2 lymphadenectomy, and fluoropyrimidine was given in 97% of patients of the control arm. In the overall population, the combined therapy decrease the risk of death by 13% (HR=0.87; 95%CI, 0.79-0.95; p=0.004) with fixed effect and by 19% (HR=0.81; 95%CI, 0.68-0.97; p=0.02) with random effect; significant heterogeneity was found. When analysis was limited to studies that required D2 lymphadenectomy a significant reduction of the risk of death was found in favor of combination CT (HR=0.86; 95%CI, 0.76-0.98; p=0.02). In the 3487 patients valuable for DFS, combination CT decreased the risk of relapse by 23% (HR=0.77; 95%CI, 0.70-0.84; p<0.001) with fixed effect and by 27% (HR=0.73; 95%CI, 0.49-1.09; p=0.12) with random effect; significant heterogeneity was found. CONCLUSIONS: This analysis reported that adjuvant combination CT decreases the risk of death over single agent therapy in patients with non-metastatic GC. PMID- 26481954 TI - Cancer specific risk in multiple sclerosis patients. AB - Multiple sclerosis (MS) is a chronic central nervous system (CNS) autoimmune disease. Studies of cancer risk in MS patients have shown inconsistent findings. A pubmed search of the literature on cancer risk in patients with MS was conducted and found published relative studies. The majority of these studies concluded that there was overall either reduced or no increased risk of developing malignancies between patients with MS compared to the general population. However, several studies suggested that patients with MS may have reduced risk in specific cancers such as of the digestive and respiratory organs, prostate, ovary, or increased risk in breast, brain and bladder tumors. At present it is uncertain if the immunologic profile of MS patients may be related to the increased or reduced frequency of some cancers and warrants further investigation. PMID- 26481955 TI - [Prevention of drink driving at academic festivals: "Tu decides" project]. AB - OBJECTIVE: Alcohol consumption among university students has reached worrying levels, its effects on driving being highly dangerous. This aspect emphasizes the need to develop prevention programs, intended to raise subjects' awareness about the effects of alcohol on driving. The aim of the present research is to evaluate the effectiveness of the intervention program "Tu decides", implemented at the Algarve University during several students festivals, between 2010-2014. METHOD: Quasi-experimental study, pre-post test without control group. A total of 5,079 participants were inquired. They were asked, at two different moments, before and after the measurement of the blood alcohol level and giving an information session with technical recommendations to prevent driving under alcohol effects. One factor ANOVA test used, in order to perform a mean comparison, as well as the Chi-square statistics, to perform a proportion comparison (p<.05). RESULTS: It was found that the intention to drive was lower at the second moment (42.1%) (chi(2)=2078.71; p=.000). This intention was influenced by blood alcohol level different levels (chi(2)=338.252; p=.000), gender (chi(2)=35.718; p=.000), age (chi(2)=62.805; p=.000) and professional situation of the participants (chi(2)=27.397; p=.001). CONCLUSIONS: We can affirm that the main objective of this intervention was achieved, since the participants followed the technical recommendations based on the blood alcohol level results. PMID- 26481956 TI - [Dermatological diseases and sexuality. How to proceed?]. AB - A variety of dermatological diseases is associated with male or female sexual dysfunction. Some sexual disorders are caused organically; erectile dysfunction in men with systemic sclerosis may be due to penile vascular alterations and corporal fibrosis. Other dermatoses such as psoriasis are associated with risk factors (metabolic syndrome) for sexual disorders and may therefore indirectly induce erectile dysfunction. However, the majority of sexual dysfunctions in dermatological patients is caused by reduced self confidence and sexual self esteem leading to affected partnership and sexuality. Dermatologists should be trained in basic sexual medicine and ask their patients for sexual problems. They may not treat sexual disorders, but they should be identified as sympathetic physicians for these problems and should be able to refer the patient to specialists in sexual medicine. PMID- 26481957 TI - [Trauma and psychological distress in dermatological patients]. AB - BACKGROUND: Although seldom diagnosed, post-traumatic stress disorder (PTSD) has a high prevalence in primary and tertiary care. In a consecutive cross-sectional study, the prevalence of traumatic experiences and the severity of post-traumatic symptoms as well as specific characteristics of traumatized patients in the context of the dermatological treatment were examined. PATIENTS AND METHODS: Standardized questionnaires for assessing general psychopathology (Brief Symptom Inventory, BSI), coping with dermatological diseases (Adjustment to Chronic Skin Diseases Questionnaire, MHF) and diagnosis of trauma (Essen Trauma-Inventory, ETI) were used in 221 patients with different skin diseases. RESULTS: In total, 85.1 % of the patients reported at least one potentially traumatic event in their lives, whereby psychometrically in 8.6 % of the cases the diagnostic criteria for a PTSD were met. Patients with suspected PTSD were more impacted by psychopathology, had more problems in coping with their skin diseases and attributed mental stress as having a greater influence on their skin disease than nontraumatized patients or traumatized patients without suspected PTSD. In addition, cumulative traumatization also leads to increased trauma symptomatology and greater difficulties in coping with skin diseases. CONCLUSION: The results emphasize the impact of a comorbid PTSD on a patient's ability to cope with skin diseases and underline the need for the inclusion of the differential diagnosis PTSD in dermatological treatment settings. PMID- 26481958 TI - Tobacco Use and Cryptogenic Stroke in Young Adults. AB - OBJECTIVE: Cryptogenic stroke is the leading subtype of ischemic stroke in the young. We sought to evaluate the association between traditional cardiovascular risk factors and cryptogenic stroke by using a case-control study. METHODS: Patients aged 18-54 years, consecutively treated for first-ever cryptogenic ischemic stroke in an academic stroke unit, were compared with subjects from the general population living in the same geographic area. Control subjects were matched for age and sex with patients. We further evaluated the association between significant risk factors and nonobstructive (<50% stenosis) carotid plaque and thrombus among patients with cryptogenic stroke. Odds ratios [OR] were calculated using logistic regression analysis. RESULTS: A total of 155 patients with cryptogenic stroke (66.4% men, mean age 43.5 years [SD 8.4]) were included in the study. Cryptogenic stroke was associated with current tobacco use (42.6% in patients versus 23.9% in control subjects; OR = 2.38, 95% confidence interval [CI] 1.40-4.05, P = .002). Current tobacco use was associated with nonobstructive carotid plaque (OR = 6.22; 95% CI, 2.43-15.9; P = .001) and nonobstructive carotid thrombus (OR = 13.7; 95% CI, 1.42-132.7; P = .03) among the patients. CONCLUSION: Our case-control study showed a strong link between current tobacco use and cryptogenic stroke in young adults. PMID- 26481960 TI - "Walking the Walk": Decisional Capacity Deficits After Right Hemisphere Subdural Hematoma. PMID- 26481959 TI - Psychosocial Evaluation in Patients Undergoing Left Ventricular Assist Device Implantation Using the Transplant Evaluation Rating Scale. AB - BACKGROUND: It has been recommended that all candidates for left ventricular assist device (LVAD) implantation undergo preoperative psychologic evaluation for risk assessment. OBJECTIVE: We used the transplant evaluation rating scale (TERS) that was established for pretransplant evaluation to investigate the psychosocial assessment of patients undergoing LVAD implantation. METHODS: This study retrospectively analyzed data from 125 patients with advanced heart failure who were evaluated by the TERS before LVAD implantation. Postoperative follow-up included survival, total length of hospital stay, readmissions, and post-LVAD out of-hospital days after discharge. The cohort was stratified according to the TERS scores into low-, moderate-, and high-risk groups. The outcomes were analyzed to evaluate whether the TERS score was associated with post-LVAD adverse events. RESULTS: The TERS, when stratified into 3 risk groups showed significant difference in 8 of the 10 psychosocial domains (p < 0.001). The mean number of outpatient days after discharge was significantly different between the low-, moderate-, and high-risk groups (p < 0.001). All other outcomes were not significantly different. CONCLUSIONS: This study showed that the TERS is successful in stratifying our patients with an LVAD into 3 risk groups, indicating the internal validity of this test. The number of out-of-hospital (outpatient) days after discharge was significantly shorter in the TERS high-risk group, which may affect the quality of life and cost of post-LVAD care. PMID- 26481961 TI - Depressive Symptom Clusters Differentially Predict Cardiovascular Hospitalization in People With Type 2 Diabetes. AB - BACKGROUND: Depression has been associated with the development of cardiovascular disease in people with type 2 diabetes. OBJECTIVE: We examined whether symptoms related to the 2 core features of depression--dysphoria and anhedonia--and anxiety were differentially associated with cardiovascular hospitalization and whether there were symptom-specific mechanisms (alcohol, smoking, physical activity, body mass index, glucose, cholesterol, and blood pressure) in play. METHOD: A total of 1465 people in Dutch primary care completed the Edinburgh Depression Scale in 2005 and were followed up until first cardiovascular hospitalization during follow-up (event) or December 31, 2010 (study end). Cox regression analyses examined (1) differences in time to hospitalization for a cardiovascular event between people with a low vs a high baseline dysphoria/anhedonia/anxiety score (adjusting for demographic and clinical confounders) and (2) mediating mechanisms. RESULTS: A total of 191 people were hospitalized for a cardiovascular event. In univariable analysis, dysphoria predicted a shorter time to cardiovascular hospitalization (hazard ratio = 1.49, 95% CI: 1.02-2.17). After adjustment for confounders, neither dysphoria (hazard ratio = 1.55, 95% CI: 0.91-2.64) nor anhedonia (hazard ratio = 0.83, 95% CI: 0.47 1.48) was significantly associated with time to cardiovascular hospitalization. Anxiety was associated with a longer time to cardiovascular hospitalization (adjusted hazard ratio = 0.49, 95% CI: 0.27-0.89). However, none of the selected factors qualified as a mediator for the (adjusted) association between anxiety and time to cardiovascular hospitalization. DISCUSSION: Dysphoria was associated with a shorter time to cardiovascular hospitalization in unadjusted analyses only, whereas anxiety predicted later hospitalization after confounder adjustment. Anhedonia did not show a significant association. Mechanistic pathways remain unclear. PMID- 26481962 TI - Delay in Diagnosis of Wilson Disease in Children With Insidious Psychiatric Symptoms: A Case Report and Review of the Literature. PMID- 26481963 TI - Delusional Parasitosis as a Treatment Complication of Parkinson Disease. PMID- 26481965 TI - Ulinastatin inhibits the inflammation of LPS-induced acute lung injury in mice via regulation of AMPK/NF-kappaB pathway. AB - BACKGROUND: Ulinastatin (ULI), a serine protease inhibitor, had been widely used as a drug for patients with acute inflammatory disorders. However, evidence regarding the anti-inflammatory effect of ulinastatin was still lacking. In this study, we investigated the protective mechanisms of ULI in LPS-induced acute lung injury (ALI). METHODS: ALI was induced in mice by intratracheal instillation of LPS. The cells in the bronchoalveolar lavage fluid (BALF) were counted. The degree of animal lung edema was evaluated by measuring the wet/dry weight ratio and oxygenation index. The levels of inflammatory mediators, tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6, were assayed by enzyme-linked immunosorbent assay. Pathological changes of lung tissues were observed by HE staining. The levels of NF-kappaB p65, AMPK, p-AMPK and IkappaBalpha expression were detected by Western blotting. Then, selective AMPK inhibitor Compound C was used to test whether AMPK activation was critical in protection process of ULI against LPS-induced ALI. RESULTS: Ulinastatin pretreatment at doses of 15, 30 and 45mg/kg decreased LPS-induced evident lung histopathological changes, lung wet-to dry weight ratio, and oxygenation index. Expression of IL-6, IL-1beta, and TNF alpha was suppressed by ULI at protein level in BALF. Additionally, the attenuation of inflammatory responses by ULI was closely associated with AMPK/NF kappaB pathway and this effect was significantly inhibited by treatment with the AMPK inhibitor, Compound C. CONCLUSIONS: The results presented here indicated that ULI has a protective effect against LPS-induced ALI and this effect may be attributed partly to decreased production of proinflammatory cytokines through the regulation of AMPK/NF-kappaB signaling pathway. PMID- 26481964 TI - A novel Lactobacillus plantarum strain P-8 activates beneficial immune response of broiler chickens. AB - To investigate whether Lactobacillus plantarum P-8 may be used as an alternative to antibiotics in the broiler chicken diet, we compared P-8 and antibiotics for their immunobiotic properties and their effect on growth performance of broiler chickens in a 42-day trial. The results showed that P-8 provided similar benefits in weight gain, feed intake and feed efficiency as antibiotics did. Importantly, P-8 activated protective immune responses of the broilers while antibiotics lacked this effect. P-8 induced higher fecal secretory IgA (sIgA) levels on day 42 (P<=0.027) and IgA(+) lymphocytes in the jejunum and Peyer's patches (PP) (P<0.001) compared to antibiotic treatment. Antibiotics reduced the IgA(+) lymphocytes in jejunum and PP on day 42 compared to the control. P-8 increased CD3(+) T cells in the small intestinal tissues in most test situations whereas antibiotics had fewer CD3(+) cells in PP and cecal tonsil compared with the control broilers at the end of the trial. In addition, P-8 increased CD4(+) T cells significantly in the intestinal tissues compared to both antibiotics and the control (P<0.0052). Both Th1 and Th2 cytokine expression were enhanced by P-8 on day 14, consistent with the clinical trial results showing probiotic benefits in diseases. Antibiotics up- and down-regulated interleukin (IL)-2, IL-4 and IL 10 transcripts in an age-dependent manner, and showed anti-inflammatory potential. These data indicate that P-8 may provide protective immune response to broilers while maintaining similar growth performance and may be a potential alternative to antibiotics supplemented in chicken feeds. PMID- 26481966 TI - Slim by Design: Kitchen Counter Correlates of Obesity. AB - Background The home is one place where people can control what foods are available and how the environment is arranged. Given the impact of environments on health, the objective of this study is to determine whether the presence of foods on a person's kitchen counter are associated with their body mass index (BMI). Method In Study 1, a nationwide sample of 500 households was asked to inventory their kitchen and provide their height and weight. In Study 2, researchers photographed and catalogued 210 households in Syracuse, New York, and measured the occupants' height and weight. Main outcome measures for the study were BMI differences between households that had various foods visible on the counter compared with those that did not. Findings The presence of fruit on the counter was associated with lower BMI in both studies, but the presence of foods such as candy, cereal, soft drinks, and dried fruit were associated with weight differences that ranged from 9.4 to 14.4 kg. Interpretations Although correlational, the findings from these two studies suggest that when counseling patients regarding their weight, physicians also suggest they clear their kitchen counter of all food except a fruit bowl. PMID- 26481967 TI - Exposure-Reducing Behaviors Among Residents Living Near a Coal Ash Storage Site. AB - Coal ash, a waste product generated from burning coal for energy, is composed of highly respirable particles containing heavy metals, radioactive elements, and polycylic aromatic hydrocarbons. Coal ash is stored in landfills and surface impoundments frequently located near neighborhoods. Fugitive dust from the storage sites exposes neighborhoods, affecting the health and welfare of residents. The research questions of interest were (1) are community members concerned about coal ash exposure from the storage site; (2) what, if any, behaviors do community members engage in to reduce exposure; and (3) do exposure reducing behaviors differ by level of concern about coal ash. A community-based mixed-methods approach was used. Focus groups (n = 26) were conducted in 2012, and a cross-sectional survey was administered in 2013 (n = 231). The majority of survey respondents (62%) worried "a lot" about being exposed to coal ash; however, most did not engage in exposure-reducing behaviors, such as wearing protective equipment when doing chores. Compared with respondents who worry "some, very little, or none," or responded "I don't know," respondents who worried "a lot" about being exposed to coal ash did more exposure-reducing behaviors outdoors (p < .001) and indoors (p = .01). For people living near environmental hazards, reducing exposure is a priority. Although challenging because of the chronic nature of exposure, some behaviors can be useful in reducing exposure, such as wearing a particle-specific respirator when mowing the lawn. Communities at risk for chronic exposure to environmental toxins could benefit from education about exposure-reducing behaviors. PMID- 26481968 TI - Mosaic gene network modelling identified new regulatory mechanisms in HCV infection. AB - Modelling of gene networks is widely used in systems biology to study the functioning of complex biological systems. Most of the existing mathematical modelling techniques are useful for analysis of well-studied biological processes, for which information on rates of reactions is available. However, complex biological processes such as those determining the phenotypic traits of organisms or pathological disease processes, including pathogen-host interactions, involve complicated cross-talk between interacting networks. Furthermore, the intrinsic details of the interactions between these networks are often missing. In this study, we developed an approach, which we call mosaic network modelling, that allows the combination of independent mathematical models of gene regulatory networks and, thereby, description of complex biological systems. The advantage of this approach is that it allows us to generate the integrated model despite the fact that information on molecular interactions between parts of the model (so-called mosaic fragments) might be missing. To generate a mosaic mathematical model, we used control theory and mathematical models, written in the form of a system of ordinary differential equations (ODEs). In the present study, we investigated the efficiency of this method in modelling the dynamics of more than 10,000 simulated mosaic regulatory networks consisting of two pieces. Analysis revealed that this approach was highly efficient, as the mean deviation of the dynamics of mosaic network elements from the behaviour of the initial parts of the model was less than 10%. It turned out that for construction of the control functional, data on perturbation of one or two vertices of the mosaic piece are sufficient. Further, we used the developed method to construct a mosaic gene regulatory network including hepatitis C virus (HCV) as the first piece and the tumour necrosis factor (TNF)-induced apoptosis and NF-kappaB induction pathways as the second piece. Thus, the mosaic model integrates the model of HCV subgenomic replicon replication with the model of TNF induced apoptosis and NF-kappaB induction. Analysis of the mosaic model revealed that the regulation of TNF-induced signaling by the HCV network is crucially dependent on the RIP1, TRADD, TRAF2, FADD, IKK, IkappaBalpha, c-FLIP, and BAR genes. Overall, the developed mosaic gene network modelling approach demonstrated good predictive power and allowed the prediction of new regulatory nodes in HCV action on apoptosis and the NF-kappaB pathway. Those theoretical predictions could be a basis for further experimental verification. PMID- 26481969 TI - Flagellar motility of the pathogenic spirochetes. AB - Bacterial pathogens are often classified by their toxicity and invasiveness. The invasiveness of a given bacterium is determined by how capable the bacterium is at invading a broad range of tissues in its host. Of mammalian pathogens, some of the most invasive come from a group of bacteria known as the spirochetes, which cause diseases, such as syphilis, Lyme disease, relapsing fever and leptospirosis. Most of the spirochetes are characterized by their distinct shapes and unique motility. They are long, thin bacteria that can be shaped like flat waves, helices, or have more irregular morphologies. Like many other bacteria, the spirochetes use long, helical appendages known as flagella to move; however, the spirochetes enclose their flagella in the periplasm, the narrow space between the inner and outer membranes. Rotation of the flagella in the periplasm causes the entire cell body to rotate and/or undulate. These deformations of the bacterium produce the force that drives the motility of these organisms, and it is this unique motility that likely allows these bacteria to be highly invasive in mammals. This review will describe the current state of knowledge on the motility and biophysics of these organisms and provide evidence on how this knowledge can inform our understanding of spirochetal diseases. PMID- 26481970 TI - Feedback regulation in cell signalling: Lessons for cancer therapeutics. AB - The notion of feedback is fundamental for understanding signal transduction networks. Feedback loops attenuate or amplify signals, change the network dynamics and modify the input-output relationships between the signal and the target. Negative feedback provides robustness to noise and adaptation to perturbations, but as a double-edged sword can prevent effective pathway inhibition by a drug. Positive feedback brings about switch-like network responses and can convert analog input signals into digital outputs, triggering cell fate decisions and phenotypic changes. We show how a multitude of protein protein interactions creates hidden feedback loops in signal transduction cascades. Drug treatments that interfere with feedback regulation can cause unexpected adverse effects. Combinatorial molecular interactions generated by pathway crosstalk and feedback loops often bypass the block caused by targeted therapies against oncogenic mutated kinases. We discuss mechanisms of drug resistance caused by network adaptations and suggest that development of effective drug combinations requires understanding of how feedback loops modulate drug responses. PMID- 26481972 TI - Ovarian development and disease: The known and the unexpected. AB - The idea that the female sexual development happens by default was born in the middle of the last century after Jost carried out his innovative experiments to study the bases of differentiation of the reproductive tract, and found that the female reproductive tract develops even in the absence of any gonad. The term default (passive) attributed to the whole female developmental pathway therefore established itself, even if it was not originally so intended. However, recent developments have demonstrated that ovarian development is an active process. WNT4, one of a few factors with a demonstrated function in the ovarian determination pathway, has been found to be involved in sexual differentiation by suppressing male sexual differentiation, promoting Mullerian ducts differentiation and maintaining oocyte health. WNT4 expression in the ovary seems to be regulated by R-spondin 1 (RSPO1), a thrombospondin family member protein. The role and interactions of WNT4, RSPO1 and other factors, such as FOXL2 as well as the possible role of chromatin modifiers such as the polycomb protein CBX2 in ovarian development and function will be discussed. PMID- 26481971 TI - Mediators of inflammation and bone remodeling in rheumatic disease. AB - Remodeling of bone is a continuous process that occurs throughout life. Under normal physiologic conditions, bone-resorbing osteoclasts and bone-forming osteoblasts are tightly coupled and regulated to ensure proper balance, such that there is no net change in bone mass. However, inflammation perturbs normal bone homeostasis. The impact of inflammation on bone is dependent upon the anatomic site affected, cell types, factors and cytokines present in the local microenvironment, and local mechanical forces. Cytokines are central to the pathogenesis of inflammation-induced bone loss and contribute to the uncoupling of osteoclast-mediated bone resorption and osteoblast-mediated bone formation, thereby disrupting normal remodeling. In this review, we will discuss the effects of cytokines on bone in two settings, rheumatoid arthritis and spondyloarthritis, a disease category that includes ankylosing spondylitis, psoriatic arthritis, reactive arthritis, inflammatory bowel disease, and juvenile onset spondyloarthropathy. The outcome for bone in these disease settings is quite different, and an understanding of the pathogenic mechanisms leading to the net impact on bone has been essential in developing new therapeutic approaches to bone health in these diseases. PMID- 26481974 TI - Defying death: Cellular survival strategies following plasmalemmal injury by bacterial toxins. AB - The perforation of the plasmalemma by pore-forming toxins causes an influx of Ca(2+) and an efflux of cytoplasmic constituents. In order to ensure survival, the cell needs to identify, plug and remove lesions from its membrane. Quarantined by membrane folds and isolated by membrane fusion, the pores are removed from the plasmalemma and expelled into the extracellular space. Outward vesiculation and microparticle shedding seem to be the strategies of choice to eliminate toxin-perforated membrane regions from the plasmalemma of host cells. Depending on the cell type and the nature of injury, the membrane lesion can also be taken up by endocytosis and degraded internally. Host cells make excellent use of an initial, moderate rise in intracellular [Ca(2+)], which triggers containment of the toxin-inflicted damage and resealing of the damaged plasmalemma. Additional Ca(2+)-dependent defensive cellular actions range from the release of effector molecules in order to warn neighbouring cells, to the activation of caspases for the initiation of apoptosis in order to eliminate heavily damaged, dysregulated cells. Injury to the plasmalemma by bacterial toxins can be prevented by the early sequestration of bacterial toxins. Artificial liposomes can act as a decoy system preferentially binding and neutralizing bacterial toxins. PMID- 26481973 TI - Cytokinesis: Robust cell shape regulation. AB - Cytokinesis, the final step of cell division, is a great example of robust cell shape regulation. A wide variety of cells ranging from the unicellular Dictyostelium to human cells in tissues proceed through highly similar, stereotypical cell shape changes during cell division. Typically, cells first round up forming a cleavage furrow in the middle, which constricts resulting in the formation of two daughter cells. Tight control of cytokinesis is essential for proper segregation of genetic and cellular materials, and its failure is deleterious to cell viability. Thus, biological systems have developed elaborate mechanisms to ensure high fidelity of cytokinesis, including the existence of multiple biochemical and mechanical pathways regulated through feedback. In this review, we focus on the built-in redundancy of the cytoskeletal machinery that allows cells to divide successfully in a variety of biological and mechanical contexts. Using Dictyostelium cytokinesis as an example, we demonstrate that the crosstalk between biochemical and mechanical signaling through feedback ensures correct assembly and function of the cell division machinery. PMID- 26481975 TI - Odontogenic sinusitis, oro-antral fistula and surgical repair by Bichat's fat pad: Literature review. AB - Odontogenic sinusitis accounts for 10-12% of maxillary sinusitis. It occurs due to an interruption of the mucoperiosteum in response to a series of conditions, most frequently the extraction of a superior tooth. Its treatment has two bases: treating the infection and managing the oroantral fistula that perpetuates the infection. Communications smaller than 5mm can resolve spontaneously; bigger ones must be closed by a flap. Bichat's fat pad flap was first used in 1977 to close an oroantral fistula. It is a pedicled flap that has been shown to be successful, with advantages that make it the best option in oroantral fistula treatment. Its location allows easy access, minimum dissection, great versatility, good mobility, good blood supply, low rate of complications, no morbidity in the donor site, low risk of infection, shortened surgical time and fast cover by epithelium, and it leaves no visible scar, amongst other benefits. That is why we encourage the use of this technique and choose it as the best option for management of our patients. PMID- 26481976 TI - Clinical Image In Gastroenterology: Epiploic appendagitis in an 80-year-old woman, an uncommon cause of acute abdominal pain in the elderly. PMID- 26481977 TI - Clinical Image In Gastroenterology: Disseminated gastrointestinal strongyloidiasis. PMID- 26481978 TI - The effect of a muscarinic receptor 1 gene variant on grey matter volume in schizophrenia. AB - Previous research has demonstrated that individuals with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism (rs2067477) within the cholinergic muscarinic M1 receptor (CHRM1) perform less well on the Wisconsin Card Sorting Test (WCST) than those who are heterozygous. This study sought to determine whether variation in the rs2067477 genotype was associated with differential changes in brain structure. Data from 227 patients with established schizophrenia or schizoaffective disorder were obtained from the Australian Schizophrenia Research Bank. Whole-brain voxel-based morphometry was performed to compare regional grey matter volume (GMV) between the 267C/C (N=191) and 267C/A (N=36) groups. Secondary analyses tested for an effect of genotype on cognition (the WCST was not available). Individuals who were homozygous (267C/C) demonstrated significantly reduced GMV in the right precentral gyrus compared to those who were heterozygous (267C/A). These preliminary results suggest that the rs2067477 genotype is associated with brain structure in the right precentral gyrus in individuals with schizophrenia/schizoaffective disorder. Future studies are required to replicate these results and directly link the volumetric reductions with specific cognitive processes. PMID- 26481980 TI - GP says "pointless" tendering of his practice caused staff to leave. PMID- 26481979 TI - Intact error monitoring in combat Veterans with post-traumatic stress disorder. AB - The error-related negativity (ERN) is a neuroelectric signature of performance monitoring during speeded response time tasks. Previous studies indicate that individuals with anxiety disorders show ERN enhancements that correlate with the degree of clinical symptomology. Less is known about the error monitoring system in post-traumatic stress disorder (PTSD). PTSD is characterized by impairments in the regulation of fear and other emotional responses, as well as deficits in maintaining cognitive control. Here, combat Veterans with PTSD were compared to control Veterans in two different versions of the flanker task (n=13 or 14 per group). Replicating and extending previous findings, PTSD patients showed an intact ERN in both experiments. In addition, task performance and error compensation behavior were intact. Finally, ERN amplitude showed no relationship with self-reported PTSD, depression, or post-concussive symptoms. These results suggest that error monitoring represents a relative strength in PTSD that can dissociate from cognitive control functions that are impaired, such as response inhibition and sustained attention. A healthy awareness of errors in external actions could be leveraged to improve interoceptive awareness of emotional state. The results could have positive implications for PTSD treatments that rely on self-monitoring abilities, such as neurofeedback and mindfulness training. PMID- 26481981 TI - Bedside Optic Nerve Sheath Diameter Assessment in the Identification of Increased Intracranial Pressure in Suspected Idiopathic Intracranial Hypertension. AB - OBJECTIVE: We determined whether the bedside assessment of the optic nerve sheath diameter could identify elevated intracranial pressure in individuals with suspected idiopathic intracranial hypertension. METHODS: This was a single center, prospective, rater-blinded study performed in a freestanding pediatric teaching hospital. Patients aged 12 to 18 years scheduled for an elective lumbar puncture with the suspicion of idiopathic intracranial hypertension were eligible to participate. Optic nerve sheath diameter was measured via ultrasonography before performing a sedated lumbar puncture for measuring cerebrospinal fluid opening pressure. Abnormal measurements were predefined as optic nerve sheath diameter >=4.5 mm and a cerebrospinal fluid opening pressure greater than 20 cmH2O. RESULTS: Thirteen patients participated in the study, 10 of whom had elevated intracranial pressure. Optic nerve sheath diameter was able to predict or rule out elevated intracranial pressure in all patients. CONCLUSIONS: Noninvasive assessment of the optic nerve sheath diameter could help to identify patients with elevated intracranial pressure when idiopathic intracranial hypertension is suspected. PMID- 26481982 TI - Recurrent Optic Neuritis in Children. PMID- 26481983 TI - Symptomatic diffuse adenomyomatosis of the gallbladder with subserosal inflammatory sclerolipomatosis: Imaging findings. PMID- 26481984 TI - ISIDORE, a probe for in situ trace metal speciation based on Donnan membrane technique with related electrochemical detection part 1: Equilibrium measurements. AB - This work presents the development of a new probe (ISIDORE probe) based on the hyphenation of a Donnan Membrane Technique device (DMT) to a screen-printed electrode through a flow-cell to determine the free zinc, cadmium and lead ion concentration in natural samples, such as a freshwater river. The probe displays many advantages namely: (i) the detection can be performed on-site, which avoids all problems inherent to sampling, transport and storage; (ii) the low volume of the acceptor solution implies shorter equilibration times; (ii) the electrochemical detection system allows monitoring the free ion concentration in the acceptor solution without sampling. PMID- 26481985 TI - A critical review on photochemical conversions in flow analysis. AB - Photochemical conversions are cost-effective and environmental friendly processes that require mild experimental conditions and avoid generation of highly acidic wastes. Treated samples are then compatible with most of the analytical techniques. These characteristics become more relevant when the photoconversions are accomplished to flow analysis, thus allowing exploitation of incomplete reactions, the effective use of the photogenerated unstable radicals and in-line sample treatment. Decreasing of reagent consumption and waste generation, sample processing in a closed environment, and improvement of efficiency of the photochemical processes are other inherent advantages. These aspects are critically reviewed in this article, which emphasizes applications to fractionation and speciation analysis, photo-induced luminescence, miniaturization, and in-line waste treatment. Design of flow-through photochemical cells, use of auxiliary reagents in homogeneous and heterogeneous media, and configurations of flow manifolds are also discussed. PMID- 26481986 TI - Hyperspectral image analysis. A tutorial. AB - This tutorial aims at providing guidelines and practical tools to assist with the analysis of hyperspectral images. Topics like hyperspectral image acquisition, image pre-processing, multivariate exploratory analysis, hyperspectral image resolution, classification and final digital image processing will be exposed, and some guidelines given and discussed. Due to the broad character of current applications and the vast number of multivariate methods available, this paper has focused on an industrial chemical framework to explain, in a step-wise manner, how to develop a classification methodology to differentiate between several types of plastics by using Near infrared hyperspectral imaging and Partial Least Squares - Discriminant Analysis. Thus, the reader is guided through every single step and oriented in order to adapt those strategies to the user's case. PMID- 26481987 TI - Water revealed as molecular mirror when measuring low concentrations of sugar with near infrared light. AB - Near infrared spectroscopy is an overtone spectroscopy regarded as a quick and non-destructive method that provides analytical solutions for components that represent approximately 1% or more of the total mass of the investigated composite samples. Aquaphotomics offers the possibility for disentanglement of information remaining hidden in the spectra when conventional data evaluation methods are used, since this concept utilizes changes of the water structure induced by the measured solute as specific molecular vibrations at water bands. Here, near infrared technique and aquaphotomics are applied for non-destructive identification and quantification of mono- and di-saccharide solutes at 100-0.02 mM concentration that is accepted as unachievable with near infrared spectroscopy. The results presented in this study support the aquaphotomics' water molecular mirror concept that explores spectral changes related to water molecular rearrangements caused by minute changes of the solutes in the aqueous systems. The method provides quick and accurate alternative for classical analytical measurements of saccharides even at millimolar concentration levels. PMID- 26481988 TI - Calibration graphs in isotope dilution mass spectrometry. AB - Isotope-based quantitation is routinely employed in chemical measurements. Whereas most analysts seek for methods with linear theoretical response functions, a unique feature that distinguishes isotope dilution from many other analytical methods is the inherent possibility for a nonlinear theoretical response curve. Most implementations of isotope dilution calibration today either eliminate the nonlinearity by employing internal standards with markedly different molecular weight or they employ empirical polynomial fits. Here we show that the exact curvature of any isotope dilution curve can be obtained from three parameter rational function, y = f(q) = (a0 + a1q)/(1 + a2q), known as the Pade[1,1] approximant. The use of this function allows eliminating an unnecessary source of error in isotope dilution analysis when faced with nonlinear calibration curves. In addition, fitting with Pade model can be done using linear least squares. PMID- 26481989 TI - Molecularly imprinted ultrathin graphitic carbon nitride nanosheets-Based electrochemiluminescence sensing probe for sensitive detection of perfluorooctanoic acid. AB - Driven by the urgent demand for the determination of low level perfluorooctanoic acid (PFOA) present in environment, a novel electrochemiluminescence (ECL) sensor has been first developed for the detection of PFOA using the molecularly imprinted polypyrrole modified two-dimensional ultrathin g-C3N4 (utg-C3N4) nanosheets as a cathodic ECL emitter with S2O8(2-) as coreactant. The prepared molecularly imprinted polymer (MIP) functionalized utg-C3N4 nanosheets (MIP@utg C3N4) exhibit a stable and significantly amplified ECL signal. It is found that the targets of PFOA could be efficiently oxidized by the electro-generated strong oxidants of SO4(-) (from the reduction of coreactant S2O8(2-)), thus leading to a low yield of the excited utg-C3N4 (g-C3N4*) and finally a decrease in ECL signal. Based on this, a highly sensitive and selective MIP@utg-C3N4-based signal-off ECL sensor is developed for sensing PFOA. Such a newly designed ECL sensor exhibits highly linear over the PFOA concentration in two ranges, from 0.02 to 40.0 ng mL( 1) and 50.0-400.0 ng mL(-1). The detection limit (S/N = 3) is estimated to be 0.01 ng mL(-1) (i.e. 0.01 ppb), comparable to the results obtained by using well established liquid chromatography-tandem mass spectrometry (LC-MS/MS). Toward practical applications, this low-cost and sensitive assay was successfully applied to measure PFOA in real water samples, showing fine applicability for the detection of PFOA in real samples. PMID- 26481990 TI - Fluorescent determination of graphene quantum dots in water samples. AB - This work presents a simple, fast and sensitive method for the preconcentration and quantification of graphene quantum dots (GQDs) in aqueous samples. GQDs are considered an object of analysis (analyte) not an analytical tool which is the most frequent situation in Analytical Nanoscience and Nanotechnology. This approach is based on the preconcentration of graphene quantum dots on an anion exchange sorbent by solid phase extraction and their subsequent elution prior fluorimetric analysis of the solution containing graphene quantum dots. Parameters of the extraction procedure such as sample volume, type of solvent, sample pH, sample flow rate and elution conditions were investigated in order to achieve extraction efficiency. The limits of detection and quantification were 7.5 MUg L(-1) and 25 MUg L(-1), respectively. The precision for 200 MUg L(-1), expressed as %RSD, was 2.8%. Recoveries percentages between 86.9 and 103.9% were obtained for two different concentration levels. Interferences from other nanoparticles were studied and no significant changes were observed at the concentration levels tested. Consequently, the optimized procedure has great potential to be applied to the determination of graphene quantum dots at trace levels in drinking and environmental waters. PMID- 26481991 TI - The role of proton mobility in determining the energy-resolved vibrational activation/dissociation channels of N-glycopeptide ions. AB - Site-specific glycoproteomic analysis largely hinges on the use of tandem mass spectrometry (MS/MS) to identify glycopeptides. Experiments of this type are usually aimed at drawing connections between individual oligosaccharide structures and their specific sites of attachment to the polypeptide chain. These determinations inherently require ion dissociation methods capable of interrogating both the monosaccharide and amino acid connectivity of the glycopeptide. Collision-induced dissociation (CID) shows potential to satisfy this requirement, as the vibrational activation/dissociation of protonated N glycopeptides has been observed to access cleavage of either glycosidic bonds of the glycan or amide bonds of the peptide in an energy-resolved manner. Nevertheless, the relative energy requirement for these fragmentation pathways varies considerably among analytes. This research addresses the influence of proton mobility on the vibrational energy necessary to achieve either glycan or peptide cleavage in a collection of protonated N-glycopeptide ions. While greater proton mobility of the precursor ion was found to correlate with lower energy requirements for precursor ion depletion and appearance of glycosidic fragments, the vibrational energy deposition necessary for appearance of peptide backbone fragments showed no relation to the precursor ion proton mobility. These results are consistent with observations suggesting that peptide fragments arise from an intermediate fragment which is generally of lower proton mobility than the precursor ion. Such findings have potential to facilitate the rational selection of CID conditions which are best suited to provide either glycan or peptide cleavage products in MS/MS based N-glycoproteomic analysis. PMID- 26481992 TI - Detection of cysteine- and lysine-based protein adductions by reactive metabolites of 2,5-dimethylfuran. AB - Many furan-containing compounds are known to be toxic and/or carcinogenic. Metabolic activation of toxic furans to cis-enediones (cis-enedials or gamma ketoenals) is generally considered as the initial step towards the processes of their toxicities. Sequential modification of key proteins by the electrophilic reactive intermediates is suggested to be an important mechanism of the toxic actions. In the present study, we developed a novel and simple analytical platform to detect protein modification resulting from metabolic activation of model compound 2,5-dimethylfuran (DMF). 4-Bromobenzylamine and 4 bromobenzylmercaptan were employed to trap protein adductions at cysteine and lysine residues, respectively. The resulting protein samples were proteolytically digested by chymotrypsin and Pronase E, followed by LC-MS/MS analysis. Modifications of cysteine and lysine residues of proteins were observed in microsomal incubations and animals after exposure to DMF. In conclusion, the approach established has been proven highly selective and reliable. This advance allows us not only to detect the protein adductions but also to define the structural identities of amino acid residues modified. This technique provides a unique platform to assess protein modifications arising from metabolic activation of potentially harmful furan-containing compounds. Hepatic protein adductions were found to be proportional to the hepatotoxicity of DMF. PMID- 26481993 TI - Matrix-assisted laser desorption/ionization mass spectrometry analysis of glycans with co-derivatization of asparaginyl-oligosaccharides. AB - As one of the most prevalent and complex post-translational modifications in biological systems, proteins glycosylation has drawn considerable attention in recent decades. Dissociation of the carbohydrates from glycoproteins may be the prerequisite step of glycomics experiments, which commonly performed by specific proteolysis. In this study, an alternative strategy was reported with nonspecific proteolysis in coupling with co-derivatization of TMPP-Ac and methylamidation for glycan moieties analysis by MALDI-MS. With the co-derivatization, a permanent positive charge was introduced to the Asn-glycans and the carboxylic groups were neutralized by methylamidation simultaneously. As a result, approximately 20 and 50-fold enhancement in the detection sensitivity was achieved for asialo-Asn and disialo-Asn respectively in comparison to their native counterparts. Ultimately, this developed strategy was successfully validated using three model glycoproteins, including ribonuclease B, ovalbumin and transferrin. PMID- 26481994 TI - Planar monolithic porous polymer layers functionalized with gold nanoparticles as large-area substrates for sensitive surface-enhanced Raman scattering sensing of bacteria. AB - For the first time, large-area surface-enhanced Raman scattering sensing active substrates using porous polymer monolithic layers have been successfully prepared. Our approach includes a simple photoinitiated polymerization process using glycidyl methacrylate and ethylene dimethacrylate in a glass mold, followed by a chemical reaction of the epoxy functionalities leading to thiols, and the attachment of preformed gold nanoparticles. We demonstrated that this very simple process produced uniform and reproducible large area surfaces that significantly enhance sensitivity of Raman spectroscopy. Experiments were also carried out that confirmed preferential adsorption of living bacteria Escherichia coli from a very dilute solution on the surface of the monolithic layer, and immediate detection of the captured microorganisms using the SERS spectrum. PMID- 26481995 TI - The nature of the salt error in the Sn(II)-reduced molybdenum blue reaction for determination of dissolved reactive phosphorus in saline waters. AB - Sn(II) is a well-known reductant used in the formation of phosphomolybdenum blue for the determination of dissolved reactive phosphorus (DRP) in waters because it provides rapid and quantitative reduction. However, in saline waters, this method suffers from a salt error which causes a significant decrease in sensitivity. This phenomenon has never been adequately explained in the literature. The Murphy and Riley method, which uses Sb(III) and ascorbic acid for the reduction step, is preferred for DRP determination in saline waters because it is unaffected by salinity, but it exhibits a sensitivity approximately 30% lower than that when Sn(II) is used as the reductant without Cl(-) interference. This study investigates the processes causing the salt error and possible ways of minimizing it, so that the benefits of Sn(II) reduction on the molybdenum blue reaction rate and sensitivity may be exploited in the determination of low levels of DRP in marine and estuarine waters. It has been established that the salt error is caused by the formation of Sn(IV) chloro-complexes which compete with the formation of Sn(IV)-substituted phosphomolybdenum blue, forcing the reaction to proceed via the much slower, less favourable process of direct reduction that occurs in methods using organic reductants such as ascorbic acid. PMID- 26481996 TI - Sensitive and rapid detection of endogenous hydrogen sulfide distributing in different mouse viscera via a two-photon fluorescent probe. AB - Development of efficient methods for detection of endogenous H2S in living cells and tissues is of considerable significance for better understanding the biological and pathological functions of H2S. Two-photon (TP) fluorescent probes are favorable as powerful molecular tools for studying physiological process due to its non-invasiveness, high spatiotemporal resolution and deep-tissues imaging. Up to date, several TP probes for intracellular H2S imaging have been designed, but real-time imaging of endogenous H2S-related biological processes in tissues is hampered due to low sensitivity, long response time and interference from other biothiols. To address this issue, we herein report a novel two-photon fluorescent probe (TPP-H2S) for highly sensitive and fast monitoring and imaging H2S levels in living cells and tissues. In the presence of H2S, it exhibits obviously improved sensitivity (LOD: 0.12 MUM) and fast response time (about 2 min) compared with the reported two-photon H2S probes. With two-photon excitation, TPP-H2S displays high signal-to-noise ratio and sensitivity even no interference in cell growth media. As further application, TPP-H2S is applied for fast imaging of H2S in living cells and different fresh tissues by two-photon confocal microscope. Most importantly we first measured the endogenous H2S level in different viscera by vivisection and found that the distribution of endogenous H2S mostly in brain, liver and lung. The excellent sensing properties of TPP-H2S make it a practically useful tool for further studying biological roles of H2S. PMID- 26481997 TI - Immobilization of Ni-Pd/core-shell nanoparticles through thermal polymerization of acrylamide on glassy carbon electrode for highly stable and sensitive glutamate detection. AB - The preparation of a persistently stable and sensitive biosensor is highly important for practical applications. To improve the stability and sensitivity of glutamate sensors, an electrode modified with glutamate dehydrogenase (GDH)/Ni Pd/core-shell nanoparticles was developed using the thermal polymerization of acrylamide (AM) to immobilize the synthesized Ni-Pd/core-shell nanoparticles onto a glassy carbon electrode (GCE). The modified electrode was characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). Electrochemical data showed that the prepared biosensor had remarkably enhanced electrocatalytic activity toward glutamate. Moreover, superior reproducibility and excellent stability were observed (relative average deviation was 2.96% after continuous use of the same sensor for 60 times, and current responses remained at 94.85% of the initial value after 60 d). The sensor also demonstrated highly sensitive amperometric detection of glutamate with a low limit of detection (0.052 MUM, S/N = 3), high sensitivity (4.768 MUA MUM(-1) cm( 2)), and a wide, useful linear range (0.1-500 MUM). No interference from potential interfering species such as l-cysteine, ascorbic acid, and l-aspartate were noted. The determination of glutamate levels in actual samples achieved good recovery percentages. PMID- 26481998 TI - Assessment of terbium (III) as a luminescent probe for the detection of tuberculosis biomarkers. AB - A detection method for nicotinic acid, a specific metabolite marker of Mycobacterium tuberculosis present in cultures and patients' breath, is studied in complex solutions containing other metabolites and in biological media such as urine, saliva and breath condensate. The method is based on the analysis of the luminescence increase of Tb(3+) complexes in the presence of nicotinic acid due to the energy transfer from the excited ligand to the lanthanide ion. It is shown that other potential markers found in M. tuberculosis culture supernatant, such as methyl phenylacetate, p-methyl anisate, methyl nicotinate and 2-methoxy biphenyl, can interfere with nicotinic acid via a competitive absorption of the excitation photons. A new strategy to circumvent these interferences is proposed with an upstream trapping of volatile markers preceding the detection of nicotinic acid in the liquid phase via the luminescence of Tb(3+) complexes. The cost of the method is evaluated and compared with the Xpert MTB/RIF test endorsed by the World Health Organization. PMID- 26481999 TI - Paper-based scanometric assay for lead ion detection using DNAzyme. AB - A facile and simple paper-based scanometric assay was developed to detect Pb(2+) using GR5-DNAzyme. Magnetic beads (MBs) and gold nanoparticles (AuNPs) were used as a signal collector and a signal indicator, respectively. They were linked together by GR5-DNAzyme, comprising an enzyme and a substrate strand pairing up with each other. In the presence of Pb(2+), the substrate strand is cut into two pieces, resulting in the disassembly of AuNPs from the MBs. These AuNPs were spotted on predefined areas on a chromatography paper, where signal is amplified through silver reduction. This sensing platform exhibits high sensitivity and selectivity toward Pb(2+), giving a detection limit of 0.3 nM and a linear fitting range from 0.1 to 1000 nM. Testing of this biosensor in river water and synthetic urine samples also showed satisfying results. Besides offering simultaneous and multi-sample analysis, this paper-based sensing platform presented here could be potentially applied and served as a general platform for on-site, naked eyes, and low-cost monitoring of other heavy metal ions in environmental and body fluid samples. PMID- 26482000 TI - Lanthanide complexes as luminogenic probes to measure sulfide levels in industrial samples. AB - A series of lanthanide-based, azide-appended complexes were investigated as hydrogen sulfide-sensitive probes. Europium complex 1 and Tb complex 3 both displayed a sulfide-dependent increase in luminescence, while Tb complex 2 displayed a decrease in luminescence upon exposure to NaHS. The utility of the complexes for monitoring sulfide levels in industrial oil and water samples was investigated. Complex 3 provided a sensitive measure of sulfide levels in petrochemical water samples (detection limit ~ 250 nM), while complex 1 was capable of monitoring MUM levels of sulfide in partially refined crude oil. PMID- 26482001 TI - Miniaturised medium pressure capillary liquid chromatography system with flexible open platform design using off-the-shelf microfluidic components. AB - Trends towards portable analytical instrumentation of the last decades have not been equally reflected in developments of portable liquid chromatography (LC) instrumentation for rapid on-site measurements. A miniaturised medium pressure capillary LC (MPLC) system with gradient elution capability has been designed based on a flexible modular microfluidic system using primarily off-the-shelf low cost components to ensure wide accessibility to other analysts. The microfluidic platform was assembled on a breadboard and contained microsyringe pumps and switch valves, complemented with an injection valve and on-capillary detectors, all controlled by a PC. Four miniaturised microsyringe pumps, with 5, 20 and 100 MUL syringe volume options, formed the basis of the pumping system. Two pairs of pumps were used for each mobile phase to create gradient elution capability. The two microsyringe pumps in each pairs were linked by two electrically operated microfluidic switching valves and both pairs of pumps were connected through a zero void volume cross-connector, thus providing a low hold-up volume for gradient formation. Sample was injected by a 20 nL nano-LC sampling valve, directly connected to a 18 cm long 100 MUm i.d. Chromolith CapRod RP-18 monolithic capillary column. On-capillary LED-based UV-vis photometric detection was conducted through a piece of equal diameter fused silica capillary connected after the column. The performance of the portable LC system was evaluated theoretically and experimentally, including the maximum operating pressure, gradient mixing performance, and the performance of the detectors. The 5 MUL microsyringe pump offered the best performance, with typical maximum operating pressures up to 11.4 +/- 0.4 MPa (water) and gradient pumping repeatability of between 4 and 9% for gradients between 0.10% s(-1) and 0.33% s(-1). Test analytes of charged and uncharged dyes and pharmaceuticals of varying hydrophobicity showed typical RSD values of 0.7-1.4% and 3.3-4.8% in isocratic mode and 1.2-4.6% and 3.2-6.4% in gradient mode, respectively for retention time and peak area repeatability. PMID- 26482002 TI - Novel application of liquid chromatography/mass spectrometry for the characterization of drying oils in art: Elucidation on the composition of original paint materials used by Edvard Munch (1863-1944). AB - Modern oil paints, introduced at the beginning of the 20th century, differ from those classically used in antiquity in their chemical and compositional features. The main ingredients were still traditional drying oils, often used in mixtures with less expensive oils and added with several classes of additives. Consequently, detailed lipid profiling, together with the study of lipid degradation processes, is essential for the knowledge and the conservation of paint materials used in modern and contemporary art. A multi-analytical approach based on mass spectrometry was used for the study of original paint materials from Munch's atelier, owned by the Munch Museum in Oslo. The results obtained in the analysis of paint tubes were compared with those obtained by characterizing a paint sample collected from one of the artist's sketches for the decoration of the Festival Hall of the University of Oslo (1909-1916). Py-GC/MS was used as screening method to evaluate the presence of lipid, proteic or polysaccaridic materials. GC/MS after hydrolysis and derivatization allowed us to determine the fatty acid profile of the paint tubes, and to evaluate the molecular changes associated to curing and ageing. The determination of the fatty acid profile is not conclusive for the characterization of complex mixtures of lipid materials, thus the characterization of the triglyceride profiles was performed using an analytical procedure based on HPLC-ESI-Q-ToF. This paper describes the first application of HPLC-ESI-Q-ToF for the acquisition of the triglyceride profile in a modern paint sample, showing the potentialities of liquid chromatography in the field of lipid characterization in modern paint materials. Moreover, our results highlighted that the application of this approach can contribute to address dating, authenticity and conservation issues relative to modern and contemporary artworks. PMID- 26482003 TI - Symptoms and self-care strategies during and six months after radiotherapy for prostate cancer - Scoping the perspectives of patients, professionals and literature. AB - PURPOSE: Under-diagnosed and uncontrolled symptoms in patients with prostate cancer during radiotherapy can have a negative impact on the individual's quality of life. An opportunity for patients to report their symptoms systematically, communicate these symptoms to cancer nurses and to receive self-care advice via an application in an Information and Communication Technology-platform could overcome this risk. The content in the application must precisely capture symptoms that are significant to both patients and health care professionals. Therefore, the aim of the study was to map and describe symptoms and self-care strategies identified by patients with prostate cancer undergoing radiotherapy, by health care professionals caring for these patients, and in the literature. METHODS: The study combines data from interviews with patients (n = 8) and health care professionals (n = 10) and a scoping review of the literature (n = 26) focusing on the period during and up to 6 months after radiotherapy. RESULTS: There was a concordance between the patients, health care professionals, and the literature on symptoms during and after radiotherapy. Urinary symptoms, bowel problems, pain, sexual problems, fatigue, anxiety, depression, cognitive impairment and irregular symptoms were commonly described during the initial treatment period. Self-care strategies were rarely described in all three of the sources. CONCLUSIONS: The results show which symptoms to regularly assess using an Information and Communication Technology-platform for patients with newly diagnosed prostate cancer during radiotherapy. The next step is to evaluate the efficacy of using the platform and the accuracy of the selected symptoms and self care advice included in a smartphone application. PMID- 26482004 TI - A home-based, nurse-led health program for postoperative patients with early stage cervical cancer: A randomized controlled trial. AB - PURPOSE: To investigate the effect of a home-based, nurse-led health program on quality of life and family function for postoperative patients with early-stage cervical cancer. METHOD: 226 cervical cancer patients, from two hospitals between December 2012 and April 2014, were randomly divided into intervention and control groups. Patients in the intervention group received an individual home-based, nurse-led health program (family-care team provision, physiological rehabilitation, emotion-release management, informal social support system, and follow-up monitoring), in addition to conventional nursing education. Patients in the control group only received conventional nursing education. The Functional Assessment Cancer Therapy-Cervix, Female Sexual Function Index, and the Family Adaptability and Cohesion Scale were used for assessment before and after the intervention. RESULTS: After the intervention, significant improvements were found for the quality of life total scores (t=-7.650, p=0.000), sexual function scores (t=-6.465, p=0.000), cohesion scores (t=-8.417, p=0.001) and adaptability scores (t=-10.735, p=0.000) in the intervention group. Moreover, proportions of family types were also improved (chi2 = 17.77, p=0.000). However, for the control group, no significant differences were found except for a decrease in sexual function scores (t = -4.035, p=0.000). Significant differences in change scores between groups were also found for quality of life (F=41.980, p=0.000), Sexual function (F=37.380, p=0.000), cohesion (F=15.268, p=0.000) and adaptability (F=16.998, p=0.000). CONCLUSION: A home-based, nurse-led health promotion program improves the quality of life, sexual function and family function in postoperative patients with early-stage cervical cancer. PMID- 26482005 TI - Effects of random rewiring on the degree correlation of scale-free networks. AB - Random rewiring is used to generate null networks for the purpose of analyzing the topological properties of scale-free networks, yet the effects of random rewiring on the degree correlation are subject to contradicting interpretations in the literature. We comprehensively analyze the degree correlation of randomly rewired scale-free networks and show that random rewiring increases disassortativity by reducing the average degree of the nearest neighbors of high degree nodes. The effect can be captured by the measures of the degree correlation that consider all links in the network, but not by analogous measures that consider only links between degree peers, hence the potential for contradicting interpretations. We furthermore find that random and directional rewiring affect the topology of a scale-free network differently, even if the degree correlation of the rewired networks is the same. Consequently, the network dynamics is changed, which is proven here by means of the biased random walk. PMID- 26482006 TI - Molecular characterization and expression profile of the melatonin receptor MT1 in the ovary of Tianzhu white yak (Bos grunniens). AB - Melatonin plays crucial roles in a wide range of ovarian physiological functions via the melatonin receptors (MRs). Structure and function of MRs have been well studied in sheep, cattle, and humans, but little information exists on the genetic characterization and function of these receptors in the ovary of the white yak. In the present study, the melatonin receptor MT1 was cloned by RT-PCR in the ovary of white yak; the MT1 cDNA fragment obtained (843bp) comprised an open reading frame (827bp) encoding a protein containing 275 residues, characterized by seven transmembrane regions and an NRY motif, two distinct amino acid replacements were found. The white yak MT1 had a 83.9-98.6% protein sequence identity with that of nine other mammals. Using RT-PCR, the expression levels of MT1, MT2, and LHR in the ovary of pregnant and non-pregnant white yaks were compared, revealing higher levels of all genes in pregnant yaks: 3.83-fold increase for MT1 (P<0.05), 1.39-fold increase for MT2, and 15.32-fold increase for LHR (P<0.05). The distribution of MT1 in yak ovaries was observed using immunohistochemistry on paraffin embedded ovarian sections: MT1 was mainly present on primordial follicles (PF), granulosa cells (GCs), oocytes, and corpus luteum (CL) cells; MT1 expression showed an increasing tendency from PF to GCs to oocytes and to large CL cells. It is suggested that melatonin and MT1 are associated with the corpus luteum function of pregnancy maintenance and follicular development during oocyte maturation in the white yak. PMID- 26482007 TI - Surgical anatomy and pathology of the middle ear. AB - Middle ear surgery is strongly influenced by anatomical and functional characteristics of the middle ear. The complex anatomy means a challenge for the otosurgeon who moves between preservation or improvement of highly important functions (hearing, balance, facial motion) and eradication of diseases. Of these, perforations of the tympanic membrane, chronic otitis media, tympanosclerosis and cholesteatoma are encountered most often in clinical practice. Modern techniques for reconstruction of the ossicular chain aim for best possible hearing improvement using delicate alloplastic titanium prostheses, but a number of prosthesis-unrelated factors work against this intent. Surgery is always individualized to the case and there is no one-fits-all strategy. Above all, both middle ear diseases and surgery can be associated with a number of complications; the most important ones being hearing deterioration or deafness, dizziness, facial palsy and life-threatening intracranial complications. To minimize risks, a solid knowledge of and respect for neurootologic structures is essential for an otosurgeon who must train him- or herself intensively on temporal bones before performing surgery on a patient. PMID- 26482008 TI - Pretreatment with beta-Boswellic Acid Improves Blood Stasis Induced Endothelial Dysfunction: Role of eNOS Activation. AB - Vascular endothelial cells play an important role in modulating anti-thrombus and maintaining the natural function of vascular by secreting many active substances. beta-boswellic acid (beta-BA) is an active triterpenoid compound from the extract of boswellia serrate. In this study, it is demonstrated that beta-BA ameliorates plasma coagulation parameters, protects endothelium from blood stasis induced injury and prevents blood stasis induced impairment of endothelium-dependent vasodilatation. Moreover, it is found that beta-BA significantly increases nitric oxide (NO) and cyclic guanosine 3', 5'-monophosphate (cGMP) levels in carotid aortas of blood stasis rats. To stimulate blood stasis-like conditions in vitro, human umbilical vein endothelial cells (HUVECs) were exposed to transient oxygen and glucose deprivation (OGD). Treatment of beta-BA significantly increased intracellular NO level. Western blot and immunofluorescence as well as immunohistochemistry reveal that beta-BA increases phosphorylation of enzyme nitric oxide synthase (eNOS) at Ser1177. In addition, beta-BA mediated endothelium-dependent vasodilatation can be markedly blocked by eNOS inhibitor L NAME in blood stasis rats. In OGD treated HUEVCs, the protective effect of beta BA is attenuated by knockdown of eNOS. In conclusion, the above findings provide convincing evidence for the protective effects of beta-BA on blood stasis induced endothelial dysfunction by eNOS signaling pathway. PMID- 26482010 TI - Health care experiences and perceptions among people with and without disabilities. AB - BACKGROUND: Little is known about health care experiences among people with and without disabilities. OBJECTIVE: We sought to explore perceptions of people with and without disabilities related to their health care experiences. METHODS: Nineteen persons with and without disabilities participated in one of four focus groups. Focus groups were conducted in the physical world in Milwaukee, WI and in the virtual world in Second Life((r)) with Virtual Ability, a well-established community designed by and for people with a wide range of disabilities. A grounded theory methodology was employed to analyze focus group data. Inclusion of physical and virtual world focus groups enabled people with a wide range of disabilities to participate. RESULTS: While some participants described instances of receiving good care, many discussed numerous barriers. The main themes that emerged in focus groups among both persons with and without disabilities related to their health care experiences including poor coordination among providers; difficulties with insurance, finances, transportation and facilities; short duration of visits with physicians; inadequate information provision; feelings of being diminished and deflated; and self-advocacy as a tool. Transportation was a major concern for persons with disabilities influencing mobility. Persons with disabilities described particularly poignant experiences wherein they felt invisible or were viewed as incompetent. CONCLUSIONS: Both persons with and without disabilities experienced challenges in obtaining high quality health care. However, persons with disabilities experienced specific challenges often related to their type of disability. Participants stressed the need for improving health care coordination and the importance of self-advocacy. PMID- 26482011 TI - Effect of enamel morphology on nanoscale adhesion forces of streptococcal bacteria : An AFM study. AB - We explore the influence of enamel surface morphology on nanoscale bacterial adhesion forces. Three dimensional morphology characteristics of enamel slices, which were treated with phosphoric acid (for 0 s, 5 s, 10 s, 20 s, and 30 s), were acquired. Adhesion forces of three initial colonizers (Streptococcus oralis, Streptococcus sanguinis, and Streptococcus mitis) and two cariogenic bacterial strains (Streptococcus mutans and Streptococcus sobrinus) with etched enamel surfaces were determined. Comparison of the forces was made by using bacterial probe method under atomic force microscope (AFM) in adhesion buffer. The results showed that enamel morphology was significantly altered by etching treatment. The roughness, peak-to-valley height, and valley-to-valley width of the depth profile, surface area, and volume increased linearly with acid exposure time, and reached the maximum at 30s, respectively. The adhesion forces of different strains increased accordingly with etching time. Adhesion forces of S. oralis, S. mitis, S. mutans, and S. sobrinus reached the maximum values of 0.81 nN, 0.84 nN, 0.73 nN, and 0.64 nN with enamel treated for 20s, respectively, whereas that of S. sanguinis at 10s (1.28nN), and dropped on coarser enamel surfaces. In conclusion, enamel micro-scale morphology may significantly alter the direct adhesion forces of bacteria. And there may be a threshold roughness for bacterial adhesion on enamel surface. PMID- 26482012 TI - Quantifying the Establishment Likelihood of Invasive Alien Species Introductions Through Ports with Application to Honeybees in Australia. AB - The cost of an uncontrolled incursion of invasive alien species (IAS) arising from undetected entry through ports can be substantial, and knowledge of port specific risks is needed to help allocate limited surveillance resources. Quantifying the establishment likelihood of such an incursion requires quantifying the ability of a species to enter, establish, and spread. Estimation of the approach rate of IAS into ports provides a measure of likelihood of entry. Data on the approach rate of IAS are typically sparse, and the combinations of risk factors relating to country of origin and port of arrival diverse. This presents challenges to making formal statistical inference on establishment likelihood. Here we demonstrate how these challenges can be overcome with judicious use of mixed-effects models when estimating the incursion likelihood into Australia of the European (Apis mellifera) and Asian (A. cerana) honeybees, along with the invasive parasites of biosecurity concern they host (e.g., Varroa destructor). Our results demonstrate how skewed the establishment likelihood is, with one-tenth of the ports accounting for 80% or more of the likelihood for both species. These results have been utilized by biosecurity agencies in the allocation of resources to the surveillance of maritime ports. PMID- 26482009 TI - Selector function of MHC I molecules is determined by protein plasticity. AB - The selection of peptides for presentation at the surface of most nucleated cells by major histocompatibility complex class I molecules (MHC I) is crucial to the immune response in vertebrates. However, the mechanisms of the rapid selection of high affinity peptides by MHC I from amongst thousands of mostly low affinity peptides are not well understood. We developed computational systems models encoding distinct mechanistic hypotheses for two molecules, HLA-B*44:02 (B*4402) and HLA-B*44:05 (B*4405), which differ by a single residue yet lie at opposite ends of the spectrum in their intrinsic ability to select high affinity peptides. We used in vivo biochemical data to infer that a conformational intermediate of MHC I is significant for peptide selection. We used molecular dynamics simulations to show that peptide selector function correlates with protein plasticity, and confirmed this experimentally by altering the plasticity of MHC I with a single point mutation, which altered in vivo selector function in a predictable way. Finally, we investigated the mechanisms by which the co-factor tapasin influences MHC I plasticity. We propose that tapasin modulates MHC I plasticity by dynamically coupling the peptide binding region and alpha3 domain of MHC I allosterically, resulting in enhanced peptide selector function. PMID- 26482013 TI - Normal-to-Abnormal NHC Rearrangement of Al(III) , Ga(III) , and In(III) Trialkyl Complexes: Scope, Mechanism, Reactivity Studies, and H2 Activation. AB - The present contribution reports experimental and theoretical mechanistic investigations on a normal-to-abnormal (C2-to-C4-bonded) NHC rearrangement processes occurring with bulky group 13 metal NHC adducts, including the scope of such a reactivity for Al compounds. The sterically congested adducts (nItBu)MMe3 (nItBu=1,3-di-tert-butylimidazol-2-ylidene; M=Al, Ga, In; 1 a-c) readily rearrange to quantitatively afford the corresponding C4-bonded complexes (aItBu)MMe3 (4 a-c), a reaction that may be promoted by THF. Thorough experimental data and DFT calculations were performed on the nNHC-to-aNHC process converting the Al-nNHC (1 a) to its aNHC analogue 4 a. A nItBu/aItBu isomerization is proposed to account for the formation of the thermodynamic product 4 a through reaction of transient aItBu with THF-AlMe3 . The reaction of benzophenone with (nItBu)AlMe3 afforded the zwitterionic species (aItBu)(CPh2 -O AlMe3 ) (6), reflecting the unusual reactivity that such bulky adducts may display. Interestingly, the nItBu/Al(iBu)3 Lewis pair behaves like a frustrated Lewis pair (FLP) since it readily reacts with H2 under mild conditions. This may open the way to future reactivity developments involving commonly used trialkylaluminum precursors. PMID- 26482014 TI - Recurrent lupus nephritis after transplantation: Clinicopathological evaluation with protocol biopsies. AB - AIM: Lupus nephritis (LN) is an important complication of systemic lupus erythematosus (SLE). The aim is to use indication and protocol biopsies to determine clinicopathological findings and outcomes of patients with LN undergoing kidney transplantation (KTx). METHODS: Patients who underwent KTx due to LN were retrospectively analyzed. Recurrent LN (RLN) was diagnosed by transplant kidney biopsy. RESULTS: Among 955 KTx patients, 12 patients with LN as the cause of end-stage renal disease were enrolled. Five patients were male. Mean follow-up time was 63 +/- 34 months. At the last follow-up visit, mean levels of serum creatinine and proteinuria were 137.0 +/- 69.0 umol/L and 0.26 +/- 0.26 g/day, respectively. Eighteen indication and 22 protocol biopsies were performed; 27 biopsies were additionally evaluated by immunofluorescence. In two recipients, subclinical RLN was confirmed by protocol biopsies. Clinical recurrence occurred in four patients. Among patients with RLN, time from diagnosis of LN to KTx was significantly shorter and use of ATG as induction treatment was significantly lower. Graft loss occurred in two recipients who had clinical RLN. Five-year overall graft survival was 85.7%. CONCLUSION: Kidney transplantation is a reasonable option for patients with ESRD secondary to SLE. However, recurrence of LN is common if protocol biopsies are included in post-transplantation surveillance. PMID- 26482015 TI - The need for evidence-based responses to address intimate partner violence perpetration among male substance misusers. PMID- 26482016 TI - Anger, problematic alcohol use, and intimate partner violence victimisation and perpetration. AB - BACKGROUND: Anger and problematic alcohol use have been established as individual risk factors for intimate partner violence (IPV) victimisation and perpetration, but it is unknown how these factors convey risk for IPV perpetration for men and women within the context of mutually violent relationships. HYPOTHESES: Anger and problematic alcohol use were hypothesised to mediate the association between IPV victimisation and perpetration for men and women, with direct and indirect influences from partner variables. METHODS: Heterosexual couples (N = 215) at high-risk for IPV completed questionnaires indexing trait anger, problematic alcohol use and extent of past-year IPV perpetration and victimisation. An actor partner interdependence modelling (APIM) framework was used to evaluate these cross-sectional data for two hypothesised models and one parsimonious alternative. RESULTS: The best-fitting model indicated that IPV victimisation showed the strongest direct effect on physical IPV perpetration for both men and women. For women, but not men, the indirect effect of IPV victimisation on physical IPV perpetration through anger approached significance. For men, but not women, the victimisation-perpetration indirect effect through problematic drinking approached significance. IMPLICATIONS FOR CLINICAL PRACTICE: The results suggest that anger and problem drinking patterns play different yet important roles for men and women in mutually violent relationships. PMID- 26482017 TI - Dyadic violence and readiness to change among male intimate partner violence offenders. AB - BACKGROUND: Although readiness to change is associated with mandated partner violence treatment compliance and subsequent violent behaviour among male offenders (e.g. Scott and Wolfe, 2003; Eckhardt et al., 2004), our understanding of the factors associated with pretreatment change remains limited. Offender research indicates that individual and dyadic violent behaviour are highly variable and that such variability may provide insight into levels of pretreatment change (Holtzworth-Munroe and Stuart, 1994; Archer, 2002). AIMS/HYPOTHESES: We sought to examine the associations between indicators of change and individual as well as dyadic violence frequency in a sample of male partner violence offenders. METHOD: To determine whether severity and perceived concordance in the use of violence among male offenders and their female partners influenced readiness to change at pretreatment, 82 recently adjudicated male perpetrators of intimate partner violence were recruited into the current study and administered measures of readiness to change violent behaviour (Revised Safe at Home Scale; Begun et al., 2008) as well as partner violence experiences (Revised Conflict Tactics Scale; Straus et al., 1996). RESULTS: Analyses revealed an interaction between offender-reported male and female violence in the prediction of pretreatment readiness to change such that greater male violence was associated with greater readiness to change among males who reported that their female partners perpetrated low, but not high, levels of violence. Consistently, greater female violence was associated with lower readiness to change only among the most violent male offenders. CONCLUSIONS AND IMPLICATIONS FOR CLINICAL PRACTICE: Results provide support for the assertion that the most violent offenders may be the most resistant to partner violence intervention efforts, particularly when they perceive themselves to be victims as well. Enhanced motivational and couples programming may facilitate treatment engagement among the high-risk group of male offenders who report concordant relationship violence. PMID- 26482018 TI - Mentoring serial and high-risk perpetrators of intimate partner violence in the community: Engagement and initiating change. AB - BACKGROUND: Mentoring has typically been used with young offenders. A pilot mentoring project has been introduced in the UK for high-risk intimate partner violence (IPV) offenders. AIMS: The aim of the study was to evaluate how serial and high-risk IPV men engaged with mentoring and how change was initiated for this population. METHODS: Interviews were conducted with two mentors, six mentees and four support workers, and file notes for 16 mentees were examined. Thematic analysis was employed to analyse the data. RESULTS: The global theme, tools and techniques that facilitate engagement comprised two organising themes, building relationships and tenacity of the mentor, which explained how engagement was initiated and driven. Catalysts to initiate change with its two organising themes, hooks and focus on the future, captured factors that act as potential turning points or triggers for the mentees to address their use of IPV and start the process of change. CONCLUSIONS: Mentoring is an innovative and alternative approach for engaging intervention-resistant serial and high-risk IPV perpetrators, enabling them to identify their need to change and laying down the foundation that could facilitate this change. PMID- 26482019 TI - Project WINGS (Women Initiating New Goals of Safety): A randomised controlled trial of a screening, brief intervention and referral to treatment (SBIRT) service to identify and address intimate partner violence victimisation among substance-using women receiving community supervision. AB - BACKGROUND: The high rate of intimate partner violence (IPV) victimisation found among substance-using women receiving community supervision underscores the need for effective IPV victimisation screening, brief intervention and referral to treatment services (SBIRT) for this population. AIMS: This randomised controlled trial (RCT) aims to assess the feasibility, safety and efficacy of a single session computerised self-paced IPV SBIRT (Computerised WINGS) in identifying IPV victimisation among women under community supervision and increasing access to IPV services, compared to the same IPV SBIRT service delivered by a case manager (Case Manager WINGS). METHODS: This RCT was conducted with 191 substance-using women in probation and community court sites in New York City. RESULTS: No significant differences were found between Computerised and Case Manager WINGS arms on any outcomes. Both arms reported identical high rates of any physical, sexual or psychological IPV victimisation in the past year (77% for both arms) during the intervention. Both arms experienced significant increases from baseline to the 3-month follow-up in receipt of IPV services, social support, IPV self-efficacy and abstinence from drug use. CONCLUSIONS: Findings suggest that both modalities of WINGS show promise in identifying and addressing IPV victimisation among substance-using women receiving community supervision. PMID- 26482020 TI - Embolic protection device use and its association with procedural safety and long term outcomes following saphenous vein graft intervention: An analysis from the British Columbia Cardiac registry. AB - BACKGROUND: Embolic protection devices (EPDs) have been designed and introduced to reduce distal embolization and peri-procedural myocardial infarction during saphenous vein graft (SVG) intervention. Current guidelines give a class I recommendation to EPD use during SVG intervention when technically feasible. However, the routine use of these devices has recently been debated. METHODS: We analyzed 1,359 patients undergoing isolated SVG intervention between 2008 and 2013 in the British Columbia Cardiac Registry. We analyzed (a) post-procedural TIMI flow; and (b) target vessel revascularization (TVR) and mortality at 1 and 2 years. RESULTS: EPD use was an independent predictor of post-procedural TIMI 2/3 flow (OR = 2.38, 95% CI: 1.51-3.74, P < 0.001). At 1 year, EPD use was an independent predictor for lower TVR (HR = 0.35, 95% CI: 0.14-0.85, P = 0.021) and a trend towards lower mortality (HR = 0.45, 95% CI: 0.18-1.10, P = 0.082). These associations were lost at 2 years where EPD use was not predictive of mortality (HR = 0.62, 95% CI: 0.33-1.17, P = 0.144) or TVR (HR = 0.70, 95% CI: 0.41-1.17, P = 0.176). These findings were confirmed in propensity-matched and inverse probability treatment weighted analyses. CONCLUSIONS: In this analysis of patients undergoing SVG intervention, EPD use was a strong predictor for improved post-procedural TIMI flow. Whilst EPD use was associated with lower TVR and a trend for lower mortality at 1 year, these associations were lost at 2 years. These findings would appear to support the use of EPD for SVG intervention. (c) 2015 Wiley Periodicals, Inc. PMID- 26482021 TI - Remarkable Differences in Reactivity between Benzothiazoline and Hantzsch Ester as a Hydrogen Donor in Chiral Phosphoric Acid Catalyzed Asymmetric Reductive Amination of Ketones. AB - Described herein are differences in behavior between a Hantzsch ester and a benzothiazoline as hydrogen donors in the chiral phosphoric acid catalyzed asymmetric reductive amination of ketones with p-anisidine. The asymmetric reductive amination of ketones with a Hantzsch ester as a hydrogen donor provided the corresponding chiral amines exclusively, regardless of the structures of the ketones, whereas a similar transformation with a benzothiazoline provided chiral amines and p-methoxyphenyl-protected primary amines in variable yields, depending on the structures of both the ketones and benzothiazolines. Because a benzothiazoline has an N,S-acetal moiety that is vulnerable to p-anisidine, the primary amine can be formed through transimination of the benzothiazoline with p anisidine followed by reduction of the resulting aldimine with remaining benzothiazoline. PMID- 26482022 TI - Authors' reply. PMID- 26482023 TI - Authors' reply. PMID- 26482024 TI - Potential signaling pathway of hypoxia-inducible factor in lung cancer and its gene polymorphism with lung cancer risk. AB - Lung cancer is becoming the leading cause of cancer death worldwide with highest morbidity and mortality, and knowing the pathogenesis and signaling pathway is very important and advances in the diagnosis and treatment of the disease are urgently needed. Gene polymorphism was reported to be associated with the lung cancer risk. We reviewed the potential signaling pathway of hypoxia-inducible factor in lung cancer and conducted a meta-analysis to explore its gene polymorphism with lung cancer risk. In the meta-analysis, hypoxia-inducible factor-1alpha (HIF-1alpha) G1790A A allele, AA genotype and GG genotype were associated with lung cancer risk (A allele: OR = 2.31, 95% CI: 1.77-3.02, p < 0.00001; AA genotype: OR = 4.52, 95% CI: 2.31-8.83, p < 0.0001; GG genotype: OR = 0.45, 95% CI: 0.33-0.63, p < 0.00001). Furthermore, HIF-1alpha C1772 TT genotype and CC genotype were associated with lung cancer risk, but the T allele was not. In conclusion, HIF-1alpha G1790A A allele, AA genotype and GG genotype, HIF 1alpha C1772 TT genotype and CC genotype were associated with lung cancer risk. However, more studies should be performed to confirm it. PMID- 26482025 TI - Role of high-mobility group box-1 protein in disruption of vascular barriers and regulation of leukocyte-endothelial interactions. AB - High-mobility group box-1 protein (HMGB1) is a highly conserved non-histone DNA binding protein present in the nuclei and cytoplasm of nearly all cell types. The results from recent research provide evidence that HMGB1 is secreted into the extracellular milieu and acts as a pro-inflammatory cytokine and exhibits angiogenic effects to fire the immunological response against the pathological effects. Recently, a great deal of evidence has indicated the critical importance of HMGB1 in mediating vascular barriers dysfunction by modulating the expression of adhesion molecules, such as intercellular adhesion molecule-1, vascular cell adhesion protein 1 and E-selectin on the surface of endothelial cells. Such process promotes the adhesion and migration of leukocytes across the endothelium, leading to breakdown of vascular barriers (blood-brain barrier and blood-retinal barrier) via modulating the expression, content, phosphorylation, and distribution of tight junction proteins. Therefore, here we give an abridged review to understand the mechanistic link between HMGB1 and vascular barriers dysfunction, including interaction with cell-surface receptors and intracellular signaling pathways. PMID- 26482027 TI - One-hour plasma glucose as a predictor of the development of Type 2 diabetes in Japanese adults. AB - AIMS: To test the hypothesis that 1-h plasma glucose in an oral glucose tolerance test is a better predictor of the development of diabetes than 2-h plasma glucose, independently of indices of insulin secretion or action in Japanese adults. METHODS: A historical cohort study was conducted in 1445 Japanese workers who did not have diabetes. The association between 1-h plasma glucose and the development of Type 2 diabetes was analysed. RESULTS: Overall, 95 of the study participants developed Type 2 diabetes during a mean follow-up of 4.5 years. The area under the receiver-operating characteristic curve for 1-h plasma glucose for future diabetes [0.88 (95% CI 0.84-0.91)] was greater than that for 2-h plasma glucose [0.79 (95% CI 0.74-0.84)], and for insulinogenic [0.73 (95% CI 0.68 0.78)] and disposition indices [0.79 (95% CI 0.74-0.84); P < 0.05]. Compared with the first quartile, the hazard ratio for future diabetes in the fourth quartile of 1-h plasma glucose was 42.5 [95% CI 5.7-315.2 (P < 0.05)] and the hazard ratio in the fourth quartile of 2-h plasma glucose was 4.4 [95% CI 1.8-10.8 (P < 0.05)], after adjustments for covariates including fasting plasma glucose. The significance of the elevated hazard ratio in the fourth quartile of 1-h plasma glucose was maintained after adjustments for 2-h plasma glucose, insulinogenic index or disposition index, whereas the elevation of the hazard ratio in the fourth quartile of 2-h plasma glucose was diminished and was no longer significant after adjustments for 1-h plasma glucose. CONCLUSIONS: One-hour plasma glucose had a greater association with the future development of Type 2 diabetes than did 2-h plasma glucose, independently of oral glucose tolerance test-derived indices of insulin action in a Japanese population. PMID- 26482026 TI - Graphene oxide as a protein matrix: influence on protein biophysical properties. AB - BACKGROUND: This study provides fundamental information on the influence of graphene oxide (GO) nanosheets and glycans on protein catalytic activity, dynamics, and thermal stability. We provide evidence of protein stabilization by glycans and how this strategy could be implemented when GO nanosheets is used as protein immobilization matrix. A series of bioconjugates was constructed using two different strategies: adsorbing or covalently attaching native and glycosylated bilirubin oxidase (BOD) to GO. RESULTS: Bioconjugate formation was followed by FT-IR, zeta-potential, and X-ray photoelectron spectroscopy measurements. Enzyme kinetic parameters (k(m) and k(cat)) revealed that the substrate binding affinity was not affected by glycosylation and immobilization on GO, but the rate of enzyme catalysis was reduced. Structural analysis by circular dichroism showed that glycosylation did not affect the tertiary or the secondary structure of BOD. However, GO produced slight changes in the secondary structure. To shed light into the biophysical consequence of protein glycosylation and protein immobilization on GO nanosheets, we studied structural protein dynamical changes by FT-IR H/D exchange and thermal inactivation. CONCLUSIONS: It was found that glycosylation caused a reduction in structural dynamics that resulted in an increase in thermostability and a decrease in the catalytic activity for both, glycoconjugate and immobilized enzyme. These results establish the usefulness of chemical glycosylation to modulate protein structural dynamics and stability to develop a more stable GO-protein matrix. PMID- 26482028 TI - A retrospective, longitudinal study of factors associated with new antipsychotic medication use among recently admitted long-term care residents. AB - BACKGROUND: Use of antipsychotic (AP) medications is high and often inappropriate among institutionalized populations. Little is known about the correlates of new AP drug use following admission to long-term care (LTC) settings. This study investigated the frequency and correlates of new AP drug use among newly admitted LTC residents. METHODS: This longitudinal, retrospective study used data from the interRAI - Nursing Home Minimum Data Set version 2.0 (MDS 2.0) instrument. Data about demographic, clinical and social characteristics, and medication use, were collected in Ontario, Canada, from 2003-2011 by trained nurses. Residents with complete admission and 3-6 month follow-up data were included (N = 47,768). Multivariate logistic regression analyses, stratified by gender, explored correlates of new AP drug use upon admission to LTC. RESULTS: New AP drug users comprised 7 % of the final cohort. Severe cognitive impairment, dementia, and motor agitation were significantly associated with new AP drug use among both sexes. Additionally, behavioural problems, conflicts with staff and reduced social engagement were strong correlates of new AP drug use. CONCLUSIONS: Social factors were as strongly associated with new AP drug use after LTC admission as clinical factors. Strategies to prevent the potential misuse of AP drugs upon LTC admission should consider the social determinants of such prescribing. PMID- 26482029 TI - Ursodeoxycholic Acid for Treatment of Enlarged Polycystic Liver. AB - Patients with autosomal dominant polycystic kidney disease and polycystic liver disease (PLD) often have elevated serum levels of alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT). Ursodeoxycholic acid (UDCA) is used to treat biliary tract diseases, but its effect on PLD remains unclear. UDCA was administered for 1 year at a dose of 300 mg daily to seven PLD patients with elevated ALP or GGT levels who were selected for this treatment by experienced clinicians. Laboratory data and liver volumes were compared among three time points: 1 year before UDCA treatment, at the start of UDCA therapy, and 1 year after the start of therapy. Median GGT did not show a significant change between 1 year before UDCA (180 IU/L) and the start of UDCA therapy (209 IU/L), but it decreased significantly to 98 IU/L after 1 year of UDCA therapy (P = 0.015 vs. the start of therapy). ALP showed a significant increase from 1 year before UDCA (456 IU/L) to the start of UDCA therapy (561 IU/L), and then decreased significantly after 1 year of UDCA therapy (364 IU/L). Median liver volume did not show any significant changes among these three time points of assessment. UDCA may be effective for reducing biliary enzyme levels and inhibiting the growth of liver cysts in patients with PLD. PMID- 26482030 TI - Dual-Function Metal-Organic Framework as a Versatile Catalyst for Detoxifying Chemical Warfare Agent Simulants. AB - The nanocrystals of a porphyrin-based zirconium(IV) metal-organic framework (MOF) are used as a dual-function catalyst for the simultaneous detoxification of two chemical warfare agent simulants at room temperature. Simulants of nerve agent (such as GD, VX) and mustard gas, dimethyl 4-nitrophenyl phosphate and 2 chloroethyl ethyl sulfide, have been hydrolyzed and oxidized, respectively, to nontoxic products via a pair of pathways catalyzed by the same MOF. Phosphotriesterase-like activity of the Zr6-containing node combined with photoactivity of the porphyrin linker gives rise to a versatile MOF catalyst. In addition, bringing the MOF crystals down to the nanoregime leads to acceleration of the catalysis. PMID- 26482031 TI - Postoperative negative-pressure incision therapy following open colorectal surgery (Poniy): study protocol for a randomized controlled trial. AB - BACKGROUND: Postoperative surgical site infections cause substantial morbidity, prolonged hospitalization, costs and even mortality, and remain one of the most frequent surgical complications. In prospective trials with adequate follow-up, more than 20 % of patients undergoing elective colorectal surgery are affected and methods to reduce surgical site infections are urgently needed. Negative pressure incision therapy is a novel intervention that holds promise to reduce postoperative wound infection rates, but has not yet been rigorously tested in a randomized controlled trial. METHODS/DESIGN: The aim is to investigate whether the postoperative application of a negative-pressure incision therapy device for 5-7 days reduces the rate of surgical site infections following open elective colorectal surgery by 50 %. This is a randomized, controlled, observer-blinded multicentre clinical trial with two parallel study groups. The primary outcome measure will be the rate of surgical site infections within 30 days postoperatively. Surgical site infections are defined according to criteria of the US Centers for Disease Control and Prevention. Statistical analysis of the primary endpoint measure will be based on the intention-to-treat population. The global level of significance is set at 5 % (two-sided) and the sample size (n = 170 per group) is determined to assure a power of 80 %. DISCUSSION: The Poniy trial will explore whether the rate of surgical site infections can be reduced by the application of a negative-pressure incision therapy device in patients undergoing open elective colorectal surgery. Its pragmatic design guarantees high external validity and clinical relevance. TRIAL REGISTRATION: Deutsches Register Klinischer Studien DRKS00006199 . PMID- 26482032 TI - Follicular regulatory T cells impair follicular T helper cells in HIV and SIV infection. AB - Human and simian immunodeficiency viruses (HIV and SIV) exploit follicular lymphoid regions by establishing high levels of viral replication and dysregulating humoral immunity. Follicular regulatory T cells (TFR) are a recently characterized subset of lymphocytes that influence the germinal centre response through interactions with follicular helper T cells (TFH). Here, utilizing both human and rhesus macaque models, we show the impact of HIV and SIV infection on TFR number and function. We find that TFR proportionately and numerically expand during infection through mechanisms involving viral entry and replication, TGF-beta signalling, low apoptosis rates and the presence of regulatory dendritic cells. Further, TFR exhibit elevated regulatory phenotypes and impair TFH functions during HIV infection. Thus, TFR contribute to inefficient germinal centre responses and inhibit HIV and SIV clearance. PMID- 26482033 TI - Changes of choroidal structure after treatment for primary intraocular lymphoma: retrospective, observational case series. AB - BACKGROUND: We report changes of choroidal structure determined by binarization of enhanced depth imaging optical coherence tomographic (EDI-OCT) images after treatment for primary intraocular lymphoma (PIOL). METHODS: Five eyes of four patients with PIOL were examined by EDI-OCT before and 6 months after intravitreal methotrexate injections. In addition, 15 eyes of 15 normal individuals controlled by age and refractive error were examined by EDI-OCT. Binarization of the EDI-OCT images was performed using publicly accessible software (ImageJ). The examined area of the subfoveal choroid was 1,500 MUm wide, and the dark areas that represented the luminal areas were traced by the Niblack method. Wilcoxon signed rank test was used to determine the significance of changes in the subfoveal choroidal thickness, interstitial area, and luminal area. Mann-Whitney U test was used to compare the parameters in the eyes with pretreatment PIOL and normal control eyes. RESULTS: The subfoveal choroidal thickness was significantly decreased after treatment (P = 0.0431). In the binarized images, the interstitial area was significantly decreased after treatment (P = 0.0431), while the luminal area was not significantly changed (P = 0.8927). After delayed onset of PIOL, increased interstitial area, thickened choroid and unchanged luminal area were observed in one eye. The interstitial area and choroidal thickness were significantly increased in the eyes with pretreatment PIOL compared with the normal control eyes (P = 0.0207, P = 0.0495, respectively), while the luminal area was not significantly different (P = 0.2752). CONCLUSIONS: After treatment for PIOL, the EDI-OCT images showed a thinner choroid, and binarization of the EDI-OCT images showed significantly decreased interstitial areas compared with the luminal areas. The binarized EDI OCT images can provide useful information on choroidal structure in eyes with PIOL, and combining these images with intraocular interleukin levels or fundus autofluorescence images should provide valuable information for determining the PIOL activity. PMID- 26482034 TI - Modern affinity reagents: Recombinant antibodies and aptamers. AB - Affinity reagents are essential tools in both basic and applied research; however, there is a growing concern about the reproducibility of animal-derived monoclonal antibodies. The need for higher quality affinity reagents has prompted the development of methods that provide scientific, economic, and time-saving advantages and do not require the use of animals. This review describes two types of affinity reagents, recombinant antibodies and aptamers, which are non-animal technologies that can replace the use of animal-derived monoclonal antibodies. Recombinant antibodies are protein-based reagents, while aptamers are nucleic acid-based. In light of the scientific advantages of these technologies, this review also discusses ways to gain momentum in the use of modern affinity reagents, including an update to the 1999 National Academy of Sciences monoclonal antibody production report and federal incentives for recombinant antibody and aptamer efforts. In the long-term, these efforts have the potential to improve the overall quality and decrease the cost of scientific research. PMID- 26482035 TI - Evidence for Degradation of the Chrome Yellows in Van Gogh's Sunflowers: A Study Using Noninvasive In Situ Methods and Synchrotron-Radiation-Based X-ray Techniques. AB - This paper presents firm evidence for the chemical alteration of chrome yellow pigments in Van Gogh's Sunflowers (Van Gogh Museum, Amsterdam). Noninvasive in situ spectroscopic analysis at several spots on the painting, combined with synchrotron-radiation-based X-ray investigations of two microsamples, revealed the presence of different types of chrome yellow used by Van Gogh, including the lightfast PbCrO4 and the sulfur-rich PbCr1-x Sx O4 (x~0.5) variety that is known for its high propensity to undergo photoinduced reduction. The products of this degradation process, i.e., Cr(III) compounds, were found at the interface between the paint and the varnish. Selected locations of the painting with the highest risk of color modification by chemical deterioration of chrome yellow are identified, thus calling for careful monitoring in the future. PMID- 26482037 TI - Dewetting transition induced by surfactants in sessile droplets at the early evaporation stage. AB - As surfactants are employed to control the wettability of solutions, we observe that the sessile droplet dewetting induced by autophobing exhibits a unique relation with the surfactant concentration. Below the critical micelle concentration (cmc) of the surfactant, the autophobic effect makes the droplet go through a rapid depinning at first (Phase 1) and then a relatively slower shrinkage (Phase 2). Unexpectedly, the rapid velocity of the three-phase contact line in Phase 1 shows a transition as the surfactant concentration increases above 0.043 cmc, while such a transition is absent for the velocity in Phase 2. The spreading of the sessile droplets as they form before retraction, the maximum contact angle led by dewetting, and the droplet lifetime are regularly sensitive to the surfactant concentration as well. These phenomena are correlated with the assembling structure and the adsorbed amount at different interfaces with the loading of surfactant inventory. PMID- 26482036 TI - Comparative analysis of microRNA expression in mouse and human brown adipose tissue. AB - BACKGROUND: In small mammals brown adipose tissue (BAT) plays a predominant role in regulating energy expenditure (EE) via adaptive thermogenesis. New-born babies require BAT to control their body temperature, however its relevance in adults has been questioned. Active BAT has recently been observed in adult humans, albeit in much lower relative quantities than small mammals. Comparing and contrasting the molecular mechanisms controlling BAT growth and development in mice and humans will increase our understanding or how human BAT is developed and may identify potential therapeutic targets to increase EE. MicroRNAs are molecular mechanisms involved in mouse BAT development however, little is known about the miRNA profile in human BAT. The aims of this study were to establish a mouse BAT-enriched miRNA profile and compare this with miRNAs measured in human BAT. To achieve this we firstly established a mouse BAT enriched-miRNA profile by comparing miRNAs expressed in mouse BAT, white adipose tissue and skeletal muscle. Following this the BAT-enriched miRNAs predicted to target genes potentially involved in growth and development were identified. METHODS: MiRNA levels were measured using PCR-based miRNA arrays. Results were analysed using ExpressionSuite software with the global mean expression value of all expressed miRNAs in a givensample used as the normalisation factor. Bio-informatic analyses was used to predict gene targets followed by Ingenuity Pathway Analysis. RESULTS: We identified 35 mouse BAT-enriched miRNAs that were predicted to target genes potentially involved in growth and development. We also identified 145 miRNAs expressed in both mouse and human BAT, of which 25 were enriched in mouse BAT. Of these 25 miRNAs, miR-20a was predicted to target MYF5 and PPARgamma, two important genes involved in brown adipogenesis, as well as BMP2 and BMPR2, genes involved in white adipogenesis. For the first time, 69 miRNAs were identified in human BAT but absent in mouse BAT, and 181 miRNAs were expressed in mouse but not in human BAT. CONCLUSION: The present study has identified a small sub-set of miRNAs common to both mouse and human BAT. From this sub-set bioinformatics analysis suggested a potential role of miR-20a in the control of cell fate and this warrants further investigation. The large number of miRNAs found only in mouse BAT or only in human BAT highlights the differing molecular profile between species that is likely to influence the functional role of BAT across species. Nevertheless the BAT-enriched miRNA profiles established in the present study suggest targets to investigate in the control BAT development and EE. PMID- 26482038 TI - Missed Opportunities and Lost Lives: Consequences of Some Proposed Changes to Regulations on Research with Human Tissues--Letter. PMID- 26482039 TI - Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells. AB - PURPOSE: The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal type (IGA), often harbors mutations in RHOA, but little is known about the role of RhoA in DGA. EXPERIMENTAL DESIGN: We examined RhoA activity and RhoA pathway inhibition in DGA cell lines and in two mouse xenograft models. RhoA activity was also assessed in patient tumor samples. RESULTS: RhoA activity was higher in DGA compared with IGA cell lines and was further increased when grown as spheroids to enrich for cancer stem-like cells (CSCs) or when sorted using the gastric CSC marker CD44. RhoA shRNA or the RhoA inhibitor Rhosin decreased expression of the stem cell transcription factor, Sox2, and decreased spheroid formation by 78% to 81%. DGA spheroid cells had 3- to 5-fold greater migration and invasion than monolayer cells, and this activity was Rho-dependent. Diffuse GA spheroid cells were resistant in a cytotoxicity assay to 5-fluorouracil and cisplatin chemotherapy, and this resistance could be reversed with RhoA pathway inhibition. In two xenograft models, cisplatin inhibited tumor growth by 40% to 50%, RhoA inhibition by 32% to 60%, and the combination by 77% to 83%. In 288 patient tumors, increased RhoA activity correlated with worse overall survival in DGA patients (P = 0.017) but not in IGA patients (P = 0.612). CONCLUSIONS: RhoA signaling promotes CSC phenotypes in DGA cells. Increased RhoA activity is correlated with worse overall survival in DGA patients, and RhoA inhibition can reverse chemotherapy resistance in DGA CSC and in tumor xenografts. Thus, the RhoA pathway is a promising new target in DGA patients. PMID- 26482040 TI - A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma. AB - PURPOSE: Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N = 55) with single-agent abexinostat in relapsed/refractory lymphoma. EXPERIMENTAL DESIGN: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m(2) twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/refractory follicular lymphoma or mantle cell lymphoma. RESULTS: The recommended phase II dose was 45 mg/m(2) twice daily (90 mg/m(2) total), 7 days/week given every other week. Of the 30 follicular lymphoma and mantle cell lymphoma patients enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell lymphoma) were response-evaluable. Tumor size was reduced in 86% of follicular lymphoma patients with an investigator-assessed ORR of 64.3% for evaluable patients [intent-to-treat (ITT) ORR 56.3%]. Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2 22.3+). Of responding follicular lymphoma patients, 89% were on study/drug >8 months. In mantle cell lymphoma, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1-11.5). Grade 3-4 treatment related adverse events (phase II) with >= 10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths. CONCLUSIONS: The pan-HDACi, abexinostat, was overall well tolerated and had significant clinical activity in follicular lymphoma, including highly durable responses in this multiply relapsed patient population. PMID- 26482042 TI - Transthoracic Needle Biopsies: It's More than Just Hitting the Bull's-eye. AB - Spectroscopy has shown to be of value in determining benign from malignant tissue. Incorporation of spectroscopic measurements may increase the diagnostic yield of transthoracic needle biopsies. Given the increasing amount of incidentally found lung lesions, such a technique may prevent unnecessary invasive procedures and uncertainty for the patient. PMID- 26482041 TI - Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild type Glioblastomas. AB - PURPOSE: p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient derived models for GBM. EXPERIMENTAL DESIGN: We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCL), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. RESULTS: MDM2-amplified PDCLs were 44 times more sensitive than TP53-mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 MUmol/L vs. 21.9 MUmol/L). MDM4-amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 MUmol/L), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 MUmol/L). In MDM2 amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. CONCLUSIONS: These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2-amplified models suggests that additional markers of response to MDM2 inhibitors must be identified. PMID- 26482044 TI - Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas. AB - PURPOSE: Most well-differentiated neuroendocrine tumors (WD-NET) of the enteropancreatic system are low-intermediate grade (G1, G2). Elevated proliferation demonstrated by either a brisk mitotic rate (>20/10 high power fields) or high Ki-67 index (>20%) defines a group of aggressive neoplasms designated as high-grade (G3) neuroendocrine carcinoma (NEC). High-grade NEC is equated with poorly differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high-grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized. EXPERIMENTAL DESIGN: We investigated 31 cases of WD-NETs with evidence of a component of a high-grade neoplasm. The primary sites included pancreas, small bowel, bile duct, and rectum. Histopathology of the cases was retrospectively reviewed and selected IHC and gene mutation analyses performed. RESULTS: The high-grade component occurred either within the primary tumor (48%) or at metastatic sites (52%). The clinical presentation, radiographic features, biomarkers, and the genotype of these WD-NETs with high-grade component remained akin to those of G1-G2 WD-NETs. The median disease-specific survival (DSS) was 55 months (16-119 months), and 2-year and 5-year DSS was 88% and 49%, respectively significantly better than that of a comparison group of true PD-NEC (DSS 11 months). CONCLUSIONS: Mixed grades can occur in WD-NETs, which are distinguished from PD-NECs by their unique phenotype, proliferative indices, and the genotype. This phenomenon of mixed grade in WD-NET provides additional evidence to the growing recognition that the current WHO G3 category contains both WD-NETs as well as PD-NECs. PMID- 26482043 TI - MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer. AB - PURPOSE: Although 67% of high-grade serous ovarian cancers (HGSOC) express the estrogen receptor (ER), most fail antiestrogen therapy. Because MAPK activation is frequent in ovarian cancer, we investigated if estrogen regulates MAPK and if MEK inhibition (MEKi) reverses antiestrogen resistance. EXPERIMENTAL DESIGN: Effects of MEKi (selumetinib), antiestrogen (fulvestrant), or both were assayed in ER-positive HGSOC in vitro and in xenografts. Response biomarkers were investigated by gene expression microarray and reverse phase protein array (RPPA). Genes differentially expressed in two independent primary HGSOC datasets with high versus low pMAPK by RPPA were used to generate a "MAPK-activated gene signature." Gene signature components that were reversed by MEKi were then identified. RESULTS: High intratumor pMAPK independently predicts decreased survival (HR, 1.7; CI > 95%,1.3-2.2; P = 0.0009) in 408 HGSOC from The Cancer Genome Atlas. A differentially expressed "MAPK-activated" gene subset was also prognostic. "MAPK-activated genes" in HGSOC differ from those in breast cancer. Combined MEK and ER blockade showed greater antitumor effects in xenografts than monotherapy. Gene set enrichment analysis and RPPA showed that dual therapy downregulated DNA replication and cell-cycle drivers, and upregulated lysosomal gene sets. Selumetinib reversed expression of a subset of "MAPK-activated genes" in vitro and/or in xenografts. Three of these genes were prognostic for poor survival (P = 0.000265) and warrant testing as a signature predictive of MEKi response. CONCLUSIONS: High pMAPK is independently prognostic and may underlie antiestrogen failure. Data support further evaluation of fulvestrant and selumetinib in ER-positive HGSOC. The MAPK-activated HGSOC signature may help identify MEK inhibitor responsive tumors. PMID- 26482046 TI - Human papillomavirus-associated neoplasms of the sinonasal tract and nasopharynx. AB - It is now well established that human papillomavirus (HPV) is an important causative factor in a subgroup of head and neck cancer. In the head and neck, while HPV is strongly associated with squamous cell carcinoma arising in the oropharynx, there is a growing interest in HPV-associated neoplasms of non oropharyngeal origin including those which arise within sinonasal and nasopharyngeal mucosa. This article reviews current literature on the association of HPV with Scheiderian papillomas, sinonasal squamous cell carcinoma, sinonasal undifferentiated carcinoma, carcinoma with adenoid cystic-like features, and nasopharyngeal carcinoma. Several clinical implications of HPV detection in sinonasal and nasopharyngeal carcinomas are briefly discussed. PMID- 26482045 TI - Is It Better to Be Rich or Relaxed? Sociobiology Meets Bone Marrow Transplant. AB - Low socioeconomic status in hematopoietic cell transplant recipients is associated with increased treatment-related mortality and relapse, resulting in reduced survival. No biologic mechanism has been identified for these associations. The stress-related gene expression profile, termed the "conserved transcriptional response to adversity," may be a predictor of these negative outcomes. PMID- 26482047 TI - Fast-twitch skeletal muscle fiber adaptation to SERCA1 deficiency in a Dutch Improved Red and White calf pseudomyotonia case. AB - Missense mutations in ATP2A1 gene, encoding SERCA1 protein, cause a muscle disorder designed as congenital pseudomyotonia (PMT) in Chianina and Romagnola cattle or congenital muscular dystonia1 (CMD1) in Belgian Blue cattle. Although PMT is not life-threatening, CMD1 affected calves usually die within a few weeks of age as a result of respiratory complication. We have recently described a muscular disorder in a double muscle Dutch Improved Red and White cross-breed calf. Mutation analysis revealed an ATP2A1 mutation identical to that described in CMD1, even though clinical phenotype was quite similar to that of PMT. Here, we provide evidence for a deficiency of mutated SERCA1 in PMT affected muscles of Dutch Improved Red and White calf, but not of its mRNA. The reduced expression of SERCA1 is selective and not compensated by the SERCA2 isoform. By contrast, pathological muscles are characterized by a broad distribution of mitochondrial markers in all fiber types, not related to intrinsic features of double muscle phenotype and by an increased expression of sarcolemmal calcium extrusion pump. Calcium removal mechanisms, operating in muscle fibers as compensatory response aimed at lowering excessive cytoplasmic calcium concentration caused by SERCA1 deficiency, could explain the difference in severity of clinical signs. PMID- 26482048 TI - How the radiologist can add value in the evaluation of the pre- and post-surgical pancreas. AB - Disease involving the pancreas can be a significant diagnostic challenge to the interpreting radiologist. Moreover, the majority of disease processes involving the pancreas carry high significant morbidity and mortality either due to their natural process or related to their treatment options. As such, it is critical for radiologists to not only provide accurate information from imaging to guide patient management, but also deliver that information in a clear manner so as to aid the referring physician. This is no better exemplified than in the case of pre-operative staging for pancreatic adenocarcinoma. Furthermore, with the changing healthcare landscape, it is now more important than ever to ensure that the value of radiology service to other providers is high. In this review, we will discuss how the radiologist can add value to the referring physician by employing novel imaging techniques in the pre-operative evaluation as well as how the information can be conveyed in the most meaningful manner through the use of structured reporting. We will also familiarize the radiologist with the imaging appearance of common complications that occur after pancreatic surgery. PMID- 26482049 TI - Serum osteocalcin in subjects with metabolic syndrome and central obesity. AB - AIMS: The aim of this study was to determine if osteocalcin is related to adiposity and hyperglycaemia in metabolic syndrome irrespective of the presence of diabetes mellitus. MATERIALS AND METHODS: This was a cross sectional study of 90 patients (59 men and 31 women) with metabolic syndrome as defined by the International Diabetes Federation criteria. Based on medical history 50 out of 90 patients had a diabetes. Anthropometric data were collected and blood taken for measurement of osteocalcin, fasting lipids, fasting glucose and insulin resistance (using homeostatic model assessment index, HOMA-IR). RESULTS: Osteocalcin correlated negatively with fasting glucose (r=-0.366, p<0.001) and HOMA-IR (r=-0.305, p<0.05) but not with waist circumference (r=0.079), body mass index (r=0.028), total cholesterol (r=0.061) or triglycerides (r=0.009). Diabetics had higher HOMA-IR (p<0.01) and lower osteocalcin levels (p<0.01) than non-diabetics. Among diabetics, osteocalcin correlated with glucose only (r= 0.341, p=0.015). In non-diabetics, osteocalcin correlated with HOMA-IR (r=-0.359, p=0.023) via insulin (r=-0.402, p=0.010). Patients with impaired fasting glucose levels (5.6-6.9mmol/L) had the same HOMA-IR as diabetics (p=0.076) but not low osteocalcin (p=0.025). CONCLUSIONS: In this cross-sectional study of subjects with metabolic syndrome and central obesity, low osteocalcin was associated with diabetes but not adiposity. PMID- 26482050 TI - Comprehensive assessment of variables affecting metabolic control in patients with type 2 diabetes mellitus in Jordan. AB - AIMS: The aim of the study was to identify variables affecting metabolic control among diabetic patients treated at diabetes and endocrine clinic in Jordan. METHODS: A total of 200 patients were studied by using a cross sectional study design. Data were collected from patients' medical records, glycemic control tests and prestructured questionnaires about variables that were potentially important based on previous researches and clinical judgment: Adherence evaluation, Patients' knowledge about drug therapy and non-pharmacological therapy, Anxiety and depression, Beliefs about diabetes treatment (benefits and barriers of treatment), Knowledge about treatment goals, Knowledge about diabetes, Self efficacy, and Social support. RESULTS: The mean (+/-SD) age was 53.5 (+/-10.38) years and mean HbA1c was 8.4 (+/-1.95). In the multivariate analysis, education level, and self efficacy found to have significantly independent association with metabolic control (P<0.03). CONCLUSION: Adequate knowledge and high self efficacy was significant in patients with good metabolic control. Emphasizing the importance of continuous educational programs and improving the self efficacy as well, could warrant achieving good metabolic control. PMID- 26482051 TI - The association between Metabolic Syndrome and serum levels of lipid peroxidation and interleukin-6 in Gorgan. AB - BACKGROUND: There are limited studies on the relationship between inflammatory marker such as IL-6 and lipid peroxidation and metabolic syndrome. OBJECTIVE: The aim of present study was to assess IL-6 and lipid peroxidation in subjects with and without the metabolic syndrome and their association with metabolic syndrome components. METHODS: Age and gender matched 40 subjects with metabolic syndrome and 40 control groups took part in this study. RESULTS: The mean malondialdehyde level was significantly higher in overweight and obese subjects with metabolic syndrome than control groups (P<0.05). The mean level of IL-6 in men and the mean level of malondialdehyde in women with metabolic syndrome was significantly higher than control groups (p<0.05). There were significant positive correlation between malondialdehyde and fasting blood glucose, triglyceride and systolic blood pressure (p<0.05). CONCLUSIONS: Our results suggest that higher levels of IL-6 and malondialdehyde may cause insulin resistance and metabolic disorders in all subjects with metabolic syndrome. Malondialdehyde level shows strong association with some metabolic syndrome components. This means the greater risk of metabolic syndrome. PMID- 26482052 TI - Mechanisms of diabetic autoimmunity: II--Is diabetes a central or peripheral disorder of effector and regulatory cells? AB - Two competing hypotheses aiming to explain the onset of autoimmune reactions are discussed in the context of genetic and environmental predisposition to type 1 diabetes (T1D). The first hypothesis has evolved along characterization of the mechanisms of self-discrimination and attributes diabetic autoimmunity to escape of reactive T cells from central regulation in the thymus. The second considers frequent occurrence of autoimmune reactions within the immune homunculus, which are adequately suppressed by regulatory T cells originating from the thymus, and occasionally, insufficient suppression results in autoimmunity. Besides thymic dysfunction, deregulation of both effector and suppressor cells can in fact result from homeostatic aberrations at the peripheral level during initial stages of evolution of adaptive immunity. Pathogenic cells sensitized in the islets are efficiently expanded in the target tissue and pancreatic lymph nodes of lymphopenic neonates. In parallel, the same mechanisms of peripheral sensitization contribute to tolerization through education of naive/effector T cells and expansion of regulatory T cells. Experimental evidence presented for each individual mechanism implies that T1D may result from a primary effector or suppressor immune abnormality. Disturbed self-tolerance leading to T1D may well result from peripheral deregulation of innate and adaptive immunity, with variable contribution of central thymic dysfunction. PMID- 26482053 TI - A disparate subset of double-negative T cells contributes to the outcome of murine fulminant viral hepatitis via effector molecule fibrinogen-like protein 2. AB - The underlying immune-mediated mechanisms involved in virus-induced severe hepatitis have not been well elucidated. In this study, we investigated the role of CD3(+)CD4(-)CD8(-) double-negative T (DN T) cells in the pathogenesis of fulminant viral hepatitis (FVH) induced by murine hepatitis virus strain 3 (MHV 3). After MHV-3 infection, the proportions of DN T cells increased significantly in BALB/cJ mice, and splenic DN T cells expressing high levels of CD69 were recruited by MHV-3-infected hepatocytes to the liver. Serum levels of alanine aminotransferase, aspartate aminotransferase and total bilirubin increased, accompanied by massive hepatocyte necrosis. These DN T cells were predominantly consisted of a TCRalphabeta(+) subset expressing high levels of CD44 and did not produce cytokine except IL-2. Adoptive transfer of this subset of DN T cells to the MHV-3-infected mice resulted in an increase in murine fibrinogen-like protein 2 (mfgl2) expressions in association with massive fibrin deposition in the liver. Following MHV-3 infection, membrane mfgl2 expression and functional procoagulant activity increased remarkably in the DN T cells. Introduction of a recombinant adenovirus which encoded a microRNA specifically targeting mfgl2 gene (Ad-mfgl2 miRNA) in vivo significantly inhibited the hepatic expression of mfgl2 and improved survival in mice. However, under this condition, adoptive transfer of the DN T cells accelerated the disease progression and reversed the benefit from mfgl2 gene silence, leading to a 100 % death rate. Our results demonstrate that DN T cells contribute to the outcome of MHV-3-induced FVH via an important effector molecule mfgl2. PMID- 26482055 TI - Social Frailty in Community-Dwelling Older Adults as a Risk Factor for Disability. AB - OBJECTIVE: To determine social frailty status using simple questions and to examine the association between social frailty and disability onset among community-dwelling older adults. DESIGN: Prospective cohort study. SETTING: Japanese community. PARTICIPANTS: A total of 4304 adults age >=65 years living in the community participated in a baseline assessment from 2011 to 2012. They were followed monthly for incident certification of care needs during the 2 years after the baseline assessment. MEASUREMENTS: Care-needs certification in the national long-term care insurance system of Japan; a self-reported questionnaire including 7 items to define social frailty status, adjustment for several potential confounders such as demographic characteristics; and Kaplan-Meier survival curves for disability incidence by social frailty. RESULTS: During the 2 years, 144 participants (3.3%) were certified as requiring long-term care insurance in accordance with incident disability. Five of the 7 items in the self reported questionnaire were significantly associated with disability incidence. In the adjusted model including potential covariates, participants who were defined as having social frailty (>=2/5) (hazard ratio 1.66, 95% confidence interval 1.00-2.74) and prefrailty (=1/5) (hazard ratio 1.53, 95% confidence interval 1.02-2.531), based on 5 items at the baseline assessment, had an increased risk of disability compared with nonfrail participants (=0/5). CONCLUSIONS: Social frailty, assessed using simple questions regarding living alone, going out less frequently compared with the prior year, visiting friends sometimes, feeling helpful to friends or family, and talking with someone every day, has a strong impact on the risk of future disability among community dwelling older people. PMID- 26482054 TI - Cargo trafficking in Alzheimer's disease: the possible role of retromer. AB - Alzheimer's disease (AD) as one of the on going neurological disorders is initiated and progressed by multiple pathological pathways. Cargoes trafficking pathways,such as recycling, play a crucial role in the pathogenesis of AD. One of the major constituents of this trafficking system in neurons is retromer which acts in endosomal sorting machinery. Defective retromer disrupts recycling of cargoes from endosomes to Golgi and leads to its mis-trafficking which may subsequently leads to AD. Also, retromer-related cargo trafficking could trigger amyloidogenic pathway and beta-amyloid production. Wingless is another cargo in Wnt pathways and its trafficking is mediated by retromer. Retromer malfunction leads to lack of Wnt and subsequent AD-related pathogenesis. Also, retromer plays role in synaptic receptor trafficking in physiologic and pathologic conditions. This review is brief survey on the recent published literatures about pathogenesis of retromer-related trafficking in amyloid precursor protein pathways, Wnt signaling, synaptic function, and also revised the structural role of retromer in AD progression. PMID- 26482056 TI - A Randomized Placebo-Controlled Discontinuation Study of Cholinesterase Inhibitors in Institutionalized Patients With Moderate to Severe Alzheimer Disease. AB - OBJECTIVES: Cholinesterase inhibitors (ChEIs) offer modest benefits in Alzheimer disease (AD), which must be balanced against risks. Relatively few data delineate the benefits and risks of long-term ChEI administration in institutionalized patients with advanced AD. This study investigated the effects of ChEI discontinuation in institutionalized patients with AD. DESIGN: Institutionalized patients with moderate to severe AD (standardized Mini- Mental Status Examination <=15) and treated with a ChEI for >=2 years were randomized, double-blind, to ChEI continuation or placebo, with a 2-week tapering phase, for 8-weeks. MEASUREMENTS: The primary outcome of this pilot study was change on the Clinician's Global Impression of Change (CGI-C) scale. Secondary outcomes included safety, efficacy, and tolerability. Baseline (BL) predictors of clinical deterioration were also determined. RESULTS: Forty patients (mean +/- standard deviation age = 89.3 +/- 3.5 years, standardized Mini-Mental Status Examination = 8.1 +/- 5.2, Neuropsychiatric Inventory-Nursing Home version total score = 21.1 +/- 15.9, 80% male) were randomized to ChEI continuation (n = 21) or placebo (n = 19). There was no significant difference in clinical worsening in the ChEI continuation (28.6%) and placebo groups (36.8%) on CGI-C (odds ratio for worsening 1.58, 95% confidence interval .38-6.55, P = .53). The occurrence of adverse events was similar in both groups. There were no significant differences in any of the secondary outcome measures. In the placebo group, BL hallucinations predicted CGI-C worsening [F(1,17) = 6.4, P = .02], and there was a trend for BL delusions to predict CGI-C worsening [F(1,15) = 3.5, P = .08]. CONCLUSIONS: These results suggest that ChEI discontinuation is safe and well tolerated in the majority of institutionalized patients with moderate to severe AD. When discontinuing ChEI, the presence of hallucinations and delusions may predict clinical deterioration, suggesting the need for increased caution. PMID- 26482057 TI - Examining Time Use of Dutch Nursing Staff in Long-Term Institutional Care: A Time Motion Study. AB - OBJECTIVES: Increasing residents' acuity levels and available resources in long term institutional care requires insight into the care provided by nursing staff so as to guide task allocation and optimal use of resources, and enhance quality of care. The purpose of this study was to examine the relationship between time use and type of nursing staff, residents' acuity levels, and unit type by using a standardized nursing intervention classification. DESIGN: A multicenter cross sectional observational study was performed using time-motion technique. SETTING: Five Dutch long-term institutional care facilities participated. In total, 4 residential care units, 3 somatic units, and 6 psycho-geriatric units were included. PARTICIPANTS: Data were collected from 136 nursing staff members: 19 registered nurses, 89 nursing assistants, 9 primary caregivers, and 19 health care assistants. MEASUREMENTS: A structured observation list was used based on the Nursing Interventions Classification (NIC). Residents' acuity levels, representing residents' needs, were based on the Dutch Care Severity Index. Medians and interquartile ranges were calculated for time spent on interventions per type of nursing staff and units. Linear mixed models were used to examine the relationship between time spent on nursing interventions and the type of nursing staff, residents' acuity levels, and unit type. RESULTS: Observations resulted in 52,628 registered minutes for 102 nursing interventions categorized into 6 NIC domains for 335 residents. Nursing staff spent the most time on direct care interventions, particularly in the domain of basic physiological care. Variances in time spent on interventions between types of nursing staff were minimal. Unit type was more significantly (P < .05) associated with time spent on interventions in domains than the type of nursing staff. Residents' acuity levels did not affect time spent by nursing staff (P > .05). CONCLUSION: The current study found limited evidence for task allocation between the types of nursing staff, which may suggest a blurring of role differentiation. Also, findings suggest that residents received similar care regardless of their needs, implying that care is predominantly task-oriented instead of person-centered. Managers may reconsider whether the needs of residents are adequately met by qualified nursing staff, considering the differences in education and taking into account increasing acuity levels of residents and available resources. PMID- 26482058 TI - Rapid extraction and purification of lumbrokinase from Lumbricus rubellus using a hollow fiber membrane and size exclusion chromatography. AB - OBJECTIVES: To develop a purification process using hollow fiber membrane separation combined with size exclusion chromatography for the extraction of lumbrokinase from earthworms (Lumbricus rubellus). RESULTS: To extract the protein, the earthworms were first homogenized for 10 min, to produce ultrafine particles. Polyether sulfone hollow fiber membranes with MW cut offs of 50 and 6 kDa were used for initial purification of the crude extract. Further purification was carried out on a Sephadex G-75 column, and yielded three fractions of high purity protein. One of these fractions showed fibrinolytic activity. CONCLUSIONS: Three samples of high purity protein were obtained and one protein (LK1) showed strong fibrinolytic activity. The method has higher purification efficiency in comparison with existing methods. PMID- 26482059 TI - Quantification of pyrrolizidine alkaloids in North American plants and honey by LC-MS: single laboratory validation. AB - Pyrrolizidine alkaloids (PAs) are a class of naturally occurring compounds produced by many flowering plants around the World. Their presence as contaminants in food systems has become a significant concern in recent years. For example, PAs are often found as contaminants in honey through pollen transfer. A validated method was developed for the quantification of four pyrrolizidine alkaloids and one pyrrolizidine alkaloid N-oxide in plants and honey grown and produced in British Columbia. The method was optimised for extraction efficiency from the plant materials and then subjected to a single laboratory validation to assess repeatability, accuracy, selectivity, LOD, LOQ and method linearity. The PA content in plants ranged from1.0 to 307.8 ug/g with repeatability precision between 3.8 and 20.8% RSD. HorRat values were within acceptable limits and ranged from 0.62 to 1.63 for plant material and 0.56-1.82 for honey samples. Method accuracy was determined through spike studies with recoveries ranging from 84.6 to 108.2% from the raw material negative control and from 82.1-106.0 % for the pyrrolizidine alkaloids in corn syrup. Based on the findings in this single-laboratory validation, this method is suitable for the quantitation of lycopsamine, senecionine, senecionine N-oxide, heliosupine and echimidine in common comfrey (Symphytum officinale), tansy ragwort (Senecio jacobaea), blueweed (Echium vulgare) and hound's tongue (Cynoglossum officinale) and for PA quantitation in honey and found that PA contaminants were present at low levels in BC honey. PMID- 26482060 TI - Swallowing Disorders in Sjogren's Syndrome: Prevalence, Risk Factors, and Effects on Quality of Life. AB - This epidemiological investigation examined the prevalence, risk factors, and quality-of-life effects of swallowing disorders in Sjogren's syndrome (SS). One hundred and one individuals with primary or secondary SS (94 females, 7 males; mean age 59.4, SD = 14.1) were interviewed regarding the presence, nature, and impact of swallowing disorders and symptoms. Associations among swallowing disorders and symptoms, select medical and social history factors, SS disease severity, and the M.D. Anderson Dysphagia Inventory (MDADI) and Short Form 36 Health Survey (SF-36) were examined. The prevalence of a current self-reported swallowing disorder was 64.4 %. SS disease severity was the strongest predictor of swallowing disorders, including significant associations with the following swallow symptoms: taking smaller bites, thick mucus in the throat, difficulty placing food in the mouth, and wheezing while eating (p < .05). Additional swallowing disorder risk factors included the presence of a self-reported voice disorder, esophageal reflux, current exposure to secondary tobacco smoke, frequent neck or throat tension, frequent throat clearing, chronic post-nasal drip, and stomach or duodenal ulcers. Swallowing disorders did not differ on the basis of primary or secondary SS. Swallowing disorders and specific swallowing symptoms were uniquely associated with reduced quality of life. Among those with swallowing disorders, 42 % sought treatment, with approximately half reporting improvement. Patient-perceived swallowing disorders are relatively common in SS and increase with disease severity. Specific swallowing symptoms uniquely and significantly reduce swallow and health-related quality of life, indicating the need for increased identification and management of dysphagia in this population. PMID- 26482061 TI - Tobacco Withdrawal Amongst African American, Hispanic, and White Smokers. AB - INTRODUCTION: Persistent tobacco use among racial and ethnic minority populations in the United States is a critical public health concern. Yet, potential sources of racial/ethnic disparities in tobacco use remain unclear. The present study examined racial/ethnic differences in tobacco withdrawal-a clinically-relevant underpinning of tobacco use that has received sparse attention in the disparities literature-utilizing a controlled laboratory design. METHODS: Daily smokers (non Hispanic African American [n = 178], non-Hispanic white [n = 118], and Hispanic [n = 28]) attended two counterbalanced sessions (non-abstinent vs. 16-hour abstinent). At both sessions, self-report measures of urge, nicotine withdrawal, and affect were administered and performance on an objective behavioral task that assessed motivation to reinstate smoking was recorded. Abstinence-induced changes (abstinent scores vs. non-abstinent scores) were analyzed as a function of race/ethnicity. RESULTS: Non-Hispanic African American smokers reported greater abstinence-induced declines in several positive affect states in comparison to other racial/ethnic groups. Relative to Hispanic smokers, non-Hispanic African American and non-Hispanic white smokers displayed larger abstinence-provoked increases in urges to smoke. No racial/ethnic differences were detected for a composite measure of nicotine withdrawal symptomatology, negative affect states, and motivation to reinstate smoking behavior. CONCLUSIONS: These results suggest qualitative differences in the expression of some components of tobacco withdrawal across three racial/ethnic groups. This research helps shed light on bio-behavioral sources of tobacco-related health disparities, informs the application of smoking cessation interventions across racial/ethnic groups, and may ultimately aid the overall effort towards reducing the public health burden of tobacco addiction in minority populations. IMPLICATIONS: The current study provides some initial evidence that there may be qualitative differences in the types of tobacco withdrawal symptoms experienced among non-Hispanic African American, Hispanic, and non-Hispanic white smokers. Extending this line of inquiry may elucidate mechanisms involved in tobacco-related health disparities and ultimately aid in reducing the public health burden of smoking in racial/ethnic minority populations. PMID- 26482062 TI - Structures of the reduced and oxidized state of the mutant D24A of yeast thioredoxin 1: insights into the mechanism for the closing of the water cavity. PMID- 26482063 TI - The case for ILI surveillance. PMID- 26482064 TI - Specific serum carotenoids are inversely associated with breast cancer risk among Chinese women: a case-control study. AB - Previous epidemiological studies have revealed the anti-cancer effect of dietary circulating carotenoids. However, the protective role of specific individual circulating carotenoids has not been elucidated. The purpose of this study was to examine whether serum carotenoids, including alpha-carotene, beta-carotene, beta cryptoxanthin, lycopene and lutein/zeaxanthin, could lower the risk for breast cancer among Chinese women. A total of 521 women with breast cancer and age matched controls (5-year interval) were selected from three teaching hospitals in Guangzhou, China. Concentrations of alpha-carotene, beta-carotene, beta cryptoxanthin, lycopene and lutein/zeaxanthin were measured using HPLC. Unconditional logistic regression models were used to calculate OR and 95% CI using quartiles defined in the control subjects. Significant inverse associations were observed between serum alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin and the risk for breast cancer. The multivariate OR for the highest quartile of serum concentration compared with the lowest quartile were 0.44 (95% CI 0.30, 0.65) for alpha-carotene, 0.27 (95% CI 0.18, 0.40) for beta carotene, 0.41 (95% CI 0.28, 0.61) for lycopene and 0.26 (95% CI 0.17, 0.38) for lutein/zeaxanthin. However, no significant association was found between serum beta-cryptoxanthin and the risk for breast cancer. Stratified analysis by menopausal status and oestrogen receptor (ER)/progesterone receptor (PR) showed that serum alpha-carotene, beta-carotene, lycopene and lutein/zeaxanthin were inversely associated with breast cancer risk among premenopausal women and among all subtypes of ER or PR status. The results suggest a protective role of alpha carotene, beta-carotene, lycopene and lutein/zeaxanthin, but not beta cryptoxanthin, in breast cancer risk. PMID- 26482065 TI - Bile duct injury repair -- earlier is not better. AB - Bile duct injury is a common complication of cholecystectomy. The timing of bile duct injury repair remains controversial. A recent review conducted in France reported 39% complications and 64% failure after immediate repair in 194 patients compared with 14% complications and 8%failure after late repair in 133 patients. A national review of 139 consecutive early repairs conducted at five hepatopancreaticobiliary centers in Denmark reported 4% mortality, 36% morbidity, and 42 restrictures (30%) at a median follow-up of 102 months, and only 64 patients (46%) demonstrated uneventful short-term and long-term outcomes. Most patients with bile duct injury present with bile leak and sepsis; thus, early repair is not recommended. Percutaneous drainage of bile and endoscopic stenting are the mainstays of treatment of bile leak because they convert acute bile duct injury into a controlled external biliary fistula. The ensuing benign biliary stricture should be repaired by a biliary surgeon after a delay of 4-6 weeks once the external biliary fistula has closed. PMID- 26482066 TI - Progress and perspectives of neural tissue engineering. AB - Traumatic injuries to the nervous system lead to a common clinical problem with a quite high incidence and affect the patient's quality of life. Based on a major challenge not yet addressed by current therapeutic interventions for these diseases, a novel promising field of neural tissue engineering has emerged, grown, and attracted increasing interest. This review provides a brief summary of the recent progress in the field, especially in combination with the research experience of the author's group. Several important aspects related to tissue engineered nerves, including the theory on their construction, translation into the clinic, improvements in fabrication technologies, and the formation of a regenerative environment, are delineated and discussed.Furthermore, potential research directions for the future development of neural tissue engineering are suggested. PMID- 26482068 TI - Loudness and acoustic parameters of popular children's toys. AB - OBJECTIVE: This project was conducted to evaluate the loudness and acoustic parameters of toys designed for children. In addition, we investigated whether occluding the toys' speaker with tape would result in a significant loudness reduction; thereby potentially reducing the risk of noise induced hearing loss. METHODS: Twenty-six toys were selected after an initial screening at two national retailers. Noise amplitudes at 0.25, 0.5, 1, 2, 4, and 8kHz were measured using a digital sound level meter at a distance of 0 and 30cm. The toys' speakers were then occluded using adhesive tape and the same acoustic parameters were re measured. RESULTS: Mean maximum noise amplitude of the toys at 0cm and 30cm was 104dBA (range, 97-125dBA) and 76dBA (range, 67-86dBA), respectively. Mean maximum noise amplitude after occlusion at 0cm and 30cm distances was 88dBA (range, 73 110dBA) and 66dBA (range, 55-82dBA), respectively, with a p-value <0.001. CONCLUSIONS: Proper use of the loudest toys at a distant of 30cm between the speaker and the child's ear will likely not pose a risk of noise-induced hearing loss. However, since most toys are used at closer distances, use of adhesive tape is recommended as an effective modification to decrease the risk of hearing loss. PMID- 26482067 TI - Mutant DNA methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property, a requisite of leukemia initiation and relapse. AB - Genetic mutations are considered to drive the development of acute myeloid leukemia (AML). With therapid progress in sequencing technologies, many newly reported genes that are recurrently mutated in AML have been found to govern the initiation and relapse of AML. These findings suggest the need to distinguish the driver mutations, especially the most primitive single mutation, from the subsequent passenger mutations. Recent research on DNA methyltransferase 3A (DNMT3A) mutations provides the first proof-of-principle investigation on the identification of preleukemic stem cells (pre-LSCs) in AML patients. Although DNMT3A mutations alone may only transform hematopoietic stem cells into pre-LSCs without causing the full-blown leukemia, the function of this driver mutation appear to persist from AML initiation up to relapse. Therefore, identifying and targeting preleukemic mutations, such as DNMT3A mutations, in AML is a promising strategy for treatment and reduction of relapse risk. PMID- 26482069 TI - Laryngeal mask airway may result in false negative imaging for carotid medialization: A case report. AB - Chromosome 22q11.2 microdeletions result in multiple congenital abnormalities, including an increased risk of carotid medialization, which is an important consideration for preoperative planning in children with velopharyngeal insufficiency. Preoperative imaging of the neck vasculature is recommended. Here we describe a case in which a child had negative imaging studies despite the presence of a medialized carotid artery on physical examination, likely secondary to the supraglottic airway use during sedated imaging, which displaced the carotid laterally. The type of airway used should be a consideration for children undergoing sedated imaging prior to pharyngeal procedures. PMID- 26482070 TI - Prevalence of 35delG and Met34Thr GJB2 variants in Portuguese samples. AB - OBJECTIVE: To estimate the prevalence of 35delG and Met34Thr variants in a Portuguese children's community sample and to compare these frequencies with nonsyndromic hearing-loss patients. METHODS: 502 children were randomly selected among the 8647 participants of the Portuguese birth cohort Generation XXI, and screened for Met34Thr and 35delG variants in the GJB2 gene. These variants were also studied on 89 index-cases, observed in the Clinic of "Hereditary Hearing loss" in Saint John's Hospital Center, presenting a mild to profound nonsyndromic hearing-loss. RESULTS: Among the 502 children from Generation XXI, 10 were heterozygous for the 35delG variant (95% Confidence Interval 1.03-3.68) and 1 homozygous (95% Confidence Interval 0.01-1.24). Other 10 children presented heterozygosity for the Met34Thr variant (95% Confidence Interval 1.03-3.68). No homozygous for the Met34Thr or compound heterozygotes (35delG/Met34Thr) were found. In the total of 89 nonsyndromic hearing-loss patients, 5 (95% Confidence Interval 2.11-12.8) were heterozygous and 7 (95% Confidence Interval 3.61-15.6) were homozygous for the 35delG variant. The Met34Thr variant was found in 4 patients, 2 heterozygous (95% Confidence Interval 0.13-8.31) and 2 homozygous (95% Confidence Interval 0.13-8.31). CONCLUSION: The carrier frequency of 35delG and Met34Thr variants in a Portuguese sample was 1 in 50. Our data suggests that the 35delG mutation has an association with deafness. For the Met34Thr variant, no association was observed. However, Met34Thr seemed to conform to an additive model in hearing-loss. PMID- 26482071 TI - Effect of Febuxostat, a Xanthine Oxidase Inhibitor, on Cardiovascular Risk in Hyperuricemic Patients with Hypertension: A Prospective, Open-label, Pilot Study. AB - BACKGROUND AND OBJECTIVE: There is growing evidence of an association between high uric acid (UA) levels and cardiovascular disease (CVD). We hypothesized that febuxostat, a xanthine oxidase inhibitor, may be associated with suppressing the renin-angiotensin-aldosterone system (RAAS) and improving renal function in hyperurecemic patients with hypertension. METHODS: We conducted a 6-month prospective study in which we randomized hypertensive hyperuricemic patients to either a febuxostat group (n = 30) or a control group (n = 30). The dose of febuxostat was adjusted to maintain the serum UA level at <6.0 mg/dL. RESULTS: In the febuxostat group, the plasma renin activity (PRA), plasma aldosterone concentration (PAC), and serum UA level significantly decreased by 33 % (p = 0.0012), 14 % (p = 0.001), and 29 % (p < 0.0001), respectively. The estimated glomerular filtration rate (eGFR) significantly increased by 5.5 % (p = 0.001). Similar changes were not observed in the control group. Furthermore, a significant correlation was observed between the percent changes in the serum UA levels and the percent changes in the PRA (r = 0.277, p = 0.033), PAC (r = 0.310, p = 0.016), serum blood urea nitrogen levels (r = 0.434, p = 0.0005), serum creatinine levels (r = 0.413, p = 0.002), and eGFR (r = -0.474, p = 0.0001). CONCLUSIONS: These results support the hypothesis that febuxostat might not only reduce serum UA levels but also suppress RAAS and improve renal function in hyperuricemic patients with hypertension, possibly leading to prevention of CVD. PMID- 26482073 TI - HIV Orphanhood Research and the Representation of Older Orphans in Sub-Saharan Africa: A Literature Review. AB - One impact of incurable HIV infection is the large number of orphans and vulnerable children (OVC) who are affected by HIV. The age-based criteria used to determine support eligibility for HIV orphans, however, exclude older orphans (>=18 years of age) from support. We conducted a literature survey in order to explore possible inclusion of older orphans (ages 18-24 years) in HIV orphanhood research. We found 17 studies conducted in eight countries that met the review inclusion criteria. Findings from the review revealed that older HIV orphans are underrepresented in the OVC literature. The emerging, but limited, evidence suggests that older orphans are at risk for poorer psychosocial and reproductive outcomes. We recommend increasing inclusion of older orphans in HIV orphan research because of their complex physical, reproductive, and psychosocial needs. This inclusion is necessary to allow their experiences and needs to become clearer. PMID- 26482074 TI - What is the point of public health in the 21st century? PMID- 26482072 TI - Aegle marmelos fruit extract attenuates Helicobacter pylori Lipopolysaccharide induced oxidative stress in Sprague Dawley rats. AB - BACKGROUND: Bael (Aegle marmelos (L.) Corr.) has been widely used in indigenous systems of Indian medicine to exploit its medicinal properties including astringent, antidiarrheal, antidysenteric, demulcent, antipyretic, antiulcer, anti-inflammatory and anti cancer activities. The present study aims to evaluate the antioxidative and antiulcer effect of methanolic extract of unripe fruit of Aegle marmelos (MEAM) against Helicobacter pylori-Lipopolysaccharide (HP-LPS) induced gastric ulcer in Sprague Dawley (SD) rats. METHODS: Dose and duration of HP-LPS and MEAM were fixed based on ulcer index of gastric tissue of experimental animals. Various gastric secretory parameters such as volume of gastric juice, free and total acidity, acid output, pepsin concentration were analyzed. The activities of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione transferase), non-enzymatic antioxidants (reduced glutathione, vitamin C and vitamin E) and the levels of lipid peroxidation products were measured. Histological analysis was performed to evaluate the effect of Aegle marmelos on HP-LPS induced gastric ulcer. RESULTS: Oral administration of HP-LPS (50 MUg per animal) for four consecutive days resulted in induction of ulcer with the increase in gastric secretory parameters such as volume of gastric juice, free and total acidity, acid output, pepsin concentration. Oral administration of methanolic extract of Aegle marmelos fruit (MEAM) (25, 50, 100, 250 and 500 mg/kg) reduced the gastric ulcer by 2.8 %, 52.4 %, 73 %, 93 % and 93.98 %, respectively, compared to 89.2 % reduction by sucralfate (100 mg/kg). MEAM treatment significantly (p < 0.05) inhibited the increase in gastric secretory parameters in ulcerated rats, and it also prevented the reduction of enzymatic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione transferase) and non-enzymatic antioxidants (reduced glutathione, vitamin C and vitamin E) after HP-LPS induction. In addition, lipid peroxidation was inhibited by MEAM in HP-LPS induced rats. Results of histological analysis correlated well with biochemical parameters. CONCLUSION: These observations explored the antioxidant properties of MEAM contributing to the gastroprotective effect in HP-LPS induced gastric ulcer model. PMID- 26482075 TI - Adult Children's Problems and Mothers' Well-Being. AB - This article explores whether understanding of the effects of children's problems on older parents' well-being can be advanced by exploring differences in parent child relationships within families. Using data from a study in which mothers reported on all adult children, we addressed the question: Do patterns of maternal favoritism moderate the impact of children's problems on psychological well-being? Based on the literature on the effects of children's problems and on parental favoritism, we hypothesized that problems in the lives of favored adult children will have a more detrimental impact than when they affect unfavored offspring. Results revealed strong and detrimental effects of any offspring's problems on mothers' well-being; these effects occurred, however, regardless of parental preference for an adult child. The findings suggest that the well documented effects of parental preference may be limited in domains such as problems and difficult transitions in adult children's lives. PMID- 26482076 TI - Resolution of severe hemolysis and paravalvular aortic regurgitation employing an Amplatzer Vascular Plug 4: the importance of detailed pre-procedural planning using CT angiography. AB - A 76-year-old woman presented with progressive heart failure and transfusion dependent hemolytic anemia due to severe paravalvular aortic regurgitation 4 years after bioprosthetic aortic valve replacement. She was deemed not to be a candidate for redo cardiac surgery due to a porcelain aorta and multiple comorbid medical conditions. We describe the role of pre-procedure contrast-enhanced, ECG gated computed tomographic angiography to characterize the anatomy of the paravalvular leak connection for appropriate occluder device selection leading to successful percutaneous closure and resolution of the paravalvular regurgitation and hemolytic anemia. PMID- 26482077 TI - [Acute kidney failure and renal replacement therapy after colonoscopy in a 63 year-old woman]. AB - A 63-year-old woman presented with intestinal disorder, alternating between obstipation and diarrhoea. Sodium phosphate/diphosphate (Fleet(r)) was used in preparation for colonoscopy. Within 24 h the patient developed severe hyperphosphatemia and oliguric acute kidney failure with the need of renal replacement therapy. This case illustrates the rare event of phosphate nephropathy after colonoscopy. PMID- 26482078 TI - [Antibiotic stewardship: Measures for optimization of antibacterial therapy]. AB - Because the development of resistance is steadily increasing, especially among Gram-negative pathogens and new developments in antibiotics are lacking, a rational antibiotic therapy is necessary now more than ever. A continuing uncritical and non-guideline-conform use of antibiotics leads to selection of multidrug-resistant pathogens, which can colonize patients and as instigators of infections make treatment more difficult. A prerequisite for targeted antibiotic therapy is a critical testing of the suspected infection diagnosis based on a guideline-conform microbiological preanalytical procedure. To promote a guideline conform antibiotic therapy in hospitals with respect to choice of substance, dosage and duration, in December 2013 so-called antibiotic stewardship (ABS) measures were summarized in a so-called S3-guideline from the Association of the Scientific Medical Societies in Germany (AWMF) under the auspices of the German Society for Infectious Diseases (DGI). With a strategy of targeted antibiotic therapy and infection prevention it is possible to achieve optimum treatment results and to minimize the development of resistance. PMID- 26482079 TI - [Ecology of antimicrobial resistance: Special aspects of extended-spectrum beta lactamases]. AB - Extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae were detected shortly after the introduction of broad spectrum cephalosporins in hospitals. Today, they are prevalent in the community, in animals, foods, and the environment. Many factors contribute to the broad distribution, especially the usage of antimicrobials in humans and animals, and due to multiple resistances, not only the usage of beta-lactams and cephalosporins.This broad distribution of ESBLs cannot be fully explained by clonal spread of successful strains. Horizontal transmission of resistance genes, located on transmissible elements, probably plays a much greater role. This gene transfer also enables new combinations of resistance genes which causes therapeutic problems.The complex interactions make it difficult to estimate the relative contribution of the different sources. Resistance genes are broadly distributed in humans, animals, and the environment and the distribution pattern seems to become more similar. It is also evident that two major transmission pathways have to be considered, human to-human transmission, frequently in hospitals and the exchange of resistance genes between humans, animals, food, and the environment. For the latter, the transfer can go in both directions.Further studies are necessary to understand the pathways between the different reservoirs, the bacterial concentration needed, and the factors having an impact on colonization and transmission. Multiple measures on both the human and veterinary side have to complement each other and interact. A One Health approach needs to be developed and rigorously established. PMID- 26482081 TI - Delivery of drugs and macromolecules to the mitochondria for cancer therapy. AB - Mitochondria are organelles that have pivotal functions in producing the energy necessary for life and executing the cell death pathway. Targeting drugs and macromolecules to the mitochondria may provide an effective means of inducing cell death for cancer therapy, and has been actively pursued in the last decade. This review will provide a brief overview of mitochondrial structure and function, how it relates to cancer, and importantly, will discuss different strategies of mitochondrial delivery including delivery using small molecules, peptides, genes encoding proteins and MTSs, and targeting polymers/nanoparticles with payloads to the mitochondria. The advantages and disadvantages for each strategy will be discussed. Specific examples using the latest strategies for mitochondrial targeting will be evaluated, as well as potential opportunities for specific mitochondrial compartment localization, which may lead to improvements in mitochondrial therapeutics. Future perspectives in mitochondrial targeting of drugs and macromolecules will be discussed. Currently this is an under-explored area that is prime for new discoveries in cancer therapeutics. PMID- 26482080 TI - Programmable insect cell carriers for systemic delivery of integrated cancer biotherapy. AB - Due to cancer's genetic complexity, significant advances in the treatment of metastatic disease will require sophisticated, multi-pronged therapeutic approaches. Here we demonstrate the utility of a Drosophila melanogaster cell platform for the production and in vivo delivery of multi-gene biotherapeutic systems. We show that cultured Drosophila S2 cell carriers can stably propagate oncolytic viral therapeutics that are highly cytotoxic for mammalian cancer cells without adverse effects on insect cell viability or gene expression. Drosophila cell carriers administered systemically to immunocompetent animals trafficked to tumors to deliver multiple biotherapeutics with little apparent off-target tissue homing or toxicity, resulting in a therapeutic effect. Cells of this Dipteran invertebrate provide a genetically tractable platform supporting the integration of complex, multi-gene biotherapies while avoiding many of the barriers to systemic administration of mammalian cell carriers. These transporters have immense therapeutic potential as they can be modified to express large banks of biotherapeutics with complementary activities that enhance anti-tumor activity. PMID- 26482082 TI - Amphiphilic drugs as surfactants to fabricate excipient-free stable nanodispersions of hydrophobic drugs for cancer chemotherapy. AB - Nanoformulations have been extensively explored to deliver water-insoluble drugs, but they generally use exotic new materials, for instance, amphiphilic block copolymers, which must first go through extensively clinical trials and be approved as drug excipients before any clinical uses. We hypothesize that using clinical amphiphilic drugs as surfactants to self-assemble with and thus solubilize hydrophobic drugs will lead to readily translational nanoformulations as they contain no new excipients. Herein, we show the first example of such excipient-free nanodispersions using an amphiphilic anti-tumor drug, irinotecan hydrochloride (CPT11). CPT11 self-assembles with its insoluble active parent drug, 7-ethyl-10-hydroxy camptothecin (SN38), into stable and water-dispersible nanoparticles, increasing SN38's water solubility by thousands of times up to 25 mg/mL with a loading efficiency close to 100%. The versatility of this approach is also demonstrated by fabricating nanodispersions of CPT11 with other water insoluble drugs including paclitaxel (PTX) and camptothecin (CPT). These nanodispersions have much increased bioavailability and thereby improved anti cancer activities. Thus, this strategy, using clinically proven amphiphilic drugs as excipients to fabricate nanodispersions, avoids new materials and makes readily translational nanoformulations of hydrophobic drugs. PMID- 26482083 TI - Micellar formulation of indocyanine green for phototherapy of melanoma. AB - Phototherapy (PT), a light activated treatment modality, is a potential therapeutic option for the treatment of melanoma. In spite of the excellent safety profile and absorption in the near infrared (NIR) range, clinical potential of indocyanine green (ICG) as PT is limited by its short half-life and inefficient tumor accumulation. In this study, we have covalently conjugated ICG NH2 to the pendant carboxyl groups of poly (ethylene glycol)-block-poly(2-methyl 2-carboxyl-propylene carbonate) (PEG-PCC) copolymer using carbodiimide coupling, which self-assembled into micelles with a particle size of 30-50 nm and high ICG loading. These ICG conjugated micelles exhibited significant in vitro photodynamic cytotoxicity. Use of sodium azide and NIR radiate on at 4 degrees C revealed photodynamic and photothermal as mechanism of cytotoxicity of ICG solution and ICG conjugated micelles, respectively. In vivo NIR imaging demonstrated that ICG conjugated micelles prolonged its circulation and increased tumor accumulation through enhanced permeability and retention (EPR) effect. Enhanced tumor accumulation improved therapeutic efficacy with complete tumor regression in NIR irradiated ICG conjugated micelles compared to ICG solution and control in a A375 human melanoma tumor model in athymic nude mice. These results suggest that ICG conjugated micelles can be potentially utilized for PT and imaging of melanoma. PMID- 26482085 TI - Characterization of the three zebrafish orthologs of the mitochondrial GTPase Miro/Rhot. AB - Mitochondria exhibit dynamic locomotion and spatial rearrangement. This movement is necessary for a cell to maintain basic metabolic functions, and disruption of motility often results in cell death. Miro is a mitochondrial outer membrane Rho GTPase essential for mitochondrial movement and distribution in diverse systems, including yeast, animals, and plants. We sought to study the previously uncharacterized Miro protein family in zebrafish. We confirmed that, like human Miro, the zebrafish Miro proteins (Rhot1a, Rhot1b, and Rhot2) localize to mitochondria in mammalian tissue culture cells by both biochemical fractionation and immunofluorescent colocalization. In addition, using whole mount in situ hybridization, we observed ubiquitous expression of all three mRNAs throughout development. By microinjecting three antisense morpholino oligonucleotides targeted to each of the rhot genes, we knocked down all three proteins simultaneously in developing zebrafish embryos. The triple morphants demonstrated a dose-dependent defect in posterior body-axis elongation, while a single knockdown of each protein at the same dose produced no effect. This phenotype could be rescued with human Miro1 mRNA and is most likely due to increased cell death. Taken altogether, this research demonstrates the importance of the Rhot proteins during vertebrate development. PMID- 26482084 TI - Post-traumatic stress disorder amongst surgical trainees: An unrecognised risk? AB - BACKGROUND: Experiences of actual/threatened death or serious injury to patients are commonplace in surgery. Pathological symptoms following stress may lead to Acute Stress Reaction (ASR) and Post-Traumatic Stress Disorder (PTSD). PTSD symptoms of insomnia, anger, poor concentration, hyper-vigilance and exaggerated startle have implications for patient safety. The current study investigates the prevalence of occult, untreated psychological morbidity amongst surgical trainees. METHODS: A web-based survey of UK surgical trainees based upon the Impact of Events Scale-Revised (IES-R) was distributed using social media platforms and email. A score of >=33 was indicative of ASR or PTSD (the former lasting <1 month, the latter >1 month). Additional questions concerned chronicity of symptoms, mentorship, team-working and access to support. RESULTS: For 167 returned surveys the mean age was 32.7 (SD 3.6) years; 102/167 (61%) were male. Mean years in training were 6.1 (SD 3.6). Median IES-R score was 14 (IQR 7-23.5). Of 144 respondents who answered about stress symptoms, 23/144 (16%) had IES-R score >= 33; 6 of these had symptoms < 1 month (suggesting ASR); 17 had symptoms lasting >1 month (suggesting PTSD). Those with IES-R >= 33 group were more likely to have repeated years of training, and have witnessed severe pain, traumatic injury, and acute haemorrhage. Seven with score >= 33 had sought support. CONCLUSION: Occult psychological morbidity amongst surgical trainees may be higher than in the general population. Recognition and management of this risk is important for the mental health of trainees and the safety of patients. PMID- 26482086 TI - Adrenergic signaling in teleost fish liver, a challenging path. AB - Adrenergic receptors or adrenoceptors (ARs) belong to the huge family of G protein coupled receptors (GPCRs) that have been well characterized in mammals primarily because of their importance as therapeutic drug targets. ARs are found across vertebrates and this review examines the path to identify and characterize these receptors in fish with emphasis on hepatic metabolism. The absence of reliable and specific pharmacological agents led investigators to define the fish hepatic AR system as relying solely on a beta2-AR, cAMP-dependent signaling transduction pathway. The use of calcium-radiometric imaging, purified membranes for ligand-binding studies, and perifused rather than static cultured fish hepatocytes, unequivocally demonstrated that both alpha1- and beta2-AR signaling systems existed in the fish liver consistent with studies in mammals. Additionally, the use of molecular tools and phylogenetic analysis clearly demonstrated the existence of multiple AR-types and -subtypes in hepatic and other tissues of a number of fish species. This review also examines the use of beta-blockers as pharmaceuticals and how these drugs that are now in the aquatic environment may be impacting aquatic species including fish and some invertebrates. Clearly there is a large conservation of structure and function within the AR system of vertebrates but there remain a number of key questions that need to be addressed before a clear understanding of these systems can be resolved. PMID- 26482087 TI - Strategies on improving the micro-fluidic devices using the nonlinear electro- and thermo-kinetic phenomena. AB - Surface science is key to innovations on microfluidics, smart materials, and future non-equilibrium systems. However, challenging issues still exist in this field. In this article, from the viewpoint of the fundamental design, we will briefly review our strategies on improving the micro-fluidic devices using the nonlinear electro- and thermo-kinetic phenomena. In particular, we will review the microfluidic applications using ICEO, the correction based on the ion conserving Poisson-Boltzmann theory, the direct simulation on ICEO, and the new horizon such as nonlinear thermo-kinetic phenomena and the artificial cilia. PMID- 26482088 TI - Nucleic acid polymeric properties and electrostatics: Directly comparing theory and simulation with experiment. AB - Nucleic acids are biopolymers that carry genetic information and are also involved in various gene regulation functions such as gene silencing and protein translation. Because of their negatively charged backbones, nucleic acids are polyelectrolytes. To adequately understand nucleic acid folding and function, we need to properly describe its i) polymer/polyelectrolyte properties and ii) associating ion atmosphere. While various theories and simulation models have been developed to describe nucleic acids and the ions around them, many of these theories/simulations have not been well evaluated due to complexities in comparison with experiment. In this review, I discuss some recent experiments that have been strategically designed for straightforward comparison with theories and simulation models. Such data serve as excellent benchmarks to identify limitations in prevailing theories and simulation parameters. PMID- 26482089 TI - Next generation of novel psychoactive substances on the horizon - A complex problem to face. AB - BACKGROUND: The last decade has seen a rapid and continuous growth in the availability and use of novel psychoactive substances (NPS) across the world. Although various products are labeled with warnings "not for human consumption", they are intended to mimic psychoactive effects of illicit drugs of abuse. Once some compounds become regulated, new analogues appear in order to satisfy consumers' demands and at the same time to avoid criminalization. This review presents updated information on the second generation of NPS, introduced as replacements of the already banned substances from this class, focusing on their pharmacological properties and metabolism, routes of administration, and effects in humans. METHODS: Literature search, covering years 2013-2015, was performed using the following keywords alone or in combination: "novel psychoactive substances", "cathinones", "synthetic cannabinoids", "benzofurans", "phenethylamines", "2C-drugs", "NBOMe", "methoxetamine", "opioids", "toxicity", and "metabolism". RESULTS: More than 400 NPS have been reported in Europe, with 255 detected in 2012-2014. The most popular are synthetic cannabimimetics and psychostimulant cathinones; use of psychedelics and opioids is less common. Accumulating experimental and clinical data indicate that potential harms associated with the use of second generation NPS could be even more serious than those described for the already banned drugs. CONCLUSIONS: NPS are constantly emerging on the illicit drug market and represent an important health problem. A significant amount of research is needed in order to fully quantify both the short and long term effects of the second generation NPS, and their interaction with other drugs of abuse. PMID- 26482090 TI - Evaluation of a brief intervention to reduce the negative consequences of drug misuse among adult emergency department patients. AB - OBJECTIVES: Determine if a brief intervention (BI) reduces the negative consequences of drug use/misuse among adult emergency department (ED) patients, and identify patients more likely to benefit from the BI. METHODS: This randomized, controlled trial enrolled 1026 18-64 year-old ED patients whose drug misuse indicated a needed for a BI. Differences in total Inventory of Drug Use Consequences (InDUC) scores between the treatment (BI) and control arms (no BI) were assessed every 90 days over a one-year period. Regression models were constructed to identify demographic and clinical factors associated with greater reductions in total InDUC scores. RESULTS: Although total InDUC scores decreased for both the treatment and control arms, there were no differences in scores between the treatment and the control arms at baseline at each follow-up. In the regression analyses, participants who were not using drugs or received drug treatment in the past 90 days generally had lower InDUC scores at each follow-up. CONCLUSIONS: Although negative consequences decreased in both study arms over time, receiving a BI did not lead to a greater reduction in the negative consequences of drug misuse than not receiving a BI. Of importance in the design of future ED drug misuse interventions, participants who were successful in stopping their drug misuse or receiving drug treatment did show fewer negative consequences of drug use/misuse. PMID- 26482092 TI - A lifetime history of alcohol use disorder increases risk for chronic medical conditions after stable remission. AB - BACKGROUND: The long-term impact of a past alcohol use disorder (AUD) among those who are currently in stable remission has not been well-explored. This study examined whether a past history of AUD was associated with increased risk for chronic medical conditions in a large U.S. nationally representative sample of adults >=30 years old. METHODS: Using 25,840 participants from Wave 1 and Wave 2 surveys of the National Epidemiologic Survey on Alcohol and Related Condition (NESARC), multiple logistic regression analysis was conducted to compare the risk for reporting metabolic, cardiovascular, liver, gastrointestinal, and inflammatory conditions between those in full-remission from AUD for longer than 5 years and those without a history of AUD diagnosis. RESULTS: Compared with a model adjusting only for age, a model adjusting for other potential psychosocial confounders revealed fewer significant associations between AUD history and chronic medical conditions, particularly for the middle-aged population and for men. For the elderly, AUD history was associated with more chronic medical conditions in fully adjusted models. AUD history was associated with severe medical conditions such as liver diseases and myocardial infarction in women. In general, longer AUD exposure and shorter remission were also associated with the risk for chronic medical conditions. CONCLUSIONS: Our findings suggest associations between past AUD diagnosis and chronic medical conditions, particularly for the elderly individuals. Screening for past alcohol use problems and associated health risks are important for the promotion of aging and prevention of chronic medical conditions even when an individual presents no current symptoms of AUD. PMID- 26482093 TI - Three-dimensional simulation of orthognathic surgery-surgeon's perspective. PMID- 26482091 TI - Genetic and environmental contributions to initiation of cigarette smoking in young African-American and European-American women. AB - BACKGROUND: Distinctions in the relative contributions of genetic and environmental factors to initiation of cigarette smoking may explain, in part, the differences between African Americans and European Americans in the prevalence of smoking. The current investigation is the first to compare heritable and environmental influences on smoking initiation between African American and European-American women. METHODS: Data were drawn from Missouri Adolescent Female Twin Study participants and female Missouri Family Study participants (n=4498; 21% African-American, the remainder European-American). Mean ages at first and last assessments were 17.0 (SD=3.5) and 24.0 (SD=3.2), respectively. Twin-sibling modeling was conducted to estimate the proportion of variance in smoking initiation (i.e., ever trying a cigarette) attributable to additive genetic, shared environmental, special twin environmental, and unique environmental factors. RESULTS: Additive genetic influences accounted for approximately half of the variance in smoking initiation in both African-American and European-American women. In the African-American subsample, the remaining variance was attributable primarily to unique environmental factors (46%; 95% CI: 28-71%). In the European-American subsample, only 12% (95% CI: 8-16%) of the variance was attributable to unique environmental factors, with the remainder accounted for by shared environmental (13%; 95% CI: 0-41%) and special twin environmental (24%; 95% CI: 0-52%) factors. CONCLUSIONS: The estimated heritability of smoking initiation is substantial and nearly identical for African-American and European-American women, but the type of environmental factors that contribute to risk differ by race/ethnicity. Whereas the primary environmental influences on European-American women's smoking initiation are at the family level, those that impact African-American women's smoking initiation are primarily individual-specific. PMID- 26482094 TI - Factors Related to the Accuracy of Self-Reported Dietary Intake of Children Aged 6 to 12 Years Elicited with Interviews: A Systematic Review. AB - BACKGROUND: Understanding the relationship between children's dietary consumption and health is important. As such, it is crucial to explore factors related to the accuracy of children's reports of what they consumed. OBJECTIVE: The objective was to evaluate factors related to the accuracy of self-reported dietary intake information elicited by interview methods from children aged 6 to 12 years. METHODS: A systematic review of English articles using PsycINFO, PsycARTICLES, PsycEXTRA, PsycBOOKS, CINAHL Complete, Global Health, and MEDLINE Complete was performed. Search terms included interview, diet, children, and recall; studies were limited to those published from 1970 onward. Additional studies were identified using the reference lists of published articles. Studies that assessed children's dietary intake using direct observation, doubly labeled water, or the double-portion method and compared it with their recall of that intake (unassisted by parents) using an interview were included. RESULTS: The 45 studies that met the inclusion criteria showed that specific interview techniques designed to enhance children's recall accuracy had little effect. Rather, the timing of the interview appeared most important: The shorter the retention interval between children's consumption and their recall, the more accurate their memories. Children's age, body mass index, social desirability, food preferences, and cognitive ability were also related to accuracy. CONCLUSIONS: Factors related to the accuracy of children's dietary reporting should be taken into consideration when asking about consumption. Further research is required to examine whether other interview techniques, such as those developed to enhance children's recall of repeated staged events, can improve children's dietary reporting accuracy. PMID- 26482096 TI - Comparison of serum and urine lead levels in opium addicts with healthy control group. AB - CONTEXT: Lead-contaminated opium is one of the new sources of lead exposure in our region. As far as the literature review is concerned, there are limited comparative studies about comparison of blood lead level (BLL) in addict patients with healthy controls. OBJECTIVE: We aimed to compare BLL and urine lead level (ULL) between opium addicts with the healthy control group. MATERIALS AND METHODS: Forty opium addict subjects (mean age: 43 +/- 10 years) as the patient group and 40 healthy subjects (mean age: 41 +/- 9 years) as the control group participated. Three milliliter of whole blood and urine was obtained from both groups and lead level was assessed using atomic absorption spectrophotometry. RESULTS: The mean value of BLL in patient group was 7.14 +/- 1.41 mcg/dL and that in the healthy control group was 5.42 +/- 1.46 mcg/dL. The mean value of ULL was 2.62 +/- 0.83 mcg/dL in the patient group and 2.50 +/- 0.76 mcg/dL in the healthy control group.BLL was different in the two groups (p < 0.001), but ULL was not (p = 0.5). There was a significant correlation between BLL with duration of opium addiction in the patient group (r = -0.403, p = 0.01). BLL and ULL were significantly correlated in controls (r = 0.436, p = 0.005) and not in patients. DISCUSSION AND CONCLUSION: It was observed that the BLL in opium addicts was significantly higher than that in the healthy control group. This can be due to use of adulterated opium with lead. Therefore, screening of blood lead concentration is helpful for opium-addict patients especially with nonspecific symptoms. PMID- 26482095 TI - Secular Trends in Meal and Snack Patterns among Adolescents from 1999 to 2010. AB - BACKGROUND: Linkages between snack patterns, diet, and obesity in adolescents likely depend on the consumption of main meals, how often snacks are prepared away from home, and whether energy-dense, nutrient-poor snack foods and sugary drinks are frequently consumed. Nutrition-based interventions need to be informed by an understanding of how secular changes in the contribution of snacks to dietary intake may be related to changes in meal frequency as well as how these trends differ by sociodemographic characteristics. OBJECTIVES: To examine secular trends from 1999 to 2010 in meal and snack patterns among adolescents. DESIGN: A repeated cross-sectional design was used. PARTICIPANTS/SETTING: Participants from Minneapolis/St Paul, MN, secondary schools completed classroom-administered surveys and food frequency questionnaires in 1999 (n=2,598) and 2010 (n=2,540). MAIN OUTCOME MEASURES: Weekly meal frequencies; number of snacks consumed on school and vacation/weekend days; frequent consumption of snacks prepared away from home (>=3 times/week); and daily servings of energy-dense, nutrient-poor food/drinks that are commonly consumed at snack occasions. STATISTICAL ANALYSES PERFORMED: Trends from 1999 to 2010 were examined using inverse probability weighting to control for differences in sociodemographic characteristics in the two samples. RESULTS: Mean frequencies of breakfast and lunch increased modestly in the overall population (both P values <0.001), and there were decreases in the number of snacks consumed on schools days (P<0.001) and vacation/weekend days (P=0.003). Although there was no change in the proportion of adolescents who reported frequent consumption of snacks prepared away from home, there was a secular decrease in energy-dense, nutrient-poor food/drink consumption (P<0.001). Sociodemographic differences in the identified trends were evident. CONCLUSIONS: The observed pattern of sociodemographic characteristic differences in meal and snack trends among adolescents suggests the need for targeted efforts to ensure public health messages reach low-income and ethnic/racial minority population subgroups most vulnerable to poor nutrition and the development of obesity. PMID- 26482097 TI - CD180 overexpression in follicular lymphoma is restricted to the lymph node compartment. AB - BACKGROUND: Altered Toll-like receptor (TLR) expression levels and/or mutations in its signaling pathway (such as MyD88 mutation) contribute to the pathogenesis of lymphoproliferative disorders (LPD). CD180 is an orphan member of the TLR family that modulates the signaling of several TLRs, but only limited studies have evaluated its expression by flow cytometry (FCM) in LPD. METHODS: Using a multiparameter FCM approach, we have assessed CD180 mean fluorescence intensity (MFI) in lymph nodes (LNs) and peripheral blood (PB) samples obtained from patients with follicular lymphoma (FL; LN/PB, n = 44/n = 15), chronic lymphocytic leukemia (CLL, n = 26/n = 21), mantle cell lymphoma (MCL, n = 13/n = 17), and marginal zone lymphoma (MZL, n = 16/n = 12). Specimens from non-tumoral PB and LN (n = 8/n = 12) were used as controls. RESULTS: In the LN specimens, FL and control B-cells showed similar CD180 expression (MFI = 1,049 vs. 1,381, P > 0.05; Mann-Whitney U-test). This level was markedly lower in the other LPDs, MCL (MFI = 396, P < 0.05), or CLL (MFI = 502 P < 0.05), and similar to MZL (MFI = 858, P > 0.05). However, the CD180 expression of FL B-cells assessed in PB was dim and/or negative, in the same range as MCL and CLL (FL MFI = 453, MCL MFI = 305, CLL MFI = 420, P > 0.05) but lower than in MZL (MFI = 895, P < 0.05). Therefore, these results suggest a modulation of CD180 expression by neoplastic FL B-cells based on the anatomical compartment. CONCLUSION: These FCM data confirm the usefulness of CD180 in the accurate diagnosis of LPDs and emphasize the need to interpret this marker according to the origin of the sample. (c) 2015 Clinical Cytometry Society. PMID- 26482098 TI - Short term effectiveness of neural sliders and neural tensioners as an adjunct to static stretching of hamstrings on knee extension angle in healthy individuals: A randomized controlled trial. AB - OBJECTIVE: To investigate the added benefit of nerve-biased interventions over static stretching in hamstring flexibility and to compare the effectiveness of two types of nerve-biased interventions over a week. DESIGN: Three-arm assessor blinded randomized controlled trial. SETTING: University Laboratory. PARTICIPANTS: Sixty healthy individuals (mean age = 22 +/- 2.4 years) with reduced hamstring flexibility were randomized to three groups who received static stretching and neurodynamic sliders (NS-SS); static stretching with neurodynamic tensioner (NT-SS) and static stretching (SS) alone. OUTCOME MEASURE: Knee extension angle (KEA) in degrees. RESULTS: Baseline characteristics including demographic, anthropomorphic and KEA between groups were comparable. A significant interaction was observed between group (intervention) and time, [F (2,114) = 3.595; p = 0.031]. Post-hoc pairwise comparisons analyses revealed significant differences at post-intervention measurement time point between NS-SS and SS (mean difference: -6.8; 95%CI = -12, -1.5; p = 0.011) and NT-SS and SS (mean difference: -11.6; 95%CI = -16.7, -6.3; p < 0.001). However there was no significant difference between NS-SS and NT-SS groups (mean difference: 4.8; 95%CI = 0.4, 9.9; p = 0.074). CONCLUSIONS: Neural sliders and tensioners are both effective in increasing hamstring flexibility as an adjunct to static hamstring stretching when compared to static stretching alone. No neural mobilization technique proved to be superior over another. CLINICAL TRIAL REGISTRATION: This clinical trial is registered in Clinical Trials Registry- India (CTRI) with registration number CTRI/2012/05/002619. PMID- 26482099 TI - Endogenous vs Exogenous Allosteric Modulators in GPCRs: A dispute for shuttling CB1 among different membrane microenvironments. AB - A Cannabinoid Receptor 1 (CB1) binding site for the selective allosteric modulator ORG27569 is here identified through an integrate approach of consensus pocket prediction, mutagenesis studies and Mass Spectrometry. This unprecedented ORG27569 pocket presents the structural features of a Cholesterol Consensus Motif, a cholesterol interacting region already found in other GPCRs. ORG27569 and cholesterol affects oppositely CB1 affinity for orthosteric ligands. Moreover, the rise in cholesterol intracellular level results in CB1 trafficking to the axonal region of neuronal cells, while, on the contrary, ORG27568 binding induces CB1 enrichment at the soma. This control of receptor migration among functionally different membrane regions of the cell further contributes to downstream signalling and adds a previously unknown mechanism underpinning CB1 modulation by ORG27569 , that goes beyond a mere control of receptor affinity for orthosteric ligands. PMID- 26482101 TI - HSFs, Stress Sensors and Sculptors of Transcription Compartments and Epigenetic Landscapes. AB - Starting as a paradigm for stress responses, the study of the transcription factor (TF) family of heat shock factors (HSFs) has quickly and widely expanded these last decades, thanks to their fascinating and significant involvement in a variety of pathophysiological processes, including development, reproduction, neurodegeneration and carcinogenesis. HSFs, originally defined as classical TFs, strikingly appeared to play a central and often pioneering role in reshaping the epigenetic landscape. In this review, we describe how HSFs are able to sense the epigenetic environment, and we review recent data that support their role as sculptors of the chromatin landscape through their complex interplay with chromatin remodelers, histone-modifying enzymes and non-coding RNAs. PMID- 26482102 TI - GMC asks for child pornography case to be referred to High Court. PMID- 26482100 TI - Hsp70 and Hsp90 of E. coli Directly Interact for Collaboration in Protein Remodeling. AB - Hsp90 is a highly conserved molecular chaperone that remodels hundreds of client proteins, many involved in the progression of cancer and other diseases. It functions with the Hsp70 chaperone and numerous cochaperones. The bacterial Hsp90 functions with an Hsp70 chaperone, DnaK, but is independent of Hsp90 cochaperones. We explored the collaboration between Escherichia coli Hsp90 and DnaK and found that the two chaperones form a complex that is stabilized by client protein binding. A J-domain protein, CbpA, facilitates assembly of the Hsp90Ec-DnaK-client complex. We identified E. coli Hsp90 mutants defective in DnaK interaction in vivo and show that the purified mutant proteins are defective in physical and functional interaction with DnaK. Understanding how Hsp90 and Hsp70 collaborate in protein remodeling will provide the groundwork for the development of new therapeutic strategies targeting multiple chaperones and cochaperones. PMID- 26482103 TI - Functional communication training during reinforcement schedule thinning: An analysis of 25 applications. AB - Two principal goals of functional communication training (FCT) are (a) to eliminate destructive behavior and (b) to establish a more acceptable, yet functionally equivalent, communication response (FCR). A related and critically important goal is to thin the schedule of reinforcement for the FCR to levels that can be reasonably managed by caregivers. Researchers have described several approaches to thinning FCT reinforcement schedules. We summarize the results of 25 consecutive applications (among 20 cases) in which schedule-thinning procedures employed discriminative stimuli to signal when the FCR would and would not produce reinforcement (i.e., using multiple schedules, response restriction, or chained schedules). Results suggest that schedule-thinning procedures that use discriminative stimuli can maintain the effectiveness of FCT while they minimize the need for punishment or other supplemental procedures. PMID- 26482104 TI - The Use of Medical Expulsive Therapy During Pregnancy: A Worldwide Perspective Among Experts. AB - INTRODUCTION: Medical expulsive therapy (MET) is a pharmacologic approach thought to augment the spontaneous passage of ureteral calculi. The usage of MET pharmacologics for presumed ureteral calculi during pregnancy has not been studied and their safety and utility are unknown. We sought to characterize the worldwide usage of MET in the setting of pregnancy with presumed ureteral calculus (P-MET), as well as factors associated with physician use. Experts in stone management were specifically sought. MATERIALS AND METHODS: A nine-question survey was delivered through society-administered e-mail. Questions gathered physician's worldwide region, degree of specialization in stone disease, practice type, interval since training, and willingness to use both MET and P-MET. We assessed drugs of choice in those using P-MET and reasons for avoidance in non-P MET users. Finally, we assessed the impact of physician-perceived medicolegal risk on usage of P-MET. RESULTS: Five hundred sixty-five responses were recorded. Sixty-three percent were US-based practitioners and the remaining represented a worldwide distribution. Worldwide usage of MET was 97.6%, and tamsulosin was globally preferred by over 90% of urologists. P-MET was endorsed by only 44.3%. 23.6% of European practitioners used this strategy compared with 51.1% of US physicians. Time from training and practice type did not significantly interact with adoption of P-MET; experts were less likely to use P-MET. Physician nonuse of MET during pregnancy was adverse outcome related: 76.7% reported either the fear of legal risk (52.8%) or concerns about safety (23.9%). CONCLUSION: Respondents report impressive worldwide adoption of MET. P-MET is less trusted, and fears of legal risk and safety far outweigh questions about effectiveness. The effectiveness of drugs during pregnancy-induced ureteral dilation is unknown. Still, 44% of global respondents embrace usage of this drug strategy despite a paucity of evidence supporting either safety or effectiveness during pregnancy. PMID- 26482105 TI - 'Visual' parsing can be taught quickly without visual experience during critical periods. AB - Cases of invasive sight-restoration in congenital blind adults demonstrated that acquiring visual abilities is extremely challenging, presumably because visual experience during critical-periods is crucial for learning visual-unique concepts (e.g. size constancy). Visual rehabilitation can also be achieved using sensory substitution-devices (SSDs) which convey visual information non-invasively through sounds. We tested whether one critical concept--visual parsing, which is highly-impaired in sight-restored patients--can be learned using SSD. To this end, congenitally blind adults participated in a unique, relatively short (~70 hours), SSD-'vision' training. Following this, participants successfully parsed 2D and 3D visual objects. Control individuals naive to SSDs demonstrated that while some aspects of parsing with SSD are intuitive, the blind's success could not be attributed to auditory processing alone. Furthermore, we had a unique opportunity to compare the SSD-users' abilities to those reported for sight restored patients who performed similar tasks visually, and who had months of eyesight. Intriguingly, the SSD-users outperformed the patients on most criteria tested. These suggest that with adequate training and technologies, key high order visual features can be quickly acquired in adulthood, and lack of visual experience during critical-periods can be somewhat compensated for. Practically, these highlight the potential of SSDs as standalone-aids or combined with invasive restoration approaches. PMID- 26482106 TI - Predictive analytics of environmental adaptability in multi-omic network models. AB - Bacterial phenotypic traits and lifestyles in response to diverse environmental conditions depend on changes in the internal molecular environment. However, predicting bacterial adaptability is still difficult outside of laboratory controlled conditions. Many molecular levels can contribute to the adaptation to a changing environment: pathway structure, codon usage, metabolism. To measure adaptability to changing environmental conditions and over time, we develop a multi-omic model of Escherichia coli that accounts for metabolism, gene expression and codon usage at both transcription and translation levels. After the integration of multiple omics into the model, we propose a multiobjective optimization algorithm to find the allowable and optimal metabolic phenotypes through concurrent maximization or minimization of multiple metabolic markers. In the condition space, we propose Pareto hypervolume and spectral analysis as estimators of short term multi-omic (transcriptomic and metabolic) evolution, thus enabling comparative analysis of metabolic conditions. We therefore compare, evaluate and cluster different experimental conditions, models and bacterial strains according to their metabolic response in a multidimensional objective space, rather than in the original space of microarray data. We finally validate our methods on a phenomics dataset of growth conditions. Our framework, named METRADE, is freely available as a MATLAB toolbox. PMID- 26482107 TI - Relationship Between Carfilzomib Dose and Efficacy Outcomes in Patients With Relapsed and/or Refractory Multiple Myeloma. AB - BACKGROUND: Carfilzomib is approved by the US Food and Drug Administration for the treatment of patients with relapsed and refractory multiple myeloma (MM) who have received at least 2 previous treatments. The approval was based on phase II trials that used a starting dose of 20 mg/m(2) escalated to a target dose of 27 mg/m(2) in cycle 2. We examined dose-outcome relationships in MM patients who received these 2 carfilzomib doses. MATERIALS AND METHODS: Patient data from 4 cohorts of MM patients treated with single-agent carfilzomib in phase II trials were examined post hoc. The relationship between administered doses and overall response rate (ORR) was assessed using logistic regression models. Secondary analyses were performed using Cox regression models to assess the association between administered doses and time to event outcomes and using generalized estimating equations for cycle-specific response status (CSRS). RESULTS: A total of 476 intention to treat patients were enrolled, 461 of whom were evaluable for efficacy. In the primary analysis, adjustment for cohort and baseline covariates yielded an odds ratio for ORR of 1.28 (95% confidence interval, 1.16-1.41; P < .001) for each 1 mg/m(2) increase in the average administered dose of carfilzomib per patient (up to 27 mg/m(2)). Qualitatively similar and statistically significant results were seen for the association between administered dose and CSRS, duration of response, time to progression, progression-free survival, and overall survival when adjusted for cohort and baseline covariates. CONCLUSION: This post hoc analysis provides evidence for a dose-response relationship between the administered dose of carfilzomib and efficacy. PMID- 26482108 TI - Prognostic Significance of Monosomal Karyotype in Adult Patients With Acute Myeloid Leukemia Treated With Risk-Adapted Protocols. AB - BACKGROUND: The monosomal karyotype (MK) is a well-known adverse prognostic factor and has been found to be related to poor outcome in patients with acute myeloid leukemia (AML). However, the outcome in MK-positive AML patients undergoing different therapies has not been well investigated. PATIENTS AND METHODS: We retrospectively analyzed clinical and laboratory features in 225 MK positive AML patients. Clinical outcome of overall survival (OS) and disease-free survival (DFS) was evaluated in patients according to age group and in patients who received different therapy protocols. RESULTS: The proportion of MK-positive patients increased along with age. Also, patients who were treated with high-dose cytarabine (HD-Ara-C) as consolidation therapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) demonstrated longer OS and DFS compared to allo-HSCT or HD-Ara-C alone. Patients treated with allo-HSCT alone exhibited longer DFS compared to patients treated with HD-Ara-C alone. No difference in OS was discovered between these 2 single protocols. CONCLUSION: MK was associated with a lower complete remission rate. HD-Ara-C therapy followed by allo-HSCT could improve the prognosis of MK-positive AML patients. PMID- 26482109 TI - Adverse Events During Hematopoietic Stem Cell Infusion: Analysis of the Infusion Product. AB - BACKGROUND: Stem cell transplantation is a treatment option for patients with cancer. However, a risk of adverse events might be associated with the infusion itself. An understanding of the types and grades of adverse events occurring during infusion and the patient and infusion characteristics that might be associated with these events could allow for interventions to minimize these complications. The risk factors associated with transplant-related adverse events are not well understood. MATERIALS AND METHODS: We retrospectively analyzed the adverse events occurring within 1 hour after infusion in 460 patients with cancer undergoing stem cell transplantation at the Northwestern University Robert H. Lurie Comprehensive Cancer Center from January 1, 2008 and May 1, 2011. Of the 460 patients, 382 received autologous transplants and 78 allogeneic transplants. The incidence, types, and National Cancer Institute Common Terminology Criteria grade of toxicity for adverse events were noted (primary objective). Univariate analyses were performed to study which patient and infusion characteristics might be associated with the occurrence of adverse events (secondary objectives). RESULTS: Of the 460 patients, 261 (56.7%) experienced adverse events (66.7% during allogeneic infusion and 54.7% during autologous infusion). Most events were cardiopulmonary. Univariate analysis of the infusion and patient characteristics revealed that a second transplant (P = .005) was associated with more adverse events for autologous transplant patients. For allogeneic transplant patients, a higher infusion red blood cell volume (P = .01) was associated with more adverse events. CONCLUSION: Adverse events are common during stem cell infusion and are generally cardiopulmonary. PMID- 26482110 TI - Intermittent oral iron supplementation during pregnancy. AB - BACKGROUND: Anaemia is a frequent condition during pregnancy, particularly among women in low- and middle-income countries. Traditionally, gestational anaemia has been prevented with daily iron supplements throughout pregnancy, but adherence to this regimen due to side effects, interrupted supply of the supplements, and concerns about safety among women with an adequate iron intake, have limited the use of this intervention. Intermittent (i.e. two or three times a week on non consecutive days) supplementation has been proposed as an alternative to daily supplementation. OBJECTIVES: To assess the benefits and harms of intermittent supplementation with iron alone or in combination with folic acid or other vitamins and minerals to pregnant women on neonatal and pregnancy outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2015), the WHO International Clinical Trials Registry Platform (ICTRP) (31 July 2015) and contacted relevant organisations for the identification of ongoing and unpublished studies (31 July 2015). SELECTION CRITERIA: Randomised or quasi-randomised trials. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy. MAIN RESULTS: This review includes 27 trials from 15 countries, but only 21 trials (with 5490 women) contributed data to the review. All studies compared daily versus intermittent iron supplementation. The methodological quality of included studies was mixed and most had high levels of attrition.The overall assessment of the quality of the evidence for primary infant outcomes was low and for maternal outcomes very low.Of the 21 trials contributing data, three studies provided intermittent iron alone, 14 intermittent iron + folic acid and four intermittent iron plus multiple vitamins and minerals in comparison with the same composition of supplements provided in a daily regimen.Overall, for women receiving any intermittent iron regimen (with or without other vitamins and minerals) compared with a daily regimen there was no clear evidence of differences between groups for any infant primary outcomes: low birthweight (average risk ratio (RR) 0.82; 95% confidence interval (CI) 0.55 to 1.22; participants = 1898; studies = eight; low quality evidence), infant birthweight (mean difference (MD) 5.13 g; 95% CI -29.46 to 39.72; participants = 1939; studies = nine; low quality evidence), premature birth (average RR 1.03; 95% CI 0.76 to 1.39; participants = 1177; studies = five; low quality evidence), or neonatal death (average RR 0.49; 95% CI 0.04 to 5.42; participants = 795; studies = one; very low quality). None of the studies reported congenital anomalies.For maternal outcomes, there was no clear evidence of differences between groups for anaemia at term (average RR 1.22; 95% CI 0.84 to 1.80; participants = 676; studies = four; I2 = 10%; very low quality). Women receiving intermittent supplementation had fewer side effects (average RR 0.56; 95% CI 0.37 to 0.84; participants = 1777; studies = 11; I2 = 87%; very low quality) and were at lower risk of having high haemoglobin (Hb) concentrations (greater than 130 g/L) during the second or third trimester of pregnancy (average RR 0.53; 95% CI 0.38 to 0.74; participants = 2616; studies = 15; I2 = 52%; (this was not a primary outcome)) compared with women receiving daily supplements. There were no significant differences in iron-deficiency anaemia at term between women receiving intermittent or daily iron + folic acid supplementation (average RR 0.71; 95% CI 0.08 to 6.63; participants = 156; studies = one). There were no maternal deaths (six studies) or women with severe anaemia in pregnancy (six studies). None of the studies reported on iron deficiency at term or infections during pregnancy.Most of the studies included in the review (14/21 contributing data) compared intermittent oral iron + folic acid supplementation compared with daily oral iron + folic acid supplementation (4653 women) and findings for this comparison broadly reflect findings for the main comparison (any intermittent versus any daily regimen).Three studies with 464 women examined supplementation with intermittent oral iron alone compared with daily oral iron alone. There were no clear differences between groups for mean birthweight, preterm birth, maternal anaemia or maternal side effects. Other primary outcomes were not reported.Four studies with a combined sample size of 412 women compared intermittent oral iron + vitamins and minerals supplementation with daily oral iron + vitamins and minerals supplementation. Results were not reported for any of the review's infant primary outcomes. One study reported fewer maternal side effects in the intermittent iron group, and two studies that more women were anaemic at term compared with those receiving daily supplementation.Where sufficient data were available for primary outcomes, we set up subgroups to look for possible differences between studies in terms of earlier or later supplementation; women's anaemia status at the start of supplementation; higher and lower weekly doses of iron; and the malarial status of the region in which the trials were conducted. There was no clear effect of these variables on results. AUTHORS' CONCLUSIONS: This review is the most comprehensive summary of the evidence assessing the benefits and harms of intermittent iron supplementation in pregnant women on haematological and pregnancy outcomes. Findings suggest that intermittent regimens produced similar maternal and infant outcomes as daily supplementation but were associated with fewer side effects and reduced the risk of high levels of Hb in mid and late pregnancy, although the risk of mild anaemia near term was increased. While the quality of the evidence was assessed as low or very low, intermittent may be a feasible alternative to daily iron supplementation among those pregnant women who are not anaemic and have adequate antenatal care. PMID- 26482111 TI - Safety of Anti-TNF Therapies in Immune-Mediated Inflammatory Diseases: Focus on Infections and Malignancy. AB - Preclinical Research The efficacy of anti-TNF agents in the treatment of multiple immune-mediated inflammatory diseases (IMIDs) has increased their daily use. However, concerns remain regarding their long-term safety profile. Using a literature-based review of the infectious and malignant complications of anti-TNF biologics in IMIDs including psoriasis, Rheumatoid Arthritis, and inflammatory bowel disease, this review presents current evidence relative to the safety of anti-TNF agents in the context infections and malignancy in adults with IMIDs. Treatment with anti-TNF biologics is an effective treatment option with known risks that can be mitigated by appreciating the safety aspects and via a thorough screening and continuous monitoring of the patient. PMID- 26482112 TI - Electrophysiological correlates of emotional meaning in context in relation to facets of schizotypal personality traits: A dimensional study. AB - AIMS: The aim of this study was to investigate the neurocognitive processes mediating the processing of emotional information during the integration of contextual and social information in a schizotypal population. METHODS: One hundred and thirty-one healthy participants were evaluated using the Schizotypal Personality Questionnaire and event-related potentials were recorded during a linguistic task in which participants read sentence pairs describing short social situations to themselves. The first sentence implicitly conveyed the positive or negative emotional state of a character. The second sentence was emotionally congruent or incongruent with the first sentence. RESULTS: Across our overall sample, our results revealed a greater N400 effect at right sites than left sites, whereas the late positive component effect was only observed at left sites. Concerning the correlation results, we observed a negative link between positive and global schizotypy and N400 modulation in response to congruent targets for positive context sentences. Results also showed a positive correlation between negative schizotypy and late positive component modulation in response to congruent targets for negative context sentences. CONCLUSIONS: These results suggest that the different facets of the schizotypal personality traits influenced the integration of emotional context at the level of both early and later-mobilized neurocognitive processes. PMID- 26482113 TI - Ring Expansions of Boroles with Diazo Compounds: Steric Control of C or N Insertion and Aromatic/Nonaromatic Products. AB - Access to novel imine-substituted 1,2-azaborinines, as well as highly arylated boracyclohexa-3,5-dienes has been developed by ring expansion of boroles with diazoalkanes with varying degrees of steric bulk. The formation of a diazoalkane intermediate is also discussed for the reaction of ortho-brominated p-tolyl-azide with 1,2,3,4,5-pentaphenylborole. Structural details as well as UV/Vis spectroscopic and cyclic voltammetric data are provided. These boron-containing heterocycles have the potential to serve as building blocks for boron-containing materials. PMID- 26482114 TI - A novel fluorescent probe based on rhodamine hydrazone derivatives bearing a thiophene group for Al3+. AB - In the present work, a novel 5-methyl-thiophene-carbaldehyde-functionalized rhodamine 6G Schiff base (RA) was designed and easily prepared as an Al(3+) fluorescent and colorimetric probe, which could selectively and sensitively detect Al(3+) by showing enhanced fluorescence emission. Meanwhile distinct color variation from colorless to pink also provided 'naked eye' detection of Al(3+), due to the ring spirolactam opening of the rhodamine derivative. Other metal ions (including K(+), Mg(2+), Na(+), Ba(2+), Mn(2+), Cd(2+), Fe(2+), Ni(2+), Pb(2+), Zn(2+), Hg(2+), Co(2+), Li(+), Sr(2+) and Cu(2+)) could only induce limited interference. The detection limit of the fluorescent probe was estimated to be 4.17 * 10(-6) M, the binding constant of the RA-Al(3+) complex was 1.4 * 10(6) M(-1). Moreover, this fluorescent probe RA possessed high reversibility. As aluminum is a ubiquitous metal in nature and plays vital roles in many biological processes, this chemosensor could be explored for biological study applications. PMID- 26482115 TI - Effect of Cross-Link Density on Carbon Dioxide Separation in Polydimethylsiloxane Norbornene Membranes. AB - The development of high-performance materials for carbon dioxide separation and capture will significantly contribute to a solution for climate change. Herein, (bicycloheptenyl)ethyl-terminated polydimethylsiloxane (PDMSPNB) membranes with varied cross-link densities were synthesized via ring-opening metathesis polymerization. The developed polymer membranes show higher permeability and better selectivity than those of conventional cross-linked PDMS membrane. The achieved performance (CO2 permeability~6800 Barrer; CO2 /N2 selectivity~14) is very promising for practical applications. The key to achieving this high performance is the use of an in situ cross-linking method for difunctional PDMS macromonomers, which provides lightly cross-linked membranes. By combining positron annihilation lifetime spectroscopy, broadband dielectric spectroscopy, and gas solubility measurements, key parameters necessary for achieving excellent performance have been elucidated. PMID- 26482116 TI - Is anxiety more common in school students with newly diagnosed specific learning disabilities? A cross-sectional questionnaire-based study in Mumbai, Maharashtra, India. AB - BACKGROUND AND OBJECTIVES: School students with specific learning disabilities (SpLDs) experience chronic academic underachievement and resultant stress. The present study aimed to determine if school students with newly diagnosed SpLD were more likely to have anxiety than their regular peers. MATERIALS AND METHODS: The study cases (aged 8-15 years) were recruited from our institute's learning disability clinic. The matched controls were recruited from four schools in Mumbai, Maharashtra, India. Anxiety was measured using the Spence Children's Anxiety Scale (SCAS)-child self-report version questionnaire. Median SCAS scores and the proportion of students with an SCAS score in the "clinical anxiety" range were compared between the groups. RESULTS: SCAS scores were significantly higher in 8-11-year-old learning-disabled male and female students (P < 0.0001 for both groups) and 12-15-year-old female students (P = 0.004), as compared with matched controls. A significantly higher number of learning-disabled students were found to have "clinical anxiety" [24.64% vs. 4.35%, crude odds ratio (OR) = 7.19, 95% confidence interval (CI) 2.91-17.78, P = 0.0001], as compared with the controls regardless of gender, age group, presence of comorbid attention deficit/hyperactivity disorder (ADHD), or associated medical conditions. A significantly higher proportion of 8-11-year-old learning-disabled students, especially males, were found to have "clinical anxiety" as compared with 12-15 year-old learning-disabled students (crude OR = 4.38, 95% CI 1.94-9.92, P = 0.0004). Gender, presence of comorbid ADHD or associated medical conditions, and type of school attended or curriculum did not impact the prevalence of "clinical anxiety" in learning-disabled students. INTERPRETATION AND CONCLUSIONS: Students with newly diagnosed SpLD have greater odds of being "clinically anxious" relative to their regular peers. We recommend screening for anxiety in children with SpLD immediately after diagnosis so that their optimum rehabilitation can be facilitated. PMID- 26482118 TI - Response to Andriy Danyliv. PMID- 26482119 TI - Skin Perfusion Pressure and the Prevalence of Atherothrombosis in Hemodialysis Patients. AB - End-stage renal disease is associated with atherothrombosis (ATIS), which, in turn, can promote peripheral arterial occlusive disease (PAOD), coronary artery disease (CAD), and/or cerebrovascular disease (CVD). The aim of this study was to determine whether low plantar skin perfusion pressure (SPP) was related to ATIS among 122 patients receiving maintenance hemodialysis (HD) from March to November 2013 at our outpatient facility. We routinely measured SPP and used the value for analysis. In addition, we retrospectively evaluated the prevalence of ATIS with patients categorized to CAD, CVD, or PAOD groups. Of the 122 outpatients, ATIS was diagnosed in about half (N = 60, 49.2% vs. 62, 50.8%; average SPP, 56.6 vs. 72.9 mm Hg, respectively). These data show that SPP was significantly lower in patients with ATIS (difference, 16.3 mm Hg; P < 0.001) and there was a negative relationship between average SPPs and past history of ATIS complications. When the patients were stratified by the presence of diabetes mellitus, this trend was stronger. Particularly, receiver operating characteristic analysis of HD patients with diabetes revealed a cutoff point of 53.0 mm Hg and an area under the curve value of 0.84, with a sensitivity of 77.0% and specificity of 91.3%. Therefore, we concluded that SPP enables the evaluation of not only local PAOD, but also systemic ATIS. Moreover, we found that a cutoff point of 53.0 mm Hg was useful for detection of ATIS in HD patients. PMID- 26482120 TI - Application of Transmitted Kikuchi Diffraction in Studying Nano-oxide and Ultrafine Metallic Grains. AB - Transmitted Kikuchi diffraction (TKD) is an emerging SEM-based technique that enables investigation of highly refined grain structures. It offers higher spatial resolution by utilizing conventional electron backscattered diffraction equipment on electron-transparent samples. A successful attempt has been made to reveal nano-oxide grain structures as well as ultrafine severely deformed metallic grains. The effect of electron beam current was studied. Higher beam currents enhance pattern contrast and intensity. Lower detector exposure times could be employed to accelerate the acquisition time and minimize drift and carbon contamination. However, higher beam currents increase the electron interaction volume and compromise the spatial resolution. Lastly, TKD results were compared to orientation mapping results in TEM (ASTAR). Results indicate that a combination of TKD and EDS is a capable tool to characterize nano-oxide grains such as Al2O3 and Cr2O3 with similar crystal structures. PMID- 26482121 TI - Quantifying randomness in real networks. AB - Represented as graphs, real networks are intricate combinations of order and disorder. Fixing some of the structural properties of network models to their values observed in real networks, many other properties appear as statistical consequences of these fixed observables, plus randomness in other respects. Here we employ the dk-series, a complete set of basic characteristics of the network structure, to study the statistical dependencies between different network properties. We consider six real networks--the Internet, US airport network, human protein interactions, technosocial web of trust, English word network, and an fMRI map of the human brain--and find that many important local and global structural properties of these networks are closely reproduced by dk-random graphs whose degree distributions, degree correlations and clustering are as in the corresponding real network. We discuss important conceptual, methodological, and practical implications of this evaluation of network randomness, and release software to generate dk-random graphs. PMID- 26482122 TI - Locomotor response to acute nicotine in adolescent mice is altered by maternal undernutrition during lactation. AB - Undernutrition during brain development causes long lasting alterations in different neurotransmitter systems that may alter responses to psychoactive drugs. Despite the recognized effects of early undernutrition on the cholinergic system, no evidence that demonstrates the influence of this insult on nicotine susceptibility has been reported. We investigated the effects of protein/calorie restriction during lactation on the susceptibility to nicotine in adolescent mice. Dams were randomly assigned to one of the following groups: Control (C, 20 litters)--free access to standard laboratory diet (23% protein); Protein Restricted (PR, 12 litters)--free access to a isoenergetic, 8% protein diet; Calorie Restricted (CR, 12 litters)--access to standard laboratory diet in restricted quantities (mean ingestion of PR: pair-fed group). Undernutrition extended from postnatal day 2 (PN2) to weaning (PN21). At PN30, animals either received an i.p. injection of nicotine (0.5mg/Kg) or saline and were immediately placed in open field (OF). After the OF, adrenal glands and serum were collected for the analyses of stress-related endocrine parameters and leptin concentration. PR and CR offspring showed less body mass gain and visceral fat mass. PR offspring presented reduced serum leptin concentration. In the OF, nicotine increased locomotor activity of C and PR, but not of CR. CR and PR offspring showed decreased adrenal catecholamine content, which was not dependent on nicotine exposure. Our results indicate that early undernutrition interferes with nicotine-elicited locomotor effects in adolescent mice and suggest that endocrine parameters alterations in malnourished animals do not influence the behavioral response to nicotine. PMID- 26482124 TI - The copper-catalyzed aerobic oxidative amidation of tertiary amines. AB - A general and efficient method for the synthesis of tertiary amides has been developed via the copper-catalyzed aerobic oxidative amidation of tertiary amines. Due to the use of the O2 oxidant, various functional groups were well tolerated under the present conditions. Extensive substrates studies demonstrated its potential as a practical approach for the synthesis of tertiary amides. PMID- 26482123 TI - Understanding the molecular aspects of oriental obesity pattern differentiation using DNA microarray. AB - BACKGROUND: Human constitution, the fundamental basis of oriental medicine, is categorized into different patterns for a particular disease according to the physical, physiological, and clinical characteristics of the individuals. Obesity, a condition of metabolic disorder, is classified according to six patterns in oriental medicine, as follows: spleen deficiency syndrome, phlegm fluid syndrome, yang deficiency syndrome (YDS), food accumulation syndrome (FAS), liver depression syndrome (LDS), and blood stasis syndrome. In oriental medicine, identification of the disease pattern for individual obese patients is performed on the basis of differentiation in obesity syndrome index and, accordingly, personalized treatment is provided to the patients. The aim of the current study was to understand the obesity patterns in oriental medicine from the genomic point of view via determining the gene expression signature of obese patients using peripheral blood mononuclear cells as the samples. METHODS: The study was conducted in 23 South Korean obese subjects (19 female and four male) with BMI >=25 kg/m(2). Identification of oriental obesity pattern was based on the software-guided evaluation of the responses of the subjects to a questionnaire developed by the Korean Institute of Oriental Medicine. The expression profiles of genes were determined using DNA microarray and the level of transcription of genes of interest was further evaluated using quantitative real-time PCR (qRT PCR). RESULTS AND CONCLUSION: Gene clustering analysis of the microarray data from the FAS, LDS, and YDS subjects exhibited disease pattern-specific upregulation of expression of several genes in a particular cluster. Further analysis of transcription of selected genes using qRT-PCR led to identification of specific genes, including prostaglandin endoperoxide synthase 2, G0/G1 switch 2, carcinoembryonic antigen-related cell adhesion molecule 3, cystein-serine-rich nuclear protein 1, and interleukin 8 receptor, alpha which were highly expressed in LDS obesity constitution. Our current study can be considered as a valuable contribution to the understanding of possible explanation for obesity pattern differentiation in oriental medicine. Further studies can address a novel possibility that the genomic and oriental empirical approaches can be combined and implemented in systematic and synergistic development of personalized medicine. This clinical trial was registered in Clinical Research Information Service of Korea National Institute of Health ( https://cris.nih.go.kr/cris/index.jsp ). REGISTRATION NUMBER: KCT0000387. PMID- 26482125 TI - Reversible Dimerization of Phosphine-Stabilized Silylenes by Silylene Insertion into Si(II) -H and Si(II) -Cl sigma-Bonds at Room Temperature. AB - Contrary to the classical silylene dimerization leading to a disilene structure, phosphine stabilized hydro- and chloro-silylenes (2 a,b) undergo an unique dimerization via silylene insertion into Si?X sigma-bonds (X=H, Cl), which is reversible at room temperature. DFT calculations indicate that the insertion reaction proceeds in one step in a concerted manner. PMID- 26482126 TI - A recommended workflow methodology in the creation of an educational and training application incorporating a digital reconstruction of the cerebral ventricular system and cerebrospinal fluid circulation to aid anatomical understanding. AB - BACKGROUND: The use of computer-aided learning in education can be advantageous, especially when interactive three-dimensional (3D) models are used to aid learning of complex 3D structures. The anatomy of the ventricular system of the brain is difficult to fully understand as it is seldom seen in 3D, as is the flow of cerebrospinal fluid (CSF). This article outlines a workflow for the creation of an interactive training tool for the cerebral ventricular system, an educationally challenging area of anatomy. This outline is based on the use of widely available computer software packages. METHODS: Using MR images of the cerebral ventricular system and several widely available commercial and free software packages, the techniques of 3D modelling, texturing, sculpting, image editing and animations were combined to create a workflow in the creation of an interactive educational and training tool. This was focussed on cerebral ventricular system anatomy, and the flow of cerebrospinal fluid. RESULTS: We have successfully created a robust methodology by using key software packages in the creation of an interactive education and training tool. This has resulted in an application being developed which details the anatomy of the ventricular system, and flow of cerebrospinal fluid using an anatomically accurate 3D model. In addition to this, our established workflow pattern presented here also shows how tutorials, animations and self-assessment tools can also be embedded into the training application. CONCLUSIONS: Through our creation of an established workflow in the generation of educational and training material for demonstrating cerebral ventricular anatomy and flow of cerebrospinal fluid, it has enormous potential to be adopted into student training in this field. With the digital age advancing rapidly, this has the potential to be used as an innovative tool alongside other methodologies for the training of future healthcare practitioners and scientists. This workflow could be used in the creation of other tools, which could be developed for use not only on desktop and laptop computers but also smartphones, tablets and fully immersive stereoscopic environments. It also could form the basis on which to build surgical simulations enhanced with haptic interaction. PMID- 26482127 TI - Resolving ambiguities in nanowire field-effect transistor characterization. AB - We have modeled InAs nanowires using finite element methods considering the actual device geometry, the semiconducting nature of the channel and surface states, providing a comprehensive picture of charge distribution and gate action. The effective electrostatic gate width and screening effects are taken into account. A pivotal aspect is that the gate coupling to the nanowire is compromised by the concurrent coupling of the gate electrode to the surface/interface states, which provide the vast majority of carriers for undoped nanowires. In conjunction with field-effect transistor (FET) measurements using two gates with distinctly dissimilar couplings, the study reveals the density of surface states that gives rise to a shallow quantum well at the surface. Both gates yield identical results for the electron concentration and mobility only at the actual surface state density. Our method remedies the flaws of conventional FET analysis and provides a straightforward alternative to intricate Hall effect measurements on nanowires. PMID- 26482130 TI - The effect of a broad activation energy distribution on deuteron spin-lattice relaxation. AB - Deuteron NMR spectra and spin-lattice relaxation were studied experimentally in zeolite NaY(2.4) samples containing 100% or 200% of CD3OH or CD3OD molecules of the total coverage of Na atoms in the temperature range 20-150K. The activation energies describing the methyl and hydroxyl motions show broad distributions. The relaxation data were interpreted by improving a recent model (Stoch et al., 2013 [16]) in which the nonexponential relaxation curves are at first described by a sum of three exponentials with adjustable relaxation rates and weights. Then a broad distribution of activation energies (the mean activation energy A0 and the width sigma) was assumed for each essentially different methyl and hydroxyl position. The correlation times were calculated from the Arrhenius equation (containing the pre-exponential factor tau0), individual relaxation rates computed and classified into three classes, and finally initial relaxation rates and weights for each class formed. These were compared with experimental data, motional parameters changed slightly and new improved rates and weights for each class calculated, etc. This method was improved by deriving for the deuterons of the A and E species methyl groups relaxation rates, which depend explicitly on the tunnel frequency omegat. The temperature dependence of omegat and of the low temperature correlation time were obtained by using the solutions of the Mathieu equation for a threefold potential. These dependencies were included in the simulations and as the result sets of A0, sigma and tau0 obtained, which describe the methyl and hydroxyl motions in different positions in zeolite. PMID- 26482128 TI - Screen-and-treat program by point-of-care of Atopobium vaginae and Gardnerella vaginalis in preventing preterm birth (AuTop trial): study protocol for a randomized controlled trial. AB - BACKGROUND: International recommendations in favor of screening for vaginal infection in pregnancy are based on heterogeneous criteria. In most developed countries, the diagnosis of bacterial vaginosis is only recommended for women with high-risk of preterm birth. The Nugent score is currently used, but molecular quantification tools have recently been reported with a high sensitivity and specificity. Their value for reducing preterm birth rates and related complications remains unexplored. This trial was designed to assess the cost-effectiveness of a systematic screen-and-treat program based on a point-of care technique for rapid molecular diagnosis, immediately followed by an appropriate antibiotic treatment, to detect the presence of abnormal vaginal flora (specifically, Atopobium vaginae and Gardnerella vaginalis) before 20 weeks of gestation in pregnant women in France. We hypothesized that this program would translate into significant reductions in both the rate of preterm births and the medical costs associated with preterm birth. METHODS/DESIGN: A multicenter, open label randomized controlled trial (RCT) will be conducted in which 20 French obstetrics and gynecology centers will recruit eligible pregnant women at less than 20 weeks gestation with singleton pregnancy and with a low-risk factor for preterm birth. Interventions will include a) an experimental group that will receive a systematic rapid screen-and-treat program from a point-of-care analysis using a molecular quantification method and b) a control group that will receive usual care management. Randomization will be in a 1:1 allocation ratio. The primary endpoint that will be assessed over a period of 12 months will be the incremental cost-effectiveness ratio (ICER) expressed as cost per avoided preterm birth before 37 weeks. Secondary endpoints will include ICER per avoided preterm birth before 24, 28 and 32 weeks, obstetrical outcomes, neonatal outcomes, rates of treatment failure and recurrence episodes for positive women. Uncertainty surrounding these estimates will be addressed using nonparametric bootstrapping and represented using cost-effectiveness acceptability curves. A total of 6,800 pregnant women will be included. DISCUSSION: This appropriate randomized controlled design will provide insight into the cost-effectiveness and therefore the potential cost savings of a rapid screen-and-treat strategy for molecular abnormal vaginal flora in pregnant women. National and international recommendations could be updated based on the findings of this study. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02288832 (registration date: 30 October 2014); Eudract: 2014-001559-22. PMID- 26482129 TI - Fever phobia: a comparison survey between caregivers in the inpatient ward and caregivers at the outpatient department in a children's hospital in China. AB - BACKGROUND: Fever in children is one of the most common clinical symptoms and a chief complaint and a main reason that caregivers took the children to the outpatient service or admitted to hospital. Studies have found that the majority of parents surveyed at a hospital pediatric clinic held unrealistic and unwarranted concerns about fevers, first termed as 'fever phobia' by Schmitt in 1980. In the present study, we explore whether 'fever phobia' exists in Chinese caregivers and investigate whether such phobia is alleviated when admitted to hospital after propaganda of fever related knowledge by doctors and nurses. METHODS: A questionnaire was distributed to caregivers of children who visited the pediatric outpatient department and those with caregivers in the wards between June 2012 and Feb 2013 in Wenzhou, China. RESULTS: Data were obtained from 621 caregivers, 305(49%) from the OPD and 316(51%) from the ward. Most caregivers of the two groups (OPD vs. ward group, 75.1 vs. 74.4%) believed fever could cause brain damage. 77.7% (76.0 vs. 81.3%) caregivers were very worried when their children had fever and 12.8% (14.1 vs. 11.4%) caregivers would check the temperature within 30 min. Moreover, 68.0% (63.0 vs. 72.8%, P < 0.05) caregivers would give their children antipyretics during sleep and 39.9% (40.3 vs. 39.6%) would administrate antipyretics when temperature was above 38 degrees C. After admitted to hospital, 83.9% caregivers stated to have received education about fever and 96.5% felt relieved. Less caregivers (ward group vs. OPD, 42.4 vs. 46.9%, P < 0.05) from ward group would give antipyretics with a temperature under 38.5 degrees C and less (0.6 vs. 4.9%, P < 0.05) preferred cold sponging as physical cooling method compared to the OPD caregivers. Alarmingly, more caregivers (42.7 vs. 34.3%, P < 0.05) in the ward group believed fever could lead to death or/and deafness (17.4 vs. 10.5%, P < 0.05) and even 0.6% caregivers in the ward group chose aspirin when the children had fever. CONCLUSION: 'Fever phobia' also exists in Chinese caregivers. Fever related knowledge propaganda after admitted to hospital did not work effectively to improve the caregivers' understanding and management of fever and an effective way to alleviate 'Fever phobia'. PMID- 26482131 TI - Frequency swept microwaves for hyperfine decoupling and time domain dynamic nuclear polarization. AB - Hyperfine decoupling and pulsed dynamic nuclear polarization (DNP) are promising techniques to improve high field DNP NMR. We explore experimental and theoretical considerations to implement them with magic angle spinning (MAS). Microwave field simulations using the high frequency structural simulator (HFSS) software suite are performed to characterize the inhomogeneous phase independent microwave field throughout a 198GHz MAS DNP probe. Our calculations show that a microwave power input of 17W is required to generate an average EPR nutation frequency of 0.84MHz. We also present a detailed calculation of microwave heating from the HFSS parameters and find that 7.1% of the incident microwave power contributes to dielectric sample heating. Voltage tunable gyrotron oscillators are proposed as a class of frequency agile microwave sources to generate microwave frequency sweeps required for the frequency modulated cross effect, electron spin inversions, and hyperfine decoupling. Electron spin inversions of stable organic radicals are simulated with SPINEVOLUTION using the inhomogeneous microwave fields calculated by HFSS. We calculate an electron spin inversion efficiency of 56% at a spinning frequency of 5kHz. Finally, we demonstrate gyrotron acceleration potentials required to generate swept microwave frequency profiles for the frequency modulated cross effect and electron spin inversions. PMID- 26482133 TI - Molecular assembly of highly symmetric molecules under a hydrogen bond framework controlled by alkyl building blocks: a simple approach to fine-tune nanoscale structures. AB - To date, molecular assemblies under the contribution of hydrogen bond in combination with weak interactions and their consequent morphologies have been variously reported; however, how the systematic variation of the structure can fine-tune the morphologies has not yet been answered. The present work finds an answer through highly symmetric molecules, i.e. diamine-based benzoxazine dimers. This type of molecule develops unique molecular assemblies with their networks formed by hydrogen bonds at the terminal, while, at the same time, their hydrogen bonded frameworks are further controlled by the hydrophobic segment at the center of the molecule. When this happens, slight differences in hydrophobic alkyl chain lengths (, , and ) bring a significant change to the molecular assemblies, thus resulting in tunable morphologies, i.e. spheres, needles and dendrites. The superimposition between the crystal lattice obtained from X-ray single crystal analysis and the electron diffraction pattern obtained from transmission electron microscopy allows us to identify the molecular alignment from single molecules to self-assembly until the morphologies developed. The present work, for the first time, shows the case of symmetric molecules, where the hydrophobic building block controls the hydrogen bond patterns, leading to the variation of molecular assemblies with tunable morphologies. PMID- 26482132 TI - Weevil endosymbiont dynamics is associated with a clamping of immunity. AB - BACKGROUND: Insects subsisting on nutritionally unbalanced diets have evolved long-term mutualistic relationships with intracellular symbiotic bacteria (endosymbionts). The endosymbiont population load undergoes changes along with insect development. In the cereal weevil Sitophilus oryzae, the midgut endosymbionts Sodalis pierantonius drastically multiply following adult metamorphosis and rapidly decline until total elimination when the insect achieves its cuticle synthesis. Whilst symbiont load was shown to timely meet insect metabolic needs, little is known about the host molecular and immune processes underlying this dynamics. METHODS: We performed RNA sequencing analysis on weevil midguts at three representative phases of the endosymbiont dynamics (i.e. increase, climax and decrease). To screen genes which transcriptional changes are specifically related to symbiont dynamics and not to the intrinsic development of the midgut, we further have monitored by RT-qPCR sixteen gene transcript levels in symbiotic and artificially non-symbiotic (aposymbiotic) weevils. We also localized the endosymbionts during the elimination process by fluorescence microscopy. RESULTS: Functional analysis of the host differentially expressed genes by RNA sequencing showed that the main transcriptional changes occur during endosymbiont growth phase and affect cell proliferation, apoptosis, autophagy, phagocytosis, and metabolism of fatty acids and nucleic acids. We also showed that symbiont dynamics alters the expression of several genes involved in insect development. Our results strengthened the implication of apoptosis and autophagy processes in symbiont elimination and recycling. Remarkably, apart from the coleoptericin A that is known to target endosymbionts and controls their division and location, no gene coding antimicrobial peptide was upregulated during the symbiont growth and elimination phases. CONCLUSION: We show that endosymbiont dynamics parallels numerous transcriptional changes in weevil developing adults and affects several biological processes, including metabolism and development. It also triggers cell apoptosis, autophagy and gut epithelial cell swelling and delamination. Strikingly, immunity is repressed during the whole process, presumably avoiding tissue inflammation and allowing insects to optimize nutrient recovery from recycled endosymbiont. PMID- 26482134 TI - A Systematic Review on the Effectiveness of Brief Interventions for Alcohol Misuse among Adults in Emergency Departments. AB - Given the frequency with which individuals seek treatment for alcohol-related consequences in emergency departments (EDs), they may be the optimal setting to deliver brief interventions (BIs) for alcohol misuse. Studies examining the effectiveness of BIs for alcohol misuse conducted in EDs have yielded mixed results, and new articles have been published since the last review in 2008. The aim of this study was to provide an updated systematic review on the effectiveness of BIs for alcohol misuse delivered to adults in EDs. Articles published in June 2014 and earlier were identified from online databases (PsycInfo, Healthstar, CINAHL, Medline, Nursing and Allied Health). Search terms included (1) alcohol, (2) "alcohol screening", "brief intervention", "brief alcohol intervention" or feedback and (3) "emergency department" or "emergency room". Once duplicates were removed, 171 abstracts were identified for review. Thirty-four studies were included in the systematic review. All studies reported a significant reduction in alcohol consumption at 3 months post-BI, with some studies finding significant differences between the BI and control groups, and other studies finding significant decreases in both conditions but no between groups differences. The majority of studies did not find significant between group differences at 6 and 12 months post-BI with regard to decreases in alcohol consumption. Individuals who received a BI were significantly less likely to have an alcohol-related injury at 6 or 12 months post-BI than individuals who did not receive a BI. BIs are unlikely to reduce subsequent hospitalizations however, they may be effective in reducing risky driving and motor vehicle crashes associated with alcohol use, which can result in hospitalization. Beyond the effects generated by visiting EDs, BIs delivered in EDs may not be effective in reducing alcohol consumption, or in reducing subsequent hospitalizations. BIs may be effective in reducing some alcohol-related consequences. Future studies ought to investigate for whom BIs are most effective, and the processes that lead to decreases in alcohol consumption and alcohol-related consequences. PMID- 26482135 TI - Six Month Outcomes of a Peer-Enhanced Community Reinforcement Approach for Emerging Adults with Substance Misuse: A Preliminary Study. AB - Little substance use disorder (SUD) treatment research with emerging adults ages 18-25 has been done in community settings, and it is well-known that peers influence emerging adult substance use. The purpose of this study was to develop and test the feasibility of a peer-enhanced behavioral treatment for emerging adults with substance use problems. Emerging adults (n=35) received a peer enhanced version of the Community Reinforcement Approach (Peer-CRA), in which their peers (n=34) were trained to provide alcohol-specific social support. Both identified clients and peers were interviewed at treatment intake, and again three and six months later. Six month outcomes included days of abstinence adjusted for controlled environment days, social costs due to substance use, and binge drinking days in the past 90 days. Treatments were delivered with high fidelity, and a high proportion of participants were retained in treatment and follow-up assessments. Growth curve analyses revealed that emerging adults and their peers significantly increased their days of abstinence and reduced their binge drinking over time. Larger randomized trials should a) test whether peer enhanced treatments are efficacious relative to treatment as usual, b) investigate whether secondary benefits exist for non-treatment seeking peers supporting another's treatment, and c) examine whether proposed mechanisms of change (i.e., peer support and peer reductions in substance use) account for any differences in outcomes. PMID- 26482136 TI - Contingency Management Abstinence Incentives: Cost and Implications for Treatment Tailoring. AB - OBJECTIVE: To examine prize-earning costs of contingency management (CM) incentives in relation to participants' pre-study enrollment drug use status (baseline (BL) positive vs. BL negative) and relate these to previously reported patterns of intervention effectiveness. METHODS: Participants were 255 substance users entering outpatient treatment who received the therapeutic educational system (TES), in addition to usual care counseling. TES included a CM component such that participants could earn up to $600 in prizes on average over 12-weeks for providing drug negative urines and completing web-based cognitive behavior therapy modules. We examined distribution of prize draws and value of prizes earned for subgroups that were abstinent (BL negative; N=136) or not (BL positive; N=119) at study entry based on urine toxicology and breath alcohol screen. RESULTS: Distribution of draws earned (median=119 vs. 17; p<.0001) and prizes redeemed (median=54 vs. 9; p<.001) for drug abstinence differed significantly for BL negative compared to BL positive participants. BL negative earned on average twice as much in prizes as BL positive participants ($245 vs. $125). Median value of prizes earned was 5.4 times greater for BL negative compared to BL positive participants ($237 vs. $44; p<.001). CONCLUSIONS: Two thirds of expenditures in an abstinence incentive program were paid to BL negative participants. These individuals had high rates of drug abstinence during treatment and did not show improved abstinence outcomes with TES versus usual care (Campbell et al., 2014). Effectiveness of the abstinence-focused CM intervention included in TES may be enhanced by tailoring delivery based on patients' drug use status at treatment entry. PMID- 26482137 TI - Regulation of intrinsic apoptosis in cycloheximide-treated macrophages by the Sichuan human strain of Chinese Leishmania isolates. AB - Leishmania spp. are able to survive and proliferate inside mammals' mononuclear phagocytes, causing Leishmaniasis. Previous studies have noted that the regulation of apoptosis in host cells by these parasites may contribute to their ability to evade the immune system. However, current results remain unclear about whether the parasites can promote or delay the apoptotic process in host cells, because the regulatory effect of Leishmania was assumed to be strain-, species- and even infection time-dependent. The aim of this study was to investigate whether the Sichuan isolates of Chinese Leishmania (SC10H2) can alter the process of intrinsic apoptosis induced by cycloheximide in different types of macrophage cell lines and to determine in which steps of the signaling pathway the parasites were involved. Human THP-1 and mouse RAW264.7 macrophages were infected by SC10H2 promastigotes followed by cycloheximide stimulation to assess the alteration of intrinsic apoptosis in these cells. The results indicated that SC10H2 infection of human THP-1 macrophages could promote the initiation of intrinsic apoptosis, but completely opposite results were found in mouse RAW264.7 macrophages. Nevertheless, the expression of Bcl-2 and the DNA fragmentation rates were not altered by SC10H2 infection in the cell lines used in the experiments. This study suggests that SC10H2 promastigote infection is able to promote and delay the transduction of early apoptotic signals induced by cycloheximide in THP-1 and RAW264.7 macrophages, revealing that the regulation of intrinsic apoptosis in host cells by SC10H2 in vitro occurs in a host cell-dependent manner. The data from this study might play a significant role in further understanding the relationship between Leishmania and different host cells. PMID- 26482138 TI - The preoperative plasma fibrinogen level is an independent prognostic factor for overall survival of breast cancer patients who underwent surgical treatment. AB - BACKGROUND: Previous studies have suggested that plasma fibrinogen contributes to tumor cell proliferation, progression and metastasis. The current study was performed to evaluate the prognostic relevance of preoperative plasma fibrinogen in breast cancer patients. METHOD: Data of 2073 consecutive breast cancer patients, who underwent surgery between January 2002 and December 2008 at the Sun Yat-sen University Cancer Center, were retrospectively evaluated. Plasma fibrinogen levels were routinely measured before surgeries. Participants were grouped by the cutoff value estimated by the receiver operating characteristic (ROC) curve analysis. Overall survival (OS) was assessed using Kaplan-Meier analysis, and multivariate Cox proportional hazards regression model was performed to evaluate the independent prognostic value of plasma fibrinogen level. RESULTS: The optimal cutoff value of preoperative plasma fibrinogen was determined to be 2.83 g/L. The Kaplan-Meier analysis showed that patients with high fibrinogen levels had shorter OS than patients with low fibrinogen levels (p < 0.001). Multivariate analysis suggested preoperative plasma fibrinogen as an independent prognostic factor for OS in breast cancer patients (HR = 1.475, 95% confidence interval (CI): 1.177-1.848, p = 0.001). Subgroup analyses revealed that plasma fibrinogen level was an unfavorable prognostic parameter in stage II III, Luminal subtypes and triple-negative breast cancer patients. CONCLUSION: Elevated preoperative plasma fibrinogen was independently associated with poor prognosis in breast cancer patients and may serve as a valuable parameter for risk assessment in breast cancer patients. PMID- 26482139 TI - Regulating BETs at central station. PMID- 26482140 TI - A phospholipase linkAGE to SARS susceptibility. PMID- 26482141 TI - ILC3s protect intestinal stem cells from chemotherapy. PMID- 26482142 TI - IL-27 shakes up the establishment of ectopic lymphoid structures. PMID- 26482143 TI - Peripheral macrophages not ADept at amyloid clearance. PMID- 26482144 TI - Confirmation of the progesterone receptor as an efficient marker of treatment with 17beta-estradiol in veal calves. AB - Under current European Union legislation the use of anabolic steroids in food producing livestock is banned because of their long-term adverse effects on human health. We examined the expression profile of the immunohistochemical marker progesterone receptor in veal calves' sex accessory glands following experimental administration of anabolic compounds. The aim was to confirm the accuracy of the immunohistochemical approach in the detection of the over-expression of the progesterone receptor induced by the administration of sexual steroids at low levels (17beta-estradiol and nandrolone alone or in combination). A total of 217 male veal calves were randomly divided into four groups: group A (104 calves) treated with 17beta-estradiol (5 mg/head; 4 weekly injections); group B (20 calves) treated with nandrolone (50 mg/head; 4 weekly injections); group C (20 calves) treated with the association of the two steroids (5 mg estradiol + 50 mg nandrolone; 4 weekly injections); and group K (73 calves) kept as a control. All the sexual accessory glands were collected at the slaughterhouse (15 days after the last administration) and subjected to immunohistochemical staining with anti progesterone receptor antibody. All the calves treated with 17beta-estradiol alone or in association with nandrolone (groups A and C) showed strong positivity, while nandrolone-treated calves and controls (groups B and K) gave negative results to the immunohistochemical investigation. The statistical analysis showed that the progesterone receptor is a significant predictor of 17beta-estradiol treatment alone or in association with nandrolone (p < 0.001): the immunohistochemical study resulted in 100% sensitivity (CI = 95%: 97.1-100%) and specificity (CI = 95%: 95.1-100%) for prostate and 99% sensitivity (CI = 95%: 95.6-100%) and 100% specificity (CI = 95%: 95.1-100%) for bulbo-urethral glands. The data confirm that this innovative biological approach offers a reliable tool to enhance the efficacy of the histological test to detect illegal treatments with estrogens alone or in association with androgens. PMID- 26482145 TI - Onset Manifestations of Spinal and Bulbar Muscular Atrophy (Kennedy's Disease). AB - Spinal and bulbar muscular atrophy (SBMA) is regarded as a disorder with adult onset between third and fifth decade of life. However, there is increasing evidence that SBMA may start already before adulthood. The present study investigated the following: (1) Which clinical manifestations have been described so far in the literature as initial manifestations? (2) Which was the age at onset of these manifestations? and (3) Is age at onset dependent on the CAG repeat length if non-motor manifestations are additionally considered? Data for this review were identified by searches of MEDLINE using appropriate search terms. Onset manifestations in SBMA can be classified as frequent, rare, motor, non-motor, or questionable. Frequent are muscle weakness, cramps, fasciculations/twitching, tremor, dysarthria, dysphagia, or gynecomastia. Rare are myalgia, easy fatigability, exercise intolerance, polyneuropathy, hyper CKemia, under-masculinized genitalia, scrotal hypospadias, microphallus, laryngospasm, or oligospermia. Questionable manifestations include sensory disturbances, cognitive impairment, increased pituitary volume, diabetes, reduced tongue pressure, elevated creatine-kinase, or low androgens/high estrogens. Age at onset is highly variable ranging from 4-76 years. Non-motor manifestations develop usually before motor manifestations. Age at onset depends on what is considered as an onset manifestation. Considering non-motor onset manifestations, age at onset is independent of the CAG-repeat size. In conclusion, age at onset of SBMA depends on what is regarded as onset manifestation. If non-motor manifestations are additionally considered, age at onset is independent of the CAG-repeat length. Since life expectancy is hardly reduced in SBMA, re investigation of patients from published studies with regard to their initial disease profiles is recommended. PMID- 26482146 TI - Individual level determinants for not receiving immunization, receiving immunization with delay, and being severely underimmunized among rural western Kenyan children. AB - BACKGROUND: Estimating vaccination coverage and delays are important because these measures can identify at risk sub-populations who can be targeted with interventions and public health policies. This paper sought to determine estimates and risk factors for children in rural western Kenya who did not receive immunization, received immunization with delay, or were severely underimmunized. METHODS: Caregivers of children aged 12-23 months old were surveyed for immunization history using written records from the immunization booklet. Risk factors for not receiving immunization, delayed immunization, and severe underimmunization were calculated using log-binomial regression. Children were categorized as delayed if a given immunization was received greater than four weeks from the age-appropriate scheduled date. Severely underimmunized children were those who were fully unvaccinated for more than 90 days and had three or more vaccines delayed or not given. RESULTS: Immunization coverage for pentavalent1, pentavalent3, measles, and fully immunized child (FIC; BCG, three doses of polio, three doses of pentavalent, and measles vaccines) were 99%, 94%, 83%, and 80%, respectively. Approximately, 10%, 24%, and 29%, of children were delayed for pentavalent1, pentavalent3, and measles, respectively. Each model produced a unique combination of risk factors with only advanced maternal age as a risk factor common to all models. Children with delayed receipt of pentavalent1 were at risk for not receiving pentavalent3 (RR: 5.20; 95%CI 3.48, 7.77), measles vaccine (RR: 1.48; 95%CI 1.12, 1.95), and not achieving FIC (RR: 1.88; 95%CI 1.51, 2.34) compared with children who received pentavalent1 on time. CONCLUSIONS: Immunization coverage among 12-23 month old children was high, yet a substantial proportion of children were vaccinated with delay. Although vaccine coverage and timeliness are often conceptualized as separate measures, the finding that delayed pentavalent1 receipt was a strong risk factor for not receiving future immunizations indicates the two measures are intertwined. PMID- 26482147 TI - Checkpoint blockade in combination with cancer vaccines. AB - Checkpoint blockade, prevention of inhibitory signaling that limits activation or function of tumor antigen-specific T cells responses, is revolutionizing the treatment of many poor prognosis malignancies. Indeed monoclonal antibodies that modulate signaling through the inhibitory molecules CTLA-4 and PD-1 are now clinically available; however, many tumors, demonstrate minimal response suggesting the need for combinations with other therapeutic strategies. Because an inadequate frequency of activated tumor antigen-specific T cells in the tumor environment, the so-called non-inflamed phenotype, is observed in some malignancies, other rationale partners are modalities that lead to enhanced T cell activation (vaccines, cytokines, toll-like receptor agonists, and other anticancer therapies such as chemo-, radio- or targeted therapies that lead to release of antigen from tumors). This review will focus on preclinical and clinical data supporting the use of cancer vaccines with anti-CTLA-4 and anti-PD 1/PD-L1 antibodies. Preliminary preclinical data demonstrate enhanced antitumor activity although the results in human studies are less clear. Broader combinations of multiple immune modulators are now under study. PMID- 26482148 TI - Consumption of anthocyanin-rich cherry juice for 12 weeks improves memory and cognition in older adults with mild-to-moderate dementia. AB - PURPOSE: Dietary flavonoids, including anthocyanins, may positively influence cognition and may be beneficial for the prevention and treatment of dementia. We aimed to assess whether daily consumption of anthocyanin-rich cherry juice changed cognitive function in older adults with dementia. Blood pressure and anti inflammatory effects were examined as secondary outcomes. METHODS: A 12-week randomised controlled trial assessed cognitive outcomes in older adults (+70 year) with mild-to-moderate dementia (n = 49) after consumption of 200 ml/day of either a cherry juice or a control juice with negligible anthocyanin content. Blood pressure and inflammatory markers (CRP and IL-6) were measured at 6 and 12 weeks. ANCOVA controlling for baseline and RMANOVA assessed change in cognition and blood pressure. RESULTS: Improvements in verbal fluency (p = 0.014), short term memory (p = 0.014) and long-term memory (p <= 0.001) were found in the cherry juice group. A significant reduction in systolic (p = 0.038) blood pressure and a trend for diastolic (p = 0.160) blood pressure reduction was evident in the intervention group. Markers of inflammation (CRP and IL-6) were not altered. CONCLUSION: Inclusion of an anthocyanin-rich beverage may be a practical and feasible way to improve total anthocyanin consumption in older adults with mild-to-moderate dementia, with potential to improve specific cognitive outcomes. PMID- 26482149 TI - Estimation of salt intake assessed by urinary excretion of sodium over 24 h in Spanish subjects aged 7-11 years. AB - PURPOSE: High intake of salt is associated with early development of cardiovascular risk factors (e.g., hypertension, obesity). In "developed" countries, individuals frequently exceed dietary recommendations for salt intake. Taking into account the limited data on sodium intake by 24-h excretion in urine in schoolchildren, we wished to determine baseline salt intake in Spanish subjects aged 7-11 years. METHODS: The present study was an observational study involving 205 schoolchildren (109 boys and 96 girls) selected from various Spanish provinces. Sodium intake was ascertained by measuring sodium excretion in urine over 24 h. Creatinine was used to validate completeness of urine collections. The correlation between fat-free mass determined by anthropometry and that determined via urinary excretion of creatinine was calculated (r = 0.651; p < 0.001). RESULTS: Mean 24-h urinary excretion of sodium was 132.7 +/- 51.4 mmol/24 h (salt equivalent: 7.8 +/- 3.1 g/day). Hence, 84.5 % of subjects aged <=10 years had intakes of >4 g salt/day, and 66.7 % of those aged >10 years had intakes of >5 g salt/day. Urinary excretion of sodium was correlated with systolic blood pressure and diastolic blood pressure (r = 0.1574 and r = 0.1400, respectively). Logistic regression analyses, adjusted by sex, showed that a high body mass index (odds ratio = 1.159; 95 % CI 1.041-1.290; p < 0.05) was associated with an increased likelihood of high urinary excretion of sodium. CONCLUSIONS: Sodium intake, as estimated by 24-h urinary excretion, was (on average) higher than recommended. Reducing the sodium content children's diet is a sound policy to reduce cardiovascular risk. PMID- 26482151 TI - A Hercule Poirot of clinical research. PMID- 26482150 TI - Associations between intake of fish and n-3 long-chain polyunsaturated fatty acids and plasma metabolites related to the kynurenine pathway in patients with coronary artery disease. AB - PURPOSE: Enhanced tryptophan degradation via the kynurenine pathway has been related to several pathological conditions. However, little is known about the effect of diet on individual metabolites of this pathway. We investigated cross sectional associations between reported intake of fish and omega-3 (n-3) long chain PUFA (LC-PUFA) and plasma metabolites related to the kynurenine pathway. METHODS: Participants were 2324 individuals with coronary artery disease from the Western Norway B Vitamin Intervention Trial. Fish and n-3 LC-PUFA intakes were assessed using a food frequency questionnaire. Plasma concentrations of tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid, neopterin, and kynurenine-to tryptophan ratio (KTR) were analyzed. Associations were investigated using partial Spearman's rank correlations and multiple linear regressions. RESULTS: Median age at inclusion was 62 years (80 % males), and 84 % had stable angina pectoris. Intake of fatty fish and n-3 LC-PUFA was inversely associated with plasma 3-hydroxykynurenine. Consumption of total fish, lean fish, and n-3 LC-PUFA was inversely associated with plasma neopterin. Intake of total fish, fatty fish, and n-3 LC-PUFA was inversely associated with KTR. All these correlations were weak (rho between -0.12 and -0.06, P < 0.01). In 306 patients with diabetes, lean fish intake was positively associated with plasma 3-hydroxyanthranilic acid (rho = 0.22, P < 0.001, P for interaction = 0.01), and total fish intake was inversely associated with KTR (rho = -0.17, P < 0.01, P for interaction = 0.02). CONCLUSION: Fish intake was not an important determinant of individual metabolites in the kynurenine pathway. However, some correlations were stronger in patients with diabetes. The inverse associations of fish or n-3 LC-PUFA with neopterin and KTR may suggest a slightly lower IFN-gamma-mediated immune activation with a higher intake. PMID- 26482152 TI - Risk factors for relapse of middle-stage squamous cell carcinoma of the submandibular region and floor of mouth: the importance of en bloc resection. AB - Our aim was to investigate retrospectively the rate of recurrence in the intervening region for middle-stage squamous cell carcinoma (SCC) of the tongue and identify the factors that predict relapse and prognosis. A total of 204 patients were included, 96 in the en bloc group and 108 in the control group. The groups were comparable. Two patients in the en bloc group (2%) and 12 in the control group (11%) developed recurrences in the intervening region. Kaplan-Meier analysis showed a reduction in the 5-year disease-specific survival once a recurrence had developed after the primary operation (77% compared with 14%, p<0.001). The en bloc group developed significantly fewer recurrences (2%) than the control group (11%) during the five years; p=0.037), and also had better 5 year disease-specific survival (80% compared with 66%, p=0.04). Cox's multivariate regression indicated that the pathological nodal status (p=0.016) and surgical technique (p=0.037) were independent predictive factors for the 5 year recurrence rate, as well as of 5-year disease-specific survival (p=0.001 and p=0.050, respectively). Recurrence in the intervening region is a negative prognostic factor for these patients, and we recommend en bloc resection as the management of choice for middle-stage SCC of the tongue. PMID- 26482153 TI - In Vitro Metabolomic Approach to Hippocampal Neurodegeneration Induced by Trimethyltin. AB - Search for indicators of neurodegenerative disorders is a hot topic where much research remains to be done. Our aim was to determine proton nuclear magnetic resonance ((1)H-NMR) spectra of brain metabolites in the trimethyltin (TMT) model of neurodegeneration. Male Wistar rats were subjected to TMT or saline and were sacrificed on day 3 or 24 after administration. (1)H-NMR spectrum was measured on the 600 MHz Varian VNMRS spectrometer in nano-probe in the volume of 40 MUl of hippocampal extracts. TMT administration resulted in reduction of the hippocampal weight on day 24. Of the sixteen identified metabolite spectra, decreased aspartate and increased glutamine contents were observed in the initial asymptomatic stage of neurodegeneration on day 3 in hippocampal extracts of TMT exposed rats compared to sham animals. Increased myo-inositol content was observed on day 24. The presented data provide further knowledge about this experimental model and putative indicators of neuronal damage. PMID- 26482154 TI - A simple microfluidic device for the deformability assessment of blood cells in a continuous flow. AB - Blood flow presents several interesting phenomena in microcirculation that can be used to develop microfluidic devices capable to promote blood cells separation and analysis in continuous flow. In the last decade there have been numerous microfluidic studies focused on the deformation of red blood cells (RBCs) flowing through geometries mimicking microvessels. In contrast, studies focusing on the deformation of white blood cells (WBCs) are scarce despite this phenomenon often happens in the microcirculation. In this work, we present a novel integrative microfluidic device able to perform continuous separation of a desired amount of blood cells, without clogging or jamming, and at the same time, capable to assess the deformation index (DI) of both WBCs and RBCs. To determine the DI of both WBCs and RBCs, a hyperbolic converging microchannel was used, as well as a suitable image analysis technique to measure the DIs of these blood cells along the regions of interest. The results show that the WBCs have a much lower deformability than RBCs when subjected to the same in vitro flow conditions, which is directly related to their cytoskeleton and nucleus contents. The proposed strategy can be easily transformed into a simple and inexpensive diagnostic microfluidic system to simultaneously separate and assess blood cells deformability. PMID- 26482155 TI - Molecular analysis of selected paramphistome isolates from cattle in southern Africa. AB - Paramphistomes are parasites of domestic and wild ruminants, the effects of which in animal health remain underestimated. Very few studies in Africa have been done using molecular techniques to resolve situations associated with taxonomical groupings and epidemiology of these parasites. In this study, the genetic variability of nine representative paramphistome isolates collected from southern African countries, namely Botswana, South Africa, Zambia and Zimbabwe, was assessed using both morphological and internal transcribed spacer 2 (ITS2) rDNA sequence data. Morphological characterization and identification were carried out using median sagittal sections of the paramphistomes. DNA of the individual paramphistomes was isolated, the ITS2 rDNA was amplified, purified and sequenced. The sequences were submitted to GenBank, which assigned them the following accession numbers: KP639631, KP639630, KP639632, KP639633, KP639634, KP639635, KP639636, KP639637 and KP639638. These sequences were used for phylogenetic analysis using MEGA 6. Morphological characterization revealed three species of paramphistomes belonging to three different sub-families: one Stephanopharynx compactus isolate, a member of the Stephanopharyngidae sub-family; one Carmyerius dollfusi isolate, a member of the Gastrothylacidae sub-family; and seven Calicophoron microbothrium isolates belonging to the Paramphistomidae sub-family. ITS2 sequence analysis using BlastN results indicated that this is the first report of S. compactus (KP639630) and C. dollfusi (KP639636). Phylogenetic reconstruction of the paramphistome isolates revealed three separate clades representing the three species. However, the clade with all the C. microbothrium isolates was the only one that was supported by a higher bootstrap value of 92%, although there was no differentiation of the isolates according to geographical locations. The low divergence values on the ITS2 sequences of the C. microbothrium isolates indicate that ITS rDNA sequences can be used as a molecular tool to infer knowledge for resolving taxonomic groupings. PMID- 26482157 TI - Evaluating the impact of a minimally invasive pediatric surgeon on hospital practice: comparison of two children's hospitals. AB - PURPOSE: Widespread adoption of minimally invasive surgery (MIS) techniques in pediatric surgery has progressed slowly, and the shift in practice patterns has been variable among surgeons. We hypothesized that a pediatric surgeon committed to MIS could effectively change surgical practice by creating an emphasis on MIS. METHODS: Annual case volumes from 2000 to 2009 at two tertiary care pediatric hospitals, one with a dedicated minimally invasive pediatric surgeon, were evaluated for trends in MIS for ten different operations. Univariate analyses of the differences between hospitals in the use of the open versus laparoscopic approach were performed. The Breslow-Day test was used to examine differences in use of laparoscopic procedures across hospitals in early versus middle and middle versus late time periods. RESULTS: Between the two hospitals, for 9 of the 10 types of surgery, the number of laparoscopic and open procedures differed significantly (p values ranged from <0.0001 to 0.003). Over the 10-year period, the hospital with a dedicated MIS surgeon had a larger proportion of procedures done laparoscopically for all years. This difference reached statistical significance for appendectomy (p < 0.0001), congenital diaphragmatic hernia (p < 0.0002), chest wall reconstruction (p < 0.0001), cholecystectomy (p = <0.0001), gastrostomy (p < 0.0001), nissen fundoplication (p < 0.0001) oophorectomy (p < 0.0001), pyloromyotomy (p < 0.0001) and splenectomy (p = 0.0006). After grouping the years into early (2000-2003), middle (2004-2006) and late (2007-2009) categories, the hospital with a dedicated MIS surgeon had a significantly higher rate of increase in use of laparoscopic surgery between the early and middle years for four procedures: diaphragmatic hernia repair (p = 0.003), chest wall reconstruction (p = 0.0086), cholecystectomy (0.0083) and endorectal pull-through (p = 0.025). CONCLUSION: The presence of a dedicated minimally invasive pediatric surgeon led to a significant change in surgical practice with an overall trend of increasing MIS several years in advance of a hospital that did not have a dedicated MIS surgeon. This has implications for resident training in academic medical centers and potential patient care outcomes. PMID- 26482156 TI - Efficacy and safety of a resorbable collagen membrane COVA+TM for the prevention of postoperative adhesions in abdominal surgery. AB - BACKGROUND: This clinical study was designed to assess the efficacy and safety of COVA+TM, a collagen membrane (CM), for the prevention of postoperative adhesions in abdominal surgery. METHODS: This prospective multicenter study concerned one hundred and thirteen patients undergoing two-stage abdominal surgeries between 2011 and 2014: either bariatric surgery (BS) or reversal of a diverting stoma (DS). They were divided into two groups, according to whether a CM was placed at the end of the first procedure or not. The primary endpoint was the evaluation of adhesions (incidence, severity, and extent) on the operative site during the second surgery using standard grading scales and a combined adhesion score. Secondary endpoints were the duration of reoperation and the overall postoperative morbidity. RESULTS: Sixty-five patients were included in the BS group, and forty-eight patients in the DS group. Mean time interval between surgeries was 33.2 +/- 51.1 weeks for BS and 14.1 +/- 10 weeks for DS. In both indications, results in the CM group were better compared to the control group regarding incidence, severity, and extent of adhesions. Mean combined adhesion scores were lower in the CM group: respectively, 2.1 +/- 1.6 versus 3.6 +/- 1.7 (p < 0.001) for BS and 1.1 +/- 1.7 versus 3.1 +/- 2.2 (p < 0.005) for DS. In BS group, the operative duration at reoperation was significantly shorter if a CM was used: 56 +/- 34 versus 77 +/- 47 min (p < 0.03). No adverse events related to the use of the CM were observed. Overall complication rate was 13.5 % in the CM group versus 27.9 % in the control group. Ease of handling and application of the CM were rated as satisfying or very satisfying in the great majority of cases. CONCLUSIONS: In abdominal surgery, COVA+TM acts efficiently on the prevention of postoperative adhesions with lower incidence, severity, and extent levels. The CM can be used safely and might render reoperations less difficult. PMID- 26482158 TI - Early hospital readmission after bariatric surgery. AB - BACKGROUND: With the rise in bariatric procedures being performed nationwide and the growing focus on quality and outcome measures, reducing early hospital readmission (EHR) rates has garnered great clinical interest. The aim of this study was to identify the incidence, reasons, and risk factors for EHR after bariatric surgery. METHODS: Using American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) dataset (2012-2013), patients with a diagnosis of obesity and body mass index >=35 who underwent bariatric surgery were identified. EHR was defined as at least one hospitalization within 30 days of bariatric procedure. The association between readmission and patient factors was assessed using multivariable logistic regression analysis. In addition, reasons for readmission were sought. RESULTS: A total of 36,042 patients were identified. The overall EHR rate was 4.70 % [laparoscopic (lap) adjustable band 1.87 %, lap gastric bypass (GBP) 5.94 %, open GBP 7.86 %, and sleeve gastrectomy 3.73 %], and it occurred at the median of 11 days postoperatively. The rate of EHR significantly decreased from 2012 to 2013 (5.15 vs. 4.32 %, p < 0.001). The median age and BMI were 44 years and 44.7 kg/m(2), respectively, 78.99 % were female, and 70.78 % were white. The most common reason for readmission was nausea/vomiting (12.95 %), followed by abdominal pain (11.75 %) and dehydration (10.54 %). On multivariable analysis, factors most strongly associated with readmission were procedure type (lap band: reference; open GBP: OR 3.78, 95 % CI 2.47-5.80; lap GBP 3.18, 2.39-4.22; sleeve gastrectomy: 2.03, 1.52-2.71; all p < 0.001), steroid use (1.82, 1.33-2.48, p < 0.001), pre-discharge complication (1.64, 1.20-2.24, p < 0.001), and black population (1.51, 1.34-1.71, p < 0.001). CONCLUSIONS: Bariatric centers should consider implementing standardized protocols for outpatient monitoring of patients identified to be at high risk of experiencing early readmission, which in turn would decrease overall costs and improve quality of care. PMID- 26482159 TI - Should high-frequency electrosurgery be discouraged during laparoscopic surgery? PMID- 26482160 TI - Planar Functionalized Surfaces for Direct Immunoaffinity Desorption/Ionization Mass Spectrometry. AB - BACKGROUND: Recent studies show that the haptoglobin phenotype in individuals with diabetes mellitus is an important factor for predicting the risk of myocardial infarction, cardiovascular death, and stroke. Current methods for haptoglobin phenotyping include PCR and gel electrophoresis. A need exists for a reliable method for high-throughput clinical applications. Mass spectrometry (MS) can in principle provide fast phenotyping because haptoglobin alpha 1 and alpha 2, which define the phenotype, have different molecular masses. Because of the complexity of the serum matrix, an efficient and fast enrichment technique is necessary for an MS-based assay. METHODS: MALDI plates were functionalized by ambient ion landing of electrosprayed antihaptoglobin antibody. The array was deposited on standard indium tin oxide slides. Fast immunoaffinity enrichment was performed in situ on the plate, which was further analyzed by MALDI-TOF MS. The haptoglobin phenotype was determined from the spectra by embedded software script. RESULTS: The MALDI mass spectra showed ion signals of haptoglobin alpha subunits at m/z 9192 and at m/z 15 945. A cohort of 116 sera was analyzed and the reliability of the method was confirmed by analyzing the identical samples by Western blot. One hundred percent overlap of results between the direct immunoaffinity desorption/ionization MS and Western Blot analysis was found. CONCLUSIONS: MALDI plates modified by antihaptoglobin antibody using ambient ion landing achieve low nonspecific interactions and efficient MALDI ionization and are usable for quick haptoglobin phenotyping. PMID- 26482162 TI - Comparison Between Banded and Nonbanded Roux-En-Y Gastric Bypass with 2-Year Follow-Up: a Preliminary Retrospective Analysis. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is one of the most widely used bariatric surgeries for treatment of moderate and severe obesity. Placing a band around the pouch to band the gastric bypass operation has been reported to increase the restriction resulting in better weight loss and weight loss maintenance. A retrospective comparative study of banded versus nonbanded gastric bypass was done to see if banding the pouch made a difference in the weight loss and quality of life outcome in the patients. METHODS: Data from all patients who had a gastric bypass in the year 2012 at our centre were reviewed. They were divided into two groups the banded and the nonbanded groups. Patients with complete 2-year follow-up were analysed in terms of weight loss, weight regain and quality of life changes. RESULTS: Two hundred ten patients had gastric bypass in 2012; 165 had complete 2-year follow-up; 64 were banded and 101 nonbanded. The preoperative patient profile in terms of weight, gender and comorbid conditions was similar in both groups except the body mass index (BMI) was significantly higher in the banded group. The perioperative and postoperative complication rates were similar. The weight, BMI and percentage excess weight loss (PEWL) at 2 years were 80.93 kg, 29.45 kg/m2 and 60.76 % in the nonbanded group and 77.06 kg, 27.66 kg/m2 and 71.45 % in the banded group, respectively. Resolution of comorbid conditions was the same in both groups. The overall Gastrointestinal Quality of Life Index went from 88.98 preoperatively to 109.33 postoperatively in the nonbanded group and 92.5 to 112.81 in the banded group, respectively. CONCLUSIONS: The patients with banded gastric bypass had significantly better results in terms of weight loss, weight stability and Gastrointestinal Quality of Life Index scores at 2 years. PMID- 26482161 TI - Pitfalls in Erythrocyte Protoporphyrin Measurement for Diagnosis and Monitoring of Protoporphyrias. AB - BACKGROUND: Laboratory diagnosis of erythropoietic protoporphyria (EPP) requires a marked increase in total erythrocyte protoporphyrin (300-5000 MUg/dL erythrocytes, reference interval <80 MUg/dL) and a predominance (85%-100%) of metal-free protoporphyrin [normal, mostly zinc protoporphyrin (reference intervals for the zinc protoporphyrin proportion have not been established)]; plasma porphyrins are not always increased. X-linked protoporphyria (XLP) causes a similar increase in total erythrocyte protoporphyrin with a lower fraction of metal-free protoporphyrin (50%-85% of the total). CONTENT: In studying more than 180 patients with EPP and XLP, the Porphyrias Consortium found that erythrocyte protoporphyrin concentrations for some patients were much higher (4.3- to 46.7 fold) than indicated by previous reports provided by these patients. The discrepant earlier reports, which sometimes caused the diagnosis to be missed initially, were from laboratories that measure protoporphyrin only by hematofluorometry, which is intended primarily to screen for lead poisoning. However, the instrument can calculate results on the basis of assumed hematocrits and reports results as "free" and "zinc" protoporphyrin (with different reference intervals), implying separate measurements of metal-free and zinc protoporphyrin. Such misleading reports impair diagnosis and monitoring of patients with protoporphyria. SUMMARY: We suggest that laboratories should prioritize testing for EPP and XLP, because accurate measurement of erythrocyte total and metal-free protoporphyrin is essential for diagnosis and monitoring of these conditions, but less important for other disorders. Terms and abbreviations used in reporting erythrocyte protoporphyrin results should be accurately defined. PMID- 26482163 TI - Conversion of Vertical Banded Gastroplasty to Laparoscopic Gastric Bypass: a Step By-Step Teaching Video. AB - PURPOSE: Vertical banded gastroplasty (VBG) has been demonstrated to be disappointing for long-term weight loss and quality of life (Br J Surg 100:222 230, 2013). Laparoscopic revisional gastric bypass has been found to be feasible, but this procedure in case of prior VBG is deemed both challenging and difficult and should be performed by experienced surgeons (Obes Surg 22:1554-1561, 2012; Surg Endosc 27:558-564, 2013). MATERIALS AND METHODS: We present the case of a 56 year-old man with a body mass index (BMI) of 39.6 kg/m2 who had undergone open VBG, 11 years ago (initial BMI 39.2 kg/m2). He was referred to our tertiary care center for weight regain and daily vomiting. RESULTS: In this high definition multimedia video, we present a step-by-step laparoscopic conversion of VBG to gastric bypass. After careful adhesiolysis, key points of such procedure are resizing of the small gastric pouch and resection of the enlarged gastric pouch with the band and the upper portion of the remnant fundus, in order to avoid leakage or blind stomach pouch. No adverse outcomes occurred during the postoperative period. CONCLUSION: Laparoscopic conversion of previous open VBG to gastric bypass is a challenging procedure. Learning the key points of such procedure is mandatory to limit postoperative complications. PMID- 26482164 TI - Laparoscopic Conversion of Sleeve Gastrectomy to Gastric Bypass for Super-Obesity (BMI >= 50 kg/m2) and Incisional Hernia: a Video Report. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is the most frequently performed procedure for morbid obesity in France. However, in case of de novo gastroesophageal reflux disease or of insufficient weight loss, LSG could be converted in rare cases to laparoscopic Roux-en-Y gastric bypass (LRYGB). In case of voluminous incisional hernia (IH) associated, this procedure could be technically challenging, especially in cases of super-obesity (body mass index (BMI) >=50 kg/m2). Furthermore, IH should be repaired in order to avoid life threatening post-operative small bowel obstruction. METHODS: We present the case of a 30-year-old woman (125 kg, 1.55 m) with a BMI of 52.1 kg/m2. She was referred to our tertiary care center for weight regain (Nadir 100 kg), 4 years after a LSG was performed for super-super obesity (BMI = 68.7 kg/m2). She also had a history of epigastric IH (single-incision LSG; diameter = 10 cm). The strategy adopted was to repair hernia with raphy. In case of hernia recurrence and of sustainable weight loss, use of prothetic mesh would be mandatory in the future. RESULTS: In this multimedia video, we present a step-by-step laparoscopic conversion of sleeve gastrectomy to LRYGB for super-obesity (BMI >=50 kg/m2) and incisional hernia. Laparoscopic procedure included adhesiolysis, dissection, and resection of the low part of the remnant stomach, gastro-jejunal circular anastomosis, and closure of aponeurosis defect. CONCLUSIONS: Incisional hernia and morbid obesity are often entangled problems. Revisional procedure of bariatric surgery with incisional hernia associated should be performed laparoscopically. PMID- 26482165 TI - Predictors of Perioperative Acute Kidney Injury in Obese Patients Undergoing Laparoscopic Bariatric Surgery: a Single-Centre Retrospective Cohort Study. AB - BACKGROUND: Obesity has been associated with increased risk of perioperative acute kidney injury (AKI). We aim to establish the incidence of AKI among patients undergoing laparoscopic bariatric surgery and identify potential risk factors. METHODS: Records of 1230 patients who underwent laparoscopic bariatric surgery in a tertiary centre from 1 December 2009 to 31 January 2014 were retrospectively studied. AKI diagnosis was made by comparing the baseline and post-operative serum creatinine to determine the presence of predefined significant change based on the Kidney Disease: Improving Global Outcomes (KDIGO) definition. Univariate analyses were performed to determine significant clinical factors, and multiple logistic regression analysis was subsequently done to determine independent predictors of AKI. RESULTS: Thirty-five (2.9 %) patients developed AKI during the first 72 h post-surgery. Multivariate logistic regression analysis revealed impaired renal function (OR 10.429, 95 % CI 3.560 to 30.552), use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (OR 3.038, 95 % CI 1.352 to 6.824), and body mass index (OR 1.048, 95 % CI 1.005 to 1.093) as independent predictors of perioperative acute kidney injury in the obese patients who underwent laparoscopic bariatric surgery. CONCLUSIONS: We found that the incidence of perioperative AKI among patients who underwent laparoscopic bariatric surgery is at 2.9 %. Impaired renal function, use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers and raised body mass index were found to be independent predictors of AKI. Patients with these risk factors could be considered at risk for developing perioperative AKI, and extra perioperative vigilance should be undertaken. PMID- 26482166 TI - Laparoscopic Gastric Plication (LGP) as an Alternative to Laparoscopic Sleeve Gastrectomy (LSG) in Patients with Morbid Obesity: A Preliminary, Short-Term, Case-Control Study. AB - BACKGROUND: Based on short-term outcome, gastric plication (LGP) could be considered as an alternative to sleeve gastrectomy (LSG) in patients with severe obesity. However, long-term follow-up of weight loss and comorbidity are yet to be available. Theoretical advantages include reduced fistula rate, no implantable device, preservation of the alimentary pathway, and no gastric resection. We report a case-control study comparing short-term outcome in two groups of patients who had either LGP or LSG, respectively. METHODS: From January 2012 to June 2013, 40 patients had LGP, matched with 40 patients who had LSG. RESULTS: No postoperative mortality was observed. Overall morbidity rate reached 22.5 % in the LGP Group and 10 % in the LSG Group (P = 0.04). The most common complication was nausea and vomiting occurring in 20 % of patients with LGP and 5 % of patients with LSG, respectively (P < 0.001). No clinical or radiological leak occurred. Mean operative time was 91.5 +/-18.6 min in the LGP group and 81 min +/ 16.8 min in the LSG group, respectively (P = 0.104). Mean hospital stay was 3.4 +/-1.1 days in the LGP Group and 3.2 +/-1.2 days the LSG group, respectively (P = 0.614). Average total operating room (OR) cost was 1736 euros for LGP as compared to 2842 euros for LSG, respectively (P < 0.001). At 18-month follow-up, mean excess weight loss (EWL) was 56.5 % +9.8 in LGP patients and 71.3 % +10.4 in patients who had LSG (P = 0.041). CONCLUSIONS: LGP for patients with severe obesity is safe and feasible with low rates of serious complications. As compared to LSG, LGP is associated to higher postoperative rate of nausea, lower operative cost, and lower EWL at 18-month follow-up (P = 0.041). PMID- 26482167 TI - Asthma in furniture and wood processing workers: a systematic review. AB - BACKGROUND: Wood dust is a common cause of occupational asthma. There is potential for high exposure to wood dust during furniture and wood manufacturing processes. AIMS: To evaluate the evidence for non-neoplastic respiratory ill health associated with work in the furniture and wood manufacturing sector. METHODS: A systematic review was performed according to PRISMA guidelines. Articles were graded using SIGN (Scottish Intercollegiate Guideline Network) and MERGE (Methods for Evaluating Research Guidelines and Evidence) criteria, with data grouped by study outcome. RESULTS: Initial searches identified 1328 references, from which 55 articles were included in the review. Fourteen studies were graded A using MERGE or >2++ using SIGN. All but one paper describing airway symptoms reported an increased risk in higher wood dust exposed workers in comparison to lower or non-exposed groups. Five studies reporting asthma examined dose response; three found a positive effect. The relative risk for asthma in exposed workers in the single meta-analysis was 1.5 (95% CI 1.25-1.87). Two studies reported more obstructive lung function (forced expiratory volume in 1 s [FEV1]/forced vital capacity < 0.7) in exposed populations. Excess longitudinal FEV1 decline was reported in female smokers with high wood dust exposures in one study population. Where measured, work-related respiratory symptoms did not clearly relate to specific wood immunoglobulin E positivity. CONCLUSIONS: Work in this sector was associated with a significantly increased risk of respiratory symptoms and asthma. The evidence for wood dust exposure causing impaired lung function is less clearly established. Further study is required to better understand the prevalence, and causes, of respiratory problems within this sector. PMID- 26482168 TI - [Overall treatment time assessment of radiotherapy delivered in a curative intent: A prospective study]. AB - PURPOSE: To assess the overall treatment time of radiotherapy delivered with curative intent in a cohort of 185 consecutive patients and the causes of this possible delay. If delay, to propose corrective actions. MATERIALS AND METHODS: We report a single-center prospective study including all consecutive patients receiving a radiation therapy with curative intent, from 1st December 2013 to 28th February 2014, on the three linear accelerators of the radiotherapy department. For each fraction missed, the causes of non-completion were prospectively collected. This analysis took into account the following parameters: age, sex, occupation, transport type and duration, tumour localization, radiation dose, concomitant chemotherapy, hospitalization, type of linear accelerator. RESULTS: One hundred and fifty-five patients were included in the study (183 evaluable, two did not complete treatment). The overall treatment time was respected for 31 patients (17%). It was lengthened on 4.6 days (d) (0-29 d; median: 3d). The mean number of delayed fractions was 3.4 (0-17; median: 2). The reasons of delay were: breakdown 32.2%; maintenance 29.3%; holiday 11%; treatment toxicity 9.4%; inadequate planning 8.6%; other disease 3.9%; treatment refusal 2.1%; unspecified personal reasons 1.5%; refusal to wait 0.8%; transportation 0.3%; error of communication 0.3%; other 0.6%. Two parameters had a significant impact on the overall treatment time: the type of linear accelerator in relation to breakdown occurrence (P<0.001) and transportation duration (more or less than 40 min, P=0.022). One hundred and thirty-eight patients (75%) and 79 patients (43%) were treated on one or more than two Saturdays. Treatment on Saturday significantly reduced the overall treatment time (median, 1.9 d; P<0.001). CONCLUSION: The overall treatment time was globally respected excluding break down and maintenance. Their impact on the overall treatment time is minimized by the systematic opening of the department on Saturdays. PMID- 26482169 TI - Comment on: "Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modelling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection". PMID- 26482170 TI - Author's Reply to Srinivas: "Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection". PMID- 26482172 TI - New Lives for Seven Transmembrane Receptors as Drug Targets. PMID- 26482171 TI - Evasion of "mandatory" social health insurance for the formal sector: evidence from Lao PDR. AB - BACKGROUND: In the last decade, almost every low- or middle-income country in the world has expressed support for universal health coverage (UHC). While at the beginning of the UHC movement, country strategies focused on increasing access to the formal sector as the first step of UHC, there is now consensus that countries should cover the entire population, with particular attention to covering the poor. However, it is often assumed that mandatory schemes will automatically cover their target populations, and consequently little is known about why firms comply or do not comply with enrolment requirements. Using the experience of Lao PDR, where the enrolment rate in the mandatory social security scheme is low and the capacity for regulation is weak, we conducted this study to better understand the determinants of enrolment of private sector firms in mandatory social security. METHODS: We used a cross-sectional case-comparison design, surveying 130 firms. We applied a structured questionnaire to explore determinants of enrolment, specifically looking at firm characteristics (e.g., industry category, ownership); sociodemographic characteristics of company heads; firms' risk perceptions; details of employment contracts; employee benefits; and exposure to social security. Closed ended questions were analysed quantitatively, while content analysis was applied to open-ended questions. Logistic regression was used to examine the determinants of enrolment. RESULTS: Smaller privately owned firms in the services industry were the least likely to enrol in social security, while firms in the trade industry were more likely to enrol than firms in manufacturing, construction, or services. The main reason for not enrolling was that firms offered a better package of benefits to their employees, although further investigation of company benefits showed that this was not the case in practice. Additional reasons for non-compliance were lack of knowledge and poor quality of care at government hospitals. CONCLUSIONS: The study contributes to the dialogue on how best to increase coverage in the formal sector, which is an important element of achieving UHC. It also provides much needed information about the motivation of private sector firms to comply with mandatory schemes. PMID- 26482173 TI - Eye-tracking devices in intensive care. PMID- 26482174 TI - Editorial: Parathyroidectomy is safe and beneficial for patients with tertiary hyperparathyroidism, and should be the preferred therapy. PMID- 26482175 TI - WT1 expression is inversely correlated with MYCN amplification or expression and associated with poor survival in non-MYCN-amplified neuroblastoma. AB - Neuroblastoma (NB) is the most common extra cranial solid tumor in childhood and the most frequently diagnosed neoplasm during infancy. A striking feature of this tumor is its clinical heterogeneity. Several tumor progression markers have been delineated so far, among which MYCN amplification, which occurs in about 25% of total NB cases, with the percentage increasing to 30% in advanced stage NB. Although MYCN amplification is strongly correlated with NB of poor outcome, the MYCN status cannot alone predict all cases of poor survival in NB. Indeed NB without MYCN amplification (about 70-80% of NB) are not always favorable. WT1 was initially identified as a tumor suppressor gene involved in the development of a pediatric renal tumor (Wilms' tumor). Here, we describe an inverse correlation between WT1 expression and MYCN amplification and expression. However and most notably, our results show that WT1 gene expression is associated with a poor outcome for patients showing non-MYCN-amplified tumors. Thus WT1 expression is clinically significant in NB and may be a prognostic marker for better risk stratification and for an optimized therapeutic management of NB. PMID- 26482176 TI - Translating G-CSF as an Adjunct Therapy to Stem Cell Transplantation for Stroke. AB - Among recently investigated stroke therapies, stem cell treatment holds great promise by virtue of their putative ability to replace lost cells, promote endogenous neurogenesis,and produce behavioral and functional improvement through their "bystander effects." Translating stem cell in the clinic, however, presents a number of technical difficulties. A strategy suggested to enhance therapeutic utility of stem cells is combination therapy, i.e., co-transplantation of stem cells or adjunct treatment with pharmacological agents and substrates,which is assumed to produce more profound therapeutic benefits by circumventing limitations of individual treatments and facilitating complementary brain repair processes. We previously demonstrated enhanced functional effects of cotreatment with granulocyte-colony stimulating factor (GCSF)and human umbilical cord blood cell (hUCB) transplantation in animal models of traumatic brain injury (TBI). Here,we suggest that the aforementioned combination therapy may also produce synergistic effects in stroke. Accordingly, G-CSF treatment may reduce expression of pro-inflammatory cytokines and enhance neurogenesis rendering a receptive microenvironment for hUCB engraftment. Adjunct treatment of GCSF with hUCB may facilitate stemness maintenance and guide neural lineage commitment of hUCB cells. Moreover, regenerative mechanisms afforded by G-CSF-mobilized endogenous stem cells, secretion of growth factors by hUCB grafts and G-CSF-recruited endothelial progenitor cells(EPCs), as well as the potential graft-host integration that may promote synaptic circuitry re-establishment could altogether produce more pronounced functional improvement in stroked rats subjected to a combination G-CSF treatment and hUCB transplantation. Nevertheless, differences in pathology and repair processes underlying TBI and stroke deserve consideration when testing the effects of combinatorial G-CSF and hUCB cell transplantation for stroke treatment. Further studies are also required to determine the safety and efficacy of this intervention in both preclinical and clinical stroke studies. PMID- 26482177 TI - High prevalence of diagnosed and undiagnosed polyneuropathy in subjects with and without diabetes participating in a nationwide educational initiative (PROTECT study). AB - AIMS: Since neuropathy screening may be underutilized in primary care practice, we conducted a nationwide educational initiative to determine the prevalence of diagnosed and previously undiagnosed polyneuropathy. METHODS: Among 1017 individuals participating in the initiative, 983 with complete data were analyzed, 359 of whom had no diabetes by history (ND), 80 had type 1 diabetes, and 544 had type 2 diabetes. Polyneuropathy was assessed by history and foot examination including pressure, temperature, and vibration perception and was classified as possible, probable, and severe. Foot pulses and HbA1c were determined in subsets of participants. RESULTS: Polyneuropathy was detected in 53.8% of ND, 43.8% of type 1, and 55.6% of type 2 diabetes subjects and was associated with higher age. In a subset of participants with polyneuropathy, the latter was declared as previously undiagnosed by 79.1% of ND, 35.7% of type 1, and 61.5% of type 2 diabetes participants. After adjustment for age and sex, prevalent polyneuropathy was associated with peripheral arterial disease. CONCLUSIONS: More than half of subjects with and without diabetes participating in an educational initiative had polyneuropathy which was reported as previously undiagnosed by two thirds. Effective strategies to avoid underdiagnosis of neuropathy and to improve preventive foot care should be implemented. PMID- 26482178 TI - Lysophosphatidic acid modulates prostaglandin signalling in bovine steroidogenic luteal cells. AB - We examined whether lysophosphatidic acid affects prostaglandin biosynthesis, transport, and signalling in bovine steroidogenic luteal cells. The aim of the present study was to determine the influence of LPA on PGE2 and PGF2alpha synthesis and on the expression of enzymes involved in PG biosynthesis (PTGS2, mPGES-1, cPGES, mPGES-2, PGFS and 9-KPR), prostaglandin transporter (PGT), and prostaglandin receptors (EP1, EP2, EP3, EP4 and FP) in bovine steroidogenic luteal cells. We found that LPA inhibited PGF2alpha synthesis in steroidogenic luteal cells. Moreover, LPA increased mPGES1 and cPGES and decreased PGFS expression in cultured bovine steroidogenic luteal cells. Additionally, LPA stimulated EP2 and EP4 receptor and PGT expression. This study suggests that LPA activity in the bovine CL directs the physiological intraluteal balance between the two main prostanoids towards luteotropic PGE2. PMID- 26482179 TI - [History of vertebral body replacement]. AB - BACKGROUND: Vertebral body replacement after corpectomy is nowadays a standard procedure in spinal surgery. OBJECTIVE: Description of the developmental process of vertebral body replacement. METHOD: Historical description of the innovations in vertebral body replacement. RESULTS: The first serious attempts to perform vertebral body replacement were initiated approximately 50 years ago. Over several decades spinal surgeons used bone grafts, polymethyl methacrylate, titanium and glass-ceramics containing apatite and wollastonite. Known vertebral surgeons, including Scoville, Polster, Kaneda and Harms, to name but a few, were involved in the continuous development of vertebral body replacement. CONCLUSION: Many different expandable and non-expandable implants are now available and both types of implant can still be justified. This article describes the historical development of these implants and shows how this innovational process has significantly increased the therapy options for surgeons. PMID- 26482180 TI - Prognostic Contribution of Exercise Capacity, Heart Rate Recovery, Chronotropic Incompetence, and Myocardial Perfusion Single-Photon Emission Computerized Tomography in the Prediction of Cardiac Death and All-Cause Mortality. AB - Chronotropic incompetence, measured by the percentage (%) of heart rate (HR) reserve achieved (%HR reserve), abnormal HR recovery, reduced exercise capacity (EC), and myocardial perfusion single-photon emission computerized tomography (SPECT MPS) abnormalities are known predictors of all-cause mortality (ACM) and cardiac death (CD). The aim of this study was to determine if EC, %HR reserve, and HR recovery add incremental value to MPS in the prediction of ACM and CD. A total of 11,218 patients without valvular disease and not on beta blockers underwent symptom-limited exercise MPS. %HR reserve was (peak HR - rest HR)/(220 age - rest HR) * 100, with %HR reserve <80 defined as low. HR recovery was peak HR - recovery HR. An HR recovery <22 beats/min at 2 minutes after peak exercise was considered abnormal. Poor EC was defined as exercise duration <=6 minutes (7 metabolic equivalents). Summed stress scores (SSSs) were calculated using a 20 segment, 5-point MPS model. Statistical analysis was performed using Cox regression models. There were 445 deaths (148 CD) during a mean follow-up of 3.2 +/- 2.5 years. In multivariate analysis, the independent predictors of ACM were age, chi(2) = 154.81; EC, chi(2) = 74.00; SSS, chi(2) = 32.99; %HR reserve, chi(2) = 24.74; abnormal electrocardiogram at rest, chi(2) = 23.13; HR recovery, chi(2) = 18.45; diabetes, chi(2) = 17.75; and previous coronary artery disease, chi(2) = 11.85 (p <=0.0006). The independent predictors of CD were SSS, chi(2) = 54.25; EC, chi(2) = 49.34; age, chi(2) = 46.45; abnormal electrocardiogram at rest, chi(2) = 30.60; previous coronary artery disease, chi(2) = 20.69; Duke treadmill score, chi(2) = 19.50; %HR reserve, chi(2) = 11.43; diabetes, chi(2) = 10.23 (all p <=0.0014); and HR recovery, chi(2) = 5.30 (p = 0.0214). The exercise variables showed increases in Harrell's C static and net improvement reclassification, with EC showing the strongest incremental improvement in predicting ACM and CD (respective C-index 76.5% and 83.3% and net reclassification index 0.3201 and 0.4996). In conclusion, EC, %HR reserve, and HR recovery are independent predictors of ACM and CD and add incremental prognostic value to extent and severity of MPS. PMID- 26482181 TI - Clinical and Biochemical Markers of Cardiovascular Structure and Function in Women With the Metabolic Syndrome. AB - The pathobiological impact of individual components of the metabolic syndrome (MS) on cardiac structural and functional parameters in women with isolated MS is not known. The objectives of this study were (1) to compare biochemical (prothrombotic, lipogenic, and inflammatory) and imaging (carotid intima-media thickening and basic cardiac structural measurements) markers in women with and without MS and (2) to examine if any of these markers associated or predicted cardiac structural differences between the 2 groups. This cross-sectional pilot study included 88 women with MS and 35 women without it. MS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. Patients with diagnosis of diabetes were excluded. Compared with healthy subjects, women with MS had higher levels of intercellular adhesion molecule, myeloperoxidase, C-reactive protein, plasminogen activator inhibitor-1, leptin, apolipoprotein-B, and lower levels of apolipoprotein-A1 (p <0.001 for all). They also had higher mean ventricular septum, posterior wall thickness, left ventricular (LV) mass, carotid intima-media thickness (p <0.001 for all), and left atrial diameter (p = 0.015). In multivariable regression models, waist circumference and systolic blood pressure (BP) were significant predictors of: ventricular septum (p = 0.005 and p = 0.001, respectively), posterior wall thickness (p = 0.008 and p = 0.040, respectively), and LV mass (p <0.001 and p = 0.013, respectively). Significant predictors for carotid intima-media thickness were systolic BP, glucose, and leptin (p <0.0001, p = 0.034, and p = 0.002, respectively). In conclusion, there are significant clinical, biochemical, and cardiovascular structural differences in women with isolated MS compared with those without. Waist circumference and systolic BP had the strongest association with cardiac structural differences in this group of women. PMID- 26482183 TI - [Encouraging comments and controversies]. PMID- 26482182 TI - Meta-Analysis of Continuous Positive Airway Pressure as a Therapy of Atrial Fibrillation in Obstructive Sleep Apnea. AB - Atrial fibrillation (AF) is a significant health care problem for patients with obstructive sleep apnea (OSA). Continuous positive airway pressure (CPAP) as a therapy for OSA is underused, and it is unknown if CPAP might reduce rates of AF. We systematically reviewed the published reports on CPAP use and risk of AF. MEDLINE, EMBASE, CINAHL, Web of Science, meeting abstracts, and Cochrane databases were searched from inception to June 2015. Studies needed to report the rates of AF in participants who were and were not on CPAP. Data were extracted by 2 authors. A total of 8 studies on OSA were identified (1 randomized controlled trial) with 698 CPAP users and 549 non-CPAP users. In a random effects model, patients treated with CPAP had a 42% decreased risk of AF (pooled risk ratio, 0.58; 95% confidence interval, 0.47 to 0.70; p <0.001). There was low heterogeneity in the results (I(2) = 30%). In metaregression analysis, benefits of CPAP were stronger for younger, obese, and male patients (p <0.05). An inverse relationship between CPAP therapy and AF recurrence was observed. Results suggest that more patients with AF also should be tested for OSA. PMID- 26482184 TI - Mesenchymal Stem Cells from Wharton's Jelly and Amniotic Fluid. AB - The discovery of mesenchymal stem cells (MSCs) in perinatal sources, such as the amniotic fluid (AF) and the umbilical connective tissue, the so-called Wharton's jelly (WJ), has transformed them into promising stem cell grafts for the application in regenerative medicine. The advantages of AF-MSCs and WJ-MSCs over adult MSCs, such as bone marrow-derived mesenchymal stem cells (BM-MSCs), include their minimally invasive isolation procedure, their more primitive cell character without being tumourigenic, their low immunogenicity and their potential autologous application in congenital disorders and when cryopreserved in adulthood. This chapter gives an overview of the biology of AF-MSCs and WJ-MSCs, and their regenerative potential based on the results of recent preclinical and clinical studies. In the end, open questions concerning the use of WJ-MSCs and AF MSCs in regenerative medicine will be emphasized. PMID- 26482185 TI - [Prevalence of vitamin D deficiency in children aged 5-10 years in western Brittany]. AB - French guidelines do not recommend systematic supplementation of vitamin D in children aged 5-10 years old owing to the lack of data on vitamin D status in this age group. Our objective was to assess the prevalence of vitamin D deficiency in these children. METHODOLOGY: Single-center, prospective, epidemiological study including 358 children aged 0-15 years. The endpoint was the concentration of vitamin D. RESULTS: In all, 316 children were divided into four groups according to age: 0-18 months (n=113); 18 months to 5 years (n=103); 5-10 years (n=62); and 10-15 years (n=38). The median concentration of vitamin D decreased with age (P<0.001): 90.2 nmol/L in the group aged 0-18 months; 56.7 nmol/L in the group aged 18 months to 5 years; 49.05 nmol/L in the group aged 5 10 years; and 42.45 nmol/L in the group aged 10-15 years. This corresponds to an increase in the prevalence of vitamin D deficiency in children aged 5-10 years (51.6% vs. 8.8% in the group aged 0-18 months, P<0.001). For children aged 5-10 years, the prevalence of deficiency was greater in the non-supplementation group (75%) compared with the supplementation group (13%; P<0.001). CONCLUSION: This study demonstrates the high prevalence of vitamin D deficiency in children aged 5 10 years and the relationship between supplementation and vitamin D status. It provides an argument in favor of supplementation in children aged 5-10 years in this region and a reconsideration of the French recommendations. PMID- 26482186 TI - Targeted delivery to bone and mineral deposits using bisphosphonate ligands. AB - The high concentration of mineral present in bone and pathological calcifications is unique compared with all other tissues and thus provides opportunity for targeted delivery of pharmaceutical drugs, including radiosensitizers and imaging probes. Targeted delivery enables accumulation of a high local dose of a therapeutic or imaging contrast agent to diseased bone or pathological calcifications. Bisphosphonates (BPs) are the most widely utilized bone-targeting ligand due to exhibiting high binding affinity to hydroxyapatite mineral. BPs can be conjugated to an agent that would otherwise have little or no affinity for the sites of interest. This article summarizes the current state of knowledge and practice for the use of BPs as ligands for targeted delivery to bone and mineral deposits. The clinical history of BPs is briefly summarized to emphasize the success of these molecules as therapeutics for metabolic bone diseases. Mechanisms of binding and the relative binding affinity of various BPs to bone mineral are introduced, including common methods for measuring binding affinity in vitro and in vivo. Current research is highlighted for the use of BP ligands for targeted delivery of BP conjugates in various applications, including (1) therapeutic drug delivery for metabolic bone diseases, bone cancer, other bone diseases, and engineered drug delivery platforms; (2) imaging probes for scintigraphy, fluorescence, positron emission tomography, magnetic resonance imaging, and computed tomography; and (3) radiotherapy. Last, and perhaps most importantly, key structure-function relationships are considered for the design of drugs with BP ligands, including the tether length between the BP and drug, the size of the drug, the number of BP ligands per drug, cleavable tethers between the BP and drug, and conjugation schemes. PMID- 26482187 TI - Current advances in self-assembled nanogel delivery systems for immunotherapy. AB - Since nanogels (nanometer-sized gels) were developed two decades ago, they were utilized as carriers of innovative drug delivery systems. In particular, immunological drug delivery via self-assembled nanogels (self-nanogels) owing to their nanometer size and molecular chaperon-like ability to encapsulate large biomolecules is one of the most well studied and successful applications of nanogels. In the present review, we focus on self-nanogel applications as immunological drug delivery systems for cancer vaccines, cytokine delivery, nasal vaccines, and nucleic acid delivery, including several clinical trials. Cancer vaccines were the first practical application of self-nanogels as vehicles for drug delivery. After successful pre-clinical studies, phase I clinical trials were conducted, and it was found that vaccines consisting of self-nanogels could be administered repeatedly to humans without serious adverse effects, and self nanogel vaccines induced antigen-specific cellular and humoral immunity. Cytokine delivery via self-nanogels led to the sustained release of IL-12, suppressed tumor growth, and increased Th1-type immune responses. Cationic self-nanogels were effective in penetrating the nasal mucosa and resulted in successful nasal vaccines in mice and nonhuman primates. Cationic self-nanogels were also used for the intracellular delivery of proteins and nucleic acids, and were successfully used to knockdown tumor growth factor expression using short interfering RNA with the immunological effect. These studies suggest that self-nanogels are currently one of the most unique and attractive immunological drug delivery systems and are edging closer to practical use. PMID- 26482188 TI - Development of a virus-mimicking nanocarrier for drug delivery systems: The bio nanocapsule. AB - As drug delivery systems, nanocarriers should be capable of executing the following functions: evasion of the host immune system, targeting to the diseased site, entering cells, escaping from endosomes, and releasing payloads into the cytoplasm. Since viruses perform some or all of these functions, they are considered naturally occurring nanocarriers. To achieve biomimicry of the hepatitis B virus (HBV), we generated the "bio-nanocapsule" (BNC)-which deploys the human hepatocyte-targeting domain, fusogenic domain, and polymerized-albumin receptor domain of HBV envelope L protein on its surface-by overexpressing the L protein in yeast cells. BNCs are capable of delivering various payloads to the cytoplasm of human hepatic cells specifically in vivo, which is achieved via formation of complexes with various materials (e.g., drugs, nucleic acids, and proteins) by electroporation, fusion with liposomes, or chemical modification. In this review, we describe BNC-related technology, discuss retargeting strategies for BNCs, and outline other virus-inspired nanocarriers. PMID- 26482189 TI - A novel platform for cancer therapy using extracellular vesicles. AB - Extracellular vesicles (EVs) are nanometer-sized membranous vesicles and are involved in cell-to-cell communication. EVs contain several types of functional molecules, such as proteins, mRNAs, and microRNAs (miRNAs). Over the past several years, EVs have emerged as potential tools for a drug delivery system (DDS) that can target organs or cells. EVs have a function of organ tropism and are naturally occurring from cells. Therefore, EVs have expected as naturally DDSs, which have the organ tropism and a low side effect. Actually, some reports showed that EVs delivered drugs to specific organ. However, despite observed the organ tropism, the mechanisms of organ tropism of EVs are still unclear. Moreover, preservation and efficient collection of EVs are desired to be investigated. Here, we provide an overview of the methods for using EVs as DDSs. PMID- 26482190 TI - "Role of intraoral color Doppler sonography in predicting delayed cervical lymph node metastasis in patients with early-stage tongue cancer"--a commentary. PMID- 26482191 TI - Influence of orthognathic surgery for symptoms of temporomandibular dysfunction. AB - OBJECTIVE: To evaluate the influence of orthognathic surgery on the clinical signs and symptoms of temporomandibular disorders (TMDs). STUDY DESIGN: In a cohort study, 54 patients undergoing orthognathic surgery were evaluated with regard to the signs and symptoms of TMDs through subjective and objective assessments. These evaluations were performed 1 week preoperatively (T1), 1 month postoperatively (T2), and 6 months postoperatively (T3). The evaluations included patient variables and surgery. Univariate analyzes were performed to verify the association of the variables (P < .05). RESULTS: The incidence of TMD 6 months after orthognathic surgery was significantly lower (P < .001). TMD intensity decreases significantly in the postoperative period. Females had a higher prevalence of TMD (P = .003) and muscular disorders preoperatively (P = .001). There was a decrease in clicks between T1 and T3 (P = .013). Mouth opening without pain worsened from T1 to T2 (P < .001) and improved from T1 to T3 (P = .015) and T2 to T3 (P < .001). The results were similar for mouth opening with pain (P < .001). In patients undergoing jaw fixation with bicortical screws, mouth opening without pain was significantly less in T3 patients than in patients undergoing fixation with plate and monocortical screws (P = .048). CONCLUSIONS: Orthognathic surgery reduces the clinical signs and symptoms of TMD. PMID- 26482192 TI - An elderly man with a gingival mass that spontaneously regressed. PMID- 26482193 TI - RNAi knockdown of acetyl-CoA carboxylase gene eliminates jinggangmycin-enhanced reproduction and population growth in the brown planthopper, Nilaparvata lugens. AB - A major challenge in ecology lies in understanding the coexistence of intraguild species, well documented at the organismal level, but not at the molecular level. This study focused on the effects of the antibiotic, jinggangmycin (JGM), a fungicide widely used in Asian rice agroecosystems, on reproduction of insects within the planthopper guild, including the brown planthopper (BPH) Nilaparvata lugens and the white-backed planthopper (WBPH) Sogatella furcifera, both serious resurgence rice pests. JGM exposure significantly increased BPH fecundity and population growth, but suppressed both parameters in laboratory and field WBPH populations. We used digital gene expression and transcriptomic analyses to identify a panel of differentially expressed genes, including a set of up regulated genes in JGM-treated BPH, which were down-regulated in JGM-treated WBPH. RNAi silencing of Acetyl Co-A carboxylase (ACC), highly expressed in JGM treated BPH, reduced ACC expression (by > 60%) and eliminated JGM-induced fecundity increases in BPH. These findings support our hypothesis that differences in ACC expression separates intraguild species at the molecular level. PMID- 26482194 TI - Constitutional de novo deletion of the FBXW7 gene in a patient with focal segmental glomerulosclerosis and multiple primitive tumors. AB - Multiple primary malignant neoplasms are rare entities in the clinical setting, but represent an important issue in the clinical management of patients since they could be expression of a genetic predisposition to malignancy. A high resolution genome wide array CGH led us to identify the first case of a de novo constitutional deletion confined to the FBXW7 gene, a well known tumor suppressor, in a patient with a syndromic phenotype characterized by focal segmental glomerulosclerosis and multiple primary early/atypical onset tumors, including Hodgkin's lymphoma, Wilms tumor and breast cancer. Other genetic defects may be associated with patient's phenotype. In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay. Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases. PMID- 26482195 TI - Derivation of Ethnically Diverse Human Induced Pluripotent Stem Cell Lines. AB - The human genome with all its ethnic variations contributes to differences in human development, aging, disease, repair, and response to medical treatments and is an exciting area of research and clinical study. The availability of well characterized ethnically diverse stem cell lines is limited and has not kept pace with other advances in stem cell research. Here we derived xenofree ethnically diverse-human induced pluripotent stem cell (ED-iPSC) lines from fibroblasts obtained from individuals of African American, Hispanic-Latino, Asian, and Caucasian ethnic origin and have characterized the lines under a uniform platform for comparative analysis. Derived ED-iPSC lines are low passage number and evaluated in vivo by teratoma formation and in vitro by high throughput microarray analysis of EB formation and early differentiation for tri-lineage commitment to endoderm, ectoderm and mesoderm. These new xenofree ED-iPSC lines represent a well-characterized valuable resource with potential for use in future research in drug discovery or clinical investigations. PMID- 26482196 TI - 3D scaffold alters cellular response to graphene in a polymer composite for orthopedic applications. AB - Graphene-based polymer nanocomposites are being studied for biomedical applications. Polymer nanocomposites can be processed differently to generate planar two-dimensional (2D) substrates and porous three-dimensional (3D) scaffolds. The objective of this work was to investigate potential differences in biological response to graphene in polymer composites in the form of 2D substrates and 3D scaffolds. Polycaprolactone (PCL) nanocomposites were prepared by incorporating 1% of graphene oxide (GO) and reduced graphene oxide (RGO). GO increased modulus and strength of PCL by 44 and 22% respectively, whereas RGO increased modulus and strength by 22 and 16%, respectively. RGO increased the water contact angle of PCL from 81 degrees to 87 degrees whereas GO decreased it to 77 degrees . In 2D, osteoblast proliferated 15% more on GO composites than on PCL whereas RGO composite showed 17% decrease in cell proliferation, which may be attributed to differences in water wettability. In 3D, initial cell proliferation was markedly retarded in both GO (36% lower) and RGO (55% lower) composites owing to increased roughness due to the presence of the protruding nanoparticles. Cells organized into aggregates in 3D in contrast to spread and randomly distributed cells on 2D discs due to the macro-porous architecture of the scaffolds. Increased cell-cell contact and altered cellular morphology led to significantly higher mineralization in 3D. This study demonstrates that the cellular response to nanoparticles in composites can change markedly by varying the processing route and has implications for designing orthopedic implants such as resorbable fracture fixation devices and tissue scaffolds using such nanocomposites. PMID- 26482202 TI - Thousands of junior doctors march against new contract. PMID- 26482203 TI - Reduced toxicological manifestations of cisplatin following encapsulation in folate grafted albumin nanoparticles. AB - AIMS: Cisplatin is one of the most potent chemotherapeutic agents acting against a variety of tumors, however, its use is mainly limited due to the dose limiting toxicities and acquired resistance to cisplatin. Folate functionalized albumin nanoparticles were developed for targeted delivery of drug to limit the adverse effects of cisplatin. MAIN METHODS: Cisplatin loaded nanoparticles functionalized with folate (CP-FA-BSA-NPs) were developed and characterized for various parameters. In order to investigate the targeting ability of folate conjugated nanoparticles, in vitro cellular uptake study was performed in folate receptor over expressing cells (MCF-7). Further, blood urea nitrogen (BUN) level, plasma creatinine level, body weight and kidney weight of the mice were measured followed by histopathological examination of various tissues to have an insight into the potential of developed formulation in the reduction of drug associated adverse effects. KEY FINDINGS: The cellular uptake studies demonstrated higher internalization of folate conjugated nanoparticles as compared to plain counterpart (CP-BSA-NPs). Following two cycles of cisplatin treatment, a week apart, BUN and plasma creatinine level were found to be significantly higher in case of free cisplatin as compared to saline, CP-BSA-NPs and CP-FA-BSA-NPs treated groups. Body weight and kidney weight of free cisplatin treated mice were significantly reduced as compared to other group. Histopathological examination of kidney from CP-BSA-NPs and CP-FA-BSA-NPs treated groups revealed no kidney damage, however, a sign of nephrotoxicity was observed in the case of free cisplatin. SIGNIFICANCE: The results demonstrated the potential of developed formulation in reducing the adverse effects of cisplatin. PMID- 26482204 TI - Sodium tanshinone IIA sulfonate ameliorates experimental coronary no-reflow phenomenon through down-regulation of FGL2. AB - AIMS: The effects of sodium tanshinone IIA sulfonate (STS) on coronary no-reflow (CNR) relevant to microvascular obstruction (MVO) remain unknown. Studies had shown that fibrinogen-like protein 2 (FGL2) expressed in microvascular endothelial cells (MECs) is a key mediator in MVO. Thus, we aimed to elucidate the roles of STS in CNR and relations between STS and FGL2. MAIN METHODS: Myocardial ischemia/reperfusion was selected to represent CNR model. The no reflow zone and infarct area were assessed using Thioflavin S and TTC staining, and cardiac functional parameters were detected using echocardiography. Western blot was used to detected FGL2 level, fibrin level, protease-activated receptor-1 (PAR-1) activation and inflammation cells infiltration. FGL2 and inflammation cells were also identified by IHC. Microthrombus was detected by Carstairs' and MSB staining. We also detected the roles of STS on FGL2 expression, thrombin generation, phospho-Akt and NF-kappaB levels in MECs. KEY FINDINGS: Upon treatment with STS in CNR model, the no-reflow and infarct areas decreased significantly and cardiac function improved. The FGL2 expression was inhibited by STS in vivo as well as in vitro with thrombin generation inhibition. In addition, STS up-regulates Akt phosphorylation and suppressed NF-kappaB expression in activated MECs. Furthermore, fibrin deposition, PAR-1 activation and inflammatory response were inhibited with STS administration in CNR model. SIGNIFICANCE: Our results displayed a novel pharmacological action of STS on CNR. STS is able to ameliorate CNR through inhibition of FGL2 expression mediated by Akt and NF kappaB pathways as well as prevention of MVO by suppressing fibrin deposition and inflammation. PMID- 26482205 TI - Long-term clinical effects of aspirin-desensitization therapy among patients with poorly controlled asthma and non-steroidal anti-inflammatory drug hypersensitivity: An exploratory study. AB - BACKGROUND: According to the Global Initiative for Asthma (GINA), the levels of asthma symptom control can be divided into controlled, partially controlled and uncontrolled asthma. Optional therapy for non-steroidal anti-inflammatory drugs (NSAIDs)-hypersensitive asthmatics uses aspirin desensitization, but until now, this therapy is not established in difficult to treat cases. The aim of this study was to evaluate the efficacy of aspirin desensitization in patients with poorly controlled asthma. METHODS: Patients with poorly controlled asthma, NDAIDs hypersensitivity and aspirin desensitization were included in the retrospective study. The data were compared to those obtained from patients with controlled asthma and aspirin therapy. Lung function, levels of asthma symptom control, asthma medication, the size of nasal polyps (NP) and smell function were evaluated over 18 months. RESULTS: Thirty-two patients were included in the study (uncontrolled/partially controlled asthma n=12; controlled asthma n=20). After 18 months of follow-up, the patients with poorly controlled asthma had significantly increased forced expiratory volume in 1s (FEV1) values, as compared to the baseline (66-82%; p=0.02), the levels of asthma control improved significantly (p<0.01). The asthma medication was reduced. In the group of controlled asthma the FEV1 values did not increase significantly (91.9-92.4%; p>0.05) and the asthma medication was constant. In relation to nasal parameters the sense of smell improved significantly in both groups, NP-scores did not differ significantly. CONCLUSIONS: Patients with a poorly controlled asthma and NSAIDs hypersensitivity profit from an add-on aspirin therapy. PMID- 26482206 TI - The hyper-fluorescent transitional bands in ultra-late phase of indocyanine green angiography in chronic central serous chorioretinopathy. AB - BACKGROUND AND OBJECTIVES: Chronic central serous chorioretinopathy (CSCR) is regarded as a type of severe diffuse retinal pigment epitheliopathy. There is an atrophic tract at level of retinal pigment epithelium (RPE) due to hyper permeability of choroidal vessels, along with photoreceptor (PR) atrophy. Indocyanine green angiography (ICGA) is considered a gold standard for diagnosis. The purpose of this work is to investigate the hyper-fluorescent transitional bands (HFTB) between hypo-fluorescent and normal regions of the retina in the ultra-late phase of ICGA in CSCR. METHODS: 26 chronic CSCR eyes and 12 relative normal eyes received spectral domain optical coherence tomography (SD-OCT), and ICGA at the 24th hour after indocyanine green (ICG) intravenous injection. RESULTS: In the ultra-late phase, images showed homogenous fluorescence in all normal eyes. On the contrary, geographical hypofluorescent lesions with atrophy of RPE was noted in 26 chronic CSCR eyes. Moreover, HFTB with intact RPE and disrupted PR was detected in 20 out of 26 chronic CSCR eyes (76.9%). CONCLUSIONS: The HFTB may indicate the early damage in chronic CSCR. Ultra-late ICGA can monitor not only metabolic status by endogenous melanin, but also membrane function in RPE by exogenous ICG molecule. PMID- 26482207 TI - Cathepsin Protease Inhibition Reduces Endometriosis Lesion Establishment. AB - Endometriosis is a gynecologic disease characterized by the ectopic presence of endometrial tissue on organs within the peritoneal cavity, causing debilitating abdominal pain and infertility. Current treatments alleviate moderate pain symptoms associated with the disorder but exhibit limited ability to prevent new or recurring lesion establishment and growth. Retrograde menstruation has been implicated for introducing endometrial tissue into the peritoneal cavity, but molecular mechanisms underlying attachment and invasion are not fully understood. We hypothesize that cysteine cathepsins, a group of powerful extracellular matrix proteases, facilitate endometrial tissue invasion and endometriosis lesion establishment in the peritoneal wall and inhibiting this activity would decrease endometriosis lesion implantation. To test this, we used an immunocompetent endometriosis mouse model and found that endometriotic lesions exhibited a greater than 5-fold increase in active cathepsins compared to tissue from peritoneal wall or eutopic endometrium, with cathepsins L and K specifically implicated. Human endometriosis lesions also exhibited greater cathepsin activity than adjacent peritoneum tissue, supporting the mouse results. Finally, we tested the hypothesis that inhibiting cathepsin activity could block endometriosis lesion attachment and implantation in vivo. Intraperitoneal injection of the broad cysteine cathepsin inhibitor, E-64, significantly reduced the number of attached endometriosis lesions in our murine model compared to vehicle-treated controls demonstrating that cathepsin proteases contribute to endometriosis lesion establishment, and their inhibition may provide a novel, nonhormonal therapy for endometriosis. PMID- 26482208 TI - Lactational Exposure to Di (2-ethylhexyl) Phthalate Impairs the Ovarian and Uterine Function of Adult Offspring Rat. AB - Phthalates, a class of chemicals used as plasticizers, are economically important due to several industrial applications. Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used phthalate plasticizer, and it has been described as a potent antiandrogen in males. In this study, lactating dams were exposed via oral gavage to corn oil (vehicle) and DEHP (1, 10, and 100 mg/kg body weight) from postnatal day 1 to 21, and the effects were evaluated in the ovary and uterus of F(1) progeny. DEHP exposure significantly decreased the body weight and organ weight in a dose-dependent manner. Serum levels of estradiol, testosterone, and progesterone were decreased but anogenital distance was unaffected. The mRNA expressions of luteinizing hormone receptor, follicle-stimulating hormone receptor, androgen receptor, estrogen receptor (ERalpha and ERbeta), progesterone receptor, peroxisome proliferator-activated receptor gamma, 3beta hydroxysteroid dehydrogenase, aromatase, and steroidogenic acute regulatory protein were altered in the ovary of F1 progeny rats. Our finding suggest that lactational exposure to DEHP has transgenerational effect on female reproductive system. PMID- 26482209 TI - Hypoxia Promotes Invasion of Endometrial Stromal Cells via Hypoxia-Inducible Factor 1alpha Upregulation-Mediated beta-Catenin Activation in Endometriosis. AB - Endometriosis is a common benign gynecological disease defined as the presence of endometrial tissue outside the uterine cavity. The aim of this study was to identify the molecular mechanism underlying hypoxia-induced increases in invasive ability of human endometrial stromal cells (HESCs). Herein, we show that the expression levels of hypoxia-inducible factor lalpha (HIF-1alpha) and beta catenin were greater in ectopic endometriotic tissue compared with eutopic tissue from controls. Exposure of eutopic endometrial stromal cells under hypoxic conditions or treated with desferrioxamine (DFO, chemical hypoxia) resulted in a time-dependent increase in beta-catenin expression and its dephosphorylation. Hypoxia/HIF-1alpha also activated the beta-catenin/T-cell factor (TCF) signaling pathway and the expression of target genes, vascular endothelial growth factor and matrix metalloproteinase 9, and knockdown of HIF-1alpha or beta-catenin abrogated hypoxia-induced increases in HESC invasiveness. These results suggest that HIF-1alpha interacting with beta-catenin/TCF signaling pathway, which is activated by hypoxia, may provide new insights into the etiology of endometriosis. PMID- 26482210 TI - Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 11, 2013.Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for which stiripentol (STP) has been recently licensed as add-on therapy. OBJECTIVES: To evaluate the efficacy and tolerability of STP and other antiepileptic drug treatments (including ketogenic diet) for patients with SMEI. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (27 April 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; 27 April 2015) and MEDLINE (1946 to 27 April 2015). We systematically searched the online trials registry ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform and the bibliographies of identified studies for additional references. We handsearched selected journals and conference proceedings and imposed no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-randomised controlled trials; double- or single blinded or unblinded trials; and parallel-group studies. Administration of at least one antiepileptic drug therapy given singly (monotherapy) or in combination (add-on therapy) compared with add-on placebo or no add-on treatment. DATA COLLECTION AND ANALYSIS: Review authors independently selected trials for inclusion according to predefined criteria, extracted relevant data and evaluated the methodological quality of trials. We assessed the following outcomes: 50% or greater seizure reduction, seizure freedom, adverse effects, proportion of dropouts and quality of life. We assessed outcomes by using a Mantel-Haenszel meta-analysis to calculate risk ratios (RRs) with 95% confidence intervals (95% CIs). MAIN RESULTS: In the updated search, we identified no additional studies suitable for inclusion. We found no RCTs assessing drugs other than STP. The previous version of this review included two RCTs evaluating use of STP (total of 64 children). Both studies were generally at unclear risk of bias. A significantly higher proportion of participants had 50% or greater reduction in seizure frequency in the STP group compared with the placebo group (22/33 vs 2/31; RR 10.40, 95% CI 2.64 to 40.87). A significantly higher proportion of participants achieved seizure freedom in the STP group compared with the placebo group (12/33 vs 1/31; RR 7.93, 95% CI 1.52 to 41.21). Investigators found no significant differences in proportions of dropouts from the STP group compared with the placebo group (2/33 vs 8/31; RR 0.24, 95% CI 0.06 to 1.03). Only one study explicitly reported the occurrence of side effects, noting that higher proportions of participants in the STP group experienced side effects than in the placebo group (100% vs 25%; RR 3.73, 95% CI 1.81 to 7.67). AUTHORS' CONCLUSIONS: Data derived from two small RCTs indicate that STP is significantly better than placebo with regards to 50% or greater reduction in seizure frequency and seizure freedom. Adverse effects occurred more frequently with STP. Additional adequately powered studies with long-term follow-up should be conducted to unequivocally establish the long-term efficacy and tolerability of STP in the treatment of patients with SMEI. PMID- 26482211 TI - Estimating causal effects for multivalued treatments: a comparison of approaches. AB - Interventions with multivalued treatments are common in medical and health research, such as when comparing the efficacy of competing drugs or interventions, or comparing between various doses of a particular drug. In recent years, there has been a growing interest in the development of multivalued treatment effect estimators using observational data. In this paper, we compare the performance of commonly used regression-based methods that estimate multivalued treatment effects based on the unconfoundedness assumption. These estimation methods fall into three general categories: (i) estimators based on a model for the outcome variable using conventional regression adjustment; (ii) weighted estimators based on a model for the treatment assignment; and (iii) 'doubly-robust' estimators that model both the treatment assignment and outcome variable within the same framework. We assess the performance of these models using Monte Carlo simulation and demonstrate their application with empirical data. Our results show that (i) when models estimating both the treatment and outcome are correctly specified, all adjustment methods provide similar unbiased estimates; (ii) when the outcome model is misspecified, regression adjustment performs poorly, while all the weighting methods provide unbiased estimates; (iii) when the treatment model is misspecified, methods based solely on modeling the treatment perform poorly, while regression adjustment and the doubly robust models provide unbiased estimates; and (iv) when both the treatment and outcome models are misspecified, all methods perform poorly. Given that researchers will rarely know which of the two models is misspecified, our results support the use of doubly robust estimation. PMID- 26482213 TI - Facile Alder-Ene Reactions of Silylallenes Involving an Allenic C(sp(2) )-H Bond. AB - Facile and selective Alder-ene reactions of silylallenes involving the activation of an allenic C(sp(2) )?H over an allylic C(sp(3) )?H bond is described. In this ene reaction, the presence of a silyl substituent was found to be critical for the observed reactivity and selectivity since the corresponding alkyl-substituted allenes show different reaction profiles. Computational studies show that the origin of this unusual reactivity is the lower bond dissociation energy of the alpha-C(sp(2) )?H bond in silylallenes compared to the corresponding nonsilylated allenes. PMID- 26482214 TI - Follow-Up of the Sinus Membrane Elevation Technique for Maxillary Sinus Implants without the Use of Graft Material. AB - BACKGROUND: There is a limited amount of studies evaluating long-term results of the sinus membrane elevation technique for bone formation around implants in the maxillary sinus floor without the use of bone graft material. PURPOSE: To investigate the long-term results of this technique with regard to implant survival and bone gain in the maxillary sinus floor. MATERIALS AND METHODS: A retrospective study was conducted on patients who had undergone the surgical procedure from November 2001 to August 2008. Thirty-six patients with a total of 87 implants (ASTRA TECH Implant SystemTM) in 53 sinuses were examined. After a submerged healing period of 6 months and at least 12 months of loading, the patients were examined clinically and radiologically. Implant stability was measured using resonance frequency analysis (RFA). RESULTS: The mean follow-up time was 4.6 years (range 1.5-7 years). Five implants were lost giving a survival rate of 94.3%.Subantral preoperative vertical bone levels were in the range of 1 to 10 mm. The average bone gain at the sinus floor was 6 mm. The 55 fixtures eligible for RFA displayed a mean implant stability quotient of 77 (range 56 85.5). CONCLUSION: The present study illustrates the long-term reliability of the technique. PMID- 26482212 TI - Impact of age-related macular degeneration in patients with glaucoma: understanding the patients' perspective. AB - BACKGROUND: The aim of the study is to measure the impact of age-related macular degeneration on vision-related activity limitation and preference-based status for glaucoma patients. DESIGN: This was a cross-sectional study. PARTICIPANTS: Two-hundred glaucoma patients of whom 73 had age-related macular degeneration were included in the research. METHODS: Sociodemographic information, visual field parameters and visual acuity were collected. Age-related macular degeneration was scored using the Age-Related Eye Disease Study system. MAIN OUTCOME MEASURES: The Rasch-analysed Glaucoma Activity Limitation-9 and the Visual Function Questionnaire Utility Index measured vision-related activity limitation and preference-based status, respectively. Regression models determined factors predictive of vision-related activity limitation and preference-based status. Differential item functioning compared Glaucoma Activity Limitation-9 item difficulty for those with and without age-related macular degeneration. RESULTS: Mean age was 73.7 (+/-10.1) years. Lower better eye mean deviation (beta: 1.42, 95% confidence interval: 1.24-1.63, P < 0.001) and age related macular degeneration (beta: 1.26 95% confidence interval: 1.10-1.44, P = 0.001) were independently associated with worse vision-related activity limitation. Worse eye visual acuity (beta: 0.978, 95% confidence interval: 0.961 0.996, P = 0.018), high risk age-related macular degeneration (beta: 0.981, 95% confidence interval: 0.965-0.998, P = 0.028) and severe glaucoma (beta: 0.982, 95% confidence interval: 0.966-0.998, P = 0.032) were independently associated with worse preference-based status. Glaucoma patients with age-related macular degeneration found using stairs, walking on uneven ground and judging distances of foot to step/curb significantly more difficult than those without age-related macular degeneration. CONCLUSIONS: Vision-related activity limitation and preference-based status are negatively impacted by severe glaucoma and age related macular degeneration. Patients with both conditions perceive increased difficulty walking safely compared with patients with glaucoma alone. PMID- 26482215 TI - High-performance Polymer Membranes with Multi-functional Amphiphilic Micelles for CO2 Capture. AB - Herein, we report a high performance polymer membrane with simultaneously large improvements in the CO2 permeability and CO2/N2 selectivity. These improvements are obtained by incorporation of a multi-functional amphiphilic comb copolymer micelle, that is, poly(dimethylsiloxane)-g-poly(oxyethylene methacrylate) (PDMS-g POEM), into a poly(amide-b-ethylene oxide) (Pebax) matrix. Both CO2 and N2 permeabilities continuously increased with PDMS-g-POEM content, whereas the CO2/N2 selectivity increased up to 40 wt % of PDMS-g-POEM, which enabled the maximum performance to approach the upper bound limit (2008). The membranes with PDMS-g-POEM exhibited greater CO2 permeability and CO2/N2 selectivity than those with a zeolitic imidazolate framework (ZIF-8), a well-known expensive inorganic filler, indicating the effectiveness of PDMS-g-POEM micelles for CO2 capture. PMID- 26482216 TI - Performance of three glomerular filtration rate estimation equations in a population of sub-Saharan Africans with Type 2 diabetes. AB - AIM: We evaluated the performance of the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft Gault (CG) equations against creatinine clearance (CrCl) to estimate glomerular filtration rate (GFR) in 51 patients with Type 2 diabetes. METHODS: The CrCl value was obtained from the average of two consecutive 24-h urine samples. Results were adjusted for body surface area using the Dubois formula. Serum creatinine was measured using the kinetic Jaffe method and was calibrated to standardized levels. Bland-Altman analysis and kappa statistic were used to examine agreement between measured and estimated GFR. RESULTS: Estimates of GFR from the CrCl, MDRD, CKD-EPI and CG equations were similar (overall P = 0.298), and MDRD (r = 0.58; 95% CI: 0.36-0.74), CKD-EPI (r = 0.55; 95% CI: 0.33-0.72) and CG (r = 0.61; 95% CI: 0.39-0.75) showed modest correlation with CrCl (all P < 0.001). Bias was -0.3 for MDRD, 1.7 for CKD-EPI and -5.4 for CG. All three equations showed fair-to-moderate agreement with CrCl (kappa: 0.38-0.51). The c statistic for all three equations ranged between 0.75 and 0.77 with no significant difference (P = 0.639 for c-statistic comparison). CONCLUSIONS: The MDRD equation seems to have a modest advantage over CKD-EPI and CG in estimating GFR and detecting impaired renal function in sub-Saharan African patients with Type 2 diabetes. The overall relatively modest correlation with CrCl, however, suggests the need for context-specific estimators of GFR or context adaptation of existing estimators. PMID- 26482217 TI - Future Blood Vessel Puncture Procedure With Use of Head Mount Display. PMID- 26482218 TI - Molecular Self-Assembly in a Poorly Screened Environment: F4TCNQ on Graphene/BN. AB - We report a scanning tunneling microscopy and noncontact atomic force microscopy study of close-packed 2D islands of tetrafluorotetracyanoquinodimethane (F4TCNQ) molecules at the surface of a graphene layer supported by boron nitride. While F4TCNQ molecules are known to form cohesive 3D solids, the intermolecular interactions that are attractive for F4TCNQ in 3D are repulsive in 2D. Our experimental observation of cohesive molecular behavior for F4TCNQ on graphene is thus unexpected. This self-assembly behavior can be explained by a novel solid formation mechanism that occurs when charged molecules are placed in a poorly screened environment. As negatively charged molecules coalesce, the local work function increases, causing electrons to flow into the coalescing molecular island and increase its cohesive binding energy. PMID- 26482219 TI - Prendre le virage des partenariats. AB - Deux projets demontrent que la mise en oeuvre de donnees colligees sur le terrain peut contribuer a regler des problemes dans le milieu de la sante pour favoriser de meilleurs resultats et de plus grandes efficiences. Dans le premier exemple, une vaste coalition de partenaires publics et prives de l'Alberta recourt aux techniques de mesures ameliorees et a la methodologie du Triple objectif pour ameliorer les resultats cliniques de populations de cas complexes et lourds du quartier Eastwood d'Edmonton. On espere que les conclusions novatrices qui en sont tirees seront adaptees a d'autres regions de la province. Dans le deuxieme exemple, la Childhood Obesity Foundation s'associe a Merck au Canada et a Ayogo (une societe de therapies numeriques situee a Vancouver) et utilise le concept novateur de la " ludification " pour mobiliser les jeunes de plus en plus sedentaires du Canada et modifier leurs comportements. PMID- 26482220 TI - "Moving the needle" through partnerships. AB - Two projects illustrate how the application of real-world evidence can help to address healthcare challenges to generate better outcomes and efficiencies. In the first example, a broad coalition of public and private partners in Alberta is applying enhanced measurement techniques and the Triple Aim methodology to improve health outcomes among complex care, high needs patients in Edmonton's Eastwood community. The innovative findings, it is hoped, will be scaled to other areas of the province. In the second example, the Childhood Obesity Foundation, with support from Merck in Canada, and Ayogo (a Vancouver-based digital therapeutics company) are partnering to use innovative "gamification" to build engagement and change behaviours among Canada's increasingly sedentary youth. PMID- 26482221 TI - Trois points de vue sur les partenariats pour corriger les lacunes en matiere de soins de sante. AB - Puisqu'ils sont en premiere ligne aupres des patients, les pharmaciens communautaires jouent un role essentiel au sein du systeme de sante. Le present article propose trois points de vue sur la maniere dont une approche concertee, qui inclut le pharmacien communautaire, peut ameliorer les soins aux patients et reduire les couts pour le systeme. C'est la reussite de ces modeles de partenariat qui contribue a susciter des changements systemiques. L'article presente les reflexions du docteur Ross Tsuyuki, l'un des chercheurs canadiens de pointe sur le sujet, et quelques decouvertes realisees tout au long de son partenariat avec Merck au Canada depuis 20 ans. La majeure partie des etudes revisees par des pairs du docteur Tsuyuki sont menees en Alberta, ou la portee de la pratique des pharmaciens est elargie. PMID- 26482222 TI - Degradation of the ABA co-receptor ABI1 by PUB12/13 U-box E3 ligases. AB - Clade A protein phosphatase 2Cs (PP2Cs) are abscisic acid (ABA) co-receptors that block ABA signalling by inhibiting the downstream protein kinases. ABA signalling is activated after PP2Cs are inhibited by ABA-bound PYR/PYL/RCAR ABA receptors (PYLs) in Arabidopsis. However, whether these PP2Cs are regulated by other factors remains unknown. Here, we report that ABI1 (ABA-INSENSITIVE 1) can interact with the U-box E3 ligases PUB12 and PUB13, but is ubiquitinated only when it interacts with ABA receptors in an in vitro assay. A mutant form of ABI1 1 that is unable to interact with PYLs is more stable than the wild-type protein. Both ABI1 degradation and all tested ABA responses are reduced in pub12 pub13 mutants compared with the wild type. Introducing the abi1-3 loss-of-function mutation into pub12 pub13 mutant recovers the ABA-insensitive phenotypes of the pub12 pub13 mutant. We thus uncover an important regulatory mechanism for regulating ABI1 levels by PUB12 and PUB13. PMID- 26482224 TI - A trifunctional cyclooctyne for modifying azide-labeled biomolecules with photocrosslinking and affinity tags. AB - A bicyclo[6.1.0]nonyne (BCN)-based cyclooctyne reagent bearing a photocrosslinking diazirine (DAz) group and a biotin affinity handle, BCN-DAz Biotin, is reported. BCN-DAz-Biotin is capable of simultaneously delivering photocrosslinking and affinity tags to azide-labeled biomolecules, enabling photoactivated capture and enrichment/detection of interacting species in native contexts. PMID- 26482225 TI - Closing the Nanographene Gap: Surface-Assisted Synthesis of Peripentacene from 6,6'-Bipentacene Precursors. AB - The thermally induced cyclodehydrogenation reaction of 6,6'-bipentacene precursors on Au(111) yields peripentacene stabilized by surface interactions with the underlying metallic substrate. STM and atomic-resolution non-contact AFM imaging reveal rectangular flakes of nanographene featuring parallel pairs of zig zag and armchair edges resulting from the lateral fusion of two pentacene subunits. The synthesis of a novel molecular precursor 6,6'-bipentacene, itself a synthetic target of interest for optical and electronic applications, is also reported. The scalable synthetic strategy promises to afford access to a structurally diverse class of extended periacenes and related polycyclic aromatic hydrocarbons as advanced materials for electronic, spintronic, optical, and magnetic devices. PMID- 26482223 TI - Minimal Clinically Important Difference in the Physical, Emotional, and Total Symptom Distress Scores of the Edmonton Symptom Assessment System. AB - CONTEXT: The Edmonton Symptom Assessment System (ESAS) is one of the most commonly used symptom batteries in clinical practice and research. OBJECTIVES: We used the anchor-based approach to identify the minimal clinically important difference (MCID) for improvement and deterioration for ESAS physical, emotional, and total symptom distress scores. METHODS: In this multicenter prospective study, we asked patients with advanced cancer to complete their ESAS at the first clinic visit and at a second visit three weeks later. The anchor for MCID determination was Patient's Global Impression regarding their physical, emotional, and overall symptom burden ("better," "about the same," or "worse"). We identified the optimal sensitivity/specificity cutoffs for both improvement and deterioration for the three ESAS scores and also determined the within patient changes. RESULTS: A total of 796 patients were enrolled from six centers. The ESAS scores had moderate responsiveness, with area under the receiver operating characteristic curve between 0.69 and 0.76. Using the sensitivity specificity approach, the optimal cutoffs for ESAS physical, emotional, and total symptom distress scores were >=3/60, >=2/20, and >=3/90 for improvement, and <= 4/60, <=-1/20, and <=-4/90 for deterioration, respectively. These cutoffs had moderate sensitivities (59%-68%) and specificities (62%-80%). The within-patient change approach revealed the MCID cutoffs for improvement/deterioration to be 3/ 4.3 for the physical score, 2.4/-1.8 for the emotional score, and 5.7/-2.9 for the total symptom distress score. CONCLUSION: We identified the MCIDs for physical, emotional, and total symptom distress scores, which have implications for interpretation of symptom response in clinical trials. PMID- 26482226 TI - Rational fabrication of a gold-coated AFM TERS tip by pulsed electrodeposition. AB - Reproducible fabrication of sharp gold- or silver-coated tips has become the bottleneck issue in tip-enhanced Raman spectroscopy, especially for atomic force microscopy (AFM)-based TERS. Herein, we developed a novel method based on pulsed electrodeposition to coat a thin gold layer over atomic force microscopy (AFM) tips to produce plasmonic TERS tips with high reproducibility. We systematically investigated the influence of the deposition potential and step time on the surface roughness and sharpness. This method allows the rational control of the radii of gold-coated TERS tips from a few to hundreds of nanometers, which allows us to systematically study the dependence of the TERS enhancement on the radius of the gold-coated AFM tip. The maximum TERS enhancement was achieved for the tip radius in the range of 60-75 nm in the gap mode. The coated gold layer has a strong adhesion with the silicon tip surface, which is highly stable in water, showing the great potential for application in the aqueous environment. PMID- 26482227 TI - Tumor size, stage and grade alterations of urinary peptidome in RCC. AB - BACKGROUND: Several promising biomarkers have been found for RCC, but none of them has been used in clinical practice for predicting tumour progression. The most widely used features for predicting tumour aggressiveness still remain the cancer stage, size and grade. Therefore, the aim of our study is to investigate the urinary peptidome to search and identify peptides whose concentrations in urine are linked to tumour growth measure and clinical data. METHODS: A proteomic approach applied to ccRCC urinary peptidome (n = 117) based on prefractionation with activated magnetic beads followed by MALDI-TOF profiling was used. A systematic correlation study was performed on urinary peptide profiles obtained from MS analysis. Peptide identity was obtained by LC-ESI-MS/MS. RESULTS: Fifteen, twenty-six and five peptides showed a statistically significant alteration of their urinary concentration according to tumour size, pT and grade, respectively. Furthermore, 15 and 9 signals were observed to have urinary levels statistically modified in patients at different pT or grade values, even at very early stages. Among them, C1RL, A1AGx, ZAG2G, PGBM, MMP23, GP162, ADA19, G3P, RSPH3, DREB, NOTC2 SAFB2 and CC168 were identified. CONCLUSIONS: We identified several peptides whose urinary abundance varied according to tumour size, stage and grade. Among them, several play a possible role in tumorigenesis, progression and aggressiveness. These results could be a useful starting point for future studies aimed at verifying their possible use in the managements of RCC patients. PMID- 26482229 TI - Circular flow formation triggered by Marangoni convection in nematic liquid crystal films with a free surface. AB - We demonstrate circular flow formation at a surface in homeotropically oriented nematic liquid crystals with a free surface using focused laser beam irradiation. Under a weak laser power, a pit together with an associated circular bulge is formed: the Marangoni effect. Here a diverging molecular flow from the pit (thermocapillary flow) also induces director tilt in the radial direction. Upon increasing the laser power, the pit becomes deeper, and eventually evolves into a circular flow associated with a deeper pit and a subsidiary circular bulge or valley structure. This phenomenon is induced by escaping from excess deformation energy due to a bend deformation of the director. Actually, we confirmed that the circular flow is never formed in the isotropic phase. The handedness of the vortex cannot be controlled by circular polarisation, but is controllable by doping with chiral molecules. This rotational motion (a nematic micro-rotor) is a unique phenomenon only exhibited by anisotropic liquids, and is expected to be applied for novel devices. PMID- 26482228 TI - Multifocal leukoencephalopathy in cocaine users: a report of two cases and review of the literature. AB - BACKGROUND: Cocaine abuse is associated with several mechanisms of brain injury including ischemic, hemorrhagic and metabolic. Recently two case reports of leukoencephalopathy in cocaine users implicated a commonly used cocaine adulterant, levamisole. One well-documented adverse effect of levamisole, when used alone as antihelminthic or immunomodulatory drug, is multifocal inflammatory leukoencephalopathy. Therefore, immune mechanisms may also contribute to cocaine induced brain injury. CASE PRESENTATIONS: Two cocaine users with multifocal leukoencephalopathy, treated with steroids and plasmapheresis, are described. The first is a 25-year-old man who presented with unilateral motor and sensory impairment progressing to bilateral deficits, dysphagia, dysarthria and confusion over several days. Serial MRI showed increasing abnormal FLAIR signal lesions with patchy restricted diffusion and heterogenous enhancement deep in the right and left hemispheres, including periventricular white matter as well as in the pons and cerebellar peduncle. The second patient is a 41-year-old woman who presented with confusion and impaired balance. MRI showed bilateral periventricular FLAIR lesions with scattered restricted diffusion and subtle gadolinium enhancement of some of the lesions. She initially stabilized with supportive care only, but after further cocaine use was re-admitted six weeks later with marked neurological deterioration and MRI showed prominent worsening of the lesions. Both patients received steroid and plasma exchange and showed substantial improvement clinically and on imaging, which was sustained during out patient follow-up. CONCLUSION: Multifocal leukoencephalopathy associated with cocaine use may have an inflammatory/immune basis, possibly related to levamisole contamination, at least in some patients. Three cases, including the present two, have been described wherein good neurological improvement was seen in association with steroid treatment. However, in the absence of appropriate clinical trials, it remains unknown whether immunotherapy is truly beneficial for these patients. PMID- 26482230 TI - Conformational control of cofactors in nature - the influence of protein-induced macrocycle distortion on the biological function of tetrapyrroles. AB - Tetrapyrrole-containing proteins are one of the most fundamental classes of enzymes in nature and it remains an open question to give a chemical rationale for the multitude of biological reactions that can be catalyzed by these pigment protein complexes. There are many fundamental processes where the same (i.e., chemically identical) porphyrin cofactor is involved in chemically quite distinct reactions. For example, heme is the active cofactor for oxygen transport and storage (hemoglobin, myoglobin) and for the incorporation of molecular oxygen in organic substrates (cytochrome P450). It is involved in the terminal oxidation (cytochrome c oxidase) and the metabolism of H2O2 (catalases and peroxidases) and catalyzes various electron transfer reactions in cytochromes. Likewise, in photosynthesis the same chlorophyll cofactor may function as a reaction center pigment (charge separation) or as an accessory pigment (exciton transfer) in light harvesting complexes (e.g., chlorophyll a). Whilst differences in the apoprotein sequences alone cannot explain the often drastic differences in physicochemical properties encountered for the same cofactor in diverse protein complexes, a critical factor for all biological functions must be the close structural interplay between bound cofactors and the respective apoprotein in addition to factors such as hydrogen bonding or electronic effects. Here, we explore how nature can use the same chemical molecule as a cofactor for chemically distinct reactions using the concept of conformational flexibility of tetrapyrroles. The multifaceted roles of tetrapyrroles are discussed in the context of the current knowledge on distorted porphyrins. Contemporary analytical methods now allow a more quantitative look at cofactors in protein complexes and the development of the field is illustrated by case studies on hemeproteins and photosynthetic complexes. Specific tetrapyrrole conformations are now used to prepare bioengineered designer proteins with specific catalytic or photochemical properties. PMID- 26482231 TI - Projection of participant recruitment to primary care research: a qualitative study. AB - BACKGROUND: Recruitment to clinical trials remains a challenge, particularly in primary care settings. Initial projections of participant recruitment need to be as accurate as possible in order to avoid the financial, clinical and ethical costs of trial extensions or failures. However, estimation of recruitment rates is challenging and often poorly executed, if attempted at all. We used qualitative methods to explore the experiences and views of researchers on the planning of recruitment in this setting. METHODS: Participants had registered accrual to a UK-based primary care research study between April 2009 and March 2012. We conducted nine interviews with chief investigators or study managers, using a semi-structured topic guide. Analysis was conducted using the framework approach. RESULTS: Three themes are presented: 1) the factors affecting recruitment rates, 2) the use of planning techniques, and 3) influences on poor estimation. 1) A large number of factors affecting recruitment rates were discussed, including those relating to the study protocol, the clinical setting and the research setting. Use of targeted mail-outs to invite apparently eligible individuals to participate was preferred in order to eliminate some of the uncertainty in the recruitment rate associated with opportunistic clinician referrals. 2) The importance of pilot work was stressed. We identified significant uncertainty as to how best to schedule trial timelines to maximise efficiency. 3) Several potential sources of bias involved in the estimation of recruitment rates were explored and framed as technological, psychological or political factors. CONCLUSIONS: We found a large number of factors that interviewees felt impact recruitment rates to primary care research and highlighted the complexity of realistic estimation. Suitable early planning of the recruitment process is essential, and there may be potential to improve the projection of trial timelines by reducing biases involved in the process. Further research is needed to develop formal approaches that would be suitable for use in this setting. PMID- 26482232 TI - Reduced middle ear infection with non-typeable Haemophilus influenzae, but not Streptococcus pneumoniae, after transition to 10-valent pneumococcal non-typeable H. influenzae protein D conjugate vaccine. AB - BACKGROUND: In October 2009, 7-valent pneumococcal conjugate vaccine (PCV7: Prevenar(TM) Pfizer) was replaced in the Northern Territory childhood vaccination schedule by 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; Synflorix(TM) GlaxoSmithKline Vaccines). This analysis aims to determine whether the reduced prevalence of suppurative otitis media measured in the PHiD-CV10 era was associated with changes in nasopharyngeal (NP) carriage and middle ear discharge (ED) microbiology in vaccinated Indigenous children. METHODS: Swabs of the NP and ED were collected in remote Indigenous communities between September 2008 and December 2012. Swabs were cultured using standardised methods for otitis media pathogens. Children less than 3 years of age and having received a primary course of 2 or more doses of one PCV formulation and not more than one dose of another PCV formulation were included in the primary analysis; children with non-mixed single formulation PCV schedules were also compared. RESULTS: NP swabs were obtained from 421 of 444 (95%) children in the PCV7 group and 443 of 451 (98%) children in the PHiD-CV10 group. Non-mixed PCV schedules were received by 333 (79%) and 315 (71%) children, respectively. Pneumococcal (Spn) NP carriage was 76% and 82%, and non-typeable Haemophilus influenzae (NTHi) carriage was 68% and 73%, respectively. ED was obtained from 60 children (85 perforations) in the PCV7 group and from 47 children (59 perforations) in the PHiD-CV10 group. Data from bilateral perforations were combined. Spn was cultured from 25% and 18%, respectively, and NTHi was cultured from 61% and 34% respectively (p = 0.008). CONCLUSIONS: The observed reduction in the prevalence of suppurative OM in this population was not associated with reduced NP carriage of OM pathogens. The prevalence of NTHi-infected ED was lower in PHiD-CV10 vaccinated children compared to PCV7 vaccinated children. Changes in clinical severity may be explained by the action of PHiD-CV10 on NTHi infection in the middle ear. Randomised controlled trials are needed to answer this question. PMID- 26482233 TI - Evaluation of the HAS-BLED, ATRIA, and ORBIT Bleeding Risk Scores in Patients with Atrial Fibrillation Taking Warfarin. AB - OBJECTIVES: Various bleeding risk prediction schemes, such as the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized Ratio, Elderly, Drugs/alcohol (HAS-BLED), Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), and Outcomes Registry for Better Informed Treatment (ORBIT) scores, have been proposed in patients with atrial fibrillation. We compared the relative predictive values of these bleeding risk scores for clinically relevant bleeding and the relationship of ATRIA and ORBIT scores to the quality of anticoagulation control on warfarin, as reflected by time in therapeutic range. METHODS: We conducted a post hoc ancillary analysis of clinically relevant bleeding and major bleeding events among 2293 patients receiving warfarin therapy in the AMADEUS trial. RESULTS: Only HAS-BLED was significantly predictive for clinically relevant bleeding, and all 3 risk scores were predictive for major bleeding. The predictive performance of HAS-BLED was modest, as reflected by c-indexes of 0.59 (P < .001) and 0.65 (P < .002) for clinically relevant bleeding and major bleeding, respectively. The HAS-BLED score performed better than the ATRIA (P = .002) or ORBIT (P = .001) score in predicting any clinically relevant bleeding. Only the HAS-BLED score was significantly associated with the risk for both bleeding outcomes on Cox regression analysis (any clinically relevant bleeding: hazard ratio, 1.85; 95% confidence interval, 1.43-2.40, P < .001; major bleeding: hazard ratio, 2.40; 95% confidence interval, 1.28-4.52; P = .007). There were strong inverse correlations of ATRIA and ORBIT scores to time in therapeutic range as a continuous variable (low risk ATRIA, r = -0.96; P = .003; ORBIT, r = -0.96; P = .003). Improvement in the predictive performance for both ATRIA and ORBIT scores for any clinically relevant bleeding was achieved by adding time in therapeutic range to both scores, with significant differences in c-indexes (P = .001 and P = .002, respectively), net reclassification improvement, and integrated discriminant improvement (both P < .001). CONCLUSIONS: All 3 bleeding risk prediction scores demonstrated modest predictive ability for bleeding outcomes, although the HAS BLED score performed better than the ATRIA or ORBIT score. Significant improvements in both ATRIA and ORBIT score prediction performances were achieved by adding time in therapeutic range to both scores. PMID- 26482234 TI - Relationships between fear of falling, balance confidence, and control of balance, gait, and reactive stepping in individuals with sub-acute stroke. AB - Fear of falling is common in individuals with stroke; however, the associations between fear of falling, balance confidence, and the control of balance and gait are not well understood for this population. This study aimed to determine whether, at the time of admission to in-patient rehabilitation, specific features of balance and gait differed between individuals with stroke who did and did not report fear of falling, and whether these features were related to balance confidence. Individuals with stroke entering in-patient rehabilitation were asked if they were afraid of falling, and completed the Activities-Specific Balance Confidence Scale. Participants performed quiet standing, gait, and reactive stepping tasks, and specific measures were extracted for each (quiet standing: centre of pressure amplitude, between-limb synchronization, and Romberg quotients; gait: walking velocity, double support time, and variability measures; reactive stepping: number of steps, frequency of grasp reactions, and frequency of assists). No significant differences were identified between individuals with and without fear of falling. Balance confidence was negatively related to centre of pressure amplitude, double support time, and step time variability, and positively related to walking velocity. Low balance confidence was related to poor quiet standing balance control and cautious behavior when walking in individuals with sub-acute stroke. While the causal relationship between balance confidence and the control of balance and gait is unclear from the current work, these findings suggest there may be a role for interventions to increase balance confidence among individuals with stroke, in order to improve functional mobility. PMID- 26482235 TI - Defining the nitrogen regulated transcriptome of Mycobacterium smegmatis using continuous culture. AB - BACKGROUND: Nitrogen is essential for microbial growth and its importance is demonstrated by the complex regulatory systems used to control the transport, assimilation and metabolism of nitrogen. Recent studies are beginning to shed light on how mycobacteria respond to nitrogen limitation and several regulators (e.g., GlnR, PII) have been characterized at a molecular level. However, despite this progress, our knowledge of the transcriptional response of mycobacteria to nitrogen limitation and its regulation is confined to batch culture. METHODS: To gain further insight into the response of mycobacteria to nitrogen limitation, we developed a nitrogen-limited chemostat. We compared the transcriptional response of nitrogen-limited cells to carbon-limited cells using RNA-seq analysis in a continuous culture model at a constant growth rate. CONCLUSIONS: Our findings revealed significant changes in the expression of 357 genes (208 upregulated, 149 downregulated; >2-fold change, false discovery rate <5 %) in response to nitrogen limitation in continuous culture. The vast majority of the GlnR regulon (68 %) was differentially expressed under nitrogen limitation in continuous culture and approximately 52 % of the 357 genes overlapped with a previously published study investigating the response of M. smegmatis to nitrogen limitation in batch culture, while expression of only 17 % of the genes identified in batch culture were affected in our chemostat model. Moreover, we identified a unique set of 45 genes involved in the uptake and metabolism of nitrogen that were exclusive to our chemostat model. We observed strong downregulation of pathways for amino acid catabolism (i.e., alanine, aspartate, valine, proline and lysine), suggesting preservation of these amino acids for critical cellular function. We found 16 novel transcriptional regulators that were directly or indirectly involved in the global transcriptomic response of M. smegmatis to nitrogen limitation and identified several non-coding RNAs that might be involved in the transcriptional or post-transcriptional regulation of nitrogen-regulated gene expression. RESULTS: Using nitrogen-limited continuous culture we identified the nitrogen responsive transcriptome of M. smegmatis, including a number of small non-coding RNAs implicated in controlling nitrogen-regulated gene expression. PMID- 26482236 TI - [Outcomes evaluation after the implementation of a pre-hospital thrombolysis protocol in rural areas]. AB - INTRODUCTION: The aim is to evaluate the outcomes obtained from the implementation of a pre-hospital thrombolysis protocol in 3 rural emergency care teams, as well as delays and strategies of reperfusion applied in the treatment of the ST-segment elevation myocardial infarction. MATERIAL AND METHODS: Retrospective cohort study (n=52) with historical control (n=20) of the patients assisted for ST-segment elevation myocardial infarction. Medical emergency care teams, hospital, computerized medical history and ARIAM register reports were revised, obtaining epidemiological and clinical features, off-hospital management, reperfusion, time intervals and mortality. RESULTS: The baseline features in both groups were not significantly different. There was a non significant improvement of emergency care teams-hospital diagnostic concordance (85.3 versus 76.9%). We found a similar use of nitroglycerin, morphine and aspirin; significant increase (P<0.0001) of clopidogrel/prasugrel (55 versus 90.4%) and enoxaparin/fondaparinux (35 versus 76.9%), as well as pre-hospital thrombolysis (5 versus 30,8%, P<0.03), that was applied within the first 2h to 71.4%, with a median door-needle of 40min, whereas in-hospital thrombolysis and primary angioplasty were performed after 3h from the symptoms onset (P<0.01). Delays are associated with the patient's own lateness (P<0.02). Pharmaco-invasive strategy increases (62.5 versus 84.6%) more than primary angioplasty (15 versus 17.3%), reducing in-hospital thrombolysis (35 versus 19.2%), all of them non significant. Complications are similar and one-year mortality is reduced (P<0.67). CONCLUSIONS: The protocol is effective, safe, and reliable. It reduces delays and improves pre-hospital attention. The pharmaco-invasive strategy is a valid option. PMID- 26482237 TI - [What you need to know about "female viagra"]. PMID- 26482238 TI - [Onychomycosis by yeast not common in diabetics of a health center]. AB - BACKGROUND: Mexican diabetic population frequently presents mycosis under foot hyperkeratosis; however, in another type of onychomycosis as the ones that is assumed Candida albicans is the causal agent, it is unknown the frequency, the prevalence and if another Candida species or other yeasts are found. OBJECTIVE: Evaluate the frequency of yeasts causing onychomycosis in diabetic patients looked after in public institutions of health of the State of Hidalgo, Mexico, and its association with clinical epidemiological variables. MATERIALS AND METHODS: An observational, descriptive and transversal study was made on 261 patients, from which one nail sample of each one was obtained, used to isolate and identify dermatophytes and yeasts; the results were statistically correlated with 24 epidemiological parameters. The clinical study was done through interrogation and by medical exploration in order to evaluate Tinea pedis and onychomycosis. RESULTS: Onychomycosis were caused by Candida guilliermondii, Candida parapsilosis, Candida glabrata, Candida krusei, Candida spp., Kodamaea ohmeri, Prototheca wickerhamii and unidentified yeasts. The prevalence for general onychomycosis, by dermatophytes, mixed onychomycosis and by yeasts were: 24.1, 19.5, 2.3 and 14.6%, respectively. Patients with significant probability to be diagnosed as having onychomycosis by yeasts are those wearing open shoes (2.59%); technicians and professionals (10.49%) and alcohol drinkers (3.72%). CONCLUSION: The fact that Candida albicans is not present in this study as causal agent of onychomycosis, and emerging and non-common yeasts were indeed isolated, creates new challenges. It is remarked the clinical criterion that when onychomycosis is suspected in diabetics, the diagnosis for culturing dermatophytes and yeasts should be included. PMID- 26482239 TI - Dislocation and its recurrence after revision total hip arthroplasty. AB - PURPOSE: Dislocation is a leading cause of failure after revision total hip arthroplasty (THA). This study was conducted to examine the risk factors for dislocation as well as their recurrence after revision THA. METHODS: We retrospectively reviewed 178 revision THAs in 162 patients between 1998 and 2013. The mean patient age was 65.2 years at operation and the mean follow-up period was 6.7 years. Multivariate logistic regression was performed to identify risk factors for dislocation, and further comparison was made between patients with single and recurrent dislocations. RESULTS: Sixteen hips in 15 patients (9.0 %) dislocated at a mean of 9.1 months (range, 0-83 months) after revision THA. Multivariate analysis identified advanced age (odds ratio [OR] = 2.94/10 years) and osteonecrosis of the femoral head (OR = 7.71) as the independent risk factors for any dislocations. Risk factors for recurrent dislocations, which were observed in eight hips (50 %), were later dislocations (>=4 months) and lower BMI. CONCLUSION: Dislocation is a serious problem after revision THA with multiple risk factors. Although our findings were limited to revision THAs done through posterolateral approach, recognition of these factors is helpful in patient education and surgical planning. PMID- 26482240 TI - Antiglide plating of vertical medial malleolus fractures provides stiffer initial fixation than bicortical or unicortical screw fixation. AB - BACKGROUND: Vertical shear fractures of the medial malleolus (44-A2 ankle fractures) occur through a supination-adduction mechanism. There are numerous methods of internal fixation for this fracture pattern. METHODS: Vertical medial malleolus osteotomies were created in synthetic distal tibiae. The models were divided into four fixation groups: two parallel unicortical cancellous screws, two divergent unicortical cancellous screws, two parallel bicortical cortical screws, or an antiglide plate construct. Specimens were subjected to offset axial loading and tracked using high-resolution video. FINDINGS: The antiglide plate construct was stiffer (P<0.05) than each of the other three constructs, and the bicortical screw construct was stiffer (P<0.05) than both unicortical screw constructs. The mean stiffness (standard deviation) was 111 (SD 35) N/mm for the parallel unicortical screw construct, 173 (SD 57) N/mm for the divergent unicortical screw construct, 279 (SD 30) N/mm for the bicortical screw construct, and 463 (SD 91) N/mm for the antiglide plate construct. The antiglide plate construct resisted displacement better (P<0.05) than each of the other three constructs. The mean force for 2mm of articular displacement was 284 (SD 51) N for the parallel unicortical screw construct, 339 (SD 46) N for the divergent unicortical screw construct, 429 (SD 112) N for the bicortical construct, and 922 (SD 297) N for the antiglide plate construct. INTERPRETATION: An antiglide plate construct provides the stiffest initial fixation while withstanding higher load to failure for vertical medial malleolus fractures when compared to unicortical and bicortical screw fixation. PMID- 26482241 TI - Molecular Cloning and Characterization of a (Lys)6-Tagged Sulfide-Reactive Hemoglobin I from Lucina pectinata. AB - A poly-Lys tag was fused to the Lucina pectinata hemoglobin I (HbI) coding sequence and purified using an efficient and fast process. HbI is a hemeprotein that binds hydrogen sulfide (H2S) with high affinity and it has been used to understand physiologically relevant reactions of this signaling molecule. The (Lys)6-tagged rHbI construct was expressed in E. coli and purified by immobilization on a cation exchange matrix, followed by size-exclusion chromatography. The identity, structure, and function of the (Lys)6-tagged rHbI were assessed by mass spectrometry, small and wide X-ray scattering, optical spectroscopy, and kinetic analysis. The scattering and spectroscopic results showed that the (Lys)6-tagged rHbI is structurally and functionally analogous to the native protein as well as to the (His)6-tagged rHbI. Kinetics studies with H2S indicated that the association (k on) and dissociation (k off) rate constants were 1.4 * 10(5)/M/s and 0.1 * 10(-3)/s, respectively. This results confirmed that the (Lys)6-tagged rHbI binds H2S with the same high affinity as its homologue. PMID- 26482242 TI - Plant chlorophyll fluorescence: active and passive measurements at canopy and leaf scales with different nitrogen treatments. AB - Most studies assessing chlorophyll fluorescence (ChlF) have examined leaf responses to environmental stress conditions using active techniques. Alternatively, passive techniques are able to measure ChlF at both leaf and canopy scales. However, the measurement principles of both techniques are different, and only a few datasets concerning the relationships between them are reported in the literature. In this study, we investigated the potential for interchanging ChlF measurements using active techniques with passive measurements at different temporal and spatial scales. The ultimate objective was to determine the limits within which active and passive techniques are comparable. The results presented in this study showed that active and passive measurements were highly correlated over the growing season across nitrogen treatments at both canopy and leaf-average scale. At the single-leaf scale, the seasonal relation between techniques was weaker, but still significant. The variability within single-leaf measurements was largely related to leaf heterogeneity associated with variations in CO2 assimilation and stomatal conductance, and less so to variations in leaf chlorophyll content, leaf size or measurement inputs (e.g. light reflected and emitted by the leaf and illumination conditions and leaf spectrum). This uncertainty was exacerbated when single-leaf analysis was limited to a particular day rather than the entire season. We concluded that daily measurements of active and passive ChlF at the single-leaf scale are not comparable. However, canopy and leaf-average active measurements can be used to better understand the daily and seasonal behaviour of passive ChlF measurements. In turn, this can be used to better estimate plant photosynthetic capacity and therefore to provide improved information for crop management. PMID- 26482243 TI - A model for the central control of airflow patterns within the human nasal cycle. AB - BACKGROUND: The nasal cycle exhibits mainly reciprocal changes in nasal airflow that may be controlled from centres in the hypothalamus and brainstem. This study aims to gather new knowledge about the nasal cycle to help develop a control model. METHOD: Right and left nasal airflow was measured in healthy human subjects by rhinomanometry. This was performed over 7-hour periods on 2 study days separated by approximately 1 week. The correlation coefficient for nasal airflow was calculated for day 1 and day 2. RESULTS: Thirty subjects (mean age, 22.7 years) completed the study. The correlation coefficient for nasal airflow varied between r = 0.97 with in-phase changes in airflow and r = -0.89 with reciprocal changes in airflow. The majority of r values were negative, indicating reciprocal changes in airflow (50 out of 60). There was a tendency for r values to become more negative between day 1 and day 2 (p < 0.001). CONCLUSION: A control model involving a hypothalamic centre and two brainstem half centres is proposed to explain both the in-phase and reciprocal changes in airflow associated with the nasal cycle. PMID- 26482244 TI - Higher plasma quercetin levels following oral administration of an onion skin extract compared with pure quercetin dihydrate in humans. AB - PURPOSE: To investigate the plasma kinetics of quercetin derived from hard capsules filled with onion skin extract powder or quercetin dihydrate in humans. METHODS: In a randomized, single-blind, diet-controlled crossover study, 12 healthy subjects (six men and six women) aged 21-33 years were administered a single oral supra-nutritional dose of approximately 163 mg quercetin derived from onion skin extract powder (containing 95.3 % of total flavonoids as quercetin aglycone) or quercetin dihydrate (134 mg quercetin aglycone equivalent). Blood samples were collected before and during a 24-h period after quercetin administration. The concentrations of quercetin and its two monomethylated derivatives, isorhamnetin (3'-O-methyl quercetin), and tamarixetin (4'-O-methyl quercetin), were measured using HPLC with fluorescence detection after plasma enzymatic treatment. RESULTS: The systemic availability, determined by comparing the plasma concentration-time curves of quercetin, was 4.8 times higher, and the maximum plasma concentration (C max) was 5.4 times higher after ingestion of the onion skin extract than after ingestion of pure quercetin dihydrate. By contrast, t max did not differ significantly between the two formulations. The C max values for isorhamnetin and tamarixetin were 3.8 and 4.4 times higher, respectively, after administration of onion skin extract than after pure quercetin dihydrate. The plasma kinetics of quercetin were not significantly different in men and women. CONCLUSION: Quercetin aglycone derived from onion skin extract powder is significantly more bioavailable than that from quercetin dihydrate powder filled hard capsules. PMID- 26482245 TI - Traumatic and non-traumatic adrenal emergencies. AB - Multiple traumatic and non-traumatic adrenal emergencies are occasionally encountered during the cross-sectional imaging of emergency department patients. Traumatic adrenal hematomas are markers of severe polytrauma, and can be easily overlooked due to multiple concomitant injuries. Patients with non-traumatic adrenal emergencies usually present to an emergency department with a non specific clinical picture. The detection and management of adrenal emergencies is based on cross-sectional imaging. Adrenal hemorrhage, adrenal infection, or rupture of adrenal neoplasm require immediate detection to avoid dire consequences. More often however, adrenal emergencies are detected incidentally in patients being investigated for non-specific acute abdominal pain. A high index of suspicion is required for the establishment of timely diagnosis and to avert potentially life-threatening complications. We describe cross-sectional imaging findings in patients with traumatic and non-traumatic adrenal hemorrhage, adrenal infarctions, adrenal infections, and complications of adrenal masses. PMID- 26482246 TI - Lean Body Mass and Survival in Hemodialysis Patients and the Roles of Race and Ethnicity. AB - BACKGROUND: Lean body mass (LBM) represents the "fat-free" muscle mass in hemodialysis (HD) patients and is an important nutritional measure. Previous studies have found that both higher LBM and body mass index (BMI) were related to greater survival in HD patients. Additional studies have shown differences in survival across racial-ethnic groups of HD patients. However, the association of LBM and mortality across racial-ethnic subgroups has not been examined. OBJECTIVE: We hypothesize that racial differences in LBM affect the mortality in HD patients. SETTING AND SUBJECTS: Chronic HD patients from a large dialysis organization in the United States. PREDICTORS: Estimated LBM (eLBM), self identified racial subgroups. MAIN OUTCOME MEASURE: 5-year survival. STUDY DESIGN: We examined the association between baseline eLBM and survival using Cox proportional hazard models adjusted for demographics, comorbidities, and laboratory measures. Associations were examined across subgroups of race ethnicity (non-Hispanic white, African American, and Hispanic) and BMI. RESULTS: The final cohort included 117,683 HD patients, who were 62 +/- 15 (mean +/- standard deviation) years old, 43% women and 59% with diabetes mellitus. Higher eLBM was linearly associated with lower mortality. Compared with the reference group (48.4-<50.5 kg), patients with the lowest eLBM (<41.3 kg) had a 1.4-fold higher risk of mortality (hazard ratio: 1.37; 95% confidence interval: 1.30-1.44) in the fully adjusted model. A similar linear association was seen among patients with BMI < 35 kg/m(2) and in non-Hispanic whites and African American subgroups. However, higher eLBM was not associated with improved survival in Hispanic patients or patients with BMI >= 35 kg/m(2). LIMITATION: Potential residual confounding. CONCLUSIONS: Higher eLBM is associated with a lower mortality risk in HD patients, especially among non-Hispanic white and African American groups. Hispanic patients do not demonstrate a similar inverse relationship. The association between LBM and mortality among different racial groups of HD patients deserves additional study. PMID- 26482247 TI - Increasing Dialysis Sodium Removal on Arterial Stiffness and Left Ventricular Hypertrophy in Hemodialysis Patients. AB - OBJECTIVE: The aim of the present study was to examine the effects of a mild increase in dialysis sodium removal on cardiovascular system in hypertensive hemodialysis (HD) patients. METHODS: Sixty four HD patients with pre-HD plasma sodium level higher than 138mmol/l, were randomly assigned into 2 groups. The dialysate sodium was reduced from 138mmol/l to 136mmol/l in the intervention group, while remained at 138mmol/l in the control group. During the study course, home systolic blood pressure (BP) target of 140mmHg was used in all patients, and bioimpedance measurements to guide ultrafiltration were performed monthly. 44 hour ambulatory BP, aortic pulse wave velocity (PWV), left ventricular mass index (LVMI), pre-HD plasma sodium concentration, interdialytic weight gain, and dietary sodium intake, were measured. RESULTS: Better BP control was achieved by 2 groups, with no significant differences. However, less annual averages of antihypertensives were used in the intervention group. The PWV values significantly decreased from 11.8+/-2.4 to 10.9+/-2.6m/s in the intervention group (P<0.001), and from 11.6+/-2.5 to 11.1+/-2.2m/s in the control group (P=0.012). LVMI regressed from 151+/-19 to 139+/-16 g/m2 (P<0.001) in the intervention group only. In addition, values for interdialytic weight gain and pre-HD plasma sodium decreased in the intervention group only. There were no significant differences in annual averages of dietary sodium intake and the frequency of adverse events between the 2 groups. CONCLUSIONS: Increasing dialysis sodium removal was associated with improvements in arterial stiffness, left ventricular hypertrophy, and better BP control in hypertensive HD patients. PMID- 26482249 TI - Osteopontin promotes aromatase expression and estradiol production in human adipocytes. AB - Breast and endometrial cancer are often estrogen dependent, and their incidence and mortality are increased by obesity in postmenopausal women. Osteopontin (OPN) is a cytokine strongly upregulated in adipose tissue (AT) in obesity. OPN function is potentiated by cleavage by matrix metalloproteinases (MMP). OPN and MMPs play a role in cancer development and are prognostic markers in breast cancer progression. While induction of the estrogen-synthesizing enzyme aromatase by TNFa and IL1 has been shown in preadipocytes, an impact of OPN on aromatase expression in AT has not been investigated yet. Gene expression was determined in AT samples of 21 morbidly obese and matched non-obese subjects. Primary human adipocytes were treated with full-length OPN or MMP-cleaved OPN (cOPN). Protein and mRNA expressions were analyzed from cell lysates, or cells were subsequently supplied with testosterone to determine estradiol production and for indirect co culture with the estrogen-dependent MCF-7 cell line. Aromatase expression strongly correlated with gene expression of OPN and various MMPs in visceral and MMPs in subcutaneous AT, but not with TNFalpha expression in both tissues. In vitro, cOPN more effectively than full-length OPN upregulated aromatase mRNA in adipocytes and significantly increased aromatase protein level and estradiol production, leading to increased MCF-7 growth in indirect co-culture. OPN and MMPs are upregulated in AT in obesity, and MMP-cleaved OPN is particularly effective in inducing aromatase activity in human adipocytes. Thereby, obesity induced OPN expression in AT may contribute to estradiol production and thus to the association of obesity with estrogen-dependent cancers. PMID- 26482248 TI - A Comparison of Structural Brain Imaging Findings in Autism Spectrum Disorder and Attention-Deficit Hyperactivity Disorder. AB - ASD and ADHD are regarded as distinct disorders in the current DSM-5. However, recent research and the RDoC initiative are recognizing considerable overlap in the clinical presentation of ASD, ADHD, and other neurodevelopmental disorders. In spite of numerous neuroimaging findings in ASD and ADHD, the extent to which either of the above views are supported remains equivocal. Here we compare structural MRI and DTI literature in ASD and ADHD. Our main findings reveal both distinct and shared neural features. Distinct expressions were in total brain volume (ASD: increased volume, ADHD: decreased volume), amygdala (ASD: overgrowth, ADHD: normal), and internal capsule (ASD: unclear, ADHD: reduced FA in DTI). Considerable overlap was noted in the corpus callosum and cerebellum (lower volume in structural MRI and decreased FA in DTI), and superior longitudinal fasciculus (reduced FA in DTI). In addition, we identify brain regions which have not been studied in depth and require more research. We discuss relationships between brain features and symptomatology. We conclude by addressing limitations of current neuroimaging research and offer approaches that account for clinical heterogeneity to better distinguish brain-behavior relationships. PMID- 26482250 TI - Sleep disorders in pediatric chronic kidney disease patients. AB - The prevalence of sleep disorders during childhood has been estimated to range from 25 to 43 %. The aim of this review is to determine the prevalence of sleep disorders and possible associations with chronic kidney disease (CKD)-related factors and health-related quality of life (HRQOL) in children with CKD. An electronic systematic literature search for sleep disorders in children with CKD in Pubmed, Embase and the Cochrane Library Databases identified seven relevant articles for review, all of which reported an increased prevalence of sleep disorders in children with CKD. Five studies included children with CKD undergoing dialysis, and two studies included only non-dialysis patients. In all studies the presence of sleep disturbances was assessed by questionnaires; only one study compared the results of a validated questionnaire with laboratory-based polysomnography. The prevalence of any sleep disorder ranged from 77 to 85 % in dialysis patients, to 32-50 % in transplanted patients and 40-50 % in non dialysis patients. The most commonly studied disorder was restless legs syndrome, which presented at a prevalence of 10-35 %. Three studies showed significant associations between presence of sleep disorders and HRQOL. We found consistent evidence of an increased prevalence of sleep disturbances in children with CKD, and these seemed to play a critical role in HRQOL. PMID- 26482251 TI - A systems-based approach to managing blood pressure in children following kidney transplantation. AB - Hypertension is one of the most common and well-known complications following kidney transplantation in children. Yet, despite numerous available therapies many pediatric kidney transplant recipients continue to have poorly controlled blood pressure, suggesting that traditional approaches to blood pressure management in this population might be inadequate. Over the last two decades, the Chronic Care Model has been developed to improve chronic illness outcomes through delivery system design and clinical information systems that support patient self management and provider decision-making. In this educational review we discuss key elements of managing blood pressure following pediatric kidney transplantation and suggest ways that they may be reliably implemented into clinical practice using principles from the Chronic Care Model. PMID- 26482252 TI - Safety and usage of darbepoetin alfa in children with chronic kidney disease: prospective registry study. AB - BACKGROUND: Limited prospective data are available on the long-term safety of darbepoetin alfa (DA) for treating anemia in children with chronic kidney disease (CKD). METHODS: In this prospective, phase IV, observational registry study, children <=16 years of age with CKD anemia and receiving DA were observed for <=2 years. Adverse events (AEs), DA dosing, hemoglobin (Hb) concentrations, and transfusions were recorded. RESULTS: A total of 319 patients were included in the analysis (mean age, 9.1 years), 158 (49.5%) of whom were on dialysis at study entry. Of 434 serious AEs reported in 162 children, the most common were peritonitis (10.0%), gastroenteritis (6.0%), and hypertension (4.1%). Six patients (1.9%) died (unrelated to DA). Four patients (1.3%) experienced six serious adverse drug reactions. The geometric mean DA dose range was 1.4-2.0 MUg/kg/month. Mean baseline Hb concentration was 11.1 g/dl; mean values for children receiving and not receiving dialysis at baseline ranged between 10.9 and 11.5 g/dl and 11.2-11.7 g/dl, respectively. Overall, 48 patients (15.0%) received >=1 transfusion. CONCLUSIONS: No new safety signals for DA were identified in children receiving DA for CKD anemia for <=2 years. Based on Hb concentrations and transfusion requirements, DA was effective at managing anemia in these patients. PMID- 26482253 TI - Long-term follow-up of blood pressure and glomerular filtration rate in patients with a solitary functioning kidney: a comparison between Wilms tumor survivors and nephrectomy for other reasons. AB - BACKGROUND: Children with unilateral Wilms tumor (WT) treated with chemotherapy and/or radiotherapy and nephrectomy have excellent survival rates. A solitary functioning kidney (SFK) is associated with progressive renal injury. This study aims to investigate the additional effect of Wilms tumor treatment on renal function compared with children with an SFK for non-oncological reasons. METHODS: A single-center retrospective cohort study on the renal injury markers of 79 survivors of unilateral WT was performed and compared with a matched group of children with an SFK for non-oncological reasons. Mean age at follow-up was 12.4 (SD 5.9) years. RESULTS: During follow-up, mean estimated glomerular filtration rate (eGFR) and blood pressure z-scores remained stable at an acceptable level. However, in the group of 31 WT patients with a follow-up of 15 years, 23% showed signs of renal injury. This proportion was smaller than the 54% in a group of SFK patients based on non-oncological causes (p = 0.004). CONCLUSIONS: A significant proportion of WT survivors develop renal injury during follow-up. Our data may be an underestimation of the true frequency of progressive renal injury, due to a lack of information on proteinuria. As with patients with a non-oncological SFK, long-term follow-up is essential to monitor WT survivors. PMID- 26482254 TI - Effect of plasma NOx values on cardiac function in obese hypertensive and normotensive pediatric patients. AB - BACKGROUND: Hypertension (HT) is a major comorbidity of obesity that is associated with an increased risk of cardiovascular disease and higher mortality. The aim of our study was to evaluate cardiac function in obese hypertensive (OHT) and obese normotensive (ONT) pediatric patients and determine the effects of plasma nitric oxide (NOx) values on cardiac function, while demonstrating the role of plasma NOx in HT in obese pediatric patients. METHODS: The study population consisted of 62 patients (27 boys, 35 girls), aged 13-18 years and 21 age-matched healthy controls. All subjects enrolled in the study underwent echocardiography (Echo) evaluation and ambulatory blood pressure monitoring for HT. Plasma NOx and biochemical values were studied in both patient groups separately. RESULTS: Plasma NOx levels were found to be lower in the OHT group than in the ONT and control groups (p < 0.001) and to be negatively correlated with left ventricular mass index values (p < 0.05). Both the OHT and ONT groups had concentric hypertrophy of the heart. CONCLUSIONS: Plasma NOx plays an essential role in obesity-induced HT. Concentric hypertrophy of the left ventricle was found in both the OHT and ONT groups, indicating structural deformation of the heart. PMID- 26482255 TI - Urinary fibrogenic cytokines ET-1 and TGF-beta1 are associated with urinary angiotensinogen levels in obese children. AB - BACKGROUND: Fibrogenic cytokines are recognized as putative drivers of disease activity and histopathological deterioration in various kidney diseases. We compared urinary transforming growth factor beta1 (U-TGF-beta1) and endothelin 1 (U-ET-1) levels across body mass index classes and assessed their association with the level of urinary angiotensinogen (U-AGT), a biomarker of intrarenal renin-angiotensin-aldosterone system (RAAS). METHODS: The was a cross-sectional evaluation of 302 children aged 8-9 years. Ambulatory blood pressure (BP), insulin resistance (HOMA-IR), aldosterone level and renal function were evaluated. U-ET-1, U-TGF-beta1 and U-AGT levels were determined by immunoenzymatic methods. RESULTS: Obese children presented with the lowest levels of U-ET-1 and U-TGF-beta1, but the difference was only significant for U-ET-1. In obese children, the median levels of both U-ET-1 and U-TGF-beta1 tended to increase across tertiles (T1-T3) of U-AGT (U-ET-1: T1, 19.9 (14.2-26.3); T2, 32.5 (23.3-141.6); T3, 24.8 (18.7-51.5) ng/g creatinine, p = 0.007; U-TGF-beta1: T1, 2.2 (1.8-4.0); T2, 4.3 (2.7-11.7); T3, 4.9 (3.8-10.1) ng/g creatinine, p = 0.004]. In multivariate models, in the obese group, U-ET-1 was associated with HOMA-IR and aldosterone and U-AGT levels, and U-TGF-beta1 was associated with U AGT levels and 24 h-systolic BP. CONCLUSIONS: Whereas the initial hypothesis of higher levels of urinary fibrogenic cytokines in obese children was not confirmed in our study, both TGF-beta1 and U-ET-1 levels were associated with U-AGT level, which likely reflects an early interplay between tissue remodeling and RAAS in obesity-related kidney injury. PMID- 26482256 TI - Inequality in pediatric kidney transplantation in Brazil. AB - BACKGROUND: The aim of this study was to describe the access and factors associated with kidney transplantation for children in different regions of Brazil. METHODS: We analyzed a cohort of 1211 children enrolled on the transplant list from January 2011 to December of 2013. We fitted regression models to investigate factors associated with: (a) undergoing kidney transplantation from a deceased donor, and (b) being removed from the waiting list. RESULTS: The incidence of transplantation was uneven across regions, with the lowest rate at 0.4 per million age-related population (pmarp) in the Midwest and the highest incidence rate of 8.3 cases pmarp in the South. Children from the North and the Midwest regions had a 3-4 times lower probability of undergoing a deceased donor transplant (p < 0.05). Apart from the geographic region, age of recipients and GDP influenced the outcome. The likelihood of undergoing transplantation was very low in the youngest children in the North and Midwest. The number of transplant centers was not associated with either outcome. CONCLUSIONS: Factors of inequality in transplantation in Brazil are of macroeconomic origin, but there is room to reduce inequalities. Training existing transplant center professionals in the care of children could diminish the discrepancies. PMID- 26482257 TI - Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. AB - We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases. PMID- 26482259 TI - Clinical features of colorectal cancer patients in advanced age: a population based approach. AB - In the immediate future, the number of geriatric patients will continue to rise; consequently we should expect an increase of colorectal cancer, a disease of the elderly population. Through the data of a Cancer Registry, we examined (a) the effect of ageing on the main features of colorectal cancer; (b) changes in management, especially for individuals older than 80 years; and (c) changes in prognosis and survival in subgroups of patients with different age. The Registry provided information on colorectal cancer up to 2010 (27 years). A total of 5293 patients were registered; these were divided into three groups: A (0-64 years), B (65-79) and C (80 or more). Three periods of observation were chosen: 1 (1984 1992), 2 (1993-2001) and 3 (2001-2010). Group A included 1571 patients (29 %), Group B 2539 (48 %) and Group C 1183 (22.3 %). The fraction of old individuals increased during the 27 years of the investigation. In these patients, tumours were predominantly localized to the right colon (42.6 %). The rate of surgery and ratio between curative and palliative approaches were similar among the three groups (p < 0.38). There was disparity (p < 0.002) in the administration of chemotherapy (5.8 % of the elderly vs 34.4 % in remaining patients). Survival increased over time in all three groups. In the elderly, average 5-year survival was 31 % in period 1 and 55 % in period 3. These data show that in Western countries, the standard of care for colorectal cancer diagnosed in geriatric patients has improved over the last 30 years. PMID- 26482258 TI - BP and Renal Outcomes in Diabetic Kidney Disease: The Veterans Affairs Nephropathy in Diabetes Trial. AB - BACKGROUND AND OBJECTIVES: Proteinuric diabetic kidney disease frequently progresses to ESRD. Control of BP delays progression, but the optimal BP to improve outcomes remains unclear. The objective of this analysis was to evaluate the relationship between BP and renal outcomes in proteinuric diabetic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BP data from all 1448 randomized participants in the Veterans Affairs Nephropathy in Diabetes Trial were included in a post hoc analysis. The associations of mean on-treatment BP with the primary end point (decline in eGFR, ESRD, or death), renal end point (decline in eGFR or ESRD), rate of eGFR decline, and mortality were measured. RESULTS: The median (25th, 75th percentile) follow-up time was 2.2 (1.2, 3.0) years. There were 284 primary end points. In univariate analyses, both mean systolic and mean diastolic BPs were strongly associated (P<0.001) with the primary end point. After multivariate adjustment, the hazard of developing the primary end point became progressively higher as mean systolic BP rose from <120 to >= 150 mmHg (P=0.02), with a significantly higher hazard ratio for 140-149 versus 120-129 mmHg (1.51 [1.06, 2.15]; P=0.02). There was also a significant association of mean diastolic BP with the hazard of developing the primary end point (P<0.01), with a significantly higher hazard ratio when mean diastolic BP was 80-89 versus 70-79 mmHg (1.54 [1.05, 2.25]; P=0.03); there was also a strong trend when mean diastolic BP was <60 mmHg. Associations between BP and both renal end point and rate of eGFR decline were similar to those with the primary end point. No association of BP with mortality was observed, possibly because of the limited number of mortality events. CONCLUSIONS: In patients with proteinuric diabetic kidney disease, mean systolic BP >= 140 mmHg and mean diastolic BP >= 80 mmHg were associated with worse renal outcomes. PMID- 26482260 TI - A Postulate on the Brain's Basic Wiring Logic. AB - How should evolution and development build the brain to be capable of flexible and generative cognition? I wish to put forth a 'power-of-two'-based wiring logic that provides the basic computational principle in organizing the microarchitecture of cell assemblies that would readily enable knowledge and adaptive behaviors to emerge upon learning. PMID- 26482262 TI - Noninfectious Generalized Bronchiolitis in the Setting of Allogeneic Stem Cell Transplantation: A Potential Mimic of Lower Respiratory Tract Infection. AB - RATIONALE AND OBJECTIVES: To describe a little-known therapy-related small-airway phenomenon presumably caused by mucosal irritation in patients undergoing allogeneic stem cell transplantation (allo-SCT). MATERIALS AND METHODS: Retrospective database search at our institution identified 739 hematologic patients who underwent chemotherapy + allo-SCT between September 2004 and March 2014. After infectious pulmonary complications were excluded, 75 patients (female = 24; male = 51; median age = 47 years) with signs of generalized bronchiolitis (GB) on chest high-resolution computed tomography were identified. Computed tomography (CT) was performed proximate to chemotherapy onset; 92% had follow-up CT (mean, 1.9 weeks). The presence of centrilobular nodules, bronchial wall thickening (BWT), tree-in-bud (distributed diffuse vs. focal), ground-glass opacity, airspace opacification, luminal impactions, and air trapping was correlated with occurrence and duration of oral mucositis and therapy characteristics. Intensity of tree-in-bud and centrilobular nodules was graded absent (grade = 0), moderate (grade = 1), or marked (grade = 2). RESULTS: Overall incidence of GB among allo-SCT patients was 10.14%. GB was diagnosed at the time point of transplantation with a mean duration of CT findings of 4 weeks (+/-2.7). Tree-in-bud (17% [grade 2] and 83% [grade 1]) and BWT were present in 100% of the patients. Centrilobular nodules diffusely distributed were found in 45.5% of patients (20% [grade 2], 24% [grade 1], and 56% [none]). Air trapping and mosaic pattern were found in 13% and 16% of the patients, respectively. Resolution of GB was spontaneous. GB and its severity correlated with the temporal course and grade of oral mucositis; frequency and degree were not significantly influenced by the chemotherapy regimen. The incidence of GB in high-resolution computed tomography was statistically and significantly higher in patients with oral mucositis (P < 0.035). CONCLUSIONS: GB is frequent during chemotherapy for allo SCT and is characterized by an even distribution of tree-in-bud, BWT, centrilobular nodules, mild clinical symptoms, and spontaneous resolution. PMID- 26482261 TI - Anxiety in Patients with Schizophrenia: Epidemiology and Management. AB - Anxiety symptoms can occur in up to 65 % of patients with schizophrenia, and may reach the threshold for diagnosis of various comorbid anxiety disorders, including obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). We review the clinical presentation, diagnosis, neurobiology, and management of anxiety in patients with schizophrenia, with a particular focus on pharmacotherapy. The prevalence of any anxiety disorder (at syndrome level) in schizophrenia is estimated to be up to 38 %, with social anxiety disorder (SAD) being the most prevalent. Severity of positive symptoms may correlate with severity of anxiety symptoms, but anxiety can occur independently of psychotic symptoms. While anxiety may be associated with greater levels of insight, it is also associated with increased depression, suicidality, medical service utilization, and cognitive impairment. Patients with anxiety symptoms are more likely to have other internalizing symptoms as opposed to externalizing symptoms. Diagnosis of anxiety in schizophrenia may be challenging, with positive symptoms obscuring anxiety, lower levels of emotional expressivity and communication impeding diagnosis, and conflation with akathisia. Higher diagnostic yield may be achieved by assessment following the resolution of the acute phase of psychosis as well as by the use of screening questions and disorder-specific self-report instruments. In schizophrenia patients with anxiety, there is evidence of underactive fear circuitry during anxiety-provoking stimuli but increased autonomic responsivity and increased responsiveness to neutral stimuli. Recent findings implicate the serotonin transporter (SERT) genes, brain-derived neurotropic factor (BDNF) genes, and the serotonin 1a (5HT1a) receptor, but are preliminary and in need of replication. There are few randomized controlled trials (RCTs) of psychotherapy for anxiety symptoms or disorders in schizophrenia. For pharmacotherapy, data from a few randomized and open trials have shown that aripiprazole and risperidone may be efficacious for obsessive compulsive and social anxiety symptoms, and quetiapine and olanzapine for generalized anxiety. Older agents such as trifluoperazine may also reduce comorbid anxiety symptoms. Alternative options include selective serotonin re uptake inhibitor (SSRI) augmentation of antipsychotics, although evidence is based on a few randomized trials, small open trials, and case series, and caution is needed with regards to cytochrome P450 interactions and QTc interval prolongation. Buspirone and pregabalin augmentation may also be considered. Diagnosis and treatment of anxiety symptoms and disorders in schizophrenia is an important and often neglected aspect of the management of schizophrenia. PMID- 26482263 TI - Prognostic Value of the Diverticular Disease Severity Score Based on CT Colonography: Follow-up in Patients Recovering from Acute Diverticulitis. AB - RATIONALE AND OBJECTIVES: To assess the prognostic value of a diverticular disease severity score (DDSS) based on computed tomography colonography (CTC) after acute diverticulitis (AD). MATERIALS AND METHODS: Of 252 patients who had an AD episode, we finally selected 46 patients who underwent both conventional CT at the acute event and CTC after 9 +/- 7 weeks. Of these 46 patients, 17 underwent elective surgery after CTC. Disease severity was assessed with a 0-4 modified Hinchey CT-based score and a 1-4 CTC-based DDSS. A phone survey was performed 27 months later (range 4-52) for the 29 patients not surgically treated. RESULTS: Significant correlation was found between CTC-based DDSS and clinical follow-up (P = 0.022) or elective surgery (P = 0.007), but not between clinical follow-up and CT-based score, extraluminal gas, C-reactive protein serum level, age, gender, or first versus recurrent AD episode. CTC demonstrated relevant additional findings in five of 46 (11%) patients: two AD complications (enterocolic and enterotubal fistulae), two colon cancers, and one extracolonic (lung) cancer. CONCLUSIONS: The CTC-based DDSS showed a prognostic value and correlated with the risk of undergoing surgery, and clinically relevant additional findings were found in more than 10% of patients. CTC could be the preferred test in patients recovering after AD. PMID- 26482264 TI - Measures to eradicate multidrug-resistant organism outbreaks: how much do they cost? AB - This study aimed to assess the economic burden of infection control measures that succeeded in eradicating multidrug-resistant organisms (MDROs) in emerging epidemic contexts in hospital settings. The MEDLINE, EMBASE and Ovid databases were systematically interrogated for original English-language articles detailing costs associated with strict measures to eradicate MDROs published between 1 January 1974 and 2 November 2014. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Overall, 13 original articles were retrieved reporting data on several MDROs, including glycopeptide-resistant enterococci (n = 5), carbapenemase-producing Enterobacteriacae (n = 1), methicillin-resistant Staphylococcus aureus (n = 5), and carbapenem-resistant Acinetobacter baumannii (n = 2). Overall, the cost of strict measures to eradicate MDROs ranged from ?285 to ?57 532 per positive patient. The major component of these overall costs was related to interruption of new admissions, representing ?2466 to ?47 093 per positive patient (69% of the overall mean cost; range, 13-100%), followed by mean laboratory costs of ?628 to ?5849 (24%; range, 3.3-56.7%), staff reinforcement costs of ?6204 to ?148 381 (22%; range, 3.3-52%), and contact precautions costs of ?166 to ?10 438 per positive patient (18%; range, 0.7-43.3%). Published data on the economic burden of strict measures to eradicate MDROs are limited, heterogeneous, and weakened by several methodological flaws. Novel economic studies should be performed to assess the financial impact of current policies, and to identify the most cost effective strategies to eradicate emerging MDROs in healthcare facilities. PMID- 26482265 TI - The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. AB - The composition of the gut microbiome with the use of non-steroidal anti inflammatory drugs (NSAIDs) has not been fully characterized. Drug use within the past 30 days was ascertained in 155 adults, and stool specimens were submitted for analysis. Area under the receiver operating characteristic curve (AUC) was calculated in logit models to distinguish the relative abundance of operational taxonomic units (OTUs) by medication class. The type of medication had a greater influence on the gut microbiome than the number of medications. NSAIDs were particularly associated with distinct microbial populations. Four OTUs (Prevotella species, Bacteroides species, family Ruminococcaceae, and Barnesiella species) discriminated aspirin users from those using no medication (AUC = 0.96; 95% CI 0.84-1.00). The microbiome profile of celecoxib users was similar to that of ibuprofen users, with both showing enrichment of Acidaminococcaceae and Enterobacteriaceae. Bacteria from families Propionibacteriaceae, Pseudomonadaceae, Puniceicoccaceae and Rikenellaceae were more abundant in ibuprofen users than in controls or naproxen users. Bacteroides species and Erysipelotrichaceae species discriminated individuals using NSAIDs plus proton pump inhibitors from those using NSAIDs alone (AUC = 0.96; 95% CI 0.87-1.00). Bacteroides species and a bacterium of family Ruminococcaceae discriminated individuals using NSAIDs in combination with antidepressants and laxatives from those using NSAIDs alone (AUC = 0.98; 95% CI 0.93-1.00). In conclusion, bacteria in the gastrointestinal tract reflect the combinations of medications that people ingest. The bacterial composition of the gut varied with the type of NSAID ingested. PMID- 26482266 TI - Contribution of APOBEC3G/F activity to the development of low-abundance drug resistant human immunodeficiency virus type 1 variants. AB - Plasma drug-resistant minority human immunodeficiency virus type 1 variants (DRMVs) increase the risk of virological failure to first-line non-nucleoside reverse transcriptase inhibitor antiretroviral therapy (ART). The origin of DRMVs in ART-naive patients, however, remains unclear. In a large pan-European case control study investigating the clinical relevance of pre-existing DRMVs using 454 pyrosequencing, the six most prevalent plasma DRMVs detected corresponded to G-to-A nucleotide mutations (V90I, V106I, V108I, E138K, M184I and M230I). Here, we evaluated if such DRMVs could have emerged from apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3G/F (APOBEC3G/F) activity. Out of 236 ART-naive subjects evaluated, APOBEC3G/F hypermutation signatures were detected in plasma viruses of 14 (5.9%) individuals. Samples with minority E138K, M184I, and M230I mutations, but not those with V90I, V106I or V108I, were significantly associated with APOBEC3G/F activity (Fisher's P < 0.005), defined as the presence of > 0.5% of sample sequences with an APOBEC3G/F signature. Mutations E138K, M184I and M230I co-occurred in the same sequence as APOBEC3G/F signatures in 3/9 (33%), 5/11 (45%) and 4/8 (50%) of samples, respectively; such linkage was not found for V90I, V106I or V108I. In-frame STOP codons were observed in 1.5% of all clonal sequences; 14.8% of them co-occurred with APOBEC3G/F signatures. APOBEC3G/F associated E138K, M184I and M230I appeared within clonal sequences containing in frame STOP codons in 2/3 (66%), 5/5 (100%) and 4/4 (100%) of the samples. In a re analysis of the parent case control study, the presence of APOBEC3G/F signatures was not associated with virological failure. In conclusion, the contribution of APOBEC3G/F editing to the development of DRMVs is very limited and does not affect the efficacy of non-nucleoside reverse transcriptase inhibitor ART. PMID- 26482267 TI - Acute hepatitis C in the Netherlands: characteristics of the epidemic in 2014. AB - Within the Dutch Acute HCV in HIV Study, a surveillance system was initiated to estimate the incidence of hepatitis C virus (HCV) infections in 2014. Following the Dutch HIV treatment guidelines, HIV-positive men having sex with men (MSM) in 19 participating centers were screened. Ninety-nine acute HCV infections were reported, which resulted in a mean incidence of 11 per 1000 patient-years of follow-up. Unfortunately, the HCV epidemic among Dutch HIV-positive MSM is not coming to a halt. PMID- 26482268 TI - Automated categorization of methicillin-resistant Staphylococcus aureus clinical isolates into different clonal complexes by MALDI-TOF mass spectrometry. AB - Early identification of methicillin-resistant Staphylococcus aureus (MRSA) dominant clones involved in infection and initiation of adequate infection control measures are essential to limit MRSA spread and understand MRSA population dynamics. In this study we evaluated the use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/MS) for the automated discrimination of the major MRSA lineages (clonal complexes, CC) identified in our hospital during a 20-year period (1990-2009). A collection of 82 well-characterized MRSA isolates belonging to the four main CCs (CC5, CC8, CC22 and CC398) was split into a reference set (n = 36) and a validation set (n = 46) to generate pattern recognition models using the ClinProTools software for the identification of MALDI-TOF/MS biomarker peaks. The supervised neural network (SNN) model showed the best performance compared with two other models, with sensitivity and specificity values of 100% and 99.11%, respectively. Eleven peaks (m/z range: 3278-6592) with the highest separation power were identified and used to differentiate all four CCs. Validation of the SNN model using ClinProTools resulted in a positive predictive value (PPV) of 99.6%. The specific contribution of each peak to the model was used to generate subtyping reference signatures for automated subtyping using the BioTyper software, which successfully classified MRSA isolates into their corresponding CCs with a PPV of 98.9%. In conclusion, we find this novel automated MALDI-TOF/MS approach to be a promising, powerful and reliable tool for S. aureus typing. PMID- 26482269 TI - Interference between respiratory syncytial virus and rhinovirus in respiratory tract infections in children. AB - An acute viral respiratory tract infection might prevent infections by other viruses because of the antiviral innate immune response. However, with the use of PCR methods, simultaneous detection of two or more respiratory viruses is frequent. We analysed the effect of respiratory syncytial virus (RSV) infection on the occurrence of simultaneous rhinovirus (RV) infection in children within a birth cohort study setting. We used PCR for virus detection in nasal swabs collected from children with an acute respiratory tract infection at the age of 0 24 months and from healthy control children, who were matched for age and date of sample collection. Of 226 children with RSV infections, 18 (8.0%) had co infections with RV, whereas RV was detected in 31 (14%) of 226 control children (p 0.049 by chi-square test). Adjustment for sex, number of siblings and socio economic status strengthened the negative association between RSV and RV (OR 0.46, 95% CI 0.24-0.90; p 0.02). The median durations of symptoms (cough, rhinorrhoea, or fever) were 11 days in children with single RSV infections and 14 days in children with RSV-RV co-infections (p 0.02). Our results suggest that the presence of RSV reduces the probability of RV infection, but that, if a co infection occurs, both viruses cause clinical symptoms. PMID- 26482270 TI - Individuals with inherited chromosomally integrated human herpes virus 6 (ciHHV 6) have functionally active HHV-6 specific T-cell immunity. AB - To evaluate the human herpes virus 6 (HHV-6) -specific immune response in individuals with chromosomally integrated HHV-6 (ciHHV-6), we measured HHV-6 antigen-specific cytokine responses (interferon-gamma, interleukin-2, tumour necrosis factor-alpha) in T cells by flow cytometry in 12 and 16 individuals with and without ciHHV-6, respectively. All individuals with ciHHV-6 showed HHV-6 specific T cells with higher frequencies of HHV-6-specific CD8(+) cells (0.03 14.93, median 2.15% of CD8(+) cells) compared with non-ciHHV-6 (0.0-10.67, median 0.36%, p 0.026). The observed increased HHV-6-specific functionally active responses in individuals with ciHHV-6 clearly disprove speculations on immune tolerance in ciHHV-6 and indicate clinical and immunological implications of ciHHV-6. PMID- 26482271 TI - A systematic review comparing the costs of chiropractic care to other interventions for spine pain in the United States. AB - BACKGROUND: Although chiropractors in the United States (US) have long suggested that their approach to managing spine pain is less costly than other health care providers (HCPs), it is unclear if available evidence supports this premise. METHODS: A systematic review was conducted using a comprehensive search strategy to uncover studies that compared health care costs for patients with any type of spine pain who received chiropractic care or care from other HCPs. Only studies conducted in the US and published in English between 1993 and 2015 were included. Health care costs were summarized for studies examining: 1. private health plans, 2. workers' compensation (WC) plans, and 3. clinical outcomes. The quality of studies in the latter group was evaluated using a Consensus on Health Economic Criteria (CHEC) list. RESULTS: The search uncovered 1276 citations and 25 eligible studies, including 12 from private health plans, 6 from WC plans, and 7 that examined clinical outcomes. Chiropractic care was most commonly compared to care from a medical physician, with few details about the care received. Heterogeneity was noted among studies in patient selection, definition of spine pain, scope of costs compared, study duration, and methods to estimate costs. Overall, cost comparison studies from private health plans and WC plans reported that health care costs were lower with chiropractic care. In studies that also examined clinical outcomes, there were few differences in efficacy between groups, and health care costs were higher for those receiving chiropractic care. The effects of adjusting for differences in sociodemographic, clinical, or other factors between study groups were unclear. CONCLUSIONS: Although cost comparison studies suggest that health care costs were generally lower among patients whose spine pain was managed with chiropractic care, the studies reviewed had many methodological limitations. Better research is needed to determine if these differences in health care costs were attributable to the type of HCP managing their care. PMID- 26482272 TI - Can thermogenic adipocytes protect from obesity? AB - The role of brown adipocytes and adipocytes of a new beige type in the energy metabolism of a healthy person and in the pathogenesis of obesity has extensively been discussed in recent years. The interest to these cells has been stimulated owing to the application of new noninvasive methods for studying the metabolic activity of tissues. Using these methods, the presence of thermogenically active adipocytes in adults and their reactivity to cold stimuli have been proved. These data, together with the results of animal experiments support the idea of thermogenic fat being a direct regulator of the energy balance of man. However, for several reasons there are some objections to this viewpoint. The main objection is that the total activity of the human thermogenic adipocytes is about 100 kJ/day, i.e., it is negligible. In addition, the burn of excessive nutrients is biologically inappropriate for an organism. Therefore, the idea that obesity is caused by the decreased activity of thermogenic adipocytes is erroneous. The statement that the causes of obesity are associated with the increased efficiency of energy-dependent processes seems more reasonable. The consequence is a reduction in energy expenditure to perform a unit of biological work. This results in excess of nutrients deposited in the form of fat. PMID- 26482274 TI - Urgent referral pathway alters cancer survival. PMID- 26482273 TI - Reducing tobacco smoking and smoke exposure to prevent preterm birth and its complications. AB - Tobacco smoking and smoke exposure during pregnancy are associated with a range of adverse health outcomes, including preterm birth. Also, children born preterm have a higher risk of complications including bronchopulmonary dysplasia and asthma when their mothers smoked during pregnancy. Smoking cessation in early pregnancy can help reduce the adverse impact on offspring health. Counselling interventions are effective in promoting smoking cessation and reducing the incidence of preterm birth. Peer support and incentive-based approaches are likely to be of additional benefit, whereas the effectiveness of pharmacological interventions, including nicotine replacement therapy, has not definitely been established. Smoke-free legislation can help reduce smoke exposure as well as maternal smoking rates at a population level, and is associated with a reduction in preterm birth. Helping future mothers to stop smoking and protect their children from second hand smoke exposure must be a key priority for health care workers and policy makers alike. PMID- 26482275 TI - Combination therapy in kidney cancer: the next revolution? PMID- 26482276 TI - Palliative chemotherapy for patients with breast cancer. PMID- 26482277 TI - Laparoscopic resection not better in rectal cancer. PMID- 26482278 TI - Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial. AB - BACKGROUND: New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer. METHODS: In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m(2) as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physician's choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101. FINDINGS: Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physician's choice. There was no significant difference in overall survival between groups (median 12.4 months [95% CI 11.0-13.6] for the etirinotecan pegol group vs 10.3 months [9.0-11.3] for the treatment of physician's choice group; hazard ratio 0.87 [95% CI 0.75-1.02]; p=0.084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of physician's choice). Serious adverse events were recorded for 128 (30%) patients treated with etirinotecan pegol and 129 (32%) treated with treatment of physician's choice. Fewer patients in the etirinotecan pegol group had grade 3 or worse toxicity than those in the treatment of physician's choice group (204 [48%] vs 256 [63%]; p<0.0001). The most common grade 3 or worse adverse events were diarrhoea (41 [10%] in the experimental group vs five [1%] in the control group), neutropenia (41 [10%] vs 125 [31%]), and peripheral neuropathy (two [<1%] vs 15 [4%]). Three patients in the etirinotecan pegol group died of treatment-related adverse events (pneumonia, myelodysplastic syndrome, and acute renal failure) and two in the treatment of physician's choice group (neutropenic sepsis and septic shock). INTERPRETATION: This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physician's choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients. FUNDING: Nektar Therapeutics. PMID- 26482280 TI - Variation in palliative care standards worldwide. PMID- 26482279 TI - Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. AB - BACKGROUND: Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma. METHODS: We did a randomised, phase 2, open label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733. FINDINGS: Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14.6 months [95% CI 5.9-20.1] vs 5.5 months [3.5-7.1]; hazard ratio [HR] 0.40, 95% CI 0.24-0.68; p=0.0005), but not compared with lenvatinib alone (7.4 months [95% CI 5.6-10.2]; HR 0.66, 95% CI 0.30-1.10; p=0.12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0.61, 95% CI 0.38-0.98; p=0.048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib. INTERPRETATION: Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma. FUNDING: Eisai Inc. PMID- 26482281 TI - Aldehyde dehydrogenase induction in arsenic-exposed rat bladder epithelium. AB - Arsenic is widely distributed in the environment. Many human cancers, including urothelial carcinoma (UC), show a dose-dependent relationship with arsenic exposure in the south-west coast of Taiwan (also known as the blackfoot disease (BFD) areas). However, the molecular mechanisms of arsenic-mediated UC carcinogenesis has not yet been defined. In vivo study, the rat bladder epithelium were exposed with arsenic for 48 h. The proteins were extracted from untreated and arsenic-treated rat bladder cells and utilized two-dimensional gel electrophoresis and mass spectrometry. Selected peptides were extracted from the gel and identified by quadrupole-time of flight (Q-TOF) Ultima-Micromass spectra. The significantly difference expression of proteins in arsenic-treated groups as compared with untreated groups was confirmed by immunohistochemistry (IHC) and western blotting. We found that thirteen proteins were down-regulated and nine proteins were up-regulated in arsenic-treated rat bladder cells when compared with untreated groups. The IHC and western blotting results confirmed that aldehyde dehydrogenase (ALDH) protein was up-regulated in arsenic-treated rat bladder epithelium. Expression of ALDH protein was significantly higher in UC patients from BFD areas than those from non-BFD areas using IHC (p=0.018). In conclusion, the ALDH protein expression could be used as molecular markers for arsenic-induced transformation. PMID- 26482282 TI - An associative account of how the obesogenic environment biases adolescents' food choices. AB - Adolescents and children are the targets of much food advertising, the majority of which is for unhealthy snacks. Although the effects of advertising on food preferences and consummatory behavior are well documented, our understanding of the underlying mechanisms is still limited. The present study investigates an associative (ideomotor) mechanism by which exposure to rewarding (snack) outcomes may activate behavior that previously resulted in these rewards. Specifically, we used a computerized task to investigate whether exposing adolescents to food pictures directly, or to Pavlovian cues predictive of those food pictures, would bias their subsequent responses towards the presented/signaled food. Furthermore, we assessed whether this effect was particularly pronounced with palatable, high calorie snacks (crisps and chocolate) relative to low-calorie snacks (tomatoes and cucumber). In two experiments, adolescents learnt that certain key presses would yield particular food pictures - some high calorie and others low calorie - before learning Pavlovian associations between cues (cartoon monsters) and these same food pictures. Subsequently, in a response-priming test, we examined the extent to which the food pictures and Pavlovian cues spontaneously primed the previously associated response. The results show that we replicated, in adolescents, previous demonstrations of ideomotor response priming in adults: food pictures biased responding towards the response that previously yielded them, and this effect transferred to the Pavlovian cues. Furthermore, the priming effect was significantly stronger for high-calorie rewards than for low-calorie. These findings indicate that the ideomotor mechanism plays an important role in the detrimental effect of our obesogenic environment, with its plethora of unhealthy food reminders, on adolescents' food-related choices. PMID- 26482283 TI - In the eye of the beholder: Visual biases in package and portion size perceptions. AB - As the sizes of food packages and portions have changed rapidly over the past decades, it has become crucial to understand how consumers perceive and respond to changes in size. Existing evidence suggests that consumers make errors when visually estimating package and portion sizes, and these errors significantly influence subsequent food choices and intake. We outline four visual biases (arising from the underestimation of increasing portion sizes, the dimensionality of the portion size change, labeling effects, and consumer affect) that shape consumers' perceptions of package and portion sizes. We discuss the causes of these biases, review their impact on food consumption decisions, and suggest concrete strategies to reduce them and to promote healthier eating. We conclude with a discussion of important theoretical and practical issues that should be addressed in the future. PMID- 26482284 TI - The stability of 'food addiction' as assessed by the Yale Food Addiction Scale in a non-clinical population over 18-months. AB - The Yale Food Addiction Scale (YFAS) is a widely used tool to assess the behavioural indicators of addictive-like eating. No studies, however, have used a longitudinal design to determine whether these addictive-like eating behaviours are a stable or transient phenomenon in a community-based population. This study aimed to evaluate whether food addiction Diagnosis and Symptom scores as assessed by the YFAS remain stable over 18-months in a non-clinical population. Young adults aged 18-35 years were recruited from the community to a web-based survey in 2013. The survey included demographics, anthropometrics and the YFAS. Participants who volunteered to be recontacted for future research were invited to complete the same survey 18-months later. The YFAS scoring outputs Diagnosis and Symptom scores were tested for agreement and reliability between the two time points. Of the 303 participants who completed the original survey and agreed to be recontacted, 69 participants (22.8% of those recontacted, 94% female, 67% normal weight at baseline) completed the 18-month follow-up survey. At baseline, thirteen participants met the YFAS predefined criteria for Diagnosis, while eleven participants met these criteria at the 18-month follow-up. YFAS Diagnosis was found to have moderate agreement [K = .50, 95% CI (.23, .77)] between the two time points while Symptom scores had good agreement [K = .70, 95% CI (.54, .83)]. Intraclass correlation coefficients were interpreted as moderate over the 18 month period for both the Diagnosis [ICC = .71, 95% CI (.45, .88)] and Symptom scores [ICC = .72, 95% CI (.58, .82)]. YFAS assessed food addiction Diagnosis and Symptom scores were found to be relatively stable over 18-months in a non clinical population of predominantly female, young adults. Future research is required to determine the impact of behavioural weight loss interventions on YFAS assessed addictive-like eating. PMID- 26482285 TI - Correction. AB - Garcia-Bournissen F, Rokach B, Karaskov T, et al. Methamphetamine detection in maternal and neonatal hair: implications for fetal safety (Arch Dis Child Fetal Neonatal Ed 2007;92:351-5). This paper states that positive results were confirmed by gas chromatography/mass spectrometry. The authors have clarified that some, but not all, samples that were positive by ELISA were confirmed with GC/MS; they further confirm that this fact had no impact on the results of comparing maternal to neonatal hair levels in the paper, so that the paper's conclusions remain the same. PMID- 26482286 TI - [The treatment terminology depends on the context]. PMID- 26482287 TI - [Fixation is not treatment]. PMID- 26482288 TI - [Coercive procedures in forensic psychiatry : Current treatment practice in forensic psychiatric hospitals from a medical ethics perspective]. AB - BACKGROUND: In 2011 the legal foundations of coercive treatment in German forensic psychiatric clinics were declared to be unconstitutional. In the present study we analyzed the frequency of coercive procedures in forensic psychiatric hospitals before and after 2011, the consequences for medical care as well as the ethical assessments by attending chief physicians. METHODS: By a questionnaire based survey of views of attending chief physicians in forensic psychiatric clinics in 2013, data on the current state of patient care were collected and analyzed from an ethical perspective. These were compared with treatment data from a large forensic psychiatric clinic collected over the period 2007-2013. RESULTS: Even after 2011 coercive forms of treatment were applied in forensic psychiatric hospitals. In practice, there is a high degree of legal uncertainty regarding the limits of coercive treatment. Of all patients treated in forensic psychiatric clinics in 2012, on average 13 % had been in isolation at least once, approximately 3 % had been treated under fixation at least once and 2.2 % had been subjected to coercive medical treatment at least once. CONCLUSION: From an ethical perspective an open debate about the practice of coercive treatment is urgently required. Legal regulations, ethical guidelines and treatment standards have to be developed for the special situation of patient care in forensic psychiatric hospitals. PMID- 26482289 TI - Molecular and antigenic characteristics of Massachusetts genotype infectious bronchitis coronavirus in China. AB - In this study, 418 IBVs were isolated in samples from 1717 chicken flocks. Twenty nine of the isolates were classified as the Massachusetts genotype. These 29 isolates, as well as two previously isolated Massachusetts genotype IBV strains, were studied further. Of the 31 strains, 24 were H120-like and two were M41-like isolates as determined by complete genomic sequence analysis, indicating that most of the IBV isolates were likely the reisolated vaccine virus. The remaining five IBV isolates, ck/CH/LHB/111172, ck/CH/LSD/111219, ck/CH/LHB/130598, ck/CH/LDL/110931, and ck/CH/LHB/130573, were shown to have originated from natural recombination events between an H120-like vaccine strain and other types of viruses. The virus cross-neutralization test found that the antigenicity of ck/CH/LHB/111172, ck/CH/LSD/111219, and ck/CH/LHB/130598 was similar to that of H120. Vaccination with the H120 vaccine offered complete protection against challenge with these isolates. However, isolates ck/CH/LDL/110931 and ck/CH/LHB/130573 were serotypically different from their parental viruses and from other serotypes in this study. Furthermore, vaccination with the H120 vaccine did not provide protection against challenge with these two isolates. The results of this study demonstrated that recombination is the mechanism that is responsible for the emergence of new serotype strains, and it has the ability to alter virus serotypes. Therefore, IBV surveillance of chicken flocks vaccinated with IBV live vaccines, as well as the consideration of new strategies to effectively control IBV infection using inactivated or/and genetically engineered vaccines, is of great importance. PMID- 26482290 TI - Time-resolved FRET reports FGFR1 dimerization and formation of a complex with its effector PLCgamma1. AB - In vitro and in vivo imaging of protein tyrosine kinase activity requires minimally invasive, molecularly precise optical probes to provide spatiotemporal mechanistic information of dimerization and complex formation with downstream effectors. We present here a construct with genetically encoded, site specifically incorporated, bioorthogonal reporter that can be selectively labelled with exogenous fluorogenic probes to monitor the structure and function of fibroblast growth factor receptor (FGFR). GyrB.FGFR1KD.TC contains a coumermycin-induced artificial dimerizer (GyrB), FGFR1 kinase domain (KD) and a tetracysteine (TC) motif that enables fluorescent labelling with biarsenical dyes FlAsH-EDT2 and ReAsH-EDT2. We generated bimolecular system for time-resolved FRET (TR-FRET) studies, which pairs FlAsH-tagged GyrB.FGFR1KD.TC and N-terminal Src homology 2 (nSH2) domain of phospholipase Cgamma (PLCgamma), a downstream effector of FGFR1, fused to mTurquoise fluorescent protein (mTFP). We demonstrated phosphorylation-dependent TR-FRET readout of complex formation between mTFP.nSH2 and GyrB.FGFR1KD.TC. By further application of TR-FRET, we also demonstrated formation of the GyrB.FGFR1KD.TC homodimer by coumermycin-induced dimerization. Herein, we present a spectroscopic FRET approach to facilitate and propagate studies that would provide structural and functional insights for FGFR and other tyrosine kinases. PMID- 26482291 TI - Why always lysine? The ongoing tale of one of the most modified amino acids. AB - The complex physiology of living organisms must be finely-tuned to permit the flexibility required to respond to the changing environment. Evolution has provided an interconnected and intricate array of regulatory mechanisms to facilitate this fine-tuning. The number of genes cannot alone explain the complexity of these mechanisms. Rather, signalling is regulated at multiple levels, from genomic to transcriptional, translational and post-translational. Post-translational modification (PTM) of proteins offers an additional level of regulation after protein synthesis that allows a rapid, controlled and reversible response to environmental cues. Many amino acid side chains are post translationally modified. These modifications can either be enzymatic, such as the phosphorylation of serine, threonine and tyrosine residues, or non-enzymatic, such as the nitrosylation of cysteine residues. Strikingly, lysine residues are targeted by a particularly high number of PTMs including acetylation, methylation, ubiquitination and sumoylation. Additionally, lysines have recently been identified as the target of the non-enzymatic PTM polyphosphorylation. This novel PTM sees linear chains of inorganic polyphosphates (polyP) covalently attached to lysine residues. Interestingly, polyphosphorylation is indirectly dependent on inositol pyrophosphates, a class of cellular messengers. The attachment of polyP to lysine occurs through the phosphoramidate bond, which, unlike the phosphester bond, is unstable under the conditions used in common mass spectroscopy. This characteristic, together with the diversity of lysine PTMs, suggests that many other lysine modifications may still remain unidentified, raising the intriguing possibility that lysine PTMs may be the major means by which signalling pathways modify protein behaviour. PMID- 26482292 TI - Evaluation of maternal serum progranulin levels in normotensive pregnancies, and pregnancies with early- and late-onset preeclampsia. AB - AIMS: To investigate the possible pathophysiological associations between progranulin (PGRN) and preeclampsia (PE), early-onset PE (EOPE) and late-onset PE (LOPE). STUDY DESIGN: A cross-sectional study was designed to include consecutive patients with uncomplicated pregnancy (n = 28), EOPE (n = 30) and LOPE (n = 22). Maternal levels of serum PGRN were measured with the use of an enzyme-linked immunosorbent assay kit. RESULTS: The mean serum PGRN level was significantly higher in women with PE compared to the control group (54.17 +/- 4.20 pg/ml versus 42.37 +/- 5.64 pg/ml, p < 0.001), in the LOPE group compared to the control group (51.63 +/- 4.61 pg/ml versus 42.37 +/- 5.64 pg/ml, p < 0.001) and also in women with EOPE compared to women with LOPE (56.03 +/- 2.68 pg/ml versus 51.63 +/- 4.61 pg/ml, p < 0.001). Serum PGRN was negatively correlated with gestational age at birth (r = -0.669, p = 0.001) and birth weight (r = -0.653, p = 0.001); and positively correlated with systolic (r = 0.653, p = 0.001) and diastolic blood pressure (r = 0.601, p = 0.001), C-reactive protein (r = 0.519, p = 0.001), uterine artery pulsatility (r = 0.441, p = 0.001) and resistance indices (r = 0.441, p = 0.001). CONCLUSIONS: Serum PGRN levels increase significantly in women with PE as an indirect sign of placental dysfunction. This increase is even more prominent in women with EOPE. The serum PGRN in the third trimester is positively correlated with gestational age at birth and birth weight. PMID- 26482293 TI - Species extinction thresholds in the face of spatially correlated periodic disturbance. AB - The spatial correlation of disturbance is gaining attention in landscape ecology, but knowledge is still lacking on how species traits determine extinction thresholds under spatially correlated disturbance regimes. Here we develop a pair approximation model to explore species extinction risk in a lattice-structured landscape subject to aggregated periodic disturbance. Increasing disturbance extent and frequency accelerated population extinction irrespective of whether dispersal was local or global. Spatial correlation of disturbance likewise increased species extinction risk, but only for local dispersers. This indicates that models based on randomly simulated disturbances (e.g., mean-field or non spatial models) may underestimate real extinction rates. Compared to local dispersal, species with global dispersal tolerated more severe disturbance, suggesting that the spatial correlation of disturbance favors long-range dispersal from an evolutionary perspective. Following disturbance, intraspecific competition greatly enhanced the extinction risk of distance-limited dispersers, while it surprisingly did not influence the extinction thresholds of global dispersers, apart from decreasing population density to some degree. As species respond differently to disturbance regimes with different spatiotemporal properties, different regimes may accommodate different species. PMID- 26482294 TI - Effects of Scorpion venom peptide B5 on hematopoietic recovery in irradiated mice and the primary mechanisms. AB - Scorpion venom peptide B5 (SVP-B5) stimulates recovery of hematopoiesis after exposure to radiation. However, its radioprotective effects and mechanisms are still unclear. The aim of this study was to investigate the effects of SVP-B5 on hematopoietic recovery in mice after total body irradiation (TBI) at a dose of 7.5 Gy and 6 Gy and to explore the possible primary mechanisms. SVP-B5 at a dose of 2.63 MUg/kg significantly reduced the mortality rate of mice after TBI (p < 0.05). It showed markedly protective effects against radiation injury. SVP-B5 also significantly increased the number of bone marrow nucleated cells (BMNCs) and increased the colony forming unit (CFU) number in irradiated mice, accelerated the post-irradiation recovery of peripheral blood leukocytes and platelets in mice. SVP-B5 treatment markedly reduced the Reactive Oxygen Species (ROS) levels in BMNCs after TBI, reduced gammaH2AX levels, and decreased the relative expression levels of p16 and p21 mRNA at day 14 (d14) after irradiation. Our study indicated that SVP-B5 could partially mitigate radiation-induced DNA damage, enhance the post-radiation hematopoietic recovery, and improve the survival rate probably through the ROS-p16/p21 pathway. PMID- 26482296 TI - Air pollution control through biotrickling filters: a review considering operational aspects and expected performance. AB - The biological removal of pollutants, especially through biotrickling filters (BTFs), has recently become attractive for the low investment and operational costs and the low secondary pollution. This paper is intended to investigate the state of the art on BTF applications. After an overview on the biodegradation process and the typical parameters involved, this paper presents the analysis of a group of 16 literature studies chosen as the references for this sector. The reference studies differ from one another by the pollutants treated (volatile organic compounds [VOC], hydrogen sulphide, nitrogen oxides and trimethylamine), the geometry and size of the BTFs, and the procedures of the tests. The reference studies are analyzed and discussed in terms of the operational conditions and the results obtained, especially with respect to the removal efficiencies (REs) and the elimination capacities (ECs) of the pollutants considered. Empty bed residence time (EBRT), pollutant loading rate, temperature, pH, oxygen availability, trickling liquid flow rate, inoculum selection and biomass control strategies revealed to be the most important operational factors influencing the removal performance of a BTF. PMID- 26482295 TI - Substitute sweeteners: diverse bacterial oligosaccharyltransferases with unique N glycosylation site preferences. AB - The central enzyme in the Campylobacter jejuni asparagine-linked glycosylation pathway is the oligosaccharyltransferase (OST), PglB, which transfers preassembled glycans to specific asparagine residues in target proteins. While C. jejuni PglB (CjPglB) can transfer many diverse glycan structures, the acceptor sites that it recognizes are restricted predominantly to those having a negatively charged residue in the -2 position relative to the asparagine. Here, we investigated the acceptor-site preferences for 23 homologs with natural sequence variation compared to CjPglB. Using an ectopic trans-complementation assay for CjPglB function in glycosylation-competent Escherichia coli, we demonstrated in vivo activity for 16 of the candidate OSTs. Interestingly, the OSTs from Campylobacter coli, Campylobacter upsaliensis, Desulfovibrio desulfuricans, Desulfovibrio gigas, and Desulfovibrio vulgaris, exhibited significantly relaxed specificity towards the -2 position compared to CjPglB. These enzymes glycosylated minimal N-X-T motifs in multiple targets and each followed unique, as yet unknown, rules governing acceptor-site preferences. One notable example is D. gigas PglB, which was the only bacterial OST to glycosylate the Fc domain of human immunoglobulin G at its native 'QYNST' sequon. Overall, we find that a subset of bacterial OSTs follow their own rules for acceptor-site specificity, thereby expanding the glycoengineering toolbox with previously unavailable biocatalytic diversity. PMID- 26482297 TI - Traumatic dental injuries among 12- and 15-year-old adolescents in Georgia: results of the pathfinder study. AB - BACKGROUND: Traumatic dental injuries (TDI) are a widespread pathology with serious dental public health concerns. OBJECTIVES: The aim of this pathfinder study was to collect initial epidemiological data on oral health in Republic of Georgia. As part of this study, the prevalence and severity of TDI in permanent teeth among seventh- and tenth-grade schoolchildren were evaluated. METHODS: Schoolchildren were examined in four schools in the capital city of Tbilisi, two schools in two other major cities, and one school in four additional villages. In addition to demographical data, the following parameters were collected and recorded: Overjet (OJ), lip competence, number and type/location of the teeth with TDI and Type of TDI. The study population comprised of children aged 12 (seventh grade) and 15 years old (10th grade). RESULTS: A total of 823 7th- and 10th-grade schoolchildren were examined. The overall prevalence of TDI among Georgian population was found to be 10.4% (86 children). The prevalence of TDI was greater in the older age cohort (P < 0.05). Lip posture did not seem to have a marked effect on TDI. Children with an OJ greater than 5 mm were more likely to present with dental injuries compared to children with an OJ equal to or smaller than 5 mm (P < 0.05). Children from rural areas presented with greater prevalence of TDI compared to their urban counterparts (P < 0.05). The maxillary central incisors were the most common teeth to be affected by trauma accounting for 85.2% of the TDI cases. Enamel fracture was the main type of TDI (91.3%). CONCLUSIONS: The prevalence of TDI in Georgian schoolchildren, as presented in this survey, population was found to be rather moderate and involved mainly minor superficial injuries. Rural communities have shown in this report substantial higher rates; thus, educational program might be directed mostly to these regions to children, teachers, and healthcare providers. PMID- 26482298 TI - Molecule Targeting Glucosyltransferase Inhibits Streptococcus mutans Biofilm Formation and Virulence. AB - Dental plaque biofilms are responsible for numerous chronic oral infections and cause a severe health burden. Many of these infections cannot be eliminated, as the bacteria in the biofilms are resistant to the host's immune defenses and antibiotics. There is a critical need to develop new strategies to control biofilm-based infections. Biofilm formation in Streptococcus mutans is promoted by major virulence factors known as glucosyltransferases (Gtfs), which synthesize adhesive extracellular polysaccharides (EPS). The current study was designed to identify novel molecules that target Gtfs, thereby inhibiting S. mutans biofilm formation and having the potential to prevent dental caries. Structure-based virtual screening of approximately 150,000 commercially available compounds against the crystal structure of the glucosyltransferase domain of the GtfC protein from S. mutans resulted in the identification of a quinoxaline derivative, 2-(4-methoxyphenyl)-N-(3-{[2-(4-methoxyphenyl)ethyl]imino}-1,4 dihydro-2-quinoxalinylidene)ethanamine, as a potential Gtf inhibitor. In vitro assays showed that the compound was capable of inhibiting EPS synthesis and biofilm formation in S. mutans by selectively antagonizing Gtfs instead of by killing the bacteria directly. Moreover, the in vivo anti-caries efficacy of the compound was evaluated in a rat model. We found that the compound significantly reduced the incidence and severity of smooth and sulcal-surface caries in vivo with a concomitant reduction in the percentage of S. mutans in the animals' dental plaque (P < 0.05). Taken together, these results represent the first description of a compound that targets Gtfs and that has the capacity to inhibit biofilm formation and the cariogenicity of S. mutans. PMID- 26482299 TI - Impact of a Cross-Kingdom Signaling Molecule of Candida albicans on Acinetobacter baumannii Physiology. AB - Multidrug-resistant (MDR) Acinetobacter baumannii is an opportunistic human pathogen that has become highly problematic in the clinical environment. Novel therapies are desperately required. To assist in identifying new therapeutic targets, the antagonistic interactions between A. baumannii and the most common human fungal pathogen, Candida albicans, were studied. We have observed that the C. albicans quorum-sensing molecule, farnesol, has cross-kingdom interactions, affecting the viability of A. baumannii. To gain an understanding of its mechanism, the transcriptional profile of A. baumannii exposed to farnesol was examined. Farnesol caused dysregulation of a large number of genes involved in cell membrane biogenesis, multidrug efflux pumps (AcrAB-like and AdeIJK-like), and A. baumannii virulence traits such as biofilm formation (csuA, csuB, and ompA) and motility (pilZ and pilH). We also observed a strong induction in genes involved in cell division (minD, minE, ftsK, ftsB, and ftsL). These transcriptional data were supported by functional assays showing that farnesol disrupts A. baumannii cell membrane integrity, alters cell morphology, and impairs virulence characteristics such as biofilm formation and twitching motility. Moreover, we showed that A. baumannii uses efflux pumps as a defense mechanism against this eukaryotic signaling molecule. Owing to its effects on membrane integrity, farnesol was tested to see if it potentiated the activity of the membrane-acting polymyxin antibiotic colistin. When coadministered, farnesol increased sensitivity to colistin for otherwise resistant strains. These data provide mechanistic understanding of the antagonistic interactions between diverse pathogens and may provide important insights into novel therapeutic strategies. PMID- 26482300 TI - Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection. AB - GSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitro activity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivo pharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection with Streptococcus pneumoniae and Haemophilus influenzae (mouse lung model) and with Staphylococcus aureus (rat abscess model) and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies with both models showed slightly higher-than-dose-proportional exposure, with 3-fold increases in area under the concentration-time curve (AUC) with doubling doses. GSK1322322 exhibited dose-dependent in vivo efficacy against multiple isolates of S. pneumoniae, H. influenzae, and S. aureus. Dose fractionation studies with two S. pneumoniae and S. aureus isolates showed that therapeutic outcome correlated best with the free AUC/MIC (fAUC/MIC) index in S. pneumoniae (R(2), 0.83), whereas fAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors for S. aureus (R(2), 0.9 and 0.91, respectively). Median daily fAUC/MIC values required for stasis and for a 1-log10 reduction in bacterial burden were 8.1 and 14.4 for 11 S. pneumoniae isolates (R(2), 0.62) and 7.2 and 13.0 for five H. influenzae isolates (R(2), 0.93). The data showed that for eight S. aureus isolates, fAUC correlated better with efficacy than fAUC/MIC (R(2), 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range, 0.5 to 4 MUg/ml). Median fAUCs of 2.1 and 6.3 MUg . h/ml were associated with stasis and 1-log10 reductions, respectively, for S. aureus. PMID- 26482301 TI - Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV Infected Patients with Tuberculosis. AB - Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.). PMID- 26482302 TI - Genomic Characteristics of NDM-Producing Enterobacteriaceae Isolates in Australia and Their blaNDM Genetic Contexts. AB - blaNDM has been reported in different Enterobacteriaceae species and on numerous plasmid replicon types (Inc). Plasmid replicon typing, in combination with genomic characteristics of the bacterial host (e.g., sequence typing), is used to infer the spread of antimicrobial resistance determinants between genetically unrelated bacterial hosts. The genetic context of blaNDM is heterogeneous. In this study, we genomically characterized 12 NDM-producing Enterobacteriaceae isolated in Australia between 2012 and 2014: Escherichia coli (n = 6), Klebsiella pneumoniae (n = 3), Enterobacter cloacae (n = 2) and Providencia rettgeri (n = 1). We describe their blaNDM genetic contexts within Tn125, providing insights into the acquisition of blaNDM into Enterobacteriaceae. IncFII-type (n = 7) and IncX3 (n = 4) plasmids were the most common plasmid types found. The IncHI1B (n = 1) plasmid was also identified. Five different blaNDM genetic contexts were identified, indicating four particular plasmids with specific blaNDM genetic contexts (NGCs), three of which were IncFII plasmids (FII-A to -C). Of note, the blaNDM genetic context of P. rettgeri was not conjugative. Epidemiological links between our NDM-producing Enterobacteriaceae were established by their acquisition of these five particular plasmid types. The combination of different molecular and genetic characterization methods allowed us to provide insight into the spread of plasmids transmitting blaNDM. PMID- 26482303 TI - Structural Basis of Metallo-beta-Lactamase Inhibition by Captopril Stereoisomers. AB - beta-Lactams are the most successful antibacterials, but their effectiveness is threatened by resistance, most importantly by production of serine- and metallo beta-lactamases (MBLs). MBLs are of increasing concern because they catalyze the hydrolysis of almost all beta-lactam antibiotics, including recent-generation carbapenems. Clinically useful serine-beta-lactamase inhibitors have been developed, but such inhibitors are not available for MBLs. l-Captopril, which is used to treat hypertension via angiotensin-converting enzyme inhibition, has been reported to inhibit MBLs by chelating the active site zinc ions via its thiol(ate). We report systematic studies on B1 MBL inhibition by all four captopril stereoisomers. High-resolution crystal structures of three MBLs (IMP-1, BcII, and VIM-2) in complex with either the l- or d-captopril stereoisomer reveal correlations between the binding mode and inhibition potency. The results will be useful in the design of MBL inhibitors with the breadth of selectivity required for clinical application against carbapenem-resistant Enterobacteriaceae and other organisms causing MBL-mediated resistant infections. PMID- 26482304 TI - Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit. AB - Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CL(CR)), such that a 30-ml/min increase in the estimated CL(CR) would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL(CR) of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL(CR) of >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved. PMID- 26482306 TI - In Vitro Pharmacodynamics of Human Simulated Exposures of Telavancin against Methicillin-Susceptible and -Resistant Staphylococcus aureus with and without Prior Vancomycin Exposure. AB - Telavancin is a lipoglycopeptide with potent activity against methicillin resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). The activity of telavancin against MRSA and MSSA after prior vancomycin exposure was studied in an in vitro pharmacodynamic model. Two clinical MRSA and two MSSA isolates, all with vancomycin MICs of 2 MUg/ml, were subjected to humanized free drug exposures of vancomycin at 1 g every 12 h (q12h) for 96 h, telavancin at 750 mg q24h for 96 h, and vancomycin at 1 g q12h for 72 h followed by telavancin at 750 mg q24h for 48 h (120 h total). The microbiological responses were measured by changes from 0 h in log10 CFU/ml at the end of experiments and area under the bacterial killing and regrowth curves over 96 h (AUBC0-96). The control isolates grew to 8.8 +/- 0.3 log10 CFU/ml. Initially, all regimens caused -4.5 +/- 0.9 reductions in log10 CFU/ml by 48 h followed by slight regrowth over the following 48 to 72 h. After 96 h, vancomycin and telavancin achieved -3.7 +/- 0.9 and -3.8 +/- 0.8 log10 CFU/ml changes from baseline, respectively (P = 0.74). Sequential exposure to telavancin after vancomycin did not result in additional CFU reductions or increases, with ultimate log10 CFU/ml reductions of -4.3 +/- 1.1 at 96 h and -4.2 +/- 1.3 at 120 h (P > 0.05 for all comparisons at 96 h). The AUBC0-96 was significantly smaller for the regimen of telavancin for 96 h than for the regimens of vancomycin for 96 h and vancomycin followed by telavancin (P <= 0.04). No resistance was observed throughout the experiment. Against these MRSA and MSSA isolates with vancomycin MICs of 2 MUg/ml, telavancin was comparable with vancomycin and its activity was unaffected by prior vancomycin exposure. PMID- 26482305 TI - Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage. AB - HIV-1 infection frequently causes HIV-associated neurocognitive disorders (HAND) despite combination antiretroviral therapy (cART). Evidence is accumulating that components of cART can themselves be neurotoxic upon long-term exposure. In addition, abuse of psychostimulants, such as methamphetamine, seems to aggravate HAND and compromise antiretroviral therapy. However, the combined effect of virus and recreational and therapeutic drugs on the brain is poorly understood. Therefore, we exposed mixed neuronal-glial cerebrocortical cells to antiretrovirals (ARVs) (zidovudine [AZT], nevirapine [NVP], saquinavir [SQV], and 118-D-24) of four different pharmacological categories and to methamphetamine and, in some experiments, the HIV-1 gp120 protein for 24 h and 7 days. Subsequently, we assessed neuronal injury by fluorescence microscopy, using specific markers for neuronal dendrites and presynaptic terminals. We also analyzed the disturbance of neuronal ATP levels and assessed the involvement of autophagy by using immunofluorescence and Western blotting. ARVs caused alterations of neurites and presynaptic terminals primarily during the 7-day incubation and depending on the specific compounds and their combinations with and without methamphetamine. Similarly, the loss of neuronal ATP was context specific for each of the drugs or combinations thereof, with and without methamphetamine or viral gp120. Loss of ATP was associated with activation of AMP activated protein kinase (AMPK) and autophagy, which, however, failed to restore normal levels of neuronal ATP. In contrast, boosting autophagy with rapamycin prevented the long-term drop of ATP during exposure to cART in combination with methamphetamine or gp120. Our findings indicate that the overall positive effect of cART on HIV infection is accompanied by detectable neurotoxicity, which in turn may be aggravated by methamphetamine. PMID- 26482307 TI - Molecular Characterization of Carbapenem-Nonsusceptible Enterobacterial Isolates Collected during a Prospective Interregional Survey in France and Susceptibility to the Novel Ceftazidime-Avibactam and Aztreonam-Avibactam Combinations. AB - An interregional surveillance program was conducted in the northwestern part of France to determine the prevalence of carbapenem-nonsusceptible Enterobacteriaceae (CNSE) isolates and their susceptibility to ceftazidime avibactam and aztreonam-avibactam combinations. Nonduplicate CNSE clinical isolates were prospectively collected from six hospitals between June 2012 and November 2013. MICs of ceftazidime and aztreonam, alone or combined with a fixed concentration of avibactam (4 MUg/ml), and those of carbapenems (comparator agents) were determined. MICs of ertapenem in combination with phenylalanine arginine-naphthylamide dihydrochloride (PAbetaN) were also determined to assess active efflux. Genes encoding carbapenemases, plasmid-mediated AmpC enzymes, extended-spectrum beta-lactamases (ESBLs), and major outer membrane proteins (OMPs) were amplified and sequenced. OMPs were also extracted for SDS-PAGE analysis. Among the 139 CNSE isolates, mainly Enterobacter spp. and Klebsiella pneumoniae, 123 (88.4%) were ertapenem nonsusceptible, 12 (8.6%) exhibited reduced susceptibility to all carbapenems, and 4 Proteeae isolates (2.9%) were resistant to imipenem. Carbapenemase production was detected in only two isolates (producing OXA-48 and IMI-3). In contrast, OMP deficiency, in association with AmpCs and/or ESBLs (mainly CTX-M-9, SHV-12, and CTX-M-15), was largely identified among CNSE isolates. The ceftazidime-avibactam and aztreonam-avibactam combinations exhibited potent activity against CNSE isolates (MIC50/MIC90, 1/1 MUg/ml and 0.5/0.5 MUg/ml, respectively) compared to that of ceftazidime and aztreonam alone (MIC50/MIC90, 512/512 MUg/ml and 128/512 MUg/ml, respectively). This study reveals the in vitro activity of ceftazidime-avibactam and aztreonam avibactam combinations against a large collection of porin-deficient enterobacterial isolates that are representative of the CNSE recovered in the northern part of France. PMID- 26482308 TI - Antimicrobial Susceptibilities of Aerobic and Facultative Gram-Negative Bacilli from Intra-abdominal Infections in Patients from Seven Regions in China in 2012 and 2013. AB - To evaluate the antimicrobial susceptibility of Gram-negative bacilli that caused hospital-acquired and community-acquired intra-abdominal infections (IAIs) in China between 2012 and 2013, we determined the susceptibilities to 12 antimicrobials and the extended-spectrum beta-lactamase (ESBL) statuses of 3,540 IAI isolates from seven geographic areas in China in a central laboratory using CLSI broth microdilution and interpretive standards. Most infections were caused by Escherichia coli (46.3%) and Klebsiella pneumoniae (19.7%). Rates of ESBL producing E. coli (P = 0.031), K. pneumoniae (P = 0.017), and Proteus mirabilis (P = 0.004) were higher in hospital-acquired IAIs than in community-acquired IAIs. Susceptibilities of enterobacteriaceae to ertapenem, amikacin, piperacillin tazobactam, and imipenem were 71.3% to 100%, 81.3% to 100%, 64.7% to 100%, and 83.1% to 100%, respectively, but imipenem was ineffective against P. mirabilis (<20%). Although most ESBL-positive hospital-acquired isolates were resistant to third- and fourth-generation cephalosporins, the majority were susceptible to cefoxitin (47.9% to 83.9%). Susceptibilities of ESBL-positive isolates to ampicillin-sulbactam (<10%) were low, whereas susceptibilities to ciprofloxacin (0% to 54.6%) and levofloxacin (0% to 63.6%) varied substantially. The prevalences of cephalosporin-susceptible E. coli and K. pneumoniae were higher in the northeastern and southern regions than in the central and eastern regions, reflecting the ESBL-positive rates in these areas, and were lowest in the Jiangsu Zhejiang (Jiang-Zhe) area where the rates of carbapenem resistance were also highest. Ertapenem, amikacin, piperacillin-tazobactam, and imipenem are the most efficacious antibiotics for treating IAIs in China, especially those caused by E. coli or K. pneumoniae. Resistance to cephalosporins and carbapenems is more common in the Jiang-Zhe area than in other regions in China. PMID- 26482309 TI - Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors. AB - Concomitant with the release of human immunodeficiency virus type 1 (HIV-1) particles from the infected cell, the viral protease cleaves the Gag polyprotein precursor at a number of sites to trigger virus maturation. We previously reported that a betulinic acid-derived compound, bevirimat (BVM), blocks HIV-1 maturation by disrupting a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. BVM was shown in multiple clinical trials to be safe and effective in reducing viral loads in HIV-1-infected patients. However, naturally occurring polymorphisms in the SP1 region of Gag (e.g., SP1-V7A) led to a variable response in some BVM treated patients. The reduced susceptibility of SP1-polymorphic HIV-1 to BVM resulted in the discontinuation of its clinical development. To overcome the loss of BVM activity induced by polymorphisms in SP1, we carried out an extensive medicinal chemistry campaign to develop novel maturation inhibitors. In this study, we focused on alkyl amine derivatives modified at the C-28 position of the BVM scaffold. We identified a set of derivatives that are markedly more potent than BVM against an HIV-1 clade B clone (NL4-3) and show robust antiviral activity against a variant of NL4-3 containing the V7A polymorphism in SP1. One of the most potent of these compounds also strongly inhibited a multiclade panel of primary HIV-1 isolates. These data demonstrate that C-28 alkyl amine derivatives of BVM can, to a large extent, overcome the loss of susceptibility imposed by polymorphisms in SP1. PMID- 26482310 TI - Activity of Isavuconazole and Other Azoles against Candida Clinical Isolates and Yeast Model Systems with Known Azole Resistance Mechanisms. AB - Isavuconazole is a novel, broad-spectrum, antifungal azole. In order to evaluate its interactions with known azole resistance mechanisms, isavuconazole susceptibility among different yeast models and clinical isolates expressing characterized azole resistance mechanisms was tested and compared to those of fluconazole, itraconazole, posaconazole, and voriconazole. Saccharomyces cerevisiae expressing the Candida albicans and C. glabrata ATP binding cassette (ABC) transporters (CDR1, CDR2, and CgCDR1), major facilitator (MDR1), and lanosterol 14-alpha-sterol-demethylase (ERG11) alleles with mutations were used. In addition, pairs of C. albicans and C. glabrata strains from matched clinical isolates with known azole resistance mechanisms were investigated. The expression of ABC transporters increased all azole MICs, suggesting that all azoles tested were substrates of ABC transporters. The expression of MDR1 did not increase posaconazole, itraconazole, and isavuconazole MICs. Relative increases of azole MICs (from 4- to 32-fold) were observed for fluconazole, voriconazole, and isavuconazole when at least two mutations were present in the same ERG11 allele. Upon MIC testing of azoles with clinical C. albicans and C. glabrata isolates with known resistance mechanisms, the MIC90s of C. albicans for fluconazole, voriconazole, itraconazole, posaconazole, and isavuconazole were 128, 2, 1, 0.5, and 2 MUg/ml, respectively, while in C. glabrata they were 128, 2, 4, 4, and 16 MUg/ml, respectively. In conclusion, the effects of azole resistance mechanisms on isavuconazole did not differ significantly from those of other azoles. Resistance mechanisms in yeasts involving ABC transporters and ERG11 decreased the activity of isavuconazole, while MDR1 had limited effect. PMID- 26482311 TI - Pharmacokinetic-Pharmacodynamic Model for the Effect of l-Arginine on Endothelial Function in Patients with Moderately Severe Falciparum Malaria. AB - Impaired organ perfusion in severe falciparum malaria arises from microvascular sequestration of parasitized cells and endothelial dysfunction. Endothelial dysfunction in malaria is secondary to impaired nitric oxide (NO) bioavailability, in part due to decreased plasma concentrations of l-arginine, the substrate for endothelial cell NO synthase. We quantified the time course of the effects of adjunctive l-arginine treatment on endothelial function in 73 patients with moderately severe falciparum malaria derived from previous studies. Three groups of 10 different patients received 3 g, 6 g, or 12 g of l-arginine as a half-hour infusion. The remaining 43 received saline placebo. A pharmacokinetic pharmacodynamic (PKPD) model was developed to describe the time course of changes in exhaled NO concentrations and reactive hyperemia-peripheral arterial tonometry (RH-PAT) index values describing endothelial function and then used to explore optimal dosing regimens for l-arginine. A PK model describing arginine concentrations in patients with moderately severe malaria was extended with two pharmacodynamic biomeasures, the intermediary biochemical step (NO production) and endothelial function (RH-PAT index). A linear model described the relationship between arginine concentrations and exhaled NO. NO concentrations were linearly related to RH-PAT index. Simulations of dosing schedules using this PKPD model predicted that the time within therapeutic range would increase with increasing arginine dose. However, simulations demonstrated that regimens of continuous infusion over longer periods would prolong the time within the therapeutic range even more. The optimal dosing regimen for l-arginine is likely to be administration schedule dependent. Further studies are necessary to characterize the effects of such continuous infusions of l-arginine on NO and microvascular reactivity in severe malaria. PMID- 26482312 TI - Case-Control Study of Telavancin as an Alternative Treatment for Gram-Positive Bloodstream Infections in Patients with Cancer. AB - Gram-positive bacterial infections are an important cause of morbidity and death among cancer patients, despite current therapy. In this case-control study, we evaluated the clinical outcomes and safety of telavancin in cancer patients with uncomplicated Gram-positive bloodstream infections (BSIs). Between March 2011 and May 2013, we enrolled cancer patients with uncomplicated Gram-positive BSIs to receive intravenous telavancin therapy for at least 14 days for Staphylococcus aureus and 7 days for other Gram-positive cocci. Patients with baseline creatinine clearance (CLCR) values of >50 ml/min received 10 mg/kg/day of telavancin, and those with CLCR values between 30 and 49 ml/min received 7.5 mg/kg/day. Patients were compared with a retrospective cohort of 39 historical patients with Gram-positive BSIs, matched for underlying malignancy, infecting organism, and neutropenia status, who had been treated with vancomycin. A total of 78 patients were analyzed, with 39 in each group. The most common pathogen causing BSIs was S. aureus (51%), followed by alpha-hemolytic streptococci (23%), Enterococcus spp. (15%), coagulase-negative staphylococci (8%), and beta hemolytic streptococci (3%). Sixty-two percent of patients had hematological malignancies, and 38% had solid tumors; 51% of the patients were neutropenic. The overall response rate determined by clinical outcome and microbiological eradication at 72 h following the initiation of therapy, in the absence of relapse, deep-seated infections, and/or infection-related death, was better with telavancin than with vancomycin (86% versus 61%; P = 0.013). Rates of drug related adverse events were similar in the two groups (telavancin, 31%; vancomycin, 23%; P = 0.79), with similar rates of renal adverse events. Telavancin may provide a useful alternative to standard vancomycin therapy for Gram-positive BSIs in cancer patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01321879.). PMID- 26482313 TI - Multidrug-Resistant Neisseria gonorrhoeae Isolates from Nanjing, China, Are Sensitive to Killing by a Novel DNA Gyrase Inhibitor, ETX0914 (AZD0914). AB - We tested the activity of ETX0914 against 187 Neisseria gonorrhoeae isolates from men with urethritis in Nanjing, China, in 2013. The MIC50, MIC90, and MIC range for ETX0914 were 0.03 MUg/ml, 0.06 MUg/ml, and <=0.002 to 0.125 MUg/ml, respectively. All isolates were resistant to ciprofloxacin, and 36.9% (69/187) were resistant to azithromycin. Of the isolates, 46.5% were penicillinase producing N. gonorrhoeae (PPNG), 36% were tetracycline-resistant N. gonorrhoeae (TRNG), and 13% (24 isolates) had an MIC of 0.125 MUg/ml for ceftriaxone. ETX0914 may be an effective treatment option for gonorrhea. PMID- 26482314 TI - The Soil Microbiota Harbors a Diversity of Carbapenem-Hydrolyzing beta-Lactamases of Potential Clinical Relevance. AB - The origin of carbapenem-hydrolyzing metallo-beta-lactamases (MBLs) acquired by clinical bacteria is largely unknown. We investigated the frequency, host range, diversity, and functionality of MBLs in the soil microbiota. Twenty-five soil samples of different types and geographical origins were analyzed by antimicrobial selective culture, followed by phenotypic testing and expression of MBL-encoding genes in Escherichia coli, and whole-genome sequencing of MBL producing strains was performed. Carbapenemase activity was detected in 29 bacterial isolates from 13 soil samples, leading to identification of seven new MBLs in presumptive Pedobacter roseus (PEDO-1), Pedobacter borealis (PEDO-2), Pedobacter kyungheensis (PEDO-3), Chryseobacterium piscium (CPS-1), Epilithonimonas tenax (ESP-1), Massilia oculi (MSI-1), and Sphingomonas sp. (SPG 1). Carbapenemase production was likely an intrinsic feature in Chryseobacterium and Epilithonimonas, as it occurred in reference strains of different species within these genera. The amino acid identity to MBLs described in clinical bacteria ranged between 40 and 69%. Remarkable features of the new MBLs included prophage integration of the encoding gene (PEDO-1), an unusual amino acid residue at a key position for MBL structure and catalysis (CPS-1), and overlap with a putative OXA beta-lactamase (MSI-1). Heterologous expression of PEDO-1, CPS-1, and ESP-1in E. coli significantly increased the MICs of ampicillin, ceftazidime, cefpodoxime, cefoxitin, and meropenem. Our study shows that MBL producers are widespread in soil and include four genera that were previously not known to produce MBLs. The MBLs produced by these bacteria are distantly related to MBLs identified in clinical samples but constitute resistance determinants of clinical relevance if acquired by pathogenic bacteria. PMID- 26482317 TI - Influence of Different Protocols of Urethral Catheterization after Pharmacological Induction (Ur.Ca.P.I.) on Semen Quality in the Domestic Cat. AB - The aim of this study was to evaluate the influence that different protocols of urethral catheterization after pharmacological induction (Ur.Ca.P.I.) may have on the semen quality of the domestic cat. The study has been divided into two experiments: one in which different dosages of medetomidine administrated are evaluated and the second one in which the timing of the catheterization after pharmacological induction is tested. In the first experiment, 18 cats were sedated with the recommended dosage of medetomidine (130 MUg/kg i.m.) while the other 18 were sedated with a lower dose of the same drug (50 MUg/kg i.m.). In the second experiment, three groups were implemented, each containing 25 subjects. In group 1, the semen collection was performed immediately once the pharmacological effect of the drug was reached; in group 2, the semen collection was performed three times every 5 min after the pharmacological effect was reached; finally, in group 3, Ur.Ca.P.I. was performed 20 min after the pharmacological effect was reached. All the different protocols permitted sperm collection, nevertheless the first experiment showed a better quality in terms of volume, concentration, total number of spermatozoa (p < 0.01) and quality of the movement (motility p < 0.05 and forward progressive motility p < 0.01), using a high medetomidine dosage rather than 50 MUg/kg i.m. In the second experiment, forward motility was statistically higher (p < 0.01) in the first group and total volume was higher (p < 0.01) in the second and third group, while other parameters were statistically not different. Results suggest that a single catheterization immediately after the onset of the pharmacological effect leads to a good-quality semen with the lowest possibility of damaging the urethra and that a sedation with 130 MUg/kg of medetomidine leads to a better quality sperm collection than 50 MUg/kg does. PMID- 26482315 TI - Risk Factors and Outcomes for Bloodstream Infections Secondary to Clostridium difficile Infection. AB - We determined the incidence, risk factors, and outcomes of bloodstream infections (BSI) subsequent to Clostridium difficile infection (CDI). We performed a retrospective study of all patients with definite diagnosis of CDI admitted from January 2014 to December 2014 in two large hospitals in Rome. Two groups of patients were analyzed: those with CDI and subsequent BSI (CDI/BSI(+)) and those with CDI and no evidence of primary BSI (CDI/BSI(-)). Data about clinical features, microbiology, treatments, and mortality were obtained. Overall, 393 cases of CDI were included in the final analysis: 72 developed a primary nosocomial BSI, while 321 had CDI without microbiological and clinical evidence of BSI. Etiologic agents of BSI were Candida species (47.3%), Enterobacteriaceae (19.4%), enterococci (13.9%), and mixed infections (19.4%). In multivariate analysis, ribotype 027 status (odds ratio [OR], 6.5), CDI recurrence (OR, 5.5), severe CDI infection (OR, 8.3), and oral vancomycin at >500 mg/day (OR, 3.1) were recognized as factors independently associated with the development of nosocomial BSI. Thirty-day mortality from CDI diagnosis was higher for patients of the CDI/BSI(+) group than for the controls (38.9 versus 13.1%; P < 0.001). Among patients of the CDI/BSI(+) group, mortality attributable to primary BSI was as high as 57%. Our findings suggest that severe CDI is complicated by the development of nosocomial BSI. Candida species and enteric bacteria appear to be the leading causative pathogens and are associated with poor outcomes. PMID- 26482318 TI - Shapes of topological RNA structures. AB - A topological RNA structure is derived by fattening the edges of a contact structure into ribbons. The shape of a topological RNA structure is obtained by collapsing the stacks of the structure into single arcs and by removing any arcs of length one, as well as isolated vertices. A shape contains the key topological information of the molecular conformation and for fixed topological genus there exist only finitely many such shapes. In this paper we compute the generating polynomial of shapes of fixed topological genus g. We furthermore derive an algorithm having O(glog g) time complexity uniformly generating shapes of genus g and discuss some applications in the context of databases of RNA pseudoknot structures. PMID- 26482319 TI - The enterovirus D68 epidemic. PMID- 26482321 TI - Genetic heterogeneity in rhabdomyosarcoma revealed by SNP array analysis. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Alveolar (ARMS) and embryonal (ERMS) histologies predominate, but rare cases are classified as spindle cell/sclerosing (SRMS). For treatment stratification, RMS is further subclassified as fusion-positive (FP-RMS) or fusion-negative (FN-RMS), depending on whether a gene fusion involving PAX3 or PAX7 is present or not. We investigated 19 cases of pediatric RMS using high resolution single-nucleotide polymorphism (SNP) array. FP-ARMS displayed, on average, more structural rearrangements than ERMS; the single FN-ARMS had a genomic profile similar to ERMS. Apart from previously known amplification (e.g., MYCN, CDK4, and MIR17HG) and deletion (e.g., NF1, CDKN2A, and CDKN2B) targets, amplification of ERBB2 and homozygous loss of ASCC3 or ODZ3 were seen. Combining SNP array with cytogenetic data revealed that most cases were polyploid, with at least one case having started as a near-haploid tumor. Further bioinformatic analysis of the SNP array data disclosed genetic heterogeneity, in the form of subclonal chromosomal imbalances, in five tumors. The outcome was worse for patients with FP-ARMS than ERMS or FN-ARMS (6/8 vs. 1/9 dead of disease), and the only children with ERMS showing intratumor diversity or with MYOD1 mutation positive SRMS also died of disease. High resolution SNP array can be useful in evaluating genomic imbalances in pediatric RMS. PMID- 26482320 TI - Severe respiratory illness associated with a nationwide outbreak of enterovirus D68 in the USA (2014): a descriptive epidemiological investigation. AB - BACKGROUND: Enterovirus D68 (EV-D68) has been infrequently reported historically, and is typically associated with isolated cases or small clusters of respiratory illness. Beginning in August, 2014, increases in severe respiratory illness associated with EV-D68 were reported across the USA. We aimed to describe the clinical, epidemiological, and laboratory features of this outbreak, and to better understand the role of EV-D68 in severe respiratory illness. METHODS: We collected regional syndromic surveillance data for epidemiological weeks 23 to 44, 2014, (June 1 to Nov 1, 2014) and hospital admissions data for epidemiological weeks 27 to 44, 2014, (June 29 to Nov 1, 2014) from three states: Missouri, Illinois and Colorado. Data were also collected for the same time period of 2013 and 2012. Respiratory specimens from severely ill patients nationwide, who were rhinovirus-positive or enterovirus-positive in hospital testing, were submitted between Aug 1, and Oct 31, 2014, and typed by molecular sequencing. We collected basic clinical and epidemiological characteristics of EV D68 cases with a standard data collection form submitted with each specimen. We compared patients requiring intensive care with those who did not, and patients requiring ventilator support with those who did not. Mantel-Haenszel chi(2) tests were used to test for statistical significance. FINDINGS: Regional and hospital level data from Missouri, Illinois, and Colorado showed increases in respiratory illness between August and September, 2014, compared with in 2013 and 2012. Nationwide, 699 (46%) of 1529 patients tested were confirmed as EV-D68. Among the 614 EV-D68-positive patients admitted to hospital, age ranged from 3 days to 92 years (median 5 years). Common symptoms included dyspnoea (n=513 [84%]), cough (n=500 [81%]), and wheezing (n=427 [70%]); 294 (48%) patients had fever. 338 [59%] of 574 were admitted to intensive care units, and 145 (28%) of 511 received ventilator support; 322 (52%) of 614 had a history of asthma or reactive airway disease; 200 (66%) of 304 patients with a history of asthma or reactive airway disease required intensive care compared with 138 (51%) of 270 with no history of asthma or reactive airway disease (p=0.0004). Similarly, 89 (32%) of 276 patients with a history of asthma or reactive airway disease required ventilator support compared with 56 (24%) of 235 patients with no history of asthma or reactive airway disease (p=0.039). INTERPRETATION: In 2014, EV-D68 caused widespread severe respiratory illness across the USA, disproportionately affecting those with asthma. This unexpected event underscores the need for robust surveillance of enterovirus types, enabling improved understanding of virus circulation and disease burden. FUNDING: None. PMID- 26482322 TI - Introduction of macarpine as a novel cell-permeant DNA dye for live cell imaging and flow cytometry sorting. AB - BACKGROUND INFORMATION: Macarpine (MA) is a quaternary benzophenanthridine plant alkaloid isolated from Macleaya microcarpa or Stylophorum lasiocarpum. Benzophenanthridine alkaloids are interesting natural products that display antiproliferative, antimicrobial, antifungal and anti-inflammatory activities, and also fluorescence properties. In a previous study, we demonstrated that thanks to its ability to interact with DNA and its spectral properties MA could be used as a supravital DNA probe for fluorescence microscopy and flow cytometry including analyses of the cell cycle. In this study, we evaluated the suitability of MA as a DNA dye for time-lapse microscopy and flow-cytometric cell sorting. RESULTS: Living A-375 and MEF cells stained with MA were monitored by time-lapse microscopy for 24 h. Mitoses were observed at MA concentrations up to 0.5 MUg/ml during the first 2-3 h. After this period of time, cells treated with MA at concentrations of 0.75 and 0.5 MUg/ml underwent apoptosis. Cells cultivated with MA at concentration of 0.25 MUg/ml or lower survived throughout the 24 h period. Toxicity of MA was dependent on light wavelength and frequency of image capturing. The intensity of MA fluorescence decreased during the incubation. MA concentration of 0.1 MUg/ml was identified as the most suitable for live cell imaging with respect to fluorescence intensity and toxicity. MA at the concentration 10 MUg/ml was used for sorting of enhanced green fluorescent protein (EGFP)-labelled neurons and fibroblasts yielding profiles similar to those obtained with DRAQ5. Contrary to DRAQ5, MA-stained cells survived in culture, and the sorted cells lost the MA signal suggesting reversible binding of the dye to the DNA. CONCLUSION: The results proved that MA may readily be used for chromosomes depicting and mitosis monitoring by time-lapse microscopy. In addition, MA has shown to be a suitable probe for sorting of EGFP-labelled cells, including neurons, that survived the labelling process. SIGNIFICANCE: In consideration of the results, we highly anticipate an onward use of MA in a broad range of applications based on live cell sorting and imaging, for example, cell synchronisation and monitoring of proliferation as an important experimental and/or diagnostic utility. PMID- 26482323 TI - Associations between statin use and non-Hodgkin lymphoma (NHL) risk and survival: a meta-analysis. AB - Evidence on the effect of statin use on non-Hodgkin lymphoma (NHL) is not clear. We conducted a systematic review and meta-analysis to examine the associations between statin use and NHL risk and survival. We searched multiple literature sources up to October 2014 and identified 10 studies on the risk of diagnosis with NHL and 9 studies on survival. Random effects model was used to calculate pooled odds ratio (PORs) for risk and pooled hazard ratio (PHR) for survival. Heterogeneity among studies was examined using the Tau-squared and the I-squared (I2 ) tests. Statin use was associated with reduced risk for total NHL (POR = 0.82, 95% CI 0.69-0.99). Among statin users, there was a lower incidence risk for marginal zone lymphoma (POR = 0.54, 95% CI 0.31-0.94), but this was not observed for other types of NHL. However, statin use did not affect overall survival (PHR = 1.02, 95% CI 0.99-1.06) or event-free survival (PHR = 0.99, 95% CI 0.87-1.12) in diffuse large B-cell lymphoma. There is suggestive epidemiological evidence that statins decrease the risk of NHL, but they do not influence survival in NHL patients. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26482324 TI - Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children. AB - BACKGROUND: Episodic viral wheeze (EVW) associated with viral respiratory tract infections is a common reason for pre-school children to utilise health care resources and for carers to take time away from employment. About a third of children experience a wheezing episode before the age of five years. EVW therefore represents a significant public health problem. Many pre-school children only wheeze in association with viral infections and in such cases EVW appears to be a separate entity from atopic asthma. Some trials have explored the effectiveness of leukotriene receptor antagonists (LTRAs) as regular (maintenance) or episodic (intermittent) treatment in this context. OBJECTIVES: To evaluate the evidence for the efficacy and safety of maintenance and intermittent LTRAs in the management of EVW in children aged one to six years. SEARCH METHODS: We searched the Cochrane Airways Group register of trials with pre-specified terms. We performed additional searches by consulting the authors of identified trials, online trial registries of manufacturers' web sites, and reference lists of identified primary papers and reviews. Search results are current to June 2015. SELECTION CRITERIA: We included randomised controlled trials with a parallel-group or cross-over (for intermittent LTRA only) design. Maintenance was considered as treatment for more than two months and intermittent as less than 14 days. EVW was defined as a history of at least one previous episode of wheezing in association with a viral respiratory tract infection in the absence of symptoms between episodes. As far as possible, relevant specific data were obtained from authors of studies that included children of a wider age group or phenotype. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion in the review and assessed risk of bias. The primary outcome was number of children with one or more viral-induced episodes requiring one or more treatments with rescue oral corticosteroids. We analysed combined continuous data outcomes with the mean difference and dichotomous data outcomes with an odds ratio (OR). MAIN RESULTS: We identified five studies eligible for inclusion in the review (one investigated maintenance treatment, three intermittent therapy and one had both maintenance and intermittent treatment arms) these included 3741 participants. Each study involved oral montelukast and was of good methodological quality, but differed in choice of outcome measures thus limiting our ability to aggregate data across studies. Only primary outcome and adverse event data are reported in this abstract.For maintenance treatment, specific data obtained from a single study, pertaining to children with only an EVW phenotype, showed no statistically significant group reduction in the number of episodes requiring rescue oral corticosteroids associated with daily montelukast versus placebo (OR 1.20, 95% CI 0.70 to 2.06, moderate quality evidence).For intermittent LTRA, pooled data showed no statistically significant reduction in the number of episodes requiring rescue oral steroids in children treated with LTRA versus placebo (OR 0.77, 95% CI 0.48 to 1.25, moderate quality evidence). Specific data for children with an EVW phenotype obtained from a single study of intermittent montelukast treatment showed a small, but statistically significant reduction in unscheduled medical attendances due to wheeze (RR 0.83, 95% CI 0.71 to 0.98).For maintenance compared to intermittent LTRA treatment no data relating to the primary outcome of the review were identified.There were no other significant group differences identified in other secondary efficacy outcomes for maintenance or intermittent LTRA treatment versus placebo, or maintenance versus intermittent LTRA treatment. We collected descriptive data on adverse events as reported by four of the five included studies, and rates were similar between treatment and placebo groups.Potential heterogeneity in the phenotype of participants within and across trials is a limitation of the evidence. AUTHORS' CONCLUSIONS: In pre-school children with EVW, there is no evidence of benefit associated with maintenance or intermittent LTRA treatment, compared to placebo, for reducing the number of children with one or more viral-induced episodes requiring rescue oral corticosteroids, and little evidence of significant clinical benefit for other secondary outcomes. Therefore until further data are available, LTRA should be used with caution in individual children. When used, we suggest a therapeutic trial is undertaken, during which efficacy should be carefully monitored. It is likely that children with an apparent EVW phenotype are not a homogeneous group and that subgroups may respond to LTRA treatment depending on the exact patho physiological mechanisms involved. PMID- 26482325 TI - Remove policies that restrict access to opioids in developing countries, says report. PMID- 26482326 TI - Influenza A H1N1 pdm09-associated myocarditis during zanamivir therapy. AB - A 9-year-old girl developed influenza A H1N1 pdm09-associated myocarditis and pericarditis 2 days after starting zanamivir therapy. The virus was detected in the respiratory tract but not in the serum or pericardial effusion. The virus sampled from the respiratory tract had normal susceptibility to neuraminidase inhibitors. Although no differences in interferon-gamma, interleukin (IL)-1beta, and tumor necrosis factor-alpha were observed between the plasma and pericardial effusion, some inflammatory cytokines or chemokines (IL-6 and IL-8) and vascular endothelial growth factor were remarkably elevated in the pericardial effusion compared with the plasma. This suggested that the influenza virus, after infecting the respiratory tract, affected the myocardium, causing myocarditis to gradually develop, which might have been followed by an autoreactive pericarditis causing increased pericardial effusion. Therefore, influenza-associated myocarditis should be considered when influenza patients have respiratory and cardiac involvement, even during treatment with a neuraminidase inhibitor. PMID- 26482327 TI - Erectile dysfunction and cardiovascular risk factors in a Mediterranean diet cohort. AB - BACKGROUND: Erectile dysfunction affects more than 100 million men worldwide, with a wide variability in prevalence. An overall association of cardiovascular risk factors, lifestyle and diet in the context of ED in a Mediterranean population is lacking. AIM: To assess ED prevalence and associated factors in a Mediterranean cohort of non-diabetic patients with cardiovascular risk factors. METHODS: Observational, cross-sectional study of patients aged over 40 treated at cardiovascular risk units in Catalonia. Anthropometric data, risk factors, lifestyle and diet habits were recorded. ED was assessed using the International Index of Erectile Function. RESULTS: Four hundred and forty patients included, 186 (42.3%) with ED (24.8% mild, 6.8% moderate and 10.7% severe). ED presence and severity were associated with age, obesity, waist circumference, hypertension, antihypertensive treatment and ischaemic disease. Patients with ED were more frequently smokers, sedentary and consumed more alcohol. In multivariate analysis, consumption of nuts (> twice a week) (OR 0.41 (95% CI 0.25 to 0.67) and vegetables (>= once a day) (OR 0.47 (95% CI 0.28-0,77)), were inversely related to ED. Obesity (as BMI >= 30 kg/m(2) ) (OR 2.49 (95% CI 1.48-4.17)), ischaemic disease (OR 2.30 (95% CI 1.22 to 4.33), alcohol consumption (alcohol-units a day) (OR 1.14 (95% CI 1.04 to 1.26), and age (year) (OR = 1.07 (95% CI 1.04-1.10) were directly related to ED. CONCLUSION: Erectile dysfunction is a common disorder in patients treated in lipid units in Catalonia for cardiovascular risk factors. This condition is associated with age, obesity, ischaemic disease and unhealthy lifestyle habits. PMID- 26482328 TI - Prevalence and determinants of HIV in tuberculosis patients in Wuxi City, Jiangsu province, China: a cross-sectional study. AB - At least one-third of the 34 million people living with human immunodeficiency virus (HIV) worldwide are infected with latent tuberculosis (TB). The aim of this study was to determine the rate of HIV infection in TB patients and its determinants in Wuxi City, China. TB patients attending health institutions (12 selected sites) for TB diagnosis and treatment were enrolled in this study. TB diagnosis, treatment and HIV testing were done according to the national guidelines. Blood samples were collected for anonymous HIV testing. Among the TB patients, the HIV prevalence was 13.66% (1493/10,926). Multivariate analysis showed that gender, age, education, marital status, per capita monthly income, patient residence, family size, distance from a health institution, knowledge of HIV-TB co-infection, and knowledge of HIV may be risk factors for HIV-TB co infection (all: odds ratio > 1, p < 0.05). The prevalence of TB in those with HIV was higher among the study participants. Improving public awareness of HIV-TB co infection, regularly screening and improving follow-up can reduce the occurrence of HIV-TB co-infection. PMID- 26482329 TI - Hydrothermal Formation of Calcium Copper Tetrasilicate. AB - We describe the first hydrothermal synthesis of CaCuSi4 O10 as micron-scale clusters of thin platelets, distinct from morphologies generated under salt-flux or solid-state conditions. The hydrothermal reaction conditions are surprisingly specific: too cold, and instead of CaCuSi4 O10 , a porous calcium copper silicate forms; too hot, and calcium silicate (CaSiO3 ) forms. The precursors also strongly impact the course of the reaction, with the most common side product being sodium copper silicate (Na2 CuSi4 O10 ). Optimized conditions for hydrothermal CaCuSi4 O10 formation from calcium chloride, copper(II) nitrate, sodium silicate, and ammonium hydroxide are 350 degrees C at 3000 psi for 72 h; at longer reaction times, competitive delamination and exfoliation causes crystal fragmentation. These results illustrate that CaCuSi4 O10 is an even more unique material than previously appreciated. PMID- 26482330 TI - Transcrestal Sinus Lift Using Platelet Concentrates in Association to Short Implant Placement: A Retrospective Study of Augmented Bone Height Remodeling. AB - BACKGROUND: No evidence has been reported yet about dimensional changes in maxillary sinuses grafted with autologous platelet concentrate. PURPOSE: This study aimed to analyze the augmented height alterations around short implants (length <= 8.5 mm) placed after transcrestal sinus lift surgery in association with plasma rich in growth factors. MATERIALS AND METHODS: A retrospective design was used. Patients with atrophic posterior maxilla were treated by inserting short implants in combination with transalveolar maxillary sinus floor augmentation. Radiographic bone level alterations over time were assessed on panoramic radiographs. RESULTS: Transalveolar sinus augmentation was performed to place 41 implants in 26 patients with a residual bone height of 4.7 +/- 1.3 mm. The alveolar bone height was increased by 3.7 +/- 1.7 mm and 4.2 +/- 2.0 mm after 12 +/- 3 months and 35 +/- 11 months of surgery, respectively, whereas the apical augmented height (beyond the implant) apex was stable around 34 implants during the follow-up. It was increasing around seven implants that were not covered by the endo-sinus augmented height at the 1-year follow-up. CONCLUSIONS: Transalveolar sinus floor augmentation in association with plasma rich in growth factors and short implants resulted in a stable augmented height gain after 3 years follow-up. Atrophic posterior maxilla could be treated by transalveolar sinus lift in association with plasma rich in growth factors and the placement of short implants. PMID- 26482331 TI - Base-Free Aqueous-Phase Oxidation of 5-Hydroxymethylfurfural over Ruthenium Catalysts Supported on Covalent Triazine Frameworks. AB - The base-free aqueous-phase oxidation of 5-hydroxymethylfurfural (HMF) to 2,5 furandicarboxilic acid (FDCA) was performed at 140 degrees C and 20 bar of synthetic air as the oxidant. Ru clusters supported on covalent triazine frameworks (CTFs) enabled superior conversion (99.9%) and FDCA yields in comparison to other support materials such as activated carbon and gamma-Al2O3 after only 1 h. The properties of the CTFs such as pore volume, specific surface area, and polarity could be tuned by using different monomers. These material properties influence the catalytic activity of Ru/CTF significantly as mesoporous CTFs showed superior activity compared to microporous materials, whereas high polarities provide further beneficial effects. The recyclability of the prepared Ru/CTF catalysts was comparable to that of Ru/C at high conversions and product yields. Nevertheless, minor deactivation in five successive recycling experiments was observed. PMID- 26482332 TI - Post-traumatic stress avoidance is attenuated by corticosterone and associated with brain levels of steroid receptor co-activator-1 in rats. AB - Individuals with post-traumatic stress disorder (PTSD) avoid trauma-related stimuli and exhibit blunted hypothalamic-pituitary-adrenal (HPA) axis activation at the time of stress. Our rodent model of stress mimics the avoidance symptom cluster of PTSD. Rats are classified as "Avoiders" or "Non-Avoiders" post-stress based on the avoidance of a predator-odor paired context. Previously, we found Avoiders exhibit an attenuated HPA stress response to predator odor. We hypothesized that corticosterone administration before stress would reduce the magnitude and incidence of stress-paired context avoidance. Furthermore, we also predicted that Avoiders would exhibit altered expression of glucocorticoid receptor (GR) signaling machinery elements, including steroid receptor co activator (SRC)-1. Male Wistar rats (n = 16) were pretreated with corticosterone (25 mg/kg) or saline and exposed to predator-odor stress paired with a context and tested for avoidance 24 h later. A second group of corticosterone-naive rats (n = 24) were stressed (or not), indexed for avoidance 24 h later, and killed 48 h post-odor exposure to measure phosphorylated GR, FKBP51 and SRC-1 levels in the paraventricular nucleus (PVN), central amygdala (CeA) and ventral hippocampus (VH), all brain sites that highly express GRs and regulate HPA function. Corticosterone pretreatment reduced the magnitude and incidence of avoidance. In Avoiders, predator-odor exposure led to lower SRC-1 expression in the PVN and CeA, and higher SRC-1 expression in the VH. SRC-1 expression in PVN, CeA and VH was predicted by prior avoidance behavior. Hence, a blunted HPA stress response may contribute to stress-induced neuroadaptations in central SRC-1 levels and behavioral dysfunction in Avoider rats. PMID- 26482333 TI - Financial costs for families of children with Type 1 diabetes in lower-income countries. AB - AIMS: To assess the direct costs of necessary consumables for minimal care of a child with Type 1 diabetes in countries where the public health system does not regularly provide such care. METHODS: Supply costs were collected between January 2013 and February 2015 from questionnaires submitted by centres requesting International Diabetes Federation Life for a Child Program support. All 20 centres in 15 countries agreed to the use of their responses. Annual costs for minimal care were estimated for: 18 * 10 ml 100 IU/ml insulin, 1/3 cost of a blood glucose meter, two blood glucose test strips/day, two syringes/week, and four HbA1c tests/year. Costs were expressed in US dollars, and as % of gross national income (purchasing power parity) per capita. RESULTS: The ranges (median) for the minimum supply costs through the private system were: insulin 10 ml 100 IU/ml equivalent vial: $5.10-$25 ($8.00); blood glucose meter: $15-$121 ($33.33); test strip: $0.15-$1.20 ($0.50); syringe: $0.10-$0.56 ($0.20); and HbA1c : $4.90-$20 ($9.75). Annual costs ranged from $255 (Pakistan) to $1,185 (Burkina Faso), with a median of $553. Annual % gross national income costs were 12-370% (median 56%). For the lowest 20% income earners the annual cost ranged 20 1535% (median 153%). St Lucia and Mongolia were the only countries whose governments consistently provided insulin. No government provided meters and strips, which were the most expensive supplies (62% of total cost). CONCLUSIONS: In less-resourced countries, even minimal care is beyond many families' means. In addition, families face additional costs such as consultations, travel and indirect costs. Action to prevent diabetes-related death and morbidity is needed. PMID- 26482334 TI - Effects of Lowering Dialysate Calcium Concentration on Mineral and Bone Disorders in Chronic Hemodialysis Patients: Conversion from 3.0 mEq/L to 2.75 mEq/L. AB - Selection of a lower dialysate calcium concentration (DCa) can reduce calcium burden and prevent vascular calcification in hemodialysis patients. However, decreased DCa can worsen mineral and bone disorders. This 1-year retrospective observational study evaluated 121 hemodialysis patients at Fukuoka Renal Clinic who underwent conversion of DCa from 3.0 mEq/L to 2.75 mEq/L. The primary outcomes were changes in serum levels of calcium, phosphate, and parathyroid hormone (PTH). The effects of baseline serum calcium and PTH levels on changes in biochemical parameters were also determined. One year after DCa conversion, mean serum calcium level decreased, while serum phosphate, alkaline phosphatase, and PTH concentrations increased. The rate of achievement of target PTH was higher in patients with lower serum PTH level at baseline, while patients with higher baseline serum PTH level tended to exceed the upper limit of the PTH target range. Patients with higher baseline serum calcium concentration showed a greater decrease in serum calcium level and a greater increase in serum PTH level at 1 year. Patients with a lower baseline serum PTH level can benefit from optimal PTH control following conversion of DCa from 3.0 mEq/L to 2.75 mEq/L. However, secondary hyperparathyroidism may be exacerbated in some patients with higher baseline serum calcium (Ca) and PTH levels. These results indicate that an individualized approach can maximize the benefits of Ca unloading after conversion to lower DCa. PMID- 26482335 TI - Nanoflow LC-MS for High-Performance Chemical Isotope Labeling Quantitative Metabolomics. AB - Nanoflow liquid chromatography mass spectrometry (nLC-MS) is frequently used in the proteomics field to analyze a small amount of protein and peptide samples. However, this technique is currently not widespread in the metabolomics field. We report a detailed investigation on the development of an nLC-MS system equipped with a trap column for high-performance chemical isotope labeling (CIL) metabolomic profiling with deep coverage and high sensitivity. Experimental conditions were optimized for profiling the amine/phenol submetabolome with (13)C /(12)C-dansylation labeling. Comparison of analytical results from nLC-MS and microbore LC-MS (mLC-MS) was made in the analysis of metabolite standards and labeled human urine and sweat samples. It is shown that, with a 5-MUL loop injection, 7 labeled amino acid standards could be detected with S/N ranging from 7 to 150 by nLC-MS with an injection of 5 nM solution containing a total of 25 fmol labeled analyte. For urine metabolome profiling where the sample amount was not limited, nLC-MS detected 13% more metabolites than mLC-MS under optimal conditions (i.e., 4524 +/- 37 peak pairs from 26 nmol injection in triplicate vs 4019 +/- 40 peak pairs from 52 nmol injection). This gain was attributed to the increased dynamic range of peak detection in nLC-MS. In the analysis of human sweat where the sample amount could be limited, nLC-MS offered the advantage of providing much higher coverage than mLC-MS. Injecting 5 nmol of dansylated sweat, 3908 +/- 62 peak pairs or metabolites were detected by nLC-MS, while only 1064 +/ 6 peak pairs were detected by mLC-MS. Because dansyl labeled metabolites can be captured on a reversed phase (RP) trap column for large volume injection and are well separated by RPLC, the CIL platform can be readily implemented in existing nLC-MS instruments such as those widely used in shotgun proteomics. PMID- 26482336 TI - Skin sensitizer identification by IL-8 secretion and CD86 expression on THP-1 cells. AB - Substantial progress has been made in the development of alternative methods for skin sensitization in the last decade in several countries around the world. Brazil is experiencing an increasing concern about using animals for product development, since the publication of the Law 9605/1998, which prohibits the use of animals when an alternative method is available. In this way, an in vitro test to evaluate allergenic potential is a pressing need.This preliminary study started setting the use of myelomonocytic THP-1 cell line, according to the human cell line activation test (h-CLAT), already under validation process. We found that 48-h chemical exposure was necessary to identify 22 out of 23 sensitizers by the analyses of CD86 expression. In addition, the CD54 expression analyses presented a poor efficiency to discriminate sensitizers from non-sensitizers in our conditions. In view of these results, we looked for changes of pro inflammatory interleukin profile. The IL-8 secretion analyses after 24-h chemical incubation seemed to be an alternative for CD54 expression assessing.Altogether, our findings showed that the combination of the analyses of CD86 expression and IL-8 secretion allowed predicting allergenicity. PMID- 26482337 TI - Structural analysis of hierarchically organized zeolites. AB - Advances in materials synthesis bring about many opportunities for technological applications, but are often accompanied by unprecedented complexity. This is clearly illustrated by the case of hierarchically organized zeolite catalysts, a class of crystalline microporous solids that has been revolutionized by the engineering of multilevel pore architectures, which combine unique chemical functionality with efficient molecular transport. Three key attributes, the crystal, the pore and the active site structure, can be expected to dominate the design process. This review examines the adequacy of the palette of techniques applied to characterize these distinguishing features and their catalytic impact. PMID- 26482338 TI - Lipid Fraction and Intracellular Metabolite Analysis Reveal the Mechanism of Arachidonic Acid-Rich Oil Accumulation in the Aging Process of Mortierella alpina. AB - The mechanism of arachidonic acid (ARA) content increase during aging of Mortierella alpina was elucidated. Lipid fraction analysis showed that ARA content increased from 46.9% to 66.4% in the triacylglycerol (TAG) molecule, and ARA residue occupation increased in the majority of TAG molecules during the aging process. For the first time, intracellular metabolite analysis was conducted to reveal the pathways closely associated with ARA biosynthesis during aging. The main reason for the increased ARA content was not only at the expense of other fatty acids degradation but also at the expense of further ARA biosynthesis during aging. Furthermore, translocation played a vital role in ARA redistribution among the glycerol moiety, and mycelium did not die immediately with key pathways activated to maintain a relatively stable intracellular environment. This study lays a foundation for further improvement of ARA content in the oil product obtained from M. alpina. PMID- 26482339 TI - Oral delivery of a platinum anticancer drug using lipid assisted polymeric nanoparticles. AB - Self-assembled cholesterol-asplatin-incorporated nanoparticles (SCANs) were prepared for oral delivery of a Pt(IV) prodrug. SCANs exhibit high gastrointestinal stability, sustained drug release and enhanced cell uptake. The oral bioavailability of SCANs was 4.32-fold higher than that of free Pt(IV) prodrugs. The oral administration of SCANs efficaciously inhibits tumor growth with negligible toxicity. PMID- 26482340 TI - Global and Local Conformation of Human IgG Antibody Variants Rationalizes Loss of Thermodynamic Stability. AB - Immunoglobulin G (IgG) monoclonal antibodies (mAbs) are a major class of medicines, with high specificity and affinity towards targets spanning many disease areas. The antibody Fc (fragment crystallizable) region is a vital component of existing antibody therapeutics, as well as many next generation biologic medicines. Thermodynamic stability is a critical property for the development of stable and effective therapeutic proteins. Herein, a combination of ion-mobility mass spectrometry (IM-MS) and hydrogen/deuterium exchange mass spectrometry (HDX-MS) approaches have been used to inform on the global and local conformation and dynamics of engineered IgG Fc variants with reduced thermodynamic stability. The changes in conformation and dynamics have been correlated with their thermodynamic stability to better understand the destabilising effect of functional IgG Fc mutations and to inform engineering of future therapeutic proteins. PMID- 26482342 TI - Keratin debris-filled ruptured salivary duct cyst. PMID- 26482341 TI - Anti-cytokine autoantibodies in postherpetic neuralgia. AB - BACKGROUND: The mechanisms by which varicella zoster virus (VZV) reactivation causes postherpetic neuralgia (PHN), a debilitating chronic pain condition, have not been fully elucidated. Based on previous studies identifying a causative role for anti-cytokine autoantibodies in patients with opportunistic infections, we explored this possibility in PHN. METHODS: Sera from herpes zoster (HZ) patients without and with PHN (N = 115 and 83, respectively) were examined for the presence of autoantibodies against multiple cytokines, and other known autoantigens. In addition, a cohort of patients with complex regional pain syndrome or neuropathic pain was tested for autoantibodies against selected cytokines. Antibody levels against VZV, Epstein Barr virus, and herpes simplex virus-2 were also measured in the HZ and PHN patients. Patient sera with high levels of anti-cytokine autoantibodies were functionally tested for in vitro neutralizing activity. RESULTS: Six PHN subjects demonstrated markedly elevated levels of single, autoantibodies against interferon-alpha, interferon-gamma, GM CSF, or interleukin-6. In contrast, the HZ and the pain control group showed low or no autoantibodies, respectively, against these four cytokines. Further analysis revealed that one PHN patient with high levels of anti-interleukin-6 autoantibodies had a markedly depressed antibody level to VZV, potentially reflecting poor T cell immunity against VZV. In vitro functional testing revealed that three of the five anti-cytokine autoantibody positive PHN subjects had neutralizing autoantibodies against interferon-alpha, GM-CSF or interleukin-6. In contrast, none of the HZ patients without PHN had neutralizing autoantibodies. CONCLUSIONS: These results suggest the possibility that sporadic anti-cytokine autoantibodies in some subjects may cause an autoimmune immunodeficiency syndrome leading to uncontrolled VZV reactivation, nerve damage and subsequent PHN. PMID- 26482343 TI - Heterogeneous vesicles: an analytical approach to equilibrium shapes. AB - We develop an analytical model to predict equilibrium shapes of two-component heterogeneous vesicles or capsules. Using a free energy functional including the bending energies of the two components and line tension contributions, the model describes shape transitions between spherical and polyhedral (faceted) states, complementing and extending results of previous numerical simulations. In the parameter space of relative area fraction, bending modulus ratio, and line tension, a region of polyhedral shapes occurs for weak line tension and large bending modulus ratio and is very robust towards changes in the modeling assumptions. At large enough line tension, the spherical shape fragments into two components. Within the polyhedral region, we compare the energies of all regular and semiregular polyhedra, as well as those of arbitrary prismatic shapes. We find that the largest bending modulus contrasts together with larger line tension favor polyhedra with small face number as optimal shapes. In this region, we also demonstrate the counter-intuitive result that the most symmetric polyhedra are not energetically optimal, with specific Archimedean solids and specific prismatic shapes beating more isotropic (e.g. Platonic) polyhedra. Furthermore, all polyhedra of lowest energy are found to be three-fold coordinated. The shape transition boundary for polyhedra can be computed analytically. The model can be utilized to predict heterogeneous vesicle shapes and to estimate physical properties of the components constituting observed vesicles. PMID- 26482344 TI - Client Experiences With Dietary, Exercise, and Behavioral Services in a Community Based Weight Management Program. AB - Compared with randomized trials, community-based interventions are delivered by a wider variety of professionals with varied training backgrounds. When evidence based programs are scaled into larger formats and disseminated to a wider audience, little is understood about how clients experience these interventions. To understand the experience of clients after meetings with nutrition, exercise, and health behavior professionals, researchers surveyed participants after 6 months in a weight management program. A total of 958 participants were recruited in monthly cohorts beginning September 2011 to complete a program evaluation survey. Qualitative inductive analysis was completed on several open-text items querying respondents as to what they found helpful from meetings with a registered dietitian, personal trainer, and health behavior counselor. Results indicate participants benefitted from gaining knowledge, learning new behavioral skills, or from interpersonal interactions. Findings suggest that the various professional services are valued by clients and that professionals appear to stay within their scope of practice. Implications for those working in weight management are discussed. PMID- 26482345 TI - Pentraxins and Collectins: Friend or Foe during Pathogen Invasion? AB - Innate immunity serves as the frontline defence against invading pathogens. Despite decades of research, new insights are constantly challenging our understanding of host-elicited immunity during microbial infections. Recently, two families of humoral innate immune proteins, pentraxins and collectins, have become a major focus of research in the field of innate immunity. Pentraxins and collectins are key players in activating the humoral arm of innate immunity, taking centre stage in immunoregulation and disease modulation. However, increasing evidence suggests that pentraxins and collectins can also mediate pathogenic effects during some infections. Herein, we discuss the protective and pathogenic effects of pentraxins and collectins, as well as their therapeutic significance. PMID- 26482346 TI - Effects of home call on obstetrics and gynecology resident sleep patterns. PMID- 26482347 TI - Impact of esophagectomy for cancer on patients' occupational status. AB - BACKGROUND: The aim of our study was to investigate the impact of esophagectomy for cancer on patients' occupational status. METHODS: All 109 consecutive patients presenting with esophageal cancer to the Surgical Oncology Unit of the Veneto Institute of Oncology Padua (Italy) between November 1, 2009 and March 15, 2012, were included in the study. Information on occupational status at diagnosis and at 1 year after esophagectomy was retrieved. Health-related quality of life was evaluated at discharge after surgery using selected aspects of the EORTC QLQ C30 questionnaire. Non parametric statistics were used. RESULTS: Sixty-one patients (49.6%) were active workers at diagnosis and 50 of them (82.0%) underwent esophagectomy. Eighteen active workers (18/50, 36.0%) quit their job within one year from esophagectomy. They received jejunostomy more often than patients still working after surgery (50.0% vs. 18.8%, respectively; p = 0.03) and reported lower social functioning at discharge (mean +/- SD 63.6 +/- 16.4 vs. 80.2 +/- 25.6 in others, p = 0.02). Multivariable analysis identified jejunostomy as independent predictor of job-quitting at 1 year after esophagectomy (p = 0.03; OR 4.75, 95% C.I. 1.11-20.39) but not social functioning at discharge (p = 0.21). CONCLUSIONS: Patients should be informed that they may experience social and work disability due to cancer treatment and adequate interventions of return-to-work support should be provided. Adequate welfare strategy should be implemented for esophageal cancer survivors, enhancing their role competences and contributing to precision care medicine. PMID- 26482349 TI - The Early Functional Abilities (EFA) scale to assess neurological and neurosurgical early rehabilitation patients. AB - BACKGROUND: It is difficult to assess neurological and neurosurgical early rehabilitation patients comprehensively. Available scales focus on activities of daily living (Barthel (BI) and Early Rehabilitation Barthel Index (ERBI)) or wakefulness (Glasgow Coma Scale (GCS), Coma Remission Scale (CRS)) while cognitive items are missing. METHODS: The Early Functional Abilities (EFA) scale comprises 20 items referring to activities of daily living (ADL), wakefulness and cognitive abilities. To evaluate its validity, n = 623 early neurological and neurosurgical rehabilitation patients (most of them after ischemic stroke or cerebral bleeding) were assessed on admission using the EFA, ERBI, GCS, CRS and measures of morbidity (co-diagnoses). RESULTS: The more co-diagnoses the lower EFA sum scores were obtained (Spearman-Rho rs = -0.509, p < 0.001). EFA predicted length of stay (LOS, rs = -0.565, p < 0.001) and BI at discharge (rs = 0.571, p < 0.001). CONCLUSIONS: The results suggest that EFA is a valid instrument to assess critically ill neurological and neurosurgical early rehabilitation patients. It may be used as a measure of morbidity and a predictor of LOS and outcome. Further studies are strongly encouraged. PMID- 26482348 TI - French current management and oncological results of locally recurrent rectal cancer. AB - BACKGROUND: There is a significant worldwide variation in practice regarding the criteria for operative intervention and overall management in patients with locally recurrent rectal cancer (LRRC). A survival benefit has been described for patients with clear resection margins in patients undergoing surgery for LRRC which is seen as an important surgical quality indicator. METHODS: A prospective French national database was established in 2008 which recorded procedures undertaken for locally recurrent rectal cancer (LRRC). Overall and Disease-Free Survival (OS, DFS) were assessed retrospectively. We report the variability and the heterogeneity of LRRC management in France as well as 5-year oncological outcomes. RESULTS: In this national report, 104 questionnaires were completed at 29 French surgical centres with a high variability of cases-loaded. Patients had preoperative treatment in 86% of cases. Surgical procedures included APER (36%), LAR (25%), Hartmann's procedure (21%) and pelvic exenterations (15.5%). Four patients had a low sacrectomy (S4/S5). There were no postoperative deaths and overall morbidity was 41%. R0 was achieved in 60%, R1 and R2 in 29% and 11%, respectively. R0 resection resulted in a 5-year OS of 35% compared to 12% and 0% for respectively R1 and R2 (OR = 2.04; 95% CI: 1.4-2.98; p < 0.001). OS was similar between R2 and non-resected patients (OR = 1.47; 95% CI: 0.58-3.76; p = 0.418). CONCLUSIONS: Our data is in accordance with the literature except the rate of extended resection procedures. This underlines the selective character of operative indications for LRRC in France as well as the care variability and the absence of optimal clinical pathway regarding these patients. PMID- 26482350 TI - The Role of Medical Air Rescue Services in Medical Transport of Organ Recipients in Poland: Organizational Solutions Supporting Transplantation Medicine. AB - BACKGROUND: The aim of this study was to analyze the use of fixed-wing air ambulance (FWAA) services in Poland during the period 2012-2013, with particular emphasis on air transport of organ recipients to transplantation centers. MATERIAL AND METHODS: This was a retrospective, cross-sectional analysis of data derived from standard FWAA medical documentation. RESULTS: In the years 2012-2013 there were 500 emergency (52.7%) and 447 elective (47.3%) missions. Children who were 1-10 years old comprised the single largest group in both emergency (EM) and elective (EL) missions, accounting for 17% of all flights. EM transports carried mainly patients aged 49-59 (18.5%), and 35.1% of all EM transports concerned patients with end-stage renal disease qualified as organ recipients who were transported to transplantation centers. With a total of 2278 kidney transplantations performed in Poland within the period analyzed, up to 7.8% recipients were transported by air medical services. For EL flights, the most numerous group were patients aged 1-10 (25.4%) and this group comprised mainly patients with congenital disorders (17.9%) and cardiovascular diseases (15.8%). The average flight duration was similar for both EM and EL groups (41.7+/-10.5 min vs. 40.4+/-8.7 min, respectively) (p=NS), as was the average distance covered (321.8+/-99.4 km vs. 310.5+/-87.4 km, respectively) (p=NS). In the case of patients with end-stage renal disease, the average distance and flight time were significantly longer than those for all other groups in total: 382.5+/-96.4 km vs. 302.6+/-87.3 km (p<0.001) and 74.9+/-10.2 min vs. 39.7+/-8.8 min (p<0.001), respectively. CONCLUSIONS: The most frequent clinical indication for FWAA transport was end-stage renal disease and most of those flights were carried out as EM. The FWAA service plays a vital role in the organization of pre transplantation transport to referral centers in Poland. This analysis supports the data for evaluation and potential changes in the Polish distribution and allocation rules for kidney transplantation. PMID- 26482352 TI - Anemia, diet and therapeutic iron among children living with HIV: a prospective cohort study. AB - BACKGROUND: Children living with HIV have higher-than-normal prevalence of anemia. The beneficial effect of therapeutic iron has been questioned in the setting of high prevalence of infections. This study examines anemia prevalence and effect of standard therapeutic iron on HIV disease progression among children. METHODS: Perinatally-infected children aged 2-12 years were enrolled at three sites in southern India, and were followed for 1 year with clinical assessments, dietary recall and anthropometry. Laboratory parameters included iron markers (ferritin, soluble transferrin receptor) and other micronutrient levels (vitamin A, B12, folate). Iron was given to anemic children based on WHO guidelines. Statistical analyses including frequency distributions, chi square tests and multivariate logistic regression were performed using Stata v13.0. RESULTS: Among 240 children enrolled (mean age 7.7 years, 54.6% males), median CD4 was 25%, 19.2% had advanced disease, 45.5% had malnutrition, and 43.3% were on antiretroviral treatment (ART) at baseline. Anemia was prevalent in 47.1% (113/240) children. Iron deficiency was present in 65.5%; vitamin A and vitamin B12 deficiency in 26.6% and 8.0% respectively; and anemia of inflammation in 58.4%. Independent risk factors for anemia were stunting, CD4 < 25%, detectable viral load >= 400 copies/ml and vitamin A deficiency. Inadequate dietary iron was prominent; 77.9% obtained less than two-thirds of recommended daily iron. Among clinically anemic children who took iron, overall adherence to iron therapy was good, and only minor self-limiting adverse events were reported. Median hemoglobin rose from 10.4 g/dl to 10.9 mg/dl among those who took iron for 3 months, and peaked at 11.3 mg/dl with iron taken for up to 6 months. Iron was also associated with a greater fall in clinical severity of HIV stage; however when adjusted for use of ART, was not associated with improvement in growth, inflammatory and CD4 parameters. CONCLUSIONS: Children living with HIV in India have a high prevalence of anemia mediated by iron deficiency, vitamin A deficiency and chronic inflammation. The use of therapeutic iron for durations up to 6 months appears to be safe in this setting, and is associated with beneficial effects on anemia, iron deficiency and HIV disease progression. PMID- 26482354 TI - Chronic rhinofacial basidiobolomycosis caused by Basidiobolus ranarum: Report of a case from Aseer Region, Kingdom of Saudi Arabia. AB - We present a case of fungal sinusitis caused by Basidiobolus ranarum in a 22-year old male patient with chronic rhinosinusitis in Aseer region, Kingdom of Saudi Arabia. The patient was admitted with nasal obstruction accompanied by itching, sneezing, rhinorrhea, epistaxis and recurrent headache. Axial computed tomography (CT) scan of the paranasal sinuses showed a clear left facial swelling chronic inflammation and granulomata. Basidiobolus ranarum fungus was isolated on Sabouraud dextrose agar from a biopsy specimen. The organism was characterized by flat, yellowish-grey, glabrous, becoming radially folded fungus that under the microscope showed broad vegetative hyaline hyphae that bear zygospores with protuberances. The patient made good recovery and was discharged home with no recurrences after receiving oral itraconazole and removal of the polyps surgically. PMID- 26482353 TI - Cyclosporin A induced toxicity in mouse liver slices is only slightly aggravated by Fxr-deficiency and co-occurs with upregulation of pro-inflammatory genes and downregulation of genes involved in mitochondrial functions. AB - BACKGROUND: The transcription factor farnesoid X receptor (FXR) governs bile acid and energy homeostasis, is involved in inflammation, and has protective functions in the liver. In the present study we investigated the effect of Fxr deficiency in mouse precision cut liver slices (PCLS) exposed to a model hepatotoxicant cyclosporin A (CsA). It was anticipated that Fxr deficiency could aggravate toxicity of CsA in PCLS and pinpoint to novel genes/processes regulated by FXR. METHODS: To test this hypothesis, PCLS obtained from livers of wild type mice (WT PCLS) and Fxr-knockout mice (FXRKO-PCLS) were treated with 40 MUM CsA for 24 h and 48 h. ATP and histological assays were applied to assess the viability of PCLS. DNA microarrays combined with bioinformatics analysis were used to identify genes and processes that were affected by CsA in WT-PCLS and/or FXRKO-PCLS. In addition, WT-PCLS and FXRKO-PCLS were exposed to the endogenous FXR ligand chenodeoxycholic acid (CDCA) and subjected to q-PCR to determine whether subsets of known FXR-targets and the identified genes were regulated upon FXR activation in an FXR-dependent manner. RESULTS: No difference in viability was observed between WT-PCLS and FXRKO-PCLS upon CsA treatment. Transcriptomics data analysis revealed that CsA significantly upregulated stress-response and inflammation and significantly downregulated processes involved in lipid and glucose metabolism in WT-PCLS and FXRKO-PCLS. However, only in FXRKO-PCLS, CsA upregulated additional pro-inflammatory genes and downregulated genes related to mitochondrial functions. Furthermore, only in WT-PCLS, CDCA upregulated a subset of known FXR target genes as well as the regulator of inflammation and mitochondrial functions peroxisome proliferator- activated receptor delta (Ppar delta). CONCLUSIONS: Although FXR governs energy metabolism, no major differences in response to CsA could be observed between WT-PCLS and FXRKO-PCLS in regulation of processes involved in lipid and glucose metabolism. This finding indicates that CsA does not directly affect FXR functions in relation to the above mentioned processes. However, the more pronounced induction of pro-inflammatory genes and the downregulation of genes involved in mitochondrial functions only in FXRKO-PCLS suggest that FXR deficiency aggravates CsA-induced inflammation and impairs mitochondrial functions. Therefore, FXR can exert its hepatoprotective functions by controlling inflammation and mitochondrial functions, possibly involving an FXR-PPAR delta cross-talk. PMID- 26482351 TI - The importance of multiparasitism: examining the consequences of co-infections for human and animal health. AB - Most parasites co-occur with other parasites, although the importance of such multiparasitism has only recently been recognised. Co-infections may result when hosts are independently infected by different parasites at the same time or when interactions among parasite species facilitate co-occurrence. Such interactions can have important repercussions on human or animal health because they can alter host susceptibility, infection duration, transmission risks, and clinical symptoms. These interactions may be synergistic or antagonistic and thus produce diverse effects in infected humans and animals. Interactions among parasites strongly influence parasite dynamics and therefore play a major role in structuring parasite populations (both within and among hosts) as well as host populations. However, several methodological challenges remain when it comes to detecting parasite interactions. The goal of this review is to summarise current knowledge on the causes and consequences of multiparasitism and to discuss the different methods and tools that researchers have developed to study the factors that lead to multiparasitism. It also identifies new research directions to pursue. PMID- 26482355 TI - Transnational issue-specific expert networking: A pathway to local policy change. AB - This article reports on key findings from a study of subnational governments in Mexico and Nigeria (O'Brien, 2013). With empirical richness of the case study method and small-n statistical analysis across the subnational units for each country, this study asks: How can we push the needle toward more progressive policy change on violence against women in developing and democratizing contexts? This study finds that issue-specific expert networking is a civic pathway to subnational policy responsiveness in Mexico and Nigeria. The dynamics of this pathway illuminate local-global political connections, and this study shows how issue-specific expert networking is important for the diffusion of an international norm and policies on violence against women. PMID- 26482356 TI - Reply to Coburn's income inequality, welfare, class and health. PMID- 26482357 TI - Preventing gender-based violence engendered by conflict: The case of Cote d'Ivoire. AB - Despite a growing awareness of the increased prevalence of intimate partner violence and sexual violence in conflict and post-conflict settings, much less is known about the dynamics, as well as the interventions that would be effective at individual, relational, and structural levels. In addition to the human capital lost by conflict violence, gender-based violence (GBV) poses a grave threat to the post-conflict rehabilitation process. With regard to violence that occurs during and post conflict, research must take into consideration the different types of violence that share similar causes as the larger conflict as well as become widespread as a result of the conflict and use existing frameworks to build future interventions. Researchers are trying to understand the interplay of personal, situational, and socio-cultural factors in conflict settings that combine to cause GBV and lead to guidelines for program planning to address the health and social needs of survivors as well as to prevent further GBV. These actions result from a growing recognition that violence represents a serious public health problem, is an important cause of many physical and psychological illnesses, and can cause social disruptions that impede reconstruction efforts for generations. This review studies the manifestations of GBV during and following the Ivoirian Civil War, juxtaposes them against narratives, as well as lists relevant interventions at the individual, relational, community, and institutional levels. Part of a growing literature that aims to better understand the nature of violence during and after conflict and to plan effective responses to it, this study hopes to suggest solutions for the situation of Cote d'Ivoire and elsewhere. PMID- 26482358 TI - The second wave of violence scholarship: South African synergies with a global research agenda. AB - Violence is a serious public health and human rights challenge with global psychosocial impacts across the human lifespan. As a middle-income country (MIC), South Africa experiences high levels of interpersonal, self-directed and collective violence, taking physical, sexual and/or psychological forms. Careful epidemiological research has consistently shown that complex causal pathways bind the social fabric of structural inequality, socio-cultural tolerance of violence, militarized masculinity, disrupted community and family life, and erosion of social capital, to individual-level biological, developmental and personality related risk factors to produce this polymorphic profile of violence in the country. Engaging with a concern that violence studies may have reached something of a theoretical impasse, 'second wave' violence scholars have argued that the future of violence research may not lie primarily in merely amassing more data on risk but rather in better theorizing the mechanisms that translate risk into enactment, and that mobilize individual and collective aspects of subjectivity within these enactments. With reference to several illustrative forms of violence in South Africa, in this article we suggest revisiting two conceptual orientations to violence, arguing that this may be useful in developing thinking in line with this new global agenda. Firstly, the definition of our object of enquiry requires revisiting to fully capture its complexity. Secondly, we advocate for the utility of specific incident analyses/case studies of violent encounters to explore the mechanisms of translation and mobilization of multiple interactive factors in enactments of violence. We argue that addressing some of the moral and methodological challenges highlighted in revisiting these orientations requires integrating critical social science theory with insights derived from epidemiology and, that combining these approaches may take us further in understanding and addressing the recalcitrant range of forms and manifestations of violence. PMID- 26482359 TI - Men's violence against women and men are inter-related: Recommendations for simultaneous intervention. AB - Men are more likely than women to perpetrate nearly all types of interpersonal violence (e.g. intimate partner violence, murder, assault, rape). While public health programs target prevention efforts for each type of violence, there are rarely efforts that approach the prevention of violence holistically and attempt to tackle its common root causes. Drawing upon theories that explain the drivers of violence, we examine how gender norms, including norms and social constructions of masculinity, are at the root of most physical violence perpetration by men against women and against other men. We then argue that simply isolating each type of violence and constructing separate interventions for each type is inefficient and less effective. We call for recognition of the commonalities found across the drivers of different types of violence and make intervention recommendations with the goal of seeking more long-standing solutions to violence prevention. PMID- 26482360 TI - GWAS analyses reveal QTL in egg layers that differ in response to diet differences. AB - BACKGROUND: The genetic architecture of egg production and egg quality traits, i.e. the quantitative trait loci (QTL) that influence these traits, is still poorly known. To date, 33 studies have focused on the detection of QTL for laying traits in chickens, but less than 10 genes have been identified. The availability of a high-density SNP (single nucleotide polymorphism) chicken array developed by Affymetrix, i.e. the 600K Affymetrix((r)) Axiom((r)) HD genotyping array offers the possibility to narrow down the localization of previously detected QTL and to detect new QTL. This high-density array is also anticipated to take research beyond the classical hypothesis of additivity of QTL effects or of QTL and environmental effects. The aim of our study was to search for QTL that influence laying traits using the 600K SNP chip and to investigate whether the effects of these QTL differed between diets and age at egg collection. RESULTS: One hundred and thirty-one QTL were detected for 16 laying traits and were spread across all marked chromosomes, except chromosomes 16 and 25. The percentage of variance explained by a QTL varied from 2 to 10 % for the various traits, depending on diet and age at egg collection. Chromosomes 3, 9, 10 and Z were overrepresented, with more than eight QTL on each one. Among the 131 QTL, 60 had a significantly different effect, depending on diet or age at egg collection. For egg production traits, when the QTL * environment interaction was significant, numerous inversions of sign of the SNP effects were observed, whereas for egg quality traits, the QTL * environment interaction was mostly due to a difference of magnitude of the SNP effects. CONCLUSIONS: Our results show that numerous QTL influence egg production and egg quality traits and that the genomic regions, which are involved in shaping the ability of layer chickens to adapt to their environment for egg production, vary depending on the environmental conditions. The next question will be to address what the impact of these genotype * environment interactions is on selection. PMID- 26482361 TI - Global Surgical Care in the U.N. Post-2015 Sustainable Development Agenda. PMID- 26482362 TI - Evaluating Mind Fitness Training and Its Potential Effects on Surgical Residents' Well-Being: A Mixed Methods Pilot Study. AB - BACKGROUND: Residents' well-being is essential for both the individual physician and the quality of patient care they deliver. Therefore, it is important to maintain or possibly enhance residents' well-being. We investigated (i) the influence of mind fitness training (MFT) on quality of care-related well-being characteristics: work engagement, empathy, work satisfaction and stress perception and explored (ii) residents' perceptions of MFT. METHODS: A multicenter study was conducted in eight Dutch teaching hospitals, from September 2012 to February 2014, using mixed methods-that is, quantitative and qualitative approaches to data collection and analysis. Eighty-nine surgical residents were invited to participate in pre- and post-intervention questionnaire surveys. Twenty-two residents participated in MFT and were additionally invited to evaluate the training by post-intervention interviews including open questions. RESULTS: At baseline 22 (100%) residents in intervention group and 47 (70.2%) residents in control group, and postintervention 20 (90.9 %) residents in intervention group and 41 (66.1%) residents in control group completed the questionnaires. In intervention-group, residents' specialty satisfaction increased by 0.23 point on 5-point Likert scale (95% CI 0.23-0.24, P < 0.001) while stress scores decreased by -0.94 point on 10-point scale (95% CI -1.77 to 0.12, P = 0.026). No substantial changes were observed in control group. Participation in MFT was positively associated with residents' empathy (b = 7.22; 95% CI 4.33-10.11; P < 0.001) and specialty satisfaction scores (b = 0.42; 95% CI 0.18-0.65; P = 0.001). Residents positively evaluated MFT with median scores of 6.80 for training design and 7.21 for outcome (10-point scale). Residents perceived improvement in focusing skills and reported being more aware of their own state of mind and feeling calmer and more in control. CONCLUSION: Mind fitness training could improve residents' empathy, specialty satisfaction, stress perception, and focusing skills, and was positively received by surgical residents. PMID- 26482363 TI - Severe Complications of Laparoscopic and Conventional Appendectomy Reported to the Finnish Patient Insurance Centre. AB - BACKGROUND: Appendectomy is considered a safe operation, the related complications being minor. Negative exploration is an accepted procedure to avoid complications of appendicitis. Treatment with antibiotics is under debate as a primary treatment for appendicitis. The aim of this study was to collect and analyze detailed information on complications and morbidity related to appendectomy using the information of the nationwide Patient Insurance Association (PIA) database and to study the incidence of patient claims and compensated injuries related to appendectomy in Finland. METHODS: Patients' claims from 1990 to 2010 were collected from the PIA register. Complications were classified using the accordion severity grading system. Severe complications were selected for more detailed analyses. Laparoscopic and open surgeries were compared. Factors related to compensated claims were assessed. For statistical analysis, Fisher's exact test, logistic multivariate regression, and the Mann Kendall function were used. RESULTS: Appendectomy complications leading to a patient insurance claim in Finland are rare (0.2 %). The rate of patients' claims after laparoscopic surgery was higher than after open surgery (p < 0.001), but the rate of compensated claims was equal. During the study period, complications after laparoscopic procedures more often led to additional surgery or organ failure (p = 0.03). Of the patients with a compensated injury, only 57 % had appendicitis. Preoperative computed tomography was used in only 6 % of these cases. CONCLUSIONS: Patient injuries and claims regarding severe complications after appendectomy are rare. The complications related to laparoscopic appendectomy were more severe than those of open surgery. PMID- 26482364 TI - The Bare Minimum Requires Caution. PMID- 26482365 TI - Clinical Usefulness of 5-FU Metabolic Enzymes as Predictive Markers of Response to Chemotherapy in Colorectal Cancer. PMID- 26482366 TI - Involving Medical Students in Informed Consent: A Pilot Study. PMID- 26482367 TI - The Establishment and Development of Neurosurgery Services in Papua New Guinea. AB - BACKGROUND: Papua New Guinea (PNG) is a developing Pacific Nation of 7.3 million people. Although neurosurgery training was introduced to PNG in the year 2000, it was in 2003 that a neurosurgery service was established. Prior to this time, neurosurgery in PNG was performed by general surgeons, with some assistance from visiting Australian neurosurgeons. Neurosurgical training was introduced to PNG in 2000. The model involved a further 3 years of training for a surgeon who had already completed 4 years of general surgical training. We aim to review the output, outcomes and impact achieved by training the first national neurosurgeon. METHODS: The data on activity (output) and outcomes were collected prospectively from 2003-2012. Ongoing mentoring and continuing professional development were provided through annual neurosurgical visits from Australia. There were serious limitations in the provision of equipment, with a lack of computerized tomographic or MR imaging, and adjuvant oncological services. RESULTS: There were 1618 neurosurgery admissions, 1020 neurosurgical procedures with a 5.74 % overall mortality. Seventy percent of cases presented as emergencies. There were improved outcomes, particularly for head injuries, whilst hydrocephalus was managed with an acceptable morbidity and revision rate. CONCLUSIONS: The training of a neurosurgeon resulted in PNG patients receiving a better range of surgical services, with a lower mortality. The outcomes able to be delivered were limited by late presentations of patients and lack of resources including imaging. These themes are familiar to all low- and middle-income countries (LMICs) and this may serve as a model for other LMIC neurosurgical services to adopt as they consider whether to establish and develop neurosurgical and other sub-specialist surgical services. PMID- 26482368 TI - Personality disorder in DSM-5: an oral history. AB - As the revision process leading to DSM-5 began, the domain of personality disorder embodied the highest aspirations for major change. After an initial prototype-based proposal failed to gain acceptance, the Personality and Personality Disorders Work Group (P&PDWG) developed a hybrid model containing categorical and dimensional components. A clash of perspectives both within the P&PDWG and between the P&PDWG and DSM-5 oversight committees led to the rejection of this proposal from the main body of DSM-5. Major issues included conflicting ways of conceptualizing validation, differences of opinion from personality disorder experts outside the P&PDWG, divergent concepts of the magnitude of evidence needed to support substantial changes, and the disagreements about clinical utility of the hybrid model. Despite these setbacks, the 'Alternative DSM-5 Model of Personality Disorder' is presented in Section III of the DSM-5. Further research should clarify its performance relative to the DSM-IV criteria reprinted in the main DSM-5 text. PMID- 26482369 TI - Net Clinical Benefits of Guidelines and Decision Tool Recommendations for Oral Anticoagulant Use among Patients with Atrial Fibrillation. AB - BACKGROUND: The 2012 American College of Chest Physicians' Evidence-Based Clinical Practice (CHEST), the 2012 European Society of Cardiology, and the 2014 American Heart Association guidelines and published decision tools by LaHaye and Casciano offer oral anticoagulant (OAC) recommendations for patients with atrial fibrillation (AF). The aim of our study was to compare the net clinical benefit (NCB) of OAC prescribing that was concordant with these decision aids. METHODS: A cohort study of the 2001-2013 LifeLink claims data was used. NCB in concordance with each decision aid was defined as adverse events (thromboembolic and major bleed events) prevented per 10,000 person-years. Cox proportional hazard models were used to assess the relative risk of AF adverse events associated in concordance with each decision aid adjusted for potential confounders. FINDINGS: The study included 15,129 patients with AF, contributing 33,512 person-years. The NCB of the CHEST guidelines was the highest (NCB = 30.07; 95% confidence interval [CI] = 28.66, 31.49) and the European Society of Cardiology guidelines the lowest (NCB = 7.38; 95% CI = 5.97, 8.80). Significant unadjusted decreases in the risk of AF adverse events associated with concordant OAC use/nonuse were found for the CHEST guidelines (hazard ratio [HR] = .825; 95% CI = .695, .979), Casciano tool (HR = .838; 95% CI = .706, .995), and LaHaye tool (HR = .841; 95% CI = .709, .999); however, none were significant after multivariate adjustment. CONCLUSION: Concordant OAC use with any of the decision aids except for the aggressive LaHaye tool led to a positive NCB. The decision aids based on the CHA2DS2-VASc algorithm did not consistently improve the NCB compared to CHADS2-based aids. Recommending OAC use when CHA2DS2-VASc score = 1 resulted in a lower NCB when all other factors guiding recommendations were held constant. PMID- 26482370 TI - Erratum to: Tonic GABAA Receptors as Potential Target for the Treatment of Temporal Lobe Epilepsy. PMID- 26482371 TI - Netrin-1 Contributes to Myelinated Afferent Fiber Sprouting and Neuropathic Pain. AB - Netrin-1 is a neuronal guidance molecule implicated in the development of spinal cord neurons and cortical neurons. In the adult spinal cord, UNC5H (repulsive receptor of netrin-1), but not deleted in colorectal cancer (DCC) (attractive receptor of netrin-1), constitutes a major mode of netrin-1 signal transduction, which may be involved in axon repulsion and inhibits neurite outgrowth. Abnormal sprouting of myelinated afferent fibers in the spinal dorsal horn can cause mechanical allodynia associated with postherpetic neuralgia (PHN, Shingles) and other neuropathic pains. However, whether netrin-1 participates in sprouting of myelinated afferent fibers and mechanical allodynia remains unknown. In an ultropotent TRPV1 agonist resiniferatoxin (RTX)-induced PHN-like model, RTX treatment for 6 weeks increased netrin-1 expression in dorsal horn neurons, including NK-1-positive projection neurons. In human neuroblastoma SH-SY5Y cells, we found that TRPV1 antagonist capsazepine antagonized RTX-induced upregulation of netrin-1. After RTX treatment, UNC5H2 expression was gradually decreased, whereas DCC expression was significantly increased. Silencing netrin-1 in the spinal dorsal horn significantly attenuated RTX-induced mechanical allodynia and sprouting of myelinated fibers into the spinal lamina II. Our results suggest that RTX treatment upregulates netrin-1 expression through activation of TRPV1 receptors and change UNC5H2-rich spinal dorsal horn into a growth-permissive environment by increasing DCC expression, thus enhancing the sprouting of myelinated afferent nerves. Netrin-1 may be targeted for reducing primary afferent sprouting and mechanical allodynia in PHN and other neuropathic pain conditions. PMID- 26482373 TI - Clinical characteristics and risk factors for community-acquired Clostridium difficile infection: A retrospective, case-control study in a tertiary care hospital in Japan. AB - The epidemiology of Clostridium difficile infection (CDI) has changed in the past decade. The incidence, prevalence, and severity of community-acquired CDI (CA CDI) have increased. However, the epidemiology of CA-CDI in Japan has not been investigated. To evaluate the clinical characteristics and risk factors for CA CDI in Japan, we conducted a retrospective, case-control study of CA-CDI at the National Hospital Organization Tokyo Medical Center between January 2010 and December 2014. Two age- and sex-matched C. difficile toxin- and culture-negative controls were assigned for each case. A total of 26 patients were identified with CA-CDI were identified. The incidence rate for CA-CDI was 1.4 per 100,000 patient years. Of the CA-CDI patients, 6 (23.1%) had no underlying comorbidity, 22 (84.6%) had prior exposure to antimicrobials, and 5 (19.2%) had prior exposure to antacids. Although 5 patients (19.2%) required hospitalization, none required intensive care or died. Recurrence was observed in 1 patient (3.8%). Patients with CA-CDI cases were more likely to have been recently exposed to antimicrobials compared to controls (odds ratio [OR]: 8.12, 95% confidence interval [CI]: 2.43-26.98). However, exposure to antacids was not associated with CA-CDI (OR: 0.59, 95% CI: 0.19-1.85). Our findings indicate that the incidence rate for CA-CDI in Japan is relatively low compared to the US and Europe, and that CA-CDI is usually not severe. Previous antimicrobial exposure was the main risk factor for CA-CDI, suggesting that clinicians should consider CDI in patients presenting with diarrhea who have recently received antimicrobials. PMID- 26482372 TI - Intranasal Delivery of RGD Motif-Containing Osteopontin Icosamer Confers Neuroprotection in the Postischemic Brain via alphavbeta3 Integrin Binding. AB - Osteopontin (OPN) is a phosphorylated glycoprotein possessing an arginine-glycine aspartate (RGD)-motif, which binds to several cell surface integrins and mediates a wide range of cellular processes. Inductions of OPN have been reported in the postischemic brain, and the neuroprotective effects of OPN have been demonstrated in animal models of stroke. In the present study, we showed a robust neuroprotective effect of RGD-containing icosamer OPN peptide (OPNpt20) in a rat model of focal cerebral ischemia (middle cerebral artery occlusion, MCAO). Intranasally administered OPNpt20 reduced mean infarct volume by 79.7 % compared to the treatment-naive MCAO control animals and markedly ameliorated neurological deficits. In addition, OPNpt20 significantly suppressed the inductions of iNOS and of inflammatory markers in postischemic brains and in primary microglial cultures, demonstrating anti-inflammatory effects. Administration of a mutant peptide, in which RGD was replaced by arginine-alanine-alanine (RAA), failed to suppress infarct volumes in MCAO animals and co-administration of OPNpt20 with anti-alphavbeta3 integrin antibody failed to suppress iNOS induction in primary microglia culture, indicating that the RGD motif in OPNpt20 and endogenous alphavbeta3 integrin play critical roles. Furthermore, pull-down assay revealed a direct binding between OPNpt20 and alphavbeta3 integrin in primary microglia culture. Together, these results indicate that RGD-containing OPN icosamer has therapeutic potential in the postischemic brain and alphavbeta3 integrin-mediated anti-inflammatory effect might be an underlying mechanism. PMID- 26482376 TI - Rationale and Design of Sodium Tanshinone IIA Sulfonate in Left Ventricular Remodeling Secondary to Acute Myocardial Infarction (STAMP-REMODELING) Trial: A Randomized Controlled Study. AB - BACKGROUND: Left ventricular (LV) remodeling in ischemic cardiomyopathy is the leading cause of heart failure and is an established prognostic factor for adverse cardiovascular events. Experimental studies suggest that sodium tanshinone IIA sulfonate attenuates cardiac remodeling in animal models of acute myocardial infarction (AMI). However, the effects of this drug in the clinical setting remain unclear. Therefore, the STAMP-REMODELING trial is set up to investigate whether treatment with sodium tanshinone IIA sulfonate would prevent the maladaptive progression to adverse LV remodeling in patients following ST segment elevation myocardial infarction (STEMI). METHODS: Approximately 80 patients with STEMI successfully treated with primary percutaneous coronary intervention (PCI) will be enrolled and randomized to receive sodium tanshinone IIA sulfonate (80 mg q.d. for 7 days) in addition to standard therapy or the same volume of hydration per day. The primary endpoint is the variation in LV end diastolic volume index (LVEDVi) assessed with cardiac magnetic resonance imaging (CMR) at baseline and 6 months. CONCLUSION: This study will provide important clinical evidence on the efficacy of sodium tanshinone IIA sulfonate treatment in patients with STEMI when used in combination with current therapies that may significantly reduce adverse LV remodeling and potentially improve clinical outcomes. TRIAL REGISTRATION: Clinical Trials.gov: NCT02524964. PMID- 26482374 TI - Prognostic impact of a single-nucleotide polymorphism near the CTSO gene in hormone receptor-positive breast cancer patients. AB - BACKGROUND: Tamoxifen can reduce the occurrence of breast cancer by a half in high-risk women. Recently, a genome-wide association study identified two single nucleotide polymorphisms (SNPs) near or in the CTSO and ZNF423 genes that were associated with breast cancer risk during tamoxifen therapy. We hypothesized that these two SNPs could be associated with increased recurrence in breast cancer patients who received adjuvant tamoxifen therapy. METHODS: A total of 586 breast carcinomas were available for SNP genotyping assays. TaqMan pre-designed SNP genotyping assays were used to identify the presence of CTSO rs10030044 and ZNF423 rs8060157. We then investigated the relationship between CTSO rs10030044 genotypes and mRNA expression levels of CTSO and BRCA1 in 290 breast cancer patients. RESULTS: We found a positive correlation between the variant GG genotype of CTSO rs10030044 and shorter disease-free survival, or overall survival in hormone receptor-positive breast cancer patients receiving adjuvant tamoxifen therapy. In contrast, this genotype was not associated with prognosis in hormone receptor-negative breast cancer patients. Multivariate Cox regression analysis revealed that this genotype was an independent factor indicating a poor prognosis in hormone receptor-positive breast cancer patients receiving adjuvant tamoxifen therapy. No association was found between CTSO genotype and mRNA expression of CTSO and BRCA1. ZNF423 rs8060157 genotype was not associated with prognosis in this study. CONCLUSION: We show that a SNP near the CTSO gene is a poor prognostic factor in breast cancer although further research might help to reveal the factors linking this genotype and prognosis. PMID- 26482377 TI - Exogenous SDF-1alpha Protects Human Myocardium from Hypoxia-Reoxygenation Injury via CXCR4. PMID- 26482379 TI - Erratum to: Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. PMID- 26482380 TI - Erratum to: Treatment patterns and outcomes in the prophylaxis of chemotherapy induced (febrile) neutropenia with biosimilar filgrastim (the MONITOR-GCSF study). PMID- 26482381 TI - Effects of aerobic exercise on cancer-related fatigue: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Cancer-related fatigue (CRF) is the most commonly reported and most distressing symptom in cancer patients. Currently, there are no effective strategies for managing this condition. OBJECTIVE: The purpose of this study is to compare the effects of aerobic exercise on CRF with the standard of care. METHODS: A systematic search for randomized controlled trials (RCTs) was performed using the Cochrane Library, JBI Library, Embase, MEDLINE, Web of Science, China Biology Medicine (CBM), and China National Knowledge Infrastructure (CNKI). The risk of bias was critically evaluated, and data were independently extracted by two reviewers. All of the analyses were performed using Review Manager 5. RESULTS: A total of 26 qualified studies that included 2830 participants (aerobic exercise, 1426; control, 1404) were included in the meta-analysis. Cancer patients who completed adjuvant therapy in the aerobic exercise group reported reduced CRF levels relative to patients undergoing the standard of care. Aerobic exercise had a moderate effect on CRF for patients not currently undergoing anticancer treatment. Supervised aerobic exercise, exercise for 20-30 min/session, or exercise three times/week had a small effect on CRF. Exercise for 50 min/session or exercise two sessions/week had a significant effect on patient CRF, whereas 8 weeks of exercise had a moderate effect. CONCLUSIONS: Aerobic exercise is effective for the management of CRF, especially for patients who have completed adjuvant therapy. IMPLICATIONS FOR PRACTICE: Cancer patients can make more informed choices regarding their cancer-related fatigue management based on the best available evidence. PMID- 26482382 TI - Effects of the lipid regulator drug gemfibrozil: A toxicological and behavioral perspective. AB - Pharmaceuticals are emerging contaminants as their worldwide consumption increases. Fibrates such as gemfibrozil (GEM) are used in human medicine to reduce blood concentrations of cholesterol and triacylglycerol and also are some of the most frequently reported pharmaceuticals in waste waters and surface waters. Despite some studies have already demonstrated the negative impact in physiological and/or reproductive endpoints in adult fish, data on survival and behavioral effects in fish larvae are lacking. This study aimed to assess the effects of GEM on zebrafish eleutheroembryo development and locomotor behavior. A fish embryo toxicity (FET) test was undertaken to evaluate GEM acute toxicity by exposing embryos to 0, 6.58, 9.87, 14.81, 22.22, 33.33 and 50mg/L. Developmental endpoints such as hatching success, edemas and malformations were recorded. A second test was undertaken by exposing embryos to 0, 1.5, 3 and 6mg/L in order to evaluate the effects of GEM on 120 and 144h post fertilization (hpf) larvae locomotor activity by video tracking, using a Zebrabox((r)) (Viewpoint, France) device. From the data recorded, several parameters such as total swimming distance (TSD) and total swimming time (TST) in each 120s integration time were calculated. Data showed that this compound has a moderate toxic effect on fish embryo development, affecting both survival and hatching success with a calculated 96h LC50 of 11.01mg/L and no effects at the developmental level at 6mg/L. GEM seems to impair locomotor activity, even at concentrations where developmental abnormalities were unperceived, at concentrations as low as 1.5mg/L. Both TSD and TST were sensitive to GEM exposure. These effects do not seem to be independent of the developmental stage as 120hpf larvae seem to present a development bias with repercussions in locomotor behavior. This study highlights the need to include behavioral endpoints in ecotoxicological assays as this seems to be a more sensitive endpoint often disregarded. PMID- 26482383 TI - Determination of the Absolute Configuration of Female-Produced Contact Sex Pheromone Components of the Longhorned Beetle, Neoclytus acuminatus acuminatus (F). AB - Cuticular hydrocarbons play important roles in contact chemical communication in insects. Many of these compounds are methyl-branched hydrocarbons with one or more chiral centers, which can exist in two or more stereoisomeric forms. Although the importance of chirality for the volatile semiochemicals that insects use for long-range communication is well established, almost nothing is known about the role of chirality in insect contact chemoreception. Here, we used reverse phase high performance liquid chromatography (RP-HPLC) and digital polarimetry to isolate and determine the absolute configuration of a component of the female-produced contact sex pheromone of the cerambycid beetle, Neoclytus acuminatus acuminatus (F.). The pheromone consists of 7-methylpentacosane (7 MeC25), 7-methylheptacosane (7-MeC27), and 9-methylheptacosane (9-MeC27). The absolute configuration of the most abundant pheromone component, 7-MeC25, was found to be (R). We then utilized enantiomerically pure synthetic pheromone components to test the hypothesis that males would respond more strongly to (R)- than to (S)-enantiomers of the three pheromone components. We also tested blends of (R)-7-MeC27, the most bioactive component, with the (S)-enantiomers of the minor components and vice versa to determine if unnatural stereoisomers might decrease behavioral responses. Males responded most strongly to solvent-washed females treated with the blend of (R)-pheromone components, and to a lesser extent to (R)-7-MeC27 alone. A blend of (R)-7-MeC27 with the (S)-minor components elicited an intermediate response. Together, these findings suggest that the insects can discriminate the absolute configuration of the major and minor pheromone components, and that the configuration of all three components is likely to be (R). PMID- 26482386 TI - WITHDRAWN: Moxifloxacin is an effective and safe candidate agent for tuberculosis treatment: a meta-analysis. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26482385 TI - Testosterone Replacement Therapy and Mortality in Older Men. AB - While US testosterone prescriptions have tripled in the last decade with lower trends in Europe, debate continues over the risks, benefits and appropriate use of testosterone replacement therapy (TRT). Several authors blame advertising and the availability of more convenient formulations, whilst others have pointed out that the routine testing of men with erectile dysfunction (ED) (a significant marker of cardiovascular risk) and those with diabetes would inevitably increase the diagnosis of hypogonadism and lead to an increase in totally appropriate prescribing. They commented that this was merely an appropriate correction of previous under-diagnosis and under-treatment in line with evidence based guidelines. It is unlikely that persuasive advertising or convenient formulations could grow a market over such a sustained period if the treatment was not effective. Urologists and primary care physicians are the most frequent initiators of TRT usually for ED. Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with a possible reduction in frailty and osteoporosis. There remains no evidence that TRT is associated with increased risk of prostate cancer or symptomatic benign prostatic hyperplasia, yet the decision to initiate and continue therapy is often decided by urologists. The cardiovascular issues associated with TRT have been clarified by recent studies showing that therapy associated with clear increases in serum testosterone levels to the normal range is associated with reduced all-cause mortality. Studies reporting to show increased risk have been subject to flawed designs with inadequate baseline diagnosis and follow-up testing. Effectively, they have compared non-treated patients with under-treated or non-compliant subjects involving a range of different therapy regimes. Recent evidence suggests long-acting injections may be associated with decreased cardiovascular risk, but the transdermal route may be associated with potentially relatively greater risk because of conversion to dihydrotestosterone by the effect of 5-alpha reductase in skin. The multiple effects of TRT may add up to a considerable benefit to the patient that might be underestimated by the physician primarily concerned with his own specialty. In a response to concerns about the possible risks associated with inappropriate prescribing expressed by Public Citizen, the Food and Drug Administration (FDA) published a complete refutation of all the concerns, only to issue a subsequent bulletin of concern over inappropriate use, whilst confirming the benefits in treating men with established testosterone deficiency. No additional evidence was provided for this apparent change of opinion, but longer term safety data on testosterone products were strongly suggested. In contrast, the European Medicines Agency (EMA), in November 2014, concluded that "there is no consistent evidence of increased cardiovascular risk with testosterone products". This paper explores the most recent evidence surrounding the benefits and risks associated with TRT. PMID- 26482387 TI - Diagnosis of bacteraemia and growth times. AB - OBJECTIVE: The objective of this study was to predict the diagnosis of bacteraemia as a function of the time at which the automated BacT/Alert system continuously detects microorganism growth. METHODS: A retrospective study of a database of 1334 patients with a positive blood culture between January 2011 and June 2013 was conducted. Together with the final blood culture results and the patient's history, growth was then analysed to assess whether it represented true bacteraemia or bacterial contamination. The earliest detection times of bacterial growth in each batch of blood cultures were analysed in a blinded fashion after classification. RESULTS: In total, 590 batches of blood cultures corresponded to true bacteraemia and 744 to bacterial contamination. In the bacteraemia group, the median growth time was 12.72 h (interquartile range (IQR) 10.08-17.58 h). In the contaminated blood culture group, the median growth time was 20.6h (IQR 17.04 32.16 h) (p<0.001). Analysis of the receiver operating characteristics (ROC) curve (area under the curve 0.80, 95% confidence interval 0.771-0.826) showed that 90% of the contaminants grew after 14.7h (sensitivity 90.5%, specificity 63.4%, positive predictive value (PPV) 65.9%, negative predictive value (NPV) 90.7%). Forty-five percent of the bacteraemia organisms grew in under 12h (sensitivity 45.3%, specificity 95%, PPV 87.8%, NPV 68.7%). Microorganisms such as Candida sp and Bacteroides sp presented median growth times significantly longer than those of the other microorganisms. The administration of antibiotics in the week prior to bacteraemia was found to delay the growth time of microorganisms (p<0.001). CONCLUSIONS: Knowing the time to detection of microorganism growth can help to distinguish between true bacteraemia and bacterial contamination, thus allowing more timely clinical decisions to be made, before definitive microorganism identification. PMID- 26482384 TI - The influence of high-intensity compared with moderate-intensity exercise training on cardiorespiratory fitness and body composition in colorectal cancer survivors: a randomised controlled trial. AB - PURPOSE: Following colorectal cancer diagnosis and anti-cancer therapy, declines in cardiorespiratory fitness and body composition lead to significant increases in morbidity and mortality. There is increasing interest within the field of exercise oncology surrounding potential strategies to remediate these adverse outcomes. This study compared 4 weeks of moderate-intensity exercise (MIE) and high-intensity exercise (HIE) training on peak oxygen consumption (VO2peak) and body composition in colorectal cancer survivors. METHODS: Forty seven post treatment colorectal cancer survivors (HIE = 27 months post-treatment; MIE = 38 months post-treatment) were randomised to either HIE [85-95 % peak heart rate (HRpeak)] or MIE (70 % HRpeak) in equivalence with current physical activity guidelines and completed 12 training sessions over 4 weeks. RESULTS: HIE was superior to MIE in improving absolute (p = 0.016) and relative (p = 0.021) VO2peak. Absolute (+0.28 L.min(-1), p < 0.001) and relative (+3.5 ml.kg(-1).min( 1), p < 0.001) VO2 peak were increased in the HIE group but not the MIE group following training. HIE led to significant increases in lean mass (+0.72 kg, p = 0.002) and decreases in fat mass (-0.74 kg, p < 0.001) and fat percentage (-1.0 %, p < 0.001), whereas no changes were observed for the MIE group. There were no severe adverse events. CONCLUSIONS: In response to short-term training, HIE is a safe, feasible and efficacious intervention that offers clinically meaningful improvements in cardiorespiratory fitness and body composition for colorectal cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: HIE appears to offer superior improvements in cardiorespiratory fitness and body composition in comparison to current physical activity recommendations for colorectal cancer survivors and therefore may be an effective clinical utility following treatment. PMID- 26482388 TI - First report of New Delhi metallo-beta-lactamase 5 (NDM-5)-producing Escherichia coli from blood cultures of three leukemia patients. AB - We report the first occurrence of New Delhi metallo-beta-lactamase 5 (NDM-5) in carbapenem-resistant Escherichia coli isolated from blood cultures of three leukemia patients in northern China. These patients had at some time been hospitalized in the hematology department of the same hospital. All isolates were ST167 with identical pulsed-field gel electrophoresis patterns, suggesting a likely hospital transmission. PMID- 26482389 TI - Successful treatment of avian-origin influenza A (H7N9) infection using convalescent plasma. AB - In January 2015, there was an outbreak of avian-origin influenza A (H7N9) virus in Zhejiang Province, China. A 45-year-old man was admitted to the First Affiliated Hospital of Zhejiang University with a high fever that had lasted 7 days, chills, and a cough with yellow sputum. Laboratory testing confirmed infection with the H7N9 virus, likely obtained from contact with poultry at a local live poultry market. A large dense shadow was apparent in the patient's left lung at the time of admission. Treatment with oseltamivir (75mg twice daily) did not improve the patient's condition. The decision was made to try using convalescent plasma to treat the infection. Convalescent plasma was administered 3 days after the patient was admitted to the hospital and led to a marked improvement. To our knowledge, this is the first report of the successful use of convalescent plasma to treat a case of H7N9 infection in China. These results suggest that the combination of convalescent plasma and antiviral drugs may be effective for the treatment of avian-origin H7N9 infection. PMID- 26482390 TI - Seroprevalence of arboviruses among blood donors in French Polynesia, 2011-2013. AB - OBJECTIVES: French Polynesia is a high epidemic/endemic area for arthropod-borne viruses (arboviruses). We recently reported the silent circulation of Ross River virus and absence of active transmission of chikungunya virus (CHIKV) among blood donors sampled before the emergence of Zika virus (ZIKV) and CHIKV in French Polynesia. In this study, the prevalence of the four serotypes of dengue virus (DENV) and the occurrence of circulation of other arboviruses were investigated in blood donors in French Polynesia. METHODS: Serum samples from 593 blood donors collected between July 2011 and October 2013 were tested by ELISA for the presence of immunoglobulin G antibodies against each of the four DENV serotypes, ZIKV, Japanese encephalitis virus (JEV), and West Nile virus (WNV). RESULTS: It was found that 80.3%, 0.8%, 1.3%, and 1.5% of blood donors were seropositive for at least one DENV serotype, ZIKV, JEV, and WNV, respectively. CONCLUSIONS: These results corroborate the expected high transmission of DENV and conversely suggest that no active circulation of ZIKV, JEV, and WNV occurred in French Polynesia before 2011. Information provided by this study may be useful for public health authorities to improve surveillance and implement strategies to prevent the transmission of arboviruses. PMID- 26482391 TI - Effect on postoperative survival of the status of distal ureteral margin: The necessity to achieve negative margins at the time of radical cystectomy. AB - BACKGROUND: Despite several studies, the adequate management of positive distal ureter margins at the time of radical cystectomy (RC) remains controversial. Particularly, it is not clear whether the achievement of negative distal ureter margins at the intraoperative frozen sections (IFS) affects postoperative cancer specific mortality (CSM). METHODS: In all, 1,447 consecutive patients treated with RC at a single center between January 1987 and August 2014 were considered. Multivariable (MVA) logistic regression analyses were used to determine predictors of positive IFS. MVA Cox regression analyses were used to test the effect on CSM of intraoperative conversion to negative margins. RESULTS: At IFS, 368 patients (25%) experienced at least 1 positive margin. Of these, a negative conversion of the margin at IFS occurred in 178 (48%) whereas 190 (52%) had a positive final ureteral margin. The mean follow-up was 95 months (median = 102). At MVA, history of carcinoma in situ (odds ratio = 6.40, P<0.001) was predictors of positive margin at IFS. At MVA, ureteral margins that were not converted to negative (hazard ratio = 1.92, P = 0.01) were associated with CSM but only in patients with negative soft tissue margin and without node metastases. CONCLUSIONS: Achieving negative IFS margins may be associated with survival benefit in patients without residual bladder cancer after RC. Patients who recorded a history of carcinoma in situ before RC are at higher risk to incur positive ureteral margin at IFS and should be investigated during RC. PMID- 26482393 TI - Propagation of ultrasonic Love waves in nonhomogeneous elastic functionally graded materials. AB - This paper presents a theoretical study of the propagation behavior of ultrasonic Love waves in nonhomogeneous functionally graded elastic materials, which is a vital problem in the mechanics of solids. The elastic properties (shear modulus) of a semi-infinite elastic half-space vary monotonically with the depth (distance from the surface of the material). The Direct Sturm-Liouville Problem that describes the propagation of Love waves in nonhomogeneous elastic functionally graded materials is formulated and solved by using two methods: i.e., (1) Finite Difference Method, and (2) Haskell-Thompson Transfer Matrix Method. The dispersion curves of phase and group velocity of surface Love waves in inhomogeneous elastic graded materials are evaluated. The integral formula for the group velocity of Love waves in nonhomogeneous elastic graded materials has been established. The effect of elastic non-homogeneities on the dispersion curves of Love waves is discussed. Two Love wave waveguide structures are analyzed: (1) a nonhomogeneous elastic surface layer deposited on a homogeneous elastic substrate, and (2) a semi-infinite nonhomogeneous elastic half-space. Obtained in this work, the phase and group velocity dispersion curves of Love waves propagating in the considered nonhomogeneous elastic waveguides have not previously been reported in the scientific literature. The results of this paper may give a deeper insight into the nature of Love waves propagation in elastic nonhomogeneous functionally graded materials, and can provide theoretical guidance for the design and optimization of Love wave based devices. PMID- 26482392 TI - Optimizing systemic therapy for metastatic renal cell carcinoma beyond the first line setting. AB - The introduction of molecularly targeted therapies (TTs) has transformed the management of metastatic renal cell carcinoma (mRCC). Within a relatively short period of time, systemic treatment of mRCC has evolved from a disease treated only by cytokines to a disease where TT is the cornerstone of patient management. Since the approval of sorafenib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), in December 2005, 7 drugs have been introduced that have provided a high level of clinical efficacy in patients with mRCC, with a median survival of ~30 months in an unselected patient population that generally fits trials eligibility. Despite such success, advancements in therapies have reached a plateau: different combinations of targeted agents have not demonstrated additional benefit mainly owing to toxicity concerns, and some novel agents have failed to show benefit over approved drugs in clinics. In this review, we aim to focus on optimizing selection of agents in mRCC after progression on first-line TT. We also review how new drugs may transform existing guidelines and break through the current plateau reached with approved agents. PMID- 26482394 TI - Analytical and numerical modeling of non-collinear shear wave mixing at an imperfect interface. AB - Non-collinear shear wave mixing at an imperfect interface between two solids can be exploited for nonlinear ultrasonic assessment of bond quality. In this study we developed two analytical models for nonlinear imperfect interfaces. The first model uses a finite nonlinear interfacial stiffness representation of an imperfect interface of vanishing thickness, while the second model relies on a thin nonlinear interphase layer to represent an imperfect interface region. The second model is actually a derivative of the first model obtained by calculating the equivalent interfacial stiffness of a thin isotropic nonlinear interphase layer in the quasi-static approximation. The predictions of both analytical models were numerically verified by comparison to COMSOL finite element simulations. These models can accurately predict the additional nonlinearity caused by interface imperfections based on the strength of the reflected and transmitted mixed longitudinal waves produced by them under non-collinear shear wave interrogation. PMID- 26482395 TI - Sonodynamic action of hypocrellin B on methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) commonly causes refractory infections and has recently become a serious public health concern. The present study was designed to investigate sonodynamic action of hypocrellin B on MRSA. A MRSA strain (ATCC BAA-43) was used in the present study. The dark toxicity of hypocrellin B on MRSA and its uptake in MRSA first were measured. And then bacteria were incubated with hypocrellin B and exposed to ultrasound. After sonodynamic treatment, colony forming unit assay and bacterial viability assay were conducted. Membrane permeability assay, DNA fragmentation assay, and DNA synthesis assay were also performed to examine the underlying mechanism. The results showed that hypocrellin B at concentrations of up to 500 MUM had no toxicity to MRSA in the dark. After incubation for 50 min, hypocrellin B could be maximally absorbed by MRSA, and exhibited significant sonodynamic activity in a dose-dependent manner. The 5-log reduction in colony forming unit (CFU) was observed after hypocrellin B (40 MUM) treatment at an intensity of 1.38 W/cm(2) ultrasound for 5 min. Compared to the control, hypocrellin B alone and ultrasound sonication alone group, more dead cells were found and bacterial membrane integrity was notably damaged after sonodynamic treatment of hypocrellin B. However, no remarkable DNA damage was found in MRSA after sonodynamic treatment of hypocrellin B. All the findings demonstrated that hypocrellin B could serve as a potential antibacterial sonosensitizer to significantly cause damage to the membrane integrity of MRSA and inhibit its growth under ultrasound sonication. PMID- 26482396 TI - Role of healthcare workers in early epidemic spread of Ebola: policy implications of prophylactic compared to reactive vaccination policy in outbreak prevention and control. AB - Ebola causes severe illness in humans and has epidemic potential. How to deploy vaccines most effectively is a central policy question since different strategies have implications for ideal vaccine profile. More than one vaccine may be needed. A vaccine optimised for prophylactic vaccination in high-risk areas but when the virus is not actively circulating should be safe, well tolerated, and provide long-lasting protection; a two- or three-dose strategy would be realistic. Conversely, a reactive vaccine deployed in an outbreak context for ring vaccination strategies should have rapid onset of protection with one dose, but longevity of protection is less important. In initial cases, before an outbreak is recognised, healthcare workers (HCWs) are at particular risk of acquiring and transmitting infection, thus potentially augmenting early epidemics. We hypothesise that many early outbreak cases could be averted, or epidemics aborted, by prophylactic vaccination of HCWs. This paper explores the potential impact of prophylactic versus reactive vaccination strategies of HCWs in preventing early epidemic transmissions. To do this, we use the limited data available from Ebola epidemics (current and historic) to reconstruct transmission trees and illustrate the theoretical impact of these vaccination strategies. Our data suggest a substantial potential benefit of prophylactic versus reactive vaccination of HCWs in preventing early transmissions. We estimate that prophylactic vaccination with a coverage >99% and theoretical 100% efficacy could avert nearly two-thirds of cases studied; 75% coverage would still confer clear benefit (40% cases averted), but reactive vaccination would be of less value in the early epidemic. A prophylactic vaccination campaign for front-line HCWs is not a trivial undertaking; whether to prioritise long-lasting vaccines and provide prophylaxis to HCWs is a live policy question. Prophylactic vaccination is likely to have a greater impact on the mitigation of future epidemics than reactive strategies and, in some cases, might prevent them. However, in a confirmed outbreak, reactive vaccination would be an essential humanitarian priority. The value of HCW Ebola vaccination is often only seen in terms of personal protection of the HCW workforce. A prophylactic vaccination strategy is likely to bring substantial additional benefit by preventing early transmission and might abort some epidemics. This has implications both for policy and for the optimum product profile for vaccines currently in development. PMID- 26482397 TI - Reply. PMID- 26482398 TI - The Effects of a Voice Education Program on VHI Scores of Elementary School Teachers. AB - INTRODUCTION: Teachers seem to be vulnerable to voice disorders because of excessive use of their voice. The purpose of this study was to investigate the effects of a voice education program on the Vocal Handicap Index (VHI) scores of elementary school teachers in the Persian education system. METHOD: This was a semi-experimental study, performed in Shiraz public schools. Ten schools were selected on their similarity in number of students and teachers, and allocated at random to training or control groups. Sixty-one teachers in the training group and 66 teachers in the control group completed the VHI in the first week. Teachers in the trained group received voice education for 4 weeks, and then continued to follow the program for a further 4 weeks. The control group received no training. After 8 weeks, all subjects completed the questionnaire again. RESULTS: Compliance was good for all practices except "breathing exercises" and "using amplifiers" where it was exceptionally poor. Teachers in the training group improved significantly in total VHI score (from 14.2 to 6.8), whereas the control group showed a significant worsening (from 10.1 to 13.7). These effects were significant (P < 0.05) for total VHI score and for all subscales. The corresponding effect sizes for the training group range from -0.53 to -0.84 ( 0.83 in the overall VHI). CONCLUSION: A voice education program can have positive effects on the voice of teachers, even without dysphonia, in the middle of their teaching. Such a program may have a place in the Persian education system. PMID- 26482399 TI - Lung Vital Capacity of Choir Singers and Nonsingers: A Comparative Study. AB - OBJECTIVES: The popularity of choir singing among Indonesian university students as an extracurricular activity has increased in the last few years. Choir singers use physiology principles especially respiration roles in the voice production process. This research aims to determine the lung vital capacity difference between singers and nonsingers. METHODS: This is a cross-sectional study which uses primary data collected from spirograms of 20 university students. Half of the students were Airlangga University choir singers, and the other half were students who are not members of the choir. The spirometry tests were performed to obtain inspiratory capacity, vital capacity, and forced vital capacity of both groups. RESULTS: The average lung vital capacity of choir singers was higher (3.12 L) than that of the nonsingers (2.73 L). The average inspiratory capacity of the singer group was 1.79 L, and the average inspiratory capacity of the nonsinger group was 1.71 L. The lung vital capacity difference between singers and nonsingers group was statistically significant (P = 0.02). There was no significant inspiratory capacity difference between singers and nonsingers group in this study (P = 0.611). The forced vital capacity measurement showed a significant difference (P = 0.01) between singers (75.28%) and nonsingers (68.14%). CONCLUSION: It can be understood that the increasing vital capacity in choir singers is most likely from the expiration phase of the respiration. Further studies need to be conducted to confirm the causes of the increasing vital capacity in singers. PMID- 26482400 TI - Egg-hatching synchrony and larval cannibalism in the dock leaf beetle Gastrophysa viridula (Coleoptera: Chrysomelidae). AB - Females of leaf beetles and many other herbivorous insects lay eggs in coherent batches. Hatchlings emerge more or less simultaneously and often prey on their late-hatching clutchmates. It is not certain, however, whether this synchrony of hatching is a mere by-product of cannibalism or whether an additional synchronizing factor exists. The following simple experiment was aimed at determining the causal relationship between cannibalism and simultaneous larval emergence. Egg clutches of the dock leaf beetle Gastrophysa viridula were split into two halves. These halves were either kept as coherent groups in two separate dishes or, alternatively, only one half remained whole, whereas the other one was divided into single eggs, each of which was incubated in a separate dish. Halving of a clutch into coherent groups only slightly disrupted the synchrony of emergence. The consequence of individual isolation was more dramatic. Half clutches consisting of disconnected solitary eggs required almost twice as much time for complete emergence of all larvae, which was significantly more than cannibalism as a sole synchronizing factor might explain. Moreover, survival rates were the same in coherent half-clutches (in the presence of cannibalism) and among isolated individuals. This group effect and the small contribution of cannibalism suggest the existence of an additional synchronizing factor. Possible mechanisms underpinning this phenomenon are discussed. PMID- 26482401 TI - Assessing progression of clinical reasoning through virtual patients: An exploratory study. AB - To avoid test-driven learning, there have been discussions regarding the use of more formative assessments in health care education to promote students' deep learning. Feedback is important in formative assessment, but many students ignore it; therefore, interventions should be introduced which stimulate them to reflect on the new knowledge. The aim for this study was to explore if Virtual Patient (VP)-based formative assessments, in connection with self-evaluations, had an impact on postgraduate pediatric nursing students' development of clinical reasoning abilities. Students' self-evaluations served as the basis for measuring progress. Data was analysed using deductive content analysis. The findings showed a clear progression of the clinical reasoning ability of the students. After the first assessment, the students described feelings of uncertainty and that their knowledge gaps were exposed. At the mid-course assessment the awareness of improved clinical reasoning was obvious and the students were more certain of knowing how to solve the VP cases. In the final assessment, self-efficacy was expressed. VP-based assessments, in connection with self-evaluations, early in the education resulted in a gain of students' own identification of the concept of clinical reasoning, awareness of what to focus on during clinical practice and visualised expected clinical competence. PMID- 26482402 TI - The effect of clinical nursing instructors on student self-efficacy. AB - Clinical practicum experiences for nursing students provides the students an opportunity to apply concepts learned in class, practice skills learned in lab, and interact with patients, families, and other nurses. Although students look forward to these experiences, they often feel intimated and anxious about them. Clinical instructors play an important role in this experience and can either help or hinder student learning and self-efficacy. Using Bandura's Social Learning Theory as foundation, this descriptive study examined the relationship between perceived instructor effectiveness and student self-efficacy. Data were collected from a BSN school of nursing at a Midwestern USA comprehensive masters university. The instruments used were the Nursing Clinical Teacher Effectiveness Inventory (NCTEI) and the student self-efficacy (SSE) questionnaire. Participants (n = 236) were from a traditional nursing program with 86% female and 14% male. Data was analyzed using Pearson's correlation and MANCOVA. Results indicated: Out of the five areas of attributes, one area showed significant (p < .01) difference between the lower and higher self-efficacy groups and with specific teacher behaviors within the Evaluation category. Students with high self-efficacy reported faculty who suggested ways to improve, identified strengths and weaknesses, observed frequently, communicated expectations, gives positive reinforcement ad corrects without belittling. This can help faculty develop behaviors that increases student learning and student self-efficacy. PMID- 26482403 TI - Opinion of the Scientific Committee on Consumer Safety (SCCS)--Opinion on the safety of the use of beta-arbutin in cosmetic products. AB - CONCLUSION OF THE OPINION: The SCCS considers the use of beta-arbutin to be safe for consumers in cosmetic products in a concentration up to 7% in face creams provided that the contamination of hydroquinone in the cosmetic formulations remain below 1 ppm. A potential combined use of beta-arbutin and other hydroquinone releasing substances in cosmetic products has not been evaluated in this Opinion. PMID- 26482404 TI - Adverse food-drug interactions. AB - Food supplements and herbal products are increasingly popular amongst consumers. This leads to increased risks of interactions between prescribed drugs and these products containing bioactive ingredients. From 1991 up to 2014, 55 cases of suspected adverse drug reactions due to concomitant intake of health-enhancing products and drugs were reported to Lareb, the Netherlands Pharmacovigilance Centre. An overview of these suspected interactions is presented and their potential mechanisms of action are described. Mainly during the metabolism of xenobiotics and due to the pharmacodynamics effects interactions seem to occur, which may result in adverse drug reactions. Where legislation is seen to distinct food and medicine, legislation concerning these different bioactive products is less clear-cut. This can only be resolved by increasing the molecular knowledge on bioactive substances and their potential interactions. Thereby potential interactions can be better understood and prevented on an individual level. By considering the dietary pattern and use of bioactive substances with prescribed medication, both health professionals and consumers will be increasingly aware of interactions and these interactive adverse effects can be prevented. PMID- 26482405 TI - Effects of dimethoate in male mice reproductive parameters. AB - The aim of the current study was to investigate the ability of dimethoate (DMT) to induce reprotoxicity in male mice. The dose (20 mg/kg/day) was given orally for 30 days. A significant decrease in sperm count, motility and viability and a significant increase of morphologically abnormal spermatozoa percent in DMT treated mice was observed. Testicular Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) activities were inhibited. Also, a significant increase in lipid peroxidation level and a significant decrease in the activities of antioxidant enzymes were observed in testis of DMT mice. In addition, gene expression of glutathione peroxidase 4 (GPx4) was quantified in RNA samples extracted from the testis by real-time reverse transcription-polymerase chain reaction (RT-PCR). Compared with control, mRNA expression of GPx4 was slightly decreased after DMT-exposure. PMID- 26482406 TI - Health and human rights in Canada: a global concern. PMID- 26482407 TI - The effect of chorionic villus sampling on the fraction of cell-free fetal DNA in maternal plasma. AB - OBJECTIVE: This study aims to assess whether the fraction of cell-free fetal DNA (cffDNA) is different at 24 h or 7 days after chorionic villus sampling (CVS), compared to subjects that do not undergo CVS. METHODS: Pregnant women undergoing CVS for genetic testing and matched subjects undergoing first trimester combined screening alone were enrolled between 11(0/7) and 13(6/7) weeks gestation. The fractions of cffDNA were compared before the procedure, 24 h after and 7 days after between CVS patients and ultrasound-only patients. RESULTS: Forty-five women underwent CVS and 45 had ultrasound alone. The women undergoing CVS were, on average, older (36.8 years versus 28.5 years, p=0.001) and had a higher baseline fraction of cffDNA than women in the comparison group (11.4% versus 9.8%, p=0.033). Both groups had a decrease in the mean fraction of cffDNA after 24 h. After 7 days, the trend of the mean fraction of cffDNA continued to decline in the CVS group but began to trend toward an increase in the ultrasound only group. CONCLUSIONS: CVS does not significantly increase the fraction of cell free fetal (placental) DNA in the maternal plasma. A downward trend in cffDNA in maternal plasma is seen at 24 h and 7 days following CVS compared to baseline. PMID- 26482408 TI - Oral Immunization with a Recombinant Lactococcus lactis-Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut. AB - The induction of a potent humoral and cellular immune response in mucosal tissue is important for the development of an effective HIV vaccine. Most of the current HIV vaccines under development use the i.m. route for immunization, which is relatively poor in generating potent and long-lived mucosal immune responses. In this article, we explore the ability of an oral vaccination with a probiotic organism, Lactococcus lactis, to elicit HIV-specific immune responses in the mucosal and systemic compartments of BALB/c mice. We expressed the HIV-1 Gag-p24 on the tip of the T3 pilus of Streptococcus pyogenes as a fusion to the Cpa protein (LL-Gag). After four monthly LL-Gag oral immunizations, we observed strong Gag-specific IgG and IgA responses in serum, feces, and vaginal secretions. However, the Gag-specific CD8 T cell responses in the blood were at or below our detection limit. After an i.m. modified vaccinia Ankara/Gag boost, we observed robust Gag-specific CD8 T cell responses both in systemic and in mucosal tissues, including intraepithelial and lamina propria lymphocytes of the small intestine, Peyer's patches, and mesenteric lymph nodes. Consistent with strong immunogenicity, the LL-Gag induced activation of CD11c(+) CD11b(+) dendritic cells in the Peyer's patches after oral immunization. Our results demonstrate that oral immunization with L. lactis expressing an Ag on the tip of the group A Streptococcus pilus serves as an excellent vaccine platform to induce strong mucosal humoral and cellular immunity against HIV. PMID- 26482409 TI - Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice. AB - Regulatory T cells (Treg) play a crucial role in the maintenance of self tolerance. In this study, we sought to expand Ag-specific Tregs in vivo and investigate whether the expanded Tregs can prevent or delay the development of type 1 diabetes (T1D) in the NOD mouse model. NOD mice were treated with a combination of IL-2/anti-IL-2 Ab complex, islet Ag peptide, and rapamycin. After the combined treatment, CD4(+)CD25(+)Foxp3(+) Tregs were significantly expanded in vivo, they expressed classical Treg markers, exerted enhanced suppressive functions in vitro, and protected against spontaneous development of T1D in NOD mice. Moreover, treated mice were almost completely protected from the adoptively transferred, aggressive form of T1D caused by in vitro-activated cytotoxic islet Ag-specific CD8 T cells. Protection from T1D was transferrable by Tregs and could be attributed to reduced islet infiltration of immune cells as well as the skewing of the immune response toward a Th2 cytokine profile. This new method of peripheral immune regulation could potentially contribute to development of novel immunotherapeutic strategies to prevent the development of T1D or to promote tolerance to islet transplants without using immunosuppressive drugs for long terms. PMID- 26482410 TI - Erratum to: Intensive care medicine curricula in Europe: docendo discimus. PMID- 26482411 TI - Citrate versus heparin anticoagulation for continuous renal replacement therapy: an updated meta-analysis of RCTs. AB - PURPOSE: The purpose of this study was to evaluate the effect and safety of citrate versus heparin anticoagulation for continuous renal replacement therapy (CRRT) in critically ill patients by performing a meta-analysis of updated evidence. METHODS: Medline, Embase, and Cochrane databases were searched for eligible studies, and manual searches were also performed to identify additional trials. Randomized controlled trials (RCTs) assessing the effect of citrate versus heparin anticoagulation for CRRT were considered eligible for inclusion. RESULTS: Eleven RCTs with 992 patients and 1998 circuits met the inclusion criteria. Heparin was regionally delivered in two trials and systemically delivered in nine trials. Citrate for CRRT significantly reduced the risk of circuit loss compared to regional (HR 0.52, 95 % CI 0.35-0.77, P = 0.001) and systemic (HR 0.76, 95 % CI 0.59-0.98, P = 0.04) heparin. Citrate also reduced the incidence of filter failure (RR 0.70, 95 % CI 0.50-0.98, P = 0.04). The citrate group had a significantly lower bleeding risk than the systemic heparin group (RR 0.36, 95 % CI 0.21-0.60, P < 0.001) and a similar bleeding risk to the regional heparin group (RR 0.34, 95 % CI 0.01-8.24, P = 0.51). The incidences of heparin induced thrombocytopenia (HIT) and hypocalcemia were increased in the heparin and citrate groups, respectively. No significant survival difference was observed between the groups. CONCLUSIONS: Given the lower risk of circuit loss, filter failure, bleeding, and HIT, regional citrate should be considered a better anticoagulation method than heparin for CRRT in critically ill patients without any contraindication. PMID- 26482412 TI - Neonatal withdrawal syndrome: reaching epidemic proportions across the globe. PMID- 26482413 TI - Vaccination Programs for Endemic Infections: Modelling Real versus Apparent Impacts of Vaccine and Infection Characteristics. AB - Vaccine effect, as measured in clinical trials, may not accurately reflect population-level impact. Furthermore, little is known about how sensitive apparent or real vaccine impacts are to factors such as the risk of re-infection or the mechanism of protection. We present a dynamic compartmental model to simulate vaccination for endemic infections. Several measures of effectiveness are calculated to compare the real and apparent impact of vaccination, and assess the effect of a range of infection and vaccine characteristics on these measures. Although broadly correlated, measures of real and apparent vaccine effectiveness can differ widely. Vaccine impact is markedly underestimated when primary infection provides partial natural immunity, when coverage is high and when post vaccination infectiousness is reduced. Despite equivalent efficacy, 'all or nothing' vaccines are more effective than 'leaky' vaccines, particularly in settings with high risk of re-infection and transmissibility. Latent periods result in greater real impacts when risk of re-infection is high, but this effect diminishes if partial natural immunity is assumed. Assessments of population level vaccine effects against endemic infections from clinical trials may be significantly biased, and vaccine and infection characteristics should be considered when modelling outcomes of vaccination programs, as their impact may be dramatic. PMID- 26482414 TI - Coupling and electrical control of structural, orbital and magnetic orders in perovskites. AB - Perovskite oxides are already widely used in industry and have huge potential for novel device applications thanks to the rich physical behaviour displayed in these materials. The key to the functional electronic properties exhibited by perovskites is often the so-called Jahn-Teller distortion. For applications, an electrical control of the Jahn-Teller distortions, which is so far out of reach, would therefore be highly desirable. Based on universal symmetry arguments, we determine new lattice mode couplings that can provide exactly this paradigm, and exemplify the effect from first-principles calculations. The proposed mechanism is completely general, however for illustrative purposes, we demonstrate the concept on vanadium based perovskites where we reveal an unprecedented orbital ordering and Jahn-Teller induced ferroelectricity. Thanks to the intimate coupling between Jahn-Teller distortions and electronic degrees of freedom, the electric field control of Jahn-Teller distortions is of general relevance and may find broad interest in various functional devices. PMID- 26482415 TI - Morphology-controlled construction of hierarchical hollow hybrid SnO2@TiO2 nanocapsules with outstanding lithium storage. AB - A novel synthesis containing microwave-assisted HCl etching reaction and precipitating reaction is employed to prepare hierarchical hollow SnO2@TiO2 nanocapsules for anode materials of Li-ion batteries. The intrinsic hollow nanostructure can shorten the lengths for both ionic and electronic transport, enlarge the electrode surface areas, and improving accommodation of the anode volume change during Li insertion/extraction cycling. The hybrid multi-elements in this material allow the volume change to take place in a stepwise manner during electrochemical cycling. In particular, the coating of TiO2 onto SnO2 can enhance the electronic conductivity of hollow SnO2 electrode. As a result, the as prepared SnO2@TiO2 nanocapsule electrode exhibits a stably reversible capacity of 770 mA hg(-1) at 1 C, and the capacity retention can keep over 96.1% after 200 cycles even at high current rates. This approach may shed light on a new avenue for the fast synthesis of hierarchical hollow nanocapsule functional materials for energy storage, catalyst and other new applications. PMID- 26482416 TI - Bioremediation techniques applied to aqueous media contaminated with mercury. AB - In recent years, the environmental and human health impacts of mercury contamination have driven the search for alternative, eco-efficient techniques different from the traditional physicochemical methods for treating this metal. One of these alternative processes is bioremediation. A comprehensive analysis of the different variables that can affect this process is presented. It focuses on determining the effectiveness of different techniques of bioremediation, with a specific consideration of three variables: the removal percentage, time needed for bioremediation and initial concentration of mercury to be treated in an aqueous medium. PMID- 26482418 TI - Uptake of a newly implemented advance care planning program in a dementia diagnostic service. AB - BACKGROUND: Advance care planning (ACP) provides a framework for discussion and documentation of future care preferences when a person loses cognitive capacity. It can assist people in the early stages of dementia to document their preferences for care at later stages of the illness. METHOD: A three-stage project introduced ACP to clients with mild cognitive impairment (MCI) or recently diagnosed dementia and their families through a specialist memory clinic. Over 8 months, all English-speaking clients (n = 97) and carers (n = 92) were mailed a survey assessing completed documentation for future care; understanding of the principles of ACP and willingness to get further information about ACP (Stage 1). Participants wanting more information were invited to a seminar introducing the ACP program and service (Stage 2). Participants wanting to complete ACP documentation could make an appointment with the ACP clinicians (Stage 3). RESULTS: Forty-eight (52.2%) carers and 34 clients (35.1%) responded to the survey. Most clients (62.1%) and carers (79.1%) expressed interest in ACP, and 78.6% of clients and 63.6% of carers believed that clients should be involved in their future medical decisions. Nine clients (26.5%; diagnoses: MCI = 5; AD = 3; mixed dementia = 1) and 9 carers (18.8%) attended the seminars, and 2/48 (4%) carers and 3/34 (8.8%) clients (diagnoses: MCI = 2; AD = 1) completed ACP. CONCLUSION: Despite initial interest, ACP completion was low. The reasons for this need to be determined. Approaches that may better meet the needs of people newly diagnosed with MCI and dementia are discussed. PMID- 26482417 TI - Integration of genome-wide association and extant brain expression QTL identifies candidate genes influencing prepulse inhibition in inbred F1 mice. AB - Genetic association mapping in structured populations of model organisms can offer a fruitful complement to human genetic studies by generating new biological hypotheses about complex traits. Here we investigated prepulse inhibition (PPI), a measure of sensorimotor gating that is disrupted in a number of psychiatric disorders. To identify genes that influence PPI, we constructed a panel of half sibs by crossing 30 females from common inbred mouse strains with inbred C57BL/6J males to create male and female F1 offspring. We used publicly available single nucleotide polymorphism (SNP) genotype data from these inbred strains to perform a genome-wide association scan using a dense panel of over 150,000 SNPs in a combined sample of 604 mice representing 30 distinct F1 genotypes. We identified two independent PPI-associated loci on Chromosomes 2 and 7, each of which explained 12-14% of the variance in PPI. Searches of available databases did not identify any plausible causative coding polymorphisms within these loci. However, previously collected expression quantitative trait locus (eQTL) data from hippocampus and striatum indicated that the SNPs on Chromosomes 2 and 7 that showed the strongest association with PPI were also strongly associated with expression of several transcripts, some of which have been implicated in human psychiatric disorders. This integrative approach successfully identified a focused set of genes which can be prioritized for follow-up studies. More broadly, our results show that F1 crosses among common inbred strains can be used in combination with other informatics and expression datasets to identify candidate genes for complex behavioral traits. PMID- 26482419 TI - Epigallocatechin-3-Gallate (EGCG) Reduces Rotenone Effect on Stallion Sperm-Zona Pellucida Heterologous Binding. AB - Stallion spermatozoa are highly dependent on oxidative phosphorylation for ATP production to achieve normal sperm function and to fuel the motility. The aim of this study was to evaluate the response of equine sperm under capacitating conditions to the inhibition of mitochondrial complex I by rotenone and to test whether epigallocatechin-3-gallate (EGCG), a natural polyphenol component of green tea, could counteract this effect. After 2-h incubation of stallion spermatozoa in modified Tyrode's medium, rotenone (100 nm, 500 nm and 5 MUm) and EGCG (10, 20 and 60 MUm), alone or in combination, did not induce any significant difference on the percentage of viable cells, live sperm with active mitochondria and spermatozoa with intact acrosome. The inhibition of complex I of mitochondrial respiratory chain of stallion sperm with rotenone exerted a negative effect on heterologous ZP binding ability. EGCG at the concentrations of 10 and 20 MUm (but not of 60 MUm) induced a significant increase in the number of sperm bound to the ZP compared with that for control. Moreover, when stallion sperm were treated with rotenone 100 nm, the presence of EGCG at all the concentrations tested (10, 20 and 60 MUm) significantly increased the number of sperm bound to the ZP up to control levels, suggesting that this green tea polyphenol is able to reduce the toxicity of rotenone. PMID- 26482420 TI - An introduction to the partial least squares approach to structural equation modelling: a method for exploratory psychiatric research. AB - In psychiatry and psychology, relationship patterns connecting disorders and risk factors are always complex and intricate. Advanced statistical methods have been developed to overcome this issue, the most common being structural equation modelling (SEM). The main approach to SEM (CB-SEM for covariance-based SEM) has been widely used by psychiatry and psychology researchers to test whether a comprehensive theoretical model is compatible with observed data. While the validity of this approach method has been demonstrated, its application is limited in some situations, such as early-stage exploratory studies using small sample sizes. The partial least squares approach to SEM (PLS-SEM) has risen in many scientific fields as an alternative method that is especially useful when sample size restricts the use of CB-SEM. In this article, we aim to provide a comprehensive introduction to PLS-SEM intended to CB-SEM users in psychiatric and psychological fields, with an illustration using data on suicidality among prisoners. Researchers in these fields could benefit from PLS-SEM, a promising exploratory technique well adapted to studies on infrequent diseases or specific population subsets. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26482421 TI - The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC MAPK. AB - The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5 HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum. PMID- 26482422 TI - Milnacipran for pain in fibromyalgia in adults. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 3, 2012. That review considered both fibromyalgia and neuropathic pain, but the efficacy of milnacipran for neuropathic pain is now dealt with in a separate review.Milnacipran is a serotonin-norepinephrine (noradrenaline) reuptake inhibitor (SNRI) that is licensed for the treatment of fibromyalgia in some countries, including Canada, Russia, and the United States. OBJECTIVES: To assess the analgesic efficacy of milnacipran for pain in fibromyalgia in adults and the adverse events associated with its use in clinical trials. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE to 18 May 2015, together with reference lists of retrieved papers and reviews, and two clinical trial registries. For the earlier review, we also contacted the manufacturer. SELECTION CRITERIA: We included randomised, double-blind studies of eight weeks' duration or longer, comparing milnacipran with placebo or another active treatment in fibromyalgia in adults. DATA COLLECTION AND ANALYSIS: We extracted efficacy and adverse event data, and two review authors examined issues of study quality independently. MAIN RESULTS: We identified one new study with 100 participants for the pooled analysis. We identified two additional reports of a study using an enriched enrolment randomised withdrawal (EERW) design that included participants from earlier randomised controlled trials and an open-label study. Because this study used the same participants already included in our main analysis, and a different design, we dealt with it separately.The main analysis included six studies (five from the earlier review; 4238 participants in total), all of which were placebo controlled, and used titration to a target dose of milnacipran 100 or 200 mg, with assessment after 8 to 24 weeks of stable treatment. There were no studies with active comparators. Study quality was generally good, although the imputation method used in analyses of the primary outcomes could overestimate treatment effect.Both doses of milnacipran provided moderate levels of pain relief (at least 30% pain intensity reduction) to about 40% of participants treated, compared to 30% with placebo, giving a number needed to treat for an additional beneficial outcome (NNT) of 6 to 10 (high quality evidence). Using a stricter definition for responder and a more conservative method of analysis gave lower levels of response (while maintaining a 10% difference between milnacipran and placebo) and increased the NNT to 11 (high quality evidence). One EERW study was broadly supportive.Adverse events were common in both milnacipran (86%) and placebo (78%) groups (high quality evidence), but serious adverse events did not differ between groups (less than 2%) (low quality evidence). Nausea, constipation, and headache were the most common events showing the greatest difference between groups (number needed to treat for an additional harmful outcome (NNH) of 5.7 for nausea, 13 for constipation, and 29 for headache) (moderate quality evidence).Withdrawals for any reason were more common with milnacipran than placebo, and more common with 200 mg (NNH 9) than 100 mg (NNH 23), compared with placebo. This was largely driven by adverse event withdrawals, where the NNH compared with placebo was 14 for 100 mg and 7.0 for 200 mg (high quality evidence). Withdrawals due to lack of efficacy were less common with milnacipran than placebo but did not differ between doses (number needed to treat to prevent an additional unwanted outcome (NNTp) of 41) (moderate quality evidence). AUTHORS' CONCLUSIONS: The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority in the treatment of pain due to fibromyalgia, providing moderate levels of pain relief (at least 30%) to about 40% of participants, compared with about 30% with placebo. There were insufficient data to assess substantial levels of pain relief (at least 50%), and the use of last observation carried forward imputation may overestimate drug efficacy. Using stricter criteria for 'responder' and a more conservative method of analysis gave lower response rates (about 26% with milnacipran versus 17% with placebo). Milnacipran was associated with increased adverse events and adverse event withdrawals, which were significantly greater for the higher dose. PMID- 26482423 TI - Non-Hodgkin lymphoma in Romania: a single-centre experience. AB - Epidemiologic studies of non-Hodgkin lymphoma (NHL) in Eastern Europe are scarce in the literature. We report the experience of the "Ion Chiricuta" Institute of Oncology in Cluj-Napoca (IOCN), Romania, in the diagnosis and outcome of patients with NHL. We studied 184 consecutive NHL patients diagnosed in the Pathology Department of IOCN during the years 2004-2006. We also obtained epidemiological data from the Northwestern (NW) Cancer Registry. In the IOCN series, the most common lymphoma subtype was diffuse large B-cell lymphoma (43.5%), followed by the chronic lymphocytic leukaemia/small lymphocytic lymphoma (21.2%). T-cell lymphomas represented a small proportion (8.2%). The median age of the patients was 57 years, with a male-to-female ratio of 0.94. Patients with indolent B-cell lymphomas had the best overall survival, whereas those with mantle cell lymphoma had the worst survival. The NW Cancer Registry data showed that the occurrence of NHL in the NW region of Romania was higher in men [world age-standardized incidence rate/100 000 (ASR)-5.9; 95% CI 5.1-6.6] than in women (ASR-4.1; 95% CI 3.5-4.7) with age-standardized male-to-female ratio of 1.44 (p = 0.038). Chronic lymphocytic leukaemia/small lymphocytic lymphoma was the most common NHL in the NW region of Romania, accounting for 43% of all cases, followed by diffuse large B-cell lymphoma (36%). The 5-year, age-standardized cumulative relative survival for NHL in the County of Cluj in NW Romania, for the period of 2006-2010, was 51.4%, with 58.4% survival for men and 43.2% for women. Additional studies of NHL in Eastern Europe are needed. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26482424 TI - Distinct kinetics of DNA repair protein accumulation at DNA lesions and cell cycle-dependent formation of gammaH2AX- and NBS1-positive repair foci. AB - BACKGROUND INFORMATION: The DNA damage response is a fundamental, well-regulated process that occurs in the genome to recognise DNA lesions. Here, we studied kinetics of proteins involved in DNA repair pathways and their recruitment to DNA lesions during the cell cycle. In non-irradiated and irradiated cells, we analysed the distribution pattern and spatiotemporal dynamics of gammaH2AX, 53BP1, BMI1, MDC1, NBS1, PCNA, coilin and BRCA1 proteins. RESULTS: We observed that spontaneous and irradiation-induced foci (IRIF) demonstrated a high abundance of phosphorylated H2AX, which was consistent with 53BP1 and BMI1 protein accumulation. However, NBS1 and MDC1 proteins were recruited to nuclear bodies (NBs) to a lesser extent. Irradiation by gamma-rays significantly increased the number of 53BP1- and gammaH2AX-positive IRIF, but cell cycle dependent differences were only observed for gammaH2AX-positive foci in both non irradiated and gamma-irradiated cells. In non-irradiated cells, the G2 phase was characterised by an increased number of spontaneous gammaH2AX-foci; this increase was more pronounced after gamma-irradiation. Cells in G2 phase had the highest number of gammaH2AX-positive foci. Similarly, gamma-irradiation increased the number of NBS1-positive NBs only in G2 phase. Moreover, NBS1 accumulated in nucleoli after gamma-irradiation showed the slowest recovery after photobleaching. Analysis of protein accumulation kinetics at locally induced DNA lesions showed that in HeLa cells, BMI1, PCNA and coilin were rapidly recruited to the lesions, 10-15 s after UVA-irradiation, whereas among the other proteins studied, BRCA1 demonstrated the slowest recruitment: BRCA1 appeared at the lesion 20 min after local micro-irradiation by UVA laser. CONCLUSION: We show that the kinetics of the accumulation of selected DNA repair-related proteins is protein specific at locally induced DNA lesions, and that the formation of gammaH2AX- and NBS1-positive foci, but not 53BP1-positive NBs, is cell cycle dependent in HeLa cells. Moreover, gammaH2AX is the most striking protein present not only at DNA lesions, but also spreading out in their vicinity. SIGNIFICANCE: Our conclusions highlight the significant role of the spatiotemporal dynamics of DNA repair related proteins and their specific assembly/disassembly at DNA lesions, which can be cell type- and cell cycle dependent. PMID- 26482425 TI - Does metabolic syndrome impact cognition and emotion in Alzheimer's disease? PMID- 26482426 TI - Outcomes of transcatheter aortic valve implantation in high surgical risk and inoperable patients with aortic stenosis: a single Australian Centre experience. AB - BACKGROUND: Degenerative aortic stenosis is the most common valvular heart disease in the elderly, and many patients are not suitable for aortic valve replacement surgery. Transcatheter aortic valve implantation (TAVI) is a new therapeutic option for selected patients at high risk for surgery. AIM: To evaluate the safety and efficacy of TAVI in Australian patients. METHODS: This is a prospective study of patients undergoing TAVI for severe symptomatic aortic stenosis at The Prince Charles Hospital, Brisbane, Australia between August 2008 and July 2013. Patients were at high risk of surgical aortic valve replacement, or inoperable, as deemed by a multidisciplinary 'heart team'. Outcomes include procedural success and complications, 30-day and 1-year mortality and stroke, combined end-points as outlined by the Valve Academic Research Consortium 2 consensus document. RESULTS: Two hundred and nine patients underwent TAVI during the study period. The mean age was 83.7 +/- 6.7 years, and 101 (48%) were men. The valve systems utilised were as follows: Edwards-SAPIEN valve in 104 (49.5%), Medtronic CoreValve in 86 (41.2%) and Boston Scientific Lotus valve in 19 (9.3%) patients. Thirty-day and 1-year mortality rates were 5.7% and 11.5% respectively. Thirty-day and 1-year stroke rates were 4.3% and 6.2% respectively. The composite end-points of device success, early safety and clinical efficacy occurred in 80.4%, 27.3% and 68.4%. CONCLUSIONS: TAVI with various valve systems, delivered through several approaches, is feasible in high surgical risk and inoperable patients with severe aortic stenosis, with acceptable outcomes at short-term and intermediate-term follow up. PMID- 26482427 TI - Initiative is launched to map state level disease burden in India. PMID- 26482428 TI - Evaluation of illness severity scoring systems and risk prediction in vascular intensive care admissions. AB - INTRODUCTION: This study examines the predictive value of intensive care unit (ICU) scoring systems in a vascular ICU population. METHODS: From April 2005 to September 2011, we examined 363 consecutive ICU admissions. Simplified Acute Physiology Score II (SAPS II), Acute Physiology and Chronic Health Evaluation II (APACHE II), APACHE IV, Multiple Organ Dysfunction Score (MODS), organ dysfunctions and/or infection (ODIN), mortality prediction model (MPM) and physiologic and operative severity score for the enumeration of mortality and morbidity (POSSUM) were calculated. The Glasgow Aneurysm Score (GAS) was calculated for patients with aneurysm-related admissions. RESULTS: Overall mortality for complex vascular intervention was 11.6%. At admission, the areas under the receiver operating characteristic curve (AUCs) was 0.884 for SAPS II, 0.894 for APACHE II, 0.895 for APACHE IV, 0.902 for MODS, 0.891 for ODIN and 0.903 for MPM. At 24 h, model discrimination was best for POSSUM (AUC = 0.906) and MPM (AUC = 0.912). CONCLUSION: The good discrimination of these scoring systems indicates their value as an adjunct to clinical assessment but should not be used on an individual basis as a clinical decision-making tool. PMID- 26482430 TI - A probable case of congenital syphilis from pre-Columbian Austria. AB - This study examines the skeletal remains of a subadult from an archeological site in Austria. Radiocarbon dating and archeological attribution indicate that this individual is of pre-Columbian origin. Most of the skeleton was recovered, and only the teeth and the orbital roofs show changes. Dental defects such as the mulberry molar and a tapered, fang-like canine suggest a diagnosis of congenital syphilis. This is the first probable case of congenital syphilis from pre Columbian Central Europe. Our findings contribute to the pre-Columbian theory, offering counter evidence to the assumption that syphilis was carried from Columbus' crew from the New to the Old World. PMID- 26482429 TI - Biceps femoris late latency responses and the "notching sign" in spasticity. AB - BACKGROUND: Spasticity is a motor impairment due to lesions in the brain and spinal cord. Despite being a well-known problem, difficulties remain in the assessment of the condition. The electrophysiological and kinesiological characteristics of the patellar pendulum changes during the movement triggered by the patellar T reflex could be used to assess spasticity. METHODS: Features of the patellar pendulum during the patellar T reflex were considered using a goniometric approach in spastic patients evaluated with the Ashworth scale. Medium and late latency responses in the rectus and biceps femoris muscles were examined electrophysiologically. For each pendulum, the maximum angle extension during an oscillation of the knee joint, maximal extension time, angular velocities of extensions of the knee joint and frequency of motion due to the patellar reflex were calculated. The damping of the amplitude in the pendulum was calculated. RESULTS: The spasticity group consisted of 65 patients (38 males and 27 females) with a mean age of 47.6 +/- 14.0 years. The normal control group consisted of 25 individuals (19 males and six females) with a mean age of 32.1 +/ 10 years. The biceps and rectus femoris long latency late responses were not observed in the normal cases. The biceps femoris medium latency response was observed only in 24 % of healthy individuals; conversely, late responses were observed in 84 % of patients. Activation of the antagonist muscles at a certain level of spasticity created a notching phenomenon. Amplitude of the reflex response and mean angular velocity of the first oscillation present in a dichotomic nature in the spasticity groups. Frequency of the first pendular oscillation increased with the increase of the Ashworth scale, while the damping ratio decreased with increasing scale. The Ashworth scale showed a correlation with the damping ratio. The damping ratio strongly distinguished the spastic subgroups and showed a strong negative correlation with the Ashworth scale. CONCLUSIONS: The Ashworth scale presents a good correlation with kinesiological parameters, but it is only possible to differentiate normal and spastic cases with electrophysiologic parameters. Furthermore, the notching phenomenon could be evaluated as a determinant of spasticity. PMID- 26482432 TI - Inhalation of Talc Induces Infiltration of Macrophages and Upregulation of Manganese Superoxide Dismutase in Rats. AB - Talc is a mineral that is widely used in cosmetic products, antiseptics, paints, and rubber manufacturing. Although the toxicological effects of talc have been studied extensively, until now no detailed inhalation study of talc focusing on oxidative stress has been done. This repeated 4 weeks whole-body inhalation toxicity study of talc involved Sprague-Dawley rats. Male and female groups of rats were exposed to inhaled talc at 0, 5, 50, and 100 mg/m(3) for 6 hours daily, 5 days/week for 4 weeks. The objective was to identify the 4-week inhalation toxicity of talc and investigate antioxidant activity after exposure to talc. There were no treatment-related symptoms or mortality in rats treated with talc. Glucose (GLU) was decreased significantly in male rats exposed to 50 and 100 mg/m(3) of talc. Histopathological examination revealed infiltration of macrophages on the alveolar walls and spaces near the terminal and respiratory bronchioles. In male and female rats exposed to 100 mg/m(3) talc, expression of superoxide dismutase 2, a typical biological indicator of oxidative damage, was significantly increased. Thus, inhalation of talc induces macrophage aggregations and oxidative damage in the lung. PMID- 26482431 TI - Infant adrenocortical reactivity and behavioral functioning: relation to early exposure to maternal intimate partner violence. AB - Prenatal stress negatively affects fetal development, which in turn may affect infant hypothalamic-pituitary-adrenal (HPA) axis regulation and behavioral functioning. We examined effects of exposure to a traumatic stressor in families [intimate partner violence (IPV)] on both infants' HPA axis reactivity to stress and their internalizing and externalizing behaviors. Infants (n = 182, 50% girls, x age = 11.77 months) were exposed to a laboratory challenge task designed to induce frustration and anger (i.e. arm restraint). Saliva samples were taken pre task and 20 and 40 min post-task and then assayed for cortisol. Mothers reported on their pregnancy and postpartum IPV history, current mental health, substance use and their infants' behaviors. Structural equation modeling revealed that prenatal, but not postnatal, IPV was independently associated with infant cortisol reactivity and problem behavior. Maternal mental health predicted infant behavioral functioning but not infant HPA axis reactivity. These findings are consistent with the prenatal programing hypothesis; that is, early life stress affects later risk and vulnerability for altered physiological and behavioral regulation. PMID- 26482434 TI - Occurrence of partial RhD alleles in the Tunisian population. PMID- 26482433 TI - DNA hypermethylation and decreased mRNA expression of MAL, PRIMA1, PTGDR and SFRP1 in colorectal adenoma and cancer. AB - BACKGROUND: Colorectal cancer (CRC) development is accompanied by changes in expression for several genes; but the details of the underlying regulatory procesess remain unknown. Our aims were to assess the role of epigenetic processes in tumour formation and to identify characteristic DNA methylation and miRNA alterations in the colorectal adenoma-carcinoma sequence. METHODS: Whole genome expression profiling was performed on colonic biopsy samples (49 healthy normal, 49 colorectal adenoma (AD), 49 CRC); on laser capture microdissected (LCM) epithelial and stromal cells from 6 CRC-normal adjacent tissue (NAT) samples pairs, and on demethylated human CRC cell lines using HGU133 Plus 2.0 microarrays (Affymetrix). Methylation status of genes with gradually altering expression along the AD-CRC sequence was further analysed on 10-10 macrodissected and 5-5 LCM samples from healthy colon, from adenoma and from CRC biopsy samples using bisulfite-sequencing PCR (BS-PCR) followed by pyrosequencing. In silico miRNA prediction for the selected genes was performed with miRWALK algorithm, miRNA expression was analysed on 3 CRC-NAT sample pairs and 3 adenoma tissue samples using the Human Panel I + II (Exiqon). SFRP1 immunohistochemistry experiments were performed. RESULTS: A set of transcripts (18 genes including MAL, SFRP1, SULT1A1, PRIMA1, PTGDR) showed decreasing expression (p < 0.01) in the biopsy samples along the adenoma-carcinoma sequence. Three of those (COL1A2, SFRP2, SOCS3) showed hypermethylation and THBS2 showed hypomethylation both in AD and in CRC samples compared to NAT, while BCL2, PRIMA1 and PTGDR showed hypermethylation only in the CRC group. miR-21 was found to be significantly (p < 0.01) upregulated in adenoma and tumour samples compared to the healthy colonic tissue controls and could explain the altered expression of genes for which DNA methylation changes do not appear to play role (e.g. BCL2, MAL, PTGS2). Demethylation treatment could upregulate gene expression of genes that were found to be hypermethylated in human CRC tissue samples. Decreasing protein levels of SFRP1 was also observed along the adenoma-carcinoma sequence. CONCLUSION: Hypermethylation of the selected markers (MAL, PRIMA1, PTGDR and SFRP1) can result in reduced gene expression and may contribute to the formation of colorectal cancer. PMID- 26482435 TI - New insights into the genetic diversity of Schistosoma mansoni and S. haematobiumin Yemen. AB - BACKGROUND: Human schistosomiasis is a neglected tropical disease of great importance that remains highly prevalent in Yemen, especially amongst rural communities. In order to investigate the genetic diversity of human Schistosoma species, a DNA barcoding study was conducted on S. mansoni and S. haematobium in Yemen. METHODS: A cross-sectional study was conducted to collect urine and faecal samples from 400 children from five provinces in Yemen. The samples were examined for the presence of Schistosoma eggs. A partial fragment of the schistosome cox1 mitochondrial gene was analysed from each individual sample to evaluate the genetic diversity of the S. mansoni and S. haematobium infections. The data was also analysed together with previous published cox1 data for S. mansoni and S. haematobium from Africa and the Indian Ocean Islands. RESULTS: Overall, 31.8 % of participants were found to be excreting schistosome eggs in either the urine or faeces (8.0 % S. mansoni and 22.5 % S. haematobium). Nineteen unique haplotypes of S. mansoni were detected and split into four lineages. Furthermore, nine unique haplotypes of S. haematobium were identified that could be split into two distinct groups. CONCLUSION: This study provides novel and interesting insights into the population diversity and structure of S. mansoni and S. haematobium in Yemen. The data adds to our understanding of the evolutionary history and phylogeography of these devastating parasites whilst the genetic information could support the control and monitoring of urogenital and intestinal schistosomiasis in these endemic areas. PMID- 26482436 TI - Variation by ethnic group in premature mortality risk following self-harm: a multicentre cohort study in England. AB - BACKGROUND: Incidence and risk factors for self-harm vary according to ethnicity. People who self-harm have been shown to have increased risk of premature death, but little is known about mortality following self-harm in ethnic minority groups. METHODS: A prospective cohort study of self-harm presentations to three English cities (Derby, Manchester, Oxford) between 2000 and 2010. We linked to a national mortality dataset to investigate premature death in South Asian and Black people in comparison with White people to the end of 2012. RESULTS: Ethnicity was known for 72% of the 28,512 study cohort members: 88% were White, 5% were South Asian, and 3% were Black. After adjusting for age, gender and area level socioeconomic deprivation, the risk of all-cause mortality was lower in South Asian (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.42 - 0.62) and Black people (HR 0.46, 95% CI 0.39 - 0.55) versus White people. Suicide risk was significantly lower in Black people (HR 0.43, 95% CI 0.19 - 0.97) than in White people. Prevalence of risk factors for premature death, such as previous self-harm, psychiatric treatment or concurrent alcohol misuse, was lower in South Asian and Black people than in White people. CONCLUSIONS: The risk of death following self-harm is lower in South Asian and Black people than White people in the UK, and they also have lower prevalence of risk factors for premature death. Awareness of both protective and risk factors might help to inform clinical decisions following assessment. PMID- 26482438 TI - A straightforward method to compute average stochastic oscillations from data samples. AB - BACKGROUND: Many biological systems exhibit sustained stochastic oscillations in their steady state. Assessing these oscillations is usually a challenging task due to the potential variability of the amplitude and frequency of the oscillations over time. As a result of this variability, when several stochastic replications are averaged, the oscillations are flattened and can be overlooked. This can easily lead to the erroneous conclusion that the system reaches a constant steady state. RESULTS: This paper proposes a straightforward method to detect and asses stochastic oscillations. The basis of the method is in the use of polar coordinates for systems with two species, and cylindrical coordinates for systems with more than two species. By slightly modifying these coordinate systems, it is possible to compute the total angular distance run by the system and the average Euclidean distance to a reference point. This allows us to compute confidence intervals, both for the average angular speed and for the distance to a reference point, from a set of replications. CONCLUSIONS: The use of polar (or cylindrical) coordinates provides a new perspective of the system dynamics. The mean trajectory that can be obtained by averaging the usual cartesian coordinates of the samples informs about the trajectory of the center of mass of the replications. In contrast to such a mean cartesian trajectory, the mean polar trajectory can be used to compute the average circular motion of those replications, and therefore, can yield evidence about sustained steady state oscillations. Both, the coordinate transformation and the computation of confidence intervals, can be carried out efficiently. This results in an efficient method to evaluate stochastic oscillations. PMID- 26482437 TI - beta-Catenin is required for the differentiation of iNKT2 and iNKT17 cells that augment IL-25-dependent lung inflammation. AB - BACKGROUND: Invariant Natural Killer T (iNKT) cells have been implicated in lung inflammation in humans and also shown to be a key cell type in inducing allergic lung inflammation in mouse models. iNKT cells differentiate and acquire functional characteristics during development in the thymus. However, the correlation between development of iNKT cells in the thymus and role in lung inflammation remains unknown. In addition, transcriptional control of differentiation of iNKT cells into iNKT cell effector subsets in the thymus during development is also unclear. In this report we show that beta-catenin dependent mechanisms direct differentiation of iNKT2 and iNKT17 subsets but not iNKT1 cells. METHODS: To study the role for beta-catenin in lung inflammation we utilize mice with conditional deletion and enforced expression of beta-catenin in a well-established mouse model for IL-25-dependen lung inflammation. RESULTS: Specifically, we demonstrate that conditional deletion of beta-catenin permitted development of mature iNKT1 cells while impeding maturation of iNKT2 and 17 cells. A role for beta-catenin expression in promoting iNKT2 and iNKT17 subsets was confirmed when we noted that enforced transgenic expression of beta-catenin in iNKT cell precursors enhanced the frequency and number of iNKT2 and iNKT17 cells at the cost of iNKT1 cells. This effect of expression of beta-catenin in iNKT cell precursors was cell autonomous. Furthermore, iNKT2 cells acquired greater capability to produce type-2 cytokines when beta-catenin expression was enhanced. DISCUSSION: This report shows that beta-catenin deficiency resulted in a profound decrease in iNKT2 and iNKT17 subsets of iNKT cells whereas iNKT1 cells developed normally. By contrast, enforced expression of beta-catenin promoted the development of iNKT2 and iNKT17 cells. It was important to note that the majority of iNKT cells in the thymus of C57BL/6 mice were iNKT1 cells and enforced expression of beta-catenin altered the pattern to iNKT2 and iNKT17 cells suggesting that beta-catenin may be a major factor in the distinct pathways that critically direct differentiation of iNKT effector subsets. CONCLUSIONS: Thus, we demonstrate that beta-catenin expression in iNKT cell precursors promotes differentiation toward iNKT2 and iNKT17 effector subsets and supports enhanced capacity to produce type 2 and 17 cytokines which in turn augment lung inflammation in mice. PMID- 26482439 TI - Sandmeyer-Type Trifluoromethylthiolation and Trifluoromethylselenolation of (Hetero)Aromatic Amines Catalyzed by Copper. AB - Aromatic and heteroaromatic diazonium salts were efficiently converted into the corresponding trifluoromethylthio- or selenoethers by reaction with Me4 NSCF3 or Me4 NSeCF3 , respectively, in the presence of catalytic amounts of copper thiocyanate. These Sandmeyer-type reactions proceed within one hour at room temperature, are applicable to a wide range of functionalized molecules, and can optionally be combined with the diazotizations into one-pot protocols. PMID- 26482440 TI - Impaired perception of sincerity after severe traumatic brain injury. AB - BACKGROUND: People with a severe traumatic brain injury (TBI) often experience problems understanding non-literal utterances such as sarcasm and lies in dyadic exchanges. This study aimed to investigate whether these problems extend to settings where speakers vary in their degree of sincerity and whether such problems are associated with deficits in social cognitive abilities (emotion perception, theory of mind, and self-reported empathy) or cognitive abilities (abstract reasoning, working memory, processing speed, attentional switching). METHODS: Thirty-one adults with severe TBI (24 males) and 25 demographically matched controls (20 males) participated. They watched video vignettes depicting four actors volunteering for additional duties. Each speaker made a limited verbal response which literally suggested a willingness to be involved, but the sincerity with which the response was made was tempered by the actor's emotional demeanour. Participants rated each speaker in the vignettes for degree of sincerity (0-100%). Standardized measures of cognitive and social cognitive function were also taken. RESULTS: Control participants had excellent agreement (alpha = .90) in their rankings of actors according to sincerity. TBI participants were less consistent (alpha = .65). Overall, they were sensitive to decreasing sincerity but generally less accurate than control participants. They were poorer at differentiating between levels of sincerity and rated insincere expressions as more sincere, although they rated sincere expressions similarly. Poorer working memory and poorer social cognition were associated with poorer sincerity/sarcasm detection in the participants with TBI, but only social cognition was uniquely associated. CONCLUSIONS: Some adults with TBI have difficulty assessing the level of sincerity of speakers. Moreover, poorer social cognition abilities are associated with this difficulty. PMID- 26482441 TI - Chemo-Enzymatic Synthesis of (13)C Labeled Complex N-Glycans As Internal Standards for the Absolute Glycan Quantification by Mass Spectrometry. AB - Methods for the absolute quantification of glycans are needed in glycoproteomics, during development and production of biopharmaceuticals and for the clinical analysis of glycan disease markers. Here we present a strategy for the chemo enzymatic synthesis of (13)C labeled N-glycan libraries and provide an example for their use as internal standards in the profiling and absolute quantification of mAb glycans by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. A synthetic biantennary glycan precursor was (13)C labeled on all four amino sugar residues and enzymatically derivatized to produce a library of 15 glycan isotopologues with a mass increment of 8 Da over the natural products. Asymmetrically elongated glycans were accessible by performing enzymatic reactions on partially protected UV-absorbing intermediates, subsequent fractionation by preparative HPLC, and final hydrogenation. Using a preformulated mixture of eight internal standards, we quantified the glycans in a monoclonal therapeutic antibody with excellent precision and speed. PMID- 26482443 TI - Fluorinated counterion-enhanced emission of rhodamine aggregates: ultrabright nanoparticles for bioimaging and light-harvesting. AB - The key to ultrabright fluorescent nanomaterials is the control of dye emission in the aggregated state. Here, lipophilic rhodamine B derivatives are assembled into nanoparticles (NPs) using tetraphenylborate counterions with varied fluorination levels that should tune the short-range dye ordering. Counterion fluorination is found to drastically enhance the emission characteristics of these NPs. Highly fluorinated counterions produce 10-20 nm NPs containing >300 rhodamine dyes with a fluorescence quantum yield of 40-60% and a remarkably narrow emission band (34 nm), whereas, for other counterions, aggregation caused quenching with a weak broad-band emission is observed. NPs with the most fluorinated counterion (48 fluorines) are ~40-fold brighter than quantum dots (QD585 at 532 nm excitation) in single-molecule microscopy, showing improved photostability and suppressed blinking. Due to exciton diffusion, revealed by fluorescence anisotropy, these NPs are efficient FRET donors to single cyanine-5 acceptors with a light-harvesting antenna effect reaching 200. Finally, NPs with the most fluorinated counterion are rather stable after entry into living cells, in contrast to their less fluorinated analogue. Thus, the present work shows the crucial role of counterion fluorination in achieving high fluorescence brightness and photostability, narrow-band emission, efficient energy transfer and high intracellular stability of nanomaterials for light harvesting and bioimaging applications. PMID- 26482442 TI - Sex-specific regulation of follicle-stimulating hormone secretion by synaptotagmin 9. AB - The anterior pituitary releases six different hormones that control virtually all aspects of vertebrate physiology, yet the molecular mechanisms underlying their Ca(2+)-triggered release remain unknown. A subset of the synaptotagmin (syt) family of proteins serve as Ca(2+) sensors for exocytosis in neurons and neuroendocrine cells, and are thus likely to regulate pituitary hormone secretion. Here we show that numerous syt isoforms are highly expressed in the pituitary gland in a lobe, and sex-specific manner. We further investigated a Ca(2+)-activated isoform, syt-9, and found that it is expressed in a subpopulation of anterior pituitary cells, the gonadotropes. Follicle-stimulating hormone (FSH) and syt-9 are highly co-localized in female, but not male, mice. Loss of syt-9 results in diminished basal and stimulated FSH secretion only in females, resulting in alterations in the oestrus cycle. This work uncovers a new function for syt-9 and reveals a novel sex difference in reproductive hormone secretion. PMID- 26482444 TI - Have a nice trip. PMID- 26482445 TI - Election 2015: Vote for public health, says CPHA. PMID- 26482446 TI - Rapid endovascular treatment for stroke. PMID- 26482447 TI - Ukraine struggles with rise in PTSD. PMID- 26482448 TI - Food introduction and allergy prevention in infants. PMID- 26482449 TI - Convulsions in a 17-year-old boy after a head injury sustained while playing hockey. PMID- 26482450 TI - The health legacy of hosting major sporting events. PMID- 26482451 TI - Election 2015: party platforms on health issues. PMID- 26482453 TI - Prostate Dose-painting Radiotherapy and Radiobiological Guided Optimisation Enhances the Therapeutic Ratio. AB - AIMS: To describe the treatment of 11 patients with radiobiologically guided dose painting radiotherapy and report on toxicity. MATERIALS AND METHODS: Boost volumes were identified with functional magnetic resonance imaging scans in 11 patients with high-risk prostate cancer. Patients were treated using a dose painting approach; the boost dose was limited to 86 Gy in 37 fractions, while keeping the rectal normal tissue complication probability to 5-6%. Rotational intensity-modulated radiotherapy was used with daily image guidance and fiducial markers. RESULTS: The median dose to the prostate (outside the boost volume) and urethra was 75.4 Gy/37 fractions (range 75.1-75.8 Gy), whereas the median boost dose was 83.4 Gy (range 79.0-87.4 Gy). The tumour control probability (TCP) (Marsden model) increased from 71% for the standard plans to 83.6% [76.6-86.8%] for the dose-painting boost plans. The mean (Lyman-Kutcher-Burman) normal tissue complication probability for rectal bleeding was 5.2% (range 3.3-6.2%) and 5.2% for faecal incontinence (range 3.6-7.8%). All patients tolerated the treatment well, with a low acute toxicity profile. At a median follow-up of 36 months (range 24-50) there was no grade 3 late toxicity. Two patients had grade 2 late urinary toxicity (urethral stricture, urinary frequency and urgency), one patient had grade 1 and one grade 2 late rectal toxicity. The mean prostate-specific antigen at follow-up was 0.81 ng/ml after stopping hormone therapy; one patient relapsed biochemically at 32 months (2.70 ng/ml). CONCLUSIONS: The toxicity for this radiobiological guided dose-painting protocol was low, but we have only treated a small cohort with limited follow-up time. The advantages of this treatment approach should be established in a clinical trial. PMID- 26482452 TI - Post-radiation Plasma Epstein-Barr Virus DNA and Local Clinical Remission After Radical Intensity-modulated Radiation Therapy for Nasopharyngeal Carcinoma. AB - AIMS: We studied if post-radiation plasma Epstein-Barr virus (EBV) DNA predicted local clinical remission after radical intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma. MATERIALS AND METHODS: Patients with non metastatic nasopharyngeal carcinoma with baseline and serial plasma EBV DNA were treated with radical IMRT +/- adjunct chemotherapy. Eight weeks after IMRT, they had plasma EBV DNA and routine six-site random nasopharyngeal biopsies on the same day. A repeat biopsy was carried out every 2 weeks if residual tumours were noted in previous biopsies until 12 weeks after IMRT when local persistence was defined. Correlation of undetectable plasma EBV DNA with local clinical remission was carried out. RESULTS: Two hundred and sixty patients with serial plasma EBV DNA completed IMRT, after a median follow-up of 3.1 years. Only one (0.4%) suffered from local persistence. Area under the curve values of receiver operating characteristics of undetectable plasma EBV DNA for negative biopsy at 8 weeks and local persistence were 0.642 and 0.439, respectively. They increased to 0.856 (P = 0.007) and 0.952 (P = 0.119), respectively, when combined with age <65 years and T1/T2 stage. CONCLUSIONS: Post-treatment plasma EBV DNA was not useful to predict local clinical remission in this study, probably because of excellent local control after IMRT. However, it may serve as a reference for high-risk patients treated with older radiation techniques. PMID- 26482454 TI - Should Elderly Prostate Cancer Patients with Comorbidity be Spared from Prostate Radiation Dose Escalation? PMID- 26482455 TI - Suppression of Aedes albopictus, the Asian tiger mosquito, using a 'hot spot' approach. AB - BACKGROUND: Recent changes in climate and human behavior have led to dramatic increases in the abundance and geographic expansion of invasive mosquito vectors such as Aedes albopictus. Although source reduction has been shown to be effective in reducing mosquito populations, thousands of backyards need to be inspected during door-to-door campaigns, which is labor intensive and expensive. We identified 'hot spots' as high (five or more female or male Ae. albopictus) adult mosquito populations at very focal locations. We tested whether hot spot source reduction efforts were effective in reducing mosquito populations in the early summer season (June to July). RESULTS: Analysis of historical data from the study sites indicated the proportion of hot spots in the control site relative to the intervention site was much greater in 2011, when hot spot treatments were applied to the intervention site, than in 2012, 2013 and 2014 combined, when no sites were treated [OR (95% CI) = 3.9 (1.8, 8.5), Z = 3.39, P < 0.001). CONCLUSION: Hot spot treatments can be incorporated into existing integrated mosquito management programs to increase effectiveness while reducing the time, cost and effort spent on methods such as door-to-door source reduction. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26482456 TI - [Prognostic factors for severe infection after flexible ureteroscopy: Clinical interest of urine culture the day before surgery?]. AB - OBJECTIVES: The objectives of this study have been to determine prognostic factors for acute pyelonephritis (AP) after flexible ureteroscopy (FU), to assess the frequency of readmission for AP and to study the usefulness of urinalysis the day before surgery. METHODS: Between 2010 and 2013, 266 patients have had at least one ureteroscopy (n=325). All infectious complications and unplanned readmissions within the month after FU were retrospectively evaluated. Several data have been collected: age, sex, BMI, surgical indication (calculis or tumor), number of previous ureteroscopies, number of previous surgeries for calculis, stones number, size and location, bilateral interventions, operating time, preoperative ureteral stenting, postoperative stenting, hospitalization stay, urine culture the day before surgery (j-1) and prescription of antibiotic therapy the week before FU. Correlation between these variables and acute pyelonephritis (AP) the month following the USSR was tested (StatView 4.5, SAS Institute) (P<0.05 significant). RESULTS: We observed 24 postoperative APs (7.4%), 17 prior to hospital discharge and 7 requiring rehospitalization. In univariate analysis, the significant prognostic factors of postoperative AP have been: stone size (>14 mm) (P=0.03); operating time (70 minutes) (P<0.005); positive day - 1 urine culture (P<0.001); antibiotics treatment the week before FU (P<0.001). In multivariate analysis, antibiotics prescription during the week before USSR remained significant (P<0.002; RR 5.8 [1.9-15]). CONCLUSION: Acute pyelonephritis requiring unplanned admission after ureteroscopy is a rare complication (2.4%). Urinalysis one day before ureteroscopy could allow early antibiotic therapy and may reduce 63% of unplanned hospital admissions for acute pyelonephritis. LEVEL OF EVIDENCE: 5. PMID- 26482457 TI - Fat graft-assisted internal auditory canal closure after retrosigmoid transmeatal resection of acoustic neuroma: Technique for prevention of cerebrospinal fluid leakage. AB - The retrosigmoid transmeatal approach remains an important strategy in the surgical management of acoustic neuromas. Gross total resection of acoustic neuromas requires removal of tumor within the cerebellopontine angle as well as tumor involving the internal auditory canal (IAC). Drilling into the petrous bone of the IAC can expose petrous air cells, which can potentially result in a fistulous tract to the nasopharynx manifesting as cerebrospinal fluid (CSF) rhinorrhea. We describe our method of IAC closure using autologous fat graft and assessed the rates of postoperative CSF leakage. We performed a retrospective study of 24 consecutive patients who underwent retrosigmoid transmeatal resection of acoustic neuroma who underwent our method of fat graft-assisted IAC closure. We assessed rates of postoperative CSF leak (incisional leak, rhinorrhea, or otorrhea), pseudomeningocele formation, and occurrence of meningitis. Twenty-four patients (10 males, 14 females) with a mean age of 47 years (range 18-84) underwent fat graft-assisted IAC closure. No lumbar drains were used postoperatively. There were no instances of postoperative CSF leak (incisional leak, rhinorrhea, or otorrhea), pseudomeningocele formation, or occurrence of meningitis. There were no graft site complications. Our results demonstrate that autologous fat grafts provide a safe and effective method of IAC defect closure to prevent postoperative CSF leakage after acoustic tumor removal via a retrosigmoid transmeatal approach. The surgical technique and operative nuances are described. PMID- 26482458 TI - Isolated bilateral abducens nerve palsy due to an inflammatory process within the sella and parasellar regions. AB - Isolated bilateral abducens nerve palsy raises concern about a serious intracranial condition. Abducens nerve palsy is a common isolated palsy due to its susceptibility to injury along its long course. Non-traumatic isolated abducens nerve palsy is often caused by a mass that indirectly stretches and compresses the nerve. Pathological processes directly causing bilateral isolated involvement of the abducens nerve are rare. We describe a 24-year-old man who presented with isolated bilateral abducens nerve palsy. Radiological imaging and laboratory tests were consistent with an aggressive bacterial infectious process located in the sellar region with parasellar extension. If promptly addressed, sixth cranial nerve palsy appears to be reversible with aggressive medical therapy and endoscopic sinus surgery. PMID- 26482459 TI - Early complications after instrumentation of the lumbar spine using cortical bone trajectory technique. AB - This retrospective chart review aimed to identify and report on a series of early complications that resulted from instrumentation of the lumbar spine using the cortical bone trajectory (CBT) technique. CBT technique is a novel method for fixation of the lumbar spine. Since it was first described in 2009 this technique has gained significant popularity. Here we report a series of early complications that have developed in patients who had lumbar spine fusion using the CBT technique. A retrospective chart review was performed in which all cases utilizing the CBT technique for instrumentation of the lumbar spine by two fellowship trained spine surgeons at our institution between July 2012 and May 2014 were reviewed. Medical records were reviewed to determine the number of patients who went on to develop an early complication after instrumentation with this technique. An early complication was defined as any of the following occurring within 3 months of surgery: (1) early screw loosening confirmed by post operative CT scan, (2) evidence of fracture development confirmed by post operative CT scan, (3) intra-operatively identified durotomy, (4) superficial or deep post-operative infection and (5) neurological injury. A total of 22 cases using the CBT technique were performed in our department. Of these cases two patients went onto develop early screw loosening, one developed an intra operative pars fracture, one developed a dural tear and lastly, one patient developed both a pedicle fracture and early screw loosening. At our institution a total of five patients thus far have developed early complications after undergoing instrumentation of the lumbar spine using the CBT technique between 2012-2014. PMID- 26482460 TI - Successful anterior fusion following posterior cervical fusion for revision of anterior cervical discectomy and fusion pseudarthrosis. AB - Pseudarthrosis occurs after approximately 2-20% of anterior cervical discectomy and fusion (ACDF) procedures; it is unclear if posterior or anterior revision should be pursued. In this study, we retrospectively evaluate the outcomes in 22 patients with pseudarthrosis following ACDF and revision via posterior cervical fusion (PCF). Baseline demographics, preoperative symptoms, operative data, time to fusion failure, symptoms of pseudarthrosis, and revision method were assessed. Fusion outcome and clinical outcome were determined at last follow-up (LFU). Thirteen females (59%) and 9 (41%) males experienced pseudarthrosis at a median of 11 (range: 3-151)months after ACDF. Median age at index surgery was 51 (range: 33-67)years. All patients with pseudarthrosis presented with progressive neck pain, with median visual analog scale (VAS) score of 8 (range: 0-10), and/or myeloradiculopathy. Patients with pseudarthrosis <12 months compared to >12 months after index surgery were older (p=0.013), had more frequent preoperative neurological deficits (p=0.064), and lower baseline VAS scores (p=0.006). Fusion was successful after PCF in all patients, with median time to fusion of 10 (range: 2-14)months. Eighteen patients fused both anteriorly and posteriorly, two patients fused anteriorly only, and two patients fused posteriorly only. Median VAS neck score at LFU significantly improved from the time of pseudarthrosis (p=0.012). While uncommon, pseudarthrosis may occur after ACDF. All patients achieved successful fusion after subsequent posterior cervical fusion, with 91% fusing a previous anterior pseudarthrosis after posterior stabilization. Neck pain significantly improved by LFU in the majority of patients in this study. PMID- 26482461 TI - Erythropoietin Attenuates the Memory Deficits in Aging Rats by Rescuing the Oxidative Stress and Inflammation and Promoting BDNF Releasing. AB - Aging is a natural process accompanied with many disorders, including the memory decline. The underlying mechanisms for the age-related memory decline are complicated. Previous work suggested that oxidative stress, inflammatory disturbance, and the neurotropic absence play important roles in the age-related disorders. Thus, to seek a drug to target those abnormalities might be a possible protective approach for aging. Here, we reported that supplements with exogenous erythropoietin (EPO) for 4 weeks could partially rescue the spatial and fear memory impairments in aged rats. The EPO treatment also suppresses the oxidative stress and inflammatory response. Most importantly, EPO supplement restores the mRNA and protein levels of brain-derived neurotrophic factor (BDNF), the critical neurotropic factor for synaptic plasticity and memory. Our study strongly suggests the potential usage of EPO in an anti-aging agent clinically. PMID- 26482463 TI - The first case of antithrombin-resistant prothrombin Belgrade mutation in Japanese. PMID- 26482462 TI - Association of XPD (Lys751Gln) and XRCC1 (Arg280His) gene polymorphisms in myelodysplastic syndrome. AB - Myelodysplastic syndromes (MDSs) are heterogeneous hematopoietic disease characterized by ineffective haematopoiesis that frequently transforms into acute leukaemia. Alterations in many individual biologic pathways have been reported in MDS pathophysiology. Disease progression along the MDS, acute myeloid leukemia (AML) continuum is believed to be a consequence of stepwise accumulation of DNA mutations which infers a defect in DNA repair. The present study investigated the association between DNA repair genes (XRCC1, XRCC3, OGG1, XPD and RAD51) and the risk of developing MDS. The study was carried out in 92 primary MDS patients. The genotyping study was carried out by PCR-RFLP technique. We have studied seven single-nucleotide polymorphisms (SNPs) of five DNA repair genes (XRCC1 (Arg194Trp, Arg280His, Arg399Gln), XRCC3, XPD, RAD51 and OGG1). Significantly, a high frequency of DNA repair gene XRCC1 (Arg280His) (p=0.05) and XPD (Lys751Gln) (p=0.01) polymorphism was observed in MDS patients compared to controls. The distribution of polymorphisms in MDS subgroups showed a significant association of XRCC1 with RAEB I compared to other subgroup. Though a high frequency of XRCC1 gene polymorphism was observed in farmers and tobacco chewers, it was not statistically significant. Our study suggests that XRCC1 (Arg280His) and XPD polymorphisms are associated with risk of MDS and XRCC1 polymorphism strongly associated with advanced MDS subgroup. Hence, these polymorphisms can be used as a prognostic marker in MDS. PMID- 26482464 TI - Integrity of blood-brain barrier in primary CNS NK/T cell lymphoma: implications in the treatment of other primary CNS lymphomas. PMID- 26482465 TI - Angiotensinogen gene polymorphisms and progression of chronic kidney disease in ADPKD patients. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a multisystemic and progressive disorder characterized by cyst formation and kidney enlargement and ultimately renal failure. Reduction of CKD progression in the ADPKD by pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) using ACE inhibitors indicated the involvement of RAAS pathway in the progression of CKD. The aim of the present study is to investigate the role of angiotensinogen tag-single nucleotide polymorphisms (AGT tag-SNPs) in progression of CKD. METHODS: Twelve AGT tag-SNPs were genotyped in 102 ADPKD patients and 106 non-ADPKD subjects using FRET-based KASPar method. Genotypes and haplotypes were compared between ADPKD and controls. The effect of genotypes and hypertension on CKD progression was assessed using univariate and multivariate logistic regression. Mantel-Haenszel (M-H) stratified analysis was performed to study the interaction between CKD stages and hypertension. RESULTS: Of the twelve tag-SNPs analyzed, only rs11122578 SNP deviated Hardy-Weinberg equilibrium in controls. Significant association between two AGT polymorphisms (rs11122577 and rs4762) and ADPKD was observed. Analysis of linkage disequilibrium revealed two haplotype blocks and haplotypes are not associated with ADPKD. The univariate analysis revealed that the age, hypertension, family history of diabetes and AGT rs4762 contributed to the progression of CKD in ADPKD. The modifier effect of these factors remained even after controlling other variables in multivariate analysis. CONCLUSIONS: The results of our study suggest significant association between Thr207Met polymorphism of AGT and CKD progression and acts as an effect modifier of renal disease progression in ADPKD. PMID- 26482466 TI - Magnesium Corrosion Triggered Spontaneous Generation of H2O2 on Oxidized Titanium for Promoting Angiogenesis. AB - Although the use of reactive oxygen species (ROS) has been extensively studied, current systems employ external stimuli such as light or electrical energy to produce ROS, which limits their practical usage. In this report, biocompatible metals were used to construct a novel electrochemical system that can spontaneously generate H2O2 without any external light or voltage. The corrosion of Mg transfers electrons to Au-decorated oxidized Ti in an energetically favorable process, and the spontaneous generation of H2O2 in an oxygen reduction reaction was revealed to occur at titanium by combined spectroscopic and electrochemical analyses. The controlled release of H2O2 noticeably enhanced in vitro angiogenesis even in the absence of growth factors. Finally, a new titanium implant prototype was developed by Mg incorporation, and its potential for promoting angiogenesis was demonstrated. PMID- 26482467 TI - Outcomes of Repeat Boston Type 1 Keratoprosthesis Implantation. AB - PURPOSE: To describe the outcomes and prognostic characteristics of patients who had a repeat Boston type 1 keratoprosthesis (KPro) implantation. DESIGN: Retrospective case series. METHODS: setting: Data regarding preoperative clinical and demographic characteristics and postoperative course during initial and repeat KPro placement were collected at multiple centers across the country. PATIENTS: Forty-eight eyes underwent explantation of KPro owing to complications between September 2003 and August 2014 at 5 participating tertiary eye care centers in the United States. Of those, 36 eyes that received a subsequent replacement device were included. MAIN OUTCOME MEASURES: Visual acuity (VA) outcomes and postoperative complications. RESULTS: Ocular surface disease was significantly more common in eyes that required a device explantation, compared to those that retained the device (P < .001). Sixty-seven percent of eyes (24/36) achieved VA >= 20/200 vision after the repeat KPro. The probability of these 24 eyes maintaining VA >= 20/200 after the repeat KPro was 87% at 1 year and 75% at 2 years. Predictors of the ability to maintain vision >= 20/200 following surgery were a better last-recorded vision before explantation (P = .0002) and better vision immediately after repeat KPro (P < .001). CONCLUSION: Ocular surface disease and its complications were associated with more frequent device removal. In these patients, repeat KPro resulted in restoration of vision. A reasonable visual acuity prior to device removal was associated with favorable long-term postoperative visual acuity and retention. PMID- 26482468 TI - Successful Hepatitis C Antiviral Therapy Induces Remission of Type 2 Diabetes: A Case Report. AB - BACKGROUND: Type 2 diabetes is a well described extra-hepatic manifestation of hepatitis C infection (HCV). Eradication of HCV has led to improvements in insulin resistance but to date has not been shown to induce remission of diabetes. CASE REPORT: We report a case of a 49-year-old man with HCV and a 2 year history of T2DM on oral agents. He was initially treated with peg interferon/ribavirin (peg-IFN/rib) but did not achieve a HCV treatment response. Four years later he was retreated with peg-IFN/rib plus an HCV protease inhibitor (boceprevir). His HbA1c at the start of treatment was 7.9%. Antiviral response to HCV-therapy correlated with a significant improvement in glucose control without a change in diabetes therapy or improvement in adherence. He achieved a sustained virological response and within a year of completing antiviral therapy he no longer required medical therapy for diabetes. Two years after the completion of HCV treatment, the patient has maintained an HbA1c of 5.8% without any diabetes medications. CONCLUSIONS: This case provides evidence of the important relationship between HCV and diabetes and highlights the potential reversibility of glucose abnormalities with successful eradication of HCV. Increased awareness of this association may improve detection of undiagnosed HCV infection, identify patients with reversible causes of diabetes, guide therapeutic decisions for HCV treatment, and improve outcomes in patients with both diseases. PMID- 26482469 TI - Exploring attitudes and opinions of pharmacists toward delivering prescribing error feedback: A qualitative case study using focus group interviews. AB - BACKGROUND: Prescribing error (PE) rates have been extensively reported in the literature. Various interventions at reducing PEs have been studied with some success, yet PEs continue to be a challenge for the health care system. Prescriber feedback has been proposed as one mechanism to reduce PEs in seminal studies. Pharmacists are viewed as an integral safety net in intercepting PEs and have been suggested as best placed to deliver feedback. However, there is very limited literature considering pharmacists; attitudes, views and opinions on facilitating PE feedback. OBJECTIVES: To explore the attitudes and views of hospital pharmacists in delivering feedback on PEs to prescribers. METHODS: Twenty-four pharmacists were recruited for one of four focus groups in a large district general hospital in the Northwest of England to explore the views of pharmacists to delivering feedback on PEs. Focus groups were transcribed verbatim and analyzed using a thematic framework approach to identify current practices, beliefs and attitudes of pharmacists toward delivering PE feedback. Transcripts were independently analyzed by the research team. RESULTS: Pharmacists' views on providing feedback on PEs were organized into eight major themes; Delivery of feedback, impact of feedback, prescription error, work environment, feedback facilitator, working relationships, education and training, and system improvements. Pharmacists recognized that timely feedback on PEs was essential for prescribers to learn from their mistakes and to reduce PEs. However, delivery of feedback appeared to be inconsistent, influenced by time pressures, workload, rapport and PE severity and prescriber availability. Pharmacists reported that ward-based pharmacists in particular, were suitable to facilitate PE feedback, but expressed concern that the process may adversely affect prescriber-pharmacist rapport. Pharmacists reported limited training on delivery of feedback with formalized training required for improved consistency, and quality, of constructive feedback. CONCLUSIONS: PE feedback should be delivered to prescribers with ward-based pharmacists best suited to the role. Both direct and indirect benefits of PE feedback were reported, although potential barriers to delivering PE feedback were also identified. Pharmacists reported additional anxieties that feedback could create tensions and compromise working relationships with prescribers. PE feedback could be considered an extension of a pharmacist's role and pharmacists welcomed formalization of feedback, but were cognizant of the potential impact on their workload and expressed the need for training in the delivery of feedback. PMID- 26482470 TI - Effect of temperature, food availability, and estradiol injection on gametogenesis and gender in the pearl oyster Pinctada margaritifera. AB - The black-lip pearl oyster Pinctada margaritifera is a protandrous hermaphrodite species. Its economic value has led to the development of controlled hatchery reproduction techniques, although many aspects remain to be optimized. In order to understand reproductive mechanisms and their controlling factors, two independent experiments were designed to test hypotheses of gametogenesis and sex ratio control by environmental and hormonal factors. In one, pearl oysters were exposed under controlled conditions at different combinations of temperature (24 and 28 degrees C) and food level (10,000 and 40,000 cells mL(-1) ); whereas in the other, pearl oysters were conditioned under natural conditions into the lagoon and subjected to successive 17beta-estradiol injections (100 MUg per injection). Gametogenesis and sex ratio were assessed by histology for each treatment. In parallel, mRNA expressions of nine marker genes of the sexual pathway (pmarg-foxl2, pmarg-c43476, pmarg-c45042, pmarg-c19309, pmarg-c54338, pmarg-vit6, pmarg-zglp1, pmarg-dmrt, and pmarg-fem1-like) were investigated. Maximum maturation was observed in the treatment combining the highest temperature (28 degrees C) and the highest microalgae concentration (40,000 cells mL(-1) ), where the female sex tended to be maintained. Injection of 17beta estradiol induced a significant increase of undetermined stage proportion 2 weeks after the final injection. These results suggest that gametogenesis and gender in adult pearl oysters can be controlled by environmental factors and estrogens. While there were no significant effects on relative gene expression, the 3-gene pair expression ratio model of the sexual pathway of P. margaritifera, suggest a probable dominance of genetic sex determinism without excluding a mixed sex determination mode (genetic + environmental). J. Exp. Zool. 325A:13-24, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26482471 TI - Analysis of the vomeronasal receptor repertoire, expression and allelic diversity in swine. AB - Here we report a comprehensive analysis of the vomeronasal receptor repertoire in pigs. We identified a total of 25 V1R sequences consisting of 10 functional genes, 3 pseudogenes, and 12 partial genes, while functional V2R and FPR genes were not present in the pig genome. Pig V1Rs were classified into three subfamilies, D, F, and J. Using direct high resolution sequencing-based typing of all functional V1Rs from 10 individuals of 5 different breeds, a total of 24 SNPs were identified, indicating that the allelic diversity of V1Rs is much lower than that of the olfactory receptors. A high expression level of V1Rs was detected in the vomeronasal organ (VNO) and testes, while a low expression level of V1Rs was observed in all other tissues examined. Our results showed that pigs could serve as an interesting large animal model system to study pheromone-related neurobiology because of their genetic simplicity. PMID- 26482473 TI - Can community midwives prevent antenatal depression? An external pilot study to test the feasibility of a cluster randomized controlled universal prevention trial. AB - BACKGROUND: Repeated epidemiological surveys show no decline in depression although uptake of treatments has grown. Universal depression prevention interventions are effective in schools but untested rigorously in adulthood. Selective prevention programmes have poor uptake. Universal interventions may be more acceptable during routine healthcare contacts for example antenatally. One study within routine postnatal healthcare suggested risk of postnatal depression could be reduced in non-depressed women from 11% to 8% by giving health visitors psychological intervention training. Feasibility and effectiveness in other settings, most notably antenatally, is unknown. METHOD: We conducted an external pilot study using a cluster trial design consisting of recruitment and enhanced psychological training of randomly selected clusters of community midwives (CMWs), recruitment of pregnant women of all levels of risk of depression, collection of baseline and outcome data prior to childbirth, allowing time for women 'at increased risk' to complete CMW-provided psychological support sessions. RESULTS: Seventy-nine percent of eligible women approached agreed to take part. Two hundred and ninety-eight women in eight clusters participated and 186 termed 'at low risk' for depression, based on an Edinburgh Perinatal Depression Scale (EPDS) score of <12 at 12 weeks gestation, provided baseline and outcome data at 34 weeks gestation. All trial protocol procedures were shown to be feasible. Antenatal effect sizes in women 'at low risk' were similar to those previously demonstrated postnatally. Qualitative work confirmed the acceptability of the approach to CMWs and intervention group women. CONCLUSION: A fully powered trial testing universal prevention of depression in pregnancy is feasible, acceptable and worth undertaking. PMID- 26482474 TI - Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity. AB - In contrast to the relative morphological uniformity of histone H3 K27-mutant high-grade gliomas, H3 G34-mutant tumors present as a histopathologically heterogeneous group of neoplasms, with microscopic characteristics typical of either glioblastoma (GBM) or central nervous system primitive neuroectodermal tumors (CNS-PNET). In the current study, we performed an integrative clinical, histopathological and molecular analysis of 81 G34-mutant CNS tumors. Routinely prepared tumor tissues were investigated for genomic and epigenomic alterations. Despite their divergent histopathological appearance, CNS tumors with H3.3 G34 mutations displayed uniform epigenetic signatures, suggesting a single biological origin. Comparative cytogenetic analysis with other GBM subtypes disclosed a high frequency and high specificity of 3q and 4q loss across G34-mutant tumors. PDGFRA amplification was more common in cases with GBM than with PNET morphology (36 vs. 5 %, respectively), while CCND2 amplifications showed the opposite trend (5 vs. 27 %). Survival analysis revealed the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively. No difference in outcome was found between morphological variants (GBM vs. PNET). Thus, different histological variants of G34-mutant CNS tumors likely comprise a single biological entity (high-grade glioma with H3 G34 mutation, HGG_G34), which should be outlined in future diagnostic and therapeutic classifications. Screening for H3.3 G34 mutation should therefore be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum. PMID- 26482475 TI - Aberrant hypermethylation of RASSF2 in tumors and peripheral blood DNA as a biomarker for malignant progression and poor prognosis of esophageal squamous cell carcinoma. AB - As a tumor suppressor gene, RAS-association domain family 2 (RASSF2) is inactivated by promoter hypermethylation in different tumor cell lines and primary tumors. However, the role of RASSF2 in esophageal squamous cell carcinoma (ESCC) has remained uninvestigated. The aims of this study were to determine the role and methylation status of RASSF2 in esophageal cancer cell lines, ESCC tissues and white blood cells, and to evaluate the potential prognostic role of RASSF2 in ESCC. In the present study, we found frequent silencing of RASSF2 and up-regulation of the gene by 5-Aza-dC treatment in esophageal cancer cell lines. Aberrant methylation of the CpG sites close to the transcription start site induced silencing of RASSF2 expression and in vitro methylation of RASSF2 led to a significant decrease in luciferase activity. The results were further verified in clinical specimens and aberrant methylation of the CpG sites close to the transcription start site of RASSF2 was found in ESCC tumor tissues and peripheral white blood cells. Furthermore, RASSF2 hypermethylation was associated with lower level of RASSF2 expression. ESCC patients in stage III and IV, with negative expression or hypermethylation of the CpG sites close to the transcription start of RASSF2 demonstrated poor patient survival. Taken together, our results suggest that RASSF2 may function as a tumor suppressor gene that is inactivated through hypermethylation of CpG sites close to the transcription start site in ESCC and its expression or methylation may have prognostic implications for ESCC patients. PMID- 26482476 TI - Treatment of brain oligometastases with hypofractionated stereotactic radiotherapy utilising volumetric modulated arc therapy. AB - Stereotactic radiosurgery (SRS) is commonly used to treat brain metastases, particularly in the oligometastatic setting. This study analyses our initial experience in treating oligometastatic brain disease using Volumetric Modulated Arc Therapy (VMAT) to deliver hypofractionated stereotactic radiotherapy (HFSRT). Sixty-one patients were treated with HFSRT with a median dose of 24 Gy (range 22 40 Gy) in a median of three fractions (range 2-10 fractions). With a median follow-up of 23 months, the local control rate was 74 % for the entire cohort. Local control was 87 % for patients who had surgery with no radiological evidence of residual disease followed by HFSRT compared with 69 % in patients treated with HFSRT alone. The overall median time post radiotherapy to local failure was 8.6 months and to extracranial failure was 7.9 months. The mean time to distant brain failure was 9.9 months. Twenty-two patients (36 %) died during the study with median time to death of 4.4 months. Median overall survival (OS) from treatment was 21 months and 12 month OS was 60 %. Our experience with HFSRT using VMAT for oligometastatic brain metastases in the post-operative setting demonstrates comparable local control and survival rates compared with international published data. In the intact brain metastasis setting, local control using the dose levels and delivery in this cohort may be inferior to radio-surgical series. Local control is independent of histology. Careful selection of patients remains critical. PMID- 26482477 TI - Identification of a regulatory element responsible for salt induction of rice OsRAV2 through ex situ and in situ promoter analysis. AB - Salt is a major environmental stress factor that can affect rice growth and yields. Recent studies suggested that members of the AP2/ERF domain-containing RAV (related to ABI3/VP1) TF family are involved in abiotic stress adaptation. However, the transcriptional response of rice RAV genes (OsRAVs) to salt has not yet been fully characterized. In this study, the expression patterns of all five OsRAVs were examined under salt stress. Only one gene, OsRAV2, was stably induced by high-salinity treatment. Further expression profile analyses indicated that OsRAV2 is transcriptionally regulated by salt, but not KCl, osmotic stress, cold or ABA (abscisic acid) treatment. To elucidate the regulatory mechanism of the stress response at the transcriptional level, we isolated and characterized the promoter region of OsRAV2 (P OsRAV2 ). Transgenic analysis indicated that P OsRAV2 is induced by salt stress but not osmotic stress or ABA treatment. Serial 5' deletions and site-specific mutations in P OsRAV2 revealed that a GT-1 element located at position -664 relative to the putative translation start site is essential for the salt induction of P OsRAV2 . The regulatory function of the GT 1 element in the salt induction of OsRAV2 was verified in situ in plants with targeted mutations generated using the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system. Taken together, our results indicate that the GT-1 element directly controls the salt response of OsRAV2. This study provides a better understanding of the putative functions of OsRAVs and the molecular regulatory mechanisms of plant genes under salt stress. PMID- 26482478 TI - Functional analysis of NtMPK2 uncovers its positive role in response to Pseudomonas syringae pv. tomato DC3000 in tobacco. AB - Mitogen-activated protein kinase cascades are highly conserved signaling modules downstream of receptors/sensors and play pivotal roles in signaling plant defense against pathogen attack. Extensive studies on Arabidopsis MPK4 have implicated that the MAP kinase is involved in multilayered plant defense pathways. In this study, we identified tobacco NtMPK2 as an ortholog of AtMPK4. Transgenic tobacco overexpressing NtMPK2 markedly enhances resistance to Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) virulent and avirulent strains. Transcriptome analysis of NtMPK2-dependent genes shows that possibly the basal resistance system is activated by NtMPK2 overexpression. In addition to NtMPK2-mediated resistance, multiple pathways are involved in response to the avirulent bacteria based on analysis of Pst-responding genes, including SA and ET pathways. Notably, it is possible that biosynthesis of antibacterial compounds is responsible for inhibition of Pst DC3000 avirulent strain when programmed cell death processes in the host. Our results uncover that NtMPK2 positively regulate tobacco defense response to Pst DC3000 and improve our understanding of plant molecular defense mechanism. PMID- 26482479 TI - Arabidopsis KLU homologue GmCYP78A72 regulates seed size in soybean. AB - Soybean (Glycine max) is one of the most important crops in the world, and its yield is largely determined by grain weight and grain size. However, the genes that regulate soybean seed size have not been identified. CYP78A, which is highly conserved within terrestrial plants, regulates organ development. In Arabidopsis, AtCYP78A5/KLU has been shown to determine seed size. In the present study, soybean CYP78A72 (GmCYP78A72), one of the orthologs of KLU, was over-expressed in both Arabidopsis and soybean to examine its function in plant development. GmCYP78A72 heterologous expression in Arabidopsis resulted in enlarged sepals, petals, seeds and carpel. Over-expression of GmCYP78A72 in soybean resulted in increased pea size, which is an extremely desirable trait for enhancing productivity. Moreover, knock-down of GmCYP78A72 does not reduce grain size. However, silencing of GmCYP78A57, GmCYP78A70 and GmCYP78A72 genes in triplet reduces the seed size significantly indicating functional redundancy of these three GmCYP78A genes. In conclusion, we investigated the role of CYP78A in soybean seed regulation, and our strategy can be effectively used to engineer large seed traits in soybean varieties as well as other crops. PMID- 26482481 TI - Internal fixation of displaced inferior pole of the patella fractures using vertical wiring augmented with Krachow suturing. AB - BACKGROUND: We present the surgical technique of separate vertical wiring for displaced inferior pole fractures of the patella combined with Krachow suture and report the surgical outcomes. MATERIALS AND METHODS: Between September 2007 to May 2012, 11 consecutive patients (mean age, 54.6 years) with inferior pole fractures of the patella (AO/OTA 34-A1) were retrospectively enrolled in this study. Through longitudinal incision, all patients underwent open reduction and internal fixation by separate vertical wiring combined with Krackow suture. The range of motion, loss of fixation, and Bostman score were primary outcome measures. RESULTS: The union time was 10 weeks after surgery on average (range: 8 12). No patient had nonunion, loss of reduction and wire breakage. There was no case of wound problem and irritation from the implant. At final follow-up, the average range of motion arc was 129.4 degrees (range: 120-140). The mean Bostman score at last follow-up was 29.6 points (range: 28-30) and graded excellent in all cases. CONCLUSION: Separate vertical wiring combined with Krackow suture for inferior pole fractures of the patella is a useful technique that is easy to perform and can provide stable fixation with excellent results in knee function. PMID- 26482480 TI - Cystine accumulation attenuates insulin release from the pancreatic beta-cell due to elevated oxidative stress and decreased ATP levels. AB - The pancreatic beta-cell has reduced antioxidant defences making it more susceptible to oxidative stress. In cystinosis, a lysosomal storage disorder, an altered redox state may contribute to cellular dysfunction. This rare disease is caused by an abnormal lysosomal cystine transporter, cystinosin, which causes excessive accumulation of cystine in the lysosome. Cystinosis associated kidney damage and dysfunction leads to the Fanconi syndrome and ultimately end-stage renal disease. Following kidney transplant, cystine accumulation in other organs including the pancreas leads to multi-organ dysfunction. In this study, a Ctns gene knockdown model of cystinosis was developed in the BRIN-BD11 rat clonal pancreatic beta-cell line using Ctns-targeting siRNA. Additionally there was reduced cystinosin expression, while cell cystine levels were similarly elevated to the cystinotic state. Decreased levels of chronic (24 h) and acute (20 min) nutrient-stimulated insulin secretion were observed. This decrease may be due to depressed ATP generation particularly from glycolysis. Increased ATP production and the ATP/ADP ratio are essential for insulin secretion. Oxidised glutathione levels were augmented, resulting in a lower [glutathione/oxidised glutathione] redox potential. Additionally, the mitochondrial membrane potential was reduced, apoptosis levels were elevated, as were markers of oxidative stress, including reactive oxygen species, superoxide and hydrogen peroxide. Furthermore, the basal and activated phosphorylated forms of the redox-sensitive transcription factor NF kappaB were increased in cells with silenced Ctns. From this study, the cystinotic-like pancreatic beta-cell model demonstrated that the altered oxidative status of the cell, resulted in depressed mitochondrial function and pathways of ATP production, causing reduced nutrient-stimulated insulin secretion. PMID- 26482482 TI - Comparison of the reconstruction trochanteric antigrade nail (TAN) with the proximal femoral nail antirotation (PFNA) in the management of reverse oblique intertrochanteric hip fractures. AB - Reverse oblique intertrochanteric fractures have unique mechanical characteristics and are often treated with intramedullary implants. We compared the outcomes of the reconstruction trochanteric antegrade nail (TAN) with the proximal femoral nail antirotation (PFNA). Between July 2008 and February 2014, we reviewed all patients with reverse oblique intertrochanteric fractures treated at our hospital. Patients with pathological fractures and those who were treated with other than TAN and PFNA nailing systems were excluded. Preoperative assessment included the Abbreviated mental test score (AMT), the ASA grade, pre injury mobility and place of residence. Postoperative outcome measures included the type of implant used, time to fracture union, failures of fixation and revision surgeries. Fifty-eight patients were included and divided into two groups based on the treatment: 22 patients treated with TAN and 36 patients treated with PFNA systems. The two groups were well matched with regards to demographics and fracture type. The overall union rate was similar in both groups but the time to union was shorter in the TAN group. There were 8 implant failures in the PFNA (22.2%) group compare to none in the TAN group. Implant failure was associated with the severity of fracture (AO 31.A3.3) but was not related to fracture malreduction or screw position (Tip-apex-distance). Our study suggests that the use of reconstruction system with two screws such as TAN may be more suitable implant for reverse oblique intertrochanteric hip fractures. PMID- 26482483 TI - Long-Term Consequences of Acute Kidney Injury After Cardiac Surgery: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To determine the effect of acute kidney injury (AKI) associated with cardiac surgery on long-term mortality. DESIGN: Systematic review and meta analysis of 9 observational studies extracted from the MEDLINE and EMBASE electronic databases. SETTING: Hospitals undertaking cardiac surgery. PARTICIPANTS: The study included 35,021 cardiac surgery patients from 9 observational studies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nine studies including 35,021 patients reported incidence of AKI data. The median incidence of AKI was 27.75% (IQR, 16.3%-38.86%). There was significant variation in the reported incidence (range, 11.97%-54%), which can be explained by the different AKI definitions used in the included studies. Eight studies provided adjusted effect size data with 95% confidence intervals on the impact of the occurrence of postoperative AKI and long-term mortality outcomes. Occurrence of postoperative AKI is associated with a significantly increased risk of long-term mortality (HR, 1.68; 95% CI, 1.45-1.95; p<0.00001). Recovery of renal function before hospital discharge is associated with a lower long-term mortality risk (HR, 1.31; 95% CI, 1.16-1.47; p<0.00001) compared with patients who experienced persistent abnormal renal function on hospital discharge (HR, 2.71; 95% CI, 1.26 5.82; p = 0.01). CONCLUSIONS: There is wide variation in the reported incidence of AKI after cardiac surgery, reflecting the different AKI classification systems used. AKI after cardiac surgery is associated with an increased risk of long-term mortality. Patients with persistent renal dysfunction after hospital discharge carry a higher risk of AKI. PMID- 26482484 TI - Global Incidence and Outcomes of Adult Patients With Acute Kidney Injury After Cardiac Surgery: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To estimate the global incidence and outcomes of acute kidney injury (AKI) after cardiac surgery in adult patients. DESIGN: A systematic review and meta-analysis. SETTING: Cardiac surgery wards. PARTICIPANTS: Adult patients after cardiac surgery INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors searched PubMed, Web of Science, Cochrane Library, OVID, and EMBASE databases for all articles on cardiac surgery patients published during 2004 to 2014. Meta analyses were conducted to generate pooled incidence, mortality, ICU length of stay, and length of hospital stay. The authors also described the variations according to study design, criteria of AKI, surgical methods, countries, continents, and their economies. After a primary and secondary screen, 91 observational studies with 320,086 patients were identified. The pooled incidence rates of AKI were 22.3% (95% confidence interval [CI], 19.8 to 25.1) in total and 13.6%, 3.8%, and 2.7% at stages 1, 2, and 3, respectively, whereas 2.3% of patients received renal replacement therapy. The pooled short-term and long-term mortality were 10.7% and 30%, respectively, and increased along with the severity of stages. The pooled unadjusted odds ratio for short-term and long-term mortality in patients with AKI relative to patients without AKI was 0.144 (95% CI, 0.108 to 0.192, p<0.001) and 0.342 (95% CI 0.287-0.407, p<0.001), respectively. The pooled average ICU length of stay and length of hospital stay in the AKI group were 5.4 and 15 days, respectively, while they were 2.2 and 10.5 days in the no-AKI group. CONCLUSIONS: AKI is a great burden for patients undergoing cardiac surgery and can affect short-term and long-term prognoses of these patients. PMID- 26482485 TI - Severe Mitral Regurgitation Complicating Minimally Invasive Aortic Valve Replacement: Is It Functional or Organic? PMID- 26482486 TI - [Living Lab MACVIA. Chronic infectious diseases]. PMID- 26482488 TI - [Living Lab CVA-LR: cerebral vascular accidents in Languedoc-Roussillon]. PMID- 26482489 TI - [The psychiatric, psychological and addiction evaluation in bariatric surgery candidates: What should we assess, why and how?]. AB - Bariatric surgery is indicated in obese patients with a BMI >= 40 kg/m(2) or >= 35 kg/m(2) with serious comorbidities, in second intention in patients who failed to achieve significant weight loss after a well-managed medical, nutritional and psychotherapeutic treatment for 6 to 12 months, and in patients who are aware of the consequences of bariatric surgery and who agree with a long term medical and surgical follow-up. Such a treatment requires a preoperative multidisciplinary assessment and management, which includes a mandatory consultation with a psychiatrist or a psychologist that should be member of the multidisciplinary staff and participate in these staffs. Although one of this consultation's aim is to screen for the few patients who for which surgery is contra-indicated, in most cases, the main aim of this assessment is to screen for and manage psychiatric and psychopathologic disorders that could be temporary contra-indication, because these disorders could lead to poorer postoperative outcome when untreated. By explaining to the patient how these disorders could affect postoperative outcome and which benefits he could retrieve from their management, the patient will increase his motivation for change and he will be more likely to seek professional help for these disorders. In all cases, a systematic examination of the patient's personality and his/her ability to understand the postoperative instructions is essential before surgery because clinicians should check that the patient is able to be adherent to postoperative instructions. In addition to clinical interview, use of self-administered questionnaires before the consultation might help to determine which psychiatric or psychopathologic factors should be more closely screened during the consultation. Psychiatric disorders and addictions are highly prevalent in this population (e.g., mood and anxiety disorders, binge eating disorder, attention deficit hyperactivity disorder, addictions, personality disorders, pathological personality traits and dimensions), and when untreated, they can lead to poorer postoperative outcome (postoperative occurrence of psychiatric disorders, poorer quality of life, and sometimes to poorer weight loss or excessive weight rebound when the disorder is present during the postoperative period). A complementary training in addiction medicine is helpful given the higher risk for addictions in this population. Given that this evaluation is often the first meeting with a psychiatrist, an empathic and motivational approach is helpful to improve the patient's ability to request for a future psychiatric consultation during the follow-up. Some conditions are required for a high quality assessment: the objectives and expectations of the consultation should be systematically explained to the patient prior to the consultation by the physician who enquires for the assessment; it needs time; the psychiatrist should systematically be member of the multidisciplinary staff and should take part in regular multisciplinary staff meetings; patients should be seen alone to assess his/her readiness to change. After the consultation, a contact with the physician who enquires for the assessment should be systematic (e.g., use of a medical letter that sum up the main conclusions of the consultation; participation in regular multisciplinary staff meetings). PMID- 26482487 TI - [Living Lab MACVIA-LR. Equilibrium and the prevention of falls]. PMID- 26482490 TI - [Epilepsy and driving]. AB - Epilepsy contributes little to road traffic accidents (0.25% of accidents) compared, for instance, to alcohol abuse (at least 30 times higher). Current factors, such as age and sex, or other chronic medical conditions also increase the risk of road traffic accidents but do not carry driving restrictions. So, the European Commission fairly established rules permitting individuals having experienced one or more epileptic seizures to drive if their road accident risk is low. Road accident risk related to epileptic seizures in various clinical situations is evaluated by the driving license commission, mainly with the aid of criteria based on seizure-free periods. A person who has had an epileptic seizure should notify the authorities. He should be advised by treating physician not to drive before. In case of an authorisation, any new relevant event should be notified to the authorities in the course of legal follow-up. Improvements of the current regulations by European data registries are under way. PMID- 26482491 TI - [Living Lab MACVIA. Disability]. PMID- 26482492 TI - Reversible improvement in severe freezing of gait from Parkinson's disease with unilateral interleaved subthalamic brain stimulation. AB - Freezing of gait causes considerable morbidity in patients with Parkinson's disease and is often refractory to conventional treatments. In this double-blind, randomized evaluation, unilateral interleaved deep brain stimulation in the subthalamic nucleus/substantia nigra pars reticulata region significantly improved freezing of gait in a patient with advanced Parkinson's disease. PMID- 26482493 TI - Electrophysiological and structural MRI correlates of dystonic head rotation in drug-naive patients with torticollis. AB - INTRODUCTION: We tested whether a change in head/neck position initiates head deviation in drug-naive patients with cervical dystonia and to identify the electrophysiological and neuroanatomical correlates of dystonic head rotation. METHODS: Twenty-five consecutive drug-naive patients with cervical dystonia and 25 healthy controls underwent the simultaneous surface electromyographic (EMG) recording of sternocleidomastoid (SCM) muscle contractions during head/neck position changes, blink reflex recovery cycle (BRrc), DAT-SPECT, and advanced structural neuroimaging analysis using voxel-based morphometry (VBM). RESULTS: Surface EMG recordings of SCM muscle activity during changes in head/neck position demonstrated an insignificant asymmetric low amplitude of the SCM muscle contractions in the horizontal position in both patients and controls, but an asymmetric high amplitude in SCM muscle contractions leading to abnormal head movements in vertical positions in patients with cervical dystonia. All controls had a symmetric low increase in amplitude of SCM muscle contractions in response to changes in head/neck position. VBM analysis in 19 patients showed abnormal decreases of gray matter (GM) volume in the bilateral motor (localized in the homunculus of the head) and premotor cortices when compared to controls. In addition, the side of these neuroanatomical changes was asymmetrically related to abnormal head deviations in these patients. All subjects had normal results during BRrc and DAT-SPECT. CONCLUSIONS: The passage from inactive horizontal position to active vertical head/neck posture initiates head deviation in drug naive patients with cervical dystonia, and the anatomical correlates of this dystonic head rotation is a restricted abnormal pattern of GM changes in the motor cortices. PMID- 26482495 TI - Erratum to: Severe back pain in elite athletes: a cross-sectional study on 929 top athletes of Germany. PMID- 26482496 TI - Erratum to: Risks of permanent disability in low back pain patients associated with different job positions: a 5-year follow-up study. PMID- 26482499 TI - Adjunctive liposuction for optimizing surgical access in the obese patient. PMID- 26482497 TI - Intraoperative monitoring of somatosensory (SSEPs) and transcranial electric motor-evoked potentials (tce-MEPs) during surgical correction of neuromuscular scoliosis in patients with central or peripheral nervous system diseases. AB - PURPOSE: Combined intraoperative monitoring (IOM) of transcranial electric motor evoked potentials (tce-MEPs) and somatosensory-evoked potentials (SSEPs) is safe and effective for spinal cord monitoring during scoliosis surgery. However, the literature data regarding the reliability of spinal cord monitoring in patients with neuromuscular scoliosis are conflicting and need to be confirmed. METHODS: We reviewed IOM records of 40 consecutive patients with neuromuscular scoliosis related to central nervous system (CNS) (29 pts) or peripheral nervous system (PNS) (11 patients) diseases, who underwent posterior fusion with instrumentation surgery for spinal deformity. Multimodalitary IOM with SSEPs and tce-MEPs was performed. RESULTS: Spinal cord monitoring using at least one modality was attempted in 38/40 (95 %) patients. No false-negative results were present in either group, but a relatively high incidence of false-positive cases (4/29, 13.8 %) was noted in the CNS group. Two patients in the CNS group and one patient in the PNS group presented transient postoperative motor deficits (true positive), related to surgical manoeuvres in two cases and to malposition in the other one. CONCLUSIONS: Multimodalitary IOM is safe and effective to detect impending spinal cord and peripheral nerves dysfunction in neuromuscular scoliosis surgery. However, the interpretation of neurophysiological data may be challenging in such patients, and the rate of false-positive results is high when pre-operatory motor deficits are severe. PMID- 26482498 TI - Spinopelvic alignment and sagittal balance of asymptomatic adults with 6 lumbar vertebrae. AB - PURPOSE: The purpose of this study was to evaluate total spinal alignment in asymptomatic individuals with 6 lumbar vertebrae (LVs). METHODS: The present study comprised 167 Japanese adult volunteers with no spinal symptoms. In all individuals, standing radiographs of the entire spine were taken to measure the pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), lumbar lordosis (LL), C7 sagittal vertical axis (C7SVA), T1 slope, thoracic kyphosis (TK), C2-C7 sagittal vertical axis (C2-C7 SVA), and C2-C7 lordosis (C2-C7L). We used these parameters to compare individuals with 5LVs to those with 6LVs. We performed additional investigations regarding the relationship between L6 morphological characteristics and parameters. RESULTS: Out of 167 individuals, 6LVs were present in 29 (17.4 %). PI was significantly greater in individuals with 6LVs (64.8 degrees +/- 9.54 degrees ) than in those with 5LVs (51.3 degrees +/- 10.1 degrees , P < 0.0001). Individuals with 6LVs also had significantly larger SS, PT, and C7SVA values (SS: P = 0.0125, PT: P < 0.0001, C7SVA: P = 0.0172). LL tended to be nonsignificantly greater in individuals with 6LVs (P = 0.1588). All of these changes were more noticeable in individuals in whom the L6 vertebra was classified as type II and III according to the Castellvi classification. Meanwhile, the presence of 6LVs has little influence on the alignment of the superior lumber vertebrae. CONCLUSIONS: Asymptomatic individuals with 6LVs presented with different spinopelvic alignment compared to those with 5LVs. We need to establish a treatment strategy for symptomatic 6LV cases. PMID- 26482500 TI - Dynamic niche-specific adaptations in Neisseria meningitidis during infection. AB - Neisseria meningitidis is an opportunistic human pathogen that usually colonizes the nasopharyngeal mucosa asymptomatically. Upon invasion into the blood and central nervous system, this bacterium triggers a fulminant inflammatory reaction with the manifestations of septicemia and meningitis, causing high morbidity and mortality. To reveal the bacterial adaptations to specific and dynamic host environments, we performed a comprehensive proteomic survey of N. meningitidis isolated from the nasal mucosa, CSF and blood of a mouse disease model. We could identify 51 proteins whose expression pattern has been changed during infection, many of which have not yet been characterized. The abundance of proteins was markedly lower in the bacteria isolated from the nasal mucosa compared to the bacteria from the blood and CSF, indicating that initiating adhesion is the harshest challenge for meningococci. The high abundance of the glutamate dehydrogenase (GdhA) and Opa1800 proteins in all bacterial isolates suggests their essential role in bacterial survival in vivo. To evaluate the biological relevance of our proteomic findings, four candidate proteins from representative functional groups, such as the bacterial chaperone GroEL, IMP dehydrogenase GuaB, and membrane proteins PilQ and NMC0101, were selected and their impact on bacterial fitness was investigated by mutagenesis assays. This study provides an integrated picture of bacterial niche-specific adaptations during consecutive infection processes. PMID- 26482501 TI - Intracellular bacterial pathogens: a reemerging field of research rich with breakthroughs and opportunities. PMID- 26482502 TI - Validation study for using lab-on-chip technology for Coxiella burnetii multi locus-VNTR-analysis (MLVA) typing: application for studying genotypic diversity of strains from domestic ruminants in France. AB - Coxiella burnetii, the etiologic bacterium of Q fever zoonosis, is still difficult to control. Ruminants are often carriers and involved in human epidemics. MLVA is a promising genotyping method for molecular epidemiology. Different techniques are used to resolve the MLVA band profiles such as electrophoresis on agarose gels, capillary electrophoresis or using the microfluidic Lab-on-Chip system. In this study, system based on microfluidics electrophoresis with Lab-on-Chip technology was assessed and applied on DNA field samples to investigate the genotypic diversity of C. burnetii strains circulating in France. The Lab-on-Chip technology was first compared to agarose gel electrophoresis. Subsequently, the set-up Lab-on-Chip technology was applied on 97 samples collected from ruminants in France using the 17 markers previously described. A discordance rate of 27% was observed between Lab-on-Chip and agarose gel electrophoresis. These discrepancies were checked and resolved by sequencing. The cluster analysis revealed classification based on host species and/or geographic origin criteria. Moreover, the circulation of different genotypic strains within the same farm was also observed. In this study, MLVA with Lab-on Chip technology was shown to be more accurate, reproducible, user friendly and safer than gel electrophoresis. It also provides an extended data set from French ruminant C. burnetii circulating strains useful for epidemiological investigations. Finally, it raises some questions regarding the standardization and harmonization of C. burnetii MLVA genotyping. PMID- 26482503 TI - miR-125b regulates procalcitonin production in monocytes by targeting Stat3. AB - Sepsis is a leading cause of mortality in clinical infection, early identification and intervention is critical to improve its outcomes. Nonetheless, it is difficult to determine whether the cause of inflammation in patients is of bacterial origin at early stage. Procalcitonin (PCT) is considered as a promising marker in clinical laboratory test of bacterial infection. But the details for the regulation of PCT expression are not fully understood. miR-125b is important to immune system development and immunological host defense, while its role in the regulation of PCT production remains unexplored. In this study, we demonstrate that the expression of PCT is regulated by miR-125b in human monocytes. miR-125b modulates PCT expression by manipulating the amount and transcriptional activity of Stat3. PMID- 26482504 TI - Streptococcus pyogenes CAMP factor attenuates phagocytic activity of RAW 264.7 cells. AB - Streptococcus pyogenes produces molecules that inhibit the function of human immune system, thus allowing the pathogen to grow and spread in tissues. It is known that S. pyogenes CAMP factor increases erythrocytosis induced by Staphylococcus aureus beta-hemolysin. However, the effects of CAMP factor for immune cells are unclear. In this study, we investigated the effects of CAMP factor to macrophages. Western blotting analysis demonstrated that all examined strains expressed CAMP factor protein. In the presence of calcium or magnesium ion, CAMP factor was significantly released in the supernatant. In addition, both culture supernatant from S. pyogenes strain SSI-9 and recombinant CAMP factor dose-dependently induced vacuolation in RAW 264.7 cells, but the culture supernatant from Deltacfa isogenic mutant strain did not. CAMP factor formed oligomers in RAW 264.7 cells in a time-dependent manner. CAMP factor suppressed cell proliferation via G2 phase cell cycle arrest without inducing cell death. Furthermore, CAMP factor reduced the uptake of S. pyogenes and phagocytic activity indicator by RAW 264.7 cells. These results suggest that CAMP factor works as a macrophage dysfunction factor. Therefore, we conclude that CAMP factor allows S. pyogenes to escape the host immune system, and contribute to the spread of streptococcal infection. PMID- 26482505 TI - Expression and role of the TGF-beta family in glial cells infected with Borna disease virus. AB - A previous study revealed that the expression of the Borna disease virus (BDV) encoding phosphoprotein in glial cells was sufficient to induce neurobehavioral abnormalities resembling Borna disease. To evaluate the involvement of the TGF beta family in BDV-induced changes in cell responses by C6 glial cells, we examined the expression levels of the TGF-beta family and effects of inhibiting the TGF-beta family pathway in BDV-infected C6 (C6BV) cells. The expression of activin betaA and BMP7 was markedly increased in BDV-infected cells. Expression of Smad7, a TGF-beta family-inducible gene, was increased by BDV infection, and the expression was decreased by treatment with A-83-01 or LDN-193189, inhibitors of the TGF-beta/activin or BMP pathway, respectively. These results suggest autocrine effects of activin A and BMP7 in C6BV cells. IGFBP-3 expression was also induced by BDV infection; it was below the detection limit in C6 cells. The expression level of IGFBP-3 was decreased by LDN-193189 in C6BV cells, suggesting that endogenous BMP activity is responsible for IGFBP-3 gene induction. Our results reveal the regulatory expression of genes related to the TGF-beta family, and the role of the enhanced BMP pathway in modulating cell responses in BDV infected glial cells. PMID- 26482506 TI - Do IgA antibodies to Chlamydia trachomatis have protective role in humoral immunity: a study in reactive arthritis patients. AB - Chlamydia trachomatis-induced genitourinary Reactive Arthritis (ReA) can serve as good model for host-pathogen interaction. However, due to poor antigen presentation, cell-mediated immunity does not contribute as anticipated. Present study aims to evaluate protective role of anti-C. trachomatis antibodies vis-a vis inflammatory chlamydial Major Outer Membrane Protein (MOMP). Prospective study was undertaken in 30 patients with genitourinary ReA. 30 Rheumatoid Arthritis (RA) and 30 osteoarthritis patients constituted controls. Subjects found to be PCR-positive for C. trachomatis were investigated for presence of MOMP in Synovial Fluid (SF) by fluorescence assay while anti-C. trachomatis IgA/IgM antibodies were estimated in SF/venous blood by ELISA. C. trachomatis MOMP was evident by the presence of elementary bodies in SF of 9 ReA PCR-positive patients (30%; p < 0.05 versus controls). Local secretory IgA antibodies were detected in 12 (40%) patients with ReA (p < 0.0001 versus controls); among 12 patients with anti-chlamydial IgA antibodies, 9 showed the presence of both MOMP and IgA antibodies in SF. 58.3% ReA patients (7/12) with secretory IgA antibodies were also positive for circulatory IgA antibodies (p < 0.01 versus controls). Serum IgM antibodies were present in 4 ReA (13.3%) and in 1 RA (3.3%) patient, respectively. In conclusion, the present study suggests that in ReA patients with chronic, persistent C. trachomatis infection in synovium, the chlamydial MOMP is triggering factor for generating a protective immune response by inducing anti-C. trachomatis IgA antibodies in the SF of large number of patients. PMID- 26482507 TI - Editor's Choice - Pharmaceutical Management of Small Abdominal Aortic Aneurysms: A Systematic Review of the Clinical Evidence. AB - BACKGROUND: Management of abdominal aortic aneurysms (AAAs) relies on surgical repair of larger AAAs. Consequently medical interventions inhibiting AAA progression could greatly reduce the need for surgical repair. A spectrum of pharmaceutical strategies has been reported, albeit conclusions often appear contradictory. Given the longstanding interest in pharmaceutical AAA stabilization, a systematic review of the available literature is relevant. OBJECTIVES: The aim is to provide an up to date systematic review of the available data on pharmaceutical therapies for stabilizing or impeding AAA growth. METHODS: A search using Pubmed, Embase, Web of science, Cochrane, CINAHL, Academic Search Premier, and Science Direct identified 27 eligible papers that studied the clinical effect of the pharmaceutical therapy on AAA diameter growth. RESULTS: This review shows that there is currently no pharmaceutical strategy that reduces AAA growth. Most studies are of poor methodological quality. Initial promising reports are often not confirmed in subsequent larger studies, raising the possibility of selective reporting. CONCLUSION: There is currently no pharmaceutical means that halts AAA growth. PMID- 26482508 TI - Trends in Abdominal Aortic and Iliac Aneurysm Repairs in Norway from 2001 to 2013. AB - OBJECTIVE/BACKGROUND: The objective was to examine trends in abdominal aortic and iliac aneurysm repairs in Norway from 2001 to 2013, and study regional variations and organizational developments in this type of vascular surgery. METHODS: This was a retrospective study on aortic and iliac aneurysm repairs using data from the Norwegian Patient Register. The vascular centers were categorized by yearly volume of repairs into small (<18), medium (18-49) and large (>=50). Incidence rates were assessed per 100,000 >= 60 years. The percentage of endovascular aneurysm repairs (EVAR) was calculated among the conducted repairs at the three categories of centers and the South-Eastern, Western, Central, and Northern Norway Regional Health Authority (NRHA). RESULTS: The national incidence rates of intact repairs per 100,000 >= 60 years increased from 57.4 to 65.7 (p < .01). Ruptured repairs decreased from 19.7 to 9.2 (p < .01). The rate of EVAR increased from 6.0 to 29.9 (p < .01) in intact and from 0.4 to 2.5 (p < .01) in ruptured repairs. The vascular centers were reduced from 25 to 16. The rate of EVAR was 27.1% (p < .01) higher at large centers and 7.9% (p < .03) higher at medium centers compared with small centers, and from 11.1% to 15.7% higher (p < .01) at the Central, Western, and Northern NRHA compared with the South-Eastern NRHA, which had the most centers (also in the large category). The national increase in intact EVAR from 10.6% to 43.3% was less compared with many other Western countries. CONCLUSION: During the study period the rates of intact repairs increased while the ruptured repairs decreased. EVAR was associated with centers performing high volumes of abdominal aortic and iliac aneurysm repairs and regional authorities organized with few centers. PMID- 26482509 TI - Angiosarcoma and Dialysis-related Arteriovenous Fistulae: A Comprehensive Review. AB - OBJECTIVE/BACKGROUND: To conduct a comprehensive review of cases, presentation, diagnosis, and management of angiosarcoma in arteriovenous fistulae (AVF) created for haemodialysis. METHODS: Two authors independently conducted systematic searches and extraction of articles from the Embase, AMED, Health Management Information Consortium, and MEDLINE databases in keeping with the inclusion/exclusion criteria and Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. RESULTS: Twenty-two unique patient cases were identified; 20 of the cases were men and mean +/- SD age of presentation was 54.9 +/- 13.6 years. Nineteen cases were post-transplant and 18 were on antirejection agents. The most common presenting symptom was pain, with or without a mass. The initial diagnosis was most often thrombosis/infection of the AVF and the diagnostic interval to a correct diagnosis of angiosarcoma was between 2 and 40 weeks. Mean +/- SD time to presentation of symptoms from fistula formation was 118.9 +/- 57.5 months, while from transplant it was 96.9 +/- 70.0 months. Amputation was the most common treatment modality and mean +/- SD survival was 8.8 +/- 3.7 months. CONCLUSION: Angiosarcoma should be suspected in previously quiescent AVF that presents with pain. The presence of a rapidly enlarging mass or bleeding/bruising should be taken as alarm indicators and warrant urgent investigation in accordance with local cancer guidelines. Any surgical procedure should involve histological samples as a matter of course. PMID- 26482510 TI - Does Routine Reversal of Heparin With Protamine Sulphate in Patients Undergoing Carotid Endarterectomy Reduce Bleeding Complications Without Leading to Increased Thromboembolic Complications? PMID- 26482511 TI - Risk factors associated with lymphedema after lymph node dissection in melanoma patients. AB - BACKGROUND: Secondary lymphedema is a frequent complication after lymphadenectomy in melanoma patients, although few studies in melanoma adequately characterize risk factors for lymphedema, and of these, sample size is limited. This study aims to identify risk factors associated with the lymphedema after axillary lymph node dissection (ALND) and inguinal lymph node dissection (ILND) in a more robust cohort of melanoma patients. METHODS: We identified 269 ALND or ILND melanoma patients treated between 2008 and 2014. Demographic, clinical, and postoperative data were collected by review of the electronic medical record. Univariate and multivariate analysis were used to determine independent predictors of lymphedema. RESULTS: Fifty-six (20.8%) of the patients developed lymphedema after lymph node dissection with a median staging group of 3. ILND (odds ratio [OR] = 4.506, P < .001, 95% confidence interval [CI]: 2.289 to 8.869) and peripheral vascular disease (PVD; OR = 3.849, P = .020, 95% CI: 1.237 to 11.975) were significant predictors of lymphedema in multivariate analysis. Obese body mass index approached significance (OR = 1.802, P = .069, 95% CI: .955 to 3.399). CONCLUSIONS: PVD and ILND were the 2 factors associated with the highest risk of lymphedema in melanoma surgery with PVD increasing risk 2-fold in ILND patients and 3-fold in ALND patients. These findings may improve surgeon-patient communication of care goals and surgical risk assessment. PMID- 26482512 TI - Novel oral anticoagulants vs warfarin for the management of postoperative atrial fibrillation: clinical outcomes and cost analysis. AB - BACKGROUND: The novel oral anticoagulants (NOACs) apixaban, rivaroxaban, and dabigatran are indicated for the treatment of nonvalvular atrial fibrillation, but their use in patients with postoperative atrial fibrillation (POAF) is less well defined. METHODS: All patients undergoing isolated coronary artery bypass grafting from 2013 to 2015 (n = 598) were studied. Patients with POAF anticoagulated with either warfarin or NOACs were evaluated for differences in length of stay, blood product use, bleeding, and cost of therapy. RESULTS: There was no significant difference between the NOAC and warfarin group for any of the clinical outcomes evaluated. Time to therapeutic anticoagulation was significantly longer with warfarin. Neither group had a major bleeding event during the initial hospitalization, but 2 patients in the warfarin group had delayed major bleeding complications. Total costs were significantly reduced in patients treated with NOACs. CONCLUSIONS: Both NOACs and warfarin are safe and effective means of anticoagulation for POAF after coronary artery bypass grafting. Patients were therapeutic more rapidly and with less cost of treatment when NOACs were used. PMID- 26482513 TI - The impact of intracranial pressure monitoring on mortality after severe traumatic brain injury. AB - BACKGROUND: The effect of intracranial pressure (ICP) monitoring on mortality after severe traumatic brain injury (sTBI) remains unclear. We hypothesized that ICP monitoring would not be associated with improved survival in patients with sTBI. METHODS: A retrospective analysis was performed on sTBI patients, defined as admission Glasgow Coma Scale score of 8 or less with intracranial hemorrhage. Patients who underwent ICP monitoring were compared with patients who did not. The primary outcome measure was inhospital mortality. RESULTS: Of 123 sTBI patients meeting inclusion criteria, 40 (32.5%) underwent ICP monitoring. On bivariate and multivariate regression analyses, ICP monitoring was associated with decreased mortality (odds ratio = .32, 95% confidence interval = .10 to .99, P = .049). This finding persisted on propensity-adjusted analysis. CONCLUSIONS: ICP monitoring is associated with improved survival in adult patients with sTBI. In addition, significant variability exists in the use of ICP monitoring among patients with sTBI. PMID- 26482514 TI - Infectious complications in combined colon resection and ablation of colorectal liver metastases. AB - BACKGROUND: The multifactorial incidence of infectious complications carries considerable consequences for patients undergoing more extensive surgery with intent to cure metastatic colorectal cancer. Advances in ablation techniques have emerged as an efficacious method in regional control for liver metastasis from colorectal cancer; however, the degree of increased risk of infectious complications when ablation is performed in combination with colon resection has not been defined. METHODS: An analysis of a single institution's prospective database from August 1998 to December 2012 was performed for patients undergoing colon resection. Patients were stratified into a colon resection combined with either microwave ablation (MWA) or radiofrequency ablation (RFA) compared to a colon resection only group. Variables included baseline clinicopathologic data, type of operation, complication grade, and infectious outcome. Fisher exact test, Student t test, and analysis of variance were used to detect significance levels of P values less than .05. RESULTS: A total of 132 patients with colon cancer of various origins were identified. The group of colon resection combined with RFA and/or MWA was 53 patients (34 male:19 female) and was compared to a matched group of 79 patients (40 male:39 female) who underwent colon resection alone. Median age (58 vs 60 years; P = .209), complication rate (60.7% vs 62.5%; P = .722), infection rate (28.7% vs 35.4%; P = 1.0), mean blood loss (352.7 vs 468.4 mL; P = .452), mean blood transfused (1.36 vs .76 U; P = .247), and receipt of neoadjuvant chemotherapy (47.1% vs 51.85%; P = .724) were all similar between the ablation group and colon only group, respectively. Transfusion rate was higher in the ablation group (39.6% vs 18.9%; P = .016). Overall complication rate was 60.6%, with 32.6% infections. One mortality was observed in each group. High grade (grade, III to V) complications (35.8% vs 18.9%; P = .0112) and liver specific complications (n = 4; P = .024) were significantly increased in the combined ablation group. CONCLUSIONS: Combining MWA or RFA techniques with colon resection for liver metastasis appears to have similar infectious and overall complication rates when compared to performing an isolated resection of the primary colon cancer alone, although there may be a higher degree of complication seen in the more aggressive approach for curative intent in patients with colorectal liver metastasis. PMID- 26482515 TI - A second look at the utility of serial routine repeat computed tomographic scans in patients with traumatic brain injury. AB - BACKGROUND: The practice of a routine repeat head computed tomographic scans in patients with traumatic brain injury (TBI) is under question. The aim of our study was to evaluate the utility of a more than 1 repeat head computed tomography (M1CT) scans in patients with TBI. METHODS: We performed a 3-year analysis of a prospectively collected database of all TBI patients presenting to our level I trauma center. Patients who received M1CT scans were included. Findings and reason (without neurologic decline vs after neurologic decline) for M1CT were recorded. Primary outcome measure was neurosurgical intervention. RESULTS: A total of 296 patients that underwent M1CT were included. Of those, 291 patients (98.6%) had M1CT without a neurologic decline, and neurosurgical intervention was performed in 1 patient (.3%) who was inexaminable (Glasgow coma scale score = 6). The remaining (n = 5) had M1CT due to a neurologic decline; 4 patients (80%) of the 5 had worsening of ICH; and neurosurgical intervention was performed in 3 (75%) of the 4 patients. CONCLUSIONS: The practice of multiple repeat head computed tomographic scans should be limited to inexaminable patients or patients with neurological deterioration. PMID- 26482516 TI - Pediatric trauma system models: do systems using adult trauma surgeons exclusively compare favorably with those using pediatric surgeons after initial resuscitation with an adult trauma surgeon? AB - BACKGROUND: A shortage of pediatric surgeons exists. The purpose of this study was to evaluate pediatric outcomes using pediatric surgeons vs adult trauma surgeons. METHODS: A review was conducted at 2 level II pediatric trauma centers. Center I provides 24-hour in-house trauma surgeons for resuscitations, with patient hand-off to a pediatric surgery service. Center II provides 24-hour in house senior surgical resident coverage with an on-call trauma surgeon. Data on demographics, resource utilization, and outcomes were collected. RESULTS: Center I patients were more severely injured (injury severity score = 8.3 vs 6.2; Glasgow coma scale score = 13.7 vs 14.3). Center I patients were more often admitted to the intensive care unit (52.2% vs 33.5%) and more often mechanically ventilated (12.9% vs 7.7%), with longer hospital length of stay (2.8 vs 2.3 days). However, mortality was not different between Center I and II (3.1% vs 2.4%). By logistic regression analyses, the only variables predictive of mortality were injury severity score and Glasgow coma scale score. CONCLUSION: As it appears that trauma surgeons' outcomes compare favorably with those of pediatric surgeons, utilizing adult trauma surgeons may help alleviate shortages in pediatric surgeon coverage. PMID- 26482518 TI - Maternal myasthenia gravis: a cause for arthrogryposis multiplex congenita. AB - BACKGROUND: Arthrogryposis multiplex congenita (AMC) is a condition defined as contractures in more than two joints and in multiple body areas. The principal mechanism leading to the development of AMC in utero is decreased fetal movement. OBJECTIVE: Both fetal and maternal factors can lead to this condition, including maternal myasthenia gravis (MG) which is the topic of this review. MG is an autoimmune disease in which antibodies (immunoglobulin G) are formed against acetylcholine receptors. The disease can affect both genders, but women are more prone to develop the disease in early adulthood, a phase of life when the focus of many women is often directed towards founding a family. During pregnancy, maternal antibodies are transmitted to the fetus. RESULTS: Although the child is unaffected in most cases, the constant transmission of antibodies in utero can lead to neonatal myasthenia post-partum, a transient condition characterized by hypotonia and swallowing/respiratory difficulties as well as AMC. CONCLUSION: The maternal antibody profile in mothers with MG seems to play a key role in whether the child develops AMC or not. There are also indications that there may be a relation between neonatal MG and AMC, as well as a high recurrence rate in siblings. PMID- 26482517 TI - Outcomes of thyroidectomy from a large California state database. AB - BACKGROUND: Thyroidectomy is an operation with infrequent but potentially significant complications. This study aimed to determine risk factors for complication after thyroidectomy in California. METHODS: The California Office of Statewide Health Planning and Development database was retrospectively analyzed from 1995 to 2010. Main outcome measures were complications including death. Logistic regression identified risk factors for complications. RESULTS: There were 106,773 patients; 61% were women and 44% Caucasian; 16,287 (15%) thyroidectomies were performed at high-volume centers. Complication rates included voice change (.5%), vocal cord dysfunction (1.1%), hypocalcemia (4.5%), tracheostomy (1.62%), hematoma (1.75%), and death (.3%). There was significantly increased risk of complications for patients older than 65 compared with those younger than 40 years (odds ratio, 2.0; 95% confidence interval, 1.8 to 2.3; P < .01). High-volume hospitals were protective against complication (odds ratio, .8; 95% confidence interval, .6 to .97; P = .026). CONCLUSIONS: Older age was a significant risk factor for complication after thyroidectomy. High-volume hospitals had lower risk. This information is useful in counseling patients about the risks of thyroid surgery. PMID- 26482519 TI - The hip in arthrogryposis. AB - PATHOLOGY: Hip dislocation is seen in approximately 30 % of children with amyoplasia and approximately 50 % of these will be bilateral. TREATMENT: Closed reduction is rarely successful. Open reduction is indicated for unilateral dislocations and for the majority of bilateral dislocations. Reduction is recommended via a medial approach. RESULTS: A long-term satisfactory outcome can be achieved but with some loss of hip range of movement. PMID- 26482520 TI - Problems with the upper limb in arthrogryposis. AB - INTRODUCTION: This short paper presents a personal view of the thinking processes around the assessment and development of individualised management plans for dealing with the problems of the upper limb in Arthrogryposis in children. BACKGROUND: The paper will offer a definition of arthrogryposis, its incidence and the range of anomalies. The problems associated with joint contractures are defined. The goals of treatment include improvement in function as well as cosmesis. PRIORITIES AND GOALS OF TREATMENT: Managing the mobility of the whole child is very important in deciding what should be offered surgically in the upper limb. Early manipulation and stretching as well as the pros and cons of splints are discussed. PRINCIPLES OF SURGICAL PROCEDURES: The principles of surgery including soft tissue release, changing the position of the arc of movement of a joint, fixing stiff joints, tendon transfers and muscle transfers are presented. The value of thumb web release and the surgical procedures commonly used are described. PMID- 26482521 TI - Arthrogryposis multiplex congenita-an update. PMID- 26482522 TI - Synthesis, Characterization and Photophysical Properties of Naphtho[2,3 b]Indolizine-6,11-Dione Derivatives. AB - This communication concerns the synthesis, structural characterization and fluorescent properties of novel naphtho[2,3-b]indolizine-6,11-dione derivatives. The target compound synthesized by one-pot multicomponent reaction between naphthoquinone, indandione and pyridine derivatives.The structures of synthesized compounds were characterized by IR, 1H NMR and 13C NMR analysis. The structure of two compounds was confirmed by single crystal X-ray diffraction. The photophysical properties of synthesized compounds were measured in a variety of organic solvents. The effects of substituents and solvents on UV-vis spectra and fluorescence emission were analyzed. All compounds were showed negative solvatochromism. The fluorescence emission of these derivatives was sensitive to solvent basicity and the large Stokes shifts (up to 129 nm, 4599 (cm-1)) were observed. The similar multicomponent reaction between naphthoquinone, bindone and pyridine derivatives provide the formation of stable non-fluorescent compound possessing zwitter-ionic structure. PMID- 26482523 TI - Organizing pneumonia/non-specific interstitial pneumonia overlap is associated with unfavorable lung disease progression. AB - BACKGROUND: Overlapping forms of interstitial pneumonia have been recognized, but are likely underappreciated, and their clinical, radiologic, and histologic characteristics are not well-defined. METHODS: We identified 38 patients with surgical lung biopsy demonstrating histologic organizing pneumonia (OP) or histologic organizing pneumonia/non-specific interstitial pneumonia overlap (OP/NSIP) who met established multi-disciplinary clinical-radiologic-histologic criteria for OP. For each patient, radiologic and co-histologic findings were assessed, and clinical outcome was characterized as disease resolution (complete or near-complete resolution of radiologic opacities and absence of chronic respiratory symptoms) or unfavorable disease progression (death due to respiratory failure or forced vital capacity < 70% predicted > six months from diagnosis). RESULTS: Seven of 38 patients had clinical-radiologic-histologic focal OP. Focal OP was associated with histologic OP (p = 0.019), and all seven patients demonstrated disease resolution. In the remaining 31 patients with cryptogenic or autoimmune-associated OP, 21 patients had histologic OP/NSIP, and 10 had histologic OP. Histologic OP/NSIP was associated with ground glass opacity (GGO, p = 0.012), reticulation (p = 0.029), traction bronchiectasis (p = 0.029), reactive pneumocytes (p = 0.013), and unfavorable disease progression (p < 0.0001). Histologic OP was associated with consolidation (p = 0.028) and disease resolution (p < 0.0001). Multivariate analysis demonstrated histologic OP/NSIP (p < 0.001) and radiologic GGO (p = 0.041) to be independently associated with unfavorable disease progression. CONCLUSIONS: OP/NSIP overlap, either idiopathic or autoimmune-associated and identified by histologic and radiologic findings, was associated with unfavorable disease progression, and should therefore be recognized as a characteristic clinical-radiologic-histologic entity. PMID- 26482524 TI - Importance of donor history of restless leg syndrome and pica to asses iron deficiency. AB - Iron deficiency is associated with neuropsychological changes such as restless leg syndrome (RLS), pica, hair loss, etc. Our objective was to assess usefulness of history of RLS and pica in relation with iron stores in blood donors. During medical examination, apart from routine questionnaires specific history of RLS and pica was elicited. Along with hemoglobin markers of iron deficiency such as s. iron, s. ferritin and mean corpuscular volume were analyzed. Out of 400 blood donors 41 had h/o pica/RLS/pagophagia. Positive and negative predictive value of above history is 73.17% and 80.5% respectively. We recommend the use of a screening question for pica and/or RLS in blood donor questionnaire. PMID- 26482525 TI - Understanding Physical Developer (PD): Part II--Is PD targeting eccrine constituents? AB - Physical developer (PD) is a fingermark development technique that deposits silver onto fingermark ridges. It is the only technique currently in routine operational use that gives results on porous substrates that have been wet. There is a reasonable understanding of the working solution chemistry, but the chemical constituent(s) contained in fingermark residue that are specifically targeted by PD are largely unknown. A better understanding of the PD technique will permit a more informed selection of alternative or complementary detection methods, and greater usage in operational laboratories. Recent research by our group has shown that PD does not selectively target the lipids present in the residue. This research investigated the hypothesis that PD targets the eccrine constituents in fingermark residue. This was tested by comparison of PD and indanedione-zinc (Ind Zn) treated natural fingermarks that had been deposited successively, and marks that had been deposited with a ten second interval in between depositions. Such an interval allows for the regeneration of secretions from the pores located on the ridges of the fingers. On fingermark depletions with no time interval between depositions, PD and Ind-Zn treated depletions successively (and comparatively) decreased in development intensity as the amount of residue diminished. Short time intervals in between successive depletions resulted in additional secretions from the pores intermittently occurring, the increased development of which was visualised by treatment with both PD and Ind-Zn. The changes in development intensity were seen with both techniques on the same split depletions in a series, comparably and proportionately. These results indicate that the components targeted by PD are contained in the material excreted by the friction ridge pores through its mirrored development with Ind-Zn. Repetition of the experiments on marks that only contained eccrine material showed good Ind-Zn development but poor results with PD. This indicates that there are other constituents contained in "natural" fingermarks that are required to be present for PD to be able to target constituents in the eccrine sweat. It may be that the required constituents in the natural residues are non-water soluble, and that these protect the eccrine constituents from solubilisation in the aqueous washes employed in the PD method. Further research is being undertaken to determine whether PD is targeting specific compounds in the pore secretions, or a mixture of compounds consisting of the eccrine material, epidermal lipids and sebaceous lipids typically present in latent fingermark residues. PMID- 26482526 TI - Alexithymia is associated with attenuated automatic brain response to facial emotion in clinical depression. AB - BACKGROUND: Alexithymia is a clinically relevant personality trait related to difficulties in recognizing and describing emotions. Previous studies examining the neural correlates of alexithymia have shown mainly decreased response of several brain areas during emotion processing in healthy samples and patients suffering from autism or post-traumatic stress disorder. In the present study, we examined the effect of alexithymia on automatic brain reactivity to negative and positive facial expressions in clinical depression. METHODS: Brain activation in response to sad, happy, neutral, and no facial expression (presented for 33 ms and masked by neutral faces) was measured by functional magnetic resonance imaging at 3 T in 26 alexithymic and 26 non-alexithymic patients with major depression. RESULTS: Alexithymic patients manifested less activation in response to masked sad and happy (compared to neutral) faces in right frontal regions and right caudate nuclei than non-alexithymic patients. CONCLUSIONS: Our neuroimaging study provides evidence that the personality trait alexithymia has a modulating effect on automatic emotion processing in clinical depression. Our findings support the idea that alexithymia could be associated with functional deficits of the right hemisphere. Future research on the neural substrates of emotion processing in depression should assess and control alexithymia in their analyses. PMID- 26482527 TI - Interpreting a randomized trial report: evidence-based practice for the clinician. AB - The purpose of this article is to present a structured approach to help the reader with the objective interpretation of published randomized clinical trials. This process will promote an organized and critical appraisal of scientific evidence, which we believe to be an essential step prior to the introduction of published scientific findings into clinical practice. The reason to personally scrutinize and critically assess published reports is that the process of peer review is by no means perfect and methodological flaws can be uncovered, even in articles published in prestigious journals. The article elaborates on the substance of the consolidated standards of reporting trials (CONSORT) statements intended to facilitate the complete reporting of trials and aid in their critical assessment. The structure of the CONSORT guidelines was used as a basis for specific commentary, including cautions for the clinical interpretation, implications and impact of published randomized trial reports. PMID- 26482528 TI - Radiation dose measurements of an on-board imager X-ray unit using optically stimulated luminescence dosimeters. AB - Cone beam computed tomography (CBCT) is now widely used to image radiotherapy patients prior to treatment for the purpose of accurate patient setup. However each CBCT image delivered to a patient increases the total radiation dose that they receive. The measurement of the dose delivered from the CBCT images is not readily performed in the clinic. In this study, we have used commercially available optically stimulated luminescence (OSLD) dosimeters to measure the dose delivered by the Varian OBI on a radiotherapy linear accelerator. Calibration of the OSLDs was achieved by using a therapeutic X-ray unit. The dose delivered by a head CBCT scan was found to be 3.2 +/- 0.3 mGy which is similar in magnitude to the dose of a head computed tomography (CT) scan. The results of this study suggest that the radiation hazard associated with CBCT is of a similar nature to that of conventional CT scans. We have also demonstrated that the OSLDs are suitable for these low X-ray dose measurements. PMID- 26482529 TI - Reducing shield thickness and backscattered radiation using a multilayered shield for 6-10 MeV electron beams. AB - Intraoral and external electron shields used in radiotherapy are designed to minimize radiation exposure to non-treatment tissue. Sites where shields are used include but are not limited to, the treatment of lips, cheeks and ears whilst shielding the underlying oral cavity, tongue, gingival or temporal region. A commonly known and published effect, concerns the enhancement in dose that can occur on the beam side on an electron shield caused by an increase in electron backscatter radiation. In this work a lead shield has been designed incorporating copper, aluminium and wax in a step down filter arrangement to minimise backscatter whilst minimizing overall shield thickness for better clinical setup and ease of use. For electron beams ranging from 6 to 10 MeV, a standard shield design of 4 mm lead, 0.6 mm copper, 1.0 mm aluminium and 1.5 mm wax (3.1 mm added filtration, 7.1 mm total thickness) provided adequate backscatter and transmission reduction to match a standard 4.5 mm lead and 10 mm wax (total thickness 14.5 mm) electron shield. Dose enhancement values of no more than 10 % were measured utilising this shield design with a 50 % reduction in shield thickness. The thinner shield will not only allow easier patient set up but should be tolerated better by patients when mucosal reactions occur as they place less physical pressure on these sites during treatment due to their smaller size. PMID- 26482530 TI - A rapid compression technique for 4-D functional MRI images using data rearrangement and modified binary array techniques. AB - Compression techniques are vital for efficient storage and fast transfer of medical image data. The existing compression techniques take significant amount of time for performing encoding and decoding and hence the purpose of compression is not fully satisfied. In this paper a rapid 4-D lossy compression method constructed using data rearrangement, wavelet-based contourlet transformation and a modified binary array technique has been proposed for functional magnetic resonance imaging (fMRI) images. In the proposed method, the image slices of fMRI data are rearranged so that the redundant slices form a sequence. The image sequence is then divided into slices and transformed using wavelet-based contourlet transform (WBCT). In WBCT, the high frequency sub-band obtained from wavelet transform is further decomposed into multiple directional sub-bands by directional filter bank to obtain more directional information. The relationship between the coefficients has been changed in WBCT as it has more directions. The differences in parent-child relationships are handled by a repositioning algorithm. The repositioned coefficients are then subjected to quantization. The quantized coefficients are further compressed by modified binary array technique where the most frequently occurring value of a sequence is coded only once. The proposed method has been experimented with fMRI images the results indicated that the processing time of the proposed method is less compared to existing wavelet based set partitioning in hierarchical trees and set partitioning embedded block coder (SPECK) compression schemes [1]. The proposed method could also yield a better compression performance compared to wavelet-based SPECK coder. The objective results showed that the proposed method could gain good compression ratio in maintaining a peak signal noise ratio value of above 70 for all the experimented sequences. The SSIM value is equal to 1 and the value of CC is greater than 0.9 for all experiments. Subjective evaluation on the reconstructed images indicated that the proposed method could reproduce the diagnostic features of fMRI images clearly. PMID- 26482531 TI - Pathophysiological analyses of cortical malformation using gyrencephalic mammals. AB - One of the most prominent features of the cerebral cortex of higher mammals is the presence of gyri. Because malformations of the cortical gyri are associated with severe disability in brain function, the mechanisms underlying malformations of the cortical gyri have been of great interest. Combining gyrencephalic carnivore ferrets and genetic manipulations using in utero electroporation, here we successfully recapitulated the cortical phenotypes of thanatophoric dysplasia (TD) by expressing fibroblast growth factor 8 in the ferret cerebral cortex. Strikingly, in contrast to TD mice, our TD ferret model showed not only megalencephaly but also polymicrogyria. We further uncovered that outer radial glial cells (oRGs) and intermediate progenitor cells (IPs) were markedly increased. Because it has been proposed that increased oRGs and/or IPs resulted in the appearance of cortical gyri during evolution, it seemed possible that increased oRGs and IPs underlie the pathogenesis of polymicrogyria. Our findings should help shed light on the molecular mechanisms underlying the formation and malformation of cortical gyri in higher mammals. PMID- 26482533 TI - Live fast die young life history in females: evolutionary trade-off between early life mating and lifespan in female Drosophila melanogaster. AB - The trade-off between survival and reproduction is fundamental to life history theory. Sexual selection is expected to favour a 'live fast die young' life history pattern in males due to increased risk of extrinsic mortality associated with obtaining mates. Sexual conflict may also drive a genetic trade-off between reproduction and lifespan in females. We found significant additive genetic variance in longevity independent of lifetime mating frequency, and in early life mating frequency. There was significant negative genetic covariance between these traits indicating that females from families characterized by high levels of multiple mating early in life die sooner than females that engage in less intense early life mating. Thus, despite heritable variation in both traits, their independent evolution is constrained by an evolutionary trade-off. Our findings indicate that, in addition to the well-known male-driven direct costs of mating on female lifespan (mediated by male harassment and harmful effects of seminal fluids), females with a genetic propensity to mate multiply live shorter lives. We discuss the potential role of sexual conflict in driving the evolutionary trade-off between reproduction and lifespan in Drosophila. More generally, our data show that, like males, females can exhibit a live fast die young life history strategy. PMID- 26482532 TI - The non-octarepeat copper binding site of the prion protein is a key regulator of prion conversion. AB - The conversion of the prion protein (PrP(C)) into prions plays a key role in transmissible spongiform encephalopathies. Despite the importance for pathogenesis, the mechanism of prion formation has escaped detailed characterization due to the insoluble nature of prions. PrP(C) interacts with copper through octarepeat and non-octarepeat binding sites. Copper coordination to the non-octarepeat region has garnered interest due to the possibility that this interaction may impact prion conversion. We used X-ray absorption spectroscopy to study copper coordination at pH 5.5 and 7.0 in human PrP(C) constructs, either wild-type (WT) or carrying pathological mutations. We show that mutations and pH cause modifications of copper coordination in the non octarepeat region. In the WT at pH 5.5, copper is anchored to His96 and His111, while at pH 7 it is coordinated by His111. Pathological point mutations alter the copper coordination at acidic conditions where the metal is anchored to His111. By using in vitro approaches, cell-based and computational techniques, we propose a model whereby PrP(C) coordinating copper with one His in the non-octarepeat region converts to prions at acidic condition. Thus, the non-octarepeat region may act as the long-sought-after prion switch, critical for disease onset and propagation. PMID- 26482534 TI - Engineered microparticles based on drug-polymer coprecipitates for ocular controlled delivery of Ciprofloxacin: influence of technological parameters. AB - Ciprofloxacin is a drug active against a broad spectrum of aerobic Gram-positive and Gram-negative bacteria, for the therapy of ocular infections. It requires frequent administrations owing to rapid ocular clearance and it is a good candidate for ocular controlled release formulations. The preparation of such drug release systems is still a challenge. Ionic interactions between ciprofloxacin and the polyelectrolytes chondroitin sulfate or lambda carrageenan result in coprecipitates that can act as microparticulate controlled release systems from which the drug is released after being displaced by the medium's ions. In some formulations, Carbopol was added to improve the mucoadhesive properties. The aim of this research was the study of the influence of the technological parameters of the preparation method of coprecipitates on their particle size, with the goal of achieving particles engineered with a size suitable for the ocular administration. Technological parameters taken into account were: concentration of drug and polymer solutions utilized for the preparation of interaction products, possible use of surfactants (kind and concentration), temperature of the solutions and stirring during the process of preparation of the coprecipitates. Preliminary stability study tests were carried out to further characterize the leader formulation. Particle size in suspensions for ocular drug delivery is a critical parameter influencing the quality of the formulation. The results obtained from this study show that chondroitin sulfate coprecipitates present the best characteristics in terms of particle size suitable for ocular administration. A further improvement of the particle size characteristics has been obtained with the addition of surfactants. PMID- 26482536 TI - The lasting impact of early-life adversity on individuals and their descendants: potential mechanisms and hope for intervention. AB - The adverse effects of early-life stress are pervasive, with well-established mental and physical health consequences for exposed individuals. The impact of early adverse experiences is also highly persistent, with documented increases in risk for mental illness across the life span that are accompanied by stable alterations in neural function and hormonal responses to stress. Here, we review some of these 'stress phenotypes', with a focus on intermediary factors that may signal risk for long-term mental health outcomes, such as altered development of the fear regulation system. Intriguingly, recent research suggests that such stress phenotypes may persist even beyond the life span of the individuals, with consequences for their offspring and grand-offspring. Phenotypic characteristics may be transmitted to future generations via either the matriline or the patriline, a phenomenon that has been demonstrated in both human and animal studies. In this review, we highlight behavioral and epigenetic factors that may contribute to this multigenerational transmission and discuss the potential of various treatment approaches that may halt the cycle of stress phenotypes. PMID- 26482535 TI - Effects of upright weight bearing and the knee flexion angle on patellofemoral indices using magnetic resonance imaging in patients with patellofemoral instability. AB - PURPOSE: This study analysed the effects of upright weight bearing and the knee flexion angle on patellofemoral indices, determined using magnetic resonance imaging (MRI), in patients with patellofemoral instability (PI). METHODS: Healthy volunteers (control group, n = 9) and PI patients (PI group, n = 16) were scanned in an open-configuration MRI scanner during upright weight bearing and supine non weight bearing positions at full extension (0 degrees flexion) and at 15 degrees , 30 degrees , and 45 degrees flexion. Patellofemoral indices included the Insall-Salvati Index, Caton-Deschamp Index, and Patellotrochlear Index (PTI) to determine patellar height and the patellar tilt angle (PTA), bisect offset (BO), and the tibial tubercle-trochlear groove (TT-TG) distance to assess patellar rotation and translation with respect to the femur and alignment of the extensor mechanism. RESULTS: A significant interaction effect of weight bearing by flexion angle was observed for the PTI, PTA, and BO for subjects with PI. At full extension, post hoc pairwise comparisons revealed a significant effect of weight bearing on the indices, with increased patellar height and increased PTA and BO in the PI group. Except for the BO, no such changes were seen in the control group. Independent of weight bearing, flexing the knee caused the PTA, BO, and TT TG distance to be significantly reduced. CONCLUSIONS: Upright weight bearing and the knee flexion angle affected patellofemoral MRI indices in PI patients, with significantly increased values at full extension. The observations of this study provide a caution to be considered by professionals when treating PI patients. These patients should be evaluated clinically and radiographically at full extension and various flexion angles in context with quadriceps engagement. LEVEL OF EVIDENCE: Explorative case-control study, Level III. PMID- 26482538 TI - Proteomic Characterization of Zinc-Binding Proteins of Canine Seminal Plasma. AB - The zinc-binding proteins (ZnBPs) of the seminal plasma are implicated in different processes related to sperm-egg fusion. The aim of this study was to characterize the ZnBPs of canine seminal plasma using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry. The ZnBPs were isolated from the ejaculates of five dogs by affinity chromatography and subjected to 2D-PAGE analysis. The acquired spots, detected across the gels, were analysed by mass spectrometry. Using 2D-PAGE analysis, it was shown that canine seminal plasma comprised about 46-57 zinc-binding polypeptides, with molecular mass ranging from 9.3 to 138.7 kDa and pI at pH 5.2-10.0. It was found that zinc binding polypeptides of low molecular masses (9.3-19.0 kDa and pI at pH 6.1-10.0) were predominant in the seminal plasma, and seven polypeptides, with molecular masses ranging from 11.7 to 15.4 kDa and pI at pH 6.8-8.7, were characterized by high optical density values. In addition, analysis with mass spectrometry (LC-MS MS/MS) revealed that the identified seven polypeptides are canine prostate specific esterase (CPSE), which is the main proteolytic enzyme of the seminal plasma. The findings of this study indicate an important regulatory role of seminal plasma zinc ions in the functional activity of CPSE, which is of great significance for maintaining the normal function of canine prostate and the spermatozoa functions. PMID- 26482537 TI - SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes. AB - Steatohepatitis occurs in up to 20% of patients with fatty liver disease and leads to its primary disease outcomes, including fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. Mechanisms that mediate this inflammation are of major interest. We previously showed that overload of saturated fatty acids, such as that which occurs with metabolic syndrome, induced sphingosine kinase 1 (SphK1), an enzyme that generates sphingosine-1-phosphate (S1P). While data suggest beneficial roles for S1P in some contexts, we hypothesized that it may promote hepatic inflammation in the context of obesity. Consistent with this, we observed 2-fold elevation of this enzyme in livers from humans with nonalcoholic fatty liver disease and also in mice with high saturated fat feeding, which recapitulated the human disease. Mice exhibited activation of NFkappaB, elevated cytokine production, and immune cell infiltration. Importantly, SphK1-null mice were protected from these outcomes. Studies in cultured cells demonstrated saturated fatty acid induction of SphK1 message, protein, and activity, and also a requirement of the enzyme for NFkappaB signaling and increased mRNA encoding TNFalpha and MCP1. Moreover, saturated fat induced NFkappaB signaling and elevation of TNFalpha and MCP1 mRNA in HepG2 cells was blocked by targeted knockdown of S1P receptor 1, supporting a role for this lipid signaling pathway in inflammation in nonalcoholic fatty liver disease. PMID- 26482540 TI - Perspective distortion in craniofacial superimposition: Logarithmic decay curves mapped mathematically and by practical experiment. AB - The superimposition of a face photograph with that of a skull for identification purposes necessitates the use of comparable photographic parameters between the two image acquisition sessions, so that differences in optics and consequent recording of images does not thwart the morphological analysis. Widely divergent, but published, speculations about the thresholds at which perspective distortion becomes negligible (0.5 to >13.5 m) must be resolved and perspective distortion (PD) relationships quantified across their full range to judge tolerance levels, and the suitability of commonly employed contemporary equipment (e.g., 1 m photographic copy-stands). Herein, basic trigonometry is employed to map PD for two same sized 179 mm linear lengths - separated anteroposteriorly by 127 mm - as a function of subject-to-camera distance (SCD; 0.2-20 m). These lengths approximate basic craniofacial heights (e.g., tr-n) and widths (e.g., zy-zy), while the latter approximates facial depth (e.g., n-t). As anticipated, PD decayed in logarithmic and continuous manner with increasing SCD. At SCD of 12 m, the within-image PD was negligible (<1%). At <2.5 m SCD, it exceeded 5% and increased sharply as SCD decreased. Since life size images of skulls and faces are commonly employed for superimposition, a relative 1% perspective distortion difference is recommended as the ceiling standard for craniofacial comparison (translates into a <=2 mm difference in physiognomical face height). Since superimposition depends on relative comparisons of a photographic pair (not one photograph), there is practically no scenario in superimposition casework where SCDs should be ignored and no single distance at which PD should be considered negligible (even if one image holds >12 m SCD). PMID- 26482539 TI - Study on the performance of different craniofacial superimposition approaches (II): Best practices proposal. AB - Craniofacial superimposition, although existing for one century, is still a controversial technique within the scientific community. Objective and unbiased validation studies over a significant number of cases are required to establish a more solid picture on the reliability. However, there is lack of protocols and standards in the application of the technique leading to contradictory information concerning reliability. Instead of following a uniform methodology, every expert tends to apply his own approach to the problem, based on the available technology and deep knowledge on human craniofacial anatomy, soft tissues, and their relationships. The aim of this study was to assess the reliability of different craniofacial superimposition methodologies and the corresponding technical approaches to this type of identification. With all the data generated, some of the most representative experts in craniofacial identification joined in a discussion intended to identify and agree on the most important issues that have to be considered to properly employ the craniofacial superimposition technique. As a consequence, the consortium has produced the current manuscript, which can be considered the first standard in the field; including good and bad practices, sources of error and uncertainties, technological requirements and desirable features, and finally a common scale for the craniofacial matching evaluation. Such a document is intended to be part of a more complete framework for craniofacial superimposition, to be developed during the FP7-founded project MEPROCS, which will favour and standardize its proper application. PMID- 26482541 TI - Mossy fiber sprouting and pyramidal cell dispersion in the hippocampal CA2 region in a mouse model of temporal lobe epilepsy. AB - Dentate granule cells and the hippocampal CA2 region are resistant to cell loss associated with mesial temporal lobe epilepsy (MTLE). It is known that granule cells undergo mossy fiber sprouting in the dentate gyrus which contributes to a recurrent, proepileptogenic circuitry in the hippocampus. Here it is shown that mossy fiber sprouting also targets CA2 pyramidal cell somata and that the CA2 region undergoes prominent structural reorganization under epileptic conditions. Using the intrahippocampal kainate mouse model for MTLE and the CA2-specific markers Purkinje cell protein 4 (PCP4) and regulator of G-Protein signaling 14 (RGS14), it was found that during epileptogenesis CA2 neurons survive and disperse in direction of CA3 and CA1 resulting in a significantly elongated CA2 region. Using transgenic mice that express enhanced green fluorescent protein (eGFP) in granule cells and mossy fibers, we show that the recently described mossy fiber projection to CA2 undergoes sprouting resulting in aberrant large, synaptoporin-expressing mossy fiber boutons which surround the CA2 pyramidal cell somata. This opens up the potential for altered synaptic transmission that might contribute to epileptic activity in CA2. Indeed, intrahippocampal recordings in freely moving mice revealed that epileptic activity occurs concomitantly in the dentate gyrus and in CA2. Altogether, the results call attention to CA2 as a region affected by MTLE-associated pathological restructuring. PMID- 26482542 TI - Chemotherapy for advanced non-small cell lung cancer in the elderly population. AB - BACKGROUND: Approximately 50% of patients with newly diagnosed non-small cell lung cancer (NSCLC) are over 70 years of age at diagnosis. Despite this fact, these patients are underrepresented in randomized controlled trials (RCTs). As a consequence, the most appropriate regimens for these patients are controversial, and the role of single-agent or combination therapy is unclear. In this setting, a critical systematic review of RCTs in this group of patients is warranted. OBJECTIVES: To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced (stage IIIB and IV) NSCLC. To also assess the impact of cytotoxic chemotherapy on quality of life. SEARCH METHODS: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (1966 to 31 October 2014), EMBASE (1974 to 31 October 2014), and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 31 October 2014). In addition, we handsearched the proceedings of major conferences, reference lists from relevant resources, and the ClinicalTrial.gov database. SELECTION CRITERIA: We included only RCTs that compared non-platinum single-agent therapy versus non platinum combination therapy, or non-platinum therapy versus platinum combination therapy in patients over 70 years of age with advanced NSCLC. We allowed inclusion of RCTs specifically designed for the elderly population and those designed for elderly subgroup analyses. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results, and a third review author resolved disagreements. We analyzed the following endpoints: overall survival (OS), one year survival rate (1yOS), progression-free survival (PFS), objective response rate (ORR), major adverse events, and quality of life (QoL). MAIN RESULTS: We included 51 trials in the review: non-platinum single-agent therapy versus non platinum combination therapy (seven trials) and non-platinum combination therapy versus platinum combination therapy (44 trials). Non-platinum single-agent versus non-platinum combination therapy Low-quality evidence suggests that these treatments have similar effects on overall survival (hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.72 to 1.17; participants = 1062; five RCTs), 1yOS (risk ratio (RR) 0.88, 95% CI 0.73 to 1.07; participants = 992; four RCTs), and PFS (HR 0.94, 95% CI 0.83 to 1.07; participants = 942; four RCTs). Non-platinum combination therapy may better improve ORR compared with non-platinum single agent therapy (RR 1.79, 95% CI 1.41 to 2.26; participants = 1014; five RCTs; low quality evidence).Differences in effects on major adverse events between treatment groups were as follows: anemia: RR 1.10, 95% 0.53 to 2.31; participants = 983; four RCTs; very low-quality evidence; neutropenia: RR 1.26, 95% CI 0.96 to 1.65; participants = 983; four RCTs; low-quality evidence; and thrombocytopenia: RR 1.45, 95% CI 0.73 to 2.89; participants = 914; three RCTs; very low-quality evidence. Only two RCTs assessed quality of life; however, we were unable to perform a meta-analysis because of the paucity of available data. Non-platinum therapy versus platinum combination therapy Platinum combination therapy probably improves OS (HR 0.76, 95% CI 0.69 to 0.85; participants = 1705; 13 RCTs; moderate quality evidence), 1yOS (RR 0.89, 95% CI 0.82 to 0.96; participants = 813; 13 RCTs; moderate-quality evidence), and ORR (RR 1.57, 95% CI 1.32 to 1.85; participants = 1432; 11 RCTs; moderate-quality evidence) compared with non platinum therapies. Platinum combination therapy may also improve PFS, although our confidence in this finding is limited because the quality of evidence was low (HR 0.76, 95% CI 0.61 to 0.93; participants = 1273; nine RCTs).Effects on major adverse events between treatment groups were as follows: anemia: RR 2.53, 95% CI 1.70 to 3.76; participants = 1437; 11 RCTs; low-quality evidence; thrombocytopenia: RR 3.59, 95% CI 2.22 to 5.82; participants = 1260; nine RCTs; low-quality evidence; fatigue: RR 1.56, 95% CI 1.02 to 2.38; participants = 1150; seven RCTs; emesis: RR 3.64, 95% CI 1.82 to 7.29; participants = 1193; eight RCTs; and peripheral neuropathy: RR 7.02, 95% CI 2.42 to 20.41; participants = 776; five RCTs; low-quality evidence. Only five RCTs assessed QoL; however, we were unable to perform a meta-analysis because of the paucity of available data. AUTHORS' CONCLUSIONS: In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities, increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy. For people who are not suitable candidates for platinum treatment, we have found low-quality evidence suggesting that non platinum combination and single-agent therapy regimens have similar effects on survival. We are uncertain as to the comparability of their adverse event profiles. Additional evidence on quality of life gathered from additional studies is needed to help inform decision making. PMID- 26482543 TI - The effect of histamine on changes in mental energy and fatigue after a single bout of exercise. AB - The purpose of this research was to determine if histamine, acting on brain H1 receptors, influences changes in feelings of energy and fatigue or cognitive test performance after acute exercise. Women (n=20) with low vigor and high fatigue were administered the H1 antagonist drug doxepin hydrocholoride (6 mg) in tomato juice and tomato juice alone (placebo) in a randomized, double-blinded, cross over experiment before performing 30 min of light intensity cycling exercise and completing energy, fatigue, sleepiness, and motivation scales, and cognitive tasks. After exercise, mental fatigue increased for the doxepin condition (p=0.014) but not placebo (p=0.700), while mental energy decreased for both PLA and DOX (p<0.001) and cognitive task performance was unaffected. It is inferred that histamine binding to H1 receptors in the brain has a role in exercise induced reductions in mental fatigue, but not increases in energy. PMID- 26482544 TI - Interleukin-21 Induces Proliferation and Proinflammatory Cytokine Profile of Fibroblast-like Synoviocytes of Patients with Rheumatoid Arthritis. AB - Fibroblast-like synoviocytes (FLS) play a pivotal role in the pathogenesis of rheumatoid arthritis (RA) through aggressive proliferation and invasion, and certain proinflammatory cytokines may affect synoviocyte proliferation. To evaluate whether interleukin-21 (IL-21) could promote proliferation and proinflammatory cytokine production by RA-FLS, immunohistochemistry and immunoblotting were performed to observe the expression of IL-21 receptor (IL 21R) in synovial tissues and FLS from RA and osteoarthritis (OA) patients. The MTS assay was used to analyse RA-FLS proliferation. The concentrations of IL-6 and tumour necrosis factor-alpha (TNF-alpha) in culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). The signalling pathways triggered by IL-21 were characterized by immunoblotting. IL-21R was upregulated in the synovial tissues and FLS of RA patients as compared with OA patients. IL 21 stimulated RA-FLS proliferation and promoted the production of TNF-alpha and IL-6 and blockade of IL-21/IL-21R pathway with IL-21R.Fc attenuated IL-21-induced proliferation and secretion of TNF-alpha and IL-6. Moreover, IL-21 induced activation of the ERK1/2, PI3K/AKT and STAT3 pathways, and blockade of these pathways attenuated IL-21-induced proliferation and secretion of TNF-alpha and IL 6. These results suggest that IL-21 could promote RA-FLS proliferation and production of proinflammatory cytokines. Therefore, therapeutic strategies targeting IL-21 might be effective for the treatment of RA. PMID- 26482545 TI - Perianchor Cyst Formation Around Biocomposite Biodegradable Suture Anchors After Rotator Cuff Repair. AB - BACKGROUND: Biodegradable anchors may lead to perianchor cyst formation or osteolysis. A new generation of anchors containing osteoconductive material was recently presented, but there is currently no solid evidence that this concept decreases cyst formation around anchors. HYPOTHESIS: The null hypothesis was that the prevalence and severity of cyst formation around anchors would be similar for all 3 anchor types. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: To evaluate differences between anchor behaviors postoperatively, this study included 2 groups of patients who underwent rotator cuff repair. In group 1 (n = 38), transosseous-equivalent rotator cuff repair was performed in all patients. At the time of repair, 2 different anchors (anchor A: 23% microstructured beta tricalcium phosphate plus 77% polylactic acid enantiomers [PLLA]; and anchor B: 30% hydroxyapatite plus 70% PLLA) were used for medial-row repair. Insertion locations (anterior or posterior) were randomly assigned. In group 2 (n = 38), the same procedure was performed; however, 1 of the anchors used in group 1 was changed (anchor A: as above; and anchor C: 30% beta-tricalcium phosphate plus 70% faster absorbing polylactic-co-glycolic acid copolymer [85% PLLA plus 15% polyglycolic acid]). The presence and severity of fluid collection around the anchors was evaluated by magnetic resonance imaging at approximately 1 year after rotator cuff repair (12.7 +/- 0.9 months for group 1 and 12.6 +/- 1.8 months for group 2). RESULTS: In group 1, a fluid signal was observed in 14 patients (36.8%) for anchor A and in 12 patients (31.6%) for anchor B (P > .05). The severity of perianchor cyst formation was no different for the 2 anchors (respective fluid signal grades [0-4]: 24, 3, 9, 1, and 1 for anchor A; and 26, 4, 7, 1, and 0 for anchor B; P > .05). However, in group 2, cysts were observed in 19 patients (50%) for anchor A and in 3 patients (7.9%) for anchor C (P < .001). For anchor C, only 2 cases of grade 1 and 1 case of grade 2 fluid collection were observed. Intergroup analysis of anchor A revealed no significant differences in the prevalence or severity of perianchor cyst formation (P > .05). Healing failure was observed in 12 patients (31.6%) in group 1 and 10 patients (26.3%) in group 2 (P > .05). CONCLUSION: New-generation biodegradable suture anchors seem to decrease the severity of perianchor cyst formation. Future research is required to optimize the compositions and proportions of osteoconductive materials and polymers to improve adverse reactions. Nevertheless, controlling the properties of polymers and adding osteoconductive material both appear to enhance biocompatibility. PMID- 26482546 TI - Development of a nano-particle-assisted PCR assay for detection of duck tembusu virus. AB - Duck tembusu virus (DTMUV) has caused significant economic losses to the poultry industry in China since the spring of 2010. In this study, a nano-PCR assay targeting E gene of DTMUV was developed and their sensitivities and specificities were investigated. Under the optimized conditions of nano-PCR assay for detection of DTMUV, the nano-PCR assay was 10-fold more sensitive than a conventional PCR assay. The lower detection limit of the nano-PCR assay was 1.8 * 10(2) copies MUl(-1) of DTMUV RNA, as no cross-reaction was observed with other viruses. This is the first report to demonstrate the application of a nano-PCR assay for the detection of DTMUV. The sensitive, and specific nano-PCR assay developed in this study can be applied widely in clinical diagnosis and field surveillance of DTMUV infection. SIGNIFICANCE AND IMPACT OF THE STUDY: A nanoparticle-assisted polymerase chain reaction (nano-PCR) assay was developed in this study for the rapid detection of duck tembusu virus (DTMUV) with high sensitivity and specificity. This technique has potential application in both clinical diagnosis and field surveillance of DTMUV-infection. PMID- 26482547 TI - Memory re-differentiation and reduced lymphocyte activation in chronic HCV infected patients receiving direct-acting antivirals. AB - Recently, the treatment of HCV has advanced significantly due to the introduction of direct-acting antivirals (DAAs). Studies using interferon (IFN)-containing regimens failed to consistently show restoration of immunologic responses. Therefore, IFN-free DAA formulations provide a unique opportunity to dissect the immunologic effect of HCV cure. This study investigates the restoration of the immune compartment as a consequence of rapid viral clearance in patients successfully treated with DAAs and in the absence of IFN and ribavirin. Here, we evaluate the immunologic changes that occurred following DAA-mediated HCV cure. Peripheral blood from nineteen previously treatment-naive patients with chronic HCV genotype 1a/1b who received an IFN and ribavirin-free regimen of daclatasvir, asunaprevir and BMS-791325 was evaluated. Immune reconstitution occurs in patients in whom HCV was successfully eradicated via DAA therapy. Restoration of the CD4(+) T-cell compartment in the peripheral blood and a re-differentiation of the T lymphocyte memory compartment resulted in a more effector memory cell population and a reduction in expression in the co-inhibitory molecule TIGIT in bulk T lymphocytes. Furthermore, we observed a partial reversal of the exhausted phenotype in HCV-specific CD8(+) T cells and a dampening of the activation state in peripheral NK cells. Collectively, our data provide the groundwork for dissecting the effect of DAA therapy on the immune system and identifying novel mechanisms by which chronic HCV infection exerts immunosuppressive effects on T cells through the recently described co-inhibitory molecule TIGIT. PMID- 26482548 TI - Systematic review of the barriers affecting medication adherence in older adults. AB - Medication adherence is a crucial part in the management of chronic diseases. As older adults form a greater proportion of the population with chronic diseases and multiple morbidities, understanding medication adherence in older adults becomes important. In the present article, we aimed to systematically review the literature for the factors associated with medication adherence in the geriatric population. We carried out a literature search using electronic databases and related keywords. 17 391 articles were reviewed in total. 65 articles were found to be relevant to our objective. A total of 80 factors of five different categories were found to be associated with medication adherence in older adults. The factors, the types of studies and the number of studies that agreed or disagreed were presented. A flower model for medication adherence was also presented to allow clinicians to better understand the complex nature of medication adherence in this population. The 80 factors reviewed were categorized into five main categories; namely, patient factors, medication factors, physician factors, system-based factors and other factors as factors affecting poor medication adherence in older adults. Clinicians need to be mindful of the complex nature of factors affecting medication adherence in this population to optimize therapeutic outcomes. Clinicians have to be more skillful to discover and to optimize the medication adherence factors in geriatric patients. The flower model is presented as a framework for clinicians to better understand the various factors affecting medication adherence in older adults. Geriatr Gerontol Int 2016; 16: 1093-1101. PMID- 26482549 TI - A review of exposure and toxicological aspects of carbon nanotubes, and as additives to fire retardants in polymers. AB - Carbon nanotubes (CNTs) have attracted considerable interest due to their unique physical, chemical, optical and electrical properties opening avenues for a large number of industrial applications. They have shown potential as fire retardant additives in polymers, reducing heat release rate and increasing time to ignition in a number of polymers. Relevant work on the types, properties and applications has been reviewed particularly considering their application in fire situations. There are concerns over the health risks associated with CNTs and many papers have likened CNTs to the health problems associated with asbestos. There are contradictions relating to the toxicity of CNTs with some papers reporting that they are toxic while others state the opposite. Directly comparing various studies is difficult because CNTs come in many combinations of size, type, purity levels and source. CNTs can potentially be released from polymers during the combustion process where human exposure may occur. While this review has shed some light regarding issues relating to toxicity under different fire scenarios much more thorough work is needed to investigate toxicity of CNTs and their evolution from CNT-polymer nanocomposites in order to reach firm conclusions. PMID- 26482550 TI - In vitro susceptibility of contagious ovine digital dermatitis associated Treponema spp. isolates to antimicrobial agents in the UK. AB - BACKGROUND: Contagious ovine digital dermatitis (CODD) is an important cause of infectious lameness in sheep in the UK and Ireland and has a severe impact on the welfare of affected individuals. The three treponemal phylogroups Treponema medium/Treponema vincentii-like, Treponema phagedenis-like and Treponema pedis spirochaetes have been associated with clinical CODD lesions and are considered to be a necessary cause of disease. There are scant data on the antimicrobial susceptibility of the treponemes cultured from CODD lesions. OBJECTIVE: The aim of this study was to determine in vitro the miniumum inhibitory concentration/ minimum bactericidal concentration (MIC/MBC) of antimicrobials used in the sheep industry for isolates of the three CODD associated treponeme phylogroups T. medium/T. vincentii-like, T. phagedenis-like and T. pedis. ANIMALS: Twenty treponeme isolates; from 19 sheep with clinical CODD lesions. METHODS: A microdilution method was used to determine in vitro the MIC/MBC of 10 antimicrobial agents for 20 treponeme isolates (five T. medium/T. vincentii-like, 10 T. phagedenis-like and five T. pedis). The antimicrobials tested were penicillin G, amoxicillin, oxytetracycline, tilmicosin, lincomycin, spectinomycin, tylosin, tildipirosin, tulathromycin and gamithromycin. RESULTS: The treponeme isolates tested showed low MICs and MBCs to all 10 antimicrobials tested. They were most susceptible to gamithromycin and tildipirosin (MIC90: 0.0469 mg/L), and were least susceptible to lincomycin, spectinomycin and oxytetracycline (MIC90: 48 mg/L, 24 mg/L and 3 mg/L, respectively). CONCLUSIONS: These data are comparable to in vitro antimicrobial susceptibility data for treponemes cultured from bovine digital dermatitis lesions. Dependent on local licensing, penicillin and tilmicosin appear to be the best candidates for future in vivo studies. PMID- 26482552 TI - Activity-related sexual dimorphism in Alaskan foragers from Point Hope: Evidences from the upper limb. AB - Ipiutak (100BCE-500CE) and Tigara (1200 - 1700CE) are two populations from Point Hope, Alaska. As commonly observed in forager communities, it may be expected males and females to have been involved in markedly different daily activities. Nevertheless, activity-related sexual dimorphism in these populations has been scarcely studied. Using humeral diaphyseal cross-sectional properties and forearm rotational efficiency, which are activity-dependent characteristics, we aim to assess differences between sexes and discuss what activities could have triggered them. Our results suggest that in Ipiutak males and females did not differ meaningfully in their cross-sectional properties. Conversely, in Tigara males had a greater rigidity of the entire humeral diaphysis than females, which suggests the existence of greater relative activity levels and more physically demanding tasks, possibly related to hunting activities. Concerning the differences between sexes in the forearm rotational efficiency, in Tigara females rotational efficiency in elbow flexion is maximal in a more supinated position than in males, which leads to an improvement of efficiency in those stages related to manipulation, and so improves the manipulative capacities of the upper limb. These differences in efficiency are caused by a more proximally oriented humeral medial epicondyle in females, which is thus confirmed to be a good feature to assess differences in labor. Therefore females in Tigara probably performed in a daily basis household activities, such as hide processing and other manipulative labors. In Ipiutak, the analysis of forearm rotational efficiency did not reveal differences between sexes. Overall, the results suggest that division of labor in Ipiutak was not as marked as in Tigara, where upper limb skeletal structure supports the idea that both sexes were involved in different daily activities. Nevertheless, the generalized lack of results in Ipiutak could be due to the small sample size, and thus interpretations should be considered with caution. PMID- 26482551 TI - A highly effective and versatile technology for the isolation of RNAs from grapevines and other woody perennials for use in virus diagnostics. AB - BACKGROUND: Isolation of pure RNA from woody perennials, especially fruit crops such as grapevine rich in complex secondary metabolites, has remained very challenging. Lack of effective RNA isolation technology has resulted in difficulties in viral diagnosis and discovery as well as studies on many biological processes of these highly important woody plants. It is imperative to develop and refine methodologies with which large amounts of pure nucleic acids can be readily isolated from woody perennials. METHODS: We compared five commonly used RNA isolation kits in isolating total RNA from twelve species of woody perennials. We made modifications to select RNA isolation systems to simplify and improve their efficiency in RNA isolation. The yield and quality of isolated RNAs were assessed via gel electrophoresis and spectrophotometric measurement. We also performed RT-PCR and RT-qPCR to detect several major viruses from grapevines. RESULTS: Two of the kits were shown to be the best in both the yield and quality of the isolated RNA from all twelve woody species. Using disposable extraction bags for tissue homogenization not only improved the yield without affecting quality, but also made the RNA isolation technology simpler, less costly, and suitable for adoption by many potential users with facility limitations. This system was successfully applied to a wide range of woody plants, including fruit crops, ornamentals and timber trees. Inclusion of polyvinylpyrrolidone in the extraction buffer drastically improved the performance of the system in isolating total RNA from old grapevine leaves collected later in the season. This modification made our system highly effective in isolating quality RNA from grapevine leaves throughout the entire growing season. We further demonstrated that the resulting nucleic acid preparations are suitable for detection of several major grapevine viruses with RNA or DNA genomes using PCR, RT-PCR and qPCR as well as for assays on plant microRNAs. CONCLUSIONS: This improved RNA isolation system would have wide applications in viral diagnostics and discovery, studies on gene expression and regulation, transcriptomics, and small RNA biology in grapevines. We believe this system will also be useful in diverse applications pertaining to research on many other woody perennials and recalcitrant plant species. PMID- 26482553 TI - Cost-Effectiveness of a Biopsy-Based 8-Protein Prostate Cancer Prognostic Assay to Optimize Treatment Decision Making in Gleason 3 + 3 and 3 + 4 Early Stage Prostate Cancer. AB - BACKGROUND: Many patients with Gleason 3 + 3 and 3 + 4 early stage prostate cancer receive invasive treatment but likely derive little or no benefit. A novel 8-protein prognostic assay generates a risk score at time of biopsy that is predictive of prostate cancer aggressiveness and can inform treatment decisions. The objective of this study was to evaluate the cost-effectiveness of using the assay to inform treatment decisions compared with usual care. PATIENTS AND METHODS: We developed a simulation model to estimate quality-adjusted life-year (QALY) and cost outcomes for the 8-protein assay and usual care strategies. Risk classification outcomes, treatment distributions, costs, health state utilities, and mortality rates were derived from the assay's validation study and the peer reviewed literature. Outcomes included incremental QALYs, costs, and cost effectiveness ratios. We conducted one-way and probabilistic sensitivity analyses to evaluate the most influential inputs and to explore joint uncertainty in outcomes, respectively. RESULTS: The 8-protein assay strategy resulted in 0.04 more QALY and $700 less in costs compared with usual care (and thus was "dominant"). The cost-effectiveness of the assay strategy was most sensitive to the assay cost, the active surveillance health state utility, and the proportion of low-risk patients receiving active surveillance (vs. treatment) in usual care. In the probabilistic sensitivity analyses, the assay strategy decreased cost and increased QALYs in 86.9% and 58.3% of simulations, respectively. CONCLUSION: Assuming that ongoing prospective studies support the results of retrospective validation studies, the 8-protein prognostic assay strategy for prostate cancer is likely to be a cost-effective alternative to usual guideline-based care in biopsy Gleason 3 + 3 and 3 + 4 early stage prostate cancer. PMID- 26482554 TI - Facile Synthesis of Size-Tunable Functional Polyimidazolium Macrocycles through a Photochemical Closing Strategy. AB - A synthetic strategy for the preparation of a series of polyimidazolium macrocycles from the corresponding dicarbene-derived metallacycles is described. Photodimerization of terminal cinnamic esters (UV-irradiation, lambda=365 nm) produces the closed metallacycles with perfect stereoselectivity and high yields. Subsequent removal of the template from the photodimerization product results in polyimidazolium macrocycles. The size and shape of the receptor can be tuned easily by changing the length and breadth of the internal bridging groups of the ligands. Preliminary investigation shows the potential of the macrocycle as iodide sensor. PMID- 26482555 TI - Genomic profile predicts the efficacy of neoadjuvant chemotherapy for cervical cancer patients. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) using platinum and irinotecan (CPT-11) followed by radical excision has been shown to be a valid treatment for locally advanced squamous cervical cancer (SCC) patients. However, in NAC-resistant or NAC-toxic cases, surgical treatment or radiotherapy might be delayed and the prognosis may be adversely affected. Therefore, it is important to establish a method to predict the efficacy of NAC. METHODS: Gene expression microarrays of SCC tissue samples (n = 12) and UGT1A1 genotyping of blood samples (n = 23) were investigated in terms of their association with NAC sensitivity. Gene expression and drug sensitivity of SCC cell lines were analyzed for validation. RESULTS: Microarray analysis revealed that the glutathione metabolic pathway (GMP) was significantly up-regulated in NAC-resistant patients (p < 0.01), and there was a positive correlation between 50 % growth inhibitory concentrations of CPT-11 and predictive scores of GMP activation in SCC cells (r = 0.32, p < 0.05). The intracellular glutathione (GSH) concentration showed a highly positive correlation with GMP scores among 4 SCC cell lines (r = 0.72). UGT1A1 genotyping revealed that patients with UGT1A1 polymorphisms exhibited significantly higher response rates to NAC than those with the wild-type (79.5 vs. 49.5 %, respectively, p < 0.05). CONCLUSIONS: These results indicate that GMP scores of cancerous tissue combined with UGT1A1 genotyping of blood samples may serve as highly potent markers for predicting the efficacy of NAC for individual SCC patients. PMID- 26482557 TI - Visualization of in Vivo Hydrogen Sulfide Production by a Bioluminescence Probe in Cancer Cells and Nude Mice. AB - Hydrogen sulfide (H2S) has emerged as an exciting endogenous gasotransmitter in addition to nitric oxide and carbon monoxide. However, its precise measurement in living cells and animals remains a challenge. In this study, a novel bioluminescence H2S probe was designed and synthesized by modifying the 6'-amino group of d-aminoluciferin into a 6'-azido group, which was highly selective against other reactive sulfur, nitrogen, and oxygen species. Our H2S probe azidoluciferin sensitively reacted with H2S to release d-aminoluciferin with a strong bioluminescence signal. On the basis of its high selectivity and sensitivity, the H2S probe was used to detect H2S production in live cancer cells and nude mice. The bioluminescence signal decreased in mice treated with propargylglycine, an inhibitor of H2S, suggesting that our H2S probe can detect endogenous H2S in real time, in vivo. Overall, the excellent sensing properties of the probe combined with its bioimaging capability make it a useful tool to study H2S biological roles. PMID- 26482556 TI - An integrative systems genetics approach reveals potential causal genes and pathways related to obesity. AB - BACKGROUND: Obesity is a multi-factorial health problem in which genetic factors play an important role. Limited results have been obtained in single-gene studies using either genomic or transcriptomic data. RNA sequencing technology has shown its potential in gaining accurate knowledge about the transcriptome, and may reveal novel genes affecting complex diseases. Integration of genomic and transcriptomic variation (expression quantitative trait loci [eQTL] mapping) has identified causal variants that affect complex diseases. We integrated transcriptomic data from adipose tissue and genomic data from a porcine model to investigate the mechanisms involved in obesity using a systems genetics approach. METHODS: Using a selective gene expression profiling approach, we selected 36 animals based on a previously created genomic Obesity Index for RNA sequencing of subcutaneous adipose tissue. Differential expression analysis was performed using the Obesity Index as a continuous variable in a linear model. eQTL mapping was then performed to integrate 60 K porcine SNP chip data with the RNA sequencing data. Results were restricted based on genome-wide significant single nucleotide polymorphisms, detected differentially expressed genes, and previously detected co-expressed gene modules. Further data integration was performed by detecting co expression patterns among eQTLs and integration with protein data. RESULTS: Differential expression analysis of RNA sequencing data revealed 458 differentially expressed genes. The eQTL mapping resulted in 987 cis-eQTLs and 73 trans-eQTLs (false discovery rate < 0.05), of which the cis-eQTLs were associated with metabolic pathways. We reduced the eQTL search space by focusing on differentially expressed and co-expressed genes and disease-associated single nucleotide polymorphisms to detect obesity-related genes and pathways. Building a co-expression network using eQTLs resulted in the detection of a module strongly associated with lipid pathways. Furthermore, we detected several obesity candidate genes, for example, ENPP1, CTSL, and ABHD12B. CONCLUSIONS: To our knowledge, this is the first study to perform an integrated genomics and transcriptomics (eQTL) study using, and modeling, genomic and subcutaneous adipose tissue RNA sequencing data on obesity in a porcine model. We detected several pathways and potential causal genes for obesity. Further validation and investigation may reveal their exact function and association with obesity. PMID- 26482558 TI - Remission of irreversible aripiprazole-induced tardive dystonia with clozapine: a case report. AB - BACKGROUND: Aripiprazole can cause irreversible tardive dystonia in some individuals, and additional intervention is sometimes needed. Here, we report the first case of aripiprazole-induced irreversible tardive dystonia in which complete recovery of motor function was achieved using the antipsychotic drug clozapine. CASE PRESENTATION: A 24-year-old man with bipolar disorder was treated with aripiprazole and gradually developed tardive dystonia. Thorough medical and neurological examinations were performed to rule out other possible causes of tardive dystonia. Clozapine was administered when the patient did not improve following long-term withdrawal of aripiprazole or adjuvant medications. Before administration of clozapine, the patient was experiencing severe dystonia as assessed by the Extrapyramidal Symptom Rating Scale. Dystonic symptoms began to improve about 1 month after starting administration of clozapine and were completely resolved 3 months after clozapine administration. CONCLUSIONS: Clinicians should note the risk of aripiprazole-induced tardive dystonia and consider clozapine as an alternative and effective treatment modality in cases of irreversible tardive dystonia, particularly when concomitant treatment of psychotic symptoms is required. PMID- 26482560 TI - Farewell Wilfred. PMID- 26482559 TI - Extremely durable biofouling-resistant metallic surfaces based on electrodeposited nanoporous tungstite films on steel. AB - Formation of unwanted deposits on steels during their interaction with liquids is an inherent problem that often leads to corrosion, biofouling and results in reduction in durability and function. Here we report a new route to form anti fouling steel surfaces by electrodeposition of nanoporous tungsten oxide (TO) films. TO-modified steels are as mechanically durable as bare steel and highly tolerant to compressive and tensile stresses due to chemical bonding to the substrate and island-like morphology. When inherently superhydrophilic TO coatings are converted to superhydrophobic, they remain non-wetting even after impingement with yttria-stabilized-zirconia particles, or exposure to ultraviolet light and extreme temperatures. Upon lubrication, these surfaces display omniphobicity against highly contaminating media retaining hitherto unseen mechanical durability. To illustrate the applicability of such a durable coating in biofouling conditions, we modified naval construction steels and surgical instruments and demonstrated significantly reduced marine algal film adhesion, Escherichia coli attachment and blood staining. PMID- 26482561 TI - Plastic waste as a novel substrate for industrial biotechnology. PMID- 26482562 TI - NMR-based analysis of the chemical composition of Japanese persimmon aqueous extracts. AB - Japanese persimmon (Diospyros kaki L.) is recognized as an outstanding source of biologically active compounds relating to many health benefits. In the present study, NMR spectroscopy provided a comprehensive metabolic overview of Japanese persimmon juice. Detailed signal assignments of Japanese persimmon juice were carried out using various 2D NMR techniques incorporated with broadband water suppression enhanced through T1 effects (BB-WET) or WET sequences, and 26 components, including minor components, were identified. In addition, most components were quantitatively evaluated by the integration of signals using conventional (1) H NMR and BB-WET NMR. This is the first detailed analysis combined with quantitative characterization of chemical components using NMR for Japanese persimmon. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26482563 TI - Conductance tomography of conductive filaments in intrinsic silicon-rich silica RRAM. AB - We present results from an imaging study of filamentary conduction in silicon suboxide resistive RAM devices. We used a conductive atomic force microscope to etch through devices while measuring current, allowing us to produce tomograms of conductive filaments. To our knowledge this is the first report of such measurements in an intrinsic resistance switching material. PMID- 26482565 TI - The lymphocyte-to-monocyte ratio: an added value for death prediction in heart failure. AB - BACKGROUND AND AIM: Leukocytes and their subpopulation have been long implicated in the progression of the syndrome of heart failure (HF), especially heart infiltration cells. Previous reports have suggested that they can predict worse outcome in patients with HF, and can also affect the function of other cells and myocardial extracellular matrix remodeling process. However, the lymphocyte-to monocyte ratio (LMR) and its possible value as prognostic marker have not been evaluated. METHODS AND RESULTS: A total of 390 patients with acute HF were recruited and followed for 6 months. Their total blood count with leukocyte differential was obtained. Two groups were formed according to the endpoints of HF death and optimal cut-off value of LMR, and were compared. A multivariate Cox regression model was used to establish the prognostic value with the endpoints of HF and all-cause mortality. Median age of the patients was 78 years and 48.5% of them were men. No major difference was observed between the clinical characteristics of the two groups. Patients who died of HF had significantly higher values of B-type natriuretic peptide and lower values of LMR. Leukocyte and monocyte counts revealed a multivariate-adjusted risk for both endpoints, whereas relative lymphocyte counts had only significant value for all-cause mortality. The multivariate-adjusted hazard ratios for the 6-month HF and all cause mortality in patients with LMR values < 2.0 were, respectively, 2.28 (95% CI: 1.25-4.15) and 2.39 (95% CI: 1.39-4.10). CONCLUSION: Our results show that, upon discharge from hospital after an episode of acute HF, a lower value of LMR is independently associated with a higher risk of mortality within 6 months. PMID- 26482564 TI - Evolutionary history of phosphatidylinositol- 3-kinases: ancestral origin in eukaryotes and complex duplication patterns. AB - BACKGROUND: Phosphatidylinositol-3-kinases (PI3Ks) are a family of eukaryotic enzymes modifying phosphoinositides in phosphatidylinositols-3-phosphate. Located upstream of the AKT/mTOR signalling pathway, PI3Ks activate secondary messengers of extracellular signals. They are involved in many critical cellular processes such as cell survival, angiogenesis and autophagy. PI3K family is divided into three classes, including 14 human homologs. While class II enzymes are composed of a single catalytic subunit, class I and III also contain regulatory subunits. Here we present an in-depth phylogenetic analysis of all PI3K proteins. RESULTS: We confirmed that PI3K catalytic subunits form a monophyletic group, whereas regulatory subunits form three distinct groups. The phylogeny of the catalytic subunits indicates that they underwent two major duplications during their evolutionary history: the most ancient arose in the Last Eukaryotic Common Ancestor (LECA) and led to the emergence of class III and class I/II, while the second - that led to the separation between class I and II - occurred later, in the ancestor of Unikonta (i.e., the clade grouping Amoebozoa, Fungi, and Metazoa). These two major events were followed by many lineage specific duplications in particular in vertebrates, but also in various protist lineages. Major loss events were also detected in Vidiriplantae and Fungi. For the regulatory subunits, we identified homologs of class III in all eukaryotic groups indicating that, for this class, both the catalytic and the regulatory subunits were presents in LECA. In contrast, homologs of the regulatory class I have a more recent origin. CONCLUSIONS: The phylogenetic analysis of the PI3K shed a new light on the evolutionary history of these enzymes. We found that LECA already contained a PI3K class III composed of a catalytic and a regulatory subunit. Absence of class II regulatory subunits and the recent origin of class I regulatory subunits is puzzling given that the class I/II catalytic subunit was present in LECA and has been conserved in most present-day eukaryotic lineages. We also found surprising major loss and duplication events in various eukaryotic lineages. Given the functional specificity of PI3K proteins, this suggests dynamic adaptation during the diversification of eukaryotes. PMID- 26482566 TI - Prospective association between the dietary inflammatory index and metabolic syndrome: findings from the SU.VI.MAX study. AB - BACKGROUND AND AIMS: The prevention of the metabolic syndrome (MetS) is of major concern and nutrition has been shown to modulate at least partly MetS risk. Our objective was to investigate whether a pro-inflammatory diet was associated with a higher risk of MetS and its components in a large cohort of French adults. METHODS AND RESULTS: A total of 3726 participants from the Supplementation en Vitamines et Mineraux AntioXydants (SU.VI.MAX) cohort were included in this study. The MetS status was identified at baseline and after 13 years of follow-up using self-reported medication, data from clinical investigations and biological measurements. The dietary inflammatory index (DII) was computed using repeated 24 h-dietary records (n = 10.1 +/- 3.1). Logistic and linear regression analyses were conducted to assess the prospective association of the DII (as Q, quartiles) with the incidence of MetS and with the traits contributing to the MetS definition (blood pressure, glycaemia, triglycerides, HDL-cholesterol, waist circumference). A diet with pro-inflammatory properties, as expressed by higher DII scores, was significantly associated with a higher risk of developing the MetS (OR comparing Q4 to Q1: 1.39, 95% confidence interval 1.01-1.92, P = 0.047). Moreover, higher DII scores were associated with higher systolic and diastolic blood pressure (Ptrend across quartiles = 0.03 and 0.05, respectively) and triglycerides (Ptrend = 0.01), and with lower HDL-cholesterol (Ptrend = 0.03). CONCLUSION: A higher DII score was prospectively associated with a higher risk of MetS, with associations with blood pressure, triglycerides and HDL-cholesterol. Promotion of a healthy diet exhibiting anti-inflammatory properties may contribute to prevent cardio-metabolic disorders. PMID- 26482568 TI - DNA Backbone BI/BII Distribution and Dynamics in E2 Protein-Bound Environment Determined by Molecular Dynamics Simulations. AB - BI and BII conformational substates in the DNA backbone typify canonical B-form DNA. The BI and BII substates are important for structural variation of DNA and have been implicated in protein-nucleic acid recognition mechanisms. Recent refinements have been made to nucleic acid force fields employed in molecular dynamics simulations that demonstrate a better ability to model the BI and BII states, leading to overall improved modeling of DNA structure and dynamics. These force field improvements have yet to be significantly demonstrated in the context of a protein-DNA system extended to long time scales. Our plan was to run molecular dynamics simulations of a well-studied protein-DNA system (E2-DNA) into the microsecond time scale and determine the ability of the force field to populate BII states in the DNA backbone consistent with dinucleotide steps crystallized in the BII conformation. The results showed that the dinucleotide steps in the E2-DNA complex with the highest BII populations from simulation trajectories corresponded to the dinucleotide steps crystallized in the BII state and that decoy BI and BII states converge to the same results within approximately one microsecond. PMID- 26482567 TI - Impact of Spodoptera frugiperda neonate pretreatment conditions on Vip3Aa19 insecticidal protein activity and laboratory bioassay variation. AB - BACKGROUND: Variation in response to insecticidal proteins is common upon repetition of insect bioassays. Understanding this variation is a prerequisite to detecting biologically important differences. We tracked neonate Spodoptera frugiperda (J.E. Smith) susceptibility to Vip3Aa19 over 17 generations using standardized bioassay methods. Five larval pretreatment conditions and one bioassay condition were tested to determine whether susceptibility was affected. These included: storage time; prefeeding; storage at reduced temperature; storage at reduced humidity; colony introgression of field-collected individuals. Extremes of photoperiod during the bioassay itself were also examined. RESULTS: LC50 values for two strains of S. frugiperda varied 6.6-fold or 8.8-fold over 17 generations. Storage time and humidity had no impact on Vip3Aa19 susceptibility, whereas prefeeding significantly reduced subsequent mortality (by 27%). Storage at reduced temperature increased mortality for one colony (from 45.6 to 73.0%) but not for the other. Introgression of field-collected individuals affected susceptibility at the first generation but not for subsequent generations. A 24 h bioassay photophase significantly reduced susceptibility (by 26%) for both colonies. CONCLUSION: Certain pretreatment and bioassay conditions were identified that can affect S. frugiperda Vip3Aa19 susceptibility, but innate larval heterogeneity was also present. Our observations should help to increase the consistency of insecticidal protein bioassay results. PMID- 26482569 TI - Synthesis and evaluation of C-5 modified 2'-deoxyuridine monophosphates as inhibitors of M. tuberculosis thymidylate synthase. AB - A series of 5'-monophosphates of 5-substituted 2'-deoxyuridine analogs, which recently demonstrated in vitro substantial suppression of two strains of Mycobacterium tuberculosis growth (virulent laboratory H37Rv and multiple resistant MS-115), has been synthesized and evaluated as potential inhibitors of M. tuberculosis thymidylate synthases: classical (ThyA) and flavin dependent thymidylate synthase (ThyX). A systematic SAR study and docking revealed 5 undecyloxymethyl-2'-deoxyuridine 5'-monophosphate 3b, displaying an IC50 value against ThyX of 8.32 MUM. All derivatives lack activity against the ThyA. It can be assumed that the mechanism of action of 3b may be partially associated with the inhibition of the ThyX. PMID- 26482570 TI - Design, synthesis and biological activity of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists. AB - The free fatty acid receptor 1 (FFA1) is a novel antidiabetic target for the treatment of type 2 diabetes based on particular mechanism in amplifying glucose stimulated insulin secretion. We have previously identified a series of phenoxyacetic acid derivatives. Herein, we describe the further chemical modification of this series directed by ligand efficiency and ligand lipophilicity efficiency. All of these efforts lead to the discovery of the promising candidate 16, an excellent FFA1 agonist with robust agonistic activity (43.6 nM), desired LE and LLE values. Moreover, compound 16 revealed a great potential for improving the hyperglycemia levels in both normal and type 2 diabetic mice without the risk of hypoglycemia even at the high dose of 40 mg/kg. PMID- 26482571 TI - Dimeric [Mo2 S12 ](2-) Cluster: A Molecular Analogue of MoS2 Edges for Superior Hydrogen-Evolution Electrocatalysis. AB - Proton reduction is one of the most fundamental and important reactions in nature. MoS2 edges have been identified as the active sites for hydrogen evolution reaction (HER) electrocatalysis. Designing molecular mimics of MoS2 edge sites is an attractive strategy to understand the underlying catalytic mechanism of different edge sites and improve their activities. Herein we report a dimeric molecular analogue [Mo2 S12 ](2-) , as the smallest unit possessing both the terminal and bridging disulfide ligands. Our electrochemical tests show that [Mo2 S12 ](2-) is a superior heterogeneous HER catalyst under acidic conditions. Computations suggest that the bridging disulfide ligand of [Mo2 S12 ](2-) exhibits a hydrogen adsorption free energy near zero (-0.05 eV). This work helps shed light on the rational design of HER catalysts and biomimetics of hydrogen-evolving enzymes. PMID- 26482572 TI - Hemocompatibility evaluation for peptide fragments of human serum albumin cleaved by cyanogens bromide. AB - We have previously demonstrated that peptide fragments of human serum albumin can be developed into potential renal targeting drug carriers. However, the interactions of these peptide fragments with red blood cells and plasma components are not evaluated well and there is yet no report on the evaluation of the hemocompatibility of peptide fragments. In this study, three kinds of peptide fragments were prepared and identified by amino acid analysis, and the blood compatibility of the peptide fragments was investigated by measuring blood coagulation, platelet and complement activation and hemolysis activity. Results indicated that all the peptide fragments prepared were highly hemocompatible without causing any clot formation, red blood cell aggregation or immune response. In addition, data from the cytotoxicity assay using HeLa cells and Madin-Darby canine kidney cells suggested that these peptide fragments do not induce toxicity towards either cell lines at concentrations up to 5 mg/ml. Therefore, it can be concluded that peptide fragments exhibit good hemocompatibility with no unwanted effect on the viability of renal cells, preliminarily demonstrating that it is safe to use peptide fragments as renal targeting drug carriers. PMID- 26482573 TI - Intermittent administration of human parathyroid hormone (1-34) increases fixation of strontium-doped hydroxyapatite coating titanium implants via electrochemical deposition in ovariectomized rat femur. AB - Previous studies have demonstrated the effect of human parathyroid hormone (1-34) (PTH) or strontium-doped hydroxyapatite coating (Sr-HA) on osteoporotic bone implantation. However, reports about effects of PTH plus Sr-HA on bone osseointegration of titanium implants in a state of osteoporosis were limited. This study was designed to investigate the effects of intermittent administration of human parathyroid hormone (1-34) on strontium-doped hydroxyapatite coating (Sr HA) implant fixation in ovariectomized (OVX) rats. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into four groups including control group, Sr group, PTH group and PTH+Sr group. Forty OVX rats accepted implant insertion in the distal femurs, control group, and PTH group with HA implants and the Sr group and PTH+Sr group with Sr-HA implants. Animals from PTH group and PTH+Sr group then randomly received PTH (60 ug/kg, 3 times a week) until death at 12 weeks. After 12-week healing period, implants from group PTH+Sr revealed improved osseointegration compared with other treatment groups, which is manifested by the exceeding increase of bone area ratio and bone-to-implant contact, the trabecular microarchitecture and the maximal push-out force displayed by tests like histomorphometry, micro-CT, and biomechanics evaluation. These results demonstrated that PTH+ Sr-HA coatings could enhance implant osseointegration in OVX rats, and suggested the feasibility of using this method to improve implant fixation in osteoporotic bone. PMID- 26482574 TI - Effects of Person-Centered Physical Therapy on Fatigue-Related Variables in Persons With Rheumatoid Arthritis: A Randomized Controlled Trial. AB - OBJECTIVE: To examine effects of person-centered physical therapy on fatigue and related variables in persons with rheumatoid arthritis (RA). DESIGN: Randomized controlled trial. SETTING: Hospital outpatient rheumatology clinic. PARTICIPANTS: Persons with RA aged 20 to 65 years (N=70): intervention group (n=36) and reference group (n=34). INTERVENTIONS: The 12-week intervention, with 6-month follow-up, focused on partnership between participant and physical therapist and tailored health-enhancing physical activity and balancing life activities. The reference group continued with regular activities; both groups received usual health care. MAIN OUTCOME MEASURES: Primary outcome was general fatigue (visual analog scale). Secondary outcomes included multidimensional fatigue (Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire) and fatigue-related variables (ie, disease, health, function). RESULTS: At posttest, general fatigue improved more in the intervention group than the reference group (P=.042). Improvement in median general fatigue reached minimal clinically important differences between and within groups at posttest and follow-up. Improvement was also observed for anxiety (P=.0099), and trends toward improvements were observed for most multidimensional aspects of fatigue (P=.023-.048), leg strength/endurance (P=.024), and physical activity (P=.023). Compared with the reference group at follow-up, the intervention group improvement was observed for leg strength/endurance (P=.001), and the trends toward improvements persisted for physical (P=.041) and living-related (P=.031) aspects of fatigue, physical activity (P=.019), anxiety (P=.015), self-rated health (P=.010), and self efficacy (P=.046). CONCLUSIONS: Person-centered physical therapy focused on health-enhancing physical activity and balancing life activities showed significant benefits on fatigue in persons with RA. PMID- 26482575 TI - C57BL/6N Mice Are More Resistant to Ehrlich Ascites Tumors Than C57BL/6J Mice: The Role of Macrophage Nitric Oxide. AB - BACKGROUND Effectiveness of the immune defense formed by the genotype often determines the predisposition to cancer. Nitric oxide (NO) produced by macrophages is an important element in this defense. MATERIAL AND METHODS We hypothesized that genetic characteristics of NO generation systems can predetermine the vulnerability to tumor development. The study was conducted on mice of 2 genetic substrains - C57BL/6J and C57BL/6N - with Ehrlich ascites carcinoma (EAC). NO production in the tumor was changed using ITU, an iNOS inhibitor; c-PTIO, a NO scavenger; and SNP, a NO donor. Macrophage NO production was estimated by nitrite concentration in the culture medium. iNOS content was measured by Western blot analysis. Macrophage phenotype was determined by changes in NO production, iNOS level, and CD markers of the phenotype. RESULTS The lifespan of C57BL/6N mice (n=10) with EAC was 25% longer (p<0.01) than in C57BL/6J mice (n=10). Decreased NO production 23% reduced the survival duration of C57BL/6N mice (p<0.05), which were more resistant to tumors. Elevated NO production 26% increased the survival duration of C57BL/6J mice (p<0.05), which were more susceptible to EAC. Both the NO production and the iNOS level were 1.5 times higher in C57BL/6N than in C57BL/6J mice (p<0.01). CD markers confirmed that C57BL/6N macrophages had the M1 and C57BL/6J macrophages had the M2 phenotype. CONCLUSIONS The vulnerability to the tumor development can be predetermined by genetic characteristics of the NO generation system in macrophages. The important role of NO in anti-EAC immunity should be taken into account in elaboration of new antitumor therapies. PMID- 26482576 TI - The effect of plasma exchange on entecavir-treated chronic hepatitis B patients with hepatic de-compensation and acute-on-chronic liver failure. AB - BACKGROUND AND AIMS: Various studies showed that entecavir (ETV) failed to improve the short-term survival in chronic hepatitis B (CHB) patients with severe acute exacerbation (SAE) and hepatic de-compensation or acute-on-chronic liver failure (ACLF). One study concluded that plasma exchange (PE) significantly decreased the short-term mortality of CHB patients with ACLF who were treated with lamivudine (LAM). Our study was designed to examine the effect of PE on CHB patients with ACLF who were treated with ETV. METHODS: From August 2010 to January 2015, 38 (PE group) and 120 (control group) consecutive CHB-naive patients with hepatic de-compensation and ACLF treated with PE plus ETV and ETV, respectively, were recruited. The primary endpoint was liver-related mortality at week 12. Biochemical and virological responses were also studied. RESULTS: At baseline, the PE group had higher serum alanine aminotransferase (ALT) levels and model for end-stage liver disease (MELD) scores, and had lower albumin levels than the control group. The cumulative survival rate at week 4 and week 12 in the PE group and control group were, respectively, 37 and 18 %, and 29 and 14 % (p < 0.001, by log rank test). While the bilirubin levels in the PE group were more quickly lowered by PE therapy (p < 0.001), the decrease of ALT levels and virological response were similar in the two groups (p > 0.05). Univariate analysis showed that the control group had a higher liver-related mortality (p = 0.038) at week 12 than the PE group. Multivariate analysis showed that hepatic encephalopathy, ascites, PE treatment, and MELD scores were independent factors for liver-related mortality at week 12. CONCLUSIONS: PE significantly improved the short-term survival of CHB patients with hepatic de-compensation and ACLF who were treated with ETV. Hepatic encephalopathy, ascites, PE treatment, and MELD scores were independent factors for liver-related mortality at week 12. PMID- 26482577 TI - Systematic review and meta-analysis on the prognostic value of complete remission status at FDG-PET in Hodgkin lymphoma after completion of first-line therapy. AB - This study aimed to systematically review and meta-analyze the prognostic value of complete remission status at 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in Hodgkin lymphoma after completion of first-line therapy. A systematic literature search was performed in the MEDLINE database for suitable original articles. The included studies were methodologically assessed using the Quality In Prognosis Studies tool. The proportion of patients who developed disease relapse during follow-up, among those patients who were in complete remission according to FDG-PET at the completion of first-line therapy, was calculated for each included study. Heterogeneity in disease relapse proportions across individual studies was assessed using the I2 statistic, with heterogeneity regarded present if I2<50 %. Weighted summary disease relapse proportion was calculated using either a random effects model (if I2>50) or a fixed effects model (if I2<=50). Ten studies comprising a total number of 1137 Hodgkin lymphoma patients with complete remission status according to FDG-PET after completion of first-line therapy were included. Overall methodological quality of included studies was reasonably good. The disease relapse rate during follow-up among all patients with complete remission status at end-of-treatment FDG-PET ranged from 0 to 26.7 %, with a weighted summary proportion of 7.5 % (95 % confidence interval 3.9-13.8 %) using the random effects model (I2=88.3 %). In conclusion, although the disease relapse rate in Hodgkin lymphoma patients who achieve an FDG-PET based complete remission after first-line therapy is low from an absolute point of view, it is actually high when considering the generally favorable outcome of Hodgkin lymphoma. PMID- 26482578 TI - Enteric-coated mycophenolate sodium in pediatric lupus nephritis: a retrospective cohort study. AB - BACKGROUND: The objective of this study was to examine the long-term efficacy and complications associated with use of enteric-coated mycophenolate sodium (EC-MPS) for treatment of pediatric lupus nephritis (LN). METHODS: This was a retrospective analysis of pediatric patients treated between 1995 and 2008. Comparisons were made between patients with LN who were and were not treated with EC-MPS (MPS and non-MPS groups). The primary endpoint was survival. The secondary endpoint was time to stage 3 chronic kidney disease (CKD). Response rates, laboratory parameters, and complications were determined. RESULTS: There were 33 patients in the MPS group and 19 patients in the non-MPS group. The MPS group had more patients with complete/partial response (72.7 vs. 31.6 %; P < 0.001) and a significantly higher survival rate (0.0 vs. 42.1 %, P < 0.001), but the groups had similar rates of stage 3 CKD. The rebound of complement 3 was more rapid in the MPS group. There were no significant between-group differences in the incidence of complications, including gastrointestinal complications. CONCLUSION: A limitation of this study is the heterogeneity in the timing of treatment and in the duration of follow-up. Nonetheless, our findings suggest that EC-MPS can be an effective treatment for pediatric LN. PMID- 26482579 TI - Transitional Hemodynamics in Preterm Neonates: Clinical Relevance. AB - BACKGROUND: Each newborn enters this world facing tremendous respiratory, hemodynamic and neuroendocrine challenges while going through drastic physiological changes during the process of adaption from fetal to postnatal life. Even though the vast majority of term infants transition smoothly without apparent consequences, this task becomes increasingly arduous for the extremely preterm infant. METHODS & RESULTS: This article reviews the physiology and pathophysiology of cardiovascular adaptation of the very preterm neonate. In particular it describes the physiology of fetal circulation, summarizes the hemodynamic changes occurring during preterm births and discusses the impact of the most frequently seen clinical scenarios that place additional burden on the premature infant during immediate transition. Finally an emphasis is placed on discussing common clinical dilemmas and practical aspects of developmental hemodynamics such as neonatal hypotension and patent ductus arteriosus; clinical presentations the neonatologist encounters on a daily basis. CONCLUSION: The review provides a physiology-based view on the hemodynamics of the immediate postnatal transitional period. PMID- 26482580 TI - Usefulness of Adenosinetriphosphate Bioluminescence Assay (ATPmetry) for Monitoring the Reprocessing of Endoscopes. AB - OBJECTIVE: To assess the diagnostic value of an adenosinetriphosphate bioluminescence assay (ATPmetry) to monitor the effectiveness of the reprocessing of endoscopes compared with microbiologic sampling. DESIGN: Diagnostic study. SETTING: A 2,200-bed teaching hospital performing 5,000 to 6,000 endoscopic procedures annually. INCLUSION CRITERIA: All samples from bronchial or gastrointestinal endoscopes whatever the context. METHODS: Samples for microbiologic analysis and ATPmetry measurements were taken when each endoscope was inspected following reprocessing. Sampling was performed by flushing each endoscope with 300 mL Neutralizing Pharmacopeia Diluent thiosulfate rinsing solution divided equally between the endoscope channels. For each endoscope a series of 3 ATPmetry measurements were made on a vial containing the first jet from each channel and a second series on the whole sample. RESULTS: Of 165 samples from endoscopes, 11 exceeded the acceptability threshold of 25 colony forming units/endoscope. In the first jet collected, the median (interquartile range) level of ATPmetry was 30.5 (15.3-37.7) relative light units (RLU) for samples with 25 or fewer colony-forming units compared with 37.0 (34.7-39.3) RLU for samples with more than 25 colony-forming units (P=.008). For the whole sample, the median (interquartile range) level of ATPmetry was 24.8 (14.3-36.3) RLU and 36.3 (36.0-38.3) RLU (P=.006), respectively. After adjusting on the batch of cleansing solution used, no difference in ATPmetry values was found between microbiologically acceptable and unacceptable samples. CONCLUSION: ATPmetry cannot be used as an alternative or complementary approach to microbiologic tests for monitoring the reprocessing of endoscopes in France. PMID- 26482581 TI - The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: A role for the NLRP3 inflammasome. AB - The alarmin high mobility group box-1 (HMGB1) has been implicated as a key factor mediating neuroinflammatory processes. Recent findings suggest that the redox state of HMGB1 is a critical molecular feature of HMGB1 such that the reduced form (fr-HMGB1) is chemotactic, while the disulfide form (ds-HMGB1) is pro inflammatory. The present study examined the neuroinflammatory effects of these molecular forms as well as the ability of these forms to prime the neuroinflammatory and microglial response to an immune challenge. To examine the neuroinflammatory effects of these molecular forms in vivo, animals were administered intra-cisterna magna (ICM) a single dose of fr-HMGB1 (10MUg), ds HMGB1 (10MUg) or vehicle and basal pro-inflammatory effects were measured 2 and 24h post-injection in hippocampus. Results of this initial experiment demonstrated that ds-HMGB1 increased hippocampal pro-inflammatory mediators at 2h (NF-kappaBIalpha mRNA, NLRP3 mRNA and IL-1beta protein) and 24h (NF-kappaBIalpha mRNA, TNFalpha mRNA, and NLRP3 protein) after injection. fr-HMGB1 had no effect on these mediators. These neuroinflammatory effects of ds-HMGB1 suggested that ds HMGB1 may function to prime the neuroinflammatory response to a subsequent immune challenge. To assess the neuroinflammatory priming effects of these molecular forms, animals were administered ICM a single dose of fr-HMGB1 (10MUg), ds-HMGB1 (10MUg) or vehicle and 24h after injection, animals were challenged with LPS (10MUg/kg IP) or vehicle. Neuroinflammatory mediators and the sickness response (3, 8 and 24h after injection) were measured 2h after immune challenge. We found that ds-HMGB1 potentiated the neuroinflammatory (NF-kappaBIalpha mRNA, TNFalpha mRNA, IL-1beta mRNA, IL-6 mRNA, NLRP3 mRNA and IL-1beta protein) and sickness response (reduced social exploration) to LPS challenge. fr-HMGB1 failed to potentiate the neuroinflammatory response to LPS. To examine whether these molecular forms of HMGB1 directly induce neuroinflammatory effects in isolated microglia, whole brain microglia were isolated and treated with fr-HMGB1 (0, 1, 10, 100, or 1000ng/ml) or ds-HMGB1 (0, 1, 10, 100, or 1000ng/ml) for 4h and pro inflammatory mediators measured. To assess the effects of these molecular forms on microglia priming, whole brain microglia were pre-exposed to these forms of HMGB1 (0, 1, 10, 100, or 1000ng/ml) and subsequently challenged with LPS (10ng/ml). We found that ds-HMGB1 increased expression of NF-kappaBIalpha mRNA and NLRP3 mRNA in isolated microglia, and potentiated the microglial pro inflammatory response (TNFalpha mRNA, IL-1beta mRNA and IL-1beta protein) to LPS. fr-HMGB1 failed to potentiate the microglial pro-inflammatory response to LPS. Consistent with prior reports, the present findings demonstrate that the disulfide form of HMGB1 not only potentiates the neuroinflammatory response to a subsequent immune challenge in vivo, but also potentiates the sickness response to that challenge. Moreover, the present findings demonstrate for the first time that ds-HMGB1 directly potentiates the microglia pro-inflammatory response to an immune challenge, a finding that parallels the effects of ds-HMGB1 in vivo. In addition, ds-HMGB1 induced expression of NLRP3 and NF-kappaBIalpha in vivo and in vitro suggesting that the NLRP3 inflammasome may play role in the priming effects of ds-HMGB1. Taken together, the present results suggest that the redox state of HMGB1 is a critical determinant of the priming properties of HMGB1 such that the disulfide form of HMGB1 induces a primed immunophenotype in the CNS, which may result in an exacerbated neuroinflammatory response upon exposure to a subsequent pro-inflammatory stimulus. PMID- 26482583 TI - Salvage of the proximal femur following pathological fractures involving benign bone tumors. AB - BACKGROUND AND OBJECTIVES: To describe the surgical treatment of patients with a pathologic fracture through a benign tumor of the proximal femur to determine if there is a difference in local recurrence, complications or functional outcome compared to patients with tumors in the same location without pathologic fractures. METHODS: From 1989-2010, of 97 patients, 29 presented with a pathologic fracture (PF) through a proximal femoral benign bone tumor and 68 presented without a pathologic fracture (NPF). Outcomes of the two groups were compared in terms of surgical management, postoperative complications, local recurrence and functional scores. RESULTS: Fibrous dysplasia, giant cell tumor of bone and chondroblastoma were the most common subtypes. Most patients were managed with joint preservation in both PF (86.2%) and NPF (98.5%) groups (P = 0.03). Local recurrence risk was similar for patients in the PF (10.3%) and NPF (8.8%) groups. Mean follow-up was 105.7 months (P = 0.8). Functional outcome scores were high in both groups and not statistically significantly different. CONCLUSIONS: The majority of pathologic fractures through a benign bone tumor of the proximal femur can be successfully treated with curettage, burring, bone grafting and internal fixation without increasing the risk of local recurrence or negatively impacting functional outcome. PMID- 26482584 TI - Sonographic fetal weight estimation in normal and overweight/obese healthy term pregnant women by gestation-adjusted projection (GAP) method. AB - PURPOSE: The objective of this study is to assess the ultrasound accuracy in fetal weight estimation related to the time distance between the actual weight recorded at delivery and the period of sonography among normal and overweight/obese pregnant women within 3 weeks prior birth at term. METHODS: Four hundred and ninety patients with healthy pregnancy were studied in a cohort study. The absolute percent error in estimation was achieved by gestation adjusted projection method from Hadlock model for weight calculation as measure of accuracy. The mean percentage error variation over the weeks was correlated to maternal body mass index (BMI, Kg/m(2)) at ultrasound. The relationship between BMI and ultrasound performance was assessed by linear regression. RESULTS: The overall proportion of supposed sonographic estimated fetal weight at birth within +/-10 % of the birth weight significantly declines over the weeks (P = .016). The trend toward a progressive deterioration in ultrasound accuracy is not statistically significant for normal weight women (P = .272) but it is for over weight/obese (P = .044). On univariate analysis, the absolute percent error and absolute error are positively related to BMI. CONCLUSIONS: Accuracy is related to the week at ultrasound scan with a gradual deterioration over the time and it worsens with increasing distance in days between the date of ultrasounds and delivery. The deterioration is greater for BMI >= 25. PMID- 26482585 TI - Risk factors for clavicle fracture concurrent with brachial plexus injury. AB - PURPOSE: The aim of this study was to evaluate the risk factors for clavicle fracture concurrent with brachial plexus injuries. METHODS: A retrospective study was conducted at a tertiary centre. The hospital records of 62,288 vaginal deliveries were evaluated retrospectively. There were 35 cases of brachial plexus injury. Of these patients, nine had brachial plexus injuries with clavicle fracture and 26 without clavicle fracture. The analysed risk factors for clavicle fracture concurrent with brachial plexus injury were gestational diabetes, labour induction and augmentation, prolonged second stage of labour, estimated foetal weight above 4000 g, birth weight above 4000 g, risky working hours, and the requirement of manoeuvres to free the impacted shoulder from behind the symphysis pubis. RESULTS: Labour augmentation with oxytocin increased the risk of clavicle fracture in cases of brachial plexus injury (OR 6.67; 95% CI 1.26-35.03). A birth weight higher than 4000 g also increased the risk of clavicle fracture. Risky working hours, gestational diabetes, estimated foetal weight higher than 4000 g, and requirement of shoulder dystocia manoeuvres did not increase the risk of clavicle fracture. CONCLUSIONS: Labour augmentation and actual birth weight higher than 4000 g were identified as risk factors for clavicle fracture in cases of brachial plexus injury. PMID- 26482586 TI - Unmet Needs of Adults in Community Mental Health Care With and Without Intellectual and Developmental Disabilities: A Cross-Sectional Study. AB - The cross-sectional study compared the clinical and need profiles for clients with and without intellectual and developmental disabilities (IDD) in seven mental health case management programs in Toronto, Canada on March 31, 2013. Unmet needs in domains within four broad clusters were measured by staff using an internationally utilized tool, the Camberwell Assessment of Need. Among the 2560 clients, 8.3 % had a co-occurring IDD. For most assessed domains rates of unmet need were not different for persons with and without IDD. However, the IDD group had greater unmet needs for adaptive functioning/skills and cognitive needs [self care (p = 0.023), education (p < 0.001), transportation (p < 0.001), and information on condition (p = 0.038)]. While clients with IDD and psychiatric diagnoses often receive poor quality care, in the case management programs examined their rates of unmet need were similar to individuals without IDD across most assessed domains, including in the areas of addictions and physical health care. PMID- 26482587 TI - Community Resilience of Civilians at War: A New Perspective. AB - A new concept of community resilience pertaining to the community's post adversity strength to vulnerability ratio was associated with five determinants: individual resilience, national resilience, well-being, community size, and sense of coherence. The data was collected four months after Israel's war in the Gaza Strip in 2014. Participants were 251 adult civilians living in southern Israel who have recently been threatened by massive missile attacks, and 259 adults living in northern Israel, which has not been under missile fire recently. The investigated variables predicted community resilience, and their effects were mediated by sense of coherence. Results which were similar for both samples were discussed in terms of the nature of resilience and in terms of proximal and distal exposure to war. PMID- 26482588 TI - Formation of photosystem II reaction centers that work as energy sinks in lichen symbiotic Trebouxiophyceae microalgae. AB - Lichens are poikilohydric symbiotic organisms that can survive in the absence of water. Photosynthesis must be highly regulated in these organisms, which live under continuous desiccation-rehydration cycles, to avoid photooxidative damage. Analysis of chlorophyll a fluorescence induction curves in the lichen microalgae of the Trebouxiophyceae Asterochloris erici and in Trebouxia jamesii (TR1) and Trebouxia sp. (TR9) phycobionts, isolated from the lichen Ramalina farinacea, shows differences with higher plants. In the presence of the photosynthetic electron transport inhibitor DCMU, the kinetics of Q(A) reduction is related to variable fluorescence by a sigmoidal function that approaches a horizontal asymptote. An excellent fit to these curves was obtained by applying a model based on the following assumptions: (1) after closure, the reaction centers (RCs) can be converted into "energy sink" centers (sRCs); (2) the probability of energy leaving the sRCs is very low or zero and (3) energy is not transferred from the antenna of PSII units with sRCs to other PSII units. The formation of sRCs units is also induced by repetitive light saturating pulses or at the transition from dark to light and probably requires the accumulation of reduced Q(A), as well as structural changes in the reaction centers of PSII. This type of energy sink would provide a very efficient way to protect symbiotic microalgae against abrupt changes in light intensity. PMID- 26482589 TI - The variability of light-harvesting complexes in aerobic anoxygenic phototrophs. AB - Light-harvesting capacity was investigated in six species of aerobic anoxygenic phototrophic (AAP) bacteria using absorption spectroscopy, fluorescence emission spectroscopy, and pigment analyses. Aerobically grown AAP cells contained approx. 140-1800 photosynthetic reaction centers per cell, an order of magnitude less than purple non-sulfur bacteria grown semiaerobically. Three of the studied AAP species did not contain outer light-harvesting complexes, and the size of their reaction center core complexes (RC-LH1 core complexes) varied between 29 and 36 bacteriochlorophyll molecules. In AAP species containing accessory antennae, the size was frequently reduced, providing between 5 and 60 additional bacteriochlorophyll molecules. In Roseobacter litoralis, it was found that cells grown at a higher light intensity contained more reaction centers per cell, while the size of the light-harvesting complexes was reduced. The presented results document that AAP species have both the reduced number and size of light harvesting complexes which is consistent with the auxiliary role of phototrophy in this bacterial group. PMID- 26482590 TI - Clinical comparison of postoperative results of balloon kyphoplasty (BKP) versus radiofrequency-targeted vertebral augmentation (RF-TVA): a prospective clinical study. AB - INTRODUCTION: Osteoporotic vertebral fractures are a frequent occurrence in geriatric traumatology. Differences in the achievement of pain reduction and restoration of the height of the vertebral body after balloon kyphoplasty (BKP) or radiofrequency-targeted vertebral augmentation (RF-TVA) were to be tested on a randomized population. METHODS: A total of 80 patients (f = 59; m = 21) with osteoporotic fractures of vertebral bodies were assigned to the groups BKP (n = 44) or RF-TVA (n = 36). The clinical analyses were compared peri- and postoperatively in a prospective study with an additional follow-up examination after 1 year. RESULTS: The operations for BKP were bipedicular in all cases; for RF-TVA, a bipedicular access was required in only five cases (14 %) (p>0.0001). There were confirmed differences with respect to the amount of cement used (ml) between the two groups (BKP = 4.9 +/- 1 vs. RFTVA= 3.4 +/- 1; p<0.001). In the BKP group, the angle of kyphosis was reduced by an average of 1.65 degrees and in the RF-TVA group by an average of 2.8 degrees by the operation. The analysis of the maximum VAS data showed a clear postoperative reduction in the intensity of pain of approximately 4.5 cm in each of the groups with no discernible difference. After 12 months, the majority of patients in both groups (BKP = 61 % vs. RF-TVA = 83 %) reported being free of pain when at rest without a significant difference(p = 0.05). CONCLUSIONS: A certain superiority of RF-TVA with respect to pain relief, amount of cement required, savings of operating time and personnel, and greater safety with respect to cement leakage noted in this study are consistent with other published literature. The differences between the two methods in the frequency of subsequent postoperative fractures and the secondary loss of high restoration were encouraging regarding RF-TVA. PMID- 26482591 TI - Results of sling surgery in a non-selected population. AB - OBJECTIVE: To evaluate sling surgery in terms of effectiveness and quality of life, and describe the effects of confounding variables on outcomes. METHODS: A retrospective cohort study using multiple validated questionnaires was conducted in a specialized pelvic floor center in the Netherlands. Women were enrolled after undergoing sling surgery between January 1, 2010, and January 31, 2012. In addition to the preoperative questionnaire, participants completed a questionnaire a minimum of 6weeks after surgery to assess outcomes. RESULTS: Of 255 eligible participants, 228 (89.4%) returned the postoperative questionnaire after a mean follow-up of 14.9months (range 2-32). At the time of follow-up, 158 (69.3%) patients considered themselves cured, and an improvement was observed in 155 (68.9%) patients; 70 (31.1%) patients rated their postoperative situation as little improved, unchanged, or deteriorated. Compared with patients who had no history of previous related surgery, patients with prior sling surgery benefited significantly less from surgery, whereas those with concomitant vaginal surgery showed similar scores in all outcome parameters. A high body mass index was found to have a negative effect on the results of surgery. CONCLUSION: midurethral sling surgery is both efficient and effective in curing stress urinary incontinence. However, patient characteristics and confounding variables can influence the outcome of surgery and should therefore always be discussed with the patient. PMID- 26482592 TI - Structurally Characterized Zn2+ Selective Ratiometric Fluorescence Probe in 100 % Water for HeLa Cell Imaging: Experimental and Computational Studies. AB - Fluorescence recognition of Zn2+ in 100% aqueous medium using 2-((1, 3 dihydroxy 2-(hydroxymethyl)propan-2 ylimino) methyl) phenol (SALTM) as ratiometric probe is reported. Moreover, SALTM can discriminate Zn2+ from Cd2+very effectively. The binding constant and detection limit of the probe for Zn2+ is 2.2*10(4) M(-1/2) and 2.79*10(-8) M respectively.Interestingly, corresponding naphthalene derivative(HNTM) having less water solubility fails to be a ratiometric sensor. SALTM can detect intracellular Zn2+ in HeLa cervical cancer cells under fluorescence microscope. Moreover, DFT and TD-DFT studies support experimental findings. PMID- 26482593 TI - Study of Binding Properties Between Two New Ibuprofen and Naproxen Based Acyl Hydrazone Derivatives and Trypsin. AB - Two acyl hydrazone derivatives, AHI and AHN,made from ibuprofen and naproxen derived hydrazides, were prepared and studied of binding properties with serine protease trypsin by UV-vis absorption and fluorescence quenching at pH 7.4. The results suggest that both hydrazones can interact strongly with trypsin and there are the formation of trypsin-hydrazone complexes. The Stern-Volmer constants, binding constants,binding sites and the corresponding thermodynamic parameters DeltaH degrees , DeltaS degrees and DeltaG degrees were calculated at different temperatures.The effect of common metal ions on the constants was also discussed. The binding modes can be explained on the basis of hydrogen bonds and van der Waals forces. The binding distance(r) ~3 nm between the donor (trypsin) and acceptors (AHI and AHN) was obtained according to Forster's non-radiative energy transfer theory. Moreover, LOD and LOQ of hydrazones were calculated in the presence of trypsin. PMID- 26482594 TI - A nonlinear-elastic constitutive model for soft connective tissue based on a histologic description: Application to female pelvic soft tissue. AB - To understand the mechanical behavior of soft tissues, two fields of science are essential: biomechanics and histology. Nonetheless, those two fields have not yet been studied together often enough to be unified by a comprehensive model. This study attempts to produce such model. Biomechanical uniaxial tension tests were performed on vaginal tissues from 7 patients undergoing surgery. In parallel, vaginal tissue from the same patients was histologically assessed to determine the elastic fiber ratio. These observations demonstrated a relationship between the stiffness of tissue and its elastin content. To extend this study, a mechanical model, based on an histologic description, was developed to quantitatively correlate the mechanical behavior of vaginal tissue to its elastic fiber content. A satisfactory single-parameter model was developed assuming that the mechanical behavior of collagen and elastin was the same for all patients and that tissues are only composed of collagen and elastin. This single-parameter model showed good correlation with experimental results. The single-parameter mechanical model described here, based on histological description, could be very useful in helping to understand and better describe soft tissues with a view to their characterization. The mechanical behavior of a tissue can thus be determined thanks to its elastin content without introducing too many unidentified parameters. PMID- 26482595 TI - Overcoming translational challenges - The delivery of mechanical stimuli in vivo. AB - Despite major medical advances, non-union bone fractures and skeletal defects continue to place significant burden on the patient, the clinicians and the healthcare system as a whole. Current bone substitute approaches are still limited in effectiveness and to date no adequate bone substitute material has been developed for routine clinical application. Tissue engineering presents a novel approach to tackling this clinical burden and developing an acceptable solution for the treatment of skeletal defects. Over the past three decades the field has evolved to appreciate the key biological, material and physical parameters influencing the development of a cell-based tissue engineered therapy and to create associated technologies to exploit such parameters. In recent years a number of therapies have started progressing along the pre-clinical pipeline to build a case for regulatory approval and ultimately clinical adoption. However, little emphasis has been given to the translational challenges faced when moving from "bench-to-bedside". One particular challenge lies in the delivery of functional mechanical stimuli to implanted cell populations to activate and promote osteogenic activities. This review introduces novel bio-magnetic approaches to overcoming this challenge. PMID- 26482596 TI - Inhibition of MEF2A prevents hyperglycemia-induced extracellular matrix accumulation by blocking Akt and TGF-beta1/Smad activation in cardiac fibroblasts. AB - Myocyte enhancer factor 2A (MEF2A) functions in muscle-specific and/or growth factor-related transcription and is involved in cell growth, survival, and apoptosis. To evaluate the role of this transcription factor in cardiac fibroblasts (CFs) in diabetes mellitus, we performed a series of in vitro and in vivo experiments. We used short hairpin RNA (shRNA) to inhibit the expression of MEF2A in CFs in vitro. Inhibition of MEF2A significantly reduced hyperglycemia induced CF proliferation and migration, myofibroblast differentiation, matrix metalloproteinase (MMP) activities, and collagen production. Furthermore, MEF2A inhibition attenuated HG-induced activation of the mitogen-activated protein kinase (MAPK), Akt, and TGF-beta1/Smad signaling pathways. For in vivo analysis in a mouse model, type-1 diabetes was induced by streptozotocinand MEF2A expression was knocked down by myocardial injection with lentivirus carrying shRNA-MEF2A. Cardiac function was assessed by echocardiography. Total collagen deposition was assessed by Masson's trichrome and Picrosirius red staining. Knockdown of MEF2A ameliorated diabetes-induced cardiac dysfunction and collagen deposition. Our study suggests that inhibition of MEF2A could alleviate HG induced extracellular matrix accumulation by blocking the activation of Akt and TGF-beta1/Smad signaling pathway in CFs. Thus, inhibition of MEF2A has therapeutic potential in the treatment of diabetic-induced cardiac remodeling. PMID- 26482598 TI - Antibiotic resistance threatens the efficacy of prophylaxis. PMID- 26482597 TI - Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study. AB - BACKGROUND: The declining efficacy of existing antibiotics potentially jeopardises outcomes in patients undergoing medical procedures. We investigated the potential consequences of increases in antibiotic resistance on the ten most common surgical procedures and immunosuppressing cancer chemotherapies that rely on antibiotic prophylaxis in the USA. METHODS: We searched the published scientific literature and identified meta-analyses and reviews of randomised controlled trials or quasi-randomised controlled trials (allocation done on the basis of a pseudo-random sequence-eg, odd/even hospital number or date of birth, alternation) to estimate the efficacy of antibiotic prophylaxis in preventing infections and infection-related deaths after surgical procedures and immunosuppressing cancer chemotherapy. We varied the identified effect sizes under different scenarios of reduction in the efficacy of antibiotic prophylaxis (10%, 30%, 70%, and 100% reductions) and estimated the additional number of infections and infection-related deaths per year in the USA for each scenario. We estimated the percentage of pathogens causing infections after these procedures that are resistant to standard prophylactic antibiotics in the USA. FINDINGS: We estimate that between 38.7% and 50.9% of pathogens causing surgical site infections and 26.8% of pathogens causing infections after chemotherapy are resistant to standard prophylactic antibiotics in the USA. A 30% reduction in the efficacy of antibiotic prophylaxis for these procedures would result in 120,000 additional surgical site infections and infections after chemotherapy per year in the USA (ranging from 40,000 for a 10% reduction in efficacy to 280,000 for a 70% reduction in efficacy), and 6300 infection-related deaths (range: 2100 for a 10% reduction in efficacy, to 15,000 for a 70% reduction). We estimated that every year, 13,120 infections (42%) after prostate biopsy are attributable to resistance to fluoroquinolones in the USA. INTERPRETATION: Increasing antibiotic resistance potentially threatens the safety and efficacy of surgical procedures and immunosuppressing chemotherapy. More data are needed to establish how antibiotic prophylaxis recommendations should be modified in the context of increasing rates of resistance. FUNDING: DRIVE-AB Consortium. PMID- 26482599 TI - Antiepileptic drug use improves overall survival in breast cancer patients with brain metastases in the setting of whole brain radiotherapy. AB - BACKGROUND AND PURPOSE: There is mounting evidence that histone deacetylase (HDAC) inhibitors, e.g. valproic acid (VPA), synergize with radiation to improve outcomes in several cancers. This study was conducted to ascertain whether VPA affected outcomes in breast cancer patients with brain metastases treated with whole brain radiotherapy (WBRT). MATERIALS AND METHODS: Records from 253 breast cancer patients with brain metastases treated with WBRT were reviewed. Data regarding use of all antiepileptic drugs (AEDs) were extracted. Kaplan-Meier survival times were calculated using the date of brain involvement as time zero. Cox proportional hazard models were used to determine the association between patient and tumor characteristics and overall survival (OS). RESULTS: Median OS for the entire patient cohort was 6 months. Patients receiving VPA (n=20) had a median OS of 11 months versus 5 months for those not receiving VPA (p=0.028). Median OS was 9 months for patients taking any AED (n=101) versus 4 months for those not taking AEDs (p=0.0003). On multivariate analysis both VPA and AED use were associated with improved OS (HR 0.61, p=0.0419; HR 0.59, p=0.0002, respectively). CONCLUSIONS: This study suggests the use of AEDs, including VPA, is associated with improved OS in breast cancer patients with brain metastases following WBRT. PMID- 26482600 TI - Temporal trends in perinatal mortality and cerebral palsy: A regional population based study in southern Japan. AB - AIM: The prevalence of cerebral palsy (CP) has not decreased in developed countries over the past 30 years. We examined gestational age-specific trends in the prevalence of CP. METHODS: This unselected, population-based study was conducted in Miyazaki prefecture, Japan (10,000 deliveries annually), where 102,999 deliveries were registered between 2001 and 2010. Of these, 312 were stillbirths (?22 weeks of gestation), 126 were neonatal deaths (<28 days of birth), and 214 infants were determined to be at risk of CP at peer-review conferences. Survival and neurological damage were compared for two 5-year periods, 2001-2005 and 2006-2010, and infants were classified according to gestational ages. RESULTS: Stillbirths and neonatal deaths decreased significantly during both periods. Likewise, the number of registered high-risk cases of CP decreased by 30.2%, from 126 to 88 cases. After excluding congenital anomalies, the corrected CP prevalence was 1.5 per 1000 (78/51,889) and 1.3 per 1000 (67/51,110), for the two periods, which was not a significant difference. The number of extremely preterm infants (22-25 weeks) did not change over the 10 year period, whereas that of moderately preterm infants (26-36 weeks) increased, and that of term infants significantly decreased (p<0.01). In term infants, asphyxia decreased from 18 to 7 cases (p<0.05). CONCLUSIONS: Perinatal deaths and CP decreased in prevalence during both 5-year periods, and the CP prevalence was 2.1 per 1000 births. Furthermore, fewer term infants were at high risk for CP mainly because of the reduced prevalence of asphyxia. PMID- 26482601 TI - High prevalence of genetic alterations in early-onset epileptic encephalopathies associated with infantile movement disorders. AB - OBJECTIVE: Recent studies have elucidated causative roles for genetic abnormalities in early-onset epileptic encephalopathies (EOEE). Accompanying characteristic features, in addition to seizures, have also been suggested to provide important clues for an early and accurate genetic diagnosis of affected patients. In this study, we investigated the underlying genetic causes in patients with EOEE associated with infantile movement disorders. METHODS: We examined 11 patients with EOEE and involuntary movements (nine with West syndrome and two with nonsyndromic epileptic encephalopathy). All showed severe developmental delay, cognitive impairment, and involuntary movements such as chorea, ballism, dyskinesia or myoclonus, and hand stereotypies. We performed whole-exome sequencing of 10 patients, while the other patient underwent high resolution melting analysis of candidate EOEE genes. RESULTS: We identified mutations in CDKL5, SCN2A, SETD5, ALG13, and TBL1XR1 in seven patients with West syndrome, and in SCN1A and GRIN1 in the two patients with unclassified epileptic encephalopathy. All mutations were validated as de novo events. The genetic cause was undetermined in the remaining two patients. CONCLUSIONS: We found pathogenic mutations in seven genes, in nine of 11 patients with EOEE and involuntary movements. Although the results of our study are preliminary because of the small number of patients, they nevertheless suggest that specific accompanying phenotypes such as hyperkinetic movements or hand stereotypies could be important in narrowing the disease spectrum and identifying causative genetic abnormalities. PMID- 26482602 TI - The long-term health impact and potential predictors of cardiopulmonary arrest in patients with childhood-onset psychomotor impairments. AB - AIM: The aim of the study was to understand the long-term health issues and potential predictors of cardiopulmonary arrest (CPA) in patients with severe childhood-onset psychomotor impairments. METHOD: In this single-center, retrospective observational study, the medical records of 140 patients with severe childhood-onset psychomotor impairments were reviewed. The medical interventions and functional status of patients with a history of CPA (n=22: 14 M/8 F; mean+/-SD age: 26.6+/-12.4 years) were compared with age- and sex-matched patients without a history of CPA (n=44: 28 M/16 F; mean+/-SD age: 26.5+/-12.3 years). RESULTS: The prevalence of CPA was 15.7%. The most frequent cause was respiratory issues, and CPA occurred most frequently between 0 and 5 years old. The patients who had a history of CPA were more likely to have required a feeding tube (p=0.0007), tracheostomy (p<0.0001), and ventilator (p=0.002) compared to the non-CPA patients, while the prevalence of tracheostomy or ventilator treatment during early infancy was comparable between both groups. Although statistically non-significant, patients who used antiepileptics or feeding tubes during the neonatal period had higher odds of a future CPA. INTERPRETATION: This single-center study indicated that the prevalence of CPA could be high among individuals with severe childhood-onset psychomotor impairments, and patients who experience CPA have more health issues. The potential predictors for a future CPA are young age (0-5 years), respiratory issues, and antiepileptic or feeding tube usage during the neonatal period. These patients may require extra attention in medical managements. PMID- 26482603 TI - Long-term weekly ACTH therapy for relapsed West syndrome in tuberous sclerosis complex: A case report. AB - BACKGROUND: In Japan, adrenocorticotropic hormone (ACTH) therapy has been the mainstay of treatment of West syndrome. Conventional ACTH therapy is administered short-term with efficacy, yet the relapse rate is high. Relapse after initial ACTH therapy is a poor prognostic factor for long-term seizure control and outcome of cognitive function. Here, we report successful long-term weekly ACTH therapy for relapsed WS in a tuberous sclerosis complex (TSC) child after conventional ACTH therapy. PATIENT: The patient had a series of epileptic spasms (ES) and hypsarrhythmia at age 3 months. She was diagnosed with WS associated with TSC, and was treated with conventional ACTH therapy at age 4 months, and a second course of ACTH therapy at age 8 months. Both courses of therapy were transiently effective. A third course of ACTH therapy was started at age 1 year and 2 months, and long-term weekly ACTH therapy was continued thereafter. During this therapy, both ES and hypsarrhythmia remained completely resolved. Therapy was continued, and dose reduction was started when the patient was 2 years and 10 months old. No serious adverse events had occurred during this therapy. CONCLUSION: This case demonstrated that long-term weekly ACTH may be safe and effective. Although at present, this therapy may only be considered for relapsed symptomatic WS patients, it may be a good alternative therapy when frequent relapses occur after favorable response to conventional ACTH therapy. PMID- 26482604 TI - Conditional robustness analysis for fragility discovery and target identification in biochemical networks and in cancer systems biology. AB - BACKGROUND: The study of cancer therapy is a key issue in the field of oncology research and the development of target therapies is one of the main problems currently under investigation. This is particularly relevant in different types of tumor where traditional chemotherapy approaches often fail, such as lung cancer. RESULTS: We started from the general definition of robustness introduced by Kitano and applied it to the analysis of dynamical biochemical networks, proposing a new algorithm based on moment independent analysis of input/output uncertainty. The framework utilizes novel computational methods which enable evaluating the model fragility with respect to quantitative performance measures and parameters such as reaction rate constants and initial conditions. The algorithm generates a small subset of parameters that can be used to act on complex networks and to obtain the desired behaviors. We have applied the proposed framework to the EGFR-IGF1R signal transduction network, a crucial pathway in lung cancer, as an example of Cancer Systems Biology application in drug discovery. Furthermore, we have tested our framework on a pulse generator network as an example of Synthetic Biology application, thus proving the suitability of our methodology to the characterization of the input/output synthetic circuits. CONCLUSIONS: The achieved results are of immediate practical application in computational biology, and while we demonstrate their use in two specific examples, they can in fact be used to study a wider class of biological systems. PMID- 26482605 TI - Prognostic impact of extent of vascular invasion in low-grade encapsulated follicular cell-derived thyroid carcinomas: a clinicopathologic study of 276 cases. AB - Continuous controversy surrounds the predictive value of the degree of vascular invasion (VI) in low-grade encapsulated follicular cell-derived thyroid carcinomas (LGEFCs). Some guidelines advocate conservative therapy in LGEFCs with focal VI. There is therefore a need to assess the survival rates of LGEFC patients with various degrees of VI to better stratify patients for subsequent therapy. Furthermore, the prognostic effect of VI within the different histotypes of LGEFCs is not well known. A total of 276 patients with LGEFCs were subjected to a meticulous histopathologic analysis. They were classified as encapsulated papillary thyroid carcinoma, encapsulated follicular carcinoma (EFC), and encapsulated Hurthle cell carcinoma (EHCC). Of the 276 patients, 24 had extensive VI (EVI) (>=4 foci) and 28 displayed focal (<4 foci) VI. EHCC and EFC showed a much higher rate of EVI than encapsulated papillary thyroid carcinoma. Median follow-up was 6 years. All 14 tumors with adverse behavior harbored distant metastases (DMs), of which 9 had DMs at presentation. All 3 patients without EVI who had aggressive carcinomas harbored DMs at presentation. EVI was an independent predictor of poor recurrence-free survival. Excluding cases with DMs at presentation, only patients with EVI had recurrence, and all relapsed cases were EHCC. EVI is an independent predictor of recurrence-free survival in LGEFCs. EHCC with EVI has a particularly high risk of recurrence. When DMs are not found at presentation, patients with focal VI are at a very low risk of recurrence even if not treated with radioactive iodine. PMID- 26482606 TI - Sixty-five thousand shades of gray: importance of color in surgical pathology diagnoses. AB - Digital whole slide imaging (WSI) is a diagnostic modality that has gained acceptance as a tool for use in some areas of surgical pathology such as remote consultations. Accurate control of color representation of digitally rendered images of histologic sections is considered an important parameter of WSI. Currently, professional societies, physicians, and other stakeholders are in the process of establishing clinical guidelines outlining the use of these devices, which include color integrity and color calibration of scanners and viewing devices. Although color is a component of surgical pathology diagnoses, it was posited that pathologists could accurately diagnose surgical specimens without color. To test this hypothesis, 5 pathologists were presented breast biopsy specimens from 20 patients consisting of 22 separate tissue specimens and WSI of 158 hematoxylin and eosin-stained slides imaged at *20. No special stains were included. The pathologists reviewed each case using a 16-bit grayscale monitor and rendered a diagnosis for each case. Diagnoses were compared to the original light microscopy diagnoses and scored for concordance. A 92.7% concordance was observed. Discordant diagnoses represented well-known areas of diagnostic disagreement in breast pathology as well as known limitations of WSI. The research demonstrated that surgical pathologists did not rely primarily on color to render accurate diagnoses of breast biopsy cases but rather used architectural features of tissue and cellular morphology to reach a diagnostic conclusion. This research did not suggest that color is an unimportant factor in pathology diagnosis, but its importance may be overstated. PMID- 26482607 TI - Using exit competencies to integrate pathology into the undergraduate clinical clerkships. PMID- 26482608 TI - Insulinoma-Associated Protein 1 Is a Crucial Regulator of Neuroendocrine Differentiation in Lung Cancer. AB - Insulinoma-associated protein 1 (INSM1) is expressed exclusively in embryonic developing neuroendocrine (NE) tissues. INSM1 gene expression is specific for small-cell lung cancer (SCLC), along with achaete-scute homolog-like 1 (ASCL1) and several NE molecules, such as chromogranin A, synaptophysin, and neural cell adhesion molecule 1. However, the underlying biological role of INSM1 in lung cancer remains largely unknown. We first showed that surgically resected SCLC samples specifically expressed INSM1. Forced expression of the INSM1 gene in adenocarcinoma cell lines (H358 and H1975) induced the expression of ASCL1, brain 2 (BRN2), chromogranin A, synaptophysin, and neural cell adhesion molecule 1; in contrast, knockdown of the INSM1 gene by siRNA in SCLC (H69 and H889) decreased their expression. However, forced/knockdown expression of ASCL1 and BRN2 did not affect INSM1 expression. A chromatin immunoprecipitation study revealed that INSM1 bound to the promoter region of the ASCL1 gene. A xenotransplantation assay using tet-on INSM1 gene-transfected adenocarcinoma cell lines demonstrated that INSM1 induced NE differentiation and growth inhibition. Furthermore, we found that INSM1 was not expressed in non-small-cell lung cancer and some SCLC cell lines expressing Notch1-Hes1. By forced/knockdown expression of Notch1 or Hes1 genes, we revealed that Notch1-Hes1 signaling suppressed INSM1, as well as ASCL1 and BRN2. INSM1, expressed exclusively in SCLC, is a crucial regulator of NE differentiation in SCLCs, and is regulated by the Notch1-Hes1 signaling pathway. PMID- 26482610 TI - Skp2 regulates non-small cell lung cancer cell growth by Meg3 and miR-3163. AB - Maternally expressed gene 3 (Meg3) encodes a long non-coding RNA that has been shown to play a role in tumorigenesis. Skp2 is a component of the E3 ubiquitin ligase SCF that specifically promotes the ubiquitination-associated degradation of CDK inhibitor p27, and has been shown to promote cancer cell growth in different types of cancers, including non-small cell lung cancer (NSCLC). Nevertheless, a regulatory relationship between Meg3 and Skp2 has not been acknowledged. Here, we showed that NSCLC specimens had significant higher levels of Skp2 and significantly lower levels of Meg3, compared to paired non-tumor lung tissue. The levels of Meg3 and Skp2 were inversely correlated in NSCLC specimens. Patients with low Meg3 levels had a poor survival. Overexpression of Meg3 decreased Skp2 protein and increased p27 protein, while depletion of Meg3 increased Skp2 protein and decreased p27 protein in NSCLC cells, without altering Skp2 mRNA. These data suggest that the Skp2 may be regulated by Meg3 at post transcriptional level. Bioinformatics analyses showed that miR-3163 bound to 3' UTR of Skp2 mRNA in NSCLC cells to inhibit its translation, which was supported by luciferase reporter assay. Meg3 augmented the effects of miR-3163 on Skp2 mRNA, possibly through binding-induced function enhancement, which was supported by the double fluorescent in situ hybridization showing co-localized intracellular Meg3 and miR-3163 signals in NSCLC cells. The miR-3163 levels in NSCLC were not different from in NT, suggesting that the regulation of Skp2 in NSCLC by miR-3163 may require coordination of Meg3. Thus, our data suggest that Meg3 and miR-3163 may coordinate suppression of translation of Skp2 mRNA in NSCLC cells to inhibit NSCLC cell growth. PMID- 26482609 TI - Effects of silibinin on growth and invasive properties of human ovarian carcinoma cells through suppression of heregulin/HER3 pathway. AB - Epithelial ovarian cancer (EOC) is the most fatal gynecological malignancy due to its high proliferative and invasive capacities. A heregulin (HRG)/HER3 autocrine loop increases proliferative and metastatic properties of EOC cells, suggesting that modulators of this signaling pathway may prove effective to trammel growth and motility of these cells. This study aimed to evaluate the effects of multi tyrosine kinase inhibitor silibinin on proliferative and invasive characteristics of EOC cell lines OVCAR8 and SKOV3 through suppression of the HRG/HER3 pathway. To achieve this, the effects of silibinin on proliferation, DNA synthesis, clonogenicity, cell cycle progression, cathepsin B enzymatic activity, and migration and invasion were explored in vitro. Silibinin suppressed proliferation, DNA synthesis, and clonogenic abilities of OVCAR8 and SKOV3 cells through inhibition of the autocrine HRG/HER3 circuit. Silibinin-mediated attenuation of the HER3 signaling disabled the HER3/AKT/survivin axis and thereby, induced G1/S cell cycle arrest. Furthermore, silibinin reduced invasive potentials of the EOC cells through quelling the HRG/HER3 pathway and suppression of cathepsin B activity. Altogether, these results suggest that silibinin is a potential anti-cancer drug to inhibit proliferative and invasive characteristics of the EOC cells that exhibit an autocrine HRG/HER3 pathway. PMID- 26482611 TI - Downregulation of lncRNA-ATB correlates with clinical progression and unfavorable prognosis in pancreatic cancer. AB - Long noncoding RNAs (lncRNAs) have been shown to play critical roles in the development and progression of diseases. lncRNA activated by transforming growth factor beta (TGF-beta) (lncRNA-ATB) was discovered as a prognostic factor in hepatocellular carcinoma, gastric cancer, and colorectal cancer. However, little is known about the role of lncRNA-ATB in pancreatic cancer. This study aimed to assess lncRNA-ATB expression in pancreatic cancer and explore its role in pancreatic cancer pathogenesis. Quantitative real-time polymerase chain reaction was performed to detect lncRNA-ATB expression in 150 pancreatic cancer tissues and five pancreatic cancer cell lines compared to paired adjacent normal tissues and normal human pancreatic ductal epithelial cell line HPDE6c-7. The correlations between lncRNA-ATB expression and clinicopathological characteristics and prognosis were also analyzed. We found that lncRNA-ATB expression was decreased in pancreatic cancer tissues and pancreatic cancer cell lines. Low lncRNA-ATB expression levels were significantly correlated with lymph node metastases (yes vs. no, P = 0.009), neural invasion (positive vs. negative, P = 0.049), and clinical stage (early stage vs. advanced stage, P = 0.014). Moreover, patients with low lncRNA-ATB expression levels exhibited markedly worse overall survival prognoses (P < 0.001). Multivariate analysis indicated that decreased lncRNA-ATB expression was an independent predictor of poor prognosis in pancreatic cancer patients (P = 0.005). In conclusion, lncRNA-ATB may play a critical role in pancreatic cancer progression and prognosis and may serve as a potential prognostic biomarker in pancreatic cancer patients. PMID- 26482612 TI - MicroRNA-221 targets PTEN to reduce the sensitivity of cervical cancer cells to gefitinib through the PI3K/Akt signaling pathway. AB - Patients with cervical cancer show minimal clinical response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). The molecular mechanisms underlying sensitivity to gefitinib are unknown. The purpose of this study was to investigate the possible mechanism by which microRNA-221 (miR-221) affects sensitivity to gefitinib. We showed that miR-221 expression was significantly increased in cervical cancer tissues compared with adjacent normal tissues. Upregulation of miR-221 expression in cervical cancer cells decreased PTEN expression levels, resulting in increased pAkt and BCL-2 expression. Importantly, gefitinib sensitivity was decreased by the upregulation of miR-221, which was blocked by pcDNA-PTEN co-transfection or by the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002. These data suggest that miR-221 can reduce the sensitivity of cervical cancer cells to gefitinib through the PTEN/PI3K/Akt signaling pathway. miR-221 represents a potential target to increase the sensitivity to gefitinib in cervical cancer treatment. PMID- 26482613 TI - Ovarian carcinoma-infiltrating regulatory T cells were more potent suppressors of CD8(+) T cell inflammation than their peripheral counterparts, a function dependent on TIM3 expression. AB - Ovarian carcinoma is one of the most severe cancers in women, with a high relapse rate and limited secondary treatment options. To assist research in novel treatment technologies, including CD8(+) T cell-base immunotherapy, we examined the effect of tumor-infiltrating regulatory T cells (Tregs) in inhibiting CD8(+) T cell inflammation. We found that compared to their peripheral blood counterparts, tumor-infiltrating Tregs exhibited more potent inhibitory function, which was associated with higher interleukin 10 (IL-10) production in tumor infiltrating Tregs. Blockade of T cell immunoglobulin mucin 3 (TIM3), a regulatory molecule overrepresented on tumor-infiltrating Tregs, had significantly reverted Treg-mediated suppression. Moreover, expression of TIM3 on tumor-infiltrating Tregs was directly correlated with tumor size. Together, our results demonstrated that ovarian tumor-infiltrating Treg cells were more immunosuppressive than their peripheral blood counterparts in a TIM3-dependent fashion. PMID- 26482614 TI - The long non-coding RNA HOTAIR affects the radiosensitivity of pancreatic ductal adenocarcinoma by regulating the expression of Wnt inhibitory factor 1. AB - Pancreatic ductal adenocarcinoma (PDAC) is seriously resistant to radiotherapy and the mechanism is largely unknown. HOX transcript antisense intergenic RNA (HOTAIR) is overexpressed in PDAC. However, the function of HOTAIR has never been related to the radiosensitivity of PDAC. In this present study, the expression of HOTAIR in the PDAC cell lines and tissues was measured by quantitative real-time PCR (qRT-PCR), and the association between HOTAIR expression levels and X-ray treatment in PDAC cell lines was investigated. Additionally, the influence of HOTAIR knockdown on radiosensitivity, proliferation, and apoptosis of PDAC cells after radiation was evaluated by colony formation assays, Cell Counting Kit-8 (CCK-8) assays, and flow cytometry, respectively. Furthermore, the correlation between HOTAIR and Wnt inhibitory factor 1 (WIF-1) expression in PDAC cell lines and tissues was studied to assess the role of HOTAIR and WIF-1 in the radiosensitivity of PDAC. The results confirmed that HOTAIR expression was significantly increased in the PDAC cell lines and tissues (n = 90) compared with human normal pancreatic ductal epithelial cell line (HPDE) and matched adjacent normal tissues (n = 90). Functionally, HOTAIR knockdown enhanced the radiosensitivity of PDAC cells, reduced the proliferation, and increased the apoptosis of cells after radiation. And HOTAIR silencing increased the expression of WIF-1. Furthermore, the overexpression of WIF-1 revealed that HOTAIR modulated the radiosensitivity of PDAC cells by regulating the expression of WIF-1. These data reveals that HOTAIR can affect the radiosensitivity of PDAC cells partly via regulating the expression of WIF-1, and HOTAIR-WIF-1 axis is a potential target for PDAC radiotherapy. PMID- 26482615 TI - Different roles of myofibroblasts in the tumorigenesis of nonsmall cell lung cancer. AB - Myofibroblasts play a critical role in the cancer cell growth, invasion, and tumor-associated vascularization during the carcinogenesis of nonsmall cell lung cancer (NSCLC), whereas the underlying molecular bases are not completely understood. We isolated Lin-negative, Sca1-low, and CD49e-high myofibroblasts from the NSCLC tissues of the patients and modified the levels of either transforming growth factor beta 1 (TGFbeta1) or vascular endothelial growth factor A (VEGF-A) in these cells. We found that coculture with TGFbeta1 overexpressing myofibroblasts significantly decreased the NSCLC cell growth in an MTT assay through proliferation suppression rather than modulation of cell apoptosis, while significantly increased the NSCLC cell invasiveness in either a transwell migration assay or a scratch wound healing migration assay. However, modulation of TGFbeta1 levels in myofibroblasts did not significantly alter vessel formation in a human umbilical vein endothelial cells (HUVECs) transwell collagen gel assay. On the other hand, overexpression of VEGF-A in myofibroblasts significantly increased vessel formation in the HUVECs transwell collagen gel assay. Together, these data suggest that myofibroblasts may regulate cancer cell growth and invasion through TGFbeta1 but modulate cancer-associated neovascularization through VEGF-A. Hence, targeting different signaling pathways in myofibroblasts may delicately control NSCLC growth and invasion. PMID- 26482616 TI - Do circulating long non-coding RNAs (lncRNAs) (LincRNA-p21, GAS 5, HOTAIR) predict the treatment response in patients with head and neck cancer treated with chemoradiotherapy? AB - Long non-coding RNAs (lncRNAs) have been shown to be aberrantly expressed in head and neck cancer (HNC). The aim of the present study was to evaluate plasma levels of three lncRNA molecules (lincRNA-p21, GAS5, and HOTAIR) in the treatment response in HNC patients treated with radical chemoradiotherapy (CRT). Forty-one patients with HNC were enrolled in the study. Most of the patients had nasopharyngeal carcinoma (n = 27, 65.9 %) and locally advanced disease. Blood was drawn at baseline and treatment evaluation 4.5 months after therapy. lncRNAs in plasma were measured by semiquantitative PCR. Treatment response was evaluated according to clinical examination, RECIST and PERCIST criteria based on magnetic resonance imaging (MRI), and positron emission tomography with computed tomography (PET/CT) findings. Complete response (CR) rates were 73.2, 36.6, and 50 % for clinical investigation, PET/CT-, or MRI-based response evaluation, respectively. Predictive value of lncRNAs was investigated in patients with CR vs. those with partial response (PR)/progressive disease (PD). We found that post treatment GAS5 levels in patients with PR/PD were significantly higher compared with patients with CR based on clinical investigation (p = 0.01). Receiver operator characteristic (ROC) analysis showed that at a cutoff value of 0.3 of GAS5, sensitivity and specificity for clinical tumor response were 82 and 77 %, respectively. Interestingly, pretreatment GAS5 levels were significantly increased in patients with PR/PD compared to those with CR upon MRI-based response evaluation (p = 0.042). In contrast to GAS5, pretreatment or post treatment lincRNA-p21 and HOTAIR levels were not informative for treatment response. Our results suggest that circulating GAS5 could be a biomarker in predicting treatment response in HNC patients. PMID- 26482617 TI - The hedgehog antagonist HHIP as a favorable prognosticator in glioblastoma. AB - Inactivation of hedgehog-interacting protein (HHIP) and overexpression of Gli1 play vital roles in the development of diverse human cancers. The aim of this study is to examine the association of HHIP and Gli1 with the clinicopathologic features and prognosis of patients with glioblastoma (GBM). The expression of HHIP and Gli1 in 103 patients with GBM and 32 control patients was investigated by immunohistochemistry. Statistical analysis was utilized to evaluate the association of HHIP as well as Gli1 with clinicopathological characteristics and prognosis of patients. HHIP and Gli1 were dysregulated in GBM. Spearman's rank analysis showed that HHIP and Gli1 had an inverse correlation (r = -0.386, P = 0.000). Expression of HHIP was significantly correlated with age (P = 0.000), gender (P = 0.003), seizure (P = 0.013), resection degree (P = 0.033), adjuvant treatment (P = 0.030), and O(6)-methylguanine-DNA methyltransferase (MGMT) methylation (P = 0.021), while Gli1 expression was significantly correlated with age (P = 0.002), gender (P = 0.033), Karnofsky performance status (KPS) score (P = 0.028), resection degree (P = 0.000), adjuvant treatment (P = 0.014), and MGMT methylation (P = 0.030). Kaplan-Meier method showed that patients with low Gli1 expression had longer overall survival (OS) than those with high Gli1 expression (P = 0.000) and the OS of the patients with HHIP-positive GBM was significantly longer than that of the patients with HHIP-negative GBM (P = 0.000). Univariate and multivariate analyses confirmed that HHIP expression and Gli1 expression were independent prognostic factors. Our data suggested that expression of HHIP could be considered as significant prognostic marker for patients with GBM. PMID- 26482618 TI - miR-29a suppresses growth and metastasis in papillary thyroid carcinoma by targeting AKT3. AB - MicroRNA-29a (miR-29a) has been reported to play important roles in tumor initiation, development, and metastasis in various cancers. However, the biological function and potential mechanisms of miR-29a in papillary thyroid carcinoma (PTC) remain unclear. In the present study, we discovered that miR-29a was frequently downregulated in PTC tissues, and its expression was significantly associated with tumor size, TNM stage, and lymph node metastasis. Functional assays showed that overexpression of miR-29a markedly suppressed PTC cell proliferation, migration, and invasion and promoted PTC apoptosis and cell cycle arrest at G0/G1 phase. In vivo, miR-29a overexpression decreased tumor growth in a xenograft mouse model. Luciferase reporter assay showed that miR-29a can directly bind to the 3' untranslated region (UTR) of AKT3 in PTC cells. Overexpreesion of miR-29a obviously decreased AKT3 expression, thereby suppressing phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation. We also confirmed that AKT3 expression was increased in PTC tissue and was inversely correlated miR-29a expression in PTC tissues. In addition, downregulation of AKT3 by siRNA mimicked the effects of miR-29a overexpression, and upregulation of AKT3 partially reversed the inhibitory effects of miR-29a. These results suggested that miR-29a could act as a tumor suppressor in PTC by targeting AKT3 and that miR-29a may potentially serve as an anti-tumor agent in the treatment of PTC. PMID- 26482619 TI - Low cytoplasmic casein kinase 1 epsilon expression predicts poor prognosis in patients with hepatocellular carcinoma. AB - Casein kinase 1 epsilon (CK1epsilon) is a member of the casein kinase 1 (CK1) family, which comprises highly conserved and ubiquitous serine/threonine protein kinases. Recent studies have demonstrated that CK1epsilon plays a role in human cancers; however, the role of CK1epsilon in hepatocellular carcinoma (HCC) remains unclear. The study used immunohistochemistry to examine CK1epsilon expression in 230 HCC specimens by tissue microarray (TMA) and assessed the effect of CK1epsilon knockdown on migration of human hepatoma cells in vitro. The immunohistochemical analyses showed that low CK1epsilon expression was significantly correlated with tumor differentiation (p = 0.008), T classification (p = 0.016), tumor vascular invasion (p = 0.002), and cancer stage (p = 0.010). The univariate and multivariate analyses showed that patients with low CK1epsilon expression had a considerably lower OS rate than that of the patients with high CK1epsilon expression (p = 0.041, hazard ratio = 1.4; p = 0.039, hazard ratio = 1.4). Moreover, CK1epsilon small interfering RNA (siRNA) treatment exerted an invasion-promoting effect in human hepatoma cells. In conclusion, our data indicated that low CK1epsilon expression is correlated with a low survival rate and CK1epsilon may play a role as a tumor suppressor in hepatocarcinogenesis. PMID- 26482620 TI - Human topoisomerase II alpha as a prognostic biomarker in cancer chemotherapy. AB - Topoisomerases are nuclear enzymes that regulate topology of DNA by facilitating the temporary cleavage and ligation cycle of DNA. Among all forms of topoisomerases, TOP-IIA is extensively associated with cell proliferation and therefore is an important therapeutic target in diseases that involved cellular proliferation such as cancers. Nearly half of present-day antitumor regimens contain at least one prescription that act as a topoisomerase inhibitor. Generally, tumor cells show divergent expression of TOP-IIA compared to normal cells. The remarkable expression of TOP-IIA in various carcinomas provides a significant biomarker toward understanding the nature of malignancy. TOP-IIA expression and amplification studies help in diagnosing cancer and to observe the disease progression, overall survival (OS) of patients, and response to therapy. This review highlights the research output and analysis in exploring the standing of TOP-IIA in various carcinomas. As some reports show contradiction within the same field of interest, the outline of that may help to induce researchers for further investigation and clarification. To the best of our knowledge, this is the first overview briefly summarizing the prognostic feature of TOP-IIA in various types of cancer. PMID- 26482621 TI - c-Myc-regulated long non-coding RNA H19 indicates a poor prognosis and affects cell proliferation in non-small-cell lung cancer. AB - Recently, long non-coding RNAs (lncRNAs) have been shown to play important roles in human cancer biology. The purpose of this study was to assess the biological role of lncRNA H19 in non-small-cell lung cancer (NSCLC). Quantitative reverse transcription PCR (qRT-PCR) was used to detect the expression of H19 in tumor tissues and corresponding non-tumor NSCLC tissues from 70 patients. The higher expression of H19 was positively correlated with advanced tumor-node-metastasis (TNM) stage and tumor size. Multivariate analyses found that H19 expression could serve as an independent prognostic factor for overall survival of NSCLC. Moreover, chromatin immunoprecipitation (ChIP) assays revealed that H19 was a direct transcriptional target of c-Myc. And, knockdown of H19 significantly inhibited NSCLC cell proliferation both in vitro and in vivo. In conclusion, our study demonstrated that H19 is involved in the oncogenesis of NSCLC, and H19 may be a potential diagnostic and target for new therapies in patients with NSCLC. PMID- 26482622 TI - Association of cytoplasmic p27 expression with an unfavorable response to cisplatin-based chemotherapy and poor outcomes in non-small cell lung cancer. AB - Reduced nuclear p27 expression is associated with a poor outcome in various cancers, including non-small cell lung cancer (NSCLC). Cytoplasmic p27 expression was shown to be associated with an unfavorable response to chemotherapy and poor outcomes in some carcinomas, but it has not been well studied in NSCLC. Herein, p27 expression in 219 tumors surgically resected from NSCLC patients was evaluated by immunohistochemistry (IHC). The most common of p27 immunostaining in lung tumors was observed in the cytoplasm (N-/C+, 32 %), followed by negative (N /C-, 29 %), nucleus (N+/C-, 24 %), and nucleus plus cytoplasm (N+/C+, 15 %). Kaplan-Meier and Cox regression models showed that p27 N-/C+ tumors exhibited the worst overall survival (OS) and relapse-free survival (RFS) among the four categories of tumors. Among 135 of 219 patients who received cisplatin-based chemotherapy, p27 N-/C+ tumors most commonly showed an unfavorable response to cisplatin-based chemotherapy, followed by p27 N-/C- tumors when p27 N+/C- tumors were used as a reference. IHC analysis for phosphorylated extracellular signal regulated kinase (p-ERK) and Bcl-2 expression in the lung tumors was performed to test whether ERK activation could enhance p27 nuclear export and the expression of Bcl-2 to test whether ERK activation could enhance p27 nuclear export and Bcl 2 expression. The data showed that p-ERK expression was positively correlated with cytoplasmic p27 (N-/C+) and Bcl-2 expression in the lung tumors. Patients with high Bcl-2-expressing tumors treated with cisplatin-based chemotherapy showed unfavorable predictive values in a subset of this study population. Therefore, we suggest that cytoplasmic p27 (N-/C+) via ERK-activated Bcl-2 expression may predict an unfavorable response to cisplatin-based chemotherapy and poor outcomes in NSCLC. PMID- 26482623 TI - [Non-vitamin K oral anticoagulants and cardioversion]. AB - Direct oral anticoagulants are now frequently used in patients experiencing atrial fibrillation. Some of these patients may need a cardioversion. How to manage the procedure in these patients? Can we perform the procedure in patients taking the direct oral anticoagulant? Should we switch the treatment to a vitamin K antagonist? When do we need to perform a transesophageal echocardiography? All these questions justify this review article. PMID- 26482624 TI - [Diagnosis of a systolic murmur among young asymptomatic patient: An assessment of professional practices for the expertise in military medicine]. AB - The finding of a systolic heart murmur is common in medical military practice. Albeit often benign among young healthy adults, it can reveal a valvular or a cardiac disease, which could worsen during workout or expose to risk of a sudden death. This study aims to evaluate the diagnostic efficiency of the military general practitioner when discovering a systolic murmur among young asymptomatic patients. MATERIALS AND METHODS: During one year, this study involved all the general practitioners of the medical military centres of Brittany and the cardiologists of the military hospital in Brest. It prospectively enrolled a cohort of all military asymptomatic patients under 40, without any underlying known heart condition. Military general practitioners listed, thanks to an anonymous form, the main features of the systolic murmur and of the ECG and proposed an auscultatory diagnosis: innocent or organic murmur. Then cardiologists did the same and finally performed a transthoracic echocardiography giving the diagnosis. RESULTS: Fifty-eight patients were referred, 5 not meeting the inclusion criteria. Of the 53 patients included, military general practitioners found 46 innocent murmurs and 7 organic ones. Cardiologists found 51 innocent murmurs and 2 organic. Transthoracic echocardiography just took on one organic murmur (linked with a bicuspid aortic valve), spotted by the specialist, though judged innocent by the general practitioner. DISCUSSION: Most of innocent murmurs diagnosed by general practitioners (45/46) were confirmed. Regarding the seven organic murmurs, the main selected criteria (intensity over 3, orthostatic persistence, diffuse irradiation) are mostly in accordance with the literature, proving right medical instincts. Authors propose a practical management of systolic murmurs among asymptomatic young patients. CONCLUSION: Military general practitioners seem to master symptoms of organic murmur. This assessment argues for a promotion of a holistic clinical examination, which will help not only to rationalize the use of transthoracic echocardiography in economic terms but also to value the medical expertise. PMID- 26482625 TI - [Partial anomalous pulmonary venous return in a 64-year-old woman]. AB - Partial anomalous pulmonary venous return (PAPVR) represents 3 % of the congenital cardiopathies. Diagnosis in adults is challenging as clinical symptomatology is non-specific and echocardiographic signs are discrete and misleading potentially confusing with idiopathic pulmonary hypertension. We report the case of a 64-year-old woman in whom we diagnosed PAPVR associated with sinus venosus atrial septal defect. We describe medical history, clinical signs, investigations and postoperative evolution. PMID- 26482626 TI - [Mechanical cardiac-assist devices in ST segment elevation myocardial infarction]. AB - A 49-year-old woman was admitted for an anterior ST segment elevation myocardial infarction (STEMI). At hospital arrival, she presented with cardiogenic shock. An immediate coronary angiogram showed an occluded ostial left anterior descending artery. During percutaneous coronary intervention (PCI), ventricular fibrillation occurred requiring multiple electrical counter-shocks. The coronary artery was opened during cardiopulmonary resuscitation and two drug-eluting stents were implanted. At the end of the procedure, an Impella CP(r) mechanical cardiac assist device was inserted. Rapid and marked improvement in the hemodynamic status was noted in the following days. The Impella CP(r) was withdrawn after five days and the patient was discharged two weeks later. Despite limited data, mechanical cardiac assistance is recommended in cardiogenic shock. Several devices are currently available; the choice of the system is based on the clinical presentation and the experience of each center. The Impella CP(r) is a microaxial pump which is inserted percutaneously and delivers up to 3.5L/min of continuous flow. In cardiogenic shock due to STEMI, this device allows temporary support while awaiting left ventricular recovery after primary PCI. PMID- 26482627 TI - [ST elevation myocardial infarction (STEMI) in patients aged 85 and over. Invasive management versus exclusive medical treatment: Departmental study]. AB - INTRODUCTION: Percutaneous coronary intervention (PCI) and/or fibrinolysis for management of an ST elevation myocardial infarction (STEMI) are at high risk in the elderly. Is there any place for an invasive management in this particular population? METHODS: It is a single-center retrospective study (CHD Vendee, La Roche-sur-Yon) including patients aged 85 and over who had STEMI between January 2008 and December 2013, divided into two groups: coronary angiogram/fibrinolysis ("invasive") versus exclusive medical treatment ("non-invasive"), comparing mortality, morbidity, complications and loss of independence. RESULTS: Among the 1373 patients hospitalized for STEMI, 118 (8.6%) were included: 71 (60.2%) underwent an invasive procedure for reperfusion whereas 47 had "non-invasive" management. All cause mortality rate was higher in the "non-invasive" group (28% versus 45%; P=0.077 NS). The identified pejorative criteria are age, female gender, past history of severe valvular disease, and delay for primary care. No difference was found in intrahospital complication rate (23 vs 21; P=0.21) nor in loss of independence. CONCLUSION: The invasive management of STEMI in the elderly may reduce the one-year mortality rate without increasing morbidity. PMID- 26482628 TI - [Intracardiac mass: Why not a liquefaction necrosis of a mitral annulus calcification?]. AB - We report the case of an asymptomatic 70-year-old woman with a liquefaction necrosis of mitral annulus calcification. This mass was discovered incidentally during an echocardiographic examination. Additional treatment was not performed because liquefaction necrosis of mitral calcification usually has a benign prognosic. A scheduled clinical review with an echocardiographic examination and cardiac MRI was planified. The patient is actually healthy without any complication. PMID- 26482629 TI - Systolic anterior motion of the mitral valve in tako-tsubo cardiomyopathy: Still a matter of debate? AB - We present a case which developed a typical tako-tsubo-like cardiomyopathy (TTC) during dobutamine stress echocardiography (DSE). Its originality is related to several findings, which have never been described simultaneously in the same patient. This 63-year-old woman with normal coronary angiography and no evidence of coronary vasospasm had a biphasic response to DSE, a finding which usually occurs in coronary artery disease. Moreover, the symmetric extensive wall motion abnormalities (WMA) occurred simultaneously with the development of a systolic anterior motion of the mitral valve (SAM) and left ventricular obstruction, and was clinically asymptomatic. Although in TTC the stunning usually occurs for several days, WMA and SAM resolved within few minutes after cessation of dobutamine and administration of a beta-blocker. And finally, exercise echo performed at the same target heart rate few days later did not induce neither a SAM nor WMA, which suggests that left ventricular obstruction could have played a role in the pathogenesis of this case by supply-demand mismatch. Concomitant coronary microvascular dysfunction was also demonstrated by a reduction of the non-invasive coronary flow reserve in the distal part of the left anterior descending artery. PMID- 26482630 TI - [Free floating thrombus in right cardiac chambers and thrombolysis]. AB - Free-floating thrombi in the right heart chambers is a rare phenomenon. Nearly 99% of detected cases are associated with the presence of proven pulmonary embolism. Its presence is associated with a poor outcome with a mortality between 27 to 44% according to studies. Despite the emergency of treatment, optimal management of free floating right heart thrombus remains controversial with no clear consensus. We present the case of a 84-year-old man hospitalised for acute decompensated heart failure. After an initial favourable evolution, a degradation of respiratory occurred with dyspnea and desaturation. A bedside transthoracic echocardiography showed a mobile serpiginous thrombus, 7cm size, moving to and across the tricuspid valve. A computed tomography of the chest demonstrated massive bilateral pulmonary embolism. After persistence of the thrombus and seven days of heparinotherapy, thrombolysis therapy was initiated. The thrombus disappeared 24h after thrombolysis. Without contra-indication, thrombolysis is a faster, readily available treatment for the management of floating thrombus in the right heart chambers associated with pulmonary embolism. PMID- 26482631 TI - [A case, a review: We have to promote radial approach for acute coronary syndrome]. AB - This overweight woman's case, who underwent a primary coronary intervention for STEMI, reminds us how much the trans-radial angioplasty is interesting in this particular case leaning on the recent literature, randomized trials and registries, in terms of major adverse events reduction including mortality. We are going to debate about hesitation of using radial approach whose only everyday's practising could make this approach a STEMI one. PMID- 26482632 TI - [Acute coronary syndromes with ST-segment elevation and anomalous connections of the coronary arteries]. AB - Acute coronary syndrome with ST-segment elevation associated with an anomalous connection of a coronary artery, when the latter is the culprit, may be problematic. Anatomic and radiologic knowledge of major congenital coronary abnormalities and some catheterization skills can help the operators not to delay a beneficial coronary reperfusion. The relationship between acute coronary syndromes with ST-segment elevation and anomalous connections of the coronary arteries needs to be analyzed with a large number of cases because the coronary artery disease frequency may vary with the type of coronary anomaly. PMID- 26482633 TI - [What is the place of bioresorbable vascular scaffolds in setting of ST-segment elevation myocardial infarction?]. AB - A 50-year-old woman was admitted for an inferior ST-segment elevation myocardial infarction; immediate coronary angiogram revealed a subocclusive stenosis of the right coronary artery. After optimal antithrombotic treatment, the type of stent could be discussed. The latest generation of drug-eluting stents showed excellent efficacy and safety in the long-term but has limitations such as potential chronic inflammation of the arterial wall and no recovery of vasoactive function. Bioresorbable vascular scaffolds, with complete resorption within several months, may reduce these limitations. Implantation of bioresorbable scaffold in the context of myocardial infarction may be interesting. However, very few studies are currently available in this setting. Preliminary results and perspectives are presented in this review. PMID- 26482634 TI - [Platypnea-orthodeoxia syndrome: A case of hypoxemia associated with a patent foramen ovale]. AB - Platypnea-orthodeoxia syndrome is a rare disease characterized by dyspnea and oxygen desaturation in the upright position with improvement in the supine position. We report a case of an 87-year-old woman with a recent history of traumatic hip, spine deformity and vertebral compression fracture, referred due to dyspnea oxygen desaturation. Thoracic tomodensitometry excluded the diagnosis of pulmonary embolism. Transthoracic echocardiography, with intravenous administration of agitated saline contrast solution, revealed the presence of atrial septal defect associated with a right to left shunting and mild enlargement of aortic root. Surgical closure of atrial septal defect resulted in resolution of the syndrome. PMID- 26482635 TI - [Medico-economic impact of an innovative management of CHF by HF unit]. AB - Chronic heart failure remains a frequent, severe and costly disease. Despite encouraging data from different countries, heart failure clinics are scarce in France. We have analyzed the impact of a heart failure clinic (UTIC of Pontoise) in terms of reduction of rehospitalizations and in hospitalization costs in 4855 consecutive patients. In our study, heart failure clinic management dramatically reduces HF related hospitalizations (RRR: -28 %, P=0.001) and HF related costs (55% reduction, P<0.001) regardless of comorbidities or disease severity. HF clinics have to be developed in France in order to optimize management of CHF and reduce the HF related costs. PMID- 26482636 TI - [The daily living activities of the cardiac patient: Monocentre study]. AB - BACKGROUND: The main aim of cardiac rehabilitation is for the patient to sustain physical activity at home. The daily living activities (DLA) are important to take into account. AIM OF THE STUDY: Analyze the DLA of patients in CR. PATIENTS AND METHODS: One thousand seven hundred and eighty patients (mean age: 60.9+/-11 years) followed a CR programme between 2010 and 2015. They were tested for several DLA with their cardiac frequency (CF). The observed CF was included in the Karvonen's formula, used for the prescription of physical activity. RESULTS: The coefficient of Karvonen was situated between 0.54 to 0.69, which was compatible with the prescribed physical training. Nevertheless, when the maximal exercise capacity was less than 5 METs, the coefficients were higher (0.53-0.89). CONCLUSION: It was useful to test the cardiac patients for DLA during a CR programme. The use of Karvonen's formula allowed to compare these exercises with recommended physical training. We must be prudent when the maximal physical capacity is less than 5 METs. PMID- 26482637 TI - Birth plans and health insurance enrolment of pregnant women: a cross-sectional survey at two secondary health facilities in Lagos, Nigeria. AB - OBJECTIVE: We evaluated birth plans and health insurance enrolment of pregnant women at secondary health care level as a strategy for post-2015 goals. METHODS: This was a cross-sectional study at two secondary health facilities in Lagos state, Nigeria. A pre-tested questionnaire was used to collect data that were analysed and results presented with frequencies. An overall estimate with 95% confidence interval was used at significant p values of less than 0.05. RESULTS: Five hundred and twenty-four women, with a mean age of 3 0 +/- 4.1 years, participated. Most women chose hospital delivery (84%) and had plan for transportation (86.3%) during labour. Few women were well prepared for birth (9.7%) and had health insurance (10.1%). Compared with women without insurance, more health-insured women had plans for transport in labour (p = 0.1383) and identified a place of birth (p = 0.2294), but did not have as much plan for someone to accompany them in the case of an emergency (p = 0.3855) and donate blood (p = 0.5065). Few health insured women saved money for delivery (p = 0.7439). CONCLUSION: Health insured women did not have better birth plans and expanding pregnant women's access to health insurance may be an insufficient strategy to achieve post MDG 2015 goals. PMID- 26482638 TI - Homogenous demineralized dentin matrix and platelet-rich plasma for bone tissue engineering in cranioplasty of diabetic rabbits: biochemical, radiographic, and histological analysis. AB - This study evaluated the effects of homogenous demineralized dentin matrix (HDDM) slices and platelet-rich plasma (PRP) in surgical defects created in the parietal bones of alloxan-induced diabetic rabbits, treated with a guided bone regeneration technique. Biochemical, radiographic, and histological analyses were performed. Sixty adult New Zealand rabbits were divided into five groups of 12: normoglycaemic (control, C), diabetic (D), diabetic with a PTFE membrane (DM), diabetic with a PTFE membrane and HDDM slices (DM-HDDM), and diabetic with PTFE membrane and PRP (DM-PRP). The quantity and quality of bone mass was greatest in the DM-HDDM group (respective radiographic and histological analyses: at 15 days, 71.70 +/- 16.50 and 50.80 +/- 1.52; 30 days, 62.73 +/- 16.51 and 54.20 +/- 1.23; 60 days, 63.03 +/- 11.04 and 59.91 +/- 3.32; 90 days, 103.60 +/- 24.86 and 78.99 +/- 1.34), followed by the DM-PRP group (respective radiographic and histological analyses: at 15 days 23.00 +/- 2.74 and 20.66 +/- 7.45; 30 days 31.92 +/- 6.06 and 25.31 +/- 5.59; 60 days 25.29 +/- 16.30 and 46.73 +/- 2.07; 90 days 38.10 +/- 14.04 and 53.38 +/- 9.20). PRP greatly enhanced vascularization during the bone repair process. Abnormal calcium metabolism was statistically significant in the DM-PRP group (P<0.001) for all four time intervals studied, especially when compared to the DM-HDDM group. Alkaline phosphatase activity was significantly higher in the DM-HDDM group (P<0.001) in comparison to the C, D, and DM-PRP groups, confirming the findings of intense osteoblastic activity and increased bone mineralization. Thus, HDDM promoted superior bone architectural microstructure in bone defects in diabetic rabbits due to its effective osteoinductive and osteoconductive activity, whereas PRP stimulated angiogenesis and red bone marrow formation. PMID- 26482639 TI - Can we predict the insertion torque using the bone density around the implant? AB - The purpose of this study was to examine the correlation between initial stability and bone density in patients undergoing implant treatment. Twenty-five screw-type dental implants were inserted in 12 patients. All patients underwent multi-detector computed tomography (CT) examination prior to implant insertion. The implant sockets were prepared according to the drilling protocol, and peak insertion torque values were measured. CT values around the implants were measured using preoperatively scanned CT data, which were combined with actual implant positions. Spearman's rank correlation coefficient was used to investigate the correlation between insertion torque values and CT values (in Hounsfield units, HU). Twenty-three implants (8 or 10 mm in length) were inserted in the mandibular molar region and two (10mm length) in the maxillary molar region. The mean CT value of the 8-mm implants was 508.6 +/- 187.0 HU and mean insertion torque was 27.2 +/- 12.1 N.cm; for the 10-mm implants, these values were 579.6 +/- 224.3 HU and 28.1 +/- 14.6 N.cm, respectively. Statistical analysis revealed a strong positive correlation between the insertion torque and mean CT values (r=0.699, 8 mm; r=0.771, 10 mm). The results revealed that bone density around the implant is a useful index. This study indicates that preoperative CT may enable the prediction of initial implant stability. PMID- 26482640 TI - Safety assessment for octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionate (CAS Reg. No. 2082-79-3) from use in food contact applications. AB - Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (CAS Reg. No. 2082-79 3), currently marketed as Irganox 1076 (I-76), is a sterically hindered phenolic antioxidant used in a variety of organic substrates, including those used in the manufacture of food contact articles. In 2012, the US Food and Drug Administration (USFDA), Office of Food Additive Safety (OFAS), initiated a post market re-evaluation of the food contact applications of I-76. This project aimed to ensure that current dietary exposures from the use of I-76 in food contact articles are accurately captured and the safety assessment considered all relevant and available toxicological information. To accomplish these aims, the USFDA reviewed the available toxicological studies and chemistry information on food contact applications of I-76. Based on this in-depth analysis, a NOAEL of 64 mg/kg-bw/d (female rats) from a chronic rat study and a cumulative estimated dietary intake (CEDI) of 4.5 mg/p/d, was used to calculate a margin of exposure (MOE) of ~850. We concluded that the previous and current exposure levels provide an adequate margin of safety (MOS) and remain protective of human health for the regulated uses. PMID- 26482641 TI - Toxic trace elements at gastrointestinal level. AB - Many trace elements are considered essential [iron (Fe), zinc (Zn), copper (Cu)], whereas others may be harmful [lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As)], depending on their concentration and chemical form. In most cases, the diet is the main pathway by which they enter our organism. The presence of toxic trace elements in food has been known for a long time, and many of the food matrices that carry them have been identified. This has led to the appearance of legislation and recommendations concerning consumption. Given that the main route of exposure is oral, passage through the gastrointestinal tract plays a fundamental role in their entry into the organism, where they exert their toxic effect. Although the digestive system can be considered to be of crucial importance in their toxicity, in most cases we do not know the events that occur during the passage of these elements through the gastrointestinal tract and of ascertaining whether they may have some kind of toxic effect on it. The aim of this review is to summarize available information on this subject, concentrating on the toxic trace elements that are of greatest interest for organizations concerned with food safety and health: Pb, Cd, Hg and As. PMID- 26482642 TI - A bright future ahead for Journal of Molecular Endocrinology. PMID- 26482643 TI - VASA (DDX4) is a Putative Marker for Spermatogonia, Spermatocytes and Round Spermatids in Stallions. AB - Expression of the protein DDX4/MVH, or VASA, has been reported in germ cells of several species. The main objectives of this study were to (i) investigate VASA expression patterns in testicular cells of stallions at two different reproductive stages (pre-pubertal and post-pubertal) and (ii) evaluate the use of VASA antibody as a molecular marker for single germ cells from stallions. Testicular tissues were obtained from stallions and categorized as pre-pubertal and post-pubertal based on the formation of lumen and status of spermatogenesis on the cross section of seminiferous tubules. The results of Western blot showed a VASA protein band located at 76 kDa, indicating that the rabbit antibody has a cross-reactivity with horse testicular tissues. The result of immunolabelling showed that VASA was expressed in the cytoplasm of spermatogonia at both reproductive stages and in spermatocytes and round spermatids at the post pubertal stage. GATA4-positive Sertoli cells and Leydig cells located in the interstitial space were not immunolabelled with VASA. These results suggest that VASA can be utilized as a molecular marker for germ cells of stallions at pre pubertal and post-pubertal stages. Interestingly, immunolabelling intensity was significantly higher in pachytene spermatocytes compared to spermatogonia and round spermatid. VASA antibody was also effective for staining of single germ cell preparations. In conclusion, VASA protein expression can be used as a marker for identification of spermatogonia, spermatocytes and round spermatids in testicular tissues of stallions. PMID- 26482644 TI - A Novel Physical Approach for Cationic-Thiolate Protected Fluorescent Gold Nanoparticles. AB - Knowledge on the synthesis of cationically charged fluorescent gold nanoparticles (Au NPs) is limited because the electrostatic repulsion between cationic ligands on the surface of NP hinders the formation of small Au NPs (usually less than ca. 2 nm) during nucleation in solvents. We herein propose a novel methodology for a synthesis of water-dispersible, cationic-thiolate protected fluorescent Au NPs by the sputtering of Au into liquid matrix containing thiolate ligands. By controlling mercaptan concentration the size and photophysical characteristics of Au NPs were directly controlled, resulting in near IR fluorescence with a 0.9% of absolute quantum yield. Cationically charged fluorescent metal NPs are promising, especially in biological fields, and this work provides a novel methodology towards the synthesis of a new series of functional metal NPs. PMID- 26482645 TI - AUDIT-C score and its association with risky behaviours among professional drivers. PMID- 26482646 TI - Assisted normality--a grounded theory of adolescent's experiences of living with personal assistance. AB - PURPOSE: The purpose of the study was to explore how adolescents with disabilities experience everyday life with personal assistants. METHOD: In this qualitative study, individual interviews were conducted at 35 occasions with 16 Swedish adolescents with disabilities, in the ages 16-21. Data were analyzed using grounded theory methodology. RESULTS: The adolescents' main concern was to achieve normality, which is about doing rather than being normal. They try to resolve this by assisted normality utilizing personal assistance. Assisted normality can be obtained by the existing relationship, the cooperation between the assistant and the adolescent and the situational placement of the assistant. Normality is obstructed by physical, social and psychological barriers. CONCLUSION: This study is from the adolescents' perspective and has implications for understanding the value of having access to personal assistance in order to achieve assisted normality and enable social interaction in everyday life. IMPLICATIONS FOR REHABILITATION: Access to personal assistance is important to enable social interaction in everyday life. A good and functional relationship is enabled through the existing relation, co-operation and situational placement of the assistant. If the assistant is not properly sensitized, young people risk turning into objects of care. Access to personal assistants cannot compensate for disabling barriers in the society as for example lack of acceptance. PMID- 26482647 TI - In search of predictive endophenotypes in addiction: insights from preclinical research. AB - Drug addiction is widely recognized to afflict some but not all individuals by virtue of underlying risk markers and traits involving multifaceted interactions between polygenic and external factors. Remarkably, only a small proportion of individuals exposed to licit and illicit drugs develop compulsive drug-seeking behavior, maintained in the face of adverse consequences and associated detrimental patterns of drug intake involving extended and repeated bouts of binge intoxication, withdrawal and relapse. As a consequence, research has increasingly endeavored to identify distinctive neurobehavioral mechanisms and endophenotypes that predispose individuals to compulsive drug use. However, research in active drug users is hampered by the difficulty in categorizing putatively causal behavioral traits prior to the initiation of drug use. By contrast, research in experimental animals is often hindered by the validity of approaches used to investigate the neural and psychological mechanisms of compulsive drug-seeking habits in humans. Herein, we survey and discuss the principal findings emanating from preclinical animal research on addiction and highlight how specific behavioral endophenotypes of presumed genetic origin (e.g. trait anxiety, novelty preference and impulsivity) differentially contribute to compulsive forms of drug seeking and taking and, in particular, how these differentiate between different classes of stimulant and non-stimulant drugs of abuse. PMID- 26482648 TI - The regulatory and predictive functions of miR-17 and miR-92 families on cisplatin resistance of non-small cell lung cancer. AB - BACKGROUND: Chemotherapy is an important therapeutic approach for non-small cell lung cancer (NSCLC). However, a successful long-term treatment can be prevented by the occurring of chemotherapy resistance frequently, and the molecular mechanisms of chemotherapy resistance in NSCLC remain unclear. In this study, abnormal expressions of miR-17 and miR-92 families are observed in cisplatin resistant cells, suggesting that miR-17 and miR-92 families are involved in the regulation of cisplatin resistance in NSCLC. METHODS: miRNA microarray shows that miR-17 and miR-92 families are all down-regulated in cisplatin-resistant A549/DDP cells compared with cisplatin-sensitive A549 cells. The aim of this study is to investigate the regulatory functions of miR-17 and miR-92 families on the formation of cisplatin resistance and the predictive functions of them as biomarkers of platinum-based chemotherapy resistance in NSCLC. RESULTS: The low expressions of miR-17 and miR-92 families can maintain cisplatin resistance through the regulation of CDKN1A and RAD21. As a result of high expressions of CDKN1A and RAD21, the inhibition of DNA synthesis and the repair of DNA damage are achieved and these may be two major contributing factors to cisplatin resistance. Moreover, we demonstrate that the expressions of miR-17 and miR-92 families in NSCLC tissues are significantly associated with platinum-based chemotherapy response. CONCLUSION: Our study indicates that miR-17 and miR-92 families play important roles in cisplatin resistance and can be used as potential biomarkers for better predicting the clinical response to platinum based chemotherapy in NSCLC. PMID- 26482649 TI - Inconclusive flow cytometric surface light chain results; can cytoplasmic light chains, Bcl-2 expression and PCR clonality analysis improve accuracy of cytological diagnoses in B-cell lymphomas? AB - BACKGROUND: Flow cytometric immunophenotyping (FCI), is widely used in cytology for distinguishing between B-cell lymphoma (BCL) and reactive lymphocytic proliferations (RLP), mainly by identifying monotypic B-cell populations. Since this cannot always be determined by ratios of surface immunoglobulin light chains (sIg LCs) we wanted to assess if cytoplasmic immunoglobulin (cIg) LCs, Bcl-2 and polymerase chain reaction (PCR) based clonality analysis can improve accuracy of cytological diagnoses of BCL. METHODS: Our study included 98 fine needle aspiration biopsies from lymph nodes suspicious for BCL with inconclusive sIg LCs. In all cases PCR clonality analysis was performed in order to determine immunoglobulin heavy chain (IGH) gene and T-cell receptor (TRC) gene rearrangement. In selected cases expression of Bcl-2 and cIg LC were determined by FC. RESULTS: Thirty patients had lymphoma and 68 had reactive lymphocytic proliferations. Three patterns of sIg LCs staining were found: negative, dual positive and difficult to interpret. Percentage of lymphomas was highest in the dual positive group (75 %). Morphology coupled with cIg LCs determination and/or Bcl-2 expression was able to give a correct diagnosis in 83 % of cases. Molecular tests would have been misleading in 15 % of cases because 7/30 BCL were polyclonal and 8/68 RLP were monoclonal. CONCLUSIONS: Determination of cIg LCs, Bcl-2 expression and PCR clonality analysis of B cells improved accuracy of cytological diagnoses in BCL with inconclusive sIg LC. However, clonality determined by PCR was misleading in some cases. PMID- 26482650 TI - Effect of Electron Energy Distribution on the Hysteresis of Plasma Discharge: Theory, Experiment, and Modeling. AB - Hysteresis, which is the history dependence of physical systems, is one of the most important topics in physics. Interestingly, bi-stability of plasma with a huge hysteresis loop has been observed in inductive plasma discharges. Despite long plasma research, how this plasma hysteresis occurs remains an unresolved question in plasma physics. Here, we report theory, experiment, and modeling of the hysteresis. It was found experimentally and theoretically that evolution of the electron energy distribution (EED) makes a strong plasma hysteresis. In Ramsauer and non-Ramsauer gas experiments, it was revealed that the plasma hysteresis is observed only at high pressure Ramsauer gas where the EED deviates considerably from a Maxwellian shape. This hysteresis was presented in the plasma balance model where the EED is considered. Because electrons in plasmas are usually not in a thermal equilibrium, this EED-effect can be regarded as a universal phenomenon in plasma physics. PMID- 26482651 TI - The age factor in Alzheimer's disease. AB - Alzheimer's disease is the most common type of dementia, and it is characterized by a decline in memory or other thinking skills. The greatest risk factor for Alzheimer's disease is advanced age. A recent genome-wide study identified a locus on chromosome 17 associated with the age at onset, and a specific variant in CCL11 is probably responsible for the association. The association of a protective haplotype with a 10-year delay in the onset of Alzheimer's disease and the identification of a CCL11 variant with possible functional roles in this association might allow the future development of immunomodulators with the potential to halve disease incidence. PMID- 26482652 TI - Paradoxical effects of VEGF on synaptic activity partially involved in notch1 signaling in the mouse hippocampus. AB - It is well known that the neuronal effects of vascular endothelial growth factor (VEGF) include modulating learning and memory, plasticity of mature neurons, and synaptic transmission in addition to neurogenesis. However, there is conflicting evidence particularly of its role in the regulation of excitatory synaptic activity. In this study, application of the patch-clamp technique revealed that lower doses (10 and 50 ng/mL) of VEGF enhanced excitatory neurotransmission in hippocampal slices of mice through both presynaptic and postsynaptic mechanisms. However, the effects were reversed by higher doses of VEGF (>100 ng/mL), which inhibited excitatory neurotransmission via a presynaptic mechanism. These competing, concentration-dependent effects of VEGF suggested that different pathways were involved. The involvement of the Notch1 receptor was tested in the modulation of VEGF on synaptic activity by using heterozygous Notch1(+/-) mice. Notch1 knockdown did not influence the inhibitory effect of high VEGF doses (200 ng/mL) but reduced the enhancement effects of low concentration of VEGF (50 ng/mL) at the postsynaptic level, which might be due to the decreased level of VEGF receptor. The results indicate that the Notch1 receptor plays a role in VEGF induced modulation of synaptic activity, which provides new insights into a complex VEGF/Notch signaling cross-talk. These findings set the groundwork for understanding new mechanisms of Notch signaling and the neurotrophic effects of VEGF, which is beneficial to develop new therapeutic targets to the VEGF/Notch axis and improve current treatments for neural diseases. PMID- 26482653 TI - Effects of nectar robbing on male and female reproductive success of a pollinator dependent plant. AB - BACKGROUND AND AIMS: Nectar robbers affect host fitness in different ways and by different magnitudes, both directly and indirectly, and potentially constitute an important part of pollination interactions. The aim of this study was to assess the effect of nectar robbing on several variables that characterize the reproductive success of Lonicera etrusca, a pollinator-dependent plant with long, tubular flowers that produce abundant nectar. METHODS: Using fluorescent powder dye as a proxy for pollen, the distance of pollen dispersal was compared for robbed and non-robbed flowers. Artificial nectar robbing treatments were applied to test its effects on four additional measures of reproductive success, namely the quantity of pollen exported, fruit set, seed/ovule ratio and seed weight. KEY RESULTS: Nectar robbing was not found to have any significant negative consequences on female and male components of reproductive success as determined through the five variables that were measured. CONCLUSIONS: Although L. etrusca exhibits high levels of nectar robbing and nectar robbers are common floral visitors, no evidence was found of detrimental changes in the components of reproductive success. A combination of morphological and ecological mechanisms is proposed to explain how plants may compensate for the energetic loss caused by the nectar robbers. PMID- 26482654 TI - Differential pollen placement on an Old World nectar bat increases pollination efficiency. AB - BACKGROUND AND AIMS: Plant species that share pollinators are potentially subject to non-adaptive interspecific pollen transfer, resulting in reduced reproductive success. Mechanisms that increase pollination efficiency between conspecific individuals are therefore highly beneficial. Many nocturnally flowering plant species in Thailand are pollinated by the nectar bat Eonycteris spelaea (Pteropodidae). This study tested the hypothesis that plant species within a community reduce interspecific pollen movement by placing pollen on different areas of the bat's body. METHODS: Using flight cage trials, pollen transfer by E. spelaea was compared between conspecific versus heterospecific flowers across four bat-pollinated plant genera. Pollen from four locations on the bat's body was also quantified to determine if pollen placement varies by plant species. KEY RESULTS: It was found that E. spelaea transfers significantly more pollen between conspecific than heterospecific flowers, and that diverse floral designs produce significantly different patterns of pollen deposition on E. spelaea. CONCLUSIONS: In the Old World tropics, differential pollen placement is a mechanism that reduces competition among bat-pollinated plant species sharing a common pollinator. PMID- 26482655 TI - Health and Employment after Fifty (HEAF): a new prospective cohort study. AB - BACKGROUND: Demographic trends in developed countries have prompted governmental policies aimed at extending working lives. However, working beyond the traditional retirement age may not be feasible for those with major health problems of ageing, and depending on occupational and personal circumstances, might be either good or bad for health. To address these uncertainties, we have initiated a new longitudinal study. METHODS/DESIGN: We recruited some 8000 adults aged 50-64 years from 24 British general practices contributing to the Clinical Practice Research Datalink (CPRD). Participants have completed questionnaires about their work and home circumstances at baseline, and will do so regularly over follow-up, initially for a 5-year period. With their permission, we will access their primary care health records via the CPRD. The inter-relation of changes in employment (with reasons) and changes in health (e.g., major new illnesses, new treatments, mortality) will be examined. DISCUSSION: CPRD linkage allows cost-effective frequent capture of detailed objective health data with which to examine the impact of health on work at older ages and of work on health. Findings will inform government policy and also the design of work for older people and the measures needed to support employment in later life, especially for those with health limitations. PMID- 26482656 TI - CGGBP1--an indispensable protein with ubiquitous cytoprotective functions. AB - The human genome contains multiple stretches of CGG trinucleotide repeats, which act as transcription- and translation-regulatory elements but at the same time form secondary structures that impede replication and give rise to sites of chromosome fragility. Proteins binding to such DNA elements may be involved in divergent cellular processes such as transcription, DNA damage, and epigenetic state of the chromatin. We review here the work done on CGG repeats and associated proteins with special focus on a factor called CGGBP1. CGGBP1 presents with an interesting example of factors that do not have any single dedicated function, but participate indispensably in multiple processes. Both experimental results and data from cancer genome sequencing have revealed that any alteration in CGGBP1 that compromises its function is not tolerated by normal or cancer cells alike. Based upon a large amount of published data, information from databases, and unpublished results, we decipher in this review how CGGBP1 is a classic example of the 'one factor, divergent functions' paradigm of cytoprotection. By taking cues from the studies on CGGBP1, more such factors can be discovered for a better understanding of the evolution of mechanisms of cellular survival. PMID- 26482657 TI - Head and neck cancer patients' perceptions of quality of life and how it is affected by the disease and enteral tube feeding during treatment. AB - AIM: To explore individual quality of life in patients with head and neck cancer from diagnosis up to 3 months after termination of radiotherapy. RESEARCH QUESTIONS: 1) Which areas in life are important to quality of life, and which are influenced by the disease and by having oral or enteral nutrition; and 2) Which areas in life are influenced by having a nasogastric feeding tube (NGT) or a percutaneous endoscopic gastrostomy (PEG) tube? MATERIAL AND METHODS: Data were collected in 36 patients. Semi-structured interviews were conducted using an extended version of the Schedule for the Evaluation of Individual Quality of Life (SEIQoL) and analysed with content analysis. RESULTS: Negative and positive experiences of quality of life in general were about relation to family, own health, and leisure activities. Negative impacts on physical, psychological, existential and social problems, but also positive experiences are described by the patients related to the disease. More than half expressed eating-related problems. Enteral nutrition entailed negative and positive experiences, and no greater variations were described by the patients with NGT or PEG tube. Overall, there were interindividual variations. CONCLUSIONS: The patients' perception of general or disease-related quality of life was not affected by whether they had enteral nutrition or not. From the patients' perspective neither of the two feeding tubes (NGT or PEG) was clearly in favour. We suggest that more studies are needed on how the choice of enteral feeding tube can be evidence-based, and incorporating the patients' perspective. PMID- 26482659 TI - Pulmonary vascular dysfunction in refractory acute respiratory distress syndrome before veno-venous extracorporeal membrane oxygenation. AB - BACKGROUND: Pulmonary vascular dysfunction has been described in patients with acute respiratory distress syndrome (ARDS). Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a well-established treatment for these patients. We hypothesized that severe pulmonary vascular dysfunction and cor pulmonale identified by echocardiography before cannulation in these patients were associated with worse survival. METHODS: Echocardiography was used to identify pulmonary hypertension in 21 patients with refractory ARDS just before ECMO implantation. Survival was compared for those with and without cor pulmonale. RESULTS: In our series, the overall mortality rate was 57.1% (12/21). Echocardiographic exams were transthoracic in 5 patients (23.8%), transesophageal in 4 patients (19%), and both (transthoracic and transesophageal) in the remaining 12 patients (57.1%). In our series, six patients (28.5%) showed LV dysfunction. Acute cor pulmonale was detectable in 2 patients (9.5%), while the remaining 19 patients showed moderate pulmonary dysfunction. Survivors had a higher pre-cannulation LV ejection fraction (EF) (P = 0.02) and tricuspid annular plane excursion (P = 0.04), and lower peak systolic pulmonary artery pressures (P = 0.02). CONCLUSIONS: In patients with refractory ARDS immediately before ECMO implantation, the prevalence of acute cor pulmonale is low (9.5%). Survival is associated with higher LVEF and lower systolic pulmonary arterial pressure. These findings support the idea that echocardiographic assessment of pulmonary artery pressure in patients with refractory ARDS before VV-ECMO implantation may have value for risk-stratification. PMID- 26482660 TI - Quantum Rabi Model with Trapped Ions. AB - We propose the quantum simulation of the quantum Rabi model in all parameter regimes by means of detuned bichromatic sideband excitations of a single trapped ion. We show that current setups can reproduce, in particular, the ultrastrong and deep strong coupling regimes of such a paradigmatic light-matter interaction. Furthermore, associated with these extreme dipolar regimes, we study the controlled generation and detection of their entangled ground states by means of adiabatic methods. Ion traps have arguably performed the first quantum simulation of the Jaynes-Cummings model, a restricted regime of the quantum Rabi model where the rotating-wave approximation holds. We show that one can go beyond and experimentally investigate the quantum simulation of coupling regimes of the quantum Rabi model that are difficult to achieve with natural dipolar interactions. PMID- 26482662 TI - Safety of Botulinum Toxin Type A for Children With Nonambulatory Cerebral Palsy. AB - OBJECTIVE: To determine safety of intramuscular botulinum toxin A (BoNT-A) injections to reduce spasticity and improve care and comfort of nonambulatory children with cerebral palsy (CP). METHODS: Nonambulatory children with CP were randomly allocated to receive either BoNT-A (n = 23) or sham procedure (n = 18) in Cycle 1. In Cycle 2, the BoNT-A group received a second episode of BoNT-A (n = 20) and sham group received their first episode of BoNT-A (n = 17). A pediatric rehabilitation specialist masked to group allocation graded each adverse event (AE) according to system, severity (mild, moderate, serious, sentinel) and causality (unlikely/unrelated; possible; probable/definite). RESULTS: There was no difference for all moderate/serious AEs between the BoNT-A and sham/control groups in either Cycle 1 (incident rate ratio = 1.30, 95% confidence interval = 0.43-4.00; P = .64) or Cycle 2 (incident rate ratio = 0.72, 95% confidence interval = 0.30-1.75; P = .47). In Cycle 2, 1 serious, 3 moderate (single-episode group), and 24 mild (single-episode group n = 10; 2 episode group n = 14) AEs were probably/definitely related to BoNT-A. CONCLUSIONS: Children receiving BoNT A were at no greater risk of moderate/serious AEs compared with a sham control procedure. There was no increased risk of moderate/serious AEs between one and two episodes of BoNT-A. PMID- 26482663 TI - Ensuring the Health of Children in Disasters. AB - Infants, children, adolescents, and young adults have unique physical, mental, behavioral, developmental, communication, therapeutic, and social needs that must be addressed and met in all aspects of disaster preparedness, response, and recovery. Pediatricians, including primary care pediatricians, pediatric medical subspecialists, and pediatric surgical specialists, have key roles to play in preparing and treating families in cases of disasters. Pediatricians should attend to the continuity of practice operations to provide services in time of need and stay abreast of disaster and public health developments to be active participants in community planning efforts. Federal, state, tribal, local, and regional institutions and agencies that serve children should collaborate with pediatricians to ensure the health and well-being of children in disasters. PMID- 26482661 TI - Lignocellulose-converting enzyme activity profiles correlate with molecular systematics and phylogeny grouping in the incoherent genus Phlebia (Polyporales, Basidiomycota). AB - BACKGROUND: The fungal genus Phlebia consists of a number of species that are significant in wood decay. Biotechnological potential of a few species for enzyme production and degradation of lignin and pollutants has been previously studied, when most of the species of this genus are unknown. Therefore, we carried out a wider study on biochemistry and systematics of Phlebia species. METHODS: Isolates belonging to the genus Phlebia were subjected to four-gene sequence analysis in order to clarify their phylogenetic placement at species level and evolutionary relationships of the genus among phlebioid Polyporales. rRNA-encoding (5.8S, partial LSU) and two protein-encoding gene (gapdh, rpb2) sequences were adopted for the evolutionary analysis, and ITS sequences (ITS1+5.8S+ITS2) were aligned for in-depth species-level phylogeny. The 49 fungal isolates were cultivated on semi-solid milled spruce wood medium for 21 days in order to follow their production of extracellular lignocellulose-converting oxidoreductases and carbohydrate active enzymes. RESULTS: Four-gene phylogenetic analysis confirmed the polyphyletic nature of the genus Phlebia. Ten species-level subgroups were formed, and their lignocellulose-converting enzyme activity profiles coincided with the phylogenetic grouping. The highest enzyme activities for lignin modification (manganese peroxidase activity) were obtained for Phlebia radiata group, which supports our previous studies on the enzymology and gene expression of this species on lignocellulosic substrates. CONCLUSIONS: Our study implies that there is a species-level connection of molecular systematics (genotype) to the efficiency in production of both lignocellulose-converting carbohydrate active enzymes and oxidoreductases (enzyme phenotype) on spruce wood. Thus, we may propose a similar phylogrouping approach for prediction of lignocellulose converting enzyme phenotypes in new fungal species or genetically and biochemically less-studied isolates of the wood-decay Polyporales. PMID- 26482664 TI - Incidence and Characteristics of Autoimmune Hepatitis. AB - BACKGROUND AND OBJECTIVES: Autoimmune hepatitis (AIH) is a progressive inflammatory liver disease of unknown etiology, with limited population-based estimates of pediatric incidence. We reported the incidence of pediatric AIH in Canada and described its clinical characteristics. METHODS: We conducted a retrospective cohort study of patients aged <18 years diagnosed with AIH between 2000-2009 at all pediatric centers in Canada. RESULTS: A total of 159 children with AIH (60.3% female, 13.2% type 2 AIH) were identified. Annual incidence was 0.23 per 100000 children. Median age at presentation for type 1 was 12 years (interquartile range: 11-14) versus 10 years for type 2 (interquartile range: 4.5 13) (P = .03). Fatigue (58%), jaundice (54%), and abdominal pain (49%) were the most common presenting symptoms. Serum albumin (33 vs 38 g/L; P = .03) and platelet count (187 000 vs 249 000; P <.001) were significantly lower and the international normalized ratio (1.4 vs 1.2; P <.001) was higher in cirrhotic versus noncirrhotic patients. Initial treatment included corticosteroids (80%), azathioprine (32%), and/or cyclosporine (13%). Response to treatment at 1 year was complete in 90%, and partial in 3%. 3% of patients had no response, and 3% responded and later relapsed. Nine patients underwent liver transplantation, and 4 patients died at a mean follow-up of 4 years. CONCLUSIONS: AIH is uncommon in children and adolescents in Canada. Type 1 AIH was diagnosed 5.5 times more frequently than type 2 AIH. Most patients respond well to conventional therapy, diminishing the need for liver transplantation. PMID- 26482665 TI - Maternal Gestational and Postdelivery Weight Gain and Child Weight. AB - BACKGROUND: Maternal gestational weight gain (GWG) is a risk factor for the development of overweight in her child. It is unknown whether GWG programs the child's health or whether GWG indicates a shared familial lifestyle during childhood. To disentangle these influences, we studied the association of GWG and postdelivery maternal weight change simultaneously with child's weight development. METHODS: We used data from 3367 children participating in a birth cohort that started in 1996 in the Netherlands. Weight and height were self reported. GWG was categorized as "inadequate," "adequate," and "excessive." Multivariable regression and mixed models were used to study maternal and child weight changes. RESULTS: Children of mothers with excessive GWG had a higher BMI z score and overweight prevalence (odds ratio [OR] 1.20; 95% confidence interval [CI], 0.99 to 1.46) throughout childhood. Children of mothers with a high (>=1 kg/year) postdelivery weight gain had a 0.14 (95% CI, -0.08 to 0.36) higher change in BMI z score between age 1 and 14 years than children of mothers with a low (<0.5 kg/year) postdelivery weight gain. Children of mothers with excessive GWG in combination with a high postdelivery weight gain had the highest BMI z score and overweight risk at age 14 years (OR 3.53; 95% CI, 1.70 to 7.33). CONCLUSIONS: Maternal GWG and postdelivery weight gain contribute to child's weight development up to adolescence independently. PMID- 26482666 TI - Derivation of Candidate Clinical Decision Rules to Identify Infants at Risk for Central Apnea. AB - BACKGROUND AND OBJECTIVES: Central apnea complicates, and may be the presenting complaint in, bronchiolitis. Our objective was to prospectively derive candidate clinical decision rules (CDRs) to identify infants in the emergency department (ED) who are at risk for central apnea. METHODS: We conducted a prospective observational study over 8 years. The primary outcome was central apnea subsequent to the initial ED visit. Infants were enrolled if they presented with central apnea or bronchiolitis. We excluded infants with obstructive apnea, neonatal jaundice, trauma, or suspected sepsis. We developed 3 candidate CDRs by using 3 techniques: (1) Poisson regression clustered on the individual, (2) classification and regression tree analysis (CART), and (3) a random forest (RF). RESULTS: We analyzed 990 ED visits for 892 infants. Central apnea subsequently occurred in the hospital in 41 (5%) patients. Parental report of apnea, previous history of apnea, congenital heart disease, birth weight <=2.5 kg, lower weight, and age <=6 weeks all identified a group at high risk for subsequent central apnea. All CDRs and RFs were 100% sensitive (95% confidence interval [CI] 91% 100%) and had a negative predictive value of 100% (95% CI 99%-100%) for the subsequent apnea. Specificity ranged from 61% to 65% (95% CI 58%-68%) for CDRs based on Poisson models; 65% to 77% (95% CI 62%-90%) for CART; and 81% to 91% (95% CI 78%-92%) for RF models. CONCLUSIONS: All candidate CDRs had a negative predictive value of 100% for subsequent central apnea. PMID- 26482667 TI - Polysomnographic Markers in Children With Cystic Fibrosis Lung Disease. AB - BACKGROUND AND OBJECTIVES: Children with cystic fibrosis (CF) often report poor sleep, increased daytime sleepiness, and fatigue. The purpose of this study was to identify respiratory patterns over the spectrum of disease severity in children with CF. The overall hypothesis for the current study is that children with CF compared with snoring control subjects demonstrate gas exchange abnormalities and increased respiratory loads during sleep that are not reported or recognized by conventional polysomnography (PSG). METHODS: Analysis of breathing patterns and gas exchange on PSG was performed in children with CF and healthy controls matched by age and BMI. For all CF and control subjects, the indication for PSG was evaluation for obstructive sleep apnea based on a history of snoring. RESULTS: Children with CF, compared with age- and BMI-matched snoring controls, demonstrated lower oxyhemoglobin saturation (95% +/- 1.6% vs 98% +/- 0.6%, P = .005), higher respiratory rate (19.5 +/- 4.9 vs 16.5 +/- 1.2 breaths per minute, P = .03), and a higher proportion of inspiratory flow limitation (44.1% +/- 24.7% vs 12.1% +/- 13.5%, P = .007) during non-rapid eye movement sleep. The respiratory disturbance index did not differ between CF and snoring control groups (1.5 +/- 2.7 vs 0.6 +/- 0.6 events per hour, P = .11). CONCLUSIONS: Children with CF exhibited abnormalities in gas exchange and increased respiratory load during sleep compared with normal age- and BMI-matched snoring controls. Because these abnormalities were independent of weight and lung function, sleep state may serve as an opportunity for early detection of breathing abnormalities and possibly CF lung disease progression. PMID- 26482669 TI - Videolaryngoscopy to Teach Neonatal Intubation: A Randomized Trial. AB - BACKGROUND: Neonatal endotracheal intubation is a necessary skill. However, success rates among junior doctors have fallen to <50%, largely owing to declining opportunities to intubate. Videolaryngoscopy allows instructor and trainee to share the view of the pharynx. We compared intubations guided by an instructor watching a videolaryngoscope screen with the traditional method where the instructor does not have this view. METHODS: A randomized, controlled trial at a tertiary neonatal center recruited newborns from February 2013 to May 2014. Eligible intubations were performed orally on infants without facial or airway anomalies, in the delivery room or neonatal intensive care, by doctors with <6 months' tertiary neonatal experience. Intubations were randomized to having the videolaryngoscope screen visible to the instructor or covered (control). The primary outcome was first-attempt intubation success rate confirmed by colorimetric detection of expired carbon dioxide. RESULTS: Two hundred six first attempt intubations were analyzed. Median (interquartile range) infant gestation was 29 (27 to 32) weeks, and weight was 1142 (816 to 1750) g. The success rate when the instructor was able to view the videolaryngoscope screen was 66% (69/104) compared with 41% (42/102) when the screen was covered (P < .001, OR 2.81, 95% CI 1.54 to 5.17). When premedication was used, the success rate in the intervention group was 72% (56/78) compared with 44% (35/79) in the control group (P < .001, OR 3.2, 95% CI 1.6 to 6.6). CONCLUSIONS: Intubation success rates of inexperienced neonatal trainees significantly improved when the instructor was able to share their view on a videolaryngoscope screen. PMID- 26482668 TI - Psychosocial Adjustment in School-age Girls With a Family History of Breast Cancer. AB - OBJECTIVE: Understanding how young girls respond to growing up with breast cancer family histories is critical given expansion of genetic testing and breast cancer messaging. We examined the impact of breast cancer family history on psychosocial adjustment and health behaviors among >800 girls in the multicenter LEGACY Girls Study. METHODS: Girls aged 6 to 13 years with a family history of breast cancer or familial BRCA1/2 mutation (BCFH+), peers without a family history (BCFH-), and their biological mothers completed assessments of psychosocial adjustment (maternal report for 6- to 13-year-olds, self-report for 10- to 13-year-olds), breast cancer-specific distress, perceived risk of breast cancer, and health behaviors (10- to 13-year-olds). RESULTS: BCFH+ girls had better general psychosocial adjustment than BCFH- peers by maternal report. Psychosocial adjustment and health behaviors did not differ significantly by self-report among 10- to 13-year-old girls. BCFH+ girls reported higher breast cancer-specific distress (P = .001) and were more likely to report themselves at increased breast cancer risk than BCFH- peers (38.4% vs 13.7%, P < .001), although many girls were unsure of their risk. In multivariable analyses, higher daughter anxiety was associated with higher maternal anxiety and poorer family communication. Higher daughter breast cancer-specific distress was associated with higher maternal breast cancer-specific distress. CONCLUSIONS: Although growing up in a family at risk for breast cancer does not negatively affect general psychosocial adjustment among preadolescent girls, those from breast cancer risk families experience greater breast cancer-specific distress. Interventions to address daughter and mother breast cancer concerns and responses to genetic or familial risk might improve psychosocial outcomes of teen daughters. PMID- 26482670 TI - Severe Central Sleep Apnea in Vici Syndrome. AB - Vici syndrome is a rare congenital multisystem disorder due to recessive mutations in the key autophagy regulator EPG5. Vici syndrome is characterized by agenesis of the corpus callosum, hypopigmentation, immunodeficiency, cataracts, and cardiomyopathy, with variable additional multisystem involvement. Here we report on a 5-year-old girl who presented with global developmental delay, seizures, callosal agenesis, cataracts, sensorineural hearing loss, hypopigmentation, and immunodeficiency with a low CD4 count and recurrent infections. EPG5 sequencing (prompted by suggestive clinical features) revealed a homozygous missense mutation, c.1007A>G (p.Gln336Arg). The patient was referred to our center for evaluation of nocturnal apnea. Overnight polysomnography showed severe central sleep apnea (CSA) with an overall apnea-hypopnea index of 100.5 events per hour of sleep (central apnea index of 97.5, mixed apnea index of 2, and obstructive hypopnea index of 1). The patient responded to bilevel positive airway pressure therapy with a backup rate with normalization of the apnea hypopnea index and maintenance of oxygen saturation >90%. Despite successful control of the severe CSA, the patient was eventually started on nocturnal oxygen therapy due to excessive upper airway secretions and the high risk of possible aspiration with positive airway pressure therapy. This is the first report of EPG5-related Vici syndrome associated with CSA. We discuss the polysomnographic findings in our patient in the context of a brief literature review of the reported sleep abnormalities in Vici syndrome. PMID- 26482671 TI - Atypical Cutaneous Blastomycosis in a Child With Juvenile Idiopathic Arthritis on Infliximab. AB - Blastomyces dermatitidis is a dimorphic fungus endemic to much of North America, particularly the soils of the midwestern and southeastern United States. Human infection typically occurs through inhalation of airborne conidia, which can be followed occasionally by dissemination to the skin, bone, genitourinary system, and central nervous system. A hallmark of the pathogen is that it can cause disease in both immunocompetent and immunosuppressed populations. Blastomycosis is rare in pediatric patients, with cutaneous manifestations occurring even less frequently. Here, we report the case of a 9-year-old boy on iatrogenic immunosuppression with infliximab and methotrexate for juvenile idiopathic arthritis who presented with a nonhealing, indurated plaque of his right ear with significant superficial yellow crusting in the absence of constitutional symptoms. After failing a prolonged course of topical and oral antibiotic therapy, biopsy and tissue culture revealed Blastomyces dermatitidis infection. The area cleared after treatment with oral fluconazole and withdrawal of infliximab. To our knowledge, this is the first report of a pediatric patient developing an infection with B dermatitidis after initiation of therapy with a tumor necrosis factor-alpha inhibitor. This case also highlights an unusual morphology of cutaneous blastomycosis in an iatrogenically immunosuppressed child. PMID- 26482672 TI - Psychosocial Interventions for Child Disruptive Behaviors: A Meta-analysis. AB - BACKGROUND: Disruptive behavior disorders are among the most common child and adolescent psychiatric disorders and associated with significant impairment. OBJECTIVE: Systematically review studies of psychosocial interventions for children with disruptive behavior disorders. METHODS: We searched Medline (via PubMed), Embase, and PsycINFO. Two reviewers assessed studies against predetermined inclusion criteria. Data were extracted by 1 team member and reviewed by a second. We categorized interventions as having only a child component, only a parent component, or as multicomponent interventions. RESULTS: Sixty-six studies were included. Twenty-eight met criteria for inclusion in our meta-analysis. The effect size for the multicomponent interventions and interventions with only a parent component had the same estimated value, with a median of -1.2 SD reduction in outcome score (95% credible interval, -1.6 to 0.9). The estimate for interventions with only a child component was -1.0 SD (95% credible interval, -1.6 to -0.4). LIMITATIONS: Methodologic limitations of the available evidence (eg, inconsistent or incomplete outcome reporting, inadequate blinding or allocation concealment) may compromise the strength of the evidence. Population and intervention inclusion criteria and selected outcome measures eligible for inclusion in the meta-analysis may limit applicability of the results. CONCLUSIONS: The 3 intervention categories were more effective than the control conditions. Interventions with a parent component, either alone or in combination with other components, were likely to have the largest effect. Although additional research is needed in the community setting, our findings suggest that the parent component is critical to successful intervention. PMID- 26482673 TI - Fetal Alcohol Spectrum Disorders. AB - Prenatal exposure to alcohol can damage the developing fetus and is the leading preventable cause of birth defects and intellectual and neurodevelopmental disabilities. In 1973, fetal alcohol syndrome was first described as a specific cluster of birth defects resulting from alcohol exposure in utero. Subsequently, research unequivocally revealed that prenatal alcohol exposure causes a broad range of adverse developmental effects. Fetal alcohol spectrum disorder (FASD) is the general term that encompasses the range of adverse effects associated with prenatal alcohol exposure. The diagnostic criteria for fetal alcohol syndrome are specific, and comprehensive efforts are ongoing to establish definitive criteria for diagnosing the other FASDs. A large and growing body of research has led to evidence-based FASD education of professionals and the public, broader prevention initiatives, and recommended treatment approaches based on the following premises:? Alcohol-related birth defects and developmental disabilities are completely preventable when pregnant women abstain from alcohol use.? Neurocognitive and behavioral problems resulting from prenatal alcohol exposure are lifelong.? Early recognition, diagnosis, and therapy for any condition along the FASD continuum can result in improved outcomes.? During pregnancy:?no amount of alcohol intake should be considered safe;?there is no safe trimester to drink alcohol;?all forms of alcohol, such as beer, wine, and liquor, pose similar risk; and?binge drinking poses dose-related risk to the developing fetus. PMID- 26482674 TI - Promoting HPV Vaccination in Safety-Net Clinics: A Randomized Trial. AB - OBJECTIVES: Evaluate effects of a multicomponent intervention (human papillomavirus [HPV] vaccine-specific brochure and recalls) on HPV vaccination and secondarily examine if race/ethnicity moderates effects. METHODS: Unvaccinated girls aged 11 to 18 years attending 4 safety-net pediatric clinics and their parent/guardian (n = 814 dyads) were randomized to (1) active comparison (general adolescent vaccine brochure), or (2) intervention consisting of a HPV vaccine-specific brochure, telephone recalls to parents who declined, and recalls to patients overdue for doses 2 and 3. HPV 1-dose and 3-dose coverages were assessed via electronic health records 12 months after randomization. Multivariate logistic regressions estimated adjusted odds and marginal predicted vaccine coverage by study arm and race/ethnicity. RESULTS: Intent-to-treat analyses found no main effect of the HPV vaccine-specific brochure on 1-dose coverage (42.0% vs 40.6%); however, secondary analyses found race/ethnicity was a significant moderator such that the intervention was effective only for Hispanic individuals (adjusted odds ratio [AOR] 1.43; 95% confidence interval [CI] 1.02-2.02), and not effective for black individuals (AOR 0.64; 95% CI 0.41-1.13). Recalls to parents who declined the vaccine during the index visit were not effective, but recalls to patients overdue for doses 2 and 3 were effective at increasing 3-dose coverage regardless of race/ethnicity (AOR 1.99; 95% CI 1.16-3.45). CONCLUSIONS: Educational materials describing only the HPV vaccine were effective for Hispanic but not black individuals. Future research should test mechanisms that may mediate intervention effects for different racial/ethnic groups, such as different informational needs or vaccine schemas (experiences, beliefs, norms). PMID- 26482675 TI - Treating EEG Seizures in Hypoxic Ischemic Encephalopathy: A Randomized Controlled Trial. AB - BACKGROUND: The impact of treating electrographic seizures in hypoxic ischemic encephalopathy (HIE) is unknown. METHODS: Neonates >=36 weeks with moderate or severe HIE were randomly assigned to either treatment of electrographic seizures alone (ESG) or treatment of clinical seizures (CSG). Conventional EEG video was monitored in both groups for up to 96 hours. Cumulative electrographic seizure burden (SB) was calculated in seconds and converted to log units for analysis. MRI scans were scored for severity of brain injury. Infants underwent neurodevelopmental evaluation at 18 to 24 months. Statistical analyses were performed by using SAS 9.3 version (SAS Institute, Inc, Cary, NC). RESULTS: Thirty-five of 69 neonates (51%) who were randomly assigned and included in the study developed seizures (15 in ESG and 20 in CSG). Excluding infants with status epilepticus, median SB (interquartile range) in seconds in ESG (n = 10) was lower than in CSG (n = 16) (449 [113-2070] vs 2226 [760-7654]; P = .02). ESG had fewer seizures with shorter time to treatment (P = .04). Twenty-four of 30 (80%) surviving infants with seizures underwent neurodevelopmental evaluation at 18 to 24 months. Increasing SB in the combined cohort was significantly associated with higher brain injury scores (P < .03) and lower performance scores across all 3 domains on BSID III (P = .03). CONCLUSIONS: In neonates with HIE, EEG monitoring and treatment of electrographic seizures results in significant reduction in SB. SB is associated with more severe brain injury and significantly lower performance scores across all domains on BSID III. PMID- 26482676 TI - Eigenanalysis of SNP data with an identity by descent interpretation. AB - Principal component analysis (PCA) is widely used in genome-wide association studies (GWAS), and the principal component axes often represent perpendicular gradients in geographic space. The explanation of PCA results is of major interest for geneticists to understand fundamental demographic parameters. Here, we provide an interpretation of PCA based on relatedness measures, which are described by the probability that sets of genes are identical-by-descent (IBD). An approximately linear transformation between ancestral proportions (AP) of individuals with multiple ancestries and their projections onto the principal components is found. In addition, a new method of eigenanalysis "EIGMIX" is proposed to estimate individual ancestries. EIGMIX is a method of moments with computational efficiency suitable for millions of SNP data, and it is not subject to the assumption of linkage equilibrium. With the assumptions of multiple ancestries and their surrogate ancestral samples, EIGMIX is able to infer ancestral proportions (APs) of individuals. The methods were applied to the SNP data from the HapMap Phase 3 project and the Human Genome Diversity Panel. The APs of individuals inferred by EIGMIX are consistent with the findings of the program ADMIXTURE. In conclusion, EIGMIX can be used to detect population structure and estimate genome-wide ancestral proportions with a relatively high accuracy. PMID- 26482677 TI - Response to the Comment by J. Grunenberg on "The Nature of the Fourth Bond in the Ground State of C2: The Quadruple Bond Conundrum''. AB - The quadruple bond structure in C2 emerges from solid quantum-chemical calculations and won't go away! There is no mystery in the rather small bond dissociation energy, and this cannot constitute the reason to reconsider the whole concept of quadruple bonding. PMID- 26482678 TI - Analysis of 5' gene regions reveals extraordinary conservation of novel non coding sequences in a wide range of animals. AB - BACKGROUND: Phylogenetic footprinting is a comparative method based on the principle that functional sequence elements will acquire fewer mutations over time than non-functional sequences. Successful comparisons of distantly related species will thus yield highly important sequence elements likely to serve fundamental biological roles. RNA regulatory elements are less well understood than those in DNA. In this study we use the emerging model organism Nasonia vitripennis, a parasitic wasp, in a comparative analysis against 12 insect genomes to identify deeply conserved non-coding elements (CNEs) conserved in large groups of insects, with a focus on 5' UTRs and promoter sequences. RESULTS: We report the identification of 322 CNEs conserved across a broad range of insect orders. The identified regions are associated with regulatory and developmental genes, and contain short footprints revealing aspects of their likely function in translational regulation. The most ancient regions identified in our analysis were all found to overlap transcribed regions of genes, reflecting stronger conservation of translational regulatory elements than transcriptional elements. Further expanding sequence analyses to non-insect species we also report the discovery of, to our knowledge, the two oldest and most ubiquitous CNE's yet described in the animal kingdom (700 MYA). These ancient conserved non-coding elements are associated with the two ribosomal stalk genes, RPLP1 and RPLP2, and were very likely functional in some of the earliest animals. CONCLUSIONS: We report the identification of the most deeply conserved CNE's found to date, and several other deeply conserved elements which are without exception, part of 5' untranslated regions of transcripts, and occur in a number of key translational regulatory genes, highlighting translational regulation of translational regulators as a conserved feature of insect genomes. PMID- 26482679 TI - A peptide mimic blocks the cross-reaction of anti-DNA antibodies with glomerular antigens. AB - Anti-DNA antibodies play a pivotal role in the pathogenesis of lupus nephritis by cross-reacting with renal antigens. Previously, we demonstrated that the binding affinity of anti-DNA antibodies to self-antigens is isotype-dependent. Furthermore, significant variability in renal pathogenicity was seen among a panel of anti-DNA isotypes [derived from a single murine immunoglobulin (Ig)G3 monoclonal antibody, PL9-11] that share identical variable regions. In this study, we sought to select peptide mimics that effectively inhibit the binding of all murine and human anti-DNA IgG isotypes to glomerular antigens. The PL9-11 panel of IgG anti-DNA antibodies (IgG1, IgG2a, IgG2b and IgG3) was used for screening a 12-mer phage display library. Binding affinity was determined by surface plasmon resonance. Enzyme-linked immunosorbent assay (ELISA), flow cytometry and glomerular binding assays were used for the assessment of peptide inhibition of antibody binding to nuclear and kidney antigens. We identified a 12 amino acid peptide (ALWPPNLHAWVP, or 'ALW') which binds to all PL9-11 IgG isotypes. Preincubation with the ALW peptide reduced the binding of the PL9-11 anti-DNA antibodies to DNA, laminin, mesangial cells and isolated glomeruli significantly. Furthermore, we confirmed the specificity of the amino acid sequence in the binding of ALW to anti-DNA antibodies by alanine scanning. Finally, ALW inhibited the binding of murine and human lupus sera to dsDNA and glomeruli significantly. In conclusion, by inhibiting the binding of polyclonal anti-DNA antibodies to autoantigens in vivo, the ALW peptide (or its derivatives) may potentially be a useful approach to block anti-DNA antibody binding to renal tissue. PMID- 26482680 TI - Impact of eradicating hepatitis C virus on the work productivity of chronic hepatitis C (CH-C) patients: an economic model from five European countries. AB - CH-C negatively affects work productivity (WP), creating a large economic burden. The aim of this study was to model the impact of sustained virologic response (SVR) on WP in CHC genotype 1 (GT1) patients in five European countries (EU5). Work Productivity and Activity Index-Specific Health Problem questionnaire was administered to patients across the ION clinical trials (n = 629 European patients). The analysis modelled a population of GT1 CHC patients over one year, who had been either not treated or treated with LDV/SOF. Sensitivity analyses assessed the possibility that CHC patients' labour costs were lower than the general population's and presented results by fibrosis stage. Before initiation of treatment, EU patients with CHC GT1 exhibited absenteeism and presenteeism impairments of 3.54% and 9.12%, respectively. About 91.8% of EU patients in the ION trials achieved SVR and improved absenteeism and presenteeism impairments by 16.3% and 19.5%, respectively. Monetizing these data, treatment with LDV/SOF resulted in an annual productivity gain of ?435 million and a weighted average per-employed patient (PEP) gain of ?900 in the EU5. PEP gains from treatment are projected to be higher in cirrhotic than in noncirrhotic patients. If CHC patients are assumed to earn 20% less than the general population, gains of ?348 million (?720 PEP) annually are projected. CHC results in a significant economic burden to European society. Due to improvements in WP, SVR with treatment could provide substantial economic gains, partly offsetting the direct costs related to its widespread use. PMID- 26482681 TI - Bifidobacteria possess inhibitory activity against dipeptidyl peptidase-IV. AB - The incretin hormones are extremely rapidly metabolized by the ubiquitous enzyme dipeptidyl peptidase IV (DPP-IV). Therefore, DPP-IV inhibitors which can prolong the incretin effect are the newest and promising drugs for management of type 2 diabetes. In this study, we investigated whether Bifidobacteria colonizing the human gut possess DPP-IV inhibitory activity. Cell-free intracellular extracts of 13 Bifidobacterium strains isolated from breast-fed infant faecal samples were prepared and screened for DPP-IV inhibitory activity, and two Bifidobacterium strains-Bif. longum BBMN68 and Bif. lactis Bb12-were used as reference strains. Most of the strains showed varying levels of DPP-IV inhibitory property (7-27%). Strains of Bifidobacterium adolescentis IF1-11 and Bifidobacterium bifidum IF3 211 showed the greatest DPP-IV inhibitory activity (27 and 25%) as well as good in vitro probiotic properties. This initial finding suggested that new beneficial function of Bifidobacteria is strain-dependent and the strains or their components may have the potential application for management of type 2 diabetes via inhibiting gastrointestinal DPP-IV activity. Further investigations into the isolation and identification of the bioactive components of Bifidobacteria are warranted. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results show that Bifidobacteria isolated from breast-fed infants' faecal samples possess DPP-IV inhibitory activity. Strains of Bifidobacterium bifidum IF3-211 and Bifidobacterium adolescentis IF1-11, which showed excellent DPP-IV inhibitory properties as well as good in vitro probiotic properties, are expected to be beneficial for application as anti-diabetic probiotics. PMID- 26482682 TI - Large Metal Heads and Vitamin E Polyethylene Increase Frictional Torque in Total Hip Arthroplasty. AB - PURPOSE: Trunnionosis has reemerged in modern total hip arthroplasty for reasons that remain unclear. Bearing frictional torque transmits forces to the modular head-neck interface, which may contribute to taper corrosion. The purpose of this study is to compare frictional torque of modern bearing couples in total hip arthroplasty. METHODS: Mechanical testing based on in vivo loading conditions was used to measure frictional torque. All bearing couples were lubricated and tested at 1 Hz for more than 2000 cycles. The bearing couples tested included conventional, highly crosslinked (XLPE) and vitamin E polyethylene, CoCr, and ceramic femoral heads and dual-mobility bearings. Statistical analysis was performed using Student t test for single-variable and analysis of variance for multivariant analysis. P <= .05 was considered statistically significant. RESULTS: Large CoCr metal heads (>=36 mm) substantially increased frictional torque against XLPE liners (P = .01), a finding not observed in ceramic heads. Vitamin E polyethylene substantially increased frictional torque compared with XLPE in CoCr and ceramic heads (P = .001), whereas a difference between conventional and XLPE was not observed (P = .69) with the numbers available. Dual mobility bearing with ceramic inner head demonstrated the lowest mean frictional torque of all bearing couples. CONCLUSION: In this simulated in vivo model, large diameter CoCr femoral heads and vitamin E polyethylene liners are associated with increased frictional torque compared with smaller metal heads and XLPE, respectively. The increased frictional torque of vitamin E polyethylene and larger-diameter femoral heads should be considered and further studied, along with reported benefits of these modern bearing couples. PMID- 26482683 TI - Down Syndrome Increases the Risk of Short-Term Complications After Total Hip Arthroplasty. AB - BACKGROUND: Down syndrome is the most common chromosomal abnormality and is associated with degenerative hip disease. Because of the recent increase in life expectancy for patients with this syndrome, orthopaedic surgeons are likely to see an increasing number of these patients who are candidates for total hip arthroplasty (THA). METHODS: Using Nationwide Inpatient Sample (NIS) data from 1998 to 2010, we compared the short-term adverse outcomes of THA among 241 patients with Down syndrome and a matched 723-patient cohort. Specifically, we assessed: (1) incidence of THA; (2) perioperative medical and surgical complications during the primary hospitalization; (3) length of stay; and (4) hospital charges. RESULTS: The annual mean number of patients with Down syndrome undergoing THA was 19. Compared to matched controls, Down syndrome patients had an increased risk of perioperative (OR, 4.33; P<.001), medical (OR, 4.59; P<.001) and surgical (OR, 3.51; P<.001) complications during the primary hospitalization. Down syndrome patients had significantly higher incidence rates of pneumonia (P=.001), urinary tract infection (P<.001), and wound hemorrhage (P=.027). The mean lengths of stay for Down syndrome patients were 26% longer (P<.001), but there were no differences in hospital charges (P=.599). CONCLUSION: During the initial evaluation and pre-operative consultation for a patient with Down syndrome who is a candidate for THA, orthopaedic surgeons should educate the patient, family and their clinical decision makers about the increased risk of medical complications (pneumonia and urinary tract infections), surgical complications (wound hemorrhage), and lengths of stay compared to the general population. PMID- 26482684 TI - Periarticular Injection After Total Knee Arthroplasty Using Liposomal Bupivacaine vs a Modified Ranawat Suspension: A Prospective, Randomized Study. AB - BACKGROUND: The purpose of this study is to compare liposomal bupivacaine to a modified (Ranawat) local injection for total knee arthroplasty (TKA). METHODS: This is a prospective, randomized study of 105 consecutive patients undergoing primary TKA. Group A patients received a periarticular injection with liposomal bupivacaine and group B with a mixture of ropivacaine, epinephrine, ketorolac, and clonidine. There were 54 patients in the group A (liposomal bupivacaine) and 51 in group B. RESULTS: There were no differences in the groups with respect to age, sex, and preoperative knee scores. There were no differences with respect to postoperative narcotic usage and knee range of motion. CONCLUSION: Liposomal bupivacaine as a periarticular injection after TKA demonstrated similar pain levels, narcotic usage, and range of motion compared to a modified Ranawat suspension but improved walking distance. PMID- 26482685 TI - Comparison of Midterm Clinical and Radiographic Results Between Total Knee Arthroplasties Using Medial Pivot and Posterior-Stabilized Prosthesis-A Matched Pair Analysis. AB - BACKGROUND: Despite the theoretical advantage of a knee design that can more reliably replicate the medial pivot (MP) of the natural knee, only a few clinical studies have compared the clinical results between the MP prosthesis and another design of prosthesis. We compared the midterm results of total knee arthroplasty (TKA) using an MP prosthesis vs a posterior-stabilized prosthesis via a matched pair analysis; we included results related to patellofemoral joint symptoms. METHODS: The midterm clinical and radiographic results of 125 consecutive patients (150 knees) who underwent a TKA with the ADVANCE MP prosthesis were compared with those of a control group who had undergone a primary TKA with a posterior-stabilized prosthesis. RESULTS: Values of the Knee Society's Knee Scoring System, Western Ontario and McMaster Universities Osteoarthritis Index, and Kujala and Feller scoring systems, as well as the range of motion after TKA, did not significantly differ between the 2 groups. No differences in femorotibial angle and component position, including the patella component, were observed between the 2 groups. No significant differences in the change of patella tilt angle and the postoperative patellar translation were observed between the 2 groups. CONCLUSION: Patients with the MP prosthesis experienced satisfactory pain relief and a functional recovery, providing results similar to those of the posterior-stabilized prosthesis, including the resolution of patellofemoral joint symptoms. PMID- 26482686 TI - Effective prevention of posttraumatic tattoo using hydrosurgical debridement in the ED. AB - Traumatic tattoos can result from the accidental deposition of foreign particles in the dermis. These pigmented particles can become permanently lodged in the dermis after wound re-epithelialization and lead to irregular black or blue skin discoloration. Different methods exist for tattoo removal. The best strategy is to prevent traumatic tattoo formation by immediately removing the foreign particles before the healing process begins. Here, we present a fine-tuned, hydrosurgical debridement system to selectively debride wounds and preserve as much viable tissue as possible. PMID- 26482687 TI - Improved Health-Related Quality of Life, and More Days out of Hospital with Supplementation with Selenium and Coenzyme Q10 Combined. Results from a Double Blind, Placebo-Controlled Prospective Study. AB - BACKGROUND: The impact of supplementation with selenium and coenzyme Q10 (CoQ10) on health-care usage and health-related quality of life (Hr-QoL) in community dwelling elderly people has, to our knowledge, not previously been investigated. AIM: To investigate the effect of 48 months supplementation with CoQ10 and selenium on community-dwelling elderly as regards: (I) the number of days out of hospital, and (II) the effect on Hr-QoL. METHODS: A 48-month double-blind randomized placebo-controlled trial was carried out. A total of 443 participants were given CoQ10 and organic selenium yeast combined, or a placebo. All admissions to the Department of Internal Medicine or Cardiology were evaluated. Hr-QoL were measured with the Short Form-36 (SF-36), the Cardiac Health Profile (CHP) and one item overall-quality of life (overall-QoL). RESULTS: A total of 206 participants were evaluated after 48 months. No changes were found in the number of days out of hospital or Hr-QoL. A sub-analysis of participants matched for age, gender and baseline cardiac wall tension as measured by NT-proBNP was performed. The mean number of days out of hospital was 1779 for those taking the active substance compared to 1533 for those taking the placebo (p=0.03). Those with active substance declined significantly less in the HR-QoL domains of physical role performance (p=0.001), vitality (p=0.001), physical component score (p=0.001), overall QoL (p=0.001), somatic dimension (p=0.001), conative dimension (p=0.001) and global function (p=0.001). CONCLUSION: In a match-group analysis selenium and CoQ10 increased the number of days out of hospital and slowed the deterioration in Hr-QoL. PMID- 26482688 TI - Association Strength of Three Adiposity Measures with Autonomic Nervous System Function in Apparently Healthy Employees. AB - OBJECTIVES: To investigate the association of different measures of central (abdominal) and overall adiposity with autonomic nervous system (ANS) function, indexed by heart rate variability (HRV), in apparently healthy human adults. DESIGN AND MEASUREMENTS: Cross-sectional data of 8,538 participants (20% female, age: 41 +/- 11 years, body mass index (BMI): 24 +/- 4 kg/m2, waist circumference (WC): 91 +/- 12 cm, waist-to-height ratio (WHtR): 0.45 +/- 0.08) were available for analysis. RESULTS: All measures of adiposity were inversely correlated with vagally-mediated HRV indexed by RMSSD (all p<0.001). Strongest associations were found with WC and RMSSD (r = -0.29). Associations were stronger in males (WC r = 0.32) than in females (WC r = -0.23). Partial correlations revealed the same pattern for RMSSD (WC all pcc = -0.12 p<0.001; WC male pcc = -0.14 p<0.001; WC female pcc = -0.06 p<0.05). Correlation strength of BMI and WHtR with RMSSD were similar and significantly weaker compared to WC (p < .001) in unadjusted analysis. Overall, nonparametric Kendall's taub led to the same conclusions. CONCLUSION: The present data supports previous findings, that HRV is related to measures of adiposity in healthy individuals. In line with previous research, we found that WC is more strongly related to measures of HRV, indicating that WC best captures adiposity related risk. PMID- 26482689 TI - Soybeans or Soybean Products Consumption and Depressive Symptoms in Older Residents in Rural Northeast China: A Cross-Sectional Study. AB - OBJECTIVE: Depression is one of the most common mental disorders among elderly subjects. The purpose of this study is to estimate the prevalence of depressive symptoms and the association between soybeans consumption and depressive symptoms among older residents in rural Northeast China. DESIGN: Cross-sectional study. SETTING: A representative sample of the rural Northeast residents. PARTICIPANTS: This survey was conducted from July 2012 to August 2013 which randomly selected and examined a total of 1717 residents aged >= 65 years from the rural Northeast China. MEASUREMENTS: All participants completed the Patient Health Questionnaire 9 (PHQ-9). Information on demographic and lifestyle characteristics and blood biochemical indexes were collected by well-trained personnel. RESULTS: The prevalence of depressive symptoms in the elderly was 8.9%. Women had significantly higher prevalence of depressive symptoms than men (13.3% vs.4.6%, P<0.001). Individuals consuming soybeans >=4times/week had statically lower possibility to have depressive symptoms than those rarely consuming (3.6%vs. 12.5%, P<0.05). In addition to some conventional risk factors like sex, annual income, educational status, current smoking and chronic diseases status were associated with depressive symptoms, proper sleep duration (7-8h/d) [OR(95%CI):0.28(0.15,0.53)] and frequently consumption of soybeans or soybean products [OR (95%CI): 0.36 (0.15,0.87) for 2-3times/week and OR (95%CI):0.50 (0.34,0.74) for >=4times/week] significantly decreased the risk of depressive symptoms among elderly in rural Northeast China. CONCLUSION: Women had significantly higher prevalence of depressive symptoms than men in rural China. Individuals who rarely consume soybeans or soybean products are more likely to suffer depressive symptoms. Rural elderly residents should be cautiously screened to prevent or treat depression. PMID- 26482690 TI - Olfactory Function, Eating Ability, and Visceral Obesity Associated with MMSE Three Years after Parkinson's Disease Diagnosis. AB - OBJECTIVES: This study examines whether risk factors for poor nutrition are associated with global cognitive function three years after confirmed Parkinson's disease (PD) diagnosis. DESIGN: The follow-up investigations for this prospective community-based study were conducted three years after PD diagnosis. SETTING: The study participants lived in Vasterbotten County, a region in northern Sweden with 142,000 inhabitants. PARTICIPANTS: This study population consisted of 118 PD outpatients from the study of Newly Diagnosed PD in Umea (NYPUM). MEASUREMENTS: Global cognition was assessed with the Mini Mental State Examination (MMSE) at baseline and at follow-up. Anthropometry, nutrition (Mini Nutritional Assessment, MNA, 3-day food registration, 3-FDR), olfactory function (Brief Smell Identification Test, B-SIT), and swallowing, cutting food, and salivation (single questions from the Unified Parkinson's Disease Rating Scale, UPDRS) were used as markers for nutritional status. RESULTS: The MMSE score decreased over three years (-1.06+/-3.38, p=0.001). Olfactory function at baseline was associated to MMSE at three years (B=0.365, p=0.004). Changes in waist/hip ratio (B=113.29, p=0.017), swallowing (B=1.18, P=0.033), and cutting food (B=-1.80, p=0.000) were associated with MMSE at follow-up. CONCLUSION: This study indicates that olfactory function, cutting food, swallowing, and visceral obesity are associated with MMSE three years after PD diagnosis. PMID- 26482691 TI - Nutritional Guidance Improves Nutrient Intake and Quality of Life, and May Prevent Falls in Aged Persons with Alzheimer Disease Living with a Spouse (NuAD Trial). AB - OBJECTIVE: The aim was to examine the effect of tailored nutritional guidance on nutrition, health-related quality of life (HRQoL) and falls in persons with Alzheimer disease (AD). DESIGN: Randomised controlled trial. SETTING AND PARTICIPANTS: Persons with AD living with a spouse. INTERVENTION: Tailored nutritional guidance with home visits during one year. The control group received a written guide about nutrition in older adults and all community-provided normal care. MEASUREMENTS: The primary outcome measure was weight change, and secondary outcomes included changes in protein and micronutrient intakes from three-day food records, HRQoL (15D) and rate of falls. RESULTS: Of the participants (n = 78) with AD (mean age 77.4, 69% males), 40% were at risk for malnutrition, 77% received < 1.2 g/bodyweight (kg) of protein at baseline. We found no difference in weight change between the groups. At 12 months, the mean change in protein intake was 0.05 g/bodyweight (kg) (95% CI -0.06 to 0.15) in the intervention group (IG), and -0.06 g/kg (95% CI -0.12 to 0.02) in the control group (CG) (p = 0.031, adjusted for baseline value, age, sex, MMSE and BMI). Participants' HRQoL improved by 0.006 (95% CI -0.016 to 0.028) in the IG, but declined by -0.036 (95% CI -0.059 to 0.013) in the CG (p = 0.007, adjusted for baseline value, age, sex, MMSE and BMI). Dimensions that differed included mental functioning, breathing, usual activities and depression. The fall rate was 0.55 falls/person per year (95% CI 0.34 to 0.83) in the IG, and 1.39 falls/person per year (95% CI 1.04 to 1.82) in the CG (IRR 0.55; 95% CI 2.16 to 6.46; p < 0.001 adjusted for age, sex and MMSE). CONCLUSIONS: Tailored nutritional guidance improves nutrition and HRQoL, and may prevent falls among AD people living with a spouse. PMID- 26482692 TI - Vitamin K Status Is not Associated with Cognitive Decline in Middle Aged Adults. AB - OBJECTIVES: The aim of this study was to examine the association between dephospho-uncarboxylated matrix Gla protein (dp-ucMGP), an indicator of vitamin K status, and cognitive decline, and the modifying role of 25(OH)D. DESIGN: Longitudinal study with six years follow-up. SETTING: Community based. PARTICIPANTS: 599 participants of the Longitudinal Aging Study Amsterdam (aged 55 65 years). MEASUREMENTS: Information processing speed and a composite Z-score by combining three domains of cognition reflecting general cognitive functioning. RESULTS: Generalized estimating equations (GEE) showed no significant associations between dp-ucMGP and decline in general cognitive functioning. Vitamin D modified the association between dp-ucMGP and speed of information processing (p<0.05). In the group with a 25(OH)D concentration > 50 nmol/l, the highest tertile of dp-ucMGP (>406 pmol/l), which corresponds to lower vitamin K levels, was associated with 1.5 higher score on information processing speed (p=0.023) as compared to the lowest tertile of dp-ucMGP. CONCLUSION: In contrast to our hypothesis, a suboptimal vitamin K was not associated with cognitive decline in middle-aged adults. PMID- 26482693 TI - Effects of Changes in Regional Body Composition on Physical Function in Older Adults: A Pilot Randomized Controlled Trial. AB - BACKGROUND/OBJECTIVE: Obesity exacerbates age-related physical disability; however, observational studies show that any weight loss in old age is associated with greater risk of mortality. Conversely, randomized controlled trials in older adults show that weight loss is beneficial. The discrepancy may be due to weight loss intention and differential changes to regional body composition. The purpose of this research was to evaluate the independent role of regional body composition remodeling in improving physical function. DESIGN: Pilot Randomized Controlled Trial. SETTING: Community based research center. PARTICIPANTS: Thirty six community dwelling, overweight to moderately obese (BMI 28.0-39.9 kg/m2) older adults (age 70.6+/-6.1 yrs). INTERVENTION: Physical activity plus weight loss (PA+WL, n=21) or PA plus successful aging (SA) education. PA consisted primary of treadmill walking supplemented with lower extremity resistance and balance training. The WL program was based on the Diabetes Prevention Project and aimed at achieving a 7% weight loss by cutting calories, specifically those from fat. MEASUREMENTS: At baseline, 6- and 12-months, body composition was measured using computerized tomography and dual x-ray absorptiometry. Abdominal visceral (VAT) and thigh intermuscular (IMAT) adipose tissue were quantified. Physical function was assessed using the short physical performance battery (SPPB). RESULTS: Separate multivariable linear regression models with both groups combined demonstrated that decreases in IMAT and VAT were significantly associated with improvements in SPPB (P<0.05) independent of change in total fat mass. PA+WL improved SPPB scores from baseline (0.8+/-1.4, P<0.05), whereas PA+SA did not; however no intergroup difference was detected. Of note, these effects were mainly achieved during the intensive intervention phase. CONCLUSION: Decreases in IMAT and VAT are important mechanisms underlying improved function following intentional weight loss plus physical activity. PMID- 26482695 TI - Preliminary Findings of the Brief Everyday Activities Measurement (BEAM) in Older Adults. AB - OBJECTIVES: Functional losses are common in healthy and cognitively impaired older adults. However, subtle declines in instrumental activities of daily living (IADLs) are not always detected in self-reports. Performance IADL measurements are financially and time burdensome, restricting their use in varied settings. To address these limitations, we developed the Brief Everyday Activities Measure (BEAM), a short (< 5 minutes) objective IADL measure that assesses medication and finance management. DESIGN AND PARTICIPANTS: The BEAM was administered to 209 cognitively non-demented community-dwellers (ages 65 - 95 years). MEASUREMENTS: Participants completed standardized motor, neuropsychological, psychological, and self-report functional assessments. RESULTS: BEAM completion time ranged from 54.16 to 259.31 seconds. Interclass correlations (ICC) for total BEAM completion time was moderate (0.65, 95% CI [.43 -.78]). Accuracy for total BEAM performance was in the low-moderate range (Kappa = 0.38, p < .001, 95% CI [.18 -.54]). As predicted, lower accuracy and longer time to complete the BEAM were both associated with worse executive functions, attention, and processing speed. CONCLUSIONS: Medication and finance management can be efficiently assessed within five minutes. The BEAM may be a valuable screening tool to evaluate these functional abilities. PMID- 26482694 TI - Effects of a One-Year Physical Activity Program on Serum C-Terminal Agrin Fragment (CAF) Concentrations among Mobility-Limited Older Adults. AB - OBJECTIVES: C-terminal Agrin Fragment (CAF) has been proposed as a potential circulating biomarker for predicting changes in physical function among older adults. To determine the effect of a one-year PA intervention on changes in CAF concentrations and to evaluate baseline and longitudinal associations between CAF concentrations and indices of physical function. DESIGN: Ancillary study to the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P), a multi-site randomized clinical trial designed to evaluate the effects of chronic exercise on the physical function of older adults at risk for mobility disability. SETTING: Four academic research centers within the U.S. PARTICIPANTS: Three hundred thirty three older adults aged 70 to 89 with mild to moderate impairments in physical function. INTERVENTION: A 12-month intervention of either structured physical activity (PA) or health education promoting successful aging (SA). MEASUREMENTS: Serum CAF concentrations and objectives measures of physical function - i.e. gait speed and performance on the Short Physical Performance Battery (SPPB). RESULTS: The group*time interaction was not significant for serum CAF concentrations (p=0.265), indicating that the PA intervention did not significantly reduce serum CAF levels compared to SA. Baseline gait speed was significantly correlated with baseline CAF level (r = -0.151, p= 0.006), however the association between CAF and SPPB was not significant. Additionally, neither baseline nor the change in CAF concentrations strongly predicted the change in either performance measure following the PA intervention. CONCLUSION: In summary, the present study shows that a one-year structured PA program did not reduce serum CAF levels among mobility-limited older adults. However, further study is needed to definitively determine the utility of CAF as a biomarker of physical function. PMID- 26482696 TI - The Relationship between Anemia, Hemoglobin Concentration and Frailty in Brazilian Older Adults. AB - OBJECTIVE: to explore the relationship between anemia, hemoglobin concentration and frailty syndrome in older adults. RESEARCH METHODS AND PROCEDURES: This was a cross-sectional population-based study, with adults >=60 years (n=1,256) from the third wave of the SABE Cohort Study (Health, Well-being and Aging) conducted in 2010 in Sao Paulo, Brazil. Frailty syndrome was evaluated according to Fried's phenotype. Anemia was defined using the WHO criteria (hemoglobin concentration <12 g/dL for women and <13 g/dL for men). Four approaches were used to verify the associations between anemia, hemoglobin concentration and frailty status or number of frailty criteria. We used logistic regression and Poisson regression in the analyses, and they were adjusted in three hierarchical models using three blocks of variables: basic characteristics; clinical characteristics; cognitive status. RESULTS: Mean hemoglobin concentration was significantly lower in frail elderly (13.3g/dL, versus 14.3g/dL in non-frail; p<0.001). Prevalence of anemia was also significantly higher in frail when compared to non-frail elderly (24.2% and 3.8%; p<0.001). Anemia was significantly associated to low physical activity, weakness and slowness. In the fully adjusted regression models, anemia was strongly associated to frailty (OR=3.27, 95%IC=1.89,5.65; p<0.001), and lower levels of hemoglobin were associated to higher number of frailty criteria. CONCLUSIONS: We found important associations between anemia, hemoglobin concentration and frailty; anemic older adults were more likely to be frail, and lower levels of hemoglobin were associated to higher number of frailty criteria showing a clear dose-response effect. PMID- 26482697 TI - A Review of Frailty in Developing Countries. AB - BACKGROUND: As the population ages, the prevalence and clinical importance of frailty are increasing. There have been few published studies about frailty in developing world. This study aims to review the evidence from developing countries on the prevalence of frailty, definition of frailty and factors associated with frailty. METHOD: A literature search was conducted via MEDLINE and EMBASE. Keywords included "frail", "frailty", "prevalence", "criteria", "definition", "risk factors", "outcomes", "developing country", "developing world", and names of low and middle income countries according to the classification of the World Bank. RESULT: A total of 14 articles were reviewed from Brazil (n=6), China (n=3), Mexico (n=2), and one each from Russia, India, and Peru. There were 9 articles from community-based studies and 5 articles from hospital-based studies. Fried's phenotype for frailty was used to define frailty in the majority of studies. The prevalence of frailty in community-dwelling older people was 17%-31% in Brazil, 15% in Mexico, 5%-31% in China, and 21%-44% in Russia. The prevalence of frailty was 49% in institutionalized older patients in Brazil and 32% in hospitalized older patients in India. The prevalence of frailty in outpatient clinics was 55%-71% in Brazil and 28% in Peru. Frailty was associated with increased mortality and comorbidities, decreased physical and cognitive function, and poor perceptions of health. CONCLUSION: The limited studies available suggest that frailty occurs frequently in older people in the developing world and it appears to be associated with adverse outcomes. This has implications for policy and health care provision for these ageing populations. PMID- 26482698 TI - Nutritional Care Needs in Elderly Residents of Long-Term Care Institutions: Potential Implications for Policies. AB - OBJECTIVES: To collect information on actual nutritional intervention requirements in long-term care institutions and on the role of institutional factors in nutritional care. DESIGN: A cross-sectional analysis of baseline data (collected between September 2011 and September 2013) within the context of a multicenter prospective cohort study. SETTING: Nineteen long-term care institutions. PARTICIPANTS: Thirteen hundred and ninety-four resident elderly (age >=60 years). MEASUREMENTS: The prevalence of nutritional derangements (MNA Short Form) and the need to introduce nutritional interventions on the residents. RESULTS: Prevalence of malnutrition and risk of malnutrition were 35.2% [95%CI, 32.8-37.8] and 52.6% [95%CI, 50.0-55.2], respectively. Malnutrition was more frequent upon admission and in larger institutions (>=50 beds). Overall, 50% of the residents requiring an individualized nutritional care plan (any type) were not receiving it. Oral diet, the use of fluid thickeners and oral nutritional supplements had to be introduced in 306 (22.5%), 201 (15%) and 175 (13%) residents, respectively. The need to implement the oral diet was mainly due to inadequacy of texture according to chewing and swallowing capabilities. In gender and age-adjusted multivariable logistic regression models, nutritional interventions were associated with worse nutritional status (P<0.001 for all). Moreover, while the duration of stay was unrelated to the need for nutritional interventions, we observed that residents living in larger long-term care institutions (>=50 beds) were more likely to require improvement in nutrition care. CONCLUSIONS: In long-term care elderly residents nutritional derangements are very common, underdiagnosed and undertreated. Nutritional screening should be part of routine care. However, also the systematic involvement of a nutritional care specialist appears to be an urgent need, particularly in larger institutions where the standards of care are likely to be lower. PMID- 26482700 TI - Novel Method for Calculating a Nonsubjective Informative Prior for a Bayesian Model in Toxicology Screening: A Theoretical Framework. AB - In toxicology screening (forensic, food-safety), due to several analytical errors (e.g., retention time shift, lack of repeatability in m/z scans, etc.), the ability to confidently identify/confirm a compound remains a challenge. Due to these uncertainties, a probabilistic approach is currently preferred. However, if a probabilistic approach is followed, the only statistical method that is capable of estimating the probability of whether the compound of interest (COI) is present/absent in a given sample is Bayesian statistics. Bayes' theorem can combine prior information (prior probability) with data (likelihood) to give an optimal probability (posterior probability) reflecting the presence/absence of the COI. In this work, a novel method for calculating an informative prior probability for a Bayesian model in targeted toxicology screening is introduced. In contrast to earlier proposals making use of literature citation rates and the prior knowledge of the analyst, this method presents a thorough and nonsubjective approach. The formulation approaches the probability calculation as a clustering and random draw problem that incorporates few analytical method parameters meticulously estimated to reflect sensitivity and specificity of the system. The practicality of the method has been demonstrated and validated using real data and simulated analytical techniques. PMID- 26482701 TI - Changes in dental fear among Finnish adults: a national survey. AB - OBJECTIVES: The aim of this study was to evaluate changes in dental fear among adult Finns aged 19 years and over at the beginning of the study in 2000-2011 in a nationally representative sample. METHODS: The study was based on Health 2000 and 2011 Surveys by the National Institute for Health and Welfare in Finland. The Health 2000 Survey used a stratified two-stage cluster sampling design (N = 9 922). Those who participated in 2000 (n = 7 964) were invited to participate in 2011. The number of participants was 3 961. Dental fear was assessed by a single question: 'How afraid are you of visiting a dentist?' (not at all, somewhat, very much). Background variables included were age (categories 30-34, 35-39, 40-44, 45 54, 55-64, 65-74, 75+ years), gender, marital status (nonsingle, single), and education (basic, secondary, higher). To match the population sizes in different areas and thus forming a nationally representative data, the data were weighted based on age, gender, and area. General linear modeling for repeated measures was used to evaluate changes in dental fear and associations with background variables. RESULTS: Between 2000 and 2011, dental fear decreased more often than increased among adults in Finland. Change from being very afraid to not at all afraid of visiting a dentist was most common in the oldest group. For most participants, dental fear remained stable; being very afraid of visiting a dentist was more stable among participants from 35 to 54 years of age than among younger or older participants. CONCLUSIONS: Dental fear is still common among adult Finns and it seems to depend on age. As the most obvious consequence of dental fear is avoidance of dental care, reducing dental fear should be taken into account when planning and reorienting oral healthcare services. PMID- 26482699 TI - Operational Definition of Active and Healthy Ageing (AHA): A Conceptual Framework. AB - Health is a multi-dimensional concept, capturing how people feel and function. The broad concept of Active and Healthy Ageing was proposed by the World Health Organisation (WHO) as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal Active and Healthy Ageing definition is not available and it may differ depending on the purpose of the definition and/or the questions raised. While the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact, a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier, France, October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (Contre les Maladies Chroniques pour un Vieillissement Actif en Languedoc Roussillon) to propose an operational definition of Active and Healthy Ageing including tools that may be used for this. The current paper describes the rationale and the process by which the aims of the meeting will be reached. PMID- 26482702 TI - Can genetically based clines in plant defence explain greater herbivory at higher latitudes? AB - Greater plant defence is predicted to evolve at lower latitudes in response to increased herbivore pressure. However, recent studies question the generality of this pattern. In this study, we tested for genetically based latitudinal clines in resistance to herbivores and underlying defence traits of Oenothera biennis. We grew plants from 137 populations from across the entire native range of O. biennis. Populations from lower latitudes showed greater resistance to multiple specialist and generalist herbivores. These patterns were associated with an increase in total phenolics at lower latitudes. A significant proportion of the phenolics were driven by the concentrations of two major ellagitannins, which exhibited opposing latitudinal clines. Our analyses suggest that these findings are unlikely to be explained by local adaptation of herbivore populations or genetic variation in phenology. Rather greater herbivory at high latitudes can be explained by latitudinal clines in the evolution of plant defences. PMID- 26482703 TI - Effects of graphene oxide nanosheets on the ultrastructure and biophysical properties of the pulmonary surfactant film. AB - Graphene oxide (GO) is the most common derivative of graphene and has been used in a large range of biomedical applications. Despite considerable progress in understanding its cytotoxicity, its potential inhalation toxicity is still largely unknown. As the pulmonary surfactant (PS) film is the first line of host defense, interaction with the PS film determines the fate of the inhaled nanomaterials and their potential toxicity. Using a coarse-grained molecular dynamics model, we reported, for the first time, a novel mechanism of toxicity caused by the inhaled GO nanosheets. Upon deposition, the GO nanosheets induce pores in the PS film and thus have adverse effects on the ultrastructure and biophysical properties of the PS film. Notably, the pores induced by GO nanosheets result in increasing the compressibility of the PS film, which is an important indication of surfactant inhibition. In vitro experiments have also been conducted to study the interactions between GO and animal-derived natural PS films, qualitatively confirming the simulation results. PMID- 26482704 TI - Structural isomerism in gold nanoparticles revealed by X-ray crystallography. [Corrected]. AB - Revealing structural isomerism in nanoparticles using single-crystal X-ray crystallography remains a largely unresolved task, although it has been theoretically predicted with some experimental clues. Here we report a pair of structural isomers, Au38T and Au38Q, as evidenced using electrospray ionization mass spectrometry, X-ray photoelectron spectroscopy, thermogravimetric analysis and indisputable single-crystal X-ray crystallography. The two isomers show different optical and catalytic properties, and differences in stability. In addition, the less stable Au38T can be irreversibly transformed to the more stable Au38Q at 50 degrees C in toluene. This work may represent an important advance in revealing structural isomerism at the nanoscale. PMID- 26482705 TI - Omega-3 fatty acids are able to modulate the painful symptoms associated to cyclophosphamide-induced-hemorrhagic cystitis in mice. AB - This study investigated the effects of the long-term dietary fish oil supplementation or the acute administration of the omega-3 fatty acid docosahexaenoic acid (DHA) in the mouse hemorrhagic cystitis (HC) induced by the anticancer drug cyclophosphamide (CYP). HC was induced in mice by a single CYP injection (300mg/kg ip). Animals received four different diets containing 10% and 20% of corn or fish oil, during 21days. Separated groups received DHA by ip (1MUmol/kg) or intrathecal (i.t.; 10MUg/site) routes, 1h or 15min before CYP. The behavioral tests (spontaneous nociception and mechanical allodynia) were carried out from 1h to 6h following CYP injection. Bladder inflammatory changes, blood cell counts and serum cytokines were evaluated after euthanasia (at 6h). Immunohistochemistry analysis was performed for assessing spinal astrocyte and microglia activation or GPR40/FFAR1 expression. Either fish oil supplementation or DHA treatment (ip and i.t.) markedly prevented visceral pain, without affecting CYP-evoked bladder inflammatory changes. Moreover, systemic DHA significantly prevented the neutrophilia/lymphopenia caused by CYP, whereas this fatty acid did not significantly affect serum cytokines. DHA also modulated the spinal astrocyte activation and the GPR40/FFAR1 expression. The supplementation with fish oil enriched in omega-3 fatty acids or parenteral DHA might be interesting nutritional approaches for cancer patients under chemotherapy schemes with CYP. PMID- 26482706 TI - Depletion of the "gamma-type carbonic anhydrase-like" subunits of complex I affects central mitochondrial metabolism in Arabidopsis thaliana. AB - "Gamma-type carbonic anhydrase-like" (CAL) proteins form part of complex I in plants. Together with "gamma carbonic anhydrase" (CA) proteins they form an extra domain which is attached to the membrane arm of complex I on its matrix exposed side. In Arabidopsis two CAL and three CA proteins are present, termed CAL1, CAL2, CA1, CA2 and CA3. It has been proposed that the carbonic anhydrase domain of complex I is involved in a process mediating efficient recycling of mitochondrial CO2 for photosynthetic carbon fixation which is especially important during growth conditions causing increased photorespiration. Depletion of CAL proteins has been shown to significantly affect plant development and photomorphogenesis. To better understand CAL function in plants we here investigated effects of CAL depletion on the mitochondrial compartment. In mutant lines and cell cultures complex I amount was reduced by 90-95% but levels of complexes III and V were unchanged. At the same time, some of the CA transcripts were less abundant. Proteome analysis of CAL depleted cells revealed significant reduction of complex I subunits as well as proteins associated with photorespiration, but increased amounts of proteins participating in amino acid catabolism and stress response reactions. Developmental delay of the mutants was slightly alleviated if plants were cultivated at high CO2. Profiling of selected metabolites revealed defined changes in intermediates of the citric acid cycle and amino acid catabolism. It is concluded that CAL proteins are essential for complex I assembly and that CAL depletion specifically affects central mitochondrial metabolism. PMID- 26482707 TI - The effect of a C298D mutation in CaHydA [FeFe]-hydrogenase: Insights into the protein-metal cluster interaction by EPR and FTIR spectroscopic investigation. AB - A conserved cysteine located in the signature motif of the catalytic center (H cluster) of [FeFe]-hydrogenases functions in proton transfer. This residue corresponds to C298 in Clostridium acetobutylicum CaHydA. Despite the chemical and structural difference, the mutant C298D retains fast catalytic activity, while replacement with any other amino acid causes significant activity loss. Given the proximity of C298 to the H-cluster, the effect of the C298D mutation on the catalytic center was studied by continuous wave (CW) and pulse electron paramagnetic resonance (EPR) and by Fourier transform infrared (FTIR) spectroscopies. Comparison of the C298D mutant with the wild type CaHydA by CW and pulse EPR showed that the electronic structure of the center is not altered. FTIR spectroscopy confirmed that absorption peak values observed in the mutant are virtually identical to those observed in the wild type, indicating that the H cluster is not generally affected by the mutation. Significant differences were observed only in the inhibited state Hox-CO: the vibrational modes assigned to the COexo and Fed-CO in this state are shifted to lower values in C298D, suggesting different interaction of these ligands with the protein moiety when C298 is changed to D298. More relevant to the catalytic cycle, the redox equilibrium between the Hox and Hred states is modified by the mutation, causing a prevalence of the oxidized state. This work highlights how the interactions between the protein environment and the H-cluster, a dynamic closely interconnected system, can be engineered and studied in the perspective of designing bio-inspired catalysts and mimics. PMID- 26482709 TI - Genome-Wide Screen Reveals Rhythmic Regulation of Genes Involved in Odor Processing in the Olfactory Epithelium. AB - Odor discrimination behavior displays circadian fluctuations in mice, indicating that mammalian olfactory function is under control of the circadian system. This is further supported by the facts that odor discrimination rhythms depend on the presence of clock genes and that olfactory tissues contain autonomous circadian clocks. However, the molecular link between circadian function and olfactory processing is still unknown. To elucidate the molecular mechanisms underlying this link, we focused on the olfactory epithelium (OE), the primary target of odors and the site of the initial events in olfactory processing. We asked whether olfactory sensory neurons (OSNs) within the OE possess an autonomous circadian clock and whether olfactory pathways are under circadian control. Employing clock gene-driven bioluminescence reporter assays and time-dependent immunohistochemistry on OE samples, we found robust circadian rhythms of core clock genes and their proteins in OSNs, suggesting that the OE indeed contains an autonomous circadian clock. Furthermore, we performed a circadian transcriptome analysis and identified several OSN-specific components that are under circadian control, including those with putative roles in circadian olfactory processing, such as KIRREL2-an established factor involved in short-term OSN activation. The spatiotemporal expression patterns of our candidate proteins suggest that they are involved in short-term anabolic processes to rhythmically prepare the cell for peak performances and to promote circadian function of OSNs. PMID- 26482708 TI - Specific degradation of phosphatidylglycerol is necessary for proper mitochondrial morphology and function. AB - In yeast, phosphatidylglycerol (PG) is a minor phospholipid under standard conditions; it can be utilized for cardiolipin (CL) biosynthesis by CL synthase, Crd1p, or alternatively degraded by the phospholipase Pgc1p. The Saccharomyces cerevisiae deletion mutants crd1Delta and pgc1Delta both accumulate PG. Based on analyses of the phospholipid content of pgc1Delta and crd1Delta yeast, we revealed that in yeast mitochondria, two separate pools of PG are present, which differ in their fatty acid composition and accessibility for Pgc1p-catalyzed degradation. In contrast to CL-deficient crd1Delta yeast, the pgc1Delta mutant contains normal levels of CL. This makes the pgc1Delta strain a suitable model to study the effect of accumulation of PG per se. Using fluorescence microscopy, we show that accumulation of PG with normal levels of CL resulted in increased fragmentation of mitochondria, while in the absence of CL, accumulation of PG led to the formation of large mitochondrial sheets. We also show that pgc1Delta mitochondria exhibited increased respiration rates due to increased activity of cytochrome c oxidase. Taken together, our results indicate that not only a lack of anionic phospholipids, but also excess PG, or unbalanced ratios of anionic phospholipids in mitochondrial membranes, have harmful consequences on mitochondrial morphology and function. PMID- 26482711 TI - In vivo imaging of porcine gastric enteric nervous system using confocal laser endomicroscopy &molecular neuronal probe. AB - BACKGROUND AND AIM: The gastric enteric nervous system (GENS) is organized into the submucosal plexus and the myenteric plexus that regulate muscle activity and mucosal functions, respectively. A non-invasive, in vivo visualization of GENS was not possible until recent introduction of needle-based confocal laser endomicroscopy (nCLE). Our aim was to determine the feasibility of in vivo visualization of GENS in the porcine stomach using endoscopic ultrasound (EUS) guided nCLE and local injection of molecular neuronal probe NeuroTrace. METHODS: In anesthetized pigs during endoscopy, NeuroTrace was injected into the submucosa and muscularis propria of distal, and proximal stomach under EUS guidance and nCLE imaging was performed using the Cellvizio AQ Flex probe. After euthanasia, transmural gastric specimens from the areas of NeuroTrace injection were obtained for histology. We performed quantitative analysis of nCLE images recorded during in vivo studies: histologic evaluation of unstained specimens under fluorescence microscope for NeuroTrace localization. We also performed immunostaining of these specimens for nerve growth factor (NGF). In in vitro studies, we examined the uptake of NeuroTrace by glial cells. RESULTS: The nCLE imaging successfully visualized neuronal cells and nerve fibers in distinctive image patterns. Fluorescence microscopy of mucosal sections showed that in vivo-injected NeuroTrace was retained in GENS components. NGF was strongly expressed in neural and glial cells, and the pattern of NGF staining was similar to that of NeuroTrace staining. CONCLUSIONS: This study demonstrates for the first time that combined use of EUS-guided nCLE and NeuroTrace is capable to visualize GENS. PMID- 26482712 TI - OnabotulinumtoxinA in the treatment of overactive bladder: a cost-effectiveness analysis versus best supportive care in England and Wales. AB - The cost-effectiveness of onabotulinumtoxinA (BOTOX((r))) 100 U + best supportive care (BSC) was compared with BSC alone in the management of idiopathic overactive bladder in adult patients who are not adequately managed with anticholinergics. BSC included incontinence pads and, for a proportion of patients, anticholinergics and/or occasional clean intermittent catheterisation. A five state Markov model was used to estimate total costs and outcomes over a 10-year period. The cohort was based on data from two placebo-controlled trials and a long-term extension study of onabotulinumtoxinA. After discontinuation of initial treatment, a proportion of patients progressed to downstream sacral nerve stimulation (SNS). Cost and resource use was estimated from a National Health Service perspective in England and Wales using relevant reference sources for 2012 or 2013. Results showed that onabotulinumtoxinA was associated with lower costs and greater health benefits than BSC in the base case, with probabilistic sensitivity analysis indicating an 89 % probability that the incremental cost effectiveness ratio would fall below L20,000. OnabotulinumtoxinA remained dominant over BSC in all but two scenarios tested; it was also economically dominant when compared directly with SNS therapy. In conclusion, onabotulinumtoxinA appears to be a cost-effective treatment for overactive bladder compared with BSC alone. PMID- 26482713 TI - Toward an Enhanced Sampling Molecular Dynamics Method for Studying Ligand-Induced Conformational Changes in Proteins. AB - Current enhanced sampling molecular dynamics methods for studying large conformational changes in proteins suffer from certain limitations. These include, among others, the need for user defined collective variables, the prerequisite of both start and end point structures of the conformational change, and the need for a priori knowledge of the amount by which to boost specific parts of the potential. In this paper, a framework is proposed for a molecular dynamics method for studying ligand-induced conformational changes, in which the nonbonded interactions between the ligand and the protein are used to calculate a biasing force. The method requires only a single input structure, and does not entail the use of collective variables. We provide a proof-of-concept for accelerating conformational changes in three simple test molecules, as well as promising results for two proteins known to undergo domain closure upon ligand binding. For the ribose-binding protein, backbone root-mean-square deviations as low as 0.75 A compared to the crystal structure of the closed conformation are obtained within 50 ns simulations, whereas no domain closures are observed in unbiased simulations. A skewed closed structure is obtained for the glutamine binding protein at high bias values, indicating that specific protein-ligand interactions might suppress important protein-protein interactions. PMID- 26482714 TI - Rare Earth Ion Mediated Fluorescence Accumulation on a Single Microbead: An Ultrasensitive Strategy for the Detection of Protein Kinase Activity at the Single-Cell Level. AB - A single microbead-based fluorescence imaging (SBFI) strategy that enables detection of protein kinase activity from single cell lysates is reported. We systematically investigated the ability of various rare earth (RE) ions, immobilized on the microbead, for specific capturing of kinase-induced phosphopeptides, and Dy(3+) was found to be the most prominent one. Through the efficient concentration of kinase-induced fluorescent phosphopeptides on a Dy(3+) -functionalized single microbead, kinase activity can be detected and quantified by reading the fluorescence on the microbead with a confocal fluorescence microscope. Owing to the extremely specific recognition of Dy(3+) towards phosphopeptides and the highly-concentrated fluorescence accumulation on only one microbead, ultrahigh sensitivity has been achieved for the SBFI strategy which allows direct kinase analysis at the single-cell level. PMID- 26482715 TI - Surgical Treatments for Infantile Purulent Meningitis Complicated by Subdural Effusion. AB - BACKGROUND: Infantile purulent meningitis (PM) is a commonly severe intracranial infectious disease in infants under age 1 year. In recent years, several diagnostic and treatment methods were reported, but in these cases the neurological complications and sequel were often observed, among which subdural effusion (SE) is the most common complication in PM. Timely diagnosis and early intervention are vital for better outcomes. In this study, the surgical treatments for infantile PM complicated by SE were investigated. MATERIAL AND METHODS: Patients who had PM complicated by SE in the Children's Hospital of Hebei Province from June 2000 to June 2012 were retrospectively analyzed and 170 patients were enrolled in the study. Surgical treatment for each patient was adopted according to producing effusion time, leucocyte count, protein content, intracranial pressure, and bacteria culture, coupled with cranial ultrasound examination, CT, and MRI scans. RESULTS: Nearly, 15 patients were cured using serial taps, with a 50% cure rate. Seventeen out of 30 (56.6%) patients receiving subcutaneous reservoir drainage had better outcome. Nearly 80% of patients (55/69) who underwent minimally invasive trepanation and drainage were positive. Surgical procedure of minimally invasive trepanation and drainage combined with drug douche was effective in 63% of patients (19/30). In addition, 6 patients were cured with subdural-peritoneal shunt. Only 1 patient died, after the recurrence of meningitis, and the remaining 4 patients were cured by craniotomy. CONCLUSIONS: For infantile PM complicated with SE, treatment needs be chosen according to the specific situation. Surgical procedure of minimally invasive trepanation and drainage is a very effective treatment in curing PM complicated by SE. The treatment was highly effective with the use of drug douche. Subdural peritoneal shunt and craniotomy were as effective as in refractory cases. PMID- 26482716 TI - Low-dose capecitabine plus trastuzumab as first-line treatment in patients 75 years of age or older with HER2-positive advanced gastric cancer: a pilot study. AB - BACKGROUND: Single-agent chemotherapy is considered a good and safe treatment option for elderly patients with advanced gastric cancer (AGC). We investigated the efficacy and safety of trastuzumab plus low-dose capecitabine in elderly patients with previously untreated human epidermal growth factor receptor 2 (HER2)-positive AGC. METHODS: Patients aged 75 years or older with tumors having HER2 overexpression defined as either immunohistochemistry (IHC) 3+ or IHC 2+ and in situ hybridization-positive were eligible for inclusion. Patients received capecitabine (1000 mg/m(2)) orally twice daily on days 1-14 and trastuzumab (8 mg/kg for cycle 1, followed by 6 mg/kg) intravenously on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). RESULTS: Twenty patients were enrolled. The median age was 79 years (range 75-91). Nine patients (45 %) had ECOG performance status 2. Median PFS was 5.2 months (95 % CI 1.9-8.4 months), and median overall survival was 9.3 months (95 % CI 4.0-14.6 months). The confirmed response rate was 40 % (95 % CI 19-64 %) with disease control rate of 80 %. Grade 3-4 toxicities were anorexia (10 %), fatigue (5 %), stomatitis (5 %), and anemia (5 %). No treatment-related deaths or symptomatic congestive heart failure were observed. CONCLUSIONS: Low-dose capecitabine plus trastuzumab is effective and well tolerated in elderly patients with HER2-positive AGC. PMID- 26482718 TI - Gender difference in lipid profile in bipolar disorder: Indian scenario. PMID- 26482717 TI - Comparing the harmful effects of nontuberculous mycobacteria and Gram negative bacteria on lung function in patients with cystic fibrosis. AB - BACKGROUND: To better understand the relative effects of infection with nontuberculous mycobacteria and Gram negative bacteria on lung function decline in cystic fibrosis, we assessed the impact of each infection in a Danish setting. METHODS: Longitudinal registry study of 432 patients with cystic fibrosis contributing 53,771 lung function measures between 1974 and 2014. We used a mixed effects model with longitudinally structured correlation, while adjusting for clinically important covariates. RESULTS: Infections with a significant impact on rate of decline in %FEV1 were Mycobacterium abscessus complex with -2.22% points per year (95% CI -3.21 to -1.23), Burkholderia cepacia complex -1.95% (95% CI 2.51 to -1.39), Achromobacterxylosoxidans -1.55% (95% CI -2.21 to -0.90), and Pseudomonas aeruginosa -0.95% (95% CI -1.24 to -0.66). Clearing M. abscessus complex was associated with a change to a slower decline, similar in magnitude to the pre-infection slope. CONCLUSIONS: In a national population we have demonstrated the impact on lung function of each chronic CF pathogen. M. abscessus complex was associated with the worst impact on lung function. Eradication of M. abscessus complex may significantly improve lung function. PMID- 26482719 TI - Frontotemporal dementia mimicking bipolar affective disorder, normal pressure hydrocephalus and Kluver-Bucy syndrome. PMID- 26482720 TI - Non-suicidal self-injury and other self-directed violent behaviors in India: A review of definitions and research. AB - The interpersonal theory of suicide suggests that most forms of self-directed violent behaviors lie on a continuum, with each behavior successively increasing the capability of committing suicide. There is increasing evidence to suggest that the continuum may begin with Non-Suicidal Self-Injury (NSSI). This theory can be important in developing interventions for suicide prevention. However, in India, consistent usage of definitions of various forms of self-directed violent behaviors is lacking. In the present study, we reviewed definitions of various forms of self-directed violent behaviors that have been investigated in India. Further, we compared the usage of these definitions with the usage by WHO. Additionally, we reviewed NSSI research in India. Thirty-eight publications were identified by a comprehensive electronic search undertaken in Indian psychiatry, psychology, and mental health-related databases. Inconsistent definitions of eight self-directed violent behaviors were observed in Indian literature. Agreement on consistent definitions of various forms of self-directed behaviors is essential. Based on the findings of the current review, it can be suggested that culturally relevant large-scale research on NSSI in India is required to confirm the limited evidence that suggests high prevalence of NSSI in India. PMID- 26482721 TI - Increasing herd immunity with influenza revaccination. AB - Seasonal influenza is a significant public health concern globally. While influenza vaccines are the single most effective intervention to reduce influenza morbidity and mortality, there is considerable debate surrounding the merits and consequences of repeated seasonal vaccination. Here, we describe a two-season influenza epidemic contact network model and use it to demonstrate that increasing the level of continuity in vaccination across seasons reduces the burden on public health. We show that revaccination reduces the influenza attack rate not only because it reduces the overall number of susceptible individuals, but also because it better protects highly connected individuals, who would otherwise make a disproportionately large contribution to influenza transmission. We also demonstrate that our results hold on an empirical contact network, in the presence of assortativity in vaccination status, and are robust for a range of vaccine coverage and efficacy levels. Our work contributes a population-level perspective to debates about the merits of repeated influenza vaccination and advocates for public health policy to incorporate individual vaccine histories. PMID- 26482722 TI - Stereotactic body radiation therapy (SBRT) delays the emergence of castration resistance in patients with oligometastatic prostate cancer. AB - PURPOSE: To investigate whether bon e metastases-directed stereotactic body radiation therapy (SBRT) delays the emergence of castration resistance in patients with oligometastatic prostate cancer (OPC). METHODS AND MATERIAL: OPC is usually managed with androgen deprivation therapy (ADT). Migration to castration resistant prostate cancer will inevitably occur in the majority of these patients. There are several strategies aimed to delay the emergence of castration resistance including intermittent ADT, second generation antiandrogens (abiraterone, enzalutamide) or metastases-directed SBRT. The present report describes two cases of patients with OPC that received SBRT 24 Gy/3Rx to the solitary bony lesion after ADT failure. RESULTS: Both cases showed complete and durable biochemical response for 13 and 17 months, respectively. CONCLUSIONS: SBRT can be used to delay the emergence of castration resistance and the need for systemic therapy when used after ADT failure. PMID- 26482723 TI - S-l combined with cisplatin plus concurrent chemoradiotherapy versus cisplatin plus concurrent chemoradiotherapy for Chinese patients with advanced gastric cancer: a multi-centre randomized controlled trial. AB - BACKGROUND: This study aimed to investigate the safety and efficacy of S-l combined with cisplatin plus concurrent chemoradiotherapy (SCCC) versus cisplatin plus concurrent chemoradiotherapy (CCC) for Chinese patients with advanced gastric cancer (AGC). METHODS: Between April 2008 and June 2010, 144 eligible patients with AGC were included and divided randomly into 2 groups. Seventy-two patients in the SCCC group received with S-1 on days 1-14 of a 21-day cycle, 24-h cisplatin infusion (70 mg/m(2) on day 1) every 4 weeks for 2 cycles, and concurrent chemoradiotherapy (30-Gy radiotherapy over 4 weeks) beginning on day 1. The other 72 patients in the CCC group were administered cisplatin and concurrent chemoradiotherapy as for SCCC. The primary outcome was overall survival. Secondary outcomes were progression-free survival and adverse events. RESULTS: The median overall survival durations were 11.7 months (range 1.7-29.7 months) and 9.5 months (range 1.2-25.4 months) in SCCC and CCC groups, respectively (P = 0.041). The median progression-free survival durations were 10.6 months for SCCC (range 1.3-24.7 months) and 8.8 months (range 0.7-22.3 months) for CCC (P = 0.046). The toxicity profile was similar in both groups. CONCLUSION: In summary, SCCC showed more promising safety and efficacy than CCC in Chinese patients with AGC. In addition, the toxicities were also acceptable in both groups. PMID- 26482724 TI - Molecular biology of testicular germ cell tumors. AB - Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men. They constitute a unique pathology because of their embryonic and germ origin and their special behavior. Genetic predisposition, environmental factors involved in their development and genetic aberrations have been under study in many works throughout the last years trying to explain the susceptibility and the transformation mechanism of TGCTs. Despite the high rate of cure in this type of tumors because its particular sensitivity to cisplatin, there are tumors resistant to chemotherapy for which it is needed to find new therapies. In the present work, it has been carried out a literature review on the most important molecular aspects involved in the onset and development of such tumors, as well as a review of the major developments regarding prognostic factors, new prognostic biomarkers and the possibility of new targeted therapies. PMID- 26482725 TI - Use of tramadol in early pregnancy and congenital malformation risk. AB - Only few studies exist regarding the risk of a teratogenic effect of tramadol when used in early pregnancy. Using the Swedish Medical Birth Register, women (deliveries in 1997-2013) who had reported the use of tramadol in early pregnancy were identified. Maternal characteristics and concomitant drug use were analyzed. Among 1,682,846 women (1,797,678 infants), 1751 (1776 infants) had used tramadol, 96 of the infants had a congenital malformation and 70 of them were relatively severe. The adjusted odds ratio for a relatively severe malformation was 1.33 (95% CI 1.05-1.70). The odds ratios for cardiovascular defects (1.56, 95% CI 1.04 2.29) and for pes equinovarus (3.63, 95% CI 1.61-6.89) were significantly increased. The study suggests a teratogenic effect of tramadol but the risk increase is moderate. PMID- 26482726 TI - Assessment of ixekizumab, an interleukin-17A monoclonal antibody, for potential effects on reproduction and development, including immune system function, in cynomolgus monkeys. AB - The reproductive and developmental toxicity of ixekizumab, a selective inhibitor of interleukin-17A (IL-17A), was assessed in the following studies in cynomolgus monkeys: fertility (3-month dosing), embryo-fetal development (EFD; dosing from gestation day (GD) 20 through 139), and pre-postnatal development (PPND; dosing from GD 20 through parturition). Because IL-17A has functional roles in innate and humoral immunity, immune system modulation was evaluated in the EFD and PPND studies; immunological evaluations in infants comprised peripheral blood immunophenotyping, Natural Killer cell cytolytic activity, and T-cell-dependent antibody (IgG and IgM) primary and secondary responses to antigen challenge. Ixekizumab exposure was sustained during the dosing periods in most adult monkeys. Fetal exposure at Cesarean section (GD 140-142; EFD study) was 18-25% of maternal exposure and ixekizumab was present in infants for up to 29 weeks postpartum. There were no adverse effects attributed to ixekizumab in any study. Importantly, immune system development and maturation were unaffected. PMID- 26482729 TI - Referral patterns, treatment and outcome of high-grade malignant bone sarcoma in Scandinavia--SSG Central Register 25 years' experience. AB - AIMS: The objectives of this study were to present changes in referral patterns, treatment and survival in patients with high-grade malignant bone sarcoma in Sweden and Norway based on data in the Scandinavian Sarcoma Group (SSG) Central Register. METHOD: Data on 1,437 patients with diagnosis 1986-2010 was analyzed. RESULTS: Osteosarcoma was the most frequentl diagnosis (45%), followed by Ewing sarcoma (21%) and chondrosarcoma (17%). Thirty-one percent of Swedish and 41% of Norwegian patients had tumors in the axial skeleton. Eighty-six percent of extremity tumors and 66% of axial tumors were referred to a sarcoma center prior to unplanned surgery or biopsy. During the past decade, limb salvage surgery has risen from under 50% to over 80%. Five-year overall survival in non-metastatic osteosarcoma was 70% for extremity tumors, and 35% for axial tumors. No improvement in osteosarcoma survival was observed during the last decade. Five year survival in Ewing sarcoma improved from 50% to 69%. CONCLUSION: Referral patterns in bone sarcomas have improved. However, greater efforts should be dedicated to improving referral of patients with possible tumors in the axial skeleton to multidisciplinary teams (MDTs). Overall survival of patients with high-grade malignant bone sarcomas in Sweden and Norway is in line with other reports. PMID- 26482727 TI - Cigarette smoke induces proteasomal-mediated degradation of DNA methyltransferases and methyl CpG-/CpG domain-binding proteins in embryonic orofacial cells. AB - Orofacial clefts, the most prevalent of developmental anomalies, occur with a frequency of 1 in 700 live births. Maternal cigarette smoking during pregnancy represents a risk factor for having a child with a cleft lip and/or cleft palate. Using primary cultures of first branchial arch-derived cells (1-BA cells), which contribute to the formation of the lip and palate, the present study addressed the hypothesis that components of cigarette smoke alter global DNA methylation, and/or expression of DNA methyltransferases (Dnmts) and various methyl CpG binding proteins. Primary cultures of 1-BA cells, exposed to 80MUg/mL cigarette smoke extract (CSE) for 24h, exhibited a >13% decline in global DNA methylation and triggered proteasomal-mediated degradation of Dnmts (DNMT-1 and -3a), methyl CpG binding protein 2 (MeCP2) and methyl-CpG binding domain protein 3 (MBD-3). Pretreatment of 1-BA cells with the proteasomal inhibitor MG-132 completely reversed such degradation. Collectively, these data allow the suggestion of a potential epigenetic mechanism underlying maternal cigarette smoke exposure induced orofacial clefting. PMID- 26482730 TI - Ovarian endometriosis during pregnancy: a series of 53 endometriomas. AB - OBJECTIVES: The sonographic features of endometriomas and their natural history during pregnancy remain poorly known. The objective of our study was to report our experience concerning the diagnosis, spontaneous progression and management of endometriomas during pregnancy. STUDY DESIGN: A retrospective observational study in 46 patients (53 cysts) presenting with an ovarian endometrioma diagnosed during ultrasound examination at the first trimester of pregnancy. Sonographic findings (according to the criteria of the International Ovarian Tumor Analysis (IOTA) group and how they changed for each cyst during pregnancy and postpartum were reviewed, together with cyst management. The median follow-up was 4 years [IQR: 3-6]. Median age at diagnosis was 31 years [IQR: 27-35]. RESULTS: Among the 53 cysts identified as "endometriomas" on the first-trimester ultrasound examination, 49 (92%) were described like "cyst fluid with ground-glass echogenicity". Fifty-two cysts (98%) had a maximum diameter<100mm, only one cyst (2%) presented papillary projection and 5 cysts (9%) were multiloculated. During the second-trimester ultrasound monitoring of these cysts, of the 33 cysts that we monitored, 8 (24%) increased in size, 11 (34%) decreased in size, 5 (15%) disappeared and 9 (27%) did not change. During the third-trimester ultrasound monitoring of these cysts, of the 13 cysts that we monitored, 5 (39%) increased in size, 5 (39%) decreased in size, 2 (15%) disappeared and 1 (7%) did not change. All children (48 newborns) were born alive at a median gestational age of 39 weeks [IQR=39-40]. Only 10 cysts (19%) required surgical treatment. In all cases, surgery consisted of cystectomy. Two cysts were operated on during pregnancy (between 14 and 17 weeks of gestation) because of symptoms of adnexal torsion, 3 during cesarean section, and 5 postpartum. Four of the 10 (40%) cysts operated on were histopathologically "endometriomas", and one of them was decidualized. Four cysts were mucinous cystadenomas, one was a serous cystadenoma and one cyst was a dermoid cyst. CONCLUSION: This study underscores the difficulty of diagnosing endometriomas during pregnancy and the absolute necessity of surgical removal when ultrasonographic findings are doubtful. PMID- 26482731 TI - Computation of ground reaction force using Zero Moment Point. AB - Motion analysis is a common clinical assessment and research tool that uses a camera system or motion sensors and force plates to collect kinematic and kinetic information of a subject performing an activity of interest. The use of force plates can be challenging and sometimes even impossible. Over the past decade, several computational methods have been developed that aim to preclude the use of force plates. Useful in particular for predictive simulations, where a new motion or change in control strategy inherently means different external contact loads. These methods, however, often depend on prior knowledge of common observed ground reaction force (GRF) patterns, are computationally expensive, or difficult to implement. In this study, we evaluated the use of the Zero Moment Point as a computationally inexpensive tool to obtain the GRFs for normal human gait. The method was applied on ten healthy subjects walking in a motion analysis laboratory and predicted GRFs are evaluated against the simultaneously measured force plate data. Apart from the antero-posterior forces, GRFs are well-predicted and errors fall within the error ranges from other published methods. Joint extension moments were underestimated at the ankle and hip but overestimated at the knee, attributable to the observed discrepancy in the predicted application points of the GRFs. The computationally inexpensive method evaluated in this study can reasonably well predict the GRFs for normal human gait without using prior knowledge of common gait kinetics. PMID- 26482732 TI - Molecular transport in collagenous tissues measured by gel electrophoresis. AB - Molecular transport in tissues is important for drug delivery, nutrient supply, waste removal, cell signaling, and detecting tissue degeneration. Therefore, the objective of this study was to investigate gel electrophoresis as a simple method to measure molecular transport in collagenous tissues. The electrophoretic mobility of charged molecules in tissue samples was measured from relative differences in the velocity of a cationic dye passing through an agarose gel in the absence and presence of a tissue section embedded within the gel. Differences in electrophoretic mobility were measured for the transport of a molecule through different tissues and tissue anisotropy, or the transport of different sized molecules through the same tissue. Tissue samples included tendon and fibrocartilage from the proximal (tensile) and distal (compressive) regions of the bovine flexor tendon, respectively, and bovine articular cartilage. The measured electrophoretic mobility was greatest in the compressive region of the tendon (fibrocartilage), followed by the tensile region of tendon, and lowest in articular cartilage, reflecting differences in the composition and organization of the tissues. The anisotropy of tendon was measured by greater electrophoretic mobility parallel compared with perpendicular to the predominate collagen fiber orientation. Electrophoretic mobility also decreased with increased molecular size, as expected. Therefore, the results of this study suggest that gel electrophoresis may be a useful method to measure differences in molecular transport within various tissues, including the effects of tissue type, tissue anisotropy, and molecular size. PMID- 26482733 TI - Fusion of clinical and stochastic finite element data for hip fracture risk prediction. AB - Hip fracture affects more than 250,000 people in the US and 1.6 million worldwide per year. With an aging population, the development of reliable fracture risk models is therefore of prime importance. Due to the complexity of the hip fracture phenomenon, the use of clinical data only, as it is done traditionally, might not be sufficient to ensure an accurate and robust hip fracture prediction model. In order to increase the predictive ability of the risk model, the authors propose to supplement the clinical data with computational data from finite element models. The fusion of the two types of data is performed using deterministic and stochastic computational data. In the latter case, uncertainties in loading and material properties of the femur are accounted for and propagated through the finite element model. The predictive capability of a support vector machine (SVM) risk model constructed by combining clinical and finite element data was assessed using a Women's Health Initiative (WHI) dataset. The dataset includes common factors such as age and BMD as well as geometric factors obtained from DXA imaging. The fusion of computational and clinical data systematically leads to an increase in predictive ability of the SVM risk model as measured by the AUC metric. It is concluded that the largest gains in AUC are obtained by the stochastic approach. This gain decreases as the dimensionality of the problem increases: a 5.3% AUC improvement was achieved for a 9 dimensional problem involving geometric factors and weight while a 1.3% increase was obtained for a 20 dimensional case including geometric and conventional factors. PMID- 26482734 TI - Development of a hyperelastic material model of subsynovial connective tissue using finite element modeling. AB - Carpal tunnel syndrome (CTS) is one of the most common disorders of the hand. Assessment of carpal tunnel tissue mechanical behavior, especially that of the subsynovial connective tissue (SSCT), is important to better understand the mechanisms of CTS. The aim of this study was to develop a hyperelastic material model of human SSCT using mechanical test data and finite element modeling (FEM). Experimental shear test data of SSCT from 7 normal subjects and 7 CTS patients collected in a prior study was used to define material response. Hyperelastic coefficients (MU and alpha) from the first-order Ogden material property definition were iteratively solved using specimen-specific FEM models simulating the mechanical test conditions. A typical Ogden hyperelastic response for the normal and CTS SSCT was characterized by doing the same with data from all samples averaged together. The mean Ogden coefficients (MU/alpha) for the normal cadaver and CTS patient SSCT were 1.25*10(-5)MPa/4.51 and 1.99*10(-6)MPa/10.6, respectively when evaluating coefficients for individual specimens. The Ogden coefficients for the typical (averaged data) model for normal cadaver and CTS patient SSCT were 1.63*10(-5)MPa/3.93 and 5.00*10(-7)MPa/9.55, respectively. Assessment of SSCT mechanical response with a hyperelastic material model demonstrated significant differences between patient and normal cadaver. The refined assessment of these differences with this model may be important for future model development and in understanding clinical presentation of CTS. PMID- 26482735 TI - Human arm posture prediction in response to isometric endpoint forces. AB - The ability to predict the musculoskeletal response to external loads has multiple applications for the design of machines with a human interface and for the prediction of outcomes of musculoskeletal interventions. In this study, we applied an inverse-inverse dynamics technique to investigate its ability to predict arm posture in response to isometric hand forces. For each subject, we made a three-dimensional musculoskeletal model using the AnyBody Modelling System (AMS). Then, we had each subject-specific model hold a weight anteriorly to the right shoulder joint at a distance of half of the arm length. We selected the glenohumeral abduction angle (GHAA) as the only free parameter. Subsequently, we used inverse-inverse dynamics to find the optimal GHAA that minimised a performance criterion with physiological constraints. In this study, we investigated the performance of two different objective functions: summation of squared muscle activity (SSMA) and summation of squared normalised joint torques (SSNJT). To validate the simulation results, arm posture responses to different isometric downward hand forces were measured for six healthy male subjects. Five trials were performed for each loading condition. The results showed that, with an increase in hand load, there was a reduced GHAA in all subjects. Another interesting finding was that self-selected postures for lighter tasks varied more than postures for heavier tasks for all subjects. To understand this, we investigated the curvature of the objective function as a function of the load and observed an increased curvature with increased load. This may explain the reduced intra-subject variations observed for increasing loads. PMID- 26482736 TI - Minocycline exacerbates apoptotic neurodegeneration induced by the NMDA receptor antagonist MK-801 in the early postnatal mouse brain. AB - NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro apoptotic effect of minocycline was even more pronounced than that elicited by MK 801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children. PMID- 26482737 TI - Immunostimulatory activity of snake fruit peel extract on murine macrophage-like J774.1 cells. AB - Snake fruit (Salacca edulis Reinw.) is a tropical fruit produced in Indonesia. Snake fruit peel is normally discarded as waste. In the present study, it was revealed that snake fruit peel has high bioactivities on stimulation of the immune system. Snake fruit peel extract (SFPE) was prepared by extracting snake fruit peel powder in water for 15 h at 4 degrees C. SFPE enhanced phagocytotic activity of murine macrophage-like J774.1 cells. Production of cytokine such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 was also stimulated by SFPE. The gene expression levels for these cytokines were elevated. Immunoblot analysis revealed that SFPE enhanced not only nuclear factor (NF)-kappaB but also mitogen-activated protein kinases signalling cascades such as JNK and p38 in macrophage. Overall findings suggested that SFPE has a potential beneficial effect to promote our body health through the stimulation of macrophage. PMID- 26482738 TI - Contribution of Macromolecular Antioxidants to Dietary Antioxidant Capacity: A Study in the Spanish Mediterranean Diet. AB - Epidemiological and clinical studies show that diets with a high antioxidant capacity, such us those rich in plant food and beverages, are associated with significant decreases in the overall risk of cardiovascular disease or colorectal cancer. Current studies on dietary antioxidants and dietary antioxidant capacity focus exclusively on low molecular weight or soluble antioxidants (vitamins C and E, phenolic compounds and carotenoids), ignoring macromolecular antioxidants. These are polymeric phenolic compounds or polyphenols and carotenoids linked to plant food macromolecules that yield bioavailable metabolites by the action of the microbiota with significant effects either local and/or systemic after absorption. This study determined the antioxidant capacity of the Spanish Mediterranean diet including for the first time both soluble and macromolecular antioxidants. Antioxidant capacity and consumption data of the 54 most consumed plant foods and beverages were used. Results showed that macromolecular antioxidants are the major dietary antioxidants, contributing a 61% to the diet antioxidant capacity (8000 MUmol Trolox, determined by ABTS method). The antioxidant capacity data for foods and beverages provided here may be used to estimate the dietary antioxidant capacity in different populations, where similar contributions of macromolecular antioxidants may be expected, and also to design antioxidant-rich diets. Including macromolecular antioxidants in mechanistic, intervention and observational studies on dietary antioxidants may contribute to a better understanding of the role of antioxidants in nutrition and health. PMID- 26482739 TI - Is time an extra dimension in 3D cell culture? AB - Time or the temporal microenvironment is a parameter that is often overlooked in 3D cell culture. However, given that the 3D system is a dynamic entity, there exists bidirectional signaling between the cells and their microenvironment and, in time, cells can develop the capacity to modulate their environment. We make this case here by illustrating the relation between the temporal dimension and other microenvironmental parameters and demonstrate how the exogenously incorporated microenvironmental factors (MEFs) can be rendered less significant with time. Such knowledge can guide construct design to make 3D platforms architecturally simpler by eliminating redundancy. We further show that there is a need to establish the point at which the construct is complex enough such that its use yields responses that more closely emulate in vivo outcomes. PMID- 26482740 TI - Precision medicine in oncology drug development: a pharma perspective. AB - A rapid expansion in precision medicine founded on the potential for durable clinical benefit through matching a drug to a predictive marker used to select patients has driven the development of targeted drugs with accompanied companion diagnostics for patient selection. Oncology has been at the forefront, with the improvements in patient survival notable. Increasing numbers of molecular subgroups require an equally increasing number (and new generation) of highly selective agents targeting inevitably lower incidence molecular segments, posing significant challenges for drug development. Innovative trial designs (umbrella or basket studies) are emerging as patient-centric approaches and public-private partnerships, cross-industry, government and non-profit sector collaborations are enabling implementation. Success will require continued innovation, new paradigms in oncology drug development and market approval and continued collaboration. PMID- 26482741 TI - Development of a simple tool to predict the risk of postpartum diabetes in women with gestational diabetes mellitus. AB - AIMS: Women with gestational diabetes mellitus (GDM) have an increased risk of diabetes postpartum. We developed a score to predict the long-term risk of postpartum diabetes using clinical and anamnestic variables recorded during or shortly after delivery. METHODS: Data from 257 GDM women who were prospectively followed for diabetes outcome over 20 years of follow-up were used to develop and validate the risk score. Participants were divided into training and test sets. The risk score was calculated using Lasso Cox regression and divided into four risk categories, and its prediction performance was assessed in the test set. RESULTS: Postpartum diabetes developed in 110 women. The computed training set risk score of 5 * body mass index in early pregnancy (per kg/m(2)) + 132 if GDM was treated with insulin (otherwise 0) + 44 if the woman had a family history of diabetes (otherwise 0) - 35 if the woman lactated (otherwise 0) had R (2) values of 0.23, 0.25, and 0.33 at 5, 10, and 15 years postpartum, respectively, and a C Index of 0.75. Application of the risk score in the test set resulted in observed risk of postpartum diabetes at 5 years of 11 % for low risk scores <=140, 29 % for scores 141-220, 64 % for scores 221-300, and 80 % for scores >300. CONCLUSIONS: The derived risk score is easy to calculate, allows accurate prediction of GDM-related postpartum diabetes, and may thus be a useful prediction tool for clinicians and general practitioners. PMID- 26482742 TI - Health risks facing travelers to Russia with special reference to natural-focal diseases. AB - BACKGROUND: Russia, an enormous country almost completely located within temperate latitudes, has a broad spectrum of natural landscapes which attract increasing numbers of tourists, from arctic deserts in the north to steppes and deserts in the south. Currently, tourism is undergoing active development in Russia: new travel routes, including ones that involve visiting the wilderness, are steadily appearing. Among the multitude of infectious diseases that can endanger travelers, natural-focal diseases, whose agents and/or carriers are integral to natural landscapes, are especially prominent. Some of the results of the study of natural-focal infections and parasitoses, which are necessary to evaluate the recreational and travel potential of the Russian Federation, are presented and discussed in this article. METHOD: A cartographical and statistical analysis of infectious and parasitic natural-focal diseases, spanning more than a decade (1997-2013), is the basis of this article. RESULTS: This analysis, along with that of additional cartographical and textual sources, reveals that natural focal infections are most diverse between 48 degrees N and 60 degrees N and least diverse in the northern regions of the Far East of Russia. Different regions have different numbers of nosoforms and different morbidity level, which signifies an irregularity in the distribution of parasitic diseases. CONCLUSIONS: This medico-geographical information may be useful both for individual tourists planning trips to Russia and tour agencies organizing tour groups. It also can be used by health advisers when they consult people before a trip, to assess the actual risks, suggest a number of precautions and pick the particular diseases out of those listed that actually constitute a risk in certain regions, and suggest a suitable preventative treatment if needed. PMID- 26482743 TI - Genetic Test Results and Disclosure to Family Members: Qualitative Interviews of Healthcare Professionals' Perceptions of Ethical and Professional Issues in France. AB - The benefit of disclosing test results to next of kin is to improve prognosis and in some cases-even prevent death though earlier monitoring or preventive therapies. Research on this subject has explored the question of intra-familial communication from the standpoint of patients and relatives but rarely, from the standpoint of healthcare professionals. The purpose of this study was to interview relevant healthcare professionals in France, where legislation framing the issue was recently passed. A qualitative study consisting of semi-structured interviews was set up to get a clearer picture of the challenges arising from this issue, its consequences in terms of medical care-service practices, and the positions that frontline professionals have taken in response to this new legal framework. The findings from eight interviews with 7 clinical geneticists and 1 genetic counselor highlight very different patterns of practices among care services and among the genetic diseases involved. It is equally crucial to investigate other issues such as the nature of genetic testing and its consequences in terms of disclosing results to kin, the question of the role of genetic counseling in the disclosure process, the question of prescription by non geneticist clinicians, and practical questions linked to information content, consent and medical follow-up for patients and their relatives. PMID- 26482744 TI - Duchenne Muscular Dystrophy: a Survey of Perspectives on Carrier Testing and Communication Within the Family. AB - Carrier testing is widely available for multiple genetic conditions, and several professional organizations have created practice guidelines regarding appropriate clinical application and the testing of minors. Previous research has focused on carrier screening, predictive testing, and testing for X-linked conditions. However, family perspectives on carrier testing for X-linked lethal diseases have yet to be described. In this study, we explored communication within the family about carrier testing and the perspectives of mothers of sons with an X-linked lethal disease, Duchenne muscular dystrophy (DMD). Twenty-five mothers of sons with DMD participated in an anonymous online survey. Survey questions included multiple choice, Likert scale, and open ended, short answer questions. Analysis of the multiple choice and Likert scale questions revealed that most mothers preferred a gradual style of communication with their daughters regarding risk status. In addition, most participants reported having consulted with a genetic counselor and found it helpful. Comparisons between groups, analyzed using Fisher's exact tests, found no differences in preferred style due to mother's carrier status or having a daughter. Thematic analysis was conducted on responses to open ended questions. Themes identified included the impact of family implications, age and maturity, and a desire for autonomy regarding the decision to discuss and undergo carrier testing with at-risk daughters, particularly timing of these discussions. Implications for genetic counseling practice are discussed. PMID- 26482745 TI - Factors associated with orthostatic hypotension in hospitalized elderly patients. AB - OBJECTIVE: To assess the factors associated with orthostatic hypotension (OH) in hospitalized elderly patients. DESIGN: Prospective observational single center study. SETTING: A French academic center. PARTICIPANTS: One hundred and thirty one patients without OH symptoms who underwent OH testing. MEASUREMENTS: The OH test was performed when the patient was able to get out of the bed and was no longer receiving parenteral fluids. The blood pressure was measured after a 10 min rest while the patients were sitting and then standing at 1 and 3 min. Demographic data, co-morbidities, current medications and biological parameters were recorded. RESULTS: The mean patient age was 84.3 +/- 7 years. The mean CIRS G score was 10.6 +/- 3.8. The OH test was performed 6.3 +/- 3.9 days after admission and was positive in 39 (29.8 %) patients (95 % confidence interval (CI) 22, 38) and positive at 1 min in 87.2 % of the cases. Multivariate analysis showed that OH prevalence correlated with diabetes (odds ratio (OR) = 4.23; 95 % CI 1.10, 16.24; P = 0.03), serum 25-hydroxyvitamin D <20 ng/ml (OR = 3.38; 95 % CI 1.36, 8.42; P = 0.008), use of tranquilizers (anxiolytic and hypnotic) (OR = 2.96; 95 % CI 1.18, 7.4; P = 0.02), CIRS-G score (OR = 1.15; 95 % CI 1.01, 1.31; P = 0.03) and lack of diuretics (OR = 0.20; 95 % CI 0.06, 0.63; P = 0.005). CONCLUSION: In older adults, OH is often misdiagnosed because it is asymptomatic. As practitioners may be reluctant to perform the OH test because of time constraints, targeting a subgroup of patients with a higher risk of OH should be worthwhile to prevent further OH complications. PMID- 26482746 TI - Effects of calpain on sevoflurane-induced aged rats hippocampal neuronal apoptosis. AB - BACKGROUND: Sevoflurane is one of the most commonly used volatile anesthetics and it has been shown to induce widespread apoptotic neurodegeneration in aged rat. Calpain is also activated during apoptosis in several types of cells. We hypothesized that calpain resulted in apoptosis under long time sevoflurane exposure, and it might play a role in the sevoflurane-induced memory impairment in aged rats. METHODS: Seventy-two 18-month-old male Sprague-Dawley rats were randomly divided into three groups (n = 24): Control group rats were exposed to simply humid 50 % O2 balanced by N2 for 3 h; While M group rats received calpain inhibitor 10 mg/kg via the tail vein intravenously at 30 min before the animals inhaled 3 % sevoflurane for 3 h, subsequently received MDL 28170 3.33 mg/kg/h for 3 h. Sev group rats were only exposed to 3 % sevoflurane for 3 h without calpain inhibitor. Morris Water Maze was used to test the ability of learning and memory. Cytosolic calcium concentration was measured by using flow cytometry. Annexin-V labeled with a fluorophore or biotin can identify apoptotic cells by binding to PS. The expression of calpain in the hippocampus of rats was tested by Western blots. RESULTS: The results showed that the M group had a shorter latency and had a larger number of times crossing over the previous platform site than that of the Sev group. Compared with Sev group, apoptosis rate and 76/80 kDa ratio of MU calpain were significantly decreased in M group on the 1st day. CONCLUSIONS: Sevoflurane might induce apoptosis through increasing [Ca(2+)]c and the activity of MU-calpain, which might be identified at least partially the molecular mechanism by which sevoflurane induces apoptosis. PMID- 26482747 TI - Differentiation of high-grade-astrocytomas from solitary-brain-metastases: Comparing diffusion kurtosis imaging and diffusion tensor imaging. AB - OBJECTIVE: To compare the value of MRI diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in differentiating high-grade-astrocytomas from solitary-brain-metastases. METHODS: Thirty-one high-grade-astrocytomas and twenty solitary-brain-metastases were retrospectively identified. DKI parameters [mean kurtosis (MK), radial kurtosis (Kr), and axial kurtosis (Ka)] and DTI parameters [fractional anisotropy (FA) and mean diffusivity (MD)] values with and without correction by contralateral normal-appearing white matter (NAWM) in the tumoral solid part and peritumoral edema, were compared using the t-test. Receiver operating characteristic (ROC) curves were used to test for the best parameters. RESULTS: The DKI values (MK, Kr, and Ka) and DTI values (FA and MD) in tumoral solid parts did not show significant differences between the two groups. Corrected and uncorrected MK, Kr, and Ka values in peritumoral edema were significantly higher in high-grade-astrocytomas than solitary-brain-metastases, and MD values without correction were lower in high-grade astrocytomas than solitary-brain-metastases. The areas under curve (AUC) of corrected Ka (1.000), MK (0.889), and Kr (0.880) values were significantly higher than those of MD (0.793) and FA (0.472) values. The optimal thresholds for corrected MK, Kr, Ka, and MD were 0.369, 0.405, 0.483, and 2.067, respectively. CONCLUSION: DKI and directional analysis could lead to improved differentiation with better sensitivity and directional specificity than DTI. PMID- 26482748 TI - [Road traffic injuries: an example of public health]. PMID- 26482749 TI - [Road traffic injuries: an example of public health]. PMID- 26482750 TI - Management of Hypertension in Children and Adolescents. AB - Hypertension in children and adolescents is becoming a greater problem in the developed world. Although traditionally thought of as usually secondary to renal, vascular, or endocrine causes, primary hypertension is becoming the most common form seen in childhood. This changing epidemiology is related to the recent obesity epidemic. The evaluation of high blood pressure in children is more involved than in adults and is aimed both at identifying secondary causes and to identify other co-morbidities of cardiovascular risk. Treatment of hypertension in childhood and adolescence is aimed at reducing cardiovascular risk. While there are a growing number of antihypertensive agents with FDA labeling for children, there remain far fewer options than for adults. This paper reviews the epidemiology, definitions, evaluations, and management of elevated blood pressure in children and adolescents. PMID- 26482751 TI - Management of Hypertension in Obstructive Sleep Apnea. AB - Obstructive sleep apnea (OSA) is considered to be a secondary form of hypertension and in clinical practice OSA is frequently associated with hypertension, even if proof of causality cannot be established. Growing evidence suggests that OSA is associated with worse blood pressure control, alterations in night-time blood pressure dipping, increased target organ damage, and arterial stiffness in patients with hypertension. This review summarizes the current evidence for managing hypertension in patients with OSA. Particular focus will be devoted to discuss the impact of lifestyle changes, preferences for anti hypertensive treatment in patients with OSA, and the effects of OSA treatment with continuous positive airway pressure on blood pressure. PMID- 26482752 TI - New Approaches in Detection and Treatment of Familial Hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that clinically leads to increased low density lipoprotein-cholesterol (LDL-C) levels. As a consequence, FH patients are at high risk for cardiovascular disease (CVD). Mutations are found in genes coding for the LDLR, apoB, and PCSK9, although FH cannot be ruled out in the absence of a mutation in one of these genes. It is pivotal to diagnose FH at an early age, since lipid lowering results in a decreased risk of cardiovascular complications especially if initiated early, but unfortunately FH is largely underdiagnosed. While a number of clinical criteria are available, identification of a pathogenic mutation in any of the three aforementioned genes is seen by many as a way to establish a definitive diagnosis of FH. It should be remembered that clinical treatment is based on LDL-C levels and not solely on presence or absence of genetic mutations as LDL-C is what drives risk. Traditionally, mutation detection has been done by means of dideoxy sequencing. However, novel molecular testing methods are gradually being introduced. These next generation sequencing-based methods are likely to be applied on broader scale once their efficacy and effect on cost are being established. Statins are the first-line therapy of choice for FH patients as they have been proven to reduce CVD risk across a range of conditions including hypercholesterolemia (though not specifically tested in FH). However, in a significant proportion of FH patients LDL-C goals are not met, despite the use of maximal statin doses and additional lipid-lowering therapies. This underlines the need for additional therapies, and inhibition of PCSK9 and CETP is among the most promising new therapeutic options. In this review, we aim to provide an overview of the latest information about the definition, diagnosis, screening, and current and novel therapies for FH. PMID- 26482753 TI - Risk Stratification for Primary Prevention of Coronary Artery Disease: Roles of C Reactive Protein and Coronary Artery Calcium. AB - Risk stratification of individuals at risk for atherosclerotic cardiovascular disease (ASCVD) plays an important role in primary prevention of cardiovascular disease. In addition to risk scores derived from conventional cardiovascular risk factors, high sensitivity C-reactive protein (hs-CRP) and coronary artery calcium (CAC) have emerged as two of the widely accepted non traditional risk factors for atherosclerotic disease that have shown incremental prognostic value in predicting cardiovascular events. This review systematically assesses the role of hs-CRP and CAC in various studies and demonstrates meta-analyses of the incremental prognostic value of hs-CRP and CAC in identifying patients at risk of future CVD events. Compared with this, CAC showed better incremental prognostic value and might be a better indicator of ASCVD risk in asymptomatic adults. PMID- 26482756 TI - Implantable Hemodynamic Monitoring in Ambulatory Heart Failure: Who, When, Why, How? AB - Despite considerable advances in therapeutics, the risk of hospitalization for patients with heart failure remains high. Since many hospitalizations in heart failure patients are driven by congestive exacerbations, optimal management of congestion is a key goal of longitudinal heart failure disease management. Existing strategies for hemodynamic optimization in heart failure patients rely heavily on remote monitoring of weights and symptoms, augmented in selected cases by data from implanted cardiac devices. When they have been systematically studied, however, none of these approaches has been demonstrated to consistently improve clinical outcomes. Recent data suggests that implantable hemodynamic monitors may facilitate early detection and treatment of worsening congestion, thereby reducing the need for hospital admission. In this review, we explore the rationale and evidence supporting the use of these novel devices as an adjunct to routine heart failure management and the strategies for appropriate patient selection. PMID- 26482755 TI - Mindfulness and Cardiovascular Disease Risk: State of the Evidence, Plausible Mechanisms, and Theoretical Framework. AB - The purpose of this review is to provide (1) a synopsis on relations of mindfulness with cardiovascular disease (CVD) and major CVD risk factors, and (2) an initial consensus-based overview of mechanisms and theoretical framework by which mindfulness might influence CVD. Initial evidence, often of limited methodological quality, suggests possible impacts of mindfulness on CVD risk factors including physical activity, smoking, diet, obesity, blood pressure, and diabetes regulation. Plausible mechanisms include (1) improved attention control (e.g., ability to hold attention on experiences related to CVD risk, such as smoking, diet, physical activity, and medication adherence), (2) emotion regulation (e.g., improved stress response, self-efficacy, and skills to manage craving for cigarettes, palatable foods, and sedentary activities), and (3) self awareness (e.g., self-referential processing and awareness of physical sensations due to CVD risk factors). Understanding mechanisms and theoretical framework should improve etiologic knowledge, providing customized mindfulness intervention targets that could enable greater mindfulness intervention efficacy. PMID- 26482757 TI - Coagulopathy in Mechanical Circulatory Support: A Fine Balance. AB - Therapeutic intervention with mechanical circulatory support has revolutionized the medical care of individuals living with advanced heart failure. Left ventricular assist devices (LVADs) have enabled patients to live longer while providing improved quality of life and functional status. However, intervention is not without risk. Over the last decade, clinicians have identified common mechanical assist device-associated complications. This appears to be multi factorial with relation to patient variables, inherent device technology, and nuances of concurrent medical management. This review will discuss the impact of adverse hematologic complications: bleeding, pump thrombosis, and hemolysis in continuous flow LVAD patients. These obstacles continue to pose a clinical challenge with regard to both diagnosis and optimal management. Heightened awareness and understanding of heterogeneous clinical presentations is essential for preventive management and early detection with intervention. PMID- 26482754 TI - Psychological Aspects of Cardiac Care and Rehabilitation: Time to Wake Up to Sleep? AB - Psychological and psychosocial factors have long been linked to cardiovascular disease. These psychosocial factors, including low socioeconomic status, social support/isolation, stress and distress, personality, and sleep disturbance increase risk of cardiovascular events and negatively impact quality of life. These factors may have direct effects on cardiovascular disease via immune or neuroendocrine pathways, or more indirect effects, by, for example, limiting adherence to recommended therapies and cardiac rehabilitation. Most psychosocial risk factors can be assessed relatively easily using standardised tools. Sleep disturbance, in particular, is gaining evidence for its importance and may be crucial to address. While the management of certain psychosocial risk factors is an ethical requirement for care and improves quality of life, unfortunately there is little evidence that such strategies impact on 'hard' endpoints such as recurrent myocardial infarction. A comprehensive biopsychosocial approach to management of these psychosocial factors is required to maximise the benefits patients derive from cardiac care. PMID- 26482758 TI - Healthcare Professional Shortage and Task-Shifting to Prevent Cardiovascular Disease: Implications for Low- and Middle-Income Countries. AB - Cardiovascular diseases (CVD) account for 18 million of annual global deaths with more than three quarters of these deaths occurring in low- and middle-income countries (LMIC). In LMIC, the distribution of risk factors is heterogeneous, with urban areas being the worst affected. Despite the availability of effective CVD interventions in developed countries, many poor countries still struggle to provide care due to lack of resources. In addition, many LMIC suffer from staff shortages which pose additional burden to the healthcare system. Regardless of these challenges, there are potentially effective strategies such as task shifting which have been used for chronic conditions such as HIV to address the human resource crisis. We propose that through task-shifting, certain tasks related to prevention be shifted to non-physician health workers as well as non nurse health workers such as community health workers. Such steps will allow better coverage of segments of the underserved population. We recognise that for task-shifting to be effective, issues such as clearly defined roles, evaluation, on-going training, and supervision must be addressed. PMID- 26482759 TI - Renal Denervation: Where to Now? AB - Resistant hypertension remains a growing problem worldwide. Renal sympathetic denervation was thought to be a new method for the treatment for resistant hypertension. Early studies demonstrated a marked benefit in patients who underwent renal denervation procedures, but the pivotal SYMPLICITY 3-HTN trial, the only sham-controlled randomized trial performed, did not show a benefit for patients treated with the procedure compared to sham. There is still much to learn about the physiology and anatomy of renal sympathetic pathways as well as careful attention to medication adherence in order to understand the role of renal sympathetic denervation in treating hypertensive patients. While renal denervation technology remains available in clinical practice outside of the USA, we expect further development of this technology in the upcoming years and the continued evaluation of this technology in patients with hypertension as well as other disease states to fully understand its role. PMID- 26482760 TI - Radial Versus Femoral Access for Acute Coronary Syndromes. AB - The feasibility and safety of transradial coronary intervention was demonstrated soon after the description of the transfemoral approach, despite which the use of the femoral artery still dominates in acute coronary syndrome intervention. The advantages of using the radial artery are virtual elimination of access site complications and an important reduction in bleeding, both of which are of utmost importance to the patient with myocardial infarction. Randomised controlled trials have now documented what seems inherent; that transradial intervention should bring with it an advantage in terms of morbidity and mortality in this cohort. The potential disadvantages in terms of speed of procedure and radiation exposure are negated by operator experience. Registries have illustrated that conversion on a large scale from the femoral to the transradial approach is safe and saves lives, most convincingly so in acute coronary syndrome intervention. This review discusses the potential benefits and risks of the alternative access sites in acute patients and explores how these are borne out in the published data. PMID- 26482761 TI - Atrial Fibrillation Monitoring in Cryptogenic Stroke: the Gaps Between Evidence and Practice. AB - Identifying occult paroxysmal atrial fibrillation as the etiology of cryptogenic stroke has been a top research priority in the past decade. This is because prompt initiation of anticoagulation has significantly decreased subsequent stroke risk. Available evidence suggests that prolonged cardiac monitoring after stroke increases the likelihood of detecting atrial fibrillation. However, further research is required to fill in the gaps in regard to the optimal period of monitoring, candidates for monitoring, etc. Here, we review the current evidence supporting the use of prolonged monitoring for cryptogenic stroke patients and discuss the directions of future research. PMID- 26482762 TI - Management of Hypertension in Patients with Ischemic Heart Disease. AB - Ischemic heart disease (IHD) affects about 16 million adults in the USA. Many more individuals likely harbor subclinical coronary disease. Hypertension (HTN) continues to be a potent and widespread risk factor for IHD. Among other Framingham risk factors of tobacco use, diabetes mellitus, dyslipidemia, and left ventricular hypertrophy, HTN plays an independent role in augmenting IHD risk, as well as a multiplicative role with respect to adverse outcomes when HTN is present concurrently with the other major IHD risk factors listed above. Over the past two decades, numerous studies and guideline reports have been presented with the aims of (a) elucidating the pathophysiology of IHD, (b) delineating an ideal blood pressure (BP) threshold at which to institute pharmacotherapy, and (c) defining the optimal pharmacologic elements of a therapeutic regimen. While there are active debates surrounding the existence and relevance of the J curve in IHD patients who have HTN, as well as the numerical level of the BP cutoff justifying drug therapy in the general population, there is a general consensus that the BP target in IHD patients should be lower than 140/90 mmHg. The most appropriate class (or classes) of medication recommended will depend on the comorbid conditions associated with each individual patient. Overall, however, there is no major evidence underscoring a significant difference between drug classes, provided the target BP is achieved, although it should be pointed out that the most recent (2015) American Heart Association (AHA)/American College of Cardiology (ACC)/American Society of Hypertension (ASH) guideline statement now elevates beta-blockers (BB) to the same level of recommendation as other classes of hypertension drugs in the treatment of patients who have hypertension and ischemic heart disease. Although most agents that reduce blood pressure will correspondingly lower myocardial workload, BB may exhibit a special advantage in IHD patients because BB (as well as verapamil and diltiazem subclasses of calcium channel blockers or CCB) act to lower HR as well as cardiac inotropy. Moreover, BB will remain an integral if not indispensable part of the management of IHD, especially in those with history of angina pectoris or MI, based on decades of favorable clinical as well as trial experience. This extensive salutary historical background has served as a foundation for the 2015 committee's decision to bring BB into the front rank of BP agents for those hypertensive individuals suffering simultaneously from IHD. PMID- 26482764 TI - Scylla and Charybdis--Stent thrombosis and major bleeding with bivalirudin and heparin. PMID- 26482763 TI - Deposition of fibrinogen on the surface of in vitro thrombi prevents platelet adhesion. AB - The initial accumulation of platelets after vessel injury is followed by thrombin mediated generation of fibrin which is deposited around the plug. While numerous in vitro studies have shown that fibrin is highly adhesive for platelets, the surface of experimental thrombi in vivo contains very few platelets suggesting the existence of natural anti-adhesive mechanisms protecting stabilized thrombi from platelet accumulation and continuous thrombus propagation. We previously showed that adsorption of fibrinogen on pure fibrin clots results in the formation of a nonadhesive matrix, highlighting a possible role of this process in surface-mediated control of thrombus growth. However, the deposition of fibrinogen on the surface of blood clots has not been examined. In this study, we investigated the presence of intact fibrinogen on the surface of fibrin-rich thrombi generated from flowing blood and determined whether deposited fibrinogen is nonadhesive for platelets. Stabilized fibrin-rich thrombi were generated using a flow chamber and the time that platelets spend on the surface of thrombi was determined by video recording. The presence of fibrinogen and fibrin on the surface of thrombi was analyzed by confocal microscopy using specific antibodies. Examination of the spatial distribution of two proteins revealed the presence of intact fibrinogen on the surface of stabilized thrombi. By manipulating the surface of thrombi to display either fibrin or intact fibrinogen, we found that platelets adhere to fibrin- but not to fibrinogen-coated thrombi. These results indicate that the fibrinogen matrix assembled on the outer layer of stabilized in vitro thrombi protects them from platelet adhesion. PMID- 26482765 TI - Unplanned admissions and the organisational management of heart failure: a multicentre ethnographic, qualitative study. AB - OBJECTIVES: Heart failure is a common cause of unplanned hospital admissions but there is little evidence on why, despite evidence-based interventions, admissions occur. This study aimed to identify critical points on patient pathways where risk of admission is increased and identify barriers to the implementation of evidence-based interventions. DESIGN: Multicentre, longitudinal, patient-led ethnography. SETTING: National Health Service settings across primary, community and secondary care in three geographical locations in England, UK. PARTICIPANTS: 31 patients with severe or difficult to manage heart failure followed for up to 11 months; 9 carers; 55 healthcare professionals. RESULTS: Fragmentation of healthcare, inequitable provision of services and poor continuity of care presented barriers to interventions for heart failure. Critical points where a reduction in the risk of current or future admission occurred throughout the pathway. At the beginning some patients did not receive a formal clinical diagnosis, in addition patients lacked information about heart failure, self-care and knowing when to seek help. Some clinicians lacked knowledge about diagnosis and management. Misdiagnoses of symptoms and discontinuity of care resulted in unplanned admissions. Approaching end of life, patients were admitted to hospital when other options including palliative care could have been appropriate. CONCLUSIONS: Findings illustrate the complexity involved in caring for people with heart failure. Fragmented healthcare and discontinuity of care added complexity and increased the likelihood of suboptimal management and unplanned admissions. Diagnosis and disclosure is a vital first step for the patient in a journey of acceptance and learning to self-care/monitor. The need for clinician education about heart failure and specialist services was acknowledged. Patient education should be seen as an ongoing 'conversation' with trusted clinicians and end-of-life planning should be broached within this context. PMID- 26482766 TI - Adherence to oral anticoagulants in patients with atrial fibrillation-a population-based retrospective cohort study linking health information systems in the Valencia region, Spain: a study protocol. AB - INTRODUCTION: Adherence to oral anticoagulation (OAC) treatment, vitamin K antagonists or new oral anticoagulants, is an essential element for effectiveness. Information on adherence to OAC in atrial fibrillation (AF) and the impact of adherence on clinical outcomes using real-world data barely exists. We aim to describe the patterns of adherence to OAC over time in patients with AF, estimate the associated factors and their impact on clinical events, and assess the same issues with conventional measures of primary and secondary adherence-proportion of days covered (PDC) and persistence-in routine clinical practice. METHODS AND ANALYSIS: This is a population-based retrospective cohort study including all patients with AF treated with OAC from 2010 to date in Valencia, Spain; data will be obtained from diverse electronic records of the Valencia Health Agency. PRIMARY OUTCOME MEASURE: adherence trajectories. SECONDARY OUTCOMES: (1) primary non-adherence; (2) secondary adherence: (a) PDC, (b) persistence. Clinical outcomes: hospitalisation for haemorrhagic or thromboembolic events and death during follow-up. ANALYSIS: (1) description of baseline characteristics, adherence patterns (trajectory models or latent class growth analysis models) and conventional adherence measures; (2) logistic or Cox multivariate regression models, to assess the associations between adherence measures and the covariates, and logistic multinomial regression models, to identify characteristics associated with each trajectory; (3) Cox proportional hazard models, to assess the relationship between adherence and clinical outcomes, with propensity score adjustment applied to further control for potential confounders; (4) to estimate the importance of different healthcare levels in the variations of adherence, logistic or Cox multilevel regression models. ETHICS AND DISSEMINATION: This study has been approved by the corresponding Clinical Research Ethics Committee. We plan to disseminate the project's findings through peer-reviewed publications and presentations at relevant health conferences. Policy reports will also be prepared in order to promote the translation of our findings into policy and clinical practice. PMID- 26482767 TI - Insights into the experiences of patients with cancer in London: framework analysis of free-text data from the National Cancer Patient Experience Survey 2012/2013 from the two London Integrated Cancer Systems. AB - OBJECTIVE: To shed light on experiences of patients with cancer in London National Health Service (NHS) trusts that may not be fully captured in national survey data, to inform improvement action plans by these trusts. DESIGN: Framework analysis of free-text data from 2012/2013 National Cancer Patient Experience Survey (NCPES) from the 2 London Integrated Cancer Systems. SETTING AND PARTICIPANTS: Patients with a cancer diagnosis treated by the NHS across 27 trusts in London. MAIN OUTCOME MEASURES: Free-text data received from patients categorised into what patients found good about their cancer care and what could be improved. METHODS: Using Framework analysis, a thematic framework was created for 15,403 comments from over 6500 patients. Themes were identified across the London data set, by tumour group and by trust. RESULTS: Two-thirds of free-text comments from patients in London were positive and one-third of those related to the good quality of care those patients received. However, the majority of comments for improvement related to quality of care, with a focus on poor care, poor communication and waiting times in outpatient departments. Additionally, 577 patients (9% of those who returned free-text data in London) commented on issues pertaining to the questionnaire itself. Some patients who experienced care from multiple trusts were unclear on how to complete the questionnaire for the single trust whose care they were asked to comment on, others said the questions did not fit their experiences. CONCLUSIONS: NCPES free-text analysis can shed light on the experiences of patients that closed questions might not reveal. It further indicates that there are issues with the survey itself, in terms of ambiguities in the questionnaire and difficulties in identifying patients within specific trusts. Both of these issues have the potential to contribute to knowledge and understanding of the uses and limitations of free-text data in improving cancer services. PMID- 26482768 TI - Decision analytic cost-effectiveness model to compare prostate cryotherapy to androgen deprivation therapy for treatment of radiation recurrent prostate cancer. AB - OBJECTIVE: To determine the cost-effectiveness of salvage cryotherapy (SC) in men with radiation recurrent prostate cancer (RRPC). DESIGN: Cost-utility analysis using decision analytic modelling by a Markov model. SETTING AND METHODS: Compared SC and androgen deprivation therapy (ADT) in a cohort of patients with RRPC (biopsy proven local recurrence, no evidence of metastatic disease). A literature review captured published data to inform the decision model, and resource use data were from the Scottish Prostate Cryotherapy Service. The model was run in monthly cycles for RRPC men, mean age of 70 years. The model was run over the patient lifetime, to assess changes in patient health states and the associated quality of life, survival and cost impacts. Results are reported in terms of the discounted incremental costs and discounted incremental quality adjusted life years (QALYs) gained between the 2 alternative interventions. Probabilistic sensitivity analysis used a 10,000 iteration Monte Carlo simulation. RESULTS: SC has a high upfront treatment cost, but delays the ongoing monthly cost of ADT. SC is the dominant strategy over the patient lifetime; it is more effective with an incremental 0.56 QALY gain (95% CI 0.28 to 0.87), and less costly with a reduced lifetime cost of L29,719 (?37,619) (95% CI -51,985 to 9243). For a ceiling ratio of L30,000, SC has a 100% probability to be cost effective. The cost neutral point was at 3.5 years, when the upfront cost of SC (plus any subsequent cumulative cost of side effects and ADT) equates the cumulative cost in the ADT arm. Limitations of our model may arise from its insensitivity to parameter or structural uncertainty. CONCLUSIONS: The platform for SC versus ADT cost-effective analysis can be employed to evaluate other treatment modalities or strategies in RRPC. SC is the dominant strategy, costing less over a patient's lifetime with improvements in QALYs. TRIAL REGISTRATION NUMBER: This economic analysis was undertaken as part of the CROP RCT study ISRCTN: 72677390; it was a pre-trial economic model developed and analysed during the pre-results stage of the RCT. PMID- 26482770 TI - The mental health of US Black women: the roles of social context and severe intimate partner violence. AB - OBJECTIVE: Black women continue to have rates of mental health conditions that can be negative for their well-being. This study examined the contribution of social and contextual factors and severe physical intimate partner violence on the mental health of US Black women (African-American and Caribbean Black). SETTING: Data were largely collected via in-person community interviews at participants' homes. PARTICIPANTS: We studied 3277 African-American and Black Caribbean women from the 2001-2003 National Survey of American Life (NSAL), the largest and most complete sample of Blacks residing in the USA. PRIMARY AND SECONDARY OUTCOMES: Key outcomes included an array of psychiatric disorders based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). RESULTS: Bivariate results revealed noticeably high rates of any anxiety disorder, post traumatic stress disorder, any substance disorder, alcohol abuse disorder, suicide ideation and attempts, and any overall mental disorder among African American women relative to Caribbean Black women. Multiple social and contextual factors were associated with various mental disorders among both sets of Black women in multivariate models, with the most consistent associations found for severe physical intimate partner violence. Everyday discrimination was associated with anxiety disorders (95% AOR=2.08 CI 1.23 to 3.51), eating disorders (95% AOR=2.69 CI 1.38 to 5.22), and any disorder (95% AOR=2.18 CI 1.40 to 3.40), while neighbourhood drug problems contributed to mood (95% AOR=1.19 CI 1.04 to 1.36), substance disorders (95% AOR=1.37 CI 1.11 to 1.69) and any disorder (95% AOR=1.18 CI 1.03 to 1.34). CONCLUSIONS: Severe physical intimate partner violence, discrimination, and to a lesser extent, neighbourhood problems are important predictors of Black women's health, findings that inform intervention and clinical services tailored to meet the needs of Black women from diverse ethnic and cultural backgrounds. PMID- 26482769 TI - Robotic, laparoscopic and open surgery for gastric cancer compared on surgical, clinical and oncological outcomes: a multi-institutional chart review. A study protocol of the International study group on Minimally Invasive surgery for GASTRIc Cancer-IMIGASTRIC. AB - INTRODUCTION: Gastric cancer represents a great challenge for healthcare providers and requires a multidisciplinary treatment approach in which surgery plays a major role. Minimally invasive surgery has been progressively developed, first with the advent of laparoscopy and recently with the spread of robotic surgery, but a number of issues are currently being debated, including the limitations in performing an effective extended lymph node dissection, the real advantages of robotic systems, the role of laparoscopy for Advanced Gastric Cancer, the reproducibility of a total intracorporeal technique and the oncological results achievable during long-term follow-up. METHODS AND ANALYSIS: A multi-institutional international database will be established to evaluate the role of robotic, laparoscopic and open approaches in gastric cancer, comprising of information regarding surgical, clinical and oncological features. A chart review will be conducted to enter data of participants with gastric cancer, previously treated at the participating institutions. The database is the first of its kind, through an international electronic submission system and a HIPPA protected real time data repository from high volume gastric cancer centres. ETHICS AND DISSEMINATION: This study is conducted in compliance with ethical principles originating from the Helsinki Declaration, within the guidelines of Good Clinical Practice and relevant laws/regulations. A multicentre study with a large number of patients will permit further investigation of the safety and efficacy as well as the long-term outcomes of robotic, laparoscopic and open approaches for the management of gastric cancer. TRIAL REGISTRATION NUMBER: NCT02325453; Pre-results. PMID- 26482772 TI - Prevalence and severity of asthmatic symptoms in Grenadian school children: the Grenada National Asthma Survey. AB - OBJECTIVE: The goal of this study was to determine the prevalence of asthma in school children in the tri-island Caribbean nation of Grenada. SETTING, PARTICIPANTS AND OUTCOMES: This was a self-report study provided to the guardians of all primary school children between ages 6 and 7 throughout Grenada, Carriacou and Petite Martinique in 2013. Of the 2362 surveys provided, 1374 were returned, resulting in a response rate of 58.2%. Only responders listing birthdays between 1 January 2006 and 31 December 2007 were included in the analysis, resulting in 1165 qualifying responders. Asthma diagnosis was based on previous physician diagnosed asthma and/or self-reported presence of wheeze in the past 12 months (current wheeze). Severity of asthma, medication usage, environmental exposures, physician and emergency department visits were compared among respondents. RESULTS: The prevalence of wheezing in the past year was 30.5+/-1.8%, and of these 68.4% were previously diagnosed with asthma. Of the current wheeze participants, 39.9+/-9.2% reported moderate to severe asthma symptoms and increased exposure to cigarette smoke, excessive dust, burning brush and landfills. Carriacou and Petite Martinique, the two smaller islands, had a lower incidence of current wheeze (14.1+/-7.7%) and exposure rates to cigarette smoke and burning brush as compared to the larger, denser island of Grenada. Although 65.7% of respondents diagnosed with asthma reported taking medication, the number of annual doctor and emergency department visits were high (2.82 and 0.86, respectively). Respondents with the most severe asthma symptoms reported the most emergency department visits with an average of 1.05 visits annually, whereas respondents with moderate asthma symptoms had the most doctor visits with an average of 3.33 visits annually. CONCLUSIONS: This study indicates that the prevalence of childhood asthma in Grenada is very high and warrants policy consideration in public health and education to decrease its morbidity. PMID- 26482771 TI - A cross-sectional study on the relationship of age, gestational age and HIV infection to bacterial vaginosis and genital mycoplasma infection. AB - OBJECTIVES: Pregnant women are especially at risk of developing complications when infected with reproductive tract infections (RTIs). The objective of this study was to determine the prevalence of bacterial vaginosis (BV) and genital mycoplasmas in pregnant women and investigate the associations between BV, genital mycoplasmas, HIV infection, age and gestational age. DESIGN: Cross sectional study with descriptive and analytical components. SETTING: Antenatal clinic of a tertiary academic hospital in South Africa. PARTICIPANTS: 220 pregnant women older than 18 were included in the study and provided self collected vaginal swabs. PRIMARY AND SECONDARY OUTCOMES: BV and genital mycoplasma colonisation and/or infection in women of differing age, gestational period and HIV status. RESULTS: The prevalence of BV was 17.7% (39/220) (95% CI 12.9 to 23.4), intermediate vaginal flora (IVF) 15% (33/220) (95% CI 10.56 to 20.42), and the overall prevalence of genital mycoplasmas was 84% (185/220) (95% CI 78.47 to 88.58). BV was significantly associated with HIV infection with an OR of 2.84 (95% CI 1.08 to 7.46 and p value=0.034). However, BV was inversely associated with gestational age with an OR of 0.08 (95% CI 0.01 to 0.42 and p value=0.003) for second trimester pregnancies and an OR of 0.03 (95% CI 0.01 to 0.17 and p value<0.001) for third trimester pregnancies using the first trimester as reference. IVF was significantly associated with HIV infection with an OR of 2.7 (95% CI 1.07 to 6.79 and p value=0.035) but not with age or gestational age. Genital mycoplasmas were not significantly associated with age, gestational age, HIV status, BV flora or IVF. CONCLUSIONS: The high infection rate of genital mycoplasmas and the association of BV with HIV found in this study reiterate the importance of screening for these RTIs in high-risk groups such as pregnant women. PMID- 26482773 TI - Beliefs underlying pain-related fear and how they evolve: a qualitative investigation in people with chronic back pain and high pain-related fear. AB - OBJECTIVES: The fear-avoidance model describes how the belief that pain is a sign of damage leads to pain-related fear and avoidance. But other beliefs may also trigger the fear and avoidance responses described by the model. Experts have called for the next generation of fear avoidance research to explore what beliefs underlie pain-related fear and how they evolve. We have previously described damage beliefs and suffering/functional loss beliefs underlying high pain-related fear in a sample of individuals with chronic back pain. The aim of this study is to identify common and differential factors associated with the beliefs in this sample. DESIGN: A qualitative study employing semistructured interviews. SETTING: Musculoskeletal clinics in Western Australia. PARTICIPANTS: 36 individuals with chronic back pain and high scores on the Tampa Scale (mean 47/68). RESULTS: The overarching theme was a pain experience that did not make sense to the participants. The experience of pain as unpredictable, uncontrollable and intense made it threatening. Attempting to make sense of the threatening pain, participants with damage beliefs drew on past personal experiences of pain, societal beliefs, and sought diagnostic certainty. Met with diagnostic uncertainty, or diagnoses of an underlying pathology that could not be fixed, they were left fearful of damage and confused about how to 'fix' it. Participants with suffering/functional loss beliefs drew on past personal experiences of pain and sought help from healthcare professionals to control their pain. Failed treatments and the repeated failure to achieve functional goals left them unable to make 'sensible' decisions of what to do about their pain. CONCLUSIONS: The findings raise the suggestion that sense-making processes may be implicated in the fear-avoidance model. Future research is needed to explore whether fear reduction may be enhanced by considering beliefs underlying fear and providing targeted intervention to help individuals make sense of their pain. PMID- 26482774 TI - Interrupting transmission of soil-transmitted helminths: a study protocol for cluster randomised trials evaluating alternative treatment strategies and delivery systems in Kenya. AB - INTRODUCTION: In recent years, an unprecedented emphasis has been given to the control of neglected tropical diseases, including soil-transmitted helminths (STHs). The mainstay of STH control is school-based deworming (SBD), but mathematical modelling has shown that in all but very low transmission settings, SBD is unlikely to interrupt transmission, and that new treatment strategies are required. This study seeks to answer the question: is it possible to interrupt the transmission of STH, and, if so, what is the most cost-effective treatment strategy and delivery system to achieve this goal? METHODS AND ANALYSIS: Two cluster randomised trials are being implemented in contrasting settings in Kenya. The interventions are annual mass anthelmintic treatment delivered to preschool- and school-aged children, as part of a national SBD programme, or to entire communities, delivered by community health workers. Allocation to study group is by cluster, using predefined units used in public health provision-termed community units (CUs). CUs are randomised to one of three groups: receiving either (1) annual SBD; (2) annual community-based deworming (CBD); or (3) biannual CBD. The primary outcome measure is the prevalence of hookworm infection, assessed by four cross-sectional surveys. Secondary outcomes are prevalence of Ascaris lumbricoides and Trichuris trichiura, intensity of species infections and treatment coverage. Costs and cost-effectiveness will be evaluated. Among a random subsample of participants, worm burden and proportion of unfertilised eggs will be assessed longitudinally. A nested process evaluation, using semistructured interviews, focus group discussions and a stakeholder analysis, will investigate the community acceptability, feasibility and scale-up of each delivery system. ETHICS AND DISSEMINATION: Study protocols have been reviewed and approved by the ethics committees of the Kenya Medical Research Institute and National Ethics Review Committee, and London School of Hygiene and Tropical Medicine. The study has a dedicated web site. TRIAL REGISTRATION NUMBER: NCT02397772. PMID- 26482775 TI - Preparation, characterization and immunological evaluation: canine parvovirus synthetic peptide loaded PLGA nanoparticles. AB - BACKGROUND: Canine parvovirus 2 (CPV-2) remains a significant worldwide canine pathogen and the most common cause of viral enteritis in dogs. The 1 L15 and 7 L15 peptides overlap each other with QPDGGQPAV residues (7-15 of VP2 capsid protein of CPV) is shown to produce high immune response. PLGA nanoparticles were demonstrated to have special properties such as; controlled antigen release, protection from degradation, elimination of booster-dose and enhancing the cellular uptake by antigen presenting cells. Nevertheless, there is no study available in literature, about developing vaccine based on PLGA nanoparticles with adjuvant properties against CPV. Thus, the aim of the present study was to synthesize and characterize high immunogenic W-1 L19 peptide (from the VP2 capsid protein of CPV) loaded PLGA nanoparticle and to evaluate their in vitro immunogenic activity. RESULTS: PLGA nanoparticles were produced with 5.26 +/- 0.05 % loading capacity and high encapsulation efficiency with 81.2 +/- 3.1 %. Additionally, it was evaluated that free NPs and W-1 L19 peptide encapsulated PLGA nanoparticles have Z-ave of 183.9 +/- 12.1 nm, 221.7 +/- 15.8 nm and polydispersity index of 0.107 +/- 0.08, 0.135 +/- 0.12 respectively. It was determined that peptide loaded PLGA nanoparticles were successfully phagocytized by macrophage cells and increased NO production at 2-folds (*P < 0.05) in contrast to free peptide, and 3-folds (*P < 0.01) in contrast to control. CONCLUSION: In conclusion, for the first time, W-1 L19 peptide loaded PLGA nanoparticles were successfully synthesized and immunogenic properties evaluated. Obtained results showed that PLGA nanoparticles enhanced the capacity of W-1 L19 peptide to induce nitric oxide production in vitro due to its adjuvant properties. Depend on the obtained results, these nanoparticles can be accepted as potential vaccine candidate against Canine Parvovirus. Studies targeting PLGA nanoparticles based delivery system must be maintained in near future in order to develop new and more effective nano-vaccine formulations. PMID- 26482776 TI - The role of MALAT1/miR-1/slug axis on radioresistance in nasopharyngeal carcinoma. AB - Recent studies demonstrated that long non-coding RNAs (lncRNAs) have a critical role in the regulation of cancer progression and metastasis. However, little is known whether lncRNA regulated nasopharyngeal carcinoma (NPC) cell radioresistance. In the present study, we found that MALAT1 was significantly upregulated in NPC cell lines and tissues. Knockdown of MALAT1 could sensitize NPC cells to radiation both in vitro and in vivo. Interestingly, we found that MALAT1 regulated radioresistance by modulating cancer stem cell (CSC) activity. Furthermore, we found that there was reciprocal repression between MALAT1 and miR 1, and slug was identified as a downstream target of miR-1. Taking these observations into consideration, we proposed that MALAT1 regulated CSC activity and radioresistance by modulating miR-1/slug axis, which indicated that MALAT1 could act as a therapeutic target for NPC patients. PMID- 26482777 TI - Leu/Val SNP polymorphism of CYP1B1 and risk of uterine leiomyoma in a Black population. AB - Uterine leiomyoma (UL) is the most commonly occurring benign tumor that affects women of reproductive ages. Studies strongly suggest that ULs are hormonally dependent and that genes acting in estrogen metabolism might be involved in their development. The focus of this case-control study was to determine whether the Leucine432Valine single-nucleotide polymorphism (SNP) in the gene encoding cytochrome P450 1B1 (CYP1B1) was associated with an increased risk of UL in Black Barbadian women. The investigation comprised 37 women clinically diagnosed with UL and 52 controls. The CYP1B1 Leu432Val polymorphism (Leu/Val) was analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. The homozygous Valine432 variant (Val/Val) was predominant in both cases and controls for this population (89 and 83 %, respectively). The odds ratio for risk of developing the disease was 1.33, but this was not statistically significant. We discuss a possible protective function for CYP1B1 based on the high prevalence of this mutant SNP and its lack of association with UL. PMID- 26482778 TI - Clinical characteristics of mirror syndrome: a comparison of 10 cases of mirror syndrome with non-mirror syndrome fetal hydrops cases. AB - OBJECTIVE: To investigate clinical features of mirror syndrome. METHODS: We retrospectively reviewed 71 cases of fetal hydrops with or without mirror syndrome, and compared with respect to maternal age, the body mass index, the primipara rate, the gestational age at delivery, the timing of fetal hydrops onset, the severity of fetal edema, placental swelling, the laboratory data and the fetal mortality. The data are expressed as the medians. RESULTS: Mirror syndrome developed in 29% (10/35) of the cases with fetal hydrops. In mirror group, the onset time of fetal hydrops was significantly earlier (29 weeks versus 31 weeks, p = 0.011), and the severity of fetal hydrops (fetal edema/biparietal diameter) was significantly higher than non-mirror group (0.23 versus 0.16, p < 0.001). There was significantly higher serum human chorionic gonadotropin (hCG) (453,000 IU/L versus 80,000 IU/L, p < 0.001) and lower hemoglobin (8.9 g/dL versus 10.1 g/dL, p =0.002), hypoalbuminemia (2.3 mg/dL versus 2.7 mg/dL, p = 0.007), hyperuricemia (6.4 mg/dL versus 5.0 mg/dL, p = 0.043) in mirror group. CONCLUSION: Mirror syndrome is occurred frequently in early and severe fetal hydrops and cause hemodilution and elevation of serum hCG. PMID- 26482779 TI - Electroencephalography During Hemiarch Replacement With Moderate Hypothermic Circulatory Arrest. AB - BACKGROUND: This study aimed to characterize intraoperative electroencephalography (EEG) during moderate hypothermic circulatory arrest (MHCA) with selective antegrade cerebral perfusion (SACP), which has not been described previously. METHODS: This was a single-institution retrospective study of patients undergoing aortic hemiarch replacement using MHCA (temperatures <28 degrees C at circulatory arrest [CA]) and unilateral SACP with EEG monitoring from July 1, 2013 to November 1, 2014. The EEG pattern was determined before and immediately after CA, as well as after establishment of SACP. Patient and procedural characteristics and outcomes were determined and compared after stratification by the presence of ischemic EEG changes. RESULTS: The study included 71 patients. Before CA, 47 patients (66%) demonstrated a continuous EEG pattern, with or without periodic complexes, and 24 (34%) had a burst suppression EEG pattern. Immediately after CA, abrupt loss of electrocerebral activity occurred in 32 patients (45%), suggestive of cerebral ischemia. Establishment of unilateral SACP rapidly restored electrocerebral activity in all but 2 patients. One patient had persistent loss of left-sided activity, which resolved after transition to bilateral SACP. Another patient had persistent global loss of activity and was placed back on cardiopulmonary bypass for further cooling before reinitiation of CA. No significant differences in characteristics or outcomes were assessed between patients with and without loss of EEG activity. CONCLUSIONS: Nearly half of patients undergoing hemiarch replacement with MHCA/SACP experience abrupt loss of electrocerebral activity after CA is initiated. Although unilateral SACP usually restores prearrest electrocerebral activity, intraoperative EEG may be particularly valuable for the identification of patients with persistent cerebral ischemia even after SACP. PMID- 26482780 TI - Predicted Risk of Mortality, Transfusion, and Postoperative Outcomes in Isolated Primary Valve Operations. AB - BACKGROUND: Transfusion has been linked with increased postoperative morbidity and death after cardiac operations. The purpose of this study was to determine the associations among The Society of Thoracic Surgeons Predicted Risk of Mortality (PROM), transfusion, and postoperative outcomes in patients who underwent isolated primary valve operations. METHODS: A retrospective review of the local Society of Thoracic Surgeons database of 1,575 adults undergoing isolated primary valve operations from 2003 to 2013 at a United States academic center was performed. Patients were compared by their postoperative transfusion status (NONE vs TRANS) and by PROM. Taking into account procedure type and preoperative hemoglobin, three-step multiple linear or logistic regression analyses were performed to assess (1) the influence of PROM on postoperative outcomes, (2) influence of PROM on transfusion, and (3) influence of PROM and transfusion on postoperative outcomes. RESULTS: Of 1,575 patients studied, 1,245 (79%) received transfusions. The mean PROM was 1.2% (95% confidence interval [CI], 1.1 to 1.3) for patients in the NONE group, and was 2.7% (95% CI, 2.6 to 2.9) for the TRANS group. The correlation between PROM and total red blood cell units transfused was r = 0.31 (p < 0.0001). Patients with a PROM of 4% to 8% (odds ratio [OR], 2.10; 95% CI, 1.28 to 3.45) and exceeding 8% (OR 3.80, 95% CI, 1.35 to 10.68) were more likely to receive transfusions than the low-risk (<4%) PROM stratum. For each percentage increase in PROM, the odds of transfusion increased by 27% (95% CI, 16% to 39%), controlling for procedure type and preoperative hemoglobin. There were no 30-day deaths in the NONE group, and rates of stroke, renal failure, and mediastinitis were lower. Composite event rates increased with increasing PROM (OR, 1.39; 95% CI, 1.19 to 1.63), with TRANS patients consistently showing a higher risk of major adverse cardiac events than NONE patients (OR, 7.47; 95% CI, 2.08 to 26.80). CONCLUSIONS: Increased PROM yielded higher risks of transfusion. Postoperative outcomes were worse in patients who received a transfusion. This study suggests that the association between transfusion and clinical outcomes may be partly explained by the higher PROM among patients who ultimately received transfusions. PMID- 26482781 TI - Nineteen-Millimeter Bioprosthetic Aortic Valves Are Safe and Effective for Elderly Patients With Aortic Stenosis. AB - BACKGROUND: Replacing a stenotic aortic valve with 19-mm bioprostheses remains controversial owing to potential patient-prosthesis mismatch concerns. We report a single-center 10 year experience with 19-mm bioprosthetic valves implanted in elderly patients. We hypothesized patients would have acceptable in-hospital and long-term outcomes. METHODS: Between January 2002 and December 2011, 257 patients underwent aortic valve replacement with a 19-mm prosthesis, of whom 182 had available follow-up echocardiographic studies. Mean age was 77.4 +/- 8.4 years, and 10 of 257 (4%) were male. Outcomes of interest included early and late mortality, peak and mean aortic valve gradients, and left ventricular mass regression. RESULTS: Operative mortality was 3.5% (9 of 257). Median postoperative echocardiographic time was 16 months. On follow-up echocardiography, mean peak aortic valve gradient decreased from 76 +/- 27 mm Hg preoperatively to 32 +/- 13 mm Hg and the mean gradient decreased from 46 +/- 17 mm Hg to 18 +/- 8 mm Hg (both p < 0.001) Mean left ventricular mass decreased from 191 g to 162 g (p < 0.001). Postoperative survival did not differ significantly between patients who met the criteria for patient-prosthesis mismatch and those who did not (p = 0.607). CONCLUSIONS: In a series of elderly patients with aortic stenosis who were implanted with 19-mm bioprosthetic valves, long-term follow-up showed significant left ventricular mass regression and peak and mean aortic valve gradient reductions. The use of 19-mm aortic valves is safe and efficacious for elderly patients with a small aortic root. PMID- 26482782 TI - Sequentially Updated Discharge Model for Optimizing Hospital Resource Use and Surgical Patients' Satisfaction. AB - BACKGROUND: The ability to estimate cardiac surgical patients' length of stay (LOS) and discharge to a continuing care facility (nonhome discharge) may allow earlier discharge planning and optimal use of limited hospital resources. We developed a sequentially updated tool for postoperative discharge planning. METHODS: Using preoperative, intraoperative, and postoperative day (POD) 2 and POD 4 variables, we created and validated a model to predict early discharge (less than 4 days), standard discharge (5 to 8 days), delayed discharge (9 to 14 days), late discharge (more than 15 days), and nonhome discharge. RESULTS: When predicting LOS, model accuracy using preoperative variables alone had a C statistic of 0.80, but improved with sequential addition of intraoperative and POD 2 (0.87) and POD 4 variables (0.89). At 48 hours, the strongest predictors of longer LOS were higher preoperative creatinine, elevated blood urea nitrogen, lower postoperative albumin, atrial fibrillation, and longer intensive care unit stay. On POD 4, the strongest predictors were red blood cell transfusion, lower postoperative albumin, white blood cell transfusion, longer intensive care unit stay, and readmission to the intensive care unit. For nonhome discharge, however, preoperative variables alone produced a highly predictive model (C-statistic 0.88), and sequential addition of intraoperative and POD 2 (C-statistic 0.91) and POD 4 data (C-statistic 0.90) did not significantly improve it. CONCLUSIONS: This sequentially updated model of postoperative LOS can be used by the discharge planning team to identify both patients imminently ready for discharge and patients with a high likelihood of nonhome discharge, with the goals of decreasing unnecessary hospital days, managing patients' expectations, and engaging patients early in the discharge process. PMID- 26482783 TI - Aortic Root Replacement in Octogenarians Offers Acceptable Perioperative and Late Outcomes. AB - BACKGROUND: As the proportion of the population more than 80 years of age increases, cardiac surgeons will increasingly be consulted to operate on this high-risk patient group. The aim of this study is to evaluate the perioperative and late outcomes of octogenarians undergoing aortic root replacement in comparison with younger patients. METHODS: All patients undergoing aortic root replacement at our institution between 2005 and 2012 (n = 592) were retrospectively reviewed. Patients were stratified according to their age at surgery: patients less than 80 years old (group LT80, n = 558) and octogenarians (group OG, n = 34). Primary outcomes of interest were inhospital mortality and perioperative complication rate. RESULTS: Patients in the OG group had significantly higher rates of preoperative stroke history, atrial fibrillation, and coronary artery disease. Indication for surgery was type A aortic dissection in 62 (10.5%), thoracic aortic aneurysm in 514 (86.8%), and endocarditis in 11 (1.9%), with no intergroup differences. Inhospital mortality was not significantly different between groups (5.9% OG versus 2.3% LT80, p = 0.21), and postoperative atrial fibrillation was more common in OG (60.6% OG versus 38.5% LT80, p = 0.01). Type A dissection, diabetes mellitus, and prior cardiac surgery were independent predictors of inhospital mortality or postoperative stroke. CONCLUSIONS: Octogenarians can safely undergo aortic root replacement with moderately worse but acceptable perioperative mortality and late survival. Further studies are necessary to determine which subset of octogenarians are at the highest operative risk and may benefit from a conservative approach. PMID- 26482784 TI - Is Thymomectomy Alone Appropriate for Stage I (T1N0M0) Thymoma? Results of a Propensity-Score Analysis. AB - BACKGROUND: The optimal mode of resection for thymoma in nonmyasthenic patients remains unclear. The aim of this study was to explore whether or not thymomectomy alone is a relevant option for patients with stage I (T1N0M0) thymoma in the proposed TNM classification. METHODS: We investigated 2,835 patients with thymic epithelial tumors treated at 32 institutions participating in the Japanese Association for Research on the Thymus (JART). A total of 1286 patients with thymomectomy: resection of thymoma with partial thymectomy (n = 289) or thymothymomectomy: resection of thymoma with total thymectomy (n = 997) for stage I thymoma were included. Surgical and oncologic outcomes were compared between the 2 groups. RESULTS: Patients who underwent thymomectomy were older (61.1 versus 57.0 years; p = 0.000) and had smaller tumors (4.77 versus 5.99 cm; p = 0.000) than those who underwent thymothymomectomy. There was a significant difference in the distribution of histologic subtype (p = 0.007). After propensity-score matching, the matched cohort consisted of 276 patients in each group. Postoperative complications were seen more frequently in the thymothymomectomy group than in the thymomectomy group (8.3% versus 4.3%; p = 0.0397). The 5-year overall survival rate was 97.3% in the thymomectomy group and 96.9% in the thymothymomectomy group (p = 0.487). Patients who underwent thymomectomy tended to have local recurrence more frequently than did those who underwent thymothymomectomy (2.2% versus 0.4%; p = 0.0613). CONCLUSIONS: Thymomectomy alone is acceptable for stage I thymoma in regard to postoperative complications and prognosis. Further studies are needed to evaluate long-term outcomes. PMID- 26482785 TI - Heparan sulfate proteoglycans undergo differential expression alterations in right sided colorectal cancer, depending on their metastatic character. AB - BACKGROUND: Heparan sulfate proteoglycans (HSPGs) are complex molecules involved in the growth, invasion and metastatic properties of cancerous cells. This study analyses the alterations in the expression patterns of these molecules in right sided colorectal cancer (CRC), both metastatic and non-metastatic. METHODS: Twenty right sided CRCs were studied. A transcriptomic approach was used, employing qPCR to analyze both the expression of the enzymes involved in heparan sulfate (HS) chains biosynthesis, as well as the proteoglycan core proteins. Since some of these proteoglycans can also carry chondroitin sulfate (CS) chains, we include the study of the genes involved in the biosynthesis of these glycosaminoglycans. Immunohistochemical techniques were also used to analyze tissue expression of particular genes showing significant expression differences, of potential interest. RESULTS: Changes in proteoglycan core proteins differ depending on their location; those located intracellularly or in the extracellular matrix show very similar alteration patterns, while those located on the cell surface vary greatly depending on the nature of the tumor: glypicans 1, 3, 6 and betaglycan are affected in the non-metastatic tumors, whereas in the metastatic, only glypican-1 and syndecan-1 are modified, the latter showing opposing alterations in levels of RNA and of protein, suggesting post transcriptional regulation in these tumors. Furthermore, in non-metastatic tumors, polymerization of glycosaminoglycan chains is modified, particularly affecting the synthesis of the tetrasaccharide linker and the initiation and elongation of CS chains, HS chains being less affected. Regarding the enzymes responsible for the modificaton of the HS chains, alterations were only found in non-metastatic tumors, affecting N-sulfation and the isoforms HS6ST1, HS3ST3B and HS3ST5. In contrast, synthesis of the CS chains suggests changes in epimerization and sulfation of the C4 and C2 in both types of tumor. CONCLUSIONS: Right sided CRCs show alterations in the expression of HSPGs, including the expression of the cell surface core proteins, many glycosiltransferases and some enzymes that modify the HS chains depending on the metastatic nature of the tumor, resulting more affected in non-metastatic ones. However, matrix proteoglycans and enzymes involved in CS fine structure synthesis are extensively modified independetly of the presence of lymph node metastasis. PMID- 26482786 TI - Testing antismoking messages for Air Force trainees. AB - INTRODUCTION: Young adults in the military are aggressively targeted by tobacco companies and are at high risk of tobacco use. Existing antismoking advertisements developed for the general population might be effective in educating young adults in the military. This study evaluated the effects of different themes of existing antismoking advertisements on perceived harm and intentions to use cigarettes and other tobacco products among Air Force trainees. METHODS: In a pretest-post-test experiment, 782 Airmen were randomised to view antismoking advertisements in 1 of 6 conditions: anti-industry, health effects+anti-industry, sexual health, secondhand smoke, environment+anti-industry or control. We assessed the effect of different conditions on changes in perceived harm and intentions to use cigarettes, electronic cigarettes, smokeless tobacco, hookah and cigarillos from pretest to post-test with multivariable linear regression models (perceived harm) and zero-inflated Poisson regression model (intentions). RESULTS: Antismoking advertisements increased perceived harm of various tobacco products and reduced intentions to use. Advertisements featuring negative effects of tobacco on health and sexual performance coupled with revealing tobacco industry manipulations had the most consistent pattern of effects on perceived harm and intentions. CONCLUSIONS: Antismoking advertisements produced for the general public might also be effective with a young adult military population and could have spillover effects on perceptions of harm and intentions to use other tobacco products besides cigarettes. Existing antismoking advertising may be a cost-effective tool to educate young adults in the military. PMID- 26482787 TI - Study protocol: identifying and delivering point-of-care information to improve care coordination. AB - BACKGROUND: The need for deliberately coordinated care is noted by many national level organizations. The Department of Veterans Affairs (VA) recently transitioned primary care clinics nationwide into Patient Aligned Care Teams (PACTs) to provide more accessible, coordinated, comprehensive, and patient centered care. To better serve this purpose, PACTs must be able to successfully sequence and route interdependent tasks to appropriate team members while also maintaining collective situational awareness (coordination). Although conceptual frameworks of care coordination exist, few explicitly articulate core behavioral markers of coordination or the related information needs of team members attempting to synchronize complex care processes across time for a shared patient population. Given this gap, we partnered with a group of frontline primary care personnel at ambulatory care sites to identify the specific information needs of PACT members that will enable them to coordinate their efforts to provide effective, coordinated care. The study has three objectives: (1) development of measurable, prioritized point-of-care criteria for effective PACT coordination; (2) identifying the specific information needed at the point of care to optimize coordination; and (3) assessing the effect of adopting the aforementioned coordination standards on PACT clinicians' coordination behaviors. METHODS/DESIGN: The study consists of three phases. In phase 1, we will employ the Productivity Measurement and Enhancement System (ProMES), a structured approach to performance measure creation from industrial/organizational psychology, to develop coordination measures with a design team of 6-10 primary care personnel; in phase 2, we will conduct focus groups with the phase 1 design team to identify point-of-care information needs. Phase 3 is a two-arm field experiment (n PACT = 28/arm); intervention arm PACTs will receive monthly feedback reports using the measures developed in phase 1 and attend brief monthly feedback sessions. Control arm PACTs will receive no intervention. PACTs will be followed prospectively for up to 1 year. DISCUSSION: This project combines both action research and implementation science methods to address important gaps in the existing care coordination literature using a partnership-based research design. It will provide an evidence-based framework for care coordination by employing a structured methodology for a systematic approach to care coordination in PACT settings and identifying the information needs that produce the most successful coordination of care. TRIAL REGISTRATION: ISRCTN15412521. PMID- 26482788 TI - Depression among people with epilepsy in Northwest Ethiopia: a cross-sectional institution based study. AB - BACKGROUND: Epilepsy is the world's most common neurological disorder, affecting approximately 50 million people worldwide and contributed to different psychiatric illness. Depression is one of the most frequent co morbid psychiatric disorders that affects the life of the patients'. This study aimed to assess the prevalence of depression and associated factors among epileptic patients attending the outpatient department of the University of Gondar Hospital, Northwest Ethiopia, 2014. METHODS: Institution based quantitative cross- sectional study was conducted among 405 individual with epilepsy. The participants were selected using systematic random sampling technique. Semistructured questionnaires were used to obtain socio-demographic and clinical data. Depression was measured using Beck's Depression Inventory Binary logistic regression used for analysis. RESULTS: The estimated, prevalence of depression was found to be 45.2 %. Out of these (29.6 %) were classified as mild, (14.8 %) as moderate and (0.8 %) were severely depressed. A lower educational status was associated with an increased prevalence of depression and the adjusted odds ratio (AOR) for the illiterate [can't read and write] was 8.32 [95 % Confidence Interval (CI): 4.83, 14.29]. Perceived stress (AOR = 6.21, CI 3.69, 10.44), onset of illness <6 years (AOR = 5.29, CI 4.09, 15.89), seizure frequency of [1-11 per year (AOR = 1.34, CI 1.41, 4.36), >=1 per month (AOR = 7.83, CI 3.52, 17.40)], poly-pharmacy (AOR = 7.63, CI 2.74, 21.26)] and difficulties of adherence to antiepileptic drugs (AOR = 4.80, CI 2.57, 8.96) were also found to be independently associated with depression. CONCLUSION: Overall, the prevalence of depression was found to be high. Lower educational status, early onset of illness, seizure frequency, poly-pharmacy and difficulties of adherence to anti epileptic drugs (AEDs) were factors statistically associated with depression. Strengthening the educational status of the patients on the effect of early onset of the illness, frequent seizure occurrence and difficulty of adherence to AEDs as a contributing factors for other co-morbid psychiatric disorder are suggested in the clinical care setting. PMID- 26482789 TI - The effect of mother's educational status on early initiation of breastfeeding: further analysis of three consecutive Nepal Demographic and Health Surveys. AB - BACKGROUND: The World Health Organization recommends initiating breastfeeding within the first hour of birth. This study is aimed at assessing the effect of the mother's education on early initiation of breastfeeding. METHODS: Data from the Nepal Demographic and Health Surveys (NDHS) 2001, 2006 and 2011 were used which included 12,845 last born children born within 5 years before the surveys. Early initiation of breastfeeding was defined as the initiation of breastfeeding within the first hour after birth. Hierarchical modelling was used to ascertain the association of maternal education and early initiation of breastfeeding, after controlling for other covariates in a multiple logistic regression. RESULTS: Maternal education was associated with a higher likelihood of early initiation of breastfeeding in each survey. Pooled data analysis revealed higher odds of early initiation of breastfeeding among the mothers with primary education (adjusted odds ratio (OR) 1.24, 95 % confidence interval (CI): 1.09, 1.42) and secondary or higher education (OR: 1.63 95 % CI: 1.42, 1.88). In the most recent NDHS 2011 survey, odds of early initiation of breastfeeding was higher among mothers with primary education (OR: 1.52; 95 % CI: 1.21, 1.91) and mothers with secondary or higher education (OR: 2.20; 95 % CI: 1.76, 2.76) compared to mothers with no education. Similarly, the odds of early initiation of breastfeeding was higher among mothers with secondary and higher education in the 2006 data (OR: 1.66; 95 % CI: 1.30, 2.12) and in 2001 (OR = 1.30; 95 % CI: 1.00, 1.67). CONCLUSIONS: As the association between a mother's educational status and her likelihood of early initiation of breastfeeding increases, long-term approaches to prioritising education for women and girls should be explored. In the short term, uneducated mothers should be targeted with breastfeeding promotion strategies such as counselling and peer education. PMID- 26482790 TI - Paramutation in Drosophila Requires Both Nuclear and Cytoplasmic Actors of the piRNA Pathway and Induces Cis-spreading of piRNA Production. AB - Transposable element activity is repressed in the germline in animals by PIWI interacting RNAs (piRNAs), a class of small RNAs produced by genomic loci mostly composed of TE sequences. The mechanism of induction of piRNA production by these loci is still enigmatic. We have shown that, in Drosophila melanogaster, a cluster of tandemly repeated P-lacZ-white transgenes can be activated for piRNA production by maternal inheritance of a cytoplasm containing homologous piRNAs. This activated state is stably transmitted over generations and allows trans silencing of a homologous transgenic target in the female germline. Such an epigenetic conversion displays the functional characteristics of a paramutation, i.e., a heritable epigenetic modification of one allele by the other. We report here that piRNA production and trans-silencing capacities of the paramutated cluster depend on the function of the rhino, cutoff, and zucchini genes involved in primary piRNA biogenesis in the germline, as well as on that of the aubergine gene implicated in the ping-pong piRNA amplification step. The 21-nt RNAs, which are produced by the paramutated cluster, in addition to 23- to 28-nt piRNAs are not necessary for paramutation to occur. Production of these 21-nt RNAs requires Dicer-2 but also all the piRNA genes tested. Moreover, cytoplasmic transmission of piRNAs homologous to only a subregion of the transgenic locus can generate a strong paramutated locus that produces piRNAs along the whole length of the transgenes. Finally, we observed that maternally inherited transgenic small RNAs can also impact transgene expression in the soma. In conclusion, paramutation involves both nuclear (Rhino, Cutoff) and cytoplasmic (Aubergine, Zucchini) actors of the piRNA pathway. In addition, since it is observed between nonfully homologous loci located on different chromosomes, paramutation may play a crucial role in epigenome shaping in Drosophila natural populations. PMID- 26482791 TI - Associating Multivariate Quantitative Phenotypes with Genetic Variants in Family Samples with a Novel Kernel Machine Regression Method. AB - The recent development of sequencing technology allows identification of association between the whole spectrum of genetic variants and complex diseases. Over the past few years, a number of association tests for rare variants have been developed. Jointly testing for association between genetic variants and multiple correlated phenotypes may increase the power to detect causal genes in family-based studies, but familial correlation needs to be appropriately handled to avoid an inflated type I error rate. Here we propose a novel approach for multivariate family data using kernel machine regression (denoted as MF-KM) that is based on a linear mixed-model framework and can be applied to a large range of studies with different types of traits. In our simulation studies, the usual kernel machine test has inflated type I error rates when applied directly to familial data, while our proposed MF-KM method preserves the expected type I error rates. Moreover, the MF-KM method has increased power compared to methods that either analyze each phenotype separately while considering family structure or use only unrelated founders from the families. Finally, we illustrate our proposed methodology by analyzing whole-genome genotyping data from a lung function study. PMID- 26482792 TI - The Roles of Two miRNAs in Regulating the Immune Response of Sea Cucumber. AB - MicroRNAs (miRNAs) have emerged as key regulators in many pathological processes by suppressing the transcriptional and post-transcriptional expression of target genes. MiR-2008 was previously found to be significantly up-regulated in diseased sea cucumber Apostichopus japonicus by high-through sequencing, whereas the reads of miR-137, a well-documented tumor repressor, displayed no significant change. In the present study, we found that miR-137 expression was slightly attenuated and miR-2008 was significantly enhanced after Vibrio splendidus infection or Lipopolysaccharides application. Further target screening and dual-luciferase reporter assay revealed that the two important miRNAs shared a common target gene of betaine-homocysteine S-methyltransferase (AjBHMT), which exhibited noncorrelated messenger RNA and protein expression patterns after bacterial challenge. In order to fully understand their regulatory mechanisms, we conducted the functional experiments in vitro and in vivo. The overexpression of miR-137 in sea cucumber or primary coelomocytes significantly decreased, whereas the inhibition of miR-137 increased the mRNA and protein expression levels of AjBHMT. In contrast, miR-2008 overexpression and inhibition showed no effect on AjBHMT mRNA levels, but the concentration of AjBHMT protein displayed significant changes both in vitro and in vivo. Consistently, the homocysteine (Hcy) contents were also accordingly altered in the aberrant expression analysis of both miRNAs, consistent with the results of the AjBHMT silencing assay in vitro and in vivo. More importantly, small interfering RNA mediated AjBHMT knockdown and Hcy exposure analyses both significantly increased reactive oxygen species (ROS) production and decreased the number of surviving invasive pathogen in sea cucumber coelomocytes. Taken together, these findings confirmed the differential roles of sea cucumber miR-137 and miR-2008 in regulating the common target AjBHMT to promote ROS production and the clearance of pathogenic microorganisms through Hcy accumulation. PMID- 26482793 TI - Targeted Chromosomal Translocations and Essential Gene Knockout Using CRISPR/Cas9 Technology in Caenorhabditis elegans. AB - Many genes play essential roles in development and fertility; their disruption leads to growth arrest or sterility. Genetic balancers have been widely used to study essential genes in many organisms. However, it is technically challenging and laborious to generate and maintain the loss-of-function mutations of essential genes. The CRISPR/Cas9 technology has been successfully applied for gene editing and chromosome engineering. Here, we have developed a method to induce chromosomal translocations and produce genetic balancers using the CRISPR/Cas9 technology and have applied this approach to edit essential genes in Caenorhabditis elegans. The co-injection of dual small guide RNA targeting genes on different chromosomes resulted in reciprocal translocation between nonhomologous chromosomes. These animals with chromosomal translocations were subsequently crossed with animals that contain normal sets of chromosomes. The F1 progeny were subjected to a second round of Cas9-mediated gene editing. Through this method, we successfully produced nematode strains with specified chromosomal translocations and generated a number of loss-of-function alleles of two essential genes (csr-1 and mes-6). Therefore, our method provides an easy and efficient approach to generate and maintain loss-of-function alleles of essential genes with detailed genetic background information. PMID- 26482794 TI - The Nature of Genetic Variation for Complex Traits Revealed by GWAS and Regional Heritability Mapping Analyses. AB - We use computer simulations to investigate the amount of genetic variation for complex traits that can be revealed by single-SNP genome-wide association studies (GWAS) or regional heritability mapping (RHM) analyses based on full genome sequence data or SNP chips. We model a large population subject to mutation, recombination, selection, and drift, assuming a pleiotropic model of mutations sampled from a bivariate distribution of effects of mutations on a quantitative trait and fitness. The pleiotropic model investigated, in contrast to previous models, implies that common mutations of large effect are responsible for most of the genetic variation for quantitative traits, except when the trait is fitness itself. We show that GWAS applied to the full sequence increases the number of QTL detected by as much as 50% compared to the number found with SNP chips but only modestly increases the amount of additive genetic variance explained. Even with full sequence data, the total amount of additive variance explained is generally below 50%. Using RHM on the full sequence data, a slightly larger number of QTL are detected than by GWAS if the same probability threshold is assumed, but these QTL explain a slightly smaller amount of genetic variance. Our results also suggest that most of the missing heritability is due to the inability to detect variants of moderate effect (~0.03-0.3 phenotypic SDs) segregating at substantial frequencies. Very rare variants, which are more difficult to detect by GWAS, are expected to contribute little genetic variation, so their eventual detection is less relevant for resolving the missing heritability problem. PMID- 26482795 TI - Regulation of CTP Synthase Filament Formation During DNA Endoreplication in Drosophila. AB - CTP synthase (CTPsyn) plays an essential role in DNA, RNA, and lipid synthesis. Recent studies in bacteria, yeast, and Drosophila all reveal a polymeric CTPsyn structure, which dynamically regulates its enzymatic activity. However, the molecular mechanism underlying the formation of CTPsyn polymers is not completely understood. In this study, we found that reversible ubiquitination regulates the dynamic assembly of the filamentous structures of Drosophila CTPsyn. We further determined that the proto-oncogene Cbl, an E3 ubiquitin ligase, controls CTPsyn filament formation in endocycles. While the E3 ligase activity of Cbl is required for CTPsyn filament formation, Cbl does not affect the protein levels of CTPsyn. It remains unclear whether the regulation of CTPsyn filaments by Cbl is through direct ubiquitination of CTPsyn. In the absence of Cbl or with knockdown of CTPsyn, the progression of the endocycle-associated S phase was impaired. Furthermore, overexpression of wild-type, but not enzymatically inactive CTPsyn, rescued the endocycle defect in Cbl mutant cells. Together, these results suggest that Cbl influences the nucleotide pool balance and controls CTPsyn filament formation in endocycles. This study links Cbl-mediated ubiquitination to the polymerization of a metabolic enzyme and reveals a role for Cbl in endocycles during Drosophila development. PMID- 26482796 TI - Genome-Wide Scan for Adaptive Divergence and Association with Population-Specific Covariates. AB - In population genomics studies, accounting for the neutral covariance structure across population allele frequencies is critical to improve the robustness of genome-wide scan approaches. Elaborating on the BayEnv model, this study investigates several modeling extensions (i) to improve the estimation accuracy of the population covariance matrix and all the related measures, (ii) to identify significantly overly differentiated SNPs based on a calibration procedure of the XtX statistics, and (iii) to consider alternative covariate models for analyses of association with population-specific covariables. In particular, the auxiliary variable model allows one to deal with multiple testing issues and, providing the relative marker positions are available, to capture some linkage disequilibrium information. A comprehensive simulation study was carried out to evaluate the performances of these different models. Also, when compared in terms of power, robustness, and computational efficiency to five other state-of-the-art genome-scan methods (BayEnv2, BayScEnv, BayScan, flk, and lfmm), the proposed approaches proved highly effective. For illustration purposes, genotyping data on 18 French cattle breeds were analyzed, leading to the identification of 13 strong signatures of selection. Among these, four (surrounding the KITLG, KIT, EDN3, and ALB genes) contained SNPs strongly associated with the piebald coloration pattern while a fifth (surrounding PLAG1) could be associated to morphological differences across the populations. Finally, analysis of Pool-Seq data from 12 populations of Littorina saxatilis living in two different ecotypes illustrates how the proposed framework might help in addressing relevant ecological issues in nonmodel species. Overall, the proposed methods define a robust Bayesian framework to characterize adaptive genetic differentiation across populations. The BayPass program implementing the different models is available at http://www1.montpellier.inra.fr/CBGP/software/baypass/. PMID- 26482797 TI - Sensitive quantification of Clostridium perfringens in human feces by quantitative real-time PCR targeting alpha-toxin and enterotoxin genes. AB - BACKGROUND: Clostridium perfringens is a widespread pathogen, but the precise quantification of this subdominant gut microbe remains difficult due to its low fecal count (particularly in asymptomatic subjects) and also due to the presence of abundant polymerase-inhibitory substances in human feces. Also, information on the intestinal carriage of toxigenic C. perfringens strains in healthy subjects is sparse. Therefore, we developed a sensitive quantitative real-time PCR assays for quantification of C. perfringens in human feces by targeting its alpha-toxin and enterotoxin genes. To validate the assays, we finally observed the occurrence of alpha-toxigenic and enterotoxigenic C. perfringens in the fecal microbiota of healthy Japanese infants and young adults. METHODS: The plc-specific qPCR assay was newly validated, while primers for 16S rRNA and cpe genes were retrieved from literature. The assays were validated for specificity and sensitivity in pre inoculated fecal samples, and were finally applied to quantify C. perfringens in stool samples from apparently healthy infants (n 124) and young adults (n 221). RESULTS: The qPCR assays were highly specific and sensitive, with a minimum detection limit of 10(3) bacterial cells/g feces. Alpha-toxigenic C. perfringens was detected in 36% infants and 33% adults, with counts ranging widely (10(3) 10(7) bacterial cells/g). Intriguingly, the mean count of alpha-toxigenic C. perfringens was significantly higher in infants (6.0+/-1.5 log10 bacterial cells/g), as compared to that in adults (4.8+/-1.2). Moreover, the prevalence of enterotoxigenic C. perfringens was also found to be significantly higher in infants, as compared to that in adults. The mean enterotoxigenic C. perfringens count was 5.9+/-1.9 and 4.8+/-0.8 log10 bacterial cells/g in infants and adults, respectively. CONCLUSIONS: These data indicate that some healthy infants and young adults carry alpha-toxigenic and enterotoxigenic C. perfringens at significant levels, and may be predisposed to related diseases. Thus, high fecal carriage of toxigenic C. perfringens in healthy children warrants further investigation on its potential sources and clinical significance in these subjects. In summary, we present a novel qPCR assay for sensitive and accurate quantification of alpha-toxigenic and enterotoxigenic C. perfringens in human feces, which should facilitate prospective studies of the gut microbiota. PMID- 26482800 TI - Effect of Different Media and Protein Source on Equine Gametes: Potential Impact During In Vitro Fertilization. AB - Equine in vitro fertilization (IVF) is still inconsistent. In the present work, we studied how modified Whitten's (MW) medium and Tissue Culture Medium 199 (TCM) added with Foetal Bovine Serum (FBS; 10% v/v) or Bovine Serum Albumin (BSA; 7 mg/ml) affected equine gametes to subsequently run IVF trials. Compact (Cp) and expanded (Ex) cumuli equine oocytes were matured and placed in TCM or MW supplemented with BSA or FBS for 18-20 h (no sperm added). In Ex oocytes, TCM-199 added with FBS or BSA resulted in higher metaphase II (MII) rates (75.7% and 62.7%, respectively) than MW added with BSA (54%) or FBS (52.2%; p < 0.05); this was not observed for Cp oocytes. Equine sperm were capacitated in the same media at 10 * 10(6) sperm/ml for 4 h at 37 degrees C; total motility and protein tyrosine phosphorylation (PY) were evaluated. While motility remained unchanged, TCM or MW added with FBS enhanced the number of sperm showing PY-stained tails (25 +/- 4.8% and 31 +/- 6.6%; mean +/- SEM, respectively) over BSA supplemented media (3 +/- 1.2% and 11.7 +/- 1.1%) for TCM and MW (p < 0.05). In view of the previous results, sperm were capacitated in TCM + FBS and MW + BSA (control); IVF trials were run in the same media supplemented with 200 ng/ml of progesterone, but no fertilization occurred. Our results show that TCM + FBS enhances Ex equine oocyte's meiotic competence over MW + BSA and TCM or MW added with FBS successfully induce equine PY over media supplemented with BSA. PMID- 26482799 TI - MC1R diversity in Northern Island Melanesia has not been constrained by strong purifying selection and cannot explain pigmentation phenotype variation in the region. AB - BACKGROUND: Variation in human skin pigmentation evolved in response to the selective pressure of ultra-violet radiation (UVR). Selection to maintain darker skin in high UVR environments is expected to constrain pigmentation phenotype and variation in pigmentation loci. Consistent with this hypothesis, the gene MC1R exhibits reduced diversity in African populations from high UVR regions compared to low-UVR non-African populations. However, MC1R diversity in non-African populations that have evolved under high-UVR conditions is not well characterized. METHODS: In order to test the hypothesis that MC1R variation has been constrained in Melanesians the coding region of the MC1R gene was sequenced in 188 individuals from Northern Island Melanesia. The role of purifying selection was assessed using a modified McDonald Kreitman's test. Pairwise FST was calculated between Melanesian populations and populations from the 1000 Genomes Project. The SNP rs2228479 was genotyped in a larger sample (n = 635) of Melanesians and tested for associations with skin and hair pigmentation. RESULTS: We observe three nonsynonymous and two synonymous mutations. A modified McDonald Kreitman's test failed to detect a significant signal of purifying selection. Pairwise FST values calculated between the four islands sampled here indicate little regional substructure in MC1R. When compared to African, European, East and South Asian populations, Melanesians do not exhibit reduced population divergence (measured as FST) or a high proportion of haplotype sharing with Africans, as one might expect if ancestral haplotypes were conserved across high UVR populations in and out of Africa. The only common nonsynonymous polymorphism observed, rs2228479, is not significantly associated with skin or hair pigmentation in a larger sample of Melanesians. CONCLUSIONS: The pattern of sequence diversity here does not support a model of strong selective constraint on MC1R in Northern Island Melanesia This absence of strong constraint, as well as the recent population history of the region, may explain the observed frequencies of the derived rs2228479 allele. These results emphasize the complex genetic architecture of pigmentation phenotypes, which are controlled by multiple, possibly interacting loci. They also highlight the role that population history can play in influencing phenotypic diversity in the absence of strong natural selection. PMID- 26482798 TI - Alcohol consumption induces global gene expression changes in VTA dopaminergic neurons. AB - Alcoholism is associated with dysregulation in the neural circuitry that mediates motivated and goal-directed behaviors. The dopaminergic (DA) connection between the ventral tegmental area (VTA) and the nucleus accumbens is viewed as a critical component of the neurocircuitry mediating alcohol's rewarding and behavioral effects. We sought to determine the effects of binge alcohol drinking on global gene expression in VTA DA neurons. Alcohol-preferring C57BL/6J * FVB/NJ F1 hybrid female mice were exposed to a modified drinking in the dark (DID) procedure for 3 weeks, while control animals had access to water only. Global gene expression of laser-captured tyrosine hydroxylase (TH)-positive VTA DA neurons was measured using microarrays. A total of 644 transcripts were differentially expressed between the drinking and nondrinking mice, and 930 transcripts correlated with alcohol intake during the last 2 days of drinking in the alcohol group. Bioinformatics analysis of alcohol-responsive genes identified molecular pathways and networks perturbed in DA neurons by alcohol consumption, which included neuroimmune and epigenetic functions, alcohol metabolism and brain disorders. The majority of genes with high and specific expression in DA neurons were downregulated by or negatively correlated with alcohol consumption, suggesting a decreased activity of DA neurons in high drinking animals. These changes in the DA transcriptome provide a foundation for alcohol-induced neuroadaptations that may play a crucial role in the transition to addiction. PMID- 26482801 TI - Evidence Supports Specific Braking Function for Inferior PFC. PMID- 26482802 TI - Synthesis of some new amide-linked bipyrazoles and their evaluation as anti inflammatory and analgesic agents. AB - Four series of new bipyrazoles comprising the N-phenylpyrazole scaffold linked to polysubstituted pyrazoles or to antipyrine moiety through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory and analgesic activities. In vitro COX-1/COX-2 inhibition study revealed that compound 16b possessed the lowest IC50 value against both COX-1 and COX-2. Moreover, the effect of the most promising compounds on inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) protein expression in lipopolysaccharide (LPS)-activated rat monocytes was also investigated. The results revealed that some of the synthesized compounds showed anti-inflammatory and/or analgesic activity with less ulcerogenic potential than the reference drug diclofenac sodium and are well tolerated by experimental animals. Moreover, they significantly inhibited iNOS and COX-2 protein expression induced by LPS stimulation. Compounds 16b and 18 were proved to display anti-inflammatory activity superior to diclofenac sodium and analgesic activity equivalent to it with minimal ulcerogenic potential. PMID- 26482803 TI - Establishment of a Human Neuronal Network Assessment System by Using a Human Neuron/Astrocyte Co-Culture Derived from Fetal Neural Stem/Progenitor Cells. AB - Using human cell models mimicking the central nervous system (CNS) provides a better understanding of the human CNS, and it is a key strategy to improve success rates in CNS drug development. In the CNS, neurons function as networks in which astrocytes play important roles. Thus, an assessment system of neuronal network functions in a co-culture of human neurons and astrocytes has potential to accelerate CNS drug development. We previously demonstrated that human hippocampus-derived neural stem/progenitor cells (HIP-009 cells) were a novel tool to obtain human neurons and astrocytes in the same culture. In this study, we applied HIP-009 cells to a multielectrode array (MEA) system to detect neuronal signals as neuronal network functions. We observed spontaneous firings of HIP-009 neurons, and validated functional formation of neuronal networks pharmacologically. By using this assay system, we investigated effects of several reference compounds, including agonists and antagonists of glutamate and gamma aminobutyric acid receptors, and sodium, potassium, and calcium channels, on neuronal network functions using firing and burst numbers, and synchrony as readouts. These results indicate that the HIP-009/MEA assay system is applicable to the pharmacological assessment of drug candidates affecting synaptic functions for CNS drug development. PMID- 26482805 TI - Taxifolin curbs NF-kappaB-mediated Wnt/beta-catenin signaling via up-regulating Nrf2 pathway in experimental colon carcinogenesis. AB - Aberrations in homeostasis mechanisms including Nrf2, inflammatory, and Wnt/beta catenin signaling are the major causative factors implicated in colon cancer development. Hence blocking these pathways through natural interventions pave a new channel for colon cancer prevention. Earlier, we reported the chemopreventive effect of taxifolin (TAX) against colon carcinogenesis. In this study, we aimed to understand the ability of TAX, to modulate the Nrf2, inflammatory and Wnt/beta catenin cascades on 1, 2-dimethyl hydrazine (DMH)-induced mouse colon carcinogenesis. In addition, in silico molecular docking studies were performed to evaluate the binding affinity between TAX and target proteins (Nrf2, beta catenin, and TNF-alpha). We perceived that the increase of serum marker enzyme levels (CEA and LDH) and mast cell infiltration that occurs in the presence of DMH is inverted after TAX treatment. Immunoblot expression and docking analysis revealed that TAX could induce antioxidant response pathway, confirming the enhanced level of Nrf2 protein. It also inhibited NF-kappaB and Wnt signaling by down-regulating the levels of regulatory metabolites such as TNF-alpha, COX-2, beta-catenin, and Cyclin-D1. Collectively, results of our hypothesis shown that TAX is an effective chemopreventive agent capable of modulating inflammatory, Wnt and antioxidant response pathway proteins in tumor microenvironment which explicating its anticancer property. PMID- 26482806 TI - Free RNA polymerase in Escherichia coli. AB - The frequencies of transcription initiation of regulated and constitutive genes depend on the concentration of free RNA polymerase holoenzyme [Rf] near their promoters. Although RNA polymerase is largely confined to the nucleoid, it is difficult to determine absolute concentrations of [Rf] at particular locations within the nucleoid structure. However, relative concentrations of free RNA polymerase at different growth rates, [Rf]rel, can be estimated from the activities of constitutive promoters. Previous studies indicated that the rrnB P2 promoter is constitutive and that [Rf]rel in the vicinity of rrnB P2 increases with increasing growth rate. Recently it has become possible to directly visualize Rf in growing Escherichia coli cells. Here we examine some of the important issues relating to gene expression based on these new observations. We conclude that: (i) At a growth rate of 2 doublings/h, there are about 1000 free and 2350 non-specifically DNA-bound RNA polymerase molecules per average cell (12 and 28%, respectively, of 8400 total) which are in rapid equilibrium. (ii) The reversibility of the non-specific binding generates more than 1000 free RNA polymerase molecules every second in the immediate vicinity of the DNA. Of these, most rebind non-specifically to the DNA within a few ms; the frequency of non specific binding is at least two orders of magnitude greater than specific binding and transcript initiation. (iii) At a given amount of RNA polymerase per cell, [Rf] and the density of non-specifically DNA-bound RNA polymerase molecules along the DNA both vary reciprocally with the amount of DNA in the cell. (iv) At 2 doublings/h an E. coli cell contains, on the average, about 1 non-specifically bound RNA polymerase per 9 kbp of DNA and 1 free RNA polymerase per 20 kbp of DNA. However some DNA regions (i.e. near active rRNA operons) may have significantly higher than average [Rf]. PMID- 26482807 TI - Quantitative analysis and reduction of the eco-toxicity risk of heavy metals for the fine fraction of automobile shredder residue (ASR) using H2O2. AB - Automobile shredder residue (ASR) fraction (size <0.25mm) can be considered as hazardous due to presence of high concentrations of heavy metals. Hydrogen peroxide combined with nitric acid has been used for the recovery of heavy metals (Zn, Cu, Mn, Fe, Ni, Pb, Cd and Cr) from the fine fraction of ASR. A sequential extraction procedure has also been used to determine the heavy metal speciation in the fine fraction of ASR before and after treatment. A risk analysis of the fine fraction of ASR before and after treatment was conducted to assess the bioavailability and eco-toxicity of heavy metals. These results showed that the recovery of heavy metals from ASR increased with an increase in the hydrogen peroxide concentration. A high concentration of heavy metals was found to be present in Cbio fractions (the sum of the exchangeable and carbonate fractions) in the fine fraction of ASR, indicating high toxicity risk. The Cbio rate of all selected heavy metals was found to range from 8.6% to 33.4% of the total metal content in the fine fraction of ASR. After treatment, Cbio was reduced to 0.3 3.3% of total metal upon a treatment with 2.0% hydrogen peroxide. On the basis of the risk assessment code (RAC), the environmental risk values for heavy metals in the fine fraction of ASR reflect high risk/medium risk. However, after treatment, the heavy metals would be categorized as low risk/no risk. The present study concludes that hydrogen peroxide combined with nitric acid is a promising treatment for the recovery and reduction of the eco-toxicity risk of heavy metals in ASR. PMID- 26482808 TI - Assessing the variables affecting on the rate of solid waste generation and recycling: An empirical analysis in Prespa Park. AB - Economic development, urbanization, and improved living standards increase the quantity and complexity of generated solid waste. Comprehensive study of the variables influencing household solid waste production and recycling rate is crucial and fundamental for exploring the generation mechanism and forecasting future dynamics of household solid waste. The present study is employed in the case study of Prespa Park. A model, based on the interrelationships of economic, demographic, housing structure and waste management policy variables influencing the rate of solid waste generation and recycling is developed and employed. The empirical analysis is based on the information derived from a field questionnaire survey conducted in Prespa Park villages for the year 2014. Another feature of this study is to test whether a household's waste generation can be decoupled from its population growth. Descriptive statistics, bivariate correlation analysis and F-tests are used to know the relationship between variables. One-way and two-way fixed effects models data analysis techniques are used to identify variables that determine the effectiveness of waste generation and recycling at household level in the study area. The results reveal that households with heterogeneous characteristics, such as education level, mean building age and income, present different challenges of waste reduction goals. Numerically, an increase of 1% in education level of population corresponds to a waste reduction of 3kg on the annual per capita basis. A village with older buildings, in the case of one year older of the median building age, corresponds to a waste generation increase of 12kg. Other economic and policy incentives such as the mean household income, pay-as-you-throw, percentage of population with access to curbside recycling, the number of drop-off recycling facilities available per 1000 persons and cumulative expenditures on recycling education per capita are also found to be effective measures in waste reduction. The mean expenditure for recycling education spent on a person for years 2010 and 2014 is 12 and 14 cents, respectively and it vary from 0 to ?1. For years 2010 and 2014, the mean percentage of population with access to curbside recycling services is 38.6% and 40.3%, and the mean number of drop-off recycling centers per 1000 persons in the population is 0.29 and 0.32, respectively. Empirical evidence suggests that population growth did not necessarily result in increases in waste generation. The results provided are useful when planning, changing or implementing sustainable municipal solid waste management. PMID- 26482809 TI - Verifying the performance of artificial neural network and multiple linear regression in predicting the mean seasonal municipal solid waste generation rate: A case study of Fars province, Iran. AB - Predicting the mass of solid waste generation plays an important role in integrated solid waste management plans. In this study, the performance of two predictive models, Artificial Neural Network (ANN) and Multiple Linear Regression (MLR) was verified to predict mean Seasonal Municipal Solid Waste Generation (SMSWG) rate. The accuracy of the proposed models is illustrated through a case study of 20 cities located in Fars Province, Iran. Four performance measures, MAE, MAPE, RMSE and R were used to evaluate the performance of these models. The MLR, as a conventional model, showed poor prediction performance. On the other hand, the results indicated that the ANN model, as a non-linear model, has a higher predictive accuracy when it comes to prediction of the mean SMSWG rate. As a result, in order to develop a more cost-effective strategy for waste management in the future, the ANN model could be used to predict the mean SMSWG rate. PMID- 26482810 TI - The Men's Health Special Sauce: Ingredients Revealed. PMID- 26482811 TI - Introducing First-Year Radiology Residents to the ACR at the AMCLC From 2009 to 2013: Summary of Experiences and Five-Year First-Cohort Follow-Up. AB - PURPOSE: The aim of this report is to provide a five-year summary of the Minnesota Radiological Society's initiative to send first-year radiology residents to the ACR at the AMCLC. The authors provide an update of the survey data for the first five years (2009-2013) and a report of the ACR membership status of the original 2009 cohort (class of 2012) five years after their conference experience. METHODS: Participating residents from 2009 to 2013 completed pre- and postconference surveys assessing their knowledge of ACR related topics, conference satisfaction, and intention to join the ACR. ACR membership status of the first cohort was determined using the ACR membership database and compared with both the previous five graduating classes and the national average for practicing radiologists. RESULTS: Seventy first-year Minnesota radiology residents attended the conference from 2009 to 2013. Knowledge of the ACR significantly increased after the conference. Most residents were highly satisfied or satisfied with their conference experience and highly likely or likely to join the ACR in the future. Two years after residency, 87% of the first cohort (13 of 15) were ACR members, compared with an average membership rate of 57% (63 of 110) for the previous five graduating classes. CONCLUSIONS: Exposing radiology residents early to the ACR at the AMCLC leads to a significant increase in knowledge pertaining to the professional organization. This exposure likely leads to increased ACR membership when residents enter practice. This early engagement in radiology affairs can lead to a higher rate of ACR membership and to a better informed membership. PMID- 26482812 TI - Direct Interactive Public Education by Breast Radiologists About Screening Mammography: Impact on Anxiety and Empowerment. AB - PURPOSE: Anxiety has been called a "harm" of screening mammography. The authors provided direct, interactive education to lay audiences and measured these sessions' impact on anxiety and any increased understanding of breast cancer screening. METHODS: Academic breast radiologist provided seven 1-hour sessions of structured lectures and question-and-answer periods. Lay language and radiologic images were used to discuss disease background, screening guidelines, and areas of debate. One hundred seventeen participants (mean age, 45 +/- 15 years) completed voluntary, anonymous, institutional review board-approved pre and postsession questionnaires relaying their attitudes regarding screening and the impact of the sessions. Results are summarized descriptively. RESULTS: Mean reported anxiety regarding screening (on a scale ranging from 1-5; 1 = no anxiety) was 2.5 +/- 1.3. Anxiety was attributed to unknown results (56.4%), anticipation of pain (21.8%), known risk factors (14.5%), general uncertainty (12.7%), waiting for results (9.1%), possibility of more procedures (3.6%), and personal breast cancer history (3.6%). Ninety-seven percent reported that immediate results would lower anxiety (78% of those women indicated a 75%-100% decrease in anxiety); 93% reported that radiologist consultation with images would lower anxiety (75.6% indicated a 75%-100% decrease in anxiety). After the lecture, women reported (on a scale ranging from 1-5) increased understanding of the topic (4.7 +/- 0.6), encouragement to screen (4.6 +/- 0.7), and reduced anxiety (4.0 +/- 1.1). Ninety-seven percent to 100% provided correct responses to these questions: rationale for screening in the absence of family history, recall does not equate to cancer diagnosis, benefit of prior films, and continued importance of physical examination. CONCLUSION: Attendees of radiologist-provided direct public lectures reported decreased anxiety and improved knowledge regarding screening mammography. The resultant reduced anxiety ("harm") and educational empowerment help enable informed decision making and may promote screening attendance. PMID- 26482813 TI - Residents and Fellows Make Significant Contributions to Radiological Organizations. PMID- 26482814 TI - Exploring the Usability of Mobile Apps Supporting Radiologists' Training in Diagnostic Decision Making. AB - PURPOSE: The objective of this study was to conduct a usability evaluation of mobile apps for supporting education and training in radiologic diagnostic decision-making processes. METHODS: Of 381 mobile apps available at two major stores (Google Play and iTunes), eight iOS apps were selected for laboratory based usability tests. Six staff radiologists completed eight app-specific task sets, using a think-aloud strategy. The triangular methods approach included quantitative performance measures, System Usability Scale (SUS), and qualitative thematic analysis using heuristic usability principles of usability issues. RESULTS: Overall, radiologists achieved higher than 70% success, with favorable SUS scores, in completing the tasks for seven of the eight apps. However, task success rate and SUS score had a weak relation (r = 0.23), indicating that the perceived usability may not reflect the holistic usability of the app. Task analysis and self-report revealed 108 usability issues, which were condensed to 55 unique issues and categorized by nine usability themes and mapped to ten usability heuristics. Nonintuitive functionality (eg, nonintuitive or misleading labels) was the most frequent theme observed, leading to inefficient navigation. These usability findings were consistent with the 13 improvements the radiologists suggested. CONCLUSIONS: This study demonstrates the feasibility of usability evaluation of radiology mobile apps and suggests potential improvements in the development of radiology mobile apps. This study also suggests that proficiency with mobile devices may not be equivalent to being an expert user, proficient in using the apps. PMID- 26482815 TI - Radiology in Medical Education: A Pediatric Radiology Elective as a Template for Other Radiology Courses. AB - PURPOSE: Traditionally, the pediatric radiology elective for medical students and pediatric residents constituted a morning teaching session focused mainly on radiography and fluoroscopy. A more structured elective was desired to broaden the exposure to more imaging modalities, create a more uniform educational experience, and include assessment tools. METHODS: In 2012, an introductory e mail and formal syllabus, including required reading assignments, were sent to participants before the start date. A rotating weekly schedule was expanded to include cross-sectional imaging (ultrasound, CT, MR) and nuclear medicine. The schedule could accommodate specific goals of the pediatric resident or medical student, as requested. Starting in 2013, an online pre-test and post-test were developed, as well as an online end-of-rotation survey specific to the pediatric radiology elective. Taking the Image Gently pledge was required. A scavenger hunt tool, cue cards, and electronic modules were added. RESULTS: Pre-test and post test scores, averaged over 2 years, showed improvement in radiology knowledge, with scores increasing by 27% for medical students and 21% for pediatric residents. Surveys at the end of the elective were overwhelmingly positive, with constructive criticism and complimentary comments. CONCLUSIONS: We have successfully created an elective experience in radiology that dedicates time to education while preserving the workflow of radiologists. We have developed tools to provide a customized experience with many self-directed learning opportunities. Our tools and techniques are easily translatable to a general or adult radiology elective. PMID- 26482816 TI - ACR White Paper-Based Comprehensive Dose Reduction Initiative Is Associated With a Reversal of the Upward Trend in Radiation Dose for Chest CT. AB - PURPOSE: In 2010, the authors' department implemented a comprehensive dose reduction strategy based on the ACR white paper on radiation dose in medicine. The aim of this study was to evaluate the effectiveness of the dose reduction program. METHODS: In total, 1,234 adult chest CT scans from 2007 to 2012 were analyzed retrospectively, with institutional review board approval and a waiver of the requirement for informed consent. The primary outcome was effective dose in millisieverts during the three-year periods before (2007-2009) and after (2010 2012) dose reduction implementation. Dose trends were analyzed by fitted linear modeling. The use and effects on total exposure of dose reduction strategies (high pitch, adaptive statistical iterative reconstruction [ASIR], and low tube voltage) were analyzed. RESULTS: The overall mean dose for chest CT was 7.3 +/- 5.1 mSv. The mean dose decreased by 30%, from 9.2 mSv (2007-2009) to 6.5 mSv (2010-2012) (P < .001). From 2007 to 2009, the mean dose increased by 1.2 mSv per year (P < .01). From 2010 to 2012, the mean dose decreased by 1.1 mSv per year (P < 0.01). High-pitch technique, ASIR, and low tube voltage increased significantly after dose reduction implementation. High pitch and ASIR were significantly associated with a reduced dose, whereas the effect of reduced voltage was not significant. CONCLUSIONS: Reductions in radiation exposure from medical imaging rely on ongoing technical developments and consistent, vigilant use of dose reduction strategies. This comprehensive dose reduction strategy significantly reduced radiation exposure from chest CT. Annual increases in radiation dose reversed after the strategy was implemented and continued to decline over the study period. PMID- 26482817 TI - Reducing Radiation Dose in Pediatric Diagnostic Fluoroscopy. AB - PURPOSE: To assess radiation dose in common pediatric diagnostic fluoroscopy procedures and determine the efficacy of dose tracking and dose reduction training to reduce radiation use. METHODS: Fluoroscopy time and radiation dose area product (DAP) were recorded for upper GIs (UGI), voiding cystourethrograms (VCUGs), and barium enemas (BEs) during a six-month period. The results were presented to radiologists followed by a 1-hour training session on radiation dose reduction methods. Data were recorded for an additional six months. DAP was normalized to fluoroscopy time, and Wilcoxon testing was used to assess for differences between groups. RESULTS: Data from 1,479 cases (945 pretraining and 530 post-training) from 9 radiologists were collected. No statistically significant difference was found in patient age, proportion of examination types, or fluoroscopy time between the pre- and post-training groups (P >= .1), with the exception of a small decrease in median fluoroscopy time for VCUGs (1.0 vs 0.9 minutes, P = .04). For all examination types, a statistically significant decrease was found in the median normalized DAP (P < .05) between pre- and post training groups. The median (quartiles) for pretraining and post-training normalized DAPs (MUGy.m(2) per minute) were 14.36 (5.00, 38.95) and 6.67 (2.67, 17.09) for UGIs; 13.00 (5.34, 32.71) and 7.16 (2.73, 19.85) for VCUGs; and 33.14 (9.80, 85.26) and 17.55 (7.96, 46.31) for BEs. CONCLUSIONS: Radiation dose tracking with feedback, paired with dose reduction training, can reduce radiation dose during diagnostic pediatric fluoroscopic procedures by nearly 50%. PMID- 26482818 TI - Interactive Volumetry Of Liver Ablation Zones. AB - Percutaneous radiofrequency ablation (RFA) is a minimally invasive technique that destroys cancer cells by heat. The heat results from focusing energy in the radiofrequency spectrum through a needle. Amongst others, this can enable the treatment of patients who are not eligible for an open surgery. However, the possibility of recurrent liver cancer due to incomplete ablation of the tumor makes post-interventional monitoring via regular follow-up scans mandatory. These scans have to be carefully inspected for any conspicuousness. Within this study, the RF ablation zones from twelve post-interventional CT acquisitions have been segmented semi-automatically to support the visual inspection. An interactive, graph-based contouring approach, which prefers spherically shaped regions, has been applied. For the quantitative and qualitative analysis of the algorithm's results, manual slice-by-slice segmentations produced by clinical experts have been used as the gold standard (which have also been compared among each other). As evaluation metric for the statistical validation, the Dice Similarity Coefficient (DSC) has been calculated. The results show that the proposed tool provides lesion segmentation with sufficient accuracy much faster than manual segmentation. The visual feedback and interactivity make the proposed tool well suitable for the clinical workflow. PMID- 26482819 TI - Increased extracellular clusterin in the prefrontal cortex in schizophrenia. AB - The expression of the gene that encodes clusterin, a glycoprotein that has been implicated in the regulation of many cellular processes, has previously been found in gene expression profiling studies to be among the most significantly differentially expressed genes in pyramidal and parvalbumin-containing inhibitory neurons in the cerebral cortex in subjects with schizophrenia. In this study, we investigated whether clusterin may also be dysregulated at the protein level in schizophrenia subjects. We found that, although the intracellular amount of clusterin may be unchanged, the level of extracellular, secreted clusterin appears to be significantly increased in schizophrenia subjects. It is speculated that this finding may represent a neuroprotective response to pathophysiological events that underlie schizophrenia. PMID- 26482820 TI - Erlotinib-related rhabdomyolysis: the role of pharmacogenetics and drug-drug interaction. PMID- 26482821 TI - Does the severity of disability matter? The opinion of parents about professional support in residential facilities. AB - BACKGROUND: Researchers have shown that the characteristics of a person with an intellectual disability (ID), in particular the severity of the disability, are related to the outcomes of professional support. Hardly any studies have asked parents and/or legal guardians for their own opinion about the quality of support given to their child/family member with ID. Therefore, this study examined the relationship between the severity of a person's disability and the opinions voiced by the parents and/or other legal guardians of that person concerning several aspects of the quality of support received in residential care. METHOD: Questionnaires were completed by 1058 parents and/or legal guardians of people with ID living in residential facilities. A multiple covariance analysis was conducted to explore the relationship between the severity of the disability and the parents' and/or legal guardians' opinions. RESULTS: Only small differences in the opinions about the quality of support were observed between parents and/or legal guardians of people with mild to moderate ID and those of people with severe to profound ID. CONCLUSION: This study showed that there are differences in parental opinions about the quality of support, but that most of these differences are not related to the severity of disability. The only significant difference related to the severity of disability is on the leisure activities domain. Parents and/or legal guardians of a person with severe/profound ID were less satisfied with leisure activities than parents and/or legal guardians of persons with mild/moderate ID. It is important to determine to what other factors parental opinions are related, as these opinions concerning the quality of support are important measures alongside client self-reports and measures of the facility itself. The quality of support should be measured using a combination of methods for different stakeholders. PMID- 26482822 TI - Phacoemulsification combined with a new ab interno gel stent to treat open-angle glaucoma: Pilot study. AB - PURPOSE: To study the effect on intraocular pressure (IOP) of implanting a new gelatin stent at the time of cataract surgery in the treatment of open-angle glaucoma (OAG). SETTING: Multicenter university and private-practice settings. DESIGN: Nonrandomized prospective clinical trial. METHODS: The implantation of 2 models of a gelatin stent (Xen140 and Xen63) was performed at the time of cataract surgery without mitomycin-C. Complete success was defined as a postoperative IOP of less than 18 mm Hg and more than a 20% reduction in IOP at 12 months without glaucoma medication. Failure was defined as loss of light perception vision or worse, a need for additional glaucoma surgery, or less than a 20% reduction in the IOP from baseline. RESULTS: The study included 37 eyes of 37 patients. The mean preoperative IOP was 22.4 mm Hg +/- 4.2 (SD) on 2.5 +/- 1.4 medication classes. Twelve months postoperatively, the mean IOP was reduced to 15.4 +/- 3.0 mm Hg on 0.9 +/- 1.0 medication classes (P < .0001). This resulted in a qualified success of 85.3% and a complete success rate off medications of 47.1%. There were no failures. CONCLUSION: Cataract surgery combined with implantation of the gelatin stent resulted in a significant reduction in IOP in eyes with OAG. FINANCIAL DISCLOSURE: Dr. Sheybani has received travel reimbursement from Aquesys, Inc. Dr. Ahmed is a paid consultant to Aquesys, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26482823 TI - Climate-driven changes to the spatio-temporal distribution of the parasitic nematode, Haemonchus contortus, in sheep in Europe. AB - Recent climate change has resulted in changes to the phenology and distribution of invertebrates worldwide. Where invertebrates are associated with disease, climate variability and changes in climate may also affect the spatio-temporal dynamics of disease. Due to its significant impact on sheep production and welfare, the recent increase in diagnoses of ovine haemonchosis caused by the nematode Haemonchus contortus in some temperate regions is particularly concerning. This study is the first to evaluate the impact of climate change on H. contortus at a continental scale. A model of the basic reproductive quotient of macroparasites, Q0 , adapted to H. contortus and extended to incorporate environmental stochasticity and parasite behaviour, was used to simulate Pan European spatio-temporal changes in H. contortus infection pressure under scenarios of climate change. Baseline Q0 simulations, using historic climate observations, reflected the current distribution of H. contortus in Europe. In northern Europe, the distribution of H. contortus is currently limited by temperatures falling below the development threshold during the winter months and within-host arrested development is necessary for population persistence over winter. In southern Europe, H. contortus infection pressure is limited during the summer months by increased temperature and decreased moisture. Compared with this baseline, Q0 simulations driven by a climate model ensemble predicted an increase in H. contortus infection pressure by the 2080s. In northern Europe, a temporal range expansion was predicted as the mean period of transmission increased by 2-3 months. A bimodal seasonal pattern of infection pressure, similar to that currently observed in southern Europe, emerges in northern Europe due to increasing summer temperatures and decreasing moisture. The predicted patterns of change could alter the epidemiology of H. contortus in Europe, affect the future sustainability of contemporary control strategies, and potentially drive local adaptation to climate change in parasite populations. PMID- 26482824 TI - EUS-Guided Drainage of Liver Abscesses: Ultra Uncertain or Sound Practice? PMID- 26482825 TI - Normative values of EQ-5D-5L: in a Spanish representative population sample from Spanish Health Survey, 2011. AB - PURPOSE: To derive EQ-5D-5L Spanish population norms based on a national representative sample adjusted by age, gender and region. METHODS: A representative sample of the Spanish general population (n = 21,007) was used in a cross-sectional study. The source of data was the Spanish National Health Survey 2011-2012. All socio-demographic factors and clinical characteristics were carried to a descriptive analysis. All variables were stratified by region, gender and age-group. RESULTS: The utility value 1 is the most repeated (62%) in this representative population sample. This study showed a deterioration of health states as age increases. Overall, men reported better health status than women. In relation to ceiling effect by regions, there was little difference with the highest scores. Conversely, the lowest score corresponds to Galicia. CONCLUSIONS: The paper reports EQ-5D-5L normative data for Spanish general population, based on a national representative sample adjusted by region, gender and age-group. These results may serve as reference data of the population health status. A regional difference in health status could be observed, which might suggest that policies aiming to reduce regional inequalities are important. PMID- 26482826 TI - The Hartford Consensus on Active Shooters: Implementing the Continuum of Prehospital Trauma Response. AB - BACKGROUND: Active shooter incidents have led to the recognition that the traditional response paradigm of sequential response and scene entry by law enforcement, first responders, and emergency medical service (EMS) personnel produced delays in care and suboptimal victim outcomes. The Hartford Consensus Group developed recommendations to improve the response to and outcomes from active shooter events and urged that a continuum of care be implemented that incorporates not only EMS response, but also the initiation of care by law enforcement officers and potentially by lay bystanders. OBJECTIVE: To develop and implement tiered educational programs designed to teach police officers and lay bystanders the principles of initial trauma care and bleeding control using as a foundation the U.S. military's Tactical Combat Casualty Care course and the guidelines of the Committee on Tactical Emergency Casualty Care. DISCUSSION: The Tactical Casualty Care for Law Enforcement and First Responders course is a 1-day program combining didactic lecture, hands-on skills stations, and clinical scenarios designed primarily for police officers. The Bleeding Control for the Injured is a 2- to 3-h program for the potential citizen responder in the skills of hemorrhage control. In addition, we document the application of these skills by law enforcement officers and first responders in several real-life incidents involving major hemorrhage. CONCLUSIONS: Developing and implementing tiered educational programs for hemorrhage control will improve response by police officers and the lay public. Educating law enforcement officers in these skills has been demonstrated to improve trauma victim survival. PMID- 26482827 TI - A Case of 5-Fluorouracil-Induced Cardiac Arrest. AB - BACKGROUND: Coronary artery vasospasm after administration of fluorouracil (5-FU) is a rare complication. Commonly presenting as chest pain during or shortly after 5-FU infusions, vasospasm can place patients at risk for ventricular dysrhythmia, myocardial ischemia, and infarction. Although not fully understood, any 5-FU cardiotoxicity seems to be multifactorial, and patients with coronary artery disease and renal dysfunction may be at particular risk. CASE REPORT: A 46-year old woman with no prior cardiovascular disease history presented with sudden onset chest pain after initial administration of 5-FU continuous infusion therapy. The patient subsequently developed ventricular fibrillation arrest and underwent successful electrocardioversion. Coronary angiography was unremarkable for coronary stenosis or vasospasm. The presumed etiology was secondary to 5-FU cardiac toxicity. The patient was re-challenged with 5-FU therapy and developed repeat chest pain. The 5-FU was completely stopped and the patient's symptoms resolved, with no further dysrhythmic events 9 months after initial presentation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients who develop chest pain during or after 5-FU infusion should warrant strong consideration for admission and continuous cardiac monitoring for potential ventricular dysrhythmias and cardiac ischemia. PMID- 26482828 TI - Point-of-Care Ultrasound Diagnosis of Deep Space Hand Infection. AB - BACKGROUND: Point-of-care ultrasound is emerging as an important imaging modality for characterizing soft-tissue infections and provides advantages over physical examination and magnetic resonance imaging (MRI). CASE REPORT: A 30-year-old man presented to the emergency department with extensive left upper extremity cellulitis. Magnetic resonance imaging of the left arm was preliminarily interpreted as soft-tissue swelling without evidence of deep-space infection. Point-of-care ultrasound revealed pockets of fluid with sonographic fluctuance tracking along the tendon sheath that were concerning for deep abscesses. Based on the ultrasound findings, the patient was taken emergently to the operating room, where multiple left hand and wrist loculated deep-space abscesses were decompressed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case report highlights the significant advantages and easy-to-learn findings present in point-of-care ultrasound of musculoskeletal infections. PMID- 26482829 TI - Pediatric Urinary Retention in the Emergency Department: A Concerning Symptom with Etiology Outside the Bladder. AB - BACKGROUND: Urinary retention in an otherwise healthy adolescent is a concerning symptom, in which etiology can range from an extracystic mass to central nervous system involvement (CNS). One possibility is acute disseminated encephalomyelitis (ADEM), a rare inflammatory autoimmune disease that affects the CNS via demyelination. The disease usually is preceded by an acute viral infection, and commonly presents with multifocal neurological deficits. The diagnosis for ADEM is made based on clinical presentation, correlating with findings characterized on magnetic resonance imaging (MRI) in the CNS. CASE REPORT: Our case involves a 16-year-old boy who presented to the Emergency Department (ED) with urinary retention. The patient was an otherwise healthy adolescent who was experiencing intermittent fevers for 1 week, and was found to be monospot positive when seen by his pediatrician. When presenting to the ED, the patient's primary complaint was urinary retention, which he experienced acutely in the middle of the night. Due to the suspicious nature of the patient's symptoms and history of present illness, the patient received a thorough workup including magnetic resonance imaging (MRI) of the patient's brain and spinal cord, which demonstrated findings consistent with ADEM. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: There is very little literature describing a case of ADEM in the ED where the primary manifesting symptom was urinary retention. In addition, it is important that clinicians address acute urinary retention in an otherwise healthy adolescent as a red flag, with the need to rule out concerning etiology. PMID- 26482830 TI - Characteristics of Medicaid-Covered Emergency Department Visits Made by Nonelderly Adults: A National Study. AB - BACKGROUND: The Affordable Care Act has added millions of new Medicaid enrollees to the health care system. These patients account for a large proportion of emergency department (ED) utilization. OBJECTIVE: Our aim was to characterize this population and their ED use at a national level. METHODS: We used the 2010 National Hospital Ambulatory Medical Care Survey (NHAMCS) to describe demographics and clinical characteristics of nonelderly adults (>=18 years old and <=64 years old) with Medicaid-covered ED visits. We defined frequent ED users as individuals who make >=4 ED visits/year and business hours as 8 am to 5 pm. We used descriptive statistics to describe the epidemiology of Medicaid-covered ED visits. RESULTS: NHAMCS included 21,800 ED visits by nonelderly adults in 2010, of which 5,659 (24.09%) were covered by Medicaid insurance. Most ED visits covered by Medicaid were made by patients who are young (25 and 44 years old) and female (67.95%; 95% confidence interval [CI] 66.00-69.89). A large proportion of the ED visits covered by Medicaid were revisits within 72 h (14.66%; 95% CI 9.13 20.19) and from frequent ED users (32.32%; 95% CI 24.29-40.35). Almost half of all ED visits covered by Medicaid occurred during business hours (45.44%; 95% CI 43.45-47.43). CONCLUSIONS: The vast majority of Medicaid enrollees who used the ED were young females, with a large proportion of visits occurring during business hours. Almost one-third of all visits were from frequent ED users. PMID- 26482831 TI - Rhabdomyolysis Secondary to Clenbuterol Use and Exercise. AB - BACKGROUND: The literature regarding rhabdomyolysis secondary to illicit drug use is sparse. Clenbuterol is a bronchodilator approved for veterinary use, which in high doses can increase protein deposition and lipolysis similarly to anabolic steroids, and is thereby abused for bodybuilding and weight loss effects. Clenbuterol has previously been described in case reports to be cardiotoxic, with patient presentations similar to overdoses of sympathomimetic substances, but reports of rhabdomyolysis are limited to a single case series in horses. CASE REPORT: We report the first case of rhabdomyolysis secondary to clenbuterol in a human. Our patient used clenbuterol for muscle-building effects in addition to exercise for multiple days prior to presentation. The patient's chief complaint at Emergency Department (ED) presentation was discolored urine. Workup for rhabdomyolysis was initiated, and an initial creatine kinase was measured at 122,933 units/L. Our patient's rhabdomyolysis was successfully treated with supportive therapy, and the patient was eventually discharged to home with no identifiable disability. The patient's kidney function remained at baseline, and no acute kidney injury was experienced secondary to rhabdomyolysis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients presenting to the ED may have been unintentionally exposed through cutting of illicit substances or through intentional use in bodybuilding. Clenbuterol has well-described cardiotoxic effects, and we report the additional toxicity of rhabdomyolysis with its use. PMID- 26482832 TI - DNA binding protein identification by combining pseudo amino acid composition and profile-based protein representation. AB - DNA-binding proteins play an important role in most cellular processes. Therefore, it is necessary to develop an efficient predictor for identifying DNA binding proteins only based on the sequence information of proteins. The bottleneck for constructing a useful predictor is to find suitable features capturing the characteristics of DNA binding proteins. We applied PseAAC to DNA binding protein identification, and PseAAC was further improved by incorporating the evolutionary information by using profile-based protein representation. Finally, Combined with Support Vector Machines (SVMs), a predictor called iDNAPro PseAAC was proposed. Experimental results on an updated benchmark dataset showed that iDNAPro-PseAAC outperformed some state-of-the-art approaches, and it can achieve stable performance on an independent dataset. By using an ensemble learning approach to incorporate more negative samples (non-DNA binding proteins) in the training process, the performance of iDNAPro-PseAAC was further improved. The web server of iDNAPro-PseAAC is available at http://bioinformatics.hitsz.edu.cn/iDNAPro-PseAAC/. PMID- 26482833 TI - [Lobular invasive breast cancer prognostic factors: About 940 patients]. AB - OBJECTIVES: To assess the prognostic factors of T1 and T2 infiltrating lobular breast cancers, and to investigate predictive factors of axillary lymph node involvement. METHODS: This is a retrospective multicentric study, conducted from 1999 to 2008, among 13 french centers. All data concerning patients with breast cancer who underwent a primary surgical treatment including a sentinel lymph node procedure have been collected (tumors was stage T1 or T2). Patients underwent partial or radical mastectomy. Axillary lymph node dissection was done systematically (at the time of sentinel procedure evaluation), or in case of sentinel lymph node involvement. Among all the 8100 patients, 940 cases of lobular infiltrating tumors were extracted. Univariate analysis was done to identify significant prognosis factors, and then a Cox regression was applied. Analysis interested factors that improved disease free survival, overall survival and factors that influenced the chemotherapy indication. Different factors that may be related with lymph node involvement have been tested with univariate than multivariate analysis, to highlight predictive factors of axillary involvement. RESULTS: Median age was 60 years (27-89). Most of patients had tumours with a size superior to 10mm (n=676, 72%), with a minority of high SBR grade (n=38, 4%), and a majority of positive hormonal status (n = 880, 93, 6%). The median duration of follow-up was 59 months (1-131). Factors significantly associated with decreased disease free survival was histological grade 3 (hazard ratio [HR]: 3,85, IC 1,21-12,21), tumour size superior to 2cm (HR: 2,85, IC: 1,43-5,68) and macrometastatic lymph node status (HR: 3,11, IC: 1,47-6,58). Concerning overall survival, multivariate analysis demonstrated a significant impact of age less than 50 years (HR: 5,2, IC: 1,39-19,49), histological grade 3 (HR: 5,03, IC: 1,19 21,25), tumour size superior to 2cm (HR: 2,53, IC: 1,13-5,69). Analysis concerning macrometastatic lymph node status nearly reached significance (HR: 2,43, IC: 0,99-5,93). There was no detectable effect of chemotherapy regarding disease free survival (odds ratio [OR] 0,8, IC: 0,35-1,80) and overall survival (OR: 0,72, IC: 0,28-1,82). Disease free survival was similar between no axillary invasion (pN0) and isolated tumor cells (pNi+), or micrometastatic lymph nodes (pNmic). There were no difference neither between one or more than one macromatastatic lymph node. But disease free survival was statistically worse for pN1 compared to other lymph node status (pN0, pNi+ or pNmic). Factors associated with lymph node involvement after logistic regression was: age from 51 to 65 years (OR: 2,1, IC 1,45-3,04), age inferior to 50 years (OR 3,2, IC: 2,05-5,03), Tumour size superior to 2cm (OR 4,4, IC: 3,2-6,14), SBR grading 2 (OR 1,9, IC: 1,30-2,90) and SBR grade 3 (OR 3,5, IC: 1,61-7,75). CONCLUSION: The analysis of this series of 940 T1 and T2 lobular invasive breast carcinomas offers several information: factors associated with axillary lymph node involvement are age under 65 years, tumor size greater than 20mm, and a SBR grade 2 or 3. The same factors were significantly associated with the OS and DFS. The macrometastatic lymph node involvement has a significant impact on DFS and OS, which is not true for isolated cells and micrometastases, which seem to have the same prognosis as pN0. PMID- 26482834 TI - [Thierry's spatulas or forceps--a comparison between maternal-fetal morbidities]. AB - OBJECTIVE: To compare maternal and fetal morbidity during forceps or Thierry spatulas operative deliveries. METHODS: Retrospective and descriptive study in a one center from 2006 to 2012. Operative deliveries were performed with forceps or spatulas, in case of no mobile fetal progression, on singleton term pregnancies with cephalic presentation, no abnormal heart rate and without any pregnancy pathology. RESULTS: Our studies included 65 operative deliveries with spatulas versus 77 with forceps, among a scientifically comparable population. At maternal level, when comparing spatulas versus forceps, there were more intact perineum (5.19% vs 15.38%; P=0.04), the same rate of vaginal tears and less severe perineal injuries (0 vs 6; P=0.05) in favor of spatulas. Extractions performed in "unfavorable" conditions were mostly conducted with forceps. In 50% of the case, an episiotomy was associated with severe perineal lesions. As far as fetal morbidity is concerned, there were more newborn's facial injuries using the forceps tool (18.18% vs 3.08%; P=0.0046). The remaining data were comparable. CONCLUSIONS: Thierry spatulas are less harmful than forceps to maternal tissues and reduce facial injuries of the newborn. Consequently, spatulas could benefit from a wider use. However, a prospective study will be needed to confirm our results. PMID- 26482835 TI - Our experience with long-term triptorelin therapy in a large endometriosis nodule arising in an episiotomy scar. PMID- 26482836 TI - Combinatorial RNA Interference Therapy Prevents Selection of Pre-existing HBV Variants in Human Liver Chimeric Mice. AB - Selection of escape mutants with mutations within the target sequence could abolish the antiviral RNA interference activity. Here, we investigated the impact of a pre-existing shRNA-resistant HBV variant on the efficacy of shRNA therapy. We previously identified a highly potent shRNA, S1, which, when delivered by an adeno-associated viral vector, effectively inhibits HBV replication in HBV transgenic mice. We applied the "PICKY" software to systemically screen the HBV genome, then used hydrodynamic transfection and HBV transgenic mice to identify additional six highly potent shRNAs. Human liver chimeric mice were infected with a mixture of wild-type and T472C HBV, a S1-resistant HBV variant, and then treated with a single or combined shRNAs. The presence of T472C mutant compromised the therapeutic efficacy of S1 and resulted in replacement of serum wild-type HBV by T472C HBV. In contrast, combinatorial therapy using S1 and P28, one of six potent shRNAs, markedly reduced titers for both wild-type and T472C HBV. Interestingly, treatment with P28 alone led to the emergence of escape mutants with mutations in the P28 target region. Our results demonstrate that combinatorial RNAi therapy can minimize the escape of resistant viral mutants in chronic HBV patients. PMID- 26482837 TI - Electroconvulsive therapy and cognitive functions in treatment-resistant depression. AB - OBJECTIVES: Electroconvulsive therapy (ECT) is the most effective treatment for drug-resistant depression (DRD). We estimated the short- and long-term effects of ECT on cognitive functions in patients with unipolar and bipolar DRD. METHODS: We investigated 63 patients (18 male, 45 female), aged 34-75 years. Cognitive assessments were performed before, immediately after 6-12 ECT sessions, and 3 months thereafter, using the Benton Visual Retention, Trail Making (TMT), Rey Osterrieth Complex Figure (ROCF) tests, the Digit Span of the Wechsler Adult Intelligence Scale, and the Rey Auditory Verbal Learning (RAVLT), verbal fluency and Stroop tests. RESULTS: Immediately after ECT, a significant worsening was noted in some indices of memory and verbal fluency. However, 3 months after ECT, the indices of both RAVLT and verbal fluency significantly improved compared to baseline, and those of the Benton and ROCF were significantly better than before ECT. The Digit Span, Stroop and TMT were not affected by the treatment. CONCLUSIONS: The negative effects of ECT on the reported measures of cognition are transient. After 3 months, the indices of memory were significantly better than before the treatment. In addition to its antidepressant effect in DRD, ECT may also exert a long-term favourable influence on some cognitive functions. PMID- 26482838 TI - Response to Evans et al. PMID- 26482839 TI - Response to the article by Jamsa. Leukocyte receptor expression as a biomarker for severe sepsis. PMID- 26482840 TI - Recent strategies for efficient production of polyhydroxyalkanoates by micro organisms. AB - Polyhydroxyalkanoates (PHAs) are polyesters accumulated by many bacteria under unbalanced growth conditions, and have been used to meet the various demands in areas of agriculture, medicine, and materials especially belong to a rapidly expanding area of biomedical research. Unfortunately, the high production cost than the traditional synthetic materials has greatly limited the wide application of PHA. Here, we systematically summarized recent progress in production of PHAs and a series of optimization strategies such as supplying renewable carbon substrates, developing better bacterial strains, optimization of fermentation processes, engineering new pathways and etc., were applied to reduce production cost, therefore providing many new ideas and methods for the production of PHAs in economically viable processes. This is believed to be a comprehensive report to show different strategies and methods for low-cost production of PHAs. Further studies are still needed to make PHAs more and more economically viable to meet a wide range of applicability. PMID- 26482841 TI - Application of electroretinography (ERG) in early drug development for assessing retinal toxicity in rats. AB - Retinal ocular toxicity is among the leading causes of drug development attrition in the pharmaceutical industry. Electroretinography (ERG) is a non-invasive functional assay used to assess neuro-retinal physiological integrity by measuring the electrical responses. To directly assess the utility of ERG, a series of studies was conducted following intravitreal and/or iv administration of pan-cyclin-dependent kinase inhibitors: AG-012,986 and AG-024,322 in rats. Both compounds have previously shown to induce retinal toxicity. Retinal injury was evaluated by ERG, histopathology and TUNEL staining. Intravitreal injection of AG-012,986 at >= 10 MUg/eye resulted in decreases (60%) in ERG b-wave and microscopic changes of mild to moderate retinal degeneration, and at 30 MUg/eye led to additional ophthalmic findings. Intravenous administration of AG-012,986 daily at >= 5 mg/kg resulted in dose-related decreases (25 to 40%) in b-wave and sporadic to intense positive TUNEL staining. Intravitreal injection of AG-024,322 at 30 MUg/eye also resulted in decreases (50 to 60%) in b-wave, mild to marked retinal degeneration and mild vitreous debris. These experiments demonstrate that ERG can be used as a sensitive and reliable functional tool to evaluate retinal toxicity induced by test compounds in rats complementing other classical ocular safety measurements. PMID- 26482842 TI - On-Chip Sequence-Specific Immunochemical Epigenomic Analysis Utilizing Outward Turned Cytosine in a DNA Bulge with Handheld Surface Plasmon Resonance Equipment. AB - This paper reports a sequence-specific immunoassay chip for DNA methylation assessment by microfluidic-based surface plasmon resonance (SPR) detection. This was achieved by utilizing an affinity measurement involving the target, (methyl)cytosine, in a single-base bulge region and an anti-methylcytosine antibody in a microchannel, following hybridization with a biotinylated bulge inducing DNA probe. The probe alters the target cytosine in a looped-out state because of the pi-pi stacking between flanking bases of the target. The probe design is simple and consists of the elimination of guanine paired with the target cytosine from a fragmented full-match sequence. We obtained the single methylation status in 6 amol (48 fg) of synthesized oligo DNA in 45 min, which is the fastest DNA methylation assessment yet reported, without employing a conventional bisulfite reaction, PCR, or sequencing. We also succeeded in discrimination of the methylation status of single cytosine in genomic lambda DNA and HCT116 human colon cancer cells. The advantages of the proposed method are its small equipment, simple microfluidics design, ease of handling (two injections of DNA and antibody), lack of need for a methylation-sensitive enzyme, and neutral buffer conditions. PMID- 26482843 TI - p73 is required for ependymal cell maturation and neurogenic SVZ cytoarchitecture. AB - The adult subventricular zone (SVZ) is a highly organized microenvironment established during the first postnatal days when radial glia cells begin to transform into type B-cells and ependymal cells, all of which will form regenerative units, pinwheels, along the lateral wall of the lateral ventricle. Here, we identify p73, a p53 homologue, as a critical factor controlling both cell-type specification and structural organization of the developing mouse SVZ. We describe that p73 deficiency halts the transition of the radial glia into ependymal cells, leading to the emergence of immature cells with abnormal identities in the ventricle and resulting in loss of the ventricular integrity. p73-deficient ependymal cells have noticeably impaired ciliogenesis and they fail to organize into pinwheels, disrupting SVZ niche structure and function. Therefore, p73 is essential for appropriate ependymal cell maturation and the establishment of the neurogenic niche architecture. Accordingly, lack of p73 results in impaired neurogenesis. Moreover, p73 is required for translational planar cell polarity establishment, since p73 deficiency results in profound defects in cilia organization in individual cells and in intercellular patch orientation. Thus, our data reveal a completely new function of p73, independent of p53, in the neurogenic architecture of the SVZ of rodent brain and in the establishment of ependymal planar cell polarity with important implications in neurogenesis. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 730-747, 2016. PMID- 26482844 TI - Laparoscopic lymphadenectomy around the left renal vein (16a2lat) by tunneling under the pancreas for advanced Siewert type II adenocarcinoma. AB - The para-aortic lymph nodes around the left renal vein (16a2lat) are now considered important to target in the treatment of advanced adenocarcinoma of the esophagogastric junction. We describe a laparoscopic approach for resecting these nodes. This new tunneling approach starts from the ligament of Treitz and then enters the retroperitoneal space. The left renal vein and left adrenal vein are dissected to identify the anatomy of the 16a2lat area. After this dissection, the 16a2lat nodes are retrieved through the suprapancreatic area. Six patients with advanced type II junctional cancer underwent laparoscopic 16a2lat lymph node dissection. The median operative time and estimated blood loss were 479 (390-750) min and 250 (130-500) ml, respectively. The median hospital stay was 22 (17-54) days and there were no deaths or serious complications. Although this series was relatively small, our technique proved effective and feasible. PMID- 26482845 TI - Robotic-assisted vs. conventional laparoscopic surgery for rectal cancer: short term outcomes at a single center. AB - PURPOSES: Several retrospective studies have demonstrated the safety and technical feasibility of robotic-assisted laparoscopic surgery (RALS). The aim of the present study was to clarify the advantages of RALS for rectal cancer by comparing its short-term outcomes with those of conventional laparoscopic surgery (CLS). METHODS: Between April, 2010 and April, 2015, a total of 974 patients underwent proctectomy for rectal cancer. After the exclusion of those who underwent open surgery, high anterior resection, lateral lymph node dissection, or multiple resection, 442 patients were enrolled in this study, including 203 who underwent RALS and 239 who underwent CLS. We compared the short-term outcomes of these two groups. RESULTS: There was no case of conversion to open surgery in the RALS group, but 8 (3.3 %) cases in the CLS group (p = 0.009). Operative time was not significantly different, but blood loss was significantly less in the RALS group than in the CLS group (p < 0.001). The postoperative hospital stay was shorter in the RALS group than in the CLS group (p < 0.001). The rate of urinary retention was significantly lower in the RALS group than in the CLS group (p = 0.018). CONCLUSION: The short-term outcomes in this series provide further evidence that RALS may be superior to CLS for rectal cancer. PMID- 26482847 TI - Microtubule-bundling activity of the centrosomal protein, Cep169, and its binding to microtubules. AB - CDK5RAP2 is a centrosomal protein that regulates the recruitment of a gamma tubulin ring complex (gamma-TuRC) onto centrosomes and microtubules (MTs) dynamics as a member of MT plus-end-tracking proteins (+TIPs). In our previous report, we found mammalian Cep169 as a CDK5RAP2 binding partner, and Cep169 accumulates at the distal ends of MTs and centrosomes, and coincides with CDK5RAP2. Depletion of Cep169 induces MT depolymerization, indicating that Cep169 targets MT tips and regulates stability and dynamics of MTs. However, how Cep169 contributes to the stabilization of MT remains unclear. Here we show that Cep169 is able to stabilize MTs and induces formation of long MT bundles with intense acetylation of MTs with CDK5RAP2, when expressed at higher levels in U2OS cells. In addition, we demonstrated that Cep169 forms homodimers through its N-terminal domain and directly interacts with MTs through its C-terminal domain. Interestingly, Cep169 mutants, which lack each domains, completely abolished the activity, respectively. Therefore, Cep169 bundles MTs and induces solid structure of MTs by crosslinking each adjacent MTs as a homodimer. PMID- 26482846 TI - Learning by subtraction: Hippocampal activity and effects of ethanol during the acquisition and performance of response sequences. AB - Learning is believed to be reflected in the activity of the hippocampus. However, neural correlates of learning have been difficult to characterize because hippocampal activity is integrated with ongoing behavior. To address this issue, male rats (n = 5) implanted with electrodes (n = 14) in the CA1 subfield responded during two tasks within a single test session. In one task, subjects acquired a new 3-response sequence (acquisition), whereas in the other task, subjects completed a well-rehearsed 3-response sequence (performance). Both tasks though could be completed using an identical response topography and used the same sensory stimuli and schedule of reinforcement. More important, comparing neural patterns during sequence acquisition to those during sequence performance allows for a subtractive approach whereby activity associated with learning could potentially be dissociated from the activity associated with ongoing behavior. At sites where CA1 activity was closely associated with behavior, the patterns of activity were differentially modulated by key position and the serial position of a response within the schedule of reinforcement. Temporal shifts between peak activity and responding on particular keys also occurred during sequence acquisition, but not during sequence performance. Ethanol disrupted CA1 activity while producing rate-decreasing effects in both tasks and error-increasing effects that were more selective for sequence acquisition than sequence performance. Ethanol also produced alterations in the magnitude of modulations and temporal pattern of CA1 activity, although these effects were not selective for sequence acquisition. Similar to ethanol, hippocampal micro-stimulation decreased response rate in both tasks and selectively increased the percentage of errors during sequence acquisition, and provided a more direct demonstration of hippocampal involvement during sequence acquisition. Together, these results strongly support the notion that ethanol disrupts sequence acquisition by disrupting hippocampal activity and that the hippocampus is necessary for the conditioned associations required for sequence acquisition. PMID- 26482848 TI - Identification of protein arginine N-methyltransferase 5 (PRMT5) as a novel interacting protein with the tumor suppressor protein RASSF1A. AB - The candidate tumor suppressor gene RASSF1A (Ras-association domain family 1, isoform A) is inactivated in many types of adult and childhood cancers. However, the mechanisms by which RASSF1A exerts tumor suppressive functions have yet to be elucidated. In this report, we sought to identify candidate proteins that interact with RASSF1A using proteomic screening. Using peptide mass fingerprinting, we identified protein arginine N-methyltransferase 5 (PRMT5), a type II protein arginine N-methyltransferase that monomethylates and symmetrically dimethylates arginine residues, as a novel protein that interacts with RASSF1A. The association between the two proteins was confirmed by co immunoprecipitation and immunofluorescence staining. Co-expressing RASSF1A and PRMT5 led to a redistribution of PRMT5 from the cytosol to stabilized microtubules, where RASSF1A and PRMT5 became co-localized. Our results demonstrate that PRMT5 translocates to bundled microtubules on stabilization by RASSF1A expression. Our results show that the tumor suppressor RASSF1A interacts with PRMT5 in vivo and in vitro. Notably, this is the first demonstration of RASSF1A-dependent microtubule recruitment of PRMT5, suggesting a novel role for RASSF1A in the anchoring of cytosolic PRMT5 to microtubules. PMID- 26482849 TI - Balanced cortical stiffness is important for efficient migration of Dictyostelium cells in confined environments. AB - Dictyostelium discoideum cells resemble in many aspects human leukocytes and serve as a model to study actin cytoskeleton dynamics and cell migration of highly motile cells. Dictyostelium cells deficient in the actin-binding protein filamin (ddFLN) showed a surprisingly subtle change in phenotype with no or only minor effects in single cell motility. These findings were in contrast to the strong actin-crosslinking activities measured for filamin in vitro. In the present study, we set out to revisit the role of ddFLN in cell migration. For this purpose, we examined migration of wild-type, ddFLN-null and ddFLN overexpressing cells under different conditions. In addition to cyclic-AMP chemotaxis assays using micropipettes, we explored cell migration under more confined conditions: an under-agarose 2D assay and a 3D assay employing a collagen matrix that was adapted from assays for leukocytes. Using 3D migration conditions, cells deficient in ddFLN displayed only a minor impairment of motility, similar to the results obtained for migration in 2D. However, cells overexpressing ddFLN showed a remarkable decrease in the speed of migration in particular in 3D environments. We suggest that these results are in line with an increased stiffening of the cortex due to the crosslinking activity of overexpressed ddFLN. Our conclusion is that the absolute level of ddFLN is critical for efficient migration. Furthermore, our results show that under conditions of increased mechanical stress, Dictyostelium cells, like leukocytes, switch to a bleb-based mode of movement. PMID- 26482850 TI - Quantitative assessment of cellular uptake and cytosolic access of antibody in living cells by an enhanced split GFP complementation assay. AB - Considering the number of cytosolic proteins associated with many diseases, development of cytosol-penetrating molecules from outside of living cells is highly in demand. To gain access to the cytosol after cellular uptake, cell penetrating molecules should be released from intermediate endosomes prior to the lysosomal degradation. However, it is very challenging to distinguish the pool of cytosolic-released molecules from those trapped in the endocytic vesicles. Here we describe a method to directly demonstrate the cytosolic localization and quantification of cytosolic amount of a cytosol-penetrating IgG antibody, TMab4, based on enhanced split GFP complementation system. We generated TMab4 genetically fused with one GFP fragment and separately established HeLa cells expressing the other GFP fragment in the cytosol such that the complemented GFP fluorescence is observed only when extracellular-treated TMab4 reaches the cytosol after cellular internalization. The high affinity interactions between streptavidin-binding peptide 2 and streptavidin was employed as respective fusion partners of GFP fragments to enhance the sensitivity of GFP complementation. With this method, cytosolic concentration of TMab4 was estimated to be about 170 nM after extracellular treatment of HeLa cells with 1 MUM TMab4 for 6 h. We also found that after cellular internalization into living cells, nearly 1.3-4.3% of the internalized TMab4 molecules escaped into the cytosol from the endocytic vesicles. Our enhanced split GFP complementation assay provides a useful tool to directly quantify cytosolic amount of cytosol-penetrating agents and allows cell based high-throughput screening for cytosol-penetrating agents with increased endosomal-escaping activity. PMID- 26482851 TI - HmuY is an important virulence factor for Porphyromonas gingivalis growth in the heme-limited host environment and infection of macrophages. AB - Porphyromonas gingivalis, the main etiologic agent and key pathogen responsible for initiation and progression of chronic periodontitis, is a haem auxotroph, and the uptake of this compound is essential for its survival and the ability to establish an infection. The aim of this study was to examine the role of a hemophore-like HmuY protein in P. gingivalis growth and infection of macrophages. Inactivation of the hmuY gene caused reduced P. gingivalis growth in vitro in the presence of serum as a heme sole source, as well as in vivo co-cultures with THP 1-derived macrophages. This resulted in diminished invasion efficiency of macrophages by live bacteria lacking functional hmuY gene. Both features were partially restored after addition of the purified HmuY protein, which was internalized when added either together with the hmuY mutant strain or alone to macrophage cultures. We conclude that HmuY is an important virulence factor of P. gingivalis for infection of macrophages in a heme-limited host environment. PMID- 26482852 TI - The role of HOXB2 and HOXB3 in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous aggressive disease and the most common form of adult leukemia. Mutations in the type III receptor tyrosine kinase FLT3 are found in more than 30% of AML patients. Drugs against FLT3 have been developed for the treatment of AML, but they lack specificity, show poor response and lead to the development of a resistant phenotype upon treatment. Therefore, a deeper understanding of FLT3 signaling will facilitate identification of additional pharmacological targets in FLT3-driven AML. In this report, we identify HOXB2 and HOXB3 as novel regulators of oncogenic FLT3-ITD-driven AML. We show that HOXB2 and HOXB3 expression is upregulated in a group of AML patients carrying FLT3-ITD. Overexpression of HOXB2 or HOXB3 in mouse pro-B cells resulted in decreased FLT3-ITD-dependent cell proliferation as well as colony formation and increased apoptosis. Expression of HOXB2 or HOXB3 resulted in a significant decrease in FLT3-ITD-induced AKT, ERK, p38 and STAT5 phosphorylation. Our data suggest that HOXB2 and HOXB3 act as tumor suppressors in FLT3-ITD driven AML. PMID- 26482853 TI - A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma. AB - Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-kappaB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development. PMID- 26482854 TI - Identification of AcMNPV GP64-binding proteins through a combinational use of a self-biotinylated virus and the cross-linking method. AB - Baculoviruses are potential vectors of gene therapy for the ability to transfer gene high efficiently into mammalian cells. However, cell membrane proteins which interact with baculoviral glycoproteins have not been identified. In this study, we developed a self-biotinylated AcMNPV bearing biotinylated GP64 glycoproteins. This recombinant virus demonstrated the capability to infect insect cells and to transduct mammalian cells. Using this biotinylated virus, a protein >170Kda which could specifically interact with GP64 proteins was identified from virus transducted BHK-21 cells through cross-linking and streptavidin purification. Our study provides a useful approach for identifying cell membrane proteins that interact with baculovirus surface proteins or proteins involved in virus attachment. PMID- 26482855 TI - Electrical breakdown in tissue electroporation. AB - Electroporation, the permeabilization of the cell membrane by brief, high electric fields, has become an important technology in medicine for diverse application ranging from gene transfection to tissue ablation. There is ample anecdotal evidence that the clinical application of electroporation is often associated with loud sounds and extremely high currents that exceed the devices design limit after which the devices cease to function. The goal of this paper is to elucidate and quantify the biophysical and biochemical basis for this phenomenon. Using an experimental design that includes clinical data, a tissue phantom, sound, optical, ultrasound and MRI measurements, we show that the phenomenon is caused by electrical breakdown across ionized electrolysis produced gases near the electrodes. The breakdown occurs primarily near the cathode. Electrical breakdown during electroporation is a biophysical phenomenon of substantial importance to the outcome of clinical applications. It was ignored, until now. PMID- 26482856 TI - Comments on: Acetabular component navigation in lateral decubitus based on EOS imaging: A preliminary study of 13 cases of A. Billaud, N. Verdier, R. de Bartolo, N. Lavoine, D. Chauveaux, T. Fabre. Published in Orthop Traumatol Surg Res 2015;101(3):271-5. PMID- 26482857 TI - Morbid Obesity Is Associated With Adverse Clinical Outcomes in Acute Pancreatitis: A Propensity-Matched Study. AB - OBJECTIVES: Morbid obesity may adversely affect the clinical course of acute pancreatitis (AP); however, there are no inpatient, population-based studies assessing the impact of morbid obesity on AP-related outcomes. We sought to evaluate the impact of morbid obesity on AP-related clinical outcomes and health care utilization. METHODS: The Nationwide Inpatient Sample (2007-2011) was reviewed to identify all adult inpatients (>=18 years) with a principal diagnosis of AP. The primary clinical outcomes (mortality, renal failure, and respiratory failure) and secondary resource outcomes (length of stay and hospital charges) were analyzed using univariate and multivariate comparisons. Propensity score matched analysis was performed to compare the outcomes in patients with and without morbid obesity. RESULTS: Morbid obesity was associated with 3.9% (52,297/1,330,302) of all AP admissions. Whereas the mortality rate decreased overall (0.97%->0.83%, P<0.001), it remained unchanged in those with morbid obesity (1.02%->1.07%, P=1.0). Multivariate analysis revealed that morbid obesity was associated with increased mortality (odds ratio (OR) 1.6; 95% confidence interval (CI) 1.3, 1.9), prolonged hospitalization (0.4 days; P<0.001), and higher hospitalization charges ($5,067; P<0.001). A propensity score-matched cohort analysis demonstrated that the primary outcomes, acute kidney failure (10.8 vs. 8.2%; P<0.001), respiratory failure (7.9 vs. 6.4%; P<0.001), and mortality (OR 1.6, 95% CI 1.2, 2.1) were more frequent in morbid obesity. CONCLUSIONS: Morbid obesity negatively influences inpatient hospitalization and is associated with adverse clinical outcomes, including mortality, organ failure, and health-care resource utilization. These observations and the increasing global prevalence of obesity justify ongoing efforts to understand the role of obesity-induced inflammation in the pathogenesis and management of AP. PMID- 26482859 TI - Inflammatory Bowel Disease Patients' Willingness to Accept Medication Risk to Avoid Future Disease Relapse. AB - OBJECTIVES: Biomarkers, endoscopy and imaging tests can identify patients at increased risk for early recurrence of symptomatic inflammatory bowel disease (IBD). However, patients may be unwilling to accept additional medical therapy risks related to therapy escalation to avoid a future disease relapse. We sought to quantify IBD patients' willingness to accept medication risk to avoid future disease relapse. METHODS: We conducted a discrete-choice experiment among 202 patients with IBD who were offered choices of therapies with varying risks of lymphoma and infection, and varying time to next IBD relapse. Random parameters logit was used to estimate patients' willingness to accept tradeoffs among treatment features in selecting medication therapy to avoid future disease relapse. RESULTS: To avoid a disease relapse over the next 5 years, IBD patients were willing to accept an average of a 28% chance of a serious infection; and an average of 1.8% chance of developing lymphoma. These results did not significantly change when patients were offered 10 years until their next disease relapse, but were lower (11 and 0.7%, respectively) when offered 1.5 years until the next disease relapse. Patients with active disease symptoms were significantly less willing to accept medication risk for time in remission. CONCLUSIONS: IBD patients are willing to accept high levels of lymphoma and serious infection risk to maintain disease remission. These preferences are congruent with the treatment paradigms emphasizing mucosal healing and early aggressive therapy and highlight patients' strong preferences for therapies resulting in durable remission of at least 5 years. PMID- 26482858 TI - Evolution of Screen-Detected Small (6-9 mm) Polyps After a 3-Year Surveillance Interval: Assessment of Growth With CT Colonography Compared With Histopathology. AB - OBJECTIVES: Volumetric growth assessment has been proposed for predicting advanced histology at surveillance computed tomography (CT) colonography (CTC). We examined whether is it possible to predict which small (6-9 mm) polyps are likely to become advanced adenomas at surveillance by assessing volumetric growth. METHODS: In an invitational population-based CTC screening trial, 93 participants were diagnosed with one or two 6-9 mm polyps as the largest lesion(s). They were offered a 3-year surveillance CTC. Participants in whom surveillance CTC showed lesion(s) of >=6 mm were offered colonoscopy. Volumetric measurements were performed on index and surveillance CTC, and polyps were classified into growth categories according to +/-30% volumetric change (>30% growth as progression, 30% growth to 30% decrease as stable, and >30% decrease as regression). Polyp growth was related to histopathology. RESULTS: Between July 2012 and May 2014, 70 patients underwent surveillance CTC after a mean surveillance interval of 3.3 years (s.d. 0.3; range 3.0-4.6 years). In all, 33 (35%) of 95 polyps progressed, 36 (38%) remained stable, and 26 (27%) regressed, including an apparent resolution in 13 (14%) polyps. In 68 (83%) of the 82 polyps at surveillance, histopathology was obtained; 15 (47%) of 32 progressing polyps were advanced adenomas, 6 (21%) of 28 stable polyps, and none of the regressing polyps. CONCLUSIONS: The majority of 6-9 mm polyps will not progress to advanced neoplasia within 3 years. Those that do progress to advanced status can in particular be found among the lesions that increased in size on surveillance CTC. PMID- 26482860 TI - Surface nanostructures for fluorescence probing of supported lipid bilayers on reflective substrates. AB - The fluorescence interference contrast (FLIC) effect prevents the use of fluorescence techniques to probe the continuity and fluidity of supported lipid bilayers on reflective materials due to a lack of detectable fluorescence. Here we show that adding nanostructures onto reflective surfaces to locally confer a certain distance between the deposited fluorophores and the reflecting surface enables fluorescence detection on the nanostuctures. The nanostructures consist of either deposited nanoparticles or epitaxial nanowires directly grown on the substrate and are designed such that they can support a lipid bilayer. This simple method increases the fluorescence signal sufficiently to enable bilayer fluorescence detection and to observe the recovery of fluorescence after photobleaching in order to assess lipid bilayer formation on any reflective surface. PMID- 26482862 TI - In Situ Solid-State Generation of (BN)2 -Pyrenes and Electroluminescent Devices. AB - New BN-heterocyclic compounds have been found to undergo double arene photoelimination, forming rare yellow fluorescent BN-pyrenes that contain two B?N units. Most significant is the discovery that the double arene elimination can also be driven by excitons generated electrically within electroluminescent (EL) devices, enabling the in situ solid-state conversion of BN-heterocycles to BN pyrenes and the use of BN-pyrenes as emitters for EL devices. The in situ exciton driven elimination (EDE) phenomenon has also been observed for other BN heterocycles. PMID- 26482863 TI - Towards a Computational Comparative Neuroprimatology: Framing the language-ready brain. AB - We make the case for developing a Computational Comparative Neuroprimatology to inform the analysis of the function and evolution of the human brain. First, we update the mirror system hypothesis on the evolution of the language-ready brain by (i) modeling action and action recognition and opportunistic scheduling of macaque brains to hypothesize the nature of the last common ancestor of macaque and human (LCA-m); and then we (ii) introduce dynamic brain modeling to show how apes could acquire gesture through ontogenetic ritualization, hypothesizing the nature of evolution from LCA-m to the last common ancestor of chimpanzee and human (LCA-c). We then (iii) hypothesize the role of imitation, pantomime, protosign and protospeech in biological and cultural evolution from LCA-c to Homo sapiens with a language-ready brain. Second, we suggest how cultural evolution in Homo sapiens led from protolanguages to full languages with grammar and compositional semantics. Third, we assess the similarities and differences between the dorsal and ventral streams in audition and vision as the basis for presenting and comparing two models of language processing in the human brain: A model of (i) the auditory dorsal and ventral streams in sentence comprehension; and (ii) the visual dorsal and ventral streams in defining "what language is about" in both production and perception of utterances related to visual scenes provide the basis for (iii) a first step towards a synthesis and a look at challenges for further research. PMID- 26482864 TI - The effects of hexafluoroisopropanol on guest binding by water-soluble capsule and cavitand hosts. AB - Encapsulation of amphiphilic guests in a water-soluble cavitand is enhanced by the addition of hexafluoroisopropanol (HFIP). While binding of n-alkanes in cavitands in HFIP/D2O mixtures was similar to that observed in 100% D2O, the binding of guests with terminal polar groups was quite different. Several alpha,omega-bolaamphiphiles: alkyldiols (C10-C12), a dinitrile (C14) and a diacid (C16) became encapsulated in HFIP/D2O solutions. As little as 15% HFIP v/v in D2O moves the guest from cavitand to the dimeric capsule. The unusual binding of polar functional groups inside the confined space is deduced from NMR COSY spectra and supported by DFT calculations. Alkane guests are also encapsulated in 100% HFIP. PMID- 26482865 TI - Vitamin C and E supplementation prevents some of the cellular adaptations to endurance-training in humans. AB - BACKGROUND: It is clear that reactive oxygen species (ROS) produced during skeletal muscle contraction have a regulatory role in skeletal muscle adaptation to endurance exercise. However, there is much controversy in the literature regarding whether attenuation of ROS by antioxidant supplementation can prevent these cellular adaptations. Therefore, the aim of this study was to determine whether vitamin C and E supplementation attenuates performance and cellular adaptations following acute endurance exercise and endurance training. METHODS: A double-blinded, placebo-controlled randomized control trial was conducted in eleven healthy young males. Participants were matched for peak oxygen consumption (VO 2peak) and randomly allocated to placebo or antioxidant (vitamin C (2 * 500 mg/day) and E (400 IU/day)) groups. Following a four-week supplement loading period, participants completed acute exercise (10 * 4 min cycling at 90% VO 2peak, 2 min active recovery). Vastus lateralis muscle samples were collected pre , immediately-post- and 3h-post-exercise. Participants then completed four weeks of training (3 days/week) using the aforementioned exercise protocol while continuing supplementation. Following exercise training, participants again completed an acute exercise bout with muscle biopsies. RESULTS: Acute exercise tended to increase skeletal muscle oxidative stress as measured by oxidized glutathione (GSSG) (P=0.058) and F2-isoprostanes (P=0.056), with no significant effect of supplementation. Acute exercise significantly increased mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), mitochondrial transcription factor A (TFAM) and PGC related coactivator (PRC), with no effect of supplementation. Following endurance training, supplementation did not prevent significantly increased VO 2peak, skeletal muscle levels of citrate synthase activity or mRNA or protein abundance of cytochrome oxidase subunit 4 (COX IV) (P<0.05). However, following training, vitamin C and E supplementation significantly attenuated increased skeletal muscle superoxide dismutase (SOD) activity and protein abundance of SOD2 and TFAM. CONCLUSION: Following acute exercise, supplementation with vitamin C and E did not attenuate skeletal muscle oxidative stress or increased gene expression of mitochondrial biogenesis markers. However, supplementation attenuated some (SOD, TFAM) of the increased skeletal muscle adaptations following training in healthy young men. PMID- 26482866 TI - 1-Methylnicotinamide ameliorates lipotoxicity-induced oxidative stress and cell death in kidney proximal tubular cells. AB - Free fatty acid-bound albumin (FFA-albumin)-related oxidative stress is involved in the pathogenesis of proximal tubular cell (PTC) damage and subsequent renal dysfunction in patients with refractory proteinuria. Nicotinamide adenine dinucleotide (NAD) metabolism has recently been focused on as a novel therapeutic target for several modern diseases, including diabetes. This study was designed to identify a novel molecule in NAD metabolism to protect PTCs from lipotoxicity related oxidative stress. Among 19 candidate enzymes involved in mammalian NAD metabolism, the mRNA expression level of nicotinamide n-methyltransferase (NNMT) was significantly increased in both the kidneys of FFA-albumin-overloaded mice and cultured PTCs stimulated with palmitate-albumin. Knockdown of NNMT exacerbated palmitate-albumin-induced cell death in cultured PTCs, whereas overexpression of NNMT inhibited it. Intracellular concentration of 1 Methylnicotinamide (1-MNA), a metabolite of NNMT, increased and decreased in cultured NNMT-overexpressing and -knockdown PTCs, respectively. Treatment with 1 MNA inhibited palmitate-albumin-induced mitochondrial reactive oxygen species generation and cell death in cultured PTCs. Furthermore, oral administration of 1 MNA ameliorated oxidative stress, apoptosis, necrosis, inflammation, and fibrosis in the kidneys of FFA-albumin-overloaded mice. In conclusion, NNMT-derived 1-MNA can reduce lipotoxicity-mediated oxidative stress and cell damage in PTCs. Supplementation of 1-MNA may have potential as a new therapy in patients with refractory proteinuria. PMID- 26482867 TI - Resveratrol inhibits collagen-induced platelet stimulation through suppressing NADPH oxidase and oxidative inactivation of SH2 domain-containing protein tyrosine phosphatase-2. AB - Reactive oxygen species (ROS) produced upon collagen stimulation are implicated in propagating various platelet-activating pathways. Among ROS-producing enzymes, NADPH oxidase (NOX) is largely responsible for collagen receptor-dependent ROS production. Therefore, NOX has been proposed as a novel target for the development of antiplatelet agent. We here investigate whether resveratrol inhibits collagen-induced NOX activation and further examine the effects of resveratrol on ROS-dependent signaling pathways in collagen-stimulated platelets. Collagen-induced superoxide anion production in platelets was inhibited by resveratrol. Resveratrol suppressed collagen-induced phosphorylation of p47(phox), a major regulatory subunit of NOX. Correlated with the inhibitory effects on NOX, resveratrol protected SH2 domain-containing protein tyrosine phosphatase-2 (SHP-2) from ROS-mediated inactivation and subsequently attenuated the specific tyrosine phosphorylation of key components (spleen tyrosine kinase, Vav1, Bruton's tyrosine kinase, and phospholipase Cgamma2) for collagen receptor signaling cascades. Resveratrol also inhibited downstream responses such as cytosolic calcium elevation, P-selectin surface exposure, and integrin alphaIIbbeta3 activation. Furthermore, resveratrol inhibited platelet aggregation and adhesion in response to collagen. The antiplatelet effects of resveratrol through the inhibition of NOX-derived ROS production and subsequent oxidative inactivation of SHP-2 suggest that resveratrol is a potential compound for prevention and treatment of thrombovascular diseases. PMID- 26482868 TI - Zeaxanthin and alpha-tocopherol reduce the inhibitory effects of photodynamic stress on phagocytosis by ARPE-19 cells. AB - Zeaxanthin and alpha-tocopherol have been previously shown to efficiently protect liposomal membrane lipids against photosensitized peroxidation, and to protect cultured RPE cells against photodynamic killing. Here the protective action of combined zeaxanthin and alpha-tocopherol was analyzed in ARPE-19 cells subjected to photodynamic (PD) stress mediated by rose Bengal (RB) or merocyanine-540 (MC 540) at sub-lethal levels. Stress-induced cytotoxicity was analyzed by the MTT assay. The peroxidation of membrane lipids was determined by HPLC-EC (Hg) measurements of cholesterol hydroperoxides using cholesterol as a mechanistic reporter molecule. The specific phagocytosis of FITC-labeled photoreceptor outer segments (POS) isolated from bovine retinas was measured by flow cytometry, and the levels of phagocytosis receptor proteins alphav integrin subunit, beta5 integrin subunit and MerTK were quantified by Western blot analysis. Cytotoxicity measures confirmed that PD stress levels used for phagocytosis analysis were sub lethal and that antioxidant supplementation protected against higher, lethal PD doses. Sub-lethal PD stress mediated by both photosensitizers induced the accumulation of 5alpha-OOH and 7alpha/beta-OOH cholesterol hydroperoxides and the addition of the antioxidants substantially inhibited their accumulation. Antioxidant delivery prior to PD stress also reduced the inhibitory effect of stress on POS phagocytosis and partially reduced the stress-induced diminution of phagocytosis receptor proteins. The use of a novel model system where oxidative stress was induced at sub-lethal levels enable observations that would not be detectable using lethal stress models. Moreover, novel observations about the protective effects of zeaxanthin and alpha-tocopherol on photodynamic damage to ARPE-19 cell membranes and against reductions in the abundance of receptor proteins involved in POS phagocytosis, a process essential for photoreceptor survival, supports the importance of the antioxidants in protecting of the retina against photooxidative injury. PMID- 26482869 TI - Comprehensive geriatric assessment in patients with gastric and gastroesophageal adenocarcinoma undergoing gastrectomy. AB - OBJECTIVE: The purpose of this study was to identify clinical and geriatric assessment variables associated with outcome in patients with gastric adenocarcinoma who have undergone gastrectomy. METHODS: We reviewed demographic, clinical, and geriatric assessment variables, including recent falls, pain, performance status, American Society of Anesthesiologists score, assistive device use, comorbidity, polypharmacy, and weight change, for patients undergoing gastrectomy between 2005 and 2014. Outcome variables included morbidity, mortality, hospital length of stay, and readmission. RESULTS: Of 279 patients, 133 (48%) underwent total gastrectomy. The 90-day major morbidity rate was 24% and the mortality rate was 1%. Length of hospital stay >= 14 days occurred in 38%, with readmission within 30 days in 13%. On multivariate analysis, gastroesophageal junction involvement, (odds ratio [OR] 2.5, 95% confidence interval [1.1-5.8]), additional organ resection, (OR 3.2, [1.6-6.3]), pain score >0 (OR 3.8, [1.6-8.7]), Eastern Cooperative Oncology Group performance status >0, (OR 2.3, [1.2-4.6]), and polypharmacy (OR 2.4, [1.1-5.2]) were associated with major morbidity. Hospital stay >= 14 days was associated with age >= 75 years (OR 3.9, [1.7-9.2]), total gastrectomy (OR 3.5, [2.0-6.3]), performance status >0 (OR 1.8, [1.0-3.2]), and preoperative chemotherapy (OR 0.3, [0.2-0.7]). CONCLUSIONS: Future studies are needed to identify methods to improve performance status, as this may improve postoperative complications and resource utilization. PMID- 26482870 TI - The Portuguese version of the RhinoQOL Questionnaire: validation and clinical application. AB - INTRODUCTION: Rhinosinusitis constitutes an important health problem, with significant interference in personal, professional, and social functioning. This study presents the validation process of the Portuguese version of the RhinoQOL, to be used as a routine procedure in the assessment of patients with chronic rhinosinusitis. OBJECTIVE: To demonstrate that the Portuguese version of the RhinoQOL is as valid as the English version to measure symptoms and health related quality of life in chronic rhinosinusitis. METHODS: The Portuguese version of the RhinoQOL was administered consecutively to 58 patients with chronic rhinosinusitis with and without nasal polyps, assessed for endoscopic sinus surgery. A follow-up survey was completed three months after surgery. Statistical analysis was performed to determine its psychometric properties. RESULTS: Face and content validity were confirmed by similar internal consistency as the original questionnaire for each sub-scale, and strong correlation between individual items and total score. The questionnaire was easy and quick to administer (5.5min). At three months, there was a significant decrease from baseline for all sub-scale scores, indicating clinical improvement, with an effect size considered as large. CONCLUSION: This study provides a questionnaire that is equivalent to the original English version, with good responsiveness to change, which can be especially valuable to measure the outcome of surgery. PMID- 26482871 TI - Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene. AB - Phosphoglucomutase 3 (PGM3) is an enzyme converting N-acetyl-glucosamine-6 phosphate to N-acetyl-glucosamine-1-phosphate, a precursor important for glycosylation. Mutations in the PGM3 gene have recently been identified as the cause of novel primary immunodeficiency with a hyper-IgE like syndrome. Here we report the occurrence of a homozygous mutation in the PGM3 gene in a family with immunodeficient children, described already in 1976. DNA from two of the immunodeficient siblings was sequenced and shown to encode the same homozygous missense mutation, causing a destabilized protein with reduced enzymatic capacity. Affected individuals were highly prone to infections, but lack the developmental defects in the nervous and skeletal systems, reported in other families. Moreover, normal IgE levels were found. Thus, belonging to the expanding group of congenital glycosylation defects, PGM3 deficiency is characterized by immunodeficiency, with or without increased IgE levels, and with variable forms of developmental defects affecting other organ systems. PMID- 26482872 TI - Feasibility of asymmetrical flow field-flow fractionation as a method for detecting protective antigen by direct recognition of size-increased target captured nanoprobes. AB - Asymmetrical flow field-flow fractionation (AF4) was evaluated as a potential analytical method for detection of a protective antigen (PA), an Anthrax biomarker. The scheme was based on the recognition of altered AF4 retention through the generation of the size-increased Au nanoparticle probes as a result of PA binding, in which a PA-selective peptide was conjugated on the probe surface. In the visible absorption-based AF4 fractograms, the band position shifted to a longer retention time as the PA concentration increased due to the presence of probe bound with PAs. The shift was insignificant when the concentration was relatively low at 84.3pM. To improve sensitivity, two separate probes conjugated with two different peptides able to bind on different PA epitopes were used together. The band shift then became distinguishable even at 84.3pM of PA sample. The formation of larger PA-probe inter-connected species using the dual-probe system was responsible for the enhanced band shift. In parallel, the feasibility of surface-enhanced Raman scattering (SERS) as a potential AF4 detection method was also evaluated. In the off-line SERS fractogram constructed using fractions collected during AF4 separation, a band shift was also observed for the 84.3pM PA sample, and the band intensity was higher when using the dual-probe system. The combination of AF4 and SERS is promising for the detection of PA and will become a potential tool if the reproducibility of SERS measurement is improved. PMID- 26482873 TI - Size-exclusion simulated moving bed for separating organophosphorus flame retardants from a polymer. AB - Over 500,000t of flame retardants in electronic wastes are consigned to landfills each year. A room-temperature, size-exclusion simulated moving bed (SEC-SMB) was developed to recover high purity (>99%) flame retardants with high yield (>99%). The SSWD method for ternary mixtures was developed for SEC-SMB. Fourteen decision variables were optimized to obtain the lowest separation cost within 1min. The estimated cost is less than 10% of the purchase cost of the flame retardants. The estimated cost of the optimized SEC-SMB is less than 3% of that of a conventional batch SEC processes. Fast start-up methods were developed to reduce the SMB start up time by more than 18-fold. SEC-SMB can be an economical method for separating small molecules from polymers. PMID- 26482874 TI - Three-dimensional anthropometric analysis of the glenohumeral joint in a normal Japanese population. AB - BACKGROUND: An understanding of normal glenohumeral geometry is important for anatomical reconstruction in shoulder arthroplasty. Unfortunately, the details of the glenohumeral joint in Asian populations have not been sufficiently evaluated. The purpose of this study was to evaluate the 3-dimensional geometry of the glenohumeral joint in the normal Japanese population and to clarify its morphologic features. METHODS: Anthropometric analysis of the glenohumeral joint was performed using computed tomography scans of 160 normal shoulders from healthy Japanese volunteers. The glenohumeral dimensions and orientation were analyzed 3-dimensionally. Sex differences and correlations between sides and among the respective parameters in the glenohumeral dimensions were evaluated. RESULTS: The normal Japanese humeral head has an average width of 41.4 mm, thickness of 13.2 mm, diameter of 42.9 mm, retroversion of 32 degrees , and inclination of 135 degrees . The glenoid has an average height of 31.5 mm, width of 23.1 mm, diameter of 62.0 mm, retroversion of 0 degrees , and inferior inclination of 2 degrees . The values of the glenohumeral dimensions were uniform in men and women, and the humeral head and glenoid were larger in men than in women. The glenohumeral size was well correlated between the 2 sides, and there were direct correlations among the heights, humeral length, humeral head size, and glenoid size. CONCLUSIONS: The present study revealed the glenohumeral geometry in the normal Japanese population. The present results would be useful to determine the size of implants and to improve the design of shoulder prostheses that reflect the normal anatomy of the Asian glenohumeral joint. PMID- 26482875 TI - Copernicus Revisited: Overturning Ptolemy's View of the GPER Universe. AB - Whether aldosterone activates the G-protein-coupled estrogen receptor (GPER) has been questioned, recently, in the name of Copernicus. However, for G-protein coupled receptors (GPCRs) multiple hormone activators are common. Further, studies in mineralocorticoid receptor (MR)-deficient systems, with pharmacological GPER-selective antagonists or regulation of GPER expression, consistently show that some aldosterone effects can be GPER mediated. PMID- 26482876 TI - Neuronal Control of Brown Fat Activity. AB - Brown adipose tissue (BAT) activation reduces body fat and metabolic disorders by the enhanced combustion of lipids and glucose into heat. The thermogenic activity of brown adipocytes is primarily driven by the sympathetic nervous system (SNS) and controlled by the brain. In this review, we present recent advances in understanding how cues, such as temperature, light, and proteins, modulate the activity of brown fat by acting on the various hypothalamic nuclei. Given that activated BAT has a high capacity to take up and burn fatty acids (FAs) and glucose, pharmacological stimulation of brown fat in humans by either targeting the hypothalamus or mimicking outflow of the sympathetic nervous system might help improve glucose metabolism and insulin sensitivity, and also lower body fat. PMID- 26482877 TI - Gaining Insights into Diabetic Cardiomyopathy from Drosophila. AB - The high degree of genetic conservation between Drosophila melanogaster and mammals has helped to translate many important findings into new knowledge, and has led to better understanding of many biological processes in vertebrates. For over a century, the Drosophila model has been used in studies aimed at understanding the molecular mechanisms implicated in heredity, development, disease progression, and aging. The current epidemic of obesity and associated diabetic cardiomyopathy and heart failure has led to a shift in Drosophila research towards understanding the basic mechanisms leading to metabolic syndrome and associated cardiac risk factors. We discuss recent findings in Drosophila that highlight the importance of this organism as an excellent model for studying the effects of metabolic imbalance on cardiac function. PMID- 26482878 TI - Poly(A)-specific ribonuclease (PARN) mediates 3'-end maturation of the telomerase RNA component. AB - Mutations in the PARN gene (encoding poly(A)-specific ribonuclease) cause telomere diseases including familial idiopathic pulmonary fibrosis (IPF) and dyskeratosis congenita, but how PARN deficiency impairs telomere maintenance is unclear. Here, using somatic cells and induced pluripotent stem cells (iPSCs) from patients with dyskeratosis congenita with PARN mutations, we show that PARN is required for the 3'-end maturation of the telomerase RNA component (TERC). Patient-derived cells as well as immortalized cells in which PARN is disrupted show decreased levels of TERC. Deep sequencing of TERC RNA 3' termini shows that PARN is required for removal of post-transcriptionally acquired oligo(A) tails that target nuclear RNAs for degradation. Diminished TERC levels and the increased proportion of oligo(A) forms of TERC are normalized by restoring PARN, which is limiting for TERC maturation in cells. Our results demonstrate a new role for PARN in the biogenesis of TERC and provide a mechanism linking PARN mutations to telomere diseases. PMID- 26482882 TI - Characterization of the PTW SourceCheck ionization chamber with the Valencia lodgment for (125)I seed verification. AB - In brachytherapy using (125)I seed implants, a verification of the air kerma strength of the sources used is required. Typically, between 40 and 100 seeds are implanted. Checking all of them is unaffordable, especially when seeds are disposed in sterile cartridges. Recently, a new procedure allowing the accomplishment of the international recommendations has been proposed for the seedSelectron system of Elekta Brachytherapy. In this procedure, the SourceCheck ionization chamber is used with a special lodgment (Valencia lodgment) that allows to measure up to 10 seeds simultaneously. In this work we analyze this procedure, showing the feasibility of the approximations required for its application, as well as the effect of the additional dependence with the air density that shows the chamber model used. Uncertainty calculations and the verification of the approximation needed to obtain a calibration factor for the Valencia lodgment are carried out. The results of the present work show that the chamber dependence with the air density is the same whether the Valencia lodgment is used or not. On the contrary, the chamber response profile is influenced by the presence of the lodgment. The determination of this profile requires various measurements due to the nonnegligible variability found between different experiments. If it is considered, the uncertainty in the determination of the air kerma strength increases from 0.5% to 1%. Otherwise, a systematic additional uncertainty of 1% would occur. This could be relevant for the comparison between user and manufacturer measurements that is mandatory in the case studied here. PMID- 26482881 TI - NRF2 regulates serine biosynthesis in non-small cell lung cancer. AB - Tumors have high energetic and anabolic needs for rapid cell growth and proliferation, and the serine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. We integrated metabolic tracing and transcriptional profiling of a large panel of non-small cell lung cancer (NSCLC) cell lines to characterize the activity and regulation of the serine/glycine biosynthetic pathway in NSCLC. Here we show that the activity of this pathway is highly heterogeneous and is regulated by NRF2, a transcription factor frequently deregulated in NSCLC. We found that NRF2 controls the expression of the key serine/glycine biosynthesis enzyme genes PHGDH, PSAT1 and SHMT2 via ATF4 to support glutathione and nucleotide production. Moreover, we show that expression of these genes confers poor prognosis in human NSCLC. Thus, a substantial fraction of human NSCLCs activates an NRF2-dependent transcriptional program that regulates serine and glycine metabolism and is linked to clinical aggressiveness. PMID- 26482880 TI - A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. AB - Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 * 10(-9)) and TM6SF2 (P = 7.89 * 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 * 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis. PMID- 26482884 TI - A waterborne norovirus gastroenteritis outbreak in a school, eastern China. AB - In late 2014, a gastroenteritis outbreak occurred in a school in Shandong Province, eastern China. Hundreds of individuals developed the symptoms of diarrhoea and vomiting. Epidemiological investigation showed that food consumption was not linked to this outbreak, and unboiled direct drinking water was identified as the independent risk factor with a relative risk of 1.37 (95% confidence interval 1.03-1.83). Furthermore, examination of common bacterial and viral gastroenteritis pathogens was conducted on different specimens. Norovirus GI.1, GI.2, GI.6, GII.4, GII.6 and GII.13 were detected in clinical specimens and a water sample. GII.4 sequences between clinical specimens and the water sample displayed a close relationship and belonged to GII.4 variant Sydney 2012. These results indicate that direct drinking water contaminated by norovirus was responsible for this gastroenteritis outbreak. This study enriches our knowledge of waterborne norovirus outbreaks in China, and presents valuable prevention and control practices for policy-makers. In future, strengthened surveillance and supervision of direct drinking-water systems is needed. PMID- 26482885 TI - Implementing Specialized Diabetes Teams in Primary Care in Southern Ontario. AB - OBJECTIVES: This study explores the implementation processes of integrating specialized diabetes teams into primary care in southern Ontario, Canada. METHODS: In-depth qualitative interviews were conducted with 23 patients, 20 diabetes educators and 16 primary care physicians. In addition, group debriefing sessions were conducted and field notes were collected from diabetes educators and diabetes education program managers to further explore the day-to-day issues of implementation. Data were analyzed using an inductive content analysis approach. RESULTS: Analysis revealed 3 main themes: Right Place, Right Time, Right Service: the convenience and comfort of local care, timely, preventive management and delivering person-centred care; Creating Partnerships: generating intervention buy-in, formal discussion, service agreements, site orientation and team development; Operational Complexities and Strategies: access to electronic medical records and documentation, referral and scheduling procedures, and costs and resources. CONCLUSIONS: Because situating diabetes teams in primary care currently involves using existing healthcare structures and human resources, pragmatic methods of fostering successful implementation of this model of practice are required. The utility of this model was perceived as being viable, and benefits were visible to all study participants. Strategies to facilitate implementation include outlining roles and expectations by educators and the primary care providers' team in the beginning, investment in the intervention by all stakeholders, and clear channels of communication that allow educators to perform their roles and leverage opportunities for team collaboration in patient care. Further evaluation of implementation processes can serve to expand this model of practice, which has proven so far to be favourable to the players involved. PMID- 26482886 TI - An Innovative Home-Based Cardiovascular Lifestyle Prevention Program for Women With Recent Gestational Diabetes: A Pilot Feasibility Study. PMID- 26482879 TI - Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. AB - Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis. PMID- 26482887 TI - Nine-year Follow-up for a Study of Diffusion-weighted Magnetic Resonance Imaging in a Prospective Prostate Cancer Active Surveillance Cohort. AB - BACKGROUND: In active surveillance (AS) for prostate cancer there are few data on long-term outcomes associated with novel imaging markers. OBJECTIVE: To determine long-term outcomes with respect to the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) in a prospective AS cohort. Early results have already been published; we now present findings with long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS: A subset of patients (n=86) underwent pre-enrolment DW-MRI in a prospective AS study between 2002 and 2006. Inclusion criteria were untreated prostate cancer, clinical T1/T2a/N0M0, Gleason <= 3+4, and prostate-specific antigen (PSA) <15 ng/ml. Protocol follow-up was by biopsy at 18-24 mo and then every 24 mo, with regular PSA measurement. INTERVENTION: Men underwent baseline DW-MRI in addition to standard sequences. ADC was measured from the index lesion on T2-weighted images. To avoid influencing treatment decisions, DW-MRI sequence results were not available to the AS study investigators. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline ADC was analysed with respect to time to radical treatment (TRT) and time to adverse histology (TAH). Kaplan-Meier analysis and univariate and multivariate regression analyses were performed. RESULTS AND LIMITATIONS: The median follow-up was 9.5 yr (interquartile range 7.9-10.0 yr). On univariate analysis, ADC below the median was associated with shorter TAH (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.17-3.89; p<0.014) and TRT (HR 2.54, 95% CI 1.49-4.32; p<0.001). Median TRT was 9.3 yr (95% CI 7.0-11.6 yr) for patients with ADC above the median and only 2.4 yr (95% CI 1.5-6.0 yr) for ADC below the median. For TRT, addition of ADC to a multivariate model of baseline variables resulted in a significant improvement in model fit (HR 1.33, 95% CI 1.14-1.54; p<0.001). Receiver operating characteristic analysis for TRT revealed an area under the curve of 0.80 (95% CI 0.70-0.88). The number of variables included in the multivariate model was limited by sample size. CONCLUSIONS: Long-term follow up for this study provides strong evidence that ADC is a useful marker when selecting patients for AS. Routine DW-MRI is now being evaluated in our ongoing AS study for initial assessment and as an alternative to repeat biopsy. PATIENT SUMMARY: Before entering a study of close monitoring for the initial management of prostate cancer, patients had a type of magnetic resonance imaging scan that looks at the movement of water within cancers. These scans may help in predicting whether patients should receive close monitoring or whether immediate treatment should be given. PMID- 26482888 TI - Ethylene: Traffic Controller on Hormonal Crossroads to Defense. AB - Ethylene (ET) is an important hormone in plant responses to microbial pathogens and herbivorous insects, and in the interaction of plants with beneficial microbes and insects. Early ET signaling events during these biotic interactions involve activities of mitogen-activated protein kinases and ETHYLENE RESPONSE FACTOR transcription factors. Rather than being the principal regulator, ET often modulates defense signaling pathways, including those regulated by jasmonic acid and salicylic acid. Hormonal signal integrations with ET steer the defense signaling network to activate specific defenses that can have direct effects on attackers, or systemically prime distant plant parts for enhanced defense against future attack. ET also regulates volatile signals that attract carnivorous enemies of herbivores or warn neighboring plants. Conversely, ET signaling can also be exploited by attackers to hijack the defense signaling network to suppress effective defenses. In this review, we summarize recent findings on the significant role of ET in the plants' battle against their enemies. PMID- 26482891 TI - Effectiveness of an Educational Intervention on Medical Students' Knowledge About and Attitude Towards Electroconvulsive Therapy. AB - OBJECTIVE: This study was done to determine the effectiveness of a lecture and exposure to electroconvulsive therapy (ECT) followed by interaction with patient, on medical students' knowledge about and attitude towards electroconvulsive therapy. METHODS: A questionnaire was administered to second year medical students to determine their baseline knowledge about and attitude towards electroconvulsive therapy. Following this, they underwent two educational interventions, a lecture on ECT and exposure to the procedure and interaction with the patient and relative, and their knowledge and attitude were reassessed after each intervention using the same questionnaire. RESULTS: Eighty-one students completed all the three assessments. Students' knowledge about ECT at baseline was minimal (mean 3.58 out of 12). Their knowledge increased significantly after the lecture (mean 10.3), and there was further increase following exposure to the procedure and subsequent interaction with the patient and relative (mean 11.1). At baseline, students had an overall negative attitude towards ECT. There was significant improvement on all attitude items following the lecture. Exposure to the procedure resulted in further improvement in attitude regarding whether ECT is a cruel treatment and has to be used as a last resort. CONCLUSIONS: Exposure to ECT in lecture and clinical scenarios followed by interaction with the patient should be included in the undergraduate medical curriculum to improve students' knowledge and attitude about this safe, effective, and potentially lifesaving treatment modality. PMID- 26482889 TI - Highly Branched Xylan Made by IRREGULAR XYLEM14 and MUCILAGE-RELATED21 Links Mucilage to Arabidopsis Seeds. AB - All cells of terrestrial plants are fortified by walls composed of crystalline cellulose microfibrils and a variety of matrix polymers. Xylans are the second most abundant type of polysaccharides on Earth. Previous studies of Arabidopsis (Arabidopsis thaliana) irregular xylem (irx) mutants, with collapsed xylem vessels and dwarfed stature, highlighted the importance of this cell wall component and revealed multiple players required for its synthesis. Nevertheless, xylan elongation and substitution are complex processes that remain poorly understood. Recently, seed coat epidermal cells were shown to provide an excellent system for deciphering hemicellulose production. Using a coexpression and sequence-based strategy, we predicted several MUCILAGE-RELATED (MUCI) genes that encode glycosyltransferases (GTs) involved in the production of xylan. We now show that MUCI21, a member of an uncharacterized clade of the GT61 family, and IRX14 (GT43 protein) are essential for the synthesis of highly branched xylan in seed coat epidermal cells. Our results reveal that xylan is the most abundant xylose-rich component in Arabidopsis seed mucilage and is required to maintain its architecture. Characterization of muci21 and irx14 single and double mutants indicates that MUCI21 is a Golgi-localized protein that likely facilitates the addition of xylose residues directly to the xylan backbone. These unique branches seem to be necessary for pectin attachment to the seed surface, while the xylan backbone maintains cellulose distribution. Evaluation of muci21 and irx14 alongside mutants that disrupt other wall components suggests that mucilage adherence is maintained by complex interactions between several polymers: cellulose, xylans, pectins, and glycoproteins. PMID- 26482890 TI - Mixed Emotions to Near-Miss Outcomes: A Psychophysiological Study with Facial Electromyography. AB - Near-misses occur across many forms of gambling and are rated as unpleasant while simultaneously increasing the motivation to continue playing. On slot machines, the icon position relative to the payline moderates the effects of near-misses, with near-misses before the payline increasing motivation, and near-misses after the payline being rated as aversive. Near-misses are also known to increase physiological arousal compared to full-misses, but physiological measures to date have not been able to dissociate positive and negative emotional responses. The present study measured facial electromyography at the corrugator (brow) and zygomaticus (cheek) sites, as well as electrodermal activity (EDA), following gambling outcomes on a two-reel slot machine simulation in 77 novice gamblers. Behavioral data was collected using trial-by-trial ratings of motivation and valence. Wins were rated as more pleasant and increased motivation to continue playing, compared to non-win outcomes. Wins were also accompanied by increased EDA and zygomaticus activity. Near-misses after the payline were rated as more aversive than other non-wins, and this was accompanied by increased EDA and zygomaticus activity. Near-misses before the payline increased motivation to continue playing, and were accompanied by increased EDA. Thus, both subjective and physiological responses to near-misses differ for events falling either side of the payline. The 'near-miss effect' is not a unitary phenomenon. Facial EMG has differential sensitivity to positive and negative valence and may be a useful measure for future studies of gambling behavior. PMID- 26482892 TI - Factors associated with latency period in preterm prelabor rupture of membranes. AB - OBJECTIVE: To determine the factors associated with prolonged latency periods in preterm prelabor rupture of membrane (PPROM). METHODS: This retrospective study analyzed data from singleton pregnant women with gestational age between 28 and 34 weeks suffering from PROM. Multivariate regression analysis was used to evaluate the association between the factors and latency period >= 2 and >= 7 days. RESULTS: A total of 231 cases of PPROM were included. Prolong latency period >=2 and 7 days were achieved in 141 (61%) and 54 (23.4%) cases. Higher gestational age at PPROM and cervical dilatation >2 cm were associated with a shorter latency period <2 days. Multiparity and presence of uterine contraction at admission were associated with a shorter latency period <7 days. Prophylactic antibiotics [odds ratio (ORs) 6.69, 95% confidence interval (CI) 3.0-14.89], and tocolysis (ORs 2.74, 95%CI 1.25-6.02) were factors associated with latency period >= 2 days. Only prophylactic antibiotics (ORs 7.7, 95%CI 2.54-23.34) was a factor associated with latency period >=7 days. CONCLUSIONS: Prophylactic antibiotics and tocolysis are two major factors associated with latency period >=2 days in PPROM, where prophylactic antibiotics is the main factor associated with latency period >=7 days in PPROM. PMID- 26482893 TI - Effects of mild hypoxia in aviation on mood and complex cognition. AB - Thirty six volunteer air force personnel were sequentially exposed in a randomized balanced order in a hypobaric chamber to 30 min of baseline (sea level) and mild hypoxia induced by a specified altitude (sea level, 8000 ft and 12,000 ft), followed immediately by breathing 100% oxygen from an oro-nasal mask. Mood and complex cognition were assessed. Analysis of variance indicated that mood (fatigue and vigour) remained the same at 8000 ft but fatigue was increased (p = 0.001) and vigour reduced (p = 0.035) at 12,000 ft and was restored by supplementary oxygen. Complex cognition was not significantly altered by the test conditions. The results of this study do not support prior evidence that mild hypoxia equivalent to either 8000 or 12,000 ft, impairs complex cognition, but suggests that some aspects of mood may be affected at 12,000 ft and can be restored by breathing 100% oxygen. PMID- 26482894 TI - Designing Fatigue Warning Systems: The perspective of professional drivers. AB - Professional drivers have been characterized as experiencing heavy fatigue resulting from long driving time in their daily work. This study aimed to explore the potential demand of Fatigue Warning Systems (FWSs) among professional drivers as a means of reducing the danger of fatigue driving and to examine their opinions regarding the design of FWSs. Six focus groups with 35 participants and a questionnaire survey with 600 respondents were conducted among Chinese truck and taxi drivers to collect qualitative and quantitative data concerning the current situation of fatigue driving and opinions regarding the design of FWSs. The results revealed that both truck and taxi drivers had a positive attitude toward FWSs, and they hoped this system could not only monitor and warn them regarding their fatigue but also somewhat relieve their fatigue before they could stop and rest. As for warning signals, participants preferred auditory warnings, as opposed to visual, vibrotactile or electric stimuli. Interestingly, it was proposed that verbal warnings involving the information regarding consequences of fatigue driving or the wishes of drivers' family members would be more effective. Additionally, different warning patterns, including graded, single and continuous warnings, were discussed in the focus group. Finally, the participants proposed many other suggestions, as well as their concerns regarding FWSs, which will provide valuable information for companies who wish to develop FWSs for professional drivers. PMID- 26482895 TI - Predictors of Renal Denervation Efficacy in the Treatment of Resistant Hypertension. AB - The aims of the study were to evaluate the effects of renal sympathetic denervation (RSD) on the heart and to identify the predictors of RSD efficacy in patients with resistant arterial hypertension. The study comprised 60 RSD patients (54.6 +/- 9.5 years) who received full-dose antihypertensive therapy (4.1 drugs) including diuretics. Initially, 58.6% of patients had abnormal left ventricular (LV) diastolic function. All patients received echocardiography before and 24 weeks after RSD. Renal sympathetic denervation was achieved through the endovascular radiofrequency ablation (RFA) of the renal arteries. Drug therapy continued for the entire period of observation. After RSD, all patients were retrospectively assigned to two groups: group 1 comprised patients (n = 22; 36.7%) in whom the myocardial mass (MM) of the left ventricle decreased by more than 10 g after RSD; group 2 comprised patients (n = 38; 63.3%) in whom LV MM increased or decreased by less than 10 g. Anthropometry, arterial blood pressure, heart rate, therapy, and LV end-diastolic dimensions (EDD) were comparable in these groups. After RSD, the values of office blood pressure significantly decreased and MM regressed by more than 10 g in 36.7% of patients; LV diastolic function normalized in 31% of patients, and diastolic dysfunction improved in 14% of patients. The study found the associations between the initial LV wall dimensions and LV MM changes. Unlike LV EDD, arterial blood pressure, or heart rate, the initial values of LV wall thickness predicted LV MM regress. TRIAL REGISTRATION: #NCT01499810 https://clinicaltrials.gov/ct2/show/NCT01499810. PMID- 26482897 TI - Comment on "The Nature of the Fourth Bond in the Ground State of C2: The Quadruple Bond Conundrum". AB - Is it time to reconsider the whole concept of quadruple bonding? Contrary to the conclusion of Shaik and co-workers in Chem. Eur. J.- 2014, 20, 6220-6232, there is no "deviation of C2 from the Badger Rule". PMID- 26482896 TI - Involvement of gelsolin in TGF-beta 1 induced epithelial to mesenchymal transition in breast cancer cells. AB - BACKGROUND: Increasing evidence suggests that transforming growth factor-beta 1 (TGF-beta1) triggers epithelial to mesenchymal transition (EMT) and facilitates breast cancer stem cell differentiation. Gelsolin (GSN) is a ubiquitous actin filament-severing protein. However, the relationship between the expression level of GSN and the TGF-beta signaling for EMT progression in breast cancer cells is not clear. RESULTS: TGF-beta1 acted on MDA-MB231 breast cancer cells by decreasing cell proliferation, changing cell morphology to a fibroblast-like shape, increasing expressions for CD44 and GSN, and increasing EMT expression and cell migration/invasion. Study with GSN overexpression (GSN op) in both MDA-MB231 and MCF-7 cells demonstrated that increased GSN expression resulted in alterations of cell proliferation and cell cycle progression, modification of the actin filament assembly associated with altering cell surface elasticity and cell detachment in these breast cancer cells. In addition, increased cell migration was found in GSN op MDA-MB231 cells. Studies with GSN op and silencing by small interfering RNA verified that GSN could modulate the expression of vimentin. Sorted by flow cytometry, TGF-beta1 increased subpopulation of CD44+/CD22- cells increasing their expressions for GSN, Nanog, Sox2, Oct4, N-cadherin, and vimentin but decreasing the E-cadherin expression. Methylation specific PCR analysis revealed that TGF-beta1 decreased 50 % methylation but increased 3-fold unmethylation on the GSN promoter in CD44+/CD22- cells. Two DNA methyltransferases, DNMT1 and DNMT3B were also inhibited by TGF-beta1. CONCLUSIONS: TGF-beta1 induced epigenetic modification of GSN could alter the EMT process in breast cancer cells. PMID- 26482898 TI - Cocaine-induced plasticity in the cerebellum of sensitised mice. AB - RATIONALE: Prior research has accumulated a substantial amount of evidence on the ability of cocaine to produce short- and long-lasting molecular and structural plasticity in the corticostriatal-limbic circuitry. However, traditionally, the cerebellum has not been included in the addiction circuitry, even though growing evidence supports its involvement in the behavioural changes observed after repeated drug experiences. OBJECTIVES: In the present study, we explored the ability of seven cocaine administrations to alter plasticity in the cerebellar vermis. METHODS: After six cocaine injections, one injection every 48 h, mice remained undisturbed for 1 month in their home cages. Following this withdrawal period, they received a new cocaine injection of a lower dose. Locomotion, behavioural stereotypes and several molecular and structural cerebellar parameters were evaluated. RESULTS: Cerebellar proBDNF and mature BDNF levels were both enhanced by cocaine. The high BDNF expression was associated with dendritic sprouting and increased terminal size in Purkinje neurons. Additionally, we found a reduction in extracellular matrix components that might facilitate the subsequent remodelling of Purkinje-nuclear neuron synapses. CONCLUSIONS: Although speculative, it is possible that these cocaine-dependent cerebellar changes were incubated during withdrawal and manifested by the last drug injection. Importantly, the present findings indicate that cocaine is able to promote plasticity modifications in the cerebellum of sensitised animals similar to those in the basal ganglia. PMID- 26482899 TI - Preoperative neutrophil-to-lymphocyte ratio is an independent prognostic marker in patients with laryngeal squamous cell carcinoma. AB - BACKGROUND: Neutrophil-lymphocyte ratio (NLR) has been shown to be associated with prognosis in various solid tumors. This study aimed to evaluate the prognostic role of NLR in patients with laryngeal squamous cell carcinoma (LSCC). METHODS: A total of 141 LSCC patients were retrospectively reviewed. Patients' demographics were analyzed along with clinical and pathologic data. The optimal cutoff value of NLR was determined using receiver operating characteristic (ROC) curve analysis. The impact of the NLR and other potential prognostic factors on disease-free survival (DFS) and overall survival (OS) was assessed using the Kaplan-Meier method and multivariate Cox regression analysis. RESULTS: The optimal cutoff value of the NLR was 2.17. In the NLR <= 2.17 group, the 1-, 3-, and 5-year DFS rates were 88.2, 73.9 and 69.1 %, respectively, while in the NLR > 2.17 group, the DFS rates were 83.0, 54.6 and 49.2 %, respectively. Correspondingly, the 1-, 3-, and 5-year OS rates were 98.9, 85.1 and 77.4 % in the NLR <= 2.17 group and 97.9, 63.8 and 53.3 % in the NLR > 2.17 group, respectively. The multivariate Cox proportional hazard model analysis showed that NLR > 2.17 was a prognostic factor for both DFS [hazard ratio (HR) = 1.869; 95 % confidence interval (CI) 1.078-3.243; P = 0.026] and OS (HR =2.177; 95 % CI 1.208 3.924; P = 0.010). CONCLUSION: Our results showed that elevated preoperative NLR was an independent predictor of poor prognosis for patients with LSCC after surgical resection. PMID- 26482900 TI - Augmentation with an ovine forestomach matrix scaffold improves histological outcomes of rotator cuff repair in a rat model. AB - BACKGROUND: Rotator cuff tears can cause significant pain and functional impairment. Without surgical repair, the rotator cuff has little healing potential, and following surgical repair, they are highly prone to re-rupture. Augmenting such repairs with a biomaterial scaffold has been suggested as a potential solution. Extracellular matrix (ECM)-based scaffolds are the most commonly used rotator cuff augments, although to date, reports on their success are variable. Here, we utilize pre-clinical in vitro and in vivo assays to assess the efficacy of a novel biomaterial scaffold, ovine forestomach extracellular matrix (OFM), in augmenting rotator cuff repair. METHODS: OFM was assessed in vitro for primary tenocyte growth and adherence, and for immunogenicity using an assay of primary human dendritic cell activation. In vivo, using a murine model, supraspinatus tendon repairs were carried out in 34 animals. Augmentation with OFM was compared to sham surgery and unaugmented control. At 6- and 12-week time points, the repairs were analysed biomechanically for strength of repair and histologically for quality of healing. RESULTS: OFM supported tenocyte growth in vitro and did not cause an immunogenic response. Augmentation with OFM improved the quality of healing of the repaired tendon, with no evidence of excessive inflammatory response. However, there was no biomechanical advantage of augmentation. CONCLUSIONS: The ideal rotator cuff tendon augment has not yet been identified or clinically implemented. ECM scaffolds offer a promising solution to a difficult clinical problem. Here, we have shown improved histological healing with OFM augmentation. Identifying materials that offset the poorer mechanical properties of the rotator cuff post-injury/repair and enhance organised tendon healing will be paramount to incorporating augmentation into surgical treatment of the rotator cuff. PMID- 26482901 TI - Is Cronbach's alpha sufficient for assessing the reliability of the OSCE for an internal medicine course? AB - BACKGROUND: The number of medical students accepted into medical programs is increasing, which has made the traditional long/short case style of examination difficult to conduct. At Dammam University, the program is shifting to the use of the Objective Structural Clinical Examination (OSCE), which may solve some of these difficulties, including issues with reliability, validity index and exam duration. RESULTS: A pilot study was conducted over one semester. A total of 207 examinees in three groups took the OSCE and written exams. The OSCE consisted of 18 clinical stations and required 3-4.3 h/day. The written exam contained 80 multiple-choice questions. The Cronbach's alpha for each group was 0.7, 0.8, and 0.9. Correlations for all stations ranged from 0.7 to 0.8, which indicated good stability and internal consistency with minor differences in the progression of the indexes. The reliability of the written exam was 0.79, and the validity of the OSCE was 0.63, as assessed using Pearson's correlation. CONCLUSION: No single reliability index can be considered a perfect assessment tool to solve this issue. Thus, at least two to three indexes should be used to ensure the reliability of the OSCE. PMID- 26482902 TI - The safety and tolerability profile of therapies for the prevention and treatment of osteoporosis in postmenopausal women. AB - At a time when the prevalence of osteoporosis and related fractures is increasing, initiation and continuation of pharmacologic therapies for prevention and treatment of postmenopausal osteoporosis have declined. This decline has been at least in part attributable to concerns about safety of these agents, such as atypical fractures with bisphosphonates and breast cancer with estrogen/progestin therapy, particularly when they are used long term by older women. However, in many cases, absolute risk of serious adverse effects is small and should be balanced against the larger potential for fracture reduction. Here, we review the safety and tolerability of available therapies for postmenopausal osteoporosis. Taking into consideration their relative efficacy, we also provide strategies for optimization of the risk:benefit ratio. PMID- 26482903 TI - Acute and short-term changes in visual function with multifocal soft contact lens wear in young adults. AB - PURPOSE: To characterise the effects on accommodation and binocular vision in young adults of 2 distance centre multifocal soft contact lenses (MFSCLs), differing in add power. METHODS: Twenty-four young adult myopes (18-28 years; 20 females, 4 males) had baseline visual acuity, accommodation, near phoria, fixation disparity and stereopsis data collected with single vision (SV) SCLs. The same set of measurements was repeated immediately after subjects were fitted with each of two MFSCLs (with either +1.50 or +3.00 D add), and after 2 weeks of daily wear in each case. The order of testing was randomised and a one-week washout period was allowed between the first and second MFSCL trials. RESULTS: Differences in distance and near acuities with MFSCLs compared to SVSCLs were small and clinically insignificant. Compared to responses with SVSCLs, MFSCLs increased accommodative lags with this change reaching statistical significance for the +1.50 D add lens. Furthermore, both MFSCLs induced significant shifts in near phorias in the exo direction. Finally, there were no significant differences in stereopsis and fixation disparity with MFSCLs compared to SVSCLs. CONCLUSION: Differences in acuities, accommodation accuracy and binocular posture with MFSCLs compared to SVSCLs were clinically small and mostly not significant. These results predict good tolerance of MFSCLs in young patients fitted with them for myopia control. PMID- 26482904 TI - Association of hypoadiponectemia with smokeless/dipping tobacco use in young men. AB - BACKGROUND: Low levels of adiponectin, an adipocytokine with anti-diabetic, antiatherogenic and cardioprotective properties, is associated with increased risk of coronary disease in young men. Previous studies have demonstrated that smokeless tobacco is linked with a reduction of plasma adiponectin levels. However, the influence of smokeless tobacco (dipping tobacco) on plasma adiponectin levels still remains unknown. This study was conducted to assess the plasma adiponectin levels in young men who were using dipping tobacco. METHODS: This was a community based study, which consisted of 186 young lean healthy males aged 20 to 35 years. Among these, 96 men were dipping tobacco users (BMI = 23.07 +/- 2.68) and 90 were non-dipping tobacco users (BMI = 23.67 +/- 1.46). Serum adiponectin levels were assessed by Enzyme Linked ImmunoSorbent Assay (ELISA). RESULTS: A statistically significant difference in the mean adiponectin level between tobacco dipper and non-dipper groups was observed (p = 0.0001). A significant difference between the two groups was also observed in baseline parameters including triglyceride and random blood sugar levels (p < 0.05). However, no significant difference was observed between the two groups in other clinical parameters. CONCLUSIONS: Findings of this study suggest that dipping tobacco use was significantly associated with low level of adiponetin in community dwelling young males. This emphasizes the importance of developing community intervention to reduce the use of dipping tobacco, which will reduce the tobacco associated disease burden in the community and will improve public health. PMID- 26482906 TI - Limited effect of mild therapeutic hypothermia on outcome after prolonged resuscitation. AB - BACKGROUND: Mild therapeutic hypothermia interferes with multiple cascades of the ischaemia/reperfusion injury that is known as primary mechanism for brain damage after cardiac arrest. First resuscitation attempts and the duration of resuscitation efforts will initiate and aggravate this pathophysiology. Therefore we investigated the interaction between the duration of basic and advanced life support and outcome after cardiac arrest in patients treated with or without mild therapeutic hypothermia. METHODS: This retrospective cohort study included patients 18 years of age or older suffering a witnessed out-of-hospital cardiac arrest with presumed cardiac cause, which remained comatose after restoration of spontaneous circulation. The basic and advanced life support 'low-flow' time, categorized into four quartiles (0-11, 12-17, 18-28, >= 29 min), was correlated with neurological outcome. RESULTS: Out of 1103 patients 613 were cooled to a target temperature of 33 +/- 1 degrees C for 24h. In the three quartiles with 'low-flow' time up to 28 min cooling was associated with >2-fold odds of favourable neurological outcome. In the fourth quartile with 'low-flow' time of >= 29 min cooling had no influence on neurological outcome (OR: 0.73; 95% CI: 0.38-1.4, test for interaction p<0.01). CONCLUSION: The duration of resuscitation efforts, defined as 'low-flow' time, influences the effectiveness of mild therapeutic hypothermia in terms of neurologic outcome. Patients with low to moderate 'low-flow' time benefit most from this treatment. PMID- 26482905 TI - Within-host microevolution of Pseudomonas aeruginosa in Italian cystic fibrosis patients. AB - BACKGROUND: Chronic infection with Pseudomonas aeruginosa is a major cause of morbidity and mortality in cystic fibrosis (CF) patients, and a more complete understanding of P. aeruginosa within-host genomic evolution, transmission, and population genomics may provide a basis for improving intervention strategies. Here, we report the first genomic analysis of P. aeruginosa isolates sampled from Italian CF patients. RESULTS: By genome sequencing of 26 isolates sampled over 19 years from four patients, we elucidated the within-host evolution of clonal lineages in each individual patient. Many of the identified mutations were located in pathoadaptive genes previously associated with host adaptation, and we correlated mutations with changes in CF-relevant phenotypes such as antibiotic resistance. In addition, the genomic analysis revealed that three patients shared the same clone. Furthermore, we compared the genomes of the Italian CF isolates to a panel of genome sequenced strains of P. aeruginosa from other countries. Isolates from two of the Italian lineages belonged to clonal complexes of P. aeruginosa that have previously been identified in Danish CF patients, and our genomic comparison showed that clonal isolates from the same country may be more distantly related than clonal isolates from different countries. CONCLUSIONS: This is the first whole-genome analysis of P. aeruginosa isolated from Italian CF patients, and together with both phenotypic and clinical information this dataset facilitates a more detailed understanding of P. aeruginosa within-host genomic evolution, transmission, and population genomics. We conclude that the evolution of the Italian lineages resembles what has been found in other countries. PMID- 26482907 TI - Residual position errors of lymph node surrogates in breast cancer adjuvant radiotherapy: Comparison of two arm fixation devices and the effect of arm position correction. AB - Residual position errors of the lymph node (LN) surrogates and humeral head (HH) were determined for 2 different arm fixation devices in radiotherapy (RT) of breast cancer: a standard wrist-hold (WH) and a house-made rod-hold (RH). The effect of arm position correction (APC) based on setup images was also investigated. A total of 113 consecutive patients with early-stage breast cancer with LN irradiation were retrospectively analyzed (53 and 60 using the WH and RH, respectively). Residual position errors of the LN surrogates (Th1-2 and clavicle) and the HH were investigated to compare the 2 fixation devices. The position errors and setup margins were determined before and after the APC to investigate the efficacy of the APC in the treatment situation. A threshold of 5mm was used for the residual errors of the clavicle and Th1-2 to perform the APC, and a threshold of 7mm was used for the HH. The setup margins were calculated with the van Herk formula. Irradiated volumes of the HH were determined from RT treatment plans. With the WH and the RH, setup margins up to 8.1 and 6.7mm should be used for the LN surrogates, and margins up to 4.6 and 3.6mm should be used to spare the HH, respectively, without the APC. After the APC, the margins of the LN surrogates were equal to or less than 7.5/6.0mm with the WH/RH, but margins up to 4.2/2.9mm were required for the HH. The APC was needed at least once with both the devices for approximately 60% of the patients. With the RH, irradiated volume of the HH was approximately 2 times more than with the WH, without any dose constraints. Use of the RH together with the APC resulted in minimal residual position errors and setup margins for all the investigated bony landmarks. Based on the obtained results, we prefer the house-made RH. However, more attention should be given to minimize the irradiation of the HH with the RH than with the WH. PMID- 26482909 TI - Genome-wide DNA methylation detection by MethylCap-seq and Infinium HumanMethylation450 BeadChips: an independent large-scale comparison. AB - Two cost-efficient genome-scale methodologies to assess DNA-methylation are MethylCap-seq and Illumina's Infinium HumanMethylation450 BeadChips (HM450). Objective information regarding the best-suited methodology for a specific research question is scant. Therefore, we performed a large-scale evaluation on a set of 70 brain tissue samples, i.e. 65 glioblastoma and 5 non-tumoral tissues. As MethylCap-seq coverages were limited, we focused on the inherent capacity of the methodology to detect methylated loci rather than a quantitative analysis. MethylCap-seq and HM450 data were dichotomized and performances were compared using a gold standard free Bayesian modelling procedure. While conditional specificity was adequate for both approaches, conditional sensitivity was systematically higher for HM450. In addition, genome-wide characteristics were compared, revealing that HM450 probes identified substantially fewer regions compared to MethylCap-seq. Although results indicated that the latter method can detect more potentially relevant DNA-methylation, this did not translate into the discovery of more differentially methylated loci between tumours and controls compared to HM450. Our results therefore indicate that both methodologies are complementary, with a higher sensitivity for HM450 and a far larger genome-wide coverage for MethylCap-seq, but also that a more comprehensive character does not automatically imply more significant results in biomarker studies. PMID- 26482908 TI - Integrated analysis of the local and systemic changes preceding the development of post-partum cytological endometritis. AB - BACKGROUND: The regulation of endometrial inflammation has important consequences for the resumption of bovine fertility postpartum. All cows experience bacterial influx into the uterus after calving; however a significant proportion fail to clear infection leading to the development of cytological endometritis (CE) and compromised fertility. We hypothesised that early immunological changes could not only act as potential prognostic biomarkers for the subsequent development of disease but also shed light on the pathogenesis of endometritis in the postpartum dairy cow. METHODS: Endometrial biopsy RNA was extracted from 15 cows at 7 and 21 days postpartum (DPP), using the Qiagen RNeasy((r)) Plus Mini kit and quality determined using an Agilent 2100 bioanalyser. Disease status was determined by histpathology based on inflammatory cell infiltrate. RNA-seq of both mRNA and miRNA libraries were performed on an Illumina(r) HiSeq(TM) 2000. Paired reads were aligned to the bovine genome with Bowtie2 and differentially expressed genes were identified using EdgeR. Significantly over-represented Gene Ontology terms were identified using GO-seq, and pathway analysis was performed using KEGG. Quanititative real-time PCR was also performed for validation (ABI 7500 fast). Haematology was assessed using an automated ADVIA 2120 analyser. Serum proteins were evaluated by ELISA and metabolite analysis was performed using a Beckman Coulter AU 400 clinical analyser. Terminal-restriction fragment length polymorphism (T-RFLP) was used to obtain fingerprints of the microbial communities present. RESULTS: Next-generation sequencing from endometrial biopsies taken at 7 DPP identified significant induction of inflammatory gene expression in all cows. Despite the common inflammatory profile and enrichment of the Toll-like receptor and NFkappaB pathways, 73 genes and 31 miRNAs were significantly differentially expressed between healthy cows (HC, n = 9) and cows which subsequently developed CE at 7 DPP (n = 6, FDR < 0.1). While significant differential expression of 4197 genes in the transcriptome of healthy cows between 7 and 21 DPP showed the transition from a proinflammatory to tissue profliferation and repair, only 31 genes were differentially expressed in cows with CE (FDR < 0.1), indicating the arrest of such a transition. A link betwene the dysregulated inflammatory response and the composition of the uterine microbial communities was suggested by the presence of significant differences in uterine bacterial tRFLP profiles between HC and CE groups. Furthermore, inflammatory activity was not confined to the uterus; decreased circulating granulocytes and increased Acute Phase Protein (SAA and HP) expression levels were detected in plasma at 7 DPP in cows that developed CE. CONCLUSION: Our data suggests that the IL1 and IL17 inflammatory cascade activated early postpartum is resolved thereby restoring homeostasis in healthy cows by 21 DPP, but this transition fails to occur in cows which develop CE. Despite a common early inflammatory profile, elevated and differential expression of specific immune genes may identify cows at risk of prolonged inflammation and the development of CE postpartum. PMID- 26482910 TI - The effects of the monoamine stabilizer (-)-OSU6162 on craving in alcohol dependent individuals: A human laboratory study. AB - Alcohol dependence is associated with a dysregulated dopamine system modulating reward, craving and cognition. The monoamine stabilizer (-)-OSU6162 (OSU6162) can counteract both hyper- and hypo-dopaminergic states and we recently demonstrated that it attenuates alcohol-mediated behaviors in long-term drinking rats. The present Phase II exploratory human laboratory study investigated to our knowledge for the first time the effects of OSU6162 on cue- and priming-induced craving in alcohol dependent individuals. Fifty-six alcohol dependent individuals were randomized to a 14-day-treatment period of OSU6162 or placebo after their baseline impulsivity levels had been determined using the Stop Signal Task. On Day 15, participants were subjected to a laboratory alcohol craving test comprised of craving sessions induced by: i) active - alcohol specific cues, ii) neutral stimuli and iii) priming - intake of an alcoholic beverage (0.20g ethanol/kg bodyweight). Subjective ratings of alcohol craving were assessed using the shortened version of the Desire for Alcohol Questionnaire and visual analog scales (VAS). OSU6162 treatment had no significant effect on cue-induced alcohol craving, but significantly attenuated priming-induced craving. Exploratory analysis revealed that this effect was driven by the individuals with high baseline impulsivity. In addition, OSU6162 significantly blunted the subjective liking of the consumed alcohol (VAS). Although the present 14-day-treatment period, showed that OSU6162 was safe and well tolerated, this exploratory human laboratory study was not designed to evaluate the efficacy of OSU6162 to affect alcohol consumption. Thus a larger placebo-controlled efficacyclinical trial is needed to further investigate the potential of OSU6162 as a novel medication for alcohol dependence. PMID- 26482911 TI - No evidence for the presence of neuronal surface autoantibodies in plasma of patients with schizophrenia. AB - The immune system has been implicated in the etiology of schizophrenia. Autoimmunity by antibodies against neuronal cell surface antigens has been proposed as one of the pathological mechanisms. We examined plasma samples of 104 patients diagnosed with schizophrenia for the presence of autoantibodies against neuronal cell surface antigens using cultured hippocampal neurons and transfected HeLa cells. None of the samples tested positive for the presence of these autoantibodies. Based on our results it seems unlikely that autoantibodies against neuronal cell surface antigens play a role in the pathogenesis of schizophrenia, although further studies using cerebrospinal fluid are needed. PMID- 26482912 TI - A Survey of DICOM Viewer Software to Integrate Clinical Research and Medical Imaging. AB - The digital imaging and communications in medicine (DICOM) protocol is the leading standard for image data management in healthcare. Imaging biomarkers and image-based surrogate endpoints in clinical trials and medical registries require DICOM viewer software with advanced functionality for visualization and interfaces for integration. In this paper, a comprehensive evaluation of 28 DICOM viewers is performed. The evaluation criteria are obtained from application scenarios in clinical research rather than patient care. They include (i) platform, (ii) interface, (iii) support, (iv) two-dimensional (2D), and (v) three dimensional (3D) viewing. On the average, 4.48 and 1.43 of overall 8 2D and 5 3D image viewing criteria are satisfied, respectively. Suitable DICOM interfaces for central viewing in hospitals are provided by GingkoCADx, MIPAV, and OsiriX Lite. The viewers ImageJ, MicroView, MIPAV, and OsiriX Lite offer all included 3D rendering features for advanced viewing. Interfaces needed for decentral viewing in web-based systems are offered by Oviyam, Weasis, and Xero. Focusing on open source components, MIPAV is the best candidate for 3D imaging as well as DICOM communication. Weasis is superior for workflow optimization in clinical trials. Our evaluation shows that advanced visualization and suitable interfaces can also be found in the open source field and not only in commercial products. PMID- 26482913 TI - Gender and motor competence affects perceived likelihood and importance of physical activity outcomes among 14 year olds. AB - BACKGROUND: Perceptions of the effects of physical activity could facilitate or deter future participation. This study explored the differences between gender and motor competence at 14 years of age in the perceptions of likelihood and importance of physical activity outcomes. METHOD: The sample comprised 1582 14 year-old adolescents (769 girls) from the Western Australian Pregnancy Cohort (Raine) Study. Four motor competence groups were formed from a standardized Neuromuscular Developmental Index score (McCarron 1997). Perceptions of the likelihood and the importance of 15 physical activity outcomes were measured by a questionnaire developed for the NSW Schools Fitness and Physical Activity Survey (Booth et al. 1997). Gender (two) * motor competence (four) analyses of variance and Tukey post hoc were conducted on outcome scores (P < 0.02) using SPSS version 17. RESULTS: Gender differences were found in the perceived likelihood and importance of physical activity outcomes within competition, social friendships and injury domains. Motor competence was significant in the perceived likelihood of physical health (P < 0.001), psychosocial (P < 0.009) and competition (P < 0.002) outcomes, with lower perceptions by the least competent groups. Significantly lower importance was perceived for academic outcomes for 14 year olds categorized with low compared with high motor competence (P < 0.005). Regardless of motor competence and gender, the same health and fun outcomes were ranked the highest in likelihood and the highest in importance. CONCLUSION: Although level of motor competence at 14 years affected the perceived likelihood of health, social and fun outcomes from future participation in physical activity, adolescents highly valued these outcomes, whereas gender affected competition and winning, outcomes that were less valued. Physical activity that promotes these key and valued outcomes may encourage young people's ongoing involvement in physical activity, especially for those at risk of low participation. PMID- 26482914 TI - Osteomyelitis of the hand. AB - Osteomyelitis of the hand is uncommon, but if not adequately and promptly treated the detrimental effects on hand function can be devastating. The majority of literature on osteomyelitis relates to the lower limb, but the principles of management are applicable to the hand, with good surgical debridement and culture guided antimicrobial therapy. For osteomyelitis in general, antibiotic therapy of 4-6 weeks' duration (intravenous and/or oral) is typically recommended. In the hand, length and mode of antibiotic administration are still under study. LEVEL OF EVIDENCE: V. PMID- 26482915 TI - What more can we learn from early learning theory? The contemporary relevance for behaviour change interventions. PMID- 26482916 TI - [Drug treatment of agitation in emergency departments: The case of elderly persons. Letter to the article: "Drug management of agitation in emergency departments: Theoretical recommendations and studies of practices"]. PMID- 26482917 TI - Y-chromosome diversity suggests southern origin and Paleolithic backwave migration of Austro-Asiatic speakers from eastern Asia to the Indian subcontinent. AB - Analyses of an Asian-specific Y-chromosome lineage (O2a1-M95)--the dominant paternal lineage in Austro-Asiatic (AA) speaking populations, who are found on both sides of the Bay of Bengal--led to two competing hypothesis of this group's geographic origin and migratory routes. One hypothesis posits the origin of the AA speakers in India and an eastward dispersal to Southeast Asia, while the other places an origin in Southeast Asia with westward dispersal to India. Here, we collected samples of AA-speaking populations from mainland Southeast Asia (MSEA) and southern China, and genotyped 16 Y-STRs of 343 males who belong to the O2a1 M95 lineage. Combining our samples with previous data, we analyzed both the Y chromosome and mtDNA diversities. We generated a comprehensive picture of the O2a1-M95 lineage in Asia. We demonstrated that the O2a1-M95 lineage originated in the southern East Asia among the Daic-speaking populations ~20-40 thousand years ago and then dispersed southward to Southeast Asia after the Last Glacial Maximum before moving westward to the Indian subcontinent. This migration resulted in the current distribution of this Y-chromosome lineage in the AA-speaking populations. Further analysis of mtDNA diversity showed a different pattern, supporting a previously proposed sex-biased admixture of the AA-speaking populations in India. PMID- 26482918 TI - The virucidal effects against murine norovirus and feline calicivirus F4 as surrogates for human norovirus by the different additive concentrations of ethanol-based sanitizers. AB - Since human norovirus is non-cultivable, murine norovirus and feline calicivirus have been used as surrogates. In this study, the virucidal effects of ethanol based sanitizers with different concentrations of additives (malic acid/sodium malate, glycerin-fatty acid ester) against murine norovirus and feline calicivirus F4 were examined. The ethanol-based sanitizers at pH 7 showed sufficient virucidal effects, but glycerin-fatty acid ester included in ethanol based sanitizers at pH 4 or 6 reduced the virucidal effects against murine norovirus. The ethanol-based sanitizers containing malic acid/sodium malate inactivated feline calicivirus F4 in shorter time, but there is no difference between ethanol-based sanitizers with and without glycerin-fatty acid ester. Traditionally, feline calicivirus has been used for long time as a surrogate virus for human norovirus. However, this study suggested that murine norovirus and feline calicivirus F4 had different sensitivity with the additive components of ethanol-based sanitizers. Therefore, using feline calicivirus alone as a surrogate for human norovirus may not be sufficient to evaluate the virucidal effect of sanitizers on food-borne infections caused by human norovirus. Sanitizers having virucidal effects against at least both murine norovirus and feline calicivirus may be more suitable to inactivate human norovirus. PMID- 26482919 TI - First report of iliacus abscess caused by Salmonella enterica serovar Othmarschen. AB - The non-typhoidal bacterium Salmonella enterica subspecies enterica serovar Othmarschen (Salmonella Othmarschen) is a rare human pathogen. Abscess formation due to non-typhoidal Salmonella infections is a very rare complication in this antibiotic era. We report the first case of iliacus abscess after a short period of gastroenteritis which was caused by non-typhoidal Salmonella enterica belonging to group C1, serovar Othmarschen in a patient without any underlying conditions. A young female presented in our hospital complaining of pain in right hip joint area. She gave a history of watery diarrhea 3 days before the onset of pain. On examination the patient was ill-looking and there was tenderness in the right hip joint area. S. enterica was identified using 16S rRNA gene amplification by PCR and serotyped to be serovar Othmarschen from the pus sample of iliacus abscess. This is the first reported case of iliacus abscess due to Salmonella serover Othmarschen infection. Our case suggests that S. enterica serovar Othmarschen can cause severe focal infections associated with gastroenteritis. The literature on the rare association of Salmonella enterica and abscess formation is reviewed. PMID- 26482921 TI - Flexible and High Performance Supercapacitors Based on NiCo2O4for Wide Temperature Range Applications. AB - Binder free nanostructured NiCo2O4 were grown using a facile hydrothermal technique. X-ray diffraction patterns confirmed the phase purity of NiCo2O4. The surface morphology and microstructure of the NiCo2O4 analyzed by scanning electron microscopy (SEM) showed flower-like morphology composed of needle-like structures. The potential application of binder free NiCo2O4 as an electrode for supercapacitor devices was investigated using electrochemical methods. The cyclic voltammograms of NiCo2O4 electrode using alkaline aqueous electrolytes showed the presence of redox peaks suggesting pseudocapacitance behavior. Quasi-solid state supercapacitor device fabricated by sandwiching two NiCo2O4 electrodes and separating them by ion transporting layer. The performance of the device was tested using cyclic voltammetry, galvanostatic charge-discharge and electrochemical impedance spectroscopy. The device showed excellent flexibility and cyclic stability. The temperature dependent charge storage capacity was measured for their variable temperature applications. Specific capacitance of the device was enhanced by ~150% on raising the temperature from 20 to 60 degrees C. Hence, the results suggest that NiCo2O4 grown under these conditions could be a suitable material for high performance supercapacitor devices that can be operated at variable temperatures. PMID- 26482922 TI - 1H, 15N, and 13C chemical shift assignments of cyanobacteriochrome NpR6012g4 in the red-absorbing dark state. AB - Cyanobacteriochrome (CBCR) photosensory proteins are phytochrome homologs using bilin chromophores for light sensing across the visible spectrum. NpR6012g4 is a CBCR from Nostoc punctiforme that serves as a model for a widespread CBCR subfamily with red/green photocycles. We report NMR chemical shift assignments for both the protein backbone and side-chain resonances of the red-absorbing dark state of NpR6012g4 (BMRB no. 26582). PMID- 26482923 TI - Backbone assignment of the N-terminal 24-kDa fragment of Escherichia coli topoisomerase IV ParE subunit. AB - Bacterial DNA topoisomerases are important drug targets due to their importance in DNA replication and low homology to human topoisomerases. The N-terminal 24 kDa region of E. coli topoisomerase IV E subunit (eParE) contains the ATP binding pocket. Structure-based drug discovery has been proven to be an efficient way to develop potent ATP competitive inhibitors against ParEs. NMR spectroscopy is a powerful tool to understand protein and inhibitor interactions in solution. In this study, we report the backbone assignment for the N-terminal domain of E. coli ParE. The secondary structural information and the assignment will aid in structure-based antibacterial agents development targeting eParE. PMID- 26482920 TI - "TRP inflammation" relationship in cardiovascular system. AB - Despite considerable advances in the research and treatment, the precise relationship between inflammation and cardiovascular (CV) disease remains incompletely understood. Therefore, understanding the immunoinflammatory processes underlying the initiation, progression, and exacerbation of many cardiovascular diseases is of prime importance. The innate immune system has an ancient origin and is well conserved across species. Its activation occurs in response to pathogens or tissue injury. Recent studies suggest that altered ionic balance, and production of noxious gaseous mediators link to immune and inflammatory responses with altered ion channel expression and function. Among plausible candidates for this are transient receptor potential (TRP) channels that function as polymodal sensors and scaffolding proteins involved in many physiological and pathological processes. In this review, we will first focus on the relevance of TRP channel to both exogenous and endogenous factors related to innate immune response and transcription factors related to sustained inflammatory status. The emerging role of inflammasome to regulate innate immunity and its possible connection to TRP channels will also be discussed. Secondly, we will discuss about the linkage of TRP channels to inflammatory CV diseases, from a viewpoint of inflammation in a general sense which is not restricted to the innate immunity. These knowledge may serve to provide new insights into the pathogenesis of various inflammatory CV diseases and their novel therapeutic strategies. PMID- 26482924 TI - Sequential backbone resonance assignments of the E. coli dihydrofolate reductase Gly67Val mutant: folate complex. AB - Occasionally, a mutation in an exposed loop region causes a significant change in protein function and/or stability. A single mutation Gly67Val of E. coli dihydrofolate reductase (DHFR) in the exposed CD loop is such an example. We have carried out the chemical shift assignments for H(N), N(H), C(alpha) and C(beta) atoms of the Gly67Val mutant of E. coli DHFR complexed with folate at pH 7.0, 35 degrees C, and then evaluated the H(N), N(H), C(alpha) and C(beta) chemical shift changes caused by the mutation. The result indicates that, while the overall secondary structure remains the same, the single mutation Gly67Val causes site specific conformational changes of the polypeptide backbone restricted around the adenosine-binding subdomain (residues 38-88) and not in the distant catalytic domain. PMID- 26482926 TI - Suitability of the Quality of Life after Brain Injury Instrument for Older People with Traumatic Brain Injury. AB - We prospectively investigated the psychometric properties of the Quality of Life after Brain Injury (QOLIBRI) instrument among older patients with traumatic brain injury (TBI). The 37-item QOLIBRI comprises six domains (cognition, self, daily life and autonomy, social relationships, emotions, and physical problems). We recruited 333 patients >=60 years of age with TBI from the neurosurgery clinics and emergency departments of three hospitals in Taipei, Taiwan. The ceiling and floor values for most QOLIBRI domains were <5%, and the internal consistency and test-retest reliability ranged from 0.84 to 0.97 and 0.83 to 0.96, respectively. For the known-groups validity, patients with TBI attained lower scores for all QOLIBRI domains, except physical problems, compared with those with soft-tissue injuries. Patients with intact cognition who had higher levels on the Glasgow Outcome Scale Extended (GOSE) and the Glasgow Coma Scale, fewer limitations in activities of daily living, and fewer chronic conditions obtained higher scores for almost all the QOLIBRI domains, compared with their counterparts. For convergent validity, the correlation coefficients for the QOLIBRI domains and the selected functional measures conceptually related to that domain were all >=0.4. A confirmatory factor analysis revealed that the original six-domain structure fit the data with a comparative fit index of >=0.9. Effect sizes for changes in the GOSE over a 6-month follow-up period were clinically meaningful (>= 0.2) for all the QOLIBRI domains except emotions. For older people with TBI, the use of the QOLIBRI is generally appropriate, and adding the domain of environment to the scale would be beneficial. PMID- 26482927 TI - Regenerative medicine legislation in Japan for fast provision of cell therapy products. AB - A new legal framework consisting of three laws for cell-based and tissue-based therapies went into effect in November 2014 in Japan. Among the provisions of the laws, the Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act (PMD Act) allows conditional and time-limited approval for regenerative medical products based on the ensured safety and estimated efficacy in small-scale clinical trials. The new legislation is expected to accelerate safe and fast provision of the innovative products to patients with intractable diseases. PMID- 26482925 TI - Mass spectrometry-based ligand binding assays on adenosine A1 and A2A receptors. AB - Conventional methods to measure ligand-receptor binding parameters typically require radiolabeled ligands as probes. Despite the robustness of radioligand binding assays, they carry inherent disadvantages in terms of safety precautions, expensive synthesis, special lab requirements, and waste disposal. Mass spectrometry (MS) is a method that can selectively detect ligands without the need of a label. The sensitivity of MS equipment increases progressively, and currently, it is possible to detect low ligand quantities that are usually found in ligand binding assays. We developed a label-free MS ligand binding (MS binding) assay on the adenosine A(1) and A(2A) receptors (A(1)AR and A(2A)AR), which are well-characterized members of the class A G protein-coupled receptor (GPCR) family. Radioligand binding assays for both receptors are well established, and ample data is available to compare and evaluate the performance of an MS binding assay. 1,3-Dipropyl-8-cyclopentyl-xanthine (DPCPX) and 4-(2-((7 amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]-[1,3,5]triazin-5 yl)amino)ethyl)phenol (ZM-241,385) are high-affinity ligands selective for the A(1)AR and A(2A)AR, respectively. To proof the feasibility of MS binding on the A(1)AR and A(2A)AR, we first developed an MS detection method for unlabeled DPCPX and ZM-241,385. To serve as internal standards, both compounds were also deuterium-labeled. Subsequently, we investigated whether the two unlabeled compounds could substitute for their radiolabeled counterparts as marker ligands in binding experiments, including saturation, displacement, dissociation, and competition association assays. Furthermore, we investigated the accuracy of these assays if the use of internal standards was excluded. The results demonstrate the feasibility of the MS binding assay, even in the absence of a deuterium-labeled internal standard, and provide great promise for the further development of label-free assays based on MS for other GPCRs. PMID- 26482928 TI - Restless legs syndrome and pregnancy: prevalence, possible pathophysiological mechanisms and treatment. AB - Restless legs syndrome (RLS) is a common sleep disorder that may be associated with pregnancy. Studies have found that the prevalence of RLS among pregnant women ranged from 10 to 34%. Typically, there is complete remission of symptoms soon after parturition; however, in some patients, they may continue postpartum. RLS has been shown to be associated with a number of complications in pregnancy including preeclampsia and increased incidence of Cesarean sections. Although multiple hypotheses have been proposed to explain this association, each individual hypothesis cannot completely explain the whole pathogenesis. Present understanding suggests that a strong family history, low serum iron and ferritin level, and high estrogen level during pregnancy might play important roles. Vitamin D deficiency and calcium metabolism may also play a role. Medical treatment of RLS during pregnancy is difficult and challenging considering the risks to mother and fetus. However, in some cases, the disease may be severe enough to require treatment. PMID- 26482929 TI - Animal and cellular models of human disease. AB - In this eighteenth (2016) Annual Review Issue of The Journal of Pathology, we present a collection of 19 invited review articles that cover different aspects of cellular and animal models of disease. These include genetically-engineered models, chemically-induced models, naturally-occurring models, and combinations thereof, with the focus on recent methodological and conceptual developments across a wide range of human diseases. PMID- 26482933 TI - Spider, bacterial and fungal phospholipase D toxins make cyclic phosphate products. AB - Phospholipase D (PLD) toxins from sicariid spiders, which cause disease in mammals, were recently found to convert their primary substrates, sphingomyelin and lysophosphatidylcholine, to cyclic phospholipids. Here we show that two PLD toxins from pathogenic actinobacteria and ascomycete fungi, which share distant homology with the spider toxins, also generate cyclic phospholipids. This shared function supports divergent evolution of the PLD toxins from a common ancestor and suggests the importance of cyclic phospholipids in pathogenicity. PMID- 26482932 TI - Cobra venom cytotoxins; apoptotic or necrotic agents? AB - Organs homeostasis is controlled by a dynamic balance between cell proliferation and apoptosis. Failure to induction of apoptosis has been implicated in tumor development. Cytotoxin-I (CTX-I) and cytotoxin-II (CTX-II) are two physiologically active polypeptides found in Caspian cobra venom. Anticancer activity and mechanism of cell death induced by these toxins have been studied. The toxins were purified by different chromatographic steps and their cytotoxicity and pattern of cell death were determined by MTT, LDH release, acridine orange/ethidium bromide (AO/EtBr) double staining, flow cytometric analysis, caspase-3 activity and neutral red assays. The IC50 of CTX-II in MCF-7, HepG2, DU-145 and HL-60 was 4.1 +/- 1.3, 21.2 +/- 4.4, 9.4 +/- 1.8 MUg/mL and 16.3 +/- 1.9 respectively while the IC50 of this toxin in normal MDCK cell line was 54.5 +/- 3.9 MUg/mL. LDH release suddenly increase after a specific toxins concentrations in all cell lines. AO/EtBr double staining, flow cytometric analysis and caspase-3 activity assay confirm dose and time-dependent induction of apoptosis by both toxins. CTX-I and CTX-II treated cells lost their lysosomal membrane integrity and couldn't uptake neutral red day. CTX-I and CTX-II showed significant anticancer activity with minimum effects on normal cells and better IC50 compared to current anticancer drug; cisplatin. They induce their apoptotic effect via lysosomal pathways and release of cathepsins to cytosol. These effects were seen in limited rage of toxins concentrations and pattern of cell death rapidly changes to necrosis by increase in toxin's concentration. In conclusion, significant apoptogenic effects of these toxins candidate them as a possible anticancer agent. PMID- 26482930 TI - Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset. AB - Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset. This analysis reveals insights into small molecule mechanisms of action, and genomic features that associate with CCL response to small-molecule treatment. We are able to recapitulate known relationships between FDA-approved therapies and cancer dependencies and to uncover new relationships, including for KRAS-mutant cancers and neuroblastoma. To enable the cancer community to explore these data, and to generate novel hypotheses, we created an updated version of the Cancer Therapeutic Response Portal (CTRP v2). SIGNIFICANCE: We present the largest CCL sensitivity dataset yet available, and an analysis method integrating information from multiple CCLs and multiple small molecules to identify CCL response predictors robustly. We updated the CTRP to enable the cancer research community to leverage these data and analyses. PMID- 26482934 TI - Assessment of emerging biotoxins (pinnatoxin G and spirolides) at Europe's first marine reserve: Lough Hyne. AB - Active and passive sampling methods were employed over a four-month period, at a site off the South-West coast of Ireland, to characterise the occurrence of cyclic imines in the water column. The marine toxins 13-desmethyl-SPXC, 20-methyl SPXG toxins and pinnatoxin G were detected using active sampling from Diaion HP 20 resin. Seven water depths were sampled to determine stratification of the toxins in the water column using Solid Phase Adsorption and Toxin Tracking (SPATT). Both 13-desmethyl-SPXC and pinnatoxin G were detected using two different resin types; Diaion HP-20 and Amberlite XAD761. HP-20 proved more effective at accumulating the toxins, with a higher percentage of positive samples and a higher ratio of toxin adsorbed relative to XAD761. No temporal variation in toxin-quantities was detected, indicating that there was no change in density of causative algal species in the water column. Pinnatoxin G was detected more frequently from surface to 30 m depth, with a similar pattern observed for 13-desmethyl-SPXC occurrence using XAD761. No difference in the occurrence of 13-desmethyl-SPXC was observed between depths using HP-20 resin. This is the first reported incidence of pinnatoxin G in Irish waters and highlights cyclic imines as emerging toxins in European waters. PMID- 26482936 TI - Dynamics of robust pattern separability in the hippocampal dentate gyrus. AB - The dentate gyrus (DG) is thought to perform pattern separation on inputs received from the entorhinal cortex, such that the DG forms distinct representations of different input patterns. Neuronal responses, however, are known to be variable, and that variability has the potential to confuse the representations of different inputs, thereby hindering the pattern separation function. This variability can be especially problematic for tissues such as the DG, in which the responses can persist for tens of seconds following stimulation: the long response duration allows for variability from many different sources to accumulate. To understand how the DG can robustly encode different input patterns, we investigated a recently developed in vitro hippocampal DG preparation that generates persistent responses to transient electrical stimulation. For 10-20 s after stimulation, the responses are indicative of the pattern of stimulation that was applied, even though the responses exhibit significant trial-to-trial variability. Analyzing the dynamical trajectories of the evoked responses, we found that, following stimulation, the neural responses follow distinct paths through the space of possible neural activations, with a different path associated with each stimulation pattern. The neural responses' trial-to-trial variability shifts the responses along these paths rather than between them, maintaining the separability of the input patterns. Manipulations that redistributed the variability more isotropically over the space of possible neural activations impeded the pattern separation function. Consequently, we conclude that the confinement of neuronal variability to these one-dimensional paths mitigates the impacts of variability on pattern encoding and, thus, may be an important aspect of the DG's ability to robustly encode input patterns. PMID- 26482935 TI - Anti-inflammatory effects of vicenin-2 and scolymoside in vitro and in vivo. AB - AIM AND OBJECTIVE: Two structurally related flavonoids found in Cyclopia subternata, namely vicenin-2 and scolymoside, were examined for its effects on inflammatory responses by monitoring the effects of vicenin-2 and scolymoside on lipopolysaccharide (LPS)-mediated vascular inflammatory responses. METHODS: The anti-inflammatory activities of vicenin-2 and scolymoside were determined by measuring permeability,monocytes adhesion and migration, and activation of pro inflammatory proteins in LPS-activated HUVECs and mice. RESULTS: We found that post-treatment of each compound inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion/transendothelial migration of human neutrophils to human endothelial cells. Each compound induced potent inhibition of phorbol-12-myristate 13-acetate (PMA) and LPS-induced endothelial cell protein C receptor (EPCR)shedding. It also suppressed LPS induced hyperpermeability and leukocytes migration in vivo. Furthermore,each compound suppressed the production of tumor necrosis factor-alpha (TNF-alpha) or Interleukin (IL)-6 and the activation of nuclear factor-kappaB (NF-kappaB) or extracellular regulated kinases (ERK) 1/2 by LPS. Moreover, posttreatment with each compound resulted in reduced LPS-induced lethal endotoxemia. CONCLUSION: Vicenin-2 and scolymoside possess anti-inflammatory functions by inhibiting hyperpermeability,expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases. PMID- 26482937 TI - Naringin protects human adipose-derived mesenchymal stem cells against hydrogen peroxide-induced inhibition of osteogenic differentiation. AB - Extensive evidence indicates that oxidative stress plays a pivotal role in the development of osteoporosis. We show that naringin, a natural antioxidant and anti-inflammatory compound, effectively protects human adipose-derived mesenchymal stem cells (hADMSCs) against hydrogen peroxide (H2O2)-induced inhibition of osteogenic differentiation. Naringin increased viability of hAMDSCs and attenuated H2O2-induced cytotoxicity. Naringin also reversed H2O2-induced oxidative stress. Oxidative stress induced by H2O2 inhibits osteogenic differentiation by decreasing alkaline phosphatase (ALP) activity, calcium content and mRNA expression levels of osteogenesis marker genes RUNX2 and OSX in hADMSCs. However, addition of naringin leads to a significant recovery, suggesting the protective effects of naringin against H2O2-induced inhibition of osteogenic differentiation. Furthermore, the H2O2-induced decrease of protein expressions of beta-catenin and clyclin D1, two important transcriptional regulators of Wnt-signaling, was successfully rescued by naringin treatment. Also, in the presence of Wnt inhibitor DKK-1, naringin is no longer effective in stimulating ALP activity, increasing calcium content and mRNA expression levels of RUNX2 and OSX in H2O2-exposed hADMSCs. These data clearly demonstrates that naringin protects hADMSCs against oxidative stress-induced inhibition of osteogenic differentiation, which may involve Wnt signaling pathway. Our work suggests that naringin may be a useful addition to the treatment armamentarium for osteoporosis and activation of Wnt signaling may represent attractive therapeutic strategy for the treatment of degenerative disease of bone tissue. PMID- 26482938 TI - Ginsenoside 20(s)-Rh2 as potent natural histone deacetylase inhibitors suppressing the growth of human leukemia cells. AB - BACKGROUND AND OBJECTIVE: Activation and abnormal expression of histone deacetylase (HDAC) which is important target for cancer therapeutics are related to the occurrence of human leukemia. 20(s)-Ginsenoside Rh2 (20(s)-Rh2) may be a potential HDAC inhibitor (HDACi) of leukemia, but the mechanism has not been reported. METHODS: The cell proliferation and apoptosis was assessed in cultured K562 and KG-1alpha cells. The protein expression was measured with immunoblotting. The activities of HDAC and histone acetyltransferase (HAT) were measured with BCA. In vivo experiments were performed on naked mice carrying K562 cells for assessment of tumor growth, apoptosis, protein expression, and HDAC/HAT activities. RESULTS: 20(s)-Rh2 effectively induced cell cycle arrest at G0/G1 phase and apoptosis in K562 and KG1-alpha cells, decreased the levels of proteins associated with cell proliferation (Cyclin D1, Bcl-2, ERK, p-ERK) and activated pro-apoptotic proteins (Bax, cleaved Caspase-3, p38, p-p38, JNK, p-JNK). 20(s) Rh2 down-regulated HDAC1, HDAC2, HDAC6, increased histone H3 acetylation and HAT activity. Moreover, 20(s)-Rh2 inhibited the growth of human leukemia xenograft tumors in vivo. CONCLUSION: 20(s)-Rh2 inhibited the proliferation of K562 and KG1 alpha cell by reducing the expression and activity of HDACs, increasing histone acetylation, and regulating key proteins in the downstream signaling pathways. Therefore, 20(s)-Rh2 could become a potential natural HDACi for chemotherapy of leukemia. PMID- 26482939 TI - Comparative study of genotoxic, antigenotoxic and cytotoxic activities of monoterpenes camphor, eucalyptol and thujone in bacteria and mammalian cells. AB - Genotoxic/antigenotoxic, mutagenic/antimutagenic and cytotoxic effects of monoterpenes camphor, eucalyptol and thujone were determined in bacteria and mammalian cells using alkaline comet assay, Escherichia coli K12 reversion test and MTT assay, respectively. When applied in low doses (up to 200 MUM in bacterial assay and 50 MUM in comet assay) monoterpenes protected repair proficient E. coli and Vero cells against UV-induced mutagenesis and 4NQO-induced DNA strand breaks, respectively. Antimutagenic response was not detected in nucleotide excision repair (NER) deficient bacteria. When monoterpenes were applied in higher doses, a weak mutagenic effect was found in mismatch repair (MMR) and NER deficient E. coli strains, while induction of DNA strand breaks was evident in human fetal lung fibroblasts MRC-5, colorectal carcinoma HT-29 and HCT 116 cells, as well as in Vero cells. Moreover, the involvement of NER, MMR and RecBCD pathways in repair of DNA lesions induced by monoterpenes was demonstrated in E. coli. Camphor, eucalyptol and thujone were cytotoxic to MRC-5, HT-29 and HCT 116 cells. The most susceptible cell line was HCT 116, with IC50 values of 4.5 mM for camphor, 4 mM for eucalyptol and 1 mM for thujone. Observed effects of monoterpenes are consistent with hormesis response, characterized by a low dose beneficial effect and a high dose adverse effect of a stressor agent, and provide a basis for further study of both chemopreventive and chemotherapeutic potential of camphor, eucalyptol and thujone. PMID- 26482940 TI - Synergistic effects of anethole and ibuprofen in acute inflammatory response. AB - This study assessed the effect of the combination of anethole and ibuprofen in comparison with monotherapy by either drug alone, using two in vivo inflammatory models, namely the pleurisy and paw edema in rats. We also measured the levels of the TNF protein in plasma, and the ability of anethole to inhibit, in vitro, the activity of the cyclooxygenase 1 and cyclooxygenase 2 enzymes. The test drugs (anethole; ibuprofen; anethole + ibuprofen), at different doses, were administered once (p.o.) 60 min before the induction of the inflammatory response. The association of anethole + ibuprofen inhibited the development of the inflammatory response in both models used. This effect can be partially explained by the inhibitory action on the production of TNF and of COX isoforms. The isobologram analysis evidenced a synergistic effect between ibuprofen and anethole, because the combination of drugs showed a higher inhibitory potential than either drug alone. PMID- 26482941 TI - Clinical and laboratory 2-year outcome of oral immunotherapy in patients with cow's milk allergy. AB - Studies examining the long-term effect of oral immunotherapy in food-allergic patients are limited. We investigated cow's milk-allergic patients, >6 months after the completion of oral immunotherapy (n = 197). Questionnaires, skin prick tests, and basophil activation assays were performed. Of the 195 patients contacted, 180 (92.3%) were consuming milk protein regularly. Half experienced adverse reactions, mostly mild. Thirteen patients (6.7%) required injectable epinephrine. Higher reaction rate after immunotherapy was associated with more anaphylactic episodes before treatment and a lower starting dose (OR = 2.1, P = 0.035 and OR = 2.3, P = 0.035, respectively). Reaction rate in patients who were 6-15 months, 15-30 months, or >30 months post-treatment decreased from 0.28/month to 0.21/month to 0.15/month, respectively (P < 0.01). Milk-induced %CD63 and %CD203c expression was significantly lower in patients >24 months vs in patients <24 months post-treatment (P = 0.038 and P = 0.047, respectively). In conclusion, many patients experience mild adverse reactions after completing oral immunotherapy and some require injectable epinephrine. Progressive desensitization, both clinically and in basophil reactivity, occurs over time. PMID- 26482942 TI - Decompressive craniectomy for massive internal carotid artery infarction after pediatric penetrating neck trauma. AB - Pediatric penetrating carotid arterial trauma is a rare unreported cause of malignant cerebral infarction. Despite increasing evidence of benefit of decompressive hemicraniectomy (DCH) in pediatric malignant stroke, indications and predictors of outcome remain controversial. We report a 4-year-old boy with penetrating zone II neck trauma with laceration of the right internal carotid artery who developed malignant cerebral infarction requiring DCH. Impressive neurological recovery and excellent functional outcome was observed with good psychomotor development and quality of life. To our knowledge, this is the first reported case of pediatric malignant ICA infarction due to penetrating arterial trauma with good neurologic outcome after DCH. PMID- 26482943 TI - Long-term outcomes in patients with pineal nongerminomatous malignant germ cell tumors treated by radical resection during initial treatment combined with adjuvant therapy. AB - BACKGROUND: For pineal nongerminomatous malignant germ cell tumors (NGMGCTs), we mainly performed radical tumor resection during initial treatment combined with adjuvant therapy. METHODS: We retrospectively analyzed 17 patients treated for pineal NGMGCTs between 1986 and 2007 at the University of Niigata. RESULTS: Twelve patients underwent total or subtotal resection of their tumor via the occipital transtentorial approach. Five patients underwent partial resection, and four of them later underwent total resection by salvage surgery. After surgery, eight patients were treated with combined radiochemotherapy including whole-brain irradiation, two received radiation monotherapy, one had chemotherapy with local irradiation, and six were treated with chemotherapy alone. The median follow-up period for surviving patients was 179 months. The 10-year overall survival and progression-free survival rates for the radiochemotherapy group were both 75.0 % (two patients had a recurrence and died); the rates for other adjuvant therapies were 77.8 % (two died) and 22.2 % (seven had a recurrence), respectively. Radiochemotherapy was significantly associated with an increased rate of progression-free survival compared with the other adjuvant therapies (p = 0.0396). CONCLUSIONS: For pineal NGMGCTs, initial treatment strategies including gross total resection of the tumor before or after whole-brain irradiation and chemotherapy provided good therapeutic outcomes. Obtaining complete remission of the primary tumor, irrespective of the timing of surgical resection (i.e., before or after adjuvant therapies), or complete response by neoadjuvant radiochemotherapy during an initial treatment appears to be essential for improving therapeutic outcomes of intracranial NGMGCTs. PMID- 26482944 TI - Influence of pyrolysis temperature on characteristics and phosphate adsorption capability of biochar derived from waste-marine macroalgae (Undaria pinnatifida roots). AB - The collected roots of Undaria pinnatifida, the main waste in farming sites, accounting for 40-60% of annual production, was pyrolyzed under temperature ranging from 200 to 800 degrees C to evaluate the influence of pyrolysis temperature on biochar properties and phosphate adsorption capacity. It was confirmed that an increase in the pyrolysis temperature led to a decrease of the yield of biochar, while ash content remained almost due to carbonization followed by mineralization. Elemental analysis results indicated an increase in aromaticity and decreased polarity at a high pyrolysis temperature. When the pyrolysis temperature was increased up to 400 degrees C, the phosphate adsorption capacity was enhanced, while a further increase in the pyrolysis temperature lowered the adsorption capacity due to blocked pores in the biochar during pyrolysis. Finally, a pot experiment revealed that biochar derived from waste marine macroalgae is a potent and eco-friendly alternative material for fertilizer after phosphate adsorption. PMID- 26482945 TI - Influence of textile dye and decolorized metabolites on microbial fuel cell assisted bioremediation. AB - As known, decolorized metabolites (DMs) were capable to act as electron shuttles (ESs) to enhance color removal of textile dye(s); however, optimal manipulation of such advantages to microbial fuel cell (MFC)-assisted dye decolorization for industrial practicability were still remained open to be disclosed. The novelty of this work was to disclose such DMs-supplementing strategies for the most promising reductive decolorization in MFC-assisted bioremediation. Quantitative assessment clearly indicated that MFCs coupled to DMs accumulation was economically-feasible strategy of bioaugmentation and biostimulation. That is, MFC technology can be applied to select appropriate on-site dye decontamination in the presence of naturally-generating DMs. PMID- 26482946 TI - Pretreatment of lignocellulose: Formation of inhibitory by-products and strategies for minimizing their effects. AB - Biochemical conversion of lignocellulosic feedstocks to advanced biofuels and other commodities through a sugar-platform process involves a pretreatment step enhancing the susceptibility of the cellulose to enzymatic hydrolysis. A side effect of pretreatment is formation of lignocellulose-derived by-products that inhibit microbial and enzymatic biocatalysts. This review provides an overview of the formation of inhibitory by-products from lignocellulosic feedstocks as a consequence of using different pretreatment methods and feedstocks as well as an overview of different strategies used to alleviate problems with inhibitors. As technologies for biorefining of lignocellulose become mature and are transferred from laboratory environments to industrial contexts, the importance of management of inhibition problems is envisaged to increase as issues that become increasingly relevant will include the possibility to use recalcitrant feedstocks, obtaining high product yields and high productivity, minimizing the charges of enzymes and microorganisms, and using high solids loadings to obtain high product titers. PMID- 26482947 TI - Delayed rotation of the cerebellar vermis: a pitfall in early second-trimester fetal magnetic resonance imaging. AB - We describe two cases in which delayed rotation of the cerebellar vermis simulated a Dandy-Walker malformation (DWM) on early second-trimester magnetic resonance imaging (MRI). Two pregnant women with suspected fetal posterior fossa anomaly on ultrasound examination underwent fetal MRI at 21 (Case 1) and 19 (Case 2) weeks' gestation. In both cases, upward rotation of the cerebellar vermis was noted; on midsagittal imaging, the brainstem-vermis angle was 28 degrees and 43 degrees , respectively, while cerebellar morphometry showed a reduced vermian anteroposterior diameter compared to reference data. The posterior fossa appeared to be mildly enlarged, while all other findings were normal. Follow-up MRI at 28 + 3 weeks' gestation (Case 1) and at 1 postnatal year (Case 2) showed completely normal findings. Both children had normal psychomotor development and neurological examinations at 1 year of age. Incomplete rotation of the cerebellar vermis can be a physiological finding on early second-trimester fetal MRI examination and can simulate DWM or other forms of cerebellar hypoplasia. Embryologically, delayed permeabilization of Blake's pouch could account for the delayed vermian rotation. Follow-up imaging at a later gestational age is crucial to ensure that this condition is not over-reported and to avoid the potential risk of unnecessary pregnancy interruption. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26482948 TI - Neglected tick-borne pathogens in the Czech Republic, 2011-2014. AB - In this study, we screened a total of 2473 questing (years 2011-2014) and 199 engorged (years 2013 and 2014) Ixodes ricinus ticks for the presence of Rickettsia spp., "Candidatus Neoehrlichia mikurensis", Anaplasma phagocytophilum, and Babesia spp. Host-seeking ticks were collected at three study sites corresponding to natural woodland, urban park and pastureland ecosystem, and analyzed using molecular techniques. All pathogens tested were present at all study sites. The prevalence rates for Rickettsia spp., 'Candidatus Neoehrlichia mikurensis', Anaplasma phagocytophilum, and Babesia spp. ranged from 2.6% to 9.2%, 0.8% to 11.6%, 0% to 12.1%, and 0% to 5.2%, respectively. Engorged I. ricinus ticks collected from sheep on pastureland in the years 2013 and 2014 yielded prevalence rates 7.4% and 6.3%, respectively, for Rickettsia spp., 38.5% and 14.1% for 'Candidatus N. mikurensis', 18.5% and 12.5% for A. phagocytophilum, and 4.4% and 0.0% for Babesia spp. Monitoring of neglected tick-borne pathogens within the scope of epidemiological surveillance is an important tool for prevention and control of human tick-borne infections. PMID- 26482949 TI - Detection of genotype-specific Ehrlichia canis exposure in Brazilian dogs by TRP36 peptide ELISA. AB - We recently characterized a novel genotype of Ehrlichia canis based on the tandem repeat (TR) sequence of the TRP36 gene in Brazil. The TR amino acid sequence of the Brazilian (Br) genotype (ASVVPEAE) was divergent from the previously described US genotype (TEDSVSAPA) of E. canis. In this study, we developed an ELISA based on TRP36 TR synthetic peptides from both Br and US E. canis TRP36 genotypes to serologically detect and distinguish infections caused by these genotypes. Sera from 30 Brazilian dogs naturally infected with E. canis, sera from dogs experimentally infected E. canis (Jake and Cuiaba #1 strains) and E. chaffeensis (Arkansas strain) and 12 seronegative E. canis dogs were evaluated. Fifteen naturally infected Brazilian dogs had antibodies that reacted with the US TRP36 (n=9) or Br TRP36 (n=6) only, and 13 dogs had antibodies that reacted with both TPR36 peptides suggesting that these dogs were exposed to both genotypes. Most dogs (n=28) had antibodies that reacted with the highly conserved E. canis TRP19 peptide; however, two dogs had antibodies to E. canis TRP19, but did not have TRP36 antibodies, raising the possibility that another novel TRP36 genotype is circulating in Brazil. Our results demonstrate that synthetic peptides based on the TR region of E. canis TRP36 can be used to serologically distinguish infections or identify coinfections by different genotypes, and to determine the seroprevalence of various E. canis genotypes in Brazil. PMID- 26482951 TI - Gasdermin D: the long-awaited executioner of pyroptosis. AB - Inflammatory caspases drive a lytic form of cell death called pyroptosis in response to microbial infection and endogenous damage-associated signals. Two studies now demonstrate that cleavage of the substrate gasdermin D by inflammatory caspases necessitates eventual pyroptotic demise of a cell. PMID- 26482952 TI - Rational synthesis of Ni nanoparticle-embedded porous graphitic carbon nanosheets with enhanced lithium storage properties. AB - Carbon-based materials have recently received increased attention as very promising anode materials for rechargeable lithium-ion batteries (LIBs) because of their non-toxicity, low cost, and excellent performances. Nanostructure engineering has been demonstrated as an effective approach to improve the electrochemical performance of electrode materials. Here, we present a facile and scalable synthesis of two-dimensional (2D) porous graphitic carbon nanosheets embedded by numerous homogeneously dispersed Ni nanoparticles. With both structural and compositional advantages, the as-synthesized nanohybrid manifests a very stable high reversible capacity of 740 mA h g(-1) after 100 cycles at a current density of 100 mA g(-1), and also excellent rate capability and cycling stability. We believe that the synthetic strategy outlined here can be extended to other rationally designed anode materials with high performances in LIBs. PMID- 26482950 TI - Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16(+) monocyte population via the IL-10/STAT3 axis. AB - The human CD14(+) monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16(+) monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti inflammatory (M2-like) macrophage activation program characterized by the CD16(+)CD163(+)MerTK(+)pSTAT3(+) phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16(+)CD163(+)MerTK(+)pSTAT3(+) cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16(+)CD163(+)MerTK(+)pSTAT3(+) monocyte-to-macrophage differentiation program and its potential as a target for TB therapy, and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoring of treatment efficacy. PMID- 26482953 TI - A methoxydiphenidine-impaired driver. AB - Methoxydiphenidine (MXP) was first reported in 1989 as a dissociative anesthetic but did not enter the market for pharmaceuticals. The substance re-appeared in 2013 as a new psychoactive substance. A case of driving under the influence of MXP is reported. The concentration of MXP has been determined from a serum sample (57 ng/mL) by liquid chromatography tandem mass spectrometry following liquid liquid extraction. In addition, amphetamine, methylenedioxymethamphetamine, and its major metabolite were present in concentrations of 111, 28, and 3 ng/mL, respectively. The subject presented with amnesia, out-of-body experiences, bizarre behavior, and decreased motor abilities. At present, information on human toxicity of MXP is not available. MXP is comparable in structure as well as in action at the N-methyl-D-aspartate (NMDA) receptor to phencyclidine or ketamine. Therefore, it is likely that MXP exerts similar severe psychotropic action in man. However, there is no information on the duration and intensity of MXP's impairing effects, the interpretation of a particular concentration in the blood or serum, and its detectability in routine drug screenings. Confirmation analysis may be confined to cases where the police has specific intelligence that points to MXP use. PMID- 26482954 TI - Internal Oxidant-Triggered Aerobic Oxygenation and Cyclization of Indoles under Copper Catalysis. AB - A concise synthesis of pyrazolo[1,5-a]indole derivatives by copper-catalyzed aerobic oxygenation and cyclization of indoles with oxime acetates is described. This protocol represents an elegant example of N-1, C-2, and C-3 tri functionalization of indoles in one-pot. Mechanistic studies indicate the reaction proceeds through a radical procedure. Oximes as an internal oxidant have been demonstrated to be a driver to initiate aerobic oxidation, which provides a new oxidative pattern for C-H functionalization even with high atom- and step economy. PMID- 26482955 TI - Adverse event methods were heterogeneous and insufficiently reported in randomized trials on persistent depressive disorder. AB - OBJECTIVES: To investigate adverse event (AE) reporting practices in a systematic review of randomized controlled trials for persistent depressive disorder (PDD). STUDY DESIGN AND SETTING: A systematic electronic database search was conducted up to October 2014 to identify randomized controlled trials investigating pharmacologic, psychotherapeutic, and combined treatments for PDD in adults. We calculated the number and percentage of studies that reported predefined AE information. All calculations were carried out including all studies and stratified for study type (pharmacologic, psychotherapeutic, and mixed) and publication year [before and after the publication of the Consolidated Standards of Reporting Trials (CONSORT) extension for harms in 2004], respectively. RESULTS: Sixty studies, reported in 126 publications, were included. Across all studies, reporting of AE information was insufficient. Substantial differences between studies that investigated different treatments emerged. Most pharmacologic studies (39/42) and mixed studies (7/9) reported any AE information, although the amount of information varied and the reported methods to assess and analyze AEs were heterogeneous. We found no substantial change in reporting practices after the publication of the CONSORT extension. Psychotherapeutic studies, although almost entirely published after the CONSORT extension, largely neglected reporting of any AE information (1/9). CONCLUSIONS: There is a strong need to improve the current practice of assessing, analyzing, and reporting AEs, especially for psychotherapeutic studies. PMID- 26482957 TI - Super-resolution Microscopy in Plant Cell Imaging. AB - Although the development of super-resolution microscopy methods dates back to 1994, relevant applications in plant cell imaging only started to emerge in 2010. Since then, the principal super-resolution methods, including structured illumination microscopy (SIM), photoactivation localization microscopy (PALM), stochastic optical reconstruction microscopy (STORM), and stimulated emission depletion microscopy (STED), have been implemented in plant cell research. However, progress has been limited due to the challenging properties of plant material. Here we summarize the basic principles of existing super-resolution methods and provide examples of applications in plant science. The limitations imposed by the nature of plant material are reviewed and the potential for future applications in plant cell imaging is highlighted. PMID- 26482956 TI - CO2 Sensing and CO2 Regulation of Stomatal Conductance: Advances and Open Questions. AB - Guard cells form epidermal stomatal gas-exchange valves in plants and regulate the aperture of stomatal pores in response to changes in the carbon dioxide (CO2) concentration ([CO2]) in leaves. Moreover, the development of stomata is repressed by elevated CO2 in diverse plant species. Evidence suggests that plants can sense [CO2] changes via guard cells and via mesophyll tissues in mediating stomatal movements. We review new discoveries and open questions on mechanisms mediating CO2-regulated stomatal movements and CO2 modulation of stomatal development, which together function in the CO2 regulation of stomatal conductance and gas exchange in plants. Research in this area is timely in light of the necessity of selecting and developing crop cultivars that perform better in a shifting climate. PMID- 26482958 TI - Dynamic Quantitative Trait Locus Analysis of Plant Phenomic Data. AB - Advanced platforms have recently become available for automatic and systematic quantification of plant growth and development. These new techniques can efficiently produce multiple measurements of phenotypes over time, and introduce time as an extra dimension to quantitative trait locus (QTL) studies. Functional mapping utilizes a class of statistical models for identifying QTLs associated with the growth characteristics of interest. A major benefit of functional mapping is that it integrates information over multiple timepoints, and therefore could increase the statistical power for QTL detection. We review the current development of computationally efficient functional mapping methods which provide invaluable tools for analyzing large-scale timecourse data that are readily available in our post-genome era. PMID- 26482959 TI - Serial assessment of accessory pathway antegrade conduction in children. AB - There is limited longitudinal data on accessory pathway (AP) antegrade conduction throughout childhood, with implications for risk stratification. Ten patients underwent serial electrophysiology study (EPS) with assessment of fastest 1:1 AP conduction. The median age at first and follow-up EPS was 0 (median 4 days) and 53 months. Median fastest 1:1 AP conduction was 255 ms at initial EPS and 275 ms at follow-up (P=0.24). The interval of time between studies had no influence on stability over time, nor was there any appreciable effect following changes in retrograde AP conduction. In conclusion, no patient displayed any marked shortening of 1:1 AP conduction over time. PMID- 26482960 TI - Glucose intolerance and General Health Questionnaire 12-item version scores of male two-shift workers stratified by precariousness of work. AB - AIMS: This study examined the relationship between precariousness of work, glucose intolerance and psychological wellbeing for male workers, stratified by age. MATERIALS AND METHODS: I recruited 2542 manufacturing two-shift workers, aged from 35 to 54 years. Glucose intolerance was defined as fasting plasma glucose of >=100mg/dL or current medication of diabetes mellitus. The rating scale of General Health Questionnaire 12-item version (GHQ-12) was used for evaluating psychological well-being. RESULTS: There was a significant increase in the prevalence of glucose intolerance by aging in permanent workers. In addition, the prevalence of glucose intolerance except 30s and the prevalence of positive GHQ-12 scores except 50s of permanent workers were both significantly higher than that of temporary workers in each age class. CONCLUSION: Temporary workers in this study sign contracts for 3 years, and heather worker's effect, compared with permanent workers, would be reflected in this study. PMID- 26482961 TI - Diabetes mellitus related biomarker: The predictive role of growth differentiation factor-15. AB - Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine, which belongs to super family of the transforming growth factor beta. GDF-15 is widely presented in the various cells (macrophages, vascular smooth muscle cells, adipocytes, cardiomyocytes, endothelial cells, fibroblasts), tissues (adipose tissue, vessels, tissues of central and peripheral nervous system) and organs (heart, brain, liver, placenta) and it plays an important role in the regulation of the inflammatory response, growth and cell differentiation. Elevated GDF-15 was found in patients with established CV diseases including hypertension, stable coronary artery disease, acute coronary syndrome, myocardial infarction, ischemic and none ischemic-induced cardiomyopathies, heart failure, atrial fibrillation, as well as stroke, type two diabetes mellitus (T2DM), chronic kidney disease, infection, liver cirrhosis, malignancy. Therefore, aging, smoking, and various environmental factors, i.e. chemical pollutants are other risk factors that might increase serum GDF-15 level. Although GDF-15 has been reported to be involved in energy homoeostasis and weight loss, to have anti-inflammatory properties, and to predict CV diseases and CV events in general or established CV disease population, there is no large of body of evidence regarding predictive role of elevated GDF-15 in T2DM subjects. The mini review is clarified the role of GDF-15 in T2DM subjects. PMID- 26482962 TI - Amenorrhea, ptosis and high insulin requirement in a young girl. AB - Lipodystrophy is an uncommon condition leading to excessive insulin requirement and menstrual abnormalities in young girls with diabetes. Neurological symptoms are uncommon in patients of generalized or partial lipodystrophy. We recently encountered a young girl, who presented with high insulin requirement, amenorrhea and neurological symptoms. Detailed evaluation led to the diagnosis of congenital lipodystrophy and we describe the same in this report. We also highlight the atypical features of the congenital lipodystrophy and the reasons for the excessive insulin requirement in patients with diabetes mellitus. PMID- 26482963 TI - Relationship between weight gain and metabolic syndrome in non-obese Japanese adults. AB - AIMS: To examine the effects of weight gain (in kg) on the parameters of metabolic syndrome (MetS) in non-obese Japanese adults over a period of 1 year. METHOD: We analyzed data on 1653 workers in a financial corporation (698 males and 955 females) who may have gained weight during 1 year but nevertheless remained non-obese. Data were collected twice: baseline data were collected between April 2010 and March 2011, and follow-up data were collected the next year. We calculated weight gains over the year and assigned all subjects into one of four groups according to the amount of weight gained: 0-0.99kg weight gain (reference), 1.00-1.99kg, 2.00-2.99kg, and more than 3.00kg. We compared changes in MetS parameters between the reference and other groups using Analysis of covariance (ANCOVA). RESULTS: Significant between-group differences were evident among males in terms of abdominal circumference (AC), blood pressure, and triglyceride (TG) levels. More weight gain was associated with worse results with regard to these MetS parameters. The AC changes were 0.60, 1.55, 2.86, and 4.42cm in the reference group, those who gained 1.00-1.99kg, those who gained 2.00 2.99kg, and those who gained over 3.00kg, respectively; the differences between the reference group and all other groups were significant (all p values <0.001). CONCLUSIONS: Weight gain (in kg) is a useful index of weight change and influences several parameters of MetS even over the course of 1 year. PMID- 26482964 TI - Association of circulating adipokines with metabolic dyslipidemia in obese versus non-obese individuals. AB - AIM: Previous studies have shown that circulating adipokines may play an important role in the pathogenesis of some obesity related chronic disease such as dyslipidemia and type2 diabetes mellitus. The aim of the present study was to investigate the association between vaspin, omentin-1 and retinol binding protein 4 levels with metabolic dyslipidemia (MD) criteria in obese and non-obese individuals. METHOD: The study was conducted on 170 obese and 81 non-obese individuals. After collecting the blood samples, serum levels metabolic parameters as well as three circulating adipokines and body composition were measured. RESULTS: No significant difference was noted regarding the mean serum levels of omentin-1 and vaspin between the obese and non-obese groups, while, serum level of RBP4 was significantly higher in the non-obese group. We found the 0.22 increased risk of MD in obese individuals with higher RBP4 concentration. After the adjustment for confounding factors, this association was still significant. No significant association was noted between MD and its components relative risks with omentin-1 and vaspin levels. CONCLUSION: Our study demonstrated that circulating RBP4 was significantly higher in the obese individuals which may increase the risk of MD in them. Further researches are needed to address this association. PMID- 26482965 TI - Gamma glutamyl transferase is an independent determinant for the association of insulin resistance with nonalcoholic fatty liver disease in Bangladeshi adults: Association of GGT and HOMA-IR with NAFLD. AB - AIMS: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and is frequently associated with insulin resistance (HOMA-IR) syndrome. Recently serum gamma glutamyl transferase (GGT) has been considered as surrogate marker of NAFLD leading to oxidative stress and hepatocellular damage. In the present study we examined the association of serum GGT and HOMA-IR with NAFLD in Bangladeshi adult subjects. MATERIALS AND METHODS: Under a cross sectional analytical design a total of 110 subjects were recruited who came for their routine health check up in the BIHS Hospital, Darussalam, Dhaka, Bangladesh. After whole abdomen ultrasonography, 62 were diagnosed as non-NAFLD and 48 were NAFLD subjects. Serum glucose was measured by glucose-oxidase method, lipid profile and liver enzymes by enzymatic colorimetric method, glycosylated hemoglobin (HbA1c) was measured by high performance liquid chromatography (HPLC), serum insulin were measured by enzyme-linked immunosorbent assay. HOMA-IR was calculated by homeostasis model assessment (HOMA). RESULTS: NAFLD subjects had significantly higher levels of GGT and HOMA-IR as compared to their non-NAFLD counterparts. Multiple linear regression analysis showed a significant positive association of HOMA-IR with GGT after adjusting the effects of waist circumference (WC) and HbA1c. In binary logistic regression analysis, HOMA-IR and GGT were found to be significant determinants of NAFLD after adjusting the effects of WC and HbA1c. CONCLUSION: These results suggest that elevated levels of GGT and insulin resistance are more likely to develop NAFLD and thus support a role of these determinants in the pathogenesis of NAFLD in Bangladeshi adult subjects. PMID- 26482966 TI - Increased C-reactive protein and decreased Interleukin-2 content in serum from obese individuals with or without insulin resistance: Associations with leukocyte count and insulin and adiponectin content. AB - AIMS: Chronic inflammation in obesity is associated with co-morbidities such as, hyperglycemia, hypertension and hyperlipidemia. Leukocytes play an important role in this inflammation and C-reactive protein (CRP) and Interleukin-2 (IL-2) can be important effectors during the immune response in obesity; however, the initial inflammatory events in obesity remain unclear. The aim of this study was to determine the circulating levels of CRP, IL-2, insulin and adiponectin, their association and the association with leukocyte count in obese individuals without co-morbidities and with or without insulin resistance (IR). MATERIALS AND METHODS: Nineteen obese non-diabetic and 9 lean subjects were studied for serum levels of CRP, IL-2, insulin, adiponectin, lipids, glycated hemoglobin, glycemia, for homeostasis model assessment of insulin resistance (HOMA-IR), arterial pressure and anthropometric parameters, and for leukocyte counts. Neutrophil/lymphocyte ratio (N/L) was calculated using the loge of leukocyte counts. Associations were determined by Pearson's correlation. RESULTS: None of the studied groups presented co-morbidities and two groups of obese individuals with normal or high levels of insulin (IR) were found. Increased CRP concentration and decreased IL-2 and adiponectin concentrations in obese were observed. Positive correlation between leukocyte type counts with CRP in obese with IR was found; however, no correlations with IL-2 in obese were observed. Insulin in obese were positively correlated with CRP and negatively correlated with IL-2 in IR obese individuals. Adiponectin in obese was negatively correlated with CRP. CONCLUSION: CRP and IL-2 may represent two important effectors in the early inflammatory events in obese individuals without co-morbidities. Adiponectin and insulin may be involved in anti-inflammatory events. PMID- 26482968 TI - Reversed-polarity T(reg) cell TCRs provide a shock. PMID- 26482969 TI - De-Mst-ifying microbicidal killing. PMID- 26482970 TI - MicroRNA miR-22 drives T(H)17 responses in emphysema. PMID- 26482971 TI - Drosha cuts the tethers of myelopoiesis. PMID- 26482979 TI - An interesting combination of anterior and posterior arch defects of atlas. PMID- 26482980 TI - A rare case of symptomatic hemangioma of the lumbar spine involving the spinous process. PMID- 26482981 TI - Caudal regression syndrome with diplomyelia (type 2 split cord malformation), tethered cord, syringomyelia, and horse-shoe kidney. PMID- 26482978 TI - The burgeoning family of unconventional T cells. AB - While most studies of T lymphocytes have focused on T cells reactive to complexes of peptide and major histocompatibility complex (MHC) proteins, many other types of T cells do not fit this paradigm. These include CD1-restricted T cells, MR1 restricted mucosal associated invariant T cells (MAIT cells), MHC class Ib reactive T cells, and gammadelta T cells. Collectively, these T cells are considered 'unconventional', in part because they can recognize lipids, small molecule metabolites and specially modified peptides. Unlike MHC-reactive T cells, these apparently disparate T cell types generally show simplified patterns of T cell antigen receptor (TCR) expression, rapid effector responses and 'public' antigen specificities. Here we review evidence showing that unconventional T cells are an abundant component of the human immune system and discuss the immunotherapeutic potential of these cells and their antigenic targets. PMID- 26482982 TI - Tuberculous spondylitis presenting with back pain. PMID- 26482983 TI - Radiotherapy for acute, high-grade spinal cord compression caused by vertebral hemangioma. PMID- 26482984 TI - Complete fracture-dislocation of the lower cervical spine without permanent neurologic sequela: the typical imaging changes. PMID- 26482985 TI - Constriction band at the craniocervical junction in Maroteaux-Lamy syndrome. PMID- 26482986 TI - Spinal cord impairment depending on body position. PMID- 26482987 TI - A rare cause of back pain: warfarin-induced spontaneous iliopsoas hemorrhage. PMID- 26482988 TI - Management of noninfected prosthetic aortic bypass failures using femoral vein. AB - OBJECTIVE: The use of femoral-popliteal vein as a conduit to treat infected aortoiliac pathologies has been described extensively and is referred to as the neoaortoiliac system procedure. We examined our center's outcomes after using deep vein as a conduit for the salvage of failed aortofemoral prosthetic bypasses in patients without infection. METHODS: Procedures using femoral vein as conduit at the University of Arkansas for Medical Sciences between January 2005 and July 2013 were retrospectively reviewed (n = 110). Patients were excluded if the reconstruction was for infectious etiologies (n = 71) or for nonaortofemoral reconstructions (n = 31). Operative variables, complications, and patency rates were collected. RESULTS: Femoral vein was used to revascularize failed aortobifemoral bypasses in eight patients. Indications included rest pain (n = 7) and short-distance claudication (n = 1). Reconstructions identified two patients each with aortobifemoral bypass or aortofemoral bypass, and one patient each with aortofemoral bypass with femorofemoral bypass, aorotoiliac bypass, iliofemoral bypass with femorofemoral bypass, or ilioprofunda bypass. Mean follow up was 27.5 months. There were no major postoperative complications. Symptoms secondary to deep vein harvest (swelling/dermatitis) developed in three of eight patients. The average ankle-brachial index improved from 0.33 to 0.73 (P = .003), with a limb salvage rate of 100%. Kaplan-Meier analysis found primary patency was 70% at 1 year and 53% at 5 years, which improved to 100% and 75%, respectively, with secondary measures. CONCLUSIONS: Despite a need for secondary interventions and venous hypertension syndromes, deep vein offers good patency and excellent limb salvage after failed prosthetic aortoiliac bypasses. PMID- 26482989 TI - Antithrombin nanoparticles inhibit stent thrombosis in ex vivo static and flow models. AB - OBJECTIVE: Despite significant advances in intravascular stent technology, safe prevention of stent thrombosis over prolonged periods after initial deployment persists as a medical need to decrease device failure. The objective of this project was to assess the potential of perfluorocarbon nanoparticles (NP) conjugated with the direct thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone (PPACK-NP) to inhibit stent thrombosis. METHODS: In a static model of stent thrombosis, 3 * 3-mm pieces of stainless steel coronary stents were cut and adsorbed with thrombin to create a procoagulant surface that would facilitate thrombus development. After treatment with PPACK-NP or control NP, stents were exposed to platelet-poor plasma (PPP) or platelet-rich plasma (PRP) for set time points up to 60 minutes. Measurements of final clot weight in grams were used for assessing the effect of NP treatment on limiting thrombosis. Additionally, groups of stents were exposed to flowing plasma containing various treatments (saline, free PPACK, control NP, and PPACK-NP) and generated thrombi were stained and imaged to investigate the treatment effects of PPACK-NP under flow conditions. RESULTS: The static model of stent thrombosis used in this study indicated a significant reduction in thrombus deposition with PPACK-NP treatment (0.00067 +/- 0.00026 g; n = 3) compared with control NP (0.0098 +/- 0.0015 g; n = 3; P = .026) in PPP. Exposure to PRP demonstrated similar effects with PPACK-NP treatment (0.00033 +/- 0.00012 g; n = 3) vs control NP treatment (0.0045 +/- 0.00012 g; n = 3; P = .000017). In additional studies, stents were exposed to both PRP pretreated with vorapaxar and PPACK-NP, which illustrated adjunctive benefit to oral platelet inhibitors for prevention of stent thrombosis. Additionally, an in vitro model of stent thrombosis under flow conditions established that PPACK-NP treatment inhibited thrombus deposition on stents significantly. CONCLUSIONS: This study demonstrates that antithrombin perfluorocarbon NPs exert marked focal antithrombin activity to prevent intravascular stent thrombosis and occlusion. PMID- 26482990 TI - Simple renal cyst and abdominal aortic aneurysm. AB - OBJECTIVE: To summarize the association of simple renal cyst (SRC) with abdominal aortic aneurysm (AAA), we reviewed currently available clinical studies with a systematic literature search and meta-analytic evaluation. METHODS: To identify all case-control studies evaluating the association of SRC with AAA, databases including MEDLINE and Embase were searched through April 2015 using web-based search engines (PubMed and Ovid). For each study, data regarding SRC prevalence in both the AAA and control groups were used to generate unadjusted odds ratios (ORs) and 95% confidence intervals. When an adjusted OR (by the use of multivariable logistic regression) was available, we preferentially abstracted the adjusted OR rather than an unadjusted OR. RESULTS: Of 139 potentially relevant articles screened initially, 5 eligible case-control studies enrolling a total of 2897 participants were identified and included. A pooled analysis of seven estimates from the five studies demonstrated a statistically significant 2.54-fold prevalence of SRC in patients with AAA relative to subjects without AAA (OR, 2.54; 95% confidence interval, 1.93-3.34; P < .00001). CONCLUSIONS: Our meta analytic evaluation demonstrated 2.5-fold prevalence of SRC in patients with AAA relative to subjects without AAA, which suggests that SRC is associated with AAA. PMID- 26482991 TI - Clinical effect of wound depth in critical limb ischemia with tissue loss after endovascular treatment. AB - OBJECTIVE: Wound severity is assessed mainly by the Rutherford classification for critical limb ischemia (CLI) with tissue loss. The Rutherford classification is based on the extent of tissue loss; however, its classification criteria are ambiguous and do not include information regarding wound depth. We investigated the effects of wound depth on clinical outcomes in CLI with tissue loss after endovascular treatment (EVT). METHODS: Between April 2007 and August 2013, we enrolled 210 consecutive patients (247 limbs) who received EVT for CLI with tissue loss. In the limbs examined, 271 individual wounds existed. We evaluated wound depth using the University of Texas grade (grade 1: superficial wound not involving the tendon, capsule, or bone, n = 97; grade 2: wound penetrating the tendon or capsule, n = 124; and grade 3: wound penetrating the bone or joint, n = 50). We also investigated the wound healing rate at 12 months and limb salvage and major amputation-free survival rates 3 years after EVT. RESULTS: The wound healing rates at 12 months in Texas 1, 2, and 3 were 88%, 48%, and 24%, respectively (log-rank P < .001). The limb salvage and major amputation-free survival rates at 3 years were lower in deep wounds than in shallow wounds (limb salvage rates: 98%, 82%, and 67%, respectively; P < .001; major amputation-free survival rates: 78%, 52%, and 42%, respectively; P < .001). In only minor tissue loss, the wound healing rates at 12 months and the limb salvage and major amputation-free survival rates at 3 years were stratified according to wound depth (wound healing rates: 92% in Texas 1 and 51% in Texas 2 or 3; P < .001; limb salvage rates: 99% in Texas 1 and 86% in Texas 2 or 3; P = .001; major amputation-free survival rates: 79% in Texas 1 and 57% in Texas 2 or 3; P = .001). In only major tissue loss, deep wounds also caused poor outcomes compared with shallow wounds (wound healing rates: 70% in Texas 1 and 36% in Texas 2 or 3; P = .019; limb salvage rates: 94% in Texas 1 and 73% in Texas 2 or 3; P = .050; major amputation-free survival rates: 75% in Texas 1 and 45% in Texas 2 or 3; P = .039). CONCLUSIONS: Wound depth is an important indicator of wound status and affects the clinical outcomes of CLI with tissue loss. PMID- 26482992 TI - Outcomes of unilateral graft limb excision for infected aortobifemoral graft limb. AB - OBJECTIVE: Aortobifemoral graft (ABFG) infections presenting with apparent single limb involvement can be managed with unilateral graft limb excision or complete graft removal. This study aimed to identify outcomes of unilateral graft limb excision for infected ABFGs and factors predictive of subsequent contralateral or main body graft limb infection. METHODS: A retrospective review of patients treated with unilateral graft limb excision for infection of an isolated limb of an ABFG from 2001 to July 2014 was performed. Endovascular and aortic tube graft infections were excluded. Outcomes were freedom from contralateral graft limb excision, overall survival, and factors predicting subsequent contralateral limb or main body infection. RESULTS: Fifteen patients underwent unilateral graft limb excision and revascularization for treatment of an infected ABFG isolated to one graft limb. Indications for the original ABFG were aortoiliac occlusive disease in 11 patients and aortoiliac aneurysm in 4 patients. All patients presented with clinical evidence consistent with unilateral graft limb infection and clinical findings confirmed radiographically. Unilateral graft explantation was performed for isolated infrainguinal graft limb infection with no retroperitoneal infection on exploration or if patients were too ill to tolerate total graft explantation despite infection in the retroperitoneum. Seven patients, all of whom underwent initial operation for aortoiliac occlusive disease, developed contralateral limb infection at a median follow-up of 23.2 months after unilateral excision. The remaining eight patients remained free of contralateral graft limb infection at median follow-up of 38.8 months. Patient demographics were similar between the two groups. Factors predictive of contralateral graft limb infection included an ABFG placed for aortoiliac occlusive disease (P = .03) and culture evidence of infection above the inguinal ligament (P = .07; positive predictive value of 71%). Median duration of targeted antibiotic therapy was 42 days, and neither duration of antibiotics nor cultured microorganism predicted recurrent graft infection. Overall mortality was 40% and was similar between patients who developed contralateral or main body graft infection and those who did not. There was no limb loss, and overall median follow-up was 44.7 months. CONCLUSIONS: Isolated unilateral infection of an ABFG limb can be managed with single graft limb excision, provided the infection is isolated to the infrainguinal graft segment. Factors predicting subsequent contralateral or main body graft infection include ABFGs originally placed for aortoiliac occlusive disease and culture positive graft infection above the inguinal ligament. PMID- 26482993 TI - Intact Toll-like receptor 9 signaling in neutrophils modulates normal thrombogenesis in mice. AB - BACKGROUND: Deletion of Toll-like receptor 9 (Tlr9) signaling, which is important for sterile inflammatory processes, results in impaired resolution of venous thrombosis (VT) in mice. The purpose of this study was to determine if deletion of Tlr9 affected sterile necrosis, apoptosis, and neutrophil extracellular trap (NET) production in VT. METHODS: Stasis and nonstasis murine models of VT were used in wild-type (WT) and Tlr9-/- mice, with assessment of thrombus size and determination of NETs, necrosis, and apoptosis markers. Anti-polymorphonuclear neutrophil (PMN) and antiplatelet antibody strategies were used to determine the cellular roles and their roles in WT and Tlr9-/- mice. RESULTS: At 2 days, stasis thrombi in Tlr9-/- mice were 62% larger (n = 6-10), with 1.4-fold increased uric acid levels, 1.7-fold more apoptotic cells, 2-fold increased citrullinated histones, 2-fold increased peptidylarginine deiminase 4 (PAD4), and 1.5-fold increased elastase and a 2.4-fold reduction in tissue factor pathway inhibitor compared with WT mice (all n = 4-7; P < .05). In contrast, the sizes of nonstasis thrombi were not significantly different in Tlr9-/- mice (n = 4-6), and they did not have elevated necrosis or NET markers. Stasis thrombus size was not reduced at the 2-day time point in WT or Tlr9-/- mice that received treatment with deoxyribonuclease I or in PAD4-/- mice, which are incapable of forming NETs. In Tlr9-/- mice undergoing PMN depletion (n = 8-10), stasis thrombus size was reduced 18% and was associated with 29-fold decreased citrullinated histones, 1.3 fold decreased elastase, and 1.5-fold increased tissue factor pathway inhibitor (all n = 6; P < .05). Last, platelet depletion (>90% reduction) did not significantly reduce stasis thrombus size in Tlr9-/- mice. CONCLUSIONS: These data suggest that the thrombogenic model affects Tlr9 thrombogenic mechanisms and that functional Tlr9 signaling in PMNs, but not in platelets or NETs, is an important mechanism in early stasis experimental venous thrombogenesis. PMID- 26482994 TI - Favorable outcomes of very elderly patients with critical limb ischemia who undergo distal bypass surgery. AB - OBJECTIVE: To determine the midterm outcomes of distal bypass surgery for very elderly patients, and to determine the ideal candidates for this procedure. METHODS: Of 268 consecutive patients (328 limbs) with critical limb ischemia who were treated between 2006 and 2013, 106 (126 limbs) underwent distal bypass and were retrospectively reviewed. Nineteen patients (22 limbs) were aged >=80 years (very elderly group) and 87 patients (104 limbs) were aged <80 years (control group). RESULTS: The baseline characteristics differed between the 2 groups in terms of regular hemodialysis rate (very elderly group, 4 [21%] vs control group, 60 [69%]; P = .0002) and the Charlson comorbidity index (very elderly group, 3.2 +/- 1.7 vs control group, 5.0 +/- 2.0; P = .0005). According to the Rutherford category of limb ischemia (4/5/6), the very elderly and control groups were classified as 5/17/0 and 11/87/6, respectively (P = .18). Before the surgery, 17 patients (77%) and 67 patients (64%) were ambulatory in the very elderly and control groups, respectively. At follow-up at 29 +/- 22 months, the rates of primary (P = .33) and secondary patency (P = .14), limb salvage (P = .50), survival (P = .26), amputation-free survival (P = .42), major adverse limb event and also perioperative death (P = .11), and major adverse cardiovascular events (P = .36) did not significantly differ between the groups. In multivariate analysis, a history of coronary artery disease (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.3-5.9; P = .005), preoperative nonambulatory status (HR, 4.2; 95% CI, 2.1-8.1; P < .0001), and serum albumin levels <3 g/dL (HR, 2.7; 95% CI, 1.3-5.4; P = .01) were significantly related to poor amputation-free survival. Thirteen patients (59%) remained ambulatory at the latest follow-up. In 91 patients (110 limbs) with tissue loss, the Society for Vascular Surgery lower extremity threatened limb classification system: risk stratification based on Wound, Ischemia, and foot Infection classification stages 3 and 4 negatively affected complete wound healing, according to multivariate analysis (HR, 0.34; 95% CI, 0.20-0.61; P = .0005). CONCLUSIONS: A very elderly age should not preclude a patient from undergoing distal bypass surgery. A history of coronary artery disease, a nonambulatory status, and hypoalbuminemia, along with the Wound, Ischemia, and foot Infection classification for patients with tissue loss, should be carefully considered to obtain the most benefit from distal bypass surgery. PMID- 26482995 TI - Secondary interventions in patients with autologous infrainguinal bypass grafts strongly improve patency rates. AB - OBJECTIVE: To describe the patency of percutaneous transluminal angioplasty (PTA) of autologous infrainguinal bypasses at risk. METHODS: This was a retrospective single-center cohort study of consecutive patients who underwent primary PTA of an infrainguinal autologous bypass at risk from January 2009 to December 2013. Duplex ultrasound surveillance was performed for at least 1 year after PTA. The primary study end point was the number of secondary interventions. Secondary end points were freedom from recurrent stenosis or bypass occlusion and the patency of the infrainguinal autologous bypass at 1 year after primary PTA. RESULTS: A total of 69 infrainguinal bypasses at risk in 69 patients were identified and treated with PTA. Technical success was achieved in 91%. The median follow-up was 17 months (range, 1-58 months). During follow-up, 30 bypasses (43%) remained free of significant stenosis or bypass occlusion, 29 bypasses (42%) developed recurrent stenosis, and 10 bypasses (14%) occluded. Rates of primary assisted, and secondary patency at 1 year were 84%, and 86%. Five (7%) major amputations were performed, all after bypass occlusion. CONCLUSIONS: Secondary interventions after PTA of a bypass at risk are common. However, repeated secondary interventions of autologous infrainguinal bypasses at risk result in patency rates of more than 80% at 1 year. PMID- 26482996 TI - Screening results from a large United Kingdom abdominal aortic aneurysm screening center in the context of optimizing United Kingdom National Abdominal Aortic Aneurysm Screening Programme protocols. AB - BACKGROUND: After its introduction in six pilot centers in 2009, the National Abdominal Aortic Aneurysm Screening Programme (NAAASP) is now established across the United Kingdom, demonstrating significant benefit in terms of fewer emergency surgeries and reduced 30-day surgical mortality. However, according to publication of data on annual screened abdominal aortic aneurysm (AAA) detection, a lower incidence than predicted in the original screening trials has been found. In this audit we assessed features and risk factors of men found to have a positive scan result in the southwest London AAA screening program, to determine screening yield for subgroups of populations and assess the case for a more targeted screening program. METHODS: Data from the NAAASP screening database for England were extracted for all men who attended screening from the April 1, 2009 through October 16, 2013 in the southwest London area. Primary outcomes were aneurysm prevalence, risk factors, and incidence within subgroups. Results were reviewed against nationally reported data and London census data. RESULTS: Of 24,891 men who were screened in the southwest London program during this period, 292 AAAs were identified (1.18%). Patients were asked to categorize their ethnic background according to classifications provided by the office of national statistics. Those at highest risk of AAA were white-British (1.35%), followed by black and black British (0.65%), and Asian/Asian British (0.23%). Number needed to screen to identify one AAA was calculated as 78, 154, and 431, respectively. The relative proportions of patients screened were similar to that described in the most recent United Kingdom census, except for white-British patients, indicating a shortfall in acceptance of screening invitations in this group. There were no AAA identified in Chinese men. A positive smoking history was found in 90%, a confirmed diagnosis of hypertension in 50%, hypercholesterolemia in 34%, and ischemic heart disease in 21%. CONCLUSIONS: Within southwest London, AAA was most strongly associated with being white-British, a previous or current smoker, and known hypertension. Targeted education in patient groups with identified risk factors for AAA should be considered to improve screening yield without excluding any subgroup from the screening program. This could draw on resources released by unused scans because of lower than predicted prevalence. AAA diagnosis should be seen as an opportunity to address the increased all-cause mortality associated with aortic aneurysmal disease. PMID- 26482998 TI - The efficacy of salvage interventions on threatened distal bypass grafts. AB - OBJECTIVE: Infrapopliteal bypass is an established and effective method for limb salvage in patients with critical limb ischemia. Secondary interventions maybe required to maintain graft patency. The aim of this study was to look at the frequency and outcomes of such interventions. METHODS: Consecutive patients undergoing bypasses onto the infrapopliteal vessels for critical limb ischemia (Rutherford 4-6) at a single institution were analyzed between 2009 and 2013. The primary end points were graft patency, amputation-free survival (AFS), and freedom from reintervention at 12 months by Kaplan-Meier analysis. RESULTS: A total of 114 infrapopliteal bypasses were performed in 102 patients. Distal anastomosis was on to the anterior tibial (n = 31), posterior tibial (n = 27), peroneal (n = 24), tibioperoneal trunk (n = 23), or dorsalis pedis artery (n = 9). Primary patency, assisted primary patency, and secondary patency was 57%, 76%, and 82%, respectively, at 12 months and 44%, 70%, and 80%, respectively, at 36 months. AFS was 80% at 12 months and 65% at 36 months. Endovascular salvage interventions were performed on 58 grafts (51%) including angioplasty of inflow/proximal anastomosis (33%), outflow/distal anastomosis (46%), and graft stenosis (20%), with a further 12 grafts (11%) undergoing thrombolysis for occlusion. Surgical salvage interventions included jump grafts (n = 7), revision of anastomotic stenosis (n = 3), and thrombectomy (n = 2). AFS was similar in salvaged threatened and acutely occluded grafts compared with nonthreatened grafts (P = .064) and better in grafts requiring reintervention later (>6 months from bypass) compared with those requiring early reintervention (<6 months; P = .047). CONCLUSIONS: Secondary interventions in threatened distal bypass grafts are successful at maintaining graft patency and AFS when compared with nonthreatened grafts, and are associated with a low morbidity rate. PMID- 26482999 TI - Avulsion injury to the profunda femoris artery after total hip arthroplasty. AB - Vascular injuries are a rare complication of total hip arthroplasty (THA). We describe the case of 71-year-old man who underwent an elective left THA and developed a pseudoaneurysm from an avulsion injury to the first branch of the profunda femoris artery. The patient underwent urgent open primary repair of the pseudoaneurysm and recovered without any complications. This case demonstrates the importance of assessing for vascular injuries after THA and of educating patients about the associated signs and symptoms. PMID- 26482997 TI - Results of the Nellix system investigational device exemption pivotal trial for endovascular aneurysm sealing. AB - OBJECTIVE: The Nellix EndoVascular Aneurysm Sealing system (Endologix, Inc, Irvine, Calif) is a novel approach to abdominal aortic aneurysm (AAA) endovascular repair whereby biocompatible polymer is employed to exclude and to seal the AAA sac. We report 30-day results of the U.S. pivotal trial. METHODS: Consecutive, eligible, consenting patients were enrolled at 29 sites in the United States and Europe. Inclusion criteria required an asymptomatic infrarenal AAA, with aortic neck length >=10 mm and angle to the sac <=60 degrees, aortic neck diameter of 18 to 32 mm, aneurysm blood lumen diameter <=6 cm, common iliac artery lumen diameter of 9 to 35 mm, access artery diameter >=6 mm, and serum creatinine level <=2 mg/dL. Follow-up at 30 days included clinical assessment and computed tomography angiography evaluation of endoleaks and device integrity as assessed by a core laboratory. The primary safety end point is the incidence of independently adjudicated 30-day major adverse events (MAEs), with success defined as superiority with reference to the Society for Vascular Surgery open repair control group (56%). RESULTS: Between January and November 2014, 150 trial patients having a mean AAA diameter of 5.8 cm were enrolled and treated with the Nellix system with 100% procedural success. One early death (0.7%) occurred secondary to multisystem organ failure. All 149 surviving patients completed 30 day follow-up. There were no aneurysm ruptures, conversions, limb thromboses, stent fractures, or stent kinking. Five early MAEs occurred in four patients (2.7%) and included one death, bowel ischemia (1), renal failure (2), and respiratory failure (1). One (0.7%) secondary intervention to treat inadvertent coverage of a renal artery was performed. The core laboratory identified nine (6%) endoleaks (one type I, eight type II) on 30-day computed tomography angiography. Freedom from MAE was 97.3% (95% confidence interval, 93.3%-99.0%). CONCLUSIONS: In selected patients, perioperative outcomes with the Nellix system for endovascular aneurysm sealing are encouraging, with very low 30-day morbidity and mortality and high procedural success. The primary safety end point has been achieved. Longer term follow-up is in progress. PMID- 26483000 TI - Open surgical revision provides a more durable repair than endovascular treatment for unfavorable vein graft lesions. AB - OBJECTIVE: Lower extremity bypass grafts that develop stenoses are commonly treated with either open surgical or endovascular revision. Vein graft stenoses with unfavorable lesions (multiple lesions, lesions >2 cm in length, lesions in grafts <3 months old, lesions in grafts <3 mm in diameter) fare worse than those with favorable lesions when treated with endovascular therapy. However, it is not known if unfavorable lesions fare better with surgical revision than with endovascular treatment or than favorable lesions treated with surgery. METHODS: We performed a retrospective review of 175 vein graft revisions performed at a single institution from 2000 to 2010. Characteristics of lesions treated with surgical and endovascular revision were identified. Cox proportional hazard models were used to identify predictors of revision failure (restenosis >75%, revision, or amputation). RESULTS: Ninety-one failing vein grafts (52%) were treated with surgical revision and 84 with endovascular treatment (48%), with a median follow-up of 30 months. Favorable lesions fared better than unfavorable lesions after endovascular treatment, with 12-month freedom from failure of 59% vs 34% (P < .01), but not after surgical revision (66% vs 62%; P = .90). Unfavorable lesions had better freedom from failure after surgery than endovascular treatment (62% vs 34%; P < .01), and results in favorable lesions were similar (66% vs 59%; P = .57). CONCLUSIONS: For the treatment of failing vein grafts, endovascular therapy appears adequate for favorable lesions and surgical revision is more durable for unfavorable lesions. PMID- 26483001 TI - The natural history of penetrating ulcers of the iliac arteries. AB - OBJECTIVE: The natural history of penetrating ulcers of the iliac arteries (PUIA) has not been previously described. The potential for degeneration into pseudoanerysm and rupture are feared complications. It is hypothesized that PUIA, similar to their thoracic aortic counterparts, signal impending vascular catastrophe. METHODS: A search of computed tomography (CT) angiography reports for the words, "penetrating ulcer" was performed. Patients with PUIA who underwent CT imaging from October 2010 to August 2011 were identified. Their clinical course was followed through December 2014. If patients with PUIA had additional vascular pathology that necessitated intervention, it was performed. A prospective and retrospective review of the imaging was performed when possible. Associated iliac diameter and ulcer dimensions were measured for patients with repeat imaging (n = 22). Demographic characteristics were compared for patients who were identified as having penetrating ulcers of the abdominal aorta. Mann Whitney U, Fisher exact, and Pearson correlation coefficient tests were performed for statistical analysis. RESULTS: The calculated incidence of PUIA for patients who underwent CT imaging was 0.3%. The age at the time of diagnosis was 70.7 +/- 10.0 years and the cohort included 28 male patients (82.3%). Median clinical and imaging follow-up was 42.0 (range, 1-82) months and 40.5 (range, 1-77) months. Most patients had a history of hypertension (82.4%), hyperlipidemia (76.5%), and tobacco use (70.6%). Twenty-one patients (61.8%) had concomitant aneurysms not necessarily associated with the PUIA. Although no PUIA rupture occurred, the population was sick because seven patients (20.6%) were deceased at the study end. Only one individual presented with symptoms that could possibly be attributed to their PUIA. Repeat imaging was performed for 22 patients (64.7%). The calculated median iliac artery diameter growth rate through the PUIA was 0.1 (range, 0-4.1) mm/y. CONCLUSIONS: PUIA are generally slow-growing and are found incidentally. Most patients with PUIA were in their eighth decade with a history of hypertension and tobacco use. Patients with PUIA frequently have concurrent aortic aneurysm disease that requires intervention. The mortality for this population was high, but was not caused by rupture of a PUIA. Diameter changes noted in the PUIA during follow-up did not suggest ulcer treatment would improve survival. PMID- 26483002 TI - Arteriovenous fistula outcomes in the elderly. AB - OBJECTIVE: Over several decades, there has been an increase in the number of elderly patients requiring hemodialysis. These older patients typically have an increased incidence of comorbidities including diabetes, hypertension, and peripheral vascular disease. We undertook a systematic review of the current literature to assess outcomes of arteriovenous fistula (AVF) formation in the elderly and to compare the results of radiocephalic AVFs vs brachiocephalic AVFs in older patients. METHODS: A literature search was performed using MEDLINE, Embase, PubMed, and the Cochrane Library. All retrieved articles published before December 31, 2014 (and in English) primarily describing the creation of hemodialysis vascular access for elderly patients were considered for inclusion. We report pooled AVF patency rates and a comparison of radiocephalic vs brachiocephalic AVF patency rates using odds ratios (ORs). RESULTS: Of 199 relevant articles reviewed, 15 were deemed eligible for the review. The pooled 12 month primary and secondary AVF patency rates were 53.6% (95% confidence interval [CI], 47.3-59.9) and 71.6% (95% CI, 59.2-82.7), respectively. Comparison of radiocephalic vs brachiocephalic AVF patency rates demonstrated that radiocephalic AVFs have inferior primary (OR, 0.72; 95% CI, 0.55-0.93; P = .01) and secondary (OR, 0.76; 95% CI, 0.58-1.00; P = .05) patency rates. CONCLUSIONS: This meta-analysis confirms that adequate 12-month primary and secondary AVF patency rates can be achieved in elderly patients. Brachiocephalic AVFs have both superior primary and secondary patency rates at 12 months compared with radiocephalic AVFs. These important data can inform clinicians' and patients' decision-making about suitability of attempting AVF formation in older persons. PMID- 26483004 TI - Results of the Valiant Mona LSA early feasibility study for descending thoracic aneurysms. AB - OBJECTIVE: Stent graft coverage of the left subclavian artery (LSA) may be required to achieve an adequate landing zone in up to 40% of descending thoracic aneurysms (DTAs). The Valiant Mona LSA Thoracic Stent Graft System (Medtronic, Santa Rosa, Calif) consists of a main stent graft and a branch stent graft designed to maintain LSA patency while diverting circulation through the encroaching aneurysm. Participating in the United States Food and Drug Administration's new Innovation Pathway, this first-in-human, early feasibility study evaluates early clinical experience of the Valiant Mona LSA Stent Graft System in patients with DTAs where the proximal landing zone necessitates LSA coverage. METHODS: This premarket, nonrandomized, single-arm prospective study recruited nine patients (age 72.9 +/- 7.6 years). Primary end points were aneurysm-related mortality, stroke, paraplegia, left arm/hand ischemia, and treatment success. Neurologic events were assessed by imaging and by independent neurologists. Inclusion criteria required patients with a DTA or penetrating aortic ulcer to have a distance of >=10 mm between the left common carotid artery and the LSA. Mean aneurysm diameter was 53.7 +/- 10.0 mm. The indication for repair was for saccular DTA in five patients or fusiform DTA in four. Seven patients were at American Society of Anesthesiologists Physical Status Classification III/IV. RESULTS: All nine patients received one main stent graft (diameter 28 to 42 mm) and one branch stent graft (diameter 10 to 14 mm). To extend device coverage distally, a commercial Valiant Captivia device was implanted in seven patients. No uncorrected endoleaks were observed at the end of the implant procedure. Four endoleaks developed before discharge in four of eight evaluable patients. Two were identified as type II and two were of undetermined type. No endoleak resulted in a secondary intervention. Technical success, defined by the clinical investigational plan, was achieved in all nine patients intraoperatively, and treatment success was achieved in all eight evaluable patients at 1 month. There were no major, disabling strokes. Four minor nondisabling strokes were reported in three patients <=30 days (days 1, 1, 5, and 24). To date, there have been no reports of death, left arm ischemia, paraplegia, rupture, conversion to open surgery, or secondary endovascular procedure. No patients required surgical LSA revascularization. CONCLUSIONS: The Valiant Mona LSA system demonstrates technical and treatment success, relative safety, and early durability in its initial use in DTA patients. Midterm results are expected as patients are monitored at regular intervals to 5 years. PMID- 26483003 TI - One-year outcomes of the U.S. and Japanese regulatory trial of the Misago stent for treatment of superficial femoral artery disease (OSPREY study). AB - OBJECTIVE: The purpose of this study was to assess the safety and efficacy of the Misago stent (Terumo Corp, Tokyo, Japan) in occlusive and stenotic superficial femoral artery (SFA) disease. METHODS: The safety and efficacy of the Misago SFA stent were evaluated prospectively in this initial collaboration trial between Japan and the United States. Because this trial enrolled patients mainly from Japan and the United States and because there is a question as to whether a race difference exists in SFA stent performance, the race difference on outcome was also analyzed. In addition, results were compared with a prior SFA stent trial. RESULTS: The Misago stent was implanted in 261 subjects with TransAtlantic Inter Society Consensus (TASC) type A and type B SFA lesions (201 subjects in the United States, 50 in Japan, 9 in Taiwan, 1 in South Korea). The mean age of the patients was 69.3 +/- 10.0 years, and the mean lesion length was 83.8 +/- 41.3 mm. The overall 12-month primary patency rate and clinically driven target lesion revascularization were 82.9% and 13.0%, respectively. Regional differences within the Occlusive/Stenotic Peripheral Artery Revascularization Study (OSPREY) and outcomes between U.S. and Asian patients were similar, including primary patency (82.9% vs 83.0%; P = .889), clinically driven target lesion revascularization (13.4% vs 11.7%; P = .829), stent fracture rate (1.3% vs 0.0%; P = 1.000), and stent thrombosis rate (0.5% vs 0.0%; P = 1.000). CONCLUSIONS: OSPREY 12-month data showed satisfactory outcome of the Misago stent for the treatment of TASC type A and type B SFA lesions and appears to be comparable to recent stent trials. In addition, the lack of difference in outcome among races supports the value of international trials. PMID- 26483005 TI - Apolipoprotein E (APOE) epsilon4 Allele Is Associated with Increased Symptom Reporting Following Sports Concussion. AB - Exploring the relationship between genetic factors and outcome following brain injury has received increased attention in recent years. However, few studies have evaluated the influence of genes on specific sequelae of concussion. The purpose of this study was to determine how the epsilon4 allele of the apolipoprotein E (APOE) gene influences symptom expression following sports related concussion. Participants included 42 collegiate athletes who underwent neuropsychological testing, including completion of the Post-Concussion Symptom Scale (PCSS), within 3 months after sustaining a concussion (73.8% were evaluated within 1 week). Athletes provided buccal samples that were analyzed to determine the make-up of their APOE genotype. Dependent variables included a total symptom score and four symptom clusters derived from the PCSS. Mann-Whitney U tests showed higher scores reported by athletes with the epsilon4 allele compared to those without it on the total symptom score and the physical and cognitive symptom clusters. Furthermore, logistic regression showed that the epsilon4 allele independently predicted those athletes who reported physical and cognitive symptoms following concussion. These findings illustrate that epsilon4+ athletes report greater symptomatology post-concussion than epsilon4- athletes, suggesting that the epsilon4 genotype may confer risk for poorer post-concussion outcome. (JINS, 2016, 22, 89-94). PMID- 26483006 TI - The Effect of the Mediterranean Diet on Hypertension: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The adoption of a Mediterranean diet (MD) pattern of eating is often described as a strategy to help prevent or manage hypertension. However, this dietary regimen has not been reviewed systematically for its efficacy against hypertension. Therefore, the purpose of this study was to analyze the effect of interventions of at least 1 year duration on blood pressure (BP) values through a systematic review and meta-analysis. The focus was on interventions comparing an MD with a low-fat diet. DESIGN: The authors accessed and searched PubMed and Scopus databases up to March, 2015. Randomized control trials comparing MD vs low fat diet were included. The researchers assessed the methodological quality, extracted the valid data, and conducted the meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: Six trials (more than 7,000 individuals) were identified. Meta-analysis showed that interventions aiming at adopting an MD pattern for at least 1 year reduced both the systolic BP and diastolic BP levels in individuals with normal BP or mild hypertension. The effect was higher for the systolic BP (-1.44 mm Hg) but also consistent for the diastolic BP (-0.70 mm Hg). However, the results have to be interpreted with caution owing to the reduced number of studies eligible for inclusion in this meta-analysis. This situation limited the statistical power of the analyses. Furthermore, in all analyses, the pooled effect estimation showed a high evidence of heterogeneity, which compromises the validity of the pooled estimates. CONCLUSIONS AND IMPLICATIONS: A positive and significant association was found between the MD and BP in adults. However, in all cases the magnitude of the effect was small. Based on this limited group of studies and their heterogeneity, the authors found insufficient convincing evidence to suggest that the MD decreased BP. Further standardized research is urgently needed to reach evidence-based conclusions to clarify the role of MD in BP management, particularly in Europe and other societies where prevalence of cardiovascular diseases is increasing. PMID- 26483007 TI - Patient, tumor, and health system factors affecting groin node dissection rates in vulvar carcinoma: A population-based cohort study. AB - OBJECTIVE: To determine the rate of groin node dissection (GND) for invasive vulvar carcinoma in a population-based cohort, and the patient, tumor, or health system factors associated with having this procedure. METHODS: This retrospective population-based cohort includes all cases of invasive squamous cell carcinoma identified in the provincial cancer registry from 1998 to 2007. Chart abstraction was completed for all clinical and pathologic factors. Descriptive analyses with chi-squared tests were used for comparing proportions between patient groups. Multivariable logistic regression analysis was implemented to determine factors associated with having a GND. RESULTS: Data was collected for 1109 patients; 1038 patients were included in this analysis. 647 (62%) had a GND as part of primary management of their vulvar cancer, while 391 (38%) did not. When those with depth of invasion <=1mm and no GND were removed, the GND rate increased to 68%. Reasons for no GND included age, obesity, advanced disease, or comorbidities. Factors significantly associated with omission of GND were increasing age (OR 0.98, CI 0.97-0.99), severe comorbidities (OR 0.57, CI 0.42-0.78), lower income quintile (OR 0.71, CI 0.54-0.95), and surgeon type (non-gynecologic oncologist vs gynecologic oncologist) (OR 0.43, CI 0.22-0.85), whereas depth of invasion >1mm was significantly associated with having a GND (OR 2.75, CI 2.08-3.62). CONCLUSION: This population-based cohort demonstrates 32% of invasive vulvar cancer patients did not have a GND at initial management. Vulvar cancer patients should be evaluated by clinicians with expertise in this rare disease to ensure that a GND is completed when feasible. PMID- 26483008 TI - The Founder Strains of the Collaborative Cross Express a Complex Combination of Advantageous and Deleterious Traits for Male Reproduction. AB - Surveys of inbred strains of mice are standard approaches to determine the heritability and range of phenotypic variation for biomedical traits. In addition, they may lead to the identification of novel phenotypes and models of human disease. Surprisingly, male reproductive phenotypes are among the least represented traits in the Mouse Phenome Database. Here we report the results of a broad survey of the eight founder inbred strains of both the Collaborative Cross (CC) and the Diversity Outbred populations, two new mouse resources that are being used as platforms for systems genetics and sources of mouse models of human diseases. Our survey includes representatives of the three main subspecies of the house mice and a mix of classical and wild-derived inbred strains. In addition to standard staples of male reproductive phenotyping such as reproductive organ weights, sperm counts, and sperm morphology, our survey includes sperm motility and the first detailed survey of testis histology. As expected for such a broad survey, heritability varies widely among traits. We conclude that although all eight inbred strains are fertile, most display a mix of advantageous and deleterious male reproductive traits. The CAST/EiJ strain is an outlier, with an unusual combination of deleterious male reproductive traits including low sperm counts, high levels of morphologically abnormal sperm, and poor motility. In contrast, sperm from the PWK/PhJ and WSB/EiJ strains had the greatest percentages of normal morphology and vigorous motility. Finally, we report an abnormal testis phenotype that is highly heritable and restricted to the WSB/EiJ strain. This phenotype is characterized by the presence of a large, but variable, number of vacuoles in at least 10% of the seminiferous tubules. The onset of the phenotype between 2 and 3 wk of age is temporally correlated with the formation of the blood-testis barrier. We speculate that this phenotype may play a role in high rates of extinction in the CC project and in the phenotypes associated with speciation in genetic crosses that use the WSB/EiJ strain as representative of the Mus muculus domesticus subspecies. PMID- 26483009 TI - Influences of LIN-12/Notch and POP-1/TCF on the Robustness of Ventral Uterine Cell Fate Specification in Caenorhabditis elegans Gonadogenesis. AB - The prospective ventral uterus of the hermaphrodite gonad primordium consists of two pairs of sister cells, with each pair consisting of a proximal "alpha" cell and a distal "beta" cell. All four cells initially are competent to become the anchor cell (AC), a unique cell type that acts as the organizer of subsequent uterine and vulval development. However, the beta cells soon lose this competence and always become ventral uterine precursor cells (VUs), whereas the alpha cells maintain their AC competence longer, until lin-12/Notch-mediated interactions between them specify one as the AC and the other as a VU. Here, we investigate this asymmetry in developmental potential and VU fate specification between the alpha and beta sister cells. We find evidence that lin-12 activity contributes to the robustness of betaVU fate at elevated temperature, that the Caenorhabditis elegans Notch paralog glp-1 is not functionally redundant with lin-12 in specifying betaVU fate, and that the activity of POP-1, the sole C. elegans TCF ortholog, influences betaVU fate. We propose a model for how Wnt and LIN-12/Notch signaling together lead to robust specification of the betaVU fate. PMID- 26483010 TI - Identification of Saccharomyces cerevisiae Genes Whose Deletion Causes Synthetic Effects in Cells with Reduced Levels of the Nuclear Pif1 DNA Helicase. AB - The multifunctional Saccharomyces cerevisiae Pif1 DNA helicase affects the maintenance of telomeric, ribosomal, and mitochondrial DNAs, suppresses DNA damage at G-quadruplex motifs, influences the processing of Okazaki fragments, and promotes breakage induced replication. All of these functions require the ATPase/helicase activity of the protein. Owing to Pif1's critical role in the maintenance of mitochondrial DNA, pif1Delta strains quickly generate respiratory deficient cells and hence grow very slowly. This slow growth makes it difficult to carry out genome-wide synthetic genetic analysis in this background. Here, we used a partial loss of function allele of PIF1, pif1-m2, which is mitochondrial proficient but has reduced abundance of nuclear Pif1. Although pif1-m2 is not a null allele, pif1-m2 cells exhibit defects in telomere maintenance, reduced suppression of damage at G-quadruplex motifs and defects in breakage induced replication. We performed a synthetic screen to identify nonessential genes with a synthetic sick or lethal relationship in cells with low abundance of nuclear Pif1. This study identified eleven genes that were synthetic lethal (APM1, ARG80, CDH1, GCR1, GTO3, PRK1, RAD10, SKT5, SOP4, UMP1, and YCK1) and three genes that were synthetic sick (DEF1, YIP4, and HOM3) with pif1-m2. PMID- 26483011 TI - Multilocus Sex Determination Revealed in Two Populations of Gynodioecious Wild Strawberry, Fragaria vesca subsp. bracteata. AB - Gynodioecy, the coexistence of females and hermaphrodites, occurs in 20% of angiosperm families and often enables transitions between hermaphroditism and dioecy. Clarifying mechanisms of sex determination in gynodioecious species can thus illuminate sexual system evolution. Genetic determination of gynodioecy, however, can be complex and is not fully characterized in any wild species. We used targeted sequence capture to genetically map a novel nuclear contributor to male sterility in a self-pollinated hermaphrodite of Fragaria vesca subsp. bracteata from the southern portion of its range. To understand its interaction with another identified locus and possibly additional loci, we performed crosses within and between two populations separated by 2000 km, phenotyped the progeny and sequenced candidate markers at both sex-determining loci. The newly mapped locus contains a high density of pentatricopeptide repeat genes, a class commonly involved in restoration of fertility caused by cytoplasmic male sterility. Examination of all crosses revealed three unlinked epistatically interacting loci that determine sexual phenotype and vary in frequency between populations. Fragaria vesca subsp. bracteata represents the first wild gynodioecious species with genomic evidence of both cytoplasmic and nuclear genes in sex determination. We propose a model for the interactions between these loci and new hypotheses for the evolution of sex determining chromosomes in the subdioecious and dioecious Fragaria. PMID- 26483013 TI - Using RNA-seq for Analysis of Differential Gene Expression in Fungal Species. AB - The ability to extract, identify and annotate large amounts of biological data is a key feature of the "omics" era, and has led to an explosion in the amount of data available. One pivotal advance is the use of Next-Generation Sequencing (NGS) techniques such as RNA-sequencing (RNA-seq). RNA-seq uses data from millions of small mRNA transcripts or "reads" which are aligned to a reference genome. Comparative transcriptomics analyses using RNA-seq can provide the researcher with a comprehensive view of the cells' response to a given environment or stimulus.Here, we describe the NGS techniques (based on Illumina technology) that are routinely used for comparative transcriptome analysis of fungal species. We describe the entire process from isolation of RNA to computational identification of differentially expressed genes. We provide instructions to allow the beginner to implement packages in R such as Bioconductor. The methods described are not limited to yeast, and can also be applied to other eukaryotic organisms. PMID- 26483012 TI - Development of INDEL Markers for Genetic Mapping Based on Whole Genome Resequencing in Soybean. AB - Soybean [Glycine max (L.) Merrill] is an important crop worldwide. In this study, a Chinese local soybean cultivar, Hedou 12, was resequenced by next generation sequencing technology to develop INsertion/DELetion (INDEL) markers for genetic mapping. 49,276 INDEL polymorphisms and 242,059 single nucleotide polymorphisms were detected between Hedou 12 and the Williams 82 reference sequence. Of these, 243 candidate INDEL markers ranging from 5-50 bp in length were chosen for validation, and 165 (68%) of them revealed polymorphisms between Hedou 12 and Williams 82. The validated INDEL markers were also tested in 12 other soybean cultivars. The number of polymorphisms in the pairwise comparisons of 14 soybean cultivars varied from 27 to 165. To test the utility of these INDEL markers, they were used to perform genetic mapping of a crinkly leaf mutant, and the CRINKLY LEAF locus was successfully mapped to a 360 kb region on chromosome 7. This research shows that high-throughput sequencing technologies can facilitate the development of genome-wide molecular markers for genetic mapping in soybean. PMID- 26483014 TI - Enhancing Structural Annotation of Yeast Genomes with RNA-Seq Data. AB - The number of fully sequenced genomes of yeasts is dramatically increasing but both structural and functional annotation quality are usually neglected, as most frequently based on automatic annotation transfer tools from reference genomes. RNA sequencing technologies offer the possibility to better characterize yeast transcriptomes and to correct or improve the prediction of mRNA, ncRNA, or miscellaneous RNA. We describe a computational approach to enhance structural annotation of yeast genomes based on RNA-Seq data exploitation. The proposed pipeline is primarily based on read mapping with TopHat2. Mapping outputs are then used for various applications such as: (1) validation of exon-exon junctions of predicted transcripts, (2) definition of new transcribed features, (3) prediction of 3' UTR, and (4) identification of extra features absent from the genome assembly. We strongly encourage curators to proceed to a manual validation and editing of the reference genome. Releasing genomes with high-quality annotation is an important issue, as they will be considered as references for further predictions. PMID- 26483015 TI - Pathogen Gene Expression Profiling During Infection Using a Nanostring nCounter Platform. AB - NanoString nCounter is a recently developed platform that can make direct multiplexed measurement of gene expression using color-coded probe pairs (Geiss et al., Nat Biotechnol 26(3):317-325, 2008; Malkov et al., BMC Res Notes 2:80, 2009). We have found that this platform is uniquely suitable for quantification of pathogen gene expression during infection, where pathogen RNA comprises a tiny portion of total RNA isolated from the infected tissue. Here, we describe a protocol that we have successfully applied to a number of pathogens across multiple infection models, including both invasive and mucosal infection by Candida albicans, and lung infection by Aspergillus fumigatus and Cryptococcus neoformans. PMID- 26483016 TI - Comparative Transcriptomics in Yeasts. AB - Comparative functional genomics approaches have already shed an important light on the evolution of gene expression that underlies phenotypic diversity. However, comparison across many species in a phylogeny presents several major challenges. Here, we describe our experimental framework for comparative transcriptomics in a complex phylogeny. PMID- 26483017 TI - Mapping the Transcriptome-Wide Landscape of RBP Binding Sites Using gPAR-CLIP seq: Experimental Procedures. AB - An estimated 5-10 % of protein-coding genes in eukaryotic genomes encode RNA binding proteins (RBPs). Through dynamic changes in RNA recognition, RBPs posttranscriptionally regulate the biogenesis, transport, inheritance, storage, and degradation of RNAs. Understanding such widespread RBP-mediated posttranscriptional regulatory mechanisms requires comprehensive discovery of the in vivo binding sites of RBPs. Here, we describe the experimental procedures of the gPAR-CLIP-seq (global photoactivatable-ribonucleoside-enhanced cross-linking and precipitation followed by deep sequencing) approach we recently developed for capturing and sequencing regions of the transcriptome bound by RBPs in budding yeast. Unlike the standard PAR-CLIP method, which identifies the bound RNA substrates for a single RBP, the gPAR-CLIP-seq method was developed to isolate and sequence all mRNA sites bound by the cellular "RBPome." The gPAR-CLIP-seq approach is readily applicable to a variety of organisms and cell lines to profile global RNA-protein interactions underlying posttranscriptional gene regulation. The complete landscape of RBP binding sites provides insights to the function of all RNA cis-regulatory elements in an organism and reveals fundamental mechanisms of posttranscriptional gene regulation. PMID- 26483018 TI - Mapping the Transcriptome-Wide Landscape of RBP Binding Sites Using gPAR-CLIP seq: Bioinformatic Analysis. AB - Protein-RNA interactions are integral components of posttranscriptional gene regulatory processes including mRNA processing and assembly of cellular architectures. Dysregulation of RNA-binding protein (RBP) expression or disruptions in RBP-RNA interactions underlie a variety of human pathologies and genetic diseases including cancer and neurodegenerative diseases (reviewed in (Cooper et al., Cell 136(4):777-793, 2009; Darnell, Cancer Res Treat 42(3):125 129, 2010; Lukong et al., Trends Genet 24 (8):416-425, 2008)). Recent studies have uncovered only a small proportion of the extensive RBP-RNA interactome in any organism (Baltz et al., Mol Cell 46(5):674-690, 2012; Castello et al., Cell 149(6):1393-1406, 2012; Freeberg et al., Genome Biol 14(2):R13, 2013; Hogan et al., PLoS Biol 6(10):e255, 2008; Mitchell et al., Nat Struct Mol Biol 20(1):127 133, 2013; Tsvetanova et al. PLoS One 5(9): pii: e12671, 2010; Schueler et al., Genome Biol 15(1):R15, 2014; Silverman et al., Genome Biol 15(1):R3, 2014). To expand our understanding of how RBP-RNA interactions govern RNA-related processes, we developed gPAR-CLIP-seq (global photoactivatable-ribonucleoside enhanced cross-linking and precipitation followed by deep sequencing) for capturing and sequencing all regions of the Saccharomyces cerevisiae transcriptome bound by RBPs (Freeberg et al., Genome Biol 14(2):R13, 2013). This chapter describes a pipeline for bioinformatic analysis of gPAR-CLIP-seq data. The first half of this pipeline can be implemented by running locally installed programs or by running the programs using the Galaxy platform (Blankenberg et al., Curr Protoc Mol Biol. Chapter 19:Unit 19 10 11-21, 2010; Giardine et al., Genome Res 15 (10):1451-1455, 2005; Goecks et al., Genome Biol 11(8):R86, 2010). The second half of this pipeline can be implemented by user-generated code in any language using the pseudocode provided as a template. PMID- 26483019 TI - Translation Analysis at the Genome Scale by Ribosome Profiling. AB - Ribosome profiling is an emerging approach using deep sequencing of the mRNA part protected by the ribosome to study protein synthesis at the genome scale. This approach provides new insights into gene regulation at the translational level. In this review we describe the protocol to prepare polysomes and extract ribosome protected fragments before to deep sequence them. PMID- 26483020 TI - Biotin-Genomic Run-On (Bio-GRO): A High-Resolution Method for the Analysis of Nascent Transcription in Yeast. AB - Transcription is a highly complex biological process, with extensive layers of regulation, some of which remain to be fully unveiled and understood. To be able to discern the particular contributions of the several transcription steps it is crucial to understand RNA polymerase dynamics and regulation throughout the transcription cycle. Here we describe a new nonradioactive run-on based method that maps elongating RNA polymerases along the genome. In contrast with alternative methodologies for the measurement of nascent transcription, the BioGRO method is designed to minimize technical noise that arises from two of the most common sources that affect this type of strategies: contamination with mature RNA and amplification-based technical biasing. The method is strand specific, compatible with commercial microarrays, and has been successfully applied to both yeasts Saccharomyces cerevisiae and Candida albicans. BioGRO profiling provides powerful insights not only into the biogenesis and regulation of canonical gene transcription but also into the noncoding and antisense transcriptomes. PMID- 26483021 TI - Genome-Wide Probing of RNA Structures In Vitro Using Nucleases and Deep Sequencing. AB - RNA structure probing is an important technique that studies the secondary and tertiary conformations of an RNA. While it was traditionally performed on one RNA at a time, recent advances in deep sequencing has enabled the secondary structure mapping of thousands of RNAs simultaneously. Here, we describe the method Parallel Analysis for RNA Structures (PARS), which couples double and single strand specific nuclease probing to high throughput sequencing. Upon cloning of the cleavage sites into a cDNA library, deep sequencing and mapping of reads to the transcriptome, the position of paired and unpaired bases along cellular RNAs can be identified. PARS can be performed under diverse solution conditions and on different organismal RNAs to provide genome-wide RNA structural information. This information can also be further used to constrain computational predictions to provide better RNA structure models under different conditions. PMID- 26483022 TI - Genome-Wide Chromatin Immunoprecipitation in Candida albicans and Other Yeasts. AB - Chromatin immunoprecipitation experiments are critical to investigating the interactions between DNA and a wide range of nuclear proteins within a cell or biological sample. In this chapter we outline an optimized protocol for genome wide chromatin immunoprecipitation that has been used successfully for several distinct morphological forms of numerous yeast species, and include an optimized method for amplification of chromatin immunoprecipitated DNA samples and hybridization to a high-density oligonucleotide tiling microarray. We also provide detailed suggestions on how to analyze the complex data obtained from these experiments. PMID- 26483023 TI - ChIPseq in Yeast Species: From Chromatin Immunoprecipitation to High-Throughput Sequencing and Bioinformatics Data Analyses. AB - Chromatin immunoprecipitation (ChIP) followed by high-throughput sequencing (ChIPseq) is a powerful technique for the genome-wide location of protein DNA binding sites. The ChIP experiment consists in treating living cells with a cross linking agent to bind proteins to their DNA substrates. After fragmentation of DNA, specific fractions associated with a particular protein of interest are purified by immunoaffinity. They are next sequenced and identified on the reference genome using dedicated bioinformatics programs. Several technical aspects are important to obtain high-quality ChIPseq results. This includes the quality of antibodies, the sequencing protocols, the use of accurate controls and the careful choice of bioinformatics tools. We present here a general protocol to perform ChIPseq analyses in yeast species. This protocol has been optimized to identify target genes of specific transcription factors but can be used for any other DNA binding proteins. PMID- 26483024 TI - Systematic Determination of Transcription Factor DNA-Binding Specificities in Yeast. AB - Understanding how genes are regulated, decoding their "regulome", is one of the main challenges of the post-genomic era. Here, we describe the in vitro method we used to associate cis-regulatory sites with cognate trans-regulators by characterizing the DNA-binding specificity of the vast majority of yeast transcription factors using Protein Binding Microarrays. This approach can be implemented to any given organism. PMID- 26483025 TI - Generation and Analysis of Chromosomal Contact Maps of Yeast Species. AB - Genome-wide derivatives of the chromosome conformation capture (3C) technique are now well-established approaches to study the multiscale average organization of chromosomes from bacteria to mammals. However, the experimental parameters of the protocol have to be optimized for different species, and the downstream experimental products (i.e., pair-end sequences) are influenced by these parameters. Here, we describe a complete pipeline to generate 3C-seq libraries and compute chromosomal contact maps of yeast species. PMID- 26483026 TI - A Versatile Procedure to Generate Genome-Wide Spatiotemporal Program of Replication in Yeast Species. AB - Here, we describe a complete protocol, comprising both the experimental and the analytical procedures, that allows to generate genome-wide spatiotemporal program of replication and to find the location of chromosomally active replication origins in yeast. The first step consists on synchronizing a cell population by physical discrimination of G1 cells according to their sedimentation coefficient. G1 cells are then synchronously released into S-phase and time-point samples are regularly taken until they reach the G2 phase. Progression through the cell cycle is monitored by measuring DNA content variation by flow cytometry. DNA samples, covering the entire S-phase, are then extracted and analyzed using deep sequencing. The gradual change of DNA copy number is measured to determine the mean replication time along the genome. A simple method of peak calling allows to infer from the replication profile the location of replication origins along the chromosomes. Our protocol is versatile enough to be applied to virtually any yeast species of interest and generate its replication profile. PMID- 26483028 TI - Label-Free Quantitative Proteomics in Yeast. AB - Label-free bottom-up shotgun MS-based proteomics is an extremely powerful and simple tool to provide high quality quantitative analyses of the yeast proteome with only microgram amounts of total protein. Although the experimental design of this approach is rather straightforward and does not require the modification of growth conditions, proteins or peptides, several factors must be taken into account to benefit fully from the power of this method. Key factors include the choice of an appropriate method for the preparation of protein extracts, careful evaluation of the instrument design and available analytical capabilities, the choice of the quantification method (intensity-based vs. spectral count), and the proper manipulation of the selected quantification algorithm. The elaboration of this robust workflow for data acquisition, processing, and analysis provides unprecedented insight into the dynamics of the yeast proteome. PMID- 26483027 TI - Single-Step Affinity Purification (ssAP) and Mass Spectrometry of Macromolecular Complexes in the Yeast S. cerevisiae. AB - Cellular functions are mostly defined by the dynamic interactions of proteins within macromolecular networks. Deciphering the composition of macromolecular complexes and their dynamic rearrangements is the key to getting a comprehensive picture of cellular behavior and to understanding biological systems. In the last decade, affinity purification coupled to mass spectrometry has emerged as a powerful tool to comprehensively study interaction networks and their assemblies. However, the study of these interactomes has been hampered by severe methodological limitations. In particular, the affinity purification of intact complexes from cell lysates suffers from protein and RNA degradation, loss of transient interactors, and poor overall yields. In this chapter, we describe a rapid single-step affinity purification method for the efficient isolation of dynamic macromolecular complexes. The technique employs cell lysis by cryo milling, which ensures nondegraded starting material in the submicron range, and magnetic beads, which allow for dense antibody-conjugation and thus rapid complex isolation, while avoiding loss of transient interactions. The method is epitope tag-independent, and overcomes many of the previous limitations to produce large interactomes with almost no contamination. The protocol described here has been optimized for the yeast S. cerevisiae. PMID- 26483029 TI - Profiling of Yeast Lipids by Shotgun Lipidomics. AB - Lipidomics is a rapidly growing technology for identification and quantification of a variety of cellular lipid molecules. Following the successful development and application of functional genomic technologies in yeast Saccharomyces cerevisiae, we witness a recent expansion of lipidomics applications in this model organism. The applications include detailed characterization of the yeast lipidome as well as screening for perturbed lipid phenotypes across hundreds of yeast gene deletion mutants. In this chapter, we describe sample handling, mass spectrometry, and bioinformatics methods developed for yeast lipidomics studies. PMID- 26483030 TI - Identification of Links Between Cellular Pathways by Genetic Interaction Mapping (GIM). AB - The yeast systematic deletion collection offered the basis for a number of different strategies that establish functional links between genes by analyzing the phenotype of cells that combine two different deletions or mutations. A distinguishing feature of the collection is the presence of molecular barcodes at each deleted locus, which can be used to quantify the presence and abundance of cells bearing a given allele in a complex mix. As a result, a large number of mutants can be tested in batch cultures, replacing tedious manipulation of thousands of individual strains with a barcode microarray readout. Barcode-based genetic screens like Genetic Interaction Mapping (GIM) thus require little investment in terms of specific equipment, are fast to perform, and allow precise measurements of double mutant growth rates for both aggravating (synthetic sick) and alleviating (epistatic) effects. We describe here protocols for preparing the pools of haploid double mutant S. cerevisiae cells, testing their composition with barcode microarrays, and analyzing the results to extract useful functional information. PMID- 26483031 TI - On the Mapping of Epistatic Genetic Interactions in Natural Isolates: Combining Classical Genetics and Genomics. AB - Genetic variation within species is the substrate of evolution. Epistasis, which designates the non-additive interaction between loci affecting a specific phenotype, could be one of the possible outcomes of genetic diversity. Dissecting the basis of such interactions is of current interest in different fields of biology, from exploring the gene regulatory network, to complex disease genetics, to the onset of reproductive isolation and speciation. We present here a general workflow to identify epistatic interactions between independently evolving loci in natural populations of the yeast Saccharomyces cerevisiae. The idea is to exploit the genetic diversity present in the species by evaluating a large number of crosses and analyzing the phenotypic distribution in the offspring. For a cross of interest, both parental strains would have a similar phenotypic value, whereas the resulting offspring would have a bimodal distribution of the phenotype, possibly indicating the presence of epistasis. Classical segregation analysis of the tetrads uncovers the penetrance and complexity of the interaction. In addition, this segregation could serve as the guidelines for choosing appropriate mapping strategies to narrow down the genomic regions involved. Depending on the segregation patterns observed, we propose different mapping strategies based on bulk segregant analysis or consecutive backcrosses followed by high-throughput genome sequencing. Our method is generally applicable to all systems with a haplodiplobiontic life cycle and allows high resolution mapping of interacting loci that govern various DNA polymorphisms from single nucleotide mutations to large-scale structural variations. PMID- 26483032 TI - Experimental Evolution and Resequencing Analysis of Yeast. AB - Experimental evolution of microbes is a powerful tool to study adaptation to strong selection, the mechanism of evolution and the development of new traits. The development of high-throughput sequencing methods has given researchers a new ability to cheaply and easily identify mutations genome wide that are selected during the course of experimental evolution. Here we provide a protocol for conducting experimental evolution of yeast using chemostats, including fitness measurement and whole genome sequencing of evolved clones or populations collected during the experiment. Depending on the number of generations appropriate for the experiment, the number of samples tested and the sequencing platform, this protocol takes from 1 month to several months to be completed, with the possibility of processing several strains or mutants at once. PMID- 26483033 TI - Reconstruction and Analysis of the Evolution of Modular Transcriptional Regulatory Programs Using Arboretum. AB - Comparative functional genomics aims to measure and compare genome-wide functional data such as transcriptomes, proteomes, and epigenomes across multiple species to study the conservation and divergence patterns of such quantitative measurements. However, computational methods to systematically compare these quantitative genomic profiles across multiple species are in their infancy. We developed Arboretum, a novel algorithm to identify modules of co-expressed genes and trace their evolutionary history across multiple species from a complex phylogeny. To interpret the results from Arboretum we developed several measures to examine the extent of conservation and divergence in modules and their relationship to species lifestyle, cis-regulatory elements, and gene duplication. We applied Arboretum to study the evolution of modular transcriptional regulatory programs controlling transcriptional response to different environmental stresses in the yeast Ascomycota phylogeny. We found that modules of similar patterns of expression captured the transcriptional responses to different stresses across species; however, the genes exhibiting these patterns were not the same. Divergence in module membership was associated with changes in lifestyle and specific clades and that gene duplication was a major factor contributing to the divergence of module membership. PMID- 26483034 TI - Predicting Gene and Genomic Regulation in Saccharomyces cerevisiae, using the YEASTRACT Database: A Step-by-Step Guided Analysis. AB - Transcriptional regulation is one of the key steps in the control of gene expression, with huge impact on the survival, adaptation, and fitness of all organisms. However, it is becoming increasingly clear that transcriptional regulation is far more complex than initially foreseen. In model organisms such as the yeast Saccharomyces cerevisiae evidence has been piling up showing that the expression of each gene can be controlled by several transcription factors, in the close dependency of the environmental conditions. Furthermore, transcription factors work in intricate networks, being themselves regulated at the transcriptional, post-transcriptional, and post-translational levels, working in cooperation or antagonism in the promoters of their target genes.In this chapter, a step-by-step guide using the YEASTRACT database is provided, for the prediction and ranking of the transcription factors required for the regulation of the expression a single gene and of a genome-wide response. These analyses are illustrated with the regulation of the PDR18 gene and of the transcriptome-wide changes induced upon exposure to the herbicide 2,4-Dichlorophenoxyacetic acid (2,4-D), respectively. The newest potentialities of this information system are explored, and the various results obtained in the dependency of the querying criteria are discussed in terms of the knowledge gathered on the biological responses considered as case studies. PMID- 26483035 TI - Participation Rates and Perceptions of Caregiving Youth Providing Home Health Care. AB - Little is known about the population of caregiving youth in the United States. We sought to describe the participation rates, demographics, and caregiving tasks among sixth graders served by the American Association of Caregiving Youth (AACY) in its Caregiving Youth Project (CYP) in Palm Beach County, FL and evaluate the perceived benefit of AACY services. Sixth grade enrollment data from eight middle schools between 2007 and 2013 were obtained from The School District of Palm Beach County and the AACY. Data were obtained using a retrospective review of AACY program participant files. These files contained responses to evaluative questions from both students and family members. Overall, 2.2 % of sixth graders enrolled and participated in the program. Among the 396 caregiving sixth graders studied, care recipients were predominantly a grandparent (40.6 %) or parent (30.5 %). Common activities included providing company for the care recipient (85.6 %), emotional support (74.5 %), and assistance with mobility (46.7 %). Youth reported a median of 2.5 h caregiving on weekdays and 4 h on weekend days, while families reported fewer hours (1.6 and 2.3, respectively). At the end of the school year, the sixth graders reported improvement in school (85.5 %), caregiving knowledge (88.5 %), and self-esteem (89.5 %). Slightly over 2 % of sixth graders participated in the CYP. While support services may mitigate the negative effects of the time spent by caregiving youth, more prospective research is needed to better define the true prevalence, tasks, and time spent caregiving among this subpopulation. PMID- 26483036 TI - Formulation and evaluation of Adapalene-loaded nanoparticulates for epidermal localization. AB - Adapalene (ADP), a topically administered antiacne drug, finds limitation due to poor penetration, limited localization, and associated incompatibility of photosensitization and skin irritation. To explicate an innovative and safe method for ADP administration and alleviating the associated limitations, solid lipid nanoparticles (SLN) of ADP have been fabricated and evaluated for efficacy in the present work. The SLN were prepared using pre-emulsion sonication method and incorporated into convenient topical dosage form, hydrogels. In vitro permeation studies of the hydrogels through HCS indicated gel containing ADP-SLN showed 2-fold more accumulation in skin layers as compared to conventional ADP gel. Rheological studies demonstrated ADP-SLN gel to possess pseudoplastic behavior, occlusion and hydration studies revealed permeation effectiveness of ADP-SLN gel over conventional ADP gel while primary skin irritation studies established safety of the ADP-SLN gel upon topical application. Hence, it was concluded that the studied ADP-SLN formulation with skin localizing ability may be a promising carrier for topical delivery of ADP. PMID- 26483040 TI - Our findings differ. PMID- 26483041 TI - Our findings differ. PMID- 26483038 TI - C-reactive protein: quantitative marker of surgical trauma and post-surgical complications in dogs: a systematic review. AB - C-reactive protein (CRP) is a major acute phase protein showing increasing serum concentrations in dogs with systemic inflammation following e.g., surgery, trauma, infections, or neoplasia. CRP is a useful diagnostic marker of systemic inflammation in dogs and automated assays have been validated for reliable measurements for routine diagnostic purposes. In the present study available evidence for the use of CRP as a marker of surgery related systemic inflammation in dogs was reviewed and assessed. Two main themes were in focus: (1) canine CRP as a potential marker of postsurgical infectious complications and (2) canine CRP as a marker of the degree of surgical trauma. As outlined in the review several studies suggest that CRP is a useful marker for both purposes. However, the evidence level is limited and studies in the field are all affected by considerable risks of bias. Thus, further studies are needed in order to confirm the assumptions from previous studies and increase the level of evidence for CRP as a useful marker for detecting inflammation after surgery in dogs. PMID- 26483037 TI - Crosstalk between endocannabinoid and immune systems: a potential dysregulation in depression? AB - BACKGROUND: The endocannabinoid (eCB) system, an endogenous lipid signaling system, appears to be dysregulated in depression. The role of endocannabinoids (eCBs) as potent immunomodulators, together with the accumulating support for a chronic low-grade inflammatory profile in depression, suggests a compelling hypothesis for a fundamental impairment in their intercommunication, in depression. OBJECTIVE: We aim to review previous literature on individual associations between the immune and eCB systems and depression. It will focus on peripheral and central mechanisms of crosstalk between the eCB and immune systems. A potential dysregulation in this crosstalk will be discussed in the context of depression. RESULTS: Investigations largely report a hypoactivity of the eCB system and increased inflammatory markers in individuals with depression. Findings depict a multifaceted communication whereby immunocompetent and eCB related cells can both influence the suppression and enhancement of the other's activity in both the periphery and central nervous system. A dysregulation of the eCB system, as seen in depression, appears to be associated with central and peripheral concentrations of inflammatory agents implicated in the pathophysiology of this illness. CONCLUSION: The eCB and immune systems have been individually associated with and implicated in pathogenic mechanisms of depression. Both systems tightly regulate the other's activity. As such, a dysregulation in this crosstalk has potential to influence the onset and maintenance of this neuropsychiatric illness. However, few studies have investigated both systems and depression conjointly. This review highlights the demand to consider joint eCB-immune interactions in the pathoetiology of depression. PMID- 26483043 TI - The Aplidin analogs PM01215 and PM02781 inhibit angiogenesis in vitro and in vivo. AB - BACKGROUND: Novel synthesized analogs of Aplidin, PM01215 and PM02781, were tested for antiangiogenic effects on primary human endothelial cells in vitro and for inhibition of angiogenesis and tumor growth in vivo. METHODS: Antiangiogenic activity of both derivatives was evaluated by real-time cell proliferation, capillary tube formation and vascular endothelial growth factor (VEGF)-induced spheroid sprouting assays. Distribution of endothelial cells in the different phases of the cell cycle was analyzed by flow cytometry. Aplidin analogs were tested in vivo in chicken chorioallantoic membrane (CAM) assays. RESULTS: Both derivatives inhibited angiogenic capacities of human endothelial cells (HUVECs) in vitro at low nanomolar concentrations. Antiangiogenic effects of both analogs were observed in the CAM. In addition, growth of human multiple myeloma xenografts in vivo in CAM was significantly reduced after application of both analogs. On the molecular level, both derivatives induced cell cycle arrest in G1 phase. This growth arrest of endothelial cells correlated with induction of the cell cycle inhibitor p16(INK4A) and increased senescence-associated beta galactosidase activity. In addition, Aplidin analogs induced oxidative stress and decreased production of the vascular maturation factors Vasohibin-1 and Dickkopf 3. CONCLUSIONS: From these findings we conclude that both analogs are promising agents for the development of antiangiogenic drugs acting independent on classical inhibition of VEGF signaling. PMID- 26483044 TI - Inter-rater reliability of a national acute stroke register. AB - BACKGROUND: Medical quality registers are useful sources of knowledge about diseases and the health services. However, there are challenges in obtaining valid and reliable data. This study aims to assess the reliability in a national medical quality register. METHODS: We randomly selected 111 patients having had a stroke in 2012. An experienced stroke nurse completed the Norwegian Stroke Register paper forms for all 111 patients by review of the medical records. We then extracted all registered data on the same patients from the Norwegian Stroke Register and calculated Cohen's kappa and Gwet's AC(1) with 95 % confidence intervals for 51 nominal variables and Cohen's quadratic weighted kappa and Gwet's AC(2) for three ordinal variables. For two time variables, we calculated the Intraclass Correlation Coefficient. RESULTS: Substantial to excellent reliability (kappa > 0.60/AC(1)> 0.80) was observed for most variables related to past medical history, functional status, stroke subtype and discharge destination. Although excellent reliability was observed for time of stroke onset (ICC 0.93), this variable was hampered with a substantial amount of missing values. Some variables related to treatment and examinations in hospital displayed low levels of agreement. This applies to heart rate monitoring (kappa 0.17/AC(1) 0.46), swallowing test performed (kappa 0.19/AC(1) 0.27) and mobilized out of bed within 24 h after admission (kappa 0.04/AC(1) -0.11). CONCLUSION: A majority of the variables in The Norwegian Stroke Register have substantial to excellent reliability. The problem areas seem to be the lack of completeness in the time variable indicating stroke onset and poor reliability in some variables concerning examinations and treatment received in hospital. PMID- 26483045 TI - Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies. AB - BACKGROUND: High expression of programmed death ligand-1 (PD-L1) on tumor cells (TC) and/or on tumor-infiltrating immune cells (IC) is associated with a high response rate in patients with advanced nonsmall-cell lung cancer (NSCLC) treated with PD-L1 inhibitors. The use of a PD-L1 immunohistochemical (IHC) test in determining the responsiveness to immunotherapy has raised the question of the reliability and reproducibility of its evaluation in lung biopsies compared with corresponding resected surgical specimens. PATIENTS AND METHODS: PD-L1 expression in TC and IC was assessed in 160 patients with operable NSCLC on both whole surgical tissue sections and matched lung biopsies, by using a highly sensitive SP142 IHC assay. The specimens were scored as TC 0-3 and IC 0-3 based on increasing PD-L1 expression. RESULTS: PD-L1 expression was frequently discordant between surgical resected and matched biopsy specimens (the overall discordance rate = 48%; 95% confidence interval 4.64-13.24) and kappa value was equal to 0.218 (poor agreement). In all cases, the biopsy specimens underestimated the PD L1 status observed on the whole tissue sample. PD-L1-positive IC tumors were more common than PD-L1-positive TC tumors on resected specimens. The discrepancies were mainly related to the lack of a PD-L1-positive IC component in matched biopsies. CONCLUSIONS: Our results indicate relatively poor association of the PD L1 expression in TC and IC between lung biopsies and corresponding resected tumors. Although these results need to be further validated in larger cohorts, they indicate that the daily routine evaluation of the PD-L1 expression in diagnostic biopsies can be misleading in defining the sensitivity to treatment with PD-L1 targeted therapy. PMID- 26483046 TI - A rational approach for salvage of testicular cancer patients. PMID- 26483047 TI - A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial. AB - BACKGROUND: Maintenance treatment (mt) with bevacizumab (bev) +/- erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev +/- erlo and low-dose capecitabine (cap). PATIENTS AND METHODS: Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev +/- erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed. RESULTS: We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt BE/mut-B/mut-C). CONCLUSIONS: Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results. CLINICALTRIALSGOV: NCT01229813. PMID- 26483048 TI - Two cases of EGFR mutation-positive lung adenocarcinoma that transformed into squamous cell carcinoma: successful treatment of one case with rociletinib. PMID- 26483049 TI - The reporting of adverse events in oncology phase III trials: a comparison of the current status versus the expectations of the EORTC members. AB - BACKGROUND: Determination of drug safety and tolerability is usually based on the frequency of certain key adverse events (AEs) rather than the frequency of all grade toxicities. We assessed the reporting of key AEs in oncology randomized, controlled trials (RCTs) and compared that with the expectations of the European Organization for Research and Treatment of Cancer (EORTC) membership. MATERIALS AND METHODS: RCTs reports published between 2007 and 2011 were reviewed regarding the reporting of key AEs, namely: grade 3/4 AEs, grade 5 AEs, and AEs resulting in study withdrawal or in dose reduction. Study characteristics associated with better reporting of key AEs were investigated. Finally, a survey was conducted among the EORTC membership to determine their expectations on key AEs reporting. RESULTS: Although the frequency of grade 3/4 was reported in most reports (96%), only 17% of them described the reporting threshold above which grade 3/4 AEs were included for reporting, raising the possibility that important but less frequent grade 3/4 AEs might be underreported. Frequency and nature of grade 5 AEs were adequately reported in 161 (50%) of manuscripts; AEs leading to study withdrawal in 61 manuscripts (19%); and AEs leading to dose reduction in 43 manuscripts (13%). In contrast, most EORTC members expected a comprehensive reporting of grade 5 AEs (96% of EORTC member's responses), AEs leading to study withdrawal (86%) and AEs leading to dose reduction (70%). In multivariate analysis, frequencies of grade 5 AEs were less frequently reported in European trials (P = 0.004). Frequencies of AEs leading to withdrawals were more frequently reported in trials funded by industry (P = 0.005) and in trials including patients with breast or urological cancers (P = 0.006). CONCLUSIONS: These findings suggest that current practice of key AEs reporting remains highly variable and sometimes inadequate in oncology RCTs reports. Current standards for safety reporting in RCTs should be revised to emphasize the importance of key AEs reporting. PMID- 26483050 TI - Prognostic impact and implications of extracapsular lymph node involvement in colorectal cancer: a systematic review with meta-analysis. AB - BACKGROUND: The extranodal extension (ENE) of nodal metastasis (i.e. the extension of tumor cells through the nodal capsule into the perinodal adipose tissue) has recently emerged as an important prognostic factor in different types of malignancies. However, the tumor-node-metastasis (TNM) staging system for colorectal cancer does not consider it as a prognostic parameter. Therefore, we conducted a systematic review and meta-analysis to determine the prognostic role of ENE in patients with lymph node-positive colorectal cancer. MATERIALS AND METHODS: Two independent authors searched PubMed and SCOPUS until 7 January 2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with colorectal cancer, comparing participants with the presence of ENE (ENE+) versus only intranodal extension (ENE-) were eligible. Data were summarized using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) together with 95% confidence intervals (CIs) for time dependent risk related to ENE+, adjusted for potential confounders. RESULTS: Thirteen studies including 1336 patients were identified with a median follow-up of 4.7 years. ENE was associated with a higher T stage and tumor grading. In addition, ENE was associated with a significantly increased risk of all-cause mortality (RR = 1.75; 95% CI 1.42-2.16, P < 0.0001, I(2) = 60%; HR = 1.69, 95% CI 1.32-2.17, P < 0.0001, I(2) = 46%) and of recurrence of disease (RR = 2.07, 95% CI 1.65-2.61, P < 0.0001, I(2) = 47%; HR = 2.31, 95% CI 1.54-3.44, P < 0.0001, I(2) = 48%). CONCLUSIONS: Based of these results, in colorectal cancer, ENE should be considered from the gross sampling to the pathology report, as well as in future oncologic staging systems. PMID- 26483051 TI - Prognostic factors for progression-free and overall survival in advanced biliary tract cancer. AB - BACKGROUND: Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease. METHODS: Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset. RESULTS: A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.20-2.02]} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival [HR 2.24 (95% CI 1.53-3.28)]. In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57-68); 1-year OS: AUC 64% (95% CI 58-69)]. CONCLUSION: These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers. PMID- 26483052 TI - Editorial overview: Microbial systems biology. PMID- 26483053 TI - Type 2 diabetes and its correlates among adults in Bangladesh: a population based study. AB - BACKGROUND: Type 2 diabetes is one of the most prevalent non-communicable diseases in Bangladesh. However, the correlates of type 2 diabetes among adults in Bangladesh remain unknown. We aimed to investigate the correlates of type 2 diabetes among the adults in Bangladesh. METHODS: We conducted a cross-sectional study using data from the nationally representative 2011 Bangladesh Demographic and Health Survey. A random sample of 7,543 (3,823 women and 3,720 men) adults of age 35 years and older from both urban and rural areas, who participated in the survey was included. Diabetes was defined as having a fasting plasma blood glucose level of >= 7 mm/L or taking diabetes medication during the survey. Hypothesized factors, e.g., age, sex, education, place of residence, social status, body mass index, and hypertension were considered in the analyses. Multivariable logistic regression models were used to identify the important correlates of type 2 diabetes. RESULTS: Among the respondents, the overall prevalence of diabetes was 11 %, and the prevalence was slightly higher in women (11.2 %) than men (10.6 %). Respondents with the age group of 55-59 years had higher odds of having diabetes (odds ratios (OR) = 2.37, 95 % confidence interval (CI): 1.76-3.21) than the age group of 35-39 years. Moreover, respondents who had higher educational attainment (OR = 1.67, 95 % CI: 1.18-2.36) and higher social status (OR = 2.01, 95 % CI: 1.50-2.70) had higher odds of having diabetes than the respondents with no education and lower social status, respectively. We also found socioeconomic status, place of residence (rural or urban), regions of residence (different divisions), overweight and obesity, and hypertension as significant correlates of type 2 diabetes in Bangladesh. CONCLUSIONS: Our study shows that older age, higher socioeconomic status, higher educational attainment, hypertension, and obesity were found to be significant correlates of type 2 diabetes. Need-based policy program strategies including early diagnosis, awareness via mass media, and health education programs for changing lifestyles should be initiated for older age, wealthy, and/or higher educated individuals in Bangladesh. Moreover, area-specific longitudinal research is necessary to find out the underlying causes of regional variations. PMID- 26483055 TI - Putting an End to It! PMID- 26483054 TI - Molecular and functional evolution of the fungal diterpene synthase genes. AB - BACKGROUND: Terpenes represent one of the largest and most diversified families of natural compounds and are used in numerous industrial applications. Terpene synthase (TPS) genes originated in bacteria as diterpene synthase (di-TPS) genes. They are also found in plant and fungal genomes. The recent availability of a large number of fungal genomes represents an opportunity to investigate how genes involved in diterpene synthesis were acquired by fungi, and to assess the consequences of this process on the fungal metabolism. RESULTS: In order to investigate the origin of fungal di-TPS, we implemented a search for potential fungal di-TPS genes and identified their presence in several unrelated Ascomycota and Basidiomycota species. The fungal di-TPS phylogenetic tree is function related but is not associated with the phylogeny based on housekeeping genes. The lack of agreement between fungal and di-TPS-based phylogenies suggests the presence of Horizontal Gene Transfer (HGTs) events. Further evidence for HGT was provided by conservation of synteny of di-TPS and neighbouring genes in distantly related fungi. CONCLUSIONS: The results obtained here suggest that fungal di-TPSs originated from an ancient HGT event of a single di-TPS gene from a plant to a fungus in Ascomycota. In fungi, these di-TPSs allowed for the formation of clusters consisting in di-TPS, GGPPS and P450 genes to create functional clusters that were transferred between fungal species, producing diterpenes acting as hormones or toxins, thus affecting fungal development and pathogenicity. PMID- 26483057 TI - The History of NCCN and JNCCN. PMID- 26483056 TI - The Right Drug for the Right Patient: Navigating Systemic Therapy Options in Metastatic Renal Cell Carcinoma and Future Directions. PMID- 26483058 TI - Next-Generation Sequencing and In Silico Analysis Facilitate Prolonged Response to Pazopanib in a Patient With Metastatic Urothelial Carcinoma of the Renal Pelvis. AB - With the advent of widespread tumor genetic profiling, an increased number of mutations with unknown significance are being identified. Often, a glut of uninterpretable findings may confuse the clinician and provide little or inappropriate guidance in therapeutic decision-making. This report describes a method of protein modeling by in silico analysis (ie, using computer simulation) that is easily accessible to the practicing clinician without need for further laboratory analysis, which can potentially serve as a guide in therapeutic decisions based on poorly characterized tumor mutations. An example of this model is given wherein poorly characterized KIT, PDGFRB, and ERBB2 mutations were discovered in a patient with treatment-refractory metastatic transitional cell carcinoma of the renal pelvis. The KIT and PDGFRB mutations were predicted to be pathogenic using in silico analysis, whereas the ERBB2 mutation was predicted to be benign. Based on these findings, the patient was treated with pazopanib and achieved a partial response that lasted for 7.5 months. We propose that in silico analysis be explored as a potential means to further characterize genetic abnormalities found by tumor profiling assays, such as next-generation sequencing. PMID- 26483059 TI - Central Nervous System Cancers, Version 1.2015. AB - The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas. PMID- 26483060 TI - Making Sense of Variations in Prevalence Estimates of Depression in Cancer: A Co Calibration of Commonly Used Depression Scales Using Rasch Analysis. AB - BACKGROUND: The use of different depression self-report scales warrants co calibration studies to establish relationships between scores from 2 or more scales. The goal of this study was to examine variations in measurement across 5 commonly used scales to measure depression among patients with cancer: Hospital Anxiety and Depression Scale-Depression subscale (HADS-D), Centre for Epidemiologic Studies Depression Scale (CES-D), Patient Health Questionnaire-9 (PHQ-9), Beck Depression Inventory-II (BDI-II), and Depression Anxiety and Stress Scale-Depression subscale (DASS-D). METHODS: The depression scales were completed by 162 patients with cancer. Participants were also assessed by the major depressive episode module of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Rasch analysis and receiver operating characteristic curves were performed. RESULTS: Rasch analysis of the 5 scales indicated that these all measured depression. The HADS and BDI-II had the widest measurement range, whereas the DASS-D had the narrowest range. Co calibration revealed that the cutoff scores across the scales were not equivalent. The mild cutoff score on the PHQ-9 was easier to meet than the mild cutoff score on the CES-D, BDI-II, and DASS-D. The HADS-D possible cutoff score was equivalent to cutoff scores for major to severe depression on the other scales. Optimal cutoff scores for clinical assessment of depression were in the mild to moderate depression range for most scales. CONCLUSIONS: The labels of depression associated with the different scales are not equivalent. Most markedly, the HADS-D possible case cutoff score represents a much higher level of depression than equivalent scores on other scales. Therefore, use of different scales will lead to different estimates of prevalence of depression when used in the same sample. PMID- 26483061 TI - Adoption of Gene Expression Profiling for Breast Cancer in US Oncology Practice for Women Younger Than 65 Years. AB - BACKGROUND: A number of practice guidelines incorporate the use of gene expression profiling (GEP) tests for early-stage, hormone receptor-positive, HER2 negative breast tumors. Few studies describe factors associated with GEP testing in US oncology practice. We assessed the relationship between clinical, demographic, and group-level socioeconomic variables and test use in women younger than 65 years. PATIENTS AND METHODS: Data from 5 state cancer registries were linked with insurance claims data and GEP test results. We assessed rates of testing and variables associated with test use in an incident cohort of 9,444 commercially insured women younger than 65 years, newly diagnosed with stage I or II hormone receptor-positive breast cancer from 2006 through 2012. RESULTS: Rates of testing for women with N0 disease increased from 20.4% in 2006 to 35.2% in 2011. Variables associated with higher rates of testing, beyond clinical factors such as nodal status (P<.001), included being diagnosed from 2008 through 2012 versus 2006 through 2007 (adjusted odds ratio [OR], 1.67; 95% CI, 1.47-1.90), having preexisting comorbidities (adjusted OR, 1.35; 95% CI, 1.14-1.59), and higher out-of-pocket pharmacy costs (adjusted OR, 1.66; 95% CI, 1.40-1.97). Women younger than 50 years were more likely to be tested if they had stage I versus stage II disease (P<.0001). CONCLUSIONS: In an insured population of women younger than 65 years, GEP testing increased after its inclusion in clinical practice guidelines and mounting evidence. Additional research is needed to better understand oncologists' decision not to order GEP testing for their patients who are otherwise eligible. PMID- 26483062 TI - Survival in Patients With Severe Lymphopenia Following Treatment With Radiation and Chemotherapy for Newly Diagnosed Solid Tumors. AB - BACKGROUND: The immune system plays an important role in cancer surveillance and therapy. Chemoradiation can cause severe treatment-related lymphopenia (TRL) (<500 cells/mm3) that is associated with reduced survival. MATERIALS AND METHODS: Data from 4 independent solid tumor studies on serial lymphocyte counts, prognostic factors, treatment, and survival were collected and analyzed. The data set included 297 patients with newly diagnosed malignant glioma (N=96), resected pancreatic cancer (N=53), unresectable pancreatic cancer (N=101), and non-small cell lung cancer (N=47). RESULTS: Pretreatment lymphocyte counts were normal in 83% of the patient population, and no patient had severe baseline lymphopenia. Two months after initiating chemoradiation, 43% developed severe and persistent lymphopenia (P=.001). An increased risk for death was attributable to TRL in each cancer cohort (gliomas: hazard rate [HR], 1.8; 95% CI, 1.13-2.87; resected pancreas: HR, 2.2; 95% CI, 1.17-4.12; unresected pancreas: HR, 2.9; 95% CI, 1.53 5.42; and lung: HR, 1.7; 95% CI, 0.8-3.61) and in the entire study population regardless of pathologic findings (HR, 2.1; 95% CI, 1.54-2.78; P<.0001). Severe TRL was observed in more than 40% of patients 2 months after initiating chemoradiation, regardless of histology or chemotherapy regimen, and was independently associated with shorter survival from tumor progression. CONCLUSIONS: Increased attention and research should be focused on the cause, prevention, and reversal of this unintended consequence of cancer treatment that seems to be related to survival in patients with solid tumors. PMID- 26483063 TI - Anemia and Functional Disability in Older Adults With Cancer. AB - OBJECTIVES: Anemia is associated with functional disability among older adults in general. However, the relationship between anemia and functional disability has not been well characterized among older adults with cancer. Therefore, we examined the association between anemia and functional disability in patients with cancer aged 65 years or older. PATIENTS AND METHODS: We conducted cross sectional analysis of data derived from a multicenter prospective study of 500 patients with cancer aged 65 years or older. The primary outcome was functional disability at chemotherapy initiation, defined as the need for assistance with at least one instrumental activity of daily living. Anemia (using WHO criteria) was defined as a hemoglobin (Hb) level of less than 12 g/dL in women and less than 13 g/dL in men. Multivariable logistic regression was used to examine the association between anemia and functional disability. RESULTS: Among 491 evaluable patients (median age, 73.1 years [range, 65-91 years]), the prevalence of functional disability and anemia was 43% and 51%, respectively. Compared with patients without anemia, patients with anemia were more likely to report functional disability. On multivariable analysis, adjusting for sex, stage, and unintentional weight loss, patients with anemia were more likely to have functional disability (odds ratio, 2.40; 95% CI, 1.61-3.59). CONCLUSIONS: Anemia was highly prevalent and independently associated with functional disability in this cohort of older adults with cancer. Given the importance of functional status in cancer treatment decision-making, longitudinal studies evaluating the causal relation between anemia and functional status among older patients with cancer are warranted to evaluate causality. PMID- 26483064 TI - Acute Lymphoblastic Leukemia, Version 2.2015. AB - Treatment of acute lymphoblastic leukemia (ALL) continues to advance, as evidenced by the improved risk stratification of patients and development of newer treatment options. Identification of ALL subtypes based on immunophenotyping and cytogenetic and molecular markers has resulted in the inclusion of Philadelphia-like ALL and early T-cell precursor ALL as subtypes that affect prognosis. Identification of Ikaros mutations has also emerged as a prognostic factor. In addition to improved prognostication, treatment options for patients with ALL have expanded, particularly with regard to relapsed/refractory ALL. Continued development of second-generation tyrosine kinase inhibitors and the emergence of immunotherapy, including blinatumomab and chimeric antigen receptor T-cell therapy, have improved survival. Furthermore, incorporation of minimal residual disease (MRD) monitoring has shown insight into patient outcomes and may lead to treatment modification or alternative treatment strategies in select populations. This excerpt focuses on the sections of the ALL guidelines specific to clinical presentation and diagnosis, treatment of relapsed/refractory ALL, and incorporation of MRD monitoring. To view the most recent complete version of these guidelines, visit NCCN.org. PMID- 26483066 TI - Stereotactic Radiotherapy Versus Surgery for Early-Stage Operable Lung Cancer: More Questions Than Answers. PMID- 26483065 TI - Second-Line Treatment of Advanced Gastric Cancer: Where Do We Stand? AB - Gastric cancer is a leading cause of cancer death and is associated with poor prognosis. The treatment of advanced gastric cancer is changing with the development of novel agents. Until recently, no standard treatment was available for patients with advanced gastric cancer in the second-line setting. Single agent chemotherapy with docetaxel or irinotecan has been shown to improve survival and quality of life in patients whose disease has progressed while on prior chemotherapy. Combination chemotherapy is associated with a modest benefit at the expense of increased toxicity. Recently, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF) receptor-2, has been approved for the treatment of refractory advanced gastric cancer as a single agent or in combination with paclitaxel. Apatinib, a small molecule tyrosine kinase inhibitor targeting VEGF, has demonstrated activity in Asian populations whose disease has progressed on 2 lines of therapy. However, much work is still needed, including the development of biomarkers that could predict response to therapy. PMID- 26483068 TI - Models of progressive neurological dysfunction originating early in life. AB - It is now well established that many of society's most devastating and costly neurological diseases and disorders arise from trauma at, or shortly after birth. In some cases deficits are seen in childhood and in others they are substantially delayed; arising in adolescence or young adulthood. In either case the initial insult initiates a metabolic and/or neurodegenerative cascade that proceeds, often undetected, for a considerable period of time before diagnosable symptoms appear. This affords a potential for detecting and slowing or arresting degenerative and/or malfunctioning processes prior to the appearance of symptoms, but requires an understanding of the mechanisms involved in the progressive dysfunction that characterizes the disease progression process. While numerous preclinical models of end-stage symptoms of neurological disease are established, animal models of progressive neurological dysfunction have received comparatively less attention. This review attempts to introduce the concept of modelling progressive dysfunction in animals and provides descriptions of the current status of several representative examples of models that have been developed and partially characterized for understanding diseases of the brain that arise either at or near the time of birth in rodents. It is our belief that such models are essential to understanding the underlying mechanisms responsible for progressive neurological dysfunction and hold the potential for identifying targets for early detection and presymptomatic therapy of these conditions. PMID- 26483069 TI - Revisional bariatric surgery can improve refractory metabolic disease. AB - BACKGROUND: It remains unclear if patients undergoing revisional surgery for inadequate weight loss/recidivism can achieve improvement of refractory metabolic syndrome (MetS). OBJECTIVE: We aimed to evaluate metabolic outcomes after reoperative bariatric surgery for unsatisfactory weight loss in patients with refractory MetS. SETTING: Academic Hospital. METHODS: We retrospectively reviewed all revisional bariatric surgery cases performed for inadequate weight loss/recidivism at our center and analyzed all cases in which the patient had ongoing uncontrolled diabetes or MetS. RESULTS: In total, 121 reoperative bariatric cases for inadequate weight loss/recidivism were identified. Of those, 31.4% (N = 38) had MetS and 33.9% (N = 41) were diabetic at the time of primary bariatric surgery. At revisional surgery, 15 (39.5%) patients still met criteria for MetS and 7 (17.1%) had hemoglobin A1c (HbA1c)>=6.0%. Of those with refractory MetS (N = 15) at revisional surgery, a mean percent excess weight loss (%EWL) of 59.4+/-21.2% at mean 40.1+/-29.9 months follow-up corresponded to a mean decrease in triglyceride of 65.2 mg/dL, mean increase in high-density lipoprotein cholesterol (HDL) of 12.1 mg/dL, and mean decrease in plasma glucose of 58.8 mg/dL. Mean percent total weight loss was 27.3%. One patient still met criteria for MetS. Of those with HbA1c>=6.0% at reoperative surgery (N = 7), a mean %EWL of 63.0+/-22.9% at mean 51.6+/-36.6 months follow-up corresponded to a mean decrease in HbA1c of 1.6%. Three patients still had HbA1c>=6.0%, but only 1 had HbA1c>= 6.5%. CONCLUSION: Although further research is needed, this report suggests that revisional bariatric surgery is capable of treating both inadequate weight loss and refractory metabolic disease. PMID- 26483071 TI - Comment on: Early effect of Roux-en-Y gastric bypass on insulin sensitivity and signaling. PMID- 26483070 TI - Early effect of Roux-en-Y gastric bypass on insulin sensitivity and signaling. AB - BACKGROUND: A large body of literature indicates the rapidity with which Roux-en Y gastric bypass (RYGB) improves glycemic control. However, the underlying physiologic mechanisms are still a matter of debate. SETTING: Catholic University, School of Medicine, Rome, Italy. METHODS: Ten morbidly obese patients, before and 4 weeks after RYGB, and 10 healthy controls were studied. We measured insulin sensitivity as the homeostasis model assessment-estimated insulin resistance (HOMA-IR) and by the euglycemic hyperinsulinemic clamp, and phosphorylation of protein kinase B (Akt) on Ser473 and Thr308 and of GSK3 alpha beta on Ser 9 and Ser21 in skeletal muscle biopsy specimens by Western blot analysis. RESULTS: Obese patients before RYGB displayed reduced insulin sensitivity (M value) and clearance and increased fasting Akt phosphorylation on Ser473 compared with controls. M significantly increased after surgery (from 2.6 +/- 0.6 to 2.8 +/- 0.7 mg/kg fat free mass/min, P = .026) but remained far below the values in controls (10.0 +/- 3.8 mg/kg fat free mass/min, P<.001). Insulin clearance increased from 453.5 +/- 117.5 to 555.2 +/- 61.6 (P = .00076), becoming similar to that of controls 582.2 +/- 59.0 mU/m(2)/min. HOMA-IR decreased from 4.1 +/- 0.07 to 2.3 +/- 0.5 (P = .004), becoming comparable with controls (2.2 +/ 0.9). The hyperphosphorylation of Akt on Ser473 observed at fasting before RYGB was significantly reduced thereafter, becoming similar to that of healthy controls; the other phosphorylation states remained unchanged. CONCLUSIONS: Following RYGB, we found a prompt improvement of hepatic insulin resistance with normalization of hepatic insulin clearance and a small amelioration of whole-body insulin sensitivity. The supranormal levels of Akt Ser473 observed at fast in the skeletal muscle tissue at baseline were normalized after RYGB, and their changes correlated with those of both hepatic and peripheral insulin resistance. Although other mechanisms of action, such as the effect of weight loss and reduced food intake, cannot be excluded, the reduction of muscle Akt hyperphosphorylation on the serine residue can play a role in the early improvement of insulin sensitivity. PMID- 26483072 TI - Additive transcriptomic variation associated with reproductive traits suggest local adaptation in a recently settled population of the Pacific oyster, Crassostrea gigas. AB - BACKGROUND: Originating from Northeast Asia, the Pacific oyster Crassostrea gigas has been introduced into a large number of countries for aquaculture purpose. Following introduction, the Pacific oyster has turned into an invasive species in an increasing number of coastal areas, notably recently in Northern Europe. METHODS: To explore potential adaptation of reproductive traits in populations with different histories, we set up a common garden experiment based on the comparison of progenies from two populations of Pacific oyster sampled in France and Denmark and their hybrids. Sex ratio, condition index and microarray gene expression in gonads, were analyzed in each progeny (n = 60). RESULTS: A female biased sex-ratio and a higher condition index were observed in the Danish progeny, possibly reflecting an evolutionary reproductive strategy to increase the potential success of natural recruitment in recently settled population. Using multifarious statistical approaches and accounting for sex differences we identified several transcripts differentially expressed between the Danish and French progenies, for which additive genetic basis is suspected (showing intermediate expression levels in hybrids, and therefore additivity). Candidate transcripts included mRNA coding for sperm quality and insulin metabolism, known to be implicated in coordinated control and success of reproduction. CONCLUSIONS: Observed differences suggest that adaptation of invasive populations might have occurred during expansion acting on reproductive traits, and in particular on a female-biased sex-ratio, gamete quality and fertility. PMID- 26483073 TI - Sexual coercion and courtship by male western gorillas. AB - Sexual coercion and courtship are possible explanations for why male primates may direct agonistic behavior towards females. If so, then in species where females exhibit mate choice by transferring between males: (a) females who are not lactating (potential migrants) should receive more agonistic behavior than other females, (b) males should exhibit more agonistic behavior towards females during intergroup encounters than when no rival males are nearby, and (c) males should show more herding behavior when their group contains potential migrant females. We tested those hypotheses in a population of approximately 150 western gorillas at Mbeli Bai, northern Congo. We also tested whether difference in male phenotypic traits influenced their rates of agonistic behavior towards females. Of the 332 observed cases of male agonistic behavior towards females, 29% represented feeding competition, 7 % involved interventions in conflicts between females, and the remaining 64 % were considered potential evidence of sexual coercion and/or courtship. After excluding the cases of feeding competition and intervention, a multivariate analysis indicated that potential migrant females received agonistic behavior at a statistically significantly higher rate than other adult females. Females also received agonistic behavior at a significantly higher rate during intergroup encounters than at other times. Herding occurred during 22% of the 292 dyadic interunit encounters, and was significantly more likely to occur when the group contained a potential migrant female, but was not influenced by the number of adult females or the type of group encountered. Males with shorter body lengths had significantly higher rates of aggression, but phenotypic traits were not significantly correlated with herding. Collectively, our results are consistent with sexual coercion and/or courtship as an explanation for male-to-female agonistic behavior, but we are unable to distinguish between those two male mating strategies. Both types of behavior are likely due to a combination of perceived risks of female transfer and opportunity to advertise protector ability. PMID- 26483074 TI - Transcutaneous bilirubinometry is a reliably conservative method of assessing neonatal jaundice. AB - OBJECTIVE: In order to reduce invasive testing in newborns prior to discharge, we tested the direction of the correlation between transcutaneous bilirubin (TcB) and total serum bilirubin (TSB), the likelihood of missing high TSBs with a raised threshold for confirmatory testing, and also calculated potential cost savings from fewer laboratory testing. METHODS: We performed a cross-sectional analysis of single paired TcB and TSB results measured at 36 +/- 2 h of life in neonates >=37 weeks admitted only to the Level 1 nursery. TcB was measured using the BiliChek(r) meter. RESULTS: Of the 552 infants, 512 (92.8%) had TSB levels below TcB values. Correlation between TcB and TSB was 0.69. If TSB confirmation was to be performed at 11.7 mg/dL (medium risk threshold for phototherapy), the negative predictive value was 99.4%, with a potential cost savings of $6555.00 ($1500.00 per 100 patients). Of the 495 infants with TcB <11.7 mg/dL, only 3 had TSB levels higher than 11.7 mg/dL, and none met phototherapy threshold for low risk infants. CONCLUSIONS: TcB screening at our institution has a high negative predictive value, and can be used as a stand-alone test until values are close to phototherapy threshold, thus reducing invasive testing and cost. PMID- 26483075 TI - Management of allergic disease in the elderly: key considerations, recommendations and emerging therapies. AB - The number of people over 65 is increasing around the world. At present, between 5 and 10% of allergic diseases affect the elderly. In particular, rhinitis is increasing worldwide; the presence of high comorbidity makes the therapy of asthma even more complicated. With reference to dermatological allergies, the dryness of the skin favors the onset of allergic contact and atopic dermatitis, while the senescence of mucous membranes and the impaired secretion of polymeric IgA could be linked to food allergy. Overcoming the problem of adverse drug reaction is limited by the diagnostic difficulty in patients taking multiple drugs. In addition, some drugs, such as beta-blockers, angiotensin-converting enzyme (ACE)-inhibitors and NSAIDs, are relevant factors of urticaria and anaphylaxis. The aim of this review is to provide updated diagnostic and therapeutic guidelines through a better understanding of the pathophysiologic mechanisms, preventive measures and adherence to therapy. PMID- 26483076 TI - Population pharmacokinetics of nalmefene in healthy subjects and its relation to MU-opioid receptor occupancy. AB - AIMS: The aims of this study were to develop a population pharmacokinetic (PK) model to describe the PK of nalmefene in healthy subjects and to relate the exposure of nalmefene to the MU-opioid receptor occupancy by simulations in the target population. METHODS: Data from nine phase I studies (243 subjects) with extensive blood sampling were pooled and used for the population PK model building. Data from four other phase I studies (85 subjects) were pooled and used as an external validation dataset. Eight subjects from an imaging study contributed occupancy data and the pharmacokinetic/pharmacodynamic (PK/PD) relationship was modelled. Combining the population PK model and the PK/PD relationship enabled simulations to predict MU-opioid occupancy. RESULTS: A two compartment model with first order absorption best described the nalmefene PK data. The typical subject in the population was estimated to have a systemic clearance of 60.4 l h(-1) and a central volume of distribution of 266 l. Absolute oral bioavailability was estimated to 41% without food intake and with food about 53%. Simulation of the MU-opioid receptor occupancy shows that the 95% confidence bound is within or above 60-90% occupancy for up to 22-24 h after a single dose of 20 mg nalmefene. CONCLUSIONS: A robust population PK model for nalmefene was developed. Based on the concentration-occupancy model the MU-opioid receptor occupancy after a single 20 mg dose of nalmefene is predicted to be above the target therapeutic occupancy for about 24 h in about 95% of the target population. PMID- 26483077 TI - Microhabitat locality allows multi-species coexistence in terrestrial plant communities. AB - Most terrestrial plant communities exhibit relatively high species diversity and many competitive species are ubiquitous. Many theoretical studies have been carried out to investigate the coexistence of a few competitive species and in most cases they suggest competitive exclusion. Theoretical studies have revealed that coexistence of even three or four species can be extremely difficult. It has been suggested that the coexistence of many species has been achieved by the fine differences in suitable microhabitats for each species, attributing to niche separation. So far there is no explicit demonstration of such a coexistence in mathematical and simulation studies. Here we built a simple lattice Lotka Volterra model of competition by incorporating the minute differences of suitable microhabitats for many species. By applying the site variations in species specific settlement rates of a seedling, we achieved the coexistence of more than 10 species. This result indicates that competition between many species is avoided by the spatial variations in species-specific microhabitats. Our results demonstrate that coexistence of many species becomes possible by the minute differences in microhabitats. This mechanism should be applicable to many vegetation types, such as temperate forests and grasslands. PMID- 26483078 TI - Biomechanical validation of computer assisted planning of periacetabular osteotomy: A preliminary study based on finite element analysis. AB - Periacetabular Osteotomy (PAO) is a joint preserving surgical intervention intended to increase femoral head coverage and thereby to improve stability in young patients with hip dysplasia. Previously, we developed a CT-based, computer assisted program for PAO diagnosis and planning, which allows for quantifying the 3D acetabular morphology with parameters such as acetabular version, inclination, lateral center edge (LCE) angle and femoral head coverage ratio (CO). In order to verify the hypothesis that our morphology-based planning strategy can improve biomechanical characteristics of dysplastic hips, we developed a 3D finite element model based on patient-specific geometry to predict cartilage contact stress change before and after morphology-based planning. Our experimental results demonstrated that the morphology-based planning strategy could reduce cartilage contact pressures and at the same time increase contact areas. In conclusion, our computer-assisted system is an efficient tool for PAO planning. PMID- 26483079 TI - Towards the assessment of local dynamic stability of level-grounded walking in an older population. AB - Local dynamic stability is a critical aspect of stable gait but its assessment for use in clinical settings has not yet been sufficiently evaluated, particularly with respect to inertial sensors applied on the feet and/or trunk. Furthermore, key questions remain as to which state-space reconstruction is most reliable and valid. In this study, we evaluated the reliability as well as the ability of different sensor placement and state-spaces to distinguish between local dynamic stability in young and older adults. Gait data of 19 older and 20 young subjects were captured with inertial sensors twice within the first day as well as after seven days. 21 different signals (and combinations of signals) were used to span the system's state-space to calculate different measures of local dynamic stability. Our data revealed moderate or high effect sizes in 12 of the 21 old vs. young comparisons. We also observed considerable differences in the reliability of these 12 results, with intra-class correlation coefficients ranging from 0.09 to 0.81. Our results demonstrate that in order to obtain reliable and valid estimates of gait stability lambda of walking time series is best evaluated using trunk data or 1-dimensional data from foot sensors. PMID- 26483080 TI - Perceived barriers and facilitators to positive therapeutic change for people with intellectual disabilities: Client, carer and clinical psychologist perspectives. AB - Studies have highlighted successful outcomes of psychological therapies for people with intellectual disabilities. However, processes underlying these outcomes are uncertain. Thematic analysis was used to explore the perceptions of three clinical psychologists, six clients and six carers of barriers and facilitators to therapeutic change for people with intellectual disabilities. Six themes were identified relating to: what the client brings as an individual and with regard to their wider system; therapy factors, including the therapeutic relationship and adaptations; psychologists acting as a 'mental health GP' to coordinate care; systemic dependency; and the concept of the revolving door in intellectual disability services. The influence of barriers and facilitators to change is complex, with facilitators overcoming barriers and yet simultaneously creating more barriers. Given their potential impact on the psychologists' roles and access to therapy for people with intellectual disabilities, findings suggest these factors should be formulated as part of the therapeutic process. PMID- 26483081 TI - Lysobacter chengduensis sp. nov. Isolated from the Air of Captive Ailuropoda melanoleuca Enclosures in Chengdu, China. AB - A novel bacterial strain, designated as CF21(T), was isolated from the air of Ailuropoda melanoleuca enclosures in China. Cells were gram-negative, aerobic, non-motile, and rod shaped. Strain CF21(T) grew at 10-40 degrees C (optimum 28 30 degrees C) and pH 6.0-9.0 (optimum pH 7.0-8.0) and in the presence of NaCl concentrations ranging from 0.0% (w/v) to 2.0 % (optimum 0.0-1.0%). 16SrRNA gene sequence analysis indicated that strain CF21(T) belonged to genus Lysobacter within class Gammaproteobacteria and was most closely related to Luteimonas dalianensi OB44-3(T) (95.8% similarity), Lysobacter ruishenii CTN-1(T) (95.1%), Lysobacter spongiicola KMM329(T) (94.8 %), and Lysobacter daejeonensis GH1-9T (94.6%). The genomic G+C DNA content was 68.72 mol%. Major cellular fatty acids of CF21(T) were iso-C16:0 (30.22%), iso-C15:0 (25.70%), and the sum of 10-methyl C16 : 0 and/or iso-C17 : 1omega9c (21.94%). The prominent isoprenoid quinone was ubiquinone 8 (Q-8). Primary polar lipids included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, and an unknown phospholipid. DNA sequence relatedness between strain CF21(T) and L. ruishenii CTN-1(T) was 56%, which was clearly below the 70% threshold for prokaryotic species delineation. These analyses indicated that CF21(T) is a novel member of genus Lysobacter, for which the name Lysobacter chengduensis sp. nov. is proposed. The type strain is CF21(T) (=CGMCC1.15145(T) = DSM 100306(T)). PMID- 26483082 TI - Tolerance to Ultraviolet Radiation of Psychrotolerant Yeasts and Analysis of Their Carotenoid, Mycosporine, and Ergosterol Content. AB - Yeasts colonizing the Antarctic region are exposed to a high ultraviolet radiation evolving mechanisms to minimize the UV radiation damages, such as the production of UV-absorbing or antioxidant compounds like carotenoid pigments and mycosporines. Ergosterol has also been suggested to play a role in this response. These compounds are also economically attractive for several industries such as pharmaceutical and food, leading to a continuous search for biological sources of them. In this work, the UV-C radiation tolerance of yeast species isolated from the sub-Antarctic region and their production of carotenoids, mycosporines, and ergosterol were evaluated. Dioszegia sp., Leuconeurospora sp. (T27Cd2), Rhodotorula laryngis, Rhodotorula mucilaginosa, and Cryptococcus gastricus showed the highest UV-C radiation tolerance. The yeasts with the highest content of carotenoids were Dioszegia sp. (OHK torulene), Rh. laryngis (torulene and lycopene), Rh. mucilaginosa, (torulene, gamma carotene, and lycopene), and Cr. gastricus (2-gamma carotene). Probable mycosporine molecules and biosynthesis intermediates were found in Rh. laryngis, Dioszegia sp., Mrakia sp., Le. creatinivora, and Leuconeurospora sp. (T27Cd2). Ergosterol was the only sterol detected in all yeasts, and M. robertii and Le. creatinivora showed amounts higher than 4 mg g-1. Although there was not a well-defined relation between UV-C tolerance and the production of these three kinds of compounds, the majority of the yeasts with lower amounts of carotenoids showed lower UV-C tolerance. Dioszegia sp., M. robertii, and Le. creatinivora were the greatest producers of carotenoids, ergosterol, and mycosporines, respectively, representing good candidates for future studies intended to increase their production for large scale applications. PMID- 26483083 TI - Inflammatory Myofibroblastic Tumor of the Nasal Cavity. PMID- 26483084 TI - The dissipation kinetics of malathion in aqueous extracts of different fruits and vegetables. AB - The dissipation of malathion in 5% aqueous extracts of some fruits and vegetables including bell pepper, tomato, cucumber, cantaloupe, carrot, and also buffer (control) was investigated at 37 degrees C for 4 h. The dissipation trend of malathion in the fruit/vegetable samples and buffer followed first-order double exponential decay (FODED) and simple first-order kinetic (SFOK) models, respectively. The initial dissipation rate of malathion in tomato (DT10=0.05 h), bell pepper (DT10=0.06 h), and carrot (DT10=0.07 h) was faster compared to the other samples. The slowest rate of pesticide decline belonged to cantaloupe (DT50=1.92 h) with a significant difference from the other samples (p<=0.01), whereas tomato (DT50=0.43 h) and carrot (DT50=0.53 h) showed the fastest dissipation rate. DT90 values derived from the models revealed no significant difference between the samples except for cantaloupe which had the slowest rate of dissipation (DT90=8.27 h) with a significant difference compared to others (p<=0.01). A direct correlation was observed between protein content of the samples and the rate of malathion decline which indicates the role of plant enzymes in degrading malathion residues. PMID- 26483085 TI - Wavelets-based clustering of air quality monitoring sites. AB - This paper aims at providing a variance/covariance profile of a set of 36 monitoring stations measuring ozone (O3) and nitrogen dioxide (NO2) hourly concentrations, collected over the period 2005-2013, in Portugal mainland. The resulting individual profiles are embedded in a wavelet decomposition-based clustering algorithm in order to identify groups of stations exhibiting similar profiles. The results of the cluster analysis identify three groups of stations, namely urban, suburban/urban/rural, and a third group containing all but one rural stations. The results clearly indicate a geographical pattern among urban stations, distinguishing those located in Lisbon area from those located in Oporto/North. Furthermore, for urban stations, intra-diurnal and daily time scales exhibit the highest variance. This is due to the more relevant chemical activity occurring in high NO2 emissions areas which are responsible for high variability on daily profiles. These chemical processes also explain the reason for NO2 and O3 being highly negatively cross-correlated in suburban and urban sites as compared with rural stations. Finally, the clustering analysis also identifies sites which need revision concerning classification according to environment/influence type. PMID- 26483086 TI - Impact of wastewater irrigation on the dynamics of metal concentrations in the vadose zone: monitoring: part I. AB - Agricultural lands in the peri-urban area of New Delhi have been irrigated with treated wastewater from the Keshopur Effluent Irrigation Scheme (KEIS) since 1979. An attempt has been made to study the influence of wastewater irrigation on pH, electrical conductivity, organic carbon, and dynamics of heavy metal concentrations in vadose zone under KEIS. For this study, agricultural lands which have been receiving the sewage irrigation for 20, 10, and 5 years were selected. Adjacent tube well water-irrigated fields were selected and used as reference. Results indicate that there was a significant decrease in soil pH and electrical conductivity (EC) of sewage water-irrigated fields as compared to tube well water-irrigated fields. Organic carbon (OC) content in 20 years sewage irrigated soil (0-15 cm) increased by 244% over tube well water-irrigated soil. The increases in organic carbon content for 10 and 5 years sewage-irrigated surface soil (0-15 cm) were 138 and 60% over tube well water-irrigated soils. The second-order polynomial model suggested that there is a possibility of accumulation of organic carbon in soil due to sewage irrigation at 1.55 t(-1) ha( 1) year. There was an increase in diethylene triamine pentaacetic acid (DTPA) extractable Zn content in 20, 10, and 5 years sewage-irrigated soils (0-15 cm) to the extent of 86, 38, and 36% over tube well water-irrigated soils, respectively, while only 20 years sewage-irrigated soils showed a significant increase in DTPA extractable Cu (289%) in surface layer (0-15 cm) over tube well-irrigated soils. In case of Fe, 127, 88, and 76.6% increases in available Fe content (DTPA-Fe) were recorded under 20, 10, and 5 years sewage-irrigated soils, respectively, over controls. Like Cu, DTPA-extractable Ni also exhibited a significant increase (42.2%) in 20 years sewage-irrigated soil over tube well-irrigated ones. It appears that due to sewage irrigation particularly in surface soil, DTPA-Mn content either remained same or showed a slight decline as compared to tube well irrigated soils. The assessment of contamination factor (CF) in respect of total metal content in soil indicated the moderate level of metal contamination even after such long-term of sewage irrigation. PMID- 26483087 TI - Lethal Neonatal Rigidity and Multifocal Seizure Syndrome--A Misnamed Disorder? AB - OBJECTIVE: Lethal neonatal rigidity and multifocal seizure syndrome is a newly recognized genetic disorder associated with early onset of rigidity, multifocal epilepsy, developmental arrest, and early death. It is an autosomal recessive condition resulting from a mutation in the BRAT1 (BRCA1 [breast cancer-1] associated ataxia telangiectasia mutated activator 1) gene. There are few cases in the literature, and all patients have died before age 2 years, most within the first 6 months of life. The objective of this report is to expand the phenotypic spectrum of BRAT1 disorders and propose new nomenclature for this condition. RESULTS: We describe a child with compound heterozygosity for mutations in BRAT1. Her neonatal course was unremarkable. Over the first year of life she was noted to have progressive global developmental delay, visual impairment, microcephaly, hypertonia, hyperreflexia, and seizures. No epileptiform discharges were seen on electroencephalogram. Serial magnetic resonance imaging of the brain showed progressive cerebellar and brainstem atrophy. Unlike previously described patients, our patient has gained a number of developmental skills and, at this time, is 3 years and 8 months old. CONCLUSION: Despite the name of this disorder, patients with lethal neonatal rigidity and multifocal seizure syndrome may not present until after the neonatal period and may have a much longer life span than previously reported. We suggest renaming the condition "BRAT1-associated neurodegenerative disorder" to avoid the assumptions associated with the original nomenclature and to encourage clinicians to consider this condition outside the neonatal period. PMID- 26483089 TI - Highly photosensitive graphene field-effect transistor with optical memory function. AB - Graphene is a promising material for use in photodetectors for the ultrawide wavelength region: from ultraviolet to terahertz. Nevertheless, only the 2.3% light absorption of monolayer graphene and fast recombination time of photo excited charge restrict its sensitivity. To enhance the photosensitivity, hybridization of photosensitive material and graphene has been widely studied, where the accumulated photo-excited charge adjacent to the graphene channel modifies the Fermi level of graphene. However, the charge accumulation process slows the response to around a few tens of seconds to minutes. In contrast, a charge accumulation at the contact would induce the efficient light-induced modification of the contact resistance, which would enhance its photosensitivity. Herein, we demonstrate a highly photosensitive graphene field-effect transistor with noise-equivalent power of ~3 * 10(-15) W/Hz(1/2) and with response time within milliseconds at room temperature, where the Au oxide on Au electrodes modulates the contact resistance because of the light-assisted relaxation of the trapped charge at the contact. Additionally, this light-induced relaxation imparts an optical memory function with retention time of ~5 s. These findings are expected to open avenues to realization of graphene photodetectors with high sensitivity toward single photon detection with optical memory function. PMID- 26483088 TI - Comparison of [(11)C]Choline ([(11)C]CHO) and [(18)F]Bombesin (BAY 86-4367) as Imaging Probes for Prostate Cancer in a PC-3 Prostate Cancer Xenograft Model. AB - PURPOSE: Carbon-11- and fluorine-18-labeled choline derivatives are commonly used in prostate cancer imaging in the clinical setting for staging and re-staging of prostate cancer. Due to a limited detection rate of established positron emission tomography (PET) tracers, there is a clinical need for innovative tumor-specific PET compounds addressing new imaging targets. The aim of this study was to compare the properties of [(18)F]Bombesin (BAY 86-4367) as an innovative biomarker for prostate cancer imaging targeting the gastrin-releasing peptide receptor and [(11)C]Choline ([(11)C]CHO) in a human prostate tumor mouse xenograft model by small animal PET/X-ray computed tomography (CT). PROCEDURES: We carried out a dual-tracer small animal PET/CT study comparing [(18)F]Bombesin and [(11)C]CHO. The androgen-independent human prostate tumor cell line PC-3 was implanted subcutaneously in the flanks of nu/nu NMRI mice (n = 10) (PET/CT measurements of two [(11)C]Choline mice could not be analyzed due to technical reasons). [(18)F]Bombesin and [(11)C]CHO PET/CT imaging was performed about 3-4 weeks after the implantation of PC-3 cells on two separate days. After the intravenous tail vein injection of 14 MBq [(18)F]Bombesin and 37 MBq [(11)C]CHO, respectively, a dynamic study over 60 min was acquired in list mode using an Inveon animal PET/CT scanner (Siemens Medical Solutions). The sequence of [(18)F]Bombesin and [(11)C]CHO was randomized. Image analysis was performed using summed images as well as dynamic data. To calculate static and dynamic tumor-to muscle (T/M), tumor-to-blood (T/B), liver-to-blood (L/B), and kidney-to-blood (K/B) ratios, 4 * 4 * 4 mm(3) volumes of interest (VOIs) of tumor, muscle (thigh), liver, kidney, and blood derived from transversal slices were used. RESULTS: The mean T/M ratio of [(18)F]Bombesin and [(11)C]CHO was 6.54 +/- 2.49 and 1.35 +/- 0.30, respectively. The mean T/B ratio was 1.83 +/- 0.79 for [(18)F]Bombesin and 0.55 +/- 0.10 for [(11)C]CHO. The T/M ratio as well as the T/B ratio for [(18)F]Bombesin were significantly higher compared to those for [(11)C]CHO (p < 0.001, respectively). Kidney and liver uptake was statistically significantly lower for [(18)F]Bombesin (K/B 3.41 +/- 0.81, L/B 1.99 +/- 0.38) compared to [(11)C]CHO [K/B 7.91 +/- 1.85 (p < 0.001), L/B 6.27 +/- 1.99 (p < 0.001)]. The magnitudes of the time course of T/M and T/B ratios (T/M and T/Bdyn ratios) were statistically significantly different (showing a higher uptake of [(18)F]Bombesin compared to [(11)C]CHO); additionally, also the change of the T/M and T/B ratios over time was significantly different between both tracers in the dynamic analysis (p < 0.001, respectively). Furthermore, there was a statistically significantly different change of the K/B and L/B ratios over time between the two tracers in the dynamic analysis (p = 0.026 and p < 0.001, respectively). CONCLUSIONS: [(18)F]Bombesin (BAY 86-4367) visually and semi quantitatively outperforms [(11)C]CHO in the PC-3 prostate cancer xenograft model. [(18)F]Bombesin tumor uptake was significantly higher compared to [(11)C]CHO. [(18)F]Bombesin showed better imaging properties compared to the clinically utilized [(11)C]CHO due to a higher tumor uptake as well as a lower liver and kidney uptake. PMID- 26483090 TI - Hydrodynamics of Normal Atomic Gases with Spin-orbit Coupling. AB - Successful realization of spin-orbit coupling in atomic gases by the NIST scheme opens the prospect of studying the effects of spin-orbit coupling on many-body physics in an unprecedentedly controllable way. Here we derive the linearized hydrodynamic equations for the normal atomic gases of the spin-orbit coupling by the NIST scheme with zero detuning. We show that the hydrodynamics of the system crucially depends on the momentum susceptibilities which can be modified by the spin-orbit coupling. We reveal the effects of the spin-orbit coupling on the sound velocities and the dipole mode frequency of the gases by applying our formalism to the ideal Fermi gas. We also discuss the generalization of our results to other situations. PMID- 26483091 TI - Association of HO-1 (GT)n Promoter Polymorphism and Cardiovascular Disease: A Reanalysis of the Literature. AB - BACKGROUND: Heme-oxygenase 1 (HO-1), an inducible heme-degrading enzyme, has antiatherogenic effects through its enzymatic end products. HO-1 gene expression is modulated by a guanidine thymidine dinucleotide ([GT]n) repeat polymorphism in the promoter region. Shorter repeats with (GT)n < 25 are associated with higher inducibility and activity of HO-1. METHODS: We performed a systematic review of all literature from 1997 to 2013 on the association of the HO-1 (GT)n and cardiovascular disease (CVD). On the basis of predefined criteria (patient characteristics, genotype data format, allelic distribution, repeat length cutoff) 41 articles were selected. Patients were redistributed into 4 homogeneous subpopulations: patients with CVD (CVD group), patients without CVD (nonCVD), 'controls' with unknown cardiovascular status (unspecified) and children younger than 20 years of age (unselected). Genotype distributions (homozygous short [SS] or long [LL], and heterozygous) of the 4 patient categories were compared and odds ratios (ORs) for CVD were calculated using logistic regression analysis. RESULTS: Overall, the proportion of the SS genotype was lower in CVD compared with nonCVD and unspecified. The ORs for CVD was highest in patients carrying the LL genotype (OR LL vs SS, 1.769 [95% confidence interval, 1.594-1.963]). Furthermore, genotype distribution differed between Caucasian and Asian individuals, the latter having a much higher proportion of the SS genotype (22% vs 11%). CONCLUSIONS: This review of the available literature on the epidemiological association between the HO-1 (GT)n repeat polymorphism and CVD supports the presumed protective effects of HO-1. The second but probably even more relevant finding of our review is that racial disparities in HO-1 (GT)n repeat length distribution exist and might influence the associations of the genotype with CVD status. PMID- 26483092 TI - Corticosteroids and Spontaneous Coronary Artery Dissection: A New Predisposing Factor? AB - We describe the case of a 39-year-old woman with spontaneous coronary artery dissection (SCAD) of the left circumflex artery. We postulate that her SCAD was precipitated by high-dose corticosteroid use for the treatment of optic neuritis. The epidemiology and known risk factors of SCAD are reviewed with an additional focus on the effect of corticosteroids on the cardiovascular system. PMID- 26483093 TI - Frailty and Anticoagulation Prescription Rate for Atrial Fibrillation in the Elderly. PMID- 26483096 TI - Telomere length is not associated with frailty in older Chinese elderly: Cross sectional and longitudinal analysis. AB - Telomere shortening has been associated with biological age and several chronic degenerative diseases. However, less is known about telomere length and frailty, which is an indicator of biological age. This study examines the association between telomere length and frailty in a prospective study over five years of 2006 men and women aged 65 years and older living in the community. The frailty status was determined by the Fried's criteria. Telomere length in leukocytes was measured using the quantitative polymerase chain reaction. Logistic regression was used to examine the association between telomere length and incidence of frailty. Among 2006 subjects (mean age 72.4+/-5.1 years, 51.3% women), the mean telomere length at baseline was 9.1+/-2.0kb and the frailty phenotype was detected in 127 subjects (6.3%). Male gender was related to shorter telomere length, with increased years of age related to a shortened telomere length (P<0.05). In both men and women, no statistically significant difference of telomere length and the frailty phenotype was observed at baseline. After 4 years of follow-up, 116 cases of frailty were identified. There was no association between telomere length and incident frailty. In conclusion, telomere length was not associated with frailty in this study population. PMID- 26483094 TI - Diffusion-Weighted Magnetic Resonance Imaging Characterization of White Matter Injury Produced by Axon-Sparing Demyelination and Severe Contusion Spinal Cord Injury in Rats. AB - Alterations in magnetic resonance imaging (MRI)-derived measurements of water diffusion parallel (D?) and perpendicular (D?) to white matter tracts have been specifically attributed to pathology of axons and myelin, respectively. We test the hypothesis that directional diffusion measurements can distinguish between axon-sparing chemical demyelination and severe contusion spinal cord white matter injury. Adult rats received either unilateral ethidium bromide (EB) microinjections (chemical demyelination) into the lateral funiculus of the spinal cord at C5 or were subjected to unilateral severe contusion spinal cord injury (SCI). Diffusion MRI metrics in the lateral funiculus were analyzed at early and late time-points following injury and correlated with histology. Early EB demyelination resulted in a significant elevation in D? and significant reduction in D? at the injury epicenter, with histological evidence of uniform axon preservation. Alterations in D? and D? at the epicenter of early EB-demyelination were not significantly different from those observed with severe contusion at the epicenter, where histology demonstrated severe combined axonal and myelin injury. Diffusion abnormalities away from the injury epicenter were seen with contusion injury, but not with EB-demyelination. Chronic EB lesions underwent endogenous remyelination with normalization of diffusion metrics, whereas chronic contusion resulted in persistently altered diffusivities. In the early setting, directional diffusion measurements at the injury epicenter associated with chemical demyelination are indistinguishable from those seen with severe contusive SCI, despite dramatic pathologic differences between injury models. Caution is advised in interpretation of diffusion metrics with respect to specific white matter structural alterations. Diffusion analysis should not be limited to the epicenter of focal spinal lesions as alterations marginal to the epicenter are useful for assessing the nature of focal white matter injury. PMID- 26483095 TI - Health-related quality of life in patients with Duchenne muscular dystrophy: a multinational, cross-sectional study. AB - AIM: To estimate health-related quality of life (HRQOL) in patients with Duchenne muscular dystrophy (DMD). METHOD: HRQOL was assessed using the Health Utilities Index Questionnaire (HUI) and the Pediatric Quality of Life Inventory (PedsQL) neuromuscular module version 3.0 online. Results were stratified by disease stage (early/late ambulatory/non-ambulatory) and caregivers' perceptions of patients' health and mental status. RESULTS: A total of 770 patient-caregiver pairs (173 German, 122 Italian, 191 UK, and 284 USA) participated. Most caregivers (>84%) perceived their patients as happy/somewhat happy and in excellent/very good/good health, irrespective of current ambulatory class. In contrast, mean patient utility (reflecting public preferences: 0, dead; 1, perfect health) deteriorated with disease course, from 0.75 in early ambulatory males to 0.15 in the most severely affected patients. Mean patient PedsQL scores (0-100, higher score indicating better HRQOL) decreased from 80 to 57 across ambulatory classes. INTERPRETATION: HRQOL in DMD, measured through public preferences, is substantially impaired in relation to the general population and significantly associated with disease progression. Still, most patients are perceived as happy and in good health by their caregivers, indicating that influential domains of HRQOL remain intact through the disease progression. Our findings emphasize the challenges in measuring HRQOL in a rare, progressive childhood condition such as DMD. PMID- 26483097 TI - Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients: Results From the ROADMAP Study. AB - BACKGROUND: Data for left ventricular assist devices (LVADs) in patients with noninotrope-dependent heart failure (HF) are limited. OBJECTIVES: The goal of this study was to evaluate HeartMate II (HMII) LVAD support versus optimal medical management (OMM) in ambulatory New York Heart Association functional class IIIB/IV patients meeting indications for LVAD destination therapy but not dependent on intravenous inotropic support. METHODS: This was a prospective, multicenter (N = 41), observational study of 200 patients (97 LVAD, 103 OMM). Entry criteria included >=1 hospitalization for HF in the last 12 months and 6 min walk distance (6MWD) <300 m. The primary composite endpoint was survival on original therapy with improvement in 6MWD >=75 m at 12 months. RESULTS: LVAD patients were more severely ill, with more patients classified as Interagency Registry for Mechanically Assisted Circulatory Support profile 4 (65% LVAD vs. 34% OMM; p < 0.001) than 5 to 7. More LVAD patients met the primary endpoint (39% LVAD vs. 21% OMM; odds ratio: 2.4 [95% confidence interval: 1.2 to 4.8]; p = 0.012). On the basis of as-treated analysis, 12-month survival was greater for LVAD versus OMM (80 +/- 4% vs. 63 +/- 5%; p = 0.022) patients. Adverse events were higher in LVAD patients, at 1.89 events/patient-year (EPPY), primarily driven by bleeding (1.22 EPPY), than with OMM, at 0.83 EPPY, primarily driven by worsening HF (0.68 EPPY). Most patients (80% LVAD vs. 62% OMM; p < 0.001) required hospitalizations. Health-related quality of life (HRQol) and depression improved from baseline more significantly with LVADs than with OMM (Delta visual analog scale: 29 +/- 25 vs. 10 +/- 22 [p < 0.001]; Delta Patient Health Questionnaire-9: -5 +/- 7 vs. -1 +/- 5 [p < 0.001]). CONCLUSIONS: Survival with improved functional status was better with HMII LVAD compared with OMM. Despite experiencing more frequent adverse events, LVAD patients improved more in HRQol and depression. The results support HMII use in functionally limited, noninotrope dependent HF patients with poor HRQoL. (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device [LVAD] and Medical Management [ROADMAP]; NCT01452802). PMID- 26483098 TI - Benefits and Challenges of Early Introduction of Left Ventricular Assist Device Placement: A Patient-Centered Perspective. PMID- 26483100 TI - Distal and Tributary Targets: A New Branching Point for Renal Denervation? PMID- 26483099 TI - Impact of Lesion Placement on Efficacy and Safety of Catheter-Based Radiofrequency Renal Denervation. AB - BACKGROUND: Insufficient procedural efficacy has been proposed to explain nonresponse to renal denervation (RDN). OBJECTIVES: The aim of this study was to examine the impact of different patterns of lesion placements on the efficacy and consistency of catheter-based radiofrequency RDN in pigs. METHODS: The impact of increasing number of lesions versus location of RDN was investigated in a porcine model (Group 1; n = 51). The effect of treating the main artery, the branches, and the 2 combined was compared in Group 2 (n = 48). The durability of response and safety of combined treatment of the main artery plus branches was examined in Group 3 (n = 16). Renal norepinephrine (NE) tissue content and renal cortical axon density were assessed. RESULTS: Increasing the number of RF lesions (4, 8, and 12) in the main renal artery was not sufficient to yield a clear dose response relationship on NE content and axon density. In contrast, targeted treatment of the renal artery branches or distal segment of the main renal artery resulted in markedly less variability of response and significantly greater reduction of both NE and axon density than conventional treatment of only the main renal artery. Combination treatment (main artery plus branches) produced the greatest change in renal NE and axon density with the least heterogeneity. The changes were durable through 28 days post-treatment. CONCLUSIONS: These data provide the rationale for investigation of an optimized approach for RDN in future clinical studies. This may have profound implications for the clinical application of RDN, as this approach may not only achieve greater reductions in sympathetic activity but also reduce treatment effect variability. PMID- 26483102 TI - Reverse Left Ventricular Remodeling After Kidney Transplantation: Unraveling the Complex Autointoxication of Uremia. PMID- 26483101 TI - Reverse Remodeling and Prognosis Following Kidney Transplantation in Contemporary Patients With Cardiac Dysfunction. AB - BACKGROUND: Cardiac dysfunction influences candidate selection for kidney transplantation. There is a paucity of data regarding predictors of myocardial recovery following kidney transplantation and long-term outcomes. OBJECTIVES: The purpose of this study was to identify the extent of reverse remodeling in our kidney transplant population and the predictors of such changes, and to assess outcomes in these patients. METHODS: We reviewed 232 patients who underwent kidney transplantation at the Cleveland Clinic from 2003 to 2013 and who had baseline and post-transplant echocardiograms; patients with simultaneous heart transplantation were excluded. RESULTS: Post-transplantation mean left ventricular ejection fraction (LVEF) improved in those with LV dysfunction (increased from 41% to 50%; p < 0.0001; n = 66). There was significant improvement in other parameters, including diastolic function, LV end-diastolic dimension, LV mass, and right ventricular systolic pressure. After adjusting for multiple clinical variables, increased hemoglobin following transplantation was associated with an improved LVEF (odds ratio: 1.50; 95% confidence interval [CI]: 1.07 to 2.14; p = 0.016) and reduced mortality (hazard ratio [HR]: 0.65; 95% CI: 0.49 to 0.87; p = 0.004). An improved LVEF >=10% predicted survival independently of a pre-transplantation LVEF (HR: 0.46; 95% CI: 0.21 to 0.93; p = 0.031). CONCLUSIONS: Kidney transplantation is associated with improved cardiac structure and function. A rise in post-transplantation hemoglobin was a significant factor associated with such changes, in addition to conferring a survival advantage. PMID- 26483104 TI - Haptoglobin 2-2 Genotyping for Refining Standard Cardiovascular Risk Assessment: A Promising Proposition in Need of Validation. PMID- 26483103 TI - The Risk of Coronary Heart Disease Associated With Glycosylated Hemoglobin of 6.5% or Greater Is Pronounced in the Haptoglobin 2-2 Genotype. AB - BACKGROUND: Research targeting glycosylated hemoglobin A1c (HbA1c) to <6.5% to prevent coronary heart disease (CHD) events has conflicting results. We previously observed the haptoglobin (Hp) Hp2-2 genotype is associated with a ~10 fold increased CHD risk among individuals with HbA1c >=6.5%, and thus might be useful in identifying those at high risk of CHD who would benefit from maintaining HbA1c <6.5%. OBJECTIVES: This study sought to model whether HbA1c >= 6.5% in the Hp2-2 genotype is associated with CHD in a prospective case-control study nested within the Health Professionals Follow-Up Study (HPFS). METHODS: HbA1c concentration and Hp genotype were determined for 695 incident cases of CHD from 1994 to 2010 and matched control participants. Logistic regression models calculated relative risk (RR) and 95% CI, for the first and second halves of follow-up, adjusting for confounding variables. A dataset from the Nurses' Health Study served as a replication cohort. RESULTS: The prevalence of the Hp2-2 genotype in HPFS was 39%. Compared with HbA1c <6.5%, the RR of CHD for HbA1c >=6.5% for the Hp2-2 genotype over full follow-up was 3.07 (95% CI: 1.37 to 6.86) to 3.88 (95% CI: 1.31 to 11.52) during the first half of follow-up and 2.16 (95% CI: 0.61 to 7.61) in the second half. The corresponding RRs for the Hp1-1 + Hp2-1 genotypes were: full follow-up, 2.19 (95% CI: 1.14 to 4.24); first half, 1.60 (95% CI: 0.73 to 3.53); and second half, 4.72 (95% CI: 1.26 to 17.65). CONCLUSIONS: In 2 independent cohorts, the risk of CHD associated with HbA1c >=6.5% is pronounced in the Hp2-2 genotype, particularly in early cases. The Hp2 2 genotype may identify individuals at greatest CHD risk from hyperglycemia. PMID- 26483106 TI - Team-Based Care and Quality: A Move Toward Evidence-Based Policy. PMID- 26483105 TI - Provider Type and Quality of Outpatient Cardiovascular Disease Care: Insights From the NCDR PINNACLE Registry. AB - BACKGROUND: The current number of physicians will not be sufficient to accommodate 30 to 40 million Americans expected to secure health coverage with Affordable Care Act implementation. One proposed solution is to use advanced practice providers (APPs) (nurse practitioners and physician assistants). OBJECTIVES: This study sought to determine whether there were clinically meaningful differences in the quality of care delivered by APPs versus physicians in a national sample of cardiology practices. METHODS: Within the American College of Cardiology's PINNACLE Registry, we compared quality of coronary artery disease (CAD), heart failure, and atrial fibrillation care delivered by physicians and APPs for outpatient visits between January 1, 2012, and December 31, 2012. We performed hierarchical regression adjusting for provider sex; panel size; duration of participation in registry; and patient's age, sex, insurance, number of outpatient visits, history of hypertension, diabetes, myocardial infarction, and percutaneous coronary intervention or coronary artery bypass grafting in the preceding 12 months. RESULTS: We included 883 providers (716 physicians and 167 APPs) in 41 practices who cared for 459,669 patients. Mean number of patients seen by APPs (260.7) was lower compared with that seen by physicians (581.2). Compliance with most CAD, heart failure, and atrial fibrillation measures was comparable, except for a higher rate of smoking cessation screening and intervention (adjusted rate ratio: 1.14; 95% confidence interval: 1.03 to 1.26) and cardiac rehabilitation referral (rate ratio: 1.40; 95% confidence interval: 1.16 to 1.70) among CAD patients receiving care from APPs. Compliance with all eligible CAD measures was low for both (12.1% and 12.2% for APPs and physicians, respectively) with no significant difference. Results were consistent when comparing practices with both physicians and APPs (n = 41) and physician-only practices (n = 49). CONCLUSIONS: Apart from minor differences, a collaborative care delivery model, using both physicians and APPs, may deliver an overall comparable quality of outpatient cardiovascular care compared with a physician-only model. PMID- 26483107 TI - National Institutes of Health Career Development Awards for Cardiovascular Physician-Scientists: Recent Trends and Strategies for Success. AB - Nurturing the development of cardiovascular physician-scientist investigators is critical for sustained progress in cardiovascular science and improving human health. The transition from an inexperienced trainee to an independent physician scientist is a multifaceted process requiring a sustained commitment from the trainee, mentors, and institution. A cornerstone of this training process is a career development (K) award from the National Institutes of Health (NIH). These awards generally require 75% of the awardee's professional effort devoted to research aims and diverse career development activities carried out in a mentored environment over a 5-year period. We report on recent success rates for obtaining NIH K awards, provide strategies for preparing a successful application and navigating the early career period for aspiring cardiovascular investigators, and offer cardiovascular division leadership perspectives regarding K awards in the current era. Our objective is to offer practical advice that will equip trainees considering an investigator path for success. PMID- 26483108 TI - Next Steps in Primary Prevention of Coronary Heart Disease: Rationale for and Design of the ECAD Trial. AB - Atherosclerotic cardiovascular disease (ASCVD) events, including coronary heart disease and stroke, are the most frequent cause of death and major disability in the world. Current American College of Cardiology/American Heart Association primary prevention guidelines are mainly on the basis of randomized controlled trials of statin-based low-density lipoprotein cholesterol (LDL-C)-lowering therapy for primary prevention of ASCVD events. Despite the clear demonstration of statin-based LDL-C lowering, substantial 10-year and lifetime risks of incident ASCVD continue. Although the 10-year risk is low in young and middle aged adults who would not be treated according to current guidelines, they ultimately account for most incident ASCVD. If statin-based LDL-C lowering were initiated in them at an age before complex coronary plaques are common in the population, a substantial reduction in lifetime risk of incident coronary heart disease might be achieved. We examine this hypothesis and introduce the design of a currently recruiting trial to address it. (Eliminate Coronary Artery Disease [ECAD]; NCT02245087). PMID- 26483109 TI - Health Care in Transition: Primary Prevention and Health Disparities in Focus. PMID- 26483110 TI - Academic Practice Plans for Early Career Clinician Investigators: The Fourth Pillar of Success. PMID- 26483111 TI - Deceleration of Age-Related Aortic Stiffening in a Population With High Longevity Rates: The IKARIA Study. PMID- 26483112 TI - Clinical Relevance of Exaggerated Exercise Blood Pressure. PMID- 26483113 TI - What Is the True Prevalence of Hypertrophic Cardiomyopathy? PMID- 26483114 TI - Reply: What Is the True Prevalence of Hypertrophic Cardiomyopathy? PMID- 26483115 TI - Reply: Hospitalizations for Endocarditis in the United States. PMID- 26483116 TI - Hospitalizations for Endocarditis in the United States. PMID- 26483117 TI - How to Control Residual Risk During the Statin Era? PMID- 26483118 TI - A Unique Plasmodium falciparum K13 Gene Mutation in Northwest Ethiopia. AB - Artemisinin combination therapy (ACT) is the first line to treat uncomplicated Plasmodium falciparum malaria worldwide. Artemisinin treatment failures are on the rise in southeast Asia. Delayed parasite clearance after ACT is associated with mutations of the P. falciparum kelch 13 gene. Patients (N = 148) in five districts of northwest Ethiopia were enrolled in a 28-day ACT trial. We identified a unique kelch 13 mutation (R622I) in 3/125 (2.4%) samples. The three isolates with R622I were from Negade-Bahir and Aykel districts close to the Ethiopia-Sudan border. One of three patients with the mutant strain was parasitemic at day 3; however, all patients cleared parasites by day 28. Correlation between kelch 13 mutations and parasite clearance was not possible due to the low frequency of mutations in this study. PMID- 26483119 TI - Sustained Presence of Cutaneous Leishmaniasis in Urban Manaus, the Largest Human Settlement in the Amazon. AB - The Amazon is responsible for approximately 40% of the American tegumentary leishmaniasis (ATL) in Brazil. Herein the sustained presence of ATL in Manaus, the largest settlement in the Amazon, was investigated. Records of notification of historic cases, and data from cases prospectively enrolled in the Tropical Medicine Foundation of the Amazonas State were used. Geographic coordinates of prospective patients' living sites were used to detect inner-city clusters of ATL. Infecting Leishmania species was determined by polymerase chain reaction. Among prospectively enrolled subjects, 94.8% were infected with Leishmania (Viannia) guyanensis, 76.7% were male, 30.2% were 0-20 years old, and 69.8% had an urban residence. Historic cases showed a profile similar to that of prospectively enrolled subjects. Several clusters of ATL, widely distributed within the city of Manaus, could be detected. In conclusion, there was a high frequency of disease in young age groups and cases clustered in urban neighborhoods. It cannot be determined from these data whether transmission of these cases occurred within or outside the city of Manaus. PMID- 26483120 TI - Efficacy and Safety of Liposomal Amphotericin B for the Treatment of Mucosal Leishmaniasis from the New World: A Retrospective Study. AB - The standard treatment of mucosal leishmaniasis (ML) is pentavalent antimonials, agents with serious adverse effects. Alternative agents include amphotericin B deoxycholate and liposomal amphotericin B. We performed a retrospective study including 29 patients treated with liposomal amphotericin B, most of whom had comorbidities, history of previous treatment of ML, and contraindications to the use of antimonial pentavalent or amphotericin B deoxycholate. We observed a cure rate of 93.1%. Kidney failure was the most important side effect, reported in five patients (17.2%). This study showed a good efficacy and safety profile of liposomal amphotericin B in patients with ML and contraindications to the use of other agents. PMID- 26483121 TI - Molecular Investigation into a Malaria Outbreak in Cusco, Peru: Plasmodium falciparum BV1 Lineage is Linked to a Second Outbreak in Recent Times. AB - In November 2013, a Plasmodium falciparum malaria outbreak of 11 cases occurred in Cusco, southern Peru, where falciparum malaria had not been reported since 1946. Although initial microscopic diagnosis reported only Plasmodium vivax infection in each of the specimens, subsequent examination by the national reference laboratory confirmed P. falciparum infection in all samples. Molecular typing of four available isolates revealed identity as the B-variant (BV1) strain that was responsible for a malaria outbreak in Tumbes, northern Peru, between 2010 and 2012. The P. falciparum BV1 strain is multidrug resistant, can escape detection by PfHRP2-based rapid diagnostic tests, and has contributed to two malaria outbreaks in Peru. This investigation highlights the importance of accurate species diagnosis given the potential for P. falciparum to be reintroduced to regions where it may have been absent. Similar molecular epidemiological investigations can track the probable source(s) of outbreak parasite strains for malaria surveillance and control purposes. PMID- 26483123 TI - Successful Global Health Research Partnerships: What Makes Them Work? AB - There are many successful global health research partnerships, but little information is available about what makes them successful. We asked 14 research colleagues from Uganda, Kenya, and the United States who have extensive global health research experience about what they considered the top three factors that led to or impeded successful international research collaborations. Four key factors were identified: 1) mutual respect and benefit, 2) trust, 3) good communication, and 4) clear partner roles and expectations. Initial and ongoing assessment of these factors in global health research partnerships may prevent misunderstandings and foster a collaborative environment that leads to successful research. PMID- 26483122 TI - Quantitative Kinetoplast DNA Assessment During Treatment of Mucosal Leishmaniasis as a Potential Biomarker of Outcome: A Pilot Study. AB - Mucosal leishmaniasis (ML) is a disfiguring manifestation of Leishmania (Viannia) infection. We evaluated parasite load (PL) over time as a potential biomarker of treatment outcome in ML. PL was assessed with kinetoplast DNA quantitative real time polymerase chain reaction (kDNA-qPCR) at enrollment, days 14 and 21-28 of therapy and 3, 6, 12-18, and 18-24 months after treatment of ML and correlated to demographic, clinical, and parasitologic factors. Forty-four patients were enrolled: 30 men and 14 women. Enrollment PL differed significantly by causative species (P < 0.001), and was higher in patients with severe ML (nasal and laryngeal involvement) compared with those with only isolated nasal involvement (median = 1,285 versus 51.5 parasites/MUg tissue DNA; P = 0.005). Two patterns of PL emerged: pattern 1 (N = 23) was characterized by a sequential decline in PL during and after therapy until kDNA was undetectable. Pattern 2 (N = 18) was characterized by clearance of detectable kDNA during treatment, followed by an increased PL thereafter. All patients who failed treatment (N = 4) demonstrated pattern 1. Leishmania (Viannia) braziliensis was overrepresented among those with pattern 2 (P = 0.019). PL can be quantified by cytology brush qPCR during and after treatment in ML. We demonstrate that treatment failure was associated with undetectable PL, and L. (V.) braziliensis infection was overrepresented in those with rebounding PL. PMID- 26483124 TI - A Potential Role for Mononuclear Phagocytes in Cutaneous Ulcer Development in Human Immunodeficiency Virus-Leishmania braziliensis Coinfection. AB - Skin ulcer development in cutaneous leishmaniasis due to Leishmania braziliensis infection is associated with a mononuclear cell infiltrate and high levels of tumor necrosis factor (TNF). Herein, we show that despite the absence of Leishmania-driven TNF, a cutaneous leishmaniasis patient with acquired immunodeficiency syndrome developed a skin ulcer. The presence of mononuclear phagocytes and high levels of TNF, chemokine (C-C motif) ligand 2 (CCL2), and metalloproteinase-9 in tissue are identified as potential contributors to immunopathology observed in L. braziliensis-infected patients. PMID- 26483125 TI - Malaria Prevention Strategies: Adherence Among Boston Area Travelers Visiting Malaria-Endemic Countries. AB - We conducted a prospective cohort study to assess adherence to malaria chemoprophylaxis, reasons for nonadherence, and use of other personal protective measures against malaria. We included adults traveling to malaria-endemic countries who were prescribed malaria chemoprophylaxis during a pre-travel consultation at three travel clinics in the Boston area and who completed three or more surveys: pre-travel, at least one weekly during travel, and post-travel (2-4 weeks after return). Of 370 participants, 335 (91%) took malaria chemoprophylaxis at least once and reported any missed doses; 265 (79%) reported completing all doses during travel. Adherence was not affected by weekly versus daily chemoprophylaxis, travel purpose, or duration of travel. Reasons for nonadherence included forgetfulness, side effects, and not seeing mosquitoes. Main reasons for declining to take prescribed chemoprophylaxis were peer advice, low perceived risk, and not seeing mosquitoes. Of 368 travelers, 79% used insect repellent, 46% used a bed net, and 61% slept in air conditioning at least once. Because travelers may be persuaded to stop taking medication by peer pressure, not seeing mosquitoes, and adverse reactions to medications, clinicians should be prepared to address these barriers and to empower travelers with strategies to manage common side effects of antimalarial medications. PMID- 26483126 TI - Characteristics of Travel-Related Severe Plasmodium vivax and Plasmodium falciparum Malaria in Individuals Hospitalized at a Tertiary Referral Center in Lima, Peru. AB - Severe Plasmodium falciparum malaria is uncommon in South America. Lima, Peru, while not endemic for malaria, is home to specialized centers for infectious diseases that admit and manage patients with severe malaria (SM), all of whom contracted infection during travel. This retrospective study describes severe travel-related malaria in individuals admitted to one tertiary care referral hospital in Lima, Peru; severity was classified based on criteria published by the World Health Organization in 2000. Data were abstracted from medical records of patients with SM admitted to Hospital Nacional Cayetano Heredia from 2006 to 2011. Of 33 SM cases with complete clinical data, the mean age was 39 years and the male/female ratio was 2.8. Most cases were contracted in known endemic regions within Peru: Amazonia (47%), the central jungle (18%), and the northern coast (12%); cases were also found in five (15%) travelers returning from Africa. Plasmodium vivax was most commonly identified (71%) among the severe infections, followed by P. falciparum (18%); mixed infections composed 11% of the group. Among the criteria of severity, jaundice was most common (58%), followed by severe thrombocytopenia (47%), hyperpyrexia (32%), and shock (15%). Plasmodium vivax mono-infection predominated as the etiology of SM in cases acquired in Peru. PMID- 26483127 TI - Rates of safety incident reporting in MRI in a large academic medical center. AB - PURPOSE: To describe our multiyear experience in incident reporting related to magnetic resonance imaging (MRI) in a large academic medical center. MATERIALS AND METHODS: This was an Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant study. Incident report data were collected during the study period from April 2006 to September 2012. The incident reports filed during the study period were searched for all reports related to MRI. Incident reports were classified with regard to the patient type (inpatient vs. outpatient), primary reason for the incident report, and the severity of patient harm resulting from the incident. RESULTS: A total of 362,090 MRI exams were performed during the study period, resulting in 1290 MRI related incident reports. The rate of incident reporting was 0.35% (1290/362,090). MRI-related incident reporting was significantly higher in inpatients compared to outpatients (0.74% [369/49,801] vs. 0.29% [921/312,288], P < 0.001). The most common reason for incident reporting was diagnostic test orders (31.5%, 406/1290), followed by adverse drug reactions (19.1%, 247/1290) and medication/IV safety (14.3%, 185/1290). Approximately 39.6% (509/1290) of reports were associated with no patient harm and did not affect the patient, followed by no patient harm but did affect the patient (35.8%, 460/1290), temporary or minor patient harm (23.9%, 307/1290), permanent or major patient harm (0.6%, 8/1290) and patient death (0.2%, 2/1290). CONCLUSION: MRI-related incident reports are relatively infrequent, occur at significantly higher rates in inpatients, and usually do not result in patient harm. Diagnostic test orders, adverse drug reactions, and medication/IV safety were the most frequent safety incidents. PMID- 26483128 TI - Performance of glycated hemoglobin (HbA(1c)) methods evaluated with EQAS studies using fresh blood samples: Still space for improvements. AB - BACKGROUND: The determination of glycated hemoglobin is a key indicator for the management of diabetic patients. A reference measurement system for its determination is available and IVD manufacturers should have aligned their assay to this system. METHODS: Two fresh blood samples were distributed by courier to 206 Italian laboratories asking for the determination of their HbA1c concentration. Target HbA1c values were assigned by the IFCC reference measurement procedure. RESULTS: From 193 laboratories using analytical systems from five manufacturers (Bio-Rad Laboratories, A. Menarini Diagnostics, Roche Diagnostics, Sebia and Tosoh), we obtained a global variability of 5.3% (in terms of CV) and of 3.8% at an HbA1c value of 37.4 mmol/mol (sample 1) and 62.0 mmol/mol (sample 2), respectively. With a goal for the allowable total error (TE) of 6.0%, 70% and 77% of the participants met this criterion for samples 1 and 2, respectively. Inter-laboratory CVs, were between 3.3 and 5.0% and between 2.2 and 3.7% for samples 1 and 2, respectively. Tosoh users registered the smallest inter laboratory CV in sample 1, and Sebia's in sample 2. With regard to trueness, all methods had a mean bias of <= 2.8% with respect to the target values, with the exception of Tosoh (bias of + 6.1 and + 5.8%, for samples 1 and 2, respectively). CONCLUSION: These results are in good agreement with those obtained by the CAP 2014 GH2-A survey, suggesting then that still there is an urgent need for improving a significant part of the methods currently used to measure HbA1c. PMID- 26483129 TI - Analytical and clinical evaluation of a rapid quantitative lateral flow immunoassay for measurement of soluble ST2 in human plasma. AB - BACKGROUND: Soluble ST2 (sST2) is gaining growing interest as a biomarker in heart failure. So far, the ELISA-format is widely used for commercially available ST2 assays, which hampers their use in clinical routine. Recently, a rapid quantitative lateral flow immunoassay for the measurement of sST2 in human plasma has been developed. METHODS: We evaluated precision and linearity of the ASPECT PLUS ST2 test, and performed an analytical and clinical assay comparison with the MBL and the PRESAGE ST2 ELISAs. We measured sST2 with these three assays in a clinical cohort of 251 consecutive patients with acute dyspnea as the chief compliant (i.e., 137 patients with dyspnea attributable to heart failure and 114 patients with dyspnea attributable to other reasons). RESULTS: Within-run and total coefficients of variation of the ASPECT-PLUS ST2 test were < 17% and the assay was linear across its measurement range. We found a constant and proportional bias between the MBL ST2 assay, the PRESAGE ST2 assay and the ASPECT PLUS ST2 test, respectively. However, at the proposed cut-off of 35 ng/mL, sST2 results obtained with the PRESAGE ST2 assay and the ASPECT-PLUS ST2 test were similar. Testing clinically, the three assays deemed equally useful for the diagnosis of heart failure (AUC, 0.670 for the MBL ST2 assay vs. 0.626 for the PRESAGE ST2 assay vs. 0.630 for the ASPECT-PLUS ST2 test) and for the prediction of 1-year mortality in dyspnoeic patients (AUC, 0.743 for the MBL assay vs. 0.742 for the PRESAGE ST2 assay vs. 0.752 for the ASPECT-PLUS ST2 test). CONCLUSION: The ASPECT-PLUS test meets the analytical requirements for point-of-care testing. Test results of the ASPECT-PLUS ST2 and the PRESAGE ST2 methods were comparable at the proposed cut-off, and the diagnostic/prognostic capabilities of the three methods were similar. PMID- 26483130 TI - Serum MiRNA panel as potential biomarkers for chronic hepatitis B with persistently normal alanine aminotransferase. AB - BACKGROUND: Circulating miRNAs, a family of miRNAs existing in plasma and serum, have a great potential to serve as novel biomarkers in body fluids for non invasive diagnosis and prognosis of many diseases. METHODS: A multistage, case control study was designed to establish a panel of serum miRNAs that could be surrogate markers for chronic hepatitis B with persistently normal alanine aminotransferase (ALT). A total of 295 CHB patients presenting persistently normal ALT levels with significant histological features (SPNALT group), 243 CHB patients presenting persistently normal ALT levels with no significant histological features (NSPNALT group), and 178 healthy controls (healthy group) were enrolled in the study. An initial screening of miRNAs was performed by Illumina sequencing using serum samples pooled from SPNALT patients and controls. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) assay was performed to evaluate the expression of selected miRNAs. A logistic regression model was constructed using a training cohort (n=380) and validated using a cohort (n=258). The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. RESULTS: We identified 9 miRNAs (hsa miR-885-5p, hsa-miR-122-5p, hsa-miR-10a-5p, hsa-miR-511-5p, hsa-miR-574-5p, hsa miR-98-5p, hsa-miR-26a-5p, hsa-miR-192-5p, hsa-miR-30b-5p) and established 3 miRNA panels that provided high diagnostic accuracy for SPNALT. The AUC of miRNA panels for SPNALT vs. healthy was 0.882 (95% CI=0.839 to 0.925), for SPNALT vs. NSPNALT was 0.894 (95% CI=0.857 to 0.930), and for SPNALT vs. control was 0.860 (95% CI=0.821 to 0.899). CONCLUSIONS: We constructed serum miRNA panels with considerable clinical value in diagnosing PNALT. PMID- 26483131 TI - Increased health service use for allergy in adults: Northumbrian hospital episodes, 2010-2015. AB - BACKGROUND: Little is known on the health service use for allergy. Therefore, the aim of this study was to investigate the hospital episode rates in allergy by sex and across age groups in order to understand whether and how the health service use for allergy might have changed in recent years in north-east of England. METHODS: Hospital episode data in mid-2010 to mid-2015 covering five full calendar years were extracted from Northumbria Healthcare NHS Foundation Trust, which is serving nearly half of a million population and free from central government control. Hospital episode rates were calculated from all admissions divided by annual and area-specific population size for each sex and age group, presented with per 100 000 person-years using Microsoft Excel. RESULTS: Health service use for allergy in adults for both men and women has increased, with large increases in young adults aged 40-49 (both male and female), 50-59 (female) and 60-69 (male). In children, there were decreases in those aged 0-9, but increases in those aged 10-19. Emergency admissions due to allergy were only minimal. Higher admissions were observed in spring and autumn than in summer and winter. CONCLUSION: Allergy admissions have increased in adults. For future research, local health policy could benefit from annual clinical records on health service use due to allergy. For clinical practice, in addition to increasing and improving the role of health and nursing professionals to reduce burden and rehabilitation, public awareness, attitude and knowledge should be continuously raised and improved as well. PMID- 26483134 TI - Pontemazines A and B, phenazine derivatives containing a methylamine linkage from Streptomyces sp. UT1123 and their protective effect to HT-22 neuronal cells. AB - New phenazine derivatives with a methylamine linker, Pontemazines A (1) and B (2), were isolated from the culture broth of Streptomyces sp. UT1123. The structures of compounds 1 and 2 were determined by NMR spectroscopy and high resolution mass spectrometry. These compounds consist of a 9-mehoxyphenazine connected to a benzamide functional group by a unique methylamine linker instead of the more common methyl ether. Pontemazines A and B possess a neuronal cell protective effect on glutamate-induced mouse hippocampal HT-22 cell damage. PMID- 26483135 TI - Inhibitory effects of compounds from Styrax obassia on NO production. AB - Two new benzofurans, 2-(3,4-dimethoxyphenyl)-5-(1,3-dihydroxypropyl)-7 methoxybenzofuran (1) and 2-(3,4-methylenedioxyphenyl)-5-(3-hydroxymethyletoxy-1 hydroxypropyl)-7-methoxybenzofuran (2), a new triterpene, 3beta, 6beta, 21beta trihydroxyolean-12-ene (3), and eleven known compounds were isolated from the stem bark of Styrax obassia. The structures of the isolated compounds were established by extensive spectroscopic analyses, including 1D and 2D NMR and HRMS. Their anti-inflammatory activities were evaluated against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages. Compound 1 was shown to reduce LPS-induced iNOS expression in a dose dependent manner. In addition, pretreating cells with 1 significantly suppressed their LPS-induced expression of COX-2 protein. PMID- 26483133 TI - The contribution of white matter lesions to Parkinson's disease motor and gait symptoms: a critical review of the literature. AB - White matter lesions (WML) associated with cerebrovascular disease (CVD) may be observed on magnetic resonance imaging in Parkinson's disease (PD) patients. WML are an important factor contributing to postural, gait, and cognitive impairment in the elderly without PD and worsening the course of Alzheimer's disease (AD). Numerous articles are available on this topic. Whether WML modify and negatively influence the clinical symptoms, and course of PD is a subject of debate. The aim of this review is to examine the available literature on the contribution of WML to PD motor symptoms in relation to clinical characteristics and methods of assessing WML on MRI. After reviewing the database, we identified 19 studies reporting the relationship between WML and PD; ten studies focusing on the impact of WML on the cognitive status in PD were excluded. We analysed altogether nine studies reporting the relationship between WML and motor signs of PD. The review found association between WML severity and freezing of gait, less significant to responsiveness to dopaminergic treatment and postural instability; no negative impact on tremor and falls was observed. The impact of WML on bradykinesia and rigidity was inconsistent. Comorbid WML is associated with worsening axial motor performance, probably independently from the degree of nigrostriatal dopaminergic denervation in PD. Reducing the vascular risk factors that cause WML may be helpful in preventing the development of axial symptoms and ultimately in improving the quality of life of patients with PD. Given the lack of systematic studies, additional research in this field is needed. PMID- 26483136 TI - Constituents of the seeds of Cassia tora with inhibitory activity on soluble expoxide hydrolease. AB - Efforts to extract soluble epoxide hydrolase (sEH) inhibitors from food sources through bioactivity-guided fractionation of Cassia tora seed extracts led to the isolation of one new compound, 1, and 15 known compounds, 2-16. Structural elucidations were performed using 1D/2D NMR spectroscopy and mass spectrometry. Compounds 1, 3, 4, 6, 10, 11, and 13-16 exhibited inhibitory activities on sEH with IC50 values of 2.2+/-2.1-40.6+/-3.4 MUM. Compound 13 was particularly active and exhibited a reversible-uncompetitive behavior in enzyme kinetic studies. A binding site on the enzyme for compound 13 was also predicted by Autodock 4.2 simulations. PMID- 26483132 TI - Redox regulation of vascular remodeling. AB - Vascular remodeling is a dynamic process of structural and functional changes in response to biochemical and biomechanical signals in a complex in vivo milieu. While inherently adaptive, dysregulation leads to maladaptive remodeling. Reactive oxygen species participate in homeostatic cell signaling in tightly regulated- and compartmentalized cellular circuits. It is well established that perturbations in oxidation-reduction (redox) homeostasis can lead to a state of oxidative-, and more recently, reductive stress. We provide an overview of the redox signaling in the vasculature and review the role of oxidative- and reductive stress in maladaptive vascular remodeling. Particular emphasis has been placed on essential processes that determine phenotype modulation, migration and fate of the main cell types in the vessel wall. Recent advances in systems biology and the translational opportunities they may provide to specifically target the redox pathways driving pathological vascular remodeling are discussed. PMID- 26483138 TI - Answer to letters of Vilallonga and Manenti on management of gastric fistula after sleeve gastrectomy. PMID- 26483137 TI - Chemical conjugation of 2-hexadecynoic acid to C5-curcumin enhances its antibacterial activity against multi-drug resistant bacteria. AB - The first total synthesis of a C5-curcumin-2-hexadecynoic acid (C5-Curc-2-HDA, 6) conjugate was successfully performed. Through a three-step synthetic route, conjugate 6 was obtained in 13% overall yield and tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Our results revealed that 6 was active against eight MRSA strains at MICs that range between 31.3 and 62.5 MUg/mL. It was found that the presence of 2-hexadecynoic acid (2-HDA, 4) in conjugate 6 increased 4-8-fold its antibacterial activity against MRSA strains supporting our hypothesis that the chemical connection of 4 to C5-curcumin (2) increases the antibacterial activity of 2 against Gram positive bacteria. Combinational index (CIn) values that range between 1.6 and 2.3 were obtained when eight MRSA strains were treated with an equimolar mixture of 2 and 4. These results demonstrated that an antagonistic effect is taking place. Finally, it was investigated whether conjugate 6 can affect the replication process of S. aureus, since this compound inhibited the supercoiling activity of the S. aureus DNA gyrase at minimum inhibitory concentrations (MIC) of 250 MUg/mL (IC50=100.2+/-13.9 MUg/mL). Moreover, it was observed that the presence of 4 in conjugate 6 improves the anti-topoisomerase activity of 2 towards S. aureus DNA gyrase, which is in agreement with results obtained from antibacterial susceptibility tests involving MRSA strains. PMID- 26483139 TI - Agreement and reliability of pelvic floor measurements during rest and on maximum Valsalva maneuver using three-dimensional translabial ultrasound and virtual reality imaging. AB - OBJECTIVES: Imaging of the levator ani hiatus provides valuable information for the diagnosis and follow-up of patients with pelvic organ prolapse (POP). This study compared measurements of levator ani hiatal volume during rest and on maximum Valsalva, obtained using conventional three-dimensional (3D) translabial ultrasound and virtual reality imaging. Our objectives were to establish their agreement and reliability, and their relationship with prolapse symptoms and POP quantification (POP-Q) stage. METHODS: One hundred women with an intact levator ani were selected from our tertiary clinic database. Information on clinical symptoms were obtained using standardized questionnaires. Ultrasound datasets were analyzed using a rendered volume with a slice thickness of 1.5 cm, at the level of minimal hiatal dimensions, during rest and on maximum Valsalva. The levator area (in cm(2) ) was measured and multiplied by 1.5 to obtain the levator ani hiatal volume (in cm(3) ) on conventional 3D ultrasound. Levator ani hiatal volume (in cm(3) ) was measured semi-automatically by virtual reality imaging using a segmentation algorithm. Twenty patients were chosen randomly to analyze intra- and interobserver agreement. RESULTS: The mean difference between levator hiatal volume measurements on 3D ultrasound and by virtual reality was 1.52 cm(3) (95% CI, 1.00-2.04 cm(3) ) at rest and 1.16 cm(3) (95% CI, 0.56-1.76 cm(3) ) during maximum Valsalva (P < 0.001). Both intra- and interobserver intraclass correlation coefficients were >= 0.96 for conventional 3D ultrasound and > 0.99 for virtual reality. Patients with prolapse symptoms or POP-Q Stage >= 2 had significantly larger hiatal measurements than those without symptoms or POP-Q Stage < 2. CONCLUSIONS: Levator ani hiatal volume at rest and on maximum Valsalva is significantly smaller when using virtual reality compared with conventional 3D ultrasound; however, this difference does not seem clinically important. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26483140 TI - Anthropogenic areas as incidental substitutes for original habitat. AB - One speaks of ecological substitutes when an introduced species performs, to some extent, the ecosystem function of an extirpated native species. We suggest that a similar case exists for habitats. Species evolve within ecosystems, but habitats can be destroyed or modified by natural and human-made causes. Sometimes habitat alteration forces animals to move to or remain in a suboptimal habitat type. In that case, the habitat is considered a refuge, and the species is called a refugee. Typically refugee species have lower population growth rates than in their original habitats. Human action may lead to the unintended generation of artificial or semiartificial habitat types that functionally resemble the essential features of the original habitat and thus allow a population growth rate of the same magnitude or higher than in the original habitat. We call such areas substitution habitats and define them as human-made habitats within the focal species range that by chance are partial substitutes for the species' original habitat. We call species occupying a substitution habitat adopted species. These are 2 new terms in conservation biology. Examples of substitution habitats are dams for European otters, wheat and rice fields for many steppeland and aquatic birds, and urban areas for storks, falcons, and swifts. Although substitution habitats can bring about increased resilience against the agents of global change, the conservation of original habitat types remains a conservation priority. PMID- 26483141 TI - Ag-NP@Ge-nanotaper/Si-micropillar ordered arrays as ultrasensitive and uniform surface enhanced Raman scattering substrates. AB - Surface-enhanced Raman scattering (SERS) is considered to be an excellent candidate for analytical detection schemes, because of its molecular specificity, rapid response and high sensitivity. Here, SERS-substrates of Ag-nanoparticle (Ag NP) decorated Ge-nanotapers grafted on hexagonally ordered Si-micropillar (denoted as Ag-NP@Ge-nanotaper/Si-micropillar) arrays are fabricated via a combinatorial process of two-step etching to achieve hexagonal Si-micropillar arrays, chemical vapor deposition of flocky Ge-nanotapers on each Si-micropillar and decoration of Ag-NPs onto the Ge-nanotapers through galvanic displacement. With high density three-dimensional (3D) "hot spots" created from the large quantities of the neighboring Ag-NPs and large-scale uniform morphology, the hierarchical Ag-NP@Ge-nanotaper/Si-micropillar arrays exhibit strong and reproducible SERS activity. Using our hierarchical 3D SERS-substrates, both methyl parathion (a commonly used pesticide) and PCB-2 (one congener of highly toxic polychlorinated biphenyls) with concentrations down to 10(-7) M and 10(-5) M have been detected respectively, showing great potential in SERS-based rapid trace-level detection of toxic organic pollutants in the environment. PMID- 26483142 TI - Integrating mRNA and Protein Sequencing Enables the Detection and Quantitative Profiling of Natural Protein Sequence Variants of Populus trichocarpa. AB - Next-generation sequencing has transformed the ability to link genotypes to phenotypes and facilitates the dissection of genetic contribution to complex traits. However, it is challenging to link genetic variants with the perturbed functional effects on proteins encoded by such genes. Here we show how RNA sequencing can be exploited to construct genotype-specific protein sequence databases to assess natural variation in proteins, providing information about the molecular toolbox driving cellular processes. For this study, we used two natural genotypes selected from a recent genome-wide association study of Populus trichocarpa, an obligate outcrosser with tremendous phenotypic variation across the natural population. This strategy allowed us to comprehensively catalogue proteins containing single amino acid polymorphisms (SAAPs), as well as insertions and deletions. We profiled the frequency of 128 types of naturally occurring amino acid substitutions, including both expected (neutral) and unexpected (non-neutral) SAAPs, with a subset occurring in regions of the genome having strong polymorphism patterns consistent with recent positive and/or divergent selection. By zeroing in on the molecular signatures of these important regions that might have previously been uncharacterized, we now provide a high resolution molecular inventory that should improve accessibility and subsequent identification of natural protein variants in future genotype-to-phenotype studies. PMID- 26483143 TI - ANGPTL-4 correlates with vascular endothelial growth factor in patients with proliferative diabetic retinopathy. AB - PURPOSE: To investigate the relationship between angiopoietin-like protein 4 (ANGPTL-4) and vascular endothelial growth factor (VEGF) in the serum and vitreous of eyes in patients with proliferative diabetic retinopathy (PDR). METHODS: Thirty-five eyes of 35 patients with PDR, 20 eyes of 20 patients with non-proliferative diabetic retinopathy, 20 eyes of 20 patients with diabetes but no diabetic retinopathy, and 14 eyes of 14 nondiabetic patients with an idiopathic macular hole (IMH) were recruited from Shanghai First People's Hospital. The ANGPTL-4 and VEGF concentrations were determined using enzyme linked immunosorbent assays. Group means were compared using one-way analysis of variance with GraphPad Prism 4.0 and SPSS ver. 17.0. The research followed the tenets of the Declaration of Helsinki. RESULTS: The ANGPTL-4 and VEGF levels were significantly higher in the vitreous and serum of patients with PDR compared with patients with IMH. There were significant correlations between the ANGPTL-4 and VEGF levels in the vitreous and serum of patients with PDR. The vitreous and serum ANGPTL-4 levels were also significantly correlated in patients with PDR. The ANGPTL-4 in both the vitreous and serum correlated with the serum triglyceride and high-density lipoprotein cholesterol levels. CONCLUSIONS: The ANGPTL-4 levels were markedly elevated and the ANGPTL-4 expression was directly correlated with the VEGF expression in the vitreous and serum of patients with PDR. The vitreous and serum ANGPTL-4 levels were also significantly correlated with serum lipids in patients with PDR. Our results suggest that the ANGPTL-4 may be used as a new therapeutic target for the treatment of PDR. PMID- 26483144 TI - Crosslinking and corneal cryotherapy in acanthamoeba keratitis -- a histological study. AB - PURPOSE: Acanthamoeba keratitis is rare, but difficult to treat. Penetrating keratoplasty is performed in therapy-resistant cases. Nevertheless, subsequent recurrences occur in 40 % of the cases. In addition to triple-topical therapy (polyhexamid, propamidinisoethionat, neomycin), treatment alternatives are corneal cryotherapy and/or crosslinking (CXL). The aim of our present histological study was to analyze the persistence of acanthamoebatrophozoites and cysts, the persistence of bacteria, and activation of keratocytes in corneas of acanthamoeba keratitis patients following corneal cryotherapy and/or CXL. PATIENTS AND METHODS: We analyzed histologically corneal buttons (from penetrating keratoplasties) of nine patients with acanthamoeba keratitis, following corneal cryotherapy (two patients) or a combination of crosslinking and corneal cryotherapy (seven patients), using haematoxilin-eosin, periodic acid Schiff (PAS), Gram and alpha-smooth muscle actin (alpha-SMA) stainings. RESULTS: Acanthamoeba trophozoites persisted in three corneas after cryotherapy and CXL. Cysts persisted in one of two corneas following corneal cryotherapy and in six of seven corneas after a combination of CXL and cryotherapy. One cornea showed positive Gram staining, but there were no alpha-SMA positive keratocytes in any of the corneas. CONCLUSIONS: Crosslinking and corneal cryotherapy have only limited impact on killing of acanthamoeba trophozoites, cysts, or bacteria. Corneal cryotherapy and CXL did not stimulate myofibroblastic transformation of keratocytes. PMID- 26483145 TI - Levodopa as a possible treatment of visual loss in nonarteritic anterior ischemic optic neuropathy. AB - PURPOSE: To determine the clinical effectiveness and potential neuroprotection of levodopa in improving visual acuity, visual field, and retinal nerve fiber layer (RNFL) thickness in eyes affected by NAION. METHOD: Retrospective cohort study involving 59 eyes of 59 participants with NAION who were evaluated within 15 days of NAION onset. Participants received 25 mg carbidopa/100 mg levodopa three times daily with meals for 12 weeks (levodopa group) or were untreated (control group). Best-corrected visual acuity converted to logMAR, mean deviation (MD) threshold sensitivity on automated perimetry, and mean RNFL thickness on optical coherence tomography (OCT) were assessed. The primary outcome was the categorization of eyes into improved visual acuity (by 0.3 logMAR difference), worsened visual acuity (by 0.3 logMAR difference), or no change in visual acuity. The proportions in each category were compared between the levodopa and control groups. RESULTS: Among participants with 20/60 or worse initial visual acuity, levodopa-treated participants had significant improvement (P < 0.0001) in the mean change from initial to final logMAR visual acuity of -0.74 +/- 0.56 (95 % CI, -0.98 to 0.50), while the mean change for the control group at -0.37 +/- 1.09 (95 % confidence interval estimate, -1.00 to +0.26) was not significant (P = 0.23). A significant difference between groups was observed (P = 0.0086) such that 19/23 (83 %) in the levodopa group improved and none got worse, as compared with 6/14 (43 %) in the control group improving while four (29 %) worsened. The change in visual field MD and RNFL thickness on OCT showed no significant difference at P = 0.23 and P = 0.75 respectively. No levodopa-treated participant had any adverse event from the levodopa. CONCLUSIONS: Treatment within 15 days of onset of NAION with levodopa improved central visual acuity by an average of 6 lines on Snellen acuity chart. Levodopa may promote neuroprotection of the maculopapular retinal ganglion cell fibers in NAION. PMID- 26483146 TI - Effect of rebamipide ophthalmic suspension on the success of lacrimal stent intubation. AB - PURPOSE: To evaluate the effect of the postoperative administration of rebamipide ophthalmic suspension on the success rate of lacrimal stent intubation (LSI) for the treatment of primary acquired nasolacrimal duct obstruction (PANDO). METHODS: This comparative interventional cohort study investigated 110 consecutive patients with PANDO who were treated with LSI and followed up for 12 months postoperatively at one institution. LSI was performed by one surgeon, and all patients received identical postoperative care. Among the total 110 patients, 71 underwent LSI with postoperative administration of rebamipide ophthalmic suspension, and 39 underwent LSI without administration of the suspension. Data related to patient age, gender, laterality, and postoperative administration of rebamipide ophthalmic suspension were collected and used as independent variables, and logistic regression analyses were performed to compare the anatomical success rate at 12 months postoperatively between patients with and without postoperative administration of the suspension. RESULTS: The anatomical success rate of LSI in patients with and without postoperative administration of rebamipide ophthalmic suspension was 90.1 and 69.2 %, respectively. A comparison of these success rates showed statistical significance, in that the rate of treatment success was higher in PANDO patients who underwent LSI with postoperative administration of the suspension [odds ratio (OR), 3.37; P < 0.05]. CONCLUSIONS: The findings of this study show that postoperative administration of rebamipide ophthalmic suspension increases the rate of anatomical success in patients who undergo LSI for the treatment of PANDO. PMID- 26483147 TI - Geoff Shellam (1942-2015). PMID- 26483150 TI - Rhodium-Catalyzed Transnitrilation of Aryl Boronic Acids with Dimethylmalononitrile. AB - An efficient transnitrilation of aryl boronic acids with dimethylmalononitrile (DMMN) is described. This rhodium-catalyzed electrophilic cyanation presents a novel approach to prepare aryl nitriles by using a carbon-bound cyanating reagent which undergoes cross-coupling with the aryl boronic acid. The reaction expands the degree of functional-group compatibility exhibited by the transnitrilation of aryl Grignard and aryllithium reagents. A variety of aryl boronic acid derivatives and dialkylmalononitriles were amenable to the transnitrilation. PMID- 26483151 TI - Deciding How To Decide: Self-Control and Meta-Decision Making. AB - Many different situations related to self control involve competition between two routes to decisions: default and frugal versus more resource-intensive. Examples include habits versus deliberative decisions, fatigue versus cognitive effort, and Pavlovian versus instrumental decision making. We propose that these situations are linked by a strikingly similar core dilemma, pitting the opportunity costs of monopolizing shared resources such as executive functions for some time, against the possibility of obtaining a better outcome. We offer a unifying normative perspective on this underlying rational meta-optimization, review how this may tie together recent advances in many separate areas, and connect several independent models. Finally, we suggest that the crucial mechanisms and meta-decision variables may be shared across domains. PMID- 26483152 TI - The Search for the Face of the Visual Homunculus. AB - The functional organization within face-sensitive regions in the brain is largely unknown. A new fMRI study provided evidence that a face-selective region contains neighboring patches of cortex that encode physically neighboring face features. We suggest that multiple mechanisms should be considered for a full understanding of the functional maps in face-selective cortex. PMID- 26483154 TI - Acute Onset Dystonia after Infarction of Premotor and Supplementary Motor Cortex. AB - OBJECTIVE: Poststroke dystonia is the second most common movement disorder after chorea and often has a delayed manifestation. Lesions of the contralateral lenticular nucleus, particularly the putamen, have been implicated in the pathogenesis of dystonia. We present an unusual case of rapid onset of focal dystonia of the left upper extremity, which developed after infarction of the right premotor cortex (PMC) and the supplementary motor area (SMA). METHOD: A retrospective chart review of the patient was performed. RESULTS AND CONCLUSION: We propose that disruption of the afferents from PMC and SMA in the setting of chronic striatal abnormality can result in acute dystonia due to disinhibition of the thalamocortical circuit. PMID- 26483153 TI - The Malleability of Intertemporal Choice. AB - Intertemporal choices are ubiquitous: people often have to choose between outcomes realized at different times. Although it is generally believed that people have stable tendencies toward being impulsive or patient, an emerging body of evidence indicates that intertemporal choice is malleable and can be profoundly influenced by context. How the choice is framed, or the state of the decision-maker at the time of choice, can induce a shift in preference. Framing effects are underpinned by allocation of attention to choice attributes, reference dependence, and time construal. Incidental affective states and prospection also influence intertemporal choice. We advocate that intertemporal choice models account for these context effects, and encourage the use of this knowledge to nudge people toward making more advantageous choices. PMID- 26483155 TI - Telerehabilitation Approaches for Stroke Patients: Systematic Review and Meta analysis of Randomized Controlled Trials. AB - BACKGROUND: Stroke remains one of the most common causes of adult disability in the world. In recent years, diverse telerehabilitation programs have been conceived and studied to improve the abilities of the activities of daily living and increased independence of stroke patients living at home. The systematic review was conducted to determine whether telerehabilitation leads to an improvement in abilities of activities of daily living for stroke patients. METHODS: Randomized controlled trials (RCTs) evaluating the effects of telerehabilitation in stroke survivors living at home were identified by searching 7 electronic databases from inception to March 2015, and by hand searching for conference literatures between 2000 and 2015. Assessments of risk bias and data extraction were conducted independently by 2 reviews. RESULTS: The search strategy identified 2587 records, of which 11 studies were thought to be eligible. Pooled results from 7 studies showed no significant differences in abilities of activities of daily living (Barthel Index scale: standardized mean difference [SMD] -.05, 95% confidence interval [CI] -.24 to .13; Berg Balance Scale: SMD -.05, 95% CI -.7 to .37) and motor function (Fugl-Meyer Extremity: SMD .05, 95% CI -.09 to 1.09) between groups. CONCLUSIONS: This review provides limited, moderate evidence that telerehabilitation of all approaches has equal effects with conventional rehabilitation in improving abilities of activities of daily living and motor function for stroke survivors. Further research of RCTs in this area (rehabilitation field of telemedicine) is ungently required to extend the evidence base. PMID- 26483156 TI - Hospital Readmission after Intracerebral Hemorrhage. AB - BACKGROUND: Intracerebral hemorrhage (ICH) is the most severe form of stroke, but limited literature exists on readmission after ICH. We aimed to assess frequencies, causes, and predictors of early and late readmissions within 1 year after ICH. METHODS: All patients admitted to the Department of Neurology at Haukeland University Hospital with acute stroke were prospectively included in the Bergen Norwegian Stroke Research Registry (NORSTROKE) registry. Surviving patients diagnosed with ICH were followed by medical chart reviews for 1 year. The first unplanned readmission was used as final outcome, and readmitted patients were defined as early readmitted (<=90 days) and late readmitted (91-365 days). Logistic regression was performed to assess predictors for early and late readmission. RESULTS: Of 121 patients discharged alive, 27 were early readmitted, and 17 were late readmitted. Within 1 year, 40.6% had at least 1 unplanned readmission. The most frequent cause of early readmission was infection, and the most frequent causes for late readmission were recurrent stroke and cardiovascular disease. Nursing home discharge was the only independent predictor of early readmission. Diabetes mellitus and increased length of the index admission were independent predictors of late readmission. Early readmitted patients were older and had more severe stroke and lower levels of fibrinogen on index admission compared with patients who were readmitted late. CONCLUSIONS: Readmission after ICH is frequent, and many patients are early readmitted. Early and late readmissions differed in both causes and predictors for readmission, reflecting different underlying mechanisms for readmission. PMID- 26483157 TI - Mitotic-dependent phosphorylation of leukemia-associated RhoGEF (LARG) by Cdk1. AB - Rho GTPases are integral to the regulation of actin cytoskeleton-dependent processes, including mitosis. Rho and leukemia-associated Rho guanine-nucleotide exchange factor (LARG), also known as ARHGEF12, are involved in mitosis as well as diseases such as cancer and heart disease. Since LARG has a role in mitosis and diverse signaling functions beyond mitosis, it is important to understand the regulation of the protein through modifications such as phosphorylation. Here we report that LARG undergoes a mitotic-dependent and cyclin-dependent kinase 1 (Cdk1) inhibitor-sensitive phosphorylation. Additionally, LARG is phosphorylated at the onset of mitosis and dephosphorylated as cells exit mitosis, concomitant with Cdk1 activity. Furthermore, using an in vitro kinase assay, we show that LARG can be directly phosphorylated by Cdk1. Through expression of phosphonull mutants that contain non-phosphorylatable alanine mutations at potential Cdk1 S/TP sites, we demonstrate that LARG phosphorylation occurs in both termini. Using phosphospecific antibodies, we confirm that two sites, serine 190 and serine 1176, are phosphorylated during mitosis in a Cdk1-dependent manner. In addition, these phosphospecific antibodies show phosphorylated LARG at specific mitotic locations, namely the mitotic organizing centers and flanking the midbody. Lastly, RhoA activity assays reveal that phosphonull LARG is more active in cells than phosphomimetic LARG. Our data thus identifies LARG as a phosphoregulated RhoGEF during mitosis. PMID- 26483158 TI - Unique electrocatalytic activity of a nucleic acid-mimicking coordination polymer for the sensitive detection of coenzyme A and histone acetyltransferase activity. AB - A nucleic acid-mimicking CoA-Ag(I) coordination polymer (CP) was in situ prepared and its unique electrocatalytic activity to H2O2 reduction was discovered. Based on it, a novel, label-free electrochemical sensor has been developed for the sensitive detection of coenzyme A (CoA) and histone acetyltransferase (HAT) activity. PMID- 26483159 TI - RETRACTED: Association between peroxisome proliferator-activated receptor, UCP3 and lipoprotein lipase gene polymorphisms and obesity in Chinese adolescents. AB - INTRODUCTION: Peroxisome proliferator-activated receptor gamma2 (PPARgamma2), uncoupling protein gene 3 (UCP3) and lipoprotein lipase (LPL) genes were all related to lipometabolism and obesity. To investigate the association between these three gene polymorphisms and obesity, a case-control study was performed in Shanghai, China. METHODS: Obese adolescents and normal healthy adolescents aged 12-18 years from Eastern China (Shanghai) were chosen in 2002. The weight, height and body mass index (BMI) of all these adolescents were measured by physical examination. Genotyping for the examined gene polymorphisms were performed by PCR/PCR-RFLP methods. The chi-square test and t-test tests were separately used for the comparison of non-continuous variable and continuous variable, and regression analysis was used for genetic association analyses. RESULTS: There was only one genotype of CC and no statistical analysis was performed for rs1805192. There was no significant association between rs1800849 gene polymorphism and obesity (TT vs. CC: OR=1.21, 95% CI=0.40-3.62, P=0.734; CT+TT vs. CC: OR=1.11, 95% CI=0.63-1.97, P=0.712; T allele vs. C allele: OR=1.09, 95% CI=0.71-1.68, P=0.698). There was also no significant association between rs328 and obesity (CG vs. CC: OR=0.75, 95% CI=0.36-1.55, P=0.436; CG+GG vs. CC: OR=0.83, 95% CI=0.41 1.69, P=0.604; G allele vs. C allele: OR=0.93, 95% CI=0.48-1.81, P=0.841). CONCLUSIONS: No significant associations were found between rs1800849 and rs328 gene polymorphisms and obesity in Chinese adolescents. PMID- 26483160 TI - Association of angiotensin-converting enzyme I/D and alpha-actinin-3 R577X genotypes with metabolic syndrome risk factors in Korean children. AB - OBJECTIVE: This study analysed the risk factors associated with metabolic syndrome through the interaction between ACTN3 and ACE gene polymorphism in Korean children. METHODS: The subjects of the study consisted of elementary school students (n=788, age 10.10+/-0.07 yr). The anthropometric parameters, blood lipid profiles, and metabolic markers were compared among groups of the ACE I/D or the ACTN3 R577X polymorphisms. RESULTS: The subjects with the DD genotype showed significantly higher systolic blood pressure than the subjects with the II and ID genotype of the ACE gene polymorphism. XX genotype had significantly lower waist-hip ratio than those with RR genotype of the ACTN3 gene polymorphism. Also, the subjects with XX genotype exhibited significantly higher blood HDL cholesterol level than those with RR or RX genotype. The interaction of ACTN3 and ACE gene polymorphism in subjects having both ACE DD and ACTN3 RR genotypes demonstrated a significantly higher metabolic syndrome score than any other groups. CONCLUSION: The children having both ACTN3 RR or RX genotype and ACE DD genotype showed high systolic blood pressure and low blood HDL cholesterol level, which may be considered a high-risk in metabolic syndrome. PMID- 26483161 TI - Do infants find snakes aversive? Infants' physiological responses to "fear relevant" stimuli. AB - In the current research, we sought to measure infants' physiological responses to snakes-one of the world's most widely feared stimuli-to examine whether they find snakes aversive or merely attention grabbing. Using a similar method to DeLoache and LoBue (Developmental Science, 2009, Vol. 12, pp. 201-207), 6- to 9-month-olds watched a series of multimodal (both auditory and visual) stimuli: a video of a snake (fear-relevant) or an elephant (non-fear-relevant) paired with either a fearful or happy auditory track. We measured physiological responses to the pairs of stimuli, including startle magnitude, latency to startle, and heart rate. Results suggest that snakes capture infants' attention; infants showed the fastest startle responses and lowest average heart rate to the snakes, especially when paired with a fearful voice. Unexpectedly, they also showed significantly reduced startle magnitude during this same snake video plus fearful voice combination. The results are discussed with respect to theoretical perspectives on fear acquisition. PMID- 26483162 TI - Preschoolers' real-time coordination of vocal and facial emotional information. AB - An eye-tracking methodology was used to examine the time course of 3- and 5-year olds' ability to link speech bearing different acoustic cues to emotion (i.e., happy-sounding, neutral, and sad-sounding intonation) to photographs of faces reflecting different emotional expressions. Analyses of saccadic eye movement patterns indicated that, for both 3- and 5-year-olds, sad-sounding speech triggered gaze shifts to a matching (sad-looking) face from the earliest moments of speech processing. However, it was not until approximately 800ms into a happy sounding utterance that preschoolers began to use the emotional cues from speech to identify a matching (happy-looking) face. Complementary analyses based on conscious/controlled behaviors (children's explicit points toward the faces) indicated that 5-year-olds, but not 3-year-olds, could successfully match happy sounding and sad-sounding vocal affect to a corresponding emotional face. Together, the findings clarify developmental patterns in preschoolers' implicit versus explicit ability to coordinate emotional cues across modalities and highlight preschoolers' greater sensitivity to sad-sounding speech as the auditory signal unfolds in time. PMID- 26483163 TI - Toe Amputation After Minor Surgery in a Patient with Behcet's Disease: A Case Report. AB - Behcet's disease is a systemic autoimmune vasculitis. Although various clinical findings can be observed depending on the pathologic features caused by the blood vessels involved, the classic triad of the disease includes oral aphthae, genital ulcers, and uveitis. Although complications involving the aorta or the vena cava inferior can prove fatal, thrombophlebitis in the superficial veins of the lower extremities are more commonly observed. Some patients can remain asymptomatic for a long period after the diagnosis. In patients with positive pathergy test findings, trauma can trigger the inflammatory cascade. This case report presents a patient with vasculitis that occurred subsequent to minor surgery and led to amputation of the great toe in a female patient with a 14-year old history of Behcet's disease. PMID- 26483164 TI - Seroprevalence survey of Babesia gibsoni infection and tick species in dogs in East China. AB - A seroprevalence survey of Babesia gibsoni infection in dogs in East China was conducted using an ELISA with recombinant B. gibsoni thrombospondin-related adhesive protein (BgTRAP). A total of 1170 dogs from East China were examined and the seroprevalence was 9.23%. The proportion of samples was 81.2%, 7.86% and 10.94% from pet, working and fighting dogs, respectively. The fighting dogs showed highest seroprevalence (39.8%) compared with working dogs (26.1%) and pet dogs (3.47%). These results indicate that B. gibsoni infection of dogs has a widespread geographic distribution throughout East China. The dominant ticks collected from the dogs were identified as Rhipicephalus sanguineus (65.57%), Haemaphysalis longicornis (21.58%) and Rhipicephalus hemaphysaloides (10.7%). Besides adult, larval and nymph stages of ticks were also recorded on dogs. This is the first report of seroprevalence of canine B. gibsoni infection and tick species in dogs in China. PMID- 26483165 TI - Genotyping of Echinococcus granulosus from goats and sheep indicating G7 genotype in goats in the Northeast of Iran. AB - Although cystic echinococcosis (CE) has been a human public health problem in the Northeast of Iran, molecular data regarding the genotypes of Echinococcus granulosus in goats and sheep in these regions are still scarce. In the present study, we determined the genotypes of E. granulosus infecting sheep and goats in northeast of Iran. During April 2013-June 2014, 50 and 30 hydatid cysts were recovered from liver tissue of sheep and goats, respectively,. Protoscoleces or germinal layers were collected from individual cysts, DNA was extracted, and the ribosomal DNA internal transcribed spacer 1 (ITS1) gene was amplified by PCR. The results of PCR-RFLP and the sequence analysis showed that all the samples isolated from sheep (n=50) and most of samples in goats (n=24) were G1 strain, the most prevalent strain in livestock ruminants of Iran. Furthermore, six parasites isolated from goats were found to correspond to E. intermedius (G7 genotype), here reported for the first time from Iran. PMID- 26483166 TI - Cryptosporidium and Giardia in Danish organic pig farms: Seasonal and age-related variation in prevalence, infection intensity and species/genotypes. AB - Although pigs are commonly infected with Cryptosporidium spp. and Giardia duodenalis, including potentially zoonotic species or genotypes, little is known about age-related infection levels, seasonal differences and genetic variation in naturally infected pigs raised in organic management systems. Therefore, the current study was conducted to assess seasonal and age-related variations in prevalence and infection intensity of Cryptosporidium and Giardia, evaluate zoonotic potential and uncover correlations between species/genotypes, infection intensity and faecal consistency. Shedding of oocysts and cysts ((oo-)cysts) was monitored at quarterly intervals (September 2011-June 2012) in piglets (n = 152), starter pigs (n = 234), fatteners (n = 230) and sows (n = 240) from three organic farms in Denmark. (oo-)Cysts were quantified by immunofluorescence microscopy; and 56/75 subsamples from Cryptosporidium infected pigs were successfully analysed by PCR amplification and partial sequencing of the small subunit (SSU) 18S rRNA and hsp70genes, while 13/67 Giardia subsamples were successfully analysed by amplification and partial sequencing of the 18S rRNA and the gdh genes. Altogether, Cryptosporidium or Giardia infections were observed in 40.9% (350/856) and 14.0% (120/856) of the pigs, respectively, including 8.2% (70/856) infected with both parasites. Prevalence, intensity of infections and presence of Cryptosporidium species varied significantly between age-groups; 53.3% piglets, 72.2% starter pigs, 40.4% fatteners and 2.9% sows were infected with Cryptosporidium, whereas 2.0% piglets, 27.4% starter pigs, 17.8% fatteners and 5.0% sows were infected with Giardia. The overall prevalence was stable throughout the year, except for dual-infections that were more prevalent in September and December (p < 0.05). The infection intensity was age-related for both parasites, and dual-infected pigs tended to excrete lower levels of oocysts compared to pigs harbouring only Cryptosporidium. Likewise, pigs infected with Cryptosporidium scrofarum excreted fewer oocysts (mean CPG: 54,848 +/- 194,508CI: 9085-118,781) compared to pigs infected with Cryptosporidium suis (mean OPG: 351,035 +/- 351,035CI: 67,953-634,117). No correlation between faecal consistency and (oo-)cyst excretion levels was observed. Of the successfully genotyped isolates, 38/56 (67.9%) were C. scrofarum and 18/56 (32.1%) were C. suis, while the livestock specific G. duodenalis Assemblage E was detected in 11/13 (84.6%) isolates and the potentially zoonotic Assemblage A was identified in 2/13 (15.4%) isolates. Piglets exclusively hosted C. suis, with one exception, while starter pigs and fatteners predominantly hosted C. scrofarum. As organic pigs are partly reared outdoors, environmental contamination with Cryptosporidium and Giardia is inevitable. Nevertheless, the present data indicate that the potential public health risk associated with both of these parasites in Danish organic pig production seems to be negligible. PMID- 26483168 TI - Diabetes diagnosis and nutrition facts label use among US adults, 2005-2010. AB - OBJECTIVE: To assess the role of diabetes diagnosis as a potential teachable moment in nutrition facts label use among US adults. DESIGN: Logistic regression analyses were conducted to examine the relationship between diabetes diagnosis status (diagnosed diabetes, undiagnosed diabetes, diagnosed prediabetes, undiagnosed prediabetes, no diabetes or prediabetes) and self-reported nutrition facts label use, adjusted by individual characteristics and survey design. SETTING: Study sample came from the National Health and Nutrition Examination Survey 2005-2010 waves. SUBJECTS: A total of 5110 US adults aged 20 years and older were included in the analyses. Diabetes/prediabetes was identified by fasting plasma glucose and glycated Hb testing. RESULTS: People with diagnosed diabetes/prediabetes were substantially more likely to report nutrition facts label use when making daily food purchase decisions compared with those with undiagnosed diabetes/prediabetes, whereas the prevalence of nutrition facts label use was similar between people with undiagnosed diabetes/prediabetes and those without diabetes/prediabetes. The adjusted prevalence (95 % CI) of any and regular nutrition facts label use was 85.93 (82.91, 88.95) % and 55.60 (50.04, 61.16) % among those with diagnosed diabetes, respectively, in comparison to 71.50 (59.64, 83.37) % and 32.88 (19.11, 46.65) % among those with undiagnosed diabetes. Analogously, the adjusted prevalence (95 % CI) of any and regular nutrition facts label use was 81.16 (75.27, 87.06) % and 45.28 (37.28, 53.29) % among those with diagnosed prediabetes, respectively, in comparison to 72.83 (68.06, 77.59) % and 39.95 (34.02, 45.89) % among those with undiagnosed prediabetes. CONCLUSIONS: As a potential teachable moment, diabetes diagnosis may positively impact nutrition facts label use and motivate diabetic patients to manage their condition through making healthier food choices. PMID- 26483169 TI - High-Tensile Strength Tape Versus High-Tensile Strength Suture: A Biomechanical Study. AB - PURPOSE: To determine which suture design, high-tensile strength tape or high tensile strength suture, performed better at securing human tissue across 4 selected suture techniques commonly used in tendinous repair, by comparing the total load at failure measured during a fixed-rate longitudinal single load to failure using a biomechanical testing machine. METHODS: Matched sets of tendon specimens with bony attachments were dissected from 15 human cadaveric lower extremities in a manner allowing for direct comparison testing. With the use of selected techniques (simple Mason-Allen in the patellar tendon specimens, whip stitch in the quadriceps tendon specimens, and Krackow stitch in the Achilles tendon specimens), 1 sample of each set was sutured with a 2-mm braided, nonabsorbable, high-tensile strength tape and the other with a No. 2 braided, nonabsorbable, high-tensile strength suture. A total of 120 specimens were tested. Each model was loaded to failure at a fixed longitudinal traction rate of 100 mm/min. The maximum load and failure method were recorded. RESULTS: In the whip stitch and the Krackow-stitch models, the high-tensile strength tape had a significantly greater mean load at failure with a difference of 181 N (P = .001) and 94 N (P = .015) respectively. No significant difference was found in the Mason-Allen and simple stitch models. Pull-through remained the most common method of failure at an overall rate of 56.7% (suture = 55%; tape = 58.3%). CONCLUSIONS: In biomechanical testing during a single load to failure, high tensile strength tape performs more favorably than high-tensile strength suture, with a greater mean load to failure, in both the whip- and Krackow-stitch models. Although suture pull-through remains the most common method of failure, high tensile strength tape requires a significantly greater load to pull-through in a whip-stitch and Krakow-stitch model. CLINICAL RELEVANCE: The biomechanical data obtained in the current study indicates that high-tensile strength tape may provide better repair strength compared with high-tensile strength suture at time zero simulated testing. PMID- 26483171 TI - Implications of non-stationarity on predictive modeling using EHRs. AB - The rapidly increasing volume of clinical information captured in Electronic Health Records (EHRs) has led to the application of increasingly sophisticated models for purposes such as disease subtype discovery and predictive modeling. However, increasing adoption of EHRs implies that in the near future, much of the data available for such purposes will be from a time period during which both the practice of medicine and the clinical use of EHRs are in flux due to historic changes in both technology and incentives. In this work, we explore the implications of this phenomenon, called non-stationarity, on predictive modeling. We focus on the problem of predicting delayed wound healing using data available in the EHR during the first week of care in outpatient wound care centers, using a large dataset covering over 150,000 individual wounds and 59,958 patients seen over a period of four years. We manipulate the degree of non-stationarity seen by the model development process by changing the way data is split into training and test sets. We demonstrate that non-stationarity can lead to quite different conclusions regarding the relative merits of different models with respect to predictive power and calibration of their posterior probabilities. Under the non stationarity exhibited in this dataset, the performance advantage of complex methods such as stacking relative to the best simple classifier disappears. Ignoring non-stationarity can thus lead to sub-optimal model selection in this task. PMID- 26483170 TI - Risk Factors for Infection After Rotator Cuff Repair. AB - PURPOSE: To identify risk factors for infection after rotator cuff repair. We hypothesized that patient characteristics and surgical technique would affect the rate of infection. METHODS: The records of 1,824 rotator cuff repairs performed by a single surgeon from 1995 to 2010 were reviewed retrospectively. Fourteen patients had an early deep postoperative wound infection that was treated with surgical irrigation and debridement. One hundred eighty-five control patients who were treated with rotator cuff repair and did not develop an infection were selected randomly for comparison and statistical analysis. Data regarding preoperative and intraoperative risk factors for infection were recorded, and a multiple logistic regression was conducted to investigate predictors of infection. RESULTS: The infection rate was 0.77% (14/1,822). On average 2.1 (range 1 to 4) surgical debridements were performed in addition to treatment with intravenous antibiotics. Patients who had open or miniopen rotator cuff repair had a significantly greater risk of acute postoperative infection (odds ratio [OR] = 8.63, P = .002). Seventy-nine percent of the patients in the infection group had an open or miniopen repair, whereas only 28% of the control group had an open or miniopen repair. Male patients also had a significantly greater risk of acute postoperative infection (OR = 9.52, P = .042). A total of 92% of the infection patients were male compared with 58% of the control group. In addition, as body mass index increased there was a reduction in the odds of infection (OR = 0.81, P = .023). CONCLUSIONS: The results of this case control study demonstrate that open or miniopen surgical technique and male sex are significant risk factors for infection after rotator cuff repair. In our study, arthroscopic rotator cuff repair reduced the risk of infection compared with open techniques. LEVEL OF EVIDENCE: Level IV. PMID- 26483172 TI - A multi-ontology approach to annotate scientific documents based on a modularization technique. AB - Scientific text annotation has become an important task for biomedical scientists. Nowadays, there is an increasing need for the development of intelligent systems to support new scientific findings. Public databases available on the Web provide useful data, but much more useful information is only accessible in scientific texts. Text annotation may help as it relies on the use of ontologies to maintain annotations based on a uniform vocabulary. However, it is difficult to use an ontology, especially those that cover a large domain. In addition, since scientific texts explore multiple domains, which are covered by distinct ontologies, it becomes even more difficult to deal with such task. Moreover, there are dozens of ontologies in the biomedical area, and they are usually big in terms of the number of concepts. It is in this context that ontology modularization can be useful. This work presents an approach to annotate scientific documents using modules of different ontologies, which are built according to a module extraction technique. The main idea is to analyze a set of single-ontology annotations on a text to find out the user interests. Based on these annotations a set of modules are extracted from a set of distinct ontologies, and are made available for the user, for complementary annotation. The reduced size and focus of the extracted modules tend to facilitate the annotation task. An experiment was conducted to evaluate this approach, with the participation of a bioinformatician specialist of the Laboratory of Peptides and Proteins of the IOC/Fiocruz, who was interested in discovering new drug targets aiming at the combat of tropical diseases. PMID- 26483173 TI - High-throughput alternative splicing detection using dually constrained correspondence analysis (DCCA). AB - Alternative splicing is an important component of tumorigenesis. Recent advent of exon array technology enables the detection of alternative splicing at a genome wide scale. The analysis of high-throughput alternative splicing is not yet standard and methodological developments are still needed. We propose a novel statistical approach-Dually Constrained Correspondence Analysis-for the detection of splicing changes in exon array data. Using this methodology, we investigated the genome-wide alteration of alternative splicing in patients with non-small cell lung cancer treated by bevacizumab/erlotinib. Splicing candidates reveal a series of genes related to carcinogenesis (SFTPB), cell adhesion (STAB2, PCDH15, HABP2), tumor aggressiveness (ARNTL2), apoptosis, proliferation and differentiation (PDE4D, FLT3, IL1R2), cell invasion (ETV1), as well as tumor growth (OLFM4, FGF14), tumor necrosis (AFF3) or tumor suppression (TUSC3, CSMD1, RHOBTB2, SERPINB5), with indication of known alternative splicing in a majority of genes. DCCA facilitates the identification of putative biologically relevant alternative splicing events in high-throughput exon array data. PMID- 26483167 TI - Mitral valve disease--morphology and mechanisms. AB - Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but--even in adult life--remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular-ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease. PMID- 26483174 TI - In utero stem cell transplantation and gene therapy: Recent progress and the potential for clinical application. AB - Advances in prenatal diagnosis have led to the prenatal management and treatment of a variety of congenital diseases. Although surgical treatment has been successfully applied to specific anatomic defects that place the fetus at a risk of death or life-long disability, the indications for fetal surgical intervention have remained relatively limited. By contrast, prenatal stem cell and gene therapy await clinical application, but they have tremendous potential to treat a broad range of genetic disorders. If there are biological advantages unique to fetal development that favor fetal stem cell or gene therapy over postnatal treatment, prenatal therapy may become the preferred approach to the treatment of any disease that can be prenatally diagnosed and cured by stem cell or gene therapy. Here, we review the field including recent progress toward clinical application and imminent clinical trials for cellular and gene therapy. PMID- 26483175 TI - Functional variants of 17q12-21 are associated with allergic asthma but not allergic rhinitis. AB - BACKGROUND: Allergic rhinitis (AR) and asthma are common allergic conditions with a shared genetic component to their cause. The 17q12-21 locus includes several genes that have been linked to asthma susceptibility, but the role of this locus in AR is unclear. Asthma and AR in adults of Chinese ethnicity in Singapore are predominately caused by sensitization against house dust mites with a nearly complete penetrance of the allergen, which presents a unique opportunity for accurately identifying genetic associations with allergic diseases. OBJECTIVE: We sought to define the functional role of 17q12-21 in patients with AR and allergic asthma. METHODS: We asked whether single nucleotide polymorphisms (SNPs) in the 17q12-21 locus were associated with AR or asthma in a cohort of 3460 ethnic Chinese subjects residing in Singapore (1435 in the discovery phase and 2025 in the validation phase). Full-blood mRNA gene expression data, plasma IgE levels, and immune cell frequencies in peripheral blood were tested against the tag SNP genotypes. Luciferase assays were used to measure the effect of putative promoter SNPs on expression of the asthma-associated orosomucoid-like 3 gene (ORMDL3). RESULTS: Within 17q12-21, only the tag SNP rs8076131 was significantly associated with asthma (P = 8.53 * 10(-10); odds ratio, 0.6715), and AR status was independent of SNPs in this region. C-A alleles at rs8076131 resulted in significantly increased ORMDL3 expression in HEK293 cells in vitro relative to T G alleles. Moreover, subjects with the risk genotype AA exhibited significantly higher total IgE levels and higher blood eosinophil counts than those with the lower-risk genotypes. CONCLUSION: The 17q12-21 locus has a strong genetic association with allergic asthma but not with AR. The polymorphic effect of this locus is attributed to the linkage set tagged by rs8076131, which affects the expression of ORMDL3, protein phosphatase 1, regulatory inhibitor subunit 1B (PPP1R1B), zona pellucida binding protein 2 (ZPBP2), and gasdermin B (GSDMB) and is correlated with high IgE levels and eosinophil counts in subjects bearing the risk genotype. PMID- 26483176 TI - Direct costs of adult chronic rhinosinusitis by using 4 methods of estimation: Results of the US Medical Expenditure Panel Survey. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is an inflammatory disease that affects 2% to 16% of the US population. Despite its increasing prevalence, there are currently limited data in the literature evaluating the economic burden of this disease. OBJECTIVE: This study aimed to determine the direct health care costs of CRS from the perspective of the US government. METHODS: A prevalence-based approach was used to estimate cost of illness for CRS from the 2011 Medical Expenditure Panel Survey database by using a 4-part model: (1) an estimated sum of all health care expenditures, (2) an attribution model for disease-specific estimation of expenditures, (3) an estimation based on a propensity score model, and (4) estimated disease-specific expenditure by using a linear regression-based approach. A disease prevalence of 3.5% was used. RESULTS: The mean CRS-specific annual expenditure was $5955 (95% CI, $5087-$6823) by using method 1 compared with $5560 (95% CI, $4689-$6431) by using method 2 and $5560 (95% CI, $4653 $6467) by using method 3. The annual expenditure, as estimated by using method 4, was $5589 (95% CI, $4986-$6192). Ambulatory expenses accounted for the largest proportion of expenditures, followed by prescription and in-hospital expenses. CONCLUSIONS: This study provided a range of estimates of the direct medical expenditures associated with CRS. We demonstrated that the economic burden attributable to this disease was an estimated $60.2 to $64.5 billion US dollars in 2011, with a wide variation in the total and incremental direct expenditures depending on the type of estimation model used and the prevalence assumed. PMID- 26483177 TI - Timing and duration of omalizumab response in patients with chronic idiopathic/spontaneous urticaria. AB - BACKGROUND: Few data are available that describe response patterns in patients with chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria (CSU) treated with omalizumab. OBJECTIVE: We sought to describe response patterns by using data from the 3 pivotal omalizumab CIU/CSU trials. METHODS: Every 4 weeks, randomized patients received dosing with placebo or 75, 150, or 300 mg of omalizumab (ASTERIA I: n = 318, 24 weeks; ASTERIA II: n = 322, 12 weeks) or placebo or 300 mg of omalizumab (GLACIAL: n = 335, 24 weeks). Response was defined as well-controlled urticaria (weekly Urticaria Activity Score [UAS7] <= 6) or complete response (UAS7 = 0). RESULTS: Response rates were dose dependent and highest with 300 mg of omalizumab. Some patients responded early (before week 4). At week 12, a higher proportion of patients treated with 300 mg of omalizumab reported a UAS7 <= 6 (26.0% [75 mg of omalizumab], 40.0% [150 mg of omalizumab], 51.9% [300 mg of omalizumab], and 11.3% [placebo] for ASTERIA I; 26.8% [75 mg of omalizumab], 42.7% [150 mg of omalizumab], 65.8% [300 mg of omalizumab], and 19.0% [placebo] for ASTERIA II; and 52.4% [300 mg of omalizumab] and 12.0% [placebo] for GLACIAL) or a UAS7 = 0 (11.7% [75 mg of omalizumab], 15.0% [150 mg of omalizumab], 35.8% [300 mg of omalizumab], and 8.8% [placebo] for ASTERIA I; 15.9% [75 mg of omalizumab], 22.0% [150 mg of omalizumab], 44.3% [300 mg of omalizumab], and 5.1% [placebo] for ASTERIA II; and 33.7% [300 mg of omalizumab] and 4.8% [placebo] for GLACIAL). In patients receiving 300 mg of omalizumab with 24 weeks of treatment, median time to achieve a UAS7 <= 6 was 6 weeks (ASTERIA I and GLACIAL) and median time to achieve a UAS7 = 0 was 12 or 13 weeks (ASTERIA I and GLACIAL, respectively). Some patients who achieved well-controlled urticaria or complete response sustained response throughout the treatment period. CONCLUSION: Benefits of omalizumab treatment were evident early (before week 4) in some patients and persisted to week 24. Use of 300 mg of omalizumab demonstrated best results in controlling CIU/CSU symptoms. PMID- 26483178 TI - The cough without a cause: Habit cough syndrome. PMID- 26483179 TI - Recent advances on D-amino acid research. PMID- 26483180 TI - Immunization Coverage in Migrant School Children Along the Thailand-Myanmar Border. AB - The objective of this project was to document and increase vaccine coverage in migrant school children on the Thailand-Myanmar border. Migrant school children (n = 12,277) were enrolled in a school-based immunization program in four Thai border districts. The children were evaluated for vaccination completion and timing, for six different vaccines: Bacille Calmette-Guerin (BCG); Oral Polio vaccine (OPV); Hepatitis B vaccine (HepB); Diphtheria, Pertussis and Tetanus vaccine (DTP); Measles Containing Vaccine or Measles, Mumps and Rubella vaccine (MMR); Tetanus and Diphtheria containing vaccine (Td). Vaccine coverage proportions for BCG, OPV3, DTP3, HepB3 and measles containing vaccine were 92.3, 85.3, 63.8, 72.2, and 90.9 % respectively. Most children were able to receive vaccines in a time appropriate manner. School-based immunization programs offer a suitable vaccine delivery mechanism for hard-to-reach populations. However, these data suggest overall low vaccine coverage in migrant populations. Further efforts toward improving appropriate vaccine coverage and methods of retaining documentation of vaccination in mobile migrant populations are necessary for improved health. PMID- 26483183 TI - Development and Evaluation of a Variable-Temperature Quadrupole Ion Trap Mass Spectrometer. AB - A new, variable-temperature mass spectrometer system is described. By applying polyimide heating tape to the end-cap electrodes of a Bruker (Bremen, Germany) Esquire ion trap, it is possible to vary the effective temperature of the system between 40 and 100 degrees C. The modification does not impact the operation of the ion trap and the heater can be used for extended periods without degradation of the system. The accuracy of the ion trap temperatures was assessed by examining two gas-phase equilibrium processes with known thermochemistry. In each case, the variable-temperature ion trap provided data that were in good accord with literature data, indicating the effective temperature in the ion trap environment was being successfully modulated by the changes in the set-point temperatures on the end-cap electrodes. The new design offers a convenient and effective way to convert commercial ion trap mass spectrometers into variable temperature instruments. PMID- 26483181 TI - Circadian Clocks as Modulators of Metabolic Comorbidity in Psychiatric Disorders. AB - Psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder are often accompanied by metabolic dysfunction symptoms, including obesity and diabetes. Since the circadian system controls important brain systems that regulate affective, cognitive, and metabolic functions, and neuropsychiatric and metabolic diseases are often correlated with disturbances of circadian rhythms, we hypothesize that dysregulation of circadian clocks plays a central role in metabolic comorbidity in psychiatric disorders. In this review paper, we highlight the role of circadian clocks in glucocorticoid, dopamine, and orexin/melanin-concentrating hormone systems and describe how a dysfunction of these clocks may contribute to the simultaneous development of psychiatric and metabolic symptoms. PMID- 26483184 TI - Neuropeptidomics Mass Spectrometry Reveals Signaling Networks Generated by Distinct Protease Pathways in Human Systems. AB - Neuropeptides regulate intercellular signaling as neurotransmitters of the central and peripheral nervous systems, and as peptide hormones in the endocrine system. Diverse neuropeptides of distinct primary sequences of various lengths, often with post-translational modifications, coordinate and integrate regulation of physiological functions. Mass spectrometry-based analysis of the diverse neuropeptide structures in neuropeptidomics research is necessary to define the full complement of neuropeptide signaling molecules. Human neuropeptidomics has notable importance in defining normal and dysfunctional neuropeptide signaling in human health and disease. Neuropeptidomics has great potential for expansion in translational research opportunities for defining neuropeptide mechanisms of human diseases, providing novel neuropeptide drug targets for drug discovery, and monitoring neuropeptides as biomarkers of drug responses. In consideration of the high impact of human neuropeptidomics for health, an observed gap in this discipline is the few published articles in human neuropeptidomics compared with, for example, human proteomics and related mass spectrometry disciplines. Focus on human neuropeptidomics will advance new knowledge of the complex neuropeptide signaling networks participating in the fine control of neuroendocrine systems. This commentary review article discusses several human neuropeptidomics accomplishments that illustrate the rapidly expanding diversity of neuropeptides generated by protease processing of pro-neuropeptide precursors occurring within the secretory vesicle proteome. Of particular interest is the finding that human specific cathepsin V participates in producing enkephalin and likely other neuropeptides, indicating unique proteolytic mechanisms for generating human neuropeptides. The field of human neuropeptidomics has great promise to solve new mechanisms in disease conditions, leading to new drug targets and therapeutic agents for human diseases. Graphical Abstract ?. PMID- 26483185 TI - Increased S100A4 expression in the vasculature of human COPD lungs and murine model of smoke-induced emphysema. AB - BACKGROUND: Chronic obstructive lung disease (COPD) is a common cause of death in industrialized countries often induced by exposure to tobacco smoke. A substantial number of patients with COPD also suffer from pulmonary hypertension that may be caused by hypoxia or other hypoxia-independent stimuli - inducing pulmonary vascular remodeling. The Ca(2+) binding protein, S100A4 is known to play a role in non-COPD-driven vascular remodeling of intrapulmonary arteries. Therefore, we have investigated the potential involvement of S100A4 in COPD induced vascular remodeling. METHODS: Lung tissue was obtained from explanted lungs of five COPD patients and five non-transplanted donor lungs. Additionally, mice lungs of a tobacco-smoke-induced lung emphysema model (exposure for 3 and 8 month) and controls were investigated. Real-time RT-PCR analysis of S100A4 and RAGE mRNA was performed from laser-microdissected intrapulmonary arteries. S100A4 immunohistochemistry was semi-quantitatively evaluated. Mobility shift assay and siRNA knock-down were used to prove hypoxia responsive elements (HRE) and HIF binding within the S100A4 promoter. RESULTS: Laser-microdissection in combination with real-time PCR analysis revealed higher expression of S100A4 mRNA in intrapulmonary arteries of COPD patients compared to donors. These findings were mirrored by semi-quantitative analysis of S100A4 immunostaining. Analogous to human lungs, in mice with tobacco-smoke-induced emphysema an up-regulation of S100A4 mRNA and protein was observed in intrapulmonary arteries. Putative HREs could be identified in the promoter region of the human S100A4 gene and their functionality was confirmed by mobility shift assay. Knock-down of HIF1/2 by siRNA attenuated hypoxia-dependent increase in S100A4 mRNA levels in human primary pulmonary artery smooth muscle cells. Interestingly, RAGE mRNA expression was enhanced in pulmonary arteries of tobacco-smoke exposed mice but not in pulmonary arteries of COPD patients. CONCLUSIONS: As enhanced S100A4 expression was observed in remodeled intrapulmonary arteries of COPD patients, targeting S100A4 could serve as potential therapeutic option for prevention of vascular remodeling in COPD patients. PMID- 26483186 TI - Digital PCR for direct quantification of viruses without DNA extraction. AB - DNA extraction before amplification is considered an essential step for quantification of viral DNA using real-time PCR (qPCR). However, this can directly affect the final measurements due to variable DNA yields and removal of inhibitors, which leads to increased inter-laboratory variability of qPCR measurements and reduced agreement on viral loads. Digital PCR (dPCR) might be an advantageous methodology for the measurement of virus concentrations, as it does not depend on any calibration material and it has higher tolerance to inhibitors. DNA quantification without an extraction step (i.e. direct quantification) was performed here using dPCR and two different human cytomegalovirus whole-virus materials. Two dPCR platforms were used for this direct quantification of the viral DNA, and these were compared with quantification of the extracted viral DNA in terms of yield and variability. Direct quantification of both whole-virus materials present in simple matrices like cell lysate or Tris-HCl buffer provided repeatable measurements of virus concentrations that were probably in closer agreement with the actual viral load than when estimated through quantification of the extracted DNA. Direct dPCR quantification of other viruses, reference materials and clinically relevant matrices is now needed to show the full versatility of this very promising and cost-efficient development in virus quantification. PMID- 26483187 TI - A direct solid sampling analysis method for the detection of silver nanoparticles in biological matrices. AB - Engineered silver nanoparticles (AgNPs) are implemented in food contact materials due to their powerful antimicrobial properties and so may enter the human food chain. Hence, it is desirable to develop easy, sensitive and fast analytical screening methods for the determination of AgNPs in complex biological matrices. This study describes such a method using solid sampling high-resolution continuum source graphite furnace atomic absorption spectrometry (GFAAS). A recently reported novel evaluation strategy uses the atomization delay of the respective GFAAS signal as significant indicator for AgNPs and thereby allows discrimination of AgNPs from ionic silver (Ag(+)) in the samples without elaborate sample pre treatment. This approach was further developed and applied to a variety of biological samples. Its suitability was approved by investigation of eight different food samples (parsley, apple, pepper, cheese, onion, pasta, maize meal and wheat flour) spiked with ionic silver or AgNPs. Furthermore, the migration of AgNPs from silver-impregnated polypropylene food storage boxes to fresh pepper was observed and a mussel sample obtained from a laboratory exposure study with silver was investigated. The differences in the atomization delays (Deltat(ad)) between silver ions and 20-nm AgNPs vary in a range from -2.01 +/- 1.38 s for maize meal to +2.06 +/- 1.08 s for mussel tissue. However, the differences were significant in all investigated matrices and so indicative of the presence/absence of AgNPs. Moreover, investigation of model matrices (cellulose, gelatine and water) gives the first indication of matrix-dependent trends. Reproducibility and homogeneity tests confirm the applicability of the method. PMID- 26483188 TI - The Hedgehog pathway as targetable vulnerability with 5-azacytidine in myelodysplastic syndrome and acute myeloid leukemia. AB - BACKGROUND: Therapy and outcome for elderly acute myeloid leukemia (AML) patients has not improved for many years. Similarly, there remains a clinical need to improve response rates in advanced myelodysplastic syndrome (MDS) patients treated with hypomethylating agents, and few combination regimens have shown clinical benefit. We conducted a 5-azacytidine (5-Aza) RNA-interference (RNAi) sensitizer screen to identify gene targets within the commonly deleted regions (CDRs) of chromosomes 5 and 7, whose silencing enhances the activity of 5-Aza. METHODS AND RESULTS: An RNAi silencing screen of 270 genes from the CDRs of chromosomes 5 and 7 was performed in combination with 5-Aza treatment in four AML cell lines (TF-1, THP-1, MDS-L, and HEL). Several genes within the hedgehog pathway (HhP), specifically SHH, SMO, and GLI3, were identified as 5-Aza sensitizing hits. The smoothened (SMO) inhibitors LDE225 (erismodegib) and GDC0449 (vismodegib) showed moderate single-agent activity in AML cell lines. Further studies with erismodegib in combination with 5-Aza demonstrated synergistic activity with combination index (CI) values of 0.48 to 0.71 in seven AML lines. Clonogenic growth of primary patient samples was inhibited to a greater extent in the combination than with single-agent erismodegib or 5-Aza in 55 % (6 of 11) primary patient samples examined. There was no association of the 5-Aza/erismodegib sensitization potential to clinical-cytogenetic features or common myeloid mutations. Activation of the HhP, as determined by greater expression of HhP-related genes, showed less responsiveness to single-agent SMO inhibition, while synergy between both agents was similar regardless of HhP gene expression. In vitro experiments suggested that concurrent dosing showed stronger synergy than sequential dosing. CONCLUSIONS: Inhibition of the HhP with SMO inhibitors in combination with the hypomethylating agent 5-Aza demonstrates synergy in vitro and inhibits long-term repopulation capacity ex vivo in AML and MDS. A clinical trial combining 5-Aza with LDE225 (erismodegib) in MDS and AML is ongoing based on these results as well as additional publications suggesting a role for HhP signaling in myeloid disease. PMID- 26483190 TI - Detection of 40 bp insertion-deletion (INDEL) in mitochondrial control region among sambar (Rusa unicolor) populations in India. AB - BACKGROUND: The mitochondrial DNA (mtDNA) control region is extensively used in the phylogeography of species. We examined sequence variations in the mtDNA control region of sambar (Rusa unicolor) populations from the South, Central and North India. RESULTS: Most of the samples collected from the south India exhibited a 40 bp insertion in the mtDNA control region. This insertion was not observed in the North and Central Indian populations. CONCLUSION: This study provided a potential marker for molecular screening and identification of sambar populations in the form of a distinct 40 bp insertion. Some populations in South India did not exhibit this insertion. It indicates that there could be an ecological barrier that might be preventing the expansion of insertion-positive sambar population. PMID- 26483189 TI - Expression of Oct3/4 and Nanog in the head and neck squamous carcinoma cells and its clinical implications for delayed neck metastasis in stage I/II oral tongue squamous cell carcinoma. AB - BACKGROUND: The side population (SP) of cancer cells is reportedly enriched with cancer stem cells (CSCs), however, the functional role and clinical relevance of CSC marker molecules upregulated in the SP of head and neck squamous carcinoma (HNSCC) cells are yet to be elucidated. Patients with clinical stage I/II (T1 2N0M0) tongue squamous cell carcinoma (TSCC) typically undergo partial glossectomy; however, development of delayed neck metastasis (DNM) tends to reduce their survival. In the present study, we aimed to determine the CSC markers in the SP of HNSCC cells along with their functions in cellular behaviors, and to clarify the association of these markers with DNM. METHODS: Flow cytometry was applied to isolate SP from main population (MP) in HNSCC cells. The expression of the CSC markers was examined by semi-quantitative RT-PCR and immunocytochemistry. In vitro proliferation, migration, and invasion assays were performed to assess cellular behaviors. Clinicopathological factors and immunohistochemical expressions of Oct3/4 and Nanog were evaluated using surgical specimens from 50 patients with stage I/II TSCC. RESULTS: SPs were isolated in all three cell lines examined. Expression levels of Oct3/4 and Nanog were higher in SP cells than MP cells. Additionally, cell migration and invasion abilities were higher in SP cells than MP cells, whereas there was no difference in proliferation. Univariate analysis showed that expression of Oct3/4 and Nanog, vascular and muscular invasion, and mode of invasion were significantly correlated with DNM. Multivariate logistic regression revealed that Oct3/4 expression (risk ratio = 14.78, p = 0.002) and vascular invasion (risk ratio = 12.93, p = 0.017) were independently predictive of DNM. Regarding the diagnostic performance, Oct3/4 showed the highest accuracy, sensitivity, and NPV of 82.0 %, 61.5 %, and 86.8 %, respectively, while vascular invasion showed the highest specificity and PPV of 94.6 % and 71.4 %, respectively. CONCLUSION: These results suggest that Oct3/4 and Nanog represent probable CSC markers in HNSCC, which contribute to the development of DNM in part by enhancing cell motility and invasiveness. Moreover, along with vascular invasion, expression of Oct3/4 can be considered a potential predictor for selecting patients at high risk of developing DNM. PMID- 26483191 TI - Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase. AB - Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. Growing evidence suggests a link between changes in lipid metabolism and ALS. Here, we used UPLC/TOF-MS to survey the lipidome in SOD1(G86R) mice, a model of ALS. Significant changes in lipid expression were evident in spinal cord and skeletal muscle before overt neuropathology. In silico analysis also revealed appreciable changes in sphingolipids including ceramides and glucosylceramides (GlcCer). HPLC analysis showed increased amounts of GlcCer and downstream glycosphingolipids (GSLs) in SOD1(G86R) muscle compared with wild-type littermates. Glucosylceramide synthase (GCS), the enzyme responsible for GlcCer biosynthesis, was up-regulated in muscle of SOD1(G86R) mice and ALS patients, and in muscle of wild-type mice after surgically induced denervation. Conversely, inhibition of GCS in wild-type mice, following transient peripheral nerve injury, reversed the overexpression of genes in muscle involved in oxidative metabolism and delayed motor recovery. GCS inhibition in SOD1(G86R) mice also affected the expression of metabolic genes and induced a loss of muscle strength and morphological deterioration of the motor endplates. These findings suggest that GSLs may play a critical role in ALS muscle pathology and could lead to the identification of new therapeutic targets. PMID- 26483193 TI - Psychological and behavioral differences between low back pain populations: a comparative analysis of chiropractic, primary and secondary care patients. AB - BACKGROUND: Psychological, behavioral and social factors have long been considered important in the development of persistent pain. Little is known about how chiropractic low back pain (LBP) patients compare to other LBP patients in terms of psychological/behavioral characteristics. METHODS: In this cross sectional study, the aim was to investigate patients with LBP as regards to psychosocial/behavioral characteristics by describing a chiropractic primary care population and comparing this sample to three other populations using the MPI-S instrument. Thus, four different samples were compared. A: Four hundred eighty subjects from chiropractic primary care clinics. B: One hundred twenty-eight subjects from a gainfully employed population (sick listed with high risk of developing chronicity). C: Two hundred seventy-three subjects from a secondary care rehabilitation clinic. D: Two hundred thirty-five subjects from secondary care clinics. The Swedish version of the Multidimensional Pain Inventory (MPI-S) was used to collect data. Subjects were classified using a cluster analytic strategy into three pre-defined subgroups (named adaptive copers, dysfunctional and interpersonally distressed). RESULTS: The data show statistically significant overall differences across samples for the subgroups based on psychological and behavioral characteristics. The cluster classifications placed (in terms of the proportions of the adaptive copers and dysfunctional subgroups) sample A between B and the two secondary care samples C and D. CONCLUSIONS: The chiropractic primary care sample was more affected by pain and worse off with regards to psychological and behavioral characteristics compared to the other primary care sample. Based on our findings from the MPI-S instrument the 4 samples may be considered statistically and clinically different. TRIAL REGISTRATION: Sample A comes from an ongoing trial registered at clinical trials.gov; NCT01539863 , February 22, 2012. PMID- 26483194 TI - Xpert MTB/RIF assay for diagnosis of pulmonary tuberculosis in sputum specimens in remote health care facility. AB - BACKGROUND: Xpert MTB/RIF assay is considered as a great advance over conventional smear and culture in the diagnosis of TB and MDR-TB by simultaneously detecting M.tuberculosis and rifampicin resistance bacilli. However, very little information regarding the performance characteristics of Xpert MTB/RIF assay is available in Ethiopia. Therefore, the purpose of this study was to evaluate the performance of Xpert MTB/RIF assay compared to conventional sputum smear and culture methods for the diagnosis of pulmonary tuberculosis in remote health care facility. METHODS: A paired expectorated sputum samples were obtained from 227 consecutively recruited patients with signs and symptoms suggestive of tuberculosis at Karamara hospital during December 2013 to May 2014. One of the sputum specimen was tested directly by Ziehl-Neelsen staining and Xpert MTB/RIF assay without NALC-NaOH decontamination. The other of pair of sputa specimen was cultured for isolation of TB bacilli by conventional methods. Diagnostic performance of Xpert MTB/RIF assay and AFB smear microscopy were calculated against culture as the gold standard. RESULTS: Overall 25.5% (58/227) samples were positive for Mycobacterium tuberculosis complex (MTBC) by MGIT and/or LJ media of which 36.2% (21/58) and 65.5% (35/58) were positive by AFB smear microscopy and Xpert MTB/RIF respectively. The sensitivity, specificity, as well as the positive and negative predictive value of Xpert MTB/RIF assay were 65.5% (95% CI: 53.3-77.7%), 96.3% (95% CI: 93.4-99.2%), 86.4% (95% CI: 76.2-96.5%), and 88.6% (95% CI: 83.9-93.3%) respectively. Eighteen of 58 (31%) cases that were smear microscopy negative, were positive by Xpert MTB/RIF assay. CONCLUSIONS: Although Xpert MTB/RIF assay demonstrated high sensitivity in detecting MTBC in sputum specimens compared with conventional AFB smear microscopy, it demonstrated suboptimal sensitivity in smear negative patients compared to conventional culture. PMID- 26483192 TI - Identification of shared and unique susceptibility pathways among cancers of the lung, breast, and prostate from genome-wide association studies and tissue specific protein interactions. AB - Results from genome-wide association studies (GWAS) have indicated that strong single-gene effects are the exception, not the rule, for most diseases. We assessed the joint effects of germline genetic variations through a pathway-based approach that considers the tissue-specific contexts of GWAS findings. From GWAS meta-analyses of lung cancer (12 160 cases/16 838 controls), breast cancer (15 748 cases/18 084 controls) and prostate cancer (14 160 cases/12 724 controls) in individuals of European ancestry, we determined the tissue-specific interaction networks of proteins expressed from genes that are likely to be affected by disease-associated variants. Reactome pathways exhibiting enrichment of proteins from each network were compared across the cancers. Our results show that pathways associated with all three cancers tend to be broad cellular processes required for growth and survival. Significant examples include the nerve growth factor (P = 7.86 * 10(-33)), epidermal growth factor (P = 1.18 * 10(-31)) and fibroblast growth factor (P = 2.47 * 10(-31)) signaling pathways. However, within these shared pathways, the genes that influence risk largely differ by cancer. Pathways found to be unique for a single cancer focus on more specific cellular functions, such as interleukin signaling in lung cancer (P = 1.69 * 10(-15)), apoptosis initiation by Bad in breast cancer (P = 3.14 * 10(-9)) and cellular responses to hypoxia in prostate cancer (P = 2.14 * 10(-9)). We present the largest comparative cross-cancer pathway analysis of GWAS to date. Our approach can also be applied to the study of inherited mechanisms underlying risk across multiple diseases in general. PMID- 26483195 TI - Risk factors for post-transplant diabetes mellitus in renal transplant: Role of genetic variability in the CYP450-mediated arachidonic acid metabolism. AB - Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to epoxyeicosatrienoic acids (EETs) and 20-hidroxyeicosatetraenoic acid (20-HETE), which play an important role both in renal transplant and diabetes mellitus (DM). We searched for associations between polymorphisms in this metabolic pathway and the risk of post-transplant diabetes mellitus (PTDM) in kidney recipients. One hundred-sixty-four patients were genotyped for common SNPs in this route, namely CYP2C8*3, CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2J2*7, CYP4A11 F434S and CYP4F2 V433M. Demographic and clinical parameters were retrospectively collected at four time points in the first year after grafting. Thirty-four patients (20.73%) developed PTDM, which was more prevalent among older patients [OR for older age = 1.06 (1.03-1.10), p < 0.001] and in those with higher body mass index (BMI) [OR for higher average BMI in the first year = 1.13 (1.04-1.23); p < 0.01]. Creatinine clearance [OR = 0.97 (0.95-0.99); p < 0.01] and exposure to tacrolimus [OR = 3.25 (1.15-9.19); p < 0.05] were also relevant for PTDM risk. With regard to genetic variants, logistic regression analysis controlling for significant demographic and clinical variables showed that the V433M polymorphism in CYP4F2, responsible for 20-HETE synthesis, was an independent risk factor for PTDM [OR = 3.94 (1.08 14.33); p < 0.05]. We have shown that a genetic variant in the CYP4F2 gene, the main gene implicated in 20-HETE synthesis, is associated with the risk for PTDM. Our findings suggest that genes in the metabolic pathways of AA may become good candidates in genetic association studies for PTDM. PMID- 26483196 TI - P2X7 receptor knockout prevents streptozotocin-induced type 1 diabetes in mice. AB - Type 1 diabetes (T1D) is caused by autoimmune destruction of islet of Langerhans beta-cells. P2X7 receptors (P2X7R) modulate proinflammatory immune responses by binding extracellular ATP, a classic 'danger signal'. Here, we evaluated whether the P2X7R has a role in T1D development. P2X7(-/-) mice are resistant to TD1 induction by streptozotocin (STZ) treatment, with no increase in blood glucose, decrease in insulin-positive cells, and pancreatic islet reduction, compared to WT (C57BL/6) mice. Also, the levels of proinflammatory mediators (IL-1beta, IFN gamma and NO) did not increase after STZ treatment in P2X7(-/-) animals, with reduced infiltration of CD4(+), CD8(+), B220(+), CD11b(+) and CD11c(+) cells in the pancreatic lymph nodes. Treatment with a P2X7 antagonist mimicked the effect of P2X7 knockout, preventing STZ-induced diabetes. Our results show that the absence of the P2X7R provides resistance in the induction of diabetes in this model, and suggest that therapy targeting the P2X7R may be useful against clinical T1D. PMID- 26483197 TI - Novel water-soluble methanofullerenes C60[C13H18O4(OH)4]6 and C60[C9H10O4(OH)4]6: Promising uncouplers of respiration and phosphorylation. AB - Here, we report for the first time on two novel water-soluble polyol methanofullerenes which uncouple respiration and oxidative phosphorylation. A cytofluorimetric JC-1-based ratiometric assay was used to quantify mitochondrial potential Psim in Yarrowia lipolytica cells exposed to the fullerenes tested. Both methanofullerenes significantly downregulated Psim, thereby decreasing the subset of cells with high mitochondrial potential compared with intact control cells. The Psim-low subset of Yarrowia lipolytica cells resulted from methanofullerenes exposure preserved physiological cell size and granularity patterns. PMID- 26483198 TI - Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2 yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-beta type I receptor kinase. AB - To further optimize a clinical candidate 5 (EW-7197), a series of 5-(3-, 4-, or 5 fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6 yl)imidazoles 19a-l have been synthesized and evaluated for their TGF-beta type I receptor kinase (ALK5) and p38alpha MAP kinase inhibitory activity in an enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5 a]pyridin-6-yl)imidazoles 19h-l displayed the similar level of potency to that of 5 against both ALK5 (IC50=7.68-13.70 nM) and p38alpha MAP kinase (IC50=1240-3370 nM). Among them, 19j inhibited ALK5 with IC50 value of 7.68 nM in a kinase assay and displayed 82% inhibition at 100 nM in a luciferase reporter assay. PMID- 26483199 TI - Dendronylation: Residue-specific chemoselective attachment of oligoglycerol dendrimers on proteins with noncanonical amino acids. AB - Polyglycerol dendrimers as an important class of polymeric materials especially attractive for covalent attachment to therapeutic proteins as a useful alternative to traditional PEGylation procedures. Herein, we combine in vivo noncanonical amino acid (ncAA) incorporation and chemoselective conjugation in vitro to produce novel hybrid protein-dendrimer conjugates with the defined architectures. We incorporated Azidohomoalanine (Aha) as methionine substitute in vivo into various protein scaffolds to allow non-invasive dendrimer conjugations (dendronylation). Our approach makes recombinant proteins accessible for the design of multivalent dendrimer conjugates since it enables the preparation of many sequences with various positions for regioselective dendronylation. PMID- 26483200 TI - Synthesis and pharmacological evaluation of piperidine (piperazine)-substituted benzoxazole derivatives as multi-target antipsychotics. AB - The present study describes the optimization of a series of novel benzoxazole piperidine (piperazine) derivatives combining high dopamine D2 and serotonin 5 HT1A, 5-HT2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D2, 5-HT1A and 5 HT2A receptors, but low affinities for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi target antipsychotic treatment. PMID- 26483201 TI - Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100. AB - Various types of Hsp90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic Hsp90 inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation. PMID- 26483202 TI - Synthesis and anti-HCV determinant motif identification in pyranone carboxamide scaffold. AB - Hepatitis C Virus exhibits high genetic diversity. The current treatment for genotype-1 with ~80% sustained virologic responses is a combination of pegylated interferon, ribavirin and boceprevir/telaprevir/simeprevir which is associated with several side effects and need close monitoring. Therefore, novel therapies are invited for safer and more efficient treatment. This study was designed for synthesis of new alpha-pyranone carboxamide analogs for evaluation of anti-HCV activity to delineate structure-activity relationship (SAR) and to identify anti HCV determinant motif on this new scaffold. Forty four new alpha-pyranone carboxamide analogs were synthesized. Six potential anti-HCV candidates 11a (EC50=0.35 MUM), 11e (EC50=0.48 MUM), 12f (EC50=0.47 MUM), 12g (EC50=0.39 MUM), 12h (EC50=0.20 MUM) and 12j (EC50=0.25 MUM) with lower cytotoxicity (CC50>20 MUM) were discovered through cell based HCV replicon system. The activity profile of forty four new alpha-pyranone carboxamide analogs suggests the role of an aromatic motif in the B region to add a synergistic effect to NHOH motif at 4 position and revels an anti-HCV activity determinants motif under this scaffold. The biochemical assay against most promising HCV target protein 'NS3 protease and NS5B polymerase' showed no activity and open a scope to explore new mechanism inhibitor. PMID- 26483203 TI - JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification. AB - Pyruvate dehydrogenase kinase PDK1 is a metabolic enzyme responsible for switching glucose metabolism from mitochondrial oxidation to aerobic glycolysis in cancer cells, a general hallmark of malignancy termed the Warburg effect. Herein we report the identification of JX06 as a selective covalent inhibitor of PDK1 in cells. JX06 forms a disulfide bond with the thiol group of a conserved cysteine residue (C240) based on recognition of a hydrophobic pocket adjacent to the ATP pocket of the PDK1 enzyme. Our investigations of JX06 mechanism suggested that covalent modification at C240 induced conformational changes at Arginine 286 through Van der Waals forces, thereby hindering access of ATP to its binding pocket and in turn impairing PDK1 enzymatic activity. Notably, cells with a higher dependency on glycolysis were more sensitive to PDK1 inhibition, reflecting a metabolic shift that promoted cellular oxidative stress and apoptosis. Our findings offer new mechanistic insights including how to therapeutically target PDK1 by covalently modifying the C240 residue. PMID- 26483205 TI - TNF Receptor-2 Facilitates an Immunosuppressive Microenvironment in the Liver to Promote the Colonization and Growth of Hepatic Metastases. AB - Successful colonization by a cancer cell of a distant metastatic site requires immune escape in the new microenvironment. TNF signaling has been implicated broadly in the suppression of immune surveillance that prevents colonization at the metastatic site and therefore must be blocked. In this study, we explored how TNF signaling influences the efficiency of liver metastasis by colon and lung carcinoma in mice that are genetically deficient for the TNF receptor TNFR2. We found a marked reduction in liver metastases that correlated with a greatly reduced accumulation at metastatic sites of CD11b(+)GR-1(+) myeloid cells with enhanced arginase activity, identified as myeloid-derived suppressor cells (MDSC). Reduced infiltration of MDSC coincided with a reduction in the number of CD4(+)FoxP3(+) T regulatory cells in the tumors. Reconstitution of TNFR2 deficient mice with normal bone marrow, or adoptive transfer of TNFR2-expressing MDSC into these mice, was sufficient to restore liver metastasis to levels in wild-type mice. Conversely, treatment with TNFR2 antisense oligodeoxynucleotides reduced liver metastasis in wild-type mice. Clinically, immunohistochemical analysis of liver metastases from chemotherapy-naive colon cancer patients confirmed the presence of CD33(+)HLA-DR(-)TNFR2(+) myeloid cells in the periphery of hepatic metastases. Overall, our findings implicate TNFR2 in supporting MDSC mediated immune suppression and metastasis in the liver, suggesting the use of TNFR2 inhibitors as a strategy to prevent metastatic progression to liver in colon, lung, and various other types of cancer. PMID- 26483204 TI - CCL9 Induced by TGFbeta Signaling in Myeloid Cells Enhances Tumor Cell Survival in the Premetastatic Organ. AB - Tumor cell survival in the hostile distant organ is a rate-limiting step in cancer metastasis. Bone marrow-derived myeloid cells can form a premetastatic niche and provide a tumor-promoting microenvironment. However, it is unclear whether these myeloid cells in the premetastatic site have any direct effect on tumor cell survival. Here, we report that chemokine CCL9 was highly induced in Gr 1(+)CD11b(+) immature myeloid cells and in premetastatic lung in tumor-bearing mice. Knockdown of CCL9 in myeloid cells decreased tumor cell survival and metastasis. Importantly, CCL9 overexpression in myeloid cells lacking TGFbeta signaling rescued the tumor metastasis defect observed in mice with myeloid specific Tgfbr2 deletion. The expression level of CCL23, the human orthologue for CCL9, in peripheral blood mononuclear cells correlated with progression and survival of cancer patients. Our study demonstrates that CCL9 could serve as a good candidate for anti-metastasis treatment by targeting the rate-limiting step of cancer cell survival. In addition, targeting CCL9 may avoid the adverse effects of TGFbeta-targeted therapy. PMID- 26483206 TI - Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/beta-Catenin Signaling. AB - Merlin, the protein encoded by the NF2 gene, is a member of the band 4.1 family of cytoskeleton-associated proteins and functions as a tumor suppressor for many types of cancer. However, the roles and mechanism of Merlin expression in pancreatic cancer have remained unclear. In this study, we sought to determine the impact of Merlin expression on pancreatic cancer development and progression using human tissue specimens, cell lines, and animal models. Decreased expression of Merlin was pronounced in human pancreatic tumors and cancer cell lines. Functional analysis revealed that restored expression of Merlin inhibited pancreatic tumor growth and metastasis in vitro and in vivo. Furthermore, Merlin suppressed the expression of Wnt/beta-catenin signaling downstream genes and the nuclear expression of beta-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/beta-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of beta-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/beta-catenin signaling, suggesting that targeting novel Merlin/FOXM1/beta-catenin signaling is an effective therapeutic strategy for pancreatic cancer. PMID- 26483207 TI - c-Myc alterations confer therapeutic response and acquired resistance to c-Met inhibitors in MET-addicted cancers. AB - Use of kinase inhibitors in cancer therapy leads invariably to acquired resistance stemming from kinase reprogramming. To overcome the dynamic nature of kinase adaptation, we asked whether a signal-integrating downstream effector might exist that provides a more applicable therapeutic target. In this study, we reported that the transcriptional factor c-Myc functions as a downstream effector to dictate the therapeutic response to c-Met inhibitors in c-Met-addicted cancer and derived resistance. Dissociation of c-Myc from c-Met control, likely overtaken by a variety of reprogrammed kinases, led to acquisition of drug resistance. Notably, c-Myc blockade by RNA interference or pharmacologic inhibition circumvented the acquired resistance to c-Met inhibition. Combining c Myc blockade and c-Met inhibition in MET-amplified patient-derived xenograft mouse models heightened therapeutic activity. Our findings offer a preclinical proof of concept for the application of c-Myc-blocking agents as a tactic to thwart resistance to kinase inhibitors. PMID- 26483208 TI - Protective effect of trans-delta-viniferin against high glucose-induced oxidative stress in human umbilical vein endothelial cells through the SIRT1 pathway. AB - Oxidative stress plays a critical role in the pathogenesis of diabetic vascular complications. Trans-delta-viniferin (TVN), a polyphenolic compound, has recently attracted much attention as an antioxidant exhibiting a hypoglycemic potential. In the present study, we aimed at investigating the protective effect of TVN against high glucose-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) and the potential mechanism involved. We found that TVN attenuated reactive oxygen species (ROS) production, increased catalase (CAT) activity and decreased malondialdehyde (MDA) levels to ameliorate cell survival induced by 35 mM glucose. Meanwhile, it inhibited high glucose-induced apoptosis by maintaining Ca(2+) and preserving mitochondrial membrane potential (MMP) levels. The immunoblot analysis indicated that TVN efficiently regulated the cleavage of caspase family, p53, Bax and Bcl-2, all mediated by SIRT1. Furthermore, the increased level of SIRT1 induced by TVN was inhibited by nicotinamide and siRNA medicated SIRT1 silencing (si-SIRT1), thereby confirming the significant role of SIRT1 in these events. In conclusion, our results indicated that TVN efficiently reduced oxidative stress and maintained mitochondrial function related with activating SIRT1 in high glucose-treated HUVECs. It suggested that TVN is pharmacologically promising for treating diabetic cardiovascular complications. PMID- 26483209 TI - Effects of an intervention with drinking chamomile tea on sleep quality and depression in sleep disturbed postnatal women: a randomized controlled trial. AB - AIM: The purpose of this study was to evaluate the effects of chamomile tea on sleep quality, fatigue and depression in postpartum women. BACKGROUND: Sleep quality is a significant issue for postnatal women. Chamomile is widely used as a folk remedy for its presumed sedative-hypnotic effects. DESIGN: A pretest-post test randomized controlled trial was used. METHODS: A total of 80 Taiwanese postnatal women with poor sleep quality (Postpartum Sleep Quality Scale; PSQS score ?16) were recruited from November 2012-August 2013. They were systematically assigned, with a random start, to either the experimental group (n = 40) or the control group (n = 40). The participants in the experimental group were instructed to drink chamomile tea for a period of 2 weeks. The participants in the control group received regular postpartum care only. The PSQS, Edinburgh Postnatal Depression Scale, and Postpartum Fatigue Scale were used to assess outcomes. Two-sample t-tests were used to examine the mean differences in outcome variables between the two groups. RESULTS: Compared with the control group, the experimental group demonstrated significantly lower scores of physical-symptoms related sleep inefficiency (t = -2.482, P = 0.015) and the symptoms of depression (t = -2.372, P = 0.020). However, the scores for all three instruments were similar for both groups at 4-week post-test, suggesting that the positive effects of chamomile tea were limited to the immediate term. CONCLUSION: Chamomile tea may be recommended to postpartum women as a supplementary approach to alleviating depression and sleep quality problems. PMID- 26483211 TI - Dach2-Hdac9 signaling regulates reinnervation of muscle endplates. AB - Muscle denervation resulting from injury, disease or aging results in impaired motor function. Restoring neuromuscular communication requires axonal regrowth and endplate reinnervation. Muscle activity inhibits the reinnervation of denervated muscle. The mechanism by which muscle activity regulates muscle reinnervation is poorly understood. Dach2 and Hdac9 are activity-regulated transcriptional co-repressors that are highly expressed in innervated muscle and suppressed following muscle denervation. Dach2 and Hdac9 control the expression of endplate-associated genes such as those encoding nicotinic acetylcholine receptors (nAChRs). Here we tested the idea that Dach2 and Hdac9 mediate the effects of muscle activity on muscle reinnervation. Dach2 and Hdac9 were found to act in a collaborative fashion to inhibit reinnervation of denervated mouse skeletal muscle and appear to act, at least in part, by inhibiting denervation dependent induction of Myog and Gdf5 gene expression. Although Dach2 and Hdac9 inhibit Myog and Gdf5 mRNA expression, Myog does not regulate Gdf5 transcription. Thus, Myog and Gdf5 appear to stimulate muscle reinnervation through parallel pathways. These studies suggest that manipulating the Dach2-Hdac9 signaling system, and Gdf5 in particular, might be a good approach for enhancing motor function in instances where neuromuscular communication has been disrupted. PMID- 26483210 TI - Human stem cells from single blastomeres reveal pathways of embryonic or trophoblast fate specification. AB - Mechanisms of initial cell fate decisions differ among species. To gain insights into lineage allocation in humans, we derived ten human embryonic stem cell lines (designated UCSFB1-10) from single blastomeres of four 8-cell embryos and one 12 cell embryo from a single couple. Compared with numerous conventional lines from blastocysts, they had unique gene expression and DNA methylation patterns that were, in part, indicative of trophoblast competence. At a transcriptional level, UCSFB lines from different embryos were often more closely related than those from the same embryo. As predicted by the transcriptomic data, immunolocalization of EOMES, T brachyury, GDF15 and active beta-catenin revealed differential expression among blastomeres of 8- to 10-cell human embryos. The UCSFB lines formed derivatives of the three germ layers and CDX2-positive progeny, from which we derived the first human trophoblast stem cell line. Our data suggest heterogeneity among early-stage blastomeres and that the UCSFB lines have unique properties, indicative of a more immature state than conventional lines. PMID- 26483213 TI - Women with borderline personality disorder do not show altered BOLD responses during response inhibition. AB - Impulsivity is central to borderline personality disorder (BPD). Response inhibition, addressing the ability to suppress or stop actions, is one aspect of behavioral impulse control which is frequently used to assess impulsivity. BPD patients display deficits in response inhibition under stress condition or negative emotions. We assessed whether response inhibition and its neural underpinnings are impaired in BPD when tested in an emotionally neutral setting and when co-morbid attention-deficit/hyperactivity disorder (ADHD) is excluded. To this end, we studied response inhibition in unmedicated BPD patients and healthy controls (HC) in two independent samples using functional magnetic resonance imaging during Simon-, Go/nogo-, and Stopsignal tasks. BPD patients and HC did not differ significantly in their performance in the Go/nogo and the Stopsignal tasks. Response interference in the Simon task was increased in BPD patients in one sample, but this could not be replicated in the second sample. In both samples, no significant differences in brain activation patterns during any of the tasks were present while the neural impulse control network was robustly activated during the inhibition tasks in both groups. Our results provide evidence that under emotionally neutral conditions response inhibition is not impaired in patients with BPD without co-occurring ADHD. PMID- 26483212 TI - Processing of decision-making and social threat in patients with history of suicidal attempt: A neuroimaging replication study. AB - Suicidal vulnerability has been related to impaired value-based decision-making and increased sensitivity to social threat, mediated by the prefrontal cortex. Using functional magnetic resonance imaging, we aimed at replicating these previous findings by measuring brain activation during the Iowa Gambling Task and an emotional faces viewing task. Participants comprised 15 euthymic suicide attempters (history of depression and suicidal behavior) who were compared with 23 euthymic patient controls (history of depression without suicidal history) and 35 healthy controls. The following five model-based regions of interest were investigated: the orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (VLPFC), anterior cingulate cortex (ACC), medial (MPFC) and dorsal prefrontal cortex (DPFC). Suicide attempters relative to patient controls showed (1) increased response to angry vs. neutral faces in the left OFC and the VLPFC, as previously reported; (2) increased response to wins vs. losses in the right OFC, DPFC and ACC; (3) decreased response to risky vs. safe choices in the left DPFC; and (4) decreased response to sad vs. neutral faces in the right ACC. This study links impaired valuation processing (here for signals of social threat, sadness and reward) to prefrontal cortex dysfunction in suicide attempters. These long term deficits may underlie the impaired decision-making and social difficulties found in suicide attempters. PMID- 26483214 TI - High variability of genomic instability and gene expression profiling in different HeLa clones. AB - The HeLa cell line is one of the most popular cell lines in biomedical research, despite its well-known chromosomal instability. We compared the genomic and transcriptomic profiles of 4 different HeLa batches and showed that the gain and loss of genomic material varies widely between batches, drastically affecting basal gene expression. Moreover, different pathways were activated in response to a hypoxic stimulus. Our study emphasizes the large genomic and transcriptomic variability among different batches, to the point that the same experiment performed with different batches can lead to distinct conclusions and irreproducible results. The HeLa cell line is thought to be a unique cell line but it is clear that substantial differences between the primary tumour and the human genome exist and that an indeterminate number of HeLa cell lines may exist, each with a unique genomic profile. PMID- 26483215 TI - [Genius between music and disease: Medical considerations on Ludwig van Beethoven]. AB - Ludwig van Beethoven is nowadays considered to be one of the greatest composers in the history of music and his myth-like reputation is enhanced by his deafness; however, deafness was not the only condition which affected his genius. Due to the many lamentations contained in his letters about continuously recurring health problems, various attempts at an interpretation of Beethoven's personality have been undertaken. These included psychoanalytical considerations with respect to his father-mother relationship and also diagnostic attempts with reference to the symptoms of a possible borderline personality syndrome. The aim of this article is to comprehensively analyze the diseases of the patient Beethoven from the perspective of specialized medical disciplines based on new research results, to summarize various discipline-specific considerations and to make a contemporary assessment from the viewpoint of current scientific results. PMID- 26483216 TI - Validation of the pectoralis minor length test: A novel approach. AB - INTRODUCTION: Pectoralis minor (PM) shortness is believed to promote faulty shoulder mechanics including reduced scapular posterior tilt. A pectoralis minor length (PML) test that measures the acromion-table distance with and without manual pressure on the coracoid process is supposed to examine the passive mechanical properties of the PM. A threshold for "shortening" has been set at 2.6 cm, but data regarding its validity are lacking. We hypothesized that, under conditions of good reliability, an evaluation of the effect of PM tenotomy, could adequately investigate the construct validity of this test. METHODS: Sixteen subjects with anterior shoulder instability who were undergoing open Latarjet procedures were recruited. We performed the PML test with and without pressure (1) in a clinical setting to check for intratester reliability and setting comparability and (2) in an intraoperative setting immediately before and after PM tenotomy to assess the construct validity. RESULTS: The PML test exhibited excellent intra-tester reliability (intracorrelation coefficients, ICC > 0.94) and reasonable setting comparability (ICC 0.31-0.54). The change following intraoperative PM tenotomy was significant (p < .008) but small (mean = 0.46-0.50 cm) compared to the measurement variability (standard deviation 1.0-1.5 cm). In 12 of the 16 subjects, the measurements remained above the threshold of 2.6 cm. CONCLUSIONS: The influence of the PM on the PML test seems to be minor compared to other factors that cause high measurement variability. A threshold of 2.6 cm cannot distinguish between short and normal PMs. Our findings suggest that the impact of the PM on restricted scapular posterior tilt might be smaller than believed. PMID- 26483217 TI - Effects of nosocomial infection trends on neonatal outcomes in preterm infants <33 weeks of gestational age in Canadian NICUs. AB - OBJECTIVE: To characterize recent trends of nosocomial infection (NI) among preterm infants admitted to Canadian Level 3 NICUs during 2008-2012, and its association with neonatal outcomes. METHODS: A retrospective observational cohort study was performed including infants born <33 weeks gestational age and admitted to 24 NICU sites participating in the Canadian Neonatal NetworkTM during 2008 2012. NICU sites were classified into three groups according to their baseline NI rates in 2008 [Low NI group (<=14%), Medium NI group (14.1%-19%) and High NI group (>19%)], and NICU sites were also classified according to their NI trend during 2008-2012 (decreased, null and increased). Trends in NI were further examined for each baseline-NI group. Trends for a composite outcome indicating mortality or severe morbidities (intraventricular hemorrhage grades>=3 or periventricular leukomalacia, retinopathy of prematurity stages>=3, bronchopulmonary dysplasia or necrotizing enterocolitis stages>=2) were examined for each baseline-NI and trend-NI NICU site groups using multivariable logistic regression analyses adjusted for potential confounders. RESULTS: Baseline high NI group showed significantly decreased trends in NI rates, while for with medium or low baseline NI groups showed no significant trends in NI rates. The composite outcome (mortality during NICU stay or any severe neonatal morbidity such as intraventricular hemorrhage grades 3-4, periventricular leukomalacia, retinopathy of prematurity stages 3-5, bronchopulmonary dysplasia and necrotizing enterocolitis stages 2-3) decreased significantly for sites with decreased (OR=0.89, 95% CI=0.85-0.93) or null (OR=0.94, 95% CI=0.90-0.98) NI trends, but no significant trends in the composite outcome were detected for sites with increased NI rates. CONCLUSIONS: The neonatal outcome is possibly influenced by NI rates and trend. The trend in the mortality and the risk of bronchopulmonary dysplasia, retinopathy of prematurity stage>=3 and intraventricular hemorrhage>2 were significantly decreased for sites with decreased NI trend, suggesting that these improved outcomes may be associated with effort to decrease NI rate. PMID- 26483218 TI - [Comparison of clinical features of purulent meningitis between small-for gestational-age and appropriate-for-gestational-age infants]. AB - OBJECTIVE: To study the differences in the clinical features of purulent meningitis (PM) between small-for-gestational-age (SGA) and appropriate-for gestational-age (AGA) infants. METHODS: The clinical data of 58 full-term infants with PM were analyzed retrospectively. The infants were classified into a SGA group (13 cases) and an AGA group (45 cases) according to their birth weight and gestational age. Clinical manifestations, laboratory results, and outcomes were compared between the two groups. RESULTS: The incidence of decreased muscle tone in the SGA group was significantly higher than that in the AGA group (P<0.05); the positive rate in the Pandy's test for cerebrospinal fluid in the SGA group was significantly higher than that in the SGA group (P<0.05). Brain imaging examination showed that the incidence of brain injuries in the SGA group was significantly higher than that in the AGA group (P<0.05). CONCLUSIONS: SGA infants with PM display a higher risk of brain injury, suggesting a poorer outcome, compared with AGA infants. PMID- 26483219 TI - [Evaluation of therapeutic effects and safety of different treatment methods for premature patent ductus arteriosus]. AB - OBJECTIVE: To explore the clinical treatment methods and their effects in the treatment of premature patent ductus arteriosus (PDA) and to summarize the experience of surgical treatment for PDA. METHODS: Nineteen premature infants who were diagnosed with PDA and received surgical treatment betwen January 2013 and December 2014 were selected as the surgical group, and 19 premature infants with PDA who did not receive surgical treatment during the same period were selected as the non-surgical group. The differences in medical history, clinical conditions, mortality, and major complications between the two groups were analyzed, and the characteristics of surgical treatment and its clinical effects were analyzed from the aspects of preoperative preparation and surgical results. RESULTS: Compared with the surgical group, the gestational age and birth weight in the non-surgical group were significantly greater (P<0.01), and Apgar scores for 1 and 5 minutes after birth were significantly higher in the non-surgical group (P<0.05). The PDA diameter, time to confirmed ultrasonic diagnosis, and duration of auxiliary ventilation in the surgical group were greater than in the non-surgical group, and the incidence of drug therapy, left atrium/aortic root (LA/AO) ratio>1.3, and the square of catheter diameter/birth weight (d2/BW) ratio>9 mm2/kg in the surgical group was significantly higher than in the non surgical group (P<0.05). Compared with the non-surgical group, the surgical group had a significantly higher incidence of bronchopulmonary dysplasia (P<0.01), and there were no significant differences in the incidence of death, cerebral white matter damage, intracranial hemorrhage, and necrotizing enterocolitis between the two groups (P>0.05). CONCLUSIONS: For premature infants with clinical symptoms and no improvement after conservative medical treatment or drug therapy, surgical ligation is a relatively safe and effective treatment method for PDA. PMID- 26483220 TI - [Clinical features, prevention and treatment of respiratory distress syndrome in neonates of different gestational ages in tertiary hospitals in Northwest China]. AB - OBJECTIVE: To investigate the clinical features, prevention and treatment of respiratory distress syndrome (RDS) in neonates of different gestational ages (GA) in the tertiary hospitals in Northwest China. METHODS: A total of 440 neonates diagnosed with RDS between January and December, 2011 in 12 tertiary hospitals in Northwest China were enrolled and classified into three groups: early preterm (GA<34 weeks; n=247), late preterm (GA 34-36(+6) weeks; n=131) and full-term (GA>=37 weeks; n=62). The clinical data, including perinatal factors, prevention and treatment, complications and prognosis, were comparatively analyzed among the three groups. RESULTS: The rate of multiple births in the early preterm group was higher than the other two groups. The two preterm groups showed a higher incidence of premature rupture of membranes than the full-term group. The full-term group had a higher rate of cesarean section without contractions than the two preterm groups. The early preterm group had the highest application rate of antenatal steroids. Compared with the other two groups, the early preterm group had a higher application rate of pulmonary surfactants (PS) and an earlier time of first application of PS. The full-term group had a lower resuscitation rate than the two preterm groups. The early preterm group showed a higher incidence of patent ductus arteriosus and intracranial hemorrhage than the other two groups. The cure rate of RDS (78.2%) was the highest in the full-term group, followed by the late preterm group (58.6%) and the early preterm group (42.9%). CONCLUSIONS: RDS infants of different GA in Northwest China have significant differences in perinatal factors, antenatal prevention, PS treatment, complications and prognosis. PMID- 26483221 TI - [Analgesic effect of fentanyl in neonates during mechanical ventilation]. AB - OBJECTIVE: To study the analgesic effect and safety of fentanyl in neonates receiving mechanical ventilation. METHODS: Thirty neonates receiving mechanical ventilation between December 2010 and February 2011 were randomized into drug intervention group and control group (n=15 each). In addition to the conventional treatment for both groups, the drug intervention group received fentanyl as the analgesic treatment. Heart rate, respiratory rate, blood pressure changes, and premature infant pain profile (PIPP) score before treatment and at 30 minutes, 2 hours, and 4 hours after treatment were recorded in both groups. Follow-up visits were performed for these infants after discharge, and the CDCC intellectual development scale for infants was applied to measure mental development index (MDI) and psychomotor development index (PDI) at 3, 6, 9, and 12 months of age. RESULTS: The respiratory rate and heart rate decreased in the drug intervention group after fentanyl treatment compared with the control group (P<0.05), and the PIPP scores in the drug intervention group was significantly lower than in the control group (P<0.05). The results of follow-up visits showed no significant differences in MDI and PDI at 3, 6, 9 and 12 months of age between the drug intervention and control groups (P>0.05). CONCLUSIONS: Fentanyl can relieve the pain response in neonates receiving mechanical ventilation, with no long-term adverse effects on neurodevelopment. PMID- 26483222 TI - [Expression and significance of toll-like receptors 7 and 8 in brain and lung tissues of death cases caused by EV71 infection]. AB - OBJECTIVE: To study the significance of toll-like receptors (TLR) -7 and -8 in the pathogenesis of infection caused by Enterovirus type 71 (EV71) through measuring the expression of TLR7 and TLR8 in brain and lung tissues from the death cases caused by EV71 infection. METHODS: Nine children who died of EV71 infection (EV71 group) were selected as study subjects, and 7 children who died of accidents or non-infectious diseases were used as the control group. Brain and lung tissues from the death cases in both groups at autopsy were collected, and immunohistochemistry was applied to detect the expression of TLR7 and TLR8 in lung and brain tissues in both groups. Integrated optical density (IOD) was applied for semi-quantitative analysis of the expression of TLR7 and TLR8. RESULTS: Immunohistochemical results showed that the expression of TLR7 and TLR8 in lung and brain tissues was strongly positive in the EV71 group, and the IOD values in the EV71 group were also significantly higher than those in the control group (P<0.05). There was no significant difference in the expression of TLR7 and TLR8 between lung and brain tissues in the EV71 group (P>0.05). CONCLUSIONS: TLR7 and TLR8 are highly expressed in lung and brain tissues from the patients who die of severe EV71 infection, suggesting that TLR7 and TLR8 may be involved in the pathogenesis of brain and lung damages caused by severe EV71 infection. PMID- 26483223 TI - [Distribution of pathogenic microorganisms and its relationship with clinical features in children with community-acquired pneumonia]. AB - OBJECTIVE: To study the distribution of pathogenic microorganisms in different genders, age groups and seasons in children with community-acquired pneumonia (CAP) and the relationship between the distribution of pathogenic microorganisms and clinical features. METHODS: A total of 1,155 children with CAP were enrolled, among whom there were 670 boys and 485 girls, with a mean age of 3.1+/-2.8 years (range: one month to 14 years). Indirect immunofluorescence assay, particle agglutination test, enzyme-linked immunosorbent assay, colloidal gold method. and bacterial culture were applied to determine common respiratory pathogenic microorganisms in sputum, throat swabs, blood samples, bronchoalveolar lavage fluid, and urine. RESULTS: A total of 758 specimens (65.63%) were tested positive by pathogen detection. The top three dominant pathogens were Mycoplasma pneumoniae (MP, 43.64%), bacteria (15.12%), and respiratory syncytial virus (RSV, 9.26%), and the rate of mixed infection was 16.02%. The rates of MP infection between boys and girls with CAP were different (40.8% vs 47.6%; P<0.05). The MP detection rate was the highest in the age group of 6-14 years (77.4%) and the lowest in children younger than 1 year (11.2%), while the detection rates of bacteria and RSV were the highest in children younger than 1 year (21.2% and 17.2%, respectively). The MP detection rate was significantly higher in summer and autumn than in winter and spring, while the detection rates of bacteria and RSV in summer and autumn were significantly lower than those in winter and spring. Among children who were MP positive, fever, chills, cough, crackles were more likely to appear; children with RSV infection were more likely to have wheezes; children with bacterial infection were less likely to have cough. Serum levels of C-reactive protein and procalcitonin were associated with bacterial infection (OR=1.747 and 1.418, respectively; both P<0.05). CONCLUSIONS: MP plays a more and more important role in the pathogenic microorganisms of CAP in children. Prevalence and outbreaks of MP infection among children should be alerted in summer and autumn. There are differences in the detection rate of various pathogenic microorganisms in CAP children with various age groups. The clinical features of children with CAP caused by different pathogenic microorganisms are different. PMID- 26483224 TI - [Clinical efficacy of montelukast for the treatment of bronchiolitis in infants]. AB - OBJECTIVE: To observe the effect of montelukast treatment on levels of serum leukotriene B4 and urinary leukotriene E4 in infants with bronchiolitis. METHODS: Seventy-five children who were diagnosed with bronchiolitis between June 2014 and December 2014 were randomly assigned into two groups, one with thirty-eight cases as the montelukast treatment group and another thirty-seven cases as the control group. All of the children were given routine medical treatment. The children in the montelukast treatment group were additionally given montelukast daily (4 mg once a day, for 7 days). The serum leukotriene B4 and urinary leukotriene E4 levels were measured using ELISA before and after treatment. The relationship between serum leukotriene B4 and urinary leukotriene E4 levels was analyzed by Peason correlation analysis. RESULTS: After 7 days of treatment, the serum leukotriene B4 and urinary leukotriene E4 levels in the montelukast treatment and control groups were significantly reduced compared with before treatment (P<0.05). The montelukast treatment group showed significantly lower serum leukotriene B4 and urinary leukotriene E4 levels than the control group (P<0.05). The remission time of cough, wheezing and lung wheezes and the length of hospital stay in the montelukast treatment group were significantly shortened compared with the control group (P<0.05). There was a positive correlation between serum leukotriene B4 and urinary leukotriene E4 levels (r=0.723, P<0.05). CONCLUSIONS: Montelukast has a reliable clinical curative efficacy for bronchiolitis in infants, possibly by decreasing serum leukotriene D4 and urinary leukotriene E4 levels. PMID- 26483225 TI - [Comparison of clinical application of exercise challenge test and methacholine challenge test in measurement of airway hyperresponsiveness]. AB - OBJECTIVE: To compare the advantages and disadvantages between exercise challenge test (ECT) and methacholine challenge test (MCT) in the measurement of airway hyperresponsiveness (AHR), in order to identify a better and safer method to measure AHR. METHODS: Forty-seven children with controlled asthma after regular treatment were enrolled. ECT and MCT were performed for each child successively, and sensitivity was obtained through comparison with the golden standard (PD20). The occurrence of bronchospasm symptoms during the two tests was recorded. RESULTS: Taking PD20 as the gold standard, in children with moderate or severe AHR, the sensitivity of MCT (61%) for the measurement of AHR was significantly higher than that of ECT (9%) (P<0.05). The consistency between MCT results and PD20 was relatively high (kappa=0.614), while the consistency between ECT results and PD20 was relatively low (kappa=0.006). However, in the MCT, the incidence of bronchospasm symptoms was high and positively correlated with the incidence of cough and chest distress (P<0.05). CONCLUSIONS: MCT has a higher sensitivity for the measurement of AHR, but has a higher incidence of adverse events, compared with ECT in children with controlled asthma after regular treatment. PMID- 26483226 TI - [Time-dependent heart rate variability in the head-up tilt test in children with postural orthostatic tachycardia syndrome]. AB - OBJECTIVE: To study the time-dependent heart rate (HR) variability in the head-up tilt test (HUTT) in children with postural orthostatic tachycardia syndrome (POTS) and to explore the HR diagnostic criteria for POTS in children. METHODS: A retrospective analysis was performed on the clinical data of 105 children diagnosed with POTS with HR>=120 beats per minute (bpm) within the first 10 minutes of HUTT between January 2007 and December 2014. Their HR variability within the first 10 minutes of HUTT was analyzed. RESULTS: The HR of children with POTS increased gradually from the supine position to a 60 degrees head-up tilt position, and the increase in HR was 24+/-12 bpm at the beginning of HUTT, 30+/-14 bpm at 3 minutes of HUTT, 32+/-13 bpm at 5 minutes of HUTT, and 38+/-12 bpm at 10 minutes of HUTT. The average maximal HR increase within the first 10 minutes of HUTT was 43+/-10 bpm. CONCLUSIONS: In children with POTS, the HR variability gradually increases with time, and therefore, it is suggested that HR increase >=40 bpm is more suitable for diagnosis of POTS in children. PMID- 26483227 TI - [Diagnosis of noncompaction of the ventricular myocardium by echocardiography]. AB - OBJECTIVE: To evaluate the value of echocardiography in the diagnosis of noncompaction of the ventricular myocardium (NCVM) and to elucidate the echocardiographic characteristics of NCVM. METHODS: This study included 53 patients (28 boys and 25 girls), with an age for initial diagnosis of 15 days to 18 years, who were diagnosed with NCVM by echocardiography between May 2006 and May 2015. Transthoracic two-dimensional echocardiography and color Doppler were performed for qualitative diagnosis, and the end-diastolic non-compacted layer/compacted layer (N/C) ratio measured in the parasternal ventricular short axis sectional view was selected as the criterion for quantitative diagnosis. RESULTS: The excessively prominent ventricular trabeculae and deep inter trabecular recesses were all seen in 53 cases, and the blood flow in the cardiac chambers was connected to the inter-trabecular recesses. The areas involved in NCVM were mainly the apex (100%) and the middle segment of the left ventricular lateral wall (98%), followed by the middle segment of the left ventricular posterior wall (49%) and the middle segment of the left ventricular inferior wall (42%). In 53 children with NCVM, the N/C ratio was 4.3+/-1.9 (2.1-10.0). Cardiac insufficiency was found in 83% (44/53) of the children with NCVM, and the left ventricular ejection fraction for these children was (43+/-9)%. CONCLUSIONS: Echocardiography can be used in the qualitative and quantitative diagnosis of NCVM and in the evaluation of cardiac function. The apex and the middle segment of the left ventricular lateral wall are often involved in NCVM, accompanied by decrease in the left ventricular ejection fraction. PMID- 26483228 TI - [Clinical characteristics of Henoch-Schonlein purpura in children]. AB - OBJECTIVE: To explore the clinical characteristics of Henoch-Schonlein purpura (HSP) in children. METHODS: The clinical data of 325 hospitalized children who were diagnosed with HSP between June 2012 and June 2014 were analyzed retrospectively. RESULTS: In the 325 children with HSP, the incidence of HSP was higher in winter and spring, with 33.9% and 27.4%, respectively. Infection was the major factor to induce HSP (57.2%). The incidence of renal damage in children with purpura accompanied by abdominal symptoms and children with purpura accompanied by abdominal and joint symptoms was 60.3% and 48.9%, respectively, with statistically significant differences compared with children with purpura alone (P<0.05). In 32 children with purpura nephritis, the pathological grades of IIIa and IIIb were more common, accounting for 28% and 31%, respectively. In 325 children, an increased serum D-dimer level was observed in 260 children (80.0%), an increased peripheral IgA content in 101 children (46.3%), and a decreased CD4+ cell percentage in 62 children (56.4%). CONCLUSIONS: A high incidence of HSP is often seen in spring and winter. HSP is often induced by upper respiratory tract infection. Renal damage is more likely to occur in children with digestive tract symptoms, with IIIa and IIIb as the common pathological grades of renal damage. PMID- 26483229 TI - [Roles of follicular helper T cells and follicular regulatory T cells in pathogenesis of Henoch-Schonlein purpura in children]. AB - OBJECTIVE: To study the roles of follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells in the pathogenesis of Henoch-Schonlein purpura (HSP) in children. METHODS: Peripheral blood samples were collected from 40 HSP children and 25 healthy controls. The percentages of Tfh and Tfr cells were measured by flow cytometry; the mRNA expression levels of Bcl-6, c-MAF, Blimp-1, and PD-1 in peripheral blood were measured by real-time polymerase chain reaction. RESULTS: Compared with the controls, the children with HSP had significantly increased percentage of Tfh cells and Tfh/Tfr ratio but a significantly reduced percentage of Tfr cells in the peripheral blood (P<0.05). Compared with the controls, the children with HSP had significantly increased mRNA expression of Bcl-6 and c-MAF but significantly reduced mRNA expression of Blimp-1 in CD4+ T cells (P<0.05), and had significantly increased mRNA expression of PD-1 but significantly reduced mRNA expression of Blimp-1 in CD4+CD25+ regulatory T cells (P<0.05). CONCLUSIONS: Abnormal percentages of Tfh and Tfr cells may be involved in the pathogenesis of HSP in children, and over-expression of Bcl-6, c-MAF, and PD-1 mRNA and inhibited expression of Blimp-1 mRNA may be considered as important reasons for abnormal percentages of Tfh and Tfr cells. PMID- 26483230 TI - [Efficacy of infliximab in the treatment of Crohn's disease in children]. AB - OBJECTIVE: To evaluate the efficacy and safety of infliximab in the treatment of Crohn's disease in children. METHODS: Thirteen children who were diagnosed with Crohn's disease and received routine comprehensive treatment and infliximab (5 mg/kg) between January 2011 and December 2014 were enrolled. The changes in their clinical manifestations, laboratory indices, and Pediatric Crohn's Disease Activity Index (PCDAI) after the 30-week treatment were analyzed retrospectively. Meanwhile, endoscopy was performed to evaluate therapeutic effects. RESULTS: The symptoms such as abdominal pain, diarrhea, and bloody stool were relieved soon after infliximab treatment, with no recurrence observed; after the 30-week treatment, the white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and the PCDAI decreased, while the hemoglobin increased significantly compared with those before treatment (P<0.05). After infliximab treatment, two children underwent endoscopy. The endoscopy showed that one child was cured, and the other child failed to respond to the treatment. No adverse drug reactions were seen in all patients. CONCLUSIONS: Infliximab treatment has significant clinical effects in children with Crohn's disease, with no obvious adverse reactions, and therefore, it can be applied as one of the preferred alternatives for treatment of Crohn's disease in children. PMID- 26483231 TI - [Effects of HPGA suppression on predicted adult height in girls with central precocious puberty]. AB - OBJECTIVE: To study the relationship between the suppression of the hypothalamic pituitary-gonadal axis (HPGA) and the predicted adult height (PAH) in girls with central precocious puberty (CPP) during the treatment with gonadotropin-releasing hormone analogue (GnRHa), in order to provide guidance for individualized GnRHa dose adjustment in clinical practice. METHODS: The clinical data of 75 CPP girls were collected, and then height, bone age (BA), uterine and ovarian volumes, and peak luteinizing hormone (LH), peak follicle-stimulating hormone (FSH), and estradiol (E2) levels were recorded at different time points of GnRHa treatment. PAH at each time point was calculated. PAH improvement (DeltaPAH=PAH-target height) and its relationship with the degree of HPGA suppression were analyzed. Threshold effect analysis was applied to determine the best HPGA suppression range forDeltaPAH. RESULTS: After GnRHa treatment, PAHs were improved markedly compared with the data in the early stage of treatment. DeltaPAH showed a negative correlation with DeltaBA. At 24 months of treatment, DeltaPAH was also negatively correlated with LH. Uterine volume controlled between 2.3 and 3.0 mL, LH level controlled below 0.8 IU/L, and FSH controlled below 2.4 IU/L could slow down the growth of BA and improve PAH. CONCLUSIONS: GnRHa treatment can improve the PAH of CPP girls. Selection of an appropriate therapeutic dose for GnRHa to control uterine volume, LH and FSH levels within certain ranges can slow down the growth of BA and improve PAH. PMID- 26483232 TI - [Changes in fasting serum cortisol levels in adolescents with type 1 diabetes and elevated depressive symptoms]. AB - OBJECTIVE: To study the changes in serum cortisol levels in adolescents with type 1 diabetes (T1DM) and elevated depressive symptoms. METHODS: Twenty-eight adolescents with T1DM and 31 healthy peers were assessed for depressive symptoms using a depression self-rating scale developed by the Epidemiological Survey Center. Selected subjects were classified into four groups: T1DM with elevated depressive symptoms group (n=15), T1DM without elevated depressive symptoms group (n=13), elevated depressive symptoms without T1DM group (n=15), and normal control group (n=16). Fasting blood samples were collected in the morning, and the levels of serum cortisol were compared among the four groups. The correlations of serum levels of cortisol and glycosylated hemoglobin A1c (HbA1c) with the score of depression self-rating scale were evaluated by Pearson correlation analysis. RESULTS: The fasting serum cortisol levels in the 28 T1DM patients were significantly higher than in the 31 healthy peers (P<0.01). The fasting cortisol levels in the T1DM with elevated depressive symptoms group were significantly higher compared with those in the elevated depressive symptoms without T1DM group and normal control group (P<0.01). In adolescents with T1DM, serum HbA1c level was positively correlated with the score of depression self rating scale (r=0.481, P=0.010). CONCLUSIONS: The fasting serum cortisol levels in adolescents with T1DM and elevated depressive symptoms are significantly increased, suggesting that the patients with comorbidity of T1DM and depression develop dysfunction of the corticotropin-releasing hormone-adrenocorticotropic hormone-cortisol axis. The elevated depressive symptoms may be associated with a poor control of glucose metabolism. PMID- 26483233 TI - [Acute brainstem encephalitis and myelitis in a girl with isolated methylmalonic aciduria due to MUT gene defect]. AB - Methylmalonyl CoA mutase deficiency due to MUT gene defect has been known as the main cause of isolated methylmalonic acidemia in Mainland China. This study reported a patient with isolated methylmalonic aciduria (MUT type) characterized as acute brainstem encephalitis and myelitis. The previously healthy girl presented with fever, lethargy and progressive weakness in her extremities at the age of 3 years and 2 months. Three day later, she had respiratory distress and consciousness. Cranial MRI revealed bilateral symmetrical lesion of pallidum, brain stem and spinal cord, indicating acute brainstem encephalitis and myelitis. Her blood propionylcarnitine (6.83 MUmol/L vs normal range 1.0 to 5.0 MUmol/L) and urinary methylmalonic acid (133.22 mmol/mol creatinine vs normal range 0.2 to 3.6 mmol/mol creatinine) increased significantly. Plasma total homocysteine was normal. On her MUT gene, a reported mutation (c.1630_1631GG>TA) and a novel mutation (c.1663C>T, p.A555T) were identified, which confirmed the diagnosis of methylmalonic aciduria (MUT type). After cobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine, progressive improvement has been observed. The clinical manifestation of patients with methylmalonic aciduria is complex. Metabolic study and gene analysis are keys for the diagnosis and treatment of the disorder. PMID- 26483234 TI - [Association of FGF23 gene polymorphism with Kawasaki disease and coronary artery lesions]. AB - OBJECTIVE: To study the distribution of polymorphism of c.212-37insC (rs3832879) in intron 1 of fibroblast growth factor 23 (FGF23) gene and its association with Kawasaki disease (KD) and coronary artery lesions (CAL). METHODS: Forty children with KD were enrolled in this study, among whom 16 children had concurrent CAL. Twenty-six age-matched healthy children were enrolled as controls. PCR and gene sequencing were applied to explore the distribution of polymorphism of c.212 37insC (rs3832879) in FGF23 gene in KD patients and controls. RESULTS: Among 40 children with KD, 14 (35%) carried the polymorphism of c.212-37insC (rs3832879) in FGF23 gene; among 26 controls, 6 (23%) carried such polymorphism. There was no significant difference in genotype distribution at this locus between the two groups (P=0.30). Among 16 children with CAL, 9 (56%) carried the polymorphism at this locus; among 24 children without CAL, 5 (21%) carried such polymorphism. As for the comparison of two subgroups with and without CAL, the difference in genotype distribution at this locus had statistical significance (P=0.02, OR=4.89, 95% CI: 1.21-19.71). CONCLUSIONS: The polymorphism of c.212-37insC (rs3832879) in FGF23 gene may not be associated with the pathogenesis of childhood KD, but it may be associated with the development of CAL in children with KD. PMID- 26483235 TI - [Association between CYP1A1*2A polymorphism and susceptibility to childhood acute lymphoblastic leukemia: a Meta analysis]. AB - OBJECTIVE: To explore the association between CYP1A1*2A polymorphism and susceptibility to childhood acute lymphoblastic leukemia (ALL) through a Meta analysis. METHODS: Inclusion and exclusion criteria were formulated and English and Chinese databases (PubMed, OVID Database, CBM, CNKI, and Wanfang Data) were searched comprehensively. The studies (from January 1999 to April 2015) related to the association between CYP1A1*2A polymorphism and susceptibility to childhood ALL were collected. STATA 12.0 Software was applied to perform the Meta analysis for the articles included. RESULTS: A total of 12 articles were included for analysis (11 English articles and 1 Chinese article), which involved 3 355 cases in total. The results of the Meta analysis showed a significant association between CYP1A1*2A polymorphism and susceptibility to childhood ALL (allele model: OR=1.31, 95% CI: 1.07-1.61; dominant model: OR=1.33, 95% CI: 1.13-1.56; codominant model: OR=1.30, 95% CI: 1.10-1.54). According to the results of a subgroup analysis based on ethnic origin, an increased risk of childhood ALL was observed in both Asian subgroup (dominant model: OR=1.57, 95% CI: 1.19-2.08; codominant model: OR=1.61, 95% CI: 1.20-2.17) and the Caucasian subgroup (allele model: OR=1.31, 95% CI: 1.04-1.63; dominant model: OR=1.22, 95% CI: 1.00-1.49). CONCLUSIONS: CYP1A1*2A polymorphism may be associated with the genetic susceptibility to childhood ALL. PMID- 26483236 TI - [Effects of hydrogen sulfide donor on production of adrenomedullin and atrial natriuretic peptide in rats with atherosclerosis]. AB - OBJECTIVE: Endogenous hydrogen sulfide (H2S), a novel gasotransmitter in cardiovascular regulation, plays an important protective role in the development and progression of atherosclerosis (AS). This study was designed to explore the effects of H2S donor on the production of adrenomedullin (ADM) and atrial natriuretic peptide (ANP) in AS rats. METHODS: Male Sprague-Dawley rats were randomly divided into control group (n=10), AS group (n=10), and AS+NaHS group (n=10). Rats in the AS and AS+NaHS groups were given 3-day intraperitoneal injections of vitamin D3 and 8-week high-fat diet to induce AS, and the rats in the AS+NaHS group were intraperitoneally injected with H2S donor NaHS. Oil red O staining was applied to detect changes in the areas of the atherosclerotic plaques in the aortic root and the coronary artery; sulfide-sensitive electrode method was used to measure the plasma concentration of H2S. ADM and ANP levels in plasma were determined by radioimmunoassay. RESULTS: Compared with the control group, marked atherosclerotic plaques were observed in the aortic root and the coronary artery in AS rats. Moreover, plasma H2S level decreased significantly, ADM level increased, and ANP level decreased significantly in AS rats (P<0.01). However, after the treatment with H2S donor NaHS for 8 weeks, the above changes in AS rats were reversed, demonstrated by significantly reduced areas of the atherosclerotic plaques in both the aortic root and the coronary artery, significantly increased plasma H2S level, significantly decreased plasma ADM level, and significantly increased plasma ANP level (P<0.01). CONCLUSIONS: H2S plays an important regulatory effect on vasoactive peptides ADM and ANP in AS rats. PMID- 26483237 TI - [Effects of intrauterine growth restriction and high-fat diet on serum lipid and transcriptional levels of related hepatic genes in rats]. AB - OBJECTIVE: To study the effects of intrauterine growth restriction (IUGR) and high-fat diet on the growth, lipid metabolism, and related hepatic genes in rat offspring. METHODS: The rat model of IUGR was established by food restriction during the entire pregnancy. After weaning, 32 normal rats and 24 offspring rats with IUGR were randomly allocated to standard diet group or high-fat diet group. At the age of 10 weeks, fasting plasma glucose and blood lipid were examined. Additionally, pathological sections for hepatic tissues were observed, and the transcriptional levels of related hepatic genes were measured. RESULTS: At the age of 10 weeks, there was a significant difference in body weight between IUGR rats and normal rats on standard diets, but no significant difference in body weight was observed between the two groups on high-fat diets. Compared with the normal rats, IUGR rats showed increased energy intake and increased levels of fasting plasma glucose, total cholesterol, and triglyceride on both standard and high-fat diets. High-fat diets reduced the concentration of serum triglyceride in both normal rats and IUGR rats. IUGR and high-fat diets aggravated the fat accumulation in the liver. Two-factor analysis of variance showed that at the age of 10 weeks, the expression of genes related to lipid metabolism in the liver, PGC-1alpha, CPT-1, SREBF-2, HMGR, LDLR and SREBF-1, differed significantly between IUGR and normal rats. Compared with standard diets, high-fat diets increased the expression of PPARalpha, SREBF-1, SREBF-2, ABCG5, and CYP7A1 in both normal rats and IUGR rats. IUGR and high-fat diets had an interactive effect on LDLR expression. CONCLUSIONS: Hyperlipidemia and fat accumulation in the liver observed in IUGR rats may be related to increased appetite and regulation disorder in genes related to fatty acid oxidation at the transcriptional level. High-fat diets may aggravate fat accumulation in the liver in rats, which may be related to increased expression of genes related to regulation of fatty acid synthesis at the transcriptional level and reduction in secretion of triglyceride. PMID- 26483238 TI - [Painless skin nodules and ecchymosis in a school-aged girl]. AB - A 7-year-old girl was admitted to Xiangya Hospital due to systemic lymphadenectasis for 2 months and skin ecchymosis for 3 days. Nine months ago, the girl experienced painless nodules in the left lower extremity with no apparent causes. Three months later, dermatorrhagia and ecchymosis occurred in many regions such as the periocular areas, conjunctiva, oral mucosa, perineal area, and groin, with a "raccoon sign" in both eyes; superficial lymphadenectasis and hepatosplenomegaly were also observed in many regions. The pathological sections for the skin nodules showed malignant tumors in lymphohematopoietic cells, and in combination with clinical manifestations, immunohistochemistry, and positive results for CD4, CD56, and CD123 by bone marrow flow cytometry, the girl was diagnosed with blastic plasmacytoid dendritic cell neoplasm. Then high-risk ALL regimen was applied as the chemotherapy for this girl. At present, the girl has been followed up for 3 months; ecchymosis has disappeared, and the enlarged lymph nodes have shrunk. No abnormal cells have been found in bone marrow morphological examination, and bone marrow flow cytometry has shown that primitive precursor cells account for 1.5% and express CD33, CD34, CD123, and CD117. PMID- 26483239 TI - [Clinical characteristics and therapy of idiopathic hypoparathyroidism in 30 infants]. PMID- 26483240 TI - [Neurofibromatosis complicated by acute lymphoblastic leukemia in a boy]. PMID- 26483241 TI - [Progress in management of patent ductus arterious in preterm infants with gestational age of <28 weeks]. AB - Patent ductus arteriosus (PDA) is a common problem encountered in the early neonatal period, particularly in preterm infants. Optimal management of PDA in preterm infants remains controversial. Despite considerable historical and physiological data indicating a persistent PDA may be harmful, robust evidence of long-term benefits or harms from treatment is lacking. This has been equated to a lack of benefit but is also a reflection of the fact that many clinical trials were designed to assess the effects of short-term (2-8 days) rather than prolonged exposure to a PDA. No clinical trials have been designed to assess the effects of prolonged exposure of persistent PDA on morbidity and mortality of very premature infants. Significant changes in management of PDA, i.e., less treatment for PDA, have evolved in recent years. This paper reviews the current literature and evidence for treatment options and research progress of PDA in infants with gestational age of <28 weeks. PMID- 26483242 TI - The Royal Australian and New Zealand College of Radiologists (RANZCR) 65th Annual Scientific Meeting, 29 October-1 November 2015, Adelaide, Australia. PMID- 26483244 TI - Lung Cancer Risk and Demographic Characteristics of Current 20-29 Pack-year Smokers: Implications for Screening. AB - BACKGROUND: Based on current recommendations, 30+ pack-years of smoking are required for eligibility for low-dose CT (LDCT) lung cancer screening; former smokers must have quit within 15 years. We investigated whether current smokers with 20 to 29 pack-years have similar lung cancer risks as eligible former smokers and also whether they have a different demographic profile. METHODS: The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) was a randomly assigned screening trial of subjects age 55 to 74 years with chest radiographs (CXR) used for lung cancer. Subjects completed a baseline questionnaire containing smoking history questions. Cox proportional hazards models, adjusted for age and sex, were utilized to estimate hazard ratios (HRs) for various smoking history groups. Next, we utilized the National Health Interview Survey (NHIS), which inquired about smoking history and race/ethnicity, to analyze the demographic profiles of various high-risk smoking history categories. All statistical tests were two-sided. RESULTS: The PLCO cohort included 18 114 former and 12 243 current LDCT-eligible smokers, plus 2283 20- to 29-pack-year current smokers. The hazard ratio for 20- to 29-pack-year current smokers compared with eligible (30+ pack-year) former smokers was 1.07 (95% confidence interval [CI] = 0.75 to 1.5). Based on the NHIS, 10 million persons in the United States are currently LDCT eligible; an additional 1.6 million (16%, 95% CI = 13.6% to 19.0%) are 20- to 29-pack-year current smokers. The percentage increase in eligibles if 20- to 29-pack-year current smokers were included was substantially greater for women than men (22.2%, 95% CI = 17.9% to 26.7%; vs 12.2%, 95% CI = 9.3% to 15.3%, P < .001) and for minorities than non-Hispanic whites (30.0%, 95% CI = 24.2% to 36.0%; vs 14.1%, 95% CI = 11.1% to 17.0%, P < .001). CONCLUSION: The potential benefits and harms of recommending LDCT screening for 20 to 29-pack-year current smokers should be assessed. PMID- 26483245 TI - Lung Cancer Screening With Low-Dose Computed Tomography Beyond the National Lung Screening Trial. PMID- 26483246 TI - [Reinhard Bollmann: 24.01.1944 - 10.11.2014]. PMID- 26483247 TI - [Report of the working group on pediatric and fetal pathology]. PMID- 26483248 TI - [Hans-Peter Putzke. 14.05.1931 - 22.07.2015]. PMID- 26483249 TI - [S3 guidelines on diagnostics and treatment of cervical cancer: Demands on pathology]. AB - Between 2011 and the end of 2014 the former consensus S2k guidelines for the diagnostics and treatment of cervical cancer were updated and upgraded to S3 level, methodologically based on the regulations of the German Cancer Society (DKG). The present article summarizes the relevant aspects for the sectioning, histopathological workup, diagnostics and reporting for the pathology of invasive cancer of the uterine cervix. The recommendations are based on the most recent World Health Organization (WHO) and TNM classification systems and consider the needs of the clinician for appropriate surgical and radiotherapeutic treatment of patients. Detailed processing rules of colposcopy-guided diagnostic biopsies, conization and trachelectomy as well as for radical hysterectomy specimens and lymph node resection (including sentinel lymph node resection) are given. In the guidelines deep stromal invasion in macroinvasive cervical cancer is defined for the first time as tumor infiltration of > 66% of the cervical stromal wall. Furthermore, morphological prognostic factors for microinvasive and macroinvasive cervical cancer are summarized. PMID- 26483250 TI - [Molecular and metabolic changes in human clear cell liver foci]. AB - Activation of the AKT/mTOR and Ras/MAPK pathways and the lipogenic phenotype are evident both in human hepatocellular carcinoma and in the rat model of insulin induced hepatocarcinogenesis in the earliest preneoplastic lesions, i.e. clear cell foci (CCF) of altered hepatocytes. These CCFs have also been described in the human liver but characterization of molecular and metabolic changes are still pending. In this study, human sporadic CCFs were investigated in a collection of human non-cirrhotic liver specimens using histology, histochemistry, immunohistochemistry, electron microscopy and molecular pathological analysis. Human CCFs occurred in approximately 33 % of non-cirrhotic livers and stored masses of glycogen in the cytoplasm, largely due to reduced activity of glucose-6 phosphatase. Hepatocytes revealed an upregulation of the AKT/mTOR and the Ras/MAPK pathways, the insulin receptor, glucose transporters and enzymes of glycolysis and de novo lipogenesis. Proliferative activity was 2-fold higher than in extrafocal tissue. The CCFs of altered hepatocytes are metabolically and proliferatively active lesions even in humans. They resemble the well-known preneoplastic lesions from experimental models in terms of morphology, glycogen storage, overexpression of protooncogenic signaling pathways and activation of the lipogenic phenotype, which are also known in human hepatocellular carcinoma. This suggests that hepatic CCFs also represent very early lesions of hepatocarcinogenesis in humans. PMID- 26483251 TI - [Cytological material for molecular pathology]. AB - Personalized therapy concepts in which the active agent is adapted to genetic alterations in the tumor of the patient, have in recent years led to a paradigm shift in oncology. A comprehensive molecular diagnostic tumor characterization is therefore essential before initiating therapy in order to select the optimal therapy for the patient. The continuously increasing number of genetic alterations which can be treated and known resistance mechanisms together with limited availability of test material represents a completely new challenge for molecular diagnostics. The possibility of being able to determine mutations, translocations and changes in the number of copies not only from paraffin embedded tumor tissue but also from cytological material and even circulating tumor DNA, substantially extends the diagnostic options. PMID- 26483252 TI - [Not Available]. PMID- 26483253 TI - Longitudinal validation of periarticular bone area and 3D shape as biomarkers for knee OA progression? Data from the FNIH OA Biomarkers Consortium. AB - OBJECTIVE: To perform a longitudinal validation study of imaging bone biomarkers of knee osteoarthritis (OA) progression. METHODS: We undertook a nested case control study within the Osteoarthritis Initiative in knees (one knee per subject) with a Kellgren and Lawrence grade of 1-3. Cases were defined as knees having the combination of medial tibiofemoral radiographic progression and pain progression at the 24-month, 36-month or 48-month follow-up compared with baseline. Controls (n=406) were eligible knees that did not meet both endpoint criteria and included 200 with neither radiographic nor pain progression, 103 with radiographic progression only and 103 with pain progression only. Bone surfaces in medial and lateral femur, tibia and patella compartments were segmented from MR images using active appearance models. Independent variables of primary interest included change from baseline to 24 months in (1) total area of bone and (2) position on three-dimensional (3D) bone shape vectors that discriminate OA versus non-OA shapes. We assessed the association of bone markers changes over 24 months with progression using logistic regression. RESULTS: 24 month changes in bone area and shape in all compartments were greater in cases than controls, with ORs of being a case per 1 SD increase in bone area ranging from 1.28 to 1.71 across compartments, and per 1 SD greater change in 3D shape vectors ranging from 1.22 to 1.64. Bone markers were associated most strongly with radiographic progression and only weakly with pain progression. CONCLUSIONS: In knees with mild-to-moderate radiographic OA, changes in bone area and shape over 24 months are associated with the combination of radiographic and pain progression over 48 months. This finding of association with longer term clinical outcome underscores their potential for being an efficacy of intervention biomarker in clinical trials. PMID- 26483254 TI - Defining an optimal referral strategy for patients with a suspicion of axial spondyloarthritis: what is really important? Response to: 'Evaluating the ASAS recommendations for early referral of axial spondyloarthritis in patients with chronic low back pain; is one parameter present sufficient for primary care practice?' by van Hoeven et al. PMID- 26483255 TI - Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment. AB - OBJECTIVE: To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial. METHODS: MBDA scores (scale 1-100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse. RESULTS: Moderate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA-/ACPA-, moderate in patients who were MBDA+/ACPA- (33.3%) and MBDA-ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%). CONCLUSIONS: MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients. TRIAL REGISTRATION NUMBER: EudraCT 2009-015740-42. PMID- 26483257 TI - Unraveling Quantum Annealers using Classical Hardness. AB - Recent advances in quantum technology have led to the development and manufacturing of experimental programmable quantum annealing optimizers that contain hundreds of quantum bits. These optimizers, commonly referred to as 'D Wave' chips, promise to solve practical optimization problems potentially faster than conventional 'classical' computers. Attempts to quantify the quantum nature of these chips have been met with both excitement and skepticism but have also brought up numerous fundamental questions pertaining to the distinguishability of experimental quantum annealers from their classical thermal counterparts. Inspired by recent results in spin-glass theory that recognize 'temperature chaos' as the underlying mechanism responsible for the computational intractability of hard optimization problems, we devise a general method to quantify the performance of quantum annealers on optimization problems suffering from varying degrees of temperature chaos: A superior performance of quantum annealers over classical algorithms on these may allude to the role that quantum effects play in providing speedup. We utilize our method to experimentally study the D-Wave Two chip on different temperature-chaotic problems and find, surprisingly, that its performance scales unfavorably as compared to several analogous classical algorithms. We detect, quantify and discuss several purely classical effects that possibly mask the quantum behavior of the chip. PMID- 26483256 TI - Differential expression of endoplasmic reticulum stress-response proteins in different renal tubule subtypes of OVE26 diabetic mice. AB - Regulation of the endoplasmic reticulum (ER) stress-response pathway during the course of diabetes specifically in renal tubules is unclear. Since tubule cell dysfunction is critical to progression of diabetic nephropathy, this study analyzed markers of ER stress response and ER chaperones at different stages of diabetes and in different renal tubule subtypes of OVE26 type-1 diabetic mice. ER stress-responseinduced chaperones GRP78, GRP94, and protein disulfide isomerase (PDI) were increased in isolated cortical tubules of older diabetic mice, while PDI was decreased in tubules of young diabetic mice. Immunofluorescence staining of kidneys from older mice showed GRP78 and PDI upregulation in all cortical tubule segments, with substantial induction of PDI in distal tubules. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) phosphorylation was increased in cortical tubules of young diabetic mice, with no differences between older diabetic and control mice. Expression of ER stress-induced PERK inhibitor p58IPK was decreased and then increased in all tubule subtypes of young and older mice, respectively. Knockdown of PERK by small interfering RNA (siRNA) increased fibronectin secretion in cultured proximal tubule cells. Tubules of older diabetic mice had significantly more apoptotic cells, and ER stress-induced proapoptotic transcription factor C/EBP homologous protein (CHOP) was increased in proximal and distal tubules of diabetic mice and diabetic humans. CHOP induction in OVE26 mice was not altered by severity of proteinuria. Overexpression of CHOP in cultured proximal tubule cells increased expression of fibronectin. These findings demonstrate differential ER stress-response signaling in tubule subtypes of diabetic mice and implicate a role for PERK and CHOP in tubule cell matrix protein production. PMID- 26483258 TI - TYR as a multifunctional reporter gene regulated by the Tet-on system for multimodality imaging: an in vitro study. AB - The human tyrosinase gene TYR is a multifunctional reporter gene with potential use in photoacoustic imaging (PAI), positron emission tomography (PET), and magnetic resonance imaging (MRI). We sought to establish and evaluate a reporter gene system using TYR under the control of the Tet-on gene expression system (gene expression induced by doxycycline [Dox]) as a multimodality imaging agent. We transfected TYR into human breast cancer cells (MDA-MB-231), naming the resulting cell line 231-TYR. Using non-transfected MDA-MB-231 cells as a control, we verified successful expression of TYR by 231-TYR after incubation with Dox using western blot, cellular tyrosinase activity, Masson-Fontana silver staining, and a cell immunofluorescence study, while the control cells and 231-TYR cells without Dox exposure revealed no TYR expression. Detected by its absorbance at 405 nm, increasing concentrations of melanin correlated positively with Dox concentration and incubation time. TYR expression by Dox-induced transfected cells shortened MRI T1 and T2 relaxation times. Photoacoustic signals were easily detected in these cells. (18)F-5-fluoro-N-(2-[diethylamino]ethyl)picolinamide ((18)F-5-FPN), which targets melanin, quickly accumulated in Dox-induced 231-TYR cells. These show that TYR induction of melanin production is regulated by the Tet-on system, and TYR-containing indicator cells may have utility in multimodality imaging. PMID- 26483259 TI - Significant Functional Improvement at 2 Years After Isolated Patellofemoral Arthroplasty With an Onlay Trochlear Implant, But Low Mental Health Scores Predispose to Dissatisfaction. AB - INTRODUCTION: We reviewed the clinical and radiographic outcomes of a consecutive series of patients who underwent patellofemoral arthroplasty (PFA) using a modern onlay-style trochlear design and all-polyethylene patellar component. An additional goal of the study was to elucidate, for the first time, the extent to which patients were satisfied with their implant and whether expectations were met after undergoing PFA. METHODS AND MATERIALS: We identified a consecutive series of 70 knees (53 patients) treated with primary isolated PFA between October 2007 and May 2012. For our clinical outcomes analysis, we included patients with a minimum follow-up of 2 years and available preoperative original Knee Society scores. RESULTS: At an average 4.9 years of follow-up, the mean range of motion and Knee Society Knee and Function scores improved significantly, and less than 4% of patients required revision arthroplasty. There was no radiographic evidence of component loosening or wear. Despite these improvements, new Knee Society scores indicated that fewer than two-thirds of patients were satisfied or had their expectations met. Dissatisfied patients and those whose expectations were not met had significantly lower Mental Health scores according to the Short Form-36 following PFA. CONCLUSIONS: Despite the clinical and radiographic success of this implant, patient satisfaction remained low, which may be partially explained by poor mental health. PMID- 26483260 TI - Predictors of Facility Discharge, Range of Motion, and Patient-Reported Physical Function Improvement After Primary Total Knee Arthroplasty: A Prospective Cohort Analysis. AB - BACKGROUND: Patients are discharged to home or inpatient settings after primary unilateral total knee arthroplasty (TKA). Few studies have compared patient outcomes following these 2 rehabilitation models for TKA patients. We identified predictors of inpatient discharge, 3-month postoperative range of motion (ROM), and 3-month postoperative patient-reported physical function improvement (Veterans RAND 12-Item Physical Component Score [PCS]) between these discharge settings. METHODS: We studied prospectively collected cohort data for 738 TKAs between April 2011 and April 2013 at a high-volume tertiary academic medical center in a rural setting. All patients followed a standardized care pathway that involved prospective data collection as part of routine clinical care. Adjusting variables included age, sex, preoperative PCS, surgeon, modified Charlson Comorbidity Index, preoperative body mass index, laterality, and preoperative ROM; the 3-month models also included length of stay and discharge disposition as adjusters. RESULTS: Significant adjusted predictors of inpatient discharge included older age, female sex, surgeon, comorbidity, lower PCS, and body mass index greater than 40. Only lower preoperative ROM predicted postoperative ROM. Inpatient discharge and higher preoperative PCS predicted lower PCS improvement. Home-based rehabilitation was associated with greater 3-month PCS improvement and showed no difference with 3-month ROM. CONCLUSION: Discharge to home-based rehabilitation after TKA, rather than inpatient facility, is associated with higher physical function at 3 months postsurgery and shows no difference with 3 month ROM. Total knee arthroplasty inpatient discharge should be based on patient care requirements rather than perceived benefit of improved ROM and physical function. PMID- 26483262 TI - Smartphone for smart living: Using new technologies to cope with everyday limitations in semantic dementia. AB - New technologies have considerable potential to support people with semantic dementia-a form of progressive aphasia-in their everyday lives, but evidence is still sparse. The first objective of the study was to document day-to-day compensation strategies, including the use of a smartphone, in ND, a 56-year-old man with semantic dementia. The second objective was to explore if, 5 years after receiving his diagnosis, ND could still learn new smartphone functions. Results for objective 1 showed that ND had adopted a large number of compensation mechanisms in his everyday life, and expanded the use of one application he had learned 4 years earlier. Results for objective 2 showed that, with an errorless learning approach, he learnt to effectively use 10 smartphone functions. He was also able to verbalise semantic knowledge about those functions and still used 40% of them in daily life 6 months post-intervention. He particularly appreciated note-taking, and spontaneously expanded his abilities in using this function's features in order to reduce his semantic difficulties. This study shows the potential of new mobile technologies for semantic dementia, how they can be adapted and modified as the disease progresses, and how some patients can creatively use external technological aids. PMID- 26483261 TI - GSK-3b participates in the regulation of hepatic lipid deposition in large yellow croaker (Larmichthys crocea). AB - In this study, the participation of glycogen synthase kinase-3beta (GSK-3beta) in the lipid deposition was investigated in the liver of large yellow croaker (Larmichthys crocea) by LiCl treatment. It was found that the expression of GSK 3beta and peroxisome proliferator-activated receptor-gamma (PPARgamma) was inhibited, but the expression of beta-catenin was induced by LiCl treatment. Furthermore, the gene expression and activity of fatty acid synthetase (FAS) and lipoprotein lipase (LPL) in the liver was inhibited by LiCl treatment. The content of total cholesterol (TC), triglyceride (TG), and non-estesterified fatty acid in the liver, as well as TC, TG, and low-density lipoprotein cholesterol in plasma, was decreased by LiCl treatment. However, high-density lipoprotein cholesterol in plasma was increased, and the number of lipid droplets in the liver was decreased by LiCl treatment. The results indicate that GSK-3beta/beta catenin may participate in regulating LPL and FAS through PPARgamma in the liver of large yellow croaker, which will lead to the inhibition of hepatic lipid deposition. PMID- 26483263 TI - Patient selection for upper airway stimulation: is concentric collapse in sleep endoscopy predictable? AB - PURPOSE: Upper airway stimulation is an effective treatment option for obstructive sleep apnea after failure of positive airway pressure (PAP) therapy. To ensure a therapeutic effect, closed-loop hypoglossal nerve implants require the absence of palatal complete concentric collapse during sleep endoscopy. The frequency and potential predictors of this exclusion criterion are unknown. METHODS: Over a 2-year period, 74 consecutive patients with sleep apnea who sought PAP alternatives were evaluated with sleep endoscopy using propofol. The influence of sleep apnea severity and anthropometric characteristics as predictors of sleep endoscopy results was investigated. RESULTS: One-fifth of all patients showed a concentric collapse. Gender and age did not predict the presence of concentric collapse, but higher body mass and apnea hypopnea index values were predictive (p = 0.011; e.g., 0.026). The most commonly used body mass index values for upper airway stimulation indications demonstrated acceptable specificity (BMI 32 kg/m(2) 0.71, 95 % confidence interval = 0.57, 0.82; e.g., 35 kg/m(2) 0.81, 95 % confidence interval = 0.69, 0.90). Despite the association with overweight, a significant number of severely overweight patients had no concentric palatal collapse. CONCLUSIONS: Concentric collapse is a somewhat common condition encountered in sleep endoscopy evaluations of PAP alternatives, and cannot be sustainably predicted with anthropometric or sleep assessments. Sleep surgeons should be aware of the possibility of concentric collapse, especially in candidates who are more overweight and have severe sleep apnea. Sleep endoscopy can be useful for providing information about continuous positive airway pressure (CPAP) alternatives or to motivate patient adherence to treatment. PMID- 26483264 TI - Obstructive sleep apnoea and non-restorative sleep induced by the interface. PMID- 26483265 TI - Effectiveness of oral pressure therapy in obstructive sleep apnea: a systematic analysis. AB - PURPOSE: Oral pressure therapy (OPT) has emerged as a novel technique to treat obstructive sleep apnea (OSA) in the past few years. Given this is a relatively new treatment approach, currently, little is known with respect to its clinical utility. The aim of this review was to explore the success rate of OPT when used to treat OSA. METHODS: PubMed, MEDLINE, Scopus, Web of Science, and the Cochrane Library databases were searched for pertinent studies. RESULTS: The OPT treatment success rates varied widely between 25 and 79 % depending on the residual apnea hypopnea index (AHI) cut off defined for treatment success. When using standard definitions (at least 50 % reduction from the baseline AHI and the post-OPT treatment residual AHI less than or equal to 10), the success rate of OPT treatment varied between 25 and 37 %. CONCLUSIONS: Although there was a significant reduction in AHI with OPT, the baseline AHI was not suppressed in majority of patients to the extent to call these patients as optimally treated. Successful treatment with OPT did not correlate with severity of OSA; however, patients with retro-palatal collapse responded better to treatment. Further research is needed to identify OSA patients who would benefit with this treatment modality. PMID- 26483266 TI - Response to: Obstructive sleep apnoea and non-restorative sleep induced by the interface. PMID- 26483267 TI - Discotic Liquid Crystals. PMID- 26483268 TI - Management of Indeterminate Cystic Kidney Lesions: Review of Contrast-enhanced Ultrasound as a Diagnostic Tool. AB - Indeterminate cystic kidney lesions found incidentally are an increasingly prevalent diagnostic challenge. Standard workup includes Bosniak classification with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). However, these tests are costly and not without risks. Contrast-enhanced ultrasound (CEUS) is a relatively new technique with lower risk of adverse events than iodine-containing contrast or gadolinium. In our review of the evidence for characterization of cystic kidney lesions with CEUS, CEUS displayed sensitivity (89%-100%) and negative predictive value (86%-100%) comparable to contrast enhanced CT or MRI, with no decrease in specificity compared with CT and only a slight decrease compared with MRI. PMID- 26483269 TI - Distortion correction of echo-planar diffusion-weighted images of uterine cervix. AB - PURPOSE: To investigate the clinical utility of the reverse gradient algorithm in correcting distortions in diffusion-weighted images of the cervix and for increasing diagnostic performance. MATERIALS AND METHODS: Forty-one patients ages 25-72 years (mean 40 +/- 11 years) with suspected or early stage cervical cancer were imaged at 3T using an endovaginal coil. T2 -weighted (W) and diffusion weighted images with right and left phase-encode gradient directions were obtained coronal to the cervix (b = 0, 100, 300, 500, 800 s mm(-2) ). Differences in angle of the endocervical canal to the x-axis between T2 W and right-gradient, left-gradient, and corrected images were measured. Uncorrected and corrected images were assessed for diagnostic performance when viewed together with T2 W images by two independent observers against subsequent histology. RESULTS: The angles of the endocervical canal relative to the x-axis were significantly different between the T2 W images and the right-gradient images (P = 0.007), approached significance for left-gradient images (P = 0.055), and were not significantly different after correction (P = 0.95). Corrected images enabled a definitive diagnosis in 34% (n = 14) of patients classified as equivocal on uncorrected images. Tumor volume in this subset was 0.18 +/- 0.44 cm(3) (mean +/- SD; sensitivity of detection 100% [8/8], specificity 50% [3/6] for an experienced observer). Correction did not improve diagnostic performance for the less experienced observer. CONCLUSION: Distortion-corrected diffusion-weighted images improved correspondence with T2 W images and diagnostic performance in a third of cases. PMID- 26483270 TI - Autism and social robotics: A systematic review. AB - Social robotics could be a promising method for Autism Spectrum Disorders (ASD) treatment. The aim of this article is to carry out a systematic literature review of the studies on this topic that were published in the last 10 years. We tried to address the following questions: can social robots be a useful tool in autism therapy? We followed the PRISMA guidelines, and the protocol was registered within PROSPERO database (CRD42015016158). We found many positive implications in the use of social robots in therapy as for example: ASD subjects often performed better with a robot partner rather than a human partner; sometimes, ASD patients had, toward robots, behaviors that TD patients had toward human agents; ASDs had a lot of social behaviors toward robots; during robotic sessions, ASDs showed reduced repetitive and stereotyped behaviors and, social robots manage to improve spontaneous language during therapy sessions. Therefore, robots provide therapists and researchers a means to connect with autistic subjects in an easier way, but studies in this area are still insufficient. It is necessary to clarify whether sex, intelligence quotient, and age of participants affect the outcome of therapy and whether any beneficial effects only occur during the robotic session or if they are still observable outside the clinical/experimental context. PMID- 26483271 TI - Targeted next-generation sequencing of the ATP7B gene for molecular diagnosis of Wilson disease. AB - OBJECTIVES: In recent years, next-generation sequencing (NGS) technologies, which enable high throughput sample processing at relatively lower costs, are adopted in both research and clinical settings. A multiplex PCR-based NGS assay to identify mutations in the ATP7B gene for routine molecular diagnosis of Wilson disease was evaluated in comparison with the gold standard direct Sanger sequencing. DESIGN AND METHODS: Five multiplex PCRs to amplify the partial promoter, 5' untranslated and the entire coding regions of the ATP7B gene were designed. Indexed paired-end libraries were generated from the pooled amplicons using Nextera XT DNA Sample Preparation Kit and subjected to NGS on the MiSeq platform. DNA from the peripheral blood of 12 patients with Wilson disease, 2 B lymphocyte cell lines and 3 external quality assurance samples were sequenced by the MiSeq and Sanger sequencing. RESULTS: Complete coverage was achieved across the targeted bases without any drop-out sequences. The observed read depth in a single run with 20 samples was >100X. Comparison of the NGS results against Sanger sequencing data on a panel of clinical specimens, cell lines and European Molecular Genetics Quality Networks (EMQN) quality assurance samples showed 100% concordance in identifying pathogenic mutations. CONCLUSION: With the capability of generating relatively higher throughput in a short time period, the NGS assay is a viable alternative to Sanger sequencing for detecting ATP7B mutations causally linked to Wilson disease in the clinical diagnostic laboratory. PMID- 26483272 TI - Corrigendum. PMID- 26483274 TI - Neuronal nitric oxide synthase localizes to utrophin expressing intercalated discs and stabilizes their structural integrity. AB - The neuronal nitric-oxide synthase (nNOS) splice variant nNOSu is essential for skeletal muscle function. Its localization is dependent on dystrophin, which stabilizes the dystrophin glycoprotein complex (DGC) at the sarcolemma of skeletal muscle fibers. In Duchenne muscular dystrophy (DMD) dystrophin is absent and sarcolemmal nNOS is lost. This leads to functional ischemia due to a decrease in contraction-induced vasodilation. In cardiomyocytes, nNOSu is believed to be the predominant NOS isoform. However, the association of nNOS with the DGC in the heart is unclear. Here, we report nNOS localization at the intercalated discs (IDs) of cardiomyocytes, where utrophin is highly expressed. In mdx, mdx:utr, nNOSu knock-out (KO), and mdx:nNOSu KO mice, we observed a gradual reduction of nNOS at IDs and disrupted ID morphology, compared to wild-type. In mdx:nNOSu KO mice, but not in mdx or nNOSu KO mice, we also observed an early development of cardiac fibrosis. These findings suggest that nNOS localization in the heart may not depend exclusively on the presence of dystrophin. Additionally, the beta1 subunit of soluble guanylyl cyclase (sGC), responsible for the production of cGMP through nitric oxide (NO) signaling, was also detected at the IDs. Together, our results suggest a new role of nNOS at the IDs for the cGMP-dependent NO pathway and the maintenance of ID morphology. PMID- 26483273 TI - Development and psychometric analysis of the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT). AB - The objective of this study was to describe the development and initial psychometric analysis of the UK English version of the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT), a patient-reported outcome (PRO) scale designed to measure functional ability in patients with Duchenne muscular dystrophy (DMD). Item selection was made by neuromuscular specialists and a Rasch analysis was performed to understand the psychometric properties of the DMDSAT. Instrument scores were also linked to cost of illness and health-related quality of life data. The administered version, completed by 186 UK patient-caregivers pairs, included eight items in four domains: Arm function, Mobility, Transfers, and Ventilation status. These items together successfully operationalized functional ability in DMD, with excellent targeting and reliability (Person Separation Index: 0.95; Cronbach's alpha: 0.93), stable item locations, and good fit to the Rasch model (mean person/item fit residual: 0.21/-0.44, SD: 0.32/1.28). Estimated item difficulty was in excellent agreement with clinical opinion (Spearman's rho: 0.95) and instrument scores mapped well onto health economic outcomes. We show that the DMDSAT is a PRO instrument fit for purpose to measure functional ability in ambulant and non-ambulant patients with DMD. Rasch analysis augments clinical expertise in the development of robust rating scales. PMID- 26483275 TI - Can third-trimester assessment of uterine scar in women with prior Cesarean section predict uterine rupture? PMID- 26483276 TI - Quinine-Based Zwitterionic Chiral Stationary Phase as a Complementary Tool for Peptide Analysis: Mobile Phase Effects on Enantio- and Stereoselectivity of Underivatized Oligopeptides. AB - Peptide stereoisomer analysis is of importance for quality control of therapeutic peptides, the analysis of stereochemical integrity of bioactive peptides in food, and the elucidation of the stereochemistry of peptides from a natural chiral pool which often contains one or more D-amino acid residues. In this work, a series of model peptide stereoisomers (enantiomers and diastereomers) were analyzed on a zwitterionic ion-exchanger chiral stationary phase (Chiralpak ZWIX(+) 5 um), in order to investigate the retention and separation performance for such compounds on this chiral stationary phase and elucidate its utility for this purpose. The goal of the study focused on 1) investigations of the effects of the sample matrix used to dissolve the peptide samples; 2) optimization of the mobile phase (enabling deriving information on factors of relevance for retention and separation); and 3) derivation of structure-selectivity relationships. It turned out that small di- and tripeptides can be well resolved under optimized conditions, typically with resolutions larger than 1.5. The optimized mobile phase often consisted of methanol-tetrahydrofuran-water (49:49:2; v/v/v) with 25 mM formic acid and 12.5 mM diethylamine. This work proposes some guidance on which mobile phases can be most efficiently used for peptide stereoisomer separations on Chiralpak ZWIX. Chirality 28:5-16, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26483277 TI - Leptospirosis acquisition following the reintroduction of wildlife. AB - Potential risks posed to domestic animals and human beings by zoonotic diseases in reintroduced animals can reduce the acceptability of reintroductions. The authors investigated the role of endangered water voles, Arvicola amphibius, as a host for leptospirosis, a waterborne zoonosis affecting a range of mammals. Based on samples from 112 individuals from across the UK, a 6.2 per cent exposure rate was found (7 animals were microscopic agglutination test (MAT) positive for serum antibodies), with 4 of 11 sites having positive animals. No individual was actively excreting leptospires in urine (PCR urine test, 0 per cent positive). The acquisition of Leptospira species by a cohort of 'clean' captive-bred voles reintroduced to one site in the wild was then examined. By four months postrelease the maximum exposure prevalence (by either MAT or culture) was 42.9 per cent. Thirty-five per cent were actively excreting leptospires. The rapidity of leptospire acquisition and comparatively high prevalence of infectious individuals is notable, exceeding expectation based on wild voles. One possible explanation is a lack of immunocompetence in reintroduced voles. Analyses of haematological parameters from reintroduced voles suggest a link between prior condition and disease acquisition. There may be potential to select the fittest animals before release to maximise reintroduction success. PMID- 26483278 TI - Identification of noreremophilane-based inhibitors of angiogenesis using zebrafish assays. AB - Noreremophilanes are a rare class of cis-hydrindanes produced by genus Ligularia herbaceous plants which are known to exhibit interesting biological activities. We synthesized cis-hydrindanes based on a naturally occurring noreremophilane scaffold using a Diels-Alder/aldol sequence and screened them for multiple biological activities using high-content zebrafish embryonic development assays. We discovered a noreremophilane that has strong anti-angiogenic effects on the developing zebrafish embryos as well as on tumor-induced angiogenesis in a zebrafish xenograft model. We synthesized several derivatives of this class of noreremophilanes and performed structure-activity relationship studies in zebrafish to identify more potent and less toxic analogs of the original structure. PMID- 26483280 TI - Genomic characteristics of coxsackievirus A8 strains associated with hand, foot, and mouth disease and herpangina. AB - Coxsackievirus A8 (CV-A8), a member of the genus Enterovirus of the family Picornaviridae, can cause a variety of infectious diseases, such as hand, foot and mouth disease (HFMD), herpangina (HA), encephalitis, paralysis, myelitis, and meningitis. This is a first report of complete genome sequences of CV-A8 strains associated with HFMD/HA since the prototype strain Donovan was identified in 1949. The complete genome sequences of eight new CV-A8 strains showed 19.2 %-20.6 % nucleotide differences when compared to the prototype strain Donovan, and 81.5 %-99.9 % similarity to each other. The topology of a polyphyletic tree based on complete capsid protein gene sequences indicated that the new CV-A8 strains and Donovan are monophyletic. However, seven CV-A8 strains clustered with CV-A10 and CV-A2 in the 5'UTR and P2 region, respectively. In the P3 region, three and four CV-A8 strains grouped with CV-A6 and CV-A2, respectively. Seven CV-A8 strains segregated from Donovan and grouped in a separate lineage in the 3'UTR. The strain CVA8/SZ266/CHN/2014 was most similar to EV71 in the nonstructural proteins regions. Phylogenetic analysis classified worldwide CV-A8 isolates into four distinct clusters, and almost all Chinese and Thai CV-A8 strains evolved independently in their respective lineages, which indicated geographical evolution of CV-A8. PMID- 26483281 TI - First detection of ungulate tetraparvovirus 1 (bovine hokovirus 1) in domestic yaks in northwestern China. AB - We describe the discovery and phylogenetic analysis of ungulate tetraparvovirus 1 (also referred to as bovine hokovirus 1, B-PARV4, or partetravirus) in domestic yaks (Bos grunniens) in northwestern China. The yak B-PARV4 genome was detected in yak blood samples by PCR, using B-PARV4 primers corresponding to conserved regions. Twenty-two of 370 samples were positive for a B-PARV4-related genome sequence, indicating an overall prevalence of 5.95 %. The prevalence in Qinghai Province (13/195, 6.67 %) and Gansu Province (9/175, 5.14 %) was similar, but it varied significantly between yaks <= 1 year old (15/177, 8.47 %) and yaks > 1 year old (7/193, 3.6 %) (p < 0.05). An alignment of the nearly full-length genome sequences of all 22 strains identified six different genomic sequences. A phylogenetic analysis revealed 99.0-99.7 % sequence identity between these six genomes and all known B-PARV4 genomes, excluding JF504698 (only 88.6 % identity), which represents another genotype. This is the first discovery of B-PARV4-related viruses in domestic yaks. PMID- 26483282 TI - Genetic variation, pathogenicity, and immunogenicity of highly pathogenic porcine reproductive and respiratory syndrome virus strain XH-GD at different passage levels. AB - Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically important infectious diseases of swine worldwide. Immunization with an attenuated vaccine is considered an effective method for reducing the economic losses resulting from porcine reproductive and respiratory syndrome virus (PRRSV) infection. Several studies have shown that PRRSV can be attenuated by passage in Marc-145 cells, but it is still not clear whether this attenuation influences the immunogenicity of PRRSV and what the mechanism of attenuation is. In order to study the mechanism of attenuation and immunogenicity of highly pathogenic (HP) PRRSV, the HP-PRRSV strain XH-GD was serially 122 times passaged in Marc-145 cells. Genomic sequence comparisons were made at selected passages. To explore the differences in pathogenicity and immunogenicity at different passages, three passages (P5, P62 and P122) were selected for an animal challenge experiment, which showed that passage in Marc-145 cells resulted in attenuation of the virus. After 122 passages, 35 amino acid changes were observed in the structural proteins and non-structural proteins. The animal challenge experiment showed that pathogenicity decreased with increasing passage number. The N antibody level and specific neutralizing (SN) antibody titers also decreased with increasing passage number in the late stage of the animal experiment. This study indicated that the virulence of XH-GD was decreased by passage in Marc-145 cells and that overattenuation might influence the immunogenicity of virus. These results might contribute to our understanding of the mechanism of attenuation. PMID- 26483284 TI - A Persistent 1,2-Dihydrophosphasilene Adduct. AB - The reaction of the arylchlorosilylene-NHC adduct ArSi(NHC)Cl [Ar=2,6-Trip2 -C6 H3 ; NHC=(MeC)2 (NMe)2 C] 1 with one molar equiv of LiPH2 (.) dme (dme=1,2 dimethoxyethane) affords the first 1,2-dihydrophosphasilene adduct 2 (ArSi(NHC)(H)?PH). The latter is labile in solution and can undergo head-to-tail dimerization to give [ArSi(H)PH]2 3 and "free" NHC. Further stabilization of 2 by complexation with {W(CO)5 } affords the isolable 1,2-dihydrophosphasilene tungsten complex 4 [ArSi(NHC)(H)?P(H)W(CO)5 ]. Additionally, the new 1-silyl-2 hydrophosphasilene ArSi(NHC)(H)?PSiMe3 5 could be synthesized and structurally characterized. DFT studies confirmed that the Si?P bond in 2 and 4 is mostly zwitterionic with drastically decreased double-bond character. PMID- 26483283 TI - Role of coxsackievirus and adenovirus receptor (CAR) expression and viral load of adenovirus and enterovirus in patients with dilated cardiomyopathy. AB - Enteroviruses (EVs) and adenoviruses (AdVs) are two important etiological agents of viral myocarditis and dilated cardiomyopathy (DCM). Both these viruses share a common receptor, the coxsackievirus and adenovirus receptor (CAR), for their infection. However, the role of viral load and CAR expression in disease severity has not yet been completely elucidated. The present study aimed to determine viral load of EV and AdV in DCM patients and correlate them with the level of CAR expression in these patients. Sixty-three DCM cases and 30 controls, each of whom died of heart disease other than DCM and non-cardiac disease respectively, were included. Viral load was determined by TaqMan real-time PCR using primers and probes specific for the AdV hexon gene and the 5'UTR region of EV. The CAR mRNA level was semi-quantitated by RT-PCR, and antigen expression was studied by immunohistochemistry. A significantly high AdV load (p < 0.05) and CAR expression (p < 0.05) were observed in DCM cases versus controls, whereas the EV load showed no significant difference. The data suggests a clinical threshold of 128 AdV copies/500 ng of DNA for DCM, with 66.7 % sensitivity and 65 % specificity. A positive correlation between AdV load and CAR expression (p < 0.001) was also observed in DCM cases. The high adenoviral load and increased CAR expression in DCM and their association with adverse disease outcome indicates role of both virus and receptor in disease pathogenesis. Thus, the need for targeting both the virus and the receptor for treatment of viral myocarditis and early DCM requires further confirmation with larger studies. PMID- 26483286 TI - [New insights into sodium in kidney and cardiovascular diseases]. AB - Recent guidelines recommend a restriction of sodium intake below 2,4 g/day (6 g/day of NaCl) in general population to prevent arterial hypertension and cardiovascular disease. Three papers published in 2014 by The New England Journal of Medecine confirm the association between high sodium intake and arterial hypertension. However, marked sodium restriction is also associated with increased mortality. On the other hand, a diet rich in potassium, over 1.5 g/day, is associated with less cardiovascular mortality, and less chronic kidney disease progression. PMID- 26483285 TI - Colony-morphology screening uncovers a role for the Pseudomonas aeruginosa nitrogen-related phosphotransferase system in biofilm formation. AB - Pseudomonas aeruginosa is an opportunistic human pathogen whose survival is aided by forming communities known as biofilms, in which cells are encased in a self produced matrix. We devised a mutant screen based on colony morphology to identify additional genes with previously unappreciated roles in biofilm formation. Our screen, which identified most known biofilm-related genes, also uncovered PA14_16550 and PA14_69700, deletions of which abrogated and augmented biofilm formation respectively. We also identified ptsP, which encodes enzyme I of the nitrogen-regulated phosphotransferase (PTS(Ntr)) system, as being important for cyclic-di-GMP production and for biofilm formation. Further experiments showed that biofilm formation is hindered in the absence of phosphotransfer through the PTS(Ntr), but only in the presence of enzyme II (PtsN), the putative regulatory module of the PTS(Ntr). These results implicate unphosphorylated PtsN as a negative regulator of biofilm formation and establish one of the first known roles of the PTS(Ntr) in P. aeruginosa. PMID- 26483287 TI - Light transmission and ultraviolet protection of contact lenses under artificial illumination. AB - PURPOSE: To determine the spectral transmission of contact lenses (CLs), with and without an ultraviolet (UV) filter to evaluate their capacity for protection under UV radiation from artificial illumination (incandescent, fluorescent, xenon (Xe) lamps, or white LEDs (light-emitting diode)). METHODS: The transmission curves of nine soft CLs were obtained by using a PerkinElmer Lambda 35 UV-vis spectrophotometer. A CIE standard was used for the emission spectra of incandescent and fluorescent lamps, and Xe lamps and white LEDs were measured by using an International Light Technologies ILT-950 spectroradiometer. RESULTS: Five of the nine soft CLs analysed state that they incorporate UV filters, but the other four do not specify anything in this regard. The spectral transmission of all the CLs studied is excellent in the visible region. The CLs with UV filters filter out this radiation more or less effectively. Xe lamps emit a part in the UV region. Incandescent, fluorescent and white LEDs do not emit at all in the UV. CONCLUSIONS: Incorporating UV filters is important when the illumination is from a Xe lamp since this light source emits in the UV region. This, however, does not occur with incandescent and fluorescent lamps or white LEDs. The CLs that do incorporate UV filters meet all the standard requirements that the U.S. FDA (Food and Drug Administration) has for UV-blocking CLs Class II (OcularScience, CooperVision and Neolens), and AcuvueMoist and HydronActifresh400 even comply with the stricter Class I. The CLs without UV filters let UVA, UVB and even some UVC through. PMID- 26483288 TI - Metabolism, excretion and avoidance of cyanogenic glucosides in insects with different feeding specialisations. AB - Cyanogenic glucosides (CNglcs) are widespread plant defence compounds releasing toxic hydrogen cyanide when hydrolysed by specific beta-glucosidases after plant tissue damage. In contrast to specialist herbivores that have mechanisms to avoid toxicity from CNglcs, it is generally assumed that non-adapted herbivores are negatively affected by CNglcs. Recent evidence, however, implies that the defence potential of CNglcs towards herbivores may not be as effective as previously anticipated. Here, performance, metabolism and excretion products of insects not adapted to CNglcs were analysed, including species with different degrees of dietary specialisation (generalists, specialists) and different feeding modes (leaf-snipping lepidopterans, piercing-sucking aphids). Insects were reared either on cyanogenic or acyanogenic plants or on an artificial cyanogenic diet. Lepidopteran generalists (Spodoptera littoralis, Spodoptera exigua, Mamestra brassicae) were compared to lepidopteran glucosinolate-specialists (Pieris rapae, Pieris brassicae, Plutella xylostella), and a generalist aphid (Myzus persicae) was compared to an aphid glucosinolate-specialist (Lipaphis erysimi). All insects were tolerant to cyanogenic plants; in lepidopterans tolerance was mainly due to excretion of intact CNglcs. The two Pieris species furthermore metabolized aromatic CNglcs to amino acid conjugates (Cys, Gly, Ser) and derivatives of these, which is similar to the metabolism of benzylglucosinolates in these species. Aphid species avoided uptake of CNglcs during feeding. Our results imply that non-adapted insects tolerate plant CNglcs either by keeping them intact for excretion, metabolizing them, or avoiding uptake. PMID- 26483289 TI - A salivary sheath protein essential for the interaction of the brown planthopper with rice plants. AB - Salivary secretions, including gel saliva and watery saliva, play crucial roles in the interaction between the insect and plant during feeding. In this study, we identified a salivary gland-specific gene encoding a salivary sheath protein (NlShp) in Nilaparvata lugens. NlShp has two alternative splicing variants; both are expressed at high levels during the nymph and adult stages. Immunohistochemical staining showed that the NlShp were synthesized in the principal gland cells of the salivary gland. LC-MS/MS and western blot analysis confirmed that NlShp was one of the components of the salivary sheath. Simultaneously knocking down the two NlShp variants by RNA interference inhibited both salivary flange and salivary sheath formation and resulted in a lethal phenotype within four days for the brown planthopper (BPH) feeding on rice plants, indicating that the salivary sheath and salivary flanges were essential for plant-associated feeding. Despite the salivary sheath deficiency, no obvious phenotype was observed in the NlShp-knockdown BPHs fed on artificial diet. The electrical penetration graph (EPG) results showed that salivary sheath-deficient BPHs exhibited a prolonged nonpenetration period, scarce sap period, and increased stylet movement on rice plants and eventually starved to death. Our results provided evidence that the interaction between the salivary sheath and host plant might be a critical step in successful BPH feeding. According to present research, we propose a salivary sheath required feeding model for piercing-sucking insects and provide a potential target for rice planthopper management. PMID- 26483290 TI - An approach to adjust standardized mortality ratios for competing cause of death in cohort studies. AB - PURPOSE: The calculation of standardized mortality ratios (SMRs) is a standard tool for the estimation of health risks in occupational epidemiology. An increasing number of studies deal with the analysis of the mortality in employees suffering from an occupational disease like silicosis or coal-worker pneumoconiosis (CWP). Their focus lies not on the mortality risk due to the occupational disease itself, but on other diseases such as lung cancer or heart diseases. Using population-based reference rates in these studies can cause misleading results because mortality rates of the general population do not reflect the elevated mortality due to the occupational disease investigated. Hence, the purpose of the present paper is to develop an approach to adjust the risk estimates for other causes of death with respect to the effect of an occupational disease as a competing cause of death in occupational mortality cohort studies. METHODS: To overcome the problems associated with SMRs, the paper makes use of proportional mortality ratios (PMR), which are a further approach for the estimation of health risks in occupational epidemiology. The cause specific SMR can be rewritten as a product of PMR times the overall SMR. The PMR can be adjusted by ignoring the competing cause of death. Hence, an adjusted cause-specific SMR can be derived by multiplying this adjusted PMR with the overall SMR. This approach is applied to studies concerning lung cancer risk in coal miners suffering from CWP. RESULTS AND CONCLUSIONS: The usual approach for calculating SMRs leads to an underestimation of the real lung cancer risk in subgroups of miners suffering from CWP. The same effect can be observed in workers exposed to respirable silica already suffering from silicosis. The presented approach results in more realistic risk estimation in mortality cohort studies of employees suffering from an occupational disease. It is easily calculable on the basis of usually published values of observed cases and the corresponding cause-specific SMR. PMID- 26483291 TI - Is Pelvic Floor Muscle Training Effective for Men With Poststroke Lower Urinary Tract Symptoms? A Single-Blinded Randomized, Controlled Trial. AB - The aim of the current study was to evaluate the effect of pelvic floor muscle training in men with poststroke lower urinary tract symptoms. Thirty-one poststroke men, median age 68 years, were included in this single-blinded randomized controlled trial. Thirty participants, 15 in each group, completed the study. The intervention consisted of 3 months (12 weekly sessions) of pelvic floor muscle training in groups and home exercises. The effect was evaluated by the DAN-PSS-1 (Danish Prostate Symptom Score) questionnaire, a voiding diary, and digital anal palpation of the pelvic floor muscle. The DAN-PSS-1, symptom score indicated a statistical significant improvement ( p < .01) in the treatment group from pretest to posttest, but not in the control group. The DAN-PSS-1, total score improved statistically significantly in both groups from pretest to posttest (treatment group: p < .01; control group: p = .03). The median voiding frequency per 24 hours decreased from 11 at pretest to 7 (36%; p = .04) at posttest and to 8 (27%; p = .02) at follow-up in treatment group, although not statistical significantly more than the control group. The treatment group but not the control group improved statistically significantly in pelvic floor muscle function ( p < .01) and strength ( p < .01) from pretest to posttest and from pretest to follow-up ( p = .03; p < .01). Compared with the control group the pretest to posttest was significantly better in the treatment group ( p = .03). The results indicate that pelvic floor muscle training has an effect for lower urinary tract symptoms, although statistical significance was only seen for pelvic floor muscle. PMID- 26483292 TI - The Validity and Reliability of Health Belief Scale for Testicular Cancer Self Examination. AB - This study aimed to create a measurement tool for the determination of university students' health beliefs about testicular cancer (TC) and self-examination. This is a methodological and cross-sectional study. The study sample included 425 university students. Consents and approvals were obtained from the relevant institutions and the ethics committee prior to the research. The data were collected using an interview form that included questions about descriptive characteristics, family history of TC, and knowledge, beliefs, and practice of self-examination. The health belief model including 41 questions about self examination and the interview form were administered to the students in their classrooms at a suitable time. Principal components analysis and varimax rotation were used for the examination of the structures of the factors. Accordingly, factor patterns, self-values, and the variance percentages they explained were evaluated. The average age of the participants is 22.2 +/- 2.3 (min = 17; max = 40). Of them, 98.8% of the participants are single ( n = 420). Of them, 56.2% have heard about TC before, and 18.4% said they were informed about TC. Factor loading of the items in the first factor was 0.64 to 0.89, while it was 0.48 to 0.75 for the items in the second factor, 0.50 to 0.87 for the items in the third factor, 0.37 to 0.68 for the items in the fourth factor, 0.51 to 0.68 for the items in the fifth factor, and 0.65 to 0.79 for the items in the sixth factor. The health belief model scale may be used in TC screenings for males to measure susceptibility, seriousness, health motivation, barriers, benefits, and self efficacy. PMID- 26483294 TI - Picturing Masculinities: Using Photoelicitation in Men's Health Research. AB - This article explores the use of photo-elicitation methods in two men's health studies. Discussed are the ways that photo-elicitation can facilitate conversation about health issues that might be otherwise challenging to access. In the first study, researchers explored 35 young men's experiences of grief following the accidental death of a male peer. In the second study, researchers describe 64 fathers' perceptions about their roles and identity with respect to child safety and risk. Photographs and accompanying narratives were analyzed and results were theorized using a masculinities framework. Discussed are the benefits of photo-elicitation, which include facilitating conversation about emotions, garnering insight into the structures and identities of masculinity in the context of men's health. Considered also are some methodological challenges amid recommendations for ensuring reflexive practices. Based on the findings it is concluded that photo-elicitation can innovatively advance qualitative research in men's health. PMID- 26483293 TI - Masculinity, Racism, Social Support, and Colorectal Cancer Screening Uptake Among African American Men: A Systematic Review. AB - Colorectal cancer (CRC) is highly preventable when CRC screening is utilized, yet CRC screening completion among African American men is relatively low and their mortality rates remain 50% higher juxtaposed to their White counterparts. Since a growing body of literature indicates masculinity, racism, and social support each have strong influences on CRC screening uptake, this systematic review examined the connections between these three sociocultural factors and CRC screening uptake among African American men. Potential studies were retrieved from MEDLINE, CINAHL, EMBASE, and PsycINFO. Cited reference searching for the final sample was employed to identify and assess additional studies for inclusion using Scopus. The methodological quality of the reviewed evidence was also evaluated. Nineteen studies met inclusion/exclusion criteria. Thirteen studies employed nonexperimental research designs; a quasi-experimental design was present in four, and two utilized experimental designs. Studies were published between 2000 and 2014; the majority between 2009 and 2013. Social support was most frequently addressed (84%) while masculinity and racism were equally studied with paucity (11%) for their influence on CRC screening. After evaluating conceptual and methodological characteristics of the studies, 42% fell below average in quality and rigor. The need for increased attention to the sociocultural correlates of CRC screening for African American men are highlighted in this systematic review, and important recommendations for research and practice are provided. Alongside a call for more rigorous research, further research examining the influence of masculinity and racism on CRC screening completion among African American men is warranted. PMID- 26483295 TI - mDCF--new standard-of-care? PMID- 26483296 TI - What can we learn from oncology surgical trials? AB - Conducting high-quality prospective clinical trials in surgical oncology remains a challenge, and many seemingly well-designed trials lack this high quality because of inadequate recruitment accrual, lack of clinician interest, or evolution of treatment strategy during the many years over which such trials are conducted. In this Perspectives we examine some of the failures in published surgical oncology trials and discuss why they failed, and we make a critical assessment of the established prospective trial methodology in oncological practice (that is, phase 0, I, II, III and IV trials, and large prospective comparative audits) and how these methods might be used more effectively in future evaluation of cancer-surgery practice. PMID- 26483297 TI - Drug repurposing in oncology--patient and health systems opportunities. AB - In most countries, healthcare service budgets are not likely to support the current explosion in the cost of new oncology drugs. Repurposing the large arsenal of approved, non-anticancer drugs is an attractive strategy to offer more effective options to patients with cancer, and has the substantial advantages of cheaper, faster and safer preclinical and clinical validation protocols. The potential benefits are so relevant that funding of academically and/or independently driven preclinical and clinical research programmes should be considered at both national and international levels. To date, successes in oncology drug repurposing have been limited, despite strong evidence supporting the use of many different drugs. A lack of financial incentives for drug developers and limited drug development experience within the non-profit sector are key reasons for this lack of success. We discuss these issues and offer solutions to finally seize this opportunity in the interest of patients and societies, globally. PMID- 26483298 TI - Post-transplantation malignancies: here today, gone tomorrow? AB - From the early days of transplantation onwards, increased cancer development in transplant recipients, who require immunosuppression to avoid graft rejection, has been recognized. Registry data indicate that approximately 10-30% of deaths are attributed to post-transplant malignancy, with an upward trend in this incidence as more patients have been exposed to chronic lifelong immunosuppression. In this Review, the overall incidence and most frequent types of cancer encountered are summarized, along with information about which transplant recipients are at the greatest risk of malignancy. Reasons for why differences exist in susceptibility to cancer in this patient population are examined, and approaches that might improve our understanding of the options available for reducing the incidence of this adverse effect of immunosuppression are described. Whether anti-rejection drugs have been successful in diminishing overall immunosuppressive burden, and consequently show any promise for decreasing post-transplant malignancies is also discussed. The topic shifts to one class of conventional anti-rejection drugs, the mammalian target of rapamycin (mTOR) inhibitors, which paradoxically have both immunosuppressive and anti neoplastic properties. The complex activities of mTOR are reviewed in order to provide context for how these seemingly opposing effects are possible, and the latest clinical data on use of mTOR inhibitors in the clinic are discussed. The current and future perspectives on how best to normalize these unacceptably high rates of post-transplantation malignancies are highlighted. PMID- 26483299 TI - Nivolumab--an effective second-line treatment for NSCLC. PMID- 26483301 TI - Population genetic testing for cancer susceptibility: founder mutations to genomes. AB - The current standard model for identifying carriers of high-risk mutations in cancer-susceptibility genes (CSGs) generally involves a process that is not amenable to population-based testing: access to genetic tests is typically regulated by health-care providers on the basis of a labour-intensive assessment of an individual's personal and family history of cancer, with face-to-face genetic counselling performed before mutation testing. Several studies have shown that application of these selection criteria results in a substantial proportion of mutation carriers being missed. Population-based genetic testing has been proposed as an alternative approach to determining cancer susceptibility, and aims for a more-comprehensive detection of mutation carriers. Herein, we review the existing data on population-based genetic testing, and consider some of the barriers, pitfalls, and challenges related to the possible expansion of this approach. We consider mechanisms by which population-based genetic testing for cancer susceptibility could be delivered, and suggest how such genetic testing might be integrated into existing and emerging health-care structures. The existing models of genetic testing (including issues relating to informed consent) will very likely require considerable alteration if the potential benefits of population-based genetic testing are to be fully realized. PMID- 26483302 TI - Low-dose 2D X-ray angiography enhancement using 2-axis PCA for the preservation of blood-vessel region and noise minimization. AB - Enhancing 2D angiography while maintaining a low radiation dose has become an important research topic. However, it is difficult to enhance images while preserving vessel-structure details because X-ray noise and contrast blood vessels in 2D angiography have similar intensity distributions, which can lead to ambiguous images of vessel structures. In this paper, we propose a novel and fast vessel-enhancement method for 2D angiography. We apply filtering in the principal component analysis domain for vessel regions and background regions separately, using assumptions based on energy compaction. First, we identify an approximate vessel region using a Hessian-based method. Vessel and non-vessel regions are then represented sparsely by calculating their optimal bases separately. This is achieved by identifying periodic motion in the vessel region caused by the flow of the contrast medium through the blood vessels when viewed on the time axis. Finally, we obtain noise-free images by removing noise in the new coordinate domain for the optimal bases. Our method was validated for an X-ray system, using 10 low-dose sets for training and 20 low-dose sets for testing. The results were compared with those for a high-dose dataset with respect to noise-free images. The average enhancement rate was 93.11+/-0.71%. The average processing time for enhancing video comprising 50-70 frames was 0.80+/-0.35s, which is much faster than the previously proposed technique. Our method is applicable to 2D angiography procedures such as catheterization, which requires rapid and natural vessel enhancement. PMID- 26483300 TI - The influence of subclonal resistance mutations on targeted cancer therapy. AB - Clinical oncology is being revolutionized by the increasing use of molecularly targeted therapies. This paradigm holds great promise for improving cancer treatment; however, allocating specific therapies to the patients who are most likely to derive a durable benefit continues to represent a considerable challenge. Evidence continues to emerge that cancers are characterized by extensive intratumour genetic heterogeneity, and that patients being considered for treatment with a targeted agent might, therefore, already possess resistance to the drug in a minority of cells. Indeed, multiple examples of pre-existing subclonal resistance mutations to various molecularly targeted agents have been described, which we review herein. Early detection of pre-existing or emerging drug resistance could enable more personalized use of targeted cancer therapy, as patients could be stratified to receive the therapies that are most likely to be effective. We consider how monitoring of drug resistance could be incorporated into clinical practice to optimize the use of targeted therapies in individual patients. PMID- 26483303 TI - Lessons learned from the implementation of remote control for the interoperability standard ISO/IEEE11073-20601 in a standard weighing scale. AB - The Point of Care (PoC) version of the interoperability standard ISO/IEEE11073 (X73) provided a mechanism to control remotely agents through documents X73-10201 and X73-20301. The newer version of X73 oriented to Personal Health Devices (PHD) has no mechanisms to do such a thing. The authors are working toward a common proposal with the PHD Working Group (PHD-WG) in order to adapt the remote control capabilities from X73PoC to X73PHD. However, this theoretical adaptation has to be implemented and tested to evaluate whether or not its inclusion entails an acceptable overhead and extra cost. Such proof-of-concept assessment is the main objective of this paper. For the sake of simplicity, a weighing scale with a configurable operation was chosen as use case. First, in a previous stage of the research - the model was defined. Second, the implementation methodology - both in terms of hardware and software - was defined and executed. Third, an evaluation methodology to test the remote control features was defined. Then, a thorough comparison between a weighing scale with and without remote control was performed. The results obtained indicate that, when implementing remote control in a weighing scale, the relative weight of such feature represents an overhead of as much as 53%, whereas the number of Implementation Conformance Statements (ICSs) to be satisfied by the manufacturer represent as much as 34% regarding the implementation without remote control. The new feature facilitates remote control of PHDs but, at the same time, increases overhead and costs, and, therefore, manufacturers need to weigh this trade-off. As a conclusion, this proof-of concept helps in fostering the evolution of the remote control proposal to extend X73PHD and promotes its inclusion as part of the standard, as well as it illustrates the methodological steps for its extrapolation to other specializations. PMID- 26483304 TI - A novel breast ultrasound image segmentation algorithm based on neutrosophic similarity score and level set. AB - Breast ultrasound (BUS) image segmentation is a challenging task due to the speckle noise, poor quality of the ultrasound images and size and location of the breast lesions. In this paper, we propose a new BUS image segmentation algorithm based on neutrosophic similarity score (NSS) and level set algorithm. At first, the input BUS image is transferred to the NS domain via three membership subsets T, I and F, and then, a similarity score NSS is defined and employed to measure the belonging degree to the true tumor region. Finally, the level set method is used to segment the tumor from the background tissue region in the NSS image. Experiments have been conducted on a variety of clinical BUS images. Several measurements are used to evaluate and compare the proposed method's performance. The experimental results demonstrate that the proposed method is able to segment the BUS images effectively and accurately. PMID- 26483305 TI - Impedance control in a wave-based teleoperator for rehabilitation motor therapies assisted by robots. AB - This paper presents an improved wave-based bilateral teleoperation scheme for rehabilitation therapies assisted by robot manipulators. The main feature of this bilateral teleoperator is that both robot manipulators, master and slave, are controlled by impedance. Thus, a pair of motion-based adaptive impedance controllers are integrated into a wave-based configuration, in order to guarantee a stable human-robot interaction and to compensate the position drift, characteristic of the available schemes of bilateral teleoperation. Moreover, the teleoperator stability, in the presence of time delays in the communication channel, is guaranteed because the wave-variable approach is included to encode the force and velocity signals. It should be noted that the proposed structure enables the implementation of several teleoperator schemes, from passive therapies, without the intervention of a human operator on the master side, to fully active therapies where both manipulators interact with humans in a stable manner. The suitable performance of the proposed teleoperator is verified through some results obtained from the simulation of the passive and active-constrained modes, by considering typical tasks in motor-therapy rehabilitation, where an improved behavior is observed when compared to implementations of the classical wave-based approach. PMID- 26483306 TI - Occlusal plane elevation to prevent lip self-mutilation: A case report. PMID- 26483307 TI - The effect of temperature during liquid storage of in vitro-matured bovine oocytes on subsequent embryo development. AB - The aim of the present study was to optimize the temperature for the temporal storage of matured bovine oocytes. In vitro-matured bovine oocytes were preserved in HEPES-buffered TCM199 medium supplemented with 10% newborn calf serum at different temperatures (4 degrees C, 15 degrees C, 25 degrees C, and 38.5 degrees C) for 20 hours. Embryo development and blastocyst quality after in vitro fertilization, cytoplasmic ATP and glutathione levels in oocytes, and the frequency of apoptotic oocytes were compared among storage groups and a control group without storage. Among the storage groups, those at 25 degrees C and 38.5 degrees C showed the highest rates of blastocyst development (19.3% and 24.5%, respectively) compared with those stored at 4 degrees C and 15 degrees C (8.5% and 14.9%, respectively); however, blastocyst formation rates in all storage groups were lower than that in the control group (39.8%; P < 0.05). Storage at 38.5 degrees C and 15 degrees C was associated with reduced cell numbers in resultant blastocysts compared with the control and the 25 degrees C storage groups. Storage at 4 degrees C reduced metabolic activity of oocytes characterized by their lower ATP levels compared with the other groups. Storage for 20 hours significantly reduced the glutathione content in oocytes in all groups in a similar manner, irrespective of the temperature. Storage at 4 degrees C or 15 degrees C but not at 25 degrees C and 38.5 degrees C significantly increased the percentage of apoptotic oocytes compared with the control group. In conclusion, 25 degrees C was found to be the most suitable temperature for the temporal storage of matured bovine oocytes regarding both the developmental competence of oocytes and the quality of resultant blastocysts. PMID- 26483308 TI - Testosterone regulates levels of cystic fibrosis transmembrane regulator, adenylate cyclase, and cAMP in the seminal vesicles of orchidectomized rats. AB - Secretions of chloride (Cl(-))- and bicarbonate (HCO3(-))-rich fluid by the seminal vesicles could involve cystic fibrosis transmembrane regulator (CFTR), which activity can be stimulated by cAMP generated from the reaction involving adenylate cyclase (AC). In this study, we investigated levels of CFTR, AC, and cAMP in the seminal vesicles under testosterone influence. Orchidectomized adult male rats received 7-day treatment with 125 or 250 MUg/kg/day of testosterone with or without flutamide or finasteride. At the end of the treatment, animals were sacrificed and seminal vesicles were harvested for analyses of CFTR and AC protein expression level by Western blotting. Distribution of CFTR and AC in seminal vesicles was observed by immunohistochemistry. Levels of cAMP and dihydrotestosterone in seminal vesicle homogenates were measured by ELISA. Cystic fibrosis transmembrane regulator, AC, and cAMP levels increased with increasing doses of testosterone (P < 0.05 compared to nontreated orchidectomized rats). Cystic fibrosis transmembrane regulator and AC were expressed at the apical membrane of the epithelium lining the seminal vesicle lumen with higher expression levels observed in testosterone-treated rats than in non-treated orchidectomized rats (P < 0.05). The inhibitory effects of flutamide or finasteride on these parameters were greater in 250 MUg/kg/day testosterone treated rats than their effects in 125 MUg/kg/day testosterone-treated rats. Higher dihydrotestosterone levels were observed in seminal vesicle homogenates after treatment with 250 MUg/kg/day than with 125 MUg/kg/day of testosterone (P < 0.05). Increased levels of CFTR, AC, and cAMP in seminal vesicles might contribute toward an increase in Cl(-) and HCO3(-) concentrations in the seminal fluid as reported under testosterone influence. PMID- 26483309 TI - Prevalence of cervicitis in dairy cows and its effect on reproduction. AB - The objective of this study was to determine whether cervicitis in dairy cows is an independent disease or occurs concomitantly with inflammation of the uterus, and to clarify possible effects of cervicitis on reproductive performance. Dairy cows (n = 416) from 33 dairy farms were examined by rectal palpation and vaginoscopy between 42 and 50 days postpartum. Inclusion criteria for this study were absence of abnormal vaginal discharge and abnormalities of the uterus (fluctuation) at rectal palpation. Cervicitis was diagnosed when the second cervical fold was swollen and prolapsed with (C2) or without (C1) reddening. Cytobrush samples from the uterus (n = 370) and the cervix (n = 402) were collected, and the percentage of neutrophils in the uterus (PMNU) and the cervix as indicators of inflammation (threshold: >=5%) was determined. In addition, endometrial biopsies for histology were collected, 300 of which were suitable for evaluation. Cervicitis (C1/C2) was diagnosed in 253 of 416 (60.8%) of cows. Of these, the prolapsed cervical mucosa was hyperemic (C2) in 29.1% of cases. Of 370 available uterine cytology samples, 221 cows had a clinical cervicitis; however, 170 (76.9%) had PMNU less than 5%. Of 300 uterine histologic examinations, 82 (27.3%) did not reveal any abnormalities; the remaining cows either had uterine inflammation and/or degenerative uterine changes such as endometriosis and angiosclerosis. Furthermore, of 300 biopsied animals, 184 revealed a cervicitis (C1/C2); however, 30.4% of these animals had no histopathologic uterine findings. For further analysis, only animals either without histopathologic findings and normal uterine cytology or with solely endometritis (defined as PMNU >= 5% and/or positive histopathology of the uterine tissue) were evaluated (n = 157). Of these, 95 cows had cervicitis. Unexpectedly, 63 of 95 (66.3%) cows had cervicitis without endometritis. With regard to reproductive performance, days to first service were not affected by cervicitis. Number of days open in animals with cervicitis but without endometritis tended to be lower than in cows with cervicitis plus endometritis (P = 0.092). Also, number of days open relative to percentage of neutrophils greater than 5% was lower when the cervical compared to the uterine mucosa was affected (P < 0.05). Total conception and pregnancy rates of animals 200 days into lactation decreased significantly in cows with severe cervical inflammation (C2). In conclusion, the results of this study suggested that cervicitis occurs independent of endometritis, and a higher degree of cervicitis is associated with poorer reproductive performance. PMID- 26483310 TI - Effect of copulation on estrus duration and ovulation time in goats. AB - The objective of the present study was to evaluate the effect of copulation on estrus duration and ovulation in goats. During the fall season, 14 multiparous Boer does were estrous synchronized with controlled internal drug release (300 mg), maintained in the vagina for 7 days, and received 50 MUg of intramuscular GnRH device insertion and 5 mg of natural intramuscular PGF2alpha at device removal. The does were randomly divided into two equal groups: a treatment group (TRE; n = 7) and a control group (CON; n = 7). The TRE group received two copulas by fertile bucks within the first 4 hours of estrus onset, and the CON group received only mounts by the same males equipped with canvas aprons. Estrus detection was performed every 12 hours after controlled internal drug release removal within the first 24 hours and then every 4 hours for 5 days. Estrus was defined when a doe accepted mounting by the bucks equipped with canvas aprons. Each doe in estrus got the first transrectal ultrasonography at 24 hours after estrus onset and then every 4 hours until all the preovulatory follicles ovulated. Estrus onset for the TRE and CON groups was 40.3 +/- 17.4 (mean +/- standard deviation) and 43.3 +/- 12.2 hours (P = 0.72), respectively. Estrus duration for the same groups was 28.6 +/- 5.4 and 36.7 +/- 5.3 hours (P = 0.02), respectively. The mean ovulation time for the TRE and CON groups was 31.4 +/- 2.2 and 35.7 +/- 3.7 hours (P = 0.04), respectively. The proportion of ovulations that occurred after the end of estrus in the TRE group was higher than in the CON group (86% vs. 33%, respectively; P = 0.05). The number of ovulations for the TRE group was 2.1 +/- 0.7; for the CON group, there were 2.2 +/- 0.5 ovulations (P = 0.92). It was concluded that copulation by a buck at the beginning of estrus reduced estrus duration and hastened the ovulation time in Boer goats. PMID- 26483311 TI - Superovulatory response to gonadotrophin FSH/LH treatment and effect of progestin supplement to recipients on survival of transferred vitrified embryos in goats. AB - Two experiments were carried out in goats to evaluate the effects of the FSH/LH ratio during treatment on ovarian response and embryo production (experiment 1) and the efficiency of progestin supplementation on pregnancy and the survival of vitrified embryos (experiment 2). In experiment 1, 30 goats were synchronized and allocated to 2 groups (n = 15) corresponding to the following superovulatory treatments with p-FSH (250 IU, over 3 days) having different doses of purified FSH and LH: (group A) control, FSH/LH ratio of 1, kept constant during treatment; (group B) FSH/LH ratio of 2 and daily FSH/LH ratio of 5.0:1.0:0.3 for the first, second, and third days of treatment, respectively. Ovarian response and embryo production were assessed 7.5 days after estrus. In experiment 2, 46 vitrified blastocysts from p-FSH-superovulated donors were transferred to 26 recipients (2 blastocysts per goat) 7.5 days after estrus. The recipients were synchronized with donors and allocated to 2 experimental groups (n = 13). Group C received progestin supplement as fluorgestone acetate (FGA) inserted into the vagina at the time of embryo transfer, replaced with a new one 16 days later, and maintained until the 45th day of pregnancy; group D, no treatment (control). Pregnancy was diagnosed by transrectal ultrasound scanning on Days 30 and 45 after estrus and followed to term. The results indicated that the increase in FSH/LH ratio from 1 to 2 with decreasing daily FSH/LH (treatment B) did not improve the superovulatory response. Superovulatory treatment A (control) advanced (P < 0.05) the onset of estrus and showed a higher ovulation rate compared to group B (14.9 vs. 10.9; P < 0.05). Fertilization rate, embryo yield, and mean number of transferable embryos in group A (7.5) were higher (P < 0.05) than those in group B (3.2). Recipient goats receiving progestin supplementation (group C) showed a higher (P < 0.05) pregnancy rate and embryo survival (kids born per embryos transferred; 69.3% and 73.1%) than the controls (group D; 23.3% and 19.2%). In conclusion, regimen A with FSH/LH ratio of 1 kept constant during the treatment gave the best ovarian response and embryo production. The progestin supplementation as FGA-pessary administered at embryo transfer time to the 45th day of pregnancy improved the pregnancy rate, kidding rate, and embryo survival of transferred vitrified embryos. Intravaginal progestin supplement has the potential to reduce the incidence of pregnancy losses during early pregnancy. PMID- 26483312 TI - Enzyme activity in energy supply of spermatozoon motility in two taxonomically distant fish species (sterlet Acipenser ruthenus, Acipenseriformes and common carp Cyprinus carpio, Cypriniformes). AB - As spermatozoon motility duration differs significantly among fish species, the mechanism of ATP generation-regeneration and its distribution along the flagellum may be species-dependent. The present study compared the role of creatine kinase (CK) with that of adenylate kinase (AK) in ATP regeneration during motility of demembranated spermatozoa of taxonomically distant fish species, sterlet, and common carp, allowing investigation for the presence of the creatine phosphocreatine (PCr) shuttle in sterlet spermatozoa. The flagellar beat frequency of demembranated spermatozoa was measured in reactivating media in the presence or absence of ATP, ADP, PCr, and CK and AK inhibitors. After demembranation, AK, CK, and total ATPase activity was measured in spermatozoon extracts. Beat frequency of demembranated spermatozoa was found to be positively correlated with ATP levels in reactivating medium and to reach a plateau at 0.8 mM and 0.6 mM ATP for carp and sterlet, respectively. It was shown for the first time that sterlet axonemal dynein ATPases have a higher affinity for ATP than do those of carp. Supplementation of reactivating medium with ADP and PCr without ATP resulted in beat frequencies comparable to that measured with 0.3 to 0.5-mM ATP for both studied species. The presence of the PCr-CK phosphagen system and its essential role in ATP regeneration were first confirmed for sturgeon spermatozoa. The inhibition of CK exerted a high impact on spermatozoon energy supply in both species, whereas the inhibition of AK was more pronounced in sterlet than in carp. This was confirmed by the quantification of enzyme activity in spermatozoon extracts. We concluded that spermatozoa of these taxonomically distant species use similar systems to supply energy for flagella motility, but with different efficacy. PMID- 26483313 TI - Associations among Trueperella pyogenes, endometritis diagnosis, and pregnancy outcomes in dairy cows. AB - The objective of this study was to evaluate three commonly used methods for endometritis diagnosis by comparing each one's association with the presence of intrauterine Trueperella pyogenes (TP) and reproductive performance. Lactating Holstein cows (n = 452) were evaluated a single time at 35 +/- 3 days postpartum to diagnose endometritis on the basis of three criteria: presence of purulent vaginal discharge (PVD) detected by a Metricheck device, presence of purulent uterine lavage fluid (PUL), presence of cytologic endometritis (CE) based on relative abundance of polymorphonuclear leukocytes in uterine lavage fluid. A threshold of polymorphonuclear leukocytes greater than 5% was used to diagnose the occurrence of CE. Also, a swab of the uterine lavage was cultured to evaluate the presence of TP and determine its association with endometritis diagnosis criteria and pregnancy outcomes. The results showed that cows positive for TP had increased prevalence of PVD and PUL and tended to have greater prevalence of CE. Median time to pregnancy was 56 days longer, and hazard of pregnancy was 34% lower for TP-positive cows than for TP-negative cows. Presence of PUL led to a 35% lower hazard of pregnancy and 34-day-longer median time to pregnancy than cows without PUL. Likewise, cows diagnosed with PVD had a 47% lower hazard of pregnancy and 57-day-longer median time to pregnancy than cows without PVD. Cows diagnosed with CE had a 27% lower hazard of pregnancy and 42-day-longer median time to pregnancy than cows without CE. When the three different diagnostic methods were used as independent variables in a Cox's proportional hazard model that evaluated hazard of pregnancy, the variable PVD was the only statistically significant variable. Combined PUL and CE or combined PUL and PVD had no additional effects on hazard of pregnancy when compared with only PUL, only PVD, or only CE as the criterion to determine endometritis. However, combined PVD and CE had an additive detrimental effect on reproductive performance. The sensitivity and specificity of each of TP, PUL, PVD, and CE for predicting nonpregnancy at 300 days postpartum were all similar. In conclusion, TP-positive cows had impaired reproductive performance and increased likelihood of PVD and PUL. Additionally, TP-positive cows tended to have an increased prevalence of CE. Cows with PVD had the lowest reproductive performance when compared to cows with PUL or CE, suggesting that PVD at 35 days postpartum is a better criterion for the diagnosis of endometritis and reproductive failure. PMID- 26483314 TI - Transrectal ultrasonographic characterization of the accessory sex glands, pelvic urethra, and ureters in normal geldings. AB - Transrectal ultrasound of the internal urogenital tract may be used to aid in the diagnosis of reproductive tract and urinary tract pathology in both stallions and geldings. Abnormalities of the accessory sex glands of geldings are uncommon, although prostatic masses have recently been described in adult geldings presenting with dysuria, stranguria, and/or hematuria. The purpose of this study was to describe the normal ultrasonographic features and sizes of the accessory sex glands, caudal ureters, and pelvic urethra in clinically normal geldings. Eleven healthy geldings with no history of urogenital tract pathology were evaluated by a single observer experienced in ultrasound of the stallion accessory sex glands. The ultrasonographic appearance, relative anatomic relationships and sizes of the accessory sex glands, caudal ureters, and pelvic urethra were investigated using both rectal linear array and microconvex array transducers. Summary statistics including mean, standard error, confidence intervals, and range were calculated for each structure. There were no statistically significant differences in measurements between the left and right sides of paired structures or between measurements obtained with different transducers. Fluid was present in the seminal vesicles of 7 of 9 subjects. Midline cysts of the urethra as well as bulbourethral gland and prostatic cysts were identified. The normal reference ranges defined in this study will be useful in the clinical evaluation of geldings with suspected internal urogenital tract pathology. PMID- 26483315 TI - Influence of a 21-Gene Recurrence Score Assay on Chemotherapy Delivery in Breast Cancer. AB - BACKGROUND: We performed an analysis to determine the relative contribution of the Oncotype DX (ODX) recurrence score (RS) results in adjuvant therapy delivery compared with traditional pathologic factors. METHODS AND MATERIALS: We performed a retrospective review of women with stage I-IIIA breast cancer treated at the Yale Comprehensive Cancer Center from 2006 to 2012 with available ODX results. We constructed separate logistic models with the clinicopathologic factors alone and also integrating RS and compared these models using the likelihood ratio test and c-statistic to determine whether integration of the RS will result in better prediction of chemotherapy (CTx) delivery. RESULTS: We identified 431 women with a median age of 58 years. The RS was low (< 18), intermediate (18-30), and high (> 30) in 56%, 37%, and 7%, respectively. CTx was delivered to 30% of the patients. Age, differentiation, lymphovascular invasion, and progesterone receptor (PR) positivity < 50% were associated with CTx delivery in multivariable logistic regression of clinicopathologic factors alone (P < .05). In the model integrating the RS, an intermediate or a high RS was the most influential factor for CTx delivery (odds ratio, 7.87 vs. 265.35, respectively; P < .0001). The PR results and grade were no longer significant (P = .74 and P = .06, respectively). The integration of the RS resulted in improved model fit and precision, indicated by the likelihood ratio test (DeltaG2, 100.782; df = 2; P < .0001) and an improved c-statistic (0.720 vs. 0.856). CONCLUSION: Gene expression profiling appears to account for a substantial amount of variability in CTx delivery in current practice. Further work is needed to ensure appropriate test usage and cost-effectiveness. PMID- 26483316 TI - Gene expression and TB pathogenesis in rhesus macaques: TR4, CD40, CD40L, FAS (CD95), and TNF are host genetic markers in peripheral blood mononuclear cells that are associated with severity of TB lesions. AB - Tuberculosis (TB) pathologic lesions in rhesus macaques resemble those in humans. The expression levels of several host TB candidate genes in the peripheral blood mononuclear cells (PBMCs) of six rhesus macaques experimentally infected with Mycobacterium tuberculosis were quantified pre-infection and at several dates post-infection. Quantitative measures of TB histopathology in the lungs including: granuloma count, granuloma size, volume of granulomatous and non granulomatous lesions, and direct bacterial load, were used as the outcomes of a multi-level Bayesian regression model in which expression levels of host genes at various dates were used as predictors. The results indicate that the expression levels of TR4, CD40, CD40L, FAS (CD95) and TNF in PBMC were associated with quantitative measures of the severity of TB histopathologic lesions in the lungs of the study animals. Moreover, no reliable association between the expression levels of IFNE in PBMCs and the severity of TB lesions in the lungs of the study animals was found. In conclusion, PBMC expression profiles derived from the above listed host genes might be appropriate biomarkers for probabilistic diagnosis and/or prognosis of TB severity in rhesus macaques. PMID- 26483317 TI - The spectroscopic (FT-IR, FT-Raman, dispersive Raman and NMR) study of ethyl-6 chloronicotinate molecule by combined density functional theory. AB - In this study, ethyl-6-chloronicotinate (E-6-ClN) molecule is recorded in the region 4000-400 cm(-1) and 3500-100 cm(-1) (FT-IR, FT-Raman and dispersive Raman, respectively) in the solid phase. ((1))H and ((13))C nuclear magnetic resonance (NMR) spectra are recorded in DMSO solution. The structural and spectroscopic data of the molecule are obtained for two possible isomers (S1 and S2) from DFT (B3LYP) with 6-311++G(d,p) basis set calculations. The geometry of the molecule is fully optimized, vibrational spectra are calculated and fundamental vibrations are assigned on the basis of the potential energy distribution (PED) of the vibrational modes. ((1))H and ((13))C NMR chemical shifts are calculated by using the gauge-invariant atomic orbital (GIAO) method. The electronic properties, such as excitation energies, oscillator strengths, wavelengths, HOMO and LUMO energies, are performed by time-dependent density functional theory (TD-DFT). Total and partial density of state and overlap population density of state diagrams analysis are presented for E-6-ClN molecule. Furthermore, frontier molecular orbitals (FMO), molecular electrostatic potential, and thermodynamic features are performed. In addition to these, reduced density gradient of the molecule is performed and discussed. As a conclusion, the calculated results are compared with the experimental spectra of the title compound. The results of the calculations are applied to simulate the vibrational spectra of the molecule, which show excellent agreement with the observed ones. The theoretical and tentative results will give us a detailed description of the structural and physicochemical properties of the molecule. Natural bond orbital analysis is done to have more information stability of the molecule arising from charge delocalization, and to reveal the information regarding charge transfer within the molecules. PMID- 26483319 TI - Clinical outcomes of endovascular treatment of TASC-II C and D femoropopliteal lesions with the Viabahn endoprosthesis. AB - OBJECTIVES: The objective of this study was to evaluate clinical outcomes and patency rates using the Viabahn endoprosthesis in complex (TASC-II C and D) femoropopliteal lesions. BACKGROUND: Traditional treatment of symptomatic TASC-II C and D femoropopliteal lesions has mainly centered on open surgical options in patients deemed appropriate candidates. Endovascular treatment of these lesions with balloon angioplasty has been historically hampered by aggressive restenosis and relatively early clinical failure. The Viabahn endoprosthesis was developed with the intent of reducing restenosis while improving overall flexibility in the femoropopliteal segment. METHODS: Between March 2009 and July 2011 a total of 51 limbs in 41 patients underwent implantation of one or more Viabahn endovascular stent grafts for the treatment of symptomatic TASC-II C or D lesions. Patients were followed clinically at regular intervals and also underwent routine surveillance duplex ultrasound at 1, 3, 6, and 12 months post-procedure. The average follow-up from the index procedure was 14.6 months (range 13-35.2 months). RESULTS: A total of 22 TASC-II C and 29 TASC-II D lesions were treated (51 limbs in 41 patients). The mean lesion length was 22.4 cm. The overall 1-year primary patency rate was 74.8% (95% CI: 61.2%-88.4%), assisted primary patency rate was 87.4% (95% CI: 70.9%-95.9%), and the secondary patency rate was 94.9% (95% CI: 88.0%-100.0%). CONCLUSIONS: The Viabahn endoprosthesis is a safe and effective option for the treatment of TASC-II C and D femoropopliteal lesions. Patency rates are favorable despite the complexity of these lesions, although multiple endovascular re-interventions may be necessary to achieve an acceptable long-term result. PMID- 26483318 TI - State-of-the-Art Imaging of the Lung for Connective Tissue Disease (CTD). AB - Involvement of the respiratory system is common in connective tissue diseases (CTDs), and the resultant lung injury can affect every part of the lung: the pleura, alveoli, interstitium, vasculature, lymphatic tissue, and large and/or small airways. Most of the parenchymal manifestations of CTD are similar to those found in interstitial lung diseases (ILDs), especially idiopathic interstitial pneumonias, and can be classified using the same system. Although there is some overlap, each CTD is associated with a characteristic pattern of pulmonary involvement. For this reason, thin-section CT as well as pulmonary function tests and serum markers are utilized for diagnosis, disease severity assessment, and therapeutic efficacy evaluation of ILD associated with CTD. In addition, newly developed pulmonary magnetic resonance imaging (MRI) procedures have been recommended as useful alternative imaging options for patients with CTD. This review article will (1) address radiological findings for chest radiography and conventional or thin-section CT currently used for six major types of CTD, rheumatoid arthritis, scleroderma (progressive systemic sclerosis), polymyositis/dermatomyositis, systemic lupus erythematosus, Sjogren syndrome and mixed connective tissue disease; (2) briefly deal with radiation dose reduction for thin-section CT examination; and (3) discuss clinically applicable or state of-the-art MR imaging for CTD patients. PMID- 26483320 TI - Combined behavioral studies and in vivo imaging of inflammatory response and expression of mGlu5 receptors in schnurri-2 knockout mice. AB - Schnurri-2 (Shn-2) knockout (KO) mice have been proposed as a preclinical neuroinflammatory schizophrenia model. We used behavioral studies and imaging markers that can be readily translated to human populations to explore brain effects of inflammation. Shn-2 KO mice and their littermate control mice were imaged with two novel PET ligands; an inflammation marker [(11)C]PBR28 and the mGluR5 ligand [(18)F]FPEB. Locomotor activity was measured using open field exploration with saline, methamphetamine or amphetamine challenge. A significantly increased accumulation of [(11)C]PBR28 was found in the cortex, striatum, hippocampus and olfactory bulb of Shn-2 KO mice. Increased mGluR5 binding was also observed in the cortex and hippocampus of the Shn-2 KO mice. Open field locomotor testing revealed a large increase in novelty-induced hyperlocomotion in Shn-2 KO mice with abnormal (decreased) responses to either methamphetamine or amphetamine. These data provide additional support to demonstrate that the Shn-2 KO mouse model exhibits several behavioral and pathological markers resembling human schizophrenia making it an attractive translational model for the disease. PMID- 26483321 TI - Acute decrease in alkaline phosphatase after brain injury: A potential mechanism for tauopathy. AB - Dephosphorylation of phosphorylated Tau (pTau) protein, which is essential for the preservation of neuronal microtubule assemblies and for protection against trauma-induced tauopathy and chronic traumatic encephalopathy (CTE), is primarily achieved in brain by tissue non-specific alkaline phosphatase (TNAP). Paired helical filaments (PHFs) and Tau isolated from Alzheimer's disease (AD) patients' brains have been shown to form microtubule assemblies with tubulin only after treatment with TNAP or protein phosphatase-2A, 2B and -1, suggesting that Tau protein in the PHFs of neurons in AD brain is hyperphosphorylated, which prevents microtubule assembly. Using blast or weight drop models of traumatic brain injury (TBI) in rats, we observed pTau accumulation in the brain as early as 6h post injury and further accumulation which varied regionally by 24h post-injury. The pTau accumulation was accompanied by reduced TNAP expression and activity in these brain regions and a significantly decreased plasma total alkaline phosphatase activity after the weight drop. These results reveal that both blast- and impact acceleration-induced head injuries cause an acute decrease in the level/activity of TNAP in the brain, which potentially contributes to trauma induced accumulation of pTau and the resultant tauopathy. The regional changes in the level/activity of TNAP or accumulation of pTau after these injuries did not correlate with the accumulation of amyloid precursor protein, suggesting that the basic mechanism underlying tauopathy in TBI might be distinct from that associated with AD. PMID- 26483322 TI - Blockade of high mobility group box-1 signaling via the receptor for advanced glycation end-products ameliorates inflammatory damage after acute intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) is a devastating disease with no specific treatment. Increasing evidence indicates that inflammatory response plays a critical role in ICH-induced damage. High mobility group box-1 protein (HMGB1) may trigger inflammatory response via three putative receptors: receptor for advanced glycation end-products (RAGE), toll-like receptor-2 (TLR2) and toll-like receptor-4 (TLR4). Which receptor participates in HMGB1-induced inflammation during acute ICH is unknown. Using a rat model to examine the early phase of injury in collagenase-induced ICH, we found that treating animals with HMGB1 antagonist significantly reduced the expression of all three receptors. Treating animals with the HMGB1 antagonist EP or RAGE antagonist FPS-ZM1 significantly reduced inflammatory cell infiltration and expression of IL-1beta, matrix metalloproteinase-9 in the perihematoma after ICH. Treatment with EP or FPS-ZM1 also led to greater neurobehavioral function and less brain edema, hemorrhage volume and brain damage after ICH. In contrast, treatment with TLR2/4 antagonists did not significantly affect these post-ICH outcomes. Our results suggest that RAGE may play a specific role in the acute phase of ICH, so targeting the HMGB1 RAGE signaling pathway may be a promising therapeutic strategy. PMID- 26483323 TI - Turn-taking: From perception to speech preparation. AB - We investigated the preparation of a spoken answer response to interrogative sentences by measuring response time (RT) and the response-related readiness potential (RP). By comparing the RT and RP results we aimed to identify whether the RP-onset is more related to the actual speech preparation process or the pure intention to speak after turn-anticipation. Additionally, we investigated if the RP-onset can be influenced by the syntactic structure (one or two completion points). Therefore, the EEG data were sorted based on two variables: the cognitive load required for the response and the syntactic structure of the stimulus questions. The results of the response utterance preparation associated event-related potential (ERP) and the RT suggest that the RP-onset is more related to the actual speech preparation process rather than the pure intention to speak after turn-anticipation. However, the RP-onset can be influenced by the syntactic structure of the question leading to an early response preparation. PMID- 26483324 TI - NSAIDs or paracetamol for short-term treatment of mild to moderate knee pain in early osteoarthritis: are they equivalent? PMID- 26483325 TI - Genetic diversity and population structure of an important wild berry crop. AB - The success of plant breeding in the coming years will be associated with access to new sources of variation, which will include landraces and wild relatives of crop species. In order to access the reservoir of favourable alleles within wild germplasm, knowledge about the genetic diversity and the population structure of wild species is needed. Bilberry (Vaccinium myrtillus) is one of the most important wild crops growing in the forests of Northern European countries, noted for its nutritional properties and its beneficial effects on human health. Assessment of the genetic diversity of wild bilberry germplasm is needed for efforts such as in situ conservation, on-farm management and development of plant breeding programmes. However, to date, only a few local (small-scale) genetic studies of this species have been performed. We therefore conducted a study of genetic variability within 32 individual samples collected from different locations in Iceland, Norway, Sweden, Finland and Germany, and analysed genetic diversity among geographic groups. Four selected inter-simple sequence repeat primers allowed the amplification of 127 polymorphic loci which, based on analysis of variance, made it possible to identify 85 % of the genetic diversity within studied bilberry populations, being in agreement with the mixed-mating system of bilberry. Significant correlations were obtained between geographic and genetic distances for the entire set of samples. The analyses also highlighted the presence of a north-south genetic gradient, which is in accordance with recent findings on phenotypic traits of bilberry. PMID- 26483326 TI - From Crystals to Disordered Crystals: A Hidden Order-Disorder Transition. AB - To distinguish between order and disorder is of fundamental importance to understanding solids. It becomes more significant with recent observations that solids with high structural order can behave like disordered solids, while properties of disordered solids can approach crystals under certain circumstance. It is then imperative to understand when and how disorder takes effect to deviate the properties of a solid from crystals and what the correct factors are to control the behaviours of solids. Here we answer these questions by reporting the finding of a hidden order-disorder transition from crystals to disordered crystals for static packings of frictionless spheres. While the geometric indicators are mostly blind to the transition, disordered crystals already exhibit properties apart from crystals. The transition approaches the close packing of hard spheres, giving rise to the singularity of the close packing point. We evidence that both the transition and properties of disordered crystals are jointly determined by the structural order and density. Near the transition, the elastic moduli and coordination number of disordered crystals show particular pressure dependence distinct from known behaviours of both crystals and jammed solids. The discovery of the transition therefore reveals some unknown aspects of solids. PMID- 26483327 TI - Membrane vesicle-mediated release of bacterial RNA. AB - Many Gram-negative bacterial species release outer membrane vesicles (OMVs) that interact with the host by delivering virulence factors. Here, we report for the first time that RNA is among the wide variety of bacterial components that are associated with OMVs. To characterize the RNA profiles of bacterial OMVs, we performed RNA deep sequencing analysis using OMV samples isolated from a wild type Vibrio cholerae O1 El Tor strain. The results showed that RNAs originating from intergenic regions were the most abundant. Our findings reveal a hitherto unrecognised feature of OMVs mimicking eukaryotic exosomes and highlight a need to evaluate the potential role of RNA-containing bacterial membrane vesicles in bacteria-host interactions. PMID- 26483328 TI - DQ-DRENAR with back-to-back (BABA) excitation: Measuring homonuclear dipole dipole interactions in multiple spin-1/2 systems. AB - A new pulse sequence entitled DQ-DRENAR, (Double-Quantum based Dipolar Recoupling Effects Nuclear Alignment Reduction) was recently described for the quantitative measurement of magnetic dipole-dipole interactions in homonuclear spin-1/2 systems involving multiple nuclei. The double quantum coherences were created via a windowless symmetry-based pulse sequence (POST-C7). The present contribution evaluates the performance of the "Back-to-Back" excitation pulse scheme BABA-xy16 in such DRENAR experiments. Using SIMPSON simulations, special attention is given to finite pulse length effects, dipolar truncation, and chemical shift anisotropy interference. Experimental results on model compounds demonstrate good stability up to long mixing times (>10 ms) as well as high accuracy. As its dipolar coupling efficiency is relatively high (the dipolar coupling scaling factor is 4.24 times as high as that of POST-C7), DQ-DRENAR-BABA-xy16 is most appropriate for the measurement of relatively weak dipolar coupling strengths (<400 Hz). Different from POST-C7, for which the spinning rate is limited to 1/7 of the nutation frequency, DQ-DRENAR-BABA-xy16 experiments can take full advantage of ultrafast MAS experiments. PMID- 26483329 TI - Minimizing the effects of RF inhomogeneity and phase transients allows resolution of two peaks in the (1)H CRAMPS NMR spectrum of adamantane. AB - One of the limiting factors to achieving highly resolved (1)H NMR spectra with (1)H homonuclear decoupling sequences is imperfections in the applied radiofrequency (RF) pulses, most notably phase transients and RF inhomogeneity. Through a series of simulations and solid-state NMR experiments, it is demonstrated that the combined effects of phase transients and RF inhomogeneity can be minimized by a combination of (i) restricting the sample to small volume of the rotor, (ii) by employing a super-cycled version of the DUMBO decoupling sequence, and (iii) by carefully adjusting the probe tuning such that the asymmetric component of phase transients is minimized. Under these optimal conditions, it was possible to clearly resolve two signals in the (1)H CRAMPS NMR spectrum of adamantane arising from the CH and CH2 protons in the molecule. It is proposed that adamantane could be a very useful setup sample for (1)H CRAMPS NMR as the two peaks are only resolved when the effects of RF inhomogeneity and phase transients are minimized. PMID- 26483330 TI - Movin' On Up: An Innovative Nurse-Led Interdisciplinary Health Care Transition Program. AB - This article provides an overview of an innovative nurse-led interdisciplinary health care transition (HCT) model of care entitled Movin' On Up for adolescents and emerging adults (AEAs) with spina bifida (SB) that was originally implemented in 2011. The components of the HCT service model include an HCT nursing specialist, who is an advanced practice nurse; interdisciplinary health care transition plans based on the individualized needs of AEAs; an interdisciplinary HCT team that meets on a weekly basis; direct HCT services provided in the weekly SB clinic; and telephonic follow-up with AEAs, families, and providers. The characteristics of this nurse-led HCT program can be described as an integrated, interdisciplinary, and comprehensive model of care based on a life span approach. To date, a total of 210 AEAs with SB, ages 10 to 20 years, have been enrolled into the program. An important feature of this HCT service model is that it is self-supporting; it generates the revenue needed for sustainability and, unlike other HCT programs, is not reliant on extramural programmatic support. Other accomplishments of Movin' On Up include the development of a transfer protocol wherein 35 AEAs with SB have been supported in their transfer to adult care; implementation of a standardized process to ensure that service referrals to community-based services for postsecondary education, employment, training, and initiation of conservatorships are made; timely performance of evaluations; close tracking of needs and outcomes of self-management knowledge and skills instruction; and attention to equipment needs prior to transfer. PMID- 26483331 TI - [Sequence-dependent Effect of Triptolide with Gefitinib on the Proliferation?and Apoptosis of Lung Adenocarcinoma Cell H1975]. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show promising therapeutic effects in patients with advanced non-small cell lung cancer (NSCLC). However, despite an initial response to TKIs treatment among responsive patients, most inevitably acquire resistance after a progression free period of about 10 months. The percentage of T790M in TKI acquired-resistant patients in most studies is around 50%. The aim of this study is to assess the effects of the sequential administration of triptolide and geftinib on cell proliferation and apoptosis of lung adenocarcinoma cell H1975. METHODS: A MTT assay was used to measure cell proliferation. The potency of the sequential administration of triptolide and geftinib were determined by isobolograms and combination index (CI). Cell apoptosis and cycle distribution were detected by flow cytometry. The Hoechst 33258 method was used to observe the apoptotic morphology. Chemical colorimetric luminescence was used to measure the caspase activity. RESULTS: The results of isobolograms and CI showed that the sequential administration of triptolide following geftinib remarkably inhibited cell proliferation and cell apoptosis compared with other sequential administration models. The cycle distribution results indicated that sequential triptolide administration following geftinib blocked the cells in the G2/M phase but not in the G0/G1 phase. The activation of the Caspase-9/Caspase-3 cascade was mainly involved in the apoptotic pathway of lung adenocarcinoma cell H1975 in all sequential administration models. CONCLUSIONS: The triptolide administration following geftinib might be a new therapeutic strategy for lung cancer with T790M mutation after having EGFR-TKIs resistance.?. PMID- 26483332 TI - [Regulation Mechanism of MTA3 in the Apoptosis of NSCLC Cells]. AB - BACKGROUND: Metastasis-associated protein 3 (MTA3) was originally found as a member of a small protein family (including MTA1, MTA2 and MTA3), and it has been proven that MTA3 had different roles in different types of human cancers. The aim of this study is to explore the function of MTA3 to regulate the cell apoptosis in lung cancer. METHODS: Western blot and Real-time PCR were used to detect the expression level of MTA3 after transfection in non-small cell lung cancer (NSCLC) cells A549 and H157. Apoptosis analysis was used to detect the change of cell apoptosis with upregulated/downregulated of MTA3, and Western blot was used to detect the the expression of the protein related with apoptosis, while downregulate the expression of MTA3 in NSCLC cells A549 and H157. RESULTS: Downregulated of endogenous MTA3 could promote apoptosis in NSCLC cells, meanwhile, siMTA3 could upregulate the protein of BAX, Cleved-Caspase-3, p-PARP, and dowmregulate the protein of Bcl-2. CONCLUSIONS: The data we present here indicate that MTA3 suppress apoptosis of A549 an H157 cells by inhibiting BAX, PARP expression.?. PMID- 26483333 TI - [Clinical Efficacy of Crizotinib in Advanced ALK Positive ?Non-small Cell Lung Cancer]. AB - BACKGROUND: The aim of this study is to explore clinical efficacy of crizotinib in advanced anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer. METHODS: patients with advanced non-small cell lung cancer habouring ALK positive were randomly divided into crizotinib group (n=14) and chemotherapy group (n=14). Patients in the crizotinib group were receive oral treatment with crizotinib (250 mg) twice daily. Patients in the chemotherapy group were administrated docetaxel injection (75 mg/m2) every three weeks and every patient was treated at least 3 period. Then clinical efficacy was observed after 12 mo followed-up. RESULTS: Effective rate of patients in the crizotinib group was 64.29%. It was significantly higher than that of the chemotherapy group (21.43%)(P=0.026). The stable rate of patients in the crizotinib group was 85.71%. It was significantly higher than that of the chemotherapy group 40.86% (chi2=5.600, P=0.018). Median progression free survival (PFS) of the crizotinib group was 7.0 mo. It was longer than that of the chemotherapy group (4.0 mo)(P=0.002). CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced ALK positive non-small cell lung cancer. The median PFS of patients is shorter. It can improve the quality of life about patients.?. PMID- 26483334 TI - [Detection and Analysis of EGFR and KRAS Mutations ?in the Patients with Lung Squamous Cell Carcinomas]. AB - BACKGROUND: Activating mutations in epidermal growth factor receptor (EGFR) and KRAS are important markers in non-small cell lung cancer. However, EGFR and KRAS gene mutations in lung squamous cell carcinoma are rarely reported. The aim of this study was to analyze EGFR and KRAS gene mutation rate and their relationship with clinical features in patients with lung squamous cell carcinomas. METHODS: A total of 139 patients undergoing treatment for naive lung squamous cell carcinomas with tumor tissue samples available for testing were recruited. EGFR and KRAS mutation statuses of the tumor samples were detected using a mutant enriched liquid chip. RESULTS: Of the 139 cases of lung squamous cell carcinoma, EGFR mutations were detected in 25 cases (18%), KRAS mutations were detected in 7 cases (5%), and the presence of both EGFR and KRAS mutations was detected in 1 case (0.7%). EGFR mutations occurred more often in females than in males (33.3% vs 16.5%) and in patients that never smoked than in those who smoke (29.6% vs 16.1%). However, the difference did not reach statistical significance (P>0.05). No significant differences were observed in age, stage, and different biopsy type. KRAS mutations occurred more often in males than in females (5.5% vs 0%), but the difference did not reach statistical significance (P>0.05). No significant differences were observed in age, stage, different biopsy type, and smoking status (P>0.05). CONCLUSIONS: EGFR and KRAS mutations were low in lung squamous cell carcinomas, and had no significant correlation with clinical features. Before using tyrosine kinase inhibitor targeted therapy, EGFR and KRAS mutations should be detected in patients with lung squamous cell carcinomas. PMID- 26483335 TI - [Diagnosis and Treatment of Leptomeningeal Metastasis in Non-small Cell Lung Cancer]. AB - Leptomeningeal metastasis (LM) is one of the disastrous events in managing advanced non-small cell lung cancer (NSCLC) due to severe clinical symptoms and a grave prognosis. Although intrathecal (IT) chemotherapy show some effects for LM in advanced NSCLC, the prognosis is still poor (12 wk-14 wk). A large majority (84%-97%) of the patients were found to have adenocarcinoma histology. Epidermal growth factor receptor (EGFR) senstive mutations were detected in 43.0%-70.5% adenocarcinoma patients with LM. EGFR tyrosine kinase inhibitors (TKIs) showed to be effective for LM in selected NSCLC patients in some reseaches, and confer a survival benefit. Furthermore, future trials need be done to determine the effect of EGFR-TKIs treatment in NSCLC-LM patients. PMID- 26483336 TI - [Advances in Lung Stem Cells and Lung Cancer Stem Cells]. AB - Cancer stem cells (CSCs) are emerging as a hot topic for cancer research. Lung CSCs share many characteristics with normal lung stem cells (SCs), including self renewal and multi-potency for differentiation. Many molecular markers expressed in various types of CSCs were also found in lung CSCs, such as CD133, CD44, aldehyde dehydrogenase (ALDH) and ATP-binding cassette sub-family G member 2 (ABCG2). Similarly, proliferation and expansion of lung CSCs are regulated not only by signal transduction pathways functioning in normal lung SCs, such as Notch, Hedgehog and Wnt pathways, but also by those acting in tumor cells, such as epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositol 3 kinase (PI3K) pathways. As CSC plays an critical role in tumor recurrence, metastasis and drug-resistance, understanding the difference between lung CSCs and normal lung SCs, identifying and targeting CSC markers or related signaling pathways may increase the efficacy of therapy on lung cancer and improved survival of lung cancer patients. PMID- 26483337 TI - [Advances in Diagnosis and Treatment of Multiple Primary Lung Cancer]. AB - Recently, the incidence and detection rates of multiple primary lung cancer (MPLC) are increasing. The diagnosis of MPLC depends mainly on the Martini Melamed criterion and ACCP criterion at present, taking all features (histological, genetic, radiologic and clinical) into account. It may be easy to diagnose cases of MPLC that exhibit different histological types, but it is difficult to diagnose cases that exhibit similar histological type. DNA polity, gene mutations, microsatellite alteration and so on provide new methods for the accurate diagnosis of MPLC. They can evaluate the clonal relationship and help differential diagnosis between MPLC and metastasis. The first therapeutic choice for MPLC is curative operation. The surgical approach includes lobectomy, wedge resection and segmentectomy. For those which cannot be resected, we can synthesize chemotherapy, radiotherapy, stereotactic ablative radiotherapy (SABR), radiofrequency ablation (RFA), molecular targeted therapy, etc. PMID- 26483338 TI - [Role of HER2 in NSCLC]. AB - The therapeutic strategy of non-small cell lung cancer (NSCLC) is dramatically changed with the introduction of molecular targeted drugs in the last years, resulting in a series of results in histologic and molecular level. The discovery of epidermal growth factor receptor (EGFR) mutation, Kirsten rat sarcoma (KRAS) viral oncogene mutation and anaplastic lymphoma kinase (ALK) rearrangement, has profoundly influenced the development of treatment of NSCLC. Recently, there is a renewed interest in the human epidermal growth receptor 2 (HER2), where genetic alteration in NSCLC is associated with the different sensetivity of EGFR tyrosine kinase inhibitors (TKIs), to have a prognostic effect. HER2 amplification in EGFR mutation tumors may become a mechanism of acquired resistance to the TKIs. Besides, HER2 mutation may become a novel therapeutic strategy of NSCLC. PMID- 26483340 TI - [Clinical Observation of Translating to Small Cell Lung Cancer Following Treatment with EGFR-Tyrosine Kinase Inhibitors in Lung Adenocarcinoma]. AB - In recent years, the chemotherapy of non-small cell lung cancer (NSCLC) has almost been reached a platform stage, and there is no obvious progress in terms of response rate (RR) and overall survival (OS); With the great development of molecular biology, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has good therapeutic effect on the NSCLC. But, almost all patients of EGFR-mutant lung cancers develop drug resistance to these agents. This paper reported a case of a 49-year-old woman with lung adenocarcinoma who had EGFR mutant (19-DEL) treated with EGFR-TKIs. After disease progression, histological examination of a secondary biopsy specimen revealed small cell lung cancer (SCLC) had transformed to SCLC treatment. Through the analysis of the process and effect of her therapy, the following is a summary of the relevant mechanism. PMID- 26483339 TI - [Value of Cell Block in the Diagnosis of Malignant Pleural Effusion]. AB - Malignant pleural effusion (MPE ) is due tumor which arises from the mesothelium or metastases from tumor origniating other sites. In large, for undiagnosed unilateral pleural effusions, the most frequent and important diagnosis to be established or excluded is malignancy. Cell block is prepared from residual fluid which is centrifuged or is naturally sedimenting to obtain clots at the bottom of the container. The cell block technique is simple, relatively non-invasive, reproducible and has a high yield for malignant plerual effusion. It plays an important role in the diagnosis, guiding the treatment of maligant pleural effusion. Herein, we summarize the technologys which make the cell block, the differential diagnostic value when multiple sections of the cell block are processed for immunhistochemistry, advantages in the diagnosis of malignant pleural effusion, the clinical value of gene screening in cell block. The aim of this article is to discuss the value of cell block in diagnosis of maligant pleural effusion. PMID- 26483341 TI - Photoacoustic "nanobombs" fight against undesirable vesicular compartmentalization of anticancer drugs. AB - Undesirable intracellular vesicular compartmentalization of anticancer drugs in cancer cells is a common cause of chemoresistance. Strategies aimed at circumventing this problem may improve chemotherapeutic efficacy. We report a novel photophysical strategy for controlled-disruption of vesicular sequestration of the anticancer drug doxorubicin (DOX). Single-walled carbon nanotubes (SWCNTs), modified with folate, were trapped in acidic vesicles after entering lung cancer cells. Upon irradiation by near-infrared pulsed laser, these vesicles were massively broken by the resulting photoacoustic shockwave, and the vesicle sequestered contents were released, leading to redistribution of DOX from cytoplasm to the target-containing nucleus. Redistribution resulted in 12-fold decrease of the EC50 of DOX in lung cancer cells, and enhanced antitumor efficacy of low-dose DOX in tumor-bearing mice. Side effects were not observed. These findings provide insights of using nanotechnology to improve cancer chemotherapy, i.e. not only for drug delivery, but also for overcoming intracellular drug transport hurdles. PMID- 26483342 TI - Unusual Case of Severe Hypertension in a 20-Year-Old Woman. PMID- 26483343 TI - Hypothalamic Paraventricular and Arcuate Nuclei Contribute to Elevated Sympathetic Nerve Activity in Pregnant Rats: Roles of Neuropeptide Y and alpha Melanocyte-Stimulating Hormone. AB - Pregnancy increases sympathetic nerve activity (SNA), but the mechanisms are unknown. Here, we investigated the contributions of the hypothalamic paraventricular and arcuate nuclei in alpha-chloralose-anesthetized pregnant and nonpregnant rats. Baseline arterial pressure (AP) was lower, and heart rate (HR), lumbar sympathetic activity, and splanchnic SNA were higher in pregnant rats compared with nonpregnant rats. Inhibition of the paraventricular nucleus via bilateral muscimol nanoinjections decreased AP and HR more in pregnant rats than in nonpregnant rats and decreased lumbar SNA only in pregnant rats. Similarly, after arcuate muscimol nanoninjections, the decreases in AP, HR, and lumbar, renal, and splanchnic sympathetic nerve activities were greater in pregnant rats than in nonpregnant rats. Major arcuate neuronal groups that project to the paraventricular nucleus express inhibitory neuropeptide Y (NPY) and excitatory alpha-melanocyte-stimulating hormone. Inhibition of paraventricular melanocortin 3/4 receptors with SHU9119 also decreased AP, HR, and lumbar SNA in pregnant rats but not in nonpregnant rats. Conversely, paraventricular nucleus NPY expression was reduced in pregnant animals, and although blockade of paraventricular NPY Y1 receptors increased AP, HR, and lumbar sympathetic activity in nonpregnant rats, it had no effects in pregnant rats. Yet, the sympathoinhibitory, depressor, and bradycardic effects of paraventricular NPY nanoinjections were similar between groups. In conclusion, the paraventricular and arcuate nuclei contribute to increased basal SNA during pregnancy, likely due in part to decreased tonic NPY inhibition and increased tonic alpha-melanocyte-stimulating hormone excitation of presympathetic neurons in the paraventricular nucleus. PMID- 26483344 TI - Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32. AB - Pathological cardiac hypertrophy is regarded as a critical intermediate step toward the development of heart failure. Many signal transduction cascades are demonstrated to dictate the induction and progression of pathological hypertrophy; however, our understanding in regulatory mechanisms responsible for the suppression of hypertrophy remains limited. In this study, we showed that exacerbated hypertrophy induced by pressure overload in cardiac-deleted Pak1 mice was attributable to a failure to upregulate the antihypertrophic E3 ligase, Fbxo32, responsible for targeting proteins for the ubiquitin-degradation pathway. Under pressure overload, cardiac overexpression of constitutively active Pak1 mice manifested strong resilience against pathological hypertrophic remodeling. Mechanistic studies demonstrated that subsequent to Pak1 activation, the binding of Smad3 on a critical singular AGAC(-286)-binding site on the FBXO32 promoter was crucial for its transcriptional regulation. Pharmacological upregulation of Fbxo32 by Berberine ameliorated hypertrophic remodeling and improved cardiac performance in cardiac-deficient Pak1 mice under pressure overload. Our findings discover Smad3 and Fbxo32 as novel downstream components of the Pak1-dependent signaling pathway for the suppression of hypertrophy. This discovery opens a new venue for opportunities to identify novel targets for the management of cardiac hypertrophy. PMID- 26483345 TI - Endothelial Hypoxia-Inducible Factor-1alpha Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a. AB - Chemokines mediate monocyte adhesion to dysfunctional endothelial cells (ECs) and promote arterial inflammation during atherosclerosis. Hypoxia-inducible factor (HIF)-1alpha is expressed in various cell types of atherosclerotic lesions and is associated with lesional inflammation. However, the impact of endothelial HIF 1alpha in atherosclerosis is unclear. HIF-1alpha was detectable in the nucleus of ECs covering murine and human atherosclerotic lesions. To study the role of endothelial HIF-1alpha in atherosclerosis, deletion of the Hif1a gene was induced in ECs from apolipoprotein E knockout mice (EC-Hif1a(-/-)) by Tamoxifen injection. The formation of atherosclerotic lesions, the lesional macrophage accumulation, and the expression of CXCL1 in ECs were reduced after partial carotid ligation in EC-Hif1a(-/-) compared with control mice. Moreover, the lesion area and the lesional macrophage accumulation were decreased in the aortas of EC-Hif1a(-/-) mice compared with control mice during diet-induced atherosclerosis. In vitro, mildly oxidized low-density lipoprotein or lysophosphatidic acid 20:4 increased endothelial CXCL1 expression and monocyte adhesion by inducing HIF-1alpha expression. Moreover, endothelial Hif1a deficiency resulted in downregulation of miR-19a in atherosclerotic arteries determined by microRNA profiling. In vitro, HIF-1alpha-induced miR-19a expression mediated the upregulation of CXCL1 in mildly oxidized low-density lipoprotein stimulated ECs. These results indicate that hyperlipidemia upregulates HIF-1alpha expression in ECs by mildly oxidized low-density lipoprotein-derived unsaturated lysophosphatidic acid. Endothelial HIF-1alpha promoted atherosclerosis by triggering miR-19a-mediated CXCL1 expression and monocyte adhesion, indicating that inhibition of the endothelial HIF-1alpha/miR-19a pathway may be a therapeutic option against atherosclerosis. PMID- 26483346 TI - miR-342-3p regulates MYC transcriptional activity via direct repression of E2F1 in human lung cancer. AB - Accumulating evidence indicates that altered miRNA expression is crucially involved in lung cancer development, though scant information is available regarding how MYC, an archetypical oncogene, is regulated by miRNAs, especially via a mechanism involving MYC cofactors. In this study, we attempted to identify miRNAs involved in regulation of MYC transcriptional activity in lung cancer. To this end, we utilized an integrative approach with combinatorial usage of miRNA and mRNA expression profile datasets of patient tumor tissues, as well as those of MYC-inducible cell lines in vitro. In addition to miRNAs previously reported to be directly regulated by MYC, including let-7 and miR-17-92, our strategy also helped to identify miR-342-3p as capable of indirectly regulating MYC activity via direct repression of E2F1, a MYC-cooperating molecule. Furthermore, miR-342 3p module activity, which we defined as a gene set reflecting the experimentally substantiated influence of miR-342-3p on mRNA expression, was found to be inversely correlated with MYC activity reflected by MYC module activity in three independent datasets of lung adenocarcinoma patients obtained from the Director's Challenge Consortium of the United States (P = 1.94 * 10(-73)), the National Cancer Center of Japan (P = 9.05 * 10(-34)) and the present study (P = 1.17 * 10( 19)). Our integrative approach appears to be useful to elucidate inter-regulatory relationships between miRNAs and protein coding genes of interest, even those present in patient tumor tissues, which remains a challenge to better understand the pathogenesis of this devastating disease. PMID- 26483347 TI - Differential expression of microRNAs in shrimp Marsupenaeus japonicus in response to Vibrio alginolyticus infection. AB - Till date numerous microRNAs (miRNAs) have been discovered from various organisms, including mammals, plants, insects, nematodes and viruses. They are known to have antiviral functions in crustaceans such as shrimp Marsupenaeus japonicas. However, little is known about the role of miRNAs against bacterial infection in this shrimp caused by Vibrio alginolyticus. We performed small RNA sequencing to characterize the differentially expressed microRNAs in V. alginolyticus challenged shrimp, in comparison to that in control uninfected shrimp, at 24 h and 48 h. In total, 55 host miRNAs were differentially expressed in response to the infection and most of these were downregulated at both the time-points. TargetScan and miRanda algorithms showed that the target genes of these down-regulated miRNAs were related to innate immune functions such as production of phenoloxidase enzyme, apoptosis and phagocytosis. Further, gene ontology analysis revealed that many immune signaling pathways were mediated by these miRNAs. This study is one of the earliest attempts at characterizing shrimp miRNAs that respond to V. alginolyticus infection, and will help unravel the miRNA pathways involved in antibacterial action in shrimp. PMID- 26483348 TI - Molecular characterization and functional analysis of IRF3 in tilapia (Oreochromis niloticus). AB - Interferon regulatory factor 3 (IRF3) plays a key role in interferon (IFN) response and binding to the IFN stimulatory response elements (ISREs) within the promoter of IFN and IFN-stimulated genes followed by virus infection. In the current study, we discovered one IRF3 homologue in tilapia genome and analyzed the characterizations and functions of tilapia IRF3. Tilapia IRF3 contains 1368 bp with an ORF of 455 aa. Structurally, tilapia IRF3 protein typically shares the conserved characterizations with other species' IRF3 homologues, displaying conserved DNA-binding domain, IRF association domain, serine-rich C terminal domain, and tryptophan residue cluster. Phylogenetic analysis illustrated that tilapia IRF3 belongs to the IRF3 subfamily. Real-time PCR revealed a broad expression pattern of tilapia IRF3 in various tissues. Subcellular localization analysis showed that tilapia IRF3 mainly resides in the cytoplasm, Western blot demonstrated that IRF3 was distributed in the cytoplasmic fraction. Functionally, IRF3 was found to be transcriptionally up-regulated by the poly I:C stimulation. Moreover, reporter assay elucidated that tilapia IRF3 serves as a regulator in mediating IFN response by increasing the activity of IFN-beta and ISRE-containing promoter. These data supported the view that tilapia IRF3 is a potential molecule in IFN immune defense system against viral infection. PMID- 26483349 TI - Trashing bibliometry? In defence of a unique approach for disciplinary development. PMID- 26483350 TI - On modeling and nanoanalysis of caries-affected dentin surfaces restored with Zn containing amalgam and in vitro oral function. AB - The aim of this research was to assess the influence of mechanical loading on the ability of Zn-free versus Zn-containing amalgams to promote remineralization at the dentin interface. Sound and caries-affected dentin surfaces (CAD) were restored using Zn-free or Zn-containing dental amalgams. Midcoronal dentin surfaces were studied by (1) atomic force microscopy analysis (including plot and phase imaging, nanoindentation test [modulus of Young (Ei), nanoroughness measurements, and fibril diameter assessment], (2) Raman spectroscopy/cluster analysis, (3) x-ray diffraction, (4) field emission electron microscope and energy-dispersive analysis, for morphological, mechanical, and physicochemical characterization. Analyses were performed before amalgam placement and after amalgam removal, at 24 h and 3 weeks of load cycling. Zn-free and Zn-containing amalgams restorations promoted an increase in the modulus of Young of CAD surfaces, after 3 weeks of load cycling; at this time, Zn-containing amalgams attained higher Ei than Zn-free restorations. Zn-containing amalgams induced tubular occlusion after load cycling, in both sound and CAD. Zn free-amalgams promoted remineralization of both intertubular and peritubular dentin in CAD substrata. These minerals were identified as calcium-phosphate deposits and crystals as hydroxyl-apatite with augmented crystallographic maturity but with some components of lattice distortion. Crosslinking of collagen diminished and secondary structure of collagen increased in CAD substrate restored with Zn containing amalgam after 3 weeks of load cycling, indicating an advanced preservation, molecular organization, and orientation of collagen fibrils after load cycling. Plot and phase images permitted to observe the topographical changes which were promoted by the mineral deposits; in general, the indexes related to higher remineralization gave rise to a decrease of nanoroughness and an augmentation of the bandwidth of the collagen fibrils. Zn-containing amalgam restorations submitted to mechanical stimuli promote remineralization of the partially mineral-depleted subjacent substrate at the caries-affected dentin. PMID- 26483351 TI - Rising to the challenge of preventing pediatric intensive care unit admissions. PMID- 26483352 TI - Reply to: Prone position in nonintubated hypoxemic respiratory failure. New tool to avoid endotracheal intubation? PMID- 26483353 TI - A comment on "Changes in end-tidal CO2 could predict fluid responsiveness in the passive leg raising test but not in the mini-fluid challenge test: A prospective and observational study". PMID- 26483354 TI - Association between blood alcohol concentration and mortality in critical illness. AB - OBJECTIVE: In animal models of renal, intestinal, liver, cardiac, and cerebral ischemia, alcohol exposure is shown to reduce ischemia-reperfusion injury. Inpatient mortality of trauma patients is shown to be decreased in a dose dependent fashion relative to blood alcohol concentration (BAC) at hospital admission. In this study, we examined the association between BAC at hospital admission and risk of 30-day mortality in critically ill patients. DESIGN: We performed a 2-center observational study of patients treated in medical and surgical intensive care units in Boston, Massachusetts. SETTING: Medical and surgical intensive care units in 2 teaching hospitals in Boston, Massachusetts. PATIENTS: We studied 11850 patients, 18 years or older, who received critical care between 1997 and 2007. The exposure of interest was the BAC determined in the first 24 hours of hospital admission and categorized a priori as BAC less than 10 mg/dL (below level of detection), 10 to 80 mg/dL, 80 to 160 mg/dL, and greater than 160 mg/dL. The primary outcome was all-cause mortality in the 30 days after critical care initiation. Secondary outcomes included 90- and 365-day mortality after critical care initiation. Mortality was determined using the US Social Security Administration Death Master File, and 365-day follow-up was present in all cohort patients. Adjusted odds ratios (ORs) were estimated by multivariable logistic regression models with inclusion of covariate terms thought to plausibly interact with both BAC and mortality. Adjustment included age, sex, race (white or nonwhite), type (surgical vs medical), Deyo-Charlson index, sepsis, acute organ failure, trauma, and chronic liver disease. RESULTS: Thirty-day mortality of the cohort was 13.7%. Compared to patients with BAC levels less than 10 mg/dL, patients with levels greater than or equal to 10 mg/dL had lower odds of 30-day mortality; for BAC levels 10 to 79.9 mg/dL, the OR was 0.53 (95% confidence interval [CI], 0.40-0.70); for BAC levels 80 to 159.9 mg/dL, it was 0.36 (95% CI, 0.26-0.49); and for BAC levels greater than or equal to 160 mg/dL, it was 0.35 (95% CI, 0.27-0.44). After multivariable adjustment, the OR of 30-day mortality was 0.97 (0.72-1.31), 0.79 (0.57-1.10), and 0.69 (0.54-0.90), respectively. When the cohort was analyzed with sepsis as the outcome of interest, the multivariable adjusted odds of sepsis in patients with BAC 80 to 160 mg/dL or greater than 160 mg/dL were 0.72 (0.50-1.04) or 0.68 (0.51-0.90), respectively, compared to those with BAC less than 10 mg/dL. In a subset of patients with blood cultures drawn (n=4065), the multivariable adjusted odds of bloodstream infection in patients with BAC 80 to 160 mg/dL or greater than 160 mg/dL were 0.53 (0.27-1.01) or 0.49 (0.29-0.83), respectively, compared to those with BAC less than 10 mg/dL. CONCLUSIONS: Analysis of 11850 adult patients showed that having a detectable BAC at hospitalization was associated with significantly decreased odds of 30-day mortality after critical care. Furthermore, BAC greater than 160 mg/dL is associated with significantly decreased odds of developing sepsis and bloodstream infection. PMID- 26483355 TI - Substance use network characteristics and drug and alcohol use behaviors among young men who have sex with men (YMSM). AB - BACKGROUND: Young men who have sex with men (YMSM) use alcohol and other drugs at rates higher than their heterosexual peers. While social networks of YMSM have been acknowledged as an important contextual influence on their health behavior, studies have largely focused on social and sexual networks rather than substance use networks, despite the potential importance of substance use alters in shaping substance use behavior. METHOD: Using data collected from a diverse sample of YMSM (n=156), two multilevel models examined the associations between network (e.g., degree and transitivity), dyadic (e.g., strength of relationship), and individual characteristics and two alter level dependent variables: recent drug use (versus no recent drug use) and frequency of substance use. RESULTS: Results indicated that transitivity was associated with both recent drug use (OR=1.21, p=0.012) and more frequent substance use (b=0.08, p=0.002). Degree was not significantly associated with either variable. Furthermore, participants were also less likely to have recently used drugs (OR=0.93, p<0.001) and tended to use substances less frequently (b=-0.01, p=0.028) with older alters. CONCLUSIONS: Despite substantial interest in network influences on health, much remains unknown about the impact of network structures on substance use. The current findings suggest that structural characteristics of substance use networks may provide important information regarding the drug and alcohol use behavior of YMSM even when controlling for dyadic and individual characteristics. PMID- 26483356 TI - States' implementation of the Affordable Care Act and the supply of physicians waivered to prescribe buprenorphine for opioid dependence. AB - BACKGROUND: Although the Affordable Care Act (ACA) is anticipated to affect substance use disorder (SUD) treatment, its impact on the supply of physicians waivered to treat opioid dependence with buprenorphine has not been considered. This study examined whether states more supportive of ACA, meaning those that had opted to expand Medicaid and establish a state-based health insurance exchange, experienced greater growth in physician supply than less supportive states. METHODS: Buprenorphine physician supply, including total physician supply, supply of 30-patient physicians, and supply of 100-patient physicians per 100,000 state residents, was measured from June 2013 to May 2015. State characteristics were drawn from multiple secondary sources, with states categorized as ACA-supportive, ACA-hybrid (where states either expanded Medicaid or established a state-based exchange), or ACA-resistant (where states took neither action). Mixed effects regression was used to estimate state-level growth curves to test whether rates of growth varied by states' approaches to implementing ACA. RESULTS: The supply of waivered physicians grew significantly over the two-year period. Rates of growth were significantly lower in ACA-hybrid and ACA-resistant states relative to growth in ACA-supportive states. Average buprenorphine physician supply at baseline varied by region, the percentage of residents covered by Medicaid, and the supply of specialty SUD treatment programs. CONCLUSIONS: This study found a positive impact of the ACA on growth in the supply of buprenorphine-waivered physicians in US states. Future research should address whether the ACA affects the number of patients receiving buprenorphine, Medicaid spending, and the quality of treatment services delivered. PMID- 26483357 TI - Safety of oral dronabinol during opioid withdrawal in humans. AB - BACKGROUND: Opioid dependence remains a significant public health problem worldwide with only three FDA-approved treatments, all targeting the mu-opioid receptor. Dronabinol, a cannabinoid (CB) 1 receptor agonist, is currently under investigation as a novel opioid withdrawal treatment. This study reports on safety outcomes of dronabinol among adults in opioid withdrawal. METHODS: Twelve adults physically dependent on short-acting opioids participated in this 5-week within-subject, randomized, double blind, placebo-controlled inpatient study. Volunteers were maintained on oral oxycodone 30 mg qid. Double-blind placebo substitutions occurred for 21 h before each of 7 experimental sessions in order to produce opioid withdrawal. A single oral test dose was administered each session (placebo, oxycodone 30 and 60 mg, dronabinol 5, 10, 20, and 30 mg [decreased from 40 mg]). Heart rate, blood pressure, respiratory outcomes and pupil diameter were assessed repeatedly. RESULTS: Dronabinol 40 mg produced sustained sinus tachycardia accompanied by anxiety and panic necessitating dose reduction to 30 mg. Sinus tachycardia and anxiety also occurred in one volunteer after dronabinol 20mg. Compared to placebo, dronabinol 20 and 30 mg produced significant increases in heart rate beginning 1h after drug administration that lasted approximately 2h (p<0.05). Dronabinol 5 and 10mg produced placebo-like effects. Oxycodone produced prototypic mu-opioid agonist effects (e.g., miosis). CONCLUSION: Dronabinol 20mg and higher increased heart rate among healthy adults at rest who were in a state of opioid withdrawal, raising concern about its safety. These results have important implications for future dosing strategies and may limit the utility of dronabinol as a treatment for opioid withdrawal. PMID- 26483359 TI - Electrical properties of doped conjugated polyelectrolytes with modulated density of the ionic functionalities. AB - We report the synthesis of a series of water-soluble anionic narrow band-gap conjugated polyelectrolytes with a varied density of the ionic functional groups. The charge density is modulated by incorporating the structural units with tetraethylene glycol (TEG) monomethyl ether side chains. These polymers are readily p-doped during dialysis in water. CPEs with TEG side chains exhibit tighter intermolecular packing in the solid state and higher electrical conductivity. PMID- 26483360 TI - An internal charge transfer-dependent solvent effect in V-shaped azacyanines. AB - New V-shaped non-centrosymmetric dyes, possessing a strongly electron-deficient azacyanine core, have been synthesized based on a straightforward two-step approach. The key step in this synthesis involves palladium-catalysed cross coupling of dibromo-N,N'-methylene-2,2'-azapyridinocyanines with arylacetylenes. The resulting strongly polarized pi-expanded heterocycles exhibit green to orange fluorescence and they strongly respond to changes in solvent polarity. We demonstrate that differently electron-donating peripheral groups have a significant influence on the internal charge transfer, hence on the solvent effect and fluorescence quantum yield. TD-DFT calculations confirm that, in contrast to the previously studied bis(styryl)azacyanines, the proximity of S1 and T2 states calculated for compounds bearing two 4-N,N dimethylaminophenylethynyl moieties establishes good conditions for efficient intersystem crossing and is responsible for its low fluorescence quantum yield. Non-linear properties have also been determined for new azacyanines and the results show that depending on peripheral groups, the synthesized dyes exhibit small to large two-photon absorption cross sections reaching 4000 GM. PMID- 26483358 TI - Age-varying associations between substance use behaviors and depressive symptoms during adolescence and young adulthood. AB - BACKGROUND: Substance use and depression often co-occur, complicating treatment of both substance use and depression. Despite research documenting age-related trends in both substance use and depression, little research has examined how the associations between substance use behaviors and depression changes across the lifespan. METHODS: This study examines how the associations between substance use behaviors (daily smoking, regular heavy episodic drinking (HED), and marijuana use) and depressive symptoms vary from adolescence into young adulthood (ages 12 31), and how these associations differ by gender. Using data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), we implemented time-varying effect models (TVEM), an analytic approach that estimates how the associations between predictors (e.g., substance use measures) and an outcome (e.g., depressive symptoms) vary across age. RESULTS: Marijuana use and daily smoking were significantly associated with depressive symptoms at most ages from 12 to 31. Regular HED was significantly associated with depressive symptoms during adolescence only. In bivariate analyses, the association with depressive symptoms for each substance use behavior was significantly stronger for females at certain ages; when adjusting for concurrent substance use in a multivariate analysis, no gender differences were observed. CONCLUSIONS: While the associations between depressive symptoms and both marijuana and daily smoking were relatively stable across ages 12-31, regular HED was only significantly associated with depressive symptoms during adolescence. Understanding age and gender trends in these associations can help tailor prevention efforts and joint treatment methods in order to maximize public health benefit. PMID- 26483361 TI - Celebrating 10 years of Nature Reviews Endocrinology. PMID- 26483362 TI - Language barriers may put patients at risk during daily hospital care. PMID- 26483363 TI - Assessing beyond vital signs to detect early patient deterioration. PMID- 26483364 TI - Computational and carbon-13 NMR studies of Pt-C bonds in P-C-P pincer complexes. AB - A (13)C{(1)H} NMR based investigation was conducted to examine the electronic properties of C(aryl)-M bonds and their trans influence in P-C(aryl)-P pincer complexes. A series of structurally related platinum pincer complexes were rationally designed and their corresponding (13)C-(195)Pt coupling constants were systematically examined. By methodical substitution of the ligand trans to the organometallic C(aryl)-Pt bond, this study revealed the significant influence of the ligands on the nature of the C(aryl)-M bonds. The single crystal X-ray analysis of the complexes and computational studies further confirmed the observations that the C-M bond exhibits significant pi-character. PMID- 26483366 TI - ANATOMO-MORPHOLOGICAL FEUTURES OF THE ROOT CANAL SYSTEM IN GEORGIAN POPULATION - CONE-BEAM COMPUTED TOMOGRAPHY STUDY. AB - Incomplete and superficial knowledge of morphological types and anatomical variations of the root canal system will become the reason leading to the failure of endodontic treatment. cone-beam computed tomography (CBCT) - it is a technologically more sophisticated, interesting, reliable, non-invasive imaging technique with high degree of visualization, considered as a particularly important and useful tool to study complexity and variability of canal system. 2753 teeth of 228 patients have been studied by CT. Ages of the patients varied within 25-55 years. Among them 122 men and 106 women. Maxillary teeth - 1394 and mandibular - 1359, respectively. The aim of our study was investigation and evaluation of: tooth length, number of roots and canals, type of configuration, root canal curvature and degree of curvature in Georgian population. The results of the study revealed interesting data and anatomical characteristics, those replicating the racial signs and differs from the data recorded by the other researchers, became evident. In studying of dental form variations were interested anatomists (description and comparison) anthropologists, biologists, palaeontologists and stomatologists. The field of human dental anatomy has not been completely explored so, the modern human teeth still remain a matter of continual curiosity and research. The knowledge of anatomical characteristics of dental root canals will help clinicians to optimize the algorithm of endodontic treatment. Thus, statistic data are not the universal criterias, however, basing on these indicators anthropometrical data of roots and canals vary according to the geographic zones and nationalities. The study of variations in tooth form has interested anatomists (description and comparison), anthropologists, biologists, palaeontologists and dentists. The field of human dental anatomy has not been completely explored and the dentition of modern man still remains a matter of continual curiosity and research. Thus, statistic data are not the universal criterias, however, basing on these indicators anthropometrical data of roots and canals vary according to the geographic zones and nationalities. The study of variations in tooth form has interested anatomists (description and comparison), anthropologists, biologists, palaeontologists and dentists. The field of human dental anatomy has not been completely explored and the dentition of modern man still remains a matter of continual curiosity and research. PMID- 26483367 TI - [COMBINED ACRYLIC-POLYPROPYLEN REMOVABLE PROSTHESES FOR PROSTHODONTIC TREATMENT]. AB - The article deals with the development of methods to prevent complications with prosthetic dentures patients with psychiatric status. The authors developed a method of manufacturing the denture using modern thermoplastic materials, the use of which in practice does not cause prosthetic stomatitis in patients with psychiatric status. The proposed methodology has been tested clinically. Based on Schiller- Pisarev and study fixation of prostheses has been shown the advantage of the prosthesis used for prosthetics partial dentition defects that can not be fixed prosthetics in this category of patients. PMID- 26483365 TI - Senescent stromal cells induce cancer cell migration via inhibition of RhoA/ROCK/myosin-based cell contractility. AB - Cells induced into senescence exhibit a marked increase in the secretion of pro inflammatory cytokines termed senescence-associated secretory phenotype (SASP). Here we report that SASP from senescent stromal fibroblasts promote spontaneous morphological changes accompanied by an aggressive migratory behavior in originally non-motile human breast cancer cells. This phenotypic switch is coordinated, in space and time, by a dramatic reorganization of the actin and microtubule filament networks, a discrete polarization of EB1 comets, and an unconventional front-to-back inversion of nucleus-MTOC polarity. SASP-induced morphological/migratory changes are critically dependent on microtubule integrity and dynamics, and are coordinated by the inhibition of RhoA and cell contractility. RhoA/ROCK inhibition reduces focal adhesions and traction forces, while promoting a novel gliding mode of migration. PMID- 26483368 TI - [THE DATA OBTAINED FROM AN ELECTROMYOGRAPHY AT DIFFERENT TIME PERIODS OF USE OF COMPLETE RELATIVELY FIXED PROSTHESIS WITH DIFFERENT ABUTMENT SYSTEMS UNDER CONDOTIONS OF DISINTEGRATION OF ONE OF THE DISTAL IMPLANT SUPPORT]. AB - The most effective method of providing a good fixation of complete dentures is the implantation. The aim of our research was the study of bioelectrical activity of masticatory muscles during the adaptation of patients to complete relatively fixed prosthesis, using rigid fixed abutments and abutments provided cushioning the loss of one of the supporting implants. Studies electromyographic indicators suggest that the process of adaptation to complete relatively fixed prostheses, there is better in patients who use prosthetic latching on implant systems with shock-absorbing abutment. These systems provide simulations micromobility teeth and largely negate the disintegration of one of the distal bearing implants, leading to better adaptation to the prosthesis patients and normalization of chewing function. PMID- 26483369 TI - ASSOCIATION BETWEEN SHORT STATURE AND HAIR ELEMENTS. AB - Aim - assessment of hair elemental status, determination of elemental imbalances and heavy metal concentration and evaluation its impact on child liner growth. Case-control study involves 112 children less than 5 years old (target group - 54 children with short stature, control - 58 children with normal physical development). Medical history, nutritional status, anthropological parameters were assessed. Patients with genetic and endocrine disorders, family short stature were excluded from the study. Child elemental status was detected in the hair, with roentgen-fluorescence spectrometer method. Statistical analysis was conduced using SPPS19. Assessment of the dietary history does not reveal any significant differences between the groups, the only exception was consumption of fish, that was statistically significantly lower than in control (p<0,05). The study revealed deficiency of some elements in both (study and control) groups, but there were significant difference between the groups: Zn deficiency 90% versus 40% (p<0,05), Ca deficiency 62 and 36 (p<0,05), Cu deficiency 50 and 16 (p<0,05) and Mn deficiency 30 and 6 (p<0,05) accordingly. Level of some elements (K, S, Br, Cl, Co, Ag, V, Ni, Rb, Sr, Ti, Ba, As, Cd, Zr, Sb) have normal values. Some element deficiency (Fe, Mo, Se) was higher in study group but the difference was not significant. The study revealed high level of hair lead in both groups: all patients (100%) of target group have elevated level of hair lead, among them in 35,8% the content of lead was above so-called minimal allowed level (p<5,0 ppm) and in 64,5% the content of lead in the hair was above so-called maximal allowed level (p>=5,0 ppm). In the control group, lead in the hair was detected in 78% of cases, though the concentration was only in 2% of cases higher than so called maximum allowed. Our study clearly indicated deficiency of trace elements, particularly essential ones and high lead contamination in children with short stature. Our study proves, that analyzing of trace elements and heavy metals levels and evaluation of its influence on health and development have great importance especially during early years, in the critical period of active growth and development. PMID- 26483370 TI - ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH HYPOTHYROIDISM AND CONCOMITANT CHRONIC CHOLECYSTITIS. AB - Activity of endothelial dysfunction markers in patients with hypothyroidism and concomitant chronic cholecystitis was investigated. In patients with hypothyroidism and chronic cholecystitis a increased lactate dehydrogenase and alkaline phosphatase activity was observed, accompanied by the manifestation of cholestasis. In this patients increased vascular endothelium growth factor plasma level and endotheliocytes number was detected, attested the accelerated severity of endothelium dysfunction. Inverse correlation between the vascular endothelium growth factor plasma concentration, desquamated endotheliocytes number in peripheral blood and bilirubin level was detected, that points to the protective role of bilirubin in the prevention of the endothelium dysfunction development. PMID- 26483371 TI - [INTERRELATIONS BETWEEN MICROALBUMINURIA AND RENAL FUNCTION WITH CONTRACTILE ABILITY OF LEFT VENTRICLE IN CARDIORENAL SYNDROME PATIENTS]. AB - Chronic kidney disease (CKD) increases the risk of all-cause mortality and cardiovascular disease as well as progression to end stage kidney failure. The relationship of glomerular filtration rate (GFR) and albuminuria with clinical outcomes in the general population are revealed. This allows to present levels of GFR and microalbuminuria (MA), which increases the risk of mortality. Renal dysfunction, which revealed by the level of GFR and creatinine, can have definite role in hemodynamic changes and heart failure progression. For mentioning the interaction of cardiovascular and renal diseases the cardiorenal syndrome (CRS) term was introduced, with its classification on 5 types, according to the presence of acute/chronic heart failure and primary/secondary origination of heart and kidney injury. We study interrelations between echocardiographic data of left ventricular remodeling, MA level and degree of renal dysfunction in 115 patients with CRS. MA was measured with diagnostic strips, contractile function of left ventricle (LV) - by echocardiography and GFR was assessed by Cocroft Gault method. The association between MA with decreased GFR and elevated creatinine levels and its connection with increased LV myocardial mass and preclinical disturbances of LV systolic function was revealed. We determined direct correlation between MA and myocardial mass index and indirect - between ejection fraction of LV and MA. Obtained data allow to mention the level of MA (25,4+/-5,8 ng/ml) in which there is more probability of LV contractile functional changes, which will allow early prediction and prevention of CRS progression and pathogenetically approved pharmacotherapy organization in this category patients. PMID- 26483372 TI - [C677T AND A1298C ALLELE POLYMORPHISM GENE OF METHYLENETETRAHYDRAFOLATEREDUCTASE IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE AND TYPE 2 DIABETES]. AB - The article presents the results of the study C677T and A1298C polymorphisms of MTHFR gene and their influence on plasma homocysteine levels in patients with nonalcoholic fatty liver disease (NAFLD). The study involved 100 patients with NAFLD and 40 apparently healthy individuals (control group). Determination of allelic polymorphism was performed by polymerase chain reaction with the detection results of hybridization by fluorescence in real-time. Determination of plasma homocysteine levels was performed by ELISA. As a result, studies have not found significant differences in the distribution of genotypes investigated C677T and A1298C MTHFR gene between patients with NAFLD and control group. We have detected statistically significant relationship between the level of homocysteine plasma C677T polymorphism of the MTHFR gene in patients with NAFLD and lack of connection with the A1298C polymorphism of the gene MTHFR. PMID- 26483373 TI - [ASSOCIATION OF CYCLIC CITRULLINATED PEPTIDE ANTIBODIES LEVEL WITH RHEUMATOID ARTHRITIS ACTIVITY BASED ON GLUCOCORTICOID RECEPTOR GENE BBL1 POLYMORPHISM]. AB - The ambiguity of facts on connection between glucocorticoid receptor gene (GR) Bcl1 polymorphism in rheumatoid arthritis (RA) and its activity as well as lack of facts on its association with serological variants of the desease, makes ir reasonable to investigate its connections between cyclic citrullinated peptide antibodiss (ACCP) concentration and clinico-laboratorial parameters of RA (DAS 28 desease activity score, C-reactive protein concentration (CRP) and erythrocyte sedimentation rate (ESR) level based on GR gene Bcl1 polymorphism. Study involved 161 RA patients aged over 40 as well as 96 healthy individuals. Routine examination of RA diagnostics, anthropometric and molecular genetic methods were used in the research. Statistical analysis of the results was performed using SPSS-17 program. It has been proved that there is no significant difference in GR gene Bcl1 polymorphism distribution based on DAS 28 RA desease activity score, ACCP concentration and ESR level. However, we have found out that G/G genotype bearers have positive correlation relationship between ACCP titre and RA activity by laboratorial parameters (CRP, ESR),DAS 28 score and rheumatoid factor (RF) which has not been found in C/C and C/G genotype bearing patients. The above indicates the association of G/G genotype by GR gene Bcl1 polymorphism with clinico-laboratorial parameters of RA inflammatory activity. In course of the study we have identified the existance of correlation relationship between ACCP concentration and DAS 28 score of RA activity, CRP concentration and ESR level in individuals bearing G/G gene by GR gene Bcl11 polymorphism gene. The association between GR gene Bcl1 polymorphism and clinico-laboratorial parameters of RA inflammatory activity has not been found. PMID- 26483374 TI - COMPARATIVE ANALYSIS OF COMBINED COURSE OF CHRONIC HEPATITIS C AND HIV DEPENDING ON THE ROUTE OF INFECTION. AB - At present, an infection caused by the hepatitis C virus is common among HIV infected patients. The rapid growth of drug addiction, sexual route of infection transmission, HIV and HCV infection among young people, low efficiency of treatment and lack of specific means of prevention clearly means that this pathology is to be listed among the first in the modern infectology. The aim of the study was to investigate the characteristics of the course of chronic hepatitis C in HIV-infected patients, depending on the route of infection. Study design was open, non-randomized and prospective. A total of 58 HIV-infected patients with chronic hepatitis C registered in the dispensary at Karaganda Regional Center for Prevention and Control of AIDS were examined. The diagnosis of HIV infection was verified by immune blotting. Etiological hepatitis verification was performed by means of enzyme immunoassay and polymerase chain reaction. We present the clinical and laboratory results of HIV-infected patients with chronic hepatitis C, depending on the route of infection. Patients with the sexually transmitted infection experienced asymptomatic course of the disease. In comparison, injecting drug users showed greater clinical symptomatology and a moderate level of activity of the infectious process. These clinical and laboratory findings suggest that the characteristics of the course of chronic hepatitis C in HIV-infected patients depends on the route of infection. PMID- 26483375 TI - EPIDEMIOLOGY, CLINICAL AND LABORATORY FEATURES OF CRIMEAN-CONGO HEMORRHAGIC FEVER IN GEORGIA. AB - Crimean-Congo hemorrhagic fever virus transmitted to humans by Hyalomma ticks or by direct contact with the blood of infected humans or domestic animals. The most common clinical signs of CCHF are fever, nausea, headache, diarrhea, myalgia, petechial rash, and bleeding. CCHF is a severe disease in humans with a fatality rate up to 15-85%. This study was undertaken to determine the predictors of fatality among patients with CCHF based on epidemiological, clinical, and laboratory findings. 34 patients were enrolled in the study, aged 4 to 77; 17 - male and 17 female. 3 of them were fatal cases. All of them were from Shua Kartli: Khashuri, Gori and Kaspi districts, involved in farming/handling livestock and the history of tick bite was present in most of patients. Evaluation of the epidemiological characteristics of this cases showed that the female to male ratio was nearly similar. The disease is common in the rural areas of the region, mostly in the actively working age group and almost all patients were farmers. The results of our study show that the most cardinal clinical and laboratory features of Crimean-Congo hemorrhagic fever are - acute beginning of disease, high fever, intoxication and hemorrhagic symptoms, thrombocytopenia, high level of aminotransferases and creatine. Predictors of fatality are: an altered mental status, in early stage of disease dramatic decreased thrombocytes count and significantly high level of aspartate aminotransferase, also longer the mean prothrombin time and INR. PMID- 26483376 TI - EPIDEMIOLOGY AND MOLECULAR TYPING OF BRUCELLA STRAINS CIRCULATING IN GEORGIA. AB - In 2009-2013, 851 cases of brucellosis were registered in Georgia. Most cases of brucellosis were found in eastern Georgia (91.3% of cases). Mainly men were infected with brucellosis (81.0%).The age group with the most frequent cases of brucellosis is 30-59 years (48.5%). Brucellosis is rarely found among children(0 4 years - 2.0%, 5-14 years - 8.0%). Brucellosis cases were linked to professional activity; mainly by farmers (33.0% of those infected) and shepherds (27.0%). Biotyping Brucella by microbiological methods alone has limitations, so molecular typing was implemented in this study to confirm species. Isolates from human blood and ruminant milk or blood were identified by a bacteriological algorithm and confirmed by real-time PCR (Brucella T1, Idaho Technology). Species identity was confirmed using the AMOS conventional PCR assay, which differentiates four human pathogenic species but cannot recognize certain biovars within them. This gap was addressed by using more universal species-specific Single Nucleotide Polymorphism (SNP) assays. Real-time PCR was used to confirm 86 Brucella strains (48 human, 38 animal isolates) obtained 2009-2011. AMOS PCR supported the biochemical test results for 53 B. melitensis and four B. abortus strains, but not for 29 suspected B. abortus human and animal isolates. SNP typing of all 86 isolates supported the AMOS PCR results but also confirmed the species of the 29 strains not amplified by AMOS PCR. In 2009-2013 years the prevalence of brucellosis was still high. Nowadays cases of brucellosis are higher in the western part of Georgia than in the 1991-2005 period by a factor of 2.62. Brucellosis continues to be mainly an infection in males, because men are mostly engaged in sheep and cattle care. Combined AMOS PCR and SNP typing in this study provided the first genetic confirmation that both B. abortus and B. melitensis are actively circulating in humans and animals in Georgia. PMID- 26483377 TI - COMPETENCE IN TOPIC OF PSORIASIS AMONG NURSES IN HEALTHCARE INSTITUTIONS. AB - Nurses in their everyday work meet patients with various diseases (including chronic skin diseases), and play an important role in improving patients' quality of life. Nurses working in dermatology clinics frequently play leading roles in the care of patients with skin disorders. The aim of the study was to investigate the knowledge about the psoriasis among nurses working in non-dermatological healthcare institutions. A cross-sectional study in randomly selected 16 healthcare institutions of Kaunas city was conducted. The study included 505 nurses. A questionnaire to assess the knowledge was developed, containing 15 questions about signs of psoriasis. Based on the responses, the nurses' level of knowledge was evaluated in points. The respondents' age was 45.34+/-10.52 years, and the mean duration of their work experience was 23.2+/-11.42 years. CONCLUSION: the nurses' level of knowledge depended on their education level and the frequency of contacts with psoriasis patients. Nurses working in non dermatological healthcare institutions had insufficient knowledge about psoriasis, and expressed willingness to learn more. PMID- 26483378 TI - [LIGHT AND ELECTRON MICROSCOPY OF CELLULAR ELEMENTS IN STATOCYSTS OF TERRESTRIAL PULMONARY SNAIL HELIX LUCORUM]. AB - Statocysts H. Lucorum appear to be the paired formations having a spherical form and locating on dorsolateral surface of pedal ganglia of subesophageal ganglionic complex. Using the method of reconstruction, as well as the method of scanning electron microscopy on paraffin and semithin slices it has been revealed that the epithelial lining of H. Lucorum appears to be a spatially ordered complex, consisting of 13 cell assemblies. in each of them one sensory cell is surrounded by the satellite cells. The sensory cell has a star shape on the front pole of statocyst because of many protoplasmic processes branching off from its body. The other 12 cells have polygonal shape and form three belts around the inside perimeter of statocyst: interior, middle or equatorial and posterior. There are 4 cells in each belt. The sensory cells forming anterior and posterior belts turned out to be displaced in relation to the cells of equatorial belt and for this reason the whole cell structure resembles a brickwork. The distribution of sensory cells on the inner surfce of statocyst creates the structural polarization of this formtion. First of all, this is evidenced by the presence of the sensory cell on the anterior pole of statocyst and by the absence of those on opposite, posterior pole. The topography of each sensory cell on the inner surface of statocyst, the sizes and shapes of the nuclei, the quantity of nucleoli, the peculiarities of cytoplasm vacuolation and interrelation of sensory and supporting cells have been established. PMID- 26483379 TI - CREATION OF OINTMENT COMPOSITIONS CONTAINING PHENOL COMPOUNDS FOR MEDICAL TREATMENT. AB - The research was aimed at studying the possibility of obtaining drug ointments with a potential anti-mycotic activity by using thick extracts obtained from the leaves of fustic, hazel, nut and bark of the oak. There were prepared the ointment compositions on different bases. As a methodology for studying the properties of the obtained ointments, there have been used the studies of colloidal stability and resorption of tanning substances in agar. The obtained results allow for making conclusion that the selected ointments are colloidally stable, and the values of movement of zones of biologically active substances in the agar body are large enough. These data allow for forecasting both the possibility of creating the similar ointment systems and their rather high properties. Based on the obtained data, there have been selected the ointment composition variants for further studies. PMID- 26483380 TI - Think back. PMID- 26483381 TI - Sqstm1-GFP knock-in mice reveal dynamic actions of Sqstm1 during autophagy and under stress conditions in living cells. AB - Sqstm1 serves as a signaling hub and receptor for selective autophagy. Consequently, dysregulation of Sqstm1 causes imbalances in signaling pathways and disrupts proteostasis, thereby contributing to the development of human diseases. Environmental stresses influence the level of Sqstm1 by altering its expression and/or autophagic degradation, and also changes the localization of Sqstm1, making it difficult to elucidate the actions and roles of this protein. In this study, we developed knock-in mice expressing Sqstm1 fused to GFP (Sqstm1 GFP(KI/+)). Using these Sqstm1-GFP(KI/+) mice, we revealed for the first time the dynamics of endogenous Sqstm1 in living cells. Sqstm1-GFP was translocated to a restricted area of LC3-positive structures, which primarily correspond to the inside of autophagosomes, and then degraded. Moreover, exposure to arsenite induced expression of Sqstm1-GFP, followed by accumulation of the fusion protein in large aggregates that were degraded by autophagy. Furthermore, suppression of autophagy in Sqstm1-GFP(KI/+) mouse livers caused accumulation of Sqstm1-GFP and formation of GFP-positive aggregate structures, leading to severe hepatic failure. These results indicate that Sqstm1-GFP(KI/+) mice are a useful tool for analyzing Sqstm1 in living cells and intact animals. PMID- 26483383 TI - SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1. AB - SLAT (also known as DEF6) promotes T cell activation and differentiation by regulating NFAT-Ca(2+) signaling. However, its role in TCR-mediated inside-out signaling, which induces integrin activation and T cell adhesion, a central process in T cell immunity and inflammation, has not been explored. Here, we show that SLAT is crucial for TCR-induced adhesion to ICAM-1 and affinity maturation of LFA-1 in CD4(+) T cells. Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion. Finally, we established that a constitutively active form of Rap1, which is present at the plasma membrane, rescues the defective LFA-1 activation and ICAM-1 adhesion in SLAT deficient (Def6(-/-)) T cells. These findings ascribe a new function to SLAT, and identify Rap1 as a target of SLAT function in TCR-mediated inside-out signaling. PMID- 26483382 TI - Regulation of dendrite growth and maintenance by exocytosis. AB - Dendrites lengthen by several orders of magnitude during neuronal development, but how membrane is allocated in dendrites to facilitate this growth remains unclear. Here, we report that Ras opposite (Rop), the Drosophila ortholog of the key exocytosis regulator Munc18-1 (also known as STXBP1), is an essential factor mediating dendrite growth. Neurons with depleted Rop function exhibit reduced terminal dendrite outgrowth followed by primary dendrite degeneration, suggestive of differential requirements for exocytosis in the growth and maintenance of different dendritic compartments. Rop promotes dendrite growth together with the exocyst, an octameric protein complex involved in tethering vesicles to the plasma membrane, with Rop-exocyst complexes and exocytosis predominating in primary dendrites over terminal dendrites. By contrast, membrane-associated proteins readily diffuse from primary dendrites into terminals, but not in the reverse direction, suggesting that diffusion, rather than targeted exocytosis, supplies membranous material for terminal dendritic growth, revealing key differences in the distribution of materials to these expanding dendritic compartments. PMID- 26483384 TI - In vivo tracking of phosphoinositides in Drosophila photoreceptors. AB - In order to monitor phosphoinositide turnover during phospholipase C (PLC) mediated Drosophila phototransduction, fluorescently tagged lipid probes were expressed in photoreceptors and imaged both in dissociated cells, and in eyes of intact living flies. Of six probes tested, Tb(R332H) (a mutant of the Tubby protein pleckstrin homology domain) was judged the best reporter for phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2], and the P4M domain from Legionella SidM for phosphatidylinositol 4-phosphate (PtdIns4P). Using accurately calibrated illumination, we found that only ~50% of PtdIns(4,5)P2 and very little PtdIns4P were depleted by full daylight intensities in wild-type flies, but both were severely depleted by ~100-fold dimmer intensities in mutants lacking Ca(2+) permeable transient receptor potential (TRP) channels or protein kinase C (PKC). Resynthesis of PtdIns4P (t1/2 ~12 s) was faster than PtdIns(4,5)P2 (t1/2 ~40 s), but both were greatly slowed in mutants of DAG kinase (rdgA) or PtdIns transfer protein (rdgB). The results indicate that Ca(2+)- and PKC-dependent inhibition of PLC is required for enabling photoreceptors to maintain phosphoinositide levels despite high rates of hydrolysis by PLC, and suggest that phosphorylation of PtdIns4P to PtdIns(4,5)P2 is the rate-limiting step of the cycle. PMID- 26483385 TI - p114RhoGEF governs cell motility and lumen formation during tubulogenesis through a ROCK-myosin-II pathway. AB - Tubulogenesis is fundamental to the development of many epithelial organs. Although lumen formation in cysts has received considerable attention, less is known about lumenogenesis in tubes. Here, we utilized tubulogenesis induced by hepatocyte growth factor (HGF) in MDCK cells, which form tubes enclosing a single lumen. We report the mechanism that controls tubular lumenogenesis and limits each tube to a single lumen. Knockdown of p114RhoGEF (also known as ARHGEF18), a guanine nucleotide exchange factor for RhoA, did not perturb the early stages of tubulogenesis induced by HGF. However, this knockdown impaired later stages of tubulogenesis, resulting in multiple lumens in a tube. Inhibition of Rho kinase (ROCK) or myosin IIA, which are downstream of RhoA, led to formation of multiple lumens. We studied lumen formation by live-cell imaging, which revealed that inhibition of this pathway blocked cell movement, suggesting that cell movement is necessary for consolidating multiple lumens into a single lumen. Lumen formation in tubules is mechanistically quite different from lumenogenesis in cysts. Thus, we demonstrate a new pathway that regulates directed cell migration and formation of a single lumen during epithelial tube morphogenesis. PMID- 26483386 TI - Carcinoma cells induce lumen filling and EMT in epithelial cells through soluble E-cadherin-mediated activation of EGFR. AB - In epithelial cancers, carcinoma cells coexist with normal cells. Although it is known that the tumor microenvironment (TME) plays a pivotal role in cancer progression, it is not completely understood how the tumor influences adjacent normal epithelial cells. In this study, a three-dimensional co-culture system comprising non-transformed epithelial cells (MDCK) and transformed carcinoma cells (MSV-MDCK) was used to demonstrate that carcinoma cells sequentially induce preneoplastic lumen filling and epithelial-mesenchymal transition (EMT) in epithelial cysts. MMP-9 secreted by carcinoma cells cleaves cellular E-cadherin (encoded by CDH1) from epithelial cells to generate soluble E-cadherin (sE-cad), a pro-oncogenic protein. We show that sE-cad induces EGFR activation, resulting in lumen filling in MDCK cysts. Long-term sE-cad treatment induced EMT. sE-cad caused lumen filling by induction of the ERK signaling pathway and triggered EMT through the sustained activation of the AKT pathway. Although it is known that sE cad induces MMP-9 release and consequent EGFR activation in tumor cells, our results, for the first time, demonstrate that carcinoma cells can induce sE-cad shedding in adjacent epithelial cells, which leads to EGFR activation and the eventual transdifferentiation of the normal epithelial cells. PMID- 26483387 TI - CaV3.2 T-type channels mediate Ca2+ entry during oocyte maturation and following fertilization. AB - Initiation of mouse embryonic development depends upon a series of fertilization induced rises in intracellular Ca(2+). Complete egg activation requires influx of extracellular Ca(2+); however, the channels that mediate this influx remain unknown. Here, we tested whether the alpha1 subunit of the T-type channel CaV3.2, encoded by Cacna1h, mediates Ca(2+) entry into oocytes. We show that mouse eggs express a robust voltage-activated Ca(2+) current that is completely absent in Cacna1h(-/-) eggs. Cacna1h(-/-) females have reduced litter sizes, and careful analysis of Ca(2+) oscillation patterns in Cacna1h(-/-) eggs following in vitro fertilization (IVF) revealed reductions in first transient length and oscillation persistence. Total and endoplasmic reticulum (ER) Ca(2+) stores were also reduced in Cacna1h(-/-) eggs. Pharmacological inhibition of CaV3.2 in wild-type CF-1 strain eggs using mibefradil or pimozide reduced Ca(2+) store accumulation during oocyte maturation and reduced Ca(2+) oscillation persistence, frequency and number following IVF. Overall, these data show that CaV3.2 T-type channels have prev8iously unrecognized roles in supporting the meiotic-maturation-associated increase in ER Ca(2+) stores and mediating Ca(2+) influx required for the activation of development. PMID- 26483388 TI - Surviving protein quality control catastrophes--from cells to organisms. AB - Organisms have evolved mechanisms to cope with and adapt to unexpected challenges and harsh conditions. Unfolded or misfolded proteins represent a threat for cells and organisms, and the deposition of misfolded proteins is a defining feature of many age-related human diseases, including the increasingly prevalent neurodegenerative diseases. These protein misfolding diseases are devastating and currently cannot be cured, but are hopefully not incurable. In fact, the aggregation-prone and potentially harmful proteins at the origins of protein misfolding diseases are expressed throughout life, whereas the diseases are late onset. This reveals that cells and organisms are normally resilient to disease causing proteins and survive the threat of misfolded proteins up to a point. This Commentary will outline the limits of the cellular resilience to protein misfolding, and discuss the possibility of pushing these limits to help cells and organisms to survive the threat of misfolding proteins and to avoid protein quality control catastrophes. PMID- 26483389 TI - Intimal (spindle cell) sarcoma of the left atrium presenting with abnormal neurological examination. AB - A 43-year-old man with an unremarkable medical history presented to our hospital with 2 weeks of headaches, ataxia and confusion. CT of the head revealed a large haemorrhagic cystic lesion. A subsequent chest CT revealed a large left atrial mass. The mass was subsequently biopsied with positive immunohistochemistry staining for MDM2, FLI1 and vimentin. Real-time PCR revealed MDM2 amplification, confirming the diagnosis of intimal sarcoma. The patient underwent surgical resection and reconstruction of the atrium with subsequent discharge to short term rehabilitation, but his symptoms continued to progress. A repeat CT of the head revealed a new cerebellar mass. He underwent a second resection, but continued to experience worsening symptoms. He was diagnosed with stage IV intimal sarcoma and referred to hospice. The patient died 5 months after initial presentation. Autopsy was performed and revealed the cause of death as pneumonia. There was no involvement of the pulmonic or aortic vessels. PMID- 26483390 TI - Spontaneous clearance of hepatitis C virus during alcoholic hepatitis: the alcohol killed the virus? AB - Spontaneous clearance of hepatitis C virus during chronic infection is uncommon. We report the case of a patient who cleared hepatitis C virus during an episode of presumed alcoholic hepatitis. A brief discussion on the immunological aspects of chronic hepatitis C and the impact of alcohol consumption on it is presented as well. PMID- 26483391 TI - Vitamin D-dependent rickets: a resurgence of the rachitic lung in the 21st century. AB - Respiratory complications of rickets may be life-threatening particularly in developing countries. A 7-month-old boy presented with recurrent infections, seizures, failure to thrive, wheezing and respiratory distress progressing to global respiratory failure. Several antimicrobial regimens, bronchodilators and corticosteroids resulted in only short-term improvement. He was transferred from Cape Verde to a third-care hospital in Portugal. He was hypotonic and undernourished, with respiratory anguish and classical skeletal signs of rickets, despite vitamin D supplementation. Hypocalcaemia, normal phosphate levels and normal vitamin D status 25(OH)D3 and 1.25(OH)2D3) pointed to vitamin D-dependent rickets type II. Treatment with high doses of calcium and calcitriol allowed progressive respiratory, musculoskeletal and neurological recovery. Although respiratory manifestations of rickets were described many years ago, the present case raises relevant issues about the level of diagnostic support, the risk of complications and how they should be assessed and monitored. PMID- 26483392 TI - Surgical treatment of massive mitral annular calcification. PMID- 26483393 TI - GLP1- and GIP-producing cells rarely overlap and differ by bombesin receptor-2 expression and responsiveness. AB - The incretin hormones glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal endocrine cells, the so-called L- and K-cells. The cells are derived from a common precursor and are highly related, and co-expression of the two hormones in so-called L/K-cells has been reported. To investigate the relationship between the GLP1- and GIP producing cells more closely, we generated a transgenic mouse model expressing a fluorescent marker in GIP-positive cells. In combination with a mouse strain with fluorescent GLP1 cells, we were able to estimate the overlap between the two cell types. Furthermore, we used primary cultured intestinal cells and isolated perfused mouse intestine to measure the secretion of GIP and GLP1 in response to different stimuli. Overlapping GLP1 and GIP cells were rare (~5%). KCl, glucose and forskolin+IBMX increased the secretion of both GLP1 and GIP, whereas bombesin/neuromedin C only stimulated GLP1 secretion. Expression analysis showed high expression of the bombesin 2 receptor in GLP1 positive cells, but no expression in GIP-positive cells. These data indicate both expressional and functional differences between the GLP1-producing 'L-cell' and the GIP-producing 'K-cell'. PMID- 26483394 TI - Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. AB - The prevalence of germline pathogenic mutations in a comprehensive panel of cancer predisposition genes is not well-defined for patients with pancreatic ductal adenocarcinoma (PDAC). To estimate the frequency of mutations in a panel of 22 cancer predisposition genes, 96 patients unselected for a family history of cancer who were recruited to the Mayo Clinic Pancreatic Cancer patient registry over a 12-month period were screened by next-generation sequencing. Fourteen pathogenic mutations in 13 patients (13.5%) were identified in eight genes: four in ATM, two in BRCA2, CHEK2, and MSH6, and one in BARD1, BRCA1, FANCM, and NBN. These included nine mutations (9.4%) in established pancreatic cancer genes. Three mutations were found in patients with a first-degree relative with PDAC, and 10 mutations were found in patients with first- or second-degree relatives with breast, pancreas, colorectal, ovarian, or endometrial cancers. These results suggest that a substantial proportion of patients with PDAC carry germline mutations in predisposition genes associated with other cancers and that a better understanding of pancreatic cancer risk will depend on evaluation of families with broad constellations of tumors. These findings highlight the need for recommendations governing germline gene-panel testing of patients with pancreatic cancer. PMID- 26483395 TI - Association of sex hormone-binding globulin and free testosterone with mortality in men with type 2 diabetes mellitus. AB - OBJECTIVE: Low circulating testosterone levels have been associated with increased mortality in men. We hypothesized that the prognostic role of testosterone in men with type 2 diabetes mellitus (T2DM) is influenced by its carrier protein sex hormone-binding globulin (SHBG). DESIGN: We conducted a prospective cohort study at a tertiary referral centre. METHODS: In total, 531 men with T2DM presenting to a diabetes clinic in 2004-2005 were followed prospectively until death, or July 31, 2014, and a survival analysis was performed. The main outcome measure was all cause mortality. RESULTS: Over a mean (S.D.) follow up of 7.6 years (2.6) 175 men (33%) died. In Cox proportional hazard models both higher SHBG (Hazard Ratio (HR) 1.012 (95% CI 1.002-1.022), P=0.02) and lower calculated free testosterone (cFT) (HR 0.995 (95% CI 0.993 0.998), P=0.001) were risk factors for all cause mortality independently of age, BMI, presence of macro- and microvascular disease, duration of T2DM, hemoglobin, renal function, insulin use, C-reactive protein and homeostatic model of insulin resistance. By contrast, the inverse association of total testosterone (TT) with mortality weakened after these adjustments (P=0.11). SHBG remained associated with mortality (P<0.001) both if substituted for or added to TT in the multivariable model. In the fully adjusted model, an increase of SHBG by 17.3 nmol/l (1 S.D.) increased mortality by 22% and a decrease in cFT by 81 pmol/l (1 S.D.) increased mortality by 45%. CONCLUSIONS: The association of SHBG with mortality in men with T2DM is novel. Whether SHBG acts via regulation of testosterone, has intrinsic biological roles, or is a marker of poor health requires further study. PMID- 26483396 TI - Regulation of Extrasynaptic GABAA alpha4 Receptors by Ethanol-Induced Protein Kinase A, but Not Protein Kinase C Activation in Cultured Rat Cerebral Cortical Neurons. AB - Ethanol produces changes in GABAA receptor trafficking and function that contribute to ethanol dependence symptomatology. Extrasynaptic gamma-aminobutyric acid A receptors (GABAA-R) mediate inhibitory tonic current and are of particular interest because they are potentiated by physiologically relevant doses of ethanol. Here, we isolate GABAA alpha4delta receptors by western blotting in subsynaptic fractions to investigate protein kinase A (PKA) and protein kinase C (PKC) modulation of ethanol-induced receptor trafficking, while extrasynaptic receptor function is determined by measurement of tonic inhibition and responses evoked by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). Rat cerebral cortical neurons were grown for 18 days in vitro and exposed to ethanol and/or PKA/PKC modulators. Ethanol exposure (1 hour) did not alter GABAA alpha4 receptor abundance, but it increased tonic current amplitude, an effect that was prevented by inhibiting PKA, but not PKC. Direct activation of PKA, but not PKC, increased the abundance and tonic current of extrasynaptic alpha4delta receptors. In contrast, prolonged ethanol exposure (4 hours) reduced alpha4delta receptor abundance as well as tonic current, and this effect was also PKA dependent. Finally, PKC activation by ethanol or phorbol-12,13-dibutyrate (PdBu) had no effect on extrasynaptic alpha4delta subunit abundance or activity. We conclude that ethanol alters extrasynaptic alpha4delta receptor function and expression in cortical neurons in a PKA-dependent manner, but ethanol activation of PKC does not influence these receptors. These results could have clinical relevance for therapeutic strategies to restore normal GABAergic functioning for the treatment of alcohol use disorders. PMID- 26483397 TI - Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression. AB - Abdominal aortic aneurysm (AAA), characterized by exuberant inflammation and tissue deterioration, is a common aortic disease associated with a high mortality rate. There is currently no established pharmacological therapy to treat this progressive disease. Andrographolide (Andro), a major bioactive component of the herbaceous plant Andrographis paniculata, has been found to exhibit potent anti inflammatory properties by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activity in several disease models. In this study, we investigated the ability of Andro to suppress inflammation associated with aneurysms, and whether it may be used to block the progression of AAA. Whereas diseased aortae continued to expand in the solvent-treated group, daily administration of Andro to mice with small aneurysms significantly attenuated aneurysm growth, as measured by the diminished expansion of aortic diameter (165.68 +/- 15.85% vs. 90.62 +/- 22.91%, P < 0.05). Immunohistochemistry analyses revealed that Andro decreased infiltration of monocytes/macrophages and T cells. Mechanistically, Andro inhibited arterial NF-kappaB activation and reduced the production of proinflammatory cytokines [CCL2, CXCL10, tumor necrosis factor alpha, and interferon-gamma] in the treated aortae. Furthermore, Andro suppressed alpha4 integrin expression and attenuated the ability of monocytes/macrophages to adhere to activated endothelial cells. These results indicate that Andro suppresses progression of AAA, likely through inhibition of inflammatory cell infiltration via downregulation of NF-kappaB-mediated cytokine production and alpha4 integrin expression. Thus, Andro may offer a pharmacological therapy to slow disease progression in patients with small aneurysms. PMID- 26483398 TI - The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation. AB - The MHC class I chain-related molecule A (MICA) is a highly polymorphic ligand for the activating natural killer (NK)-cell receptor NKG2D. A single nucleotide polymorphism causes a valine to methionine exchange at position 129. Presence of a MICA-129Met allele in patients (n = 452) undergoing hematopoietic stem cell transplantation (HSCT) increased the chance of overall survival (hazard ratio [HR] = 0.77, P = 0.0445) and reduced the risk to die due to acute graft-versus host disease (aGVHD) (odds ratio [OR] = 0.57, P = 0.0400) although homozygous carriers had an increased risk to experience this complication (OR = 1.92, P = 0.0371). Overall survival of MICA-129Val/Val genotype carriers was improved when treated with anti-thymocyte globulin (HR = 0.54, P = 0.0166). Functionally, the MICA-129Met isoform was characterized by stronger NKG2D signaling, triggering more NK-cell cytotoxicity and interferon-gamma release, and faster co-stimulation of CD8(+) T cells. The MICA-129Met variant also induced a faster and stronger down-regulation of NKG2D on NK and CD8(+) T cells than the MICA-129Val isoform. The reduced cell surface expression of NKG2D in response to engagement by MICA 129Met variants appeared to reduce the severity of aGVHD. PMID- 26483399 TI - Dopamine D3 Receptor Modulates l-DOPA-Induced Dyskinesia by Targeting D1 Receptor Mediated Striatal Signaling. AB - The dopamine D3 receptor (D3R) belongs to the dopamine D2-like receptor family and is principally located in the ventral striatum. However, previous studies reported D3R overexpression in the dorsal striatum following l-DOPA treatment in parkinsonian animals. This fact has drawn attention in the importance of D3R in l DOPA-induced dyskinesia (LID). Here, we used D3R knockout mice to assess the role of D3R in LID and rotational sensitization in the hemiparkinsonian model. Mice lacking D3R presented a reduction in dyskinesia without interfering with the antiparkinsonian l-DOPA effect and were accompanied by a reduction in the l-DOPA induced rotations. Interestingly, deleting D3R attenuated important molecular markers in the D1R-neurons such as FosB, extracellular signal-regulated kinase, and histone-3 (H3)-activation. Colocalization studies in D1R-tomato and D2R-green fluorescent protein BAC-transgenic mice indicated that l-DOPA-induced D3R overexpression principally occurs in D1R-containing neurons although it is also present in the D2R-neurons. Moreover, D3R pharmacological blockade with PG01037 reduced dyskinesia and the molecular markers expressed in D1R-neurons. In addition, this antagonist further reduced dyskinetic symptoms in D1R heterozygous mice, indicating a direct interaction between D1R and D3R. Together, our results demonstrate that D3R modulates the development of dyskinesia by targeting D1R mediated intracellular signaling and suggest that decreasing D3R activity may help to ameliorate LID. PMID- 26483400 TI - Three-Dimensional Representations of Objects in Dorsal Cortex are Dissociable from Those in Ventral Cortex. AB - An established conceptualization of visual cortical function is one in which ventral regions mediate object perception while dorsal regions support spatial information processing and visually guided action. This division has been contested by evidence showing that dorsal regions are also engaged in the representation of object shape, even when actions are not required. The critical question is whether these dorsal, object-based representations are dissociable from ventral representations, and whether they play a functional role in object recognition. We examined the neural and behavioral profile of patients with impairments in object recognition following ventral cortex damage. In a functional magnetic resonanace imaging experiment, the blood oxygen level dependent response in the ventral, but not dorsal, cortex of the patients evinced less sensitivity to object 3D structure compared with that of healthy controls. Consistently, in psychophysics experiments, the patients exhibited significant impairments in object perception, but still revealed residual sensitivity to object-based structural information. Together, these findings suggest that, although in the intact system there is considerable crosstalk between dorsal and ventral cortices, object representations in dorsal cortex can be computed independently from those in ventral cortex. While dorsal representations alone are unable to support normal object perception, they can, nevertheless, support a coarse description of object structural information. PMID- 26483401 TI - A conformational RNA zipper promotes intron ejection during non-conventional XBP1 mRNA splicing. AB - The kinase/endonuclease IRE1 is the most conserved signal transducer of the unfolded protein response (UPR), an intracellular signaling network that monitors and regulates the protein folding capacity of the endoplasmic reticulum (ER). Upon sensing protein folding perturbations in the ER, IRE1 initiates the unconventional splicing of XBP1 mRNA culminating in the production of the transcription factor XBP1s, which expands the ER's protein folding capacity. We show that an RNA-intrinsic conformational change causes the intron of XBP1 mRNA to be ejected and the exons to zipper up into an extended stem, juxtaposing the RNA ends for ligation. These conformational rearrangements are important for XBP1 mRNA splicing in vivo. The features that point to such active participation of XBP1 mRNA in the splicing reaction are highly conserved throughout metazoan evolution, supporting their importance in orchestrating XBP1 mRNA processing with efficiency and fidelity. PMID- 26483402 TI - RNA Helicase Important for Listeria monocytogenes Hemolytic Activity and Virulence Factor Expression. AB - RNA helicases have been shown to be important for the function of RNA molecules at several levels, although their putative involvement in microbial pathogenesis has remained elusive. We have previously shown that Listeria monocytogenes DExD box RNA helicases are important for bacterial growth, motility, ribosomal maturation, and rRNA processing. We assessed the importance of the RNA helicase Lmo0866 (here named CshA) for expression of virulence traits. We observed a reduction in hemolytic activity in a strain lacking CshA compared to the wild type. This phenomenon was less evident in strains lacking other RNA helicases. The reduced hemolysis was accompanied by lower expression of major listerial virulence factors in the DeltacshA strain, mainly listeriolysin O, but also to some degree the actin polymerizing factor ActA. Reduced expression of these virulence factors in the strain lacking CshA did not, however, correlate with a decreased level of the virulence regulator PrfA. When combining the DeltacshA knockout with a mutation creating a constitutively active PrfA protein (PrfA*), the effect of the DeltacshA knockout on LLO expression was negated. These data suggest a role for the RNA helicase CshA in posttranslational activation of PrfA. Surprisingly, although the expression of several virulence factors was reduced, the DeltacshA strain did not demonstrate any reduced ability to infect nonphagocytic cells compared to the wild-type strain. PMID- 26483403 TI - Surface Polysaccharide Mutants Reveal that Absence of O Antigen Reduces Biofilm Formation of Actinobacillus pleuropneumoniae. AB - Actinobacillus pleuropneumoniae is a Gram-negative bacterium belonging to the Pasteurellaceae family and the causative agent of porcine pleuropneumonia, a highly contagious lung disease causing important economic losses. Surface polysaccharides, including lipopolysaccharides (LPS) and capsular polysaccharides (CPS), are implicated in the adhesion and virulence of A. pleuropneumoniae, but their role in biofilm formation is still unclear. In this study, we investigated the requirement for these surface polysaccharides in biofilm formation by A. pleuropneumoniae serotype 1. Well-characterized mutants were used: an O-antigen LPS mutant, a truncated core LPS mutant with an intact O antigen, a capsule mutant, and a poly-N-acetylglucosamine (PGA) mutant. We compared the amount of biofilm produced by the parental strain and the isogenic mutants using static and dynamic systems. Compared to the findings for the biofilm of the parental or other strains, the biofilm of the O antigen and the PGA mutants was dramatically reduced, and it had less cell-associated PGA. Real-time PCR analyses revealed a significant reduction in the level of pgaA, cpxR, and cpxA mRNA in the biofilm cells of the O-antigen mutant compared to that in the biofilm cells of the parental strain. Specific binding between PGA and LPS was consistently detected by surface plasmon resonance, but the lack of O antigen did not abolish these interactions. In conclusion, the absence of the O antigen reduces the ability of A. pleuropneumoniae to form a biofilm, and this is associated with the reduced expression and production of PGA. PMID- 26483404 TI - Lysine11-Linked Polyubiquitination of the AnkB F-Box Effector of Legionella pneumophila. AB - The fate of the polyubiquitinated protein is determined by the lysine linkages involved in the polymerization of the ubiquitin monomers, which has seven lysine residues (K(6), K(11), K(27), K(29), K(33), K(48), and K(63)). The translocated AnkB effector of the intravacuolar pathogen Legionella pneumophila is a bona fide F-box protein, which is localized to the cytosolic side of the Legionella containing vacuole (LCV) and is essential for intravacuolar proliferation within macrophages and amoebae. The F-box domain of AnkB interacts with the host SCF1 E3 ubiquitin ligase that triggers the decoration of the LCV with K(48)-linked polyubiquitinated proteins that are targeted for proteasomal degradation. Here we report that AnkB becomes rapidly polyubiquitinated within the host cell, and this modification is independent of the F-box domain of AnkB, indicating host-mediated polyubiquitination. We show that the AnkB effector interacts specifically with the host E3 ubiquitin ligase Trim21. Mass spectrometry analyses have shown that AnkB is modified by K(11)-linked polyubiquitination, which has no effect on its stability. This work shows the first example of K(11)-linked polyubiquitination of a bacterial effector and its interaction with the host Trim21 ubiquitin ligase. PMID- 26483405 TI - Treatment with Interleukin-7 Restores Host Defense against Pneumocystis in CD4+ T Lymphocyte-Depleted Mice. AB - Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality in patients with HIV infection. CD4(+) T lymphocytes are critical for host defense against this infection, but in the absence of CD4(+) T lymphocytes, CD8(+) T lymphocytes may provide limited host defense. The cytokine interleukin-7 (IL-7) functions to enhance lymphocyte proliferation, survival, and recruitment of immune cells to sites of infection. However, there is little known about the role of IL-7 in PCP or its potential use as an immunotherapeutic agent. We hypothesized that treatment with recombinant human IL-7 (rhIL-7) would augment host defense against Pneumocystis and accelerate pathogen clearance in CD4 depleted mice. Control and CD4-depleted mice were infected with Pneumocystis, and rhIL-7 was administered via intraperitoneal injection. Our studies indicate that endogenous murine IL-7 is part of the normal host response to Pneumocystis murina and that administration of rhIL-7 markedly enhanced clearance of Pneumocystis in CD4-depleted mice. Additionally, we observed increased recruitment of CD8(+) T lymphocytes to the lungs and decreased apoptosis of pulmonary CD8(+) T lymphocytes in rhIL-7-treated animals compared to those in untreated mice. The antiapoptotic effect of rhIL-7 was associated with increased levels of Bcl-2 protein in T lymphocytes. rhIL-7 immunotherapy in CD4-depleted mice also increased the number of gamma interferon (IFN-gamma)-positive CD8(+) central memory T lymphocytes in the lungs. We conclude that rhIL-7 has a potent therapeutic effect in the treatment of murine Pneumocystis pneumonia in CD4 depleted mice. This therapeutic effect is mediated through enhanced recruitment of CD8(+) T cells and decreased apoptosis of lung T lymphocytes, with a preferential action on central memory CD8(+) T lymphocytes. PMID- 26483406 TI - Bovine Immunoinhibitory Receptors Contribute to Suppression of Mycobacterium avium subsp. paratuberculosis-Specific T-Cell Responses. AB - Johne's disease (paratuberculosis) is a chronic enteritis in cattle that is caused by intracellular infection with Mycobacterium avium subsp. paratuberculosis. This infection is characterized by the functional exhaustion of T-cell responses to M. avium subsp. paratuberculosis antigens during late subclinical and clinical stages, presumably facilitating the persistence of this bacterium and the formation of clinical lesions. However, the mechanisms underlying T-cell exhaustion in Johne's disease are poorly understood. Thus, we performed expression and functional analyses of the immunoinhibitory molecules programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3)/major histocompatibility complex class II (MHC-II) in M. avium subsp. paratuberculosis-infected cattle during the late subclinical stage. Flow cytometric analyses revealed the upregulation of PD-1 and LAG-3 in T cells in infected animals, which suffered progressive suppression of interferon gamma (IFN gamma) responses to the M. avium subsp. paratuberculosis antigen. In addition, PD L1 and MHC-II were expressed on macrophages from infected animals, consistent with PD-1 and LAG-3 pathways contributing to the suppression of IFN-gamma responses during the subclinical stages of M. avium subsp. paratuberculosis infection. Furthermore, dual blockade of PD-L1 and LAG-3 enhanced M. avium subsp. paratuberculosis-specific IFN-gamma responses in blood from infected animals, and in vitro LAG-3 blockade enhanced IFN-gamma production from M. avium subsp. paratuberculosis-specific CD4(+) and CD8(+) T cells. Taken together, the present data indicate that M. avium subsp. paratuberculosis-specific T-cell exhaustion is in part mediated by PD-1/PD-L1 and LAG-3/MHC-II interactions and that LAG-3 is a molecular target for the control of M. avium subsp. paratuberculosis-specific T cell responses. PMID- 26483407 TI - Subgingival Plaque in Periodontal Health Antagonizes at Toll-Like Receptor 4 and Inhibits E-Selectin Expression on Endothelial Cells. AB - The ability of the subgingival microbial community to induce an inappropriate inflammatory response ultimately results in the destruction of bone and gingival tissue. In this study, subgingival plaque samples from both healthy and diseased sites in the same individual were obtained from adults with chronic periodontitis and screened for their ability to either activate Toll-like receptor 2 (TLR2) or TLR4 and to antagonize TLR4-specific activation by agonist, Fusobacterium nucleatum LPS. Subgingival plaque from diseased sites strongly activated TLR4, whereas matched plaque samples obtained from healthy sites were significantly more variable, with some samples displaying strong TLR4 antagonism, while others were strong TLR4 agonists when combined with F. nucleatum LPS. Similar results were observed when TLR4 dependent E-selectin expression by endothelial cells was determined. These results are the first to demonstrate TLR4 antagonism from human plaque samples and demonstrate that healthy but not diseased sites display a wide variation in TLR4 agonist and antagonist behavior. The results have identified a novel characteristic of clinically healthy sites and warrant further study on the contribution of TLR4 antagonism in the progression of a healthy periodontal site to a diseased one. PMID- 26483408 TI - Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin Induced Inflammation. AB - Infection with enterohemorrhagic Escherichia coli (EHEC) can result in severe disease, including hemorrhagic colitis and the hemolytic uremic syndrome. Shiga toxins (Stx) are the key EHEC virulence determinant contributing to severe disease. Despite inhibiting protein synthesis, Shiga toxins paradoxically induce the expression of proinflammatory cytokines from various cell types in vitro, including intestinal epithelial cells (IECs). This effect is mediated in large part by the ribotoxic stress response (RSR). The Shiga toxin-induced RSR is known to involve the activation of the stress-activated protein kinases (SAPKs) p38 and JNK. In some cell types, Stx also can induce the classical mitogen-activated protein kinases (MAPKs) or ERK1/2, but the mechanism(s) by which this activation occurs is unknown. In this study, we investigated the mechanism by which Stx activates ERK1/2s in IECs and the contribution of ERK1/2 activation to interleukin-8 (IL-8) expression. We demonstrate that Stx1 activates ERK1/2 in a biphasic manner: the first phase occurs in response to StxB1 subunit, while the second phase requires StxA1 subunit activity. We show that the A subunit dependent ERK1/2 activation is mediated through ZAK-dependent signaling, and inhibition of ERK1/2 activation via the MEK1/2 inhibitors U0126 and PD98059 results in decreased Stx1-mediated IL-8 mRNA. Finally, we demonstrate that ERK1/2 are activated in vivo in the colon of Stx2-intoxicated infant rabbits, a model in which Stx2 induces a primarily neutrophilic inflammatory response. Together, our data support a role for ERK1/2 activation in the development of Stx-mediated intestinal inflammation. PMID- 26483409 TI - The A1 Subunit of Shiga Toxin 2 Has Higher Affinity for Ribosomes and Higher Catalytic Activity than the A1 Subunit of Shiga Toxin 1. AB - Shiga toxin (Stx)-producing Escherichia coli (STEC) infections can lead to life threatening complications, including hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS), which is the most common cause of acute renal failure in children in the United States. Stx1 and Stx2 are AB5 toxins consisting of an enzymatically active A subunit associated with a pentamer of receptor binding B subunits. Epidemiological evidence suggests that Stx2-producing E. coli strains are more frequently associated with HUS than Stx1-producing strains. Several studies suggest that the B subunit plays a role in mediating toxicity. However, the role of the A subunits in the increased potency of Stx2 has not been fully investigated. Here, using purified A1 subunits, we show that Stx2A1 has a higher affinity for yeast and mammalian ribosomes than Stx1A1. Biacore analysis indicated that Stx2A1 has faster association and dissociation with ribosomes than Stx1A1. Analysis of ribosome depurination kinetics demonstrated that Stx2A1 depurinates yeast and mammalian ribosomes and an RNA stem-loop mimic of the sarcin/ricin loop (SRL) at a higher catalytic rate and is a more efficient enzyme than Stx1A1. Stx2A1 depurinated ribosomes at a higher level in vivo and was more cytotoxic than Stx1A1 in Saccharomyces cerevisiae. Stx2A1 depurinated ribosomes and inhibited translation at a significantly higher level than Stx1A1 in human cells. These results provide the first direct evidence that the higher affinity for ribosomes in combination with higher catalytic activity toward the SRL allows Stx2A1 to depurinate ribosomes, inhibit translation, and exhibit cytotoxicity at a significantly higher level than Stx1A1. PMID- 26483411 TI - Expectations and perceptions of care among victims of sexual assault who first seek care from emergency, primary care and gynaecological doctors. AB - BACKGROUND: The role of health professionals is pivotal in providing support to victims of sexual assault. Our aim was to identify patient expectations of doctors after a sexual assault and to assess how they rated the doctors' responses. METHODS: We conducted a prospective observational study (May 2010 December 2012) involving victims of sexual assault (age >10 years) in a Department of Forensic Medicine near Paris, France. The patients included were those who had first sought care from a doctor prior to arriving at the Department of Forensic Medicine. Victims were asked by questionnaire and interviewed by the forensic physician about medical consultations before arriving at the Department, their expectations about those consultations and their feelings about the quality of support provided. Each patient's feelings were rated on a five-point scale. RESULTS: Among 1112 victims reporting sexual assault, 232 previously had a consultation, and were included in the study. Patients expected trauma care in 44% of cases, and received it in 40% (p=0.42), psychological support in 31% of cases, and received it in 21% (p=0.02), gynaecological care in 28%, and received it in 31% (p=0.52) and forensic support in 21%, and received it in 54% (p<0.001). The patients more frequently considered the provided support to be crucial when they received both forensic support and trauma care, psychological support or gynaecological care than when they only received trauma care, psychological support or gynaecological care (25% vs 3%, p=0.001). CONCLUSIONS: Physicians who are the first medical provider to see a patient after a sexual assault often fail to meet patients' expectations, particularly with regard to psychological support. Care received was perceived as best when physicians provided both forensic support and trauma care, psychological support or gynaecological care. PMID- 26483410 TI - Morphology-Independent Virulence of Candida Species during Polymicrobial Intra abdominal Infections with Staphylococcus aureus. AB - Intra-abdominal polymicrobial infections cause significant morbidity and mortality. An experimental mouse model of Candida albicans-Staphylococcus aureus intra-abdominal infection (IAI) results in 100% mortality by 48 to 72 h postinoculation, while monomicrobial infections are avirulent. Mortality is associated with robust local and systemic inflammation without a requirement for C. albicans morphogenesis. However, the contribution of virulence factors coregulated during the yeast-to-hypha transition is unknown. This also raised the question of whether other Candida species that are unable to form hyphae are as virulent as C. albicans during polymicrobial IAI. Therefore, the purpose of this study was to evaluate the ability of non-albicans Candida (NAC) species with various morphologies and C. albicans transcription factor mutants (efg1/efg1 and cph1/cph1) to induce synergistic mortality and the accompanying inflammation. Results showed that S. aureus coinoculated with C. krusei or C. tropicalis was highly lethal, similar to C. albicans, while S. aureus-C. dubliniensis, S. aureus C. parapsilosis, and S. aureus-C. glabrata coinoculations resulted in little to no mortality. Local and systemic interleukin-6 (IL-6) and prostaglandin E2 (PGE2) levels were significantly elevated during symptomatic and/or lethal coinfections, and hypothermia strongly correlated with mortality. Coinoculation with C. albicans strains deficient in the transcription factor Efg1 but not Cph1 reversed the lethal outcome. These results support previous findings and demonstrate that select Candida species, without reference to any morphological requirement, induce synergistic mortality, with IL-6 and PGE2 acting as key inflammatory factors. Mechanistically, signaling pathways controlled by Efg1 are critical for the ability of C. albicans to induce mortality from an intra-abdominal polymicrobial infection. PMID- 26483412 TI - MARRIED-cocaine score: validating a tool for detecting the risk of ED revisit in cocaine users. AB - OBJECTIVE: According to a previous study, 17% of patients who attended an emergency department (ED) following cocaine use returned to the same ED over the next year for a problem related to drug use. This previous study proposed a scale (Multicenter Assessment of the Revisit Risk In the Emergency Department (MARRIED) cocaine score) to quantify the risk of ED revisit. The aim of the present study was to validate this scale by analysing a new set of patients attending for cocaine use in nine Spanish EDs. METHODS: We performed a retrospective, multicentre, cohort study with consecutive patient inclusion, and without an intervention or control group. During 12 months (January-December 2010) we collected data from patients attending the ED after cocaine use. The MARRIED cocaine score, ranging from 0 to 400 points, was calculated for each patient. The dependent variable was the identification of further visits associated with drug consumption to the same ED. Further analysis was performed to define risk categories. RESULTS: The study included 933 patients, with a mean follow-up of 466 (SD 189) days, and 185 patients returned to the same ED for problems related to drug consumption. The cumulative probability of ED revisit was 4.2%, 8.3%, 16.8% and 21.2% at 1 month, 3 months, 12 months and 24 months, respectively. The area under the curve receiver operating characteristic for the MARRIED-cocaine scale was 0.69 (p<0.001). Four categories for ED revisit risk were defined: low risk (0-40 points, n=416), moderate risk (41-100 points, n=235), high risk (101 210 points, n=71) and very high risk (210-400 points, n=211), with HRs for ED revisit (with respect to the low-risk group) of 1.82 (95% CI 1.18 to 2.80, p=0.007), 2.65 (95% CI 1.50 to 4.66, p=0.001) and 5.06 (95% CI 3.49 to 7.35, p<0.001), respectively. CONCLUSIONS: The MARRIED-cocaine score has a moderate discriminative capacity to predict revisit among patients who attend the ED for cocaine drug-related emergencies, and allows classification of patients according to the risk of ED revisit. PMID- 26483413 TI - Phosphatidylinositol 3,4,5-Trisphosphate Phosphatase SKIP Links Endoplasmic Reticulum Stress in Skeletal Muscle to Insulin Resistance. AB - Insulin resistance is critical in the pathogenesis of type 2 diabetes. Endoplasmic reticulum (ER) stress in liver and adipose tissues plays an important role in the development of insulin resistance. Although skeletal muscle is a primary site for insulin-dependent glucose disposal, it is unclear if ER stress in those tissues contributes to insulin resistance. In this study, we show that skeletal muscle kidney-enriched inositol polyphosphate phosphatase (SKIP), a PIP3 (phosphatidylinositol-3,4,5-trisphosphate) phosphatase, links ER stress to insulin resistance in skeletal muscle. SKIP expression was increased due to ER stress and was higher in the skeletal muscle isolated from high-fat-diet-fed mice and db/db mice than in that from wild-type mice. Mechanistically, ER stress promotes activating transcription factor 6 (ATF6) and X-box binding protein 1 (XBP1)-dependent expression of SKIP. These findings underscore the specific and prominent role of SKIP in the development of insulin resistance in skeletal muscle. PMID- 26483414 TI - NFAT2 Isoforms Differentially Regulate Gene Expression, Cell Death, and Transformation through Alternative N-Terminal Domains. AB - The NFAT (nuclear factor of activated T cells) family of transcription factors is composed of four calcium-responsive proteins (NFAT1 to -4). The NFAT2 (also called NFATc1) gene encodes the isoforms NFAT2alpha and NFAT2beta that result mainly from alternative initiation exons that provide two different N-terminal transactivation domains. However, the specific roles of the NFAT2 isoforms in cell physiology remain unclear. Because previous studies have shown oncogenic potential for NFAT2, this study emphasized the role of the NFAT2 isoforms in cell transformation. Here, we show that a constitutively active form of NFAT2alpha (CA NFAT2alpha) and CA-NFAT2beta distinctly control death and transformation in NIH 3T3 cells. While CA-NFAT2alpha strongly induces cell transformation, CA-NFAT2beta leads to reduced cell proliferation and intense cell death through the upregulation of tumor necrosis factor alpha (TNF-alpha). CA-NFAT2beta also increases cell death and upregulates Fas ligand (FasL) and TNF-alpha in CD4(+) T cells. Furthermore, we demonstrate that differential roles of NFAT2 isoforms in NIH 3T3 cells depend on the N-terminal domain, where the NFAT2beta-specific N terminal acidic motif is necessary to induce cell death. Interestingly, the NFAT2alpha isoform is upregulated in Burkitt lymphomas, suggesting an isoform specific involvement of NFAT2 in cancer development. Finally, our data suggest that alternative N-terminal domains of NFAT2 could provide differential mechanisms for the control of cellular functions. PMID- 26483415 TI - Identification of Novel Death-Associated Protein Kinase 2 Interaction Partners by Proteomic Screening Coupled with Bimolecular Fluorescence Complementation. AB - Death-associated protein kinase 2 (DAPK2) is a Ca(2+)/calmodulin-dependent Ser/Thr kinase that possesses tumor-suppressive functions and regulates programmed cell death, autophagy, oxidative stress, hematopoiesis, and motility. As only few binding partners of DAPK2 have been determined, the molecular mechanisms governing these biological functions are largely unknown. We report the identification of 180 potential DAPK2 interaction partners by affinity purification-coupled mass spectrometry, 12 of which are known DAPK binding proteins. A small subset of established and potential binding proteins detected in this screen was further investigated by bimolecular fluorescence complementation (BiFC) assays, a method to visualize protein interactions in living cells. These experiments revealed that alpha-actinin-1 and 14-3-3-beta are novel DAPK2 binding partners. The interaction of DAPK2 with alpha-actinin-1 was localized at the plasma membrane, resulting in massive membrane blebbing and reduced cellular motility, whereas the interaction of DAPK2 with 14-3-3-beta was localized to the cytoplasm, with no impact on blebbing, motility, or viability. Our results therefore suggest that DAPK2 effector functions are influenced by the protein's subcellular localization and highlight the utility of combining mass spectrometry screening with bimolecular fluorescence complementation to identify and characterize novel protein-protein interactions. PMID- 26483417 TI - Are children's dental panoramic tomographs and lateral cephalometric radiographs sufficiently optimized? AB - OBJECTIVES: Children are especially vulnerable to harmful effects of ionizing radiation. Cutting down the dimensions of the X-ray beam is the most effective way to reduce the patient dose. We evaluated the appropriateness of field-size in the most frequent radiographs, dental panoramic tomographs (DPTs) and lateral cephalometric radiographs (LCRs) among 7- to 12-year-olds. MATERIALS AND METHODS: The image field-size of 241 DPTs and 118 LCRs was analysed. The image field was considered appropriate when it did not include anatomic structures beyond the area of clinical interest. The image field was compared with factors such as the age of the patient, the radiographic equipment used and the programme selected. Moreover, we assessed the use of thyroid shield in LCR. RESULTS: The field-size was too large in 70% of the DPTs horizontally and in 96% vertically. None of the DPTs were segmented. Every LCR showed appropriate limitation anteriorly, but the image field was too large in 54% posteriorly, in 86% superiorly, and in 76% inferiorly. A thyroid shield had been used in only 71% of cases. CONCLUSION: Most DPTs and LCRs had been performed sub-optimally. An abundancy of DPTs had been taken using an adult programme, and the field-size had not been sufficiently adjusted in LCRs, possibly for technical reasons. To facilitate adherence to radiological best practice the equipment used for DPTs and LCRs should facilitate the adjustment of field-size in both the vertical and horizontal planes. In addition, those involved in taking radiographs should maintain their skills through regular update courses. PMID- 26483416 TI - Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor beta-KLF5 Pathway. AB - Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17beta-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor beta (ERbeta) or Kruppel-like zinc finger transcription factor 5 (KLF5). Iotan addition, E2 suppressed KLF5-mediated transcription through ERbeta, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ERbeta-KLF5 pathway and regulated prostate tumor growth without ERbeta transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ERbeta and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation. PMID- 26483418 TI - Rosuvastatin Alters the Proteome of High Density Lipoproteins: Generation of alpha-1-antitrypsin Enriched Particles with Anti-inflammatory Properties. AB - Statins lower plasma cholesterol by as much as 50%, thus reducing future cardiovascular events. However, the physiological effects of statins are diverse and not all are related to low density lipoprotein cholesterol (LDL-C) lowering. We performed a small clinical pilot study to assess the impact of statins on lipoprotein-associated proteins in healthy individuals (n = 10) with normal LDL-C (<130 mg/dL), who were treated with rosuvastatin (20 mg/day) for 28 days. Proteomic analysis of size-exclusion chromatography isolated LDL, large high density lipoprotein (HDL-L), and small HDL (HDL-S) fractions and spectral counting was used to compare relative protein detection before and after statin therapy. Significant protein changes were found in each lipoprotein pool and included both increases and decreases in several proteins involved in lipoprotein metabolism, complement regulation and acute phase response. The most dramatic effect of the rosuvastatin treatment was an increase in alpha-1-antirypsin (A1AT) spectral counts associated with HDL-L particles. Quantitative measurement by ELISA confirmed an average 5.7-fold increase in HDL-L associated A1AT. Molecular modeling predictions indicated that the hydrophobic reactive center loop of A1AT, the functional domain responsible for its protease inhibitor activity, is likely involved in lipid binding and association with HDL was found to protect A1AT against oxidative inactivation. Cell culture experiments, using J774 macrophages, demonstrated that the association of A1AT with HDL enhances its antiprotease activity, preventing elastase induced production of tumor necrosis factor alpha. In conclusion, we show that statins can significantly alter the protein composition of both LDL and HDL and our studies reveal a novel functional relationship between A1AT and HDL. The up-regulation of A1AT on HDL enhances its anti-inflammatory functionality, which may contribute to the non-lipid lowering beneficial effects of statins. PMID- 26483424 TI - Appendiceal neuroendocrine neoplasms: diagnosis and management. AB - Gastrointestinal neuroendocrine neoplasms (GI-NENs) are increasingly being recognised, while appendiceal NENs (aNENs) currently constitute the third most common GI-NEN. Appendiceal NENs are generally considered to follow an indolent course with the majority being localised at diagnosis. Thus, the initial surgical approach is not that of a planned oncological resection. Due to the localised nature of the disease in the majority of cases, subsequent biochemical and radiological assessment are not routinely recommended. Histopathological criteria (size, mesoappendiceal invasion, Ki-67 proliferation index, neuro- and angio invasion) are mainly used to identify those patients who are also candidates for a right hemicolectomy. Goblet cell carcinoids are a distinct entity and should be treated as adenocarcinomas. Despite the absence of any substantial prospective data regarding optimal management and follow-up, recent consensus statements and guidelines have been published. The purpose of this review is to overview the published studies on the diagnosis and management of appendiceal NENs and to suggest a possible management protocol. PMID- 26483423 TI - Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer. AB - Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa. PMID- 26483425 TI - "It's Back! My Remission Is Over": Online Communication of Disease Progression Among Adolescents With Cancer. AB - Cancer in adolescence presents unique challenges to patients and families due to the dramatic physical and psychological vulnerabilities that occur during a time of identity development. Additionally, adolescents who experience progression of their cancer, or failure of first-line therapies, represent an understudied group within pediatric oncology. Illness blogs offer a unique opportunity to understand the experience of a chronic or serious illness through a naturalistic and longitudinal perspective that is inherently patient centered. The purpose of this exploratory qualitative study was to describe the experiences of adolescents with cancer who experienced disease progression through analysis of their online illness blogs. Seven illness blogs written by adolescents with cancer diagnosed between the ages of 13 and 18 years were analyzed using thematic analysis. Several key themes were described among the adolescents, including normalizing the news, facing treatment failure, and reconciling chronos-the finite concept of time. These findings provide vital descriptive evidence for the experience of disease progression as described by adolescents, as well as identifying key points of further study and intervention development for nurse researchers and nurses who care for this vulnerable patient population. PMID- 26483426 TI - Factors Related to Healthy Siblings' Psychosocial Adjustment to Children With Cancer: An Integrative Review. AB - PURPOSE: To identify factors related to the psychosocial adjustment of healthy siblings of children with cancer (HSCC). DESIGN AND METHOD: An integrative review was conducted. Controlled vocabularies relevant to siblings, pediatrics, children, neoplasms, and psychosocial adaptation were used to search Cumulative Index to Nursing & Allied Health Literature and PubMed. Articles that met inclusion criteria (eg, quantitative studies related to HSCC's psychosocial adjustment; had sample sizes of at least 30; and HSCC age between 1 and 19 years) were reviewed. Key findings of selected articles were analyzed according to sibling characteristics, social support, and contextual factors. RESULTS: Seven nonexperimental and 5 quasi-experimental studies were reviewed. HSCC's characteristics (eg, age, gender), perceived social support from family and summer camp, and perceived contextual factors (eg, role overload, family adaptability) were significant factors that correlated with HSCC's psychosocial adjustment. CONCLUSION: When caring for a child diagnosed with cancer, nurses need to include HSCC in the assessment of a family unit's adaptation to cancer distress and provide appropriate interventions to promote HSCC's psychosocial well-being. PMID- 26483427 TI - Participants' Understanding of Informed Consent in a Randomized Controlled Trial for Chronic Knee Pain. AB - This study explored participants' experiences of randomized controlled trial (RCT) participation to examine their understanding of the trial design and whether their consent was indeed informed. A nested qualitative interview study was conducted with 38 participants from a sample of 282 who participated in a complex RCT evaluating the effectiveness of laser compared with needle acupuncture for chronic knee pain. Overall participants had a good understanding of the RCT, and concepts such as randomization and placebo. Their experiences of being in the trial were largely positive, even if they did not experience any knee pain improvement. Their responses to unblinding at the end of the study were accepting. Participants had a good functional understanding of the RCT, sufficient for valid informed consent. PMID- 26483428 TI - Human Invariant Natural Killer T cells possess immune-modulating functions during Aspergillus infection. AB - Aspergillus fumigatus is the most common cause for invasive fungal infections, a disease associated with high mortality in immune-compromised patients. CD1d restricted invariant natural killer T (iNKT) cells compose a small subset of T cells known to impact the immune response toward various infectious pathogens. To investigate the role of human iNKT cells during A. fumigatus infection, we studied their activation as determined by CD69 expression and cytokine production in response to distinct fungal morphotypes in the presence of different CD1d(+) antigen presenting cells using flow cytometry and multiplex enzyme-linked immunosorbent assay (ELISA). Among CD1d(+) subpopulations, CD1d(+)CD1c(+) mDCs showed the highest potential to activate iNKT cells on a per cell basis. The presence of A. fumigatus decreased this effect of CD1d(+)CD1c(+) mDCs on iNKT cells and led to reduced secretion of TNF-alpha, G-CSF and RANTES. Production of other Th1 and Th2 cytokines was not affected by the fungus, suggesting an immune modulating function for human iNKT cells during A. fumigatus infection. PMID- 26483429 TI - Severe feline sporotrichosis associated with an increased population of CD8low cells and a decrease in CD4+ cells. AB - Sporotrichosis is a subcutaneous mycosis with worldwide distribution, especially in tropical and subtropical areas. Zoonotic transmission is described with cats being the main animal species involved. The occurrence of severe feline sporotrichosis with high fungal levels demonstrates the susceptibility of cats to this disease and the importance of studying its pathogenesis. This study describes the leukocytes profile in blood of cats with sporotrichosis by flow cytometry and its correlation with histopathology and fungal load. The cats with sporotrichosis were separated into groups L1, L2, and L3 (lesions at one, two, and three or more noncontiguous skin locations, respectively) and were classified as good, fair, or poor general conditions. The highest percentage of CD4+ cells was associated to L1 (P = .04) and to good general condition (P = .03). The percentage of CD8+ cells was greater in L2 and L3 (P = .01). CD8(low) expression occurred in 20 animals with sporotrichosis, mainly in L3 (P = .01) and was not observed in healthy controls. This expression was related to macrophage granulomas (P = .01) and predominated in cases with high fungal load. Altogether, the results indicated that control over feline sporotrichosis, with maintenance of a good general condition, fixed lesions, well-organized response and lower fungal load, is associated with increased CD4+ cells percentages. In contrast, a poor general condition, disseminated lesions and high fungal load were related to increased CD8+ cell percentages and increased expression of CD8(low). As conclusion these results point to an important role of the CD4:CD8 balance in determining the clinical outcome in feline sporotrichosis. PMID- 26483430 TI - Brain abscess due to Cladophialophora bantiana: a review of 124 cases. AB - Brain abscess caused by Cladophialophora bantiana is a rare disease associated with high mortality due to delay in diagnosis and absence of standardized therapy. We reviewed 124 culture proven C. bantiana brain abscess cases; 103 cases published in English literature during 1952 through 2014 and 21 unpublished cases from our reference center. The majority (57.3%) of the patients was from Asian countries especially from India (62/124, 50%). The diagnosis of the cases was delayed with mean duration 115 days after developing symptoms. The disease was nearly equally distributed in immunocompetent and immunosuppressed hosts but associated with significantly higher mortality (77.1%) in later group. Complete excision of brain lesion in immunocompetent host led to significantly better survival (43.7%). Though all commercially available antifungal drugs have been used in these patients, amphotericin B deoxycholate or lipid preparations were most commonly (62.83%) prescribed agent. None of the drugs used was found to be independently associated with improved outcome. In vitro antifungal susceptibility testing of 13 isolates of our center, demonstrated good activity to voriconazole, posaconazole, and itraconazole, but these triazoles were prescribed in only 29.2% patients. Increased awareness with early suspicion of the disease, and aggressive medical and surgical approach in treating these patients may improve the outcome. PMID- 26483431 TI - Population Structure of Candida albicans from Three Teaching Hospitals in Ghana. AB - Previous studies on Candida species in a clinical setting in Ghana have shown a prevalence of Candida albicans. Despite this, very little is known about the various strain types and their population genetic structure. In this study three microsatellite loci, CAI, CAIII and CAVI, were used to investigate the population genetic structure of C. albicans from clinical isolates in Ghana. In all, 240 clinically unrelated C. albicans isolates were recovered from patients reporting at three teaching hospitals. All the isolates were heterozygous for at least one of the three loci, except for one isolate, which was homozygous for all three loci. Sixty-seven unique alleles and 240 different genotypes were generated by the three polymorphic microsatellite loci, resulting in a very high discriminatory potential of approximately 0.98. There was no significant difference in allele frequencies from the small number of anatomical sites sampled, regardless of the host conditions although high genotypic diversities were observed among the isolates. There was evidence for clonal reproduction, including over-expression of observed heterozygotes across the populations. The populations deviated significantly from Hardy-Weinberg equilibrium and pair-wise genotypic linkage disequilibria comparisons across the three loci were significant, also suggesting a clonal population. The overall Wright FIS for the three loci was negative, and the overall FST value was not significantly different from zero for the three loci analyzed, indicating a clonal and homogeneous population across the three sampling locations from Ghana. PMID- 26483432 TI - Emergence of Magnusiomyces capitatus infections in Western Nepal. AB - Magnusiomyces capitatus is an emerging opportunistic yeast in the Mediterranean region. We report from Nepal one case of M. capitatus infection and six other cases of colonization/probable infection due to M. capitatus at a tertiary care center. Majority of the patients were immunocompromised, at extreme age, associated with comorbidities, and had history of close contact with livestock and poultry. The isolates were identified by phenotypic and genotypic (ITS and D1/D2 region of 26S rDNA sequence) methods. Molecular typing of the isolates was carried out by amplified fragment length polymorphism. Minimum inhibitory concentration (MIC) of the isolates for amphotericin B, caspofungin, fluconazole, itraconazole, voriconazole, posaconazole, anidulafungin, and micafungin were 2, 0.1-4, 2, 0.12-0.5, 0.12-0.5, 0.25, 1-4, and 1-4 MUg/ml, respectively. Presence of M. capitatus infection was not known in Nepal, and the study should alert the clinicians and infectious disease specialists. PMID- 26483433 TI - Posaconazole plasma concentration in pediatric patients receiving antifungal prophylaxis after allogeneic hematopoietic stem cell transplantation. AB - Posaconazole has been proven to be effective for antifungal prophylaxis in adults after hematopoietic stem cell transplantation (HSCT). Due to low gastrointestinal resorption of posaconazole suspension, bioavailability is impaired. Fatty food improves the uptake of posaconazole, but insufficient data on the pharmacokinetics of posaconazole in pediatric patients are available so far. The single-center analysis investigated 161 posaconazole serum concentrations in 27 pediatric patients after HSCT receiving 12 mg.kg BW(-1).d(-1) posaconazole suspension depending on age, gender, and intestinal graft-versus-host (iGvHD) disease, and the influence of posaconazole on cyclosporine A plasma concentrations. To improve the uptake of posaconazole, one patient cohort received higher fat nutrition with the drug administration. A comparison of the regular nutrition and higher-fat nutrition groups revealed the following values: 31 (27.4%) versus 8 (16.7%) < 500 ng/ml; 12 (10.6%) versus 7 (14.6%) 500-700 ng/ml; 8 (7.1%) versus 6 (12.5%) 700-1000 ng/ml; 51 (45.1%) versus 21 (43.8%) 1000-2000 ng/ml; and 11 (9.7%) versus 6 (12.5%) > 2000 ng/ml. The mean posaconazole concentrations in patients with regular nutrition was 1123 +/- 811 ng/ml and with higher-fat nutrition was 1191 +/- 673 ng/ml. Posaconazole levels in patients with iGvHD were significantly lower (P = 0.0003) than in patients without GvHD. The majority of samples showed a sufficient posaconazole concentration above 700 ng/ml. Posaconazole levels were slightly higher in patients with higher-fat nutrition and significantly lower in patients with iGvHD. Cyclosporine A levels were not significantly higher during posaconazole administration. PMID- 26483434 TI - Switching of colony morphology and adhesion activity of Trichosporon asahii clinical isolates. AB - Trichosporon asahii is a pathogenic yeast that causes trichosporonosis, a deep seated infection, in immunocompromised hosts. Pathogenic factors involved in this infection have not been investigated in detail, but morphological phenotype switching is thought to be important for T. asahii pathogenesis. Therefore, we analyzed adhesion, which may be a key early step in T. asahii infection, after morphological phenotype switching. T. asahii clinical isolates show several colony morphologies. In this study, colonies showing white-farinose (W), off white-smooth (O), off-white-rugose (OR), smooth (S), and yellowish-white (Y) morphologies were obtained from three isolates and compared in an adhesion assay performed in cell culture dishes. At least one type of colony morphology from each clinical isolate adhered strongly to the culture dish surface, although the colony type that displayed strong adherence varied among the strains. Thus, morphological phenotype switching altered the adhesion of T. asahii strains. PMID- 26483435 TI - Trends in antifungal susceptibility and virulence of Candida spp. from the nasolacrimal duct of horses. AB - This was a cross-sectional study to investigate the antifungal susceptibility and production of virulence factors in strains of Candida isolated from the outlet and the lumen of the nasolacrimal duct of horses in the state of Ceara, Brazil. The samples were obtained from 103 horses. Sterile cotton swabs were used to collect the material from the outlet of the nasolacrimal duct and urethral probes, for the instillation of 2 ml of saline solution, were used to collect samples from the lumen of the nasolacrimal duct. A total of 77 Candida isolates were obtained, with C. famata, C. tropicalis, C. guilliermondii, and C. parapsilosis sensu lato as the most prevalent species. One isolate (C. glabrata) was resistant to caspofungin. One isolate was resistant only to fluconazole (C. parapsilosis sensu lato), 11 were resistant only to itraconazole (7 C. tropicalis, 2 C. guilliermondii, 1 C. famata, 1 C. parapsilosis sensu lato), while eight C. tropicalis showed resistance to both azoles. Overall, 28 isolates produced phospholipases and 12 produced proteases. These results highlight the importance of investigating the antifungal susceptibility and virulence trends of Candida spp. from the microbiota of the nasolacrimal duct of horses. PMID- 26483436 TI - Yeast Transcriptome and In Vivo Hypoxia Detection Reveals Histoplasma capsulatum Response to Low Oxygen Tension. AB - Although there is growing understanding of the microenvironmental conditions fungal pathogens encounter as they colonize their host, nothing is known about Histoplasma capsulatum's response to hypoxia. Here we characterized hypoxia during murine histoplasmosis using an in vivo hypoxia detection agent, Hypoxyprobe-2 (HP-2); and analyzed H. capsulatum's transcriptional profile in response to in vitro hypoxia. Immunohistopathology and flow cytometry analyses revealed distinct regions of hypoxia during infection. Granuloma cells, enriched with macrophages and T-cells isolated from infected livers were 66-76% positive for HP-2, of which, 95% of macrophages and 55% of T-cells were hypoxic. Although inhibited, H. capsulatum was able to survive under in vitro hypoxic conditions (<1% O2), and restored growth when replaced in normoxia. Next-generation sequencing (RNA-seq) analysis after 24 hours of hypoxia demonstrated a significant increase in NIT50 (swirm domain DNA binding protein), a predicted ABC transporter (ABC), NADPH oxidoreductase (NADP/FAD), and guanine nucleotide exchange factor (RSP/GEF); and other genes with no known designated function. Computational transcription factor binding site analysis predicted human sterol regulatory element binding protein (SREBP) binding sites upstream of NIT50, ABC, NADP/FAD and RSP/GEF. Hypoxia resulted in a time-dependent increase in the H. capsulatum homolog of SREBP, here named Srb1. Srb1 peaked at 8 hours and returned to basal levels by 24 hours. Our findings demonstrate that H. capsulatum encounters and survives severe hypoxia during infection. Additionally, the hypoxic response may be regulated at the level of transcription, and these studies contribute to the understanding of hypoxic regulation and adaptation in H. capsulatum. PMID- 26483437 TI - Genetic and Phenotypic analyses of Calcineurin A subunit in Arthroderma vanbreuseghemii. AB - Calcineurin is a serine/threonine protein phosphatase that consists of catalytic (calcineurin A) and regulatory (calcineurin B) subunits. The conserved protein plays important roles in various biological processes. Drug combination of fluconazole and the calcineurin inhibitor (FK506) showed synergistic effects against dermatophytes. In the current study, we identified the calcineurin A homologous gene (TmcanA) in the dermatophyte Arthroderma vanbreuseghemii (anamorph: Trichophyton mentagrophytes). Knockdown mutants were produced from A. vanbreuseghemii, resulting in a defection in growth properties in accordance with dose of the suppressing reagent. The TmcanA gene restored the ability of calcineurin A-deficient Cryptococcus neoformans strain to grow at elevated temperatures. Repression of TmcanA at 37 degrees C resulted in severely stunted growth, suggesting that this protein plays a role in tolerance to elevated temperatures. In addition, TMCANA showed an interaction with high osmolarity glycerol (HOG) signalling pathway by governing the secretion of a secondary metabolite. Moreover, expression of the hydrophobin A gene (TmHF) decreased significantly under the TmcanA-repressive condition, suggesting that TMCANA is involved in its regulation. In conclusion, calcineurin A is a multifunctional gene that is involved in the regulation of several biological processes and therefore is worth being considered as a drug target for treatment of dermatophytoses. PMID- 26483438 TI - Towards evidence based medicine for paediatricians. PMID- 26483439 TI - Question 2: Unexpected neutropenia in a febrile, but immunocompetent, child. PMID- 26483441 TI - Exposure rate of unwrapped hydroxyapatite orbital implants in enucleation surgery. AB - OBJECTIVE: To document the long-term exposure rate of unwrapped coralline hydroxyapatite (HA) orbital implants and explore possible risk factors. DESIGN: This retrospective case series (May 2008-April 2013) reviewed the 234 patients with anophthalmia who underwent insertion of an unwrapped HA orbital implant by one of two different surgical closing techniques. RESULTS: Of the 234 cases, 151 underwent a rectus end-to-end suturing closure technique and 83 underwent a rectus orthotopic suturing closure technique. The time of follow-up ranged from 25 months to 69 months (mean 41.9 months). Implant exposure developed in 11 cases. Three in the rectus end-to-end suturing closure group (2.0%) and eight in the rectus orthotopic suturing closure group (9.6%). In the rectus end-to-end suturing technique, a crosswise fixation of vascularised rectus muscle tissue is formed across the front of the implant; in this group the incidence of implant exposure was reduced (OR=8.11, p=0.013). Prior ocular surgery was found to be a factor increasing the incidence of HA exposure (OR=2.73, p=0.032). CONCLUSIONS: The placement of an unwrapped HA orbital implant with rectus end-to-end suturing in enucleation surgery was associated with a low rate of exposure in most cases. The end-to-end suturing creates a joint-like structure over the HA sphere, protecting the Tenon's capsule and conjunctiva from its rough surface and reducing the risk of implant exposure. Prior ocular surgery may be another risk factor for HA exposure. PMID- 26483442 TI - Retinopathy of prematurity in Korean infants with birthweight greater than 1500 g. AB - OBJECTIVE: To determine the incidence and clinical features of, and risk factors for, retinopathy of prematurity (ROP) in Korean infants with birthweight (BW) >1500 g. METHODS: A total of 201 consecutive infants with BW >1500 g from January 2009 to December 2013 were included. The location and maximal stage of retinopathy observed were recorded for each infant. The associated systemic and maternal risk factors in infants with mild or absent ROP were compared with those in infants with treatment-requiring ROP. RESULTS: The total incidence of ROP was 11.94% and that of treatment-requiring ROP was 3.98%. Two patients with gestational age (GA) >32 weeks and BW >1500 g had treatment-requiring ROP. 15 eyes from eight infants with type I ROP required laser photocoagulation. The mean BWs and GAs in the treatment-requiring ROP group were significantly lower than those in the no or mild ROP group. Total duration of oxygen supplementation, surfactant usage, respiratory distress syndrome, bronchopulmonary dysplasia, antibiotic use for more than 14 days and the number of ROP-associated risk factors significantly increased the likelihood of treatment-requiring ROP (p=0.002, p=0.008, p=0.008, p=0.000, p=0.015, and p=0.004, respectively). CONCLUSION: Our study confirmed that treatment-requiring ROP does occur in infants with BW >1500 g. To avoid overlooking infants with vision-threatening ROP, an evaluation of the data from larger BW preterm infants is advisable so that screening guidelines in neonatal care units may be refined. PMID- 26483443 TI - Making every contact count for physical activity--for tomorrow's patients: the launch of the interdisciplinary, undergraduate, resources on exercise medicine and health in the U.K. PMID- 26483444 TI - eComment. Systemic inflammation and pulmonary metastasectomy: ideas for further development. PMID- 26483445 TI - eComment. Double edge closure for reducing post-thoracotomy pain: is it the best? PMID- 26483446 TI - eReply re: eComment. Double edge closure for reducing post-thoracotomy pain: is it the best? PMID- 26483447 TI - eComment. Diagnostic and therapeutical considerations in post-lobectomy chronic pulmonary aspergillosis. PMID- 26483448 TI - eComment. Not all new valve technologies are meant to be used in the same way. PMID- 26483449 TI - eReply. Long-term follow-up data are needed in new valve technologies! PMID- 26483452 TI - Topographic representations of object size and relationships with numerosity reveal generalized quantity processing in human parietal cortex. AB - Humans and many animals analyze sensory information to estimate quantities that guide behavior and decisions. These quantities include numerosity (object number) and object size. Having recently demonstrated topographic maps of numerosity, we ask whether the brain also contains maps of object size. Using ultra-high-field (7T) functional MRI and population receptive field modeling, we describe tuned responses to visual object size in bilateral human posterior parietal cortex. Tuning follows linear Gaussian functions and shows surround suppression, and tuning width narrows with increasing preferred object size. Object size-tuned responses are organized in bilateral topographic maps, with similar cortical extents responding to large and small objects. These properties of object size tuning and map organization all differ from the numerosity representation, suggesting that object size and numerosity tuning result from distinct mechanisms. However, their maps largely overlap and object size preferences correlate with numerosity preferences, suggesting associated representations of these two quantities. Object size preferences here show no discernable relation to visual position preferences found in visuospatial receptive fields. As such, object size maps (much like numerosity maps) do not reflect sensory organ structure but instead emerge within the brain. We speculate that, as in sensory processing, optimization of cognitive processing using topographic maps may be a common organizing principle in association cortex. Interactions between object size and numerosity maps may associate cognitive representations of these related features, potentially allowing consideration of both quantities together when making decisions. PMID- 26483451 TI - The human gene damage index as a gene-level approach to prioritizing exome variants. AB - The protein-coding exome of a patient with a monogenic disease contains about 20,000 variants, only one or two of which are disease causing. We found that 58% of rare variants in the protein-coding exome of the general population are located in only 2% of the genes. Prompted by this observation, we aimed to develop a gene-level approach for predicting whether a given human protein-coding gene is likely to harbor disease-causing mutations. To this end, we derived the gene damage index (GDI): a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population. We found that the GDI was correlated with selective evolutionary pressure, protein complexity, coding sequence length, and the number of paralogs. We compared GDI with the leading gene-level approaches, genic intolerance, and de novo excess, and demonstrated that GDI performed best for the detection of false positives (i.e., removing exome variants in genes irrelevant to disease), whereas genic intolerance and de novo excess performed better for the detection of true positives (i.e., assessing de novo mutations in genes likely to be disease causing). The GDI server, data, and software are freely available to noncommercial users from lab.rockefeller.edu/casanova/GDI. PMID- 26483453 TI - Dystrophin-glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling. AB - Patients deficient in dystrophin, a protein that links the cytoskeleton to the extracellular matrix via the dystrophin-glycoprotein complex (DGC), exhibit muscular dystrophy, cardiomyopathy, and impaired muscle nitric oxide (NO) production. We used live-cell NO imaging and in vitro cyclic stretch of isolated adult mouse cardiomyocytes as a model system to investigate if and how the DGC directly regulates the mechanical activation of muscle NO signaling. Acute activation of NO synthesis by mechanical stretch was impaired in dystrophin deficient mdx cardiomyocytes, accompanied by loss of stretch-induced neuronal NO synthase (nNOS) S1412 phosphorylation. Intriguingly, stretch induced the acute activation of AMP-activated protein kinase (AMPK) in normal cardiomyocytes but not in mdx cardiomyocytes, and specific inhibition of AMPK was sufficient to attenuate mechanoactivation of NO production. Therefore, we tested whether direct pharmacologic activation of AMPK could bypass defective mechanical signaling to restore nNOS activity in dystrophin-deficient cardiomyocytes. Indeed, activation of AMPK with 5-aminoimidazole-4-carboxamide riboside or salicylate increased nNOS S1412 phosphorylation and was sufficient to enhance NO production in mdx cardiomyocytes. We conclude that the DGC promotes the mechanical activation of cardiac nNOS by acting as a mechanosensor to regulate AMPK activity, and that pharmacologic AMPK activation may be a suitable therapeutic strategy for restoring nNOS activity in dystrophin-deficient hearts and muscle. PMID- 26483455 TI - El Nino-Southern Oscillation frequency cascade. AB - The El Nino-Southern Oscillation (ENSO) phenomenon, the most pronounced feature of internally generated climate variability, occurs on interannual timescales and impacts the global climate system through an interaction with the annual cycle. The tight coupling between ENSO and the annual cycle is particularly pronounced over the tropical Western Pacific. Here we show that this nonlinear interaction results in a frequency cascade in the atmospheric circulation, which is characterized by deterministic high-frequency variability on near-annual and subannual timescales. Through climate model experiments and observational analysis, it is documented that a substantial fraction of the anomalous Northwest Pacific anticyclone variability, which is the main atmospheric link between ENSO and the East Asian Monsoon system, can be explained by these interactions and is thus deterministic and potentially predictable. PMID- 26483454 TI - The future of airborne sulfur-containing particles in the absence of fossil fuel sulfur dioxide emissions. AB - Sulfuric acid (H2SO4), formed from oxidation of sulfur dioxide (SO2) emitted during fossil fuel combustion, is a major precursor of new airborne particles, which have well-documented detrimental effects on health, air quality, and climate. Another precursor is methanesulfonic acid (MSA), produced simultaneously with SO2 during the atmospheric oxidation of organosulfur compounds (OSCs), such as dimethyl sulfide. In the present work, a multidisciplinary approach is used to examine how contributions of H2SO4 and MSA to particle formation will change in a large coastal urban area as anthropogenic fossil fuel emissions of SO2 decline. The 3-dimensional University of California Irvine-California Institute of Technology airshed model is used to compare atmospheric concentrations of gas phase MSA, H2SO4, and SO2 under current emissions of fossil fuel-associated SO2 and a best-case futuristic scenario with zero fossil fuel sulfur emissions. Model additions include results from (i) quantum chemical calculations that clarify the previously uncertain gas phase mechanism of formation of MSA and (ii) a combination of published and experimental estimates of OSC emissions, such as those from marine, agricultural, and urban processes, which include pet waste and human breath. Results show that in the zero anthropogenic SO2 emissions case, particle formation potential from H2SO4 will drop by about two orders of magnitude compared with the current situation. However, particles will continue to be generated from the oxidation of natural and anthropogenic sources of OSCs, with contributions from MSA and H2SO4 of a similar order of magnitude. This could be particularly important in agricultural areas where there are significant sources of OSCs. PMID- 26483456 TI - Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. AB - Epigenetic signatures in germ cells, capable of both responding to the parental environment and shaping offspring neurodevelopment, are uniquely positioned to mediate transgenerational outcomes. However, molecular mechanisms by which these marks may communicate experience-dependent information across generations are currently unknown. In our model of chronic paternal stress, we previously identified nine microRNAs (miRs) that were increased in the sperm of stressed sires and associated with reduced hypothalamic-pituitary-adrenal (HPA) stress axis reactivity in offspring. In the current study, we rigorously examine the hypothesis that these sperm miRs function postfertilization to alter offspring stress responsivity and, using zygote microinjection of the nine specific miRs, demonstrated a remarkable recapitulation of the offspring stress dysregulation phenotype. Further, we associated long-term reprogramming of the hypothalamic transcriptome with HPA axis dysfunction, noting a marked decreased in the expression of extracellular matrix and collagen gene sets that may reflect an underlying change in blood-brain barrier permeability. We conclude by investigating the developmental impact of sperm miRs in early zygotes with single cell amplification technology, identifying the targeted degradation of stored maternal mRNA transcripts including sirtuin 1 and ubiquitin protein ligase E3a, two genes with established function in chromatin remodeling, and this potent regulatory function of miRs postfertilization likely initiates a cascade of molecular events that eventually alters stress reactivity. Overall, these findings demonstrate a clear mechanistic role for sperm miRs in the transgenerational transmission of paternal lifetime experiences. PMID- 26483457 TI - Transgenic expression of the proneural transcription factor Ascl1 in Muller glia stimulates retinal regeneration in young mice. AB - Muller glial cells are the source of retinal regeneration in fish and birds; although this process is efficient in fish, it is less so in birds and very limited in mammals. It has been proposed that factors necessary for providing neurogenic competence to Muller glia in fish and birds after retinal injury are not expressed in mammals. One such factor, the proneural transcription factor Ascl1, is necessary for retinal regeneration in fish but is not expressed after retinal damage in mice. We previously reported that forced expression of Ascl1 in vitro reprograms Muller glia to a neurogenic state. We now test whether forced expression of Ascl1 in mouse Muller glia in vivo stimulates their capacity for retinal regeneration. We find that transgenic expression of Ascl1 in adult Muller glia in undamaged retina does not overtly affect their phenotype; however, when the retina is damaged, the Ascl1-expressing glia initiate a response that resembles the early stages of retinal regeneration in zebrafish. The reaction to injury is even more pronounced in Muller glia in young mice, where the Ascl1 expressing Muller glia give rise to amacrine and bipolar cells and photoreceptors. DNaseI-seq analysis of the retina and Muller glia shows progressive reduction in accessibility of progenitor gene cis-regulatory regions consistent with the reduction in their reprogramming. These results show that at least one of the differences between mammal and fish Muller glia that bears on their difference in regenerative potential is the proneural transcription factor Ascl1. PMID- 26483458 TI - Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells. AB - Inhibition of Mek/Erk signaling by pharmacological Mek inhibitors promotes self renewal and pluripotency of mouse embryonic stem cells (ESCs). Intriguingly, Erk signaling is essential for human ESC self-renewal. Here we demonstrate that Erk signaling is critical for mouse ESC self-renewal and genomic stability. Erk depleted ESCs cannot be maintained. Lack of Erk leads to rapid telomere shortening and genomic instability, in association with misregulated expression of pluripotency genes, reduced cell proliferation, G1 cell-cycle arrest, and increased apoptosis. Erk signaling is also required for the activation of differentiation genes but not for the repression of pluripotency genes during ESC differentiation. Furthermore, we find an Erk-independent function of Mek, which may explain the diverse effects of Mek inhibition and Erk knockout on ESC self renewal. Together, in contrast to the prevailing view, Erk signaling is required for telomere maintenance, genomic stability, and self-renewal of mouse ESCs. PMID- 26483460 TI - Soothing touch of CD31 protects endothelium during cellular immune responses. PMID- 26483459 TI - Survival of human lymphoma cells requires B-cell receptor engagement by self antigens. AB - The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) relies on chronic active B-cell receptor (BCR) signaling. BCR pathway inhibitors induce remissions in a subset of ABC DLBCL patients. BCR microclusters on the surface of ABC cells resemble those generated following antigen engagement of normal B cells. We speculated that binding of lymphoma BCRs to self-antigens initiates and maintains chronic active BCR signaling in ABC DLBCL. To assess whether antigenic engagement of the BCR is required for the ongoing survival of ABC cells, we developed isogenic ABC cells that differed solely with respect to the IgH V region of their BCRs. In competitive assays with wild-type cells, substitution of a heterologous V region impaired the survival of three ABC lines. The viability of one VH4-34(+) ABC line and the ability of its BCR to bind to its own cell surface depended on V region residues that mediate the intrinsic autoreactivity of VH4-34 to self-glycoproteins. The BCR of another ABC line reacted with self-antigens in apoptotic debris, and the survival of a third ABC line was sustained by reactivity of its BCR to an idiotypic epitope in its own V region. Hence, a diverse set of self-antigens is responsible for maintaining the malignant survival of ABC DLBCL cells. IgH V regions used by the BCRs of ABC DLBCL biopsy samples varied in their ability to sustain survival of these ABC lines, suggesting a screening procedure to identify patients who might benefit from BCR pathway inhibition. PMID- 26483461 TI - Examining the effects of birth order on personality. AB - This study examined the long-standing question of whether a person's position among siblings has a lasting impact on that person's life course. Empirical research on the relation between birth order and intelligence has convincingly documented that performances on psychometric intelligence tests decline slightly from firstborns to later-borns. By contrast, the search for birth-order effects on personality has not yet resulted in conclusive findings. We used data from three large national panels from the United States (n = 5,240), Great Britain (n = 4,489), and Germany (n = 10,457) to resolve this open research question. This database allowed us to identify even very small effects of birth order on personality with sufficiently high statistical power and to investigate whether effects emerge across different samples. We furthermore used two different analytical strategies by comparing siblings with different birth-order positions (i) within the same family (within-family design) and (ii) between different families (between-family design). In our analyses, we confirmed the expected birth-order effect on intelligence. We also observed a significant decline of a 10th of a SD in self-reported intellect with increasing birth-order position, and this effect persisted after controlling for objectively measured intelligence. Most important, however, we consistently found no birth-order effects on extraversion, emotional stability, agreeableness, conscientiousness, or imagination. On the basis of the high statistical power and the consistent results across samples and analytical designs, we must conclude that birth order does not have a lasting effect on broad personality traits outside of the intellectual domain. PMID- 26483462 TI - Population genomics of Mycobacterium tuberculosis in the Inuit. AB - Nunavik, Quebec suffers from epidemic tuberculosis (TB), with an incidence 50 fold higher than the Canadian average. Molecular studies in this region have documented limited bacterial genetic diversity among Mycobacterium tuberculosis isolates, consistent with a founder strain and/or ongoing spread. We have used whole-genome sequencing on 163 M. tuberculosis isolates from 11 geographically isolated villages to provide a high-resolution portrait of bacterial genetic diversity in this setting. All isolates were lineage 4 (Euro-American), with two sublineages present (major, n = 153; minor, n = 10). Among major sublineage isolates, there was a median of 46 pairwise single-nucleotide polymorphisms (SNPs), and the most recent common ancestor (MRCA) was in the early 20th century. Pairs of isolates within a village had significantly fewer SNPs than pairs from different villages (median: 6 vs. 47, P < 0.00005), indicating that most transmission occurs within villages. There was an excess of nonsynonymous SNPs after the diversification of M. tuberculosis within Nunavik: The ratio of nonsynonymous to synonymous substitution rates (dN/dS) was 0.534 before the MRCA but 0.777 subsequently (P = 0.010). Nonsynonymous SNPs were detected across all gene categories, arguing against positive selection and toward genetic drift with relaxation of purifying selection. Supporting the latter possibility, 28 genes were partially or completely deleted since the MRCA, including genes previously reported to be essential for M. tuberculosis growth. Our findings indicate that the epidemiologic success of M. tuberculosis in this region is more likely due to an environment conducive to TB transmission than a particularly well-adapted strain. PMID- 26483463 TI - Cyclic deformation leads to defect healing and strengthening of small-volume metal crystals. AB - When microscopic and macroscopic specimens of metals are subjected to cyclic loading, the creation, interaction, and accumulation of defects lead to damage, cracking, and failure. Here we demonstrate that when aluminum single crystals of submicrometer dimensions are subjected to low-amplitude cyclic deformation at room temperature, the density of preexisting dislocation lines and loops can be dramatically reduced with virtually no change of the overall sample geometry and essentially no permanent plastic strain. This "cyclic healing" of the metal crystal leads to significant strengthening through dramatic reductions in dislocation density, in distinct contrast to conventional cyclic strain hardening mechanisms arising from increases in dislocation density and interactions among defects in microcrystalline and macrocrystalline metals and alloys. Our real time, in situ transmission electron microscopy observations of tensile tests reveal that pinned dislocation lines undergo shakedown during cyclic straining, with the extent of dislocation unpinning dependent on the amplitude, sequence, and number of strain cycles. Those unpinned mobile dislocations moving close enough to the free surface of the thin specimens as a result of such repeated straining are then further attracted to the surface by image forces that facilitate their egress from the crystal. These results point to a versatile pathway for controlled mechanical annealing and defect engineering in submicrometer-sized metal crystals, thereby obviating the need for thermal annealing or significant plastic deformation that could cause change in shape and/or dimensions of the specimen. PMID- 26483464 TI - Synaptic circuits and their variations within different columns in the visual system of Drosophila. AB - We reconstructed the synaptic circuits of seven columns in the second neuropil or medulla behind the fly's compound eye. These neurons embody some of the most stereotyped circuits in one of the most miniaturized of animal brains. The reconstructions allow us, for the first time to our knowledge, to study variations between circuits in the medulla's neighboring columns. This variation in the number of synapses and the types of their synaptic partners has previously been little addressed because methods that visualize multiple circuits have not resolved detailed connections, and existing connectomic studies, which can see such connections, have not so far examined multiple reconstructions of the same circuit. Here, we address the omission by comparing the circuits common to all seven columns to assess variation in their connection strengths and the resultant rates of several different and distinct types of connection error. Error rates reveal that, overall, <1% of contacts are not part of a consensus circuit, and we classify those contacts that supplement (E+) or are missing from it (E-). Autapses, in which the same cell is both presynaptic and postsynaptic at the same synapse, are occasionally seen; two cells in particular, Dm9 and Mi1, form >= 20 fold more autapses than do other neurons. These results delimit the accuracy of developmental events that establish and normally maintain synaptic circuits with such precision, and thereby address the operation of such circuits. They also establish a precedent for error rates that will be required in the new science of connectomics. PMID- 26483465 TI - Pressure-tuned quantum criticality in the antiferromagnetic Kondo semimetal CeNi2 deltaAs2. AB - The easily tuned balance among competing interactions in Kondo-lattice metals allows access to a zero-temperature, continuous transition between magnetically ordered and disordered phases, a quantum-critical point (QCP). Indeed, these highly correlated electron materials are prototypes for discovering and exploring quantum-critical states. Theoretical models proposed to account for the strange thermodynamic and electrical transport properties that emerge around the QCP of a Kondo lattice assume the presence of an indefinitely large number of itinerant charge carriers. Here, we report a systematic transport and thermodynamic investigation of the Kondo-lattice system CeNi2-deltaAs2 (delta ~ 0.28) as its antiferromagnetic order is tuned by pressure and magnetic field to zero temperature boundaries. These experiments show that the very small but finite carrier density of ~0.032 E-/formular unit in CeNi2-deltaAs2 leads to unexpected transport signatures of quantum criticality and the delayed development of a fully coherent Kondo-lattice state with decreasing temperature. The small carrier density and associated semimetallicity of this Kondo-lattice material favor an unconventional, local-moment type of quantum criticality and raises the specter of the Nozieres exhaustion idea that an insufficient number of conduction electron spins to separately screen local moments requires collective Kondo screening. PMID- 26483467 TI - Solar energy development impacts on land cover change and protected areas. AB - Decisions determining the use of land for energy are of exigent concern as land scarcity, the need for ecosystem services, and demands for energy generation have concomitantly increased globally. Utility-scale solar energy (USSE) [i.e., >= 1 megawatt (MW)] development requires large quantities of space and land; however, studies quantifying the effect of USSE on land cover change and protected areas are limited. We assessed siting impacts of >160 USSE installations by technology type [photovoltaic (PV) vs. concentrating solar power (CSP)], area (in square kilometers), and capacity (in MW) within the global solar hot spot of the state of California (United States). Additionally, we used the Carnegie Energy and Environmental Compatibility model, a multiple criteria model, to quantify each installation according to environmental and technical compatibility. Last, we evaluated installations according to their proximity to protected areas, including inventoried roadless areas, endangered and threatened species habitat, and federally protected areas. We found the plurality of USSE (6,995 MW) in California is sited in shrublands and scrublands, comprising 375 km(2) of land cover change. Twenty-eight percent of USSE installations are located in croplands and pastures, comprising 155 km(2) of change. Less than 15% of USSE installations are sited in "Compatible" areas. The majority of "Incompatible" USSE power plants are sited far from existing transmission infrastructure, and all USSE installations average at most 7 and 5 km from protected areas, for PV and CSP, respectively. Where energy, food, and conservation goals intersect, environmental compatibility can be achieved when resource opportunities, constraints, and trade offs are integrated into siting decisions. PMID- 26483468 TI - Structure of an RNA polymerase II preinitiation complex. AB - The structure of a 33-protein, 1.5-MDa RNA polymerase II preinitiation complex (PIC) was determined by cryo-EM and image processing at a resolution of 6-11 A. Atomic structures of over 50% of the mass were fitted into the electron density map in a manner consistent with protein-protein cross-links previously identified by mass spectrometry. The resulting model of the PIC confirmed the main conclusions from previous cryo-EM at lower resolution, including the association of promoter DNA only with general transcription factors and not with the polymerase. Electron density due to DNA was identifiable by the grooves of the double helix and exhibited sharp bends at points downstream of the TATA box, with an important consequence: The DNA at the downstream end coincides with the DNA in a transcribing polymerase. The structure of the PIC is therefore conducive to promoter melting, start-site scanning, and the initiation of transcription. PMID- 26483466 TI - Molecular signatures of plastic phenotypes in two eusocial insect species with simple societies. AB - Phenotypic plasticity is important in adaptation and shapes the evolution of organisms. However, we understand little about what aspects of the genome are important in facilitating plasticity. Eusocial insect societies produce plastic phenotypes from the same genome, as reproductives (queens) and nonreproductives (workers). The greatest plasticity is found in the simple eusocial insect societies in which individuals retain the ability to switch between reproductive and nonreproductive phenotypes as adults. We lack comprehensive data on the molecular basis of plastic phenotypes. Here, we sequenced genomes, microRNAs (miRNAs), and multiple transcriptomes and methylomes from individual brains in a wasp (Polistes canadensis) and an ant (Dinoponera quadriceps) that live in simple eusocial societies. In both species, we found few differences between phenotypes at the transcriptional level, with little functional specialization, and no evidence that phenotype-specific gene expression is driven by DNA methylation or miRNAs. Instead, phenotypic differentiation was defined more subtly by nonrandom transcriptional network organization, with roles in these networks for both conserved and taxon-restricted genes. The general lack of highly methylated regions or methylome patterning in both species may be an important mechanism for achieving plasticity among phenotypes during adulthood. These findings define previously unidentified hypotheses on the genomic processes that facilitate plasticity and suggest that the molecular hallmarks of social behavior are likely to differ with the level of social complexity. PMID- 26483469 TI - Metalloregulator CueR biases RNA polymerase's kinetic sampling of dead-end or open complex to repress or activate transcription. AB - Metalloregulators respond to metal ions to regulate transcription of metal homeostasis genes. MerR-family metalloregulators act on sigma(70)-dependent suboptimal promoters and operate via a unique DNA distortion mechanism in which both the apo and holo forms of the regulators bind tightly to their operator sequence, distorting DNA structure and leading to transcription repression or activation, respectively. It remains unclear how these metalloregulator-DNA interactions are coupled dynamically to RNA polymerase (RNAP) interactions with DNA for transcription regulation. Using single-molecule FRET, we study how the copper efflux regulator (CueR)--a Cu(+)-responsive MerR-family metalloregulator- modulates RNAP interactions with CueR's cognate suboptimal promoter PcopA, and how RNAP affects CueR-PcopA interactions. We find that RNAP can form two noninterconverting complexes at PcopA in the absence of nucleotides: a dead-end complex and an open complex, constituting a branched interaction pathway that is distinct from the linear pathway prevalent for transcription initiation at optimal promoters. Capitalizing on this branched pathway, CueR operates via a "biased sampling" instead of "dynamic equilibrium shifting" mechanism in regulating transcription initiation; it modulates RNAP's binding-unbinding kinetics, without allowing interconversions between the dead-end and open complexes. Instead, the apo-repressor form reinforces the dominance of the dead end complex to repress transcription, and the holo-activator form shifts the interactions toward the open complex to activate transcription. RNAP, in turn, locks CueR binding at PcopA into its specific binding mode, likely helping amplify the differences between apo- and holo-CueR in imposing DNA structural changes. Therefore, RNAP and CueR work synergistically in regulating transcription. PMID- 26483470 TI - Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties. AB - Phosphorylation is a major mechanism regulating the activity of ion channels that remains poorly understood with respect to T-type calcium channels (Cav3). These channels are low voltage-activated calcium channels that play a key role in cellular excitability and various physiological functions. Their dysfunction has been linked to several neurological disorders, including absence epilepsy and neuropathic pain. Recent studies have revealed that T-type channels are modulated by a variety of serine/threonine protein kinase pathways, which indicates the need for a systematic analysis of T-type channel phosphorylation. Here, we immunopurified Cav3.2 channels from rat brain, and we used high-resolution MS to construct the first, to our knowledge, in vivo phosphorylation map of a voltage gated calcium channel in a mammalian brain. We identified as many as 34 phosphorylation sites, and we show that the vast majority of these sites are also phosphorylated on the human Cav3.2 expressed in HEK293T cells. In patch-clamp studies, treatment of the channel with alkaline phosphatase as well as analysis of dephosphomimetic mutants revealed that phosphorylation regulates important functional properties of Cav3.2 channels, including voltage-dependent activation and inactivation and kinetics. We also identified that the phosphorylation of a locus situated in the loop I-II S442/S445/T446 is crucial for this regulation. Our data show that Cav3.2 channels are highly phosphorylated in the mammalian brain and establish phosphorylation as an important mechanism involved in the dynamic regulation of Cav3.2 channel gating properties. PMID- 26483471 TI - Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters. AB - Bacteriophages (phages) defend mucosal surfaces against bacterial infections. However, their complex interactions with their bacterial hosts and with the mucus covered epithelium remain mostly unexplored. Our previous work demonstrated that T4 phage with Hoc proteins exposed on their capsid adhered to mucin glycoproteins and protected mucus-producing tissue culture cells in vitro. On this basis, we proposed our bacteriophage adherence to mucus (BAM) model of immunity. Here, to test this model, we developed a microfluidic device (chip) that emulates a mucosal surface experiencing constant fluid flow and mucin secretion dynamics. Using mucus-producing human cells and Escherichia coli in the chip, we observed similar accumulation and persistence of mucus-adherent T4 phage and nonadherent T4?hoc phage in the mucus. Nevertheless, T4 phage reduced bacterial colonization of the epithelium >4,000-fold compared with T4?hoc phage. This suggests that phage adherence to mucus increases encounters with bacterial hosts by some other mechanism. Phages are traditionally thought to be completely dependent on normal diffusion, driven by random Brownian motion, for host contact. We demonstrated that T4 phage particles displayed subdiffusive motion in mucus, whereas T4?hoc particles displayed normal diffusion. Experiments and modeling indicate that subdiffusive motion increases phage-host encounters when bacterial concentration is low. By concentrating phages in an optimal mucus zone, subdiffusion increases their host encounters and antimicrobial action. Our revised BAM model proposes that the fundamental mechanism of mucosal immunity is subdiffusion resulting from adherence to mucus. These findings suggest intriguing possibilities for engineering phages to manipulate and personalize the mucosal microbiome. PMID- 26483472 TI - Genetic and socioeconomic study of mate choice in Latinos reveals novel assortment patterns. AB - Nonrandom mating in human populations has important implications for genetics and medicine as well as for economics and sociology. In this study, we performed an integrative analysis of a large cohort of Mexican and Puerto Rican couples using detailed socioeconomic attributes and genotypes. We found that in ethnically homogeneous Latino communities, partners are significantly more similar in their genomic ancestries than expected by chance. Consistent with this, we also found that partners are more closely related--equivalent to between third and fourth cousins in Mexicans and Puerto Ricans--than matched random male-female pairs. Our analysis showed that this genomic ancestry similarity cannot be explained by the standard socioeconomic measurables alone. Strikingly, the assortment of genomic ancestry in couples was consistently stronger than even the assortment of education. We found enriched correlation of partners' genotypes at genes known to be involved in facial development. We replicated our results across multiple geographic locations. We discuss the implications of assortment and assortment specific loci on disease dynamics and disease mapping methods in Latinos. PMID- 26483473 TI - Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission. AB - Elucidation of maternal immune correlates of protection against congenital cytomegalovirus (CMV) is necessary to inform future vaccine design. Here, we present a novel rhesus macaque model of placental rhesus CMV (rhCMV) transmission and use it to dissect determinants of protection against congenital transmission following primary maternal rhCMV infection. In this model, asymptomatic intrauterine infection was observed following i.v. rhCMV inoculation during the early second trimester in two of three rhCMV-seronegative pregnant females. In contrast, fetal loss or infant CMV-associated sequelae occurred in four rhCMV seronegative pregnant macaques that were CD4(+) T-cell depleted at the time of inoculation. Animals that received the CD4(+) T-cell-depleting antibody also exhibited higher plasma and amniotic fluid viral loads, dampened virus-specific CD8(+) T-cell responses, and delayed production of autologous neutralizing antibodies compared with immunocompetent monkeys. Thus, maternal CD4(+) T-cell immunity during primary rhCMV infection is important for controlling maternal viremia and inducing protective immune responses that prevent severe CMV associated fetal disease. PMID- 26483474 TI - VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish. AB - Physiological functions of vascular endothelial growth factor (VEGF)-B remain an enigma, and deletion of the Vegfb gene in mice lacks an overt phenotype. Here we show that knockdown of Vegfba, but not Vegfbb, in zebrafish embryos by specific morpholinos produced a lethal phenotype owing to vascular and neuronal defects in the brain. Vegfba morpholinos also markedly prevented development of hyaloid vasculatures in the retina, but had little effects on peripheral vascular development. Consistent with phenotypic defects, Vegfba, but not Vegfaa, mRNA was primarily expressed in the brain of developing zebrafish embryos. Interestingly, in situ detection of Neuropilin1 (Nrp1) mRNA showed an overlapping expression pattern with Vegfba, and knockdown of Nrp1 produced a nearly identically lethal phenotype as Vegfba knockdown. Furthermore, zebrafish VEGF-Ba protein directly bound to NRP1. Importantly, gain-of-function by exogenous delivery of mRNAs coding for NRP1-binding ligands VEGF-B or VEGF-A to the zebrafish embryos rescued the lethal phenotype by normalizing vascular development. Similarly, exposure of zebrafish embryos to hypoxia also rescued the Vegfba morpholino-induced vascular defects in the brain by increasing VEGF-A expression. Independent evidence of VEGF-A gain-of-function was provided by using a functionally defective Vhl-mutant zebrafish strain, which again rescued the Vegfba morpholino-induced vascular defects. These findings show that VEGF-B is spatiotemporally required for vascular development in zebrafish embryos and that NRP1, but not VEGFR1, mediates the essential signaling. PMID- 26483475 TI - Deciduous forest responses to temperature, precipitation, and drought imply complex climate change impacts. AB - Changes in spring and autumn phenology of temperate plants in recent decades have become iconic bio-indicators of rapid climate change. These changes have substantial ecological and economic impacts. However, autumn phenology remains surprisingly little studied. Although the effects of unfavorable environmental conditions (e.g., frost, heat, wetness, and drought) on autumn phenology have been observed for over 60 y, how these factors interact to influence autumn phenological events remain poorly understood. Using remotely sensed phenology data from 2001 to 2012, this study identified and quantified significant effects of a suite of environmental factors on the timing of fall dormancy of deciduous forest communities in New England, United States. Cold, frost, and wet conditions, and high heat-stress tended to induce earlier dormancy of deciduous forests, whereas moderate heat- and drought-stress delayed dormancy. Deciduous forests in two eco-regions showed contrasting, nonlinear responses to variation in these explanatory factors. Based on future climate projection over two periods (2041-2050 and 2090-2099), later dormancy dates were predicted in northern areas. However, in coastal areas earlier dormancy dates were predicted. Our models suggest that besides warming in climate change, changes in frost and moisture conditions as well as extreme weather events (e.g., drought- and heat-stress, and flooding), should also be considered in future predictions of autumn phenology in temperate deciduous forests. This study improves our understanding of how multiple environmental variables interact to affect autumn phenology in temperate deciduous forest ecosystems, and points the way to building more mechanistic and predictive models. PMID- 26483476 TI - The evolution of parental cooperation in birds. AB - Parental care is one of the most variable social behaviors and it is an excellent model system to understand cooperation between unrelated individuals. Three major hypotheses have been proposed to explain the extent of parental cooperation: sexual selection, social environment, and environmental harshness. Using the most comprehensive dataset on parental care that includes 659 bird species from 113 families covering both uniparental and biparental taxa, we show that the degree of parental cooperation is associated with both sexual selection and social environment. Consistent with recent theoretical models parental cooperation decreases with the intensity of sexual selection and with skewed adult sex ratios. These effects are additive and robust to the influence of life-history variables. However, parental cooperation is unrelated to environmental factors (measured at the scale of whole species ranges) as indicated by a lack of consistent relationship with ambient temperature, rainfall or their fluctuations within and between years. These results highlight the significance of social effects for parental cooperation and suggest that several parental strategies may coexist in a given set of ambient environment. PMID- 26483477 TI - Emergence of system roles in normative neurodevelopment. AB - Adult human cognition is supported by systems of brain regions, or modules, that are functionally coherent at rest and collectively activated by distinct task requirements. However, an understanding of how the formation of these modules supports evolving cognitive capabilities has not been delineated. Here, we quantify the formation of network modules in a sample of 780 youth (aged 8-22 y) who were studied as part of the Philadelphia Neurodevelopmental Cohort. We demonstrate that the brain's functional network organization changes in youth through a process of modular evolution that is governed by the specific cognitive roles of each system, as defined by the balance of within- vs. between-module connectivity. Moreover, individual variability in these roles is correlated with cognitive performance. Collectively, these results suggest that dynamic maturation of network modules in youth may be a critical driver for the development of cognition. PMID- 26483479 TI - High-speed spelling with a noninvasive brain-computer interface. AB - The past 20 years have witnessed unprecedented progress in brain-computer interfaces (BCIs). However, low communication rates remain key obstacles to BCI based communication in humans. This study presents an electroencephalogram-based BCI speller that can achieve information transfer rates (ITRs) up to 5.32 bits per second, the highest ITRs reported in BCI spellers using either noninvasive or invasive methods. Based on extremely high consistency of frequency and phase observed between visual flickering signals and the elicited single-trial steady state visual evoked potentials, this study developed a synchronous modulation and demodulation paradigm to implement the speller. Specifically, this study proposed a new joint frequency-phase modulation method to tag 40 characters with 0.5-s long flickering signals and developed a user-specific target identification algorithm using individual calibration data. The speller achieved high ITRs in online spelling tasks. This study demonstrates that BCIs can provide a truly naturalistic high-speed communication channel using noninvasively recorded brain activities. PMID- 26483478 TI - Genome sequence of the Asian Tiger mosquito, Aedes albopictus, reveals insights into its biology, genetics, and evolution. AB - The Asian tiger mosquito, Aedes albopictus, is a highly successful invasive species that transmits a number of human viral diseases, including dengue and Chikungunya fevers. This species has a large genome with significant population based size variation. The complete genome sequence was determined for the Foshan strain, an established laboratory colony derived from wild mosquitoes from southeastern China, a region within the historical range of the origin of the species. The genome comprises 1,967 Mb, the largest mosquito genome sequenced to date, and its size results principally from an abundance of repetitive DNA classes. In addition, expansions of the numbers of members in gene families involved in insecticide-resistance mechanisms, diapause, sex determination, immunity, and olfaction also contribute to the larger size. Portions of integrated flavivirus-like genomes support a shared evolutionary history of association of these viruses with their vector. The large genome repertory may contribute to the adaptability and success of Ae. albopictus as an invasive species. PMID- 26483480 TI - Metabolic plasticity of central carbon metabolism protects mycobacteria. PMID- 26483481 TI - Potentially biogenic carbon preserved in a 4.1 billion-year-old zircon. AB - Evidence of life on Earth is manifestly preserved in the rock record. However, the microfossil record only extends to ~ 3.5 billion years (Ga), the chemofossil record arguably to ~ 3.8 Ga, and the rock record to 4.0 Ga. Detrital zircons from Jack Hills, Western Australia range in age up to nearly 4.4 Ga. From a population of over 10,000 Jack Hills zircons, we identified one >3.8-Ga zircon that contains primary graphite inclusions. Here, we report carbon isotopic measurements on these inclusions in a concordant, 4.10 +/- 0.01-Ga zircon. We interpret these inclusions as primary due to their enclosure in a crack-free host as shown by transmission X-ray microscopy and their crystal habit. Their delta(13)CPDB of -24 +/- 50/00 is consistent with a biogenic origin and may be evidence that a terrestrial biosphere had emerged by 4.1 Ga, or ~ 300 My earlier than has been previously proposed. PMID- 26483482 TI - Preventing fibril formation of a protein by selective mutation. AB - The origins of formation of an intermediate state involved in amyloid formation and ways to prevent it are illustrated with the example of the Formin binding protein 28 (FBP28) WW domain, which folds with biphasic kinetics. Molecular dynamics of protein folding trajectories are used to examine local and global motions and the time dependence of formation of contacts between C(alpha)s and C(beta)s of selected pairs of residues. Focus is placed on the WT FBP28 WW domain and its six mutants (L26D, L26E, L26W, E27Y, T29D, and T29Y), which have structures that are determined by high-resolution NMR spectroscopy. The origins of formation of an intermediate state are elucidated, viz. as formation of hairpin 1 by a hydrophobic collapse mechanism causing significant delay of formation of both hairpins, especially hairpin 2, which facilitates the emergence of an intermediate state. It seems that three-state folding is a major folding scenario for all six mutants and WT. Additionally, two-state and downhill folding scenarios were identified in ~ 15% of the folding trajectories for L26D and L26W, in which both hairpins are formed by the Matheson-Scheraga mechanism much faster than in three-state folding. These results indicate that formation of hairpins connecting two antiparallel beta-strands determines overall folding. The correlations between the local and global motions identified for all folding trajectories lead to the identification of the residues making the main contributions in the formation of the intermediate state. The presented findings may provide an understanding of protein folding intermediates in general and lead to a procedure for their prevention. PMID- 26483483 TI - Theory for rates, equilibrium constants, and Bronsted slopes in F1-ATPase single molecule imaging experiments. AB - A theoretical model of elastically coupled reactions is proposed for single molecule imaging and rotor manipulation experiments on F1-ATPase. Stalling experiments are considered in which rates of individual ligand binding, ligand release, and chemical reaction steps have an exponential dependence on rotor angle. These data are treated in terms of the effect of thermodynamic driving forces on reaction rates, and lead to equations relating rate constants and free energies to the stalling angle. These relations, in turn, are modeled using a formalism originally developed to treat electron and other transfer reactions. During stalling the free energy profile of the enzymatic steps is altered by a work term due to elastic structural twisting. Using biochemical and single molecule data, the dependence of the rate constant and equilibrium constant on the stall angle, as well as the Bornsted slope are predicted and compared with experiment. Reasonable agreement is found with stalling experiments for ATP and GTP binding. The model can be applied to other torque-generating steps of reversible ligand binding, such as ADP and Pi release, when sufficient data become available. PMID- 26483484 TI - Vertebrate community on an ice-age Caribbean island. AB - We report 95 vertebrate taxa (13 fishes, 11 reptiles, 63 birds, 8 mammals) from late Pleistocene bone deposits in Sawmill Sink, Abaco, The Bahamas. The >5,000 fossils were recovered by scuba divers on ledges at depths of 27-35 m below sea level. Of the 95 species, 39 (41%) no longer occur on Abaco (4 reptiles, 31 birds, 4 mammals). We estimate that 17 of the 39 losses (all of them birds) are linked to changes during the Pleistocene-Holocene Transition (PHT) (~ 15-9 ka) in climate (becoming more warm and moist), habitat (expansion of broadleaf forest at the expense of pine woodland), sea level (rising from -80 m to nearly modern levels), and island area (receding from ~ 17,000 km(2) to 1,214 km(2)). The remaining 22 losses likely are related to the presence of humans on Abaco for the past 1,000 y. Thus, the late Holocene arrival of people probably depleted more populations than the dramatic physical and biological changes associated with the PHT. PMID- 26483486 TI - Repairing hearts with AKT. PMID- 26483485 TI - Diverse oligomeric states of CEACAM IgV domains. AB - Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) comprise a large family of cell surface adhesion molecules that bind to themselves and other family members to carry out numerous cellular functions, including proliferation, signaling, differentiation, tumor suppression, and survival. They also play diverse and significant roles in immunity and infection. The formation of CEACAM oligomers is caused predominantly by interactions between their N-terminal IgV domains. Although X-ray crystal structures of CEACAM IgV domain homodimers have been described, how CEACAMs form heterodimers or remain monomers is poorly understood. To address this key aspect of CEACAM function, we determined the crystal structures of IgV domains that form a homodimeric CEACAM6 complex, monomeric CEACAM8, and a heterodimeric CEACAM6-CEACAM8 complex. To confirm and quantify these interactions in solution, we used analytical ultracentrifugation to measure the dimerization constants of CEACAM homodimers and isothermal titration calorimetry to determine the thermodynamic parameters and binding affinities of CEACAM heterodimers. We found the CEACAM6-CEACAM8 heterodimeric state to be substantially favored energetically relative to the CEACAM6 homodimer. Our data provide a molecular basis for the adoption of the diverse oligomeric states known to exist for CEACAMs and suggest ways in which CEACAM6 and CEACAM8 regulate the biological functions of one another, as well as of additional CEACAMs with which they interact, both in cis and in trans. PMID- 26483487 TI - Genetic basis of transcriptome diversity in Drosophila melanogaster. AB - Understanding how DNA sequence variation is translated into variation for complex phenotypes has remained elusive but is essential for predicting adaptive evolution, for selecting agriculturally important animals and crops, and for personalized medicine. Gene expression may provide a link between variation in DNA sequence and organismal phenotypes, and its abundance can be measured efficiently and accurately. Here we quantified genome-wide variation in gene expression in the sequenced inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP), increasing the annotated Drosophila transcriptome by 11%, including thousands of novel transcribed regions (NTRs). We found that 42% of the Drosophila transcriptome is genetically variable in males and females, including the NTRs, and is organized into modules of genetically correlated transcripts. We found that NTRs often were negatively correlated with the expression of protein coding genes, which we exploited to annotate NTRs functionally. We identified regulatory variants for the mean and variance of gene expression, which have largely independent genetic control. Expression quantitative trait loci (eQTLs) for the mean, but not for the variance, of gene expression were concentrated near genes. Notably, the variance eQTLs often interacted epistatically with local variants in these genes to regulate gene expression. This comprehensive characterization of population-scale diversity of transcriptomes and its genetic basis in the DGRP is critically important for a systems understanding of quantitative trait variation. PMID- 26483488 TI - Antipredator defenses predict diversification rates. AB - The "escape-and-radiate" hypothesis predicts that antipredator defenses facilitate adaptive radiations by enabling escape from constraints of predation, diversified habitat use, and subsequently speciation. Animals have evolved diverse strategies to reduce the direct costs of predation, including cryptic coloration and behavior, chemical defenses, mimicry, and advertisement of unprofitability (conspicuous warning coloration). Whereas the survival consequences of these alternative defenses for individuals are well-studied, little attention has been given to the macroevolutionary consequences of alternative forms of defense. Here we show, using amphibians as the first, to our knowledge, large-scale empirical test in animals, that there are important macroevolutionary consequences of alternative defenses. However, the escape-and radiate hypothesis does not adequately describe them, due to its exclusive focus on speciation. We examined how rates of speciation and extinction vary across defensive traits throughout amphibians. Lineages that use chemical defenses show higher rates of speciation as predicted by escape-and-radiate but also show higher rates of extinction compared with those without chemical defense. The effect of chemical defense is a net reduction in diversification compared with lineages without chemical defense. In contrast, acquisition of conspicuous coloration (often used as warning signals or in mimicry) is associated with heightened speciation rates but unchanged extinction rates. We conclude that predictions based on the escape-and-radiate hypothesis must incorporate the effect of traits on both speciation and extinction, which is rarely considered in such studies. Our results also suggest that knowledge of defensive traits could have a bearing on the predictability of extinction, perhaps especially important in globally threatened taxa such as amphibians. PMID- 26483489 TI - Comprehensive analysis reveals how single nucleotides contribute to noncoding RNA function in bacterial quorum sensing. AB - Five homologous noncoding small RNAs (sRNAs), called the Qrr1-5 sRNAs, function in the Vibrio harveyi quorum-sensing cascade to drive its operation. Qrr1-5 use four different regulatory mechanisms to control the expression of ~ 20 mRNA targets. Little is known about the roles individual nucleotides play in mRNA target selection, in determining regulatory mechanism, or in defining Qrr potency and dynamics of target regulation. To identify the nucleotides vital for Qrr function, we developed a method we call RSort-Seq that combines saturating mutagenesis, fluorescence-activated cell sorting, high-throughput sequencing, and mutual information theory to explore the role that every nucleotide in Qrr4 plays in regulation of two mRNA targets, luxR and luxO. Companion biochemical assays allowed us to assign specific regulatory functions/underlying molecular mechanisms to each important base. This strategy yielded a regional map of nucleotides in Qrr4 vital for stability, Hfq interaction, stem-loop formation, and base pairing to both luxR and luxO, to luxR only, and to luxO only. In terms of nucleotides critical for sRNA function, the RSort-Seq analysis provided strikingly different results from those predicted by commonly used regulatory RNA folding algorithms. This approach is applicable to any RNA-RNA interaction, including sRNAs in other bacteria and regulatory RNAs in higher organisms. PMID- 26483490 TI - Nanopurification of silicon from 84% to 99.999% purity with a simple and scalable process. AB - Silicon, with its great abundance and mature infrastructure, is a foundational material for a range of applications, such as electronics, sensors, solar cells, batteries, and thermoelectrics. These applications rely on the purification of Si to different levels. Recently, it has been shown that nanosized silicon can offer additional advantages, such as enhanced mechanical properties, significant absorption enhancement, and reduced thermal conductivity. However, current processes to produce and purify Si are complex, expensive, and energy-intensive. Here, we show a nanopurification process, which involves only simple and scalable ball milling and acid etching, to increase Si purity drastically [up to 99.999% (wt %)] directly from low-grade and low-cost ferrosilicon [84% (wt %) Si; ~$1/kg]. It is found that the impurity-rich regions are mechanically weak as breaking points during ball milling and thus, exposed on the surface, and they can be conveniently and effectively removed by chemical etching. We discovered that the purity goes up with the size of Si particles going down, resulting in high purity at the sub-100-nm scale. The produced Si nanoparticles with high purity and small size exhibit high performance as Li ion battery anodes, with high reversible capacity (1,755 mAh g(-1)) and long cycle life (73% capacity retention over 500 cycles). This nanopurification process provides a complimentary route to produce Si, with finely controlled size and purity, in a diverse set of applications. PMID- 26483491 TI - Genetic structure in village dogs reveals a Central Asian domestication origin. AB - Dogs were the first domesticated species, originating at least 15,000 y ago from Eurasian gray wolves. Dogs today consist primarily of two specialized groups--a diverse set of nearly 400 pure breeds and a far more populous group of free ranging animals adapted to a human commensal lifestyle (village dogs). Village dogs are more genetically diverse and geographically widespread than purebred dogs making them vital for unraveling dog population history. Using a semicustom 185,805-marker genotyping array, we conducted a large-scale survey of autosomal, mitochondrial, and Y chromosome diversity in 4,676 purebred dogs from 161 breeds and 549 village dogs from 38 countries. Geographic structure shows both isolation and gene flow have shaped genetic diversity in village dog populations. Some populations (notably those in the Neotropics and the South Pacific) are almost completely derived from European stock, whereas others are clearly admixed between indigenous and European dogs. Importantly, many populations--including those of Vietnam, India, and Egypt-show minimal evidence of European admixture. These populations exhibit a clear gradient of short--range linkage disequilibrium consistent with a Central Asian domestication origin. PMID- 26483492 TI - Coevolutionary patterning of teeth and taste buds. AB - Teeth and taste buds are iteratively patterned structures that line the oro pharynx of vertebrates. Biologists do not fully understand how teeth and taste buds develop from undifferentiated epithelium or how variation in organ density is regulated. These organs are typically studied independently because of their separate anatomical location in mammals: teeth on the jaw margin and taste buds on the tongue. However, in many aquatic animals like bony fishes, teeth and taste buds are colocalized one next to the other. Using genetic mapping in cichlid fishes, we identified shared loci controlling a positive correlation between tooth and taste bud densities. Genome intervals contained candidate genes expressed in tooth and taste bud fields. sfrp5 and bmper, notable for roles in Wingless (Wnt) and bone morphogenetic protein (BMP) signaling, were differentially expressed across cichlid species with divergent tooth and taste bud density, and were expressed in the development of both organs in mice. Synexpression analysis and chemical manipulation of Wnt, BMP, and Hedgehog (Hh) pathways suggest that a common cichlid oral lamina is competent to form teeth or taste buds. Wnt signaling couples tooth and taste bud density and BMP and Hh mediate distinct organ identity. Synthesizing data from fish and mouse, we suggest that the Wnt-BMP-Hh regulatory hierarchy that configures teeth and taste buds on mammalian jaws and tongues may be an evolutionary remnant inherited from ancestors wherein these organs were copatterned from common epithelium. PMID- 26483493 TI - CG gene body DNA methylation changes and evolution of duplicated genes in cassava. AB - DNA methylation is important for the regulation of gene expression and the silencing of transposons in plants. Here we present genome-wide methylation patterns at single-base pair resolution for cassava (Manihot esculenta, cultivar TME 7), a crop with a substantial impact in the agriculture of subtropical and tropical regions. On average, DNA methylation levels were higher in all three DNA sequence contexts (CG, CHG, and CHH, where H equals A, T, or C) than those of the most well-studied model plant Arabidopsis thaliana. As in other plants, DNA methylation was found both on transposons and in the transcribed regions (bodies) of many genes. Consistent with these patterns, at least one cassava gene copy of all of the known components of Arabidopsis DNA methylation pathways was identified. Methylation of LTR transposons (GYPSY and COPIA) was found to be unusually high compared with other types of transposons, suggesting that the control of the activity of these two types of transposons may be especially important. Analysis of duplicated gene pairs resulting from whole-genome duplication showed that gene body DNA methylation and gene expression levels have coevolved over short evolutionary time scales, reinforcing the positive relationship between gene body methylation and high levels of gene expression. Duplicated genes with the most divergent gene body methylation and expression patterns were found to have distinct biological functions and may have been under natural or human selection for cassava traits. PMID- 26483495 TI - Correction for Kowalewski et al., HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL). PMID- 26483494 TI - The mitochondrial monothiol glutaredoxin S15 is essential for iron-sulfur protein maturation in Arabidopsis thaliana. AB - The iron-sulfur cluster (ISC) is an ancient and essential cofactor of many proteins involved in electron transfer and metabolic reactions. In Arabidopsis, three pathways exist for the maturation of iron-sulfur proteins in the cytosol, plastids, and mitochondria. We functionally characterized the role of mitochondrial glutaredoxin S15 (GRXS15) in biogenesis of ISC containing aconitase through a combination of genetic, physiological, and biochemical approaches. Two Arabidopsis T-DNA insertion mutants were identified as null mutants with early embryonic lethal phenotypes that could be rescued by GRXS15. Furthermore, we showed that recombinant GRXS15 is able to coordinate and transfer an ISC and that this coordination depends on reduced glutathione (GSH). We found the Arabidopsis GRXS15 able to complement growth defects based on disturbed ISC protein assembly of a yeast Deltagrx5 mutant. Modeling of GRXS15 onto the crystal structures of related nonplant proteins highlighted amino acid residues that after mutation diminished GSH and subsequently ISC coordination, as well as the ability to rescue the yeast mutant. When used for plant complementation, one of these mutant variants, GRXS15K83/A, led to severe developmental delay and a pronounced decrease in aconitase activity by approximately 65%. These results indicate that mitochondrial GRXS15 is an essential protein in Arabidopsis, required for full activity of iron-sulfur proteins. PMID- 26483496 TI - Correction for Lu et al., Label-free DNA imaging in vivo with stimulated Raman scattering microscopy. PMID- 26483498 TI - Correction for Lin et al., Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6. PMID- 26483497 TI - Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus. AB - The fate and numbers of hematopoietic stem cells (HSC) and their progeny that seed the thymus constitute a fundamental question with important clinical implications. HSC transplantation is often complicated by limited T-cell reconstitution, especially when HSC from umbilical cord blood are used. Attempts to improve immune reconstitution have until now been unsuccessful, underscoring the need for better insight into thymic reconstitution. Here we made use of the NOD-SCID-IL-2Rgamma(-/-) xenograft model and lentiviral cellular barcoding of human HSCs to study T-cell development in the thymus at a clonal level. Barcoded HSCs showed robust (>80% human chimerism) and reproducible myeloid and lymphoid engraftment, with T cells arising 12 wk after transplantation. A very limited number of HSC clones (<10) repopulated the xenografted thymus, with further restriction of the number of clones during subsequent development. Nevertheless, T-cell receptor rearrangements were polyclonal and showed a diverse repertoire, demonstrating that a multitude of T-lymphocyte clones can develop from a single HSC clone. Our data imply that intrathymic clonal fitness is important during T cell development. As a consequence, immune incompetence after HSC transplantation is not related to the transplantation of limited numbers of HSC but to intrathymic events. PMID- 26483499 TI - Latent hydrocarbons from cyanobacteria. PMID- 26483501 TI - Correction for Lee et al., RNA design rules from a massive open laboratory. PMID- 26483500 TI - Digoxin derivatives with selectivity for the alpha2beta3 isoform of Na,K-ATPase potently reduce intraocular pressure. AB - The ciliary epithelium in the eye consists of pigmented epithelial cells that express the alpha1beta1 isoform of Na,K-ATPase and nonpigmented epithelial cells that express mainly the alpha2beta3 isoform. In principle, a Na,K-ATPase inhibitor with selectivity for alpha2beta3 that penetrates the cornea could effectively reduce intraocular pressure, with minimal systemic or local toxicity. We have recently synthesized perhydro-1,4-oxazepine derivatives of digoxin by NaIO4 oxidation of the third digitoxose and reductive amination with various R NH2 substituents and identified derivatives with significant selectivity for human alpha2beta1 over alpha1beta1 (up to 7.5-fold). When applied topically, the most alpha2-selective derivatives effectively prevented or reversed pharmacologically raised intraocular pressure in rabbits. A recent structure of Na,K-ATPase, with bound digoxin, shows the third digitoxose approaching one residue in the beta1 subunit, Gln84, suggesting a role for beta in digoxin binding. Gln84 in beta1 is replaced by Val88 in beta3. Assuming that alkyl substituents might interact with beta3Val88, we synthesized perhydro-1,4 oxazepine derivatives of digoxin with diverse alkyl substituents. The methylcyclopropyl and cyclobutyl derivatives are strongly selective for alpha2beta3 over alpha1beta1 (22-33-fold respectively), as determined either with purified human isoform proteins or intact bovine nonpigmented epithelium cells. When applied topically on rabbit eyes, these derivatives potently reduce both pharmacologically raised and basal intraocular pressure. The cyclobutyl derivative is more efficient than Latanoprost, the most widely used glaucoma drug. Thus, the conclusion is that alpha2beta3-selective digoxin derivatives effectively penetrate the cornea and inhibit the Na,K-ATPase, hence reducing aqueous humor production. The new digoxin derivatives may have potential for glaucoma drug therapy. PMID- 26483502 TI - A distinct pathway for tetrahymanol synthesis in bacteria. AB - Tetrahymanol is a polycyclic triterpenoid lipid first discovered in the ciliate Tetrahymena pyriformis whose potential diagenetic product, gammacerane, is often used as a biomarker for water column stratification in ancient ecosystems. Bacteria are also a potential source of tetrahymanol, but neither the distribution of this lipid in extant bacteria nor the significance of bacterial tetrahymanol synthesis for interpreting gammacerane biosignatures is known. Here we couple comparative genomics with genetic and lipid analyses to link a protein of unknown function to tetrahymanol synthesis in bacteria. This tetrahymanol synthase (Ths) is found in a variety of bacterial genomes, including aerobic methanotrophs, nitrite-oxidizers, and sulfate-reducers, and in a subset of aquatic and terrestrial metagenomes. Thus, the potential to produce tetrahymanol is more widespread in the bacterial domain than previously thought. However, Ths is not encoded in any eukaryotic genomes, nor is it homologous to eukaryotic squalene-tetrahymanol cyclase, which catalyzes the cyclization of squalene directly to tetrahymanol. Rather, heterologous expression studies suggest that bacteria couple the cyclization of squalene to a hopene molecule by squalene hopene cyclase with a subsequent Ths-dependent ring expansion to form tetrahymanol. Thus, bacteria and eukaryotes have evolved distinct biochemical mechanisms for producing tetrahymanol. PMID- 26483504 TI - Correction to Supporting Information for Jiang et al., Gene-expression analysis of hair cell regeneration in the zebrafish lateral line. PMID- 26483503 TI - Targeted binding of nucleocapsid protein transforms the folding landscape of HIV 1 TAR RNA. AB - Retroviral nucleocapsid (NC) proteins are nucleic acid chaperones that play a key role in the viral life cycle. During reverse transcription, HIV-1 NC facilitates the rearrangement of nucleic acid secondary structure, allowing the transactivation response (TAR) RNA hairpin to be transiently destabilized and annealed to a cDNA hairpin. It is not clear how NC specifically destabilizes TAR RNA but does not strongly destabilize the resulting annealed RNA-DNA hybrid structure, which must be formed for reverse transcription to continue. By combining single-molecule optical tweezers measurements with a quantitative mfold based model, we characterize the equilibrium TAR stability and unfolding barrier for TAR RNA. Experiments show that adding NC lowers the transition state barrier height while also dramatically shifting the barrier location. Incorporating TAR destabilization by NC into the mfold-based model reveals that a subset of preferential protein binding sites is responsible for the observed changes in the unfolding landscape, including the unusual shift in the transition state. We measure the destabilization induced at these NC binding sites and find that NC preferentially targets TAR RNA by binding to specific sequence contexts that are not present on the final annealed RNA-DNA hybrid structure. Thus, specific binding alters the entire RNA unfolding landscape, resulting in the dramatic destabilization of this specific structure that is required for reverse transcription. PMID- 26483505 TI - Correction for Lee et al., Development of a histone deacetylase 6 inhibitor and its biological effects. PMID- 26483506 TI - Correction to Supporting Information for Carvalho et al., Birth of a new gene on the Y chromosome of Drosophila melanogaster. PMID- 26483507 TI - Taking time to consider the causes and consequences of large wildfires. PMID- 26483508 TI - Reply to Kirchhoff: Homogenous and mutually exclusive conservation typologies are neither possible nor desirable. PMID- 26483509 TI - Inquiry into congruencies and trade-offs among conservation objectives requires a consistent typology of homogeneous types. PMID- 26483510 TI - Reply to Wootton and Pfister: The search for general context should include synthesis with laboratory model systems. PMID- 26483511 TI - Processes affecting extinction risk in the laboratory and in nature. PMID- 26483513 TI - Clinical, virological and phylogenetic characterization of a multiresistant HIV-1 strain outbreak in naive patients in southern Spain. AB - BACKGROUND: We describe the characteristics of an HIV-1 strain with six viral reverse transcriptase mutations (D67N, T69N/D, V118I, V179D, T215S and K219Q), which we have called the Malaga strain. This strain was detected in treatment naive patients from southern Spain. METHODS: The study was undertaken at the Virgen de la Victoria Hospital, Malaga, a reference centre for the study of HIV-1 genotype resistance in Andalusia (the 'Costa del Sol'), Spain. Genotypic resistance testing was done in an automated sequencer. Phylogenetic analysis was performed using a 630 bp region of the reverse transcriptase with the mutations mentioned. RESULTS: Between 2007 and 2014, we detected the Malaga strain in 30 treatment-naive patients. All were MSM, seen at five hospitals on the Costa del Sol. In all cases, the HIV-1 was subtype B with viral tropism R5. Phylogenetic analysis based on the reverse transcriptase sequence showed consistent grouping (with a bootstrap value of the common node of 100%) of the isolates that shared the mutation pattern mentioned. This strain has not been detected elsewhere or in previously treated patients. All of the patients treated with first-line combination ART responded. CONCLUSIONS: We report a cluster of an HIV-1 strain with multiple resistance mutations that was transmitted over a period of >8 years, affecting 30 naive patients from the same geographical area. The strain was susceptible to first-line combination ART. PMID- 26483514 TI - Potential of Staphylococcus aureus isolates carrying different PBP2a alleles to develop resistance to ceftaroline. AB - OBJECTIVES: Infections caused by MRSA continue to cause significant morbidity worldwide. Ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) is a cephalosporin that possesses activity against MRSA due to its having high affinity for PBP2a while maintaining activity against the other essential PBPs. PBP2a sequence variations, including some outside of the transpeptidase binding pocket, impact ceftaroline susceptibility. This study evaluated the potential of ceftaroline to select for resistant Staphylococcus aureus clones in isolates containing a variety of PBP2a alleles and with a range of ceftaroline MIC values from different MLST lineages. METHODS: Direct resistance selection experiments were performed by plating 20 S. aureus isolates (18 MRSA and 2 MSSA) on agar plates containing increasing concentrations of ceftaroline. Colonies that emerged were tested by standard broth microdilution for changes in ceftaroline susceptibility and genetically characterized. RESULTS: The frequency of spontaneous resistance to ceftaroline was low for all isolates and, although resistant variants were not obtained on plates containing >=4-fold the MIC of ceftaroline, six MRSA isolates had a small number of colonies emerge on plates containing 2-fold the MIC of ceftaroline and had a 2- to 8-fold elevation of the ceftaroline MIC, while also impacting the MIC of methicillin compared with the parental isolate. Additional PBP2a mutations located in the ceftaroline-binding pocket, Y446N or A601S, were observed in several of the resistant isolates. CONCLUSIONS: These studies demonstrate that there is a low risk of generating ceftaroline-resistant MRSA isolates, which appears independent of any pre existing variation in the PBP2a protein sequence or initial ceftaroline MIC. PMID- 26483515 TI - Relevance of tcrYAZB operon acquisition for Enterococcus survival at high copper concentrations under anaerobic conditions. PMID- 26483516 TI - Telaprevir-based therapy in patients coinfected with chronic hepatitis C virus infection and HIV: INSIGHT study. AB - OBJECTIVES: INSIGHT (ClinicalTrials.gov NCT01513941) evaluated the efficacy, safety and pharmacokinetics of telaprevir-based therapy and specific antiretroviral agents in hepatitis C virus genotype 1 (HCV-1)/HIV-1-coinfected patients. PATIENTS AND METHODS: Open-label, Phase IIIb, multicentre study of telaprevir with pegylated-IFN (Peg-IFN) alpha2a and ribavirin in treatment-naive or -experienced HCV-1/HIV-1-coinfected patients on stable HIV HAART comprising efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir, etravirine or rilpivirine with two nucleos(t)ide analogues. Patients received 750 mg telaprevir (1125 mg, if on efavirenz) every 8 h plus 180 MUg/week Peg-IFNalpha2a and 800 mg/day ribavirin for 12 weeks, followed by Peg-IFNalpha2a and ribavirin alone for 12 weeks (HCV treatment naive and relapsers without cirrhosis, with extended rapid virological response) or 36 weeks (all others). RESULTS: Overall, 162 patients (median age of 46 years, 78% male, 92% Caucasian and mean CD4 count of 687 cells/mm(3)) were treated; 13% had cirrhosis. One-hundred-and-thirty-two patients (81%) completed telaprevir; 14 (9%) discontinued due to an adverse event (AE). Sustained virological response (SVR) 12 rates (<25 IU/mL HCV RNA 12 weeks after the last planned treatment dose) in treatment-naive patients, relapsers and non-responders were 64% (41 of 64), 62% (18 of 29) and 49% (34 of 69), respectively. SVR12 rates ranged from 51% (33 of 65) (patients receiving efavirenz) to 77% (13 of 17) (patients receiving raltegravir). Most frequently reported AEs during telaprevir treatment were pruritus (43%) and rash (34%) special search categories. Anaemia special search category occurred in 15% of patients; 6% of patients reported a serious AE. CONCLUSIONS: In treatment-naive/ experienced HCV-1/HIV-1 patients there were significantly higher SVR rates with telaprevir-based therapy compared with pre-specified historical controls, and safety comparable to that in HCV-monoinfected patients. PMID- 26483517 TI - Lipopolysaccharide enhances apoptosis of corpus luteum in isolated perfused bovine ovaries in vitro. AB - Lipopolysaccharide (LPS), the endotoxin of Gram-negative bacteria, has detrimental effects on the structure and function of bovine corpus luteum (CL) in vivo. The objective was to investigate whether these effects were mediated directly by LPS or via LPS-induced release of PGF2alpha. Bovine ovaries with a mid-cycle CL were collected immediately after slaughter and isolated perfused for 240 min. After 60 min of equilibration, LPS (0.5 MUg/ml) was added to the medium of five ovaries, whereas an additional six ovaries were not treated with LPS (control). After 210 min of perfusion, all ovaries were treated with 500 iu of hCG. In the effluent perfusate, concentrations of progesterone (P4) and PGF2alpha were measured every 10 and 30 min, respectively. Punch biopsies of the CL were collected every 60 min and used for RT-qPCR to evaluate mRNA expression of receptors for LPS (TLR2, -4) and LH (LHCGR); the cytokine TNFA; steroidogenic (STAR, HSD3B), angiogenic (VEGFA121, FGF2), and vasoactive (EDN1) factors; and factors of prostaglandin synthesis (PGES, PGFS, PTGFR) and apoptosis (CASP3, -8, 9). Treatment with LPS abolished the hCG-induced increase in P4 (P<=0.05); however, there was a tendency (P=0.10) for increased release of PGF2alpha at 70 min after LPS challenge. Furthermore, mRNA abundance of TLR2, TNFA, CASP3, CASP8, PGES, PGFS, and VEGFA121 increased (P<=0.05) after LPS treatment, whereas all other factors remained unchanged (P>0.05). In conclusion, reduced P4 responsiveness to hCG in LPS-treated ovaries in vitro was not due to reduced steroidogenesis, but was attributed to enhanced apoptosis. However, an impact of luteal PGF2alpha could not be excluded. PMID- 26483518 TI - Water and Small-Molecule Permeation of Dormant Bacillus subtilis Spores. AB - We use a suspended microchannel resonator to characterize the water and small molecule permeability of Bacillus subtilis spores based on spores' buoyant mass in different solutions. Consistent with previous results, we found that the spore coat is not a significant barrier to small molecules, and the extent to which small molecules may enter the spore is size dependent. We have developed a method to directly observe the exchange kinetics of intraspore water with deuterium oxide, and we applied this method to wild-type spores and a panel of congenic mutants with deficiencies in the assembly or structure of the coat. Compared to wild-type spores, which exchange in approximately 1 s, several coat mutant spores were found to have relatively high water permeability with exchange times below the ~200-ms temporal resolution of our assay. In addition, we found that the water permeability of the spore correlates with the ability of spores to germinate with dodecylamine and with the ability of TbCl3 to inhibit germination with l-valine. These results suggest that the structure of the coat may be necessary for maintaining low water permeability. IMPORTANCE: Spores of Bacillus species cause food spoilage and disease and are extremely resistant to standard decontamination methods. This hardiness is partly due to spores' extremely low permeability to chemicals, including water. We present a method to directly monitor the uptake of molecules into B. subtilis spores by weighing spores in fluid. The results demonstrate the exchange of core water with subsecond resolution and show a correlation between water permeability and the rate at which small molecules can initiate or inhibit germination in coat-damaged spores. The ability to directly measure the uptake of molecules in the context of spores with known structural or genetic deficiencies is expected to provide insight into the determinants of spores' extreme resistance. PMID- 26483519 TI - Protein Analysis of Sapienic Acid-Treated Porphyromonas gingivalis Suggests Differential Regulation of Multiple Metabolic Pathways. AB - Lipids endogenous to skin and mucosal surfaces exhibit potent antimicrobial activity against Porphyromonas gingivalis, an important colonizer of the oral cavity implicated in periodontitis. Our previous work demonstrated the antimicrobial activity of the fatty acid sapienic acid (C(16:1Delta6)) against P. gingivalis and found that sapienic acid treatment alters both protein and lipid composition from those in controls. In this study, we further examined whole-cell protein differences between sapienic acid-treated bacteria and untreated controls, and we utilized open-source functional association and annotation programs to explore potential mechanisms for the antimicrobial activity of sapienic acid. Our analyses indicated that sapienic acid treatment induces a unique stress response in P. gingivalis resulting in differential expression of proteins involved in a variety of metabolic pathways. This network of differentially regulated proteins was enriched in protein-protein interactions (P = 2.98 * 10(-8)), including six KEGG pathways (P value ranges, 2.30 * 10(-5) to 0.05) and four Gene Ontology (GO) molecular functions (P value ranges, 0.02 to 0.04), with multiple suggestive enriched relationships in KEGG pathways and GO molecular functions. Upregulated metabolic pathways suggest increases in energy production, lipid metabolism, iron acquisition and processing, and respiration. Combined with a suggested preferential metabolism of serine, which is necessary for fatty acid biosynthesis, these data support our previous findings that the site of sapienic acid antimicrobial activity is likely at the bacterial membrane. IMPORTANCE: P. gingivalis is an important opportunistic pathogen implicated in periodontitis. Affecting nearly 50% of the population, periodontitis is treatable, but the resulting damage is irreversible and eventually progresses to tooth loss. There is a great need for natural products that can be used to treat and/or prevent the overgrowth of periodontal pathogens and increase oral health. Sapienic acid is endogenous to the oral cavity and is a potent antimicrobial agent, suggesting a potential therapeutic or prophylactic use for this fatty acid. This study examines the effects of sapienic acid treatment on P. gingivalis and highlights the membrane as the likely site of antimicrobial activity. PMID- 26483520 TI - Identification of the PhoB Regulon and Role of PhoU in the Phosphate Starvation Response of Caulobacter crescentus. AB - An ability to sense and respond to changes in extracellular phosphate is critical for the survival of most bacteria. For Caulobacter crescentus, which typically lives in phosphate-limited environments, this process is especially crucial. Like many bacteria, Caulobacter responds to phosphate limitation through a conserved two-component signaling pathway called PhoR-PhoB, but the direct regulon of PhoB in this organism is unknown. Here we used chromatin immunoprecipitation-DNA sequencing (ChIP-Seq) to map the global binding patterns of the phosphate responsive transcriptional regulator PhoB under phosphate-limited and -replete conditions. Combined with genome-wide expression profiling, our work demonstrates that PhoB is induced to regulate nearly 50 genes under phosphate-starved conditions. The PhoB regulon is comprised primarily of genes known or predicted to help Caulobacter scavenge for and import inorganic phosphate, including 15 different membrane transporters. We also investigated the regulatory role of PhoU, a widely conserved protein proposed to coordinate phosphate import with expression of the PhoB regulon by directly modulating the histidine kinase PhoR. However, our studies show that it likely does not play such a role in Caulobacter, as PhoU depletion has no significant effect on PhoB-dependent gene expression. Instead, cells lacking PhoU exhibit striking accumulation of large polyphosphate granules, suggesting that PhoU participates in controlling intracellular phosphate metabolism. IMPORTANCE: The transcription factor PhoB is widely conserved throughout the bacterial kingdom, where it helps organisms respond to phosphate limitation by driving the expression of a battery of genes. Most of what is known about PhoB and its target genes is derived from studies of Escherichia coli. Our work documents the PhoB regulon in Caulobacter crescentus, and comparison to the regulon in E. coli reveals significant differences, highlighting the evolutionary plasticity of transcriptional responses driven by highly conserved transcription factors. We also demonstrated that the conserved protein PhoU, which is implicated in bacterial persistence, does not regulate PhoB activity, as previously suggested. Instead, our results favor a model in which PhoU affects intracellular phosphate accumulation, possibly through the high-affinity phosphate transporter. PMID- 26483521 TI - FleQ DNA Binding Consensus Sequence Revealed by Studies of FleQ-Dependent Regulation of Biofilm Gene Expression in Pseudomonas aeruginosa. AB - The transcription factor FleQ from Pseudomonas aeruginosa derepresses expression of genes involved in biofilm formation when intracellular levels of the second messenger cyclic diguanosine monophosphate (c-di-GMP) are high. FleQ also activates transcription of flagellar genes, and the expression of these genes is highest at low intracellular c-di-GMP. FleQ thus plays a central role in mediating the transition between planktonic and biofilm lifestyles of P. aeruginosa. Previous work showed that FleQ controls expression of the pel operon for Pel exopolysaccharide biosynthesis by converting from a repressor to an activator upon binding c-di-GMP. To explore the activity of FleQ further, we carried out DNase I footprinting at three additional biofilm gene promoters, those of psl, cdrAB, and PA2440. The expression of cdrAB, encoding a cell surface adhesin, was sufficiently responsive to FleQ to allow us to carry out in vivo promoter assays. The results showed that, similarly to our observations with the pel operon, FleQ switches from a repressor to an activator of cdrAB gene expression in response to c-di-GMP. From the footprinting data, we identified a FleQ DNA binding consensus sequence. A search for this conserved sequence in bacterial genome sequences led to the identification of FleQ binding sites in the promoters of the siaABCD operon, important for cell aggregation, and the bdlA gene, important for biofilm dispersal, in P. aeruginosa. We also identified FleQ binding sites upstream of lapA-like adhesin genes in other Pseudomonas species. IMPORTANCE: The transcription factor FleQ is widely distributed in Pseudomonas species. In all species examined, it is a master regulator of flagellar gene expression. It also regulates diverse genes involved in biofilm formation in P. aeruginosa when intracellular levels of the second messenger c-di-GMP are high. Unlike flagellar genes, biofilm-associated genes are not always easy to recognize in genome sequences. Here, we identified a consensus DNA binding sequence for FleQ. This allowed us to survey Pseudomonas strains and find new genes that are likely regulated by FleQ and possibly involved in biofilm formation. PMID- 26483522 TI - Global and Targeted Lipid Analysis of Gemmata obscuriglobus Reveals the Presence of Lipopolysaccharide, a Signature of the Classical Gram-Negative Outer Membrane. AB - Planctomycete bacteria possess many unusual cellular properties, contributing to a cell plan long considered to be unique among the bacteria. However, data from recent studies are more consistent with a modified Gram-negative cell plan. A key feature of the Gram-negative plan is the presence of an outer membrane (OM), for which lipopolysaccharide (LPS) is a signature molecule. Despite genomic evidence for an OM in planctomycetes, no biochemical verification has been reported. We attempted to detect and characterize LPS in the planctomycete Gemmata obscuriglobus. We obtained direct evidence for LPS and lipid A using electrophoresis and differential staining. Gas chromatography-mass spectrometry (GC-MS) compositional analysis of LPS extracts identified eight different 3 hydroxy fatty acids (3-HOFAs), 2-keto 3-deoxy-d-manno-octulosonic acid (Kdo), glucosamine, and hexose and heptose sugars, a chemical profile unique to Gram negative LPS. Combined with molecular/structural information collected from matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS analysis of putative intact lipid A, these data led us to propose a heterogeneous hexa-acylated lipid A structure (multiple-lipid A species). We also confirmed previous reports of G. obscuriglobus whole-cell fatty acid (FA) and sterol compositions and detected a novel polyunsaturated FA (PUFA). Our confirmation of LPS, and by implication an OM, in G. obscuriglobus raises the possibility that other planctomycetes possess an OM. The pursuit of this question, together with studies of the structural connections between planctomycete LPS and peptidoglycans, will shed more light on what appears to be a planctomycete variation on the Gram-negative cell plan. IMPORTANCE: Bacterial species are classified as Gram positive or negative based on their cell envelope structure. For 25 years, the envelope of planctomycete bacteria has been considered a unique exception, as it lacks peptidoglycan and an outer membrane (OM). However, the very recent detection of peptidoglycan in planctomycete species has provided evidence for a more conventional cell wall and raised questions about other elements of the cell envelope. Here, we report direct evidence of lipopolysaccharide in the planctomycete G. obscuriglobus, suggesting the presence of an OM and supporting the proposal that the planctomycete cell envelope is an extension of the canonical Gram-negative plan. This interpretation features a convoluted cytoplasmic membrane and expanded periplasmic space, the functions of which provide an intriguing avenue for future investigation. PMID- 26483523 TI - Tobramycin-Treated Pseudomonas aeruginosa PA14 Enhances Streptococcus constellatus 7155 Biofilm Formation in a Cystic Fibrosis Model System. AB - Cystic fibrosis (CF) is a human genetic disorder which results in a lung environment that is highly conducive to chronic microbial infection. Over the past decade, deep-sequencing studies have demonstrated that the CF lung can harbor a highly diverse polymicrobial community. We expanded our existing in vitro model of Pseudomonas aeruginosa biofilm formation on CF-derived airway cells to include this broader set of CF airway colonizers to investigate their contributions to CF lung disease, particularly as they relate to the antibiotic response of the population. Using this system, we identified an interspecies interaction between P. aeruginosa, a bacterium associated with declining lung function and worsening disease, and Streptococcus constellatus, a bacterium correlated with the onset of pulmonary exacerbations in CF patients. The growth rate and cytotoxicity of S. constellatus 7155 and P. aeruginosa PA14 were unchanged when grown together as mixed biofilms in the absence of antibiotics. However, the addition of tobramycin, the frontline maintenance therapy antibiotic for individuals with CF, to a mixed biofilm of S. constellatus 7155 and P. aeruginosa PA14 resulted in enhanced S. constellatus biofilm formation. Through a candidate genetic approach, we showed that P. aeruginosa rhamnolipids were reduced upon tobramycin exposure, allowing for S. constellatus 7155 biofilm enhancement, and monorhamnolipids were sufficient to reduce S. constellatus 7155 biofilm viability in the absence of tobramycin. While the findings presented here are specific to a biofilm of S. constellatus 7155 and P. aeruginosa PA14, they highlight the potential of polymicrobial interactions to impact antibiotic tolerance in unanticipated ways. IMPORTANCE: Deep-sequencing studies have demonstrated that the CF lung can harbor a diverse polymicrobial community. By recapitulating the polymicrobial communities observed in the CF lung and identifying mechanisms of interspecies interactions, we have the potential to select the best therapy for a given bacterial community and reveal potential opportunities for novel therapeutic interventions. Using an in vitro model of bacterial infection on CF airway cells, we tested how a particular polymicrobial community grows, damages human cells, and responds to antibiotics in single and mixed infections. We describe here the mechanism of an interspecies interaction between two pathogens in the CF lung, P. aeruginosa and S. constellatus, which is potentiated by a commonly prescribed antibiotic, tobramycin. PMID- 26483524 TI - The Trk Potassium Transporter Is Required for RsmB-Mediated Activation of Virulence in the Phytopathogen Pectobacterium wasabiae. AB - Pectobacterium wasabiae (previously known as Erwinia carotovora) is an important plant pathogen that regulates the production of plant cell wall-degrading enzymes through an N-acyl homoserine lactone-based quorum sensing system and through the GacS/GacA two-component system (also known as ExpS/ExpA). At high cell density, activation of GacS/GacA induces the expression of RsmB, a noncoding RNA that is essential for the activation of virulence in this bacterium. A genetic screen to identify regulators of RsmB revealed that mutants defective in components of a putative Trk potassium transporter (trkH and trkA) had decreased rsmB expression. Further analysis of these mutants showed that changes in potassium concentration influenced rsmB expression and consequent tissue damage in potato tubers and that this regulation required an intact Trk system. Regulation of rsmB expression by potassium via the Trk system occurred even in the absence of the GacS/GacA system, demonstrating that these systems act independently and are both required for full activation of RsmB and for the downstream induction of virulence in potato infection assays. Overall, our results identified potassium as an essential environmental factor regulating the Rsm system, and the consequent induction of virulence, in the plant pathogen P. wasabiae. IMPORTANCE: Crop losses from bacterial diseases caused by pectolytic bacteria are a major problem in agriculture. By studying the regulatory pathways involved in controlling the expression of plant cell wall-degrading enzymes in Pectobacterium wasabiae, we showed that the Trk potassium transport system plays an important role in the regulation of these pathways. The data presented further identify potassium as an important environmental factor in the regulation of virulence in this plant pathogen. We showed that a reduction in virulence can be achieved by increasing the extracellular concentration of potassium. Therefore, this work highlights how elucidation of the mechanisms involved in regulating virulence can lead to the identification of environmental factors that can influence the outcome of infection. PMID- 26483525 TI - Characterization of a Unique Tetrasaccharide and Distinct Glycoproteome in the O Linked Protein Glycosylation System of Neisseria elongata subsp. glycolytica. AB - Broad-spectrum O-linked protein glycosylation is well characterized in the major Neisseria species of importance to human health and disease. Within strains of Neisseria gonorrhoeae, N. meningitidis, and N. lactamica, protein glycosylation (pgl) gene content and the corresponding oligosaccharide structure are fairly well conserved, although intra- and interstrain variability occurs. The status of such systems in distantly related commensal species, however, remains largely unexplored. Using a strain of deeply branching Neisseria elongata subsp. glycolytica, a heretofore unrecognized tetrasaccharide glycoform consisting of di N-acetylbacillosamine-glucose-di-N-acetyl hexuronic acid-N-acetylhexosamine (diNAcBac-Glc-diNAcHexA-HexNAc) was identified. Directed mutagenesis, mass spectrometric analysis, and glycan serotyping confirmed that the oligosaccharide is an extended version of the diNAcBac-Glc-based structure seen in N. gonorrhoeae and N. meningitidis generated by the successive actions of PglB, PglC, and PglD and glucosyltransferase PglH orthologues. In addition, a null mutation in the orthologue of the broadly conserved but enigmatic pglG gene precluded expression of the extended glycoform, providing the first evidence that its product is a functional glycosyltransferase. Despite clear evidence for a substantial number of glycoprotein substrates, the major pilin subunit of the endogenous type IV pilus was not glycosylated. The latter finding raises obvious questions as to the relative distribution of pilin glycosylation within the genus, how protein glycosylation substrates are selected, and the overall structure-function relationships of broad-spectrum protein glycosylation. Together, the results of this study provide a foundation upon which to assess neisserial O-linked protein glycosylation diversity at the genus level. IMPORTANCE: Broad-spectrum protein glycosylation systems are well characterized in the pathogenic Neisseria species N. gonorrhoeae and N. meningitidis. A number of lines of evidence indicate that the glycan components in these systems are subject to diversifying selection and suggest that glycan variation may be driven in the context of glycosylation of the abundant and surface-localized pilin protein PilE, the major subunit of type IV pili. Here, we examined protein glycosylation in a distantly related, nonpathogenic neisserial species, Neisseria elongata subsp. glycolytica. This system has clear similarities to the systems found in pathogenic species but makes novel glycoforms utilizing a glycosyltransferase that is widely conserved at the genus level but whose function until now remained unknown. Remarkably, PilE pilin is not glycosylated in this species, a finding that raises important questions about the evolutionary trajectories and overall structure-function relationships of broad-spectrum protein glycosylation systems in bacteria. PMID- 26483526 TI - Percussive technology in human evolution: an introduction to a comparative approach in fossil and living primates. AB - Percussive technology is part of the behavioural suite of several fossil and living primates. Stone Age ancestors used lithic artefacts in pounding activities, which could have been most important in the earliest stages of stone working. This has relevant evolutionary implications, as other primates such as chimpanzees and some monkeys use stone hammer-and-anvil combinations to crack hard-shelled foodstuffs. Parallels between primate percussive technologies and early archaeological sites need to be further explored in order to assess the emergence of technological behaviour in our evolutionary line, and firmly establish bridges between Primatology and Archaeology. What are the anatomical, cognitive and ecological constraints of percussive technology? How common are percussive activities in the Stone Age and among living primates? What is their functional significance? How similar are archaeological percussive tools and those made by non-human primates? This issue of Phil. Trans. addresses some of these questions by presenting case studies with a wide chronological, geographical and disciplinary coverage. The studies presented here cover studies of Brazilian capuchins, captive chimpanzees and chimpanzees in the wild, research on the use of percussive technology among modern humans and recent hunter gatherers in Australia, the Near East and Europe, and archaeological examples of this behaviour from a million years ago to the Holocene. In summary, the breadth and depth of research compiled here should make this issue of Philosophical Transactions of the Royal Society B, a landmark step forward towards a better understanding of percussive technology, a unique behaviour shared by some modern and fossil primates. PMID- 26483527 TI - Primate archaeology reveals cultural transmission in wild chimpanzees (Pan troglodytes verus). AB - Recovering evidence of past human activities enables us to recreate behaviour where direct observations are missing. Here, we apply archaeological methods to further investigate cultural transmission processes in percussive tool use among neighbouring chimpanzee communities in the Tai National Park, Cote d'Ivoire, West Africa. Differences in the selection of nut-cracking tools between neighbouring groups are maintained over time, despite frequent female transfer, which leads to persistent cultural diversity between chimpanzee groups. Through the recovery of used tools in the suggested natal territory of immigrants, we have been able to reconstruct the tool material selection of females prior to migration. In combination with direct observations of tool selection of local residents and immigrants after migration, we uncovered temporal changes in tool selection for immigrating females. After controlling for ecological differences between territories of immigrants and residents our data suggest that immigrants abandoned their previous tool preference and adopted the pattern of their new community, despite previous personal proficiency of the same foraging task. Our study adds to the growing body of knowledge on the importance of conformist tendencies in animals. PMID- 26483528 TI - Perspectives on object manipulation and action grammar for percussive actions in primates. AB - The skill of object manipulation is a common feature of primates including humans, although there are species-typical patterns of manipulation. Object manipulation can be used as a comparative scale of cognitive development, focusing on its complexity. Nut cracking in chimpanzees has the highest hierarchical complexity of tool use reported in non-human primates. An analysis of the patterns of object manipulation in naive chimpanzees after nut-cracking demonstrations revealed the cause of difficulties in learning nut-cracking behaviour. Various types of behaviours exhibited within a nut-cracking context can be examined in terms of the application of problem-solving strategies, focusing on their basis in causal understanding or insightful intentionality. Captive chimpanzees also exhibit complex forms of combinatory manipulation, which is the precursor of tool use. A new notation system of object manipulation was invented to assess grammatical rules in manipulative actions. The notation system of action grammar enabled direct comparisons to be made between primates including humans in a variety of object-manipulation tasks, including percussive tool use. PMID- 26483530 TI - Limestone percussion tools from the late Early Pleistocene sites of Barranco Leon and Fuente Nueva 3 (Orce, Spain). AB - In recent years, there is growing interest in the study of percussion scars and breakage patterns on hammerstones, cores and tools from Oldowan African and Eurasian lithic assemblages. Oldowan stone toolkits generally contain abundant small-sized flakes and their corresponding cores, and are characterized by their structural dichotomy of heavy- and light-duty tools. This paper explores the significance of the lesser known heavy-duty tool component, providing data from the late Lower Pleistocene sites of Barranco Leon and Fuente Nueva 3 (Orce, Spain), dated 1.4-1.2 Myr. Using quantitative and qualitative data from the large sized limestone industries from these two major sites, we present a new methodology highlighting their morpho-technological features. In the light of the results, we discuss the shortfalls of extant classificatory methods for interpreting the role of percussive technology in early toolkits. This work is rooted in an experimental program designed to reproduce the wide range of percussion marks observed on the limestone artefacts from these two sites. A visual and descriptive reference is provided as an interpretative aid for future comparative research. Further experiments using a variety of materials and gestures are still needed before the elusive traces yield the secrets of the kinds of percussive activities carried out by hominins at these, and other, Oldowan sites. PMID- 26483529 TI - Percussive tool use by Tai Western chimpanzees and Fazenda Boa Vista bearded capuchin monkeys: a comparison. AB - Percussive tool use holds special interest for scientists concerned with human origins. We summarize the findings from two field sites, Tai and Fazenda Boa Vista, where percussive tool use by chimpanzees and bearded capuchins, respectively, has been extensively investigated. We describe the ecological settings in which nut-cracking occurs and focus on four aspects of nut-cracking that have important cognitive implications, namely selection of tools, tool transport, tool modification and modulation of actions to reach the goal of cracking the nut. We comment on similarities and differences in behaviour and consider whether the observed differences reflect ecological, morphological, social and/or cognitive factors. Both species are sensitive to physical properties of tools, adjust their selection of hammers conditionally to the resistance of the nuts and to transport distance, and modulate the energy of their strikes under some conditions. However, chimpanzees transport hammers more frequently and for longer distances, take into account a higher number of combinations of variables and occasionally intentionally modify tools. A parsimonious interpretation of our findings is that morphological, ecological and social factors account for the observed differences. Confirmation of plausible cognitive differences in nut-cracking requires data not yet available. PMID- 26483531 TI - A new type of anvil in the Acheulian of Gesher Benot Ya'aqov, Israel. AB - We report here on the identification and characterization of thin basalt anvils, a newly discovered component of the Acheulian lithic inventory of Gesher Benot Ya'aqov (GBY). These tools are an addition to the array of percussive tools (percussors, pitted stones and anvils) made of basalt, flint and limestone. The thin anvils were selected from particularly compact, horizontally fissured zones of basalt flows. This type of fissuring produces a natural geometry of thick and thin slabs. Hominins at GBY had multiple acquisition strategies, including the selection of thick slabs for the production of giant cores and cobbles for percussors. The selection of thin slabs was carried out according to yet another independent and targeted plan. The thinness of the anvils dictated a particular range of functions. The use of the anvils is well documented on their surfaces and edges. Two main types of damage are identified: those resulting from activities carried out on the surfaces of the anvils and those resulting from unintentional forceful blows (accidents de travaille). Percussive activities that may have been associated with the thin anvils include nut cracking and the processing of meat and bones, as well as plants. PMID- 26483532 TI - Identifying bipolar knapping in the Mesolithic site of Font del Ros (northeast Iberia). AB - Despite recent advances in the identification of bipolar knapping, its role in many sites is not well known. We propose to assess the significance of this technique in the context of changes that occur in the Mesolithic. A lithic assemblage was recovered from unit SG at Font del Ros (Catalunya, Spain) in which pitted stones, cores and products arising from bipolar reduction (flakes, fragments and splintered pieces) were identified. This study indicates that the bipolar technique is fundamental in the settlement. These results are key to defining the organization of Holocene hunter-gatherer subsistence in northeast Iberia. PMID- 26483534 TI - Insights into early lithic technologies from ethnography. AB - Oldowan lithic assemblages are often portrayed as a product of the need to obtain sharp flakes for cutting into animal carcases. However, ethnographic and experimental research indicates that the optimal way to produce flakes for such butchering purposes is via bipolar reduction of small cryptocrystalline pebbles rather than from larger crystalline cores resembling choppers. Ethnographic observations of stone tool-using hunter-gatherers in environments comparable with early hominins indicate that most stone tools (particularly chopper forms and flake tools) were used for making simple shaft tools including spears, digging sticks and throwing sticks. These tools bear strong resemblances to Oldowan stone tools. Bipolar reduction for butchering probably preceded chopper-like core reduction and provides a key link between primate nut-cracking technologies and the emergence of more sophisticated lithic technologies leading to the Oldowan. PMID- 26483533 TI - How similar are nut-cracking and stone-flaking? A functional approach to percussive technology. AB - Various authors have suggested similarities between tool use in early hominins and chimpanzees. This has been particularly evident in studies of nut-cracking which is considered to be the most complex skill exhibited by wild apes, and has also been interpreted as a precursor of more complex stone-flaking abilities. It has been argued that there is no major qualitative difference between what the chimpanzee does when he cracks a nut and what early hominins did when they detached a flake from a core. In this paper, similarities and differences between skills involved in stone-flaking and nut-cracking are explored through an experimental protocol with human subjects performing both tasks. We suggest that a 'functional' approach to percussive action, based on the distinction between functional parameters that characterize each task and parameters that characterize the agent's actions and movements, is a fruitful method for understanding those constraints which need to be mastered to perform each task successfully, and subsequently, the nature of skill involved in both tasks. PMID- 26483535 TI - The development of plant food processing in the Levant: insights from use-wear analysis of Early Epipalaeolithic ground stone tools. AB - In recent years, the study of percussive, pounding and grinding tools has provided new insights into human evolution, more particularly regarding the development of technology enabling the processing and exploitation of plant resources. Some of these studies focus on early evidence for flour production, an activity frequently perceived as an important step in the evolution of plant exploitation. The present paper investigates plant food preparation in mobile hunter-gatherer societies from the Southern Levant. The analysis consists of a use-wear study of 18 tools recovered from Ohalo II, a 23 000-year-old site in Israel showing an exceptional level of preservation. Our sample includes a slab previously interpreted as a lower implement used for producing flour, based on the presence of cereal starch residues. The use-wear data we have obtained provide crucial information about the function of this and other percussive tools at Ohalo II, as well as on investment in tool manufacture, discard strategies and evidence for plant processing in the Late Pleistocene. The use-wear analysis indicates that the production of flour was a sporadic activity at Ohalo II, predating by thousands of years the onset of routine processing of plant foods. PMID- 26483536 TI - Variability in an early hominin percussive tradition: the Acheulean versus cultural variation in modern chimpanzee artefacts. AB - Percussion makes a vital link between the activities of early human ancestors and other animals in tool-use and tool-making. Far more of the early human actions are preserved as archaeology, since the percussion was largely used for making hard tools of stone, rather than for direct access to food. Both primate tools and early hominin tools, however, offer a means to exploring variability in material culture, a strong focus of interest in recent primate studies. This paper charts such variability in the Acheulean, the longest-lasting tool tradition, extant form about 1.7 to about 0.1 Ma, and well known for its characteristic handaxes. The paper concentrates on the African record, although the Acheulean was also known in Europe and Asia. It uses principal components and discriminant analysis to examine the measurements from 66 assemblages (whole toolkits), and from 18 sets of handaxes. Its review of evidence confirms that there is deep-seated pattern in the variation, with variability within a site complex often matching or exceeding that between sites far distant in space and time. Current techniques of study allow comparisons of handaxes far more easily than for other components, stressing a need to develop common practice in measurement and analysis. The data suggest, however, that a higher proportion of traits recurs widely in Acheulean toolkits than in the chimpanzee record. PMID- 26483537 TI - Experimental studies illuminate the cultural transmission of percussive technologies in Homo and Pan. AB - The complexity of Stone Age tool-making is assumed to have relied upon cultural transmission, but direct evidence is lacking. This paper reviews evidence bearing on this question provided through five related empirical perspectives. Controlled experimental studies offer special power in identifying and dissecting social learning into its diverse component forms, such as imitation and emulation. The first approach focuses on experimental studies that have discriminated social learning processes in nut-cracking by chimpanzees. Second come experiments that have identified and dissected the processes of cultural transmission involved in a variety of other force-based forms of chimpanzee tool use. A third perspective is provided by field studies that have revealed a range of forms of forceful, targeted tool use by chimpanzees, that set percussion in its broader cognitive context. Fourth are experimental studies of the development of flint knapping to make functional sharp flakes by bonobos, implicating and defining the social learning and innovation involved. Finally, new and substantial experiments compare what different social learning processes, from observational learning to teaching, afford good quality human flake and biface manufacture. Together these complementary approaches begin to delineate the social learning processes necessary to percussive technologies within the Pan-Homo clade. PMID- 26483539 TI - Preface. PMID- 26483540 TI - Proceedings: Using Stem Cell Therapies to Reestablish Osteogenic Capability for Bone Regeneration. AB - The California Institute for Regenerative Medicine (CIRM) has invested approximately $70 million in programs targeting various orthopedic indications, including osteoporosis, bone fracture healing, vertebral compression fractures, and several others. The present article serves to outline the current state of CIRM's more advanced programs, comparing and contrasting them with the current standard of care and several other novel approaches under development. SIGNIFICANCE: This report describes CIRM bone programs that are in contrast to current cell therapy approaches. These projects aim to enhance stem cell activity for bone regeneration. PMID- 26483538 TI - Evidence in hand: recent discoveries and the early evolution of human manual manipulation. AB - For several decades, it was largely assumed that stone tool use and production were abilities limited to the genus Homo. However, growing palaeontological and archaeological evidence, comparative extant primate studies, as well as results from methodological advancements in biomechanics and morphological analyses, have been gradually accumulating and now provide strong support for more advanced manual manipulative abilities and tool-related behaviours in pre-Homo hominins than has been traditionally recognized. Here, I review the fossil evidence related to early hominin dexterity, including the recent discoveries of relatively complete early hominin hand skeletons, and new methodologies that are providing a more holistic interpretation of hand function, and insight into how our early ancestors may have balanced the functional requirements of both arboreal locomotion and tool-related behaviours. PMID- 26483541 TI - TatE as a Regular Constituent of Bacterial Twin-arginine Protein Translocases. AB - Twin-arginine translocation (Tat) systems mediate the transmembrane translocation of completely folded proteins that possess a conserved twin-arginine (RR) motif in their signal sequences. Many Tat systems consist of three essential membrane components named TatA, TatB, and TatC. It is not understood why some bacteria, in addition, constitutively express a functional paralog of TatA called TatE. Here we show, in live Escherichia coli cells, that, upon expression of a Tat substrate protein, fluorescently labeled TatE-GFP relocates from a rather uniform distribution in the plasma membrane into a number of discrete clusters. Clustering strictly required an intact RR signal peptide and the presence of the TatABC subunits, suggesting that TatE-GFP associates with functional Tat translocases. In support of this notion, site-specific photo cross-linking revealed interactions of TatE with TatA, TatB, and TatC. The same approach also disclosed a pronounced tendency of TatE and TatA to hetero-oligomerize. Under in vitro conditions, we found that TatE replaces TatA inefficiently. Our collective results are consistent with TatE being a regular constituent of the Tat translocase in E. coli. PMID- 26483542 TI - Structural and Functional Studies of a Newly Grouped Haloquadratum walsbyi Bacteriorhodopsin Reveal the Acid-resistant Light-driven Proton Pumping Activity. AB - Retinal bound light-driven proton pumps are widespread in eukaryotic and prokaryotic organisms. Among these pumps, bacteriorhodopsin (BR) proteins cooperate with ATP synthase to convert captured solar energy into a biologically consumable form, ATP. In an acidic environment or when pumped-out protons accumulate in the extracellular region, the maximum absorbance of BR proteins shifts markedly to the longer wavelengths. These conditions affect the light driven proton pumping functional exertion as well. In this study, wild-type crystal structure of a BR with optical stability under wide pH range from a square halophilic archaeon, Haloquadratum walsbyi (HwBR), was solved in two crystal forms. One crystal form, refined to 1.85 A resolution, contains a trimer in the asymmetric unit, whereas another contains an antiparallel dimer was refined at 2.58 A. HwBR could not be classified into any existing subgroup of archaeal BR proteins based on the protein sequence phylogenetic tree, and it showed unique absorption spectral stability when exposed to low pH values. All structures showed a unique hydrogen-bonding network between Arg(82) and Thr(201), linking the BC and FG loops to shield the retinal-binding pocket in the interior from the extracellular environment. This result was supported by R82E mutation that attenuated the optical stability. The negatively charged cytoplasmic side and the Arg(82)-Thr(201) hydrogen bond may play an important role in the proton translocation trend in HwBR under acidic conditions. Our findings have unveiled a strategy adopted by BR proteins to solidify their defenses against unfavorable environments and maintain their optical properties associated with proton pumping. PMID- 26483543 TI - The Hydroxyl Side Chain of a Highly Conserved Serine Residue Is Required for Cation Selectivity and Substrate Transport in the Glial Glutamate Transporter GLT 1/SLC1A2. AB - Glutamate transporters maintain synaptic concentration of the excitatory neurotransmitter below neurotoxic levels. Their transport cycle consists of cotransport of glutamate with three sodium ions and one proton, followed by countertransport of potassium. Structural studies proposed that a highly conserved serine located in the binding pocket of the homologous GltPh coordinates L-aspartate as well as the sodium ion Na1. To experimentally validate these findings, we generated and characterized several mutants of the corresponding serine residue, Ser-364, of human glutamate transporter SLC1A2 (solute carrier family 1 member 2), also known as glutamate transporter GLT-1 and excitatory amino acid transporter EAAT2. S364T, S364A, S364C, S364N, and S364D were expressed in HEK cells and Xenopus laevis oocytes to measure radioactive substrate transport and transport currents, respectively. All mutants exhibited similar plasma membrane expression when compared with WT SLC1A2, but substitutions of serine by aspartate or asparagine completely abolished substrate transport. On the other hand, the threonine mutant, which is a more conservative mutation, exhibited similar substrate selectivity, substrate and sodium affinities as WT but a lower selectivity for Na(+) over Li(+). S364A and S364C exhibited drastically reduced affinities for each substrate and enhanced selectivity for L-aspartate over D-aspartate and L-glutamate, and lost their selectivity for Na(+) over Li(+). Furthermore, we extended the analysis of our experimental observations using molecular dynamics simulations. Altogether, our findings confirm a pivotal role of the serine 364, and more precisely its hydroxyl group, in coupling sodium and substrate fluxes. PMID- 26483544 TI - Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking. AB - Conversion of vitamin B12 (cobalamin, Cbl) into the cofactor forms methyl-Cbl (MeCbl) and adenosyl-Cbl (AdoCbl) is required for the function of two crucial enzymes, mitochondrial methylmalonyl-CoA mutase and cytosolic methionine synthase, respectively. The intracellular proteins MMACHC and MMADHC play important roles in processing and targeting the Cbl cofactor to its destination enzymes, and recent evidence suggests that they may interact while performing these essential trafficking functions. To better understand the molecular basis of this interaction, we have mapped the crucial protein regions required, indicate that Cbl is likely processed by MMACHC prior to interaction with MMADHC, and identify patient mutations on both proteins that interfere with complex formation, via different mechanisms. We further report the crystal structure of the MMADHC C-terminal region at 2.2 A resolution, revealing a modified nitroreductase fold with surprising homology to MMACHC despite their poor sequence conservation. Because MMADHC demonstrates no known enzymatic activity, we propose it as the first protein known to repurpose the nitroreductase fold solely for protein-protein interaction. Using small angle x-ray scattering, we reveal the MMACHC-MMADHC complex as a 1:1 heterodimer and provide a structural model of this interaction, where the interaction region overlaps with the MMACHC Cbl binding site. Together, our findings provide novel structural evidence and mechanistic insight into an essential biological process, whereby an intracellular "trafficking chaperone" highly specific for a trace element cofactor functions via protein-protein interaction, which is disrupted by inherited disease mutations. PMID- 26483545 TI - Mechanistic and Kinetic Differences between Reverse Transcriptases of Vpx Coding and Non-coding Lentiviruses. AB - Among lentiviruses, HIV Type 2 (HIV-2) and many simian immunodeficiency virus (SIV) strains replicate rapidly in non-dividing macrophages, whereas HIV Type 1 (HIV-1) replication in this cell type is kinetically delayed. The efficient replication capability of HIV-2/SIV in non-dividing cells is induced by a unique, virally encoded accessory protein, Vpx, which proteasomally degrades the host antiviral restriction factor, SAM domain- and HD domain-containing protein 1 (SAMHD1). SAMHD1 is a dNTPase and kinetically suppresses the reverse transcription step of HIV-1 in macrophages by hydrolyzing and depleting cellular dNTPs. In contrast, Vpx, which is encoded by HIV-2/SIV, kinetically accelerates reverse transcription by counteracting SAMHD1 and then elevating cellular dNTP concentration in non-dividing cells. Here, we conducted the pre-steady-state kinetic analysis of reverse transcriptases (RTs) from two Vpx non-coding and two Vpx coding lentiviruses. At all three sites of the template tested, the two RTs of the Vpx non-coding viruses (HIV-1) displayed higher kpol values than the RTs of the Vpx coding HIV-2/SIV, whereas there was no significant difference in the Kd values of these two groups of RTs. When we employed viral RNA templates that induce RT pausing by their secondary structures, the HIV-1 RTs showed more efficient DNA synthesis through pause sites than the HIV-2/SIV RTs, particularly at low dNTP concentrations found in macrophages. This kinetic study suggests that RTs of the Vpx non-coding HIV-1 may have evolved to execute a faster kpol step, which includes the conformational changes and incorporation chemistry, to counteract the limited dNTP concentration found in non-dividing cells and still promote efficient viral reverse transcription. PMID- 26483546 TI - The Central Region of the Drosophila Co-repressor Groucho as a Regulatory Hub. AB - Groucho (Gro) is a Drosophila co-repressor that regulates the expression of a large number of genes, many of which are involved in developmental control. Previous studies have shown that its central region is essential for function even though its three domains are poorly conserved and intrinsically disordered. Using these disordered domains as affinity reagents, we have now identified multiple embryonic Gro-interacting proteins. The interactors include protein complexes involved in chromosome organization, mRNA processing, and signaling. Further investigation of the interacting proteins using a reporter assay showed that many of them modulate Gro-mediated repression either positively or negatively. The positive regulators include components of the spliceosomal subcomplex U1 small nuclear ribonucleoprotein (U1 snRNP). A co immunoprecipitation experiment confirms this finding and suggests that a sizable fraction of nuclear U1 snRNP is associated with Gro. The use of RNA-seq to analyze the gene expression profile of cells subjected to knockdown of Gro or snRNP-U1-C (a component of U1 snRNP) showed a significant overlap between genes regulated by these two factors. Furthermore, comparison of our RNA-seq data with Gro and RNA polymerase II ChIP data led to a number of insights, including the finding that Gro-repressed genes are enriched for promoter-proximal RNA polymerase II. We conclude that the Gro central domains mediate multiple interactions required for repression, thus functioning as a regulatory hub. Furthermore, interactions with the spliceosome may contribute to repression by Gro. PMID- 26483547 TI - Matrix Metalloproteinase-9 Protects Islets from Amyloid-induced Toxicity. AB - Deposition of human islet amyloid polypeptide (hIAPP, also known as amylin) as islet amyloid is a characteristic feature of the pancreas in type 2 diabetes, contributing to increased beta-cell apoptosis and reduced beta-cell mass. Matrix metalloproteinase-9 (MMP-9) is active in islets and cleaves hIAPP. We investigated whether hIAPP fragments arising from MMP-9 cleavage retain the potential to aggregate and cause toxicity, and whether overexpressing MMP-9 in amyloid-prone islets reduces amyloid burden and the resulting beta-cell toxicity. Synthetic hIAPP was incubated with MMP-9 and the major hIAPP fragments observed by MS comprised residues 1-15, 1-25, 16-37, 16-25, and 26-37. The fragments 1-15, 1-25, and 26-37 did not form amyloid fibrils in vitro and they were not cytotoxic when incubated with beta cells. Mixtures of these fragments with full-length hIAPP did not modulate the kinetics of fibril formation by full-length hIAPP. In contrast, the 16-37 fragment formed fibrils more rapidly than full-length hIAPP but was less cytotoxic. Co-incubation of MMP-9 and fragment 16-37 ablated amyloidogenicity, suggesting that MMP-9 cleaves hIAPP 16-37 into non amyloidogenic fragments. Consistent with MMP-9 cleavage resulting in largely non amyloidogenic degradation products, adenoviral overexpression of MMP-9 in amyloid prone islets reduced amyloid deposition and beta-cell apoptosis. These findings suggest that increasing islet MMP-9 activity might be a strategy to limit beta cell loss in type 2 diabetes. PMID- 26483548 TI - The Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma. AB - Resistance to the proteasome inhibitor bortezomib is an emerging clinical problem whose mechanisms have not been fully elucidated. We considered the possibility that this could be associated with enhanced proteasome activity in part through the action of the proteasome maturation protein (POMP). Bortezomib-resistant myeloma models were used to examine the correlation between POMP expression and bortezomib sensitivity. POMP expression was then modulated using genetic and pharmacologic approaches to determine the effects on proteasome inhibitor sensitivity in cell lines and in vivo models. Resistant cell lines were found to overexpress POMP, and while its suppression in cell lines enhanced bortezomib sensitivity, POMP overexpression in drug-naive cells conferred resistance. Overexpression of POMP was associated with increased levels of nuclear factor (erythroid-derived 2)-like (NRF2), and NRF2 was found to bind to and activate the POMP promoter. Knockdown of NRF2 in bortezomib-resistant cells reduced POMP levels and proteasome activity, whereas its overexpression in drug-naive cells increased POMP and proteasome activity. The NRF2 inhibitor all-trans-retinoic acid reduced cellular NRF2 levels and increased the anti-proliferative and pro apoptotic activities of bortezomib in resistant cells, while decreasing proteasome capacity. Finally, the combination of all-trans-retinoic acid with bortezomib showed enhanced activity against primary patient samples and in a murine model of bortezomib-resistant myeloma. Taken together, these studies validate a role for the NRF2/POMP axis in bortezomib resistance and identify NRF2 and POMP as potentially attractive targets for chemosensitization to this proteasome inhibitor. PMID- 26483549 TI - IL-1R/TLR2 through MyD88 Divergently Modulates Osteoclastogenesis through Regulation of Nuclear Factor of Activated T Cells c1 (NFATc1) and B Lymphocyte induced Maturation Protein-1 (Blimp1). AB - Toll-like receptors (TLR) and the receptor for interleukin-1 (IL-1R) signaling play an important role in bacteria-mediated bone loss diseases including periodontitis, rheumatoid arthritis, and osteomyelitis. Recent studies have shown that TLR ligands inhibit the receptor activator of NF-kappaB ligand (RANKL) induced osteoclast differentiation from un-committed osteoclast precursors, whereas IL-1 potentiates RANKL-induced osteoclast formation. However, IL-1R and TLR belong to the same IL-1R/TLR superfamily, and activate similar intracellular signaling pathways. Here, we investigate the molecular mechanisms underlying the distinct effects of IL-1 and Porphyromonas gingivalis lipopolysaccharide (LPS-PG) on RANKL-induced osteoclast formation. Our results show that LPS-PG and IL-1 differentially regulate RANKL-induced activation of osteoclast genes encoding Car2, Ctsk, MMP9, and TRAP, as well as expression of NFATc1, a master transcription factor of osteoclastogenesis. Regulation of osteoclast genes and NFATc1 by LPS-PG and IL-1 is dependent on MyD88, an important signaling adaptor for both TLR and IL-1R family members. Furthermore, LPS-PG and IL-1 differentially regulate RANKL-costimulatory receptor OSCAR (osteoclast-associated receptor) expression and Ca(2+) oscillations induced by RANKL. Moreover, LPS-PG completely abrogates RANKL-induced gene expression of B lymphocyte-induced maturation protein-1 (Blimp1), a global transcriptional repressor of anti osteoclastogenic genes encoding Bcl6, IRF8, and MafB. However, IL-1 enhances RANKL-induced blimp1 gene expression but suppresses the gene expression of bcl6, irf8, and mafb. Our study reveals the involvement of multiple signaling molecules in the differential regulation of RANKL-induced osteoclastogenesis by TLR2 and IL 1 signaling. Understanding the signaling cross-talk among TLR, IL-1R, and RANK is critical for identifying therapeutic strategies to control bacteria-mediated bone loss. PMID- 26483550 TI - Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with an overall survival rate of less than 5%. The poor patient outcome in PDAC is largely due to the high prevalence of systemic metastasis at the time of diagnosis and lack of effective therapeutics that target disseminated cells. The fact that the underlying mechanisms driving PDAC cell migration and dissemination are poorly understood have hindered drug development and compounded the lack of clinical success in this disease. Recent evidence indicates that mutational activation of K-Ras up-regulates eIF5A, a component of the cellular translational machinery that is critical for PDAC progression. However, the role of eIF5A in PDAC cell migration and metastasis has not been investigated. We report here that pharmacological inhibition or genetic knockdown of eIF5A reduces PDAC cell migration, invasion, and metastasis in vitro and in vivo. Proteomic profiling and bioinformatic analyses revealed that eIF5A controls an integrated network of cytoskeleton-regulatory proteins involved in cell migration. Functional interrogation of this network uncovered a critical RhoA/ROCK signaling node that operates downstream of eIF5A in invasive PDAC cells. Importantly, eIF5A mediates PDAC cell migration and invasion by modulating RhoA/ROCK protein expression levels. Together our findings implicate eIF5A as a cytoskeletal rheostat controlling RhoA/ROCK protein expression during PDAC cell migration and metastasis. Our findings also implicate the eIF5A/RhoA/ROCK module as a potential new therapeutic target to treat metastatic PDAC cells. PMID- 26483551 TI - Integrin alpha5 Suppresses the Phosphorylation of Epidermal Growth Factor Receptor and Its Cellular Signaling of Cell Proliferation via N-Glycosylation. AB - Integrin alpha5beta1-mediated cell adhesion regulates a multitude of cellular responses, including cell proliferation, survival, and cross-talk between different cellular signaling pathways. Integrin alpha5beta1 is known to convey permissive signals enabling anchorage-dependent receptor tyrosine kinase signaling. However, the effects of integrin alpha5beta1 on cell proliferation are controversial, and the molecular mechanisms involved in the regulation between integrin alpha5beta1 and receptor tyrosine kinase remain largely unclear. Here we show that integrin alpha5 functions as a negative regulator of epidermal growth factor receptor (EGFR) signaling through its N-glycosylation. Expression of WT integrin alpha5 suppresses the EGFR phosphorylation and internalization upon EGF stimulation. However, expression of the N-glycosylation mutant integrin alpha5, S3-5, which contains fewer N-glycans, reversed the suppression of the EGFR mediated signaling and cell proliferation. In a mechanistic manner, WT but not S3 5 integrin alpha5 forms a complex with EGFR and glycolipids in the low density lipid rafts, and the complex formation is disrupted upon EGF stimulation, suggesting that the N-glycosylation of integrin alpha5 suppresses the EGFR activation through promotion of the integrin alpha5-glycolipids-EGFR complex formation. Furthermore, consistent restoration of those N-glycans on the Calf-1,2 domain of integrin alpha5 reinstated the inhibitory effects as well as the complex formation with EGFR. Taken together, these data are the first to demonstrate that EGFR activation can be regulated by the N-glycosylation of integrin alpha5, which is a novel molecular paradigm for the cross-talk between integrins and growth factor receptors. PMID- 26483552 TI - Salt Bridge Swapping in the EXXERFXYY Motif of Proton-coupled Oligopeptide Transporters. AB - Proton-coupled oligopeptide transporters (POTs) couple the inward transport of di or tripeptides with an inwardly directed transport of protons. Evidence from several studies of different POTs has pointed toward involvement of a highly conserved sequence motif, E1XXE2RFXYY (from here on referred to as E1XXE2R), located on Helix I, in interactions with the proton. In this study, we investigated the intracellular substrate accumulation by motif variants with all possible combinations of glutamate residues changed to glutamine and arginine changed to a tyrosine, the latter being a natural variant found in the Escherichia coli POT YjdL. We found that YjdL motif variants with E1XXE2R, E1XXE2Y, E1XXQ2Y, or Q1XXE2Y were able to accumulate peptide, whereas those with E1XXQ2R, Q1XXE2R, or Q1XXQ2Y were unable to accumulate peptide, and Q1XXQ2R abolished uptake. These results suggest a mechanism that involves swapping of an intramotif salt bridge, i.e. R-E2 to R-E1, which is consistent with previous structural studies. Molecular dynamics simulations of the motif variants E1XXE2R and E1XXQ2R support this mechanism. The simulations showed that upon changing conformation arginine pushes Helix V, through interactions with the highly conserved FYING motif, further away from the central cavity in what could be a stabilization of an inward facing conformation. As E2 has been suggested to be the primary site for protonation, these novel findings show how protonation may drive conformational changes through interactions of two highly conserved motifs. PMID- 26483553 TI - NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin. AB - The proliferation of normal cells is inhibited at confluence, but the molecular basis of this phenomenon, known as contact-dependent inhibition of proliferation, is unclear. We previously identified the neurofibromatosis type 2 (NF2) tumor suppressor Merlin as a critical mediator of contact-dependent inhibition of proliferation and specifically found that Merlin inhibits the internalization of, and signaling from, the epidermal growth factor receptor (EGFR) in response to cell contact. Merlin is closely related to the membrane-cytoskeleton linking proteins Ezrin, Radixin, and Moesin, and localization of Merlin to the cortical cytoskeleton is required for contact-dependent regulation of EGFR. We show that Merlin and Ezrin are essential components of a mechanism whereby mechanical forces associated with the establishment of cell-cell junctions are transduced across the cell cortex via the cortical actomyosin cytoskeleton to control the lateral mobility and activity of EGFR, providing novel insight into how cells inhibit mitogenic signaling in response to cell contact. PMID- 26483554 TI - The dynein cortical anchor Num1 activates dynein motility by relieving Pac1/LIS1 mediated inhibition. AB - Cortically anchored dynein orients the spindle through interactions with astral microtubules. In budding yeast, dynein is offloaded to Num1 receptors from microtubule plus ends. Rather than walking toward minus ends, dynein remains associated with plus ends due in part to its association with Pac1/LIS1, an inhibitor of dynein motility. The mechanism by which dynein is switched from "off" at the plus ends to "on" at the cell cortex remains unknown. Here, we show that overexpression of the coiled-coil domain of Num1 specifically depletes dynein-dynactin-Pac1/LIS1 complexes from microtubule plus ends and reduces dynein Pac1/LIS1 colocalization. Depletion of dynein from plus ends requires its microtubule-binding domain, suggesting that motility is required. An enhanced Pac1/LIS1 affinity mutant of dynein or overexpression of Pac1/LIS1 rescues dynein plus end depletion. Live-cell imaging reveals minus end-directed dynein-dynactin motility along microtubules upon overexpression of the coiled-coil domain of Num1, an event that is not observed in wild-type cells. Our findings indicate that dynein activity is directly switched "on" by Num1, which induces Pac1/LIS1 removal. PMID- 26483555 TI - Spindle assembly checkpoint proteins regulate and monitor meiotic synapsis in C. elegans. AB - Homologue synapsis is required for meiotic chromosome segregation, but how synapsis is initiated between chromosomes is poorly understood. In Caenorhabditis elegans, synapsis and a checkpoint that monitors synapsis depend on pairing centers (PCs), cis-acting loci that interact with nuclear envelope proteins, such as SUN-1, to access cytoplasmic microtubules. Here, we report that spindle assembly checkpoint (SAC) components MAD-1, MAD-2, and BUB-3 are required to negatively regulate synapsis and promote the synapsis checkpoint response. Both of these roles are independent of a conserved component of the anaphase-promoting complex, indicating a unique role for these proteins in meiotic prophase. MAD-1 and MAD-2 localize to the periphery of meiotic nuclei and interact with SUN-1, suggesting a role at PCs. Consistent with this idea, MAD-1 and BUB-3 require full PC function to inhibit synapsis. We propose that SAC proteins monitor the stability of pairing, or tension, between homologues to regulate synapsis and elicit a checkpoint response. PMID- 26483557 TI - Cell biology of the future: Nanometer-scale cellular cartography. AB - Understanding cellular structure is key to understanding cellular regulation. New developments in super-resolution fluorescence imaging, electron microscopy, and quantitative image analysis methods are now providing some of the first three dimensional dynamic maps of biomolecules at the nanometer scale. These new maps- comprehensive nanometer-scale cellular cartographies--will reveal how the molecular organization of cells influences their diverse and changeable activities. PMID- 26483556 TI - A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia. AB - Lethal giant larvae (Lgl) plays essential and conserved functions in regulating both cell polarity and tumorigenesis in Drosophila melanogaster and vertebrates. It is well recognized that plasma membrane (PM) or cell cortex localization is crucial for Lgl function in vivo, but its membrane-targeting mechanisms remain poorly understood. Here, we discovered that hypoxia acutely and reversibly inhibits Lgl PM targeting through a posttranslational mechanism that is independent of the well-characterized atypical protein kinase C (aPKC) or Aurora kinase-mediated phosphorylations. Instead, we identified an evolutionarily conserved polybasic (PB) domain that targets Lgl to the PM via electrostatic binding to membrane phosphatidylinositol phosphates. Such PB domain-mediated PM targeting is inhibited by hypoxia, which reduces inositol phospholipid levels on the PM through adenosine triphosphate depletion. Moreover, Lgl PB domain contains all the identified phosphorylation sites of aPKC and Aurora kinases, providing a molecular mechanism by which phosphorylations neutralize the positive charges on the PB domain to inhibit Lgl PM targeting. PMID- 26483558 TI - Molecular control of irreversible bistability during trypanosome developmental commitment. AB - The life cycle of Trypanosoma brucei involves developmental transitions that allow survival, proliferation, and transmission of these parasites. One of these, the differentiation of growth-arrested stumpy forms in the mammalian blood into insect-stage procyclic forms, can be induced synchronously in vitro with cis aconitate. Here, we show that this transition is an irreversible bistable switch, and we map the point of commitment to differentiation after exposure to cis aconitate. This irreversibility implies that positive feedback mechanisms operate to allow commitment (i.e., the establishment of "memory" of exposure to the differentiation signal). Using the reversible translational inhibitor cycloheximide, we show that this signal memory requires new protein synthesis. We further performed stable isotope labeling by amino acids in cell culture to analyze synchronized parasite populations, establishing the protein and phosphorylation profile of parasites pre- and postcommitment, thereby defining the "commitment proteome." Functional interrogation of this data set identified Nek-related kinase as the first-discovered protein kinase controlling the initiation of differentiation to procyclic forms. PMID- 26483559 TI - Nup132 modulates meiotic spindle attachment in fission yeast by regulating kinetochore assembly. AB - During meiosis, the kinetochore undergoes substantial reorganization to establish monopolar spindle attachment. In the fission yeast Schizosaccharomyces pombe, the KNL1-Spc7-Mis12-Nuf2 (KMN) complex, which constitutes the outer kinetochore, is disassembled during meiotic prophase and is reassembled before meiosis I. Here, we show that the nucleoporin Nup132 is required for timely assembly of the KMN proteins: In the absence of Nup132, Mis12 and Spc7 are precociously assembled at the centromeres during meiotic prophase. In contrast, Nuf2 shows timely dissociation and reappearance at the meiotic centromeres. We further demonstrate that depletion of Nup132 activates the spindle assembly checkpoint in meiosis I, possibly because of the increased incidence of erroneous spindle attachment at sister chromatids. These results suggest that precocious assembly of the kinetochores leads to the meiosis I defects observed in the nup132-disrupted mutant. Thus, we propose that Nup132 plays an important role in establishing monopolar spindle attachment at meiosis I through outer kinetochore reorganization at meiotic prophase. PMID- 26483561 TI - Elevated expression of ASCL2 is an independent prognostic indicator in lung squamous cell carcinoma. AB - AIMS: ASCL2, a basic helix-loop-helix (bHLH) transcription factor, is putatively involved in tumour progression. This study aimed to evaluate ASCL2 expression level in non-small-cell carcinoma (NSCLC) and assess its prognostic value for patients. METHODS: ASCL2 protein expression was detected by immunohistochemistry (IHC cohort) in 79 cases of squamous cell carcinoma (SCC) and 67 cases of adenocarcinoma (AC). Kaplan-Meier analysis and Cox regression analysis were performed to evaluate the prognostic significance of ASCL2. The same analyses were conducted in a cohort (n=790) from The Cancer Genome Atlas database (TCGA) to validate the expression pattern and prognostic value of ASCL2. RESULTS: ASCL2 expression levels were significantly increased in SCC compared with normal lung tissue (p<0.001) and AC (p=0.008). High ASCL2 expression was associated with advanced tumour-node-metastasis (TNM) stage (p=0.023) and worse differentiation status (p=0.001) in SCC, but a positive correlation between ASCL2 expression level and advanced TNM stage (p=0.016) was observed in AC. Kaplan-Meier analysis showed that ASCL2 was prognostic in SCC (p=0.004) but not in AC (p=0.183). Multivariable Cox regression analysis indicated that elevated expression of ASCL2 was an independent prognostic factor (HR 2.764; p=0.030) in SCC patients. The expression pattern and prognostic significance of ASCL2 in SCC and AC were validated using the TCGA cohort. CONCLUSIONS: Elevated expression of ASCL2 may identify an aggressive subgroup in SCC and serve as an independent prognostic indicator in these patients. PMID- 26483562 TI - Professor Stephen Halloran FRCPath, MBE: a career in clinical biochemistry. PMID- 26483560 TI - Rootletin organizes the ciliary rootlet to achieve neuron sensory function in Drosophila. AB - Cilia are essential for cell signaling and sensory perception. In many cell types, a cytoskeletal structure called the ciliary rootlet links the cilium to the cell body. Previous studies indicated that rootlets support the long-term stability of some cilia. Here we report that Drosophila melanogaster Rootletin (Root), the sole orthologue of the mammalian paralogs Rootletin and C-Nap1, assembles into rootlets of diverse lengths among sensory neuron subtypes. Root mutant neurons lack rootlets and have dramatically impaired sensory function, resulting in behavior defects associated with mechanosensation and chemosensation. Root is required for cohesion of basal bodies, but the cilium structure appears normal in Root mutant neurons. We show, however, that normal rootlet assembly requires centrioles. The N terminus of Root contains a conserved domain and is essential for Root function in vivo. Ectopically expressed Root resides at the base of mother centrioles in spermatocytes and localizes asymmetrically to mother centrosomes in neuroblasts, both requiring Bld10, a basal body protein with varied functions. PMID- 26483563 TI - A simple approach to derive Z-score of reference change value involving more than two serial results. PMID- 26483564 TI - Authors' reply to the letter to Editor (Annals of Clinical Biochemistry): 'A simple approach to derive Z-score of reference change value involving more than two serial results'. PMID- 26483565 TI - Prognostic value of different biomarkers for cardiovascular death in unselected older patients in the emergency department. AB - BACKGROUND: Risk stratification of elderly patients presenting with heart failure (HF) to an emergency department (ED) is an unmet challenge. We prospectively investigated the prognostic performance of different biomarkers in unselected older patients in the ED. METHODS: We consecutively enrolled 302 non-surgical patients ?70 years presenting to the ED with a wide range of cardiovascular and non-cardiovascular comorbid conditions. N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1), ultrasensitive C-terminal pro-arginine-vasopressin (Copeptin-us) and high sensitivity cardiac troponin T (hs-cTnT) were measured at admission. Two cardiologists independently adjudicated the final diagnosis of HF after reviewing all available baseline data using circulating NT-proBNP levels. A final diagnosis of HF was found in 120 (40%) of the 302 patients. All patients were followed up for cardiovascular death within the following 12 months. In order to test the prognostic performance of the investigated biomarkers we used boosting models with age and sex as mandatory covariates. Boosting is a statistical learning technique with built-in variable selection developed to obtain sparse and interpretable prediction models. RESULTS: Follow-up was 100% complete. During a median follow-up time of 225 days (interquartile range (IQR) 156-319 days), 30 (9.9%) of 302 patients (aged 81+/-6 years) had cardiovascular deaths. Of these 30 patients, 21 had HF and nine had no HF diagnosed prior to admission. The boosting model selected MR-proADM and hs-cTNT as predictors of cardiovascular deaths. The median values of MR-proADM and hs-cTnT at presentation were significantly higher in patients with cardiovascular deaths compared to surviving patients during follow-up (2.56 nmol/L (IQR 1.62-4.48) vs. 1.11 nmol/L (IQR 0.83-1.80), P<0.001 and 81 ng/L (IQR 38-340) vs. 17 ng/L (IQR 0.9-38), P=0.004). One unit increase in the log-transformed MR-proADM levels was associated with a 1.99-fold risk of death (95% confidence interval (CI) 1.61-2.45, P<0.001). The second marker, hs cTnT, showed an increased predicted risk but was not significantly correlated to event-free survival (hazard ratio 3.22, 95% CI 0.97-10.68, P=0.056). CONCLUSION: Within different biomarkers, MR-proADM was the only predictor of cardiovascular deaths in unselected older patients presenting to the ED. PMID- 26483566 TI - Orchestrated Testing. AB - Health care quality improvement collaboratives implement care bundles to target critical parts of a complex system to improve a specific health outcome. The quantitative impact of each component of the care bundle is often unknown. Orchestrated testing (OT) is an application of planned experimentation that allows simultaneous examination of multiple practices (bundle elements) to determine which intervention or combination of interventions affects the outcome. The purpose of this article is to describe the process needed to design and implement OT methodology for improvement collaboratives. Examples from a multicenter collaborative to reduce central line-associated bloodstream infections highlight the practical application of this approach. The key components for implementation of OT are the following: (1) define current practice and evidence, (2) develop a factorial matrix and calculate power, (3) formulate structure for engagement, (4) analyze results, and (5) replicate findings. PMID- 26483567 TI - Bariatric Surgery and Decreasing Vascular Risk. PMID- 26483568 TI - The Neutrophil-Lymphocyte Ratio and Behcet Disease. PMID- 26483569 TI - Efficacy of Drug-Eluting Balloons for Patients With In-Stent Restenosis: A Meta Analysis of 8 Randomized Controlled Trials. AB - The optimal treatment for in-stent restenosis (ISR) of both bare-metal stent (BMS) and drug-eluting stent (DES) is currently unclear. The aim of this meta analysis was to assess the role of drug-eluting balloon (DEB) as an optional treatment for ISR. We searched PubMed, MEDLINE, EMBASE, BIOS, and Web of Science from 2005 to July 2014. Eight studies, enrolling 1413 patients were included. Main end points were late lumen loss (LLL), binary in-segment restenosis (BR), major adverse cardiac events (MACEs), target lesion revascularization (TLR), death, myocardial infarction (MI), and stent thrombosis (ST). When compared to plain old balloon angioplasty (POBA), DEB treatment significantly reduced the risk of MACE (risk rato [RR] 0.37, P < .01), death (RR 0.44, P = .04), TLR (RR 0.27, P < .01), BR (RR [95% CI]: 0.23[0.12 to 0.43], P < .01) and associated with better outcomes of LLL ( 0.50 [ 0.65 to 0.35] mm, P < .01). However, the differences were not significant between DEB treatment and DES treatment in all primary and secondary end points. The DEB was a better option to treat ISR when compared to POBA. However, it had similar effects as DES. PMID- 26483570 TI - Delay in Revascularization and Prognosis After Myocardial Infarction. PMID- 26483571 TI - Relationship Between Pain and CEAP C Categories of Chronic Venous Disease. AB - In this study, we investigated whether the occurrence and intensity of leg pain are related to C class of the clinical, etiological, anatomical, and pathophysiological (CEAP) classification for chronic venous disease (CVeD). This cross-sectional study, conducted in Serbia, included 2841 patients: 2027 (71.3%) women and 814 (28.7%) men with CVeD diagnosed by general practitioners. For the first time, the Numeric Rating Scale of 0 to 5 units was used to assess the intensity of pain. For the analysis, univariate and multivariate logistic and linear regressions were applied. Pain in the legs was reported by 90.5% of the patients. The occurrence of pain significantly (P < .001) increased with increasing C class. Of the patients who reported pain in the legs, 42.0% had moderate pain, 23.7% had moderate to severe pain, 22.8% had light pain, 11.2% had severe pain, and 0.3% had very severe pain. Severity of pain differed significantly (P < .001) according to C class. Light and moderate pain gradually decreased and severe pain gradually increased from C0 to C6 class. These associations remained significant after adjustment for age, body mass index, and family history of CVeD. PMID- 26483573 TI - Skeptical of medical science reports? PMID- 26483572 TI - Comparison of Long-Term Outcomes in Real-World Patients Between Resolute Zotarilumus-Eluting and Paclitaxel-Eluting Stents in Small Vessel. AB - OBJECTIVE: To compare the long-term clinical outcomes between Resolute zotarolimus-eluting stent (R-ZES) and paclitaxel-eluting stent (PES) in patients with small coronary artery disease. BACKGROUND: Patients with a small vessel diameter are independently associated with increased risk of adverse cardiac events after drug-eluting stent implantation. METHODS: A cohort of 265 patients treated with R-ZES (185 patients with 211 lesions) or PES (80 patients with 100 lesions) in small vessel (<=2.5 mm) lesions were retrospectively analyzed. The primary end point of the study was the composite of major adverse cardiac events. The secondary end points included target lesion revascularization (TLR), target vessel revascularization (TVR), and stent thrombosis at 3 years. RESULTS: The baseline characteristics were similar between the 2 groups. In the R-ZES group, the mean stent diameter was smaller and the total stent length per lesion was longer. Major adverse cardiac events occurred in 8 (10%) patients who had received PES and in 7 (3.8%) patients who had received R-ZES (P = .07). The rates of 3-year TLR (2.2% vs 2.5%; P = 1.00) and TVR (5.4% vs 10.0%; P = .17) showed no statistically significant difference between the R-ZES and PES groups. The rate of stent thrombosis was 0.5% in the R-ZES group and 2.5% in the PES group (P = .21). CONCLUSION: The rates of major adverse cardiac events and cardiac death were similar in the R-ZES-treated group compared with the PES-treated group. PMID- 26483574 TI - An ethicist's commentary on global food shortage and animal feed. PMID- 26483575 TI - Abnormal changes in both mandibular salivary glands in a dog: Non-mineral radiopaque sialoliths. AB - A 10-year-old Maltese dog was presented with a firm mass on the left side of his neck. Physical examination confirmed a firm mass in the left and a submandibular swelling in the right cervical region. Sialolithiasis and associated sialocele in both mandibular salivary glands were suspected and bilateral sialoadenectomy was performed. The stones were identified as non-mineral sialoliths. PMID- 26483576 TI - Failure to thrive and life-threatening complications due to inherited selective cobalamin malabsorption effectively managed in a juvenile Australian shepherd dog. AB - A juvenile Australian shepherd dog exhibited failure to grow, inappetence, weakness, nonregenerative anemia, neutropenia, and cobalamin deficiency. DNA testing confirmed homozygosity of an amnionless mutation (AMN c.3G > A). Clinical signs resolved with supportive care and parenteral cobalamin supplementation. Inherited selective intestinal cobalamin malabsorption requiring lifelong parenteral supplementation should be considered in Australian shepherds, giant schnauzers, border collies, and beagles that fail to thrive. PMID- 26483577 TI - Arrhythmogenic right ventricular cardiomyopathy in a weimaraner. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) was diagnosed postmortem in a weimaraner dog. Syncope, ventricular arrhythmias, and sudden death in this patient combined with the histopathological fatty tissue infiltration affecting the right ventricular myocardium are consistent with previous reports of ARVC in non-boxer dogs. Arrhythmogenic right ventricular cardiomyopathy has not been previously reported in weimaraners. PMID- 26483578 TI - Presentation, treatment, and outcome of squamous cell carcinoma in the perineal region of 9 goats. AB - Nine goats were treated for squamous cell carcinoma (SCC) of the perineal and/or tail region. This case series is the first detailed description of clinical presentation and treatment of caprine SCC in North America and characterizes the potential risk factors and outcomes. PMID- 26483579 TI - Acute pancreatitis following granulosa cell tumor removal in a mare. AB - Acute pancreatitis is a rare disease in horses and is often associated with gastrointestinal disorders. Accurate diagnosis is challenging due to the presence of nonspecific clinical signs. This case represents the first documentation of acute pancreatitis in a horse following surgery of the reproductive tract. PMID- 26483580 TI - Gastric malpositioning and chronic, intermittent vomiting following prophylactic gastropexy in a 20-month-old great Dane dog. AB - A 20-month-old castrated male great Dane dog was presented for evaluation of chronic intermittent vomiting of 2 months' duration. A prophylactic incisional gastropexy performed at 6 mo of age resulted in gastric malpositioning and subsequent partial gastric outflow tract obstruction. PMID- 26483581 TI - Retrospective analysis of survey data relating to the employment conditions of Canadian veterinary graduates for the years 2008 to 2013. AB - Six years of survey data generated from the "Annual New Graduate Survey" were collated and analyzed for trends. Canadian veterinary colleges graduated 14.9% more veterinarians in 2013 than 2008; 79.3% of graduates were female and this percentage was similar across all colleges (P = 0.51). The average base salary for new graduates remained constant at ~$69 000/annum for the years 2011 to 2013. However, the mean base salary of those employed in western Canada and Ontario was higher than that of employees in Quebec and the Maritimes (P < 0.001). There were no differences in the base salaries paid to males and females (P = 0.18) nor in what small animal, food animal, and equine practices were paying new graduates (P = 0.94). The 3 most common employee benefits were: a continuing education allowance, paid licensing fees, and paid malpractice insurance premiums. PMID- 26483582 TI - Retrospective comparison of abdominal ultrasonography and radiography in the investigation of feline abdominal disease. AB - Abdominal radiography and ultrasonography are commonly used as part of the initial diagnostic plan for cats with nonspecific signs of abdominal disease. This retrospective study compared the clinical usefulness of abdominal radiography and ultrasonography in 105 feline patients with signs of abdominal disease. The final diagnosis was determined more commonly with ultrasonography (59%) compared to radiography (25.7%). Ultrasonography was also able to provide additional clinically relevant information in 76% of cases, and changed or refined the diagnosis in 47% of cases. Based on these findings, ultrasonography may be sufficient as an initial diagnostic test for the investigation of feline abdominal disease. PMID- 26483583 TI - Effects of administration of a synthetic low molecular weight/low molar substitution hydroxyethyl starch solution in healthy neonatal foals. AB - This study compared the effects of IV administration of isotonic fluid therapy and colloidal fluid therapy in healthy neonatal foals. Fifteen healthy neonatal foals were used in a randomized blinded prospective clinical study. Foals were randomly assigned to receive a bolus of 20 mL/kg of tetrastarch (TES) or balanced crystalloid solution. Vital parameters, colloid osmotic pressure (COP), and various clinicopathologic variables were assessed prior to infusion and at various time points up to 120 h after infusion. The treatment group (TES) had a significant increase in both COP and percentage increase in COP at 1 and 3 h. The COP was significantly lower than baseline at 3 h in the control group. No significant changes were observed in coagulation parameters in either group. Tetrastarch was effective in increasing COP for 3 h after infusion and had no notable adverse clinical effects in this group of healthy foals. Further studies are warranted regarding optimal dosing and effects in clinically ill foals. PMID- 26483585 TI - Prevalence of methicillin-resistant staphylococci in canine pyoderma cases in primary care veterinary practices in Canada: A preliminary study. AB - Pyoderma in dogs is most commonly caused by Staphylococcus spp., and significant emergence of methicillin resistance in staphylococcal pyoderma has been reported. This preliminary study of the prevalence of methicillin resistance in canine pyoderma cases in Canadian primary care veterinary practices revealed that methicillin-resistant Staphylococcus spp. were present in 12.1% of 149 staphylococcal positive skin culture cases. PMID- 26483586 TI - Comparison between the 2013-2014 and 2009-2012 annual porcine reproductive and respiratory syndrome virus epidemics in a cohort of sow herds in the United States. AB - The purpose of this study was to describe the 2013/2014 porcine reproductive and respiratory syndrome virus (PRRSV) epidemic in the United States and compare it with the previous 4 y of data from 2009 to 2012. A total of 371 herds participated in the study, representing nearly 1.2 million sows in 15 States. There were significantly fewer PRRSV cases during this study period and the onset of the annual epidemic was delayed approximately 3 wk. Cluster analysis revealed a pattern similar to previous years. The roles of spurious observations, increased awareness of PRRSV epidemics, and porcine epidemic diarrhea virus detection in the United States swine herd are considered. PMID- 26483584 TI - Acute BVDV-2 infection in beef calves delays humoral responses to a non infectious antigen challenge. AB - Immunosuppressive effects of an intranasal challenge with non-cytopathic bovine viral diarrhea virus (BVDV) 2a (strain 1373) were assessed through acquired and innate immune system responses to ovalbumin (OVA). Concurrent BVDV infection was hypothesized to delay and reduce the humoral response to ovalbumin (administered on days 3 and 15 post-inoculation). Infected animals followed the expected clinical course. BVDV titers, and anti-BVDV antibodies confirmed the course of infection and were not affected by the administration of OVA. Both the T-helper (CD4(+)) and B-cell (CD20(+)) compartments were significantly (P < 0.05) reduced in infected animals, while the gamma-delta T-cell population (Workshop cluster 1+, WC1(+)) decreased slightly in numbers. Infection with BVDV delayed the increase in OVA IgG by approximately 3 d from day 12 through day 21 post inoculation. Between days 25 and 37 post-inoculation following BVDV infection the IgM concentration in the BVDV- group decreased while the OVA IgM titer still was rising in the BVDV+ animals. Thus, active BVDV infection delays IgM and IgG responses to a novel, non-infectious antigen. PMID- 26483587 TI - Suspected adverse reactions to vaccination in Canadian dogs and cats. PMID- 26483588 TI - Canada: Distribution of Streptococcus suis (from 2012 to 2014) and Actinobacillus pleuropneumoniae (from 2011 to 2014) serotypes isolated from diseased pigs. PMID- 26483589 TI - Accidental communication. PMID- 26483590 TI - Those Responsible for Approving Research Studies Have Poor Knowledge of Research Study Design: a Knowledge Assessment of Institutional Review Board Members. AB - BACKGROUND: Institutional Review Board (IRB) members have a duty to protect the integrity of the research process, but little is known about their basic knowledge of clinical research study designs. METHODS: A nationwide sample of IRB members from major US research universities completed a web-based questionnaire consisting of 11 questions focusing on basic knowledge about clinical research study designs. It included questions about randomized controlled trials (RCTs) and other observational research study designs. Potential predictors (age, gender, educational attainment, type of IRB, current IRB membership, years of IRB service, clinical research experience, and self-identification as a scientist) of incorrect answers were evaluated using multivariate logistic regression models. RESULTS: 148 individuals from 36 universities participated. The majority of participants, 68.9% (102/148), were holding a medical or doctoral degree. Overall, only 26.5% (39/148) of participants achieved a perfect score of 11. On the six-question subset addressing RCTs, 46.6% (69/148) had a perfect score. Most individual questions, and the summary model of overall quiz score (perfect vs. not perfect), revealed no significant predictors - indicating that knowledge deficits were not limited to specific subgroups of IRB members. For the RCT knowledge score there was one significant predictor: compared with MDs, IRB members without a doctoral degree were three times as likely to answer at least one RCT question incorrectly (Odds Ratio: 3.00, 95% CI 1.10-8.20). However, even among MD IRB members, 34.1% (14/41) did not achieve a perfect score on the six RCT questions. CONCLUSIONS: This first nationwide study of IRB member knowledge about clinical research study designs found significant knowledge deficits. Knowledge deficits were not limited to laypersons or community advocate members of IRBs, as previously suggested. Akin to widespread ethical training requirements for clinical researchers, IRB members should undergo systematic training on clinical research designs. PMID- 26483591 TI - Family Medicine Education with Virtual Patients: a Qualitative Study. AB - OBJECTIVES: Virtual patients (VP) have been present within the medical education process for some time. Although they are assumed to be of great benefit for student learning, very little is know about student perception and outcomes of learning, especially during the pre-clerkship years. Therefore we have decided to investigate the use of VPs during lectures, which has never been analyzed before, but could present an opportunity for more effective and holistic learning. METHODS: This was a qualitative study among the 4th year undergraduate medical students at the Medical Faculty, University of Maribor, Slovenia. Students, after completing 4 virtual patient cases during the semester, were asked to participate in focus groups. Using these focus groups we asked students to provide information about their perceptions of VP cases, their learning, and suggestions for educational improvements. Data was transcribed and analyzed using the grounded theory-based coding method (open coding). RESULTS: Medical students reported having a positive attitude towards virtual patient learning. They perceived them as helpful for filling in knowledge gaps, learning appropriate patient care and clinical reasoning. However, especially within the setting of early clinical learning, students felt the need to discuss their questions with their tutors in order to achieve better learning outcomes. CONCLUSION: Students on teaching courses feel the need for structured instructor sessions and the integration of VPs in the course planning in order to maximize their learning outcomes. PMID- 26483592 TI - Scientific Production of Medical Universities in the West of Iran: a Scientometric Analysis. AB - INTRODUCTION: This study aimed to compare scientific production by providing quantitative evaluation of science output in five Western Iranian Medical Universities including Hamedan, Ilam, Kermanshah, Kurdistan and Lorestan University of Medical Sciences using scientometrics indicators based on data indexed in Scopus for period between the years 2010 to 2014. METHODS: In this scientometric study data were collected using Scopus database. Both searching and analyzing features of Scopus were used to data retrieval and analysis. We used Scientometrics indicators including number of publications, number of citations, nationalization index (NI), Internationalization Index (INI), H-index, average number of citations per paper, and growth index. RESULTS: Five Western Iranian Universities produced over 3011 articles from 2010 to 2014. These articles were cited 7158 times with an average rate of 4.2 citations per article. H- Index of under study universities are varying from 14 to 30. Ilam University of Medical Sciences had the highest international collaboration with an INI of 0.33 compared to Hamedan and Kermanshah universities with INI of 0.20 and 0.16 respectively. The lowest international collaboration belonged to Lorestan University of Medical Sciences (0.07). The highest Growth Index belonged to Kurdistan University of Medical Sciences (69.7). CONCLUSION: Although scientific production of five Western Iranian Medical Universities was increasing, but this trend was not stable. To achieve better performance it is recommended that five Western Iranian Universities stabilize their budgeting and investment policies in research. PMID- 26483593 TI - A Map for Clinical Laboratories Management Indicators in the Intelligent Dashboard. AB - INTRODUCTION: management challenges of clinical laboratories are more complicated for educational hospital clinical laboratories. Managers can use tools of business intelligence (BI), such as information dashboards that provide the possibility of intelligent decision-making and problem solving about increasing income, reducing spending, utilization management and even improving quality. Critical phase of dashboard design is setting indicators and modeling causal relations between them. The paper describes the process of creating a map for laboratory dashboard. METHODS: the study is one part of an action research that begins from 2012 by innovation initiative for implementing laboratory intelligent dashboard. Laboratories management problems were determined in educational hospitals by the brainstorming sessions. Then, with regard to the problems key performance indicators (KPIs) specified. RESULTS: the map of indicators designed in form of three layered. They have a causal relationship so that issues measured in the subsequent layers affect issues measured in the prime layers. CONCLUSION: the proposed indicator map can be the base of performance monitoring. However, these indicators can be modified to improve during iterations of dashboard designing process. PMID- 26483594 TI - The Webometric Status of Isfahan University of Medical Sciences, Iran. AB - BACKGROUND: Webometrics refers to the quantitative study of science production, application, structure and technology in the cyber environment. Impact analysis, website collaboration, and recognition of core websites are regarded as the most practical advantages of webometrics. Furthermore, webometrics is applied in ranking studies for universities and academic institutes. This serves as an internationally approved means of academic ranking worldwide. Our study aimed to evaluate the webometric status of Isfahan University of Medical Sciences (IUMS) and its place in the Webometric Ranking of World Universities. We also tried to comment on how to improve the university's webometric rank at national, regional, and international levels. MATERIAL AND METHODS: This was a descriptive cross sectional study including all websites of Iranian universities. Census sampling was applied to cover all Iranian university websites. Then the websites were evaluated according to the latest criteria for the international webometric ranking methodology (Cyberometric Lab, July 2012) and their webometric rank at the international level as well as the changes in the rank between July 2012 and January 2013 were analyzed. The webometric rank of IUMS was compared with other medical universities at different levels as well. FINDINGS: According to the findings, from July 2012 to January 2013, IUMS webometric rank improved by 707, 5 and 2 at international, national and ministerial levels, respectively. Moreover, the rank of IUMS for openness rose from 4477 to 193 during the mentioned period (? 4284). In excellence, the university rank did not change sensibly (1537 /1538). In the same period, the rank in presence shifted from 1137 to 1091. Meanwhile, growth in website impact was negative as the university impact rank declined from 3369 to 3393. CONCLUSION: It seems that impact as the most influential ranking indicator fails to grow proportionately as other factors of IUMS website. This is potentially due to the content language (Farsi) which is an important barrier to easy retrieval of information by non-Farsi speakers. However, the scientific content and SEO (Search Engine Optimization) standards of the website need serious improvement. PMID- 26483595 TI - Developing an Intelligent System for Diagnosis of Asthma Based on Artificial Neural Network. AB - INTRODUCTION: Lack of proper diagnosis and inadequate treatment of asthma, leads to physical and financial complications. This study aimed to use data mining techniques and creating a neural network intelligent system for diagnosis of asthma. METHODS: The study population is the patients who had visited one of the Lung Clinics in Tehran. Data were analyzed using the SPSS statistical tool and the chi-square Pearson's coefficient was the basis of decision making for data ranking. The considered neural network is trained using back propagation learning technique. RESULTS: According to the analysis performed by means of SPSS to select the top factors, 13 effective factors were selected, in different performances, data was mixed in various forms, so the different modes was made for training the data and testing networks and in all different modes, the network was able to predict correctly 100% of all cases. CONCLUSION: Using data mining methods before the design structure of system, aimed to reduce the data dimension and the optimum choice of the data, will lead to a more accurate system. So considering the data mining approaches due to the nature of medical data is necessary. PMID- 26483596 TI - Electronic Health Record for Intensive Care based on Usual Windows Based Software. AB - BACKGROUND AND OBJECTIVES: In Intensive Care Units, the amount of data to be processed for patients care, the turn over of the patients, the necessity for reliability and for review processes indicate the use of Patient Data Management Systems (PDMS) and electronic health records (EHR). To respond to the needs of an Intensive Care Unit and not to be locked with proprietary software, we developed an EHR based on usual software and components. METHODS: The software was designed as a client-server architecture running on the Windows operating system and powered by the access data base system. The client software was developed using Visual Basic interface library. The application offers to the users the following functions: medical notes captures, observations and treatments, nursing charts with administration of medications, scoring systems for classification, and possibilities to encode medical activities for billing processes. RESULTS: Since his deployment in September 2004, the EHR was used to care more than five thousands patients with the expected software reliability and facilitated data management and review processes. Communications with other medical software were not developed from the start, and are realized by the use of basic functionalities communication engine. Further upgrade of the system will include multi-platform support, use of typed language with static analysis, and configurable interface. CONCLUSION: The developed system based on usual software components was able to respond to the medical needs of the local ICU environment. The use of Windows for development allowed us to customize the software to the preexisting organization and contributed to the acceptability of the whole system. PMID- 26483597 TI - Regulation by Phloroglucinol of Nrf2/Maf-Mediated Expression of Antioxidant Enzymes and Inhibition of Osteoclastogenesis via the RANKL/RANK Signaling Pathway: In Silico study. AB - INTRODUCTION: Phloroglucinol is an antioxidant compound with many positive effects on health. The purpose of this study was to determine the role of phloroglucinol in osteoclastogenesis via the RANKL/RANK signaling pathway and the activity of the transcription factor Nrf2. MATERIAL AND METHODS: Analysis was performed in silico using the primary method of docking by the use of Hex 8.0 software and Haddock web server. Analysis of interactions was then performed to determine interactions between the ligand and its receptors by using the software LigPlus and LigandScout 3.1. RESULTS: Results indicated that phloroglucinol compound was thought to inhibit osteoclastogenesis via three mechanisms: inhibiting RANKL-RANK interaction, sustaining the RANKL-OPG bond, and increasing the activity of the transcription factor Nrf2. PMID- 26483598 TI - Inhibition on JAK-STAT3 Signaling Transduction Cascade Is Taken by Bioactive Peptide Alpha-S2 Casein Protein from Goat Ethawah Breed Milk. AB - BACKGROUND: RA is a systemic inflammatory disease that causes developing comorbidity conditions. This condition can cause by overproduction of pro inflammatory cytokine. In a previous study, we have found bioactive peptide CSN1S2 from Ethawah goat milk for anti-inflammatory for repair the ileum destruction. However, the signaling transduction cascade of bioactive peptides inhibits inflammation still not clear yet. Therefore, we analyzed the signaling transduction cascade via JAK-STAT3 pathway by in vivo and in silico. METHODS: The ileum was isolated DNA and amplification with specific primer. The sequence was analyzed using the Sanger sequencing method. Modeling 3D-structure was predicted by SWISS-MODEL and virtual interaction was analyzed by docking system using Pymol and Discovery Studio 4.0 software. RESULTS: This study showed that STAT3 has target gene 480bp. The normal group and normal treating- CSN1S2 of goat milk have similarity from gene bank. Whereas, RA group had transversion mutation that the purine change into pyrimidine even cause frameshift mutation. Interestingly, after treating with the CSN1S2 protein of goat milk shows reverse to the normal acid sequence group. Based on in silico study, from eight peptides, only three peptides of CSN1S2 protein, which carried by PePT1 to enter the small intestine. The fragments are PepT1-41-NMAIHPR-47; PepT1-182-KISQYYQK-189 and PepT1-214 TNAIPYVR-221. We have found just one bioactive peptide of f182-KISQYYQK-189 is able bind to STAT3. The energy binding of f182-KISQYYQK-189 and RA-STAT3 amino acid, it was Sigma = -402.43 kJ/mol and the energy binding of f182-KISQYYQK-189 and RAS-STAT3 amino acid is decreasing into Sigma = -407.09 kJ/mol. CONCLUSION: This study suggested that the fragment 182-KISQYYQK-189 peptides from Ethawah goat milk may act as an anti-inflammatory agent via JAK-STAT3 signal transduction cascade at the cellular level. PMID- 26483599 TI - Hemodialysis Adequacy Monitoring Information System: Minimum Data Set and Capabilities Required. AB - INTRODUCTION: In dialysis centers both nephrologists and nurses are faced with the challenge of ensuring reliable and efficient care accordance with the clinical guideline. Hemodialysis adequacy monitoring information system therefore enable the automation of tasks, which ultimately allows doctors and nursing staff more time to dedicate to the individual treatment of patients. Development of the information systems in healthcare has made the use of the Minimum data set inevitable. The purpose of this study was determined MDS and capabilities required in hemodialysis adequacy monitoring information system. METHOD AND MATERIALS: This is a cross-sectional survey conducted with participation of 320 nephrology specialists in 2015. Data were collected using an electronic questionnaire which was estimated as both reliable and valid. The data were analyzed by SPSS software descriptive statistics and analytical statistics. RESULTS: Overall 42 data elements were determined as final set in 4 major categories (patient demographics, medical history, treatment plan and hemodialysis adequacy). The most capabilities required of hemodialysis information system were related to calculate of dialysis adequacy Index (4.80), advice optimal dose of dialysis for each patient (4.63), Easy access to information system without restrictions of time and place (4.61), providing alerts when dialysis adequacy index below the standard (4.55) and Interchange to other information systems in hospitals (4.46) respectively. CONCLUSION: In design and implementation of information systems focus on MDS and identification IS capabilities based on the users' needs, due to the wide participation users and also the success of the information system. Therefore it is necessary that MDS evaluated carefully with regard to the intended uses of the data. Also information systems based on capabilities the ability to meet the needs of their users. PMID- 26483600 TI - Suggested Minimum Data Set for Speech Therapy Centers Affiliated to Tabriz University of Medical Sciences. AB - BACKGROUND: The minimum data considered as a conceptual framework, based on the achievement of effectiveness indicators and it ensures to access of precise and clear health data. The aims of the present study were identified and proposed a data element set of speech therapy centers affiliated with Tabriz University of Medical Sciences. MATERIAL AND METHODS: This study that was cross - sectional type, performed in 9 speech therapy clinic from medical university in 2014. Firstly, the minimum data elements set evaluated using the check list in these centers. Using the findings from the first step and survey of internal and external documentation forms, designed a questionnaire containing a minimum data speech therapy files and it shared between 36 Speech therapy experts using 5 options of Likert scale. Validity of questionnaire was examined through its validity and reliability of content by retest. For data analysis, data processing was performed using descriptive statistics by SPSS21 software. RESULTS: The minimum data set for speech therapy were divided into two categories: clinical and administrative data. The Name and surname, date of birth, gender, address, telephone number, date of admission and the number of treatments, the patient's complaint, the time of occurrence of injury or disorder, reason and age of disease considered as the most important elements for management data and health history. For the most important elements of clinical information were selected Short-term and long-term aims and development of speech history. CONCLUSION: The design and implementation of suitable data collection of speech therapy for gathering of data, we recommended planning for the control and prevention of speech disorders to providing high quality and good care of patient in speech therapy centers. PMID- 26483601 TI - MRI Findings of Talocalcaneal Coalition: Two Case Reports. AB - INTRODUCTION: Tarsal coalition is abnormal fusion of two or more tarsal bones and is a common cause of foot pain. There are osseous, cartilaginous and fibrous subtypes. Calcaneonavicular and talocalcaneal coalitions are more frequent. Radiography is the primary diagnostic tool, however CT and MRI are precious examinations for differential diagnosis of osseous /non-osseous coalitions separations. Furthermore, cross-sectional imaging methods indicate the extension and secondary degenerative joint changes. CASE REPORTS: The detection of bone marrow of edema in the articulation area is valuable for diagnosis Hereby, we present two cases, 24 years old female and 35 years old male, with the diagnosis of talocalcaneal coaliation. We also discuss MRI and radiographic findings. PMID- 26483602 TI - The Most Influential Scientists in the Development of the Medical Informatics (7): Shigekoto Kaihara. PMID- 26483603 TI - International Joint Meeting EuroMISE 2015 Prague, Czech Republic, June 16-18, 2015. PMID- 26483604 TI - 13th International Conference on Informatics, Management and Technology in Healthcare, Athens, Greece, 9-11 July, 2015. PMID- 26483607 TI - Organophosphate Hydrolase in Conductometric Biosensor for the Detection of Organophosphate Pesticides. AB - The research has developed an enzyme biosensor for the detection organophosphate pesticide residues. The biosensor consists of a pair of screen-printed carbon electrode (SPCEs). One of electrodes contains immobilized organophosphate hydrolase (OPH) on a chitosan membrane by cross-linking it with glutaraldehyde. The area of the electrodes was optimized to 3, 5, and 7 mm(2). The OPH was isolated from Pseudomonas putida, and was purified by the ammonium sulfate precipitation method, with 6444 ppm (A) and 7865 ppm (B). The organophosphate pesticide samples were 0-100 ppb in tris-acetate buffer 0.05 M, pH 8.5. The results showed that the best performance of the biosensor was achieved by the enzyme A with an electrode area of 5 mm(2). The sensitivity of the biosensor was between 3 and 32 uS/ppb, and the detection limit for the organophosphate pesticides was 40 ppb (diazinon), 30 ppb (malathion), 20 ppb (chlorpyrifos), and 40 ppm (profenofos). PMID- 26483605 TI - Apoptosis, Necrosis, and Necroptosis in the Gut and Intestinal Homeostasis. AB - Intestinal epithelial cells (IECs) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is critical for electrolyte passage, nutrient absorption, and interaction with commensal microbiota. Moreover, IECs are strongly involved in the intestinal mucosal inflammatory response as well as in mucosal innate and adaptive immune responses. Cell death in the intestinal barrier is finely controlled, since alterations may lead to severe disorders, including inflammatory diseases. The emerging picture indicates that intestinal epithelial cell death is strictly related to the maintenance of tissue homeostasis. This review is focused on previous reports on different forms of cell death in intestinal epithelium. PMID- 26483606 TI - More than a Decade of Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors: What We Have Learned and What the Future Holds. AB - The use of tyrosine kinase inhibitors (TKIs) in the treatment of solid tumors is the expected standard of care for many types of tumors. Since the description of signal transduction pathways, followed by the development of small molecules designed to inhibit those pathways, there has been significant improvement not only in progression-free survival and overall survival but also in aiming toward chemotherapy-free treatment of solid tumors to maximize quality of life. This article reviews available TKIs and discusses toxicity, dosing, and resistance. PMID- 26483608 TI - The Interface Between Iron Metabolism and Gene-Based Iron Contrast for MRI. AB - Using a gene-based approach to track cellular and molecular activity with magnetic resonance imaging (MRI) has many advantages. The strong correlation between transverse relaxation rates and total cellular iron content provides a basis for developing sensitive and quantitative detection of MRI reporter gene expression. In addition to biophysical concepts, general features of mammalian iron regulation add valuable context for interpreting molecular MRI predicated on gene-based iron labeling. With particular reference to the potential of magnetotactic bacterial gene expression as a magnetic resonance (MR) contrast agent for mammalian cell tracking, studies in different cell culture models highlight the influence of intrinsic iron regulation on the MRI signal. The interplay between dynamic regulation of mammalian iron metabolism and expression systems designed to sequester iron biominerals for MRI is presented from the perspective of their potential influence on MR image interpretation. PMID- 26483611 TI - What was Glaucoma Called Before the 20th Century? AB - Glaucoma involves a characteristic optic neuropathy, often with elevated intraocular pressure. Before 1850, poor vision with a normal eye appearance, as occurs in primary open-angle glaucoma, was termed amaurosis, gutta serena, or black cataract. Few observers noted palpable hardness of the eye in amaurosis. On the other hand, angle-closure glaucoma can produce a green or gray pupil, and therefore was called, variously, glaucoma (derived from the Greek for glaucous, a nonspecific term connoting blue, green, or light gray) and viriditate oculi. Angle closure, with palpable hardness of the eye, mydriasis, and anterior prominence of the lens, was described in greater detail in the 18th and 19th centuries. The introduction of the ophthalmoscope in 1850 permitted the visualization of the excavated optic neuropathy in eyes with a normal or with a dilated greenish-gray pupil. Physicians developed a better appreciation of the role of intraocular pressure in both conditions, which became subsumed under the rubric "glaucoma". PMID- 26483609 TI - Iron Oxide as an MRI Contrast Agent for Cell Tracking. AB - Iron oxide contrast agents have been combined with magnetic resonance imaging for cell tracking. In this review, we discuss coating properties and provide an overview of ex vivo and in vivo labeling of different cell types, including stem cells, red blood cells, and monocytes/macrophages. Furthermore, we provide examples of applications of cell tracking with iron contrast agents in stroke, multiple sclerosis, cancer, arteriovenous malformations, and aortic and cerebral aneurysms. Attempts at quantifying iron oxide concentrations and other vascular properties are examined. We advise on designing studies using iron contrast agents including methods for validation. PMID- 26483612 TI - Ameloblastoma: A Review of Recent Molecular Pathogenetic Discoveries. AB - Ameloblastoma is an odontogenic neoplasm whose molecular pathogenesis has only recently been elucidated. The discovery of recurrent activating mutations in FGFR2, BRAF, and RAS in a large majority of ameloblastomas has implicated dysregulation of MAPK pathway signaling as a critical step in the pathogenesis of this tumor. Some degree of controversy exists regarding the role of mutations affecting the sonic hedgehog (SHH) pathway, specifically Smoothened (SMO), which have been postulated to serve as either an alternative pathogenetic mechanism or secondary mutations. Here, we review recent advances in our understanding of the molecular pathogenesis of ameloblastoma as well as the diagnostic, prognostic, and therapeutic implications of these discoveries. PMID- 26483610 TI - Current State of Animal (Mouse) Modeling in Melanoma Research. AB - Despite the considerable progress in understanding the biology of human cancer and technological advancement in drug discovery, treatment failure remains an inevitable outcome for most cancer patients with advanced diseases, including melanoma. Despite FDA-approved BRAF-targeted therapies for advanced stage melanoma showed a great deal of promise, development of rapid resistance limits the success. Hence, the overall success rate of melanoma therapy still remains to be one of the worst compared to other malignancies. Advancement of next generation sequencing technology allowed better identification of alterations that trigger melanoma development. As development of successful therapies strongly depends on clinically relevant preclinical models, together with the new findings, more advanced melanoma models have been generated. In this article, besides traditional mouse models of melanoma, we will discuss recent ones, such as patient-derived tumor xenografts, topically inducible BRAF mouse model and RCAS/TVA-based model, and their advantages as well as limitations. Although mouse models of melanoma are often criticized as poor predictors of whether an experimental drug would be an effective treatment, development of new and more relevant models could circumvent this problem in the near future. PMID- 26483613 TI - Disseminated Mycobacterium Simiae with Pelvic Malakoplakia in an AIDS Patient. AB - Malakoplakia in an acquired immunodeficiency syndrome (AIDS) patient with disseminated Mycobacterium simiae infection presented with a large pelvic mass that caused organ dysfunction from mimicking a tumor. Malakoplakia is a rare, chronic granulomatous abnormal host response toward infectious agents, presenting as a tumor-like lesion. This is the first report of pelvic malakoplakia after disseminated M. simiae infection in an AIDS patient. PMID- 26483614 TI - Beta-Adrenergic Blockade Therapy for Autonomic Dysfunction is Less Effective for Elderly Patients with Heart Failure and Reduced Left Ventricular Ejection Fraction. AB - OBJECTIVE: Heart rate variability (HRV) has been reported to be an independent predictor of all-cause and sudden cardiac death in patients with heart failure. In the aging heart, however, both autonomic and cardiac functions appear to be altered. We assessed the relationship between aging and responsiveness of HRV and ventricular remodeling to beta-adrenergic blockade therapy in patients with heart failure and reduced ejection fraction (HFREF). METHODS: Twenty-eight clinically stable patients with chronic heart failure, sinus rhythm, and left ventricular ejection fraction <50% as confirmed by echocardiography were included. At baseline and after carvedilol treatment, 24-hour ambulatory Holter monitor recording was used to analyze HRV indices by the maximum entropy method. Changes in these parameters were compared among three age groups. RESULTS: HR decreased in all groups after carvedilol treatment, but was still highest in the youngest group despite the same treatment doses. Time and frequency domain variables improved. The response of time domain variables (the standard deviation of all normal sinus to normal sinus [NN] intervals and the standard deviation of the averages of NN intervals in all 5-minute or 30-minute segments) to carvedilol therapy significantly decreased with increasing age. Ventricular reverse remodeling induced by carvedilol therapy significantly decreased with increasing age. Increases in time domain variables and a low-frequency domain moderately correlated with left ventricular reverse remodeling. CONCLUSION: Beta-adrenergic blockade therapy improved HRV variables and ventricular remodeling in HFREF patients; however, the response tended to be milder in the elderly. HRV improvement was associated with ventricular reverse remodeling. PMID- 26483615 TI - Biochemical Characterisation of Phage Pseudomurein Endoisopeptidases PeiW and PeiP Using Synthetic Peptides. AB - Pseudomurein endoisopeptidases cause lysis of the cell walls of methanogens by cleaving the isopeptide bond Ala-epsilon-Lys in the peptide chain of pseudomurein. PeiW and PeiP are two thermostable pseudomurein endoisopeptidases encoded by phage PsiM100 of Methanothermobacter wolfei and phages PsiM1 and PsiM2 of Methanothermobacter marburgensis, respectively. A continuous assay using synthetic peptide substrates was developed and used in the biochemical characterisation of recombinant PeiW and PeiP. The advantages of these synthetic peptide substrates over natural substrates are sensitivity, high purity, and characterisation and the fact that they are more easily obtained than natural substrates. In the presence of a reducing agent, purified PeiW and PeiP each showed similar activity under aerobic and anaerobic conditions. Both enzymes required a divalent metal for activity and showed greater thermostability in the presence of Ca(2+). PeiW and PeiP involve a cysteine residue in catalysis and have a monomeric native conformation. The kinetic parameters, K(M) and k(cat), were determined, and the epsilon-isopeptide bond between alanine and lysine was confirmed as the bond lysed by these enzymes in pseudomurein. The new assay may have wider applications for the general study of peptidases and the identification of specific methanogens susceptible to lysis by specific pseudomurein endoisopeptidases. PMID- 26483616 TI - Peritonitis following Endoscopy in a Patient on Peritoneal Dialysis with a Discussion of Current Recommendations on Antibiotic Prophylaxis. AB - Patients on peritoneal dialysis (PD) are at increased risk for peritonitis. We report a case of a patient with end-stage renal disease on continuous ambulatory PD (CAPD) who developed peritonitis within 24 h of upper endoscopy with biopsy and colonoscopy with polypectomy. He had a previous history of peritonitis unrelated to invasive procedures and eventually was transitioned to hemodialysis because of his recurrent peritonitis. The International Society for Peritoneal Dialysis (ISPD) and newly revised American Society for Gastrointestinal Endoscopy (ASGE) guidelines recommend prophylactic antibiotics for CAPD patients undergoing endoscopic procedures. Other guidelines do not address this issue, and there has been limited evidence to support recommendations. PMID- 26483617 TI - A New Etiology for the Abdominal Compartment Syndrome: Pseudomyxoma Peritonei. AB - Pseudomyxoma peritonei (PMP) is a rare diagnosis with an incidence of 1-2 per million. Most cases originate from an appendix which ruptures and releases mucin into the peritoneal cavity. The progression of the disease results in obstruction and cutaneous leak. Abdominal compartment syndrome is an uncommon complication of peritoneal pseudomyxoma. In the present article, we report the case of a patient with PMP and abdominal compartment syndrome. A laparotomy to decrease the abdominal pressure was performed. Three months later, a peritonectomy with hyperthermic intraperitoneal chemotherapy was performed. The patient was still alive 1 year after the procedure without any recurrence. In conclusion, acute abdominal pain and respiratory failure in patients with peritoneal PMP should lead to the measurement of the abdominal pressure but are not a contra indication for curative treatment of PMP. PMID- 26483619 TI - Mitochondria-controlled signaling mechanisms of brain protection in hypoxia. AB - The article is focused on the role of the cell bioenergetic apparatus, mitochondria, involved in development of immediate and delayed molecular mechanisms for adaptation to hypoxic stress in brain cortex. Hypoxia induces reprogramming of respiratory chain function and switching from oxidation of NAD related substrates (complex I) to succinate oxidation (complex II). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of immediate adaptation to hypoxia necessary for (1) succinate-related energy synthesis in the conditions of oxygen deficiency and formation of urgent resistance in the body; (2) succinate-related stabilization of HIF-1alpha and initiation of its transcriptional activity related with formation of long-term adaptation; (3) succinate-related activation of the succinate-specific receptor, GPR91. This mechanism participates in at least four critical regulatory functions: (1) sensor function related with changes in kinetic properties of complex I and complex II in response to a gradual decrease in ambient oxygen concentration; this function is designed for selection of the most efficient pathway for energy substrate oxidation in hypoxia; (2) compensatory function focused on formation of immediate adaptive responses to hypoxia and hypoxic resistance of the body; (3) transcriptional function focused on activated synthesis of HIF-1 and the genes providing long-term adaptation to low pO2; (4) receptor function, which reflects participation of mitochondria in the intercellular signaling system via the succinate-dependent receptor, GPR91. In all cases, the desired result is achieved by activation of the succinate dependent oxidation pathway, which allows considering succinate as a signaling molecule. Patterns of mitochondria-controlled activation of GPR-91- and HIF-1 dependent reaction were considered, and a possibility of their participation in cellular-intercellular-systemic interactions in hypoxia and adaptation was proved. PMID- 26483620 TI - Reward processing and drug addiction: does sex matter? PMID- 26483618 TI - Characterizing autism spectrum disorders by key biochemical pathways. AB - The genetic and phenotypic heterogeneity of autism spectrum disorders (ASD) presents a substantial challenge for diagnosis, classification, research, and treatment. Investigations into the underlying molecular etiology of ASD have often yielded mixed and at times opposing findings. Defining the molecular and biochemical underpinnings of heterogeneity in ASD is crucial to our understanding of the pathophysiological development of the disorder, and has the potential to assist in diagnosis and the rational design of clinical trials. In this review, we propose that genetically diverse forms of ASD may be usefully parsed into entities resulting from converse patterns of growth regulation at the molecular level, which lead to the correlates of general synaptic and neural overgrowth or undergrowth. Abnormal brain growth during development is a characteristic feature that has been observed both in children with autism and in mouse models of autism. We review evidence from syndromic and non-syndromic ASD to suggest that entities currently classified as autism may fundamentally differ by underlying pro- or anti-growth abnormalities in key biochemical pathways, giving rise to either excessive or reduced synaptic connectivity in affected brain regions. We posit that this classification strategy has the potential not only to aid research efforts, but also to ultimately facilitate early diagnosis and direct appropriate therapeutic interventions. PMID- 26483622 TI - Evolving perceptual biases for antisynchrony: a form of temporal coordination beyond synchrony. PMID- 26483621 TI - Development of social skills in children: neural and behavioral evidence for the elaboration of cognitive models. AB - Social skills refer to a wide group of abilities that allow us to interact and communicate with others. Children learn how to solve social situations by predicting and understanding other's behaviors. The way in which humans learn to interact successfully with others encompasses a complex interaction between neural, behavioral, and environmental elements. These have a role in the accomplishment of positive developmental outcomes, including peer acceptance, academic achievement, and mental health. All these social abilities depend on widespread brain networks that are recently being studied by neuroscience. In this paper, we will first review the studies on this topic, aiming to clarify the behavioral and neural mechanisms related to the acquisition of social skills during infancy and their appearance in time. Second, we will briefly describe how developmental diseases like Autism Spectrum Disorders (ASD) can inform about the neurobiological mechanisms of social skills. We finally sketch a general framework for the elaboration of cognitive models in order to facilitate the comprehension of human social development. PMID- 26483623 TI - Effects of age on electrophysiological correlates of speech processing in a dynamic "cocktail-party" situation. AB - Successful speech perception in multi-speaker environments depends on auditory scene analysis, comprising auditory object segregation and grouping, and on focusing attention toward the speaker of interest. Changes in speaker settings (e.g., in speaker position) require object re-selection and attention re focusing. Here, we tested the processing of changes in a realistic multi-speaker scenario in younger and older adults, employing a speech-perception task, and event-related potential (ERP) measures. Sequences of short words (combinations of company names and values) were simultaneously presented via four loudspeakers at different locations, and the participants responded to the value of a target company. Voice and position of the speaker of the target information were kept constant for a variable number of trials and then changed. Relative to the pre change level, changes caused higher error rates, and more so in older than younger adults. The ERP analysis revealed stronger fronto-central N2 and N400 components in younger adults, suggesting a more effective inhibition of concurrent speech stimuli and enhanced language processing. The difference ERPs (post-change minus pre-change) indicated a change-related N400 and late positive complex (LPC) over parietal areas in both groups. Only the older adults showed an additional frontal LPC, suggesting increased allocation of attentional resources after changes in speaker settings. In sum, changes in speaker settings are critical events for speech perception in multi-speaker environments. Especially older persons show deficits that could be based on less flexible inhibitory control and increased distraction. PMID- 26483624 TI - The entorhinal cortex is involved in conditioned odor and context aversions. AB - In a natural environment, avoidance of a particular food source is mostly determined by a previous intake experience during which sensory stimuli such as food odor, become aversive through a simple associative conditioned learning. Conditioned odor aversion learning (COA) is a food conditioning paradigm that results from the association between a tasteless scented solution (conditioned stimulus, CS) and a gastric malaise (unconditioned stimulus, US) that followed its ingestion. In the present experimental conditions, acquisition of COA also led to acquisition of aversion toward the context in which the CS was presented (conditioned context aversion, CCA). Previous data have shown that the entorhinal cortex (EC) is involved in the memory processes underlying COA acquisition and context fear conditioning, but whether EC lesion modulates CCA acquisition has never be investigated. To this aim, male Long-Evans rats with bilateral EC lesion received CS-US pairings in a particular context with different interstimulus intervals (ISI). The results showed that the establishment of COA with long ISI obtained in EC-lesioned rats is associated with altered CCA learning. Since ISI has been suggested to be the determining factor in the odor- and context-US association, our results show that the EC is involved in the processes that control both associations relative to ISI duration. PMID- 26483625 TI - The past and the future of Alzheimer's disease CSF biomarkers-a journey toward validated biochemical tests covering the whole spectrum of molecular events. AB - This paper gives a short review on cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD), from early developments to high-precision validated assays on fully automated lab analyzers. We also discuss developments on novel biomarkers, such as synaptic proteins and Abeta oligomers. Our vision for the future is that assaying a set of biomarkers in a single CSF tube can monitor the whole spectrum of AD molecular pathogenic events. CSF biomarkers will have a central position not only for clinical diagnosis, but also for the understanding of the sequence of molecular events in the pathogenic process underlying AD and as tools to monitor the effects of novel drug candidates targeting these different mechanisms. PMID- 26483627 TI - Classifying multiple types of hand motions using electrocorticography during intraoperative awake craniotomy and seizure monitoring processes-case studies. AB - In this work, some case studies were conducted to classify several kinds of hand motions from electrocorticography (ECoG) signals during intraoperative awake craniotomy & extraoperative seizure monitoring processes. Four subjects (P1, P2 with intractable epilepsy during seizure monitoring and P3, P4 with brain tumor during awake craniotomy) participated in the experiments. Subjects performed three types of hand motions (Grasp, Thumb-finger motion and Index-finger motion) contralateral to the motor cortex covered with ECoG electrodes. Two methods were used for signal processing. Method I: autoregressive (AR) model with burg method was applied to extract features, and additional waveform length (WL) feature has been considered, finally the linear discriminative analysis (LDA) was used as the classifier. Method II: stationary subspace analysis (SSA) was applied for data preprocessing, and the common spatial pattern (CSP) was used for feature extraction before LDA decoding process. Applying method I, the three-class accuracy of P1~P4 were 90.17, 96.00, 91.77, and 92.95% respectively. For method II, the three-class accuracy of P1~P4 were 72.00, 93.17, 95.22, and 90.36% respectively. This study verified the possibility of decoding multiple hand motion types during an awake craniotomy, which is the first step toward dexterous neuroprosthetic control during surgical implantation, in order to verify the optimal placement of electrodes. The accuracy during awake craniotomy was comparable to results during seizure monitoring. This study also indicated that ECoG was a promising approach for precise identification of eloquent cortex during awake craniotomy, and might form a promising BCI system that could benefit both patients and neurosurgeons. PMID- 26483626 TI - Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity. AB - Long-term potentiation (LTP) of synaptic transmission is recognized as a cellular mechanism for learning and memory storage. Although de novo gene transcription is known to be required in the formation of stable LTP, the molecular mechanisms underlying synaptic plasticity remain elusive. Noncoding RNAs have emerged as major regulatory molecules that are abundantly and specifically expressed in the mammalian brain. By combining RNA-seq analysis with LTP induction in the dentate gyrus of live rats, we provide the first global transcriptomic analysis of synaptic plasticity in the adult brain. Expression profiles of mRNAs and long noncoding RNAs (lncRNAs) were obtained at 30 min, 2 and 5 h after high-frequency stimulation of the perforant pathway. The temporal analysis revealed dynamic expression profiles of lncRNAs with many positively, and highly, correlated to protein-coding genes with known roles in synaptic plasticity, suggesting their possible involvement in LTP. In light of observations suggesting a role for retrotransposons in brain function, we examined the expression of various classes of repeat elements. Our analysis identifies dynamic regulation of LINE1 and SINE retrotransposons, and extensive regulation of tRNA. These experiments reveal a hitherto unknown complexity of gene expression in long-term synaptic plasticity involving the dynamic regulation of lncRNAs and repeat elements. These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity in both the healthy brain and in neurodegenerative and neuropsychiatric disorders. PMID- 26483628 TI - Musical neurofeedback for treating depression in elderly people. AB - We introduce a new neurofeedback approach, which allows users to manipulate expressive parameters in music performances using their emotional state, and we present the results of a pilot clinical experiment applying the approach to alleviate depression in elderly people. Ten adults (9 female and 1 male, mean = 84, SD = 5.8) with normal hearing participated in the neurofeedback study consisting of 10 sessions (2 sessions per week) of 15 min each. EEG data was acquired using the Emotiv EPOC EEG device. In all sessions, subjects were asked to sit in a comfortable chair facing two loudspeakers, to close their eyes, and to avoid moving during the experiment. Participants listened to music pieces preselected according to their music preferences, and were encouraged to increase the loudness and tempo of the pieces, based on their arousal and valence levels. The neurofeedback system was tuned so that increased arousal, computed as beta to alpha activity ratio in the frontal cortex corresponded to increased loudness, and increased valence, computed as relative frontal alpha activity in the right lobe compared to the left lobe, corresponded to increased tempo. Pre and post evaluation of six participants was performed using the BDI depression test, showing an average improvement of 17.2% (1.3) in their BDI scores at the end of the study. In addition, an analysis of the collected EEG data of the participants showed a significant decrease of relative alpha activity in their left frontal lobe (p = 0.00008), which may be interpreted as an improvement of their depression condition. PMID- 26483629 TI - Implementation of a spike-based perceptron learning rule using TiO2-x memristors. AB - Synaptic plasticity plays a crucial role in allowing neural networks to learn and adapt to various input environments. Neuromorphic systems need to implement plastic synapses to obtain basic "cognitive" capabilities such as learning. One promising and scalable approach for implementing neuromorphic synapses is to use nano-scale memristors as synaptic elements. In this paper we propose a hybrid CMOS-memristor system comprising CMOS neurons interconnected through TiO2-x memristors, and spike-based learning circuits that modulate the conductance of the memristive synapse elements according to a spike-based Perceptron plasticity rule. We highlight a number of advantages for using this spike-based plasticity rule as compared to other forms of spike timing dependent plasticity (STDP) rules. We provide experimental proof-of-concept results with two silicon neurons connected through a memristive synapse that show how the CMOS plasticity circuits can induce stable changes in memristor conductances, giving rise to increased synaptic strength after a potentiation episode and to decreased strength after a depression episode. PMID- 26483632 TI - Extracellular environment contribution to astrogliosis-lessons learned from a tissue engineered 3D model of the glial scar. AB - Glial scars are widely seen as a (bio)mechanical barrier to central nervous system regeneration. Due to the lack of a screening platform, which could allow in-vitro testing of several variables simultaneously, up to now no comprehensive study has addressed and clarified how different lesion microenvironment properties affect astrogliosis. Using astrocytes cultured in alginate gels and meningeal fibroblast conditioned medium, we have built a simple and reproducible 3D culture system of astrogliosis mimicking many features of the glial scar. Cells in this 3D culture model behave similarly to scar astrocytes, showing changes in gene expression (e.g., GFAP) and increased extra-cellular matrix production (chondroitin 4 sulfate and collagen), inhibiting neuronal outgrowth. This behavior being influenced by the hydrogel network properties. Astrocytic reactivity was found to be dependent on RhoA activity, and targeting RhoA using shRNA-mediated lentivirus reduced astrocytic reactivity. Further, we have shown that chemical inhibition of RhoA with ibuprofen or indirectly targeting RhoA by the induction of extracellular matrix composition modification with chondroitinase ABC, can diminish astrogliosis. Besides presenting the extracellular matrix as a key modulator of astrogliosis, this simple, controlled and reproducible 3D culture system constitutes a good scar-like system and offers great potential in future neurodegenerative mechanism studies, as well as in drug screenings envisaging the development of new therapeutic approaches to minimize the effects of the glial scar in the context of central nervous system disease. PMID- 26483631 TI - Neo-synthesis of estrogenic or androgenic neurosteroids determine whether long term potentiation or depression is induced in hippocampus of male rat. AB - Estrogenic and androgenic steroids synthesized in the brain may rapidly modulate synaptic plasticity interacting with specific membrane receptors. We explored by electrophysiological recordings in hippocampal slices of male rat the influence of 17beta-estradiol (E2) and 5alpha-dihydrotestosterone (DHT) neo-synthesis on the synaptic changes induced in the CA1 region. Induction of long-term depression (LTD) and depotentiation (DP) by low frequency stimulation (LFS, 15 min-1 Hz) and of long-term potentiation (LTP) by high frequency stimulation (HFS, 1 s-100 Hz), medium (MFS, 1 s-50 Hz), or weak (WFS, 1 s-25 Hz) frequency stimulation was assayed under inhibitors of enzymes converting testosterone (T) into DHT (5alpha reductase) and T into E2 (P450-aromatase). We found that LFS-LTD depends on DHT synthesis, since it was fully prevented under finasteride, an inhibitor of DHT synthesis, and rescued by exogenous DHT, while the E2 synthesis was not involved. Conversely, the full development of HFS-LTP requires the synthesis of E2, as demonstrated by the LTP reduction observed under letrozole, an inhibitor of E2 synthesis, and its full rescue by exogenous E2. For intermediate stimulation protocols DHT, but not E2 synthesis, was involved in the production of a small LTP induced by WFS, while the E2 synthesis was required for the MFS-dependent LTP. Under the combined block of DHT and E2 synthesis all stimulation frequencies induced partial LTP. Overall, these results indicate that DHT is required for converting the partial LTP into LTD whereas E2 is needed for the full expression of LTP, evidencing a key role of the neo-synthesis of sex neurosteroids in determining the direction of synaptic long-term effects. PMID- 26483630 TI - Associating schizophrenia, long non-coding RNAs and neurostructural dynamics. AB - Several lines of evidence indicate that schizophrenia has a strong genetic component. But the exact nature and functional role of this genetic component in the pathophysiology of this mental illness remains a mystery. Long non-coding RNAs (lncRNAs) are a recently discovered family of molecules that regulate gene transcription through a variety of means. Consequently, lncRNAs could help us bring together apparent unrelated findings in schizophrenia; namely, genomic deficiencies on one side and neuroimaging, as well as postmortem results on the other. In fact, the most consistent finding in schizophrenia is decreased brain size together with enlarged ventricles. This anomaly appears to originate from shorter and less ramified dendrites and axons. But a decrease in neuronal arborizations cannot explain the complex pathophysiology of this psychotic disorder; however, dynamic changes in neuronal structure present throughout life could. It is well recognized that the structure of developing neurons is extremely plastic. This structural plasticity was thought to stop with brain development. However, breakthrough discoveries have shown that neuronal structure retains some degree of plasticity throughout life. What the neuroscientific field is still trying to understand is how these dynamic changes are regulated and lncRNAs represent promising candidates to fill this knowledge gap. Here, we present evidence that associates specific lncRNAs with schizophrenia. We then discuss the potential role of lncRNAs in neurostructural dynamics. Finally, we explain how dynamic neurostructural modifications present throughout life could, in theory, reconcile apparent unrelated findings in schizophrenia. PMID- 26483633 TI - Pharmacological activation of CB2 receptors counteracts the deleterious effect of ethanol on cell proliferation in the main neurogenic zones of the adult rat brain. AB - Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations. Cannabinoid receptor agonists promote adult neural progenitor cell (NPC) proliferation. We evaluated the protective effects of the selective CB1 receptor agonist ACEA, the selective CB2 receptor agonist JWH133 and the fatty-acid amide hydrolase (FAAH) inhibitor URB597, which enhances endocannabinoid receptor activity, on NPC proliferation in rats with forced consumption of ethanol (10%) or sucrose liquid diets for 2 weeks. We performed immunohistochemical and stereological analyses of cells expressing the mitotic phosphorylation of histone 3 (phospho-H3+) and the replicating cell DNA marker 5-bromo-2'-deoxyuridine (BrdU+) in the main neurogenic zones of adult brain: subgranular zone of dentate gyrus (SGZ), subventricular zone of lateral ventricles (SVZ) and hypothalamus. Animals were allowed ad libitum ethanol intake (7.3 +/- 1.1 g/kg/day) after a controlled isocaloric pair-feeding period of sucrose and alcoholic diets. Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus. The treatments (URB597, ACEA, JWH133) exerted a differential increase in alcohol consumption over time, but JWH133 specifically counteracted the deleterious effect of ethanol on NPC proliferation in the SVZ and SGZ, and ACEA reversed this effect in the SGZ only. JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific beta3-tubulin in the SVZ and SGZ. These results indicated that the specific activation of CB2 receptors rescued alcohol-induced impaired NPC proliferation, which is a potential clinical interest for the risk of neural damage in alcohol dependence. PMID- 26483634 TI - Editorial: Homeostatic and retrograde signaling mechanisms modulating presynaptic function and plasticity. PMID- 26483635 TI - Regulation of cytoskeletal dynamics by redox signaling and oxidative stress: implications for neuronal development and trafficking. AB - A proper balance between chemical reduction and oxidation (known as redox balance) is essential for normal cellular physiology. Deregulation in the production of oxidative species leads to DNA damage, lipid peroxidation and aberrant post-translational modification of proteins, which in most cases induces injury, cell death and disease. However, physiological concentrations of oxidative species are necessary to support important cell functions, such as chemotaxis, hormone synthesis, immune response, cytoskeletal remodeling, Ca(2+) homeostasis and others. Recent evidence suggests that redox balance regulates actin and microtubule dynamics in both physiological and pathological contexts. Microtubules and actin microfilaments contain certain amino acid residues that are susceptible to oxidation, which reduces the ability of microtubules to polymerize and causes severing of actin microfilaments in neuronal and non neuronal cells. In contrast, inhibited production of reactive oxygen species (ROS; e.g., due to NOXs) leads to aberrant actin polymerization, decreases neurite outgrowth and affects the normal development and polarization of neurons. In this review, we summarize emerging evidence suggesting that both general and specific enzymatic sources of redox species exert diverse effects on cytoskeletal dynamics. Considering the intimate relationship between cytoskeletal dynamics and trafficking, we also discuss the potential effects of redox balance on intracellular transport via regulation of the components of the microtubule and actin cytoskeleton as well as cytoskeleton-associated proteins, which may directly impact localization of proteins and vesicles across the soma, dendrites and axon of neurons. PMID- 26483636 TI - BACE1 activity impairs neuronal glucose oxidation: rescue by beta-hydroxybutyrate and lipoic acid. AB - Glucose hypometabolism and impaired mitochondrial function in neurons have been suggested to play early and perhaps causative roles in Alzheimer's disease (AD) pathogenesis. Activity of the aspartic acid protease, beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), responsible for beta amyloid peptide generation, has recently been demonstrated to modify glucose metabolism. We therefore examined, using a human neuroblastoma (SH-SY5Y) cell line, whether increased BACE1 activity is responsible for a reduction in cellular glucose metabolism. Overexpression of active BACE1, but not a protease-dead mutant BACE1, protein in SH-SY5Y cells reduced glucose oxidation and the basal oxygen consumption rate, which was associated with a compensatory increase in glycolysis. Increased BACE1 activity had no effect on the mitochondrial electron transfer process but was found to diminish substrate delivery to the mitochondria by inhibition of key mitochondrial decarboxylation reaction enzymes. This BACE1 activity-dependent deficit in glucose oxidation was alleviated by the presence of beta hydroxybutyrate or alpha-lipoic acid. Consequently our data indicate that raised cellular BACE1 activity drives reduced glucose oxidation in a human neuronal cell line through impairments in the activity of specific tricarboxylic acid cycle enzymes. Because this bioenergetic deficit is recoverable by neutraceutical compounds we suggest that such agents, perhaps in conjunction with BACE1 inhibitors, may be an effective therapeutic strategy in the early-stage management or treatment of AD. PMID- 26483637 TI - Meninges harbor cells expressing neural precursor markers during development and adulthood. AB - Brain and skull developments are tightly synchronized, allowing the cranial bones to dynamically adapt to the brain shape. At the brain-skull interface, meninges produce the trophic signals necessary for normal corticogenesis and bone development. Meninges harbor different cell populations, including cells forming the endosteum of the cranial vault. Recently, we and other groups have described the presence in meninges of a cell population endowed with neural differentiation potential in vitro and, after transplantation, in vivo. However, whether meninges may be a niche for neural progenitor cells during embryonic development and in adulthood remains to be determined. In this work we provide the first description of the distribution of neural precursor markers in rat meninges during development up to adulthood. We conclude that meninges share common properties with the classical neural stem cell niche, as they: (i) are a highly proliferating tissue; (ii) host cells expressing neural precursor markers such as nestin, vimentin, Sox2 and doublecortin; and (iii) are enriched in extracellular matrix components (e.g., fractones) known to bind and concentrate growth factors. This study underlines the importance of meninges as a potential niche for endogenous precursor cells during development and in adulthood. PMID- 26483638 TI - Increased phosphorylation of Cx36 gap junctions in the AII amacrine cells of RD retina. AB - Retinal degeneration (RD) encompasses a family of diseases that lead to photoreceptor death and visual impairment. Visual decline due to photoreceptor cell loss is further compromised by emerging spontaneous hyperactivity in inner retinal cells. This aberrant activity acts as a barrier to signals from the remaining photoreceptors, hindering therapeutic strategies to restore light sensitivity in RD. Gap junctions, particularly those expressed in AII amacrine cells, have been shown to be integral to the generation of aberrant activity. It is unclear whether gap junction expression and coupling are altered in RD. To test this, we evaluated the expression and phosphorylation state of connexin36 (Cx36), the gap junction subunit predominantly expressed in AII amacrine cells, in two mouse models of RD, rd10 (slow degeneration) and rd1 (fast degeneration). Using Ser293-P antibody, which recognizes a phosphorylated form of connexin36, we found that phosphorylation of connexin36 in both slow and fast RD models was significantly greater than in wildtype controls. This elevated phosphorylation may underlie the increased gap junction coupling of AII amacrine cells exhibited by RD retina. PMID- 26483639 TI - Editorial: What can simple brains teach us about how vision works. PMID- 26483640 TI - Corticofugal projection patterns of whisker sensorimotor cortex to the sensory trigeminal nuclei. AB - The primary (S1) and secondary (S2) somatosensory cortices project to several trigeminal sensory nuclei. One putative function of these corticofugal projections is the gating of sensory transmission through the trigeminal principal nucleus (Pr5), and some have proposed that S1 and S2 project differentially to the spinal trigeminal subnuclei, which have inhibitory circuits that could inhibit or disinhibit the output projections of Pr5. Very little, however, is known about the origin of sensorimotor corticofugal projections and their patterns of termination in the various trigeminal nuclei. We addressed this issue by injecting anterograde tracers in S1, S2 and primary motor (M1) cortices, and quantitatively characterizing the distribution of labeled terminals within the entire rostro-caudal chain of trigeminal sub-nuclei. We confirmed our anterograde tracing results by injecting retrograde tracers at various rostro caudal levels within the trigeminal sensory nuclei to determine the position of retrogradely labeled cortical cells with respect to S1 barrel cortex. Our results demonstrate that S1 and S2 projections terminate in largely overlapping regions but show some significant differences. Whereas S1 projection terminals tend to cluster within the principal trigeminal (Pr5), caudal spinal trigeminal interpolaris (Sp5ic), and the dorsal spinal trigeminal caudalis (Sp5c), S2 projection terminals are distributed in a continuum across all trigeminal nuclei. Contrary to the view that sensory gating could be mediated by differential activation of inhibitory interconnections between the spinal trigeminal subnuclei, we observed that projections from S1 and S2 are largely overlapping in these subnuclei despite the differences noted earlier. PMID- 26483642 TI - Fear learning through the two visual systems, a commentary on: "A parvalbumin positive excitatory visual pathway to trigger fear responses in mice". PMID- 26483641 TI - Frequency-specific adaptation and its underlying circuit model in the auditory midbrain. AB - Receptive fields of sensory neurons are considered to be dynamic and depend on the stimulus history. In the auditory system, evidence of dynamic frequency receptive fields has been found following stimulus-specific adaptation (SSA). However, the underlying mechanism and circuitry of SSA have not been fully elucidated. Here, we studied how frequency-receptive fields of neurons in rat inferior colliculus (IC) changed when exposed to a biased tone sequence. Pure tone with one specific frequency (adaptor) was presented markedly more often than others. The adapted tuning was compared with the original tuning measured with an unbiased sequence. We found inhomogeneous changes in frequency tuning in IC, exhibiting a center-surround pattern with respect to the neuron's best frequency. Central adaptors elicited strong suppressive and repulsive changes while flank adaptors induced facilitative and attractive changes. Moreover, we proposed a two layer model of the underlying network, which not only reproduced the adaptive changes in the receptive fields but also predicted novelty responses to oddball sequences. These results suggest that frequency-specific adaptation in auditory midbrain can be accounted for by an adapted frequency channel and its lateral spreading of adaptation, which shed light on the organization of the underlying circuitry. PMID- 26483643 TI - Corrigendum: Morphological evidence for dopamine interactions with pallidal neurons in primates. AB - [This corrects the article on p. 111 in vol. 9, PMID: 26321923.]. PMID- 26483644 TI - Cajal and the Conceptual Weakness of Neural Sciences. AB - The experimental and conceptual contributions of Santiago Ramon y Cajal remain almost as fresh and valuable as when his original proposals were published more than a century ago-a rare example, contrasting with other related sciences. His basic concepts on the neuron as the main building block of the central nervous system, the dynamic polarization principle as a way to understand how neurons deal with ongoing active processes, and brain local structural arrangements as a result of the functional specialization of selected neural circuits are concepts still surviving in present research papers dealing with brain function during the performance of cognitive and/or behavioral activities. What is more, the central dogma of the Neuroscience of today, i.e., brain plasticity as the morpho functional substrate of memory and learning processes, was already proposed and documented with notable insights by Ramon y Cajal. From this background, I will try to discuss in this chapter which new functional and structural concepts have been introduced in contemporary Neuroscience and how we will be able to construct a set of basic principles underlying brain functions for the twenty-first century. PMID- 26483646 TI - Mechanical neuroscience: Emil du Bois-Reymond's innovations in theory and practice. PMID- 26483645 TI - fMRI investigation of response inhibition, emotion, impulsivity, and clinical high-risk behavior in adolescents. AB - High-risk behavior in adolescents is associated with injury, mental health problems, and poor outcomes in later life. Improved understanding of the neurobiology of high-risk behavior and impulsivity shows promise for informing clinical treatment and prevention as well as policy to better address high-risk behavior. We recruited 21 adolescents (age 14-17) with a wide range of high-risk behavior tendencies, including medically high-risk participants recruited from psychiatric clinics. Risk tendencies were assessed using the Adolescent Risk Behavior Screen (ARBS). ARBS risk scores correlated highly (0.78) with impulsivity scores from the Barratt Impulsivity scale (BIS). Participants underwent 4.7 Tesla functional magnetic resonance imaging (fMRI) while performing an emotional Go/NoGo task. This task presented an aversive or neutral distractor image simultaneously with each Go or NoGo stimulus. Risk behavior and impulsivity tendencies exhibited similar but not identical associations with fMRI activation patterns in prefrontal brain regions. We interpret these results as reflecting differences in response inhibition, emotional stimulus processing, and emotion regulation in relation to participant risk behavior tendencies and impulsivity levels. The results are consistent with high impulsivity playing an important role in determining high risk tendencies in this sample containing clinically high-risk adolescents. PMID- 26483648 TI - Erratum: Optimal feedback control successfully explains changes in neural modulations during experiments with brain-machine interfaces. AB - [This corrects the article on p. 71 in vol. 9, PMID: 26042002.]. PMID- 26483647 TI - Corticofugal modulation of peripheral auditory responses. AB - The auditory efferent system originates in the auditory cortex and projects to the medial geniculate body (MGB), inferior colliculus (IC), cochlear nucleus (CN) and superior olivary complex (SOC) reaching the cochlea through olivocochlear (OC) fibers. This unique neuronal network is organized in several afferent efferent feedback loops including: the (i) colliculo-thalamic-cortico-collicular; (ii) cortico-(collicular)-OC; and (iii) cortico-(collicular)-CN pathways. Recent experiments demonstrate that blocking ongoing auditory-cortex activity with pharmacological and physical methods modulates the amplitude of cochlear potentials. In addition, auditory-cortex microstimulation independently modulates cochlear sensitivity and the strength of the OC reflex. In this mini-review, anatomical and physiological evidence supporting the presence of a functional efferent network from the auditory cortex to the cochlear receptor is presented. Special emphasis is given to the corticofugal effects on initial auditory processing, that is, on CN, auditory nerve and cochlear responses. A working model of three parallel pathways from the auditory cortex to the cochlea and auditory nerve is proposed. PMID- 26483649 TI - Behavioral correlates of the decision process in a dynamic environment: post choice latencies reflect relative value and choice evaluation. AB - One characteristic of natural environments is that outcomes vary across time. Animals need to adapt to these environmental changes and adjust their choices accordingly. In this experiment, we investigated the sensitivity with which rats could detect, and adapt to, multiple changes in the environment. Rats chose between two spouts which delivered 5% sucrose rewards with distinct probabilities. Across three phases, reward probabilities changed in size (large or small) and direction (increase or decrease). A discrete trial-structure was used, which allowed the choice process to be decomposed into three distinct response latency measures (choice execution latency, spout sampling duration, and trial-initiation latency). We found that a large decrease in reward probabilities rapidly produced the greatest change in choice proportions. The time taken to execute a choice reflected the differences in reward probabilities across the two spouts in some cases, but also reflected training history. By contrast, the amount of time rats spent responding at reward spouts in anticipation of reward consistently reflected the relative likelihood of reward across the two spouts and not the absolute probability of reward. The latency to initiate the subsequent trial reflected choice evaluation. These three response latencies thus indexed key behavioral correlates of the choice process as it unfolds in time. We discuss how this paradigm can be used to assess the corresponding neural correlates of decision-making. PMID- 26483651 TI - Marvels of illusion: illusion and perception in the art of Salvador Dali. AB - The surrealist movement aimed to blur the distinction between the real and the imagined. Such lack of a border between demonstrable truth and fantasy is perhaps most apparent in the art of Spanish painter Salvador Dali (1904-1989). Dali included numerous illusions in his artworks, with the intent to challenge the viewers' perceptions of reality and to enable them to see beyond the surface. The "Marvels of Illusion" exhibit, shown at The Dali Museum in St. Petersburg, FL., from June 14 to October 12, 2014, showcased Dali paintings, prints and sculptures centered on illusory themes. Here, we review the significance of illusions in Dali's art, focusing on the pieces displayed at the "Marvels of Illusion" exhibit. PMID- 26483650 TI - Event-related brain potential correlates of prospective memory in symptomatically remitted male patients with schizophrenia. AB - Prospective memory (PM) refers to the ability to remember to perform intended actions in the future. Although PM deficits are a prominent impairment in schizophrenia, little is still known about the nature of PM in symptomatically remitted patients with schizophrenia. To address this issue, event-related brain potentials (ERPs) were recorded from 20 symptomatically remitted patients with schizophrenia and 20 healthy controls during an event-based PM paradigm. Behavioral results showed that symptomatically remitted patients with schizophrenia performed poorly on the PM task compared with healthy controls. On the neural level, the N300, a component of the ERPs related to PM cue detection, was reliable across these two groups, suggesting a degree of functional recovery of processes supporting cue detection in patients with symptomatically remitted schizophrenia. By contrast, the amplitude of the prospective positivity, a component of the ERPs related to PM intention retrieval, was significantly attenuated in symptomatically remitted schizophrenia patients relative to healthy controls. Furthermore, a significant positive correlation between the amplitude of the prospective positivity and accuracy on the PM task was found in those patients, indicating that patients' poor performance on this task may result from the failure to recover PM cue-induced intention from memory. These results provide evidence for the existence of altered PM processing in patients with symptomatically remitted schizophrenia, which is characterized by a selective deficit in retrospective component (intention retrieval) of PM. Therefore, these findings shed new light on the neurophysiological processes underlying PM in schizophrenia patients during clinical remission. PMID- 26483652 TI - Dysfunctional putamen modulation during bimanual finger-to-thumb movement in patients with Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder affecting middle-aged and elderly people. PD can be viewed as "circuit disorder," indicating that large scale cortico-subcortical pathways were involved in its pathophysiology. The brain network in an experimental context is emerging as an important biomarker in disease diagnosis and prognosis prediction. This context-dependent network for PD and the underling functional mechanism remains unclear. In this paper, the brain network profiles in 11 PD patients without dementia were studied and compared with 12 healthy controls. The functional magnetic resonance imaging (fMRI) data were acquired when the subjects were performing a pseudorandomized unimanual or bimanual finger-to-thumb movement task. The activation was detected and the network profiles were analyzed by psychophysiological interaction (PPI) toolbox. For the controls and PD patients, the motor areas including the primary motor and premotor areas, supplementary motor area, the cerebellum and parts of the frontal, temporal and parietal gyrus were activated. The right putamen exhibited significant control > PD activation and weaker activity during the bimanual movement relative to the unimanual movement in the control group. The decreased putamen modulation on some nucleus in basal ganglia, such as putamen, thalamus and caudate, and some cortical areas, such as cingulate, parietal, angular, frontal, temporal and occipital gyrus was detected in the bimanual movement condition relative to the unimanual movement condition. Between-group PPI difference was detected in cingulate gyrus, angular gyrus and precuneus (control > PD) and inferior frontal gyrus (PD > control). The deficient putamen activation and its enhanced connectivity with the frontal gyrus could be a correlate of impaired basal ganglia inhibition and frontal gyrus compensation to maintain the task performance during the motor programs of PD patients. PMID- 26483653 TI - Sustained attention and prediction: distinct brain maturation trajectories during adolescence. AB - Adolescence is a key period for frontal cortex maturation necessary for the development of cognitive ability. Sustained attention and prediction are cognitive functions critical for optimizing sensory processing, and essential to efficiently adapt behaviors in an ever-changing world. The aim of the current study was to investigate the brain developmental trajectories of attentive and predictive processing through adolescence. We recorded EEG in 36 participants from the age of 12-24 years (three age groups: 12-14, 14-17, 18-24 years) to target development during early and late adolescence, and early adulthood. We chose a visual target detection task which loaded upon sustained attention, and we manipulated target predictability. Continued maturation of sustained attention after age 12 was evidenced by improved performance (hits, false alarms (FAs) and sensitivity) in a detection task, associated with a frontal shift in the scalp topographies of the Contingent Negative Variation (CNV) and P3 responses, with increasing age. No effect of age was observed on predictive processing, with all ages showing similar benefits in reaction time, increases in P3 amplitude (indexing predictive value encoding and memorization), increases in CNV amplitude (corresponding to prediction implementation) and reduction in target-P3 latency (reflecting successful prediction building and use), with increased predictive content. This suggests that adolescents extracted and used predictive information to generate predictions as well as adults. The present results show that predictive and attentive processing follow distinct brain developmental trajectories: prediction abilities seem mature by the age of 12 and sustained attention continues to improve after 12-years of age and is associated with maturational changes in the frontal cortices. PMID- 26483654 TI - Linking unfounded beliefs to genetic dopamine availability. AB - Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter individual variability in the propensity toward unfounded beliefs. One hundred two healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818, and rs4680, also known as val (158) met) that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioral experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity toward unfounded beliefs, and that this effect was statistically mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world. PMID- 26483655 TI - Facial blindsight. AB - Blindsight denotes unconscious residual visual capacities in the context of an inability to consciously recollect or identify visual information. It has been described for color and shape discrimination, movement or facial emotion recognition. The present study investigates a patient suffering from cortical blindness whilst maintaining select residual abilities in face detection. Our patient presented the capacity to distinguish between jumbled/normal faces, known/unknown faces or famous people's categories although he failed to explicitly recognize or describe them. Conversely, performance was at chance level when asked to categorize non-facial stimuli. Our results provide clinical evidence for the notion that some aspects of facial processing can occur without perceptual awareness, possibly using direct tracts from the thalamus to associative visual cortex, bypassing the primary visual cortex. PMID- 26483656 TI - Technique of Stepwise Intracranial Decompression Combined with External Ventricular Drainage Catheters Improves the Prognosis of Acute Post-Traumatic Cerebral Hemispheric Brain Swelling Patients. AB - BACKGROUND: Acute post-traumatic cerebral hemispheric brain swelling (ACHS) is a serious disorder that occurs after traumatic brain injury, and it often requires immediate treatment. The aim of our clinical study was to assess the effects of stepwise intracranial decompression combined with external ventricular drainage (EVD) catheters on the prognosis of ACHS patients. METHODS: A retrospective study was performed on 172 cases of severe craniocerebral trauma patients with ACHS. The patients were divided into two groups: unilateral stepwise standard large trauma craniectomy (S-SLTC) combined with EVD catheter implants (n = 86) and unilateral routine frontal temporal parietal SLTC (control group, n = 86). RESULT: No significant differences in age, sex, or pre-operative Glasgow Coma Scale score were observed between groups (P < 0.05). There were no significant differences in the ipsilateral subdural effusion incidence rates between the S SLTC + EVD treatment group and the routine SLTC group. However, the incidence rates of intraoperative acute encephalocele and contralateral epidural and subdural hematoma in the S-SLTC + EVD group were significantly lower than those in the SLTC group (17.4 and 3.5 vs. 37.2 and 23.3%, respectively). The mean intracranial pressure (ICP) values of patients in the S-SLTC + EVD group were also lower than those in the SLTC group at days 1 through 7 (P < 0.05). A positive neurological outcome [Glasgow Outcome Scale (GOS) score 4-5, 50.0%] and decreased mortality (15.1%) was observed in the S-SLTC + EVD group compared to the neurological outcome (GOS score 4-5, 33.8%; 36.0%) in the SLTC group (P < 0.05). CONCLUSION: Our data suggest that S-SLTC + EVD is more effective for controlling ICP, improving neurological outcome, and decreasing mortality rate compared with routine SLTC. PMID- 26483657 TI - Correlates of Near-Infrared Spectroscopy Brain-Computer Interface Accuracy in a Multi-Class Personalization Framework. AB - Brain-computer interfaces (BCIs) provide individuals with a means of interacting with a computer using only neural activity. To date, the majority of near infrared spectroscopy (NIRS) BCIs have used prescribed tasks to achieve binary control. The goals of this study were to evaluate the possibility of using a personalized approach to establish control of a two-, three-, four-, and five class NIRS-BCI, and to explore how various user characteristics correlate to accuracy. Ten able-bodied participants were recruited for five data collection sessions. Participants performed six mental tasks and a personalized approach was used to select each individual's best discriminating subset of tasks. The average offline cross-validation accuracies achieved were 78, 61, 47, and 37% for the two , three-, four-, and five-class problems, respectively. Most notably, all participants exceeded an accuracy of 70% for the two-class problem, and two participants exceeded an accuracy of 70% for the three-class problem. Additionally, accuracy was found to be strongly positively correlated (Pearson's) with perceived ease of session (rho = 0.653), ease of concentration (rho = 0.634), and enjoyment (rho = 0.550), but strongly negatively correlated with verbal IQ (rho = -0.749). PMID- 26483658 TI - It wasn't me! Motor activation from irrelevant spatial information in the absence of a response. AB - Embodied cognition postulates that perceptual and motor processes serve higher order cognitive faculties like language. A major challenge for embodied cognition concerns the grounding of abstract concepts. Here we zoom in on abstract spatial concepts and ask the question to what extent the sensorimotor system is involved in processing these. Most of the empirical support in favor of an embodied perspective on (abstract) spatial information has derived from so-called compatibility effects in which a task-irrelevant feature either facilitates (for compatible trials) or hinders (in incompatible trials) responding to the task relevant feature. This type of effect has been interpreted in terms of (task irrelevant) feature-induced response activation. The problem with such approach is that incompatible features generate an array of task-relevant and -irrelevant activations [e.g., in primary motor cortex (M1)], and lateral hemispheric interactions render it difficult to assign credit to the task-irrelevant feature per se in driving these activations. Here, we aim to obtain a cleaner indication of response activation on the basis of abstract spatial information. We employed transcranial magnetic stimulation (TMS) to probe response activation of effectors in response to semantic, task-irrelevant stimuli (i.e., the words left and right) that did not require an overt response. Results revealed larger motor evoked potentials (MEPs) for the right (left) index finger when the word right (left) was presented. Our findings provide support for the grounding of abstract spatial concepts in the sensorimotor system. PMID- 26483659 TI - Corrigendum: EEG beta suppression and low gamma modulation are different elements of human upright walking. AB - [This corrects the article on p. 485 in vol. 8, PMID: 25071515.]. PMID- 26483661 TI - Editorial: The safety and efficacy of noninvasive brain stimulation in development and neurodevelopmental disorders. PMID- 26483660 TI - Task-related functional connectivity dynamics in a block-designed visual experiment. AB - Studying task modulations of brain connectivity using functional magnetic resonance imaging (fMRI) is critical to understand brain functions that support cognitive and affective processes. Existing methods such as psychophysiological interaction (PPI) and dynamic causal modeling (DCM) usually implicitly assume that the connectivity patterns are stable over a block-designed task with identical stimuli. However, this assumption lacks empirical verification on high temporal resolution fMRI data with reliable data-driven analysis methods. The present study performed a detailed examination of dynamic changes of functional connectivity (FC) in a simple block-designed visual checkerboard experiment with a sub-second sampling rate (TR = 0.645 s) by estimating time-varying correlation coefficient (TVCC) between BOLD responses of different brain regions. We observed reliable task-related FC changes (i.e., FCs were transiently decreased after task onset and went back to the baseline afterward) among several visual regions of the bilateral middle occipital gyrus (MOG) and the bilateral fusiform gyrus (FuG). Importantly, only the FCs between higher visual regions (MOG) and lower visual regions (FuG) exhibited such dynamic patterns. The results suggested that simply assuming a sustained FC during a task block may be insufficient to capture distinct task-related FC changes. The investigation of FC dynamics in tasks could improve our understanding of condition shifts and the coordination between different activated brain regions. PMID- 26483662 TI - Editorial: Neural implementation of expertise. PMID- 26483663 TI - Corrigendum: The role of action representations in thematic object relations. AB - [This corrects the article on p. 140 in vol. 8, PMID: 24672461.]. PMID- 26483664 TI - Covert preparation of a manual response in a 'go'/'no-go' saccadic task is driven by execution of the eye movement and not by visual stimulus occurrence. AB - It has been recently demonstrated that visually guided saccades are linked to changes in muscle excitability in the relaxed upper limb, which are compatible with a covert motor plan encoding a hand movement toward the gaze target. In this study we investigated whether these excitability changes are time locked to the visual stimulus, as predicted by influential attention models, or are strictly dependent on saccade execution. Single-pulse transcranial magnetic stimulation was applied to the motor cortex at eight different time delays during a 'go'/'no go' task, which involved overt or covert orienting of attention. By analyzing the time course of excitability in three hand muscles, synchronized with the onset of either the attentional cue or the eye movement, we demonstrated that side- and muscle-specific excitability changes were strictly time locked to the saccadic response and were not correlated to the onset of the visual attentive stimulus. Furthermore, muscle excitability changes were absent following a covert shift of attention. We conclude that a sub-threshold manual motor plan is automatically activated by the saccade decision-making process, as part of a covert eye-hand coordination program. We found no evidence for a representation of spatial attention within the upper limb motor map. PMID- 26483665 TI - Low-dimensional attractor for neural activity from local field potentials in optogenetic mice. AB - We used optogenetic mice to investigate possible nonlinear responses of the medial prefrontal cortex (mPFC) local network to light stimuli delivered by a 473 nm laser through a fiber optics. Every 2 s, a brief 10 ms light pulse was applied and the local field potentials (LFPs) were recorded with a 10 kHz sampling rate. The experiment was repeated 100 times and we only retained and analyzed data from six animals that showed stable and repeatable response to optical stimulations. The presence of nonlinearity in our data was checked using the null hypothesis that the data were linearly correlated in the temporal domain, but were random otherwise. For each trail, 100 surrogate data sets were generated and both time reversal asymmetry and false nearest neighbor (FNN) were used as discriminating statistics for the null hypothesis. We found that nonlinearity is present in all LFP data. The first 0.5 s of each 2 s LFP recording were dominated by the transient response of the networks. For each trial, we used the last 1.5 s of steady activity to measure the phase resetting induced by the brief 10 ms light stimulus. After correcting the LFPs for the effect of phase resetting, additional preprocessing was carried out using dendrograms to identify "similar" groups among LFP trials. We found that the steady dynamics of mPFC in response to light stimuli could be reconstructed in a three-dimensional phase space with topologically similar "8"-shaped attractors across different animals. Our results also open the possibility of designing a low-dimensional model for optical stimulation of the mPFC local network. PMID- 26483666 TI - Pycortex: an interactive surface visualizer for fMRI. AB - Surface visualizations of fMRI provide a comprehensive view of cortical activity. However, surface visualizations are difficult to generate and most common visualization techniques rely on unnecessary interpolation which limits the fidelity of the resulting maps. Furthermore, it is difficult to understand the relationship between flattened cortical surfaces and the underlying 3D anatomy using tools available currently. To address these problems we have developed pycortex, a Python toolbox for interactive surface mapping and visualization. Pycortex exploits the power of modern graphics cards to sample volumetric data on a per-pixel basis, allowing dense and accurate mapping of the voxel grid across the surface. Anatomical and functional information can be projected onto the cortical surface. The surface can be inflated and flattened interactively, aiding interpretation of the correspondence between the anatomical surface and the flattened cortical sheet. The output of pycortex can be viewed using WebGL, a technology compatible with modern web browsers. This allows complex fMRI surface maps to be distributed broadly online without requiring installation of complex software. PMID- 26483667 TI - Bilateral Glaucomatous Optic Neuropathy Caused by Eye Rubbing. AB - In this report, we describe a particular condition of a 52-year-old man who showed advanced bilateral glaucomatous-like optic disc damage, even though the intraocular pressure resulted normal during all examinations performed. Visual field test, steady-state pattern electroretinogram, retinal nerve fiber layer and retinal tomographic evaluations were performed to evaluate the optic disc damage. Over a 4-year observational period, his visual acuity decreased to 12/20 in the right eye and counting fingers in the left eye. Visual fields were severely compromised, and intraocular pressure values were not superior to 14 mm Hg during routine examinations. An accurate anamnesis and the suspicion of this disease represent a crucial aspect to establish the correct diagnosis. In fact, our patient strongly rubbed his eyes for more than 10 h per day. Recurrent and continuous eye rubbing can induce progressive optic neuropathy, causing severe visual field damage similar to the pathology of advanced glaucoma. PMID- 26483668 TI - Atypical Bilateral Fuchs Uveitis: Diagnostic Challenges. AB - Bilateral Fuchs uveitis associated with vitreous infiltration and posterior segment involvement requires a thorough diagnostic evaluation. The lack of well defined diagnostic criteria makes identification of this entity difficult. The aim of this case report was to present the characteristics of a patient with atypical Fuchs uveitis and the procedures needed to rule out the differential diagnosis with specific attention to the utility of in vivo confocal microscopy (IVCM). CASE REPORT: One case of chronic bilateral uveitis with severe vitreous opacities is presented. After extensive systemic workup, including vitrectomy, the case had no identifiable systemic etiology. IVCM of the cornea revealed the presence of dendritiform keratic precipitates. CONCLUSION: The diagnosis of Fuchs uveitis is based on clinical findings as no confirmatory laboratory tests are available. A high index of suspicion is key to an early diagnosis, especially in the cases with vitreous opacities and posterior segment manifestations. Auxiliary tests such as IVCM may aid the clinician in the diagnosis of Fuchs uveitis. PMID- 26483669 TI - Ozurdex for the Treatment of a Patient with Birdshot Chorioretinopathy. AB - We report a 57-year-old patient with birdshot chorioretinopathy (BCR) who was treated with bilateral Ozurdex injections. The patient's vitritis resolved, and visual acuity improved following this treatment. This is only the second case report focused on the treatment of BCR with Ozurdex and the first to report its use for treating vitritis. A concise review of the literature on the use of intravitreal steroids for this disease is provided. This case serves to report the clinical usefulness of Ozurdex in treating posterior vitritis associated with BCR even in the absence of macular edema. PMID- 26483670 TI - Ocular Tuberculosis with Progressive Unilateral Corneal Melting. AB - OBJECTIVES: In this case report, we present a patient with ocular tuberculosis presenting with progressive unilateral corneal melting. PATIENT: A 47-year-old female was admitted with melting at the inferior half of the peripheral cornea and inferior subconjunctival nodules. Biopsy material of the nodules was negative for tuberculosis bacillus. However, polymerase chain reaction of the biopsy sample revealed the DNA of the bacillus, and the diagnosis was confirmed. CONCLUSION: In endemic areas, ocular tuberculosis should be kept in mind in the differential diagnosis of patients with chronic and atypical corneal involvement. PMID- 26483671 TI - Bilateral Simultaneous Retinal Detachment in Pseudophakia. AB - Cataract surgery is the most frequent surgical intervention, with approximately 700,000 operations per year in Germany alone. One of the most serious complications is retinal detachment, with a reported incidence rate of pseudophakic retinal detachment of 0.75-1.65%. We report the case of a patient who suffered from a simultaneous bilateral pseudophakic retinal detachment. Interestingly, the bilateral detachments in the left and the right eye started with only some hours' delay. He had no acute trigger for the retinal detachment and no risk factors besides the cataract surgery performed on both eyes some weeks earlier. Simultaneous bilateral retinal detachments will be more common, due to increasing numbers of cataract surgeries and the demographic development. We conclude that funduscopy should be regularly performed in mydriasis to avoid sight-threatening simultaneous bilateral retinal detachments. PMID- 26483672 TI - CD5-Positive Primary Intraocular B-Cell Lymphoma Arising during Methotrexate and Tumor Necrosis Factor Inhibitor Treatment. AB - PURPOSE: To report a case of CD5+ primary intraocular B-cell lymphoma arising during methotrexate (MTX) and tumor necrosis factor (TNF) inhibitor treatment in a young patient with rheumatoid arthritis and uveitis. CASE PRESENTATION: A 39 year-old woman treated with MTX and a TNF inhibitor for rheumatoid arthritis and uveitis had steroid-resistant vitreous opacity. A vitreous sample was obtained by using diagnostic vitrectomy and was categorized as class V based on cytologic examination. Flow cytometric analysis of the vitreous sample revealed that abnormal cells were CD5+, CD10-, CD19+, CD20+ and immunoglobulin light-chain kappa+, suggesting the diagnosis of CD5+ primary intraocular B-cell lymphoma. Polymerase chain reaction (PCR) detected immunoglobulin heavy-chain gene rearrangement. Epstein-Barr virus (EBV) DNA was detected in the vitreous sample by using PCR, and immunohistochemistry revealed EBV latent membrane protein-1 expression in the abnormal cells infiltrating the vitreous. Optic nerve invasion was observed on magnetic resonance imaging. CONCLUSION: Primary intraocular lymphoma (PIOL) may develop in patients receiving MTX and TNF inhibitor treatment. EBV infection may play an important role in the pathogenesis of PIOL arising during immunosuppressive therapy. PMID- 26483673 TI - An Unusual Case of Nasolacrimal Obstruction Caused by Foodstuffs. AB - Here we report a case of nasolacrimal obstruction resulting from rice grains ingested over many years that had formed an obstructive mass. This is a hitherto unreported cause of nasolacrimal obstruction. We exclusively treated the obstruction safely with repeated irrigation with physiological saline. Although there have been various reports on new techniques such as the blind insertion of a bougie and insertion of a silicon tube under endoscopic guidance, successful treatment of this condition is possible with an old-fashioned approach using the time-honored tools of a syringe and an irrigation needle, if utilized patiently and repeatedly. In Japan, we call this 'learning new lessons from the past'. This implies that newer techniques may not necessarily be superior and traditional techniques can offer advantages of safety and simplicity in treating this condition. PMID- 26483674 TI - A Case Report of Vogt's Limbal Girdle and Retinitis Pigmentosa in a Thirteen-Year Old Boy: A Rare and Unusual Association. AB - AIM: To describe a rare case of Vogt's limbal girdle in a boy with retinitis pigmentosa. METHODS: A 13-year-old boy from India presented to us with progressive diminution of vision and nyctalopia for 5 years. On examination, he had the characteristic features of retinitis pigmentosa with the fundus showing disc pallor, bony spicules and arteriolar attenuation. His anterior segment examination showed Vogt's limbal girdle in both eyes. RESULTS: Vogt's limbal girdle is a corneal degeneration usually seen in elderly individuals. This is the first time it is seen in association with retinitis pigmentosa. It has also never been reported at such a young age. CONCLUSION: We report a rare case where Vogt's limbal girdle was observed in a 13-year-old boy with retinitis pigmentosa. This gives further insight into the pathogenesis of the disease. PMID- 26483675 TI - Isolated Optic Disc Tuberculosis. AB - We present a healthy male subject who developed progressive visual loss in the left eye initially diagnosed as optic neuritis. Upon suspicion of infectious etiology, testing was positive for tuberculosis. There were no signs or symptoms of active systemic tuberculosis infection. The patient responded swiftly to antimycobacterial therapy with return of vision and resolution of disc swelling. Positive purified protein derivative skin test, negative chest radiograph, negative systemic workup, negative workup for other causes of unilateral optic neuritis and quick response to mycobacterial therapy reaffirm the entity of isolated optic disc tuberculosis similar to isolated choroidal tuberculosis without systemic manifestation. PMID- 26483676 TI - A 25-Year-Old Man with Exudative Retinal Detachments and Infiltrates without Hematological or Neurological Findings Found to Have Relapsed Precursor T-Cell Acute Lymphoblastic Leukemia. AB - BACKGROUND: Precursor T-cell acute lymphoblastic leukemia (pre-T-ALL) may cause ocular pathologies such as cotton-wool spots, retinal hemorrhage, and less commonly, retinal detachment or leukemic infiltration of the retina itself. However, these findings are typically accompanied by the pathognomonic hematological signs of acute leukemia. CASE PRESENTATION: In this case report and review of the literature, we describe a particularly unusual case of a 25-year old man who presented to our hospital with bilateral exudative retinal detachments associated with posterior pole thickening without any hematological or neurological findings. The patient, who had a history of previously treated pre-T-ALL in complete remission, was found to have leukemia cell infiltration on retinal biopsy. CONCLUSION: Our case underscores the fact that the ophthalmologist may be the first provider to detect the relapse of previously treated leukemia, and that ophthalmic evaluation is critical for detecting malignant ocular infiltrates. PMID- 26483677 TI - Macular Hole Associated with Vogt-Koyanagi-Harada Disease at the Acute Uveitic Stage. AB - We describe a case with macular hole (MH) associated with Vogt-Koyanagi-Harada (VKH) disease. A 71-year-old Japanese woman presented with visual loss and headaches. The best-corrected visual acuity (BCVA) was 0.02 in the right eye (RE) and 0.1 in the left eye (LE). The patient was diagnosed with VKH based on circumferential choroidal detachments, multiple serous retinal detachments, and optic disc hyperemia. The multiple serous retinal detachments improved with high dose corticosteroid therapy and gradual tapering. The BCVA was recovered to 1.2/0.7 in the RE/LE. Six weeks after the initial administration of steroid, vitreomacular traction was found by optical coherence tomography in the LE, which progressed to stage 4 MH with the BCVA of 0.2 in the LE. Twenty-three weeks after the initial treatment, vitrectomy was performed with the standard surgical procedures, including inner limiting membrane peeling around the fovea and air tamponade. The MH was closed successfully and the BCVA was 0.4 in the LE 5 weeks after the vitrectomy. This is the first report of a case with MH secondary to the acute uveitic stage of VKH. Successful closure of MH was achieved with the standard surgical intervention for an idiopathic MH. To conclude, at the early stage of VKH, there is a possibility of MH formation due to the rapid progress of vitreous traction following the inflammation, and the surgical procedure could be effective to resolve this secondary disorder. PMID- 26483678 TI - A Case Report of Nystagmus with Acute Comitant Esotropia Secondary to Heroin Withdrawal: A Novel Presentation. AB - BACKGROUND: Acute comitant esotropia secondary to heroin withdrawal is a rarely reported phenomenon that has never been described with nystagmus. Adverse effects of heroin on eye alignment were first reported in soldiers returning from Vietnam, yet no theory is generally accepted as the cause of these abnormalities. METHOD: We present a case of a 22-year-old female who developed 40 prism diopters of alternating comitant esotropia with nystagmus 8 days after abrupt heroin cessation, review the existing literature, and propose a novel hypothesis for this phenomenon. RESULTS: After 76 days, her esotropia resolved, and she was left with 7 prism diopters of esophoria. CONCLUSION: This case demonstrates that acquired nystagmus can present in addition to acute-onset esotropia after abrupt heroin cessation. We compare and contrast the theories of this mechanism and review the literature. PMID- 26483679 TI - Astrocytic estrogen receptors and impaired neurotrophic responses in a rat model of perimenopause. AB - In a perimenopausal model of middle-aged rats, the astrocyte estrogen receptor alpha (ERa): ER-beta (ERb) ratio increased with the onset of acyclicity (constant estrus, CE) in association with impaired neurotrophic responses to estradiol (E2). We report additional data on irregular cycling (IR) from this study of 9 month old perimenopausal subgroups. In particular, irregular cyclers (IR) also show increased ERa:ERb ratio in cerebral cortex astrocytes comparable to acyclic individuals in CE. In mixed glial cultures from these same cycling subgroups, the E2-dependent neurotrophic activity and glial fibrillary acidic protein (GFAP) repression by E2 were impaired in IR to the same degree as in CE-derived glia. The greater importance of cycling status than age during the perimenopause to astrocyte ERs are attributable to individual variations of the residual ovarian follicle pool, which determine the onset of acyclicity. The corresponding loss of E2-dependent GFAP repression and E2-dependent neurotrophic activity add further to the inverse relationship of GFAP expression and astrocyte neurotrophic activity across aging in both sexes. These findings are relevant to impairments of spatial learning and of hippocampal long-term potentiation during the onset of IR in middle-aged rats, and to perimenopausal factors mediating the higher risk of women for Alzheimer disease. PMID- 26483680 TI - Comparison of regional brain atrophy and cognitive impairment between pure akinesia with gait freezing and Richardson's syndrome. AB - Pure akinesia with gait freezing (PAGF) is considered a clinical phenotype of progressive supranuclear palsy. The brain atrophy and cognitive deficits in PAGF are expected to be less prominent than in classical Richardson's syndrome (RS), but this hypothesis has not been explored yet. We reviewed the medical records of 28 patients with probable RS, 19 with PAGF, and 29 healthy controls, and compared cortical thickness, subcortical gray matter volume, and neuropsychological performance among the three groups. Patients with PAGF had thinner cortices in frontal, inferior parietal, and temporal areas compared with controls; however, areas of cortical thinning in PAGF patients were less extensive than those in RS patients. In PAGF patients, hippocampal, and thalamic volumes were also smaller than controls, whereas subcortical gray matter volumes in PAGF and RS patients were comparable. In a comparison of neuropsychological tests, PAGF patients had better cognitive performance in executive function, visual memory, and visuospatial function than RS patients had. These results demonstrate that cognitive impairment, cortical thinning, and subcortical gray matter atrophy in PAGF patients resemble to those in RS patients, though the severity of cortical thinning and cognitive dysfunction is milder. Our results suggest that, PAGF and RS may share same pathology but that it appears to affect a smaller proportion of the cortex in PAGF. PMID- 26483682 TI - Visual-motor embodiment of language: a few implications for the neuropsychological evaluation (in Alzheimer's disease). PMID- 26483681 TI - The Vallecas Project: A Cohort to Identify Early Markers and Mechanisms of Alzheimer's Disease. AB - INTRODUCTION: Alzheimer's disease (AD) is a major threat for the well-being of an increasingly aged world population. The physiopathological mechanisms of late onset AD are multiple, possibly heterogeneous, and not well understood. Different combinations of variables from several domains (i.e., clinical, neuropsychological, structural, and biochemical markers) may predict dementia conversion, according to distinct physiopathological pathways, in different groups of subjects. METHODS: We launched the Vallecas Project (VP), a cohort study of non-demented people aged 70-85, to characterize the social, clinical, neuropsychological, structural, and biochemical underpinnings of AD inception. Given the exploratory nature of the VP, multidimensional and machine learning techniques will be applied, in addition to the traditional multivariate statistical methods. RESULTS: A total of 1169 subjects were recruited between October 2011 and December 2013. Mean age was 74.4 years (SD 3.9), 63.5% of the subjects were women, and 17.9% of the subjects were carriers of at least one epsilon4 allele of the apolipoprotein E gene. Cognitive diagnoses at inclusion were as follows: normal cognition 93.0% and mild cognitive impairment (MCI) 7.0% (3.1% amnestic MCI, 0.1% non-amnestic MCI, 3.8% mixed MCI). Blood samples were obtained and stored for future determinations in 99.9% of the subjects and 3T magnetic resonance imaging study was conducted in 89.9% of the volunteers. The cohort is being followed up annually for 4 years after the baseline. CONCLUSION: We have established a valuable homogeneous single-center cohort which, by identifying groups of variables associated with high risk of MCI or dementia conversion, should help to clarify the early physiopathological mechanisms of AD and should provide avenues for prompt diagnosis and AD prevention. PMID- 26483683 TI - Brain activation during visual working memory correlates with behavioral mobility performance in older adults. AB - Functional mobility and cognitive function often decline with age. We previously found that functional mobility as measured by the Timed Up and Go Test (TUG) was associated with cognitive performance for visually-encoded (i.e., for location and face) working memory (WM) in older adults. This suggests a common neural basis between TUG and visual WM. To elucidate this relationship further, the present study aimed to examine the neural basis for the WM-mobility association. In accordance with the well-known neural compensation model in aging, we hypothesized that "attentional" brain activation for easy WM would increase in participants with lower mobility. The data from 32 healthy older adults were analyzed, including brain activation during easy WM tasks via functional Magnetic Resonance Imaging (fMRI) and mobility performance via both TUG and a simple walking test. WM performance was significantly correlated with TUG but not with simple walking. Some prefrontal brain activations during WM were negatively correlated with TUG performance, while positive correlations were found in subcortical structures including the thalamus, putamen and cerebellum. Moreover, activation of the subcortical regions was significantly correlated with WM performance, with less activation for lower WM performers. These results indicate that older adults with lower mobility used more cortical (frontal) and fewer subcortical resources for easy WM tasks. To date, the frontal compensation has been proposed separately in the motor and cognitive domains, which have been assumed to compensate for dysfunction of the other brain areas; however, such dysfunction was less clear in previous studies. The present study observed such dysfunction as degraded activation associated with lower performance, which was found in the subcortical regions. We conclude that a common dysfunction compensation activation pattern is likely the neural basis for the association between visual WM and functional mobility. PMID- 26483684 TI - Plasmalemmal VDAC-1 corroborated as amyloid Abeta-receptor. PMID- 26483686 TI - From cumulative cultural transmission to evidence-based medicine: evolution of medicinal plant knowledge in Southern Italy. AB - In Mediterranean cultures written records of medicinal plant use have a long tradition. This written record contributed to building a consensus about what was perceived to be an efficacious pharmacopeia. Passed down through millennia, these scripts have transmitted knowledge about plant uses, with high fidelity, to scholars and laypersons alike. Herbal medicine's importance and the long-standing written record call for a better understanding of the mechanisms influencing the transmission of contemporary medicinal plant knowledge. Here we contextualize herbal medicine within evolutionary medicine and cultural evolution. Cumulative knowledge transmission is approached by estimating the causal effect of two seminal scripts about materia medica written by Dioscorides and Galen, two classical Greco-Roman physicians, on today's medicinal plant use in the Southern Italian regions of Campania, Sardinia, and Sicily. Plant-use combinations are treated as transmissible cultural traits (or "memes"), which in analogy to the biological evolution of genetic traits, are subjected to mutation and selection. Our results suggest that until today ancient scripts have exerted a strong influence on the use of herbal medicine. We conclude that the repeated empirical testing and scientific study of health care claims is guiding and shaping the selection of efficacious treatments and evidence-based herbal medicine. PMID- 26483687 TI - Antinociceptive and neuropharmacological activities of methanol extract of Phoenix sylvestris fruit pulp. AB - Fruits of Phoenix sylvestris Roxb. (Arecaceae) are used to treat back pain, toothache, headache, arthritis, nervous debility and as sedative. The aim of this study was to evaluate the antinociceptive and neuropharmacological activities of methanol extract of P. sylvestris fruit pulp (MEPS). The antinociceptive activity of MEPS was evaluated by heat-induced (hot plate, tail immersion test) and chemical-induced pain models (acetic acid-induced writhing, formalin-induced nociception, glutamate-induced nociception and paw edema test). The effect of MEPS on central nervous system (CNS) was studied using hole cross test, open field test, sodium thiopental-induced sleeping time and elevated plus maze test. MEPS showed strong, significant and dose-dependent antinociceptive activity in all heat-induced and chemical-induced pain models at all experimental doses. Involvement of opioid receptor mediated analgesia was evident from the reversal of analgesic effect by naloxone. MEPS also showed reduced locomotor activity in both hole cross and open field tests. The increase in sleeping time in sodium thiopental-induced sleeping test and anxiolytic activity in elevated plus maze test were also significant. So, it is evident that MEPS possesses strong central and peripheral antinociceptive activity as well as CNS depressant, sedative and anxiolytic activity. The results justify the ethnomedicinal use of P. sylvestris fruit in different painful conditions and CNS disorders. PMID- 26483688 TI - Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats. AB - Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA), a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM)-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition, and activation of transforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis. PMID- 26483685 TI - Cardiac cAMP: production, hydrolysis, modulation and detection. AB - Cyclic adenosine 3',5'-monophosphate (cAMP) modulates a broad range of biological processes including the regulation of cardiac myocyte contractile function where it constitutes the main second messenger for beta-adrenergic receptors' signaling to fulfill positive chronotropic, inotropic and lusitropic effects. A growing number of studies pinpoint the role of spatial organization of the cAMP signaling as an essential mechanism to regulate cAMP outcomes in cardiac physiology. Here, we will briefly discuss the complexity of cAMP synthesis and degradation in the cardiac context, describe the way to detect it and review the main pharmacological arsenal to modulate its availability. PMID- 26483689 TI - Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study. AB - Heshouwu (HSW), the dry roots of Polygonum multiflorum, a classical traditional Chinese medicine is used as a tonic for a wide range of conditions, particularly those associated with aging. However, it tends to be taken overdose or long term in these years, which has resulted in liver damage reported in many countries. In this study, the indicative roles of nine bile acids (BAs) were evaluated to offer potential biomarkers for HSW induced liver injury. Nine BAs including cholic acid (CA) and chenodeoxycholic acid (CDCA), taurocholic acid (TCA), glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), deoxycholic acid (DCA), glycodeoxycholic acid (GDCA), ursodeoxycholic acid (UDCA), and hyodeoxycholic acid (HDCA) in rat bile and serum were detected by a developed LC-MS method after 42 days treatment. Partial least square-discriminate analysis (PLS-DA) was applied to evaluate the indicative roles of the nine BAs, and metabolism of the nine BAs was summarized. Significant change was observed for the concentrations of nine BAs in treatment groups compared with normal control; In the PLS-DA plots of nine BAs in bile, normal control and raw HSW groups were separately clustered and could be clearly distinguished, GDCA was selected as the distinguished components for raw HSW overdose treatment group. In the PLS-DA plots of nine BAs in serum, the normal control and raw HSW overdose treatment group were separately clustered and could be clearly distinguished, and HDCA was selected as the distinguished components for raw HSW overdose treatment group. The results indicated the perturbation of nine BAs was associated with HSW induced liver injury; GDCA in bile, as well as HDCA in serum could be selected as potential biomarkers for HSW induced liver injury; it also laid the foundation for the further search on the mechanisms of liver injury induced by HSW. PMID- 26483690 TI - Lipid-based nano-delivery systems for skin delivery of drugs and bioactives. PMID- 26483691 TI - beta-Amyloid: the key peptide in the pathogenesis of Alzheimer's disease. AB - The amyloid beta peptide (Abeta) is a critical initiator that triggers the progression of Alzheimer's Disease (AD) via accumulation and aggregation, of which the process may be caused by Abeta overproduction or perturbation clearance. Abeta is generated from amyloid precursor protein through sequential cleavage of beta- and gamma-secretases while Abeta removal is dependent on the proteolysis and lysosome degradation system. Here, we overviewed the biogenesis and toxicity of Abeta as well as the regulation of Abeta production and clearance. Moreover, we also summarized the animal models correlated with Abeta that are essential in AD research. In addition, we discussed current immunotherapeutic approaches targeting Abeta to give some clues for exploring the more potentially efficient drugs for treatment of AD. PMID- 26483693 TI - Pharmacokinetics of single oral dose trazodone: a randomized, two-period, cross over trial in healthy, adult, human volunteers under fed condition. AB - OBJECTIVE: To assess the bioequivalence of single dose trazodone hydrochloride USP 100 mg tablets administered as an oral dose under fed condition. METHODS: This study was an open-label, balanced, randomized, two-sequence, two-treatment, two-period, single oral dose, crossover bioequivalence study in healthy, adult, human subjects under fed conditions. After an overnight fast of at least 10 h, the subjects were served a high fat and high calorie vegetarian breakfast, which they were required to consume within 30 min. A single oral dose (100 mg) of either the test or the reference product was administered to the subjects. The primary pharmacokinetic parameters, maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time zero to last measurable concentration (AUC0-t ) and extrapolated to infinity (AUC0-infinity) were compared by an analysis of variance using log-transformed data. Bioequivalence was concluded if the 90% confidence intervals (CIs) of the adjusted geometric mean (gMean) ratios for C max and AUC were within the predetermined range of 80 125%, in accordance with regulatory requirements. RESULTS: For the test formulation, the trazodone gMean Cmax was 1480.9 ng/mL (vs. 1520.2 ng/mL for reference), AUC0-t was 18193.0 ng.h/mL (vs. 18209.8 ng.h/mL) and AUC0-infinity was 19346.3 ng.h/mL (vs. 19393.4 ng.h/mL). The 90% CIs for the ratio (test/reference) were 93.0-102.0% for Cmax, 96.7-103.2% for AUC0-t and 96.1 103.5% for AUC0-infinity. There were no deaths or serious adverse events during the conduct of the study. CONCLUSION: Test product when compared with the Reference product meets the bioequivalence criteria with respect to the extent of absorption of trazodone under fed condition. PMID- 26483692 TI - Designing modulators of monoamine transporters using virtual screening techniques. AB - The plasma-membrane monoamine transporters (MATs), including the serotonin (SERT), norepinephrine (NET) and dopamine (DAT) transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission through the reuptake of their respective monoamine neurotransmitters. The transporters are the main target of clinically used psychostimulants and antidepressants. Despite the availability of several potent and selective MAT substrates and inhibitors the continuing need for therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason to identify novel ways of targeting and modulating the MATs. Designing novel modulators of MAT function have been limited by the lack of three dimensional structure information of the individual MATs. However, crystal structures of LeuT, a bacterial homolog of MATs, in a substrate-bound occluded, substrate-free outward-open, and an apo inward-open state and also with competitive and non-competitive inhibitors have been determined. In addition, several structures of the Drosophila DAT have also been resolved. Together with computational modeling and experimental data gathered over the past decade, these structures have dramatically advanced our understanding of several aspects of SERT, NET, and DAT transporter function, including some of the molecular determinants of ligand interaction at orthosteric substrate and inhibitor binding pockets. In addition progress has been made in the understanding of how allosteric modulation of MAT function can be achieved. Here we will review all the efforts up to date that has been made through computational approaches employing structural models of MATs to design small molecule modulators to the orthosteric and allosteric sites using virtual screening techniques. PMID- 26483694 TI - Vaginal biogenic amines: biomarkers of bacterial vaginosis or precursors to vaginal dysbiosis? AB - Bacterial vaginosis (BV) is the most common vaginal disorder among reproductive age women. One clinical indicator of BV is a "fishy" odor. This odor has been associated with increases in several biogenic amines (BAs) that may serve as important biomarkers. Within the vagina, BA production has been linked to various vaginal taxa, yet their genetic capability to synthesize BAs is unknown. Using a bioinformatics approach, we show that relatively few vaginal taxa are predicted to be capable of producing BAs. Many of these taxa (Dialister, Prevotella, Parvimonas, Megasphaera, Peptostreptococcus, and Veillonella spp.) are more abundant in the vaginal microbial community state type (CST) IV, which is depleted in lactobacilli. Several of the major Lactobacillus species (L. crispatus, L. jensenii, and L. gasseri) were identified as possessing gene sequences for proteins predicted to be capable of putrescine production. Finally, we show in a small cross sectional study of 37 women that the BAs putrescine, cadaverine and tyramine are significantly higher in CST IV over CSTs I and III. These data support the hypothesis that BA production is conducted by few vaginal taxa and may be important to the outgrowth of BV-associated (vaginal dysbiosis) vaginal bacteria. PMID- 26483696 TI - Localized nuclear and perinuclear Ca(2+) signals in intact mouse skeletal muscle fibers. AB - Nuclear Ca(2+) is important for the regulation of several nuclear processes such as gene expression. Localized Ca(2+) signals (LCSs) in skeletal muscle fibers of mice have been mainly studied as Ca(2+) release events from the sarcoplasmic reticulum. Their location with regard to cell nuclei has not been investigated. Our study is based on the hypothesis that LCSs associated with nuclei are present in skeletal muscle fibers of adult mice. Therefore, we carried out experiments addressing this question and we found novel Ca(2+) signals associated with nuclei of skeletal muscle fibers (with possibly attached satellite cells). We measured localized nuclear and perinuclear Ca(2+) signals (NLCSs and PLCSs) alongside cytosolic localized Ca(2+) signals (CLCSs) during a hypertonic treatment. We also observed NLCSs under isotonic conditions. The NLCSs and PLCSs are Ca(2+) signals in the range of micrometer [FWHM (full width at half maximum): 2.75 +/- 0.27 MUm (NLCSs) and 2.55 +/- 0.17 MUm (PLCSs), S.E.M.]. Additionally, global nuclear Ca(2+) signals (NGCSs) were observed. To investigate which type of Ca(2+) channels contribute to the Ca(2+) signals associated with nuclei in skeletal muscle fibers, we performed measurements with the RyR blocker dantrolene, the DHPR blocker nifedipine or the IP3R blocker Xestospongin C. We observed Ca(2+) signals associated with nuclei in the presence of each blocker. Nifedipine and dantrolene had an inhibitory effect on the fraction of fibers with PLCSs. The situation for the fraction of fibers with NLCSs is more complex indicating that RyR is less important for the generation of NLCSs compared to the generation of PLCSs. The fraction of fibers with NLCSs and PLCSs is not reduced in the presence of Xestospongin C. The localized perinuclear and intranuclear Ca(2+) signals may be a powerful tool for the cell to regulate adaptive processes as gene expression. The intranuclear Ca(2+) signals may be particularly interesting in this respect. PMID- 26483695 TI - On the mathematical modeling of wound healing angiogenesis in skin as a reaction transport process. AB - Over the last 30 years, numerous research groups have attempted to provide mathematical descriptions of the skin wound healing process. The development of theoretical models of the interlinked processes that underlie the healing mechanism has yielded considerable insight into aspects of this critical phenomenon that remain difficult to investigate empirically. In particular, the mathematical modeling of angiogenesis, i.e., capillary sprout growth, has offered new paradigms for the understanding of this highly complex and crucial step in the healing pathway. With the recent advances in imaging and cell tracking, the time is now ripe for an appraisal of the utility and importance of mathematical modeling in wound healing angiogenesis research. The purpose of this review is to pedagogically elucidate the conceptual principles that have underpinned the development of mathematical descriptions of wound healing angiogenesis, specifically those that have utilized a continuum reaction-transport framework, and highlight the contribution that such models have made toward the advancement of research in this field. We aim to draw attention to the common assumptions made when developing models of this nature, thereby bringing into focus the advantages and limitations of this approach. A deeper integration of mathematical modeling techniques into the practice of wound healing angiogenesis research promises new perspectives for advancing our knowledge in this area. To this end we detail several open problems related to the understanding of wound healing angiogenesis, and outline how these issues could be addressed through closer cross-disciplinary collaboration. PMID- 26483697 TI - Overexpression of GhWRKY27a reduces tolerance to drought stress and resistance to Rhizoctonia solani infection in transgenic Nicotiana benthamiana. AB - WRKY proteins constitute transcriptional regulators involved in various biological processes, especially in coping with diverse biotic and abiotic stresses. However, in contrast to other well-characterized WRKY groups, the functions of group III WRKY transcription factors are poorly understood in the economically important crop cotton (Gossypium hirsutum). In this study, a group III WRKY gene from cotton, GhWRKY27a, was isolated and characterized. Our data indicated that GhWRKY27a localized to the nucleus and that GhWRKY27a expression could be strongly induced by abiotic stresses, pathogen infection, and multiple defense-related signaling molecules. Virus-induced gene silencing (VIGS) of GhWRKY27a enhanced tolerance to drought stress in cotton. In contrast, GhWRKY27a overexpression in Nicotiana benthamiana markedly reduced plant tolerance to drought stress, as determined through physiological analyses of leaf water loss, survival rates, and the stomatal aperture. This susceptibility was coupled with reduced stomatal closure in response to abscisic acid and decreased expression of stress-related genes. In addition, GhWRKY27a-overexpressing plants exhibited reduced resistance to Rhizoctonia solani infection, mainly demonstrated by the transgenic lines exhibiting more severe disease symptoms, accompanied by attenuated expression of defense-related genes in N. benthamiana. Taken together, these findings indicated that GhWRKY27a functions in negative responses to drought tolerance and in resistance to R. solani infection. PMID- 26483698 TI - Therapeutic effects of LASSBio-596 in an elastase-induced mouse model of emphysema. AB - Emphysema is an intractable pulmonary disease characterized by an inflammatory process of the airways and lung parenchyma and ongoing remodeling process in an attempt to restore lung structure. There is no effective drug therapy that regenerates lung tissue or prevents the progression of emphysema; current treatment is aimed at symptomatic relief. We hypothesized that LASSBio-596, a molecule with potent anti-inflammatory and immunomodulatory effects, might reduce pulmonary inflammation and remodeling and thus improve lung function in experimental emphysema. Emphysema was induced in BALB/c mice by intratracheal administration of porcine pancreatic elastase (0.1 IU) once weekly during 4 weeks. A control group received saline using the same protocol. After the last instillation of saline or elastase, dimethyl sulfoxide, or LASSBio-596 were administered intraperitoneally, once daily for 8 days. After 24 h, in elastase induced emphysema animals, LASSBio-596 yielded: (1) decreased mean linear intercept, hyperinflation and collagen fiber content, (2) increased elastic fiber content, (3) reduced number of M1 macrophages, (4) decreased tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and transforming growth factor beta protein levels in lung tissue, and increased vascular endothelial growth factor. These changes resulted in increased static lung elastance. In conclusion, LASSBio-596 therapy reduced lung inflammation, airspace enlargement, and small airway wall remodeling, thus improving lung function, in this animal model of elastase-induced emphysema. PMID- 26483700 TI - Dietary fat overload reprograms brown fat mitochondria. AB - Chronic nutrient overload accelerates the onset of several aging-related diseases reducing life expectancy. Although the mechanisms by which overnutrition affects metabolic processes in many tissues are known, its role on BAT physiology is still unclear. Herein, we investigated the mitochondrial responses in BAT of female mice exposed to high fat diet (HFD) at different steps of life. Although adult mice showed an unchanged mitochondrial amount, both respiration and OxPHOS subunits were strongly affected. Differently, offspring pups exposed to HFD during pregnancy and lactation displayed reduced mitochondrial mass but high oxidative efficiency that, however, resulted in increased bioenergetics state of BAT rather than augmented uncoupling respiration. Interestingly, the metabolic responses triggered by HFD were accompanied by changes in mitochondrial dynamics characterized by decreased content of the fragmentation marker Drp1 both in mothers and offspring pups. HFD-induced inactivation of the FoxO1 transcription factor seemed to be the up-stream modulator of Drp1 levels in brown fat cells. Furthermore, HFD offspring pups weaned with normal diet only partially reverted the mitochondrial dysfunctions caused by HFD. Finally these mice failed in activating the thermogenic program upon cold exposure. Collectively our findings suggest that maternal dietary fat overload irreversibly commits BAT unresponsiveness to physiological stimuli such as cool temperature and this dysfunction in the early stage of life might negatively modulate health and lifespan. PMID- 26483699 TI - The role of the renal afferent and efferent nerve fibers in heart failure. AB - Renal nerves contain afferent, sensory and efferent, sympathetic nerve fibers. In heart failure (HF) there is an increase in renal sympathetic nerve activity (RSNA), which can lead to renal vasoconstriction, increased renin release and sodium retention. These changes are thought to contribute to renal dysfunction, which is predictive of poor outcome in patients with HF. In contrast, the role of the renal afferent nerves remains largely unexplored in HF. This is somewhat surprising as there are multiple triggers in HF that have the potential to increase afferent nerve activity, including increased venous pressure and reduced kidney perfusion. Some of the few studies investigating renal afferents in HF have suggested that at least the sympatho-inhibitory reno-renal reflex is blunted. In experimentally induced HF, renal denervation, both surgical and catheter-based, has been associated with some improvements in renal and cardiac function. It remains unknown whether the effects are due to removal of the efferent renal nerve fibers or afferent renal nerve fibers, or a combination of both. Here, we review the effects of HF on renal efferent and afferent nerve function and critically assess the latest evidence supporting renal denervation as a potential treatment in HF. PMID- 26483702 TI - RNA-seq analysis of glycosylation related gene expression in STZ-induced diabetic rat kidney inner medulla. AB - The UT-A1 urea transporter is crucial to the kidney's ability to generate concentrated urine. Native UT-A1 from kidney inner medulla (IM) is a heavily glycosylated protein with two glycosylation forms of 97 and 117 kDa. In diabetes, UT-A1 protein abundance, particularly the 117 kD isoform, is significantly increased corresponding to an increased urea permeability in perfused IM collecting ducts, which plays an important role in preventing the osmotic diuresis caused by glucosuria. However, how the glycan carbohydrate structure change and the glycan related enzymes regulate kidney urea transport activity, particularly under diabetic condition, is largely unknown. In this study, using sugar-specific binding lectins, we found that the carbohydrate structure of UT-A1 is changed with increased amounts of sialic acid, fucose, and increased glycan branching under diabetic conditions. These changes were accompanied by altered UT A1 association with the galectin proteins, beta-galactoside glycan binding proteins. To explore the molecular basis of the alterations of glycan structures, the highly sensitive next generation sequencing (NGS) technology, Illumina RNA seq, was employed to analyze genes involved in the process of UT-A1 glycosylation using streptozotocin (STZ)-induced diabetic rat kidney. Differential gene expression analysis combining with quantitative PCR revealed that expression of a number of important glycosylation related genes were changed under diabetic conditions. These genes include the glycosyltransferase genes Mgat4a, the sialylation enzymes St3gal1 and St3gal4 and glycan binding protein galectin-3, 5, -8, and -9. In contrast, although highly expressed in kidney IM, the glycosyltransferase genes Mgat1, Mgat2, and fucosyltransferase Fut8, did not show any changes. CONCLUSIONS: In diabetes, not only is UT-A1 protein abundance increased but the protein's glycan structure is also significantly changed. UT-A1 protein becomes highly sialylated, fucosylated and branched. Consistently, a number of crucial glycosylation related genes are changed under diabetic conditions. The alteration of these genes may contribute to changes in the UT-A1 glycan structure and therefore modulate kidney urea transport activity and alleviate osmotic diuresis caused by glucosuria in diabetes. PMID- 26483701 TI - Repetitive transcranial magnetic stimulation over the supplementary motor area modifies breathing pattern in response to inspiratory loading in normal humans. AB - In awake humans, breathing depends on automatic brainstem pattern generators. It is also heavily influenced by cortical networks. For example, functional magnetic resonance imaging and electroencephalographic data show that the supplementary motor area becomes active when breathing is made difficult by inspiratory mechanical loads like resistances or threshold valves, which is associated with perceived respiratory discomfort. We hypothesized that manipulating the excitability of the supplementary motor area with repetitive transcranial magnetic stimulation would modify the breathing pattern response to an experimental inspiratory load and possibly respiratory discomfort. Seven subjects (three men, age 25 +/- 4) were studied. Breathing pattern and respiratory discomfort during inspiratory loading were described before and after conditioning the supplementary motor area with repetitive stimulation, using an excitatory paradigm (5 Hz stimulation), an inhibitory paradigm, or sham stimulation. No significant change in breathing pattern during loading was observed after sham conditioning. Excitatory conditioning shortened inspiratory time (p = 0.001), decreased tidal volume (p = 0.016), and decreased ventilation (p = 0.003), as corroborated by an increased end-tidal expired carbon dioxide (p = 0.013). Inhibitory conditioning did not affect ventilation, but lengthened expiratory time (p = 0.031). Respiratory discomfort was mild under baseline conditions, and unchanged after conditioning of the supplementary motor area. This is the first study to show that repetitive transcranial magnetic stimulation conditioning of the cerebral cortex can alter breathing pattern. A 5 Hz conditioning protocol, known to enhance corticophrenic excitability, can reduce the amount of hyperventilation induced by inspiratory threshold loading. Further studies are needed to determine whether and under what circumstances rTMS can have an effect on dyspnoea. PMID- 26483703 TI - HEMA but not TEGDMA induces autophagy in human gingival fibroblasts. AB - Polymerized resin-based materials are successfully used in restorative dentistry. Despite their growing popularity, one drawback is the release of monomers from the polymerized matrix due to an incomplete polymerization or degradation processes. Released monomers are responsible for several adverse effects in the surrounding biological tissues, inducing high levels of oxidative stress. Reactive oxygen species are important signaling molecules that regulate many signal-trasduction pathways and play critical roles in cell survival, death, and immune defenses. Reactive oxygen species were recently shown to activate autophagy as a mechanism of cell survival and cell death. Although the toxicity induced by dental resin monomers is widely studied, the cellular mechanisms underlying these phenomena are still unknown. The aim of the study was to investigate the behavior of human gingival cells exposed to 2-hydroxy-ethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) to better elucidate the mechanisms of cell survival and cell death induced by resin monomers. Primary culture of human gingival cells were exposed to 3 mmol/L of HEMA or 3 mmol/L of TEGDMA for 24, 48, and 72 h. Morphological investigations were performed by transmission electron microscopy to analyze the ultrastructure of cells exposed to the monomers. The expression of protein markers for apoptosis (caspase - 3 and PARP) and autophagy (beclin - 1 and LC3B I/II) were analyzed by western blot to investigate the influence of dental resin monomers on mechanisms underlying cell death. Results showed that HEMA treatment clearly induced autophagy followed by apoptosis while the lack of any sign of autophagy activation is observed in HGFs exposed to TEGDMA. These data indicate that cells respond to monomer-induced stress by the differential induction of adaptive mechanisms to maintain cellular homeostasis. PMID- 26483705 TI - Commentary: Interaction of the ADRB2 Gene Polymorphism with Childhood Trauma in Predicting Adult Symptoms of Posttraumatic Stress Disorder. PMID- 26483704 TI - A 4-Year Follow-Up Study of Attention-Deficit Hyperactivity Symptoms, Comorbidities, and Psychostimulant Use in a Brazilian Sample of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. AB - The aim of this study was to evaluate symptom persistence in attention deficit/hyperactivity disorder (ADHD), the development of comorbidities, and psychostimulant usage patterns. Follow-up studies were conducted in 37 patients with ADHD and 22 healthy controls, aged 10 and 18, 4 years after their first assessment. The ADHD was rated as persistent if participants met all DSM-IV criteria for syndromic or sub-threshold persistence, or had functional impairments (functional persistence). Of the 37 ADHD patients we reevaluated, 75% had persistent symptoms, and psychiatric comorbidities with additional functional impairments and academic problems were more common than in controls. These follow up findings show a high comorbidity associated with ADHD and support the importance of evaluation and treatment for ADHD and comorbidities throughout life. PMID- 26483706 TI - Computerized Cognitive Training for Major Depressive Disorder: What's Next? PMID- 26483707 TI - The relationship between mood state and perceived control in contingency learning: effects of individualist and collectivist values. AB - Perceived control in contingency learning is linked to psychological wellbeing with low levels of perceived control thought to be a cause or consequence of depression and high levels of control considered to be the hallmark of mental healthiness. However, it is not clear whether this is a universal phenomenon or whether the value that people ascribe to control influences these relationships. Here we hypothesize that values affect learning about control contingencies and influence the relationship between perceived control and symptoms of mood disorders. We tested these hypotheses with European university samples who were categorized as endorsing (or not) values relevant to control-individualist and collectivist values. Three online experimental contingency learning studies (N 1 = 127, N 2 = 324, N 3 = 272) were carried out. Evidence suggested that individualist values influenced basic learning processes via an effect on learning about the context in which events took place. Participants who endorsed individualist values made control judgments that were more in line with an elemental associative learning model, whilst those who were ambivalent about individualist values made judgments that were more consistent with a configural process. High levels of perceived control and individualist values were directly associated with increased euphoric symptoms of bipolar disorder, and such values completely mediated the relation between perceived control and symptoms. The effect of low perceived control on depression was moderated by collectivist values. Anxiety created by dissonance between values and task may be a catalyst for developing mood symptoms. Conclusions are that values play a significant intermediary role in the relation between perceived control and symptoms of mood disturbance. PMID- 26483708 TI - Olfaction in eating disorders and abnormal eating behavior: a systematic review. AB - The study provides a systematic review that explores the current literature on olfactory capacity in abnormal eating behavior. The objective is to present a basis for discussion on whether research in olfaction in eating disorders may offer additional insight with regard to the complex etiopathology of eating disorders (ED) and abnormal eating behaviors. Electronic databases (Medline, PsycINFO, PubMed, Science Direct, and Web of Science) were searched using the components in relation to olfaction and combining them with the components related to abnormal eating behavior. Out of 1352 articles, titles were first excluded by title (n = 64) and then by abstract and fulltext resulting in a final selection of 14 articles (820 patients and 385 control participants) for this review. The highest number of existing literature on olfaction in ED were carried out with AN patients (78.6%) followed by BN patients (35.7%) and obese individuals (14.3%). Most studies were only conducted on females. The general findings support that olfaction is altered in AN and in obesity and indicates toward there being little to no difference in olfactory capacity between BN patients and the general population. Due to the limited number of studies and heterogeneity this review stresses on the importance of more research on olfaction and abnormal eating behavior. PMID- 26483710 TI - Amplitude-modulated stimuli reveal auditory-visual interactions in brain activity and brain connectivity. AB - The temporal congruence between auditory and visual signals coming from the same source can be a powerful means by which the brain integrates information from different senses. To investigate how the brain uses temporal information to integrate auditory and visual information from continuous yet unfamiliar stimuli, we used amplitude-modulated tones and size-modulated shapes with which we could manipulate the temporal congruence between the sensory signals. These signals were independently modulated at a slow or a fast rate. Participants were presented with auditory-only, visual-only, or auditory-visual (AV) trials in the fMRI scanner. On AV trials, the auditory and visual signal could have the same (AV congruent) or different modulation rates (AV incongruent). Using psychophysiological interaction analyses, we found that auditory regions showed increased functional connectivity predominantly with frontal regions for AV incongruent relative to AV congruent stimuli. We further found that superior temporal regions, shown previously to integrate auditory and visual signals, showed increased connectivity with frontal and parietal regions for the same contrast. Our findings provide evidence that both activity in a network of brain regions and their connectivity are important for AV integration, and help to bridge the gap between transient and familiar AV stimuli used in previous studies. PMID- 26483711 TI - Finding an apprenticeship: hidden curriculum and social consequences. AB - In Switzerland, the majority of students are oriented toward professional training after compulsory schooling. At this stage, one of the biggest challenges for them is to find an apprenticeship position. Matching supply and demand is a complex process that not only excludes some students from having direct access to professional training but also forces them to make early choices regarding their future sector of employment. So, how does one find an apprenticeship? And what do the students' descriptions of their search for apprenticeships reveal about the institutional determinants of social inequalities at play in the system? Based on 29 interviews conducted in 2014 with 23 apprentices and 6 recruiters in the Canton of Vaud, this article interrogates how the dimensions of educational and social trajectories combine to affect access to apprenticeships and are accentuated by recruiters using a "hidden curriculum" during the recruitment process. A hidden curriculum consists of knowledge and skills not taught by the educational institution but which appear decisive in obtaining an apprenticeship. By analyzing the contrasting experiences of students in their search for an apprenticeship, we identify four types of trajectories that explain different types of school-to-apprenticeship transitions. We show how these determinants are reinforced by the "hidden curriculum" of recruitment based on the soft skills of feeling, autonomy, anticipation, and reflexivity that are assessed in the context of recruitment interactions. The discussion section debates how the criteria that appear to be used to identify the "right apprentice" tend to (re)produce inequalities between students. This not only depends on their academic results but also on their social and cultural skills, their ability to anticipate their choices and, more widely, their ability to be a subject in their recruitment search. "The Subject is neither the individual, nor the self, but the work through which an individual transforms into an actor, meaning an agent able to transform his/her situation instead of reproducing it." (Touraine, 1992, p. 476). PMID- 26483712 TI - The experience of premature birth for fathers: the application of the Clinical Interview for Parents of High-Risk Infants (CLIP) to an Italian sample. AB - AIM: The study explored fathers' experience of premature birth during the hospitalization of their infants, analyzing levels of depressive and anxiety symptoms as compared with mothers. Moreover the Italian version of the Clinical Interview for Parents of High-Risk Infant (CLIP) was tested through confirmatory factor analysis. METHODS: Couples of parents (N = 64) of preterm infants (gestational age < 37 weeks) were administered a socio-demographic questionnaire, the Edinburgh Postnatal Depression Scale, the State-Trait Anxiety Inventory and the CLIP after the admission to the Neonatal Intensive Care Unit (NICU). RESULTS: Significant levels of anxiety and depressive symptoms and high percentages of subjects above the corresponding risk thresholds were found among fathers and mothers with higher scores among the latters. Confirmatory factor analysis of the CLIP showed an adequate structure, with better fit for mothers than for fathers. CONCLUSION: RESULTS highlighted the importance for nurses and clinicians working in the NICU to consider not only the maternal difficulties but also the paternal ones, even if these are often more hidden and silent. In addition the CLIP may be considered an useful interview for research and clinical purposes to be used with parents of high-risk infants. PMID- 26483713 TI - The computational psychiatry of reward: broken brains or misguided minds? AB - Research into the biological basis of emotional and motivational disorders is in danger of riding roughshod over a patient-centered psychiatry and falling into the dualist errors of the past, i.e., by treating mind and brain as conceptually distinct. We argue that a psychiatry informed by computational neuroscience, computational psychiatry, can obviate this danger. Through a focus on the reasoning processes by which humans attempt to maximize reward (and minimize punishment), and how such reasoning is expressed neurally, computational psychiatry can render obsolete the polarity between biological and psychosocial conceptions of illness. Here, the term 'psychological' comes to refer to information processing performed by biological agents, seen in light of underlying goals. We reflect on the implications of this perspective for a definition of mental disorder, including what is entailed in asserting that a particular disorder is 'biological' or 'psychological' in origin. We propose that a computational approach assists in understanding the topography of mental disorder, while cautioning that the point at which eccentric reasoning constitutes disorder often remains a matter of cultural judgment. PMID- 26483709 TI - The role of REM sleep theta activity in emotional memory. AB - While non-REM (NREM) sleep has been strongly implicated in the reactivation and consolidation of memory traces, the role of rapid-eye movement (REM) sleep remains unclear. A growing body of research on humans and animals provide behavioral evidence for a role of REM sleep in the strengthening and modulation of emotional memories. Theta activity-which describes low frequency oscillations in the local field potential within the hippocampus, amygdala and neocortex-is a prominent feature of both wake and REM sleep in humans and rodents. Theta coherence between the hippocampus and amygdala drives large-scale pontine geniculo-occipital (PGO) waves, the density of which predicts increases in plasticity-related gene expression. This could potentially facilitate the processing of emotional memory traces within the hippocampus during REM sleep. Further, the timing of hippocampal activity in relation to theta phase is vital in determining subsequent potentiation of neuronal activity. This could allow the emotionally modulated strengthening of novel and gradual weakening of consolidated hippocampal memory traces during REM sleep. Hippocampal theta activity is also correlated with REM sleep levels of achetylcholine - which is thought to reduce hippocampal inputs in the neocortex. The additional low levels of noradrenaline during REM sleep, which facilitate feedback within the neocortex, could allow the integration of novel memory traces previously consolidated during NREM sleep. We therefore propose that REM sleep mediates the prioritized processing of emotional memories within the hippocampus, the integration of previously consolidated memory traces within the neocortex, as well as the disengagement of consolidated neocortical memory traces from the hippocampus. PMID- 26483714 TI - Early literacy experiences constrain L1 and L2 reading procedures. AB - Computational models of reading posit that there are two pathways to word recognition, using sublexical phonology or morphological/orthographic information. They further theorize that everyone uses both pathways to some extent, but the division of labor between the pathways can vary. This review argues that the first language one was taught to read, and the instructional method by which one was taught, can have profound and long-lasting effects on how one reads, not only in one's first language, but also in one's second language. Readers who first learn a transparent orthography rely more heavily on the sublexical phonology pathway, and this seems relatively impervious to instruction. Readers who first learn a more opaque orthography rely more on morphological/orthographic information, but the degree to which they do so can be modulated by instructional method. Finally, readers who first learned to read a highly opaque morphosyllabic orthography use less sublexical phonology while reading in their second language than do other second language learners and this effect may be heightened if they were not also exposed to an orthography that codes for phonological units during early literacy acquisition. These effects of early literacy experiences on reading procedure are persistent despite increases in reading ability. PMID- 26483715 TI - Quantum structure of negation and conjunction in human thought. AB - We analyze in this paper the data collected in a set of experiments investigating how people combine natural concepts. We study the mutual influence of conceptual conjunction and negation by measuring the membership weights of a list of exemplars with respect to two concepts, e.g., Fruits and Vegetables, and their conjunction Fruits And Vegetables, but also their conjunction when one or both concepts are negated, namely, Fruits And Not Vegetables, Not Fruits And Vegetables, and Not Fruits And Not Vegetables. Our findings sharpen and advance existing analysis on conceptual combinations, revealing systematic deviations from classical (fuzzy set) logic and probability theory. And, more important, our results give further considerable evidence to the validity of our quantum theoretic framework for the combination of two concepts. Indeed, the representation of conceptual negation naturally arises from the general assumptions of our two-sector Fock space model, and this representation faithfully agrees with the collected data. In addition, we find a new significant and a priori unexpected deviation from classicality, which can exactly be explained by assuming that human reasoning is the superposition of an "emergent reasoning" and a "logical reasoning," and that these two processes are represented in a Fock space algebraic structure. PMID- 26483716 TI - When the theory of mind would be very useful. PMID- 26483717 TI - Issues and advances in research methods on video games and cognitive abilities. AB - The impact of video game playing on cognitive abilities has been the focus of numerous studies over the last 10 years. Some cross-sectional comparisons indicate the cognitive advantages of video game players (VGPs) over non-players (NVGPs) and the benefits of video game trainings, while others fail to replicate these findings. Though there is an ongoing discussion over methodological practices and their impact on observable effects, some elementary issues, such as the representativeness of recruited VGP groups and lack of genre differentiation have not yet been widely addressed. In this article we present objective and declarative gameplay time data gathered from large samples in order to illustrate how playtime is distributed over VGP populations. The implications of this data are then discussed in the context of previous studies in the field. We also argue in favor of differentiating video games based on their genre when recruiting study samples, as this form of classification reflects the core mechanics that they utilize and therefore provides a measure of insight into what cognitive functions are likely to be engaged most. Additionally, we present the Covert Video Game Experience Questionnaire as an example of how this sort of classification can be applied during the recruitment process. PMID- 26483718 TI - Becoming popular: interpersonal emotion regulation predicts relationship formation in real life social networks. AB - Building relationships is crucial for satisfaction and success, especially when entering new social contexts. In the present paper, we investigate whether attempting to improve others' feelings helps people to make connections in new networks. In Study 1, a social network study following new networks of people for a 12-week period indicated that use of interpersonal emotion regulation (IER) strategies predicted growth in popularity, as indicated by other network members' reports of spending time with the person, in work and non-work interactions. In Study 2, linguistic analysis of the tweets from over 8000 Twitter users from formation of their accounts revealed that use of IER predicted greater popularity in terms of the number of followers gained. However, not all types of IER had positive effects. Behavioral IER strategies (which use behavior to reassure or comfort in order to regulate affect) were associated with greater popularity, while cognitive strategies (which change a person's thoughts about his or her situation or feelings in order to regulate affect) were negatively associated with popularity. Our findings have implications for our understanding of how new relationships are formed, highlighting the important the role played by intentional emotion regulatory processes. PMID- 26483719 TI - Female social response to male sexual harassment in poeciliid fish: a comparison of six species. AB - Sexual harassment is common among poeciliid fish. In some fishes, males show a high frequency of sneak copulation; such sexual activity is costly to the females in terms of foraging efficiency. In mosquitofish (Gambusia holbrooki), when males are present, the distance between females tends to decrease, and this behavior has been interpreted as an adaptive strategy to dilute the costs of male sexual activity. In this study, the tendency to reduce distance in the presence of a male has been investigated in females of six poeciliid species (Girardinus metallicus, Girardinus falcatus, G. holbrooki, Poecilia reticulata, Xiphophorus hellerii, and Xiphophorus mayae) that exhibit different male mating strategies and different levels of sexual activity. Results revealed large interspecific differences in the pattern of female aggregation. Females of species with a high frequency of sneak copulations tended to reduce their social distance in the presence of a male. By contrast, species that rely mainly on courtship showed little or no variation in social distance. The proportion of sneak copulations predicts the degree of variation in female social response, but the amount of total sexual activity does not, suggesting that the change in females' social distance when a male is present may indeed serve to reduce the costs of male sexual harassment. PMID- 26483720 TI - The segment as the minimal planning unit in speech production and reading aloud: evidence and implications. AB - Speech production and reading aloud studies have much in common, especially the last stages involved in producing a response. We focus on the minimal planning unit (MPU) in articulation. Although most researchers now assume that the MPU is the syllable, we argue that it is at least as small as the segment based on negative response latencies (i.e., response initiation before presentation of the complete target) and longer initial segment durations in a reading aloud task where the initial segment is primed. We also discuss why such evidence was not found in earlier studies. Next, we rebut arguments that the segment cannot be the MPU by appealing to flexible planning scope whereby planning units of different sizes can be used due to individual differences, as well as stimulus and experimental design differences. We also discuss why negative response latencies do not arise in some situations and why anticipatory coarticulation does not preclude the segment MPU. Finally, we argue that the segment MPU is also important because it provides an alternative explanation of results implicated in the serial vs. parallel processing debate. PMID- 26483721 TI - Literacy transforms speech production. PMID- 26483722 TI - Understanding help-seeking amongst university students: the role of group identity, stigma, and exposure to suicide and help-seeking. AB - BACKGROUND: Despite a high prevalence of suicide ideation and mental health issues amongst university students, the stigma of help-seeking remains a barrier to those who are in real need of professional support. Social identity theory states that help received from an ingroup source is more welcome and less threatening to one's identity than that from a source perceived as outgroup. Therefore, we hypothesized that students' stigma toward seeking help from their university mental health service would differ based on the strength of their identification with the university. METHOD: An online survey including measures of stigma of suicide, group identification, experience with help-seeking and exposure to suicide was administered to Irish university students (N = 493). RESULTS: Group identification was a significant predictor of help-seeking attitudes after controlling for already known predictors. Contrary to our expectations, those who identified more strongly with their university demonstrated a higher stigma of seeking help from their university mental health service. CONCLUSIONS: RESULTS are discussed in relation to self-categorization theory and the concept of normative fit. Practical implications for mental health service provision in universities are also addressed, specifically the need for a range of different mental health services both on and off-campus. PMID- 26483723 TI - Spontaneous recovery of effects of contrast adaptation without awareness. AB - Prolonged exposure to a high contrast stimulus reduces the neural sensitivity to subsequent similar patterns. Recent work has disclosed that contrast adaptation is controlled by multiple mechanisms operating over differing timescales. Adaptation to high contrast for a relatively longer period can be rapidly eliminated by adaptation to a lower contrast (or meanfield in the present study). Such rapid deadaptation presumably causes a short-term mechanism to signal for a sensitivity increase, canceling ongoing signals from long-term mechanisms. Once deadaptation ends, the short-term mechanism rapidly returns to baseline, and the slowly decaying effects in the long-term mechanisms reemerge, allowing the perceptual aftereffects to recover during continued testing. Although this spontaneous recovery effect is considered strong evidence supporting the multiple mechanisms theory, it remains controversial whether the effect is mainly driven by visual memory established during the initial longer-term adaptation period. To resolve this debate, we used a modified Continuous Flash Suppression (CFS) and visual crowding paradigms to render the adapting stimuli invisible, but still observed the spontaneous recovery phenomenon. These results exclude the possibility that spontaneous recovery found in the previous work was merely the consequence of explicit visual memory. Our findings also demonstrate that contrast adaptation, even at the unconscious processing levels, is controlled by multiple mechanisms. PMID- 26483724 TI - Priming of conflicting motivational orientations in heavy drinkers: robust effects on self-report but not implicit measures. AB - We report results from three experimental studies that investigated the independence of approach and avoidance motivational orientations for alcohol, both of which operate within controlled and automatic cognitive processes. In order to prime their approach or avoidance motivational orientations, participants watched brief videos, the content of which (positive or negative depictions of alcohol, or neutral) varied by experimental group. Immediately after watching the videos, participants completed self-report (Approach and Avoidance of Alcohol Questionnaire; all studies) and implicit (visual probe task in study 1, stimulus-response compatibility task in studies 2 and 3) measures of alcohol-related approach and avoidance. In study 3, we incorporated an additional experimental manipulation of thought suppression in an attempt to maximize the influence of the videos on implicit measures. Findings were consistent across all three studies: increases in self-reported approach inclinations were mirrored by decreases in avoidance inclinations, and vice versa. However, a combined analysis of data from all studies demonstrated that changes in approach inclinations were partially independent of changes in avoidance inclinations. There were no effects on implicit alcohol-related processing biases, although methodological issues may partially account for these findings. Our findings demonstrate that subjective approach and avoidance inclinations for alcohol tend to fluctuate in parallel, but changes in approach inclinations may be partially independent from changes in avoidance inclinations. We discuss methodological issues that may partially account for our findings. PMID- 26483725 TI - Theoretical pluralism in psychoanalytic case studies. AB - The aim of this study is to provide an overview of the scientific activity of different psychoanalytic schools of thought in terms of the content and production of case studies published on ISI Web of Knowledge. Between March 2013 and November 2013, we contacted all case study authors included in the online archive of psychoanalytic and psychodynamic case studies (www.singlecasearchive.com) to inquire about their psychoanalytic orientation during their work with the patient. The response rate for this study was 45%. It appears that the two oldest psychoanalytic schools, Object-relations psychoanalysis and Ego psychology or "Classical psychoanalysis" dominate the literature of published case studies. However, most authors stated that they feel attached to two or more psychoanalytic schools of thought. This confirms that the theoretical pluralism in psychoanalysis stretches to the field of single case studies. The single case studies of each psychoanalytic school are described separately in terms of methodology, patient, therapist, or treatment features. We conclude that published case studies features are fairly similar across different psychoanalytic schools. The results of this study are not representative of all psychoanalytic schools, as some do not publish their work in ISI ranked journals. PMID- 26483726 TI - The conjunction of non-consciously perceived object identity and spatial position can be retained during a visual short-term memory task. AB - Although non-consciously perceived information has previously been assumed to be short-lived (< 500 ms), recent findings show that non-consciously perceived information can be maintained for at least 15 s. Such findings can be explained as working memory without a conscious experience of the information to be retained. However, whether or not working memory can operate on non-consciously perceived information remains controversial, and little is known about the nature of such non-conscious visual short-term memory (VSTM). Here we used continuous flash suppression to render stimuli non-conscious, to investigate the properties of non-consciously perceived representations in delayed match-to-sample (DMS) tasks. In Experiment I we used variable delays (5 or 15 s) and found that performance was significantly better than chance and was unaffected by delay duration, thereby replicating previous findings. In Experiment II the DMS task required participants to combine information of spatial position and object identity on a trial-by-trial basis to successfully solve the task. We found that the conjunction of spatial position and object identity was retained, thereby verifying that non-conscious, trial-specific information can be maintained for prospective use. We conclude that our results are consistent with a working memory interpretation, but that more research is needed to verify this interpretation. PMID- 26483727 TI - Lucid dreams: their advantage and disadvantage in the frame of search activity concept. AB - Search activity (SA) is the behavioral and mental activity that is oriented to changes of the environment or of the subject's view and approach to the environment according to personal needs without the definite probability forecast of the outcomes of such activity, but with a regular consideration of the outcomes in the process of active behavior. Dream's lucidity (the subject's realization that he/she is dreaming) protects dreamer from awakenings during emotionally disturbing or frustrating dreams, because lucid dreams allow subject to feel separated from the dream events that may cause a feeling of helplessness. Due to such a protection from awakenings that can bring subject back to the frustration in wakefulness, subject can turn in the further sleep to normal non lucid dreams that are restoring subject's SA in the subsequent wakefulness (activity in the uncertain situation with the feedback between behavior and its outcome). It is the advantage of lucid dreams. Their disadvantage is that due to the separation from the dream events that are in lucid dreams accepted as rationalized dreams, not as real stories where the dreamer acts like in wakefulness, their ability to restore SA is decreased until they are not displaced by the normal non-lucid dreams accepted as real stories. PMID- 26483728 TI - Similarities between the target and the intruder in naturally occurring repeated person naming errors. AB - The present study investigated an intriguing phenomenon that did not receive much attention so far: repeatedly calling a familiar person with someone else's name. From participants' responses to a questionnaire, these repeated naming errors were characterized with respect to a number of properties (e.g., type of names being substituted, error frequency, error longevity) and different features of similarity (e.g., age, gender, type of relationship with the participant, face resemblance and similarity of the contexts of encounter) between the bearer of the target name and the bearer of the wrong name. Moreover, it was evaluated whether the phonological similarity between names, the participants' age, the difference of age between the two persons whose names were substituted, and face resemblance between the two persons predicted the frequency of error. Regression analyses indicated that phonological similarity between the target name and the wrong name predicted the frequency of repeated person naming errors. The age of the participant was also a significant predictor of error frequency: the older the participant the higher the frequency of errors. Consistent with previous research stressing the importance of the age of acquisition of words on lexical access in speech production, results indicated that bearer of the wrong name was on average known for longer than the bearer of the target name. PMID- 26483729 TI - Through a glass darkly: facial wrinkles affect our processing of emotion in the elderly. AB - The correct interpretation of emotional expressions is crucial for social life. However, emotions in old relative to young faces are recognized less well. One reason for this may be decreased signal clarity of older faces due to morphological changes, such as wrinkles and folds, obscuring facial displays of emotions. Across three experiments, the present research investigates how misattributions of emotions to elderly faces impair emotion discrimination. In a preliminary task, neutral expressions were perceived as more expressive in old than in young faces by human raters (Experiment 1A) and an automatic system for emotion recognition (Experiment 1B). Consequently, task difficulty was higher for old faces relative to young faces in a visual search task (Experiment 2). Specifically, participants detected old faces expressing negative emotions less accurately and slower among neutral faces of their peers than young faces among neutral faces of their peers. Thus, we argue that age-related changes in facial features are the most plausible explanation for the differences in emotion perception between young and old faces. These findings are of relevance for the social interchange with the elderly, especially when multiple older individuals are present. PMID- 26483730 TI - Nonlinear response speedup in bimodal visual-olfactory object identification. AB - Multisensory processes are vital in the perception of our environment. In the evaluation of foodstuff, redundant sensory inputs not only assist the identification of edible and nutritious substances, but also help avoiding the ingestion of possibly hazardous substances. While it is known that the non chemical senses interact already at early processing levels, it remains unclear whether the visual and olfactory senses exhibit comparable interaction effects. To address this question, we tested whether the perception of congruent bimodal visual-olfactory objects is facilitated compared to unimodal stimulation. We measured response times (RT) and accuracy during speeded object identification. The onset of the visual and olfactory constituents in bimodal trials was physically aligned in the first and perceptually aligned in the second experiment. We tested whether the data favored coactivation or parallel processing consistent with race models. A redundant-signals effect was observed for perceptually aligned redundant stimuli only, i.e., bimodal stimuli were identified faster than either of the unimodal components. Analysis of the RT distributions and accuracy data revealed that these observations could be explained by a race model. More specifically, visual and olfactory channels appeared to be operating in a parallel, positively dependent manner. While these results suggest the absence of early sensory interactions, future studies are needed to substantiate this interpretation. PMID- 26483731 TI - Prosodic cues enhance rule learning by changing speech segmentation mechanisms. AB - Prosody has been claimed to have a critical role in the acquisition of grammatical information from speech. The exact mechanisms by which prosodic cues enhance learning are fully unknown. Rules from language often require the extraction of non-adjacent dependencies (e.g., he plays, he sings, he speaks). It has been proposed that pauses enhance learning because they allow computing non adjacent relations helping word segmentation by removing the need to compute adjacent computations. So far only indirect evidence from behavioral and electrophysiological measures comparing learning effects after exposure to speech with and without pauses support this claim. By recording event-related potentials during the acquisition process of artificial languages with and without pauses between words with embedded non-adjacent rules we provide direct evidence on how the presence of pauses modifies the way speech is processed during learning to enhance segmentation and rule generalization. The electrophysiological results indicate that pauses as short as 25 ms attenuated the N1 component irrespective of whether learning was possible or not. In addition, a P2 enhancement was present only when learning of non-adjacent dependencies was possible. The overall results support the claim that the simple presence of subtle pauses changed the segmentation mechanism used reflected in an exogenously driven N1 component attenuation and improving segmentation at the behavioral level. This effect can be dissociated from the endogenous P2 enhancement that is observed irrespective of the presence of pauses whenever non-adjacent dependencies are learned. PMID- 26483732 TI - An object-identity probability cueing paradigm during grasping observation: the facilitating effect is present only when the observed kinematics is suitable for the cued object. AB - Electrophysiological and psychophysical data indicate that grasping observation automatically orients attention toward the incoming interactions between the actor's hand and the object. The aim of the present study was to clarify if this effect facilitates the detection of a graspable object with the observed action as compared to an ungraspable one. We submitted participants to an object identity probability cueing experiment in which the two possible targets were of the same dimensions but one of them presented sharp tips at one extreme while the other presented flat faces. At the beginning of each trial the most probable target was briefly shown. After a variable interval, at the same position, the same (75%) or a different target (25%) was presented. Participants had to press a key in response to target appearance. Superimposed to the video showing cue and target, an agent performing the reaching and grasping of the target was presented. The kinematics of the action was or was not suitable for grasping the cued target, according to the absence or presence of the sharp tips. Results showed that response was modulated by the probability of target identity but only when the observed kinematics was suitable to grasp the attended target. A further experiment clarified that response modulation was never present when the superimposed video always showed the agent at a rest position. These findings are discussed at the light of neurophysiological and psychophysical literature, considering the relationship between the motor system and the perception of objects and of others' actions. We conclude that the prediction of the mechanical events that arise from the interactions between the hand and the attended object is at the basis of the capability to select a graspable object in space. PMID- 26483733 TI - Frontal EEG alpha activity and obsessive-compulsive behaviors in non-clinical young adults: a pilot study. AB - Previous studies have shown that the resting electroencephalogram (EEG) alpha patterns of non-clinical participants who score high on measures of negative affect, such as depression and shyness, are different from those who score low. However, we know relatively little about patterns of resting EEG alpha patterns in a non-clinical sample of individuals with high levels of obsessive-compulsive behaviors indicative of obsessive-compulsive disorder (OCD). Here we measured resting EEG alpha activity in frontal and parietal regions of non-clinical participants who scored high and low on the Padua-R, a measure of the severity of OCD-related behaviors. We found that participants who scored high on the Padua-R exhibited decreased overall activity in frontal regions relative to individuals who scored low on the measure. We speculate that frontal hypoactivity may be a possible marker and/or index of risk for OCD. PMID- 26483734 TI - Brief quiet ego contemplation reduces oxidative stress and mind-wandering. AB - Excessive self-concern increases perceptions of threat and defensiveness. In contrast, fostering a more inclusive and expanded sense of self can reduce stress and improve well-being. We developed and tested a novel brief intervention designed to strengthen a student's compassionate self-identity, an identity that values balance and growth by reminding them of four quiet ego characteristics: detached awareness, inclusive identity, perspective taking, and growth. Students (N = 32) in their first semester of college who reported greater self-protective (e.g., defensive) goals in the first 2 weeks of the semester were invited to participate in the study. Volunteers were randomly assigned to one of three conditions: quiet ego contemplation (QEC), QEC with virtual reality (VR) headset (QEC-VR), and control. Participants came to the lab three times to engage in a 15 min exercise in a 30-days period. The 15-min QEC briefly described each quiet ego characteristic followed by a few minutes time to reflect on what that characteristic meant to them. Those in the QEC condition reported improved quiet ego characteristics and pluralistic thinking, decreases in a urinary marker of oxidative stress, and reduced mind-wandering on a cognitive task. Contrary to expectation, participants who wore the VR headsets while listening to the QEC demonstrated the least improvement. Results suggest that a brief intervention that reduces self-focus and strengthens a more compassionate self-view may offer an additional resource that individuals can use in their everyday lives. PMID- 26483735 TI - The dampening effect of employees' future orientation on cyberloafing behaviors: the mediating role of self-control. AB - Previous studies on reducing employees' cyberloafing behaviors have primarily examined the external control factors but seldomly taken individual internal subjective factors into consideration. Future orientation, an important individual factor, is defined as the extent to which one plans for future time and considers future consequences of one's current behavior. To explore further whether and how employees' future orientation can dampen their cyberloafing behaviors, two studies were conducted to examine the relationship between employees' future orientation and cyberloafing behaviors. The mediation effect of employees' objective and subjective self-control between them was also examined. In Study 1, a set of questionnaires was completed, and the results revealed that the relationship between employees' future orientation and cyberloafing behaviors was negative, and objective self-control mediated the relationship. Next, we conducted a priming experiment (Study 2) to examine the causal relationship and psychological mechanism between employees' future orientation and cyberloafing behaviors. The results demonstrated that employees' future-orientation dampened their attitudes and intentions to engage in cyberloafing, and subjective self control mediated this dampening effect. Theoretical and practical implications of these findings are also discussed. PMID- 26483736 TI - Commentary: Do motivations for using Facebook moderate the association between Facebook use and psychological well-being? PMID- 26483737 TI - Using interpersonal affect regulation in simulated healthcare consultations: an experimental investigation of self-control resource depletion. AB - Controlled Interpersonal Affect Regulation -the process of deliberately influencing the internal feeling states of others- occurs in a variety of interpersonal relationships and contexts. An incipient corpus of research shows that interpersonal affect regulation can be characterized as a goal-directed behavior that uses self-control processes which, according to the strength model of self-regulation, consumes a limited resource that is also used by other self control processes. Using interpersonal affect-improving and affect-worsening regulation strategies can increase agent's resource depletion but there is reason to think that effects will partially rely on target's feedback in response to the regulation. Using a healthcare paradigm, an experiment was conducted to test the combined effects of interpersonal affect regulation use and patient feedback on healthcare workers' resource depletion, measured as self-reported experienced and expected emotional exhaustion, and persistence on a self-regulation task. Medical students (N = 78) were randomly assigned to a 2(interpersonal affect regulation: affect-worsening vs. affect-improving) * 2(patients' feedback: positive vs. negative) factorial between-subjects design and given instructions to play the role of doctors in interactions with two professional actors trained to act as patients. Analysis of covariance showed that affect-worsening was more depleting than affect-improving for all measures, whereas the recovery effects of positive feedback varied depending on strategy type and measure. The findings confirm the characterization of interpersonal affect regulation as potentially depleting, but suggest that the correspondence between the agent's strategy and the target's response needs to be taken into consideration. Use of affect-improving and positive feedback showed positive effects on self-rated performance, indicating that interpersonal affect regulation is relevant for organizational as well as personal outcomes. PMID- 26483738 TI - Modulation of executive attention by threat stimulus in test-anxious students. AB - The study examined whether test anxiety (TA) is related to impaired attentional networks under emotional distraction. High and low test-anxious students completed a modified version of the attention network test (ANT) in which emotional distracters, specifically threat-related or neutral words, were embedded in centrally presented hollow arrows in Experiment 1. Results showed a significant reduction in efficiency of the executive attention in test-anxious students compared to controls when the fillers were threat/test-related words. To evaluate the effect of the test adaptation, the original ANT, which utilized no emotional distracter, was employed as a control task in Experiment 2. We then consolidated the data on efficiency of attentional networks, which were derived from both tasks. Contrasting the two tasks showed that TA reduced executive attention in the revised task only, suggesting an enhanced sensitivity provided by the adaptation from the original task. Taken together, these findings indicate that the attentional deficit in test-anxious individuals represents a situation related defect of a single component of attention rather than an underlying structural and universal attentional deficit. The results support the hypothesis of attentional control theory and contribute to the understanding of attentional mechanisms in individuals with TA. PMID- 26483739 TI - Cognitive foundations of organizational learning: re-introducing the distinction between declarative and non-declarative knowledge. AB - Contemporary research into socio-cognitive foundations of organizational learning tends to disregard the distinction between declarative and non-declarative knowledge. By reviewing the literature from organizational learning research and cognitive psychology we explain that this distinction is crucial. We describe the foundations of organizational learning by referring to models that consider the interplay between individual and collective knowledge-related processes in organizations. We highlight the existence of a research gap resulting from the finding that these approaches have widely neglected the existence of different types of knowledge. We then elaborate on characteristics of declarative and non declarative knowledge in general, consider organizations as structures of distributed cognition, and discuss the relationship between organizational knowledge and practice. Subsequently, we examine the role of declarative and non declarative knowledge in the context of organizational learning. Here, we analyze (1) the cognitive and social mechanisms underlying the development of declarative and non-declarative knowledge within structures of distributed cognition; and (2) the relationship between alterations in declarative and non-declarative types of knowledge on the one hand and changes in organizational practice on the other. Concluding, we discuss implications of our analysis for organizational learning research. We explain how our integrative perspective may offer starting points for a refined understanding of the sub-processes involved in organizational learning and unlearning and may support a better understanding of practical problems related to organizational learning and change. PMID- 26483740 TI - Neural correlates of gratitude. AB - Gratitude is an important aspect of human sociality, and is valued by religions and moral philosophies. It has been established that gratitude leads to benefits for both mental health and interpersonal relationships. It is thus important to elucidate the neurobiological correlates of gratitude, which are only now beginning to be investigated. To this end, we conducted an experiment during which we induced gratitude in participants while they underwent functional magnetic resonance imaging. We hypothesized that gratitude ratings would correlate with activity in brain regions associated with moral cognition, value judgment and theory of mind. The stimuli used to elicit gratitude were drawn from stories of survivors of the Holocaust, as many survivors report being sheltered by strangers or receiving lifesaving food and clothing, and having strong feelings of gratitude for such gifts. The participants were asked to place themselves in the context of the Holocaust and imagine what their own experience would feel like if they received such gifts. For each gift, they rated how grateful they felt. The results revealed that ratings of gratitude correlated with brain activity in the anterior cingulate cortex and medial prefrontal cortex, in support of our hypotheses. The results provide a window into the brain circuitry for moral cognition and positive emotion that accompanies the experience of benefitting from the goodwill of others. PMID- 26483741 TI - Early developmental changes in the timing of turn-taking: a longitudinal study of mother-infant interaction. AB - To accomplish a smooth transition in conversation from one speaker to the next, a tight coordination of interaction between speakers is required. Recent studies of adult conversation suggest that this close timing of interaction may well be a universal feature of conversation. In the present paper, we set out to assess the development of this close timing of turns in infancy in vocal exchanges between mothers and infants. Previous research has demonstrated an early sensitivity to timing in interactions (e.g., Murray and Trevarthen, 1985). In contrast, less is known about infants' abilities to produce turns in a timely manner and existing findings are rather patchy. We conducted a longitudinal study of 12 mother-infant dyads in free-play interactions at the ages of 3, 4, 5, 9, 12, and 18 months. Based on existing work and the predictions made by the Interaction Engine Hypothesis (Levinson, 2006), we expected that infants would begin to develop the temporal properties of turn-taking early in infancy but that their timing of turns would slow down at 12 months, which is around the time when infants start to produce their first words. Findings were consistent with our predictions: infants were relatively fast at timing their turn early in infancy but slowed down toward the end of the first year. Furthermore, the changes observed in infants' turn-timing skills were not caused by changes in maternal timing, which remained stable across the 3-18 months period. However, the slowing down of turn timing started somewhat earlier than predicted: at 9 months. PMID- 26483742 TI - Income, personality, and subjective financial well-being: the role of gender in their genetic and environmental relationships. AB - Increasing levels of financial inequality prompt questions about the relationship between income and well-being. Using a twins sample from the Survey of Midlife Development in the U. S. and controlling for personality as core self-evaluations (CSE), we found that men, but not women, had higher subjective financial well being (SFWB) when they had higher incomes. This relationship was due to 'unshared environmental' factors rather than genes, suggesting that the effect of income on SFWB is driven by unique experiences among men. Further, for women and men, we found that CSE influenced income and SFWB, and that both genetic and environmental factors explained this relationship. Given the relatively small and male-specific relationship between income and SFWB, and the determination of both income and SFWB by personality, we propose that policy makers focus on malleable factors beyond merely income in order to increase SFWB, including financial education and building self-regulatory capacity. PMID- 26483743 TI - A crisis in comparative psychology: where have all the undergraduates gone? PMID- 26483744 TI - A cross-cultural study on emotion expression and the learning of social norms. AB - When we do not know how to correctly behave in a new context, the emotions that people familiar with the context show in response to the behaviors of others, can help us understand what to do or not to do. The present study examined cross cultural differences in how group emotional expressions (anger, sadness, neutral) can be used to deduce a norm violation in four cultures (Germany, Israel, Greece, and the US), which differ in terms of decoding rules for negative emotions. As expected, in all four countries, anger was a stronger norm violation signal than sadness or neutral expressions. However, angry and sad expressions were perceived as more intense and the relevant norm was learned better in Germany and Israel than in Greece and the US. Participants in Greece were relatively better at using sadness as a sign of a likely norm violation. The results demonstrate both cultural universality and cultural differences in the use of group emotion expressions in norm learning. In terms of cultural differences they underscore that the social signal value of emotional expressions may vary with culture as a function of cultural differences, both in emotion perception, and as a function of a differential use of emotions. PMID- 26483746 TI - Evolution of speech-specific cognitive adaptations. AB - This paper argues that an evolutionary perspective is natural when investigating cognitive adaptations related to language. This is because there appears to be correspondence between traits that linguists consider interesting and traits that have undergone selective pressure related to language. The paper briefly reviews theoretical results that shed light on what kind of adaptations we can expect to have evolved and then reviews concrete work related to the evolution of adaptations for combinatorial speech. It turns out that there is as yet no strong direct evidence for cognitive traits that have undergone selection related to speech, but there is indirect evidence that indicates selection. However, the traits that may have undergone selection are expected to be continuously variable ones, rather than the discrete ones that linguists have focused on traditionally. PMID- 26483745 TI - Walking indoors, walking outdoors: an fMRI study. AB - An observation/execution matching system for walking has not been assessed yet. The present fMRI study was aimed at assessing whether, as for object-directed actions, an observation/execution matching system is active for walking and whether the spatial context of walking (open or narrow space) recruits different neural correlates. Two experimental conditions were employed. In the execution condition, while being scanned, participants performed walking on a rolling cylinder located just outside the scanner. The same action was performed also while observing a video presenting either an open space (a country field) or a narrow space (a corridor). In the observation condition, participants observed a video presenting an individual walking on the same cylinder on which the actual action was executed, the open space video and the narrow space video, respectively. Results showed common bilateral activations in the dorsal premotor/supplementary motor areas and in the posterior parietal lobe for both execution and observation of walking, thus supporting a matching system for this action. Moreover, specific sectors of the occipital-temporal cortex and the middle temporal gyrus were consistently active when processing a narrow space versus an open one, thus suggesting their involvement in the visuo-motor transformation required when walking in a narrow space. We forward that the present findings may have implications for rehabilitation of gait and sport training. PMID- 26483747 TI - Self-construal priming selectively modulates the scope of visual attention. AB - Self-concept is one of the major factors to explain the cultural differences between East Asians and Westerners. In the field of visual attention, most studies have focused on the modulation of visual spatial-based attention, whereas possible influences of culture or self-concept on other types of visual attention remain largely unexplored. The present study investigated the possible modulation of visual feature-based attention by self-concept, using a within-group self construal priming design. The experiment paradigm employed visual stimuli consisted of two intermixing random dot clouds presented in the focal visual field with red and green colors. After primed with an interdependent, independent, or neutral self-construal, the participants were instructed to attend to one of the focally presented dot cloud and respond to occasional luminance decrement events of the attended dot cloud. The detection of the focal events was found to be significantly faster when exogenously cued by a peripheral dot cloud of either the same or different colors as the attended focal dot cloud (congruent/incongruent), compared to the uncued condition. More importantly, the self-construal priming took effect only on the reaction time (RT) differences between the congruent and incongruent cued conditions: the participants responded much slower to incongruent cued events than congruent cued events under interdependent self-construal priming, while the RT difference was significantly smaller under independent self-construal priming. A closer look on the results suggests that the attention scope is selectively modulated by self-construal priming, and the modulation is mainly reflected by varying the degree of suppression on the processing of the incongruent contextual stimuli that do not share visual features with the focal object. Our findings provide new evidences that could possibly extend the current understanding on the cultural influence on visual attention. PMID- 26483748 TI - Sexual orientation and gender identity: review of concepts, controversies and their relation to psychopathology classification systems. AB - Numerous controversies and debates have taken place throughout the history of psychopathology (and its main classification systems) with regards to sexual orientation and gender identity. These are still reflected on present reformulations of gender dysphoria in both the Diagnostic and Statistical Manual and the International Classification of Diseases, and in more or less subtle micro-aggressions experienced by lesbian, gay, bisexual and trans patients in mental health care. The present paper critically reviews this history and current controversies. It reveals that this deeply complex field contributes (i) to the reflection on the very concept of mental illness; (ii) to the focus on subjective distress and person-centered experience of psychopathology; and (iii) to the recognition of stigma and discrimination as significant intervening variables. Finally, it argues that sexual orientation and gender identity have been viewed, in the history of the field of psychopathology, between two poles: gender transgression and gender variance/fluidity. PMID- 26483749 TI - Activation of the intermediate sum in intentional and automatic calculations. AB - Most research investigating how the cognitive system deals with arithmetic has focused on the processing of two addends. Arithmetic that involves more addends has specific cognitive demands such as the need to compute and hold the intermediate sum. This study examines the intermediate sums activations in intentional and automatic calculations. Experiment 1 included addition problems containing three operands. Participants were asked to calculate the sum and to remember the digits that appeared in the problem. The results revealed an interference effect in which it was hard to identify that the digit representing the intermediate sum was not actually one of the operands. Experiment 2, further examined if the intermediate sum is activated automatically when a task does not require calculation. Here, participants were presented with a prime of an addition problem followed by a target number. The task was to determine whether the target number is odd or even, while ignoring the addition problem in the prime. The results suggested that the intermediate sum of the addition problem in the prime was activated automatically and facilitated the target. Overall, the implications of those findings in the context of theories that relate to cognitive mathematical calculation is further discussed. PMID- 26483751 TI - Erratum: An other-race effect for configural and featural processing of faces: upper and lower face regions play different roles. AB - [This corrects the article on p. 559 in vol. 6, PMID: 26005427.]. PMID- 26483750 TI - Trait rejection sensitivity is associated with vigilance and defensive response rather than detection of social rejection cues. AB - Prior studies suggest that psychological difficulties arise from higher trait Rejection Sensitivity (RS)-heightened vigilance and differential detection of social rejection cues and defensive response to. On the other hand, from an evolutionary perspective, rapid and efficient detection of social rejection cues can be considered beneficial. We conducted a survey and an electrophysiological experiment to reconcile this seeming contradiction. We compared the effects of RS and Rejection Detection Capability (RDC) on perceived interpersonal experiences (Study 1) and on neurocognitive processes in response to cues of social rejection (disgusted faces; Study 2). We found that RS and RDC were not significantly related, although RS was positively related to perceived social rejection experiences and RDC was positively related to perceived social inclusion experiences. Event-related brain potentials (ERPs) revealed that higher RS was related to cognitive avoidance (i.e., P1) and heightened motivated attention (i.e., late positive potential: LPP), but not to facial expression encoding (i.e., N170) toward disgusted faces. On the other hand, higher RDC was related to heightened N170 amplitude, but not to P1 and LPP amplitudes. These findings imply that sensitivity to rejection is apparently distinct from the ability to detect social rejection cues and instead reflects intense vigilance and defensive response to those cues. We discussed an alternative explanation of the relationship between RS and RDC from a signal detection perspective. PMID- 26483752 TI - Time to broaden the scope of research on anticipatory behavior: a case for the role of probabilistic information. PMID- 26483753 TI - Facilitating the Validation of Novel Protein Biomarkers for Dementia: An Optimal Workflow for the Development of Sandwich Immunoassays. AB - Different neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), lead to dementia syndromes. Dementia will pose a huge impact on society and thus it is essential to develop novel tools that are able to detect the earliest, most sensitive, discriminative, and dynamic biomarkers for each of the disorders. To date, the most common assays used in large-scale protein biomarker analysis are enzyme-linked immunosorbent assays (ELISA), such as the sandwich immunoassays, which are sensitive, practical, and easily implemented. However, due to the novelty of many candidate biomarkers identified during proteomics screening, such assays or the antibodies that specifically recognize the desired marker are often not available. The development and optimization of a new ELISA should be carried out with considerable caution since a poor planning can be costly, ineffective, time consuming, and it may lead to a misinterpretation of the findings. Previous guidelines described either the overall biomarker development in more general terms (i.e., the process from biomarker discovery to validation) or the specific steps of performing an ELISA procedure. However, a workflow describing and guiding the main issues in the development of a novel ELISA is missing. Here, we describe a specific and detailed workflow to develop and validate new ELISA for a successful and reliable validation of novel dementia biomarkers. The proposed workflow highlights the main issues in the development of an ELISA and covers several critical aspects, including production, screening, and selection of specific antibodies until optimal fine-tuning of the assay. Although these recommendations are designed to analyze novel biomarkers for dementia in cerebrospinal fluid, they are generally applicable for the development of immunoassays for biomarkers in other human body fluids or tissues. This workflow is designed to maximize the quality of the developed ELISA using a time- and cost efficient strategy. This will facilitate the validation of the dementia biomarker candidates ultimately allowing accurate diagnostic conclusions. PMID- 26483754 TI - Circadian Phenotype Composition is a Major Predictor of Diurnal Physical Performance in Teams. AB - Team performance is a complex phenomenon involving numerous influencing factors including physiology, psychology, and management. Biological rhythms and the impact of circadian phenotype have not been studied for their contribution to this array of factors so far despite our knowledge of the circadian regulation of key physiological processes involved in physical and mental performance. This study involved 216 individuals from 12 different teams who were categorized into circadian phenotypes using the novel RBUB chronometric test. The composition of circadian phenotypes within each team was used to model predicted daily team performance profiles based on physical performance tests. Our results show that the composition of circadian phenotypes within teams is variable and unpredictable. Predicted physical peak performance ranged from 1:52 to 8:59 p.m. with performance levels fluctuating by up to 14.88% over the course of the day. The major predictor for peak performance time in the course of a day in a team is the occurrence of late circadian phenotypes. We conclude that circadian phenotype is a performance indicator in teams that allows new insight and a better understanding of team performance variation in the course of a day as often observed in different groupings of individuals. PMID- 26483755 TI - Genetic Models for the Study of Luteinizing Hormone Receptor Function. AB - The luteinizing hormone/chorionic gonadotropin receptor (LHCGR) is essential for fertility in men and women. LHCGR binds luteinizing hormone (LH) as well as the highly homologous chorionic gonadotropin. Signaling from LHCGR is required for steroidogenesis and gametogenesis in males and females and for sexual differentiation in the male. The importance of LHCGR in reproductive physiology is underscored by the large number of naturally occurring inactivating and activating mutations in the receptor that result in reproductive disorders. Consequently, several genetically modified mouse models have been developed for the study of LHCGR function. They include targeted deletion of LH and LHCGR that mimic inactivating mutations in hormone and receptor, expression of a constitutively active mutant in LHCGR that mimics activating mutations associated with familial male-limited precocious puberty and transgenic models of LH and hCG overexpression. This review summarizes the salient findings from these models and their utility in understanding the physiological and pathological consequences of loss and gain of function in LHCGR signaling. PMID- 26483756 TI - Endocrine FGFs: Evolution, Physiology, Pathophysiology, and Pharmacotherapy. AB - The human fibroblast growth factor (FGF) family comprises 22 structurally related polypeptides that play crucial roles in neuronal functions, development, and metabolism. FGFs are classified as intracrine, paracrine, and endocrine FGFs based on their action mechanisms. Paracrine and endocrine FGFs are secreted signaling molecules by acting via cell-surface FGF receptors (FGFRs). Paracrine FGFs require heparan sulfate as a cofactor for FGFRs. In contrast, endocrine FGFs, comprising FGF19, FGF21, and FGF23, require alpha-Klotho or beta-Klotho as a cofactor for FGFRs. Endocrine FGFs, which are specific to vertebrates, lost heparan sulfate-binding affinity and acquired a systemic signaling system with alpha-Klotho or beta-Klotho during early vertebrate evolution. The phenotypes of endocrine FGF knockout mice indicate that they play roles in metabolism including bile acid, energy, and phosphate/active vitamin D metabolism. Accumulated evidence for the involvement of endocrine FGFs in human genetic and metabolic diseases also indicates their pathophysiological roles in metabolic diseases, potential risk factors for metabolic diseases, and useful biomarkers for metabolic diseases. The therapeutic utility of endocrine FGFs is currently being developed. These findings provide new insights into the physiological and pathophysiological roles of endocrine FGFs and potential diagnostic and therapeutic strategies for metabolic diseases. PMID- 26483757 TI - Interaction of drugs of abuse and microRNA with HIV: a brief review. AB - MicroRNAs (miRNAs), the post-transcriptional regulators of gene expression, play key roles in modulating many cellular processes. The changes in the expression profiles of several specific miRNAs affect the interactions between miRNA and their targets in various illnesses, including addiction, HIV, cancer etc. The presence of anti-HIV-1 microRNAs (which regulate the level of infectivity of HIV 1) have been validated in the cells which are the primary targets of HIV infection. Drugs of abuse impair the intracellular innate anti-HIV mechanism(s) in monocytes, contributing to cell susceptibility to HIV infection. Emerging evidence has implicated miRNAs are differentially expressed in response to chronic morphine treatment. Activation of mu opioid receptors (MOR) by morphine is shown to down regulate the expression of anti-HIV miRNAs. In this review, we summarize the results which demonstrate that several drugs of abuse related miRNAs have roles in the mechanisms that define addiction, and how they interact with HIV. PMID- 26483758 TI - New drug target in protozoan parasites: the role of thioredoxin reductase. AB - Amebiasis causes approximately 70,000 deaths annually and is the third cause of death due to parasites worldwide. It is treated primarily with metronidazole, which has adverse side effects, is mutagenic and carcinogenic, and emergence of resistance is an increasing concern. Unfortunately, better therapeutic alternatives are lacking. Re-purposing of older FDA approved drugs is advantageous to drug discovery since safety and pharmacokinetic effects in humans are already known. In high throughput screening studies, we recently demonstrated that auranofin, a gold containing compound originally approved to treat rheumatoid arthritis, has activity against trophozoites of E. histolytica, the causative agent of amebiasis. Auranofin's anti-parasitic activity is attributed to its monovalent gold molecule that readily inhibits E. histolytica thioredoxin reductase. This anti-oxidant enzyme is the only thiol-dependent flavo-reductase present in E. histolytica. Auranofin has also shown promising activity against other protozoans of significant public health importance. Altogether, this evidence suggests that auranofin has the potential to become a broad spectrum alternative therapeutic agent for diseases with a large global burden. PMID- 26483759 TI - Diverse and abundant multi-drug resistant E. coli in Matang mangrove estuaries, Malaysia. AB - E.coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant, and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34%) of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83%) and beta-lactams (37%). Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level and prevalence of integrons (integron I, 21%; integron II, 3%). Detection of phylogenetic group B23 downstream of fishing villages indicates human fecal contamination as a source of E. coli pollution. Enteroaggregative E. coli (1%) were also detected immediately downstream of the fishing village. The results indicated multi-drug resistance among E. coli circulating in Matang estuaries, which could be reflective of anthropogenic activities and aggravated by bacterial and antibiotic discharges from village lack of a sewerage system, aquaculture farms and upstream animal husbandry. PMID- 26483760 TI - Metabolomic and high-throughput sequencing analysis-modern approach for the assessment of biodeterioration of materials from historic buildings. AB - Preservation of cultural heritage is of paramount importance worldwide. Microbial colonization of construction materials, such as wood, brick, mortar, and stone in historic buildings can lead to severe deterioration. The aim of the present study was to give modern insight into the phylogenetic diversity and activated metabolic pathways of microbial communities colonized historic objects located in the former Auschwitz II-Birkenau concentration and extermination camp in Oswiecim, Poland. For this purpose we combined molecular, microscopic and chemical methods. Selected specimens were examined using Field Emission Scanning Electron Microscopy (FESEM), metabolomic analysis and high-throughput Illumina sequencing. FESEM imaging revealed the presence of complex microbial communities comprising diatoms, fungi and bacteria, mainly cyanobacteria and actinobacteria, on sample surfaces. Microbial diversity of brick specimens appeared higher than that of the wood and was dominated by algae and cyanobacteria, while wood was mainly colonized by fungi. DNA sequences documented the presence of 15 bacterial phyla representing 99 genera including Halomonas, Halorhodospira, Salinisphaera, Salinibacterium, Rubrobacter, Streptomyces, Arthrobacter and nine fungal classes represented by 113 genera including Cladosporium, Acremonium, Alternaria, Engyodontium, Penicillium, Rhizopus, and Aureobasidium. Most of the identified sequences were characteristic of organisms implicated in deterioration of wood and brick. Metabolomic data indicated the activation of numerous metabolic pathways, including those regulating the production of primary and secondary metabolites, for example, metabolites associated with the production of antibiotics, organic acids and deterioration of organic compounds. The study demonstrated that a combination of electron microscopy imaging with metabolomic and genomic techniques allows to link the phylogenetic information and metabolic profiles of microbial communities and to shed new light on biodeterioration processes. PMID- 26483761 TI - Trichoderma volatiles effecting Arabidopsis: from inhibition to protection against phytopathogenic fungi. AB - Trichoderma species are present in many ecosystems and some strains have the ability to reduce the severity of plant diseases by activating various defense pathways via specific biologically active signaling molecules. Hence we investigated the effects of low molecular weight volatile compounds of Trichoderma asperellum IsmT5 on Arabidopsis thaliana. During co-cultivation of T. asperellum IsmT5 without physical contact to A. thaliana we observed smaller but vital and robust plants. The exposed plants exhibit increased trichome numbers, accumulation of defense-related compounds such as H2O2, anthocyanin, camalexin, and increased expression of defense-related genes. We conclude that A. thaliana perceives the Trichoderma volatiles as stress compounds and subsequently initiates multilayered adaptations including activation of signaling cascades to withstand this environmental influence. The prominent headspace volatile of T. asperellum IsmT5 was identified to be 6-pentyl-alpha-pyrone (6PP), which was solely applied to A. thaliana to verify the growth and defense reactions. Most noticeable is that A. thaliana preexposed to 6PP showed significantly reduced symptoms when challenged with Botrytis cinerea and Alternaria brassicicola, indicating that defense-activated plants subsequently became more resistant to pathogen attack. Together, these results support that products that are based on Trichoderma volatiles have the potential being a useful biocontrol agent in agriculture. PMID- 26483762 TI - Ranking of persister genes in the same Escherichia coli genetic background demonstrates varying importance of individual persister genes in tolerance to different antibiotics. AB - Despite the identification of many genes and pathways involved in the persistence phenomenon of bacteria, the relative importance of these genes in a single organism remains unclear. Here, using Escherichia coli as a model, we generated mutants of 21 known candidate persister genes and compared the relative importance of these mutants in persistence to various antibiotics (ampicillin, gentamicin, norfloxacin, and trimethoprim) at different times. We found that oxyR, dnaK, sucB, relA, rpoS, clpB, mqsR, and recA were prominent persister genes involved in persistence to multiple antibiotics. These genes map to the following pathways: antioxidative defense pathway (oxyR), global regulators (dnaK, clpB, and rpoS), energy production (sucB), stringent response (relA), toxin-antitoxin (TA) module (mqsR), and SOS response (recA). Among the TA modules, the ranking order was mqsR, lon, relE, tisAB, hipA, and dinJ. Intriguingly, rpoS deletion caused a defect in persistence to gentamicin but increased persistence to ampicillin and norfloxacin. Mutants demonstrated dramatic differences in persistence to different antibiotics at different time points: some mutants (oxyR, dnaK, phoU, lon, recA, mqsR, and tisAB) displayed defect in persistence from early time points, while other mutants (relE, smpB, glpD, umuD, and tnaA) showed defect only at later time points. These results indicate that varying hierarchy and importance of persister genes exist and that persister genes can be divided into those involved in shallow persistence and those involved in deep persistence. Our findings suggest that the persistence phenomenon is a dynamic process with different persister genes playing roles of variable significance at different times. These findings have implications for improved understanding of persistence phenomenon and developing new drugs targeting persisters for more effective cure of persistent infections. PMID- 26483763 TI - Present and future medical applications of microbial exopolysaccharides. AB - Microbial exopolysaccharides (EPS) have found outstanding medical applications since the mid-20th century, with the first clinical trials on dextran solutions as plasma expanders. Other EPS entered medicine firstly as conventional pharmaceutical excipients (e.g., xanthan - as suspension stabilizer, or pullulan in capsules and oral care products). Polysaccharides, initially obtained from plant or animal sources, became easily available for a wide range of applications, especially when they were commercially produced by microbial fermentation. Alginates are used as anti-reflux, dental impressions, or as matrix for tablets. Hyaluronic acid and derivatives are used in surgery, arthritis treatment, or wound healing. Bacterial cellulose is applied in wound dressings or scaffolds for tissue engineering. The development of drug controlled-release systems and of micro- and nanoparticulated ones, has opened a new era of medical applications for biopolymers. EPS and their derivatives are well-suited potentially non-toxic, biodegradable drug carriers. Such systems concern rating and targeting of controlled release. Their large area of applications is explained by the available manifold series of derivatives, whose useful properties can be thereby controlled. From matrix inclusion to conjugates, different systems have been designed to solubilize, and to assure stable transport in the body, target accumulation and variable rate-release of a drug substance. From controlled drug delivery, EPS potential applications expanded to vaccine adjuvants and diagnostic imaging systems. Other potential applications are related to the bioactive (immunomodulator, antitumor, antiviral) characteristics of EPS. The numerous potential applications still wait to be developed into commercial pharmaceuticals and medical devices. Based on previous and recent results in important medical-pharmaceutical domains, one can undoubtedly state that EPS medical applications have a broad future ahead. PMID- 26483764 TI - Evolutionary history influences the salinity preference of bacterial taxa in wetland soils. AB - Salinity is a major driver of bacterial community composition across the globe. Despite growing recognition that different bacterial species are present or active at different salinities, the mechanisms by which salinity structures community composition remain unclear. We tested the hypothesis that these patterns reflect ecological coherence in the salinity preferences of phylogenetic groups using a reciprocal transplant experiment of fresh- and saltwater wetland soils. The salinity of both the origin and host environments affected community composition (16S rRNA gene sequences) and activity (CO2 and CH4 production, and extracellular enzyme activity). These changes in community composition and activity rates were strongly correlated, which suggests the effect of environment on function could be mediated, at least in part, by microbial community composition. Based on their distribution across treatments, each phylotype was categorized as having a salinity preference (freshwater, saltwater, or none) and phylogenetic analyses revealed a significant influence of evolutionary history on these groupings. This finding was corroborated by examining the salinity preferences of high-level taxonomic groups. For instance, we found that the majority of alpha- and gamma-proteobacteria in these wetland soils preferred saltwater, while many beta-proteobacteria prefer freshwater. Overall, our results indicate the effect of salinity on bacterial community composition results from phylogenetically-clustered salinity preferences. PMID- 26483765 TI - Prevalence, enumeration, and pheno- and genotypic characteristics of Listeria monocytogenes isolated from raw foods in South China. AB - Listeria monocytogenes is an important foodborne pathogen that can cause serious illness in immunocompromised individuals, pregnant women, the elderly, and newborns. The aim of this study was to: (i) evaluate the prevalence and contamination level [most probable number (MPN)] of L. monocytogenes in 567 retail raw foods (fishery products, n = 154; raw/fresh meat, n = 123; frozen foods, n = 110; edible fungi, n = 108; vegetables, n = 72) collected from South China and (ii) to gain further knowledge on the phenotype and genotype distributions of this important foodborne pathogen. Approximately 22% of the samples were positive for L. monocytogenes. The contamination levels were between 0.3 and 10 MPN/g in 75.0%, between 10 and 100 MPN/g in 11.0% and less than 100 MPN/g in 14.0% of the countable samples. Five serogroups were identified among the 177 foodborne L. monocytogenes isolates, with 1/2a-3a (42.4%) and 1/2b-3b (26.0%) serogroups being the most dominant. Serogroups I.1 and II.2 were only found in the edible mushrooms, while serogroup III was dominant in the fishery products, suggesting that specific serogroups of L. monocytogenes may have distinct ecological niches. Ten (5.6%) L. monocytogenes isolates exhibited multidrug resistance. Genetic relatedness analysis revealed the absence of distinct associations between specific food types, antibiotic resistance, serogroups, and genetic diversity. The present study provided the first baseline data on the prevalence, contamination level, and characteristics of L. monocytogenes isolated from raw foods in South China. Some multidrug resistant strains belonged to the epidemiologically important serogroups (I.1 and II.1), implying a potential public health risk. In addition, these findings also provide basic information for the Chinese food safety associated authorities to draft appropriate standards to control L. monocytogenes contamination and improve microbiological safety of raw foods. PMID- 26483766 TI - A unique assemblage of cosmopolitan freshwater bacteria and higher community diversity differentiate an urbanized estuary from oligotrophic Lake Michigan. AB - Water quality is impacted significantly by urbanization. The delivery of increased nutrient loads to waterways is a primary characteristic of this land use change. Despite the recognized effects of nutrient loading on aquatic systems, the influence of urbanization on the bacterial community composition of these systems is not understood. We used massively-parallel sequencing of bacterial 16S rRNA genes to examine the bacterial assemblages in transect samples spanning the heavily urbanized estuary of Milwaukee, WI to the relatively un impacted waters of Lake Michigan. With this approach, we found that genera and lineages common to freshwater lake epilimnia were common and abundant in both the high nutrient, urban-impacted waterways, and the low nutrient Lake Michigan. Although the two environments harbored many taxa in common, we identified a significant change in the community assemblage across the urban-influence gradient, and three distinct community features drove this change. First, we found the urban-influenced waterways harbored significantly greater bacterial richness and diversity than Lake Michigan (i.e., taxa augmentation). Second, we identified a shift in the relative abundance among common freshwater lineages, where acI, acTH1, Algoriphagus and LD12, had decreased representation and Limnohabitans, Polynucleobacter, and Rhodobacter had increased representation in the urban estuary. Third, by oligotyping 18 common freshwater genera/lineages, we found that oligotypes (highly resolved sequence clusters) within many of these genera/lineages had opposite preferences for the two environments. With these data, we suggest many of the defined cosmopolitan freshwater genera/lineages contain both oligotroph and more copiotroph species or populations, promoting the idea that within-genus lifestyle specialization, in addition to shifts in the dominance among core taxa and taxa augmentation, drive bacterial community change in urbanized waters. PMID- 26483768 TI - Lassa virus isolates from Mali and the Ivory Coast represent an emerging fifth lineage. AB - Previous imported cases of Lassa fever (LF) into the United Kingdom from the Ivory Coast and Mali, as well as the detection of Lassa virus (LASV) among the Mastomys natalensis population within Mali has led to the suggestion that the endemic area for LF is expanding. Initial phylogenetic analyses arrange isolates from Mali and the Ivory Coast separately from the classical lineage IV isolates taken from Sierra Leone, Guinea, and Liberia. The availability of full genome sequences continues to increase, allowing for a more complete phylogenetic comparison of the isolates from Mali and the Ivory Coast to the other existing isolates. In this study, we utilized a Bayesian approach to infer the demographic histories of each LASV isolate for which the full sequence was available. Our results indicate that the isolates from Mali and the Ivory Coast group separately from the isolates of lineage IV, comprising a distinct fifth lineage. The split between lineages IV and V is estimated to have occurred around 200-300 years ago, which coincides with the colonial period of West Africa. PMID- 26483767 TI - Clinical utilization of genomics data produced by the international Pseudomonas aeruginosa consortium. AB - The International Pseudomonas aeruginosa Consortium is sequencing over 1000 genomes and building an analysis pipeline for the study of Pseudomonas genome evolution, antibiotic resistance and virulence genes. Metadata, including genomic and phenotypic data for each isolate of the collection, are available through the International Pseudomonas Consortium Database (http://ipcd.ibis.ulaval.ca/). Here, we present our strategy and the results that emerged from the analysis of the first 389 genomes. With as yet unmatched resolution, our results confirm that P. aeruginosa strains can be divided into three major groups that are further divided into subgroups, some not previously reported in the literature. We also provide the first snapshot of P. aeruginosa strain diversity with respect to antibiotic resistance. Our approach will allow us to draw potential links between environmental strains and those implicated in human and animal infections, understand how patients become infected and how the infection evolves over time as well as identify prognostic markers for better evidence-based decisions on patient care. PMID- 26483769 TI - Turbulence-driven shifts in holobionts and planktonic microbial assemblages in St. Peter and St. Paul Archipelago, Mid-Atlantic Ridge, Brazil. AB - The aim of this study was to investigate the planktonic and the holobiont Madracis decactis (Scleractinia) microbial diversity along a turbulence-driven upwelling event, in the world's most isolated tropical island, St Peter and St Paul Archipelago (SPSPA, Brazil). Twenty one metagenomes were obtained for seawater (N = 12), healthy and bleached holobionts (N = 9) before, during and after the episode of high seawater turbulence and upwelling. Microbial assemblages differed between low turbulence-low nutrient (LLR) and high turbulence-high nutrient (HHR) regimes in seawater. During LLR there was a balance between autotrophy and heterotrophy in the bacterioplankton and the ratio cyanobacteria:heterotrophs ~1 (C:H). Prochlorales, unclassified Alphaproteobacteria and Euryarchaeota were the dominant bacteria and archaea, respectively. Basic metabolisms and cyanobacterial phages characterized the LLR. During HHR C:H < < 0.05 and Gammaproteobacteria approximated 50% of the most abundant organisms in seawater. Alteromonadales, Oceanospirillales, and Thaumarchaeota were the dominant bacteria and archaea. Prevailing metabolisms were related to membrane transport, virulence, disease, and defense. Phages targeting heterotrophs and virulence factor genes characterized HHR. Shifts were also observed in coral microbiomes, according to both annotation-indepent and dependent methods. HHR bleached corals metagenomes were the most dissimilar and could be distinguished by their di- and tetranucleotides frequencies, Iron Acquision metabolism and virulence genes, such as V. cholerae-related virulence factors. The healthy coral holobiont was shown to be less sensitive to transient seawater-related perturbations than the diseased animals. A conceptual model for the turbulence-induced shifts is put forward. PMID- 26483770 TI - Commentary: Incorporation of membrane-anchored flagellin or Escherichia coli heat labile enterotoxin B subunit enhances the immunogenicity of rabies virus-like particles in mice and dogs. PMID- 26483771 TI - Variability in subpopulation formation propagates into biocatalytic variability of engineered Pseudomonas putida strains. AB - Pivotal challenges in industrial biotechnology are the identification and overcoming of cell-to-cell heterogeneity in microbial processes. While the development of subpopulations of isogenic cells in bioprocesses is well described (intra-population variability), a possible variability between genetically identical cultures growing under macroscopically identical conditions (clonal variability) is not. A high such clonal variability has been found for the recombinant expression of the styrene monooxygenase genes styAB from Pseudomonas taiwanensis VLB120 in solvent-tolerant Pseudomonas putida DOT-T1E using the alk regulatory system from P. putida GPo1. In this study, the oxygenase subunit StyA fused to eGFP was used as readout tool to characterize the population structure in P. putida DOT-T1E regarding recombinant protein content. Flow cytometric analyses revealed that in individual cultures, at least two subpopulations with highly differing recombinant StyA-eGFP protein contents appeared (intra population variability). Interestingly, subpopulation sizes varied from culture to-culture correlating with the specific styrene epoxidation activity of cells derived from respective cultures (clonal variability). In addition, flow cytometric cell sorting coupled to plasmid copy number (PCN) determination revealed that detected clonal variations cannot be correlated to the PCN, but depend on the combination of the regulatory system and the host strain employed. This is, to the best of our knowledge, the first work reporting that intra population variability (with differing protein contents in the presented case study) causes clonal variability of genetically identical cultures. Respective impacts on bioprocess reliability and performance and strategies to overcome respective reliability issues are discussed. PMID- 26483772 TI - Relations of microbiome characteristics to edaphic properties of tropical soils from Trinidad. AB - Understanding how community structure of Bacteria, Archaea, and Fungi varies as a function of edaphic characteristics is key to elucidating associations between soil ecosystem function and the microbiome that sustains it. In this study, non managed tropical soils were examined that represented a range of edaphic characteristics, and a comprehensive soil microbiome analysis was done by Illumina sequencing of amplicon libraries that targeted Bacteria (universal prokaryotic 16S rRNA gene primers), Archaea (primers selective for archaeal 16S rRNA genes), or Fungi (internal transcribed spacer region). Microbiome diversity decreased in the order: Bacteria > Archaea > Fungi. Bacterial community composition had a strong relationship to edaphic factors while that of Archaea and Fungi was comparatively weak. Bacterial communities were 70-80% alike, while communities of Fungi and Archaea had 40-50% similarity. While each of the three component communities differed in species turnover patterns, soils having relatively similar bacterial communities also housed similar archaeal communities. In contrast, the composition of fungal communities had no correlation to bacterial or archaeal communities. Bacterial and archaeal diversity had significant (negative) correlations to pH, whereas fungal diversity was not correlated to pH. Edaphic characteristics that best explained variation between soils in bacterial community structure were: total carbon, sodium, magnesium, and zinc. For fungi, the best variables were: sodium, magnesium, phosphorus, boron, and C/N. Archaeal communities had two sets of edaphic factors of equal strength, one contained sulfur, sodium, and ammonium-N and the other was composed of clay, potassium, ammonium-N, and nitrate-N. Collectively, the data indicate that Bacteria, Archaea, and Fungi did not closely parallel one another in community structure development, and thus microbiomes in each soil acquired unique identities. This divergence could in part reflect the finding that unknown factor(s) were stronger than edaphic characteristics in shaping fungal and archaeal communities. PMID- 26483773 TI - Actinomycetes from the South China Sea sponges: isolation, diversity, and potential for aromatic polyketides discovery. AB - Marine sponges often harbor dense and diverse microbial communities including actinobacteria. To date no comprehensive investigation has been performed on the culturable diversity of the actinomycetes associated with South China Sea sponges. Structurally novel aromatic polyketides were recently discovered from marine sponge-derived Streptomyces and Saccharopolyspora strains, suggesting that sponge-associated actinomycetes can serve as a new source of aromatic polyketides. In this study, a total of 77 actinomycete strains were isolated from 15 South China Sea sponge species. Phylogenetic characterization of the isolates based on 16S rRNA gene sequencing supported their assignment to 12 families and 20 genera, among which three rare genera (Marihabitans, Polymorphospora, and Streptomonospora) were isolated from marine sponges for the first time. Subsequently, beta-ketoacyl synthase (KSalpha) gene was used as marker for evaluating the potential of the actinomycete strains to produce aromatic polyketides. As a result, KSalpha gene was detected in 35 isolates related to seven genera (Kocuria, Micromonospora, Nocardia, Nocardiopsis, Saccharopolyspora, Salinispora, and Streptomyces). Finally, 10 strains were selected for small-scale fermentation, and one angucycline compound was detected from the culture extract of Streptomyces anulatus strain S71. This study advanced our knowledge of the sponge-associated actinomycetes regarding their diversity and potential in producing aromatic polyketides. PMID- 26483775 TI - Probing the regulatory effects of specific mutations in three major binding domains of the pleiotropic regulator CcpA of Bacillus subtilis. AB - Carbon catabolite control is required for efficient use of available carbon sources to ensure rapid growth of bacteria. CcpA is a global regulator of carbon metabolism in Gram-positive bacteria like Bacillus subtilis. In this study the genome-wide gene regulation of a CcpA knockout and three specific CcpA mutants were studied by transcriptome analysis, to further elucidate the function of specific binding sites in CcpA. The following three amino acids were mutated to characterize their function: M17(R) which is involved in DNA binding, T62(H) which is important for the allosteric switch in CcpA upon HPr-Ser46-P binding, and R304(W) which is important for binding of the coeffectors HPr-Ser46-P and fructose-1,6-bisphosphate. The results confirm that CcpA was also involved in gene regulation in the absence of glucose. CcpA-M17R showed a small relief of Carbon Catabolite Control; the CcpA-M17R mutant regulates fewer genes than the CcpA-wt and the palindromicity of the cre site is less important for CcpA-M17R. CcpA-T62H was a stronger repressor than CcpA-wt and also acted as a strong repressor in the absence of glucose. CcpA-R304W was shown here to be less dependent on HPr-Ser46-P for its carbon catabolite control activities. The results presented here provide detailed information on alterations in gene regulation for each CcpA-mutant. PMID- 26483776 TI - Hydrological pulse regulating the bacterial heterotrophic metabolism between Amazonian mainstems and floodplain lakes. AB - We evaluated in situ rates of bacterial carbon processing in Amazonian floodplain lakes and mainstems, during both high water (HW) and low water (LW) phases (p < 0.05). Our results showed that bacterial production (BP) was lower and more variable than bacterial respiration, determined as total respiration. Bacterial carbon demand was mostly accounted by BR and presented the same pattern that BR in both water phases. Bacterial growth efficiency (BGE) showed a wide range (0.2 23%) and low mean value of 3 and 6%, (in HW and LW, respectively) suggesting that dissolved organic carbon was mostly allocated to catabolic metabolism. However, BGE was regulated by BP in LW phase. Consequently, changes in BGE showed the same pattern that BP. In addition, the hydrological pulse effects on mainstems and floodplains lakes connectivity were found for BP and BGE in LW. Multiple correlation analyses revealed that indexes of organic matter (OM) quality (chlorophyll-a, N stable isotopes and C/N ratios) were the strongest seasonal drivers of bacterial carbon metabolism. Our work indicated that: (i) the bacterial metabolism was mostly driven by respiration in Amazonian aquatic ecosystems resulting in low BGE in either high or LW phase; (ii) the hydrological pulse regulated the bacterial heterotrophic metabolism between Amazonian mainstems and floodplain lakes mostly driven by OM quality. PMID- 26483774 TI - Choosing a suitable method for the identification of replication origins in microbial genomes. AB - As the replication of genomic DNA is arguably the most important task performed by a cell and given that it is controlled at the initiation stage, the events that occur at the replication origin play a central role in the cell cycle. Making sense of DNA replication origins is important for improving our capacity to study cellular processes and functions in the regulation of gene expression, genome integrity in much finer detail. Thus, clearly comprehending the positions and sequences of replication origins which are fundamental to chromosome organization and duplication is the first priority of all. In view of such important roles of replication origins, tremendous work has been aimed at identifying and testing the specificity of replication origins. A number of computational tools based on various skew types have been developed to predict replication origins. Using various in silico approaches such as Ori-Finder, and databases such as DoriC, researchers have predicted the locations of replication origins sites for thousands of bacterial chromosomes and archaeal genomes. Based on the predicted results, we should choose an effective method for identifying and confirming the interactions at origins of replication. Here we describe the main existing experimental methods that aimed to determine the replication origin regions and list some of the many the practical applications of these methods. PMID- 26483777 TI - Emerging spatial patterns in Antarctic prokaryotes. AB - Recent advances in knowledge of patterns of biogeography in terrestrial eukaryotic organisms have led to a fundamental paradigm shift in understanding of the controls and history of life on land in Antarctica, and its interactions over the long term with the glaciological and geological processes that have shaped the continent. However, while it has long been recognized that the terrestrial ecosystems of Antarctica are dominated by microbes and their processes, knowledge of microbial diversity and distributions has lagged far behind that of the macroscopic eukaryote organisms. Increasing human contact with and activity in the continent is leading to risks of biological contamination and change in a region whose isolation has protected it for millions of years at least; these risks may be particularly acute for microbial communities which have, as yet, received scant recognition and attention. Even a matter apparently as straightforward as Protected Area designation in Antarctica requires robust biodiversity data which, in most parts of the continent, remain almost completely unavailable. A range of important contributing factors mean that it is now timely to reconsider the state of knowledge of Antarctic terrestrial prokaryotes. Rapid advances in molecular biological approaches are increasingly demonstrating that bacterial diversity in Antarctica may be far greater than previously thought, and that there is overlap in the environmental controls affecting both Antarctic prokaryotic and eukaryotic communities. Bacterial dispersal mechanisms and colonization patterns remain largely unaddressed, although evidence for regional evolutionary differentiation is rapidly accruing and, with this, there is increasing appreciation of patterns in regional bacterial biogeography in this large part of the globe. In this review, we set out to describe the state of knowledge of Antarctic prokaryote diversity patterns, drawing analogy with those of eukaryote groups where appropriate. Based on our synthesis, it is clear that spatial patterns of Antarctic prokaryotes can be unique at local scales, while the limited evidence available to date supports the group exhibiting overall regional biogeographical patterns similar to the eukaryotes. We further consider the applicability of the concept of "functional redundancy" for the Antarctic microbial community and highlight the requirements for proper consideration of their important and distinctive roles in Antarctic terrestrial ecosystems. PMID- 26483778 TI - Ubiquity, diversity and physiological characteristics of Geodermatophilaceae in Shapotou National Desert Ecological Reserve. AB - The goal of this study was to gain insight into the diversity of culturable actinobacteria in desert soil crusts and to determine the physiological characteristics of the predominant actinobacterial group in these crusts. Culture dependent method was employed to obtain actinobacterial strains from desert soil samples collected from Shapotou National Desert Ecological Reserve (NDER) located in Tengger Desert, China. A total of 376 actinobacterial strains were isolated and 16S rRNA gene sequences analysis indicated that these isolates belonged to 29 genera within 18 families, among which the members of the family Geodermatophilaceae were predominant. The combination of 16S rRNA gene information and the phenotypic data allowed these newly-isolated Geodermatophilaceae members to be classified into 33 "species clusters," 11 of which represented hitherto unrecognized species. Fermentation broths from 19.7% of the isolated strains showed activity in at least one of the six screens for antibiotic activity. These isolates exhibited bio-diversity in enzymatic characteristics and carbon utilization profiles. The physiological characteristics of the isolates from different types of crusts or bare sand samples were specific to their respective micro-ecological environments. Our study revealed that members of the family Geodermatophilaceae were ubiquitous, abundant, and diverse in Shapotou NDER, and these strains may represent a new major group of potential functional actinobacteria in desert soil. PMID- 26483780 TI - Comparison of methods for the enumeration of enterohemorrhagic Escherichia coli from veal hides and carcasses. AB - The increased association of enterohemorrhagic Escherichia coli (EHEC) with veal calves has led the United States Department of Agriculture Food Safety and Inspection Service to report results of veal meat contaminated with the Top 7 serogroups separately from beef cattle. However, detection methods that can also provide concentration for determining the prevalence and abundance of EHEC associated with veal are lacking. Here we compared the ability of qPCR and a molecular based most probable number assay (MPN) to detect and enumerate EHEC from veal hides at the abattoir and the resulting pre-intervention carcasses. In addition, digital PCR (dPCR) was used to analyze select samples. The qPCR assay was able to enumerate total EHEC in 32% of the hide samples with a range of approximately 34 to 91,412 CFUs/100 cm(2) (95% CI 4-113,460 CFUs/100 cm(2)). Using the MPN assay, total EHEC was enumerable in 48% of the hide samples and ranged from approximately 1 to greater than 17,022 CFUs/100 cm(2) (95% CI 0.4 72,000 CFUs/100 cm(2)). The carcass samples had lower amounts of EHEC with a range of approximately 4-275 CFUs/100 cm(2) (95% CI 3-953 CFUs/100 cm(2)) from 17% of samples with an enumerable amount of EHEC by qPCR. For the MPN assay, the carcass samples ranged from 0.1 to 1 CFUs/100 cm(2) (95% CI 0.02-4 CFUs/100 cm(2)) from 29% of the samples. The correlation coefficient between the qPCR and MPN enumeration methods indicated a moderate relation (R (2) = 0.39) for the hide samples while the carcass samples had no relation (R (2) = 0.002), which was likely due to most samples having an amount of total EHEC below the reliable limit of quantification for qPCR. Interestingly, after enrichment, 81% of the hide samples and 94% of the carcass samples had a detectable amount of total EHEC by qPCR. From our analysis, the MPN assay provided a higher percentage of enumerable hide and carcass samples, however determining an appropriate dilution range and the limited throughput offer additional challenges. PMID- 26483781 TI - Carbon assimilation and accumulation of cyanophycin during the development of dormant cells (akinetes) in the cyanobacterium Aphanizomenon ovalisporum. AB - Akinetes are spore-like non-motile cells that differentiate from vegetative cells of filamentous cyanobacteria from the order Nostocales. They play a key role in the survival and distribution of these species and contribute to their perennial blooms. Here, we demonstrate variations in cellular ultrastructure during akinete formation concomitant with accumulation of cyanophycin; a copolymer of aspartate and arginine that forms storage granules. Cyanophycin accumulation is initiated in vegetative cells few days post-exposure to akinete inducing conditions. This early accumulated cyanophycin pool in vegetative cells disappears as a nearby cell differentiates to an akinete and stores large pool of cyanophycin. During the akinete maturation, the cyanophycin pool is further increased and comprise up to 2% of the akinete volume. The cellular pattern of photosynthetic activity during akinete formation was studied by a nano-metric scale secondary ion mass spectrometry (NanoSIMS) analysis in (13)C-enriched cultures. Quantitative estimation of carbon assimilation in vegetative cells and akinetes (filament attached and -free) indicates that vegetative cells maintain their basal activity while differentiating akinetes gradually reduce their activity. Mature-free akinetes practically lost their photosynthetic activity although small fraction of free akinetes were still photosynthetically active. Additional (13)C pulse chase experiments indicated rapid carbon turnover during akinete formation and de novo synthesis of cyanophycin in vegetative cells 4 days post-induction of akinete differentiation. PMID- 26483779 TI - NK cell function and receptor diversity in the context of HCV infection. AB - Hepatitis C virus (HCV) infects over 170 million people in the world. While a minority of individuals are able to naturally clear this hepatotropic virus using their immune system, most people go on to develop a lifetime chronic infection that can result in severe liver pathology, potentially leading to liver cirrhosis and hepatic cellular carcinoma. Investigations into acute immune responses and spontaneous clearance of the virus are severely hampered by difficulties in identification of relevant patient cohorts. While the role for the adaptive immune response in viral clearance is well established, it is becoming clear that the innate immune system also impacts on HCV outcome. The innate immune response to infection is likely to influence the type of adaptive immune response that develops and will ultimately influence if the virus is cleared or develops into a chronic infection. Natural Killer (NK) cells are lymphocytes that have important anti-viral functions including direct cytotoxicity of infected cells and the production of inflammatory cytokines, e.g., IFN-gamma. They are generally considered to be cells of the innate immune system, although there is increasing evidence that NK cells adapt and persist in response to particular viral infections. NK cells are altered in patients with acute and chronic HCV infection. There is increasing evidence from both cellular and genetic studies that NK cells modulate HCV outcome. This review will describe and discuss the current experimental and clinical evidence of a role for NK cells in HCV infection and describe recent discoveries that are likely to play a role in future research. PMID- 26483783 TI - A comparative study of infrared and microwave heating for microbial decontamination of paprika powder. AB - There is currently a need in developing new decontamination technologies for spices due to limitations of existing technologies, mainly regarding their effects on spices' sensory quality. In the search of new decontamination solutions, it is of interest to compare different technologies, to provide the industry with knowledge for taking decisions concerning appropriate decontamination technologies for spices. The present study compares infrared (IR) and microwave decontamination of naturally contaminated paprika powder after adjustment of water activity to 0.88. IR respectively microwave heating was applied to quickly heat up paprika powder to 98 degrees C, after which the paprika sample was transferred to a conventional oven set at 98 degrees C to keep the temperature constant during a holding time up to 20 min. In the present experimental set-up microwave treatment at 98 degrees C for 20 min resulted in a reduction of 4.8 log units of the total number of mesophilic bacteria, while the IR treatment showed a 1 log unit lower reduction for the corresponding temperature and treatment time. Microwave and IR heating created different temperature profiles and moisture distribution within the paprika sample during the heating up part of the process, which is likely to have influenced the decontamination efficiency. The results of this study are used to discuss the difficulties in comparing two thermal technologies on equal conditions due to differences in their heating mechanisms. PMID- 26483782 TI - Recovering full-length viral genomes from metagenomes. AB - Infectious disease metagenomics is driven by the question: "what is causing the disease?" in contrast to classical metagenome studies which are guided by "what is out there?" In case of a novel virus, a first step to eventually establishing etiology can be to recover a full-length viral genome from a metagenomic sample. However, retrieval of a full-length genome of a divergent virus is technically challenging and can be time-consuming and costly. Here we discuss different assembly and fragment linkage strategies such as iterative assembly, motif searches, k-mer frequency profiling, coverage profile binning, and other strategies used to recover genomes of potential viral pathogens in a timely and cost-effective manner. PMID- 26483784 TI - Functional characterization and stability improvement of a 'thermophilic-like' ene-reductase from Rhodococcus opacus 1CP. AB - Ene-reductases (ERs) are widely applied for the asymmetric synthesis of relevant industrial chemicals. A novel ER OYERo2 was found within a set of 14 putative old yellow enzymes (OYEs) obtained by genome mining of the actinobacterium Rhodococcus opacus 1CP. Multiple sequence alignment suggested that the enzyme belongs to the group of 'thermophilic-like' OYEs. OYERo2 was produced in Escherichia coli and biochemically characterized. The enzyme is strongly NADPH dependent and uses non-covalently bound FMNH2 for the reduction of activated alpha,beta-unsaturated alkenes. In the active form OYERo2 is a dimer. Optimal catalysis occurs at pH 7.3 and 37 degrees C. OYERo2 showed highest specific activities (45-50 U mg(-1)) on maleimides, which are efficiently converted to the corresponding succinimides. The OYERo2-mediated reduction of prochiral alkenes afforded the (R)-products with excellent optical purity (ee > 99%). OYERo2 is not as thermo-resistant as related OYEs. Introduction of a characteristic intermolecular salt bridge by site-specific mutagenesis raised the half-life of enzyme inactivation at 32 degrees C from 28 to 87 min and improved the tolerance toward organic co-solvents. The suitability of OYERo2 for application in industrial biocatalysis is discussed. PMID- 26483785 TI - Metagenomic evidence for reciprocal particle exchange between the mainstem estuary and lateral bay sediments of the lower Columbia River. AB - Lateral bays of the lower Columbia River estuary are areas of enhanced water retention that influence net ecosystem metabolism through activities of their diverse microbial communities. Metagenomic characterization of sediment microbiota from three disparate sites in two brackish lateral bays (Baker and Youngs) produced ~100 Gbp of DNA sequence data analyzed subsequently for predicted SSU rRNA and peptide-coding genes. The metagenomes were dominated by Bacteria. A large component of Eukaryota was present in Youngs Bay samples, i.e., the inner bay sediment was enriched with the invasive New Zealand mudsnail, Potamopyrgus antipodarum, known for high ammonia production. The metagenome was also highly enriched with an archaeal ammonia oxidizer closely related to Nitrosoarchaeum limnia. Combined analysis of sequences and continuous, high resolution time series of biogeochemical data from fixed and mobile platforms revealed the importance of large-scale reciprocal particle exchanges between the mainstem estuarine water column and lateral bay sediments. Deposition of marine diatom particles in sediments near Youngs Bay mouth was associated with a dramatic enrichment of Bacteroidetes (58% of total Bacteria) and corresponding genes involved in phytoplankton polysaccharide degradation. The Baker Bay sediment metagenome contained abundant Archaea, including diverse methanogens, as well as functional genes for methylotrophy and taxonomic markers for syntrophic bacteria, suggesting that active methane cycling occurs at this location. Our previous work showed enrichments of similar anaerobic taxa in particulate matter of the mainstem estuarine water column. In total, our results identify the lateral bays as both sources and sinks of biogenic particles significantly impacting microbial community composition and biogeochemical activities in the estuary. PMID- 26483786 TI - Direct involvement of ombB, omaB, and omcB genes in extracellular reduction of Fe(III) by Geobacter sulfurreducens PCA. AB - The tandem gene clusters orfR-ombB-omaB-omcB and orfS-ombC-omaC-omcC of the metal reducing bacterium Geobacter sulfurreducens PCA are responsible for trans-outer membrane electron transfer during extracellular reduction of Fe(III)-citrate and ferrihydrite [a poorly crystalline Fe(III) oxide]. Each gene cluster encodes a putative transcriptional factor (OrfR/OrfS), a porin-like outer-membrane protein (OmbB/OmbC), a periplasmic c-type cytochrome (c-Cyt, OmaB/OmaC) and an outer membrane c-Cyt (OmcB/OmcC). The individual roles of OmbB, OmaB and OmcB in extracellular reduction of Fe(III), however, have remained either uninvestigated or controversial. Here, we showed that replacements of ombB, omaB, omcB, and ombB omaB with an antibiotic gene in the presence of ombC-omaC-omcC had no impact on reduction of Fe(III)-citrate by G. sulfurreducens PCA. Disruption of ombB, omaB, omcB, and ombB-omaB in the absence of ombC-omaC-omcC, however, severely impaired the bacterial ability to reduce Fe(III)-citrate as well as ferrihydrite. These results unequivocally demonstrate an overlapping role of ombB-omaB-omcB and ombC omaC-omcC in extracellular Fe(III) reduction by G. sulfurreducens PCA. Involvement of both ombB-omaB-omcB and ombC-omaC-omcC in extracellular Fe(III) reduction reflects the importance of these trans-outer membrane protein complexes in the physiology of this bacterium. Moreover, the kinetics of Fe(III)-citrate and ferrihydrite reduction by these mutants in the absence of ombC-omaC-omcC were nearly identical, which suggests that absence of any protein subunit eliminates function of OmaB/OmbB/OmcB protein complex. Finally, orfS was found to have a negative impact on the extracellular reduction of Fe(III)-citrate and ferrihydrite in G. sulfurreducens PCA probably by serving as a transcriptional repressor. PMID- 26483788 TI - Systemic Sclerosis Patients Present Alterations in the Expression of Molecules Involved in B-Cell Regulation. AB - The activation threshold of B cells is tightly regulated by an array of inhibitory and activator receptors in such a way that disturbances in their expression can lead to the appearance of autoimmunity. The aim of this study was to evaluate the expression of activating and inhibitory molecules involved in the modulation of B cell functions in transitional, naive, and memory B-cell subpopulations from systemic sclerosis patients. To achieve this, blood samples were drawn from 31 systemic sclerosis patients and 53 healthy individuals. Surface expression of CD86, MHC II, CD19, CD21, CD40, CD22, Siglec 10, CD35, and FcgammaRIIB was determined by flow cytometry. IL-10 production was evaluated by intracellular flow cytometry from isolated B cells. Soluble IL-6 and IL-10 levels were measured by ELISA from supernatants of stimulated B cells. Systemic sclerosis patients exhibit an increased frequency of transitional and naive B cells related to memory B cells compared with healthy controls. Transitional and naive B cells from patients express higher levels of CD86 and FcgammaRIIB than healthy donors. Also, B cells from patients show high expression of CD19 and CD40, whereas memory cells from systemic sclerosis patients show reduced expression of CD35. CD19 and CD35 expression levels associate with different autoantibody profiles. IL-10(+) B cells and secreted levels of IL-10 were markedly reduced in patients. In conclusion, systemic sclerosis patients show alterations in the expression of molecules involved in B-cell regulation. These abnormalities may be determinant in the B-cell hyperactivation observed in systemic sclerosis. PMID- 26483787 TI - Stage-Specific Role of Interferon-Gamma in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. AB - The role of interferon (IFN)-gamma in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), has remained as an enigmatic paradox for more than 30 years. Several studies attribute this cytokine a prominent proinflammatory and pathogenic function in these pathologies. However, accumulating evidence shows that IFN-gamma also plays a protective role inducing regulatory cell activity and modulating the effector T cell response. Several innate and adaptive immune cells also develop opposite functions strongly associated with the production of IFN-gamma in EAE. Even the suppressive activity of different types of regulatory cells is dependent on IFN-gamma. Interestingly, recent data supports a stage-specific participation of IFN-gamma in EAE providing a plausible explanation for previous conflicting results. In this review, we will summarize and discuss such literature, emphasizing the protective role of IFN gamma on immune cells. These findings are fundamental to understand the complex role of IFN-gamma in the pathogenesis of these diseases and can provide basis for potential stage-specific therapy for MS targeting IFN-gamma-signaling or IFN gamma-producing immune cells. PMID- 26483789 TI - IL-17A Promotes Intracellular Growth of Mycobacterium by Inhibiting Apoptosis of Infected Macrophages. AB - The fate of infected macrophages is a critical aspect of immunity to mycobacteria. By depriving the pathogen of its intracellular niche, apoptotic death of the infected macrophage has been shown to be an important mechanism to control bacterial growth. Here, we show that IL-17 inhibits apoptosis of Mycobacterium bovis BCG- or Mycobacterium tuberculosis-infected macrophages thus hampering their ability to control bacterial growth. Mechanistically, we show that IL-17 inhibits p53, and impacts on the intrinsic apoptotic pathway, by increasing the Bcl2 and decreasing Bax expression, decreasing cytochrome c release from the mitochondria, and inhibiting caspase-3 activation. The same effect of IL-17 was observed in infected macrophages upon blockade of p53 nuclear translocation. These results reveal a previously unappreciated role for the IL 17/p53 axis in the regulation of mycobacteria-induced apoptosis and can have important implications in a broad spectrum of diseases where apoptosis of the infected cell is an important host defense mechanism. PMID- 26483790 TI - Interplay between Transcription Factors and the Epigenome: Insight from the Role of RUNX1 in Leukemia. AB - The genome has the ability to respond in a precise and co-ordinated manner to cellular signals. It achieves this through the concerted actions of transcription factors and the chromatin platform, which are targets of the signaling pathways. Our understanding of the molecular mechanisms through which transcription factors and the chromatin landscape each control gene activity has expanded dramatically over recent years, and attention has now turned to understanding the complex, multifaceted interplay between these regulatory layers in normal and disease states. It has become apparent that transcription factors as well as the components and modifiers of the epigenetic machinery are frequent targets of genomic alterations in cancer cells. Through the study of these factors, we can gain unique insight into the dynamic interplay between transcription factors and the epigenome, and how their dysregulation leads to aberrant gene expression programs in cancer. Here, we will highlight how these factors normally co-operate to establish and maintain the transcriptional and epigenetic landscape of cells, and how this is reprogramed in cancer, focusing on the RUNX1 transcription factor and oncogenic derivative RUNX1-ETO in leukemia as paradigms of transcriptional and epigenetic reprograming. PMID- 26483792 TI - Editorial: A Living History of Immunology. PMID- 26483791 TI - Modulation of APC Function and Anti-Tumor Immunity by Anti-Cancer Drugs. AB - Professional antigen-presenting cells (APCs), such as dendritic cells (DCs), are central to the initiation and regulation of anti-cancer immunity. However, in the immunosuppressive environment within a tumor APCs may antagonize anti-tumor immunity by inducing regulatory T cells (Tregs) or anergy of effector T cells due to lack of efficient costimulation. Hence, in an optimal setting, anti-cancer drugs have the power to reduce tumor size and thereby may induce the release of tumor antigens and, at the same time, modulate APC function toward efficient priming of antigen-specific effector T cells. Selected cytotoxic agents may revert APC dysfunction either by directly maturing DCs or through induction of immunogenic tumor cell death. Furthermore, specific cytotoxic agents may support adaptive immunity by selectively depleting regulatory subsets, such as Tregs or myeloid-derived suppressor cells. Perspectively, this will allow developing effective combination strategies with novel immunotherapies to exert complementary pressure on tumors via direct toxicity as well as immune activation. We, here, review our current knowledge on the capacity of anti-cancer drugs to modulate APC functions to promote durable anti-cancer immune responses. PMID- 26483793 TI - Mucosal-Associated Invariant T Cells in Multiple Sclerosis: The Jury is Still Out. AB - The immune system is strongly implicated in the pathophysiology of multiple sclerosis (MS), as demonstrated by the efficacy of therapies targeting various components of adaptive immunity. However, the disease still progresses despite these treatments in many patients, while others experience life-threatening adverse effects, urging for the discovery of new immune-targeting medications. Among the immune cell types participating to MS pathogenesis, decades of work have highlighted the prominent role of CD4 T cells. More recent data demonstrate the involvement of CD8 T cells as well. The existence of both pathogenic and protective CD8 T cells subsets has been suggested, adding an additional layer of complexity to the picture. Mucosal-associated invariant T (MAIT) cells are innate like lymphocytes that make up to 25% of CD8 T cells in healthy subjects. They are specific for conserved microbial ligands and may constitute an important barrier against invasive bacterial and fungal infection. An increasing number of reports also suggest their possible involvement in chronic inflammatory diseases, including MS. MAIT cells could participate through their ability to produce IFNgamma and/or IL-17, two major cytokines in the pathogenesis of several chronic inflammatory/autoimmune diseases. However, the mechanisms by which MAIT cells could be activated in these sterile conditions are not known. Furthermore, contradictory observations have been made, reporting either a protective or a pro inflammatory behavior of MAIT cells in MS or its murine model, experimental autoimmune encephalomyelitis. In this review article, we will describe the current knowledge on MAIT cell biology in health and disease, and discuss the possible mechanisms behind their role in MS. The specific features of this new non-conventional T cell subset make it an interesting candidate as a biomarker or as the target of immune-mediated intervention. PMID- 26483794 TI - Memory T Cell Migration. AB - Immunological memory is a key feature of adaptive immunity. It provides the organism with long-lived and robust protection against infection. In organ transplantation, memory T cells pose a significant threat by causing allograft rejection that is generally resistant to immunosuppressive therapy. Therefore, a more thorough understanding of memory T cell biology is needed to improve the survival of transplanted organs without compromising the host's ability to fight infections. This review will focus on the mechanisms by which memory T cells migrate to the site where their target antigen is present, with particular emphasis on their migration to transplanted organs. First, we will define the known subsets of memory T cells (central, effector, and tissue resident) and their circulation patterns. Second, we will review the cellular and molecular mechanisms by which memory T cells migrate to inflamed and non-inflamed tissues and highlight the emerging paradigm of antigen-driven, trans-endothelial migration. Third, we will discuss the relevance of this knowledge to organ transplantation and the prevention or treatment of allograft rejection. PMID- 26483797 TI - Corrigendum: Quantity and Quality of Inhaled Dose Predicts Immunopathology in Tuberculosis. AB - [This corrects the article on p. 313 in vol. 6, PMID: 26175730.]. PMID- 26483796 TI - Regulatory T Cells Modulate DNA Vaccine Immunogenicity at Early Time via Functional CD4(+) T Cells and Antigen Duration. AB - The development of an effective vaccine against HIV has proved to be difficult. Many factors including natural regulatory T cells (Treg cells) can dampen the CD8 T-cell immunogenicity. In this study, we aimed to understand how Treg cells control CD8(+) T-cell immune responses during DNA prime-boost immunization. Animals were immunized with plasmid HIV IIIB gp120 DNA following elimination of Treg cells by administration of anti-CD25 neutralizing antibody. Results demonstrated that the pool size of CD4(+) T cells producing both IL-2 and/or IFN gamma (CD4(+)/IL-2(+)/IFN-gamma(+)) was increased solely during the priming phase. An increment of tetramer binding and intracellular cytokine IFN-gamma expression, however, were elevated in both primary and secondary stages in CD8(+) T cells. The speed of antigen clearance was also investigated by using DNA luciferase. Surprisingly, DNA luciferase expression was declined to basal level over the ensuing observation period when Treg cells were depleted. Importantly, we found for the first time that DNA expression pattern in Treg-depleted animals was similar to that of the regular memory phase. Moreover, in mice that were exposed to antigen over 5 days prior to Treg cell depletion, CD8(+) T-cell memory response was not affected. Thus, in the present study, we propose a new concept and prove that the enhanced immune response following the depletion of Treg cells during the priming phase likely adds one more set of memory response to the immune system. Taken together, our findings support the notion that Treg cells control DNA vaccine immunogenicity at an early time via antigen duration and functional CD4(+) T-cell responses. PMID- 26483795 TI - Challenges and Opportunities for T-Cell-Mediated Strategies to Eliminate HIV Reservoirs. AB - HIV's ability to establish latent reservoirs of reactivation-competent virus is the major barrier to cure. "Shock and kill" methods consisting of latency reversing agents (LRAs) followed by elimination of reactivating cells through cytopathic effects are under active development. However, the clinical efficacy of LRAs remains to be established. Moreover, recent studies indicate that reservoirs may not be reduced efficiently by either viral cytopathic or CD8(+) T cell-mediated mechanisms. In this perspective, we highlight challenges to T-cell mediated elimination of HIV reservoirs, including characteristics of responding T cells, aspects of the cellular reservoirs, and properties of the latent virus itself. We also discuss potential strategies to overcome these challenges by targeting the antiviral activity of T cells toward appropriate viral antigens following latency. PMID- 26483798 TI - Molecular marker assisted gene stacking for biotic and abiotic stress resistance genes in an elite rice cultivar. AB - Severe yield loss due to various biotic stresses like bacterial blight (BB), gall midge (insect) and Blast (disease) and abiotic stresses like submergence and salinity are a serious constraint to the rice productivity throughout the world. The most effective and reliable method of management of the stresses is the enhancement of host resistance, through an economical and environmentally friendly approach. Through the application of marker assisted selection (MAS) technique, the present study reports a successful pyramidization of genes/QTLs to confer resistance/tolerance to blast (Pi2, Pi9), gall Midge (Gm1, Gm4), submergence (Sub1), and salinity (Saltol) in a released rice variety CRMAS2621-7 1 as Improved Lalat which had already incorporated with three BB resistance genes xa5, xa13, and Xa21 to supplement the Xa4 gene present in Improved Lalat. The molecular analysis revealed clear polymorphism between the donor and recipient parents for all the markers that are tagged to the target traits. The conventional backcross breeding approach was followed till BC3F1 generation and starting from BC1F1 onwards, marker assisted selection was employed at each step to monitor the transfer of the target alleles with molecular markers. The different BC3F1s having the target genes/QTLs were inter crossed to generate hybrids with all 10 stress resistance/tolerance genes/QTLs into a single plant/line. Homozygous plants for resistance/tolerance genes in different combinations were recovered. The BC3F3 lines were characterized for their agronomic and quality traits and promising progeny lines were selected. The SSR based background selection was done. Most of the gene pyramid lines showed a high degree of similarity to the recurrent parent for both morphological, grain quality traits and in SSR based background selection. Out of all the gene pyramids tested, two lines had all the 10 resistance/tolerance genes and showed adequate levels of resistance/tolerance against the five target stresses. The study demonstrates the potential of MAS for stacking of several genes into a single line with a high degree of parental genome recovery. PMID- 26483799 TI - Root discrimination of closely related crop and weed species using FT MIR-ATR spectroscopy. AB - Root discrimination of species is a pre-condition for studying belowground competition processes between crop and weed species. In this experiment, we tested Fourier transform mid-infrared (FT MIR)-attenuated total reflection (ATR) spectroscopy to discriminate roots of closely related crop and weed species grown in the greenhouse: maize/barnyard grass, barley/wild oat, wheat/blackgrass (Poaceae), and sugar beet/common lambsquarters (Chenopodiaceae). Fresh (moist) and dried root segments as well as ground roots were analyzed by FT MIR-ATR spectroscopy. Root absorption spectra showed species specific peak distribution and peak height. A clear separation according to species was not possible with fresh root segments. Dried root segments (including root basis, middle section, and root tip) of maize/barnyard grass and sugar beet/common lambsquarters formed completely separated species clusters. Wheat and blackgrass separated in species specific clusters when root tips were removed from cluster analysis. A clear separation of dried root segments according to species was not possible in the case of barley and wild oat. Cluster analyses of ground roots revealed a 100% separation of all tested crop and weed species combinations. Spectra grouped in Poaceae and Chenopodiaceae clusters. Within the Poaceae cluster, C3 and C4 species differed significantly in heterogeneity. Thus, root spectra reflected the degree of kinship. To quantify species proportion in root mixtures, a two- and a three-species model for species quantification in root mixtures of maize, barnyard grass, and wild oat was calculated. The models showed low standard errors of prediction (RMSEP) and high residual predictive deviation values in an external test set validation. Hence, FT MIR-ATR spectroscopy seems to be a promising tool for root research even between closely related plant species. PMID- 26483800 TI - Editorial: Current advances and challenges in understanding plant desiccation tolerance. PMID- 26483801 TI - A genome-wide analysis of the auxin/indole-3-acetic acid gene family in hexaploid bread wheat (Triticum aestivum L.). AB - The Auxin/indole-3-acetic acid (Aux/IAA) gene family plays key roles in the primary auxin-response process and controls a number of important traits in plants. However, the characteristics of the Aux/IAA gene family in hexaploid bread wheat (Triticum aestivum L.) have long been unknown. In this study, a comprehensive identification of the Aux/IAA gene family was performed using the latest draft genome sequence of the bread wheat "Chinese Spring." Thirty-four Aux/IAA genes were identified, 30 of which have duplicated genes on the A, B or D sub-genome, with a total of 84 Aux/IAA sequences. These predicted Aux/IAA genes were non-randomly distributed in all the wheat chromosomes except for chromosome 2D. The information of wheat Aux/IAA proteins is also described. Based on an analysis of phylogeny, expression and adaptive evolution, we prove that the Aux/IAA family in wheat has been replicated twice in the two allopolyploidization events of bread wheat, when the tandem duplication also occurred. The duplicated genes have undergone an evolutionary process of purifying selection, resulting in the high conservation of copy genes among sub-genomes and functional redundancy among several members of the TaIAA family. However, functional divergence probably existed in most TaIAA members due to the diversity of the functional domain and expression pattern. Our research provides useful information for further research into the function of Aux/IAA genes in wheat. PMID- 26483802 TI - ROS-mediated enhanced transcription of CYP38 promotes the plant tolerance to high light stress by suppressing GTPase activation of PsbO2. AB - As a member of the Immunophilin family, cyclophilin38 (CYP38) is discovered to be localized in the thylakoid lumen, and is reported to be a participant in the function regulation of thylakoid membrane protein. However, the molecule mechanisms remain unclear. We found that, CYP38 plays an important role in the process of regulating and protecting the plant to resist high light (HL) stress. Under HL condition, the gene expression of CYP38 is enhanced, and if CYP38 gene is deficient, photochemistry efficiency, and chlorophyll content falls distinctly, and excessive reactive oxygen species synthesis occurs in the chloroplast. Western blot results showed that the D1 degradation rate of cyp38 mutant plants is faster than that of wide type plants. Interestingly, both gene expression and activity of PsbO2 were drastically enhanced in cyp38 mutant plants and less changed when the deleted gene of CYP38 was restored under HL treatment. This indicates that CYP38 may impose a negative regulation effect on PsbO2, which exerts a positive regulation effect in facilitating the dephosphorylation and subsequent degradation of D1. It is also found that, under HL condition, the cytoplasmic calcium ([Ca(2+)]cyt) concentration and the gene expression level of calmodulin 3 (CaM3) arose markedly, which occurs upstream of CYP38 gene expression. In conclusion, our results indicate that CYP38 plays an important role in plant strengthening HL resistibility, which provides a new insight in the research of mechanisms of CYP38 protein in plants. PMID- 26483803 TI - Breeding blueberries for a changing global environment: a review. AB - Today, blueberries are recognized worldwide as one of the foremost health foods, becoming one of the crops with the highest productive and commercial projections. Over the last 100 years, the geographical area where highbush blueberries are grown has extended dramatically into hotter and drier environments. The expansion of highbush blueberry growing into warmer regions will be challenged in the future by increases in average global temperature and extreme fluctuations in temperature and rainfall patterns. Considerable genetic variability exists within the blueberry gene pool that breeders can use to meet these challenges, but traditional selection techniques can be slow and inefficient and the precise adaptations of genotypes often remain hidden. Marker assisted breeding (MAB) and phenomics could aid greatly in identifying those individuals carrying adventitious traits, increasing selection efficiency and shortening the rate of cultivar release. While phenomics have begun to be used in the breeding of grain crops in the last 10 years, their use in fruit breeding programs it is almost non existent. PMID- 26483804 TI - The transporter GAT1 plays an important role in GABA-mediated carbon-nitrogen interactions in Arabidopsis. AB - Glutamate derived gamma-aminobutyric acid (GABA) is synthetized in the cytosol prior to delivery to the mitochondria where it is catabolized via the TCA cycle. GABA accumulates under various environmental conditions, but an increasing number of studies show its involvement at the crossroad between C and N metabolism. To assess the role of GABA in modulating cellular metabolism, we exposed seedlings of A. thaliana GABA transporter gat1 mutant to full nutrition medium and media deficient in C and N combined with feeding of different concentrations (0.5 and 1 mM) of exogenous GABA. GC-MS based metabolite profiling showed an expected effect of medium composition on the seedlings metabolism of mutant and wild type alike. That being said, a significant interaction between GAT1 deficiency and medium composition was determined with respect to magnitude of change in relative amino acid levels. The effect of exogenous GABA treatment on metabolism was contingent on both the medium and the genotype, leading for instance to a drop in asparagine under full nutrition and low C conditions and glucose under all tested media, but not to changes in GABA content. We additionally assessed the effect of GAT1 deficiency on the expression of glutamate metabolism related genes and genes involved in abiotic stress responses. These results suggest a role for GAT1 in GABA-mediated metabolic alterations in the context of the C-N equilibrium of plant cells. PMID- 26483805 TI - Pseudomonas spp. as models for plant-microbe interactions. PMID- 26483806 TI - Transcriptomic analysis of fruit stored under cold conditions using controlled atmosphere in Prunus persica cv. "Red Pearl". AB - Cold storage (CS) can induce a physiological disorder known as chilling injury (CI) in nectarine fruits. The main symptom is mealiness that is perceived as non juicy fruit by consumers. Postharvest treatments such as controlled atmosphere (CA; a high CO2 concentration and low O2) have been used under cold conditions to avoid this disorder. With the objective of exploring the mechanisms involved in the CA effect on mealiness prevention, we analyzed transcriptomic changes under six conditions of "Red Pearl" nectarines by RNA-Seq. Our analysis included just harvested nectarines, juicy non-stored fruits, fruits affected for CI after CS and fruits stored in a combination of CA plus CS without CI phenotype. Nectarines stored in cold conditions combined with CA treatment resulted in less mealiness; we obtained 21.6% of juice content compared with just CS fruits (7.7%; mealy flesh). RNA-Seq data analyses were carried out to study the gene expression for different conditions assayed. During ripening, we detected that nectarines exposed to CA treatment expressed a similar number of genes compared with fruits that were not exposed to cold conditions. Firm fruits have more differentially expressed genes than soft fruits, which suggest that most important changes occur during CS. On the other hand, gene ontology analysis revealed enrichment mainly in metabolic and cellular processes. Differentially expressed genes analysis showed that low O2 concentrations combined with cold conditions slows the metabolic processes more than just the cold storage, resulting mainly in the suppression of primary metabolism and cold stress response. This is a significant step toward unraveling the molecular mechanism that explains the effectiveness of CA as a tool to prevent CI development on fruits. PMID- 26483807 TI - Molecular cloning of AtRS4, a seed specific multifunctional RFO synthase/galactosylhydrolase in Arabidopsis thaliana. AB - Stachyose is among the raffinose family oligosaccharides (RFOs) one of the major water-soluble carbohydrates next to sucrose in seeds of a number of plant species. Especially in leguminous seeds, e.g. chickpea, stachyose is reported as the major component. In contrast to their ambiguous potential as essential source of carbon for germination, RFOs are indigestible for humans and can contribute to diverse abdominal disorders. In the genome of Arabidopsis thaliana, six putative raffinose synthase genes are reported, whereas little is known about these putative raffinose synthases and their biochemical characteristics or their contribution to the RFO physiology in A. thaliana. In this paper, we report on the molecular cloning, functional expression in Escherichia coli and purification of recombinant AtRS4 from A. thaliana and the biochemical characterisation of the putative stachyose synthase (AtSTS, At4g01970) as a raffinose and high affinity stachyose synthase (Km for raffinose 259.2 +/- 21.15 MUM) as well as stachyose and galactinol specific galactosylhydrolase. A T-DNA insertional mutant in the AtRS4 gene was isolated. Only semi-quantitative PCR from WT siliques showed a specific transcriptional AtRS4 PCR product. Metabolite measurements in seeds of DeltaAtRS4 mutant plants revealed a total loss of stachyose in DeltaAtRS4 mutant seeds. We conclude that AtRS4 is the only stachyose synthase in the genome of A. thaliana that AtRS4 represents a key regulation mechanism in the RFO physiology of A. thaliana due to its multifunctional enzyme activity and that AtRS4 is possibly the second seed specific raffinose synthase beside AtRS5, which is responsible for Raf accumulation under abiotic stress. PMID- 26483808 TI - Sequence composition of BAC clones and SSR markers mapped to Upland cotton chromosomes 11 and 21 targeting resistance to soil-borne pathogens. AB - Genetic and physical framework mapping in cotton (Gossypium spp.) were used to discover putative gene sequences involved in resistance to common soil-borne pathogens. Chromosome (Chr) 11 and its homoeologous Chr 21 of Upland cotton (G. hirsutum) are foci for discovery of resistance (R) or pathogen-induced R (PR) genes underlying QTLs involved in response to root-knot nematode (Meloidogyne incognita), reniform nematode (Rotylenchulus reniformis), Fusarium wilt (Fusarium oxysporum f.sp. vasinfectum), Verticillium wilt (Verticillium dahliae), and black root rot (Thielaviopsis basicola). Simple sequence repeat (SSR) markers and bacterial artificial chromosome (BAC) clones from a BAC library developed from the Upland cotton Acala Maxxa were mapped on Chr 11 and Chr 21. DNA sequence through Gene Ontology (GO) of 99 of 256 Chr 11 and 109 of 239 Chr 21 previously mapped SSRs revealed response elements to internal and external stimulus, stress, signaling process, and cell death. The reconciliation between genetic and physical mapping of gene annotations from new DNA sequences of 20 BAC clones revealed 467 (Chr 11) and 285 (Chr 21) G. hirsutum putative coding sequences, plus 146 (Chr 11) and 98 (Chr 21) predicted genes. GO functional profiling of Unigenes uncovered genes involved in different metabolic functions and stress response elements (SRE). Our results revealed that Chrs 11 and 21 harbor resistance gene rich genomic regions. Sequence comparisons with the ancestral diploid D5 (G. raimondii), A2 (G. arboreum) and domesticated tetraploid TM-1 AD1 (G. hirsutum) genomes revealed abundance of transposable elements and confirmed the richness of resistance gene motifs in these chromosomes. The sequence information of SSR markers and BAC clones and the genetic mapping of BAC clones provide enhanced genetic and physical frameworks of resistance gene-rich regions of the cotton genome, thereby aiding discovery of R and PR genes and breeding for resistance to cotton diseases. PMID- 26483809 TI - Proline accumulation and metabolism-related genes expression profiles in Kosteletzkya virginica seedlings under salt stress. AB - Proline accumulation is a common response to salt stress in many plants. Salt stress also increased proline concentration in roots, stems, and leaves of Kosteletzkya virginica seedling treated with 300 mM NaCl for 24 h and reached 3.75-, 4.76-, and 6.83-fold higher than controls. Further study on proline content in leaves under salt stress showed that proline content increased with increasing NaCl concentrations or time. The proline level peaked at 300 mM NaCl for 24 h and reached more than sixfold higher than control, but at 400 mM NaCl for 24 h proline content fell back slightly along with wilting symptom. To explore the cause behind proline accumulation, we first cloned full length genes related to proline metabolism including KvP5CS1, KvOAT, KvPDH, and KvProT from K. virginica and investigated their expression profiles. The results revealed that the expressions of KvP5CS1 and KvProT were sharply up-regulated by salt stress and the expression of KvOAT showed a slight increase with increasing salt concentrations or time, while the expression of KvPDH was not changed much and slightly decreased before 12 h and then returned to the original level. As the key enzyme genes for proline biosynthesis, the up-regulated expression of KvP5CS1 played a more important role than KvOAT for proline accumulation in leaves under salt stress. The low expression of KvPDH for proline catabolism also made a contribution to proline accumulation before 12 h. PMID- 26483810 TI - Genomics for greater efficiency in pigeonpea hybrid breeding. AB - Cytoplasmic genic male sterility (CGMS) based hybrid technology has demonstrated its immense potential in increasing the productivity of various crops, including pigeonpea. This technology has shown promise for breaking the long-standing yield stagnation in pigeonpea. There are difficulties in commercial hybrid seed production due to non-availability of field-oriented technologies such as time bound assessment of genetic purity of hybrid seeds. Besides this, there are other routine breeding activities which are labor oriented and need more resources. These include breeding and maintenance of new fertility restorers and maintainer lines, diversification of cytoplasm, and incorporation of biotic and abiotic stress resistances. The recent progress in genomics research could accelerate the existing traditional efforts to strengthen the hybrid breeding technology. Marker based seed purity assessment, identification of heterotic groups; selection of new fertility restorers are few areas which have already been initiated. In this paper efforts have been made to identify critical areas and opportunities where genomics can play a leading role and assist breeders in accelerating various activities related to breeding and commercialization of pigeonpea hybrids. PMID- 26483811 TI - Role of Large Cabbage White butterfly male-derived compounds in elicitation of direct and indirect egg-killing defenses in the black mustard. AB - To successfully exert defenses against herbivores and pathogens plants need to recognize reliable cues produced by their attackers. Up to now, few elicitors associated with herbivorous insects have been identified. We have previously shown that accessory reproductive gland secretions associated with eggs of Cabbage White butterflies (Pieris spp.) induce chemical changes in Brussels sprouts plants recruiting egg-killing parasitoids. Only secretions of mated female butterflies contain minute amounts of male-derived anti-aphrodisiac compounds that elicit this indirect plant defense. Here, we used the black mustard (Brassica nigra) to investigate how eggs of the Large Cabbage White butterfly (Pieris brassicae) induce, either an egg-killing direct [i.e., hypersensitive response (HR)-like necrosis] or indirect defense (i.e., oviposition-induced plant volatiles attracting Trichogramma egg parasitoids). Plants induced by P. brassicae egg-associated secretions expressed both traits and previous mating enhanced elicitation. Treatment with the anti-aphrodisiac compound of P. brassicae, benzyl cyanide (BC), induced stronger HR when compared to controls. Expression of the salicylic (SA) pathway- and HR-marker PATHOGENESIS RELATED GENE1 was induced only in plants showing an HR-like necrosis. Trichogramma wasps were attracted to volatiles induced by secretion of mated P. brassicae females but application of BC did not elicit the parasitoid-attracting volatiles. We conclude that egg-associated secretions of Pieris butterflies contain specific elicitors of the different plant defense traits against eggs in Brassica plants. While in Brussels sprouts plants anti-aphrodisiac compounds in Pieris egg-associated secretions were clearly shown to elicit indirect defense, the wild relative B. nigra, recognizes different herbivore cues that mediate the defensive responses. These results add another level of specificity to the mechanisms by which plants recognize their attackers. PMID- 26483812 TI - Transcriptome profiling reveals differential gene expression in proanthocyanidin biosynthesis associated with red/green skin color mutant of pear (Pyrus communis L.). AB - Anthocyanin concentration is the key determinant for red skin color in pear fruit. However, the molecular basis for development of red skin is complicated and has not been well-understood thus far. "Starkrimson" (Pyrus communis L.), an introduced red pear cultivated in the north of China and its green mutant provides a desirable red/green pair for identification of candidate genes involved in color variation. Here, we sequenced and annotated the transcriptome for the red/green color mutant at three stages of development using Illumina RNA seq technology. The total number of mapped reads ranged from 26 to 46 million in six libraries. About 70.11-71.95% of clean reads could be mapped to the reference genome. Compared with green colored fruit, a total of 2230 differentially expressed genes (DEGs) were identified in red fruit. Gene Ontology (GO) terms were defined for 4886 differential transcripts involved in 15 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Three DEGs were identified as candidate genes in the flavonoid pathway, LAR, ANR, and C3H. Tellingly, higher expression was found for genes encoding ANR and LAR in the green color mutant, promoting the proanthocyanidin (PA) pathway and leading to lower anthocyanin. MYB-binding cis motifs were identified in the promoter region of LAR and ANR. Based on these findings, we speculate that the regulation of PA biosynthesis might be a key factor for this red/green color mutant. Besides the known MYB and MADS transcription families, two new families, AP2 and WRKY, were identified as having high correlation with anthocyanin biosynthesis in red skinned pear. In addition, qRT-PCR was used to confirm the transcriptome results for 17 DEGs, high correlation of gene expression, further proved that AP2 and WARK regulated the anthocyanin biosynthesis in red skinned "Starkrimson," and ANR and LAR promote PA biosynthesis and contribute to the green skinned variant. This study can serve as a valuable new resource laying a solid foundation for functional gene identification in the anthocyanin pathway of red-skinned pear and provide a good reference for relevant research on molecular mechanisms of color variation in other pear species. PMID- 26483813 TI - Ethylene and plant responses to phosphate deficiency. AB - Phosphorus is an essential macronutrient for plant growth and development. Phosphate (Pi), the major form of phosphorus that plants take up through roots, however, is limited in most soils. To cope with Pi deficiency, plants activate an array of adaptive responses to reprioritize internal Pi use and enhance external Pi acquisition. These responses are modulated by sophisticated regulatory networks through both local and systemic signaling, but the signaling mechanisms are poorly understood. Early studies suggested that the phytohormone ethylene plays a key role in Pi deficiency-induced remodeling of root system architecture. Recently, ethylene was also shown to be involved in the regulation of other signature responses of plants to Pi deficiency. In this article, we review how researchers have used pharmacological and genetic approaches to dissect the roles of ethylene in regulating Pi deficiency-induced developmental and physiological changes. The interactions between ethylene and other signaling molecules, such as sucrose, auxin, and microRNA399, in the control of plant Pi responses are also examined. Finally, we provide a perspective for the future research in this field. PMID- 26483814 TI - OsCYP21-4, a novel Golgi-resident cyclophilin, increases oxidative stress tolerance in rice. AB - OsCYP21-4 is a rice cyclophilin protein that binds to cyclosporine A, an immunosuppressant drug. CYP21-4s in Arabidopsis and rice were previously shown to function as mitochondrial cyclophilins, as determined by TargetP analysis. In the current study, we found that OsCYP21-4-GFP localized to the Golgi, rather than mitochondria, in Nicotiana benthamiana leaves, which was confirmed based on its co-localization with cis Golgi alpha-ManI-mCherry protein. OsCYP21-4 transcript levels increased in response to treatments with various abiotic stresses and the phytohormone abscisic acid, revealing its stress-responsiveness. CYP21-4 homologs do not possess key peptidyl prolyl cis/trans isomerase (PPIase) activity/cyclosporine A (CsA) binding residues, and recombinant OsCYP21-4 protein did not convert the synthetic substrate Suc-AAPF-pNA via cis- trans- isomerization in vitro. In addition, transgenic plants overexpressing OsCYP21-4 exhibited increased tolerance to salinity and hydrogen peroxide treatment, along with increased peroxidase activity. These results demonstrate that OsCYP21-4 is a novel Golgi-localized cyclophilin that plays a role in oxidative stress tolerance, possibly by regulating peroxidase activity. PMID- 26483816 TI - Photoinhibition of photosystem I under high light in the shade-established tropical tree species Psychotria rubra. AB - The photosynthetic sensitivity to high light differs among understory plants of shade- and sun- established tree species. Shade-established tree species are sensitive to high light but the underlying photosynthetic mechanism has not been fully resolved. In the present study, we examined the responses of photosystem I (PSI) and photosystem II (PSII) to high light in shade leaves of a shade established tree species Psychotria rubra and a sun-established tree species Pometia tomentosa. After exposure to 2000 MUmol photons m(-2) s(-1) for 2 h, the maximum photo-oxidizable P700 (Pm ) decreased by 40 and 9% in P. rubra and P. tomentosa, respectively. These results indicate that the shade-established species P. rubra is incapable of protecting PSI under high light. Strong photoinhibition of PSII under high light led to large depression of electron transfer from PSII to PSI and then prevented further photodamage to PSI. During the high light treatment of 2000 MUmol photons m(-2) s(-1), PSI photoinhibition in P. rubra was accompanied with high levels of cyclic electron flow (CEF) and P700 oxidation ratio. Therefore, we propose that PSI photoinhibition under high light in P. rubra is dependent on electron transfer from PSII to PSI, and CEF is unlikely to play a major role in photoprotection for PSI in P. rubra. These findings suggest that photoinhibition of PSI is another important mechanism underlying why shade-established species cannot survive under high light. PMID- 26483815 TI - Plant derived substances with anti-cancer activity: from folklore to practice. AB - Plants have had an essential role in the folklore of ancient cultures. In addition to the use as food and spices, plants have also been utilized as medicines for over 5000 years. It is estimated that 70-95% of the population in developing countries continues to use traditional medicines even today. A new trend, that involved the isolation of plant active compounds begun during the early nineteenth century. This trend led to the discovery of different active compounds that are derived from plants. In the last decades, more and more new materials derived from plants have been authorized and subscribed as medicines, including those with anti-cancer activity. Cancer is among the leading causes of morbidity and mortality worldwide. The number of new cases is expected to rise by about 70% over the next two decades. Thus, there is a real need for new efficient anti-cancer drugs with reduced side effects, and plants are a promising source for such entities. Here we focus on some plant-derived substances exhibiting anti cancer and chemoprevention activity, their mode of action and bioavailability. These include paclitaxel, curcumin, and cannabinoids. In addition, development and use of their synthetic analogs, and those of strigolactones, are discussed. Also discussed are commercial considerations and future prospects for development of plant derived substances with anti-cancer activity. PMID- 26483817 TI - Interspecific hybridization in Cucumis leads to the divergence of phenotypes in response to low light and extended photoperiods. AB - With the aim of improving shade tolerance of cucumber, Cucumis * hytivus, a newly synthesized allotetraploid, was obtained by crossing a shade tolerant wild relative, Cucumis hystrix, with a cultivated cucumber, Cucumis sativus L. 'BejingJietou.' The results show that the new C. * hytivus only partly is an intermediate hybrid and it has not only chlorophyll deficiency, which recovers during leaf development, but also lower carotenoid content. Three light conditions with the combination of different light intensities and photoperiods were employed to investigate the photosynthetic response of these three Cucumis species to low light and long photoperiod. The consistent order of P max and DWS being lowest in C. hystrix, medium in C. * hytivus and highest in 'BejingJietou' suggests the three species to have genetically different photosynthetic efficiency, which relates well with the natural habitats of the parent species and the hybrid as intermediate. C. * hytivus appears to be inhibited by the low light levels to the same extent as the cultivated 'BeijingJietou,' which indicates neither improvement of shade tolerance nor hypothetical heterosis effect in C. * hytivus. However, unexpectedly, the PSII of C. hystrix was affected by the long photoperiod in the long term, suggested by the decrease of F v/F m. This sensitivity toward day length has not been passed on to C. * hytivus. PMID- 26483818 TI - Origin of worldwide cultivated barley revealed by NAM-1 gene and grain protein content. AB - The origin, evolution, and distribution of cultivated barley provides powerful insights into the historic origin and early spread of agrarian culture. Here, population-based genetic diversity and phylogenetic analyses were performed to determine the evolution and origin of barley and how domestication and subsequent introgression have affected the genetic diversity and changes in cultivated barley on a worldwide scale. A set of worldwide cultivated and wild barleys from Asia and Tibet of China were analyzed using the sequences for NAM-1 gene and gene associated traits-grain protein content (GPC). Our results showed Tibetan wild barley distinctly diverged from Near Eastern barley, and confirmed that Tibet is one of the origin and domestication centers for cultivated barley, and in turn supported a polyphyletic origin of domesticated barley. Comparison of haplotype composition among geographic regions revealed gene flow between Eastern and Western barley populations, suggesting that the Silk Road might have played a crucial role in the spread of genes. The GPC in the 118 cultivated and 93 wild barley accessions ranged from 6.73 to 12.35% with a mean of 9.43%. Overall, wild barley had higher averaged GPC (10.44%) than cultivated barley. Two unique haplotypes (Hap2 and Hap7) caused by a base mutations (at position 544) in the coding region of the NAM-1 gene might have a significant impact on the GPC. Single nucleotide polymorphisms and haplotypes of NAM-1 associated with GPC in barley could provide a useful method for screening GPC in barley germplasm. The Tibetan wild accessions with lower GPC could be useful for malt barley breeding. PMID- 26483819 TI - Grain setting defect1 (GSD1) function in rice depends on S-acylation and interacts with actin 1 (OsACT1) at its C-terminal. AB - Grain setting defect1 (GSD1), a plant-specific remorin protein specifically localized at the plasma membrane (PM) and plasmodesmata of phloem companion cells, affects grain setting in rice through regulating the transport of photoassimilates. Here, we show new evidence demonstrating that GSD1 is localized at the cytoplasmic face of the PM and a stretch of 45 amino acid residues at its C-terminal is required for its localization. Association with the PM is mediated by S-acylation of cysteine residues Cys-524 and Cys-527, in a sequence of 45 amino acid residues essential for GSD1 function in rice. Furthermore, the coiled coil domain in GSD1 is necessary for sufficient interaction with OsACT1. Together, these results reveal that GSD1 attaches to the PM through S-acylation and interacts with OsACT1 through its coiled-coil domain structure to regulate plasmodesmata conductance for photoassimilate transport in rice. PMID- 26483820 TI - Genome-wide analysis of the CaHsp20 gene family in pepper: comprehensive sequence and expression profile analysis under heat stress. AB - The Hsp20 genes are present in all plant species and play important roles in alleviating heat stress and enhancing plant thermotolerance by preventing the irreversible aggregation of denaturing proteins. However, very little is known about the CaHsp20 gene family in pepper (Capsicum annuum L.), an important vegetable crop with character of temperate but thermosensitive. In this study, a total of 35 putative pepper Hsp20 genes (CaHsp20s) were identified and renamed on the basis of their molecular weight, and then their gene structure, genome location, gene duplication, phylogenetic relationship, and interaction network were also analyzed. The expression patterns of CaHsp20 genes in four different tissues (root, stem, leaf, and flower) from the thermotolerant line R9 under heat stress condition were measured using semi-quantitative RT-PCR. The transcripts of most CaHsp20 genes maintained a low level in all of the four tissues under normal temperature condition, but were highly induced by heat stress, while the expression of CaHsp16.6b, 16.7, and 23.8 were only detected in specific tissues and were not so sensitive to heat stress like other CaHsp20 genes. In addition, compared to those in thermotolerant line R9, the expression peak of most CaHsp20 genes in thermosensitive line B6 under heat stress was hysteretic, and several CaHsp20 genes (CaHsp16.4, 18.2a, 18.7, 21.2, 22.0, 25.8, and 25.9) showed higher expression levels in both line B6 and R9. These data suggest that the CaHsp20 genes may be involved in heat stress and defense responses in pepper, which provides the basis for further functional analyses of CaHsp20s in the formation of pepper acquired thermotoleance. PMID- 26483821 TI - Ascorbic acid mitigation of water stress-inhibition of root growth in association with oxidative defense in tall fescue (Festuca arundinacea Schreb.). AB - Root growth inhibition by water stress may be related to oxidative damages. The objectives of this study were to determine whether exogenous application of ascorbic acid (ASA) could mitigate root growth decline due to water stress and whether ASA effects on root growth could be regulated through activating non enzymatic or enzymatic antioxidant systems in perennial grass species. Tall fescue (Festuca arundinacea Schreb. cv. "K-31") plants were grown in nutrient solution, and polyethylene glycol (PEG)-8000 was added into the solution to induce water stress. For exogenous ASA treatment, ASA (5 mM) was added into the solution with or without PEG-8000. Plants treated with ASA under water stress showed significantly increased root growth rate, and those roots had significantly lower content of reactive oxygen species (ROS) (H2O2 and O[Formula: see text] content) than those without ASA treatment. Malondialdehyde content in root tips treated with ASA under water stress was also significantly reduced compared with those under water stress alone. In addition, free ascorbate and total ascorbate content were significantly higher in roots treated with ASA under water stress than those without ASA treatment. The enzymatic activities for ROS scavenging-related genes were not significantly altered by ASA treatment under water stress, while transcript abundances of genes encoding superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase, dehydroascorbate reductase, and monohydroascorbate reductase showed significant decreases in the root elongation zone and significant increases in the root maturation zone treated with ASA under water stress. Transcripts of genes for expansins and xyloglucan endotransglycosylases showed increased abundances in ASA-treated root maturation zone under water stress, indicating that ASA could accelerated cell wall loosening and cell expansion. The results suggested that exogenous treatment of roots with ASA enhanced root elongation under water stress, which could be attributed by increasing non-enzymatic antioxidant production, suppressing ROS toxicity and up-regulating gene expression of cell-wall loosening proteins controlling cell expansion. PMID- 26483822 TI - RNAi-based functional elucidation of PtrPRP, a gene encoding a hybrid proline rich protein, in cold tolerance of Poncirus trifoliata. AB - Hybrid proline-rich proteins (HyPRPs) have been suggested to play important roles in various plant development and stress response. In this study, we report the cloning and functional analysis of PtrPRP, a HyPRP-encoding gene of Poncirus trifoliata. PtrPRP contains 176 amino acids, among which 21% are proline residues, and has an 8-cysteine motif (8 CM) domain at the C terminal, a signal peptide and a proline-rich region at the N terminal. PtrPRP is constitutively expressed in root, stem and leaf, with the highest expression levels in leaf. It was progressively induced by cold, but transiently upregulated by salt and ABA. Transgenic P. trifoliata plants with knock-down PtrPRP by RNA interference (RNAi) were generated to investigate the role of PtrPRP in cold tolerance. When challenged by low temperature, the PtrPRP-RNAi plants displayed more sensitive performance compared with wild type (WT), as shown by higher electrolyte leakage and malondialdehyde content. In addition, the RNAi lines accumulated more reactive oxygen species (ROS) and lower levels of proline relative to WT. These results suggested that PtrPRP might be positively involved in cold tolerance by maintaining membrane integrity and ROS homeostasis. PMID- 26483824 TI - Additive interactions of unrelated viruses in mixed infections of cowpea (Vigna unguiculata L. Walp). AB - This study was carried out to determine the effects of single infections and co infections of three unrelated viruses on three cowpea cultivars (one commercial cowpea cultivar "White" and 2 IITA lines; IT81D-985 and TVu 76). The plants were inoculated with Cowpea aphid-borne mosaic virus (CABMV), genus Potyvirus, Cowpea mottle virus (CMeV), genus Carmovirus and Southern bean mosaic virus (SBMV), genus Sobemovirus singly and in mixture (double and triple) at 10, 20, and 30 days after planting (DAP). The treated plants were assessed for susceptibility to the viruses, growth, and yield. In all cases of infection, early inoculation resulted in higher disease severity compared with late infection. The virus treated cowpea plants were relatively shorter than buffer inoculated control plants except the IT81D-985 plants that were taller and produced more foliage. Single infections by CABMV, CMeV, and SBMV led to a complete loss of seeds in the three cowpea cultivars at 10 DAP; only cultivar White produced some seeds at 30 DAP. Double and triple virus infections led to a total loss of seeds in all three cowpea cultivars. None of the virus infected IITA lines produced any seeds except IT81D-985 plants co-infected with CABMV and SBMV at 30 DAP with a reduction of 80%. Overall, the commercial cultivar "White" was the least susceptible to the virus treatments and produced the most yield (flowers, pods, and seeds). CABMV was the most aggressive of these viruses and early single inoculations with this virus resulted in the premature death of some of the seedlings. The presence of the Potyvirus, CABMV in the double virus infections did not appear to increase disease severity or yield loss. There was no strong evidence for synergistic interactions between the viruses in the double virus mixtures. PMID- 26483823 TI - Burkholderia phytofirmans PsJN reduces impact of freezing temperatures on photosynthesis in Arabidopsis thaliana. AB - Several plant growth-promoting rhizobacteria (PGPR) are known to improve plant tolerance to multiple stresses, including low temperatures. However, mechanisms underlying this protection are still poorly understood. The aim of this study was to evaluate the role of the endophytic PGPR, Burkholderia phytofirmans strain PsJN (Bp PsJN), on Arabidopsis thaliana cold tolerance using photosynthesis parameters as physiological markers. Under standard conditions, our results indicated that Bp PsJN inoculation led to growth promotion of Arabidopsis plants without significant modification on photosynthesis parameters and chloroplast organization. However, bacterial colonization induced a cell wall strengthening in the mesophyll. Impact of inoculation modes (either on seeds or by soil irrigation) and their effects overnight at 0, -1, or -3 degrees C, were investigated by following photosystem II (PSII) activity and gas exchanges. Following low temperatures stress, a decrease of photosynthesis parameters was observed. In addition, during three consecutive nights or days at -1 degrees C, PSII activity was monitored. Pigment contents, RuBisCO protein abundance, expression of several genes including RbcS, RbcL, CBF1, CBF2, CBF3, ICE1, COR15a, and COR78 were evaluated at the end of exposure. To assess the impact of the bacteria on cell ultrastructure under low temperatures, microscopic observations were achieved. Results indicated that freezing treatment induced significant changes in PSII activity as early as the first cold day, whereas the same impact on PSII activity was observed only during the third cold night. The significant effects conferred by PsJN were differential accumulation of pigments, and reduced expression of RbcL and COR78. Microscopical observations showed an alteration/disorganization in A. thaliana leaf mesophyll cells independently of the freezing treatments. The presence of bacteria during the three successive nights or days did not significantly improved A. thaliana responses but prevented the plasmalemma disruption under freezing stress. PMID- 26483825 TI - Landscape genomics reveal signatures of local adaptation in barley (Hordeum vulgare L.). AB - Land plants are sessile organisms that cannot escape the adverse climatic conditions of a given environment. Hence, adaptation is one of the solutions to surviving in a challenging environment. This study was aimed at detecting adaptive loci in barley landraces that are affected by selection. To that end, a diverse population of barley landraces was analyzed using the genotyping by sequencing approach. Climatic data for altitude, rainfall and temperature were collected from 61 weather sites near the origin of selected landraces across Ethiopia. Population structure analysis revealed three groups whereas spatial analysis accounted significant similarities at shorter geographic distances (< 40 Km) among barley landraces. Partitioning the variance between climate variables and geographic distances indicated that climate variables accounted for most of the explainable genetic variation. Markers by climatic variables association analysis resulted in altogether 18 and 62 putative adaptive loci using Bayenv and latent factor mixed model (LFMM), respectively. Subsequent analysis of the associated SNPs revealed putative candidate genes for plant adaptation. This study highlights the presence of putative adaptive loci among barley landraces representing original gene pool of the farming communities. PMID- 26483826 TI - Live substrate positively affects root growth and stolon direction in the woodland strawberry, Fragaria vesca. AB - Studies of clonal plant foraging generally focus on growth responses to patch quality once rooted. Here we explore the possibility of true plant foraging; the ability to detect and respond to patch resource status prior to rooting. Two greenhouse experiments were conducted to investigate the morphological changes that occur when individual daughter ramets of Fragaria vesca (woodland strawberry) were exposed to air above live (non-sterilized) or dead (sterilized) substrates. Contact between daughter ramets and substrate was prohibited. Daughter ramet root biomass was significantly larger over live versus dead substrate. Root:shoot ratio also increased over live substrate, a morphological response we interpret as indicative of active nutrient foraging. Daughter ramet root biomass was positively correlated with mother ramet size over live but not dead substrate. Given the choice between a live versus a dead substrate, primary stolons extended preferentially toward live substrates. We conclude that exposure to live substrate drives positive nutrient foraging responses in F. vesca. We propose that volatiles emitted from the substrates might be effecting the morphological changes that occur during true nutrient foraging. PMID- 26483827 TI - Soil inoculation with symbiotic microorganisms promotes plant growth and nutrient transporter genes expression in durum wheat. AB - In a field experiment conducted in a Mediterranean area of inner Sicily, durum wheat was inoculated with plant growth-promoting rhizobacteria (PGPR), with arbuscular mycorrhizal fungi (AMF), or with both to evaluate their effects on nutrient uptake, plant growth, and the expression of key transporter genes involved in nitrogen (N) and phosphorus (P) uptake. These biotic associations were studied under either low N availability (unfertilized plots) and supplying the soil with an easily mineralizable organic fertilizer. Regardless of N fertilization, at the tillering stage, inoculation with AMF alone or in combination with PGPR increased the aboveground biomass yield compared to the uninoculated control. Inoculation with PGPR enhanced the aboveground biomass yield compared to the control, but only when N fertilizer was added. At the heading stage, inoculation with all microorganisms increased the aboveground biomass and N. Inoculation with PGPR and AMF+PGPR resulted in significantly higher aboveground P compared to the control and inoculation with AMF only when organic N was applied. The role of microbe inoculation in N uptake was elucidated by the expression of nitrate transporter genes. NRT1.1, NRT2, and NAR2.2 were significantly upregulated by inoculation with AMF and AMF+PGPR in the absence of organic N. A significant down-regulation of the same genes was observed when organic N was added. The ammonium (NH4 (+)) transporter genes AMT1.2 showed an expression pattern similar to that of the NO3 (-) transporters. Finally, in the absence of organic N, the transcript abundance of P transporters Pht1 and PT2-1 was increased by inoculation with AMF+PGPR, and inoculation with AMF upregulated Pht2 compared to the uninoculated control. These results indicate the soil inoculation with AMF and PGPR (alone or in combination) as a valuable option for farmers to improve yield, nutrient uptake, and the sustainability of the agro ecosystem. PMID- 26483828 TI - CrBPF1 overexpression alters transcript levels of terpenoid indole alkaloid biosynthetic and regulatory genes. AB - Terpenoid indole alkaloid (TIA) biosynthesis in Catharanthus roseus is a complex and highly regulated process. Understanding the biochemistry and regulation of the TIA pathway is of particular interest as it may allow the engineering of plants to accumulate higher levels of pharmaceutically important alkaloids. Toward this end, we generated a transgenic C. roseus hairy root line that overexpresses the CrBPF1 transcriptional activator under the control of a beta estradiol inducible promoter. CrBPF1 is a MYB-like protein that was previously postulated to help regulate the expression of the TIA biosynthetic gene STR. However, the role of CrBPF1 in regulation of the TIA and related pathways had not been previously characterized. In this study, transcriptional profiling revealed that overexpression of CrBPF1 results in increased transcript levels for genes from both the indole and terpenoid biosynthetic pathways that provide precursors for TIA biosynthesis, as well as for genes in the TIA biosynthetic pathway. In addition, overexpression of CrBPF1 causes increases in the transcript levels for 11 out of 13 genes postulated to act as transcriptional regulators of genes from the TIA and TIA feeder pathways. Interestingly, overexpression of CrBPF1 causes increased transcript levels for both TIA transcriptional activators and repressors. Despite the fact that CrBPF1 overexpression affects transcript levels of a large percentage of TIA biosynthetic and regulatory genes, CrBPF1 overexpression has only very modest effects on the levels of the TIA metabolites analyzed. This finding may be due, at least in part, to the up-regulation of both transcriptional activators and repressors in response to CrBPF1 overexpression, suggesting that CrBPF1 may serve as a "fine-tune" regulator for TIA biosynthesis, acting to help regulate the timing and amplitude of TIA gene expression. PMID- 26483829 TI - Music Therapy Using Singing Training Improves Psychomotor Speed in Patients with Alzheimer's Disease: A Neuropsychological and fMRI Study. AB - BACKGROUND/AIMS: To investigate the effect of singing training on the cognitive function in Alzheimer's disease (AD) patients. METHODS: Ten AD patients (mean age 78.1 years) participated in music therapy using singing training once a week for 6 months (music therapy group). Each session was performed with professional musicians using karaoke and a unique voice training method (the YUBA Method). Before and after the intervention period, each patient was assessed by neuropsychological batteries, and functional magnetic resonance imaging (fMRI) was performed while the patients sang familiar songs with a karaoke device. As the control group, another 10 AD patients were recruited (mean age 77.0 years), and neuropsychological assessments were performed twice with an interval of 6 months. RESULTS: In the music therapy group, the time for completion of the Japanese Raven's Colored Progressive Matrices was significantly reduced (p = 0.026), and the results obtained from interviewing the patients' caregivers revealed a significant decrease in the Neuropsychiatric Inventory score (p = 0.042) and a prolongation of the patients' sleep time (p = 0.039). The fMRI study revealed increased activity in the right angular gyrus and the left lingual gyrus in the before-minus-after subtraction analysis of the music therapy intervention. CONCLUSION: Music therapy intervention using singing training may be useful for dementia patients by improving the neural efficacy of cognitive processing. PMID- 26483830 TI - Writing Impairments in Japanese Patients with Mild Cognitive Impairment and with Mild Alzheimer's Disease. AB - BACKGROUND/AIMS: We investigated writing abilities in patients with the amnestic type of mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD). To examine the earliest changes in writing function, we used writing tests for both words and sentences with different types of Japanese characters (Hiragana, Katakana, and Kanji). METHODS: A total of 25 aMCI patients, 38 AD patients, and 22 healthy controls performed writing to dictation for Kana and Kanji words, copied Kanji words, and wrote in response to a picture story task. Analysis of variance was used to test the subject group effects on the scores in the above writing tasks. RESULTS: For the written Kanji words, the mild AD group performed worse than the aMCI group and the controls, but there was no difference between the aMCI group and the controls. For the picture story writing task, the mild AD and aMCI groups performed worse than the controls, but the difference between the AD and the aMCI groups was not significant. CONCLUSIONS: The mild AD group showed defects in writing Kanji characters, and the aMCI group showed impairments in narrative writing. Our study suggests that narrative writing, which demands complex integration of multiple cognitive functions, can be used to detect the subtle writing deficits in aMCI patients. PMID- 26483831 TI - Predictors for Nursing Home Admission and Death among Community-Dwelling People 70 Years and Older Who Receive Domiciliary Care. AB - AIM: The aim of this study was to analyze which variables predicted nursing home admission (NHA) and death. METHODS: 1,001 recipients of domiciliary care were assessed three times in a 3-year period. Through bivariate and multivariate Cox proportional hazards regression models, associations between a covariate and the outcomes were analyzed. RESULTS: Participants with dementia had a higher risk of NHA (odds ratio 3.88, 95% confidence interval 2.92-5.16) compared to participants without dementia. The Neuropsychiatric Inventory sub-syndrome psychosis, poorer functional impairment and age were associated with NHA. Female sex, age, worse medical health and functional impairment were associated with death. CONCLUSION: Support to the caregiver and education on how to meet and cope with behavioral disturbance, depressive mood and sub-syndrome psychosis will probably enable the family to better adapt to late life changes. PMID- 26483832 TI - Cognitive Rehabilitation of Dementia in Adults with Down Syndrome: A Review of Non-Pharmacological Interventions. AB - BACKGROUND: There is a close genetic relationship between Alzheimer's disease (AD) and Down syndrome (DS), AD being the most severe mental disorder affecting ageing individuals with DS. The objective of the present study was to evaluate the efficacy of cognitive rehabilitation interventions in DS patients with AD by means of a critical literature review. SUMMARY: Because AD is progressive and irreversible, treatment is aimed at delaying and reducing the cognitive and functional decline in order to preserve or improve quality of life. The effects that pharmacological treatments and cognitive interventions have on elderly individuals with AD are well documented. Recent clinical trials have investigated the use of pharmacological treatment in DS patients with AD, generating preliminary results that have been unfavourable. KEY MESSAGES: There is a clear lack of studies addressing the efficacy of cognitive rehabilitation interventions in DS patients with AD, and there is an urgent need for studies providing evidence to inform decisions regarding the appropriate choice of treatment strategies. PMID- 26483833 TI - A Brief Dementia Test with Subjective and Objective Measures. AB - BACKGROUND: The development of an effective brief dementia test will help in the early identification of dementia. AIM: This study investigates the diagnostic utility of a brief cognitive test for dementia which combines a short subjective informant-rated questionnaire (AD8) with an objective cognitive measure (Mini Mental State Examination, MMSE) or its subcomponents. METHODS: Subjects with mild dementia (Clinical Dementia Rating Scale score <=1) were matched with community dwelling, cognitively intact controls. MMSE and Clinical Dementia Rating Scale were administered to all subjects, while AD8 was completed by a reliable informant. Receiver operating characteristics analysis determined the diagnostic accuracies of AD8, MMSE, and AD8 combined with MMSE (AD8+MMSE). Stepwise logistic regression identified the subcomponents of MMSE which, combined with AD8, best discriminated dementia patients from controls. RESULTS: The AD8 (area under the curve [AUC] = 0.92, 95% confidence interval [CI] 0.89-0.95) was superior to the MMSE (AUC = 0.87, 95% CI 0.83-0.92) in discriminating mild dementia patients from controls, and AD8+MMSE (AUC = 0.95, 0.92-0.98) increased its superior discrimination over MMSE alone. AD8 combined with three-item recall and intersecting pentagon copy (AUC = 0.95, 95% CI 0.92-0.97) performed as well as AD8 combined with full MMSE. CONCLUSION: AD8 combined with the MMSE subcomponents three-item recall and intersecting pentagon copy has excellent diagnostic utility and is a promising brief cognitive test for early dementia. PMID- 26483835 TI - Evolution of epithelial morphogenesis: phenotypic integration across multiple levels of biological organization. AB - Morphogenesis involves the dynamic reorganization of cell and tissue shapes to create the three-dimensional body. Intriguingly, different species have evolved different morphogenetic processes to achieve the same general outcomes during embryonic development. How are meaningful comparisons between species made, and where do the differences lie? In this Perspective, we argue that examining the evolution of embryonic morphogenesis requires the simultaneous consideration of different levels of biological organization: (1) genes, (2) cells, (3) tissues, and (4) the entire egg, or other gestational context. To illustrate the importance of integrating these levels, we use the extraembryonic epithelia of insects-a lineage-specific innovation and evolutionary hotspot-as an exemplary case study. We discuss how recent functional data, primarily from RNAi experiments targeting the Hox3/Zen and U-shaped group transcription factors, provide insights into developmental processes at all four levels. Comparisons of these data from several species both challenge and inform our understanding of homology, in assessing how the process of epithelial morphogenesis has itself evolved. PMID- 26483836 TI - Lipid changes due to fenofibrate treatment are not associated with changes in DNA methylation patterns in the GOLDN study. AB - Fenofibrate lowers triglycerides (TG) and raises high density lipoprotein cholesterol (HDLc) in dyslipidemic individuals. Several studies have shown genetic variability in lipid responses to fenofibrate treatment. It is, however, not known whether epigenetic patterns are also correlated with the changes in lipids due to fenofibrate treatment. The present study was therefore undertaken to examine the changes in DNA methylation among the participants of Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. A total of 443 individuals were studied for epigenome-wide changes in DNA methylation, assessed using the Illumina Infinium HumanMethylation450 array, before and after a 3-week daily treatment with 160 mg of fenofibrate. The association between the change in DNA methylation and changes in TG, HDLc, and low-density lipoprotein cholesterol (LDLc) were assessed using linear mixed models adjusted for age, sex, baseline lipids, and study center as fixed effects and family as a random effect. Changes in DNA methylation were not significantly associated with changes in TG, HDLc, or LDLc after 3 weeks of fenofibrate for any CpG. CpG changes in genes known to be involved in fenofibrate response, e.g., PPAR-alpha, APOA1, LPL, APOA5, APOC3, CETP, and APOB, also did not show evidence of association. In conclusion, changes in lipids in response to 3-week treatment with fenofibrate were not associated with changes in DNA methylation. Studies of longer duration may be required to detect treatment-induced changes in methylation. PMID- 26483834 TI - Mapping asthma-associated variants in admixed populations. AB - Admixed populations arise when two or more previously isolated populations interbreed. Mapping asthma susceptibility loci in an admixed population using admixture mapping (AM) involves screening the genome of individuals of mixed ancestry for chromosomal regions that have a higher frequency of alleles from a parental population with higher asthma risk as compared with parental population with lower asthma risk. AM takes advantage of the admixture created in populations of mixed ancestry to identify genomic regions where an association exists between genetic ancestry and asthma (in contrast to between the genotype of the marker and asthma). The theory behind AM is that chromosomal segments of affected individuals contain a significantly higher-than-average proportion of alleles from the high-risk parental population and thus are more likely to harbor disease-associated loci. Criteria to evaluate the applicability of AM as a gene mapping approach include: (1) the prevalence of the disease differences in ancestral populations from which the admixed population was formed; (2) a measurable difference in disease-causing alleles between the parental populations; (3) reduced linkage disequilibrium (LD) between unlinked loci across chromosomes and strong LD between neighboring loci; (4) a set of markers with noticeable allele-frequency differences between parental populations that contributes to the admixed population (single nucleotide polymorphisms (SNPs) are the markers of choice because they are abundant, stable, relatively cheap to genotype, and informative with regard to the LD structure of chromosomal segments); and (5) there is an understanding of the extent of segmental chromosomal admixtures and their interactions with environmental factors. Although genome-wide association studies have contributed greatly to our understanding of the genetic components of asthma, the large and increasing degree of admixture in populations across the world create many challenges for further efforts to map disease-causing genes. This review, summarizes the historical context of admixed populations and AM, and considers current opportunities to use AM to map asthma genes. In addition, we provide an overview of the potential limitations and future directions of AM in biomedical research, including joint admixture and association mapping for asthma and asthma-related disorders. PMID- 26483837 TI - Rice transcriptome analysis to identify possible herbicide quinclorac detoxification genes. AB - Quinclorac is a highly selective auxin-type herbicide and is widely used in the effective control of barnyard grass in paddy rice fields, improving the world's rice yield. The herbicide mode of action of quinclorac has been proposed, and hormone interactions affecting quinclorac signaling has been identified. Because of widespread use, quinclorac may be transported outside rice fields with the drainage waters, leading to soil and water pollution and other environmental health problems. In this study, we used 57K Affymetrix rice whole-genome array to identify quinclorac signaling response genes to study the molecular mechanisms of action and detoxification of quinclorac in rice plants. Overall, 637 probe sets were identified with differential expression levels under either 6 or 24 h of quinclorac treatment. Auxin-related genes such as GH3 and OsIAAs responded to quinclorac treatment. Gene Ontology analysis showed that genes of detoxification related family genes were significantly enriched, including cytochrome P450, GST, UGT, and ABC and drug transporter genes. Moreover, real-time RT-PCR analysis showed that top candidate genes of P450 families such as CYP81, CYP709C, and CYP72A were universally induced by different herbicides. Some Arabidopsis genes of the same P450 family were up-regulated under quinclorac treatment. We conducted rice whole-genome GeneChip analysis and the first global identification of quinclorac response genes. This work may provide potential markers for detoxification of quinclorac and biomonitors of environmental chemical pollution. PMID- 26483838 TI - Some Epidemiological Aspects of Cutaneous Leishmaniasis in a New Focus, Central Iran. AB - Following the epidemic of cutaneous leishmaniasis in Khatam County, Yazd Province, this study was carried out to determine vector, and animal reservoir host(s) and investigate the human infection during 2005-2006. Four rural districts where the disease had higher prevalence were selected. Sticky paper traps were used to collect sand flies during April to November, biweekly. Meanwhile rodents were captured using Sherman traps from August to November. Households and primary schools were visited and examined for human infection in February 2006. The parasite was detected by RAPD-PCR method. The rate of ulcers and scars among the inhabitants was 4.8% and 9.8%, respectively. Three rodent species were captured during the study: Meriones libycus, Rhombomys opimus, and Tatera indica. Six sand fly species were also collected and identified; among them Phlebotomus papatasi had the highest frequency. Leishmania major was detected as the agent of the disease in the area. It was detected from R. opimus and native people. PMID- 26483839 TI - Study of the Etiological Causes of Toe Web Space Lesions in Cairo, Egypt. AB - Background. The etiology of foot intertrigo is varied. Several pathogens and skin conditions might play a role in toe web space lesions. Objective. To identify the possible etiological causes of toe web space lesions. Methods. 100 Egyptian patients were enrolled in this study (72 females and 28 males). Their ages ranged from 18 to 79 years. For every patient, detailed history taking, general and skin examinations, and investigations including Wood's light examination, skin scraping for potassium hydroxide test, skin swabs for bacterial isolation, and skin biopsy all were done. Results. Among the 100 patients, positive Wood's light fluorescence was observed in 24 and positive bacterial growth was observed in 85. With skin biopsy, 52 patients showed features characteristic for eczema, 25 showed features characteristic for fungus, 19 showed features characteristic for callosity, and 3 showed features characteristic for wart while in only 1 patient the features were characteristic for lichen planus. Conclusion. Toe web space lesions are caused by different etiological factors. The most common was interdigital eczema (52%) followed by fungal infection (25%). We suggest that patients who do not respond to antifungals should be reexamined for another primary or secondary dermatologic condition that may resemble interdigital fungal infection. PMID- 26483840 TI - Corrigendum to "Incidence and Paris Classification of Pediatric Inflammatory Bowel Disease". AB - [This corrects the article DOI: 10.1155/2014/904307.]. PMID- 26483841 TI - Regulation of Expression of Oxacillin-Inducible Methionine Sulfoxide Reductases in Staphylococcus aureus. AB - Cell wall-active antibiotics cause induction of a locus that leads to elevated synthesis of two methionine sulfoxide reductases (MsrA1 and MsrB) in Staphylococcus aureus. To understand the regulation of this locus, reporter strains were constructed by integrating a DNA fragment consisting of the msrA1/msrB promoter in front of a promoterless lacZ gene in the chromosome of wild-type and MsrA1-, MsrB-, MsrA1/MsrB-, and SigB-deficient methicillin sensitive S. aureus strain SH1000 and methicillin-resistant S. aureus strain COL. These reporter strains were cultured in TSB and the cellular levels of beta galactosidase activity in these cultures were assayed during different growth phases. beta-galactosidase activity assays demonstrated that the lack of MsrA1, MsrB, and SigB upregulated the msrA1/msrB promoter in S. aureus strain SH1000. In S. aureus strain COL, the highest level of beta-galactosidase activity was observed under the conditions when both MsrA1 and MsrB proteins were absent. The data suggest that the msrA1/msrB locus, in part, is negatively regulated by MsrA1, MsrB, and SigB in S. aureus. PMID- 26483842 TI - Improvement in Long-Term Memory following Chronic Administration of Eryngium planum Root Extract in Scopolamine Model: Behavioral and Molecular Study. AB - Eryngium planum L. (EP) is as a rare medicinal plant with a lot of potentials as pharmaceutical crops. The aim of our study was to assess the effect of subchronic (28-fold) administration of a 70% ethanol extract of EP roots (200 mg/kg, p.o.) on behavioral and cognitive responses in Wistar rats linked with acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase (BACE-1) mRNA levels and AChE and BuChE activities in the hippocampus and frontal cortex. On the last day of experiment, 30 min after the last dose of EP or Huperzine A (HU), scopolamine (SC) was given at a dose of 0.5 mg/kg b.w. intraperitoneally. The results of a passive avoidance test showed an improvement in long-term memory produced by the EP extract in both scopolamine-induced rats and control group. EP caused an insignificant inhibition of AChE and BuChE activities in the frontal cortex and the hippocampus. EP decreased mRNA AChE, BuChE, and BACE-1 levels, especially in the cortex. Our results suggest that the EP extract led to the improvement of the long-term memory in rats coupled with total saponin content. The mechanism of EP action is probably complicated, since HPLC-MS analysis showed 64 chemical compounds (phenolics, saponins) in the extract of EP roots. PMID- 26483843 TI - Antiplatelet Aggregation and Antithrombosis Efficiency of Peptides in the Snake Venom of Deinagkistrodon acutus: Isolation, Identification, and Evaluation. AB - Two peptides of Pt-A (Glu-Asn-Trp 429 Da) and Pt-B (Glu-Gln-Trp 443 Da) were isolated from venom liquor of Deinagkistrodon acutus. Their antiplatelet aggregation effects were evaluated with platelet-rich human plasma in vitro; the respective IC50 of Pt-A and Pt-B was 66 MUM and 203 MUM. Both peptides exhibited protection effects on ADP-induced paralysis in mice. After ADP administration, the paralysis time of different concentration of Pt-A and Pt-B lasted as the following: 80 mg/kg Pt-B (152.8 +/- 57.8 s) < 40 mg/kg Pt-A (163.5 +/- 59.8 s) < 20 mg/kg Pt-A (253.5 +/- 74.5 s) < 4 mg/kg clopidogrel (a positive control, 254.5 +/- 41.97 s) < 40 mg/kg Pt-B (400.8 +/- 35.9 s) < 10 mg/kg Pt-A (422.8 +/- 55.4 s), all of which were statistically shorter than the saline treatment (666 +/- 28 s). Pulmonary tissue biopsy confirmed that Pt-A and Pt-B prevented the formation of thrombi in the lung. Unlike ADP injection alone, which caused significant reduction of peripheral platelet count, Pt-A treatment prevented the drop of peripheral platelet counts; interestingly, Pt-B could not, even though the same amount of Pt-B also showed protection effects on ADP-induced paralysis and thrombosis. More importantly, intravenous injection of Pt-A and Pt-B did not significantly increase the hemorrhage risks as clopidogrel. PMID- 26483844 TI - Curcuma aromatica Water Extract Attenuates Ethanol-Induced Gastritis via Enhancement of Antioxidant Status. AB - Curcuma aromatica is an herbal medicine and traditionally used for the treatment of various diseases in Asia. We investigated the effects of C. aromatica water extract (CAW) in the stomach of rats with ethanol-induced gastritis. Gastritis was induced in rats by intragastric administration of 5 mL/kg body weight of absolute ethanol. The CAW groups were given 250 or 500 mg of extract/kg 2 h before administration of ethanol, respectively. To determine the antioxidant effects of CAW, we determined the level of lipid peroxidation, the level of reduced glutathione (GSH), the activities of catalase, degree of inflammation, and mucus production in the stomach. CAW reduced ethanol-induced inflammation and loss of epithelial cells and increased the mucus production in the stomach. CAW reduced the increase in lipid peroxidation associated with ethanol-induced gastritis (250 and 500 mg/kg, p < 0.01, resp.) and increased mucosal GSH content (500 mg/kg, p < 0.01) and the activity of catalase (250 and 500 mg/kg, p < 0.01, resp.). CAW increased the production of prostaglandin E2. These findings suggest that CAW protects against ethanol-induced gastric mucosa injury by increasing antioxidant status. We suggest that CAW could be developed for the treatment of gastritis induced by alcohol. PMID- 26483845 TI - Qualitative Evaluation of Baduanjin (Traditional Chinese Qigong) on Health Promotion among an Elderly Community Population at Risk for Ischemic Stroke. AB - Background. Baduanjin is a traditional Chinese qigong that has been practiced for a long time in China as a mind-body exercise in community elderly populations. The objective of this study was to qualitatively evaluate the perceived benefit of regular Baduanjin qigong in community elders. Methods. A total of 20 participants who had completed the 12-week Baduanjin qigong training were interviewed regarding their perceived effect on physical and psychological health and whether Baduanjin qigong was suitable for the elderly. Results. Almost all participants agreed that Baduanjin qigong could promote their multisystem or organ functions (e.g., digestive and circulatory systems), increase their immunity, make their bodies relax, and improve their mood and confidence. Most of the participants also agreed that Baduanjin qigong was appropriate for elderly individuals. Few individuals felt bored because of an hour Baduanjin training each day. Conclusions. The findings suggest that regular Baduanjin qigong may be potentially helpful to promote the overall physical and psychological health of elderly community populations and may be useful and feasible as a body-mind exercise in the health promotion in the elderly community populations. PMID- 26483846 TI - Traditional Korean Herbal Formula Samsoeum Attenuates Adipogenesis by Regulating the Phosphorylation of ERK1/2 in 3T3-L1 Cells. AB - Adipogenesis is the cell differentiation process from preadipocytes into adipocytes and the critical action in the development of obesity. In the present study, we conducted in vitro analyses to investigate the inhibitory effects of Samsoeum (SSE), a traditional herbal decoction. SSE had no significant cytotoxic effect against either the undifferentiated or differentiated 3T3-L1 cells. Oil Red O staining results showed that SSE significantly inhibited fat accumulation in adipocytes. SSE treatment consistently reduced the intracellular triglyceride content in the cells. SSE significantly inactivated glycerol-3-phosphate dehydrogenase (GPDH), a major link between carbohydrate and lipid metabolisms in 3T3-L1 adipocytes, and markedly inhibited the production of leptin, an important adipokine, in differentiated cells. SSE markedly suppressed the mRNA expression of the adipogenesis-related genes peroxisome proliferator-activated receptor gamma (PPAR-gamma), CCAAT/enhancer binding protein-alpha (C/EBP-alpha), fatty acid synthase (FAS), lipoprotein lipase (LPL), and fatty acid binding protein 4 (FABP4). Importantly, SSE increased the phosphorylation of ERK1/2, but not p38 MAPK and JNK, in adipose cells. Overall, our results indicate that SSE exerts antiadipogenic activity and modulates expressions of adipogenesis-related genes and ERK1/2 activation in adipocytes. PMID- 26483847 TI - Chinese Herbal Bath Therapy for the Treatment of Knee Osteoarthritis: Meta Analysis of Randomized Controlled Trials. AB - Objective. Chinese herbal bath therapy (CHBT) has traditionally been considered to have analgesic and anti-inflammatory effects. We conducted the first meta analysis evaluating its benefits for patients with knee osteoarthritis (OA). Methods. We searched three English and four Chinese databases through October, 2014. Randomized trials evaluating at least 2 weeks of CHBT for knee OA were selected. The effects of CHBT on clinical symptoms included both pain level (via the visual analog scale) and total effectiveness rate, which assessed pain, physical performance, and wellness. We performed random-effects meta-analyses using mean difference. Results. Fifteen studies totaling 1618 subjects met eligibility criteria. Bath prescription included, on average, 13 Chinese herbs with directions to steam and wash around the knee for 20-40 minutes once or twice daily. Mean treatment duration was 3 weeks. Results from meta-analysis showed superior pain improvement (mean difference = -0.59 points; 95% confidence intervals [CI], -0.83 to -0.36; p < 0.00001) and higher total effectiveness rate (risk ratio = 1.21; 95% CI, 1.15 to 1.28; p < 0.00001) when compared with standard western treatment. No serious adverse events were reported. Conclusion. Chinese herbal bath therapy may be a safe, effective, and simple alternative treatment modality for knee OA. Further rigorously designed, randomized trials are warranted. PMID- 26483848 TI - Merkel cell polyomavirus (MCV) T-antigen seroreactivity, MCV DNA in eyebrow hairs, and squamous cell carcinoma. AB - BACKGROUND: The role of Merkel cell polyomavirus (MCV) infection in the etiology of non-melanoma skin cancers, other than Merkel cell carcinoma, is unclear. Previously, we reported a significant association between seropositivity to MCV capsid antigen and MCV DNA-positive cutaneous squamous cell carcinoma (SCC). Here we present associations between SCC and seroreactivity to MCV T-antigen (T-Ag) oncoprotein, as well as MCV DNA detected in eyebrow hairs. FINDINGS: A clinic based case-control study, including 171 SCC cases and 300 controls without skin cancer, was conducted at Moffitt Cancer Center in Tampa, Florida. Multiplex assays were used to measure serum antibodies against MCV small and large T-Ag and MCV DNA in both eyebrow hairs and SCC tumors (n = 144). Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated using logistic regression to evaluate the associations between MCV and SCC. No significant association was observed between seroreactivity to MCV full-length large or small T-Ag and SCC, overall [ORlarge T-Ag = 0.99 (0.48-2.08), ORsmall T-Ag = 0.31 (0.06-1.62)] or when comparing tumor MCV DNA-positive cases to controls [ORlarge T-Ag = 1.06 (0.38 2.93)]. Only presence of MCV DNA in eyebrow hairs was significantly associated with MCV DNA-positive SCC [OR = 4.05 (2.01-8.18)]. CONCLUSION: MCV infection is unlikely to play a direct role in SCC. PMID- 26483849 TI - Survey of small intestinal and systemic immune responses following murine Arcobacter butzleri infection. AB - BACKGROUND: Arcobacter (A.) butzleri has been described as causative agent for sporadic cases of human gastroenteritis with abdominal pain and acute or prolonged watery diarrhea. In vitro studies revealed distinct adhesive, invasive and cytotoxic properties of A. butzleri. Information about the underlying immunopathological mechanisms of infection in vivo, however, are scarce. The aim of this study was to investigate the immunopathological properties of two different A. butzleri strains in a well-established murine infection model. RESULTS: Gnotobiotic IL-10(-/-) mice, in which the intestinal microbiota was depleted by broad-spectrum antibiotic treatment, were perorally infected with two different A. butzleri strains isolated from a diseased patient (CCUG 30485) or fresh chicken meat (C1), respectively. Eventhough bacteria of either strain could stably colonize the intestinal tract at day 6 and day 16 postinfection (p.i.), mice did not exert infection induced symptoms such as diarrhea or wasting. In small intestines of infected mice, however, increased numbers of apoptotic cells could be detected at day 16, but not day 6 following infection with either strain. A strain-dependent influx of distinct immune cell populations such as T and B cells as well as of regulatory T cells could be observed upon A. butzleri infection which was accompanied by increased small intestinal concentrations of pro-inflammatory cytokines such as TNF, IFN-gamma, MCP-1 and IL-6. Remarkably, inflammatory responses following A. butzleri infection were not restricted to the intestinal tract, given that the CCUG 30485 strain induced systemic immune responses as indicated by increased IFN-gamma concentrations in spleens at day 6, but not day 16 following infection. CONCLUSION: Upon peroral infection A. butzleri stably colonized the intestinal tract of gnotobiotic IL-10(-/-) mice. The dynamics of distinct local and systemic inflammatory responses could be observed in a strain-dependent fashion pointing towards an immunopathogenic potential of A. butzleri in vivo. These results indicate that gnotobiotic IL-10( /-) mice are well suited to further investigate the molecular mechanisms underlying arcobacteriosis in vivo. PMID- 26483850 TI - 8th meeting of the medical assessment consortium UCAN: "Collaborative Perspectives for Competency-based and Quality-assured Medical Assessment". PMID- 26483851 TI - Influence of a revision course and the gender of examiners on the grades of the final ENT exam--a retrospective review of 3961 exams. AB - Revision courses should repeat already acquired knowledge and skills and mostly provide a basis for passing the following exam. AIM: The aim of the study is to investigate the influence of a previously attended revision course on the grades achieved in a final exam (Ear, Nose and Throat Diseases). Additionally we ask the question whether the gender of the examiners plays a role concerning the marks or not. METHODS: 3961 exams at the Department of Ear, Nose and Throat (ENT) Diseases in Vienna were investigated, 725 with revision course (experimental group) and 3236 without previous revision course (comparison group). The revision courses were performed in a standardized way concerning form and content, interactive and case based. Both groups were examined uniform in regard to topics and time duration. 16 male and 6 female examiners were involved. The grading followed a five-level scale. The examination marks were calculated in the arithmetic mean and median value for the entire sample, gender dependence was calculated according to the Wilcoxon-Mann-Whitney-Test. The inferential statistics included single- and multiple factorial analyses of variance as well as uni- and multivariate regression models. RESULTS: The experimental group achieved a grade average of 2.54 compared with 2.46 for the comparison group. Splitting up into male and female examiners, an average of 2.54 and 2.58 resp. for the experimental group and 2.44 and 2.61 resp. for the comparison group resulted. Female examiner marked significantly lower grades in comparison to their male colleagues (P= 0.001926). CONCLUSIONS: The ENT revision course did not improve the grade averages of the final ENT exam. Female examiners grade stricter than male examiners. There was no difference concerning grades 4 (pass) and 5 (fail) but female examiners grade less with mark 1. PMID- 26483852 TI - The Final Oral/Practical State Examination at Freiburg Medical Faculty in 2012- Analysis of grading to test quality assurance. AB - AIM: The aim of this study is to analyze the grades given for the oral/practical part of the German State Examination at the Medical Faculty of Freiburg. We examined whether or not the grades given for the written and the oral/practical examinations correlated and if differences in grading between the Freiburg University Medical Center (UMC) and the other teaching hospitals could be found. In order to improve the quality of the state examination, the medical school has been offering standardized training for examiners for several years. We evaluated whether or not trained and untrained examiners differed in their grading of the exam and how these differences have changed over time. METHODS: The results of the 2012 spring and fall exams were analyzed (N=315). The relevant data set was made available to us by the Baden-Wurttemberg Examination Office (Landesprufungsamt). The data were analyzed by means of descriptive and inferential statistics. RESULTS: We observed a correlation of rho=0.460** between the grades for the written and the oral/practical exams. The UMC and the teaching hospitals did not differ significantly in their grade distributions. Compared to untrained examiners, trained ones assigned the grade of "very good" less often. Furthermore, they displayed a significantly higher variance in the grades given (p=0.007, phi=0.165). This effect is stronger when concentrating specifically on those examiners who took part in the training less than a year before. CONCLUSION: The results of this study suggest that the standardized training for examiners at the Medical Faculty of Freiburg is effective for quality assurance. As a consequence, more examiners should be motivated to take part in the training. PMID- 26483853 TI - The new final Clinical Skills examination in human medicine in Switzerland: Essential steps of exam development, implementation and evaluation, and central insights from the perspective of the national Working Group. AB - OBJECTIVE: Since 2011, the new national final examination in human medicine has been implemented in Switzerland, with a structured clinical-practical part in the OSCE format. From the perspective of the national Working Group, the current article describes the essential steps in the development, implementation and evaluation of the Federal Licensing Examination Clinical Skills (FLE CS) as well as the applied quality assurance measures. Finally, central insights gained from the last years are presented. METHODS: Based on the principles of action research, the FLE CS is in a constant state of further development. On the foundation of systematically documented experiences from previous years, in the Working Group, unresolved questions are discussed and resulting solution approaches are substantiated (planning), implemented in the examination (implementation) and subsequently evaluated (reflection). The presented results are the product of this iterative procedure. RESULTS: The FLE CS is created by experts from all faculties and subject areas in a multistage process. The examination is administered in German and French on a decentralised basis and consists of twelve interdisciplinary stations per candidate. As important quality assurance measures, the national Review Board (content validation) and the meetings of the standardised patient trainers (standardisation) have proven worthwhile. The statistical analyses show good measurement reliability and support the construct validity of the examination. Among the central insights of the past years, it has been established that the consistent implementation of the principles of action research contributes to the successful further development of the examination. CONCLUSION: The centrally coordinated, collaborative iterative process, incorporating experts from all faculties, makes a fundamental contribution to the quality of the FLE CS. The processes and insights presented here can be useful for others planning a similar undertaking. PMID- 26483854 TI - Electronic acquisition of OSCE performance using tablets. AB - BACKGROUND: Objective Structured Clinical Examinations (OSCEs) often involve a considerable amount of resources in terms of materials and organization since the scores are often recorded on paper. Computer-assisted administration is an alternative with which the need for material resources can be reduced. In particular, the use of tablets seems sensible because these are easy to transport and flexible to use. AIM: User acceptance concerning the use of tablets during OSCEs has not yet been extensively investigated. The aim of this study was to evaluate tablet-based OSCEs from the perspective of the user (examiner) and the student examinee. METHOD: For two OSCEs in Internal Medicine at the University of Heidelberg, user acceptance was analyzed regarding tablet-based administration (satisfaction with functionality) and the subjective amount of effort as perceived by the examiners. Standardized questionnaires and semi-standardized interviews were conducted (complete survey of all participating examiners). In addition, for one OSCE, the subjective evaluation of this mode of assessment was gathered from a random sample of participating students in semi-standardized interviews. RESULTS: Overall, the examiners were very satisfied with using tablets during the assessment. The subjective amount of effort to use the tablet was found on average to be "hardly difficult". The examiners identified the advantages of this mode of administration as being in particular the ease of use and low rate of error. During the interviews of the examinees, acceptance for the use of tablets during the assessment was also detected. DISCUSSION: Overall, it was found that the use of tablets during OSCEs was well accepted by both examiners and examinees. We expect that this mode of assessment also offers advantages regarding assessment documentation, use of resources, and rate of error in comparison with paper-based assessments; all of these aspects should be followed up on in further studies. PMID- 26483855 TI - The reliability of the pass/fail decision for assessments comprised of multiple components. AB - OBJECTIVE: The decision having the most serious consequences for a student taking an assessment is the one to pass or fail that student. For this reason, the reliability of the pass/fail decision must be determined for high quality assessments, just as the measurement reliability of the point values. Assessments in a particular subject (graded course credit) are often composed of multiple components that must be passed independently of each other. When "conjunctively" combining separate pass/fail decisions, as with other complex decision rules for passing, adequate methods of analysis are necessary for estimating the accuracy and consistency of these classifications. To date, very few papers have addressed this issue; a generally applicable procedure was published by Douglas and Mislevy in 2010. Using the example of an assessment comprised of several parts that must be passed separately, this study analyzes the reliability underlying the decision to pass or fail students and discusses the impact of an improved method for identifying those who do not fulfill the minimum requirements. METHOD: The accuracy and consistency of the decision to pass or fail an examinee in the subject cluster Internal Medicine/General Medicine/Clinical Chemistry at the University of Heidelberg's Faculty of Medicine was investigated. This cluster requires students to separately pass three components (two written exams and an OSCE), whereby students may reattempt to pass each component twice. Our analysis was carried out using the method described by Douglas and Mislevy. RESULTS: Frequently, when complex logical connections exist between the individual pass/fail decisions in the case of low failure rates, only a very low reliability for the overall decision to grant graded course credit can be achieved, even if high reliabilities exist for the various components. For the example analyzed here, the classification accuracy and consistency when conjunctively combining the three individual parts is relatively low with kappa=0.49 or kappa=0.47, despite the good reliability of over 0.75 for each of the three components. The option to repeat each component twice leads to a situation in which only about half of the candidates who do not satisfy the minimum requirements would fail the overall assessment, while the other half is able to continue their studies despite having deficient knowledge and skills. CONCLUSION: The method put forth by Douglas and Mislevy allows the analysis of the decision accuracy and consistency for complex combinations of scores from different components. Even in the case of highly reliable components, it is not necessarily so that a reliable pass/fail decision has been reached - for instance in the case of low failure rates. Assessments must be administered with the explicit goal of identifying examinees that do not fulfill the minimum requirements. PMID- 26483856 TI - Overcome the 60% passing score and improve the quality of assessment. AB - It is not unusual for institutions around the world to have fixed standards (e.g., 60%) for all of their examinations. This creates problems in the creation of examinations, since all of the content has to be chosen with an eye toward this fixed standard. As a result, the validity of the decisions based on these examinations can be adversely influenced, making them less useful for their intended purposes. Over the past several decades, many institutions have addressed this problem by using standard setting methods which are defensible, acceptable, and credible [1], [2]. Many methods are available and the major reasons to use them is to ensure that test content is appropriately selected and to be as fair to the students and other test users as possible [2], [3]. One barrier to the wider use of these methods is that some institutions object to the fact that the fixed standard (e.g., 60%) has not been applied. However, it is possible to rescale the passing score so that it is equal to the fixed standard, and then apply that same rescaling calculation to all of the test scores. This ensures that the institutional guidelines are not violated and allows the application of accepted methods of standard-setting. In turn, the application of these methods allow the content of the test to be selected without regard to a fixed standard, increases the validity of the decisions being made, and ensures a fairer and more accurate test of students. PMID- 26483857 TI - Impact of the Medical Faculty on Study Success in Freiburg: Results from Graduate Surveys. AB - AIM: Using the data from graduate surveys, this study aims to analyze which factors related to teaching and learning at the Freiburg Faculty of Medicine can influence study success. BACKGROUND: Study success and the factors influencing it have long been the subject of investigation, with study success being measured in terms of easily quantifiable indicators (final grades, student satisfaction, etc.). In recent years, it has also frequently been assessed in terms of graduate competency levels. Graduate surveys are considered suitable instruments for measuring these dimensions of study success. METHOD: Data from three Freiburg graduate surveys conducted one and a half years after graduation were drawn upon for the analysis. Study success was operationalized using four indicators: results on the written section of the M2 exam, self-assessment of medical expertise and scientific expertise, and student satisfaction. Using multiple regression analyses, the predictive power was calculated for selected variables, also measured by the graduate surveys, for the different study success indicators. RESULTS: It was possible to identify models that contribute slightly or moderately to the prediction of study success. The score earned on the university entrance qualification demonstrated itself to be the strongest predictor for forecasting the M2 written exam: R(2) is between 0.08 and 0.22 for the three surveys. Different variables specific to degree program structure and teaching are helpful for predicting medical expertise (R(2)=0.04-0.32) and student satisfaction (R(2)=0.12-0.35). The two variables, structure and curricular sequencing of the degree program and combination of theory and practice, show themselves to be significant, sample-invariant predictors (beta weight(Structure)=0.21-0.58, beta-weight(Combination)=0.27-0.56). For scientific expertise, no sample-independent predictors could be determined. CONCLUSION: Factors describing teaching hardly provide any assistance when predicting the written M2 exam score, which makes sense to the extent that teaching goes far beyond the heavily knowledge-based content of the written M2 exam. The lack of predictability for scientific expertise is most likely explained in that these have been only rarely included in the curriculum and often inexplicitly so. The variable combination of theory and practice appears to be significant for imparting medical expertise and the development of student satisfaction. The extent to which these relationships are practically relevant needs to be explored in further studies. A specific limitation is that the measurement of expertise and skill is based solely on self-assessments. PMID- 26483858 TI - DOPS (Direct Observation of Procedural Skills) in undergraduate skills-lab: Does it work? Analysis of skills-performance and curricular side effects. AB - OBJECTIVE: Sufficient teaching and assessing clinical skills in the undergraduate setting becomes more and more important. In a surgical skills-lab course at the Medical University of Innsbruck fourth year students were teached with DOPS (direct observation of procedural skills). We analyzed whether DOPS worked or not in this setting, which performance levels could be reached compared to tutor teaching (one tutor, 5 students) and which curricular side effects could be observed. METHODS: In a prospective randomized trial in summer 2013 (April - June) four competence-level-based skills were teached in small groups during one week: surgical abdominal examination, urethral catheterization (phantom), rectal digital examination (phantom), handling of central venous catheters. Group A was teached with DOPS, group B with a classical tutor system. Both groups underwent an OSCE (objective structured clinical examination) for assessment. 193 students were included in the study. Altogether 756 OSCE's were carried out, 209 (27,6%) in the DOPS- and 547 (72,3%) in the tutor-group. RESULTS: Both groups reached high performance levels. In the first month there was a statistically significant difference (p<0,05) in performance of 95% positive OSCE items in the DOPS-group versus 88% in the tutor group. In the following months the performance rates showed no difference anymore and came to 90% in both groups. In practical skills the analysis revealed a high correspondence between positive DOPS (92,4%) and OSCE (90,8%) results. DISCUSSION: As shown by our data DOPS furnish high performance of clinical skills and work well in the undergraduate setting. Due to the high correspondence of DOPS and OSCE results DOPS should be considered as preferred assessment tool in a students skills-lab. The approximation of performance-rates within the months after initial superiority of DOPS could be explained by an interaction between DOPS and tutor system: DOPS elements seem to have improved tutoring and performance rates as well. DOPS in students 'skills lab afford structured feedback and assessment without increased personnel and financial resources compared to classic small group training. CONCLUSION: In summary, this study shows that DOPS represent an efficient method in teaching clinical skills. Their effects on didactic culture reach beyond the positive influence of performance rates. PMID- 26483860 TI - On the journey to competency-based assessment for safe patient care. PMID- 26483859 TI - Development of a competency-based formative progress test with student-generated MCQs: Results from a multi-centre pilot study. AB - INTRODUCTION: Progress tests provide students feedback on their level of proficiency over the course of their medical studies. Peer-assisted learning and competency-based education have become increasingly important in medical education. Although progress tests have been proven to be useful as a longitudinal feedback instrument, there are currently no progress tests that have been created in cooperation with students or that focus on competency in medical education. In this study, we investigated the extent to which students can be included in the development of a progress test and demonstrated that aspects of knowledge related to competency can be represented on a competency-based progress test. METHODS: A two-dimensional blueprint for 144 multiple-choice questions (MCQs) covering groups of medical subjects and groups of competency areas was generated by three expert groups for developing the competency-based progress test. A total of 31 students from seven medical schools in Germany actively participated in this exercise. After completing an intensive and comprehensive training programme, the students generated and reviewed the test questions for the competency-based progress test using a separate platform of the ItemManagementSystem (IMS). This test was administered as a formative test to 469 students in a pilot study in November 2013 at eight medical schools in Germany. The scores were analysed for the overall test and differentiated according to the subject groups and competency areas. RESULTS: A pool of more than 200 MCQs was compiled by the students for pilot use, of which 118 student-generated MCQs were used in the progress test. University instructors supplemented this pool with 26 MCQs, which primarily addressed the area of scientific skills. The post-review showed that student-generated MCQs were of high quality with regard to test statistic criteria and content. Overall, the progress test displayed a very high reliability. When the academic years were compared, the progress test mapped out over the course of study not only by the overall test but also in terms of the subject groups and competency areas. OUTLOOK: Further development in cooperation with students will be continued. Focus will be on compiling additional questions and test formats that can represent competency at a higher skill level, such as key feature questions, situational judgement test questions and OSCE. In addition, the feedback formats will be successively expanded. The intention is also to offer the formative competency-based progress test online. PMID- 26483861 TI - A Comparison of Postoperative Outcomes in Immediate Versus Delayed Reconstruction After Mastectomy. AB - OBJECTIVE: The objective of this study was to evaluate the frequency of various postoperative complications in patients undergoing either immediate or delayed breast reconstruction after mastectomy for malignancy. METHODS: The ACS-NSQIP 2005-2012 database was queried for patients who underwent mastectomy for the treatment of breast malignancy. These mastectomy cases were then stratified, generating "mastectomy alone" and "mastectomy with immediate reconstruction" cohorts. Database analysis also identified "delayed-reconstruction" oncologic patients. All patients undergoing reconstruction were then stratified into the tissue expander/implant or flap-based reconstruction group. The frequency of postoperative complications was assessed. A multiplicative risk model was used to calculate the probability of postoperative complications after undergoing a mastectomy alone, followed by reconstruction on a different date. These values were compared with the frequency of postoperative complications in the "mastectomy with immediate reconstruction" cohort, and 1-sample binomial tests were performed to determine statistical significance. RESULTS: A total of 49,450 cases that underwent either mastectomy alone (n = 30,226), mastectomy with immediately tissue expander/implant reconstruction (n = 13,513), mastectomy with immediate flap reconstruction (n = 2854), delayed tissue expander/implant reconstruction (n = 2047), or delayed flap reconstruction (n = 810) were identified. When compared with a delayed reconstructive model, immediate reconstruction after mastectomy was associated with increased flap or tissue expander/implant failure. However, delayed reconstructive modalities were associated with increased postoperative medical and surgical complications. Finally, in flap-based reconstruction, the incidence of return to the operating room was higher in delayed reconstruction than in immediate reconstruction. CONCLUSIONS: Awareness of complications associated with each reconstructive modality will allow both surgeons and patients to effectively decide upon reconstructive options. PMID- 26483862 TI - M-plasty for Full-Thickness Skin Graft Donor Site. PMID- 26483863 TI - Comment on "New Antioxidant Drugs for Neonatal Brain Injury". PMID- 26483864 TI - Antiviral therapy for chronic hepatitis B: Combination of nucleoside analogs and interferon. AB - The ideal goal of chronic hepatitis B (CHB) treatment should be suppression of emergence of hepatocellular carcinoma through the disappearance of hepatitis B s antigen (HBsAg) rather than the control of serum hepatitis B virus-DNA level. For this purpose, various types of combination therapies using nucleoside analogs (NAs) and interferon (IFN) have been conducted. The therapeutic effects of combination of two different kinds of agents are better than those of the monotherapy using NAs or IFN alone, probably because different pharmaceutical properties might act in a coordinated manner. Recently, combination therapies with NAs and IFN and sequential therapies with NAs administration followed by IFN therapy have been routinely employed. We previously reported that combination therapy using entecavir (ETV) and pegylated (PEG)-IFN showed antiviral effects in 71% of CHB patients; the effect of this combination was better than that using lamivudine (LAM) and PEG-IFN. This is partially explained by the better antiviral effects of ETV than those of LAM. In our analysis, the cohort of CHB consisted of the patients who showed a flare-up of hepatitis before antiviral therapy, and their baseline HBsAg levels were relatively low. Therefore, in addition to the combination of the agents, the appropriate selection of patients is critical to achieve a good viral response. PMID- 26483865 TI - Transoesophageal echocardiography during liver transplantation. AB - Liver transplantation (LT) has become the standard of care for patients with end stage liver disease. The allocation of organs, which prioritizes the sickest patients, has made the management of liver transplant candidates more complex both as regards their comorbidities and their higher risk of perioperative complications. Patients undergoing LT frequently display considerable physiological changes during the procedures as a result of both the disease process and the surgery. Transoesophageal echocardiography (TEE), which visualizes dynamic cardiac function and overall contractility, has become essential for perioperative LT management and can optimize the anaesthetic management of these highly complex patients. Moreover, TEE can provide useful information on volume status and the adequacy of therapeutic interventions and can diagnose early intraoperative complications, such as the embolization of large vessels or development of pulmonary hypertension. In this review, directed at clinicians who manage TEE during LT, we show why the procedure merits a place in challenging anaesthetic environment and how it can provide essential information in the perioperative management of compromised patients undergoing this very complex surgical procedure. PMID- 26483866 TI - Programmed death-1/programmed death-L1 signaling pathway and its blockade in hepatitis C virus immunotherapy. AB - Chronic hepatitis C virus (HCV) infection is a public health issue that often progresses to life-threatening complications, including liver cirrhosis, fibrosis, and hepatocellular carcinoma. Impaired immune responses to HCV are key features of chronic HCV infection. Therefore, intervention strategies usually involve enhancing the immune responses against HCV. Cytotoxic CD8(+) T lymphocytes (CTLs) play a critical role in the control of HCV infection. However, their cytolytic function can be impaired by the expression of co-inhibitory molecules. Programmed death-1 (PD-1) receptor and its ligand PD-L1 function in a T cell co-inhibitory pathway, which either blocks the function of CTLs or the differentiation of CD8(+) T cells. During chronic HCV infection, the immune inhibitory receptor PD-1 is upregulated on dysfunctional HCV-specific CD8(+) T cells. As such, blockade of the PD-1/PD-L1 pathway in these CD8(+) T cells might restore their functional capabilities. Indeed, clinical trials using therapies to block this pathway have shown promise in the fostering of anti-HCV immunity. Understanding how chronic HCV infection induces upregulation of PD-1 on HCV specific T cells and how the PD-1/PD-L1 interaction develops HCV specific T cell dysfunction will accelerate the development of an efficacious prophylactic and therapeutic vaccination against chronic HCV infections, which will significantly improve HCV treatments and patient survival. In this review, we discuss the relationship between PD-1 expression and clinical responses and the potential use of PD-1 blockade for anti-HCV therapy. PMID- 26483868 TI - Training vs practice: A tale of opposition in acute cholecystitis. AB - Acute cholecystitis is one of the most common surgical diagnoses encountered by general surgeons. Despite its high incidence there remains a range of treatment of approaches. Current practices in biliary surgery vary as to timing, intraoperative utilization of biliary imaging, and management of bile duct stones despite growing evidence in the literature defining best practice. Management of patients with acute cholecystitis with early laparoscopic cholecystectomy (LC) results in better patient outcomes when compared with delayed surgical management techniques including antibiotic therapy or percutaneous cholecystostomy. Regardless of this data, many surgeons still prefer to utilize antibiotic therapy and complete an interval LC to manage acute cholecystitis. The use of intraoperative biliary imaging by cholangiogram or laparoscopic ultrasound has been demonstrated to facilitate the safe completion of cholecystectomy, minimizing the risk for inadvertent injury to surrounding structures, and lowering conversion rates, however it is rarely utilized. Choledocholithiasis used to be a diagnosis managed exclusively by surgeons but current practice favors referral to gastroenterologists for performance of preoperative endoscopic removal. Yet, there is evidence that intraoperative laparoscopic stone extraction is safe, feasible and may have added advantages. This review aims to highlight the differences between existing management of acute cholecystitis and evidence supported in the literature regarding best practice with the goal to change surgical practice to adopt these current recommendations. PMID- 26483867 TI - Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The main etiologies of HCC are hepatitis B virus and hepatitis C virus (HCV), and non-hepatitis B/non-hepatitis C HCC (NBNC-HCC) has also been identified as an etiological factor. Although the incidence of HCV-related HCC in Japan has decreased slightly in recent years, that of NBNC-HCC has increased. The onset mechanism of NBNC-HCC, which has various etiologies, remains unclear; however, nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is known to be an important risk factor for NBNC-HCC. Among the different advanced glycation end-products (AGEs) formed by the Maillard reaction, glyceraldehyde-derived AGEs, the predominant components of toxic AGEs (TAGE), have been associated with NASH and NBNC-HCC, including NASH-related HCC. Furthermore, the expression of the receptor for AGEs (RAGE) has been correlated with the malignant progression of HCC. Therefore, TAGE induce oxidative stress by binding with RAGE may, in turn, lead to adverse effects, such as fibrosis and malignant transformation, in hepatic stellate cells and tumor cells during NASH or NASH-related HCC progression. The aim of this review was to examine the contribution of the TAGE-RAGE axis in NASH-related HCC. PMID- 26483869 TI - Role of biomarkers in the prediction and diagnosis of hepatocellular carcinoma. AB - The prevalence of hepatocellular carcinoma (HCC) has progressively increased in recent years and is now the fifth and the second most common cancer in the World and in Egypt, respectively. Much work has focused in the development of assays for detecting hepatic carcinogensis before the observance of hepatic focal lesions. Particular attention has been directed towards HCC-specific biomarkers for use in the early diagnosis of HCC and in the confirmation of radiological studies. Although a number of biomarkers have been identified, none have been considered reliable indicators of early HCC lesions. This review presents a few of the most relevant HCC biomarkers and suggests improvements to the accuracy of diagnostic assays through their combined use. Furthermore, we present an algorithm for the biomarker-based diagnosis of HCC and highlight its important role in the early prediction of HCC. PMID- 26483871 TI - Arterial ischemia in the deportalized liver following associating liver partition and portal vein ligation for staged hepatectomy. AB - Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel 2-stage technique intended to induce rapid growth of the future liver remnant (FLR). Initial reports of a 12% mortality rate have sparked debate regarding the safety of the procedure. A 64 years old male was planned for a right-sided hemi-hepatectomy due to colorectal cancer liver metastases. Intra operatively it was decided to convert to an ALPPS due to unexpectedly small segments 2-4. Post-operative serum laboratory tests indicated an acute liver failure and radiological imaging showed no sign of arterial blood flow to the right hemi-liver. A computed tomography examination on post-operative day 3 revealed that the FLR had increased from 290 to 690 mL in 3 d (138% growth). In the following days serum values gradually improved and stage 2 was carried out on post-operative day 7. The rest of the hospital stay was uneventful and the patient made a full recovery. ALPPS is a fascinating advancement in liver surgery. Despite severe post-operative complications, in properly selected cases it provides successful outcomes that other modalities of treatment cannot offer. PMID- 26483870 TI - Detection of hepatitis B virus infection: A systematic review. AB - AIM: To review published methods for detection of hepatitis B virus (HBV) infection. METHODS: A thorough search on Medline database was conducted to find original articles describing different methods or techniques of detection of HBV, which are published in English in last 10 years. Articles outlining methods of detection of mutants or drug resistance were excluded. Full texts and abstracts (if full text not available) were reviewed thoroughly. Manual search of references of retrieved articles were also done. We extracted data on different samples and techniques of detection of HBV, their sensitivity (Sn), specificity (Sp) and applicability. RESULTS: A total of 72 studies were reviewed. HBV was detected from dried blood/plasma spots, hepatocytes, ovarian tissue, cerumen, saliva, parotid tissue, renal tissue, oocytes and embryos, cholangiocarcinoma tissue, etc. Sensitivity of dried blood spot for detecting HBV was > 90% in all the studies. In case of seronegative patients, HBV DNA or serological markers have been detected from hepatocytes or renal tissue in many instances. Enzyme linked immunosorbent assay and Chemiluminescent immunoassay (CLIA) are most commonly used serological tests for detection. CLIA systems are also used for quantitation. Molecular techniques are used qualitatively as well as for quantitative detection. Among the molecular techniques version 2.0 of the CobasAmpliprep/CobasTaqMan assay and Abbott's real time polymerase chain reaction kit were found to be most sensitive with a lower detection limit of only 6.25 IU/mL and 1.48 IU/mL respectively. CONCLUSION: Serological and molecular assays are predominant and reliable methods for HBV detection. Automated systems are highly sensitive and quantify HBV DNA and serological markers for monitoring. PMID- 26483872 TI - Targeted therapies for pancreatic adenocarcinoma: Where do we stand, how far can we go? AB - Pancreatic adenocarcinoma (usually referred to as pancreatic cancer) is a highly lethal and aggressive malignancy with a disease-related mortality almost equaling its incidence, and one of the most challenging cancers to treat. The notorious resistance of pancreatic cancer not only to conventional cytotoxic therapies but also to almost all targeted agents developed to date, continues to puzzle the oncological community and represents one of the biggest hurdles to reducing the death toll from this ominous disease. This editorial highlights the most important recent advances in preclinical and clinical research, with regards to targeted therapeutics for pancreatic cancer, outlines current challenges and provides an overview of potential future perspectives in this rapidly evolving field. PMID- 26483873 TI - Fecal DNA testing for colorectal cancer screening: Molecular targets and perspectives. AB - The early detection of colorectal cancer with effective screening is essential for reduction of cancer-specific mortality. The addition of fecal DNA testing in the armamentarium of screening methods already in clinical use launches a new era in the noninvasive part of colorectal cancer screening and emanates from a large number of previous and ongoing clinical investigations and technological advancements. In this review, we discuss the molecular rational and most important genetic alterations hallmarking the early colorectal carcinogenesis process. Also, representative DNA targets-markers and key aspects of their testing at the clinical level in comparison or/and association with other screening methods are described. Finally, a critical view of the strengths and limitations of fecal DNA tests is provided, along with anticipated barriers and suggestions for further exploitation of their use. PMID- 26483874 TI - Role of retinoids in the prevention and treatment of colorectal cancer. AB - Vitamin A and its derivatives, retinoids, have been widely studied for their use as cancer chemotherapeutic agents. With respect to colorectal cancer (CRC), several critical mutations dysregulate pathways implicated in progression and metastasis, resulting in aberrant Wnt/beta-catenin signaling, gain-of-function mutations in K-ras and phosphatidylinositol-3-kinase/Akt, cyclooxygenase-2 over expression, reduction of peroxisome proliferator-activated receptor gamma activation, and loss of p53 function. Dysregulation leads to increased cellular proliferation and invasion and decreased cell-cell interaction and differentiation. Retinoids affect these pathways by various mechanisms, many involving retinoic acid receptors (RAR). RAR bind to all-trans-retinoic acid (ATRA) to induce the transcription of genes responsible for cellular differentiation. Although most research concerning the chemotherapeutic efficacy of retinoids focuses on the ability of ATRA to decrease cancer cell proliferation, increase differentiation, or promote apoptosis; as CRC progresses, RAR expression is often lost, rendering treatment of CRCs with ATRA ineffective. Our laboratory focuses on the ability of dietary vitamin A to decrease CRC cell proliferation and invasion via RAR-independent pathways. This review discusses our research and others concerning the ability of retinoids to ameliorate the defective signaling pathways listed above and decrease tumor cell proliferation and invasion through both RAR-dependent and RAR-independent mechanisms. PMID- 26483876 TI - Immune cell interplay in colorectal cancer prognosis. AB - The immune response to colorectal cancer has proven to be a reliable measure of patient outcome in several studies. However, the complexity of the immune response in this disease is not well understood, particularly the interactions between tumour-associated cells and cells of the innate and adaptive immune system. This review will discuss the relationship between cancer associated fibroblasts and macrophages, as well as between macrophages and T cells, and demonstrate how each population may support or prevent tumour growth in a different immune environment. PMID- 26483875 TI - Treatment of colorectal cancer in the elderly. AB - Colorectal cancer has a high incidence, and approximately 60% of colorectal cancer patients are older than 70, with this incidence likely increasing in the near future. Elderly patients (> 70-75 years of age) are a very heterogeneous group, ranging from the very fit to the very frail. Traditionally, these patients have often been under-treated and recruited less frequently to clinical trials than younger patients, and thus are under-represented in publications about cancer treatment. Recent studies suggest that fit elderly patients can be treated in the same way as their younger counterparts, but the treatment of frail patients with comorbidities is still a matter of controversy. Many factors should be taken into account, including fitness for treatment, the wishes of the patient and family, and quality of life. This review will focus on the existing evidence for surgical, oncologic, and palliative treatment in patients over 70 years old with colorectal cancer. Careful patient assessment is necessary in order to individualize treatment approach, and this should rely on a multidisciplinary process. More well-designed controlled trials are needed in this patient population. PMID- 26483877 TI - Relationship between intestinal microbiota and colorectal cancer. AB - The human gastrointestinal tract hosts a complex and vast microbial community with up to 10(11)-10(12) microorganisms colonizing the colon. The gut microbiota has a serious effect on homeostasis and pathogenesis through a number of mechanisms. In recent years, the relationship between the intestinal microbiota and sporadic colorectal cancer has attracted much scientific interest. Mechanisms underlying colonic carcinogenesis include the conversion of procarcinogenic diet related factors to carcinogens and the stimulation of procarcinogenic signaling pathways in luminal epithelial cells. Understanding each of these mechanisms will facilitate future studies, leading to the development of novel strategies for the diagnosis, treatment, and prevention of colorectal cancer. In this review, we discuss the relationship between colorectal cancer and the intestinal microbiota. PMID- 26483878 TI - Management of borderline resectable pancreatic cancer. AB - Pancreatic cancer is the fourth most common cause of cancer death in the United States. Surgery remains the only curative option; however only 20% of the patients have resectable disease at the time of initial presentation. The definition of borderline resectable pancreatic cancer is not uniform but generally denotes to regional vessel involvement that makes it unlikely to have negative surgical margins. The accurate staging of pancreatic cancer requires triple phase computed tomography or magnetic resonance imaging of the pancreas. Management of patients with borderline resectable pancreatic cancer remains unclear. The data for treatment of these patients is primarily derived from retrospective single institution experience. The prospective trials have been plagued by small numbers and poor accrual. Neoadjuvant therapy is recommended and typically consists of chemotherapy and radiation therapy. The chemotherapeutic regimens continue to evolve along with type and dose of radiation therapy. Gemcitabine or 5-fluorouracil based chemotherapeutic combinations are administered. The type and dose of radiation vary among different institutions. With neoadjuvant treatment, approximately 50% of the patients are able to undergo surgical resections with negative margins obtained in greater than 80% of the patients. Newer trials are attempting to standardize the definition of borderline resectable pancreatic cancer and treatment regimens. In this review, we outline the definition, imaging requirements and management of patients with borderline resectable pancreatic cancer. PMID- 26483880 TI - Paraneoplastic leukemoid reaction in pancreatic cancer: A case report. AB - Paraneoplastic leukemoid reaction is a rare syndrome defined by a leukocyte count exceeding 50 Giga/Liter (G/L), mostly described with progressive lung or renal carcinoma. We report a case of a 68-year-old man with recurrent pancreatic carcinoma presenting a leukemoid reaction with a white blood cell count of 63.87 G/L without identified infectious, iatrogenic or hematologic causes. His overall condition quickly degraded and he died three weeks after the discovery of the leukemoid reaction. This is the first case in French literature of leukemoid reaction in a patient with pancreatic carcinoma with poor prognostic value. PMID- 26483879 TI - Genomic alterations in pancreatic cancer and their relevance to therapy. AB - Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations in pancreatic cancer is becoming increasingly well understood. In this review, we summarize current knowledge of genomic alterations in 12 core signaling pathways or cellular processes in pancreatic ductal adenocarcinoma, which is the most common type of malignancy in the pancreas, including four commonly mutated genes and many other genes that are mutated at low frequencies. We also describe the potential implications of these genomic alterations for development of novel therapeutic approaches in the context of personalized medicine. PMID- 26483881 TI - Total Diet Studies as a Tool for Ensuring Food Safety. AB - With the diversification and internationalization of the food industry and the increased focus on health from a majority of consumers, food safety policies are being implemented based on scientific evidence. Risk analysis represents the most useful scientific approach for making food safety decisions. Total diet study (TDS) is often used as a risk assessment tool to evaluate exposure to hazardous elements. Many countries perform TDSs to screen for chemicals in foods and analyze exposure trends to hazardous elements. TDSs differ from traditional food monitoring in two major aspects: chemicals are analyzed in food in the form in which it will be consumed and it is cost-effective in analyzing composite samples after processing multiple ingredients together. In Korea, TDSs have been conducted to estimate dietary intakes of heavy metals, pesticides, mycotoxins, persistent organic pollutants, and processing contaminants. TDSs need to be carried out periodically to ensure food safety. PMID- 26483882 TI - Total Diet Study: For a Closer-to-real Estimate of Dietary Exposure to Chemical Substances. AB - Recent amendment on the Food Sanitation Act in Korea mandated the Minister of Food & Drug Safety to secure the scientific basis for management and reevaluation of standards and specifications of foods. Especially because the current food safety control is limited within the scope of 'Farm to Market' covering from production to retail in Korea, safety control at the plane of true 'Farm to Fork' scope is urgently needed and should include 'total diet' of population instead of individual food items. Therefore, 'Total Diet Study (TDS)' which provides 'closer to-real' estimates of exposure to hazardous materials through analysis on table ready (cooked) samples of foods would be the solution to more comprehensive food safety management, as suggested by World Health Organization and Food and Agriculture Organization of the United Nations. Although the protection of diets from hazards must be considered as one of the most essential public health functions of any country, we may need to revisit the value of foods which has been too much underrated by the meaningless amount of some hazardous materials in Korea. Considering the primary value of foods lies on sustaining life, growth, development, and health promotion of human being, food safety control should be handled not only by the presence or absence of hazardous materials but also by maximizing the value of foods via balancing with the preservation of beneficial components in foods embracing total diet. In this regard, this article aims to provide an overview on TDS by describing procedures involved except chemical analysis which is beyond our scope. Also, details on the ongoing TDS in Korea are provided as an example. Although TDS itself might not be of keen interest for most readers, it is the main user of the safety reference values resulted from toxicological research in the public health perspective. PMID- 26483883 TI - [Not Available]. PMID- 26483885 TI - Evaluation of Chemical Analysis Method and Determination of Polycyclic Aromatic Hydrocarbons Content from Seafood and Dairy Products. AB - This study was carried out to investigate contents of 8 polycyclic aromatic hydrocarbons (PAHs) from frequently consumed seafood and dairy products and to evaluate their chemical analysis methods. Samples were collected from markets of 9 cities in Korea chosen as the population reference and evaluated. The methodology involved saponification, extraction with n-hexane, clean-up on Sep Pak silica cartridges and gas chromatograph-mass spectrometry analysis. Validation proceeded on 2 matrices. Recoveries for 8 PAHs ranged from 86.87 to 103.57%. The limit of detection (LOD) 8 PAHs was 0.04~0.20 ug/kg, and limit of quantification (LOQ) of 8 PAHs was 0.12~0.60 ug/kg. The mean concentration of benzo[a]pyrene (BaP) was 0.34 ug/kg from seafood and 0.34 ug/kg from dairy products. The total PAHs concentration was 1.06 ug/kg in seafood and 1.52 ug/kg in dairy products. PMID- 26483884 TI - Determination of Heterocyclic Amines and Acrylamide in Agricultural Products with Liquid Chromatography-Tandem Mass Spectrometry. AB - Heterocyclic amines (HCAs) and acrylamide are unintended hazardous substances generated by heating or processing of foods and are known as carcinogenic and mutagenic agents by the animal experiments. A simple method was established for a rapid and accurate determination of 12 types of HCAs (IQ, MeIQ, Glu-P-1, Glu-P-2, MeIQx, Trp-P-1, Trp-P-2, PhIP, AalphaC, MeAalphaC, Harman and Norharman) and acrylamide in three food matrices (non-fat liquid, non-fat solid and fat solid) by isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS). In every sample, a mixture of internal standards including IQ-d3, MeIQx-d3, PhIP-d3, Trp-P-2-(13)C2-(15)N and MeAalphaC-d3 was spiked for quantification of HCAs and (13)C3-acrylamide was also spiked for the analysis of acrylamide. HCAs and acrylamide in sample were extracted with acetonitrile and water, respectively, and then two solid-phase extraction cartridges, ChemElut: HLB for HCAs and Accucat: HLB for acrylamide, were used for efficiently removing interferences such as pigment, lipid, polar, nonpolar and ionic compounds. Established method was validated in terms of recovery, accuracy, precision, limit of detection, limit of quantitation, and linearity. This method showed good precision (RSD < 20%), accuracy (71.8~119.1%) and recovery (66.0~118.9%). The detection limits were < 3.1 ng/g for all analytes. The correlation coefficients for all the HCAs and acrylamide were > 0.995, showing excellent linearity. These methods for the detection of HCAs and acrylamide by LC-MS/MS were applied to real samples and were successfully used for quantitative monitoring in the total diet study and this can be applied to risk assessment in various food matrices. PMID- 26483886 TI - Validation and Determination of the Contents of Acetaldehyde and Formaldehyde in Foods. AB - The aim of this study was to develop an efficient quantitative method for the determination of acetaldehyde (AA) and formaldehyde (FA) contents in solid and liquid food matrices. The determination of those compounds was validated and performed using gas chromatography-mass spectrometry combined by solid phase micro-extraction after derivatization with O-(2,3,4,5,6-pentafluoro-benzyl) hydroxylamine hydrochloride. Validation was carried out in terms of limit of detection, limit of quantitation, linearity, precision, and recovery. Then their contents were analyzed in various food samples including 15 fruits, 22 milk products, 31 alcohol-free beverages, and 13 alcoholic beverages. The highest contents of AA and FA were determined in a white wine (40,607.02 ng/g) and an instant coffee (1,522.46 ng/g), respectively. PMID- 26483887 TI - Distribution of Seven N-Nitrosamines in Food. AB - N-nitrosamines, which are classified as carcinogens by IARC and US EPA, can be easily found in various foods. They are reaction products between nitrogen oxide and secondary amines, but can also be generated during fermentation. Ever since the 1960s, when nitrite, used as a preservative in processed meats, was suspected to generate N-nitrosamines, the usage of the food additive has been debated. However, the benefit of nitrite in food supply could not be ignored and the risk benefit analysis has become a key issue in the use of the additive. For a risk analysis, an accurate estimation of the hazardous material is necessary; therefore, analytical methods for nitrosamines have continuously evolved from the 1950s. Solid supported liquid-liquid extraction and solid phase extractions have replaced the distillation for the clean-up steps, and tandem mass spectrometry is employed for higher selectivity and sensitivity. In the present study, for a better estimation of N-nitrosamine intake, the total diet study samples were prepared for the N-nitrosamines analysis. In order to obtain the most sensitive results, a partial preparation procedure was developed and modified for different food matrices. Among seven N-nitrosamines (N-nitrosodimethylamine, N nitrosomethylethylamine, N-nitrosodiethylamine, N-nitrosodibutylamine, N nitrosopiperidine, N-nitrosopyrrolidine, and N-nitrosomorpholine) analyzed in the present study, N-nitrosodiethylamine has shown the highest detection rate in agricultural foods, while N-nitrosodimethylamine has appeared most frequently in livestock and fishery food products. The concentration of N-nitrosodimethylamine was the highest in seasoning. PMID- 26483888 TI - Determination of Ethyl Carbamate in Alcoholic Beverages and Fermented Foods Sold in Korea. AB - Ethyl carbamate (EC) classified as a probable human carcinogen (Group 2A) is naturally formed in alcoholic beverages and fermented foods during fermentation process and/or during storage. The objective of this study was to analyze EC in 34 food items including 14 alcoholic beverages and 20 fermented foods sold in Korea. Each food was collected from 18 supermarkets in 9 metropolitan cities in Korea, and then made into composite. According to food composition and alcohol content, samples were divided into four matrices such as apple juice, milk, Soju (liquor containing about 20% alcohol), and rice porridge. The maximum EC value of 151.06 ug/kg was found in Maesilju (liquor made from Maesil and Soju). Whisky and Bokbunjaju (Korean black raspberry wine) contained 9.90 ug/kg and 6.30 ug/kg, respectively. EC was not detected in other alcoholic beverages. Of 20 fermented foods, Japanese-style soy sauce had highest level of 15.59 ug/kg and traditional one contained 4.18 ug/kg. Soybean paste had 1.18 ug/kg, however, EC was not found in other fermented foods. PMID- 26483889 TI - Validation of an HPLC Analytical Method for Determination of Biogenic Amines in Agricultural Products and Monitoring of Biogenic Amines in Korean Fermented Agricultural Products. AB - An HPLC analytical method was validated for the quantitative determination of biogenic amines in agricultural products. Four agricultural foods, including apple juice, Juk, corn oil and peanut butter, were selected as food matrices based on their water and fat contents (i.e., non-fatty liquid, non-fatty solid, fatty liquid and fatty solid, respectively). The precision, accuracy, recovery, limit of detection (LOD) and quantification (LOQ) were determined to test the validity of an HPLC procedure for the determination of biogenic amines, including tryptamine, beta-phenylethylamine, putrescine, cadaverine, histamine, tyramine, spermidine and spermine, in each matrix. The LODs and LOQs for the biogenic amines were within the range of 0.01~0.10 mg/kg and 0.02~0.31 mg/kg, respectively. The relative standard deviation (RSD) of intraday for biogenic amine concentrations ranged from 1.86 to 5.95%, whereas the RSD of interday ranged from 2.08 to 5.96%. Of the matrices spiked with biogenic amines, corn oil with tyramine and Juk with putrescine exhibited the least accuracy of 84.85% and recovery rate of 89.63%, respectively, at the lowest concentration (10 mg/kg). Therefore, the validation results fulfilled AOAC criteria and recommendations. Subsequently, the method was applied to the analysis of biogenic amines in fermented agricultural products for a total dietary survey in Korea. Although the results revealed that Korean traditional soy sauce and Doenjang contained relatively high levels of histamine, the amounts are of no concern if these fermented agricultural products serve as condiments. PMID- 26483890 TI - Analysis of Trans Fat in Edible Oils with Cooking Process. AB - Trans fat is a unsaturated fatty acid with trans configuration and separated double bonds. Analytical methods have been introduced to analyze trans fat content in foods including infrared (IR) spectroscopy, gas chromatography (GC), Fourier transform-infrared (FT-IR) spectroscopy, reverses-phase silver ion high performance liquid chromatography, and silver nitrate thin layer chromatography. Currently, FT-IR spectroscopy and GC are mostly used methods. Trans fat content in 6 vegetable oils were analyzed and processing effects including baking, stir frying, pan-frying, and frying on the formation of trans fat in corn oil was evaluated by GC. Among tested vegetable oils, corn oil has 0.25 g trans fat/100 g, whereas other oils including rapeseed, soybean, olive, perilla, and sesame oils did not have detectable amount of trans fat content. Among cooking methods, stir-frying increased trans fat in corn oil whereas baking, pan-frying, and frying procedures did not make changes in trans fat content compared to untreated corn oils. However, the trans fat content was so low and food label can be declared as '0' trans based on the regulation of Ministry of Food ad Drug Safety (MFDS) (< 2 g/100 g edible oil). PMID- 26483891 TI - Analysis of 3-MCPD and 1,3-DCP in Various Foodstuffs Using GC-MS. AB - 3-Monochloro-1,2-propanediol (3-MCPD) and 1,3-dichloro-2-propanol (1,3-DCP) are not only produced in the manufacturing process of foodstuffs such as hydrolyzed vegetable proteins and soy sauce but are also formed by heat processing in the presence of fat and low water activity. 3-MCPD exists both in free and ester forms, and the ester form has been also detected in various foods. Free 3-MCPD and 1,3-DCP are classified as Group 2B by the International Agency for Research on Cancer. Although there is no data confirming the toxicity of either compound in humans, their toxicity was evidenced in animal experimentation or in vitro. Although few studies have been conducted, free 3-MCPD has been shown to have neurotoxicity, reproductive toxicity, and carcinogenicity. In contrast, 1,3-DCP only has mutagenic activity. The purpose of this study was to analyze 3-MCPD and 1,3-DCP in various foods using gas chromatography -mass spectrometry. 3-MCPD and 1,3-DCP were analyzed using phenyl boronic acid derivatization and the liquid liquid extraction method, respectively. The analytical method for 3-MCPD and 1,3 DCP was validated in terms of linearity, limit of detection (LOD), limit of quantitation, accuracy and precision. Consequently, the LODs of 3-MCPD and 1,3 DCP in various matrices were identified to be in the ranges of 4.18~10.56 ng/g and 1.06~3.15 ng/g, respectively. PMID- 26483892 TI - ERRATUM. PMID- 26483893 TI - Narcolepsy - Between the dream and reality. PMID- 26483894 TI - A journey through narcolepsy diagnosis: From ICSD 1 to ICSD 3. PMID- 26483895 TI - Narcolepsy and the Sickness Impact Profile: A general health status measure. AB - OBJECTIVE: We characterized functional impact of narcolepsy on patients using a general health status measure, the Sickness Impact Profile (SIP). It has 136 items grouped into 12 categories and 2 dimensions. METHODS: We ascertained patients with physician-diagnosed narcolepsy in King County, Washington using multiple overlapping methods over four years starting July 2001. We recruited 226 patients (mean age 48 years, 65% female) who underwent in-person interviews and completed: Epworth Sleepiness Scale (ESS), Ullanlinna Narcolepsy Scale (UNS), and SIP. Linear regression was used to assess correlations between measures. RESULTS: Mean percent of total dysfunction was higher for psychosocial dimension (13.2) and independent categories (13.4) than physical dimension (5.0). Mean percent of total dysfunction in descending order for categories was: Sleep and Rest (23.6), Alertness Behavior (22.6), and Recreation and Pastimes (20.6). Ten items were endorsed by at least a third of all patients but only two of them concerned sleep. Unexpectedly, among the top ten items were, "My sexual activity is decreased," and "I forget a lot, for example, things that happened recently, where I put things, appointments." Percent of overall dysfunction on SIP (mean 10.3) was significantly correlated with ESS (r=0.36, p<0.001) and UNS (r=0.47, p<0.001). In this population-based sample, mean percent of total dysfunction on SIP in patients with narcolepsy (10.3) was higher than previously reported in the general population (3.6) and similar to that in other chronic disabling conditions. DISCUSSION: The SIP correlated with ESS and UNS, and captured unique aspects of the impact of narcolepsy on patients. PMID- 26483896 TI - The nature of excessive sleepiness and sudden sleep onset in Parkinson's disease. AB - OBJECTIVES: Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes are frequent in Parkinson's disease (PD). The objectives are to identify clinical characteristics and factors associated with EDS and SOS episodes. METHODS: Clinical demographic data were recorded (N=100, mean age=65.0+/-10.4). EDS was identified by the Epworth Sleepiness Scale (ESS>10) and SOS episodes were registered. Disease severity was evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS, I, II, and III), sleep disturbances by the Parkinson's Disease Sleep Scale (PDSS<100), depressive symptoms by the Beck Depression Inventory (BDI>10) and rapid eye movement (REM) sleep behavior disorder (RBD) by the REM sleep behavior scale. Levodopa equivalent dose was measured. RESULTS: PD patients with EDS (67%) were predominately male (73.1%) and had worse disease severity (UPDRS II and III p= 0.005); SOS episodes (39%) were associated with disease duration, diabetes, sleep disturbances (PDSS Scale), disease severity (UPDRS I, II, III) and RBD symptoms (p<0.05). Stepwise regression analysis showed that EDS was independently associated with motor-symptoms severity (UPDRS III scale, p=0.003). SOS episodes were independently associated with disease duration (p=0.006) and sleep disturbances (PDSS scale, p=0.03): patients had more uncomfortable immobility at night, tremor on waking and snoring or difficult breathing. DISCUSSION: EDS and or SOS episodes are frequent and manifest a differential pattern in PD. SOS episodes are associated with longer disease duration, diabetes, sleep disturbances and RBD symptoms indicating that these "sleep attacks" are of multifactorial origin and probably influenced by brain structural abnormalities. PMID- 26483897 TI - The hypocretins (orexins) mediate the "phasic" components of REM sleep: A new hypothesis. AB - In 1998, a group of phenotypically distinct neurons were discovered in the postero-lateral hypothalamus which contained the neuropeptides hypocretin 1 and hypocretin 2 (also called orexin A and orexin B), which are excitatory neuromodulators. Hypocretinergic neurons project throughout the central nervous system and have been involved in the generation and maintenance of wakefulness. The sleep disorder narcolepsy, characterized by hypersomnia and cataplexy, is produced by degeneration of these neurons. The hypocretinergic neurons are active during wakefulness in conjunction with the presence of motor activity that occurs during survival-related behaviors. These neurons decrease their firing rate during non-REM sleep; however there is still controversy upon the activity and role of these neurons during REM sleep. Hence, in the present report we conducted a critical review of the literature of the hypocretinergic system during REM sleep, and hypothesize a possible role of this system in the generation of REM sleep. PMID- 26483898 TI - Cognitive behavioral treatment for narcolepsy: can it complement pharmacotherapy? AB - Sleep medicine in general and psychology in particular have recently developed cognitive behavioral treatment for narcolepsy (CBT-N). Despite a growing interest in this topic, most studies since 2007 have reviewed CBT applications for other sleep disorders. Currently, 6 reviews have been published on narcolepsy, with an expert consensus being reached that CBT represented an important adjunctive treatment for the disease. The current paper reviews the need for CBT applications for narcolepsy by generalizing the application of multicomponent treatments and performing studies that extrapolate the results obtained from multicenter studies. Nineteen studies were found in which the need-for-treatment guidelines identified the use of CBT for narcolepsy. Three additional studies were identified that evaluated the effectiveness of cognitive behavioral measures and multicomponent treatments for which treatment protocols have been proposed. PMID- 26483899 TI - Moebius syndrome and narcolepsy: A case dissertation. AB - Moebius syndrome (MS) is a congenital syndrome characterized by unilateral or bilateral aplasia of the VI and VII cranial nerves, with consequent convergent strabismus and bilateral peripheral facial paralysis. This syndrome might be associated with diurnal excessive sleepiness and muscular hypotony, mimetizing in this manner, narcolepsy. The diagnostic criteria for narcolepsy depend on the presence of REM sleep during the day. As with patients with MS we do not have ocular movements due to the VI nerve paralysis, the absence of horizontal ocular movements might make it difficult to confirm narcolepsy in these patients. The common clinical characteristics of these patients are due to a possible impairment of the same structures that are affected in the central nervous system. However, the mechanism by which it occurs remains to be fully understood. Further electrophysiological researches are necessary to better clarify the association of these two diseases. The objective of this dissertation is to describe and discuss a case of Moebius syndrome with diurnal excessive sleepiness as a differential diagnosis for narcolepsy. PMID- 26483900 TI - Cataplexy as a side effect of modafinil in a patient without narcolepsy. AB - Narcolepsy is a disease in which there is diurnal excessive sleepiness with sleep attacks and a prevalence in the general population of 1/4000 individuals. Classically, it is characterized by cataplexy, sleep paralysis, hypnagogic hallucinations and fragmented sleep. The use of modafinil in the treatment of narcolepsy is the first option of treatment for diurnal excessive sleepiness. Although considered a safe drug for use in patients with narcolepsy, being utilized for more than 20 years, modafinil possesses a series of side effects, some of them still not fully researched or described. Side effects such as headache, nausea, anxiety, insomnia, lumbago, diarrhea, dyspepsia, rhinitis and vertigo are the most frequent. However, the clinical follow-up of patients under treatment with modafinil must be intensive and the side effects ought to be noted and evaluated. The under-response to treatment or the unexpected side effects must always be directed to differential diagnostics. The objective of this article is to describe an unexpected side effect of the use of modafinil in a patient with incorrect diagnosis of narcolepsy. PMID- 26483901 TI - The use of citalopram for the treatment of cataplexy. AB - This is a series of cases describing the use of citalopram for the treatment of cataplexy in patients with narcolepsy. Cataplexy is the most specific symptom of narcolepsy, being characterized by a sudden and temporary loss of muscle tonus, triggered by episodes of emotion during vigil. Some antidepressants, besides gamma-hydroxybutyrate, are used for the control of cataplexy. As gamma hydroxybutyrate is not available in Brazil, local treatment is usually done by the use of antidepressants. Citalopram is a selective inhibitor of serotonin reuptake, with reasonable price and with fewer side effects when compared with other drugs of the same type. In this study, we report a series of cases with patients with narcolepsy and cataplexy, treated with citalopram for the control of cataplexy. PMID- 26483902 TI - Narcolepsy in pediatric age - Experience of a tertiary pediatric hospital. AB - Narcolepsy, a chronic disorder of the sleep-wake cycle of multifactorial etiology, is characterized by excessive daytime sleepiness, often associated with cataplexy, hypnagogic/hypnopompic hallucinations and sleep paralysis. Both early clinical suspicion and therapeutic approach are essential for promotion of cognitive development and social integration of these children. The authors present a descriptive retrospective study of a series of eight children in whom symptoms first started between 6.8 and 10.5 years of age. Diagnostic delay ranged from 4 months to 2 years. One child had H1N1 flu vaccination eight months before the clinical onset. The first multiple sleep latency test was positive in 6 of 8 cases. All cases were treated with methylphenidate, and venlafaxine was associated in 4 of them. In one case the initial therapy was exclusively behavioral. In all cases, symptomatic improvement, better school performance and social integration were achieved after therapeutic adjustment. PMID- 26483903 TI - Narcolepsy with cataplexy after A/H1N1 vaccination - A case reported from Cuba. AB - Narcolepsy with cataplexy is a rare sleep disorder with a neurological basis which has been recently linked to H1N1 vaccination either in children or adults. Cases from Europe, United States and Brasil were registered. Authors describe a case report of a 15 years old boy who developed narcolepsy with cataplexy after H1N1 vaccination in Havana. As far as it is concerned this is the first case reported from Cuba. PMID- 26483904 TI - Narcolepsy with cataplexy in monozygotic twins. AB - INTRODUCTION: This paper describes narcolepsy with cataplexy in two monozygotic twin sisters. OBJECTIVE: To clinically illustrate the involvement of neurological, genetic and immunologic systems in narcolepsy. MATERIAL AND METHODS: We performed a restropective study of these patients that were followed in the sleep medicine ambulatory clinic of the Faculdade de Medicina de Ribeirao Preto. RESULTS: These sisters are two of the few cases in the literature concordant for narcolepsy with catalepsy and without a "positive HLA" for narcolepsy. They had a typical clinical course of narcolepsy with cataplexy and attended all the neurophysiological diagnostic criteria for narcolepsy. CONCLUSION: In addition to known possible genetical similarity, this report stresses the role of environmental or unknown genetical factors acting on a specific neuro-imuno-genetical background and resulting in narcolepsy. PMID- 26483905 TI - Experience with the use of modafinil in the treatment of narcolepsy in a outpatient facility specialized in diurnal excessive sleepiness in Sao Paulo. AB - Narcolepsy is a chronic neurological disease characterized by diurnal excessive sleepiness and catapleaxy. It affects 1 in every 2000 to 4000 individuals with personal, social and familiar significant repercussions. The treatment of narcolepsy is mainly based on the use of stimulants for the control of the diurnal excessive sleepiness, in conjunction with behavioral measures and sleep hygiene. Among the stimulants, modafinil has presently been the drug of choice for the treatment of the diurnal excessive sleepiness in patients with narcolepsy. In the worldwide experience, its use is better tolerated and the majority of its side effects is considered light or moderate. However, the clinical use in Brazil was initiated at the end of 2008, with little experience on the narcolepsy population of this country. In this context, the objective of this study was the evaluation of the use of modafinil, verifying the indication of use, causes for discontinuation, daily dosage, efficiency of the treatment in a patient sample of narcoleptics consulted in a specialized center in Brazil. In this study, modafinil was effective for the control of the symptoms related do narcolepsy in 66% of the studied patients. The side effects such as headache, parestesias and diarrhea were the main reasons for the discontinuation of treatment with modafinil. It is important to clinically follow up the patients for a long period to evaluate symptomatology, control of use, tolerability and re evaluation of the more effective therapeutic dosage able to control narcolepsy. Due to its high cost and clinical benefits, this drug should be on the government's list of free drugs for the treatment of these patients. PMID- 26483907 TI - Editorial. PMID- 26483906 TI - Prevalence of periodical leg movements in patients with narcolepsy in an outpatient facility in Sao Paulo. AB - Studies have pointed out that approximately 50-60% of narcolepsy patients may demonstrate higher prevalence of periodical leg movements. However, we highlight that the prevalence studies and the effects of periodical leg movements in patients with narcolepsy are limited and with conflicting results. The objective of this study was that of describing and discussing the prevalence of periodical leg movements in patients with narcolepsy in the outpatient facility of diurnal excessive sleepiness of the Federal University of Sao Paulo, Brazil. We revised 59 files of patients with the clinical and electrophysiological diagnosis of narcolepsy according to the American Academy of Sleep Medicine. Of these 59 cases of patients with narcolepsy, 12 (20.3%) demonstrated periodical leg movements. Thirty five patients (59.3%) had history of cataplexy and 38 patients (64.4%) had the presence of the allele HLA-DQB1*0602. There was a higher prevalence of periodical leg movements in patients with cataplexy (p<0.0001) and in patients with the presence of the allele HLA-DQB1*0602 (p<0.0001). Our study characterized the higher prevalence of periodical leg movement in patients with narcolepsy, mainly in patients with cataplexy and with the presence of the allele HLA DQB1*0602. PMID- 26483908 TI - Sedentary behavior and sleep efficiency in active community-dwelling older adults. AB - OBJECTIVES: Previous studies have demonstrated that aerobic exercise interventions have a positive impact on sleep efficiency in older adults. However, little work has been done on the impact of sedentary behavior (sitting, watching television, etc.) on sleep efficiency. METHODS: 54 Community-dwelling men and women >65 years of age living in Whistler, British Columbia (mean 71.5 years) were enrolled in this cross-sectional observational study. Measures of sleep efficiency as well as average waking sedentary (ST), light (LT), and moderate (MT) activity were recorded with Sensewear accelerometers worn continuously for 7 days. RESULTS: From the univariate regression analysis, there was no association between sleep efficiency and the predictors LT and MT. There was a small negative association between ST and sleep efficiency that remained significant in our multivariate regression model containing alcohol consumption, age and gender as covariates. (standardized beta correlation coefficient -0.322, p=0.019). Although significant, this effect was small (an increase in sedentary time of 3 hours per day was associated with an approximately 5% reduction in sleep efficiency). CONCLUSIONS: This study found a small significant association between the time spent sedentary and sleep efficiency, despite high levels of activity in this older adult group. PMID- 26483909 TI - Measurement properties of a screening questionnaire of obstructive sleep apnea risk: Little information, great prediction?(?). AB - INTRODUCTION: Previous research had shown the suitability of several questionnaires predicting the obstructive sleep apnea syndrome. Measurement properties of an online screening questionnaire were studied. METHODS: The sample consisted of 184 Portuguese adults (89 men and 95 women); 46 of them were polysomnographically diagnosed with the untreated obstructive sleep apnea syndrome. The participants were assessed with an online questionnaire of sleep apnea risk, from University of Maryland. RESULTS: A principal component factor analysis was performed, revealing a single factor (49.24% of the total variance). Internal consistency was minimally adequate (alpha=0.74). The mean of inter-item correlation was of 0.35 (0.120.61), whereas the item-total correlations were considered good (0.520.81). The total score for patients was significantly higher than for healthy participants (p<0.000), but no significant statistical differences between severity groups of patients were found (p>0.05). Furthermore, the ability of the measure in discriminating between healthy subjects and OSA subjects was good. Overall data from the Rasch analysis was consistent with the guidelines of Linacre, scores show good model fit and psychometric adequacy. CONCLUSIONS: The measure showed an adequate structural, internal and criterion validity, suggesting this as a useful and effective screening for sleep apnea risk in Portuguese adults. PMID- 26483910 TI - Relationship between chronotype and quality of sleep in medical students at the Federal University of Paraiba, Brazil. AB - OBJECTIVE: The aim of this study was to identify chronotypes of medical students at the Federal University of Paraiba (UFPB) and its relationship to quality of sleep, daytime sleepiness, age, sex and season of birth. METHODS: The final sample consisted of 221 students, assessed by four questionnaires: demographic questionnaire, Morningness-Eveningness Questionnaire (MEQ), Pittsburgh Sleep Quality lndex (PSQI) and Epworth Sleepiness Scale (ESS). RESULTS: There was a statistically significant difference between groups with respect to chronotypes and PSQI score (p<0.0005), but not with excessive daytime sleepiness. A significant negative correlation was found between the scores of MEQ and PSQI (rho=-0.3, p<0.0005), demonstrating that the greater the eveningness, the worse the sleep quality. It was observed that 51.6% of students were classified as indifferent chronotype, 61.5% had poor quality of sleep, while 42.1% had excessive daytime sleepiness. Sex and season at birth did not differ between chronotypes. CONCLUSION: These findings demonstrate that the evening chronotype was associated with poor quality of sleep in medical students, but not with increased daytime sleepiness, with potential impairment to their academic performance and quality of life. PMID- 26483911 TI - Sleep apnea and oxygen saturation in adults at 2640 m above sea level. AB - PURPOSE: To describe the SpO2 in wakefulness, sleep and during the apnea-hypopnea in adults living in Bogota, located at 2640 m above sea level. METHODS: Descriptive observational study in adults referred for polysomnogram (PSG). A normal Apnea hypopnea index (AHI) was defined as <=5 and obstructive sleep apnea (OSA) was classified as mild (AHI 5-15), moderate (AHI 15-30), and severe (AHI >30). T-test or ANOVA test for SpO2 differences between groups was used. RESULTS: 1799 patients, 33% women. 222 (12.8%) did not have OSA (normal IAH), 268 (14.9%) mild OSA, 315 (17.5%) moderate ,and 993 (55.2%) severe. In all cases a low SpO2 (SpO2<90%) was found. The SpO2 was lower when the AHI was higher, in wakefulness, in non-REM and in REM (p<0.001). For all grades of severity, SpO2 decreased significantly from wakefulness to non-REM sleep and to REM sleep (p<0.001). Patients with severe OSA had higher desaturation during wakefulness (85.2+/ 6.6%), non-REM sleep (83.1+/-7.7%), REM sleep (78.8+/-10.2), and during events (75.1+/-9.1%). CONCLUSIONS: Patients with OSA at 2640 m have nocturnal desaturation lower than 88%, which decreases with higher severity of OSA. The clinical impact of sleep disorders at this point may be greater than at sea level and should be studied. PMID- 26483912 TI - The impact of sleep duration on self-rated health. AB - PURPOSE: To review the association between sleep duration and self-rated health. METHODS: A search for original and review articles focusing on sleep duration and self-rated health was performed in PubMed. The general search strategy was [("sleep duration" OR "total sleep time" OR "time in bed") AND "self-rated health"]. RESULTS: We found 22 articles in the English language; 8 articles with no direct association between sleep duration and self-rated health were excluded. Of these articles, 14 were considered potentially relevant and examined in detail, and 9 were excluded for not having self-rated health as the primary outcome. This work was compounded by 5 papers. The extremes of sleep duration (short or long) exhibited an interaction with poor or worse self-rated health. CONCLUSION: The sleep duration issue should be considered when inquiring about health conditions, as this factor can lead to adverse results in global health status. PMID- 26483913 TI - The beneficial effects of massage therapy for insomnia in postmenopausal women. AB - With increases life expectancy, the incidence of undesirable manifestations of menopause has increased as well. The effects of lost ovarian function include progressive decrease in estradiol secretion, trophic changes in the breast, vasomotor symptoms, anxiety, depression, and sleep disorders. Insomnia, which has physiological consequences and can result in a loss of quality of life, is prevalent in women after menopause. Hormone therapy has been widely used to reduce menopausal symptoms, but its use in recent years has been questioned because of the reported risks of cardiovascular events and increased incidence of tumors. This controversy has generated significant interest in non-hormonal treatments among both physicians and patients. Our previous research has shown a positive effect of massage therapy on menopausal symptoms. We explored the hypothesis that massage therapy would produce beneficial effects in postmenopausal women through inflammatory and immunological changes. Recent results from self-report questionnaires have shown improvements in sleep pattern and quality of life following massage therapy. These findings demonstrate the effectiveness of massage therapy for the treatment of postmenopausal symptoms, particularly insomnia, and indicate that it is a promising line of research. PMID- 26483914 TI - Treatment of sleep central apnea with non-invasive mechanical ventilation with 2 levels of positive pressure (bilevel) in a patient with myotonic dystrophy type 1. AB - We are reporting a case of a 29 year-old female with diagnosis of myotonic dystrophy type 1 (Steinert's disease) with excessive daytime sleepiness, muscle fatigue, snoring, frequent arousals, non-restorative sleep, and witnessed apneas. Pulmonary function tests revealed a mild decrease of forced vital capacity. Nocturnal polysomnography showed an increase of apnea/hypopnea index (85.9 events/h), mainly of central type (236), minimal oxygen saturation of 72%, and end-tidal carbon dioxide values that varied from 45 to 53 mmHg. Bi-level positive airway pressure titration was initiated at an inspiratory pressure (IPAP) of 8 and an expiratory pressure (EPAP) of 4 cm H2O. IPAP was then gradually increased to eliminate respiratory events and improve oxygen saturation. An IPAP of 12cm H20 and an EPAP of 4cm H2O eliminated all respiratory events, and the oxygen saturation remained above 90%. Bi-level positive airway pressure treatment at spontaneous/timed mode showed an improvement in snoring, apneas, and Epworth sleepiness scale decreased from 20 to 10. This case illustrates the beneficial effects of Bi-level positive airway pressure support in central sleep apnea syndrome of a patient with myotonic dystrophy type 1. PMID- 26483915 TI - Kleine-Levin Syndrome: A case report. AB - The Kleine-Levin Syndrome is a differential diagnosis for patients with diurnal excessive sleepiness and a suspicion of narcolepsy. It is characterized by paroxysmal attacks of diurnal excessive sleepiness, associated with one or more symptoms of hyperphagia, hypersexuality, coprolalia and copropraxia. During crisis intervals, there are no symptoms. This pathology predominantly manifests itself in teenagers, being more frequent among males. The course of this disease is unpredictable, with variable duration and frequency. The most accepted physiopathology is that of a hypothalamic dysfunction, although and recently, there has appeared a hypothesis of a post-infectious autoimmune disorder. These patients show an elevated body mass index, which can predispose to association with comorbidities such as the sleep obstructive apnea syndrome. Treatment involves medications with different effects, but there is no specific and effective therapy. Our article shows a classic case of Kleine-Levin Syndrome associated with sleep obstructive apnea syndrome, a rare association in the literature. PMID- 26483916 TI - Erratum to "Screening for polymorphisms in the AANAT gene and their association with extreme diurnal preference" [Sleep Sci. 6 (4) (2013) 141-145. PMID- 26483917 TI - The far side of sleep: Towards a deeper understanding of parasomnias and nocturnal seizures. PMID- 26483918 TI - Sleep complaints in the Brazilian population: Impact of socioeconomic factors. AB - National surveys are relevant for the study of sleep epidemiology since they can provide specific data about sleep in large dimension with important implications for the health system. Thus, the aim of this study was to investigate the prevalence of sleep complaints among the Brazilian population using a randomized cluster sample according to region and socioeconomic class. For this, a 3-stage sampling technique was used to randomly select Brazilian subjects of both genders older than 16 years. A total of 2017 subjects, from 132 different cities, were selected to estimate prevalence in the Brazilian population with a sampling error of +/-2%. Questions about sleep complaints were administered face-to-face by Instituto Datafolha interviewers on April 10 and 16, 2012. Data were expanded using a weighted variable. The results showed that 76% of the study population suffers from at least 1 sleep complaint, indicating that approximately 108 million Brazilians may be affected by sleep disorders. On average, each subject had 1.9 sleep problems with the most common complaints being light and insufficient sleep, snoring, moving a lot during sleep, and insomnia, which usually occurred more than 3 times per week. Low income was associated with higher number of sleep complaints only in Northeast and Southeast regions. In conclusion, this study showed a high prevalence of sleep complaints in a sample of the Brazilian population, suggesting that sleep disorders may be markedly frequent in the Brazilian population with a possible correlation with the socioeconomic situation of the interviewed subjects. PMID- 26483919 TI - The Impact of Sound on Electroencephalographic Waves during Sleep in Patients Suffering from Tinnitus. AB - Based on the knowledge that sensory processing continues during sleep and that a relationship exists between sleep and learning, a new strategy for treatment of idiopathic subjective tinnitus, consisted of customized sound stimulation presented during sleep, was tested. It has been previously shown that this treatment induces a sustained decrease in tinnitus intensity; however, its effect on brain activity has not yet been studied. In this work, we compared the impact of sound stimulation in tinnitus patients in the different sleep stages. Ten patients with idiopathic tinnitus were treated with sound stimulation mimicking tinnitus during sleep. Power spectra and intra- and inter-hemispheric coherence of electroencephalographic waves from frontal and temporal electrodes were measured with and without sound stimulation for each sleep stage (stages N2 with sleep spindles; N3 with slow wave sleep and REM sleep with Rapid Eye Movements). The main results found were that the largest number of changes, considering both the power spectrum and wave's coherence, occurred in stages N2 and N3. The delta and theta bands were the most changed, with important changes also in coherence of spindles during N2. All changes were more frequent in temporal areas. The differences between the two hemispheres do not depend, at least exclusively, on the side where the tinnitus is perceived and, hence, of the stimulated side. These results demonstrate that sound stimulation during sleep in tinnitus patients' influences brain activity and open an avenue for investigating the mechanism underlying tinnitus and its treatment. PMID- 26483920 TI - Temporal sleep patterns in adults using actigraph. AB - The aim of the present study was to characterize the temporal patterns of sleep and wakefulness in a sample of the adult subjects from Sao Paulo city. All subjects filled the Morningness/Eveningness Questionnaire (MEQ) and wore an actigraph for at least three consecutive days. A total of 359 subjects were considered for the analyses. The mean age was 43+/-14 years, the mean body mass index was 26.7+/-5.7 kg/m(2), and 60% were female. The mean MEQ score was 58.0+/ 10.7. The sleep pattern evaluated by the actigraphic analyses showed that 92% had a monophasic sleep pattern, 7% biphasic, and 1% polyphasic sleep pattern. Cluster analysis, based on time to sleep onset, sleep efficiency, sleep latency, and total sleep time, was able to identify three different groups denominated: morning type, evening type, and undefined type. Morning type subjects were more frequent, older, and had higher MEQ scores than evening type subjects. Our results showed that the actigraph objectively assessed the sleep-wake cycle and was able to discriminate between morning and evening type individuals. These findings suggest that the actigraph could be a valuable tool for assessing temporal sleep patterns, including the circadian preferences. PMID- 26483921 TI - Nonparametric methods in actigraphy: An update. AB - Circadian rhythmicity in humans has been well studied using actigraphy, a method of measuring gross motor movement. As actigraphic technology continues to evolve, it is important for data analysis to keep pace with new variables and features. Our objective is to study the behavior of two variables, interdaily stability and intradaily variability, to describe rest activity rhythm. Simulated data and actigraphy data of humans, rats, and marmosets were used in this study. We modified the method of calculation for IV and IS by modifying the time intervals of analysis. For each variable, we calculated the average value (IVm and ISm) results for each time interval. Simulated data showed that (1) synchronization analysis depends on sample size, and (2) fragmentation is independent of the amplitude of the generated noise. We were able to obtain a significant difference in the fragmentation patterns of stroke patients using an IVm variable, while the variable IV60 was not identified. Rhythmic synchronization of activity and rest was significantly higher in young than adults with Parkinson's when using the ISM variable; however, this difference was not seen using IS60. We propose an updated format to calculate rhythmic fragmentation, including two additional optional variables. These alternative methods of nonparametric analysis aim to more precisely detect sleep-wake cycle fragmentation and synchronization. PMID- 26483922 TI - Update of sleep alterations in depression. AB - Sleep disturbances in depression are up to 70%. Patients frequently have difficulty in falling asleep, frequent awakenings during the night and non restorative sleep. Sleep abnormalities in depression are mainly characterized by increased rapid eye movement (REM) sleep and reduced slow wave sleep. Among the mechanisms of sleep disturbances in depression are hyperactivation of the hypothalamic-pituitary-adrenal axis, CLOCK gene polymorphism and primary sleep disorders. The habenula is a structure regulating the activities of monoaminergic neurons in the brain. The hyperactivation of the habenula has also been implicated, together with sleep disturbances, in depression. The presence of depression in primary sleep disorders is common. Sleep disturbances treatment include pharmacotherapy or Cognitive Behavioral Therapy. PMID- 26483923 TI - Sporadic nocturnal frontal lobe epilepsy: A consecutive series of 8 cases. AB - OBJECTIVE: To present findings on a series of cases of sporadic nocturnal frontal lobe epilepsy (NFLE), a form of NFLE that is infrequently reported, in contrast to familial (autosomal dominant) NFLE. Both forms of NFLE need to be distinguished from parasomnias, nocturnal temporal lobe epilepsy, and other nocturnal disorders. METHODS: Eight consecutive cases of sporadic NFLE were evaluated at a sleep clinic in Taiwan. All patients had clinical evaluations, daytime waking and sleeping EEGs, brain MRIs, and overnight video-polysomnography (vPSG) with seizure montage. RESULTS: Gender was equal (four males, four females); mean age was 18.4 yrs (range, 7-41 yrs). Age of NFLE onset was by puberty. Premorbid history was negative for any neurologic, medical or psychiatric disorder. NFLE subtypes: nocturnal paroxysmal dystonia, n=6; paroxysmal arousals, n=2. MRI brain scan abnormalities with clinical correlates were found in one patient. Daytime awake EEGs were negative for ictal/interictal activity in all patients, but two patients had daytime sleep EEGs with interictal epileptiform EEG activity. During vPSG studies, three of eight patients with NFLE seizure events had concurrent epileptiform EEG activity, and two patients had interictal epileptiform EEG activity during their vPSG studies. No case had a spontaneous remission. Anticonvulsant therapy was highly effective in all eight cases (>75% reduction in seizure frequency). DISCUSSION: These cases confirm that sporadic NFLE closely resembles familial NFLE, and comprises a set of distinct clinical manifestations, with variable intensity, and variable scalp EEG epileptiform abnormalities across sleep and wakefulness, which have previously been identified in Caucasian patients from Europe and North America. PMID- 26483924 TI - Restless leg syndrome exacerbated by amytriptiline in a patient with Duchenne Muscular Dystrophy. AB - We report an unusual case of a Duchenne Muscular Dystrophy(DMD) patient who initiated a restless leg syndrome after the use of amytriptiline. The prescription and use of this medication for patients with persistent neuropathic pain is relatively common, especially for patients with DMD. Normally, this medication is well tolerated, however, we now report the occurrence of an induction or intensification of a restless leg syndrome case in a young patient with DMD, treated with amytriptiline for his chronic pain. PMID- 26483925 TI - A boy infant with sleep related rhythmic movement disorder showing arm banging. AB - OBJECTIVE: To present a male patient who performed arm banging on his face during sleep every night since 7 months of age. METHODS: Clinical course of this patient with electroencephalographic recording with video recording at 23 months of age was shown. RESULTS: His arm banging began at the age of 7 months and showed no complete remission at the age of 57 months of age, although clonazepam revealed mild effects on its intensity and frequency. DISCUSSION: We diagnosed him as having arm banging type of sleep related rhythmic movement disorder. To our knowledge, no precise description on this type of sleep related rhythmic movement disorder has been found. In addition, this patient seemed to be the youngest case of sleep related rhythmic movement disorder showing arm banging. PMID- 26483926 TI - Editorial. PMID- 26483927 TI - Excessive daytime somnolence and cardiovascular health: A population-based study in rural Ecuador. AB - In a population-based study conducted in rural Ecuador, 635 stroke-free persons aged >=40 years were interviewed with the Epworth sleepiness scale and screened to assess their cardiovascular health (CVH) status. Excessive daytime somnolence was present in 22% persons and a poor CVH status in 69%. In a generalized linear model after adjusting for age and sex, excessive daytime somnolence was not associated with a poor CVH status or with any of the individual metrics in the poor range. Excessive daytime somnolence may not be linked to cardiovascular risk factors at the rural level. PMID- 26483928 TI - The relationship between self-reported sleep quality and reading comprehension skills. AB - Inadequate sleep undermines many cognitive functions, including memory, concentration, and attention, which are vital in everyday activities. We hypothesized that poor quality or shorter sleep length may impair reading-related skills, resources, and outcomes, specifically verbal working memory span, verbal efficiency, and reading comprehension. Contrary to the hypotheses, neither short sleep length nor self-reported sleep quality were related to reading skills performance. However, longer sleep times were significantly related to lower verbal efficiency, and participants with the poorest sleep quality fared significantly better on the reading comprehension task than participants with moderate sleep quality. Given the paucity of research examining sleep and reading specifically, as well as these surprising data, more research in this area is warranted. PMID- 26483929 TI - Validation of a three-dimensional model about sleep: Habits, personal factors and environmental factors. AB - OBJECTIVES: The present study aims to test the factor structure of two sleep questionnaires and their internal consistency in a sample of adolescents and their respective parents and to evaluate the validity and robustness of a three dimensional model about sleep, addressing nine subcategories related to sleep habits, personal and environmental factors. METHODS: Participants were 654 adolescents from Portuguese schools, who completed "My Sleep and I" questionnaire, and 664 parents who completed "My child's sleep" questionnaire; to them confirmatory factor analysis was applied. RESULTS: Confirmatory factor analysis indicate that a nine-factor model has better fit indices compared with the others tested models for both samples (adolescents: chi (2)/df (Chi square/degrees of freedom)=2.59, Comparative Fit Index (CFI)=.82, Goodness-of-Fit Index (GFI)=.92, Root Mean Square Error of Approximation (RMSEA)=.049, Expected Cross-Validation Index (ECVI)=1.416; Parents: chi (2)/df=2.89, CFI=.85, GFI=.91, RMSEA=.053, ECVI=1.528). Moreover, the comparison of the models through Deltachi (2) index (chi-square difference between rival models) indicates a better fit for this model, Deltachi (2) (24)=186.5, p<.001 for adolescents and Deltachi (2) (24)=209, p<.001 for parents. Also, the three second-order factors have good internal consistency, convergent and discriminant validity for all factors in both samples. CONCLUSIONS: Results postulate that the three factors and their nine subcategories account for correlations between sleep habits, self perceptions and knowledge about sleep. PMID- 26483930 TI - The effects of long-term dopaminergic treatment on locomotor behavior in rats. AB - Long-term treatments with dopaminergic agents are associated with adverse effects, including augmentation. Augmentation consists of an exacerbation of restless legs syndrome (a sleep-related movement disorder) symptoms during treatment compared to those experienced during the period before therapy was initiated. The objective of this study was to examine locomotor activity in rats after long-term dopaminergic treatment and its relationship with expression of the D2 receptor, in addition to demonstrating possible evidence of augmentation. The rats were divided into control (CTRL) and drug (Pramipexole-PPX) groups that received daily saline vehicle and PPX treatments, respectively, for 71 days. The locomotor behavior of the animals was evaluated weekly in the Open Field test for 71 days. The expression of the dopamine D2 receptor was evaluated by Western Blot analysis. The animals that received the PPX demonstrated a significant reduction in locomotor activity from day 1 to day 57 and a significant increase in immobility time from day 1 to day 64 relative to baseline values, but these values had returned to baseline levels at 71 days. No changes in the expression of the D2 receptor were demonstrated after treatment with a dopaminergic agonist. This study suggests changes in locomotor activity in rats after long-term PPX treatment that include an immediate reduction of locomotion and an increase in immobilization, and after 64 days, these values returned to baseline levels without evidence of augmentation. In addition, it was not possible to demonstrate a relationship between locomotor activity and the expression of D2 receptors under these conditions. PMID- 26483931 TI - Environmental noise and sleep disturbances: A threat to health? AB - Environmental noise, especially that caused by transportation means, is viewed as a significant cause of sleep disturbances. Poor sleep causes endocrine and metabolic measurable perturbations and is associated with a number of cardiometabolic, psychiatric and social negative outcomes both in adults and children. Nocturnal environmental noise also provokes measurable biological changes in the form of a stress response, and clearly affects sleep architecture, as well as subjective sleep quality. These sleep perturbations are similar in their nature to those observed in endogenous sleep disorders. Apart from these measurable effects and the subjective feeling of disturbed sleep, people who struggle with nocturnal environmental noise often also suffer the next day from daytime sleepiness and tiredness, annoyance, mood changes as well as decreased well-being and cognitive performance. But there is also emerging evidence that these short-term effects of environmental noise, particularly when the exposure is nocturnal, may be followed by long-term adverse cardiometabolic outcomes. Nocturnal environmental noise may be the most worrying form of noise pollution in terms of its health consequences because of its synergistic direct and indirect (through sleep disturbances acting as a mediator) influence on biological systems. Duration and quality of sleep should thus be regarded as risk factors or markers significantly influenced by the environment and possibly amenable to modification through both education and counseling as well as through measures of public health. One of the means that should be proposed is avoidance at all costs of sleep disruptions caused by environmental noise. PMID- 26483932 TI - The effects of sleep loss on capacity and effort. AB - Sleep loss appears to affect the capacity for performance and access to energetic resources. This paper reviews research examining the physical substrates referred to as resource capacity, the role of sleep in protecting that capacity and the reaction of the system as it attempts to respond with effort to overcome the limitations on capacity caused by sleep loss. Effort is the extent to which an organism will exert itself beyond basic levels of functioning or attempt alternative strategies to maintain performance. The purpose of this review is to bring together research across sleep disciplines to clarify the substrates that constitute and influence capacity for performance, consider how the loss of sleep influences access to those resources, examine cortical, physiological, perceptual, behavioral and subjective effort responses and consider how these responses reflect a system reacting to changes in the resource environment. When sleep deprived, the ability to perform tasks that require additional energy is impaired and the ability of the system to overcome the deficiencies caused by sleep loss is limited. Taking on tasks that require effort including school work, meal preparation, pulling off the road to nap when driving drowsy appear to be more challenging during sleep loss. Sleep loss impacts the effort-related choices we make and those choices may influence our health and safety. PMID- 26483933 TI - Model of oronasal rehabilitation in children with obstructive sleep apnea syndrome undergoing rapid maxillary expansion: Research review. AB - Rapid maxillary expansion (RME) is a widely used practice in orthodontics. Scientific evidence shows that RME can be helpful in modifying the breathing pattern in mouth-breathing patients. In order to promote the restoration of physiological breathing we have developed a rehabilitation program associated with RME in children. The aim of the study was a literature review and a model of orofacial rehabilitation in children with obstructive sleep apnea undergoing treatment with rapid maxillary expansion. Muscular training (local exercises and general ones) is the key factor of the program. It also includes hygienic and behavior instructions as well as other therapeutic procedures such as rhinosinusal washes, a postural re-education (Alexander technique) and, if necessary, a pharmacological treatment aimed to improve nasal obstruction. The program should be customized for each patient. If RME is supported by an adequate functional rehabilitation, the possibility to change the breathing pattern is considerably amplified. Awareness, motivation and collaboration of the child and their parents, as well as the cooperation among specialists, such as orthodontist, speech therapist, pediatrician and otolaryngologist, are necessary conditions to achieve the goal. PMID- 26483934 TI - Sleep disorders: A review of the interface between restless legs syndrome and iron metabolism. AB - Restless legs syndrome (RLS) is characterized by unpleasant sensations mainly in the legs. 43% of RLS-associated conditions have also been associated with systemic iron deficiency. The objective of this study was to review in the literature the relationship between iron metabolism and RLS. With an initial search using the keywords combination "Iron Metabolism OR Iron Deficiency AND Restless Legs Syndrome," 145 articles were screened, and 20 articles were selected. Few studies were found for this review in the period of 2001-2014, however, the correlation between RLS and iron was evident. PMID- 26483935 TI - FLASS, A new awakening: For the dissemination of clinical and basic sleep science in Latin America. PMID- 26483936 TI - Re-examining sleep's effect on motor skills: How to access performance on the finger tapping task? AB - Here our goal was to determine the magnitude of sleep-related motor skill enhancement. Performance on the finger tapping task (FTT) was evaluated after a 90 min daytime nap (n=15) or after quiet wakefulness (n=15). By introducing a slight modification in the formula used to calculate the offline gains we were able to refine the estimated magnitude of sleep's effect on motor skills. The raw value of improvement after a nap decreased after this correction (from ~15% to ~5%), but remained significantly higher than the control. These results suggest that sleep does indeed play a role in motor skill consolidation. PMID- 26483937 TI - The validity of Actiwatch2 and SenseWear armband compared against polysomnography at different ambient temperature conditions. AB - There were no validation studies on portable sleep devices under different ambient temperature, thus this study evaluated the validity of wrist Actiwatch2 (AW2) or SenseWear armband (SWA) against polysomnography (PSG) in different ambient temperatures. Nine healthy young participants (6 males, aged 23.3+/-4.1 y) underwent nine nights of study at ambient temperature of 17 degrees C, 22 degrees C and 29 degrees C in random order, after an adaptation night. They wore the AW2 and SWA while being monitored for PSG simultaneously. A linear mixed model indicated that AW2 is valid for sleep onset latency (SOL), total sleep time (TST) and sleep efficiency (SE) but significantly overestimated wake after sleep onset (WASO) at 17 degrees C and 22 degrees C. SWA is valid for WASO, TST and SE at these temperatures, but severely underestimates SOL. However, at 29 degrees C, SWA significantly overestimated WASO and underestimated TST and SE. Bland-Altman plots showed small biases with acceptable limits of agreement (LoA) for AW2 whereas, small biases and relatively wider LoA for most sleep variables were observed in SWA. The kappa statistic showed a moderate sleep-wake epoch agreement, with a high sensitivity but poor specificity; wake detection remains suboptimal. AW2 showed small biases for most of sleep variables at all temperature conditions, except for WASO. SWA is reliable for measures of TST, WASO and SE at 17-22 degrees C but not at 29 degrees C, and SOL approximates that of PSG only at 29 degrees C, thus caution is needed when monitoring sleep at different temperatures, especially in home sleep studies, in which temperature conditions are more variable. PMID- 26483938 TI - Principal component analysis of the EEG spectrum can provide yes-or-no criteria for demarcation of boundaries between NREM sleep stages. AB - Human sleep begins in stage 1 and progresses into stages 2 and 3 of Non-Rapid-Eye Movement (NREM) sleep. These stages were defined using several arbitrarily defined thresholds for subdivision of albeit continuous process of sleep deepening. Since recent studies indicate that stage 3 (slow wave sleep) has unique vital functions, more accurate measurement of this stage duration and continuity might be required for both research and practical purposes. However, the true neurophysiological boundary between stages 2 and 3 remains unknown. In a search for non-arbitrary threshold criteria for distinguishing the boundaries between NREM sleep stages, scores on the principal components of the electroencephalographic (EEG) spectrum were analyzed in relation to stage onsets. Eighteen young men made 12-20-minute attempts to nap during 24-hour wakefulness. Single-minute intervals of the nap EEG records were assigned relative to the minute of onsets of polysomnographically determined stages 1, 2, and 3. The analysis of within-nap time courses of principal components scores revealed that, unlike any conventional spectral EEG index, score on the 4th principal component exhibited a rather rapid rise on the boundary between stages 2 and 3. This was mostly a change from negative to positive score. Therefore, it might serve as yes or-no criterion of stage 3 onset. Additionally, similarly rapid changes in sign of scores were exhibited by the 1st and 2nd principal components on the boundary of stages 2 and 1 and on the boundary between stage 1 and wakefulness, respectively. PMID- 26483939 TI - Beyond mean values: Quantifying intraindividual variability in pre-sleep arousal and sleep in younger and older community-dwelling adults. AB - Intraindividual variability is an often understudied aspect of health outcomes research that may provide additional, complementary information to average values. The current paper aims to further our understanding of intraindividual variability in health research by presenting the results of a daily diary study of sleep and pre-sleep arousal. Pre-sleep arousal is often implicated in poor sleep outcomes, although the arousal-sleep association is not uniform across age groups. The examination of intraindividual variability in different age groups may provide a more complete understanding of these constructs, which, in turn, can inform future research. The overall objectives of the current study are to quantify the amount of intraindividual variability in pre-sleep arousal and sleep and to examine age differences in this variability. A sample of older (n=50) and younger (n=50) adults recruited from North Central Florida and online completed 14-consecutive-day diaries assessing pre-sleep arousal and sleep outcomes. Significant age differences were found for sleep and pre-sleep arousal; older adults displayed poorer, more variable sleep for the majority of sleep outcomes, and higher levels of pre-sleep arousal than younger adults. The high amount of intraindividual variability has implications for the assessment of pre-sleep arousal and sleep across age groups. PMID- 26483940 TI - Clinical factors associated with extreme sleep apnoea [AHI>100 events per hour] in Peruvian patients: A case-control study-A preliminary report. AB - PURPOSE: The severity of obstructive sleep apnoea (OSA) ranges from mild or moderate to severe sleep apnoea. However, there is no information available on the clinical characteristics associated with cases involving more than 100 events per hour. This is a preliminary report and our goal was to characterise the demographics and sleep characteristics of patients with Extreme OSA and compare with patients with sleep apnoea of lesser severity. We hypothesised that patients with Extreme OSA (AHI>100) is associated with an increased comorbidities and/or risk factors. METHODS: We carried out a case-control study on male patients with OSA who were seen in a private hospital in Lima, Peru between 2006 and 2012. Cases were identified if their apnoea/hypopnea index (AHI) was higher than 100 (Extreme OSA), and four controls were selected per case: two with 15-29 AHI and two with 30-50 AHI, matched according to case diagnosis dates. We evaluated demographic, past medical history, and oxygen saturation variables. RESULTS: We identified 19 cases that were matched with 54 controls. In the multivariate model, only arterial hypertension, neck circumference, age, and over 10% in SatO2Hb<=90% in total sleep time (T90) were associated with Extreme OSA. Arterial hypertension had an OR=6.31 (CI95%: 1.71-23.23) of Extreme OSA. Each 5-cm increment in neck circumference was associated with an increase of OR=4.34 (CI95%: 1.32-14.33), while T90>10% had an OR=19.68 (CI95%: 4.33-89.49). Age had a marginal relevance (OR=0.95; CI95%: 0.92-0.99). CONCLUSION: Our results suggest that arterial hypertension, neck circumference, and over 10% SatO2Hb<=90% in total sleep time were associated with a higher probability of Extreme OSA. We recommend investigators to study this population of Extreme OSA looking for an early diagnosis and the identification of prognostic factors in comparison with moderate to severe levels. PMID- 26483941 TI - Sleep disturbances and mild cognitive impairment: A review. AB - OBJECTIVE: Mild cognitive impaired (MCI) is viewed as a transitional stage from normal to dementia. The aim of this study is analyze the sleep disturbances in subjects diagnosed as carries MCI. METHODS: A review of the literature was conducted in order to document sleeps problems in the context of MCI. RESULTS: Among the studies that compares the prevalence of sleep disturbances between subjects with MCI and those with normal cognition demonstrated that night time behaviors are more common in MCI patients (18.3-45.5%) than in normal population (10.9-23.3%). CONCLUSIONS: Sleep disturbance is prevalent and predictive of cognitive decline in older people and in those with neurodegenerative disorders. The sleep problems have to be identified and treat to preserve the cognition and the MCI subjects with sleep disturbances have to be follow more closely to identify the initial signs of dementia. PMID- 26483942 TI - Treatment of upper airway resistance syndrome in adults: Where do we stand? AB - OBJECTIVE: To evaluate the available literature regarding Upper Airway Resistance Syndrome (UARS) treatment. METHODS: Keywords "Upper Airway Resistance Syndrome," "Sleep-related Breathing Disorder treatment," "Obstructive Sleep Apnea treatment" and "flow limitation and sleep" were used in main databases. RESULTS: We found 27 articles describing UARS treatment. Nasal continuous positive airway pressure (CPAP) has been the mainstay therapy prescribed but with limited effectiveness. Studies about surgical treatments had methodological limitations. Oral appliances seem to be effective but their efficacy is not yet established. CONCLUSION: Randomized controlled trials with larger numbers of patients and long-term follow up are important to establish UARS treatment options. PMID- 26483943 TI - Infancy narcolepsy: Streptococcus infection as a causal factor. AB - Streptococcal infections are suggested as a risk factor for narcolepsy. This hypothesis is supported by the presence of anti-streptolysin antibodies in 65% of patients with narcolepsy. These infections are associated with the activation of general immunity and concomitant increased permeability of blood-brain barrier after T cell activation during inflammation and fever. It has also been shown a significant association between birth order and narcolepsy in genetically susceptible patients, with positivity for HLA-DQB1*0602 allele. Watson and colleagues showed a significant association between birth order and narcolepsy in genetically susceptible patients, with positivity for HLA-DQB1*0602 allele. In that study, the disease was predominant in young children cases compared to controls. We report here the case of a child diagnosed with narcolepsy with cataplexy, positivity for the HLA-DQB1*0602 and previous history of streptococcal infection. PMID- 26483944 TI - Mysteries of pedunculopontine nucleus physiology: Towards a deeper understanding of arousal and neuropsychiatric disorders. PMID- 26483945 TI - Misleading sleep-diagnostic results in a patient with variable nasal airflow obstruction. PMID- 26483946 TI - Urinary proteomic profiling in severe obesity and obstructive sleep apnoea with CPAP treatment. AB - INTRODUCTION: Obstructive sleep apnoea (OSA) is common in obesity and is associated with cardiovascular and metabolic complications. Continuous positive airway pressure (CPAP) in OSA may lead to physiological changes reflected in the urinary proteome. The aim of this study was to characterise the urinary proteome in severely obese adult subjects with OSA who were receiving CPAP compared with severely obese subjects without OSA. METHODS: Severely obese subjects with and without OSA were recruited. Subjects with OSA were receiving CPAP. Body composition and blood pressure measurements were recorded. Urinary samples were analysed by Capillary Electrophoresis-Mass Spectrometry (CE-MS). RESULTS: Twenty seven subjects with OSA-on-CPAP (age 49+/-7years, BMI 43+/-7 kg/m(2)) and 25 controls without OSA (age 52+/-9years, BMI 39+/-4 kg/m(2)) were studied. Age and BMI were not significantly different between groups. Mean CPAP use for OSA patients was 14.5+/-1.0 months. Metabolic syndrome was present in 14(52%) of those with OSA compared with 6(24%) of controls (p=0.039). A urinary proteome comprising 15 peptides was identified showing differential expression between the groups (p<0.01). Although correction for multiple testing did not reach significance, sequences were determined for 8 peptides demonstrating origins from collagens, fibrinogen beta chain and T-cadherin that may be associated with underlying cardiovascular disease mechanisms in OSA. CONCLUSIONS: The urinary proteome is compared in OSA with CPAP and without OSA in severe obesity. The effects of CPAP on OSA may lead to changes in the urinary peptides but further research work is needed to investigate the potential role for urinary proteomics in characterising urinary peptide profiles in OSA. PMID- 26483947 TI - Effects of sleep reduction on the phonological and visuospatial components of working memory. AB - Sleep reduction impairs the performance of many tasks, so it may affect a basic cognitive process, such as working memory, crucial for the execution of a broad range of activities. Working memory has two storage components: a phonological and a visuospatial component. The objective of this study was to analyze the effects of sleep reduction for 5 days on the storage components of working memory. Thirteen undergraduate students (18.77+/-2.20 years of age), 5 men and 8 women, responded two N-Back tasks (auditory and visual), with three sections each (0-Back, 1-Back, and 2-Back). These tasks were performed at 13:00 h under the following conditions: before sleep reduction (control; C); on the first (SR1), fourth (SR4), and fifth (SR5) days of sleep reduction (4 h of sleep per night); and one day after they slept freely (recovery, R). Sleep reduction produced a decrement in accuracy on the auditory 2-Back section the fifth day of sleep reduction (C=87.86+/-13.35%; SR5=74.76+/-16.37%; F=14.57, p<0.01). In the visual 2-Back section accuracy decreased (C=88.10+/-9.95%; SR1=82.45+/-11.57%; SR5=77.76+/-14.14%; F=10.80, p<0.05), and reaction time increased (C=810.02+/ 173.96 ms; SR1=913.51+/-172.25 ms; SR5=874.78+/-172.27 ms; F=10.80, p<0.05) on the first and fifth day of sleep reduction. In conclusion, five days of sleep reduction produces a decrease in the phonological and visuospatial storage components of working memory, which may interfere with processing verbal information and solving problems that require spatial analysis. PMID- 26483948 TI - Relationship between perceived sleep and polysomnography in older adult patients. AB - BACKGROUND AND AIMS: Aging is a multifactorial process that elicits changes in the duration and quality of sleep. Polysomnography is considered to be the standard examination for the analysis of sleep and consists of the simultaneous recording of selected physiological variables during sleep. OBJECTIVE: The objective of this study was to use polysomnography to compare sleep reported by senior citizens. METHODS: We selected 40 patients, both male and female, with ages ranging from 64 to 89 years from the Center for the Study of Aging at the Federal University of Sao Paulo. Patients answered questions about sleep on the Comprehensive Geriatric Assessment and underwent polysomnography. RESULTS: The results were compared, and agreement between perceived sleep and polysomnography was found in several areas. There was an association between difficulty sleeping and sleep onset latency (p=0.015), waking up at night with sleep onset latency (p=0.005), total sleep time with daytime sleepiness (0.005) and snoring (0.027), sleep efficiency with sleepiness (0.004), snoring (0.033) and pause in breathing (p=0.024), awakenings with snoring (p=0.012) and sleep apnea with pauses in breathing (p=0.001). CONCLUSION: These results suggest that the older adult population have a good perception of their sleep. The questionnaires aimed at this population should be used as an alternative to polysomnography. PMID- 26483949 TI - Pedunculopontine arousal system physiology-Implications for schizophrenia. AB - Schizophrenia is characterized by major sleep/wake disturbances including increased vigilance and arousal, decreased slow wave sleep, and increased REM sleep drive. Other arousal-related symptoms include sensory gating deficits as exemplified by decreased habituation of the blink reflex. There is also dysregulation of gamma band activity, suggestive of disturbances in a host of arousal-related mechanisms. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of the disease. Recent discoveries on the physiology of the pedunculopontine nucleus help explain many of these disorders of arousal in, and point to novel therapeutic avenues for, schizophrenia. PMID- 26483951 TI - Recurrent hypersomnia: Report of medication-responsive cases. AB - INTRODUCTION: Recurrent hypersomnia (RH) is a rare disorder without established treatment. METHODS: We report 2 RH medication-responsive cases with typical characteristics of Kleine-Levin syndrome (KLS). CASE-REPORTS: A 10 y.o. girl and a 14 y.o. boy presented with sudden sleepiness for 3-9 days (every 2-3 weeks). Physical examination, brain images and blood tests were normal. Polysomnographic findings were heterogenous, including disrupted sleep architecture. MSLTs revealed 2-3 SOREMPs and short sleep latency. Carbamazepine rendered girl's sleep normalization, while risperidone normalized boy's sleep cycles. CONCLUSIONS: Facing the absence of clinical trials in RH, reports of responsive cases are the available therapeutic evidence. PMID- 26483950 TI - Pedunculopontine arousal system physiology - Implications for insomnia. AB - We consider insomnia a disorder of waking rather than a disorder of sleep. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of insomnia, mainly representing an overactive waking drive. We determined that high frequency activity during waking and REM sleep is controlled by two different intracellular pathways and channel types in PPN cells. We found three different PPN cell types that have one or both channels and may be active during waking only, REM sleep only, or both. These discoveries point to a specific mechanism and novel therapeutic avenues for insomnia. PMID- 26483952 TI - Treatment of obstructive sleep apnea with mandibular advancement appliance over prostheses: A case report. AB - Treatment with a mandibular advancement device (MAD) is recommended for mild obstructive sleep apnea (OSA), primary snoring and as a secondary option for Continuous Positive Airway Pressure, because it has better adherence and acceptance. However, edentulous patients do not have supports to hold the MAD. This study aimed to present a possible to OSA treatment with MAD in over complete upper and partial lower dentures. The patient, a 38-year-old female with mild OSA, was treated with a MAD. The respiratory parameter, such as apnea-hypopnea index, arousal index and oxyhemoglobin saturation was improved after treatment. PMID- 26483954 TI - Regulatory withdrawal of medicines marketed with uncertain benefits: the bevacizumab case study. AB - BACKGROUND: Withdrawal of conditional regulatory approval or subsidization of new medicines when subsequent evidence does not confirm early trial results may not be well understood or accepted by the public. OBJECTIVES: We present a case study of the US Food and Drug Administration (FDA)'s decision to withdraw the indication of bevacizumab for the treatment of advanced breast cancer and include an analysis of the reactions of stakeholders with a view to identifying opportunities for improving risk management for new medicines with conditional approval or funding. METHODS: We drew on a range of information sources, including FDA documents, medical journals and media reports, to describe the evidentiary basis of the FDA decisions. We analysed the reactions and perspectives of the stakeholders. RESULTS: In 2008 bevacizumab was granted conditional approval for treatment of advanced breast cancer by the FDA pending submission of supplementary satisfactory evidence. In 2011 the FDA decision to withdraw the indication was met with a hostile reaction from many clinicians and cancer survivors. There were different interpretations of the therapeutic value of bevacizumab with strong beliefs among cancer survivors that the medicine was effective and potential harm was manageable. High expectations of the public may have been encouraged by overly positive media reports and limited understanding by the public of the complexity of the scientific evaluation of new medicines and of the regulatory processes. CONCLUSIONS: Improving understanding and acceptance of approval or coverage schemes conditional to evidence development may require the development of risk management plans by regulatory and funding institutions. They may include a range of strategies such as requirements for formal patient acknowledgment of the conditional availability of the medicine, 'black-triangle' equivalent labels that identify full approval is based on pending evidence, and ongoing communication with the media, public and health professionals. PMID- 26483955 TI - Biodegradation kinetics and interactions of styrene and ethylbenzene as single and dual substrates for a mixed bacterial culture. AB - This study examined biodegradation kinetics of styrene and ethylbenzene as representatives of alkenylbenzenes and mono-alkylbenzenes, respectively. The compounds were studied independently and as binary mixtures using a series of aerobic batch degradation experiments introduced by acclimatized mix culture. Initial concentration of styrene and ethylbenzene in the liquid phase vacillated from 0 to 220 mg/l. The Andrew model was applied for the biodegradation of individual substrates and the estimated constants of the equation for styrene and ethylbenzene were MUmax = 0.1581, 0.2090 (1/h), KS =25.91, 37.77 (mg/L), KI =13.15, 62.62 (mg/L), respectively. The accomplished parameters from single substrate degradation tests were used to predict possible interaction factors achieved from dual substrate experiments. The Sum Kinetics with Interaction Parameters (SKIP) model and the purely competitive enzyme kinetics model were employed to evaluate any interactions. The SKIP model was found to accurately describe these interactions. Moreover, it was revealed that ethylbenzene plays an influential role on styrene consumption (e.g. IE,S = 1.64) compared to styrene which has insignificant inhibitory effect on ethylbenzene usage (e.g. IS,E =0.4) . The active site differences for styrene and ethylbenzene biodegradation and the pathway variations for biodegradation are among the major potential reasons for failure of the estimation that occurred in purely competitive kinetics model. This study is the first to calculate the interactions between styrene and ethylbenzene. PMID- 26483956 TI - Regulatory Elements in Vectors for Efficient Generation of Cell Lines Producing Target Proteins. AB - To date, there has been an increasing number of drugs produced in mammalian cell cultures. In order to enhance the expression level and stability of target recombinant proteins in cell cultures, various regulatory elements with poorly studied mechanisms of action are used. In this review, we summarize and discuss the potential mechanisms of action of such regulatory elements. PMID- 26483957 TI - PARP1 Inhibitors: antitumor drug design. AB - The poly (ADP-ribose) polymerase 1 (PARP1) enzyme is one of the promising molecular targets for the discovery of antitumor drugs. PARP1 is a common nuclear protein (1-2 million molecules per cell) serving as a "sensor" for DNA strand breaks. Increased PARP1 expression is sometimes observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. The PARP1 expression level is a prognostic indicator and is associated with a poor survival prognosis. There is evidence that high PARP1 expression and treatment-resistance of tumors are correlated. PARP1 inhibitors are promising antitumor agents, since they act as chemo- and radiosensitizers in the conventional therapy of malignant tumors. Furthermore, PARP1 inhibitors can be used as independent, effective drugs against tumors with broken DNA repair mechanisms. Currently, third-generation PARP1 inhibitors are being developed, many of which are undergoing Phase II clinical trials. In this review, we focus on the properties and features of the PARP1 inhibitors identified in preclinical and clinical trials. We also describe some problems associated with the application of PARP1 inhibitors. The possibility of developing new PARP1 inhibitors aimed at DNA binding and transcriptional activity rather than the catalytic domain of the protein is discussed. PMID- 26483953 TI - Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles. AB - Therapeutic effects of molecular hydrogen for a wide range of disease models and human diseases have been investigated since 2007. A total of 321 original articles have been published from 2007 to June 2015. Most studies have been conducted in Japan, China, and the USA. About three-quarters of the articles show the effects in mice and rats. The number of clinical trials is increasing every year. In most diseases, the effect of hydrogen has been reported with hydrogen water or hydrogen gas, which was followed by confirmation of the effect with hydrogen-rich saline. Hydrogen water is mostly given ad libitum. Hydrogen gas of less than 4 % is given by inhalation. The effects have been reported in essentially all organs covering 31 disease categories that can be subdivided into 166 disease models, human diseases, treatment-associated pathologies, and pathophysiological conditions of plants with a predominance of oxidative stress mediated diseases and inflammatory diseases. Specific extinctions of hydroxyl radical and peroxynitrite were initially presented, but the radical-scavenging effect of hydrogen cannot be held solely accountable for its drastic effects. We and others have shown that the effects can be mediated by modulating activities and expressions of various molecules such as Lyn, ERK, p38, JNK, ASK1, Akt, GTP Rac1, iNOS, Nox1, NF-kappaB p65, IkappaBalpha, STAT3, NFATc1, c-Fos, and ghrelin. Master regulator(s) that drive these modifications, however, remain to be elucidated and are currently being extensively investigated. PMID- 26483958 TI - Injured Nerve Regeneration using Cell-Based Therapies: Current Challenges. AB - This paper reviews the recent research progress in the past several years on promoting peripheral nerve recovery using stem and progenitory cells. The emphasis is placed on studies aimed at assessing various stem cells capable of expressing neurotrophic and growth factors and surviving after implantation in the nerve or a conduit. Approaches to improving nerve conduit design are summarized. The contribution of stem cells to axonal regeneration and neural repair is discussed. The side effects associated with cell-based treatment are highlighted. From the studies reviewed, it is concluded that the fate of transplanted stem cells needs further elucidation in a microenvironment-dependent manner. PMID- 26483960 TI - Additivity of the Stabilization Effect of Single Amino Acid Substitutions in Triple Mutants of Recombinant Formate Dehydrogenase from the Soybean Glycine max. AB - Recently, we demonstrated that the amino acid substitutions Ala267Met and Ala267Met/Ile272Val (Alekseeva et al., Biochemistry, 2012), Phe290Asp, Phe290Asn and Phe290Ser (Alekseeva et al., Prot. Eng. Des. Select, 2012) in recombinant formate dehydrogenase from soya Glycine max (SoyFDH) lead to a significant (up to 30-100 times) increase in the thermal stability of the enzyme. The substitutions Phe290Asp, Phe290Asn and Phe290Ser were introduced into double mutant SoyFDH Ala267Met/Ile272Val by site-directed mutagenesis. Combinations of three substitutions did not lead to a noticeable change in the catalytic properties of the mutant enzymes. The stability of the resultant triple mutants was studied through thermal inactivation kinetics and differential scanning calorimetry. The thermal stability of the new mutant SoyFDHs was shown to be much higher than that of their precursors. The stability of the best mutant SoyFDH Ala267Met/Ile272Val/Phe290Asp turned out to be comparable to that of the most stable wild-type formate dehydrogenases from other sources. The results obtained with both methods indicate a great synergistic contribution of individual amino acid substitutions to the common stabilization effect. PMID- 26483959 TI - Extracellular Nucleic Acids in Urine: Sources, Structure, Diagnostic Potential. AB - Cell-free nucleic acids (cfNA) may reach the urine through cell necrosis or apoptosis, active secretion of nucleic acids by healthy and tumor cells of the urinary tract, and transport of circulating nucleic acids (cir- NA) from the blood into primary urine. Even though urinary DNA and RNA are fragmented, they can be used to detect marker sequences. MicroRNAs are also of interest as diagnostic probes. The stability of cfNA in the urine is determined by their structure and packaging into supramolecular complexes and by nuclease activity in the urine. This review summarizes current data on the sources of urinary cfNA, their structural features, diagnostic potential and factors affecting their stability. PMID- 26483961 TI - Structural and Functional Characterization of Recombinant Isoforms of the Lentil Lipid Transfer Protein. AB - The recombinant isoforms Lc-LTP1 and Lc-LTP3 of the lentil lipid transfer protein were overexpressed in E. coli cells. It was confirmed that both proteins are stabilized by four disulfide bonds and characterized by a high proportion of the alpha-helical structure. It was found that Lc-LTP1 and Lc-LTP3 possess antimicrobial activity and can bind fatty acids. Both isoforms have the ability to bind specific IgE from sera of patients with food allergies, which recognize similar epitopes of the major peach allergen Pru p 3. Both isoforms were shown to have immunological properties similar to those of other plant allergenic LTPs, but Lc-LTP3 displayed a less pronounced immunoreactivity. PMID- 26483962 TI - The Use of Transcription Terminators to Generate Transgenic Lines of Chinese Hamster Ovary Cells (CHO) with Stable and High Level of Reporter Gene Expression. AB - Mammalian cell lines are widely used to produce recombinant proteins. Stable transgenic cell lines usually contain many insertions of the expression vector in one genomic region. Transcription through transgene can be one of the reasons for target gene repression after prolonged cultivation of cell lines. In the present work, we used the known transcription terminators from the SV40 virus, as well as the human beta- and gamma-globin genes, to prevent transcription through transgene. The transcription terminators were shown to increase and stabilize the expression of the EGFP reporter gene in transgenic lines of Chinese hamster ovary (CHO) cells. Hence, transcription terminators can be used to create stable mammalian cells with a high and stable level of recombinant protein production. PMID- 26483963 TI - The Same Synaptic Vesicles Originate Synchronous and Asynchronous Transmitter Release. AB - Transmitter release and synaptic vesicle exo- and endocytosis during high frequency stimulation (20 pulses/s) in the extracellular presence of different bivalent cations (Ca(2+), Sr2+ or Ba2+) were studied in frog cutaneous pectoris nerve-muscle preparations. It was shown in electrophysiological experiments that almost only synchronous transmitter release was registered in a Ca(2+)-containing solution; a high intensity of both synchronous and asynchronous transmitter release was registered in a Sr2+-containing solution, and asynchronous transmitter release almost only was observed in a Ba2+-containing solution. It was shown in experiments with a FM 1-43 fluorescent dye that the synaptic vesicles that undergo exocytosis-endocytosis during synchronous transmitter release (Ca-solutions) are able to participate in asynchronous exocytosis in Ba solutions. The vesicles that had participated in the asynchronous transmitter release (Ba-solutions) could subsequently participate in a synchronous release (Ca-solutions). It was shown in experiments with isolated staining of recycling and reserve synaptic vesicle pools that both types of evoked transmitter release originate from the same synaptic vesicle pool. PMID- 26483964 TI - Genomic Study of Cardiovascular Continuum Comorbidity. AB - Comorbidity or a combination of several diseases in the same individual is a common and widely investigated phenomenon. However, the genetic background for non-random disease combinations is not fully understood. Modern technologies and approaches to genomic data analysis enable the investigation of the genetic profile of patients burdened with several diseases (polypathia, disease conglomerates) and its comparison with the profiles of patients with single diseases. An association study featuring three groups of patients with various combinations of cardiovascular disorders and a control group of relatively healthy individuals was conducted. Patients were selected as follows: presence of only one disease, ischemic heart disease (IHD); a combination of two diseases, IHD and arterial hypertension (AH); and a combination of several diseases, including IHD, AH, type 2 diabetes mellitus (T2DM), and hypercholesterolemia (HC). Genotyping was performed using the "My Gene" genomic service (www.i gene.ru). An analysis of 1,400 polymorphic genetic variants and their associations with the studied phenotypes are presented. A total of 14 polymorphic variants were associated with the phenotype "IHD only," including those in the APOB, CD226, NKX2-5, TLR2, DPP6, KLRB1, VDR, SCARB1, NEDD4L, and SREBF2 genes, and intragenic variants rs12487066, rs7807268, rs10896449, and rs944289. A total of 13 genetic markers were associated with the "IHD and AH" phenotype, including variants in the BTNL2, EGFR, CNTNAP2, SCARB1, and HNF1A genes, and intragenic polymorphisms rs801114, rs10499194, rs13207033, rs2398162, rs6501455, and rs1160312. A total of 14 genetic variants were associated with a combination of several diseases of cardiovascular continuum (CVC), including those in the TAS2R38, SEZ6L, APOA2, KLF7, CETP, ITGA4, RAD54B, LDLR, and MTAP genes, along with intragenic variants rs1333048, rs1333049, and rs6501455. One common genetic marker was identified for the "IHD only" and "IHD and AH" phenotypes: rs4765623 in the SCARB1 gene; two common genetic markers, rs663048 in SEZ6L and intragenic rs6501455, were identified for the "IHD and AH" phenotype and a combination of several diseases (syntropy); there were no common genetic markers for the "syntropy" and "IHD only" phenotypes. Classificatory analysis of the relationships between the associated genes and metabolic pathways revealed that lipid-metabolizing genes are involved in the development of all three CVC variants, whereas immunity-response genes are specific to the "IHD only" phenotype. The study demonstrated that comorbidity presents additional challenges in association studies of disease predisposition, since the genetic profile of combined forms of pathology can be markedly different from those for isolated "single" forms of a disease. PMID- 26483965 TI - Regulation of Human Adenovirus Replication by RNA Interference. AB - Adenoviruses cause a wide variety of human infectious diseases. Adenoviral conjunctivitis and epidemic keratoconjunctivitis are commonly associated with human species D adenoviruses. Currently, there is no sufficient or appropriate treatment to counteract these adenovirus infections. Thus, there is an urgent need for new etiology-directed therapies with selective activity against human adenoviruses. To address this problem, the adenoviral early genes E1A and E2B (viral DNA polymerase) seem to be promising targets. Here, we propose an effective approach to downregulate the replication of human species D adenoviruses by means of RNA interference. We generated E1A expressing model cell lines enabling fast evaluation of the RNA interference potential. Small interfering RNAs complementary to the E1A mRNA sequences of human species D adenoviruses mediate significant suppression of the E1A expression in model cells. Furthermore, we observed a strong downregulation of replication of human adenoviruses type D8 and D37 by small hairpin RNAs complementary to the E1A or E2B mRNA sequences in primary human limbal cells. We believe that our results will contribute to the development of efficient anti-adenoviral therapy. PMID- 26483966 TI - The Novel Dipeptide Translocator Protein Ligand, Referred to As GD-23, Exerts Anxiolytic and Nootropic Activities. AB - The translocator protein (TSPO) promotes the translocation of cholesterol to the inner mitochondrial membrane and mediates steroid formation. In this study, we first report on a biological evaluation of the dipeptide GD-23 (N-carbobenzoxy-L tryptophanyl-L isoleucine amide), a structural analogue of Alpidem, the principal TSPO ligand. We show that GD-23 in a dose range of 0.05 to 0.5 mg/kg (i.p.) exhibits anxiolytic activity in the elevated plus maze test and nootropic activity in the object recognition test in scopolamine-induced amnesia in rodents. It was shown that GD-23 did not affect spontaneous locomotor activity, holding promise as a nonsedative anxiolytic agent. The anxiolytic and nootropic activities of GD-23 were abrogated by the TSPO specific ligand PK11195, which thus suggests a role for TSPO in mediating the pharmacological activity of GD-23. PMID- 26483967 TI - 5-Arylaminouracil Derivatives as Potential Dual-Action Agents. AB - Several 5-aminouracil derivatives that have previously been shown to inhibit Mycobacterium tuberculosis growth at concentrations of 5-40 MUg/mL are demonstrated to act also as noncompetitive non-nucleoside inhibitors of HIV-1 reverse transcriptase without causing toxicity in vitro (MT-4 cells) and ex vivo (human tonsillar tissue). PMID- 26483968 TI - Clonal rearrangements and Malignant Clones in Peripheral T-cell Lymphoma. AB - AIM: To assess the feasibility and informative value of T-cell clonality testing in peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS: Biopsies of involved sites, blood, and bone marrow samples from 30 PTCL patients are included in the study. Rearranged TCRG and TCRB gene fragments were PCR-amplified according to the BIOMED-2 protocol and analyzed by capillary electrophoresis on ABI PRISM 3130 (Applied Biosystems). RESULTS: TCRG and TCRB gene clonality assay was valuable in confirming diagnosis in 97% of PTCL patients. T-cell clonality assay performed on blood or bone marrow samples reaffirmed lymphoma in 93% of cases, whereas morphological methods were informative in 73% of cases only. We observed multiple TCRG and TCRB gene rearrangements, loss of certain clones in the course of the disease, as well as acquisition of new clones in 63% of PTCL cases, which can be attributed to the genetic instability of the tumor. CONCLUSION: TCRG and TCRB gene clonality assay is beneficial for the diagnosis of PTCL. However, the presence of multiple clonal rearrangements should be considered. Clonal evolution in PTCL, particularly acquisition of new clones, should not be treated as a second tumor. Multiple TCRG and TCRB gene rearrangements may interfere with minimal residual disease monitoring in PTCL. PMID- 26483969 TI - Internalization and Recycling of the HER2 Receptor on Human Breast Adenocarcinoma Cells Treated with Targeted Phototoxic Protein DARPinminiSOG. AB - Design and evaluation of new high-affinity protein compounds that can selectively and efficiently destroy human cancer cells are a priority research area in biomedicine. In this study we report on the ability of the recombinant phototoxic protein DARPin-miniSOG to interact with breast adenacarcinoma human cells overexpressing the extracellular domain of human epidermal growth factor receptor 2 (HER2). It was found that the targeted phototoxin DARPin-miniSOG specifically binds to the HER2 with following internalization and slow recycling back to the cell membrane. An insight into the role of DARPin-miniSOG in HER2 internalization could contribute to the treatment of HER2-positive cancer using this phototoxic protein. PMID- 26483970 TI - Apigenin Inhibits Growth of Breast Cancer Cells: The Role of ERalpha and HER2/neu. AB - Phytoestrogens are a group of plant-derived compounds with an estrogen-like activity. In mammalians, phytoestrogens bind to the estrogen receptor (ER) and participate in the regulation of cell growth and gene transcription. There are several reports of the cytotoxic effects of phytoestrogens in different cancer cell lines. The aim of this study was to measure the phytoestrogen activity against breast cancer cells with different levels of ER expression and to elucidate the molecular pathways regulated by the leader compound. Methods used in the study include immunoblotting, transfection with a luciferase reporter vector, and a MTT test. We demonstrated the absence of a significant difference between ER+ and ER- breast cancer cell lines in their response to cytotoxic stimuli: treatment with high doses of phytoestrogens (apigenin, genistein, quercetin, naringenin) had the same efficiency in ER-positive and ER-negative cells. Incubation of breast cancer cells with apigenin revealed the highest cytotoxicity of this compound; on the contrary, naringenin treatment resulted in a low cytotoxic activity. It was shown that high doses of apigenin (50 MUM) do not display estrogen-like activity and can suppress ER activation by 17beta estradiol. Cultivation of HER2-positive breast cancer SKBR3 cells in the presence of apigenin resulted in a decrease in HER2/neu expression, accompanied by cleavage of an apoptosis substrate PARP. Therefore, the cytotoxic effects of phytoestrogens are not associated with the steroid receptors of breast cancer cells. Apigenin was found to be the most effective phytoestrogen that strongly inhibits the growth of breast cancer cells, including HER2-positive ones. PMID- 26483971 TI - Lack of Association between Toxocara Exposure and Suicide Attempts in Psychiatric Patients. AB - Infection with Toxocara may affect the central nervous system. A high seroprevalence of Toxocara infection has been reported in psychiatric patients. To the best of our knowledge, there is no previous report about an association of Toxocara infection with suicide attempts. Therefore, we sought to determine whether Toxocara exposure is associated with suicide attempts in psychiatric patients. We studied 282 psychiatric outpatients (156 with suicide attempts and 126 without suicide attempts). Sera of patients were analyzed for the presence of anti-Toxocara IgG antibodies by using a commercially available enzyme immunoassay. One of the 156 (0.6%) suicide attempters and 1 (0.8%) of the 126 controls were positive for anti-Toxocara IgG antibodies (OR = 0.80; 95% CI: 0.04 13.02; P = 1.00). Toxocara seropositivity was significantly higher (P = 0.01) in male patients with consumption of raw dried goat meat than male patients without this consumption. Results suggest that Toxocara exposure is not associated with suicide attempts in psychiatric outpatients in Durango City, Mexico. However, further studies with larger samples sizes to confirm our results should be conducted. Too few patients were seropositive to assess further associations of Toxocara exposure with sociodemographic, clinical, and behavioral characteristics of the psychiatric patients. PMID- 26483972 TI - Posterior Corneal Surface Stability after Femtosecond Laser-Assisted Keratomileusis. AB - The purpose of this study was to evaluate posterior corneal surface variation after femtosecond laser-assisted keratomileusis in patients with myopia and myopic astigmatism. Patients were evaluated by corneal tomography preoperatively and at 1, 6, and 12 months. We analyzed changes in the posterior corneal curvature, posterior corneal elevation, and anterior chamber depth. Moreover, we explored correlation between corneal ablation depth, residual corneal thickness, percentage of ablated corneal tissue, and preoperative corneal thickness. During follow-up, the posterior corneal surface did not have a significant forward corneal shift: no significant linear relationships emerged between the anterior displacement of the posterior corneal surface and corneal ablation depth, residual corneal thickness, or percentage of ablated corneal tissue. PMID- 26483973 TI - A Comparison of Different Operating Systems for Femtosecond Lasers in Cataract Surgery. AB - The introduction of femtosecond lasers is potentially a major shift in the way we approach cataract surgery. The development of increasingly sophisticated intraocular lenses (IOLs), coupled with heightened patient expectation of high quality postsurgical visual outcomes, has generated the need for a more precise, highly reproducible and standardized method to carry out cataract operations. As femtosecond laser-assisted cataract surgery (FLACS) becomes more commonplace in surgical centers, further evaluation of the potential risks and benefits needs to be established, particularly in the medium/long term effects. Healthcare administrators will also have to weigh and balance out the financial costs of these lasers relative to the advantages they put forth. In this review, we provide an operational overview of three of five femtosecond laser platforms that are currently commercially available: the Catalys (USA), the Victus (USA), and the LDV Z8 (Switzerland). PMID- 26483974 TI - Excimer versus Femtosecond Laser Assisted Penetrating Keratoplasty in Keratoconus and Fuchs Dystrophy: Intraoperative Pitfalls. AB - Purpose. To assess the intraoperative results comparing two non-mechanical laser assisted penetrating keratoplasty approaches in keratoconus and Fuchs dystrophy. Patients and Methods. 68 patients (age 18 to 87 years) with keratoconus or Fuchs dystrophy were randomly distributed to 4 groups. 35 eyes with keratoconus and 33 eyes with Fuchs dystrophy were treated with either excimer laser ([Exc] groups I and II) or femtosecond laser-assisted ([FLAK] groups III and IV) penetrating keratoplasty. Main intraoperative outcome measures included intraoperative decentration, need for additional interrupted sutures, alignment of orientation markers, and intraocular positive pressure (vis a tergo). Results. Intraoperative recipient decentration occurred in 4 eyes of groups III/IV but in none of groups I/II. Additional interrupted sutures were not necessary in groups I/II but in 5 eyes of groups III/IV. Orientation markers were all aligned in groups I/II but were partly misaligned in 8 eyes of groups III/IV. Intraocular positive pressure grade was recognized in 12 eyes of groups I/II and in 19 eyes of groups III/IV. In particular, in group III, severe vis a tergo occurred in 8 eyes. Conclusions. Intraoperative decentration, misalignment of the donor in the recipient bed, and need for additional interrupted sutures as well as high percentage of severe intraocular positive pressure were predominantly present in the femtosecond laser in keratoconus eyes. PMID- 26483975 TI - The Correlation Analysis between Corneal Biomechanical Properties and the Surgically Induced Corneal High-Order Aberrations after Small Incision Lenticule Extraction and Femtosecond Laser In Situ Keratomileusis. AB - Background. To investigate the correlation between corneal biomechanics and the surgically induced corneal high-order aberrations (HOAs) after small incision lenticule extraction (SMILE) and femtosecond laser in situ keratomileusis (FS LASIK). Methods. A total of 150 right myopic eyes that underwent SMILE or FS LASIK surgery were included in this retrospective study, 75 eyes in each group. The corneal hysteresis (CH) and the corneal resistance factor (CRF) with the corneal HOAs of the anterior, posterior, and total cornea were assessed preoperatively and three months postoperatively. Multivariate linear regression was applied to determine the correlations. Results. The preoperative CRF was significantly correlated with the induced 3rd-6th-order HOAs and spherical aberration of the anterior surface and the total cornea after SMILE and FS-LASIK surgeries (P < 0.05), postoperatively. The CRF was significantly correlated with the induced vertical coma of the anterior and posterior surfaces and the total cornea after SMILE surgery (P < 0.05). There was a significant correlation between the CRF and the induced posterior corneal horizontal coma after FS-LASIK surgery (P = 0.013). Conclusions. The corneal biomechanics affect the surgically induced corneal HOAs after SMILE and FS-LASIK surgery, which may be meaningful for screening the patients preoperatively and optimizing the visual qualities postoperatively. PMID- 26483976 TI - The Association between Patient-Reported Pain and Doctors' Language Proficiency in Clinical Practice. AB - Patients' limited literacy and language fluency of different kinds cause them problems in navigating the medical interview. However, it is not known how physicians' native language skills affect the reported intensity of pain among Finnish emergency patients. Data were collected with two consecutive questionnaires in 16 healthcare centres and outpatient departments along the Finnish coast. Swedish and Finnish speaking 18-65-year-old emergency patients were eligible for this study. Our patients were predominantly Finnish speakers. Patient-rated poor language skills in Finnish among the physicians in ED setting increased statistically significantly pain reported by the Finnish speaking patients and their dissatisfaction with the health service. These patients were also less motivated to adhere to the instructions given by their physician. Patients speaking various languages reported less degree of pain. Foreign physicians' poor language proficiency in Finnish was expected to explain only some of the patients' pain experience. Physicians' good native language skills may help to reduce pain experience. Despite concordant language communication, other unknown barriers in the interaction might reduce the magnitude of pain reported. PMID- 26483977 TI - Corrigendum to "Development of a Tool to Identify Poverty in a Family Practice Setting: A Pilot Study". AB - [This corrects the article DOI: 10.1155/2011/812182.]. PMID- 26483979 TI - Periodic Breathing and Behavioral Awakenings at High Altitude. AB - Objectives. To study the relationship between nocturnal periodic breathing episodes and behavioral awakenings at high altitude. Methods. Observational study. It is 6-day ascent of 4 healthy subjects from Besisahar (760 meters) to Manang (3540 meters) in Nepal in March 2012. A recording pulse oximeter was worn by each subject to measure their oxygen saturation and the presence of periodic breathing continuously through the night. An actigraph was simultaneously worn in order to determine nocturnal behavioral awakenings. There were no interventions. Results. 187-hour sleep at high altitude was analyzed, and of this, 145 hours (78%) had at least one PB event. At high altitude, 10.5% (95% CI 6.5-14.6%) of total sleep time was spent in PB while 15 out of 50 awakenings (30%, 95% CI: 18 45%) occurring at high altitudes were associated with PB (P < 0.001). Conclusions. Our data reveals a higher than expected number of behavioral awakenings associated with PB compared to what would be expected by chance. This suggests that PB likely plays a role in behavioral awakenings at high altitude. PMID- 26483980 TI - The Angle of Progression at Station 0 and in Magnetic Resonance and Transperineal Ultrasound Assessment. AB - The transperineal ultrasound (TPU) value of the angle of progression (AOP) during fetal head engagement, at station 0, is a critical cut-off for current obstetrical practice, especially when intrapartum instrumental interventions are required. Still, controversial measurements were reported in previous high resolution imagistic studies. Our TPU and direct "gold-standard" magnetic resonance (MRI) measurements confirm that station 0 corresponds to a 120 degrees AOP, concordantly. Based on these findings, the fact that an AOP of 120 degrees or greater was previously strongly associated with vaginal delivery may be due to the achievement of head engagement in labor. PMID- 26483978 TI - Neuroimaging of Natalizumab Complications in Multiple Sclerosis: PML and Other Associated Entities. AB - Natalizumab (Tysabri) is a monoclonal antibody (alpha4 integrin antagonist) approved for treatment of multiple sclerosis, both for patients who fail therapy with other disease modifying agents and for patients with aggressive disease. Natalizumab is highly effective, resulting in significant decreases in rates of both relapse and disability accumulation, as well as marked decrease in MRI evidence of disease activity. As such, utilization of natalizumab is increasing, and the presentation of its associated complications is increasing accordingly. This review focuses on the clinical and neuroimaging features of the major complications associated with natalizumab therapy, focusing on the rare but devastating progressive multifocal leukoencephalopathy (PML). Associated entities including PML associated immune reconstitution inflammatory syndrome (PML-IRIS) and the emerging phenomenon of rebound of MS disease activity after natalizumab discontinuation are also discussed. Early recognition of neuroimaging features associated with these processes is critical in order to facilitate prompt diagnosis, treatment, and/or modification of therapies to improve patient outcomes. PMID- 26483981 TI - Preterm Delivery in the Setting of Left Calyceal Rupture. AB - Spontaneous rupture of the renal collecting system is a rare but serious complication of pregnancy. We report a case of nontraumatic left renal calyceal rupture in a pregnancy which ultimately progressed to preterm delivery. A 29-year old primigravida with a remote history of urolithiasis presented with left flank pain, suprapubic pain, and signs of preterm labor at 33 weeks of gestation. The patient was believed to have urolithiasis, although initial renal ultrasound failed to demonstrate definitive calculi. After a temporary improvement in flank pain with medication, the patient experienced acute worsening of her left flank pain. Urology was consulted and further imaging was obtained. Magnetic resonance imaging (MRI) was consistent with bilateral hydronephrosis and rupture of the left renal calyx. Given the patient's worsening pain in the setting of left calyceal rupture, the urology team planned for placement of a left ureteral stent. However, before the patient could receive her stent, she progressed to active labor and delivered a viable female infant vaginally. Following delivery, the patient's flank pain resolved rapidly and spontaneously, so no surgical intervention was performed. A summary of the literature and the details of this specific clinical situation are provided. PMID- 26483982 TI - Sporadic Multifocal Venous Malformations of the Head and Neck. AB - Objective. To report a case of unusually widespread sporadic venous malformations of the head and neck associated with normal D-dimer levels and, due to the protean clinical manifestations and increased risk of coagulopathy of these lesions, to review their diagnosis and clinical management. Case Report. A 25 year-old man presented with a one-year history of intermittent right-sided neck swelling and tongue swelling. Physical exam revealed additional lesions present throughout the head and neck. There was no family history suggestive of heritable vascular malformations. Radiographic imaging demonstrated 15 lesions located in various tissue layers consistent with venous malformations. A coagulation screen showed a normal prothrombin time, activated partial thromboplastin time, international normalized ratio, D-dimer level, and fibrinogen level. It was determined that the patient was not at increased risk for intraoperative coagulopathy and preoperative heparin administration would not be necessary. The patient's buccal and tongue lesions were subsequently excised with no complications. The patient also underwent sclerotherapy evaluation for his neck mass. Conclusion. This case describes a unique presentation of sporadic multifocal venous malformations. It also emphasizes the importance of prompt diagnosis and workup when multiple venous malformations are present to prevent morbidity during surgical excision secondary to intravascular coagulopathy. PMID- 26483983 TI - Eumycetoma Osteomyelitis of the Calcaneus in a Child: A Radiologic-Pathologic Correlation following Total Calcanectomy. AB - Fungi are unusual causes of pedal osteomyelitis in children and adolescents. Eumycetoma is a chronic cutaneous and subcutaneous infection caused by various genera of fungi. A provisional diagnosis of foot mycetoma is made after clinical assessment. Radiologic-pathologic correlation is an essential supplement for the accurate diagnosis of osteoarticular infections. This paper aims to sensitize orthopedic surgeons, radiologists, and pathologists to the importance of correlative imaging findings in relation to surgical and microscopic pathology in osteoarticular infections, specifically eumycetoma osteomyelitis of the foot. From our review of the published data, the present case is the first report of radiologic-pathologic correlation in eumycetoma osteomyelitis of the calcaneus. This paper describes a case of eumycetoma osteomyelitis of the calcaneus in a child in which diagnostic X-rays and magnetic resonance imaging (MRI) were correlated with the surgical and microscopic pathologic features, for establishing an appropriate diagnosis and treatment. We conclude that there is a significant agreement between radiologic and pathologic evaluation for assessment of eumycetoma osteomyelitis of the calcaneus. Radiologic-pathologic correlation amplified our interpretation of imaging information available on plain radiographs and MRI and augmented diagnostic confidence. Similarly, anatomic histopathological correlations consolidated diagnostic accuracy. PMID- 26483984 TI - Comorbidity of Obsessive-Compulsive Disorder and Schizophrenia in an Adolescent. AB - We report a case of a girl with a history of obsessive-compulsive disorder (OCD) subsequently exhibiting psychosis. She never attained remission since the outset. Initially she seemed to be resistant to most antipsychotics, namely, risperidone, haloperidol, paliperidone, quetiapine, and clozapine. However, she later responded remarkably better to risperidone after it was reintroduced for the second time. Recognizing and understanding the various pathogenesis of OCD or obsessive-compulsive symptoms (OCS) in schizophrenia are vital in laying out plan to manage the patient effectively. PMID- 26483985 TI - Testicular Interposition Flap for Repair of Perineal Urinary Fistulae: A Novel Surgical Technique. AB - Rectourinary fistulae and urinary-cutaneous fistulae are a rare yet devastating complication. Current options for tissue interposition include rectus, gracilis, or gluteal muscle, omentum, or intestine for use in coloanal pull-through procedures. In elderly patients, testicular interposition flaps may be an excellent tissue option to use when vitalized tissue is necessary to supplement fistula repair. Elderly patients frequently have increased spermatic cord length, potentially offering a longer flap reach than use of a muscle flap. Additionally, mobilizing one of the testicles and developing it through the external inguinal ring may be a less morbid and less costly procedure than harvesting and tunneling a muscle flap. Longer follow-up and further studies are needed to determine the outcomes of this novel technique. PMID- 26483986 TI - Improving Consumer Satisfaction with Addiction Treatment: An Analysis of Alumni Preferences. AB - Objective. The primary objective of this investigation is to determine which individual and aggregate factors of residential addiction treatment centers are most significant influencers of alumni satisfaction. Design. Survey targeted alumni of residential addiction treatment facilities. Alumni were queried through a survey, which utilized Likert-scale matrices and binary response options: 379 respondents met the completion threshold. Alumni rated amenities and individual and group counseling factors; additionally, respondents provided feedback on two satisfaction proxies: cost worthiness and future recommendations. Descriptive and relational analyses were conducted, with the latter utilizing logistic regression models. Results. Individual factors' scores of group counseling, and overall aggregate group counseling score, are most enthusiastically positive. Group counseling is also the most significant influencer of satisfaction. Other significant influencers of satisfaction are met expectations for individual counseling and psychiatric care offerings. Conclusions. While individual counseling and facility amenities should not be ignored, group counseling may be the most significant influencer of alumni satisfaction. Long-term outcomes are not single-faceted; however, treatment providers should be encouraged to invest in high-quality group counseling offerings in order to best satisfy, and thereby empower, clients. PMID- 26483987 TI - Human Papilloma Virus Associated Squamous Cell Carcinoma of the Head and Neck. AB - Oral cancer is one of the commonest causes for mortality and morbidity with squamous cell carcinoma being the sixth most frequent malignant tumour worldwide. In addition to tobacco and alcohol, human papilloma virus (HPV) is associated with a proportion of head and neck cancers. As in cervical cancers, HPV types 16 and 18 are the cause of malignant transformation. HPV-positive cancers of head and neck have unique characteristics such as occurrence in a younger age group, distinct clinical and molecular features, and better prognosis as compared to HPV negative carcinomas. They also possess the potential for prevention by using vaccination. The present review describes in detail the salient features of HPV associated oral squamous cell carcinoma (OSCC), its differences from HPV-negative OSCC, diagnostic features, and recent strategies in prevention and management. PMID- 26483988 TI - Potential Biomarkers of the Earliest Clinical Stages of Parkinson's Disease. AB - Parkinson's disease (PD) is a widespread neurodegenerative disorder. Despite the intensive studies of this pathology, in general, the picture of the etiopathogenesis has still not been clarified fully. To understand better the mechanisms underlying the pathogenesis of PD, we analyzed the expression of 10 genes in the peripheral blood of treated and untreated patients with PD. 35 untreated patients with PD and 12 treated patients with Parkinson's disease (Hoehn and Yahr scores 1-2) were studied. An analysis of the mRNA levels of ATP13A2, PARK2, PARK7, PINK1, LRRK2, SNCA, ALDH1A1, PDHB, PPARGC1A, and ZNF746 genes in the peripheral blood of patients was carried out using reverse transcription followed by real-time PCR. A statistically significant and specific increase by more than 1.5-fold in the expression of the ATP13A2, PARK7, and ZNF746 genes was observed in patients with PD. Based on these results, it can be suggested that the upregulation of the mRNA levels of ATP13A2, PARK7, and ZNF746 in untreated patients in the earliest clinical stages can also be observed in the preclinical stages of PD, and that these genes can be considered as potential biomarkers of the preclinical stage of PD. PMID- 26483989 TI - Febrile Illness with Skin Rashes. AB - Skin rashes that appear during febrile illnesses are in fact caused by various infectious diseases. Since infectious exanthematous diseases range from mild infections that disappear naturally to severe infectious diseases, focus on and basic knowledge of these diseases is very important. But, these include non infectious diseases, so that comprehensive knowledge of these other diseases is required. Usually, early diagnostic testing for a febrile illness with a rash is inefficient. For clinical diagnosis of diseases accompanied by skin rash and fever, a complete history must be taken, including recent travel, contact with animals, medications, and exposure to forests and other natural environments. In addition, time of onset of symptoms and the characteristics of the rash itself (morphology, location, distribution) could be helpful in the clinical diagnosis. It is also critical to understand the patient's history of specific underlying diseases. However, diagnostic basic tests could be helpful in diagnosis if they are repeated and the clinical course is monitored. Generally, skin rashes are nonspecific and self-limited. Therefore, it could be clinically meaningful as a characteristic diagnostic finding in a very small subset of specific diseases. PMID- 26483990 TI - Detection of Carbapenemases in Clinical Enterobacteriaceae Isolates Using the VITEK AST-N202 Card. AB - BACKGROUND: The rapid and accurate detection of carbapenemase-producing Enterobacteriaceae (CPE) in clinical microbiology laboratories is essential for the treatment and control of infections caused by these microorganisms. This study was performed to evaluate the ability of the VITEK AST-N202 card to detect CPE isolates. MATERIALS AND METHODS: A total of 43 (Klebsiella pneumoniae, n = 37; Escherichia coli, n = 3; and Enterobacter cloacae, n = 3) CPE isolates and 79 carbapenemase-non-producing Enterobacteriaceae (CNE) isolates were included in this study. The CPE isolates harbored KPC-2 (n = 11), KPC-3 (n = 20), GES-5 (n = 5), VIM-2 (n = 2), IMP-1 (n = 1), NDM-1 (n = 2), or OXA-232 (n = 2). Of the 79 CNE isolates, eight K. pneumoniae isolates were resistant to ertapenem, imipenem, and meropenem, while the remaining 71 isolates were susceptible to the carbapenems. Antimicrobial susceptibilities were tested using the VITEK AST-N202 card, and the results were interpreted as positive when the isolates showed resistant or intermediate results. Modified-Hodge tests (MHTs) were performed using ertapenem or meropenem disks for the screening of carbapenemase production. Polymerase chain reaction (PCR) and direct sequencing were used to identify beta lactamase genes. RESULTS: Sensitivity of MHT with ertapenem and meropenem disks for the detection of carbapenemase was 81.4% (35/43) and 81.4% (35/43), respectively, and a combination with both antibiotic disks increased the sensitivity to 88.4% (38/43). Specificity of the MHT was 100% (79/79) for the CNE isolates. Sensitivity of ertapenem, imipenem, and meropenem as assessed by the VITEK AST-N202 card was 100% (43/43), 93% (40/43), and 95.3% (41/43), respectively. Specificity (89.8%, 71/79) of the test with each carbapenem was improved to 100% (71/71) when eight carbapenem-resistant CNE isolates were excluded from the testing. CONCLUSION: The VITEK AST-N202 card showed high sensitivity for the detection of carbapenemases in Enterobacteriaceae strains. PCR and sequencing experiments for the detection of carbapenemases are recommended when clinical Enterobacteriaceae isolates show non-susceptibility to carbapenems. PMID- 26483992 TI - Human Anaplasmosis in Acute Febrile Patients during Scrub Typhus Season in Korea. PMID- 26483991 TI - In vitro Antibacterial Activity of Doripenem against Gram-Negative Blood Isolates in a Korean Tertiary Care Center. AB - BACKGROUND: Doripenem is the most recently introduced antimicrobial agent of the carbapenem class. It is a valuable therapeutic option in the context of increasing antimicrobial resistance to imipenem and meropenem among gram-negative bacilli (GNB) clinical isolates. However, clinicians are usually reluctant to prescribe doripenem, because susceptibility to doripenem is not automatically reported by most clinical laboratories and the in vitro activity of doripenem against clinically significant GNB isolates remains uncertain. MATERIALS AND METHODS: We investigated the in vitro antibacterial activity of doripenem in GNB blood isolates in a tertiary care center. Over a period of 10 months, 212 adult bacteremia cases were treated at the study hospital. Doripenem susceptibility testing was performed for the 212 blood isolates by the disk diffusion method, and clinical data were collected. RESULTS: Among the blood isolates, the rate of doripenem resistance (7.5%) was lower than that of imipenem (12.9%) or other anti GNB antimicrobial agents, except amikacin (2.1%). Almost all imipenem-susceptible GNB blood isolates (181/182, 99.5%) were susceptible to doripenem. Whereas doripenem resistance was rarely observed in Enterobacteriaceae (2/181, 1.1%), it was frequently observed in patients with non-fermentatative GNB (12/27, 44.4%), hospital-acquired infections (7/27, 25.9%), and pneumonia (11/49, 22.4%). CONCLUSION: Doripenem exhibited more potent in vitro activity against GNB blood isolates than other anti-GNB antimicrobial agents in a tertiary care center where it was infrequently prescribed compared with other carbapenems. However, its clinical utility may be limited due to the increasing number of carbapenem resistant non-fermentative GNB infections. PMID- 26483993 TI - A Case of Recurrent Meningitis Caused by Rhodococcus species Successfully Treated with Antibiotic Treatment and Intrathecal Injection of Vancomycin through an Ommaya Reservoir. AB - Human infection by Rhodococcus species is rare and mostly limited to immunocompromised hosts such as patients infected with the human immunodeficiency virus (HIV) or organ transplant recipients. The most common strain is R. equi, and the most common clinical presentation is pulmonary infection, reported in 80% of Rhodococcus spp. infections. The central nervous system is an uncommon infection site. We report a case of a patient with pneumonia, brain abscess, and recurrent meningitis caused by Rhodococcus spp. He initially presented with pneumonia with necrosis, which progressed to brain abscess and recurrent meningitis. Rhodococcus spp. was identified from the cerobrospinal fluid (CSF) collected during his fourth hospital admission. Despite prolonged treatment with appropriate antibiotics, meningitis recurred three times. Finally, in order to administer antibiotics directly into the CSF and bypass the blood-brain barrier, an Ommaya reservoir was inserted for administration of 90 days of intrathecal vancomycin and amikacin in conjunction with intravenous and oral antibiotics; the patient was finally cured with this treatment regimen. PMID- 26483994 TI - FDG PET-CT in the Diagnosis of Takayasu Arteritis Presenting as Fever of Unknown Origin: A Case Report. AB - Takayasu arteritis is a chronic vasculitis involving the large vessels. At diagnosis, ischemic symptom are usually present in the affected vessels. However, fever of unknown origin (FUO) is rare as an initial presentation and renders the condition difficult to diagnose. In this case report, we describe a patient who presented with a fever of unknown origin. A 68-year-old female was diagnosed with Takayasu arteritis after fluorodeoxyglucose (FDG) positron-emission tomography computed tomography (PET-CT) was performed at the prepulseless stage. FDG PET-CT can assist in the early diagnosis of Takayasu arteritis patients with FUO and can improve the prognosis of such patients. PMID- 26483995 TI - Infectious Spondylitis with Bacteremia Caused by Roseomonas mucosa in an Immunocompetent Patient. AB - Roseomonas are a gram-negative bacteria species that have been isolated from environmental sources. Human Roseomonas infections typically occur in immunocompromised patients, most commonly as catheter-related bloodstream infections. However, Roseomonas infections are rarely reported in immunocompetent hosts. We report what we believe to be the first case in Korea of infectious spondylitis with bacteremia due to Roseomonas mucosa in an immunocompetent patient who had undergone vertebroplasty for compression fractures of his thoracic and lumbar spine. PMID- 26483996 TI - Pertussis Accompanying Recent Mycoplasma Infection in a 10-Year-Old Girl. AB - Recently, the incidence of pertussis has been increasing; however, reports on mixed infection of pertussis with other respiratory pathogens are rare in highly immunized populations. We report the case of a 10-year-old girl who presented with cough, post-tussive emesis, and fever. She was subsequently diagnosed with bronchopneumonia. Although she had received five doses of diphtheria-tetanus acellular pertussis vaccine, polymerase chain reaction of her nasopharyngeal aspirate confirmed Bordetella pertussis infection. In addition, serologic testing for Mycoplasma pneumoniae was also positive. The patient was treated with roxithromycin without any complications. This is the first report of mixed B. pertussis and M. pneumoniae infection in Korea. To avoid under-diagnosis, pertussis should be considered in patients with chronic cough even when other respiratory pathogens have been documented. PMID- 26483997 TI - Optimal Diagnosis and Treatment of Group A Streptococcal Pharyngitis. PMID- 26483998 TI - The 2015 Clinical Guidelines for the Diagnosis and Treatment of HIV/AIDS in HIV Infected Koreans. AB - The Committee for Clinical Guidelines for the Diagnosis and Treatment of HIV/AIDS of the Korean Society for AIDS was founded in 2010. The first edition of the Korean guidelines was published in 2011, and revised in 2013. The recommendations in the guideline contain important information for physicians working with HIV/AIDS in the clinical field. However, due to the rapid discovery of new data in the field of HIV and the evolution of the clinical environment in Korea, it has become necessary to revise the guideline again. This guideline aims to provide up-to-date comprehensive information regarding the diagnosis and management of HIV/AIDS in Korea. This guideline deals with issues regarding the initial assessment of newly diagnosed patients, timing of antiretroviral treatment (ART) initiation, preferred ART regimens in treatment-naive as well as treatment-experienced patients and special populations such as HBV/HCV co infected patients, or pregnant women. A brief summary of the revised guidelines and key changes to the original version of the guidelines are summarized below. PMID- 26483999 TI - Antiviral Treatment Guidelines for Middle East Respiratory Syndrome. AB - Middle East respiratory syndrome (MERS) is an acute infectious disease of the respiratory system caused by the new betacoronavirus (MERS coronavirus, MERS CoV), which shows high mortality rates. The typical symptoms of MERS are fever, cough, and shortness of breath, and it is often accompanied by pneumonia. The MERS-CoV was introduced to Republic of Korea in May 2015 by a patient returning from Saudi Arabia. The disease spread mostly through hospital infections, and by the time the epidemic ended in August, the total number of confirmed diagnoses was 186, among which 36 patients died. Reflecting the latest evidence for antiviral drugs in the treatment of MERS-CoV infection and the experiences of treating MERS patients in Republic of Korea, these guidelines focus on antiviral drugs to achieve effective treatment of MERS-CoV infections. PMID- 26484000 TI - Erratum: Vaccination guideline for Immigrant in Korea by Korean Society of Infectious Diseases. AB - [This corrects the article on p. 145 in vol. 47, PMID: 26157598.]. PMID- 26484001 TI - Dysphagia Management in Acute and Sub-acute Stroke. AB - Swallowing dysfunction is common after stroke. More than 50% of the 665 thousand stroke survivors will experience dysphagia acutely of which approximately 80 thousand will experience persistent dysphagia at 6 months. The physiologic impairments that result in post-stroke dysphagia are varied. This review focuses primarily on well-established dysphagia treatments in the context of the physiologic impairments they treat. Traditional dysphagia therapies including volume and texture modifications, strategies such as chin tuck, head tilt, head turn, effortful swallow, supraglottic swallow, super-supraglottic swallow, Mendelsohn maneuver and exercises such as the Shaker exercise and Masako (tongue hold) maneuver are discussed. Other more recent treatment interventions are discussed in the context of the evidence available. PMID- 26484002 TI - Corrigendum. AB - [This corrects the article DOI: 10.4161/rdis.26314.]. PMID- 26484004 TI - Percutaneous Transforaminal Lumbar Interbody Fusion (pTLIF) with a Posterolateral Approach for the Treatment of Denegerative Disk Disease: Feasibility and Preliminary Results. AB - BACKGROUND: Interbody fusion by open discectomy is the usual treatment for degenerative disk disease but requires a relatively long recovery period. The transforaminal posterolateral approach is a well-known standard in endoscopic spine surgery that allows direct access to the disk with progressive tissue dilation. The aim of this study was to assess the feasibility of percutaneous transforaminal interbody fusion (pTLIF) with insertion of an expandable or a standard rigid interbody implant for patients with degenerative disk disease with or without spondylolisthesis and for revision surgery. METHODS: Between 2009 and 2014, the pTLIF procedure was performed in 30 patients. Ten patients underwent insertion of a rigid implant (group A) and the remaining 20 underwent insertion of an expandable titanium interbody implant as the initial procedure (n = 10) (group B) or after failed back surgery (n = 10) (group C). Patient outcomes were scored with visual analogic scale (VAS), Oswestry disability index (ODI) and modified Macnab criteria. RESULTS: The mean follow-up period was 38 (17) (range 11 to 67) months. The outcome was excellent in 18, good in 10 and fair in 2. No poor results and no major complications were reported. No differences in VAS and ODI scores according to the study group were found. Median postoperative time until hospital discharge was 26 hours (20 to 68 hours). Postoperative values for VAS and ODI scores improved significantly (p<0.05) compared to preoperative data in all study groups. CONCLUSIONS: These preliminary results have shown the feasibility and efficacy of the pTLIF procedure using a posterolateral approach for the treatment of degenerative disk disease with or without spondylolisthesis up to grade 2 and in revision surgery. No significant differences in outcome were observed between an expandable and a rigid cage. Median postoperative time until hospital discharge was faster compared to standard TLIF (26 hours vs. 9.3 days). PMID- 26484006 TI - Placement of C1 Pedicle Screws Using Minimal Exposure: Radiographic, Clinical, and Literature Validation. AB - BACKGROUND: Traditional C1-2 fixation involves placement of C1 lateral mass screws. Evolving techniques have led to the placement of C1 pedicle screws to avoid exposure of the C1-C2 joint capsule. Our minimal dissection technique utilizes anatomical landmarks with isolated exposure of C2 and the inferior posterior arch of C1. We evaluate this procedure clinically and radiographically through a technical report. METHODS: Consecutive cases of cranial-vertebral junction surgery were reviewed for one fellowship trained spinal surgeon from 2008-2014. Information regarding sex, age, indication for surgery, private or public hospital, intra-operative complications, post-operative neurological deterioration, death, and failure of fusion was extracted. Measurement of pre operative axial and sagittal CT scans were performed for C1 pedicle width and C1 posterior arch height respectively. RESULTS: 64 patients underwent posterior cranio-vertebral junction fixation surgery. 40 of these patients underwent occipital-cervical fusion procedures. 7/9 (77.8%) C1 instrumentation cases were from trauma with the remaining two (22.2%) from oncologic lesions. The average blood loss among isolated C1-C2 fixation was 160cc. 1/9 patients (11.1%) suffered pedicle breech requiring sub-laminar wiring at the C1 level. On radiographic measurement, the average height of the C1 posterior arch was noted at 4.3mm (range 3.8mm to 5.7mm). The average width of the C1 pedicle measured at 5.3mm (range 2.8 to 8.7mm). The patient with C1 pedicle screw failure had a pedicle width of 2.78mm on pre-operative axial CT imaging. CONCLUSION: Our study directly adds to the literature with level four evidence supporting a minimal dissection of C1 arch in the placement of C1 pedicle screws with both radiographic and clinical validation. CLINICAL RELEVANCE: Justification of this technique avoids C2 nerve root manipulation or sacrifice, reduces bleeding associated with the venous plexus, and leaves the third segment of the vertebral artery unexplored. Pre-operative review of imaging is critical in the placement of C1-C2 instrumentation. PMID- 26484005 TI - A Review of Symptomatic Lumbosacral Transitional Vertebrae: Bertolotti's Syndrome. AB - BACKGROUND: Lumbosacral transitional vertebrae (LSTV) are increasingly recognized as a common anatomical variant associated with altered patterns of degenerative spine changes. This review will focus on the clinical significance of LSTV, disruptions in normal spine biomechanics, imaging techniques, diagnosis, and treatment. METHODS: A Pubmed search using the specific key words "LSTV," "lumbosacral transitional vertebrae," and "Bertolotti's Syndrome" was performed. The resulting group of manuscripts from our search was evaluated. RESULTS: LSTV are associated with alterations in biomechanics and anatomy of spinal and paraspinal structures, which have important implications on surgical approaches and techniques. LSTV are often inaccurately detected and classified on standard AP radiographs and MRI. The use of whole-spine images as well as geometric relationships between the sacrum and lumbar vertebra increase accuracy. Uncertainty regarding the cause, clinical significance, and treatment of LSTV persists. Some authors suggest an association between LSTV types II and IV and low back pain. Pseudoarticulation between the transverse process and the sacrum creates a "false joint" susceptible to arthritic changes and osteophyte formation potentially leading to nerve root entrapment. The diagnosis of symptomatic LSTV is considered with appropriate patient history, imaging studies, and diagnostic injections. A positive radionuclide study along with a positive effect from a local injection helps distinguish the transitional vertebra as a significant pain source. Surgical resection is reserved for a subgroup of LSTV patients who fail conservative treatment and whose pain is definitively attributed to the anomalous pseudoarticulation. CONCLUSIONS: Due to the common finding of low back pain and the wide prevalence of LSTV in the general population, it is essential to differentiate between symptoms originating from an anomalous psuedoarticulation from other potential sources of low back pain. Further studies with larger sample sizes and longer follow-up time would better demonstrate the effectiveness of surgical resection and help guide treatment. PMID- 26484007 TI - Painless squeaking following cervical disc replacement: A case report. AB - BACKGROUND: We present a case of painless squeaking following cervical disc replacement which to our knowledge has not previously been reported in the literature. METHODS: A 45 year old gentleman presented with severe right sided C6 radiculopathy. He complained of more than 6 weeks of severe dysaesthesia in the right arm with pain radiating into the hand, thumb, index, middle and ring fingers. MRI confirmed severe impingement of C6 and C7 nerve roots. After trying a period of conservative treatment he underwent anterior cervical decompression with total cervical disc replacement of C5-6 and C6-7. RESULTS: Being a keen athlete he started running at 6 months post operatively. At his 12 month outpatient he presented us with an audio file containing squeaking from his neck. This was recorded immediately following a 9.5 mile hard surface run. The squeak got progressively less in intensity over 12 hours and disappeared after 24 hours. All instances of squeaking occurred after exercise where impact (running) or vibration (cycling) took place. This was first noticed 6 months post operatively when he restarted exercising. All episodes were completely painless. At his 18 month outpatient review the squeaking had reduced in frequency and intensity. At his 24 month review it had abated completely. CONCLUSION: The aetiology of this painless squeaking has been elusive and is likely to be multifactorial. However we hypothesise that the audible squeak associated with the prestige LP disc maybe related to specific design characteristics and needs further evaluation. PMID- 26484008 TI - Hybrid Surgery Combined with Dynamic Stabilization System and Fusion for the Multilevel Degenerative Disease of the Lumbosacral Spine. AB - BACKGROUND: As motion-preserving technique has been developed, the concept of hybrid surgery involves simultaneous application of two different kinds of devices, dynamic stabilization system and fusion technique. In the present study, the application of hybrid surgery for lumbosacral degenerative disease involving two-segments and its long-term outcome were investigated. METHODS: Fifteen patients with hybrid surgery (Hybrid group) and 10 patients with two-segment fusion (Fusion group) were retrospectively compared. RESULTS: Preoperative grade for disc degeneration was not different between the two groups, and the most common operated segment had the most degenerated disc grade in both groups; L4-5 and L5-S1 in the Hybrid group, and L3-4 and L4-5 in Fusion group. Over 48 months of follow-up, lumbar lordosis and range of motion (ROM) at the T12-S1 global segment were preserved in the Hybrid group, and the segmental ROM at the dynamic stabilized segment maintained at final follow-up. The Fusion group had a significantly decreased global ROM and a decreased segmental ROM with larger angles compared to the Hybrid group. Defining a 2-mm decrease in posterior disc height (PDH) as radiologic adjacent segment pathology (ASP), these changes were observed in 6 and 7 patients in the Hybrid and Fusion group, respectively. However, the last PDH at the above adjacent segment had statistically higher value in Hybrid group. Pain score for back and legs was much reduced in both groups. Functional outcome measured by Oswestry disability index (ODI), however, had better improvement in Hybrid group. CONCLUSION: Hybrid surgery, combined dynamic stabilization system and fusion, can be effective surgical treatment for multilevel degenerative lumbosacral spinal disease, maintaining lumbar motion and delaying disc degeneration. PMID- 26484003 TI - Stabilizing versus destabilizing the microtubules: a double-edge sword for an effective cancer treatment option? AB - Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy. PMID- 26484009 TI - Cortical and Standard Trajectory Pedicle Screw Fixation Techniques in Stabilizing Multisegment Lumbar Spine with Low Grade Spondylolisthesis. AB - BACKGROUND: Cortical screw (CS) fixation has been recently proposed as an alternative to the standard pedicle screw (PS) fixation technique. Biomechanical studies involving individual screw pullout and single level motion segment stabilization showed comparable performance of both techniques. However, whether this new fixation technique can be applied to the stabilization of multilevel lumbar segments with significant destabilization has been unclear. PURPOSE: To compare stability of CS fixation to the traditional PS fixation in an unstable 3 level spondylolisthesis model. STUDY DESIGN: This is a biomechanical study comparing cortical trajectory pedicle screw fixation to traditional trajectory pedicle screw fixation in an unstable cadaveric model using nondestructive flexibility test. METHODS: Eight fresh frozen cadaveric lumbar spines (T12- S1) were obtained. After intact baseline testing, a 3-level lowgrade spondylolisthesis was simulated at the L1-4. Each specimen was instrumented with the PS and CS fixation systems. Standard nondestructive flexibility test was performed. Range of motion at each level was compared between the constructs during flexion-extension, lateral bending, and axial rotation. RESULTS: The destabilization model significantly increased the ROM in all planes (P<0.05). Both fixation techniques provided significant reduction in the ROM (P<0.05). There was no significant difference in ROM between the PS and CS groups in any of planes (P>0.05). CONCLUSIONS: Cortical trajectory pedicle screw fixation provided stabilization to multilevel lumbar segment with low-grade spondylolisthesis comparable to the standard trajectory pedicle screw construct. PMID- 26484010 TI - Sodium Content of Foods Contributing to Sodium Intake: Comparison between Selected Foods from the CDC Packaged Food Database and the USDA National Nutrient Database for Standard Reference. AB - The sodium concentration (mg/100g) for 23 of 125 Sentinel Foods (e.g. white bread) were identified in the 2009 CDC Packaged Food Database (PFD) and compared with data in the USDA's 2013 National Nutrient Database for Standard Reference(SR 26). Sentinel Foods are foods identified by USDA to be monitored as primary indicators to assess the changes in the sodium content of commercially processed foods from stores and restaurants. Overall, 937 products were evaluated in the CDC PFD, and between 3 (one brand of ready-to-eat cereal) and 126 products (white bread) were evaluated per selected food. The mean sodium concentrations of 17 of the 23 (74%) selected foods in the CDC PFD were 90%-110% of the mean sodium concentrations in SR 26 and differences in sodium concentration were statistically significant for 6 Sentinel Foods. The sodium concentration of most of the Sentinel Foods, as selected in the PFD, appeared to represent the sodium concentrations of the corresponding food category. The results of our study help improve the understanding of how nutrition information compares between national analytic values and the label and whether the selected Sentinel Foods represent their corresponding food category as indicators for assessment of change of the sodium content in the food supply. PMID- 26484011 TI - First case of chromoblastomycosis from Bangladesh. AB - Chromoblastomycosis is a rare and chronic cutaneous and subcutaneous infection caused by black fungi and mostly reported in tropical and subtropical areas. Here we report the first case of chromoblastomycosis from Bangladesh. Molecular biology permitted to identify Fonsecaea nubica, and the patient responded well to antifungal treatment alone. PMID- 26484012 TI - Acute intradialytic exercise and oxidative stress in hemodialysis patients. PMID- 26484013 TI - Management of chronic kidney disease-mineral and bone disorder: Korean working group recommendations. AB - For Korean dialysis patients, chronic kidney disease-mineral bone disorder is a serious burden because of cardiovascular calcification and mortality. However, recent epidemiologic data have demonstrated that many patients undergoing maintenance hemodialysis are out of the target ranges of serum calcium, phosphorus, and intact parathyroid hormone. Thus, we felt the necessity for the development of practical recommendations to treat abnormal serum phosphorus, calcium, and iPTH in dialysis patients. In this paper, we briefly comment on the measurement of serum calcium, phosphorus, iPTH, dialysate calcium concentration, dietary phosphorus restriction, use of phosphate binders, and medical and surgical options to correct secondary hyperparathyroidism. In particular, for the optimal management of secondary hyperparathyroidism, we suggest a simplified medication adjustment according to certain ranges of serum phosphorus and calcium. Large-scale, well-designed clinical studies are required to support our strategies to control chronic kidney disease-mineral bone disorder in this country. Based on such data, our practice guidelines could be established and better long-term outcomes should be anticipated in our dialysis patients. PMID- 26484014 TI - Etiology and outcomes of anuria in acute kidney injury: a single center study. AB - BACKGROUND: It was previously known that anuric acute kidney injury (AKI) is uncommon and its occurrence suggests complete ureteral obstruction, shock, or a major vascular event. As the epidemiology of AKI has significantly changed over the past decade, it is possible that the incidence, etiology, or clinical characteristics of anuric AKI have also changed. METHODS: A prospective cohort study was conducted that included all patients undergoing renal replacement therapy (RRT) for AKI during a 2-year period in a tertiary hospital. Patients were classified as having anuric, oliguric, or nonoliguric AKI based on their volume of urine when RRT started using the modified Acute Kidney Injury Network criteria. RESULTS: Of the 203 patients included in the study, 21.2% met the criteria for anuric AKI. Septic and postoperative AKI were the main causes of anuric AKI, with 60.5% of incidences occurring in hospital. Anuric AKI was associated with a younger age, a lower prevalence of pre-morbid chronic kidney disease and diabetes, more frequent continuous RRT requirement, and multi-organ dysfunction. In addition, patients with anuric AKI had a higher rate of in hospital mortality and long-term dependence on RRT than patients with nonanuric AKI. CONCLUSION: Anuric AKI is common, with sepsis as the main etiological insult, and is associated with adverse outcomes among patients with AKI who require RRT. PMID- 26484015 TI - Optimal hemoglobin level for anemia treatment in a cohort of hemodialysis patients. AB - BACKGROUND: Anemia is a major risk factor that contributes to mortality in patients with chronic kidney disease. There is controversy over the optimal hemoglobin (Hb) target in these patients. This study investigated the association between Hb level and mortality in a cohort of hemodialysis (HD) patients in Korea. METHODS: This study was a multicenter prospective observational study of maintenance HD patients that was performed for 5 years in western Seoul, Korea. Three hundred and sixty-two participants were enrolled. Laboratory values and mortality were accessed every 6 months. Repeated measures of laboratory values in each interval were averaged to obtain one semiannual mean value. The Hb values were divided into six groups: (1) Hb<9 g/dL; (2) 9 g/dL<=Hb<10 g/dL; (3) 10 g/dL<=Hb<11 g/dL; (4) 11 g/dL<=Hb<12 g/dL; (5) 12 g/dL<=Hb<13 g/dL; and (6) Hb>=13 g/dL. We analyzed the odds ratio for all-cause mortality, based on the Hb group, and adjusted for demographics and various laboratory values. Statistics were performed with SAS, version 9.1 software (SAS Institute Inc., Cary, NC, USA). RESULTS: Mortality odds ratios relative to the reference group (10-11 g/dL) in the fully adjusted model were 3.61 for<9 g/dL; 3.17 for 9-10 g/dL(*); 4.65 for 11-12 g/dL(*); 5.50 for 12-13 g/dL(*); and 2.05 for>=13 g/dL ((*) indicates P<0.05). CONCLUSION: In this study, a Hb level of 10-11 g/dL was associated with the lowest mortality among the groups with Hb level<13 g/dL. Larger interventional trials are warranted to determine the optimal Hb target for Korean HD patients. PMID- 26484016 TI - Relationship between pulmonary hypertension, peripheral vascular calcification, and major cardiovascular events in dialysis patients. AB - BACKGROUND: Pulmonary hypertension (PHT) is a recently recognized complication of chronic kidney disease. In this study, we investigated the association between PHT, peripheral vascular calcifications (VCs), and major cardiovascular events. METHODS: In this retrospective study, we included 172 end-stage renal disease (ESRD) patients undergoing dialysis [hemodialysis (HD)=84, peritoneal dialysis=88]. PHT was defined as an estimated pulmonary artery systolic pressure>37 mmHg using echocardiography. The Simple Vascular Calcification Score (SVCS) was measured using plain radiographic films of the hands and pelvis. RESULTS: The prevalence of PHT was significantly higher in HD patients (51.2% vs. 22.7%). Dialysis patients with PHT had a significantly higher prevalence of severe VCs (SVCS>=3). In multivariate analysis, the presence of severe VCs [odds ratio (OR), 2.68], mitral valve disease (OR, 7.79), HD (OR, 3.35), and larger left atrial diameter (OR, 11.39) were independent risk factors for PHT. In addition to the presence of anemia, severe VCs, or older age, the presence of PHT was an independent predictor of major cardiovascular events in ESRD patients. CONCLUSION: The prevalence of PHT was higher in HD patients and was associated with higher rates of major cardiovascular events. Severe VCs are thought to be an independent risk factor for predicting PHT in ESRD patients. Therefore, in dialysis patients with PHT, careful attention should be paid to the presence of VCs and the occurrence of major cardiovascular events. PMID- 26484017 TI - Effect of acute intradialytic strength physical exercise on oxidative stress and inflammatory responses in hemodialysis patients. AB - BACKGROUND: Oxidative stress and inflammation are common findings in chronic kidney disease (CKD) patients, and they are directly related to the increased risk of developing cardiovascular disease, which is the major cause of death in these patients, particularly for those undergoing hemodialysis (HD). Strength physical exercise is a new therapeutic approach to reduce these complications in CKD patients. Following this, the purpose of this study was to assess the effect of acute intradialytic strength physical exercise on oxidative stress and inflammatory responses in HD patients. METHODS: Sixteen HD patients were studied (11 women; 44.4+/-14.6 years; body mass index 23.3+/-4.9 kg/m(2); 61.6+/-43.1 months of dialysis) and served as their own controls. Acute (single session) intradialytic physical exercise were performed at 60% of the one-repetition maximum test for three sets of 10 repetitions for four exercise categories in both lower limbs during 30 minutes. Blood samples were collected on two different days at exactly the same time (30 minutes and 60 minutes after initiating the dialysis-with and without exercise). Antioxidant enzymes activity [superoxide dismutase (SOD), catalase, and glutathione peroxidase], lipid peroxidation marker levels (malondialdehyde), and inflammatory marker levels (high-sensitivity C reactive protein) were determined. RESULTS: SOD plasma levels were significantly reduced after acute physical exercise from 244.8+/-40.7 U/mL to 222.4+/-28.9 U/mL (P=0.03) and, by contrast, increased on the day without exercise (218.2+/-26.5 U/mL to 239.4+/-38.6 U/mL, P=0.02). There was no alteration in plasma catalase, glutathione peroxidase, malondialdehyde, or high-sensitivity C-reactive protein levels in on either day (with or without exercise). Additionally, there was no association between these markers and clinical, anthropometric, or biochemical parameters. CONCLUSION: These data suggest that acute intradialytic strength physical exercise was unable to reduce oxidative stress and inflammation, and in addition, it seems to reduce plasma SOD levels, which could exacerbate the oxidative stress in HD patients. PMID- 26484018 TI - Hyperphosphatemia is associated with patency loss of arteriovenous fistula after 1 year of hemodialysis. AB - BACKGROUND: The patency of arteriovenous access is important for stable and effective hemodialysis, and long-term technical survival is best achieved with a native arteriovenous fistula (AVF). However, maintaining AVF patency remains a challenge. This study was designed to determine the independent prognostic factors for AVF patency according to hemodialysis duration. METHODS: The primary study end point was unassisted patency of the AVF, which was defined as the time from the first fistula surgery to the first AVF failure. AVF failure was defined as an event that required percutaneous intervention or surgery to revise or replace the fistula, which occurred at least 2 months after fistula formation. RESULTS: We enrolled 478 patients with a mean age of 55.5+/-14.0 years, and mean duration of dialysis was 2.5+/-2.1 years. There were 109 cases (22.8%) of AVF failure. The factors related to AVF patency differed according to hemodialysis duration. Using a Cox-adjusted model, we observed a significant correlation between the incidence of AVF failure and diabetes within the initial 12 months of hemodialysis. Uncontrolled hyperphosphatemia (mean serum phosphorus>5.5 mg/dL during hemodialysis) was associated with patency loss of AVF after 1 year of hemodialysis. CONCLUSION: Various factors were associated with the development of patency loss of AVF as hemodialysis duration differed, and a preventive role of hyperphosphatemia control in AVF survival needs further clinical study. PMID- 26484019 TI - Genetic predisposition of donors affects the allograft outcome in kidney transplantation: Single-nucleotide polymorphism of aquaporin-11. AB - BACKGROUND: Aquaporin-11 (AQP11) is a novel member of the aquaporin family. Disruption of the murine Aqp11 gene causes severe proximal tubular injury and renal failure. The rs2276415 (G>A) single-nucleotide polymorphism in the human AQP11 gene results in glycine to serine substitution in a functionally important domain. In this study, the role of the genetic predispositions of AQP11 rs2276415 (G>A) on renal allograft outcomes was evaluated. METHODS: A total of 198 pairs of donors and recipients were enrolled in this study. Long-term graft survival was traced and clinical parameters that could have influenced graft outcome were collected through the electronic medical record system. RESULTS: The genotype distribution and allele frequency of rs2276415 polymorphism were not different between donors and recipients. Despite similar allele frequencies between donors and recipients, the minor allele rs2276415 (GA+AA) of AQP11 from the donors, but not from the recipients, had a harmful effect on the graft survival compared with the wild-type donor (GG; P=0.029). This association was significant after adjusting for several risk factors including age, sex, human leukocyte antigen mismatch, donor type, hypertension, and diabetes mellitus (P=0.032). CONCLUSION: A donor-derived, not recipient-derived, genetic AQP11 polymorphism has different effects on graft outcome. Thus, the genetic influence from donors should be carefully considered for proper management of allografts after kidney transplantation. PMID- 26484020 TI - MYH9 nephropathy. AB - MYH9-related disorder is an autosomal dominant disease caused by a mutation in the MYH9 gene, which encodes nonmuscle myosin heavy chain IIA (NMMHC-IIA). This disease is characterized by giant platelets, thrombocytopenia, granulocyte inclusion bodies, proteinuria, and high-pitch sensorineural deafness. Nephropathy has been observed in 30% of patients with MYH9-related disorder. The characteristic features are early onset proteinuria and rapidly progressing renal disorder. However, the prognosis of MYH9 nephropathy remains unclear. Herein, we describe a 36-year-old woman who presented with proteinuria and was diagnosed with MYH9 nephropathy via renal biopsy and gene analysis. Her proteinuria improved after administration of an angiotensin II receptor blocker, but was aggravated after changing to a calcium channel blocker. PMID- 26484021 TI - Immunoglobulin E-mediated hypersensitivity reaction after intraperitoneal administration of vancomycin. AB - Intraperitoneal (IP) vancomycin is widely used to treat Gram-positive peritonitis associated with peritoneal dialysis. There have been two cases of red man syndrome (RMS), a vancomycin-specific nonimmunologic reaction, associated with IP vancomycin. However, immune-mediated hypersensitivity reaction to IP vancomycin has not yet been reported. A 49 year old woman on continuous ambulatory peritoneal dialysis developed her first peritonitis episode. The patient was treated with IP vancomycin once/wk for 4 weeks. She experienced mild itching and flushing throughout her body for 1 day after the second treatment. Whenever vancomycin was administered, generalized urticaria and a prickling sensation developed, and the intensity increased gradually; however, these symptoms improved after vancomycin was discontinued. An allergic skin test was performed 6 weeks after the previous urticarial episode, and an intradermal skin test revealed a positive response to vancomycin. To our knowledge, this is the first case report of immunoglobulin E-mediated hypersensitivity reaction to IP vancomycin administration. PMID- 26484022 TI - Idiopathic erythrocytosis in a patient on chronic hemodialysis. AB - A 78-year-old man on hemodialysis presented to our hospital with erythrocytosis. He had started hemodialysis 4 years previously, with a hemoglobin level of 9.8 g/dL, and was administered erythropoiesis stimulating agents and ferrous sulfate. Two years previously, his hemoglobin level increased to 14.5 g/dL and the treatment for anemia was discontinued. He continued hemodialysis thrice weekly; however, the hemoglobin level had increased to 17.0 g/dL at the time of presenting to our hospital. His serum erythropoietin level was 31.4 mIU/mL (range, 3.7-31.5 mIU/mL), carboxyhemoglobin level was 0.6% (range, 0-1.5%), and oxygen saturation in ambient air was 95.4%. The JAK2 V617F mutation was not observed and other bone marrow abnormalities were not identified. The patient was diagnosed with bladder cancer and a transurethral resection was performed. Eight months after the treatment of bladder cancer, his hemoglobin level was 15.1 g/dL, and he was diagnosed with idiopathic erythrocytosis. PMID- 26484023 TI - Toll-like receptor 4 antagonist and obesity associated kidney disease: Where should we go from here? PMID- 26484024 TI - Increased intra-abdominal pressure in acute kidney injury: a cause or an effect? PMID- 26484025 TI - Nonimmunologic targets of immunosuppressive agents in podocytes. AB - Proteinuria is a characteristic finding in glomerular diseases and is closely associated with renal outcomes. In addition, therapeutic interventions that reduce proteinuria improve renal prognosis. Accumulating evidence has demonstrated that podocytes act as key modulators of glomerular injury and proteinuria. The podocyte, or glomerular visceral epithelial cell, is a highly specialized and differentiated cell that forms interdigitated foot processes with neighboring podocytes, which are bridged together by an extracellular structure known as the "slit diaphragm" (SD). The SD acts as a size- and charge-selective barrier to plasma protein. Derangement of SD structure or loss of SD-associated protein results in podocyte injury and proteinuria. During the past decades, several immune-modulating agents have been used for the treatment of glomerular diseases and for the reduction of proteinuria. Interestingly, recent studies have demonstrated that immunosuppressive agents can have a direct effect on the SD associated proteins and stabilize actin cytoskeleton in podocyte and have therefore introduced the concept of nonimmunologic mechanism of renoprotection by immunomodulators. This review focuses on the evidence that immuno-modulating agents directly target podocytes. PMID- 26484026 TI - Pathogenesis of endothelial cell dysfunction in chronic kidney disease: a retrospective and what the future may hold. AB - Cardiovascular complications dominate the landscape of chronic kidney diseases (CKD). Endothelial cell dysfunction (ECD) is a well-known culprit of cardiovascular morbidity and it develops in CKD with remarkable frequency. This brief overview of ECD in CKD scans two decades of studies performed in my laboratory, from genetic analyses to proteomic and metabolomics screens. I provide a detailed description of findings related to the premature senescence of endothelial cells, cell transition from the endothelial to mesenchymal phenotype, and stages of development of ECD. Clinical utility of some of these findings is illustrated with data on laser-Doppler flowmetry and imaging in patients with CKD. Some currently available and emerging therapeutic options for the management of ECD are briefly presented. PMID- 26484027 TI - Effect of aldosterone on epithelial-to-mesenchymal transition of human peritoneal mesothelial cells. AB - BACKGROUND: Peritoneal fibrosis is one of the major causes of technical failure in patients on peritoneal dialysis. Epithelial-to-mesenchymal transition (EMT) of the peritoneum is an early and reversible mechanism of peritoneal fibrosis. Human peritoneal mesothelial cells (HPMCs) have their own renin-angiotensin-aldosterone system (RAAS), however, it has not been investigated whether aldosterone, an end product of the RAAS, induces EMT in HPMCs, and which mechanisms are responsible for aldosterone-induced EMT. METHODS: EMT of HPMCs was evaluated by comparing the expression of epithelial cell marker, E-cadherin, and mesenchymal cell marker, alpha-smooth muscle actin after stimulation with aldosterone (1-100nM) or spironolactone. Activation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) and generation of reactive oxygen species (ROS) were assessed by western blotting and 2',7'-dichlorofluororescein diacetate staining, respectively. The effects of MAPK inhibitors or antioxidants (N-acetyl cysteine, apocynin, and rotenone) on aldosterone-induced EMT were evaluated. RESULTS: Aldosterone induced EMT in cultured HPMCs, and spironolactone blocked aldosterone-induced EMT. Aldosterone induced activation of both ERK1/2 and p38 MAPK from 1 hour. Either PD98059, an inhibitor of ERK1/2, or SB20358, an inhibitor of p38 MAPK, attenuated aldosterone-induced EMT. Aldosterone induced ROS in HPMCs from 5 minutes, and antioxidant treatment ameliorated aldosterone induced EMT. N-acetyl cysteine and apocynin alleviated activation of ERK and p38 MAPK. CONCLUSION: Aldosterone induced EMT in HPMCs by acting through the mineralocorticoid receptor. Aldosterone-induced generation of ROS followed by activation of ERK, and p38 MAPK served as one of the mechanisms of aldosterone induced EMT of HPMCs. PMID- 26484028 TI - Transforming growth factor-beta receptor 2 gene polymorphisms are associated with end-stage renal disease. AB - BACKGROUND: Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine involved in immune disorders, cancer, asthma, lung fibrosis, and chronic kidney disease, and its signal pathways are considered crucial mediators of a variety of cellular processes. In addition, several recent studies have reported that TGF-beta receptor (TGF-betaR) gene polymorphism is associated with chronic kidney disease. However, the association between end-stage renal disease (ESRD) and the TGF-beta gene polymorphism has not been sufficiently investigated. In this study, we hypothesized that polymorphisms of the TGF-beta ligands or their receptors may be related to ESRD. METHODS: We assessed the relationship between four single-nucleotide polymorphisms (SNPs) in the TGF-betaR2 and TGF-beta2 genes and ESRD, in 312 patients with ESRD and 258 controls. RESULTS: Compared with the control participants, the frequencies of the TGF-betaR2 (rs764522(*)C) and TGF betaR2 (rs3087465(*)G) alleles were significantly higher in the patients with ESRD. Genotyping analysis demonstrated that two SNPs in TGF-betaR2 of the four SNPs included in the study were significantly associated with ESRD in the codominant 1 [rs764522, odds ratio (OR)=1.65; rs3087465, OR=1.63], dominant (rs764522, OR=1.63; rs3087465, OR=1.57), and log-additive (rs764522, OR=1.54; rs3087465, OR=1.39) models after adjusting for age and sex. CONCLUSION: We suggest that TGF-betaR2 polymorphisms (rs764522 and rs3087465) increase the risk of development of ESRD. PMID- 26484029 TI - Changes in serum magnesium concentration after use of a proton pump inhibitor in patients undergoing percutaneous coronary intervention. AB - BACKGROUND: Although cross-sectional studies have suggested a relationship between proton pump inhibitor (PPI) use and hypomagnesemia, no large-scale cohort study has been conducted to date. Here, we examined the changes in serum magnesium levels in response to PPI use. We hypothesized that PPI use might change the serum magnesium concentration. METHODS: Of the 2,892 patients hospitalized for percutaneous coronary intervention between January 2007 and May 2012, 1,076 patients with normal baseline (1.6-2.5 mg/dL) and follow-up serum magnesium concentrations were enrolled. These patients were divided into two groups: the PPI group and the control group. RESULTS: The mean follow-up period was 9.51 +/- 2.94 months. The incidence of hypomagnesemia (< 1.6 mg/dL) was 0.4% (3/834) in the PPI group and 0.4% (1/242) in the control group (P = 0.904). The change in magnesium levels did not differ between the two groups, and this result was maintained in the analysis of covariance after adjusting for confounding factors (P = 0.381). Moreover, magnesium levels did not significantly differ between the long-term (duration of use >= 12 months, n = 71) and short-term PPI groups (duration of use < 12 months, n = 763), and the control group (n = 242; P = 0.620). The effect of PPI use on change in serum magnesium concentration was affected by the use of multiple diuretics (-0.01 +/- 0.25 mg/dL; P = 0.025), although a single diuretic use with PPI did not alter the change in magnesium level (0.12 +/- 0.27 mg/dL). CONCLUSION: Changes in magnesium levels might be subtle after PPI use in patients with normal baseline magnesium values. PMID- 26484030 TI - Intra-abdominal hypertension does not predict renal recovery or in-hospital mortality in critically ill patients with acute kidney injury. AB - BACKGROUND: Although emerging evidence suggests that intra-abdominal hypertension (IAH) is a predictor of the development of acute kidney injury (AKI), it remains unclear whether the presence of IAH is a predictor of prognosis in patients with AKI. The purpose of this study was to assess whether the presence of IAH could predict prognosis in critically ill patients with AKI. The prognostic value of urinary biomarkers was also determined. METHODS: In this prospective observational study, we enrolled 57 patients with established AKI, who were admitted to the intensive care unit between February 2012 and June 2014. IAH was defined as a sustained elevation in intra-abdominal pressure of >=12 mmHg, in three consecutive measurements performed daily on the first 3 days. Urinary neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein, and simplified acute physiology score II score at the time of admission were also examined. RESULTS: IAH was observed in 78.9% of patients. The in hospital mortality was 21.1%, and renal recovery during hospitalization was achieved in 40.4% of patients. Although high urinary NGAL [odds ratio (OR), 1.015] and liver-type fatty acid-binding protein (OR, 1.003) were found to be independent predictors of renal recovery, IAH was not. High urinary NGAL (OR, 1.003) and a high simplified acute physiology score II score (OR, 1.102) were independent predictors of in-hospital mortality, while IAH or urinary liver-type fatty acid-binding protein was not. CONCLUSION: Although IAH is prevalent in critically ill patients with AKI, it did not predict AKI prognosis. However, urinary NGAL was found to be a useful predictor of both renal recovery and in hospital mortality. PMID- 26484031 TI - Does hypokalemia contribute to acute kidney injury in chronic laxative abuse? AB - Prolonged hypokalemia from chronic laxative abuse is recognized as the cause of chronic tubulointerstitial disease, known as "hypokalemic nephropathy," but it is not clear whether it contributes to acute kidney injury (AKI). A 42-year-old woman with a history of chronic kidney disease as a result of chronic laxative abuse from a purging type of anorexia nervosa (AN-P), developed an anuric AKI requiring hemodialysis and a mild AKI 2 months later. Both episodes of AKI involved severe to moderate hypokalemia (1.2 and 2.7 mmol/L, respectively), volume depletion, and mild rhabdomyolysis. The histologic findings of the first AKI revealed the remnants of acute tubular necrosis with advanced chronic tubulointerstitial nephritis and ischemic glomerular injury. Along with these observations, the intertwined relationship among precipitants of recurrent AKI in AN-P is discussed, and then we postulate a contributory role of hypokalemia involved in the pathophysiology of the renal ischemia-induced AKI. PMID- 26484034 TI - Endovascular procedures performed by interventional nephrologists in Korea: Time to intervene. PMID- 26484032 TI - A rare case of hyperoxaluria presenting with acute liver injury and stone-free kidney injury. AB - A 49-year-old woman visited the clinic because of acute hepatitis and acute kidney injury with decreased urine output presenting microscopic hematuria and proteinuria. An abdominal computed tomography revealed a localized, hypoattenuated lesion in a hepatic lateral segment, and kidney biopsy showed oxalate crystal deposition with tubular necrosis. In addition, the patient's 24 hour urinary excretion of oxalate was increased. Her kidney and liver injury improved after sessions of hemodialysis, and urinary oxalate excretion was normalized. Major mutations in primary hyperoxaluria have not been proven. A full sequencing of target genes may be helpful to diagnose a rare form of primary hyperoxaluria. PMID- 26484035 TI - Does the timing of acute rejection matter with the graft outcome in kidney transplantation? PMID- 26484033 TI - Fibrillary glomerulonephritis combined with chronic inflammatory demyelinating polyneuropathy. AB - A 58-yr-old man presented with leg edema and subacute weakness of his bilateral lower extremities. Urinary and serum immunoelectrophoresis revealed the presence of lambda-type Bence Jones proteins. He was ultimately diagnosed with monoclonal gammopathy of undetermined significance (MGUS). A renal biopsy specimen showed fibrillary glomerulonephritis (FGN), which was randomly arranged as 12-20 m nonbranching fibrils in the basement membranes. Immunofluorescence studies were negative for immunoglobulin (Ig)G, IgM, IgA, C3, and kappa light chains in the capillary walls and mesangial areas. A Congo red stain for amyloid was negative. Electromyography and nerve conduction velocity examinations results were compatible with the presence of demyelinating polyneuropathy. This case showed a rare combination of FGN, without Ig deposition, and MGUS combined with chronic inflammatory demyelinating polyneuropathy (CIDP). PMID- 26484036 TI - Role of interventional nephrology in the multidisciplinary approach to hemodialysis vascular access care. AB - Dialysis vascular access planning, creation, and management is of critical importance to the dialysis patient population. It requires a multidisciplinary approach involving patients and their families, dialysis facility staff, the nephrologist, the surgeon, and the interventionalist. With the emergence of interventional nephrology as a subspecialty of nephrology, the nephrologist is increasingly providing both the nephrology and interventional aspects of care, and in some areas, the surgical functions as well. Most of these interventional nephrologists work in freestanding outpatient dialysis access centers (DACs). Large clinical studies published over the past 10 years demonstrate that the interventional nephrologist can manage the problems associated with dialysis access dysfunction effectively, safely, and economically. A recently published study based upon United States Medicare claims data in which a DAC patient group (n = 27,613) and a hospital outpatient department patient group (HOPD group; n = 27,613) were compared using propensity score matching techniques showed that patients treated in the DACs had significantly better clinical outcomes (P<0.001). This included fewer vascular access-related infections (0.18 vs. 0.29), fewer septicemia-related hospitalizations (0.15 vs. 0.18), and a lower mortality rate (47.9% vs. 53.5%). PMID- 26484037 TI - Lessons from 30 years' data of Korean end-stage renal disease registry, 1985 2015. AB - The Korean Society of Nephrology (KSN) launched a nationwide official survey program about dialysis therapy in 1985. Nowadays, the accumulated data for 30 years by this "Insan Prof. Min Memorial end-stage renal disease (ESRD) Registry" program have been providing the essential information for dialysis clinical practice, academic nephrology research, and health management policy. We reviewed 30 years of data to identify important changes and implications for the future improvement of dialysis therapy in Korea. Hemodialysis patients, especially diabetics and elderly patients have increased in number very rapidly during recent years in Korea. The Korean prevalence rate of ESRD patients was about 70% of the United States and about 50% of Japan according to the international comparisons in the annual data report of United States Renal Data System. The blood pressure control, anemia control, and dialysis adequacy have continuously improved year by year. The importance of calcium and phosphorus control has also been increasing because of the increase in long-term dialysis patients. In addition, chronic dialysis complications should be closely monitored and dialysis modifications, such as hemodiafiltration therapy, might be considered. Because of the increase of private clinics and nursing hospitals in dialysis practice, the role of dialysis specialists and continuing education are thought to be essential. For strict cost-effective dialysis control of increasing elderly, diabetic, and long-term dialysis patients, the KSN ESRD patient registration should be run by the KSN and health ministry in cooperation, in which the dialysis fee reimbursement should be accompanied. PMID- 26484038 TI - Early predictors of acute kidney injury in patients with cirrhosis and bacterial infection: urinary neutrophil gelatinase-associated lipocalin and cardiac output as reliable tools. AB - BACKGROUND: Hemodynamic abnormalities and acute kidney injury (AKI) are often present in infected cirrhotic patients. Hence, an early diagnosis of AKI is necessary, which might require the validation of new predictors as the determinations of urinary neutrophil gelatinase-associated lipocalin (uNGAL) and cardiac output. METHODS: We evaluated 18 infected cirrhotic patients subdivided into two groups at admission (0 hours). In Group I, we collected urine samples at 0 hours, 6 hours, 24 hours, and 48 hours for uNGAL and fractional excretion of sodium determinations. In Group II, we measured cardiac output using echocardiography. RESULTS: The age of patients was 55.0+/-1.9 years, and 11 patients were males. The Model for End-Stage Liver Disease score was 21+/-1, whereas the Child-Pugh score was C in 11 patients and B in 7 patients. Both patients in Group I and Group II showed similar baseline characteristics. In Group I, we diagnosed AKI in 5 of 9 patients, and the mean time to this diagnosis by measuring serum creatinine was 5.4 days. Patients with AKI showed higher uNGAL levels than those without AKI from 6 hours to 48 hours. The best accuracy using the cutoff values of 68 ng uNGAL/mg creatinine was achieved at 48 hours when we distinguished patients with and without AKI in all cases. In Group II, we diagnosed AKI in 4 of 9 patients, and cardiac output was significantly higher in patients who developed AKI at 0 hours. CONCLUSION: Both uNGAL and cardiac output determinations allow the prediction of AKI in infected cirrhotic patients earlier than increments in serum creatinine. PMID- 26484039 TI - Psychosocial stress and changes in estimated glomerular filtration rate among adults with diabetes mellitus. AB - BACKGROUND: Psychosocial stress has been hypothesized to impact renal changes, but this hypothesis has not been adequately tested. The aim of this study was to examine the relationship between psychosocial stress and estimated glomerular filtration rate (eGFR) and to examine other predictors of eGFR changes among persons with diabetes mellitus (DM). METHODS: Data from a survey conducted in 2005 by a major health maintenance organization located in the southeastern part of the United States, linked to patients' clinical and pharmacy records (n=575) from 2005 to 2008, was used. Study participants were working adults aged 25-59 years, diagnosed with DM but without advanced microvascular or macrovascular complications. eGFR was estimated using the Modification of Diet in Renal Disease equation. A latent psychosocial stress variable was created from five psychosocial stress subscales. Using a growth factor model in a structural equation framework, we estimated the association between psychosocial stress and eGFR while controlling for important covariates. RESULTS: The psychosocial stress variable was not directly associated with eGFR in the final model. Factors found to be associated with changes in eGFR were age, race, insulin use, and mean arterial pressure. CONCLUSION: Among fairly healthy DM patients, we did not find any evidence of a direct association between psychosocial stress and eGFR changes after controlling for important covariates. Predictors of eGFR change in our population included age, race, insulin use, and mean arterial pressure. PMID- 26484041 TI - The impact of early and late acute rejection on graft survival in renal transplantation. AB - BACKGROUND: Advances in immunosuppression after kidney transplantation have decreased the influence of early acute rejection (EAR) on graft survival. Several studies have suggested that late acute rejection (LAR) has a poorer effect on long-term graft survival than EAR. We investigated whether the timing of acute rejection (AR) influences graft survival, and analyzed the risk factors for EAR and LAR. METHODS: We performed a retrospective cohort study involving 709 patients who underwent kidney transplantation between 2000 and 2009 at the Samsung Medical Center, Seoul, Korea. Patients were divided into three groups: no AR, EAR, and LAR. EAR and LAR were defined as rejection before 1 year and after 1 year, respectively. Differences in graft survival between the three groups and risk factors of graft failure were analyzed. RESULTS: Of the 709 patients, 198 (30%) had biopsy-proven AR [EAR=152 patients (77%); LAR=46 patients (23%)]. A total of 65 transplants were lost. The 5-year graft survival rates were 97%, 89%, and 85% for patients with no AR, EAR, and LAR, respectively. These differences were significant (P<0.001 for both by log-rank test). In time-dependent Cox regression analysis, EAR (hazards ratio, 3.37; 95% confidence interval, 1.90 5.99) and LAR (hazards ratio, 5.32; 95% confidence interval, 2.65-10.69) were significantly related to graft failure. When we set LAR as standard and compared it with EAR, there was no statistical difference between EAR and LAR (P=0.21). CONCLUSION: AR, regardless of its timing, significantly worsened graft survival. Treatments to reduce the incidence of AR and improve prognosis are needed. PMID- 26484040 TI - Risk factors for in-hospital mortality in patients starting hemodialysis. AB - BACKGROUND: Incident hemodialysis patients have the highest mortality in the first several months after starting dialysis. This study evaluated the in hospital mortality rate after hemodialysis initiation, as well as related risk factors. METHODS: We examined in-hospital mortality and related factors in 2,692 patients starting incident hemodialysis. The study population included patients with acute kidney injury, acute exacerbation of chronic kidney disease, and chronic kidney disease. To determine the parameters associated with in-hospital mortality, patients who died in hospital (nonsurvivors) were compared with those who survived (survivors). Risk factors for in-hospital mortality were determined using logistic regression analysis. RESULTS: Among all patients, 451 (16.8%) died during hospitalization. The highest risk factor for in-hospital mortality was cardiopulmonary resuscitation, followed by pneumonia, arrhythmia, hematologic malignancy, and acute kidney injury after bleeding. Albumin was not a risk factor for in-hospital mortality, whereas C-reactive protein was a risk factor. The use of vancomycin, inotropes, and a ventilator was associated with mortality, whereas elective hemodialysis with chronic kidney disease and statin use were associated with survival. The use of continuous renal replacement therapy was not associated with in-hospital mortality. CONCLUSION: Incident hemodialysis patients had high in-hospital mortality. Cardiopulmonary resuscitation, infections such as pneumonia, and the use of inotropes and a ventilator was strong risk factors for in-hospital mortality. However, elective hemodialysis for chronic kidney disease was associated with survival. PMID- 26484042 TI - Organ-on-a-chip and the kidney. AB - Traditional approaches to pathophysiology are advancing but still have many limitations that arise from real biologic systems and their associated physiological phenomena being too complicated. Microfluidics is a novel technology in the field of engineering, which provides new options that may overcome these hurdles. Microfluidics handles small volumes of fluids and may apply to various applications such as DNA analysis chips, other lab-on-a-chip analyses, micropropulsion, and microthermal technologies. Among them, organ-on-a chip applications allow the fabrication of minimal functional units of a single organ or multiple organs. Relevant to the field of nephrology, renal tubular cells have been integrated with microfluidic devices for making kidneys-on-a chip. Although still early in development, kidneys-on-a-chip are showing potential to provide a better understanding of the kidney to replace some traditional animal and human studies, particularly as more cell types are incorporated toward the development of a complete glomeruli-on-a-chip. PMID- 26484044 TI - Antineutrophil cytoplasmic antibody-negative pauci-immune glomerulonephritis with massive intestinal bleeding. AB - A 61-year-old woman was admitted to hospital because of generalized edema and proteinuria. Her renal function deteriorated rapidly. Serum immunoglobulin and complement levels were within normal ranges. An autoantibody examination showed negative for antinuclear antibody and antineutrophil cytoplasmic antibody. Histologic examination of a renal biopsy specimen revealed that all of the glomeruli had severe crescent formations with no immune deposits. The patient was treated with steroid pulse therapy with cyclophosphamide followed by oral prednisolone. Fifteen days later, she experienced massive recurrent hematochezia. Angiography revealed an active contrast extravasation in a branch of the distal ileal artery. We selectively embolized with a permanent embolic agent. On the 45(th) hospital day, the patient suddenly lost consciousness. Brain computed tomography showed intracerebral hemorrhage. We report a case of antineutrophil cytoplasmic antibody-negative pauci-immune glomerulonephritis with massive intestinal bleeding and cerebral hemorrhage. PMID- 26484045 TI - A case of peritoneal dialysis-associated peritonitis by Rothia mucilaginosa. AB - Rothia muciliaginosa (R. mucilaginosa) is a facultative, Gram-positive coccus that is considered to be part of the normal flora of the mouth and respiratory tract. There are sporadic reports of the organism causing endocarditis in patients with heart valve abnormalities, as well as meningitis, septicemia, and pneumonia associated with intravenous drug abuse. However, it is an unusual pathogen in cases of peritoneal dialysis (PD)-associated peritonitis. Although R. mucilaginosa is generally susceptible to penicillin, ampicillin, cefotaxime, imipenem, rifampicin, and glycopeptides, there are no guidelines for the treatment of PD-associated peritonitis. Herein, we report a case of PD-associated peritonitis due to R. mucilaginosa that was resolved with intraperitoneal antibiotic treatment. PMID- 26484043 TI - Current progress in ABO-incompatible kidney transplantation. AB - ABO-incompatible kidney transplantation (ABOi KT) was introduced to expand the donor pool and minimize shortage of kidneys for transplantation. Because improved outcomes of ABOi KT were reported in Japan in the early 2000s, the number of ABOi KTs has been increasing worldwide. In addition, a better understanding of immune pathogenesis and subsequent aggressive immunosuppression has helped to make effective desensitization protocols. Current strategies of ABOi KT consist of pretransplant antibody removal using plasmapheresis or immunoadsorption to prevent hyperacute rejection and potent maintenance immunosuppression, such as tacrolimus and mycophenolate mofetil, to inhibit antibody-mediated rejection. Recent outcomes of ABOi KT are comparable with ABO-compatible KT. However, there are still many problems to be resolved. Very high anti-ABO antibody producers are difficult to desensitize. In addition, ABOi KT is associated with an increased risk of infection and possibly malignancy due to aggressive immunosuppression. Optimization of desensitization and patient-tailored immunosuppression protocols are needed to achieve better outcomes of ABOi KT. This review provides an overview of the history, immune mechanism, immunosuppressive protocol, outcomes, current obstacles, and future perspectives in ABOi KT. PMID- 26484046 TI - A new water channel aquaporin-11: extension to renal transplantation. PMID- 26484049 TI - Accelerating genomic data publishing and sharing. PMID- 26484047 TI - Default mode network segregation and social deficits in autism spectrum disorder: Evidence from non-medicated children. AB - Functional pathology of the default mode network is posited to be central to social-cognitive impairment in autism spectrum disorders (ASD). Altered functional connectivity of the default mode network's midline core may be a potential endophenotype for social deficits in ASD. Generalizability from prior studies is limited by inclusion of medicated participants and by methods favoring restricted examination of network function. This study measured resting-state functional connectivity in 22 8-13 year-old non-medicated children with ASD and 22 typically developing controls using seed-based and network segregation functional connectivity methods. Relative to controls the ASD group showed both under- and over-functional connectivity within default mode and non-default mode regions, respectively. ASD symptoms correlated negatively with the connection strength of the default mode midline core-medial prefrontal cortex-posterior cingulate cortex. Network segregation analysis with the participation coefficient showed a higher area under the curve for the ASD group. Our findings demonstrate that the default mode network in ASD shows a pattern of poor segregation with both functional connectivity metrics. This study confirms the potential for the functional connection of the midline core as an endophenotype for social deficits. Poor segregation of the default mode network is consistent with an excitation/inhibition imbalance model of ASD. PMID- 26484048 TI - Abnormalities in personal space and parietal-frontal function in schizophrenia. AB - Schizophrenia is associated with subtle abnormalities in day-to-day social behaviors, including a tendency in some patients to "keep their distance" from others in physical space. The neural basis of this abnormality, and related changes in social functioning, is unknown. Here we examined, in schizophrenic patients and healthy control subjects, the functioning of a parietal-frontal network involved in monitoring the space immediately surrounding the body ("personal space"). Using fMRI, we found that one region of this network, the dorsal intraparietal sulcus (DIPS), was hyper-responsive in schizophrenic patients to face stimuli appearing to move towards the subjects, intruding into personal space. This hyper-responsivity was predicted both by the size of personal space (which was abnormally elevated in the schizophrenia group) and the severity of negative symptoms. In contrast, in a second study, the activity of two lower-level visual areas that send information to DIPS (the fusiform face area and middle temporal area) was normal in schizophrenia. Together, these findings suggest that changes in parietal-frontal networks that support the sensory-guided initiation of behavior, including actions occurring in the space surrounding the body, contribute to social dysfunction and negative symptoms in schizophrenia. PMID- 26484050 TI - Computational identification of microRNAs and their targets in Catharanthus roseus expressed sequence tags. AB - No study has been performed on identifying microRNAs (miRNAs) and their targets in the medicinal plant, Catharanthus roseus. In the present study, using the comparative genomics approach, we have predicted two potential C. roseus miRNAs. Furthermore, twelve potential mRNA targets were identified in C. roseus genome based on the characteristics that miRNAs exhibit perfect or nearly perfect complementarity with their targeted mRNA sequences. Among them many of the targets were predicted to encode enzymes that regulate the biosynthesis of terpenoid indole alkaloids (TIA). In addition, most of the predicted targets were the gene coding for transcription factors which are mainly involved in cell growth and development, signaling and metabolism. This is the first in silico study to indicate that miRNA target gene encoding enzymes involved in vinblastine and vincristine biosynthesis, which may help to understand the miRNA-mediated regulation of TIA alkaloid biosynthesis in C. roseus. PMID- 26484051 TI - Genome-wide gene expression profiling to predict resistance to anthracyclines in breast cancer patients. AB - Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER)-negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-alpha (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Here we describe in details the contents and quality controls for the gene expression and clinical data associated with the study published by Desmedt and colleagues in the Journal of Clinical Oncology in 2011 (Desmedt et al., 2011). We also provide R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset. PMID- 26484052 TI - Genome sequencing and annotation of Acinetobacter guillouiae strain MSP 4-18. AB - The genus Acinetobacter consists of 31 validly published species ubiquitously distributed in nature and primarily associated with nosocomial infection. We report the 4.8 Mb genome of Acinetobacter guillouiae MSP 4-18, isolated from a mangrove soil sample from Parangipettai (11 degrees 30'N, 79 degrees 47'E), Tamil Nadu, India. The draft genome of A. guillouiae MSP 4-18 has a G + C content of 38.0% and includes 3 rRNA genes (5S, 23S, 16S) and 69 aminoacyl-tRNA synthetase genes. PMID- 26484053 TI - Genome sequencing and annotation of Acinetobacter gyllenbergii strain MTCC 11365(T). AB - The genus Acinetobacter consists of 31 validly published species ubiquitously distributed in nature and primarily associated with nosocomial infection. We report 4.3 Mb genome of the Acinetobacter gyllenbergii strain MTCC 11365(T). The draft genome of A. gyllenbergii has a G + C content of 41.0% and includes 3 rRNA genes (5S, 23S, 16S) and 67 aminoacyl-tRNA synthetase genes. PMID- 26484054 TI - Genome sequencing and annotation of Acinetobacter gerneri strain MTCC 9824(T). AB - The genus Acinetobacter consists of 31 validly published species ubiquitously distributed in nature and primarily associated with nosocomial infection. We report the 4.4 Mb genome of Acinetobacter gerneri strain MTCC 9824(T). The genome has a G + C content of 38.0% and includes 3 rRNA genes (5S, 23S16S) and 64 aminoacyl-tRNA synthetase genes. PMID- 26484055 TI - Genome sequencing and annotation of Acinetobacter haemolyticus strain MTCC 9819(T). AB - The genus Acinetobacter consists of 31 validly published species ubiquitously distributed in nature and primarily associated with nosocomial infection. We report the 3.4 Mb genome of Acinetobacter haemolyticus strain MTCC 9819(T). The genome has a G + C content of 40.0% and includes 3 rRNA genes (5S, 23S, 16S) and 65 aminoacyl-tRNA synthetase genes. PMID- 26484056 TI - Genome sequencing and annotation of Acinetobacter junii strain MTCC 11364. AB - The genus Acinetobacter consists of 31 validly published species ubiquitously distributed in nature and primarily associated with nosocomial infection. We report the 3.5 Mb draft genome of the Acinetobacter junii strain MTCC 11364. The genome has a G + C content of 38.0% and includes 3 rRNA genes (5S, 23S, 16S) and 64 aminoacyl-tRNA synthetase genes. PMID- 26484057 TI - Genome sequencing and annotation of Amycolatopsis vancoresmycina strain DSM 44592(T). AB - We report the 9.0-Mb draft genome of Amycolatopsis vancoresmycina strain DSM 44592(T), isolated from Indian soil sample; produces antibiotic vancoresmycin. Draft genome of strain DSM44592T consists of 9,037,069 bp with a G+C content of 71.79% and 8340 predicted protein coding genes and 57 RNAs. RAST annotation indicates that strains Streptomyces sp. AA4 (score 521), Saccharomonospora viridis DSM 43017 (score 400) and Actinosynnema mirum DSM 43827 (score 372) are the closest neighbors of the strain DSM 44592(T). PMID- 26484058 TI - Genome sequencing and annotation of Laceyella sacchari strain GS 1-1, isolated from hot spring, Chumathang, Leh, India. AB - We report the 3.3-Mb draft genome of Laceyella sacchari strain GS 1-1, isolated from hot spring water sample, Chumathang, Leh, India. Draft genome of strain GS 1 1 consists of 3, 324, 316 bp with a G + C content of 48.8% and 3429 predicted protein coding genes and 75 RNAs. Geobacillus thermodenitrificans strain NG80-2, Geobacillus kaustophilus strain HTA426 and Geobacillus sp. Strain G11MC16 are the closest neighbors of the strain GS 1-1. PMID- 26484059 TI - Genome-wide analysis of SRSF10-regulated alternative splicing by deep sequencing of chicken transcriptome. AB - Splicing factor SRSF10 is known to function as a sequence-specific splicing activator that is capable of regulating alternative splicing both in vitro and in vivo. We recently used an RNA-seq approach coupled with bioinformatics analysis to identify the extensive splicing network regulated by SRSF10 in chicken cells. We found that SRSF10 promoted both exon inclusion and exclusion. Functionally, many of the SRSF10-verified alternative exons are linked to pathways of response to external stimulus. Here we describe in detail the experimental design, bioinformatics analysis and GO/pathway enrichment analysis of SRSF10-regulated genes to correspond with our data in the Gene Expression Omnibus with accession number GSE53354. Our data thus provide a resource for studying regulation of alternative splicing in vivo that underlines biological functions of splicing regulatory proteins in cells. PMID- 26484060 TI - Dataset of microarray analysis to identify endoglin-dependent bone morphogenetic protein-2-responsive genes in the murine periodontal ligament cell line PDL-L2. AB - The periodontal ligament (PDL), connective tissue located between the cementum of teeth and alveolar bone of the mandibula, plays a crucial role in the maintenance and regeneration of periodontal tissues. We previously reported that endoglin was involved in the bone morphogenetic protein (BMP)-2-induced osteogenic differentiation of mouse PDL cells, which is associated with Smad-2 phosphorylation but not Smad-1/5/8 phosphorylation. Further, we found that the BMP-2-induced Smad-2 phosphorylation was, at least in part, dependent upon endoglin. In this study, to elucidate the detailed mechanism underlying the BMP-2 induced signaling pathway unique to PDL cells, we performed a cDNA microarray analysis to identify endoglin-dependent BMP-2-responsive genes in PDL-L2, a mouse PDL-derived cell line. Here we provide experimental methods and obtained dataset to correspond with our data in Gene Expression Omnibus (GEO) Datasets. PMID- 26484061 TI - Transcriptomic profiling of cartilage ageing. AB - The musculoskeletal system is severely affected by the ageing process, with many tissues undergoing changes that lead to loss of function and frailty. Articular cartilage is susceptible to age related diseases, such as osteoarthritis. Applying RNA-Seq to young and old equine cartilage, we identified an over representation of genes with reduced expression relating to extracellular matrix, degradative proteases, matrix synthetic enzymes, cytokines and growth factors in cartilage from older donors. Here we describe the contents and quality controls in detail for the gene expression and related results published by Peffers and colleagues in Arthritis Research and Therapy 2013 associated with the data uploaded to ArrayExpress (E-MTAB-1386). PMID- 26484062 TI - Colorectal cancer driver genes identified by patient specific comparison of cytogenetic microarray. AB - Colorectal cancer (CRC), which has high prevalence in Saudi Arabia and worldwide, needs better understanding by exploiting the latest available cytogenetic microarrays. We used biopsy tissue from consenting colorectal cancer patients to extract DNA and carry out microarray analysis using a CytoScan HD platform from Affymetrix. Patient specific comparisons of tumor-normal pairs were carried out. To find out the high probability key players, we performed Genomic Identification of Significant Targets in Cancer analysis and found 144 genes to form the list of driver genes. Of these, 24 genes attained high GISTIC scores and suggest being significantly associated with CRC. Loss of heterozygosity and uniparental disomy were found to affect 9 genes and suggest different mechanisms associated with CRC in every patient. Here we present the details of the methods used in carrying out the above analyses. Also, we provide some additional data on biomarker analysis that would complement the findings. PMID- 26484063 TI - Transcriptome analysis of the mouse E14.5 (TS23) developing humerus and differential expression in muscle-less mutant embryos lacking mechanical stimulation. AB - Mechanical stimulation is important for the correct formation of the skeleton. Splotch-delayed mutant embryos (Pax3 (Spd/Spd) ) that develop with no limb muscle and therefore no limb movement experience an altered mechanical environment resulting in specific defects in ossification and joint formation, particularly in the forelimb. To test the hypothesis that mechanical stimuli influence the regulation of genes important in skeletal development we generated a transcriptome profile of the developing humerus at Theiler stage 23 (TS23), and then identified differentially expressed genes in muscle-less mutant embryos compared to control littermates. Here we describe the experimental methods and analysis of the resulting data, publically available in the ArrayExpress database under E-MTAB-1745 (Transcriptome of control humerus), E-MTAB-1744 (Microarray; differential expression) and E-MTAB-1746 (RNA-sequencing; differential expression). Our data provide a resource for exploring the transcriptome that underlies skeletal development at TS23 in the mouse humerus. The interpretation and description of this data can be found in a recent publication in BMC Genomics [1]. This is a resource for exploring the molecular mechanisms that are involved in skeletal development and mechanotransduction. PMID- 26484064 TI - Report from the 2nd Summer School in Computational Biology organized by the Queen's University of Belfast. AB - In this paper, we present a meeting report for the 2nd Summer School in Computational Biology organized by the Queen's University of Belfast. We describe the organization of the summer school, its underlying concept and student feedback we received after the completion of the summer school. PMID- 26484065 TI - Genome sequencing, annotation of Citrobacter freundii strain GTC 09479. AB - We report the 4.9-Mb genome sequence of Citrobacter freundii strain GTC 09479, isolated from urine sample collected during the year 1983 at Gifu University Graduate School of Medicine, Japan. This draft genome consist of 4,899,578 bp with 51.62% G + C, 4,574 predicted CDSs, 72 tRNAs and 10 rRNAs. PMID- 26484066 TI - Genome-wide profiling to analyze the effects of high fat diet induced obesity on renal gene expression in mouse with reduced renal mass. AB - To assess the relationship between a reduced nephron number and a particular susceptibility to obesity-induced renal damage, mice underwent uninephrectomy (UNX) followed by either normal chow or high-fat diet (HFD) and were compared with sham-operated control mice. Analysis of gene expression in the mouse kidney by whole genome microarrays indicated that high fat diet led to more changes in gene expression than uninephrectomy. However, the combination of UNX and HFD additionally altered the effects of obesity on gene expression pattern. Here we describe in details the contents and quality controls for the gene expression and related results associated with the data uploaded to Gene Expression Omnibus (accession number GSE53996). PMID- 26484067 TI - Genome sequencing and annotation of Amycolatopsis azurea DSM 43854(T). AB - We report the 9.2 Mb genome of the azureomycin A and B antibiotic producing strain Amycolatopsis azurea isolated from a Japanese soil sample. The draft genome of strain DSM 43854(T) consists of 9,223,451 bp with a G + C content of 69.0% and the genome contains 3 rRNA genes (5S-23S-16S) and 58 aminoacyl-tRNA synthetase genes. The homology searches revealed that the PKS gene clusters are supposed to be responsible for the biosynthesis of naptomycin, macbecin, rifamycin, mitomycin, maduropeptin enediyne, neocarzinostatin enediyne, C-1027 enediyne, calicheamicin enediyne, landomycin, simocyclinone, medermycin, granaticin, polyketomycin, teicoplanin, balhimycin, vancomycin, staurosporine, rubradirin and complestatin. PMID- 26484068 TI - Returning to more finished genomes. AB - Genomic data have become commonplace in most branches of the biological sciences and have fundamentally altered the way research is conducted. However, the predominance of short-read sequence data from second-generation sequencing technologies has commonly resulted in fragmented and partial genomic data characteristics. In this opinion, I will highlight how long, unbiased reads from single molecule, real-time (SMRT) sequencing now allow for a return to more contiguous and comprehensive views of genomes. PMID- 26484069 TI - Data collaboration will lead precision medicine. PMID- 26484070 TI - A definitive haplotype map of structural variations determined by microarray analysis of duplicated haploid genomes. AB - Complete hydatidiform moles (CHMs) are tissues carrying duplicated haploid genomes derived from single sperms, and detecting copy number variations (CNVs) in CHMs is assumed to be sensitive and straightforward methods. We genotyped 108 CHM genomes using Affymetrix SNP 6.0 (GEO#: GSE18642) and Illumina 1 M-duo (GEO#: GSE54948). After quality control, we obtained 84 definitive haplotype consisting of 1.7 million SNPs and 2339 CNV regions. The results are presented in the database of our web site (http://orca.gen.kyushu-u.ac.jp/cgi bin/gbrowse/humanBuild37D4_1/). PMID- 26484071 TI - Genome-wide copy number analysis of cerebrospinal fluid tumor cells and their corresponding archival primary tumors. AB - A debilitating complication of breast cancer is the metastatic spread of tumor cells to the leptomeninges or cerebrospinal fluid (CSF). Patients diagnosed with this aggressive clinical syndrome, known as leptomeningeal carcinomatosis, have very poor prognosis. Despite improvements in detecting cerebrospinal fluid tumor cells (CSFTCs), information regarding their molecular biology is extremely limited. In our recent work, we utilized a protocol previously used for circulating tumor cell isolation to purify tumor cells from the CSF. We then performed genomic characterization of CSFTCs as well as archival tumors from the same patient. Here, we describe the microarray data and quality controls associated with our study published in the Cancer Research journal in 2013 [1]. We also provide an R script containing code for quality control of microarray data and assessment of copy number calls. The microarray data has been deposited into Gene Expression Omnibus under accession # GSE46068. PMID- 26484072 TI - Genome-wide mapping of Painting of fourth on Drosophila melanogaster salivary gland polytene chromosomes. AB - The protein Painting of fourth (POF) in Drosophila melanogaster specifically targets and stimulates expression output from the heterochromatic 4th chromosome, thereby representing an autosome specific protein [1,2]. Despite the high specificity for chromosome 4 genes, POF is occasionally observed binding to the cytological region 2L:31 in males and females [3] and two loci on the X chromosome, PoX1 and PoX2 only in females [4]. Here we provide a detailed description of the experimental design and analysis of the tiling array data presented by Lundberg and colleagues in G3: Genes, Genomes, Genetics 2013 [4], where the female specific POF binding to PoX1 and PoX2 loci on the X chromosome was reported. We show the genome-wide high resolution binding profile of the POF protein where these different POF binding sites are detected. The complete data set is available at http://www.ncbi.nlm.nih.gov/geo/ (accession: GSE45402). PMID- 26484074 TI - Identification of the new gene Zrsr1 to associate with the pluripotency state in induced pluripotent stem cells (iPSCs) using high throughput sequencing technology. AB - Finding the markers to predict the quality of induced pluripotent stem cells (iPSCs) will accelerate its practical application. The fully pluripotent iPSCs has been determined as viable all-iPSC mice can be generated through tetraploid (4N) complementation. The activation of the imprinted Dlk1-Dio3 gene cluster was reported to correlate with the pluripotency of iPSCs. However, recent studies demonstrated that the loss of imprinting at the Dlk1-Dio3 locus does not strictly correlate with the reduced pluripotency of iPSCs. In our study (ref [1]), iPSC lines with the same genetic background and proviral integration sites were established, and the pluripotency state of each iPSC line was well characterized using tetraploid (4N) complementation assay. The gene expression and global epigenetic modifications of "4N-ON" and the corresponding "4N-OFF" iPSC lines were compared through deep sequencing analysis of mRNA expression, small RNA profiling, histone modifications (H3K4me3, H3K27me3 and H3K4me2) and DNA methylation. Very few differences were detected in the iPSC lines that were investigated. However, an imprinted gene, Zrsr1 was disrupted in the "4N-OFF" iPSC lines. Here we provide more detail about the dataset and the R script with additional data for others to repeat the finding. PMID- 26484073 TI - Identification of deleterious nsSNPs in alpha, MU, pi and theta class of GST family and their influence on protein structure. AB - GST family genes have a critical role in xenobiotic metabolism and drug resistance. Among the GST family the GST-MU, GST-pi, GST-alpha and GST-theta are the most abundant classes and have a major role in the carcinogen detoxification process. Nevertheless the activity of these enzymes may differ due to polymorphisms which ultimately results in interindividual susceptibility to cancer development. In this work, we have analyzed the potentially deleterious nsSNPs that can alter the function of these genes. As a result among the nsSNPs, 101 (42.61%) were found to be deleterious by a sequence homology-based tool, 67 (28.27%) by a structure homology based tool and a total of 59 (24.89%) by both. We propose a modeled structure of the five highly deleterious mutant proteins. Our results will provide useful information in selecting target SNPs that are likely to have an impact on GST activity and contribute to an individual's susceptibility to the disease. PMID- 26484075 TI - A ChIP-on-chip tiling array approach detects functional histone-free regions associated with boundaries at vertebrate HOX genes. AB - Hox genes impart segment identity to body structures along the anterior-posterior axis and are crucial for proper development. A unique feature of the Hox loci is the collinearity between the gene position within the cluster and its spatial expression pattern along the body axis. However, the mechanisms that regulate collinear patterns of Hox gene expression remain unclear, especially in higher vertebrates. We recently identified novel histone-free regions (HFRs) that can act as chromatin boundary elements demarcating successive murine Hox genes and help regulate their precise expression domains (Srivastava et al., 2013). In this report, we describe in detail the ChIP-chip analysis strategy associated with the identification of these HFRs. We also provide the Perl scripts for HFR extraction and quality control analysis for this custom designed tiling array dataset. PMID- 26484076 TI - CTCF regulates positioning of the human cystic fibrosis gene in association with a histone deacetylase. AB - The nuclear positioning of mammalian genes often correlates with their functional state. For instance, the human cystic fibrosis transmembrane conductance regulator (CFTR) gene associates with the nuclear periphery in its inactive state, but occupies interior positions when active. Treatment with the histone deacetylase inhibitor trichostatin a (TSA) changes the radial positioning of the CFTR gene in HeLa S3 cells. The gene relocates from the nuclear periphery to the nuclear interior. In Calu-3 cells the gene is located in the nuclear interior. To identify potential regulatory elements for the positioning of CFTR, the histone H3 and H4 acetylation patterns of untreated and TSA-treated HeLa S3 and untreated Calu-3 cells were determined by ChIP-chip. Here is a detailed description of the datasets associated with the study by Muck et al. published in the Journal of Cellular Biochemistry in 2012. PMID- 26484077 TI - Identification of TEL-AML1 (ETV6-RUNX1) associated DNA and its impact on mRNA and protein output using ChIP, mRNA expression arrays and SILAC. AB - The contribution of the most common reciprocal translocation in childhood B-cell precursor leukemia t(12;21)(p13;q22) to leukemia development is still under debate. Direct as well as secondary indirect effects of the TEL-AML1 fusion protein are commonly recorded by using cell lines and patient samples, often bearing the TEL-AML1 fusion protein for decades. To identify direct targets of the fusion protein a short-term induction of TEL-AML1 is needed. We here describe in detail the experimental procedure, quality controls and contents of the ChIP, mRNA expression and SILAC datasets associated with the study published by Linka and colleagues in the Blood Cancer Journal [1] utilizing a short term induction of TEL-AML1 in an inducible precursor B-cell line model. PMID- 26484078 TI - Genome-wide profiling of YY1 binding sites during skeletal myogenesis. AB - Skeletal muscle differentiation is regulated by a network of transcription factors, epigenetic regulators and noncoding RNAs. We have recently performed ChIP-seq experiments to explore the genome-wide binding of transcription factor YY1 in skeletal muscle cells. Our results identified thousands of YY1 binding peaks, underscoring its multifaceted functions in muscle cells. In particular, we identified a very high proportion of YY1 binding peaks residing in the intergenic regions, which led to the discovery of some novel lincRNAs under YY1 regulation. Here we describe the details of the ChIP-seq experiments and data analysis procedures associated with the study published by Lu et al. in the EMBO Journal in 2013 [1]. PMID- 26484079 TI - Using SNP array to identify aneuploidy and segmental imbalance in translocation carriers. AB - Translocation is one of the more common structural rearrangements of chromosomes, with a prevalence of 0.2%. The two most common types of chromosomal translocations, Robertsonian and reciprocal, usually result in no obvious phenotypic abnormalities when balanced. However, these are still associated with reproductive risks, such as infertility, spontaneous abortion and the delivery of babies with mental retardation or developmental delay. In recent years, array based whole-genome amplification (WGA) technologies, including microarray comparative genomic hybridization (array CGH; aCGH) and single-nucleotide polymorphism (SNP) micro-arrays, have enabled the screening of every chromosome for whole-chromosome aneuploidy and segmental imbalance. These techniques have been shown to have clinical application for translocation carriers. Promising studies have indicated that array-based PGD of translocation carriers can lead to transfer pregnancy rates of 45-70% [2]. In addition to genetic testing techniques, the embryo biopsy stage (polar body, cleavage embryo or blastocyst) and the mode of embryo transfer (fresh or frozen embryos) can affect the outcome of PGD. It is now generally recommended that blastomere biopsy should be replaced by blastocyst biopsy to avoid a high mosaic rate and biopsy-related damage to cleavage-stage embryos, which might affect embryo development. However, more clinical data are required to confirm that the technique of SNP array-based PGD (SNP-PGD) combined with trophectoderm (TE) biopsy and frozen embryo transfer (FET) is superior to traditional FISH-PGD combined with Day 3 (D3) blastomere biopsy and fresh embryo transfer. PMID- 26484080 TI - Transcriptional dysregulation of the multifunctional zinc finger factor 423 in acute lymphoblastic leukemia of childhood. AB - Differentiation arrest is a hallmark of acute lymphoblastic leukemia (ALL). Among a variety of structural and chromosomal alterations, especially mutations in genes encoding for regulators of B cell differentiation are common. The objective of this study was a comprehensive assessment of transcriptional dysregulation and high-resolution genomic profiling of B cell differentiation factors. Here we provide extended materials and methods regarding transcriptome and genome-wide copy number variation analyses published by Harder et al. [1]. Our data provide a resource for the identification of yet undefined factors that play a putative functional role in leukemogenesis such as ZNF423, whose aberrant expression interferes with B-cell differentiation. PMID- 26484082 TI - Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU) treatment. AB - Standard methodology for identifying chemical carcinogens is both time-consuming and resource intensive. Researchers are actively investigating how new technologies can be used to identify chemical carcinogens in a more rapid and cost-effective manner. Here we performed a toxicogenomic case study of the liver carcinogen furan. Full study and mode of action details were previously published in the Journal of Toxicology and Applied Pharmacology. Female B6C3F1 mice were sub-chronically treated with two non-carcinogenic (1 and 2 mg/kg bw) and two carcinogenic (4 and 8 mg/kg bw) doses of furan for 21 days. Half of the mice in each dose group were also treated with 0.02% bromodeoxyuridine (BrdU) for five days prior to sacrifice [13]. Agilent gene expression microarrays were used to measure changes in liver gene and long non-coding RNA expression (published in Toxicological Sciences). Here we describe the experimental and quality control details for the microarray data. We also provide the R code used to analyze the raw data files, produce fold change and false discovery rate (FDR) adjusted p values for each gene, and construct hierarchical clustering between datasets. PMID- 26484081 TI - cFLIP expression is altered in severe corticosteroid-resistant asthma. AB - Dysregulation of alternative splicing of mRNA precursors is known to contribute to numerous human diseases. In this study we carried out the first systematic search for asthma-associated changes in alternative splicing events, using a model of Aspergillus fumigatus (A. fumigatus)-sensitized mice and an exon junction microarray to detect potential changes in alternative splicing. One of the sensitization-associated changes identified in the search was a shift in alternative splicing of the mRNA encoding cFLIP, a modulator of the caspase mediated extrinsic apoptosis pathway. Expanding these studies to human asthma patients, we discovered a significant decrease in the expression of both cFLIP isoforms in severe corticosteroid-resistant asthmatics. Although it is unclear whether these changes were due solely to differences in alternative splicing, these findings provide evidence that dysregulation of the extrinsic apoptosis pathway is part of the underlying immunopathogenesis of severe refractory asthma. PMID- 26484083 TI - GeoChip as a metagenomics tool to analyze the microbial gene diversity along an elevation gradient. AB - To examine microbial responses to climate change, we used a microarray-based metagenomics tool named GeoChip 4.0 to profile soil microbial functional genes along four sites/elevations of a Tibetan mountainous grassland. We found that microbial communities differed among four elevations. Soil pH, temperature, NH4 (+)-N and vegetation diversity were four major attributes affecting soil microbial communities. Here we describe in details the experiment design, the data normalization process, soil and vegetation analyses associated with the study published on ISME Journal in 2014 [1], whose raw data have been uploaded to Gene Expression Omnibus (accession number GSM1185243). PMID- 26484084 TI - Transcriptome profiling for discovery of genes involved in shoot apical meristem and flower development. AB - Flower development is one of the major developmental processes that governs seed setting in angiosperms. However, little is known about the molecular mechanisms underlying flower development in legumes. Employing RNA-seq for various stages of flower development and few vegetative tissues in chickpea, we identified differentially expressed genes in flower tissues/stages in comparison to vegetative tissues, which are related to various biological processes and molecular functions during flower development. Here, we provide details of experimental methods, RNA-seq data (available at Gene Expression Omnibus database under GSE42679) and analysis pipeline published by Singh and colleagues in the Plant Biotechnology Journal (Singh et al., 2013), along with additional analysis for discovery of genes involved in shoot apical meristem (SAM) development. Our data provide a resource for exploring the complex molecular mechanisms underlying SAM and flower development and identification of gene targets for functional and applied genomics in legumes. PMID- 26484085 TI - Genome-wide analysis of high risk human papillomavirus E2 proteins in human primary keratinocytes. AB - The E2 protein is expressed in the early stage of human papillomavirus (HPV) infection that is associated with cervical lesions. This protein plays important roles in regulation of viral replication and transcription. To characterize the role of E2 protein in modulation of cellular gene expression in HPV infected cells, genome-wide expression profiling of human primary keratinocytes (HPK) harboring HPV16 E2 and HPV18 E2 was investigated using microarray. The Principle Components Analysis (PCA) revealed that the expression data of HPV16 E2 and HPV18 E2-transduced HPKs were rather closely clustered. The Venn diagram of modulated genes showed an overlap of 10 common genes in HPV16 E2 expressing HPK and HPV18 E2 expressing HPK. These genes were expressed with significant difference by comparison with control cells. In addition, the distinct sets of modulated genes were detected 14 and 34 genes in HPV16 E2 and HPV18 E2 expressing HPKs, respectively. PMID- 26484086 TI - Genome-wide copy number profiling to detect gene amplifications in neural progenitor cells. AB - DNA sequence amplification occurs at defined stages during normal development in amphibians and flies and seems to be restricted in humans to drug-resistant and tumor cells only. We used array-CGH to discover copy number changes including gene amplifications and deletions during differentiation of human neural progenitor cells. Here, we describe cell culture features, DNA extraction, and comparative genomic hybridization (CGH) analysis tailored towards the identification of genomic copy number changes. Further detailed analysis of amplified chromosome regions associated with this experiment, was published by Fischer and colleagues in PLOS One in 2012 (Fischer et al., 2012). We provide detailed information on deleted chromosome regions during differentiation and give an overview on copy number changes during differentiation induction for two representative chromosome regions. PMID- 26484087 TI - GeoChip profiling of microbial community in response to global changes simulated by soil transplant and cropping. AB - Microbe plays an important role in driving biogeochemical cycles, thus it is of great interest to understand microbial responses and feedbacks to global changes. We have recently analyzed functional potentials of soil microbial community via a high-throughput, microarray-based metagenomic tool named GeoChip 3.0 to illustrate microbial responses to global changes simulated by soil transplant and/or maize cropping. Here we describe detailed experimental design, data collection and pre-processing to support our published studies by Liu et al. [5] and Zhao et al. [14]. PMID- 26484088 TI - Genome-wide binding of transcription factors in inv(16) acute myeloid leukemia. AB - The inv(16) translocation is associated with 5% of AML cases and gives rise to expression of the oncofusion protein CBFbeta-MYH11. Although different molecular mechanisms for the oncogenic activity of this fusion protein have been proposed these were mostly based on in vitro experiments or single loci analysis. Recently, we investigated the genome-wide action of this fusion protein in the context of other hematopoietic transcription factors (Mandoli et al., 2014). Here, we describe in detail the ChIP-seq and RNA-seq methods used to generate the data associated with this study. Our analysis of CBFbeta-MYH11 as well as multiple other hematopoietic transcription factors using ChIP-seq data revealed RUNX1 dependent binding of CBFbeta-MYH11 as well as interaction of the RUNX1/CBFbeta-MYH11 complex with other hematopoietic regulators. Further RNA-seq based analysis suggested that CBFbeta-MYH11 can act both as activator and repressor. PMID- 26484089 TI - Transcriptome analysis of Rpl11-deficient zebrafish model of Diamond-Blackfan Anemia. AB - To comprehensively reflect the roles of Rpl11 on the transcriptome of zebrafish model of Diamond-Blackfan Anemia (DBA), we performed whole-genome transcriptome sequencing on the Illumina Hi-Seq 2000 sequencing platform. Two different transcriptomes of zebrafish Rpl11-deficient and control Morpholino (Mo) embryos were collected and analyzed. The experimental design and methods, including sample preparation, RNA-Seq data evaluation and treatment, were described in details so that representative high-throughput sequencing data were acquired for assessing the actual impacts of Rpl11 on zebrafish embryos. We provided the accession number GSE51326 for easy access to the database. PMID- 26484090 TI - Pitfalls in global normalization of ChIP-seq data in CD4(+) T cells treated with butyrate: A possible solution strategy. AB - Regulatory T cells (Treg) play a central role in the suppression of inflammatory and allergic responses. Colonization of certain gut commensal microbes such as Clostridia class IV and XIVa in the gut can induce development of colonic Treg cells contributing to the maintenance of gut immune homeostasis. Clostridia derived butyrate promotes the differentiation of naive T cells into Treg cells through upregulation of Foxp3, the master transcription factor of Treg cells. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that treatment of naive T cells with butyrate induces Treg-polarizing conditions by enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus. In general, global normalization was utilized for ChIP-seq analysis to compare the data obtained from two or more samples. However, global normalization is not appropriate for the evaluation of ChIP-seq data when treatment can affect the total amount of target protein. Here, we introduce a unique normalization method for ChIP-seq analysis in cells treated with butyrate, a pan-HDAC inhibitor that is likely to affect total acetylation levels of histone H3. PMID- 26484091 TI - Next-generation sequencing of microRNAs in primary human polarized macrophages. AB - Macrophages are important for mounting inflammatory responses to tissue damage or infection by invading pathogens, and therefore modulation of their cellular functions is essential for the success of the immune system as well as for maintaining tissue homeostasis. Small non-coding RNAs are important regulatory elements of gene expression and microRNAs are the most widely known to be fundamental for the proper development of cells of the immune system. Macrophages can exhibit different phenotypes, depending on the cytokine environment they encounter in the affected tissues. We have analyzed the microRNA expression profiles during maturation of human primary monocytes into macrophages and polarization by pro- or anti-inflammatory cytokines. Here we describe the analysis of next-generation sequencing data deposited in EMBL-EBI ArrayExpress under accession number E-MTAB-1969 and associated with the study published by Cobos Jimenez and collaborators in Physiological Genomics in 2014 (1). The data presented here contributes to our understanding of microRNA expression profiles in human monocytes and macrophages and will also serve as a resource for novel microRNAs and other small RNA species expressed in these cells. PMID- 26484092 TI - Human miRNome profiling in colorectal cancer and liver metastasis development. AB - Qualitative alterations or abnormal expression of microRNAs (miRNAs) in colorectal cancer has mainly been demonstrated in primary tumors. The miRNA expression profiles in 78 samples from 46 patients were analyzed to identify changes in miRNA expression level among normal colon mucosa, primary tumor and liver metastasis samples. Using this dataset, we describe the interplay of miRNA groups in regulating pathways that are important for tumor development. Here we describe in details the contents and quality controls for the miRNA expression and clinical data associated with the study published by Pizzini and colleagues in the BMC Genomics in 2013 (Pizzini et al., 2013). Data are deposited in GEO database as GSE35834 series. PMID- 26484093 TI - Gene expression profiling to define the cell intrinsic role of the SKI proto oncogene in hematopoiesis and myeloid neoplasms. AB - The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced gene signatures associated with hematopoietic stem cells and myeloid differentiation. Here we provide detailed experimental methods and analysis for the gene expression profiling described in our recently published study of Singbrant et al. (2014) in Haematologica. Our data sets (available at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE39457) provide a resource for exploring the underlying molecular mechanisms of the involvement of the proto oncogene SKI in hematopoietic stem cell function and development of myeloid neoplasms. PMID- 26484094 TI - Genome-wide epigenetic profiling of breast cancer tumors treated with aromatase inhibitors. AB - Aromatase inhibitors (AI) are extensively used in the treatment of estrogen receptor-positive breast cancers, however resistance to AI treatment is commonly observed. Apart from Estrogen receptor (ERalpha) expression, no predictive biomarkers for response to AI treatment are clinically applied. Yet, since other therapeutic options exist in the clinic, such as tamoxifen, there is an urgent medical need for the development of treatment-selective biomarkers, enabling personalized endocrine treatment selection in breast cancer. In the described dataset, ERalpha chromatin binding and histone marks H3K4me3 and H3K27me3 were assessed in a genome-wide manner by Chromatin Immunoprecipitation (ChIP) combined with massive parallel sequencing (ChIP-seq). These datasets were used to develop a classifier to stratify breast cancer patients on outcome after AI treatment in the metastatic setting. Here we describe in detail the data and quality control metrics, as well as the clinical information associated with the study, published by Jansen et al. [1]. The data is publicly available through the GEO database with accession number GSE40867. PMID- 26484095 TI - Dataset of natural antisense transcripts in P. vivax clinical isolates derived using custom designed strand-specific microarray. AB - Natural antisense transcripts (NATs) have been detected in many organisms and shown to regulate gene expression. Similarly, NATs have also been observed in malaria parasites with most studies focused on Plasmodium falciparum. There were no reports on the presence of NATs in Plasmodium vivax, which has also been shown to cause severe malaria like P. falciparum, until a recent study published by us. To identify in vivo prevalence of antisense transcripts in P. vivax clinical isolates, we performed whole genome expression profiling using a custom designed strand-specific microarray that contains probes for both sense and antisense strands. Here we describe the experimental methods and analysis of the microarray data available in Gene Expression Omnibus (GEO) under GSE45165. Our data provides a resource for exploring the presence of antisense transcripts in P. vivax isolated from patients showing varying clinical symptoms. Related information about the description and interpretation of the data can be found in a recent publication by Boopathi and colleagues in Infection, Genetics and Evolution 2013. PMID- 26484096 TI - Transcriptome profiling of LGR5 positive colorectal cancer cells. AB - The concept of cancer stem cells (CSCs) claims that colorectal carcinomas (CRCs), like normal colorectal epithelium, are organized hierarchically and contain a subpopulation of qualitatively distinct cancer cells. The expression of distinctive surface markers or of certain enzymes is a prerequisite for the isolation and characterization of the CSC population. With respect to CRCs, putative CSCs can be identified by leucine-rich-repeat-containing G-protein coupled receptor 5 (Lgr5, also known as G-protein-coupled receptor 49, Gpr49). However, the precise function of the intestinal stem cell marker Lgr5 in CRCs remains largely unknown. We silenced LGR5 expression in SW480 CRC cells via lentiviral shRNA constructs. This led to the depletion of a morphologically distinct subpopulation of SW480 CRC cells. Microarray gene expression profiling revealed a down-regulation of NOTCH signaling upon LGR5 silencing that could be confirmed by immunohistochemistry. Furthermore, we induced inflammation-driven colon tumors in Lgr5-EGFP-IRES-Cre-ERT2 mice via administration of azoxymethane and dextrane sodium sulfate. The induced tumors were flow-sorted into fractions of epithelial cells that expressed high or low levels of Lgr5 and were characterized using gene expression profiling. Lgr5 high tumor cells showed higher levels of several stem cell-associated genes and higher Wnt signaling than Lgr5 low tumor cells and Lgr5 high normal stem cells. Here we provide a thorough description of our two gene expression datasets including quality control checks uploaded to Gene Expression Omnibus database (data accession number: GSE46200). The analysis and interpretation of our gene expression data and related results have been published recently by Hirsch and colleagues in Carcinogenesis in 2014. PMID- 26484097 TI - Genome comparison of Listeria monocytogenes serotype 4a strain HCC23 with selected lineage I and lineage II L. monocytogenes strains and other Listeria strains. AB - More than 98% of reported human listeriosis cases are caused by specific serotypes within genetic lineages I and II. The genome sequence of Listeria monocytogenes lineage III strain HCC23 (serotype 4a) enables whole genomic comparisons across all three L. monocytogenes lineages. Protein cluster analysis indicated that strain HCC23 has the most unique protein pairs with nonpathogenic species Listeria innocua. Orthology analysis of the genome sequences of representative strains from the three L. monocytogenes genetic lineages and L. innocua (CLIP11262) identified 319 proteins unique to nonpathogenic strains HCC23 and CLIP11262 and 58 proteins unique to pathogenic strains F2365 and EGD-e. BLAST comparison of these proteins with all the sequenced L. monocytogenes and L. innocua revealed 126 proteins unique to serotype 4a and/or L. innocua; 14 proteins were only found in pathogenic serotypes. Some of the 58 proteins unique to pathogenic strains F2365 and EGD-e were previously published and are already known to contribute to listerial virulence. PMID- 26484099 TI - ChIP-seq profiling of the active chromatin marker H3K4me3 and PPARgamma, CEBPalpha and LXR target genes in human SGBS adipocytes. AB - Transcription factors (TFs) represent key factors to establish a cellular phenotype. It is known that several TFs could play a role in disease, yet less is known so far how their targets overlap. We focused here on identifying the most highly induced TFs and their putative targets during human adipogenesis. Applying chromatin immunoprecipitation coupled with deep sequencing (ChIP-Seq) in the human SGBS pre-adipocyte cell line, we identified genes with binding sites in their vicinity for the three TFs studied, PPARgamma, CEBPalpha and LXR. Here we describe the experimental design and quality controls in detail for the deep sequencing data and related results published by Galhardo et al. in Nucleic Acids Research 2014 [1] associated with the data uploaded to NCBI Gene Expression Omnibus (GSE41578). PMID- 26484098 TI - Data in brief: Transcriptome analysis of induced pluripotent stem cells from monozygotic twins discordant for trisomy 21. AB - Down syndrome (DS, trisomy 21), is the most common viable chromosomal disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. In this "Data in Brief" paper, we sum up the whole genome analysis by mRNA sequencing of normal and DS induced pluripotent stem cells that was recently published by Hibaoui et al. in EMBO molecular medicine. PMID- 26484100 TI - Gene expression profiling of non-polyadenylated RNA-seq across species. AB - Transcriptomes are dynamic and unique, with each cell type/tissue, developmental stage and species expressing a different repertoire of RNA transcripts. Most mRNAs and well-characterized long noncoding RNAs are shaped with a 5' cap and 3' poly(A) tail, thus conventional transcriptome analyses typically start with the enrichment of poly(A)+ RNAs by oligo(dT) selection, followed by deep sequencing approaches. However, accumulated lines of evidence suggest that many RNA transcripts are processed by alternative mechanisms without 3' poly(A) tails and, therefore, fail to be enriched by oligo(dT) purification and are absent following deep sequencing analyses. We have described an enrichment strategy to purify non polyadenylated (poly(A)-/ribo-) RNAs from human total RNAs by removal of both poly(A)+ RNA transcripts and ribosomal RNAs, which led to the identification of many novel RNA transcripts with non-canonical 3' ends in human. Here, we describe the application of non-polyadenylated RNA-sequencing in rhesus monkey and mouse cell lines/tissue, and further profile the transcription of non-polyadenylated RNAs across species, providing new resources for non-polyadenylated RNA identification and comparison across species. PMID- 26484101 TI - RNA-Seq analysis of laser-capture microdissected cells of the developing central starchy endosperm of maize. AB - Endosperm is a product of double fertilization, and provides nutrients and signals to the embryo during seed development in flowering plants. Early stages of endosperm development are critical for the development of its storage capacity through synthesis and accumulation of starch and storage proteins. Here we report on the isolation and sequencing of mRNAs from the central portion of the starchy endosperm of Zea mays (maize) B73 at 6 days after pollination. We detected a high level of correlation among the four biological replicates of RNAs isolated using laser-capture microdissection of the cell type. Because the assayed developmental stage precedes the synthesis and accumulation of the major storage proteins and starch in the endosperm, our dataset likely include mRNAs for genes that are involved in control and establishment of these storage programs. The mRNA-Seq data has been deposited in Gene Expression Omnibus (accession number GSE58504). PMID- 26484102 TI - Transcriptomics profiling of human SGBS adipogenesis. AB - Obesity is an ever-growing epidemic where tissue homeostasis is influenced by the differentiation of adipocytes that function in lipid metabolism, endocrine and inflammatory processes. While this differentiation process has been well characterized in mice, limited data is available from human cells. Applying microarray expression profiling in the human SGBS pre-adipocyte cell line, we identified genes with differential expression during differentiation in combination with constraint-based modeling of metabolic pathway activity. Here we describe the experimental design and quality controls in detail for the gene expression and related results published by Galhardo et al. in Nucleic Acids Research 2014 associated with the data uploaded to NCBI Gene Expression Omnibus (GSE41352). PMID- 26484103 TI - The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells - A data description. AB - A large number of breast cancers are characterized by amplification and overexpression of the chromosome segment surrounding the HER2 (ERBB2) oncogene. As the HER2 amplicon at 17q12 contains multiple genes, we have systematically explored the role of the HER2 co-amplified genes in breast cancer cell growth and their relation to trastuzumab resistance. We integrated array comparative genomic hybridization (aCGH) data of the HER2 amplicon from 71 HER2 positive breast tumors and 10 cell lines with systematic functional RNA interference analysis of 23 core amplicon genes with several phenotypic endpoints in a panel of trastuzumab responding and non-responding HER2 positive breast cancer cells. In this Data in Brief we give a detailed description of the experimental procedures and the data analysis methods used in the study (1). PMID- 26484104 TI - Transcriptional profiling of apoptosis-deficient Drosophila mutants. AB - Apoptosis is a fundamental way to remove damaged or unwanted cells during both developmental and post-developmental stages. Apoptosis deficiency leads to various diseases including cancer. To know the physiological changes in apoptosis deficient mutants, we conducted non-biased transcriptomic analysis of Drosophila dark(cd4) mutants. As recently reported, combined with metabolome and genetic analysis, we identified systemic immune response, energy wasting, as well as alteration in S-adenosyl-methionine metabolism in response to necrotic cells [1]. Here, we describe in detail how we obtained validated microarray dataset deposited in Gene Expression Omnibus (GSE47853). Our data provide a resource for searching transcriptional alterations in Drosophila apoptosis-deficient mutants. PMID- 26484105 TI - Third party annotation gene data set of eutherian lysozyme genes. AB - The eutherian comparative genomic analysis protocol annotated most comprehensive eutherian lysozyme gene data set. Among 209 potential coding sequences, the third party annotation gene data set of eutherian lysozyme genes included 116 complete coding sequences that first described seven major gene clusters. As one new framework of future experiments, the present integrated gene annotations, phylogenetic analysis and protein molecular evolution analysis proposed new classification and nomenclature of eutherian lysozyme genes. PMID- 26484106 TI - Profiling DNA supercoiling domains in vivo. AB - Transitions in DNA structure have the capacity to regulate genes, but have been poorly characterised in eukaryotes due to a lack of appropriate techniques. One important example is DNA supercoiling, which can directly regulate transcription initiation, elongation and coordinated expression of neighbouring genes. DNA supercoiling is the over- or under-winding of the DNA double helix, which occurs as a consequence of polymerase activity and is modulated by topoisomerase activity [5]. To map the distribution of DNA supercoiling in nuclei, we developed biotinylated 4,5,8-trimethylpsoralen (bTMP) pull-down to preferentially enrich for under-wound DNA. Here we describe in detail the experimental design, quality controls and analyses associated with the study by Naughton et al. [13] that characterised for the first time the large-scale distribution of DNA supercoiling in human cells (GEO: GSE43488 and GSE43450GSE43488GSE43450). PMID- 26484107 TI - Assessing quality standards for ChIP-seq and related massive parallel sequencing generated datasets: When rating goes beyond avoiding the crisis. AB - Massive parallel DNA sequencing combined with chromatin immunoprecipitation and a large variety of DNA/RNA-enrichment methodologies is at the origin of data resources of major importance. Indeed these resources, available for multiple genomes, represent the most comprehensive catalogue of (i) cell, development and signal transduction-specified patterns of binding sites for transcription factors ('cistromes') and for transcription and chromatin modifying machineries and (ii) the patterns of specific local post-translational modifications of histones and DNA ('epigenome') or of regulatory chromatin binding factors. In addition, (iii) the resources specifying chromatin structure alterations are emerging. Importantly, these types of "omics" datasets populate increasingly public repositories and provide highly valuable resources for the exploration of general principles of cell function in a multi-dimensional genome-transcriptome-epigenome chromatin structure context. However, data mining is critically dependent on the data quality, an issue that, surprisingly, is still largely ignored by scientists and well-financed consortia, data repositories and scientific journals. So what determines the quality of ChIP-seq experiments and the datasets generated therefrom and what refrains scientists from associating quality criteria to their data? In this 'opinion' we trace the various parameters that influence the quality of this type of datasets, as well as the computational efforts that were made until now to qualify them. Moreover, we describe a universal quality control (QC) certification approach that provides a quality rating for ChIP-seq and enrichment-related assays. The corresponding QC tool and a regularly updated database, from which at present the quality parameters of more than 8000 datasets can be retrieved, are freely accessible at www.ngs-qc.org. PMID- 26484108 TI - The miRNAome of Opisthorchis viverrini induced intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer, arising in the biliary ducts that extend into the liver. The highest incidence of ICC occurs in Southeast Asia, particularly in the Mekong River Basin countries of Thailand, Laos, Cambodia, and Vietnam, where it is strongly associated with chronic infection by the food-borne liver fluke Opisthorchis viverrini (OV), one of only three eukaryote pathogens considered Group one carcinogens. Intrahepatic cholangiocarcinoma is usually diagnosed at an advanced stage, with a poor prognosis and survival often less than 24 months. Hence, biomarkers that enable the early detection of ICC would be desirable and have a potentially important impact on the public health in the resource-poor regions where this cancer is most prevalent. As microRNAs (miRNAs) remain well preserved after formalin fixation, there is much interest in developing them as biomarkers that can be investigated using tumor biopsy samples preserved in formalin fixed paraffin embedded (FFPE) tumor blocks. Recently, we reported the first comprehensive profiling of tissue-based miRNA expression using FFPE from the three most common subtypes of OV-induced ICC tumors: moderately differentiated ICC, papillary ICC, and well-differentiated ICC. We observed that each subtype of OV-induced ICC exhibited a distinct miRNA profile, which suggested the involvement of specific sets of miRNAs in the progression of this cancer. In addition, non-tumor tissue adjacent to ICC tumor tissue on the same FFPE block shared a similar miRNA dysregulation profile with the tumor tissue than with normal (non-tumor) liver tissue (individuals without ICC or OV infection). Herein, we provide a detailed description of the microarray analysis procedures used to derive these findings. PMID- 26484109 TI - Transcriptome profiling of gene expression in fall dormant and nondormant alfalfa. AB - Fall dormancy (FD) is an adaptive trait in alfalfa (Medicago sativa L.). It appeared in the regrowth process in late summer or early autumn after alfalfa was harvested. FD affects the biomass accumulation and winter survival in high latitude area. However, the molecular mechanism under FD is still not clear at present. Performing RNA-seq of fall dormant and nondormant alfalfa varieties at different time points, we obtained differentially expressed genes between different FD types or time points. These differentially expressed genes may relate to FD in alfalfa. Here, we provide detailed experimental methods and analysis pipeline in our study (Zhang S et al., De novo Characterization of Fall Dormant and Nondormant Alfalfa (Medicago sativa L.) Transcriptome and Identification of Candidate Genes Relate to Fall Dormancy, submitted for publication) for reproducible research. Data generated in our work provide a resource to help decipher the molecular mechanism of FD in alfalfa. PMID- 26484110 TI - Profiling miRNAs in nasopharyngeal carcinoma FFPE tissue by microarray and Next Generation Sequencing. AB - Nasopharyngeal carcinoma (NPC) is a non-lymphomatous, squamous-cell carcinoma that occurs in the epithelial lining of the nasopharynx. Nasopharyngeal carcinoma has a geographically well-defined distribution worldwide, with the highest prevalence in China, Southeast Asia, and Northern Africa. Symptoms of nascent NPC may be unapparent or trivial, with diagnosis based on the histopathology of biopsied tissue following endoscopy of the nasopharynx. The tumor node metastasis (TNM) staging system is the benchmark for the prognosis of NPC and guides treatment strategy. However, there is a consensus that the TNM system is not sufficiently specific for the prognosis of NPC, as it does not reflect the biological heterogeneity of this tumor, making another biomarker for the detection of NPC a priority. We have previously reported on different approaches for microRNA (miRNA) biomarker discovery for Formalin Fixed Paraffin Embedded (FFPE) NPC tissue samples by both a targeted (microarray) and an untargeted (small RNA-Seq) discovery platform. Both miRNA discovery platforms produced similar results, narrowing the miRNA signature to 1-5% of the known mature human miRNAs, with untargeted (small RNA-Seq approach) having the advantage of indicating "unknown" miRNAs associated with NPC. Both miRNA profiles strongly associated with NPC, providing two potential discovery platforms for biomarker signatures for NPC. Herein, we provide a detailed description of the methods that we used to interrogate FFPE samples to discover biomarkers for NPC. PMID- 26484111 TI - Genome-wide profiling of alternative splicing in Alzheimer's disease. AB - Alternative splicing is a highly regulated process which generates transcriptome and proteome diversity through the skipping or inclusion of exons within gene loci. Identification of aberrant alternative splicing associated with human diseases has become feasible with the development of new genomic technologies and powerful bioinformatics. We have previously reported genome-wide gene alterations in the neocortex of a well-characterized cohort of Alzheimer's disease (AD) patients and matched elderly controls using a commercial exon microarray platform [1]. Here, we provide detailed description of analyses aimed at identifying differential alternative splicing events associated with AD. PMID- 26484112 TI - Does gene length play a role? - Transient regulation of Gcn5 histone acetyltransferase under stress conditions. AB - Gcn5 is a histone modification enzyme that performs its function by global or locus-specific histone acetylation. It is known that Gcn5 involves in stress responses in yeast. Our previous data showed that Gcn5 relocalized to the long genes under IM KCl stress conditions in yeast. Here we use a stress adaptation and recovery model and performed 52 microarrays. By investigating the gene regulation pattern, genome-wide localization of Gcn5, as well as histone modification, we aim to understand the regulation mechanism. The data is available in Gene Expression Omnibus (GEO: SuperSeriesGSE 36601). PMID- 26484113 TI - Gene expression response to EWS-FLI1 in mouse embryonic cartilage. AB - Ewing's sarcoma is a rare bone tumor that affects children and adolescents. We have recently succeeded to induce Ewing's sarcoma-like small round cell tumor in mice by expression of EWS-ETS fusion genes in murine embryonic osteochondrogenic progenitors. The Ewing's sarcoma precursors are enriched in embryonic superficial zone (eSZ) cells of long bone. To get insights into the mechanisms of Ewing's sarcoma development, gene expression profiles between EWS-FLI1-sensitive eSZ cells and EWS-FLI1-resistant embryonic growth plate (eGP) cells were compared using DNA microarrays. Gene expression of eSZ and eGP cells (total, 30 samples) was evaluated with or without EWS-FLI1 expression 0, 8 or 48 h after gene transduction. Our data provide useful information for gene expression responses to fusion oncogenes in human sarcoma. PMID- 26484114 TI - The role of Cockayne Syndrome Protein B in transcription regulation. AB - We investigated the question if CSB (Cockayne Syndrome complementation B) protein actively regulates gene transcription and how mutations in CSB gene affect that regulatory role. Here we describe how we processed and interpreted ChIP-seq data (deposited in Gene Expression Omnibus with accession number GSE50171) obtained during an investigation of that question, and how this analysis assisted in the generation of hypothesis that were subsequently validated using other types of experiment. PMID- 26484115 TI - Deep sequencing of the microRNA expression in fall dormant and non-dormant alfalfa. AB - MicroRNAs (miRNAs) play a critical role in post-transcriptional gene regulation that down-regulates target genes by mRNA degradation or translational repression. Evidence is increasing for their crucial roles during plant development. Identification of miRNAs at the global genome-level by high-throughput sequencing is essential to functionally characterize miRNAs in plants. Alfalfa (Medicago sativa L.) is one of the most widely cultivated perennial forage legumes worldwide. Fall dormancy is an adaptive character related to the biomass production and winter survival in alfalfa. However, little is known about miRNA mediated developmental regulation of fall dormancy in alfalfa. Here, we provide detailed experimental methods and analysis pipeline in our study to identify miRNAs that were responsive to fall dormancy (Fan W et al., Genome-wide identification of different dormant Medicago sativa L. microRNAs in response to fall dormancy, submitted for publication) for reproducible research. The data generated in our work provide meaningful information for understanding the roles of miRNAs in response to seasonal change and growth regulation in alfalfa. PMID- 26484116 TI - Interaction between bisphenol A and dietary sugar affects global gene transcription in Drosophila melanogaster. AB - Human exposure to environmental toxins is a public health issue. The microarray data available in the Gene Expression Omnibus database under accession number GSE55655 and GSE55670GSE55655GSE55670 show the isolated and combined effects of dietary sugar and two organic compounds present in a variety of plastics [bisphenol A (BPA) and Bis(2-ethylhexyl) phthalate (DEHP)] on global gene expression in Drosophila melanogaster. The study was carried out with samples collected from flies exposed to these compounds for a limited period of time (48 h) in the adult stage, or throughout the entire development of the insect. The arrays were normalized using the limma/Bioconductor package. Differential expression was inferred using linear models in limma and BAGEL. The data show that each compound had its unique consequences to gene expression, and that the individual effect of each organic compound is maximized with the joint ingestion of dietary sugar. PMID- 26484117 TI - Differential gene expression of Moraxella catarrhalis upon exposure to human serum. AB - The complement system is an important part of the innate defense against invading pathogens (Blom et al., 2009; [1]). The ability to resist complement-mediated killing is considered to be an important virulence trait for the human-restricted respiratory tract pathogen Moraxella catarrhalis, as most disease-associated M. catarrhalis isolates are complement-resistant (Wirth et al., 2007; [2]). Here we provide a detailed overview of the experimental methods that we have used to study the molecular basis of M. catarrhalis complement-resistance by transcriptome profiling of the bacterium upon exposure to 10% normal human serum (NHS), associated with the study of de Vries et al. published in Molecular Microbiology in 2014 [3]. PMID- 26484118 TI - Transcriptional profiling of the postnatal brain of the Ts1Cje mouse model of Down syndrome. AB - The Ts1Cje mouse model of Down syndrome (DS) has partial trisomy of mouse chromosome 16 (MMU16), which is syntenic to human chromosome 21 (HSA21). It develops various neuropathological features demonstrated by DS patients such as reduced cerebellar volume [1] and altered hippocampus-dependent learning and memory [2,3]. To understand the global gene expression effect of the partially triplicated MMU16 segment on mouse brain development, we performed the spatiotemporal transcriptome analysis of Ts1Cje and disomic control cerebral cortex, cerebellum and hippocampus harvested at four developmental time-points: postnatal day (P)1, P15, P30 and P84. Here, we provide a detailed description of the experimental and analysis procedures of the microarray dataset, which has been deposited in the Gene Expression Omnibus (GSE49050) database. PMID- 26484119 TI - MicroRNA of the fifth-instar posterior silk gland of silkworm identified by Solexa sequencing. AB - No special studies have been focused on the microRNA (miRNA) in the fifth-instar posterior silk gland of Bombyx mori. Here, using next-generation sequencing, we acquired 93.2 million processed reads from 10 small RNA libraries. In this paper, we tried to thoroughly describe how our dataset generated from deep sequencing which was recently published in BMC genomics. Results showed that our findings are largely enriched silkworm miRNA depository and may benefit us to reveal the miRNA functions in the process of silk production. PMID- 26484120 TI - Genome-wide mRNA and miRNA expression data analysis to screen for markers involved in sarcomagenesis in human chondrosarcoma cell lines. AB - Genes and miRNAs involved in sarcomagenesis related pathways are unknown and therefore signaling events leading to mesenchymal cell transformation to sarcoma are poorly elucidated. Exiqon and Illumina microarray study on human chondrosarcoma JJ012 and chondrocytes C28 cell lines to compare and analyze the differentially expressed miRNAs and their gene targets was recently published in the Journal Tumor Biology in 2014. Here we describe in details the contents and quality controls for the miRNA and gene expression data associated with the study that is relevant to this dataset. PMID- 26484121 TI - Genome-wide analysis of thapsigargin-induced microRNAs and their targets in NIH3T3 cells. AB - Disruption of the endoplasmic reticulum (ER) homeostasis is the cause of ER stress. We performed microRNA (miRNA) analysis (deep sequencing) to search for coping responses (including signaling pathways) induced by disrupted ER Ca(2 +) homeostasis. Our focus was on a specific branch of UPR namely the bi-functional protein kinase/endoribonuclease inositol-requiring element 1alpha (IRE1alpha). Activated IRE1alpha undergoes autophosphorylation and oligomerization, leading to the activation of the endoribonuclease domain and splicing of the mRNA encoding XBP1 specific transcription factor. This processing changes the coding reading frame, producing a potent transcription factor termed XBP1s. We utilized the XBP1 splicing luciferase reporter to screen for modulators of the IRE1alpha branch of the unfolded protein response (UPR). Here, we describe a detailed experimental design and bioinformatics analysis of ER Ca(2 +) depletion (thapsigargin treated) induced microRNA (deep sequencing) profile. The data can be access at the Gene Expression Omnibus (GEO), the National Center for Biotechnology Information (NCBI), reference number GSE57138. PMID- 26484122 TI - Genome-wide profiling to analyze the effects of Ox-LDL induced THP-1 macrophage derived foam cells on gene expression. AB - Atherosclerosis has a high incidence and is harmful to human health. An elevated level of oxidized low-density lipoprotein (Ox-LDL) is one of the major risk factors for atherosclerosis. During atherogenesis progression, circulating monocytes adhere to the intima and differentiate into macrophages. After differentiation, intimal macrophages intake Ox-LDL via scavenger receptors, thereby transforming into foam cells. Foam cell formation due to excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis. To gain a molecular understanding of the effect of Ox-LDL in atherosclerosis development, we conducted a genome-wide analysis of the Ox-LDL induced macrophage transformation by microarray gene expression profiling. Here we describe in details the contents and quality controls for the gene expression and related results associated with the data uploaded to Gene Expression Omnibus (accession number GSE54039). PMID- 26484123 TI - Gene expression profiling of mononuclear cells from patients with sepsis secondary to community-acquired pneumonia. AB - Mechanisms governing the inflammatory response during sepsis involve crosstalk between diverse signaling pathways, but current knowledge provides an incomplete picture of the syndrome. Microarray-based expression profiling is a powerful approach for the investigation of complex clinical conditions such as sepsis. In this study, we investigated whole-genome expression profiles in mononuclear cells from septic patients admitted in intensive care units with community-acquired pneumonia. Blood samples were collected at the time of sepsis diagnosis and seven days later since we aimed to evaluate the role of biological processes or genes possibly involved in patient recovery. Here we provide a detailed description of the study design, including clinical information, experimental methods and procedures regarding data analysis. Metadata corresponding to microarray results deposited in the database Gene Expression Omnibus (GEO) under the accession number GSE48080 are also described in this report. Our dataset allows the identification of genes possibly associated with host defense to infection as well as gene expression patterns associated with patient outcome. PMID- 26484124 TI - Gene expression in response to cyclic mechanical stretch in primary human dermal fibroblasts. AB - The human dermal skin is permanently exposed to mechanical stress, for instance during facial expression, which might cause wrinkles with age. Cyclic mechanical stretching of cells results in cellular and cytoskeleton alignment perpendicular to the stretch direction regulating cellular response. With gene expression profiling it was aimed to identify the differentially expressed genes associated with the regulation of the cytoskeleton to investigate the stretch-induced cell alignment mechanism. Here, the transcription activity of the genome in response to cyclic mechanical stress was measured using DNA microarray technology with Agilent SurePrint G3 Human GE 8x60k Microarrays, based on the overall measurement of the mRNA. Gene expression was measured at the beginning of the alignment process showing first reoriented cells after 5 h stretching and at the end after 24 h, where nearly all cells are aligned. Gene expression data of control vs. stretched primary human dermal fibroblasts after 5 h and 24 h demonstrated the regulation of differentially expressed genes associated with metabolism, differentiation and morphology and were deposited at http://www.ncbi.nlm.nih.gov/geo with the accession number GSE58389. PMID- 26484125 TI - Global transcriptional analysis of short-term hepatic stress responses in Atlantic salmon (Salmo salar) exposed to depleted uranium. AB - Potential environmental hazards of radionuclides are often studied at the individual level. Sufficient toxicogenomics data at the molecular/cellular level for understanding the effects and modes of toxic action (MoAs) of radionuclide is still lacking. The current article introduces transcriptomic data generated from a recent ecotoxicological study, with the aims to characterize the MoAs of a metallic radionuclide, deplete uranium (DU) in an ecologically and commercially important fish species, Atlantic salmon (Salmo salar). Salmon were exposed to three concentrations (0.25, 0.5 and 1.0 mg/L) of DU for 48 h. Short-term global transcriptional responses were studied using Agilent custom-designed high density 60,000-feature (60 k) salmonid oligonucleotide microarrays (oligoarray). The microarray datasets deposited at Gene Expression Omnibus (GEO ID: GSE58824) were associated with a recently published study by Song et al. (2014) in BMC Genomics. The authors describe the experimental data herein to build a platform for better understanding the toxic mechanisms and ecological hazard of radionuclides such as DU in fish. PMID- 26484126 TI - Base-resolution DNA methylation landscape of zebrafish brain and liver. AB - Zebrafish (Danio rerio) is a vertebrate model organism that is widely used for studying a plethora of biological questions, including developmental processes, effects of external cues on phenotype, and human disease modeling. DNA methylation is an important epigenetic mechanism that contributes to gene regulation, and is prevalent in all vertebrates. Reduced representation bisulfite sequencing (RRBS) is a cost-effective technique to generate genome-wide DNA methylation maps and has been used in mammalian genomes (e.g., human, mouse and rat) but not in zebrafish. High-resolution DNA methylation data in zebrafish are limited: increased availability of such data will enable us to model and better understand the roles, causes and consequences of changes in DNA methylation. Here we present five high-resolution DNA methylation maps for wild-type zebrafish brain (two pooled male and two pooled female methylomes) and liver. These data were generated using the RRBS technique (includes 1.43 million CpG sites of zebrafish genome) on the Illumina HiSeq platform. Alignment to the reference genome was performed using the Zv9 genome assembly. To our knowledge, these datasets are the only RRBS datasets and base-resolution DNA methylation data available at this time for zebrafish brain and liver. These datasets could serve as a resource for future studies to document the functional role of DNA methylation in zebrafish. In addition, these datasets could be used as controls while performing analysis on treated samples. PMID- 26484127 TI - Microarray profiling to analyse adult cardiac fibroblast identity. AB - Heart failure is one of the leading causes of death worldwide [1-4]. Current therapeutic strategies are inefficient and cannot cure this chronic and debilitating condition [5]. Ultimately, heart transplants are required for patient survival, but donor organs are scarce in availability and only prolong the life-span of patients for a limited time. Fibrosis is one of the main pathological features of heart failure [6,7], caused by inappropriate stimulation of fibroblasts and excessive extracellular matrix production. Therefore, an in depth understanding of the cardiac fibroblast is essential to underpin effective therapeutic treatments for heart failure [5]. Fibroblasts in general have been an underappreciated cell type, regarded as relatively inert and providing only basic functionality; they are usually referred to as the 'biological glue' of all tissues in the body. However, more recent literature suggests that they actively participate in organ homeostasis and disease [7,8]. We have recently uncovered a unique molecular identity for fibroblasts isolated from the heart [9], expressing a set of cardiogenic transcription factors that have been previously associated with cardiomyocyte ontogenesis. This signature suggests that cardiac fibroblasts may be ideal for use in stem cell replacement therapies, as they may retain the memory of where they derive from embryologically. Our data also revealed that about 90% of fibroblasts from both tail and heart origins share a cell surface signature that has previously been described for mesenchymal stem cells (MSCs), raising the possibility that fibroblasts and MSCs may in fact be the same cell type. Thus, our findings carry profound implications for the field of regenerative medicine. Here, we describe detailed methodology and quality controls related to the gene expression profiling of cardiac fibroblasts, deposited at the Gene Expression Omnibus (GEO) under the accession number GSE50531. We also provide the R code to easily reproduce the data quantification and analysis processes. PMID- 26484128 TI - Gene expression in rat models for inter-generational transmission of islet dysfunction and obesity. AB - Paternal high fat diet (HFD) consumption triggers unique gene signatures, consistent with premature aging and chronic degenerative disorders, in both white adipose tissue (RpWAT) and pancreatic islets of daughters. In addition to published data in Nature, 2010, 467, 963-966 (GSE: 19877, islet) and FASEB J 2014, 28, 1830-1841 (GSE: 33551, RpWAT), we describe here additional details on systems-based approaches and analysis to develop our observations. Our data provides a resource for exploring the complex molecular mechanisms that underlie intergenerational transmission of obesity. PMID- 26484129 TI - Control of dataset bias in combined Affymetrix cohorts of triple negative breast cancer. AB - Heterogenous subtypes of breast cancer need to be analyzed separately. Pooling of datasets can provide reasonable sample sizes but dataset bias is an important concern. We assembled a combined dataset of 579 Affymetrix microarrays from triple negative breast cancer (TNBC) in Gene Expression Omnibus (GEO) series GSE31519. We developed a method for selecting comparable datasets and to control for the amount of dataset bias of individual probesets. PMID- 26484130 TI - A pathogenesis-based transcript signature in donor-specific antibody-positive kidney transplant patients with normal biopsies. AB - Affymetrix Human Gene 1.0-ST arrays were used to assess the gene expression profiles of kidney transplant patients who presented with donor-specific antibodies (DSAs) but showed normal biopsy histopathology and did not develop antibody-mediated rejection (AMR). Biopsy and whole-blood profiles for these DSA positive, AMR-negative (DSA +/AMR-) patients were compared to both DSA-positive, AMR-positive (DSA +/AMR +) patients as well as DSA-negative (DSA -) controls. While individual gene expression changes across sample groups were relatively subtle, gene-set enrichment analysis using previously identified pathogenesis based transcripts (PBTs) identified a clear molecular signature involving increased rejection-associated transcripts in AMR - patients. Results from this study have been published in Kidney International (Hayde et al., 2014 [1]) and the associated data have been deposited in the GEO archive and are accessible via the following link: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE50084. PMID- 26484131 TI - Genome-wide gene expression profiling of acute metal exposures in male zebrafish. AB - To capture global responses to metal poisoning and mechanistic insights into metal toxicity, gene expression changes were evaluated in whole adult male zebrafish following acute 24 h high dose exposure to three metals with known human health risks. Male adult zebrafish were exposed to nickel chloride, cobalt chloride or sodium dichromate at concentrations corresponding to their respective 96 h LC20, LC40 and LC60 (i.e. 96 h concentrations at which 20%, 40% and 60% lethality is expected, respectively). Histopathology was performed on a subset of metal-exposed zebrafish to phenotypically anchor transcriptional changes associated with each metal exposure. Here we describe in detail the contents and quality controls for the gene expression and other data associated with the study published by Hussainzada and colleagues in BMC Pharmacology and Toxicology (Hussainzada et al., 2014) with the data uploaded to Gene Expression Omnibus (accession number GSE50648). PMID- 26484132 TI - Transcriptome analysis of bladder biopsy from interstitial cystitis/bladder pain syndrome patients. AB - Interstitial cystitis and bladder pain syndrome (IC/BPS) are terms used to describe a heterogeneous chronic pelvic and bladder pain disorder. Despite its significant prevalence, the disease etiology is not well understood and providing diagnosis and treatment can be challenging. In our study, published recently in the Journal of Urology (Colaco et al., 2014), we describe the use of microarrays as a tool to characterize IC/BPS and to determine if there are clinical factors that correlate with gene expression. This data-in-brief article describes the methodology for that study, including data analysis, in further detail. Deposited data can be found in the Gene Expression Omnibus (GEO) database: GSE57560. PMID- 26484133 TI - Lysophosphatidic acid (LPA) 18:1 transcriptional regulation of primary human gingival fibroblasts. AB - The pleiotropic, bioactive lipid lysophosphatidic acid [(LPA), 1-acyl-sn-glycerol 3-phosphate] exerts critical regulatory actions in physiology and pathophysiology in many systems. It is present in normal bodily fluids, and is elevated in pathology (1). In vivo, "LPA" exists as distinct molecular species, each having a single fatty acid of varying chain length and degree of unsaturation covalently attached to the glycerol backbone via an acyl, alkyl, or alkenyl link. These species differ in affinities for the individual LPA receptors [(LPARs), LPA1-6] and coupling to G proteins (2). However, LPA 18:1 has been and continues to be the most commonly utilized species in reported studies. The actions of "LPA" remain poorly defined in oral biology and pathophysiology. Our laboratory has addressed this knowledge gap by studying in vitro the actions of the major human salivary LPA species [18:1, 18:0, and 16:0 (3)] in human oral cells (4-7). This includes gingival fibroblasts (GF), which our flow cytometry data from multiple donors found that they express LPA1-5 (6). We have also reported that these species are ten-fold elevated to pharmacologic levels in the saliva and gingival crevicular fluid obtained from patients with moderate-severe periodontitis (8). As the potential of LPA to regulate transcriptional activity had not been examined in the oral system, this study used whole human genome microarray analysis to test the hypothesis that LPA 18:1-treated human GF would show significant changes in gene transcripts relevant to their biology, wound-healing, and inflammatory responses. LPA 18:1 was found to significantly regulate a large, complex set of genes critical to GF biology in these categories and to periodontal disease. The raw data has been deposited at NCBI's GEO database as record GSE57496. PMID- 26484134 TI - Transcriptional ontogeny of first trimester human fetal and placental mesenchymal stem cells: Gestational age versus niche. AB - Early fetal and placental MSCs have translationally-advantageous characteristics compared to later pregnancy MSCs. During the first trimester, the fetus and placenta grow rapidly with divergent developmental requirements, but studies comparing mesenchymal stem cells (MSCs) from different origins have paid little attention to the effect of gestational age over this temporal window. Here we present the transcriptome through first trimester development of MSC isolated from fetal bone marrow (BM) or placental structures. Samples were collected weekly from 8 to 12 weeks. The raw microarray data are available on the ArrayExpress database (www.ebi.ac.uk/arrayexpress) under accession number E-TABM 1224. Additionally, the data have been integrated into the stem cell collaboration platform www.Stemformatics.org. These data provide a valuable resource for developmental biology and stem cell investigation. PMID- 26484135 TI - Gene expression profiling of human fibrocytic myeloid-derived suppressor cells (f MDSCs). AB - Myeloid-derived suppressor cells (MDSCs) have been shown to control self-reactive and anti-graft effector T-cells in autoimmunity and transplantation, but their therapeutic use is limited by their scarce availability in the peripheral blood of tumor-free donors. We isolated and characterized a novel population of myeloid suppressor cells, named fibrocytic MDSC (f-MDSC), which are differentiated from umbilical cord blood (UCB) precursors (Zoso et al., 2014). This MDSC subset promotes regulatory T-cell expansion and induces normoglycemia in a xenogeneic model of type 1 diabetes. Here we describe in details the experimental design and the bioinformatics analyses of the gene expression dataset used to investigate the molecular mechanisms at the base of MDSC tolerogenic and suppressive properties. We also provide an R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset. Raw and pre processed data are available at Gene Expression Omnibus under accession GSE52376. PMID- 26484136 TI - An in vivo transcriptome data set of natural antisense transcripts from Plasmodium falciparum clinical isolates. AB - Antisense transcription is pervasive among biological systems and one of the products of antisense transcription is natural antisense transcripts (NATs). Emerging evidences suggest that they are key regulators of gene expression. With the discovery of NATs in Plasmodium falciparum, it has been suggested that these might also be playing regulatory roles in this parasite. However, all the reports describing the diversity of NATs have come from parasites in culture condition except for a recent study published by us. In order to explore the in vivo diversity of NATs in P. falciparum clinical isolates, we performed a whole genome expression profiling using a strand-specific 244 K microarray that contains probes for both sense and antisense transcripts. In this report, we describe the experimental procedure and analysis thereof of the microarray data published recently in Gene Expression Omnibus (GEO) under accession number GSE44921. This published data provide a wealth of information about the prevalence of NATs in P. falciparum clinical isolates from patients with diverse malaria related disease conditions. Supplementary information about the description and interpretation of the data can be found in a recent publication by Subudhi et al. in Experimental Parasitology (2014). PMID- 26484137 TI - Whole transcriptome analysis for T cell receptor-affinity and IRF4-regulated clonal expansion of T cells. AB - Clonal population expansion of T cells during an immune response is dependent on the affinity of the T cell receptor (TCR) for its antigen [1]. However, there is little understanding of how this process is controlled transcriptionally. We found that the transcription factor IRF4 was induced in a manner dependent on TCR affinity and was critical for the clonal expansion and maintenance of effector function of antigen-specific CD8(+) T cells. We performed a genome-wide expression profiling experiment using RNA sequencing technology (RNA-seq) to interrogate global expression changes when IRF4 was deleted in CD8(+) T cells activated with either a low or high affinity peptide ligand. This allowed us not only to determine IRF4-dependent transcriptional changes but also to identify transcripts dependent on TCR-affinity [2]. Here we describe in detail the analyses of the RNA-seq data, including quality control, read mapping, quantification, normalization and assessment of differential gene expression. The RNA-seq data can be accessed from Gene Expression Omnibus database (accession number GSE49929). PMID- 26484138 TI - The high-throughput sequencing of small RNAs profiling in wide hybridisation and allopolyploidisation between Brassica rapa and Brassica nigra. AB - Small RNAs play an important role in maintaining the genome reconstruction and stability in the plant. However, little is known regarding the role of small RNAs during the process of wide hybridisation and chromosome doubling. Therefore, the changes in the small RNAs were assessed during the formation of an allodiploid (genome: AB) and its allotetraploid (genome: AABB) between Brassica rapa (?) and Brassica nigra (?) in the present study. Here, the experimental methods described in details, RNA-seq data (available at Gene Expression Omnibus database under GSE61872) and analysis published by Ghani et al. [1]. The study showed that small RNAs play an important role in maintaining the genome stability, and regulate gene expression which induces the phenotype variation in the formation of an allotetraploid. This may play an important role in the occurrence of heterosis in the allotetraploid. PMID- 26484139 TI - Expression-profiling of apoptosis induced by ablation of the long ncRNA TRPM2-AS in prostate cancer cell. AB - We recently identified the long non-coding RNA (ncRNA) TRPM2-AS as a key regulator of survival in prostate cancer [1]. This essential role, coupled to the TRPM2-AS low-expression levels in healthy tissues, makes this ncRNA a suitable therapeutic target for further clinical studies. To get insights into the survival mechanism controlled by this molecule, we ablated its expression in prostate cancer cells and performed a genome-wide analysis of the transcripts differentially regulated in dying cells. Here, we describe in detail the experimental system, methods and quality control for the generation of the microarray data associated with our recent publication [1]. The data are related to [1]. Data have been deposited to the Gene Expression Omnibus (GEO) database repository with the dataset identifier GSE40687. PMID- 26484140 TI - High-throughput whole-genome sequencing of E14 mouse embryonic stem cells. AB - Mouse E14 embryonic stem cells (ESCs) are the most used ESC line, often employed for genome-wide studies involving next generation sequencing analysis [1-5]. More than 2 * 10 E9 sequences made on Illumina platform derived from the genome of E14 embryonic stem cells cultured in our laboratory were used to build a database of about 2.7 * 10 E6 single nucleotide variant [6]. The database was validated using other two sequencing datasets from other laboratory and high overlap was observed. The identified variants are enriched on intergenic regions, but several thousands reside on gene exons and regulatory regions, such as promoters, enhancers, splicing site and untranslated regions of RNA, thus indicating high probability of an important functional impact on the molecular biology of these cells. We created a new E14 genome assembly including the new identified variants and used it to map reads from next generation sequencing data generated in our laboratory or in others on E14 cell line. We observed an increase in the number of mapped reads of about 5%. CpG dinucleotide showed the higher variation frequency, probably because it could be a target of DNA methylation. Data were deposited in GEO datasets under reference GSM1283021 and here: http://epigenetics.hugef-research.org/data.php. PMID- 26484141 TI - Global gene expression profiling data analysis reveals key gene families and biological processes inhibited by Mithramycin in sarcoma cell lines. AB - The role of Mithramycin as an anticancer drug has been well studied. Sarcoma is a type of cancer arising from cells of mesenchymal origin. Though incidence of sarcoma is not of significant percentage, it becomes vital to understand the role of Mithramycin in controlling tumor progression of sarcoma. In this article, we have analyzed the global gene expression profile changes induced by Mithramycin in two different sarcoma lines from whole genome gene expression profiling microarray data. We have found that the primary mode of action of Mithramycin is by global repression of key cellular processes and gene families like phosphoproteins, kinases, alternative splicing, regulation of transcription, DNA binding, regulation of histone acetylation, negative regulation of gene expression, chromosome organization or chromatin assembly and cytoskeleton. PMID- 26484142 TI - Mapping of genomic double-strand breaks by ligation of biotinylated oligonucleotides to forum domains: Analysis of the data obtained for human rDNA units. AB - DNA double-strand breaks (DSBs) are associated with different physiological and pathological processes in different organisms. To understand the role of DSBs in multiple cellular mechanisms, a robust method for genome-wide mapping of chromosomal breaks at one-nucleotide resolution is required. Many years ago, we detected large DNA fragments migrating from DNA-agarose plugs in pulsed-field gels, which we named 'forum domains' [1,2]. Recently, we developed a method for genome-wide mapping of DSBs that produces these 50-150 kb DNA domains using microarrays or 454 sequencing (Tchurikov et al., 2011; 2013). Now we have used Illumina sequencing to map DSBs in repetitive rDNA units in human HEK293T cells. Here we describe in detail the experimental design and bioinformatics analysis of the data deposited in the Gene Expression Omnibus with accession number GSE49302 and associated with the study published in the Journal of Molecular Cell Biology (Tchurikov et al., 2014). PMID- 26484144 TI - The role of protein kinase-C theta in control of epithelial to mesenchymal transition and cancer stem cell formation. AB - The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) induces transition of the epithelial MCF-7 cell line to a mesenchymal phenotype. A subset of the resulting mesenchymal cells has surface markers characteristics of a cancer stem cell (CSC) population. We profiled the transcriptome changes associated with the epithelial to mesenchymal transition and those that occurred in the CSC subset. Using a siRNA knockdown strategy, we examined the extent to which these changes were dependent on the PKC family member, PKC-theta. The importance of the cytoplasmic signaling role of this kinase is well established and in this study, we have shown by PKC-theta ChIP-sequencing analysis that this kinase has a dual role with the ability to also associate with chromatin on a subset of PKC-theta dependent genes. In the associated manuscript (Zafar et al., 2014 [5]) we presented evidence for the first time showing that this nuclear role of PKC-theta is also important for gene induction and mesenchymal/CSC phenotype. Here we describe the analysis associated with the transcriptome and ChIP-seq data presented in Zafar et al. (2014) [5] and uploaded to NCBI Gene Expression Omnibus (GSE53335). PMID- 26484143 TI - Small molecule inhibition of FOXM1: How to bring a novel compound into genomic context. AB - Deregulation of transcription factor (TF) networks is emerging as a major pathogenic event in many human cancers (Darnell, 2002 [1]; Libermann and Zerbini, 2006 [2]; Laoukili et al., 2007 [3]). Small molecule intervention is an attractive avenue to understand TF regulatory mechanisms in healthy and disease state, as well as for exploiting these targets therapeutically (Koehler et al., 2003 [4]; Berg, 2008 [5]; Koehler, 2010 [6]). However, because of their physico chemical properties, TF targeting has been proven to be difficult (Verdine and Walensky, 2007 [7]). The TF FOXM1 is an important mitotic player (Wonsey and Follettie, 2005 [8]; Laoukili et al., 2005 [9]; McDonald, 2005 [10]) also implicated in cancer progression (Laoukili et al., 2007 [3]; Teh, 2011 [11]; Koo, 2012 [12]) and drug resistance development (Kwok et al., 2010 [13]; Carr et al., [14]). Therefore, its inhibition is an attractive goal for cancer therapy. Here, we describe a computational biology approach, by giving detailed insights into methodologies and technical results, which was used to analyze the transcriptional RNA-Seq data presented in our previous work (Gormally et al., 2014 [20]). Our Bioinformatics analysis shed light on the cellular effect of a novel FOXM1 inhibitor (FDI-6) newly identified through a biophysical screen. The data for this report is available at the public GEO repository (accession number http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE58626). PMID- 26484145 TI - Comparison of genomic DNA methylation pattern among septic and non-septic newborns - An epigenome wide association study. AB - DNA methylation is the current strategy in the field of biomarker discovery due to its prognostic efficiency. Its role in prognosis and early diagnosis has been recognized in various types of cancer. Sepsis still remains one of the major causes of neonatal mortality. Delay in diagnosis of sepsis leads to treatment difficulties and poor outcome. In this study, we have done an epigenome wide search to identify potential markers for prognosis of neonatal sepsis which may improve the treatment strategies. We analyzed the CpG methylation status in the epigenome of three septic and non-septic babies using Illumina Infinium HumanMethylation450K methylation microarray. The microarray data was analyzed with Illumina GenomeStudio v2011.1. After screening for biological and clinical significance, we found 81 differentially methylated CpGs located in 64 genes. Bioinformatic analysis using DAVID and GeneMania revealed a panel of differentially methylated protocadherin beta (PCDHB) genes that play vital role in leukocyte cell adhesion and Wnt signaling pathway. Apart, genes like CCS, DNAJA3, and DEGS2 were potentially hyper/hypo methylated which can be utilized in the development of novel biomarkers. This study will be helpful in exploring the role of DNA methylation in the pathophysiology of neonatal sepsis. The complete microarray data can be accessed from the public domain, Gene Expression Omnibus of NCBI (http://www.ncbi.nlm.nih.gov/geo/). The accession number is GSE58651. PMID- 26484146 TI - Whole blood gene expression profiling of neonates with confirmed bacterial sepsis. AB - Neonatal infection remains a primary cause of infant morbidity and mortality worldwide and yet our understanding of how human neonates respond to infection remains incomplete. Changes in host gene expression in response to infection may occur in any part of the body, with the continuous interaction between blood and tissues allowing blood cells to act as biosensors for the changes. In this study we have used whole blood transcriptome profiling to systematically identify signatures and the pathway biology underlying the pathogenesis of neonatal infection. Blood samples were collected from neonates at the first clinical signs of suspected sepsis alongside age matched healthy control subjects. Here we report a detailed description of the study design, including clinical data collected, experimental methods used and data analysis workflows and which correspond with data in Gene Expression Omnibus (GEO) data sets (GSE25504). Our data set has allowed identification of a patient invariant 52-gene classifier that predicts bacterial infection with high accuracy and lays the foundation for advancing diagnostic, prognostic and therapeutic strategies for neonatal sepsis. PMID- 26484147 TI - Comparison of inter- and intraspecies variation in humans and fruit flies. AB - Variation is essential to species survival and adaptation during evolution. This variation is conferred by the imperfection of biochemical processes, such as mutations and alterations in DNA sequences, and can also be seen within genomes through processes such as the generation of antibodies. Recent sequencing projects have produced multiple versions of the genomes of humans and fruit flies (Drosophila melanogaster). These give us a chance to study how individual gene sequences vary within and between species. Here we arranged human and fly genes in orthologous pairs and compared such within-species variability with their degree of conservation between flies and humans. We observed that a significant number of proteins associated with mRNA translation are highly conserved between species and yet are highly variable within each species. The fact that we observe this in two species whose lineages separated more than 700 million years ago suggests that this is the result of a very ancient process. We hypothesize that this effect might be attributed to a positive selection for variability of virus interacting proteins that confers a general resistance to viral hijacking of the mRNA translation machinery within populations. Our analysis points to this and to other processes resulting in positive selection for gene variation. PMID- 26484148 TI - Draft genome sequence of Phomopsis longicolla isolate MSPL 10-6. AB - Phomopsis longicolla is the primary cause of Phomopsis seed decay in soybean. This disease severely affects soybean seed quality by reducing seed viability and oil content, altering seed composition, and increasing frequencies of moldy and/or split beans. It is one of the most economically important soybean diseases. Here, we report the de novo assembled draft genome sequence of the P. longicolla isolate MSPL10-6, which was isolated from field-grown soybean seed in Mississippi, USA. This study represents the first reported genome sequence of a seedborne fungal pathogen in the Diaporthe-Phomopsis complex. The P. longicolla genome sequence will enable research into the genetic basis of fungal infection of soybean seed and provide information for the study of soybean-fungal interactions. The genome sequence will also be valuable for molecular genetic marker development, manipulation of pathogenicity-related genes and development of new control strategies for this pathogen. PMID- 26484149 TI - Whole transcriptome RNA sequencing data from blood leukocytes derived from Parkinson's disease patients prior to and following deep brain stimulation treatment. AB - Recent evidence demonstrates the power of RNA sequencing (RNA-Seq) for identifying valuable and urgently needed blood biomarkers and advancing both early and accurate detection of neurological diseases, and in particular Parkinson's disease (PD). RNA sequencing technology enables non-biased, high throughput, probe-independent inspection of expression data and high coverage and both quantification of global transcript levels as well as the detection of expressed exons and junctions given a sufficient sequencing depth (coverage). However, the analysis of sequencing data frequently presents a bottleneck. Tools for quantification of alternative splicing from sequenced libraries hardly exist at the present time, and methods that support multiple sequencing platforms are especially lacking. Here, we describe in details a whole RNA-Seq transcriptome dataset produced from PD patient's blood leukocytes. The samples were taken prior to, and following deep brain stimulation (DBS) treatment while being on stimulation and following 1 h of complete electrical stimulation cessation and from healthy control volunteers. We describe in detail the methodology applied for analyzing the RNA-Seq data including differential expression of long noncoding RNAs (lncRNAs). We also provide details of the corresponding analysis of in-depth splice isoform data from junction and exon reads, with the use of the software AltAnalyze. Both the RNA-Seq raw (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE42608) and analyzed data (https://www.synapse.org/#!Synapse:syn2805267) may be found valuable towards detection of novel blood biomarkers for PD. PMID- 26484150 TI - Identification and profiling of conserved and novel microRNAs in Laodelphax striatellus in response to rice black-streaked dwarf virus (RBSDV) infection. AB - MicroRNAs (miRNAs) are small non-coding endogenous RNA molecules that play important roles in various biological processes. This study examined microRNA profiles of Laodelphax striatellus using the small RNA libraries derived from virus free (VF) and rice black-streaked dwarf virus (RBSDV) infected (RB) insects. A total of 59 mature miRNAs (46 miRNA families) were identified as conserved insect miRNAs in both VF and RB libraries. Among these conserved miRNAs, 24 were derived from the two arms of 12 miRNA precursors. Nine conserved L. striatellus miRNAs were up-regulated and 12 were down-regulated in response to RBSDV infection. In addition, a total of 20 potential novel miRNA candidates were predicted in the VF and RB libraries. The miRNA transcriptome profiles and the identification of L. striatellus miRNAs differentially expressed in response to RBSDV infection will contribute to future studies to elucidate the complex miRNA mediated regulatory network activated by pathogen challenge in insect vectors. PMID- 26484151 TI - Multipotent human stromal cells isolated from cord blood, term placenta and adult bone marrow show distinct differences in gene expression pattern. AB - Multipotent mesenchymal stromal cells derived from human placenta (pMSCs), and unrestricted somatic stem cells (USSCs) derived from cord blood share many properties with human bone marrow-derived mesenchymal stromal cells (bmMSCs) and are currently in clinical trials for a wide range of clinical settings. Here we present gene expression profiles of human cord blood-derived unrestricted somatic stem cells (USSCs), human placental-derived mesenchymal stem cells (hpMSCs), and human bone marrow-derived mesenchymal stromal cells (bmMSCs), all derived from four different donors. The microarray data are available on the ArrayExpress database (www.ebi.ac.uk/arrayexpress) under accession number E-TABM-880. Additionally, the data has been integrated into a public portal, www.stemformatics.org. Our data provide a resource for understanding the differences in MSCs derived from different tissues. PMID- 26484152 TI - miRNA expression profiling of formalin-fixed paraffin-embedded (FFPE) hereditary breast tumors. AB - Hereditary breast cancer constitutes only 5-10% of all breast cancer cases and is characterized by strong family history of breast and/or other associated cancer types. Only ~ 25% of hereditary breast cancer cases carry a mutation in BRCA1 or BRCA2 gene, while mutations in other rare high and moderate-risk genes and common low penetrance variants may account for additional 20% of the cases. Thus the majority of cases are still unaccounted for and designated as BRCAX tumors. MicroRNAs are small non-coding RNAs that play important roles as regulators of gene expression and are deregulated in cancer. To characterize hereditary breast tumors based on their miRNA expression profiles we performed global microarray miRNA expression profiling on a retrospective cohort of 80 FFPE breast tissues, including 66 hereditary breast tumors (13 BRCA1, 10 BRCA2 and 43 BRCAX), 10 sporadic breast carcinomas and 4 normal breast tissues, using Exiqon miRCURY LNATM microRNA Array v.11.0. Here we describe in detail the miRNA microarray expression data and tumor samples used for the study of BRCAX tumor heterogeneity (Tanic et al., 2013) and biomarkers associated with positive BRCA1/2 mutation status (Tanic et al., 2014). Additionally, we provide the R code for data preprocessing and quality control. PMID- 26484153 TI - An integrated functional genomic analysis identifies the antitumorigenic mechanism of action for PPARgamma in lung cancer cells. AB - Integrating the analysis of the cistrome of a transcription factor by ChIP-Seq with the study of its transcriptional output by microarray or RNA-Seq analysis is a powerful approach to elucidate the genomic functions of a transcription factor. Recently, we employed this approach to determine the mechanism of action by which the nuclear receptor PPARgamma elicits its antitumorigenic effects in lung cancer cells upon activation by TZDs (1). Here we describe in detail the design, contents and quality controls for the gene expression and cistrome analyses associated with our study published in Cell Metabolism in 2014. PMID- 26484154 TI - Impact of the DNA polymerase Theta on the DNA replication program. AB - The physiological function of the human DNA polymerase theta (pol theta) is still unclear despite its in vitro translesion synthesis capacity during DNA damage repair process. However this DNA polymerase is always present along the cell cycle in the absence of replication stress and DNA damage. Is there a different molecular function? We present the genomic data of replication timing in depleted pol theta cells (GSE49693) and in cells overexpressing pol theta (GSE53070) indicating that Pol theta holds a novel role in the absence of external stress as a critical determinant of the replication timing program in human cells. PMID- 26484155 TI - Genome-wide nucleosome occupancy and DNA methylation profiling of four human cell lines. AB - DNA methylation and nucleosome positioning are two key mechanisms that contribute to the epigenetic control of gene expression. During carcinogenesis, the expression of many genes is altered alongside extensive changes in the epigenome, with repressed genes often being associated with local DNA hypermethylation and gain of nucleosomes at their promoters. However the spectrum of alterations that occur at distal regulatory regions has not been extensively studied. To address this we used Nucleosome Occupancy and Methylation sequencing (NOMe-seq) to compare the genome-wide DNA methylation and nucleosome occupancy profiles between normal and cancer cell line models of the breast and prostate. Here we describe the bioinformatic pipeline and methods that we developed for the processing and analysis of the NOMe-seq data published by (Taberlay et al., 2014 [1]) and deposited in the Gene Expression Omnibus with accession GSE57498. PMID- 26484156 TI - Digital gene-expression of alfalfa saponin extract on laying hens. AB - Cardiovascular disease is a major cause of death worldwide, so people are advised to limit their intake of dietary cholesterol [1]. Egg consumption has been seriously reduced because of the high levels of cholesterol [2]. The objective of this study was to evaluate the cholesterol metabolism effects of alfalfa saponin extract (ASE) in liver and ovary tissues using digital gene-expression (DGE) profiling analysis. The liver and ovary tissues were isolated from laying hens fed with ASE for RNA sequencing. Here, we provide detailed experimental methods and analysis pipeline in our study to identify digital gene expression of alfalfa saponin extract on laying hens and analysis pipeline published by Singh and colleagues in the PLOS ONE [3]. The data generated in our work provide meaningful information for understanding the molecular mechanisms underlying the cholesterol lowering effects of ASE. PMID- 26484157 TI - Microarray analysis of Arabidopsis under gold exposure to identify putative genes involved in the synthesis of gold nanoparticles (AuNPs). AB - Very little is known about the genes responsible for Au uptake, reduction and detoxification in plants, which indeed essential to understand the complex trait of AuNP biosynthesis. We designed a targeted experiment to elucidate the response of plant at transcriptional level under Au exposure, and a microarray was performed on root tissue treated with AuCl4 (-) in the absence of nutrient media to record specific gene expression signature. Here, we describe the experimental procedures and data analysis in detail to reproduce the results (available at GEO database under GSE55436) published by Shukla et al. (2014) [1] in the Frontiers in Plant Sciences. The data produced from this study provide significant information of genes which may be used to enhance the AuNP biosynthesis. PMID- 26484158 TI - Transcriptome profiling of male gametophyte development in Nicotiana tabacum. AB - Pollen, an extremely reduced bicellular or tricellular male reproductive structure of flowering plants, serves as a model for numerous studies covering wide range of developmental and physiological processes. The pollen development represents a fragile and vital phase of plant ontogenesis and pollen was among the first singular plant tissues thoroughly characterized at the transcriptomic level (Honys and Twell [5]). Arabidopsis pollen developmental transcriptome has been published over a decade ago (Honys and Twell, 2004) and transcriptomes of developing pollen of other species have followed (Rice, Deveshwar et al. [2]; Triticeae, Tran et al. [11]; upland cotton, Ma et al. [8]). However, the transcriptomic data describing the development of tobacco pollen, a bicellular model for cell biology studies, have been missing. Here we provide the transcriptomic data covering three stages (Tupy et al., 1983) of wild type tobacco (Nicotiana tabacum, cv. Samsun) pollen development: uninucleate microspores (UNM, stage 1), early bicellular pollen (eBCP, stage 3) and late bicellular pollen (lBCP, stage 5) as a supplement to the mature pollen (MP), 4 h pollen tube (PT4), 24 h-pollen tubes (PT24), leaf (LF) and root (RT) transcriptomic data presented in our previous studies (Hafidh et al., 2012a; Hafidh et al., 2012b). We characterized these transcriptomes to refine the knowledge base of male gametophyte-enriched genes as well as genes expressed preferentially at the individual stages of pollen development. Alongside updating the list of tissue-specific genes, we have investigated differentially expressed genes with respect to early expressed genes. Pollen tube growth and competition of pollen tubes in female pistil can be viewed as a race of the fittest. Accordingly, there is an apparent evolutionary trend among higher plants to store significant material reserves and nutrients during pollen maturation. This supply ensures that after pollen germination, the pollen tube utilizes its resource predominantly for its rapid elongation in the female pistil. Previous transcriptomic data from Arabidopsis showed massive expression of genes encoding proteins forming both ribosomal subunits that were accumulated in developing pollen, whereas their expression was not detectable in growing pollen tubes (Honys and Twell, 2004). We observed a similar phenomenon in less advanced bicellular tobacco pollen. Here, we describe in detail how we obtained and analyzed validated microarray dataset deposited in Gene Expression Omnibus (GSE62349). PMID- 26484160 TI - Genome wide mapping of UBF binding-sites in mouse and human cell lines. AB - The upstream binding transcription factor (UBTF, also called UBF) is thought to function exclusively in RNA polymerase I (Pol I)-specific transcription of the ribosomal genes. We recently reported in Sanij et al. (2014) [1] that the two isoforms of UBF (UBF1/2) are enriched at Pol II-transcribed genes throughout the mouse and human genomes. By using chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) of UBF1/2, Pol I, Pol II, H3K9me3, H3K4me4, H3K9ac and H4 hyperacetylation, we reported a correlation of UBF1/2 binding with enrichments in Pol II and markers of active chromatin. In addition, we examined a functional role for UBF1/2 in mediating Pol II transcription by performing expression array analysis in control and UBF1/2 depleted NIH3T3 cells. Our data demonstrate that UBF1/2 bind highly active Pol II-transcribed genes and mediate their expression without recruiting Pol I. Furthermore, we reported ChIP-sequencing analysis of UBF1/2 in immortalized human epithelial cells and their isogenically matched transformed counterparts. Here we report the experimental design and the description of the ChIP-sequencing and microarray expression datasets uploaded to NCBI Sequence Research Archive (SRA) and Gene Expression Omnibus (GEO). PMID- 26484159 TI - Kuwaiti population subgroup of nomadic Bedouin ancestry-Whole genome sequence and analysis. AB - Kuwaiti native population comprises three distinct genetic subgroups of Persian, "city-dwelling" Saudi Arabian tribe, and nomadic "tent-dwelling" Bedouin ancestry. Bedouin subgroup is characterized by presence of 17% African ancestry; it owes it origin to nomadic tribes of the deserts of Arabian Peninsula and North Africa. By sequencing whole genome of a Kuwaiti male from this subgroup at 41X coverage, we report 3,752,878 SNPs, 411,839 indels, and 8451 structural variations. Neighbor-joining tree, based on shared variant positions carrying disease-risk alleles between the Bedouin and other continental genomes, places Bedouin genome at the nexus of African, Asian, and European genomes in concordance with geographical location of Kuwait and Peninsula. In congruence with participant's medical history for morbid obesity and bronchial asthma, risk alleles are seen at deleterious SNPs associated with obesity and asthma. Many of the observed deleterious 'novel' variants lie in genes associated with autosomal recessive disorders characteristic of the region. PMID- 26484161 TI - Motif content comparison between monocot and dicot species. AB - While a number of DNA sequence motifs have been functionally characterized, the full repertoire of motifs in an organism (the motifome) is yet to be characterized. The present study wishes to widen the scope of motif content analysis in different monocot and dicot species that include both rice species, Brachypodium, corn, wheat as monocots and Arabidopsis, Lotus japonica, Medicago truncatula, and Populus tremula as dicots. All possible existing motifs were analyzed in different regions of genomes such as were found in different sets of sequences in these species: the whole genome, core proximal and distal promoters, 5' and 3' UTRs, and the 1st introns. Due to the increased number of species involved in this study compared to previous works, species relationships were analyzed based on the similarity of common motif content. Certain secondary structure elements were inferred in the genomes of these species as well as new unknown motifs. The distribution of 20 motifs common to the studied species were found to have a significantly larger occurrence within the promoters and 3' UTRs of genes, both being regulatory regions. Motifs common to the promoter regions of japonica rice, Brachypodium, and corn were also found in a number of orthologous and paralogous genes. Some of our motifs were found to be complementary to miRNA elements in Brachypodium distachyon and japonica rice. PMID- 26484162 TI - Metagenomic sequence of saline desert microbiota from wild ass sanctuary, Little Rann of Kutch, Gujarat, India. AB - We report Metagenome from the saline desert soil sample of Little Rann of Kutch, Gujarat State, India. Metagenome consisted of 633,760 sequences with size 141,307,202 bp and 56% G + C content. Metagenome sequence data are available at EBI under EBI Metagenomics database with accession no. ERP005612. Community metagenomics revealed total 1802 species belonged to 43 different phyla with dominating Marinobacter (48.7%) and Halobacterium (4.6%) genus in bacterial and archaeal domain respectively. Remarkably, 18.2% sequences in a poorly characterized group and 4% gene for various stress responses along with versatile presence of commercial enzyme were evident in a functional metagenome analysis. PMID- 26484163 TI - Transcriptomic profiling of trichloroethylene exposure in male mouse liver. AB - Chronic Trichloroethylene (TCE) exposure could induce hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s) for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE for 5 days. As a beginning step, we profiled gene expression alterations induced by the TCE in mouse livers. Here we describe in detail the experimental methods, quality controls, and other information associated with our data deposited into Gene Expression Omnibus (GEO) under GSE58819. Our data provide useful information for gene expression responses to TCE in mouse liver. PMID- 26484164 TI - Transcriptome analysis of response to drought in poplar interspecific hybrids. AB - To investigate the response of poplar hybrids to drought, leaves were collected from plants to which water was suspended for 8 and 13 days. After measuring the respective relative water content, RNAs were isolated from leaves of moderately and severely droughted plants and from control plants, and Illumina RNA sequencing was performed to analyze RNA synthesis in these tissues. Our data provide a resource (available at Gene Expression Omnibus database under GSE64044) to be employed for comparative analyses of drought response in different poplar species, with the long-term aim of developing strategies to improve plant productivity under drought. PMID- 26484165 TI - Stimulation of the Drosophila immune system alters genome-wide nucleosome occupancy. AB - In eukaryotes, nucleosomes participate in all DNA-templated events by regulating access to the underlying DNA sequence. However, nucleosome dynamics during a genome response have not been well characterized [1,2]. We stimulated Drosophila S2 cells with heat-killed Gram-negative bacteria Salmonella typhimurium, and mapped genome-wide nucleosome occupancy at high temporal resolution by MNase-seq using Illumina HiSeq 2500. We show widespread nucleosome occupancy change in S2 cells during the immune response, with the significant nucleosomal loss occurring at 4 h after stimulation. Data have been deposited to the Gene Expression Omnibus (GEO) database repository with the dataset identifier GSE64507. PMID- 26484166 TI - Two-color Dye-swap DNA Microarray approach toward confident gene expression profiling in PMCAO mouse model for ischemia-related and PACAP38-influenced genes. AB - Toward twin goals of identifying molecular factors in brain injured by ischemic stroke, and the effects of neuropeptide pituitary adenylate-cyclase activating polypeptide (PACAP) on the ischemic brain, we have established the permanent middle cerebral artery occlusion (PMCAO) mouse model and utilized the Agilent mouse whole genome 4 * 44 K DNA chip. PACAP38 (1 pmol) injection was given intracerebroventrically in comparison to a control saline (0.9% NaCl) injection, to screen genes responsive to PACAP38. Two sets of tissues were prepared, whole hemispheres (ischemic and non-ischemic) and infract core and penumbra regions at 6 and 24 h. In this study, we have detailed the experimental design and protocol used therein and explained the quality controls for the use of total RNA in the downstream DNA microarray experiment utilizing a two-color dye-swap approach for stringent and confident gene identification published in a series of papers by Hori and coworkers (Hori et al., 2012-2015). PMID- 26484167 TI - Analysis of changes to mRNA levels and CTCF occupancy upon TFII-I knockdown. AB - CTCF is a key regulator of nuclear chromatin structure, chromatin organization and gene regulation. The impact of CTCF on transcriptional output is quite varied, ranging from repression, to transcriptional pausing and transactivation. The multifunctional nature of CTCF is mediated, in part, through differential association with protein partners having unique properties. We identified the general transcription factor TFII-I as an interacting partner of CTCF. To gain an understanding of the function of TFII-I in regulating gene expression and CTCF binding genome wide, we conducted microarray experiments following TFII-I knockdown and chromatin immunoprecipitation of CTCF followed by next generation sequencing (ChIP-seq) from the same TFII-I depleted cells. Here, we described the experimental design and the quality control and analysis that were performed on the dataset. The data is publicly available through the GEO database with accession number GSE60918. The interpretation and description of these data are included in a manuscript in revision (1). PMID- 26484169 TI - Data for chromosome contacts and matched transcription profiles at three cell cycle phases in the fission yeast. AB - The data described in this article pertains to Grand et al. (2014), "Chromosome conformation maps in fission yeast reveal cell cycle dependent sub nuclear structure" [1]. Temperature sensitive Schizosaccharomyces pombe cell division cycle (cdc) mutants, which are induced by a shift in temperature to 36 degrees C, were chosen for the analysis of genome structure in the G1 phase, G2 phase and mitotic anaphase of the cell cycle. Chromatin and total RNA were isolated from the same cell culture following synchronization. Two biological replicates were analyzed for each condition. The global, three-dimensional organization of the chromosomes was captured at high resolution using Genome Conformation Capture (GCC). GCC libraries and RNA samples were sequenced using an Illumina Hi-Seq 2000 platform (Beijing Genomics Institute (China)). DNA sequences were processed using the Topography suite v1.19 [2] to obtain chromosome contact frequency matrices. RNA sequences were processed using the Cufflinks pipeline [3] to measure gene transcript levels and how these varied between the conditions. All sequence data, processed GCC and transcriptome files are available under the Gene Expression Omnibus (GEO) accession number GSE52287 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE52287). PMID- 26484168 TI - Bacterial tag encoded FLX titanium amplicon pyrosequencing (bTEFAP) based assessment of prokaryotic diversity in metagenome of Lonar soda lake, India. AB - Bacterial diversity and archaeal diversity in metagenome of the Lonar soda lake sediment were assessed by bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP). Metagenome comprised 5093 sequences with 2,531,282 bp and 53 +/- 2% G + C content. Metagenome sequence data are available at NCBI under the Bioproject database with accession no. PRJNA218849. Metagenome sequence represented the presence of 83.1% bacterial and 10.5% archaeal origin. A total of 14 different bacteria demonstrating 57 species were recorded with dominating species like Coxiella burnetii (17%), Fibrobacter intestinalis (12%) and Candidatus Cloacamonas acidaminovorans (11%). Occurrence of two archaeal phyla representing 24 species, among them Methanosaeta harundinacea (35%), Methanoculleus chikugoensis (12%) and Methanolinea tarda (11%) were dominating species. Significant presence of 11% sequences as an unclassified indicated the possibilities for unknown novel prokaryotes from the metagenome. PMID- 26484170 TI - Draft genome sequence of the intestinal parasite Blastocystis subtype 4-isolate WR1. AB - The intestinal protistan parasite Blastocystis is characterized by an extensive genetic variability with 17 subtypes (ST1-ST17) described to date. Only the whole genome of a human ST7 isolate was previously sequenced. Here we report the draft genome sequence of Blastocystis ST4-WR1 isolated from a laboratory rodent at Singapore. PMID- 26484171 TI - Draft genome sequence of the Algerian bee Apis mellifera intermissa. AB - Apis mellifera intermissa is the native honeybee subspecies of Algeria. A. m. intermissa occurs in Tunisia, Algeria and Morocco, between the Atlas and the Mediterranean and Atlantic coasts. This bee is very important due to its high ability to adapt to great variations in climatic conditions and due to its preferable cleaning behavior. Here we report the draft genome sequence of this honey bee, its Whole Genome Shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession JSUV00000000. The 240-Mb genome is being annotated and analyzed. Comparison with the genome of other Apis mellifera sub species promises to yield insights into the evolution of adaptations to high temperature and resistance to Varroa parasite infestation. PMID- 26484172 TI - Transcription profiling of the Neurospora crassa response to a group of synthetic (thio)xanthones and a natural acetophenone. AB - Xanthones are a class of heterocyclic compounds characterized by a dibenzo-gamma pyrone nucleus. Analysis of their mode of action in cells, namely uncovering alterations in gene expression, is important because these compounds have potential therapeutic applications. Thus, we studied the transcriptional response of the filamentous fungus Neurospora crassa to a group of synthetic (thio)xanthone derivatives with antitumor activity using high throughput RNA sequencing. The induction of ABC transporters in N. crassa, particularly atrb and cdr4, is a common consequence of the treatment with xanthones. In addition, we found a group of genes repressed by all of the tested (thio)xanthone derivatives, that are evocative of genes downregulated during oxidative stress. The transcriptional response of N. crassa treated with an acetophenone isolated from the soil fungus Neosartorya siamensis shares some features with the (thio)xanthone-elicited gene expression profiles. Two of the (thio)xanthone derivatives and the N. siamensis-derived acetophenone inhibited the growth of N. crassa. Our work also provides framework datasets that may orientate future studies on the mechanisms of action of some groups of xanthones. PMID- 26484174 TI - Analytical sequence to study G-CSF effect on the transcriptome of isolated spinal motoneurons from SOD1 G93A mice, an animal model for amyotrophic lateral sclerosis. AB - Granulocyte-colony stimulating factor (G-CSF) has been recently identified as a neurotrophic factor able to preserve motor functions, rescue motor units and extent survival in an animal model of amyotrophic lateral sclerosis, the SOD1 G93A mice. To gain insight into the mode of action of G-CSF, we have recently performed gene expression profiling on isolated lumbar motoneurons from SOD1G93A mice, and shown that G-CSF re-adjusted gene expression in motoneurons of symptomatic SOD1G93A mice and modulates genes related to neuromuscular function (Henriques et al., 2015). Here, we provide quality controls for the microarray experiment (GO accession number GSE60856) and describe the experimental strategy. PMID- 26484173 TI - Comparative genomic analysis and phenazine production of Pseudomonas chlororaphis, a plant growth-promoting rhizobacterium. AB - Pseudomonas chlororaphis HT66, a plant growth-promoting rhizobacterium that produces phenazine-1-carboxamide with high yield, was compared with three genomic sequenced P. chlororaphis strains, GP72, 30-84 and O6. The genome sizes of four strains vary from 6.66 to 7.30 Mb. Comparisons of predicted coding sequences indicated 4833 conserved genes in 5869-6455 protein-encoding genes. Phylogenetic analysis showed that the four strains are closely related to each other. Its competitive colonization indicates that P. chlororaphis can adapt well to its environment. No virulence or virulence-related factor was found in P. chlororaphis. All of the four strains could synthesize antimicrobial metabolites including different phenazines and insecticidal protein FitD. Some genes related to the regulation of phenazine biosynthesis were detected among the four strains. It was shown that P. chlororaphis is a safe PGPR in agricultural application and could also be used to produce some phenazine antibiotics with high-yield. PMID- 26484175 TI - Gene expression profiling during intensive cardiovascular lifestyle modification: Relationships with vascular function and weight loss. AB - Heart disease and related sequelae are a leading cause of death and healthcare expenditure throughout the world. Although many patients opt for surgical interventions, lifestyle modification programs focusing on nutrition and exercise have shown substantial health benefits and are becoming increasing popular. We conducted a year-long lifestyle modification program to mediate cardiovascular risk through traditional risk factors and to investigate how molecular changes, if present, may contribute to long-term risk reduction. Here we describe the lifestyle intervention, including clinical and molecular data collected, and provide details of the experimental methods and quality control parameters for the gene expression data generated from participants and non-intervention controls. Our findings suggest successful and sustained modulation of gene expression through healthy lifestyle changes may have beneficial effects on vascular health that cannot be discerned from traditional risk factor profiles. The data are deposited in the Gene Expression Omnibus, series GSE46097 and GSE66175. PMID- 26484176 TI - Cultivation-independent comprehensive survey of bacterial diversity in Tulsi Shyam Hot Springs, India. AB - A taxonomic description of bacteria was deduced from 5.78 Mb metagenomic sequence retrieved from Tulsi Shyam hot spring, India using bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP). Metagenome contained 10,893 16S rDNA sequences that were analyzed by MG-RAST server to generate the comprehensive profile of bacteria. Metagenomic data are available at EBI under EBI Metagenomics database with accession no. ERP009559. Metagenome sequences represented the 98.2% bacteria origin, 1.5% of eukaryotic and 0.3% were unidentified. A total of 16 bacterial phyla demonstrating 97 families and 287 species were revealed in the hot spring metagenome. Most abundant phyla were Firmicutes (65.38%), Proteobacteria (21.21%) and unclassified bacteria (10.69%). Whereas, Peptostreptococcaceae (37.33%), Clostridiaceae (23.36%), and Enterobacteriaceae (16.37%) were highest reported families in metagenome. Ubiquitous species were Clostridium bifermentans (17.47%), Clostridium lituseburense (13.93%) and uncultured bacterium (10.15%). Our data provide new information on hot spring bacteria and shed light on their abundance, diversity, distribution and coexisting organisms. PMID- 26484177 TI - Transcriptional profiling of UlaR-regulated genes in Streptococcus pneumoniae. AB - The transcriptional regulator UlaR belongs to the family of PRD-containing transcriptional regulators, which are mostly involved in the regulation of carbohydrate metabolism. The role of the transcriptional regulator UlaR in Streptococcus pneumoniae has recently been described [1]. Here, we report detailed genome-wide transcriptional profiling of UlaR-regulated genes in S. pneumoniae D39 and its ?ulaR derivative, either in the presence of 10 mM ascorbic acid in M17 medium using microarray analysis. 10 mM concentration of ascorbic acid was supplemented to the M17 medium because our lacZ-fusion studies indicated that UlaR acts as a transcriptional activator of its targets in the presence of ascorbic acid and the expression of the ula operon was maximal at a 10 mM ascorbic acid concentration [1]. All transcriptional profiling data of UlaR regulated genes was deposited to Gene Expression Omnibus (GEO) database under accession number GSE61649. PMID- 26484178 TI - DNA microarray global gene expression analysis of influenza virus-infected chicken and duck cells. AB - The data described in this article pertain to the article by Kuchipudi et al. (2014) titled "Highly Pathogenic Avian Influenza Virus Infection in Chickens But Not Ducks Is Associated with Elevated Host Immune and Pro-inflammatory Responses" [1]. While infection of chickens with highly pathogenic avian influenza (HPAI) H5N1 virus subtypes often leads to 100% mortality within 1 to 2 days, infection of ducks in contrast causes mild or no clinical signs. The rapid onset of fatal disease in chickens, but with no evidence of severe clinical symptoms in ducks, suggests underlying differences in their innate immune mechanisms. We used Chicken Genechip microarrays (Affymetrix) to analyse the gene expression profiles of primary chicken and duck lung cells infected with a low pathogenic avian influenza (LPAI) H2N3 virus and two HPAI H5N1 virus subtypes to understand the molecular basis of host susceptibility and resistance in chickens and ducks. Here, we described the experimental design, quality control and analysis that were performed on the data set. The data are publicly available through the Gene Expression Omnibus (GEO)database with accession number GSE33389, and the analysis and interpretation of these data are included in Kuchipudi et al. (2014) [1]. PMID- 26484179 TI - Identification of genetic variations of a Chinese family with paramyotonia congenita via whole exome sequencing. AB - Paramyotonia congenita (PC) is a rare autosomal dominant neuromuscular disorder characterized by juvenile onset and development of cold-induced myotonia after repeated activities. The disease is mostly caused by genetic mutations of the sodium channel, voltage-gated, type IV, alpha subunit (SCN4A) gene. This study intended to systematically identify the causative genetic variations of a Chinese Han PC family. Seven members of this PC family, including four patients and three healthy controls, were selected for whole exome sequencing (WES) using the Illumina HiSeq platform. Sequence variations were identified using the SoftGenetics program. The mutation R1448C of SCN4A was found to be the only causative mutation. This study applied WES technology to sequence multiple members of a large PC family and was the first to systematically confirm that the genetic change in SCN4A is the only causative variation in this PC family and the SCN4A mutation is sufficient to lead to PC. PMID- 26484180 TI - Human pluripotent stem cell-derived cardiomyocytes: Genome-wide expression profiling of long-term in vitro maturation in comparison to human heart tissue. AB - Cardiomyocyte-like cells (CMs) derived from human pluripotent stem cells (hPSCs) present a valuable model for human disease modeling, studying early human development and, potentially, developing cell therapeutic approaches. However, the specification of early hPSC-derived CMs into defined cardiac subtypes such as atrial and ventricular cells is not well understood and, thus, poorly controlled. Moreover, the maturation status of hPSC-CMs is not well defined, yet it is known that these cells undergo at least some degree of maturation upon longer term in vitro culture. To gain insight into this process, and to assess their developmental status, we have recently generated a data set of hPSC-CMs monitoring global changes in gene expression upon long term maintenance in vitro, in comparison to human atrial and ventricular heart samples (GEO accession number GEO: GSE64189). These data present a rich resource for evaluating the maturation status of hPSC-CMs, for identifying suitable markers for subtype-specific gene expression, as well as for the generation of functional hypotheses. Here, we provide additional details and quality checks of this data set, and exemplify how it can be used to identify maturation-associated as well as cardiac subtype specific markers. PMID- 26484181 TI - Shotgun metagenomic sequencing based microbial diversity assessment of Lasundra hot spring, India. AB - This is the first report on the metagenomic approach for unveiling the microbial diversity of Lasundra hot spring, Gujarat State, India. High-throughput sequencing of community DNA was performed on an Ion Torrent PGM platform. Metagenome consisted of 606,867 sequences represent 98,567,305 bps size with an average length of 162 bps and 46% G + C content. Metagenome sequence information is available at EBI under EBI Metagenomic database with accession no. ERP009313. MG-RAST assisted community analysis revealed that 99.21% sequences were bacterial origin, 0.43% was fit to eukaryotes and 0.11% belongs to archaea. A total of 29 bacterial, 20 eukaryotic and 4 archaeal phyla were detected. Abundant genera were Bacillus (86.7%), Geobacillus (2.4%), Paenibacillus (1.0%), Clostridium (0.7%) and Listeria (0.5%), that represent 91.52% in metagenome. In functional analysis, Cluster of Orthologous Group (COG) based annotation revealed that 45.4% was metabolism connected and 19.6% falls in poorly characterized group. Subsystem based annotation approach suggests that the 14.0% was carbohydrates, 7.0% was protein metabolism and 3.0% genes for various stress responses together with the versatile presence of commercially useful traits. PMID- 26484182 TI - Murine heart gene expression during acute Chagasic myocarditis. AB - Chagas disease is transmitted by the parasite, Trypanosoma cruzi. Acute infection is characterized by acute myocarditis, although it is largely asymptomatic. Initial cardiac insult could be a determinant to the posterior development of chronic Chagasic cardiomyopathy, usually after 10 years in only approximately 30% of chronically infected patients. Herein, we characterized the acute gene expression profiling in heart tissue of two strains of mice infected with T. cruzi (tulahuen strain) at 4 weeks and their respective controls. Gene sequence data are available at NCBI under GEO accession number: GSE63847. The output of the genes expression suggests differences in involvement of protein kinase B (AKT), NCAM1, HLA-DRA, and ubiquitin C genes networks. These gene activation differences may correlate with myocardial contractility during the acute infection. PMID- 26484183 TI - Time course transcriptional profiling of senescing barley leaves. AB - Cell senescence occurs as a part of developmental or stress-induced process. It is tightly regulated and involves a sequence of metabolic and structural alterations, eventually leading to cell death. Dark-induced leaf senescence is a useful model for studying senescence-related events. To facilitate the integration of physiological and molecular studies utilizing this model, we generated the microarray data set providing time course gene expression profiles in senescing barley leaves. Here, we describe the detailed procedures and data analysis scheme of our experiment. The entire data set (available at NCBI/GEO database under GSE62539) has been successively explored to find the genes differentially expressed during the senescence process as well as to identify genes with the invariant expression as reliable references for qPCR or ddPCR experiments. PMID- 26484184 TI - Snai1 represses Nanog to promote embryonic stem cell differentiation. AB - Embryonic stem cell (ESC) self-renewal and pluripotency is maintained by an external signaling pathways and intrinsic regulatory networks involving ESC specific transcriptional complexes (mainly formed by OCT3/4, Sox2 and Nanog proteins), the Polycomb repressive complex 2 (PRC2) and DNA methylation [1-8]. Among these, Nanog represents the more ESC specific factor and its repression correlates with the loss of pluripotency and ESC differentiation [9-11]. During ESC early differentiation, many development-associated genes become upregulated and although, in general, much is known about the pluripotency self-renewal circuitry, the molecular events that lead ESCs to exit from pluripotency and begin differentiation are largely unknown. Snai1 is one the most early induced genes during ESC differentiation in vitro and in vivo [12,13]. Here we show that Snai1 is able to directly repress several stemness-associated genes including Nanog. We use a ESC stable-line expressing a inducible Snai1 protein. We here show microarray analysis of embryonic stem cells (ESC) expressing Snail-ER at various time points of induction with 4-OH. Data were deposited in Gene Expression Omnibus (GEO) datasets under reference GSE57854 and here: http://epigenetics.hugef-research.org/data.php. PMID- 26484185 TI - Global gene analysis identifying genes commonly regulated by the Ras/Raf/MEK and type I IFN pathways. AB - Oncolytic viruses exploit alterations in cancer cells to specifically infect cancer cells but not normal healthy cells. Previous work has shown that oncogenic Ras interferes with interferon (IFN) signaling to promote viral replication. Furthermore, inhibition of the Ras/Raf/MEK/ERK pathway at the level of Ras, MEK, or ERK was sufficient to restore IFN signaling. In order to identify genes that were commonly regulated by the inhibition of the Ras pathway and the IFN pathway, we treated NIH/3T3 cells that overexpress oncogenic Ras with the MEK inhibitor, U0126, or IFN-alpha for 6 h, and performed DNA microarray analysis (Gene Expression Omnibus accession number GSE49469). Here, we also provide additional information on the experimental and functional analysis of the genes responsive to U0126 and IFN. PMID- 26484186 TI - Transcriptomic analyses of Onecut1 and Onecut2 deficient retinas. AB - In this article, we further explore the data generated for the research article "Onecut1 and Onecut2 play critical roles in the development of the mouse retina". To better understand the functionality of the Onecut family of transcription factors in retinogenesis, we investigated the retinal transcriptomes of developing and mature mice to identify genes with differential expression. This data article reports the full transcriptomes resulting from these experiments and provides tables detailing the differentially expressed genes between wildtype and Onecut1 or 2 deficient retinas. The raw array data of our transcriptomes as generated using Affymetrix microarrays are available on the NCBI Gene Expression Omnibus (GEO) browser (Reference number GSE57917 and GSE57918GSE57917GSE57918). PMID- 26484187 TI - Cataloguing the bacterial diversity of the Sundarbans mangrove, India in the light of metagenomics. AB - In this present study we report the profile of bacterial community at variable depth of soil sediment in the world's largest tropical mangrove sediments of Sundarbans, India using 16S rRNA gene amplicon sequencing. Metagenome of three samples consisted of 61301 sequences with 32.0 Mbp and 55.6% G + C content. Metagenome data of this study are available at NCBI under the Biosample data base accession no. SRX883521. The taxonomic analysis of 2746 species belonged to 33 different phyla revealing the dominance of Proteobacteria, Firmicutes, Chloroflexi, Bacteroidetes, Acidobacteria, Nitrospirae and Actinobacteria respectively. Remarkably less than 5.0% sequences belong to a poorly characterized group. Our pyrosequencing data report unfolds the bacterial community profile at different depth of soil sediment indicating the changing community pattern, in the light of specific chronology. PMID- 26484188 TI - The genome-wide gene expression profiling to predict competitive endogenous RNA network in hepatocellular cancer. AB - To assess the potential competitive endogenous RNA (ceRNA) network in hepatocellular cancer (HCC), the lncRNA, mRNA, and microRNA microarrays were conducted on 3 pairs of HCC and paired normal liver tissue. After that, the arrays were normalized and analyzed with gene oncology (GO) and pathway analysis. Next, we screened out the pseudogenes and their cognate protein coding genes which are both down-regulated in HCC. Finally, the up-regulated microRNA binding sites were predicted on the most down-regulated pseudogene and its cognate protein-coding gene. All the array data were uploaded to Gene Expression Omnibus (accession number GSE64633). PMID- 26484189 TI - Profiling of embryonic nuclear vs. cellular RNA in Arabidopsis thaliana. AB - In Arabidopsis, various cell type-specific whole-genome expression analyses have been conducted. However, the vast majority of these were performed with cellular RNA from root tissues or other easily accessible cell types [1]. Nuclear RNA was neglected for a long time as not being representative for transcriptomic studies. In recent years, however, there have been reports describing the validity of nuclear RNA for these types of studies [2,3]. Here we describe the generation, quality assessment and analysis of nuclear transcriptomic data from Arabidopsis embryos published by Slane et al. (2014) [4]. Comparison of nuclear with cellular gene expression demonstrated the usefulness of nuclear transcriptomics. PMID- 26484190 TI - First report of bacterial community from a Bat Guano using Illumina next generation sequencing. AB - V4 hypervariable region of 16S rDNA was analyzed for identifying the bacterial communities present in Bat Guano from the unexplored cave - Pnahkyndeng, Meghalaya, Northeast India. Metagenome comprised of 585,434 raw Illumina sequences with a 59.59% G+C content. A total of 416,490 preprocessed reads were clustered into 1282 OTUs (operational taxonomical units) comprising of 18 bacterial phyla. The taxonomic profile showed that the guano bacterial community is dominated by Chloroflexi, Actinobacteria and Crenarchaeota which account for 70.73% of all sequence reads and 43.83% of all OTUs. Metagenome sequence data are available at NCBI under the accession no. SRP051094. This study is the first to characterize Bat Guano bacterial community using next-generation sequencing approach. PMID- 26484192 TI - Toxicogenomic analysis of placenta samples from mice exposed to different doses of BPA. AB - Bisphenol A (BPA), a widespread Endocrine Disrupter mainly used in food contact plastics, may induce adverse effects especially on susceptible lifestages, first of all pregnancy. The present study considered placental development as a potential target of BPA and investigated potential differences in the modes of action of two doses of BPA by a toxicogenomic approach. Pregnant CD-1 mice were administered with vehicle, 0.5 (BPA05) or 50 mg/kg (BPA50) body weight (bw)/die of BPA, from gestational day (GD) 1 to GD11. At GD12 dams were sacrificed and transcriptomic analysis was performed on placenta samples. Histological, histomorphometrical and immunohistochemical analyses were also performed to phenotypically anchor transcriptional changes associated with BPA exposure. The interpretation and description of the overall data are included in a manuscript under revision [1]. Here we describe the experimental design and the analysis performed on the gene expression data which are publicly available through the Gene Expression Omnibus (GEO) database with accession number GSE63852. PMID- 26484191 TI - Gene expression profiling of loss of TET2 and/or JAK2V617F mutant hematopoietic stem cells from mouse models of myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) are clinically characterized by the chronic overproduction of differentiated peripheral blood cells and the gradual expansion of malignant intramedullary/extramedullary hematopoiesis. In MPNs mutations in JAK2 MPL or CALR are detected mutually exclusive in more than 90% of cases [1,2]. Mutations in them lead to the abnormal activation of JAK/STAT signaling and the autonomous growth of differentiated cells therefore they are considered as "driver" gene mutations. In addition to the above driver gene mutations mutations in epigenetic regulators such as TET2 DNMT3A ASXL1 EZH2 or IDH1/2 are detected in about 5%-30% of cases respectively [3]. Mutations in TET2 DNMT3A EZH2 or IDH1/2 commonly confer the increased self-renewal capacity on normal hematopoietic stem cells (HSCs) but they do not lead to the autonomous growth of differentiated cells and only exhibit subtle clinical phenotypes [4,6-8,5]. It was unclear how mutations in such epigenetic regulators influenced abnormal HSCs with driver gene mutations how they influenced the disease phenotype or whether a single driver gene mutation was sufficient for the initiation of human MPNs. Therefore we focused on JAK2V617F and loss of TET2-the former as a representative of driver gene mutations and the latter as a representative of mutations in epigenetic regulators-and examined the influence of single or double mutations on HSCs (Lineage(-)Sca-1(+)c-Kit(+) cells (LSKs)) by functional analyses and microarray whole-genome expression analyses [9]. Gene expression profiling showed that the HSC fingerprint genes [10] was statistically equally enriched in TET2-knockdown LSKs but negatively enriched in JAK2V617F-LSKs compared to that in wild-type LSKs. Double-mutant-LSKs showed the same tendency as JAK2V617F-LSKs in terms of their HSC fingerprint genes but the expression of individual genes differed between the two groups. Among 245 HSC fingerprint genes 100 were more highly expressed in double-mutant-LSKs than in JAK2V617F-LSKs. These altered gene expressions might partly explain the mechanisms of initiation and progression of MPNs which was observed in the functional analyses [9]. Here we describe gene expression profiles deposited at the Gene Expression Omnibus (GEO) under the accession number GSE62302 including experimental methods and quality control analyses. PMID- 26484193 TI - Pyrosequencing based profiling of the bacterial community in the Chilika Lake, the largest lagoon of India. AB - Brackish water lake is the most extraordinary reservoir for bacterial community with an adaptability of tolerance to saline stress. In the present study, metagenomic approach was implemented utilising 454-pyrosequencing platform to gain deeper insights into the bacterial diversity profile of the soil sediment of Chilika Lake, Odisha, India. Metagenome contained 68,150 sequences with 31,896,430 bp and 56.79% G + C content. Metagenome sequences data are now available at NCBI under the Sequence Read Archive (SRA) database with accession no. SRX753382. Bacterial community metagenome sequences were analysed by MG-RAST server representing the presence of 16,212 species belonging to 45 different phyla. The dominating phyla were Proteobacteria, Chloroflexi, Firmicutes, Acidobacteria, Actinobacteria, Bacteroidetes and Planctomycetes. The analysis of bacterial community datasets obtained from two different saline soil sediments revealed significant differences in bacterial community composition and diversity value providing better understanding of the ecosystem dynamics of Chilika Lake. PMID- 26484194 TI - A microarray analysis of two distinct lymphatic endothelial cell populations. AB - We have recently identified lymphatic endothelial cells (LECs) to form two morphologically different populations, exhibiting significantly different surface protein expression levels of podoplanin, a major surface marker for this cell type. In vitro shockwave treatment (IVSWT) of LECs resulted in enrichment of the podoplanin(high) cell population and was accompanied by markedly increased cell proliferation, as well as 2D and 3D migration. Gene expression profiles of these distinct populations were established using Affymetrix microarray analyses. Here we provide additional details about our dataset (NCBI GEO accession number GSE62510) and describe how we analyzed the data to identify differently expressed genes in these two LEC populations. PMID- 26484195 TI - Using shRNA experiments to validate gene regulatory networks. AB - Quantitative validation of gene regulatory networks (GRNs) inferred from observational expression data is a difficult task usually involving time intensive and costly laboratory experiments. We were able to show that gene knock down experiments can be used to quantitatively assess the quality of large-scale GRNs via a purely data-driven approach (Olsen et al. 2014). Our new validation framework also enables the statistical comparison of multiple network inference techniques, which was a long-standing challenge in the field. In this Data in Brief we detail the contents and quality controls for the gene expression data (available from NCBI Gene Expression Omnibus repository with accession number GSE53091) associated with our study published in Genomics (Olsen et al. 2014). We also provide R code to access the data and reproduce the analysis presented in this article. PMID- 26484196 TI - Contribution of nuclear actin to transcription regulation. AB - Actin, an integral component of the cytoskeleton, plays crucial roles in a variety of cell functions, including cell migration, adhesion, polarity and shape change. Studies performed during the last couple of decades have revealed that the actin also exists in the nucleus. However, the function and properties of nuclear actin remained elusive so far. Recently, we showed that an actin tagged with EYFP and fused with a nuclear localization signal (EYFP-NLS-actin) formed visible filamentous (F)-actin bundles in cells. To obtain further details about the individual genes that are affected by the nuclear actin, we have used the microarray analysis to determine the changes in the expression levels of RNAs in HeLa cells as a result of EYFP-NLS-actin expression. Our results suggest that the nuclear actin plays a role in the activation of genes rather than their repression. The data has been deposited in the Gene Expression Omnibus (GEO) database under the accession number GSE59799. PMID- 26484197 TI - Microarray analysis of lexA gene deletion mutant of deep-sea bacterium Shewanella piezotolerans WP3 at low-temperature and high-pressure. AB - Addressing DNA lesion, the SOS response is conserved in bacterial domain and governed by DNA binding protein LexA, which have been well characterized in model microorganism such as Escherichia coli. However, our understanding of the roles of SOS pathway in deep-sea bacteria is limited. To indentify the composition of SOS regulon and function of LexA, we performed whole genome transcriptional profiling using a custom designed microarray which contains 95% open reading frames of Shewanella piezotolerans WP3. Here we describe the experimental procedures and methods in detail to reproduce the results (available at Gene Expression Omnibus database under GSE66790) and provide resource to be employed for comparative analyses of SOS response in microorganisms which inhabited in different environments, and thus broaden our understanding of life strategy of bacteria against various environment stresses. PMID- 26484198 TI - Technical data of the transcriptomic analysis performed on tsetse fly symbionts, Sodalis glossinidius and Wigglesworthia glossinidia, harbored, respectively by non-infected, Trypanosoma brucei gambiense infected and self-cured Glossina palpalis gambiensis tsetse flies. AB - Microarray is a powerful and cheap method to identify and quantify gene expression in particular in a mix of total RNA extracted from biological samples such as the tsetse fly gut, including several organisms (here, the fly tissue and the intestinal microorganisms). Besides, biostatistics and bioinformatics allow comparing the transcriptomes from samples collected from differently treated flies, and thus to identify and quantify differential expressed genes. Here, we describe in details a whole microarray transcriptome dataset produced from tsetse flies symbionts, Sodalis glossinidius and Wigglesworthia glossinidia. The tsetse fly midguts were sampled at key steps of tsetse fly infection by trypanosomes, 3 day and 10-day sampling times to target differentially expressed genes involved, respectively, in early events associated with trypanosome entry into the midgut and with the establishment of infection; 20 days to target the genes involved in events occurring later in the infection process. We describe in detail the methodology applied for analyzing the microarray data including differential expression as well as functional annotation of the identified symbiont genes. Both the microarray data and design are available at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE48360;http://www.ncbi.nlm.ni .gov/geo/query/acc.cgi?acc=GSE48361;http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi acc=GSE55931. PMID- 26484199 TI - Microarray profiling of L1-overexpressing endothelial cells reveals STAT3 activation via IL-6/IL-6Ralpha axis. AB - We recently identified a novel role for the L1 transmembrane glycoprotein (also known as L1CAM or CD171) in the regulation of tumor angiogenesis and vessels stabilization. L1 overexpression in cultured endothelial cells of the lung (luECs) exerted a pleiotropic effect in that it regulated proliferation, migration, tubulogenesis, vascular permeability, and endothelial-to-mesenchymal transition (EndMT). In addition, we provided strong evidence that antibody mediated targeting of L1 may be an effective strategy for vessel normalization with the potential to increase efficacy of chemotherapeutic agents. High throughput microarray expression profile revealed that L1 modulates the expression of hundreds of genes mainly involved in cell cycle regulation, DNA replication, cellular assembly, migration, development and organization. By using a 'pathway-oriented' analysis strategy we were able to identify a network of 105 genes modulated by L1 through the predicted activation of five transcription factors: STAT1, STAT2, STAT3, IRF7, and ATF4. Indeed, L1 overexpression resulted in the strong induction of STAT3 phosphorylation which was abolished by antibody mediated neutralization of IL-6Ralpha. These results indicated that L1 promoted STAT3 activation via the IL-6/IL-6Ralpha axis. PMID- 26484200 TI - Effect of glucocorticoids on lncRNA and mRNA expression profiles of the bone microcirculatory endothelial cells from femur head of Homo sapiens. AB - Appropriate gene expression patterns form the basis for bone microvascular endothelial cells' function in femoral head. Although previous studies have elucidated the impact of glucocorticoids on these cells' specific gene expression the exact differential transcriptomes and comprehensive gene expression profiles remain unknown. Using microarray-based platforms we investigated the transcriptome patterns before and after hydrocortisone administration of bone microvascular endothelial cells from human femoral head. Our results highlight the involvement of development differentiation and apoptosis in the bone microvascular endothelial cells. Elucidation of differential gene expression before and after hydrocortisone administration emphasizes the importance of regulatory networks to gene co-expression within biological processes induced by glucocorticoids. With Benjamini-Hochberg characterization we identified 73 up regulated and 166 down-regulated long noncoding RNAs the expression of 107 of which significantly correlated with 172 mRNAs after administration of hydrocortisone. Transcriptome analysis of bone microvascular endothelial cells from human femoral head samples is highly informative because it is deduced from data comprised of large number of genes expressed above background. The data have been submitted to the repository of Gene Expression Omnibus (Series GSE60332). PMID- 26484201 TI - Genome-wide gene expression profiling to investigate molecular phenotypes of Arabidopsis mutants deprived in distinct histone methyltransferases and demethylases. AB - Histone lysine (K) methylation is a type of epigenetic modification involved in regulation of DNA-based processes, including transcription, replication and repair. It can either activate or repress transcription depending on the histone K residue on which methylation occurs and on chromatin context of additional other modifications. In both animals and plants, methylation on one histone K residue can be deposited by several different histone methyltransferases and vice versa removed by different histone demethylases. It is of great interest to know which histone enzyme regulates which genes in the genome. Here we describe in details the contents and quality controls for the gene expression data of Arabidopsis mutants deprived in distinct histone methyltransferases (SDG26, SDG25, ATX1, CLF) and histone demethylases (LDL1, LDL2), in association with the study recently published by Berr and colleagues in The Plant Journal (Berr et al., 2015). The microarray dataset has been deposited in Gene Expression Omnibus with accession number GSE55167. PMID- 26484202 TI - Genome-wide DNA binding pattern of two-component system response regulator RhpR in Pseudomonas syringae. AB - Although Pseudomonas syringae uses the two-component system RhpRS to modulate the expression of type III secretion system (T3SS) genes and pathogenicity, the molecular mechanisms and the regulon of RhpRS have yet to be fully demonstrated. We have performed a genome-wide analysis of RhpR binding to DNA prepared from P. syringae pv. phaseolicola in order to identify candidate direct targets of RhpR mediated transcriptional regulation, as described in our recent article [1]. The data are available from NCBI Gene Expression Omnibus (GEO) with the accession number GSE58533. Here we describe the detailed methods and data analyses of our RhpR ChIP-seq dataset. PMID- 26484203 TI - Expression profiling of wild type and beta-catenin gene disrupted human BxPC-3 pancreatic adenocarcinoma cells. AB - To study the role of WNT/beta-catenin signaling in pancreatic adenocarcinoma, human BxPC-3 cell lines deficient of the central canonical WNT signaling protein beta-catenin were established by using zinc-finger nuclease mediated targeted genomic disruption of the beta-catenin gene (CTNNB1). Comparison of the global transcription levels in wild type cells with two beta-catenin gene disrupted clones identified 85 transcripts that were the most differentially regulated. Gene ontology (GO) term enrichment analysis of these transcripts identified "cell adhesion" as the most significantly enriched GO term. Here we describe the data from the transcription profiling analysis published in the article "Implications of Targeted Genomic Disruption of beta-Catenin in BxPC-3 Pancreatic Adenocarcinoma Cells" [1]. Data have been deposited to the Gene Expression Omnibus (GEO) database repository with the dataset identifier GSE63072. PMID- 26484204 TI - Deciphering the microbiota of Tuwa hot spring, India using shotgun metagenomic sequencing approach. AB - Here, we report metagenome from the Tuwa hot spring, India using shotgun sequencing approach. Metagenome consisted of 541,379 sequences with 98.7 Mbps size with 46% G + C content. Metagenomic sequence reads were deposited into the EMBL database under accession number ERP009321. Community analysis presented 99.1% sequences belong to bacteria, 0.3% of eukaryotic origin, 0.2% virus derived and 0.05% from archea. Unclassified and unidentified sequences were 0.4% and 0.07% respectively. A total of 22 bacterial phyla include 90 families and 201 species were observed in the hot spring metagenome. Firmicutes (97.0%), Proteobacteria (1.3%) and Actinobacteria (0.4%) were reported as dominant bacterial phyla. In functional analysis using Cluster of Orthologous Group (COG), 21.5% drops in the poorly characterized group. Using subsystem based annotation, 4.0% genes were assigned for stress responses and 3% genes were fit into the metabolism of aromatic compounds. The hot spring metagenome is very rich with novel sequences affiliated to unclassified and unidentified lineages, suggesting the potential source for novel microbial species and their products. PMID- 26484205 TI - Investigations on microbial diversity of Jakrem hot spring, Meghalaya, India using cultivation-independent approach. AB - Jakrem hot water spring is located in the West Khasi Hill District of the state of Meghalaya, and is one of the most popular hot springs of the state. There is a populist belief among the inhabitants and people that the hot spring water has got curative properties against various skin ailments. This is the first report on V3 hyper-variable region of 16S rDNA metagenome sequence employing Illumina platform to profile the microbial community of this less known hot spring from Meghalaya, India. Metagenome comprised of 10, 74,120 raw sequences with a sequence length of 151 bp and 56.35% G + C content. Metagenome sequence information is now available at NCBI, SRA database accession no. SRP056897. A total of 8, 77, 364 pre-processed reads were clustered into 694 OTUs (operational taxonomical units) comprising of 14 bacterial phyla including unknown phylum demonstrating 49 families. Hot spring bacterial community is dominated by Firmicutes (61.60%), Chloroflexi (21.37%), Cyanobacteria (12.96%) and unclassified bacteria (1.2%) respectively. PMID- 26484206 TI - Global gene expression profiling analysis reveals reduction of stemness after B RAF inhibition in colorectal cancer cell lines. AB - Cancer cell differentiation is an important field of discussion in the light of cancer stem cells. In a recent study by Herr et al. (2015) "B-RAF inhibitors induce epithelial differentiation in BRAF-mutant colorectal cancer cells" we described how inhibition of mutant BRAF in colorectal cancer cell lines induces cell re-differentiation that is correlated with the loss of tumor growth in vitro and in vivo. We used Illumina HumanHT-12 v4 Expression BeadChip to characterize the gain of differentiation of PLX4720-treated 3D cultures of HT29 and Colo-205 cells. Here, we describe the experimental design and statistical analysis that were performed on the data set leading to the above hypothesis. The data are publicly available at the Gene Expression Omnibus (GEO) database under the accession number GSE50791. PMID- 26484207 TI - Transcriptome analysis of the aquaporin AtPIP1;2 deficient line in Arabidopsis thaliana. AB - Atmospheric CO2 impacts all aspects of plant development. It has changed in the past and is predicted to change further on. Studies on the response of crop plants to low and elevated CO2 concerning growth, productivity and physiological processes are intense. In contrast, the molecular mechanisms of cellular CO2 exchange are still under discussion. At the same time it becomes more and more accepted that carbon dioxide is transported across cellular biomembranes by CO2 conducting aquaporins. Our recent study (Boudichevskaia et al., 2015) demonstrates that the lack of a single gene product - aquaporin AtPIP1;2 - resulted in massive transcriptional reprogramming in Arabidopsis as a consequence of reduced tissue CO2 diffusion rates. Therefore, the transcriptome data of the aquaporin AtPIP1;2 deficient line can be used in the comparative expression analyses for better understanding the role of aquaporins with regard to CO2 and water transport in plants. Here we describe a gene expression dataset generated for three biological replicates per genotype on Affymetrix platform. We provide detailed methods and analysis on microarray data which has been deposited in Gene Expression Omnibus (GEO): GSE62167. Additionally, we provide the R code for data preprocessing and quality control. PMID- 26484208 TI - Transcriptome analysis of bone marrow mesenchymal stromal cells from patients with primary myelofibrosis. AB - Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm whose severity and treatment complexity are attributed to the presence of bone marrow (BM) fibrosis and alterations of stroma impairing the production of normal blood cells. Despite the recently discovered mutations including the JAK2V617F mutation in about half of patients, the primitive event responsible for the clonal proliferation is still unknown. In the highly inflammatory context of PMF, the presence of fibrosis associated with a neoangiogenesis and an osteosclerosis concomitant to the myeloproliferation and to the increase number of circulating hematopoietic progenitors suggests that the crosstalk between hematopoietic and stromal cells is deregulated in the PMF BM microenvironmental niches. Within these niches, mesenchymal stromal cells (BM-MSC) play a hematopoietic supportive role in the production of growth factors and extracellular matrix which regulate the proliferation, differentiation, adhesion and migration of hematopoietic stem/progenitor cells. A transcriptome analysis of BM-MSC in PMF patients will help to characterize their molecular alterations and to understand their involvement in the hematopoietic stem/progenitor cell deregulation that features PMF. PMID- 26484209 TI - Genome-wide copy number profiling of mouse neural stem cells during differentiation. AB - There is growing evidence that gene amplifications were present in neural stem and progenitor cells during differentiation. We used array-CGH to discover copy number changes including gene amplifications and deletions during differentiation of mouse neural stem cells using TGF-beta and FCS for differentiation induction. Array data were deposited in GEO (Gene Expression Omnibus, NCBI) under accession number GSE35523. Here, we describe in detail the cell culture features and our TaqMan qPCR-experiments to validate the array-CGH analysis. Interpretation of array-CGH experiments regarding gene amplifications in mouse and further detailed analysis of amplified chromosome regions associated with these experiments were published by Fischer and colleagues in Oncotarget (Fischer et al., 2015). We provide additional information on deleted chromosome regions during differentiation and give an impressive overview on copy number changes during differentiation induction at a time line. PMID- 26484210 TI - Genome-wide analysis of uncapped mRNAs under heat stress in Arabidopsis. AB - Recently, we have showed that Tudor Staphylococcal Nuclease (TSN or Tudor-SN) proteins (TSN1 and TSN2) are localized in cytoplasmic messenger ribonucleoprotein (mRNP) complexes called stress granules (SG) and processing bodies (PB) under heat stress in Arabidopsis. One of the primary functions of these mRNP complexes is mRNA decay, which generates uncapped mRNAs by the action of endonucleases and decapping enzymes (Thomas et al., 2011) [1]. In order to figure out whether TSN proteins could be implicated in mRNA decay, we isolated uncapped and total mRNAs of Wild type (WT; Col and Ler) and TSN double knock-out (tsn1tsn2) seedlings grown under heat stress (39 degrees C for 40 min) and control (23 degrees C) conditions. Here, we provide the experimental procedure to reproduce the results (NCBI GEO accession number GSE63522) published by Gutierrez-Beltran et al. (2015) in The Plant Cell [2]. PMID- 26484211 TI - Gene expression analysis of laryngeal squamous cell carcinoma. AB - Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignancies of the head and neck tumors Zhang et al., 2013 [1]). Previous studies have associated its occurrence with social activities, such as tobacco and alcohol consumption (Hashibe et al., 2007a [2]; Hashibe et al., 2007b [3]; Shangina et al., 2006 [4]). Here, we performed a genome-wide gene expression profiling in thirty-one patients positively diagnosed for LSCC, in order to investigate new targets involved in tumorigenesis. PMID- 26484212 TI - Illumina-based analysis of bacterial community in Khuangcherapuk cave of Mizoram, Northeast India. AB - Bacterial community of the Khuangcherapuk cave sediment was assessed by Illumina amplicon sequencing. The metagenome comprised of 533,120 raw reads with an average base quality (Phred score) 36.75 and G + C content is 57.61%. A total of 18 bacterial phyla were detected with following abundant genus - Mycobacterium (21.72%), Rhodococcus (7.09%), Alteromonas (1.42%), Holomonas (0.7%) and Salinisphaera (0.20%). Majority portion of the sequences (68%) is unclassified at the genus level indicating the possibilities for the presence of novel species in this cave. This study reports the cave bacterial diversity from the biodiversity hotspot region of Eastern Himalayas. Metagenome sequence data are available at NCBI under the Bioproject database with accession no. SRP056890. PMID- 26484213 TI - Genome-wide analysis of histone acetylation dynamics during mouse embryonic stem cell neural differentiation. AB - Epigenetic modification as an intrinsic fine-tune program cooperates with key transcription factors to regulate the cell fate determination. The histone acetylation participating in neural differentiation of pluripotent stem cells is expected but not well studied. Here, using acetylated histone H3 ChIP-sequencing (ChIP-seq), we demonstrate that the histone H3 acetylation level is gradually increased on the neural gene loci while decreased on the neural-inhibitory gene loci during mouse embryonic stem cell (mESC) neural differentiation. We further show that histone deacetylase 1 (HDAC1) is essential for neural commitment by targeting Nodal signaling. Thus, our study reveals a mechanism by which the epigenetic modification of histone acetylation/deacetylation interacts with extracellular signaling in mESC neural fate determination. Data were deposited in Gene Expression Omnibus (GEO) datasets under reference number GSE66025. PMID- 26484214 TI - Microarray-based analysis of plasma cirDNA epigenetic modification profiling in xenografted mice exposed to intermittent hypoxia. AB - Intermittent hypoxia (IH) during sleep is one of the major abnormalities occurring in patients suffering from obstructive sleep apnea (OSA), a highly prevalent disorder affecting 6-15% of the general population, particularly among obese people. IH has been proposed as a major determinant of oncogenetically related processes such as tumor growth, invasion and metastasis. During the growth and expansion of tumors, fragmented DNA is released into the bloodstream and enters the circulation. Circulating tumor DNA (cirDNA) conserves the genetic and epigenetic profiles from the tumor of origin and can be isolated from the plasma fraction. Here we report a microarray-based epigenetic profiling of cirDNA isolated from blood samples of mice engrafted with TC1 epithelial lung cancer cells and controls, which were exposed to IH during sleep (XenoIH group, n = 3) or control conditions, (i.e., room air (RA); XenoRA group, n = 3) conditions. To prepare the targets for microarray hybridization, we applied a previously developed method that enriches the modified fraction of the cirDNA without amplification of genomic DNA. Regions of differential cirDNA modification between the two groups were identified by hybridizing the enriched fractions for each sample to Affymetrix GeneChip Human Promoter Arrays 1.0R. Microarray raw and processed data were deposited in NCBI's Gene Expression Omnibus (GEO) database (accession number: GSE61070). PMID- 26484215 TI - Gene expression profiling of the Peyer's patch mononuclear phagocyte system. AB - Peyer's patches (PPs) are primary inductive sites of mucosal immunity. The PP mononuclear phagocyte system, which encompasses both dendritic cells (DCs) and macrophages, is essential for the initiation of the mucosal immune response. We recently developed a method to isolate each mononuclear phagocyte subset of PP (Bonnardel et al., 2015). We performed a transcriptional analysis of three of these subsets: the CD11b(+) conventional DC, the lysozyme-expressing monocyte derived DC termed LysoDC and the CD11c(hi) lysozyme-expressing macrophages. Here, we provide details of the gating strategy we used to isolate each phagocyte subset and show the quality controls and analysis associated with our gene array data deposited into Gene Expression Omnibus (GEO) under GSE65514. PMID- 26484216 TI - Bacterial diversity of Murlen National Park located in Indo-Burman Biodiversity hotspot region: A metagenomic approach. AB - Paired end Illumina Mi-Seq sequencing of 16S rRNA gene amplicon was carried out to study the bacterial community in the soil of Murlen National Park located in Indo-Burman Biodiversity hotspot region. Metagenome consisted of 302,416 reads with 151.81 Mb data and G + C content of 56.48%. More than 85% sequence was having a Phred score >=Q30 and individual sequence length was 251 bp. Metagenome sequence data are available at NCBI under the Bioproject database with accession no. SRP057136. Community metagenomics revealed a total of 1802 species belonging to 29 different phyla dominated by Acidobacteria (39.45%), Proteobacteria (26.95%) and Planctomycetes (7.81%). Our data detected a wide group of bacterial community which will be useful in further isolating and characterizing the economic importance of bacteria from this region. PMID- 26484217 TI - Gene expression profiling of WDR5 regulated genes in bladder cancer. AB - WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription (Wysocka et al., 2005 [1]; Sandstrom et al., 2014[2]; Ang et al., 2011[3]). Recently, our study found that WDR5 was upregulated in bladder cancer tissues, promoted bladder cancer cell proliferation, self-renewal and chemoresistance to cisplatin in bladder cancer cells in vitro, and tumor growth in vivo (Chen et al., 2015). To gain a molecular understanding of the role of WDR5 in promoting bladder cancer, we performed a genome-wide analysis on WDR5 knockdown by microarray gene expression profiling. Here we provide detailed experimental methods and analysis for the microarray data, which have been deposited into Gene Expression Omnibus (GEO): GSE59132. PMID- 26484218 TI - Disruption of O-GlcNAc cycling by deletion of O-GlcNAcase (Oga/Mgea5) changed gene expression pattern in mouse embryonic fibroblast (MEF) cells. AB - Adding a single O-GlcNAc moiety to a Ser/Thr molecule of a protein by O-GlcNAc transferase and transiently removing it by O-GlcNAcase is referred to as O-GlcNAc cycling (or O-GlcNAcylation). This O-GlcNAc modification is sensitive to nutrient availability and also shows cross talk with phosphorylation signaling, affecting downstream targets. A mouse model system was developed and evaluated to show genome wide transcriptional changes associated with disruption of O-GlcNAc cycling. Mouse embryonic fibroblast cells derived from O-GlcNAcase (Oga) knock out (KO), heterozygous (Het) and wild type (WT) embryos were used for an Affymetrix based microarray. Results are deposited in GEO dataset GSE52721. Data reveals that Oga KO MEFs had 2534 transcripts differentially expressed at 1.5 fold level while Oga heterozygous MEFs had 959 transcripts changed compared to WT MEFs. There were 1835 transcripts differentially expressed at 1.5 fold Het versus WT comparison group. Gene ontology analysis indicated differentially expressed genes enriched in metabolic, growth, and cell proliferation categories. PMID- 26484219 TI - High-quality draft genome sequence of Kocuria marina SO9-6, an actinobacterium isolated from a copper mine. AB - An actinobacterial strain, designated SO9-6, was isolated from a copper iron sulfide mineral. The organism is Gram-positive, facultatively anaerobic, and coccoid. Chemotaxonomic and phylogenetic properties were consistent with its classification in the genus Kocuria. Here, we report the first draft genome sequence of Kocuria marina SO9-6 under accession JROM00000000 (http://www.ncbi.nlm.nih.gov/nuccore/725823918), which provides insights for heavy metal bioremediation and production of compounds of biotechnological interest. PMID- 26484220 TI - Genome sequencing and annotation of Aeromonas sp. HZM. AB - We report the draft genome sequence of Aeromonas sp. strain HZM, isolated from tropical peat swamp forest soil. The draft genome size is 4,451,364 bp with a G + C content of 61.7% and contains 10 rRNA sequences (eight copies of 5S rRNA genes, single copy of 16S and 23S rRNA each). The genome sequence can be accessed at DDBJ/EMBL/GenBank under the accession no. JEMQ00000000. PMID- 26484221 TI - Genome sequencing and annotation of Cellulomonas sp. HZM. AB - We report the draft genome sequence of Cellulomonas sp. HZM, isolated from a tropical peat swamp forest. The draft genome size is 3,559,280 bp with a G + C content of 73% and contains 3 rRNA sequences (single copies of 5S, 16S and 23S rRNA). PMID- 26484222 TI - Interval-value Based Particle Swarm Optimization algorithm for cancer-type specific gene selection and sample classification. AB - Microarray technology allows simultaneous measurement of the expression levels of thousands of genes within a biological tissue sample. The fundamental power of microarrays lies within the ability to conduct parallel surveys of gene expression using microarray data. The classification of tissue samples based on gene expression data is an important problem in medical diagnosis of diseases such as cancer. In gene expression data, the number of genes is usually very high compared to the number of data samples. Thus the difficulty that lies with data are of high dimensionality and the sample size is small. This research work addresses the problem by classifying resultant dataset using the existing algorithms such as Support Vector Machine (SVM), K-nearest neighbor (KNN), Interval Valued Classification (IVC) and the improvised Interval Value based Particle Swarm Optimization (IVPSO) algorithm. Thus the results show that the IVPSO algorithm outperformed compared with other algorithms under several performance evaluation functions. PMID- 26484223 TI - Transcriptional profiling of CRP-regulated genes in deep-sea bacterium Shewanella piezotolerans WP3. AB - The cAMP receptor protein (CRP) is a conserved regulator in bacteria and involved in regulation of energy metabolism, such as glucose, galactose, and citrate (Green et al., 2014 [1]). As an important catabolite activator protein, it has been well characterized in model microorganism such as Escherichia coli. However, our understanding of the roles of CRP in deep-sea bacteria is rather limited. To indentify the function of CRP, we performed whole genome transcriptional profiling using a custom designed microarray which contains 95% open reading frames of Shewanella piezotolerans WP3, which was isolated from West Pacific sediment at a depth of 1914 m (Xiao et al., 2007 [2]; Wang et al., 2008 [3]). Here we describe the experimental procedures and methods in detail to reproduce the results (available at Gene Expression Omnibus database under GSE67731 and GSE67732) and provide resource to be employed for comparative analyses of CRP regulon and the regulatory network of anaerobic respiration in microorganisms which inhabited in different environments, and thus broaden our understanding of mechanism of bacteria against various environment stresses. PMID- 26484224 TI - Transcriptional profiling of HOXA9-regulated genes in human glioblastoma cell models. AB - The data here described pertain to the article by Pojo et al. (2015) [10] titled "A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomide" (Pojoet al., 2015 [10]). HOX genes are part of the homeobox gene family, which encodes transcription factors crucial during embryonic development (Grier et al., 2005; Pearson et al., 2005 [6,9]) and also in post developmental regulation(Neville et al., 2002; Yamamoto et al., 2003; Takahashi et al., 2004;Morgan 2006 [8,14,13,7]). Alterations interfering with the regulation of these genes may lead to tumorigenesis in adults. Due to their contributions in the control of important cellular processes, the deregulation of HOX genes is ultimately correlated with cancer treatment failure and patients' poor prognosis (Golub et al., 1999; Abdel-Fattah et al., 2006 [5,1]; Costa et al.,2010 [4]; Pojo et al., 2015 [10]). Recently, our studies showed that HOXA9 overexpression is associated with poor prognosis in patients with glioblastoma (GBM), the most common and most malignant primary brain tumor. Mechanistically, HOXA9 is associated with resistance to chemotherapy and with pro-proliferative, pro invasive and anti apoptotic features (Costa et al., 2010 [4]; Pojo et al., 2015 [10]) in GBM in vitro models. Since HOXA9 is a transcription factor, its target genes can be the true biological effectors of its aggressiveness. In this context, whole genome Agilent's microarrays were used to obtain the full transcriptome of HOXA9 in a variety of GBM cell models, including human immortalized astrocytes, established GBM cell lines, and GBM patient derived cell cultures. Here, we provide detailed methods, including experimental design and microarray data analyses,which can be accessed in Gene Expression Omnibus (GEO) under the accession number GSE56517. Additional interpretation of the data is included and supplemented in (Pojo et al., 2015 [10]). PMID- 26484225 TI - MicroRNA expression profiles of human left ventricle derived cardiac cells in normoxic and hypoxic conditions. AB - Studies in the cardiovascular research field have demonstrated the vital roles of microRNAs for proper cardiovascular development and functional maintenance. The involvement of aberrant microRNA expression leading to ontogenesis of cardiovascular diseases lends further support of the regulatory role of microRNAs in heart function. Hypoxic insult is one of the major factors that trigger downstream signal cascades which contribute to the pathogenesis of hypoxic/ischemic-related heart diseases. Here, we report the microRNA expression profile in human cardiac-derived cells subjected to 120-h hypoxic treatment. By comparing with the normoxic control state, we identified microRNAs differentially expressed in cardiac cells subjected to hypoxic challenge. MicroRNA microarray data are available at NCBI under the GEO accession number, GSE55387. PMID- 26484226 TI - Transcriptome profiling of tobacco under water deficit conditions. AB - Drought is one of the limiting environmental factors that affect crop production. Understanding the molecular basis of how plants respond to this water deficit stress is key to developing drought tolerant crops. In this study we generated time course-based transcriptome profiles of tobacco plants under water deficit conditions using microarray technology. In this paper, we describe in detail the experimental procedures and analyses performed in our study. The data set we generated (available in the NCBI/GEO database under GSE67434) has been analysed to identify genes that are involved in the regulation of tobacco's responses to drought. PMID- 26484227 TI - Gene expression changes of single skeletal muscle fibers in response to modulation of the mitochondrial calcium uniporter (MCU). AB - The mitochondrial calcium uniporter (MCU) gene codifies for the inner mitochondrial membrane (IMM) channel responsible for mitochondrial Ca(2 +) uptake. Cytosolic Ca(2 +) transients are involved in sarcomere contraction through cycles of release and storage in the sarcoplasmic reticulum. In addition cytosolic Ca(2 +) regulates various signaling cascades that eventually lead to gene expression reprogramming. Mitochondria are strategically placed in close contact with the ER/SR, thus cytosolic Ca(2 +) transients elicit large increases in the [Ca(2 +)] of the mitochondrial matrix ([Ca(2 +)]mt). Mitochondrial Ca(2 +) uptake regulates energy production and cell survival. In addition, we recently showed that MCU-dependent mitochondrial Ca(2 +) uptake controls skeletal muscle trophism. In the same report, we dissected the effects of MCU-dependent mitochondrial Ca(2 +) uptake on gene expression through microarray gene expression analysis upon modulation of MCU expression by in vivo AAV infection. Analyses were performed on single skeletal muscle fibers at two time points (7 and 14 days post-AAV injection). Raw and normalized data are available on the GEO database (http://www.ncbi.nlm.nih.gov/geo/) (GSE60931). PMID- 26484228 TI - Whole transcriptome microarrays identify long non-coding RNAs associated with cardiac hypertrophy. AB - Long non-coding RNAs (lncRNAs) have recently emerged as a novel group of non coding RNAs able to regulate gene expression. While their role in cardiac disease is only starting to be understood, their involvement in cardiac hypertrophy is poorly known. We studied the association between lncRNAs and left ventricular hypertrophy using whole transcriptome microarrays. Wild-type mice and mice overexpressing the adenosine A2A receptor were subjected to transverse aortic constriction (TAC) to induce left ventricular hypertrophy. Expression profiles of lncRNAs in the heart were characterized using genome-wide microarrays. An analytical pipeline was specifically developed to extract lncRNA data from microarrays. We identified 2 lncRNAs up-regulated and 3 lncRNAs down-regulated in the hearts of A2A-receptor overexpressing-mice subjected to TAC compared to wild type mice. Differential expression of these 2 lncRNAs was validated by quantitative PCR. Complete microarray dataset is available at Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE45423. Here, we describe in details the experimental design, microarray performance and analysis. PMID- 26484229 TI - In silico analysis of consequences of non-synonymous SNPs of Slc11a2 gene in Indian bovines. AB - The aim of our study was to analyze the consequences of non-synonymous SNPs in Slc11a2 gene using bioinformatic tools. There is a current need of efficient bioinformatic tools for in-depth analysis of data generated by the next generation sequencing technologies. SNPs are known to play an imperative role in understanding the genetic basis of many genetic diseases. Slc11a2 is one of the major metal transporter families in mammals and plays a critical role in host defenses. In this study, we performed a comprehensive analysis of the impact of all non-synonymous SNPs in this gene using multiple tools like SIFT, PROVEAN, I Mutant and PANTHER. Among the total 124 SNPs obtained from amplicon sequencing of Slc11a2 gene by Ion Torrent PGM involving 10 individuals of Gir cattle and Murrah buffalo each, we found 22 non-synonymous. Comparing the prediction of these 4 methods, 5 nsSNPs (G369R, Y374C, A377V, Q385H and N492S) were identified as deleterious. In addition, while tested out for polar interactions with other amino acids in the protein, from above 5, Y374C, Q385H and N492S showed a change in interaction pattern and further confirmed by an increase in total energy after energy minimizations in case of mutant protein compared to the native. PMID- 26484230 TI - Noncoding RNAs in human intervertebral disc degeneration: An integrated microarray study. AB - Accumulating evidence indicates that noncoding RNAs play important roles in a multitude of biological processes. The striking findings of miRNAs (microRNAs) and lncRNAs (long noncoding RNAs) as members of noncoding RNAs open up an exciting era in the studies of gene regulation. More recently, the reports of circRNAs (circular RNAs) add fuel to the noncoding RNAs research. Human intervertebral disc degeneration (IDD) is a main cause of low back pain as a disabling spinal disease. We have addressed the expression profiles if miRNAs, lncRNAs and mRNAs in IDD (Wang et al., J Pathology, 2011 and Wan et al., Arthritis Res Ther, 2014). Furthermore, we thoroughly analysed noncoding RNAs, including miRNAs, lncRNAs and circRNAs in IDD using the very same samples. Here we delineate in detail the contents of the aforementioned microarray analyses. Microarray and sample annotation data were deposited in GEO under accession number GSE67567 as SuperSeries. The integrated analyses of these noncoding RNAs will shed a novel light on coding-noncoding regulatory machinery. PMID- 26484231 TI - Use of multiple time points to model parotid differentiation. AB - In order to understand the process of terminal differentiation in salivary acinar cells, mRNA and microRNA expression was measured across the month long process of differentiation in the parotid gland of the rat. Acinar cells were isolated at either nine time points (mRNA) or four time points (microRNA) in triplicate using laser capture microdissection (LCM). One of the values of this dataset comes from the high quality RNA (RIN > 7) that was used in this study, which can be prohibitively difficult to obtain from such an RNaseI-rich tissue. Global mRNA expression was measured by rat genome microarray hybridization (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE65586), and expression of microRNAs by qPCR array (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE65324). Comparing expression at different ages, 2656 mRNAs and 64 microRNAs were identified as differentially expressed. Because mRNA expression was sampled at many time points, clustering and regression analysis were able to identify dynamic expression patterns that had not been implicated in acinar differentiation before. Integration of the two datasets allowed the identification of microRNA target genes, and a gene regulatory network. Bioinformatics R code and additional details of experimental methods and data analysis are provided. PMID- 26484232 TI - Genome-wide mapping of hot spots of DNA double-strand breaks in human cells as a tool for epigenetic studies and cancer genomics. AB - Hot spots of DNA double-strand breaks (DSBs) are associated with coordinated expression of genes in chromosomal domains (Tchurikov et al., 2011 [1]; 2013). These 50-150-kb DNA domains (denoted "forum domains") can be visualized by separation of undigested chromosomal DNA in pulsed-field agarose gels (Tchurikov et al., 1988; 1992) and used for genome-wide mapping of the DSBs that produce them. Recently, we described nine hot spots of DSBs in human rDNA genes and observed that, in rDNA units, the hot spots coincide with CTCF binding sites and H3K4me3 marks (Tchurikov et al., 2014), suggesting a role for DSBs in active transcription. Here we have used Illumina sequencing to map DSBs in chromosomes of human HEK293T cells, and describe in detail the experimental design and bioinformatics analysis of the data deposited in the Gene Expression Omnibus with accession number GSE53811 and associated with the study published in DNA Research (Kravatsky et al., 2015). Our data indicate that H3K4me3 marks often coincide with hot spots of DSBs in HEK293T cells and that the mapping of these hot spots is important for cancer genomic studies. PMID- 26484233 TI - Gene expression profiling by high throughput sequencing to determine signatures for the bovine receptive uterus at early gestation. AB - The uterus plays a central role among the reproductive tissues in the context of early embryo-maternal communication and a successful pregnancy depends on a complex series of endometrial molecular and cellular events. The factors responsible for the initial interaction between maternal and embryonic tissues, leading to the establishment of pregnancy, remain poorly understood. In this context, Illumina's next-generation sequencing technology has been used to discover the uterine transcriptome signature that is favourable for ongoing pregnancy. More specifically, the present report documents on a retrospective in vivo study in which data on pregnancy outcome were linked to uterine gene expression signatures on day 6 (bovine model). Using the RNA-Seq method, 14.654 reference genes were effectively analysed for differential expression between pregnant and non-pregnant uterine tissue. Transcriptome data revealed that 216 genes were differently expressed when comparing uterine tissue from pregnant and non-pregnant cows. All read sequences were deposited in the Sequence Read Archive (SRA) of the NCBI (http://www.ncbi.nlm.nih.gov/sra). An overview of the gene expression data has been deposited in NCBI's Gene Expression Omnibus (GEO) and is accessible through GEO Series accession number GSE65117. This allows the research community to enhance reproducibility and allows for new discoveries by comparing datasets of signatures linked to receptivity and/or pregnancy success. The resulting information can serve as tool to identify valuable and urgently needed biomarkers for scoring maternal receptivity and even for accurate detection of early pregnancy, which is a matter of cross-species interest. Beyond gene expression analysis as a marker tool, the RNA-Seq information on pregnant uterine tissue can be used to gain novel mechanistic insights, such as by identifying alternative splicing events, allele-specific expression, and rare and novel transcripts that might be involved in the onset of maternal receptivity. This concept is unique and provides a new approach towards strategies that are highly needed to improve efficiency of fertility treatments. PMID- 26484234 TI - Transcriptomic analyses of maize ys1 and ys3 mutants reveal maize iron homeostasis. AB - To acquire iron (Fe), graminaceous plants secrete mugineic acid family phytosiderophores (MAs) (Takagi, 1976 [1]) through the MAs efflux transporter TOM1 (Nozoye et al., 2011 [2]) and take up Fe in the form of Fe(III)-MAs complexes through the Fe(III)-MAs transporter YS1 (Curie et al., 2001 [3]). Yellow stripe 1 (ys1) and ys3 are recessive mutants of maize (Zea mays L.) that result in symptoms typical of Fe deficiency, i.e., interveinal chlorosis of the leaves. The ys1 mutant is defective in the YS1 transporter and is therefore unable to take up Fe(III)-MAs complexes. While the ys3 mutant has been shown to be defective in MA release, the causative gene has not been identified. The objective of the present work was to identify the genes responsible for the ys1 and ys3 phenotypes, so as to extend our understanding of Fe homeostasis in maize by qRT-PCR. In agreement with previous reports, the expression level of YS1 was decreased in the ys1 mutant. Moreover, we identified that the expression level of a homolog of TOM1 in maize (ZmTOM1) was significantly decreased in the ys3 mutant. Here described the quality control and analysis that were performed on the dataset. The data is publicly available through the GEO database with accession number GSE44557. The interpretation and description of these data are included in a manuscript (Nozoye et al., 2013 [4]). PMID- 26484235 TI - Global transcriptome analysis of T-competent progenitors in the bone marrow. AB - T cells are known to develop in the thymus. However, molecular events that control the transition from hematopoietic progenitor cells in the bone marrow to T precursor cells seeded in the thymus remained poorly defined. Our recent report showed that osteocalcin (Ocn)-expressing bone cells in the bone marrow have major impact on T cell immunity by regulating T progenitor development in the bone marrow (Yu et al., 2015) [1]. Selective endogenous depletion of Ocn(+) cells by inducible diphtheria toxin receptor expression (OcnCre;iDTR) led to reduction of T-competent common lymphoid progenitors (Ly6D(-) CLPs) in the bone marrow and loss of T cells in the thymus. Expression of the Notch ligand DLL4 by Ocn(+) cells in the bone marrow ensures the production of Ly6D(-) CLPs, and expression of chemotactic molecules CCR7 and PSGL1 to enable subsequent thymic seeding. These data indicate that specific mesenchymal cells in bone marrow provide key molecular drivers enforcing thymus-seeding progenitor generation and thereby directly link skeletal biology to the production of T cell based adaptive immunity. Here we present the transcriptome profiles of Ly6D(-) CLPs derived from Ocn(+) cells deleted mice (OcnCre(+);iDTR) compared to those derived from control littermates (OcnCre(-);iDTR). These data are publically available from NCBI Gene Expression Omnibus (GEO) with the accession number GSE66102. PMID- 26484236 TI - Isolation of chitinolytic Clostridium sp. NCR from Mehsani buffalo rumen, its genomic analysis and potential role in rumen. AB - Genomic analysis of Clostridium sp. NCR, an anaerobic Gram positive bacterium which was isolated from rumen fluid of Mehsani breed of buffalo revealed presence of various environmental gene tags (EGTs) involved in pathways for utilizing a wide range of substrates. Here we report the sequence of this rumen isolate, its whole genome sequence has been deposited in DDBJ/EMBL/GenBank under the accession number JQHY00000000. The genome comprises of a 3.62-Mb draft genome with a G + C content of 28.10%, which encodes a total of 3126 proteins. Functional analysis provides information about the microbe's role in maintaining host homeostasis and its fiber degradation potential. PMID- 26484237 TI - Association of aging with gene expression profiling in mouse submandibular glands. AB - Aging, also called senescence, is thought to be a physiological phenomenon that commonly occurs in various organs and tissues (Enoki et al., 2007 [1]). Many older adults experience dysfunction in their salivary glands, for example xerostomia, which is defined as dry mouth resulting from reduced or absent saliva flow (Nagler et al., 2004 [2]). In the present study, we investigated gene expression in submandibular glands of young (8 weeks old) and adult (50 weeks old) mice to analyze association of aging with gene expression profiling in mouse submandibular glands. Whole-genome gene expression profiles were analyzed using an Illumina Sentrix system with Mouse-WG-6 v.2 Expression BeadChips (Illumina). Of the genes screened, 284 showed detection values at a significance level of P < 0.01. Among those, the expression of 94 genes (33%) showed a greater decrease in adult mice as compared to young mice. On the other hand, that of 190 genes (77%) was increased in the adults more than in young mice. The data obtained in this study are publicly available in the Gene Expression Omnibus (GEO) database (accession number GSE66857). PMID- 26484238 TI - Comparative transcriptome analysis of latex from rubber tree clone CATAS8-79 and PR107. PMID- 26484239 TI - RNA-Seq analysis of isolated satellite cells in Prmt5 deficient mice. AB - Satellite cells (SCs) represent a distinct population of stem cells, essential for maintenance, growth and regeneration of adult skeletal muscle. SCs are mononuclear and are located between the basal lamina and the plasma membrane of myofibers. They are typically characterized by presence of the transcription factor paired-box 7 (PAX7) that is widely used as a satellite cell marker. Under normal physiological conditions SCs are quiescent but are activated by insults such as injury, disease or exercise. Once activated, satellite cells proliferate and subsequently differentiate into myoblasts to finally fuse to form new myofibers or with preexisting myofibers to repair or rebuild the skeletal muscle. A minority of SCs retains stem cell characteristics and self-renews to assure future bouts of regeneration throughout most of adult life. While a comprehensive picture of the regulatory events controlling SC fate has not yet been achieved, several factors were recently identified playing important roles in functional processes. One example is the arginine methyltransferase Prmt5 that is known to have multiple roles in germ cells and is involved in the maintenance of ES cell pluripotency. We have previously shown that Prmt5 is required for muscle stem cell proliferation and regenerative myogenesis due to direct epigenetic regulation of the cell cycle inhibitor p21. Here we provide a dataset that investigates the loss of Prmt5 in isolated Pax7(+) primary SCs using the Pax7(CreERT2)/Prmt5(loxP/loxP) knockout mouse model. RNA-Seq raw and analyzed data have been deposited in GEO under accession code GSE66822. PMID- 26484240 TI - Anti-apoptotic genes are synergistically activated in OVSAYO cells cultured under conditions of serum starvation and hypoxia. AB - The tumor microenvironment is generally hypoxic because of the limited oxygen supply from inefficient or insufficient vasculature. Hypoxic tumor tissues are also poorly supplied with serum components. We have previously demonstrated that expression of the FVII gene is induced in response to hypoxia in ovarian clear cell carcinoma (CCC) cells. This gene activation is synergistically enhanced when cells are simultaneously subjected to serum starvation, and is dependent on the transcription factor Sp1 directly associating with the FVII promoter. We have identified additional genes activated via a similar Sp1-dependent mechanism by conducting cDNA microarray analysis (GSE55565). ICAM1, which encodes intercellular adhesion molecule-1 (ICAM-1), is one such gene. ICAM-1 confers an anti-apoptotic effect upon CCC cells in vitro and promotes growth of CCC tumors. Here we describe the transcriptome analysis performed in our recently published study (Koizume et al., 2015). We further show that autonomous activation of the TNFalpha-NFkappaB axis is responsible for the synergistic activation of ICAM1 under hypoxic and serum starvation conditions. This study provides additional information as to how CCC cell survival can be facilitated under conditions of serum starvation and hypoxia. PMID- 26484241 TI - Analysis of cutaneous MRGPRD free nerve endings and C-LTMRs transcriptomes by RNA sequencing. AB - The skin is the largest sensory organ that is densely innervated by highly specialized sensory neurons allowing the detection of a wide range of stimulations including light touch, temperature, itch and pain. Our knowledge of the sets of genes instructing the functional specialization of sensory neurons is just emerging. In a previous study, we have identified a new Galphai inhibitory interacting protein (GINIP) that marks two distinct subsets of skin-innervating sensory neurons conveying noxious and pleasant touch: the MRGPRD-expressing C fibers specialized in noxious touch and the TH(+)/TAFA4(+)/V-GLUT3(+) C-Low Threshold MechanoReceptors (C-LTMRs), part of neurons processing pleasant touch. In the recent study published by Reynders et al. (2015), we took advantage of GINIP(mCherry) mouse model in combination with Isolectin B4 (IB4) cell surface labeling and fluorescence activated cell sorting (FACS). We successfully purified MRGPRD(+), C-LTMRs and a heterogeneous population of sensory neurons and subjected their RNA contents RNA-deep sequencing (RNA-seq). The subsequent RNA seq experiment led to the generation of unique sets of data representative of pure transcriptome profiles of each subset. As a result of this pioneering approach, we established the combinatorial expression of the sets of genes that could dictate the functional specializations of MRGPRD(+) neurons and C-LTMRs. Herein we provide details regarding the experimental design, the quality controls and statistical analysis of the data deposited at Gene Expression Omnibus under the accession number GSE64091. PMID- 26484242 TI - Identification of sRNA interacting with a transcript of interest using MS2 affinity purification coupled with RNA sequencing (MAPS) technology. AB - RNA sequencing (RNAseq) technology recently allowed the identification of thousands of small RNAs (sRNAs) within the prokaryotic kingdom. However, drawing the comprehensive interaction map of a sRNA remains a challenging task. To address this problem, we recently developed a method called MAPS (MS2 affinity purification coupled with RNA sequencing) to characterize the full targetome of specific sRNAs. This method enabled the identification of target RNAs interacting with sRNAs, regardless of the type of regulation (positive or negative), type of targets (mRNA, tRNA, sRNA) or their abundance. We also demonstrated that we can use this technology to perform a reverse MAPS experiment, where an RNA fragment of interest is used as bait to identify interacting sRNAs. Here, we demonstrated that RybB and MicF sRNAs co-purified with internal transcribed spacers (ITS) of metZ-metW-metV tRNA transcript, confirming results obtained with MS2-RybB MAPS. Both raw and analyzed RNAseq data are available in GEO database (GSE66517). PMID- 26484243 TI - Identification of genome-specific transcripts in wheat-rye translocation lines. AB - Studying gene expression in wheat-rye translocation lines is complicated due to the presence of homeologs in hexaploid wheat and high levels of synteny between wheat and rye genomes (Naranjo and Fernandez-Rueda, 1991 [1]; Devos et al., 1995 [2]; Lee et al., 2010 [3]; Lee et al., 2013 [4]). To overcome limitations of current gene expression studies on wheat-rye translocation lines and identify genome-specific transcripts, we developed a custom Roche NimbleGen Gene Expression microarray that contains probes derived from the sequence of hexaploid wheat, diploid rye and diploid progenitors of hexaploid wheat genome (Lee et al., 2014). Using the array developed, we identified genome-specific transcripts in a wheat-rye translocation line (Lee et al., 2014). Expression data are deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE58678. Here we report the details of the methods used in the array workflow and data analysis. PMID- 26484244 TI - Time-series analysis of the transcriptome of the re-establishment of desiccation tolerance by ABA in germinated Arabidopsis thaliana seeds. AB - Expression analyses of time series have become a very popular method for studying the dynamics of a wide range of biological processes. Here, we present expression analysis of a time series with the help of microarrays used to study the re establishment of desiccation tolerance (DT) in germinated Arabidopsis thaliana seeds. Mature seeds of A. thaliana are desiccation tolerant (survive the loss of most of their water content), but they become desiccation sensitive while progressing to germination. Yet, there is a small developmental window during which DT can be re-established by treatment with the plant hormone abscisic acid (ABA). We studied germinated A. thaliana seeds at the stage of radicle protrusion during ABA incubation for 0 h, 2 h, 12 h, 24 h and 72 h. We describe in detail the methodology applied for generating and analyzing this expression data of time series. The microarray raw data (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE62876) may be valuable for further studies on this experimental system, such as the construction of a gene co-expression network [1]. PMID- 26484245 TI - Transcriptional profiling of CcpE-regulated genes in Staphylococcus aureus. AB - The transcriptional regulator CcpE is an important citrate-sensing regulator that modulates metabolic state, virulence factor expression, and bacterial virulence of Staphylococcus aureus (Ding et al., 2014 [1]). In this article, we report detailed methods for genome-wide transcriptional profiling of CcpE-regulated genes generated for the research article "Metabolic sensor governing bacterial virulence in Staphylococcus aureus" (Ding et al., 2014 [1]). All transcriptional profiling data was deposited to Gene Expression Omnibus (GEO) database under accession number GSE57260. PMID- 26484246 TI - Genome-wide p63-regulated gene expression in differentiating epidermal keratinocytes. AB - The transcription factor p63 is a key regulator in epidermal keratinocyte proliferation and differentiation. However, the role of p63 in gene regulation during these processes is not well understood. To investigate this, we recently generated genome-wide profiles of gene expression, p63 binding sites and active regulatory regions with the H3K27ac histone mark (Kouwenhoven et al., 2015). We showed that only a subset of p63 binding sites are active in keratinocytes, and that differentiation-associated gene expression dynamics correlate with the activity of p63 binding sites rather than with their occurrence per se. Here we describe in detail the generation and processing of the ChIP-seq and RNA-seq datasets used in this study. These data sets are deposited in the Gene Expression Omnibus (GEO) repository under the accession number GSE59827. PMID- 26484247 TI - Transcriptomics analyses of soybean leaf and root samples during water-deficit. AB - Drought being a major challenge for crop productivity and yield affects multigenic and quantitative traits. It is also well documented that water stress shows a cross talk with other abiotic stresses such as high temperature and high light intensities (Tripathi et al., 2013) [1]. In this report, we documented the details of the methods and quality controls used and considered in our time course-based transcriptome profile of soybean plants under water deficit conditions using microarray technology. The findings of this study are recently published by the Rushton lab in BMC Genomics for a comparative study of tobacco and Soybean (Rabara et al., 2015) [2]. The raw microarray data set is deposited in GEO database with accession number GSE49537. PMID- 26484248 TI - The Porphyromonas gingivalis ferric uptake regulator orthologue does not regulate iron homeostasis. AB - Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that has an absolute requirement for iron which it transports from the host as heme and/or Fe(2 +). Iron transport must be regulated to prevent toxic effects from excess metal in the cell. P. gingivalis has one ferric uptake regulator (Fur) orthologue encoded in its genome called Har, which would be expected to regulate the transport and usage of iron within this bacterium. As a gene regulator, inactivation of Har should result in changes in gene expression of several genes compared to the wild-type. This dataset (GEO accession number GSE37099) provides information on expression levels of genes in P. gingivalis in the absence of Har. Surprisingly, these genes do not relate to iron homeostasis. PMID- 26484249 TI - Gene expression profiling in peripheral blood mononuclear cells of early-onset schizophrenia. AB - Schizophrenia (SZ) is a severe chronic psychiatric disorder with wide prevalence and high morbidity. We know little about SZ's etiology and pathophysiology at present. The study of gene expression profile is useful for us to identify potential biomarkers at molecular level and explain possible pathogenesis of SZ. Therefore we recently compared gene expression profiles in PMBCs from EOS cases and healthy controls using microarrays. Here we will describe in detail the contents and quality control of the microarray experiment. The raw microarray data are accessible through GEO series accession number GSE54913. PMID- 26484250 TI - miRNAs modified by dietary lipids in Caco-2 cells. A microarray screening. AB - We performed a screening of miRNAs regulated by dietary lipids in a cellular model of enterocytes, Caco-2 cells. Our aim was to describe new lipid-modified miRNAs with an implication in lipid homeostasis and cardiovascular disease [1,2]. For that purpose, we treated differentiated Caco-2 cells with micelles containing the assayed lipids (cholesterol, conjugated linoleic acid and docosahexaenoic acid) and the screening of miRNAs was carried out by microarray using the MUParaflo(r)Microfluidic Biochip Technology of LC Sciences (Huston, TX, USA). Experimental design, microarray description and raw data have been made available in the GEO database with the reference number of GSE59153. Here we described in detail the experimental design and methods used to obtain the relative expression data. PMID- 26484251 TI - Identification of novel differentially expressed lncRNA and mRNA transcripts in clear cell renal cell carcinoma by expression profiling. AB - Clear cell renal cell carcinoma (ccRCC) is a common human malignancy. Despite numerous efforts, there is still no reliable biomarker or combination of biomarkers available for daily practice. Our study was designed to explore the expression profile of messenger RNA (mRNA) and long non-coding RNA (lncRNA) transcripts in ccRCC in order to identify potential diagnostic biomarkers for patients with ccRCC. Total RNA from corresponding normal and malignant tissue of 15 patients with ccRCC was isolated. Expression profiling was performed using a custom Agilent gene expression microarray which allowed the analysis of 34,144 mRNA and 32,183 lncRNA transcripts. We observed that a subset of mRNA (n = 1064; 3.1%) and lncRNA (n = 1308; 4.1%) transcripts are dysregulated (fold change > 2) in ccRCC tissue. The relative higher number of differentially expressed lncRNAs indicates that lncRNA profiling may be better suited for diagnostic purposes; a number of so far unknown RNAs with potential diagnostic interest in ccRCC are identified by our gene expression profiling study. The data are deposited in the Gene Expression Omnibus (GSE61763). PMID- 26484252 TI - Gene expression profiling of Gram-negative bacteria-induced inflammation in human whole blood: The role of complement and CD14-mediated innate immune response. AB - Non-sterile pathogen-induced sepsis and sterile inflammation like in trauma or ischemia-reperfusion injury may both coincide with the life threatening systemic inflammatory response syndrome and multi-organ failure. Consequently, there is an urgent need for specific biomarkers in order to distinguish sepsis from sterile conditions. The overall aim of this study was to uncover putative sepsis biomarkers and biomarker pathways, as well as to test the efficacy of combined inhibition of innate immunity key players complement and Toll-like receptor co receptor CD14 as a possible therapeutic regimen for sepsis. We performed whole blood gene expression analyses using microarray in order to profile Gram-negative bacteria-induced inflammatory responses in an ex vivo human whole blood model. The experiments were performed in the presence or absence of inhibitors of complement proteins (C3 and CD88 (C5a receptor 1)) and CD14, alone or in combination. In addition, we used blood from a C5-deficient donor. Anti coagulated whole blood was challenged with heat-inactivated Escherichia coli for 2 h, total RNA was isolated and microarray analyses were performed on the Affymetrix GeneChip Gene 1.0 ST Array platform. The initial experiments were performed in duplicates using blood from two healthy donors. C5-deficiency is very rare, and only one donor could be recruited. In order to increase statistical power, a technical replicate of the C5-deficient samples was run. Subsequently, log2-transformed intensities were processed by robust multichip analysis and filtered using a threshold of four. In total, 73 microarray chips were run and analyzed. The normalized and filtered raw data have been deposited in NCBI's Gene Expression Omnibus (GEO) and are accessible with GEO Series accession number GSE55537. Linear models for microarray data were applied to estimate fold changes between data sets and the respective multiple testing adjusted p-values (FDR q-values). The interpretation of the data has been published by Lau et al. in an open access article entitled "CD14 and Complement Crosstalk and Largely Mediate the Transcriptional Response to Escherichia coli in Human Whole Blood as revealed by DNA Microarray" (Lau et al., 2015). PMID- 26484253 TI - Identifying type 1 diabetes candidate genes by DNA microarray analysis of islet specific CD4 + T cells. AB - Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease resulting from the destruction of insulin-producing pancreatic beta cells and is fatal unless treated with insulin. During the last four decades, multiple insulin-dependent diabetes (Idd) susceptibility/resistance loci that regulate T1D development have been identified in humans and non-obese diabetic (NOD) mice, an established animal model for T1D. However, the exact mechanisms by which these loci confer diabetes risk and the identity of the causative genes remain largely elusive. To identify genes and molecular mechanisms that control the function of diabetogenic T cells, we conducted DNA microarray analysis in islet-specific CD4 + T cells from BDC2.5 TCR transgenic NOD mice that contain the Idd9 locus from T1D susceptible NOD mice or T1D-resistant C57BL/10 mice. Here we describe in detail the contents and analyses for these gene expression data associated with our previous study [1]. Gene expression data are available at the Gene Expression Omnibus (GEO) repository from the National Center for Biotechnology Information (accession number GSE64674). PMID- 26484254 TI - Gene expression profiling can predict the fate of HeLa cells exposed to X-ray irradiation with or without protoporphyrin accumulation. AB - Protoporphyrin IX (PpIX) enhances the generation of reactive oxygen species in cells following physicochemical interactions with X-rays. To evaluate the use of porphyrins as radio-sensitizers in radiotherapy, the transcriptomic effects of PpIX and/or X-ray irradiation were investigated in HeLa cells. Microarray experiments were performed using Agilent-014,850 Whole Human Genome Microarray 4x44K G4112F (GEO#: GSE61805). We selected the condition corresponding to 1 MUg/mL PpIX exposure prior to 3 Gy-irradiation of cells, and collected cells 24 h post irradiation. X-ray exposure at a dose of 3 Gy did not affect cell survival 24 h post irradiation, regardless of the concentration of PpIX. Approximately 50% cells exposed to X-ray irradiation alone (XT) and 70% cells exposed to PpIX treatment for 6 h before X-ray irradiation (PpIX-XT) lost clonogenic ability. Based on p-values (p < 0.01), we selected genes for functional analysis. The majority of the regulated genes in the XT and PpIX-XT groups were related to cell cycle arrest. Furthermore, transcriptome analysis of the cells collected 24 h post irradiation revealed the fate of the cells that lost clonogenic ability due to cell cycle arrest. PMID- 26484255 TI - Metagenomic analysis of bacterial and archaeal assemblages in the soil-mousse surrounding a geothermal spring. AB - The soil-mousse surrounding a geothermal spring was analyzed for bacterial and archaeal diversity using 16S rRNA gene amplicon metagenomic sequencing which revealed the presence of 18 bacterial phyla distributed across 109 families and 219 genera. Firmicutes, Actinobacteria, and the Deinococcus-Thermus group were the predominant bacterial assemblages with Crenarchaeota and Thaumarchaeota as the main archaeal assemblages in this largely understudied geothermal habitat. Several metagenome sequences remained taxonomically unassigned suggesting the presence of a repertoire of hitherto undescribed microbes in this geothermal soil mousse econiche. PMID- 26484256 TI - MicroRNA expression profile of bone marrow mesenchymal stem cell-derived neural progenitor by microarray under the influence of EGF, bFGF and IGF-1. AB - Recently there has been growing interest in the differentiation of mesenchymal stem cells (MSCs) into neural lineages. Research suggests that MSCs can be differentiated into neural progenitor-like cells (NPCs) under the specific influence of paracrine factors particularly epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Our recent research has found that the addition of insulin-like growth factor 1 (IGF-1) with the combination of the EGF and bFGF could significantly improve the growth and survivability of MSC-derived NPCs. To unravel the molecular mechanism of the improved differentiation we compared the microRNA expression profiles of the differentiation under various combinations of growth factors. MSCs were differentiated into neural lineage in 3 groups; Group A (EGF + bFGF), Group B (EGF + bFGF + IGF-1), and Group C (without growth factor). Regulated microRNAs during the early differentiation were identified by detailed microRNA profiling using Affymetrix GeneChip version 2.0 at three time intervals (day 1, day 3 and day 5). The data were deposited in the Gene Expression Omnibus, series GSE60060. PMID- 26484257 TI - Expression profiling of genes modulated by estrogen, EGCG or both in MCF-7 breast cancer cells. AB - (-)-Epigallocatechin-3-gallate (EGCG) is one of the most potent and the most studied green tea catechin. Reports on mechanisms of EGCG action and its cellular targets are plenty. Compelling evidences in the literature in favor of ER being one of its targets suggest that EGCG may have a significant impact on estrogen regulated gene expression. Despite the possible implications on breast cancer chemoprevention or therapy, this aspect of EGCG action has not been adequately investigated. In order to address this issue, we have obtained gene expression profiles of MCF-7 breast cancer cells treated with ethanol (vehicle control) and those treated with estrogen, EGCG or both, using microarrays. Here, we have presented in detail the design and execution of the microarray experiment, quality control checks and analysis of microarray data. The utility and importance of the data generated in this work have been discussed in the context of the background literature. Our data is available in the Gene Expression Omnibus (GEO) database with the identifier GSE56245. PMID- 26484258 TI - Secondary structure and feature of mitochondrial tRNA genes of the Ussurian tube nosed bat Murina ussuriensis (Chiroptera: Vespertilionidae). AB - The complete mitogenome (NC_021119) of the Ussurian tube-nosed bat Murina ussuriensis (Chiroptera: Vespertilionidae) was annotated and characterized in our recent publication (http://www.ncbi.nlm.nih.gov/nuccore/NC_021119). Here we provide additional information on methods in detail for obtaining the complete sequence of M. ussuriensis mitogenome. In addition, we describe characteristics of 22 tRNA genes and secondary structure and feature of 22 tRNAs of M. ussuriensis mitogenome. PMID- 26484259 TI - Simple and efficient way to detect small polymorphic bands in plants. AB - There are many ways to detect polymorphism. In this study we use the microsatellite markers to detect the polymorphism for the salt tolerance. This method has been successfully conducted in Oryza sativa and Brassica juncea. The results are reproducible. In contrast to previous methods, our method is simple and quite accurate for detecting the polymorphic bands. In this study instead of using agarose gel and ethidium bromide staining, we used non-denaturing polyacrylamide gel and a low-cost improved method for silver staining when we compare it to 11 other methods for their ability to detect simple sequence repeat polymorphisms as small as 50 bp in denaturing polyacrylamide gels. All methods detected the same alleles and banding pattern. However, important differences in sensitivity, contrast, time consumption and background were observed. PMID- 26484260 TI - Transcriptomic profiling comparison of YAP over-expression and conditional knockout mouse tooth germs. AB - To identify the downstream target genes of YAP, we used RNA-Seq technology to compare the transcriptomic profilings of Yap conditional knockout (Yap CKO) and YAP over-expression mouse tooth germs. Our results showed that some Hox, Wnt and Laminin family genes had concurrent changes with YAP transcripts, indicating that the expression of these genes may be regulated by YAP. Here, we provide the detailed experimental procedure for the transcriptomic profiling results (NCBI GEO accession number GSE65524). The associated study on the regulation of Hoxa1 and Hoxc13 genes by YAP was published in Molecular Cellular Biology in 2015 [Liu et al., 2015]. PMID- 26484261 TI - Microarray analysis of Neosartorya fischeri using different carbon sources, petroleum asphaltenes and glucose-peptone. AB - Asphaltenes are considered as the most recalcitrant petroleum fraction and represent a big problem for the recovery, separation and processing of heavy oils and bitumens. Neosartorya fischeri is a saprophytic fungus that is able to grow using asphaltenes as the sole carbon source [1]. We performed transcription profiling using a custom designed microarray with the complete genome from N. fischeri NRRL 181 in order to identify genes related to the transformation of asphaltenes [1]. Data analysis was performed using the genArise software. Results showed that 287 genes were up-regulated and 118 were down-regulated. Here we describe experimental procedures and methods about our dataset (NCBI GEO accession number GSE68146) and describe the data analysis to identify different expression levels in N. fischeri using this recalcitrant carbon source. PMID- 26484262 TI - Dataset of transcriptional landscape of B cell early activation. AB - Signaling via B cell receptors (BCR) and Toll-like receptors (TLRs) result in activation of B cells with distinct physiological outcomes, but transcriptional regulatory mechanisms that drive activation and distinguish these pathways remain unknown. At early time points after BCR and TLR ligand exposure, 0.5 and 2 h, RNA seq was performed allowing observations on rapid transcriptional changes. At 2 h, ChIP-seq was performed to allow observations on important regulatory mechanisms potentially driving transcriptional change. The dataset includes RNA-seq, ChIP seq of control (Input), RNA Pol II, H3K4me3, H3K27me3, and a separate RNA-seq for miRNA expression, which can be found at Gene Expression Omnibus Dataset GSE61608. Here, we provide details on the experimental and analysis methods used to obtain and analyze this dataset and to examine the transcriptional landscape of B cell early activation. PMID- 26484263 TI - Draft genome sequence of Paenibacillus dauci sp. nov., a carrot-associated endophytic actinobacteria. AB - Paenibacillus dauci sp. nov., a new kind of endophytic actinobacteria, is separated from the inner tissues of carrot sample, which forms intimated associations with carrot acting as biological control agents. Here we report a 5.37-Mb assembly of its genome sequence and other useful information, including the coding sequences (CDSs) responsible for biological processes such as antibiotic metabolic process, antimicrobial metabolism, anaerobic regulation and the biosynthesis of vitamin B and polysaccharide. This novel strain can be a potential source of novel lead products for exploitation in the field of pharmaceutical, agriculture and industry. PMID- 26484264 TI - Aristolochic acids - Induced transcriptomic responses in rat renal proximal tubule cells in vitro. AB - Aristolochic acids (AAs) are the active components of herbal drugs derived from Aristolochia species that have been used for medicinal purposes since antiquity. However, AAs have recently been discovered to be highly nephrotoxic and induced urothelial cancer in humans and malignant tumors in the kidney and urinary tract of rodents. In this study, we exposed rat renal proximal tubule cells in vitro to a sub-cytotoxic level of AAs at three different time points (6 h, 24 h and 72 h). We then analyzed the gene expression profile after the compound exposure. Functional analysis with Ingenuity Pathways Analysis and DAVID tools revealed that at the late time point (72 h) there are many significantly altered genes involved in cancer-related pathways such as p53 signaling. MIAMI-compliant microarray data are deposited in the NCBI GEO database under accession number GSE68687 and can be found at: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE68687. PMID- 26484265 TI - Genome-wide transcriptional profiling of wheat infected with Fusarium graminearum. AB - Fusarium head blight (FHB) is a destructive disease in wheat caused by Fusarium graminearum (F. g). It infects during the flowering stage favored by warm and highly humid climates. In order to understand possible wheat defense mechanism, gene expression analysis in response to F. g was undertaken in three genotypes of wheat, Japanese landrace cultivar Nobeokabouzu (highly resistant), Chinese cv. Sumai 3 (resistant) and Australian cv. Gamenya (susceptible). For microarray analysis, 3 and 7 days after inoculation (dai) samples were used in Agilent wheat custom array 4x38k. At 3 dai, the highest number of genes was up-regulated in Nobeokabouzu followed by Sumai 3 and minimum expression in Gamenya. Whereas at 7 dai, Sumai 3 expressed more genes compared to others. Further narrowing down by excluding commonly expressed genes in three genotypes and grouping according to the gene function has identified differentially high expression of genes involved in detoxification process such as multidrug resistant protein, multidrug resistance-associated protein, UDP-glycosyltransferase and ABC transporters in Nobeokabouzu at 3 dai. However in Sumai 3 many defense-related genes such as peroxidase, proteases and genes involved in plant cell wall defense at 7 dai were identified. These findings showed the difference of molecular defense mechanism among the cultivars in response to the pathogen. The complete data was accessed in NCBI GEO database with accession number GSE59721. PMID- 26484266 TI - Global gene expression profiling reveals a suppressed immune response pathway associated with 3q amplification in squamous carcinoma of the lung. AB - Chromosome 3q26-28 is a critical region of genomic amplification in non-small cell lung cancer (NSCLC), particularly lung squamous cell carcinomas (SCCs). No molecular therapeutic target has shown clinical utility for SCC, in contrast with adenocarcinomas of the lung. To identify novel candidate drivers in this region, we performed both Array Comparative Genomic Hybridization (array CGH, Agilent Human Genome CGH 244A oligo-microarrays) and Gene Expression Microarray (Agilent Human Gene Expression 4 * 44 K microarray) on 24 untreated lung SCC specimens. Using our previously published integrative genomics approach, we identified 12 top amplified driver genes within this region that are highly correlated and overexpressed in lung SCC. We further demonstrated one of the 12 top amplified driver Fragile X mental retardation-related protein 1 (FXR1) as a novel cancer gene in NSCLC and FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota ( PRKCI) and epithelial cell transforming 2 (ECT2) within the same amplicon in lung cancer cell. Here we report that immune response pathways are significantly suppressed in lung SCC and negatively associated with 3q driver gene expression, implying a potential role of 3q drivers in cancer immune-surveillance. In light of the attractive immunotherapy strategy using blockade of negative regulators of T cell function for multiple human cancer including lung SCC, our findings may provide a rationale for targeting 3q drivers in combination of immunotherapies for human tumors harboring the 3q amplicon. The data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE40089. PMID- 26484267 TI - LncRNA analysis of mouse spermatogonial stem cells following glial cell-derived neurotrophic factor treatment. AB - Spermatonial stem cells (SSCs) are the foundation of spermatogenesis. Long non coding RNAs (lncRNAs) are a class of non-coding RNAs with at least 200 bp in length, which play important roles in various biological processes. Growth factor glial cell line-derived neurotrophic factor (GDNF), secreted from testis niches, is critical for self-renewal of SSCs in vitro and in vivo. Using Illumina HiSeqTM 2000 high throughput sequencing, we found 55924 lncRNAs which were regulated by GDNF in SSCs in vitro; these included 21,929 known lncRNAs from NONCODE library (version 3.0) and 33,975 predicted lncRNAs which were identified using Coding Potential Calculator. Analyses of these data should provide new insights into regulated mechanism in SSC self-renewal and proliferation. The data have been deposited in the Gene Expression Omnibus (series GSE66998). PMID- 26484268 TI - Gene expression profiling in rats with depressive-like behavior. AB - Individual differences indicate stronger phenotypes than model animals especially in behavioral studies, and some animals show unexpected behaviors in control and animal model groups. High-throughput analysis including cDNA microarray analysis are more affected by individual differences, because more samples are needed to reduce the difference in multiple factor analysis than single factor analysis such as real-time PCR. We measured the depressive-like behavior of over 100 normal rats in the forced swimming test and selected the rats for control and depression group from them to minimize the individual difference using data of force swimming test. Here, we provided the detail of methods and quality control parameters for the cDNA microarray data. This dataset can reflect the increase of depressive-like behavior. The dataset is deposited in the gene expression omnibus (GEO), series GSE63377. PMID- 26484269 TI - Genome-wide transcriptional profiling of human glioblastoma cells in response to ITE treatment. AB - A ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is recently revealed to play a key role in embryogenesis and tumorigenesis (Feng et al. [1], Safe et al. [2]) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) (Song et al. [3]) is an endogenous AhR ligand that possesses anti-tumor activity. In order to gain insights into how ITE acts via the AhR in embryogenesis and tumorigenesis, we analyzed the genome-wide transcriptional profiles of the following three groups of cells: the human glioblastoma U87 parental cells, U87 tumor sphere cells treated with vehicle (DMSO) and U87 tumor sphere cells treated with ITE. Here, we provide the details of the sample gathering strategy and show the quality controls and the analyses associated with our gene array data deposited into the Gene Expression Omnibus (GEO) under the accession code of GSE67986. PMID- 26484270 TI - Genome analysis of rice-blast fungus Magnaporthe oryzae field isolates from southern India. AB - The Indian subcontinent is the center of origin and diversity for rice (Oryza sativa L.). The O. sativa ssp. indica is a major food crop grown in India, which occupies the first and second position in area and production, respectively. Blast disease caused by Magnaporthe oryzae is a major constraint to rice production. Here, we report the analysis of genome architecture and sequence variation of two field isolates, B157 and MG01, of the blast fungus from southern India. The 40 Mb genome of B157 and 43 Mb genome of MG01 contained 11,344 and 11,733 predicted genes, respectively. Genomic comparisons unveiled a large set of SNPs and several isolate specific genes in the Indian blast isolates. Avr genes were analyzed in several sequenced Magnaporthe strains; this analysis revealed the presence of Avr-Pizt and Avr-Ace1 genes in all the sequenced isolates. Availability of whole genomes of field isolates from India will contribute to global efforts to understand genetic diversity of M. oryzae population and to track the emergence of virulent pathotypes. PMID- 26484271 TI - Computational analysis of miRNA-target community network reveals cross talk among different metabolisms. AB - To date, only a few conserved miRNAs have been predicted in hexaploid (AABBDD) bread wheat and till now community behavior among miRNA is still in dark. Analysis of publically available 1287279 ESTs from NCBI resulted 262 putative pre miRNAs and 39 novel mature miRNAs. A total 22,468 targets were identified on 21 chromosomes. MiRNA target community was identified for genomes with different levels of cross talks. Gene ontology of these community targets suggests their differential involvement in different metabolisms along with common and stringent involvement in nitrogen metabolism. PMID- 26484272 TI - Genome-wide RNA profiling of long-lasting stem cell-like memory CD8 T cells induced by Yellow Fever vaccination in humans. AB - The live-attenuated Yellow Fever (YF) vaccine YF-17D induces a broad and polyfunctional CD8 T cell response in humans. Recently, we identified a population of stem cell-like memory CD8 T cells induced by YF-17D that persists at stable frequency for at least 25 years after vaccination. The YF-17D is thus a model system of human CD8 T cell biology that furthermore allows to track and study long-lasting and antigen-specific human memory CD8 T cells. Here, we describe in detail the sample characteristics and preparation of a microarray dataset acquired for genome-wide gene expression profiling of long-lasting YF specific stem cell-like memory CD8 T cells, compared to the reference CD8 T cell differentiation subsets from total CD8 T cells. We also describe the quality controls, annotations and exploratory analyses of the dataset. The microarray data is available from the Gene Expression Omnibus (GEO) public repository with accession number GSE65804. PMID- 26484273 TI - Draft genome sequence of Paenibacillus algorifonticola sp. nov., an antimicrobial producing strain. AB - Paenibacillus algorifonticola sp. nov. is isolated from a cold spring sample from Xinjiang Uyghur Autonomous Region (China), a novel strain that can produce antimicrobial substance against human pathogenic bacteria and fungi, including Staphylococcus aureus and Candida albicans. Here we report a 7.60-Mb assembly of its genome sequence and other useful information, including the coding sequences (CDSs) responsible for the biosynthesis of antibacterial factors, anaerobic respiration and several immune-associated reactions. Also, prospective studies on P. algorifonticola sp. nov. in the cold spring might offer a potential source for the discovery of bioactive compounds with medical value. The data repository is deposited on the website http://www.ncbi.nlm.nih.gov/nuccore/LAQO00000000 and the accession number is LAQO00000000. PMID- 26484274 TI - Piwi proteins and piRNAs in mammalian oocytes and early embryos: From sample to sequence. AB - The role of the Piwi/piRNA pathway during mammalian oogenesis has remained enigmatic thus far, especially since experiments with Piwi knockout mice did not reveal any phenotypic defects in female individuals. This is in striking contrast with results obtained from other species including flies and zebrafish. In mouse oocytes, however, only low levels of piRNAs are found and they are not required for their function. We recently demonstrated dynamic expression of PIWIL1, PIWIL2, and PIWIL3 during mammalian oogenesis and early embryogenesis. In addition, small RNA analysis of human, crab-eating macaque and cattle revealed that piRNAs are also expressed in the female germline and closely resemble piRNAs from testis. Here, we thoroughly describe the experimental and computational methods that we applied for the generation, processing and analyses of next generation sequencing (NGS) data associated with our study on Piwi proteins and piRNAs in mammalian oocytes and embryos (Roovers et al., 2015). The complete sequence data is available at NCBI's Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under the accession GSE64942. PMID- 26484275 TI - Transcriptome analysis of TH2 CD4(+) T cells differentiated from wild-type and NLRP3KO mice. AB - The Nod-like receptor NLRP3 is involved in the formation of NLRP3. Up to now, the immunological functions of NLRP3 independently of inflammasome is unclear. In this dataset containing 6 samples (TH0, TH2 cells at day 3 and day 6 in wild type or Nlrp3 deficient cells), we show that NLRP3 expression in CD4(+) T cells supports a T helper 2 (TH2) transcriptional program in a cell-intrinsic manner (raw and normalized data are accessible on Gene Expression Omnibus database under the number GSE54561, http://www.dtd.nlm.nih.gov/geo/query/acc.cgi?acc=GSE54561). Indeed, NLRP3 positively-regulated TH2 program independently of inflammasome formation. These data indicated that TH2 specific genes such as cMaf or Il4 were not induced in Nlrp3 deficient cells. These results demonstrate the capacity of NLRP3 to act as a key transcription factor in TH2 differentiation. PMID- 26484276 TI - High-quality complete genome sequence of Microbacterium sp. SUBG005, a plant pathogen. AB - Microbacterium sp. SUBG005 is a Gram positive bacterium, isolated from infected leaf of Mangifera indica L. in Rajkot (22.30 degrees N, 70.78 degrees E), Gujarat, India. The genome sequencing of Microbacterium sp. SUBG005 is having type I secretion system genes of pathogenicity as well as heavy metal resistance unique genes. The genome size is 7.01 Mb with G + C content of 64.80% and contains rRNA sequences. Genome sequencing analysis provides information about the microbe role in host-pathogen interaction. The whole genome sequencing has been deposited in DDBJ/EMBL/GenBank under the accession number JNNT00000000. PMID- 26484277 TI - Transcriptome comparison of distinct osteolineage subsets in the hematopoietic stem cell niche using a triple fluorescent transgenic mouse model. AB - The bone marrow niche is recognized as a central player in maintaining and regulating the behavior of hematopoietic stem and progenitor cells. Specific gain of and loss-of function experiments perturbing a range of osteolineage cells or their secreted proteins had been shown to affect stem cell maintenance (Calvi et al, 2003 [1]; Stier et al., 2005 [2]; Zhang et al., 2003 [3]; Nilsson et al., 2005 [4]; Greenbaum et al., 2013 [5]) and engraftment (Adam et al., 2006, 2009 [6,7]). We used specific in vivo cell deletion approaches to dissect the niche cell-parenchymal cell dependency in a complex bone marrow microenvironment. Endogenous deletion of osteocalcin-expressing (Ocn(+)) cells led to a loss of T immune cells (Yu et al., 2015 [8]. Ocn(+) cells express the Notch ligand DLL4 to communicate with T-competent progenitors, and thereby ensuring T precursor production and expression of chemotactic molecules on their cell surface for subsequent thymic seeding. In contrast, depletion of osterix-expressing (Osx(+)) osteoprogenitors led to reduced B immune cells. These distinct hematopoietic phenotypes suggest specific pairing of mesenchymal niche cells and parenchymal hematopoietic cells in the bone marrow to create unique functional units to support hematopoiesis. Here, we present the global gene expression profiles of these osteolineage subtypes utilizing a triple fluorescent transgenic mouse model (OsxCre(+);Rosa-mCh(+);Ocn:Topaz(+)) that labels Osx(+) cells red, Ocn(+) cells green, and Osx(+) Ocn(+) cells yellow. This system allows isolation of distinct osteolineage subsets within the same animal by flow cytometry. Array data that have been described in our study [8] are also publically available from NCBI Gene Expression Omnibus (GEO) with the accession number GSE66042. Differences in gene expression may correlate with functional difference in supporting hematopoiesis. PMID- 26484278 TI - Genomic analysis of novel phytopathogenic Georgenia sp. strain SUB25. AB - A Gram positive bacterium, Georgenia sp. SUB25 was isolated from infected leaves of Solanum lycopersicum L. in Rajkot (22.30 degrees N, 70.78 degrees E), Gujarat, India. We sequenced and analyzed Georgenia sp. SUB25 that is novel plant pathogen using next generation sequencing platform and assembly yielded contigs representing a size of 4.84 Mb with 81 tRNAs and 88 rRNAs. The whole genome sequencing has been deposited in DDBJ/EMBL/GenBank under the accession number JNFL00000000. This genome sequence contains Type II secretion system genes, which involved in pathogenicity mechanism that may help to understand plant microbial interaction. PMID- 26484279 TI - Gene expression profiling of DBA/2J mice cochleae treated with l-methionine and valproic acid. AB - DBA/2J mice, which have homozygous mutations in Cdh23 and Fscn2, are characterized by early onset hearing loss at as early as three-weeks of age (Noben-Trauth et al., 2003 [1]) and are an animal model for progressive hearing loss research. Recently, it has been reported that epigenetic regulatory pathways likely play an important role in hearing loss (Provenzano and Domann, 2007 [2]; Mutai et al., 2009 [3]; Waldhaus et al., 2012 [4]). We previously reported that DBA/2J mice injected subcutaneously with a combination of epigenetic modifying reagents, l-methionine (MET) as methyl donor and valproic acid (VPA) as a pan histone deacetylases (Hdac) inhibitor, showed a significant attenuation of progressive hearing loss by measuring their auditory brainstem response (ABR) thresholds (Mutai et al., 2015 [5]). Here we present genome wide expression profiling of the DBA/2J mice cochleae, with and without treatment of MET and VPA, to identify the genes involved in the reduction of progressive hearing loss. The raw and normalized data were deposited in NCBI's Gene Expression Omnibus (GEO ID: GSE62173) for ease of reproducibility and reanalysis. PMID- 26484280 TI - Gene expression profile in the fat tissue of Fsp27 deficient mice. AB - Fsp27 is a lipid droplet-associated protein almost exclusively expressed in adipocytes where it facilitates unilocular lipid droplet formation. In mice, Fsp27 deficiency is associated with increased basal lipolysis, browning of white fat and a healthy metabolic profile, whereas energetically challenged Fsp27 deficient mice (ob/ob/Fsp27 (-/-)) show dramatically reduced fat mass, hepatic steatosis and insulin resistance which represents a typical lipodystrophy phenotype. Here, we investigate the effect of Fsp27 depletion on the gene expression of gonadal white adipose tissue (GWAT) under normal or energetically challenged condition (Fsp27 (-/-) vs Wild type; ob/ob/Fsp27 (-/-) vs ob/ob). We systematically analyzed the change in signaling pathway in Fsp27 deficient mice. The raw data have been deposited into Gene Expression Omnibus (GEO): GSE59807 and GSE22693. PMID- 26484281 TI - Global gene expression profiling of a mouse model of ovarian clear cell carcinoma caused by ARID1A and PIK3CA mutations implicates a role for inflammatory cytokine signaling. AB - Ovarian clear-cell carcinoma (OCCC) is an aggressive form of epithelial ovarian cancer (EOC). OCCC represents 5-25% of all EOC incidences and is the second leading cause of death from ovarian cancer (Glasspool and McNeish, 2013) [1]. A recent publication by Chandler et al. reported the first mouse model of OCCC that resembles human OCCC both genetically and histologically by inducing a localized deletion of ARID1A and the expression of the PIK3CA(H1047R) substitution mutation (Chandler et al., 2015) [2]. We utilized Affymetrix Mouse Gene 2.1 ST arrays for the global gene expression profiling of mouse primary OCCC tumor samples and animal-matched normal ovaries to identify cancer-dependent gene expression. We describe the approach used to generate the differentially expressed genes from the publicly available data deposited at the Gene Expression Omnibus (GEO) database under the accession number GSE57380. These data were used in cross species comparisons to publically available human OCCC gene expression data and allowed the identification of coordinately regulated genes in both mouse and human OCCC and supportive of a role for inflammatory cytokine signaling in OCCC pathogenesis (Chandler et al., 2015) [2]. PMID- 26484282 TI - Analyzing alternative splicing data of splice junction arrays from Parkinson patients' leukocytes before and after deep brain stimulation as compared with control donors. AB - Few studies so far examined alternative splicing alterations in blood cells of neurodegenerative disease patients, particularly Parkinson's disease (PD). Prototype junction microarrays interrogate known human genome junctions and enable characterization of alternative splicing events; however, the analysis is not straightforward and different methods can be used to estimate junction specific alternative splicing events (some of which can also be applied for analyzing RNA sequencing junction-level data). In this study, we characterized alternative splicing changes in blood leukocyte samples from Parkinson's patients prior to, and following deep brain stimulation (DBS) treatment; both on stimulation and following 1 h off electrical stimulation. Here, we describe in detail analysis approaches for junction microarrays and provide suggestions for further analyses to delineate transcript level effects of the observed alterations as well as detection of microRNA binding sites and protein domains in the alternatively spliced target regions spanning across both untranslated and the coding regions of the targets. The raw expression data files are publically available in the Gene Expression Omnibus (GEO) database (accession number: GSE37591) and in Synapse, and can be re-analyzed. The results may be useful for designing of future experiments and cross correlations with other datasets from PD or patients having other neurodegenerative diseases. PMID- 26484283 TI - Transcriptomic analyses of nitrogen assimilation processes in a Chinese strain of Aureococcus anophagefferens. PMID- 26484284 TI - Transcriptome and H3K27 tri-methylation profiling of Ezh2-deficient lung epithelium. AB - The adaptation of the lungs to air breathing at birth requires the fine orchestration of different processes to control lung morphogenesis and progenitor cell differentiation. However, there is little understanding of the role that epigenetic modifiers play in the control of lung development. We found that the histone methyl transferase Ezh2 plays a critical role in lung lineage specification and survival at birth. We performed a genome-wide transcriptome study combined with a genome-wide analysis of the distribution of H3K27 tri methylation marks to interrogate the role of Ezh2 in lung epithelial cells. Lung cells isolated from Ezh2-deficient and control mice at embryonic day E16.5 were sorted into epithelial and mesenchymal populations based on EpCAM expression. This enabled us to dissect the transcriptional and epigenetic changes induced by the loss of Ezh2 specifically in the lung epithelium. Here we provide a detailed description of the analysis of the RNA-seq and ChIP-seq data, including quality control, read mapping, differential expression and differential binding analyses, as well as visualisation methods used to present the data. These data can be accessed from the Gene Expression Omnibus database (super-series accession number GSE57393). PMID- 26484285 TI - Ameliorated de novo transcriptome assembly using Illumina paired end sequence data with Trinity Assembler. AB - Advent of Next Generation Sequencing has led to possibilities of de novo transcriptome assembly of organisms without availability of complete genome sequence. Among various sequencing platforms available, Illumina is the most widely used platform based on data quality, quantity and cost. Various de novo transcriptome assemblers are also available today for construction of de novo transcriptome. In this study, we aimed at obtaining an ameliorated de novo transcriptome assembly with sequence reads obtained from Illumina platform and assembled using Trinity Assembler. We found that, primary transcriptome assembly obtained as a result of Trinity can be ameliorated on the basis of transcript length, coverage, and depth and protein homology. Our approach to ameliorate is reproducible and could enhance the sensitivity and specificity of the assembled transcriptome which could be critical for validation of the assembled transcripts and for planning various downstream biological assays. PMID- 26484286 TI - DNA methylation fingerprint of neuroblastoma reveals new biological and clinical insights. AB - Neuroblastoma (NB) is one of the most frequently occurring extracranial solid tumors of childhood (Maris et al., 2007 [1]; Brodeur, 2003 [2]). Probability of cure varies according to patient's age, extent of disease and tumor biology (Maris et al., 2007 [1]; Brodeur, 2003 [2]; Cohn et al., 2009 [3]). However, the etiology of this developmental tumor is unknown. Recent evidence has shown that pediatric solid tumors, including NB, harbor a paucity of recurrent genetic mutations, with a significant proportion of recurrent events converging on epigenetic mechanisms (Cheung et al., 2012 [4]; Molenaar et al., 2012 [5]; Pugh et al., 2013 [6]; Sausen et al., 2013 [7]. We have analyzed the DNA methylome of neuroblastoma using high-density microarrays (Infinium Human Methylation 450k BeadChip) to define the epigenetic landscape of this pediatric tumor and its potential clinicopathological impact. Here, we provide the detail of methods and quality control parameters of the microarray data used for the study. Methylation data has been deposited at NCBI Gene Expression Omnibus data repository, accession number GSE54719; superseries record GSE54721. PMID- 26484287 TI - Transcriptomic study on the impact of temporomandibular joint internal derangement in the condylar cartilage of rabbits. AB - Internal derangement (ID) in the temporomandibular joint (TMJ) compromises a group of clinical problems, and holds a relative high prevalence in populations. However, the temporal genomic change in gene expression of condylar cartilage during continuous ID remains unclear. Here we reported the differentially expressed gene pattern in condylar cartilage of rabbits with ID from 1 to 8 weeks by microarray analysis. The whole genome project was deposited at GenBank under the accession PRJNA278127. The microarray analysis showed that 6478 genes have more than two-fold changes among all the tested transcripts. Many inflammation gene increased rapidly in the early stage while decrease later. On the contrary, the bone construction related genes showed a low level at first and increased at later period in the ID progression. Besides, the current study found some genes such as HLA2G, which had never been reported, might be relevant with ID. PMID- 26484288 TI - Description of an optimized ChIP-seq analysis pipeline dedicated to genome wide identification of E4F1 binding sites in primary and transformed MEFs. AB - This Data in Brief report describes the experimental and bioinformatic procedures that we used to analyze and interpret E4F1 ChIP-seq experiments published in Rodier et al. (2015) [10]. Raw and processed data are available at the GEO DataSet repository under the subseries # GSE57228. E4F1 is a ubiquitously expressed zinc-finger protein of the GLI-Kruppel family that was first identified in the late eighties as a cellular transcription factor targeted by the adenoviral oncoprotein E1A13S (Ad type V) and required for the transcription of adenoviral genes (Raychaudhuri et al., 1987) [8]. It is a multifunctional factor that also acts as an atypical E3 ubiquitin ligase for p53 (Le Cam et al., 2006) [2]. Using KO mouse models we then demonstrated that E4F1 is essential for early embryonic development (Le Cam et al., 2004), for proliferation of mouse embryonic cell (Rodier et al., 2015), for the maintenance of epidermal stem cells (Lacroix et al., 2010) [6], and strikingly, for the survival of cancer cells (Hatchi et al., 2007) [4]; (Rodier et al., 2015) [10]. The latter survival phenotype was p53 independent and suggested that E4F1 was controlling a transcriptional program driving essential functions in cancer cells. To identify this program, we performed E4F1 ChIP-seq analyses in primary Mouse Embryonic Fibroblasts (MEF) and in p53(-/-), H-Ras(V12)-transformed MEFs. The program directly controlled by E4F1 was obtained by intersecting the lists of E4F1 genomic targets with the lists of genes differentially expressed in E4F1 KO and E4F1 WT cells (Rodier et al., 2015). We describe hereby how we improved our ChIP-seq analyses workflow by applying prefilters on raw data and by using a combination of two publicly available programs, Cisgenome and QESEQ. PMID- 26484289 TI - Transcriptional profiling of intestinal CD4(+) T cells in the neonatal and adult mice. AB - The adult small intestine contains more than half of the body's lymphocytes in order to maintain homeostasis with the commensal microbiota. Birth marks a transition of the intestine from a sterile to an increasingly colonized environment. The data described in this article are incremented into the work published by Torow et al. titled "Active suppression of intestinal CD4(+) TCRalphabeta(+) T lymphocyte maturation during the postnatal period" [1]. While most of the CD4 T cells found in the adult small intestine have an activated phenotype marked by expression of helper lineage specific genes neonatal lymphocytes exhibit a naive phenotype. Further, direct comparison of neonatal CD4 T cells from the small intestine and the gut draining mesenteric lymph node (mLN) reveals a global transcriptional 'inactivity' of the small intestinal CD4 T cells. Here, we describe in more detail the experimental design, sample preparation and analysis that were performed to obtain and interpret the microarray data. The data set is publicly available through the Gene Expression Omnibus (GEO) database with accession number GSE60515, and the analysis and interpretation of these data are included in Torow et al. [1]. PMID- 26484290 TI - Genome-wide ChIP-seq and RNA-seq analyses of Pou3f1 during mouse pluripotent stem cell neural fate commitment. AB - Appropriate neural initiation of the pluripotent stem cells in the early embryos is critical for the development of the central nervous system. This process is regulated by the coordination of extrinsic signals and intrinsic programs. However, how the coordination is achieved to ensure proper neural fate commitment is largely unknown. Here, taking advantage of genome-wide ChIP-sequencing (ChIP seq) and RNA-sequencing (RNA-seq) analyses, we demonstrate that the transcriptional factor Pou3f1 is an upstream activator of neural-promoting genes, and it is able to repress neural-inhibitory signals as well. Further studies revealed that Pou3f1 could directly bind neural lineage genes like Sox2 and downstream targets of neural inhibition signaling such as BMP and Wnt. Our results thus identify Pou3f1 as a critical dual-regulator of the intrinsic transcription factors and the extrinsic cellular signals during neural fate commitment. Data were deposited in Gene Expression Omnibus (GEO) datasets under reference number GSE69865. PMID- 26484291 TI - RNAome sequencing delineates the complete RNA landscape. AB - Standard RNA expression profiling methods rely on enrichment steps for specific RNA classes, thereby not detecting all RNA species. For example, small and large RNAs from the same sample cannot be sequenced in a single sequence run. We designed RNAome sequencing, which is a strand-specific method to determine the expression of small and large RNAs from ribosomal RNA-depleted total RNA in a single sequence run. RNAome sequencing quantitatively preserves all RNA classes. This characteristic allows comparisons between RNA classes, thereby facilitating relationships between different RNA classes. Here, we describe in detail the experimental procedure associated with RNAome sequencing published by Derks and colleagues in RNA Biology (2015) [1]. We also provide the R code for the developed Total Rna Analysis Pipeline (TRAP), an algorithm to analyze RNAome sequencing datasets (deposited at the Gene Expression Omnibus data repository, accession number GSE48084). PMID- 26484292 TI - Microarray expression profile of circular RNAs in human pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) remains a common and deadly cancer. Despite numerous efforts, no reliable biomarker is available for daily clinical practice. Circular RNAs (circRNAs) are an abundant, stable and conserved class of RNA molecules that exhibit tissue/developmental-stage-specific expression (Salzman et al., 2012; Jeck et al., 2013; Memczak et al., 2013). CircRNAs play a crucial role in disease, especially in cancer, and provide new potential diagnostic and therapeutic targets for disease (Hansen et al., 2013; Qu et al., 2015).This research was designed to explore the expression profile of circRNAs in PDAC to serve as new diagnosis and treatment strategies for PDAC. Microarray and sample annotation data were deposited in Gene Expression Omnibus (GEO) under accession number GSE69362. PMID- 26484293 TI - Distinct microRNA expression profiles in follicle-associated epithelium and villous epithelium. AB - M cells in follicle-associated epithelium (FAE) covering intestinal lymphoid follicles serve as a portal of entry for particulate antigens (Kanaya and Ohno, 2014 [1]). Despite their biological significance, molecular mechanisms that govern M-cell differentiation and function have not been fully elucidated. MicroRNAs (miRNAs) have a role to control host gene expression profiles that modulate cellular physiology and characteristic. Many studies have shown that miRNAs regulate diverse biological processes including developmental timing, differentiation and growth control of cells and tissues (Ivey and Srivastava, 2010 [2]). miRNAs are also relevant to differentiation and function of intestinal epithelium (McKenna et al., 2010 [3]; Runtsch et al., 2014 [4]). Expression profiles and functions of miRNAs in the intestinal epithelium have been examined in jejunal and colonic mucosa [3]. In contrast, those in FAE remain uncharacterized. To address this deficiency, we isolated Peyer's Patch (PP) FAE and villous epithelium (VE) surrounding the FAE, and compared the miRNA expression profiles of FAE and VE by microarray analysis. This revealed that 43 miRNAs were up-regulated, whereas 9 miRNAs were down-regulated, in FAE compared to VE. A unique pattern of miRNA expression by FAE may reflect important diversity in cellular phenotypes and/or functional features of FAE. All microarray data has been deposited at GEO under accession number GSE46264. PMID- 26484294 TI - Transcriptional profiling of suberoylanilide hydroxamic acid (SAHA) regulated genes in mineralizing dental pulp cells at early and late time points. AB - Dental pulp tissue can be damaged by a range of irritants, however, if the irritation is removed and/or the tooth is adequately restored, pulp regeneration is possible (Mjor and Tronstad, 1974 [1]). At present, dental restorative materials limit healing by impairing mineralization and repair processes and as a result new biologically-based materials are being developed (Ferracane et al., 2010 [2]). Previous studies have highlighted the benefit of epigenetic modification by histone deacetylase inhibitor (HDACi) application to dental pulp cells (DPCs), which induces changes to chromatin architecture, promoting gene expression and cellular-reparative events (Duncan et al., 2013 [3]; Paino et al., 2014 [4]). In this study a genome-wide transcription profiling in epigenetically modified mineralizing primary DPC cultures was performed, at relatively early and late time-points, to identify differentially regulated transcripts that may provide novel therapeutic targets for use in restorative dentistry. Here we provide detailed methods and analysis on these microarray data which has been deposited in Gene Expression Omnibus (GEO): GSE67175. PMID- 26484295 TI - Transcriptome profiling of white adipose tissue in a mouse model for 15q duplication syndrome. AB - Obesity is not only associated with unhealthy lifestyles, but also linked to genetic predisposition. Previously, we generated an autism mouse model (patDp/+) that carries a 6.3 Mb paternal duplication homologous to the human 15q11-q13 locus. Chromosomal abnormalities in this region are known to cause autism spectrum disorder, Prader-Willi syndrome, and Angelman syndrome in humans. We found that, in addition to autistic-like behaviors, patDp/+ mice display late onset obesity and hypersensitivity to a high-fat diet. These phenotypes are likely to be the results of genetic perturbations since the energy expenditures and food intakes of patDp/+ mice do not significantly differ from those of wild type mice. Intriguingly, we found that an enlargement of adipose cells precedes the onset of obesity in patDp/+ mice. To understand the underlying molecular networks responsible for this pre-obese phenotype, we performed transcriptome profiling of white adipose tissue from patDp/+ and wild-type mice using microarray. We identified 230 genes as differentially expressed genes. Sfrp5 - a gene whose expression is positively correlated with adipocyte size, was found to be up-regulated, and Fndc5, a potent inducer of brown adipogenesis was identified to be the top down-regulated gene. Subsequent pathway analysis highlighted a set of 35 molecules involved in energy production, lipid metabolism, and small molecule biochemistry as the top candidate biological network responsible for the pre-obese phenotype of patDp/+. The microarray data were deposited in NCBI Gene Expression Omnibus database with accession number GSE58191. Ultimately, our dataset provides novel insights into the molecular mechanism of obesity and demonstrated that patDp/+ is a valuable mouse model for obesity research. PMID- 26484296 TI - Analyses of the influencing factors of soil microbial functional gene diversity in tropical rainforest based on GeoChip 5.0. AB - To examine soil microbial functional gene diversity and causative factors in tropical rainforests, we used a microarray-based metagenomic tool named GeoChip 5.0 to profile it. We found that high microbial functional gene diversity and different soil microbial metabolic potential for biogeochemical processes were considered to exist in tropical rainforest. Soil available nitrogen was the most associated with soil microbial functional gene structure. Here, we mainly describe the experiment design, the data processing, and soil biogeochemical analyses attached to the study in details, which could be published on BMC microbiology Journal in 2015, whose raw data have been deposited in NCBI's Gene Expression Omnibus (accession number GSE69171). PMID- 26484297 TI - Deep sequencing of mRNA in CD24(-) and CD24(+) mammary carcinoma Mvt1 cell line. AB - CD24 is an anchored cell surface marker that is highly expressed in cancer cells (Lee et al., 2009) and its expression is associated with poorer outcome of cancer patients (Kristiansen et al., 2003). Phenotype comparison between two subpopulations derived from the Mvt1 cell line, CD24(-) cells (with no CD24 cell surface expression) and the CD24(+) cells, identified high tumorigenic capacity for the CD24(+) cells. In order to reveal the transcripts that support the CD24(+) aggressive and invasive phenotype we compared the gene profiles of these two subpopulations. mRNA profiles of CD24(-) and CD24(+) cells were generated by deep sequencing, in triplicate, using an Illumina HiSeq 2500. Here we provide a detailed description of the mRNA-seq analysis from our recent study (Rostoker et al., 2015). The mRNA-seq data have been deposited in the NCBI GEO database (accession number GSE68746). PMID- 26484299 TI - Image-guided radiation therapy in lymphoma management. AB - Image-guided radiation therapy (IGRT) is a process of incorporating imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), Positron emission tomography (PET), and ultrasound (US) during radiation therapy (RT) to improve treatment accuracy. It allows real-time or near real-time visualization of anatomical information to ensure that the target is in its position as planned. In addition, changes in tumor volume and location due to organ motion during treatment can be also compensated. IGRT has been gaining popularity and acceptance rapidly in RT over the past 10 years, and many published data have been reported on prostate, bladder, head and neck, and gastrointestinal cancers. However, the role of IGRT in lymphoma management is not well defined as there are only very limited published data currently available. The scope of this paper is to review the current use of IGRT in the management of lymphoma. The technical and clinical aspects of IGRT, lymphoma imaging studies, the current role of IGRT in lymphoma management and future directions will be discussed. PMID- 26484300 TI - Clinical outcomes of synchronous head and neck and esophageal cancer. AB - PURPOSE: To investigate clinical outcomes of synchronous head and neck and esophageal cancer (SHNEC). MATERIALS AND METHODS: We retrospectively reviewed 27 SHNEC patients treated with curative intent at a single institution. The treatment modality for individual cases was usually determined on a case by case basis. RESULTS: The median follow-up duration for the surviving patients was 28.2 months. The most common site of head and neck cancer was hypopharyngeal carcinoma (n = 21, 77.7%). The lower esophagus was the most common location of esophageal carcinoma (n = 16, 59.3%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 57.5% and 39.6%. Major pattern of failure was locoregional recurrence in the study patients. Esophageal cancer stage, the Eastern Cooperative Oncology Group (ECOG) performance status, and pretreatment weight loss were significant prognostic factors for OS in univariate analysis. Treatment-related death was observed in two patients, and one patient developed a grade 4 late treatment-related complication. CONCLUSION: Although the survival outcome for SHNEC is poor, long-term survival might be achievable with aggressive treatment with stage I-II esophageal cancer and good performance. PMID- 26484298 TI - Interventional Therapies for Chronic Low Back Pain: A Focused Review (Efficacy and Outcomes). AB - CONTEXT: Lower back pain is considered to be one of the most common complaints that brings a patient to a pain specialist. Several modalities in interventional pain management are known to be helpful to a patient with chronic low back pain. Proper diagnosis is required for appropriate intervention to provide optimal benefits. From simple trigger point injections for muscular pain to a highly complex intervention such as a spinal cord stimulator are very effective if chosen properly. The aim of this article is to provide the reader with a comprehensive reading for treatment of lower back pain using interventional modalities. EVIDENCE ACQUISITION: Extensive search for published literature was carried out online using PubMed, Cochrane database and Embase for the material used in this manuscript. This article describes the most common modalities available to an interventional pain physician along with the most relevant current and past references for the treatment of lower back pain. All the graphics and images were prepared by and belong to the author. RESULTS: This review article describes the most common modalities available to an interventional pain physician along with the most relevant current and past references for the treatment of lower back pain. All the graphics and images belong to the author. Although it is beyond the scope of this review article to include a very detailed description of each procedure along with complete references, a sincere attempt has been made to comprehensively cover this very complex and perplexing topic. CONCLUSION: Lower back pain is a major healthcare issue and this review article will help educate the pain practitioners about the current evidence based treatment options. PMID- 26484301 TI - Prognostic value of pretreatment (18)F-FDG PET-CT in radiotherapy for patients with hepatocellular carcinoma. AB - PURPOSE: The purpose of this study was to investigate the predictable value of pretreatment (18)F-fluorodeoxyglucose positron emission tomography-computed tomography ((18)F-FDG PET-CT) in radiotherapy (RT) for patients with hepatocellular carcinoma (HCC) or portal vein tumor thrombosis (PVTT). MATERIALS AND METHODS: We conducted a retrospective analysis of 36 stage I-IV HCC patients treated with RT. (18)F-FDG PET-CT was performed before RT. Treatment target was determined HCC or PVTT lesions by treatment aim. They were irradiated at a median prescription dose of 50 Gy. The response was evaluated within 3 months after completion of RT using the Response Evaluation Criteria in Solid Tumors (RECIST). Response rate, overall survival (OS), and the pattern of failure (POF) were analyzed. RESULTS: The response rate was 61.1%. The statistically significant prognostic factor affecting response in RT field was maximal standardized uptake value (maxSUV) only. The high SUV group (maxSUV >= 5.1) showed the better radiologic response than the low SUV group (maxSUV < 5.1). The median OS were 996.0 days in definitive group and 144.0 days in palliative group. Factors affecting OS were the %reduction of alpha-fetoprotein (AFP) level in the definitive group and Child-Pugh class in the palliative group. To predict the POF, maxSUV based on the cutoff value of 5.1 was the only significant factor in distant metastasis group. CONCLUSION: The results of this study suggest that the maxSUV of (18)F-FDG PET-CT may be a prognostic factor for treatment outcome and the POF after RT. A %reduction of AFP level and Child-Pugh class could be used to predict OS in HCC. PMID- 26484302 TI - Patterns of care for patients with nasopharyngeal carcinoma (KROG 11-06) in South Korea. AB - PURPOSE: To investigate the patterns of care for patients with nasopharyngeal carcinoma (NPC) in South Korea. MATERIALS AND METHODS: A multi-institutional retrospective study was performed (Korean Radiation Oncology Group [KROG] 11-06) on a total of 1,445 patients from 15 institutions. RESULTS: Of the 1,445 patients, more than half were stages III (39.9%) and IV (35.8%). In addition to patterns of care, we also investigated trends over time with the periods 1988 1993, 1994-2002, and 2003-2011. The frequencies of magnetic resonance imaging and positron emission tomography-computed tomography were markedly increased in the third period compared to previous 2 periods. Concurrent chemoradiation (CCRT) was performed on 894 patients (61.9%), neoadjuvant chemotherapy on 468 patients (32.4%), and adjuvant chemotherapy on 366 patients (25.3%). Of stage II-IV patients, CCRT performed on 78.8% in 2003-2011 compared to 15.0% in 1988-1993. For patients treated with CCRT, cisplatin was the most commonly used agent in 81.3% of patients. Over the periods of time, commonly used radiotherapy (RT) techniques were changed from 2-dimensional RT (1988-1993, 92.5%) to 3-dimensional RT (2003-2011, 35.5%) or intensity-modulated RT (IMRT; 2003-2011, 56.5%). Median RT doses given to primary tumors, high-risk lymphatics, and low-risk lymphatics were 70.0 Gy, 58.1 Gy, and 48.0 Gy, respectively. Adoption of IMRT increased the dose per fraction and escalated total radiation dose. CONCLUSION: Assessment of the patterns of care for NPC patients in South Korea demonstrated that management for NPC including diagnostic imaging, treatment regimen, RT techniques and dose schedule, advanced in accordance with the international guidelines. PMID- 26484303 TI - Treatment outcomes of curative radiotherapy in patients with vulvar cancer: results of the retrospective KROG 1203 study. AB - PURPOSE: We evaluated the prognostic factors and clinical outcomes of 56 patients with vulvar cancer treated with curative radiotherapy (RT) or concurrent chemoradiotherapy. MATERIALS AND METHODS: Overall survival (OS) and disease-free survival (DFS) were assessed retrospectively. Prognostic factors evaluated included age, International Federation of Gynecology and Obstetrics (FIGO) stage, TNM classification, tumor size, treatment modality, RT duration, and RT field. The association between the tumor human papillomavirus (HPV) status and survival was analyzed in 35 patients. RESULTS: During the median follow-up of 2.8 years (range, 0.3 to 18.9 years), 21 patients (37.5%) experienced treatment failure. Fifteen patients (27%) had local failure: nine (16%) local failure only, three (5%) locoregional failure, two (4%) local and distant failure, and one (2%) locoregional and distant failure. Of 56 patients, seven (13%) had persistent disease at the first follow-up at 2 months and all but one died within a year after completing RT. The 5-year OS and DFS were 51.6% and 44.0%, respectively. In multivariate analysis, clinical size >=3 cm predicted a poor prognostic factor for DFS (p = 0.040) and age (>=70 years) was poor prognostic for DFS (p = 0.032) and OS (p = 0.048). Patients with HPV-positive tumors tended to have better 5 year OS and DFS, but the differences were not significant statistically. CONCLUSION: Clinical size >=3 cm was a significant prognostic factor for DFS. However, age was the most important prognostic factor for DFS and OS in patients treated with curative RT. Further studies are needed to determine which treatment should be considered for old age >=70 years. PMID- 26484304 TI - Stereotactic radiosurgery for brain metastasis in non-small cell lung cancer. AB - PURPOSE: Stereotactic radiosurgery (SRS) has been introduced for small-sized single and oligo-metastases in the brain. The aim of this study is to assess treatment outcome, efficacy, and prognostic variables associated with survival and intracranial recurrence. MATERIALS AND METHODS: This study retrospectively reviewed 123 targets in 64 patients with non-small cell lung cancer (NSCLC) treated with SRS between January 2006 and December 2012. Treatment responses were evaluated using magnetic resonance imaging. Overall survival (OS) and intracranial progression-free survival (IPFS) were determined. RESULTS: The median follow-up was 13.9 months. The median OS and IPFS were 14.1 and 8.9 months, respectively. Fifty-seven patients died during the follow-up period. The 5-year local control rate was achieved in 85% of 108 evaluated targets. The 1- and 2-year OS rates were 55% and 28%, respectively. On univariate analysis, primary disease control (p < 0.001), the Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2; p = 0.002), recursive partitioning analysis class (1 vs. 2; p = 0.001), and age (<65 vs. >=65 years; p = 0.036) were significant predictive factors for OS. Primary disease control (p = 0.041) and ECOG status (p = 0.017) were the significant prognostic factors for IPFS. Four patients experienced radiation necrosis. CONCLUSION: SRS is a safe and effective local treatment for brain metastases in patients with NSCLC. Uncontrolled primary lung disease and ECOG status were significant predictors of OS and intracranial failure. SRS might be a tailored treatment option along with careful follow-up of the intracranial and primary lung disease status. PMID- 26484305 TI - Clinical outcomes of stereotactic body radiotherapy for spinal metastases from hepatocellular carcinoma. AB - PURPOSE: To investigate the outcomes of patients with spinal metastases from hepatocellular carcinoma (HCC), who were treated by stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: This retrospective study evaluated 23 patients who underwent SBRT from October 2008 to August 2012 for 36 spinal metastases from HCC. SBRT consisted of approximately 2 fractionation schedules, which were 18 to 40 Gy in 1 to 4 fractions for group A lesions (n = 15) and 50 Gy in 10 fractions for group B lesions (n = 21). RESULTS: The median follow-up period was 7 months (range, 2 to 16 months). Seven patients developed grade 1 or 2 gastrointestinal toxicity, and one developed grade 2 leucopenia. Compression fractures occurred in association with 25% of the lesions, with a median time to fracture of 2 months. Pain relief occurred in 92.3% and 68.4% of group A and B lesions, respectively. Radiologic response (complete and partial response) occurred in 80.0% and 61.9% of group A and B lesions, respectively. The estimated 1-year spinal-tumor progression-free survival rate was 78.5%. The median overall survival period and 1-year overall survival rate were 9 months (range, 2 to 16 months) and 25.7%, respectively. CONCLUSION: SBRT for spinal metastases from HCC is well tolerated and effective at providing pain relief and radiologic response. Because compression fractures develop at a high rate following SBRT for spinal metastases from primary HCC, careful follow up of the patient is required. PMID- 26484306 TI - Feasibility of normal tissue dose reduction in radiotherapy using low strength magnetic field. AB - PURPOSE: Toxicity of mucosa is one of the major concerns of radiotherapy (RT), when a target tumor is located near a mucosal lined organ. Energy of photon RT is transferred primarily by secondary electrons. If these secondary electrons could be removed in an internal cavity of mucosal lined organ, the mucosa will be spared without compromising the target tumor dose. The purpose of this study was to present a RT dose reduction in near target inner-surface (NTIS) of internal cavity, using Lorentz force of magnetic field. MATERIALS AND METHODS: Tissue equivalent phantoms, composed with a cylinder shaped internal cavity, and adjacent a target tumor part, were developed. The phantoms were irradiated using 6 MV photon beam, with or without 0.3 T of perpendicular magnetic field. Two experimental models were developed: single beam model (SBM) to analyze central axis dose distributions and multiple beam model (MBM) to simulate a clinical case of prostate cancer with rectum. RT dose of NTIS of internal cavity and target tumor area (TTA) were measured. RESULTS: With magnetic field applied, bending effect of dose distribution was visualized. The depth dose distribution of SBM showed 28.1% dose reduction of NTIS and little difference in dose of TTA with magnetic field. In MBM, cross-sectional dose of NTIS was reduced by 33.1% with magnetic field, while TTA dose were the same, irrespective of magnetic field. CONCLUSION: RT dose of mucosal lined organ, located near treatment target, could be modulated by perpendicular magnetic field. PMID- 26484307 TI - Dosimetric comparison of volumetric modulated arc therapy with robotic stereotactic radiation therapy in hepatocellular carcinoma. AB - PURPOSE: To compare volumetric modulated arc therapy of RapidArc with robotic stereotactic body radiation therapy (SBRT) of CyberKnife in the planning and delivery of SBRT for hepatocellular carcinoma (HCC) treatment by analyzing dosimetric parameters. MATERIALS AND METHODS: Two radiation treatment plans were generated for 29 HCC patients, one using Eclipse for the RapidArc plan and the other using Multiplan for the CyberKnife plan. The prescription dose was 60 Gy in 3 fractions. The dosimetric parameters of planning target volume (PTV) coverage and normal tissue sparing in the RapidArc and the CyberKnife plans were analyzed. RESULTS: The conformity index was 1.05 +/- 0.02 for the CyberKnife plan, and 1.13 +/- 0.10 for the RapidArc plan. The homogeneity index was 1.23 +/- 0.01 for the CyberKnife plan, and 1.10 +/- 0.03 for the RapidArc plan. For the normal liver, there were significant differences between the two plans in the low-dose regions of V1 and V3. The normalized volumes of V60 for the normal liver in the RapidArc plan were drastically increased when the mean dose of the PTVs in RapidArc plan is equivalent to the mean dose of the PTVs in the CyberKnife plan. CONCLUSION: CyberKnife plans show greater dose conformity, especially in small-sized tumors, while RapidArc plans show good dosimetric distribution of low dose sparing in the normal liver and body. PMID- 26484308 TI - Influence of different boost techniques on radiation dose to the left anterior descending coronary artery. AB - PURPOSE: The purpose of this study is to compare the dosimetry of electron beam (EB) plans and three-dimensional helical tomotherapy (3DHT) plans for the patients with left-sided breast cancer, who underwent breast conserving surgery. MATERIALS AND METHODS: We selected total of 15 patients based on the location of tumor, as following subsite: subareolar, upper outer, upper inner, lower lateral, and lower medial quadrants. The clinical target volume (CTV) was defined as the area of architectural distortion surrounded by surgical clip plus 1 cm margin. The conformity index (CI), homogeneity index (HI), quality of coverage (QC) and dose-volume parameters for the CTV, and organ at risk (OAR) were calculated. The following treatment techniques were assessed: single conformal EB plans; 3DHT plans with directional block of left anterior descending artery (LAD); and 3DHT plans with complete block of LAD. RESULTS: 3DHT plans, regardless of type of LAD block, showed significantly better CI, HI, and QC for the CTVs, compared with the EB plans. However, 3DHT plans showed increase in the V1Gy at skin, left lung, and left breast. In terms of LAD, 3DHT plans with complete block of LAD showed extremely low dose, while dose increase in other OARs were observed, when compared with other plans. EB plans showed the worst conformity at upper outer quadrants of tumor bed site. CONCLUSION: 3DHT plans offer more favorable dose distributions to LAD, as well as improved target coverage in comparison with EB plans. PMID- 26484309 TI - Comparison between audio-only and audiovisual biofeedback for regulating patients' respiration during four-dimensional radiotherapy. AB - PURPOSE: To compare audio-only biofeedback to conventional audiovisual biofeedback for regulating patients' respiration during four-dimensional radiotherapy, limiting damage to healthy surrounding tissues caused by organ movement. MATERIALS AND METHODS: Six healthy volunteers were assisted by audiovisual or audio-only biofeedback systems to regulate their respirations. Volunteers breathed through a mask developed for this study by following computer generated guiding curves displayed on a screen, combined with instructional sounds. They then performed breathing following instructional sounds only. The guiding signals and the volunteers' respiratory signals were logged at 20 samples per second. RESULTS: The standard deviations between the guiding and respiratory curves for the audiovisual and audio-only biofeedback systems were 21.55% and 23.19%, respectively; the average correlation coefficients were 0.9778 and 0.9756, respectively. The regularities between audiovisual and audio-only biofeedback for six volunteers' respirations were same statistically from the paired t-test. CONCLUSION: The difference between the audiovisual and audio-only biofeedback methods was not significant. Audio-only biofeedback has many advantages, as patients do not require a mask and can quickly adapt to this method in the clinic. PMID- 26484310 TI - Radioprotective effect of mefenamic acid against radiation-induced genotoxicity in human lymphocytes. AB - PURPOSE: Mefenamic acid (MEF) as a non-steroidal anti-inflammatory drug is used as a medication for relieving of pain and inflammation. Radiation-induced inflammation process is involved in DNA damage and cell death. In this study, the radioprotective effect of MEF was investigated against genotoxicity induced by ionizing radiation in human blood lymphocytes. MATERIALS AND METHODS: Peripheral blood samples were collected from human volunteers and incubated with MEF at different concentrations (5, 10, 50, or 100 uM) for two hours. The whole blood was exposed to ionizing radiation at a dose 1.5 Gy. Lymphocytes were cultured with mitogenic stimulation to determine the micronuclei in cytokinesis blocked binucleated lymphocyte. RESULTS: A significant decreasing in the frequency of micronuclei was observed in human lymphocytes irradiated with MEF as compared to irradiated lymphocytes without MEF. The maximum decreasing in frequency of micronuclei was observed at 100 uM of MEF (38% decrease), providing maximal protection against ionizing radiation. CONCLUSION: The radioprotective effect of MEF is probably related to anti-inflammatory property of MEF on human lymphocytes. PMID- 26484311 TI - A case report of a patient with squamous cell carcinoma of the face irradiated using a stereotactic technique. AB - External beam radiotherapy can be used to treat cutaneous squamous cell carcinomas (SCC). Acute skin toxicity is the most common adverse event. In this case study we report on an elderly patient with nasal root cutaneous SCC treated with stereotactic technique using a dedicated linear accelerator (CyberKnife system). Grade 3 skin toxicity was observed but it was resolved after 6 weeks. The use of stereotactic radiotherapy permitted a clinical remission of SCC with good cosmetic results. PMID- 26484312 TI - Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. AB - BACKGROUND: Multigene panels can be a cost- and time-effective alternative to sequentially testing multiple genes, especially with a mixed family cancer phenotype. However, moving beyond our single-gene testing paradigm has unveiled many new challenges to the clinician. The purpose of this article is to familiarize the reader with some of the challenges, as well as potential opportunities, of expanded hereditary cancer panel testing. METHODS: We include results from 348 commercial multigene panel tests ordered from January 1, 2014, through October 1, 2014, by clinicians associated with the City of Hope's Clinical Cancer Genetics Community of Practice. We also discuss specific challenging cases that arose during this period involving abnormalities in the genes: CDH1, TP53, PMS2, PALB2, CHEK2, NBN, and RAD51C. RESULTS: If historically high risk genes only were included in the panels (BRCA1, BRCA2, MSH6, PMS2, TP53, APC, CDH1), the results would have been positive only 6.2% of the time, instead of 17%. Results returned with variants of uncertain significance (VUS) 42% of the time. CONCLUSION: These figures and cases stress the importance of adequate pre test counseling in anticipation of higher percentages of positive, VUS, unexpected, and ambiguous test results. Test result ambiguity can be limited by the use of phenotype-specific panels; if found, multiple resources (the literature, reference laboratory, colleagues, national experts, and research efforts) can be accessed to better clarify counseling and management for the patient and family. For pathogenic variants in low and moderate risk genes, empiric risk modeling based on the patient's personal and family history of cancer may supersede gene-specific risk. Commercial laboratory and patient contributions to public databases and research efforts will be needed to better classify variants and reduce clinical ambiguity of multigene panels. PMID- 26484313 TI - Current Status of CTCs as Liquid Biopsy in Lung Cancer and Future Directions. AB - Circulating tumor cells (CTCs) have garnered a lot of attention in the past few decades. Isolation of these rare cells from the billions of blood cells has been a challenge until recent times. With the advent of new sensitive technologies that permit live cell isolation and downstream genomic analysis, the existing paradigm of CTC research has evolved to explore clinical utility of these cells. CTCs have been identified as prognostic and pharmacodynamic biomarkers in many solid tumors, including lung cancer. As a means of liquid biopsy, CTCs could play a major role in the development of personalized medicine and targeted therapies. This review discusses the state of various isolation strategies, cell separation techniques and key studies that illustrate the application of liquid biopsy to lung cancer. PMID- 26484314 TI - Well-known surface and extracellular antigens of pathogenic microorganisms among the immunodominant proteins of the infectious microalgae Prototheca zopfii. AB - Microalgae of the genus Prototheca (P.) are associated with rare but severe infections (protothecosis) and represent a potential zoonotic risk. Genotype (GT) 2 of P. zopfii has been established as pathogenic agent for humans, dogs, and cattle, whereas GT1 is considered to be non-pathogenic. Since pathogenesis is poorly understood, the aim of this study was to determine immunogenic proteins and potential virulence factors of P. zopfii GT2. Therefore, 2D western blot analyses with sera and isolates of two dogs naturally infected with P. zopfii GT2 have been performed. Cross-reactivity was determined by including the type strains of P. zopfii GT2, P. zopfii GT1, and P. blaschkeae, a close relative of P. zopfii, which is known to cause subclinical forms of bovine mastitis. The sera showed a high strain-, genotype-, and species-cross-reactivity. A total of 198 immunogenic proteins have been analyzed via MALDI-TOF MS. The majority of the 86 identified proteins are intracellularly located (e.g., malate dehydrogenase, oxidoreductase, 3-dehydroquinate synthase) but some antigens and potential virulence factors, known from other pathogens, have been found (e.g., phosphomannomutase, triosephosphate isomerase). One genotype-specific antigen could be identified as heat shock protein 70 (Hsp70), a well-known antigen of eukaryotic pathogens with immunological importance when located extracellularly. Both sera were reactive to glyceraldehyde-3-phosphate-dehydrogenase of all investigated strains. This house-keeping enzyme is found to be located on the surface of several pathogens as virulence factor. Flow-cytometric analysis revealed its presence on the surface of P. blaschkeae. PMID- 26484315 TI - Quantitative PCR analysis of salivary pathogen burden in periodontitis. AB - Our aim was to investigate the value of salivary concentrations of four major periodontal pathogens and their combination in diagnostics of periodontitis. The Parogene study included 462 dentate subjects (mean age 62.9 +/- 9.2 years) with coronary artery disease (CAD) diagnosis who underwent an extensive clinical and radiographic oral examination. Salivary levels of four major periodontal bacteria were measured by quantitative real-time PCR (qPCR). Median salivary concentrations of Porphyromonas gingivalis, Tannerella forsythia, and Prevotella intermedia, as well as the sum of the concentrations of the four bacteria, were higher in subjects with moderate to severe periodontitis compared to subjects with no to mild periodontitis. Median salivary Aggregatibacter actinomycetemcomitans concentrations did not differ significantly between the subjects with no to mild periodontitis and subjects with moderate to severe periodontitis. In logistic regression analysis adjusted for age, gender, diabetes, and the number of teeth and implants, high salivary concentrations of P. gingivalis, T. forsythia, and P. intermedia were significantly associated with moderate to severe periodontitis. When looking at different clinical and radiographic parameters of periodontitis, high concentrations of P. gingivalis and T. forsythia were significantly associated with the number of 4-5 mm periodontal pockets, >=6 mm pockets, and alveolar bone loss (ABL). High level of T. forsythia was associated also with bleeding on probing (BOP). The combination of the four bacteria, i.e., the bacterial burden index, was associated with moderate to severe periodontitis with an odds ratio (OR) of 2.40 (95% CI 1.39 4.13). When A. actinomycetemcomitans was excluded from the combination of the bacteria, the OR was improved to 2.61 (95% CI 1.51-4.52). The highest OR 3.59 (95% CI 1.94-6.63) was achieved when P. intermedia was further excluded from the combination and only the levels of P. gingivalis and T. forsythia were used. Salivary diagnostics of periodontitis has potential especially in large-scale population studies and health promotion. The cumulative strategy appears to be useful in the analysis of salivary bacteria as markers of periodontitis. PMID- 26484317 TI - Hemophagocytic lymphohistiocytosis: a rare diagnosis, an even rarer opportunity to appraise our understanding of the immune system. PMID- 26484316 TI - The icmF3 locus is involved in multiple adaptation- and virulence-related characteristics in Pseudomonas aeruginosa PAO1. AB - The type VI secretion system (T6SS) is widely distributed in Gram-negative bacteria. Three separate T6SSs called H1-, H2-, and H3-T6SS have been discovered in Pseudomonas aeruginosa PAO1. Recent studies suggest that, in contrast to the H1-T6SS that targets prokaryotic cells, H2- and H3-T6SS are involved in interactions with both prokaryotic and eukaryotic cells. However, the detailed functions of T6SS components are still uncharacterized. The intracellular multiplication factor (IcmF) protein is conserved in type VI secretion systems (T6SS) of all different bacterial pathogens. Bioinformatic analysis revealed that IcmF3 in P. aeruginosa PAO1 is different from other IcmF homologs and may represent a new branch of these proteins with distinct functions. Herein, we have investigated the function of IcmF3 in this strain. We have shown that deletion of the icmF3 gene in P. aeruginosa PAO1 is associated with pleiotropic phenotypes. The icmF3 mutant has variant colony morphology and an hypergrowth phenotype in iron-limiting medium. Surprisingly, this mutant is also defective for the production of pyoverdine, as well as defects in swimming motility and virulence in a C. elegans worm model. The icmF3 mutant exhibits higher conjugation frequency than the wild type and increased biofilm formation on abiotic surfaces. Additionally, expression of two phenazine biosynthetic loci is increased in the icmF3 mutant, leading to the overproduction of pyocyanin. Finally, the mutant exhibits decreased susceptibility to aminoglycosides such as tobramycin and gentamicin. And the detected phenotypes can be restored completely or partially by trans complementation of wild type icmF3 gene. The pleiotropic effects observed upon icmF3 deletion demonstrate that icmF3 plays critical roles in both pathogenesis and environmental adaptation in P. aeruginosa PAO1. PMID- 26484318 TI - Hereditary hemochromatosis. PMID- 26484319 TI - Hemophagocytic syndrome: a dilemma chasing the intensivists. AB - Hemophagocytic lymphohistiocytosis or hemophagocytic syndrome is represented by an uncontrolled inflammatory response characterized by marked histiocyte activation and a cytokine storm. The entity may present a primary or genetic type, and the secondary type is usually triggered by infectious diseases of any kind, autoimmune disease, or neoplasia. This entity, although well described and with definite diagnostic criteria, still remains misdiagnosed because of the overlap presentation with other inflammatory processes. The authors present the case of a 13-year-old girl who was submitted to an appendicectomy complicated with a pericolic abscess, which required a second operation in order to be drained surgically. During the postoperative period of this second surgical procedure, the patient remained febrile, developing cytopenias, and multiple organ failure. Unfortunately, she died despite the efforts of the intensive care staff. The autopsy findings were characteristic of hemophagocytic syndrome. The authors report the case to call attention to this diagnosis whenever unexpected outcomes of infections are experienced. PMID- 26484320 TI - Recurrence of alveolar capillary dysplasia with misalignment of pulmonary veins in two consecutive siblings. AB - Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, developmental lung disorder, which has been increasingly reported. This entity usually presents as neonatal persistent pulmonary hypertension that is unresponsive to treatment, and is known to be uniformly fatal. Recent discoveries in the genetic field, and intensive treatments, may change the natural course of this disease, permitting easier diagnosis and giving new hope for the dismal prognosis. The authors present two cases of siblings, with two years of difference, from different fathers - one of them was a first-degree and the other a second-degree cousin of the mother. Both patients were full-term babies born apparently without malformations and were sent to the nursery. Both siblings near 35 hours of age presented severe respiratory failure due to pulmonary hypertension. The outcome was fatal in both cases and at autopsy ACD/MPV was diagnosed. The authors call attention to this entity in the differential diagnosis of acute respiratory distress in early life. PMID- 26484321 TI - Pulmonary agenesis and respiratory failure in childhood. AB - Pulmonary agenesis (PA) is a rare congenital anomaly, which may be unilateral or bilateral. Unilateral PA may be associated with nonspecific respiratory symptoms. We report the case of 5-month-old infant who presented a normal development until the age of 4 months when a respiratory infection caused an acute respiratory distress syndrome with a fatal outcome. The autopsy findings depicted the right lung agenesis without any other concomitant malformation. Although respiratory symptoms represent frequent complaints in pediatrics, the aim of this study is not only to draw attention to the unilateral pulmonary agenesis as a possible underlying malformation in children who present recurrent and severe respiratory symptoms, but also to report a case diagnosed at autopsy. PMID- 26484322 TI - Occult esophageal squamous cell carcinoma with metastases to the spine and central nervous system. AB - Esophageal malignancy encompasses a group of diseases that are mostly represented by the squamous cell carcinoma and the adenocarcinoma. Quite frequently, these neoplasms present aggressive behavior; therefore, the diagnosis is often made when the condition is in advanced stages. Dysphagia is the typical clinical complaint, although it is present only when most of the lumen is obstructed. Therefore, quite often, the metastatic disease is first diagnosed, which contributes to the patient's poor survival expectancy. The authors report the case of a 58-year-old man who looked for medical care complaining of a long-term history of scapular pain. The diagnostic work-up disclosed a cervical spine lytic lesion surrounded by a tumoral mass shown by computed tomography. The cervical tumor was sampled by fine needle aspiration, revealing an undifferentiated carcinoma. The outcome was unfavorable and the patient died. The autopsy findings revealed metastatic disease to the spine and central nervous system, and the primary tumor was found to be an esophageal squamous cell carcinoma, which had progressed without typical dysphagia. PMID- 26484323 TI - Pulmonary nodules: a challenging diagnosis during the follow up of cancer patients. AB - Pulmonary nodules (PN), frequently found on imaging studies, represent a diagnostic challenge during the follow up of cancer patients. However, published data about investigation of PNs incidentally found on chest imaging is scarce. The PN may be present at the time of cancer diagnosis, or arise during the treatment or follow-up periods. In the context of the oncologic patient these lesions are quite invariably considered as metastases, what impacts directly on patients' treatment and prognosis. The present study reports 2 cases of pulmonary nodules found in two patients already diagnosed with cancer. Case 1 referred to a woman with squamous cell carcinoma and two pulmonary nodules, and in case 2 the patient was diagnosed with duodenal adenocarcinoma. Both patients were submitted to pulmonary biopsies before the oncologic treatment. In both cases the nodules were of infectious origin, what changed significantly the neoplasia staging and the oncologic treatment intention. The authors performed a literature review as well as a discussion about the management of PN in cancer patients. PMID- 26484324 TI - Huge interparietal posterior fontanel meningohydroencephalocele. AB - Congenital encephalocele is a neural tube defect characterized by a sac-like protrusion of the brain, meninges, and other intracranial structures through the skull, which is caused by an embryonic development abnormality. The most common location is at the occipital bone, and its incidence varies according to different world regions. We report a case of an 1-month and 7-day-old male child with a huge interparietal-posterior fontanel meningohydroencephalocele, a rare occurrence. Physical examination and volumetric computed tomography were diagnostic. The encephalocele was surgically resected. Intradural and extradural approaches were performed; the bone defect was not primarily closed. Two days after surgery, the patient developed hydrocephaly requiring ventriculoperitoneal shunting. The surgical treatment of the meningohydroencephalocele of the interparietal-posterior fontanel may be accompanied by technical challenges and followed by complications due to the presence of large blood vessels under the overlying skin. In these cases, huge sacs herniate through large bone defects including meninges, brain, and blood vessels. The latter present communication with the superior sagittal sinus and ventricular system. A favorable surgical outcome generally follows an accurate strategy taking into account individual features of the lesion. PMID- 26484325 TI - Feeding tube replacement: not always that simple! AB - Although surgical gastrostomy is not a technically troublesome surgery, the procedure may be accompanied by unfavorable outcomes. Most complications occur early in the post-operative period and include feeding tube dislodgment, stomal infection, peritonitis, and pneumonia. The authors report the case of an 83-year old man who underwent a surgical gastrostomy because of a swallowing disorder after an ischemic stroke. Nine months after the procedure, the feeding tube dislodged and a new tube was inserted with a certain delay and with some difficulty, causing a false path and consequently an intrabdominal abscess after diet infusion. The outcome was fatal. The authors call attention for meticulous care with the insertion of feeding tubes and advise the performance of imaging control to assure its precise positioning. PMID- 26484326 TI - Late treatment of a mandibular gunshot wound. AB - Mandibular gunshot injuries are esthetically and functionally devastating, causing comminuted fractures and adjacent tissue destruction depending on the weapon gauge, projectile shape, impact kinetic energy, and density of the injured structures. If the mandibular fracture is not adequate or promptly treated, the broken fragments will fail to heal. In case of a treatment delay, progressive bone loss and fracture contracture will require a customized approach, which includes open reduction, removal of fibrous tissue between the bony stumps, and fixation of the fracture with a reconstruction plate and autogenous graft. The authors report the case of a 34-year-old man wounded on the mandible 15 years ago. With the aid of computed tomography and a prototype, a surgical plan was designed including open reduction and internal fixation of the segmental mandibular defect with a reconstruction plate and bone graft harvested from the iliac crest. The postoperative follow-up was uneventful and the 12-month follow up showed a positive aesthetic and functional result. PMID- 26484327 TI - Pertussis in young infants: a severe vaccine-preventable disease. PMID- 26484328 TI - Crohn disease. PMID- 26484329 TI - Pertussis: the resurgence of a public health threat. AB - Pertussis is an acute and very contagious pulmonary disease, clinically characterized by periods of coughing and paroxysms that may cause death. The disease afflicts mainly the pediatric population and is life threatening to children under the age of 1 year. Since the beginning of the second millennium, the number of cases of pertussis has increased, menacing public health, despite the availability of the pertussis vaccine. The resurgence of the disease among adults and older children creates a reservoir of infection that will afflict the unimmunized or incompletely immunized children. As newborns and infants show the highest mortality rate, immunization during pregnancy is a new strategy to reduce the burden of pertussis. The authors report the case of a newborn that presented respiratory distress accompanied by marked leukocytosis. Bronchiolitis was the initial diagnostic hypothesis, but the clinical picture became typical of pertussis when paroxysmal coughing ensued. Isolation of the Bordetella pertussis and antigenic demonstration by polymerase chain reaction were positive from respiratory secretion. Despite appropriate antibiotic therapy and intensive care management the child died and the autopsy showed characteristic diagnostic findings. The authors call attention to this diagnosis when facing respiratory failure among young children, mainly in the presence of marked leukocytosis. Thorough research on the immunization status of the patient's social environment is of crucial importance. PMID- 26484330 TI - Budd-Chiari Syndrome: an unnoticed diagnosis. AB - Budd-Chiari syndrome (BCS) encompasses a group of disorders caused by the obstruction to the hepatic venous outflow at the level of the small or large hepatic veins, the inferior vena cava, or any combination thereof. Clinical manifestation of the subacute form is characterized by supramesocolic abdominal discomfort, abdominal distension, fever, and lower limbs edema. Imaging work-up with hepatic Doppler ultrasound and abdominal computed tomography (CT) enables the diagnosis in the majority of cases. Treatment comprises long-term anticoagulation associated with measures that attempt to re-establish the flow in the thrombosed vessel (thrombolysis or angioplasty) or through the venous blood flow bypasses (transjugular intrahepatic portosystemic shunt or surgical bypass); however, the outcome is often dismal. The authors report the case of a 37-year old woman presenting a 2-month history of dyspeptic complaints and abdominal distention. Fever was present at the beginning of symptoms. The laboratory work up disclosed mild hepatic dysfunction, and the ultrasound showed evidence of chronic liver disease. Despite a thorough etiologic investigation, diagnosis was missed and, therefore, management could not be directed towards the physiopathogenetic process. The outcome was characterized by portal hypertension and esophageal varices bleeding. The patient died and the autopsy findings were characteristic of BCS, although an abdominal CT, close to death, had showed signs consistent with this diagnosis. The authors highlight the importance of knowledge of this entity, the diagnostic methods, and the multidisciplinary approach. BCS should be considered whenever investigating etiology for chronic or acute hepatopathy. PMID- 26484332 TI - Pulmonary cryptococcoma: a rare and challenging diagnosis in immunocompetent patients. AB - Cryptococcal infection is commonly seen in immunocompromised patients, although immunocompetent patients may also be infected. The pathogen's portal of entry is the respiratory tract; however, the central nervous system is predominantly involved. Pulmonary involvement varies from interstitial and alveolar infiltrations to large masses, which are frequently first interpreted as lung neoplasm. The diagnosis of pulmonary cryptococcosis, in these cases, is frequently challenging, which, in most cases, requires histopathological examination. The authors report the case of a young female patient who presented a 20-day history of chest pleuritic pain and fever at the onset of symptoms. HIV serology was negative and CD4 count was normal. The imaging work-up was characterized by a huge opacity in the left inferior pulmonary lobe with a wide pleural base. Computed tomography showed a heterogeneous mass involving the bronchial tree. Mediastinal involvement was poor, and there was a splenomegaly. The patient underwent an exploratory thoracotomy and inferior lobectomy. The histopathological examination revealed a cryptococcoma. As the serum antigenemia was positive, the patient was scheduled for long-term treatment with fluconazole. The authors call attention to including the cryptococcal infection in the differential diagnosis of lung mass, mainly when localized in the lung bases in immunocompetent patients. PMID- 26484331 TI - Strongyloides stercoralis hyperinfection associated with impaired intestinal motility disorder. AB - Infection by Strongyloides stercoralis is a highly prevalent helminthiasis, which is mostly distributed in the tropical and subtropical regions of the world. Although a substantial number of cases are asymptomatic or paucisymtomatic, severe and life-threatening forms of this infection still occur and not infrequently is lately diagnosed. Gram-negative bacteria septicemia, which frequently accompanies the severe helminthiasis, contributes to the high mortality rate. Severe infection is invariably triggered by any imbalance in the host's immunity, favoring the auto-infective cycle, which increases the intraluminal parasite burden enormously. Clinical presentation of severe cases is varied, and diagnosis requires a high suspicion index. Acute abdomen has been reported in association with S. stercoralis infection, but intestinal necrosis is rarely found during the surgical approach. The authors report the case of a man who sought the emergency unit with recent onset abdominal pain. Clinical and imaging features were consistent with obstructive acute abdomen. Scattered adhesions and a necrotic ileal segment with a tiny perforation represented the surgical findings. The patient outcome was unfavorable and respiratory distress required an open lung biopsy. Both surgical specimens showed S. stercoralis infection. Unfortunately the patient underwent multiple organ failure and septicemia, and subsequently died. The authors call attention to the finding of intestinal necrosis and impaired intestinal motility disorder as possibilities for the diagnosis and risk factor, respectively, for a severe infection of S. stercoralis. PMID- 26484333 TI - An interesting finding in the uterine cervix: Schistosoma hematobium calcified eggs. AB - Schistosoma hematobium infection is an endemic parasitic disease in Africa, which is frequently associated with urinary schistosomiasis. The parasite infection causes epithelial changes and disruption, facilitating the infection by the human papilloma virus and human immunodeficiency virus (HIV). The authors report the case of a 44-year-old African HIV-positive woman who presented an abnormal routine Pap smear. Colposcopy examination revealed dense acetowhite micropapillary epithelium covering the ectocervix, iodine-negative, an erosion area in endocervical canal, and atypical vessels. Histologic examination of the surgical specimens showed numerous calcified schistosome eggs (probably S. hematobium) and a high-grade cervical intraepithelial neoplasia. The relation between S. hematobium infection and bladder cancer is well known; however, this relationship with cervical cancer remains controversial. The symptoms of schistosomiasis of the female genital tract are rather non-specific, and are often misdiagnosed with other pelvic diseases. The familiarity of health professionals with schistosomiasis of the female genital tract is less than expected, even in endemic regions. Therefore, great awareness of this differential diagnosis in routine gynecological practice is of paramount importance. PMID- 26484335 TI - Peripheral pulmonary artery aneurysm presenting as a solitary pulmonary nodule. AB - We report the case of a 63-year-old female patient who was evaluated due to a solitary pulmonary nodule. The final diagnosis was a solitary peripheral pulmonary artery saccular aneurysm. The patient was submitted to a pulmonary lobectomy with excellent recovery. Peripheral pulmonary artery aneurysms that arise from segmental or intrapulmonary branches are extremely rare, and their management is still controversial. PMID- 26484334 TI - Immune thrombocytopenia and autoimmune thyroid disease: a controversial overlap. AB - Immune thrombocytopenia (ITP) is an entity characterized by a platelet count of less than 100 * 10(9)/L in the absence of other causes of thrombocytopenia, such as viral infections, rheumatic diseases, or drugs. Grave's disease is also an autoimmune condition in which thrombocytopenia is often observed. Moreover, in the literature, many reports show a marked interference of the thyroid dysfunction (mainly hyperthyroidism) in the control of thrombocytopenia. Although this issue still remains debatable, the authors report the case of a young woman with a previous diagnosis of ITP with a brilliant initial response to corticotherapy. Some years after this diagnosis, the patient presented thyrotoxicosis due to Grave's disease and the thrombocytopenia relapsed, but this time there was no response to the glucocorticoids. Only after the radioiodine I 131 thyroid ablation the control of thrombocytopenia was achieved. The authors call attention to this overlap and for testing thyroid function in every patient with an unexpected negative response to corticotherapy. PMID- 26484336 TI - Acquired hemophilia A in a patient with advanced prostate cancer. AB - Acquired hemophilia A (AHA) is a rare disorder that results from the presence of autoantibodies against the clotting factor VIII (FVIII) causing hemorrhagic disorders. This entity is mostly associated with autoimmune diseases, pregnancy, the postpartum period, drugs and malignancy. Among the solid cancers, prostate neoplasm is the most common cause of AHA. The management of AHA involves the control of active bleeding and the use of specific therapies to eliminate the inhibitor. The authors describe the case of an 87-year-old man with prostate cancer who developed a bleeding disorder 5 years after the cancer diagnosis. Treatment with prednisone did not reach a satisfactory clinical response, which was only achieved with the association of azathioprine. The patient became asymptomatic with no further bleeding episodes, but developed a fatal sepsis after 3 months of treatment with these immunosuppressive agents. PMID- 26484337 TI - Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort. AB - Evans syndrome (ES) is a rare autoimmune disorder whose long-term outcome is not well known. In France, a collaborative pediatric network set up via the National Rare Disease Plan now provides comprehensive clinical data in children with this disease. Patients aged less than 18 years at the initial presentation of autoimmune cytopenia have been prospectively included into a national observational cohort since 2004. The definition of ES was restricted to the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). Cases were deemed secondary if associated with a primitive immunodeficiency or systemic lupus erythematosus. In December 2014, we analyzed the data pertaining to 156 children from 26 centers with ES whose diagnosis was made between 1981 and 2014. Median age (range) at the onset of cytopenia was 5.4 years (0.2-17.2). In 85 sequential cases, the time lapse between the first episodes of AIHA and ITP was 2.4 years (0.1-16.3). The follow up period as from ES diagnosis was 6.5 years (0.1-28.8). ES was secondary, revealing another underlying disease, in 10% of cases; various associated immune manifestations (mainly lymphoproliferation, other autoimmune diseases, and hypogammaglobulinemia) were observed in 60% of cases; and ES remained primary in 30% of cases. Five-year ITP and AIHA relapse-free survival were 25 and 61%, respectively. Overall, 69% of children required one or more second-line immune treatments, and 15 patients (10%) died at the age of 14.3 years (1.7-28.1). To our knowledge, this is the first consistent long-term clinical description of this rare syndrome. It underscores the high rate of associated immune manifestations and the burden of long-term complications and treatment toxicity. Future challenges include (1) the identification of the underlying genetic defects inducing immune dysregulation and (2) the need to better characterize patient subgroups and second-line treatment strategies. PMID- 26484339 TI - Are Geographical "Cold Spots" of Male Circumcision Driving Differential HIV Dynamics in Tanzania? AB - BACKGROUND: Growing evidence suggests significant geographic clustering of male circumcision (MC) in Tanzania. The impact of spatial heterogeneity of MC prevalence on HIV transmission dynamics in this country is not well documented. The aim of this study was to assess the spatial association between MC and HIV infection in Tanzania. METHODS: Data from three Demographic and Health Survey rounds conducted in Tanzania were analyzed to identify spatial associations between MC and HIV using bivariate local indicators of spatial association (LISA). Spatial clusters with low MC prevalence (MC cold spots) were identified using scan statistics. HIV incidence rates for males and females within and outside the MC cold spots were calculated. RESULTS: Local indicators of spatial association analysis indicated a significant association between MC and HIV in the northern and southwestern regions of Tanzania. Scan statistics identified two MC cold spots in the same locations. Males located outside the MC cold spots had the lowest HIV incidence rate at 0.28 per 100 person-years at risk (pyar). HIV incidence in females located outside the MC cold spots increased from 0.40/100 pyar during 2004-2008 to 0.68/100 pyar in 2008-2012. CONCLUSION: Our study provides evidence for a geographic association between MC and HIV in Tanzania. MC could be one of the key factors driving the geographical distribution of the HIV epidemic in the country. Furthermore, in areas where most males are circumcised, the HIV infection burden could be concentrating in the female population. Therefore, along with the voluntary medical MC program, efforts targeting the female population should also be considered. PMID- 26484338 TI - Beyond CD19: Opportunities for Future Development of Targeted Immunotherapy in Pediatric Relapsed-Refractory Acute Leukemia. AB - Chimeric antigen receptor (CAR) T cell therapy has been used as a targeted approach in cancer therapy. Relapsed and refractory acute leukemia in pediatrics has been difficult to treat with conventional therapy due to dose-limiting toxicities. With the recent success of CD 19 CAR in pediatric patients with B cell acute lymphoblastic leukemia (ALL), this mode of therapy has become a very attractive option for these patients with high-risk disease. In this review, we will discuss current treatment paradigms of pediatric acute leukemia and potential therapeutic targets for additional high-risk populations, including T cell ALL, AML, and infant ALL. PMID- 26484340 TI - Interferon Gamma-Based Detection of Latent Tuberculosis Infection in the Border States of Nuevo Leon and Tamaulipas, Mexico. AB - Nearly one-third of the world's population is infected with latent tuberculosis (LTBI). Tuberculosis (TB) rates in the border states are higher than national rates in both the US and Mexico, with the border accounting for 30% of total registered TB cases in both countries. However, LTBI rates in the general population in Mexican border states are unknown. In this region, LTBI is diagnosed using the tuberculin skin test (TST). New methods of detection more specific than TST have been developed, although there is currently no gold standard for LTBI detection. Our objective is to demonstrate utility of the Quantiferon TB gold In-Tube (QFT-GIT) test compared with the TST to detect LTBI among border populations. This is an observational, cross-sectional study carried out in border areas of the states of Nuevo Leon and Tamaulipas, Mexico. Participants (n = 210) provided a TST and blood sample for the QFT-GIT. Kappa coefficients assessed the agreement between TST and QFT-GIT. Participant characteristics were compared using Fisher exact tests. Thirty-eight percent of participants were diagnosed with LTBI by QFT-GIT. The proportion of LTBI detected using QFT-GIT was almost double [38% (79/210)] that found by TST [19% (39/210)] (P < 0.001). Concordance between TST and QFT-GIT was low (kappa = 0.37). We recommend further studies utilizing the QFT-GIT test to detect LTBI among border populations. PMID- 26484342 TI - Excitation-contraction coupling of human induced pluripotent stem cell-derived cardiomyocytes. AB - Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold enormous potential in many fields of cardiovascular research. Overcoming many of the limitations of their embryonic counterparts, the application of iPSC-CMs ranges from facilitating investigation of familial cardiac disease and pharmacological toxicity screening to personalized medicine and autologous cardiac cell therapies. The main factor preventing the full realization of this potential is the limited maturity of iPSC-CMs, which display a number of substantial differences in comparison to adult cardiomyocytes. Excitation-contraction (EC) coupling, a fundamental property of cardiomyocytes, is often described in iPSC CMs as being more analogous to neonatal than adult cardiomyocytes. With Ca(2+) handling linked, directly or indirectly, to almost all other properties of cardiomyocytes, a solid understanding of this process will be crucial to fully realizing the potential of this technology. Here, we discuss the implications of differences in EC coupling when considering the potential applications of human iPSC-CMs in a number of areas as well as detailing the current understanding of this fundamental process in these cells. PMID- 26484341 TI - Stimulating endogenous cardiac repair. AB - The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair. However, the potential of these cells to completely regenerate the heart is limited. Efforts are now being focused on ways to augment these natural pathways to improve cardiac healing, primarily after ischemic injury but in other cardiac pathologies as well. Cell and gene therapy or pharmacological interventions are proposed mechanisms. Cell therapy has demonstrated modest results and has passed into clinical trials. However, the beneficial effects of cell therapy have primarily been their ability to produce paracrine effects on the cardiac tissue and recruit endogenous stem cell populations as opposed to direct cardiac regeneration. Gene therapy efforts have focused on prolonging or reactivating natural signaling pathways. Positive results have been demonstrated to activate the endogenous stem cell populations and are currently being tested in clinical trials. A potential new avenue may be to refine pharmacological treatments that are currently in place in the clinic. Evidence is mounting that drugs such as statins or beta blockers may alter endogenous stem cell activity. Understanding the effects of these drugs on stem cell repair while keeping in mind their primary function may strike a balance in myocardial healing. To maximize endogenous cardiac regeneration, a combination of these approaches could ameliorate the overall repair process to incorporate the participation of multiple cellular players. PMID- 26484343 TI - Thyroxine transfer from cerebrospinal fluid into choroid plexus and brain is affected by brefeldin A, low sodium, BCH, and phloretin, in ventriculo-cisternal perfused rabbits. AB - BACKGROUND: Thyroxine (T4) hormone is synthesized by the thyroid gland and then released into the systemic circulation where it binds to a number of proteins. Dysfunction in T4 transport mechanisms has been demonstrated in multiple central nervous system (CNS) diseases including Alzheimer's disease. In the presence of different compounds that inhibit potential T4 transport mechanisms, this study investigated the transfer of T4 from cerebrospinal fluid (CSF) into Choroid Plexus (CP) and other brain tissues. The compounds used were brefeldin A, low sodium artificial CSF (aCSF), BCH, phloretin, and taurocholate (TA). METHODS: Radiolabeled T4 ((125)I-T4) was perfused continuously into the CSF and was assessed in several brain compartments with reference molecule (14)C-mannitol and blue dextran, using the in vivo ventriculo-cisternal perfusion (V-C) technique in the rabbit. The aCSF containing the drug of interest was infused after 1 h of perfusion. Drugs were applied independently to the aCSF after 1 h of control perfusion. RESULTS: Of interest, in presence of low sodium or BCH, the percentage recovery of (125)I-T4, was increased compared to controls, with concomitant increase in T4 clearance. Conversely, brefeldin A, phloretin, and TA did not exert any significant effect on the recovery and clearance of (125)I-T4 assessed in aCSF. On the other hand, the uptake of (125)I-T4 into CP was raised by 18 fold compared to controls in the presence of brefeldin A. In addition, low sodium, BCH, or phloretin alone, enhanced the uptake of (125)I-T4 by almost 3-fold, whereas TA did not show any significant effect. Finally, the uptake and distribution of (125)I-T4 into other brain regions including ependymal region (ER) and caudate putamen (CAP) were significantly higher than in controls. CONCLUSION: Our study suggests the involvement of different mechanisms for the transfer of (125)I-T4 from CSF into CP and other brain regions. This transfer may implicate sodium-dependent mechanisms, amino acid "L" system, or organic anion transporting polypeptide (OATP). PMID- 26484344 TI - How PI3K-derived lipids control cell division. AB - To succeed in cell division, intense cytoskeletal and membrane remodeling are required to allow accurate chromosome segregation and cytoplasm partitioning. Spatial restriction of the actin dynamics and vesicle trafficking define the cell symmetry and equivalent membrane scission events, respectively. Protein complexes coordinating mitosis are recruited to membrane microdomains characterized by the presence of the phosphatidylinositol lipid members (PtdIns), like PtdIns(3,4,5)P 3,PtdIns(4,5)P 2, and PtdIns(3)P. These PtdIns represent a minor component of cell membranes, defining membrane domain identity, ultimately controlling cytoskeleton and membrane dynamics during mitosis. The coordinated presence of PtdIns(3,4,5)P 3 at the cell poles and PtdIns(4,5)P 2 at the cleavage furrow controls the polarity of the actin cytoskeleton leading to symmetrical cell division. In the endosomal compartment, the trafficking of PtdIns(3)P positive vesicles allows the recruitment of the protein machinery required for the abscission. PMID- 26484346 TI - Commentary: A Hypothesis for Examining Skeletal Muscle Biopsy-Derived Sarcolemmal nNOSMU as Surrogate for Enteric nNOSalpha Function. PMID- 26484347 TI - Microsurgical Reconstruction of Extensive Oncological Scalp Defects. AB - Although most small to medium defects of the scalp can be covered by local flaps, large defects or complicating factors, such as a history of radiotherapy, often require a microsurgical reconstruction. Several factors need to be considered in such procedures. A sufficient preoperative planning is based on adequate imaging of the malignancy and a multi-disciplinary concept. Several flaps are available for such reconstructions, of which the latissimus dorsi and anterior-lateral thigh flaps are the most commonly used ones. In very large defects, combined flaps, such as a parascapular/latissimus dorsi flaps, can be highly useful or necessary. The most commonly used recipient vessels for microsurgical scalp reconstructions are the superficial temporal vessels, but various other feasible choices exist. If the concomitant veins are not sufficient, the jugular veins represent a safe back-up alternative but require a vessel interposition or long pedicle. Post-operative care and patient positioning can be difficult in these patients but can be facilitated by various devices. Overall, microsurgical reconstruction of large scalp defects is a feasible undertaking if the mentioned key factors are taken into account. PMID- 26484349 TI - Corrigendum to "Heat Shock Protein 70 and 90 Genes in the Harmful Dinoflagellate Cochlodinium polykrikoides: Genomic Structures and Transcriptional Responses to Environmental Stresses". AB - [This corrects the article DOI: 10.1155/2015/484626.]. PMID- 26484348 TI - Light-induced structural changes in a short light, oxygen, voltage (LOV) protein revealed by molecular dynamics simulations-implications for the understanding of LOV photoactivation. AB - The modularity of light, oxygen, voltage (LOV) blue-light photoreceptors has recently been exploited for the design of LOV-based optogenetic tools, which allow the light-dependent control of biological functions. For the understanding of LOV sensory function and hence the optimal design of LOV-based optogentic tools it is essential to gain an in depth atomic-level understanding of the underlying photoactivation and intramolecular signal-relay mechanisms. To address this question we performed molecular dynamics simulations on both the dark- and light-adapted state of PpSB1-LOV, a short dimeric bacterial LOV-photoreceptor protein, recently crystallized under constant illumination. While LOV dimers remained globally stable during the light-state simulation with regard to the Jalpha coiled-coil, distinct conformational changes for a glutamine in the vicinity of the FMN chromophore are observed. In contrast, multiple Jalpha-helix conformations are sampled in the dark-state. These changes coincide with a displacement of the Ibeta and Hbeta strands relative to the light-state structure and result in a correlated rotation of both LOV core domains in the dimer. These global changes are most likely initiated by the reorientation of the conserved glutamine Q116, whose side chain flips between the Abeta (dark state) and Hbeta strand (light state), while maintaining two potential hydrogen bonds to FMN-N5 and FMN-O4, respectively. This local Q116-FMN reorientation impacts on an inter subunit salt-bridge (K117-E96), which is stabilized in the light state, hence accounting for the observed decreased mobility. Based on these findings we propose an alternative mechanism for dimeric LOV photoactivation and intramolecular signal-relay, assigning a distinct structural role for the conserved "flipping" glutamine. The proposed mechanism is discussed in light of universal applicability and its implications for the understanding of LOV-based optogenetic tools. PMID- 26484345 TI - Mitochondrial dysfunction in inflammatory bowel disease. AB - Inflammatory Bowel Disease (IBD) represents a group of idiopathic disorders characterized by chronic or recurring inflammation of the gastrointestinal tract. While the exact etiology of disease is unknown, IBD is recognized to be a complex, multifactorial disease that results from an intricate interplay of genetic predisposition, an altered immune response, changes in the intestinal microbiota, and environmental factors. Together, these contribute to a destruction of the intestinal epithelial barrier, increased gut permeability, and an influx of immune cells. Given that most cellular functions as well as maintenance of the epithelial barrier is energy-dependent, it is logical to assume that mitochondrial dysfunction may play a key role in both the onset and recurrence of disease. Indeed several studies have demonstrated evidence of mitochondrial stress and alterations in mitochondrial function within the intestinal epithelium of patients with IBD and mice undergoing experimental colitis. Although the hallmarks of mitochondrial dysfunction, including oxidative stress and impaired ATP production are known to be evident in the intestines of patients with IBD, it is as yet unclear whether these processes occur as a cause of consequence of disease. We provide a current review of mitochondrial function in the setting of intestinal inflammation during IBD. PMID- 26484350 TI - Application of Molecular Modeling to Development of New Factor Xa Inhibitors. AB - In consequence of the key role of factor Xa in the clotting cascade and absence of its activity in the processes that do not affect coagulation, this protein is an attractive target for development of new blood coagulation inhibitors. Factor Xa is more effective and convenient target for creation of anticoagulants than thrombin, inhibition of which may cause some side effects. This study is aimed at finding new inhibitors of factor Xa by molecular computer modeling including docking SOL and postdocking optimization DISCORE programs. After validation of molecular modeling methods on well-known factor Xa inhibitors the virtual screening of NCI Diversity and Voronezh State University databases of ready-made low molecular weight species has been carried out. Seventeen compounds selected on the basis of modeling results have been tested experimentally in vitro. It has been found that 12 of them showed activity against factor Xa (IC50 = 1.8-40 MUM). Based on analysis of the results, the new original compound was synthesized and experimentally verified. It shows activity against factor Xa with IC50 value of 0.7 MUM. PMID- 26484351 TI - Successive Intramuscular Boosting with IFN-Alpha Protects Mycobacterium bovis BCG Vaccinated Mice against M. lepraemurium Infection. AB - Leprosy caused by Mycobacterium leprae primarily affects the skin and peripheral nerves. As a human infectious disease, it is still a significant health and economic burden on developing countries. Although multidrug therapy is reducing the number of active cases to approximately 0.5 million, the number of cases per year is not declining. Therefore, alternative host-directed strategies should be addressed to improve treatment efficacy and outcome. In this work, using murine leprosy as a model, a very similar granulomatous skin lesion to human leprosy, we have found that successive IFN-alpha boosting protects BCG-vaccinated mice against M. lepraemurium infection. No difference in the seric isotype and all IgG subclasses measured, neither in the TH1 nor in the TH2 type cytokine production, was seen. However, an enhanced iNOS/NO production in BCG-vaccinated/i.m. IFN alpha boosted mice was observed. The data provided in this study suggest a promising use for IFN-alpha boosting as a new prophylactic alternative to be explored in human leprosy by targeting host innate cell response. PMID- 26484352 TI - Glycated Albumin Levels in Patients with Type 2 Diabetes Increase Relative to HbA1c with Time. AB - We recently reported that glycated albumin (GA) is increased in subjects with longer duration of diabetes and with decreased insulin secretory function. Based on this, we investigated whether GA increases with time relative to glycated hemoglobin (HbA1c) and the association between GA and beta-cell function. We analyzed 340 type 2 diabetes patients whose serum GA and HbA1c levels had been repeatedly measured over 4 years. We assessed the pattern of changes with time in glycemic indices (GA, HbA1c, and GA/HbA1c ratio) and their relationship with beta cell function. In all patients, glycemic indices decreased and maintained low levels around 15 and 27 months. However, from 39 months to 51 months, GA significantly increased but HbA1c tended to increase without statistical significance. We defined DeltaGA/HbA1c as the difference between the nadir point (at 15 to 27 months) and the end point (at 39 to 51 months) and found that DeltaGA/HbA1c was positively correlated with diabetes duration and negatively related to beta-cell function. In multivariable linear regression analyses, DeltaGA/HbA1c was independently associated with diabetes duration. In conclusion, this study demonstrated that serum GA levels increase relative to HbA1c levels with time. PMID- 26484354 TI - Gene Expression-Genotype Analysis Implicates GSDMA, GSDMB, and LRRC3C as Contributors to Inflammatory Bowel Disease Susceptibility. AB - To investigate the biological foundation of the inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease, susceptibility locus rs2872507, we have investigated the expression of 13 genes using ileal and colonic biopsies from patients with IBD (inflamed and noninflamed mucosa) or from individuals without IBD (noninflamed mucosa). The susceptibility allele was consistently associated with reduced expression of GSDMB (P = 4.1 * 10(-3)-7.2 * 10(-10)). The susceptibility allele was also associated with the increased expression of GSDMA (P = 1.6 * 10(-4)) and LRRC3C (P = 7.8 * 10(-6)) in colon tissue from individuals without IBD and with the reduced expression of PGAP3 (IBD; P = 2.0 * 10(-3)) and ZPBP2 (Crohn's disease; P = 7.7 * 10(-4)) in noninflamed ileum. Inflammation resulted in the reduced colonic expression of ERBB2, GRB7, MIEN1, and PGAP3 (P = 1.0 * 10(-4)-1.0 * 10(-9)) and the increased colonic expression of IKZF3 and CSF3 (P = 2.4 * 10(-7)-3.5 * 10(-8)). Based on our results and published findings on GSDMA, GSDMB, LRRC3C, and related proteins, we propose that this locus in part affects IBD susceptibility via effects on apoptosis and cell proliferation and believe this hypothesis warrants further experimental investigation. PMID- 26484353 TI - Antiviral Potential of Algae Polysaccharides Isolated from Marine Sources: A Review. AB - From food to fertilizer, algal derived products are largely employed in assorted industries, including agricultural, biomedical, food, and pharmaceutical industries. Among different chemical compositions isolated from algae, polysaccharides are the most well-established compounds, which were subjected to a variety of studies due to extensive bioactivities. Over the past few decades, the promising results for antiviral potential of algae-derived polysaccharides have advocated them as inordinate candidates for pharmaceutical research. Numerous studies have isolated various algal polysaccharides possessing antiviral activities, including carrageenan, alginate, fucan, laminaran, and naviculan. In addition, different mechanisms of action have been reported for these polysaccharides, such as inhibiting the binding or internalization of virus into the host cells or suppressing DNA replication and protein synthesis. This review strives for compiling previous antiviral studies of algae-derived polysaccharides and their mechanism of action towards their development as natural antiviral agents for future investigations. PMID- 26484355 TI - High Prevalence of Neutrophil Cytoplasmic Autoantibodies in Infants with Food Protein-Induced Proctitis/Proctocolitis: Autoimmunity Involvement? AB - Background. Food protein-induced proctitis/proctocolitis (FPIP) is the most common noninfectious colitis in children in the first year of life. Along with the overall clinical symptoms, diarrhoea and rectal bleeding are the main manifestations of the disease. There is no routine noninvasive test that would be specific for this type of colitis. The aim of our study was to find a noninvasive laboratory test or tests that may be helpful in differential diagnosis of food protein-induced proctitis/proctocolitis. Methods. ANA, ANCA, ASCA, a-EMA, a-tTg, specific IgE, total IgE, IgG, IgA, IgM, and concentration of serum calprotectin were measured in a group of 25 patients with colitis and 18 children with other diagnoses. Results. Atypical-pANCA antibodies of IgG isotype were detected in the sera of 24 patients by the method of indirect immunofluorescence, and 5 patients showed also the positivity of IgA isotype. In control samples these autoantibodies were not detected. Other autoantibodies were not demonstrated in either patient or control group. Conclusions. Of the parameters tested in noninfectious colitis, atypical-pANCA on ethanol-fixed granulocytes appears to be a suitable serological marker of food protein-induced proctitis/proctocolitis and suggests a possible involvement of an autoimmune mechanisms in the pathogenesis of this disease. PMID- 26484356 TI - An Automated Surveillance Strategy to Identify Infectious Complications After Cardiac Implantable Electronic Device Procedures. AB - Background. The optimum approach for infectious complication surveillance for cardiac implantable electronic device (CIED) procedures is unclear. We created an automated surveillance tool for infectious complications after CIED procedures. Methods. Adults having CIED procedures between January 1, 2005 and December 31, 2011 at Duke University Hospital were identified retrospectively using International Classification of Diseases, 9th revision (ICD-9) procedure codes. Potential infections were identified with combinations of ICD-9 diagnosis codes and microbiology data for 365 days postprocedure. All microbiology-identified and a subset of ICD-9 code-identified possible cases, as well as a subset of procedures without microbiology or ICD-9 codes, were reviewed. Test performance characteristics for specific queries were calculated. Results. Overall, 6097 patients had 7137 procedures. Of these, 1686 procedures with potential infectious complications were identified: 174 by both ICD-9 code and microbiology, 14 only by microbiology, and 1498 only by ICD-9 criteria. We reviewed 558 potential cases, including all 188 microbiology-identified cases, 250 randomly selected ICD 9 cases, and 120 with neither. Overall, 65 unique infections were identified, including 5 of 250 reviewed cases identified only by ICD-9 codes. Queries that included microbiology data and ICD-9 code 996.61 had good overall test performance, with sensitivities of approximately 90% and specificities of approximately 80%. Queries with ICD-9 codes alone had poor specificity. Extrapolation of reviewed infectious rates to nonreviewed cases yields an estimated rate of infection of 1.3%. Conclusions. Electronic queries with combinations of ICD-9 codes and microbiologic data can be created and have good test performance characteristics for identifying likely infectious complications of CIED procedures. PMID- 26484357 TI - Stx-Producing Shigella Species From Patients in Haiti: An Emerging Pathogen With the Potential for Global Spread. AB - Shiga toxins (Stx) are commonly produced by Shigella dysenteriae serotype 1 and Stx-producing Escherichia coli. However, the toxin genes have been detected in additional Shigella species. We recently reported the emergence of Stx-producing Shigella in travelers in the United States and France who had recently visited Hispaniola (Haiti and the Dominican Republic). In this study, we confirm this epidemiological link by identifying Stx-producing Shigella from Haitian patients attending clinics near Port-au-Prince. We also demonstrate that the bacteriophage encoding Stx is capable of dissemination to stx-negative Shigella species found in Haiti, suggesting that Stx-producing Shigella may become more widespread within that region. PMID- 26484358 TI - Data from subjects receiving intrathecal laronidase for cervical spinal stenosis due to mucopolysaccharidosis type I. AB - Five subjects with mucopolysaccharidosis type I and symptomatic cervical spinal stenosis received intrathecal laronidase in a 4-month pilot study and/or a 12 month extension study [1]. Clinical descriptions of study subjects, nonserious adverse events, individual data tables, and scoring system methods are provided. There were ten nonserious adverse events that occurred in more than one study subject. Somatosensory evoked potentials were absent in two subjects and normal in two subjects, limiting their utility as an endpoint. There were no significant changes in magnetic resonance imaging of cervical spinal cord or brain, pulmonary function tests, or cerebrospinal fluid opening pressure. These data are presented along with the scoring methods used in evaluation of the study subjects. PMID- 26484359 TI - Supporting data of spatiotemporal proliferation of human stromal cells adjusts to nutrient availability and leads to stanniocalcin-1 expression in vitro and in vivo. AB - This data article contains seven figures and two tables supporting the research article entitled: spatiotemporal proliferation of human stromal cells adjusts to nutrient availability and leads to stanniocalcin-1 expression in vitro and in vivo[1]. The data explain the culture of stromal cells in vitro in three culture systems: discs, scaffolds and scaffolds in a perfusion bioreactor system. Also, quantification of extracellular matrix components (ECM) in vitro and staining of ECM components in vivo can be found here. Finally the quantification of blood vessels dimensions from CD31 signals and representative histograms of stanniocalcin-1 fluorescent signals in negative controls and experimental conditions in vivo are presented. PMID- 26484360 TI - An update of the macaque testis proteome. AB - The genome sequence of rhesus macaque is a draft version with many errors and is lack of Y chromosome annotation. In the present dataset, we reanalyzed the previously published macaque testis proteome. We searched for refined protein sequences, potential Y chromosome proteins and transcripts predicted proteins in addition to the latest Ensembl protein sequences of macaque. A total of 74,433 peptides corresponding to 9247 protein groups were identified, and the data are supplied in this paper. The updated version of macaque testis proteome provided evidences for predicted genes or transcripts at the peptide level. It can be used for further in-depth proteogenomic annotation of macaque genome and is useful for studying the mechanisms of macaque spermatogenesis. PMID- 26484361 TI - Privacy Preserved and Secured Reliable Routing Protocol for Wireless Mesh Networks. AB - Privacy preservation and security provision against internal attacks in wireless mesh networks (WMNs) are more demanding than in wired networks due to the open nature and mobility of certain nodes in the network. Several schemes have been proposed to preserve privacy and provide security in WMNs. To provide complete privacy protection in WMNs, the properties of unobservability, unlinkability, and anonymity are to be ensured during route discovery. These properties can be achieved by implementing group signature and ID-based encryption schemes during route discovery. Due to the characteristics of WMNs, it is more vulnerable to many network layer attacks. Hence, a strong protection is needed to avoid these attacks and this can be achieved by introducing a new Cross-Layer and Subject Logic based Dynamic Reputation (CLSL-DR) mechanism during route discovery. In this paper, we propose a new Privacy preserved and Secured Reliable Routing (PSRR) protocol for WMNs. This protocol incorporates group signature, ID-based encryption schemes, and CLSL-DR mechanism to ensure strong privacy, security, and reliability in WMNs. Simulation results prove this by showing better performance in terms of most of the chosen parameters than the existing protocols. PMID- 26484362 TI - Striving for Excellence in Health Promotion Pedagogy. PMID- 26484363 TI - Glycyrrhetinic acid-decorated and reduction-sensitive micelles to enhance the bioavailability and anti-hepatocellular carcinoma efficacy of tanshinone IIA. AB - It remains a challenge to increase drug tumor-specific accumulation as well as to achieve intracellular-controlled drug release for hepatocellular carcinoma (HCC) chemotherapy. Herein, we developed a dual-functional biodegradable micellar system constituted by glycyrrhetinic acid coupling poly(ethylene glycol) disulfide linkage-poly(lactic-co-glycolic acid) (GA-PEG-SS-PLGA) to achieve both hepatoma-targeting and redox-responsive intracellular drug release. Tanshinone IIA (TAN IIA), an effective anti-HCC drug, was encapsulated. Notably, it exhibited rapid aggregation and faster drug release in 10 mM dithiothreitol compared with the redox-insensitive control. Furthermore, GA-decorated micelles revealed HCC-specific cellular uptake in human liver cancer HepG2 cells with an energy-dependent manner, in which micropinocytosis and caveolae-mediated endocytosis were demonstrated as the major cellular pathways. The enhanced cytotoxicity and pro-apoptotic effects against HepG2 cells in vitro were observed, mediated by up-regulation of the intracellular ROS level, the increased cell cycle arrest at S phase, enhanced necrocytosis and up-regulation of caspase 3/7, P38 protein expression. In addition, TAN IIA-loaded micelles had a significantly prolonged circulation time, improved bioavailability, and resulted in an increased accumulation of TAN IIA in the liver. With the synergistic effects of HCC-targeting and controlled drug release, TAN IIA-loaded GA-PEG-SS PLGA micelles significantly inhibited tumor growth and increased survival time in a mouse HCC-xenograft model. Collectively, the GA-PEG-SS-PLGA micelles with HCC targeting and redox-sensitive characters would provide a novel strategy to deliver TAN IIA effectively for HCC therapy. PMID- 26484364 TI - Preparation of pH-responsive mesoporous hydroxyapatite nanoparticles for intracellular controlled release of an anticancer drug. AB - A well-defined core-shell nano-carrier (PAA-MHAPNs) was successfully synthesized based on a graft-onto method by using mesoporous hydroxyapatite nanoparticles (MHAPNs) as the core and polyacrylic acid (PAA) as the shell. Given that MHAPNs are regarded as one of the most promising drug delivery vehicles due to their excellent performance and the nature of their cancer cell anti-proliferative effect, and the grafted PAA, as a pH-responsive switch, could improve the loading amount of the drug doxorubicin hydrochloride (DOX) effectively by electrostatic interactions, all these advantages mean that the designed models show promise for application in pH-responsive drug delivery systems. The loading content and entrapment efficiency of DOX could reach up to 3.3% and 76%, respectively. The drug release levels of the constructed DOX@PAA-MHAPNs were low under normal physiological conditions (pH 7.4), but they could be increased significantly with a decrease of pH. Cytotoxicity assays indicated that the PAA-MHAPNs was biocompatible, and more importantly, the DOX@PAA-MHAPNs demonstrated an obvious ability to induce apoptosis of cancer cells. Overall, the synthesized systems should show great potential as drug nanovehicles with excellent biocompatibility, high drug loading, and pH-responsive features for future intracellular drug delivery. PMID- 26484365 TI - Utilising inorganic nanocarriers for gene delivery. AB - The delivery of genetic materials into cells to elicit cellular responses has been extensively studied by biomaterials scientists globally. Many materials such as lipids, peptides, viruses, synthetically modified cationic polymers and certain inorganic nanomaterials could be used to complex the negatively charged plasmids and deliver the formed package into cells. The recent literature on the delivery of genetic materials utilising inorganic nanoparticles is carefully examined in this review. We have picked out the most relevant references and concisely summarised the findings with illustrated examples. We further propose alternative approaches and suggest future pathways towards the practical use of multifunctional nanocarriers. PMID- 26484366 TI - Retraction notice to "Common genetic variants in the microRNA biogenesis pathway are associated with malignant peripheral nerve sheath tumor risk in a Chinese population" [Cancer Epidemiol. 37 (2013) 913-916]. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This paper has been retracted at the request of the Editor-in-Chief. The Editors of Cancer Epidemiology were recently contacted by a reader who stated that the number of cases of malignant peripheral nerve sheath tumour (MPNST) reported in the paper referenced above was unfeasibly high and, furthermore, that the reader had evidence that the data reported in the paper was not true. The Editors contacted the authors for an explanation. The Editors of Cancer Epidemiology then received a communication from the Chief of the Department of Hand Surgery at Wuhan Union Hospital, the institution where the authors stated that the research took place, who confirmed that the hospital had not treated the number of patients reported in the paper and that there was no evidence that the research on MPNST was conducted at all. The authors of the paper have not responded to the Editors. PMID- 26484367 TI - Reflections: Neurology and The Humanities. Caring for Maggie. PMID- 26484368 TI - Author Response. PMID- 26484369 TI - Author Response. PMID- 26484370 TI - 50th anniversary of the Centre for Rheumatic Diseases. PMID- 26484371 TI - [Not Available]. PMID- 26484372 TI - Number of school nurses drops as health problems rise. PMID- 26484373 TI - [Not Available]. PMID- 26484374 TI - [Not Available]. PMID- 26484375 TI - [Not Available]. PMID- 26484376 TI - Retraction. PMID- 26484377 TI - You've Got the Power. PMID- 26484378 TI - Study Scrutinizes Emergency Room Visits for Nontraumatic Dental Conditions. Dramatic 41% Increase in These Visits Spurs Call to Action. PMID- 26484379 TI - Should Dentists Screen Patients for Drug Misuse? Columbia University Study Asks Question; 71% of Queried Dentists Respond. PMID- 26484380 TI - Researchers Turn to the Silkworm to Regenerate Salivary Gland Cells. PMID- 26484381 TI - Computational Studies on Pd-Catalyzed Functionalization of Csp(2)-H Bonds Using a 1,2,3-Triazole Directing Group: Cyclization versus Substitution. AB - The Pd-catalyzed functionalization of Csp(2)-H bonds using a 1,2,3-triazole directing group has been investigated by density functional theory calculations at the B3LYP level. The results of these calculations showed that the substitution pathway was kinetically favored over the cyclization pathway for the N2-pyridine-1,2,3-triazole-4-carboxylic acid (TAPy)-directed functionalization of Csp(2)-H bonds, while the cyclization pathway was kinetically favored over the substitution pathway for the N1-aryl-1,2,3-triazole-4-carboxylic acid (TAA) directed Csp(2)-H functionalization. The kinetic preference of the TAPy directing group for the substitution reaction can be attributed the reduced level of bond cleavage in the transition structure of the substitution step because the pyridine moiety of the TAPy directing group can act as a ligand for the Pd center. PMID- 26484382 TI - Increased subcortical neural activity among HIV+ individuals during a lexical retrieval task. AB - BACKGROUND: Deficits in lexical retrieval, present in approximately 40% of HIV+ patients, are thought to reflect disruptions to frontal-striatal functions and may worsen with immunosuppression. Coupling frontal-striatal tasks such as lexical retrieval with functional neuroimaging may help delineate the pathophysiologic mechanisms underlying HIV-associated neurological dysfunction. OBJECTIVE: We examined whether HIV infection confers brain functional changes during lexical access and retrieval. It was expected that HIV+ individuals would demonstrate greater brain activity in frontal-subcortical regions despite minimal differences between groups on neuropsychological testing. Within the HIV+ sample, we examined associations between indices of immunosuppression (recent and nadir CD4+ count) and task-related signal change in frontostriatal structures. Method16 HIV+ participants and 12 HIV- controls underwent fMRI while engaged in phonemic/letter and semantic fluency tasks. Participants also completed standardized measures of verbal fluency RESULTS: HIV status groups performed similarly on phonemic and semantic fluency tasks prior to being scanned. fMRI results demonstrated activation differences during the phonemic fluency task as a function of HIV status, with HIV+ individuals demonstrating significantly greater activation in BG structures than HIV- individuals. There were no significant differences in frontal brain activation between HIV status groups during the phonemic fluency task, nor were there significant brain activation differences during the semantic fluency task. Within the HIV+ group, current CD4+ count, though not nadir, was positively correlated with increased activity in the inferior frontal gyrus and basal ganglia. CONCLUSION: During phonemic fluency performance, HIV+ patients recruit subcortical structures to a greater degree than HIV- controls despite similar task performances suggesting that fMRI may be sensitive to neurocompromise before overt cognitive declines can be detected. Among HIV+ individuals, reduced activity in the frontal-subcortical structures was associated with lower CD4+ count. PMID- 26484384 TI - blaNDM-1 Carriage on IncR Plasmid in Enterobacteriaceae Strains. AB - Four NDM-1-producing Enterobacteriaceae strains (three Klebsiella pneumoniae and one Citrobacter koseri) were isolated between 2009 and 2011 through a nationwide surveillance for carbapenem-resistant Enterobacteriaceae in Croatia to study the molecular genetic background of blaNDM and the responsible plasmid types. Phenotypically, the clinical strains proved to be multidrug resistant. All strains remained susceptible to tigecycline and colistin. The clinical strains harbored variable antibiotic resistance determinants, notably, blaNDM-1, blaTEM 1, blaSHV-1, blaSHV-12, blaOXA-1, blaOXA-9, blaCTX-M-15, blaCMY-4, qnrB1, and aac(6')Ib-cr in different combinations. Two K. pneumoniae belonged to sequence type ST15 and one strain to ST16. As for the plasmid types, C. koseri and one of the ST15 K. pneumoniae carried IncR, and the second ST15 K. pneumoniae carried IncR and colE. The K. pneumoniae ST16 strain hosted A/C and colE plasmids. The blaNDM-1 gene was detected on conjugative high-molecular-weight plasmids, namely, A/C and IncR types. It is noteworthy that this is the first description of K. pneumoniae ST16 expressing NDM-1 in Europe. Remarkably, our study underscores the importance of the IncR plasmid as a reservoir of multidrug resistance. To the best of our knowledge, the IncR plasmid carrying blaNDM-1 in C. koseri is reported for the first time. PMID- 26484383 TI - Reward, attention, and HIV-related risk in HIV+ individuals. AB - Human immunodeficiency virus (HIV) is often contracted through engaging in risky reward-motivated behaviors such as needle sharing and unprotected sex. Understanding the factors that make an individual more vulnerable to succumbing to the temptation to engage in these risky behaviors is important to limiting the spread of HIV. One potential source of this vulnerability concerns the degree to which an individual is able to resist paying attention to irrelevant reward information. In the present study, we examine this possible link by characterizing individual differences in value-based attentional bias in a sample of HIV+ individuals with varying histories of risk-taking behavior. Participants learned associations between experimental stimuli and monetary reward outcome. The degree of attentional bias for these reward-associated stimuli, reflected in their ability to capture attention when presented as task-irrelevant distractors, was then assessed both immediately and six months following reward learning. Value-driven attentional capture was related to substance abuse history and non planning impulsiveness during the time leading up to contraction of HIV as measured via self-report. These findings suggest a link between the ability to ignore reward-associated information and prior HIV-related risk-taking behavior. Additionally, particular aspects of HIV-associated neurocognitive disorders were related to attentional bias, including motor deficits commonly associated with HIV-induced damage to the basal ganglia. PMID- 26484386 TI - Stability of Metal-Encapsulating Boron Fullerene B40. AB - The structural stability of MB40 (M = Li, Na, K, Ba, and Tl) is investigated on the basis of density-functional theory calculations at the PBE0 level. Particular attention is placed on the relative stability between the endohedral and exohedral configurations of metalloborospherenes. It is found that the Na and Ba atoms can be stably encapsulated inside the B40 cage, whereas the Li, K, and Tl atoms favor the exohedral configuration where the dopant caps one of heptagons of B40 cage. In-depth analysis of the endohedral versus exohedral configurations with different dopants suggests that besides the comparable atomic size with the cage size, another key factor that can affect stability of endohedral versus exohedral configuration is the interaction between the dopant and B atoms. The infrared (IR) spectra of the endohedral C2v Na@B40 and exohedral Cs Na&B40 clusters are also computed, from which some useful spectral indictors may be used for identification of the structures in the future experiments. PMID- 26484385 TI - Trifunctional Polymeric Nanocomposites Incorporated with Fe3O4/Iodine-Containing Rare Earth Complex for Computed X-ray Tomography, Magnetic Resonance, and Optical Imaging. AB - In this study, a novel polymerizable CT contrast agent integrating iodine with europium(III) has been developed by a facile and universal coordination chemistry method. The Fe3O4 nanoparticles are then incorporated into this iodine-containing europium complex by seed-emulsifier-free polymerization. The nanocomposites combining the difunctional complex and superparamagnetic Fe3O4 nanoparticles, which have uniform size dispersion and high encapsulation rate, are suitable for computed X-ray tomography (CT), magnetic resonance imaging (MRI), and optical imaging. They possess good paramagnetic properties with a maximum saturation magnetization of 2.16 emu/g and a transverse relaxivity rate of 260 mM(-1) s(-1), and they exhibit obvious contrast effects with an iodine payload less than 4.8 mg I/mL. In the in vivo optical imaging assessment, vivid fluorescent dots can be observed in the liver and spleen by two-photon confocal scanning laser microscopy (CLSM). All the results showed that nanocomposites as polymeric trifunctional contrast agents have great clinical potential in CT, MR, and optical imaging. PMID- 26484387 TI - Analysis of Hormone-Protein Binding in Solution by Ultrafast Affinity Extraction: Interactions of Testosterone with Human Serum Albumin and Sex Hormone Binding Globulin. AB - Ultrafast affinity extraction was used to study hormone-protein interactions in solution, using testosterone and its transport proteins human serum albumin (HSA) and sex hormone binding globulin (SHBG) as models. Both single column and two dimensional systems based on HSA microcolumns were utilized to measure the free fraction of testosterone in hormone/protein mixtures at equilibrium or that were allowed to dissociate for various lengths of time. These data were used to determine the association equilibrium constants (Ka) or global affinities (nKa') and dissociation rate constants (kd) for testosterone with soluble HSA and SHBG. This method was also used to measure simultaneously the free fraction of testosterone and its equilibrium constants with both these proteins in physiological mixtures of these agents. The kd and Ka values obtained for HSA were 2.1-2.2 s(-1) and 3.2-3.5 * 10(4) M(-1) at pH 7.4 and 37 degrees C. The corresponding constants for SHBG were 0.053-0.058 s(-1) and 0.7-1.2 * 10(9) M( 1). All of these results gave good agreement with literature values, indicating that this approach could provide information on a wide range of rate constants and binding strengths for hormone-protein interactions in solution and at clinically relevant concentrations. The same method could be extended to alternative hormone-protein systems or other solutes and binding agents. PMID- 26484388 TI - Personalized Adaptive Control of Training Load in Cardio-Exergames--A Feasibility Study. AB - OBJECTIVE: This article presents a feasibility study of using an algorithm for an individual and adaptive control of training load in an ergometer-controlled exergame for aerobic training. An additional goal was to investigate the effects of the adaptive game on the players' motivation. MATERIALS AND METHODS: A two phase approach (calibration and exercise phase) was applied in a sample of 16 physically active adults. In the cardio-exergame "LetterBird," the flight of a pigeon was controlled by the pedaling rate of a bike ergometer as input device. During the calibration phase the individual heart rate (HR) responses of the players were measured. In the exercise phase, these data were used to adjust the resistance of the ergometer using the proposed algorithm. The purpose of this algorithm was to induce an individually defined target HR and to keep it in a steady state. In order to establish a reference for further studies, the game experience was measured using the kids-Game Experience Questionnaire. RESULTS: In 15 of 16 participants the actual HR reached the intended individual HR range within 10 minutes after onset of exercise. However, the induced HR initially exceeded the target HR in 13 participants, which made load adjustments necessary. The analysis of the kids-Game Experience Questionnaire confirmed the motivational effect of the exergame "LetterBird." CONCLUSIONS: The results confirm that the proposed algorithm for personalized HR control in the game "LetterBird" is feasible. Furthermore, the cardio-exergame "LetterBird" seems to have a substantial short-term motivating effect. PMID- 26484389 TI - USA300 Methicillin-Resistant Staphylococcus aureus, United States, 2000-2013. AB - In the United States, methicillin-resistant Staphylococcus aureus (MRSA) with the USA300 pulsed-field gel electrophoresis type causes most community-associated MRSA infections and is an increasingly common cause of health care-associated MRSA infections. USA300 probably emerged during the early 1990s. To assess the spatiotemporal diffusion of USA300 MRSA and USA100 MRSA throughout the United States, we systematically reviewed 354 articles for data on 33,543 isolates, of which 8,092 were classified as USA300 and 2,595 as USA100. Using the biomedical literature as a proxy for USA300 prevalence among genotyped MRSA samples, we found that USA300 was isolated during 2000 in several states, including California, Texas, and midwestern states. The geographic mean center of USA300 MRSA then shifted eastward from 2000 to 2013. Analyzing genotyping studies enabled us to track the emergence of a new, successful MRSA type in space and time across the country. PMID- 26484391 TI - DSEP: A Tool Implementing Novel Method to Predict Side Effects of Drugs. AB - Drug side effects, or adverse drug reactions, have become a focus of public health concern. Anticipating side effects before the drugs are granted marketing authorization for clinical use can help reduce health threats. An increasing need for methods and tools that facilitate side-effect prediction still remains. Here, we present DSEP, which is a tool that is able to analyze chemistry files to predict side effects of drugs that are under development and have not been included into any database. Meanwhile, DSEP provides three computational methods, one of which is a novel method proposed by us. The method can obtain higher AUC(0.8927) and AUPR(0.4143) scores than previous work. The advantage characteristic and method made DSEP a useful tool to predict potential side effects for a given drug or compound. We use DSEP to conduct uncharacterized drugs' side-effect prediction and confirm interesting results. PMID- 26484390 TI - Tau Aggregation Propensity Engrained in Its Solution State. AB - A peptide fragment of the human tau protein which stacks to form neat cross beta sheet fibrils, resembling that found in pathological aggregation, (273)GKVQIINKKLDL(284) (here "R2/WT"), was modified with a spin-label at the N terminus. With the resulting peptide, R2/G273C-SL, we probed events at time scales spanning seconds to hours after aggregation is initiated using transmission electron microscopy (TEM), thioflavin T (THT) fluorescence, ion mobility mass spectrometry (IMMS), electron paramagnetic resonance (EPR), and Overhauser dynamic nuclear polarization (ODNP) to determine if deliberate changes to its conformational states and population in solution influence downstream propensity to form fibrillar aggregates. We find varying solution conditions by adding the osmolyte urea or TMAO, or simply using different buffers (acetate buffer, phosphate buffer, or water), produces significant differences in early monomer/dimer populations and conformations. Crucially, these characteristics of the peptide in solution state before aggregation is initiated dictate the fibril formation propensity after aggregation. We conclude the driving forces that accelerate aggregation, when heparin is added, do not override the subtle intra- or interprotein interactions induced by the initial solvent conditions. In other words, the balance of protein-protein vs protein-solvent interactions present in the initial solution conditions is a critical driving force for fibril formation. PMID- 26484392 TI - Description and comparative study of physico-chemical parameters of the teleost fish skin mucus. AB - The study of mucosal surfaces, and in particular the fish skin and its secreted mucus, has been of great interest recently among immunologists. Measurement of the viscosity and other physico-chemical parameters (protein concentration, pH, conductivity, redox potential, osmolality and density) of the skin mucus can help to understand its biological functions. We have used five marine species of teleost: gilthead seabream (Sparus aurata L.), European sea bass (Dicentrarchus labrax L.), shi drum (Umbrina cirrosa L.), common dentex (Dentex dentex L.) and dusky grouper (Epinephelus marginatus L.), all of them with commercial interest in the aquaculture of the Mediterranean area. Mucus showed a direct shear- and temperature-dependent viscosity, with a non-Newtonian behavior, which differed however between two groups: one with higher viscosity (D. labrax, U. cirrosa, D. dentex) and the other with lower viscosity (S. aurata, E. marginatus). In addition, there was a clear interrelation between density and osmolality, as well as between density and temperature. Taking into account that high values of viscosity should improve the barrier effect against pathogens but low values of viscosity are needed for good locomotion characteristics, our results may help elucidate the relationship between physico-chemical and biological parameters of skin mucus, and disease susceptibility. PMID- 26484393 TI - MicroRNA-29c overexpression inhibits proliferation and promotes apoptosis and differentiation in P19 embryonal carcinoma cells. AB - Compared to healthy controls, microRNA-29c (miR-29c) is highly expressed in the heart during progression towards ventricular septal defect. However, studies on miR-29c function in heart development are scarce. We investigated the role of miR 29c in P19 cell proliferation, apoptosis, and differentiation and the underlying mechanisms. We evaluated proliferation and cell cycle progression, detected morphological changes; apoptosis rate; BAX, BCL2, GATA binding protein 4 (GATA4), cardiac troponin T (cTnT), and myocyte enhancer factor 2C (MEF2C) expression; and caspase-3, -8, and -9 activity in miR-29c-overexpressing P19 cells, and investigated whether WNT4 was a miR-29c target. MiR-29c-overexpressing cells had decreased proliferation, increased G1 cells, and significantly higher apoptotic rate than the controls. Expression of the apoptosis-related BAX and BCL2 genes and caspase-3, -8, and -9 activity were significantly increased in miR-29c overexpressing cells. Expression of the cardiac-specific markers GATA4, cTnT, and MEF2C revealed promoted differentiation in miR-29c-overexpressing cells compared to the controls. Luciferase assay confirmed that WNT4 is a miR-29c target. Wnt4 and beta-catenin expression was decreased in miR-29c-overexpressing cells. MiR 29c inhibits P19 cell proliferation and promotes apoptosis and differentiation, possibly by suppressing Wnt4 signaling, whose deregulation contributes to congenital heart disease development. PMID- 26484394 TI - Effect of heparin on the biological properties and molecular signature of human mesenchymal stem cells. AB - Chronic use of heparin as an anti-coagulant for the treatment of thrombosis or embolism invokes many adverse systemic events including thrombocytopenia, vascular reactions and osteoporosis. Here, we addressed whether adverse effects might also be directed to mesenchymal stem cells that reside in the bone marrow compartment. Harvested human bone marrow-derived mesenchymal stem cells (hMSCs) were exposed to varying doses of heparin and their responses profiled. At low doses (<200 ng/ml), serial passaging with heparin exerted a variable effect on hMSC proliferation and multipotentiality across multiple donors, while at higher doses (>= 100 MUg/ml), heparin supplementation inhibited cell growth and increased both senescence and cell size. Gene expression profiling using cDNA arrays and RNA-seq analysis revealed pleiotropic effects of low-dose heparin on signaling pathways essential to hMSC growth and differentiation (including the TGFbeta/BMP superfamily, FGFs, and Wnts). Cells serially passaged in low-dose heparin possess a donor-dependent gene signature that reflects their altered phenotype. Our data indicate that heparin supplementation during the culturing of hMSCs can alter their biological properties, even at low doses. This warrants caution in the application of heparin as a culture supplement for the ex vivo expansion of hMSCs. It also highlights the need for careful evaluation of the bone marrow compartment in patients receiving chronic heparin treatment. PMID- 26484395 TI - Identification of differentially methylated regions in new genes associated with knee osteoarthritis. AB - Epigenetic changes in articular chondrocytes are associated with osteoarthritis (OA) disease progression. Numerous studies have identified differentially methylated cytosines in OA tissues; however, the consequences of altered CpG methylation at single nucleotides on gene expression and phenotypes are difficult to predict. With the objective of detecting novel genes relevant to OA, we conducted a genome-wide assessment of differentially methylated sites (DMSs) and differentially methylated regions (DMRs). DNA was extracted from visually damaged and normal appearing, non-damaged human knee articular cartilage from the same joint and then subjected to reduced representation bisulfite sequencing. DMRs were identified using a genome-wide systematic bioinformatics approach. A sliding window of 500 bp was used for screening the genome for regions with clusters of DMSs. Gene expression levels were assessed and cell culture demethylation experiments were performed to further examine top candidate genes associated with damaged articular cartilage. More than 1000 DMRs were detected in damaged osteoarthritic cartilage. Nineteen of these contained five or more DMSs and were located in gene promoters or first introns and exons. Gene expression assessment revealed that hypermethylated DMRs in damaged samples were more consistently associated with gene repression than hypomethylated DMRs were with gene activation. Accordingly, a demethylation agent induced expression of most hypermethylated genes in chondrocytes. Our study revealed the utility of a systematic DMR search as an alternative to focusing on single nucleotide data. In particular, this approach uncovered promising candidates for functional studies such as the hypermethylated protein-coding genes FOXP4 and SHROOM1, which appear to be linked to OA pathology in humans and warrant further investigation. PMID- 26484396 TI - Near-peer teaching in medical education. PMID- 26484397 TI - Catalytic N-Alkylation of Amines Using Carboxylic Acids and Molecular Hydrogen. AB - A convenient, practical and green N-alkylation of amines has been accomplished by applying readily available carboxylic acids in the presence of molecular hydrogen. Applying an in situ formed ruthenium/triphos complex and an organic acid as cocatalyst, a broad range of alkylated secondary and tertiary amines are obtained in good to excellent yields. This novel method is also successfully applied for the synthesis of unsymmetrically substituted N-methyl/alkyl anilines through a direct three-component coupling reaction of the corresponding amines, carboxylic acids, and CO2 as a C1 source. PMID- 26484398 TI - Exploring culturally competent primary care diabetes services: a single-city survey. AB - AIMS: To determine the cultural competence of diabetes services delivered to minority ethnic groups in a multicultural UK city with a diabetes prevalence of 4.3%. METHODS: A semi-structured survey comprising 35 questions was carried out across all 66 general practices in Coventry between November 2011 and January 2012. Data were analysed using descriptive statistics. The cultural competence of diabetes services reported in the survey was assessed using a culturally competent assessment tool (CCAT). RESULTS: Thirty-four general practices (52%) responded and six important findings emerged across those practices. (1) Ninety four per cent of general practices reported the ethnicity of their populations. (2) One in three people with diabetes was from a minority ethnic group. (3) Nine (26.5%) practices reported a diabetes prevalence of between 55% and 96% in minority ethnic groups. (4) The cultural competences of diabetes services were assessed using CCAT; 56% of practices were found to be highly culturally competent and 26% were found to be moderately culturally competent. (5) Ten practices (29%) reported higher proportionate attendance at diabetes annual checks in the majority white British population compared with minority ethnic groups. (6) Cultural diversity in relation to language and strong cultural traditions around food were most commonly reported as barriers to culturally competent service delivery. CONCLUSIONS: Seven of the eight cultural barriers identified in the global evidence were present in the city. Use of the CCAT to assess existing service provision and the good baseline recording of ethnicity provide a sound basis for commissioning culturally competent interventions in the future. PMID- 26484400 TI - A Comparison of Kinetic Photon Cell Survival Models. AB - We report here on a qualitative and quantitative comparison of four kinetic photon cell survival models. The commonly used linear-quadratic model extended by a dose protraction factor, the lethal potentially lethal model, the repair misrepair model and the recently reported Giant LOop Binary LEsion (GLOBLE) model are discussed with respect to the proposed underlying biological mechanisms explaining the cellular response to radiation. Furthermore, with the use of eight benchmarks, the accuracy, reliability, resolution power and robustness of the models are assessed and compared. This work demonstrates that the linear quadratic, lethal potentially lethal and GLOBLE models often perform equivalently and that the repair misrepair model appears to have some drawbacks regarding the end points under investigation. PMID- 26484399 TI - High Levels of Dietary Supplement Vitamins A, C and E are Absorbed in the Small Intestine and Protect Nutrient Transport Against Chronic Gamma Irradiation. AB - We examined nutrient transport in the intestines of mice exposed to chronic low LET 137Cs gamma rays. The mice were whole-body irradiated for 3 days at dose rates of 0, 0.13 and 0.20 Gy/h, for total dose delivery of 0, 9.6 or 14.4 Gy, respectively. The mice were fed either a control diet or a diet supplemented with high levels of vitamins A, C and E. Our results showed that nutrient transport was perturbed by the chronic irradiation conditions. However, no apparent alteration of the macroscopic intestinal structures of the small intestine were observed up to day 10 after initiating irradiation. Jejunal fructose uptake measured in vitro was strongly affected by the chronic irradiation, whereas uptake of proline, carnosine and the bile acid taurocholate in the ileum was less affected. D-glucose transport did not appear to be inhibited significantly by either 9.6 or 14.4 Gy exposure. In the 14.4 Gy irradiated groups, the diet supplemented with high levels of vitamins A, C and E increased intestinal transport of fructose compared to the control diet (day 10; t test, P = 0.032), which correlated with elevated levels of vitamins A, C and E in the plasma and jejunal enterocytes. Our earlier studies with mice exposed acutely to 137Cs gamma rays demonstrated significant protection for transport of fructose, glucose, proline and carnosine. Taken together, these results suggest that high levels of vitamins A, C and E dietary supplements help preserve intestinal nutrient transport when intestines are irradiated chronically or acutely with low-LET gamma rays. PMID- 26484401 TI - Inhibition of Fatty Acid Synthase Sensitizes Prostate Cancer Cells to Radiotherapy. AB - Many common human cancers, including colon, prostate and breast cancer, express high levels of fatty acid synthase compared to normal human tissues. This elevated expression is associated with protection against apoptosis, increased metastasis and poor prognosis. Inhibitors of fatty acid synthase, such as the cerulenin synthetic analog C75, decrease prostate cancer cell proliferation, increase apoptosis and decrease tumor growth in experimental models. Although radiotherapy is widely used in the treatment of prostate cancer patients, the risk of damage to neighboring normal organs limits the radiation dose that can be delivered. In this study, we examined the potential of fatty acid synthase inhibition to sensitize prostate cancer cells to radiotherapy. The efficacy of C75 alone or in combination with X irradiation was examined in monolayers and in multicellular tumor spheroids. Treatment with C75 alone decreased clonogenic survival, an effect that was abrogated by the antioxidant. C75 treatment also delayed spheroid growth in a concentration-dependent manner. The radiosensitizing effect of C75 was indicated by combination index values between 0.65 and 0.71 and the reduced surviving fraction of clonogens, in response to 2 Gy X irradiation, from 0.51 to 0.30 and 0.11 in the presence of 25 and 35 MUM C75, respectively. This increased sensitivity to radiation was reduced by the presence of the antioxidant. The C75 treatment also enhanced the spheroid growth delay induced by X irradiation in a supra-additive manner. The level of radiation-induced apoptosis in prostate cancer cells was increased further by C75, which induced cell cycle arrest in the G2/M phase, but only at a concentration greater than that required for radiosensitization. Radiation-induced G2/M blockade was not affected by C75 treatment. These results suggest the potential use of fatty acid synthase inhibition to enhance the efficacy of radiotherapy of prostate carcinoma and that C75-dependent cell cycle arrest is not responsible for its radiosensitizing effect. PMID- 26484403 TI - THE EMERGING ROLE OF ADJUNCTIVE NONINSULIN ANTIHYPERGLYCEMIC THERAPY IN THE MANAGEMENT OF TYPE 1 DIABETES. AB - OBJECTIVE: Review available data on adjunctive therapies for type 1 diabetes (T1D), with a special focus on newer antihyperglycemic agents. METHODS: Published data on hypoglycemia, obesity, mortality, and goal attainment in T1D were reviewed to determine unmet therapeutic needs. PubMed databases and abstracts from recent diabetes meetings were searched using the term "type 1 diabetes" and the available and investigational sodium-glucose cotransporter (SGLT) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 inhibitors, and metformin. RESULTS: The majority of patients with T1D do not meet glycated hemoglobin (A1C) goals established by major diabetes organizations. Hypoglycemia risks and a rising incidence of obesity and metabolic syndrome featured in the T1D population limit optimal use of intensive insulin therapy. Noninsulin antihyperglycemic agents may enable T1D patients to achieve target A1C levels using lower insulin doses, which may reduce the risk of hypoglycemia. In pilot studies, the SGLT2 inhibitor dapagliflozin and the GLP-1 receptor agonist liraglutide reduced blood glucose, weight, and insulin dose in patients with T1D. Phase 2 studies with the SGLT2 inhibitor empagliflozin and the dual SGLT1 and SGLT2 inhibitor sotagliflozin, which acts in the gut and the kidney, have demonstrated reductions in A1C, weight, and glucose variability without an increased incidence of hypoglycemia. CONCLUSION: Newer antihyperglycemic agents, particularly GLP-1 agonists, SGLT2 inhibitors, and dual SGLT1 and SGLT2 inhibitors, show promise as adjunctive treatment for T1D that may help patients achieve better glucose control without weight gain or increased hypoglycemia. PMID- 26484402 TI - Quantification of a bifunctional drug in the presence of an immune response: a ligand-binding assay specific for 'active' drug. AB - AIM: During development of biologics, safety and efficacy assessments are often hampered by immune responses to the treatment. The raised antidrug antibodies (ADA) might interfere with the bioanalytical method and complicate result interpretation if non-fully characterized bioanalytical methods were applied. METHODS: Here, we report an approach to characterize a ligand-binding assay (LBA) for the quantification of active drug exposure of a bifunctional therapeutic protein in the presence of antidrug antibodies, by correlating LBA results with those of a cell-based PK assay. RESULTS: A clear correlation between both assays could be observed when monoclonal and polyclonal antibodies against the toxin moiety of the drug were used as ADA surrogates, and results were confirmed with human ADA-positive sera. CONCLUSION: The observed correlation between the LBA based and cell-based PK assay indicated the suitability of the developed LBA for the determination of active drug exposure in the presence of an immune response. PMID- 26484404 TI - OPPORTUNISTIC SCREENING FOR DIABETES AND PREDIABETES USING HEMOGLOBIN A1C IN AN URBAN PRIMARY CARE SETTING. AB - OBJECTIVE: In 2010, the American Diabetes Association (ADA) endorsed hemoglobin A1c (HbA1c) as 1 of 3 tests for diabetes and prediabetes screening. We describe the use of HbA1c testing for screening during routine visits in primary care clinics of an urban health care system in the U.S. METHODS: In 2013 to 2014, retrospective analyses of deidentified electronic health records over a 2-year period, January 2010 to December 2011, for academic private practices (clinic group 1) and federally-qualified Community Health Centers (clinic group 2) identified 11,885 adults without prior diabetes or recent HbA1c testing. We estimated the proportion of patients eligible for screening according to ADA and U.S. Preventative Services Task Force (USPSTF) guidelines and calculated the potential yield of previously undiagnosed diabetes or prediabetes among those who received at least 1 HbA1c test. RESULTS: Overall, 3,316 and 5,613 patients of clinic groups 1 and 2 (75.2% of each) were eligible for screening by ADA guidelines, while only 1,764 (39.9%) of clinic group 1 and 3,799 (50.9%) of clinic group 2 were eligible by USPSTF guidelines. In those eligible by either guideline, 731 (21.4%) patients of clinic group 1 and 1,293 (21.5%) of clinic group 2 received HbA1c testing; among these, in 71 (9.7%) and 121 (9.4%) patients from clinic groups 1 and 2, respectively, HbA1c results were in the diabetes range, and in 330 (45.2%) and 733 (56.7%), results were in the prediabetes range. CONCLUSION: In urban primary care settings, appropriate HbA1c testing could result in the detection of a substantial number of previously undiagnosed diabetes and prediabetes cases needing treatment. PMID- 26484405 TI - GLUCAGON PRESCRIPTION PATTERNS IN PATIENTS WITH EITHER TYPE 1 OR 2 DIABETES WITH NEWLY PRESCRIBED INSULIN. AB - OBJECTIVE: To describe glucagon prescription patterns in patients with type 1 (T1DM) or type 2 diabetes (T2DM) who received an initial insulin prescription. METHODS: Retrospective analyses were conducted with data from Truven Health MarketScan databases to assess time to glucagon prescriptions: filled within 1.5 months after index date (early) or after 1.5 months postindex (nonearly). The index date was the date of first insulin prescription between January 1, 2009 and December 31, 2011; for T2DM, without an insulin prescription in the previous 6 months; for T1DM, diabetes diagnosis preindex or within 3 months postindex. RESULTS: Analysis included 8,814 patients with T1DM and 47,051 with T2DM (49.3% and 2.4%, respectively) who had glucagon prescriptions filled. The median times to first glucagon prescription were 196 days (T1DM) and 288 days (T2DM). The rates of filling glucagon were highest in the first 1.5 months. The times to first hypoglycemia-related emergency room (ER) visit for T1DM and T2DM cohorts were initially similar for those with early glucagon versus nonearly glucagon prescriptions. After 10.8 and 2.5 months postindex, respectively, the percentage of hypoglycemia-related ER visits was lower for those with early glucagon prescriptions. CONCLUSION: Glucagon prescriptions filled for patients with diabetes who are initiating insulin are low. Patients with T1DM who were younger and healthier filled glucagon prescriptions more often; patients with T2DM who were younger and sicker and had a higher percentage of hypoglycemia-related ER visit history filled glucagon prescriptions more often. Glucagon filled early was associated with a lower incidence of hypoglycemia-related ER visits. PMID- 26484406 TI - EMPLOYING CONTINUOUS SUBCUTANEOUS INSULIN INFUSION THERAPY IN THE OPERATING SUITE: CURRENT STATE AND FUTURE DIRECTIONS. PMID- 26484408 TI - SGLT-2 INHIBITION ADDED TO GLP-1 AGONIST THERAPY FOR TYPE 2 DIABETES: WHAT IS THE BENEFIT? PMID- 26484407 TI - INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 1 PREDICTS INSULIN SENSITIVITY AND INSULIN AREA-UNDER-THE-CURVE IN OBESE, NONDIABETIC ADOLESCENTS. AB - OBJECTIVE: To compare fasting insulin-like growth factor binding protein 1 (IGFBP 1) to other fasting indices as a surrogate marker of insulin sensitivity and resistance calculated from a 3-hour oral glucose tolerance test (oGTT). METHODS: Fasting IGFBP-1 and oGTT were performed at 0 (n = 77), 52 (n = 54), and 100 (n = 38) weeks in a study investigating metformin treatment of obesity in adolescents. Insulin area-under-the-curve (IAUC) and the composite insulin sensitivity index (CISI) calculated from the oGTT were compared to fasting IGFBP-1, homeostasis model assessment-insulin resistance, and corrected insulin release at the glucose peak (CIRgp). RESULTS: IGFBP-1 and the ratio of IGFBP-1 to fasting insulin were significantly correlated with indices based on timed sampling, including IAUC, CISI, and CIRgp. In addition, a significant effect of IGFBP-1, but not IGFBP-1 to insulin at time zero, was observed for IAUC and CISI. CONCLUSION: Our results indicate that fasting IGFBP-1 may be a useful marker of insulin sensitivity and secretion. PMID- 26484409 TI - SERUM ADIPONECTIN AND INSULIN-LIKE GROWTH FACTOR 1 IN PREDOMINANTLY FEMALE PATIENTS WITH THYROID CANCER: ASSOCIATION WITH THE HISTOLOGIC CHARACTERISTICS OF THE TUMOR. AB - OBJECTIVE: Insulin-like growth factor (IGF)-1 and adiponectin have been proposed to contribute to the pathogenesis of different malignancies. However, data regarding their association with histologic characteristics of thyroid cancer are scarce. The main aims of the present study were the comparative evaluation of IGF 1, IGF-binding protein 3 (BP3), and adiponectin serum levels between different histologic types of thyroid cancer, as well as within specific histologic characteristics of the tumors. METHODS: A total of 179 thyroid cancer patients (126 [70.4%] women) were recruited. A total of 129 (72.1%) had papillary thyroid carcinoma (including variants), 26 had follicular thyroid carcinoma (14.5%), and 24 had medullary thyroid carcinoma (13.4%). Parameters from history, physical examination, and thyroid histology were selected. Serum adiponectin, IGF-1, and IGF-BP3 were measured in fasting morning samples. RESULTS: IGF-1, IGF-BP3, and adiponectin levels were similar among different histologic types of thyroid carcinoma, with a trend towards higher IGF-1 and IGF-BP3 levels in patients with intrathyroid invasion, compared to those without. In addition, ratios of IGF-1 to adiponectin (P = .012) and IGF-1 to (adiponectin * IGF-BP3) (P = .003), as well as type 2 diabetes (P = .001), were positively associated with tumor size. CONCLUSION: Although IGF-1, IGF-BP3, and adiponectin were not separately different between groups or within specific histologic lesions, when they were combined to produce IGF-1 to adiponectin and IGF-1 to (adiponectin * IGF-BP3) ratios, they were independently associated with tumor size. Future prospective studies are needed to evaluate whether these ratios could serve as prognostic markers of thyroid tumor aggressiveness. PMID- 26484410 TI - Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago gastric adenocarcinoma. AB - BACKGROUND: Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo. METHODS: Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/- Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity. RESULTS: The trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules. CONCLUSIONS: Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo. PMID- 26484411 TI - Impact of mutational status on survival in low-grade serous carcinoma of the ovary or peritoneum. AB - BACKGROUND: Low-grade serous carcinoma of the ovary or peritoneum is a distinct, well- recognized histologic subtype characterized by young age at diagnosis, relative chemoresistance, and prolonged overall survival. Common mutations reported to be found within this subtype include KRAS and BRAF. METHODS: Using clinical information of patients from our IRB-approved registry and tissue from a subset of these patients, we performed mutational analysis for KRAS and BRAF using the direct Sanger sequencing technique and correlated findings with the clinical outcome, overall survival (OS). RESULTS: In 79 cases, patients with KRAS or BRAF mutations (n=21) had a significantly better OS than those with wild-type KRAS or BRAF (n=58) (106.7 months (95% CI, 50.6, 162.9) vs 66.8 months (95% CI, 43.6, 90.0)), respectively (P=0.018). CONCLUSIONS: Mutational status appears to be a potential prognostic factor in low-grade serous carcinoma of the ovary or peritoneum. PMID- 26484412 TI - Residential exposure to extremely low-frequency magnetic fields and risk of childhood leukaemia, CNS tumour and lymphoma in Denmark. AB - BACKGROUND: We previously reported that children exposed to elevated extremely low-frequency magnetic fields (ELF-MF) had a five to six times higher risk of leukaemia, central nervous system (CNS) tumour and malignant lymphoma. Here we extend the study from 1968 to 1986 through 2003. METHODS: We included 3277 children with leukaemia, CNS tumour or malignant lymphoma during 1968-2003 recorded in the Danish Cancer Registry and 9129 controls randomly selected from the Danish childhood population. ELF-MF from 50 to 400 kV facilities were calculated at the residences. RESULTS: For recently diagnosed cases (1987-2003), the relative risk (RR) was 0.88 (95% confidence interval (CI): 0.32-2.42), while for the total period (1968-2003) it was 1.63 (95% CI: 0.77-3.46) for leukaemia, CNS tumour and malignant lymphoma combined for exposures ?0.4 MUT compared with <0.1 MUT. These results were based on five cases (recent period) and 11 cases (total period) in the highest exposure group. CONCLUSIONS: We did not confirm the previous finding of a five- to six-fold higher risk for leukaemia, CNS tumour and malignant lymphoma when including data from the more recent time period. For the total time period, the results for childhood leukaemia were in line with large pooled analyses showing RRs between 1.5 and 2. PMID- 26484413 TI - The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma. AB - BACKGROUND: The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations. METHODS: Performance of the msGPA was assessed in Cohort I (1997-2008, n=231) and Cohort II (2008-2013, n=162) using Kaplan-Meier methods and Harrell's c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance. RESULTS: The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models. CONCLUSIONS: An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care. PMID- 26484414 TI - 3D Hydrogel Scaffolds for Articular Chondrocyte Culture and Cartilage Generation. AB - Human articular cartilage is highly susceptible to damage and has limited self repair and regeneration potential. Cell-based strategies to engineer cartilage tissue offer a promising solution to repair articular cartilage. To select the optimal cell source for tissue repair, it is important to develop an appropriate culture platform to systematically examine the biological and biomechanical differences in the tissue-engineered cartilage by different cell sources. Here we applied a three-dimensional (3D) biomimetic hydrogel culture platform to systematically examine cartilage regeneration potential of juvenile, adult, and osteoarthritic (OA) chondrocytes. The 3D biomimetic hydrogel consisted of synthetic component poly(ethylene glycol) and bioactive component chondroitin sulfate, which provides a physiologically relevant microenvironment for in vitro culture of chondrocytes. In addition, the scaffold may be potentially used for cell delivery for cartilage repair in vivo. Cartilage tissue engineered in the scaffold can be evaluated using quantitative gene expression, immunofluorescence staining, biochemical assays, and mechanical testing. Utilizing these outcomes, we were able to characterize the differential regenerative potential of chondrocytes of varying age, both at the gene expression level and in the biochemical and biomechanical properties of the engineered cartilage tissue. The 3D culture model could be applied to investigate the molecular and functional differences among chondrocytes and progenitor cells from different stages of normal or aberrant development. PMID- 26484415 TI - Oncogenomic portals for the visualization and analysis of genome-wide cancer data. AB - Somatically acquired genomic alterations that drive oncogenic cellular processes are of great scientific and clinical interest. Since the initiation of large scale cancer genomic projects (e.g., the Cancer Genome Project, The Cancer Genome Atlas, and the International Cancer Genome Consortium cancer genome projects), a number of web-based portals have been created to facilitate access to multidimensional oncogenomic data and assist with the interpretation of the data. The portals provide the visualization of small-size mutations, copy number variations, methylation, and gene/protein expression data that can be correlated with the available clinical, epidemiological, and molecular features. Additionally, the portals enable to analyze the gathered data with the use of various user-friendly statistical tools. Herein, we present a highly illustrated review of seven portals, i.e., Tumorscape, UCSC Cancer Genomics Browser, ICGC Data Portal, COSMIC, cBioPortal, IntOGen, and BioProfiling.de. All of the selected portals are user-friendly and can be exploited by scientists from different cancer-associated fields, including those without bioinformatics background. It is expected that the use of the portals will contribute to a better understanding of cancer molecular etiology and will ultimately accelerate the translation of genomic knowledge into clinical practice. PMID- 26484416 TI - Targeting mitochondrial RNA polymerase in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) cells have high oxidative phosphorylation and mitochondrial mass and low respiratory chain spare reserve capacity. We reasoned that targeting the mitochondrial RNA polymerase (POLRMT), which indirectly controls oxidative phosphorylation, represents a therapeutic strategy for AML. POLRMT-knockdown OCI-AML2 cells exhibited decreased mitochondrial gene expression, decreased levels of assembled complex I, decreased levels of mitochondrially-encoded Cox-II and decreased oxidative phosphorylation. POLRMT knockdown cells exhibited an increase in complex II of the electron transport chain, a complex comprised entirely of subunits encoded by nuclear genes, and POLRMT-knockdown cells were resistant to a complex II inhibitor theonyltrifluoroacetone. POLRMT-knockdown cells showed a prominent increase in cell death. Treatment of OCI-AML2 cells with 10-50 uM 2-C-methyladenosine (2-CM), a chain terminator of mitochondrial transcription, reduced mitochondrial gene expression and oxidative phosphorylation, and increased cell death in a concentration-dependent manner. Treatment of normal human hematopoietic cells with 2-CM at concentrations of up to 100 uMdid not alter clonogenic growth, suggesting a therapeutic window. In an OCI-AML2 xenograft model, treatment with 2 CM (70 mg/kg, i.p., daily) decreased the volume and mass of tumours to half that of vehicle controls. 2-CM did not cause toxicity to major organs. Overall, our results in a preclinical model contribute to the functional validation of the utility of targeting the mitochondrial RNA polymerase as a therapeutic strategy for AML. PMID- 26484417 TI - Pattern of distant metastases in colorectal cancer: a SEER based study. AB - More and more evidences suggest that primary colon and rectum tumors should not be considered as a single disease entity. In this manuscript, we evaluate the metastatic patterns of colon and rectum cancers and analyze the potential distribution of metastatic disease in these two malignancies. Data queried for this analysis include colorectal adenocarcinoma (2010-2011) from the Surveillance, Epidemiology, and End Results Program (SEER) database. Metastatic distribution information was provided for liver, lung, bone and brain. All of statistical analyses were performed using the Intercooled Stata 13.0 (Stata Corporation, College Station, TX). All statistical tests were two-sided. Totally, there were 46,027 eligible patients for analysis. We found that colon cancer had a higher incident rate of liver metastasis than rectum cancer (13.8% vs 12.3%), while rectum cancer had a higher incident rate of lung (5.6% vs 3.7%) and bone (1.2% vs 0.8%) metastasis than colon cancer, P<0.001. Colorectal cancer patients with lung metastasis had a higher risk of bone (10.0% vs 4.5%) or brain metastasis (3.1% vs 0.1%) than patients without lung metastases. The 1-year cause specific survival was not significant different for bone or brain metastasis patients with and without lung metastasis (32.9% vs 38.7%, P=0.3834 for bone, 25.8% vs 36.9%, P=0.6819 for brain). Knowledge of these differences in metastatic patterns may help to better guide pre-treatment evaluation of colorectal cancer patients, especially in making determinations regarding curative-intent interventions. PMID- 26484418 TI - 4-hydroxynonenal regulates mitochondrial function in human small airway epithelial cells. AB - Prolonged exposure to oxidative stress causes Acute Lung Injury (ALI) and significantly impairs pulmonary function. Previously we have demonstrated that mitochondrial dysfunction is a key pathological factor in hyperoxic ALI. While it is known that hyperoxia induces the production of stable, but toxic 4 hydroxynonenal (4-HNE) molecule, it is unknown how the reactive aldehyde disrupts mitochondrial function. Our previous in vivo study indicated that exposure to hyperoxia significantly increases 4-HNE-Protein adducts, as well as levels of MDA in total lung homogenates. Based on the in vivo studies, we explored the effects of 4-HNE in human small airway epithelial cells (SAECs). Human SAECs treated with 25 MUM of 4-HNE showed a significant decrease in cellular viability and increased caspase-3 activity. Moreover, 4-HNE treated SAECs showed impaired mitochondrial function and energy production indicated by reduced ATP levels, mitochondrial membrane potential, and aconitase activity. This was followed by a significant decrease in mitochondrial oxygen consumption and depletion of the reserve capacity. The direct effect of 4-HNE on the mitochondrial respiratory chain was confirmed using Rotenone. Furthermore, SAECs treated with 25 MUM 4-HNE showed a time-dependent depletion of total Thioredoxin (Trx) proteins and Trx activity. Taken together, our results indicate that 4-HNE induces cellular and mitochondrial dysfunction in human SAECs, leading to an impaired endogenous antioxidant response. PMID- 26484419 TI - Effect of photoperiod change on chronobiology of cercarial emergence of Schistosoma japonicum derived from hilly and marshy regions of China. AB - The chronobiology of cercarial emergence appeared to be a genetically controlled behavior, adapted to definitive host species, for schistosome. However, a few physiological and ecological factors, for example the change of photoperiod, were reported to affect the rhythmic emergence of cercariae. Therefore, the effect of photoperiod change on cercarial emergence of two Schistosoma japonicum isolates, the hilly and the marshland, was investigated. Four shedding experiments each under a different photoperiod were conducted. Under a natural photoperiod, two distinct shedding modes, one from the hilly region and one from the marshland, were observed. Under a reversed photoperiod, the regular pattern (i.e. under a natural photoperiod) of S. japonicum cercarial emergence was reversed for the marshland isolate and disappeared for the hilly isolate. With an input of a 2 h darkness from 7am to 9am, the cercarial emergence peak were delayed for the two isolates; whereas with an input of a 2 h darkness from 5pm to 7pm, neither effect on the cercarial emergence rhythm was observed. The total cercariae emerged for both parasite isolates varied with a different photoperiod. The results indicate that the change of photoperiod could affect the chronobiology of S japonicum cercarial emergence. PMID- 26484420 TI - Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury, clinical implications. AB - In the past decade our understanding of idiosyncratic drug induced liver injury (IDILI) and the contribution of genetic susceptibility and the adaptive immune system to the pathogenesis of this disease process has grown tremendously. One of the characteristics of IDILI is that it occurs rarely and only in a subset of individuals with a presumed susceptibility to the drug. Despite a clear association between single nucleotide polymorphisms in human leukocyte antigen (HLA) genes and certain drugs that cause IDILI, not all individuals with susceptible HLA genotypes develop clinically significant liver injury when exposed to drugs. The adaptation hypothesis has been put forth as an explanation for why only a small percentage of susceptible individuals develop overt IDILI and severe injury, while the majority with susceptible genotypes develop only mild abnormalities that resolve spontaneously upon continuation of the drug. This spontaneous resolution is referred to as clinical adaptation. Failure to adapt or defective adaptation leads to clinically significant liver injury. In this review we explore the immuno-tolerant microenvironment of the liver and the mechanisms of clinical adaptation in IDILI with a focus on the role of immune-tolerance and cellular adaptive responses. PMID- 26484421 TI - Association of common variations of the E-cadherin with endometriosis. AB - Endometriosis is a polygenic and multifactorial disease. E-cadherin (CDH1) gene encodes an epithelial cell-cell adhesion glycoprotein that modulates a wide variety of processes, including cell polarization, migration and cancer metastasis. Decreased expression of CDH1 in epithelial cells in peritoneal endometriosis has been reported in advanced stages of endometriotic lesions. We investigated the CDH1 -160C/A and +54C/T variations with susceptibility to endometriosis in an Iranian population. In this case-control study, 149 patients with endometriosis (stages I-IV) and 151 healthy women as controls were included. Genotyping was performed using PCR-RFLP method. A p value of <0.05 was considered statistically significant. The CDH1 + 54TT genotype was significantly lower (p = 0.012; OR = 0.30, 95% CI: 0.12-0.77) in the patients (11.6%) than the control group (26.7%). The CDH1 + 54T allele was significantly lower (p = 0.001; OR = 0.55, 95% CI: 0.38-0.77) in the cases (35.7%) compared with the control group (50.3%). No association was found between CDH1 - 160C/A polymorphism and endometriosis. The CDH1 +54C/T was associated with susceptibility to endometriosis in Iranian population, and +54T allele may have a protective role in progression of endometriosis. PMID- 26484422 TI - Chiral Catalyst-Directed Dynamic Kinetic Diastereoselective Acylation of Lactols for De Novo Synthesis of Carbohydrate. AB - The control of the stereochemistry at the anomeric position is still one of the major challenges of synthetic carbohydrate chemistry. We have developed a new strategy consisting of a chiral catalyst-directed acylation followed by a palladium-catalyzed glycosidation to achieve high alpha- and beta stereoselectivity on the anomeric position. The former process involves a dynamic kinetic diastereoselective acylation of lactols derived from Achmatowicz rearrangement, while the latter is a stereospecific palladium-catalyzed allylic alkylation. PMID- 26484423 TI - Evaluation of Selection Bias in an Internet-based Study of Pregnancy Planners. AB - Selection bias is a potential concern in all epidemiologic studies, but it is usually difficult to assess. Recently, concerns have been raised that internet based prospective cohort studies may be particularly prone to selection bias. Although use of the internet is efficient and facilitates recruitment of subjects that are otherwise difficult to enroll, any compromise in internal validity would be of great concern. Few studies have evaluated selection bias in internet-based prospective cohort studies. Using data from the Danish Medical Birth Registry from 2008 to 2012, we compared six well-known perinatal associations (e.g., smoking and birth weight) in an internet-based preconception cohort (Snart Gravid n = 4,801) with the total population of singleton live births in the registry (n = 239,791). We used log-binomial models to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for each association. We found that most results in both populations were very similar. For example, maternal obesity was associated with an increased risk of delivering a macrosomic infant in Snart Gravid (RR = 1.5; 95% CI: 1.2, 1.7) and the total population (RR = 1.5; 95% CI: 1.45, 1.53), and maternal smoking of >10 cigarettes per day was associated with a higher risk of low birth weight (RR = 2.7; 95% CI: 1.2, 5.9 vs. RR = 2.9; 95% CI: 2.6, 3.1) in Snart Gravid and the total population, respectively. We cannot be certain that our results would apply to other associations or different populations. Nevertheless, our results suggest that recruitment of reproductive aged women via the internet may be no more prone to selection bias than traditional methods of recruitment. PMID- 26484424 TI - Selection Bias Due to Loss to Follow Up in Cohort Studies. AB - Selection bias due to loss to follow up represents a threat to the internal validity of estimates derived from cohort studies. Over the past 15 years, stratification-based techniques as well as methods such as inverse probability-of censoring weighted estimation have been more prominently discussed and offered as a means to correct for selection bias. However, unlike correcting for confounding bias using inverse weighting, uptake of inverse probability-of-censoring weighted estimation as well as competing methods has been limited in the applied epidemiologic literature. To motivate greater use of inverse probability-of censoring weighted estimation and competing methods, we use causal diagrams to describe the sources of selection bias in cohort studies employing a time-to event framework when the quantity of interest is an absolute measure (e.g., absolute risk, survival function) or relative effect measure (e.g., risk difference, risk ratio). We highlight that whether a given estimate obtained from standard methods is potentially subject to selection bias depends on the causal diagram and the measure. We first broadly describe inverse probability-of censoring weighted estimation and then give a simple example to demonstrate in detail how inverse probability-of-censoring weighted estimation mitigates selection bias and describe challenges to estimation. We then modify complex, real-world data from the University of North Carolina Center for AIDS Research HIV clinical cohort study and estimate the absolute and relative change in the occurrence of death with and without inverse probability-of-censoring weighted correction using the modified University of North Carolina data. We provide SAS code to aid with implementation of inverse probability-of-censoring weighted techniques. PMID- 26484425 TI - Learning About Missing Data Mechanisms in Electronic Health Records-based Research: A Survey-based Approach. AB - BACKGROUND: Bias due to missing data is a major concern in electronic health record (EHR)-based research. As part of an ongoing EHR-based study of weight change among patients treated for depression, we conducted a survey to investigate determinants of missingness in the available weight information and to evaluate the missing-at-random assumption. METHODS: We identified 8,345 individuals enrolled in a large EHR-based health care system who had monotherapy treatment for depression from April 2008 to March 2010. A stratified sample of 1,153 individuals completed a detailed survey. Logistic regression was used to investigate determinants of whether a patient (1) had an opportunity to be weighed at treatment initiation (baseline), and (2) had a weight measurement recorded. Parallel analyses were conducted to investigate missingness during follow-up. Throughout, inverse-probability weighting was used to adjust for the design and survey nonresponse. Analyses were also conducted to investigate potential recall bias. RESULTS: Missingness at baseline and during follow-up was associated with numerous factors not routinely collected in the EHR including whether or not the patient had ever chosen not to be weighed, external weight control activities, and self-reported baseline weight. Patient attitudes about their weight and perceptions regarding the potential impact of their depression treatment on weight were not related to missingness. CONCLUSION: Adopting a comprehensive strategy to investigate missingness early in the research process gives researchers information necessary to evaluate key assumptions. While the survey presented focuses on outcome data, the overarching strategy can be applied to any and all data elements subject to missingness. PMID- 26484427 TI - Divergent Reactivity in the Reaction of beta-Oxodithioesters and Hydroxylamine: Access to beta-Ketonitriles and Isoxazoles. AB - Starting from beta-oxodithioesters and hydroxylamine, two completely different transformations afford either beta-ketonitriles or isoxazoles with high chemoselectivity depending on the reaction conditions. The reaction of beta oxodithioesters with hydroxylamine in EtOH at room temperature in daylight gave beta-ketonitriles in high yields. On the other hand, 3-methylthio-isoxazoles were efficiently obtained as the final products by heating the mixture of beta oxodithioesters and hydroxylamine in HOAc at 90 degrees C. PMID- 26484426 TI - Gender Differences in Caregiving at End of Life: Implications for Hospice Teams. AB - BACKGROUND: Researchers have identified important gender differences in the experience of caring for a family member or friend living with advanced disease; however, trends suggest that these differences may be diminishing over time in response to changing gender roles. In addition, while many studies have found caregiving experiences and outcomes to be poorer among female caregivers, noteworthy exceptions exist. OBJECTIVE: The primary aim of this exploratory study was to determine how, if at all, current day caregiving at end of life varies by gender. METHODS: We conducted a secondary analysis of data from a multisite randomized controlled trial of a family caregiving intervention performed between 2010 and 2014. We compared female and male hospice family caregivers on baseline variables using chi(2) tests for association of categorical variables and t-tests for continuous variables. Our sample included 289 family caregivers of individuals receiving services from one of two hospice agencies located in the northwestern United States. Demographic data and other categorical variables of interest were provided via caregiver self-report using an instrument created specifically for this study. Reaction to caregiving and caregiving burden were measured using the Caregiver Reaction Assessment (CRA). RESULTS: As it related to caregiving, females had significantly lower self-esteem and more negative impact on their schedule, health, and family support than males. No gender differences were detected with regard to the impact of caregiving on individuals' finances. CONCLUSIONS: Despite changing social expectations, pronounced gender differences persist in caregiving at the end of life. PMID- 26484428 TI - Mother-to-child Transmission of HIV From 1999 to 2011 in the Amazonas, Brazil: Risk Factors and Remaining Gaps in Prevention Strategies. AB - BACKGROUND: The purpose of the study was to estimate rates of mother-to-child transmission (MTCT) of HIV in the Amazonas, Brazil, and to identify the associated factors. METHODS: This was a retrospective cohort study of 1210 children born to HIV-infected women between 1999 and 2011 and enrolled before age of 18 months in a reference HIV/AIDS pediatrics service in Manaus. We used multivariable logistic regression to assess the effect of maternal, obstetric and prophylactic interventions on MTCT of HIV. RESULTS: Ten children were excluded because of undocumented maternal HIV status. Among 1200 children, 163 (13.6%) were lost to follow-up. We included in the analysis 1037 children with known HIV status. Of those, 68 children were HIV infected, resulting in a MTCT rate of 6.6% [95% confidence interval (CI): 5.3-8.3]. Among mothers, 76.1% had received antiretroviral therapy during pregnancy, 59.3% elective caesarean, and 9.7% were breastfed. Factors associated with lower odds of MTCT of HIV were antiretroviral therapy during pregnancy [odds ratio (OR): 0.26; 95% CI: 0.12-0.58], elective caesarean (OR: 0.48; 95% CI: 0.23-0.98) and with MTCT: being breastfed (OR: 4.56; 95% CI: 2.19-9.50). Transmission decreased from 7.5% in 2007-2008 to 3.2% in 2011, while breastfeeding decreased from 30.8% in 1999-2000 to 3.9% in 2011-2012. CONCLUSIONS: The HIV rate of MTCT is still high in the Amazonas and challenges for its prevention prevail including lost to follow-up and gaps in critical strategies such as antiretroviral use during pregnancy. More efforts are needed to increase the number of women and babies who successfully complete the prevention of MTCT cascade and work toward elimination of MTCT of HIV. PMID- 26484433 TI - Drug leads for interactive protein targets with unknown structure. AB - The disruption of protein-protein interfaces (PPIs) remains a challenge in drug discovery. The problem becomes daunting when the structure of the target protein is unknown and is even further complicated when the interface is susceptible to disruptive phosphorylation. Based solely on protein sequence and information about phosphorylation-susceptible sites within the PPI, a new technology has been developed to identify drug leads to inhibit protein associations. Here we reveal this technology and contrast it with current structure-based technologies for the generation of drug leads. The novel technology is illustrated by a patented invention to treat heart failure. The success of this technology shows that it is possible to generate drug leads in the absence of target structure. PMID- 26484430 TI - Use of Daptomycin in Critically Ill Children With Bloodstream Infections and Complicated Skin and Soft-tissue Infections. AB - We report our clinical experience with the use of daptomycin, administered in the dosage of 8 mg/kg/d in 3 minutes, in treating 12 critically ill children younger than 12 years, with bloodstream infections (n = 9) and complicated skin and soft tissue infections (n = 3). Mean treatment duration was 14 +/- 5 days; microbiologic eradication was achieved in all patients, and no drug related adverse events occurred. PMID- 26484429 TI - Final Height and Associated Factors in Perinatally HIV-infected Asian Adolescents. AB - We analyzed final height of 273 perinatally HIV-infected Asian adolescents older than 18 years at their last clinic visit. By the World Health Organization child growth reference, 30% were stunted, but by the Thai child growth reference, 19% were stunted. Half of those who were stunted at antiretroviral therapy initiation remained stunted over time. Being male and having a low baseline height-for-age Z score of less than -1.0 were associated with low final height Z score. PMID- 26484434 TI - Proteomics and drug discovery in cancer. AB - Proteomics has emerged as an invaluable tool in the quest to unravel the biochemical changes that give rise to the hallmarks of cancer. In this review, we present the advances and challenges facing proteomics technology as applied to cancer research, and address how the information gathered so far has helped to enhance understanding of the mechanisms underlying the disease and contributed to the discovery of biomarkers and new drug targets. We conclude by presenting a perspective on how proteomics could be applied in the future to determine prognostic biomarkers and direct strategies for effective cancer treatment. PMID- 26484436 TI - Laparoscopic repair of a complex, recurrent incisional hernia with sac excision and primary closure of the fascial defect--a video vignette. PMID- 26484437 TI - [Recognizing - assessing - managing structural and legal guidelines for prevention of nosocomial infections]. PMID- 26484435 TI - Reduced prefrontal activation during working and long-term memory tasks and impaired patient-reported cognition among cancer survivors postchemotherapy compared with healthy controls. AB - BACKGROUND: Patients who receive adjuvant chemotherapy have reported cognitive impairments that may last for years after the completion of treatment. Working memory-related and long-term memory-related changes in this population are not well understood. The objective of this study was to demonstrate that cancer related cognitive impairments are associated with the under recruitment of brain regions involved in working and recognition memory compared with controls. METHODS: Oncology patients (n = 15) who were receiving adjuvant chemotherapy and had evidence of cognitive impairment according to neuropsychological testing and self-report and a group of age-matched, education group-matched, cognitively normal control participants (n = 14) underwent functional magnetic resonance imaging. During functional magnetic resonance imaging, participants performed a nonverbal n-back working memory task and a visual recognition task. RESULTS: On the working memory task, when 1-back and 2-back data were averaged and contrasted with 0-back data, significantly reduced activation was observed in the right dorsolateral prefrontal cortex for oncology patients versus controls. On the recognition task, oncology patients displayed decreased activity of the left middle hippocampus compared with controls. Neuroimaging results were not associated with patient-reported cognition. CONCLUSIONS: Decreased recruitment of brain regions associated with the encoding of working memory and recognition memory was observed in the oncology patients compared with the control group. These results suggest that there is a reduction in neural functioning postchemotherapy and corroborate patient-reported cognitive difficulties after cancer treatment, although a direct association was not observed. Cancer 2016;122:258-268. (c) 2015 American Cancer Society. PMID- 26484438 TI - [Classic Limberg Flap Procedure for Treatment of a Sacrococcygeal Pilonidal Sinus Disease - Explanation of the Surgical Technique]. AB - INTRODUCTION: Sacrococcygeal pilonidal sinus disease is frequently encountered in surgical practice. Besides excision only, the current pilonidal sinus guideline of the Association of the Scientific Medical Societies in Germany (AWMF-S3) also recommends plastic surgical procedures such as the cleft-lift operation described by Bascom, the Karydakis flap procedure and, due to the low recurrence rates, the Limberg flap procedure, for the treatment of this disease. INDICATION: In our case we show the surgical procedure performed on a 23-year-old male patient, who was previously treated for an acute abscess-forming sacrococcygeal pilonidal sinus. METHOD: Our video shows the fasciocutaneous rhombic flap procedure described by Limberg step by step. CONCLUSION: The Limberg flap procedure is a simple operation for the treatment of sacrococcygeal pilonidal sinus disease. PMID- 26484439 TI - [20 Years of Vascular Surgery/Medicine in the Journal "Zentralblatt fur Chirurgie" - EDITORIAL]. PMID- 26484440 TI - [An Experimental Set-Up for Navigated-Contrast-Agent and Radiation Sparing Endovascular Aortic Repair (Nav-CARS EVAR)]. AB - INTRODUCTION: Over the last decade endovascular stenting of aortic aneurysm (EVAR) has been developed from single centre experiences to a standard procedure. With increasing clinical expertise and medical technology advances treatment of even complex aneurysms are feasible by endovascular methods. One integral part for the success of this minimally invasive procedure is innovative and improved vascular imaging to generate exact measurements and correct placement of stent prosthesis. One of the greatest difficulty in learning and performing this endovascular therapy is the fact that the three-dimensional vascular tree has to be overlaid with the two-dimensional angiographic scene by the vascular surgeon. MATERIAL AND METHODS: We report the development of real-time navigation software, which allows a three-dimensional endoluminal view of the vascular system during an EVAR procedure in patients with infrarenal aortic aneurysm. We used the preoperative planning CT angiography for three-dimensional reconstruction of aortic anatomy by volume-rendered segmentation. At the beginning of the intervention the relevant landmarks are matched in real-time with the two dimensional angiographic scene. During the intervention the software continously registers the position of the guide-wire or the stent. An additional 3D-screen shows the generated endoluminal view during the whole intervention in real-time. RESULTS: We examined the combination of hardware and software components including complex image registration and fibre optic sensor technology (fibre bragg navigation) with integration in stent graft introducer sheaths using patient-specific vascular phantoms in an experimental setting. From a technical point of view the feasibility of fibre-Bragg navigation has been proven in our experimental setting with patient-based vascular models. Three-dimensional preoperative planning including registration and simulation of virtual angioscopy in real time are realised. CONCLUSION: The aim of the Nav-CARS-EVAR concept is reduction of contrast medium and radiation dose by a three-dimensional navigation during the EVAR procedure. To implement fibre-Bragg navigation further experimental studies are necessary to verify accuracy before clinical application. PMID- 26484442 TI - The evolving concept of acute kidney injury in patients with cirrhosis. AB - Renal dysfunction is prevalent in patients with advanced cirrhosis and decompensation. The presence of type 1 hepatorenal syndrome (HRS) has traditionally been defined by a set of stringent criteria based on serum creatinine levels. These diagnostic criteria have been found to be too stringent to be widely applicable to patients with cirrhosis, leading to underdiagnosis of renal failure in this population. Acute kidney injury (AKI) has now been proposed to characterize renal dysfunction in patients with cirrhosis and is defined as an increase in serum creatinine by 0.3 mg/dl in <48 h or an increase in serum creatinine by 50% from a stable baseline reading within 3 months. Type 1 HRS is renamed HRS-AKI. Stage 1 AKI is defined by 0.3 mg/dl serum creatinine or a 50% increase, stages 2 and 3 AKI are defined by a two-fold and three-fold increase in serum creatinine levels, respectively. Data collected so far suggests that even stage 1 AKI is associated with worse prognosis in patients with cirrhosis. The progression of AKI usually indicates substantially worse outcomes. A panel of biomarkers, including inflammatory markers, are envisaged to complement and enhance our current diagnostic criteria in the future and provide aetiology of the AKI. PMID- 26484444 TI - Pancreatic cancer: Classifying pancreatic cancer using gene expression profiling. AB - Despite some advances in our understanding of the molecular characteristics of pancreatic cancer, much more progress is needed. In a new study, RNA profiling of pancreatic cancers was used to identify gene signatures of tumour cells and stromal cells to help predict patient outcomes. PMID- 26484445 TI - Diabetes: Circulating factors implicated in diabetic enteropathy. PMID- 26484443 TI - Immunological landscape and immunotherapy of hepatocellular carcinoma. AB - Advanced hepatocellular carcinoma (HCC) is a serious therapeutic challenge and targeted therapies only provide a modest benefit in terms of overall survival. Novel approaches are urgently needed for the treatment of this prevalent malignancy. Evidence demonstrating the antigenicity of tumour cells, the discovery that immune checkpoint molecules have an essential role in immune evasion of tumour cells, and the impressive clinical results achieved by blocking these inhibitory receptors, are revolutionizing cancer immunotherapy. Here, we review the data on HCC immunogenicity, the mechanisms for HCC immune subversion and the different immunotherapies that have been tested to treat HCC. Taking into account the multiplicity of hyperadditive immunosuppressive forces acting within the HCC microenvironment, a combinatorial approach is advised. Strategies include combinations of systemic immunomodulation and gene therapy, cell therapy or virotherapy. PMID- 26484449 TI - Inhaled Anesthesia, Apoptosis, and the Developing Retina: A Window into the Brain? PMID- 26484450 TI - Delirium After Hip Fracture: Still a Problem. PMID- 26484451 TI - A New Monitor of Pressure Autoregulation: What Does It Add? PMID- 26484452 TI - Medical Use of Marijuana: Truth in Evidence. PMID- 26484453 TI - An Overview of the American College of Cardiology/American Heart Association 2014 Valve Heart Disease Practice Guidelines: What Is Its Relevance for the Anesthesiologist and Perioperative Medicine Physician? PMID- 26484454 TI - Supramitral Ring: A Rare Anomaly Presenting with Mitral Inflow Obstruction in Association with an Atrial Septal Defect. PMID- 26484455 TI - Echocardiography of Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery. PMID- 26484456 TI - Left Ventricular Outflow Tract Obstruction After a Mitral Valve Repair. PMID- 26484457 TI - The Usefulness of Three-Dimensional Transesophageal Echocardiography for a Primum Atrial Septal Defect. PMID- 26484458 TI - The Impact of Anesthetic Management on Surgical Site Infections in Patients Undergoing Total Knee or Total Hip Arthroplasty. AB - BACKGROUND: Surgical site infection (SSI) is one of the most challenging and costly complications associated with total joint arthroplasty. Our primary aim in this case-controlled trial was to compare the risk of SSI within a year of surgery for patients undergoing primary total knee arthroplasty (TKA) or total hip arthroplasty (THA) and revision TKA or THA under general anesthesia versus neuraxial anesthesia. Our secondary aim was to determine which patient, anesthetic, and surgical variables influence the risk of SSI. We hypothesized that patients who undergo neuraxial anesthesia may have a lesser risk of SSI compared with those who had a general anesthetic. METHODS: We conducted a retrospective, case-control study of patients undergoing primary or revision TKA and THA between January 1, 1998, and December 31, 2008, who subsequently were diagnosed with an SSI. The cases were matched 1:2 with controls based on type of joint replacement (TKA versus THA), type of procedure (primary, bilateral, revision), sex, date of surgery (within 1 year), ASA physical status (I and II versus III, IV, and V), and operative time (<3 vs >3 hours). RESULTS: During the 11-year period, 202 SSIs were identified. Of the infections identified, 115 (57%) occurred within the first 30 days and 87 (43%) occurred between 31 and 365 days. From both univariate and multivariable analyses, no significant association was found between the use of central neuraxial anesthesia and the postoperative infection (univariate odds ratio [OR] = 0.92; 95% confidence interval [CI], 0.63 1.34; P = 0.651; multivariable OR = 1.10; 95% CI, 0.72-1.69; P = 0.664). The use of peripheral nerve block also was not found to influence the risk of postoperative infection (univariate OR = 1.41; 95% CI, 0.84-2.37; P = 0.193; multivariable OR = 1.35; 95% CI, 0.75-2.44; P = 0.312). The factors that were found to be associated with postoperative infection in multivariable analysis included current smoking (OR = 5.10; 95% CI, 2.30-11.33) and higher body mass index (BMI) (OR = 2.68; 95% CI, 1.42-5.06 for BMI >= 35 kg/m compared with those with BMI < 25 kg/m). CONCLUSIONS: Recent studies using large databases have concluded that the use of neuraxial compared with general anesthesia is associated with a decreased incidence of SSI in patients undergoing total joint arthroplasty. In this retrospective, case-controlled study, we found no difference in the incidence of SSI in patients undergoing total joint arthroplasty under general versus neuraxial anesthesia. We also concluded that the use of peripheral nerve blocks does not influence the incidence of SSI. Increasing BMI and current smoking were found to significantly increase the incidence of SSI in patients undergoing lower extremity total joint arthroplasty. PMID- 26484459 TI - Ventilator-Associated Events: What Does It Mean? PMID- 26484460 TI - Polydatin Inhibits Mitochondrial Dysfunction in the Renal Tubular Epithelial Cells of a Rat Model of Sepsis-Induced Acute Kidney Injury. AB - BACKGROUND: Mitochondrial injury is a major cause of sepsis-induced organ failure. Polydatin (PD), a natural polyphenol, demonstrates protective mitochondrial effects in neurons and arteriolar smooth muscle cells during severe shock. In this study, we investigated the effects of PD on renal tubular epithelial cell (RTEC) mitochondria in a rat model of sepsis-induced acute kidney injury. METHODS: Rats underwent cecal ligation and puncture (CLP) to mimic sepsis induced acute kidney injury. Rats were randomly divided into sham, CLP + normal saline, CLP + vehicle, and CLP + PD groups. Normal saline, vehicle, and 30 mg/kg PD were administered at 6, 12, and 18 hours after CLP or sham surgery via the tail vein. Mitochondrial morphology, metabolism, and function in RTECs were then assessed. Serum cytokines, renal function, survival, and histologic changes in the kidney were also evaluated. RESULTS: CLP increased lipid peroxide content, lysosomal instability, and opening of the mitochondrial permeability transition pore and caused mitochondrial swelling. Moreover, mitochondrial membrane potential (DeltaPsim) was decreased and ATP levels reduced after CLP. PD inhibited all the above effects. It also inhibited the inflammatory response, improved renal function, attenuated histologic indicators of kidney damage, and prolonged survival. CONCLUSIONS: PD protects RTECs against mitochondrial dysfunction and prolongs survival in a rat model of sepsis-induced acute kidney injury. These effects may partially result from reductions in interleukin-6 and oxidative stress. PMID- 26484461 TI - Using Nursing Activities Score to Assess Nursing Workload on a Medium Care Unit. AB - BACKGROUND: The medium care unit (MCU) or "stepdown" unit is an increasingly important, but understudied care environment. With an aging population and more patients with complex multiple diseases, many patients often require a higher level of inpatient care even when full intensive care is not indicated. However, the nurse-to-patient ratio required on a MCU is neither well defined nor clear whether this ratio should be adjusted per shift. The Nursing Activities Score (NAS) is an effective instrument for measuring nursing workload in the intensive care unit (ICU) but has not been used in an MCU. The aim of this study was to measure the nursing workload per 8-hour shift on an MCU using the NAS and compare it with the NAS from an ICU in the same hospital. We also compared the NAS between groups of patients with different admission sources. METHODS: The NAS was prospectively measured per patient per shift for 2 months in a 9-bed tertiary referral university hospital MCU and during a similar period in an ICU in the same hospital. RESULTS: The mean NAS per patient did not differ between day (7:30 AM to 4:00 PM) and evening (3:00 PM to 11:30 PM) shifts, but the NAS was significantly lower during the night shift (11:00 PM to 8:00 AM) than during the day (P < 0.0001) and evening (P < 0.0001) shifts. The mean NASs in the ICU for day and night shifts were significantly lower than the scores in the MCU (P = 0.0056 and P < 0.0001, respectively), but NAS during the evening shift did not differ between the ICU and the MCU. The mean NAS for patients admitted to the MCU from the accident and emergency department was significantly higher than for those admitted from the ICU (P = 0.002), recovery (P = 0.002), and general ward (P < 0.0001). Patients on the MCU had a NAS comparable with that of ICU patients. CONCLUSIONS: In our university hospital, NAS was higher during the day and evening hours and lower at night. We also found that patients from accident and emergency had a higher NAS than those admitted to the MCU from other locations. NAS in the MCU was not lower than the NAS in the ICU. Because of its ability to discriminate between day and evening workloads and between patients from different sources, the NAS may assist MCU managers in assessing staffing needs. PMID- 26484462 TI - Anesthetic Management of Patients with Congenital Insensitivity to Pain with Anhidrosis: A Retrospective Analysis of 358 Procedures Performed Under General Anesthesia. AB - BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by recurrent episodic fevers, anhidrosis, absent reaction to noxious stimuli, self-mutilating behavior, and mental retardation. The anesthetic management of patients with CIPA is challenging. Autonomic nervous system abnormalities are common, and patients are at increased risk for perioperative complications. METHODS: In this study, we describe our experience with 35 patients with CIPA who underwent 358 procedures requiring general anesthesia between 1990 and 2013. RESULTS: During surgery, 3 patients developed hyperthermia intraoperatively (>37.5 degrees C) without prior fever. There were no cases of intraoperative hyperpyrexia (>40 degrees C). Aspiration was suspected in 2 patients, and in another patient aspiration was prevented by the use of endotracheal tube, early detection of regurgitation, and aggressive suctioning. One patient had cardiac arrest requiring cardiopulmonary resuscitation. Intraoperative bradycardia was observed in 10 cases, and postoperative bradycardia was observed in 11 cases. CONCLUSIONS: Regurgitation, hyperthermia, and aspiration were uncommon, but the incidence of bradycardia was higher than has been reported in previous studies. CIPA remains a challenge for anesthesiologists. Because of the rare nature of this disorder, the risk of various complications is difficult to predict. PMID- 26484463 TI - Nitrous Oxide for the Treatment of Chronic Low Back Pain. AB - BACKGROUND: Neuropathic back pain is mediated, at least partially, by N-methyl-D aspartate (NMDA) receptors. Nitrous oxide (N2O) is an NMDA receptor antagonist. We therefore tested the primary hypothesis that patients receiving N2O have lower pain scores after epidural steroid injection than patients not receiving N2O. METHODS: Patients with recurrent low back pain scheduled for epidural steroid blocks were randomly assigned to receive either oxygen (O2, n = 39) or the combination of 50% O2 and 50% N2O during and after each block (N2O, n = 39). Before each injection and at a 3-month follow-up visit, patients completed questionnaires: Oswestry survey, 12-Item Short Form Health Survey questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs pain scale, and Visual Analog Scale. Total opioid use per 24 hours was recorded. The serum samples for tumor necrosis factor-alpha, interleukin (IL)-6, interferon-gamma, IL-10, IL-17A, and IL-1beta assays were collected at every visit and evaluated. Standard descriptive statistics were used to compare the randomized groups on baseline variables. Any imbalanced covariates with an absolute standardized difference >0.44 were adjusted for in both primary and secondary analyses. Both modified intention-to treat and per-protocol analyses were conducted for our outcomes. Our secondary analyses were per protocol. RESULTS: in patients given N2O (mean [SD], -1.6 [3.0] cm) and O2 (-1.2 [2.6] cm), with difference -0.13 (95% confidence interval: 1.43, 1.17), N2O - O2; P = 0.84. No difference was found between the 2 randomized groups on changes in Leeds Assessment of Neuropathic Symptoms and Signs pain score, Oswestry score, or 12-Item Short Form Health Survey from baseline, or in satisfaction with the procedure, satisfaction with pain treatment, or use of opioid overtime. Overall, no significant differences on any cytokine were found between the 2 groups. The estimated odds ratios of taking opioid was 0.46 (0.12, 1.84) (N2O versus O2; P = 0.12). CONCLUSIONS: N2O administration did not improve pain or psychological or physical aspects of health-related quality of life. N2O does not appear to be an effective treatment for chronic neuropathic back pain. PMID- 26484464 TI - The First Shot Is Often the Best Shot: First-Pass Intubation Success in Emergency Airway Management. PMID- 26484465 TI - What Is the True Incidence of Postpartum Hemorrhage? PMID- 26484466 TI - In Response. PMID- 26484467 TI - Apical Hypertrophic Cardiomyopathy. PMID- 26484468 TI - There Is More to Postcraniotomy Emergence Hypertension Than Simply Blood Pressure Control-Why Nicardipine May Not Be the Drug of Choice. PMID- 26484469 TI - In Response. PMID- 26484470 TI - The Validity of Eadyn in Spontaneously Breathing Patients. PMID- 26484471 TI - In Response. PMID- 26484472 TI - A Multimodal Approach to Prevent Laparoscopic High Peritoneal Air Fraction. PMID- 26484473 TI - In Response. PMID- 26484474 TI - Editorial from Under the Volcano. PMID- 26484479 TI - Development and application of a screening model for evaluating bioenhanced dissolution in DNAPL source zones. AB - In-situ bioremediation, a widely applied treatment technology for source zones contaminated with dense non-aqueous phase liquids (DNAPLs), has proven economical and reasonably efficient for long-term management of contaminated sites. Successful application of this remedial technology, however, requires an understanding of the complex interaction of transport, mass transfer, and biotransformation processes. The bioenhancement factor, which represents the ratio of DNAPL mass transfer under microbially active conditions to that which would occur under abiotic conditions, is commonly used to quantify the effectiveness of a particular bioremediation remedy. To date, little research has been directed towards the development and validation of methods to predict bioenhancement factors under conditions representative of real sites. This work extends an existing, first-order, bioenhancement factor expression to systems with zero-order and Monod kinetics, representative of many source-zone scenarios. The utility of this model for predicting the bioenhancement factor for previously published laboratory and field experiments is evaluated. This evaluation demonstrates the applicability of these simple bioenhancement factors for preliminary experimental design and analysis, and for assessment of dissolution enhancement in ganglia-contaminated source zones. For ease of application, a set of nomographs is presented that graphically depicts the dependence of bioenhancement factor on physicochemical properties. Application of these nomographs is illustrated using data from a well-documented field site. Results suggest that this approach can successfully capture field-scale, as well as column-scale, behavior. Sensitivity analyses reveal that bioenhanced dissolution will critically depend on in-situ biomass concentrations. PMID- 26484481 TI - Entomopathogenic nematodes for the control of the codling moth (Cydia pomonella L.) in field and laboratory trials. AB - Three commercially available entomopathogenic nematode (EPN) strains (Steinernema feltiae and Heterorhabditis bacteriophora Hb1 and Hb2) and two local species (S. jeffreyense and S. yirgalemense) were evaluated for the control of the codling moth (Cydia pomonella). In field spray trials, the use of S. jeffreyense resulted in the most effective control (67%), followed by H. bacteriophora (Hb1) (42%) and S. yirgalemense (41%). Laboratory bioassays using spray application in simulated field conditions indicate S. feltiae to be the most virulent (67%), followed by S. yirgalemense (58%). A laboratory comparison of the infection and penetration rate of the different strains showed that, at 14 degrees C, all EPN strains resulted in slower codling moth mortality than they did at 25 degrees C. After 48 h, 98% mortality was recorded for all species involved. However, the washed codling moth larvae, cool-treated (at 14 degrees C) with S. feltiae or S. yirgalemense, resulted in 100% mortality 24 h later at room temperature, whereas codling moth larvae treated with the two H. bacteriophora strains resulted in 68% and 54% control, respectively. At 14 degrees C, S. feltiae had the highest average penetration rate of 20 IJs/larva, followed by S. yirgalemense, with 14 IJs/larva. At 25 degrees C, S. yirgalemense had the highest penetration rate, with 39 IJs/larva, followed by S. feltiae, with 9 IJs/larva. This study highlights the biocontrol potential of S. jeffreyense, as well as confirming that S. feltiae is a cold-active nematode, whereas the other three EPN isolates tested prefer warmer temperatures. PMID- 26484480 TI - Rapid, High-Throughput, and Direct Molecular Beacon Delivery to Human Cancer Cells Using a Nanowire-Incorporated and Pneumatic Pressure-Driven Microdevice. AB - Tracking and monitoring the intracellular behavior of mRNA is of paramount importance for understanding real-time gene expression in cell biology. To detect specific mRNA sequences, molecular beacons (MBs) have been widely employed as sensing probes. Although numerous strategies for MB delivery into the target cells have been reported, many issues such as the cytotoxicity of the carriers, dependence on the random probability of MB transfer, and critical cellular damage still need to be overcome. Herein, we have developed a nanowire-incorporated and pneumatic pressure-driven microdevice for rapid, high-throughput, and direct MB delivery to human breast cancer MCF-7 cells to monitor survivin mRNA expression. The proposed microdevice is composed of three layers: a pump-associated glass manifold layer, a monolithic polydimethylsiloxane (PDMS) membrane, and a ZnO nanowire-patterned microchannel layer. The MB is immobilized on the ZnO nanowires by disulfide bonding, and the glass manifold and PDMS membrane serve as a microvalve, so that the cellular attachment and detachment on the MB-coated nanowire array can be manipulated. The combination of the nanowire-mediated MB delivery and the microvalve function enable the transfer of MB into the cells in a controllable way with high cell viability and to detect survivin mRNA expression quantitatively after docetaxel treatment. PMID- 26484483 TI - A GP primer for understanding upper gastrointestinal tract biopsy reports. AB - BACKGROUND: Endoscopic biopsies of the upper gastrointestinal (GI) tract are taken to make a diagnosis of inflammation, dysplasia or malignancy, to assess treatment success and monitor patients' progress. OBJECTIVE: This article provides a guide to understanding histology reports sent to general practitioners (GPs) from endoscopy and anatomical pathology providers for the diagnosis of increasingly prevalent upper GI diseases. DISCUSSION: Many upper GI diseases are increasing in prevalence and new diseases are emerging that require biopsy for diagnosis. Oesophageal disease (particularly gastro-oesophageal reflux disease and eosinophilic oesophagitis) and coeliac disease (real and perceived wheat sensitivity) are common. However, infection with Helicobacter pylori is declining. Drugs can also affect the GI tract, and endoscopy can detect damage with biopsy confirmation. PMID- 26484482 TI - Gastro-oesophageal reflux disease (GORD) in Australian general practice patients. AB - Gastro-oesophageal reflux disease (GORD) imposes a high level of societal and financial burden on the community. Recently, concern has been expressed regarding the number of prescriptions for proton pump inhibitors (PPIs), mostly for GORD, in Australia. This study investigated changes in the management of GORD since 2006-08. This was a secondary analysis of data from the Bettering the Evaluation and Care of Health (BEACH) program. There was an increase of about 15% in the management rate of GORD between 2006-08 and 2012-14. Medication rates were high, with 95 prescriptions per 100 GORD problems managed, of which 83% were for PPIs. Most patients with GORD are on long-term PPI therapy, usually at full dosage. Trials of cessation or dosage reduction may be appropriate in many patients. PMID- 26484484 TI - From the hospital to the home--the rise and rise of Clostridium difficile infection. AB - BACKGROUND: Clostridium difficile infection (CDI) has emerged as a serious worldwide public health threat. Although C. difficile has always been a cause of diarrhoeal disease in patients presenting to general practice, the rates of community-associated CDI (CA CDI) have increased. OBJECTIVE: This article provides a summary of what is currently known about CA CDI and the implications for Australian general practitioners (GPs). DISCUSSION: Changes in the colonic flora (most often because of antibiotic use) and exposure to C. difficile are both required for the disease to develop. Potential sources of C. difficile in the community include the home environment, food and water, workplace and environment. Identification of risk factors for CDI may help in the early diagnosis and subsequent management of infection, and these are being explored further. GPs have a role in understanding and managing CA CDI through prudent prescribing, patient education and adequate testing. PMID- 26484485 TI - Chronic pancreatitis: Negotiating the complexities of diagnosis and management. AB - BACKGROUND: Chronic pancreatitis is a debilitating condition, where the pathology and management are often overlooked in favour of the more recognisable acute form of the disease. OBJECTIVE: This article draws on experiences gleaned from a cohort of patients with pancreatitis in Far North Queensland, and evidence from selected literature, to formulate strategies for managing disease presentations likely to be encountered in the primary care setting. A supplementary case report serves to illustrate some of the management issues raised. DISCUSSION: A number of clinically useful key messages pertaining to the investigation, diagnosis and management of chronic pancreatitis are provided. PMID- 26484486 TI - Eosinophilic oesophagitis--a guide for primary care. AB - BACKGROUND: Eosinophilic oesophagitis (EoE) is an increasingly recognised inflammatory disorder of the oesophagus. The incidence of this chronic, food triggered disease is rising in Australia and diagnosis should be considered in patients who complain of dysphagia. OBJECTIVE: This article provides an overview of the pathogenesis, evaluation and management of EoE. It is intended as a useful tool for general practitioners (GPs) in the primary care setting and to raise awareness of EoE. DISCUSSION: EoE is an increasingly prevalent allergic disorder of the oesophagus. It is characterised clinically by symptoms of oesophageal dysfunction and microscopically by eosinophilic inflammation of the oesophagus. Treatment involves avoiding trigger foods and corticosteroid therapy, which may be necessary intermittently or long term, given the relapsing nature of the condition. EoE can significantly impair quality of life and GPs are key to recognising the disease and directing patients' long-term care. PMID- 26484487 TI - Wound closure involving fragile skin. AB - Fragile skin can be difficult to repair due to tearing. Horizontal mattress sutures with bolsters placed at either side can prevent skin tearing and allow effective wound closure. PMID- 26484488 TI - Ear wax management. AB - BACKGROUND: Ear syringing is a very common practice among general practitioners (GPs). It is used by many as the treatment of choice for cerumen (ear wax), and is usually effective and safe. However, complications from syringing are an increasingly common reason for presentation to ear, nose and throat (ENT) specialists and medico-legal complaints against GPs. OBJECTIVE: The aim of this article is to provide GPs with the knowledge to safely manage cerumen. DISCUSSION: Ear wax is an important part of a normal functioning ear. It is mostly asymptomatic and requires no treatment. Softening ear drops may be necessary to help the ear fulfil its self-cleaning function, and should be considered first-line treatment. Syringing can be safely performed if this fails by taking a thorough history and examination to exclude contraindications, gaining patient consent and ensuring the appropriate use of equipment. Referral to an ENT clinic for manual removal with microsuctioning may be necessary in the event of contraindications, complications or failure. PMID- 26484489 TI - A fast-growing tumour. PMID- 26484490 TI - Premature ejaculation: A clinical review for the general physician. AB - BACKGROUND: Premature ejaculation is one of the most common sexual dysfunctions in men. Recent epidemiological studies suggest its prevalence in Australia may range from 21-31% OBJECTIVE: This article will discuss the current definition of premature ejaculation from a urological perspective. It will provide an understanding of the pathogenesis of premature ejaculation, as well as assessment and management options. DISCUSSION: Premature ejaculation can have a significant adverse effect on the quality of life for the patient and his sexual partners. It can potentially lead to psychological distress, diminished self- esteem, anxiety, erectile dysfunction, reduced libido and poor interpersonal relationships. Most men feel reluctant to discuss premature ejaculation with their general practitioner despite its psychological, emotional and relational effects. Effective, evidence-based treatment options are available and physicians should feel confident when exploring ways to improve the quality of life for men with sexual dysfunction. PMID- 26484491 TI - Enlarging knuckle bumps. PMID- 26484492 TI - Doctors on the move: National estimates of geographical mobility among general practitioners in Australia. AB - BACKGROUND: The aim of this study was to examine the geographical mobility patterns on a national level of general practitioners (GPs) across degrees of rurality. While this is a topic with great policy implications, negligible published research exists in Australia on this topic. METHODS: Publicly available data for all registered GPs with specialist 'general practice' registration for 2011 and 2013 were obtained from the Australian Health Professional Registration Agency (AHPRA) and analysed. RESULTS: Annually, about 10% of Australian GPs have changed their principal place of practice (PPP), and about 1% of GPs moved between states. A net move into major cities was observed. Major cities were the most favoured destination of GPs moving out of a remote area, and the largest source of GPs moving into remote and very remote areas. Among GPs, there was a gradient of increasing distances moved with increasing rurality. DISCUSSION: This study shows for the first time that annually, about 10% of GPs change their PPP over a short time period. The drift of GPs away from rural areas indicates that policymakers should focus on recruitment and retention in these areas, preferably providing incentives for moving specifically from metropolitan areas. PMID- 26484493 TI - A brief experience for medical students in a remote Aboriginal community. AB - BACKGROUND: Aboriginal and Torres Strait Islander peoples, particularly those in remote communities, have lower access to health services when compared with the rest of the Australian population. This research examined the expectations and outcomes of medical students who went on a 2-day trip to a remote Aboriginal community. METHODS: Activities were organised by community members, ground staff and fly-in fly-out health professionals. Students wrote about their expectations and post-trip reflections on personal, medical and cultural themes. RESULTS: Twenty-three students participated in this study. Themes included complex, different and increased illnesses; how culture affects day-to-day life and health; personal growth; administrative, health delivery and advocacy skills; learning cultural awareness first-hand; and future career options. DISCUSSION: The 2-day trip gave students a profound learning experience. To build a culturally appropriate and dedicated workforce for Aboriginal and Torres Strait Islander peoples, medical schools should consider incorporating short trips to remote Aboriginal and Torres Strait Islander communities into their curriculum. PMID- 26484494 TI - General practitioners learning qualitative research: A case study of postgraduate education. AB - BACKGROUND: Qualitative research is increasingly being recognised as a vital aspect of primary healthcare research. Teaching and learning how to conduct qualitative research is especially important for general practitioners and other clinicians in the professional educational setting. This article examines a case study of postgraduate professional education in qualitative research for clinicians, for the purpose of enabling a robust discussion around teaching and learning in medicine and the health sciences. METHODS: A series of three workshops was delivered for primary healthcare academics. The workshops were evaluated using a quantitative survey and qualitative free-text responses to enable descriptive analyses. RESULTS: Participants found qualitative philosophy and theory the most difficult areas to engage with, and learning qualitative coding and analysis was considered the easiest to learn. DISCUSSION: Key elements for successful teaching were identified, including the use of adult learning principles, the value of an experienced facilitator and an awareness of the impact of clinical subcultures on learning. PMID- 26484495 TI - General practice ethics: Overdiagnosis, harm and paternalism. PMID- 26484497 TI - I see what you say: Prior knowledge of other's goals automatically biases the perception of their actions. AB - We investigated whether top-down expectations about an actor's intentions affect action perception in a representational momentum (RM) paradigm. Participants heard an actor declare an intention to either take or leave an object and then saw him either reach for or withdraw from it, such that action and intention were either congruent or incongruent. Observers generally misperceived the hand's disappearance point further along the trajectory than it actually was, in line with the idea that action perception incorporates predictions of the action's future course. Importantly, this RM effect was larger for actions congruent with the actor's goals than for incongruent actions. These results demonstrate that action prediction integrates both current motion and top-down knowledge about the actor's intention. They support recent theories that emphasise the role of prior expectancies and prediction errors in social (and non-social) cognitive processing. PMID- 26484498 TI - Infants use temporal regularities to chunk objects in memory. AB - Infants, like adults, can maintain only a few items in working memory, but can overcome this limit by creating more efficient representations, or "chunks." Previous research shows that infants can form chunks using shared features or spatial proximity between objects. Here we asked whether infants also can create chunked representations using regularities that unfold over time. Thirteen-month old infants first were familiarized with four objects of different shapes and colors, presented in successive pairs. For some infants, the identities of objects in each pair varied randomly across familiarization (Experiment 1). For others, the objects within a pair always co-occurred, either in consistent relative spatial positions (Experiment 2a) or varying spatial positions (Experiment 2b). Following familiarization, infants saw all four objects hidden behind a screen and then saw the screen lifted to reveal either four objects or only three. Infants in Experiment 1, who had been familiarized with random object pairings, failed to look longer at the unexpected 3-object outcome; they showed the same inability to concurrently represent four objects as in other studies of infant working memory. In contrast, infants in Experiments 2a and 2b, who had been familiarized with regularly co-occurring pairs, looked longer at the unexpected outcome. These infants apparently used the co-occurrence between individual objects during familiarization to form chunked representations that were later deployed to track the objects as they were hidden at test. In Experiment 3, we confirmed that the familiarization affected infants' ability to remember the occluded objects rather than merely establishing longer-term memory for object pairs. Following familiarization to consistent pairs, infants who were not shown a hiding event (but merely saw the same test outcomes as in Experiments 2a and b) showed no preference for arrays of three versus four objects. Finally, in Experiments 4 and 5, we asked whether infants also remembered the specific identities of the objects in each chunk. In Experiment 4, we confirmed that infants remembered objects' identities in smaller arrays that did not require chunking. Next, in Experiment 5, we asked whether infants also remembered objects' identities in larger arrays that had been chunked on the basis of temporal regularities. Following a familiarization phase identical to that in Experiment 2a, we hid all four objects and then revealed either these same four objects, or four objects of which two had unexpectedly changed shape and color. Surprisingly, infants failed to look longer at the identity change outcome. Taken together, our results suggest that infants can use temporal regularities between objects to increase memory for objects' existence, but not necessarily for objects' identities. PMID- 26484499 TI - Evolution, plasticity and evolving plasticity of phenology in the tree species Alnus glutinosa. AB - Both traits and the plasticity of these traits are subject to evolutionary change and therefore affect the long-term persistence of populations and their role in local communities. We subjected clones from 12 different populations of Alnus glutinosa, located along a latitudinal gradient, to two different temperature treatments, to disentangle the distribution of genetic variation in timing of bud burst and bud burst plasticity within and among genotypes, populations, and regions. We calculated heritability and evolvability estimates for bud burst and bud burst plasticity and assessed the influence of divergent selection relative to neutral drift. We observed higher levels of heritability and evolvability for bud burst than for its plasticity, whereas the total phenological heritability and evolvability (i.e. combining timing of bud burst and bud burst plasticity) suggest substantial evolutionary potential with respect to phenology. Earlier bud burst was observed for the low-latitudinal populations than for the populations from higher latitudes, whereas the high-latitudinal populations did not show the expected delayed bud burst. This countergradient variation can be due to evolution towards increased phenological plasticity at higher latitudes. However, because we found little evidence for adaptive differences in phenological plasticity across the latitudinal gradient, we suggest differential frost tolerance as the most likely explanation for the observed phenological patterns in A. glutinosa. PMID- 26484501 TI - Is escalation of plant defence a common macroevolutionary outcome of plant herbivore interactions? PMID- 26484500 TI - Advanced Organic Permeable-Base Transistor with Superior Performance. AB - An optimized vertical organic permeable-base transistor (OPBT) competing with the best organic field-effect transistors in performance, while employing low-cost fabrication techniques, is presented. The OPBT stands out by its excellent power efficiency at the highest frequencies. PMID- 26484502 TI - Postoperative Epidural Hematomas in the Lumbar Spine. AB - Postoperative epidural hematomas are rare complications following lumbar spine surgery, but if they are not quickly identified and treated they can lead to permanent neurological deficits. Epidural hematomas occur in approximately 0.10% 0.24% of all spine surgeries, and despite the fact that multiple large studies have been performed attempting to identify risk factors for this complication, there is still significant debate about the effect of subfascial drains, postoperative anticoagulation, and antiplatelet medication on the incidence of postoperative hematoma. The purpose of this manuscript is to review the epidemiology, etiology, diagnosis, and treatment of patients who develop a postoperative lumbar epidural hematoma. PMID- 26484503 TI - Expression of Concern. PMID- 26484504 TI - Reversal effects of crocin on amyloid beta-induced memory deficit: Modification of autophagy or apoptosis markers. AB - Crocin, as a carotenoid, is one of the main and active constituents of saffron stigmas (Crocus sativus L.) that is widely used in folk medicine. Several studies have pointed out the potent antioxidant and neuroprotective properties of crocin which may have therapeutic values for management of neurodegenerative disorders such as Alzheimer's disease. Alzheimer's disease is the most common form of dementia among the elderly and is characterized by massive neuronal loss and progressive cognitive impairment. Beta amyloid hypothesis is the main theoretical research framework for Alzheimer's disease which states that extracellular aggregation of beta amyloid results in synaptic loss and eventually cell apoptosis. Recent findings suggest that autophagy and apoptosis are extensively involved in Alzheimer's disease. In order to investigate therapeutic values of crocin, we examined the effect of crocin on memory, cell apoptosis, and autophagy using in vivo models of Alzheimer's disease. We also compared the effect of crocin administration on spatial memory with nicotine as positive control. Morris water maze results show that intra-peritoneal and intra-hippocampal administration of crocin significantly improve spatial memory indicators such as escape latency, traveled distance and time spent in target quadrant when compared to beta amyloid injection. Furthermore, we measured certain biomarkers of cell autophagy and apoptosis using Western blot analysis. Our results reveal that crocin administration does not cause any significant alteration in Beclin-1 and ratio of LC3-II/LC3-I compared to the group received beta amyloid by hippocampal injection. However, in contrast to autophagy, crocin administration significantly decreases Bax/Bcl-2 ratio and cleaved Caspase-3 level. This demonstrates that crocin inhibits beta amyloid induced apoptosis, which is possibly associated with its antioxidant properties. Our results further confirm the neuroprotective properties of crocin as a potential pharmaceutical agent for management of Alzheimer's disease. PMID- 26484506 TI - Dopamine D1 receptor (DRD1) 5' region haplotypes significantly affect transcriptional activity in vitro. AB - The role of dopamine D1 receptor (DRD1) gene promoter polymorphisms in schizophrenia remains controversial. We aimed to characterize the polymorphisms in the promoter region because little is known about the extent of variance in this region and potential roles in gene transcription activity. In a previous case-control study, we amplified and genotyped the polymorphisms of DRD1 gene. According to its haplotype estimation, we identified eight SNPs and confirmed ten different haplotypes by cloning and sequencing the fragment spanning -1990 to +10. The promoter activity of these haplotypes was analyzed using dual luciferase assays in SH-SY5Y and HEK293 cells. Compared with the reference haplotype, the constructed haplotypes containing different variation sites could significantly alter the luciferase activity. Additionally, the prediction of the transcription factor binding sites was performed. Our examination could provide the informative reference for the role of DRD1 gene promoter in schizophrenia. PMID- 26484507 TI - Mechanism of inhibition by olanzapine of cloned hERG potassium channels. AB - Olanzapine is widely used in the treatment of schizophrenia and related psychoses. We investigated the effects of olanzapine on human ether-a-go-go related gene (hERG) channels stably expressed in human embryonic kidney (HEK) cells using the whole-cell patch-clamp technique. Olanzapine inhibited hERG tail currents at -50mV in a concentration-dependent manner with an IC50 value of 8.0MUM and a Hill coefficient of 0.9. The voltage-dependent inhibition of the hERG currents by olanzapine increased steeply in the voltage range of channel activation. Olanzapine also shifted the steady-state activation curve of the hERG currents in a hyperpolarizing direction. At more depolarized potentials where the channels were fully activated (between 0 and +50mV), the olanzapine inhibition was voltage-independent. The steady-state inactivation curve of the hERG currents was shifted in the hyperpolarizing direction in the presence of olanzapine. A fast application of olanzapine induced a reversible inhibition of the hERG tail currents during repolarization in a concentration-dependent manner with an IC50 value of 11.9MUM, suggesting an open-channel block. Olanzapine also decreased the hERG current elicited by a 5s depolarizing pulse to +60mV to inactivate the hERG currents, suggesting an inhibition of the activated (open and/or inactivated) states of the channels. These results indicated that olanzapine inhibited the hERG current by preferentially interacting with the activated states of the channel. PMID- 26484505 TI - TIMP-1 couples RhoK activation to IL-1beta-induced astrocyte responses. AB - Interleukin-1beta (IL-1beta) is a pleotropic cytokine known to influence the central nervous system (CNS) responses to injury or infection. IL-1beta also directly induces astrocytic expression of tissue inhibitor of metalloproteinases (TIMP)-1, a potent trophic factor and regulator of matrix metalloproteinase activity. In this study, we examined the functional relationship between IL-1beta and TIMP-1 and determined that the behavior of astrocytes in response to IL-1beta is determined by TIMP-1 expression. Using primary astrocytes from C57Bl/6 mice, we found astrocytes from wildtype (Wt) mice exhibited a robust wound healing response to a scratch wound that was arrested in response to IL-1beta. In contrast, TIMP-1 knockout (TIMP-1KO) astrocytes, exhibited minimal response to the scratch wound but an accelerated response following IL-1beta-treatment. We also determined that the scratch wound effect in Wt cultures was attenuated by inhibition of Rho kinase but amplified in the TIMP-1KO cultures. We propose that the specific induction of TIMP-1 from astrocytes in response to IL-1beta reflects a previously unrecognized physiological relationship where the directionality of astrocytic behavior is determined by the actions of TIMP-1. These findings may provide additional insight into glial responses in the context of neuropathology where expression of TIMP-1 may vary and astrocytic responses may be impacted by the inflammatory milieu of the CNS. PMID- 26484508 TI - Determining cut-off points in functional assessment scales in stroke. AB - BACKGROUND: A wide variety of well-validated assessment scales of functioning and disability have been developed for stroke population. However, these instruments have limitations in their interpretation. Therefore, determining cut-off points for their categorization becomes necessary. OBJECTIVES: To determine cut-off points for the BI, FIM and FAM scales to differentiate clinical disability categories and to establish the relationship between mRS and DOS scales. METHODS: One hundred and six adults with ischemic or haemorrhagic stroke were mainly recruited from a rehabilitation facility (Hospitales Nisa, Valencia, Spain). RESULTS: A high correlation was observed between the DOS and mRS scales (Kendall's tau-b = 0.475; p = 0.000) although a certain amount of disagreement between the two scales was detected. The cut-off points were 62.90 (95% CI, 57.26 69.29) and 21.30 (95% CI, 16.34-26.03) for the BI; 70.62 (95% CI, 66.65-75.22) and 38.29 (95% CI, 34.07-42.25) for the FIM; and 116.07 (95% CI, 110.30-122.68) and 66.02 (95% CI, 59.20-72.35) for the FAM. CONCLUSION(S): DOS was observed to be more demanding than the mRS, in terms of patient independence. Additionally, the lower cut-off points separating the levels of severe and moderate disability in the BI, FIM and FAM were determined. These findings would facilitate practitioners clinical interpretation of disability levels in post-stroke patients. PMID- 26484509 TI - Predicting discharge destination with admission outcome scores in stroke patients. AB - BACKGROUND: The goal of this study was to predict the discharge location for stroke patients. OBJECTIVE: To design a tool to assess a community discharge that will assist in development of individualized care plans and discharge planning. METHODS: Patients (N = 407) hospitalized for an acute stroke in an inpatient rehabilitation facility were used for this retrospective study. Admission data from the Functional Independence Measure (FIM) and Simplified Stroke Rehabilitation Assessment of Movement (S-STREAM) were used to determine predictive factors for a community discharge. RESULTS: Logistic regressions and chi-square analyses were used to determine admission factors that predict a community discharge and the cut off score for each predictive variable. The S STREAM, Motor FIM, Total FIM, FIM Bladder, FIM bed transfer, FIM toilet transfer, FIM bathing, and FIM memory were predictive of a community discharge. A predictive tool with a sensitivity and specificity of 76% and 64% was developed using the combined relative risk scores of the S-Stream, FIM Bladder, FIM Bed Transfer and FIM Memory. CONCLUSIONS: By using outcome data at the time of admission, a discharge destination can be predicted for stroke patients with significant sensitivity and specificity. PMID- 26484511 TI - Comparison between treadmill training with rhythmic auditory stimulation and ground walking with rhythmic auditory stimulation on gait ability in chronic stroke patients: A pilot study. AB - BACKGROUND: Generally, treadmill training is very effective intervention, and rhythmic auditory stimulation is designed to feedback during gait training in stroke patients. OBJECTIVE: The purpose of this study was to compare the gait abilities in chronic stroke patients following either treadmill walking training with rhythmic auditory stimulation (TRAS) or over ground walking training with rhythmic auditory stimulation (ORAS). METHODS: Nineteen subjects were divided into two groups: a TRAS group (9 subjects) and an ORAS group (10 subjects). Temporal and spatial gait parameters and motor recovery ability were measured before and after the training period. Gait ability was measured by the Biodex Gait trainer treadmill system, Timed up and go test (TUG), 6 meter walking distance (6MWD) and Functional gait assessment (FGA). RESULTS: After the training periods, the TRAS group showed a significant improvement in walking speed, step cycle, step length of the unaffected limb, coefficient of variation, 6MWD, and, FGA when compared to the ORAS group (p < 0.05). CONCLUSION: Treadmill walking training during the rhythmic auditory stimulation may be useful for rehabilitation of patients with chronic stroke. PMID- 26484510 TI - A double-blinded randomised controlled trial exploring the effect of anodal transcranial direct current stimulation and uni-lateral robot therapy for the impaired upper limb in sub-acute and chronic stroke. AB - BACKGROUND: Neurorehabilitation technologies such as robot therapy (RT) and transcranial Direct Current Stimulation (tDCS) can promote upper limb (UL) motor recovery after stroke. OBJECTIVE: To explore the effect of anodal tDCS with uni lateral and three-dimensional RT for the impaired UL in people with sub-acute and chronic stroke. METHODS: A pilot randomised controlled trial was conducted. Stroke participants had 18 one-hour sessions of RT (ArmeoSpring) over eight weeks during which they received 20 minutes of either real tDCS or sham tDCS during each session. The primary outcome measure was the Fugl-Meyer assessment (FMA) for UL impairments and secondary were: UL function, activities and stroke impact collected at baseline, post-intervention and three-month follow-up. RESULTS: 22 participants (12 sub-acute and 10 chronic) completed the trial. No significant difference was found in FMA between the real and sham tDCS groups at post intervention and follow-up (p = 0.123). A significant 'time' x 'stage of stroke' was found for FMA (p = 0.016). A higher percentage improvement was noted in UL function, activities and stroke impact in people with sub-acute compared to chronic stroke. CONCLUSIONS: Adding tDCS did not result in an additional effect on UL impairment in stroke. RT may be of more benefit in the sub-acute than chronic phase. PMID- 26484512 TI - Prevalence and association of visual functional deficits with lesion characteristics and functional neurological deficits in patients with stroke. AB - BACKGROUND: Stroke frequently induces visual problems, which impair activities of daily living, lead to falls, and require rehabilitation. However, visual dysfunction has not been well characterized in stroke. OBJECTIVE: The purpose of this study was to characterize visual function in patients with stroke and the association of these characteristics with neurological dysfunction and lesion hemisphere. METHODS: In 40 patients with stroke and 321 control subjects, we carried out an assessment of a broad panel of visual and neurological functional metrics to identify risk factors for specific visual impairments in stroke. RESULTS: Patients with stroke exhibited a significantly higher rate of occurrence for impairments in all visual metrics assessed, when compared to healthy controls. Risk for particular visual deficits varied according to lesion side (right versus left hemisphere) and specific types of neurological dysfunction. CONCLUSIONS: Detailed assessment of visual function in patients with stroke can help to clarify the risk of various types of visual impairment. Moreover, as visual function assessment in patients with stroke is difficult, knowledge of the correlation of visual impairments with different neurological dysfunctions observed in stroke and lesion side will help predict vision problems and inform optimal corrective measures in treating patients with stroke. PMID- 26484513 TI - Fatty replacement of rotator cuff in brain-injured patients is associated with hemiplegic arm function, but not with tendon tear: A multicenter study. AB - BACKGROUND: The association between fatty replacement of rotator cuff and hemiplegic upper extremity function has not been defined yet. Moreover, the relationships among rotator cuff tears, shoulder pain, spasticity, and fatty replacement were not clearly studied. OBJECTIVE: We investigated the association of fatty replacement of the supraspinatus and infraspinatus muscles with tendon tear in stroke or brain-injured patients. METHODS: A total of 72 hemiplegic patients were enrolled in 3 hospitals, and ultrasonography of both shoulders was performed once. Fatty replacement of the supraspinatus and infraspinatus was graded by the visibility of outer contours, pennate pattern, central tendon, and echogenicity. RESULTS: Fatty replacement was observed in 22 (30.6%) out of the 72 patients (in 18 supraspinatus muscles and 12 infraspinatus). Inter-rater agreement (kappa value) between the 2 physiatrists was 0.530 for the supraspinatus, and 0.411 for the infraspinatus. The Fugl-Meyer assessment score, Brunnstrom stage, and modified Barthel index were significantly lower in patients with fatty replacement of the supraspinatus or infraspinatus (group 1) than in those without (group 2). The motor power of both shoulders, the pain-free range of motion, spasticity, and hemiplegic shoulder pain were comparable between the two groups. The tear rate of the supraspinatus, infraspinatus, or subscapularis tendon at the hemiplegic side was higher than that at the contralesional side in each group, although there was no significant difference between group 1 and group 2. CONCLUSION: Disuse leading to muscle atrophy rather than rotator cuff tear might be the cause of fatty replacement of these muscles, which may be associated with decreased function of the hemiplegic upper extremities. PMID- 26484514 TI - Language and cognitive communication during post-traumatic amnesia: A critical synthesis. AB - BACKGROUND: There is minimal speech pathology literature on communication presentation during post-traumatic amnesia (PTA) and the early recovery period after traumatic brain injury. While a body of research reports on other cognitive and behavioural functions during PTA, language and/or cognitive communication are not routinely the primary focus of current research literature. OBJECTIVE: This critical synthesis provides an overview of research to date on communication during PTA to inform speech pathology assessment practice and to assist with information provision to the multidisciplinary team and family members. METHODS: A search was conducted of studies reporting on language, cognition, and cognitive communication during the acute, inpatient and early recovery period after TBI. These were examined for relevance to speech pathology practice during PTA and acute confusional state. RESULTS: Historic and recent literature has described types of language and communication impairment during PTA and early recovery after TBI. Recently, aspects of communication impairment during PTA have been found relevant for outcome prediction. Few studies were found originating from speech pathology on communication during PTA. CONCLUSIONS: Communication disruption forms a key feature of PTA. Existing literature indicates that speech pathology monitoring of communication during PTA may be of benefit as part of multidisciplinary team management during early recovery. PMID- 26484515 TI - Return to Learn: A review of cognitive rest versus rehabilitation after sports concussion. AB - BACKGROUND: Cognitive rest is the recommendation for all patients with acute sports concussion. OBJECTIVE/METHODS: A comprehensive literature search was conducted for the research question "What is the optimal cognitive load for patients with a sports concussion?" RESULTS: Seven studies met the inclusion criteria. The optimal cognitive load for patients after sports concussion is yet to be determined. CONCLUSIONS: Additional controlled trials of cognitive rehabilitation are needed to establish best clinical practice. The authors suggest memory training, cognitive behavioral therapy, and environmental interventions as areas of future research for sports concussion injuries. PMID- 26484516 TI - Effects of a Nordic Walking program on motor and non-motor symptoms, functional performance and body composition in patients with Parkinson's disease. AB - BACKGROUND: Several studies have clearly shown that physical exercise can reduce the progression of motor symptoms in Parkinson's Disease (PD). However, little is known about the effects of a Nordic Walking (NW) program in PD patients. OBJECTIVE: To determine the effects of a NW program on motor and non-motor symptoms, functional performances and body composition in PD patients. METHODS: Twenty PD patients (16M, 4F, 67.3+/-7.8 years) were enrolled and randomly assigned to NW group (NWg, n = 10) and Control group (Cg, n = 10). The training consisted in 2 sessions per week for 12 weeks. Training effects were assessed by functional and instrumental tests and motor and non-motor symptoms were assessed by UPDRS-III, Hoehn and Yahr scale, PD Fatigue Scale, Beck Depression Inventory II, Starkstein Apathy Scale, and Non-Motor Symptoms Scale. RESULTS: Significant changes in resting HR, in walked distance (p < 0.05), and in lower limbs muscles strength (p < 0.005) were observed in NWg. Both balance abilities and safety with mobility were increased (p < 0.005). Significant variations in some circumferences and body composition were registered. Finally, a significant improvement in motor and non-motor symptoms was detected: UPDRS-III, HY scale, PFS-16, BDI-II, SAS, NMSS. CONCLUSIONS: A tailored exercise program including NW proved to be an effective way to improve daily activities and both motor and non motor symptoms in PD patients. PMID- 26484517 TI - Is customized vestibular rehabilitation effective in patients with Parkinson's? AB - BACKGROUND: Patients with Parkinson's disease complain about restrictions in their daily life activities and impairment in their mobility and balance. OBJECTIVE: The aim of this study was to compare the effects of vestibular rehabilitation on functioning, quality of life, balance, and postural stability in patients with Parkinson's disease. METHODS: The patients with Parkinson's disease divided into a rehabilitation group (Group 1, n: 29) and a control group(Group 2, n: 11). All patients were evaluated before and after eight weeks of customized vestibular rehabilitation for motor score (Unified Parkinson's Disease Rating Scale); quality of life (Parkinson's Disease Questionnaire-39); balance (Activities-Specific Balance Confidence Scale [ABC], Timed Up and Go Test, Dynamic Gait Index [DGI], and Berg Balance Scale [BBS]); and postural stability (Modified Clinical Test for Sensory Interaction on Balance [mCTSIB]. RESULTS: There were significant differences in the pre- and post-exercise ABC, BBS, and DGI scores in Group 1 (p < 0.05). A statistically significant impairment was observed in mCTSIB (firm and foam eyes closed [EC]) in the control group (p < 0.05). There were no significant intergroup differences in any of the parameters evaluated (p > 0.05). CONCLUSION: In this study, vestibular rehabilitation was found to be effective for improving balance in patients with Parkinson's disease. PMID- 26484518 TI - Immediate effects of adding mental practice to physical practice on the gait of individuals with Parkinson's disease: Randomized clinical trial. AB - BACKGROUND: Mental practice has shown benefits in the rehabilitation of neurological patients, however, there is no evidence of immediate effects on gait of individuals with Parkinson's disease. OBJECTIVE: Determine the effects of mental practice activity added to physical practice on the gait of individuals with Idiopathic Parkinson's Disease (IPD). METHODS: 20 patients classified with stage 2 and 3, according to the Hoehn and Yahr scale were randomized into 2 groups. The experimental group (N = 10) was submitted to a single session of mental practice and physical practice gait protocol and the control group (N = 10) only to physical practice. The primary outcomes were stride length and total stance and swing time. Secondary outcomes were hip range of motion, velocity and mobility. Subjects were reassessed 10 minutes, 1 day and 7 days after the end of the session. RESULTS: There was no statistically significant difference between the groups. An intragroup difference was observed in velocity, stride length, hip range of motion, and mobility, as well as total stance and swing time. These results were also observed on follow-ups. CONCLUSIONS: Mental practice did not have a greater effect on the gait of individuals with IPD than physical practice, after a single session. PMID- 26484519 TI - Efficacy of exercise intervention programs on cognition in people suffering from multiple sclerosis, stroke and Parkinson's disease: A systematic review and meta analysis of current evidence. AB - BACKGROUND: Cognitive impairment is a well-established sequela of people suffering from neurological pathologies. OBJECTIVE: To examine the effects of exercise intervention programs on cognitive performance in participants suffering from stroke, multiple sclerosis and Parkinson's disease. METHODS: Four online databases (CINAHL, Cochrane Library, MEDLINE, PEDro) were comprehensively searched from their inception through December 2014. The search query was phrased as follows: In people suffering from MS, stroke or Parkinson's disease, do exercise intervention programs improve cognitive performance? RESULTS: Twelve controlled clinical trials met our inclusion criteria. Studies were classified according to three clinical subgroups: Parkinson's disease (n = 3), stroke (n = 1) and multiple sclerosis (n = 8). Eight studies employed an aerobic intervention program; one used an active exercise program based on virtual reality systems, three reports examined the effect of yoga and one compared the intervention program with sport climbing. Significant improvements in cognition were found in nine out of the twelve studies. Nevertheless, the total effect size was non significant (0.18 (95% CI, - 4.1, 3.8)) for changes in executive functions. CONCLUSION: Due to lack of commonality between measures of cognition, training sequences and intervention period, it remains unclear as to whether exercise training can be effective in improving the cognitive functions of neurological patients. PMID- 26484520 TI - How various self-reported impairments influence walking ability in persons with late effects of polio. AB - BACKGROUND: Many persons with late effects of polio experience new or increased impairments, which can lead to walking limitations in daily life. No study has comprehensively analyzed how various self-reported impairments are associated with different aspects of self-reported walking limitations. OBJECTIVE: To determine the associations between self-reported impairments and self-reported walking limitations in persons with late effects of polio. METHODS: Three hundred and twenty-five persons (175 women and 150 men) with verified late effects of polio responded to the Self-reported Impairments in Persons with late effects of Polio (SIPP; 13-items) and to the Walking Impact Scale (Walk-12; 12 items). RESULTS: The overall correlation (rho) between the total sum scores of the SIPP and the Walk-12 was 0.61 (p < 0.01). Of the 156 correlation coefficients (SIPP vs Walk-12), 151 (97% ) were significant at the 1% level. Self-reported muscle weakness, muscle fatigue, muscle and/or joint pain during physical activity and general fatigue had the strongest correlations (rho: 0.33 to 0.64) to the self reported walking limitations, whereas memory difficulties, sleep disturbances and concentration difficulties had the weakest correlations (rho: 0.10 to 0.34). CONCLUSION: There are weak to moderate associations between self-reported impairments and walking limitations in persons with late effects of polio. By limiting the impact of those impairments that are strongest associated with walking, clinicians may improve walking ability. However, the strength of the associations implies that other rehabilitation interventions should be considered for improving overall performance in daily activities related to walking. PMID- 26484521 TI - Swallowing function after occipitocervical arthrodesis for cervical deformity in patients with rheumatoid arthritis. AB - BACKGROUND: Some patients develop dysphagia after OC arthrodesis with RA. A previous report has indicated that establishing appropriate occipito-C2 is important for avoiding these side effects. However, a more recent report has demonstrated that the O-C2 angle did not have a significant effect on the incidence of postoperative dysphagia. OBJECTIVE: To investigate the swallowing function of patients with rheumatoid arthritis (RA) before and after they underwent occipitocervical (OC) fusion. METHODS: The study was performed in collaboration with the Departments of Orthopaedic, Otorhinolaryngology, and Rehabilitation. Seven consecutive patients (3 men and 4 women; mean age, 66.4 years) with RA-induced upper cervical deformity were enrolled from 2013 to 2014. The patients underwent deglutition analysis, which was performed by otorhinolaryngologists, before and after surgery, and comprised videofluoroscopy and fiberoptic endoscopy. We examined the relationship between imaging studies and swallowing function. RESULTS: Preoperatively, subjective dysphagia was reported by 2 patients. Videofluoroscopy identified dysmotility of the epiglottis and incomplete closure of the laryngeal inlet in 2 patients, with contrast medium entering the larynx, and endoscopy identified food residue in the larynx of 1 patient during swallowing evaluation. Postoperatively, 2 patients with preoperative impaired deglutition showed dysphagia. Imaging examinations of the 2 patients revealed a 10 degrees -reduction in the O-C2 angle of 1 patient, but the angle was unchanged in the other patient. CONCLUSIONS: To the best of our knowledge, this is the first report to evaluate swallowing function before and after O-C3 arthrodesis. The preoperative O-C2 angle was unchanged after surgery. Impairment of deglutition may be closely associated with air leakage from the oropharynx due to impaired mobility of the soft palate. Because the precise mechanism of dysphagia has not been fully elucidated, further study using dynamic videofluoroscopy and videoendoscopy is needed to examine the swallowing mechanism. PMID- 26484522 TI - Risk of fall (RoF) intervention by affecting visual egocenter through gait analysis and yoked prisms. AB - BACKGROUND: Following a neurologic event such as traumatic brain injury (TBI), cerebrovascular accident (CVA), and chronic neurological conditions including Parkinson's disease, multiple sclerosis, and cerebral palsy a shift in the visual midline (egocenter) can directly affect posture, balance and spatial orientation. As a consequence, this increases the risk of fall (RoF) and injury that imposes a major financial burden on the public health system. OBJECTIVE: To determine if there is a statistically significant change in balance with the intervention of yoked prisms to reduce the risk of fall in subjects with neurological impairments. METHODS: Ambulation of thirty-six subjects was evaluated on a pressure sensitive mat before and after intervention with yoked prisms. Changes in gait and balance were analyzed in the anterior-posterior (AP) and medial lateral (ML) axes during ambulation. RESULTS: T-tests for each measure comparing the difference-of-differences to a zero change at baseline returned statistically significant reductions in both AP (p < 0.0001; 95% CI: 1.368- 2.976) and ML (p = 0.0002; 95% CI: 1.472- 4.173) imbalances using specifically directed yoked prisms to correct the visual midline deviation. CONCLUSION: These findings demonstrate that yoked prisms have the potential to provide a cost-effective means to restore the visual midline thereby improving balance, reduce RoF and subsequent injury. PMID- 26484523 TI - How people with cognitive disabilities experience electronic planning devices. AB - BACKGROUND: People with cognitive disabilities have difficulties in accomplishing everyday tasks. Electronic planning devices (EPDs) may compensate for the gap between a person's capacity and everyday challenges. However, the devices are not always used as intended. Despite that, cognitive assistive technology has been investigated in several studies, knowledge regarding when and what makes adults decide to use EPDs is incomplete. OBJECTIVE: The aim was to explore the subjective experiences of people with cognitive disabilities in relation to the use of EPDs. METHODS: A qualitative approach was applied with a qualitative content analysis. Twelve respondents were interviewed with support from a study specific guide. RESULTS: A model representing the respondents' experiences in the use of EPDs, comprising one theme, Possibility to master my daily life, four categories, Degree of fit to my needs, I am aware of my cognitive disability, I get help to structure my everyday life and The EPD improves my volition and ten subcategories, was developed. CONCLUSIONS: EPDs allow people with cognitive disabilities the possibility to deal with daily challenges; those who find EPDs beneficial tend to use them. EPDs can help people with cognitive disabilities in organisation, managing time and improve volition. PMID- 26484524 TI - Patterns in workplace accommodations for people with multiple sclerosis to overcome cognitive and other disease-related limitations. AB - BACKGROUND: Cognitive symptoms and other functional limitations associated with multiple sclerosis (MS) have a significant negative impact on employment status. Work accommodations positively impact the ability of a person with MS to obtain and retain employment, however, current understanding of the role of accommodations in the careers of adults with MS is limited. OBJECTIVE: To analyze the percentage of American workers with MS who utilize workplace accommodations as per Title I of the ADA, the types of accommodations most frequently required, and differences in disease variables, job-related factors, and quality of life between workers using and not using work accommodations. METHODS: Data from 746 employed adult members of the National MS Society surveyed about career concerns were analyzed. Descriptive and inferential statistics were used as appropriate to address the research questions. RESULTS: Approximately 25% reported having requested accommodations, and 87.7% reported receiving the requested accommodation. Participants with progressive MS, cognitive impairment, higher number of MS symptoms and greater symptom severity were more likely to use work accommodations. Participants with accommodations reported poorer job match and career optimism than those using no accommodations. CONCLUSION: This large-scale analysis addresses several outstanding questions concerning work accommodations among workers with MS. Cognitive symptoms and disease severity are strongly associated with need for accommodations, however accommodations do not appear to promote job satisfaction or longevity. The accommodation request process and the impact of accommodations on employment retention remain important research foci. PMID- 26484525 TI - Activities and interim outcomes of a multi-site development project to promote cognitive support technology use and employment success among postsecondary students with traumatic brain injuries. AB - BACKGROUND: This article describes the activities and interim outcomes of a multi site development project called Project Career, designed to promote cognitive support technology (CST) use and employment success for college and university students with traumatic brain injuries (TBIs). OBJECTIVES: To obtain early intervention results from participants in Project Career's first 18 months of operation. METHODS: Fifty-six students with TBI have participated to date across three implementation sites in Massachusetts, Ohio, and West Virginia, with 25 of these participants being military veterans. Descriptive analyses provide information regarding the participants, the barriers they face due to their TBI in obtaining a post-secondary education, and the impact services provided by Project Career have had to date in ameliorating those difficulties. Inferential statistical analyses provide preliminary results regarding program effectiveness. RESULTS: Preliminary results indicate the program is encouraging students to use CST strategies in the form of iPads and cognitive enhancement applications (also known as 'apps'). Significant results indicate participants are more positive, independent, and social; participants have a more positive attitude toward technology after six months in the program; and participants reported significantly improved experiences with technology during their first six months in the program. CONCLUSION: Participating students are actively preparing for their careers after graduation through a wide range of intensive vocational supports provided by project staff members. PMID- 26484526 TI - Psychological Frailty in the Aging Patient. AB - There is little written in the geriatric literature about the concept of psychological frailty which encompasses cognitive, mood, and motivational components. The concept is intended to consider brain changes that are beyond normal aging, but not necessarily inclusive of disease, that result in decreased cognitive or mood resilience in the presence of modest stressors, and may eventually lead to negative health outcomes in a manner parallel to physical frailty, an entity well known to clinicians. Most work exploring the interface between cognition, mood, and physical frailty has demonstrated a bidirectional association between the two domains. Psychological symptoms or deficits have been described as either worsening the degree of physical frailty, or physical frailty has been viewed as a risk to a worsening cognition or depression. However, psychological frailty, a consequence of age-altered brain function, has not been studied for itself. By what possible mechanism does the brain reveal its loss of resiliency under modest stress and how can this be visualized? Are there markers that predate a psychological decline that might permit a preventive intervention which could delay the appearance of negative health outcomes such as reduced functional capacity or increased dependency? The present review will explore these concepts and possibilities. PMID- 26484527 TI - Proteomics Analysis of Dorsal Striatum Reveals Changes in Synaptosomal Proteins following Methamphetamine Self-Administration in Rats. AB - Methamphetamine is a widely abused, highly addictive drug. Regulation of synaptic proteins within the brain's reward pathway modulates addiction behaviours, the progression of drug addiction and long-term changes in brain structure and function that result from drug use. Therefore, using large scale proteomics studies we aim to identify global protein expression changes within the dorsal striatum, a key brain region involved in the modulation of addiction. We performed LC-MS/MS analyses on rat striatal synaptosomes following 30 days of methamphetamine self-administration (2 hours/day) and 14 days abstinence. We identified a total of 84 differentially-expressed proteins with known roles in neuroprotection, neuroplasticity, cell cytoskeleton, energy regulation and synaptic vesicles. We identify significant expression changes in stress-induced phosphoprotein and tubulin polymerisation-promoting protein, which have not previously been associated with addiction. In addition, we confirm the role of amphiphysin and phosphatidylethanolamine binding protein in addiction. This approach has provided new insight into the effects of methamphetamine self administration on synaptic protein expression in a key brain region associated with addiction, showing a large set of differentially-expressed proteins that persist into abstinence. The mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD001443. PMID- 26484528 TI - Ultrasound-Guided Tissue Core Biopsies in Supraclavicular Lymph Nodes in Patients with Suspected Thoracic Malignancies. AB - BACKGROUND: Supraclavicular (SC) lymph node metastases are important in the analysis of thoracic malignancies for staging as well as for diagnosing purposes. Ultrasound (US) guidance visualises lesions very precisely, enabling tissue biopsies in real-time mode. OBJECTIVES: To report on the diagnostic qualities of SC tissue core biopsies (TCB). METHODS: A retrospective database analysis was performed in TCB performed under US guidance in SC nodes in patients suspected of having a thoracic malignancy. Clinical characteristics and results of diagnostic evaluations were analysed. RESULTS: Between October 2008 and October 2014, 67 sessions for TCB in 65 patients were performed. The diagnostic accuracy of TCB for all diagnoses is 90%, with a sensitivity of 89%. For malignant diagnoses, the sensitivity of US-guided TCB is 93%. In 20 patients, molecular analysis for EGFR and KRAS was performed, with a diagnostic success rate of 95%. One patient suffered a moderate haemorrhage after TCB. CONCLUSION: TCB of SC nodes in the analysis of suspected thoracic malignancy is safe and has a high diagnostic accuracy in determining tumour subtype as well as molecular analysis. PMID- 26484529 TI - Distant Recurrence Risk after Late Ipsilateral Breast Tumor Recurrence: Results of a Retrospective, Single-Institution Study. AB - OBJECTIVES: There is limited information regarding risk factors for distant recurrence in patients with late ipsilateral breast tumor recurrence (IBTR). METHODS: Late IBTR was defined as IBTR occurring >5 years after the initial surgery. Seventy-eight patients with late IBTR were reviewed to examine the risk factors of distant recurrence. RESULTS: The negative estrogen receptor and positive HER2 statuses of IBTR were significantly correlated with poorer distant disease-free survival (p=0.03 and 0.02, respectively). Multivariate analyses demonstrated that the HER2 status of IBTR was an independent predictive factor of distant recurrence (p=0.04). CONCLUSIONS: The results of our retrospective, single-institution study revealed that the HER2 status of IBTR was an independent predictive factor of distant recurrence in patients with late IBTR. PMID- 26484530 TI - Loss of Glycosaminoglycan Receptor Binding after Mosquito Cell Passage Reduces Chikungunya Virus Infectivity. AB - Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that can cause fever and chronic arthritis in humans. CHIKV that is generated in mosquito or mammalian cells differs in glycosylation patterns of viral proteins, which may affect its replication and virulence. Herein, we compare replication, pathogenicity, and receptor binding of CHIKV generated in Vero cells (mammal) or C6/36 cells (mosquito) through a single passage. We demonstrate that mosquito cell-derived CHIKV (CHIKV mos) has slower replication than mammalian cell-derived CHIKV (CHIKV vero), when tested in both human and murine cell lines. Consistent with this, CHIKV mos infection in both cell lines produce less cytopathic effects and reduced antiviral responses. In addition, infection in mice show that CHIKV mos produces a lower level of viremia and less severe footpad swelling when compared with CHIKV vero. Interestingly, CHIKV mos has impaired ability to bind to glycosaminoglycan (GAG) receptors on mammalian cells. However, sequencing analysis shows that this impairment is not due to a mutation in the CHIKV E2 gene, which encodes for the viral receptor binding protein. Moreover, CHIKV mos progenies can regain GAG receptor binding capability and can replicate similarly to CHIKV vero after a single passage in mammalian cells. Furthermore, CHIKV vero and CHIKV mos no longer differ in replication when N-glycosylation of viral proteins was inhibited by growing these viruses in the presence of tunicamycin. Collectively, these results suggest that N-glycosylation of viral proteins within mosquito cells can result in loss of GAG receptor binding capability of CHIKV and reduction of its infectivity in mammalian cells. PMID- 26484531 TI - Investigating the Relationships among Stressors, Stress Level, and Mental Symptoms for Infertile Patients: A Structural Equation Modeling Approach. AB - OBJECTIVE: Patients with infertility are a high risk group in depression and anxiety. However, an existing theoretically and empirically validated model of stressors, stress, and mental symptoms specific for infertile patients is still a void. This study aimed to determine the related factors and their relational structures that affect the level of depressive and anxiety symptoms among infertile patients. METHODS: A cross-sectional sample of 400 infertility outpatients seeking reproduction treatments in three teaching hospitals across Taiwan participated in the structured questionnaire survey in 2011. The hypothesized model comprising 10 latent variables was tested by Structural Equation Modeling using AMOS 17. RESULTS: Goodness-of-fit indexes, including chi2/DF = 1.871, PGFI = 0.746, PNFI = 0.764, and others, confirmed the modified model fit the data well. Marital stressor, importance of children, guilt-and blame, and social stressor showed a direct effect on perceived stress. Instead of being a factor of stress, social support was directly and positively related to self-esteem. Perceived stress and self-esteem were the two major mediators for the relationships between stressors and mental symptoms. Increase in social support and self-esteem led to decrease in mental symptoms among the infertile patients. CONCLUSIONS: The relational structures were identified and named as the Stressors Stress Symptoms Model, clinically applied to predict anxiety and depression from various stressors. Assessing sources and level of infertility related stress and implementing culturally-sensitive counseling with an emphasis on positive personal value may assist in preventing the severity of depression and anxiety. PMID- 26484532 TI - Minimal Internal Radiation Exposure in Residents Living South of the Fukushima Daiichi Nuclear Power Plant Disaster. AB - Following the Fukushima nuclear power plant disaster, assessment of internal radiation exposure was indispensable to predict radiation-related health threats to residents of neighboring areas. Although many evaluations of internal radiation in residents living north and west of the crippled Fukushima nuclear power plant are available, there is little information on residents living in areas south of the plant, which were similarly affected by radio-contamination from the disaster. To assess the internal radio-contamination in residents living in affected areas to the south of the plant or who were evacuated into Iwaki city, a whole body counter (WBC) screening program of internal radio contamination was performed on visitors to the Jyoban hospital in Iwaki city, which experienced less contamination than southern areas adjacent to the nuclear plant. The study included 9,206 volunteer subjects, of whom 6,446 were schoolchildren aged 4-15 years. Measurements began one year after the incident and were carried out over the course of two years. Early in the screening period only two schoolchildren showed Cs-137 levels that were over the detection limit (250 Bq/body), although their Cs-134 levels were below the detection limit (220 Bq/body). Among the 2,760 adults tested, 35 (1.3%) had detectable internal radio contamination, but only for Cs-137 (range: 250 Bq/body to 859 Bq/body), and not Cs-134. Of these 35 subjects, nearly all (34/35) showed elevated Cs-137 levels only during the first year of the screening. With the exception of potassium 40, no other radionuclides were detected during the screening period. The maximum annual effective dose calculated from the detected Cs-137 levels was 0.029 and 0.028 mSv/year for the schoolchildren and adults, respectively, which is far below the 1 mSv/year limit set by the government of Japan. Although the data for radiation exposure during the most critical first year after the incident are unavailable due to a lack of systemic measurements, the present results suggest that internal radio-contamination levels more than one year after the incident were minimal for residents living south of the crippled Fukushima nuclear plant, and that the annual additional effective doses derived from internal Cs contamination were negligible. Thus, internal radio-contamination of residents living in southern radio-contaminated areas appears to be generally well controlled. PMID- 26484533 TI - Prevalence of Naegleria fowleri in Environmental Samples from Northern Part of India. AB - Naegleria fowleri the causative agent of Primary Amoebic Meningoencephalitis, is ubiquitously distributed worldwide in various warm aquatic environments and soil habitats. The present study reports on the presence of Naegleria spp. in various water bodies present in Rohtak and Jhajjar district, of state Haryana, India. A total of 107 water reservoirs were screened from summer till autumn (2012 and 2013). In order to isolate Naegleria spp. from the collected water samples, the water samples were filtered and the trapped debris after processing were transferred to non-nutrient agar plates already seeded with lawn culture of Escherichia coli. Out of total 107 water samples, 43 (40%) samples were positive by culture for free living amoeba after incubation for 14 days at 37 degrees C. To identify the isolates, the ITS1, 5.8SrDNA and ITS2 regions were targeted for PCR assay. Out of total 43 positive samples, 37 isolates were positive for Naegleria spp. using genus specific primers and the most frequently isolated species was Naegleria australiensis. Out of 37 Naegleria spp. positive isolates, 1 isolate was positive for Naegleria fowleri. The sequence analysis revealed that the Naegleria fowleri strain belonged to Type 2. PMID- 26484534 TI - What is the effect of chest physiotherapy in hospitalized children with pneumonia? AB - Chest physiotherapy is applied in clinical practice for the treatment of pneumonia. However, its use is still controversial. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified one systematic review including two relevant randomized controlled trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded it is unclear whether chest physiotherapy increases or decreases the length of hospitalization, severity, or the time to clinical improvement in children with pneumonia because the certainty of the evidence is very low. PMID- 26484535 TI - Using Fluorescent Proteins to Visualize and Quantitate Chlamydia Vacuole Growth Dynamics in Living Cells. AB - The obligate intracellular bacterium Chlamydia elicits a great burden on global public health. C. trachomatis is the leading bacterial cause of sexually transmitted infection and also the primary cause of preventable blindness in the world. An essential determinant for successful infection of host cells by Chlamydia is the bacterium's ability to manipulate host cell signaling from within a novel, vacuolar compartment called the inclusion. From within the inclusion, Chlamydia acquire nutrients required for their 2-3 day developmental growth, and they additionally secrete a panel of effector proteins onto the cytosolic face of the vacuole membrane and into the host cytosol. Gaps in our understanding of Chlamydia biology, however, present significant challenges for visualizing and analyzing this intracellular compartment. Recently, a reverse imaging strategy for visualizing the inclusion using GFP expressing host cells was described. This approach rationally exploits the intrinsic impermeability of the inclusion membrane to large molecules such as GFP. In this work, we describe how GFP- or mCherry-expressing host cells are generated for subsequent visualization of chlamydial inclusions. Furthermore, this method is shown to effectively substitute for costly antibody-based enumeration methods, can be used in tandem with other fluorescent labels, such as GFP-expressing Chlamydia, and can be exploited to derive key quantitative data about inclusion membrane growth from a range of Chlamydia species and strains. PMID- 26484536 TI - Axon Regeneration Is Regulated by Ets-C/EBP Transcription Complexes Generated by Activation of the cAMP/Ca2+ Signaling Pathways. AB - The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. In Caenorhabditis elegans, the JNK and p38 MAPK pathways are important for axon regeneration. Axonal injury induces expression of the svh-2 gene encoding a receptor tyrosine kinase, stimulation of which by the SVH-1 growth factor leads to activation of the JNK pathway. Here, we identify ETS-4 and CEBP-1, related to mammalian Ets and C/EBP, respectively, as transcriptional activators of svh-2 expression following axon injury. ETS-4 and CEBP-1 function downstream of the cAMP and Ca2+-p38 MAPK pathways, respectively. We show that PKA-dependent phosphorylation of ETS-4 promotes its complex formation with CEBP-1. Furthermore, activation of both cAMP and Ca2+ signaling is required for activation of svh-2 expression. Thus, the cAMP/Ca2+ signaling pathways cooperatively activate the JNK pathway, which then promotes axon regeneration. PMID- 26484537 TI - The Distribution and Diversity of Bartonella Species in Rodents and Their Ectoparasites across Thailand. AB - Our study highlights the surveillance of Bartonella species among rodents and their associated ectoparasites (ticks, fleas, lice, and mites) in several regions across Thailand. A total of 619 rodents and 554 pooled ectoparasites (287 mite pools, 62 flea pools, 35 louse pools, and 170 tick pools) were collected from 8 provinces within 4 regions of Thailand. Bandicota indica (279), Rattus rattus (163), and R. exulans (96) were the most prevalent species of rats collected in this study. Real-time PCR assay targeting Bartonella-specific ssrA gene was used for screening and each positive sample was confirmed by PCR using nuoG gene. The prevalence of Bartonella DNA in rodent (around 17%) was recorded in all regions. The highest prevalence of Bartonella species was found in B. savilei and R. rattus with the rate of 35.7% (5/14) and 32.5% (53/163), respectively. High prevalence of Bartonella-positive rodent was also found in B. indica (15.1%, 42/279), and R. norvegicus (12.5%, 5/40). In contrast, the prevalence of Bartonella species in ectoparasites collected from the rats varied significantly according to types of ectoparasites. A high prevalence of Bartonella DNA was found in louse pools (Polyplax spp. and Hoplopleura spp., 57.1%) and flea pools (Xenopsylla cheopis, 25.8%), while a low prevalence was found in pools of mites (Leptotrombidium spp. and Ascoschoengastia spp., 1.7%) and ticks (Haemaphysalis spp., 3.5%). Prevalence of Bartonella DNA in ectoparasites collected from Bartonella-positive rodents (19.4%) was significantly higher comparing to ectoparasites from Bartonella-negative rodents (8.7%). The phylogenetic analysis of 41 gltA sequences of 16 Bartonella isolates from rodent blood and 25 Bartonella-positive ectoparasites revealed a wide range of diversity among Bartonella species with a majority of sequences (61.0%) belonging to Bartonella elizabethae complex (11 rodents, 1 mite pool, and 5 louse pools), while the remaining sequences were identical to B. phoceensis (17.1%, 1 mite pool, 5 louse pools, and 1 tick pool), B. coopersplainensis (19.5%, 5 rodents, 1 louse pool, and 2 tick pools), and one previously unidentified Bartonella species (2.4%, 1 louse pool). PMID- 26484538 TI - The Impact of Different Sources of Fluctuations on Mutual Information in Biochemical Networks. AB - Stochastic fluctuations in signaling and gene expression limit the ability of cells to sense the state of their environment, transfer this information along cellular pathways, and respond to it with high precision. Mutual information is now often used to quantify the fidelity with which information is transmitted along a cellular pathway. Mutual information calculations from experimental data have mostly generated low values, suggesting that cells might have relatively low signal transmission fidelity. In this work, we demonstrate that mutual information calculations might be artificially lowered by cell-to-cell variability in both initial conditions and slowly fluctuating global factors across the population. We carry out our analysis computationally using a simple signaling pathway and demonstrate that in the presence of slow global fluctuations, every cell might have its own high information transmission capacity but that population averaging underestimates this value. We also construct a simple synthetic transcriptional network and demonstrate using experimental measurements coupled to computational modeling that its operation is dominated by slow global variability, and hence that its mutual information is underestimated by a population averaged calculation. PMID- 26484541 TI - Ocean Heat Content Reveals Secrets of Fish Migrations. AB - For centuries, the mechanisms surrounding spatially complex animal migrations have intrigued scientists and the public. We present a new methodology using ocean heat content (OHC), a habitat metric that is normally a fundamental part of hurricane intensity forecasting, to estimate movements and migration of satellite tagged marine fishes. Previous satellite-tagging research of fishes using archival depth, temperature and light data for geolocations have been too coarse to resolve detailed ocean habitat utilization. We combined tag data with OHC estimated from ocean circulation and transport models in an optimization framework that substantially improved geolocation accuracy over SST-based tracks. The OHC-based movement track provided the first quantitative evidence that many of the tagged highly migratory fishes displayed affinities for ocean fronts and eddies. The OHC method provides a new quantitative tool for studying dynamic use of ocean habitats, migration processes and responses to environmental changes by fishes, and further, improves ocean animal tracking and extends satellite-based animal tracking data for other potential physical, ecological, and fisheries applications. PMID- 26484540 TI - Identification of QTLs Conferring Resistance to Deltamethrin in Culex pipiens pallens. AB - Culex pipiens pallens is the most abundant Culex mosquito species in northern China and is an important vector of bancroftian filariasis and West Nile virus. Deltamethrin is an insecticide that is widely used for mosquito control, however resistance to this and other insecticides has become a major challenge in the control of vector-borne diseases that appear to be inherited quantitatively. Furthermore, the genetic basis of insecticide resistance remains poorly understood. In this study, quantitative trait loci (QTL) mapping of resistance to deltamethrin was conducted in F2 intercross segregation populations using bulked segregation analysis (BSA) and amplified fragment length polymorphism markers (AFLP) in Culex pipiens pallens. A genetic linkage map covering 381 cM was constructed and a total of seven QTL responsible for resistance to deltamethrin were detected by composite interval mapping (CIM), which explained 95% of the phenotypic variance. The major QTL in linkage group 2 accounted for 62% of the variance and is worthy of further study. 12 AFLP markers in the map were cloned and the genomic locations of these marker sequences were determined by applying the Basic Local Alignment Search Tool (BLAST) tool to the genome sequence of the closely related Culex quinquefasciatus. Our results suggest that resistance to deltamethrin is a quantitative trait under the control of a major QTL in Culex pipiens pallens. Cloning of related AFLP markers confirm the potential utility for anchoring the genetic map to the physical map. The results provide insight into the genetic architecture of the trait. PMID- 26484539 TI - Dissociation of Tissue Destruction and Bacterial Expansion during Bubonic Plague. AB - Activation and/or recruitment of the host plasmin, a fibrinolytic enzyme also active on extracellular matrix components, is a common invasive strategy of bacterial pathogens. Yersinia pestis, the bubonic plague agent, expresses the multifunctional surface protease Pla, which activates plasmin and inactivates fibrinolysis inhibitors. Pla is encoded by the pPla plasmid. Following intradermal inoculation, Y. pestis has the capacity to multiply in and cause destruction of the lymph node (LN) draining the entry site. The closely related, pPla-negative, Y. pseudotuberculosis species lacks this capacity. We hypothesized that tissue damage and bacterial multiplication occurring in the LN during bubonic plague were linked and both driven by pPla. Using a set of pPla-positive and pPla-negative Y. pestis and Y. pseudotuberculosis strains in a mouse model of intradermal injection, we found that pPla is not required for bacterial translocation to the LN. We also observed that a pPla-cured Y. pestis caused the same extensive histological lesions as the wild type strain. Furthermore, the Y. pseudotuberculosis histological pattern, characterized by infectious foci limited by inflammatory cell infiltrates with normal tissue density and follicular organization, was unchanged after introduction of pPla. However, the presence of pPla enabled Y. pseudotuberculosis to increase its bacterial load up to that of Y. pestis. Similarly, lack of pPla strongly reduced Y. pestis titers in LNs of infected mice. This pPla-mediated enhancing effect on bacterial load was directly dependent on the proteolytic activity of Pla. Immunohistochemistry of Pla negative Y. pestis-infected LNs revealed extensive bacterial lysis, unlike the numerous, apparently intact, microorganisms seen in wild type Y. pestis-infected preparations. Therefore, our study demonstrates that tissue destruction and bacterial survival/multiplication are dissociated in the bubo and that the primary action of Pla is to protect bacteria from destruction rather than to alter the tissue environment to favor Y. pestis propagation in the host. PMID- 26484542 TI - Asymptomatic Carotid Stenosis: Risk of Progression and Development of Symptoms. AB - BACKGROUND: The aim of this study is to evaluate the rate of progression of stenosis and development of symptoms in patients with asymptomatic carotid artery stenosis (aCAS) treated with contemporary medical therapy over a prolonged time interval. METHODS: This study is a retrospective review of consecutive patients diagnosed with moderate or severe aCAS at our institution between 2000 and 2001. Data were gathered from both carotid arteries for each patient excluding vessels operated within 1 year of diagnosis and occlusions. Multivariate analysis was performed to analyze factors associated with ipsilateral transient ischemic attack (TIA)/stroke. RESULTS: We identified 214 patients (58.8% men; median age 70 years) and collected data on 349 vessels. Degree of stenosis was severe (>70%) upon diagnosis in 92 (26.4%) vessels. Median length of follow-up was 13 years (interquartile range 10-14), and mean number of time points for follow-up imaging were 8.1 +/- 3.9. Progression of stenosis was observed in 237 (67.9%) vessels, and 72 (20.6%) patients developed symptoms ipsilateral to the stenosis (TIA in 14.4%, non-disabling stroke in 4%, disabling stroke in 2.2%). Median time to appearance of first symptom was 6 years (range 1-13). On multivariate analysis, degree of baseline stenosis, intracranial stenosis >50%, plaque ulceration, silent infarction and previous history of TIA/stroke were associated with ipsilateral TIA/stroke, but progression of stenosis was not. CONCLUSIONS: There was a substantial rate of progression of stenosis in patients with aCAS over time despite adequate medical therapy, but progression of stenosis did not increase the risk of ipsilateral TIA/stroke. Over long-term follow-up, 1 in 5 patients with aCAS developed ipsilateral TIA/stroke, though most events were either transient or non-disabling. PMID- 26484543 TI - Yield Gap, Indigenous Nutrient Supply and Nutrient Use Efficiency for Maize in China. AB - Great achievements have been attained in agricultural production of China, while there are still many difficulties and challenges ahead that call for put more efforts to overcome to guarantee food security and protect environment simultaneously. Analyzing yield gap and nutrient use efficiency will help develop and inform agricultural policies and strategies to increase grain yield. On-farm datasets from 2001 to 2012 with 1,971 field experiments for maize (Zea mays L.) were collected in four maize agro-ecological regions of China, and the optimal management (OPT), farmers' practice (FP), a series of nutrient omission treatments were used to analyze yield gap, nutrient use efficiency and indigenous nutrient supply by adopting meta-analysis and ANOVA analysis. Across all sites, the average yield gap between OPT and FP was 0.7 t ha-1, the yield response to nitrogen (N), phosphorus (P), and potassium (K) were 1.8, 1.0, and 1.2 t ha-1, respectively. The soil indigenous nutrient supply of N, P, and K averaged 139.9, 33.7, and 127.5 kg ha-1, respectively. As compared to FP, the average recovery efficiency (RE) of N, P, and K with OPT increased by percentage point of 12.2, 5.5, and 6.5, respectively. This study indicated that there would be considerable potential to further improve yield and nutrient use efficiency in China, and will help develop and inform agricultural policies and strategies, while some management measures such as soil, plant and nutrient are necessary and integrate with advanced knowledge and technologies. PMID- 26484544 TI - Evaluating Subcriticality during the Ebola Epidemic in West Africa. AB - The 2014-2015 Ebola outbreak is the largest and most widespread to date. In order to estimate ongoing transmission in the affected countries, we estimated the weekly average number of secondary cases caused by one individual infected with Ebola throughout the infectious period for each affected West African country using a stochastic hidden Markov model fitted to case data from the World Health Organization. If the average number of infections caused by one Ebola infection is less than 1.0, the epidemic is subcritical and cannot sustain itself. The epidemics in Liberia and Sierra Leone have approached subcriticality at some point during the epidemic; the epidemic in Guinea is ongoing with no evidence that it is subcritical. Response efforts to control the epidemic should continue in order to eliminate Ebola cases in West Africa. PMID- 26484545 TI - Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC). AB - Renal cell carcinoma (RCC) is diagnosed in >200,000 individuals worldwide each year, accounting for ~2% of all cancers, but the spread of this disease amongst genders is distinctly uneven. In the U.S. the male:female incidence ratio is approximately 2:1. A potential hypothesis is mutation spectra may differ between tumors dependent upon the gender of the patient, such as mutations of X chromosome encoded genes being more prevalent in male-derived tumors. Combined analysis of three recent large-scale clear cell renal cell carcinoma (CCRCC) mutation sequencing projects identified a significantly increased mutation frequency of PBRM1 and the X chromosome encoded KDM5C in tumors from male patients and BAP1 in tumors from female patients. Mutation of BAP1 had previously been significantly associated with poorer overall survival; however, when stratified by gender, mutation of BAP1 only significantly affected overall survival in female patients. Mutation of chromatin remodeling genes alters gene regulation, but the overall effect of these alterations may also be modified by the presence of other gender specific factors. Thus, the combination of gender and mutation of a specific gene, such as BAP1, may have implications not only for prognosis but also for understanding the role of chromatin remodeling gene mutations in kidney cancer progression. PMID- 26484546 TI - The Direct Interaction between Two Morphogenetic Proteins Is Essential for Spore Coat Formation in Bacillus subtilis. AB - In Bacillus subtilis the protective layers that surround the mature spore are formed by over seventy different proteins. Some of those proteins have a regulatory role on the assembly of other coat proteins and are referred to as morphogenetic factors. CotE is a major morphogenetic factor, known to form a ring around the forming spore and organize the deposition of the outer surface layers. CotH is a CotE-dependent protein known to control the assembly of at least nine other coat proteins. We report that CotH also controls the assembly of CotE and that this mutual dependency is due to a direct interaction between the two proteins. The C-terminal end of CotE is essential for this direct interaction and CotH cannot bind to mutant CotE deleted of six or nine C-terminal amino acids. However, addition of a negatively charged amino acid to those deleted versions of CotE rescues the interaction. PMID- 26484548 TI - Correction: The Association between Polyclonal Combined Serum Free Light Chain Concentration and Mortality in Individuals with Early Chronic Kidney Disease. PMID- 26484547 TI - Genotypic and Phenotypic Heterogeneity in Alicyclobacillus acidoterrestris: A Contribution to Species Characterization. AB - Alicyclobacillus acidoterrestris is the main cause of most spoilage problems in fruit juices and acidic products. Since soil borne species often contaminate fruit juices and do not need strict extreme requirements for survival, it is a great concern to investigate whether and how soil species could evolve from their ecological niches in microbial community to new environments as fruit juices. In this study, 23 isolates of thermo-acidophilic, spore-forming bacteria from soil were characterized by cultural and molecular methods. In addition, 2 strains isolated from a spoilage incident in pear juice were typed. Strains phenotyping showed that they could be grouped into 3 different clusters, and some isolates showed identical or quite similar patterns. Analyzing pH and temperature ranges for growth, the majority of strains were able to grow at values described for many species of Alicyclobacillus. Qualitative utilization of lysine, arginine and indole production from tryptophan revealed, for the first time, deamination of lysine and decarboxylation of arginine. Resistance to 5% NaCl as well as the ability to hydrolyze starch and gelatin, nitrate reduction, catalase and oxidase activities confirmed literature evidences. Examining of 16S rRNA, showed that isolates were divided into three blocks represented by effectively soil species and strains that are moving from soil to other possible growing source characterized by parameters that could strongly influence bacterial survival. RAPD PCR technique evidenced a great variability in banding patterns and, although it was not possible to obtain genotypically well-distinguished groups, it was feasible to appreciate genetic similarity between some strains. In conclusion, the investigation of a microbial community entails a combination of metagenomic and classic culture-dependent approaches to expand our knowledge about Alicyclobacillus and to look for new subspecies. PMID- 26484549 TI - Molecular Epidemiology of Hospital Outbreak of Middle East Respiratory Syndrome, Riyadh, Saudi Arabia, 2014. AB - We investigated an outbreak of Middle East respiratory syndrome (MERS) at King Fahad Medical City (KFMC), Riyadh, Saudi Arabia, during March 29-May 21, 2014. This outbreak involved 45 patients: 8 infected outside KFMC, 13 long-term patients at KFMC, 23 health care workers, and 1 who had an indeterminate source of infection. Sequences of full-length MERS coronavirus (MERS-CoV) from 10 patients and a partial sequence of MERS-CoV from another patient, when compared with other MERS-CoV sequences, demonstrated that this outbreak was part of a larger outbreak that affected multiple health care facilities in Riyadh and possibly arose from a single zoonotic transmission event that occurred in December 2013 (95% highest posterior density interval November 8, 2013-February 10, 2014). This finding suggested continued health care-associated transmission for 5 months. Molecular epidemiology documented multiple external introductions in a seemingly contiguous outbreak and helped support or refute transmission pathways suspected through epidemiologic investigation. PMID- 26484550 TI - A method to visualize transdermal nickel permeation in mouse skin using a nickel allergy patch. AB - Metal patch test is often used in clinical settings when metal-induced contact dermatitis is suspected. However, the transdermal permeation behavior of metal ions from the patch test remains unclear. Current patch tests using high concentrations of metal salt solutions have some side effects, e.g. acute skin reactions to high concentrations of metal salt. To resolve these, estimating metal ion transdermal permeation is wished. In this study, synchrotron radiation X-ray fluorescence (SR-XRF) and micro-focused particle-induced X-ray emission (micro-PIXE) were used to visualize the time-dependent Ni permeation in mouse skin. The cross-sectional diffusion of Ni was visualized in a time-dependent manner. Our results indicate that maximum Ni permeation occurs after 24 h of patch treatment, and the permeated Ni content was high in the epidermis and spread into the dermis beyond the basal layer. This method may be useful to determine the appropriate solution concentration and duration of administration for the patch test. PMID- 26484551 TI - In vivo evaluation of a Ti-based bulk metallic glass alloy bar. AB - Ti-based bulk metallic glasses are reported with high strength, low Young modulus and high corrosion resistance, suggesting their potentials in biomedical applications. However a thorough in vivo evaluation of its biocompatibilities has not been conducted yet. In this study, we implanted bars of Ti-based bulk metallic glass in the femoral bone of rats, followed up local tissue reaction as well as its component ions' diffusion in local area and whole body. The Ti-based BMG (Ti40Zr10Cu34Pd14Sn2) alloy exhibited favorable features of both high strength and high elasticity. In vivo implant evaluation showed that it has a good tissue compatibility, equivalent bone integration and bonding ability with Ti sample. No component ion diffusion was detected up to 3 months post implantation. The possibility and efficacy of its use for bone implant is confirmed. Thus further long term implant study is recommended. PMID- 26484552 TI - Preparation of decellularized vascular matrix by co-crosslinking of procyanidins and glutaraldehyde. AB - BACKGROUND: Vascular extracellular matrices (vECMs) have shown potential for small-diameter blood vessel tissue engineering applications. However, problems such as chemical instability and easy calcification are still remained. Chemical crosslinking using crosslinkers such as glutaraldehyde (GA) can improve mechanical properties and proteolysis resistance of vECMs, but leads to calcification and cytotoxicity. Procyanidins (PC) can crosslink ECMs with anti calcification property and cytocompatibility, but the mechanical properties and chemical stability are unsatisfactory. OBJECTIVE: A novel co-crosslinking technique using PC and GA was developed, which combines the advantages of both PC and GA for enhancing mechanical properties and stability of vECMs with reduced calcification and cytotoxicity. METHODS: Fresh carotid were decellularized and then crosslinked by PC and subsequent GA for 6 h respectively. The mechanical properties, dynamic release of PC, enzymatic degradation, calcification and cytotoxicity of crosslinked samples were evaluated. RESULTS: The co-crosslinked vECMs showed enhanced tensile strength, chemical and biological stability, comparable anti-calcification property as compared to pure PC-crosslinked samples. Cytotoxicity assay showed that the co-crosslinked vECMs were cytocompatible for supporting the adhesion and proliferation of HUVECs. CONCLUSIONS: Co-crosslinking with PC and GA might be a useful method for preparation of vECM scaffolds with potential applications in small-diameter blood vessel tissue engineering. PMID- 26484553 TI - Biocompatibility of hydroxyapatite scaffolds processed by lithography-based additive manufacturing. AB - The fabrication of hydroxyapatite scaffolds for bone tissue engineering applications by using lithography-based additive manufacturing techniques has been introduced due to the abilities to control porous structures with suitable resolutions. In this research, the use of hydroxyapatite cellular structures, which are processed by lithography-based additive manufacturing machine, as a bone tissue engineering scaffold was investigated. The utilization of digital light processing system for additive manufacturing machine in laboratory scale was performed in order to fabricate the hydroxyapatite scaffold, of which biocompatibilities were eventually evaluated by direct contact and cell-culturing tests. In addition, the density and compressive strength of the scaffolds were also characterized. The results show that the hydroxyapatite scaffold at 77% of porosity with 91% of theoretical density and 0.36 MPa of the compressive strength are able to be processed. In comparison with a conventionally sintered hydroxyapatite, the scaffold did not present any cytotoxic signs while the viability of cells at 95.1% was reported. After 14 days of cell-culturing tests, the scaffold was able to be attached by pre-osteoblasts (MC3T3-E1) leading to cell proliferation and differentiation. The hydroxyapatite scaffold for bone tissue engineering was able to be processed by the lithography-based additive manufacturing machine while the biocompatibilities were also confirmed. PMID- 26484554 TI - Mechanical behavior and blood compatibility of copper-containing films as potential biomaterials. AB - Surface modification is one approach to enhance the biocompatibility of implanted cardiovascular devices. In this work, a copper-containing film used to blood contacted biomaterials was prepared by vacuum arc deposition. The phase composition of the films was investigated via X-ray diffraction, and the adherence strength of the films was evaluated with conventional deformation tests. Blood compatibility of the films was characterized by hemolysis ratio, clotting time and platelet adhesion etc. The surface of inferior vena cava filters were smooth and uniform, no cracks or delaminations were observed on the deformed surface. These results indicate that the mechanical behavior of the films is suitable for withstanding deformation stresses as operation in clinic. Good blood compatibility of the copper-containing films was identified through experiment in vitro, the activated partial thromboplastin times (APTTs) of Cu/Ti films were similar to that of the uncoated substrate, and Cu/Ti films were also found to inhibit platelet adhesion comparing to the nitinol substrate. However, with increasing ratio of Cu/Ti, the hemolysis ratio increased, resulting in platelet damage. These results indicate that the copper-containing film has potential application on blood contacted devices. PMID- 26484555 TI - Adaptive learning based heartbeat classification. AB - Cardiovascular diseases (CVD) are a leading cause of unnecessary hospital admissions as well as fatalities placing an immense burden on the healthcare industry. A process to provide timely intervention can reduce the morbidity rate as well as control rising costs. Patients with cardiovascular diseases require quick intervention. Towards that end, automated detection of abnormal heartbeats captured by electronic cardiogram (ECG) signals is vital. While cardiologists can identify different heartbeat morphologies quite accurately among different patients, the manual evaluation is tedious and time consuming. In this chapter, we propose new features from the time and frequency domains and furthermore, feature normalization techniques to reduce inter-patient and intra-patient variations in heartbeat cycles. Our results using the adaptive learning based classifier emulate those reported in existing literature and in most cases deliver improved performance, while eliminating the need for labeling of signals by domain experts. PMID- 26484556 TI - Development of phantom for quantitative analyses of human dentin mineral density. AB - The purpose of the present study was to develop a novel-designed phantom that could be scanned with a sample in the same image, that specialize for quantitative analyses of human dentin mineral density using the X-ray attenuation method. A further attempt was made to demonstrate the intracoronal dentin mineral density using this phantom in mandibular incisors. The phantom prepared with a 15 mm hole in the center of an acrylic resin bar having an outside diameter of 25 mm and 8 small holes (diameter, 3 mm) were made at equal intervals around the center. Liquid dipotassium hydrogen phosphate (K2HPO4) solutions were established at 0.4, 0.6, 0.8 and 1.0 g/cm3, and were arranged to these holes. The mean value of the intracoronal dentin mineral density was 1.486 +/- 0.016 g/cm3 in the present study. As the results of the present study corresponded to previous reports, this new phantom was considered to be useful. This phantom enables the analysis of samples that are not readily available by conventional mechanical tests and may facilitate biomechanical investigations using X-ray images. It was suggested that this system is a simple, accurate and novel mineralization measuring system. PMID- 26484557 TI - Reliability performance of titanium sputter coated Ni-Ti arch wires: mechanical performance and nickel release evaluation. AB - The present research was aimed at developing surface coatings on NiTi archwires capable of protection against nickel release and to investigate the stability, mechanical performance and prevention of nickel release of titanium sputter coated NiTi arch wires. Coated and uncoated specimens immersed in artificial saliva were subjected to critical evaluation of parameters such as surface analysis, mechanical testing, element release, friction coefficient and adhesion of the coating. Titanium coatings exhibited high reliability on exposure even for a prolonged period of 30 days in artificial saliva. The coatings were found to be relatively stable on linear scratch test with reduced frictional coefficient compared to uncoated samples. Titanium sputtering adhered well with the Ni-Ti substrates at the molecular level, this was further confirmed by Inductive coupled plasma emission spectroscopy (ICPE) analysis which showed no dissolution of nickel in the artificial saliva. Titanium sputter coatings seem to be promising for nickel sensitive patients. The study confirmed the superior nature of the coating, evident as reduced surface roughness, friction coefficient, good adhesion and minimal hardness and elastic modulus variations in artificial saliva over a given time period. PMID- 26484559 TI - Wear in ceramic on ceramic type lumbar total disc replacement: effect of radial clearance. AB - The wear of the bearing surfaces of total disc replacement (TDR) is a key problem leads to reduction in the lifetime of the prosthesis and it mainly occurs due to the range of clearances of the articulating surface between the superior plate and core. The objective of this paper is to estimate the wear using finite element concepts considering the different radial clearances between the articulating surfaces of ceramic on ceramic type Lumbar Total Disc Replacement (LTDR). The finite element (FE) model was subjected to wear testing protocols according to loading profile of International Standards Organization (ISO) 18192 standards through 10 million cycles. The radial clearance value of 0.05 mm showed less volumetric wear when compared with other radial clearance values. Hence, low radial clearance values are suitable for LTDR to minimize the wear. PMID- 26484558 TI - Safety and efficacy of a novel iopromide-based paclitaxel-eluting balloon following bare metal stent implantation in rabbit aorta abdominalis. AB - BACKGROUND: Drug-eluting balloons (DEB) may be promising technology for treating atherosclerotic arterial disease. In fact, several DEBs have been clinically available for the treatment of coronary in-stent restenosis (ISR), de novo coronary lesions, and peripheral artery disease. OBJECTIVE: We sought to elucidate the mechanism of action and in vivo safety and efficacy of a novel iopromide-based paclitaxel-eluting balloon. METHODS: In vitro cytotoxicity of a novel DEB on human umbilical vein endothelial cells (HUVECs) and in vivo pharmacokinetics of DEB in a rabbit aorta abdominalis were assessed. Then, bare metal stents (BMS) were implanted at both the proximal and distal sites of the rabbit aorta abdominalis. Stented vascular segments were immediately dilated with a bare balloon (control group) or the DEB (DEB group) randomly. Histological evaluation was performed in all treated segments at 28 days. Because paclitaxel is a tubulin-disrupting agent that binds preferentially to beta-tubulin, we measured beta-tubulin expression in aortal stent specimens via immunohistochemistry. RESULTS: We observed that DEB was compatible and could reduce neointimal hyperplasia compared with the bare balloon. Meanwhile, immunohistochemistry revealed that beta-tubulin expression in the DEB group increased compared with the control group, indirectly suggesting successful uptake of paclitaxel by vessel walls after DEB dilation. CONCLUSIONS: The novel DEB is safe and has a favorable vascular healing response on neointimal hyperplasia. PMID- 26484560 TI - The Competition between Elimination Pathways in the Reactions of a Wide Variety of Bases with 2-Fluoro- and 2-Chlorobutane in the Gas Phase. AB - Ab initio methods are used to examine the regio- and stereoselectivities of the elimination reactions of 2-fluorobutane and 2-chlorobutane with a series of nucleophiles (F(-), HO(-), CH3O(-), (CH3)3CO(-), NH2(-), CH3(-), H(-), Cl(-), HS( ), and PH2(-)). The data suggest that regiochemistry is most closely related to the nature of the transition state on the E2 spectrum with E1cb-like reactions favoring the least-substituted alkene product and E1-like reactions favoring the most-substituted alkene product. There appears to be no correlation between the extent of pi-bond formation (as measured by the Calpha-Cbeta distance) and the preference for forming the more highly substituted alkene. The stereochemistry (E vs Z) is less sensitive to the nucleophile and is relatively constant with the exception of a few systems that appear to have long-range interactions that reduce the bias against the Z product. Comparisons with experimental results in solution show, with a few exceptions, similar reactivity trends in solution and the gas phase. PMID- 26484561 TI - Synthesis and Characterization of High c-axis ZnO Thin Film by Plasma Enhanced Chemical Vapor Deposition System and its UV Photodetector Application. AB - In this study, zinc oxide (ZnO) thin films with high c-axis (0002) preferential orientation have been successfully and effectively synthesized onto silicon (Si) substrates via different synthesized temperatures by using plasma enhanced chemical vapor deposition (PECVD) system. The effects of different synthesized temperatures on the crystal structure, surface morphologies and optical properties have been investigated. The X-ray diffraction (XRD) patterns indicated that the intensity of (0002) diffraction peak became stronger with increasing synthesized temperature until 400 (o)C. The diffraction intensity of (0002) peak gradually became weaker accompanying with appearance of (10-10) diffraction peak as the synthesized temperature up to excess of 400 (o)C. The RT photoluminescence (PL) spectra exhibited a strong near-band-edge (NBE) emission observed at around 375 nm and a negligible deep-level (DL) emission located at around 575 nm under high c-axis ZnO thin films. Field emission scanning electron microscopy (FE-SEM) images revealed the homogeneous surface and with small grain size distribution. The ZnO thin films have also been synthesized onto glass substrates under the same parameters for measuring the transmittance. For the purpose of ultraviolet (UV) photodetector application, the interdigitated platinum (Pt) thin film (thickness ~100 nm) fabricated via conventional optical lithography process and radio frequency (RF) magnetron sputtering. In order to reach Ohmic contact, the device was annealed in argon circumstances at 450 (o)C by rapid thermal annealing (RTA) system for 10 min. After the systematic measurements, the current-voltage (I-V) curve of photo and dark current and time-dependent photocurrent response results exhibited a good responsivity and reliability, indicating that the high c axis ZnO thin film is a suitable sensing layer for UV photodetector application. PMID- 26484562 TI - Optimizing Photovoltaic Response by Tuning Light-Harvesting Nanocrystal Shape Synthesized Using a Quick Liquid-Gas Phase Reaction. AB - The electron recombination lifetime in a sensitized semiconductor assembly is greatly influenced by the crystal structure and geometric form of the light harvesting semiconductor nanocrystal. When such light harvesters with varying structural characteristics are configured in a photoanode, its interface with the electrolyte becomes equally important and directly influences the photovoltaic efficiency. We have systematically probed here the influence of nanocrystal crystallographic structure and shape on the electron recombination lifetime and its eventual influence on the light to electricity conversion efficiency of a liquid junction semiconductor sensitized solar cell. The light-harvesting cadmium sulfide (CdS) nanocrystals of distinctly different and controlled shapes are obtained using a novel and simple liquid-gas phase synthesis method performed at different temperatures involving very short reaction times. High-resolution synchrotron X-ray diffraction and spectroscopic studies respectively exhibit different crystallographic phase content and optical properties. When assembled on a mesoscopic TiO2 film by a linker molecule, they exhibit remarkable variation in electron recombination lifetime by 1 order of magnitude, as determined by ac impedance spectroscopy. This also drastically affects the photovoltaic efficiency of the differently shaped nanocrystal sensitized solar cells. PMID- 26484563 TI - Determining Parameters and Mechanisms of Colloid Retention and Release in Porous Media. AB - A modeling framework is presented to determine fundamental parameters and controlling mechanisms of colloid (microbes, clays, and nanoparticles) retention and release on surfaces of porous media that exhibit wide distributions of nanoscale chemical heterogeneity, nano- to microscale roughness, and pore water velocity. Primary and/or secondary minimum interactions in the zone of electrostatic influence were determined over the heterogeneous solid surface. The Maxwellian kinetic energy model was subsequently employed to determine the probability of immobilization and diffusive release of colloids from each of these minima. In addition, a balance of applied hydrodynamic and resisting adhesive torques was conducted to determine locations of immobilization and hydrodynamic release in the presence of spatially variable water flow and microscopic roughness. Locations for retention had to satisfy both energy and torque balance conditions for immobilization, whereas release could occur either due to diffusion or hydrodynamics. Summation of energy and torque balance results over the elementary surface area of the porous medium provided estimates for colloid retention and release parameters that are critical to predicting environmental fate, including the sticking and release efficiencies and the maximum concentration of retained colloids on the solid phase. Nanoscale roughness and chemical heterogeneity produced localized primary minimum interactions that controlled long-term retention, even when mean chemical conditions were unfavorable. Microscopic roughness played a dominant role in colloid retention under low ionic strength and high hydrodynamic conditions, especially for larger colloids. PMID- 26484564 TI - Probing the Structure, Pseudorotation, and Radial Vibrations of Cyclopentane by Femtosecond Rotational Raman Coherence Spectroscopy. AB - Femtosecond time-resolved Raman rotational coherence spectroscopy (RCS) is employed to determine accurate rotational, vibration-rotation coupling constants, and centrifugal distortion constants of cyclopentane (C5H10). Its lowest frequency vibration is a pseudorotating ring deformation that interconverts 10 permutationally distinct but energetically degenerate "twist" minima interspersed by 10 "bent" conformers. While the individual twist and bent structures are polar asymmetric tops, the pseudorotation is fast on the time scale of external rotation, rendering cyclopentane a fluxionally nonpolar symmetric top molecule. The pseudorotational level pattern corresponds to a one-dimensional internal rotor with a pseudorotation constant Bps ~ 2.8 cm(-1). The pseudorotational levels are significantly populated up to l = +/- 13 at 298 K; <10% of the molecules are in the l = 0 level. The next-higher vibration is the "radial" nu23 ring deformation mode at 273 cm-1, which is far above the pseudorotational fundamental. Femtosecond Raman RCS measurements were performed in a gas cell at T = 293 K and in a pulsed supersonic jet at T ~ 90 K. The jet cooling reduces the pseudorotational distribution to l < +/-8 and eliminates the population of nu23, allowing one to determine the rotational constant as A0 = B0 = 6484.930(11) MHz. This value is ~300 times more precise than the previous value. The fit of the RCS transients reveals that the rotation-pseudorotation coupling constant alphae,psB = -0.00070(1) MHz is diminutive, implying that excitation of the pseudorotation has virtually no effect on the B0 rotational constant of cyclopentane. The smallness of alphae,psB can be realized when comparing to the vibration-rotation coupling constant of the nu23 vibration, alphae,23B = -9.547(1) MHz, which is about 104 times larger. PMID- 26484565 TI - Wnt2 complements Wnt/beta-catenin signaling in colorectal cancer. AB - Wnt2 is implicated in various human cancers. However, it remains unknown how Wnt2 is upregulated in human cancer and contributes to tumorigenesis. Here we found that Wnt2 is highly expressed in colorectal cancer (CRC) cells. In addition to co expression of Wnt2 with Wnt/beta-catenin target genes in CRC, knockdown or knockout of Wnt2 significantly downregulates Wnt/beta-catenin target gene expression in CRC cells. Importantly, depletion or ablation of endogenous Wnt2 inhibits CRC cell proliferation. Similarly, neutralizing secreted Wnt2 reduces Wnt target gene expression and suppresses CRC cell proliferation. Conversely, Wnt2 increases cell proliferation of intestinal epithelial cells. Intriguingly, WNT2 expression is transcriptionally silenced by EZH2-mediated H3K27me3 histone modification in non-CRC cells, However, WNT2 expression is de-repressed by the loss of PRC2's promoter occupancy in CRC cells. Our results reveal the unexpected roles of Wnt2 in complementing Wnt/beta-catenin signaling for CRC cell proliferation. PMID- 26484566 TI - Targeting metabolic flexibility by simultaneously inhibiting respiratory complex I and lactate generation retards melanoma progression. AB - Melanoma is a largely incurable skin malignancy owing to the underlying molecular and metabolic heterogeneity confounded by the development of resistance. Cancer cells have metabolic flexibility in choosing either oxidative phosphorylation (OXPHOS) or glycolysis for ATP generation depending upon the nutrient availability in tumor microenvironment. In this study, we investigated the involvement of respiratory complex I and lactate dehydrogenase (LDH) in melanoma progression. We show that inhibition of complex I by metformin promotes melanoma growth in mice via elevating lactate and VEGF levels. In contrast, it leads to the growth arrest in vitro because of enhanced extracellular acidification as a result of increased glycolysis. Inhibition of LDH or lactate generation causes decrease in glycolysis with concomitant growth arrest both in vitro and in vivo. Blocking lactate generation in metformin-treated melanoma cells results in diminished cell proliferation and tumor progression in mice. Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inhibiting both together causes depletion in cellular ATP pool resulting in metabolic catastrophe induced apoptosis. Overall, our study suggests that LDH and complex I play distinct roles in regulating glycolysis and cell proliferation. Inhibition of these two augments synthetic lethality in melanoma. PMID- 26484567 TI - Honokiol inhibits bladder tumor growth by suppressing EZH2/miR-143 axis. AB - The oncoprotein EZH2, as a histone H3K27 methyltransferase, is frequently overexpressed in various cancer types. However, the mechanisms underlying its role in urinary bladder cancer (UBC) cells have not yet fully understood. Herein, we reported that honokiol, a biologically active biphenolic compound isolated from the Magnolia officinalis inhibited human UBC cell proliferation, survival, cancer stemness, migration, and invasion, through downregulation of EZH2 expression level, along with the reductions of MMP9, CD44, Sox2 and the induction of tumor suppressor miR-143. Either EZH2 overexpression or miR-143 inhibition could partially reverse honokiol-induced cell growth arrest and impaired clonogenicity. Importantly, it was first revealed that EZH2 could directly bind to the transcriptional regulatory region of miR-143 and repress its expression. Furthermore, honokiol treatment on T24 tumor xenografts confirmed its anticancer effects in vivo, including suppression tumor growth and tumor stemness, accompanied by the dysregulation of EZH2 and miR-143 expressions. Our data suggest a promising therapeutic option to develop drugs targeting EZH2/miR-143 axis, such as honokiol, for bladder cancer treatment. PMID- 26484569 TI - The Genotype-Tissue Expression (GTEx) Project. PMID- 26484568 TI - Changes in the expression and protein level of matrix metalloproteinases after exposure to waterpipe tobacco smoke. AB - Waterpipe smoking has become a worldwide epidemic with health consequences that only now are beginning to be understood fully. Because waterpipe use involves inhaling a large volume of toxicant-laden smoke that can cause inflammation, some health consequences may include inflammation-mediated lung injury. Excess matrix metalloproteinase expression is a key step in the etiology of toxicant exposure driven inflammation and injury. In this study, changes in the level and mRNA of major matrix metalloproteinases (MMP-1, -9, and -12) in the lungs of mice following exposure to waterpipe smoke were investigated. Balb/c mice were exposed to waterpipe smoke for one hour daily, over a period of 2 or 8 weeks. Control mice were exposed to fresh air only. ELISA and real-time PCR techniques were used to determine the protein and mRNA levels of MMP-1, -9, and -12 in the lungs. Our findings showed that MMP-1, -9, and -12 levels in the lung significantly increased after both 2 (p < 0.05) and 8 weeks (p < 0.01) exposures. Similarly, RT PCR findings showed that mRNA of those proteinases significantly increased following 2 (p < 0.01) and 8 weeks (p < 0.001) exposures. In conclusion, waterpipe smoking is associated strongly with lung injury as measured by elevation in the expression of MMPs in the lung tissue. PMID- 26484570 TI - Times Are Changing: 35 Years of Human Biospecimen Procurements for the National Disease Research Interchange. PMID- 26484572 TI - Surgical Specimens of Colorectal Cancer Fixed with PAXgene Tissue System Preserve High-Quality RNA. AB - BACKGROUND: RNA analysis of surgical specimens is one of the most useful methods for exploring biomarkers of advanced cancer. The most readily available source for RNA is formalin-fixed, paraffin-embedded (FFPE) specimens, but RNA isolated from FFPE tissue is of limited use. The PAXgene Tissue (PAX) system is a formalin free system designed to improve the quality of molecular analysis without diminishing the quality of histopathological analysis. In this human colorectal cancer tissue study, we aimed to evaluate whether surgical specimens fixed with PAX can preserve high-quality RNA in comparison with FFPE and fresh-frozen tissue specimens. METHODS: Ten consecutive advanced colorectal cancer patients undergoing colectomy were examined. Each specimen was processed in three ways: as frozen tissue, as PAX-fixed tissue, and as formalin-fixed tissue. RNA integrity numbers (RINs) were assessed using an Agilent Bioanalyzer. RNA transcript levels and stability were investigated by quantitative real-time PCR. We also evaluated the immunohistochemical intensity of Ki-67, CEA, and EGFR in the PAX samples. RESULTS: The average RINs of RNA extracted from frozen and PAX samples were significantly higher than those from FFPE samples (p < 0.001). The cycle threshold (Ct) values were similar in PAX and frozen samples, but significantly increased in FFPE samples (p < 0.001). Most of the DeltaCt values in the PAX samples did not differ significantly from those in the matched frozen samples. On the other hand, most of the DeltaCt values in the FFPE samples differed significantly from those in the matched frozen samples. The immunohistochemical intensity in the PAX samples was well preserved. CONCLUSIONS: The quality of RNA extracted from PAX samples may be slightly inferior to that from frozen samples, but is greatly superior to that from FFPE samples. PMID- 26484573 TI - The Impact of Different Preservation Conditions and Freezing-Thawing Cycles on Quality of RNA, DNA, and Proteins in Cancer Tissue. AB - BACKGROUND: High-quality cancer tissues are essential for future research, especially molecular research. For the sake of better quality of tissues, some storage methods are chosen according to lab conditions. But the impact of different storing conditions on the quality of RNA, DNA (especially the degree of DNA methylation), and protein of tissues that have undergone a thawing process, is not clear. METHODS: We analyzed the influence of different storage conditions including in RNALater solution, normal saline, Opti-mum Cutting Temperature compound (OCT), and snap frozen with no protective reagent (as control) in paired tissue samples on the quality of RNA (RNA Integrity Number value and mRNA expression), DNA quality (DNA amplification and DNA methylation degree of gene RASSF1a), and protein quality. Further, we analyzed the RNA quality of tissues that underwent three freeze-thaw cycles. RESULTS: The RNALater-treated group retained good RNA quality as expected on three repeated freeze-thaw cycles (RIN>8), but the snap-frozen tissues showed relatively poor results after one freeze-thaw cycle (RIN<7) and three times repeated freeze-thaw cycles (RIN<6). RNA from saline- and OCT-treated groups also yielded good results when we repeated freezing and thawing one time (RIN>7) and two times (RIN>6). The impact of different storing conditions on DNA amplification is small. However, DNA methylation and protein quality are different with different storing conditions. OCT seems to be more secure and stable compared with other two experimental groups, and show a similar trend with control group. CONCLUSIONS: In consideration of budget and efficiency, we suggest OCT as the best storing method that not only preserves RNA quality during the freezing-thawing process well, but also ensures more secure and stable DNA and protein. PMID- 26484574 TI - Recent International Activities. PMID- 26484571 TI - A Novel Approach to High-Quality Postmortem Tissue Procurement: The GTEx Project. AB - The Genotype-Tissue Expression (GTEx) project, sponsored by the NIH Common Fund, was established to study the correlation between human genetic variation and tissue-specific gene expression in non-diseased individuals. A significant challenge was the collection of high-quality biospecimens for extensive genomic analyses. Here we describe how a successful infrastructure for biospecimen procurement was developed and implemented by multiple research partners to support the prospective collection, annotation, and distribution of blood, tissues, and cell lines for the GTEx project. Other research projects can follow this model and form beneficial partnerships with rapid autopsy and organ procurement organizations to collect high quality biospecimens and associated clinical data for genomic studies. Biospecimens, clinical and genomic data, and Standard Operating Procedures guiding biospecimen collection for the GTEx project are available to the research community. PMID- 26484576 TI - Isotopic Effects on Covalent Bond Confined in a Penetrable Sphere. AB - A model of confinement of the covalent bond by a finite potential beyond the Born Oppenheimer approximation is presented. A two-electron molecule is located at the center of a penetrable spherical cavity. The Schrodinger equation has been solved by using the diffusion Monte Carlo method. Total energies, internuclear distances, and vibrational frequencies of the confined molecular system have been obtained. Even for confining potentials of a few electronvolts, a noticeable increase in the bond energy and the nuclear vibrational frequency is observed, and the internuclear distance is lowered. The gap between the zero point energy of different molecular isotopes increases with confinement. The confinement of the electron pair might play a role in chemical reactivity, providing an alternative explanation for the tunnel effect, when large values of primary kinetic isotopic effect are observed. The Swain-Schaad relation is still verified when confinement changes the zero point energy. A semiquantitative illustration is proposed using the data relative to an hydrogen transfer involving a C-H cleavage catalyzed by the bovine serum amine oxidase. Changes on the confining conditions, corresponding to a confinement/deconfinement process, result in a significant decrease in the activation energy of the chemical transformation. It is proposed that confinement/deconfinement of the electron-pair bonding by external electrostatic forces inside the active pocket of an enzyme could be one of the basic mechanisms of the enzyme catalysis. PMID- 26484575 TI - Genome-wide association for heifer reproduction and calf performance traits in beef cattle. AB - The aim of this study was to identify SNP markers that associate with variation in beef heifer reproduction and performance of their calves. A genome-wide association study was performed by means of the generalized quasi-likelihood score (GQLS) method using heifer genotypes from the BovineSNP50 BeadChip and estimated breeding values for pre-breeding body weight (PBW), pregnancy rate (PR), calving difficulty (CD), age at first calving (AFC), calf birth weight (BWT), calf weaning weight (WWT), and calf pre-weaning average daily gain (ADG). Data consisted of 785 replacement heifers from three Canadian research herds, namely Brandon Research Centre, Brandon, Manitoba, University of Alberta Roy Berg Kinsella Ranch, Kinsella, Alberta, and Lacombe Research Centre, Lacombe, Alberta. After applying a false discovery rate correction at a 5% significance level, a total of 4, 3, 3, 9, 6, 2, and 1 SNPs were significantly associated with PBW, PR, CD, AFC, BWT, WWT, and ADG, respectively. These SNPs were located on chromosomes 1, 5-7, 9, 13-16, 19-21, 24, 25, and 27-29. Chromosomes 1, 5, and 24 had SNPs with pleiotropic effects. New significant SNPs that impact functional traits were detected, many of which have not been previously reported. The results of this study support quantitative genetic studies related to the inheritance of these traits, and provides new knowledge regarding beef cattle quantitative trait loci effects. The identification of these SNPs provides a starting point to identify genes affecting heifer reproduction traits and performance of their calves (BWT, WWT, and ADG). They also contribute to a better understanding of the biology underlying these traits and will be potentially useful in marker- and genome assisted selection and management. PMID- 26484577 TI - Long-term prognosis and causes of death after spondylodiscitis: A Danish nationwide cohort study. AB - BACKGROUND: Data on long-term prognosis after spondylodiscitis are scarce. The purpose of this study was to determine long-term mortality and the causes of death after spondylodiscitis. METHODS: A nationwide, population-based cohort study using national registries of patients diagnosed with non-post-operative pyogenic spondylodiscitis from 1994-2009, alive 1 year after diagnosis (n = 1505). A comparison cohort from the background population individually matched for sex and age was identified (n = 7525). Kaplan-Meier survival curves were constructed and Poisson regression analyses used to estimate mortality rate ratios (MRR). RESULTS: Three hundred and sixty-five patients (24%) and 1115 individuals from the comparison cohort (15%) died. Unadjusted MRR for spondylodiscitis patients was 1.76 (95% CI = 1.57-1.98) and 1.47 (95% CI = 1.30 1.66) after adjustment for comorbidity. No deaths were observed in 128 patients under the age of 16 years. Siblings of patients did not have increased long-term mortality compared with siblings of the individuals from the comparison cohort. This study observed increased mortality due to infections (MRR = 2.57), neoplasms (MRR = 1.40), endocrine (MRR = 3.72), cardiovascular (MRR = 1.62), respiratory (MRR = 1.71), gastrointestinal (MRR = 3.35), musculoskeletal (MRR = 5.39) and genitourinary diseases (MRR = 3.37), but also due to trauma, poisoning and external causes (MRR = 2.78), alcohol abuse-related diseases (MRR = 5.59) and drug abuse-related diseases (6 vs 0 deaths, MRR not calculable). CONCLUSIONS: Patients diagnosed with spondylodiscitis have increased long-term mortality, mainly due to comorbidities, particularly substance abuse. PMID- 26484578 TI - The effects of forearm fatigue on baseball fastball pitching, with implications about elbow injury. AB - This study investigated the contribution of flexor muscles to the forearm through fatigue; therefore, the differences in forearm mechanisms on the pitching motion in fastball were analysed. Fifteen baseball pitchers were included in this study. Ultrasonographical examination of participants' ulnar nerve in the cubital tunnel with the elbow extended and at 45 degrees , 90 degrees and 120 degrees of flexion was carried. A three-dimensional motion analysis system with 14 reflective markers attached on participants was used for motion data collection. The electromyography system was applied over the flexor carpi ulnaris, flexor carpi radialis and extensor carpi radialis muscles of the dominant arm. Flexor carpi ulnaris muscle activity showed a significant difference during the acceleration phase, with a peak value during fastball post-fatigue (P = 0.02). Significant differences in the distance between ulnar nerve and medial condyle on throwing arm and non-throwing arm were observed as the distance increased with the elbow movement from 0 degrees to 120 degrees of flexion (P = 0.01). The significant increase of the flexor carpi ulnaris muscle activity might be responsible for maintaining the stability of the wrist joint. The increased diameter might compress the ulnar nerve and cause several pathological changes. Therefore, fatigue in baseball pitchers still poses a threat to the ulnar nerve because the flexor carpi ulnaris and flexor carpi radialis all originate from the medial side of the elbow, and the swelling tendons after fatigue might be a key point. PMID- 26484579 TI - Uterine Activin-Like Kinase 4 Regulates Trophoblast Development During Mouse Placentation. AB - The placenta is the first organ to develop after fertilization. It forms an interface between the maternal uterus and growing fetus to allow nutrient uptake, waste elimination, and gas exchange for a successful pregnancy in both mice and humans. In the past 2 decades, in vivo and in vitro approaches have been used to show that several members of the TGF-beta superfamily regulate embryo implantation and placental development. Nodal, a TGF-beta superfamily ligand, is essential for mesendoderm formation and left-right axis patterning during embryogenesis, and Nodal null mutants exhibit abnormal placental organization with expansion of trophoblast giant cells and a decrease of spongiotrophoblast and labyrinth. To better understand the importance of Nodal signaling in the uterus, we established a mouse model to conditionally ablate activin-like kinase 4 (ALK4; the Nodal type 1 receptor) using Cre recombinase driven by the progesterone receptor promoter sequences (Pgr-Cre). Alk4 conditional knockout females are subfertile due to placental abnormalities and fetal loss in pregnancy, with a placental disorganization phenotype similar to what is observed in Nodal null mice. Thus, Nodal likely functions as an indirect regulator of placental development by binding to type 1 and type 2 receptors on maternal decidual cells to stimulate expression of unknown regulators of placental development. Our findings not only describe the generation of a mouse model that enables study of Nodal signaling in placentation but also provides insights into the pathogenesis of pregnancy complications in humans, including spontaneous abortion, preeclampsia, intrauterine growth restriction, and preterm birth. PMID- 26484580 TI - Germ Cell Nuclear Factor (GCNF/RTR) Regulates Transcription of Gonadotropin Regulated Testicular RNA Helicase (GRTH/DDX25) in Testicular Germ Cells--The Androgen Connection. AB - Gonadotropin-regulated testicular RNA helicase (GRTH) (GRTH/DDX25), is a testis specific protein essential for completion of spermatogenesis. Transgenic mice carrying 5'-flanking regions of the GRTH gene/green fluorescence protein (GFP) reporter revealed a region (-6.4/-3.6 kb) which directs its expression in germ cells (GCs) via androgen action. This study identifies a functional cis-binding element on the GRTH gene for GC nuclear factor (GCNF) (GCNF/RTR) required to regulate GRTH gene expression in postmeiotic testis GCs and explore the action of androgen on GCNF and GRTH transcription/expression. GCNF expression decreased in mice testis upon flutamide (androgen receptor antagonist) treatment, indicating the presence of an androgen/GCNF network to direct GRTH expression in GC. Binding studies and chromatin immunoprecipitation demonstrated specific association of GCNF to a consensus half-site (-5270/-5252) of the GRTH gene in both round spermatids and spermatocytes, which was abolished by flutamide treatment in round spermatids. Moreover, flutamide treatment of wild-type mice caused selective reduction of GCNF and GRTH in round spermatids. GCNF knock-down in seminiferous tubules from GRTH-transgenic mice (dark zone, round spermatid rich) caused decreased GFP expression. Exposure of tubules to flutamide caused decrease in GCNF and GFP expression, whereas androgen exposure induced significant increase. Our studies provide evidence for actions of androgen on GCNF cell-specific regulation of GRTH expression in GC. GRTH associates with GCNF mRNA, its absence caused increase on GCNF expression and mRNA stability indicative of a negative autocrine regulation of GCNF by GRTH. These in vivo/in vitro models link androgen actions to GC through GCNF, as regulated transfactor that controls transcription/expression of GRTH. PMID- 26484581 TI - Minireview: Familiar Faces in Unfamiliar Places: The Emerging Role of Nuclear Receptors in Lung Cancer. AB - Nuclear hormone receptors (NRs) are a superfamily of 48 transcription factors that are frequently modulated by ligands and control various cancer-relevant cellular pathways, such as differentiation, proliferation, migration, and metabolism. These properties make them excellent therapeutic targets in cancers dependent upon their activity, and as such, 3 NRs, estrogen receptor-alpha, androgen receptor, and retinoic acid receptor-alpha (more specifically, the promyelocytic leukemia-retinoic acid receptor-alpha translocation), have been targeted clinically in breast cancer, prostate cancer, and acute promyelocytic leukemia, respectively. Recently, a number of studies have highlighted a putative role for NRs in nonsmall cell lung cancer (NSCLC), a highly lethal type of lung cancer with relatively few targeted agents. Here, we review the potential roles of selected NRs in NSCLC and offer insights on how NRs may be leveraged in NSCLC to improve patient outcomes. PMID- 26484583 TI - The pharmacokinetics and extracorporeal removal of N-acetylcysteine during renal replacement therapies. AB - OBJECTIVE: Acetaminophen-induced fulminant hepatic failure is associated with acute kidney injury, metabolic acidosis, and fluid and electrolyte imbalances, requiring treatment with renal replacement therapies. Although antidote, acetylcysteine, is potentially extracted by renal replacement therapies, pharmacokinetic data are lacking to guide potential dosing alterations. We aimed to determine the extracorporeal removal of acetylcysteine by various renal replacement therapies. METHODS: Simultaneous urine, plasma and effluent specimens were serially collected to measure acetylcysteine concentrations in up to three stages: before, during and upon termination of renal replacement therapy. Alterations in pharmacokinetics were determined by applying standard pharmacokinetic equations. RESULTS: Over 2 years, 10 critically ill patients in fulminant hepatic failure requiring renal replacement therapy coincident with acetylcysteine were consecutively enrolled. All 10 patients required continuous venovenous hemofiltration (n = 10) and 2 of the 10 also required hemodialysis (n = 2). There was a significant alteration in the pharmacokinetics of acetylcysteine during hemodialysis; the area under the curve (AUC) decreased 41%, the mean extraction ratio was 51%, the mean hemodialytic clearance was 114.01 ml/kg/h, and a mean 166.75 mg/h was recovered in the effluent or 41% of the hourly dose. Alteration in the pharmacokinetics of acetylcysteine during continuous venovenous hemofiltration did not appear to be significant: the AUC decreased 13%, the mean clearance was 31.77 ml/kg/h and a mean 62.12 mg/h was recovered in the effluent or 14% of the hourly dose. CONCLUSIONS: There was no significant extraction of acetylcysteine from continuous venovenous hemofiltration. In contrast, there was significant extracorporeal removal of acetylcysteine during hemodialysis. A reasonable dose adjustment may be to double the IV infusion rate or possibly supplement with oral acetylcysteine during hemodialysis. PMID- 26484582 TI - Minireview: CNS Mechanisms of Leptin Action. AB - Leptin is an adipocytokine that circulates in proportion to body fat to signal the repletion of long-term energy stores. Leptin acts via its receptor, LepRb, on specialized neuronal populations in the brain (mainly in the hypothalamus and brainstem) to alter motivation and satiety, as well as to permit energy expenditure and appropriate glucose homeostasis. Decreased leptin, as with prolonged caloric restriction, promotes a powerful orexigenic signal, decreases energy use via a number of neuroendocrine and autonomic axes, and disrupts glucose homeostasis. Here, we review what is known about cellular leptin action and focus on the roles for specific populations of LepRb-expressing neurons for leptin action. PMID- 26484584 TI - Correction to "Convenient Synthesis of Triphenylphosphanylidene Spiro[cyclopentane-1,3'-indolines] and Spiro[cyclopent[2]ene-1,3'-indolines] via Three-Component Reactions". PMID- 26484585 TI - Identification of Challenges to the Availability and Accessibility of Opioids in Twelve European Countries: Conclusions from Two ATOME Six-Country Workshops. AB - BACKGROUND: Access to many controlled medicines is inadequate in a number of European countries. This leads to deficits in the treatment of moderate to severe pain as well as in opioid agonist therapy. OBJECTIVE: The study objective was to elaborate the reasons for this inadequacy. The work plan of the Access to Opioid Medication in Europe (ATOME) project included two six-country workshops. These workshops comprised a national situational analysis, drafting tailor-made recommendations for improvement and developing action plans for their implementation. METHODS: In total, 84 representatives of the national Ministries of Health, national controlled substances authorities, experts representing regulatory and law enforcement authorities, leading health care professionals, and patient representatives from 13 European countries participated in either one of the workshops. The delegates used breakout sessions to identify key common challenges. Content analysis was used for the evaluation of protocols and field notes. RESULTS: A number of challenges to opioid accessibility in the countries was identified in the domains of knowledge and educational, regulatory, legislative, as well as public awareness and training barriers that limit opioid prescription. In addition, short validity of prescriptions and bureaucratic practices resulting in overregulation impeded availability of some essential medicines. Stigmatization and criminalisation of people who use drugs remained the major impediment to increasing opioid agonist program coverage. CONCLUSIONS: The challenges identified during outcomes of the workshops were used as the basis for subsequent dissemination and implementation activities in the ATOME project, and in some countries the workshop proceedings already served as a stepping-stone for the first changes in regulations and legislation. PMID- 26484586 TI - Editorial. PMID- 26484587 TI - Comparative analysis of CD4 and CD8 lymphocytes - evidences for different distribution in primary and secondary liver tumors. AB - INTRODUCTION: The impact of tumor cells on tumor-infiltrating lymphocytes (TILs) in cancer development is not yet clarified. Our study analyzed the distribution and prognostic value of CD4+ and CD8+ T lymphocytes in hepatocellular carcinoma (HCC) and liver metastases (LM). MATERIAL AND METHODS: Archival tissue specimens of 35 HCC and 39 LM patients were immunohistochemically processed. The number of intratumoral (IT) and peritumoral (PT) CD4+ and CD8+ T cells was quantitatively analyzed. RESULTS: We noted large variances of T lymphocyte subpopulations. Similar number of CD4+ and CD8+ lym-phocytes was present in HCC, whereas in LM the number of CD8+ cells was approximately two times higher than CD4+ lymphocytes. A significant prevalence of T cells in PT over IT areas was observed. The prognostic value was demonstrated only for PT CD8+ lymphocytes in LM, their reduced number being associated with shorter survival. CONCLUSIONS: The differences between proportions of T lymphocytes within tumor and its environment might be explained by proapoptotic effect of cancer cells on TILs. PMID- 26484588 TI - The In Ovo Chick Chorioallantoic Membrane (CAM) Assay as an Efficient Xenograft Model of Hepatocellular Carcinoma. AB - The chick chorioallantoic membrane (CAM) begins to develop by day 7 after fertilization and matures by day 12. The CAM is naturally immunodeficient and highly vascularized, making it an ideal system for tumor implantation. Furthermore, the CAM contains extracellular matrix proteins such as fibronectin, laminin, collagen, integrin alpha(v)beta3, and MMP-2, making it an attractive model to study tumor invasion and metastasis. Scientists have long taken advantage of the physiology of the CAM by using it as a model of angiogenesis. More recently, the CAM assay has been modified to work as an in vivo xenograft model system for various cancers that bridges the gap between basic in vitro work and more complex animal cancer models. The CAM assay allows for the study of tumor growth, anti-tumor therapies, and pro-tumor molecular pathways in a biologically relevant system that is both cost- and time-effective. Here, we describe the development of CAM xenograft model of hepatocellular carcinoma (HCC) with embryonic survival rates of up to 93% and reliable tumor take leading to growth of three-dimensional, vascularized tumors. PMID- 26484590 TI - Climatic Influences on Cryptococcus gattii [corrected] Populations, Vancouver Island, Canada, 2002-2004. AB - Vancouver Island, Canada, reports the world's highest incidence of Cryptococcus gattii infection among humans and animals. To identify key biophysical factors modulating environmental concentrations, we evaluated monthly concentrations of C. gatti in air, soil, and trees over a 3-year period. The 2 study datasets were repeatedly measured plots and newly sampled plots. We used hierarchical generalized linear and mixed effect models to determine associations. Climate systematically influenced C. gattii concentrations in all environmental media tested; in soil and on trees, concentrations decreased when temperatures were warmer. Wind may be a key process that transferred C. gattii from soil into air and onto trees. C. gattii results for tree and air samples were more likely to be positive during periods of higher solar radiation. These results improve the understanding of the places and periods with the greatest C. gattii colonization. Refined risk projections may help susceptible persons avoid activities that disturb the topsoil during relatively cool summer days. PMID- 26484591 TI - Neuroprotective coordination of cell mitophagy by the ATPase Inhibitory Factor 1. AB - The mitochondrial ATPase Inhibitory Factor 1 (hereafter referred to as IF1) blocks the reversal of the F1Fo-ATPsynthase to prevent detrimental consumption of cellular ATP and associated demise. Herein, we infer further its molecular physiology by assessing its protective function in neurons during conditions of challenged homeostatic respiration. By adopting in vitro and in vivo protocols of hypoxia/ischemia and re-oxygenation, we show that a shift in the IF1:F1Fo ATPsynthase expression ratio occurs in neurons. This increased IF1 level is essential to induce accumulation of the PTEN-induced putative kinase 1 (PINK-1) and recruitment of the mitophagic ubiquitin ligase PARK-2 to promote autophagic "control" of the mitochondrial population. In IF1 overexpressing neurons ATP depletion is reduced during hypoxia/ischemia and the mitochondrial membrane potential (DeltaYm) resilient to re-oxygenation as well as resistant to electrogenic, Ca(2+) dependent depolarization. These data suggest that in mammalian neurons mitochondria adapt to respiratory stress by upregulating IF1, which exerts a protective role by coordinating pro-survival cell mitophagy and bioenergetics resilience. PMID- 26484592 TI - A nonlinear parameterization of multivariate electrohysterographical signals. AB - Electrohysterography is a technique which measures a bioelectrical activity of a uterus. This paper presents an application of a nonlinear parameterization of multivariate electrohysterographical signals for a uterine activity assessment to improve unsatisfactory a labor prediction accuracy by methods published in the literature. A multivariate sample entropy used for differentiated 4-channel electrohysterographical signals, general Spearman's correlation and a combined index being the sum of them, were tested. These nonlinear measures use joint information contained in a multivariate signal. The results confirm that the combined index provides the best assessment of uterine contractions: 87% sensitivity and 50% specificity of labor prediction in the studied data. These results should be verified in a prospective study. PMID- 26484593 TI - "Intermetamorphic" developmental stages in 150 million-year-old achelatan lobsters--The case of the species tenera Oppel, 1862. AB - We re-investigated the fossil species tenera Oppel, 1862, an achelatan lobster (traditionally named Palinurina tenera) found in 150 million years old limestones of southern Germany. All known specimens attributed to this species show a mixture of characters, which in modern forms occur either in larvae or post larval juveniles. Hence these specimens provide insight into a phase in ontogeny that is no longer present in the developmental sequence of any modern achelatan lobster, as the latter ones skip this phase and replace it by a drastic metamorphosis. Comparable cases have been described earlier, yet did only comprise single stages or two successive ones at most. In the here described case four developmental stages are preserved. The reconstructed ontogeny of tenera therefore represents the currently best known sequence of an early achelatan lobster that covers this specific intermediate phase. The largest known stage most likely still represents an immature of a yet undiscovered adult. These findings support the interpretation that early achelatan lobsters developed in a more gradual ontogenetic sequence than modern forms. It furthermore demonstrates that it was even more gradual than anticipated previously. PMID- 26484594 TI - Agonist mobility on supported lipid bilayers affects Fas mediated death response. AB - Extrinsic apoptosis is initiated by recognition and clustering of the single-pass transmembrane proteins Fas ligand and Fas expressed at the surface of closely apposed lymphocytes and target cells, respectively. Since Fas-mediated death response was mainly studied with soluble antibodies, the mobility constraints for receptor activation by a membrane embedded agonist is not well understood. We explored this influence by stimulating apoptosis on functionalized supported lipid bilayers, where we quantified agonist mobility by z-scan fluorescence correlation spectroscopy. Using different lipid compositions, we show that the apoptotic response correlates with increased lateral mobility of the agonist in the lipid bilayer. PMID- 26484595 TI - Systemic control of protein synthesis through sequestration of translation and ribosome biogenesis factors during severe heat stress. AB - Environmental stress causes the sequestration of proteins into insoluble deposits including cytoplasmic stress granules (SGs), containing mRNA and a variety of translation factors. Here we systematically identified proteins sequestered in Saccharomyces cerevisiae at 46 degrees C by a SG co-localization screen and proteomic analysis of insoluble protein fractions. We identified novel SG components including essential aminoacyl-tRNA synthetases. Moreover, we discovered nucleus-associated deposits containing ribosome biogenesis factors. Our study suggests downregulation of cytosolic protein synthesis and nuclear ribosome production at multiple levels through heat shock induced protein sequestrations. PMID- 26484596 TI - Alzheimer's disease is associated with disordered localization of ganglioside GM1 molecular species in the human dentate gyrus. AB - Alzheimer's disease (AD) is a progressive dementia associated with loss of memory and cognitive dysfunction. In a previous study, we demonstrated a decrease in b series gangliosides along with a change in ganglioside molecular species in the hippocampal grey matter of patients with AD. The present study demonstrates the use of imaging mass spectrometry for analyzing the spatial arrangement of ganglioside GM1 (GM1) molecular species in the hippocampus. In AD patients, we found a decrease in the ratio of GM1(d20:1/C18:0) to GM1 d18:1/C18:0) in the outer molecular layer (ML) of the dentate gyrus. Because the outer ML is the region of main input into the hippocampus, our findings may have a direct relationship to the mechanism of dysfunction in AD. PMID- 26484597 TI - Structure-activity relationship of sulfated hetero/galactofucan polysaccharides on dopaminergic neuron. AB - Parkinson's disease (PD) is associated with progressive loss of dopaminergic neurons and more-widespread neuronal changes that cause complex symptoms. The aim of this study was to investigate the structure-activity relationship of sulfated hetero-polysaccharides (DF1) and sulfated galactofucan polysaccharides (DF2) on dopaminergic neuron in vivo and in vitro. Treatment with samples significantly ameliorated the depletion of both DA and TH-, Bcl-2- and Bax-positive neurons in MPTP-induced PD mice, DF1 showed the highest activity. The in vitro results found that DF1 and DF2 could reverse the decreased mitochondrial activity and the increased LDL release induced by MPP(+) (P<0.01 or P<0.001) which provides further evidence that DF1 and DF2 also exerts a direct protection against the neuronal injury caused by MPP(+). Furthermore, the administration of samples effectively decreased lipid peroxidation and increased the level/activities of GSH, GSH-PX, MDA and CAT in MPTP mice. Thus, the neuron protective effect may be mediated, in part, through antioxidant activity and the prevention of cell apoptosis. The chemical composition of DF1, DF2 and DF differed markedly, the DF1 fraction had the most complex chemical composition and showed the highest neuron protective activity. These results suggest that diverse monosaccharides and uronic acid might contribute to neuron protective activity. PMID- 26484598 TI - Characterization of medium chain length polyhydroxyalkanoate produced from olive oil deodorizer distillate. AB - Olive oil deodorizer distillate (OODD) was used for the first time as the sole substrate for polyhydroxyalkanoates (PHA) production by the bacterium Pseudomonas resinovorans in bioreactor cultivation. A PHA content in the biomass of 36 +/- 0.8 wt% was attained within 19 h of cultivation. A final polymer concentration of 4.7 +/- 0.3 gL(-1) was reached, corresponding to a volumetric productivity of 5.9 +/- 0.2 gL(-1)day(-1). The PHA was composed of 3-hydroxyoctanoate (48.3 +/- 7.3 mol%), 3-hydroxydecanoate (31.6 +/- 2.6 mol%), 3-hydroxyhexanoate (12.1 +/- 1.1 mol%) and 3-hydroxydodecanoate (8.0 +/- 0.7 mol%) and it had a glue-like consistency that did not solidify at room temperature. The polymer was highly amorphous, as shown by its low crystallinity of 6 +/- 0.2%, with low melting and glass transition temperatures of 36 +/- 1.2 and -16 +/- 0.8 degrees C, respectively. The polymer exhibited a shear thinning behavior and a mechanical spectrum with a predominant viscous contribution. Its shear bond strength for wood (67 +/- 9.4 kPa) and glass (65 +/- 7.3 kPa) suggests it may be used for the development of biobased glues. PMID- 26484599 TI - Modification of collagen-chitosan matrix by the natural crosslinker alginate dialdehyde. AB - In the present study, collagen (Coll) was mixed with the natural crosslinker chitosan (CTS), and then, alginate dialdehyde (ADA) was added to crosslink the mixtures. The properties of these Coll matrix sponges were investigated afterwards. Fourier transform infrared spectroscopy (FTIR) analysis and in vitro fiber formation analysis showed the intact retention of the classical triple helical structure after crosslinking. Scanning electron microscopy (SEM) showed that microfibril structural interactions between Coll structures became more compact. Significant improvement in the thermostability of the crosslinked mixtures was observed with the pure mixtures of Coll and CTS. Antibacterial activity measurements indicated no affect of ADA on Coll/CTS sponges. In conclusion, the modification of the Coll/CTS mixtures with ADA preserves the classical triple-helical structure, enhances stabilization, maintains good biocompatibility and may pave the way for new medical applications. PMID- 26484600 TI - Influence of lignin level on release of hemicellulose-derived sugars in liquid hot water. AB - Lignin layers surrounding hemicelluloses and cellulose in the plant cell walls protect them from deconstruction. This recalcitrance to sugar release is a major limitation for cost-effective industrial conversion of lignocellulosic biomass to biofuels. Many literatures had reported the contribution of lignin removal to cellulose accessibility to enzyme, but less to the hemicellulose hydrolysis. Herein, beech xylan with lignin addition, partly delignified sugarcane bagasse (SB), energy sorghum hybrids (ESH) were treated in liquid hot water (LHW) to investigate the effect of lignin on hemicellulose decomposition. The addition of lignin can enhance the low degree of polymerization of xylooligomers production resulted from the acid catalyzed cleavage of lignin-derived acidic products. However, a negative correlation was observed initially between the lignin level and the total xylose yield from ESH. Furthermore, samples with lignin addition or high lignin content had a great resistant to harsh reaction environment, about 93.5% total xylose lost but only 52.3% released due to the lack of lignin protection for the sample with 100% lignin removal. PMID- 26484601 TI - Optimization, characterization, and biological activity of polysaccharides from Berberis dasystachya Maxim. AB - In this study, the extraction of water-soluble polysaccharides (BDPs) from Berberis dasystachya Maxim using dynamic microwave-assisted extraction (DMAE) was discussed. A Box-Behnken design combined with response surface methodology has been employed to optimize extraction parameters of DMAE. The BDPs have been analyzed in order to identify a variety of chemical properties. Antioxidant and anti-tumor activities in vitro have been studied by DPPH, ABTS, reducing power assay, and MTT assay, respectively. The results obtained showed that the optimal extraction conditions were as follows: ratio of water to raw material (X1) 25.84 mg/L, extraction power (X2) 433.13W, extraction time (X3) 35.18 min, and the maximum yield of extraction was 6.472 +/- 0.384%, which was in good agreement with the predicted value. The physicochemical tests demonstrated that the BDPs mainly consist of rhamnose, arabinose, xylose, mannose, glucose and lactose in a molar ratio of 1:17.3:1.33:7:2.33:1.78; the average molecular weight of the BDPs was estimated to be from 2.95*10(5) and 1.52*10(3)Da, respectively. Furthermore, the BDPs exhibited effective antioxidant and anti-proliferative properties in vitro. Such pharmaceutical activities could prove useful for potential future applications involving the berries of B. dasystachya Maxim. PMID- 26484602 TI - Greenhouse gas emissions and soil properties following amendment with manure derived biochars: Influence of pyrolysis temperature and feedstock type. AB - Manure-derived biochars can offer a potential option for the stabilization of manure, while mitigating climate change through carbon sequestration and the attenuation of nitrous oxide emission. A laboratory incubation study was conducted to assess the effects of four different manure-derived biochars produced from different feedstocks (poultry litter and swine manure) at different temperatures (400 or 600 degrees C). A commonly available standard wood chip biochar, produced at a greater temperature (1000 degrees C), and non-amended treatments were used as references. Two different soils (sandy and silt-loam) were amended with 2% (w/w) biochar on a dry soil weight basis (corresponding to 20 Mg ha(-1)), with the soil moisture being adjusted to 75% saturation level. After a pre-incubation period (21 days), 170 kg N ha(-1) of NH4NO3 fertilizer was added. Measurements of CO2, N2O, CH4 emissions and soil N mineralisation were carried out on different days during the 85 days of incubation. The net C mineralization and N2O emissions from both soils amended with poultry litter biochar at 400 degrees C were significantly greater than the other biochar treatments. Nitrate availability was greater in both soils in which the manure derived biochar was used instead of the standard biochar. All of the biochars increased the pH of the silt-loam, sub-acid soil, but failed to improve the cation exchange capacities (CEC) in either soil. Total C and N, P, K and Mg (except Ca) were significantly increased in the manure-derived biochar amended soils, compared to the Control, and were positively correlated to the biochar nutrient contents. This study indicates that the soil application of biochar engenders effects that can vary considerably according to the biochar properties, as determined on the basis of the feedstock types and process conditions. Low temperature biochar production from manure represents a possible way of producing a soil amendment that can stabilize C while supplying a significant quantity of nutrients. PMID- 26484603 TI - Preparation of highly stable fullerene C60 decorated graphene oxide nanocomposite and its sensitive electrochemical detection of dopamine in rat brain and pharmaceutical samples. AB - The research community has continuously paid much attention on the preparation of hybrid of carbon nanomaterials owing to combine their unique properties. Herein, we report the preparation of highly stable fullerene C60 (C60) wrapped graphene oxide (GO) nanocomposite by using a simple sonication method. The fabricated GO C60 nanocomposite modified glassy carbon electrode shows a good sensitivity and lower oxidation overpotential towards dopamine (DA) than that of pristine GO and C60. The fabricated sensor detects the DA in the linear response range of 0.02 73.5MUM. The limit of detection is estimated to be 0.008MUM based on 3sigma with a sensitivity of 4.23MUAMUM(-1)cm(-2). The fabricated sensor also exhibits other features such as good selectivity, stability, reproducibility and repeatability. The proposed sensor exhibits good practicality towards the detection of DA in rat brain and commercial DA injection samples. PMID- 26484604 TI - In situ growth of Ag3PO4 on N-BiPO4 nanorod: A core-shell heterostructure for high performance photocatalyst. AB - Enhanced light absorption and effective separation of photogenerated charges are the main strategies to improve the performance of photocatalytic materials. In this study, Ag3PO4/N-doped BiPO4 (N-BiPO4) core-shell structure photocatalyst was synthesized by a simple in-situ growth strategy in an organic solvent. The separation of photogenerated electron-hole was enhanced by the doping of nitrogen, because of the emergence of N-O impurity energy levels. The increased photocatalytic activity of Ag3PO4/N-BiPO4 could be attributed to the in-situ formation of chemical bonds between Ag3PO4 and N-BiPO4, which accelerate the separation of electron-hole pairs. The photocatalytic performance of the as synthesized Ag3PO4/N-BiPO4 was evaluated by monitoring the decolorization of methyl orange under sunlight irradiation. Ag3PO4/N-BiPO4 was capable of bleaching 95% MO within 40min. PMID- 26484605 TI - Chronic social defeat stress increases dopamine D2 receptor dimerization in the prefrontal cortex of adult mice. AB - The present study aimed to examine the effects of chronic social defeat stress on the dopamine receptors and proteins involved in post-endocytic trafficking pathways. Adult mice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress. Western blot analysis was used to measure the protein expression levels of dopamine D2 receptors (D2Rs), a short (D2S) and a long form (D2L) and, D2R monomers and dimers, dopamine D1 receptors (D1Rs), neuronal calcium sensor-1 (NCS-1) and G protein-coupled receptor-associated sorting protein-1 (GASP-1), and reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA expression levels of D2S, D2L, D2R monomers and dimers, and D1Rs in different brain areas. We observed increased expression of D2S, D2L and D2Rs dimers in the prefrontal cortex (PFC) of susceptible and/or unsusceptible mice compared with controls. The only significant findings with regard to mRNA expression levels were lower expression of D2S mRNA in the amygdala (AMYG) of susceptible and unsusceptible mice compared with controls. The present study demonstrated that chronic social defeat stress induced increased expression of D2S, D2L, and D2R dimers in the PFC of susceptible and/or unsusceptible mice. PMID- 26484606 TI - The effects of RNA interference mediated VEGF gene silencing on biological behavior of renal cell carcinoma and transplanted renal tumor in nude mice. AB - OBJECTIVE: This study was to explore the effects of RNA interference mediated vascular endothelial growth factor (VEGF) gene silencing on biological behavior of renal cell carcinoma (RCC), transplanted renal tumor and angiogenesis in nude mice. METHODS: The specific siRNA sequence targeting VEGF were designed and synthesized to construct hVEGF-siRNA plasmid which was transfected into RCC 786-O cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used for the detection of VEGF gene expression and western blot was adopted for the examination of VEGF protein expression. The 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay was used to detect cell growth as well as cell migration and invasion. The transplanted renal tumor models in nude mice were established, and the growth condition of nude mice, and VEGF protein expression in transplanted tumor slices and the microvessel density (MVD) were detected. RESULTS: The expression level of VEGF mRNA in VEGF-siRNA group was significant lower than that in the control group and negative group, suggesting that establishment of plasmid specifically inhibited the expression of VEGF gene The expression level of VEGF protein in VEGF-siRNA group was significant lower than that in the control group and negative group. VEGF gene silencing has the significant inhibition effects on proliferation, migration and invasion of RCC 786-O cells. The tumor weight, VEGF protein positive rate and MVD in VEGF-siRNA group were significant lower than those in negative group and blank group. CONCLUSION: The VEGF gene silencing could inhibit the cell proliferation, migration and invasion of RCC 786-O cells; inhibition of VEGF protein expression could prevent transplanted RCC growth and tumor angiogenesis. PMID- 26484607 TI - The relationship between functional promoter -94 ins/del ATTG polymorphism in NF kappa B1 gene and the risk of urinary cancer. AB - OBJECTIVE: A functional -94 insertion/deletion polymorphism (rs28362491) in the promoter of the NF-kappa B1 gene was reported to influence NF-kappa B1 expression and confer susceptibility to different types of cancer. This study aims to determine whether the polymorphism is associated with the risk of urinary cancer, including renal cancer, bladder cancer and prostate cancer. METHODS: TaqMan method was applied to genotype the NF-kappa B1 -94 ins/del ATTG promoter polymorphism in three case-control studies: renal cell carcinoma group (1216 cases and 1588 controls), bladder cancer group (730 cases and 780 controls), and prostate cancer group (820 cases and 945 controls). Logistic regression was used to assess the association between the polymorphism and urinary cancer risk. RESULTS: The del/del genotype was detected to be associated with a statistically significant increased risk of bladder cancer when taking the ins/ins genotypes as reference (P < 0.001, adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.14-1.52). Furthermore, in bladder cancer, the same results were observed in the del/del genotype compared with the ins/ins + ins/del genotypes (P < 0.001, OR = 1.82, 95% CI = 1.41-2.35), and the del allele compared with the ins allele (P < 0.001, OR = 1.29, 95% CI = 1.12-1.49). However, no significant difference was observed in the associations between the NF-kappa B1 polymorphism and the risk of renal cell carcinoma or prostate cancer in all kinds of models. CONCLUSIONS: In the Chinese population, the -94 ins/del ATTG polymorphism in NF kappa B1 promoter may contribute to the etiology of bladder cancer instead of renal cell carcinoma or prostate cancer. PMID- 26484608 TI - A prospective study of the use of circulating markers as predictors for epidermal growth factor receptor-tyrosine kinase inhibitor treatment in pulmonary adenocarcinoma. AB - BACKGROUND: The use of liquid tissue, such as circulating cells, to predict treatment response is attracting more attention. OBJECTIVE: The aim of this study was to evaluate association between circulating markers and treatment response. METHODS: One hundred and twelve advanced pulmonary adenocarcinoma patients who were going to receive epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were included. Tumor tissue and plasma specimens were collected before treatment and analyzed for EGFR mutation and plasma IL-6 and IL-8. Pre treatment peripheral blood CD146+/CD3- cells (as circulating endothelial cells, CECs), CD34+/CD45- cells (as endothelial progenitor cells, EPCs), and CD133+ cells (as cancer stem cells, CSCs) were measured with flow cytometry. RESULTS: The progression-free survival (PFS) was significantly longer in patients with low CEC, low EPC, and low CSC counts than in those with high cell counts (p < 0.001, 0.041, and 0.001, respectively). Multivariate analysis showed that mutant plasma EGFR (pEGFR) was a poor prognostic factor in EGFR-mutated patients (p = 0.048), and there was a tendency for EGFR mutation-negative patients with high IL-6 level to have worse overall survival (p = 0.051). CONCLUSIONS: CECs, EPCs, CSCs, and mutant pEGFR are useful predictive biomarkers of EGFR-TKI treatment efficacy. IL 6 may predict prognosis in advanced lung cancer. PMID- 26484609 TI - A systems biology approach for miRNA-mRNA expression patterns analysis in non small cell lung cancer. AB - Non-small cell lung cancers (NSCLCs) is a prevalent and heterogeneous subtype of lung cancer accounting for 85 percent of patients. MicroRNAs (miRNAs), a class of small endogenous non-coding RNAs, incorporate into regulation of gene expression post-transcriptionally. Therefore, deregulation of miRNAs' expression has provided further layers of complexity to the molecular etiology and pathogenesis of different diseases and malignancies. Although, until now considerable number of studies has been carried out to illuminate this complexity in NSCLC, they have remained less effective in their goal due to lack of a holistic and integrative systems biology approach which considers all natural elaborations of miRNAs' function. It is able to reliably nominate most affected signaling pathways and therapeutic target genes by deregulated miRNAs during a particular pathological condition. Herein, we utilized a holistic systems biology approach, based on appropriate re-analyses of microarray datasets followed by reliable data filtering, to analyze integrative and combinatorial deregulated miRNA-mRNA interaction network in NSCLC, aiming to ascertain miRNA-dysregulated signaling pathway and potential therapeutic miRNAs and mRNAs which represent a lion' share during various aspects of NSCLC's pathogenesis. Our systems biology approach introduced and nominated 1) important deregulated miRNAs in NSCLCs compared with normal tissue 2) significant and confident deregulated mRNAs which were anti correlatively targeted by deregulated miRNA in NSCLCs and 3) dysregulated signaling pathways in association with deregulated miRNA-mRNAs interactions in NSCLCs. These results introduce possible mechanism of function of deregulated miRNAs and mRNAs in NSCLC that could be used as potential therapeutic targets. PMID- 26484610 TI - The impact of lung cancer resection surgery on fibrinogen and C-reactive protein and their relationship with patients outcomes: A prospective follow up study. AB - BACKGROUND: Major thoracic surgery is characterized by release of inflammatory markers.The objective of this study was to assess the preoperative and postoperative systemic inflammatory markers of patients undergoing lung cancer resection. METHODS: This is a prospective follow up study conducted with 48 patients submitted to lung cancer resection.All patients were assessed before and 1 month after surgery through measurement of fibrinogen and C-reative protein(CRP), pulmonary function tests, 6- minute Walk Test (6 MWT), maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax), anxiety and depression scale and karnofsky performance status scale. RESULTS: Both fibrinogen and CRP were higher 1 month after surgery, although only the change in CRP was statistically significant (p= 0.03). The following functional parameters: 6 MWT, PImax, PEmax, FEV1(%) and FVC(%) decreased after surgery with p <= 0.001 for all the parameters. Anxiety and depression improved and Karnofsky decrease after surgery (p= 0.03, p= 0.01 and p= 0.02; respectively). Change in CRP score following lung resection correlated significantly with changes in fibrinogen (r= 0.40; p= 0.003), change in Karnofsky scale (r= -0.50; p< 0.001) and a borderline significant trend with the 6 MWT (r= -0.28; p= 0.05). With the exception of video assisted thoracoscopic surgery (VATS), who had a significantly lower fibrinogen level 1 month after surgery compared with thoracotomy (p= 0.01), no significant differences in fibrinogen or CRP were noted in other subgroups of patients considered at increased risk for higher levels of inflammation compared with lower risk counterparts. CONCLUSION: Lung cancer resection surgery was associated with increased level of CRP, 1 month after surgery, and correlated directly with change in fibrinogen and inversely with measurement of performance status. VATS provided lower level of fibrinogen after surgery. PMID- 26484611 TI - Unpredictable changes of selected miRNA in expression profile of HNSCC. AB - BACKGROUND: The necessity of prediction and treatment outcome improvement of HNSCC needs to find new biomarkers. miRNAs seem to be good candidate for that. OBJECTIVE: Analysis of selected 5 miRNAs (let-7d, miR-18a, miR-21, miR-205 and miR-375) as potential biomarkers that allows to distinguish tumor and healthy tissue taken from HNSCC patients. METHODS: Tumor and normal epithelial tissues were obtained from 75 HNSCC patients to analyze selected miRNAs. RESULTS: Analysis indicated significant increase of miR-21 and miR-205 in tumor when compared with healthy tissue (p= 0.0069 and p= 0.0029, respectively). There was a significant correlation between let-7d and miR-18a. let-7d was down-regulated in 34.67% cases, miR-18a in 29.33%, miR-21 in 20%, miR-205 in 30.67% and miR-375 in 52% cases. At the same time over-expression of let-7d was detected in 18.67% cases, miR-18a in 22.67%, miR-21 in 48%, miR-205 in 41.33% and miR-375 in 52% cases. There was no correlation between miRNA expression and clinical data and the course of illness. CONCLUSION: Our study indicated that miR-21 and miR-205 can be used to analyze the clarity of surgical margins and that concomitant changes in the expression of let-7 and miR-18a in tumor tissues might represent important future markers indicating the biology of HNSCC. These observations will help with developing personalization for HNSCC patients' treatment. PMID- 26484612 TI - First-Principles Molecular Structure Search with a Genetic Algorithm. AB - The identification of low-energy conformers for a given molecule is a fundamental problem in computational chemistry and cheminformatics. We assess here a conformer search that employs a genetic algorithm for sampling the low-energy segment of the conformation space of molecules. The algorithm is designed to work with first-principles methods, facilitated by the incorporation of local optimization and blacklisting conformers to prevent repeated evaluations of very similar solutions. The aim of the search is not only to find the global minimum but to predict all conformers within an energy window above the global minimum. The performance of the search strategy is (i) evaluated for a reference data set extracted from a database with amino acid dipeptide conformers obtained by an extensive combined force field and first-principles search and (ii) compared to the performance of a systematic search and a random conformer generator for the example of a drug-like ligand with 43 atoms, 8 rotatable bonds, and 1 cis/trans bond. PMID- 26484613 TI - Analysis of Yersinia enterocolitica Effector Translocation into Host Cells Using Beta-lactamase Effector Fusions. AB - Many gram-negative bacteria including pathogenic Yersinia spp. employ type III secretion systems to translocate effector proteins into eukaryotic target cells. Inside the host cell the effector proteins manipulate cellular functions to the benefit of the bacteria. To better understand the control of type III secretion during host cell interaction, sensitive and accurate assays to measure translocation are required. We here describe the application of an assay based on the fusion of a Yersinia enterocolitica effector protein fragment (Yersinia outer protein; YopE) with TEM-1 beta-lactamase for quantitative analysis of translocation. The assay relies on cleavage of a cell permeant FRET dye (CCF4/AM) by translocated beta-lactamase fusion. After cleavage of the cephalosporin core of CCF4 by the beta-lactamase, FRET from coumarin to fluorescein is disrupted and excitation of the coumarin moiety leads to blue fluorescence emission. Different applications of this method have been described in the literature highlighting its versatility. The method allows for analysis of translocation in vitro and also in in vivo, e.g., in a mouse model. Detection of the fluorescence signals can be performed using plate readers, FACS analysis or fluorescence microscopy. In the setup described here, in vitro translocation of effector fusions into HeLa cells by different Yersinia mutants is monitored by laser scanning microscopy. Recording intracellular conversion of the FRET reporter by the beta-lactamase effector fusion in real-time provides robust quantitative results. We here show exemplary data, demonstrating increased translocation by a Y. enterocolitica YopE mutant compared to the wild type strain. PMID- 26484614 TI - Frailty and geography: should these two factors be added to the ABCDE contemporary guide to diabetes therapy? AB - On the road towards personalized treatments for type 2 diabetes, we suggest here that two parameters could be added to the ABCDE algorithm, 'F' for frailty and 'G' for geography. Indeed, the progressive ageing of population is causing a simultaneous increase of frailty worldwide. The identification of the optimal therapeutic approach is often difficult in frail subjects because of the complexity of 'frailty syndrome'. Nevertheless, given the relevance of diabetes in the development and progression of frailty, a safe and effective cure of diabetes is extremely important to guarantee a good medical outcome. There are few data about diabetes treatment in this delicate category of patients, and the choice of the appropriate therapy mostly remains a challenge. Moreover, type 2 diabetes affects more than 382 million people of different countries, races and ethnicities. To face the lack of solid evidence-based medicine for the treatment of diabetes in different ethnic groups, it is extremely important to increase knowledge about the different pathophysiology of diabetes according to ethnicity. In this way, a tailored approach to treatment of various ethnic groups living in the same or different regions can eventually be developed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26484615 TI - Synergetic Effect of Yolk-Shell Structure and Uniform Mixing of SnS-MoS2 Nanocrystals for Improved Na-Ion Storage Capabilities. AB - Mixed metal sulfide composite microspheres with a yolk-shell structure for sodium ion batteries are studied. Tin-molybdenum oxide yolk-shell microspheres prepared by a one-pot spray pyrolysis process transform into yolk-shell SnS-MoS2 composite microspheres. The discharge capacities of the yolk-shell and dense-structured SnS MoS2 composite microspheres for the 100th cycle are 396 and 207 mA h g(-1), and their capacity retentions measured from the second cycle are 89 and 47%, respectively. The yolk-shell SnS-MoS2 composite microspheres with high structural stability during repeated sodium insertion and desertion processes have low charge-transfer resistance even after long-term cycling. The synergetic effect of the yolk-shell structure and uniform mixing of the SnS and MoS2 nanocrystals result in the excellent sodium-ion storage properties of the yolk-shell SnS-MoS2 composite microspheres by improving their structural stability during cycling. PMID- 26484616 TI - WAYS OF ACQUIRING FLYING PHOBIA. AB - BACKGROUND: The few studies that have explored how flying phobia is acquired have produced contradictory results. We hypothesized that classical conditioning plays a role in acquiring flying phobia and investigated if vicarious (model) learning, informational learning through media, and experiencing stressful life events at the time of onset of phobia also play a role. METHOD: Thirty patients with flying phobia and thirty healthy controls matched on age, sex, and education were interviewed with the Mini-DIPS, the short German version of the Anxiety Disorders Interview Schedule (DSM-IV diagnostic criteria) and the Fear-of-Flying History Interview. RESULTS: Fifty Percent of patients with flying phobia and 53% of healthy controls reported frightening events in the air. There was no significant difference between the two samples. Thus there were not more classical conditioning events for patients with flying phobia. There also was no significant difference between the two samples for vicarious (model) learning: 37% of flying phobia patients and 23% of healthy controls felt influenced by model learning. The influence of informational learning through media was significantly higher for the clinical sample (70%) than for the control group (37%). Patients with flying phobia experienced significantly more stressful life events in the period of their frightening flight experience (60%) than healthy controls (19%). CONCLUSIONS: Frightening experiences while flying are quite common, but not everybody develops a flying phobia. Stressful life events and other factors might enhance conditionability. Informational learning through negative media reports probably reinforces the development of flying phobia. Clinical implications are discussed. PMID- 26484617 TI - Mechanisms of Particle Charging by Surfactants in Nonpolar Dispersions. AB - Electric charging of colloidal particles in nonpolar solvents plays a crucial role for many industrial applications and products, including rubbers, engine oils, toners, or electronic displays. Although disfavored by the low solvent permittivity, particle charging can be induced by added surfactants, even nonionic ones, but the underlying mechanism is poorly understood, and neither the magnitude nor the sign of charge can generally be predicted from the particle and surfactant properties. The conclusiveness of scientific studies has been limited partly by a traditional focus on few surfactant types with many differences in their chemical structure and often poorly defined composition. Here we investigate the surface charging of poly(methyl methacrylate) particles dispersed in hexane-based solutions of three purified polyisobutylene succinimide polyamine surfactants with "subtle" structural variations. We precisely vary the surfactant chemistry by replacing only a single electronegative atom located at a fixed position within the polar headgroup. Electrophoresis reveals that these small differences between the surfactants lead to qualitatively different particle charging. In the respective particle-free surfactant solutions we also find potentially telling differences in the size of the surfactant aggregates (inverse micelles), the residual water content, and the electric solution conductivity as well as indications for a significant size difference between oppositely charged inverse micelles of the most hygroscopic surfactant. An analysis that accounts for the acid/base properties of all constituents suggests that the observed particle charging is better described by asymmetric adsorption of charged inverse micelles from the liquid bulk than by charge creation at the particle surface. Intramicellar acid-base interaction and intermicellar surfactant exchange help rationalize the formation of micellar ions pairs with size asymmetry. PMID- 26484618 TI - One Pot Synthesis of a Polyisoprene Polyrotaxane and Conversion to a Slide-Ring Gel. AB - Synthesis of a cyclodextrin (CD) polyrotaxane is achieved for the first time by simultaneous free radical polymerization of isoprene, threading by CD, and stoppering by copolymerization of styrene. This reaction is performed in an eco friendly manner in an aqueous medium similar to classical emulsion polymerization. Threaded CD rings of the polyrotaxane are cross-linked by hexamethylene diisocyanate, leading to highly elastic slide-ring gels. PMID- 26484619 TI - Maternal and pediatric health and disease: integrating biopsychosocial models and epigenetics. AB - The concepts of allostasis (stability through adaptation) and accumulated life stress (McEwen's allostatic load) aim to understand childhood and adult outcomes. Chronic malnutrition, changes in social condition, and adverse early-life experiences may program phenotypes and contribute to long-lasting disease risk. However, integration of life course approaches, social and economic contexts, and comparison among different biopsychosocial models has not generally been explored. This review critically examines the literature and evaluates recent insights into how environmental stress can alter lifelong hypothalamic-pituitary adrenal axis and immune system responsiveness and induce metabolic and neurodevelopmental maladaptation. Models of biopsychosocial stress overlap but may consider different conditions. Concepts include allostasis, which incorporates hormonal responses to predictable environmental changes, and Geronimus's "weathering," which aims to explain how socially structured, repeated stress can accumulate and increase disease vulnerability. Weathering emphasizes roles of internalized/interpersonal racism in outcomes disparities. For Mexican immigrants and Mexican Americans, the "acculturation" framework has proven especially useful to explore disparities, including preterm birth and neuropsychiatric risks in childhood. Complexities of stress assessments and recent research into epigenetic mechanisms mediating effects of physical, nutritional, psychological, and social stress are reviewed. PMID- 26484620 TI - Beyond screening: a review of pediatric primary care models to address maternal depression. AB - Depression is one of the most debilitating chronic disorders in the United States, affecting 15 million children in homes with depressed mothers, many of whom endure household chaos, inconsistent nurturing, inadequate safety practices, and harsh discipline. Depressed mothers are under diagnosed and undertreated, yet there is broad consensus about the importance of identifying and managing maternal depression, as reflected in recommendations by pediatric and obstetric professional organizations to routinely screen for perinatal depression. Screening was shown to be acceptable to women and most pediatric providers, and adding a screening component need not impair clinic efficiency. Screening, however, is not sufficient, and there are few models in the literature to guide medical practices in implementing successful interventions to identify, treat, and prevent maternal depression, particularly in the pediatric setting. We reviewed the literature and identified six studies that evaluated models for screening and managing mothers' depression in pediatric primary care settings. Some of these interventions have promise, but no studies characterized health outcomes of the depressed mothers and children. We discuss the components of these models, their implementation, and the practice and research needed to create effective pediatrics-based systems to reduce the negative effects of maternal depression on mothers, children, and families. PMID- 26484621 TI - Effect of socioeconomic status disparity on child language and neural outcome: how early is early? AB - It is not news that poverty adversely affects child outcome. The literature is replete with reports of deleterious effects on developmental outcome, cognitive function, and school performance in children and youth. Causative factors include poor nutrition, exposure to toxins, inadequate parenting, lack of cognitive stimulation, unstable social support, genetics, and toxic environments. Less is known regarding how early in life adverse effects may be detected. This review proposes to elucidate "how early is early" through discussion of seminal articles related to the effect of socioeconomic status on language outcome and a discussion of the emerging literature on effects of socioeconomic status disparity on brain structure in very young children. Given the young ages at which such outcomes are detected, the critical need for early targeted interventions for our youngest is underscored. Further, the fiscal reasonableness of initiating quality interventions supports these initiatives. As early life adversity produces lasting and deleterious effects on developmental outcome and brain structure, increased focus on programs and policies directed to reducing the impact of socioeconomic disparities is essential. PMID- 26484622 TI - Effect of phototherapy with turquoise vs. blue LED light of equal irradiance in jaundiced neonates. AB - BACKGROUND: Blue light with peak emission around 460 nm is the preferred treatment of neonatal hyperbilirubinemia. However, studies using fluorescent light tubes have suggested that turquoise light with peak emission at 490 nm may be more efficient. At present, the predominant light source for phototherapy is light emitting diodes (LEDs). Hence, the aim of this study was to compare the bilirubin-reducing effect in jaundiced neonates treated either with turquoise or with blue LED light with peak emission at 497 or 459 nm, respectively, with equal irradiance on the infants. METHODS: Infants with gestational age >=33 wk and uncomplicated hyperbilirubinemia were randomized to either turquoise or blue LED light and were treated for 24 h. The mean irradiance footprint at skin level was 5.2 * 10(15) and 5.1 * 10(15) photons/cm(2)/s, respectively. RESULTS: Forty-six infants received turquoise light and 45 received blue light. The median (95% confidence interval) decrease of total serum bilirubin was 35.3% (32.5; 37.3) and 33.1% (27.1; 36.8) for infants treated with turquoise and blue lights, respectively. The difference was nonsignificant (P = 0.53). The decrease was positively correlated to postnatal age and negatively to birth weight. CONCLUSION: Using LED light of equal irradiance, turquoise and blue lights had equal bilirubin-reducing effect on hyperbilirubinemia of neonates. PMID- 26484624 TI - The state of evidence-based parenting interventions for parents who are substance involved. AB - Approximately 70 million children and adolescents live with at least one parent who abuses or is dependent on alcohol or an illicit substance. Given the negative parenting practices that substance-involved mothers and fathers tend to exhibit as well as the poor outcomes that their children, particularly their young children, experience, evidence-based parenting interventions are an important complement to substance abuse treatments. At this time, there are few studies that compare the efficacy of parenting interventions for these parents, however. Nonetheless, research has begun to examine skill-based and attachment-based parenting interventions for substance-involved families with young children. These parenting interventions should be considered within the context of the neurobiology of substance abuse, which emphasizes the role of dopamine in the reward systems that promote substance use. In the context of these neurobiological connections, parenting interventions that engender repeated intense emotional experiences may stimulate this same reward system and, therefore, may be more efficacious. Attachment-based interventions are particularly promising when such connections are considered. More attention needs to be paid to bringing impactful parenting interventions to substance-involved parents with young children. PMID- 26484625 TI - A pilot study of factors associated with glycaemic control in adults with Type 1 diabetes mellitus on insulin pump therapy. AB - AIMS: To identify the knowledge and management factors associated with glycaemic control among adults with Type 1 diabetes mellitus treated with insulin pump therapy. METHODS: A cross-sectional study of adults with Type 1 diabetes mellitus on insulin pump therapy for at least 12 months (n = 50, 18-70 years old) was undertaken between December 2013 and May 2014. A new questionnaire was developed to evaluate participants' knowledge and management related to insulin pump therapy, and were correlated with insulin pump data, HbA1c and frequency of hypoglycaemia. RESULTS: Participants who changed their insulin pump settings when indicated had significantly better glycaemic control than those who did not (P = 0.04). Multivariate logistic regression analysis found that better overall insulin pump therapy management was a significant predictor of better glycaemic control (odds ratio 4.45, 95% confidence interval 1.61-12.3; P = 0.004) after adjusting for potential confounders including age, gender, duration of diabetes and insulin pump therapy. However, overall insulin pump therapy knowledge was not a significant predictor of glycaemic control (P = 0.058). There was no significant association between frequency of hypoglycaemia and insulin pump therapy knowledge or management. CONCLUSIONS: We identified some key knowledge and management factors associated with glycaemic control in adults with Type 1 diabetes mellitus on insulin pump therapy using a newly designed questionnaire. The pilot study assessed the clinical utility of this evaluation tool, which may facilitate provision of targeted education to insulin pump therapy users to achieve optimal glycaemic control. PMID- 26484623 TI - Biological, environmental, and social influences on childhood obesity. AB - The prevalence of childhood obesity has increased globally over the past three decades, with evidence of recent leveling off in developed countries. Reduction in the, currently high, prevalence of obesity will require a full understanding of the biological and social pathways to obesity in order to develop appropriately targeted prevention strategies in early life. Determinants of childhood obesity include individual level factors, including biological, social, and behavioral risks, acting within the influence of the child's family environment, which is, in turn, imbedded in the context of the community environment. These influences act across childhood, with suggestions of early critical periods of biological and behavioral plasticity. There is evidence of sex and gender differences in the responses of boys and girls to their environments. The evidence that determinants of childhood obesity act at many levels and at different stages of childhood is of policy relevance to those planning early health promotion and primary prevention programs as it suggests the need to address the individual, the family, the physical environment, the social environment, and social policy. The purpose of this narrative review is to summarize current, and emerging, literature in a multilevel, life course framework. PMID- 26484626 TI - A combination of stereological methods, biochemistry and electron microscopy for the investigation of drug treatment effects in experimental animals. AB - Some chemotherapeutic agents used for breast cancer (BC) treatment can induce severe side effects in the ovarian tissue. The combination of cyclophosphamide and docetaxel (TC) is widely used for BC treatment; however, its late effects in the ovary are not completely understood. The main purpose of this study was to evaluate the structural and ultrastructural alterations in the ovarian stroma induced by TC treatment. Wistar rats were divided into two groups: a control group and a TC group. They were euthanized 5 months after the end of treatment, and their plasma and ovaries were collected. Important alterations were noted. The serum estradiol level was significantly reduced in the TC group compared with the control group. Additionally, the number of apoptotic nuclei was higher in the TC group. The role of the inflammatory response in the development of ovarian damage was investigated, and we found an increased number of mast cells and increased expression of TNF-alpha in the TC group. The involvement of fibrosis was also investigated. The results showed that the TC group had increased expression levels of TGF-beta1, collagen type I (col-I) and collagen type III (col-III) compared with the control group. Ultrastructural analysis revealed the presence of collagen fibrils in the treated group and illustrated that the ovarian tissue architecture was more disorganized in this group than in the control group. The results from this study are important in the study of chemotherapy-induced ovarian failure and provide further insight into the mechanisms involved in the development of this disease. PMID- 26484628 TI - Interfacial Control of Magnetic Properties at LaMnO3/LaNiO3 Interfaces. AB - The functional properties of oxide heterostructures ultimately rely on how the electronic and structural mismatches occurring at interfaces are accommodated by the chosen materials combination. We discuss here LaMnO3/LaNiO3 heterostructures, which display an intrinsic interface structural asymmetry depending on the growth sequence. Using a variety of synchrotron-based techniques, we show that the degree of intermixing at the monolayer scale allows interface-driven properties such as charge transfer and the induced magnetic moment in the nickelate layer to be controlled. Further, our results demonstrate that the magnetic state of strained LaMnO3 thin films dramatically depends on interface reconstructions. PMID- 26484629 TI - Clinical Trials Integrating Immunotherapy and Radiation for Non-Small-Cell Lung Cancer. AB - Methods of harnessing the immune system to treat cancer have been investigated for decades, but yielded little clinical progress. However, in recent years, novel drugs that allow immune recognition and destruction of tumor cells are emerging as potent cancer therapies. Building upon previous immunotherapy strategies that included therapeutic vaccines, recombinant cytokines, and other immunostimulatory agents, newer immunotherapy agents targeting immune checkpoints including programmed cell death 1, programmed cell death ligand-1, and cytotoxic T-lymphocyte-associated protein 4, among others, have garnered substantial enthusiasm after demonstrating clinical activity in a broad spectrum of tumor types. Trials evaluating immune checkpoint inhibitors in metastatic non-small cell lung cancer (NSCLC) demonstrate robust and durable responses in a subset of patients. However, with overall response rates less than 20%, combinatorial strategies that extend the benefit of these agents to more patients are desirable. The integration of radiotherapy with immunotherapy is a conceptually promising strategy, as radiotherapy has potent immunomodulatory effects and may contribute not only to local control but may also augment systemic antitumor immune response. Preclinical data and case reports suggest the potential for robust clinical responses in metastatic NSCLC patients using this strategy, but prospective clinical trials evaluating the integration of radiation and immunotherapy are limited. The use of immunotherapy in nonmetastatic settings is also intriguing but understudied. We review the potential clinical settings of interest for the partnering of immunotherapy and radiation in NSCLC, including early stage, locally advanced, and metastatic disease, and review completed, accruing, and developing clinical trials. PMID- 26484630 TI - Prognostic Significance of CT-Determined Sarcopenia in Patients with Small-Cell Lung Cancer. AB - INTRODUCTION: The primary objective of this study was to determine the prognostic significance of computed tomography (CT)-determined sarcopenia in small-cell lung cancer (SCLC) patients. METHODS: This retrospective study consisted of a total of 149 consecutive SCLC patients. The cross-sectional area of muscle at the level of the third lumbar vertebra (L3) was measured using baseline CT images. Sarcopenia was defined as a L3 muscle index of less than 55 cm/m for men and of less than 39 cm/m for women as proposed by international consensus of cancer cachexia. In addition, Korean-specific cutoffs for sarcopenia was also applied (49 cm/m for men and 31 cm/m for women). Overall survival (OS) and clinical characteristics of patients with or without sarcopenia were compared. RESULTS: Mean patient age was 68.6 +/- 9.5 years. Most were male (85.3%) and 67.8% had extensive disease at time of diagnosis. Sarcopenia was present in 118 patients (79.2%) and was significantly related to an advanced age (p = 0.028), male sex (p < 0.001), lower body mass index (p < 0.001), and poor performance status (p = 0.049). Sarcopenic patients had shorter OS than nonsarcopenic patients (median: 8.6 months versus 16.8 months; p = 0.031). Multivariable analysis revealed that sarcopenia was an independent prognostic factor of poor survival (hazards ratio: 1.68; 95% confidence interval: 1.04-2.72; p = 0.034), along with extensive stage (p < 0.001), supportive care only (p < 0.001), and an elevated lactate dehydrogenase level (p = 0.020). Using Korean sarcopenia cutoffs, sarcopenic patients were also found to have poorer OS than nonsarcopenic patients, however, the survival difference was not statistically significant (median: 8.4 months versus 12.7 months; p = 0.144 by the log-rank test). CONCLUSIONS: Sarcopenia as determined by CT could be used to predict prognosis in patients with SCLC. Optimum reference values to predict cancer-specific outcomes should be tailored by further studies. PMID- 26484631 TI - A Prospective Phase II Study of Cisplatin and Cremophor EL-Free Paclitaxel (Genexol-PM) in Patients with Unresectable Thymic Epithelial Tumors. AB - BACKGROUND: We conducted a prospective phase II study of cisplatin plus cremophor EL-free paclitaxel (Genexol-PM) in patients with unresectable thymic epithelial tumors to determine the efficacy and tolerability of the combination therapy. METHODS: Patients were treated with cisplatin (70 mg/m) and Genexol-PM (230 mg/m) on day 1 of a 3-week cycle as first-line palliative chemotherapy. The primary end point of this study was objective response rate, and the secondary end points included toxicity, progression-free survival (PFS), overall survival, correlation between early 18F-fluorodeoxyglucose positron emission tomography/computed tomography response and PFS, and correlation between baseline flurododeoxyglucose uptake and histology. RESULTS: Forty-two patients with unresectable thymoma (n = 14) or thymic carcinoma (n = 28) were enrolled between May 2012 and October 2014. The median age was 59 years (range: 25-77) and 30 patients (71%) were male, and 39 patients (93%) had an ECOG PS of 1. The median number of treatment cycles was six (range: 1-6). For 40 assessable patients, the objective response rate was 62.5% (95% confidence interval [CI]: 47.6-77.4) with rates of 46% (95% CI: 23.3 76.9) for advanced thymoma (n = 13) and 70% (95% CI: 52.0-82.1) for thymic carcinoma (n = 27). With a median follow-up of 15.5 months, the median PFS for all 42 patients was 9.8 months (11.4 months for thymoma versus 8.1 months for thymic carcinoma). The 2-year overall survival was 77.9% for thymoma and 65.9% for thymic carcinoma. There were no treatment-related deaths. The most common grade 3 and 4 treatment-related adverse event was neutropenia in 11 patients (26%). Eight patients (19%) experienced grade 2 hypersensitivity reactions. There was no correlation between early positron emission tomography response and PFS, but tumor histology (thymoma versus thymic carcinoma) was correlated with SUVmax before chemotherapy. CONCLUSIONS: These data suggest that combination of cisplatin and Genexol-PM is highly effective and tolerable for the treatment of unresectable thymic epithelial tumors. PMID- 26484632 TI - Identification of Unsaturated and 2H Polyfluorocarboxylate Homologous Series and Their Detection in Environmental Samples and as Polymer Degradation Products. AB - A pair of homologous series of polyfluorinated degradation products have been identified, both having structures similar to perfluorocarboxylic acids but (i) having a H substitution for F on the alpha carbon for 2H polyfluorocarboxylic acids (2HPFCAs) and (ii) bearing a double bond between the alpha-beta carbons for the unsaturated PFCAs (2uPFCAs). Obtaining an authentic sample containing 2uPFOA and 2HPFOA, we optimized a mass-spectrometric multiple-reaction-monitoring (MS/MS) technique and then identified uPFCA and HPFCA homologous series in sludge applied agricultural soils and fodder grasses for cattle grazing. Analysis of samples from a degradation experiment of commercial fluorotelomer-based polymers (FTPs), the dominant product of the fluorotelomer industry, confirmed that commercial FTPs are a potential source of uPFCAs and HPFCAs to the environment. We further confirmed the identity of the uPFCAs by imposing high-energy ionization to decarboxylate the uPFCAs then focused on the fluorinated chains in the first MS quadrupole. We also employed this high-energy ionization to decarboxylate and analyze PFCAs by MS/MS (for the first time, to our knowledge). In exploratory efforts, we report the possible detection of unsaturated perfluorooctanesulfonate in environmental samples, having a conceptual double bond structure analogous to uPFOA. Using microcosms spiked with fluorotelomer compounds, we found 2uPFOA and 2HPFOA to be generated from unsaturated 8:2 fluorotelomer acid (8:2 FTUCA) and propose beta- and alpha-oxidation mechanisms for generation of these compounds from 8:2 FTUCA. In light of these experimental results, we also reexamined the proposed biodegradation pathways of 8:2 fluorotelomer alcohol. PMID- 26484633 TI - Balanced TH1 and TH2 immunopotentiating effects of silicates partly containing nanoparticles present in calcined serpentine. AB - Calcined Serpentine (CS) is used in various formulations of alternative systems of medicine as a tonic to vital organs and as an anti-inflammatory agent. The process of calcination or incineration is believed to render non-toxic, gently absorbable, adaptable and digestible properties to the mineral compounds. The present study characterized CS and also evaluated its immunostimulatory potential. CS was characterized by using transmission electron microscopy (TEM), X-ray powder diffraction, atomic absorption spectroscopy and CHNS analysis. The characterized CS was further evaluated for its immunomodulatory potential in Swiss mice. X-Ray diffraction analysis revealed that the CS contained silicates of magnesium, calcium and iron as major minerals. Elemental composition and heavy metal analyses showed a presence of various inorganic elements/heavy metals, albeit at levels well below daily permissive intake values. TEM analysis of the test CS revealed a presence of nano particles with an average size of 10-20 nm (~ 26% of total material). Oral administration of CS to mice at 50, 75, 100 or 200 MUg/kg body weight for 10 days led to enhanced levels of total IgG, IgG1, IgG2a and IgG2b in ovalbumin-immunized mice as well as ex vivo lymphocyte proliferation and levels of TH1 (IL-2, IFNgamma) and TH2 (IL-4, IL-10) cytokines produced by their cultured splenocytes. Similarly, CS treatment resulted in enhanced delayed type hypersensitivity responses in GRBC-primed hosts. CS also activated host peritoneal macrophages, as indicated by increases in phagocytic activity and in TLR-2, CD80 and CD86 expression. The CS did not affect liver, kidney and spleen histology. Taken together, the results indicated that absorbed CS was stimulatory of host cell-mediated immune responses. It is hypothesized for now that the immunomodulatory effect of CS may have been due, in part, to a presence of nanoparticles on the CS; further study is required to validate this viewpoint. PMID- 26484635 TI - Mortality Trends in Crohn's Disease and Ulcerative Colitis: A Population-based Study in Quebec, Canada. AB - BACKGROUND: Mortality rates greater than in the general population have been reported in the population with Crohn's disease (CD), but reports for ulcerative colitis (UC) are conflicting. Trends with time were rarely described. We aimed to assess whether CD and UC mortality in Quebec differs from that in the general population and to describe the trends over a 10-year observation period. METHODS: This is a population-based cohort study using the Quebec administrative health databases and death certificates registry. All-cause and cause-specific standardized mortality ratios (SMRs) were computed for 1999 to 2008. A time trend analysis was used to assess changes in the SMR with the calendar year. RESULTS: All-cause mortality was significantly increased in CD and UC compared to the general population: SMR: CD 1.45 (95% confidence interval: 1.34-1.58), UC 1.21 (95% confidence interval: 1.12-1.32). In CD, mortality from digestive conditions, all neoplasms, digestive neoplasms, and colorectal, lymphatic, and lung cancer was significantly higher than in the general population. In UC, mortality from digestive, respiratory, and infectious conditions was also significantly increased. In both CD and UC, there was a decrease with time in all-cause SMRs and in digestive conditions, digestive neoplasms, colorectal cancer, and infectious diseases. SMRs for lung cancer and respiratory conditions increased over time in CD. CONCLUSIONS: All-cause mortality was significantly higher in CD and UC populations than in the general population. However, a decreasing trend with time was observed in all-cause and some cause-specific SMRs. In CD, SMRs for lung cancer and respiratory conditions increased during the observation period. PMID- 26484634 TI - Decomposition of spontaneous fluctuations in tumour oxygenation using BOLD MRI and independent component analysis. AB - BACKGROUND: Solid tumours can undergo cycles of hypoxia, followed by reoxygenation, which can have significant implications for the success of anticancer therapies. A need therefore exists to develop methods to aid its detection and to further characterise its biological basis. We present here a novel method for decomposing systemic and tumour-specific contributions to fluctuations in tumour deoxyhaemoglobin concentration, based on magnetic resonance imaging measurements. METHODS: Fluctuations in deoxyhaemoglobin concentration in two tumour xenograft models of colorectal carcinoma were decomposed into distinct contributions using independent component analysis. These components were then correlated with systemic pulse oximetry measurements to assess the influence of systemic variations in blood oxygenation in tumours, compared with those that arise within the tumour itself (tumour-specific). Immunohistochemical staining was used to assess the physiological basis of each source of fluctuation. RESULTS: Systemic fluctuations in blood oxygenation were found to contribute to cycling hypoxia in tumours, but tumour-specific fluctuations were also evident. Moreover, the size of the tumours was found to influence the degree of systemic, but not tumour-specific, oscillations. The degree of vessel maturation was related to the amplitude of tumour-specific, but not systemic, oscillations. CONCLUSIONS: Our results provide further insights into the complexity of spontaneous fluctuations in tumour oxygenation and its relationship with tumour pathophysiology. These observations could be used to develop improved drug delivery strategies. PMID- 26484636 TI - Reproductive Planning and Contraception for Women with Inflammatory Bowel Diseases. AB - Women with chronic medical conditions, such as inflammatory bowel diseases, are at increased risk for adverse pregnancy outcomes. Pregnancy outcomes for these conditions are best during stable disease remission. Unfortunately, women with inflammatory bowel disease are equally as likely as the general population to have unintended pregnancies. Patients look to their gastroenterologist for contraceptive counseling; however, the current standards for disease management do not prioritize this topic. Guidelines based on available evidence and expert opinion, such as the Centers for Disease Control U.S. Medical Eligibility Criteria for Contraceptive Use, exist to help practitioners provide safe and effective contraception to women with chronic medical conditions. If health care providers were to educate themselves and screen women with inflammatory bowel disease for risk of unintended pregnancy, there would be a reduction in the number of unintended pregnancies and subsequent adverse neonatal and maternal outcomes. PMID- 26484637 TI - Colloidal Moderate-Refractive-Index Cu2O Nanospheres as Visible-Region Nanoantennas with Electromagnetic Resonance and Directional Light-Scattering Properties. AB - Moderate-refractive-index dielectric nano-spheres are found to possess strong electric and magnetic dipole resonances in the visible region. Owing to the overlap of the electric and magnetic dipole resonances, moderate-refractive-index dielectric nanospheres exhibit directional forward scattering at the strongest scattering peak. Such directional scattering is experimentally observed on colloidal Cu2O nanospheres, which are readily prepared through wet-chemistry methods. PMID- 26484638 TI - Importance of post-translational modifications on the function of key haemostatic proteins. AB - Post-translational modifications (PTMs) such as glycosylation and phosphorylation play an important role on the function of haemostatic proteins and are critical in the setting of disease. Such secondary level changes to haemostatic proteins have wide ranging effects on their ability to interact with other proteins. This review aimed to summarize the knowledge of the common PTMs associated with haemostatic proteins and the implications of such modifications on protein function. Haemostatic proteins that represent the main focus for studies specific to PTMs are von Willebrand factor, tissue factor, factor VIII, antithrombin and fibrinogen. These proteins are susceptible to PTMs by glycosylation, phosphorylation, sulphation, citrullination and nitration, respectively, with a significant impact on their function. During synthesis, vWF must undergo extensive PTMs, with N-linked glycosylation being the most common. Increased phosphorylation of tissue factor results in increased affinity for platelets to the vessel endothelium. Citrullination of antithrombin leads to an increased anticoagulant function of this protein and therefore an anticoagulant state that inhibits clot formation. On the contrary, nitration of fibrinogen has been shown to result in a prothrombotic state, whilst sulphation is required for the normal function of Factor VIII. From this review, it is evident that PTMs of haemostatic proteins as a change in protein structure at a secondary level greatly influences the behaviour of the protein at a tertiary level. PMID- 26484639 TI - Successful immune tolerance induction with low-dose coagulation factor VIII in a patient with hemophilia A from a developing country. AB - Inhibitor development is the most frequent and serious complication of the treatment in patients with hemophilia. Immune tolerance induction (ITI) is the only option of treatment for the eradication of factor VIII (FVIII) inhibitor. We would like to present our case with hemophilia whose FVIII inhibitor eradication was done by a low-dose ITI regimen. Our patient has been applied on-demand therapy until 8 years of age. Secondary prophylaxis was began because of having hemophilic arthropathy. A low titer of FVIII inhibitor (4.2 BU/ml) was detected in the fifth month of the prophylaxis. The peak inhibitor titer of patient was 4.6 BU/ml, and there was no decrease in inhibitor titer in the follow-up duration. The low-dose ITI (50 IU/kg, 3 days a week) was started. His inhibitor level was detected negative and the recovery test was ameliorated in the 15th of the ITI therapy. High-dose regimen ITI could not be given particularly in developing countries such as Turkey in view of the high cost of treatment. Patients who had good risk factors might be successfully treated by using low dose ITI regimen as effective as high-dose ITI regimen. PMID- 26484640 TI - Does intermittent pneumatic compression increase the risk of pulmonary embolism in deep venous thrombosis after joint surgery? AB - The present study aimed to identify the incidence and risk factors of symptomatic pulmonary embolism and evaluate the safety of early intermittent pneumatic compression application in patients with deep venous thrombosis (DVT) after joint surgery. A total of 144 patients with DVT undergoing joint surgery were divided into two groups according to the appearance of symptomatic pulmonary embolism. Venography and computed tomographic pulmonary angiography were utilized as the assessment methods. The total incidence of symptomatic pulmonary embolism was 0.39% after joint surgery. However, the prevalence increased to 3.5% when computed in patients with DVT. Patients with symptomatic pulmonary embolism were older than those without symptomatic pulmonary embolism (69 +/- 4 versus 61 +/- 15 years, P = 0.04). The occurrence rate of symptomatic pulmonary embolism in patients with diabetes mellitus was much higher than that in the patients without diabetes mellitus (40.0% versus 8.6%, respectively, P = 0.02). The prevalence of symptomatic pulmonary embolism after joint surgery in patients with DVT was not distinctive. Increased age and diabetes mellitus put patients with DVT at risk of suffering symptomatic pulmonary embolism after joint surgery. In addition, early postoperative application of intermittent pneumatic compression was safe in these patients. PMID- 26484641 TI - Fatal massive and recurring pulmonary embolism followed by thrombocytopenia developed after heparin and warfarin treatment in a patient with metastatic breast cancer with an incidental large right atrial thrombus. AB - A thromboembolic complication such as pulmonary embolism in patients who had cancer and mobile thrombi in the heart is a rare but fatal complication. Surgical thromboembolectomy is considered as the classical treatment of choice. In case of inoperable patient, catheter-directed therapy may be an alternative treatment. We report an interesting case of metastatic breast cancer with a large and mobile right atrial thrombus complicated by a massive and subsequently recurring pulmonary embolism, followed by thrombocytopenia developed after heparin and warfarin treatment. PMID- 26484642 TI - Interleukin-17-producing CD4+ T lymphocytes are increased in patients with primary immune thrombocytopenia. AB - The present study was performed to investigate the role of interleukin-17 producing CD4-positive T cells in the pathogenesis of primary immune thrombocytopenia (ITP). Peripheral blood was collected from ITP patients and healthy controls. The immunophenotyping of T lymphocytes and the detection of T helper 1/2/17 (Th1/Th2/Th17) cells were performed by flow cytometry, Th1/Th2/Th17 associated cytokines were determined by cytokines microarray and ELISA. The association between Th17 and T regulatory cells (Tregs) was also investigated. The percentage of Th17 and Th1 cells were markedly increased in ITP patients especially in those with severe ITP compared with normal controls. Th17 cytokines microarray revealed the upregulation of proinflammatory cytokines and downregulation of inflammatory inhibitory cytokines in ITP patients compared with that in the normal controls. Further ELISA analysis verified high levels of Th17 associated proinflammatory cytokines such as interleukin-17A/F, interleukin-6 and interleukin-23 and low levels of inflammatory inhibitory factors including interleukin-10 and transforming growth factor-beta in ITP patients compared with normal controls. We also observed that the ratio of Th17/Treg was significantly higher in severe ITP than that in mild ITP and normal controls and inversely correlated with platelet count. In addition, Tregs from ITP patients could suppress the secretion of interferon-gamma by effector CD4-positive T cells, but had no effect on interleukin-17 production in vitro. Th17 cells are increased in ITP patients, and the inversion of Th17/Treg may contribute to the activation of autoimmunity. PMID- 26484643 TI - Efficacy and safety of factor eight inhibitor bypassing activity prophylaxis evaluation in young patients with hemophilia and high titer inhibitor. PMID- 26484644 TI - Yes or no for secondary prophylaxis in afibrinogenemia? PMID- 26484645 TI - Dabigatran etexilate versus low-molecular weight heparin to control consumptive coagulopathy secondary to diffuse venous vascular malformations. AB - Diffuse venous malformations can be associated with a consumptive coagulopathy characterized by a reduction of fibrinogen level, platelet count and elevated D dimer level. We report a case of a patient with extensive venous malformations, hemorrhagic symptoms and biological signs of intravascular coagulopathy. She was initially treated effectively with low-molecular weight heparin (LMWH) (enoxaparin 1 mg/kg, bid) and switched to low-dose dabigatran etexilate (110 mg bid) for more than 2 years. Both treatments showed a similar clinical efficacy with the absence of bleeding or thrombotic complications. Compared with LMWH, dabigatran etexilate provided a similar correction of the fibrinogen level and platelet count but was less effective to reduce the D-dimer level. Although dabigatran etexilate can be safely used to control the consumptive coagulopathy secondary to venous malformation and provides a practical alternative to LMWH, its efficacy in vivo at a low dose to reduce the D-dimer level was lower than that of LMWH. PMID- 26484646 TI - Severe hemophilia in a girl infant with mosaic Turner syndrome and persistent hyperplastic primary vitreous. AB - A 6-month-old girl was referred by an ophthalmologist because of postoperative bleeding. She was scheduled for operation because of persistent hyperplastic primary vitreous. Workups were done and prolonged partial thromboplastin time with normal platelet count, normal bleeding time, and prothrombin time were detected. There was negative family history of bleeding tendency in both maternal and paternal family, so at the first step, Factor XI assay was requested which was normal. Then, von Willebrand factor and factor VIII were assayed which was 127% and less than 1%, respectively. Severe factor VIII deficiency was not suspected in a girl unless in siblings of a hemophilic patient who gets married with her carrier cousin. Chromosomal study and genetic testing were requested and mosaic Turner syndrome (45 XO) with ring X (p22, 2q13) along with inversion 22 (hemizygote) was detected. Abdominal and pelvic sonography showed absence of both ovaries with presence of infantile uterus. Maternal genetic study was in favor of carrier of hemophilia (heterozygote inversion 22). To the best of our knowledge, this is the first case of association of Turner syndrome with severe hemophilia A and persistent hyperplastic primary vitreous. PMID- 26484647 TI - Factors determining clot resolution in patients with acute pulmonary embolism. AB - There are limited data on the rate of clot resolution after acute pulmonary embolism and risk factors for residual emboli. The aim of the present study was to investigate the rate of clot resolution over time and identify risk factors of residual emboli in pulmonary embolism patients. We retrospectively analyzed pulmonary embolism patients with follow-up computed tomography (CT) scans taken between day 3 and day 90. The patients were classified into three cohorts, depending on the time of CT scan: day 3-7, day 8-21, and day 22-90. Each cohort was regrouped into the residual embolus and complete resolution groups. The rate of complete resolution of pulmonary emboli was 24% at 3-7 days, 47% at 8-21 days, and 78% at 22-90 days. In a multivariate analysis, independent predictors in each cohort were lobar or larger pulmonary artery pulmonary embolism and a right ventricle/left ventricle diameter ratio within 1 week, lobar or larger pulmonary artery pulmonary embolism at 1-3 weeks, and central pulmonary embolism at 3 weeks to 3 months. The rate of venous thromboembolism (VTE) recurrence, frequency of an adverse outcome, and in-hospital mortality did not differ between the two groups in each cohort. Complete resolution of pulmonary emboli occurred in most pulmonary embolism patients. Regardless of the time interval, larger pulmonary artery involvement by pulmonary emboli was only independent predictor of residual emboli. The presence of residual emboli was not associated with an adverse outcome of pulmonary embolism and rate of VTE recurrence. PMID- 26484648 TI - Rate Coefficient for the (4)HeMU + CH4 Reaction at 500 K: Comparison between Theory and Experiment. AB - The rate constant for the H atom abstraction reaction from methane by the muonic helium atom, HeMU + CH4 -> HeMUH + CH3, is reported at 500 K and compared with theory, providing an important test of both the potential energy surface (PES) and reaction rate theory for the prototypical polyatomic CH5 reaction system. The theory used to characterize this reaction includes both variational transition state (CVT/MUOMT) theory (VTST) and ring polymer molecular dynamics (RPMD) calculations on a recently developed PES, which are compared as well with earlier calculations on different PESs for the H, D, and Mu + CH4 reactions, the latter, in particular, providing for a variation in atomic mass by a factor of 36. Though rigorous quantum calculations have been carried out for the H + CH4 reaction, these have not yet been extended to the isotopologues of this reaction (in contrast to H3), so it is important to provide tests of less rigorous theories in comparison with kinetic isotope effects measured by experiment. In this regard, the agreement between the VTST and RPMD calculations and experiment for the rate constant of the HeMU + CH4 reaction at 500 K is excellent, within 10% in both cases, which overlaps with experimental error. PMID- 26484649 TI - Occupational therapists' pain knowledge: a national survey. AB - PURPOSE: This study surveyed Canadian occupational therapists to identify whether their pain knowledge is current or if the gaps identified in past studies have remained the same. The findings will provide information to guide the development of targeted pain knowledge translation strategies for occupational therapists. METHOD: A self-report survey, including demographic questions and part of the City of Boston's Rehabilitation Professionals' Knowledge and Attitude Survey (COBS), was disseminated electronically to all members of the Canadian Association of Occupational Therapists. RESULTS: A total of 354 therapists, most came from Ontario, Alberta and Nova Scotia and working in the community, acute care and private practice, participated. Over 50% had 10 years or less of experience. Deficit knowledge areas were identified in pediatric pain, chronic versus acute pain, pain assessment and medications. These findings are largely consistent with deficits identified in pre-2000 studies. CONCLUSIONS: Pain knowledge gaps persist among Canadian occupational therapists and this can, and should, be addressed within the occupational therapist (OT) curriculum and in professional development initiatives. It is concerning that this study identified similar knowledge gaps as those identified in previous studies of OT students and clinicians. Pain is a growing and complex issue with negative impact on occupational performance across the lifespan. Knowledge dissemination of occupational therapy pain assessment and management approaches should be a priority for the profession. IMPLICATIONS FOR REHABILITATION: Pain is a prevalent condition in all age groups of occupational therapists' clients. There appear to be gaps in occupational therapists' evidence-based knowledge of aspects of pain. Occupational therapy training programs and occupational therapy associations should provide education with a particular focus on identified pain knowledge gaps. PMID- 26484650 TI - Exploring phlebotomy technique as a pre-analytical factor in proteomic analyses by mass spectrometry. AB - Multiple reaction monitoring mass spectrometry (MRM-MS) is an emerging technology for blood biomarker verification and validation; however, the results may be influenced by pre-analytical factors. This exploratory study was designed to determine if differences in phlebotomy techniques would significantly affect the abundance of plasma proteins in an upcoming biomarker development study. Blood was drawn from 10 healthy participants using four techniques: (1) a 20-gauge IV with vacutainer, (2) a 21-gauge direct vacutainer, (3) an 18-gauge butterfly with vacutainer, and (4) an 18-gauge butterfly with syringe draw. The abundances of a panel of 122 proteins (117 proteins, plus 5 matrix metalloproteinase (MMP) proteins) were targeted by LC/MRM-MS. In addition, complete blood count (CBC) data were also compared across the four techniques. Phlebotomy technique significantly affected 2 of the 11 CBC parameters (red blood cell count, p = 0.010; hemoglobin concentration, p = 0.035) and only 12 of the targeted 117 proteins (p < 0.05). Of the five MMP proteins, only MMP7 was detectable and its concentration was not significantly affected by different techniques. Overall, most proteins in this exploratory study were not significantly influenced by phlebotomy technique; however, a larger study with additional patients will be required for confirmation. PMID- 26484651 TI - Outcome of total hip arthroplasty, but not of total knee arthroplasty, is related to the preoperative radiographic severity of osteoarthritis. A prospective cohort study of 573 patients. AB - BACKGROUND AND PURPOSE: There is no consensus on the impact of radiographic severity of hip and knee osteoarthritis (OA) on the clinical outcome of total hip arthroplasty (THA) and total knee arthroplasty (TKA). We assessed whether preoperative radiographic severity of OA is related to improvements in functioning, pain, and health-related quality of life (HRQoL) 1 year after THA or TKA. PATIENTS AND METHODS: This prospective cohort study included 302 THA patients and 271 TKA patients with hip or knee OA. In the THA patients, preoperatively 26% had mild OA and 74% had severe OA; in the TKA patients, preoperatively 27% had mild OA and 73% had severe OA. Radiographic severity was determined according to the Kellgren and Lawrence (KL) classification. Clinical assessments preoperatively and 1 year postoperatively included: sociodemographic characteristics and patient-reported outcomes (PROMs): Oxford hip/knee score, hip/knee injury and osteoarthritis outcome score (HOOS/KOOS), SF36, and EQ5D. Change scores of PROMs were compared with mild OA (KL 0-2) and severe OA (KL 3-4) using a multivariate linear regression model. RESULTS: Adjusted for sex, age, preoperative scores, BMI, and Charnley score, radiographic severity of OA in THA was associated with improvement in HOOS "Activities of daily living", "Pain", and "Symptoms", and SF36 physical component summary ("PCS") scale. In TKA, we found no such associations. INTERPRETATION: The decrease in pain and improvement in function in THA patients, but not in TKA patients, was positively associated with the preoperative radiographic severity of OA. PMID- 26484652 TI - The application of the mortality-to-incidence ratio for the evaluation of cancer care disparities globally. PMID- 26484654 TI - Inhibition of an Allergen-Antibody Reaction Related to Japanese Cedar Pollinosis Using DNA Aptamers Against the Cry j 2 Allergen. AB - Japanese cedar pollinosis is one of the most prevalent allergies in Japan. Reducing the allergen content of pollen plays a major role in the alleviation of allergy symptoms. Aptamers, oligonucleotides with an affinity for specific molecules, have great potential for reducing allergic activity. In this study, we report that the anti-Cry j 2 aptamers, CJ2-04 and CJ2-08, inhibited allergen antibody reactions between Cry j 2, one of the major allergens in Japanese cedar pollen, and immunoglobulin E in serum collected from a patient with Japanese cedar pollinosis. In addition, the suppression of Ca(2+) mobilization in basophils, which is related to degranulation, was observed in samples preincubated with either of these DNA aptamers. This study indicates that anti Cry j 2 aptamers may inhibit allergen-antibody reactions and suppress the induction of Japanese cedar pollinosis, possibly leading to a novel external defense against this and other types of allergens. PMID- 26484655 TI - dbHT-Trans: An Efficient Tool for Filtering the Protein-Encoding Transcripts Assembled by RNA-Seq According to Search for Homologous Proteins. AB - In RNA-Seq studies, there are still many challenges for reliably assembling transcripts. Both genome-guided and de novo methods always produce too many false transcripts because of known and unknown factors. Therefore, the postassembly quality filtering is necessary before performing downstream analyses. Here, we present an automatic and efficient tool of dbHT-Trans for filtering the protein encoding transcripts assembled by RNA-Seq. For each candidate transcript, we first deduced all potential open reading frames and translated them into amino acid sequences. By searching against the reference protein database, a transcript would be predicted a false one when it has no homologous sequence. Using this method, it is expected to filter out the falsely assembled transcripts of protein encoding genes. Application of dbHT-Trans to the annotated transcriptome of mouse revealed that the sensitivity was almost 90% for recalling protein-encoding transcripts. After this quality filtering, the numbers of assembled genes became more consistent between Cufflinks and Trinity tools. To significantly decrease the data storage, we transformed all intermediate data into descriptive metadata and stored by the MySQL database, which will be utilized by downstream analyses in a real-time style. The source codes, example data, and manual of dbHT-Trans are freely available on the GitHub repository. PMID- 26484653 TI - A novel nematode effector suppresses plant immunity by activating host reactive oxygen species-scavenging system. AB - Evidence is emerging that plant-parasitic nematodes can secrete effectors to interfere with the host immune response, but it remains unknown how these effectors can conquer host immune responses. Here, we depict a novel effector, MjTTL5, that could suppress plant immune response. Immunolocalization and transcriptional analyses showed that MjTTL5 is expressed specifically within the subventral gland of Meloidogyne javanica and up-regulated in the early parasitic stage of the nematode. Transgenic Arabidopsis lines expressing MjTTL5 were significantly more susceptible to M. javanica infection than wild-type plants, and vice versa, in planta silencing of MjTTL5 substantially increased plant resistance to M. javanica. Yeast two-hybrid, coimmunoprecipitation and bimolecular fluorescent complementation assays showed that MjTTL5 interacts specifically with Arabidopsis ferredoxin : thioredoxin reductase catalytic subunit (AtFTRc), a key component of host antioxidant system. The expression of AtFTRc is induced by the infection of M. javanica. Interaction between AtFTRc and MjTTL could drastically increase host reactive oxygen species-scavenging activity, and result in suppression of plant basal defenses and attenuation of host resistance to the nematode infection. Our results demonstrate that the host ferredoxin : thioredoxin system can be exploited cunningly by M. javanica, revealing a novel mechanism utilized by plant-parasitic nematodes to subjugate plant innate immunity and thereby promoting parasitism. PMID- 26484656 TI - Glycated Hemoglobin Value Combined with Initial Glucose Levels for Evaluating Mortality Risk in Patients with Ischemic Stroke. AB - BACKGROUND: Hyperglycemia is a marker of poor outcome in acute ischemic stroke (IS) patients. We aimed at evaluating the effect of combined HbA1c and first glucose measurement values on 3-month mortality prediction. METHODS: In a prospective analysis, 1,317 first-ever IS patients with HbA1c values were classified by first glycemia value (<155, 155-199, >=200 mg/dl). Three-month mortality was analyzed by glycemia category in nondiabetics, diabetics with good previous glucose control (PGC) (HbA1c <7%), and diabetics with poor PGC (HbA1c >=7.0%). RESULTS: Mortality at 3 months was 13.1%, with no differences (p = 0.339) between non-diabetes mellitus (DM) (12.3%), good PGC-DM (12.4%), and poor PGC-DM (15.6%) patients. The unadjusted relative risk of 3-month mortality for patients with glucose >=200 mg/dl was 3.76 (95% CI 1.48-9.56) in non-DM, 6.10 (95% CI 1.76-21.09) in good PGC-DM, and 1.44 (95% CI 0.77-2.69) in poor PGC-DM. Glycemia cutoffs most highly correlated with mortality increased as PGC declined: 107 mg/dl in non-DM, 152 mg/dl in good PGC-DM, and 229 mg/dl in poor PGC-DM patients. Glycemia correlated with stroke severity in nondiabetics and diabetic patients with good PGC, but not in those with poor PGC. CONCLUSIONS: HbA1c determination combined with first measured glucose value is useful to stratify mortality risk in IS patients: hyperglycemia is a poor prognostic marker in non DM and DM patients with good PGC; results are inconsistent in poor PGC-DM patients. Our data suggest the relationship between hyperglycemia and poor outcome reflects stress response rather than a deleterious effect of glucose. PMID- 26484657 TI - Cardiac Electromechanical Abnormalities in Hemodialysis Patients: Indicators of Cardiomyopathy and Future Risk. PMID- 26484658 TI - Predictive Value of Atrial Electromechanical Delay on Long-Term Cardiovascular Outcomes in Hemodialysis Patients. AB - BACKGROUND: Atrial electromechanical delay (AEMD) times were considered independent predictors of cardiovascular morbidity among the general population. We aimed at evaluating AEMD times and other risk factors associated with 2-year combined cardiovascular (CV) events in HD patients. MATERIAL AND METHODS: Sixty hemodialysis (HD) and 44 healthy individuals were enrolled in this prospective study. Echocardiography was performed before the mid-week dialysis session for HD patients. Data were expressed as mean +/- SD. Spearman test was used to assess linear associations. Survival was examined with the Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the predictors of combined CV events in this cohort. RESULTS: At the beginning of the study, left intra-atrial-AEMD times were significantly longer in HD patients compared to the left intra-atrial-AEMD times in healthy individuals. After 24 months, 41 patients were still on HD treatment and 19 (31.6%) had died. Serum triglyceride, total cholesterol and albumin were found to be higher and C-reactive protein (CRP) levels, left intra-atrial EMD time (LIAT) and interatrial EMD times were found to be lower in survived HD patients. With the cut-off median values of 3.5 g/dl for albumin, 0.87 mg/dl for CRP, 157 mg/dl for total cholesterol and 151 mg/dl for triglyceride, the Kaplan-Meier curves demonstrated significant differences in terms of all-cause mortality. We also demonstrated the Kaplan-Meier survival curves of HD patients according to tertile values of LIAT. Cox regression analysis revealed that increased CRP and higher LIAT were found to be independent predictors of combined CV events. CONCLUSIONS: Increased LIAT and inflammation were found to be closely associated with 2 years combined CV events and all-cause mortality in HD patients. PMID- 26484659 TI - Anti-Phospholipase A2 Receptor Antibody as Prognostic Indicator in Idiopathic Membranous Nephropathy. AB - BACKGROUND: Anti-phospholipase A2 receptor antibody (PLA2R-Ab) is useful in diagnosing idiopathic membranous nephropathy (IMN). We investigated the clinical relevance of PLA2R-Ab enzyme-linked immunosorbent assay (ELISA) in patients with IMN. METHODS: We measured PLA2R-Ab with an ELISA kit from the serum of 160 patients with IMN (n = 93), secondary MN (n = 14) and other glomerulonephritis (n = 41) as well as healthy controls (n = 12) at the time of renal biopsy and investigated the correlation of titers of PLA2R-Ab with clinical parameters. RESULTS: PLA2R-Ab was positive in 41 of 93 patients (44.1%) with IMN. No samples from the patients with secondary MN and other glomerulonephritis or healthy controls were positive with the ELISA test. The PLA2R-Ab-positive patients showed severe disease activity and a low remission rate. The PLA2R-Ab titer positively correlated with proteinuria and was negatively associated with renal function and serum albumin. The patients with a high titer of PLA2R-Ab had significantly decreased remission rates. The cumulative probabilities of remission was significantly lower in patients with PLA2R-Ab (p = 0.01) and even so in patients with a high titer of PLA2R-Ab (p = 0.04). When we compared the ELISA titers with Western blot (WB) data of 43 patients who had been enrolled in our previous study, 18 and 30 patients were positive on ELISA (41.9%) and WB (69.8%), respectively. WB and ELISA had a concordance rate of 72.1% and were positively correlated (r = 0.590, p < 0.001). CONCLUSION: The presence, as well as a high titer, of PLA2R-Ab on ELISA was associated with poor prognosis of IMN. Assessment of PLA2R-Ab with ELISA is an easy and reliable tool for the diagnosis and guidance of therapeutic plans. PMID- 26484660 TI - Prevalence of and Attitudes towards Smoking among Spanish Health Professionals. AB - BACKGROUND: The MPOWER strategy encourages suitable monitoring of the tobacco epidemic among health professionals in all countries. OBJECTIVE: To analyse the prevalence of and attitudes towards tobacco use among Spanish health professionals. METHODS: A study was conducted based on an online survey. The study population consisted of health professionals (primary care physicians, specialist physicians and nurses). The questionnaire used included questions about tobacco consumption, knowledge of and attitudes towards smoking. The sample size was calculated according to a database with 9,500 e-mail addresses and listings of health centres and hospitals all over Spain. Statistical analysis was done using the SPSS software programme. RESULTS: The study group comprised a total of 612 health professionals: 322 were women (52.6%), 196 were nurses and 416 were physicians. 11.7% of health professionals were smokers (9.6% regular smokers and 2.1% occasional smokers) and 41.3% were ex-smokers. Within the group of daily smokers, differences were observed between the nurses and the physicians: 11.2 versus 8.9% (p = 0.009). Smoking was recognized as a chronic disorder by 58.2% of health professionals, and 54.6% knew that the most effective intervention to help quit is a combination of psychological and pharmacological treatment. 56% of health professionals always asked their patients about their tobacco consumption. CONCLUSIONS: 11.7% of Spanish health professionals are smokers. We found that they have low knowledge about strategies to quit smoking and that there is a low level of therapeutic intervention on smokers. PMID- 26484661 TI - The Shape of an Auxin Pulse, and What It Tells Us about the Transport Mechanism. AB - Auxin underlies many processes in plant development and physiology, and this makes it of prime importance to understand its movements through plant tissues. In stems and coleoptiles, classic experiments showed that the peak region of a pulse of radio-labelled auxin moves at a roughly constant velocity down a stem or coleoptile segment. As the pulse moves it becomes broader, at a roughly constant rate. It is shown here that this 'spreading rate' is larger than can be accounted for by a single channel model, but can be explained by coupling of channels with differing polar transport rates. An extreme case is where strongly polar channels are coupled to completely apolar channels, in which case auxin in the apolar part is 'dragged along' by the polar part in a somewhat diffuse distribution. The behaviour of this model is explored, together with others that can account for the experimentally observed spreading rates. It is also shown that saturation of carriers involved in lateral transport can explain the characteristic shape of pulses that result from uptake of large amounts of auxin. PMID- 26484662 TI - Correction: Genetic Diversity and Population Structure in Aromatic and Quality Rice (Oryza sativa L.) Landraces from North-Eastern India. PMID- 26484663 TI - Pangenome Analysis of Burkholderia pseudomallei: Genome Evolution Preserves Gene Order despite High Recombination Rates. AB - The pangenomic diversity in Burkholderia pseudomallei is high, with approximately 5.8% of the genome consisting of genomic islands. Genomic islands are known hotspots for recombination driven primarily by site-specific recombination associated with tRNAs. However, recombination rates in other portions of the genome are also high, a feature we expected to disrupt gene order. We analyzed the pangenome of 37 isolates of B. pseudomallei and demonstrate that the pangenome is 'open', with approximately 136 new genes identified with each new genome sequenced, and that the global core genome consists of 4568+/-16 homologs. Genes associated with metabolism were statistically overrepresented in the core genome, and genes associated with mobile elements, disease, and motility were primarily associated with accessory portions of the pangenome. The frequency distribution of genes present in between 1 and 37 of the genomes analyzed matches well with a model of genome evolution in which 96% of the genome has very low recombination rates but 4% of the genome recombines readily. Using homologous genes among pairs of genomes, we found that gene order was highly conserved among strains, despite the high recombination rates previously observed. High rates of gene transfer and recombination are incompatible with retaining gene order unless these processes are either highly localized to specific sites within the genome, or are characterized by symmetrical gene gain and loss. Our results demonstrate that both processes occur: localized recombination introduces many new genes at relatively few sites, and recombination throughout the genome generates the novel multi-locus sequence types previously observed while preserving gene order. PMID- 26484664 TI - Transcriptional Derepression Uncovers Cryptic Higher-Order Genetic Interactions. AB - Disruption of certain genes can reveal cryptic genetic variants that do not typically show phenotypic effects. Because this phenomenon, which is referred to as 'phenotypic capacitance', is a potential source of trait variation and disease risk, it is important to understand how it arises at the genetic and molecular levels. Here, we use a cryptic colony morphology trait that segregates in a yeast cross to explore the mechanisms underlying phenotypic capacitance. We find that the colony trait is expressed when a mutation in IRA2, a negative regulator of the Ras pathway, co-occurs with specific combinations of cryptic variants in six genes. Four of these genes encode transcription factors that act downstream of the Ras pathway, indicating that the phenotype involves genetically complex changes in the transcriptional regulation of Ras targets. We provide evidence that the IRA2 mutation reveals the phenotypic effects of the cryptic variants by disrupting the transcriptional silencing of one or more genes that contribute to the trait. Supporting this role for the IRA2 mutation, deletion of SFL1, a repressor that acts downstream of the Ras pathway, also reveals the phenotype, largely due to the same cryptic variants that were detected in the IRA2 mutant cross. Our results illustrate how higher-order genetic interactions among mutations and cryptic variants can result in phenotypic capacitance in specific genetic backgrounds, and suggests these interactions might reflect genetically complex changes in gene expression that are usually suppressed by negative regulation. PMID- 26484665 TI - Evidence for a Cystic Fibrosis Enteropathy. AB - BACKGROUND: Previous studies have suggested the existence of enteropathy in cystic fibrosis (CF), which may contribute to intestinal function impairment, a poor nutritional status and decline in lung function. This study evaluated enterocyte damage and intestinal inflammation in CF and studied its associations with nutritional status, CF-related morbidities such as impaired lung function and diabetes, and medication use. METHODS: Sixty-eight CF patients and 107 controls were studied. Levels of serum intestinal-fatty acid binding protein (I FABP), a specific marker for enterocyte damage, were retrospectively determined. The faecal intestinal inflammation marker calprotectin was prospectively studied. Nutritional status, lung function (FEV1), exocrine pancreatic insufficiency (EPI), CF-related diabetes (CFRD) and use of proton pump inhibitors (PPI) were obtained from the medical charts. RESULTS: Serum I-FABP levels were elevated in CF patients as compared with controls (p<0.001), and correlated negatively with FEV1 predicted value in children (r-.734, p<0.05). Faecal calprotectin level was elevated in 93% of CF patients, and correlated negatively with FEV1 predicted value in adults (r-.484, p<0.05). No correlation was found between calprotectin levels in faeces and sputum. Faecal calprotectin level was significantly associated with the presence of CFRD, EPI, and PPI use. CONCLUSION: This study demonstrated enterocyte damage and intestinal inflammation in CF patients, and provides evidence for an inverse correlation between enteropathy and lung function. The presented associations of enteropathy with important CF-related morbidities further emphasize the clinical relevance. PMID- 26484666 TI - Ectopic Bone Formation by Mesenchymal Stem Cells Derived from Human Term Placenta and the Decidua. AB - Mesenchymal stem cells (MSCs) are one of the most attractive cell types for cell based bone tissue repair applications. Fetal-derived MSCs and maternal-derived MSCs have been isolated from chorionic villi of human term placenta and the decidua basalis attached to the placenta following delivery, respectively. Chorionic-derived MSCs (CMSCs) and decidua-derived MSCs (DMSCs) generated in this study met the MSCs criteria set by International Society of Cellular Therapy. These criteria include: (i) adherence to plastic; (ii) >90% expression of CD73, CD105, CD90, CD146, CD44 and CD166 combined with <5% expression of CD45, CD19 and HLA-DR; and (iii) ability to differentiate into osteogenic, adipogenic, and chondrogenic lineages. In vivo subcutaneous implantation into SCID mice showed that both bromo-deoxyuridine (BrdU)-labelled CMSCs and DMSCs when implanted together with hydroxyapatite/tricalcium phosphate particles were capable of forming ectopic bone at 8-weeks post-transplantation. Histological assessment showed expression of bone markers, osteopontin (OPN), osteocalcin (OCN), biglycan (BGN), bone sialoprotein (BSP), and also a marker of vasculature, alpha-smooth muscle actin (alpha-SMA). This study provides evidence to support CMSCs and DMSCs as cellular candidates with potent bone forming capacity. PMID- 26484667 TI - Detoxification Processes from Vanadate at the Root Apoplasm Activated by Caffeic and Polygalacturonic Acids. AB - In the root apoplasm, V(V) and V(IV) toxicity can be alleviated through redox and complexation reactions involving phenolic substances and the polyuronic components. In such context we report the role of polygalacturonic acid (PGA) on the reducing activity of caffeic acid (CAF) towards V(V). The redox reaction was particularly effective at pH 2.8 leading to the formation of oxidation products with redox activity towards V(V). An o-quinone was identified as the first product of the reaction which is further involved in the formation of CAF dimers. At pH >= 3.6 the redox activity decreased and a yield in V(IV) equal to 38, 31, 21 and 14% was found at pH 3.6, 4.0. 5.0 and 6.0 respectively compared with that obtained at pH 2.8. The redox reaction was faster in the presence of PGA and a higher yield of V(IV) was found in the 4.0-6.0 pH range with respect to the CAF V(V) binary system. The higher efficiency of the redox reaction in the presence of PGA was related with the ability of PGA to bind V(IV). The biological significance of the redox reaction between CAF and V(V), as well as the role of PGA in such reaction, was established "in vivo" using triticale plants. Results showed that PGA reduced significantly the phytotoxic effects of the V(V)-CAF system. PMID- 26484668 TI - Rabies Cases in the West of China Have Two Distinct Origins. AB - In China, rabies remains an ongoing threat to public health. Although control efforts have been effective in reducing the number of annual cases, the virus continues to spread into new areas. Tibet, Qinghai, Gansu and Ningxia in western China have, until recently, reported only a handful of events. However, since 2011, there have been increasing numbers of cases recorded in these areas. In this study, we report the collection and analysis of samples collected from these regions. We find that cases originate from two different sources. Strains collected from Gansu and Ningxia are closely related to the primary lineage associated with the current epizootic, whereas those from Tibet and Qinghai are related to the Arctic-like-2 lineage that is most commonly associated with wildlife cases in China. Thus, it appears that while the epizootic is beginning to encroach into Gansu and Ningxia, Tibet and Qinghai a significant number of rabies cases originate from wildlife. PMID- 26484669 TI - OmpA Binding Mediates the Effect of Antimicrobial Peptide LL-37 on Acinetobacter baumannii. AB - Multidrug-resistant Acinetobacter baumannii has recently emerged as an important pathogen in nosocomial infection; thus, effective antimicrobial regimens are urgently needed. Human antimicrobial peptides (AMPs) exhibit multiple functions and antimicrobial activities against bacteria and fungi and are proposed to be potential adjuvant therapeutic agents. This study examined the effect of the human cathelicidin-derived AMP LL-37 on A. baumannii and revealed the underlying mode of action. We found that LL-37 killed A. baumannii efficiently and reduced cell motility and adhesion. The bacteria-killing effect of LL-37 on A. baumannii was more efficient compared to other AMPs, including human beta-defensin 3 (hBD3) and histatin 5 (Hst5). Both flow cytometric analysis and immunofluorescence staining showed that LL-37 bound to A. baumannii cells. Moreover, far-western analysis demonstrated that LL-37 could bind to the A. baumannii OmpA (AbOmpA) protein. An ELISA assay indicated that biotin-labelled LL-37 (BA-LL37) bound to the AbOmpA74-84 peptide in a dose-dependent manner. Using BA-LL37 as a probe, the ~38 kDa OmpA signal was detected in the wild type but the ompA deletion strain did not show the protein, thereby validating the interaction. Finally, we found that the ompA deletion mutant was more sensitive to LL-37 and decreased cell adhesion by 32% compared to the wild type. However, ompA deletion mutant showed a greatly reduced adhesion defect after LL-37 treatment compared to the wild strain. Taken together, this study provides evidence that LL-37 affects A. baumannii through OmpA binding. PMID- 26484670 TI - Plant-Pathogen Interaction-Related MicroRNAs and Their Targets Provide Indicators of Phytoplasma Infection in Paulownia tomentosa * Paulownia fortunei. AB - Paulownia witches' broom (PaWB) caused by a phytoplasma, has caused extensive losses in the yields of paulownia timber and resulted in significant economic losses. However, the molecular mechanisms in Paulownia that underlie the phytoplasma stress are poorly characterized. In this study, we use an Illumina platform to sequence four small RNA libraries and four degradome sequencing libraries derived from healthy, PaWB-infected, and PaWB-infected 15 mg.L-1 and 30 mg.L-1 methyl methane sulfonate (MMS)-treated plants. In total, 125 conserved and 118 novel microRNAs (miRNAs) were identified and 33 miRNAs responsive to PaWB disease were discovered. Furthermore, 166 target genes for 18 PaWB disease related miRNAs were obtained, and found to be involved in plant-pathogen interaction and plant hormone signal transduction metabolic pathways. Eleven miRNAs and target genes responsive to PaWB disease were examined by a quantitative real-time PCR approach. Our findings will contribute to studies on miRNAs and their targets in Paulownia, and provide new insights to further understand plant-phytoplasma interactions. PMID- 26484671 TI - Frailty Clinical Phenotype: A Physical and Cognitive Point of View. AB - Frailty is recognized as a clinical geriatric syndrome used to describe the weakest or most vulnerable older adults. Although the term frailty is commonly used in clinical practice, and the theoretical phenomenon is well accepted, it remains an evolving concept that lacks a universally accepted definition and specific diagnostic criteria. Different perspectives on frailty have led to two distinct viewpoints of this phenomenon in the literature. The first describes the phenomenon based solely on physical attributes and capabilities. In contrast, more recent perspectives describe the phenomenon in broader, multidimensional terms by incorporating the concept of cognitive frailty. In support of this view, there is increasing evidence that consideration of both cognitive and physical factors can better improve the ability to predict adverse health outcomes among frail older adults over physical factors alone. The recent recognition of the importance of cognitive factors has increased the complexity of this phenomenon and difficulty in developing a consensus definition. To add to this challenge, frailty can present in different stages of severity (from mild to severe), and there appears to be a dynamic relationship between these stages. Despite these challenges, a consensus on an international definition of frailty including physical and cognitive criteria is essential in order to advance research and treatment of this condition. PMID- 26484672 TI - Percutaneous Aspiration Thrombectomy for Arterial Thromboembolism during Infrainguinal Endovascular Recanalization. AB - OBJECTIVES: To evaluate the efficacy of percutaneous aspiration thrombectomy (PAT) for infrainguinal arterial thromboembolism in patients undergoing endovascular recanalization (EVR) and to investigate the predictors for thromboembolic complications. MATERIALS AND METHODS: In total, 23 patients (23 limbs) who underwent PAT for thromboembolism (PAT group, PG) during EVR and 237 patients (302 limbs) who underwent successful EVR without thromboembolic complications (control group, CG) were enrolled. Immediate post-operation and follow-up outcomes were compared between the two groups. Multivariate analysis was performed to identify the predictors of thromboembolic complications. Technical success of PAT was defined as achievement of <30% residual stenosis and restoration of mTIMI grade 3. RESULTS: The technical success rate was 95.7% in PG. After intervention, the ankle-brachial index (ABI), restoration of blood flow and improvement in dorsal/plantar arterial pulse score showed no significant differences between PG and CG. During follow-up in PG, a sustained ABI improvement was observed in 63.6% (70.9% in CG), an improvement in walking distance in 68.8% (79.9% in CG,), ulcer healing in 75.0% (71.7% in CG) and restenosis/occlusion in 31.8% (25.2% in CG). The limb salvage rate was 100% in PG (96.0% in CG), and pain relief was observed in 66.7% patients with critical limb ischaemia (81.6% in CG). Superficial femoral artery involvement [0.233; 95% confidence interval (CI), 0.108-0.461; P < 0.001], de-novo lesion occlusion (683.8; 95% CI, 36.5-12804.6; P < 0.001) and intraluminal angioplasty (118.4; 95% CI, 8.0-1758.0; P = 0.001) was associated with high incidence of thromboembolism. CONCLUSION: PAT is a safe and effective treatment for thromboembolism during infrainguinal arterial EVR. SFA involvement, de-novo lesion occlusion and intraluminal angioplasty may be predictors of thromboembolic complications. PMID- 26484673 TI - Rescue of a Plant Negative-Strand RNA Virus from Cloned cDNA: Insights into Enveloped Plant Virus Movement and Morphogenesis. AB - Reverse genetics systems have been established for all major groups of plant DNA and positive-strand RNA viruses, and our understanding of their infection cycles and pathogenesis has benefitted enormously from use of these approaches. However, technical difficulties have heretofore hampered applications of reverse genetics to plant negative-strand RNA (NSR) viruses. Here, we report recovery of infectious virus from cloned cDNAs of a model plant NSR, Sonchus yellow net rhabdovirus (SYNV). The procedure involves Agrobacterium-mediated transcription of full-length SYNV antigenomic RNA and co-expression of the nucleoprotein (N), phosphoprotein (P), large polymerase core proteins and viral suppressors of RNA silencing in Nicotiana benthamiana plants. Optimization of core protein expression resulted in up to 26% recombinant SYNV (rSYNV) infections of agroinfiltrated plants. A reporter virus, rSYNV-GFP, engineered by inserting a green fluorescence protein (GFP) gene between the N and P genes was able to express GFP during systemic infections and after repeated plant-to-plant mechanical passages. Deletion analyses with rSYNV-GFP demonstrated that SYNV cell to-cell movement requires the sc4 protein and suggested that uncoiled nucleocapsids are infectious movement entities. Deletion analyses also showed that the glycoprotein is not required for systemic infection, although the glycoprotein mutant was defective in virion morphogenesis. Taken together, we have developed a robust reverse genetics system for SYNV that provides key insights into morphogenesis and movement of an enveloped plant virus. Our study also provides a template for developing analogous systems for reverse genetic analysis of other plant NSR viruses. PMID- 26484674 TI - Revisiting Unplanned Endotracheal Extubation and Disease Severity in Intensive Care Units. AB - Most reports regarding unplanned extubation (UE) are case-control studies with matching age and disease severity. To avoid diminishing differences in matched factors, this study with only matching duration of mechanical ventilation aimed to re-examine the risk factors and the factors governing outcomes of UE in intensive care units (ICUs). This case-control study was conducted on 1,775 subjects intubated for mechanical ventilation. Thirty-seven (2.1%) subjects with UE were identified, and 156 non-UE subjects were randomly selected as the control group. Demographic data, acute Physiological and Chronic Health Evaluation II (APACHE II) scores, and outcomes of UE were compared between the two groups. Logistic regression analysis was used to identify the risk factors of UE. Milder disease, younger age, and higher Glasgow Coma Scale (GCS) scores with more frequently being physically restrained (all p<0.05) were related to UE. Logistic regression revealed that APACHE II score (odds ratio (OR) 0.91, p<0.01), respiratory infection (OR 0.24, p<0.01), physical restraint (OR 5.36, p<0.001), and certain specific diseases (OR 3.79-5.62, p<0.05) were related to UE. The UE patients had a lower ICU mortality rate (p<0.01) and a trend of lower in-hospital mortality rate (p = 0.08). Cox regression analysis revealed that in-hospital mortality was associated with APACHE II score, age, shock, and oxygen used, all of which were co-linear, but not UE. The results showed that milder disease with higher GCS scores thereby requiring a higher use of physical restraints were related to UE. Disease severity but not UE was associated with in-hospital mortality. PMID- 26484675 TI - Epistemology for Beginners: Two- to Five-Year-Old Children's Representation of Falsity. AB - This paper investigates the ontogeny of human's naive concept of truth. Surprisingly, children find it hard to treat assertions as false before their fifth birthday. Yet, we show in six studies (N = 140) that human's concept of falsity develops early. Two-year-olds use truth-functional negation to exclude one term in an alternative (Study 1). Three-year-olds can evaluate discrepancies between the content of a representation and what it aims at representing (Study 2). They use this knowledge to treat beliefs and assertions as false (Study 3). Four-year-olds recognise the involutive nature of falsity ascriptions: they properly infer 'p' from 'It is not true that "It is not true that "p""' (Study 4), an inference that rests on second-order representations of representations. Controls confirm that children do not merely equate being mistaken with failing to achieve one's goal (Studies 5 and 6). These results demonstrate remarkable capacities to evaluate representations, and indicate that in the absence of formal training, young children develop the building blocks of a theory of truth and falsity-a naive epistemology. We suggest that children's difficulties in discarding false assertions need not reflect any conceptual lacuna, and may originate from their being trustful. PMID- 26484676 TI - Self-Reporting Tool On Pain in People with Intellectual Disabilities (STOP-ID!): a Usability Study. AB - The use of the Self-reporting Tool On Pain in people with Intellectual Disabilities (STOP-ID!), an online application developed by the authors to aid in the self-reporting of pain, was evaluated in 40 adults with Down syndrome. Comprehension of the use of the tool (the ability to recognize representations for vocabulary and pain, and to navigate the tool interface), and the use of the tool to self-report pain experience, were investigated. The use of the online tool was investigated with both a laptop and a tablet computer in a crossover design. The results provide evidence that more participants recognized representations of pain location and pain affect than representations of pain intensity and pain quality. A small percentage of participants demonstrated the ability to recognize all of the representations of vocabulary items and to navigate the tool without assistance (18% laptop, 18% tablet). Half of the participants were able to report at least one pain component of a current or remembered pain experience without assistance (50% laptop, 53% tablet). Ways to improve the design of tools for reporting pain and to improve performance are suggested. PMID- 26484677 TI - Integrated Analysis Reveals together miR-182, miR-200c and miR-221 Can Help in the Diagnosis of Prostate Cancer. AB - Research has shown that microRNAs are promising biomarkers that can be used to promote a more accurate diagnosis of cancer. In this study, we developed an integrated multi-step selection process to analyze available high-throughput datasets to obtain information on microRNAs as cancer biomarkers. Applying this approach to the microRNA expression profiles of prostate cancer and the datasets in The Cancer Genome Atlas Data Portal, we identified miRNA-182, miRNA-200c and miRNA-221 as possible biomarkers for prostate cancer. The associations between the expressions of these three microRNAs with clinical parameters as well as their diagnostic capability were studied. Several online databases were used to predict the target genes of these three microRNAs, and the results were confirmed by significant statistical correlations. Comparing with the other 18 types of cancers listed in The Cancer Genome Atlas Data Portal, we found that the combination of both miRNA-182 and miRNA-200c being up-regulated and miRNA-221 being down-regulated only happens in prostate cancer. This provides a unique biological characteristic for prostate cancer that can potentially be used for diagnosis based on tissue testing. In addition, our study also revealed that these three microRNAs are associated with the pathological status of prostate cancer. PMID- 26484680 TI - Learning by "SWARMing" Adverse Events. PMID- 26484679 TI - Reductions in Sepsis Mortality and Costs After Design and Implementation of a Nurse-Based Early Recognition and Response Program. AB - BACKGROUND: Sepsis is a leading cause of death, but evidence suggests that early recognition and prompt intervention can save lives. In 2005 Houston Methodist Hospital prioritized sepsis detection and management in its ICU. In late 2007, because of marginal effects on sepsis death rates, the focus shifted to designing a program that would be readily used by nurses and ensure early recognition of patients showing signs suspicious for sepsis, as well as the institution of prompt, evidence-based interventions to diagnose and treat it. METHODS: The intervention had four components: organizational commitment and data-based leadership; development and integration of an early sepsis screening tool into the electronic health record; creation of screening and response protocols; and education and training of nurses. Twice-daily screening of patients on targeted units was conducted by bedside nurses; nurse practitioners initiated definitive treatment as indicated. Evaluation focused on extent of implementation, trends in inpatient mortality, and, for Medicare beneficiaries, a before-after (2008-2011) comparison of outcomes and costs. A federal grant in 2012 enabled expansion of the program. RESULTS: By year 3 (2011) 33% of inpatients were screened (56,190 screens in 9,718 unique patients), up from 10% in year 1 (2009). Inpatient sepsis associated death rates decreased from 29.7% in the preimplementation period (2006 2008) to 21.1% after implementation (2009-2014). Death rates and hospital costs for Medicare beneficiaries decreased from preimplementation levels without a compensatory increase in discharges to postacute care. CONCLUSION: This program has been associated with lower inpatient death rates and costs. Further testing of the robustness and exportability of the program is under way. PMID- 26484681 TI - "SWARMing" to Improve Patient Care: A Novel Approach to Root Cause Analysis. AB - BACKGROUND: When errors occur with adverse events or near misses, root cause analysis (RCA) is the standard approach to investigate the "how" and "why" of system vulnerabilities. However, even for facilities experienced in conducting RCAs, the process can be fraught with inconsistencies; provoke discomfort for participants; and fail to lead to meaningful, focused discussions of system issues that may have contributed to events. In 2009 University of Kentucky HealthCare Lexington developed a novel rapid approach to RCAs-colloquially called "SWARMing"--to establish a consistent approach to investigate adverse or other undesirable events. METHODS: In SWARMs, which are conducted without unnecessary delay after an event, an interdisciplinary team undertakes thoughtful analysis of events reported by frontline staff. The SWARM process consist of five key steps: (1) introductory explanation of the process; (2) introduction of everyone in the room; (3) review of the facts that prompted the SWARM; (4) discussion of what happened, with investigation of the underlying systems factors; and (5) conclusion, with proposed focus areas for action and assignment of task leaders with specific deliverables and completion dates. RESULTS: Since its implementation, incident reporting increased by 52%-from an average of 608 incidents per month (June-December 2011) to an average of 923 per month (January May 2014). The overall health system experienced a 37% decrease in the observed to-expected mortality ratio-from 1.17 (October 2010) to 0.74 (April 2015). CONCLUSION: SWARMs, more than an error-analysis exercise or simple RCA, represent an organizational-messaging, culture-changing, and capacity-building effort to address the challenges of creating and implementing processes that serve to promote transparency and a culture of safety. PMID- 26484682 TI - The Family Caregiver Activation in Transitions (FCAT) Tool: A New Measure of Family Caregiver Self-Efficacy. AB - BACKGROUND: Family caregivers play an instrumental role in executing the care plan of patients during care transitions and yet may lack preparation and confidence to be effective. Yet there has been little attempt by health care professionals to identify and strengthen family caregivers' sense of preparation and confidence. The Family Caregiver Activation in TransitionsTM (FCATTM) tool was developed to guide the care team in better understanding patient and family needs and deploying appropriate resources accordingly. METHODS: The development and psychometric testing of the FCAT tool was guided by a "partial credit" Rasch model. The validation was completed in three phases. In Phase 1, cognitive testing was conducted in convenience samples of family caregivers (N=54) participating in support groups in two geographic locations. In Phase 2, pilot testing was conducted (N=50) to determine item fit and item difficulty. In Phase 3, the tool's psychometric properties were examined in two waves of recruitment (N=187; N=247) from Web-based national samples. RESULTS: Participants recommended revising the script, reducing redundancy, and simplifying item structure and language. Analysis of item fit and difficulty guided subsequent item reduction. The estimated person-separation reliability was 0.84. CONCLUSIONS: The FCAT tool was developed to foster more productive interactions between health care professionals and family caregivers. Because it was developed with direct input from family caregivers, the items are both relevant to actual experience and relatively easy to understand. Psychometric testing supports the hypothesis that the FCAT tool items function as a unidimensional construct with a high level of reliability. The FCAT tool has the potential to guide interventions intended to enhance family caregiver preparation and confidence, and thereby positively influence clinical practice during care transitions. PMID- 26484683 TI - Development of "SWARM" as a Model for High Reliability, Rapid Problem Solving, and Institutional Learning. PMID- 26484684 TI - Implementing an Obstetric Emergency Team Response System: Overcoming Barriers and Sustaining Response Dose. PMID- 26484685 TI - Physician Motivation: Listening to What Pay-for-Performance Programs and Quality Improvement Collaboratives Are Telling Us. PMID- 26484686 TI - A Novel Algorithm for Movement Artifact Removal in ECG Signals Acquired from Wearable Systems Applied to Horses. AB - This study reports on a novel method to detect and reduce the contribution of movement artifact (MA) in electrocardiogram (ECG) recordings gathered from horses in free movement conditions. We propose a model that integrates cardiovascular and movement information to estimate the MA contribution. Specifically, ECG and physical activity are continuously acquired from seven horses through a wearable system. Such a system employs completely integrated textile electrodes to monitor ECG and is also equipped with a triaxial accelerometer for movement monitoring. In the literature, the most used technique to remove movement artifacts, when noise bandwidth overlaps the primary source bandwidth, is the adaptive filter. In this study we propose a new algorithm, hereinafter called Stationary Wavelet Movement Artifact Reduction (SWMAR), where the Stationary Wavelet Transform (SWT) decomposition algorithm is employed to identify and remove movement artifacts from ECG signals in horses. A comparative analysis with the Normalized Least Mean Square Adaptive Filter technique (NLMSAF) is performed as well. Results achieved on seven hours of recordings showed a reduction greater than 40% of MA percentage (between before- and after- the application of the proposed algorithm). Moreover, the comparative analysis with the NLMSAF, applied to the same ECG recordings, showed a greater reduction of MA percentage in favour of SWMAR with a statistical significant difference (p-value < 0.0.5). PMID- 26484688 TI - Coccidioidomycosis among Workers Constructing Solar Power Farms, California, USA, 2011-2014. AB - Coccidioidomycosis is associated with soil-disruptive work in Coccidioides endemic areas of the southwestern United States. Among 3,572 workers constructing 2 solar power-generating facilities in San Luis Obispo County, California, USA, we identified 44 patients with symptom onset during October 2011-April 2014 (attack rate 1.2 cases/100 workers). Of these 44 patients, 20 resided in California outside San Luis Obispo County and 10 resided in another state; 9 were hospitalized (median 3 days), 34 missed work (median 22 days), and 2 had disseminated disease. Of the 25 patients who frequently performed soil-disruptive work, 6 reported frequent use of respiratory protection. As solar farm construction in Coccidioides-endemic areas increases, additional workers will probably be exposed and infected unless awareness is emphasized and effective exposure reduction measures implemented, including limiting dust generation and providing respiratory protection. Medical providers, including those in non Coccidioides-endemic areas, should suspect coccidioidomycosis in workers with compatible illness and report cases to their local health department. PMID- 26484687 TI - Membrane Transition Temperature Determines Cisplatin Response. AB - Cisplatin is a classical chemotherapeutic agent used in treating several forms of cancer including head and neck. However, cells develop resistance to the drug in some patients through a range of mechanisms, some of which are poorly understood. Using isolated plasma membrane vesicles as a model system, we present evidence suggesting that cisplatin induced resistance may be due to certain changes in the bio-physical properties of plasma membranes. Giant plasma membrane vesicles (GPMVs) isolated from cortical cytoskeleton exhibit a miscibility transition between a single liquid phase at high temperature and two distinct coexisting liquid phases at low temperature. The temperature at which this transition occurs is hypothesized to reflect the magnitude of membrane heterogeneity at physiological temperature. We find that addition of cisplatin to vesicles isolated from cisplatin-sensitive cells result in a lowering of this miscibility transition temperature, whereas in cisplatin-resistant cells such treatment does not affect the transition temperature. To explore if this is a cause or consequence of cisplatin resistance, we tested if addition of cisplatin in combination with agents that modulate GPMV transition temperatures can affect cisplatin sensitivity. We found that cells become more sensitive to cisplatin when isopropanol, an agent that lowers GPMV transition temperature, was combined with cisplatin. Conversely, cells became resistant to cisplatin when added in combination with menthol that raises GPMV transition temperatures. These data suggest that changes in plasma membrane heterogeneity augments or suppresses signaling events initiated in the plasma membranes that can determine response to cisplatin. We postulate that desired perturbations of membrane heterogeneity could provide an effective therapeutic strategy to overcome cisplatin resistance for certain patients. PMID- 26484689 TI - Physical Accessibility of Routine Prenatal Care for Women with Mobility Disability. AB - BACKGROUND: Routine prenatal care includes physical examinations and weight measurement. Little is known about whether access barriers to medical diagnostic equipment, such as examination tables and weight scales, affect prenatal care among pregnant women with physical disabilities. METHODS: We conducted 2-hour, in depth telephone interviews with 22 women using a semistructured, open-ended interview protocol. All women had significant mobility difficulties before pregnancy and had delivered babies within the prior 10 years. We recruited most participants through social networks. We sorted interview transcript texts using used NVivo software and conducted conventional content analyses to identify major themes. RESULTS: Interviewee's mean (standard deviation) age was 34.8 (5.3) years. Most were white, well-educated, and higher income; 8 women had spinal cord injuries, 4 cerebral palsy, and 10 had other conditions; 18 used wheeled mobility aids. Some women's obstetricians had height adjustable examination tables, which facilitated transfers for physical examinations. Other women had difficulty transferring onto fixed height examination tables and were examined while sitting in their wheelchairs. Family members and/or clinical staff sometimes assisted with transfers; some women reported concerns about transfer safety. No women reported being routinely weighed on an accessible weight scale by their prenatal care clinicians. A few were never weighed during their pregnancies. CONCLUSIONS: Inaccessible examination tables and weight scales impede some pregnant women with physical disabilities from getting routine prenatal physical examinations and weight measurement. This represents substandard care. Adjustable height examination tables and wheelchair accessible weight scales could significantly improve care and comfort for pregnant women with physical disabilities. PMID- 26484690 TI - A remarkable difference in CO2 hydrogenation to methanol on Pd nanoparticles supported inside and outside of carbon nanotubes. AB - An obvious difference was found in CO2 hydrogenation to methanol on Pd nanoparticles (NPs) supported inside and outside of carbon nanotubes (CNTs). The turnover frequency of methanol synthesis on the Pd NPs supported inside of CNTs was 3.7 times those supported outside of CNTs. It was found that the amount of Pd(delta+) species inside of CNTs was much higher than that outside of CNTs. We proposed that one of the major reasons for the difference in CO2 hydrogenation to methanol might be relative to the concentration of the Pd(delta+) species. PMID- 26484691 TI - Functional neuro-oncological surgery: understanding brain functioning to enhance survival and quality of life. PMID- 26484692 TI - Relating Stomatal Conductance to Leaf Functional Traits. AB - Leaf functional traits are important because they reflect physiological functions, such as transpiration and carbon assimilation. In particular, morphological leaf traits have the potential to summarize plants strategies in terms of water use efficiency, growth pattern and nutrient use. The leaf economics spectrum (LES) is a recognized framework in functional plant ecology and reflects a gradient of increasing specific leaf area (SLA), leaf nitrogen, phosphorus and cation content, and decreasing leaf dry matter content (LDMC) and carbon nitrogen ratio (CN). The LES describes different strategies ranging from that of short-lived leaves with high photosynthetic capacity per leaf mass to long-lived leaves with low mass-based carbon assimilation rates. However, traits that are not included in the LES might provide additional information on the species' physiology, such as those related to stomatal control. Protocols are presented for a wide range of leaf functional traits, including traits of the LES, but also traits that are independent of the LES. In particular, a new method is introduced that relates the plants' regulatory behavior in stomatal conductance to vapor pressure deficit. The resulting parameters of stomatal regulation can then be compared to the LES and other plant functional traits. The results show that functional leaf traits of the LES were also valid predictors for the parameters of stomatal regulation. For example, leaf carbon concentration was positively related to the vapor pressure deficit (vpd) at the point of inflection and the maximum of the conductance-vpd curve. However, traits that are not included in the LES added information in explaining parameters of stomatal control: the vpd at the point of inflection of the conductance-vpd curve was lower for species with higher stomatal density and higher stomatal index. Overall, stomata and vein traits were more powerful predictors for explaining stomatal regulation than traits used in the LES. PMID- 26484693 TI - Functional reorganization and prediction of motor recovery after a stroke: A graph theoretical analysis of functional networks. AB - PURPOSE: This study investigated the changes in the network topological configuration of the ipsilesional and contralesional hemispheres after a stroke and the indicators for the prediction of motor recovery using a graph theoretical approach in networks obtained from functional magnetic resonance imaging (fMRI). METHODS: A longitudinal observational experiments (2 weeks and 1, 3, and 6 months after onset) were conducted on 12 patients after a stroke. We investigated the network reorganization during recovery in the ipsilesional and contralesional hemispheres by examining changes of graph indices related to network randomization. We predicted the recovery of motor function by examining the relationship between specific network measures and improved motor function scores. RESULTS: The ipsilesional hemispheric network showed active reorganization during recovery after a stroke. The randomness of the network significantly increased for 3 months post-stroke. We described an indicator for the prediction of the recovery of motor function from graph indices: the characteristic path length. As the path length of the ipsilesional network was lower immediately after onset, the better recovery could be expected after 3 months. CONCLUSIONS: This approach were helpful for understanding dynamic reorganizations of both hemispheric networks after a stroke and finding the implication for recovery. PMID- 26484694 TI - Effects of implantable peroneal nerve stimulation on gait quality, energy expenditure, participation and user satisfaction in patients with post-stroke drop foot using an ankle-foot orthosis. AB - PURPOSE: To investigate whether an implantable functional electrical stimulation (FES) system of the common peroneal nerve (ActiGait(r)) improves relevant aspects of gait in chronic stroke patients with a drop foot typically using an ankle-foot orthosis (AFO). METHODS: Ten community-dwelling patients participated, of whom eight patients could be analysed. Gait quality (kinematic, kinetic, and spatiotemporal characteristics) during a 10-meter comfortable walk test, normalised net energy expenditure during a 6-minute walk test, participation (physical activity and stroke impact) and user satisfaction were tested before implantation and at various moments after FES-system activation up to 26 weeks. RESULTS: Walking with FES yielded increased maximum paretic ankle plantarflexion (FES: -0.12; AFO: -4.79 degrees , p < 0.01), higher paretic peak ankle power (FES: 1.46; AFO: 0.98 W/kg, p < 0.05) and better step length symmetry (FES: 14.90; AFO: 21.45% , p < 0.05). User satisfaction was higher for FES, but was unrelated to objective gait improvements. Energy expenditure and participation did not change. CONCLUSION: Implantable FES improved the use of residual ankle plantarflexion motion, ankle power of the paretic leg and step length symmetry compared to using an AFO, however, not resulting in decreased energy expenditure or improved participation. User satisfaction was highest with FES, but this was not related to the observed gait improvements. PMID- 26484695 TI - Injectable phenytoin loaded polymeric microspheres for the control of temporal lobe epilepsy in rats. AB - PURPOSE: Epilepsy is a prevalent neurological disorder with a high frequency of drug resistance. While significant advancements have been made in drug delivery systems to overcome anti-epileptic drug resistance, efficacies of materials in biological systems have been poorly studied. The purpose of the study was to evaluate the anti-epileptic effects of injectable poly(epsilon-caprolactone) (PCL) microspheres for controlled release of an anticonvulsant, phenytoin (PHT), in an animal model of epilepsy. METHODS: PHT-PCL and Blank-PCL microspheres formulated using an oil-in-water (O/W) emulsion solvent evaporation method were evaluated for particle size, encapsulation efficiency, surface morphology and in vitro drug release profile. Microspheres with the most suitable morphology and release characteristics weresubsequently injected into the hippocampus of a rat tetanus toxin model of temporal lobe epilepsy. Electrocorticography (ECoG)from the cerebral cortex were recorded for all animals. The number of seizure events, severity of seizures, and seizure duration were then compared between the two treatment groups. RESULTS: We have shown that small injections of drug-loaded microspheres are biologically tolerated and released PHT can control seizures for the expected period of time that is in accord with in-vitro release data. CONCLUSION: The study demonstrated the feasibility of polymer-based delivery systems incontrolling focal seizures. PMID- 26484696 TI - Changes in structural integrity are correlated with motor and functional recovery after post-stroke rehabilitation. AB - PURPOSE: Diffusion tensor imaging (DTI) studies indicate the structural integrity of the ipsilesional corticospinal tract (CST) and the transcallosal motor tract, which are closely linked to stroke recovery. However, the individual contribution of these 2 fibers on different levels of outcomes remains unclear. Here, we used DTI tractography to investigate whether structural changes of the ipsilesional CST and the transcallosal motor tracts associate with motor and functional recovery after stroke rehabilitation. METHODS: Ten participants with post-acute stroke underwent the Fugl-Meyer Assessment (FMA), the Wolf Motor Function Test (WMFT), the Functional Independence Measure (FIM), and DTI before and after bilateral robotic training. RESULTS: All participants had marked improvements in motor performance, functional use of the affected arm, and independence in daily activities. Increased fractional anisotropy (FA) in the ipsilesional CST and the transcallosal motor tracts was noted from pre-treatment to the end of treatment. Participants with higher pre-to-post differences in FA values of the transcallosal motor tracts had greater gains in the WMFT and the FIM scores. A greater improvement on the FMA was coupled with increased FA changes along the ipsilesional CST. CONCLUSIONS: These findings suggest 2 different structural indicators for post-stroke recovery separately at the impairment-based and function-based levels. PMID- 26484697 TI - Evolution of brain activation after stroke in a constant-effort versus constant output motor task. AB - PURPOSE: Recovery of hand function after stroke has been associated with transient overactivation of the cerebral sensorimotor network. One open question has been as to how much this transient overactivation is related to 'true' reorganisation of the network or reflecting the fact that a simple motor task is difficult to perform for a patient with a motor deficit, i.e. reflecting 'effort'. METHODS: To address this, we combined a constant-output (varying effort) and constant-effort (varying output) task in a longitudinal (T1 = 3-5 days, T2 = 6 weeks, T3 = 3 months after stroke) multimodal (functional magnetic resonance imaging (FMRI), electroencephalography (EEG)) study of 12 (EEG)/8 (FMRI) patients (7 male, age 67 +/- 9 years) showing significant recovery from a hand motor deficit. RESULTS: The reduction of sensorimotor activation from T1 to T3 was significant (p = 0.012). But task effort did not exhibit any significant impact on the evolution of task-related brain activation over time. This proved to be equally applicable to FMRI and EEG data. CONCLUSION: We conclude that initial up-regulation of brain activity after stroke is not simply a consequence of enhanced effort early after stroke but rather reflects neural processes involved in reorganisation and recovery of function. PMID- 26484698 TI - The Synapse Project: Engagement in mentally challenging activities enhances neural efficiency. AB - PURPOSE: Correlational and limited experimental evidence suggests that an engaged lifestyle is associated with the maintenance of cognitive vitality in old age. However, the mechanisms underlying these engagement effects are poorly understood. We hypothesized that mental effort underlies engagement effects and used fMRI to examine the impact of high-challenge activities (digital photography and quilting) compared with low-challenge activities (socializing or performing low-challenge cognitive tasks) on neural function at pretest, posttest, and one year after the engagement program. METHODS: In the scanner, participants performed a semantic-classification task with two levels of difficulty to assess the modulation of brain activity in response to task demands. RESULTS: The High Challenge group, but not the Low-Challenge group, showed increased modulation of brain activity in medial frontal, lateral temporal, and parietal cortex-regions associated with attention and semantic processing-some of which were maintained a year later. This increased modulation stemmed from decreases in brain activity during the easy condition for the High-Challenge group and was associated with time committed to the program, age, and cognition. CONCLUSIONS: Sustained engagement in cognitively demanding activities facilitated cognition by increasing neural efficiency. Mentally-challenging activities may be neuroprotective and an important element to maintaining a healthy brain into late adulthood. PMID- 26484699 TI - Inhibition of glial proliferation, promotion of axonal growth and myelin production by synthetic glycolipid: A new approach for spinal cord injury treatment. AB - PURPOSE: After spinal cord injury (SCI) a glial scar is generated in the area affected that forms a barrier for axon growth and myelination, preventing functional recovery. Recently, we have described a synthetic glycolipid (IG20) that inhibited proliferation of human glioma cells. We show now that IG20 inhibited the proliferation of astrocytes and microglial cells, the principal cellular components of the glial scar, and promoting axonal outgrowth and myelin production in vitro. METHODS: Glial cells were inhibited with IG20 (IC50~10 MUM) and studied by RT-PCR, Western Blotting, immunoprecipitation and fluorescence microscopy. Axonal outgrowth in dorsal root ganglia (DRG) and myelin production by oligodendrocytes were analyzed by immunocytochemistry. Adult rats were assayed in spinal cord contusion model and the recovery of treated animals (n = 6) and controls (n = 6) was followed. RESULTS: The IG20 was localized in the cytosol of glial cells, forming a complex with RhoGDIalpha, a regulator of RhoGTPases. Treatment of astroglial cultures with IG20 increase the expression of BDNF receptor genes (TrkBT1, TrkB Full). IG20 reduced the astroglial marker GFAP, while increasing production of myelin basic protein in oligodendrocytes and promoted axonal outgrowth from DRG neurons. Local injection of IG20, near a spinal cord contusion, promoted the recovery of lesioned animals analyzed by BBB test (P < 0.05). CONCLUSIONS: We propose that inhibition of astrocytes and microglia by IG20 could be diminished the glial scar formation, inducing the re growth and myelination of axons, these elements constitute a new approach for SCI therapy. PMID- 26484701 TI - Anti-edema effects of rhEpo in experimental traumatic brain injury. AB - PURPOSE: Traumatic brain injury (TBI) is one of the leading causes of disability and death which begins with the formation of edema as the persistent primary causative factor in TBI. Although medical management of cerebral edema by hypothermia, ventriculostomy, mannitol or hypertonic saline have been effective in treating edema, many of these therapies end up with some neurologic deficits, necessitating novel treatment options for treating post-TBI edema. This study investigated edema reducing effects of recombinant human Erythropoietin (rhEPO) in reducing acute brain edema in the CCI mouse model of TBI. METHODS: Anti-edema effects of rhEpo in reducing acute brain edema after injury in the CCI mouse model of TBI were assessed by T2 weighted magnetic resonance imaging (T2wMRI) as the accurate detector of brain edema in correlation with Western blot analysis of cerebral aquaporin 4 (AQP4) index as the critical marker of edema. RESULTS: Results show that rhEpo treatment significantly reduced brain edema with concomitant reduction in AQP4 immunoexpression in the CCI mouse model of TBI. CONCLUSION: Current results emphasize clinical utility of rhEpo in treating post TBI edema. PMID- 26484700 TI - Stimulation targeting higher motor areas in stroke rehabilitation: A proof-of concept, randomized, double-blinded placebo-controlled study of effectiveness and underlying mechanisms. AB - PURPOSE: To demonstrate, in a proof-of-concept study, whether potentiating ipsilesional higher motor areas (premotor cortex and supplementary motor area) augments and accelerates recovery associated with constraint induced movement. METHODS: In a randomized, double-blinded pilot clinical study, 12 patients with chronic stroke were assigned to receive anodal transcranial direct current stimulation (tDCS) (n = 6) or sham (n = 6) to the ipsilesional higher motor areas during constraint-induced movement therapy. We assessed functional and neurophysiologic outcomes before and after 5 weeks of therapy. RESULTS: Only patients receiving tDCS demonstrated gains in function and dexterity. Gains were accompanied by an increase in excitability of the contralesional rather than the ipsilesional hemisphere. CONCLUSIONS: Our proof-of-concept study provides early evidence that stimulating higher motor areas can help recruit the contralesional hemisphere in an adaptive role in cases of greater ipsilesional injury. Whether this early evidence of promise translates to remarkable gains in functional recovery compared to existing approaches of stimulation remains to be confirmed in large-scale clinical studies that can reasonably dissociate stimulation of higher motor areas from that of the traditional primary motor cortices. PMID- 26484702 TI - Hyperbaric oxygen may induce angiogenesis in patients suffering from prolonged post-concussion syndrome due to traumatic brain injury. AB - PURPOSE: Recent clinical studies present convincing evidence that hyperbaric oxygen therapy (HBOT) may be the coveted neurotherapeutic method for brain repair. One of the most interesting ways in which HBOT can induce neuroplasticity is angiogenesis. The objective in this study was to assess the neurotherapeutic effect of HBOT in post TBI patients using brain perfusion imaging and clinical cognitive functions. METHODS: Retrospective analysis of patients suffering from chronic neuro-cognitive impairment from TBI treated with HBOT. The HBOT protocol included 60 daily HBOT sessions, 5 days per week. All patients had pre and post HBOT objective computerized cognitive tests (NeuroTrax) and brain perfusion MRI. RESULTS: Ten post-TBI patients were treated with HBOT with mean of 10.3+/-3.2 years after their injury. After HBOT, whole-brain perfusion analysis showed significantly increased cerebral blood flow and cerebral blood volume. Clinically, HBOT induced significant improvement in the global cognitive scores (p = 0.007). The most prominent improvements were seen in information processing speed, visual spatial processing and motor skills indices. CONCLUSION: HBOT may induce cerebral angiogenesis, which improves perfusion to the chronic damage brain tissue even months to years after the injury. PMID- 26484703 TI - Functional fluxolipidomics of polyunsaturated fatty acids and oxygenated metabolites in the blood vessel compartment. AB - Synthesis of bioactive oxygenated metabolites of polyunsaturated fatty acids and their degradation or transformation products are made through multiple enzyme processes. The kinetics of the enzymes responsible for the different steps are known to be quite diverse, although not precisely determined. The location of the metabolites biosynthesis is diverse as well. Also, the biological effects of the primary and secondary products, and their biological life span are often completely different. Consequently, phenotypes of cells in response to these bioactive lipid mediators must then depend on their concentrations at a given time. This demands a fluxolipidomics approach that can be defined as a mediator lipidomics, with all measurements done as a function of time and biological compartments. This review points out what is known, even qualitatively, in the blood vascular compartment for arachidonic acid metabolites and number of other metabolites from polyunsaturated fatty acids of nutritional value. The functional consequences are especially taken into consideration. PMID- 26484704 TI - The Male Predominance in Esophageal Adenocarcinoma. AB - The incidence of esophageal adenocarcinoma (EAC) has increased rapidly during the past 4 decades in many Western populations, including North America and Europe. The established etiological factors for EAC include gastroesophageal reflux and obesity, Helicobacter pylori infection, tobacco smoking, and consumption of fruit and vegetables. There is a marked male predominance of EAC with a male-to-female ratio in incidence of up to 9:1. This review evaluates the available literature on the reasons for the male predominance, particularly an update on epidemiologic evidence from human studies during the past decade. The striking sex difference does not seem to be explained by established risk factors, given that the prevalence of the etiological factors and the strengths of associations between these factors and EAC risk are similar between the sexes. Sex hormonal factors may play a role in the development of EAC; estrogenic exposures may prevent such development, whereas androgens might increase the risk of EAC. However, continuing research efforts are still needed to fully understand the reasons for the male predominance of EAC. PMID- 26484705 TI - Striving for Efficient, Patient-centered Endoscopy. PMID- 26484706 TI - Investigating Pharmacological Similarity by Charting Chemical Space. AB - In this study, biologically relevant areas of the chemical space were analyzed using ChemGPS-NP. This application enables comparing groups of ligands within a multidimensional space based on principle components derived from physicochemical descriptors. Also, 3D visualization of the ChemGPS-NP global map can be used to conveniently evaluate bioactive compound similarity and visually distinguish between different types or groups of compounds. To further establish ChemGPS-NP as a method to accurately represent the chemical space, a comparison with structure-based fingerprint has been performed. Interesting complementarities between the two descriptions of molecules were observed. It has been shown that the accuracy of describing molecules with physicochemical descriptors like in ChemGPS-NP is similar to the accuracy of structural fingerprints in retrieving bioactive molecules. Lastly, pharmacological similarity of structurally diverse compounds has been investigated in ChemGPS-NP space. These results further strengthen the case of using ChemGPS-NP as a tool to explore and visualize chemical space. PMID- 26484707 TI - Statins Are Associated With a Decreased Risk of Decompensation and Death in Veterans With Hepatitis C-Related Compensated Cirrhosis. AB - BACKGROUND & AIMS: Statins decrease portal pressure in patients with cirrhosis and increase survival times of patients who have bled from varices. However, statins can be hepatotoxic. It is important to determine whether long-term statin use will be beneficial or detrimental for patients with cirrhosis because physicians are reluctant to prescribe statins to patients with liver disease. We investigated the effects of statins on decompensation and survival times in patients with compensated cirrhosis. METHODS: We performed a retrospective cohort using the Veteran Affairs Clinical Case Registry, which contains nationwide data from veterans infected with the hepatitis C virus (HCV). We identified patients with compensated cirrhosis from January 1996 through December 2009. Statin use was according to filled prescriptions. Cirrhosis and decompensation were determined from International Classification of Diseases, 9th revision codes, using a validated algorithm. RESULTS: Among 40,512 patients with HCV compensated cirrhosis (98% male; median age, 56 y), 2802 statin users were identified. We developed a propensity score model using variables associated with statin prescription, and new statin users were matched with up to 5 nonusers; 685 statin users were matched with 2062 nonusers. Discrimination of the propensity score model was 0.92. Statin users had a lower risk of decompensation (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.39-0.77) and death (HR, 0.56; 95% CI, 0.46-0.69), compared with nonusers. Findings persisted after adjustment for age, FIB-4 index score, serum level of albumin, model for end-stage liver disease and Child-Turcotte-Pugh scores (HR for decompensation, 0.55; 95% CI, 0.39-0.78), and death (HR, 0.55; 95% CI, 0.45-0.68). CONCLUSIONS: Based on data from the Veteran Affairs Clinical Case Registry, statin use among patients with HCV and compensated cirrhosis is associated with a more than 40% lower risk of cirrhosis decompensation and death. Although statins cannot yet be recommended widely for these patients, their use should not be avoided. PMID- 26484709 TI - High levels of impulsivity in rats are not accompanied by sensorimotor gating deficits and locomotor hyperactivity. AB - High levels of impulsivity have been linked to a number of psychiatric disorders, including attention-deficit/hyperactivity disorder, drug abuse and schizophrenia. Additionally, schizophrenia patients commonly show deficits in another rather preattentive form of response inhibition, called sensorimotor gating. Given that higher-order functions, such as impulse control, are protected by early and preattentive processes, disturbed gating mechanisms may hamper more complex cognitive-executive functions. In the present study, we therefore tested whether high levels of impulsivity are accompanied by impaired sensorimotor gating in rats. High (HI) and low impulsive (LI) rats were identified based on the number of premature responses in the 5-choice serial reaction time task. Here, LI rats showed higher numbers of omission errors which may suggest attentional deficits while HI rats completed significantly less trials which could indicate a decrease in motivation. However, HI and LI rats did not differ in terms of impulsive decision-making in a delay-based decision-making T-maze task, prepulse inhibition of the acoustic startle response (a measure of sensorimotor gating mechanisms) or locomotor activity levels. Overall, our data indicate that high motor impulsivity is not a suitable predictor of deficient sensorimotor gating and is further not necessarily associated with attentional deficits and/or locomotor hyperactivity in rats. PMID- 26484708 TI - Hepatic Arterial Infusion of Low-Density Lipoprotein Docosahexaenoic Acid Nanoparticles Selectively Disrupts Redox Balance in Hepatoma Cells and Reduces Growth of Orthotopic Liver Tumors in Rats. AB - BACKGROUND & AIMS: Dietary intake of the natural omega-3 fatty acid docosahexaenoic acid (DHA) has been implicated in protecting patients with viral hepatitis B or C from developing hepatocellular carcinoma (HCC). Little is known about the effects of DHA on established solid tumors. Here we describe a low density lipoprotein-based nanoparticle that acts as a transporter for unesterified DHA (LDL-DHA) and demonstrates selective cytotoxicity toward HCC cells. We investigated the ability of LDL-DHA to reduce growth of orthotopic hepatomas in rats. METHODS: AxC-Irish (ACI) rats were given intrahepatic injections of rat hepatoma cells (H4IIE); 24 tumor-bearing rats (mean tumor diameter, ~1 cm) were subject to a single hepatic artery injection of LDL nanoparticles (2 mg/kg) loaded with DHA (LDL-DHA), triolein (LDL-TO), or sham surgery controls. Tumor growth was measured by magnetic resonance imaging and other methods; tumor, liver, and serum samples were collected and assessed by histochemical, immunofluorescence, biochemical, and immunoblot analyses. RESULTS: Three days after administration of LDL-TO or sham surgery, the control rats had large, highly vascularized tumors that contained proliferating cells. However, rats given LDL-DHA had smaller, pale tumors that were devoid of vascular supply and >80% of the tumor tissue was necrotic. Four to 6 days after injection of LDL DHA, the tumors were 3-fold smaller than those of control rats. The liver tissue that surrounded the tumors showed no histologic or biochemical evidence of injury. Injection of LDL-DHA into the hepatic artery of rats selectively deregulated redox reactions in tumor tissues by increasing levels of reactive oxygen species and lipid peroxidation, depleting and oxidizing glutathione and nicotinamide adenine dinucleotide phosphate, and significantly down-regulating the antioxidant enzyme glutathione peroxidase-4. Remarkably, the redox balance in the surrounding liver was not disrupted. CONCLUSION: LDL-DHA nanoparticle selectively kills hepatoma cells and reduces growth of orthotopic liver tumors in rats. It induces tumor-specific necrosis by selectively disrupting redox balance within the cancer cell. PMID- 26484710 TI - Employing Digital Droplet PCR to Detect BRAF V600E Mutations in Formalin-fixed Paraffin-embedded Reference Standard Cell Lines. AB - ddPCR is a highly sensitive PCR method that utilizes a water-oil emulsion system. Using a droplet generator, an extracted nucleic acid sample is partitioned into ~20,000 nano-sized, water-in-oil droplets, and PCR amplification occurs in individual droplets. The ddPCR approach is in identifying sequence mutations, copy number alterations, and select structural rearrangements involving targeted genes. Here, we demonstrate the use of ddPCR as a powerful technique for precisely quantitating rare BRAF V600E mutations in FFPE reference standard cell lines, which is helpful in identifying individuals with cancer. In conclusion, ddPCR technique offers the potential to precisely profile the specific rare mutations in different genes in various types of FFPE samples. PMID- 26484711 TI - Characterization of histological subtypes of clear cell renal cell carcinoma using contrast-enhanced ultrasound (CEUS). AB - INTRODUCTION: The aim of this study was to analyze the histological subtypes of clear cell renal cell carcinoma (RCC) examined by means of contrast-enhanced ultrasound (CEUS) and a second generation blood pool agent (SonoVue(r), Bracco, Milan, Italy) during the pre-operative phase. MATERIALS AND METHODS: 29 patients with histologically proven subtypes of clear cell RCC were examined. A total of three patients were diagnosed with highly differentiated clear cell RCC, 21 out of 29 cases with moderately differentiated clear cell RCC and five out of 29 patients had insufficiently differentiated clear cell RCC. An experienced radiologist examined the patients with CEUS. The following parameters were analyzed: maximum signal intensity (PEAK), time elapsed until PEAK is reached (MTT), local blood flow (RBF), area under the time intensity curve (AUC) and the signal intensity (SI) during the course of time. For the groups all comparisons are made based on healthy renal parenchyma. RESULTS: In the clear cell RCC significant differences (significance level p < 0.05) between cancerous tissue and the healthy renal parenchyma were noticed in all four parameters. Therefore, the clear cell RCC stands out due to its reduced blood volume. However, it reached the PEAK reading relatively rapidly and its signal intensity was always lower than that of the healthy renal parenchyma. In the arterial phase retarded absorption of the contrast agent was observed, followed by fast washing out of the contrast agent bubbles.In all three histological subgroups no significant differences were noticed in PEAK and SI. However, the diagrams showed the possible bias, that the group of the insufficiently differentiated clear cell RCC had the highest PEAK-value and the highest signal intensity when compared with highly and moderately differentiated clear cell RCC. CONCLUSION: Our study suggests that CEUS may be an additional tool for non-invasive characterisation and differentiation of the three histological subtypes of clear cell RCC. Furthermore, it seems to have an additional diagnostic value in daily clinical. PMID- 26484713 TI - Comparison of portable ultrasound system and high end ultrasound system in detection of endoleaks. AB - PURPOSE: To compare the value of a portable ultrasound system and a high end ultrasound system in detection of endoleaks after EVAR. MATERIAL AND METHODS: In this retrospective study, a cohort of 25 patients underwent both standard examination using a portable ultrasound system (Philips VISIQ) and a second examination using a high end ultrasound system (Philips EPIQ 7). The examination included B-mode and color Doppler in detection of endoleaks. Additional the maximum diameter of the aneurysm was measured in two planes (right-left and ventral-dorsal). The gold standard was contrast-enhanced ultrasound (CEUS) in detection of endoleaks. RESULTS: 25 patients were included in the study. Patients were predominantly male (n = 23) with an average age of 73,30+/-7.82 years (range 54-85). Diameters of the treated aneurysms were in the right-left plane 5,32+/ 1.88 cm and ventral-dorsal 4,99+/-1.78 cm using the high end system. Diameters of the treated aneurysms were in the right-left plane 5,30+/-1.82 cm and ventral dorsal 4,87+/-1.74 cm using portable ultrasound system. In 80% of the cases CEUS could detect an endoleak. Whereas the high end system could detect in B-mode 40% and color Doppler 45% of the cases an endoleak. The portable system could detect in B-mode 30% and in color Doppler 35% of the cases an endoleak. On both systems in B-mode a false positive endoleak was found on the same patient. All high flow endoleaks, which needed intervention, could be detected on all systems. CONCLUSION: The high end ultrasound system does not seem to have an additional advantage in the measurement of the aneurysm diameter. Due to a higher resolution, more endoleaks could be detected in B-mode and color Doppler by using the high end system. The presence of small endoleaks could only be detected by using contrast enhanced ultrasound on an high end ultrasound system. High flow endoleaks could be reliable seen on both systems. PMID- 26484712 TI - Parametric imaging of clear cell and papillary renal cell carcinoma using contrast-enhanced ultrasound (CEUS). AB - PURPOSE: The aim of this study was to analyse clear cell and papillary renal cell carcinoma (RCC) examined with contrast-enhanced ultrasound (CEUS) and a second generation blood pool agent (SonoVue(r), Bracco, Milan, Italy) before clinical intervention. MATERIALS AND METHODS: A total of 41 patients with histologically proven subtypes of RCC were examined. 29 patients had a clear cell RCC and 12 patients showed a papillary RCC. Average size in the clear cell RCC group was 6.07 cm and 1.88 cm in the papillary RCC group. An experienced radiologist examined all patients with CEUS. The following parameters were analysed: maximum signal intensity (PEAK), time elapsed until PEAK is reached (MTT), local blood flow (RBF), area under the time intensity curve (AUC) and the signal intensity (SI) during the course of time. For both groups all comparisons were made based on healthy renal parenchyma. RESULTS: In the clear cell RCC significant differences (significance level p < 0.05) between cancerous tissue and the healthy renal parenchyma were noticed in all four parameters. The clear cell RCC showed a significant reduced blood volume. It reached the PEAK reading relatively rapidly and its signal intensity was always lower than that of the healthy renal parenchyma. In the arterial phase retarded absorption of the contrast agent was observed, followed by fast washing out of the contrast agent bubbles.In the papillary RCC group, significant findings as to PEAK and RBF as well as a slightly significant difference as to AUC were recorded. The papillary RCC had a lower blood supply and reached its PEAK reading later. Its signal intensity was also reduced. The signal intensity of papillary NCC was significantly lower compared with clear cell RCC; absorption and washing out of the contrast agent was delayed. CONCLUSION: CEUS seems to be an useful additional method to clinically differentiate between clear cell and papillary RCC. In daily clinical use, patients with contraindication for other imaging methods, especially the magnetic resonance imaging, might particularly benefit from this method. PMID- 26484714 TI - Standardized 2D ultrasound versus 3D/4D ultrasound and image fusion for measurement of aortic aneurysm diameter in follow-up after EVAR. AB - PURPOSE: To compare standardised 2D ultrasound (US) to the novel ultrasonographic imaging techniques 3D/4D US and image fusion (combined real-time display of B mode and CT scan) for routine measurement of aortic diameter in follow-up after endovascular aortic aneurysm repair (EVAR). METHOD AND MATERIALS: 300 measurements were performed on 20 patients after EVAR by one experienced sonographer (3rd degree of the German society of ultrasound (DEGUM)) with a high end ultrasound machine and a convex probe (1-5 MHz). An internally standardized scanning protocol of the aortic aneurysm diameter in B mode used a so called leading-edge method. In summary, five different US methods (2D, 3D free-hand, magnetic field tracked 3D - CurefabTM, 4D volume sweep, image fusion), each including contrast-enhanced ultrasound (CEUS), were used for measurement of the maximum aortic aneurysm diameter. Standardized 2D sonography was the defined reference standard for statistical analysis. CEUS was used for endoleak detection. RESULTS: Technical success was 100%. In augmented transverse imaging the mean aortic anteroposterior (AP) diameter was 4.0+/-1.3 cm for 2D US, 4.0+/ 1.2 cm for 3D CurefabTM, and 3.9+/-1.3 cm for 4D US and 4.0+/-1.2 for image fusion. The mean differences were below 1 mm (0.2-0.9 mm). Concerning estimation of aneurysm growth, agreement was found between 2D, 3D and 4D US in 19 of the 20 patients (95%). Definitive decision could always be made by image fusion. CEUS was combined with all methods and detected two out of the 20 patients (10%) with an endoleak type II. In one case, endoleak feeding arteries remained unclear with 2D CEUS but could be clearly localized by 3D CEUS and image fusion. CONCLUSION: Standardized 2D US allows adequate routine follow-up of maximum aortic aneurysm diameter after EVAR. Image Fusion enables a definitive statement about aneurysm growth without the need for new CT imaging by combining the postoperative CT scan with real-time B mode in a dual image display. 3D/4D CEUS and image fusion can improve endoleak characterization in selected cases but are not mandatory for routine practice. PMID- 26484715 TI - The Cytocam video microscope. A new method for visualising the microcirculation using Incident Dark Field technology. AB - We report a new microcirculatory assessment device, the Braedius Cytocam, an Incident Dark Field (IDF) video microscope, and compare it with a precursor device utilising side stream dark field (SDF) imaging. METHODS: Time matched measurements were made with both devices from the sublingual microcirculation of pigs subjected to traumatic injury and hemorrhagic shock at baseline and during a shock phase. Images were analysed for vessel density, microcirculatory flow and image quality. RESULTS: There were no differences in density or flow data recorded from the two devices at baseline [TVD IDF 14.2 +/- 2.4/TVD SDF 13.2 +/- 2.0, p 0.17] [MFI IDF 3 (2.8-3.0)/MFI SDF 3 (2.9-3.0), p 0.36] or during the shock state [TVD IDF 11.64 +/- 3.3/TVD SDF 11.4 +/- 4.0 p = 0.98] [MFI IDF 1.9 (0.6-2.7)/MFI SDF 1.7 (0.3-2.6) p 0.55]. Bland and Altman analysis showed no evidence of significant bias. Vessel contrast was significantly better with the IDF device for both capillaries [17.1 +/- 3.9 (IDF) v 3.4 +/- 3.6 (SDF), p = 0.0006] and venules [36.1 +/- 11.4 (IDF) v 26.4 +/- 7.1 (SDF) p 0.014] CONCLUSION: The Braedius Cytocam showed comparable vessel detection to a precursor device during both baseline and low flow (shock) states. PMID- 26484716 TI - The paradox of the serrated sickle erythrocyte: The importance of the red blood cell membrane topography. AB - Red blood cell rheology and adhesiveness play a key role in the occurrence of vaso-occlusive like events in sickle cell anemia. The present paper reviews counter-intuitive findings supporting that rigid and serrated sickle red blood cells do not initiate vaso-occlusion. Instead, the less rigid red blood cells could initiate vaso-occlusion because of their increased adhesiveness to the vascular wall. We suspect that stiffness of sickle erythrocytes and the topography of RBC membrane are factors affecting adhesion to the endothelium. PMID- 26484717 TI - Intravital microscopy - A novel tool in characterizing congestive heart failure in experimental autoimmune myocarditis. AB - AIMS: Experimental autoimmune myocarditis (EAM) is a widely used murine model, in which cellular myocardial infiltration resembles human viral myocarditis. Although myocarditis can be readily assessed on histology, heart failure has not been fully characterized, as there are limitations in available markers and difficulties in hemodynamic measurements, especially on small rodents. We investigated whether intravital microscopy of the microcirculation can be used to characterize heart failure in EAM. METHODS: BALB/c mice (n = 10 versus n = 5 controls) were immunized with alpha myosin heavy chain peptide and myocarditis was confirmed on hematoxylin-eosin (HE) histology on day 21. Echocardiography assessment included ejection fraction (EF), fractional shortening (FS), mitral valve doppler, left-ventricular end-diastolic diameter (LVEDd) and diastolic intra-ventricular septum thickness (IVSd). Microcirculatory analysis was performed using a sidestream dark field (SDF) microcirculation camera. The proportion of perfused vessels (PPV) and perfused vessel density (PVD) were recorded on the intestinal mucosa of the anaesthesized mice. RESULTS: Immunized mice developed EAM with typical cellular infiltration (p < 0.003), left ventricular hypertrophy (IVSd, p = 0.027) and diastolic dysfunction (E/A, p = 0.028) without significant EF reduction (p = 0.845) or LV dilation (p = 0.854). SDF recording consisted mainly of venules, as capillaries were too small. PPV and PVD were significantly increased in EAM mice (p 0.001 and 0.01 respectively) and correlated significantly with the histological myocarditis severity score (r = 0.557, p = 0.03 and r = 0.57, p = 0.025 respectively), whereas PPV but not PVD correlated with IVSd (r = 0.588, p = 0.02) and E/A ratio (r = 0.703, p = 0.003). CONCLUSIONS: Intravital microscopy can be used to characterize post-capillary intestinal perfusion of EAM mice. Thus we show a congestion of intestinal venules in EAM which correlates to the severity of myocarditis. PMID- 26484718 TI - Lipid peroxidation and nitric oxide metabolites in a group of subjects with obstructive sleep apnea syndrome. AB - It is known that in OSAS the plasma lipid peroxidation has an opposite behavior in comparison with nitric oxide metabolites. In the re-examination of our survey of OSAS subjects we calculated the ratio between thiobarbituric acid reactive substances (TBARS) and nitric oxide metabolites (NOx) in relation to OSAS severity. The study has regarded 48 OSAS subjects subdivided in two subgroups according to the apnea/hypopnea index - AHI- (Low = 21 subjects with AHI <30 and High = 27 subjects with AHI >30). From the obtained data it is evident that the TBARS/NOx ratio is significantly higher in the H subgroup compared to L subgroup as well as this ratio is reduced in L subgroup in comparison with the whole group of OSAS subjects. In the entire group of OSAS subjects the TBARS/NOx ratio results positively correlated with AHI and ODI and inversely correlated with mSO2. PMID- 26484719 TI - Effects of lipopolysaccharide on changes in red blood cells in a mice endotoxemia model. AB - The aim of this study was to evaluate changes in RBC aggregation and deformability over 24 hr and suggest specific shear stress values for detecting RBC deformability in a mouse endotoxemia model using lipopolysaccharide (LPS).Six week-old male BALB/c mice received LPS (20 mg/kg) intraperitoneally. Aggregation indices (AIs) and T1/2 were measured to assess RBC aggregation, and elongation indices (EIs) were used to assess RBC deformability at shear stress values of 0.3, 0.5, 1, 3, 7, 10, 15 and 20 Pascals (Pa) 0, 30 min, 1, 2, 4, 6, 9, 12, 18 and 24 hours after the LPS injection.No significant differences were detected in the AIs during the study period, however, T1/2 shortened significantly 2, 6, 12, 18, and 24 hr after the LPS injection. The EIs increased significantly 24 hr after LPS injection at 0.5 and 1 Pa shear stress, whereas it decreased significantly at 10 Pa of shear stress 24 hr after the LPS injection.Altered RBC deformability was detectable 24 hr after the LPS injection and T1/2 may be a sensitive marker for detecting changes in RBC aggregation. The EIs should be measured at 1 Pa to detect changes in RBC deformability in LPS-induced septic mice. PMID- 26484720 TI - Effects of cigarette smoking on hemorheologic parameters, plasma osmolality and lung function. AB - BACKGROUND: Cigarette smoking deteriorates human health via vascular disorders, cancer and especially respiratory diseases. The aim of this study is to investigate effects of cigarette smoking on hemorheologic parameters, plasma osmolality and lung function in individuals without diagnosis of chronic obstructive pulmonary disease (COPD). METHODS: Patients diagnosed without COPD utilizing respiratory function test were enrolled in the study with three groups, ex-smokers (n = 21), current-smokers (n = 35) and never-smokers (n = 43). Hemorheologic parameters and plasma osmolality were measured in hemorheology laboratory. SPSS 17.0 was used for statistical analysis. RESULTS: Blood and plasma viscosity, fibrinogen and hematocrit levels, mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly elevated in ex smokers and current-smokers compared to never-smokers. The standardized red blood cell deformability and oxygen delivery index and lung function were statistically lower in current-smokers than never-smokers. Pulmonary blood flow rate was statistically lower in current-smokers and ex-smokers than never-smokers. Plasma osmolality was statistically significantly higher in ex-smokers and current smokers than never-smokers. CONCLUSIONS: Our findings clearly show that cigarette smoking has severe effects on hemorheologic parameters, plasma osmolality and lung function even in individuals without COPD. Blood and plasma viscosity with plasma osmolality might be useful markers to detect early hemorheologic hemodynamic alterations in cigarette smokers. PMID- 26484721 TI - Sympathetic nerves: How do they affect angiogenesis, particularly during wound healing of soft tissues? AB - Angiogenesis is essential for wound healing, and angiogenesis impairment can result in chronic ulcers. Studies have shown that the sympathetic nervous system has an important role in angiogenesis. In recent years, researchers have focused on the roles of sympathetic nerves in tumor angiogenesis. In fact, sympathetic nerves can affect angiogenesis in the wound healing of soft tissues, and may have a similar mechanism of action as that seen in tumorigenesis. Sympathetic nerves act primarily through interactions between the neurotransmitters released from nerve endings and receptors present in target organs. Among this, activation or inhibition of adrenergic receptors (mainly beta-adrenergic receptors) influence formation of new blood vessels considerably. As sympathetic nerves locate near pericytes in microvessel, go along the capillaries and there are adrenergic receptors present in endothelial cells and pericytes, sympathetic nerves may participate in angiogenesis by influencing the endothelial cells and pericytes of new capillaries. Studying the roles of sympathetic nerves on the angiogenesis of wound healing can contribute to understanding the mechanisms of tissue repair, tissue regeneration, and tumorigenesis, thereby providing new therapeutic perspectives. PMID- 26484722 TI - Impact of stuttering severity on adolescents' domain-specific and general self esteem through cognitive and emotional mediating processes. AB - PURPOSE: The theory that self-esteem is substantially constructed based on social interactions implies that having a stutter could have a negative impact on self esteem. Specifically, self-esteem during adolescence, a period of life characterized by increased self-consciousness, could be at risk. In addition to studying mean differences between stuttering and non-stuttering adolescents, this article concentrates on the influence of stuttering severity on domain-specific and general self-esteem. Subsequently, we investigate if covert processes on negative communication attitudes, experienced stigma, non-disclosure of stuttering, and (mal)adaptive perfectionism mediate the relationship between stuttering severity and self-esteem. METHODS: Our sample comprised 55 stuttering and 76 non-stuttering adolescents. They were asked to fill in a battery of questionnaires, consisting of: Subjective Screening of Stuttering, Self Perception Profile for Adolescents, Erickson S-24, Multidimensional Perfectionism Scale, and the Stigmatization and Disclosure in Adolescents Who Stutter Scale. RESULTS: SEM (structural equation modeling) analyses showed that stuttering severity negatively influences adolescents' evaluations of social acceptance, school competence, the competence to experience a close friendship, and global self-esteem. Maladaptive perfectionism and especially negative communication attitudes fully mediate the negative influence of stuttering severity on self esteem. Group comparison showed that the mediation model applies to both stuttering and non-stuttering adolescents. CONCLUSION: We acknowledge the impact of having a stutter on those domains of the self in which social interactions and communication matter most. We then accentuate that negative attitudes about communication situations and excessive worries about saying things in ways they perceive as wrong are important processes to consider with regard to the self esteem of adolescents who stutter. Moreover, we provide evidence that these covert processes also need to be addressed when helping adolescents who are insecure about their fluency in general. PMID- 26484723 TI - Can perioperative acupuncture reduce the pain and vomiting experienced after tonsillectomy? A meta-analysis. AB - OBJECTIVES: Acupuncture has been shown to reduce pain, nausea, and vomiting. However, its use alongside surgical interventions remains a novel practice, despite the increasing applications of alternative medicine. The goal of this meta-analysis was to perform a systematic review of the literature addressing the effect of acupuncture on postoperative pain, nausea, and vomiting following tonsillectomy. DATA SOURCES: MEDLINE, SCOPUS, and Cochrane database. METHODS: Two authors independently searched the databases from the inception of article collection until June 2015. We included 1) analysis studies that compared groups of patients who had received perioperative acupuncture (acupuncture groups) with those who had received a pain control agent or sham treatment (control group); and 2) analysis studies in which the outcomes of interest were postoperative pain intensity, rescue analgesic consumption, or nausea and vomiting. RESULTS: The pain score reported by patients during the first 48 hours and the postoperative need for analgesics were significantly lower in the acupuncture group versus the control group. Additionally, the incidence of postoperative nausea and vomiting was significantly lower in the acupuncture group than in the control group. No major adverse effects of perioperative acupuncture were reported in the enrolled studies. CONCLUSION: Perioperative acupuncture may provide pain relief without side effects in patients undergoing tonsillectomy. However, there were high levels of heterogeneity in several of the measured parameters; thus, the efficacy of acupuncture cannot be considered to have been evaluated sufficiently. For this reason, additional large well-designed trials are required to further support the results of this study. LEVEL OF EVIDENCE: NA. Laryngoscope, 126:608-615, 2016. PMID- 26484724 TI - Automated Segmentation and Reconstruction of the Subthalamic Nucleus in Parkinson's Disease Patients. AB - OBJECTIVE: In the treatment of Parkinson's disease for deep brain stimulation (DBS), the subthalamic nucleus (STN) is the most important target on a specific brain nucleus. Although procedural details are well established, targeting STN remains problematic because of its variable location and relatively small size. MATERIALS AND METHODS: Data were collected from 10 patients with Parkinson's disease implanted with deep brain stimulation devices. This paper presents an automated algorithm for 3.0T magnetic resonance (MR) image segmentation using the level set method to reconstruct the STN based on automatic segmentation. Implicit polynomial surfaces are used for the reconstruction of the STN segmentation. RESULTS: The method was applied to 10 Parkinson's disease (PD) patients to automatically extract and rebuild the STN. A comparison of the Euclidean distances and dice overlap coefficient showed no significant differences with the segmentation-based method, with the present method having smaller prediction errors and being more robust than expert systems. CONCLUSIONS: This paper presents an automated algorithm to segment and reconstruct the small human STN using MR images. This method for STN should provide an effective method for advancing STN localization and direct visualization. PMID- 26484725 TI - Macromolecular Systems with MSA-Capped CdTe and CdTe/ZnS Core/Shell Quantum Dots as Superselective and Ultrasensitive Optical Sensors for Picric Acid Explosive. AB - This work reports the development of highly fluorescent materials for the selective and efficient detection of picric acid explosive in the nanomolar range by fluorescence quenching phenomenon. Poly(vinyl alcohol) grafted polyaniline (PPA) and its nanocomposites with 2-mercaptosuccinic acid (MSA)-capped CdTe quantum dots (PPA-Q) and with MSA-capped CdTe/ZnS core/shell quantum dots (PPA CSQ) are synthesized in a single step free radical polymerization reaction. The thermal stability and photo stability of the polymer increases in the order of PPA < PPA-Q < PPA-CSQ. The polymers show remarkably high selectivity and efficient sensitivity toward picric acid, and the quenching efficiency for PPA CSQ reaches up to 99%. The detection limits of PPA, PPA-Q, and PPA-CSQ for picric acid are found to be 23, 1.6, and 0.65 nM, respectively, which are remarkably low. The mechanism operating in the quenching phenomenon is proposed to be a combination of a strong inner filter effect and ground state electrostatic interaction between the polymers and picric acid. A portable and cost-effective electronic device for the visual detection of picric acid by the sensory system is successfully fabricated. The device is further employed for quantitative detection of picric acid in real water samples. PMID- 26484726 TI - Self-Assembled Binary Nanoscale Systems: Multioutput Model with LFER-Covariance Perturbation Theory and an Experimental-Computational Study of NaGDC-DDAB Micelles. AB - Studies of the self-aggregation of binary systems are of both theoretical and practical importance. They provide an opportunity to investigate the influence of the molecular structure of the hydrophobe on the nonideality of mixing. On the other hand, linear free energy relationship (LFER) models, such as Hansch's equations, may be used to predict the properties of chemical compounds such as drugs or surfactants. However, the task becomes more difficult once we want to predict simultaneaously the effect over multiple output properties of binary systems of perturbations under multiple input experimental boundary conditions (b(j)). As a consequence, we need computational chemistry or chemoinformatics models that may help us to predict different properties of the autoaggregation process of mixed surfactants under multiple conditions. In this work, we have developed the first model that combines perturbation theory (PT) and LFER ideas. The model uses as input covariance PT operators (CPTOs). CPTOs are calculated as the difference between covariance DeltaCov((i)MU(k)) functions before and after multiple perturbations in the binary system. In turn, covariances calculated as the product of two Box-Jenkins operators (BJO) operators. BJOs are used to measure the deviation of the structure of different chemical compounds from a set of molecules measured under a given subset of experimental conditions. The best CPT-LFER model found predicted the effects of 25,000 perturbations over 9 different properties of binary systems. We also reported experimental studies of different experimental properties of the binary system formed by sodium glycodeoxycholate and didodecyldimethylammonium bromide (NaGDC-DDAB). Last, we used our CPT-LFER model to carry out a 1000 data point simulation of the properties of the NaGDC-DDAB system under different conditions not studied experimentally. PMID- 26484727 TI - A meta-analysis of rate ratios for nocturnal confirmed hypoglycaemia with insulin degludec vs. insulin glargine using different definitions for hypoglycaemia. AB - AIMS: A prospective meta-analysis of phase 3 trials showed lower rates of nocturnal hypoglycaemia with insulin degludec vs. insulin glargine. We investigated the consistency of the results across different definitions of hypoglycaemia. METHODS: This post-hoc, patient-level meta-analysis included six randomized, controlled, 26- or 52-week phase 3a trials in insulin-naive participants with Type 2 diabetes mellitus (Type 2 diabetesinsulin naive ), participants with Type 2 diabetes mellitus using basal-bolus therapy (Type 2 diabetesBB ) and those with Type 1 diabetes mellitus. We used three definitions of hypoglycaemia and different timescales for the nocturnal period. Rates were analysed for the entire core trial period, the 'maintenance period' only, and the extension trial set population. Analyses utilized a negative binomial regression model. RESULTS: In Type 2 diabetesinsulin naive participants, risk of nocturnal hypoglycaemia was significantly lower with insulin degludec vs. insulin glargine for all hypoglycaemia definitions and trial periods. Risk was also lower for the timescale 21.59-05.59, but not 00.01-07.59. For Type 2 diabetesBB , nocturnal hypoglycaemia rates were lower with insulin degludec vs. insulin glargine across all definitions, timescales and trial periods, with one exception. For individuals with Type 1 diabetes mellitus, nocturnal hypoglycaemia risk was significantly lower with insulin degludec during the maintenance period for the original definition (plasma glucose < 3.1 mmol/l, timescale 00.01-05.59) and in the extension trial set population for all hypoglycaemia definitions except for the nocturnal timescale 00.01-07.59. CONCLUSIONS: Compared with insulin glargine, insulin degludec is associated with lower rates of nocturnal hypoglycaemia in people with Type 2 diabetes mellitus, and similar or lower rates in Type 1 diabetes mellitus, across different definitions. PMID- 26484729 TI - Corrigendum: Method for Controlling Electrical Properties of Single-Layer Graphene Nanoribbons via Adsorbed Planar Molecular Nanoparticles. PMID- 26484728 TI - Effects of intravenous and topical laryngeal lidocaine on heart rate, mean arterial pressure and cough response to endotracheal intubation in dogs. AB - OBJECTIVE: To compare the effects of intravenous (IV) and topical laryngeal lidocaine on heart rate (HR), mean arterial pressure (MAP) and cough response to endotracheal intubation (ETI) in dogs. STUDY DESIGN: Prospective, randomized, blinded clinical study. ANIMALS: Forty-two client-owned dogs (American Society of Anesthesiologists class I and II status) undergoing elective orthopaedic surgery. METHODS: Dogs were randomized to three groups. Dogs in group SALIV received 0.1 mL kg(-1) IV saline. Dogs in group LIDIV received 2 mg kg(-1) IV 2% lidocaine. Dogs in group LIDTA received 0.4 mg kg(-1) topically sprayed laryngeal 2% lidocaine. All dogs were premedicated with methadone (0.2 mg kg(-1) IV). After 30 minutes, IV propofol was administered to abolish the lateral palpebral reflex and produce jaw relaxation. The allocated treatment was then administered and, after 30 seconds, further propofol was administered to abolish the medial palpebral reflex and facilitate ETI. HR and MAP were measured at four time-points using cardiac auscultation and automated oscillometry, respectively. The cough response at ETI was recorded. One-way anova and post hoc Tukey adjustment were used to analyse parametric data. The Kruskal-Wallis test was used to analyse non parametric data. Odds ratios were calculated for the cough response. A p-value of <=0.05 was considered to indicate statistical significance. RESULTS: In response to ETI, changes in MAP differed significantly between groups. In SALIV, MAP increased (4 +/- 6 mmHg), whereas it decreased in LIDIV (6 +/- 13 mmHg) (p = 0.013) and LIDTA (7 +/- 11 mmHg) (p = 0.003). Dogs in SALIV were almost 10 times more likely to cough than dogs in LIDIV (odds ratio 9.75, 95% confidence interval 0.98-96.60; p = 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: In propofol anaesthetized dogs, IV and topical laryngeal lidocaine attenuated the pressor response to ETI, whereas IV lidocaine reduced the cough response. PMID- 26484730 TI - Improved longitudinal resolution in tomographic diffractive microscopy with an ellipsoidal mirror. AB - Tomographic diffractive microscopy is a technique, which is able to image transparent unstained samples with high resolution. The three-dimensional distribution of the complex refractive index can be reconstructed quantitatively from the measured scattered fields under various illumination and detection angles, according to the diffraction tomography theorem. We propose a tomographic diffractive microscopy setup with an ellipsoidal mirror as the light collector. We demonstrate analytically and with numerical simulation that this approach permits to obtain images with drastically improved resolution. PMID- 26484731 TI - Association between insertion/deletion polymorphism in intron 3 of XRCC4 and susceptibility to type I bipolar disorder. PMID- 26484732 TI - High Acetic Acid Production Rate Obtained by Microbial Electrosynthesis from Carbon Dioxide. AB - High product specificity and production rate are regarded as key success parameters for large-scale applicability of a (bio)chemical reaction technology. Here, we report a significant performance enhancement in acetate formation from CO2, reaching comparable productivity levels as in industrial fermentation processes (volumetric production rate and product yield). A biocathode current density of -102 +/- 1 A m(-2) and an acetic acid production rate of 685 +/- 30 (g m(-2) day(-1)) have been achieved in this study. High recoveries of 94 +/- 2% of the CO2 supplied as the sole carbon source and 100 +/- 4% of electrons into the final product (acetic acid) were achieved after development of a mature biofilm, reaching an elevated product titer of up to 11 g L(-1). This high product specificity is remarkable for mixed microbial cultures, which would make the product downstream processing easier and the technology more attractive. This performance enhancement was enabled through the combination of a well acclimatized and enriched microbial culture (very fast start-up after culture transfer), coupled with the use of a newly synthesized electrode material, EPD 3D. The throwing power of the electrophoretic deposition technique, a method suitable for large-scale production, was harnessed to form multiwalled carbon nanotube coatings onto reticulated vitreous carbon to generate a hierarchical porous structure. PMID- 26484733 TI - Building cell models and simulations from microscope images. AB - The use of fluorescence microscopy has undergone a major revolution over the past twenty years, both with the development of dramatic new technologies and with the widespread adoption of image analysis and machine learning methods. Many open source software tools provide the ability to use these methods in a wide range of studies, and many molecular and cellular phenotypes can now be automatically distinguished. This article presents the next major challenge in microscopy automation, the creation of accurate models of cell organization directly from images, and reviews the progress that has been made towards this challenge. PMID- 26484734 TI - A tale of the epidermal growth factor receptor: The quest for structural resolution on cells. AB - The challenge of determining the architecture and geometry of oligomers of the epidermal growth factor receptor (EGFR) on the cell surface has been approached using a variety of biochemical and biophysical methods. This review is intended to provide a narrative of how key concepts in the field of EGFR research have evolved over the years, from the origins of the prevalent EGFR signalling dimer hypothesis through to the development and implementation of methods that are now challenging the conventional view. The synergy between X-ray crystallography and cellular fluorescence microscopy has become particularly important, precisely because the results from these two methods diverged and highlighted the complexity of the challenge. We illustrate how developments in super-resolution microscopy are now bridging this gap. Exciting times lie ahead where knowledge of the nature of the complexes can assist with the development of a new generation of anti-cancer drugs. PMID- 26484735 TI - Microbial metagenomes from three aquifers in the Fennoscandian shield terrestrial deep biosphere reveal metabolic partitioning among populations. AB - Microorganisms in the terrestrial deep biosphere host up to 20% of the earth's biomass and are suggested to be sustained by the gases hydrogen and carbon dioxide. A metagenome analysis of three deep subsurface water types of contrasting age (from <20 to several thousand years) and depth (171 to 448 m) revealed phylogenetically distinct microbial community subsets that either passed or were retained by a 0.22 MUm filter. Such cells of <0.22 MUm would have been overlooked in previous studies relying on membrane capture. Metagenomes from the three water types were used for reconstruction of 69 distinct microbial genomes, each with >86% coverage. The populations were dominated by Proteobacteria, Candidate divisions, unclassified archaea and unclassified bacteria. The estimated genome sizes of the <0.22 MUm populations were generally smaller than their phylogenetically closest relatives, suggesting that small dimensions along with a reduced genome size may be adaptations to oligotrophy. Shallow 'modern marine' water showed community members with a predominantly heterotrophic lifestyle. In contrast, the deeper, 'old saline' water adhered more closely to the current paradigm of a hydrogen-driven deep biosphere. The data were finally used to create a combined metabolic model of the deep terrestrial biosphere microbial community. PMID- 26484736 TI - Editorial. PMID- 26484737 TI - High sensitivity flow cytometry of membrane vesicles. AB - Extracellular vesicles (EVs) are attracting attention as vehicles for inter cellular signaling that may have value as diagnostic or therapeutic targets. EVs are released by many cell types and by different mechanisms, resulting in phenotypic heterogeneity that makes them a challenge to study. Flow cytometry is a popular tool for characterizing heterogeneous mixtures of particles such as cell types within blood, but the small size of EVs makes them difficult to measure using conventional flow cytometry. To address this limitation, a high sensitivity flow cytometer was constructed and EV measurement approaches that allowed them to enumerate and estimate the size of individual EVs, as well as measure the presence of surface markers to identify phenotypic subsets of EVs. Several fluorescent membrane probes were evaluated and it was found that the voltage sensing dye di-8-ANEPPS could produce vesicle fluorescence in proportion to vesicle surface area, allowing for accurate measurements of EV number and size. Fluorescence-labeled annexin V and anti-CD61 antibody was used to measure the abundance of these surface markers on EVs in rat plasma. It was shown that treatment of platelet rich plasma with calcium ionophore resulted in an increase in the fraction of annexin V and CD61-positive EVs. Vesicle flow cytometry using fluorescence-based detection of EVs has the potential to realize the potential of cell-derived membrane vesicles as functional biomarkers for a variety of applications. PMID- 26484738 TI - Robotic radiosurgery for the treatment of medium and large uveal melanoma. AB - The aim of the study was to analyze the local efficacy and eye retention rate after frameless, image-guided robotic radiosurgery against uveal melanoma. A total of 217 patients, mostly with medium and large unilateral uveal melanomas (3% small, 62% medium, and 35% large) were treated. The median age was 64 years (range 21-95 years). All patients underwent a single-session procedure beginning with retrobulbar anesthesia, followed by MRI and computerized tomography scanning to generate the treatment plan. The tumor dose was 18-22 Gy (mean, 20.3 Gy) prescribed to the 70% isodose line. Follow-up occurred at 3, 6, 12, and 18 months and yearly thereafter with clinical, ultrasound, and MRI studies. The median follow-up time was 26.4 months. All patients were treated in the frameless setup within 3 h. The actuarial 3- and 5-year eye retention rates were 86.7 and 73%, respectively. Local control at 3 and 5 years was 87.4 and 70.8%, respectively. Serviceable vision was maintained in 30.9% of patients at last follow-up. Treatment-induced glaucoma developed in 33 patients at a median 20.8 months (range, 5.8-54.0 months). Other adverse effects were hemorrhage (26 patients) and macular edema (seven patients). Frameless, single-session, image-guided robotic radiosurgery is an effective and straightforward treatment option for patients with medium and large uveal melanoma that are otherwise difficult to treat. PMID- 26484739 TI - Interaction of the P-Glycoprotein Multidrug Transporter with Sterols. AB - The ABC transporter P-glycoprotein (Pgp, ABCB1) actively exports structurally diverse substrates from within the lipid bilayer, leading to multidrug resistance. Many aspects of Pgp function are altered by the phospholipid environment, but its interactions with sterols remain enigmatic. In this work, the functional interaction between purified Pgp and various sterols was investigated in detergent solution and proteoliposomes. Fluorescence studies showed that dehydroergosterol, cholestatrienol, and NBD-cholesterol interact intimately with Pgp, resulting in both quenching of protein Trp fluorescence and enhancement of sterol fluorescence. Kd values indicated binding affinities in the range of 3-9 MUM. Collisional quenching experiments showed that Pgp-bound NBD cholesterol was protected from the external milieu, resonance energy transfer was observed between Pgp Trp residues and the sterol, and the fluorescence emission of bound sterol was enhanced. These observations suggested an intimate interaction of bound sterols with the transporter at a protected nonpolar site. Cholesterol hemisuccinate altered the thermal unfolding of Pgp and greatly stabilized its basal ATPase activity in both a detergent solution and reconstituted proteoliposomes of certain phospholipids. Other sterols, including dehydroergosterol, did not stabilize the basal ATPase activity of detergent solubilized Pgp, which suggests that this is not a generalized sterol effect. The phospholipid composition and cholesterol hemisuccinate content of Pgp proteoliposomes altered the basal ATPase and drug transport cycles differently. Sterols may interact with Pgp and modulate its structure and function by occupying part of the drug-binding pocket or by binding to putative consensus cholesterol-binding (CRAC/CARC) motifs located within the transmembrane domains. PMID- 26484741 TI - Implementation and Operational Research: The Navigation Program: An Intervention to Reengage Lost Patients at 7 HIV Clinics in Los Angeles County, 2012-2014. AB - The Navigation Program is a health department-community agency collaboration to reengage lost HIV clinic patients in Los Angeles County using best practices from disease investigator services locator activities and the Antiretroviral Treatment Access Study (ARTAS), a CDC-recommended intervention. Clinic databases were reviewed to identify HIV patients who: (1) had no HIV care visits in 6-12 months and last viral load was greater than 200 copies per milliliter; (2) had no HIV care visits in >12 months; (3) were newly diagnosed and never in care; or (4) were recently released from jail/prison/other institution with no regular HIV medical provider. Patients were contacted by trained Navigators using locator information from clinic medical records, HIV/sexually transmitted disease surveillance, and people-finder databases and offered enrollment in a modified ARTAS intervention. Among the 1139 lost clinic patients identified, 36% were in care elsewhere, 29% could not be located, 8% returned to the clinic independently, 4% declined enrollment, and 7% (n = 78) were located and enrolled in the intervention. Participants received an average of 4.5 Navigator sessions over 11.6 hours. Among reengaged patients, 68% linked within 3 months, 85% linked within 6 months, and 94% linked within 12 months, and 82% of linked patients were retained in care 12 months after study enrollment. The percentage of linked patients virally suppressed was compared at time of linkage by the Navigators (52%) with a second viral load measure after linkage to care (63%) (chi(2) = 11.8; P = 0.01). The combined disease investigator services/ARTAS model of reengagement was effective for locating and reengaging lost HIV clinic patients. Access to HIV surveillance data is critical for the efficient identification of persons truly in need of reengagement. PMID- 26484740 TI - Brief Report: Virologic Monitoring Can Be a Cost-Effective Strategy to Diagnose Treatment Failure on First-Line ART. AB - CD4 count testing is perceived to be an affordable strategy to diagnose treatment failure on first-line antiretroviral therapy. We hypothesize that the superior accuracy of viral load (VL) testing will result in less patients being incorrectly switched to more expensive and toxic second-line regimens. Using data from a drug resistance cohort, we show that CD4 testing is approximately double the cost to make 1 correct regimen switch under certain diagnostic thresholds (CD4 = US $499 vs. VL = US $186 or CD4 = US $3031 vs. VL = US $1828). In line with World Health Organization guidelines, our findings show that VL testing can be both an accurate and cost-effective treatment monitoring strategy. PMID- 26484742 TI - Implementation and Operational Research: Implementation of Multiple Point-of-Care Testing in 2 HIV Antiretroviral Treatment Clinics in South Africa. AB - BACKGROUND: A plethora of point-of-care (POC) tests exist in the HIV and tuberculosis diagnostic pipeline which require rigorous evaluation to ensure performance in the field. The accuracy and feasibility of nurse-operated multidisciplinary-POC testing for HIV antiretroviral therapy (ART) initiation/monitoring was evaluated. METHODS: Random HIV-positive adult patients presenting at 2 treatment clinics in South Africa for ART initiation/monitoring were consented and enrolled. POCT was performed by a dedicated nurse on a venipuncture specimen; Pima (CD4), HemoCue (hemoglobin), Reflotron (alanine aminotransferase, creatinine), Accutrend (lactate) and compared with laboratory testing. External quality assessment, training, workflow, and errors were assessed. RESULTS: n = 324 enrolled at site1; n = 469 enrolled at site 2. Clinical data on n = 305 participants: 65% (n = 198) female with a mean age of 39.8 (21-61) years; mean age of males 43.2 (26-61) years; 70% of patients required 3 or more POC tests/visit. External quality assessment material was suitable for POCT. CD4, hemoglobin and alanine aminotransferase testing showed good agreement with predicate methodology; creatinine and lactate had increased variability. Pima CD4 misclassified up to 11.6% of patients at 500 cells per microliter and reported 4.3%-6% error rate. A dedicated nurse could perform POCT on 7 patients/day; inclusion of Pima CD4 increased time for testing from 6 to 110 minutes. Transcription error rate was 1%. CONCLUSIONS: Nurses can accurately perform multidisciplinary POCT for HIV ART initiation/monitoring. This will however, require a dedicated nurse as current duties will increase if POC is added to workflow. The use of Pima CD4 will increase patients initiated on ART. Connectivity will be central to ensure quality management of results, but overall impact will need to still be addressed. PMID- 26484743 TI - Successive blood pressure measurements to evaluate suspected and treated hypertension. AB - INTRODUCTION: According to the published literature, blood pressure (BP) measurements performed in the outpatient clinical setting are often inaccurate. The white coat effect and improper technique are the main causes of this imprecision. Construction of a set of readings without them could improve the accuracy of BP measurement. OBJECTIVE: To evaluate the accuracy and agreement of successive office BP measurements using the awake blood pressure average (ABPa) as the gold standard. METHODS: BP was measured in 852 patients using three techniques: in office (OBPa); seven successive measurements performed by a nurse using an automatic device; and 24 h of ambulatory BP monitoring. BP averages (BPa) were obtained from the nurse's measurements: 1-2BPa (first and second), 3 7BPa (third to seventh), and 1-7BPa (first to seventh). OBPa and successive measurements were tested against ABPa by calculating the following: average difference in BP of 1-2BPa, 3-7BPa and OBPa, and the area under the curve. RESULTS: Among the 834 patients eligible, 374 (43.9%) were considered to be hypertensive on the basis of the ABPa (>=135/85 mmHg). 3-7BPa showed the lowest average difference (4/3 mmHg). By contrast, OBPa showed the highest result (21/11 mmHg). The mean difference with 1-2BPa was 8/4 mmHg. The areas under the curve were better with 3-7BPa (0.82-0.85) and 1-2BPa (0.82-0.83) than OBPa (0.67-0.71) for both systolic and diastolic BP. CONCLUSION: All means from successive measurements showed a better precision than OBPa, even the two first readings. However, more research needs to be carried out before recommendation of the use of this technique in routine practice. PMID- 26484744 TI - Dorsalis pedis arterial pressure is lower than noninvasive arm blood pressure in normotensive patients under sevoflurane anesthesia. AB - BACKGROUND: It is widely known that blood pressure (BP) in the lower extremity is higher than in the upper extremity. However, whether this phenomenon remains the same during general anesthesia is still unclear. This study aims to investigate the difference between invasive dorsalis pedis artery (DPA) pressure and the most commonly used noninvasive arm pressure during sevoflurane anesthesia. METHODS: A total of 50 normotensive Chinese patients were enrolled in this observational study. Invasive DPA pressure, noninvasive arm pressure, and systemic vascular resistance index were assessed simultaneously. BP data during the entire surgery were analyzed through a Bland-Altman plot for repeated measures. The concordance of BP variation in the DPA and the arm was analyzed using four-quadrant plots and linear regression. The time-dependent changes in BP and the systemic vascular resistance index were also evaluated. RESULTS: Data from 46 effective cases were analyzed. Bias (95% limits of agreement) was -7.40 mmHg (-20.36 to +5.57 mmHg) for mean blood pressure, +3.54 mmHg (-20.32 to +27.41 mmHg) for systolic blood pressure, and -10.20 mmHg (-23.66 to +3.26 mmHg) for diastolic blood pressure, respectively. The concordance of BP variation at the two measurement sites was clinically acceptable. DPA pressure and vascular resistance in the lower limb decreased gradually during surgery. CONCLUSION: DPA pressure tends to be lower than arm pressure under sevoflurane anesthesia, especially the mean blood pressure and the diastolic blood pressure. Hence, noninvasive arm BP monitoring is recommend to be retained when invasive BP is measured at the DPA, so as to allow clinicians to comprehensively evaluate the BP condition of the patients and make appropriate therapeutic decisions. PMID- 26484745 TI - The Detour of an Obstetric Technology: Active Management of Labor Across Cultures. AB - Active management of labor (AML) is an obstetric technology developed in Ireland in the 1970s to accelerate labor in nulliparous women. This technology achieved rapid success in Great Britain and in English-speaking countries outside America, which adopted it before many other states around the world. In this article, I explore AML's technical and social characteristics when it was first designed, and then examine its local inflections in a Jordanian and a Swiss maternity hospital to shed light on the ways its transnational circulation modifies its script. I argue that its application is shaped by local material constraints and specific sociocultural configurations, gender regimes, and hospital cultures. Finally, I make a comparative analysis of AML practices in these two settings and in the foundational textbook to disentangle the technical and sociocultural components modeling its local applications. PMID- 26484746 TI - Memristive Physically Evolving Networks Enabling the Emulation of Heterosynaptic Plasticity. AB - A nanoscale, solid-state physically evolving network is experimentally demonstrated, based on the self-organization of Ag nanoclusters under an electric field. The adaptive nature of the network is determined by the collective inputs from multiple terminals and allows the emulation of heterosynaptic plasticity, an important learning rule in biological systems. These effects are universally observed in devices based on different switching materials. PMID- 26484747 TI - Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients. AB - INTRODUCTION: Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target binding kinetics in drug discovery. A meaningful application of in vitro drug target binding kinetics in drug discovery requires insight into the relation between in vivo drug effect and in vitro measured drug-target binding kinetics. AREAS COVERED: In this review, the authors discuss both the relation between in vitro and in vivo measured binding kinetics and the relation between in vivo binding kinetics, target occupancy and effect profiles. EXPERT OPINION: More scientific evidence is required for the rational selection and development of drug-candidates on the basis of in vitro estimates of drug-target binding kinetics. To elucidate the value of in vitro binding kinetics measurements, it is necessary to obtain information on system-specific properties which influence the kinetics of target occupancy and drug effect. Mathematical integration of this information enables the identification of drug-specific properties which lead to optimal target occupancy and drug effect in patients. PMID- 26484748 TI - Presence of cytomegalovirus in the perilymphatic fluid of patients with profound sensorineural hearing loss caused by congenital cytomegalovirus infection. AB - CONCLUSION: Not all patients diagnosed with congenital infection using umbilical cord assay were found to be positive for CMV-DNA by perilymphatic fluid assay. In addition, a CMV-DNA-positive result was observed in one patient who had not been diagnosed with congenital infection. Sampling of perilymphatic fluid from a large population of patients with congenital SNHL caused by congenital CMV infection or of unknown etiology is required to determine the prevalence of CMV-related profound HL. OBJECTIVES: Sensorineural hearing loss (SNHL) is one of the most frequent manifestations in patients with congenital cytomegalovirus (CMV) infection. Using dried umbilical cord, a PCR-based assay was recently developed for the retrospective detection of congenital CMV infection. This study analyzed the presence of CMV in the perilymphatic fluid and evaluated differences in the effect of cochlear implantation between CMV-positive and -negative groups. METHOD: Perilymphatic fluid was collected from each patient at the time of cochlear implantation and analyzed for the presence of CMV using a PCR method. RESULTS: The perilymphatic fluid in two of the five patients suffering from congenital CMV infection and in one of the 17 patients without congenital CMV infection was found to be positive for CMV. PMID- 26484749 TI - Combining parallel detection of proton echo planar spectroscopic imaging (PEPSI) measurements with a data-consistency constraint improves SNR. AB - One major challenge of MRSI is the poor signal-to-noise ratio (SNR), which can be improved by using a surface coil array. Here we propose to exploit the spatial sensitivity of different channels of a coil array to enforce the k-space data consistency (DC) in order to suppress noise and consequently to improve MRSI SNR. MRSI data were collected using a proton echo planar spectroscopic imaging (PEPSI) sequence at 3 T using a 32-channel coil array and were averaged with one, two and eight measurements (avg-1, avg-2 and avg-8). The DC constraint was applied using a regularization parameter lambda of 1, 2, 3, 5 or 10. Metabolite concentrations were quantified using LCModel. Our results show that the suppression of noise by applying the DC constraint to PEPSI reconstruction yields up to 32% and 27% SNR gain for avg-1 and avg-2 data with lambda = 5, respectively. According to the reported Cramer-Rao lower bounds, the improvement in metabolic fitting was significant (p < 0.01) when the DC constraint was applied with lambda >= 2. Using the DC constraint with lambda = 3 or 5 can minimize both root-mean-square errors and spatial variation for all subjects using the avg-8 data set as reference values. Our results suggest that MRSI reconstructed with a DC constraint can save around 70% of scanning time to obtain images and spectra with similar SNRs using lambda = 5. PMID- 26484751 TI - Conceptual considerations and methodological recommendations for the use of the mortality-to-incidence ratio in time-lagged, ecological-level analysis for public health systems-oriented cancer research. PMID- 26484750 TI - RTP1 encodes a novel endoplasmic reticulum (ER)-localized protein in Arabidopsis and negatively regulates resistance against biotrophic pathogens. AB - Oomycete pathogens cause serious damage to a wide spectrum of plants. Although host pathogen recognition via pathogen effectors and cognate plant resistance proteins is well established, the genetic basis of host factors that mediate plant susceptibility to oomycete pathogens is relatively unexplored. Here, we report on RTP1, a nodulin-related MtN21 family gene in Arabidopsis that mediates susceptibility to Phytophthora parasitica. RTP1 was identified by screening a T DNA insertion mutant population and encoded an endoplasmic reticulum (ER) localized protein. Overexpression of RTP1 rendered Arabidopsis more susceptible, whereas RNA silencing of RTP1 led to enhanced resistance to P. parasitica. Moreover, an RTP1 mutant, rtp1-1, displayed localized cell death, increased reactive oxygen species (ROS) production and accelerated PR1 expression, compared to the wild-type Col-0, in response to P. parasitica infection. rtp1-1 showed a similar disease response to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst) DC3000, including increased disease resistance, cell death and ROS production. Furthermore, rpt1-1 exhibited resistance to the fungal pathogen Golovinomyces cichoracearum, but not to the necrotrophic pathogen Botrytis cinerea. Taken together, these results suggest that RTP1 negatively regulates plant resistance to biotrophic pathogens, possibly by regulating ROS production, cell death progression and PR1 expression. PMID- 26484752 TI - Prediction of Ionizing Radiation Resistance in Bacteria Using a Multiple Instance Learning Model. AB - Ionizing-radiation-resistant bacteria (IRRB) are important in biotechnology. In this context, in silico methods of phenotypic prediction and genotype-phenotype relationship discovery are limited. In this work, we analyzed basal DNA repair proteins of most known proteome sequences of IRRB and ionizing-radiation sensitive bacteria (IRSB) in order to learn a classifier that correctly predicts this bacterial phenotype. We formulated the problem of predicting bacterial ionizing radiation resistance (IRR) as a multiple-instance learning (MIL) problem, and we proposed a novel approach for this purpose. We provide a MIL based prediction system that classifies a bacterium to either IRRB or IRSB. The experimental results of the proposed system are satisfactory with 91.5% of successful predictions. PMID- 26484753 TI - Enantioselective N-Heterocyclic Carbene Catalyzed Diene Regenerative (4 + 2) Annulation. AB - An enantioselective N-heterocyclic carbene (NHC)-catalyzed diene regenerative (4 + 2) annulation has been achieved through the use of highly nucleophilic morpholinone-derived catalysts. The reaction proceeds with good to excellent yields, high enantioselectivity (most >92% ee), and good diastereoselectivity (most >7:1). The generality of the reaction is high, with 19 examples reported. The utility of the products has been examined with subsequent derivatization in Diels-Alder reactions using electron-poor dienophiles. Furthermore, interception of the proposed beta-lactone intermediate has been achieved, allowing the synthesis of compounds bearing four contiguous stereocenters with high levels of enantio- and diastereoselectivity. PMID- 26484754 TI - 'Stroke Room': Diagnosis and Treatment at a Single Location for Rapid Intraarterial Stroke Treatment. AB - BACKGROUND: For patients with acute ischemic stroke, intra-arterial treatment (IAT) is considered to be an effective strategy for removing the obstructing clot. Because outcome crucially depends on time to treatment ('time-is-brain' concept), we assessed the effects of an intervention based on performing all the time-sensitive diagnostic and therapeutic procedures at a single location on the delay before intra-arterial stroke treatment. METHODS: Consecutive acute stroke patients with large vessel occlusion who obtained IAT were evaluated before and after implementation (April 26, 2010) of an intervention focused on performing all the diagnostic and therapeutic measures at a single site ('stroke room'). RESULT: After implementation of the intervention, the median intervals between admission and first angiography series were significantly shorter for 174 intervention patients (102 min, interquartile range (IQR) 85-120 min) than for 81 control patients (117 min, IQR 89-150 min; p < 0.05), as were the intervals between admission and clot removal or end of angiography (152 min, IQR 123-185 min vs. 190 min, IQR 163-227 min; p < 0.001). However, no significant differences in clinical outcome were observed. CONCLUSION: This study shows for the, to our knowledge, first time that for patients with acute ischemic stroke, stroke diagnosis and treatment at a single location ('stroke room') saves crucial time until IAT. PMID- 26484755 TI - Epigenetics in Clinical Practice: Characterizing Patient and Provider Experiences with MTHFR Polymorphisms and Methylfolate. AB - BACKGROUND: Observational research associating 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms with risk of autism, depression, cancer, and cardiovascular disease has led to increased diagnoses of MTHFR; however, doctors lack knowledge about safety, effectiveness, and clinical implications of MTHFR treatment. Treatment strategies are hypothetical and mechanistically based, including methylfolate with or without other B vitamins. AIMS: This study was designed to formally describe patient and health care provider experiences with the diagnosis and clinical management of MTHFR. METHODS: Guided by a structured interview guide, a qualitative study queried patients' and providers' observations regarding: testing indications, reaction to results, treatment protocols, and clinical response including adverse effects. RESULTS: Thirty patients and 8 doctors participated. Patient themes included emotionality associated with diagnosis, classification of signs and symptoms, and challenges with treatment. They expressed confusion over their diagnosis, and frustration with the state of knowledge their providers had regarding MTHFR. Testing indications included: fatigue (21%), hormone imbalances (13%), and neurological symptoms (13%) including brain fog (8%). Patients reported improvements in physical (60%) and mental/behavioral symptoms (36%) following treatment. A minority of participants reported side effects, but they occurred in almost every body system and ranged in severity. Doctors relied on trial and error to determine treatment doses, frequency and components. CONCLUSIONS: MTHFR testing results in variable clinical processes in domains related to delivery of diagnosis and prognosis, and therapeutic options. However, patients report largely positive experiences. Clinicians and patients would benefit from therapeutic algorithms based on rigorous research. PMID- 26484756 TI - Chemical Pleurodesis for Malignant Pleural Effusion: How Far Have We Come in 80 Years? PMID- 26484758 TI - Analysis of Apoptosis in Ultraviolet-Induced Sea Cucumber (Stichopus japonicus) Melting Using Terminal Deoxynucleotidyl-Transferase-Mediated dUTP Nick End Labeling Assay and Cleaved Caspase-3 Immunohistochemistry. AB - The sea cucumber body wall melting phenomenon occurs under certain circumstances, and the mechanism of this phenomenon remains unclear. This study investigated the apoptosis in the ultraviolet (UV)-induced sea cucumber melting phenomenon. Fresh sea cucumbers (Stichopus japonicus) were exposed to UV radiation for half an hour at an intensity of 0.056 mW/cm(2) and then held at room temperature for melting development. The samples were histologically processed into formalin-fixed paraffin-embedded tissues. The apoptosis of samples was analyzed with the terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TUNEL) assay and cleaved caspase-3 immunohistochemistry. The emergence of TUNEL-positive cells speeds up between 0.5 and 2 h after UV irradiation. Cleaved caspase-3 positive cells were obviously detected in sample tissues immediately after the UV irradiation. These results demonstrated that sea cucumber melting induced by UV irradiation was triggered by the activation of caspase-3 followed by DNA fragmentation in sea cucumber tissue, which was attributed to apoptosis but was not a consequence of autolysis activity. PMID- 26484757 TI - Perm-seq: Mapping Protein-DNA Interactions in Segmental Duplication and Highly Repetitive Regions of Genomes with Prior-Enhanced Read Mapping. AB - Segmental duplications and other highly repetitive regions of genomes contribute significantly to cells' regulatory programs. Advancements in next generation sequencing enabled genome-wide profiling of protein-DNA interactions by chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq). However, interactions in highly repetitive regions of genomes have proven difficult to map since short reads of 50-100 base pairs (bps) from these regions map to multiple locations in reference genomes. Standard analytical methods discard such multi mapping reads and the few that can accommodate them are prone to large false positive and negative rates. We developed Perm-seq, a prior-enhanced read allocation method for ChIP-seq experiments, that can allocate multi-mapping reads in highly repetitive regions of the genomes with high accuracy. We comprehensively evaluated Perm-seq, and found that our prior-enhanced approach significantly improves multi-read allocation accuracy over approaches that do not utilize additional data types. The statistical formalism underlying our approach facilitates supervising of multi-read allocation with a variety of data sources including histone ChIP-seq. We applied Perm-seq to 64 ENCODE ChIP-seq datasets from GM12878 and K562 cells and identified many novel protein-DNA interactions in segmental duplication regions. Our analysis reveals that although the protein-DNA interactions sites are evolutionarily less conserved in repetitive regions, they share the overall sequence characteristics of the protein-DNA interactions in non repetitive regions. PMID- 26484759 TI - Correction: A New Late Miocene Odobenid (Mammalia: Carnivora) from Hokkaido, Japan Suggests Rapid Diversification of Basal Miocene Odobenids. PMID- 26484761 TI - Time Trend Analysis of the Prevalence and Incidence of Diagnosed Asthma and Traditional Chinese Medicine Use among Adults in Taiwan from 2000 to 2011: A Population-Based Study. AB - BACKGROUND: The aim of this study was to determine the annual trends of traditional Chinese medicine (TCM) use for prevalent and incident asthmatic adults in Taiwan from 2000 to 2011. The annual prevalence and incidence of asthma in adults among subgroups of sociodemographic factors were also investigated. METHODS: A population-based study was conducted using a random sample with one million beneficiaries of all residents aged >=18 years enrolled in the National Health Insurance program. Adults diagnosed with asthma were identified from the National Health Insurance Research Database. The annual prevalence and incidence of asthma in the adult population were estimated by using International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes to identify relevant cases from 2000 to 2011. RESULTS: The number of annual prevalent cases of diagnosed asthma increased from 56,885 in 2000 to 101,535 in 2011. The prevalence increased significantly on annual basis, whereas the incidence rate fluctuated over time. The prevalence of TCM use by adults with asthma decreased significantly (p<0.05), from 38.58% in 2000 to 29.26% in 2011. The number of annual incident cases of diagnosed asthma decreased from 3,896 in 2000 to 2,684 in 2011. TCM use rates in asthma incident adults decreased significantly (p<0.05), from 54.24% in 2000 to 38.19% in 2011. CONCLUSION: The prevalence of TCM utilization is high among adults with asthma in Taiwan. However, our study demonstrated a substantial decrease in the annual prevalence of TCM use by prevalent and incident asthmatic adults in Taiwan from 2000 to 2011. In addition, the prevalence of TCM use was higher among incident cases, compared with those with prevalent cases. PMID- 26484760 TI - Canonical Poly(A) Polymerase Activity Promotes the Decay of a Wide Variety of Mammalian Nuclear RNAs. AB - The human nuclear poly(A)-binding protein PABPN1 has been implicated in the decay of nuclear noncoding RNAs (ncRNAs). In addition, PABPN1 promotes hyperadenylation by stimulating poly(A)-polymerases (PAPalpha/gamma), but this activity has not previously been linked to the decay of endogenous transcripts. Moreover, the mechanisms underlying target specificity have remained elusive. Here, we inactivated PAP-dependent hyperadenylation in cells by two independent mechanisms and used an RNA-seq approach to identify endogenous targets. We observed the upregulation of various ncRNAs, including snoRNA host genes, primary miRNA transcripts, and promoter upstream antisense RNAs, confirming that hyperadenylation is broadly required for the degradation of PABPN1-targets. In addition, we found that mRNAs with retained introns are susceptible to PABPN1 and PAPalpha/gamma-mediated decay (PPD). Transcripts are targeted for degradation due to inefficient export, which is a consequence of reduced intron number or incomplete splicing. Additional investigation showed that a genetically-encoded poly(A) tail is sufficient to drive decay, suggesting that degradation occurs independently of the canonical cleavage and polyadenylation reaction. Surprisingly, treatment with transcription inhibitors uncouples polyadenylation from decay, leading to runaway hyperadenylation of nuclear decay targets. We conclude that PPD is an important mammalian nuclear RNA decay pathway for the removal of poorly spliced and nuclear-retained transcripts. PMID- 26484762 TI - Factors Affecting Accuracy of Data Abstracted from Medical Records. AB - OBJECTIVE: Medical record abstraction (MRA) is often cited as a significant source of error in research data, yet MRA methodology has rarely been the subject of investigation. Lack of a common framework has hindered application of the extant literature in practice, and, until now, there were no evidence-based guidelines for ensuring data quality in MRA. We aimed to identify the factors affecting the accuracy of data abstracted from medical records and to generate a framework for data quality assurance and control in MRA. METHODS: Candidate factors were identified from published reports of MRA. Content validity of the top candidate factors was assessed via a four-round two-group Delphi process with expert abstractors with experience in clinical research, registries, and quality improvement. The resulting coded factors were categorized into a control theory based framework of MRA. Coverage of the framework was evaluated using the recent published literature. RESULTS: Analysis of the identified articles yielded 292 unique factors that affect the accuracy of abstracted data. Delphi processes overall refuted three of the top factors identified from the literature based on importance and five based on reliability (six total factors refuted). Four new factors were identified by the Delphi. The generated framework demonstrated comprehensive coverage. Significant underreporting of MRA methodology in recent studies was discovered. CONCLUSION: The framework generated from this research provides a guide for planning data quality assurance and control for studies using MRA. The large number and variability of factors indicate that while prospective quality assurance likely increases the accuracy of abstracted data, monitoring the accuracy during the abstraction process is also required. Recent studies reporting research results based on MRA rarely reported data quality assurance or control measures, and even less frequently reported data quality metrics with research results. Given the demonstrated variability, these methods and measures should be reported with research results. PMID- 26484763 TI - Understanding the Odour Spaces: A Step towards Solving Olfactory Stimulus-Percept Problem. AB - Odours are highly complex, relying on hundreds of receptors, and people are known to disagree in their linguistic descriptions of smells. It is partly due to these facts that, it is very hard to map the domain of odour molecules or their structure to that of perceptual representations, a problem that has been referred to as the Structure-Odour-Relationship. We collected a number of diverse open domain databases of odour molecules having unorganised perceptual descriptors, and developed a graphical method to find the similarity between perceptual descriptors; which is intuitive and can be used to identify perceptual classes. We then separately projected the physico-chemical and perceptual features of these molecules in a non-linear dimension and clustered the similar molecules. We found a significant overlap between the spatial positioning of the clustered molecules in the physico-chemical and perceptual spaces. We also developed a statistical method of predicting the perceptual qualities of a novel molecule using its physico-chemical properties with high receiver operating characteristics(ROC). PMID- 26484764 TI - Surveillance of Human Echinococcosis in Castilla-Leon (Spain) between 2000-2012. AB - BACKGROUND: Cystic echinococcosis (CE) is an important health problem in many areas of the world including the Mediterranean region. However, the real CE epidemiological situation is not well established. In fact, it is possible that CE is a re-emerging disease due to the weakness of current control programs. METHODOLOGY: We performed a retrospective observational study of inpatients diagnosed with CE from January 2000 to December 2012 in the Western Spain Public Health-Care System. PRINCIPAL FINDINGS: During the study period, 5510 cases of CE were diagnosed and 3161 (57.4%) of the cases were males. The age mean and standard deviation were 67.8 +/- 16.98 years old, respectively, and 634 patients (11.5%) were younger than 45 years old. A total of 1568 patients (28.5%) had CE as the primary diagnosis, and it was most frequently described in patients <45 years old. Futhermore, a secondary diagnosis of CE was usually found in patients >70 year old associated with other causes of comorbidity. The period incidence rate was 17 cases per 105 person-years and was significantly higher when compared to the incidence declared through the Notifiable Disease System (1.88 cases per 105 person-years; p<0.001). CONCLUSIONS: CE in western Spain is an underestimated parasitic disease. It has an active transmission, with an occurrence in pediatric cases, but has decreased in the recent years. The systematic search of Hospital Discharge Records of the National Health System Register (HDR) may be a more accurate method than other methods for the estimation of the incidence of CE in endemic areas. PMID- 26484765 TI - Analysis of the DNA-Binding Activities of the Arabidopsis R2R3-MYB Transcription Factor Family by One-Hybrid Experiments in Yeast. AB - The control of growth and development of all living organisms is a complex and dynamic process that requires the harmonious expression of numerous genes. Gene expression is mainly controlled by the activity of sequence-specific DNA binding proteins called transcription factors (TFs). Amongst the various classes of eukaryotic TFs, the MYB superfamily is one of the largest and most diverse, and it has considerably expanded in the plant kingdom. R2R3-MYBs have been extensively studied over the last 15 years. However, DNA-binding specificity has been characterized for only a small subset of these proteins. Therefore, one of the remaining challenges is the exhaustive characterization of the DNA-binding specificity of all R2R3-MYB proteins. In this study, we have developed a library of Arabidopsis thaliana R2R3-MYB open reading frames, whose DNA-binding activities were assayed in vivo (yeast one-hybrid experiments) with a pool of selected cis-regulatory elements. Altogether 1904 interactions were assayed leading to the discovery of specific patterns of interactions between the various R2R3-MYB subgroups and their DNA target sequences and to the identification of key features that govern these interactions. The present work provides a comprehensive in vivo analysis of R2R3-MYB binding activities that should help in predicting new DNA motifs and identifying new putative target genes for each member of this very large family of TFs. In a broader perspective, the generated data will help to better understand how TF interact with their target DNA sequences. PMID- 26484766 TI - Imaging Cellular Inorganic Phosphate in Caenorhabditis elegans Using a Genetically Encoded FRET-Based Biosensor. AB - Inorganic phosphate (Pi) has central roles in metabolism, cell signaling and energy conversion. The distribution of Pi to each cell and cellular compartment of an animal must be tightly coordinated with its dietary supply and with the varied metabolic demands of individual cells. An analytical method for monitoring Pi dynamics with spatial and temporal resolution is therefore needed to gain a comprehensive understanding of mechanisms governing the transport and recycling of this essential nutrient. Here we demonstrate the utility of a genetically encoded FRET-based Pi sensor to assess cellular Pi levels in the nematode Caenorhabditis elegans. The sensor was expressed in different cells and tissues of the animal, including head neurons, tail neurons, pharyngeal muscle, and the intestine. Cytosolic Pi concentrations were monitored using ratiometric imaging. Injection of phosphate buffer into intestinal cells confirmed that the sensor was responsive to changes in Pi concentration in vivo. Live Pi imaging revealed cell specific and developmental stage-specific differences in cytosolic Pi concentrations. In addition, cellular Pi levels were perturbed by food deprivation and by exposure to the respiratory inhibitor cyanide. These results suggest that Pi concentration is a sensitive indicator of metabolic status. Moreover, we propose that live Pi imaging in C. elegans is a powerful approach to discern mechanisms that govern Pi distribution in individual cells and throughout an animal. PMID- 26484767 TI - Effects of Topical Bimatoprost 0.01% and Timolol 0.5% on Circadian IOP, Blood Pressure and Perfusion Pressure in Patients with Glaucoma or Ocular Hypertension: A Randomized, Double Masked, Placebo-Controlled Clinical Trial. AB - PURPOSE: To compare the 24-hour (24h) effects on intraocular pressure (IOP) and cardiovascular parameters of timolol 0.5% and bimatoprost 0.01% in open angle glaucoma and ocular hypertensive subjects. METHODS: In this prospective, randomized, double masked, crossover, clinical trial, after washout from previous medications enrolled subjects underwent 24h IOP, blood pressure (BP) and heart rate (HR) measurements and were randomized to either topical bimatoprost 0.01% at night plus placebo in the morning or to timolol 0.5% bid. After 8 weeks of treatment a second 24h assessment of IOP, BP and HR was performed and then subjects switched to the opposite treatment for additional 8 weeks when a third 24h assessment was performed. The primary endpoint was the comparison of the mean 24h IOP after each treatment. Secondary endpoints included the comparisons of IOP at each timepoint of the 24h curve and the comparison of BP, HR, ocular perfusion pressure and tolerability. RESULTS: Mean untreated 24h IOP was 20.3 mmHg (95%CI 19.0 to 21.6). Mean 24h IOP was significantly lower after 8 weeks of treatment with bimatoprost 0.01% than after 8 weeks of treatment with timolol 0.5% bid (15.7 vs 16.8 mmHg, p = 0.0003). Mean IOP during the day hours was significantly reduced from baseline by both drugs while mean IOP during the night hours was reduced by -2.3 mmHg (p = 0.0002) by bimatoprost 0.01% plus placebo and by -1.1 mmHg by timolol 0.5% bid (p = 0.06). Timolol 0.5% significantly reduced the mean 24h systolic BP from baseline, the diastolic BP during the day hours, the HR during the night hours, and the mean 24h systolic ocular perfusion pressure. CONCLUSION: Both Bimatoprost 0.01% and Timolol 0.5% are effective in reducing the mean 24h IOP from an untreated baseline but Bimatoprost 0.01% is more effective than timolol 0.5% throughout the 24h. Timolol 0.5% effect on IOP is reduced during the night hours and is associated with reduced BP, HR and ocular perfusion pressure. TRIAL REGISTRATION: EU Clinical Trial Register and EudraCT# 2010-024272 26. PMID- 26484768 TI - Characterization of Staphylococcus aureus from Humans and a Comparison with Isolates of Animal Origin, in North Dakota, United States. AB - Different clones of methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus have been found in humans as well as in animals and retail meat. However, more information about the genetic characteristics and similarities between strains is needed. The aim of this study was to identify and characterize Staphylococcus aureus from humans, and to compare their characteristics with isolates of animal origin. A total of 550 nasal swabs were taken from healthy humans, and S. aureus was isolated and identified. Positive S. aureus isolates were subjected to molecular typing and susceptibility testing. In addition, 108 MRSA isolates recovered from clinical patients in the state of North Dakota and 133 S. aureus isolates from animals and meat previously analyzed were included. The nasal carriage of S. aureus in healthy people was 7.6% and, in general, clones were genetically diverse. None of the S. aureus strains obtained from healthy people were mecA- or PVL-positive. A total of 105 (97.2%) MRSA isolates from clinical cases harbored the mecA gene and 11 (10.2%) isolated from blood stream infections harbored the PVL gene. The most common resistance profile among S. aureus from healthy people was penicillin, and from clinical cases were erythromycin-penicillin-ciprofloxacin. The rate of multidrug resistance (MDR) was 70% in humans. Most of the S. aureus harboring mecA and PVL genes were identified as ST5 and ST8, and exhibited MDR. However, S. aureus isolates of animal origin used for comparison exhibited a lower rate of MDR. The most common resistance profiles in isolates of animal origin were penicillin-tetracycline and penicillin tetracycline-erythromycin, in animals and raw meat, respectively. The ST5 was also found in animals and meat, with ST9 and ST398 being the major clones. The genetic similarity between clones from humans and meat suggests the risk of spread of S. aureus in the food chain. PMID- 26484769 TI - PD-L1 Expression on Retrovirus-Infected Cells Mediates Immune Escape from CD8+ T Cell Killing. AB - Cytotoxic CD8+ T Lymphocytes (CTL) efficiently control acute virus infections but can become exhausted when a chronic infection develops. Signaling of the inhibitory receptor PD-1 is an important mechanism for the development of virus specific CD8+ T cell dysfunction. However, it has recently been shown that during the initial phase of infection virus-specific CD8+ T cells express high levels of PD-1, but are fully competent in producing cytokines and killing virus-infected target cells. To better understand the role of the PD-1 signaling pathway in CD8+ T cell cytotoxicity during acute viral infections we analyzed the expression of the ligand on retrovirus-infected cells targeted by CTLs. We observed increased levels of PD-L1 expression after infection of cells with the murine Friend retrovirus (FV) or with HIV. In FV infected mice, virus-specific CTLs efficiently eliminated infected target cells that expressed low levels of PD-L1 or that were deficient for PD-L1 but the population of PD-L1high cells escaped elimination and formed a reservoir for chronic FV replication. Infected cells with high PD-L1 expression mediated a negative feedback on CD8+ T cells and inhibited their expansion and cytotoxic functions. These findings provide evidence for a novel immune escape mechanism during acute retroviral infection based on PD-L1 expression levels on virus infected target cells. PMID- 26484770 TI - Overlaps between Frailty and Sarcopenia Definitions. AB - Aging is characterized by the catabolism of muscles leading to sarcopenia and frailty. These are two geriatric syndromes with partly overlapping phenotypes. Primary sarcopenia, i.e. loss of muscle mass and function related to aging alone, usually precedes frailty. Thus, robustness passes from sarcopenia over frailty to disability leading eventually to a mortal outcome. Frailty (defined according to the phenotype model) encompasses states as exhaustion, weakness, and slowness, whereas sarcopenia, combining mass and function, is more strictly focused on muscles. Frailty is age related, whereas sarcopenia is also related to disease, starvation, and disuse. In general, the criteria for the two conditions overlap, but frailty requires weight loss, whereas sarcopenia requires muscle loss. Both gait speed and hand grip strength are suggested to be used as diagnostic measures for the two conditions since muscle function is crucial for any of the two syndromes. It is suggested that frailty screening should be part of the geriatric comprehensive assessment starting with measuring walking capacity and complemented by taking a history of fatigue and low activity. For younger adults (i.e. <70 years), sarcopenia screening could first register gait speed or hand grip strength and then body composition measurements. Simple questionnaires are feasible clinical alternatives. Treatment of frailty and sarcopenia overlaps, i.e. provide adequate protein and vitamin D supplementation, and encourage resistance exercise. PMID- 26484771 TI - MAS C-Terminal Tail Interacting Proteins Identified by Mass Spectrometry- Based Proteomic Approach. AB - Propagation of signals from G protein-coupled receptors (GPCRs) in cells is primarily mediated by protein-protein interactions. MAS is a GPCR that was initially discovered as an oncogene and is now known to play an important role in cardiovascular physiology. Current literature suggests that MAS interacts with common heterotrimeric G-proteins, but MAS interaction with proteins which might mediate G protein-independent or atypical signaling is unknown. In this study we hypothesized that MAS C-terminal tail (Ct) is a major determinant of receptor scaffold protein interactions mediating MAS signaling. Mass-spectrometry based proteomic analysis was used to comprehensively identify the proteins that interact with MAS Ct comprising the PDZ-binding motif (PDZ-BM). We identified both PDZ and non-PDZ proteins from human embryonic kidney cell line, mouse atrial cardiomyocyte cell line and human heart tissue to interact specifically with MAS Ct. For the first time our study provides a panel of PDZ and other proteins that potentially interact with MAS with high significance. A 'cardiac-specific finger print' of MAS interacting PDZ proteins was identified which includes DLG1, MAGI1 and SNTA. Cell based experiments with wild-type and mutant MAS lacking the PDZ-BM validated MAS interaction with PDZ proteins DLG1 and TJP2. Bioinformatics analysis suggested well-known multi-protein scaffold complexes involved in nitric oxide signaling (NOS), cell-cell signaling of neuromuscular junctions, synapses and epithelial cells. Majority of these protein hits were predicted to be part of disease categories comprising cancers and malignant tumors. We propose a 'MAS signalosome' model to stimulate further research in understanding the molecular mechanism of MAS function. Identifying hierarchy of interactions of 'signalosome' components with MAS will be a necessary step in future to fully understand the physiological and pathological functions of this enigmatic receptor. PMID- 26484773 TI - Profiling of sperm proteins and association of sperm PDC-109 with bull fertility. AB - The composition of sperm proteins influences the fertilizing ability of sperm and hence the present study was conducted (i) to profile sperm proteins expression patterns in bulls of differing fertility index and (ii) to identify and relate the abundant sperm proteins with bull fertility. The semen samples were collected from Holstein-Friesian bulls (n = 12) varying in conception rate (CR) (high/low). The frozen semen straws (three ejaculates, from each bull) were used to study (a) sperm kinetic parameters, (b) plasmalemma integrity, (c) mitochondrial membrane potential, and (d) chromatin distribution. Three bulls were randomly selected from each group (n = 3) and the neat sperm pellets were subjected to percoll purification, followed by protein isolation using 0.1% Triton X100. The sperm kinetic parameters, plasmalemma integrity, mitochondrial membrane potential, and the chromatin distribution did not differ significantly between groups. The number of acidic (pI; 3.1-5.6, 37%) and basic (pI; 7.9-10.0, 27%) proteins and their pattern of expression varied significantly (p < 0.05) between high and low fertile bulls. The abundant sperm protein spots in 2D-gel electrophoresis (2DE) were identified as seminal plasma protein PDC-109 (i.e., protein with N-terminus aspartic acid, D and carboxy terminus cystine, having 109 amino acids) and its isoform and spermadhesin-1 (SPADH1). The western blot analysis confirmed the presence of PDC-109 isoform proteins at 15.4 kDa (pI 5.3 and 5.5). The seminal plasma protein PDC-109 was abundant in the low fertile when compared to the high fertile group (p < 0.05). This study suggests that the imbalance in acidic and basic sperm proteins may influence sperm fertility and sperm PDC-109 levels above a certain threshold affects bull fertility. PMID- 26484772 TI - Investigation of Repeat Client Drop-Out and Re-Enrolment Cycles in Fourteen Methadone Maintenance Treatment Clinics in Guangdong, China. AB - OBJECTIVE: Client adherence is vital for effective methadone maintenance treatment (MMT). This study explores the pattern and associated factors of client adherence, drop-out and re-enrolment in the Chinese MMT programme over the period of 2006-2013. METHODS: This retrospective study was conducted in 14 MMT clinics in Guangdong Province, China. We employed Kaplan-Meier survival analysis to estimate the rates of drop-out and re-enrolment of MMT clients and multivariate Cox regression to identify associated factors. RESULTS: Among 1,512 study participants, 79% have experienced 'drop-out' during the 7-year study period. However, 82% 'dropped-out' clients resumed treatment at a later time. Low education level (junior high or below versus otherwise, HR = 1.21, 1.05-1.40), low methadone dosage in the first treatment episode (<50 ml versus >=50 ml, HR = 1.84, 1.64-2.06) and higher proportion of positive urine test (>=50% versus<50%, HR = 3.72, 3.30-4.20) during the first treatment episode were strong predictors of subsequent drop-outs of the participants. Among the 'dropped-out' clients, being female (HR = 1.40, 1.23-1.60), being married (HR = 1.19, 1.09-1.30), and having a higher proportion of positive urine tests in the first treatment episode (>=50% versus<50%, HR = 1.35, 1.20-1.51) had greater likelihood of subsequent re enrolment in MMT. Clients receiving lower methadone dosage (first treatment episode <50 ml versus >=50 ml, HR = 1.12, 1.03-1.23; the last intake before drop out <50 ml versus >=50 ml, HR = 1.16, 1.04-1.30) were also more likely to re enrol. CONCLUSION: Persistent cycling in-and-out of clients in MMT programmes is common. Insufficient dosage and higher proportion of positive urine samples in the first treatment episode are the key determinants for subsequent client drop out and re-enrolment. Interventions should target clients in their early stage of treatment to improve retention in the long term. PMID- 26484774 TI - Streptococcus pyogenes Sortase Mutants Are Highly Susceptible to Killing by Host Factors Due to Aberrant Envelope Physiology. AB - Cell wall anchored virulence factors are critical for infection and colonization of the host by Gram-positive bacteria. Such proteins have an N-terminal leader sequence and a C-terminal sorting signal, composed of an LPXTG motif, a hydrophobic stretch, and a few positively charged amino acids. The sorting signal halts translocation across the membrane, allowing sortase to cleave the LPXTG motif, leading to surface anchoring. Deletion of sortase prevents the anchoring of virulence factors to the wall; the effects on bacterial physiology however, have not been thoroughly characterized. Here we show that deletion of Streptococcus pyogenes sortase A leads to accumulation of sorting intermediates, particularly at the septum, altering cellular morphology and physiology, and compromising membrane integrity. Such cells are highly sensitive to cathelicidin, and are rapidly killed in blood and plasma. These phenomena are not a loss-of function effect caused by the absence of anchored surface proteins, but specifically result from the accumulation of sorting intermediates. Reduction in the level of sorting intermediates leads to a return of the sortase mutant to normal morphology, while expression of M protein with an altered LPXTG motif in wild type cells leads to toxicity in the host environment, similar to that observed in the sortase mutant. These unanticipated effects suggest that inhibition of sortase by small-molecule inhibitors could similarly lead to the rapid elimination of pathogens from an infected host, making such inhibitors much better anti-bacterial agents than previously believed. PMID- 26484775 TI - Estrogen Receptor (ER)-alpha36 Is Involved in Estrogen- and Tamoxifen-Induced Neuroprotective Effects in Ischemic Stroke Models. AB - The neuroprotection by estrogen (E2) and tamoxifen is well documented in experimental stroke models; however, the exact mechanism is unclear. A membrane based estrogen receptor, ER-alpha36, has been identified. Postmenopausal-levels of E2 act through ER-alpha36 to induce osteoclast apoptosis due to a prolonged activation of the mitogen-activated protein kinase (MAPK)/extracellular signal related kinase (ERK) signaling. We hypothesized that ER-alpha36 may play a role in the neuroprotective activities of estrogen and tamoxifen. Here, we studied ER alpha36 expression in the brain, as well as its neuroprotective effects against oxygen and glucose deprivation (OGD) in PC12 cells. We found that ER-alpha36 was expressed in both rat and human brain. In addition, OGD-induced cell death was prevented by l nmol/L 17beta-estradiol (E2beta). E2beta activates the MAPK/ERK signaling pathway in PC12 cells under basal and OGD conditions by interacting with ER-alpha36 and also induces ER-alpha36 expression. Low-dose of tamoxifen up regulated ER-alpha36 expression and enhanced neuronal survival in an ovariectomized ischemic stroke model. Furthermore, low-dose of tamoxifen enhanced neuroprotective effects by modulating activates or suppress ER-alpha36. Our results thus demonstrated that ER-alpha36 is involved in neuroprotective activities mediated by both estrogen and tamoxifen. PMID- 26484776 TI - Phylogeny and Historical Biogeography of Asian Pterourus Butterflies (Lepidoptera: Papilionidae): A Case of Intercontinental Dispersal from North America to East Asia. AB - The phylogenetic status of the well-known Asian butterflies often known as Agehana (a species group, often treated as a genus or a subgenus, within Papilio sensu lato) has long remained unresolved. Only two species are included, and one of them especially, Papilio maraho, is not only rare but near-threatened, being monophagous on its vulnerable hostplant, Sassafras randaiense (Lauraceae). Although the natural history and population conservation of "Agehana" has received much attention, the biogeographic origin of this group still remains enigmatic. To clarify these two questions, a total of 86 species representatives within Papilionidae were sampled, and four genes (concatenated length 3842 bp) were used to reconstruct their phylogenetic relationships and historical scenarios. Surprisingly, "Agehana" fell within the American Papilio subgenus Pterourus and not as previously suggested, phylogenetically close to the Asian Papilio subgenus Chilasa. We therefore formally synonymize Agehana with Pterourus. Dating and biogeographic analysis allow us to infer an intercontinental dispersal of an American ancestor of Asian Pterourus in the early Miocene, which was coincident with historical paleo-land bridge connections, resulting in the present "East Asia-America" disjunction distribution. We emphasize that species exchange between East Asia and America seems to be a quite frequent occurrence in butterflies during the Oligocene to Miocene climatic optima. PMID- 26484778 TI - Shigella Infections in Household Contacts of Pediatric Shigellosis Patients in Rural Bangladesh. AB - To examine rates of Shigella infections in household contacts of pediatric shigellosis patients, we followed contacts and controls prospectively for 1 week after the index patient obtained care. Household contacts of patients were 44 times more likely to develop a Shigella infection than were control contacts (odds ratio 44.7, 95% CI 5.5-361.6); 29 (94%) household contacts of shigellosis patients were infected with the same species and serotype as the index patient's. Pulsed-field gel electrophoresis showed that 14 (88%) of 16 with infected contacts had strains that were indistinguishable from or closely related to the index patient's strain. Latrine area fly counts were higher in patient households compared with control households, and 2 patient household water samples were positive for Shigella. We show high susceptibility of household contacts of shigellosis patients to Shigella infections and found environmental risk factors to be targeted in future interventions. PMID- 26484779 TI - How should pediatric anesthesia respond on the discussion about neurotoxicity in daily practice? PMID- 26484777 TI - Meconium aspiration syndrome: a role for fetal systemic inflammation. AB - BACKGROUND: Meconium aspiration syndrome (MAS) is a leading cause of morbidity and mortality in term infants. Meconium-stained amniotic fluid (MSAF) occurs in approximately 1 of every 7 pregnancies, but only 5% of neonates exposed to MSAF develop MAS. Why some infants exposed to meconium develop MAS while others do not is a fundamental question. Patients with MSAF have a higher frequency of intraamniotic inflammation/infection than those with clear fluid. We propose that fetal systemic inflammation is a risk factor for the development of MAS in patients with MSAF. OBJECTIVE: We sought to investigate whether intraamniotic inflammation and funisitis, the histopathologic landmark of a fetal inflammatory response, predispose to MAS. STUDY DESIGN: A prospective cohort study was conducted from 1995 through 2009. Amniotic fluid (AF) samples (n = 1281) were collected at the time of cesarean delivery from women who delivered singleton newborns at term (gestational age >=38 weeks). Intraamniotic inflammation was diagnosed if the AF concentration of matrix metalloproteinase-8 was >23 ng/mL. Funisitis was diagnosed by histologic examination if inflammation was present in the umbilical cord. RESULTS: The prevalence of MSAF was 9.2% (118/1281), and 10.2% (12/118) of neonates exposed to MSAF developed MAS. There were no significant differences in the median gestational age or umbilical cord arterial pH at birth between neonates who developed MAS and those who did not (each P > .1). Mothers whose newborns developed MAS had a higher median of AF matrix metalloproteinase-8 (456.8 vs 157.2 ng/mL, P < .05). Newborns exposed to intraamniotic inflammation had a higher rate of MAS than those who were not exposed to intraamniotic inflammation [13.0% (10/77) vs 0% (0/32), P = .03], as did those exposed to funisitis [31.3% (5/16) vs 7.3% (6/82); relative risk, 4.3; 95% confidence interval, 1.5-12.3]. Among the 89 newborns for whom both AF and placental histology were available, MAS was more common in patients with both intraamniotic inflammation and funisitis than in those without intraamniotic inflammation and funisitis [28.6% (4/14) vs 0% (0/28), P = .009], while the rate of MAS did not show a significant difference between patients with intraamniotic inflammation alone (without funisitis) and those without intraamniotic inflammation and funisitis [10.9% (5/46) vs 0% (0/28)]. CONCLUSION: The combination of intraamniotic inflammation with fetal systemic inflammation is an important antecedent of MAS. This concept has implications for the understanding of the mechanisms of disease responsible for MAS and for the development of prognostic models and therapeutic interventions for this disorder. PMID- 26484780 TI - Breast Cancer Screening in the Setting of Dense Breast Tissue. PMID- 26484781 TI - Asherman syndrome: an unsolved clinical definition and management. PMID- 26484782 TI - Automated Cell Enrichment of Cytomegalovirus-specific T cells for Clinical Applications using the Cytokine-capture System. AB - The adoptive transfer of pathogen-specific T cells can be used to prevent and treat opportunistic infections such as cytomegalovirus (CMV) infection occurring after allogeneic hematopoietic stem-cell transplantation. Viral-specific T cells from allogeneic donors, including third party donors, can be propagated ex vivo in compliance with current good manufacturing practice (cGMP), employing repeated rounds of antigen-driven stimulation to selectively propagate desired T cells. The identification and isolation of antigen-specific T cells can also be undertaken based upon the cytokine capture system of T cells that have been activated to secrete gamma-interferon (IFN-gamma). However, widespread human application of the cytokine capture system (CCS) to help restore immunity has been limited as the production process is time-consuming and requires a skilled operator. The development of a second-generation cell enrichment device such as CliniMACS Prodigy now enables investigators to generate viral-specific T cells using an automated, less labor-intensive system. This device separates magnetically labeled cells from unlabeled cells using magnetic activated cell sorting technology to generate clinical-grade products, is engineered as a closed system and can be accessed and operated on the benchtop. We demonstrate the operation of this new automated cell enrichment device to manufacture CMV pp65 specific T cells obtained from a steady-state apheresis product obtained from a CMV seropositive donor. These isolated T cells can then be directly infused into a patient under institutional and federal regulatory supervision. All the bio processing steps including removal of red blood cells, stimulation of T cells, separation of antigen-specific T cells, purification, and washing are fully automated. Devices such as this raise the possibility that T cells for human application can be manufactured outside of dedicated good manufacturing practice (GMP) facilities and instead be produced in blood banking facilities where staff can supervise automated protocols to produce multiple products. PMID- 26484783 TI - The direction of the acceleration and rotational forces associated with mild traumatic brain injury in rodents effect behavioural and molecular outcomes. AB - BACKGROUND: The translation of research to clinical application is only as good as the modelling platforms employed. This study sought to improve understanding of mild traumatic brain injury (mTBI), by examining the importance of acceleration and rotational force directions on behavioural and molecular outcomes. It is believed that many symptoms associated with concussive forms of mTBI are related to white matter and fibre tract damage. Given that rodents have significantly less white matter, could changes in acceleration/rotational force directionality alter outcomes? NEW METHOD/COMPARISON WITH EXISTING METHODS: Comparison of mTBIs with two distinct injury platforms, the lateral impact (LI) device, which produces horizontal acceleration/rotation; or the modified weight drop (WD) device, which produces sagittal or vertical acceleration/rotation. Male and female rats underwent a behavioural test battery followed by analysis of 5 TBI-associated biomarkers (BDNF, Eno2, GFAP, MAPT, TERT) from the prefrontal cortex and hippocampus. RESULTS: Acute behavioural impairments were similar for both injury models; animals exhibited increased time-to-wake, and deficits of balance and motor control. However, as the post-injury interval increased LI animals displayed deficits on tasks related to emotional functioning, whereas WD animals showed impairment in cognitive measures. Biomarker expression varied as a function of injury platform, sex, and brain region. CONCLUSION: Just as with humans, the direction of the acceleration and rotational forces produced injuries in different networks and connections, resulting in altered functional deficits for rodents as well. These findings suggest that rodents are a valuable resource for the study of mTBI, when appropriately modelled. PMID- 26484785 TI - Objective selection of epilepsy-related independent components from EEG data. AB - BACKGROUND: Independent Component Analysis (ICA) is commonly used for the identification of sources of interest in electroencephalographic (EEG) data, but the selection of the relevant components remains an open issue depending on the specific application. NEW METHOD: We propose a novel approach for the objective selection of epilepsy-related independent components (ICs) from EEG data collected during functional Magnetic Resonance Imaging (fMRI) acquisitions, called PROJection onto Independent Components (PROJIC). Inter-ictal epileptiform discharges (IEDs) are identified on a reference EEG dataset collected outside the MRI scanner by an expert neurophysiologist, and the resulting average IED is projected onto the IC space of the EEG data collected simultaneously with fMRI. The power of the IED projection is then used to inform a k-means clustering algorithm of the ICs, allowing for the classification of epilepsy-related ICs. COMPARISON WITH EXISTING METHODS: The performance of PROJIC was compared with two methods previously proposed for the objective selection of EEG ICs of interest, which are based on the explicit similarity of the ICs with spatio-temporal templates of the events of interest, instead of the projection power. RESULTS: The proposed PROJIC method outperformed the others for both artificial and real data (19 datasets collected from 6 patients with drug-refractory focal epilepsy), with an average accuracy of 98.6%. CONCLUSIONS: The ability of our method to accurately and objectively select epilepsy-related ICs makes it an important contribution for simultaneous EEG-fMRI epilepsy studies, with potential applications in the analysis of event-related EEG activity more generally, and also in EEG artefact correction. PMID- 26484784 TI - Models of drug-induced epileptiform synchronization in vitro. AB - Models of epileptiform activity in vitro have many advantages for recording and experimental manipulation. Neural tissues can be maintained in vitro for hours, and in neuronal or organotypic slice cultures for several weeks. A variety of drugs and other agents increase activity in these in vitro conditions, in many cases resulting in epileptiform activity, thus providing a direct model of symptomatic seizures. We review these preparations and the experimental manipulations used to induce epileptiform activity. The most common of drugs used are GABAA receptor antagonists and potassium channel blockers (notably 4 aminopyridine). Muscarinic agents also can induce epileptiform synchronization in vitro, and include potassium channel inhibition amongst their cellular actions. Manipulations of extracellular ions are reviewed in another paper in this special issue, as are ex vivo slices prepared from chronically epileptic animals and from people with epilepsy. More complex slices including extensive networks and/or several connected brain structures can provide insights into the dynamics of long range connections during epileptic activity. Visualization of slices also provides opportunities for identification of living neurons and for optical recording/stimulation and manipulation. Overall, the analysis of the epileptiform activity induced in brain tissue in vitro has played a major role in advancing our understanding of the cellular and network mechanisms of epileptiform synchronization, and it is expected to continue to do so in future. PMID- 26484786 TI - Evaluation of aggressiveness of female mice using a semi-automated apparatus for measurement of aggressive biting behavior toward an inanimate object. AB - BACKGROUND: Most laboratory research on aggressive behavior has focused on intraspecific intermale aggression tests. The intraspecific confrontation is not available for the evaluation of female aggressiveness, since androgens are critical for maintenance of this behavior, whereas aggressive biting behavior toward inanimate objects (ABI) occurs in both males and females. NEW METHOD: We propose an experimental method for evaluating female aggressiveness. We improved the previously developed semi-automated apparatus (Aggression Response Meter, ARM) to apply it to measurement of female ABI, and measured changes of ABI in stressed mice and drug actions on ABI. RESULTS: ABI assessment was performed daily in sexually mature female mice using ARM. The intensity and number of ABI in one session did not significantly change during an estrous cycle, suggesting that ABI is not influenced by the dynamics of sex hormones. Additional female mice were socially isolated for 7 weeks and then re-socialized for 2 weeks, and ABI was monitored weekly. ABI significantly increased during the isolation period, and then significantly decreased during re-socialization; both were time dependent. In prolonged-isolated aggressive mice, a serotonin 1A receptor agonist, buspirone, significantly decreased ABI. COMPARISON WITH EXISTING METHOD: There are no experimental methods or apparatus available for evaluating female aggressiveness using one individual repeatedly. We could measure ABI semi quantitatively using the ARM. CONCLUSIONS: ABI is a useful behavioral paradigm in the evaluation of aggressiveness in female mice, regardless of the estrous cycle, and can also be used for evaluating the actions of drugs on aggressiveness. PMID- 26484787 TI - An automated task for the training and assessment of distal forelimb function in a mouse model of ischemic stroke. AB - BACKGROUND: Behavioral models relevant to stroke research seek to capture important aspects of motor skills typically impaired in human patients, such as coordination of distal musculature. Such models may focus on mice since many genetic tools are available for use only in that species and since the training and behavioral demands of mice can differ from rats even for superficially similar behavioral readouts. However, current mouse assays are time consuming to train and score, especially in a manner producing continuous quantification. An automated assay of mouse forelimb function may provide advantages for quantification and speed, and may be useful for many applications including stroke research. NEW METHOD: We present an automated assay of distal forelimb function. In this task, mice reach forward, grip and pull an isometric handle with a prescribed force. The apparatus partially automates the training process so that mice can be trained quickly and simultaneously. RESULTS: Using this apparatus, it is possible to measure long-lasting impairment in success rate, force pulled, latency to pull, and latency to success up to 22 weeks following photothrombotic cortical strokes in mice. COMPARISON WITH EXISTING METHOD(S): This assessment measures forelimb function as do pellet reach tasks, but it utilizes a different motion and provides automatic measures that can ease and augment the research process. CONCLUSIONS: This high-throughput behavioral assay can detect long-lasting motor impairments, eliminates the need for subjective scoring, and produces a rich, continuous data set from which many aspects of the reach and grasp motion can be automatically extracted. PMID- 26484788 TI - Beta-blockers in the treatment of catecholaminergic polymorphic ventricular tachycardia. PMID- 26484789 TI - Progression of atrial remodeling in patients with high-burden atrial fibrillation: Implications for early ablative intervention. AB - BACKGROUND: Advanced atrial remodeling predicts poor clinical outcomes in human atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to define the magnitude and predictors of change in left atrial (LA) structural remodeling over 12 months of AF. METHODS: Thirty-eight patients with paroxysmal AF managed medically (group 1), 20 undergoing AF ablation (group 2), and 25 control patients with no AF history (group 3) prospectively underwent echocardiographic assessment of strain variables of LA reservoir function at baseline and at 4, 8, and 12 months. In addition, P-wave duration (Pmax,, Pmean) and dispersion (Pdis) were measured. AF burden was quantified by implanted recorders. Twenty patients undergoing ablation underwent electroanatomic mapping (mean 333 +/- 40 points) for correlation with LA strain. RESULT: Group 1 demonstrated significant deterioration in total LA strain (26.3% +/- 1.2% to 21.7% +/- 1.2%, P < .05) and increases in Pmax (132 +/- 3 ms to 138 +/- 3 ms, P < .05) and Pdis (37 +/- 2 ms to 42 +/- 2 ms, P < .05). AF burden >=10% was specifically associated with decline in strain and with P-wave prolongation. Conversely, group 2 manifest improvement in total LA strain (21.3% +/- 1.7% to 28.6% +/- 1.7%, P <.05) and reductions in Pmax (136 +/- 4 ms to 119 +/- 4 ms, P < .05) and Pdis (47 +/- 3 ms to 32 +/- 3 ms, P < .05). Change was not significant in group 3. LA mean voltage (r = 0.71, P = .0005), percent low voltage electrograms (r = -0.59, P = .006), percent complex electrograms (r = -0.68, P = .0009), and LA activation time (r = 0.69, P = .001) correlated with total strain as a measure of LA reservoir function. CONCLUSION: High-burden AF is associated with progressive LA structural remodeling. In contrast, AF ablation results in significant reverse remodeling. These data may have implications for timing of ablative intervention. PMID- 26484790 TI - Characterization of a novel gene involved in cadmium accumulation screened from sponge-associated bacterial metagenome. AB - Metagenome research has brought much attention for the identification of important and novel genes of industrial and pharmaceutical value. Here, using a metagenome library constructed from bacteria associated with the marine sponge, Styllisa massa, a high-throughput screening technique using radioisotope was implemented to screen for cadmium (Cd) binding or accumulation genes. From a total of 3301 randomly selected clones, a clone 247-11C was identified as harboring an open reading frame (ORF) showing Cd accumulation characteristics. The ORF, termed as ORF5, was further analyzed by protein functional studies to reveal the presence of a protein, Cdae-1. Cdae-1, composed of a signal peptide and domain harboring an E(G/A)KCG pentapeptide motif, enhanced Cd accumulation when expressed in Escherichia coli. Although showing no direct binding to Cd in vitro, the presence of important amino acid residues related to Cd detoxification suggests that Cdae-1 may possess a different mechanism from known Cd binding proteins such as metallothioneins (MTs) and phytochelatins (PCs). In summary, using the advantage of bacterial metagenomes, our findings in this work suggest the first report on the identification of a unique protein involved in Cd accumulation from bacteria associated with a marine sponge. PMID- 26484791 TI - Three-dimensional Quantification of Dendritic Spines from Pyramidal Neurons Derived from Human Induced Pluripotent Stem Cells. AB - Dendritic spines are small protrusions that correspond to the post-synaptic compartments of excitatory synapses in the central nervous system. They are distributed along the dendrites. Their morphology is largely dependent on neuronal activity, and they are dynamic. Dendritic spines express glutamatergic receptors (AMPA and NMDA receptors) on their surface and at the levels of postsynaptic densities. Each spine allows the neuron to control its state and local activity independently. Spine morphologies have been extensively studied in glutamatergic pyramidal cells of the brain cortex, using both in vivo approaches and neuronal cultures obtained from rodent tissues. Neuropathological conditions can be associated to altered spine induction and maturation, as shown in rodent cultured neurons and one-dimensional quantitative analysis (1). The present study describes a protocol for the 3D quantitative analysis of spine morphologies using human cortical neurons derived from neural stem cells (late cortical progenitors). These cells were initially obtained from induced pluripotent stem cells. This protocol allows the analysis of spine morphologies at different culture periods, and with possible comparison between induced pluripotent stem cells obtained from control individuals with those obtained from patients with psychiatric diseases. PMID- 26484792 TI - A novel 3D absorption correction method for quantitative EDX-STEM tomography. AB - This paper presents a novel 3D method to correct for absorption in energy dispersive X-ray (EDX) microanalysis of heterogeneous samples of unknown structure and composition. By using STEM-based tomography coupled with EDX, an initial 3D reconstruction is used to extract the location of generated X-rays as well as the X-ray path through the sample to the surface. The absorption correction needed to retrieve the generated X-ray intensity is then calculated voxel-by-voxel estimating the different compositions encountered by the X-ray. The method is applied to a core/shell nanowire containing carbon and oxygen, two elements generating highly absorbed low energy X-rays. Absorption is shown to cause major reconstruction artefacts, in the form of an incomplete recovery of the oxide and an erroneous presence of carbon in the shell. By applying the correction method, these artefacts are greatly reduced. The accuracy of the method is assessed using reference X-ray lines with low absorption. PMID- 26484793 TI - Simplified reintervention method of EUS-guided hepaticogastrostomy stent obstruction. PMID- 26484794 TI - Open-label randomized non-inferiority trial of a fixed-dose combination of glimepiride and atorvastatin for the treatment of people whose Type 2 diabetes is uncontrolled on metformin. AB - AIMS: To evaluate, in a randomized, open-label study, the non-inferiority of a bioequivalent fixed-dose combination of glimepiride and atorvastatin vs. separately co-administered tablets in people with Type 2 diabetes mellitus. METHODS: Participants with HbA1c >= 53 to < 80 mmol/mol (>= 7.0 to < 9.5%), average fasting blood glucose > 7.0 mmol/l, who were on metformin for >= 3 months, were randomized to combination (n = 215) or co-administered glimepiride and atorvastatin (n = 212) once daily for 20 weeks. Up-titration of glimepiride (1-4 mg) and atorvastatin (10-20 mg) were based on average fasting blood glucose and LDL cholesterol, respectively. Co-primary endpoints were change from baseline to week 20 in HbA1c and LDL cholesterol. RESULTS: Non-inferiority was demonstrated for both co-primary endpoints: the upper limits of 95% CIs for differences (combination-reference) were less than the prespecified margins of 3.3 mmol/mol (0.3%) for change from baseline in HbA1c [difference 0.1 mmol/mol (95% CI -1.6, 1.9); 0.01% (95% CI -0.15, 0.17)] and 6% for percentage change from baseline in LDL cholesterol [difference 0.87% (95% CI -2.47, 4.21)]. Similar proportions of participants on combination and reference had treatment-emergent adverse events (64 vs. 61%). More participants on combination had hypoglycaemia (21 vs. 13%); most events were considered by the treating physician to be unrelated to study drug. CONCLUSIONS: The combination was non-inferior to separately co-administered tablets and the safety profile was consistent with the known profiles of glimepiride and atorvastatin. The observed increase in hypoglycaemia on the combination cannot be explained, but may be attributable to non-systematic collectiof glucose readings and may have been influenced by reporting bias in this open-label trial. PMID- 26484795 TI - Long-Acting Reversible Contraceptives for Incarcerated Women: Feasibility and Safety of On-Site Provision. AB - CONTEXT: Many incarcerated women have an unmet need for contraception. Providing access to long-acting reversible contraceptive (LARC) methods--IUDs and implants- before release is one strategy to meet this need and potentially prepare them for reentry to the community, but the safety and feasibility of providing these methods in this setting have not been described. METHODS: A retrospective descriptive study of all LARC insertions at the San Francisco County Jail in 2009 2014 was conducted. Data from community clinic and jail clinic databases were assessed to examine baseline characteristics of LARC initiators, complications from insertion, method continuation, and pregnancy and reincarceration rates. Correlates of method discontinuation were assessed in multivariate logistic regression analyses. RESULTS: Eighty-seven LARC devices were inserted during the study period--53 IUDs and 34 implants. There were no cases of pelvic inflammatory disease or other insertion complications in IUD users and no serious complications in implant users. Median duration of known use was 11.4 months for IUDs and 12.9 months for implants. Women who discontinued a LARC method most commonly cited a desire to get pregnant (32%). Black women were more likely than whites to discontinue use (odds ratio, 4.4). CONCLUSIONS: It is safe and feasible to provide LARC methods to incarcerated women. Correctional facilities should consider increasing access to all available contraceptives, including LARC methods, in a noncoercive manner as a strategy to reduce reproductive health disparities among marginalized women at high risk of unplanned pregnancies. PMID- 26484797 TI - The Use of p-Aminobenzoic Acid as a Probe Substance for the Targeted Profiling of Glycine Conjugation. AB - Glycine conjugation facilitates the metabolism of toxic aromatic acids, capable of disrupting mitochondrial integrity. Owing to the high exposure to toxic substrates, characterization of individual glycine conjugation capacity, and its regulatory factors has become increasingly important. Aspirin and benzoate have been employed for this purpose; however, adverse reactions, aspirin intolerance, and Reye's syndrome in children are substantial drawbacks. The goal of this study was to investigate p-aminobenzoic acid (PABA) as an alternative glycine conjugation probe. Ten human volunteers participated in a PABA challenge test, and p-aminohippuric acid (PAHA), p-acetamidobenzoic acid, and p-acetamidohippuric acid were quantified in urine. The glycine N-acyltransferase gene of the volunteers was also screened for two polymorphisms associated with normal and increased enzyme activity. All of the individuals were homozygous for increased enzyme activity, but excretion of PAHA varied significantly (16-56%, hippurate ratio). The intricacies of PABA metabolism revealed possible limiting factors and the potential of PABA as an indicator of Phase 0 biotransformation. PMID- 26484798 TI - Erratum: High frequency of deficient consumption and low blood levels of 25 hydroxyvitamin D in HIV-1-infected adults from Sao Paulo city, Brazil. PMID- 26484799 TI - High-Energy Faceted SnO2-Coated TiO2 Nanobelt Heterostructure for Near-Ambient Temperature-Responsive Ethanol Sensor. AB - A SnO2 gas sensor was prepared by a two-step oxidation process whereby a Sn(II) precursor was partially oxidized by a hydrothermal process and the resulting Sn3O4 nanoplates were thermally oxidized to yield SnO2 nanoplates. The SnO2 sensor was selective and responsive toward ethanol at a temperature as low as 43 degrees C. This low sensing temperature stems from the rapid charge transport within SnO2 and from the presence of high-energy (001) facets available for oxygen chemisorption. SnO2/TiO2 nanobelt heterostructures were fabricated by a similar two-step process in which TiO2 nanobelts acted as support for the epitaxial growth of intermediate Sn3O4. At temperatures ranging from 43 to 276 degrees C, the response of these branched nanobelts is more than double the response of SnO2 for ethanol detection. Our observations demonstrate the potential of low-cost SnO2-based sensors with controlled morphology and reactive facets for detecting gases around room temperature. PMID- 26484800 TI - To What Extent Does Surface Hydrophobicity Dictate Peptide Folding and Stability near Surfaces? AB - Protein-surface interactions are ubiquitous in both the cellular setting and in modern bioengineering devices, but how such interactions impact protein stability is not well understood. We investigate the folding of the GB1 hairpin peptide in the presence of self-assembled monolayers and graphite like surfaces using replica exchange molecular dynamics simulations. By varying surface hydrophobicity, and decoupling direct protein-surface interactions from water mediated interactions, we show that surface wettability plays a surprisingly minor role in dictating protein stability. For both the beta-hairpin GB1 and the helical miniprotein TrpCage, adsorption and stability is largely dictated by the nature of the direct chemical interactions between the protein and the surface. Independent of the surface hydrophobicity profile, strong protein-surface interactions destabilize the folded structure while weak interactions stabilize it. PMID- 26484801 TI - Awake examination versus DISE for surgical decision making in patients with OSA: A systematic review. AB - OBJECTIVE: Traditionally, upper airway examination is performed while the patient is awake. However, in the past two decades, drug-induced sleep endoscopy (DISE) has been used as a method of tridimensional evaluation of the upper airway during pharmacologically induced sleep. This study aimed to systematically review the evidence regarding the usefulness of DISE compared with that of traditional awake examination for surgical decision making in patients with obstructive sleep apnea (OSA). DATA SOURCES: Scopus, PubMed, and Cochrane Library databases were searched. REVIEW METHODS: Only studies with a primary objective of evaluating the usefulness of DISE for surgical decision making in patients with OSA were selected. The included studies directly compared awake examination data with DISE outcome data in terms of possible influences on surgical decision making and operation success. RESULTS: A total of eight studies with 535 patients were included in this review. Overall, the surgical treatment changed after DISE in 50.24% (standard deviation 8.4) cases. These changes were more frequently associated with structures contributing to hypopharyngeal or laryngeal obstruction. However, these differences do not automatically indicate a higher success rate. CONCLUSION: This review emphasized the direct impact of DISE compared with that of awake examination on surgical decision making in OSA patients. However, it is also clear that the available published studies lack evidence on the association between this impact and surgical outcomes. Laryngoscope, 126:768-774, 2016. PMID- 26484804 TI - CHOROIDAL EFFUSION AS AN OCULAR MANIFESTATION OF IMMUNOGLOBULIN G4-RELATED DISEASE. AB - PURPOSE: To report a unique ocular manifestation of immunoglobulin G4-related disease (IgG4-RD) as choroidal effusion. METHODS: Case report. RESULTS: An 81 year-old man presented with clinical manifestations of choroidal effusion, confirmed by fluorescein angiography, ophthalmic ultrasound (posterior segment), high-frequency ultrasound biomicroscopy, Heidelberg Spectralis spectral domain optical coherence tomography, and enhanced depth imaging spectral domain optical coherence tomography. Systemic multi-organ findings included chronic pancreatitis, irregularity of the intrahepatic bile ducts, lymphadenopathy, aortitis, fibrotic changes of the lungs, hypophysitis, and sialadenitis. Extensive workup revealed elevated IgG4 serum levels, and lymph nodes biopsy showed reactive pattern with polyclonal IgG4 positive plasma cells. These findings were compatible with IgG4-related disease. Treatment with oral corticosteroids resulted in complete resolution of the choroidal effusion. CONCLUSION: Choroidal effusion may be an ocular manifestation of IgG4-related disease. Oral corticosteroids is an effective treatment. Ophthalmologists should be aware of this possible finding. PMID- 26484803 TI - Nerve growth factor (NGF) and pro-NGF increase low-density lipoprotein (LDL) receptors in neuronal cells partly by different mechanisms: role of LDL in neurite outgrowth. AB - Low-density lipoprotein receptors (LDLRs) mediate the uptake of lipoprotein particles into cells, as studied mainly in peripheral tissues. Here, we show that nerve growth factor (NGF) increases LDLR levels in PC6.3 cells and in cultured septal neurons from embryonic rat brain. Study of the mechanisms showed that NGF enhanced transcription of the LDLR gene, acting mainly via Tropomyosin receptor kinase A receptors. Simvastatin, a cholesterol-lowering drug, also increased the LDLR expression in PC6.3 cells. In addition, pro-NGF and pro-brain-derived neurotrophic factor, acting via the p75 neurotrophin receptor (p75NTR) also increased LDLRs. We further observed that Myosin Regulatory Light Chain Interacting Protein/Inducible Degrader of the LDLR (Mylip/Idol) was down regulated by pro-NGF, whereas the other LDLR regulator, proprotein convertase subtilisin kexin 9 (PCSK9) was not significantly changed. On the functional side, NGF and pro-NGF increased lipoprotein uptake by neuronal cells as shown using diacetyl-labeled LDL. The addition of serum-derived lipoprotein particles in conjunction with NGF or simvastatin enhanced neurite outgrowth. Collectively, these results show that NGF and simvastatin are able to stimulate lipoprotein uptake by neurons with a positive effect on neurite outgrowth. Increases in LDLRs and lipoprotein particles in neurons could play a functional role during brain development, in neuroregeneration and after brain injuries. Nerve growth factor (NGF) and pro-NGF induce the expression of low-density lipoprotein receptors (LDLRs) in neuronal cells leading to increased LDLR levels. Pro-NGF also down regulated myosin regulatory light chain-interacting protein/inducible degrader of the LDLR (Mylip/Idol) that is involved in the degradation of LDLRs. NGF acts mainly via Tropomyosin receptor kinase A (TrkA) receptors, whereas pro-NGF stimulates p75 neurotrophin receptor (p75NTR). Elevated LDLRs upon NGF and pro NGF treatments enhanced lipoprotein uptake by neurons. Addition of LDL particles further led to the stimulation of neurite outgrowth in PC6.3 cells after NGF or simvastatin treatments, suggesting a stimulatory role of lipoproteins on neuronal differentiation. In contrast, pro-NGF had no effect on neurite outgrowth either in the absence or presence of LDL particles. The precise mechanisms by which increased lipoproteins uptake can affect neurite outgrowth warrant further studies. PMID- 26484807 TI - Gut microbes ward off obesity. PMID- 26484806 TI - Import/export imbalance in ALS. PMID- 26484809 TI - Modeling aberrant bone growth. PMID- 26484810 TI - T cells on the trail. PMID- 26484812 TI - Uncommon uses for a common fish. PMID- 26484813 TI - Response to Protocol Review Scenario: Where loopholes linger, intent should prevail. PMID- 26484814 TI - To register or not to register. PMID- 26484815 TI - Response to Protocol Review Scenario: Get registered (and accredited)! PMID- 26484816 TI - Response to Protocol Review Scenario: Down the rabbit hole. PMID- 26484817 TI - A word from USDA. PMID- 26484802 TI - Reperfusion injury and reactive oxygen species: The evolution of a concept. AB - Reperfusion injury, the paradoxical tissue response that is manifested by blood flow-deprived and oxygen-starved organs following the restoration of blood flow and tissue oxygenation, has been a focus of basic and clinical research for over 4-decades. While a variety of molecular mechanisms have been proposed to explain this phenomenon, excess production of reactive oxygen species (ROS) continues to receive much attention as a critical factor in the genesis of reperfusion injury. As a consequence, considerable effort has been devoted to identifying the dominant cellular and enzymatic sources of excess ROS production following ischemia-reperfusion (I/R). Of the potential ROS sources described to date, xanthine oxidase, NADPH oxidase (Nox), mitochondria, and uncoupled nitric oxide synthase have gained a status as the most likely contributors to reperfusion induced oxidative stress and represent priority targets for therapeutic intervention against reperfusion-induced organ dysfunction and tissue damage. Although all four enzymatic sources are present in most tissues and are likely to play some role in reperfusion injury, priority and emphasis has been given to specific ROS sources that are enriched in certain tissues, such as xanthine oxidase in the gastrointestinal tract and mitochondria in the metabolically active heart and brain. The possibility that multiple ROS sources contribute to reperfusion injury in most tissues is supported by evidence demonstrating that redox-signaling enables ROS produced by one enzymatic source (e.g., Nox) to activate and enhance ROS production by a second source (e.g., mitochondria). This review provides a synopsis of the evidence implicating ROS in reperfusion injury, the clinical implications of this phenomenon, and summarizes current understanding of the four most frequently invoked enzymatic sources of ROS production in post-ischemic tissue. PMID- 26484819 TI - Free resources for the veterinary community. PMID- 26484818 TI - Basic research support for shared magnetic resonance imaging resources. AB - Procedures that enable the collection of longitudinal physiologic and anatomic information can contribute to the reduction and refinement of animal use. Scientists are increasingly turning to noninvasive magnetic resonance imaging (MRI) to obtain such information from animal research subjects. As they make this important investment, research support veterinarians are often tasked with ensuring the proper care and use of laboratory animal research subjects. A basic understanding of MRI equipment, personnel practices, safety, and monitoring of animals and their recoveries is key to implementing a centralized animal MRI facility. PMID- 26484820 TI - Evaluation of a novel technique for intraperitoneal injections in mice. AB - Intraperitoneal injection is a common technique that safely delivers a substance into the peritoneal cavity but can induce high stress in animals. The authors have developed a new method for administering intraperitoneal injections in mice, with the goal of causing less stress during handling and injection. Here, they compare their novel technique with a conventional technique in three experiments. In the first experiment, the authors administered intraperitoneal injections of contrast medium using either technique and then used micro-computed tomography to evaluate the placement and retention of the medium. In the second and third experiments, the authors administered intraperitoneal injections or control treatments, then sampled blood to determine circulating concentrations of stress related hormones. Imaging showed that both the novel and the conventional techniques properly delivered a contrast medium into the peritoneal cavity. The novel technique was also associated with lower concentrations of stress-related hormones than was the conventional technique. These results indicate that this novel technique might be beneficial to investigators that use intraperitoneal injections with mice. PMID- 26484821 TI - Gross and histological description of the epidermal membrane found on normal neonatal piglets. AB - The structure and composition of fetal and placental tissues vary among different species of placental mammals. Some mammals, including camelids and pigs, possess an epidermal membrane during the fetal stage, called the epithelion, that is absent from other domestic mammals. Because neonatal piglets are a common animal model for many research techniques, it is important that researchers correctly identify this tissue and recognize its lack of pathological consequence when working with fetal and neonatal piglets. Here, the authors describe gross and histological examinations of the epithelion, comparing this tissue with other extra-fetal tissues and coatings. PMID- 26484822 TI - LAWTE turns 21! PMID- 26484823 TI - To Slinky, with love, part 2. PMID- 26484824 TI - Privileged to work with animals. PMID- 26484825 TI - State-of-the-art equipment for sterilization and biocontainment since 1925. AB - Tuttnauer is a worldwide leader in the market for sterilization and infection control. An expansive global presence has aided Tuttnauer's growth over the past four decades. Tuttnauer's products are marketed through seven subsidiaries with local dealers in over 120 countries. The company also holds offices in the United States, Netherlands, India, China, and Vietnam. Facing the most challenging and complex projects worldwide, Tuttnauer has become a driving force in advancing technology in this market to a new standard. PMID- 26484826 TI - Diminished neural adaptation during implicit learning in autism. AB - Neuroimaging studies have shown evidence of disrupted neural adaptation during learning in individuals with autism spectrum disorder (ASD) in several types of tasks, potentially stemming from frontal-posterior cortical underconnectivity (Schipul et al., 2012). The aim of the current study was to examine neural adaptations in an implicit learning task that entails participation of frontal and posterior regions. Sixteen high-functioning adults with ASD and sixteen neurotypical control participants were trained on and performed an implicit dot pattern prototype learning task in a functional magnetic resonance imaging (fMRI) session. During the preliminary exposure to the type of implicit prototype learning task later to be used in the scanner, the ASD participants took longer than the neurotypical group to learn the task, demonstrating altered implicit learning in ASD. After equating task structure learning, the two groups' brain activation differed during their learning of a new prototype in the subsequent scanning session. The main findings indicated that neural adaptations in a distributed task network were reduced in the ASD group, relative to the neurotypical group, and were related to ASD symptom severity. Functional connectivity was reduced and did not change as much during learning for the ASD group, and was related to ASD symptom severity. These findings suggest that individuals with ASD show altered neural adaptations during learning, as seen in both activation and functional connectivity measures. This finding suggests why many real-world implicit learning situations may pose special challenges for ASD. PMID- 26484827 TI - A hemodynamic model for layered BOLD signals. AB - High-resolution blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at the sub-millimeter scale has become feasible with recent advances in MR technology. In principle, this would enable the study of layered cortical circuits, one of the fundaments of cortical computation. However, the spatial layout of cortical blood supply may become an important confound at such high resolution. In particular, venous blood draining back to the cortical surface perpendicularly to the layered structure is expected to influence the measured responses in different layers. Here, we present an extension of a hemodynamic model commonly used for analyzing fMRI data (in dynamic causal models or biophysical network models) that accounts for such blood draining effects by coupling local hemodynamics across layers. We illustrate the properties of the model and its inversion by a series of simulations and show that it successfully captures layered fMRI data obtained during a simple visual experiment. We conclude that for future studies of the dynamics of layered neuronal circuits with high-resolution fMRI, it will be pivotal to include effects of blood draining, particularly when trying to infer on the layer-specific connections in cortex--a theme of key relevance for brain disorders like schizophrenia and for theories of brain function such as predictive coding. PMID- 26484828 TI - Dissociation of the functional relevance of different pre-stimulus oscillatory activity for memory formation. AB - The state of a neural assembly preceding an incoming stimulus modulates the processing of that subsequently presented stimuli. For human memory formation, the role of oscillatory brain activity within different frequency ranges has been discussed but a more functional relation could not be established. In the present Experiment I, an increase of pre-stimulus theta- (3-7Hz) and beta- (13-17Hz) band oscillations during encoding for later remembered stimuli was observed. To establish a more direct functional relation, we adopted a novel brain-computer interface (BCI) method to selectively detect oscillatory activity in real-time combined with an adaptive stimulus presentation at different levels of activity. Therefore, in the second experiment the BCI was used to present the visual stimuli with a high temporal resolution directly within defined brain states of beta- or theta-band activity. The quality of the subsequent processing of the stimuli was assessed at the behavioral level with a surprise recognition task. Results revealed a variation of memory performance in direct relation to the amount of pre-stimulus beta- but not theta-band oscillations, suggesting a functional relevance of beta-band oscillations for memory encoding. Thus, the BCI method enabled a more functional differentiation of the effective role of ongoing oscillatory activity. PMID- 26484830 TI - Role of the human retrosplenial cortex/parieto-occipital sulcus in perspective priming. AB - The ability to imagine the world from a different viewpoint is a fundamental competence for spatial reorientation and for imagining what another individual sees in the environment. Here, we investigated the neural bases of such an ability using functional magnetic resonance imaging. Healthy participants detected target displacements across consecutive views of a familiar virtual room, either from the perspective of an avatar (primed condition) or in the absence of such a prime (unprimed condition). In the primed condition, the perspective at test always corresponded to the avatar's perspective, while in the unprimed condition it was randomly chosen as 0, 45 or 135deg of viewpoint rotation. We observed a behavioral advantage in performing a perspective transformation during the primed condition as compared to an equivalent amount of unprimed perspective change. Although many cortical regions (dorsal parietal, parieto-temporo-occipital junction, precuneus and retrosplenial cortex/parieto occipital sulcus or RSC/POS) were involved in encoding and retrieving target location from different perspectives and were modulated by the amount of viewpoint rotation, the RSC/POS was the only area showing decreased activity in the primed as compared to the unprimed condition, suggesting that this region anticipates the upcoming perspective change. The retrosplenial cortex/parieto occipital sulcus appears to play a special role in the allocentric coding of heading directions. PMID- 26484831 TI - Coping with mental health issues: subjective experiences of self-help and helpful contextual factors at the start of mental health treatment. AB - BACKGROUND: Self-help strategies and various contextual factors support recovery. However, more in-depth knowledge is needed about how self-help strategies and supportive environments facilitate the recovery process. AIMS: To explore what individuals who have recently been referred to a specialist Community Mental Health Center experience as helpful and what they do to help themselves. METHOD: Ten service users participated in in-depth interviews within a collaborative reflexive framework. A hermeneutic-phenomenological approach was used. RESULTS: Participants described a variety of helpful strategies and environmental supports. Four relevant main themes were identified: helpful activities, helpful people and places, self-instruction and learning about mental problems and medication and self-medication. CONCLUSIONS: The process of recovery is initiated before people become users of mental health services. This study confirms that recovery takes place within the person's daily life context and involves the interplay of contextual factors, such as family, friends, good places, work and other meaningful activities. The coping strategies reported may represent an important focus for attention and clinical intervention. PMID- 26484832 TI - The effect of time perspectives on mental health information processing and help seeking attitudes and intentions in younger versus older adults. AB - : Socioemotional selectivity theory posits that changes in time perspective over the lifespan are associated with distinct goals and motivations. Time perspectives and their associated socioemotional motivations have been shown to influence information processing and memory, such that motivation-consistent information is more likely to be remembered and evaluated more positively. OBJECTIVE: The aim of this study was to examine the effect of motivation consistent mental health information on memory for and evaluations of this information, as well as help-seeking attitudes and intentions to seek mental health services. METHOD: We randomly assigned an Internet-based sample of 160 younger (18-25) and 175 older (60-89) adults to read a mental health information pamphlet that emphasized time perspectives and motivations relevant to either young adulthood (future-focused) or late adulthood (present-focused). Participants completed measures assessing their time perspective, memory for and subjective evaluation of the pamphlet, and help-seeking attitudes and intentions. RESULTS: The time perspective manipulation had no effect on memory for pamphlet information or help-seeking attitudes and intentions. There was, however, a significant interaction between time perspective and pamphlet version on the rated liking of the pamphlet. CONCLUSION: Although motivation-consistent information only affected perceptions of that information for present-focused (mostly older) individuals, this finding has important implications for enhancing older adults' mental health literacy. PMID- 26484829 TI - Integrative Bayesian analysis of neuroimaging-genetic data with application to cocaine dependence. AB - Neuroimaging and genetic studies provide distinct and complementary information about the structural and biological aspects of a disease. Integrating the two sources of data facilitates the investigation of the links between genetic variability and brain mechanisms among different individuals for various medical disorders. This article presents a general statistical framework for integrative Bayesian analysis of neuroimaging-genetic (iBANG) data, which is motivated by a neuroimaging-genetic study in cocaine dependence. Statistical inference necessitated the integration of spatially dependent voxel-level measurements with various patient-level genetic and demographic characteristics under an appropriate probability model to account for the multiple inherent sources of variation. Our framework uses Bayesian model averaging to integrate genetic information into the analysis of voxel-wise neuroimaging data, accounting for spatial correlations in the voxels. Using multiplicity controls based on the false discovery rate, we delineate voxels associated with genetic and demographic features that may impact diffusion as measured by fractional anisotropy (FA) obtained from DTI images. We demonstrate the benefits of accounting for model uncertainties in both model fit and prediction. Our results suggest that cocaine consumption is associated with FA reduction in most white matter regions of interest in the brain. Additionally, gene polymorphisms associated with GABAergic, serotonergic and dopaminergic neurotransmitters and receptors were associated with FA. PMID- 26484833 TI - Biomimetic Mn-Catalases Based on Dimeric Manganese Complexes in Mesoporous Silica for Potential Antioxidant Agent. AB - Two new structural and functional models of the Mn-catalase with formula [{Mn(III)(bpy)(H2O)}(MU-2-MeOC6H4CO2)2(MU-O){Mn(III)(bpy)(X)}]X, where X = NO3 (1) and ClO4 (2) and bpy = 2,2'-bipyridine, were synthesized and characterized by X-ray diffraction. In both cases, a water molecule and an X ion occupy the monodentate positions. The magnetic properties of these compounds reveal a weak antiferromagnetic behavior (2J = -2.2 cm(-1) for 1 and -0.7 cm(-1) for 2, using the spin Hamiltonian H = -2J S1.S2) and negative zero-field splitting parameter DMn (-4.6 cm(-1) and -3.0 cm(-1) for 1 and 2, respectively). This fact, together with the nearly orthogonal orientation of the Jahn-Teller axes of the Mn(III) ions explain the unusual shape of chiMT versus T plot at low temperature. Compound 1 presents a better catalase activity than 2 in CH3CN-H2O media, probably due to a beneficial interaction of the NO3(-) ion with the Mn complex in solution. These compounds were successfully inserted inside two-dimensional hexagonal mesoporous silica (MCM-41 type) leading to the same hybrid material ([Mn2O]@SiO2), without the X group. The manganese complex occupies approximately half of the available pore volume, keeping the silica's hexagonal array intact. Magnetic measurements of [Mn2O]@SiO2 suggest that most of the dinuclear unit is preserved, as a non-negligible interaction between Mn ions is still observed. The X-ray photoelectron spectroscopy analysis of the Mn 3s peak confirms that Mn remains as Mn(III) inside the silica. The catalase activity study of material [Mn2O]@SiO2 reveals that the complex is more active inside the porous silica, probably due to the surface silanolate groups of the pore wall. Moreover, the new material shows catalase activity in water media, while the coordination compounds are not active. PMID- 26484834 TI - The AJT Report. PMID- 26484836 TI - Surgical technique in transplantation: how much does it matter? PMID- 26484837 TI - The effect of anastomosis time on outcome in recipients of kidneys donated after brain death: a cohort study. AB - Whether warm ischemia during the time to complete the vascular anastomoses determines renal allograft function has not been investigated systematically. We investigated the effect of anastomosis time on allograft outcome in 669 first, single kidney transplantations from brain-dead donors. Anastomosis time independently increased the risk of delayed graft function (odds ratio per minute [OR] 1.05, 95% confidence interval [CI] 1.02-1.07, p < 0.001) and independently impaired allograft function after transplantation (p = 0.009, mixed-models repeated-measures analysis). In a subgroup of transplant recipients, protocol specified biopsies at 3 months (n = 186), 1 year (n = 189), and 2 years (n = 153) were blindly reviewed. Prolonged anastomosis time independently increased the risk of interstitial fibrosis and tubular atrophy on these protocol-specified biopsies posttransplant (p < 0.001, generalized linear models). In conclusion, prolonged anastomosis time is not only detrimental for renal allograft outcome immediately after transplantation, also longer-term allograft function and histology are affected by the duration of this warm ischemia. PMID- 26484838 TI - A registry analysis of damage to the deceased donor pancreas during procurement. AB - Surgical injury to the pancreas is thought to occur commonly during procurement. The UK Transplant Registry was analyzed to determine the frequency of pancreatic injuries, identify factors associated with damage, and assess the impact of injuries on graft survival. Twelve hundred ninety-six pancreata were procured from donation after brain death donors, with 314 (19.5%) from donation after circulatory death donors. More than 50% of recovered pancreata had at least one injury, most commonly a short portal vein (21.5%). Liver donation, procurement team origin, hepatic artery (HA) arising from the superior mesenteric artery (SMA), and increasing donor BMI were associated with increased rates of pancreas damage on univariate analyses; on multivariate analysis only the presence of an HA from the SMA remained significant (p = 0.02). Six hundred forty solid organ pancreas transplants were performed; 238 had some form of damage. Overall, there was no difference in graft survival between damaged and undamaged organs (p = 0.28); however, graft loss was significantly more frequent in pancreata with arterial damage (p = 0.04) and in those with parenchymal damage (p = 0.05). Damage to the pancreas during organ recovery is more common than other organs, and meticulous surgical technique and awareness of damage risk factors are essential to reduce rates of procurement-related injuries. PMID- 26484841 TI - A 71-year-old kidney transplant recipient with hemorrhagic mucocutaneous lesions. PMID- 26484839 TI - Hospital-onset Clostridium difficile infection among solid organ transplant recipients. AB - Clostridium difficile infection (CDI) is a considerable health issue in the United States and represents the most common healthcare-associated infection. Solid organ transplant recipients are at increased risk of CDI, which can affect both graft and patient survival. However, little is known about the impact of CDI on health services utilization posttransplantation. We examined hospital-onset CDI from 2012 to 2014 among transplant recipients in the University HealthSystem Consortium, which includes academic medical center-affiliated hospitals in the United States. Infection was five times more common among transplant recipients than among general medicine inpatients (209 vs 40 per 10 000 discharges), and factors associated with CDI among transplant recipients included transplant type, risk of mortality, comorbidities, and inpatient complications. Institutional risk standardized CDI varied more than 3-fold across high-volume hospitals (infection ratio 0.54-1.82, median 1.04, interquartile range 0.78-1.28). CDI was associated with increased 30-day readmission, transplant organ complications, cytomegalovirus infection, inpatient costs, and lengths of stay. Total observed inpatient days and direct costs for those with CDI were substantially higher than risk-standardized expected values (40 094 vs 22 843 days, costs $198 728 368 vs $154 020 528). Further efforts to detect, prevent, and manage CDI among solid organ transplant recipients are warranted. PMID- 26484842 TI - Effectiveness of a 2-year menopause medicine curriculum for obstetrics and gynecology residents. AB - OBJECTIVE: Previous work has shown American obstetrics and gynecology (OB/GYN) residents are lacking in menopause training. Our objective was to assess the effectiveness of a 2-year menopause medicine curriculum in improving OB/GYN residents' knowledge and self-assessed competency in menopause topics. METHODS: We developed a menopause medicine-teaching curriculum for OB/GYN residents at our academic hospital-based residency program. The 2-year curriculum was composed of year 1: four 1-hour lectures and one 2-hour lab with cases presentations, and year 2: three 1-hour lectures and one 2-hour lab. Core topics included menopause physiology, hormone therapy, breast health, bone health, cardiovascular disease, and autoimmune disease. Pre- and posttests assessed resident knowledge and comfort in core topics, and a pre- and postcurriculum survey assessed utility and learning satisfaction. RESULTS: From July 2011 to June 2013, 34 OB/GYN residents completed the menopause curriculum annually with an average attendance at each module of 23 residents. Pre-/posttest scores improved from a mean pretest score of 57.3% to a mean posttest score of 78.7% (P < 0.05). Before the curriculum, most residents did not feel comfortable managing menopause patients with 75.8% reporting feeling "barely comfortable" and 8.4% feeling "not at all comfortable." After the 2-year curriculum, 85.7% reported feeling "comfortable/very comfortable" taking care of menopause patients. The majority of residents (95.2%) reported the menopause curriculum was "extremely useful." CONCLUSIONS: A 2-year menopause medicine curriculum for OB/GYN residents utilizing lectures and a lab with case studies is an effective modality to improve resident knowledge required to manage menopause patients. PMID- 26484844 TI - DSPMP: Discriminating secretory proteins of malaria parasite by hybridizing different descriptors of Chou's pseudo amino acid patterns. AB - Identification of the proteins secreted by the malaria parasite is important for developing effective drugs and vaccines against infection. Therefore, we developed an improved predictor called "DSPMP" (Discriminating Secretory Proteins of Malaria Parasite) to identify the secretory proteins of the malaria parasite by integrating several vector features using support vector machine-based methods. DSPMP achieved an overall predictive accuracy of 98.61%, which is superior to that of the existing predictors in this field. We show that our method is capable of identifying the secretory proteins of the malaria parasite and found that the amino acid composition for buried and exposed sequences, denoted by AAC(b/e), was the most important feature for constructing the predictor. This article not only introduces a novel method for detecting the important features of sample proteins related to the malaria parasite but also provides a useful tool for tackling general protein-related problems. The DSPMP webserver is freely available at http://202.207.14.87:8032/fuwu/DSPMP/index.asp. PMID- 26484843 TI - Evaluating the Effectiveness of First-Time Methadone Maintenance Therapy Across Northern, Rural, and Urban Regions of Ontario, Canada. AB - OBJECTIVES: Our objective was to determine the impact that a patient's geographic status has on the efficacy of first-time methadone maintenance therapy (MMT) retention. METHODS: We conducted an observational cohort study using administrative health care databases for patients who commenced methadone therapy between 2003 and 2012. Patients were stratified on the basis of their location of residence into 1 of 4 groups-Southern Urban, Southern Rural, Northern Urban, or Northern Rural. The primary outcome was continuous retention in treatment, defined as 1 year of uninterrupted therapy on the basis of prescription refill data. Mortality was measured as a secondary outcome. RESULTS: We identified 17,211 patients initiating first-time MMT during this 10-year period. Nearly half of patients initiating therapy in northern regions completed 1 year of treatment (48.9%; N = 258 and 47.0%; N = 761 in Northern Rural and Urban regions, respectively), whereas lower rates of 40.6% (N = 410) and 39.3% (N = 5,518) occurred in Southern Rural and Urban regions, respectively. Patients residing in Northern Rural and Northern Urban regions were 31% (adjusted odds ratio = 1.31; 95% confidence interval [CI], 1.09%-1.58%] and 14% (adjusted odds ratio = 1.14; 95% CI, 1.02%-1.27%] more likely to be retained in treatment compared with those residing in Southern Urban regions. There was no significant difference in treatment retention between those residing in Southern Rural and Southern Urban regions. A mortality rate of 3% was observed within 1 year of patients initiating treatment, with patients in the Southern Rural region having the highest rate (4.85%). CONCLUSIONS: Our study identified regional differences in retention rates and mortality of first-time MMT. These findings may relate to geographic isolation and limited methadone program availability experienced in northern regions. We interpret the data to suggest that patients who have reduced access to treatment experience higher retention rates when they are able to access therapy. PMID- 26484845 TI - The Frequency of c.550delA Mutation of the CANP3 Gene in the Polish LGMD2A Population. AB - BACKGROUND: Limb girdle muscular dystrophy 2A (LGMD2A) is the most frequent LGMD variant in the European population, representing about 40% of LGMD. The c.550delA mutation in the CANP3 (calcium activated neutral protease 3) gene is the most commonly reported mutation in LGMD2A. Prevalence of this mutation in the Polish population has not been previously investigated. The aim of this study was to identify and estimate the frequency of the c.550delA mutation in Polish LGMD2A patients. METHODS: Polymerase chain reaction-sequencing analysis, restriction fragment length polymorphism polymerase chain reaction method. RESULTS: We analyzed 76 families affected with LGMD and identified 62 probands with mutations in the CANP3 gene. C.550delA was the most common mutation identified, being found in 78% of the LGMD2A families. The remaining mutations observed multiple times were as follows: c.598-612del15ntd; c.2242C>T; c.418dupC; c.1356insT, listed in terms of decreasing frequency. Two novel variants in the CANP3 gene, that is, c.700G>A Gly234Arg and c.661G>A Gly221Ser were also characterized. Overall, mutations in the LGMD2A gene were estimated to be present in 81% of patients with the LGMD phenotype who were without sarcoglycans and dysferlin deficiency on immunocytochemical analysis. The frequency of the heterozygous c.550delA mutation in the healthy Polish population was estimated at 1/124. CONCLUSIONS: The c.550delA is the most frequent CANP3 mutation in the Polish population, thus sequencing of exon 4 of this gene could identify the majority of LGMD2A patients in Poland. PMID- 26484846 TI - A Low-Temperature, Solution-Processable, Cu-Doped Nickel Oxide Hole-Transporting Layer via the Combustion Method for High-Performance Thin-Film Perovskite Solar Cells. AB - Low-temperature, solution-processable Cu-doped NiOX (Cu:NiOx ), prepared via combustion chemistry, is demonstrated as an excellent hole-transporting layer (HTL) for thin-film perovskite solar cells (PVSCs). Its good crystallinity, conductivity, and hole-extraction properties enable the derived PVSC to have a high power conversion efficiency (PCE) of 17.74%. Its general applicability for various elecrode materials is also revealed. PMID- 26484847 TI - Drug safety evaluation of lenvatinib for thyroid cancer. AB - INTRODUCTION: Lenvatinib is an oral multitargeted tyrosine kinase inhibitor of VEGFR1,2,3,4, FGFR1,2,3,4, PDGFR-alpha as well as RET and KIT signaling network. Its activity against radioiodine-resistant differentiated thyroid cancer (DTC) has been recently demonstrated. Patients, who were given lenvatinib, showed significantly longer median progression free survival than placebo group, 18.3 vs 3.6 months, respectively. This review is focused on lenvatinib safety profile in patients treated due to DTC and medullary thyroid carcinoma. Among the most frequent lenvatinib-related adverse events (AEs) were hypertension, proteinuria, diarrhea, appetite decrease, weight loss, nausea and stomatitis. Although a lot of them were manageable, in 35-68% of patients dose reduction was required. Nevertheless, only 15% of subjects withdrew the drug due to its toxicity. AREAS COVERED: published results of clinical trials phase II and III investigating both safety and efficacy of lenvatinib in thyroid cancer. EXPERT OPINION: Lenvatinib shows acceptable safety profile in patients with thyroid carcinoma. Treatment related side effects are usually manageable by dose modifications or by concomitant non-pharmacological and pharmacological treatment. However, the early recognition of any potential drug toxicity is crucial to avoid serious complications as well as to keep a patient on drug as long as the treatment is beneficial. PMID- 26484848 TI - Diffusion MRI in the heart. AB - Diffusion MRI provides unique information on the structure, organization, and integrity of the myocardium without the need for exogenous contrast agents. Diffusion MRI in the heart, however, has proven technically challenging because of the intrinsic non-rigid deformation during the cardiac cycle, displacement of the myocardium due to respiratory motion, signal inhomogeneity within the thorax, and short transverse relaxation times. Recently developed accelerated diffusion weighted MR acquisition sequences combined with advanced post-processing techniques have improved the accuracy and efficiency of diffusion MRI in the myocardium. In this review, we describe the solutions and approaches that have been developed to enable diffusion MRI of the heart in vivo, including a dual gated stimulated echo approach, a velocity- (M1 ) or an acceleration- (M2 ) compensated pulsed gradient spin echo approach, and the use of principal component analysis filtering. The structure of the myocardium and the application of these techniques in ischemic heart disease are also briefly reviewed. The advent of clinical MR systems with stronger gradients will likely facilitate the translation of cardiac diffusion MRI into clinical use. The addition of diffusion MRI to the well-established set of cardiovascular imaging techniques should lead to new and complementary approaches for the diagnosis and evaluation of patients with heart disease. (c) 2015 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd. PMID- 26484849 TI - Inflammation (or synovitis)-driven osteoarthritis: an opportunity for personalizing prognosis and treatment? AB - The disabling and painful disease osteoarthritis (OA) is the most common form of arthritis. Strong evidence suggests that a subpopulation of OA patients has a form of OA driven by inflammation. Consequently, understanding when inflammation is the driver of disease progression and which OA patients might benefit from anti-inflammatory treatment is a topic of intense research in the OA field. We have reviewed the current literature on OA, with an emphasis on inflammation in OA, biochemical markers of structural damage, and anti-inflammatory treatments for OA. The literature suggests that the OA patient population is diverse, consisting of several subpopulations, including one associated with inflammation. This inflammatory subpopulation may be identified by a combination of novel serological inflammatory biomarkers. Preliminary evidence from small clinical studies suggests that this subpopulation may benefit from anti-inflammatory treatment currently reserved for other inflammatory arthritides. PMID- 26484850 TI - Chitinase-resistant hydrophilic symbiotic factors secreted by Frankia activate both Ca(2+) spiking and NIN gene expression in the actinorhizal plant Casuarina glauca. AB - Although it is now well-established that decorated lipo-chitooligosaccharide Nod factors are the key rhizobial signals which initiate infection/nodulation in host legume species, the identity of the equivalent microbial signaling molecules in the Frankia/actinorhizal association remains elusive. With the objective of identifying Frankia symbiotic factors we present a novel approach based on both molecular and cellular pre-infection reporters expressed in the model actinorhizal species Casuarina glauca. By introducing the nuclear-localized cameleon Nup-YC2.1 into Casuarina glauca we show that cell-free culture supernatants of the compatible Frankia CcI3 strain are able to elicit sustained high frequency Ca(2+) spiking in host root hairs. Furthermore, an excellent correlation exists between the triggering of nuclear Ca(2+) spiking and the transcriptional activation of the ProCgNIN:GFP reporter as a function of the Frankia strain tested. These two pre-infection symbiotic responses have been used in combination to show that the signal molecules present in the Frankia CcI3 supernatant are hydrophilic, of low molecular weight and resistant to chitinase degradation. In conclusion, the biologically active symbiotic signals secreted by Frankia appear to be chemically distinct from the currently known chitin-based rhizobial/arbuscular mycorrhizal signaling molecules. Convenient bioassays in Casuarina glauca are now available for their full characterization. PMID- 26484851 TI - Strategies to Maximize Data Collection Response Rates in a Randomized Control Trial Focused on Children with Medical Complexity. AB - INTRODUCTION: Obtaining complete and timely subject data is key to the success of clinical trials, particularly for studies requiring data collected from subjects at home or other remote sites. A multifaceted strategy for data collection in a randomized controlled trial (RCT) focused on care coordination for children with medical complexity is described. The influences of data collection mode, incentives, and study group membership on subject response patterns are analyzed. Data collection included monthly healthcare service utilization (HCSU) calendars and annual surveys focused on care coordination outcomes. MATERIALS AND METHODS: One hundred sixty-three families were enrolled in the 30-month TeleFamilies RCT. Subjects were 2-15 years of age at enrollment. HCSU data were collected by parent/guardian self-report using mail, e-mail, telephone, or texting. Surveys were collected by mail. Incentives were provided for completed surveys after 8 months to improve collection returns. Outcome measures were the number of HCSU calendars and surveys returned, the return interval, data collection mode, and incentive impact. RESULTS: Return rates of 90% for HCSU calendars and 82% for annual surveys were achieved. Mean return intervals were 72 and 65 days for HCSU and surveys, respectively. Survey response increased from 55% to 95% after introduction of a gift card and added research staff. CONCLUSIONS: High return rates for HCSU calendars and health-related surveys are attainable but required a flexible and personnel-intensive approach to collection methods. Family preference for data collection approach should be obtained at enrollment, should be modified as needed, and requires flexible options, training, intensive staff/family interaction, and patience. PMID- 26484852 TI - Neutralization of Interleukin-17 Attenuates Cholestatic Liver Fibrosis in Mice. AB - Anti-inflammation strategy is one of the proposed therapeutic approaches to hepatic fibrosis. IL-17 is critical in inflammation, but the role of IL-17 in liver fibrosis has not yet been elucidated. In this study, we investigate the role of IL-17 on bile duct ligation-induced liver injury and fibrosis in C57BL/6 mice. Animals were sacrificed at designated times, and serum and liver tissues were collected for analysis of liver function and serum IL-6, IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) levels. IL-17 blockade with anti-IL-17A mAb significantly improved liver function and decreased hepatocellular necrosis, pro-inflammatory cytokines, neutrophils and macrophages influx. Furthermore, CD3 + and CD8 + lymphocytes, neutrophils and macrophages were found to express IL-17, and neutrophils are the principal IL-17 producing cells after BDL-induced liver injury. These data indicated that IL-17 signal contributes to the pathogenesis of cholestatic liver injury and blocked of IL-17 could potentially benefit patients with cholestatic liver disease. PMID- 26484853 TI - Is computed tomography a necessary part of a metastatic evaluation for castration resistant prostate cancer? Results from the Shared Equal Access Regional Cancer Hospital Database. AB - BACKGROUND: Metastatic lesions in prostate cancer beyond the bone have prognostic importance and affect clinical therapeutic decisions. Few data exist regarding the prevalence of soft-tissue metastases at the initial diagnosis of metastatic castration-resistant prostate cancer (mCRPC). METHODS: This study analyzed 232 men with nonmetastatic (M0) castration-resistant prostate cancer (CRPC) who developed metastases detected by a bone scan or computed tomography (CT). All bone scans and CT scans within the 30 days before or after the mCRPC diagnosis were reviewed. The rate of soft-tissue metastases among those undergoing CT was determined. Then, predictors of soft-tissue metastases and visceral and lymph node metastases were identified. RESULTS: Compared with men undergoing CT (n = 118), men undergoing only bone scans (n = 114) were more likely to have received primary treatment (P = .048), were older (P = .013), and less recently developed metastases (P = .018). Among those undergoing CT, 52 (44%) had soft-tissue metastases, including 20 visceral metastases (17%) and 41 lymph node metastases (35%), whereas 30% had no bone involvement. In a univariable analysis, only prostate-specific antigen (PSA) predicted soft-tissue metastases (odds ratio [OR], 1.27; P = .047), and no statistically significant predictors of visceral metastases were found. A higher PSA level was associated with an increased risk of lymph node metastases (OR, 1.38; P = .014), whereas receiving primary treatment was associated with decreased risk (OR, 0.36; P = .015). CONCLUSIONS: The data suggest that there is a relatively high rate of soft-tissue metastasis (44%) among CRPC patients undergoing CT at the initial diagnosis of metastases, including some men with no bone involvement. Therefore, forgoing CT during a metastatic evaluation may lead to an underdiagnosis of soft-tissue metastases and an underdiagnosis of metastases in general. Cancer 2015. (c) 2015 American Cancer Society. Cancer 2016;122:222-229. (c) 2015 American Cancer Society. PMID- 26484855 TI - WITHDRAWN: Drug-eluting stents versus bare metal stents for angina or acute coronary syndromes. PMID- 26484854 TI - Top Guns: The "Maverick" and "Goose" of Empiric Therapy. AB - BACKGROUND: Vancomycin and piperacillin-tazobactam are commonly used first guns in the empiric management of critically ill patients. Current studies suggest an increased prevalence of acute kidney injury with concomitant use, however, these studies are few and limited by small sample size. The purpose of this study was to compare the prevalence of nephrotoxicity after treatment with vancomycin alone and concomitant vancomycin and piperacillin-tazobactam treatment at our institution. HYPOTHESIS: Concomitant vancomycin and piperacillin-tazobactam treated patients will experience greater prevalence of nephrotoxicity compared with vancomycin-only treated patients. METHODS: This was a retrospective cohort of patients treated with vancomycin for gram-positive or mixed infections in our facility from 2005 to 2009 who were not receiving hemodialysis at the time of admission. Included patients were stratified by treatment with vancomycin, vancomycin/piperacillin-tazobactam, or vancomycin/an alternative gram-negative rod (GNR) antibiotic. p values for categorical variables were computed using chi(2) while continuous variables were computed using Kruskal-Wallis. Variables deemed statistically significant (< 0.05) were included in the multivariable, log binomial regression model. Relative risk (RR) and 95% confidence intervals (CI), and p values were computed using a generalized estimating equation (GEE) approach with robust standard errors (i.e., Huber White "sandwich variance" estimates) to accommodate a correlated data structure corresponding to multiple episodes of infection per individual. RESULTS: A total of 530 patients with 1,007 episodes of infection, were treated with vancomycin (150 patients/302 episodes of infection), vancomycin/piperacillin-tazobactam (213 patients/372 episodes of infection), or vancomycin/GNR alternative (167 patients/333 episodes of infection). Patient demographics, comorbidities, sites of infection, and organisms of infection were compared among groups. After adjusting for statistically significant variables, neither vancomycin/piperacillin-tazobactam (RR = 1.1, 95% CI = 0.99-1.2; p = 0.073) nor vancomycin/GNR alternative (RR = 1.1, 95% CI = 0.98-1.2; p = 0.097) were found to be associated with an increased risk for nephrotoxicity compared with vancomycin alone. CONCLUSION: A difference in nephrotoxicity was not observed between vancomycin and vancomycin/piperacillin-tazobactam-treated patients at our institution. Concomitant use as empiric therapy is appropriate, although larger sample sizes are needed to analyze closely this relation among at risk subsets of this population. PMID- 26484856 TI - Structure Elucidation of Verucopeptin, a HIF-1 Inhibitory Polyketide-Hexapeptide Hybrid Metabolite from an Actinomycete. AB - The transcriptional factor, hypoxia inducible factor-1 (HIF-1), is a promising target for cancer chemotherapy. From an actinomycete, verucopeptin (1) was identified as a HIF-1 signaling inhibitor. By a combination of chemical degradation and spectroscopic analyses, the absolute stereochemistry of metabolite 1 was determined to be 10R, 15S, 16S, 23S, 27S, 28R, 31S, 33S, 35R. Moreover, metabolite 1 was revealed to attenuate the HIF-1alpha and mTORC1 pathway, indicating that verucopeptin (1) would be a potent lead compound for anticancer chemotherapy. PMID- 26484858 TI - Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems. AB - Angiogenesis critically sustains the progression of both physiological and pathological processes. Copper behaves as an obligatory co-factor throughout the angiogenic signalling cascades, so much so that a deficiency causes neovascularization to abate. Moreover, the progress of several angiogenic pathologies (e.g. diabetes, cardiac hypertrophy and ischaemia) can be tracked by measuring serum copper levels, which are being increasingly investigated as a useful prognostic marker. Accordingly, the therapeutic modulation of body copper has been proven effective in rescuing the pathological angiogenic dysfunctions underlying several disease states. Vascular copper transport systems profoundly influence the activation and execution of angiogenesis, acting as multi functional regulators of apparently discrete pro-angiogenic pathways. This review concerns the complex relationship among copper-dependent angiogenic factors, copper transporters and common pathological conditions, with an unusual accent on the multi-faceted involvement of the proteins handling vascular copper. Functions regulated by the major copper transport proteins (CTR1 importer, ATP7A efflux pump and metallo-chaperones) include the modulation of endothelial migration and vascular superoxide, known to activate angiogenesis within a narrow concentration range. The potential contribution of prion protein, a controversial regulator of copper homeostasis, is discussed, even though its angiogenic involvement seems to be mainly associated with the modulation of endothelial motility and permeability. PMID- 26484857 TI - The Prognostic Value of CT Angiography and CT Perfusion in Acute Ischemic Stroke. AB - BACKGROUND: CT angiography (CTA) and CT perfusion (CTP) are important diagnostic tools in acute ischemic stroke. We investigated the prognostic value of CTA and CTP for clinical outcome and determined whether they have additional prognostic value over patient characteristics and non-contrast CT (NCCT). METHODS: We included 1,374 patients with suspected acute ischemic stroke in the prospective multicenter Dutch acute stroke study. Sixty percent of the cohort was used for deriving the predictors and the remaining 40% for validating them. We calculated the predictive values of CTA and CTP predictors for poor clinical outcome (modified Rankin Scale score 3-6). Associations between CTA and CTP predictors and poor clinical outcome were assessed with odds ratios (OR). Multivariable logistic regression models were developed based on patient characteristics and NCCT predictors, and subsequently CTA and CTP predictors were added. The increase in area under the curve (AUC) value was determined to assess the additional prognostic value of CTA and CTP. Model validation was performed by assessing discrimination and calibration. RESULTS: Poor outcome occurred in 501 patients (36.5%). Each of the evaluated CTA measures strongly predicted outcome in univariable analyses: the positive predictive value (PPV) was 59% for Alberta Stroke Program Early CT Score (ASPECTS) <=7 on CTA source images (OR 3.3; 95% CI 2.3-4.8), 63% for presence of a proximal intracranial occlusion (OR 5.1; 95% CI 3.7-7.1), 66% for poor leptomeningeal collaterals (OR 4.3; 95% CI 2.8-6.6), and 58% for a >70% carotid or vertebrobasilar stenosis/occlusion (OR 3.2; 95% CI 2.2 4.6). The same applied to the CTP measures, as the PPVs were 65% for ASPECTS <=7 on cerebral blood volume maps (OR 5.1; 95% CI 3.7-7.2) and 53% for ASPECTS <=7 on mean transit time maps (OR 3.9; 95% CI 2.9-5.3). The prognostic model based on patient characteristics and NCCT measures was highly predictive for poor clinical outcome (AUC 0.84; 95% CI 0.81-0.86). Adding CTA and CTP predictors to this model did not improve the predictive value (AUC 0.85; 95% CI 0.83-0.88). In the validation cohort, the AUC values were 0.78 (95% CI 0.73-0.82) and 0.79 (95% CI 0.75-0.83), respectively. Calibration of the models was satisfactory. CONCLUSIONS: In patients with suspected acute ischemic stroke, admission CTA and CTP parameters are strong predictors of poor outcome and can be used to predict long-term clinical outcome. In multivariable prediction models, however, their additional prognostic value over patient characteristics and NCCT is limited in an unselected stroke population. PMID- 26484860 TI - A Comparison between Clinical and Metabolic Features of Renal Calyceal Microlithiasis and Overt Urolithiasis in Different Pediatric Age Groups. AB - INTRODUCTION: This study assesses the differences in the presentations, complications and metabolic abnormalities of children with renal calyceal microlithiasis (RCM) and overt urolithiasis in different pediatric ages. MATERIALS AND METHODS: A total of 465 children with urolithiasis were investigated retrospectively. Patients were categorized based on their ages to infancy, early childhood, middle childhood and adolescence. When the hyperechogenic spots on ultrasound imaging were <3 mm, they were considered RCM, and if they were >=3 mm, they were considered overt urolithiasis. RESULTS: Metabolic abnormalities were detected in 71%; hyperuricosuria in infants, hyperoxaluria in younger children and hypocitraturia in older children were the most common metabolic abnormalities. Hypercalciuria was the only metabolic abnormality that was significantly associated with overt urolithiasis in all pediatric ages (OR 2.25, 95% CI 1.21-4.19). The clinical presentations were not significantly different between RCM and overt urolithiasis; however, complications such as urinary tract infection was significantly higher with overt urolithiasis in infancy (p = 0.01), early childhood (p = 0.02), middle childhood (p = 0.007) and adolescence (p = 0.01). Also, growth retardation was significantly higher with overt urolithiasis in infancy and early childhood (p = 0.02). CONCLUSIONS: Most children with urolithiasis have underlying urinary metabolic abnormalities that differ according to the child's age. Despite these differences, hypercalciuria is significantly associated with overt urolithiasis in all pediatric ages. Clinical and laboratory features cannot differentiate RCM and overt urolithiasis; however, complications are significantly higher with overt urolithiasis. PMID- 26484861 TI - Correction: Stating Appointment Costs in SMS Reminders Reduces Missed Hospital Appointments: Findings from Two Randomised Controlled Trials. PMID- 26484859 TI - At the Edge of Chaos: How Cerebellar Granular Layer Network Dynamics Can Provide the Basis for Temporal Filters. AB - Models of the cerebellar microcircuit often assume that input signals from the mossy-fibers are expanded and recoded to provide a foundation from which the Purkinje cells can synthesize output filters to implement specific input-signal transformations. Details of this process are however unclear. While previous work has shown that recurrent granule cell inhibition could in principle generate a wide variety of random outputs suitable for coding signal onsets, the more general application for temporally varying signals has yet to be demonstrated. Here we show for the first time that using a mechanism very similar to reservoir computing enables random neuronal networks in the granule cell layer to provide the necessary signal separation and extension from which Purkinje cells could construct basis filters of various time-constants. The main requirement for this is that the network operates in a state of criticality close to the edge of random chaotic behavior. We further show that the lack of recurrent excitation in the granular layer as commonly required in traditional reservoir networks can be circumvented by considering other inherent granular layer features such as inverted input signals or mGluR2 inhibition of Golgi cells. Other properties that facilitate filter construction are direct mossy fiber excitation of Golgi cells, variability of synaptic weights or input signals and output-feedback via the nucleocortical pathway. Our findings are well supported by previous experimental and theoretical work and will help to bridge the gap between system-level models and detailed models of the granular layer network. PMID- 26484862 TI - Protein Homeostasis Imposes a Barrier on Functional Integration of Horizontally Transferred Genes in Bacteria. AB - Horizontal gene transfer (HGT) plays a central role in bacterial evolution, yet the molecular and cellular constraints on functional integration of the foreign genes are poorly understood. Here we performed inter-species replacement of the chromosomal folA gene, encoding an essential metabolic enzyme dihydrofolate reductase (DHFR), with orthologs from 35 other mesophilic bacteria. The orthologous inter-species replacements caused a marked drop (in the range 10-90%) in bacterial growth rate despite the fact that most orthologous DHFRs are as stable as E.coli DHFR at 37 degrees C and are more catalytically active than E. coli DHFR. Although phylogenetic distance between E. coli and orthologous DHFRs as well as their individual molecular properties correlate poorly with growth rates, the product of the intracellular DHFR abundance and catalytic activity (kcat/KM), correlates strongly with growth rates, indicating that the drop in DHFR abundance constitutes the major fitness barrier to HGT. Serial propagation of the orthologous strains for ~600 generations dramatically improved growth rates by largely alleviating the fitness barriers. Whole genome sequencing and global proteome quantification revealed that the evolved strains with the largest fitness improvements have accumulated mutations that inactivated the ATP dependent Lon protease, causing an increase in the intracellular DHFR abundance. In one case DHFR abundance increased further due to mutations accumulated in folA promoter, but only after the lon inactivating mutations were fixed in the population. Thus, by apparently distinguishing between self and non-self proteins, protein homeostasis imposes an immediate and global barrier to the functional integration of foreign genes by decreasing the intracellular abundance of their products. Once this barrier is alleviated, more fine-tuned evolution occurs to adjust the function/expression of the transferred proteins to the constraints imposed by the intracellular environment of the host organism. PMID- 26484863 TI - Enhancements to the Rosetta Energy Function Enable Improved Identification of Small Molecules that Inhibit Protein-Protein Interactions. AB - Protein-protein interactions are among today's most exciting and promising targets for therapeutic intervention. To date, identifying small-molecules that selectively disrupt these interactions has proven particularly challenging for virtual screening tools, since these have typically been optimized to perform well on more "traditional" drug discovery targets. Here, we test the performance of the Rosetta energy function for identifying compounds that inhibit protein interactions, when these active compounds have been hidden amongst pools of "decoys." Through this virtual screening benchmark, we gauge the effect of two recent enhancements to the functional form of the Rosetta energy function: the new "Talaris" update and the "pwSHO" solvation model. Finally, we conclude by developing and validating a new weight set that maximizes Rosetta's ability to pick out the active compounds in this test set. Looking collectively over the course of these enhancements, we find a marked improvement in Rosetta's ability to identify small-molecule inhibitors of protein-protein interactions. PMID- 26484864 TI - Crystal Structure and Identification of Two Key Amino Acids Involved in AI-2 Production and Biofilm Formation in Streptococcus suis LuxS. AB - Streptococcus suis has emerged as an important zoonotic pathogen that causes meningitis, arthritis, septicemia and even sudden death in pigs and humans. Quorum sensing is the signaling network for cell-to-cell communication that bacterial cells can use to monitor their own population density through production and exchange of signal molecules. S-Ribosylhomocysteinase (LuxS) is the key enzyme involved in the activated methyl cycle. Autoinducer 2 (AI-2) is the adduct of borate and a ribose derivative and is produced from S adenosylhomocysteine (SAH). AI-2 can mediate interspecies communication and in some species facilitate the bacterial behavior regulation such as biofilm formation and virulence in both Gram-positive and Gram-negative bacteria. Here, we reported the overexpression, purification and crystallographic structure of LuxS from S. suis. Our results showed the catalytically active LuxS exists as a homodimer in solution. Inductively coupled plasma-mass spectrometry (ICP-MS) revealed the presence of Zn2+ in LuxS. Although the core structure shares the similar topology with LuxS proteins from other bacterial species, structural analyses and comparative amino acid sequence alignments identified two key amino acid differences in S. suis LuxS, Phe80 and His87, which are located near the substrate binding site. The results of site-directed mutagenesis and enzymology studies confirmed that these two residues affect the catalytic activity of the enzyme. These in vitro results were corroborated in vivo by expression of the LuxS variants in a S. suis DeltaluxS strain. The single and two amino acid of LuxS variant decreased AI-2 production and biofilm formation significantly compared to that of the parent strain. Our findings highlight the importance of key LuxS residues that influence the AI-2 production and biofilm formation in S.suis. PMID- 26484865 TI - Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis. AB - Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs for the treatment of epileptic seizures. Although it is well known that the doses of VPA and its plasma concentrations are highly correlated, the plasma concentrations do not correlate well with the therapeutic effects of the VPA. In this study, we developed a population-based pharmacokinetic (PK)-pharmacodynamic (PD) model to determine the optimal concentration of VPA according to the clinical characteristics of each patient. This retrospective study included 77 VPA-treated Japanese patients with epilepsy. A nonlinear mixed-effects model best represented the relationship between the trough concentrations of VPA at steady state and an over 50% reduction in seizure frequency. The model was fitted using a logistic regression model, in which the logit function of the probability was a linear function of the predicted trough concentration of VPA. The model showed that the age, seizure locus, the sodium channel neuronal type I alpha subunit rs3812718 polymorphism and co-administration of carbamazepine, clonazepam, phenytoin or topiramate were associated with an over 50% reduction in the seizure frequency. We plotted the receiver operating characteristic (ROC) curve for the logit(Pr) value of the model and the presence or absence of a more than 50% reduction in seizure frequency, and the areas under the curves with the 95% confidence interval from the ROC curve were 0.823 with 0.793-0.853. A logit(Pr) value of 0.1 was considered the optimal cut-off point (sensitivity = 71.8% and specificity = 80.4%), and we calculated the optimal trough concentration of VPA for each patient. Such parameters may be useful to determine the recommended therapeutic concentration of VPA for each patient, and the procedure may contribute to the further development of personalized pharmacological therapy for epilepsy. PMID- 26484866 TI - Mansonella, including a Potential New Species, as Common Parasites in Children in Gabon. AB - BACKGROUND: Like other tropical African countries, Gabon is afflicted by many parasitic diseases, including filariases such as loiasis and mansonellosis. This study aimed to assess the prevalence of these two filarial diseases in febrile and afebrile children using quantitative real-time PCR and standard PCR assays coupled with sequencing. METHODOLOGY/PRINCIPAL FINDINGS: DNA from blood specimens of 1,418 Gabonese children (1,258 febrile and 160 afebrile) were analyzed. Overall, filarial DNA was detected in 95 (6.7%) children, including 67 positive for M. perstans (4.7%), which was the most common. M. perstans was detected in 61/1,258 febrile children (4.8%) and 6/160 afebrile children (3.8%, P = 0.6). Its prevalence increased statistically with age: 3.5%, 7.7% and 10.6% in children aged <= 5, 6-10 and 11-15 years, respectively. M. perstans prevalence was significantly higher in Koulamoutou and Lastourville (12% and 10.5%, respectively) than in Franceville and Fougamou (2.6% and 2.4%, respectively). Loa loa was detected in seven febrile children including one co-infection with M. perstans. Finally, 21 filarial DNA positive were negative for M. perstans and Loa loa, but ITS sequencing could be performed for 12 and allowed the identification of a potential new species of Mansonella provisionally called "DEUX". Mansonella sp. "DEUX" was detected only in febrile children. CONCLUSIONS/SIGNIFICANCE: Further study should be performed to characterize Mansonella sp. "DEUX" and evaluate the clinical significance of mansonellosis in humans. PMID- 26484867 TI - Decrease in an Inwardly Rectifying Potassium Conductance in Mouse Mammary Secretory Cells after Forced Weaning. AB - Mammary glands are physiologically active in female mammals only during nursing. Immediately after weaning, most lactation-related genes are downregulated and milk production ceases. In our previous study, we have detected an inwardly rectifying potassium channel (Kir) 2.1-like current in mammary secretory (MS) cells freshly isolated from lactating mice. This current is highly sensitive to external Ba2+. The potassium permeability of the Kir channels may contribute to the secretion and/or preservation of ions in milk. We hypothesized that the functions of the Kir channels in MS cells are regulated after weaning. To test this hypothesis, we examined the effect of forced weaning on the Ba2+-sensitive Kir current and Kir2.1 expression in the mouse mammary glands. Twenty-four hours after weaning, the lumina of mammary acini were histologically enlarged by milk accumulation. The whole-cell patch-clamp analyses showed that the Ba2+-sensitive Kir current in the post-weaning MS cells was smaller than in the lactating MS cells. The inward conductances of the current in the lactating and post-weaning cells were 4.25 +/- 0.77 and 0.93 +/- 0.34 nS, respectively. Furthermore, real time PCR and Western blot analyses showed that Kir2.1 mRNA and protein expression decreased in the post-weaning mammary gland (mRNA, 90% reduction; protein, 47% reduction). Moreover, the local milk accumulation caused by teat sealing decreased Kir conductance in MS cells (2.74 +/- 0.45 and 0.36 +/- 0.27 nS for control and sealed mammary glands, respectively). This was concomitant with the reduction in the Kir2.1 mRNA expression. Our results suggest that milk stasis after weaning immediately decreases the Kir conductance in MS cells. This decrease in the Kir conductance may be partly caused by the reduction in the Kir2.1 mRNA and protein expression. These alterations during the post-weaning period may be involved in the cessation of ion secretion and/or preservation in the milk. PMID- 26484868 TI - A Novel Human scFv Library with Non-Combinatorial Synthetic CDR Diversity. AB - The present work describes the construction and validation of a human scFv library with a novel design approach to synthetic complementarity determining region (CDR) diversification. The advantage of synthetic antibody libraries includes the possibility of exerting fine control over factors like framework sequences, amino acid and codon usage, and CDR diversity. However, random combinatorial synthesis of oligonucleotides for CDR sequence diversity also produces many clones with unnatural sequences and/or undesirable modification motifs. To alleviate these issues, we designed and constructed a novel semi synthetic human scFv library with non-combinatorial, pre-designed CDR diversity and a single native human framework each for heavy, kappa, and lambda chain variable domains. Next-generation sequencing analysis indicated that the library consists of antibody clones with highly nature-like CDR sequences and the occurrence of the post-translational modification motifs is minimized. Multiple unique clones with nanomolar affinity could be isolated from the library against a number of target antigens, validating the library design strategy. The results demonstrate that it is possible to construct a functional antibody library using low, non-combinatorial synthetic CDR diversity, and provides a new strategy for the design of antibody libraries suitable for demanding applications. PMID- 26484869 TI - Cost-effectiveness of a voucher-based intervention for smoking cessation. AB - BACKGROUND: Contingency management (CM) has been shown to be effective in reducing smoking consumption, but has traditionally been criticized for its costs. OBJECTIVES: This study assessed the cost-effectiveness of using a voucher based CM protocol added to a cognitive behavioral treatment (CBT) for smoking cessation among treatment-seeking patients from the general population. METHODS: A total of 92 patients were randomly assigned to CBT or CBT plus CM for abstinence. Incremental cost-effectiveness ratios (ICERs) were calculated by dividing the increase in costs by the increase in effects (continuous abstinence, longest duration of abstinence at 6-month follow-up and cotinine results during the treatment). An acceptability curve illustrated the statistical uncertainty surrounding the cost-effectiveness estimate. We also determined the optimum cost per participant for predicting the smoking status at 6-month follow-up. RESULTS: The average cost per participant in the CBT condition was ?138.73 (US$ 150.23) as opposed to ?411.61 (US$ 445.73) in the CBT plus CM condition (p < 0.01). The incremental cost of using voucher-based CM to increase the number of participants that maintained abstinence at 6-month follow-up by one extra participant was ?68.22 (US$ 73.88), and to lengthen the longest duration of abstinence by 1 week was ?53.92 (US$ 58.39). The incremental cost to obtain an extra cotinine-negative result was ?181.90 (US$ 196.98). CONCLUSION: Compared with CBT alone, the voucher based protocol required additional costs but achieved significantly better outcomes. These results will allow stakeholders to make policy decisions about CM implementation for smoking cessation in the broader community. PMID- 26484870 TI - Crystal Structure of the Human Cytomegalovirus Glycoprotein B. AB - Human cytomegalovirus (HCMV), a dsDNA, enveloped virus, is a ubiquitous pathogen that establishes lifelong latent infections and caused disease in persons with compromised immune systems, e.g., organ transplant recipients or AIDS patients. HCMV is also a leading cause of congenital viral infections in newborns. Entry of HCMV into cells requires the conserved glycoprotein B (gB), thought to function as a fusogen and reported to bind signaling receptors. gB also elicits a strong immune response in humans and induces the production of neutralizing antibodies although most anti-gB Abs are non-neutralizing. Here, we report the crystal structure of the HCMV gB ectodomain determined to 3.6-A resolution, which is the first atomic-level structure of any betaherpesvirus glycoprotein. The structure of HCMV gB resembles the postfusion structures of HSV-1 and EBV homologs, establishing it as a new member of the class III viral fusogens. Despite structural similarities, each gB has a unique domain arrangement, demonstrating structural plasticity of gB that may accommodate virus-specific functional requirements. The structure illustrates how extensive glycosylation of the gB ectodomain influences antibody recognition. Antigenic sites that elicit neutralizing antibodies are more heavily glycosylated than those that elicit non neutralizing antibodies, which suggest that HCMV gB uses glycans to shield neutralizing epitopes while exposing non-neutralizing epitopes. This glycosylation pattern may have evolved to direct the immune response towards generation of non-neutralizing antibodies thus helping HCMV to avoid clearance. HCMV gB structure provides a starting point for elucidation of its antigenic and immunogenic properties and aid in the design of recombinant vaccines and monoclonal antibody therapies. PMID- 26484871 TI - Transcriptome Analysis in Haematococcus pluvialis: Astaxanthin Induction by Salicylic Acid (SA) and Jasmonic Acid (JA). AB - Haematococcus pluvialis is an astaxanthin-rich microalga that can increase its astaxanthin production by salicylic acid (SA) or jasmonic acid (JA) induction. The genetic transcriptome details of astaxanthin biosynthesis were analyzed by exposing the algal cells to 25 mg/L of SA and JA for 1, 6 and 24 hours, plus to the control (no stress). Based on the RNA-seq analysis, 56,077 unigenes (51.7%) were identified with functions in response to the hormone stress. The top five identified subcategories were cell, cellular process, intracellular, catalytic activity and cytoplasm, which possessed 5600 (~9.99%), 5302 (~9.45%), 5242 (~9.35%), 4407 (~7.86%) and 4195 (~7.48%) unigenes, respectively. Furthermore, 59 unigenes were identified and assigned to 26 putative transcription factors (TFs), including 12 plant-specific TFs. They were likely associated with astaxanthin biosynthesis in Haematococcus upon SA and JA stress. In comparison, the up regulation of differential expressed genes occurred much earlier, with higher transcript levels in the JA treatment (about 6 h later) than in the SA treatment (beyond 24 h). These results provide valuable information for directing metabolic engineering efforts to improve astaxanthin biosynthesis in H. pluvialis. PMID- 26484873 TI - Recovery after Hip Fracture: Interventions and Their Timing to Address Deficits and Desired Outcomes--Evidence from the Baltimore Hip Studies. AB - Hip fracture is a significant public health problem affecting an estimated 1.6 million persons annually. The consequences of hip fracture are also significant, with more than half of those who sustain a fracture either dying or not returning to functional abilities present before fracture required to function independently. The Baltimore Hip Studies (BHS) is a program of research that for more than 30 years has been doing investigations to identify, develop, and evaluate strategies to optimize recovery from hip fracture. This paper provides an overview of known outcomes and recovery patterns following a hip fracture, which are derived primarily from the BHS. Target areas and timing for interventions based on this recovery sequence are suggested. The paper concludes with a discussion of some of the areas that the next generation of studies needs to concentrate on in order to advance knowledge about the care of hip fracture patients to maximize their recovery. PMID- 26484874 TI - Measurement of exhaled nitric oxide concentration in asthma: a systematic review and economic evaluation of NIOX MINO, NIOX VERO and NObreath. AB - BACKGROUND: High fractions of exhaled nitric oxide (FeNO) in the breath of patients with symptoms of asthma are correlated with high levels of eosinophils and indicate that a patient is likely to respond to inhaled corticosteroids. This may have a role in the diagnosis and management of asthma. OBJECTIVE: To assess the diagnostic accuracy, clinical effectiveness and cost-effectiveness of the hand-held electrochemical devices NIOX MINO((r)) (Aerocrine, Solna, Sweden), NIOX VERO((r)) (Aerocrine) and NObreath((r)) (Bedfont Scientific, Maidstone, UK) for the diagnosis and management of asthma. DATA SOURCES: Systematic searches were carried out between March 2013 and April 2013 from database inception. Databases searched included MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, Science Citation Index Expanded and Conference Proceedings Citation Index - Science. Trial registers such as ClinicalTrials.gov and the metaRegister of Controlled Trials were also searched in March 2013. All searches were updated in September 2013. REVIEW METHODS: A rapid review was conducted to assess the equivalence of hand-held and chemiluminescent FeNO monitors. Systematic reviews of diagnostic accuracy and management efficacy were conducted. A systematic review of economic analyses was also conducted and two de novo health economic models were developed. All three reviews were undertaken according to robust high-quality methodology. RESULTS: The rapid review (27 studies) found varying levels of agreement between monitors (Bland-Altman 95% limits of agreement up to +/-10 parts per billion), with better agreement at lower FeNO values. Correlation was good (generally r > 0.9). The diagnostic accuracy review identified 22 studies in adults (all ages) and four in children. No studies used NObreath or NIOX VERO and seven used NIOX MINO. Estimates of diagnostic accuracy varied widely. FeNO used in combination with another test altered diagnostic accuracy only slightly. High levels of heterogeneity precluded meta-analysis. Limited observations included that FeNO may be more reliable and useful as a rule-in than as a rule-out test; lower cut off values in children and in smokers may be appropriate; and FeNO may be less reliable in the elderly. The management review identified five randomised controlled trials in adults, one in pregnant asthmatics and seven in children. Despite clinical heterogeneity, exacerbation rates were lower in all studies but not generally statistically significantly so. Effects on inhaled corticosteroid (ICS) use were inconsistent, possibly because of differences in management protocols, differential effectiveness in adults and children and differences in population severity. One UK diagnostic model and one management model were identified. Aerocrine also submitted diagnostic and management models. All had significant limitations including short time horizons and the selective use of efficacy evidence. The de novo diagnostic model suggested that the expected difference in quality-adjusted life-year (QALY) gains between diagnostic options is likely to be very small. Airway hyper-responsiveness by methacholine challenge test is expected to produce the greatest QALY gain but with an expected incremental cost-effectiveness ratio (ICER) compared with FeNO (NObreath) in combination with bronchodilator reversibility of L1.125M per QALY gained. All remaining options are expected to be dominated. The de novo management model indicates that the ICER of guidelines plus FeNO monitoring using NObreath compared with guidelines alone in children is expected to be approximately L45,200 per QALY gained. Within the adult subgroup, FeNO monitoring using NObreath compared with guidelines alone is expected to have an ICER of approximately L2100 per QALY gained. The results are particularly sensitive to assumptions regarding changes in ICS use over time, the number of nurse visits for FeNO monitoring and duration of effect. CONCLUSIONS: Limitations of the evidence base impose considerable uncertainty on all analyses. Equivalence of devices was assumed but not assured. Evidence for diagnosis is difficult to interpret in the context of inserting FeNO monitoring into a diagnostic pathway. Evidence for management is also inconclusive, but largely consistent with FeNO monitoring resulting in fewer exacerbations, with a small or zero reduction in ICS use in adults and a possible increased ICS use in children or patients with more severe asthma. It is unclear which specific management protocol is likely to be most effective. The economic analysis indicates that FeNO monitoring could have value in diagnostic and management settings. The diagnostic model indicates that FeNO monitoring plus bronchodilator reversibility dominates many other diagnostic tests. FeNO-guided management has the potential to be cost-effective, although this is largely dependent on the duration of effect. The conclusions drawn from both models require strong technical value judgements with respect to several aspects of the decision problem in which little or no empirical evidence exists. There are many potential directions for further work, including investigations into which management protocol is best and long-term follow-up in both diagnosis and management studies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013004149. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26484872 TI - Increased Sensitivity to Binge Alcohol-Induced Gut Leakiness and Inflammatory Liver Disease in HIV Transgenic Rats. AB - The mechanisms of alcohol-mediated advanced liver injury in HIV-infected individuals are poorly understood. Thus, this study was aimed to investigate the effect of binge alcohol on the inflammatory liver disease in HIV transgenic rats as a model for simulating human conditions. Female wild-type (WT) or HIV transgenic rats were treated with three consecutive doses of binge ethanol (EtOH) (3.5 g/kg/dose oral gavages at 12-h intervals) or dextrose (Control). Blood and liver tissues were collected at 1 or 6-h following the last dose of ethanol or dextrose for the measurements of serum endotoxin and liver pathology, respectively. Compared to the WT, the HIV rats showed increased sensitivity to alcohol-mediated gut leakiness, hepatic steatosis and inflammation, as evidenced with the significantly elevated levels of serum endotoxin, hepatic triglycerides, histological fat accumulation and F4/80 staining. Real-time PCR analysis revealed that hepatic levels of toll-like receptor-4 (TLR4), leptin and the downstream target monocyte chemoattractant protein-1 (MCP-1) were significantly up-regulated in the HIV-EtOH rats, compared to all other groups. Subsequent experiments with primary cultured cells showed that both hepatocytes and hepatic Kupffer cells were the sources of the elevated MCP-1 in HIV-EtOH rats. Further, TLR4 and MCP-1 were found to be upregulated by leptin. Collectively, these results show that HIV rats, similar to HIV-infected people being treated with the highly active anti retroviral therapy (HAART), are more susceptible to binge alcohol-induced gut leakiness and inflammatory liver disease than the corresponding WT, possibly due to additive or synergistic interaction between binge alcohol exposure and HIV infection. Based on these results, HIV transgenic rats can be used as a surrogate model to study the molecular mechanisms of many disease states caused by heavy alcohol intake in HIV-infected people on HAART. PMID- 26484875 TI - Inhibition of epithelial growth factor receptor can play an important role in reducing cell growth and survival in adrenocortical tumors. AB - Medical treatment of adrenocortical carcinoma (ACC) is still far from optimal, since even molecular targeted therapy failed to demonstrate striking results. Clinical trials enrolling ACC patients with high tissue vascular endothelial growth factor receptor (VEGFR) expression levels showed controversial results after treatment with Sunitinib, possibly due to variability in the expression of drug targets, which include epidermal growth factor receptor (EGFR). To better clarify this issue, we evaluated whether VEGFR may play a crucial role in ACC responsiveness to Sunitinib and whether EGFR may represent an alternative target in ACC medical treatment, by employing two ACC cell lines, the NCI-H295 and SW13 cells lines, and adrenocortical tissues primary cultures. Our data show that VEGF/VEGFR system may not be crucial in modulating ACC proliferation and responsiveness to Sunitinib. In addition, by cell viability, proliferation and caspase activation assays we found that Sunitinib inhibits adrenocortical cell viability acting, at least in part, through EGFR, that, in turn, is crucial for EGF proliferative effect on adrenocortical cells. The latter depends, at least in part, on ERK 1/2 activation. An EGFR selective inhibitor was highly effective in reducing cell viability in an adrenocortical tumor primary culture and in the SW13 cells, which express high EGFR levels. Our results suggest that EGFR inhibitors could represent effective therapeutic tools in ACC patients whose tumors express high EGFR levels, that, in turn, may be considered a predictive factor of response. Accurate molecular tumor profiling is crucial to predict drug efficacy and to tailor ACC patients therapeutic approach. PMID- 26484876 TI - Photobiomodulation Suppresses Alpha-Synuclein-Induced Toxicity in an AAV-Based Rat Genetic Model of Parkinson's Disease. AB - Converging lines of evidence indicate that near-infrared light treatment, also known as photobiomodulation (PBM), may exert beneficial effects and protect against cellular toxicity and degeneration in several animal models of human pathologies, including neurodegenerative disorders. In the present study, we report that chronic PMB treatment mitigates dopaminergic loss induced by unilateral overexpression of human alpha-synuclein (alpha-syn) in the substantia nigra of an AAV-based rat genetic model of Parkinson's disease (PD). In this model, daily exposure of both sides of the rat's head to 808-nm near-infrared light for 28 consecutive days alleviated alpha-syn-induced motor impairment, as assessed using the cylinder test. This treatment also significantly reduced dopaminergic neuronal loss in the injected substantia nigra and preserved dopaminergic fibers in the ipsilateral striatum. These beneficial effects were sustained for at least 6 weeks after discontinuing the treatment. Together, our data point to PBM as a possible therapeutic strategy for the treatment of PD and other related synucleinopathies. PMID- 26484877 TI - Reconstructing the Rasch-Built Myotonic Dystrophy Type 1 Activity and Participation Scale. AB - INTRODUCTION: A previously published Rasch-built activity and participation scale specifically designed for patients with myotonic dystrophy type 1 (DM1) was criticized for having been constructed in a relatively small cohort of patients and containing items too broadly phrased for DM1 patients, thus hampering its clinical use. METHODS: We report the results of the reconstructed Rasch-built DM1 activity and participation scale for clinical use (DM1-ActivC) through Rasch analyses using an expanded questionnaire containing 146 more simply phrased activity and participation inquiries completed by 340 patients with DM1. RESULTS: Through stepwise investigation including data quality control, model fit, response category ordering, local dependency and item bias, we succeeded in reconstructing the DM1-ActivC consisting of 25 items that showed good Rasch model fit, including construct convergent validity, items' weights and persons' locations reliability, and unidimensionality. CONCLUSION: The DM1-ActivC scale has been reconstructed and fulfills all modern clinimetric requirements. Its use is recommended in future longitudinal trials in patients with DM1 to determine its responsiveness. PMID- 26484879 TI - Preliminary results of the application of a disease activity score in a patient with relapsing polychondritis. PMID- 26484880 TI - Genetic mutations in primary malignant melanoma of the esophagus: case report and literature review. AB - INTRODUCTION: The most frequent genetic aberrations in mucosal melanoma are activating mutations of c-KIT. Primary malignant melanomas of esophagus (PMME) are uncommon entities, with aggressive biological behavior and poor prognosis. The better definition of their genotype could improve therapeutic options. CASE REPORT: We report a case of a 66 years old man with a PMME in the lower third of the esophagus. Analysis of c-kit, KRAS, NRAS and BRAF genes resulted negative for mutations. On the basis of a computerized (PuMed/Medline) bibliography search we retrieved a total of other 35 cases of PMME analyzed for genetic alterations in RAS, BRAF, and KIT. DISCUSSION: When we compared mutations frequency of PMME with those of other mucosal melanomas, it appeared that PMME are characterized by a relative higher percentage of NRAS mutations. CONCLUSIONS: PMME seem to show a specific pattern of genetic alterations suggesting that they could represent a distinct entity among mucosal melanomas. PMID- 26484878 TI - Urban-Rural Differences in Bone Mineral Density: A Cross Sectional Analysis Based on the Hyderabad Indian Migration Study. AB - BACKGROUND: Fracture risk is rising in countries undergoing rapid rural to urban migration, but whether this reflects an adverse effect of urbanization on intrinsic bone strength, as reflected by bone mineral density (BMD), is currently unknown. METHODS: Lumbar spine (LS) and total hip (TH) BMD, and total body fat and lean mass, were obtained from DXA scans performed in the Hyderabad arm of the Indian Migration Study (54% male, mean age 49 years). Sib-pair comparisons were performed between rural-urban migrants (RUM) and rural non-migrated (RNM) siblings (N = 185 sib-pairs). RESULTS: In analyses adjusted for height, gender, age and occupation, rural to urban migration was associated with higher lumbar and hip BMD and greater predicted hip strength; DeltaLS BMD 0.030 (0.005, 0.055) g/cm2, DeltaTH BMD 0.044 (0.024; 0.064) g/cm2, Deltacross-sectional moment of inertia 0.162 (0.036, 0.289) cm4. These differences were largely attenuated after adjusting for body composition, insulin levels and current lifestyle factors ie. years of smoking, alcohol consumption and moderate to vigorous physical activity. Further analyses suggested that differences in lean mass, and to a lesser extent fat mass, largely explained the BMD differences which we observed. CONCLUSIONS: Rural to urban migration as an adult is associated with higher BMD and greater predicted hip strength, reflecting associated alterations in body composition. It remains to be seen how differences in BMD between migration groups will translate into fracture risk in becoming years. PMID- 26484881 TI - Mycological visits requested in a tertiary referral center: what can be hiding behind a suspected skin mycosis? AB - BACKGROUND: Few studies have so far specifically addressed referrals for mycological visits to analyze the requests for mycological visits in a tertiary referral centre, with particular regard to the rate of true mycoses, the correlation between correct diagnostic hypothesis and specialization of the referring physicians, and the most frequently misdiagnosed dermatological disorders. METHODS: A number of 415 consecutive patients attending our Mycology Unit for suspected superficial fungal infections were enrolled. Final diagnosis was made on clinical features, history, microscopic and cultural analyses and, when necessary, histology. RESULTS: The results show that 118 patients (28.43%) were diagnosed to be affected with fungi, mainly dermatophytes (57%) and Candida (29%). Among nail referrals, onychoystrophies due to mechanical injuries and psoriasis were the most frequently misdiagnosed disorders. Eczema accounted for the main part of the suspected mycoses of glabrous skin, while tinea capitis was the most common referral for hair diseases. The rate of confirmed dermatomychosis was higher among patients referred by dermatologists than by other physicians. The majority of the study patients had undergone previous therapies, mainly antimycotics. CONCLUSIONS: Clinical assessment is often insufficient for diagnosing cutaneous mycoses. Mycological examination is advisable not only for a conclusive diagnosis but also to avoid unnecessary treatments. Nevertheless, clinical competence is relevant for correct suspicion of dermatomycosis. PMID- 26484882 TI - Perception of receiving SMS based health messages among hypertensive individuals in urban slums. AB - BACKGROUND: Hypertension rates are increasing in India, and prior research has not explored the perception of using mobile based SMS among urban hypertensive individuals living in slum settings in India. OBJECTIVE: To explore the perception of receiving SMS based health messages among hypertensive individuals in urban slums. METHODS: A cross sectional study was conducted during the period of December 2013 in an urban slum setting of South Delhi, New Delhi, India. Eligible study participants included: 45 individuals aged 30 years and above, with confirmed diagnosis of high blood pressure, owned a mobile phone/landline and were willing to participate. RESULTS: Results of our study showed participants (n= 45) had an average age of 48 years (SD = 12), mostly female (64%, n= 29), and currently married (80%, n= 36). Their most common perceived hypertension risk factors included: worry/anxiety/stress (84%, n= 38), and high fat diet (68%, n= 30). Mobile calls were the most preferred mode of receiving lifestyle counseling among study participants (71%, n= 32). Majority preferred to receive counseling in Hindi language (67%, n= 30), and more than half were willing to pay for these services (60%, n= 27). CONCLUSION: Our findings suggest the need for innovations that utilize basic phone platforms, mobile calling feature, and language tailored interventions. PMID- 26484883 TI - Visible light communication applications in healthcare. AB - With the development in science, methods of communication are also improved, replacing old ones with new advanced ways in an attempt to make data transfer more secure, safer for health, and time as well as cost efficient. One of such methods is Visible Light Communication, as the name implies data is transferred through a light equipment such as incandescent or florescent bulb having speed of 10 Kb/s or LEDs approaching speed of 500 Mb/s [1]. VLC uses visible light between 384 and 789 THz [2,3]. Though range is limitation of VLC, however data transfer up-to distance of 1 to 2 km although at lower transfer rate has been reached.The VLC system comprises of light source like LED and receiver equipment, however, with advancement, now LEDs are used for both sending and receiving data. LED remains on all the time, and there is no change in brightness level during the whole process, making it safe for eyes. Currently, VLC system is facing some serious technical challenges before it could be applied in daily life. PMID- 26484884 TI - The untapped potential of smartphone sensors for stroke rehabilitation and after care. AB - With the increasing incidences of cerebrovascular disease, as well as the morbidity and mortality associated with it, it is of no surprise that there have been much global governmental interest in the primary prevention of this disorder; or at least in the secondary and tertiary prevention and rehabilitation of individuals who have suffered disabilities arising from a recent cerebrovascular attack. Developers and clinicians have not considered one of the key areas in Stroke prevention and management, which is that of secondary prevention, and in particular that of tapping onto smartphone technologies for stroke rehabilitation. There has been much interest in the development of devices for rehabilitation of stroke patients instead. One of the concerns with regards to conventional bio and mechanical sensors are the costs involved in development, as well as the costs involved when stroke survivors and their caregivers are required to purchase the devices for monitoring and rehabilitation. In view of the current limitations, the S3 Rehab application, which makes use of the smartphone build in sensors, has been conceptualized and has been developed for the two major platforms (Apple and Android platforms). The authors believe that by tapping onto these sensors and by programming a smartphone application that is specifically catered for rehabilitation, it would keep costs minimal for researchers, patients and caregivers. Whilst there is a growing interest in wearable devices and sensors, it is important for developers and researchers to be cognizant that certain interventions, such as rehabilitation could still be done through a smartphone device, instead of investing in new research and development. There are various untapped potential in the smartphone that researchers and developers need to be cognizant of. PMID- 26484885 TI - Analysis of compressive load on intervertebral joint in standing and sitting postures. AB - BACKGROUND: There have been some disagreements on the comparison of disc pressures in the standing and sitting postures in literature. Most research on in vivo pressure needle measurement found higher disc pressure in sitting than in standing. The disc pressure data can help to advocate better postures for clinical advice. OBJECTIVE: The aim of this paper is to develop a procedure to study the compressive load on intervertebral joint in the standing and sitting postures through the approach of motion capture and musculoskeletal modeling. METHODS: The marker data of six subjects performing various standing and sitting postures was obtained during the motion capture experiment and used to train the musculoskeletal model with an enhanced discretized spine developed for subject in the inverse and forward simulations. RESULTS: Compressive loads on L3-L4 and L4 L5 joints are found higher in upright sitting than in upright standing. Slumped sitting, cross-legged sitting and flexion sitting can introduce higher compressive loads on intervertebral joints compared with upright sitting. CONCLUSIONS: These findings indicate the effects of standing and sitting postures on the spinal joint loads. The results can provide doctors and therapists with more information on clinical advice on better postures for people with spinal problems. PMID- 26484886 TI - Influence of various bleaching regimes on surface roughness of resin composite and ceramic dental biomaterials. AB - BACKGROUND: Bleaching agents are commonly used in dentistry for treating the discolored teeth. A number of biomaterials and methods are in clinical applications. OBJECTIVE: The major aim of this study was to evaluate the effects of two different bleaching agents on the surface roughness properties of dental resin nanocomposites and dental porcelains using various regimes. METHODS: This study was conducted using direct restorative hybrid and nanocomposite materials and dental porcelains. The specimens were treated using the bleaching gels [(Opalescence Boost 40% OP) and (Whiteness HP 35% WHP)] for 30, 45, 60 and 120 minutes respectively. Treated samples were analyzed for surface roughness properties using contact mode surface profilometry and surface topography using scanning electron microscopy (SEM). Data was analyzed statistically using analysis of variance (ANOVA). RESULTS: There were no significant changes observed in the roughness of nanofill, nanohybrid composites and ceramic materials compared to microhybrid resin composites (p> 0.05). The SEM photomicrographs confirmed the results of the profilometer showing slight changes in the microhybrid resin composite. CONCLUSIONS: No remarkable difference was observed between the bleaching agents (Opalescence Boost and Whiteness HP Blue) for the surface roughness of tested dental materials. The bleaching agents can be used without harming the ceramic, nanofilled or nanohybrid resin restorations. However, if microhybrid or microfilled composite restorations are present in the oral cavity, bleaching may damage the surface finish and requiring replacement of restorations. PMID- 26484887 TI - Correction: Oxygen reduction and oxygen evolution in DMSO based electrolytes: the role of the electrocatalyst. AB - Correction for 'Oxygen reduction and oxygen evolution in DMSO based electrolytes: the role of the electrocatalyst' by C. J. Bondue et al., Phys. Chem. Chem. Phys., 2015, 17, 25593-25606. PMID- 26484888 TI - Peroxisomal Import Reduces the Proapoptotic Activity of Deubiquitinating Enzyme USP2. AB - The human deubiquitinating enzyme ubiquitin-specific protease 2 (USP2) regulates multiple cellular pathways, including cell proliferation and apoptosis. As a result of alternative splicing four USP2 isoenzymes are expressed in human cells of which all contain a weak peroxisome targeting signal of type 1 (PTS1) at their C-termini. Here, we systematically analyzed apoptotic effects induced by overexpression and intracellular localization for each isoform. All isoforms exhibit proapoptotic activity and are post-translationally imported into the matrix of peroxisomes in a PEX5-dependent manner. However, a significant fraction of the USP2 pool resides in the cytosol due to a weaker PTS1 and thus low affinity to the PTS receptor PEX5. Blocking of peroxisomal import did not interfere with the proapoptotic activity of USP2, suggesting that the enzyme performs its critical function outside of this compartment. Instead, increase of the efficiency of USP2 import into peroxisomes either by optimization of its peroxisomal targeting signal or by overexpression of the PTS1 receptor did result in a reduction of the apoptotic rate of transfected cells. Our studies suggest that peroxisomal import of USP2 provides additional control over the proapoptotic activity of cytosolic USP2 by spatial separation of the deubiquitinating enzymes from their interaction partners in the cytosol and nucleus. PMID- 26484889 TI - Prevalence of Mental Illness among Homeless People in Hong Kong. AB - METHOLODOGY: This study examined the prevalence and correlates of mental illness in homeless people in Hong Kong and explored the barriers preventing their access to health care. Ninety-seven Cantonese-speaking Chinese who were homeless during the study period were selected at random from the records of the three organisations serving the homeless population. The response rate was 69%. Seventeen subjects could not give valid consent due to their poor mental state, so their responses were excluded from the data analysis. A psychiatrist administered the Structured Clinical Interview for DSM-IV Axis-I disorders (SCID I) and the Mini -Mental State Examination. Consensus diagnoses for subjects who could not complete the SCID-I were established by three independent psychiatrists. FINDINGS: The point prevalence of mental illness was 56%. Seventy one percent of the subjects had a lifetime history of mental illness, 30% had a mood disorder, 25% had an alcohol use disorder, 25% had a substance use disorder, 10% had a psychotic disorder, 10% had an anxiety disorder and 6% had dementia. Forty-one percent of the subjects with mental illness had undergone a previous psychiatric assessment. Only 13% of the subjects with mental illness were receiving psychiatric care at the time of interview. The prevalence of psychotic disorders, dementia and the rate of under treatment are hugely underestimated, as a significant proportion (18%) of the subjects initially selected were too ill to give consent to join the study. CONCLUSION: The low treatment rate and the presence of this severely ill and unreached group of homeless people reflect the fact that the current mode of service delivery is failing to support the most severely ill homeless individuals. PMID- 26484890 TI - Unusual Upper Gastrointestinal Bleeding. PMID- 26484891 TI - Isolation and Propagation of Circulating Tumor Cells from a Mouse Cancer Model. AB - Cancer metastasis is the foremost cause of cancer-associated deaths. Recent studies have shown that circulating tumor cells (CTCs) are important in cancer metastasis. Indeed, the number of CTCs correlates with tumor size. Here, a detailed description is provided of a methodology for isolation and propagation of CTCs from a syngeneic mouse model of hepatocellular carcinoma (HCC) which allows for downstream analysis of potentially important molecular mechanisms of solid organ tumor metastasis. This method is efficient and reproducible. It is a non-invasive technique and, therefore, has potential to replace the invasive biopsy of tissues from humans which may be associated with complications. Therefore, the method discussed here allows for the isolation and propagation of CTCs from whole blood samples such that they can be examined and characterized. This has potential for future adaptation for clinical applications such as diagnosis, and personalized targeted therapy. PMID- 26484892 TI - Molecular cloning and characterization of a phospholipid hydroperoxide glutathione peroxidase gene from a blood fluke Schistosoma japonicum. AB - Phospholipid hydroperoxide glutathione peroxidase (PHGPx) is a major antioxidant enzyme and plays critical roles in the protection of cells against oxidative stress by catalysing reduction of lipid hydroperoxides. A full-length cDNA sequence corresponding to GPx gene from Schistosoma japonicum (designated SjGPx) was isolated and characterized. SjGPx contained an in-frame TGA codon for selenocysteine (Sec) and a concurrent Sec insertion sequence in its 3' untranslated region. Protein encoded by SjGPx demonstrated a primary structure characteristic to the PHGPx family, including preservation of catalytic domains and absence of the subunit interaction domains. Phylogenetic analysis revealed that the SjGPx was highly related to the other PHGPx-related members, and clustered into the trematode subclade II. Semi-quantitative reverse transcription PCR and western blotting showed that the SjGPx was mainly expressed in the female adults and eggs. RNA interference was employed to investigate the effects of knockdown of SjGPx. SjGPx expression level was significantly reduced on the 5th day post-RNAi. We observed a 53.86% reduction in total GPx activity and the eggs severely deformed. Oxidative stimulation of viable worms with H2O2 or paraquat resulted in 1.6- to 2.1-fold induction of the GPx activity. Our results revealed that the SjGPx protein is selenium-dependent PHGPx, which might actively participate in the detoxification of oxidative damage during egg production. PMID- 26484893 TI - Alpha, delta and theta rhythms in a neural net model. Comparison with MEG data. AB - The aim of this study is to provide information regarding the comparison of a neural model to MEG measurements. Our study population consisted of 10 epileptic patients and 10 normal subjects. The epileptic patients had high MEG amplitudes characterized with theta (4-7 Hz) or delta (2-3 Hz) rhythms and absence of alpha rhythm (8-13 Hz). The statistical analysis of such activities corresponded to Poisson distribution. Conversely, the MEG from normal subjects had low amplitudes, higher frequencies and presence of alpha-rhythm (8-13 Hz). Such activities were not synchronized and their distributions were Gauss. These findings were in agreement with our theoretical neural model. The comparison of the neural network with MEG data provides information about the status of brain function in epileptic and normal states. PMID- 26484894 TI - Hybrid aerogel preparations as drug delivery matrices for low water-solubility drugs. AB - A comprehensive study of 14 hybrid aerogels of different composition with applications in drug delivery has been carried out. The overall objective was to modulate the release behavior of drug-impregnated aerogels, from an almost instantaneous release to a semi-retarded delivery prolonged during several hours, through internal surface functionalization. The designed hybrid aerogels were composed of silica and gelatin and functionalized with either phenyl, long (16) hydrocarbon chain or methyl moiety. As model systems, three class II active agents (pKa<5.5), ibuprofen, ketoprofen and triflusal, were chosen to impregnate the aerogels. The work relied on the use of supercritical fluid technology for both the synthesis and functionalization of the hybrid aerogels, as well as for the impregnation with an active agent using supercritical CO2 as a solvent. For the impregnated aerogels, in vitro release profiles were recorded under gastric and intestinal pH-conditions using HPLC techniques. The release behavior observed for the three studied drugs was explained considering the measured dissolution profiles of the crystalline drugs, the aerogel composition and its functionalization. Such features are considered of great interest to tailor the bioavailability of drugs with low water solubility. PMID- 26484895 TI - Immunesenescence and inflammaging: A contributory factor in the poor outcome of the geriatric trauma patient. AB - Compared to younger patients, traumatic injury in older patients is associated with increased mortality and a range of adverse outcomes such as higher rates of infectious episodes, longer length of hospital stay and poor functional outcome at follow up. Data emerging from human and murine-based studies suggest age related changes in immune function, collectively termed immunesenescence, and the chronic sub-clinical systemic inflammatory state of older adults, termed inflammaging, may contribute to these poor outcomes. Here, we review the findings of these studies, whose results demonstrate that the geriatric trauma patient elicits an immune response to injury that is distinct to that of younger adults, being characterised by reduced immune cell activation, impaired function and abnormal haematopoiesis, defects that are accompanied by an altered inflammatory response that fails to return to a homeostatic baseline in the days following injury. Although considerable evidence is accumulating that demonstrates clear and significant age-related differences in the immune and inflammatory response to traumatic injury, our current understanding of the mechanism(s) that underlie these changes is limited. Future studies that provide a mechanistic explanation for the unique immune and inflammatory response of older adults to traumatic injury are therefore essential if we are to determine whether manipulation of the immune system has potential as a future therapeutic strategy by which to improve the outcome of the geriatric trauma patient. PMID- 26484896 TI - Comparing the Affinity of GTPase-binding Proteins using Competition Assays. AB - In this protocol we demonstrate a method for comparing the competition between GTPase-binding proteins. Such an approach is important for determining the binding capabilities of GTPases for two reasons: The fact that all interactions involve the same face of the GTPases means that binding events must be considered in the context of competitors, and the fact that the bound nucleotide must also be controlled means that conventional approaches such as immunoprecipitation are unsuitable for GTPase biochemistry. The assay relies on the use of purified proteins. Purified Rac1 immobilized on beads is used as the bait protein, and can be loaded with GDP, a non-hydrolyzable version of GTP or left nucleotide free, so that the signaling stage to be investigated can be controlled. The binding proteins to be investigated are purified from mammalian cells, to allow correct folding, by means of a GFP tag. Use of the same tag on both proteins is important because not only does it allow rapid purification and elution, but also allows detection of both competitors with the same antibody during elution. This means that the relative amounts of the two bound proteins can be determined accurately. PMID- 26484897 TI - Cloning and functional characterization of the Arabidopsis N-acetylserotonin O methyltransferase responsible for melatonin synthesis. AB - The N-acetylserotonin O-methyltransferase (ASMT) gene encodes the enzyme that catalyzes the conversion of N-acetylserotonin to melatonin as the last step in melatonin biosynthesis. The first plant ASMT gene to be cloned was from rice. An orthologous gene encoding a protein with ASMT activity and only 39.7% amino acid sequence identity to the rice ASMT protein was recently isolated from apple (Malus zumi). The low homology of the apple ASMT sequence prompted us to screen the Arabidopsis genome for a homologous ASMT gene. The At4g35160 gene exhibited the highest sequence identity (31%) to the rice ASMT gene, followed by the At1g76790 gene with 29% sequence identity. We purified recombinant proteins expressed from the two Arabidopsis genes. The At4g35160 recombinant protein exhibited ASMT enzyme activity, but the At1g76790 recombinant protein did not; thus, we designated At4g35160 as an Arabidopsis thaliana ASMT (AtASMT) gene. The AtASMT protein catalyzed the conversion of N-acetylserotonin to melatonin and serotonin to 5-methoxytryptamine with Vmax values of 0.11 and 0.29 pkat/mg protein, respectively. However, AtASMT exhibited no caffeic acid O methyltransferase activity, suggesting that its function was highly specific to melatonin synthesis. AtASMT transcripts were induced by cadmium treatment in Arabidopsis followed by increased melatonin synthesis. Similar to other ASMT proteins, AtASMT was localized in the cytoplasm and its ectopic overexpression in rice resulted in increased ASMT enzyme activity and melatonin production, indicating the involvement of AtASMT in melatonin synthesis. PMID- 26484898 TI - Roflumilast inhibits leukocyte-platelet interactions and prevents the prothrombotic functions of polymorphonuclear leukocytes and monocytes. AB - ESSENTIALS: Thrombosis is a major comorbidity in patients with chronic obstructive pulmonary disease (COPD). Roflumilast is a selective phosphodiesterase type-4 (PDE4) inhibitor approved for treatment of severe COPD. PDE4 blockade by roflumilast inhibits prothrombotic functions of neutrophils and monocytes. PDE4 inhibitors may reduce thrombotic risk in COPD as well as in other vascular diseases. BACKGROUND: Roflumilast, an oral selective phosphodiesterase type 4 inhibitor, is approved for the treatment of severe chronic obstructive pulmonary disease (COPD). A recent meta-analysis of trials on COPD revealed that treatment with roflumilast was associated with a significant reduction in the rate of major cardiovascular events. The mechanisms of this effect remain unknown. OBJECTIVES: We tested the hypothesis that roflumilast N-oxide (RNO), the active metabolite of roflumilast, curbs the molecular mechanisms required for leukocyte-platelet (PLT) interactions and prevents the prothrombotic functions of polymorphonuclear leukocytes (PMNs) and monocytes (MNs). METHODS: Using well characterized in vitro models, we analysed the effects of RNO on: (i) PMN adhesiveness; (ii) the release of neutrophil extracellular traps (NETs); and (iii) tissue factor expression in MNs. Key biochemical events underlying the inhibitory effects of RNO were defined. RESULTS AND CONCLUSIONS: In PMNs, RNO prevented phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of Akt on Ser473, and Src family kinase (SFK)-mediated Pyk2 phosphorylation on Tyr579-580, while inducing protein kinase A-mediated phosphorylation of C-terminal Src kinase, the major negative regulator of SFKs. Modulation of these signaling pathways by RNO resulted in a significant impairment of PMN adhesion to activated PLTs or human umbilical vein endothelial cells, mainly mediated by inhibition of the adhesive function of Mac-1. Moreover RNO curbed SFK/PI3K-mediated NET release by PMNs adherent on fibrinogen-coated surfaces. In MNs interacting with activated PLTs, RNO curbed PI3K-mediated expression of tissue factor. The efficacy of RNO was significantly potentiated by formoterol, a long acting beta-adrenergic receptor agonist. This study reveals novel antithrombotic activities by which roflumilast may exert protective effects against cardiovascular comorbodities in COPD. PMID- 26484899 TI - Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer's Disease Mouse Model. AB - It is unclear whether pre-symptomatic Alzheimer's disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2-/- model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels. PMID- 26484900 TI - Associations between Neuropsychiatric Symptoms and Cerebral Amyloid Deposition in Cognitively Impaired Elderly People. AB - BACKGROUND: Neuropsychiatric symptoms, also known as behavioral and psychological symptoms of dementia (BPSD), affect the majority of patients with dementia, and result in a greater cognitive and functional impairment. OBJECTIVE: To investigate associations between BPSD and amyloid cerebral deposition as measured by 18F-Florbetapir-PET quantitative uptake in elderly subjects with and without cognitive impairment. METHODS: Participants with cognitive impairment [mild cognitive impairment (MCI) or Alzheimer's disease (AD)] and healthy controls (HC) from the ADNI cohort (Alzheimer Disease Neuroimaging Initiative) who underwent an 18F-florbetapir PET scan between May 2010 and March 2014 were included. Clinical assessments included the Clinical Dementia Rating, the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory. Freesurfer software was used to extract PET counts based on T1-based structural ROI (frontal, cingulate, parietal, and temporal). Spearman's partial correlation scores between BPSD severity and regional amyloid uptake were calculated. RESULTS: Data for 657 participants [age = 72.6 (7.19); MMSE = 27.4 (2.67)] were analyzed, including 230 HC [age = 73.1 (6.02); MMSE = 29 (1.21)], 308 MCI [age = 71.5 (7.44); MMSE = 28.0 (1.75)], and 119 AD subjects [age = 74.7 (8.05); MMSE = 23.1 (2.08)]. Considering all diagnostic groups together, positive significant correlations were found between anxiety and 18F-florbetapir uptake in the frontal (r = 0.102; p = 0.009), cingulate (r = 0.083; p = 0.034), and global cerebral uptake (r = 0.099; p = 0.011); between irritability and frontal (r = 0.089; p = 0.023), cingulate (r = 0.085; p = 0.030), parietal (r = 0.087; p = 0.025), and global cerebral uptake (r = 0.093; p = 0.017); in the MCI subgroup, between anxiety and frontal (r = 0.126; p = 0.03) and global uptake (r = 0.14; p = 0.013); in the AD subgroup, between irritability and parietal uptake (r = 0.201; p = 0.03). CONCLUSION: Anxiety and irritability are associated with greater amyloid deposition in the neurodegenerative process leading to AD. PMID- 26484901 TI - Effect of Tween-20 on Core Biomarkers Measured in Cerebrospinal Fluid from Patients with Alzheimer's Disease, Mild Cognitive Impairment, or Healthy Control Individuals. AB - BACKGROUND: There is substantial variation caused by preanalytical procedures in the measurement of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) reported in the literature. OBJECTIVE: Determine whether the detergent Tween 20 improves diagnostic accuracy. METHODS: CSF proteins (Abeta42, Abeta40, total tau, and phosphorylated tau) were measured by standard ELISA, in uncentrifuged CSF with or without 0.05% Tween-20 from patients with AD or amnestic mild cognitive impairment, and healthy elderly controls. In the main study, collection tubes containing Tween-20 (Sarstedt 15 mL) were filled with 5 mL CSF to ensure consistent detergent concentration across subsequent aliquots into Corning 2 mL tubes. These latter were also the primary collection vessel for samples without Tween-20. The effect of centrifugation, and extra tube transfer of samples with Tween-20 were also examined. RESULTS: 0.05% Tween-20 significantly increased mean measured CSF concentration of Abeta42 (30% ), Abeta40 (23% ), and total tau (4% ), but not phosphorylated tau. Generally, these increases were similar in all groups, although for Abeta42, the mean percentage increase with Tween-20 was slightly larger for AD. Areas under receiver-operator characteristic curves were similar whether Tween-20 was present or not. Centrifuged CSF without Tween-20 significantly reduced the measured concentration of Abeta42 versus non centrifuged samples, a difference not seen when detergent was added. Similar CSF Abeta42 levels were found whether Tween-20 was added at collection in an extra tube or directly to the main collection tube. CONCLUSION: Addition of Tween-20 to CSF did not improve differentiation of patients from controls. PMID- 26484903 TI - Psychotropic Drug Prescription in Patients with Dementia: Nursing Home Residents Versus Patients Living at Home. AB - BACKGROUND: Psychotropic drugs are frequently prescribed in nursing homes (NH). Nonetheless, we hoped that institutionalization decreases the number of psychotropic drug classes prescribed, because NH residents may have more psychosocial interventions than patients living at home. OBJECTIVE: The aim was to compare the type and number of psychotropic drugs prescribed in elderly NH residents with dementia with those in community-living patients. METHODS: This cross-sectional study included elderly patients (at least 75 years old) with dementia recorded in the National Alzheimer's data Bank ("Banque Nationale Alzheimer") during the year 2012 and who were taking at least one psychotropic drug. Psychotropic drugs were classified as follows: antidepressant, anxiolytic, hypnotic, and antipsychotic drugs. Patients were classified into three categories of dementia severity according to the MMSE score. RESULTS: Among the 50,932 patients with dementia recorded in the BNA, 40.1% had at least one psychotropic drug prescribed. Most of the patients who were treated by at least one psychotropic drug class had antidepressant therapy (69.0%), whatever their residence type, and 16.1% were treated with antipsychotics. Among the study population, 51.9% of the NH residents and 67.4% of the patients living at home had only one psychotropic drug class prescribed. Living in a NH was significantly associated with the more frequent prescription of anxiolytic, hypnotic, and antipsychotic drugs, and with a greater number of psychotropic drug classes prescribed, whatever the severity of the dementia. CONCLUSION: We underlined the more frequent prescription of psychotropic drugs in NH residents regardless of MMSE scores. PMID- 26484902 TI - The Latent Dementia Phenotype delta is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment. AB - BACKGROUND: The recently proposed latent variable delta is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials. OBJECTIVE: To investigate the association of delta with AD biomarkers and to compare the prediction of delta with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). METHODS: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable delta and compared delta with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. RESULTS: In patients with MCI, delta based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Abeta42/tau ratio indicative of AD (n = 340, AUC = 0.78, p < 0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p < 0.001). These associations were generally stronger than for any other scale or cognitive functional composite examined. Homologs of delta based on reduced test batteries yielded somewhat lower effects. CONCLUSION: These findings support the interpretation of delta as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that delta might become an analytical tool for dementia research. PMID- 26484904 TI - Clinical Impact of a Second FDG-PET in Atypical/Unclear Dementia Syndromes. AB - Diagnosis of atypical/unclear dementia is often difficult and this delays treatment initiation. Several authors have shown that beyond standard dementia workup, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) reduces the number of unclear diagnoses, leads to earlier treatment, and has a beneficial impact on families. However, it is not uncommon that the FDG-PET findings are equivocal in this setting. For those cases, a repeat FDG-PET may clarify the diagnosis and prevent treatment delay. We retrospectively assessed the clinical impact of a repeat FDG-PET in 59 patients with atypical/unclear dementia syndromes and inconclusive initial FDG-PET. Changes in primary diagnosis, diagnostic confidence, and management following the second FDG-PET were examined. Conducting a second FDG-PET reduced the number of unclear diagnoses from 80% to 34% , led to diagnostic change in 24% of cases, and treatment modification in 22% of patients. Overall, the clinical impact was higher when initial diagnostic confidence was low and the second FDG-PET repeated >=12 months after the first one. In tertiary care memory clinic settings, when diagnostic incertitude persists despite extensive evaluation and an equivocal FDG-PET, repeating the FDG PET 12 months later can greatly clarify the diagnosis and improve management. PMID- 26484905 TI - Altered Affective Evaluations of Smells in Alzheimer's Disease. AB - BACKGROUND: Studies of olfaction in Alzheimer's disease (AD) mainly focused on deficits in odor detection and identification, with very few investigations of olfactory emotional changes and their consequences for hedonics. OBJECTIVE: The aim of the present study was to characterize affective evaluations of odors in AD patients. METHODS: To this end, 20 AD patients and 20 matched controls were tested. Participants were screened for odor detection and identification ability and then asked to rate the intensity, pleasantness, and edibility of 20 odorants. RESULTS: Results showed that, overall, AD patients had lower detection ability and perceived all odors as weaker than controls. As expected, they had lower identification ability on both cued and non-cued tasks. In addition, when smelling pleasant odors, patients had significantly lower hedonic ratings than controls (p < 0.02), whereas no group difference was found for neutral or unpleasant odors (p > 0.05 in both cases). Moreover, an analysis combining both intensity and pleasantness ratings showed that whereas intensity increased as a function of pleasantness and unpleasantness in controls, this quadratic relationship was not observed in AD patients. CONCLUSIONS: The study suggests that the simplest categorization criteria of odors (intensity and hedonic valence) are impaired in AD patients (especially for pleasant odors). PMID- 26484906 TI - Age-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-beta Peptide in a Mouse Model of Alzheimer's Disease (3xTg-AD). AB - The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Abeta levels, and thereby in Alzheimer's disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Abeta influx (Rage) and efflux (Abcb1-Abcg2-Abcg4-Lrp-1) transporters and cholesterol transporter (Abca1) in 3-18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup) of [3H]cholesterol and [3H]Abeta1 - 40 was then evaluated in these mice, using the in situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Abeta influx receptor (Rage) and decrease in efflux receptor (Lrp-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, Abcg4 and Abca1 are up regulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Abeta is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that Abcg4 and Abca1 control the efflux of Abeta through the BBB by a direct (Abcg4) or indirect (Abca1) mechanism. At 18 months, the BBB Abeta efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant up regulation of both Abcg2 and Abcb1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Abeta and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Abeta. PMID- 26484907 TI - Early in vivo Effects of the Human Mutant Amyloid-beta Protein Precursor (hAbetaPPSwInd) on the Mouse Olfactory Bulb. AB - The amyloid-beta protein precursor (AbetaPP) has long been linked to Alzheimer's disease (AD). Using J20 mice, which express human AbetaPP with Swedish and Indiana mutations, we studied early pathological changes in the olfactory bulb. The presence of AbetaPP/amyloid-beta (Abeta) was examined in mice aged 3 months (before the onset of hippocampal Abeta deposition) and over 5 months (when hippocampal Abeta deposits are present). The number of neurons, non-neurons, and proliferating cells was assessed using the isotropic fractionator method. Our results demonstrate that although AbetaPP is overexpressed in some of the mitral cells, widespread Abeta deposition and microglia aggregates are not prevalent in the olfactory bulb. The olfactory bulbs of the younger J20 group harbored significantly fewer neurons than those of the age-matched wild-type mice (5.57+/ 0.13 million versus 6.59+/-0.36 million neurons; p = 0.011). In contrast, the number of proliferating cells was higher in the young J20 than in the wild-type group (i.e., 6617+/-425 versus 4455+/-623 cells; p = 0.011). A significant increase in neurogenic activity was also observed in the younger J20 olfactory bulb. In conclusion, our results indicate that (1) neurons participating in the mouse olfactory function overexpress AbetaPP; (2) the cellular composition of the young J20 olfactory bulb is different from that of wild-type littermates; (3) these differences may reflect altered neurogenic activity and/or delayed development of the J20 olfactory system; and (4) AbetaPP/Abeta-associated pathological changes that take place in the J20 hippocampus and olfactory bulb are not identical. PMID- 26484908 TI - Higher Fasting Plasma Glucose Levels, within the Normal Range, are Associated with Decreased Processing Speed in High Functioning Young Elderly. AB - We explored the association of plasma glucose levels within the normal range with processing speed in high functioning young elderly, free of type 2 diabetes mellitus (T2DM). A sample of 41 participants (mean age = 64.7, SD = 10; glucose 94.5 mg/dL, SD = 9.3), were examined with a computerized cognitive battery. Hierarchical linear regression analysis showed that higher plasma glucose levels, albeit within the normal range (<110 mg/dL), were associated with longer reaction times (p < 0.01). These findings suggest that even in the subclinical range and in the absence of T2DM, monitoring plasma glucose levels may have an impact on cognitive function. PMID- 26484909 TI - The Utilization of Retinal Nerve Fiber Layer Thickness to Predict Cognitive Deterioration. AB - Our previous studies have shown that longitudinal reduction in retinal nerve fiber layer (RNFL) thickness is associated with cognitive deterioration. However, whether the combination of longitudinal reduction in RNFL thickness with baseline episodic memory performance can better predict cognitive deterioration remains unknown. Therefore, we set out to re-analyze the data obtained from our previous studies with 78 elderly adults (mean age 74.4 +/- 3.83 years, 48.7% male) in the community over a 25-month period. The participants were categorized as either stable participants whose cognitive status did not change (n = 60) or converted participants whose cognitive status deteriorated (n = 18). A logistic regression analysis was applied to determine a conversion score for predicting the cognitive deterioration in the participants. We found that the area under the receiver operating characteristic curve (AUC) for the multivariable model was 0.854 (95% CI 0.762-0.947) using baseline story recall as a predictor, but the AUC increased to 0.915 (95% CI 0.849-0.981) with the addition of the longitudinal reduction of RNFL thickness in the inferior quadrant. The conversion score was significantly higher for the converted participants than the stable participants (0.59 +/- 0.30 versus 0.12 +/- 0.19, p < 0.001). Finally, the optimal cutoff value of the conversion score (0.134) was determined by the analysis of receiver operating characteristic curve, and this conversion score generated a sensitivity of 0.944 and a specificity of 0.767 in predicting the cognitive deterioration. These findings have established a system to perform a larger scale study to further test whether the longitudinal reduction in RNFL thickness could serve as a biomarker of Alzheimer's disease. PMID- 26484911 TI - Dementia Apraxia Test (DATE): A Brief Tool to Differentiate Behavioral Variant Frontotemporal Dementia from Alzheimer's Dementia Based on Apraxia Profiles. AB - BACKGROUND: Standardized praxis assessments with modern, empirically validated screening tests have substantially improved clinical evaluation of apraxia in patients with stroke. Although apraxia may contribute to early differential diagnosis of Alzheimer's dementia (AD) and behavioral variant frontotemporal dementia (bvFTD), no comparable test is readily available to clinicians for this purpose to date. OBJECTIVE: To design a clinically useful apraxia test for the differentiation of AD and bvFTD. METHODS: 84 test items pertaining to twelve praxis subdomains were evaluated for their efficacy to discriminate between patients with bvFTD (n = 24), AD (n = 28), and elderly healthy controls (HC; n = 35). Items were then selected based on discriminative value and psychometric properties. RESULTS: Items indicative of mild AD comprised spatially complex imitation of hand and finger postures and to a lesser degree, pantomime of common object-use. Buccofacial apraxia including imitation of face postures, emblematic face postures, and repetition of multisyllabic pseudowords differentiated bvFTD from HC and AD. The final test version consisting of 20 items proved highly efficient for the discrimination of biologically confirmed dementia patients from HC (sensitivity 91% , specificity 71%) but also for differential diagnosis of bvFTD and AD (sensitivity 74% , specificity 93%). CONCLUSIONS: Assessment of praxis profiles effectively contributes to diagnosis and differential diagnosis of AD and bvFTD. The Dementia Apraxia Test (DATE) is a brief and easy to administer cognitive tool for dementia assessment, has a high inter-rater reliability (Cohen's kappa= 0.885) and demonstrates content validity. PMID- 26484910 TI - A Pathway Based Classification Method for Analyzing Gene Expression for Alzheimer's Disease Diagnosis. AB - BACKGROUND: Recent studies indicate that gene expression levels in blood may be able to differentiate subjects with Alzheimer's disease (AD) from normal elderly controls and mild cognitively impaired (MCI) subjects. However, there is limited replicability at the single marker level. A pathway-based interpretation of gene expression may prove more robust. OBJECTIVES: This study aimed to investigate whether a case/control classification model built on pathway level data was more robust than a gene level model and may consequently perform better in test data. The study used two batches of gene expression data from the AddNeuroMed (ANM) and Dementia Case Registry (DCR) cohorts. METHODS: Our study used Illumina Human HT 12 Expression BeadChips to collect gene expression from blood samples. Random forest modeling with recursive feature elimination was used to predict case/control status. Age and APOE E4 status were used as covariates for all analysis. RESULTS: Gene and pathway level models performed similarly to each other and to a model based on demographic information only. CONCLUSIONS: Any potential increase in concordance from the novel pathway level approach used here has not lead to a greater predictive ability in these datasets. However, we have only tested one method for creating pathway level scores. Further, we have been able to benchmark pathways against genes in datasets that had been extensively harmonized. Further work should focus on the use of alternative methods for creating pathway level scores, in particular those that incorporate pathway topology, and the use of an endophenotype based approach. PMID- 26484912 TI - Dysregulation and diagnostic potential of microRNA in Alzheimer's disease. AB - Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is considered to be the main cause of cognitive impairment in elderly people. The major symptom of AD is progressive dementia that eventually results in dysfunction of daily life. Due to the fact that AD has a long period of incubation before clinical symptoms emerge, the available therapeutic treatments can only improve the symptoms but not delay the progression of AD. Therefore, there is an urgent need to explore effective diagnostic approaches to catch and better treat the disease before clinical symptoms appear. Recent research revealed that abnormal expression of certain miRNA could have a crucial role in the pathological process of neurodegenerative disease including AD. Furthermore, given that AD patients show increased level of miRNAs in the blood and cerebrospinal fluid, miRNAs are considered promising non-invasive candidates for AD diagnosis and prognosis. Here, we reviewed the current research related to implications of miRNAs during the development of AD, summarized of actively used approaches to identifying potential miRNA biomarkers in body fluids, and discussed the diagnostic potential of microRNAs as biomarkers for AD. PMID- 26484913 TI - Increased Total Homocysteine Levels Predict the Risk of Incident Dementia Independent of Cerebral Small-Vessel Diseases and Vascular Risk Factors. AB - BACKGROUND: Homocysteine has been identified as a potential risk factor for stroke, cerebral small-vessel diseases (SVD), and dementia. OBJECTIVE: The present study aimed to investigate the predictive value of homocysteine levels on incident dementia while simultaneously controlling for MRI findings and vascular risk factors. METHODS: Within a Japanese cohort of participants with vascular risk factors in an observational study, we evaluated the association between baseline total homocysteine (tHcy) levels (per 1 MUmol/L and the tertile of tHcy), the prevalence of MRI-findings at baseline, and incident all-cause dementia. Baseline brain MRI was used to determine SVD (lacunas, white matter hyperintensities, and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy and bicaudate ratio). Logistic regression analyses were used to estimate the cross-sectional association between tHcy and each of MRI findings. Cox proportional hazards analyses were performed to estimate the longitudinal association between tHcy and dementia. RESULTS: In the 643 subjects (age: 67.2 +/ 8.4 years, male: 59% ; education: 12.9 +/- 2.6 years), multivariable analyses adjusted for several potential confounders, including estimated glomerular filtration rate (eGFR) and intima-media thickness, showed that highest tHcy tertile was associated with lacunas, CMBs, and strictly deep CMBs. During the mean 7.3-year follow-up (range: 2-13), 47 patients were diagnosed with dementia (Alzheimer's disease: 24; vascular dementia: 18; mixed-type: 3; other: 2). After adjusting for age, gender, APOE E4, education, BMI, MMSE, hypertension, cerebrovascular events, eGFR, and MRI-findings, tHcy level (hazard ratios [HR]: 1.08, p = 0.043) and the highest tertile of tHcy (HR: 2.50, p = 0.047) for all cause dementia remained significant. CONCLUSIONS: Our results provide additional evidence of tHcy that contributes to increased susceptibility to dementia risk. PMID- 26484914 TI - LRP/LR Antibody Mediated Rescuing of Amyloid-beta-Induced Cytotoxicity is Dependent on PrPc in Alzheimer's Disease. AB - The neuronal perturbations in Alzheimer's disease are attributed to the formation of extracellular amyloid-beta (Abeta) neuritic plaques, composed predominantly of the neurotoxic Abeta42 isoform. Although the plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to soluble Abeta42 oligomers. The 37kDa/67kDa laminin receptor has been implicated in Abeta42 shedding and Abeta42-induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and Abeta42, the mechanism underlying this cytotoxicity may be indirectly due to the PrPc-Abeta42 interaction with LRP/LR. The effects of this interaction were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assays. PrPc overexpression significantly enhanced Abeta42 cytotoxicity in vitro, while PrP-/- cells were more resistant to the cytotoxic effects of Abeta42 and exhibited significantly less cell death than PrPc expressing N2a cells. Although anti-LRP/LR specific antibody IgG1-iS18 significantly enhanced cell viability in both pSFV1-huPrP1-253 transfected and non-transfected cells treated with exogenous Abeta42, it failed to have any cell rescuing effect in PrP-/- HpL3-4 cells. These results suggest that LRP/LR plays a significant role in Abeta42-PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer's disease. PMID- 26484915 TI - The Korean Size/Weight Attribute Test: A Semantic Knowledge Test for Korean Older Adults and Brain-Imaging Evidence. AB - BACKGROUND: A standardized tool for evaluating semantic knowledge of the Korean population is needed. OBJECTIVE: The purpose of this study was to develop a neuropsychological test for the evaluation of semantic knowledge in the Korean elderly population. METHODS: The Korean version of the Size/Weight Attribute Test (SWAT-K) was developed in reference to the original version. The diagnostic validity of SWAT-K was evaluated with 95 elderly outpatients [67 normal controls; 18 with Alzheimer's disease (AD); 10 with semantic-variant progressive aphasia (SV-PPA)]. Voxel-based morphometry (VBM) was employed to examine associations between SWAT-K scores and morphological changes of the brain. RESULTS: SWAT-K could discriminate the three subject groups (normal >AD, p < 0.001; AD >SV-PPA, p = 0.040), whereas Boston Naming Test could not distinguish SV-PPA from AD. ROC curve analysis confirmed high levels of sensitivity (0.90) and specificity (0.93) for SWAT-K. The test's inter-rater reliability (ICC = 0.827) and test-retest reliability (ICC = 0.666) were assessed as well. VBM found a significant positive correlation (uncorrected p < 0.005, k > 100) between SWAT-K scores and gray matter volume in right inferior frontal cortex (T = 4.08, k = 191) and bilateral temporal cortices (left, T = 4.42, k = 135; right, T = 3.55, k = 253), the areas the most affected in SV-PPA. CONCLUSIONS: SWAT-K is a sensitive and reliable test for evaluating semantic knowledge in the Korean elderly population. Strong positive correlations between SWAT-K scores and the brain areas responsible for semantic processing further corroborate the validity of SWAT-K. PMID- 26484916 TI - GSK-3beta is Dephosphorylated by PP2A in a Leu309 Methylation-Independent Manner. AB - Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase-3beta (GSK-3beta) and protein phosphate 2A (PP2A) are crucial enzymes to regulate tau phosphorylation. GSK-3beta activity is regulated by its inhibitory phosphorylation at Ser9. We previously reported the cross-talk between GSK-3beta and PP2A signaling and showed that PP2A could dephosphorylate GSK-3beta at Ser9. Here, we investigated the dephosphorylation of GSK-3beta in brain extracts in the presence of phosphatase inhibitors and found that a PP2A-like phosphatase activity was required for dephosphorylation of GSK-3beta at Ser9. PP2A interacted with GSK-3beta and suppressed its Ser9 phosphorylation in vitro and in HEK-293FT cells. Activity of PP2A negatively correlated to the level of phosphorylated GSK 3beta in kainic acid-induced excitotoxic mouse brain. Alteration of methylation of the catalytic subunit of PP2A (PP2Ac) at Leu309 did not affect GSK-3beta phosphorylation. These findings suggest that Leu309 methylation is not required for PP2A to dephosphorylate GSK-3beta at Ser9. PMID- 26484917 TI - Discovery and Subsequent Confirmation of Novel Serum Biomarkers Diagnosing Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD) remains challenging to diagnose, especially early disease. Having serum AD biomarkers would be of significant interest both in the clinical setting and in drug development efforts. OBJECTIVE: We applied a novel serum proteomic approach to interrogate the low-molecular weight proteome for serum AD biomarkers. METHODS: A discovery study used sera from 58 any-stage AD cases and 55 matched controls analyzed by capillary liquid chromatography electrospray ionization-tandem mass spectrometry. Candidate biomarkers were statistically modeled and promising biomarkers were retested in a second, blinded confirmatory study (AD cases = 68, controls = 57). Biomarkers that replicated in the second study were modeled for the diagnosis of any-stage and very early stage AD. Further, they were chemically identified by tandem MS. RESULTS: The initial discovery study found 59 novel potential AD biomarkers. Thirteen recurred in more than one multi-marker panel. In a second, blinded, confirmatory study, these same biomarkers were retested in separate specimens. In that study, four markers validated comparing controls to patients with any-stage AD and also with very early AD. The four biomarkers with replicable ability to diagnose AD were then chemically identified. CONCLUSION: These results suggest novel serum AD diagnostic biomarkers can be found using this approach. PMID- 26484919 TI - Transferring cut-off values between assays for cerebrospinal fluid Alzheimer's disease biomarkers. AB - Current technologies quantifying cerebrospinal fluid biomarkers to identify subjects with Alzheimer's disease pathology report different concentrations in function of technology and suffer from between-laboratory variability. Hence, lab and technology-specific cut-off values are required. It is common practice to establish cut-off values on small datasets and, in the absence of well characterized samples, to transfer the cut-offs to another assay format using 'side-by-side' testing of samples with both assays. We evaluated the uncertainty in cut-off estimation and the performance of two methods of cut-off transfer by using two clinical datasets and simulated data. The cut-off for the new assay was transferred by applying the commonly-used linear regression approach and a new Bayesian method, which consists of using prior information about the current assay for estimation of the biomarker's distributions for the new assay. Simulations show that cut-offs established with current sample sizes are insufficiently precise and also show the effect of increasing sample sizes on the cut-offs' precision. The Bayesian method results in unbiased and less variable cut-offs with substantially narrower 95% confidence intervals compared to the linear-regression transfer. For the BIODEM datasets, the transferred cut-offs for INNO-BIA Abeta1-42 are 167.5 pg/mL (95% credible interval [156.1, 178.0] and 172.8 pg/mL (95% CI [147.6, 179.6]) with Bayesian and linear regression methods, respectively. For the EUROIMMUN assay, the estimated cut-offs are 402.8 pg/mL (95% credible interval [348.0, 473.9]) and 364.4 pg/mL (95% CI [269.7, 426.8]). Sample sizes and statistical methods used to establish and transfer cut-off values have to be carefully considered to guarantee optimal diagnostic performance of biomarkers. PMID- 26484918 TI - Characterizing White Matter Tract Degeneration in Syndromic Variants of Alzheimer's Disease: A Diffusion Tensor Imaging Study. AB - BACKGROUND: Different clinical syndromes can arise from Alzheimer's disease (AD) neuropathology, including dementia of the Alzheimer's type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA). OBJECTIVE: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD. METHODS: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-beta deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups. RESULTS: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum. CONCLUSION: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology. PMID- 26484920 TI - The Oral Iron Chelator, Deferasirox, Reverses the Age-Dependent Alterations in Iron and Amyloid-beta Homeostasis in Rat Brain: Implications in the Therapy of Alzheimer's Disease. AB - The altered metabolism of iron impacts the brain function in multiple deleterious ways during normal aging as well as in Alzheimer's disease. We have shown in this study that chelatable iron accumulates in the aged rat brain along with overexpression of transferrin receptor 1 (TfR1) and ferritin, accompanied by significant alterations in amyloid-beta (Abeta) peptide homeostasis in the aging brain, such as an increased production of the amyloid-beta protein precursor, a decreased level of neprilysin, and increased accumulation of Abeta42. When aged rats are given daily the iron chelator, deferasirox, over a period of more than 4 months starting from the 18th month, the age-related accumulation of iron and overexpression of TfR1 and ferritin in the brain are significantly prevented. More interestingly, the chelator treatment also considerably reverses the altered Abeta peptide metabolism in the aging brain implying a significant role of iron in the latter phenomenon. Further, other results indicate that iron accumulation results in oxidative stress and the activation of NF-kappaB in the aged rat brain, which are also reversed by the deferasirox treatment. The analysis of the results together suggests that iron accumulation and oxidative stress interact at multiple levels that include transcriptional and post-transcriptional mechanisms to bring about changes in the expression levels of TfR1 and ferritin and also alterations in Abeta peptide metabolism in the aging rat brain. The efficacy of deferasirox in preventing age-related changes in iron and Abeta peptide metabolism in the aging brain, as shown here, has obvious therapeutic implications for Alzheimer's disease. PMID- 26484921 TI - Linguistic Features Identify Alzheimer's Disease in Narrative Speech. AB - BACKGROUND: Although memory impairment is the main symptom of Alzheimer's disease (AD), language impairment can be an important marker. Relatively few studies of language in AD quantify the impairments in connected speech using computational techniques. OBJECTIVE: We aim to demonstrate state-of-the-art accuracy in automatically identifying Alzheimer's disease from short narrative samples elicited with a picture description task, and to uncover the salient linguistic factors with a statistical factor analysis. METHODS: Data are derived from the DementiaBank corpus, from which 167 patients diagnosed with "possible" or "probable" AD provide 240 narrative samples, and 97 controls provide an additional 233. We compute a number of linguistic variables from the transcripts, and acoustic variables from the associated audio files, and use these variables to train a machine learning classifier to distinguish between participants with AD and healthy controls. To examine the degree of heterogeneity of linguistic impairments in AD, we follow an exploratory factor analysis on these measures of speech and language with an oblique promax rotation, and provide interpretation for the resulting factors. RESULTS: We obtain state-of-the-art classification accuracies of over 81% in distinguishing individuals with AD from those without based on short samples of their language on a picture description task. Four clear factors emerge: semantic impairment, acoustic abnormality, syntactic impairment, and information impairment. CONCLUSION: Modern machine learning and linguistic analysis will be increasingly useful in assessment and clustering of suspected AD. PMID- 26484922 TI - Cerebrospinal Fluid Fatty Acid-Binding Protein 3 is Related to Dementia Development in a Population-Based Sample of Older Adult Women Followed for 8 Years. AB - BACKGROUND: Increased fatty acid-binding protein 3 (FABP-3) levels have been reported in neurodegenerative diseases, including Alzheimer's disease (AD). Cerebrospinal fluid (CSF) FABP-3 has therefore been proposed as a putative marker for dementia. Population-based studies examining whether CSF FABP-3 predicts later development of dementia are lacking. OBJECTIVE: The aim of this study was to examine CSF levels of FABP-3 in relation to later development of dementia in elderly women and in relation to Abeta42, T-tau, P-tau181, and CSF: serum albumin ratio. METHODS: 86 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-93. CSF-FABP-3, Abeta42, T-tau, P-tau181, and the CSF: serum albumin ratio were measured at baseline. Participants were examined with a neuropsychiatric exam at baseline and at follow-up in 2000. Dementia was diagnosed in accordance with DSM-III-R criteria. RESULTS: Between 1992 and 2000, 8 women developed dementia (4 AD, 3 vascular dementia, 1 mixed vascular dementia and AD). Higher levels of CSF-FABP-3 at baseline were related to development of dementia (OR 1.36 CI [1.05-1.76] p = 0.022) and the subtype AD (OR 1.38 CI [1.06 1.82), p = 0.019) during follow-up. FABP-3 correlated with CSF T-tau (r = 0.88, p < 0.001), P-tau181 (r = 0.619, p < 0.001), and CSF:serum albumin ratio (r = 0.233, p = 0.031), but not with Abeta42 (r = -0.08, p = 0.444)CONCLUSION:CSF FABP 3 may be an early marker for later development of dementia, probably related to neuronal degeneration, but independent of Abeta metabolism. PMID- 26484923 TI - Unstable Body Mass Index and Progression to Probable Alzheimer's Disease Dementia in Patients with Amnestic Mild Cognitive Impairment. AB - BACKGROUND AND OBJECTIVE: We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients. METHODS: The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0-2.3 years), and risk of progression to probable Alzheimer's disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value. RESULTS: Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07-3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49-0.999). After controllingfor baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41-3.72) and increased BMI (HR: 3.96, 95% CI: 2.62-6.00) groups were at increased risk of progression to pADD. CONCLUSIONS: Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline. PMID- 26484925 TI - Sensitivity of Neuropsychological Tests to Identify Cognitive Decline in Highly Educated Elderly Individuals: 12 Months Follow up. AB - Highly educated individuals have a lower risk of developing dementia and Alzheimer's disease (AD). A common assumption is that their "cognitive reserve" protects them from cognitive decline and postpones the clinical manifestation of dementia. These highly educated individuals usually obtain normal scores on cognitive screening tests, although at the same time they can experience subjective cognitive decline and difficulty in multiple cognitive domains. Although comprehensive neuropsychological evaluations usually identify subtle changes in cognition, they demand extensive resources and thus are expensive and difficult to obtain. Therefore, lack of sensitivity of screening tests on the one hand, along with difficulty to acquire a comprehensive neuropsychological evaluation on the other hand, impede identification of cognitive decline at its earliest stages in this special population. Accordingly, this study aims to identify which neuropsychological tests have the highest sensitivity to detect the earliest stages of cognitive decline among highly educated elderly [n = 27, ages 66-80 (mean = 72.6 SD = 4.54), mean education level = 17.14 (SD = 3.21 range: 12-24 years)]. Baseline scores and scores at one-year follow up were obtained. We also conducted MRI scans to characterize the relation between brain volume and cognitive performance. Results show significant reductions in RVALT, Semantic verbal Fluency, ROCF copy, and MoCA scores whereas PF, TMT, ROCF delay, digit span, and knowledge tests were not significant. The study stresses the importance of using sensitive neuropsychological tests to examine this special population and the need to create norms that combine an individual's education with age. PMID- 26484924 TI - Quantitative Neuroimaging Software for Clinical Assessment of Hippocampal Volumes on MR Imaging. AB - BACKGROUND: Multiple neurological disorders including Alzheimer's disease (AD), mesial temporal sclerosis, and mild traumatic brain injury manifest with volume loss on brain MRI. Subtle volume loss is particularly seen early in AD. While prior research has demonstrated the value of this additional information from quantitative neuroimaging, very few applications have been approved for clinical use. Here we describe a US FDA cleared software program, NeuroreaderTM, for assessment of clinical hippocampal volume on brain MRI. OBJECTIVE: To present the validation of hippocampal volumetrics on a clinical software program. METHOD: Subjects were drawn (n = 99) from the Alzheimer Disease Neuroimaging Initiative study. Volumetric brain MR imaging was acquired in both 1.5 T (n = 59) and 3.0 T (n = 40) scanners in participants with manual hippocampal segmentation. Fully automated hippocampal segmentation and measurement was done using a multiple atlas approach. The Dice Similarity Coefficient (DSC) measured the level of spatial overlap between NeuroreaderTM and gold standard manual segmentation from 0 to 1 with 0 denoting no overlap and 1 representing complete agreement. DSC comparisons between 1.5 T and 3.0 T scanners were done using standard independent samples T-tests. RESULTS: In the bilateral hippocampus, mean DSC was 0.87 with a range of 0.78-0.91 (right hippocampus) and 0.76-0.91 (left hippocampus). Automated segmentation agreement with manual segmentation was essentially equivalent at 1.5 T (DSC = 0.879) versus 3.0 T (DSC = 0.872). CONCLUSION: This work provides a description and validation of a software program that can be applied in measuring hippocampal volume, a biomarker that is frequently abnormal in AD and other neurological disorders. PMID- 26484926 TI - Effect of Early Referral to Specialist in Dementia on Institutionalization and Functional Decline: Findings from a Population-Based Study. AB - BACKGROUND: Although early diagnosis has been hypothesized to benefit both patients and caregivers, until now studies evaluating the effect of early dementia diagnosis are lacking. OBJECTIVE: To investigate the influence of early specialist referral for dementia on the risk of institutionalization and functional decline in Activity of Daily Living (ADL). METHODS: Incident dementia cases were screened in a prospective population-based cohort, the Three-City Study, and initial specialist consultation for cognitive complaint was assessed at dementia diagnosis. Proportional hazard regression and illness-death models were used to test the association between specialist referral and, respectively, institutionalization and functional decline. RESULTS: Only one third of the incident individuals with dementia had consulted a specialist for cognitive problems early (36%). After adjustment on potential confounders (including cognitive and functional decline) and competing risk of death, participants who had consulted a specialist early in the disease course presented a higher rate of being institutionalized than those who did not (Hazard Ratio = 2.00, 95% Confidence Interval (CI): 1.09- 3.64). But early specialist referral was not associated with further functional decline (HR = 1.09, 95% CI: 0.71- 1.67). CONCLUSIONS: Early specialist referral in dementia is associated with increased risk of institutionalization but not with functional decline in ADL. These findings suggest that early care referral in dementia may be a marker of concern for patients and/or caregivers; subsequent medical and social care could be suboptimal or inappropriate to allow patients to stay longer at home. PMID- 26484928 TI - Circulating microRNAs as Biomarkers of Alzheimer's Disease: A Systematic Review. AB - BACKGROUND: In recent years, microRNAs (miRNA), a class of non-coding RNA known to regulate protein expression post-transcriptionally, have been recognized as novel biomarkers of diseases. OBJECTIVE: In this systematic review, we identify miRNAs that are differentially expressed in Alzheimer's disease (AD) and/or mild cognitive impairment (MCI) and evaluate their accuracy as potential blood biomarkers. METHODS: Eligible studies of miRNAs in peripheral blood distinguishing patients with AD or MCI from cognitively normal controls were identified through standardized search strategies in Medline, PubMed, and Embase. MiRNAs that were differentially expressed were identified and where available their sensitivity and specificity for AD or MCI extracted from the retrieved studies. RESULTS: Eighteen studies investigated the diagnostic value of miRNAs as peripheral biomarkers of AD/MCI. Twenty miRNAs were significantly upregulated and 32 miRNAs downregulated in AD compared to controls in ten AD studies. Nine miRNAs were consistently dysregulated in more than one study. Of the 8 MCI studies, only one miRNA, miR-132, was consistently upregulated in three independent studies. Of the studies that reported diagnostic accuracy data, the majority of miRNA panels and individual miRNAs had a sensitivity and specificity greater than 0.75. CONCLUSION: Individual studies suggest that miRNAs can differentiate patients with AD/MCI from cognitively normal controls with modest accuracy. However, the literature is constrained by methodological differences between studies, with few studies assessing the same miRNAs. To become potential biomarkers for AD, further studies with standardized study designs for replication and validation are required. Results from this review may help researchers select candidate miRNAs for further investigation. PMID- 26484927 TI - Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease. AB - Alzheimer's disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid beta, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer's disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid beta elevation. However, molecules currently available as effective calpain inhibitors lack adequate selectivity. This work is aimed at characterizing the efficacy of a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against the disease. PMID- 26484929 TI - Divergent Longitudinal Propagation of White Matter Degradation in Logopenic and Semantic Variants of Primary Progressive Aphasia. AB - BACKGROUND: Clinico-pathological distinction of primary progressive aphasia (PPA) can be challenging at clinic presentation. In particular, cross-sectional neuroimaging signatures across the logopenic (lvPPA) and semantic (svPPA) variants are difficult to establish, with longitudinal profiles showing greater divergence. OBJECTIVE: Assess longitudinal propagation of white matter degradation in lvPPA and svPPA to determine disease progression over time, and whether this reflects distinct underlying pathology. METHOD: A cohort of 27 patients with dementia (12 lvPPA; 15 svPPA) and 12 healthy controls were assessed at baseline and 1-year follow-up on the Addenbrooke's Cognitive Examination Revised and Sydney Language Battery. Diffusion weighted images were collected at both time-points and analyzed for longitudinal white matter change using DTI-TK and TBSS. RESULTS: LvPPA patients showed a significant decline in naming and repetition, over 1 year, while svPPA patients declined in naming and comprehension. Longitudinal imaging revealed widespread bilateral degradation of white matter tracts in lvPPA over a 1-year period with early involvement of the left posterior inferior longitudinal fasciculus (ILF). SvPPA demonstrated focal left lateralized white matter degradation involving the uncinate fasciculus (UF) and anterior ILF, propagating to the right UF with disease progression. CONCLUSIONS: LvPPA and svPPA cohorts showed distinct longitudinal cognitive and white matter profiles. We propose differences in multi-centric and focal white matter dysfunction in lvPPA and svPPA, respectively, reflect underlying pathological differences. The clinical relevance of white matter degradation and mechanisms underlying disease propagation are discussed. PMID- 26484930 TI - The Incidence of Benzodiazepine and Related Drug Use in Persons with and without Alzheimer's Disease. AB - BACKGROUND: Benzodiazepines and related drugs (BZDR) are occasionally used to treat certain symptoms of Alzheimer's disease (AD). However, the risks related to BZDR use are high in older persons. Although frequent BZDR use has been reported in persons with AD, no previous study has focused specifically on the incidence of BZDR use in this population. OBJECTIVE: We investigated the incidence of BZDR use in persons with and without AD during a five-year follow-up. METHODS: The Finnish nationwide, register-based MEDALZ cohort includes all AD cases who received a clinically verified AD diagnosis in 2005-2011 (n = 70,718) and their matched comparison persons. Incidence of BZDR, including benzodiazepines (lorazepam, oxazepam, temazepam, alprazolam, chlordiazepoxide, diazepam, and nitrazepam) and Z-drugs (zolpidem and zopiclone), use was investigated in the cohort from two years before to three years after the diagnosis of AD. Further, initial BZDRs were investigated. RESULTS: The incidence of BZDR use was higher in persons with AD starting from 12 months before the diagnosis and peaked at six months after the diagnosis of AD (incidence rate ratio [IRR] = 2.6, 95% confidence interval [CI] = 2.5-2.8). Benzodiazepines were more frequently initiated by persons with AD, with the incidence peaking at six months after the diagnosis (IRR = 4.5, 95% CI = 4.1-4.9) and remaining over three times higher than in comparison persons until three years after the diagnosis. CONCLUSION: Early symptomatic treatment with BZDRs is contrary to AD treatment guidelines. As BZDRs impair cognition, the observed early treatment with BZDRs may complicate the monitoring of AD treatment effectiveness. PMID- 26484932 TI - Use of telbivudine in kidney transplant recipients with chronic hepatitis B virus infection: A preliminary experience. AB - Telbivudine is a relatively novel oral nucleoside analogue with favourable efficacy and tolerability in treatment-naive chronic hepatitis B virus (HBV) infection, but its data in kidney transplant recipients (KTRs) was lacking. The efficacy and tolerability of telbivudine in four treatment-naive HBsAg-positive KTRs were reviewed (treatment duration 54 (36-72) months) HBV DNA declined from 2.6 * 10(5) (7.8 * 10(3) -1.5 * 10(7) ) copies/mL at baseline to 170 (0.0-3.2 * 10(4) ) copies/mL at 12 months, and became undetectable at 24 and 36 months (P = 0.060, 0.118 and 0.005 compared with baseline). Alanine aminotransferase levels dropped from 46.5 (30-48) IU/mL at baseline to 28 (13-45) IU/mL, 34.5 (15-71) IU/mL and 26 (12-41) IU/mL at 12, 24 and 36 months, respectively (P = 0.109, 0.715 and 0.068 compared with baseline). Serum creatinine level and estimated glomerular filtration rate (eGFR) remained stable after 36 months of treatment (P all > 0.05 compared with baseline). No virological breakthrough, cirrhosis or hepatocellular carcinoma occurred. Our pilot data suggests that telbivudine has favourable efficacy and renal safety profiles in HBsAg-positive KTRs. PMID- 26484931 TI - Timely Diagnosis for Alzheimer's Disease: A Literature Review on Benefits and Challenges. AB - BACKGROUND: Timely diagnosis of Alzheimer's disease (AD) refers to a diagnosis at the stage when patients come to the attention of clinicians because of concerns about changes in cognition, behavior, or functioning and can be still free of dementia and functionally independent. OBJECTIVES: To comprehensively review existing scientific evidence on the benefits and potential challenges of making a timely diagnosis of AD. METHODS: Relevant studies were identified by searching electronic databases (Medline, Embase) and bibliographies for studies published in English between 1 January 2000 and 2 June 2014 on the consequences of a timely diagnosis of AD. RESULTS: Nine studies were identified that investigated the consequences of diagnosing AD at the initial stages; none were specifically focused on prodromal AD. A timely diagnosis potentially offers the opportunities of early intervention, implementation of coordinated care plans, better management of symptoms, patient safety, cost savings, and postponement of institutionalization. Barriers to making a timely diagnosis include stigma, suicide risk, lack of training, diagnostic uncertainty, shortage of specialized diagnostic services, and the reluctance of healthcare providers to make a diagnosis when no effective disease-modifying options are available. CONCLUSIONS: Despite its potential benefits, few published studies have explored the advantages or risks of a timely diagnosis of AD. In light of the cultural shift toward diagnosis at the initial stage of the disease continuum, when the patient does not yet have dementia, more investigations are needed to evaluate the benefits and address the barriers that may impede making a timely AD diagnosis. PMID- 26484933 TI - Corrigendum: Decoupling the role of stiffness from other hydroxyapatite signalling cues in periosteal derived stem cell differentiation. PMID- 26484935 TI - Organics Substantially Reduce HO2 Uptake onto Aerosols Containing Transition Metal ions. AB - A HO2 mass accommodation coefficient of alpha = 0.23 +/- 0.07 was measured onto submicron copper(II)-doped ammonium sulfate aerosols at a relative humidity of 60 +/- 3%, at 293 +/- 2 K and at an initial HO2 concentration of ~ 1 * 10(9) molecules cm(-3) by using an aerosol flow tube coupled to a sensitive fluorescence assay by gas expansion (FAGE) HO2 detection system. The effect upon the HO2 uptake coefficient gamma of adding different organic species (malonic acid, citric acid, 1,2-diaminoethane, tartronic acid, ethylenediaminetetraacetic acid (EDTA), and oxalic acid) into the copper(II)-doped aerosols was investigated. The HO2 uptake coefficient decreased steadily from the mass accommodation value to gamma = 0.008 +/- 0.009 when EDTA was added in a one-to one molar ratio with the copper(II) ions, and to gamma = 0.003 +/- 0.004 when oxalic acid was added into the aerosol in a ten-to-one molar ratio with the copper(II). EDTA binds strongly to copper(II) ions, potentially making them unavailable for catalytic destruction of HO2, and could also be acting as a surfactant or changing the viscosity of the aerosol. The addition of oxalic acid to the aerosol potentially forms low-volatility copper-oxalate complexes that reduce the uptake of HO2 either by changing the viscosity of the aerosol or by causing precipitation out of the aerosol forming a coating. It is likely that there is a high enough oxalate to copper(II) ion ratio in many types of atmospheric aerosols to decrease the HO2 uptake coefficient. No observable change in the HO2 uptake coefficient was measured when the other organic species (malonic acid, citric acid, 1,2-diaminoethane, and tartronic acid) were added in a ten-to-one molar ratio with the copper(II) ions. PMID- 26484934 TI - Critical role of Rab11a-mediated recycling endosomes in the assembly of type I parainfluenza viruses. AB - Paramyxoviruses replicate in the cytoplasm of infected cells and newly synthesized viral nucleocapsids (vRNPs) are transported to the plasma membrane to be incorporated into progeny virions. In this study, we analyzed the impact of the Rab11-mediated recycling pathway in Sendai virus (SeV) and human parainfluenza virus type 1 (hPIV1) vRNP transport. We found that suppression of Rab11 expression caused vRNP aggregation in the cytoplasm and reduced progeny virion formation. Overexpression of constitutively active Rab11Q70L, but not dominant negative Rab11S25N co-localized with vRNP, showing that vRNP specifically recognizes the GTP-bound active form of Rab11. Moreover, Rab11Q70L co-localized with the dominant negative tails of all three subtypes of myosins, Va, Vb, and Vc, while SeV and hPIV1 vRNPs co-localized with only myosin Vb and Vc. These results highlight the critical role of Rab11 in vRNP trafficking, and suggest a specificity in the recycling endosomes parainfluenza viruses utilize for virus assembly. PMID- 26484936 TI - Enhanced Wettability and Transport Control of Ultrafiltration and Reverse Osmosis Membranes with Grafted Polyelectrolytes. AB - End-functionalized poly(acrylic acid) (PAA-silane) was synthesized with reversible addition-fragmentation chain-transfer (RAFT) polymerization and attached to both polysulfone ultrafiltration (UF) and polyamide reverse osmosis (RO) membranes through a nonimpairing, one-step grafting to approach in order to improve membrane surface wettability with minimal impact on membrane transport performance. After PAA grafting, composition and morphology changes on the membrane surface were characterized with Fourier transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM). Static contact angle on PAA grafted membranes exhibited an increase in surface hydrophilicity and hence a potential enhancement in antifouling performance. The native contact angle on the polysulfone membrane systems was 86 degrees and was reduced to 24 degrees after modification, while the polyamide film contact angle decreased from 58 degrees to 25 degrees . The PAA layer endowed the porous UF membrane with dynamic control over the permeability and selectivity through the manipulation of the solution pH. The UF membrane with a 35 nm average pore size displayed a 115% increase in flux when the contact solution was changed from pH 11 to pH 3. This effect was diminished to 70% and 32% as the average pore size decreased to 20 and 10 nm, respectively. Modified RO membranes displayed no reduction in membrane performance indicating that the underlying materials were unaffected by the modification environment or added polymer. Model polyamide and polysulfone surfaces were reacted with the PAA-silane inside a quartz crystal microbalance (QCM) to help inform the deposition behavior for the respective membrane chemistries. PMID- 26484937 TI - Relationship between Targeting Efficacy of Liposomes and the Dosage of Targeting Antibody Using Surface Plasmon Resonance. AB - Surface plasmon resonance (SPR) was used in this research to investigate the targeting efficacy (i.e., the binding affinity) of antibody-modified liposomes. The results indicated that liposomes modified by targeting antibodies exhibited an increase in apparent binding affinity, a result attributed to the avidity effect. More specifically, the targeting effect improved as the surface density of the targeting antibody increased, an increase primarily attributed to the decrease of the dissociation rate. However, this trend stopped when the surface density reached a threshold of approximately 1.5 * 10(8) antibody/mm(2). This surface density was found to be quite consistent regardless of the liposome size and the type of targeting antibody. In addition, a traditional cell binding experiment was conducted to confirm the saturation point obtained from SPR. PMID- 26484938 TI - Natural history and management of Fanconi anemia patients with head and neck cancer: A 10-year follow-up. AB - OBJECTIVES/HYPOTHESIS: To describe the management and outcomes of Fanconi anemia (FA) patients with head and neck squamous cell carcinoma. STUDY DESIGN: Cohort study. METHODS: Demographic information, prognostic factors, therapeutic management, and survival outcomes for FA patients enrolled in the International Fanconi Anemia Registry who developed head and neck squamous cell carcinoma (HNSCC) were analyzed. RESULTS: Thirty-five FA patients were diagnosed with HNSCC at a mean age of 32 years. The most common site of primary cancer was the oral cavity (26 of 35, 74%). Thirty patients underwent surgical resection of the cancer. Sixteen patients received radiation therapy with an average radiation dose of 5,050 cGy. The most common toxicities were high-grade mucositis (9 of 16, 56%), hematologic abnormalities (8 of 16, 50%), and dysphagia (8 of 16, 50%). Three patients received conventional chemotherapy and had significant complications, whereas three patients who received targeted chemotherapy with cetuximab had fewer toxicities. The 5-year overall survival rate was 39%, with a cause-specific survival rate of 47%. CONCLUSIONS: Fanconi anemia patients have a high risk of developing aggressive HNSCC at an early age. Fanconi anemia patients can tolerate complex ablative and reconstructive surgeries, but careful postoperative care is required to reduce morbidity. The treatment of FA associated HNSCC is difficult secondary to the poor tolerance of radiation and chemotherapy. However, radiation should be used for high-risk cancers due to the poor survival in these patients. LEVEL OF EVIDENCE: 4. PMID- 26484939 TI - New Insights into the Disease Progression Control Mechanisms by Comparing Long Term-Nonprogressors versus Normal-Progressors among HIV-1-Positive Patients Using an Ion Current-Based MS1 Proteomic Profiling. AB - For decades, epidemiological studies have found significant differences in the susceptibility to disease progression among HIV-carrying patients. One unique group of HIV-1-positive patients, the long-term-nonprogressors (LTNP), exhibits far superior ability in virus control compared with normal-progressors (NP), which proceed to Acquired Immune Deficiency Syndrome (AIDS) much more rapidly. Nonetheless, elucidation of the underlying mechanisms of virus control in LTNP is highly valuable in disease management and treatment but remains poorly understood. Peripheral blood mononuclear cells (PBMC) have been known to play important roles in innate immune responses and thereby would be of great interest for the investigation of the mechanisms of virus defense in LTNP. Here, we described the first comparative proteome analysis of PBMC from LTNP (n = 10) and NP (n = 10) patients using a reproducible ion-current-based MS1 approach, which includes efficient and reproducible sample preparation and chromatographic separation followed by an optimized pipeline for protein identification and quantification. This strategy enables analysis of many biological samples in one set with high quantitative precision and extremely low missing data. In total, 925 unique proteins were quantified under stringent criteria without missing value in any of the 20 subjects, and 87 proteins showed altered expressions between the two patient groups. These proteins are implicated in key processes such as cytoskeleton organization, defense response, apoptosis regulation, intracellular transport, etc., which provided novel insights into the control of disease progressions in LTNP versus NP, and the expression and phosphorylation states of key regulators were further validated by immunoassay. For instance, (1) SAMH1, a potent and "hot" molecule facilitating HIV-1 defense, was for the first time found elevated in LTNP compared with NP or healthy controls; elevated proteins from IFN-alpha response pathway may also contribute to viral control in LTNP; (2) decreased proapoptotic protein ASC along with the elevation of antiapoptotic proteins may contribute to the less apoptotic profile in PBMC of LTNP; and (3) elevated actin polymerization and less microtubule assembly that impede viral protein transport were first observed in LTNP. These results not only enhanced the understanding of the mechanisms for nonprogression of LTNP, but also may afford highly valuable clues to direct therapeutic efforts. Moreover, this work also demonstrated the ion-current-based MS1 approach as a reliable tool for large-scale clinical research. PMID- 26484940 TI - Ebola in West Africa--CDC's Role in Epidemic Detection, Control, and Prevention. AB - Since Ebola virus disease was identified in West Africa on March 23, 2014, the Centers for Disease Control and Prevention (CDC) has undertaken the most intensive response in the agency's history; >3,000 staff have been involved, including >1,200 deployed to West Africa for >50,000 person workdays. Efforts have included supporting incident management systems in affected countries; mobilizing partners; and strengthening laboratory, epidemiology, contact investigation, health care infection control, communication, and border screening in West Africa, Nigeria, Mali, Senegal, and the United States. All efforts were undertaken as part of national and global response activities with many partner organizations. CDC was able to support community, national, and international health and public health staff to prevent an even worse event. The Ebola virus disease epidemic highlights the need to strengthen national and international systems to detect, respond to, and prevent the spread of future health threats. PMID- 26484941 TI - Deformation Twinning of a Silver Nanocrystal under High Pressure. AB - Within a high-pressure environment, crystal deformation is controlled by complex processes such as dislocation motion, twinning, and phase transitions, which change materials' microscopic morphology and alter their properties. Understanding a crystal's response to external stress provides a unique opportunity for rational tailoring of its functionalities. It is very challenging to track the strain evolution and physical deformation from a single nanoscale crystal under high-pressure stress. Here, we report an in situ three-dimensional mapping of morphology and strain evolutions in a single-crystal silver nanocube within a high-pressure environment using the Bragg Coherent Diffractive Imaging (CDI) method. We observed a continuous lattice distortion, followed by a deformation twining process at a constant pressure. The ability to visualize stress-introduced deformation of nanocrystals with high spatial resolution and prominent strain sensitivity provides an important route for interpreting and engineering novel properties of nanomaterials. PMID- 26484942 TI - The bladed Bangiales (Rhodophyta) of the South Eastern Pacific: Molecular species delimitation reveals extensive diversity. AB - A molecular taxonomic study of the bladed Bangiales of the South Eastern Pacific (coast of Chile) was undertaken based on sequence data of the mitochondrial COI and chloroplast rbcL for 193 specimens collected from Arica (18 degrees S) in the north to South Patagonia (53 degrees S) in the south. The results revealed for the first time that four genera, Porphyra, Pyropia, Fuscifolium and Wildemania were present in the region. Species delimitation was determined based on a combination of a General Mixed Yule Coalescence model (GMYC) and Automatic Barcode Gap Discovery (ABGD) coupled with detection of monophyly in tree reconstruction. The overall incongruence between the species delimitation methods within each gene was 29%. The GMYC method led to over-splitting groups, whereas the ABGD method had a tendency to lump groups. Taking a conservative approach to the number of putative species, at least 18 were recognized and, with the exception of the recently described Pyropia orbicularis, all were new to the Chilean flora. Porphyra and Pyropia were the most diverse genera with eight 'species' each, whereas only a 'single' species each was found for Fuscifolium and Wildemania. There was also evidence of recently diverging groups: Wildemania sp. was distinct but very closely related to W. amplissima from the Northern Hemisphere and raises questions in relation to such disjunct distributions. Pyropia orbicularis was very closely related to two other species, making species delimitation very difficult but provides evidence of an incipient speciation. The difference between the 'species' discovered and those previously reported for the region is discussed in relation to the difficulty of distinguishing species based on morphological identification. PMID- 26484943 TI - Improved Learning Performance of Hardware Self-Organizing Map Using a Novel Neighborhood Function. AB - Many self-organizing maps (SOMs) implemented on hardware restrict their neighborhood function values to negative powers of two. In this paper, we propose a novel hardware friendly neighborhood function that is aimed to improve the vector quantization performance of hardware SOM. The quantization performance of the hardware SOM with the proposed neighborhood function is examined by simulations. Simulation results show that the proposed function can improve the hardware SOM's vector quantization capability even though the function value is restricted to negative powers of two. Then, the hardware SOM is implemented on field-programmable gate array to find out the hardware cost and performance speed of the proposed neighborhood function. Experimental results show that the proposed neighborhood function can improve SOM's quantization performance without additional hardware cost or slowing down the operating speed. Due to fully parallel operation, the proposed SOM with 16*16 neurons achieves a performance of 25 344 million connections updates per second. PMID- 26484944 TI - Novel Types of Small RNA Exhibit Sequence- and Target-dependent Angiogenesis Suppression Without Activation of Toll-like Receptor 3 in an Age-related Macular Degeneration (AMD) Mouse Model. AB - RNA interference (RNAi) has become a powerful tool for suppressing gene expression in vitro and in vivo. A great deal of evidence has demonstrated the potential for the use of synthetic small interfering RNAs (siRNAs) as therapeutic agents. However, the application of siRNA to clinical medicine is still limited, mainly due to sequence-independent suppression of angiogenesis mediated by Toll like receptor 3 (TLR3). Here, we describe novel types of synthetic RNA, named nkRNA and PnkRNA, that exhibit sequence-specific gene silencing through RNAi without activating TLRs or RIG-I-like receptor signaling. In addition, we confirmed the therapeutic effect for the novel types of RNA in an animal model of age-related macular degeneration (AMD) without retinal degeneration. These data indicate that nkRNA and PnkRNA are of great potential utility as therapies against blinding choroidal neovascularization due to AMD. PMID- 26484946 TI - When the science fails and the ethics works: 'Fail-safe' ethics in the FEM-PrEP study. AB - This paper will explore the concept of 'fail safe' ethics in the FEM PrEP trial, and the practice of research and ethics on the ground. FEM-PrEP examined the efficacy of PrEP in African women after promising outcomes in research conducted with MSM. This was a hugely optimistic time and FEM-PrEP was mobilised using rights-based ethical arguments that women should have access to PrEP. This paper will present data collected during an ethnographic study of frontline research workers involved in FEM-PrEP. During our discussions, 'fail-safe' ethics emerged as concept that encapsulated their confidence that their ethics could not fail. However, in 2011, FEM-PrEP was halted and deemed a failure. The women involved in the study were held responsible because contrary to researcher's expectations they were not taking the oral PrEP being researched. This examination of FEM-PrEP will show that ethical arguments are increasingly deployed to mobilise, maintain and in some cases stop trials in ways which, at times, are superseded or co-opted by other interests. While promoting the interests of women, rights-based approaches are argued to indirectly justify the continuation of individualised, biomedical interventions which have been problematic in other women-centred trials. In this examination of FEM-PrEP, the rights-based approach obscured: ethical concerns beyond access to PrEP; the complexities of power relationships between donor and host countries; the operations of the HIV industry in research saturated areas and the cumulative effect of unfilled expectations in HIV research and how this has shaped ideas of research and ethics. PMID- 26484945 TI - Modulation of GABA release from the thalamic reticular nucleus by cocaine and caffeine: role of serotonin receptors. AB - Serotonin receptors are targets of drug therapies for a variety of neuropsychiatric and neurodegenerative disorders. Cocaine inhibits the re-uptake of serotonin (5-HT), dopamine, and noradrenaline, whereas caffeine blocks adenosine receptors and opens ryanodine receptors in the endoplasmic reticulum. We studied how 5-HT and adenosine affected spontaneous GABAergic transmission from thalamic reticular nucleus. We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) in ventrobasal thalamic neurons during local (puff) application of 5-HT in wild type (WT) or knockout mice lacking 5-HT2A receptors (5-HT2A -/-). Inhibition of mIPSCs frequency by low (10 MUM) and high (100 MUM) 5-HT concentrations was observed in ventrobasal neurons from 5-HT2A -/- mice. In WT mice, only 100 MUM 5-HT significantly reduced mIPSCs frequency. In 5-HT2A -/- mice, NAN-190, a specific 5-HT1A antagonist, prevented the 100 MUM 5-HT inhibition while blocking H-currents that prolonged inhibition during post-puff periods. The inhibitory effects of 100 MUM 5-HT were enhanced in cocaine binge-treated 5-HT2A -/- mice. Caffeine binge treatment did not affect 5-HT-mediated inhibition. Our findings suggest that both 5-HT1A and 5 HT2A receptors are present in pre-synaptic thalamic reticular nucleus terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine. Our findings suggest that both 5-HT1A , 5-HT2A and A1 receptors are present in pre synaptic TRN terminals. 5-HT1A and A1 receptors would down-regulate adenylate cyclase, whereas 5-HT1A would also increase the probability of the opening of G protein-activated inwardly rectifying K(+) channels (GIRK). Sustained opening of GIRK channels would hyperpolarize pre-synaptic terminals activating H-currents, resulting in less GABA release. 5-HT2A -would activate PLC and IP3 , increasing intracellular [Ca(2+) ] and thus facilitating GABA release. PMID- 26484948 TI - New Ways of Working in UK mental health services: developing distributed responsibility in community mental health teams? AB - BACKGROUND: This paper examines the introduction and operation of a number of support roles in mental health services. This is done in the context of concerns about the effectiveness of CMHTs. AIMS: Three questions are addressed: the degree to which concern for the work of consultant psychiatrists informed the introduction of the new roles; what the reforms implied for the work of the psychiatrist and those in new roles; and the impact of any changes on the operation of CMHTs. METHOD: Data were collected as part of a national-level evaluation. The main means of collection was the semi-structured interview. RESULTS: The study shows: that reform was underpinned by concerns about the workload of psychiatrists; and that while in principle the responsibilities of the psychiatrist were to be distributed across other team members, those in new roles felt themselves to be isolated. CONCLUSIONS: Despite the intentions of policy, the creation of the new roles did little to extend the idea of distributed responsibility in CMHTs. PMID- 26484949 TI - Na4MgM2Se6 (M = Si, Ge): The First Noncentrosymmetric Compounds with Special Ethane-like [M2Se6](6-) Units Exhibiting Large Laser-Damage Thresholds. AB - Two new noncentrosymmetric compounds, Na4MgM2Se6 (I, M = Si; II, M = Ge), that contain special ethane-like [M2Se6](6-) units were reported for the first time. Remarkably, they exhibit high laser-damage thresholds [9 (I) and 7 (II) * benchmark AgGaS2] and moderate second-harmonic-generation responses with type I phase matching. PMID- 26484950 TI - Deceased Donor Intervention Research: A Survey of Transplant Surgeons, Organ Procurement Professionals, and Institutional Review Board Members. AB - Innovative deceased donor intervention strategies have the potential to increase the number and quality of transplantable organs. Yet there is confusion over regulatory and legal requirements, as well as ethical considerations. We surveyed transplant surgeons (n = 294), organ procurement organization (OPO) professionals (n = 83), and institutional review board (IRB) members (n = 317) and found wide variations in their perceptions about research classification, risk assessment for donors and organ transplant recipients, regulatory oversight requirements, and informed consent in the context of deceased donor intervention research. For instance, when presented with different research scenarios, IRB members were more likely than transplant surgeons and OPO professionals to feel that study review and oversight were necessary by the IRBs at the investigator, donor, and transplant center hospitals. Survey findings underscore the need to clarify ethical, legal, and regulatory requirements and their application to deceased donor intervention research to accelerate the pace of scientific discovery and facilitate more transplants. PMID- 26484951 TI - Ventilation Increases with Lower Extremity Venous Occlusion in Young Adults. AB - INTRODUCTION: Venous distention via subsystolic occlusion of the lower limbs may augment ventilation via stimulation of group III/IV afferent neurons. PURPOSE: The purpose of this study was to examine the ventilatory response to graded lower extremity venous occlusion during exercise in healthy adults. METHODS: Nineteen adults (9 men, 25 +/- 5 yr) completed two visits. Visit 1 included a maximal cycle ergometry exercise test. Visit 2 included a 30% peak workload cycle exercise with randomized inflations of bilateral thigh pressure tourniquets to 20, 40, 60, 80, and 100 mm Hg for 2 min each, separated by 2 min of deflation. Three minutes of cycling occurred before cuffing (control [CTL]). Expired minute ventilation (VE), whole body gas exchange, rating of perceived exertion, and dyspnea were measured during each session. RESULTS: VE increased significantly from the control condition (exercise only, CTL) to each occlusion pressure (P < 0.05) with the greatest increase at 100 mm Hg (CTL to 100 mm Hg: 31.5 +/- 6.6 to 40.1 +/- 10.7 L.min). Respiratory rate (RR) increased as well (CTL to 100 mm Hg: 24.8 +/- 6.0 to 30.9 +/- 11.5 breaths per minute, P < 0.05, condition effect) with no change in tidal volume (P > 0.05). Tidal volume to inspiratory time (VT/TI) increased significantly from the CTL condition to each occlusion pressure (CTL to 100 mm Hg: 1.5 +/- 0.3 to 1.8 +/- 0.4 L.min, P < 0.05, all pressures). Dyspnea and RPE increased with all occlusion pressures from CTL exercise (P < 0.05, all pressures). CONCLUSIONS: Our findings suggest that mild-to-moderate venous occlusion of the lower extremity evokes a tachypneic breathing pattern which, in turn, augments VE and perceived breathing effort during exercise. PMID- 26484952 TI - Low-Active Male Adolescents: A Dose Response to High-Intensity Interval Training. AB - PURPOSE: High-intensity interval training (HIIT) is a potential alternative to traditionally recommended steady state exercise for providing health benefits in adolescents, yet its dose-response relationship in this cohort remains unclear, as does its translatability to real-world, nonclinical settings. The present study adopts a novel dose-response design to investigate the effects of undertaking 8 wk of HIIT on the cardiometabolic health of low-active male adolescents. METHODS: Twenty-six male adolescents (age 16 +/- 1 yr), identified as low active by nonparticipation in structured sport and physical education classes, were randomly assigned to one of five treatment groups. Corresponding with their group numbers (1-5), participants completed a number of HIIT "sets," which consisted of 4 repeated bouts of 20-s near-maximal exertion interspersed with 10-s passive recovery. Participants performed two HIIT sessions and one resistance training session each week for 8 wk. Baseline and follow-up health measures consisted of peak oxygen uptake (VO2peak) with an incremental ramp test to volitional exhaustion; body composition (including visceral fat mass, body fat, and lean tissue mass) with dual-energy x-ray absorptiometry; and lipid profile, glucose, insulin, and interleukin-6 from blood analysis. All health outcomes were analyzed as percentage changes, and data were modeled using a quadratic function to explore dose-response relationships. RESULTS: Significant improvements were observed for VO2peak (~6%), body fat percentage (~4%), visceral fat mass (~10%), and waist circumference-to-height ratio (~3%), but there was no clear effect of dose across groups. CONCLUSIONS: Low-active adolescent males performing a single HIIT set twice weekly, in addition to one resistance training session, gained meaningful improvements in fitness and body composition. Performing additional HIIT sets provided no additional improvements to those of the lowest dose in this study. PMID- 26484953 TI - Twenty-four Hours of Sleep, Sedentary Behavior, and Physical Activity with Nine Wearable Devices. AB - Getting enough sleep, exercising, and limiting sedentary activities can greatly contribute to disease prevention and overall health and longevity. Measuring the full 24-h activity cycle-sleep, sedentary behavior (SED), light-intensity physical activity (LPA), and moderate-to-vigorous physical activity (MVPA)-may now be feasible using small wearable devices. PURPOSE: This study compared nine devices for accuracy in a 24-h activity measurement. METHODS: Adults (n = 40, 47% male) wore nine devices for 24 h: ActiGraph GT3X+, activPAL, Fitbit One, GENEactiv, Jawbone Up, LUMOback, Nike Fuelband, Omron pedometer, and Z-Machine. Comparisons (with standards) were made for total sleep time (Z-machine), time spent in SED (activPAL), LPA (GT3X+), MVPA (GT3X+), and steps (Omron). Analysis included mean absolute percent error, equivalence testing, and Bland-Altman plots. RESULTS: Error rates ranged from 8.1% to 16.9% for sleep, 9.5% to 65.8% for SED, 19.7% to 28.0% for LPA, 51.8% to 92% for MVPA, and 14.1% to 29.9% for steps. Equivalence testing indicated that only two comparisons were significantly equivalent to standards: the LUMOback for SED and the GT3X+ for sleep. Bland Altman plots indicated GT3X+ had the closest measurement for sleep, LUMOback for SED, GENEactiv for LPA, Fitbit for MVPA, and GT3X+ for steps. CONCLUSIONS: Currently, no device accurately captures activity data across the entire 24-h day, but the future of activity measurement should aim for accurate 24-h measurement as a goal. Researchers should continue to select measurement devices on the basis of their primary outcomes of interest. PMID- 26484954 TI - Basic Principles and Clinical Applications of Magnetic Resonance Spectroscopy in Neuroradiology. AB - Magnetic resonance spectroscopy is a powerful tool to assist daily clinical diagnostics. This review is intended to give an overview on basic principles of the technology, discuss some of its technical aspects, and present typical applications in daily clinical routine in neuroradiology. PMID- 26484955 TI - Non-Electrocardiogram-Triggered 70-kVp High-Pitch Computed Tomography Angiography of the Whole Aorta With Iterative Reconstruction: Initial Results. AB - OBJECTIVES: To evaluate the feasibility of non-electrocardiogram (ECG)-triggered 70-kVp high-pitch aortic computed tomography angiography (CTA) with iterative reconstruction (IR) and reduced contrast agent using second-generation dual source CT (DSCT). METHODS: Seventy-seven patients were examined: group A (n = 21), 70-kVp high-pitch (3.2) CTA, 60 mL contrast agent and IR on second generation DSCT; group B (n = 29), standard-pitch (1.2) CTA, automatic tube voltage selection, filtered back projection and 80 mL contrast agent on second generation DSCT; group C (n = 27), 120-kVp standard-pitch (1.2) CTA, filtered back projection, and 80 mL contrast agent on first-generation DSCT. Computed tomography values, noise, signal-to-noise ratio, contrast-to-noise ratio, and subjective image quality were compared. RESULTS: Computed tomography values and noise of all aortic segments in group A were increased compared with groups B and C (P < 0.05). Group B showed the highest signal-to-noise ratio and contrast-to noise ratio for all aortic segments (P < 0.05), whereas no significant differences were found between groups A and C (P > 0.05). Mean effective dose was 0.88 +/- 0.08 mSv for group A, reduced by 93% compared to group C and by 90% compared to group B. CONCLUSIONS: Non-ECG-triggered 70-kVp high-pitch aortic CTA with IR provides equivalent diagnostic image quality with 90% reduction of radiation dose and 25% reduction of contrast volume compared with standard 120 kVp CTA. PMID- 26484956 TI - Viruses, Immunity and Unusual Lymphoproliferative Disorders of the Chest: Integrating Imaging With Pathogenesis and Clinical Presentations. AB - Unusual lymphoproliferative diseases result from the stimulation of intrathoracic lymphoid tissue by viruses and immune dysfunction, ranging from benign hyperplasia to malignant transformation. We review the clinical, radiological, and histopathological findings of unusual lymphoproliferative disorders, which have been linked to viruses or immune dysfunction, focusing on thoracic manifestations. Understanding these advances in science enhances the radiologist's skills in integrating the imaging findings to the clinical scenario to suggest the correct diagnosis. PMID- 26484957 TI - Intraobserver and Interobserver Agreement in the Evaluation of Tumor Vascularization With Computed Tomography Perfusion in Cirrhotic Patients With Hepatocellular Carcinoma. AB - OBJECTIVES: To evaluate intrareader and inter-reader agreement in CT perfusion (Perf) measurements in cirrhotic patients with hepatocellular carcinoma (HCC) lesions. METHODS: Sixteen patients with HCC (9 untreated, 5 recurrence/residual disease after transarterial chemoembolization, and 2 after radiofrequency ablation treatment) underwent standard CT examination and a Perf study; a quantitative map of arterial and portal Perf by means of a color scale was generated. With dedicated Perf software, the following parameters were calculated on untreated and treated HCC lesions and on cirrhotic parenchyma: hepatic Perf, tissue blood volume, hepatic perfusion index, arterial perfusion, and time to peak. Intraobserver and interobserver agreements were assessed for 2 readers with Bland-Altman plots, intraclass correlation coefficients (ICCs), coefficients of variation, and repeatability. RESULTS: In HCC lesions, agreement analysis demonstrated higher intra-agreement values in comparison with interagreement (range of ICC values, 0.26-0.59 between readers and 0.67-0.94 between readings). Lower interagreement was found for treated HCC lesions in comparison with untreated lesions (range of ICC values, respectively, 0.12-0.54 and 0.31-0.89). CONCLUSIONS: For all Perf parameters intra-agreement was higher than interagreement, even though a relatively wide range of 95% limits of agreement was found in both cases. PMID- 26484958 TI - Interobserver Variation in Cerebellar Tonsillar Tip Localization: Comparison of 3 Different Osseous Landmarks on Magnetic Resonance Imaging. AB - PURPOSE: The aim was to evaluate the interobserver agreement in the assessment of cerebellar tonsil position on sagittal magnetic resonance imaging using 3 different osseous landmarks. MATERIALS AND METHODS: This retrospective study consisted of brain magnetic resonance imagings performed at our institution in patients with and without Chiari I malformation between January 2010 and 2012. Sagittal T1-weighted images were reviewed by 2 senior board-certified neuroradiologists (blinded to underlying clinical diagnosis) with measurement of both cerebellar tonsillar positions based on lines drawn perpendicular from the tonsillar tip to the foramen magnum [FM] line, C1 line, and C2 line. Spearman correlation coefficients were calculated. Interobserver variation between the readers was assessed using Bland-Altman analysis and intraclass correlation coefficient. RESULTS: A total of 320 cerebellar tonsils on 160 patients, 50 with Chiari I malformations, and 110 control subjects without Chiari I malformation were evaluated. The Spearman correlation coefficients for the entire cohort were 0.86 (FM), 0.94 (C1), and 0.90 (C2). Bland-Altman analysis for the entire cohort showed the best interobserver agreement for C1 line (-0.3 mm bias) and the least for C2 line (4.6 mm bias). The Intraclass correlation coefficients for all patients were 0.84 (FM), 0.92 (C1), and 0.54 (C2). The least bias and highest correlation coefficients were also seen individually in the Chiari and non-Chiari cohorts with the C1 technique. CONCLUSIONS: Determination of cerebellar tonsillar position using a C1 arch landmark may be superior to the currently more commonly used FM-based landmark with lesser interobserver variability and higher interobserver correlation. PMID- 26484959 TI - Ovarian Torsion: Multimodality Review of Imaging Characteristics. AB - We present a case of ovarian torsion in pregnancy with demonstration of vascular flow on sequential Doppler ultrasonography. Magnetic resonance imaging demonstrated ovarian enlargement and edema. Mild symptoms and low clinical suspicion, in addition to risks associated with pregnancy prevented early laparoscopic examination, though torsion was considered. Progressive ovarian enlargement supported surgical intervention, which confirmed the presence of torsion. This case report reviews multimodality imaging characteristics of ovarian torsion, re-emphasizing the significance of ovarian morphology. PMID- 26484960 TI - Preoperative Coil Embolization in Patients With a Replaced Hepatic Artery Scheduled for Pancreatectomy With Splanchnic Artery Resection Helps to Prevent Ischemic Organ Injury. AB - OBJECTIVE: The aim of this study was to evaluate the prevention of liver ischemic injury by preoperative coil embolization in patients with a replaced hepatic artery scheduled for pancreatectomy with splanchnic artery resection. METHODS: Between July 2009 and May 2012, 4 patients with replaced hepatic artery underwent pancreatectomy plus splanchnic artery resection. The replaced right hepatic artery was preoperatively embolized in 2 patients. In the other 2 patients, the common hepatic artery was embolized preoperatively. We evaluated the complications encountered in the perioperative period. RESULTS: There were no embolization-related complications. Although 2 patients presented with small liver infarcts, the aspartate aminotransferase and alanine aminotransferase levels did not exceed 1000 IU/L in any of the patients, and none experienced severe liver injury. CONCLUSIONS: Coil embolization before pancreatectomy with splanchnic artery resection in patients with a replaced hepatic artery may help to prevent severe ischemic liver injury in the perioperative period. PMID- 26484961 TI - The Role of Positron Emission Tomography/Computed Tomography in Management and Prediction of Survival in Pancreatic Cancer. AB - The role of positron emission tomography (PET) and PET/computed tomography (CT) in the management of pancreatic cancer patients has not been clearly established. Although value of PET/CT in the staging of pancreatic cancer is still being debated, several studies pointed to its superior role in determining therapy response, recurrence detection, and survival prediction in comparison to conventional imaging including contrast-enhanced CT. This article reviews the current literature on usefulness of PET/CT in the management of pancreatic cancer patients. PMID- 26484962 TI - Management of Postembolization Syndrome Following Hepatic Transarterial Chemoembolization for Primary or Metastatic Liver Cancer. AB - BACKGROUND: Transarterial chemoembolization (TACE) is an established treatment in managing liver primary neoplasms or liver metastases. Postembolization syndrome (PES) is a common adverse event defined as fever without associated sepsis, pain in the right upper quadrant, and nausea and/or vomiting. OBJECTIVE: This integrative review aims to identify effective management strategies for PES or one of its characterizing symptoms (fever, pain, and nausea and/or vomiting). METHODS: Searches of electronic databases MEDLINE, EMBASE, and CINAHL were conducted. Fifteen articles were identified for inclusion. Seven addressed all symptoms of PES, and 8 studies focused on individual symptoms of PES. RESULTS: Interventions identified are intra-arterial lidocaine, oral and intravenous analgesics, steroids, wrist-ankle acupuncture, antibiotics, and 5-HT3 receptor antagonists. Findings are explicated according to individual symptoms of PES. Intra-arterial lidocaine, steroids, and a 5-HT3 receptor antagonist are found to offer potential benefit in the management of PES symptoms. CONCLUSION: A number of interventions have shown potential benefit in the management of PES. A systemic approach using combination therapy is necessary to effectively manage characterizing symptoms. Further research is needed to determine the impact of primary disease site, TACE technique, and chemotherapeutic agent on PES. IMPLICATIONS FOR PRACTICE: Oncology nurses are uniquely placed to undertake thorough patient assessment after TACE and implement early intervention to effectively manage PES. PMID- 26484963 TI - We as Spouses Have Experienced a Real Disaster!: A Qualitative Study of Women With Breast Cancer and Their Spouses. AB - BACKGROUND: Breast cancer is the most common cancer in women in Turkey. The emotional effects of this condition are experienced by the women and their families. OBJECTIVE: The aim of the study was to describe the experiences of women with breast cancer and their spouses from diagnosis to treatment completion. METHODS: This qualitative study with a descriptive qualitative design was conducted at participants' homes. Fourteen women and their spouses were enrolled in the study (n = 28). Data were collected during in-depth interviews and analyzed with inductive content analysis. RESULTS: The women with breast cancer and their spouses' experiences were categorized into 4 main themes: "facing breast cancer," "treatment process," "coping with disease and treatment," and "life after treatment." Subthemes were also identified and described. CONCLUSIONS: The women with breast cancer and their spouses reported that they had positive and negative experiences in terms of their physical, psychological, and social status from diagnosis to completion of treatment, indicating that breast cancer is a disease of women and a condition of families. IMPLICATIONS FOR PRACTICE: Knowledge of these experiences can help nurses plan care that is designed to improve the quality of life of women and their husbands. PMID- 26484964 TI - Statistical investigation of surface bound ions and further development of BION server to include pH and salt dependence. AB - Ions are engaged in multiple biological processes in cells. By binding to the macromolecules or being mobile in the solvent, they maintain the integrity of the structure of macromolecules; participate in their enzymatic activity; or screen electrostatic interactions. While experimental methods are not always able to assign the exact location of ions, computational methods are in demand. Although the majority of computational methods are successful in predicting the position of ions buried inside macromolecules, they are less effective in deciphering positions of surface bound ions. Here, we propose the new BION algorithm (http://compbio.clemson.edu/bion_server_ph/) that predicts the location of the surface bound ions. It is more efficient and accurate compared to the previous version since it uses more advanced clustering algorithm in combination with pairing rules. In addition, the BION webserver allows specifying the pH and the salt concentration in predicting ions positions. PMID- 26484965 TI - Characteristics of Adopted Thoroughbred Racehorses in Second Careers. AB - The unwanted horse issue continues to be a major concern in the U.S. equine industry. Nonprofit organizations dedicated to rescuing, retraining, and rehoming unwanted horses are critical in minimizing this problem. This study utilized data collected nationwide from organizations that provide these services for thoroughbreds retired from racing to identify individual horse characteristics that influenced length of stay at the adoption facility as well as characteristics that increased the probability that an adopted horse would be returned to the facility. The results suggested that horses with fewer activity limitations were rehomed more quickly (p < .01), as were gray horses (relative to bays, p < .03) and stallions (relative to geldings, p < .04). Older horses took longer to rehome (p < .05). Interestingly, the results also suggested that gray horses were more likely to be returned to the facility postadoption (p < .02). Results from this study could benefit thoroughbreds retired from racing, nonprofit organizations, end consumers, and the thoroughbred racing industry. PMID- 26484966 TI - Visible-Light-Induced Self-Healing Diselenide-Containing Polyurethane Elastomer. AB - Visible light is an easily achievable and mild trigger for self-healing materials. By incorporating dynamic diselenide bonds into polyurethane, visible light-induced self-healing materials can be fabricated. Besides mild visible light, the healing process can also be realized using directional laser irradiation, which makes the system a remotely controllable self-healing system. PMID- 26484967 TI - Novel investigational therapies for treating pulmonary arterial hypertension. AB - INTRODUCTION: Despite the development of new therapies, pulmonary arterial hypertension (PAH) has a median survival of 6 - 7 years. This is likely because the currently approved therapies affect predominantly pulmonary vasoconstriction. The past two decades have witnessed greater insights into the pathogenesis of PAH, from the role of inflammation to molecular signaling and epigenetics. Multiple pharmacological agents targeting these newly identified pathways are currently being investigated in preclinical and early clinical studies. AREAS COVERED: Herein, the authors review the modalities targeting recently identified molecular targets in PAH. These include: prostaglandin receptor agonists, agents that alter the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways, vasoactive peptides, receptor tyrosine kinase inhibitors, Rho-kinase inhibitors, serotonin pathway inhibitors, anti-inflammatory agents, antioxidants, agents that alter nitric oxide signaling, various cardiac medications, mitochondrial metabolism modifying agents, epigenetic agents and cell-based therapies. The authors also address the gaps in the knowledge and explain why certain agents may or may not be promising PAH pharmacotherapeutics. EXPERT OPINION: Newer agents target multiple pathways including vasoconstriction, cellular proliferation and inflammatory response. And while only a few of the current investigational drugs will likely be further developed, the authors expect that the next two decades will bring some major breakthroughs in PAH management. PMID- 26484968 TI - Effect of respiratory hyperoxic challenge on magnetic susceptibility in human brain assessed by quantitative susceptibility mapping (QSM). AB - The purpose of this study was to measure the regional change of magnetic susceptibility in human brain upon inhalation of 100% oxygen by MRI quantitative susceptibility mapping (QSM). Fourteen healthy volunteers were scanned in a 3 T MR scanner with a 3D multi-gradient-echo sequence while breathing medical air (normoxia) and pure oxygen (hyperoxia). QSM images and R2* maps were calculated. Mean susceptibility differences versus white matter were measured in regions of interest covering veins, gray matter (GM), and cerebrospinal fluid (CSF) under both conditions. Hyperoxia resulted in a strong susceptibility decrease in large veins (-154.4 +/- 65.9 ppb, p < 10(-6)), in a smaller reduction in GM (-1.3 +/- 1 ppb, p < 0.001), and in a susceptibility increase in ventricular CSF (3.8 +/- 1.8 ppb, p < 10(-5)). The susceptibility decrease in veins implied an increase of venous oxygen saturation (SvO2) by 10.1 +/- 4.0%. Compared with QSM, R2* was more seriously affected by long-distance effects not related to local tissue oxygenation and increased in cerebral frontal regions (3 +/- 2 s(-1), p < 0.0004) due to paramagnetic molecular oxygen in cavities. The results highlight the potential of QSM to yield region-specific quantitative oxygenation information, and, thus, for applications such as oxygen-therapy monitoring or identification of hypoxic tumor tissue during radiotherapy planning. PMID- 26484969 TI - How do we acquire high-level evidence in urology? A 30 year perspective. PMID- 26484970 TI - The acceptance of mobile teledermoscopy by primary care nurse practitioners in the state of Arizona. AB - PURPOSE: To conduct a pilot survey to assess acceptance of mobile teledermoscopy (MTD) by primary care nurse practitioners (NPs) working in Arizona. DATA SOURCES: Sixty-two participants recruited from NP and academic listservs in Arizona completed an online survey prefaced by a MTD definition, device photographs, and a practice case, followed by 33 items measuring Teledermatology Technology Acceptance Model (TeleTAM) constructs. CONCLUSIONS: Participants were highly interested in using MTD to assess skin lesions. They perceived MTD utility to greatly improve diagnosis and positively impact their practice. Most participants had never used MTD, but had high mean scores for MTD attitude and moderate scores for MTD perceived ease of use, perceived use, and facilitators of MTD. They had moderate scores for intention to use MTD. The construct facilitators (organizational infrastructure) were most strongly associated with intention to use MTD. Cronbach alphas were 0.70 or higher for all subscales except compatibility and habit. IMPLICATIONS FOR PRACTICE: Moderate acceptance of MTD may reflect NPs' knowledge of the technology, self-confidence for using it, or MTD financial constraints. Future research will address these factors to foster use of MTD by NPs, thereby improving patients' access to early skin lesion assessment and diagnosis. PMID- 26484971 TI - Gianni Bonadonna, MD: 1934-2015. PMID- 26484972 TI - The Results of a Propensity Score Matching Analysis of the Efficacy of Abdominal Fascia and Skin Closure Using PDS(r) Plus Antibacterial (Polydioxanone) Sutures on the Incidence of Superficial Incisional Surgical Site Infections after Gastroenterologic Surgery. AB - BACKGROUND: Surgical site infections (SSIs) lead to prolonged hospitalization and increased cost of hospital stay after surgery. Therefore, the prevention of SSIs is one of the most critical tasks facing surgeons and nursing staff. In the present study, the efficacy of using triclosan-coated polidioxanone sutures (PDS(r) Plus Antibacterial Suture, (Ethicon Inc., Somerville, NJ) for abdominal closure was analyzed retrospectively using a propensity score matching analysis. PATIENTS AND METHODS: Of 1,768 patients who underwent gastroenterologic surgery at Fukuoka University Hospital between January 2009 and September 2013, 812 underwent abdominal closure using PDS Plus. These patients were compared retrospectively regarding the incidence of SSIs using a propensity score matching method with 956 patients treated in the previous period without abdominal closure using PDS Plus sutures. The propensity score was calculated from the age, gender, body mass index, smoking status, diabetes mellitus, use of steroid medication, malignant or benign disease, organ location, emergency or planned surgery, wound classification, the American Society of Anesthesiologists score, open or laparoscopic surgery, the length of the operation, and blood loss. RESULTS: Nine hundred sixty-six patients (483 matched sets) were enrolled by the propensity score matching method. No parameter used for the propensity score was different between the PDS Plus and control groups. Closure using PDS Plus could reduce the incidence of SSIs compared with that in the control group (p = 0.022). Of the parameters used for the propensity score, malignant disease (p = 0.0002), open surgery (p = 0.0020), a prolonged operation (p < 0.0001), high blood loss (p < 0.0001), the need for a transfusion (p = 0.019), and gastrointestinal tract surgery (p = 0.0059) were significant risk factors for the development of SSIs in the univariable analysis. In a multivariable regression model, open surgery (p < 0.0001), prolonged operation (p < 0.0001), gastrointestinal tract surgery (p = 0.001), and abdominal closure without PDS Plus (p < 0.0001) were the independent risk factors for the development of an SSI. The development of an SSI prolonged the hospital stay (p < 0.0001) and the use of antibiotic medication (p < 0.0001); abdominal closure using PDS Plus affected the antibiotic medication period (p = 0.013) but not the hospital stay (p = 0.40). CONCLUSION: Although abdominal fascia and skin closure using PDS Plus was compared with variable abdominal closure, the present findings suggest that abdominal fascia and skin closure using PDS Plus sutures could help prevent the development of SSIs after gastroenterologic surgery, as determined by a propensity score matching analysis. PMID- 26484973 TI - Connecting air quality and climate change. PMID- 26484974 TI - Adsorption-desorption characteristics of methyl ethyl ketone with modified activated carbon and inhibition of 2,3-butanediol production. AB - Activated carbon (AC) is seldom applied for recovering ketone-based volatile organic compounds because of safety concerns. Adsorption of methyl ethyl ketone (MEK) with AC is a highly exothermic reaction that potentially causes fires in AC beds. Moreover, 2,3-butanediol (BDO) is produced in the desorbed solvent, causing yellowing and odor of the recovered solvent. This study applied a continuous adsorption-desorption apparatus for evaluating the operating capacities and BDO concentration in recovered MEK containing modified and original ACs. AC-1 (TAKETA G2X) was used as the target for modification. The experimental results indicate that using MgO as the modifier increases the ignition point by 12 degrees C and that applying KNO3 as the modifier reduces the AC ignition point by 28 degrees C (compared with AC-1). The BDO concentration of the desorbed MEK solvent can be reduced by increasing the loading of the modifying agent (Ethanolamine) (Im-1: 3.1 wt%; Im-5: 6.2 wt%). Moreover, applying the AC pretreated with nitrogen (Im 6) as adsorbent significantly reduces the BDO concentration (from 0.123 wt% to 0.073 wt%). Because desorption and purging procedures were performed in N2 atmospheres, the BDO concentrations of the desorbed MEK solvents were relatively low and ranged from 0.032 wt% to 0.043 wt%. When the MEK concentration was reduced to 2000 ppm, lower BDO concentrations (0.012-0.022 wt%) were measured in the recovered MEK solvent. The way to modify activated carbon and a better desorbing sequence to effectively inhibit the oxidation of MEK to BDO are developed. The results obtained indicate that the BDO concentration in the desorbed solvent was lower than the original MEK solvent (0.023 wt%). Different approaches can be applied simultaneously to achieve high inhibition effects; however, carbon adsorption performance may be negatively affected. IMPLICATIONS: The study is motivated to improve the quality of recovered solvent and reduce fire hazards, particularly when AC is applied for adsorbing a ketone-based solvent (e.g., MEK). The experimental results indicate that the BDO concentration in the recovered solvent can be reduced and the ignition point of AC can be increased by modifying the AC with an appropriate agent. PMID- 26484975 TI - Role of future scenarios in understanding deep uncertainty in long-term air quality management. AB - The environment and its interactions with human systems, whether economic, social, or political, are complex. Relevant drivers may disrupt system dynamics in unforeseen ways, making it difficult to predict future conditions. This kind of "deep uncertainty" presents a challenge to organizations faced with making decisions about the future, including those involved in air quality management. Scenario Planning is a structured process that involves the development of narratives describing alternative future states of the world, designed to differ with respect to the most critical and uncertain drivers. The resulting scenarios are then used to understand the consequences of those futures and to prepare for them with robust management strategies. We demonstrate a novel air quality management application of Scenario Planning. Through a series of workshops, important air quality drivers were identified. The most critical and uncertain drivers were found to be "technological development" and "change in societal paradigms." These drivers were used as a basis to develop four distinct scenario storylines. The energy and emissions implications of each storyline were then modeled using the MARKAL energy system model. NOx emissions were found to decrease for all scenarios, largely a response to existing air quality regulations, whereas SO2 emissions ranged from 12% greater to 7% lower than 2015 emissions levels. Future-year emissions differed considerably from one scenario to another, however, with key differentiating factors being transition to cleaner fuels and energy demand reductions. IMPLICATIONS: Application of scenarios in air quality management provides a structured means of sifting through and understanding the dynamics of the many complex driving forces affecting future air quality. Further, scenarios provide a means to identify opportunities and challenges for future air quality management, as well as a platform for testing the efficacy and robustness of particular management options across wide-ranging conditions. PMID- 26484976 TI - Assessment of exhaust emissions from carbon nanotube production and particle collection by sampling filters. AB - This study performed a workplace evaluation of emission control using available air sampling filters and characterized the emitted particles captured in filters. Characterized particles were contained in the exhaust gas released from carbon nanotube (CNT) synthesis using chemical vapor deposition (CVD). Emitted nanoparticles were collected on grids to be analyzed using transmission electron microscopy (TEM). CNT clusters in the exhaust gas were collected on filters for investigation. Three types of filters, including Nalgene surfactant-free cellulose acetate (SFCA), Pall A/E glass fiber, and Whatman QMA quartz filters, were evaluated as emission control measures, and particles deposited in the filters were characterized using scanning transmission electron microscopy (STEM) to further understand the nature of particles emitted from this CNT production. STEM analysis for collected particles on filters found that particles deposited on filter fibers had a similar morphology on all three filters, that is, hydrophobic agglomerates forming circular beaded clusters on hydrophilic filter fibers on the collecting side of the filter. CNT agglomerates were found trapped underneath the filter surface. The particle agglomerates consisted mostly of elemental carbon regardless of the shapes. Most particles were trapped in filters and no particles were found in the exhaust downstream from A/E and quartz filters, while a few nanometer-sized and submicrometer-sized individual particles and filament agglomerates were found downstream from the SFCA filter. The number concentration of particles with diameters from 5 nm to 20 um was measured while collecting particles on grids at the exhaust piping. Total number concentration was reduced from an average of 88,500 to 700 particle/cm(3) for the lowest found for all filters used. Overall, the quartz filter showed the most consistent and highest particle reduction control, and exhaust particles containing nanotubes were successfully collected and trapped inside this filter. IMPLICATIONS: As concern for the toxicity of engineered nanoparticles grows, there is a need to characterize emission from carbon nanotube synthesis processes and to investigate methods to prevent their environmental release. At this time, the particles emitted from synthesis were not well characterized when collected on filters, and limited information was available about filter performance to such emission. This field study used readily available sampling filters to collect nanoparticles from the exhaust gas of a carbon nanotube furnace. New agglomerates were found on filters from such emitted particles, and the performance of using the filters studied was encouraging in terms of capturing emissions from carbon nanotube synthesis. PMID- 26484977 TI - OMICS 2.0: An Accelerator for Global Science, Systems Medicine and Responsible Innovation. PMID- 26484979 TI - Veterinary Medicine and Omics (Veterinomics): Metabolic Transition of Milk Triacylglycerol Synthesis in Sows from Late Pregnancy to Lactation. AB - Mammalian milk is a key source of lipids, providing not only important calories but also essential fatty acids. Veterinary medicine and omics systems sciences intersection, termed as "veterinomics" here, has received little attention to date but stands to offer much promise for building bridges between human and animal health. We determined the changes in porcine mammary genes and proteomics expression associated with milk triacylglycerol (TAG) synthesis and secretion from late pregnancy to lactation. TAG content and fatty acid (FA) composition were determined in porcine colostrum (the 1st day of lactation) and milk (the 17th day of lactation). The mammary transcriptome for 70 genes and 13 proteins involved in TAG synthesis and secretion from six sows, each at d -17(late pregnancy), d 1(early lactation), and d 17 (peak lactation) relative to parturition were analyzed using quantitative real-time PCR and Western blot analyses. The TAG content and the concentrations of de novo synthesized FAs, saturated FAs, and monounsaturated FAs were higher in milk than in colostrum (p<0.05). Robust upregulation with high relative mRNA abundance was evident during lactation for genes associated with FA uptake (VLDLR, LPL, CD36), FA activation (ACSS2, ACSL3), and intracellar transport (FABP3), de novo FA synthesis (ACACA, FASN), FA elongation (ELOVL1), FA desaturation (SCD, FADS1), TAG synthesis (GPAM, AGPAT1, LPIN1, DGAT1), lipid droplet formation (BTN2A1, XDH, PLIN2), and transcription factors and nuclear receptors (SREBP1, SCAP, INSIG1/2). In conclusion, a wide variety of lipogenic genes and proteins regulate the channeling of FAs towards milk TAG synthesis and secretion in porcine mammary gland tissue. These findings inform future omics strategies to increase milk fat production and lipid profile and attest to the rise of both veterinomics and lipidomics in postgenomics life sciences. PMID- 26484980 TI - Sexting Among Married Couples: Who Is Doing It, and Are They More Satisfied? AB - This study examined the prevalence and correlates of sexting (i.e., sending sexual messages via mobile phones) within a sample of married/cohabiting couples (180 wives and 175 husbands). Married adults do sext each other, but it is much less common than within young adult relationships, and consists mainly of sexy or intimate talk (29% reported engaging in sexy talk with partners) rather than sexually explicit photos or videos (12% reported sending nude or nearly-nude photos). Sending sexy talk messages was positively related to relationship satisfaction only among those with high levels of avoidance, and sending sexually explicit pictures was related to satisfaction for men, and for women with high levels of attachment anxiety. Additionally, sending sexually explicit pictures was related to greater ambivalence among both men and women. These findings support and extend previous research with young adults. PMID- 26484978 TI - Systems Biology for Smart Crops and Agricultural Innovation: Filling the Gaps between Genotype and Phenotype for Complex Traits Linked with Robust Agricultural Productivity and Sustainability. AB - In recent years, rapid developments in several omics platforms and next generation sequencing technology have generated a huge amount of biological data about plants. Systems biology aims to develop and use well-organized and efficient algorithms, data structure, visualization, and communication tools for the integration of these biological data with the goal of computational modeling and simulation. It studies crop plant systems by systematically perturbing them, checking the gene, protein, and informational pathway responses; integrating these data; and finally, formulating mathematical models that describe the structure of system and its response to individual perturbations. Consequently, systems biology approaches, such as integrative and predictive ones, hold immense potential in understanding of molecular mechanism of agriculturally important complex traits linked to agricultural productivity. This has led to identification of some key genes and proteins involved in networks of pathways involved in input use efficiency, biotic and abiotic stress resistance, photosynthesis efficiency, root, stem and leaf architecture, and nutrient mobilization. The developments in the above fields have made it possible to design smart crops with superior agronomic traits through genetic manipulation of key candidate genes. PMID- 26484981 TI - Hormone receptor-negative, thyroid transcription factor 1-positive uterine and ovarian adenocarcinomas: report of a series of mesonephric-like adenocarcinomas. AB - AIMS: To report a series of uterine corpus (n = 7) and ovarian (n = 5) neoplasms which we believe probably represent mesonephric adenocarcinomas based on their characteristic morphology and immunophenotype. METHODS AND RESULTS: All neoplasms exhibited a relatively constant and characteristic morphological appearance with an admixture of architectural patterns with small glands or tubules, some containing luminal eosinophilic colloid-like material, typically predominating. Solid and papillary architectures were also often present. The nuclear features were characteristic with atypical angulated clear vesicular nuclei which often exhibited overlapping. All the tumours were 'flat' negative with oestrogen receptor and progesterone receptor and all except one exhibited nuclear staining with thyroid transcription factor 1 (TTF1), which was often diffuse. All tumours exhibited wild-type staining with p53. CD10, calretinin and GATA binding protein 3 (GATA3) were positive in a variable proportion of the neoplasms. CONCLUSIONS: We believe these neoplasms to represent mesonephric adenocarcinomas which have only rarely been reported to arise in the uterine corpus and never in the ovary. We recommend they be termed mesonephric-like adenocarcinomas until their histogenesis is firmly established. PMID- 26484982 TI - Additional plerixafor to granulocyte colony-stimulating factors for haematopoietic stem cell mobilisation for autologous transplantation in people with malignant lymphoma or multiple myeloma. AB - BACKGROUND: Autologous stem cell transplantation is widely used to restore functioning bone marrow in people with malignant lymphoma or multiple myeloma after myeloablative chemotherapy. Results of some clinical trials indicate that plerixafor in addition to granulocyte colony-stimulating factors (G-CSF) compared to G-CSF only could lead to an increased mobilisation and release of CD34 positive cells, facilitating effective apheresis. OBJECTIVES: To evaluate the efficacy and safety of additional plerixafor to G-CSF for haematopoietic stem cell mobilisation in people with malignant lymphoma or multiple myeloma. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1990 to September 2015), as well as conference proceedings (American Society of Hematology; American Society of Clinical Oncology; European Hematology Association; American Society for Blood and Marrow Transplantation; European Group for Blood and Marrow Transplantation) for studies. Two review authors independently screened search results. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing plerixafor in addition to G-CSF compared to G-CSF only for stem cell mobilisation in people with malignant lymphoma or multiple myeloma of all stages and ages. We included full text as well as abstracts and unpublished data if sufficient information on study design, participant characteristics, interventions, and outcomes was available. We excluded cross-over trials, quasi-randomised trials, and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the search strategies, extracted data, assessed quality, and analysed data according to standard Cochrane methods. We performed final interpretation with an experienced clinician. MAIN RESULTS: We identified four RCTs fitting the inclusion criteria. However, two of these closed prematurely due to low recruitment and did not report results. The remaining two trials evaluated 600 participants with multiple myeloma or non-Hodgkin lymphoma. In both studies the experimental group received G-CSF plus plerixafor and the control group received G-CSF plus placebo.The meta-analysis showed no evidence for differences between plerixafor and placebo group regarding mortality at 12 months (600 participants; risk ratio (RR) 1.00, 95% confidence interval (CI) 0.59 to 1.69; P = 1.00; moderate-quality evidence) and adverse events during stem cell mobilisation and collection (593 participants; RR 1.02, 95% CI 0.99 to 1.06; P = 0.19; high-quality evidence).Regarding the outcome successful stem cell collection, the meta-analysis showed an advantage for those participants randomised to the plerixafor group (600 participants; RR 2.42, 95% CI 1.98 to 2.96; P < 0.00001; high-quality evidence).As there was high heterogeneity between studies for the number of transplanted participants, we did not meta-analyse these data. In the multiple myeloma study, 95.9% (142 participants) in the plerixafor arm and 88.3% (136 participants) in the placebo arm underwent transplantation (RR 1.09, 95% CI 1.02 to 1.16); in the non-Hodgkin lymphoma trial, 90% (135 participants) in the plerixafor group versus 55.4% (82 participants) in the placebo group could be transplanted (RR 1.62, 95% CI 1.39 to 1.89). In both trials there was no evidence for a difference between participants in the plerixafor and placebo group in terms of time to neutrophil and platelet engraftment in transplanted participants.None of the trials reported on the outcomes quality of life and progression-free survival. AUTHORS' CONCLUSIONS: The results of the analysed data suggest that additional plerixafor leads to increased stem cell collection in a shorter time. There was insufficient evidence to determine whether additional plerixafor affects survival or adverse events.The two trials included in the meta-analysis, both of which were conducted by the Genzyme Corporation, the manufacturer of plerixafor, were published several times. Two more RCTs examining the addition of plerixafor to a G-CSF mobilisation regimen terminated early without publishing any outcome. The trials included nine and five participants, respectively. Another RCT with 100 participants was recently completed, but has not yet published outcomes. Due to the unpublished RCTs, it is possible that our review is affected by publication bias, even though two trials failed to recruit a sufficient number of participants to analyse any data. PMID- 26484983 TI - Development of a Direct Photocatalytic C-H Fluorination for the Preparative Synthesis of Odanacatib. AB - Late-stage C-H fluorination is an appealing reaction for medicinal chemistry. However, the application of this strategy to process research appears less attractive due to the formation and necessary purification of mixtures of organofluorines. Here we demonstrate that gamma-fluoroleucine methyl ester, an intermediate critical to the large-scale synthesis of odanacatib, can be accessed directly from leucine methyl ester using a combination of the decatungstate photocatalyst and N-fluorobenzenesulfonimide in flow. This efficient C-H fluorination reaction compares favorably with several generations of classical gamma-fluoroleucine process syntheses. PMID- 26484984 TI - A Monte Carlo-based radiation safety assessment for astronauts in an environment with confined magnetic field shielding. AB - The active shielding technique has great potential for radiation protection in space exploration because it has the advantage of a significant mass saving compared with the passive shielding technique. This paper demonstrates a Monte Carlo-based approach to evaluating the shielding effectiveness of the active shielding technique using confined magnetic fields (CMFs). The International Commission on Radiological Protection reference anthropomorphic phantom, as well as the toroidal CMF, was modeled using the Monte Carlo toolkit Geant4. The penetrating primary particle fluence, organ-specific dose equivalent, and male effective dose were calculated for particles in galactic cosmic radiation (GCR) and solar particle events (SPEs). Results show that the SPE protons can be easily shielded against, even almost completely deflected, by the toroidal magnetic field. GCR particles can also be more effectively shielded against by increasing the magnetic field strength. Our results also show that the introduction of a structural Al wall in the CMF did not provide additional shielding for GCR; in fact it can weaken the total shielding effect of the CMF. This study demonstrated the feasibility of accurately determining the radiation field inside the environment and evaluating the organ dose equivalents for astronauts under active shielding using the CMF. PMID- 26484985 TI - Sodium Hydroxide Enhances Extractability and Analysis of Proanthocyanidins in Ensiled Sainfoin (Onobrychis viciifolia). AB - Little information exists on the effects of ensiling on condensed tannins or proanthocyanidins. The acetone-butanol-HCl assay is suitable for measuring proanthocyanidin contents in a wide range of samples, silages included, but provides limited information on proanthocyanidin composition, which is of interest for deciphering the relationships between tannins and their bioactivities in terms of animal nutrition or health. Degradation with benzyl mercaptan (thiolysis) provides information on proanthocyanidin composition, but proanthocyanidins in several sainfoin silages have proved resistant to thiolysis. We now report that a pretreatment step with sodium hydroxide prior to thiolysis was needed to enable their analysis. This alkaline treatment increased their extractability from ensiled sainfoin and facilitated especially the release of larger proanthocyanidins. Ensiling reduced assayable proanthocyanidins by 29%, but the composition of the remaining proanthocyanidins in silage resembled that of the fresh plants. PMID- 26484986 TI - Psychiatric Emergencies in the Intensive Care Unit. PMID- 26484988 TI - Automated Charting and Systems Integration: For Patients' Safety and Our Sanity. PMID- 26484989 TI - Left Ventricular Assist Device Driveline Infections: The Achilles' Heel of Destination Therapy. AB - Heart failure is a chronic progressive disease that affects millions of people in the United States. Although medical management of heart failure has helped improve quality of life and survival, end-stage heart failure ultimately requires a heart transplant or long-term left ventricular assist device (LVAD) support. With more patients awaiting transplant, the demand for hearts outweighs the supply of donor hearts. The use of LVADs is increasing in patients with advanced heart failure as a treatment option for those awaiting a heart transplant or as a long-term solution if they are ineligible for a transplant. Although the LVAD is a marvel of modern medicine, infection is a cause of concern because today's LVADs are powered externally through a percutaneous driveline that can be a major source of infection. PMID- 26484990 TI - Cardiac Implantable Electronic Devices: What You Need to Know in Critical Care Nursing Practice. PMID- 26484991 TI - Cardiac Implantable Electronic Device Implantation: Intraoperative, Acute, and Remote Complications. AB - Implantation of cardiac implantable electronic devices (CIEDs), including pacemakers, implantable cardioverter-defibrillators, and biventricular pacemakers/cardioverter-defibrillators, is becoming increasingly common with new implants now exceeding 1.5 million per year globally. As a result, health care providers in all disciplines are caring for an increasing number of patients with CIEDs. Although the risk of complications associated with implantation of CIEDs is relatively low, the sequela can be catastrophic. Management requires an understanding of an individual patient's indication for CIED implant, the steps of implant procedures, device function, and natural history of each complication. PMID- 26484992 TI - Transvenous Lead Extraction for Cardiac Implantable Electronic Devices. AB - This article illustrates the important role that lead extraction plays in the management of patients with cardiac implantable electronic devices. Individualized care of the patient is paramount when considering lead management strategies. The critical care nurse must have a comprehensive understanding of the indications, procedural considerations, and preprocedural and postprocedural care for patients undergoing lead extraction procedures, thereby improving patient safety and maximizing patient outcomes. PMID- 26484993 TI - Current Technology to Maximize Cardiac Resynchronization Therapy Benefit for Patients With Symptomatic Heart Failure. AB - The incidence of heart failure (HF) continues to increase, affecting millions of people in the United States each year. Cardiac resynchronization therapy (CRT) has been used and studied for patients with symptomatic HF for more than 20 years. The purpose of this article is to review technologies and developments to help maximize CRT for patients with symptomatic HF. Although most interventions to optimize CRT are physician directed, nurses also have an important role in the care and education of patients with symptomatic HF and can affect clinical outcomes. Therefore, nurses' understanding of CRT and measures to maximize this life-saving therapy is critical in HF management. PMID- 26484995 TI - Home Monitoring for Cardiovascular Implantable Electronic Devices: Benefits to Patients and to Their Follow-up Clinic. AB - Recent technological advances in the management of patients with cardiovascular implantable electronic devices (CIEDs) have expanded clinicians' ability to remotely monitor patients with CIEDs. Remote monitoring, in addition to periodic in-person device evaluation, provides many advantages to patients and clinicians. Aside from the therapeutic and diagnostic benefits of pacemakers, implantable cardioverter-defibrillators, cardiac resynchronization therapy devices, and implantable loop recorders, improvement in clinical outcomes, clinical efficiencies, and patient experience can be realized with the adoption of remote CIED monitoring. These advantages create significant value to both patients and CIED follow-up centers. PMID- 26484996 TI - Considerations in Patients With Cardiac Implantable Electronic Devices at End of Life. AB - Since the introduction of implantable cardiac pacemakers in 1958 and implantable cardioverter-defibrillators in 1980, these devices have been proven to save and prolong lives. Pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy are deemed life-sustaining therapies. Despite these life-saving technologies, all patients ultimately will reach the end of their lives from either their heart disease or development of a terminal illness. Clinicians may be faced with patient and family requests to withdraw these life sustaining therapies. The purpose of this article is to educate clinicians about the legal and ethical principles that underlie withdrawal of life-sustaining therapies such as device deactivation and to highlight the importance of proactive communication with patients and families in these situations. PMID- 26484998 TI - Blending Quality Improvement and Research Methods for Implementation Science, Part II: Analysis of the Quality of Implementation. PMID- 26484999 TI - Ethical Implications of Workarounds in Critical Care. PMID- 26485000 TI - Sick Sinus Syndrome. PMID- 26485001 TI - Reply to Comments on 'Sleep Disordered Breathing and Periodic Limb Movements in Patients with Narcolepsy with Cataplexy'. PMID- 26485002 TI - Measures to Assure that Ebola Guidelines Are Correctly Applied. AB - OBJECTIVE: The purpose of this study was to assure the application, in our primary care health district, of the World Health Organisation and Spanish Ebola virus disease (EVD) guidelines, and to identify and resolve gaps, in order to protect professionals from the risks associated with attending to patients with Ebola. MATERIALS AND METHODS: A checklist was drawn up and an audit procedure of the structural, functional and operational conditions was designed for managing a self-presenting patient suspected with EVD in general practice. This audit was applied twice (before and after assessment) in 9 health centres of a health district in Spain. The checklist was structured according to 9 categories (51 elements in total). This tool was designed to avoid errors in the management of EVD patients that are considered very serious in view of their potential consequences. RESULTS: Of the 51 elements on the checklist, 7-26 (14-51%) required direct intervention to rectify deficits in the first audit. The following elements requiring improvement were identified: the incorporation of memory aids to ensure the correct application of the EVD protocol, defining what information should be provided to the patient and (where applicable) anyone accompanying them as well as incorporating advice on how to deal with any individuals with whom they might have come into contact. A second audit assured the adequacy of the proposed solutions. CONCLUSION: In this study, the tool achieved the successful application of EVD protocol, assuring that primary care centres were able to handle an Ebola suspect patient safely. PMID- 26485004 TI - Correction: Antigenicity, Immunogenicity and Protective Efficacy of Three Proteins Expressed in the Promastigote and Amastigote Stages of Leishmania infantum against Visceral Leishmaniasis. PMID- 26485003 TI - A Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces. AB - Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated. PMID- 26485005 TI - Inpatient hospitalization for substance use disorders one year after residential rehabilitation: predictors among US veterans. AB - BACKGROUND: The Veterans Health Administration (VHA) is among the principal providers of the full range of substance use disorders (SUD) treatment in the US. Relatively little, however, is known about patient outcomes after residential rehabilitation. OBJECTIVE: To identify predictors of SUD inpatient hospitalization (primarily medically managed detoxification) in the year after SUD residential rehabilitation among US veterans. METHODS: Medical records of 64 veterans admitted to one of two residential rehabilitation programs in the Northeast during the first quarter of FY 2012 were abstracted. Data included demographic, clinical, and treatment (inpatient and outpatient) information for the year before and after residential rehabilitation. Annual rates of treatment utilization were compared. RESULTS: The veterans (mean age, 48.2 years) used substances for a mean of 27.6 years. Alcohol was the primary drug of choice (69%). More than half had SUD inpatient hospitalizations in the year before (79%) and after (53%) residential rehabilitation; SUD inpatient admission occurred an average of 64 days after discharge. According to the multivariate Cox regression model, the estimated risk of SUD inpatient hospitalization increased by 25% for each past year SUD inpatient hospitalization, decreased by 74% if there was no opiate use disorder diagnosis, and decreased by 2% for each day increase in residential rehabilitation length of stay when extent of service connected disability, marital status, and days since last SUD inpatient admission are taken into account. CONCLUSIONS: Risk factors for SUD inpatient hospitalization after residential rehabilitation have been identified and, if confirmed, may represent opportunities for targeted program change. PMID- 26485006 TI - Monitoring mortality in forced migrants--can Bayesian methods help us to do better with the (little) data we have? AB - In crisis situations, data are scarce-Peter Heudtlass and colleagues explore ways of best understanding the extra risk of death borne by forced migrants. PMID- 26485007 TI - Are three generations of quantitative molecular methods sufficient in medical virology? Brief review. AB - In the last two decades, development of quantitative molecular methods has characterized the evolution of clinical virology more than any other methodological advancement. Using these methods, a great deal of studies has addressed efficiently in vivo the role of viral load, viral replication activity, and viral transcriptional profiles as correlates of disease outcome and progression, and has highlighted the physio-pathology of important virus diseases of humans. Furthermore, these studies have contributed to a better understanding of virus-host interactions and have sharply revolutionized the research strategies in basic and medical virology. In addition and importantly from a medical point of view, quantitative methods have provided a rationale for the therapeutic intervention and therapy monitoring in medically important viral diseases. Despite the advances in technology and the development of three generations of molecular methods within the last two decades (competitive PCR, real-time PCR, and digital PCR), great challenges still remain for viral testing related not only to standardization, accuracy, and precision, but also to selection of the best molecular targets for clinical use and to the identification of thresholds for risk stratification and therapeutic decisions. Future research directions, novel methods and technical improvements could be important to address these challenges. PMID- 26485008 TI - May some HCV genotype 1 patients still benefit from dual therapy? The role of very early HCV kinetics. AB - When treating HCV patients with conventional dual therapy in the current context of rapidly evolving HCV therapy, outcome prediction is crucial and HCV kinetics, as early as 48 hours after the start of treatment, may play a major role. We aimed at clarifying the role of HCV very early kinetics. We consecutively enrolled mono-infected HCV patients at 7 treatment sites in Central Italy and evaluated the predictive value of logarithmic decay of HCV RNA 48 hours after the start of dual therapy (Delta48). Among the 171 enrolled patients, 144 were evaluable for early and sustained virological response (EVR, SVR) prediction; 108 (75.0%) reached EVR and 84 (58.3%) reached SVR. Mean Delta 48 was 1.68 +/- 1.22 log10 IU/ml, being higher in patients with SVR and EVR. Those genotype-1 patients experiencing a Delta 48 >2 logs showed a very high chance of success (100% positive predictive value), even in the absence of rapid virological response (RVR). Evaluation of very early HCV kinetics helped identify a small but significant proportion of genotype-1 patients (close to 10%) in addition to those identified with RVR, who could be treated with dual therapy in spite of not reaching RVR. In the current European context, whereby sustainability of HCV therapy is a crucial issue, conventional dual therapy may still play a reasonable role in patients with good tolerance and early prediction of success. PMID- 26485009 TI - Genetic polymorphisms of IL28b gene as predictors of response to dual therapy in genotypes 1 and 4-HCV and HIV/HCV-infected patients. AB - We describe the genotypes and allele distribution of interleukin 28B (IL28B) rs12979860 and rs8099917 single nucleotide polymorphisms (SNPs) in hepatitis C virus (HCV) G1-4 infected patients, to assess predictive ability and to determine whether the combined determination of two IL28B SNPs might improve sustained virologic response (SVR) prediction of both in HCV mono- and HIV/HCV co-infected patients. IL28B SNPs were genotyped in 269 patients, 181 mono- and 88 co infected, treated with pegylated interferon and ribavirin. Data stratified by HCV mono- and HCV/HIV co-infected patients showed that 58% and 31% of the rs12979860CC carriers and 49% and 21% of the rs8099917TT carriers had SVR. IL28B SNPs, HCV mono-infection and HCV RNA load were associated with SVR as independent predictors in the two study groups as a whole. ROC curve analyses in the two populations separately, based on gender, age, baseline HCV RNA load and rs12979860/rs8099917 revealed similar receiver operating characteristics (ROC) areas under the curve values. Combining the determination of IL28B SNPs, rs8099917 genotyping improved the response prediction in rs12979860CT carriers only in mono-infected patients. In the era of direct-acting antiviral agents, adopting SVR baseline predictors to orientate naive-patient management represents an important issue. A model involving IL28B SNPs appears able to predict SVR in both populations. PMID- 26485010 TI - Biofilm production in Staphylococcus epidermidis strains, isolated from the skin of hospitalized patients: genetic and phenotypic characteristics. AB - A major virulence factor of Staphylococcus epidermidis is its ability to form biofilms, permitting it to adhere to a surface and, in turn, to form a mucoid layer on polymer surfaces. Multiple factors have been found to influence bacterial attachment. Currently, this bacterium is commonly associated with hospital infections as a consequence of its ability to colonize, albeit accidentally, medical devices. This study investigated the genetic and phenotypic formation of biofilm in 105 S. epidermidis strains isolated from the skin of hospitalized patients. Fifty-eight of these patients were positive for the mecA gene (MRSE) and 47 were found to be negative (MSSE). Genetic characterizations were performed for the detection of the mecA, icaADBC, atlE, aap, bhp, IS256 and agr groups by PCR. Biofilm production was examined by culturing the strains in TBS medium and TBS with 0.5 and 1% respectively of glucose, and a semiquantitative assay on tissue culture plates was used. Although a molecular analysis estimate of detailed biofilm formation is costly in terms of time and complexity, a semiquantitative assay can be proposed as a rapid and cheap diagnostic method for initial screening to discover virulent strains. We confirmed a close correlation between genetic and phenotypic characteristics, highlighting the fact that, when S. epidermidis isolates were cultured in TSB with 1% of glucose, an increase in biofilm production was observed, as confirmed by positivity for the ica locus by molecular analysis. PMID- 26485011 TI - Backbone switch to abacavir/lamivudine fixed-dose combination: implications for antiretroviral therapy optimization. AB - Current guidelines recommend treatment optimization in virologically suppressed patients through switching/ simplification strategies to minimize long-term toxicities and improve adherence. The assessment of inflammation/ coagulation profiles may support therapeutic decisions. We undertook a prospective, non randomized study to evaluate the efficacy and safety of switching to ABC/3TC from ZDV/3TC or TDF/FTC backbones, in 40 HIV-1 infected patients with HIV-RNA levels <37 copies/mL (>24 months). Main endpoints were viral load levels, CD4+ T cells and toxicities after 48 weeks. Serum inflammation/coagulation markers (ESR, CRP, D-dimer and fibrinogen) and pro-inflammatory cytokines (IL-6, TNF-alpha, adiponectin, resistin) were evaluated. Baseline characteristics were similar in the two arms, with significantly lower values of e-GFR in patients on TDF/FTC. Markers of inflammation/ coagulation and cytokine profile were also similar, except for higher values of resistin in patients on TDF/ FTC. During follow up, CD4+ T cells increased and viral load remained undetectable in both groups. Patient from ZDV/3TC had significantly greater changes in total cholesterol and serum creatinine. Markers of inflammation/ coagulation remained unchanged. Adiponectin significantly increased in patients from ZDV/3TC. Switching to ABC/3TC was effective and safe. Inflammatory markers remained low in both groups. Some changes in metabolic, kidney and cytokine profiles were apparently specific for baseline cART treatment. PMID- 26485013 TI - Antimicrobial activity of silver doped fabrics for the production of hospital uniforms. AB - Among several alternatives to control hospital-acquired infections (HAIs), a strategy could be the use of hospital uniforms imbued with antimicrobial substances. For this purpose we evaluated the antibacterial activity of two different silver doped fabrics employed for the production of hospital uniforms. The study was conducted in two-step. In the first the antimicrobial activity was evaluated in vitro against Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 6538, Enterococcus faecalis ATCC 29212. In the second, we tested the total viable counts detected from beginning to end of the work shift on experimental silver doped uniforms worn by doctors, nurses, allied health assistants in different hospital wards. The in vitro tests showed a remarkable antibacterial activity of both silver doped samples (>99.9% reduction within 4h of exposure for Gram-positive and within 24 h for Gram-negative bacteria). The experimental uniforms provided results only slightly in agreement with in vitro data. Even if the increase of total viable counts was somewhat lower for experimental uniforms than traditional ones, significant differences were not observed. Despite the results on the uniforms worn, the addition of silver in fabrics to make medical equipment (supplies) remains an interesting option for HAI control. PMID- 26485012 TI - MALDI-TOF mass spectrometry and blakpc gene phylogenetic analysis of an outbreak of carbapenem-resistant K. pneumoniae strains. AB - Carbapenem-resistant Klebsiella pneumoniae isolates are an important cause of nosocomial infections. This study evaluated a rapid cost-saving method based on MALDI-TOF technology, was and compared it with phenotypic, genotypic and epidemiological data for characterization of KPC-Kp strains consecutively isolated during a supposed outbreak. Twenty-five consecutive KPC Klebsiella pneumoniae isolates were identified and clustered by the MALDI Biotyper (Bruker, Daltonics). To display and rank the variance within a data set, principal component analysis (PCA) was performed. ClinProTools models were generated to investigate the highest sum of recognition capability and cross-validation. A Class dendrogram of isolates was constructed using ClinproTool. MLST was performed sequencing gapA, infB, mdh, pgi, rpoB, phoE and tonB genes. blakpc and cps genes were typed. Phylogenetic analysis and genetic distance of the KPC gene were performed using the MEGA6 software. PCA analysis defined two clusters, I and II, which were identified in a dendrogram by both temporal split and different antimicrobial susceptibility profiles. These clusters were composed mostly of strains of the same sequence type (ST512), the most prevalent ST in Italy, and the same cps (type 2). In cluster II, blakpc genotype resulted more variable than in cluster I. Phylogenetic analysis confirmed the genetic diversity in both clusters supported by the epidemiological data. Our study confirms that MALDI-TOF can be a rapid and cost-saving method for epidemiological clustering of KPC K. pneumoniae isolates and its association with blakpc genotyping represents a reliable method to recognize possible clonal strains in nosocomial settings. PMID- 26485014 TI - Association of sexually transmitted infections, Candida species, gram-positive flora and perianal flora with bacterial vaginosis. AB - Bacterial vaginosis (BV) is characterised by depletion of the normal Lactobacillus spp. and overgrowth of commensal anaerobic bacteria. We investigated the composition of vaginal microbiota and their association with BV in women of reproductive age. Vaginal samples from 1197 women were analysed, whereby n=451 patients had normal flora and n=614 were diagnosed with BV, the remaining patients were diagnosed with having either intermediate flora (n=42) or dysbacteriosis (n=90). The reported results show that pathogens are associated with BV. This knowledge will further expand our understanding of events leading to BV, which may lead to more effective prevention and treatment strategies. PMID- 26485016 TI - Use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect carbapenemase production in Enterobacteriaceae by a rapid meropenem degradation assay. AB - We evaluated the analytical performance of a liquid chromatography-tandem mass spectrometry assay to detect carbapenemase activity in a group of carbapenemase producing Enterobacteriaceae by meropenem hydrolysis. This one-hour method showed a sensitivity of 94% and a specificity of 100%, representing a rapid and reliable option compared to conventional phenotypic assays. PMID- 26485017 TI - A rapid qPCR method to investigate the circulation of the yeast Wickerhamomyces anomalus in humans. AB - The yeast Wickerhamomyces anomalus has been proposed for many biotechnological applications in the food industry. However, a number of opportunistic pathogenic strains have been reported as causative agents of nosocomial fungemia. Recognition of potentially pathogenic isolates is an important challenge for the future commercialization of this yeast. The isolation of W. anomalus from different matrices and, recently, from mosquitoes, requires further investigations into its circulation in humans. Here we present a qPCR protocol for the detection of W. anomalus in human blood samples and the results of a screening of 525 donors, including different classes of patients and healthy people. PMID- 26485015 TI - First Italian Ebola virus disease case: management of hospital internal and external communication. AB - On November 25, 2014, an Italian physician infected by Ebola virus in Sierra Leone was admitted to the "Lazzaro Spallanzani" National Institute for Infectious Diseases in Rome, Italy. He was the first Italian case and was successfully cured in 38 days. The staff responsible for communication had a critical role ensuring that this challenging mission went smoothly. The Institutional Press Office working together with the press offices of the Ministry of Health was able to provide the high level of expertise necessary within both medical and communication contexts. Communication strategy, tools and procedures adopted before and after the arrival of the patient are summarized. PMID- 26485018 TI - In vitro antifungal activity of fluconazole and voriconazole against non-Candida yeasts and yeast-like fungi clinical isolates. AB - The risk of opportunistic infections caused by non-Candida yeasts and yeast-like fungi is increasingly common, mainly in immunocompromised patients. Appropriate first-line therapy has not been defined and standardized, mainly due to the low number of cases reported. To improve empirical treatment guidelines, we describe the susceptibility profile to fluconazole and voriconazole of 176 non-Candida yeasts and yeast-like fungi collected from hospitals in Piedmont, North West Italy from January 2009 to December 2013. The results showed that most isolates are susceptible to voriconazole (94%), but less susceptible to fluconazole (78%), suggesting that voriconazole could be used as first-line therapy in infections caused by these fungi. PMID- 26485019 TI - A rare case of infant sepsis due to the emm-89 genotype of Group A Streptococcus within a community-acquired cluster. AB - Invasive Group A Streptococcus disease is a severe and sometimes life-threatening infection with only few cases reported in literature. We describe the case of a 49-day-old male infant with invasive Group A Streptococcus infection characterized by acute otitis media and development of septicemia within a probably community-acquired cluster. The causative agent resulted to be a rare emm-89 genotype of Streptococcus pyogenes. Group A Streptococcus must be considered responsible for sepsis in newborns and young infants. PMID- 26485020 TI - Lack of KIs virus DNA in plasma and cerebrospinal fluid in Italy. AB - Dear Sirs, Satoh et al. recently screened 516 Japanese blood donors with PCR using primers constructed from the consensus domain of the helicase of positive stranded RNA viruses. They reported a novel enveloped virus with a circular double-stranded DNA genome (tentatively named KIs virus, KIs-V) (Satoh et al., 2011) occurring in 36 out of the 100 hepatitis E (HEV) antibody-positive donors with elevated alanine aminotransferase (ALT) levels (>60 IU/L). More recently, Biagini et al. failed to find KIs-V in plasma from 576 French blood donors with unknown HEV serostatus and unknown ALT values (Biagini et al., 2012). Based on an HEV seroprevalence of 3-52% in France, the authors suggested an uncommon frequency of KIs-V infection in healthy persons in France. To date, no information has been available on the prevalence of KIs-V DNA in Italy. In the present paper, we analyzed KIs-V in 242 plasma samples of blood donors, transplant recipients, and patients with chronic viral infections, and in 52 cerebrospinal fluid (CSF) samples of patients with different neurological disorders. Informed consent was obtained from all patients and the study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its amendments. Viral DNA extraction was carried out on 200 MUl of plasma or 200 MUl of CSF by using QIAamp DNA blood kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions. Extracted nucleic acids were amplified for KIs-V DNA with the nested PCR protocol developed by Satoh et al. (2011) and used for screening Japanese blood donors. The first and second PCR rounds were designed on 458 and 304 nt-length fragments, respectively. To validate the amplification process, positive controls obtained from plasma dilutions of a synthetic template corresponding to the target sequence were run in each PCR. PCR sensitivity was less than 5 copies of target sequence. Fourteen liver and 16 kidney and/or pancreas transplant recipients were tested before transplantation and at the time after transplantation when viremia levels of TTV were highest, TTV having been validated by our group and others as a marker of functional immune deficiency (Focosi et al., 2014). None of the samples tested positive for KIs-V. At the same time, we also tested 79 healthy blood donors. Since determination of ALT is a mandatory part of on blood donation according to Italian law we could establish that only 2 donors had ALT values >60 IU/L but in any case <80 IU/L: all of them tested negative for KIs-V. No information on HEV status was available and HEV seroprevalence studies are limited in Italy (Arends et al., 2014). However regional studies show prevalences ranging from 2.9% to 8.8% (Masia et al., 2009). We also tested 50 HIV-positive patients, 41 HCV positive patients, and 42 HBV-positive patients. None of the samples tested positive for KIs-V. Finally, cerebrospinal fluid from 52 patients with different neurological disorders was also tested. All these samples were negative for KIs-V DNA. Thus, although we cannot rule out the possibility that KIs-V circulates in Italy at a very low level and genetically different from the virus found in Japanese population, the results seem to demonstrate a very low prevalence of this novel virus in the Italian population. While the implication of KIs-V in human health remains under debate, extensive regional surveys will help to elucidate the geographical spread of KIs-V and to understand the natural history of the infection in human beings. PMID- 26485021 TI - Early diagnosis and retention in care of HIV-infected patients through rapid salivary testing: a test-and-treat fast track pilot study. AB - Aim of this study was to evaluate the efficacy and the retention-in-care of individuals diagnosed during six years of salivary HIV testing (EASY-test project). Among those linked-to-care at the Infectious Diseases Department of San Raffaele Hospital (Milan, Italy), the proportion of patients engaged, retained in care and virologically suppressed after the antiretroviral treatment was 96%, 100% and 95.2%, respectively. Results from our study suggest that salivary HIV testing may help bring to light cases of HIV infection otherwise undiagnosed, and thus favour a more rapid and wider reduction of the HIV infection burden at the population level. PMID- 26485022 TI - Overexpressing the Multiple-Stress Responsive Gene At1g74450 Reduces Plant Height and Male Fertility in Arabidopsis thaliana. AB - A subset of genes in Arabidopsis thaliana is known to be up-regulated in response to a wide range of different environmental stress factors. However, not all of these genes are characterized as yet with respect to their functions. In this study, we used transgenic knockout, overexpression and reporter gene approaches to try to elucidate the biological roles of five unknown multiple-stress responsive genes in Arabidopsis. The selected genes have the following locus identifiers: At1g18740, At1g74450, At4g27652, At4g29780 and At5g12010. Firstly, T DNA insertion knockout lines were identified for each locus and screened for altered phenotypes. None of the lines were found to be visually different from wildtype Col-0. Secondly, 35S-driven overexpression lines were generated for each open reading frame. Analysis of these transgenic lines showed altered phenotypes for lines overexpressing the At1g74450 ORF. Plants overexpressing the multiple stress responsive gene At1g74450 are stunted in height and have reduced male fertility. Alexander staining of anthers from flowers at developmental stage 12 13 showed either an absence or a reduction in viable pollen compared to wildtype Col-0 and At1g74450 knockout lines. Interestingly, the effects of stress on crop productivity are most severe at developmental stages such as male gametophyte development. However, the molecular factors and regulatory networks underlying environmental stress-induced male gametophytic alterations are still largely unknown. Our results indicate that the At1g74450 gene provides a potential link between multiple environmental stresses, plant height and pollen development. In addition, ruthenium red staining analysis showed that At1g74450 may affect the composition of the inner seed coat mucilage layer. Finally, C-terminal GFP fusion proteins for At1g74450 were shown to localise to the cytosol. PMID- 26485023 TI - Using Agent-Based Modelling to Predict the Role of Wild Refugia in the Evolution of Resistance of Sea Lice to Chemotherapeutants. AB - A major challenge for Atlantic salmon farming in the northern hemisphere is infestation by the sea louse parasite Lepeophtheirus salmonis. The most frequent method of controlling these sea louse infestations is through the use of chemical treatments. However, most major salmon farming areas have observed resistance to common chemotherapeutants. In terrestrial environments, many strategies employed to manage the evolution of resistance involve the use of refugia, where a portion of the population is left untreated to maintain susceptibility. While refugia have not been deliberately used in Atlantic salmon farming, wild salmon populations that migrate close to salmon farms may act as natural refugia. In this paper we describe an agent-based model that explores the influence of different sizes of wild salmon populations on resistance evolution in sea lice on a salmon farm. Using the model, we demonstrate that wild salmon populations can act as refugia that limit the evolution of resistance in the sea louse populations. Additionally, we demonstrate that an increase in the size of the population of wild salmon results in an increased effect in slowing the evolution of resistance. We explore the effect of a population fitness cost associated with resistance, finding that in some cases it substantially reduces the speed of evolution to chemical treatments. PMID- 26485024 TI - Advances in the Diagnosis of Human Opisthorchiasis: Development of Opisthorchis viverrini Antigen Detection in Urine. AB - BACKGROUND: Many strategies to control opisthorchiasis have been employed in Thailand, but not in the other neighbouring countries. Specific control methods include mass drug administration (MDA) and health education to reduce raw fish consumption. These control efforts have greatly shifted the epidemiology of Opisthorchis viverrini (OV) infection over the last decade from presenting as densely concentrated "heavy" infections in single villages to widespread "light" OV infections distributed over wide geographical areas. Currently, the "gold standard" detection method for OV infection is formalin ethyl-acetate concentration technique (FECT), which has limited diagnostic sensitivity and diagnostic specificity for light OV infections, with OV eggs often confused with eggs of minute intestinal flukes (MIFs) in feces. In this study, we developed and evaluated the diagnostic performance of a monoclonal antibody-based enzyme-linked immunosorbent assay for the measurement of OV excretory-secretory (ES) antigens in urine (urine OV-ES assay) for the diagnosis of opisthorchiasis compared to the gold standard detection FECT method. METHODOLOGY: We tested several methods for pre-treating urine samples prior to testing the diagnostic performance of the urine OV-ES assay. Using trichloroacetic acid (TCA) pre-treated urine, we compared detection and quantification of OV infection using the urine OV-ES assay versus FECT in OV-endemic areas in Northeastern Thailand. Receiver operating characteristic (ROC) curves were used to determine the diagnostic sensitivity and specificity of the urine OV-ES assay using TCA pre-treated urine, and to establish diagnostic positivity thresholds. The Positive Predictive Value as well as the likelihood of obtaining a positive test result (LR+) or a negative test result (LR-) were calculated for the established diagnostic positivity threshold. Diagnostic risks (Odds Ratios) were estimated using logistic regression. RESULTS: When urine samples were pre-treated with TCA prior to use in the urine OV-ES assay, the analytical sensitivity was significantly improved. Using TCA pre treatment of urine, the urine OV-ES assay had a limit of detection (LoD) of 39 ng/ml compared to the LoD of 52 ng/mL reported for coprological antigen detection methods. Similarly, the urine OV-ES assay correlated significantly with intensity of OV infection as measured by FECT. The urine OV-ES assay was also able to detect 28 individuals as positive from the 63 (44.4%) individuals previously determined to be negative using FECT. The likelihood of a positive diagnosis of OV infection by urine OV-ES assay increased significantly with the intensity of OV infection as determined by FECT. With reference to FECT, the sensitivity and specificity of the urine OV-ES assay was 81% and 70%, respectively. CONCLUSION: The detection of OV-infection by the urine OV-ES assay showed much greater diagnostic sensitivity and diagnostic specificity than the current "gold standard" FECT method for the detection and quantification of OV infection. Due to its ease-of-use, and noninvasive sample collection (urine), the urine OV-ES assay offers the potential to revolutionize the diagnosis of liver fluke infection and provide an effective tool for control and elimination of these tumorigenic parasites. PMID- 26485026 TI - Mapping Atmospheric Moisture Climatologies across the Conterminous United States. AB - Spatial climate datasets of 1981-2010 long-term mean monthly average dew point and minimum and maximum vapor pressure deficit were developed for the conterminous United States at 30-arcsec (~800m) resolution. Interpolation of long term averages (twelve monthly values per variable) was performed using PRISM (Parameter-elevation Relationships on Independent Slopes Model). Surface stations available for analysis numbered only 4,000 for dew point and 3,500 for vapor pressure deficit, compared to 16,000 for previously-developed grids of 1981-2010 long-term mean monthly minimum and maximum temperature. Therefore, a form of Climatologically-Aided Interpolation (CAI) was used, in which the 1981-2010 temperature grids were used as predictor grids. For each grid cell, PRISM calculated a local regression function between the interpolated climate variable and the predictor grid. Nearby stations entering the regression were assigned weights based on the physiographic similarity of the station to the grid cell that included the effects of distance, elevation, coastal proximity, vertical atmospheric layer, and topographic position. Interpolation uncertainties were estimated using cross-validation exercises. Given that CAI interpolation was used, a new method was developed to allow uncertainties in predictor grids to be accounted for in estimating the total interpolation error. Local land use/land cover properties had noticeable effects on the spatial patterns of atmospheric moisture content and deficit. An example of this was relatively high dew points and low vapor pressure deficits at stations located in or near irrigated fields. The new grids, in combination with existing temperature grids, enable the user to derive a full suite of atmospheric moisture variables, such as minimum and maximum relative humidity, vapor pressure, and dew point depression, with accompanying assumptions. All of these grids are available online at http://prism.oregonstate.edu, and include 800-m and 4-km resolution data, images, metadata, pedigree information, and station inventory files. PMID- 26485025 TI - Limonoids from Melia azedarach Fruits as Inhibitors of Flaviviruses and Mycobacterium tubercolosis. AB - The biological diversity of nature is the source of a wide range of bioactive molecules. The natural products, either as pure compounds or as standardized plant extracts, have been a successful source of inspiration for the development of new drugs. The present work was carried out to investigate the cytotoxicity, antiviral and antimycobacterial activity of the methanol extract and of four identified limonoids from the fruits of Melia azedarach (Meliaceae). The extract and purified limonoids were tested in cell-based assays for antiviral activity against representatives of ssRNA, dsRNA and dsDNA viruses and against Mycobacterium tuberculosis. Very interestingly, 3-alpha-tigloyl-melianol and melianone showed a potent antiviral activity (EC50 in the range of 3-11MUM) against three important human pathogens, belonging to Flaviviridae family, West Nile virus, Dengue virus and Yellow Fever virus. Mode of action studies demonstrated that title compounds were inhibitors of West Nile virus only when added during the infection, acting as inhibitors of the entry or of a very early event of life cycle. Furthermore, 3-alpha-tigloyl-melianol and methyl kulonate showed interesting antimycobacterial activity (with MIC values of 29 and 70 MUM respectively). The limonoids are typically lipophilic compounds present in the fruits of Melia azeradach. They are known as cytotoxic compounds against different cancer cell lines, while their potential as antiviral and antibacterial was poorly investigated. Our studies show that they may serve as a good starting point for the development of novel drugs for the treatment of infections by Flaviviruses and Mycobacterium tuberculosis, for which there is a continued need. PMID- 26485027 TI - Familial Clarification of Saucrosmylidae stat. nov. and New Saucrosmylids from Daohugou, China (Insecta, Neuroptera). AB - BACKGOUND: Saucrosmylids are characterized by the typically large body size, complicated venation and diverse wing markings, which were only discovered in Middle Jurassic of Daohugou, Ningcheng county, Inner Mongolia, China. PRINCIPAL FINDINGS: Saucrosmylinae Ren, 2003, originally included as a subfamily in the Osmylidae, was transferred and elevated to family rank based on the definitive synapomorphic character. The updated definition of Saucrosmylidae stat. nov. was outlined in detail: presence of nygma and trichosors; diverse markings on membrane; complicated cross-veins; distal fusion of Sc and R1; expanded space between R1 and Rs having 2-7 rows of cells that should be a synapomorphic character of the family; proximal MP fork. And the previous misuses of Saucrosmylidae are also clarified. Furthermore, a new genus with a new species and an indeterminate species of Saucrosmylidae are described as Ulrikezza aspoeckae gen. et sp. nov. and Ulrikezza sp. from the Middle Jurassic of Daohugou, Inner Mongolia, China. A key to genera of Saucrosmylidae is provided. CONCLUSIONS/SIGNIFICANCE: The intriguing group represents a particular lineage of Neuroptera in the Mesozoic Era. The familial status of Saucrosmylidae was firstly advanced that clarified the former incorrect citation and use of the family name. As an extinct clade, many species of the saucrosmylids were erected just based on a single fore- or hindwing, and it should be realized that providing more stable characters is necessary when describing new lacewing taxa just based on an isolated hindwing. It is vital for the systematics of Saucrosmylidae. PMID- 26485028 TI - Antigenic Characterization of the HCMV gH/gL/gO and Pentamer Cell Entry Complexes Reveals Binding Sites for Potently Neutralizing Human Antibodies. AB - Human Cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and in fetuses following congenital infection. The glycoprotein complexes gH/gL/gO and gH/gL/UL128/UL130/UL131A (Pentamer) are required for HCMV entry in fibroblasts and endothelial/epithelial cells, respectively, and are targeted by potently neutralizing antibodies in the infected host. Using purified soluble forms of gH/gL/gO and Pentamer as well as a panel of naturally elicited human monoclonal antibodies, we determined the location of key neutralizing epitopes on the gH/gL/gO and Pentamer surfaces. Mass Spectrometry (MS) coupled to Chemical Crosslinking or to Hydrogen Deuterium Exchange was used to define residues that are either in proximity or part of neutralizing epitopes on the glycoprotein complexes. We also determined the molecular architecture of the gH/gL/gO- and Pentamer-antibody complexes by Electron Microscopy (EM) and 3D reconstructions. The EM analysis revealed that the Pentamer specific neutralizing antibodies bind to two opposite surfaces of the complex, suggesting that they may neutralize infection by different mechanisms. Together, our data identify the location of neutralizing antibodies binding sites on the gH/gL/gO and Pentamer complexes and provide a framework for the development of antibodies and vaccines against HCMV. PMID- 26485029 TI - Ibuprofen and Diclofenac Restrict Migration and Proliferation of Human Glioma Cells by Distinct Molecular Mechanisms. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with anti-tumorigenic effects in different tumor entities. For glioma, research has generally focused on diclofenac; however data on other NSAIDs, such as ibuprofen, is limited. Therefore, we performed a comprehensive investigation of the cellular, molecular, and metabolic effects of ibuprofen and diclofenac on human glioblastoma cells. METHODS: Glioma cell lines were treated with ibuprofen or diclofenac to investigate functional effects on proliferation and cell motility. Cell cycle, extracellular lactate levels, lactate dehydrogenase-A (LDH A) expression and activity, as well as inhibition of the Signal Transducer and Activator of Transcription 3 (STAT-3) signaling pathway, were determined. Specific effects of diclofenac and ibuprofen on STAT-3 were investigated by comparing their effects with those of the specific STAT-3 inhibitor STATTIC. RESULTS: Ibuprofen treatment led to a stronger inhibition of cell growth and migration than treatment with diclofenac. Proliferation was affected by cell cycle arrest at different checkpoints by both agents. In addition, diclofenac, but not ibuprofen, decreased lactate levels in all concentrations used. Both decreased STAT-3 phosphorylation; however, diclofenac led to decreased c-myc expression and subsequent reduction in LDH-A activity, whereas treatment with ibuprofen in higher doses induced c-myc expression and less LDH-A alteration. CONCLUSIONS: This study indicates that both ibuprofen and diclofenac strongly inhibit glioma cells, but the subsequent metabolic responses of both agents are distinct. We postulate that ibuprofen may inhibit tumor cells also by COX- and lactate-independent mechanisms after long-term treatment in physiological dosages, whereas diclofenac mainly acts by inhibition of STAT-3 signaling and downstream modulation of glycolysis. PMID- 26485030 TI - Comparative De Novo Transcriptome Analysis of Fertilized Ovules in Xanthoceras sorbifolium Uncovered a Pool of Genes Expressed Specifically or Preferentially in the Selfed Ovule That Are Potentially Involved in Late-Acting Self Incompatibility. AB - Xanthoceras sorbifolium, a tree species endemic to northern China, has high oil content in its seeds and is recognized as an important biodiesel crop. The plant is characterized by late-acting self-incompatibility (LSI). LSI was found to occur in many angiosperm species and plays an important role in reducing inbreeding and its harmful effects, as do gametophytic self-incompatibility (GSI) and sporophytic self-incompatibility (SSI). Molecular mechanisms of conventional GSI and SSI have been well characterized in several families, but no effort has been made to identify the genes involved in the LSI process. The present studies indicated that there were no significant differences in structural and histological features between the self- and cross-pollinated ovules during the early stages of ovule development until 5 days after pollination (DAP). This suggests that 5 DAP is likely to be a turning point for the development of the selfed ovules. Comparative de novo transcriptome analysis of the selfed and crossed ovules at 5 DAP identified 274 genes expressed specifically or preferentially in the selfed ovules. These genes contained a significant proportion of genes predicted to function in the biosynthesis of secondary metabolites, consistent with our histological observations in the fertilized ovules. The genes encoding signal transduction-related components, such as protein kinases and protein phosphatases, are overrepresented in the selfed ovules. X. sorbifolium selfed ovules also specifically or preferentially express many unique transcription factor (TF) genes that could potentially be involved in the novel mechanisms of LSI. We also identified 42 genes significantly up regulated in the crossed ovules compared to the selfed ovules. The expression of all 16 genes selected from the RNA-seq data was validated using PCR in the selfed and crossed ovules. This study represents the first genome-wide identification of genes expressed in the fertilized ovules of an LSI species. The availability of a pool of specifically or preferentially expressed genes from selfed ovules for X. sorbifolium will be a valuable resource for future genetic analyses of candidate genes involved in the LSI response. PMID- 26485031 TI - Mechanisms of neurodegeneration after severe hypoxic-ischemic injury in the neonatal rat brain. AB - PURPOSE: Apoptosis is implicated in mild-moderate ischemic injury. Cell death pathways in the severely ischemic brain are not characterized. We sought to determine the role of apoptosis in the severely ischemic immature brain. METHODS: Seven-day old rats were randomly assigned to mild-moderate or severe cerebral hypoxia-ischemia (HI) group. After ligating the right common carotid artery, animals were subjected to hypoxia for 90min in the mild-moderate HI or 180min in the severe HI. The core and peri-infarct area were measured in H&E stained brain sections using NIS Elements software. Brain sections were processed for caspase 3, AIF and RIP3 immuno-staining. Number of positive cells were counted and compared between the two groups. RESULTS: The core constituted a significantly higher proportion of the ischemic lesion in the severely compared to the moderately injured brain (P<0.04) up to 7 days post-injury. Apoptotic cell death was significantly higher (P<0.05) in the core than the peri-infarct of the severe HI brain. In the peri-infarct area of severe HI, AIF-induced cell death increased over time and caspase-3 and AIF equally mediated neuronal death. Necroptosis was significantly higher (P=0.02) in the peri-infarct of the severe HI lesion compared to the moderate HI lesion. In males, but not in females, apoptosis was higher in moderate compared to severe HI. CONCLUSIONS: Caspase-independent cell death plays an important role in severe ischemic injury. Injury severity, timing of intervention post-injury and sex of the animal are important determinants in designing neuroprotective intervention for the severely ischemic immature brain. PMID- 26485032 TI - Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain. AB - Organisms need to adapt to the ecological constraints in their habitat. How specific processes reflect such adaptations are difficult to model experimentally. We tested whether environmental shifts in oxygen tension lead to events in the adult newt brain that share features with processes occurring during neuronal regeneration under normoxia. By experimental simulation of varying oxygen concentrations, we show that hypoxia followed by re-oxygenation lead to neuronal death and hallmarks of an injury response, including activation of neural stem cells ultimately leading to neurogenesis. Neural stem cells accumulate reactive oxygen species (ROS) during re-oxygenation and inhibition of ROS biosynthesis counteracts their proliferation as well as neurogenesis. Importantly, regeneration of dopamine neurons under normoxia also depends on ROS production. These data demonstrate a role for ROS-production in neurogenesis in newts and suggest that this role may have been recruited to the capacity to replace lost neurons in the brain of an adult vertebrate. PMID- 26485033 TI - The evolution of non-reproductive workers in insect colonies with haplodiploid genetics. AB - Eusociality is a distinct form of biological organization. A key characteristic of advanced eusociality is the presence of non-reproductive workers. Why evolution should produce organisms that sacrifice their own reproductive potential in order to aid others is an important question in evolutionary biology. Here, we provide a detailed analysis of the selective forces that determine the emergence and stability of non-reproductive workers. We study the effects, in situations where the queen of the colony has mated once or several times, of recessive and dominant sterility alleles acting in her offspring. Contrary to widespread belief based on heuristic arguments of genetic relatedness, non-reproductive workers can easily evolve in polyandrous species. The crucial quantity is the functional relationship between a colony's reproductive rate and the fraction of non-reproductive workers present in that colony. We derive precise conditions for natural selection to favor the evolution of non-reproductive workers. PMID- 26485035 TI - Frailty in Clinical Practice. AB - Frailty is a geriatric syndrome characterized by reduced homeostatic reserves, exposing the organism to extreme vulnerability to endogenous and exogenous stressors. Since disability is considered as an almost irreversible condition at advanced age, frailty has been indicated as a promising target for specific interventions in order to prevent disability. From a theoretical viewpoint, the concept of frailty has been well established, but its operationalization is still subject to controversy. This impediment leads to the postponement of the integration of frailty in the clinical setting. In the present article, we discuss the main issues regarding the frailty syndrome in the clinical setting, describe possible solutions (especially on the basis of our experience derived from the frailty clinic we have set up in Toulouse, France), and present the most relevant research perspectives in the field. PMID- 26485034 TI - Human blindsight is mediated by an intact geniculo-extrastriate pathway. AB - Although damage to the primary visual cortex (V1) causes hemianopia, many patients retain some residual vision; known as blindsight. We show that blindsight may be facilitated by an intact white-matter pathway between the lateral geniculate nucleus and motion area hMT+. Visual psychophysics, diffusion weighted magnetic resonance imaging and fibre tractography were applied in 17 patients with V1 damage acquired during adulthood and 9 age-matched controls. Individuals with V1 damage were subdivided into blindsight positive (preserved residual vision) and negative (no residual vision) according to psychophysical performance. All blindsight positive individuals showed intact geniculo-hMT+ pathways, while this pathway was significantly impaired or not measurable in blindsight negative individuals. Two white matter pathways previously implicated in blindsight: (i) superior colliculus to hMT+ and (ii) between hMT+ in each hemisphere were not consistently present in blindsight positive cases. Understanding the visual pathways crucial for residual vision may direct future rehabilitation strategies for hemianopia patients. PMID- 26485036 TI - Current status and future directions of pharmacological therapy for acromegaly. AB - Acromegaly is a chronic systemic disorder caused in the vast majority of cases by a GH-secreting pituitary adenoma and resulting in significant morbidity and mortality if left untreated. The treatment of choice is the trans-sphenoidal resection of the adenoma, and although 80% of patients with microadenomas or confined macroadenomas achieve biochemical remission, the surgical success rate for patients harboring tumors with extrasellar extension is below 50%. Thus, a considerable proportion of patients will require some form of adjuvant treatment. Acromegaly can be approached pharmacologically by inhibiting GH secretion by the tumor (somatostatin analogues, dopamine agonists) or by antagonizing GH actions at its target tissues (GH receptor antagonists). The primary pharmacological treatment of acromegaly is increasingly gaining acceptance by both physicians and patients. The decision to use primary pharmacological treatment has to take into account the clinical characteristics of the patient (presence of comorbidities that significantly increase the surgical risk) and the biological nature of the adenoma (tumor size and location), as well as other aspects such as the availability of a pituitary surgeon and the cost of medications. This review provides a critical summary and update of the pharmacological treatment of acromegaly focusing both, on well-established agents and strategies as well as on novel compounds that are currently being developed. PMID- 26485038 TI - Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats. AB - Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography-tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney. PMID- 26485039 TI - The Effects of Direction of Exertion, Path, and Load Placement in Nursing Cart Pushing and Pulling Tasks: An Electromyographical Study. AB - The purpose of this study was to explore the effects of direction of exertion (DOE) (pushing, pulling), path (walking in a straight line, turning left, walking uphill), and load placement (LP) (the 18 blocks were indicated by X, Y and Z axis; there were 3 levels on the X axis, 2 levels on the Y axis, and 3 levels on the Z axis) on muscle activity and ratings of perceived exertion in nursing cart pushing and pulling tasks. Ten participants who were female students and not experienced nurses were recruited to participate in the experiment. Each participant performed 108 experimental trials in the study, consisting of 2 directions of exertion (push and pull), 3 paths, and 18 load placements (indicated by X, Y and Z axes). A 23kg load was placed into one load placement. The dependent variables were electromyographic (EMG) data of four muscles collected bilaterally as follows: Left (L) and right (R) trapezius (TR), flexor digitorum superficialis (FDS), extensor digitorum (ED), and erector spinae (ES) and subjective ratings of perceived exertion (RPE). Split-split-plot ANOVA was conducted to analyze significant differences between DOE, path, and LP in the EMG and RPE data. Pulling cart tasks produced a significantly higher activation of the muscles (RTR:54.4%, LTR:50.3%, LFDS:57.0%, LED:63.4%, RES:40.7%, LES:36.7%) than pushing cart tasks (RTR:42.4%, LTR:35.1%, LFDS:32.3%, LED:55.1%, RES:33.3%, LES:32.1%). A significantly greater perceived exertion was found in pulling cart tasks than pushing cart tasks. Significantly higher activation of all muscles and perceived exertion were observed for walking uphill than walking in a straight line and turning left. Significantly lower muscle activity of all muscles and subject ratings were observed for the central position on the X axis, the bottom position on the Y axis, and the posterior position on the Z axis. These findings suggest that nursing staff should adopt forward pushing when moving a nursing cart, instead of backward pulling, and that uphill paths should be avoided in the design of work environments. In terms of distribution of the load in a nursing cart, heavier materials should be positioned at bottom of the cabinet, centered on the horizontal plane and close to the handle, to reduce the physical load of the nursing staff. PMID- 26485041 TI - An In Vitro Model for Measuring Immune Responses to Malaria in the Context of HIV Co-infection. AB - Malaria and HIV co-infection is a growing health priority. However, most research on malaria or HIV currently focuses on each infection individually. Although understanding the disease dynamics for each of these pathogens independently is vital, it is also important that the interactions between these pathogens are investigated and understood. We have developed a versatile in vitro model of HIV malaria co-infection to study host immune responses to malaria in the context of HIV infection. Our model allows the study of secreted factors in cellular supernatants, cell surface and intracellular protein markers, as well as RNA expression levels. The experimental design and methods used limit variability and promote data reliability and reproducibility. All pathogens used in this model are natural human pathogens (Plasmodium falciparum and HIV-1), and all infected cells are naturally infected and used fresh. We use human erythrocytes parasitized with P. falciparum and maintained in continuous in vitro culture. We obtain freshly isolated peripheral blood mononuclear cells from chronically HIV infected volunteers. Every condition used has an appropriate control (P. falciparum parasitized vs. normal erythrocytes), and every HIV-infected donor has an HIV uninfected control, from which cells are harvested on the same day. This model provides a realistic environment to study the interactions between malaria parasites and human immune cells in the context of HIV infection. PMID- 26485040 TI - NMR Based Cerebrum Metabonomic Analysis Reveals Simultaneous Interconnected Changes during Chick Embryo Incubation. AB - To find out if content changes of the major functional cerebrum metabolites are interconnected and formed a network during the brain development, we obtained high-resolution magic-angle-spinning (HR-MAS) 1H NMR spectra of cerebrum tissues of chick embryo aged from incubation day 10 to 20, and postnatal day 1, and analyzed the data with principal component analysis (PCA). Within the examined time window, 26 biological important molecules were identified and 12 of them changed their relative concentration significantly in a time-dependent manner. These metabolites are generally belonged to three categories, neurotransmitters, nutrition sources, and neuronal or glial markers. The relative concentration changes of the metabolites were interconnected among/between the categories, and, more interestingly, associated with the number and size of Nissl-positive neurons. These results provided valuable biochemical and neurochemical information to understand the development of the embryonic brain. PMID- 26485042 TI - Gene-specific DNA methylation of DNMT3B and MTHFR and colorectal adenoma risk. AB - DNA methyltransferase 3B (DNMT3B) and methylenetetrahydrofolate reductase (MTHFR) are genes which encode enzymes critical to one-carbon metabolism. Polymorphisms in these genes have been implicated in colorectal cancer etiology; however, epigenetic modifications such as gene-specific DNA methylation also affect gene expression. DNA methylation of DNMT3B and MTHFR was quantified in blood leukocytes using Sequenom EpiTYPER(r) among 272 participants undergoing a screening colonoscopy. DNA methylation was quantified in 66 and 28CpG sites of DNMT3B and MTHFR respectively, and conceptualized using two approaches. First, measures representing average methylation across all CpG sites were created. Second, unsupervised principal component (PC) analysis was used to identify summary variables representing methylation around the transcription start site and in the gene-coding area for both DNMT3B and MTHFR. Logistic regression was used to compare methylation levels between participants diagnosed with colorectal adenoma(s) versus those with a normal colonoscopy via the estimation of odds ratios (ORs) and 95% confidence intervals (95% CIs) for the risk of colorectal adenomas. No association was observed between average DNA methylation of either DNMT3B or MTHFR and colorectal adenoma risk. For DNMT3B, increasing DNA methylation of CpG sites in the gene-coding area was associated with a higher risk of colorectal adenomas (OR=1.34; 95% CI: 1.01-1.79 per SD). This research provides preliminary evidence that methylation of DNMT3B may have functional significance with respect to colorectal adenomas, precursors to the vast majority of colorectal cancers. PMID- 26485043 TI - cAMP/PKA Pathways and S56 Phosphorylation Are Involved in AA/PGE2-Induced Increases in rNaV1.4 Current. AB - Arachidonic acid (AA) and its metabolites are important second messengers for ion channel modulation. The effects of extracellular application of AA and its non metabolized analogue on muscle rNaV1.4 Na+ current has been studied, but little is known about the effects of intracellular application of AA on this channel isoform. Here, we report that intracellular application of AA significantly augmented the rNaV1.4 current peak without modulating the steady-state activation and inactivation properties of the rNaV1.4 channel. These results differed from the effects of extracellular application of AA on rNaV1.4 current. The effects of intracellular AA were mimicked by prostaglandin E2 but not eicosatetraynoic acid (ETYA), the non-metabolized analogue of AA, and were eliminated by treatment with cyclooxygenase inhibitors, flufenamic acid, or indomethacin. AA/PGE2-induced activation of rNaV1.4 channels was mimicked by a cAMP analogue (db-cAMP) and eliminated by a PKA inhibitor, PKAi. Furthermore, inhibition of EP2 and EP4 (PGE2 receptors) with AH6809 and AH23848 reduced the intracellular AA/PGE2-induced increase of rNaV1.4 current. Two mutated channels, rNaV1.4S56A and rNaV1.4T21A, were designed to investigate the role of predicted phosphorylation sites in the AA/PGE2-mediated regulation of rNaV1.4 currents. In rNaV1.4S56A, the effects of intracellular db-cAMP, AA, and PGE2 were significantly reduced. The results of the present study suggest that intracellular AA augments rNaV1.4 current by PGE2/EP receptor-mediated activation of the cAMP/PKA pathway, and that the S56 residue on the channel protein is important for this process. PMID- 26485045 TI - Genetically engineered mesenchymal stem cell therapy using self-assembling supramolecular hydrogels. AB - Stem cell therapy has attracted a great deal of attention for treating intractable diseases such as cancer, stroke, liver cirrhosis, and ischemia. Especially, mesenchymal stem cells (MSCs) have been widely investigated for therapeutic applications due to the advantageous characteristics of long life span, facile isolation, rapid proliferation, prolonged transgene expression, hypo immunogenicity, and tumor tropism. MSCs can exert their therapeutic effects by releasing stress-induced therapeutic molecules after their rapid migration to damaged tissues. Recently, to improve the therapeutic efficacy, genetically engineered MSCs have been developed for therapeutic transgene expression by viral gene transduction and non-viral gene transfection. In general, the number of therapeutic cells for injection should be more than several millions for effective cell therapy. Adequate carriers for the controlled delivery of MSCs can reduce the required cell numbers and extend the duration of therapeutic effect, which provide great benefits for chronic disease patients. In this review, we describe genetic engineering of MSCs, recent progress of self-assembling supramolecular hydrogels, and their applications to cell therapy for intractable diseases and tissue regeneration. PMID- 26485044 TI - Physical Activity in Vietnam: Estimates and Measurement Issues. AB - INTRODUCTION: Our aims were to provide the first national estimates of physical activity (PA) for Vietnam, and to investigate issues affecting their accuracy. METHODS: Measurements were made using the Global Physical Activity Questionnaire (GPAQ) on a nationally-representative sample of 14706 participants (46.5% males, response 64.1%) aged 25-64 years selected by multi-stage stratified cluster sampling. RESULTS: Approximately 20% of Vietnamese people had no measureable PA during a typical week, but 72.9% (men) and 69.1% (women) met WHO recommendations for PA by adults for their age. On average, 52.0 (men) and 28.0 (women) Metabolic Equivalent Task (MET)-hours/week (largely from work activities) were reported. Work and total PA were higher in rural areas and varied by season. Less than 2% of respondents provided incomplete information, but an additional one-in-six provided unrealistically high values of PA. Those responsible for reporting errors included persons from rural areas and all those with unstable work patterns. Box-Cox transformation (with an appropriate constant added) was the most successful method of reducing the influence of large values, but energy scaled values were most strongly associated with pathophysiological outcomes. CONCLUSIONS: Around seven-in-ten Vietnamese people aged 25-64 years met WHO recommendations for total PA, which was mainly from work activities and higher in rural areas. Nearly all respondents were able to report their activity using the GPAQ, but with some exaggerated values and seasonal variation in reporting. Data transformation provided plausible summary values, but energy-scaling fared best in association analyses. PMID- 26485046 TI - Continuous delivery of rhBMP2 and rhVEGF165 at a certain ratio enhances bone formation in mandibular defects over the delivery of rhBMP2 alone--An experimental study in rats. AB - The aim of the present study was to test the hypothesis that different amounts of vascular endothelial growth factor and bone morphogenic protein differentially affect bone formation when applied for repair of non-healing defects in the rat mandible. Porous composite PDLLA/CaCO3 carriers were fabricated as slow release carriers and loaded with rhBMP2 and rhVEGF165 in 10 different dosage combinations using gas foaming with supercritical carbon dioxide. They were implanted in non healing defects of the mandibles of 132 adult Wistar rats with additional lateral augmentation. Bone formation was assessed both radiographically (bone volume) and by histomorphometry (bone density). The use of carriers with a ratio of delivery of VEGF/BMP between 0.7 and 1.2 was significantly related to the occurrence of significant increases in radiographic bone volume and/or histologic bone density compared to the use of carriers with a ratio of delivery of <= 0.5 when all intervals and all outcome parameters were considered. Moreover, simultaneous delivery at this ratio helped to "save" rhBMP2 as both bone volume and bone density after 13 weeks were reached/surpassed using half the dosage required for rhBMP2 alone. It is concluded, that the combined delivery of rhVEGF165 and rhBMP2 for repair of critical size mandibular defects can significantly enhance volume and density of bone formation over delivery of rhBMP2 alone. It appears from the present results that continuous simultaneous delivery of rhVEGF165 and rhBMP2 at a ratio of approximately 1 is favourable for the enhancement of bone formation. PMID- 26485047 TI - beta-glucan microparticles targeted to epithelial APN as oral antigen delivery system. AB - Enteric diseases still have a devastating impact on global health. Oral vaccination is crucial to prevent intestinal infections, since only vaccines delivered to the intestinal tract elicit potent immune responses at the site of pathogen entry. However, oral vaccines encounter multiple barriers, including poor uptake and tolerance mechanisms, preventing the immune system to react to innocuous environmental antigens. Antigen delivery systems combined with selective targeting seem a promising strategy to overcome these obstacles. The current study evaluates the capacity of aminopeptidase N (APN)-targeted beta glucan microparticles (GPs) as antigen delivery system. Antibodies against APN, an intestinal epithelial receptor, are efficiently oriented conjugated to GPs via the biolinker protein G. The resultant microparticles were analyzed for their antigen load, adjuvanticity and interaction with enterocytes and dendritic cells (DCs). Functionalization of GPs with antibodies neither impedes antigen load nor adjuvanticity. In addition, targeting to APN increases the uptake of microparticles by enterocytes and DCs, leading to an enhanced maturation of the latter as evidenced by an upregulation of maturation markers and a strong pro inflammatory cytokine response. Finally, oral administration of APN-targeted antigen-loaded particles to piglets elicits higher serum antigen-specific antibody responses as compared to control particles. Taken together, these data support the use of APN-targeted GPs for oral delivery of antigens. PMID- 26485048 TI - Medication Nonadherence and Effectiveness of Preventive Pharmacological Therapy for Kidney Stones. AB - PURPOSE: Among patients with kidney stones rates of adherence to thiazide diuretics, alkali citrate therapy and allopurinol, collectively referred to as preventive pharmacological therapy, are low. This lack of adherence may reduce the effectiveness of secondary prevention efforts, leading to poorer clinical health outcomes in patients with kidney stones. To examine the impact that medication nonadherence has on the secondary prevention of kidney stones, we compared clinical health outcomes between patients who adhered to their regimen and those who did not. MATERIALS AND METHODS: Using medical and pharmacy claims data we identified adult patients with a physician coded diagnosis for kidney stones. Among the subset with a prescription fill for a preventive pharmacological therapy agent, we then measured adherence to therapy within the first 6 months of initiating treatment using the proportion of days covered formula. We defined adherence as a proportion of days covered value of 80% or greater. Finally, we fitted multivariable logistic regression models to examine the association between medication adherence and the occurrence of a stone related clinical health outcome (an emergency department visit, hospitalization or surgery for stone disease). RESULTS: Of the 8,950 patients who met the study eligibility criteria slightly more than half (51.1%) were adherent to preventive pharmacological therapy. The frequency of emergency department visits, hospitalization and surgery for stone disease was significantly lower among adherent patients. After controlling for sociodemographic factors and the level of comorbid illness, patients who were adherent to therapy had 27% lower odds of an emergency department visit (OR 0.73, 95% CI 0.64-0.84), 41% lower odds of hospital admission (OR 0.59, 95% CI 0.49-0.71) and 23% lower odds of surgery for stone disease (OR 0.77, 95% CI 0.69-0.85) than nonadherent patients. CONCLUSIONS: Our data highlight the consequences of nonadherence to preventive pharmacological therapy among patients with kidney stones. To improve adherence further research is needed to understand patient and provider level factors that contribute to lower rates of adherence. PMID- 26485049 TI - Direct Comparison of GreenLight Laser XPS Photoselective Prostate Vaporization and GreenLight Laser En Bloc Enucleation of the Prostate in Enlarged Glands Greater than 80 ml: a Study of 120 Patients. AB - PURPOSE: We compare patient outcomes after 180 W XPSTM GreenLightTM photoselective vaporization of the prostate and GreenLight laser enucleation of the prostate used to surgically manage benign prostatic obstruction. MATERIALS AND METHODS: Two groups of 60 consecutive patients with enlarged glands (greater than 80 ml) underwent GreenLight laser prostate enucleation or photoselective prostate vaporization (performed by the same surgeon and including the learning curve) and were retrospectively evaluated. Perioperative data from both groups were compared. RESULTS: The operative time was significantly shorter in the GreenLight laser prostate enucleation group (60 vs 82 minutes, p <0.0001). Complication rates were comparable between the groups. At 2 months the rate of urinary incontinence was significantly higher in the GreenLight laser prostate enucleation group (25% vs 3.4%, p <0.0001) but incontinence rates were similar at 6 months (3.4% vs 0%, p=0.50). At 6 months International Prostate Symptom Score quality of life and post-void residual urine volume had similarly decreased in the 2 groups after the procedure (compared to baseline), whereas the maximum urinary flow rate had greatly improved, significantly favoring the GreenLight laser prostate enucleation group (+78% vs +64%, p <0.0001). Prostate size and prostate specific antigen reductions were significantly higher in the GreenLight laser prostate enucleation group (74% vs 57%, p <0.0001 and 67% vs 40%, respectively, p=0.007). The unplanned hospital readmission rates were similar in both groups (16.7% vs 6.7%, p=0.16). CONCLUSIONS: Photoselective vaporization of the prostate and GreenLight laser enucleation of the prostate are safe and provide satisfactory short-term functional outcomes in patients with a prostate volume greater than 80 ml. However, the surgical time was longer in the photoselective prostate vaporization group, which also had a higher rate of unplanned hospital readmission, and lower decreases in prostate specific antigen and prostate size. PMID- 26485050 TI - Global medicinal uses of Euphorbia L. (Euphorbiaceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: The genus Euphorbia (spurges, Euphorbiaceae) is the third largest genus of flowering plants, with almost 2000 species. Its exceptional diversity of growth forms and near-cosmopolitan distribution have attracted human interest since ancient times. For instance in Australia, topical application of latex of Euphorbia peplus L. is used as a home treatment for skin cancer and actinic keratosis. Its use in Australian folk medicine has inspired the release of the drug Picato(r) (ingenol mebutate), and further fostered interest in natural products and medicinal uses of Euphorbia in recent years. AIM OF THE STUDY: To provide an indicative overview of medicinal uses of the genus Euphorbia driven by the recent interest in biologically active natural products from Euphorbia in drug discovery. We assess documented medicinal knowledge and value of the genus Euphorbia and the taxonomic distribution of this value. MATERIALS AND METHODS: We undertook an extensive survey of over 260 multidisciplinary publications on the online repository JSTOR using the search term "Euphorbia medicinal". RESULTS: Medicinal uses were identified for >5% of the species in the genus, including descriptions of treatments for a variety of diseases. The most-cited medicinal uses around the world were treatments for digestive system disorders, skin ailments and, especially in the Southern hemisphere, infections. Consensus ratios indicated that the most-valued medicinal uses of Euphorbia species are in the treatment of digestive and respiratory complaints, inflammation and injuries, especially by members of Euphorbia subg. Chamaesyce. CONCLUSIONS: The present study gives a first indicative overview of Euphorbia species used for health and wellbeing around the world. The exceptional diversity of the genus Euphorbia is not only represented by its growth forms but also by its diverse medicinal uses. Our results highlight the importance of research into medicinal uses of Euphorbia species and their importance as a source of natural products. Furthermore the medicinally highly valuable subgenus Chamaesyce was identified as chemically under-investigated, emphasizing the need for further studies investigating the chemical diversity to which the high medicinal value of Euphorbia subg. Chamaesyce can be attributed. PMID- 26485051 TI - The Sensor Histidine Kinases AHK2 and AHK3 Proceed into Multiple Serine/Threonine/Tyrosine Phosphorylation Pathways in Arabidopsis thaliana. PMID- 26485052 TI - A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS. AB - The SOD1-G93A transgenic mouse is the most widely used animal model of amyotrophic lateral sclerosis (ALS). At ALS TDI we developed a phenotypic screening protocol, demonstrated in video herein, which reliably assesses the neuromuscular function of SOD1-G93A mice in a quick manner. This protocol encompasses a simple neurological scoring system (NeuroScore) designed to assess hindlimb function. NeuroScore is focused on hindlimb function because hindlimb deficits are the earliest reported neurological sign of disease in SOD1-G93A mice. The protocol developed by ALS TDI provides an unbiased assessment of onset of paresis (slight or partial paralysis), progression and severity of paralysis and it is sensitive enough to identify drug-induced changes in disease progression. In this report, the combination of a detailed manuscript with video minimizes scoring ambiguities and inter-experimenter variability thus allowing for the protocol to be adopted by other laboratories and enabling comparisons between studies taking place at different settings. We believe that this video protocol can serve as an excellent training tool for present and future ALS researchers. PMID- 26485053 TI - Melatonin inhibits apoptosis and improves the developmental potential of vitrified bovine oocytes. AB - Vitrification of oocytes has been shown to be closely associated with increased levels of reactive oxygen species (ROS) and apoptotic events. However, little information is available the effect of melatonin on the ROS levels and apoptotic events in vitrified oocytes. Therefore, we studied the effect of melatonin on ROS and apoptotic events in vitrified bovine oocytes by supplementing vitrification solution or in vitro maturation (IVM) and vitrification solution with 10(-9) m melatonin. We analyzed the ROS, mitochondrial Ca(2+) (mCa(2+) ) and membrane potential (DeltaPsim), externalization of phosphatidylserine (PS), caspase-3 activation, DNA fragmentation, mRNA expression levels of Bax and Bcl2 l1, and developmental potential of vitrified bovine oocytes. Vitrified bovine oocytes exhibited increased levels of ROS, mCa(2+) , Bax mRNA, and caspase-3 protein and higher rates of PS externalization and DNA fragmentation, and decreased DeltaPsim and Bcl2 l1 mRNA expression level. However, melatonin supplementation in vitrification solution or IVM and vitrification solution significantly decreased the levels of ROS, mCa(2+) , Bax mRNA expression, and caspase-3 protein, and PS externalization and DNA fragmentation rates, and increased the DeltaPsim and Bcl2 l1 mRNA expression level in vitrified oocytes, resulting in an increased developmental ability of vitrified bovine oocytes after parthenogenetic activation. The developmental ability of vitrified oocytes with melatonin supplementation in IVM and vitrification solution was similar to that of fresh ones. This study showed that supplementing the IVM and vitrification medium or vitrification medium with 10(-9) m melatonin significantly decreased the ROS level and inhibited apoptotic events of vitrified bovine oocytes, consequently increasing their developmental potential. PMID- 26485055 TI - The potential of immobilized artificial membrane chromatography to predict human oral absorption. AB - The potential of immobilized artificial membrane (IAM) chromatography to estimate human oral absorption (%HOA) was investigated. For this purpose, retention indices on IAM stationary phases reported previously by our group or measured by other authors under similar conditions were used to model %HOA data, compiled from literature sources. Considering the pH gradient in gastrointestinal tract, the highest logkw(IAM) values were considered, obtained either at pH7.4 or 5.5, defined as logkw(IAM)(best). Non linear models were established upon introduction of additional parameters and after exclusion of drugs which are substrates either to efflux or uptake transporters. The best model included Abraham's hydrogen-bond acidity parameter, molecular weight as well as the positively and negatively charged molecular fractions. For reasons of comparison between IAM chromatography and traditional lipophilicity, corresponding models were derived by replacing IAM retention factors with octanol-water distribution coefficients (logD). An overexpression of electrostatic interactions with phosphate anions was observed in the case of IAM retention as expressed by the negative contribution of the positively charged fraction F(+). The same parameter is statistically significant also in the logD model, but with a positive sign, indicating the attraction of basic drugs in the negatively charged inner membrane. To validate the obtained models a blind test set of 22 structurally diverse drugs was used, whose logkw(IAM)(best) values were determined and analyzed in the present study under similar conditions. IAM retention factors were further compared with MDCK cell lines permeability data taken from literature for a set of validation drugs. The overexpression of electrostatic interactions with phosphate anions on IAM surface was also evident in respect to MDCK permeability. In contrast to the clear classification between drugs with high and poor (or intermediate) absorption provided by MDCK permeability, %HOA plotted versus both IAM and logD data result in a saturation curve with a smoother ascending line. PMID- 26485054 TI - Outcome of Children with Standard-Risk T-Lineage Acute Lymphoblastic Leukemia- Comparison among Different Treatment Strategies. AB - BACKGROUND: Children with T-lineage acute lymphoblastic leukemia ALL (T-ALL) historically have had inferior outcomes compared with the children with precursor B ALL (B-ALL). After 1995, the Children's Cancer Group (CCG) treated patients with B- and T-ALL according to the National Cancer Institute (NCI) risk criteria, basing risk stratification on age and white blood cell (WBC) count regardless of immunophenotype. The Pediatric Oncology Group (POG) treated all the patients with T-ALL on separate, generally more intensive protocols than those used to treat the patients with B-ALL. PROCEDURE: We compared the outcomes of children with T ALL and NCI standard-risk (SR) criteria treated on CCG and POG trials between 1996 and 2005. CCG SR-ALL 1952 and 1991 enrolled 80 and 86 patients with T-ALL, respectively, utilizing a reduced intensity Berlin-Frankfurt-Munster backbone. Treatment was intensified for slow early responders and only patients with overt central nervous system leukemia received cranial irradiation. Eighty-four patients with T-ALL and SR features were enrolled on POG 9404 comprising more intensive therapy with all patients receiving cranial irradiation. RESULTS: The 7 year event-free survival (EFS) for patients with SR T-ALL on CCG 1952, CCG 1991, and POG 9404 were 74.1 +/- 5.8%, 81.8 +/- 5.3%, and 84.2 +/- 4.3%, respectively (P = 0.18). Overall 7-year survivals were 86.1 +/- 4.6%, 88.3 +/- 4.4%, 89.1 +/- 3.6%, respectively (P = 0.84). CONCLUSIONS: Comparable high rates of EFS and long term survival were achieved with all three regimens, with the CCG regimens utilizing a less intensive chemotherapy backbone without prophylactic cranial irradiation for patients with SR T-ALL. PMID- 26485056 TI - A synthesis of the effect of grazing exclusion on carbon dynamics in grasslands in China. AB - Grazing exclusion (GE) is considered to be an effective approach to restore degraded grasslands and to improve their carbon (C) sequestration. However, the C dynamics and related controlling factors in grasslands with GE have not been well characterized. This synthesis examines the dynamics of soil C content and vegetation biomass with the recovery age through synthesizing results of 51 sites in grasslands in China. The results illustrate increases in soil C content and vegetation biomass with GE at most sites. Generally, both soil C content and vegetation biomass arrive at steady state after 15 years of GE. In comparison, the rates of increase in above- and belowground biomass declined exponentially with the age of GE, whereas soil C content declined in a milder (linear) way, implying a lagged response of soil C to the inputs from plant biomass. Mean annual precipitation (MAP) and the rate of soil nitrogen (N) change were the main factors affecting the rate of soil C content change. MAP played a major role at the early stage, whereas the rate of soil N change was the major contributor at the middle and late stages. Our results imply that the national grassland restoration projects in China may be more beneficial for C sequestration in humid regions with high MAP. In addition, increased soil N supply to grasslands with GE at the latter recovery stage may enhance ecosystem C sequestration capacity. PMID- 26485057 TI - Erratum: Martian outflow channels: How did their source aquifers form, and why did they drain so rapidly? PMID- 26485058 TI - Nail polish as a source of exposure to triphenyl phosphate. AB - Triphenyl phosphate (TPHP) is primarily used as either a flame retardant or plasticizer, and is listed as an ingredient in nail polishes. However, the concentration of TPHP in nail polish and the extent of human exposure following applications have not been previously studied. We measured TPHP in ten different nail polish samples purchased from department stores and pharmacies in 2013-2014. Concentrations up to 1.68% TPHP by weight were detected in eight samples, including two that did not list TPHP as an ingredient. Two cohorts (n=26 participants) were recruited to assess fingernail painting as a pathway of TPHP exposure. Participants provided urine samples before and after applying one brand of polish containing 0.97% TPHP by weight. Diphenyl phosphate (DPHP), a TPHP metabolite, was then measured in urine samples (n=411) and found to increase nearly seven-fold 10-14h after fingernail painting (p<0.001). To determine relative contributions of inhalation and dermal exposure, ten participants also painted their nails and painted synthetic nails adhered to gloves on two separate occasions, and collected urine for 24h following applications. Urinary DPHP was significantly diminished when wearing gloves, suggesting that the primary exposure route is dermal. Our results indicate that nail polish may be a significant source of short-term TPHP exposure and a source of chronic exposure for frequent users or those occupationally exposed. PMID- 26485059 TI - Desynchronization of fronto-temporal networks during working memory processing in autism. AB - BACKGROUND: Mounting evidence suggests that autism is a network disorder, characterized by atypical brain connectivity, especially in the context of high level cognitive processes such as working memory (WM). Accordingly, atypical WM processes have been related to the social and cognitive deficits observed in children with autism spectrum disorder (ASD). METHODS: We used magnetoencephalography (MEG) to investigate connectivity differences during a high memory load (2-back) WM task between 17 children with ASD and 20 age-, sex-, and IQ-matched controls. RESULTS: We identified reduced inter-regional alpha-band (9-15 Hz) phase synchronization in children with ASD during the WM task. Reduced WM-related brain synchronization encompassed fronto-temporal networks (ps < 0.04 corrected) previously associated with challenging high-level conditions (i.e. the left insula and the anterior cingulate cortex (ACC)) and memory encoding and/or recognition (i.e. the right middle temporal gyrus and the right fusiform gyrus). Additionally, we found that reduced connectivity processes related to the right fusiform were correlated with the severity of symptoms in children with ASD, suggesting that such atypicalities could be directly related to the behavioural deficits observed. DISCUSSION: This study provides new evidence of atypical long range synchronization in children with ASD in fronto-temporal areas that crucially contribute to challenging WM tasks, but also emotion regulation and social cognition processes. Thus, these results support the network disorder hypothesis of ASD and argue for a specific pathophysiological contribution of brain processes related to working memory and executive functions on the symptomatology of autism. PMID- 26485060 TI - Molecular and Dissociative Adsorption of Water on (TiO2)n Clusters, n = 1-4. AB - The low energy structures of the (TiO2)n(H2O)m (n <= 4, m <= 2n) and (TiO2)8(H2O)m (m = 3, 7, 8) clusters were predicted using a global geometry optimization approach, with a number of new lowest energy isomers being found. Water can molecularly or dissociatively adsorb on pure and hydrated TiO2 clusters. Dissociative adsorption is the dominant reaction for the first two H2O adsorption reactions for n = 1, 2, and 4, for the first three H2O adsorption reactions for n = 3, and for the first four H2O adsorption reactions for n = 8. As more H2O's are added to the hydrated (TiO2)n cluster, dissociative adsorption becomes less exothermic as all the Ti centers become 4-coordinate. Two types of bonds can be formed between the molecularly adsorbed water and TiO2 clusters: a Lewis acid-base Ti-O(H2) bond or an O...H hydrogen bond. The coupled cluster CCSD(T) results show that at 0 K the H2O adsorption energy at a 4-coordinate Ti center is ~15 kcal/mol for the Lewis acid-base molecular adsorption and ~7 kcal/mol for the H-bond molecular adsorption, in comparison to that of 8-10 kcal/mol for the dissociative adsorption. The cluster size and geometry independent dehydration reaction energy, ED, for the general reaction 2(-TiOH) -> -TiOTi- + H2O at 4-coordinate Ti centers was estimated from the aggregation reaction of nTi(OH)4 to form the monocyclic ring cluster (TiO3H2)n + nH2O. ED is estimated to be -8 kcal/mol, showing that intramolecular and intermolecular dehydration reactions are intrinsically thermodynamically allowed for the hydrated (TiO2)n clusters with all of the Ti centers 4-coordinate, which can be hindered by cluster geometry changes caused by such processes. Bending force constants for the TiOTi and OTiO bonds are determined to be 7.4 and 56.0 kcal/(mol.rad(2)). Infrared vibrational spectra were calculated using density functional theory, and the new bands appearing upon water adsorption were assigned. PMID- 26485061 TI - Chitosan-Based Aerogel Membrane for Robust Oil-in-Water Emulsion Separation. AB - Here, we demonstrate direct recovery of water from stable emulsion waste using aerogel membrane. Chitosan-based gel was transformed into highly porous aerogel membrane using bio-origin genipin as cross-linking agent. Aerogel membranes were characterized for their morphology using SEM, chemical composition by FTIR and solid-UV. Further, aerogel was tested for recovery of high quality water from oil spill sample collected from ship breaking yard. High quality (with >99% purity) water was recovered with a flux rate of >600 L.m(-2).h(-1).bar(-1). After repeated use, aerogel membranes were tested for greener disposal possibilities by biodegrading membrane in soil. PMID- 26485062 TI - Electron Propagation within Redox-Active Microdomains in Thin Films of Ferrocene Containing Diblock Copolymers. AB - This paper reports the electrochemical behavior of redox-active microdomains in thin films of ferrocene-containing diblock copolymers, polystyrene-block-poly(2 (acryloyloxy)ethyl ferrocenecarboxylate) (PS-b-PAEFc). PS-b-PAEFc with different PAEFc volume fractions (PS154-b-PAEFc51, PS154-b-PAEFc26, and PS154-b-PAEFc12, where the subscripts represent the polymerization degree of each block; f(PAEFc) = 0.47, 0.30, and 0.17, respectively) was synthesized by sequential atom transfer radical polymerization. PS-b-PAEFc films of controlled thicknesses (20-160 nm) were prepared on gold substrates via spin-coating and characterized by ellipsometry. Microdomains were observed via atomic force microscopy on the surfaces of PS154-b-PAEFc51 and PS154-b-PAEFc26 thin films but not on the surfaces of PS154-b-PAEFc12 thin films. Electrochemical behavior of films was assessed by cyclic voltammetry and chronocoulometry in acetonitrile solution. The redox potential of ferrocene moieties was similar (ca. + 0.29 V vs Fc(+)/Fc) regardless of fPAEFc and film thickness. For PS154-b-PAEFc51 and PS154-b-PAEFc26, thicker films afforded larger faradaic peak currents and exhibited diffusion controlled voltammograms at faster sweep rates. PS154-b-PAEFc26 produced voltammograms less influenced by solvent-induced swelling than PS154-b-PAEFc51, reflecting the improved morphological stability of PAEFc microdomains by redox inert PS frameworks. In contrast, PS154-b-PAEFc12 films yielded similar faradaic peak currents regardless of film thickness and exhibited voltammograms indicative of surface-confined species. These observations suggest that PS154-b-PAEFc51 and PS154-b-PAEFc26 films contain continuous PAEFc microdomains extending from the electrode to the surface, in contrast to the PS154-b-PAEFc12 films which contain isolated PAEFc microdomains buried within the PS matrix. Electron propagation took place only through PAEFc microdomains that could electrically communicate with the underlying electrode. Apparent diffusion coefficients within PAEFc microdomains were similar (~ 2 * 10(-11) cm(2)/s) for PS154-b-PAEFc51 and PS154-b PAEFc26. The relatively low efficiency in electron propagation was attributable to ineffective electron self-exchange reaction within the PAEFc microdomains and/or limited counterion migration through the acetonitrile-swollen microdomains. These results provide guidance in design of redox-active metalloblock copolymers for various applications, which include electrocatalysis, electrochemical mediation in enzyme sensors, and redox-controlled molecular deposition. PMID- 26485064 TI - Accelerated Nucleation Due to Trace Additives: A Fluctuating Coverage Model. AB - We develop a theory to account for variable coverage of trace additives that lower the interfacial free energy for nucleation. The free energy landscape is based on classical nucleation theory and a statistical mechanical model for Langmuir adsorption. Dynamics are modeled by diffusion-controlled attachment and detachment of solutes and adsorbing additives. We compare the mechanism and kinetics from a mean-field model, a projection of the dynamics and free energy surface onto nucleus size, and a full two-dimensional calculation using Kramers Langer-Berezhkovskii-Szabo theory. The fluctuating coverage model predicts rates more accurately than mean-field models of the same process primarily because it more accurately estimates the potential of mean force along the size coordinate. PMID- 26485063 TI - Quantitative Label-Free Phosphoproteomics Reveals Differentially Regulated Protein Phosphorylation Involved in West Nile Virus-Induced Host Inflammatory Response. AB - West Nile virus (WNV) can cause neuro-invasive and febrile illness that may be fatal to humans. The production of inflammatory cytokines is key to mediating WNV induced immunopathology in the central nervous system. Elucidating the host factors utilized by WNV for productive infection would provide valuable insights into the evasion strategies used by this virus. Although attempts have been made to determine these host factors, proteomic data depicting WNV-host protein interactions are limited. We applied liquid chromatography-tandem mass spectrometry for label-free, quantitative phosphoproteomics to systematically investigate the global phosphorylation events induced by WNV infection. Quantifiable changes to 1,657 phosphoproteins were found; of these, 626 were significantly upregulated and 227 were downregulated at 12 h postinfection. The phosphoproteomic data were subjected to gene ontology enrichment analysis, which returned the inflammation-related spliceosome, ErbB, mitogen-activated protein kinase, nuclear factor kappa B, and mechanistic target of rapamycin signaling pathways. We used short interfering RNAs to decrease the levels of glycogen synthase kinase-3 beta, bifunctional polynucleotide phosphatase/kinase, and retinoblastoma 1 and found that the activity of nuclear factor kappa B (p65) is significantly decreased in WNV-infected U251 cells, which in turn led to markedly reduced inflammatory cytokine production. Our results provide a better understanding of the host response to WNV infection and highlight multiple targets for the development of antiviral and anti-inflammatory therapies. PMID- 26485065 TI - Vocal fold varices and risk of hemorrhage. AB - OBJECTIVES/HYPOTHESIS: To establish risk of hemorrhage in patients with varices compared to those without, determine additional risk factors, and make evidence based treatment recommendations. STUDY DESIGN: Retrospective cohort study. METHODS: Patients who were vocal performers presenting for care during a 24-month period were analyzed to determine incidence of hemorrhage. Patients with varices were compared to those without. Demographic information and examination findings (presence, location, character, and size of varices; presence of mucosal lesions or paresis) were analyzed to determine predictors of hemorrhage. RESULTS: A total of 513 patients (60.4% female, mean age 36.6 years +/- 13.95 years) were evaluated; 14 patients presenting with hemorrhage were excluded. One hundred and twelve (22.4%) patients had varices; 387 (77.6%) did not. The rate of hemorrhage in patients with varices was 2.68% at 12 months compared to 0.8% in patients without. Cox proportional hazard regression analysis revealed a hazard ratio of 10.1 for patients with varix developing hemorrhage compared to nonvarix patients (P < 0.0001). The incidence rate of hemorrhage was 3.3 cases per 1,000 person months for varix patients compared to 0.5 cases per 1,000 person-months in the nonvarix group. There was no significant difference in the incidence of paresis, mucosal lesions, location of varix (left or right side; medial or lateral), or varix morphology (pinpoint, linear, lake) between patients who hemorrhaged and those that did not. CONCLUSION: The presence of varices increases the risk of hemorrhage. Varix patients had 10 times the rate of hemorrhage compared to nonvarix patients, although the overall incidence is low. This data may be used to inform treatment of patients with varices. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1163-1168, 2016. PMID- 26485066 TI - Use of Internet Search Queries to Enhance Surveillance of Foodborne Illness. AB - As a supplement to or extension of methods used to determine trends in foodborne illness over time, we propose the use of Internet search metrics. We compared Internet query data for foodborne illness syndrome-related search terms from the most popular 5 Korean search engines using Health Insurance Review and Assessment Service inpatient stay data for 26 International Classification of Diseases, Tenth Revision, codes for foodborne illness in South Korea during 2010-2012. We used time-series analysis with Seasonal Autoregressive Integrated Moving Average (SARIMA) models. Internet search queries for "food poisoning" correlated most strongly with foodborne illness data (r=0.70, p<0.001); furthermore, "food poisoning" queries correlated most strongly with the total number of inpatient stays related to foodborne illness during the next month (beta=0.069, SE 0.017, p<0.001). This approach, using the SARIMA model, could be used to effectively measure trends over time to enhance surveillance of foodborne illness in South Korea. PMID- 26485067 TI - Reply to "Comment on 'Breakdown of Interference Rules in Azulene, a Nonalternant Hydrocarbon'". PMID- 26485068 TI - Danshen prevents articular cartilage degeneration via antioxidation in rabbits with osteoarthritis. AB - OBJECTIVE: To evaluate the efficacy of Danshen on histological parameters and antioxidative activity in the articular cartilage of rabbits with osteoarthritis (OA). DESIGN: Twenty-four rabbits were randomly divided into three groups (control, OA, and Danshen OA; eight rabbits per group). Anterior cruciate ligament transection (ACLT) of the left hind knees was performed in all rabbits in the OA and Danshen OA group for induction of OA. The rabbits in the control group underwent a sham operation. After surgery, 3 g/kg body weight of Danshen granules dissolved in 5 mL distilled water was administered by gastric intubation once per day and over a 6-week period to the Danshen OA group. The same volume of distilled water was administered to the OA and control groups. After 6 weeks, the medial femoral condyles and synoviums of the left hind knees in all three groups were harvested and used for histological and biochemical analyses. RESULTS: Severe articular cartilage degeneration as well as lower proteoglycan (PG) content were noted in the OA group compared to the Danshen OA group (P < 0.05). The glutathione (GSH) levels in the synovium and articular cartilage of the rabbits in the Danshen OA group were significantly higher compared to the OA group (P < 0.001). The malondialdehyde (MDA) levels of the synovium and articular cartilage in the Danshen OA group was markedly depleted compared to the OA group (P < 0.001). CONCLUSION: Danshen can prevent articular cartilage degeneration in OA through the defense against oxidative stress. PMID- 26485069 TI - The ins and outs of selective kinase inhibitor development. PMID- 26485071 TI - Voices of chemical biology. PMID- 26485070 TI - Membrane curvature bends the laws of physics and chemistry. PMID- 26485078 TI - Metabolism: Plugging the leak. PMID- 26485079 TI - Antibiotics: Synergistic MRSA combinations. PMID- 26485080 TI - Corrigendum: The promise and peril of chemical probes. PMID- 26485081 TI - Corrigendum: Protein degradation: Prime time for PROTACs. PMID- 26485082 TI - Erratum: Reinvigorating natural product combinatorial biosynthesis with synthetic biology. PMID- 26485083 TI - Glial fibrillar acidic protein in the cerebrospinal fluid of Alzheimer's disease, dementia with Lewy bodies, and frontotemporal lobar degeneration. AB - Biomarkers in the cerebrospinal fluid (CSF) are currently regarded as indispensable indicators for accurate differential diagnosis of neurodegenerative disorders. Although high levels of astrocyte-secreted glial fibrillar acidic protein (GFAP) in the CSF of patients with Alzheimer's disease (AD) have been reported, the levels of GFAP in the CSF have not been fully investigated in other neurological disorders that cause dementia, such as dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD). In this study, we determined the levels of GFAP in the CSF of healthy control subjects and AD, DLB, and FTLD patients to address two questions: (i) Do the levels of GFAP differ among these disorders? and (ii) Can GFAP be used as a biomarker for the differential diagnosis of these neurodegenerative disorders? The levels of GFAP in AD, DLB, and FTLD patients were significantly higher than those in the healthy control subjects. Although the levels of GFAP were not significantly different between AD and DLB patients, a higher level of GFAP was observed in FTLD patients than in AD and DLB patients. It is concluded that representative neurological disorders causing dementia were associated with higher levels of GFAP in the CSF. We propose the following mechanism concerning the amount of glial fibrillar acidic protein (GFAP) in the cerebrospinal fluid (CSF) in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). The increase in the release of GFAP into CSF is considered to reflect the sum of degeneration of astrocytes and astrocytosis. The sum of degeneration and astrocytosis or the GFAP release could be in the order of FTLD > DLB > AD > normal condition. PMID- 26485084 TI - Pronounced Interindividual But Not Intraindividual Variation in Tamoxifen and Metabolite Levels in Plasma During Adjuvant Treatment of Women With Early Breast Cancer. AB - BACKGROUND: Tamoxifen is still an important antihormonal treatment option for patients with breast cancer and estrogen receptor-positive tumors. More than 20% of patients relapse despite treatment. The drug is usually dosed 20 mg/d irrespective of interindividual variation in drug clearance. To study interindividual and intraindividual variation in plasma levels we measured tamoxifen and metabolite levels in plasma on 2 occasions, with at least 4 weeks in between, of 39 women (19 premenopausal and 20 postmenopausal women) on adjuvant treatment (20 mg/d) of early breast cancer. METHODS: We used an ultra performance liquid chromatography with a mass spectrometry detection method for identification and quantification of tamoxifen, N-desmethyltamoxifen, 4-OH tamoxifen, and endoxifen. Follicle-stimulating hormone, luteinizing hormone, and estradiol levels were also measured. RESULTS: The plasma concentrations of tamoxifen and its metabolites showed a pronounced interindividual variation, whereas intraindividual concentrations were rather stable. Despite the same dosage, interindividual tamoxifen concentrations varied from 51 to 307 ng/mL (124 +/- 57, mean +/- SD) and endoxifen values showed a range from 3.2 to 19 ng/mL (10.4 +/- 5.2, mean +/- SD), that is, 6-fold variation for both. CONCLUSIONS: Large interindividual variation of tamoxifen and endoxifen with stable intraindividual levels, and too low levels of endoxifen in a considerable proportion of patients strongly support that therapeutic drug monitoring and individualized dosing could lead to optimal exposure and hopefully better outcome. A randomized outcome study between conventional dosing and therapeutic drug monitoring-guided dosing is needed to show whether this approach works. PMID- 26485085 TI - From the Editor-in-Chief's Desk. PMID- 26485086 TI - Low Dose Loxapine: Neuromotor Side Effects and Tolerability in Autism Spectrum Disorders. AB - OBJECTIVE: New and repurposed drugs are urgently needed to treat individuals with autism spectrum disorders (ASD). Loxapine (LOX) in low doses of 5-15 mg/day resembles an atypical antipsychotic (Stahl 2002 ). Our recent open pilot study of LOX found significant behavioral improvements and overall weight neutrality in 16 adolescents and adults with ASD. The present study examined an outpatient sample for LOX neuromotor tolerability. METHODS: Consecutive outpatients with Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM-IV-TR) ASD diagnoses receiving LOX were examined for tardive dyskinesia (TD) and extrapyramidal side effects (EPS) using the Dyskinesia Identification System: Condensed User Scale (DISCUS), and for akathisia using the Barnes Akathisia Rating Scale. Data were also then retrospectively extracted from clinic charts regarding age, gender, diagnoses, LOX doses, treatment duration, concomitant medications, and LOX dosage reductions. RESULTS: Thirty-four subjects (25 male, 9 female) participated. Mean age was 23.4 years at LOX initiation (range 8-52). Thirteen subjects (38.2%) received loxapine for >=5 years. Mean LOX dose was 8.9 mg/day (range 5-30 mg) and mean duration was 4.2 years (range 0.8-13). Fourteen subjects (41.2%) received concomitant atypical antipsychotics. Benztropine was prescribed in 5 of 34 subjects (14.7%). Three subjects manifested tics at baseline, but lower final DISCUS scores. Subject 26, with Prader-Willi syndrome, manifested TD. Apart from LOX 5 mg daily he received paroxetine 40 mg daily, which reduces LOX metabolism significantly. Akathisia objective scores were positive in 6 subjects (17.6%): Subject 2 scored 3 (pacing was present also at baseline); subjects 6, 7, and 11 each scored 1; and subjects 18 and 23 each scored 2. Six of 9 subjects (66.7%) with expressive language were positive for subjective akathisia. CONCLUSIONS: Low dose LOX was well tolerated, with lower than expected TD rates. This confirms clinical resemblance to an atypical antipsychotic. Individuals with neuromuscular problems including Prader-Willi Syndrome receiving LOX require close monitoring. Further study of LOX in ASD is warranted. PMID- 26485087 TI - Negative Symptoms in a Depressed Teen? Primary Hyperparathyroidism and its Psychiatric Manifestations. PMID- 26485088 TI - Urinary Retention in an Adolescent Patient Caused by Fluoxetine Alone. PMID- 26485089 TI - Mirtazapine for Choking Phobia: Report of a Pediatric Case. PMID- 26485090 TI - Integrating DNA-strand-displacement circuitry with self-assembly of spherical nucleic acids. AB - Programmable and algorithmic behaviors of DNA molecules allow one to control the structures of DNA-assembled materials with nanometer precision and to construct complex networks with digital and analog behaviors. Here we developed a way of integrating a DNA-strand-displacement circuit with self-assembly of spherical nucleic acids, wherein a single DNA strand was used to initiate and catalyze the operation of upstream circuits to release a single strand that subsequently triggers self-assembly of spherical nucleic acids in downstream circuits, realizing a programmable kinetic control of self-assembly of spherical nucleic acids. Through utilizing this method, single-nucleotide polymorphisms or indels occurring at different positions of a sequence of oligonucleotide were unambiguously discriminated. We provide here a sophisticated way of combining the DNA-strand-displacement-based characteristic of DNA with the distinct assembly properties of inorganic nanoparticles, which may find broad potential applications in the fabrication of a wide range of complex multicomponent devices and architectures. PMID- 26485091 TI - Does the use of atypical antipsychotics as adjunctive therapy in depression result in cost savings? Comparing healthcare costs and utilization between second line treatment options. AB - BACKGROUND: Several atypical antipsychotics (AAPs) are used as second-line agents for treatment resistant depression. AAPs can be expensive compared to other treatment options and can cause several side effects. OBJECTIVES: To estimate healthcare costs and utilization of AAPs compared to other second-line agents. METHODS: Observational study using Medicaid claims data (2006-2011). Subjects were depression-diagnosed adult members with at least two prescriptions of antidepressant medications followed by a second-line agent. Gamma generalized linear models (GLM) produced estimates of the difference in mean expenditures among treatment groups after adjusting for individual baseline characteristics using propensity scores. Negative binomial models produced estimates of the difference in number of hospitalizations and emergency department (ED) visits. RESULTS: A total of 3910 members received second-line treatment. Treatment groups were AAPs (n = 2211), augmentation agents other than AAPs (n = 1008), and antidepressant switching (n = 691). AAPs resulted in higher mean adjusted pharmacy costs and higher mean adjusted total mental health-related costs. Mean adjusted total healthcare costs and number of inpatient and ED visits were not different among treatments. CONCLUSION: The results show no evidence that AAPs used as second-line treatment for depression results in overall cost savings or lower inpatient and ED visits compared to other treatment strategies. PMID- 26485093 TI - Recent Advances in the Theory and Molecular Simulation of Biological Electron Transfer Reactions. PMID- 26485094 TI - White matter volume change and its correlation with symptom severity in patients with schizophrenia: a VBM-DARTEL study. AB - The aim of this study was to evaluate the white matter (WM) volume change and its correlation with symptom severity in patients with schizophrenia using voxel based morphometry. A total of 20 patients with schizophrenia and 20 age-matched healthy controls participated in this study. MR image data were processed using SPM8 software with diffeomorphic anatomical registration through an exponentiated Lie algebra (DARTEL) algorithm. The patients with schizophrenia showed significant decreases (P=0.042) in the WM volumes of the temporal lobe and superior frontal gyrus compared with the healthy controls. The WM volumes of the middle temporal gyrus were negatively correlated with the scores of both the Positive Subscale (Pearson's rho=-0.68, P=0.001) and the Negative Subscale (rho= 0.71, P=0.0005) in the Positive and Negative Syndrome Scale. In addition, the scores of the General Psychopathology Subscale were negatively correlated with the WM volumes of the superior frontal gyrus (rho=-0.68, P=0.0009). This study evaluated the WM volume of patients with schizophrenia compared with healthy controls using DARTEI-based voxel-based morphometry and also assessed the correlation of the localized WM volume changes with the Positive and Negative Syndrome Scale. These findings will be useful to understand the neuropathology associated with WM abnormality in schizophrenia. PMID- 26485092 TI - Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles. AB - We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation. PMID- 26485095 TI - Differential regulation of expression of RNA-editing enzymes, ADAR1 and ADAR2, by 5-aza-2'-deoxycytidine and trichostatin A in human neuronal SH-SY5Y cells. AB - Adenosine deaminase acting on RNA (ADAR) enzymes, ADAR1 and ADAR2, mediates adenosine-to-inosine RNA editing, and their mRNA expressions are altered during developmental, physiological, and pathophysiological processes in the nervous system. The present study attempted to investigate the involvement of epigenetic modifying enzymes, such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC), in the regulation of ADAR1 and ADAR2 mRNA expressions in neuronal cells. Using human neuronal SH-SY5Y cells, we found that the DNMT inhibitor 5-aza-2' deoxycytidine led to an increase in ADAR2, but not ADAR1, mRNA expression in a concentration-dependent and time-dependent manner. However, treatment with HDAC inhibitor trichostatin A elicited an increase in ADAR2 mRNA expression and a decrease in ADAR1 mRNA expression, and these changes were blocked by actinomycin D, a transcription inhibitor. Taken together, these findings suggest that ADAR1 and ADAR2 expressions are subject to different regulations by DNMT and HDAC enzymes in neuronal SH-SY5Y cells. PMID- 26485096 TI - Newborn screening for severe combined immune deficiency (technical and political aspects). AB - PURPOSE OF REVIEW: Newborn screening for severe combined immune deficiency (SCID) has been implemented in more than half of the states in the United States. Despite the success of these programs, numerous challenges remain for implementing newborn screening. The present review will focus on technical, programmatic, and political aspects pertinent to newborn screening for SCID. (Figure is included in full-text article.) RECENT FINDINGS: Recent data from newborn screening in 11 U.S. programs suggest that the birth prevalence of SCID is higher than previous estimates. In addition, a large number of other conditions causing T-cell lymphopenia have been detected. Several European countries have initiated pilot screening for SCID. Significant cost savings for treatment of infants with SCID detected at birth, compared with later in life, has been demonstrated. Published evidence of the favorable cost-benefit ratio for screening supports implementation of universal SCID newborn screening. SUMMARY: SCID fulfills criteria for a condition that should be included in routine newborn screening. Data presented from multiple newborn screening programs in the United States and Europe have shown that high throughput screening of all newborns is cost-effective. Screening improves early detection of this life-threatening condition and follow-up studies have shown a clear improvement in survival for early treatment. PMID- 26485097 TI - The immunological and genetic basis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. AB - PURPOSE OF REVIEW: This article presents a comprehensive review of the immunodysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX) syndrome, covering both the clinical and molecular aspects of the disease. (Figure is included in full-text article.) RECENT FINDINGS: The IPEX syndrome is a rare immunological disorder in humans caused by inheritable mutations in the FOXP3 gene, the master transcriptional regulator for the development and function of CD4 regulatory T (Treg) cells. Forkhead box protein 3 (FOXP3) Treg cells represent a unique T-cell lineage with inhibitory functions, and are responsible for immune homeostasis and tolerance to self and nonself antigens. Evidence shows that a Treg developmental deficiency or dysfunction underlies the severe, multiorgan, autoimmune disease of IPEX. SUMMARY: An in-depth structural and functional analysis of the molecular domains of FOXP3 is essential for our understanding of the observed clinical heterogeneity and prognosis in IPEX. PMID- 26485098 TI - Patient selection for subcutaneous versus sublingual immunotherapy. AB - PURPOSE OF REVIEW: With the Food and Drug Administration's approval of sublingual allergen-specific immunotherapy (SL-AIT) tablets for grass and ragweed pollen, SL AIT is progressively gathering importance not only in Europe, but also in the United States and other parts of the world. We reviewed issues related to the selection of patients for the sublingual or the subcutaneous route for allergic patients, based on what has been published since January 2014 on subcutaneous versus-SL-AIT efficacy, safety and other issues. (Figure is included in full-text article.) RECENT FINDINGS: As patient's adherence seems one of the major problems in real-life AIT, investigators have sought how to enhance AIT simplicity by changing the route to home-administrated SL-AIT, and by shortening the subcutaneous-allergen-specific immunotherapy (SC-AIT) build-up or maintenance phase. The latter was safe with several hypoallergenic extracts. As for SL-AIT, double blind placebo-controlled large trials in patients with allergic rhinitis and asthma have shown the efficacy and safety of ragweed pollen and house dust mite SLIT tablets and highly concentrated liquid formulations, primarily in adults. A large trial with SLIT in 3-year-old children was effective. SUMMARY: With the improvement of SL-AIT efficacy, the selection of SC-versus-SL-AIT will probably increasingly be based not on efficacy, but on practical aspects, without losing sight of which SL-AIT products have proven efficacy. PMID- 26485099 TI - The autoimmune conundrum in common variable immunodeficiency disorders. AB - PURPOSE OF REVIEW: Autoimmune and inflammatory manifestations are the biggest clinical challenge in the care of patients with common variable immunodeficiency (CVID). The increasing pathogenic knowledge and potential therapeutic implications require a new evaluation of the status quo. (Figure is included in full-text article.) RECENT FINDINGS: The conundrum of the simultaneous manifestation of primary immunodeficiency and autoimmune disease (AID) is increasingly elucidated by newly discovered genetic defects. Thus, cytotoxic T lymphocyte-associated antigen 4 or caspase-9 deficiency presenting with CVID-like phenotypes reiterate concepts of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and autoimmune lymphoproliferative syndrome. Activating signaling defects downstream of antigen or cytokine receptors are often associated with loss-of-tolerance in the affected patients. Increasingly, forms of combined immunodeficiency are discovered among CVID-like patients. Although different autoimmune manifestations often coincide in the same patient their immunopathology varies. Treatment of AID in CVID remains a challenge, but based on a better definition of the immunopathology first attempts of targeted treatment have been made. SUMMARY: The increasing comprehension of immunological concepts promoting AID in CVID will allow better and in some cases possibly even targeted treatment. A genetic diagnosis therefore becomes important information in this group of patients, especially in light of the fact that some patients might require hematopoietic stem cell transplantation because of their underlying immunodeficiency. PMID- 26485100 TI - Allergen immunotherapy: an update on protocols of administration. AB - PURPOSE OF REVIEW: Allergen immunotherapy (AIT) is still the only causal treatment for allergic rhinitis and asthma. However, conventional subcutaneous AIT administration schedules are time-consuming and safety issues still play a role; for sublingual AIT, the best efficacy is still investigated and for food allergy the best efficacy-safety balance is not yet completely discovered. Investigators have made progress in these fields lately. (Figure is included in full-text article.) RECENT FINDINGS: Since January 2014, several (ultra) rush or cluster build-up phases with hypoallergic variants of extracts have been explored with success. Also, the efficacy of only preseasonal subcutaneous AIT was demonstrated for tree and grass pollen. Sublingual AIT was shown to be effective and well tolerated in allergic rhinitis and asthma with tablets and with highly concentrated liquid formulations (ragweed, house dust mite), but not cockroach. For food allergy, oral immunotherapy is promising, but close attention should be paid to the exact administration schedule, maintenance dose, and the definition of efficacy (desensitization or real tolerance, as defined by a negative challenge test at least 4 months off treatment). SUMMARY: The practicing physician should be watchful for advances in the field of aeroallergen AIT and food oral immunotherapy, analyzing the presented information in detail and interpreting conclusions product specifically, without generalizing. PMID- 26485101 TI - Current Management of Eosinophilic Esophagitis 2015. AB - Eosinophilic esophagitis (EoE) is a chronic inflammatory condition characterized by esophageal dysfunction and eosinophilic infiltrate (>=15/hpf) in the esophageal epithelium and the absence of other potential causes of eosinophilia. The prevalence is increasing and is the most common cause of solid food dysphagia in children and young adults. This article will review the diagnosis and management of EoE based on consensus conferences, systematic reviews, and meta analysis and highlights seminal studies in our evolving treatment of this disease. However, all answers are not available and I will remark about the lessons learned in my clinical practice seeing EoE patients over the last 25 years. The complicated etiology of the complaint of dysphagia in EoE patients will be reviewed. The importance of utilizing endoscopy, biopsies, and barium esophagram to help define the 2 phenotypes (inflammatory, fibrostenosis) of EoE will be highlighted. The controversy about PPI-responsive esophageal eosinophilia will be discussed and contrasted with idiopathic EoE. Finally, the 3 treatment options for EoE (drugs, diet, dilation) will be reviewed in detail and a useful clinical management algorithm presented. PMID- 26485102 TI - Ursodeoxycholic Acid Inhibits Clostridium difficile Spore Germination and Vegetative Growth, and Prevents the Recurrence of Ileal Pouchitis Associated With the Infection. AB - GOALS: To test whether ursodeoxycholic acid (UDCA) is inhibitory to Clostridium difficile and can be used in the treatment of C. difficile-associated ileal pouchitis. BACKGROUND: The restoration of secondary bile metabolism may be the key mechanism for fecal microbiota transplantation (FMT) in treating recurrent C. difficile infections (RCDI). Therefore, it is possible that exogenous administration of inhibitory bile acids may be used directly as nonantibiotic therapeutics for this indication. The need for such a treatment alternative is especially significant in patients with refractory C. difficile-associated pouchitis, where the efficacy of FMT may be limited. STUDY: We measured the ability of UDCA to suppress the germination and the vegetative growth of 11 clinical isolate strains of C. difficile from patients treated with FMT for RCDI. In addition, we used oral UDCA to treat a patient with RCDI pouchitis that proved refractory to multiple antibiotic treatments and FMT. RESULTS: UDCA was found to be inhibitory to the germination and the vegetative growth of all C. difficile strains tested. Fecal concentrations of UDCA from the patient with RCDI pouchitis exceeded levels necessary to inhibit the germination and the growth of C. difficile in vitro. The patient has remained infection free for over 10 months after the initiation of UDCA. CONCLUSIONS: UDCA can be considered as a therapeutic option in patients with C. difficile-associated pouchitis. Further studies need to be conducted to define the optimal dose and duration of such a treatment. In addition, bile acid derivatives inhibitory to C. difficile that are able to achieve high intracolonic concentrations may be developed as therapeutics for RCDI colitis. PMID- 26485103 TI - Five-Year Period Prevalence and Characteristics of Anemia in a Large US Inflammatory Bowel Disease Cohort. AB - BACKGROUND: Anemia is a common manifestation of inflammatory bowel disease (IBD), but its prevalence in the United States is not well defined. Aim of this study was to determine the prevalence and characteristics of anemia in IBD patients who were followed in a US referral center. MATERIALS AND METHODS: Demographic, clinical, laboratory, and treatment data from a prospective, consented longitudinal IBD registry between the years 2009 and 2013 were analyzed. Disease activity was evaluated using Harvey-Bradshaw index in Crohn's disease (CD) and ulcerative colitis (UC) activity index in UC as well as C-reactive protein and erythrocyte sedimentation rate. Anemia was defined based on the World Health Organization criteria. RESULTS: A total of 1821 IBD patients (1077 with CD, 744 with UC, median age 43.8 y, 51.9% female) were included. The 5-year period prevalence of anemia in IBD patients was 50.1%, (CD: 53.3% vs. UC: 44.7%, P=0.001). In multivariate logistic regression analysis, anemia was associated with surgery for IBD [odds ratio (OR)=2.77; 95% confidence interval (CI), 2.21 3.48; P<0.0001], female gender (OR=1.29; 95% CI, 1.04-1.61; P=0.02), C-reactive protein (OR=1.26; 95% CI, 1.16-1.37; P<0.0001), erythrocyte sedimentation rate (OR=1.02; 95% CI, 1.01-1.03; P=0.0002), and use of biologics (OR=2.00; 95% CI, 1.58-2.52; P=0.0001) or immunomodulators (OR=1.51; 95% CI, 1.21-1.87; P=0.0003). Iron replacement therapy was administered to 46.8% of the anemic patients. CONCLUSION: Anemia has a high period prevalence in IBD patients followed at a tertiary center. Anemia is more common in CD than in UC, is associated with disease activity, and in current practice is undertreated. PMID- 26485104 TI - Clinical Characteristics of Multiple Colorectal Adenoma Patients Without Germline APC or MYH Mutations. AB - BACKGROUND: Patients with multiple colorectal adenomas (MCRA) without genetic cause are increasingly being diagnosed. The characteristics and natural history of this condition are not well studied. MATERIALS AND METHODS: Twenty-seven patients with MCRA, with cumulatively 10 to 99 colorectal adenomas and without deleterious mutations of APC or MYH genes, were investigated. Results of colonoscopies with a mean follow-up of 4.9 years (range, 0 to 27 y) were evaluated. Findings from esophagogastroduodenoscopy and extracolonic manifestations were assessed. RESULTS: The mean age at polyp diagnosis and MCRA diagnosis was 47.8+/-13.1 years (range, 21 to 72 y) and 50.4+/-14.6 years (range, 21 to 72 y), respectively. In 22% of patients another family member had MCRA. At first colonoscopy, the mean number of adenomas was 35.0+/-35.9 (range, 0 to 99). Serrated polyps were rare. Esophagogastroduodenoscopy revealed 47% of patients had upper tract neoplasia. Patients with upper tract findings were diagnosed with MCRA at significantly younger mean age than those without findings, P<0.05. Eighteen patients (67%) underwent colectomy with a mean time from diagnosis of MCRA of 3.1+/-1.3 years. After surgery, surveyed patients developed recurrent adenomas in retained colorectum. Nine patients (33%) had extracolonic cancers. CONCLUSIONS: MCRA patients have a similar clinicopathologic phenotype to known syndromes of attenuated adenomatous polyposis and the majority have need for colectomy. The management of MCRA patients and families should parallel that of attenuated familial adenomatous polyposis and MUTYH-associated polyposis including surveillance of the upper tract. PMID- 26485105 TI - Small Intestinal Angioectasias Are Not Randomly Distributed in the Small Bowel and Most May Be Reached by Push Enteroscopy. AB - GOALS: The goal was to describe the location of angioectasias within small bowel on capsule endoscopy and the utility of push enteroscopy versus deep enteroscopy in treatment of overt bleeding from these. BACKGROUND: Overt bleeding from small bowel angioectasias is a clinical challenge. Thalidomide and octreotide can be difficult to prescribe and may not be effective. Endoscopy remains a mainstay of treatment for overt bleeding from angioectasias but data regarding the long-term efficacy of endoscopic therapy are limited. We sought to define the location of small bowel angioectasias using capsule endoscopy and review our outcomes for push and double-balloon enteroscopy. METHODS: We retrospectively reviewed all 428 capsule endoscopy studies from the Veterans Administration Hospital in West Haven, CT from 2005 to 2012. Location of angioectasias was evaluated using lead mapping and small bowel transit time. RESULTS: We identified 69 patients with small bowel angioectasia. At least 66.8% of lesions were in duodenum or ligament of Treitz, with 78.3% within the first 25% of small bowel transit. Twenty-four patients underwent endoscopic treatment of overt bleeding from small bowel angioectasias. Thirty-three percent rebled requiring multiple procedures. Eight patients had 10 anterograde double-balloon examinations. Only 2 patients had both cessation of bleeding with double balloon and lesions outside the reach of push enteroscopy. CONCLUSIONS: Push enteroscopy for bleeding angioectasias is effective in many patients. Deep enteroscopy may not benefit most patients as most angioectasias are proximal. Patients with deeper lesions tended to have multiple lesions and rebleeding despite deep enteroscopy. PMID- 26485106 TI - Role of Nonsteroidal Anti-Inflammatory Drugs in Exacerbations of Inflammatory Bowel Disease. AB - GOALS: To determine the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in activation of inflammatory bowel disease (IBD). BACKGROUND: NSAIDs may activate inflammatory pathways in IBD. STUDY: Crohn's and Colitis Foundation of American Partners is an ongoing cohort study of patients living with IBD. All data are self-reported using the internet. We identified a subcohort of participants whose disease activity, based on short Crohn's Disease Activity Index and simple clinical colitis activity index, indicated remission. Pattern of use of NSAIDs was measured at baseline, and disease activity assessment was performed 6 months later. We used multivariate binomial regression to determine effects of NSAIDs on disease activity. RESULTS: A total of 791 individuals in remission had baseline and follow-up data available for analysis. Of these, 247 Crohn's disease (CD) patients (43.2%) and 89 ulcerative colitis (UC) patients (40.6%) reported NSAID use. CD patients with NSAID use >=5 times/month had greater risk of active disease at follow-up (23% vs. 15%, P=0.04); [adjusted risk ratio (RR), 1.65; 95% confidence interval (CI), 1.12-2.44). No effect was observed in patients with UC (22% vs. 21%, P=0.98; adjusted RR, 1.25; 95% CI, 0.81-1.92). Acetaminophen use was associated with active disease at follow-up in CD (adjusted RR, 1.72; 95% CI, 1.11-2.68). CONCLUSIONS: Regular (>=5 times/mo) NSAID and acetaminophen use were associated with active CD, but not UC. Less frequent NSAID use was not associated with active CD or UC. These findings indicate that regular NSAID use may increase CD activity, or that NSAID use may be a marker of a less robust remission; thus reflecting subclinical disease activity. PMID- 26485107 TI - Impact of Screening on Survival in Familial Adenomatous Polyposis. AB - GOALS: Our aim was to determine whether the screening of family members of familial adenomatous polyposis (FAP) patients significantly influences survival, and to gauge the extent of FAP-related causes of death. BACKGROUND: The screening of families with FAP has been shown to be profitable in reducing colorectal cancer-related mortality, but conclusions about the screening effect on overall survival has been controversial. STUDY: This is a nationwide population-based retrospective cohort study, and the primary outcome of interest was overall mortality and survival. A total of 154 families with at least 1 clinically diagnosed FAP patient between 1963 and 2015 were included. There were altogether 194 probands and 225 call-ups. During the follow-up period, 2639 person-years with 92 deaths among probands were observed and 3634 person-years and 30 deaths among call-ups. We report crude mortality rates and standardized mortality ratios together with descriptive statistics. We compared the survival of probands and call-ups to the population by relative survival method. RESULTS: The crude mortality rate among probands was 34.9 per 1000 person-years and 8.3 among call ups. The standardized mortality ratios for call-ups was 2.47 (confidence interval, 1.69-3.46) and for probands 4.07 (confidence interval, 3.29-4.96) (P=0.014). The relative survival of probands was significantly lower than call ups (P=0.0018), and 20-year relative survival for call-ups was 94% (88% to 100%). Over two thirds of all deaths were FAP related. CONCLUSIONS: Survival of screened family members of FAP patients is comparable to the general population within 20 years after diagnosis. Therefore, participation in surveillance should not be delayed when a family member with FAP has been detected. PMID- 26485108 TI - Fulminant Hepatosplenic B-Cell Lymphoma Without Hepatitis C Infection. PMID- 26485109 TI - Reduced Sleep Acutely Influences Sedentary Behavior and Mood But Not Total Energy Intake in Normal-Weight and Obese Women. AB - Using a crossover design, 22 normal-weight and 22 obese women completed two free living sleep conditions: (a) Normal Sleep: night of ~8 hr time in bed; and (b) Reduced Sleep: night of < 5 hr time in bed). Outcome measures were energy intake, physical activity and sedentary time, and mood. Sleep time was 7.7 +/- 0.3 and 4.8 +/- 0.2 hrs during the Normal Sleep and Reduced Sleep conditions, respectively (F = 1791.94; p < 0.0001). Energy intake did not differ between groups or as a function of sleep condition (F = 2.46; p = 0.1244). Sedentary time was ~ 30 min higher after the Reduced Sleep condition (F = 4.98; p = 0.0318); other physical activity outcomes were not different by condition (p > 0.05). Total mood score, depression, anger, vigor, fatigue, and confusion were worse after Reduced Sleep (p < 0.05). Reducing sleep acutely and negatively influenced sedentary time and mood in normal-weight and obese women. PMID- 26485110 TI - Stepwise Formation of Photoconductive Nanotubes through a New Top-Down Method. AB - In contrast to the widely used bottom-up strategy for preparing various complex nanostructures, the top-down strategy is rarely applied to generate complex nanostructures. This study reports the use of a unique combination of bottom-up and top-down processes for the time-resolved stepwise fabrication of novel photoconductive nanotubes from elaborately designed asymmetric perylene diimide molecules. PMID- 26485112 TI - Insulin Does Not Target CamkIIalpha Neurones to Critically Regulate the Neuroendocrine Reproductive Axis in Mice. AB - Insulin signalling in the brain plays an important role in the central regulation of energy homeostasis and fertility, such that mice exhibiting widespread deletion of insulin receptors (InsR) throughout the brain and peripheral nervous system display diet sensitive obesity and hypothalamic hypogonadism. However, the specific cell types mediating the central effects of insulin on fertility remain largely unidentified. To date, the targeted deletion of InsR from individual neuronal populations implicated in the metabolic control of fertility has failed to recapitulate the hypogonadic and subfertile phenotype observed in brain specific InsR knockout mice. Because insulin and leptin share similar roles as centrally-acting metabolic regulators of fertility, we used the Cre-loxP system to generate mice with a selective inactivation of the Insr gene from the same widespread neuronal population previously shown to mediate the central effects of leptin on fertility by crossing Insr-flox mice with calcium/calmodulin-dependent protein kinase type IIalpha (CamkIIalpha)-Cre mice. Multiple reproductive and metabolic parameters were then compared between male and female Insr-flox/Cre positive (CamK-IRKO) and Insr-flox/Cre-negative control mice. Consistent with brain-specific InsR knockout mice, CamK-IRKO mice exhibited a mild but significant obesogenic phenotype. Unexpectedly, CamK-IRKO mice exhibited normal reproductive maturation and function compared to controls. No differences in the age of puberty onset, oestrous cyclicity or fecundity were observed between CamK IRKO and control mice. We conclude that the central effects of insulin on the neuroendocrine reproductive axis are not critically mediated via the same neuronal populations targeted by leptin. PMID- 26485111 TI - Advances in PARP inhibitors for the treatment of breast cancer. AB - INTRODUCTION: Poly(ADP-Ribose) polymerases (PARPs) are one of the important components of base excision repair pathway for single strand DNA breaks. Currently accepted hypothesis for the mechanism of action for PARP inhibitors in tumors with homologous recombination deficiency is synthetic lethality, as the simultaneous blockage of both pathways prevents the tumor cells from repairing DNA damage. Other proposed mechanisms include PARP trapping, defective BRCA1 and POLQ recruitment to sites of DNA repair. Breast cancer subgroups with germline BRCA mutations or non-mutational functional defects in BRCA proteins exemplify potential targets for PARP inhibitors. AREAS COVERED: Promising results have been achieved with PARP inhibitors in BRCA associated cancers, particularly in ovarian and breast cancer. Olaparib is the only PARP inhibitor approved by FDA in the treatment of patients with germline BRCA mutated advanced ovarian cancer pretreated with >=3 prior lines of chemotherapy. In this article, we reviewed the current status of PARP inhibitors, completed and ongoing trials, safety and resistance issues in patients with breast cancer. EXPERT OPINION: PARP inhibitors show promise in cancers with BRCA mutation and in the treatment of sporadic cancers with defective homologous recombination. Predictors of response, strategies to overcome resistance, combination with other chemotherapies and targeted agents, optimum dose and schedule of administration should be investigated in future trials. PMID- 26485113 TI - Can the use of urgent care clinics improve access to care without undermining continuity in primary care? AB - PURPOSE: There is a niche for urgent care clinics as an alternate source of health care in the United States. This systematic review examines whether the use of urgent care clinics can improve access to care or if these facilities undermine continuity of primary care. DATA SOURCES: Databases used were Cumulative Index for Nursing and Allied Health (CINAHL) and Medical Literature Analysis and Retrieval System Online (MEDLINE). Articles from 2004 to 2014 were searched using keywords-access, barriers, continuity of care, nurse practitioner (NP), urgent care, retail clinic, emergency, and primary care. CONCLUSIONS: Urgent care clinics can improve access to care, but may also negatively impact continuity of care, preventative services, and ongoing management of chronic conditions. Barriers to primary care and benefits of urgent care are inversely related. Insufficient knowledge regarding navigation of the healthcare system, perceived urgency of medical need, and deflection of care contribute to use of urgent care over primary care. IMPLICATIONS FOR PRACTICE: NPs are frontline healthcare providers essential to developing and maintaining successful communication and collaboration among providers across healthcare settings. In both primary care and urgent care facilities, NPs can ensure continuity of care, decreased healthcare costs, and optimized health outcomes for patients. PMID- 26485115 TI - Nematoda of Kinosternon scorpioides (Testudines: Kinosternidae) from Northeastern Brazil. AB - The scorpion mud turtle (Kinosternon scorpioides) is a small freshwater turtle broadly distributed in South America and commonly consumed in some Brazilian regions. This study aimed to identify the species of helminths that parasitize the digestive tract of K. scorpioides and report infection parameters such as parasite prevalence, mean intensity of the infection, abundance, and the relationship between these nematodes and host body size in this species. We captured 20 adult male K. scorpioides, and 6 animals had nematodes in their gastrointestinal tract. These animals had Serpinema magathi (prevalence = 0.3) and Spiroxys figueiredoi (prevalence = 0.25). There were no correlations between the number of total parasites and carapace length (rs = 0.17, n = 6, P = 0.74) or the length of the gastrointestinal tract (rs = 0.18, n = 6, P = 0.73). PMID- 26485116 TI - Establishment of Lipofection Protocol for Efficient miR-21 Transfection into Cortical Neurons In Vitro. AB - Dysregulated microRNAs in neurons could cause many nervous system diseases. The therapeutic manipulation of these pathogenic microRNAs necessitates novel, efficient delivery systems to facilitate microRNA modulators targeting neurons with minimal off-target effects. The study aimed to establish a lipofection protocol to upregulate expression levels of miR-21 in neurons under different conditions, including different serum-free medium, transfection conditions, and reagent concentration, by evaluating the expression levels of miR-21 and neuron injury. The expression levels of miR-21 were higher in neurons transfected by Neurobasal-A than by DMEM. Expression levels of miR-21 were already the highest at the ratio RNAiMAX:miR-21 = 3:5, but the increase of RNAiMAX's concentration had not caused the further upregulation of expression level of miR-21. Neuron injury was condition dependent and dose dependent after transfection. Compared to S-Neurobasal groups, neurons have a smaller injury in N-Neurobasal groups, and compared to ratios RNAiMAX:miR-21 = 4:5, 5:5, neuron injury was smaller at ratios of RNAiMAX:miR-21 = 1:5, 2:5, 3:5. Without the pretreatment of starvation in vitro, the lipofection protocol was that RNAiMAX/miR-21 agomir complexes were diluted in Neurobasal-A at the ratio of RNAiMAX:miR-21 = 3:5. PMID- 26485117 TI - Treatment effect heterogeneity for univariate subgroups in clinical trials: Shrinkage, standardization, or else. AB - Treatment effect heterogeneity is a well-recognized phenomenon in randomized controlled clinical trials. In this paper, we discuss subgroup analyses with prespecified subgroups of clinical or biological importance. We explore various alternatives to the naive (the traditional univariate) subgroup analyses to address the issues of multiplicity and confounding. Specifically, we consider a model-based Bayesian shrinkage (Bayes-DS) and a nonparametric, empirical Bayes shrinkage approach (Emp-Bayes) to temper the optimism of traditional univariate subgroup analyses; a standardization approach (standardization) that accounts for correlation between baseline covariates; and a model-based maximum likelihood estimation (MLE) approach. The Bayes-DS and Emp-Bayes methods model the variation in subgroup-specific treatment effect rather than testing the null hypothesis of no difference between subgroups. The standardization approach addresses the issue of confounding in subgroup analyses. The MLE approach is considered only for comparison in simulation studies as the "truth" since the data were generated from the same model. Using the characteristics of a hypothetical large outcome trial, we perform simulation studies and articulate the utilities and potential limitations of these estimators. Simulation results indicate that Bayes-DS and Emp-Bayes can protect against optimism present in the naive approach. Due to its simplicity, the naive approach should be the reference for reporting univariate subgroup-specific treatment effect estimates from exploratory subgroup analyses. Standardization, although it tends to have a larger variance, is suggested when it is important to address the confounding of univariate subgroup effects due to correlation between baseline covariates. The Bayes-DS approach is available as an R package (DSBayes). PMID- 26485118 TI - Dynamics of body burdens and doses due to internal irradiation from intakes of long-lived radionuclides by residents of Ozyorsk situated near Mayak PA. AB - This paper presents and discusses new autopsy results and other historic data from earlier autopsies and environmental monitoring linked to releases from the Mayak PA facilities in the Chelyabinsk oblast in the southern Urals. The focus is on residents of the town of Ozyorsk located near to Mayak PA and the dynamics of body burdens and radiation doses from inhalation of plutonium alpha and americium 241, and ingestion of strontium-90 and caesium-137. It is demonstrated that accumulation and exposure from these radionuclides was mainly due to unplanned releases in the 1950s and 60s. The mean content of plutonium alpha at the time of autopsy of people commencing residence in Ozyorsk from 1949 to 1959 was about 3.5 Bq, falling to 0.2 Bq in those arriving after 1990. A reducing trend was also seen for (241)Am. The highest (90)Sr content in Ozyorsk residents was measured in 1967. The (137)Cs body content of residents arriving in Ozyorsk at any time was in almost all cases below the limit of detection. The committed effective dose from internal exposure to these long-lived radionuclides which would have been accumulated in Ozyorsk residents if present from 1949 to 2013 is estimated to be 13 mSv. This dose is primarily attributed to intakes during 1949 to 1959 when the annual effective dose rate was approximately 1 mSv y(-1). The current value is about 0.1 mSv y(-1). This dose is about 20 times higher than the dose from global man-made fallout, which is about 0.005 mSv y(-1) at present, but much lower than that from natural background radiation, i.e. about 2 mSv y(-1). The experience gained from this work and continuing activities can contribute to the development of improved international guidance in legacy situations, particularly as regards the provision and use of monitoring data to test and thereby build confidence in prognostic models for radiation conditions and potential future exposures. The scope includes evidence for the rate of reduction in radionuclide concentrations in environmental media and in their bioavailability, resuspension of long-lived alpha radionuclides, uptake of (90)Sr and (137)Cs in the food-chain, and confirmation of cumulative uptake via autopsy and whole body counting measurements. Continuing investigations will thus support decisions on future planned releases and contribute to planning of remediation of other areas affected by historic releases. PMID- 26485119 TI - Assessment of myometrial invasion in endometrial cancer using three-dimensional ultrasound and magnetic resonance imaging. AB - INTRODUCTION: Preoperative knowledge of myometrial invasion in endometrial cancer is important for surgical planning. This study aimed to assess the diagnostic efficiency of two-dimensional (2D) and three-dimensional (3D) transvaginal ultrasonography (TVS) with and without saline infusion (SIS) and magnetic resonance imaging (MRI) for assessment of myometrial invasion in endometrial cancer. MATERIAL AND METHODS: 110 women with atypical endometrial hyperplasia or endometrial adenocarcinoma underwent preoperative 2D- and 3D-TVS with and without SIS and MRI. Offline 3D-TVS measurement was performed of the minimal tumor-free margin in relation to myometrial thickness expressed as deep (>= 50%) myometrial invasion and subjective impression of cervix involvement. The quality of images was also evaluated. Diagnostic efficiencies were calculated for myometrial and cervical involvement for each method. The pathologist's final diagnosis served as the reference standard. RESULTS: For myometrial involvement, MRI showed greater accuracy than 3D-TVS or 2D-TVS (83, 71 and 75%, respectively). The efficiency of 3D-TVS was not superior to 2D-TVS and did not improve with SIS. The sensitivities of 2D-TVS and 3D-TVS were similar to that of MRI, and the efficiency of 3D-TVS improved when volumes of inadequate quality (39%) were excluded. For evaluating cervical involvement, the accuracy of 3D-TVS was 85%, comparable to the results of 2D-TVS (80%) and MRI (85%). The results did not improve when saline was added. CONCLUSION: 3D-TVS or 3D-SIS was not more efficient than 2D-TVS or MRI for assessment of myometrial invasion in endometrial cancer. 3D-TVS assessment without 2D-TVS was impeded by difficulties in obtaining 3D-TVS volumes of sufficient quality. PMID- 26485120 TI - Photosensitizer-Loaded Branched Polyethylenimine-PEGylated Ceria Nanoparticles for Imaging-Guided Synchronous Photochemotherapy. AB - A multifunctional theranostic platform based on photosensitizer (chlorin e6, Ce6) loaded branched polyethylenimine-PEGylated ceria nanoparticles (PPCNPs-Ce6) was created for the development of effective cancer treatments involving the use of imaging-guided synchronous photochemotherapy. PPCNPs-Ce6 with high Ce6 photosensitizer loading (Ce6: cerium ~40 wt %) significantly enhanced the delivery of Ce6 into cells and its accumulation in lysosomes, remarkably improving photodynamic therapeutic (PDT) efficacy levels compared to those in the administration of free Ce6 at ultralow drug doses (~200 nM). Interestingly, PPCNPs-Ce6 efficiently induced HeLa cell death even at low concentrations (~10 MUM) without the use of laser irradiation and exhibit chemocytotoxicity. Inductively coupled plasma mass spectrometry (ICP-MS) and biology transmission electron microscopy (Bio-TEM) analyses demonstrated that ceria nanoparticles enter cells abundantly and accumulate in lysosomes or large vesicles. We then evaluated the effects of the different materials on lysosomal integrity and function, which revealed that PPCNPs-Ce6 catastrophically impaired lysosomal function compared to results with PPCNPs and Ce6. Studies of apoptosis revealed greater induction of apoptosis by PPCNPs-Ce6 treatment. This multifunctional nanocarrier also exhibited a high degree of solubility and stability in aqueous solutions, suggesting its applicability for extensive biomedical application. PMID- 26485121 TI - Predicting the extinction of HIV-2 in rural Guinea-Bissau. AB - OBJECTIVE: This article predicts the future epidemiology of HIV-2 in Caio, a rural region of Guinea Bissau; and investigates whether HIV-2, which has halved in prevalence between 1990 and 2007 and is now almost absent in young adults in Caio, can persist as an infection of the elderly. DESIGN: A mathematical model of the spread of HIV-2 was tailored to the epidemic in Caio, a village in Guinea Bissau. METHODS: An age-stratified difference equation model of HIV-2 transmission was fitted to age-stratified HIV-2 incidence and prevalence data from surveys conducted in Caio in 1990, 1997 and 2007. A stochastic version of the same model was used to make projections. RESULTS: HIV-2 infection is predicted to continue to rapidly decline in Caio such that new infections will cease and prevalence will reach low levels (e.g. below 0.1%) within a few decades. HIV-2 is not predicted to persist in the elderly. CONCLUSION: HIV-2 is predicted go extinct in Caio during the second half of this century. PMID- 26485122 TI - Diastereodivergent Synthesis of Fluorinated Cyclic beta(3)-Amino Acid Derivatives. AB - The ability of 2-p-tolylbenzyl carbanions to behave as a source of chiral benzylic nucleophiles has been shown in its reaction with fluorinated imines. The process takes place with high levels of stereocontrol, rendering the corresponding amines as single diastereoisomers. Subsequent cross-metathesis followed by intramolecular aza-Michael reaction makes the synthesis of fluorinated homoproline derivatives bearing three stereogenic centers possible. Furthermore, the selectivity of the cyclization process can easily be tuned up in a diastereodivergent manner simply by changing the reaction conditions. PMID- 26485123 TI - Glucosinolate Accumulation and Related Gene Expression in Pak Choi (Brassica rapa L. ssp. chinensis var. communis [N. Tsen & S.H. Lee] Hanelt) in Response to Insecticide Application. AB - Glucosinolates and their breakdown products are well-known for their cancer chemoprotective functions and biocidal activities against pathogens and generalist herbivores. Insecticides are commonly used in the production of pak choi (Brassica rapa L. ssp. chinensis var. communis [N. Tsen & S.H. Lee] Hanelt). We studied the effects of four commonly used insecticides, namely, beta cypermethrin, acephate, pymetrozine, and imidacloprid, on glucosinolate metabolism in pak choi. All insecticides significantly increased both the transcription of glucosinolate biosynthetic genes and the aliphatic and total glucosinolate accumulations in pak choi. beta-Cypermethrin and acephate caused gradual and continuous up-regulation of gene expression from 0.5 to 24 h after treatment, whereas pymetrozine and imidacloprid did so more rapidly, reaching a peak at 1 h and returning to normal at 3 h. Our findings indicate that the four insecticides affect glucosinolate metabolism in pak choi plants to various degrees and suggest that glucosinolates may be involved in plant insecticide metabolism. PMID- 26485124 TI - The Number of Endovascular Trophoblasts in Maternal Blood Increases Overnight and after Physical Activity: An Experimental Study. AB - INTRODUCTION: Fetal cells in maternal blood may be used for noninvasive prenatal diagnostics, although their low number is a challenge. This study's objectives were to evaluate whether physical activity, transabdominal and transvaginal ultrasound scans of the uterus, as well as overnight or day-to-day variation affect the number of isolated fetal cells, more specifically the presumed endovascular trophoblast (pEVT). MATERIAL AND METHODS: In each of 3 different experiments, 10 normal singleton pregnant women (gestational age 10+4-14+4 weeks) participated. The number of pEVTs was assessed in 30-36 ml blood using specific markers for enrichment and identification. RESULTS: The number of pEVTs increased overnight (p = 0.001) from a median of 1.5 to 3.5 and even further to a median of 6.0 after 30 min of physical activity (p = 0.04) but was not affected by transabdominal and transvaginal ultrasound scans. Repeated sampling showed that the interindividual variation of pEVTs was higher than the intraindividual variation (p < 0.001). However, even in pregnant women with a consistently low number of pEVTs, isolation of the pEVTs for prenatal diagnoses was possible in all cases by doing 2 separate blood samplings a few days apart. DISCUSSION: The number of pEVTs identified in maternal blood can be increased by presampling conditions or repeated sampling. PMID- 26485126 TI - Advancing the Use of Clinical Decision Support to Prevent Drug-Associated AKI. AB - Clinical decision support (CDS) has repeatedly been successful in improving the physicians' drug prescribing for patients with kidney disease. Alerts aimed at drug dosing may address prevention of drug accumulation, but might miss situations when a high-risk patient still receives a nephrotoxin. Alert advancement requires CDS that is focused on the appropriate use of potentially nephrotoxic medications. Unfortunately, the literature is replete with examples of inaccurate or ineffective alerts. However, analyzing these efforts will allow us to advance CDS to be more effective and to better understand how to include early detection of drug-associated acute kidney injury. Attempts have been made to address these limitations of CDS, but there are still opportunities for improvement. PMID- 26485125 TI - Established Microbial Colonies Can Survive Type VI Secretion Assault. AB - Type VI secretion (T6S) is a cell-to-cell injection system that can be used as a microbial weapon. T6S kills vulnerable cells, and is present in close to 25% of sequenced Gram-negative bacteria. To examine the ecological role of T6S among bacteria, we competed self-immune T6S+ cells and T6S-sensitive cells in simulated range expansions. As killing takes place only at the interface between sensitive and T6S+ strains, while growth takes place everywhere, sufficiently large domains of sensitive cells can achieve net growth in the face of attack. Indeed T6S sensitive cells can often outgrow their T6S+ competitors. We validated these findings through in vivo competition experiments between T6S+ Vibrio cholerae and T6S-sensitive Escherichia coli. We found that E. coli can survive and even dominate so long as they have an adequate opportunity to form microcolonies at the outset of the competition. Finally, in simulated competitions between two equivalent and mutually sensitive T6S+ strains, the more numerous strain has an advantage that increases with the T6S attack rate. We conclude that sufficiently large domains of T6S-sensitive individuals can survive attack and potentially outcompete self-immune T6S+ bacteria. PMID- 26485127 TI - Correction: Quality along the Continuum: A Health Facility Assessment of Intrapartum and Postnatal Care in Ghana. PMID- 26485128 TI - A Cluster-Randomized Controlled Intervention Study to Assess the Effect of a Contact Intervention in Reducing Leprosy-Related Stigma in Indonesia. AB - BACKGROUND: Can deliberate interaction between the public and persons affected by leprosy reduce stigmatization? The study described in this paper hypothesises that it can and assesses the effectiveness of a 'contact intervention'. METHODS/PRINCIPAL FINDINGS: This cluster-randomized controlled intervention study is part of the Stigma Assessment and Reduction of Impact (SARI) project conducted in Cirebon District, Indonesia. Testimonies, participatory videos and comics given or made by people affected by leprosy were used as methods to facilitate a dialogue during so-called 'contact events'. A mix of seven quantitative and qualitative methods, including two scales to assess aspects of stigma named the SDS and EMIC-CSS, were used to establish a baseline regarding stigma and knowledge of leprosy, monitor the implementation and assess the impact of the contact events. The study sample were community members selected using different sampling methods. The baseline shows a lack of knowledge about leprosy, a high level of stigma and contrasting examples of support. In total, 91 contact events were organised in 62 villages, directly reaching 4,443 community members (mean 49 per event). The interview data showed that knowledge about leprosy increased and that negative attitudes reduced. The adjusted mean total score of the EMIC-CSS reduced by 4.95 points among respondents who had attended a contact event (n = 58; p < 0.001, effect size = 0.75) compared to the score at baseline (n = 213); for the SDS this was 3.56 (p < 0.001, effect size = 0.81). About 75% of those attending a contact event said they shared the information with others (median 10 persons). CONCLUSIONS/SIGNIFICANCE: The contact intervention was effective in increasing knowledge and improving public attitudes regarding leprosy. It is relatively easy to replicate elsewhere and does not require expensive technology. More research is needed to improve scalability. The effectiveness of a contact intervention to reduce stigma against other neglected tropical diseases and conditions should be evaluated. PMID- 26485130 TI - [Early repolarization in ECG. Definition, prevalence and prognostic significance]. AB - Early repolarization defined as antero-lateral ST-segment elevation exists in 1-2 % of the general population and has been considered a benign ECG finding for decades. However, early repolarization, defined as infero-lateral J-waves, has in recent studies been associated with an increased - albeit low - risk of sudden and cardiovascular death. This ECG pattern is present in 3-13% of the general population. However, exercise training can induce all types of early repolarization, and the prevalence in the athletic population rises to 20-90%. There is large variability between sports (higher in endurance athletes) and also throughout the season (higher during times of peak fitness). In athletes, early repolarization, regardless of type, is considered benign. In asymptomatic non athletes, the absolute risk is too low to use this ECG finding in clinical practice. In individuals with J-wave syndrome, on the other hand, ICD implantation should be strongly considered to prevent sudden cardiac death. PMID- 26485129 TI - The Relationship between Corvis ST Tonometry Measured Corneal Parameters and Intraocular Pressure, Corneal Thickness and Corneal Curvature. AB - The purpose of the study was to investigate the correlation between Corneal Visualization Scheimpflug Technology (Corvis ST tonometry: CST) parameters and various other ocular parameters, including intraocular pressure (IOP) with Goldmann applanation tonometry. IOP with Goldmann applanation tonometry (IOP-G), central corneal thickness (CCT), axial length (AL), corneal curvature, and CST parameters were measured in 94 eyes of 94 normal subjects. The relationship between ten CST parameters against age, gender, IOP-G, AL, CST-determined CCT and average corneal curvature was investigated using linear modeling. In addition, the relationship between IOP-G versus CST-determined CCT, AL, and other CST parameters was also investigated using linear modeling. Linear modeling showed that the CST measurement 'A time-1' is dependent on IOP-G, age, AL, and average corneal curvature; 'A length-1' depends on age and average corneal curvature; 'A velocity-1' depends on IOP-G and AL; 'A time-2' depends on IOP-G, age, and AL; 'A length-2' depends on CCT; 'A velocity-2' depends on IOP-G, age, AL, CCT, and average corneal curvature; 'peak distance' depends on gender; 'maximum deformation amplitude' depends on IOP-G, age, and AL. In the optimal model for IOP-G, A time-1, A velocity-1, and highest concavity curvature, but not CCT, were selected as the most important explanatory variables. In conclusion, many CST parameters were not significantly related to CCT, but IOP usually was a significant predictor, suggesting that an adjustment should be made to improve their usefulness for clinical investigations. It was also suggested CST parameters were more influential for IOP-G than CCT and average corneal curvature. PMID- 26485131 TI - [Patient safety in the operating room is not just a matter of cutting correctly. Social interaction, psychological factors and organization does also play a role]. PMID- 26485132 TI - [Modified British model shortened lead times for CT scans of the colon]. AB - The British national Institute for Health and Care Excellence (NICE) has presented guidelines based on signs and symptoms which should raise a suspicion of colorectal cancer. A slightly modified version of these guidelines, adapted to Swedish conditions, named Swedish NICE (sNICE) criteria, was implemented at eight primary care centres. By following the sNICE criteria, cases with higher degree of suspicion of colorectal cancer were advised for computer tomography (CT) of the colon, whereas cases of low degree of suspicion were advised for the considerably less time and patient demanding CT of the abdomen. For patients with isolated anal symptoms without presence of sNICE criteria, active expectancy for six weeks was recommended, followed by renewed consideration. Results showed that the ratio between CT colon and CT abdomen was reduced from 2.2 to 1.1 after introduction of the sNICE criteria. Also, the proportion of patients undergoing CT colon within two weeks from admittance was increased from 3 to 25 %. We conclude that the sNICE criteria may be a useful supportive tool for the primary care physician. PMID- 26485133 TI - [The hunt for the toxicant from Clostridium difficile]. PMID- 26485134 TI - [Introduce a new regime for blood tests in clozapine treatment]. PMID- 26485135 TI - [When nothing goes as planned. Time for a holistic approach in the analysis]. PMID- 26485136 TI - [The debate on antidepressants. Most of what is good can be used wrong]. PMID- 26485137 TI - [Opiates or opioids? Time to clean amongst the concepts]. PMID- 26485138 TI - [Not Available]. PMID- 26485139 TI - [Not Available]. PMID- 26485140 TI - [Comment regarding Group A Streptococcus: Manage throat infections according to the current recommendations]. PMID- 26485141 TI - Enhanced protective activity of nano formulated andrographolide against arsenic induced liver damage. AB - Chronic exposure to arsenic over a period of time induces toxicity, primarily in liver but gradually in all systems of the body. Andrographolide (AG), a major diterpene lactone of Andrographis paniculata, shows a wide array of physiological functions including hepatoprotection. Therapeutic applications of AG are however seriously constrained because of its insolubility, poor bioavailability, and short plasma half-life. Nanoparticulation of AG is a possible solution to these problems. In the present study we investigated the effectiveness of polylactide co-glycolide (PLGA) nanocapsulated andrographolide (NA) against arsenic induced liver damage in mice. NA of average diameter 65.8 nm and encapsulation efficiency of 64% were prepared. Sodium arsenite at a dose of 40 mg/L supplied via drinking water in mice significantly raised the serum level of liver function markers such as AST, ALT, and ALP, and caused arsenic deposition in liver and ROS generation, though it did not show any lethality up to 30 days of exposure. However, even liver toxicity was not observed when mice were given AG and NA orally at doses up to 100 mg/kg bwt and 20 mg/kg bwt respectively on alternate days for one month. Treatment of non-toxic doses of AG or NA on alternate days along with arsenic significantly decreased the arsenic induced elevation of the serum level of ALT, AST and ALP, and arsenic deposition in liver. AG and NA increased the level of hepatic antioxidant enzymes such as superoxide dismutase (SOD), and catalase (CAT), and the level of reduced glutathione (GSH). Also, the ROS level was lowered in mice exposed to arsenic but treated with AG or NA. Protective efficiency of NA is about five times more than that of AG. Administration of NA to arsenic-treated mice caused signs of improvement in liver tissue architecture. In conclusion, the results of this study suggest that NA could be beneficial against arsenic-induced liver toxicity. PMID- 26485142 TI - The Genetic Structure of Phellinus noxius and Dissemination Pattern of Brown Root Rot Disease in Taiwan. AB - Since the 1990s, brown root rot caused by Phellinus noxius (Corner) Cunningham has become a major tree disease in Taiwan. This fungal pathogen can infect more than 200 hardwood and softwood tree species, causing gradual to fast decline of the trees. For effective control, we must determine how the pathogen is disseminated and how the new infection center of brown root rot is established. We performed Illumina sequencing and de novo assembly of a single basidiospore isolate Daxi42 and obtained a draft genome of ~40 Mb. By comparing the 12,217 simple sequence repeat (SSR) regions in Daxi42 with the low-coverage Illumina sequencing data for four additional P. noxius isolates, we identified 154 SSR regions with potential polymorphisms. A set of 13 polymorphic SSR markers were then developed and used to analyze 329 P. noxius isolates collected from 73 tree species from urban/agricultural areas in 14 cities/counties all around Taiwan from 1989 to 2012. The results revealed a high proportion (~98%) of distinct multilocus genotypes (MLGs) and that none of the 329 isolates were genome-wide homozygous, which supports a possible predominant outcrossing reproductive mode in P. noxius. The diverse MLGs exist as discrete patches, so brown root rot was most likely caused by multiple clones rather than a single predominant strain. The isolates collected from diseased trees near each other tend to have similar genotype(s), which indicates that P. noxius may spread to adjacent trees via root to-root contact. Analyses based on Bayesian clustering, FST statistics, analysis of molecular variance, and isolation by distance all suggest a low degree of population differentiation and little to no barrier to gene flow throughout the P. noxius population in Taiwan. We discuss the involvement of basidiospore dispersal in disease dissemination. PMID- 26485143 TI - Carboplatin with Decitabine Therapy, in Recurrent Platinum Resistant Ovarian Cancer, Alters Circulating miRNAs Concentrations: A Pilot Study. AB - OBJECTIVE: Plasma miRNAs represent potential minimally invasive biomarkers to monitor and predict outcomes from chemotherapy. The primary goal of the current study-consisting of patients with recurrent, platinum-resistant ovarian cancer was to identify the changes in circulating miRNA concentrations associated with decitabine followed by carboplatin chemotherapy treatment. A secondary goal was to associate clinical response with changes in circulating miRNA concentration. METHODS: We measured miRNA concentrations in plasma samples from 14 patients with platinum-resistant, recurrent ovarian cancer enrolled in a phase II clinical trial that were treated with a low dose of the hypomethylating agent (HMA) decitabine for 5 days followed by carboplatin on day 8. The primary endpoint was to determine chemotherapy-associated changes in plasma miRNA concentrations. The secondary endpoint was to correlate miRNA changes with clinical response as measured by progression free survival (PFS). RESULTS: Seventy-eight miRNA plasma concentrations were measured at baseline (before treatment) and at the end of the first cycle of treatment (day 29). Of these, 10 miRNAs (miR-193a-5p, miR-375, miR 339-3p, miR-340-5p, miR-532-3p, miR-133a-3p, miR-25-3p, miR-10a-5p, miR-616-5p, and miR-148b-5p) displayed fold changes in concentration ranging from -2.9 to 4 (p<0.05), in recurrent platinum resistant ovarian cancer patients, that were associated with response to decitabine followed by carboplatin chemotherapy. Furthermore, lower concentrations of miR-148b-5p after this chemotherapy regimen were associated (P<0.05) with the PFS. CONCLUSIONS: This is the first report demonstrating altered circulating miRNA concentrations following a combination platinum plus HMA chemotherapy regiment. In addition, circulating miR-148b-5p concentrations were associated with PFS and may represent a novel biomarker of therapeutic response, with this chemotherapy regimen, in women with recurrent, drug-resistant ovarian cancer. PMID- 26485144 TI - Auxosporulation in Paralia guyana MacGillivary (Bacillariophyta) and Possible New Insights into the Habit of the Earliest Diatoms. AB - BACKGROUND: Diatoms are one of the most ecologically important aquatic micro eukaryotes. As a group unambiguously recognized as diatoms, they seem to have appeared relatively recently with a limited record of putative remains from oldest sediments. In contrast, molecular clock estimates for the earliest possible emergence of diatoms suggest a considerably older date. Depending on the analysis, Paralia and Leptocylindrus have been recovered within the basal molecular divergences of diatoms. Thus these genera may be in the position to inform on characters that the earliest diatoms possessed. FINDINGS: Here we present auxospore development and structure of initial and post-auxospore cells in a representative of the ancient non-polar centric genus Paralia. Their initial frustules showed unusual, but not unprecedented, spore-like morphology. Similarly, initial frustules of Leptocylindrus have been long considered resting spores and a unique peculiarity of this genus. However, even though spore-like in appearance, initial cells of Paralia readily resumed mitotic divisions. In addition, Paralia post-auxospore cells underwent several rounds of mitoses in a multi-step process of building a typical, "perfect" vegetative valve. This degree of heteromorphy immediately post-auxosporulation is thus far unknown among the diatoms. IMPLICATIONS: A spore-related origin of diatoms has already been considered, most recently in the form of the "multiplate diploid cyst" hypothesis. Our discovery that the initial cells in some of the most ancient diatom lineages are structurally spore-like is consistent with that hypothesis because the earliest diatoms may be expected to look somewhat similar to their ancestors. We speculate that because the earliest diatoms may have appeared less diatom-like and more spore-like, they could have gone unrecognized as such in the Triassic/Jurassic sediments. If correct, diatoms may indeed be much older than the fossil record indicates, and possibly more in line with some molecular clock predictions. PMID- 26485145 TI - Development of a Luminex Bead Based Assay for Diagnosis of Toxocariasis Using Recombinant Antigens Tc-CTL-1 and Tc-TES-26. AB - The clinical spectrum of human disease caused by the roundworms Toxocara canis and Toxocara cati ranges from visceral and ocular larva migrans to covert toxocariasis. The parasite is not typically recovered in affected tissues, so detection of parasite-specific antibodies is usually necessary for establishing a diagnosis. The most reliable immunodiagnostic methods use the Toxocara excretory secretory antigens (TES-Ag) in ELISA formats to detect Toxocara-specific antibodies. To eliminate the need for native parasite materials, we identified and purified immunodiagnostic antigens using 2D gel electrophoresis followed by electrospray ionization mass spectrometry. Three predominant immunoreactive proteins were found in the TES; all three had been previously described in the literature: Tc-CTL-1, Tc-TES-26, and Tc-MUC-3. We generated Escherichia coli expressed recombinant proteins for evaluation in Luminex based immunoassays. We were unable to produce a functional assay with the Tc-MUC-3 recombinant protein. Tc-CTL-1 and Tc-TES-26 were successfully coupled and tested using defined serum batteries. The use of both proteins together generated better results than if the proteins were used individually. The sensitivity and specificity of the assay for detecting visceral larval migrans using Tc-CTL-1 plus Tc-TES-26 was 99% and 94%, respectively; the sensitivity for detecting ocular larval migrans was 64%. The combined performance of the new assay was superior to the currently available EIA and could potentially be employed to replace current assays that rely on native TES-Ag. PMID- 26485146 TI - Abiotic Stresses Antagonize the Rice Defence Pathway through the Tyrosine Dephosphorylation of OsMPK6. AB - Plants, as sessile organisms, survive environmental changes by prioritizing their responses to the most life-threatening stress by allocating limited resources. Previous studies showed that pathogen resistance was suppressed under abiotic stresses. Here, we show the mechanism underlying this phenomenon. Phosphorylation of WRKY45, the central transcription factor in salicylic-acid (SA)-signalling dependent pathogen defence in rice, via the OsMKK10-2-OsMPK6 cascade, was required to fully activate WRKY45. The activation of WRKY45 by benzothiadiazole (BTH) was reduced under low temperature and high salinity, probably through abscisic acid (ABA) signalling. An ABA treatment dephosphorylated/inactivated OsMPK6 via protein tyrosine phosphatases, OsPTP1/2, leading to the impaired activation of WRKY45 and a reduction in Magnaporthe oryzae resistance, even after BTH treatment. BTH induced a strong M. oryzae resistance in OsPTP1/2 knockdown rice, even under cold and high salinity, indicating that OsPTP1/2 is the node of SA-ABA signalling crosstalk and its down-regulation makes rice disease resistant, even under abiotic stresses. These results points to one of the directions to further improve crops by managing the tradeoffs between different stress responses of plants. PMID- 26485147 TI - Flea-Associated Bacterial Communities across an Environmental Transect in a Plague-Endemic Region of Uganda. AB - The vast majority of human plague cases currently occur in sub-Saharan Africa. The primary route of transmission of Yersinia pestis, the causative agent of plague, is via flea bites. Non-pathogenic flea-associated bacteria may interact with Y. pestis within fleas and it is important to understand what factors govern flea-associated bacterial assemblages. Six species of fleas were collected from nine rodent species from ten Ugandan villages between October 2010 and March 2011. A total of 660,345 16S rRNA gene DNA sequences were used to characterize bacterial communities of 332 individual fleas. The DNA sequences were binned into 421 Operational Taxonomic Units (OTUs) based on 97% sequence similarity. We used beta diversity metrics to assess the effects of flea species, flea sex, rodent host species, site (i.e. village), collection date, elevation, mean annual precipitation, average monthly precipitation, and average monthly temperature on bacterial community structure. Flea species had the greatest effect on bacterial community structure with each flea species harboring unique bacterial lineages. The site (i.e. village), rodent host, flea sex, elevation, precipitation, and temperature also significantly affected bacterial community composition. Some bacterial lineages were widespread among flea species (e.g. Bartonella spp. and Wolbachia spp.), but each flea species also harbored unique bacterial lineages. Some of these lineages are not closely related to known bacterial diversity and likely represent newly discovered lineages of insect symbionts. Our finding that flea species has the greatest effect on bacterial community composition may help future investigations between Yersinia pestis and non-pathogenic flea-associated bacteria. Characterizing bacterial communities of fleas during a plague epizootic event in the future would be helpful. PMID- 26485148 TI - Human-Robot Interaction: Does Robotic Guidance Force Affect Gait-Related Brain Dynamics during Robot-Assisted Treadmill Walking? AB - In order to determine optimal training parameters for robot-assisted treadmill walking, it is essential to understand how a robotic device interacts with its wearer, and thus, how parameter settings of the device affect locomotor control. The aim of this study was to assess the effect of different levels of guidance force during robot-assisted treadmill walking on cortical activity. Eighteen healthy subjects walked at 2 km.h-1 on a treadmill with and without assistance of the Lokomat robotic gait orthosis. Event-related spectral perturbations and changes in power spectral density were investigated during unassisted treadmill walking as well as during robot-assisted treadmill walking at 30%, 60% and 100% guidance force (with 0% body weight support). Clustering of independent components revealed three clusters of activity in the sensorimotor cortex during treadmill walking and robot-assisted treadmill walking in healthy subjects. These clusters demonstrated gait-related spectral modulations in the mu, beta and low gamma bands over the sensorimotor cortex related to specific phases of the gait cycle. Moreover, mu and beta rhythms were suppressed in the right primary sensory cortex during treadmill walking compared to robot-assisted treadmill walking with 100% guidance force, indicating significantly larger involvement of the sensorimotor area during treadmill walking compared to robot-assisted treadmill walking. Only marginal differences in the spectral power of the mu, beta and low gamma bands could be identified between robot-assisted treadmill walking with different levels of guidance force. From these results it can be concluded that a high level of guidance force (i.e., 100% guidance force) and thus a less active participation during locomotion should be avoided during robot-assisted treadmill walking. This will optimize the involvement of the sensorimotor cortex which is known to be crucial for motor learning. PMID- 26485150 TI - Predictors of depression and anxiety during adolescence: the impact of birth weight. AB - BACKGROUND: A complex association has been observed between birth weight (BW) and depression/anxiety symptoms at various stages of life. The purpose of this study was to evaluate whether adolescents with low or insufficient BW were more likely to report depressive/anxiety symptoms. METHODS: A cross-sectional study was conducted with 102 adolescents (40 boys and 62 girls). RESULTS: Our results demonstrated that the incidence of depressive symptoms was 63% in the first BW quartile and 20% in the fourth quartile. Similarly, we observed that anxiety symptoms were present in 83% of the adolescents in the first BW quartile, followed by 36% in the fourth BW quartile. After adjustment, our study identified potential risk factors that were associated with anxiety symptoms, including female gender (P=0.026) and having a BW in the first quartile (P=0.049). Moreover, the adjusted odds of having depression were 4.5 times higher in adolescents with BW in the lowest quartile (P=0.035). We also found that the incidence of depressive symptoms among females was 61% in the first BW quartile and 30% in the fourth BW quartile and that it was 67% versus 12%, respectively, among males. Finally, a model that used anxiety symptoms as the dependent variable produced similar data. CONCLUSIONS: Our findings suggest that a deleterious fetal environment appears to have a significant impact on psychiatric issues. PMID- 26485149 TI - Antiretroviral Regimens and CD4/CD8 Ratio Normalization in HIV-Infected Patients during the Initial Year of Treatment: A Cohort Study. AB - BACKGROUND: As CD4/CD8 ratio inversion has been associated with non-AIDS morbidity and mortality, predictors of ratio normalization after cART need to be studied. Here, we aimed to investigate the association of antiretroviral regimens with CD4/CD8 ratio normalization within an observational cohort. METHODS: We selected, from a French cohort at the Nice University Hospital, HIV-1 positive treatment-naive patients who initiated cART between 2000 and 2011 with a CD4/CD8 ratio <1. Association between cART and ratio normalization (>1) in the first year was assessed using multivariate logistic regression models. Specific association with INSTI-containing regimens was examined. RESULTS: 567 patients were included in the analyses; the median CD4/CD8 ratio was 0.36. Respectively, 52.9%, 29.6% and 10.4% initiated a PI-based, NNRTI-based or NRTI-based cART regimens. About 8% of the population started an INSTI-containing regimen. 62 (10.9%) patients achieved a CD4/CD8 ratio >=1 (N group). cART regimen was not associated with normalization when coded as PI-, NNRTI- or NRTI-based regimen. However, when considering INSTI-containing regimens alone, there was a strong association with normalization [OR, 7.67 (2.54-23.2)]. CONCLUSIONS: Our findings suggest an association between initiation of an INSTI-containing regimen and CD4/CD8 ratio normalization at one year in naive patients. Should it be confirmed in a larger population, it would be another argument for their use as first-line regimen as it is recommended in the recent update of the "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents". PMID- 26485151 TI - Synthesis, crystal structure, optical and thermal properties of lanthanide hydrogen-polyphosphates Ln[H(PO3)4] (Ln = Tb, Dy, Ho). AB - Lanthanide hydrogen-polyphosphates Ln[H(PO3)4] (Ln = Tb, Dy, Ho) were synthesised as colourless (Ln = Tb, Dy) and light pink (Ln = Ho) crystalline powders by reaction of Tb4O7/Dy2O3/Ho2O3 with H3PO3 at 380 degrees C. All compounds crystallise isotypically (P2(1)/c (no. 14), Z = 4, a(Tb) = 1368.24(4) pm, b(Tb) = 710.42(2) pm, c(Tb) = 965.79(3) pm, beta(Tb) = 101.200(1) degrees , 3112 data, 160 parameters, wR2 = 0.062, a(Ho) = 1363.34(5) pm, b(Ho) = 709.24(3) pm, c(Ho) = 959.07(4) pm, beta(Ho) = 101.055(1) degrees , 1607 data, 158 parameters, wR2 = 0.058). The crystal structure comprises two different infinite helical chains of corner-sharing phosphate tetrahedra. In-between these chains the lanthanide ions are located, coordinated by seven oxygen atoms belonging to four different polyphosphate chains. Vibrational, UV/Vis and fluorescence spectra of Ln[H(PO3)4] (Ln = Tb, Dy, Ho) as well as Dy[H(PO3)4]:Ln (Ln = Ce, Eu) and the magnetic and thermal behaviour of Tb[H(PO3)4] are reported. PMID- 26485153 TI - Integrating Frailty into Clinical Practice to Prevent the Risk of Dependency in the Elderly. AB - Geriatric medicine started to be developed approximately 40 years ago when the increasing number of older adults with disability and dementia admitted to hospital emergency units threatened the sustainability of the healthcare organizations. Today, almost 90% of the geriatric medicine forces are devoted to the care of age-related disabilities. The epidemiological scenario and the high healthcare costs required for the management of dependent individuals require the adoption of strategies aimed at preventing the loss of physical function and anticipate the take in charge of older persons at risk of negative outcomes. Major medical specialties (e.g., oncology, cardiology, neurology...) have already moved to an early stage of the diseases to be more effective. Geriatric medicine must do the same moving to frailty an early stage of disability were intervention are more likely to be effective. PMID- 26485154 TI - Orthotopic Implantation and Peripheral Immune Cell Monitoring in the II-45 Syngeneic Rat Mesothelioma Model. AB - The enormous upsurge of interest in immune-based treatments for cancer such as vaccines and immune checkpoint inhibitors, and increased understanding of the role of the tumor microenvironment in treatment response, collectively point to the need for immune-competent orthotopic models for pre-clinical testing of these new therapies. This paper demonstrates how to establish an orthotopic immune competent rat model of pleural malignant mesothelioma. Monitoring disease progression in orthotopic models is confounded by the internal location of the tumors. To longitudinally monitor disease progression and its effect on circulating immune cells in this and other rat models of cancer, a single tube flow cytometry assay requiring only 25 ul whole blood is described. This provides accurate quantification of seven immune parameters: total lymphocytes, monocytes and neutrophils, as well as the T-cell subsets CD4 and CD8, B-cells and Natural Killer cells. Different subsets of these parameters are useful in different circumstances and models, with the neutrophil to lymphocyte ratio having the greatest utility for monitoring disease progression in the mesothelioma model. Analyzing circulating immune cell levels using this single tube method may also assist in monitoring the response to immune-based treatments and understanding the underlying mechanisms leading to success or failure of treatment. PMID- 26485155 TI - Prevalence and Impact on Stroke in Patients Receiving Maintenance Hemodialysis versus Peritoneal Dialysis: A Prospective Observational Study. AB - BACKGROUND: Patients undergoing maintenance dialysis are at increased risk of stroke, however, less is known about the prevalence and impact on stroke in the patients. METHODS: In this prospective cohort study, 590 patients undergoing hemodialysis (HD; n = 285) or peritoneal dialysis (PD; n = 305) from January 1, 2008 to December 31, 2012 were recruited. Baseline demographic, clinical, and laboratory data were collected. Timeline incidence data were analyzed using a Poisson model. The Cox proportional hazards regression assessed adjusted differences in stroke risk, a multivariate analysis was also performed. RESULTS: 62 strokes occurred during 1258 total patient-years of follow-up. Stroke occurred at a rate of 49.2/1,000 patient-years with a predominance in HD patients compared with PD patients (74.0 vs. 31.8/1,000 patient-years). The cumulative hazard of developing stroke was significantly higher in HD patients (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.15-3.62; p = 0.046) after adjusting for potential confounders. HD patients had an increased risk of ischemic stroke (HR, 2.62; 95% CI, 1.56-4.58; p = 0.002). The risk of hemorrhagic stroke was not significantly different between PD and HD patients. On multivariate Cox analysis, risk factors of stroke in both HD and PD patients were older age, diabetes, and cardiovascular disease. Other independent risk factors of stroke were lower albumin-corrected calcium in HD patients and higher triglycerides in PD patients. CONCLUSIONS: Patients undergoing PD were less likely to develop ischemic stroke than those undergoing HD. Comprehensive control of diabetes, cardiovascular disease, calcium-phosphorus metabolism, and triglyceride levels may be useful preventive strategies for stroke in dialysis patients. PMID- 26485156 TI - In vitro cancer cell-ECM interactions inform in vivo cancer treatment. AB - The general progression of cancer drug development involves in vitro testing followed by safety and efficacy evaluation in clinical trials. Due to the expense of bringing candidate drugs to trials, in vitro models of cancer cells and tumor biology are required to screen drugs. There are many examples of drugs exhibiting cytotoxic behavior in cancer cells in vitro but losing efficacy in vivo, and in many cases, this is the result of poorly understood chemoresistant effects conferred by the cancer microenvironment. To address this, improved methods for culturing cancer cells in biomimetic scaffolds have been developed; along the way, a great deal about the nature of cancer cell-extracellular matrix (ECM) interactions has been discovered. These discoveries will continue to be leveraged both in the development of novel drugs targeting these interactions and in the fabrication of biomimetic substrates for efficient cancer drug screening in vitro. PMID- 26485157 TI - Developing a Workflow to Identify Inconsistencies in Volunteered Geographic Information: A Phenological Case Study. AB - Recent improvements in online information communication and mobile location-aware technologies have led to the production of large volumes of volunteered geographic information. Widespread, large-scale efforts by volunteers to collect data can inform and drive scientific advances in diverse fields, including ecology and climatology. Traditional workflows to check the quality of such volunteered information can be costly and time consuming as they heavily rely on human interventions. However, identifying factors that can influence data quality, such as inconsistency, is crucial when these data are used in modeling and decision-making frameworks. Recently developed workflows use simple statistical approaches that assume that the majority of the information is consistent. However, this assumption is not generalizable, and ignores underlying geographic and environmental contextual variability that may explain apparent inconsistencies. Here we describe an automated workflow to check inconsistency based on the availability of contextual environmental information for sampling locations. The workflow consists of three steps: (1) dimensionality reduction to facilitate further analysis and interpretation of results, (2) model-based clustering to group observations according to their contextual conditions, and (3) identification of inconsistent observations within each cluster. The workflow was applied to volunteered observations of flowering in common and cloned lilac plants (Syringa vulgaris and Syringa x chinensis) in the United States for the period 1980 to 2013. About 97% of the observations for both common and cloned lilacs were flagged as consistent, indicating that volunteers provided reliable information for this case study. Relative to the original dataset, the exclusion of inconsistent observations changed the apparent rate of change in lilac bloom dates by two days per decade, indicating the importance of inconsistency checking as a key step in data quality assessment for volunteered geographic information. Initiatives that leverage volunteered geographic information can adapt this workflow to improve the quality of their datasets and the robustness of their scientific analyses. PMID- 26485158 TI - Spatial frequency selection and integration of global and local information in visual processing: A selective review and tribute to Shlomo Bentin. AB - Previous research has suggested a relationship between processing lower versus higher spatial frequencies (SFs) and global/local perception, respectively. Here we honor Shlomo Bentin by reviewing the work we conducted with him regarding this issue. This work was aimed at investigating the mechanisms by which selective attention to spatial frequency (SF) mediates global and local perception in general and how these perceptual levels are integrated with the shapes that define them. The experiments demonstrate that attention to global and local aspects of a hierarchical display biases the flexible selection of relatively lower and relatively higher SFs during image processing. Additionally, attentional selection of SF allows for the shapes in a hierarchical display to be integrated with the level (global/local) at which they occur. The studies reviewed here provide strong evidence that the flexible, top-down selection of low-level SF channels mediates the perception of global and local elements of visual displays. The studies also support a hemisphere asymmetry in this process, with right hemisphere functions biased toward global perception and left hemisphere functions biased toward local. PMID- 26485160 TI - Microfluidic Leaching of Soil Minerals: Release of K+ from K Feldspar. AB - The rate of K+ leaching from soil minerals such as K-feldspar is believed to be too slow to provide agronomic benefit. Currently, theories and methods available to interpret kinetics of mineral processes in soil fail to consider its microfluidic nature. In this study, we measure the leaching rate of K+ ions from a K-feldspar-bearing rock (syenite) in a microfluidic environment, and demonstrate that at the spatial and temporal scales experienced by crop roots, K+ is available at a faster rate than that measured with conventional apparatuses. We present a device to investigate kinetics of mineral leaching at an unprecedented simultaneous resolution of space (~101-102 MUm), time (~101-102 min) and fluid volume (~100-101 mL). Results obtained from such a device challenge the notion that silicate minerals cannot be used as alternative fertilizers for tropical soils. PMID- 26485159 TI - Neural substrates of spontaneous narrative production in focal neurodegenerative disease. AB - Conversational storytelling integrates diverse cognitive and socio-emotional abilities that critically differ across neurodegenerative disease groups. Storytelling patterns may have diagnostic relevance and predict anatomic changes. The present study employed mixed methods discourse and quantitative analyses to delineate patterns of storytelling across focal neurodegenerative disease groups, and to clarify the neuroanatomical contributions to common storytelling characteristics. Transcripts of spontaneous social interactions of 46 participants (15 behavioral variant frontotemporal dementia (bvFTD), 7 semantic variant primary progressive aphasia (svPPA), 12 Alzheimer's disease (AD), and 12 healthy older normal controls (NC)) were analyzed for storytelling frequency and characteristics, and videos of the interactions were rated for patients' level of social attentiveness. Compared to controls, svPPAs told more stories and autobiographical stories, and perseverated on aspects of self during the interaction, whereas ADs told fewer autobiographical stories than NCs. svPPAs and bvFTDs were rated as less attentive to social cues. Aspects of storytelling were related to diverse cognitive and socio-emotional functions, and voxel-based anatomic analysis of structural magnetic resonance imaging revealed that temporal organization, narrative evaluations patterns, and social attentiveness correlated with atrophy corresponding to known intrinsic connectivity networks, including the default mode, limbic, salience, and stable task control networks. Differences in spontaneous storytelling among neurodegenerative groups elucidated diverse cognitive, socio-emotional, and neural contributions to narrative production, with implications for diagnostic screening and therapeutic intervention. PMID- 26485161 TI - Potent Sensitisation of Cancer Cells to Anticancer Drugs by a Quadruple Mutant of the Human Deoxycytidine Kinase. AB - Identifying enzymes that, once introduced in cancer cells, lead to an increased efficiency of treatment constitutes an important goal for biomedical applications. Using an original procedure whereby mutant genes are generated based on the use of conditional lentivector genome mobilisation, we recently described, for the first time, the identification of a human deoxycytidine kinase (dCK) mutant (G12) that sensitises a panel of cancer cell lines to treatment with the dCK analogue gemcitabine. Here, starting from the G12 variant itself, we generated a new library and identified a mutant (M36) that triggers even greater sensitisation to gemcitabine than G12. With respect to G12, M36 presents an additional mutation located in the region that constitutes the interface of the dCK dimer. The simple presence of this mutation halves both the IC50 and the proportion of residual cells resistant to the treatment. Furthermore, the use of vectors with self-inactivating LTRs leads to an increased sensitivity to treatment, a result compatible with a relief of the transcriptional interference exerted by the U3 promoter on the internal promoter that drives the expression of M36. Importantly, a remarkable effect is also observed in treatments with the anticancer compound cytarabine (AraC), for which a 10,000 fold decrease in IC50 occurred. By triggering the sensitisation of various cancer cell types with poor prognosis to two commonly used anticancer compounds M36 is a promising candidate for suicide gene approaches. PMID- 26485162 TI - Cytomegalovirus infection accelerates epigenetic aging. AB - Epigenetic mechanisms such as DNA methylation (DNAm) have a central role in the regulation of gene expression and thereby in cellular differentiation and tissue homeostasis. It has recently been shown that aging is associated with profound changes in DNAm. Several of these methylation changes take place in a clock-like fashion, i.e. correlating with the calendar age of an individual. Thus, the epigenetic clock based on these kind of DNAm changes could provide a new biomarker for human aging process, i.e. being able to separate the calendar and biological age. Information about the correlation of the time indicated by this clock to the various aspects of immunosenescence is still missing. As chronic cytomegalovirus (CMV) infection is probably one of the major driving forces of immunosenescence, we now have analyzed the correlation of CMV seropositivity with the epigenetic age in the Vitality 90+cohort 1920 (122 nonagenarians and 21 young controls, CMV seropositivity rates 95% and 57%, respectively). The data showed that CMV seropositivity was associated with a higher epigenetic age in both of these age groups (median 26.5 vs. 24.0 (p < 0.02,Mann-Whitney U-test) in the young controls and 76.0 vs. 70.0 (p < 0.01) in the nonagenarians). Thus, these data provide a new aspect to the CMV associated pathological processes. PMID- 26485163 TI - Discovering Preferential Patterns in Sectoral Trade Networks. AB - We analyze the patterns of import/export bilateral relations, with the aim of assessing the relevance and shape of "preferentiality" in countries' trade decisions. Preferentiality here is defined as the tendency to concentrate trade on one or few partners. With this purpose, we adopt a systemic approach through the use of the tools of complex network analysis. In particular, we apply a pattern detection approach based on community and pseudocommunity analysis, in order to highlight the groups of countries within which most of members' trade occur. The method is applied to two intra-industry trade networks consisting of 221 countries, relative to the low-tech "Textiles and Textile Articles" and the high-tech "Electronics" sectors for the year 2006, to look at the structure of world trade before the start of the international financial crisis. It turns out that the two networks display some similarities and some differences in preferential trade patterns: they both include few significant communities that define narrow sets of countries trading with each other as preferential destinations markets or supply sources, and they are characterized by the presence of similar hierarchical structures, led by the largest economies. But there are also distinctive features due to the characteristics of the industries examined, in which the organization of production and the destination markets are different. Overall, the extent of preferentiality and partner selection at the sector level confirm the relevance of international trade costs still today, inducing countries to seek the highest efficiency in their trade patterns. PMID- 26485164 TI - pH sensitive nano layered double hydroxides reduce the hematotoxicity and enhance the anticancer efficacy of etoposide on non-small cell lung cancer. AB - Etoposide (VP16), used for the treatment of many carcinomas, can cause leukopenia, thrombocytopenia and hair loss. To overcome the side effects and achieve target therapy, layered double hydroxides (LDHs), a pH sensitive layered double hydroxide nanohybrid, was used here as a nano-carrier. The functions of LDHs-VP16 on non-small cell lung cancer (NSCLC) were firstly explored both in vitro and in vivo. In A549 cell line, LDH-VP16 induced apoptosis 2.3-fold as that of plain VP16 by targeting to mitochondrial, stocking cells in G1 phase. The cellular uptake demonstrated the delivery of LDH for VP16 to pass through the membrane and accumulate in mitochondria. As a carrier, LDH greatly decreased the liver toxicity and hematotoxicity of VP16. The detected liver parameters, including glutamic-oxaloacetic transaminase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), were all turn back to normal range after the delivery of LDH, except ALP. In vivo, LDH-VP16 reduced A549 tumor growth significantly by 60.5%, whereas native VP16 exerted no significant anticancer activity. In LDH-VP16 treated mice, the AUC was increased by 6.26 folds as the native drug, and t1/2 of LDH-VP16 was prolonged from 6.68 to 98.78h. LDH-VP16 showed a targeting effect, which largely increase the concentration in tumor and lung. The phosphorylation antibody array and Western Blot of proteins from xenografts revealed that PI3K-AKT signaling was suppressed in the LDH-VP16 treated tumor, while in VP16 treated mice, ERBB signaling pathway was involved. These results suggested that LDH-VP16 diminishes hematotoxicity, targets NSCLC tumor, performs more effectively than VP16, and different signaling pathway is involved compared to VP16. STATEMENT OF SIGNIFICANCE: This paper explored that nano-sized layered double hydroxide (LDH) could be used as a pH sensitive delivery system to overcome hematotoxicity and enhance the bioavailability and anticancer efficacy of etoposide (VP16) against non small cell lung cancer, which was not reported before, as the best of our knowledge. We found that the liver and hematotoxicity is nearly recovered after the loading of VP16 in pH sensitive LDH, which prongs the half time from 6.68h to 98h, helps target VP16 to tumor and lung, and protects white blood cells by its pH sensitive and nano-size property. LDH-VP16 achieve markedly performance on non-small cell lung cancer by targeting to mitochondria of A549 cells in vitro and effectively inhibiting the PI3K-AKT signaling pathway in vivo. The inhibition ratio of VP16 on A549 tumor growth is increased from less than 20% (no significance compared to control) to 60.5% after the delivery of LDH. This work provides a novel system for the safe and efficient use of etoposide on non-small cell lung cancer and explores the mechanism of the function of nano carrier in cancer therapy both in vitro and in vivo. PMID- 26485165 TI - Fabrication of a magnesium alloy with excellent ductility for biodegradable clips. AB - To develop a biodegradable clip, the equivalent plastic strain distribution during occlusion was evaluated by the finite element analysis (FEA) using the material data of pure Mg. Since the FEA suggested that a maximum plastic strain of 0.40 is required to allow the Mg clips, the alloying of magnesium with essential elements and the control of microstructure by hot extrusion and annealing were conducted. Mechanical characterization revealed that the Mg-Zn-Ca alloy obtained by double extrusion followed by annealing at 673K for 2h possessed a fracture strain over 0.40. The biocompatibility of the alloy was confirmed here by investigating its degradation behavior and the response of extraperitoneal tissue around the Mg-Zn-Ca alloy. Small gas cavity due to degradation was observed following implantation of the developed Mg-Zn-Ca clip by in vivo micro CT. Histological analysis, minimal observed inflammation, and an only small decrease in the volume of the implanted Mg-Zn-Ca clip confirmed its excellent biocompatibility. FEA using the material data for ductile Mg-Zn-Ca also showed that the clip could occlude the simulated vessel without fracture. In addition, the Mg-Zn-Ca alloy clip successfully occluded the renal vein. Microstructural observations using electron backscattering diffraction confirmed that dynamic recovery occurred during the later stage of plastic deformation of the ductile Mg Zn-Ca alloy. These results suggest that the developed Mg-Zn-Ca alloy is a suitable material for biodegradable clips. STATEMENT OF SIGNIFICANCE: Since conventional magnesium alloys have not exhibited significant ductility for applying the occlusion of vessels, the alloying of magnesium with essential elements and the control of microstructure by hot extrusion and annealing were conducted. Mechanical characterization revealed that the Mg-Zn-Ca alloy obtained by double extrusion followed by annealing at 673K for 2h possessed a fracture strain over 0.40. The biocompatibility of the alloy was confirmed by investigating its degradation behavior and the response of extraperitoneal tissue around the Mg-Zn-Ca alloy. Finite element analysis using the material data for the ductile Mg-Zn-Ca alloy also showed that the clip could occlude the simulated vessel without fracture. In addition, the Mg-Zn-Ca alloy clip successfully occluded the renal vein. Microstructural observations using electron backscattering diffraction confirmed that dynamic recovery occurred during the later stage of plastic deformation of the ductile Mg-Zn-Ca alloy. PMID- 26485166 TI - Controlled co-immobilization of EGF and VEGF to optimize vascular cell survival. AB - Growth factors (GFs) are potent signaling molecules that act in a coordinated manner in physiological processes such as tissue healing or angiogenesis. Co immobilizing GFs on materials while preserving their bioactivity still represents a major challenge in the field of tissue regeneration and bioactive implants. In this study, we explore the potential of an oriented immobilization technique based on two high affinity peptides, namely the Ecoil and Kcoil, to allow for the simultaneous capture of the epidermal growth factor (EGF) and the vascular endothelial growth factor (VEGF) on a chondroitin sulfate coating. This glycosaminoglycan layer was selected as it promotes cell adhesion but reduces non specific adsorption of plasma proteins. We demonstrate here that both Ecoil tagged GFs can be successfully immobilized on chondroitin sulfate surfaces that had been pre-decorated with the Kcoil peptide. As shown by direct ELISA, changing the incubation concentration of the various GFs enabled to control their grafted amount. Moreover, cell survival studies with endothelial and smooth muscle cells confirmed that our oriented tethering strategy preserved GF bioactivity. Of salient interest, co-immobilizing EGF and VEGF led to better cell survival compared to each GF captured alone, suggesting a synergistic effect of these GFs. Altogether, these results demonstrate the potential of coiled-coil oriented GF tethering for the co-immobilization of macromolecules; it thus open the way to the generation of biomaterials surfaces with fine-tuned biological properties. STATEMENT OF SIGNIFICANCE: Growth factors are potent signaling molecules that act in a coordinated manner in physiological processes such as tissue healing or angiogenesis. Controlled coimmobilization of growth factors on biomaterials while preserving their bioactivity represents a major challenge in the field of tissue regeneration and bioactive implants. This study demonstrates the potential of an oriented immobilization technique based on two high affinity peptides to allow for the simultaneous capture of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). Our system allowed an efficient control on growth factor immobilization by adjusting the incubation concentrations of EGF and VEGF. Of salient interest, co-immobilizing of specific ratios of EGF and VEGF demonstrated a synergistic effect on cell survival compared to each GF captured alone. PMID- 26485167 TI - Submicron-sized hydrogels incorporating cyclic dinucleotides for selective delivery and elevated cytokine release in macrophages. AB - Despite the emerging evidences supporting the potential of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as a vaccine adjuvant, few properly designed micro-/nanocarriers for the delivery of cyclic dinucleotides have been developed. In this study, we formulated cGAMP within linear polyethyleneimine (LPEI)/hyaluronic acid (HA) hydrogels via inverse water-in-oil (W/O) emulsion/crosslinking. Spherical and cationic LPEI/HA hydrogels (LH gels) with a size of 455.3+/-3.1nm and a surface charge of 48.7+/-3.7mV were selectively and efficiently delivered into phagocytic macrophage cells, which are one type of antigen-presenting cells (APCs), but not into non-phagocytic fibroblast cells. LH gels incorporating cGAMP (LH/cGAMP gels) elicited excellent induction of the cytokines interferon-beta (IFN-beta) and interleukin-6 (IL-6). In particular, the amount of IFN-beta released by LH hydrogels was significantly increased by 2.5 fold compared to that released by conventional cationic liposomes, such as Lipofectamine. In addition, fabricated LH gels showed superior biocompatibility in phagocytic cell lines and primary bone marrow-derived macrophages (BMDMs). After intramuscular injection with ovalbumin into C57BL/6 mice, LH/cGAMP gels exhibited significantly elevated levels of anti-ovalbumin total IgG in serum and IFN-beta mRNA in spleens. Thus, the newly designed cGAMP-incorporating hydrogels can serve as safe and potent adjuvants for vaccination and immunotherapy. STATEMENT OF SIGNIFICANCE: Since cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) was first found as a second messenger of immune signaling in human systems in February 2013 (Science, 15, 826), several scientific studies have been reported related to the potential of cGAMP as a vaccine adjuvant or additive for immunotherapy. However, only naked cGAMP without carriers were studied via intramuscular or intranasal administration so far. In our study, we first investigated the feasibility of polymeric hydrogels incorporating cGAMP in terms of selective uptake into phagocytic antigen presenting cells (APCs), induction of cytokines, production of target antibodies, and biocompatibility for vaccination and immunotherapy in vitro and in vivo. Therefore, we believe this manuscript would be of great interest to the biomaterial communities especially who are studying immunotherapy. PMID- 26485168 TI - A tumor-specific cleavable nanosystem of PEG-modified C60@Au hybrid aggregates for radio frequency-controlled release, hyperthermia, photodynamic therapy and X ray imaging. AB - Taking advantages of fullerene (C60) and gold nanoparticles (AuNPs) for potentials in photodynamic therapy (PDT), drug delivery and radio frequency thermal therapy (RTT), a C60@Au hybrid nanocomposite was synthesized by chemical deposition of Au nanoparticles onto C60, and functionalized by PEG5000 via a pH cleavable hydrazone bond, making C60@Au-PEG keep the PEG on the surface of drug delivery system during circulation but dissociate PEG from the system after accumulation in tumor tissue, then doxorubicin (DOX) was loaded onto C60@Au-PEG with a very high drug loading efficiency. The release profiles of DOX from C60@Au PEG/DOX showed strong dependences on radio frequency (RF). For the drug delivery, C60@Au-PEG/DOX afforded much higher antitumor efficacy owing to 8.6-fold higher DOX uptake of tumor than DOX. Besides, in this work, C60@Au-PEG/DOX not only served as a powerful RTT agent for RF-thermal ablation of tumor and a strong photosensitizer (PS) for PDT, but also as an X-ray contrast agent for tumor diagnosis. In the in vitro and in vivo studies, C60@Au-PEG/DOX showed excellent chemo-RF thermal-photodynamic therapeutic efficacy, RF-controlled drug releasing function, tumor targeting property, tumoral acid PEG dissociating character and X ray imaging ability, demonstrating that there is a great potential of C60@Au PEG/DOX for simultaneous diagnosis and therapy in cancer treatment. STATEMENT OF SIGNIFICANCE: A significant challenge in cancer therapy is to maximize the therapeutic efficacy and minimize the side effects. In the past decade, a lot of nanoparticles have been used as the carriers for efficient drug delivery. However, the design of drug delivery system (DDS) with stimuli-responsive controlled-release property, simultaneous diagnosis and therapy functions is still a challenge. Herein, we developed a new drug delivery system (C60@Au PEG/DOX), and explored its applications in tumor therapy. The in vitro and in vivo results showed C60@Au-PEG/DOX could significantly improve the therapeutic efficacy and reduce the systemic toxicity through X-ray imaging guided locatable DOX release, photodynamic and photothermal therapies. These results are of interest as they demonstrate a multi-functional DDS for tumor theranostic applications. PMID- 26485169 TI - Using an Ingestible Telemetric Temperature Pill to Assess Gastrointestinal Temperature During Exercise. AB - Exercise results in an increase in core body temperature (Tc), which may reduce exercise performance and eventually can lead to the development of heat-related disorders. Therefore, accurate measurement of Tc during exercise is of great importance, especially in athletes who have to perform in challenging ambient conditions. In the current literature a number of methods have been described to measure the Tc (esophageal, external tympanic membrane, mouth or rectum). However, these methods are suboptimal to measure Tc during exercise since they are invasive, have a slow response or are influenced by environmental conditions. Studies described the use of an ingestible telemetric temperature pill as a reliable and valid method to assess gastrointestinal temperature (Tgi), which is a representative measurement of Tc. Therefore, the goal of this study was to provide a detailed description of the measurement of Tgi using an ingestible telemetric temperature pill. This study addresses important methodological factors that must be taken into account for an accurate measurement. It is recommended to read the instructions carefully in order to ensure that the ingestible telemetric temperature pill is a reliable method to assess Tgi at rest and during exercise. PMID- 26485170 TI - Validation of the Asia Pacific Colorectal Screening (APCS) score in a Western population: An alternative screening tool. AB - BACKGROUND AND AIM: Colorectal cancer (CRC) screening is based on colonoscopy or fecal occult blood tests, but is imperfect and costly. The Asia Pacific Colorectal Screening Score (APCS) is derived from age, sex, family history of CRC, and smoking history and has been validated in Asian populations. Validation in a Western population is, however, yet to be tested. METHODS: In a teaching hospital, patients underwent colonoscopy for standard indications and screening over 18 months. Data was collected on age, sex, family history of CRC, smoking, weight, ethnicity, and symptoms. Evaluation of the APCS to predict colonoscopy findings (polyps, adenoma, high risk adenoma, and CRC) was performed. RESULTS: A total of 645 patients were prospectively recruited (46.7% male, median age 57 years); 17.8% were average risk (AR), 50.9% were moderate risk (MR), and 31.3% high risk (HR) on APCS. High risk adenomas (AA) were seen in 14.9% of the HR, 5.2% MR, and 0.9% LR patients, P < 0.0001. Comparing HR and MR to AR patients demonstrated significantly elevated relative risk (RR) for AA: 17.1 (95% confidence interval [CI] 2.4-123; P = 0.0001), and adenoma 6.0 (0.80-44.3; P = 0.044). Comparing HR to MR groups for AA, the RR was 2.87 (1.62-5.06; P = 0.0001). Symptoms did not predict findings (odds ratio [OR]: 1.06 [0.75-1.48]; P = 0.75). Body mass index (BMI) <20 kg/m(2) was protective against colonic polyps (OR: 0.28, 95%CI: 0.11-0.74; P = 0.010), adenoma (0.08, 0.01-0.62; P = 0.015), and AA (perfect prediction, OR 2.35 * 10(-8)). CONCLUSIONS: APCS predicts colonic findings in a Western population, to a greater extent than in Asians, independent to symptoms. Low body weight carries a strong protective effect against colonic neoplasia. PMID- 26485171 TI - A Cytokine-Based Diagnostic Program in Pediatric Aplastic Anemia and Hypocellular Refractory Cytopenia of Childhood. AB - BACKGROUND: Distinguishing hypocellular refractory cytopenia of childhood (RCC) from aplastic anemia (AA) is challenging. Thus far, no studies have compared the cytokine profiles in patients with AA to those with hypocellular RCC. In the present study, we addressed whether thrombopoietin (TPO) and interleukin 17 (IL 17) plasma levels are useful for differentiating between the two diseases. METHODS: We measured the endogenous plasma concentrations of TPO and IL-17 in 29 patients with AA, 34 patients with hypocellular RCC, and 31 healthy controls using sensitive enzyme-linked immunosorbent assays. RESULTS: The TPO and IL-17 plasma levels were significantly lower in patients with hypocellular RCC than in patients with AA (P < 0.001 and P = 0.007, respectively). The multivariate logistic regression analysis identified moderate disease severity, TPO levels of <1,369.8 pg/ml (TPO-low group, n = 32; odds ratio (OR), 13.40; 95% confidence intervals (CI), 3.001-51.254; P < 0.001), and IL-17 levels of <22.2 pg/ml (IL-17 low group, n = 33; OR, 4.11; 95% CI, 1.033-19.404; P = 0.031) as independent factors discriminating hypocellular RCC from AA. Importantly, 25 (78.1%) of 32 patients in the TPO-low group and 25 (75.8%) of 33 patients in the IL-17-low group were diagnosed as having hypocellular RCC. Moreover, 22 (71%) of 31 patients in the TPO-high group and 21 (70%) of 30 patients in the IL-17-high group were diagnosed as having AA. CONCLUSIONS: TPO and IL-17 levels are useful for differentiating hypocellular RCC from AA. Prospective studies are required to confirm our findings. PMID- 26485172 TI - Variation in attrition at subnational level: review of the Botswana National HIV/AIDS Treatment (Masa) programme data (2002-2013). AB - OBJECTIVE: To evaluate the variation in all-cause attrition [mortality and loss to follow-up (LTFU)] among HIV-infected individuals in Botswana by health district during the rapid and massive scale-up of the National Treatment Program. METHODS: Analysis of routinely collected longitudinal data from 226 030 patients who received ART through the Botswana National HIV/AIDS Treatment Program across all 24 health districts from 2002 to 2013. A time-to-event analysis was used to measure crude mortality and loss to follow-up rates (LTFU). A marginal structural model was used to evaluate mortality and LTFU rates by district over time, adjusted for individual-level risk factors (e.g. age, gender, baseline CD4, year of treatment initiation and antiretroviral regimen). RESULTS: Mortality rates in the districts ranged from the lowest 1.0 (95% CI 0.9-1.1) in Selibe-Phikwe, to the highest 5.0 (95% CI 4.0-6.1), in Mabutsane. There was a wide range of overall LTFU across districts, including rates as low as 4.6 (95% CI 4.4-4.9) losses per 100 person-years in Ngamiland, and 5.9 (95% CI 5.6-6.2) losses per 100 person years in South East district, to rates as high as 25.4 (95% CI 23.08-27.89) losses per 100 person-years in Mabutsane and 46.3 (95% CI 43.48-49.23) losses per 100 person-years in Okavango. Even when known risk factors for mortality and LTFU were adjusted for, district was a significant predictor of both mortality and LTFU rates. CONCLUSION: We found statistically significant variation in attrition (mortality and LTFU) and data quality among districts. These findings suggest that district-level contextual factors affect retention in treatment. Further research needs to investigate factors that can potentially cause this variation. PMID- 26485173 TI - Erratum: Screening for recombinants of Crambe abyssinica after transformation by the pMF1 marker-free vector based on chemical selection and meristematic regeneration. PMID- 26485174 TI - Controllable synthesis of green and blue fluorescent carbon nanodots for pH and Cu(2+) sensing in living cells. AB - We report a controllable strategy for fabrication of green and blue fluorescent carbon nanodots (CDs), and demonstrate their applications for pH and Cu(2+) sensing in living cells. Green and blue fluorescent CDs have been synthesized by hydrothermal method and pyrolysis of leeks, respectively, providing an easy way for the production of CDs without the request of tedious synthetic methodology or the use of toxic/expensive solvents and starting materials. Green fluorescent CDs (G-CDs) exhibit high tolerance to pH values and external cations. Blue fluorescent CDs (B-CDs) can be applied to pH and Cu(2+) sensing. The linear range of Cu(2+) detection is 0.01-10.00 MUM and the detection limit is 0.05 MUM. For pH detection, there is a good linearity in the pH range of 3.5-10.0. The linear and rapid response of B-CDs to Cu(2+) and pH is valuable for Cu(2+) and pH sensing in living cells. Confocal fluorescent imaging of human cervical carcinoma cells indicates that B-CDs could visualize Cu(2+) and pH fluctuations in living cells with negligible autofluorescence. PMID- 26485175 TI - Design of nuclease-based target recycling signal amplification in aptasensors. AB - Compared with conventional antibody-based immunoassay methods, aptasensors based on nucleic acid aptamer have made at least two significant breakthroughs. One is that aptamers are more easily used for developing various simple and rapid homogeneous detection methods by "sample in signal out" without multi-step washing. The other is that aptamers are more easily employed for developing highly sensitive detection methods by using various nucleic acid-based signal amplification approaches. As many substances playing regulatory roles in physiology or pathology exist at an extremely low concentration and many chemical contaminants occur in trace amounts in food or environment, aptasensors for signal amplification contribute greatly to detection of such targets. Among the signal amplification approaches in highly sensitive aptasensors, the nuclease based target recycling signal amplification has recently become a research focus because it shows easy design, simple operation, and rapid reaction and can be easily developed for homogenous assay. In this review, we summarized recent advances in the development of various nuclease-based target recycling signal amplification with the aim to provide a general guide for the design of aptamer based ultrasensitive biosensing assays. PMID- 26485176 TI - Molecular imprinting ratiometric fluorescence sensor for highly selective and sensitive detection of phycocyanin. AB - A facile strategy was developed to prepare molecular imprinting ratiometric fluorescence sensor for highly selective and sensitive detection of phycocyanin (PC) based on fluorescence resonance energy transfer (FRET), via a sol-gel polymerization process using nitrobenzoxadiazole (NBD) as fluorescent signal source. The ratio of two fluorescence peak emission intensities of NBD and PC was utilized to determine the concentration of PC, which could effectively reduce the background interference and fluctuation of diverse conditions. As a result, this sensor obtained high sensitivity with a low detection limit of 0.14 nM within 6 min, and excellent recognition specificity for PC over its analogues with a high imprinting factor of 9.1. Furthermore, the sensor attained high recoveries in the range of 93.8-110.2% at three spiking levels of PC, with precisions below 4.7% in seawater and lake water samples. The developed sensor strategy demonstrated simplicity, reliability, rapidity, high selectivity and high sensitivity, proving to be a feasible way to develop high efficient fluorescence sensors and thus potentially applicable for ultratrace analysis of complicated matrices. PMID- 26485177 TI - Electrical dual-sensing method for real-time quantitative monitoring of cell secreted MMP-9 and cellular morphology during migration process. AB - MMP-9 (92 kDa gelatinease), which is member of matrix metalloproteinases (MMPs) family, plays a crucial role in the breakdown of extracellular matrix (ECM) by degrading the major components of ECM that lead to tumor cell invasion and metastasis through the basement membrane. Our study presents the on-chip dual sensing device for rapid detection of cell-secreted MMP-9 and corresponding cell morphology changes in real-time domain. The device consists of 2 sensing platforms (both are interdigitated array microelectrodes - IDAMs) within 1 common fluidic chamber: one detects the cell morphology responses via Electric Cell substrate Impedance Sensing (ECIS) technique, meanwhile the other records the cleavage effect between cell-secreted MMP-9 and the surface immobilized peptide via the capacitance-based sensing method. Thanks to the selectivity of designed peptide, this approach allows the rapid and specific detection of MMP-9. In comparison with gold standard ELISA assay, the detection time was significantly reduced from over 4h to within 30 min with the wide detection range from 10 pM to 10nM. Finally, this study provides the novel model for MMP-9 protease direct detection from living cell and new insights in multi-purpose detection of cancer associated enzyme and cell migration behavior. PMID- 26485180 TI - Rotationally Selected and Resolved State-to-State Photoelectron Study of Vanadium Monoxide Cation VO(+)(X(3)Sigma(-); v(+) = 0-3). AB - Vanadium monoxide cation VO(+)(X(3)Sigma(-)) has been investigated by two-color visible (VIS)-ultraviolet (UV) pulsed field ionization-photoelectron (PFI-PE) methods. The unambiguous rotational assignment of rotationally selected and resolved VIS-UV-PFI-PE spectra thus obtained confirms the ground state term symmetry of VO(+) to be X(3)Sigma(-). The rotational analysis also yields the rotational constants Be(+) = 0.5716 +/- 0.0012 cm(-1) and alphae(+) = 0.0027 +/- 0.0005 cm(-1) for VO(+)(X(3)Sigma(-)), from which the equilibrium bond distance of VO(+)(X(3)Sigma(-)) is determined to be re(+) = 1.557 +/- 0.002 A. This PFI-PE study covers the vibrational bands, VO(+)(X(3)Sigma(-); v(+) = 0, 1, 2, and 3) <- VO(X(4)Sigma(-); v" = 0), which has made possible the determination of the vibrational constants for VO(+)(X(3)Sigma(-)) to be omegae(+) = 1068.0 +/- 0.7 cm(-1) and omegae(+)xe(+) = 5.5 +/- 0.7 cm(-1). The present state-to-state measurement also yields a more precise value (58 380.0 +/- 0.7 cm(-1) or 7.238 20 +/- 0.000 09 eV) for the ionization energy of VO [IE(VO)]. This value along with the known IE(V) has allowed the determination of the difference between the 0 K bond dissociation energy (D0) of VO(+)(X(3)Sigma(-)) and that of VO(X(4)Sigma(-)) to be D0(V(+)-O) - D0(V-O) = IE(V) - IE(VO) = -3967 +/- 1 cm(-1). PMID- 26485178 TI - CD/AuNPs/MWCNTs based electrochemical sensor for quercetin dual-signal detection. AB - A dual-signal strategy was developed in the present work for quercetin (QR) electrochemical recognition and detection. Mercapto-beta-cyclodextrin (HS-beta CD) self-assembled on gold nanoparticles and multi-walled carbon nanotubes modified electrode surface to fabricate an electrochemical sensor. Scanning electron microscope, electrochemical impedance spectroscopy, and cyclic voltammetry were employed to characterize the preparation process of the sensor. Hydroquinone (HQ) was chosen as an electrochemical marker for QR detection due to its small molecular size for the formation of inclusion with HS-beta-CD. The results of UV-vis and differential pulse voltammetry demonstrate that the added QR can replace the included HQ in CD cavities, resulting in the dual-signal in electrochemical experiments composed of the decrease of oxidized current of HQ and the increase of oxidized current of QR. Compared with the sensor for QR detection in the absence of HQ, the sensor based dual-signal strategy exhibited a higher sensitivity with a wider detection range from 5.0 * 10(-9) to 7.0 * 10( 6)mol/L. With good selectivity, reproducibility, and stability, the sensor was applied for real samples detection with satisfactory results. The proposed dual signal strategy can be readily extended to the selective recognition and sensitive detection of other molecules. PMID- 26485179 TI - Induction of apoptosis in leukemia cell lines by new copper(II) complexes containing naphthyl groups via interaction with death receptors. AB - The synthesis, physico-chemical characterization and cytotoxicity of four new ligands and their respective copper(II) complexes toward two human leukemia cell lines (THP-1 and U937) are reported (i.e. [(HL1)Cu(MU-Cl)2Cu(HL1)]Cl2.H2O (1), [(H2L2)Cu(MU-Cl)2Cu(H2L2)]Cl2.5H2O (2), [(HL3)Cu(MU-Cl)2Cu(HL3)]Cl2.4H2O (3), [(H2L4)Cu(MU-Cl)2Cu(H2L4)]Cl2.6H2O (4)). Ligands HL1 and HL3 contain two pyridines, amine and alcohol moieties with a naphthyl pendant unit yielding a N3O coordination metal environment. Ligands H2L2 and H2L4 have pyridine, phenol, amine and alcohol groups with a naphthyl pendant unit providing a N2O2 coordination metal environment. These compounds are likely to be dinuclear in the solid state but form mononuclear species in solution. The complexes have an antiproliferative effect against both leukemia cell lines; complex (2) exhibits higher activity than cisplatin against U937 (8.20 vs 16.25MUmoldm(-3)) and a comparable one against THP-1. These human neoplastic cells are also more susceptible than peripheral blood mononuclear cells (PBMCs) toward the tested compounds. Using C57BL/6 mice an LD50 of 55mgkg(-1) was determined for complex (2), suggesting that this compound is almost four times less toxic than cisplatin (LD50=14.5mgkg(-1)). The mechanism of cell death promoted by ligand H2L2 and by complexes (2) and (4) was investigated by a range of techniques demonstrating that the apoptosis signal triggered at least by complex (2) starts from an extrinsic pathway involving the activation of caspases 4 and 8. This signal is amplified by mitochondria with the concomitant release of cytochrome c and the activation of caspase 9. PMID- 26485181 TI - Role of Additives in Composite PEI/Oxide CO2 Adsorbents: Enhancement in the Amine Efficiency of Supported PEI by PEG in CO2 Capture from Simulated Ambient Air. AB - Supported amines are promising candidate adsorbents for the removal of CO2 from flue gases and directly from ambient air. The incorporation of additives into polymeric amines such as poly(ethylenimine) (PEI) supported on mesoporous oxides is an effective strategy to improve the performance of the materials. Here, several practical aspects of this strategy are addressed with regards to direct air capture. The influence of three additives (CTAB, PEG200, PEG1000) was systematically explored under dry simulated air capture conditions (400 ppm of CO2, 30 degrees C). With SBA-15 as a model support for poly(ethylenimine) (PEI), the nature of the additive induced heterogeneities in the deposition of organic on the interior and exterior of the particles, an important consideration for future scale up to practical systems. The PEG200 additive increased the observed thermodynamic performance (~60% increase in amine efficiency) of the adsorbents regardless of the PEI content, while the other molecules had less positive effects. A threshold PEG200/PEI value was identified at which the diffusional limitations of CO2 within the materials were nearly eliminated. The threshold PEG/PEI ratio may have physical origin in the interactions between PEI and PEG, as the optimal ratio corresponded to nearly equimolar OH/reactive (1 degrees , 2 degrees ) amine ratios. The strategy is shown to be robust to the characteristics of the host support, as PEG200 improved the amine efficiency of PEI when supported on two varieties of mesoporous gamma-alumina with PEI. PMID- 26485183 TI - CO2-Induced Reversible Dispersion of Graphene by a Melamine Derivative. AB - Smart graphene with stimuli-responsive dispersity has great potential for applications in medical and biochemical fields. Nevertheless, reversible dispersion/aggregation of graphene in water with biocompatible and removable trigger still represents a crucial challenge. Here, we report CO2-induced reversible graphene dispersion by noncovalent functionalization of reduced graphene oxide with N(2),N(4),N(6)-tris(3-(dimethylamino)propyl)-1,3,5-triazine 2,4,6-triamine (MET). It was demonstrated that MET can be strongly adsorbed on graphene surface through van der Waals interaction to facilitate dispersing graphene in water. Moreover, reversible aggregation/dispersion of graphene can be achieved simply by alternately bubbling CO2 and N2 to control the desorption/adsorption of MET on graphene surface. PMID- 26485184 TI - Kinetic Isotope Effects in Multipath VTST: Application to a Hydrogen Abstraction Reaction. AB - In this work we apply multipath canonical variational transition state theory with small-tunneling corrections (MP-CVT/SCT) to the hydrogen abstraction reaction from ethanol by atomic hydrogen in aqueous solution at room temperature. This reaction presents two transition states which can interconvert by internal rotations about single bonds and another two transition states that are non interconvertible enantiomers to the former structures. The study also includes another three reactions with isotopically substituted species for which there are experimental values of thermal rate constants and kinetic isotope effects (KIEs). The agreement between the MP-CVT/SCT thermal rate constants and the experimental data is good. The KIEs obtained by the MP-CVT/SCT methodology are factorized in terms of individual transition state contributions to facilitate the analysis. It was found that the percentage contribution of each transition state to the total KIE is independent of the isotopic substitution. PMID- 26485182 TI - Recurrent major depression and right hippocampal volume: A bivariate linkage and association study. AB - Previous work has shown that the hippocampus is smaller in the brains of individuals suffering from major depressive disorder (MDD) than those of healthy controls. Moreover, right hippocampal volume specifically has been found to predict the probability of subsequent depressive episodes. This study explored the utility of right hippocampal volume as an endophenotype of recurrent MDD (rMDD). We observed a significant genetic correlation between the two traits in a large sample of Mexican American individuals from extended pedigrees (rhog = 0.34, p = 0.013). A bivariate linkage scan revealed a significant pleiotropic quantitative trait locus on chromosome 18p11.31-32 (LOD = 3.61). Bivariate association analysis conducted under the linkage peak revealed a variant (rs574972) within an intron of the gene SMCHD1 meeting the corrected significance level (chi(2) = 19.0, p = 7.4 * 10(-5)). Univariate association analyses of each phenotype separately revealed that the same variant was significant for right hippocampal volume alone, and also revealed a suggestively significant variant (rs12455524) within the gene DLGAP1 for rMDD alone. The results implicate right hemisphere hippocampal volume as a possible endophenotype of rMDD, and in so doing highlight a potential gene of interest for rMDD risk. PMID- 26485185 TI - Auditory brainstem implant in postlingual postmeningitic patients. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to evaluate outcomes of postlingual postmeningitic patients who received an auditory brainstem implant (ABI). STUDY DESIGN: Retrospective analysis was performed on postlingual postmeningitic patients with bilateral profound sensorineural hearing loss who underwent ABI between the years 2007 and 2014 METHODS: All patients were postlingually deaf due to cochlear ossification as a consequence of bacterial meningitis. The patients received a MED-EL or Neurelec ABI. All patients were operated on at different hospitals by the same primary surgeon. The patients were tested using Ling 5 sound detection, sound field implant thresholds between 250 Hz and 6 kHz, and 6 to 12 choice closed-set word and sentence tests. RESULTS: Nine patients with postmeningitic cochlear ossification received an ABI. Five of nine ABI users (55.5%) wear their audio processors (AP) most of the time. Four (44.5%) with no perceivable benefit have become nonusers. Three of the five consistent ABI users reported good benefit. The other two ABI users who do wear their APs do not respond to sound in daily living but reported benefits such as "feeling sound" in a good way. CONCLUSIONS: In this study, five of nine patients (55.5%) with bilateral ossified cochlea had some degree of benefit from their ABI. An ABI may be useful in hearing restoration in postlingual patients with bilateral ossified cochlea due to meningitis. However, poor results may be related to side effects, which may necessitate deactivation of electrodes, long duration of auditory deprivation, or impairments in the auditory neural structures as a result of meningitis. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1889-1892, 2016. PMID- 26485186 TI - Atrial myocardial infarction: A tale of the forgotten chamber. AB - It has been almost a century since atrial infarction was first described, yet data describing its significance remain limited. To date, there are still no universally accepted criteria for the diagnosis of atrial infarction. Atherosclerosis is the leading cause of atrial infarction but it has also been described in cor pulmonale and pulmonary hypertension. Atrial infarction almost always occurs concomitantly with ventricular infarction. Its clinical presentation depends largely on the extent and site of ventricular involvement. Atrial infarction can present with supraventricular tachyarrhythmias. Electrocardiographic (ECG) criteria for diagnosing atrial infarction have been described but none have yet to be validated by prospective studies. Atrial ECG patterns include abnormal P-wave morphologies, PR-segment deviations, as well as transient rhythm abnormalities, including atrial fibrillation, atrial flutter, atrial tachycardia, wandering atrial pacemaker (WAP) and atrioventricular (AV) blocks. Complications of atrial infarction include thromboembolic events and cardiogenic shock. There are no specific additional recommendations in the management of myocardial infarction with suspected involvement of the atria. The primary goal remains coronary reperfusion and maintenance of, or conversion to, sinus rhythm. PMID- 26485187 TI - Prevalence of diabetes mellitus in patients with Takotsubo syndrome: The value of registries. PMID- 26485188 TI - Achievements in and Challenges of Tuberculosis Control in South Korea. AB - After the Korean War (1950-1953), nearly 6.5% of South Korea's population had active tuberculosis (TB). In response, South Korea implemented the National Tuberculosis Program in 1962. From 1965 to 1995, the prevalence of bacteriologically confirmed pulmonary TB in South Korea decreased from 940 to 219 cases per 100,000 population. Astounding economic growth might have contributed to this result; however, TB incidence in South Korea remains the highest among high-income countries. The rate of decrease in TB incidence seems to have slowed over the past 15 years. A demographic shift toward an older population, many of whom have latent TB and various concurrent conditions, is challenging TB control efforts in South Korea. The increasing number of immigrants also plays a part in the prolonged battle against TB. A historical review of TB in South Korea provides an opportunity to understand national TB control efforts that are applicable to other parts of the world. PMID- 26485189 TI - Comment on "Breakdown of Interference Rules in Azulene, a Nonalternant Hydrocarbon". PMID- 26485190 TI - Altered neurotrophic factors' expression profiles in the nucleus of the solitary tract of spontaneously hypertensive rats. AB - AIM: Our previous findings suggest that the nucleus of the solitary tract (NTS), a pivotal region for regulating the set point of arterial pressure, exhibits abnormal inflammation in pre-hypertensive and spontaneously hypertensive rats (SHRs), with elevated anti-apoptotic and low apoptotic factor levels compared with that of normotensive Wistar-Kyoto (WKY) rats. Whether this chronic condition affects neuronal growth and plasticity in the NTS remains unknown. To unveil the characteristics of the neurodevelopmental environment in the NTS of SHRs, we investigated the expression of neurotrophic factors transcripts in SHRs. METHODS: RT(2) Profiler PCR Array targeting rat neurotrophins and their receptors was used to screen for differentially expressed transcripts in the NTS of SHRs compared to that of WKY rats. Protein expression and physiological functions of some of the differentially expressed transcripts were also studied. RESULTS: Gene and protein expressions of glial cell line-derived neurotrophic factor family receptor alpha 3 (Gfralpha-3) factor were both upregulated in the NTS of adult SHRs. Gene expressions of corticotropin-releasing hormone-binding protein (Crhbp), interleukin-10 receptor alpha (Il-10ra) and hypocretin (Hcrt) were downregulated in the NTS of adult SHRs. The Gfralpha-3 transcript was increased and the Hcrt transcript was decreased in the NTS of young pre-hypertensive SHRs, suggesting that these profiles are not secondary to hypertension. Moreover, microinjection in the NTS of hypocretin-1 decreased blood pressure in adult SHRs. CONCLUSION: These results suggest that altered neurotrophic factors transcript profiles may affect the normal development and function of neuronal circuitry that regulates cardiovascular autonomic activity, thereby resulting in manifestations of neurogenic hypertension in SHRs. PMID- 26485192 TI - First case of infectious endocarditis caused by Parvimonas micra. AB - P. micra is an anaerobic Gram-positive cocci, and a known commensal organism of the human oral cavity and gastrointestinal tract. Although it has been classically described in association with endodontic disease and peritonsillar infection, recent reports have highlighted the role of P. micra as the primary pathogen in the setting of invasive infections. In its most recent taxonomic classification, P. micra has never been reported causing infectious endocarditis in humans. Here, we describe a 71 year-old man who developed severe native valve endocarditis complicated by aortic valvular destruction and perivalvular abscess, requiring emergent surgical intervention. Molecular sequencing enabled identification of P. micra. PMID- 26485191 TI - Clostridium polynesiense sp. nov., a new member of the human gut microbiota in French Polynesia. AB - Strain MS1, a Gram-positive, obligately anaerobic, motile and spore-forming rod belonging to the Clostridium genus, was isolated from the feces of a healthy Polynesian male living in French Polynesia. The temperature range for growth was 30-45 degrees C. We sequenced its complete genome and studied its phenotypic characteristics. The 3,560,738-bp long genome (one chromosome, no plasmid, G + C content 34%) contained 3535 protein-coding and 70 RNA genes. Strain MS1 exhibited a 98.24% 16S rRNA similarity with Clostridium amylolyticum, the phylogenetically closest species. When compared with other Clostridium species with standing in nomenclature, it had an average genomic similarity of 68.8-70%, a unique MALDI TOF spectrum, and differed in nitrate reduction, motility and L-arabinose and D lactose metabolism with most of the closest species. Therefore, strain MS1 is sufficiently distinct from type strains of the genus Clostridium to represent a novel species within this genus, for which the name Clostridium polynesiense sp. nov. is proposed. The type strain of C. polynesiense is MS1(T) (= CSUR P630 = DSM 27072). PMID- 26485193 TI - Loss-of-function mutation of serine racemase attenuates excitotoxicity by intravitreal injection of N-methyl-D-aspartate. AB - Convincing data demonstrate that D-serine, a racemized product of serine racemase (SR), contributes to neurotoxicity. Furthermore, a line of evidence suggests that SR/D-serine contributes to retinal neurodegeneration in a diabetic retinopathy rat model and diabetic retinopathy patients. However, the connection between SR/D serine and retinal neurodegeneration remains unclear. Herein, we report that intravitreal injection of N-methyl-D-aspartate (NMDA) induces excitotoxicity in rodent retina; this retinal neurodegeneration was attenuated in retina carrying a loss-of-function of mutation in Srr, the gene for SR, termed Srr(ochre269). Under the condition of NMDA injection, either posterior pole or middle - but not peripheral - retina from Srr(ochre269) mice was found to retain more retinal ganglion cells (RGC) than the counterpart from w/t (RGCs were identified with retrograde labeling). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining further demonstrated reduced RGC apoptosis from Srr(ochre269) compared to w/t mice under the condition of NMDA injection. Collectively, our studies demonstrate a pivotal role of SR/D-serine in retinal neurotoxicity. We demonstrated that loss-of-function mutation of the gene encoding serine racemase significantly attenuates excitotoxicity in retina; excitotoxicity accounts for retinal ganglion cell (RGC) demise in diabetic retinopathy (DR). We think that our findings deepen the current knowledge of the mechanisms of RGC degeneration. PMID- 26485195 TI - "Smart" Ag Nanostructures for Plasmon-Enhanced Spectroscopies. AB - Silver is an ideal candidate for surface plasmon resonance (SPR)-based applications because of its great optical cross-section in the visible region. However, the uses of Ag in plasmon-enhanced spectroscopies have been limited due to their interference via direct contact with analytes, the poor chemical stability, and the Ag(+) release phenomenon. Herein, we report a facile chemical method to prepare shell-isolated Ag nanoparticle/tip. The as-prepared nanostructures exhibit an excellent chemical stability and plasmonic property in plasmon-enhanced spectroscopies for more than one year. It also features an alternative plasmon-mediated photocatalysis pathway by smartly blocking "hot" electrons. Astonishingly, the shell-isolated Ag nanoparticles (Ag SHINs), as "smart plasmonic dusts", reveal a ~1000-fold ensemble enhancement of rhodamine isothiocyanate (RITC) on a quartz substrate in surface-enhanced fluorescence. The presented "smart" Ag nanostructures offer a unique way for the promotion of ultrahigh sensitivity and reliability in plasmon-enhanced spectroscopies. PMID- 26485196 TI - High-Tc Ferromagnetism and Electron Transport in p-Type Fe(1-x)Sn(x)Sb2Se4 Semiconductors. AB - Single-phase polycrystalline powders of Fe(1-x)Sn(x)Sb2Se4 (x = 0 and 0.13) were synthesized by a solid-state reaction of the elements at 773 K. X-ray diffraction on Fe0.87Sn0.13Sb2Se4 single-crystal and powder samples indicates that the compound is isostructural to FeSb2Se4 in the temperature range from 80 to 500 K, crystallizing in the monoclinic space group C2/m (No. 12). Electron-transport data reveal a marginal alteration in the resistivity, whereas the thermopower drops by ~60%. This suggests a decrease in the activation energy upon isoelectronic substitution of 13% Fe by Sn. Magnetic susceptibility and magnetization measurements from 2 to 500 K reveal that the Fe(1-x)Sb2Sn(x)Se4 phases exhibit ferromagnetic behavior up to ~450 K (x = 0) and 325 K (x = 0.13). Magnetotransport data for FeSb2Se4 reveal large negative magnetoresistance, suggesting spin polarization of free carriers in the sample. The high-Tc ferromagnetism in Fe(1-x)Sn(x)Sb2Se4 phases and the decrease in Tc of the Fe0.87Sn0.13Sb2Se4 sample are rationalized by taking into account (1) the separation between neighboring magnetic centers in the crystal structures and (2) the formation of bound magnetic polarons, which overlap to induce long-range ferromagnetic ordering. PMID- 26485194 TI - Activation and lysis of human CD4 cells latently infected with HIV-1. AB - The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. Here we report an approach to reduce the viral reservoir by activating dormant viral gene expression and directing T lymphocytes to lyse previously latent, HIV-1-infected cells. An immunomodulatory protein was created that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. CD3 engagement by the protein can stimulate T-cell activation that induces proviral gene expression in latently infected T cells. It further stimulates CD8 T-cell effector function and redirects T cells to lyse these previously latent-infected cells through recognition of newly expressed Env. This immunomodulatory protein could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals. PMID- 26485197 TI - "Reading maketh a full man". PMID- 26485198 TI - Online emotional support delivered by trained volunteers: users' satisfaction and their perception of the service compared to psychotherapy. AB - BACKGROUND: Technology could answer the substantial need in human resources available for supporting those who suffer from mental illness, by providing scalable methods to train and engage non-professionals to those who need their support. 7 Cups of Tea (7COT) platform was chosen for this study, because it provides a good case study for examining this kind of solution. AIM: The aim of this paper was to provide empirical findings regarding users' satisfaction with online emotional support provided by trained volunteers and how it is perceived in comparison to psychotherapy. METHODS: An online survey was conducted among a convenience sample of 7COT users. RESULTS: The findings showed high user satisfaction with the support provided by 7COT listeners and, on average, users who indicated to receive psychotherapy in their past marked the listeners' support to be as helpful as psychotherapy. Relating to psychotherapy and online emotional support advantages, different advantages were found. The findings suggest that receiving support from volunteers makes users feel that the support is more genuine. CONCLUSION: The paper provides preliminary evidence that people in emotional distress may find non-professionals support delivered through the use of technology to be helpful. Limitations and implications are discussed. PMID- 26485202 TI - Brainstem Auditory Evoked Potential in HIV-Positive Adults. AB - BACKGROUND: To characterize the findings of brainstem auditory evoked potential in HIV-positive individuals exposed and not exposed to antiretroviral treatment. MATERIAL AND METHODS: This research was a cross-sectional, observational, and descriptive study. Forty-five HIV-positive individuals (18 not exposed and 27 exposed to the antiretroviral treatment - research groups I and II, respectively and 30 control group individuals) were assessed through brainstem auditory evoked potential. RESULTS: There were no significant between-group differences regarding wave latencies. A higher percentage of altered brainstem auditory evoked potential was observed in the HIV-positive groups when compared to the control group. The most common alteration was in the low brainstem. CONCLUSIONS: HIV-positive individuals have a higher percentage of altered brainstem auditory evoked potential that suggests central auditory pathway impairment when compared to HIV-negative individuals. There was no significant difference between individuals exposed and not exposed to antiretroviral treatment. PMID- 26485203 TI - Information without Implementation: A Practical Example for Developing a Best Practice Education Control Group. AB - This article considers methodology for developing an education-only control group and proposes a simple approach to designing rigorous and well-accepted control groups. This approach is demonstrated in a large randomized trial. The Lifestyles trial (n = 367) compared three group interventions: (a) cognitive-behavioral treatment (CBT) for osteoarthritis pain, (b) CBT for osteoarthritis pain and insomnia, and (c) education-only control (EOC). EOC emulated the interventions excluding hypothesized treatment components and controlling for nonspecific treatment effects. Results showed this approach resulted in a control group that was highly credible and acceptable to patients. This approach can be an effective and practical guide for developing high-quality control groups in trials of behavioral interventions. PMID- 26485204 TI - Providing value in ambulatory anesthesia. AB - PURPOSE OF REVIEW: The purpose of this review is to discuss current practices and changes in the field of ambulatory anesthesia, in both hospital and ambulatory surgery center settings. New trends in ambulatory settings are discussed and a review of the most current and comprehensive guidelines for the care of ambulatory patients with comorbid conditions such as postoperative nausea and vomiting (PONV), obstructive sleep apnea and diabetes mellitus are reviewed. Future direction and challenges to the field are highlighted. RECENT FINDINGS: Ambulatory anesthesia continues to be in high demand for many reasons; patients and surgeons want their surgical procedures to be swift, involve minimal postoperative pain, have a transient recovery time, and avoid an admission to the hospital. Factors that have made this possible for patients are improved surgical equipment, volatile anesthetic improvement, ultrasound-guided regional techniques, non-narcotic adjuncts for pain control, and the minimization of PONV. The decrease in time spent in a hospital also decreases the risk of wound infection, minimizes missed days from work, and is a socioeconomically favorable model, when possible. Recently proposed strategies which will allow surgeons and anesthesiologists to continue to meet the growing demand for a majority of surgical cases being same-day include pharmacotherapies with less undesirable side-effects, integration of ultrasound-guided regional techniques, and preoperative evaluations in appropriate candidates via a telephone call the night prior to surgery. Multidisciplinary communication amongst caregivers continues to make ambulatory settings efficient, safe, and socioeconomically favorable.It is also important to note the future impact that healthcare reform will have specifically on ambulatory anesthesia. The enactment of the Patient Protection and Affordable Care Act of 2010 will allow 32 million more people to gain access to preventive services that will require anesthesia such as screening colonoscopies. With this projected increase in the demand for anesthesia services nationwide comes the analysis of its financial feasibility. Some early data looking at endoscopist-administered sedation conclude that it offers higher patient satisfaction, there were less adverse effects than anesthesiologist administered sedation, and is economically advantageous. This and future retrospective studies will help to guide healthcare policymakers and physicians to come to a conclusion about providing ambulatory services for these millions of patients. SUMMARY: Ambulatory anesthesia's popularity continues to rise and anesthetic techniques will continue to morph and adapt to the needs of patients seeking ambulatory surgery. Alterations in already existing medications are promising as these modifications allow for quicker recovery from anesthesia or minimization of the already known undesirable side-effects. PONV, pain, obstructive sleep apnea, and chronic comorbidities (hypertension, cardiac disease, and diabetes mellitus) are perioperative concerns in ambulatory settings as more patients are safely being treated in ambulatory settings. Regional anesthesia stands out as a modality that has multiple advantages to general anesthesia, providing a minimal recovery period and a decrease in postanesthesia care unit stay. The implementation of the Affordable Healthcare Act specifically affects ambulatory settings as the demand and need for patients to have screening procedures with anesthesia. The question remains what the best strategy is to meet the needs of our future patients while preserving economically feasibility within an already strained healthcare system. PMID- 26485205 TI - State-of-the-art usage of simulation in anesthesia: skills and teamwork. AB - PURPOSE OF REVIEW: This review describes the level of evidence for the use of medical simulation in anesthesia. It also discusses the topic of realism in simulation and its use for assessment. RECENT FINDINGS: Medical simulation in anesthesia covers a variety of techniques used for training and assessment. The current level of evidence for the use of medical simulation strongly supports a shift from learning on patients to learning on simulators. Skill and multidisciplinary team training are effective modalities and improve (team) performance and patient outcome.Well defined learning objectives, not a high level of realism should be the main focus of a simulation activity. Simulation centers should focus on faculty development as emphasis on simulation facilities and simulator fidelity alone does not guarantee effective training.Formative and summative assessment can help identify the omissions in knowledge, skills, and the ability to work in a team for both residents and anesthesiologists. Not only does it help to obtain competence, it also helps to maintain it. SUMMARY: Simulation for skill and team training should be a mandatory component for anesthesia residency programs and continuous medical education. The 'see one, do one, teach one' approach is obsolete and should be abandoned. PMID- 26485206 TI - Editorial: Ambulatory anesthesia in 2015. PMID- 26485207 TI - Editorial: From problem description to solutions and a new way of thinking about 'Safety'. PMID- 26485208 TI - Mitofusin 2 Downregulation Triggers Pulmonary Artery Smooth Muscle Cell Proliferation and Apoptosis Imbalance in Rats With Hypoxic Pulmonary Hypertension Via the PI3K/Akt and Mitochondrial Apoptosis Pathways. AB - During hypoxia-induced pulmonary hypertension (HPH), pulmonary artery smooth muscle cells (PASMCs) proliferate as part of the characteristic pulmonary vascular remodeling. We investigated the expression of mitofusin 2(Mfn2) and its role in maintaining the balance between PASMC proliferation and apoptosis during hypoxia. In an experimental model of HPH, we exposed rats to hypoxia (10% +/- 0.5% O2) or room air for 4 weeks. We found that Mfn2 messenger RNA and protein levels were reduced and that proliferating cell nuclear antigen protein expression was upregulated in HPH rat lung tissues. We also exposed primary cultured PASMCs from rat pulmonary arterioles to normoxia (21% O2/5% CO2) or hypoxia (2.5% O2/5% CO2) for 24 hours. We found that PASMC proliferation increased under hypoxic conditions and that more hypoxic cells than normoxic cells entered the S + G2/M phase. Additionally, phosphorylated Akt and proliferating cell nuclear antigen expression increased, whereas Mfn2 expression, cleaved caspase 9 expression, and the ratio of mitochondrial to cytosolic cytochrome C expression each decreased. These hypoxia-induced effects were reversed in PASMCs by Mfn2 overexpression and by phosphatidylinositide 3-kinases (PI3K) inhibition. Our results indicate that downregulation of Mfn2 in HPH may activate the PI3K/Akt pathway, thereby causing more cells to enter the S + G2/M phase of the cell cycle and inhibiting the mitochondrial apoptosis pathway. PMID- 26485209 TI - NaoXinTong Inhibits the Advanced Atherosclerosis and Enhances the Plaque Stability in Apolipoprotein E Deficient Mice. AB - Buchang NaoXinTong (NXT), a Chinese medicine, has been widely used to treat patients with coronary heart disease in China. However, the underlying mechanisms need more elucidations. In this study, we investigated if NXT can inhibit the progression of the established lesions while stabilizing plaques. Apolipoprotein E deficient (apoE(-/-)) mice in 3 groups received following treatment: group 1 was fed a high-fat diet (HFD) for 18 weeks; group 2 was prefed HFD for 12 weeks followed by HFD containing NXT for additional 6 weeks; group 3 was prefed HFD for 8 weeks followed by HFD containing NXT for additional 10 weeks. After treatment, serum and aorta samples were collected and determined lipid profiles, lesions, collagen content, mineralization, and macrophage accumulation in aortic root, respectively. NXT had slight effect on serum lipid profiles but significantly reduced progression of the advanced lesions. In aortic wall, NXT increased smooth muscle cell/collagen content in lesion cap while reducing buried fibrous caps, mineralization, and macrophage accumulation within lesions, which suggests that NXT can stabilize plaques. In addition, NXT increased expression of smooth muscle 22alpha mRNA while inhibiting expression of matrix metalloproteinase-2 and tumor necrosis factor alpha mRNA in aortas. Our study demonstrates that NXT can reduce advanced atherosclerosis and enhance the plaque stability in apoE(-/-) mice. PMID- 26485210 TI - NAMPT and NAMPT-controlled NAD Metabolism in Vascular Repair. AB - Vascular repair plays important roles in postischemic remodeling and rehabilitation in cardiovascular and cerebrovascular disease, such as stroke and myocardial infarction. Nicotinamide adenine dinucleotide (NAD), a well-known coenzyme involved in electron transport chain for generation of adenosine triphosphate, has emerged as an important controller regulating various biological signaling pathways. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme for NAD biosynthesis in mammals. NAMPT may also act in a nonenzymatic manner, presumably mediated by unknown receptor(s). Rapidly accumulating data in the past decade show that NAMPT and NAMPT-controlled NAD metabolism regulate fundamental biological functions in endothelial cells, vascular smooth muscle cells, and endothelial progenitor cells. The NAD-consuming proteins, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38, may contribute to the regulatory effects of NAMPT-NAD axis in these cells and vascular repair. This review discusses the current data regarding NAMPT and NAMPT controlled NAD metabolism in vascular repair and the clinical potential translational application of NAMPT-related products in treatment of cardiovascular and cerebrovascular disease. PMID- 26485211 TI - Stabilization of Hypoxia-inducible Factor by DMOG Inhibits Development of Chronic Hypoxia-Induced Right Ventricular Remodeling. AB - BACKGROUND: One important determinant of longevity in congenital heart disease is right ventricular (RV) function, and this is especially true in cyanotic congenital heart disease. However, there is a paucity of data concerning right ventricular remodeling (RVR) in the setting of chronic hypoxia. Dimethyloxalylglycine (DMOG) is a competitive inhibitor of hypoxia-inducible factor (HIF)-hydroxylated prolyl hydroxylase and has been shown to play an important role against ischemia-reperfusion myocardial injury. METHODS: We tested the hypothesis that DMOG prevents the development RVR after chronic hypoxia exposure. Rats were injected with saline or DMOG and exposed to room air or continued hypoxia for 4 weeks. In addition, we explored the response of myocardial erythropoietin and its receptor to hypoxic exposure. RESULTS: Treatment with DMOG attenuated myocardial fibrosis, apoptosis, and oxidative stress, which lead to enhanced RV contractile function. As an endpoint of HIF dependent cardioprotection, a novel pathway in which nuclear factor kappa B links HIF-1 transcription was defined. CONCLUSIONS: This study supports a role for HIF 1 stabilizers in the treatment of RVR and brings into question the commonly held concept that RVR follows a linear relationship with increased RV afterload. PMID- 26485212 TI - Growing Uniform Graphene Disks and Films on Molten Glass for Heating Devices and Cell Culture. AB - The direct growth of uniform graphene disks and their continuous film is achieved by exploiting the molten state of glass. The use of molten glass enables highly uniform nucleation and an enhanced growth rate (tenfold) of graphene, as compared to those scenarios on commonly used insulating solids. The obtained graphene glasses show promising application potentials in daily-life scenarios such as smart heating devices and biocompatible cell-culture mediums. PMID- 26485213 TI - Deciphering the human immunome. AB - Technological advances in next-generation DNA sequencing offer great potential to probe the human immune system. On 3 April 2015, leading immunologists and bioinformatics scientists met to consider how best to harness these advances for decoding the human immunome. PMID- 26485214 TI - Strategic development of the conserved region of the M protein and other candidates as vaccines to prevent infection with group A streptococci. AB - Group A streptococcal (Streptococcus pyogenes) diseases remain a major public health problem in developing countries as well as in the indigenous populations of developed countries. In view of the large number of Group A streptococcal infections and the potential for sequelae such as rheumatic heart disease, control strategies including the development of an anti-streptococcal vaccine that is able to prevent infection and colonization is important. In this article, we discuss the epidemiology and strain variability of Group A streptococcus and how this is rendering vaccine development more challenging. We discuss vaccine strategies with a focus on the conserved region of the M protein and present a viewpoint for the impediments and the way forward. PMID- 26485216 TI - An evidence-based review of the rectovaginal examination during well-woman visits. AB - BACKGROUND AND PURPOSE: Women's health promotion and disease prevention has experienced considerable transformation over the past decade. This includes introduction of the Human Papillomavirus (HPV) vaccination, updated recommendations for mammography screening, Papanicolaou smear and HPV testing, and pelvic examinations. Despite significant literature about these subjects, one area that has not been reviewed is the rectovaginal examination (RVE). This article will examine available evidence regarding the RVE and make evidence-based recommendations that nurse practitioners (NPs) can integrate into practice METHODS: An electronic search was completed using PubMed, CINAHL, National Guideline Clearinghouse, and Cochrane Data Bases. Medical Subject Heading terms and keywords included Physical Examination, Vagina, Rectum, Digital Rectal Examination, Gynecological Examination, and Rectovaginal Examination in combination with Well-Woman, Screening, and Pelvic Examination. CONCLUSIONS: Available literature shows the RVE to have low sensitivity in detecting uterosacral nodularity, rectal compression, cervical involvement of endometrial cancer, and colorectal cancer. IMPLICATIONS FOR PRACTICE: This critical review of available literature found no evidence to support the use of the RVE in well woman visits. NPs should limit the use of the RVE to patients presenting with rectovaginal or pelvic complaints. PMID- 26485215 TI - Cucumber metal tolerance protein CsMTP9 is a plasma membrane H+-coupled antiporter involved in the Mn2+ and Cd2+ efflux from root cells. AB - Members of the plant metal tolerance protein (MTP) family have been classified into three major groups - Zn-CDF, Mn-CDF and Zn/Fe-CDF - however, the selectivity of most of the MTPs has not been confirmed yet. Cucumber gene CsMTP9 encoding a putative CDF transporter homologous to members of the Mn-CDF cluster is expressed exclusively in roots. The relative abundance of CsMTP9 transcript and protein in roots is significantly increased under Mn excess and Cd. Immunolocalization with specific antibodies revealed that CsMTP9 is a plasma membrane transporter that localizes to the inner PM domain of root endodermal cells. The plasma membrane localization of CsMTP9 was confirmed by the expression of the fusion proteins of GFP (green fluorescent protein) and CsMTP9 in yeast and protoplasts prepared from Arabidopsis cells. In yeast, CsMTP9 transports Mn(2+) and Cd(2+) via a proton antiport mechanism with an apparent Km values of approximately 10 MUm and 2.5 MUm for Mn(2+) and Cd(2+) , respectively. In addition, CsMTP9 expression in yeast rescues the Mn- and Cd-hypersensitive phenotypes through the enhanced efflux of Mn(2+) and Cd(2+) from yeast cells. Similarly, the overexpression of CsMTP9 in A. thaliana confers increased resistance of plants to Mn excess and Cd but not to other heavy metals and leads to the enhanced translocation of manganese and cadmium from roots to shoots. These findings indicate that CsMTP9 is a plasma membrane H(+) -coupled Mn(2+) and Cd(2+) antiporter involved in the efflux of manganese and cadmium from cucumber root cells by the transport of both metals from endodermis into vascular cylinder. PMID- 26485217 TI - Vitamin D Supplementation Decreases TGF-beta1 Bioavailability in PCOS: A Randomized Placebo-Controlled Trial. AB - CONTEXT: There is an abnormal increase in TGF-beta1 bioavailability in women with polycystic ovary syndrome (PCOS), which might play a role in the pathophysiology of this syndrome. Vitamin D (VD) supplementation improves various clinical manifestations of PCOS and decreases TGF-beta1 levels in several diseases including myelofibrosis. OBJECTIVE: The objective of the study was to determine the effect of VD supplementation on TGF-beta1 bioavailability in VD-deficient women with PCOS and assess whether changes in TGF-beta1/soluble endoglin (sENG) levels correlate with an improvement in PCOS clinical manifestations. DESIGN: This was a prospective, randomized, placebo-controlled trial. SETTING: The study was conducted at an academic-affiliated medical center. PARTICIPANTS: Sixty-eight VD-deficient women with PCOS who were not pregnant or taking any exogenous hormones were recruited between October 2013 and January 2015. INTERVENTIONS: Forty-five women received 50 000 IU of oral vitamin D3 and 23 women received oral placebo once weekly for 8 weeks. MAIN OUTCOMES MEASURES: Serum TGF-beta1, sENG, lipid profile, testosterone, dehydroepiandrosterone sulfate, and insulin resistance were measured. The clinical parameters were evaluated before and 2 months after treatment. RESULTS: The VD level significantly increased and normalized after VD supplementation (16.3 +/- 0.9 [SEM] to 43.2 +/- 2.4 ng/mL; P < .01), whereas it did not significantly change after placebo. After the VD supplementation, there was a significant decrease in the following: the interval between menstrual periods (80 +/- 9 to 60 +/- 6 d; P = .04), Ferriman-Gallwey score (9.8 +/- 1.5 to 8.1 +/- 1.5; P < .01), triglycerides (138 +/- 22 to 117 +/- 20 mg/dL; P = .03), and TGF-beta1 to sENG ratio (6.7 +/- 0.4 to 5.9 +/- 0.4; P = .04). In addition, the DeltaTGF-beta1 to sENG ratio was positively correlated with Deltatriglycerides (r = 0.59; P = .03). CONCLUSIONS: VD supplementation in VD-deficient women with PCOS significantly decreases the bioavailability of TGF beta1, which correlates with an improvement in some abnormal clinical parameters associated with PCOS. This is a novel mechanism that could explain the beneficial effects of VD supplementation in women with PCOS. These findings may support new treatment modalities for PCOS, such as the development of anti-TGF-beta drugs. PMID- 26485219 TI - Relative Hyperglycemia, a Marker of Critical Illness: Introducing the Stress Hyperglycemia Ratio. AB - CONTEXT: Hyperglycemia in hospitalized patients is associated with increased morbidity and mortality. OBJECTIVE: We examined whether critical illness is more strongly associated with relative or absolute hyperglycemia. DESIGN: The study was an observational cohort study. PATIENTS AND SETTING: A total of 2290 patients acutely admitted to a tertiary hospital. MAIN OUTCOME MEASURE: The relative hyperglycemia (stress hyperglycemia ratio [SHR]) was defined as admission glucose divided by estimated average glucose derived from glycosylated hemoglobin. The relationships between glucose and SHR with critical illness (in-hospital death or critical care) were examined. RESULTS: In univariable analyses, SHR (odds ratio, 1.23 per 0.1 increment [95% confidence interval, 1.18-1.28]; P < .001) and glucose (odds ratio, 1.18 per mmol/L [1.13-1.23]; P < .001) were associated with critical illness. In multivariable analysis, the association was maintained for SHR (odds ratio, 1.20 per 0.1 increment [1.13-1.28]; P < .001), but not glucose (odds ratio, 1.03 per mmol/L [0.97-1.11]; P = .31). Background hyperglycemia affected the relationship between glucose (P = .002) and critical illness, but not SHR (P = .35) and critical illness. In patients with admission glucose <= 10 mmol/L, the odds ratio for critical illness was higher in the fourth (2.4 [1.4 4.2]; P = .001) and fifth (3.9 [2.3-6.8]; P < .001) SHR quintiles than in the lowest SHR quintile. CONCLUSIONS: SHR controls for background glycemia and is a better biomarker of critical illness than absolute hyperglycemia. SHR identifies patients with relative hyperglycemia at risk of critical illness. Future studies should explore whether basing glucose-lowering therapy on relative, rather than absolute, hyperglycemia improves outcomes in hospitalized patients. PMID- 26485218 TI - Intra-Individual Consistency in Endocrine Profiles Across Successive Pregnancies. AB - CONTEXT: It is yet unknown how similar women's hormone levels are during successive pregnancies, and very little is known about the degree to which siblings experience similar prenatal environments. Given the importance of understanding how women's reproductive life histories exert cumulative effects on health via hormone exposure, and the importance of understanding how fetal programming via endocrine signaling affects sibling trait concordance, here, we address this important lacuna in the literature. OBJECTIVE: This study aimed to investigate how consistent women's hormone profiles are across two successive pregnancies. DESIGN AND MAIN OUTCOME MEASURES: This longitudinal, prospective study followed a cohort of 28 women across two pregnancies (PREG 1 and PREG 2). Women's circulating hormone levels were assessed from blood samples at 25, 31, and 37 weeks' gestation for adrenocorticotropic hormone (ACTH), placental corticotropin-releasing hormone (pCRH), cortisol, estradiol, and progesterone. ACTH and cortisol levels were assessed 3 months postpartum. Research questions include: Are hormone levels in PREG 2 significantly different from levels in PREG 1? What proportion of variance in PREG 2 hormone levels is attributable to variance in PREG 1 levels? Are hormone levels more stable between PREG 1 and PREG 2 compared with postpartum phases following these pregnancies? Is pCRH, which is completely placentally derived, less similar than other hormones across successive pregnancies? PARTICIPANTS AND SETTING: Pregnant women attended study visits at a university psychobiology laboratory in Southern California. RESULTS AND CONCLUSIONS: Comparisons of hormone concentrations across women's successive pregnancies via paired t test revealed substantial consistency from one pregnancy to another, with only significant differences between pregnancies for pCRH. Regressions revealed substantial predictability from one pregnancy to another, with between 17-56% of PREG 2 variances accounted for by PREG 1 values. Women exhibited lower degrees of consistency and predictability in hormone levels across postpartum phases compared with gestational concentrations. This is the first study to describe maternal and placental hormone levels across successive pregnancies. PMID- 26485220 TI - HoxA13 Regulates Phenotype Regionalization of Human Pregnant Myometrium. AB - CONTEXT: Bipedalism separates humans from most other animal species, but results in significant physiologic challenges, particularly with respect to the maintenance of pregnancy and induction of parturition. A contracted lower uterine segment (LUS) and a relaxed uterine fundal myometrium (FUN) during pregnancy are required to prevent pressure on the cervix from the fetal head due to gravity. With the onset of labor, this regionalization of myometrial function must be reversed, allowing descent of the fetus, dilation of the cervix, and expulsion of the fetus through the birth canal. However, the molecular mechanisms remain unclear. OBJECTIVE AND DESIGN: This study sought to identify phenotypic regionalization of LUS and FUN during pregnancy, RNA sequencing was performed to analyze the human myometrial transcriptome. Real-time PCR and immunoblotting were applied to validate sequencing results. Cell contraction/adhesion assays and gene microarrays were used to study the cellular functions of the identified genes. RESULTS: Homeobox A13 (HoxA13), prostacyclin synthase (PTGIS), and periostin (POSTN) genes are more highly expressed in LUS than FUN of nonlaboring, but not laboring, myometrial cells at term. HoxA13 up-regulates transcription of PTGIS and POSTN genes. Elevated HoxA13 expression enhances myometrial cell contractility and cell-cell adhesion. Gene microarray studies show that HoxA13 regulated genes are associated with immune response, gap junction/cell adhesion, and pregnancy. CONCLUSION: The LUS expresses higher levels of HoxA13, PTGIS, and POSTN, and is more contractile than the FUN at term prior to labor. This pregnancy-maintaining regionalization of myometrial function may be mediated by HoxA13. PMID- 26485221 TI - Vitamin D, Muscle Function, and Cardiorespiratory Fitness in Adolescents From the Young Hearts Study. AB - CONTEXT: Vitamin D insufficiency is common among the adolescent population and may have implications for health outcomes in later life. Few studies have investigated the role of vitamin D status in muscle function and cardiorespiratory fitness (CRF) during adolescence. OBJECTIVE: The aim of this study was to investigate the association between vitamin D status and fat-free mass (FFM), muscle strength, muscle power, and CRF in a representative sample of adolescents from Northern Ireland. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study involving 1015 adolescents (age 12 and 15 y), who had 25 hydroxyvitamin D [25(OH)D] data available as part of the Young Hearts Study 2000. MAIN OUTCOME MEASURES: The main outcome measures of this study were FFM (kg) and FFM corrected for height [fat-free mass index; FFM (kg)/height (m(2))], muscle strength (kg), peak muscle power (kW) and VO2 max (CRF; mL/kg/min). RESULTS: Multinomial regression analyses, controlling for environmental and lifestyle factors, demonstrated that boys age 15 years in the highest tertile of standardized serum 25(OH)D concentration (> 51 nmol/L) had significantly higher muscle strength (beta = 3.90; P <= .001) compared with those in the lowest tertile (< 32 nmol/L). These results were not evident in any other age-sex group and vitamin D status was not significantly associated with muscle power or CRF in any of the four age-sex groups. CONCLUSION: These results support a role for vitamin D in muscle function in adolescent males and suggest the need for more research in this vulnerable age group. PMID- 26485222 TI - IGHD II: A Novel GH-1 Gene Mutation (GH-L76P) Severely Affects GH Folding, Stability, and Secretion. AB - CONTEXT: The autosomal dominant form of GH deficiency (IGHD II) is characterized by markedly reduced GH secretion combined with low concentrations of IGF-1 leading to short stature. OBJECTIVE: Structure-function analysis of a missense mutation in the GH-1 gene converting codon 76 from leucine (L) to proline (P) yielding a mutant GH-L76P peptide. DESIGN, SETTINGS, AND PATIENTS: Heterozygosity for GH-L76P/wt-GH was identified in a nonconsanguineous Spanish family. The index patients, two siblings, a boy and a girl, were referred for assessment of their short stature (-3.2 and -3.8 SD). Their grandmother, father, and aunt were also carrying the same mutation and showed severe short stature; therefore, IGHD II was diagnosed. INTERVENTIONS AND RESULTS: AtT-20 cells coexpressing both wt-GH and GH-L76P showed a reduced GH secretion (P < .001) after forskolin stimulation when compared with the cells expressing only wt-GH. In silico mutagenesis and molecular dynamics simulations presented alterations of correct folding and mutant stability compared with wt-GH. Therefore, further structural analysis of the GH-L76P mutant was performed using expressed and purified proteins in Escherichia coli by thermofluor assay and fast degradation proteolysis assay. Both assays revealed that the GH-L76P mutant is unstable and misfolded compared to wt-GH confirming the bioinformatic model prediction. CONCLUSIONS: This is the first report of a family suffering from short stature caused by IGHD II, which severely affects intracellular GH folding and stability as well as secretion, highlighting the necessity of functional analysis of any GH variant for defining new mechanisms as a cause for IGHD II. PMID- 26485223 TI - Genetic Determinants of Enterovirus Infections: Polymorphisms in Type 1 Diabetes and Innate Immune Genes in the MIDIA Study. AB - Enteroviruses have been suggested as triggers of type 1 diabetes (T1D). We aimed to assess whether established T1D susceptibility single nucleotide polymorphisms (SNPs) and candidate SNPs in innate immune genes were associated with the frequency of enterovirus infection in otherwise healthy children. Fifty-six established T1D SNPs and 97 other candidate immunity SNPs were typed in 419 children carrying the T1D high-risk genotype, HLA-DR4-DQ8/DR3-DQ2 genotype, and 373 children without this genotype. Enteroviral RNA was detected using real-time polymerase chain reaction, with primers detecting essentially all enterovirus serotypes, in 7,393 longitudinal stool samples collected monthly (age range 3-36 months). The most significant association was with two T1D SNPs, rs12150079 (ZPBP2/ORMDL3/GSDMB region) (enterovirus frequency: AA 7.3%, AG 8.7%, GG 9.7%, RR = 0.86, overall p = 1.87E-02) and rs229541 (C1QTNF6/SSTR3/RAC2) (enterovirus frequency: CC 7.8%, CT 9.7%, TT 9.4%, RR = 1.13, overall p = 3.6E-02), followed by TLR8 (rs2407992) (p = 3.8E-02), TLR3 (1914926) (p = 4.9E-02), and two other T1D SNPs (IFIH1 rs3747517, p = 4.9E-02 and PTPN22, rs2476601, p = 5.3E-02). However, the quantile-quantile plot of p-values with confidence intervals for all 153 SNPs did not reveal clear evidence for rejection of the complete null hypothesis. Among a number of SNPs in candidate genes, we found no evidence for strong associations with enterovirus presence in stool samples from Norwegian children. PMID- 26485224 TI - What role could organoids play in the personalization of cancer treatment? AB - Cancer treatments are increasingly being targeted to specific patient populations based on the molecular and genetic features of their tumor, so called precision or personalized cancer medicine. Preclinical cancer models are essential tools for cancer research, but unfortunately our current models often fail to effectively represent patient tumors and can be poorly predictive of clinical responses. In this perspective, we discuss the use of new in vitro 3D cell models called 'organoids' as preclinical cancer models in the context of other commonly used models, namely cancer cell lines and patient-derived xenografts. We consider the relative strengths and limitations of each model, and discuss how organoid culture models could facilitate the personalization of cancer medicine. PMID- 26485226 TI - Management of apical compartment prolapse (uterine and vault prolapse): A FIGO Working Group report. AB - AIM: Apical prolapse includes descent of the uterus, vagina cuff, or rarely solely of the cervix. It is estimated that women have an 11-19% life-time risk of undergoing surgery for POP. This rate is projected to increase over the next 2-3 decades. In this FIGO working group report we address the conservative and surgical treatment options for apical prolapse. METHODS: The FIGO working group "Pelvic Floor Medicine and Reconstructive Surgery" describes the different treatments for apical prolapse based on the literature evidence, the cost effectiveness, the degree of difficulty and summed them up with an experts recommendation. RESULTS: Among the conservative treatment options, pessaries are the most successful options since centuries with a low complication rate and low costs. Among the vaginal operative procedures the sacrospinous ligament fixation (SSLF) and the uterosacral ligament suspension (USLS) show comparable outcomes and efficacy with a different, however, rather low complication pattern and a favorable cost-benefit profile. Sacrocolpopexy, independent on the open abdominal, laparoscopic, or robotic-assisted laparoscopic technique has a good durability and quality of life performance. The minimal invasive techniques are as effective as the open abdominal techniques and there is no difference in mesh exposure. CONCLUSION: Vaginal procedures are well described procedures with favorable outcomes and cost-benefit profiles. Sacral colpopexy has a high effectivity; data on the route of performance and long-term outcome are awaited. The cost with mesh implants are higher compared to the operations with autologous tissue or any conservative treatment and further studies are recommended to evaluate the cure rates in the span of decades and the possible long-term mesh complications. Neurourol. Urodynam. 36:507-513, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26485227 TI - Radiation dose response simulation for biomechanical-based deformable image registration of head and neck cancer treatment. AB - Biomechanical-based deformable image registration is conducted on the head and neck region. Patient specific 3D finite element models consisting of parotid glands (PG), submandibular glands (SG), tumor, vertebrae (VB), mandible, and external body are used to register pre-treatment MRI to post-treatment MR images to model the dose response using image data of five patients. The images are registered using combinations of vertebrae and mandible alignments, and surface projection of the external body as boundary conditions. In addition, the dose response is simulated by applying a new loading technique in the form of a dose induced shrinkage using the dose-volume relationship. The dose-induced load is applied as dose-induced shrinkage of the tumor and four salivary glands. The Dice Similarity Coefficient (DSC) is calculated for the four salivary glands, and tumor to calculate the volume overlap of the structures after deformable registration. A substantial improvement in the registration is found by including the dose-induced shrinkage. The greatest registration improvement is found in the four glands where the average DSC increases from 0.53, 0.55, 0.32, and 0.37 to 0.68, 0.68, 0.51, and 0.49 in the left PG, right PG, left SG, and right SG, respectively by using bony alignment of vertebrae and mandible (M), body (B) surface projection and dose (D) (VB+M+B+D). PMID- 26485228 TI - Layer-by-Layer Fabrication of High-Performance Polyamide/ZIF-8 Nanocomposite Membrane for Nanofiltration Applications. AB - The conventional blending fabrication for thin-film nanocomposite (TFN) membranes is to disperse porous fillers in aqueous/organic phases prior to interfacial polymerization, and the aggregation of fillers may lead to the significant decrease in membrane performance. To overcome this limitation, we proposed a novel layer-by-layer (LBL) fabrication to prepare a polyamide (PA)/ZIF-8 nanocomposite membrane with a multilayer structure: a porous substrate, a ZIF-8 interlayer, and a PA coating layer. The PA/ZIF-8 (LBL) membrane for nanofiltration applications was prepared by growing an interlayer of ZIF-8 nanoparticles on an ultrafiltration membrane through in situ growth and then coating it with an ultrathin PA layer through interfacial polymerization. The obtained PA/ZIF-8 (LBL) membrane exhibited both better permeance and selectivity than did the conventional PA/ZIF-8 TFN membrane because of the ZIF-8 in situ growth producing a ZIF-8 interlayer with more ZIF-8 nanoparticles but fewer aggregates. Compared with the pure PA membrane (the flux of 11.2 kg/m(2)/h and rejection of 99.6%) for dye removal, the obtained PA/ZIF-8 (LBL) membranes achieved a significant improvement in membrane permeance and selectivity. (Flux was up to 27.1 kg/m(2)/h, and the rejection reaches 99.8%.) This LBL fabrication is a promising methodology for other polymer nanocomposite membranes simultaneously having high permeance and good selectivity. PMID- 26485229 TI - Alternative regimens of magnesium sulfate for treatment of preeclampsia and eclampsia: a systematic review of non-randomized studies. AB - INTRODUCTION: The optimal dosing regimen of magnesium sulfate for treating preeclampsia and eclampsia is unclear. Evidence from the Cochrane review of randomized controlled trials (RCTs) was inconclusive due to lack of relevant data. MATERIAL AND METHODS: To complement the evidence from the Cochrane review, we assessed available data from non-randomized studies on the comparative efficacy and safety of alternative magnesium sulfate regimens for the management of preeclampsia and eclampsia. Sources included Medline, EMBASE, Popline, CINAHL, Global Health Library, African Index Medicus, Biological abstract, BIOSIS and reference lists of eligible studies. We selected non-randomized study designs including quasi-RCTs, cohort, case-control and cross-sectional studies that compared magnesium sulfate regimens in women with preeclampsia or eclampsia. RESULTS: Of 6178 citations identified, 248 were reviewed in full text and five studies of low to very low quality were included. Compared with standard regimens, lower-dose regimens appeared equally as good in terms of preventing seizures [odds ratio (OR) 1.02, 95% confidence interval (CI) 0.46-2.28, 899 women, four studies], maternal morbidity (OR 0.47, 95%CI 0.32-0.71, 796 women, three studies), and fetal and/or neonatal mortality (OR 0.87, 95%CI 0.38-2.00, 800 women, four studies). Comparison of loading dose only with maintenance dose regimens showed no differences in seizure rates (OR 0.99, 95%CI 0.22-4.50, 146 women, two studies), maternal morbidity (OR 0.53, 95%CI 0.15-1.93, 146 women, two studies), maternal mortality (OR 0.63, 95%CI 0.05-7.50, 146 women, two studies), and fetal and/or neonatal mortality (OR 0.49, 95%CI 0.23-1.03, 146 women, two studies). CONCLUSION: Lower-dose and loading dose-only regimens could be as safe and efficacious as standard regimens; however, this evidence comes from low to very low quality studies and further high quality studies are needed. PMID- 26485230 TI - Barriers and Facilitators to Implementing Access to HIV Care Interventions: A Qualitative Analysis of the Positive Charge Initiative. AB - Research indicates that less than half of people living with HIV (PLWH) have undetectable levels of virus, despite recent findings that viral load suppression dramatically reduces the transmissibility of HIV. Linkage to HIV care is a crucial initial step, yet we know relatively little about how to effectively implement linkage interventions to reach PLWH who are not in care. AIDS United's initiative, Positive Charge (PC), funded five U.S. sites to develop and implement comprehensive linkage interventions. Evaluation of the initiative included qualitative interviews with management and service staff from each intervention site. Sites experienced barriers and facilitators to implementation on multiple environmental, organization, and personnel levels. Successful strategies included developing early relationships with collaborating partners, finding ways to share key information among agencies, and using evaluation data to build support among leadership staff. Lessons learned will be useful for organizations that develop and implement future interventions targeting hard-to-reach, out-of-care PLWH. PMID- 26485231 TI - Unpacking Linkage and Reengagement in HIV Care: A Day in the Life of a Positive Charge Care Coordinator. AB - AIDS United's Positive Charge (PC) was a multiorganizational HIV linkage to care program implemented in five U.S. LOCATIONS: To better understand the process of linkage and reengagement in care, we conducted interviews with care coordinators and program supervisors at 20 PC implementing agencies. Though linkage to care is often considered a single column in the HIV continuum of care, we found that it contains several underlying and often complex steps. The steps described are: identifying individuals in need of services; contacting those individuals through a variety of means; assessing and addressing needs and barriers to care; initial engagement (or reengagement) in HIV primary care; and provision of ongoing support to promote retention. We highlight strategies used to complete these steps. These findings will be of utility to other HIV interventions that aim to improve linkage and engagement in HIV care. PMID- 26485232 TI - Healing Our Women for Transgender Women: Adaptation, Acceptability, and Pilot Testing. AB - Healing Our Women (HOW) is a group-level HIV risk-reduction intervention developed to address the role of prior sexual victimization in HIV risk and protective behaviors among HIV-positive women of color. This article describes the process of adapting HOW for transgender women of color in New York City in accordance with CDC guidance for the adaptation of efficacious interventions. Twenty-one transgender women were enrolled in a study to evaluate the acceptability and fidelity of the adapted intervention, and to assess HIV knowledge, depressive symptoms, coping, condom use self-efficacy, and condom use via pre- and post-intervention surveys. We found the adapted program to be feasible to implement and acceptable to participants. We also found significant decreases in depressive symptoms and increases in positive coping from pre- to post-intervention, although replication with a larger sample and a control group comparison is needed to determine efficacy with this population. PMID- 26485233 TI - Defining Success: Insights From a Random Assignment, Multisite Study of Implementing HIV Prevention, Testing, and Linkage to Care in U.S. Jails and Prisons. AB - In the emerging field of implementation science, measuring the extent to which a new or modified healthcare program or practice is successfully implemented following an intervention is a critical component in understanding how evidence based treatments become part of regular practice. This paper is intended to expand our understanding of factors that influence the successful adoption of new or modified HIV services in correctional settings. The nine-site project developed and directed an organization-level intervention designed to implement improvements in preventing, detecting, and treating HIV for persons under correctional supervision. Using semi-structured interviews to elicit perceptions from Senior Researchers and Executive Sponsors at each of the nine sites, this paper presents their views and observations regarding the success of the experimental intervention in their criminal justice setting. Within the areas of focus for implementation (either HIV prevention, testing, or linkage to community treatment) the complexity of programmatic needs was very influential with regards to perceptions of success. An organization's pre-existing characteristics, staffing, funding, and interorganizational relationships contributed to either the ease or difficulty of programmatic implementation. Results are discussed pertaining to furthering our understanding of why new or modified healthcare interventions achieve success, including whether the intervention is a modification of existing practice or is a new intervention, and the choice of implementation strategy. PMID- 26485234 TI - Effectiveness of a Peer-Assisted Multicomponent Behavioral Intervention in HIV Risk Reduction Among Female Entertainment Workers in China. AB - This study examined the effectiveness of a behavioral intervention that combined cognitive and social influence approaches. The intervention consisted of small group sessions targeting HIV knowledge, protection motivation, behavioral skills, and social influences of risk reduction. The control was an attention-controlled HIV/STI health education and counseling. Two-group comparisons were conducted to assess the effectiveness of the intervention; risk reduction over time was analyzed to determine the sustainability of the effectiveness. The analyses revealed that the intervention was effective in reducing/increasing HIV risk/protective behaviors and the effect was sustainable. While participants in the control reported a greater reduction/increase in risk/protective behaviors 3 month post-intervention, the initial strong effect quickly faded and completely disappeared 12-month post-intervention. By contrast, the moderate initial effect of the intervention was not only sustained but actually strengthened over time. The intervention was well received by participants and holds promise for HIV risk reduction behavior change among female entertainment workers in China. PMID- 26485225 TI - Regulation of Long Bone Growth in Vertebrates; It Is Time to Catch Up. AB - The regulation of organ size is essential to human health and has fascinated biologists for centuries. Key to the growth process is the ability of most organs to integrate organ-extrinsic cues (eg, nutritional status, inflammatory processes) with organ-intrinsic information (eg, genetic programs, local signals) into a growth response that adapts to changing environmental conditions and ensures that the size of an organ is coordinated with the rest of the body. Paired organs such as the vertebrate limbs and the long bones within them are excellent models for studying this type of regulation because it is possible to manipulate one member of the pair and leave the other as an internal control. During development, growth plates at the end of each long bone produce a transient cartilage model that is progressively replaced by bone. Here, we review how proliferation and differentiation of cells within each growth plate are tightly controlled mainly by growth plate-intrinsic mechanisms that are additionally modulated by extrinsic signals. We also discuss the involvement of several signaling hubs in the integration and modulation of growth-related signals and how they could confer remarkable plasticity to the growth plate. Indeed, long bones have a significant ability for "catch-up growth" to attain normal size after a transient growth delay. We propose that the characterization of catch-up growth, in light of recent advances in physiology and cell biology, will provide long sought clues into the molecular mechanisms that underlie organ growth regulation. Importantly, catch-up growth early in life is commonly associated with metabolic disorders in adulthood, and this association is not completely understood. Further elucidation of the molecules and cellular interactions that influence organ size coordination should allow development of novel therapies for human growth disorders that are noninvasive and have minimal side effects. PMID- 26485235 TI - Once a Navegante, Always a Navegante: Latino Men Sustain Their Roles as Lay Health Advisors to Promote General and Sexual Health to Their Social Network. AB - Little is known about the sustainability of male- and men's health-focused lay health advisors. HoMBReS Por un Cambio was a community-level social network intervention designed to improve sexual health among Latino men who were members of soccer teams. During the year after the intervention implementation, lay health advisors (Navegantes) continued to promote sexual health; over 84% (16 of the 19) Navegantes conducted 9 of 10 primary health promotion activities. Describing where to get condoms was the activity that the most Navegantes reported having conducted. Navegantes had broad reach with their social networks, although the number of Navegantes that conducted each activity differed across the categories of social network members (soccer teammates, nonteammates, and women). Results suggest that HIV-related health disparities may be addressed through lay health advisor interventions because they are sustained after the intervention ends and reach large numbers of community members. PMID- 26485237 TI - Erratum. PMID- 26485238 TI - Role of immunohistochemistry in the diagnosis of sebaceous carcinoma: a clinicopathologic and immunohistochemical study. AB - Sebaceous carcinoma (SC) is a relatively uncommon malignant epithelial neoplasm with a predilection for the periocular region. The diagnosis of SC can be difficult to make at initial presentation, as it can clinically and histopathologically resemble other common benign and malignant epithelial lesions. A diagnosis of SC is made by confirmation of sebaceous differentiation of neoplastic cells, which can often be accomplished by conventional microscopic findings; however, its recognition may be sometimes difficult and requires ancillary studies such as immunohistochemistry (IHC). Many studies have evaluated the role of IHC as a potential technique to differentiate SC from its mimics; however, most of these studies have used a limited panel of antibodies with variable results. The aim of this study was to determine the efficacy of IHC in the diagnosis of SC and to provide some guidelines for interpretation in the diagnosis of these neoplasms. We studied 27 cases of SC with a broad panel of IHC markers using a tissue microarray technique. We also studied 21 control cases of basal cell carcinoma (BCC) and 22 control cases of squamous cell carcinoma (SCC). Representative tissue cores were taken and processed from each case, and the tissue microarrays were stained by standard methods using antibodies to EMA, CK7, Ber-EP4, Factor XIIIA, androgen receptor, p53, adipophilin, progesterone receptor membrane component 1 (PGRMC1), squalene synthase (SQS), and alpha/beta hydrolase domain-containing protein 5 (ABHD5). Our studies show that EMA was expressed in all cases of SC, CK7 was expressed in 24 of 27 cases, Ber-EP4 was expressed in 7 of 27 cases, Factor XIIIA was negative in all cases, androgen receptor was expressed in 9 of 27 cases, P53 was expressed in 12 of 27 cases, adipophilin was expressed in all cases, PGRMC1 was expressed in 22 of 27 cases, SQS was expressed in 11 of 27 cases, and ABHD5 was expressed in 9 of 27 cases. EMA was negative in all cases of BCC, CK7 was expressed in 6 of 21 cases, Ber-EP4 was expressed in 21 of 21 cases, Factor XIIIA was negative in all cases, androgen receptor was expressed in 3 of 21 cases, P53 was expressed in 4 of 21 cases, adipophilin, PGRMC1, SQS, and ABHD5 were negative in all cases of BCC. Similarly, EMA was expressed in 16 of 22 cases of SCC, CK7 was expressed in 2 of 22 cases, Ber-EP4, Factor XIIIA, and androgen receptor were negative in all cases, P53 was expressed in 3 of 22 cases, adipophilin, PGRMC1, SQS, and ABHD5 were negative in all cases of SCC. Our study indicates that adipophilin represents a sensitive and reliable marker for the diagnosis of SC and can be of help in separating this tumor from some of its mimics. Additionally, inclusion of various epithelial markers in the panel will be of help if adequately used. Other antibodies against the PAT family of lipid droplet-associated proteins including PGRMC1, SQS, and ABHD5 were not as sensitive as adipophilin for identifying sebaceous differentiation and may therefore not be as useful for differential diagnosis as adipophilin. PMID- 26485236 TI - HIV and Childhood Sexual Violence: Implications for Sexual Risk Behaviors and HIV Testing in Tanzania. AB - Prior research has established an association between sexual violence and HIV. Exposure to sexual violence during childhood can profoundly impact brain architecture and stress regulatory response. As a result, individuals who have experienced such trauma may engage in sexual risk-taking behavior and could benefit from targeted interventions. In 2009, nationally representative data were collected on violence against children in Tanzania from 13-24 year old respondents (n=3,739). Analyses show that females aged 19-24 (n=579) who experienced childhood sexual violence, were more likely to report no/infrequent condom use in the past 12 months (AOR=3.0, CI [1.5, 6.1], p=0.0017) and multiple sex partners in the past 12 months (AOR=2.3, CI [1.0, 5.1], p=0.0491), but no more likely to know where to get HIV testing or to have ever been tested. Victims of childhood sexual violence could benefit from targeted interventions to mitigate impacts of violence and prevent HIV. PMID- 26485239 TI - Characterization of primary cutaneous CD8+/CD30+ lymphoproliferative disorders. AB - CD30 primary cutaneous lymphoproliferative diseases include both lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (PCALCL). The neoplastic cell of most primary CD30 lymphoproliferative disorders is CD4 positive. The terminology LyP "type D" has been used to describe a growing number of cases of LyP with a predominantly CD8 infiltrate. PCALCL with a CD8 phenotype has also been described, which presents a particularly difficult diagnostic and management challenge, given the difficulty in distinguishing it histologically from other cytotoxic lymphomas such as primary cutaneous aggressive epidermotropic CD8 cytotoxic T-cell lymphoma and CD8 gamma/delta and natural killer/T-cell lymphoma. We report 7 additional cases of these rare cutaneous CD8/CD30 lymphoproliferative disorders. We also present a unique case of CD8/CD30 LyP with histologic similarities to LyP type B. In all 7 of our cases of CD8 LyP and CD8 anaplastic large cell lymphoma, we found focal to diffuse MUM-1 positivity. We propose that MUM-1 may represent an adjunctive marker for CD8 lymphoproliferative disease. Finally, we review the current literature on cases of CD8 LyP and PCALCL. For the 106 cases examined, we found similar clinical and histologic features to those reported for traditional CD4CD30 LyP and PCALCL. PMID- 26485240 TI - Consumption of the epidermis: a suggested precursor of ulceration associated with increased proliferation of melanoma cells. AB - It has recently been demonstrated that the extent of ulceration and the presence of epidermal involvement that theoretically precede ulceration (consumption of epidermis, COE) or seen subsequent to inflammation (reactive epidermal hyperplasia or re-epithelialization) allowed better prognostic stratification of ulcerated melanoma. Understanding why these histopathologic markers have prognostic potential is important, not least because accurate consensual assessment of ulceration lies at the root of proper staging and clinical management. The authors therefore performed immunohistochemical analyses of tumor cell proliferation (Melan-A/Ki67) and infiltration of inflammatory cells (CD66b neutrophils and CD163 macrophages) to better understand the biology of the epidermal changes described. Tumors with a COE configuration showed 37% (95% CI: 4-54, P = 0.0046) increased tumor cell proliferation compared with tumors of normal epidermal configuration. COE is therefore suggested a precursor of ulceration associated with increased proliferation of melanoma cells. There was no observed correlation between COE and an increased inflammatory response (CD163 macrophages or CD66b neutrophils), which supports that the proliferation drive is noninflammatory. In contrast, the presence of re-epithelialization and/or reactive epidermal hyperplasia demonstrated an 18% (95% CI: 6-53, P = 0.0021) increased density of neutrophils compared with tumor with no evidence of these possibly prolonged late-stage or resolved ulcerations. These results further support the relevance of including these epidermal changes into the definition of ulceration and to define ulceration of a primary melanoma as loss of epidermis with evidence of a host response (infiltration of neutrophils or fibrin deposition) and thinning, effacement, or reactive hyperplasia of the surrounding epidermis. PMID- 26485241 TI - An enormous tumor in a patient with clinically amyopathic dermatomyositis: challenge. PMID- 26485243 TI - Nodular amyloidosis derived from keratinocytes: an unusual type of primary localized cutaneous nodular amyloidosis. AB - Primary, localized cutaneous amyloidosis includes macular, lichen, and nodular (tumefactive) types in which the amyloid deposits are limited to the dermis without systemic involvement. The material in lichen and macular amyloidosis is derived from epidermal keratinocytes [keratinocyte-derived amyloid (AK)], whereas that in nodular amyloidosis is derived from immunoglobulin light-chains amyloid (AL). Primary, localized cutaneous nodular amyloidosis (PLCNA) is a form of primary, localized cutaneous amyloidosis that has been associated with a risk of progression to systemic amyloidosis. We report an unusual case of nodular AK-type amyloid deposited in the dermis of the feet. The patient is a 60-year-old woman with asymptomatic verrucoid-like lesions present around the medial and lateral aspects of the bilateral heels for 1-2 years. A biopsy showed massive deposition of eosinophilic amorphous material in the papillary and reticular dermis. The material stained positive for Congo red with apple-green birefringence on polarized light. It was also positive for pan-cytokeratin and negative for kappa and lambda light-chain immunostains. An extensive workup was negative for systemic involvement. Lipid chromatography tandem mass spectrometry confirmed that the deposition was AK-type amyloid. We believe that this is the first case of PLCNA with AK deposition. This entity should be included in the differential diagnosis of PLCNA so that an extensive systemic workup may be avoided. PMID- 26485244 TI - Punctate follicular porokeratosis: clinical and pathologic features. AB - Porokeratosis is a disorder of keratinization characterized by an abnormal cornoid lamella surrounding an annular, scaly plaque with an atrophic center. A histologic variant of this condition has been proposed, termed follicular porokeratosis, in cases where follicular involvement was contiguous with an annular cornoid lamella. There has been only 1 report of punctate follicular porokeratosis, in which cornoid lamellae originated exclusively from hair follicles with no associated annular plaque. The authors present the second case of punctate follicular porokeratosis, further supporting the contention that this entity is a unique form of porokeratosis rather than a histologic variant. A 56 year-old African American female presented to the dermatology clinic with a 3 month history of keratotic lesions localized on the right posterior shoulder. Examination revealed an area of perifollicular keratotic papules, each surrounded by an erythematous rim. Histopathology revealed a cornoid lamella originating within a hair follicle, with the parakeratotic column protruding through the follicular orifice. The static nature of the condition along with exclusive involvement of hair follicles supports the notion of punctate follicular porokeratosis as a distinct clinical entity. The diagnosis of this condition relies heavily on proper histopathologic sampling revealing punctate follicular cornoid lamellae. PMID- 26485245 TI - Moving forward together: The Lancet Commission on Global Surgery report and its implications for neurosurgical procedures. PMID- 26485246 TI - Application of "Hydrogen-Bonding Interaction" in Drug Design. Part 2: Design, Synthesis, and Structure-Activity Relationships of Thiophosphoramide Derivatives as Novel Antiviral and Antifungal Agents. AB - On the basis of the structure of natural product harmine, lead compound 18, and the structure of compounds in part 1, a series of thiophosphoramide derivatives 1 17 were designed and synthesized from various amines in one step. Their antiviral and antifungal activities were evaluated. Most of the compounds showed significantly higher antiviral activity against tobacco mosaic virus (TMV) than commercial virucide ribavirin. Compound (R,R)-17 showed the best anti-TMV activity in vitro (70%/500 MUg/mL and 33%/100 MUg/mL) and in vivo (inactivation effect, 68%/500 MUg/mL and 30%/100 MUg/mL; curative effect, 64%/500 MUg/mL and 31%/100 MUg/mL; protection effect, 66%/500 MUg/mL and 31%/100 MUg/mL), which is higher than that of ningnanmycin and lead compound 18. The antiviral activity of (R,R)-17.HCl is about similar to that of (R,R)-17. However, the antifungal activity of (R,R)-17.HCl against Puccinia sorghi is slightly lower than that of (R,R)-17. The systematic study provides compelling evidence that these simple thiophosphoramide compounds could become efficient antiviral and antifungal agents. PMID- 26485248 TI - Resident Attitudes on Ethical and Medical Decision-Making for Neonates at the Limit of Viability. AB - OBJECTIVE: This study aims to identify pediatric resident knowledge and attitudes on current practices and ideal gestational age (GA) thresholds for offering and mandating resuscitation, and the role of influencing factors in decision-making. STUDY DESIGN: Pediatric residents were assessed via electronic survey at a large academic institution. RESULT: A total of 62% of the residents identified 23 weeks as the lower threshold for resuscitation, despite 84 and 89% reporting that practices are inconsistent and unclear, respectively. Only 21% identified 24 weeks as the latest GA that parents may decline. The majority disagreed with our current practices, identifying older GA as appropriate for all thresholds. They reported scientific evidence as undervalued, and attending physicians' personal beliefs as overvalued in decision-making. CONCLUSION: Our residents recognize decision-making for extremely preterm infants consistent with general guidelines for management based on population outcomes, but attribute these decisions to physicians' personal beliefs. Preferences for higher GA thresholds for resuscitation may reflect disproportionate pessimism about these patients or diverse values regarding autonomy. PMID- 26485247 TI - Complement Split Products C3a/C5a and Receptors: Are They Regulated by Circulating Angiotensin II Type 1 Receptor Autoantibody in Severe Preeclampsia? AB - BACKGROUND: This study measured the serum levels of complement component (C)3a and C5a and the placental expressions of C3a receptor (R) and C5aR to determine a potential correlation with circulating angiotensin II type 1 (AT1) receptor agonistic autoantibody (AT1-AA) in severe pre-eclampsia. METHODS: A total of 118 women were recruited and divided into 2 groups: the control group (normotensive preterm pregnancies, n = 66) and severe pre-eclampsia group (n = 52). Levels of C3a, C5a and AT1-AA in serum were measured by enzyme-linked immunosorbent assay and C3aR and C5aR in placenta by Western blotting. RESULTS: Levels of C3a, C5a and AT1-AA in serum from the severe pre-eclampsia group were significantly higher than in controls (p < 0.05). Placental expression of C3aR and C5aR in the pre eclampsia group was lower than that in controls (p < 0.05). There were significant positive correlations between levels of C3a, C5a and AT1-AA in serum from the pre-eclampsia group (p < 0.05). In contrast, there was no correlation between C3aR and C5aR in the placenta and AT1-AA in serum in the pre-eclampsia group (p > 0.05). CONCLUSION: Increased C3a, C5a and AT1-AA in the serum provide indirect evidence that AT1-AA-mediated activation contributes to activate complement, which is a key mechanism underlying the pathogenesis of severe pre eclampsia. PMID- 26485249 TI - Insulin, Hyperglycemia, and Severe Retinopathy of Prematurity in Extremely Low Birth-Weight Infants. AB - OBJECTIVE: This study aims to determine the association between hyperglycemia, insulin therapy, and severe retinopathy of prematurity (ROP) in extremely low birth-weight (ELBW) infants. STUDY DESIGN: In this retrospective database study, we included all ELBW infants who were <= 32 weeks gestational age (GA). We excluded infants without any ophthalmology evaluation and infants who died before 28 days of life. A multivariable model was constructed to determine the association between hyperglycemia, insulin use, and severe ROP. We defined hyperglycemia as blood glucose (BG) > 180 mg/dL. Covariates were GA, small for GA status, discharge year, sex, Apgar score at 5 minutes, mechanical ventilation, oxygen use, bacteremia, and postnatal steroid exposure. We defined severe ROP as ROP requiring bevacizumab, cryotherapy, laser therapy, or vitrectomy. Sensitivity analysis using BG > 150 mg/dL and > 200 mg/dL was performed. RESULTS: A total of 24,548 infants were included; 2,547 (10%) had severe ROP. Hyperglycemia alone was not associated with severe ROP (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.66-1.17). Hyperglycemia and insulin use were not associated with severe ROP (OR, 1.43; 95% CI, 0.91-2.23). BG > 150 mg/dL and insulin use were associated with severe ROP (OR, 1.34; 95% CI, 1.02-1.76). CONCLUSIONS: Hyperglycemia alone was not associated with severe ROP in ELBW infants. However, we did observe a possible trend between the use of insulin and severe ROP. PMID- 26485250 TI - Teenage Pregnancies: Risk Factors and Associated Neonatal Outcomes in an Eastern European Academic Perinatal Care Center. AB - OBJECTIVES: This study aims to compare women with early (13-16 years), late teenage (17-19 years), and adult (25-29 years) pregnancies regarding pregnancy risk factors and reproductive outcomes. METHODS: An observational study, utilizing medical charts and direct interview, conducted in an academic hospital during January 2011 and December 2012. Our sample comprised 395 teenage and 736 adult pregnancies. RESULTS: Pregnant teenagers were more likely than adults to be single (41.7 vs. 33.2%; odds ratio [OR]: 1.43, 95% confidence interval [CI]: 1.11 1.84), to live in a rural area (70.9 vs. 53.9%; OR: 2.07, 95% CI: 1.60-2.69), and to live with extended family (74.2 vs. 16.0%; OR: 15.04, 95% CI: 11.15-20.29). Adolescent mothers were more likely than adult mothers to give birth by vaginal delivery (78.5 vs. 69.6%; OR: 1.82, 95% CI: 1.17-2.84), and rate of operative delivery was lower amongst this group (8.6 vs. 9.8%; OR: 0.8, 95% CI: 0.5-1.3). The newborns of adolescent mothers were more likely to be low birth weight (14.9 vs. 9.1%; OR: 1.75, 95% CI: 1.20-2.54) and more likely to successfully breastfeed (91.9 vs. 82.2%; OR: 2.45; 95% CI: 1.63-3.69) but the length of hospital stay was similar with adult mothers' newborns. CONCLUSIONS: The distinct risk factors and behaviors associated with pregnancy, among teenagers may help address the health needs of this unique and vulnerable group and their offspring. PMID- 26485251 TI - Impact of Standardized Communication Techniques on Errors during Simulated Neonatal Resuscitation. AB - AIM: Current patterns of communication in high-risk clinical situations, such as resuscitation, are imprecise and prone to error. We hypothesized that the use of standardized communication techniques would decrease the errors committed by resuscitation teams during neonatal resuscitation. METHODS: In a prospective, single-blinded, matched pairs design with block randomization, 13 subjects performed as a lead resuscitator in two simulated complex neonatal resuscitations. Two nurses assisted each subject during the simulated resuscitation scenarios. In one scenario, the nurses used nonstandard communication; in the other, they used standardized communication techniques. The performance of the subjects was scored to determine errors committed (defined relative to the Neonatal Resuscitation Program algorithm), time to initiation of positive pressure ventilation (PPV), and time to initiation of chest compressions (CC). RESULTS: In scenarios in which subjects were exposed to standardized communication techniques, there was a trend toward decreased error rate, time to initiation of PPV, and time to initiation of CC. While not statistically significant, there was a 1.7-second improvement in time to initiation of PPV and a 7.9-second improvement in time to initiation of CC. CONCLUSIONS: Should these improvements in human performance be replicated in the care of real newborn infants, they could improve patient outcomes and enhance patient safety. PMID- 26485252 TI - Clinical whole-exome sequencing reveals a novel missense pathogenic variant of GNAO1 in a patient with infantile-onset epilepsy. AB - BACKGROUND: The cause of infantile-onset epilepsy is complex and is not easily recognized clinically, particularly in paediatric patients who present with non specific neurological signs, no radiological abnormalities and no metabolic changes. CASE: We report a case of infantile-onset epilepsy in a 10-month-old Chinese girl who presented with non-specific neurological signs, no radiological abnormalities and no biochemical disturbances. She first presented at birth with twitching movements and convulsions of an unknown aetiology. Ambulatory EEG showed epileptic rhythmic activities, the presence of asynchrony and runs of sharp waves over the right parietal and central areas. Given the non-specific neurological features and negative structural and biochemical findings, we applied clinical whole-exome sequencing (WES) to determine the underlying aetiology. WES revealed a novel heterozygous missense pathogenic variant, GNAO1:NM_020988.2:c.118G>A; NP_066268.1:p.Gly40Arg. A genetic analysis of the family confirmed the variant identified is a de novo mutation. CONCLUSIONS: Clinical WES can streamline genetic analysis and sort out pathogenic genes in an unbiased approach. GNAO1 is a disease-causing gene for the autosomal dominant form of early infantile epileptic encephalopathy. The novel pathogenic variant identified in this case should contribute to our understanding of the expanding spectrum of infantile-onset epilepsy. PMID- 26485253 TI - Pre-analytical phase: The automated ProTube device supports quality assurance in the phlebotomy process. AB - BACKGROUND: Most errors in laboratory medicine occur in the pre-analytical phase of the total testing process. Phlebotomy, a crucial step in the pre-analytical phase influencing laboratory results and patient outcome, calls for quality assurance procedures and automation in order to prevent errors and ensure patient safety. METHODS: We compared the performance of a new small, automated device, the ProTube Inpeco, designed for use in phlebotomy with a complete traceability of the process, with a centralized automated system, BC ROBO. RESULTS: ProTube was used for 15,010 patients undergoing phlebotomy with 48,776 tubes being labeled. The mean time and standard deviation (SD) for blood sampling was 3:03 (min:sec; SD +/- 1:24) when using ProTube, against 5:40 (min:sec; SD +/- 1:57) when using BC ROBO. The mean number of patients per hour managed at each phlebotomy point was 16 +/- 3 with ProTube, and 10 +/- 2 with BC ROBO. No tubes were labeled erroneously or incorrectly, even if process failure occurred in 2.8% of cases when ProTube was used. CONCLUSIONS: Thanks to its cutting edge technology, the ProTube has many advantages over BC ROBO, above all in verifying patient identity, and in allowing a reduction in both identification error and tube mislabeling. PMID- 26485254 TI - Thimerosal: An allergen for patch testing. PMID- 26485255 TI - Refinement of the Central Steps of Substrate Transport by the Aspartate Transporter GltPh: Elucidating the Role of the Na2 Sodium Binding Site. AB - Glutamate homeostasis in the brain is maintained by glutamate transporter mediated accumulation. Impaired transport is associated with several neurological disorders, including stroke and amyotrophic lateral sclerosis. Crystal structures of the homolog transporter GltPh from Pyrococcus horikoshii revealed large structural changes. Substrate uptake at the atomic level and the mechanism of ion gradient conversion into directional transport remained enigmatic. We observed in repeated simulations that two local structural changes regulated transport. The first change led to formation of the transient Na2 sodium binding site, triggered by side chain rotation of T308. The second change destabilized cytoplasmic ionic interactions. We found that sodium binding to the transiently formed Na2 site energized substrate uptake through reshaping of the energy hypersurface. Uptake experiments in reconstituted proteoliposomes confirmed the proposed mechanism. We reproduced the results in the human glutamate transporter EAAT3 indicating a conserved mechanics from archaea to humans. PMID- 26485257 TI - Correction: Evidence for the Convergence Model: The Emergence of Highly Pathogenic Avian Influenza (H5N1) in Viet Nam. PMID- 26485256 TI - Hepatorenal Acute Kidney Injury and the Importance of Raising Mean Arterial Pressure. AB - BACKGROUND: The efficacy of vasoconstrictors in hepatorenal syndrome (HRS) is variable. We hypothesized that the effectiveness of vasoconstrictor therapy in improving kidney function ultimately relates to the magnitude of the achieved mean arterial pressure (MAP) increase. METHODS: A retrospective study was conducted to identify cirrhotic individuals treated with vasoconstrictors for acute kidney injury (AKI) presumably caused by HRS to examine the relationship between change in MAP and change in serum creatinine (sCr) using multivariate mixed linear regression. RESULTS: Among 73 patients treated with midodrine/octreotide, change in MAP inversely correlated with change in sCr (p = 0.0005). The quartile with the greatest increase in MAP (+15.9 to +29.4 mm Hg) was associated with a subsequent absolute decrease in sCr. The strength of the correlation increased when the analysis was restricted to those who met the HRS criteria (n = 27, p = 0.002), where the third (+5.3 to +15.6 mm Hg) and fourth (+15.9 to +20.9 mm Hg) quartiles of MAP change were associated with a decrease in sCr. A similar but stronger correlation was found among 14 patients treated with norepinephrine either after failing midodrine/octreotide (n = 10) or de novo (n = 4; p = 0.002), where a rise in MAP of +19.2 to 25 mm Hg was associated with a larger reduction in sCr. Associations remained significant after adjustment for baseline parameters. CONCLUSIONS: The magnitude of MAP rise during HRS therapy with midodrine/octreotide or norepinephrine correlated with a reduction in sCr concentration. Our results suggest that achieving a pre-specified target of MAP increase might improve renal outcomes in hepatorenal AKI. PMID- 26485259 TI - Have we done enough to educate patients about e-cigarettes? PMID- 26485258 TI - Delayed Onset of Symptoms and Atovaquone-Proguanil Chemoprophylaxis Breakthrough by Plasmodium malariae in the Absence of Mutation at Codon 268 of pmcytb. AB - Plasmodium malariae is widely distributed across the tropics, causing symptomatic malaria in humans with a 72-hour fever periodicity, and may present after latency periods lasting up to many decades. Delayed occurrence of symptoms is observed in humans using chemoprophylaxis, or patients having received therapies targeting P. falciparum intraerythrocytic asexual stages, but few investigators have addressed the biological basis of the ability of P. malariae to persist in the human host. To investigate these interesting features of P. malariae epidemiology, we assembled, here, an extensive case series of P. malariae malaria patients presenting in non-endemic China, Sweden, and the UK who returned from travel in endemic countries, mainly in Africa. Out of 378 evaluable P. malariae cases, 100 (26.2%) reported using at least partial chemoprophylaxis, resembling the pattern seen with the relapsing parasites P. ovale spp. and P. vivax. In contrast, for only 7.5% of imported UK cases of non-relapsing P. falciparum was any chemoprophylaxis use reported. Genotyping of parasites from six patients reporting use of atovaquone-proguanil chemoprophylaxis did not reveal mutations at codon 268 of the cytb locus of the P. malariae mitochondrial genome. While travellers with P. malariae malaria are significantly more likely to report prophylaxis use during endemic country travel than are those with P. falciparum infections, atovaquone-proguanil prophylaxis breakthrough was not associated with pmcytb mutations. These preliminary studies, together with consistent observations of the remarkable longevity of P. malariae, lead us to propose re examination of the dogma that this species is not a relapsing parasite. Further studies are needed to investigate our favoured hypothesis, namely that P. malariae can initiate a latent hypnozoite developmental programme in the human hepatocyte: if validated this will explain the consistent observations of remarkable longevity of parasitism, even in the presence of antimalarial prophylaxis or treatment. PMID- 26485260 TI - Practice invites patients to run a 5K with their doctor. PMID- 26485261 TI - Targeting neuropathic pain: consider these alternatives. AB - When patients with painful peripheral neuropathy fail to respond to--or are unable to tolerate--standard therapies, consider these lesser-known treatments. PMID- 26485262 TI - Long-acting reversible contraception: who, what, when, and how. AB - This review provides practical tips--and dispels some common misconceptions- about these devices, which have higher rates of patient satisfaction and lower rates of failure than any other reversible contraceptives.. PMID- 26485263 TI - Right foot pain while walking . no erythema or edema . no evidence of structural abnormalities . Dx? AB - A 24-year-old woman came to our clinic because she had pain in her right foot. Over the previous 4 weeks, she'd noticed increasing pain in the ball of her foot while walking and climbing stairs, particularly in the push-off portion of her gait. She described it as a nagging, localized pain that she rated as a 2 or 3 out of 10. It was an annoyance, but not unbearable. PMID- 26485264 TI - Vomiting and abdominal pain in a woman with diabetes. AB - A CT scan of this patient's abdomen led us to an unusual and life-threatening diagnosis. PMID- 26485265 TI - Erratum. PMID- 26485266 TI - Treating depression: what works besides meds? AB - How effective are cognitive behavioral therapy, prescribed exercise, dietary supplements, and other nonpharmacologic options for alleviating depression? Here's what the evidence tells us. PMID- 26485267 TI - Familial hypercholesterolemia: clues to catching it early. AB - Here's how to spot the red flags that could signal your patient is at risk and steps you can take to potentially extend his or her life. PMID- 26485268 TI - The mainstreaming of alternative therapies. PMID- 26485269 TI - HelpDesk Answers: What treatments best prevent chronic tension headaches? PMID- 26485270 TI - HelpDesk Answers: Does team-based care improve outcomes for patients with chronic diseases? PMID- 26485271 TI - Congo Red Interactions with Curli-Producing E. coli and Native Curli Amyloid Fibers. AB - Microorganisms produce functional amyloids that can be examined and manipulated in vivo and in vitro. Escherichia coli assemble extracellular adhesive amyloid fibers termed curli that mediate adhesion and promote biofilm formation. We have characterized the dye binding properties of the hallmark amyloid dye, Congo red, with curliated E. coli and with isolated curli fibers. Congo red binds to curliated whole cells, does not inhibit growth, and can be used to comparatively quantify whole-cell curliation. Using Surface Plasmon Resonance, we measured the binding and dissociation kinetics of Congo red to curli. Furthermore, we determined that the binding of Congo red to curli is pH-dependent and that histidine residues in the CsgA protein do not influence Congo red binding. Our results on E. coli strain MC4100, the most commonly employed strain for studies of E. coli amyloid biogenesis, provide a starting point from which to compare the influence of Congo red binding in other E. coli strains and amyloid-producing organisms. PMID- 26485272 TI - Pathos & Ethos: Emotions and Willingness to Pay for Tobacco Products. AB - JEL CLASSIFICATION: C26, C99, D03, I18. PSYCINFO CLASSIFICATION: 2360; 3920. PMID- 26485273 TI - Correction: Modified Clonidine Testing for Growth Hormone Stimulation Reveals alpha2-Adrenoreceptor Sub Sensitivity in Children with Idiopathic Growth Hormone Deficiency. PMID- 26485274 TI - Layer-by-layer Collagen Deposition in Microfluidic Devices for Microtissue Stabilization. AB - Although microfluidics provides exquisite control of the cellular microenvironment, culturing cells within microfluidic devices can be challenging. 3D culture of cells in collagen type I gels helps to stabilize cell morphology and function, which is necessary for creating microfluidic tissue models in microdevices. Translating traditional 3D culture techniques for tissue culture plates to microfluidic devices is often difficult because of the limited channel dimensions. In this method, we describe a technique for modifying native type I collagen to generate polycationic and polyanionic collagen solutions that can be used with layer-by-layer deposition to create ultrathin collagen assemblies on top of cells cultured in microfluidic devices. These thin collagen layers stabilize cell morphology and function, as shown using primary hepatocytes as an example cell, allowing for the long term culture of microtissues in microfluidic devices. PMID- 26485276 TI - Metal carbonyl complexes of phosphaamidines. Coordinative integrity detected in C amino(lambda(3),sigma(2))-phosphaalkene isomers coordinated through n(P) HOMO-1 donor orbitals. AB - Metal(0) complexes L(Cr,Mo,W)(CO)5 have been prepared from 1,3-bis(2,6 diisopropylphenyl)-2-(4-methylphenyl)-3-aza-1(lambda(3),sigma(2))-phosphapropene and 1,3-bis(2,6-diisopropylphenyl)-2-(4-methoxyphenyl)-3-aza 1(lambda(3),sigma(2))-phosphapropene using standard methods. Full characterization of four products and crystal structures of these complexes as well as the methoxyphenyl-phosphapropene are reported. The ligands coordinate kappaP, common for simple phosphaalkenes, despite the strongly-perturbing amino substitution at the double bond C atoms. Analyses of the NMR and vibrational spectroscopic data reveal that the complexes have very similar character to similarly-coordinated phosphaalkenes, with strong sigma-donor character. The presence of some net pi-interactions (acceptor or donor) is indicated by structures in which the ligands coordinate fully eclipsed with the M-CO groups. The synthetic and structural results have been augmented by B3PW91/LANL2DZ calculations that reproduce the structures of the Cr complexes accurately. The calculated vibrational spectra are used to confirm the assignment of the nu(C = O) vibrational data. Detailed orbital interaction diagrams based on DFT calculations are reported for the title complexes as well as for the Cr(CO)5 complex of Mes-P=CPh2. The electronic absorption spectra of the title complexes have intense low-energy absorptions ranging from 24,500 to 25,300 cm(-1), which can be interpreted qualitatively using the DFT results. PMID- 26485275 TI - The Prognostic Role of SOCS3 and A20 in Human Cholangiocarcinoma. AB - As an antagonist of the JAK/STAT pathway, suppressor of cytokine signaling 3 (SOCS3) plays an integral role in shaping the inflammatory environment, tumorigenesis and disease progression in cholangiocarcinoma (CCA); however, its prognostic significance remains unclear. Although tumor necrosis factor alpha induced protein 3 (TNFAIP3, also known as A20) can decrease SOCS3 expression and is involved in the regulation of tumorigenesis in certain malignancies, its role in CCA remains unknown. In this study, we investigated the expression of SOCS3 and A20 in human CCA tissues to assess the prognostic significance of these proteins. The expression of SOCS3 and A20 was initially detected by western blot in 22 cases of freshly frozen CCA tumors with corresponding peritumoral tissues and 22 control normal bile duct tissues. Then, these proteins were investigated in 86 CCA patients by immunohistochemistry (IHC) and were evaluated for their association with clinicopathological parameters in human CCA. The results indicated that SOCS3 expression was significantly lower in CCA tumor tissues than in corresponding peritumoral biliary tissues and normal bile duct tissues. Conversely, A20 was overexpressed in CCA tissues. Thus, an inverse correlation between the expression of SOCS3 and A20 was discovered. Furthermore, patients with low SOCS3 expression or high A20 expression showed a dramatically lower overall survival rate. These proteins were both associated with CCA lymph node metastasis, postoperative recurrence and overall survival rate. However, only A20 showed a significant association with the tumor node metastasis (TNM) stage, while SOCS3 showed a significant association with tumor differentiation. Multivariate Cox analysis revealed that SOCS3 and A20 were independent prognostic indicators for overall survival in CCA. Thus, our study demonstrated that SOCS3 and A20 represent novel prognostic factors for human CCA. PMID- 26485277 TI - Correction: Cyclooxygenase-2 and Prostaglandin E2 Signaling through Prostaglandin Receptor EP-2 Favor the Development of Myocarditis during Acute Trypanosoma cruzi Infection. PMID- 26485278 TI - Deterministic Factors Overwhelm Stochastic Environmental Fluctuations as Drivers of Jellyfish Outbreaks. AB - Jellyfish outbreaks are increasingly viewed as a deterministic response to escalating levels of environmental degradation and climate extremes. However, a comprehensive understanding of the influence of deterministic drivers and stochastic environmental variations favouring population renewal processes has remained elusive. This study quantifies the deterministic and stochastic components of environmental change that lead to outbreaks of the jellyfish Pelagia noctiluca in the Mediterranen Sea. Using data of jellyfish abundance collected at 241 sites along the Catalan coast from 2007 to 2010 we: (1) tested hypotheses about the influence of time-varying and spatial predictors of jellyfish outbreaks; (2) evaluated the relative importance of stochastic vs. deterministic forcing of outbreaks through the environmental bootstrap method; and (3) quantified return times of extreme events. Outbreaks were common in May and June and less likely in other summer months, which resulted in a negative relationship between outbreaks and SST. Cross- and along-shore advection by geostrophic flow were important concentrating forces of jellyfish, but most outbreaks occurred in the proximity of two canyons in the northern part of the study area. This result supported the recent hypothesis that canyons can funnel P. noctiluca blooms towards shore during upwelling. This can be a general, yet unappreciated mechanism leading to outbreaks of holoplanktonic jellyfish species. The environmental bootstrap indicated that stochastic environmental fluctuations have negligible effects on return times of outbreaks. Our analysis emphasized the importance of deterministic processes leading to jellyfish outbreaks compared to the stochastic component of environmental variation. A better understanding of how environmental drivers affect demographic and population processes in jellyfish species will increase the ability to anticipate jellyfish outbreaks in the future. PMID- 26485279 TI - Vitamin D Receptor Gene FOKI Polymorphism Contributes to Increasing the Risk of HIV-Negative Tuberculosis: Evidence from a Meta-Analysis. AB - BACKGROUND: Vitamin D receptor (VDR) gene FokI polymorphism have been studied in relation to tuberculosis (TB) in many populations and provided inconsistent results. In this study, we carried out a meta-analysis to derive a more reliable assessment on FokI polymorphism and the risk of HIV-negative TB. METHODS: The Embase, PubMed, and Cochrane Library databases were used to undertake a comprehensive systematic literature review of all current published VDR gene FOKI association studies aimed at the risk of TB up to June 30, 2015. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were used to measure the strength of the models. RESULTS: A total of 14 studies (1,668 cases and 1,893 controls) were retrieved in the meta-analysis. The pooled OR was 1.60 (95% = 1.28 1.97, P<0.001; I2 = 29.5%, and P = 0.141 for heterogeneity) in the best genetic model (recessive model: ff vs. fF+FF). In the subgroup analysis by ethnicities, a significantly increased risk was found in the Asian group (OR = 1.82, 95% CI = 1.42-2.33, P<0.001; I2 = 31.0%, and P = 0.150 for heterogeneity) in the recessive model. Similarly, significant associations were also found in the polymerase chain reaction-restriction fragment length polymorphism group, high-quality studies, and the population based or hospital based groups. Moderate heterogeneity was found in this study. CONCLUSION: Our results suggested that VDR FokI polymorphism contributes to increasing the risk of TB in HIV-negative individuals, especially in the Asian region. Further studies on this topic in other races are expected to be conducted in future. PMID- 26485280 TI - Evaluation of Electrical Impedance as a Biomarker of Myostatin Inhibition in Wild Type and Muscular Dystrophy Mice. AB - OBJECTIVES: Non-invasive and effort independent biomarkers are needed to better assess the effects of drug therapy on healthy muscle and that affected by muscular dystrophy (mdx). Here we evaluated the use of multi-frequency electrical impedance for this purpose with comparison to force and histological parameters. METHODS: Eight wild-type (wt) and 10 mdx mice were treated weekly with RAP-031 activin type IIB receptor at a dose of 10 mg kg-1 twice weekly for 16 weeks; the investigators were blinded to treatment and disease status. At the completion of treatment, impedance measurements, in situ force measurements, and histology analyses were performed. RESULTS: As compared to untreated animals, RAP-031 wt and mdx treated mice had greater body mass (18% and 17%, p < 0.001 respectively) and muscle mass (25% p < 0.05 and 22% p < 0.001, respectively). The Cole impedance parameters in treated wt mice, showed a 24% lower central frequency (p < 0.05) and 19% higher resistance ratio (p < 0.05); no significant differences were observed in the mdx mice. These differences were consistent with those seen in maximum isometric force, which was greater in the wt animals (p < 0.05 at > 70 Hz), but not in the mdx animals. In contrast, maximum force normalized by muscle mass was unchanged in the wt animals and lower in the mdx animals by 21% (p < 0.01). Similarly, myofiber size was only non-significantly higher in treated versus untreated animals (8% p = 0.44 and 12% p = 0.31 for wt and mdx animals, respectively). CONCLUSIONS: Our findings demonstrate electrical impedance of muscle reproduce the functional and histological changes associated with myostatin pathway inhibition and do not reflect differences in muscle size or volume. This technique deserves further study in both animal and human therapeutic trials. PMID- 26485281 TI - Over-salting ruins the balance of the immune menu. AB - Regulatory components of the immune system are critical for preventing unintended activation of immune cells. Failure to prevent this unintended activation raises the risk of developing exaggerated inflammation and autoimmunity. In this issue of the JCI, Binger et al. and Hernandez et al. report that salt can play an important role in undermining regulatory mechanisms of the innate and adaptive immune systems. High salt levels interfere with alternative activation of macrophages (M2), which function in attenuating tissue inflammation and promoting wound healing. High salt also impairs Treg function by inducing IFNgamma production in these cells. Together, these results provide evidence that environmental signals in the presence of high dietary salt enhance proinflammatory responses by interfering with both innate and adaptive regulatory mechanisms. PMID- 26485282 TI - Poreless eggshells. AB - The oocyte is the sole source of the female genetic material that will be fertilized by sperm to form an embryo. Many extrinsic and intrinsic factors are critical for oocyte development and survival; however, these mediators are incompletely understood. In this issue of the JCI, Weinberg-Shukron et al. uncover a novel recessive missense mutation in the gene encoding nucleoporin-107 (NUP107) that results in abnormal ovarian development. Recapitulation of the human mutation in the Drosophila NUP107 ortholog resulted in poor follicular development and demonstrated an evolutionarily conserved and ovary-specific role of NUP107. While NUP107 is required for nuclear pore complex function in somatic cells of flies and women, this specific amino acid change appears only to be disruptive in the ovary. All together, these findings imply that missense mutations in other genes could be specifically disruptive of ovarian or testicular function, while leaving extragonadal function intact. PMID- 26485283 TI - A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis. AB - Ovarian development and maintenance are poorly understood; however, diseases that affect these processes can offer insights into the underlying mechanisms. XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder that is characterized by underdeveloped, dysfunctional ovaries, with subsequent lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism. Here, we report an extended consanguineous family of Palestinian origin, in which 4 females exhibited XX-GD. Using homozygosity mapping and whole-exome sequencing, we identified a recessive missense mutation in nucleoporin-107 (NUP107, c.1339G>A, p.D447N). This mutation segregated with the XX-GD phenotype and was not present in available databases or in 150 healthy ethnically matched controls. NUP107 is a component of the nuclear pore complex, and the NUP107-associated protein SEH1 is required for oogenesis in Drosophila. In Drosophila, Nup107 knockdown in somatic gonadal cells resulted in female sterility, whereas males were fully fertile. Transgenic rescue of Drosophila females bearing the Nup107D364N mutation, which corresponds to the human NUP107 (p.D447N), resulted in almost complete sterility, with a marked reduction in progeny, morphologically aberrant eggshells, and disintegrating egg chambers, indicating defective oogenesis. These results indicate a pivotal role for NUP107 in ovarian development and suggest that nucleoporin defects may play a role in milder and more common conditions such as premature ovarian failure. PMID- 26485284 TI - Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection. AB - Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID- 26485285 TI - Inhibition of cyclooxygenase-2 in hematopoietic cells results in salt-sensitive hypertension. AB - Inhibition of prostaglandin (PG) production with either nonselective or selective inhibitors of cyclooxygenase-2 (COX-2) activity can induce or exacerbate salt sensitive hypertension. This effect has been previously attributed to inhibition of intrinsic renal COX-2 activity and subsequent increase in sodium retention by the kidney. Here, we found that macrophages isolated from kidneys of high-salt treated WT mice have increased levels of COX-2 and microsomal PGE synthase-1 (mPGES-1). Furthermore, BM transplantation (BMT) from either COX-2-deficient or mPGES-1-deficient mice into WT mice or macrophage-specific deletion of the PGE2 type 4 (EP4) receptor induced salt-sensitive hypertension and increased phosphorylation of the renal sodium chloride cotransporter (NCC). Kidneys from high-salt-treated WT mice transplanted with Cox2-/- BM had increased macrophage and T cell infiltration and increased M1- and Th1-associated markers and cytokines. Skin macrophages from high-salt-treated mice with either genetic or pharmacologic inhibition of the COX-2 pathway expressed decreased M2 markers and VEGF-C production and exhibited aberrant lymphangiogenesis. Together, these studies demonstrate that COX-2-derived PGE2 in hematopoietic cells plays an important role in both kidney and skin in maintaining homeostasis in response to chronically increased dietary salt. Moreover, these results indicate that inhibiting COX-2 expression or activity in hematopoietic cells can result in a predisposition to salt-sensitive hypertension. PMID- 26485288 TI - A Summary of the Biological Basis of Frailty. AB - Frailty has been defined as a geriatric syndrome that is characterized by a reduction in the physiological reserve required for an individual to respond to endogenous and exogenous stressors. Using a discrete definition of frailty that includes sedentariness, involuntary weight loss, fatigue, poor muscle strength, and slow gait speed, 'frailty' has been associated with increased disability, postsurgical complications, and increased mortality. Despite the strong associations between frailty and subsequent poor outcomes, limited attention to this common geriatric condition has been paid in clinical settings. A more fundamental basic understanding of the biological factors that contribute to the frailty phenotype has begun to emerge. Multiple underlying biological factors such as dysregulation of inflammatory processes, genomic instability, oxidative stress, mitochondrial dysfunction, and cellular senescence appear to contribute to the clinical presentation of frailty. This chapter summarizes the papers presented on the biological basis of frailty from the 83rd Nestle Nutrition Institute Workshop on 'Frailty, Pathophysiology, Phenotype and Patient Care' held in Barcelona, Spain, in March 2014. PMID- 26485286 TI - High salt reduces the activation of IL-4- and IL-13-stimulated macrophages. AB - A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL 4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis. PMID- 26485287 TI - Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model. AB - Angelman syndrome (AS) is a severe neurological disorder that is associated with prominent movement and balance impairments that are widely considered to be due to defects of cerebellar origin. Here, using the cerebellar-specific vestibulo ocular reflex (VOR) paradigm, we determined that cerebellar function is only mildly impaired in the Ube3am-/p+ mouse model of AS. VOR phase-reversal learning was singularly impaired in these animals and correlated with reduced tonic inhibition between Golgi cells and granule cells. Purkinje cell physiology, in contrast, was normal in AS mice as shown by synaptic plasticity and spontaneous firing properties that resembled those of controls. Accordingly, neither VOR phase-reversal learning nor locomotion was impaired following selective deletion of Ube3a in Purkinje cells. However, genetic normalization of alphaCaMKII inhibitory phosphorylation fully rescued locomotor deficits despite failing to improve cerebellar learning in AS mice, suggesting extracerebellar circuit involvement in locomotor learning. We confirmed this hypothesis through cerebellum-specific reinstatement of Ube3a, which ameliorated cerebellar learning deficits but did not rescue locomotor deficits. This double dissociation of locomotion and cerebellar phenotypes strongly suggests that the locomotor deficits of AS mice do not arise from impaired cerebellar cortex function. Our results provide important insights into the etiology of the motor deficits associated with AS. PMID- 26485289 TI - Immunofluorescence to Monitor the Cellular Uptake of Human Lactoferrin and its Associated Antiviral Activity Against the Hepatitis C Virus. AB - Immunofluorescence is a laboratory technique commonly used to study many aspects of biology. It is typically used to visualize the distribution and/or localization of a target molecule in cells and tissues. Immunofluorescence relies on the specificity of fluorescent-labelled antibodies against their corresponding antigens within a cell. Both direct and indirect immunofluorescence approaches can be used which rely on the use of antibodies linked with a fluorochrome. Direct immunofluorescence is less frequently used because it provides lower signal, involves higher cost and less flexibility. In contrast, indirect immunofluorescence is more commonly used because of its high sensitivity and provides an amplified signal since more than one secondary antibody can attach to each primary antibody. In this manuscript, both epifluorescence microscopy and confocal microscopy were used to monitor the internalization of human lactoferrin, an important component of the immune system, into hepatic cells. Moreover, we monitored the inhibitory potential of hLF on the intracellular replication of the Hepatitis C virus using immunofluorescence. Both the advantages and disadvantages associated with these approaches are discussed. PMID- 26485290 TI - SWOT analysis to evaluate the programme of a joint online/onsite master's degree in environmental education through the students' perceptions. AB - This study shows the use of SWOT to analyse students' perceptions of an environmental education joint master's programme in order to determine if it runs as originally planned. The open answers given by students highlight the inter university nature of the master's, the technological innovation used as major points, and the weaknesses in the management coordination or the duplicate contents as minor points. The external analysis is closely linked with the students' future jobs, their labour opportunities available to them after graduation. The innovative treatment of the data is exportable to the evaluation of programmes of other degrees because it allows the description linked to its characteristics and its design through the students' point of view. PMID- 26485291 TI - Look who's cooking. Investigating the relationship between watching educational and edutainment TV cooking shows, eating habits and everyday cooking practices among men and women in Belgium. AB - Television (TV) cooking shows have evolved from focusing on educating to focusing on entertaining, as well. At present, educational TV cooking shows focus on the transfer of cooking knowledge and skills, whereas edutainment TV cooking shows focus on entertaining their viewers. Both types of shows are ongoing success stories. However, little is known regarding the shows' links with the cooking and eating habits of their audiences. Therefore, the current study investigates the relationship between watching an educational or edutainment TV cooking show and one's cooking and eating habits. Given public health concerns regarding the decline in cooking behaviors and the simultaneous increase in caloric intake from food outside the home, this study suggests a promising intervention. The results of a cross-sectional survey in Belgium (n = 845) demonstrate that the audiences of educational and edutainment TV cooking shows do not overlap. Although there is little connection between watching specific shows and eating behavior, the connection between watching shows and cooking behaviors varies across gender and age lines. Behaviors also differ depending on whether the viewer is watching an educational or edutainment cooking show. For example, men of all ages appear to cook more often if they watch an educational show. However, only older men (above 38 years) seem to cook more often if they watch an edutainment TV show. The results demonstrate that the relationship between watching TV cooking shows and cooking habits warrants further investigation. PMID- 26485292 TI - BALB/c and SWR inbred mice differ in post-oral fructose appetition as revealed by sugar versus non-nutritive sweetener tests. AB - Recent studies indicate that C57BL/6J (B6) and FVB inbred mouse strains differ in post-oral fructose conditioning. This was demonstrated by their differential flavor conditioning response to intragastric fructose and their preference for fructose versus a non-nutritive sweetener. The present study extended this analysis to SWR and BALB/c inbred strains which are of interest because they both show robust flavor conditioning responses to fructose. In the first experiment, ad-libitum fed mice were given a series of 2-day, two-bottle preference tests between 8% fructose and a more preferred, but non-nutritive 0.1% sucralose +0.1% saccharin (S+S) solution (tests 1 & 4), and fructose or S+S versus water (tests 2 and 3). In test 1, SWR mice preferred S+S to fructose, and in tests 2 and 3, they preferred both sweeteners to water. In test 4, SWR mice switched their preference and consumed more fructose than S+S. In contrast, ad-libitum fed BALB/c mice strongly preferred S+S to fructose in both tests 1 and 4, although they preferred both sweeteners to water in tests 2 and 3. Food-restricted BALB/c mice also preferred the non-nutritive S+S to fructose in tests 1 and 4. The experience induced fructose preference reversal observed in SWR, but not BALB/c mice indicates that fructose has a post-oral reinforcing effect in SWR mice as in FVB mice. Because B6 and FVB mice prefer glucose to fructose based on the post-oral actions of the two sugars, the second experiment compared the preferences of SWR and BALB/c mice for 8% glucose and fructose solutions. Ad-libitum fed and food restricted SWR mice strongly preferred glucose to fructose. In contrast, ad libitum fed BALB/c mice were indifferent to the sugars, perhaps because of their overall low intakes. Food-restricted BALB/c mice, however, strongly preferred glucose. These findings indicate that SWR and BALB/c mice differ in their preference response to the post-oral actions of fructose. PMID- 26485293 TI - Combined parental obesity augments single-parent obesity effects on hypothalamus inflammation, leptin signaling (JAK/STAT), hyperphagia, and obesity in the adult mice offspring. AB - We aimed to evaluate the effects of maternal and/or paternal obesity on offspring body mass, leptin signaling, appetite-regulating neurotransmitters and local inflammatory markers. C57BL/6 mice received standard chow (SC, lean groups) or high-fat diet (HF, obese groups) starting from one month of age. At three months, HF mice became obese relative to SC mice. They were then mated as follows: lean mother and lean father, lean mother and obese father, obese mother and lean father, and obese mother and obese father. The offspring received the SC diet from weaning until three months of age, when they were sacrificed. In the offspring, paternal obesity did not lead to changes in the Janus kinase (JAK)/signal transducer and activation of the transcription (STAT) pathway or feeding behavior but did induce hypothalamic inflammation. On the other hand, maternal obesity resulted in increased weight gain, hyperleptinemia, decreased leptin OBRb receptor expression, JAK/STAT pathway impairment, and increased SOCS3 signaling in the offspring. In addition, maternal obesity elevated inflammatory markers and altered NPY and POMC expression in the hypothalamus. Interestingly, combined parental obesity exacerbated the deleterious outcomes compared to single parent obesity. In conclusion, while maternal obesity is known to program metabolic changes and obesity in offspring, the current study demonstrated that obese fathers induce hypothalamus inflammation in offspring, which may contribute to the development of metabolic syndromes in adulthood. PMID- 26485294 TI - Operant licking for intragastric sugar infusions: Differential reinforcing actions of glucose, sucrose and fructose in mice. AB - Intragastric (IG) flavor conditioning studies in rodents indicate that isocaloric sugar infusions differ in their reinforcing actions, with glucose and sucrose more potent than fructose. Here we determined if the sugars also differ in their ability to maintain operant self-administration by licking an empty spout for IG infusions. Food-restricted C57BL/6J mice were trained 1 h/day to lick a food baited spout, which triggered IG infusions of 16% sucrose. In testing, the mice licked an empty spout, which triggered IG infusions of different sugars. Mice shifted from sucrose to 16% glucose increased dry licking, whereas mice shifted to 16% fructose rapidly reduced licking to low levels. Other mice shifted from sucrose to IG water reduced licking more slowly but reached the same low levels. Thus IG fructose, like water, is not reinforcing to hungry mice. The more rapid decline in licking induced by fructose may be due to the sugar's satiating effects. Further tests revealed that the Glucose mice increased their dry licking when shifted from 16% to 8% glucose, and reduced their dry licking when shifted to 32% glucose. This may reflect caloric regulation and/or differences in satiation. The Glucose mice did not maintain caloric intake when tested with different sugars. They self-infused less sugar when shifted from 16% glucose to 16% sucrose, and even more so when shifted to 16% fructose. Reduced sucrose self administration may occur because the fructose component of the disaccharide reduces its reinforcing potency. FVB mice also reduced operant licking when tested with 16% fructose, yet learned to prefer a flavor paired with IG fructose. These data indicate that sugars differ substantially in their ability to support IG self-administration and flavor preference learning. The same post-oral reinforcement process appears to mediate operant licking and flavor learning, although flavor learning provides a more sensitive measure of sugar reinforcement. PMID- 26485295 TI - Chitosan oligosaccharide based Gd-DTPA complex as a potential bimodal magnetic resonance imaging contrast agent. AB - A new gadolinium diethylenetriamine pentaacetic acid (DTPA) complex (Gd-DTPA DMABA-CS11) as a potential bimodal magnetic resonance imaging (MRI) contrast agent with fluorescence was synthesized. It was synthesized by the incorporation of 4-dimethylaminobenzaldehyde (DMABA) and chitosan oligosaccharide (CSn; n=11) with low polydispersity index to DTPA anhydride and then chelated with gadolinium chloride. The structure was characterized by Fourier transform infrared (FTIR), (1)H NMR, elemental analysis and size exclusion chromatography (SEC). MRI measurements in vitro were evaluated. The results indicated that Gd-DTPA-DMABA CS11 provided higher molar longitudinal relaxivity (r1) (12.95mM(-1).s(-1)) than that of commercial Gd-DTPA (3.63mM(-1).s(-1)) at 0.5T. Gd-DTPA-DMABA-CS11 also emitted fluorescence, and the intensity was much stronger than that of Gd-DTPA. Therefore, it can be meanwhile used in fluorescent imaging for improving the sensitivity in clinic diagnosis. Gd-DTPA-DMABA-CS11 as a potential contrast agent is preliminarily stable in vitro. The results of thermodynamic action between Gd DTPA-DMABA-CS11 and bovine serum albumin (BSA) illustrated that the binding process was exothermic and spontaneous, and the main force was van der Waals' interaction and hydrogen bond. The preliminary study suggested that Gd-DTPA-DMABA CS11 could be used in both magnetic resonance and fluorescent imaging as a promising bimodal contrast agent. PMID- 26485296 TI - Influenza Illness among Case-Patients Hospitalized for Suspected Dengue, El Salvador, 2012. AB - We estimate the proportion of patients hospitalized for suspected dengue that tested positive for influenza virus in El Salvador during the 2012 influenza season. We tested specimens from 321 hospitalized patients: 198 patients with SARI and 123 patients with suspected dengue. Among 121 hospitalized suspected dengue (two co-infected excluded) patients, 28% tested positive for dengue and 19% positive for influenza; among 35 with suspected dengue and respiratory symptoms, 14% were positive for dengue and 39% positive for influenza. One percent presented co-infection between influenza and dengue. Clinicians should consider the diagnosis of influenza among patients with suspected dengue during the influenza season. PMID- 26485297 TI - Olanzapine or chlorpromazine plus lithium in first episode psychotic mania: An 8 week randomised controlled trial. AB - BACKGROUND: Treatment strategies for mental disorders may vary according to illness stage. However no data currently exist to guide treatment in first episode psychotic mania. The aim of this study was to compare the safety and efficacy profile of chlorpromazine and olanzapine, as add-on to lithium, in patients with a first episode of psychotic mania, expecting better safety profile and adherence to olanzapine but similar efficacy for both treatments. METHODS: Data from 83 patients were collected in an 8-week randomised controlled trial on clinical variables, side effects, vital signs, and weight. Analyses of treatment differences over time were based on intent-to-treat principles. Kaplan-Meier estimated survival curves were used to analyse time-to-event data and mixed effects models repeated measures analysis of variance were used to determine treatment group differences over time on safety and efficacy measures. RESULTS: Ethics committee approval to delay informed consent procedure until recovery from the acute episode allowed the inclusion of 83 patients highly representative of those treated in the public sector. Contrary to our hypotheses, safety profile of both medications was similar. A signal for higher rate (P=.032) and earlier occurrence (P=.043) of mania remission was observed in the olanzapine group which did not survive correction for multiple comparisons. CONCLUSIONS: Olanzapine and chlorpromazine have a similar safety profile in a uniquely representative cohort of patients with first episode psychotic mania. The possibility for a greater impact of olanzapine on manic symptoms leading to earlier remission of the episode needs exploration in a large sample. PMID- 26485298 TI - Seroprofiling at the Candida albicans protein species level unveils an accurate molecular discriminator for candidemia. AB - Serum antibodies to specific Candida proteins have been reported as potential diagnostic biomarkers for candidemia. However, their diagnostic usefulness at the protein species level has hardly been examined. Using serological proteome analysis, we explored the IgG-antibody responses to Candida albicans protein species in candidemia and control patients. We found that 87 discrete protein species derived from 34 unique proteins were IgG-targets, although only 43 of them were differentially recognized by candidemia and control sera. An increase in the speciation of the immunome, connectivity and modularity of antigenic species co-recognition networks, and heterogeneity of antigenic species recognition patterns was associated with candidemia. IgG antibodies to certain discrete protein species were better predictors of candidemia than those to their corresponding proteins. A molecular discriminator delineated from the combined fingerprints of IgG antibodies to two distinct species of phosphoglycerate kinase and enolase accurately classified candidemia and control patients. These results provide new insight into the anti-Candida IgG-antibody response development in candidemia, and demonstrate that an immunoproteomic signature at the molecular level may be useful for its diagnosis. Our study further highlights the importance of defining pathogen-specific antigens at the chemical and molecular level for their potential application as immunodiagnostic reagents or even vaccine candidates. PMID- 26485299 TI - Comprehensive glycosylation profiling of IgG and IgG-fusion proteins by top-down MS with multiple fragmentation techniques. AB - We employed top- and middle-down analyses with multiple fragmentation techniques including electron transfer dissociation (ETD), electron capture dissociation (ECD), and matrix-assisted laser desorption ionization in-source decay (MALDI ISD) for characterization of a reference monoclonal antibody (mAb) IgG1 and a fusion IgG protein. Fourier transform ion cyclotron resonance (FT-ICR) or high performance liquid chromatography electrospray ionization (HPLC-ESI) on an Orbitrap was employed. These experiments provided a comprehensive view on the protein species; especially for different glycosylation level in these two proteins, which showed good agreement with oligosaccharide profiling. Top- and middle-down MS provided additional information regarding glycosylation sites and different combinational protein species that were not available from oligosaccharide mapping or conventional bottom-up analysis. Finally, incorporating a limited enzymatic digestion by immunoglobulin G-degrading enzyme of Streptococcus pyogene (IdeS) with MALDI-ISD analysis enabled extended sequence coverage of the internal region of protein without pre-fractionation. BIOLOGICAL SIGNIFICANCE: Oligosaccharide profiling together with top- and middle-down methods enabled: 1) detection of heterogeneous glycosylated protein species and sites in intact IgG1 and fusion proteins with high mass accuracy, 2) estimation of relative abundance levels of protein species in the sample, 3) confirmation of the protein termini structural information, and 4) improved sequence coverage by MALDI-ISD analysis for the internal regions of the proteins without sample pre fractionation. PMID- 26485300 TI - The Role of Tourism and Recreation in the Spread of Non-Native Species: A Systematic Review and Meta-Analysis. AB - Managing the pathways by which non-native species are introduced and spread is considered the most effective way of preventing species invasions. Tourism and outdoor recreation involve the frequent congregation of people, vehicles and vessels from geographically diverse areas. They are therefore perceived to be major pathways for the movement of non-native species, and ones that will become increasingly important with the continued growth of these sectors. However, a global assessment of the relationship between tourism activities and the introduction of non-native species-particularly in freshwater and marine environments-is lacking. We conducted a systematic review and meta-analysis to determine the impact of tourism and outdoor recreation on non-native species in terrestrial, marine and freshwater environments. Our results provide quantitative evidence that the abundance and richness of non-native species are significantly higher in sites where tourist activities take place than in control sites. The pattern was consistent across terrestrial, freshwater and marine environments; across a variety of vectors (e.g. horses, hikers, yachts); and across a range of taxonomic groups. These results highlight the need for widespread biosecurity interventions to prevent the inadvertent introduction of invasive non-native species (INNS) as the tourism and outdoor recreation sectors grow. PMID- 26485301 TI - Bacterial Leaf Infiltration Assay for Fine Characterization of Plant Defense Responses using the Arabidopsis thaliana-Pseudomonas syringae Pathosystem. AB - In the absence of specialized mobile immune cells, plants utilize their localized programmed cell death and Systemic Acquired Resistance to defend themselves against pathogen attack. The contribution of a specific Arabidopsis gene to the overall plant immune response can be specifically and quantitatively assessed by assaying the pathogen growth within the infected tissue. For over three decades, the hemibiotrophic bacterium Pseudomonas syringae pv. maculicola ES4326 (Psm ES4326) has been widely applied as the model pathogen to investigate the molecular mechanisms underlying the Arabidopsis immune response. To deliver pathogens into the leaf tissue, multiple inoculation methods have been established, e.g., syringe infiltration, dip inoculation, spray, vacuum infiltration, and flood inoculation. The following protocol describes an optimized syringe infiltration method to deliver virulent Psm ES4326 into leaves of adult soil-grown Arabidopsis plants and accurately screen for enhanced disease susceptibility (EDS) towards this pathogen. In addition, this protocol can be supplemented with multiple pre-treatments to further dissect specific immune defects within different layers of plant defense, including Salicylic Acid (SA) Triggered Immunity (STI) and MAMP-Triggered Immunity (MTI). PMID- 26485302 TI - The More the Better? A Comparison of the Information Sources Used by the Public during Two Infectious Disease Outbreaks. AB - Recent infectious disease outbreaks have resulted in renewed recognition of the importance of risk communication planning and execution to public health control strategies. Key to these efforts is public access to information that is understandable, reliable and meets their needs for informed decision-making on protective health behaviours. Learning from the trends in sources used in previous outbreaks will enable improvements in information access in future outbreaks. Two separate random-digit dialled telephone surveys were conducted in Alberta, Canada, to explore information sources used by the public, together with their perceived usefulness and credibility, during the 2003 Severe Acute Respiratory Syndrome (SARS) epidemic (n = 1209) and 2009-2010 H1N1 pandemic (n = 1206). Traditional mass media were the most used information sources in both surveys. Although use of the Internet increased from 25% during SARS to 56% during H1N1, overall use of social media was not as high as anticipated. Friends and relatives were commonly used as an information source, but were not deemed very useful or credible. Conversely, doctors and health professionals were considered credible, but not consulted as frequently. The use of five or more information sources increased by almost 60% between the SARS and H1N1 surveys. There was a shift to older, more educated and more affluent respondents between the surveys, most likely caused by a decrease in the use of landlines amongst younger Canadians. It was concluded that people are increasingly using multiple sources of health risk information, presumably in a complementary manner. Subsequently, although using online media is important, this should be used to augment rather than replace more traditional information channels. Efforts should be made to improve knowledge transfer to health care professionals and doctors and provide them with opportunities to be more accessible as information sources. Finally, the future use of telephone surveys needs to account for the changing demographics of the respondents accessed through such surveys. PMID- 26485303 TI - Type Six Secretion System of Bordetella bronchiseptica and Adaptive Immune Components Limit Intracellular Survival During Infection. AB - The Type Six Secretion System (T6SS) is required for Bordetella bronchiseptica cytotoxicity, cytokine modulation, infection, and persistence. However, one-third of recently sequenced Bordetella bronchiseptica strains of the predominantly human-associated Complex IV have lost their T6SS through gene deletion or degradation. Since most human B. bronchiseptica infections occur in immunocompromised patients, we determine here whether loss of Type Six Secretion is beneficial to B. bronchiseptica during infection of immunocompromised mice. Infection of mice lacking adaptive immunity (Rag1-/- mice) with a T6SS-deficient mutant results in a hypervirulent phenotype that is characterized by high numbers of intracellular bacteria in systemic organs. In contrast, wild-type B. bronchiseptica kill their eukaryotic cellular hosts via a T6SS-dependent mechanism that prevents survival in systemic organs. High numbers of intracellular bacteria recovered from immunodeficient mice but only low numbers from wild-type mice demonstrates that B. bronchiseptica survival in an intracellular niche is limited by B and T cell responses. Understanding the nature of intracellular survival during infection, and its effects on the generation and function of the host immune response, are important to contain and control the spread of Bordetella-caused disease. PMID- 26485304 TI - Improved Outcomes of Hematopoietic Stem Cell Transplantation in Patients With Infantile Malignant Osteopetrosis Using Fludarabine-Based Conditioning. AB - BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for infantile malignant osteopetrosis (IMO), but is associated with a high incidence of adverse outcomes. In this study, we present our experience with HSCT for IMO patients comparing different types of conditioning regimens. METHODS: Thirty-eight patients with IMO (aged from 1 month to 6 years, median 0.66 years) who underwent allogeneic HSCT from 1983 in our hospital were included in this retrospective study. Fludarabine-based conditioning regimens were used in 26 patients and 12 patients were transplanted using other conditioning regimens. RESULTS: The overall survival after conditioning with fludarabine was 96% (25/26) versus 58% (7/12) for the alternative regimens (P = 0.004), with significantly fewer adverse effects including hypercalcemia and veno-occlusive disease of liver. All patients who survive are clinically well. CONCLUSIONS: We conclude that fludarabine-based conditioning regimens are safe and effective in patients with IMO, improving morbidity and mortality related to HSCT. PMID- 26485306 TI - Erratum: Whole genome and transcriptome sequencing of matched primary and peritoneal metastatic gastric carcinoma. PMID- 26485305 TI - MiR-486 and miR-92a Identified in Circulating HDL Discriminate between Stable and Vulnerable Coronary Artery Disease Patients. AB - Small non-coding microRNAs (miRNAs) are implicated in gene regulation, including those involved in coronary artery disease (CAD). Our aim was to identify whether specific serum miRNAs present in the circulating lipoproteins (Lp) are associated with stable or vulnerable CAD patients. A cardiovascular disease-focused screening array was used to assess miRNAs distribution in sera collected from 95 CAD patients: 30 with stable angina (SA), 39 with unstable angina (UA), 26 at one month after myocardial infarction (MI) and 16 healthy control subjects. We found that miR-486, miR-92a and miR-122 presented the highest expression in CAD sera. These miRNA together with miR-125a, miR-146a and miR-33a were further individually analyzed by TaqMan assays. The results were consistent with PCR array screening data that all of these miRNAs were significantly increased in CAD patients compared to controls. Using a binary logistic regression model, we established that miR-486 and miR-92a in association with some high-density lipoprotein (HDL) components can designate vulnerable CAD patients. Further, all classes of Lp were isolated from sera by density gradient ultracentrifugation. Analysis of the selected miRNAs in each Lp class showed that they were associated mainly with HDL, miR-486 and miR-92a having the highest levels. In UA and MI patients, miR-486 prevailed in HDL2, while miR-92a prevailed in HDL3, and their levels discriminate between stable and vulnerable CAD patients. We identified two circulating miRNAs that in association with some lipid metabolism biomarkers can be used as an additional tool to designate vulnerable CAD patients. PMID- 26485307 TI - Linking mortuary data improves vital statistics on cause of death of children under five years in the Western Cape Province of South Africa. AB - OBJECTIVES: Reducing child mortality requires good information on its causes. Whilst South African vital registration data have improved, the quality of cause of-death data remains inadequate. To improve this, data from death certificates were linked with information from forensic mortuaries in Western Cape Province. METHODS: A local mortality surveillance system was established in 2007 by the Western Cape Health Department to improve data quality. Cause-of-death data were captured from copies of death notification forms collected at Department of Home Affairs Offices. Using unique identifiers, additional forensic mortuary data were linked with mortality surveillance system records. Causes of death were coded to the ICD-10 classification. Causes of death in children under five were compared with those from vital registration data for 2011. RESULTS: Cause-of-death data were markedly improved with additional data from forensic mortuaries. The proportion of ill-defined causes was halved (25-12%), and leading cause rankings changed. Lower respiratory tract infections moved above prematurity to rank first, accounting for 20.8% of deaths and peaking in infants aged 1-3 months. Only 11% of deaths from lower respiratory tract infections occurred in hospital, resulting in 86% being certified in forensic mortuaries. Road traffic deaths increased from 1.1-3.1% (27-75) and homicides from 3 to 28. CONCLUSIONS: The quality and usefulness of cause-of-death information for children in the WC was enhanced by linking mortuary and vital registration data. Given the death profile, interventions are required to prevent and manage LRTI, diarrhoea and injuries and to reduce neonatal deaths. PMID- 26485308 TI - Extraordinarily High Conductivity of Stretchable Fibers of Polyurethane and Silver Nanoflowers. AB - Stretchable conductive composites have received considerable attention recently, and they should have high conductivity and mechanical strength. Here we report highly conductive stretchable fibers synthesized by the scalable wet spinning process using flower-shaped silver nanoparticles with nanodisc-shaped petals (Ag nanoflowers) and polyurethane. An extraordinarily high conductivity (41,245 S cm( 1)) was obtained by Ag nanoflowers, which is 2 orders of magnitude greater than that of fibers synthesized using spherical Ag nanoparticles. This was due to the enhanced surface area and vigorous coalescence of nanodisc-shaped petals during the curing process. There was a trade-off relationship between conductivity and stretchability, and the maximum rupture strain was 776%. An analytical model revealed that the enhanced adhesion between Ag nanoflowers and polyurethane provided a high Young's modulus (731.5 MPa) and ultimate strength (39.6 MPa) of the fibers. The fibers exhibited an elastic property after prestretching, and the resistance change of weft-knitted fabric was negligible up to 200% strain. The fibers with extraordinarily high conductivity, stretchability, and mechanical strength may be useful for wearable electronics applications. PMID- 26485310 TI - Cortical localization of phase and amplitude dynamics predicting access to somatosensory awareness. AB - Neural dynamics leading to conscious sensory perception have remained enigmatic in despite of large interest. Human functional magnetic resonance imaging (fMRI) studies have revealed that a co-activation of sensory and frontoparietal areas is crucial for conscious sensory perception in the several second time-scale of BOLD signal fluctuations. Electrophysiological recordings with magneto- and electroencephalography (MEG and EEG) and intracranial EEG (iEEG) have shown that event related responses (ERs), phase-locking of neuronal activity, and oscillation amplitude modulations in sub-second timescales are greater for consciously perceived than for unperceived stimuli. The cortical sources of ER and oscillation dynamics predicting the conscious perception have, however, remained unclear because these prior studies have utilized MEG/EEG sensor-level analyses or iEEG with limited neuroanatomical coverage. We used a somatosensory detection task, magnetoencephalography (MEG), and cortically constrained source reconstruction to identify the cortical areas where ERs, local poststimulus amplitudes and phase-locking of neuronal activity are predictive of the conscious access of somatosensory information. We show here that strengthened ERs, phase locking to stimulus onset (SL), and induced oscillations amplitude modulations all predicted conscious somatosensory perception, but the most robust and widespread of these was SL that was sustained in low-alpha (6-10 Hz) band. The strength of SL and to a lesser extent that of ER predicted conscious perception in the somatosensory, lateral and medial frontal, posterior parietal, and in the cingulate cortex. These data suggest that a rapid phase-reorganization and concurrent oscillation amplitude modulations in these areas play an instrumental role in the emergence of a conscious percept. PMID- 26485309 TI - Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: Relation to genes regulating histone acetylation and HTT. AB - Huntington's disease (HD) is a fatal neurodegenerative disease characterized by metabolic, cognitive, and motor deficits. HD is caused by an expanded CAG repeat in the first exon of the HTT gene, resulting in an expanded polyglutamine section. Dietary restriction (DR) increases lifespan and ameliorates age-related pathologies, including in a model of HD, but the mechanisms mediating these protective effects are unknown. We report metabolic and behavioral effects of DR in the full-length YAC128 HD mouse model, and associated transcriptional changes in hypothalamus and striatum. DR corrected many effects of the transgene including increased body weight, decreased blood glucose, and impaired motor function. These changes were associated with reduced striatal human (but not mouse) HTT expression, as well as alteration in gene expression regulating histone acetylation modifications, particularly Hdac2. Other mRNAs related to Huntington's pathology in striatal tissue showed significant modulation by the transgene, dietary restriction or both. These results establish a protective role of DR in a transgenic model that contains the complete human HTT gene and for the first time suggest a role for DR in lowering HTT level, which correlates with severity of symptoms. PMID- 26485311 TI - Why is major depression prevalence not changing? AB - BACKGROUND: Increasing provision of treatment should theoretically lead to a decreased burden of major depressive episodes (MDE) in the population. However, there is no evidence yet that this has occurred. Among possible explanations are that: (1) treatment may not be sufficiently accessible, effective or effectively delivered to make a difference at the population level or (2) treatment benefits such as diminished episode duration may be offset by other trends such as increasing episode incidence, or vice versa. METHODS: MDE prevalence has been assessed in a series of national surveys and in a single national longitudinal study in Canada. These studies included a short form version of the Composite International Diagnostic Interview module for major depression. Indicators of incidence and episode duration of MDE were estimated. Meta-regression methods were used to examine trends over time. RESULTS: No evidence of increasing incidence nor of diminishing duration of MDE was found. The analysis failed to uncover evidence that the epidemiology of this condition has been changing. LIMITATIONS: Most studies included in this analysis used an abbreviated interview for MDE which may lack sensitivity and/or specificity. These studies could not address potential benefits of treatment on prevention of suicide. Some potentially offsetting effects could not be assessed, e.g. economic or societal changes. CONCLUSION: These results suggest that more effective efforts to prevent MDE, or to improve the volume or quality of treatment, are necessary to reduced burden of MDE in the population. PMID- 26485312 TI - Dependence of Thermal Conductivity of Carbon Nanopeapods on Filling Ratios of Fullerene Molecules. AB - Focusing on carbon nanopeapods (CNPs), i.e., carbon nanotubes (CNTs) filled with fullerene C60 molecules, the thermal conductivity and its dependence on the filling ratio of C60 molecules have been investigated by equilibrium molecular dynamics simulations. It turns out that the CNP thermal conductivity increases first, reaches its maximum value at filling ratio of 50%, and then decreases with increasing filling ratio. The heat transfer mechanisms were analyzed by the motion of C60 molecules, the mass transfer contribution, the phonon vibrational density of states, and the relative contributions of tube and C60 molecules to the total heat flux. The mass transfer in CNPs is mainly attributed to the rotational and translational motion of C60 molecules in tubes. As the filling ratio is larger than 50%, the axially translational motion of C60 molecules gets more and more restricted with increasing filling ratio. For either the mass transfer contribution to heat transfer or the phonon coupling between the tube wall and C60, the peaking behavior occurs at a filling ratio of 50%, which confirms the corresponding maximum thermal conductivity of CNP. With the filling ratio increasing, the dominating contribution to heat transfer changes from tube wall atoms to fullerene atoms. Their relative contributions almost keep stable when the filling ratio is larger than 50% until it reaches 100%, where the contribution from fullerene atoms suddenly drops because of strong confinement of translational motion of C60 molecules. This work may offer valuable routes for probing heat transport in CNT hybrid structures, and possible device applications. PMID- 26485313 TI - Atomistic Molecular Simulations Suggest a Kinetic Model for Membrane Translocation by Arginine-Rich Peptides. AB - Arginine-rich cell penetrating peptides (ARCPPs) are known to quickly permeate cell membranes through a non-endocytotic pathway. Potential clinical applications of this facility have prompted enormous effort, both experimental and theoretical, to better understand how ARCPPs manage to overcome the prodigious thermodynamic cost of lipid bilayer permeation by these highly charged peptides. In this work we report the results of all-atom simulations, which suggest that a kinetic (rather than thermodynamic) mechanism may explain how ARCPPs are able to achieve this. Our simulations reveal that octaarginine significantly hinders the closing of membrane pores, either individually or via aggregation in the membrane pore, while octalysine (not an ARCPP) lacks this ability. Our proposed mechanism is an alternative to current attempts to explain pore-mediated translocation of ARCPPs. It asserts that ARCPPs need not lower the equilibrium thermodynamic cost of pore formation. Instead, they can achieve rapid bilayer translocation by instead slowing down the kinetics of naturally occurring thermal pores. Linking the pore lifetime to the characteristic time for peptide diffusion out of the pore, ARCPPs are able to cooperatively permeate the membrane pore. PMID- 26485314 TI - Assessing delays in laryngeal cancer treatment. AB - OBJECTIVES/HYPOTHESIS: To see if there has been a decrease in patient delay, professional delay, diagnostic delay, and treatment delay in laryngeal cancer. STUDY DESIGN: Institutional review board-approved retrospective chart review of patients diagnosed with laryngeal cancer. METHODS: Nine hundred sixty-six patients with International Classification of Diseases, Ninth Revision code for laryngeal cancer were identified from 1993 to 2013. Two hundred fifty patients met inclusion criteria. Patients were placed into two groups based on time at presentation to primary care physician, 1993 to 2004 and 2005 to 2013. Patient delay, professional delay, diagnostic delay, and treatment delay were calculated. Statistical analysis was applied using the Student t test and generalized linear model. RESULTS: From 1993 to 2004, patient delay was 88.7 days, professional delay was 40.9 days, diagnosis delay was 33.1 days, and treatment delay was 24.7 days. From 2005 to 2013, patient delay was 119.2 days, professional delay was 37.9 days, diagnosis delay was 23.8 days, and treatment delay was 23.2 days. Comparison using the Student t test demonstrated the difference in patient delay (shorter before 2005) was statistically significant (P = .045), whereas professional delay (P = .269), diagnosis delay (P = .289), and treatment delay (P = .328) did not reveal any significant differences. There was no association between stage at initial diagnosis and days prior to ear, nose, and throat visit (P = .402). CONCLUSIONS: Delays in the presentation of patients to primary care physicians and otolaryngologists have significantly increased in the past 9 years. Earlier referral to otolaryngologists from primary care physicians in high risk patients with voice changes will lead to more prompt diagnosis and treatment of laryngeal cancer. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1612-1615, 2016. PMID- 26485315 TI - Mechanism of Cooperativity and Nonlinear Release Kinetics in Multivalent Dendrimer-Atropine Complexes. AB - Despite extensive studies on drug delivery using multivalent complexation systems, the biophysical basis for release kinetics remains poorly defined. The present study addresses this aspect involved in the complexation of a fifth generation poly(amidoamine) (PAMAM) dendrimer with atropine, an essential antidote used for treating organophosphate poisoning. First, we designed (1)H NMR titration studies for determining the molecular basis of the drug complexation with a glutarate-modified anionic dendrimer. These provide evidence pointing to a combination of electrostatic and hydrophobic interactions as the driving forces for dendrimer complexation with the alkaloid drug molecule. Second, using LC MS/MS spectrometry, we determined the dissociation constants (KD) at steady state and also measured the drug release kinetics of atropine complexes with four negatively charged dendrimer types. Each of these dendrimers has a high payload capacity for up to ~ 100 atropine molecules. However, the affinity of the atropine to the carrier was highly dependent on the drug to dendrimer ratio. Thus, a complex made at a lower loading ratio (<= 0.1) displayed greater atropine affinity (KD ~ MUM) than other complexes prepared at higher ratios (>10), which showed only mM affinity. This negative cooperative variation in affinity is tightly associated with the nonlinear release kinetics observed for each complex in which drug release occurs more slowly at the later time phase at a lower loading ratio. In summary, the present study provides novel insights on the cooperativity as the mechanistic basis for nonlinear release kinetics observed in multivalent carrier systems. PMID- 26485316 TI - Adsorption of ochratoxin A from grape juice by yeast cells immobilised in calcium alginate beads. AB - Grape juice can be easily contaminated with ochratoxin A (OTA), one of the known mycotoxins with the greatest public health significance. Among the different approaches to decontaminate juice from this mycotoxin, microbiological methods proved efficient, inexpensive and safe, particularly the use of yeast or yeast products. To ascertain whether immobilisation of the yeast biomass would lead to successful decontamination, alginate beads encapsulating Candida intermedia yeast cells were used in our experiments to evaluate their OTA-biosorption efficacy. Magnetic calcium alginate beads were also prepared by adding magnetite in the formulation to allow fast removal from the aqueous solution with a magnet. Calcium alginate beads were added to commercial grape juice spiked with 20 MUg/kg OTA and after 48 h of incubation a significant reduction (>80%), of the total OTA content was achieved, while in the subsequent phases (72-120 h) OTA was slowly released into the grape juice by alginate beads. Biosorption properties of alginate-yeast beads were tested in a prototype bioreactor consisting in a glass chromatography column packed with beads, where juice amended with OTA was slowly flowed downstream. The adoption of an interconnected scaled-up bioreactor as an efficient and safe tool to remove traces of OTA from liquid matrices is discussed. PMID- 26485317 TI - Ebola Virus Outbreak Investigation, Sierra Leone, September 28-November 11, 2014. AB - During 2014-2015, an outbreak of Ebola virus disease (EVD) swept across parts of West Africa. The China Mobile Laboratory Testing Team was dispatched to support response efforts; during September 28-November 11, 2014, they conducted PCR testing on samples from 1,635 suspected EVD patients. Of those patients, 50.4% were positive, of whom 84.6% lived within a 3-km zone along main roads connecting rural towns and densely populated cities. The median time from symptom onset to testing was 5 days. At testing, 75.7% of the confirmed patients had fever, and 94.1% reported at least 1 gastrointestinal symptom; all symptoms, except rash and hemorrhage, were more frequent in confirmed than nonconfirmed patients. Virus loads were significantly higher in EVD patients with fever, diarrhea, fatigue, or headache. The case-fatality rate was lower among patients 15-44 years of age and with virus loads of <100,000 RNA copies/mL. These findings are key for optimizing EVD control and treatment measures. PMID- 26485318 TI - Construction of Enantiopure Taxoid and Natural Product-like Scaffolds Using a C-C Bond Cleavage/Arylation Reaction. AB - An approach to construct enantiopure complex natural product-like frameworks, including the first reported synthesis of a C17 oxygenated taxoid scaffold, is presented. A palladium-catalyzed C-C activation/cross-coupling is utilized to access these structures in a short sequence from (+)-carvone; the scope of this reaction is explored. PMID- 26485319 TI - Does exercise increase insulin sensitivity through angiotensin 1-7? PMID- 26485321 TI - Misinterpretation of Anogenital Findings and Misdiagnosis of Child Sexual Abuse: The Role of the Forensic Pathologist. AB - BACKGROUND: The interpretation of anogenital postmortem findings is an issue of main concern, because the nature and appearance of anogenital tissues during the postmortem interval is not widely known by health providers. CASE: An 8-year-old girl died in the hospital 48 hours after hospitalization. On the basis of the atypical anogenital findings, the health care professionals notified the fact to the Public Prosecutor as an alleged child abuse. The forensic pathologist ruled out this possibility, interpreting the anal findings due to physiological postmortem anal alterations and to the insertion of suppositories before death. SUMMARY AND CONCLUSION: Forensic pathological analysis should be included in routine postmortem evaluation in the case of suspected child sexual abuse, because normal postmortem findings could be misinterpreted by physicians, whose sole experience is on the basis of antemortem scenarios. PMID- 26485320 TI - Fertility Preservation in Women with Turner Syndrome: A Comprehensive Review and Practical Guidelines. AB - In this article we review the existing fertility preservation options for women diagnosed with Turner syndrome and provide practical guidelines for the practitioner. Turner syndrome is the most common sex chromosome abnormality in women, occurring in approximately 1 in 2500 live births. Women with Turner syndrome are at extremely high risk for primary ovarian insufficiency and infertility. Although approximately 70%-80% have no spontaneous pubertal development and 90% experience primary amenorrhea, the remainder might possess a small residual of ovarian follicles at birth or early childhood. The present challenge is to identify these women as early in life as is possible, to allow them to benefit from a variety of existing fertility preservation options. To maximize the benefits of fertility preservation, all women with Turner syndrome should be evaluated by an expert as soon as possible in childhood because the vast majority will have their ovarian reserve depleted before adulthood. Cryopreservation of mature oocytes and embryos is a proven fertility preservation approach, and cryopreservation of ovarian tissue is a promising technique with a growing number of live births, but remains investigational. Oocyte cryopreservation has been performed in children with Turner syndrome as young as 13 years of age and ovarian tissue cryopreservation in affected prepubertal children. However, current efficacy of these approaches is unknown in this cohort. For those who have already lost their ovarian reserve, oocyte or embryo donation and adoption are strategies that allow fulfillment of the desire for parenting. For those with Turner syndrome-related cardiac contraindications to pregnancy, use of gestational surrogacy allows the possibility of biological parenting using their own oocytes. Alternatively, gestational surrogacy can serve to carry pregnancy resulting from the use of donor oocytes or embryos, if needed. PMID- 26485322 TI - Enterobius Vermicularis-Associated Pelvic Inflammatory Disease in a Child. AB - BACKGROUND: Enterobius vermicularis is the most highly prevalent intestinal worm in childhood and is generally considered of low pathogenicity. Little is known about the inflammatory complications of the female genital tract induced by E. vermicularis in childhood. CASE: A case of E. vermicularis-associated pelvic inflammatory disease with right salpingitis mimicking acute abdomen due to appendicitis in an 11-year-old girl is presented. CONCLUSION: E. vermicularis related pelvic inflammatory disease should be included in the differential diagnosis of abdominal pain in children. Increased awareness is necessary to avoid an unnecessary surgery and to choose the correct antibiotic treatment. PMID- 26485323 TI - Can history repeat itself? Improved assessment of the best biomarker is the first step. PMID- 26485324 TI - Regulation of neuronal migration, an emerging topic in autism spectrum disorders. AB - Autism spectrum disorders (ASD) encompass a group of neurodevelopmental diseases that demonstrate strong heritability, however, the inheritance is not simple and many genes have been associated with these disorders. ASD is regarded as a neurodevelopmental disorder, and abnormalities at different developmental stages are part of the disease etiology. This review provides a general background on neuronal migration during brain development and discusses recent advancements in the field connecting ASD and aberrant neuronal migration. We propose that neuronal migration impairment may be an important common pathophysiology in autism spectrum disorders (ASD). This review provides a general background on neuronal migration during brain development and discusses recent advancements in the field connecting ASD and aberrant neuronal migration. PMID- 26485325 TI - Landscape simplification filters species traits and drives biotic homogenization. AB - Biodiversity loss can affect the viability of ecosystems by decreasing the ability of communities to respond to environmental change and disturbances. Agricultural intensification is a major driver of biodiversity loss and has multiple components operating at different spatial scales: from in-field management intensity to landscape-scale simplification. Here we show that landscape-level effects dominate functional community composition and can even buffer the effects of in-field management intensification on functional homogenization, and that animal communities in real-world managed landscapes show a unified response (across orders and guilds) to both landscape-scale simplification and in-field intensification. Adults and larvae with specialized feeding habits, species with shorter activity periods and relatively small body sizes are selected against in simplified landscapes with intense in-field management. Our results demonstrate that the diversity of land cover types at the landscape scale is critical for maintaining communities, which are functionally diverse, even in landscapes where in-field management intensity is high. PMID- 26485326 TI - A New Tool for NMR Crystallography: Complete (13)C/(15)N Assignment of Organic Molecules at Natural Isotopic Abundance Using DNP-Enhanced Solid-State NMR. AB - NMR crystallography of organic molecules at natural isotopic abundance (NA) strongly relies on the comparison of assigned experimental and computed NMR chemical shifts. However, a broad applicability of this approach is often hampered by the still limited (1)H resolution and/or difficulties in assigning (13)C and (15)N resonances without the use of structure-based chemical shift calculations. As shown here, such difficulties can be overcome by (13)C-(13)C and for the first time (15)N-(13)C correlation experiments, recorded with the help of dynamic nuclear polarization. We present the complete de novo (13)C and (15)N resonance assignment at NA of a self-assembled 2'-deoxyguanosine derivative presenting two different molecules in the asymmetric crystallographic unit cell. This de novo assignment method is exclusively based on aforementioned correlation spectra and is an important addition to the NMR crystallography approach, rendering firstly (1)H assignment straightforward, and being secondly a prerequisite for distance measurements with solid-state NMR. PMID- 26485327 TI - Characterization of functional properties of Enterococcus faecium strains isolated from human gut. AB - The aim of this work was to characterize the functional properties of Enterococcus faecium strains identified after isolation from human faeces. Of these isolates, strain R13 showed the best resistance to low pH, bile salts, and survival in the simulated in vitro digestion assay, and demonstrated an important level of adhesion to hexadecane as a potential probiotic candidate. Analysis of the antibiotic resistance of E. faecium strains indicated that in general these isolates were sensitive to the tested antibiotics and no strain appeared to be resistant to vancomycin. Examination of the virulence determinants for E. faecium strains demonstrated that all strains contained the virulence genes common in gut and food-originated enterococci, and strain R13 harboured the lowest number of virulence genes. Additionally, no strain contained the genes related to cytolysin metabolism and showed hemolytic activity. The antimicrobial role of E. faecium strains was tested against several pathogens, in which different levels of inhibitory effects were observed, and strain R13 was inhibitory to all tested pathogens. PCR screening of genes encoding enterocin A and B indicated the presence of these genes in E. faecium strains. Preliminary characterization of bacteriocins revealed that their activity was lost after proteolytic enzyme treatments, but no alteration in antimicrobial activity was observed at different pHs (3.5 to 9.5) and after heat treatments. In conclusion, this study revealed the functional characteristics of E. faecium R13 as a gut isolate, and this strain could be developed as a new probiotic after further tests. PMID- 26485330 TI - Correction. PMID- 26485328 TI - A Long-Lived Fe(III)-(Hydroperoxo) Intermediate in the Active H200C Variant of Homoprotocatechuate 2,3-Dioxygenase: Characterization by Mossbauer, Electron Paramagnetic Resonance, and Density Functional Theory Methods. AB - The extradiol-cleaving dioxygenase homoprotocatechuate 2,3-dioxygenase (HPCD) binds substrate homoprotocatechuate (HPCA) and O2 sequentially in adjacent ligand sites of the active site Fe(II). Kinetic and spectroscopic studies of HPCD have elucidated catalytic roles of several active site residues, including the crucial acid-base chemistry of His200. In the present study, reaction of the His200Cys (H200C) variant with native substrate HPCA resulted in a decrease in both kcat and the rate constants for the activation steps following O2 binding by >400 fold. The reaction proceeds to form the correct extradiol product. This slow reaction allowed a long-lived (t1/2 = 1.5 min) intermediate, H200C-HPCAInt1 (Int1), to be trapped. Mossbauer and parallel mode electron paramagnetic resonance (EPR) studies show that Int1 contains an S1 = 5/2 Fe(III) center coupled to an SR = 1/2 radical to give a ground state with total spin S = 2 (J > 40 cm(-1)) in Hexch = JS1.SR. Density functional theory (DFT) property calculations for structural models suggest that Int1 is a (HPCA semiquinone(*))Fe(III)(OOH) complex, in which OOH is protonated at the distal O and the substrate hydroxyls are deprotonated. By combining Mossbauer and EPR data of Int1 with DFT calculations, the orientations of the principal axes of the (57)Fe electric field gradient and the zero-field splitting tensors (D = 1.6 cm( 1), E/D = 0.05) were determined. This information was used to predict hyperfine splittings from bound (17)OOH. DFT reactivity analysis suggests that Int1 can evolve from a ferromagnetically coupled Fe(III)-superoxo precursor by an inner sphere proton-coupled-electron-transfer process. Our spectroscopic and DFT results suggest that a ferric hydroperoxo species is capable of extradiol catalysis. PMID- 26485331 TI - Correction. PMID- 26485332 TI - Correction. PMID- 26485333 TI - Headache in Patients With Pituitary Lesions: A Longitudinal Cohort Study. AB - BACKGROUND: Headache is a presenting feature in 37% to 70% of patients with pituitary tumor. Other pituitary lesions may also present with headache, and together these lesions account for about 20% of all primary brain lesions. Although pituitary lesions have been associated with headache, the exact nature of the relationship remains undefined. It is not always clear whether the presenting headache is an unrelated primary headache, a lesion-induced aggravation of a preexisting primary headache, or a separate secondary headache related to the lesion. OBJECTIVE: To characterize headache in patients referred to a multidisciplinary neuroendocrine clinic with suspected pituitary lesions and to assess changes in headache in those who underwent surgery. METHODS: We used a self-administered survey of headache characteristics completed by patients upon presentation and after any pituitary surgical procedure. RESULTS: One hundred thirty-three participants completed the preoperative questionnaire (response rate of 99%). The overall prevalence of headache was 63%. Compared to patients without headache, the group with headache was more likely to be female (P = .001), younger (P = .001), and to have had a prior headache diagnosis (P < .001). Seventy-two percent of patients reported headache localized to the anterior region of the head. Fifty-one patients with headache underwent transsphenoidal pituitary surgery. Headache was not associated with increased odds of having surgery (odds ratio, 0.90). At 3 months, 81% of surgically treated patients with headache who completed the postoperative questionnaire (21/26) reported improvement or resolution of headaches. No patient who completed the postoperative questionnaire (44/84) reported new or worsened headache. CONCLUSION: Frequent, disabling headaches are common in patients with pituitary lesions referred for neuroendocrine consultation, especially in younger females with a preexisting headache disorder. Surgery in this group was associated with headache improvement or resolution in the majority and was not found to cause or worsen headaches. Suggestions for revision of the International Classification of Headache Disorders diagnostic criteria pertaining to pituitary disorders are supported by these findings. PMID- 26485334 TI - Clostridium difficile Infection After Subarachnoid Hemorrhage: A Nationwide Analysis. AB - BACKGROUND: Clostridium difficile infection (CDI) is an important cause of hospital-acquired morbidity and mortality. OBJECTIVE: To evaluate the incidence of, predictors for, and effects on outcome by CDI after aneurysmal subarachnoid hemorrhage. METHODS: Data were extracted from the Nationwide Inpatient Sample (2002-2011). Patients with subarachnoid hemorrhage who underwent microsurgical or endovascular aneurysm repair were included. Multivariate logistic regression was used to determine the independent predictors of developing CDI. Additional models were constructed to assess the impact of CDI on mortality, length of stay, and discharge disposition. RESULTS: Of the 18 007 patients who were included, 1.9% (n = 346) developed CDI. Patients who developed CDI were significantly older and had more comorbidities (P <= .001). Independent predictors of developing CDI were Medicaid payer status; ventriculostomy; mechanical ventilation; a greater number of noninfectious complications; and the development of a urinary tract infection; pneumonia; meningitis/ventriculitis; and sepsis (all P <= .02). Only 1.5% of patients with CDI required gastrointestinal surgery. Although CDI was not associated with differential mortality, it was associated with increased adjusted odds of a hospital stay of at least 24 days (odds ratio, 3.16; 95% confidence interval, 2.32-4.29; P < .001) and of a nonroutine hospital discharge (odds ratio, 1.64; 95% confidence interval, 1.13-2.39; P = .01). CONCLUSION: In this nationwide analysis, both infectious and noninfectious complications, as well as ventriculostomy, mechanical ventilation, and insurance status were independent predictors of CDI. Although CDI was not associated with mortality, it was associated with a longer hospital stay and nonroutine hospital discharge. PMID- 26485337 TI - Branched-chain amino acids as biomarkers in diabetes. AB - PURPOSE OF REVIEW: Numerous human studies have consistently demonstrated that concentrations of branched-chain amino acids (BCAAs) in plasma and urine are associated with insulin resistance and have the quality to predict diabetes development. However, it is not known how altered BCAA levels link to insulin action and diabetes. This review addresses some recent findings in BCAA metabolism and discusses their role as reporter molecules of insulin sensitivity and diabetes and their possible contribution to disease progression. RECENT FINDINGS: Changes in plasma and urine levels result mainly from altered metabolism in tissues and recent studies have thus focused on organ-specific changes in BCAA handling using animal models and human tissue samples. A decreased mitochondrial oxidation has been demonstrated in peripheral tissues and that was shown to be associated with an increased inflammatory tone and changes in adipokine levels (adiponectin and leptin). These changes appear already before insulin resistance is established. Key findings demonstrating the discordance between changes in BCAA and insulin resistance are derived from studies using insulin sensitizers and from data collected in patients undergoing Roux-en-Y bypass bariatric surgery. Intermediates derived from BCAA breakdown rather than BCAA itself were recently proposed to contribute to the development of insulin resistance and studies now explore the biomarker qualities of these metabolites. SUMMARY: Understanding the mechanisms and putative causalities in the alterations in BCAA levels as found in obesity, metabolic syndrome and diabetes is crucial for any intervention options but also for the use of BCAA and derivatives as biomarkers in clinical routine. PMID- 26485336 TI - Nutrients and ageing: what can we learn about ageing interactions from animal biology? AB - PURPOSE OF REVIEW: Many prevalent clinical conditions, such as chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary, and cardiovascular disease associate with features of premature ageing, such as muscle wasting, hypogonadism, osteoporosis, and arteriosclerosis. Studies on various animal models have shown that caloric restriction prolongs lifespan. Studies of animals with unusual long or short life for their body size may also contribute to better understanding of ageing processes. The aim of the present article is to review what we can learn about nutritional modulations and ageing interactions from animal biology. RECENT FINDINGS: Caloric restriction is a powerful intervention that increases longevity in animals ranging from short-lived species, such as worms and flies, to primates. As long-term studies on caloric restriction are not feasible to conduct in humans, much interest has focused on the impact of caloric restriction mimetics, such as resveratrol, on ageing processes. Recent data from studies on the long-lived naked mole rat have provided important novel information on metabolic alterations and antioxidative defense mechanisms that characterize longevity. SUMMARY: Better understanding of the biology of exceptionally long-lived animals will contribute to better understanding of ageing processes and novel interventions to extend lifespan also in humans. PMID- 26485338 TI - Prescription Stimulant Use and Hospitalization for Psychosis or Mania: A Population-Based Study. AB - Small studies suggest that prescription stimulants can precipitate psychosis and mania. We conducted a population-based case-crossover study to examine whether hospitalization for psychosis or mania was associated with initiation of stimulant therapy. Between October 1, 1999 and March 31, 2013, we studied 12,856 young people who received a stimulant prescription and were subsequently hospitalized for psychosis or mania. Of these, 183 commenced treatment during 1 of 2 prespecified 60-day intervals (defined as the "risk interval" and "control interval," respectively) prior to admission. We found that stimulant initiation was associated with an increased risk of hospitalization for psychosis or mania in the subsequent 60 days (odds ratio, 1.86; 95% confidence interval, 1.39-2.56). The risk was marginally higher in patients treated with antipsychotic drugs (odds ratio, 2.06; 95% confidence interval, 1.38-3.28), but remained in patients with no such history (odds ratio, 1.66; 95% confidence interval, 1.09-2.66). One third of subjects received another stimulant prescription after hospital discharge. Of these, 45% were readmitted with psychosis or mania shortly thereafter. We conclude that initiation of prescription stimulants is associated with an increased risk of hospitalization for psychosis or mania. Resumption of therapy is common, which may reflect a lack of awareness of the potential causative role of these drugs. PMID- 26485339 TI - Incidence of Oculogyric Crisis and Long-Term Outcomes With Second-Generation Antipsychotics in a First-Episode Psychosis Program. AB - Oculogyric crisis (OGC) is an often recurrent dystonic adverse effect of antipsychotic treatment characterized by a sustained fixed upward gaze lasting minutes to hours. The risk of OGC has not been established. We prospectively estimated the incidence rate of OGC in an early intervention service for psychosis and provided details regarding the antipsychotics implicated, clinical presentation, and long-term outcomes of OGC. The Nova Scotia Early Psychosis Program provides comprehensive, team-based care to youth and young adults with schizophrenia spectrum disorder. For 6 years (April 2008 to March 2014), 452 new patients were admitted to the program and participated in an individualized program of care. Eight patients (4 females; mean age, 19.8 years) developed recurrent episodes of OGC after 3 months to 2 years of treatment with 1 or more second-generation antipsychotics, yielding an incidence rate of 1.8% (95% confidence interval, 0.9%-3.4%). Risperidone or olanzapine (alone or in combination with a second antipsychotic) seemed causative in each case. Also implicated in the onset or recurrence of oculogyric episodes were ziprasidone, quetiapine, clozapine, aripiprazole, and the first-generation antipsychotic loxapine. Follow-up ranged between 2 and 7 years. Episodes stopped after switching antipsychotic treatment in 4 cases and after stopping antipsychotic treatment in 2 cases. In the other 2 cases, recurrences were ongoing at last follow-up 2 and 6 years after onset with antipsychotic treatment continuing. We observed a high rate of tardive-onset, recurrent, and potentially chronic ocular dystonias in patients with first-episode psychosis caused by the use of second generation antipsychotics. PMID- 26485340 TI - Neurocognitive Recovery After Hospital-Treated Deliberate Self-Poisoning With Central Nervous System Depressant Drugs: A Longitudinal Cohort Study. AB - Hospital-treated deliberate self-poisoning (DSP) by central nervous system depressant drugs (CNS-D) has been associated with impairments in cognitive and psychomotor functions at the time of discharge. We aimed to replicate this finding and to compare recovery in the first month after discharge for CNS-D and CNS nondepressant drug ingestions. We also examined a series of multivariate explanatory models of recovery of neurocognitive outcomes over time. The CNS-D group was impaired at discharge compared with the CNS-nondepressant group in cognitive flexibility, cognitive efficiency, and working memory. There were no significant differences at discharge in visual attention, processing speed, visuomotor speed, or inhibition speed. Both groups improved in the latter measures over 1 month of follow-up. However, the CNS-D group's recovery was significantly slower for key neurocognitive domains underlying driving in complex traffic situations, namely, cognitive flexibility, cognitive efficiency, and working memory. Patients discharged after DSP with CNS-D drugs have impairments of some critical cognitive functions that may require up to 1 month to recover. Although more pre- than post-DSP variables were retained as explanatory models of neurocognitive performance overall, recovery over time could not be explained by any one of the measured covariates. Tests of cognitive flexibility could be used in clinical settings as a proxy measure for recovery of driving ability. Regulatory authorities should also consider the implications of these results for the period of nondriving advised after ingestion of CNS-D in overdose. Future research, with adequate sample size, should examine contributions of other variables to the pattern of recovery over time. PMID- 26485341 TI - Agents in the preclinical development stage for non-small cell lung cancer. AB - Despite recent advancements in identifying distinct molecular subtypes with driver oncogenes and advances in developing targeted treatments such as epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors, current therapeutic approaches for tumors with no driver mutation have achieved a plateau of effectiveness. Thus, the overall outlook of lung cancer survival for most patients remains dismal. Moreover, the inevitable acquisition of resistance to targeted therapies has prompted significant efforts to develop second-generation inhibitors. In recent years, several agents for targeted therapy of lung cancers are rapidly migrating from bench to bedside and multiple small molecule inhibitors with activity against distinct receptors, genes or molecular pathways have been developed. PMID- 26485342 TI - Ethylene production in Botrytis cinerea- and oligogalacturonide-induced immunity requires calcium-dependent protein kinases. AB - Plant immunity against pathogens is achieved through rapid activation of defense responses that occur upon sensing of microbe- or damage-associated molecular patterns, respectively referred to as MAMPs and DAMPs. Oligogalacturonides (OGs), linear fragments derived from homogalacturonan hydrolysis by pathogen-secreted cell wall-degrading enzymes, and flg22, a 22-amino acid peptide derived from the bacterial flagellin, represent prototypical DAMPs and MAMPs, respectively. Both types of molecules induce protection against infections. In plants, like in animals, calcium is a second messenger that mediates responses to biotic stresses by activating calcium-binding proteins. Here we show that simultaneous loss of calcium-dependent protein kinases CPK5, CPK6 and CPK11 affects Arabidopsis thaliana basal as well as elicitor- induced resistance to the necrotroph Botrytis cinerea, by affecting pathogen-induced ethylene production and accumulation of the ethylene biosynthetic enzymes 1-aminocyclopropane-1-carboxylic acid (ACC) synthase 2 (ACS2) and 6 (ACS6). Moreover, ethylene signaling contributes to OG triggered immunity activation, and lack of CPK5, CPK6 and CPK11 affects the duration of OG- and flg22-induced gene expression, indicating that these kinases are shared elements of both DAMP and MAMP signaling pathways. PMID- 26485343 TI - Jaw disorders in the pediatric population. AB - PURPOSE: This article will review the etiology, risk factors, history, and physical assessment of temporomandibular joint disorders (TMDs). In particular, this article discusses the role of the pediatric provider in diagnosing and beginning the initial treatment of TMDs, as well as the appropriate treatment plans. It also reveals some of the controversies regarding etiology and treatment of TMDs, as well as the paucity of research specific to TMDs in pediatrics. DATA SOURCES: A computerized search in PubMed and Ovid Medline, from 2006 to 2012, was conducted. A few seminal articles were included that were published before 2006. Hand searching was also performed, which included a few articles between 2012 and 2015. CONCLUSIONS: Although TMDs are mostly found in adults, it is also a finding in pediatrics, which increases in prevalence during adolescence. More research specific to pediatric patients with TMDs needs to be conducted so that pediatric specific care can be provided. IMPLICATIONS FOR PRACTICE: TMD is a condition found in the pediatric population, and it is important for providers to take an adequate history and physical examination that incorporates the temporomandibular joint (TMJ) and muscles of mastication. It is also critical that providers begin initial education and management, followed by appropriate referrals. PMID- 26485344 TI - Pylephlebitis: case report and literature review. AB - We present the case of a 50-year-old man who comes to the emergency department of Dos de Mayo Hospital, Lima, Peru, with fever, abdominal pain, diarrhea and jaundice. An intestinal infection arises as initial diagnosis. He is referred to the area of Internal Medicine where various laboratory tests and imaging studies were conducted, including an abdominal computerized tomography scan. The scan confirmed the diagnosis of pylephlebitis; treatment with antibiotics and anticoagulant therapy was immediately established. Response and evolution were favorable. PMID- 26485345 TI - A Lower PBMC Estrogen Receptor alpha Gene Expression in Chronic Hepatitis B Is Associated with a Sustained Virological Response to Pegylated Interferon. AB - The aim of this study was to investigate possible involvement of estrogen receptor alpha (ESR1) in responding to pegylated interferon alpha-2a (PEG IFNalpha-2a) therapy in chronic hepatitis B (CHB) patients. A total of 106 HBeAg positive patients and 52 healthy controls were enrolled into this study. ESR1 messenger RNA (mRNA) expression in peripheral blood mononuclear cells was quantified at the baseline, during treatment (weeks 4 and 12), and at the end of treatment (week 48) by real-time reverse transcriptase-polymerase chain reaction assay (RT-PCR). The sequence polymorphism of ESR1 (rs2077647, rs2234693, rs9340799, and rs9322354) was analyzed using the Sequenom MassARRAY Analyzer. Our results suggested that the most accurate prediction of nonresponder in female patients was the baseline alanine aminotransferase (ALT) in combination with ESR1 expression at week 4 of treatment (area under the receiver operating characteristic curve [AUC] = 0.908). Combining the baseline ALT with ESR1 mRNA expression at the end of treatment showed the best prediction of sustained virological response in male patients (AUC = 0.818). Internal validation was assessed by bootstrap cross-validation. These results may have clinical relevance and warrant future validation in studies with larger cohorts. PMID- 26485346 TI - Are RIG-1 and MDA5 Expressions Associated with Chronic HBV Infection? AB - Melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene 1 (RIG-1) as the pattern recognition receptors play important roles in viral mRNA recognition. Chronic HBV-infected (CHB) patients are unable to properly respond to hepatitis B virus (HBV). Therefore, the aim of the present study was to evaluate the mRNA levels of MDA5 and RIG-1 in the peripheral blood immune cells of CHB patients in comparison to healthy controls. In this cross-sectional study, the mRNA levels of MDA5 and RIG-1 were examined in 60 CHB patients and 60 healthy controls using the real-time polymerase chain reaction (PCR) technique. Our results showed that mRNA levels of MDA5 and RIG-1 were significantly decreased and increased, respectively, in CHB patients when compared to healthy controls. Our results also revealed that mRNA levels of MDA5 and RIG-1 were not altered among CHB patients with various states of e-antigen of hepatitis B and HBV-DNA viral loads. According to the results presented here, it may be concluded that downregulation of MDA5 may be a responsible mechanism from several reasons, which leads to HBV persistence in CHB patients. PMID- 26485348 TI - Ill-posed problem and regularization in reconstruction of radiobiological parameters from serial tumor imaging data. AB - The main objective of this article is to improve the stability of reconstruction algorithms for estimation of radiobiological parameters using serial tumor imaging data acquired during radiation therapy. Serial images of tumor response to radiation therapy represent a complex summation of several exponential processes as treatment induced cell inactivation, tumor growth rates, and the rate of cell loss. Accurate assessment of treatment response would require separation of these processes because they define radiobiological determinants of treatment response and, correspondingly, tumor control probability. However, the estimation of radiobiological parameters using imaging data can be considered an inverse ill-posed problem because a sum of several exponentials would produce the Fredholm integral equation of the first kind which is ill posed. Therefore, the stability of reconstruction of radiobiological parameters presents a problem even for the simplest models of tumor response. To study stability of the parameter reconstruction problem, we used a set of serial CT imaging data for head and neck cancer and a simplest case of a two-level cell population model of tumor response. Inverse reconstruction was performed using a simulated annealing algorithm to minimize a least squared objective function. Results show that the reconstructed values of cell surviving fractions and cell doubling time exhibit significant nonphysical fluctuations if no stabilization algorithms are applied. However, after applying a stabilization algorithm based on variational regularization, the reconstruction produces statistical distributions for survival fractions and doubling time that are comparable to published in vitro data. This algorithm is an advance over our previous work where only cell surviving fractions were reconstructed. We conclude that variational regularization allows for an increase in the number of free parameters in our model which enables development of more-advanced parameter reconstruction algorithms. PMID- 26485347 TI - Patterns of IgE sensitization in house dust mite-allergic patients: implications for allergen immunotherapy. AB - BACKGROUND: Understanding patterns of IgE sensitization in Dermatophagoides allergic patients living in various geographical areas is necessary to design a product suitable for worldwide allergen immunotherapy (AIT). METHODS: Using a HIFI Allergy customized microarray assay, IgEs specific for 12 purified allergens from Dermatophagoides pteronyssinus or D. farinae were assessed in sera from 1302 house dust mite (HDM)-allergic patients living in various areas. Comprehensive mass spectrometric (MS) analyses were conducted to characterize HDM extracts, as well as purified bodies and feces. RESULTS: Patterns of IgE reactivity to HDM allergens are comparable in all cohorts of patients analyzed, encompassing adults and 5- to 17-year-old children, as well as American, Canadian, European, and Japanese patients. Overall, >70% and >80% of HDM-allergic patients are sensitized to group 1 and group 2 allergens, respectively, from D. pteronyssinus and/or D. farinae species. Furthermore, 20-47% of patients also have IgEs to allergens from groups 4, 5, 7, 13, 15, 21, and 23. All patients have IgEs to allergens present in mite bodies and feces. MS-based analyses confirmed the presence of mite allergens recorded by IUIS in D. pteronyssinus and D. farinae extracts, with groups 2, 8, 10, 11, 14, and 20 prominent in bodies and groups 1, 6, 18, and 23 well represented in feces. CONCLUSIONS: Mite-specific AIT should rely upon a mixture of D. pteronyssinus and D. farinae extracts, manufactured from both feces and bodies. Such a combination is appropriate to treat children and adult Dermatophagoides-allergic patients from Asia, Europe, and North America. PMID- 26485349 TI - Characterizing blood-brain barrier perturbations after exposure to human triglyceride-rich lipoprotein lipolysis products using MRI in a rat model. AB - PURPOSE: Previous studies indicated hyperlipidemia may be a risk factor for Alzheimer's disease, but the contributions of postprandial triglyceride-rich lipoprotein (TGRL) are not known. In this study, changes in blood-brain barrier diffusional transport following exposure to human TGRL lipolysis products were studied using MRI in a rat model. METHODS: Male Sprague-Dawley rats (~180-250 g) received an i.v. injection of lipoprotein lipase (LpL)-hydrolyzed TGRL (n = 8, plasma concentration ~ 150 mg human TGRL/dL). Controls received i.v. injection of either saline (n = 6) or LpL only (n = 6). The (1) H longitudinal relaxation rate R1 = 1/T1 was measured over 18 min using a rapid-acquired refocus-echo (RARE) sequence after each of three injections of the contrast agent Gd-DTPA. Patlak plots were generated for each pixel yielding blood-to-brain transfer coefficients, Ki , chosen for best fit to impermeable, uni-directional influx or bi-directional flux models using the F-test. RESULTS: Analysis from a 2-mm slice, 2-mm rostral to the bregma showed a 275% increase of mean Ki during the first 20 min after infusion of human TGRL lipolysis product that differed significantly compared with saline and LpL controls. This difference disappeared by 40 min mark. CONCLUSION: These results suggest human TGRL lipolysis products can lead to a transient increase in rat BBB permeability. Magn Reson Med 76:1246-1251, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 26485350 TI - A Simple Model to Estimate Plantarflexor Muscle-Tendon Mechanics and Energetics During Walking With Elastic Ankle Exoskeletons. AB - GOAL: A recent experiment demonstrated that when humans wear unpowered elastic ankle exoskeletons with intermediate spring stiffness, they can reduce their metabolic energy cost to walk by ~7%. Springs that are too compliant or too stiff have little benefit. The purpose of this study was to use modeling and simulation to explore the muscle-level mechanisms for the "sweet spot" in stiffness during exoskeleton assisted walking. METHODS: We developed a simple lumped uniarticular musculoskeletal model of the plantarflexors operating in parallel with an elastic "exo-tendon." Using an inverse approach with constrained kinematics and kinetics, we rapidly simulated human walking over a range of exoskeleton stiffness values and examined the underlying neuromechanics and energetics of the biological plantarflexors. RESULTS: Stiffer ankle exoskeleton springs resulted in larger decreases in plantarflexor muscle forces, activations, and metabolic energy consumption. However, in the process of unloading the compliant biological muscle tendon unit, the muscle fascicles experienced larger excursions that negatively impacted series elastic element recoil that is characteristic of a tuned "catapult mechanism." CONCLUSION: The combination of disrupted muscle-tendon dynamics and the need to produce compensatory forces/moments to maintain overall net ankle moment invariance could explain the "sweet spot" in metabolic performance at intermediate ankle exoskeleton stiffness. Future work will aim to provide experimental evidence to support the model predictions presented here using ultrasound imaging of muscle-level dynamics during walking with elastic ankle exoskeletons. SIGNIFICANCE: Engineers must account for the muscle-level effects of exoskeleton designs in order to achieve maximal performance objectives. PMID- 26485351 TI - Patient-Specific Oscillometric Blood Pressure Measurement. AB - OBJECTIVE: Most automatic cuff blood pressure (BP) measurement devices are based on oscillometry. These devices estimate BP from the envelopes of the cuff pressure oscillations using fixed ratios. The values of the fixed ratios represent population averages, so the devices may only be accurate in subjects with normal BP levels. The objective was to develop and demonstrate the validity of a patient-specific oscillometric BP measurement method. METHODS: The idea of the developed method was to represent the cuff pressure oscillation envelopes with a physiologic model, and then estimate the patient-specific parameters of the model, which includes BP levels, by optimally fitting it to the envelopes. The method was investigated against gold standard reference BP measurements from 57 patients with widely varying pulse pressures. A portion of the data was used to optimize the patient-specific method and a fixed-ratio method, while the remaining data were used to test these methods and a current office device. RESULTS: The patient-specific method yielded BP root-mean-square-errors ranging from 6.0 to 9.3 mmHg. On an average, these errors were nearly 40% lower than the errors of each existing method. CONCLUSION: The patient-specific method may improve automatic cuff BP measurement accuracy. SIGNIFICANCE: A patient-specific oscillometric BP measurement method was proposed and shown to be more accurate than the conventional method and a current device. PMID- 26485352 TI - Design and Control of a Mechatronic Tracheostomy Tube for Automated Tracheal Suctioning. AB - GOAL: Mechanical ventilation is required to aid patients with breathing difficulty to breathe more comfortably. A tracheostomy tube inserted through an opening in the patient neck into the trachea is connected to a ventilator for suctioning. Currently, nurses spend millions of person-hours yearly to perform this task. To save significant person-hours, an automated mechatronic tracheostomy system is needed. This system allows for relieving nurses and other carers from the millions of person-hours spent yearly on tracheal suctioning. In addition, it will result in huge healthcare cost savings. METHODS: We introduce a novel mechatronic tracheostomy system including the development of a long suction catheter, automatic suctioning mechanisms, and relevant control approaches to perform tracheal suctioning automatically. To stop the catheter at a desired position, two approaches are introduced: 1) Based on the known travel length of the catheter tip; 2) Based on a new sensing device integrated at the catheter tip. It is known that backlash nonlinearity between the suction catheter and its conduit as well as in the gear system of the actuator are unavoidable. They cause difficulties to control the exact position of the catheter tip. For the former case, we develop an approximate model of backlash and a direct inverse scheme to enhance the system performances. The scheme does not require any complex inversions of the backlash model and allows easy implementations. For the latter case, a new sensing device integrated into the suction catheter tip is developed and backlash compensation controls are avoided. RESULTS: Automated suctioning validations are successfully carried out on the proposed experimental system. Comparisons and discussions are also introduced. SIGNIFICANCE: The results demonstrate a significant contribution and potential benefits to the mechanical ventilation areas. PMID- 26485353 TI - Multiatlas-Based Segmentation Editing With Interaction-Guided Patch Selection and Label Fusion. AB - We propose a novel multiatlas-based segmentation method to address the segmentation editing scenario, where an incomplete segmentation is given along with a set of existing reference label images (used as atlases). Unlike previous multiatlas-based methods, which depend solely on appearance features, we incorporate interaction-guided constraints to find appropriate atlas label patches in the reference label set and derive their weights for label fusion. Specifically, user interactions provided on the erroneous parts are first divided into multiple local combinations. For each combination, the atlas label patches well-matched with both interactions and the previous segmentation are identified. Then, the segmentation is updated through the voxelwise label fusion of selected atlas label patches with their weights derived from the distances of each underlying voxel to the interactions. Since the atlas label patches well-matched with different local combinations are used in the fusion step, our method can consider various local shape variations during the segmentation update, even with only limited atlas label images and user interactions. Besides, since our method does not depend on either image appearance or sophisticated learning steps, it can be easily applied to general editing problems. To demonstrate the generality of our method, we apply it to editing segmentations of CT prostate, CT brainstem, and MR hippocampus, respectively. Experimental results show that our method outperforms existing editing methods in all three datasets. PMID- 26485354 TI - A Circuit Model of Real Time Human Body Hydration. AB - Changes in human body hydration leading to excess fluid losses or overload affects the body fluid's ability to provide the necessary support for healthy living. We propose a time-dependent circuit model of real-time human body hydration, which models the human body tissue as a signal transmission medium. The circuit model predicts the attenuation of a propagating electrical signal. Hydration rates are modeled by a time constant tau, which characterizes the individual specific metabolic function of the body part measured. We define a surrogate human body anthropometric parameter theta by the muscle-fat ratio and comparing it with the body mass index (BMI), we find theoretically, the rate of hydration varying from 1.73 dB/min, for high theta and low tau to 0.05 dB/min for low theta and high tau. We compare these theoretical values with empirical measurements and show that real-time changes in human body hydration can be observed by measuring signal attenuation. We took empirical measurements using a vector network analyzer and obtained different hydration rates for various BMI, ranging from 0.6 dB/min for 22.7 [Formula: see text] down to 0.04 dB/min for 41.2 [Formula: see text]. We conclude that the galvanic coupling circuit model can predict changes in the volume of the body fluid, which are essential in diagnosing and monitoring treatment of body fluid disorder. Individuals with high BMI would have higher time-dependent biological characteristic, lower metabolic rate, and lower rate of hydration. PMID- 26485355 TI - FDA funds research to help guide tobacco regulation: New tobacco products, young adult smokers, and race among focus of studies. PMID- 26485356 TI - Removing more breast tissue in mastectomy can reduce need for second surgery. PMID- 26485357 TI - Middle east war veterans experience higher skin cancer risk. PMID- 26485358 TI - Han X, Lin CC, Li C, de Moor JS, Rodriguez JL, Kent EE and Forsythe LP. Association between serious psychological distress and health care use and expenditures by cancer history. Cancer. 2015;121:614-622. PMID- 26485359 TI - Impact of Antibiotic Choice on Pneumonia Readmission Rates. AB - There are many patient and institutional variables associated with a higher risk of rehospitalization within 30 days of an admission for community-acquired pneumonia. However, less is known regarding the impact of antibiotics. A retrospective cohort study of 271 patients was performed to determine whether, when controlling for known factors for readmission, the choice of antibiotic affects 30-day rehospitalization after an index admission of pneumonia. Multivariate logistic regression analysis was performed to determine correlation between antibiotic choice and readmission rates. Empiric tobramycin was associated with a 31.2% increased risk of readmission for any reason (P < 0.01). Empiric and treatment aztreonam were associated with a 13.7% and 13.5% increased risk of readmission with recurrent pneumonia, respectively (both P < 0.05). Further research evaluating these associations is warranted. PMID- 26485360 TI - Pain and functional outcomes following vertebroplasty for vertebral compression fractures - A tertiary centre experience. AB - OBJECTIVES: There is a dearth of comparative outcome data on vertebroplasty for the treatment of vertebral compression fractures (VCF) according to vertebral level, the number of levels and aetiology. The aim of this study was to investigate the improvement of pain and function following vertebroplasty for a heterogeneous cohort of patients with medically refractory VCF. METHODS: A prospective observational study was conducted on a cohort of consecutive patients undergoing vertebroplasty following at least 4 weeks of failed medical management, between April 2007 and March 2012 at a single neurosurgical centre. Pain visual analogue scale (VAS) scores, Oswestry Disability Index (ODI) scores, analgesic usage and complications were recorded preoperatively and at day 1, week 1, 1 month, 6 months and 1 year postoperatively. Intraoperative vertebral body biopsy was performed routinely. RESULTS: Two hundred and two levels were augmented in 147 patients. The most common levels augmented were T12 (17%), L1 (18%) and L4 (10%). Significant reductions in pain VAS and ODI scores were evident at day 1 and sustained at up to 1 year postoperatively (p < 0.001). They were not dependent on the level of fracture (T3-10, T11-L2 and L3-S1) (p > 0.05), the number of levels treated (single level, two-level and > two level) (p > 0.05) or aetiology of VCF (p > 0.05). At 1 year postoperatively, 79% (113/142) had no or reduced analgesic usage. The complication rate was 6% (9/147). There were five mortalities, none of which was directly related to surgery. CONCLUSION: Vertebroplasty for medically refractory VCF may offer sustained improvement in pain and function. The procedure is associated with low morbidity and mortality. PMID- 26485361 TI - Chicken Egg Shell Membrane Associated Proteins and Peptides. AB - Egg shells are poultry industry byproducts with potential for use in various biological and agricultural applications. We have been interested in the membranes underlying the calcareous shell as a feed supplement, which showed potential to improve immunity and performance of post hatch poultry. Therefore, to determine their protein and peptide profiles, we extracted the egg shell membranes (ESM) from fresh unfertilized eggs with methanol and guanidine hydrochloride (GdHCl) to obtain soluble proteins for analysis by mass spectrometry. The methanol extract was subjected to matrix-assisted laser desorption ionization (MALDI), electrospray ionization (ESI), high-performance reverse phase liquid chromatographic separation (HPLC), and tandem mass spectrometry (MS/MS) to determine its peptide and protein profiles. The GdHCl extract was subjected to ESI-HPLC-MS/MS following trypsin digestion of reduced/alkylated proteins. Nine proteins from the methanol extract and >275 proteins from the GdHCl extract were tentatively identified. The results suggested the presence of several abundant proteins from egg whites, such as ovoalbumin, ovotransferrin, and lysozyme as well as many others associated with antimicrobial, biomechanical, cytoskeletal organizational, cell signaling, and enzyme activities. Collagens, keratin, agrin, and laminin were some of the structural proteins present in the ESM. The methanol-soluble fraction contained several clusterin peptides and defensins, particularly, two isoforms of gallin. The ratios of the two isoforms of gallin differed between the membranes obtained from brown and white eggs. The high abundance of several antimicrobial, immunomodulatory, and other bioactive proteins in the ESM along with its potential to entrap various microbes and antigens may make it a suitable vehicle for oral immunization of post hatch poultry and improve their disease resistance. PMID- 26485362 TI - The Effects of Gonadotropin Replacement Therapy on Metabolic Parameters and Body Composition in Men with Idiopathic Hypogonadotropic Hypogonadism. AB - Testosterone replacement therapy (TRT) in idiopathic hypogonadotrophic hypogonadism (IHH) slows the process of metabolic syndrome (MetS), diabetes mellitus, and cardiovascular diseases by its inversing effects on insulin resistance, dyslipidemia, and blood pressure. Since there are not enough data regarding the effects of gonadotropin replacement therapy (GRT), we aimed to investigate the impact of GRT on MetS parameters in IHH patients. Sixteen patients with IHH and 20 age and body mass index (BDI)-matched healthy controls were enrolled into the study. Patients were evaluated at baseline and 6 months after the GRT. Sex hormones, insulin like growth factor-1, prolactin, insulin, C reactive protein (CRP), homocysteine, and lipid levels were measured at baseline and after the treatment. Anthropometric measurements, including BMI, body fat ratio (BFR), fat free mass (FFM), waist circumference, and waist-to-hip ratio (WHR), were also performed. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was calculated. Body fat ratio, triglyceride, HOMA-IR, and CRP levels were higher, whereas bone age, fat free mass, and creatinine levels were lower in the patients with hypogonadism. HOMA-IR indices and basal insulin levels decreased significantly after 6 months of GRT compared with baseline levels. Triglyceride levels, and BFRs diminished significantly by an accompanying decline in WHR. FFM of the patients increased following the GRT. No significant changes were detected in CRP, homocysteine, total and LDL-cholesterol levels. Similar to TRT, hCG treatment decreases HOMA-IR, triglyceride levels, BFR and WHRs, and increases FFM in patients with IHH. PMID- 26485363 TI - Clarification of mammalian cloacal morphogenesis using high-resolution episcopic microscopy. AB - The developmental process through which the cloaca transforms from one hollow structure to two separated urinary and digestive outlets remains controversial and speculative. Here, we use high-resolution episcopic microscopy to examine a comprehensive series of normal and mutant mouse cloaca in which the detailed 3 dimensional (3-D) morphological features are illuminated throughout the development. We provide evidence that the dorsal peri-cloacal mesenchyme (dPCM) remains stationary while other surrounding tissues grow towards it. This causes dramatic changes of spatial relationship among caudal structures and morphological transformation of the cloaca. The 3-D characterizations of Dkk1 mutants reveal a hyperplastic defect of dPCM, which leads to a significant anterior shift of the caudal boundary of the cloaca, premature occlusion of the cloaca and, imperforate anus phenotype. Conversely, Shh knockout causes a severe hypoplastic defect of cloaca mesenchyme including dPCM and persistent cloaca. Collectively, these findings suggest that formation of the dPCM is critical for cloacal morphogenesis and furthermore, growth and movement of the mesenchymal tissues towards the dPCM lead to the cloaca occlusion and separation of the urinary and digestive outlets. PMID- 26485364 TI - Patterns of First Recurrence in African American Patients with High Grade Epithelial Ovarian Carcinoma. AB - BACKGROUND/AIMS: The aim of this study is to compare the distribution of anatomic sites of first recurrence in African American (AA) patients with ovarian carcinoma compared to Caucasians. METHODS: Patients diagnosed with high-grade epithelial ovarian, fallopian tube or peritoneal carcinoma from 2007 to 2013 were identified. Patterns of recurrence were compared for AA and Caucasian patients. Progression-free survival (PFS) and overall survival (OS) were compared. RESULTS: A total of 238 patients were included - 210 Caucasians and 28 AAs. At a follow-up time of 28 months, AAs were more likely to have multiple anatomic sites of recurrence rather than a single site when compared to Caucasians (63.6 vs. 35.5%, p = 0.01). Time to first recurrence was shorter for AA patients (12 vs. 18 months, p < 0.01). PFS and OS did not differ. AA patients with multiple sites of first recurrence had a significantly shorter OS than Caucasian patients with multiple sites of first recurrence (24 vs. 30 months, p = 0.022). CONCLUSION: Patterns of first recurrence differ between AAs and Caucasians. AAs have shorter times to first recurrence and are more likely to have multiple anatomic sites involved. AA patients with multiple sites of recurrence have a shorter OS than Caucasian patients with multiple sites. PMID- 26485366 TI - Freshwater sharks and rays. PMID- 26485365 TI - The Molecular Biology of Spindle Assembly Checkpoint Signaling Dynamics. AB - The spindle assembly checkpoint is a safeguard mechanism that coordinates cell cycle progression during mitosis with the state of chromosome attachment to the mitotic spindle. The checkpoint prevents mitotic cells from exiting mitosis in the presence of unattached or improperly attached chromosomes, thus avoiding whole-chromosome gains or losses and their detrimental effects on cell physiology. Here, I review a considerable body of recent progress in the elucidation of the molecular mechanisms underlying checkpoint signaling, and identify a number of unresolved questions. PMID- 26485367 TI - Equids. AB - Alongside domestic horses and donkeys, the horse family, also known as equids, comprises six extant wild species of asses and zebras (Figure 1). Equids are extremely well represented in the fossil record, comprising a 55 million-year evolutionary history, punctuated by many episodes of innovation, extinction and migration. Limited to the single genus Equus today, in the Miocene (23.0-5.3 million years ago) the equid family flourished, comprising more than twenty genera. The group originated in Northern America, where the earliest fossil forms have been found, the so-called Hyracotheres, no larger than small dogs. These animals were soft-leaf browsers and in contrast to modern equids, which roam on a single toe with a solid keratin hoof, their hindlimbs were three-toed and their forelimbs four-toed. Equids thus form, together with rhinos and tapirs, the perissodactyls, an order of mammals characterized by an odd number of toes. Unlike ruminants, they are hindgut fermenters, which digest plant cellulose in their intestines and not in differentiated multiple stomach chambers. PMID- 26485368 TI - Human infants' ability to perceive touch in external space develops postnatally. AB - Arriving in the outside world, the newborn infant has to determine how the tactile stimulation experienced in utero relates to the spatial environment newly offered up by vision, hearing and olfaction. We investigated this developmental process by tracing the origins of the influence of external spatial representation on young infants' orienting responses to tactile stimuli. When adults cross their hands or feet they typically make more tactile localization errors than otherwise, and this has been attributed to the conflicts between skin based and external frames of reference and/or the usual and current locations of touches in external space [1,2]. Here, we report that a group of six-month-olds, like adults, showed a tactile localisation deficit with their feet crossed, indicating external spatial coding of touch; in striking contrast, four-month olds outperformed the older infants showing no crossed-feet deficit. Thus, in the first months of life, infants perceive touches solipsistically, and only come to locate them in the external world after significant postnatal experience. PMID- 26485369 TI - Nutritional Physiology: Sex Elicits a Taste for Salt in Drosophila. AB - Increased salt intake has been found to boost egg production in Drosophila. Females develop a specific appetite for salt following mating. This is not triggered by demand for sodium from developing eggs, but by release of a Sex Peptide into the female's reproductive tract by the male during mating. PMID- 26485370 TI - Functional Morphology: 'Point and Shoot' Prey Capture in Fishes. AB - The ability to protrude the jaws and capture elusive prey is a hallmark of fish evolution. New analyses provide insight into how jaw protrusion changed predator prey relationships and fueled species diversification in ancient seas. PMID- 26485371 TI - Reproductive Evolution: Pulling the Plug on Selection. AB - Hermaphroditism leads to reduced sexual selection and can result in the retention of deleterious mutations. A new study characterizes one such mutation that results in male-male copulation in nematodes, while also implicating a previously undescribed source of chemical signaling. PMID- 26485372 TI - Multisensory Perception: The Building of Flavor Representations. AB - The perceptual construct of flavor is built on the basis of interactions between taste and odor processing. Recent work sheds new light on how intimately coupled these two senses are, and call into question conventional views about the 'unisensory' processing of odors. PMID- 26485373 TI - Circannual Biology: The Double Life of the Seasonal Thyrotroph. AB - Endogenous long-term timing is a key component of seasonality. Where and how are such rhythms generated? Recent findings pointed to the pituitary pars tuberalis, already implicated in photoperiod responsiveness. Now, a new study provides mechanistic insights which support this hypothesis. PMID- 26485374 TI - Sensory-Motor Integration: More Variability Reduces Individuality. AB - Motor neural networks and muscles produce identifiably common outputs, such as a trot or gallop, despite varations in intrinsic properties across individuals. New work shows that sensory input can induce the requisite decrease in across individual variability even as it increases within-individual variability. PMID- 26485375 TI - Time Cognition: Entangled Neuronal Firing. AB - The neuroscience of time frequently focuses on either measuring short time intervals (sensory timing) or reproducing them (motor timing); during cognition, the two are integrated. New experiments using a combined sensory and motor timing task suggest that neuronal firing during the sensory and motor phases are linked. PMID- 26485376 TI - Insect Olfaction: Telling Food from Foe. AB - The same sensory signal can be interpreted differently according to context. A new study in Drosophila uses cell-type-specific tools to identify neural circuits that integrate context during olfactory processing and surprisingly implicates memory-recall neurons. PMID- 26485377 TI - Neuroplasticity: Unexpected Consequences of Early Blindness. AB - A pair of recent studies shows that congenital blindness can have significant consequences for the functioning of the visual system after sight restoration, particularly if that restoration is delayed. PMID- 26485379 TI - Headache Attributed to Masticatory Myofascial Pain: Clinical Features and Management Outcomes. AB - AIMS: To describe the characteristics of headaches attributed to temporomandibular disorders (TMD) and assess the effects of two management strategies used for the management of TMD on headache intensity and frequency. METHODS: The initial sample (n=60) of this randomized controlled trial comprised patients with masticatory myofascial pain according to the Research Diagnostic Criteria for TMD (RDC/TMD), and headache. The patients were divided into two groups: group 1 received only counseling for behavioral changes, and group 2 received counseling and an occlusal appliance. A 5-month follow-up period included three assessments. TMD-related headache characteristics, eg, headache intensity (scored on a visual analog scale [VAS]) and frequency were measured by a questionnaire. Two-way analysis of variance, chi-square, Friedman, and Mann Whitney tests were used to test for differences considering a 5% significance level. RESULTS: The main clinical features of headache attributed to masticatory myofascial pain were the long duration (>=4 hours), frontotemporal bilateral location, and a pressing/tightening quality. Forty-one subjects (group 1, 17 subjects; group 2, 24 subjects) were included in the final analysis. There was a reduction in headache intensity and frequency, with no significant differences between groups (P>.05). The mean (+/-SD) baseline VAS was 7.6 (+/-2.2) for group 1 and 6.5 (+/-1.6) for group 2; final values were 3.1 (+/-2.2) (P<.001) and 2.5 (+/-2.3) (P<.001), respectively. CONCLUSION: Headache attributed to masticatory myofascial pain was mainly characterized by long duration, frontotemporal bilateral location, and a pressing/tightening quality. Also, counseling and behavioral management of masticatory myofascial pain improved headache, regardless of the use of an occlusal appliance. PMID- 26485380 TI - Short-Term Sensorimotor Effects of Experimental Occlusal Interferences on the Wake-Time Masseter Muscle Activity of Females with Masticatory Muscle Pain. AB - AIMS: To investigate the effects of the application of an acute alteration of the occlusion (ie, interference) on the habitual masseter electromyographic (EMG) activity of females with temporomandibular disorders (TMD)-related muscular pain during wakefulness. METHODS: Seven female volunteers with masticatory myofascial pain participated in a crossover randomized clinical trial. Gold foils were glued on an occlusal contact area (active occlusal interference, AI) or on the vestibular surface of the same molar (dummy interference, DI) and left for 8 days. The masseter electromyogram was recorded during wakefulness in the natural environment by portable recorders under interference-free, dummy-interference, and active-interference conditions. The number, amplitude, and duration of EMG signal fractions with amplitudes above 10% of the maximum voluntary contraction (activity periods, APs) were computed in all experimental conditions. Muscle pain, headache, and perceived stress were each assessed with a visual analog scale (VAS), and an algometer was used to assess masseter and temporalis pressure pain thresholds. Data were analyzed by means of analysis of variance. RESULTS: The frequency and duration of the recorded APs did not differ significantly between the experimental conditions (P>.05), but a small and significant reduction of the EMG mean amplitude of the APs occurred with AI (P<.05). Neither the VAS scores for muscular pain, headache, and perceived stress nor the pressure pain thresholds changed significantly throughout the entire experiment (P>.05). CONCLUSION: An active occlusal interference in female volunteers with masticatory muscle pain had little influence on the masseter EMG activity pattern during wakefulness and did not affect the pressure tenderness of the masseter and temporalis. PMID- 26485378 TI - Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response. AB - The RIG-I-like receptor (RLR) pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNalpha/beta) that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular signatures of known RLR pathway components that collectively predict novel members. We demonstrate that RLR pathway genes, among others, tend to evolve rapidly, interact with viral proteins, contain a limited set of protein domains, are regulated by specific transcription factors, and form a tightly connected interaction network. Using a Bayesian approach to integrate these signatures, we propose likely novel RLR regulators. RNAi knockdown experiments revealed a high prediction accuracy, identifying 94 genes among 187 candidates tested (~50%) that affected viral RNA induced production of IFNbeta. The discovered antiviral regulators may participate in a wide range of processes that highlight the complexity of antiviral defense (e.g. MAP3K11, CDK11B, PSMA3, TRIM14, HSPA9B, CDC37, NUP98, G3BP1), and include uncharacterized factors (DDX17, C6orf58, C16orf57, PKN2, SNW1). Our validated RLR pathway list (http://rlr.cmbi.umcn.nl/), obtained using a combination of integrative genomics and experiments, is a new resource for innate antiviral immunity research. PMID- 26485381 TI - Alterations in Masticatory Muscle Activation in People with Persistent Neck Pain Despite the Absence of Orofacial Pain or Temporomandibular Disorders. AB - AIM: To assess whether patients with persistent neck pain display evidence of altered masticatory muscle behavior during a jaw-clenching task, despite the absence of orofacial pain or temporomandibular disorders. METHODS: Ten subjects with persistent, nonspecific neck pain and 10 age- and sex-matched healthy controls participated. Maximal voluntary contractions (MVCs) of unilateral jaw clenching followed by 5-second submaximal contractions at 10%, 30%, 50%, and 70% MVC were recorded by two flexible force transducers positioned between the first molar teeth. Task performance was quantified by mean distance and offset error from the reference target force as error indices, and standard deviation of force was used as an index of force steadiness. Electromyographic (EMG) activity was recorded bilaterally from the masseter muscle with 13 X 5 grids of electrodes and from the anterior temporalis with bipolar electrodes. Normalized EMG root mean square (RMS) was computed for each location of the grid to form a map of the EMG amplitude distribution, and the average normalized RMS was determined for the bipolar acquisition. Between-group differences were analyzed with the Kruskal Wallis analysis of variance. RESULTS: Task performance was similar in patients and controls. However, patients displayed greater masseter EMG activity bilaterally at higher force levels (P<.05). CONCLUSION: This study has provided novel evidence of altered motor control of the jaw in people with neck pain despite the absence of orofacial pain or temporomandibular disorders. PMID- 26485383 TI - Psychometric Properties of the Multidimensional Pain Inventory Applied to Brazilian Patients with Orofacial Pain. AB - AIMS: To evaluate the psychometric properties of the Multidimensional Pain Inventory (MPI) in a Brazilian sample of patients with orofacial pain. METHODS: A total of 1,925 adult patients, who sought dental care in the School of Dentistry of Sao Paulo State University's Araraquara campus, were invited to participate; 62.5% (n=1,203) agreed to participate. Of these, 436 presented with orofacial pain and were included. The mean age was 39.9 (SD=13.6) years and 74.5% were female. Confirmatory factor analysis was conducted using chi2/df, comparative fit index, goodness of fit index, and root mean square error of approximation as indices of goodness of fit. Convergent validity was estimated by the average variance extracted and composite reliability, and internal consistency by Cronbach's alpha standardized coefficient (alpha). The stability of the models was tested in independent samples (test and validation; dental pain and orofacial pain). The factorial invariance was estimated by multigroup analysis (Deltachi2). RESULTS: Factorial, convergent validity, and internal consistency were adequate in all three parts of the MPI. To achieve this adequate fit for Part 1, item 15 needed to be deleted (lambda=0.13). Discriminant validity was compromised between the factors "activities outside the home" and "social activities" of Part 3 of the MPI in the total sample, validation sample, and in patients with dental pain and with orofacial pain. A strong invariance between different subsamples from the three parts of the MPI was detected. CONCLUSION: The MPI produced valid, reliable, and stable data for pain assessment among Brazilian patients with orofacial pain. PMID- 26485384 TI - Association Between Clinical Signs of Temporomandibular Disorders and Psychological Distress Among an Adult Finnish Population. AB - AIMS: To evaluate the association between signs of temporomandibular disorders (TMD) and psychological distress in a general population-based sample of Finnish adults. METHODS: The Health 2000 Survey was conducted in 2000-2001 by the National Institute for Health and Welfare in Finland. Of the sample of adults aged 30 or over (n=8,028), 79% participated in a clinical oral health examination, which included examination of TMD signs. The participants (n=6,155) also completed questionnaires, including the 12-item General Health Questionnaire (GHQ-12), which measured psychological distress. Associations between TMD signs and psychological distress measured by the GHQ-12 were examined in both genders. Statistical measures included chi-square tests, t tests, and logistic regression analyses. RESULTS: The prevalence of the TMD signs (limited opening, clicking, crepitation, temporomandibular joint [TMJ] palpation pain, and muscle palpation pain) was 11.2%, 17.6%, 10.5%, 5.1%, and 18.9% in women, and 6.1%, 12.9%, 5.3%, 2.4%, and 7.2% in men, respectively. High GHQ-12 scores, measured as continuous variables and in quartiles by distress level, were significantly associated with masticatory muscle pain on palpation in both genders (P<.05) and with TMJ pain on palpation in women (P<.05). Additionally, high GHQ-12 scores as continuous were associated with TMJ crepitation in men (P<.05). The logistic regression analyses showed that higher GHQ-12 scores were associated significantly with masticatory muscle pain on palpation both in women (odds ratio [OR]=2.18; 95% confidence interval [CI]=1.6-2.9) and men (OR=2.03; 95% CI=1.3-3.1). CONCLUSION: TMD signs and psychological distress appear to be associated. However, due to the limitations of the study, the findings can be regarded as preliminary. PMID- 26485382 TI - Amplified Brain Processing of Dentoalveolar Pressure Stimulus in Persistent Dentoalveolar Pain Disorder Patients. AB - AIMS: (1) To determine the brain regions activated by dentoalveolar pressure stimulation in persistent dentoalveolar pain disorder (PDAP) patients, and (2) to compare these activation patterns to those seen in pain-free control subjects. METHODS: A total of 13 PDAP patients and 13 matched controls completed the study. Clinical pain characteristics and psychosocial data were collected. Dentoalveolar mechanical pain thresholds were determined with a custom-made device over the painful area for patients and were used as the stimulation level during functional magnetic resonance imaging (fMRI) data acquisition. Control subjects received two stimulation levels over matched locations during fMRI scanning: one determined (as above) that evoked equally subjective pain ratings matching those of patients (subjective-pain match) and another nonpainful stimulation level matching the average stimulus intensity provided to patients (stimulus-intensity match). Clinical and psychosocial data were analyzed using independent samples t tests, Mann-Whitney U test, and Spearman rank-order correlation coefficient. fMRI data were analyzed using validated neuroimaging software and tested using a general linear model. RESULTS: PDAP patients had greater anxiety (P<.0001) and depression scores (P=.001), more jaw function impairment (P<.0001), and greater social impact (P<.0001) than controls. No significant differences were found for brain activation spatial extent (PDAP X Controls subjective pain: P=.48; PDAP X Controls stimulus intensity: P=.12). Brain activations were significantly increased for PDAP patients compared to control subjects when matched to stimulus intensity in several regions related to the sensory-discriminative and cognitive components of pain perception, including the primary and secondary somatosensory cortices, inferior parietal lobule, insula, premotor cortex, prefrontal cortex, and thalamus. When matched to subjective pain ratings, increased brain activations were still present for PDAP patients compared to controls, although to a lesser extent. CONCLUSION: The present results suggest that dentoalveolar pressure is processed differently in the brain of PDAP patients, and the increased activation in several brain areas is consistent with amplified pain processing. PMID- 26485385 TI - Preoperative Local Administration of Morphine as an Add-on Therapy in Patients Undergoing Surgical Removal of an Odontogenic Maxillary Cyst. A Randomized, Double-Blind Pilot Study. AB - AIMS: To evaluate whether a combination of locally administered morphine (1 mg) and lidocaine as part of a multimodal analgesic approach is safe, and whether it improves pain control during the first 24 hours after odontogenic maxillary cyst removal under general anesthesia compared to local lidocaine alone. METHODS: In a double-blind, sham-controlled, single-center trial, patients scheduled for surgical removal of an odontogenic maxillary cyst under general anesthesia were randomly assigned to receive a local injection of lidocaine solution with either 1 mg of morphine (MLA group) or with no morphine (LA group). Pain management included intravenous acetaminophen (1 g every 6 hours) in all patients. Upon request, the patients could additionally receive ketoprofen (first-line additional analgesia) or tramadol (second-line additional analgesia). Pain intensity was assessed using a numeric rating scale. Primary outcome measures were (1) no need for any additional analgesic therapy and (2) time to the first rescue analgesic therapy during the first 24 hours after the surgery. RESULTS: Of 48 eligible patients, 24 were allocated to the MLA group and 24 to the LA group. The necessity of additional ketoprofen therapy did not differ significantly between the groups (25.0% vs 50.0%, P=.074). According to the Kaplan-Meier analysis, the probability of remaining without additional analgesic intervention was significantly higher in the MLA group (log-rank test, P=.040), but there were no significant (P>.05) differences in overall and maximum pain severity between the two groups. No adverse effects of morphine were recorded. CONCLUSION: Within the limitations of this study, local administration of 1 mg of morphine prior to the surgical removal of an odontogenic maxillary cyst was safe, but it did not prove to be very effective as an add-on therapy for postoperative pain control. PMID- 26485386 TI - The Prevalence and Awareness of Migraine Among University Students in Harbin, China. AB - AIMS: To determine the prevalence and the awareness of migraine among university students in Harbin, China. METHODS: A cross-sectional study of students was conducted in Harbin Medical University from April 1 to June 30, 2012. The Chinese version of the Identification of Migraine Screener (ID-Migraine) was used as the screening tool, and the awareness of migraine was evaluated by a structured questionnaire. A subgroup of the students was randomly selected to fill out the questionnaire again to evaluate its test-retest reliability. The internal consistency reliability and structured validity were tested using Cronbach's alpha coefficient and exploratory factor analyses. RESULTS: Of the 5,129 registered students, 4,406 students (85.9%) signed a consent form and completed the questionnaire. Three hundred ninety-five students were screened positive for migraine, with a prevalence of 9.0%, and the migraine prevalence increased with age (z=-2.82, P<.01). Gender (chi2=0.12, P=.73) and body mass index (chi2=0.51, P=.78) did not significantly influence migraine prevalence, and the prevalence showed no significant difference between medical and nonmedical students (chi2=2.10, P=.15). The awareness of fundamental details (definition, classification, symptoms), treatment, and trigger factors of migraine were 40.4%, 42.4%, and 68.6%, respectively. The test-retest reliability of these parts of the questionnaire was 0.61 (95% confidence interval [CI]: 0.48-0.75), 0.77 (95% CI: 0.66-0.88), and 0.80 (95% CI: 0.69-0.91), respectively. Three components accumulatively explained 52.1% of the total variance of the scale, and the rotated factor loadings (the correlation coefficient between the items and the common factor) in each part were all higher than 0.50 excluding item C11. CONCLUSION: The prevalence of migraine in university students was 9.0%, which is comparable to the prevalence found in Chinese adults from the general population in two previous studies. University students have limited awareness of migraine. PMID- 26485387 TI - Noxious Stimulation of the Rat Tooth Pulp May Impair Learning and Memory Through the Induction of Hippocampal Apoptosis. AB - AIMS: To determine whether noxious stimulation of the rat tooth pulp induces learning and memory impairment through the induction of apoptosis in the hippocampus. METHODS: Thirty-five adult rats were divided randomly into five groups (each n=7) as follows: control, sham-operated, sham-vehicle, capsaicin treated, and capsaicin plus ibuprofen-treated group. After preparing dental cavities via cutting 2 mm of the distal extremities of the mandibular incisors, polyethylene crowns were placed on the teeth. Based on the study groups, different injections were administered into the cavities. Nociceptive scores for each block were obtained by measuring the number of seconds that the animal spent rubbing and flicking the lower jaw. After recording the nociceptive behaviors, spatial learning and memory were assessed by using the Morris Water Maze (MWM) test. The hippocampal levels of Bcl-2, Bax, and caspase-3 protein were determined by immunoblotting. Statistical analyses were performed using one- or two-way analysis of variance. RESULTS: Noxious pulp stimulation induced by intradental application of capsaicin significantly increased time and traveled distance in the MWM test. Capsaicin stimulation of the pulp also significantly increased the Bax:Bcl-2 ratio and activated caspase-3 in the hippocampus (P<.01), which was inhibited by ibuprofen pretreatment (P<.05). CONCLUSION: Memory and learning impairment induced by noxious stimulation of the rat tooth pulp may be correlated with activation of apoptotic pathways in the hippocampus. PMID- 26485388 TI - Reducing Transitional Hypothermia in Outborn Very Low Birth Weight Infants. AB - BACKGROUND: Transitional hypothermia (TH) is associated with increased morbidity and mortality in very low birth weight (VLBW) infants worldwide. OBJECTIVES: To assess the effect of a quality improvement project (QIP) on outborn TH and the associated mortality/morbidity among VLBW neonates. METHODS: We conducted a multi intervention QIP to reduce TH (<36 degrees C) among outborn VLBW neonates. This cohort study compared a historical group (group I, n = 86) to a prospective group (group II, established after QIP implementation, n = 86). The primary outcome was axillary temperature measured in the delivery room (DR) and upon admission to the neonatal intensive care unit (NICU). RESULTS: The baseline characteristics of the two groups were similar. After introducing the QIP, the mean DR and NICU admission temperatures of the patients rose from 35.5 to 36.1 degrees C and from 34.6 to 36.2 degrees C, respectively (p < 0.01), and the percentage of patients with temperatures <36 degrees C in the DR and NICU decreased from 80 to 40% and from 81 to 42% (p < 0.01), respectively. Meanwhile, the percentage of patients with a normal temperature in the DR and NICU rose from 20 to 58% and from 19 to 56% (p < 0.01), respectively, which was accompanied by significantly decreased mortality (p < 0.02) and other improvements. CONCLUSION: Implementation of a QIP resulted in a decrease in the number of moderately hypothermic VLBW neonates and a sustained improvement in normothermia rates during DR stabilization and transfer to the NICU in outborn VLBW neonates. PMID- 26485389 TI - Structure Elucidation of Coxsackievirus A16 in Complex with GPP3 Informs a Systematic Review of Highly Potent Capsid Binders to Enteroviruses. AB - The replication of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), which are the major cause of hand, foot and mouth disease (HFMD) in children, can be inhibited by the capsid binder GPP3. Here, we present the crystal structure of CVA16 in complex with GPP3, which clarifies the role of the key residues involved in interactions with the inhibitor. Based on this model, in silico docking was performed to investigate the interactions with the two next-generation capsid binders NLD and ALD, which we show to be potent inhibitors of a panel of enteroviruses with potentially interesting pharmacological properties. A meta analysis was performed using the available structural information to obtain a deeper insight into those structural features required for capsid binders to interact effectively and also those that confer broad-spectrum anti-enterovirus activity. PMID- 26485390 TI - Experimental and Natural Infections of Goats with Severe Fever with Thrombocytopenia Syndrome Virus: Evidence for Ticks as Viral Vector. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome virus (SFTSV), the causative agent for the fatal life-threatening infectious disease, severe fever with thrombocytopenia syndrome (SFTS), was first identified in the central and eastern regions of China. Although the viral RNA was detected in free-living and parasitic ticks, the vector for SFTSV remains unsettled. METHODOLOGY/PRINCIPAL FINDINGS: Firstly, an experimental infection study in goats was conducted in a bio-safety level-2 (BSL-2) facility to investigate virus transmission between animals. The results showed that infected animals did not shed virus to the outside through respiratory or digestive tract route, and the control animals did not get infected. Then, a natural infection study was carried out in the SFTSV endemic region. A cohort of naive goats was used as sentinel animals in the study site. A variety of daily samples including goat sera, ticks and mosquitoes were collected for viral RNA and antibody (from serum only) detection, and virus isolation. We detected viral RNA from free-living and parasitic ticks rather than mosquitoes, and from goats after ticks' infestation. We also observed sero conversion in all members of the animal cohort subsequently. The S segment sequences of the two recovered viral isolates from one infected goat and its parasitic ticks showed a 100% homology at the nucleic acid level. CONCLUSIONS/SIGNIFICANCE: In our natural infection study, close contact between goats does not appear to transmit SFTSV, however, the naive animals were infected after ticks' infestation and two viral isolates derived from an infected goat and its parasitic ticks shared 100% of sequence identity. These data demonstrate that the etiologic agent for goat cohort's natural infection comes from environmental factors. Of these, ticks, especially the predominant species Haemaphysalis longicornis, probably act as vector for this pathogen. The findings in this study may help local health authorities formulate and focus preventive measures to contain this infection. PMID- 26485391 TI - Preparation of Mitochondrial Enriched Fractions for Metabolic Analysis in Drosophila. AB - Since mitochondria play roles in amino acid metabolism, carbohydrate metabolism and fatty acid oxidation, defects in mitochondrial function often compromise the lives of those who suffer from these complex diseases. Detecting mitochondrial metabolic changes is vital to the understanding of mitochondrial disorders and mitochondrial responses to pharmacological agents. Although mitochondrial metabolism is at the core of metabolic regulation, the detection of subtle changes in mitochondrial metabolism may be hindered by the overrepresentation of other cytosolic metabolites obtained using whole organism or whole tissue extractions. Here we describe an isolation method that detected pronounced mitochondrial metabolic changes in Drosophila that were distinct between whole fly and mitochondrial enriched preparations. To illustrate the sensitivity of this method, we used a set of Drosophila harboring genetically diverse mitochondrial DNAs (mtDNA) and exposed them to the drug rapamycin. Using this method we showed that rapamycin modifies mitochondrial metabolism in a mitochondrial-genotype-dependent manner. However, these changes are much more distinct in metabolomics studies when metabolites were extracted from mitochondrial enriched fractions. In contrast, whole tissue extracts only detected metabolic changes mediated by the drug rapamycin independently of mtDNAs. PMID- 26485392 TI - Coinage metal complexes supported by a "PN(3)P" scaffold. AB - A series of monovalent group 11 complexes, [2,6-{Ph2PNMe}2(NC5H3)]CuBr 1, [2,6 {Ph2PNMe}2(NC5H3)]CuOTf 2, [2,6-{Ph2PNMe}2(NC5H3)]AgOTf 3, and [2,6 {Ph2PNMe}2(NC5H3)](AuCl)24, supported by a neutral PN(3)P ligand have been synthesized and characterized by multinuclear NMR and single crystal X-ray diffraction studies. The variation of the coordination properties were analyzed and electronic structure calculations have been carried out to provide insight on the bonding details in these complexes. The Cu(I) complexes displayed an unusual coordination geometry with a tridentate pincer ligand and an overall four coordinate trigonal pyramidal geometry. In contrast the Ag(I) analogue displayed a bidentate kappa(2)-P,P' ligation leaving the pyridyl-N atom uncoordinated and yielding a pyramidalized trigonal planar geometry around Ag. The bimetallic Au(I) complex completed the series and displayed a monodentate P-bonded ligand and a linear coordination geometry. PMID- 26485393 TI - The Association between Near Work Activities and Myopia in Children-A Systematic Review and Meta-Analysis. AB - Myopia has a multifactorial etiology, although environmental factors are predominant in determining its current patterns. Currently, associations between near work activities and myopia have not been consistently observed. Therefore, we performed a systematic review to quantify the effect of near work activities on myopia in children. Relevant articles published between 1989 and 2014 were identified in MEDLINE, Embase, and the Cochrane Library, and the citation lists were reviewed. Twelve cohort studies and 15 cross-sectional studies were included (25,025 children aged between 6 and 18 years). The I2 statistic was used to assess heterogeneity. Study-level data were pooled using a random-effects model or a fixed-effects model (when less than 5 studies were included). We found that more time spent on near work activities was associated with higher odds of myopia (odds ratio [OR] = 1.14; 95% confidence interval [CI] = 1.08-1.20) and that the odds of myopia increased by 2% (OR:1.02; 95% CI = 1.01-1.03) for every one diopter-hour (hr) more of near work per week. Therefore, the development of a strategy to reduce the impact of near work on myopia would be important for preventing myopia in children. PMID- 26485395 TI - Correction: Expression of Protein Kinase C Isoforms in Pancreatic Islets and Liver of Male Goto-Kakizaki Rats, a Model of Type 2 Diabetes. PMID- 26485394 TI - Human Adipose-Derived Mesenchymal Stem Cells in Cell Therapy: Safety and Feasibility in Different "Hospital Exemption" Clinical Applications. AB - Based on immunomodulatory, osteogenic, and pro-angiogenic properties of adipose derived stem cells (ASCs), this study aims to assess the safety and efficacy of ASC-derived cell therapies for clinical indications. Two autologous ASC-derived products were proposed to 17 patients who had not experienced any success with conventional therapies: (1) a scaffold-free osteogenic three-dimensional graft for the treatment of bone non-union and (2) a biological dressing for dermal reconstruction of non-healing chronic wounds. Safety was studied using the quality control of the final product (genetic stability, microbiological/mycoplasma/endotoxin contamination) and the in vivo evaluation of adverse events after transplantation. Feasibility was assessed by the ability to reproducibly obtain the final ASC-based product with specific characteristics, the time necessary for graft manufacturing, the capacity to produce enough material to treat the lesion, the surgical handling of the graft, and the ability to manufacture the graft in line with hospital exemption regulations. For 16 patients (one patient did not undergo grafting because of spontaneous bone healing), in-process controls found no microbiological/mycoplasma/endotoxin contamination, no obvious deleterious genomic anomalies, and optimal ASC purity. Each type of graft was reproducibly obtained without significant delay for implantation and surgical handling was always according to the surgical procedure and the implantation site. No serious adverse events were noted for up to 54 months. We demonstrated that autologous ASC transplantation can be considered a safe and feasible therapy tool for extreme clinical indications of ASC properties and physiopathology of disease. PMID- 26485397 TI - Molecular Cloning, Recombinant Expression, and Funtional Characterization of APRIL (TNFSF13) in Cat (felis catus). AB - A proliferation-inducing ligand (APRIL) is a critical member of the tumor necrosis factor (TNF) superfamily, which is involved in immune regulation. In the present study, the cDNA of cat APRIL (cAPRIL) was successfully amplified. Sequence analysis showed that the open reading frame (ORF) of cAPRIL contains a putative furin protease cleavage site (R-R-K-R), a conserved putative N glycosylation site (Asn(124)), and two conservative cysteine residues (Cys(196) and Cys(211)). Real-time quantitative PCR (qPCR) analysis revealed that cAPRIL could be detected in various tissues. The phylogenetic analysis and predicted three dimensional (3D) structure revealed that it is similar to its counterparts. The extracellular soluble domain of the cAPRIL (csAPRIL) fragment was cloned into the expression vector pET43.1a. SDS-PAGE and Western blotting analysis indicated a high-level expression of csAPRIL protein in Escherichia coli BL21 (DE3). MTT assays revealed that purified recombinant csAPRIL protein was able to stimulate proliferation of mouse B-cells. These findings indicate that cAPRIL plays an important role in proliferation of B-cells and provide the basis for investigation on the roles of APRIL in this important domestic species. PMID- 26485396 TI - Divergent Inhibitor Susceptibility among Airway Lumen-Accessible Tryptic Proteases. AB - Tryptic serine proteases of bronchial epithelium regulate ion flux, barrier integrity, and allergic inflammation. Inhibition of some of these proteases is a strategy to improve mucociliary function in cystic fibrosis and asthmatic inflammation. Several inhibitors have been tested in pre-clinical animal models and humans. We hypothesized that these inhibitors inactivate a variety of airway protease targets, potentially with bystander effects. To establish relative potencies and modes of action, we compared inactivation of human prostasin, matriptase, airway trypsin-like protease (HAT), and beta-tryptase by nafamostat, camostat, bis(5-amidino-2-benzimidazolyl)methane (BABIM), aprotinin, and benzamidine. Nafamostat achieved complete, nearly stoichiometric and very slowly reversible inhibition of matriptase and tryptase, but inhibited prostasin less potently and was weakest versus HAT. The IC50 of nafamostat's leaving group, 6 amidino-2-naphthol, was >104-fold higher than that of nafamostat itself, consistent with suicide rather than product inhibition as mechanisms of prolonged inactivation. Stoichiometric release of 6-amidino-2-naphthol allowed highly sensitive fluorometric estimation of active-site concentration in preparations of matriptase and tryptase. Camostat inactivated all enzymes but was less potent overall and weakest towards matriptase, which, however was strongly inhibited by BABIM. Aprotinin exhibited nearly stoichiometric inhibition of prostasin and matriptase, but was much weaker towards HAT and was completely ineffective versus tryptase. Benzamidine was universally weak. Thus, each inhibitor profile was distinct. Nafamostat, camostat and aprotinin markedly reduced tryptic activity on the apical surface of cystic fibrosis airway epithelial monolayers, suggesting prostasin as the major source of such activity and supporting strategies targeting prostasin for inactivation. PMID- 26485398 TI - The Immunology of a Healing Response in Cutaneous Leishmaniasis Treated with Localized Heat or Systemic Antimonial Therapy. AB - BACKGROUND: The effectiveness of systemic antimonial (sodium stibogluconate, Pentostam, SSG) treatment versus local heat therapy (Thermomed) for cutaneous leishmaniasis was studied previously and showed similar healing rates. We hypothesized that different curative immune responses might develop with systemic and local treatment modalities. METHODS: We studied the peripheral blood immune cells in a cohort of 54 cutaneous Leishmania major subjects treated with SSG or TM. Multiparameter flow cytometry, lymphoproliferative assays and cytokine production were analyzed in order to investigate the differences in the immune responses of subjects before, on and after treatment. RESULTS: Healing cutaneous leishmaniasis lead to a significant decline in circulating T cells and NKT-like cells, accompanied by an expansion in NK cells, regardless of treatment modality. Functional changes involved decreased antigen specific CD4+ T cell proliferation (hyporesponsiveness) seen with CD8+ T cell depletion. Moreover, the healing (or healed) state was characterized by fewer circulating regulatory T cells, reduced IFN-gamma production and an overall contraction in polyfunctional CD4+ T cells. CONCLUSION: Healing from cutaneous Leishmaniasis is a dynamic process that alters circulating lymphocyte populations and subsets of T, NK and NKT-like cells. Immunology of healing, through local or systemic treatments, culminated in similar changes in frequency, quality, and antigen specific responsiveness with immunomodulation possibly via a CD8+ T cell dependent mechanism. Understanding the evolving immunologic changes during healing of human leishmaniasis informs protective immune mechanisms. PMID- 26485399 TI - Use of In Vitro and Predictive In Silico Models to Study the Inhibition of Cytochrome P4503A by Stilbenes. AB - CYP3A4 is recognized as the main enzyme involved in the metabolism of drugs and xenobiotics in the human body and its inhibition may lead to undesirable consequences. Stilbenes, including resveratrol, belong to a group of dietary health-promoting compounds that also act as inhibitors of CYP3A4. The aim of this study was to examine the use of computer modeling of enzyme-ligand interactions to analyze and predict the inhibition of structurally related compounds. To this end, an aldehyde group was attached to resveratrol and the interactions of CYP3A4 with resveratrol, its aldehyde analogue (RA) and a known synthetic inhibitor were studied and compared in two biological models. Specifically, the metabolism of testosterone was examined in a human intestine cell line (Caco-2/TC7) and in rat liver microsomes (RLM). The results demonstrated a weak inhibitory effect of RA on CYP3A4, as compared to resveratrol itself, in both biological models. Human CYP3A4 was more susceptible to inhibition than the commonly used model isozyme from rat. Modeling of the binding site of CYP3A4 revealed a combination of three types of interactions: hydrophobic interactions, electrostatic interactions and hydrogen bonds. A docking simulation revealed that the RA lacked an important binding feature, as compared to resveratrol, and that that difference may be responsible for its lower level of affinity for CYP3A4. Software analysis of binding affinity may serve as a predictive tool for designing new therapeutic compounds in terms of inhibition of CYP3A4 and help to reveal the biochemical nature of the interactions of dietary compounds, herbal compounds and drugs whose metabolism is mediated by this enzyme. PMID- 26485400 TI - Use of Enzymatic Biosensors to Quantify Endogenous ATP or H2O2 in the Kidney. AB - Enzymatic microelectrode biosensors have been widely used to measure extracellular signaling in real-time. Most of their use has been limited to brain slices and neuronal cell cultures. Recently, this technology has been applied to the whole organs. Advances in sensor design have made possible the measuring of cell signaling in blood-perfused in vivo kidneys. The present protocols list the steps needed to measure ATP and H2O2 signaling in the rat kidney interstitium. Two separate sensor designs are used for the ex vivo and in vivo protocols. Both types of sensor are coated with a thin enzymatic biolayer on top of a permselectivity layer to give fast responding, sensitive and selective biosensors. The permselectivity layer protects the signal from the interferents in biological tissue, and the enzymatic layer utilizes the sequential catalytic reaction of glycerol kinase and glycerol-3-phosphate oxidase in the presence of ATP to produce H2O2. The set of sensors used for the ex vivo studies further detected analyte by oxidation of H2O2 on a platinum/iridium (Pt-Ir) wire electrode. The sensors for the in vivo studies are instead based on the reduction of H2O2 on a mediator coated gold electrode designed for blood-perfused tissue. Final concentration changes are detected by real-time amperometry followed by calibration to known concentrations of analyte. Additionally, the specificity of the amperometric signal can be confirmed by the addition of enzymes such as catalase and apyrase that break down H2O2 and ATP correspondingly. These sensors also rely heavily on accurate calibrations before and after each experiment. The following two protocols establish the study of real-time detection of ATP and H2O2 in kidney tissues, and can be further modified to extend the described method for use in other biological preparations or whole organs. PMID- 26485401 TI - Treating Depressive Symptoms in Psychosis: A Network Meta-Analysis on the Effects of Non-Verbal Therapies. AB - AIMS: The aim of this study was to examine whether non-verbal therapies are effective in treating depressive symptoms in psychotic disorders. MATERIAL AND METHODS: A systematic literature search was performed in PubMed, Psychinfo, Picarta, Embase and ISI Web of Science, up to January 2015. Randomized controlled trials (RCTs) comparing a non-verbal intervention to a control condition in patients with psychotic disorders, whilst measuring depressive symptoms as a primary or secondary outcome, were included. The quality of studies was assessed using the 'Clinical Trials Assessment Measure for psychological treatments' (CTAM) scale. Cohen's d was calculated as a measure of effect size. Using a Network Meta-analysis, both direct and indirect evidence was investigated. RESULTS: 10 RCTs were included, of which three were of high quality according to the CTAM. The direct evidence demonstrated a significant effect on the reduction in depressive symptoms relative to treatment as usual (TAU), in favor of overall non-verbal therapy (ES: -0.66, 95% C.I. = -0.88, -0.44) and music therapy (ES: 0.59, 95% C.I. = -0.85, -0.33). Combining both direct and indirect evidence, yoga therapy (ES: -0.79, 95% C.I. = -1.24, -0.35) had a significant effect on depressive symptoms, and occupational therapy (ES: 1.81, 95% C.I. = 0.81, 2.81) was less effective, relative to TAU. Exercise therapy did not show a significant effect on depressive symptoms in comparison to TAU (ES: -0.02 95% C.I. = -0.67, 0.62). Due to inconsistency of study evidence, the indirect effects should be interpreted cautiously. CONCLUSIONS: Non-verbal therapies appear to be effective in reducing depressive symptomatology in psychotic disorders, in particular music therapy and yoga therapy. PMID- 26485402 TI - Transcriptome Reveals 1400-Fold Upregulation of APOA4-APOC3 and 1100-Fold Downregulation of GIF in the Patients with Polycythemia-Induced Gastric Injury. AB - High-altitude polycythemia (HAPC) inducing gastric mucosal lesion (GML) is still out of control and molecular mechanisms remain widely unknown. To address the issues, endoscopy and histopathological analyses were performed. Meanwhile, microarray-based transcriptome profiling was conducted in the gastric mucosa from 3 pairs of healthy subjects and HAPC-induced GML patients. HAPC caused morphological changes and pathological damages of the gastric mucosa of GML patients. A total of 10304 differentially expressed genes (DEGs) were identified, including 4941 up-regulated and 5363 down-regulated DEGs in gastric mucosa of GML patients compared with healthy controls (fold change >=2, P<0.01 and FDR <0.01). Particularly, apolipoprotein genes APOA4 and APOC3 were 1473-fold and 1468-fold up-regulated in GML patients compared with the controls. In contrast, gastric intrinsic factor (GIF) was 1102-fold down-regulated in GML patients compared with the controls. APOA4 (chr11:116691770-116691711), APOC3 (chr11:116703530 116703589) and GIF (chr11:59603362-59603303) genes are all located on chromosome 11. APOA4 and APOC3 act as an inhibitor of gastric acid secretion while gastric acid promotes ulceration. GIF deficiency activates a program of acute anemia, which may antagonize polycythemia while polycythemia raises the risk of GML. Therefore, the present findings reveal that HAPC-induced GML inspires the protection responses by up-regulating APOA4 and APOC3, and down-regulating GIF. These results may offer the basic information for the treatment of HAPC-induced gastric lesion in the future. PMID- 26485403 TI - Robust and enduring atorvastatin-mediated memory recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats. AB - Chronic cerebral hypoperfusion (CCH) is a common condition associated with the development and/or worsening of age-related dementia.We previously reported persistent memory loss and neurodegeneration after CCH in middle-aged rats. Statin-mediated neuroprotection has been reported after acute cerebral ischemia. Unknown, however, is whether statins can alleviate the outcome of CCH. The present study investigated whether atorvastatin attenuates the cognitive and neurohistological outcome of CCH. Rats (12-15 months old) were trained in a non food-rewarded radial maze, and then subjected to CCH. Atorvastatin (10 mg/kg, p.o.) was administered for 42 days or 15 days, beginning 5 h after the first occlusion stage. Retrograde memory performance was assessed at 7, 14, 21, 28, and 35 days of CCH, and expressed by "latency," "number of reference memory errors" and "number of working memory errors." Neurodegeneration was then examined at the hippocampus and cerebral cortex. Compared to sham, CCH caused profound and persistent memory loss in the vehicle-treated groups, as indicated by increased latency (91.2% to 107.3%) and number of errors (123.5% to 2508.2%), effects from which the animals did not spontaneously recover across time. This CCH-induced retrograde amnesia was completely prevented by atorvastatin (latency: -4.3% to 3.3%; reference/working errors: -2.5% to 45.7%), regardless of the treatment duration. This effect was sustained during the entire behavioral testing period (5 weeks), even after discontinuing treatment. This robust and sustained memory protective effect of atorvastatin occurred in the absence of neuronal rescue (39.58% to 56.45% cell loss). We suggest that atorvastatin may be promising for the treatment of cognitive sequelae associated with CCH. PMID- 26485404 TI - Oxidant-Antioxidant Capacity of Dietary Guanidinoacetic Acid. AB - BACKGROUND/AIMS: Guanidinoacetic acid (GAA) is an experimental nutritional additive under the functional group amino acids and derivatives, yet its use in human nutrition is hindered by limited data on GAA safety. In this double blind, placebo-controlled pilot study, we evaluated the effects of dietary GAA (3 g/day) administered for 2 weeks on the oxidant-antioxidant system in healthy men. METHODS: Twelve healthy men (age 22.3 +/- 2.1 years) were recruited for blood sampling at baseline (day 0) and at the end of the intervention period (day 14). Fasting venous blood samples were assessed for plasma total antioxidant capacity, superoxide dismutase (SOD), glutathione peroxidase, total oxidant status and malondialdehyde. RESULTS: Fasting plasma SOD increased significantly from before to after administration in GAA-supplemented participants (91.4 +/- 19.6 vs. 122.8 +/- 25.9 ng/ml; p = 0.04). Other markers of oxidant-antioxidant system were not affected by the placebo or GAA intervention (p > 0.05). CONCLUSIONS: Oral GAA did not impact the cumulative action of antioxidants present in plasma, yet its SOD boosting capacity might be considered beneficial when GAA is used as a dietary supplement. Further studies are needed to reveal the direct effects of GAA ingestion on markers of lipid and protein oxidation and on DNA damage. PMID- 26485405 TI - Association between Ocular Axial Length-Related Genes and High Myopia in a Han Chinese Population. AB - AIMS: A previous genome-wide association study of high myopia identified five genome-wide loci for ocular axial length (C3orf26, ZC3H11B, RSPO1, GJD2, and ZNRF3). The aim of our study was to investigate the association between high myopia and genetic variants in the five loci in Han Chinese subjects. METHODS: Five single nucleotide polymorphisms were genotyped in 296 unrelated high-myopia subjects and 300 matched emmetropic controls by the SNaPshot method. The distribution of genotypes in the cases and controls was compared in codominant, dominant, and recessive genetic models by using SNPStats online software. RESULTS: Significant associations between rs994767 near ZC3H11B (p = 0.001), rs4074961 in RSPO1 (p < 0.001), and rs11073058 in GJD2 (p = 0.029) and high myopia were observed. Odds ratios (95% confidence intervals) were 1.532 (1.200 1.955), 1.603 (1.267-2.029), and 1.290 (1.027-1.621) for the rs994767 T allele, rs4074961 T allele, and rs11073058 T allele, respectively. But rs9811920 in C3orf26 and rs12321 in ZNRF3 were not associated with high myopia. CONCLUSION: Our findings suggested that genetic variants in ZC3H11B, RSPO1, and GJD2 are associated with susceptibility to the development of high myopia in a Han Chinese population. Functional roles of ZC3H11B, RSPO1, and GJD2 in the pathology of high myopia need to be further investigated. PMID- 26485406 TI - Low dose evaluation of the antiandrogen flutamide following a Mode of Action approach. AB - The dose-response characterization of endocrine mediated toxicity is an on-going debate which is controversial when exploring the nature of the dose-response curve and the effect at the low-end of the curve. To contribute to this debate we have assessed the effects of a wide range of dose levels of the antiandrogen flutamide (FLU) on 7-week male Wistar rats. FLU was administered by oral gavage at doses of 0, 0.001, 0.01, 0.1, 1 and 10mg/kg/day for 28 days. To evaluate the reproducibility, the study was performed 3 times. The molecular initiating event (MIE; AR antagonism), the key events (LH increase, Leydig cell proliferation and hyperplasia increases) and associated events involved in the mode of action (MOA) of FLU induced testicular toxicity were characterized to address the dose response concordance. Results showed no effects at low doses (<0.1mg/kg/day) for the different key events studied. The histopathological changes (Leydig cell hyperplasia) observed at 1 and 10mg/kg/day were associated with an increase in steroidogenesis gene expression in the testis from 1mg/kg/day, as well as an increase in testosterone blood level at 10mg/kg/day. Each key event dose-response was in good concordance with the MOA of FLU on the testis. From the available results, only monotonic dose-response curves were observed for the MIE, the key events, associated events and in effects observed in other sex related tissues. All the results, so far, show that the reference endocrine disruptor FLU induces threshold effects in a standard 28-day toxicity study on adult male rats. PMID- 26485407 TI - Photonic hydrogel sensors. AB - Analyte-sensitive hydrogels that incorporate optical structures have emerged as sensing platforms for point-of-care diagnostics. The optical properties of the hydrogel sensors can be rationally designed and fabricated through self-assembly, microfabrication or laser writing. The advantages of photonic hydrogel sensors over conventional assay formats include label-free, quantitative, reusable, and continuous measurement capability that can be integrated with equipment-free text or image display. This Review explains the operation principles of photonic hydrogel sensors, presents syntheses of stimuli-responsive polymers, and provides an overview of qualitative and quantitative readout technologies. Applications in clinical samples are discussed, and potential future directions are identified. PMID- 26485408 TI - Glucose homeostasis after simultaneous pancreas and kidney transplantation: a comparison of subjects with C-peptide-positive non-type 1 diabetes mellitus and type 1 diabetes mellitus. AB - BACKGROUND: While simultaneous pancreas kidney transplant (SPKTx) is a therapeutic option for patients with type 1 diabetes (T1DM) and renal failure, few centers offer SPKTx to "select" non-T1DM patients. To address concerns that existing insulin resistance may limit the benefits of the pancreas allograft among non-T1DM, we compared several indices of glucose homeostasis, in "select" non-T1DM and T1DM patients who received SPKTx. METHODS: Criteria for "select" non T1DM included the following: positive C-peptide, BMI <30 kg/m(2) , treatment with oral agents before insulin initiation, and insulin at <1 unit/kg/d. We compared several indices of glucose homeostasis within 1 yr post-SPKTx among seven "select" patients with non-T1DM and nine patients with T1DM with similar age, BMI, and immunosuppression. Measurements of insulin resistance included the following: homeostatic model, insulin sensitivity index, and insulin-glucose ratio; insulin secretion measures included the following: corrected insulin response. RESULTS: Non-T1DM had similar pre-transplant metabolic (fasting glucose, HbA1c, blood pressure, and lipid) parameters to the T1DM cohort. There were no significant differences in the various measures of insulin resistance and secretion between T1DM and "select" non-T1DM patients. CONCLUSION: Our results suggest SPKTx should be considered in the therapeutic armamentarium among carefully select non-T1DM with features of minimal insulin resistance; however, a larger cohort with longer follow-up is needed to confirm our results. PMID- 26485409 TI - A Novel Experimental and Analytical Approach to the Multimodal Neural Decoding of Intent During Social Interaction in Freely-behaving Human Infants. AB - Understanding typical and atypical development remains one of the fundamental questions in developmental human neuroscience. Traditionally, experimental paradigms and analysis tools have been limited to constrained laboratory tasks and contexts due to technical limitations imposed by the available set of measuring and analysis techniques and the age of the subjects. These limitations severely limit the study of developmental neural dynamics and associated neural networks engaged in cognition, perception and action in infants performing "in action and in context". This protocol presents a novel approach to study infants and young children as they freely organize their own behavior, and its consequences in a complex, partly unpredictable and highly dynamic environment. The proposed methodology integrates synchronized high-density active scalp electroencephalography (EEG), inertial measurement units (IMUs), video recording and behavioral analysis to capture brain activity and movement non-invasively in freely-behaving infants. This setup allows for the study of neural network dynamics in the developing brain, in action and context, as these networks are recruited during goal-oriented, exploration and social interaction tasks. PMID- 26485410 TI - Intraneural Granular Cell Tumor of a Cervical Dorsal Nerve Root: A Case Report and Review of the Literature. AB - BACKGROUND: Granular cell tumor (GCT) is a relatively uncommon predominantly benign lesion that usually presents as a solitary, painless cutaneous or submucosal nodule. Most of these tumors are found in the tongue. Although GCT is believed to have a Schwann cell origin, reports of GCT in peripheral and spinal nerves are uncommon. CASE DESCRIPTION: We report the case of a 43-year-old man with neck pain and hand numbness who was found to have a heterogeneously enhancing left-sided C2 nerve sheath tumor on magnetic resonance imaging. He underwent C2 decompression and resection of the left-sided C2 nerve sheath tumor with subsequent C1-C2 arthrodesis and instrumentation. Histopathologic review showed GCT. Review of the literature yielded 4 other reported cases of GCT within the vicinity of a spinal nerve root. Only one of these explicitly showed spinal nerve root involvement. This is a rare case of a GCT presenting as cervical nerve root mass, and what we believe is the first reported case of this in the literature. CONCLUSIONS: The surgeon should be aware of GCT when encountering spinal nerve root tumors because it may alter the surgical approach necessary for adequate resection compared with more commonly encountered nerve sheath tumors. PMID- 26485411 TI - Recurrent Atypical Meningiomas: Combining Surgery and Radiosurgery in One Effective Multimodal Treatment. AB - OBJECTIVE: Owing to their rarity and proteiform pathologic features, the clinical behavior of atypical meningiomas is not yet well characterized. Though the extent of resection is believed to be a key determinant of prognosis, limited data exist regarding optimal management of patients with recurrent disease. METHODS: In this 20-year retrospective case series, we reviewed the medical records of 46 patients with recurrent atypical meningiomas (185 lesions, 89 of which were local, 78 marginal, and 18 distant recurrences); treatment was radiosurgery (n = 60), surgery (n = 56), or both (n = 8). The median follow-up period was 53 months. Outcome measures were length of overall survival and disease-free intervals and prognostic factors for survival. RESULTS: Overall, the median progression-free survival was 26 months at the first recurrence and 100 months thereafter (the sum of the later intervals). Multivariate analysis showed that no treatment-related factors influenced prognosis, whereas recurrence at the skull base was a significant tumor-related factor limiting further treatment. Irrespective of treatment type, the recurrence-free interval was increasingly shorter during the clinical course, with a higher occurrence of marginal and distant lesions migrating to the midline and to the skull base. In sporadic cases, disease-free intervals were longer after wide craniotomy, tumor and dural resection with tumor free margin. CONCLUSIONS: The disease-free interval was substantially similar after surgery and radiosurgery for treating recurrent disease in patients with atypical meningiomas. Surgery is the mainstay for prolonging survival, while radiosurgery can be an adjuvant strategy to gain time for clinical observation and planning aggressive surgical treatment. PMID- 26485412 TI - Surgical Treatments for Chronic Subdural Hematomas: A Comprehensive Systematic Review. AB - BACKGROUND: Chronic subdural hematomas (CSDHs) are common neurosurgical conditions among elderly patients. OBJECTIVE: To perform a detailed critical appraisal of all randomized controlled trials (RCTs) of surgical treatments for chronic subdural hematomas and to quantify their intervention effects. METHODS: We performed a broad search for all RCTs with no language or date restrictions, asked the authors for missing data, and applied the Cochrane methods. RESULTS: A total of 24 RCTs involved 1900 patients and 15 comparisons. All outcomes of practical interest were analyzed. Postoperative drainage after burr-hole evacuation reduced the rate of recurrence (risk ratio 0.48, 95% confidence interval 0.34-0.66, P < 0.00001) with no other clear benefits or complications. CONCLUSIONS: This comprehensive, best evidence-based, quantitative, systematic review indicates that the use of a closed system drainage after burr-hole evacuation reduces the rate of recurrences but has no other significant differences. The findings also suggest that: (1) treatment with twist drills is equivalent to that with burr holes; (2) the postoperative bed header in the elevated position might reduce the length of hospital stay; (3) irrigation of the subdural space with thrombin solution in patients with high risk of recurrence might reduce this risk; and (4) treatment with twist drill followed by a closed system drainage during 48 hours, instead of 96 hours, might reduce general complication rates. Most of the trials suffered from unclear or high risks of bias and many involved small samples, precluding strong and definitive conclusions. PMID- 26485413 TI - Diagnosis and Management of Combined Central Diabetes Insipidus and Cerebral Salt Wasting Syndrome After Traumatic Brain Injury. AB - BACKGROUND: Combined central diabetes insipidus and cerebral salt wasting syndrome after traumatic brain injury (TBI) is rare, is characterized by massive polyuria leading to severe water and electrolyte disturbances, and usually is associated with very high mortality mainly as a result of delayed diagnosis and improper management. METHODS: We retrospectively reviewed the clinical presentation, management, and outcomes of 11 patients who developed combined central diabetes insipidus and cerebral salt wasting syndrome after traumatic brain injury to define distinctive features for timely diagnosis and proper management. RESULTS: The most typical clinical presentation was massive polyuria (10,000 mL/24 hours or >1000 mL/hour) refractory to vasopressin alone but responsive to vasopressin plus cortisone acetate. Other characteristic presentations included low central venous pressure, high brain natriuretic peptide precursor level without cardiac dysfunction, high 24-hour urine sodium excretion and hypovolemia, and much higher urine than serum osmolarity; normal serum sodium level and urine specific gravity can also be present. Timely and adequate infusion of sodium chloride was key in treatment. Of 11 patients, 5 had a good prognosis 3 months later (Extended Glasgow Outcome Scale score >=6), 1 had an Extended Glasgow Outcome Scale score of 4, 2 died in the hospital of brain hernia, and 3 developed a vegetative state. CONCLUSIONS: For combined diabetes insipidus and cerebral salt wasting syndrome after traumatic brain injury, massive polyuria is a major typical presentation, and intensive monitoring of fluid and sodium status is key for timely diagnosis. To achieve a favorable outcome, proper sodium chloride supplementation and cortisone acetate and vasopressin coadministration are key. PMID- 26485414 TI - Endovascular Treatment of a Fusiform Aneurysm at the M3-M4 Junction of the Middle Cerebral Artery Using the Pipeline Embolization Device. AB - BACKGROUND: Peripheral fusiform cerebral aneurysms remain difficult to treat. Current surgical approaches to the treatment of fusiform aneurysms include wrapping, clip occlusion or vessel reconstruction without parent vessel sacrifice, and aneurysm trapping with or without bypass, although these may carry high morbidity (36%). Classic endovascular approaches to the treatment of peripheral aneurysms include selective or parent artery occlusion, which imparts the risk of distal infarction. It may be possible to use a flow diversion device off label to treat the aneurysm and preserve flow to the distal territory. CASE DESCRIPTION: After a presyncopal event, a patient was found to have an unruptured fusiform aneurysm at the junction of the M3 and M4 segments of the right middle cerebral artery. After initiating dual antiplatelet therapy, the aneurysm was successfully treated with a Pipeline embolization device. Three months after treatment, the aneurysm has completely thrombosed, the parent artery remains widely patent, and the patient remains at her neurologic baseline. CONCLUSIONS: Flow diversion devices may provide the neurointerventional surgeon with an opportunity to treat fusiform peripheral aneurysms and preserve flow to the distal territory. PMID- 26485415 TI - Relationship Between Clinical Features and T2-Weighted Magnetic Resonance Images in Symptomatic Rathke Cleft Cysts. AB - BACKGROUND: It is not known when surgery is appropriate for the treatment for incidental Rathke cleft cysts because knowledge of their natural history is lacking. In this study, we sought to determine whether symptomatic Rathke cleft cysts could be distinguished by their signal intensities in magnetic resonance (MR) images. We analyzed the relationship between these signal intensities and clinical manifestations of the cysts and their patterns of expansion. METHODS: MR signal intensities on T1-weighted (T1W) and T2-weighted (T2W) images for 52 cases were categorized into 3 types. Type 1 (20 cases) showed low signal intensities on T1W images and hyperintensity on T2W images. Type 2 (10 cases) showed hyperintensity on both T1W and T2W images. Type 3 (22 cases) showed hypointensity on T2W images. RESULTS: A significantly higher proportion of patients with type 1 signal intensities had large cysts compressing their third ventricle than patients with the other 2 types of signal intensities. Patients with type 1 signal intensities also frequently had visual disturbances. Anterior pituitary dysfunction was observed more often in patients with type 2 or 3 signal intensities than in patients with type 1 intensities. CONCLUSIONS: We conclude that Rathke cleft cysts that show an MR signal intensity similar to that of cerebrospinal fluid grow slowly and are frequently diagnosed as cysts associated with visual disturbance when they become large. It may be possible to predict the clinical progression of Rathke cleft cysts by assessing MR signal intensities. PMID- 26485416 TI - Cerebellar Enterogenous Cyst with Atypical Appearance and Pathological Findings. AB - BACKGROUND: Intracranial enterogenous cysts are rare and occur mainly in the posterior fossa. These cysts are usually extra-axial, midline, anterior to the brainstem, or at the cerebellopontine angle. Intracranial intra-axial enterogenous cysts are extremely rare. We report a case of an intra-axial cerebellar enterogenous cyst in which diagnosis was difficult because the lesion resembled an arachnoid cyst in appearance and showed atypical pathologic findings. CASE DESCRIPTION: A 69-year-old woman had a 2-year history of progressive headache, giddiness, and unsteadiness of gait. Magnetic resonance imaging showed a cystic lesion with isointensity to cerebrospinal fluid in the left cerebellar hemisphere, reaching into the fourth ventricle. The patient underwent fenestration of the cyst and creation of a communication between the fourth ventricle and cyst because the tight attachment of the cyst wall to the cerebellum prevented total removal of the cyst. Although pathologic examinations did not show findings typical of enterogenous cyst, the diagnosis was finally made based on the presence of basement membrane and immunohistochemical results. CONCLUSION: The diagnosis of enterogenous cyst is based mainly on histologic findings, because characteristic findings on neuroimaging have not been defined. Although total resection of enterogenous cysts is recommended in general, partial resection while ensuring the cyst communicates adequately with the surrounding cerebrospinal fluid space with or without a shunt procedure may be useful if the cyst is adherent to surrounding neurovascular structures. PMID- 26485417 TI - Gamma Knife Radiosurgery for Atypical and Anaplastic Meningiomas. AB - BACKGROUND: Atypical and anaplastic meningiomas have much higher recurrence rates after surgical resection compared with benign meningiomas, but the role of adjuvant radiosurgery remains unclear. This study was undertaken to evaluate the outcomes of gamma knife radiosurgery for patients with atypical and anaplastic meningiomas. METHODS: In this retrospective analysis of a prospectively maintained database, 46 patients with histologically proven atypical or anaplastic meningiomas by current World Health Organization (WHO) criteria underwent postoperative Gamma Knife radiosurgery between 1993 and 2013. The median follow-up period was 32.6 months. The median tumor volume and margin dose were 11.7 mL (range, 2-53 mL) and 13.1 Gy (range, 12.0-16.5 Gy), respectively. RESULTS: Local control at 3 and 5 years was 50.6% and 32.1%, respectively. Gender (P = 0.013) and marginal dose less than or equal to 13 Gy (P = 0.049) were associated with the local control. The 3- and 5-year overall survival for patients with WHO grade II was 97.1% and 88.3%, respectively, compared with 66.7% and 66.7% for patients with WHO grade III meningiomas. Radiation therapy before Gamma Knife radiosurgery (GKRS; P = 0.018) and tumor grade (P = 0.019) were the factors associated with a worse overall survival rate. Fourteen patients (30.4%) developed adverse radiation effects after GKRS treatment, and all were Radiation Therapy Oncology Group grade I. CONCLUSIONS: Postoperative GKRS treatment for patients with atypical and anaplastic meningioma is challenging. More aggressive treatment, including of safely maximizing the extent of surgical resection and using a higher margin dose (>13Gy), should be applied to achieve better local control. PMID- 26485418 TI - Extensive Multilocular Spinal Extradural Meningeal Cyst That Developed 16 Years After Traumatic Brachial Plexus Injury: A Case Report. AB - BACKGROUND: Symptomatic extensive spinal extradural meningeal cyst (SEMC) developing after traumatic brachial plexus injury (TBPI) is rare. We discuss the mechanism of extensive SEMC development, surgical strategies, and preventive measures against SEMC after TBPI. CASE DESCRIPTION: A 58-year-old man with TBPI 16 years previously developed spastic paraparesis of the lower limbs, sensory disturbance below the periumbilical level, and dysfunction of bladder and bowel over 2 years. The patient couldn't walk and was wheelchair bound. Magnetic resonance imaging (MRI) revealed an extensive multilocular extradural cyst posterior to the spinal cord ranging from the C4 to Th6 level, associated with severe spinal cord compression. On constructive interference in steady-state MRI, the cyst was divided, with many septa, and extended to the root sleeves. During the operation, transdural communication sites of cerebrospinal fluid (CSF) into the cyst were revealed at C5/6, C6/7, and C7/Th1 levels around the nerve root sleeves. Treatment involved unroofing of the cyst wall and closure of the transdural CSF communication without cyst removal. Autologous muscle pieces were placed over the defect to close the transdural communication. Two weeks postoperatively, MRI showed decreased cyst size and reduced spinal cord compression, and the patient could walk without support. It was thought that the patient's daily lifting of heavy weights at work and an excessive exercise regimen increased CSF pressure and cyst size after TBPI. CONCLUSION: For patients with TBPI, it is necessary to prevent greater CSF pressure and to perform long term follow-up MRI after injury. PMID- 26485419 TI - Traumatic Brain Injury Epidemiology in Brazil. AB - BACKGROUND: Traumatic brain injury (TBI) stands out as a grave social and economic problem. Emerging countries possess few epidemiologic studies on the range and impact of TBI. OBJECTIVE: Our study aimed to characterize the demographic, social, and economic profile of people suffering from TBI in Brazil. METHODS: Data on TBI cases in Brazil between 2008 and 2012 were collected through the website of the Information Technology Department of the Unified Health System (DATASUS) maintained by the Brazilian Ministry of Health. This database is fed by public hospital admission authorization forms provided nationwide. RESULTS: There were around 125,000 hospital admissions due to TBI a year, an incidence of 65.7 admissions per 100,000 inhabitants per year. Hospital mortality was 5.1/100,000/year, and the case fatality rate was 7.7%. The average annual cost of hospital expenses was US$ 70,960,000, with an average cost per admission of US$ 568. The age group 20-29, frequently admitted to the hospital due to TBI, presented the largest number of hospital deaths; however, the population >80 years of age showed the highest admission rate per age group, around 138/100,000/year, followed by the age group 70-79. CONCLUSIONS: TBI should be recognized as an important public health problem in Brazil because it is responsible for considerable social and economic costs. Besides the young adult age group (20-29 years old), the geriatric age group is especially vulnerable to the frequent and devastating consequences of TBI. The implementation of a system of effective epidemiologic vigilance for neurotrauma is urgent in Brazil and other countries worldwide. PMID- 26485420 TI - Transorbital Ultrasonographic Measurement of Optic Nerve Sheath Diameter for Intracranial Midline Shift in Patients with Head Trauma. AB - OBJECTIVE: Measurement of the optic nerve sheath diameter (ONSD) by using sonography is a straightforward, noninvasive technique to detect an increased intracranial pressure, which can even be conducted at the bedside. However, the correlation between ONSD and intracranial midline shift has not been studied. METHODS: The authors performed a prospective, blinded observational study in an intensive care unit. Forty-five patients were divided into groups. Of those, 19 patients had a midline shift, whereas 26 had no intracranial pathology or shift and served as control individuals. RESULTS: Spearman rank correlation coefficient of difference of ONSD and midline shift was 0.761 (P < 0.0005), demonstrating a significant positive correlation between patients with midline shift and control group. CONCLUSIONS: Despite small numbers and selection bias, this study suggests that bedside ultrasound may be useful in the diagnosis of midline intracranial shift by measurement of ONSD. PMID- 26485421 TI - Which Strategy for Petroclival Tumors? PMID- 26485424 TI - Erratum: Selective Connexin43 Inhibition Prevents Isoproterenol-Induced Arrhythmias and Lethality in Muscular Dystrophy Mice. PMID- 26485423 TI - Successful treatment of hepatitis C virus infection with sofosbuvir and simeprevir in the early phase of an allogeneic stem cell transplant. AB - Currently, a lack of consensus exists on how to manage a hepatitis C virus (HCV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ribavirin alone, or in combination with interferon, has been the mainstream therapy for HCV infection after transplantation. However, very few patients have been regularly treated owing to concerns about poor tolerability, frequent side effects, and limited efficacy. The present case illustrates the striking efficacy of the combination therapy of sofosbuvir with simeprevir, early after transplantation, as it was able to completely eliminate viral replication within 1 month of initiation of treatment. Moreover, tolerance was good, with only minor interactions between the immunosuppressive drugs. This case report supports the feasibility of using this combination therapy early after allo-HSCT for patients with HCV infection. PMID- 26485422 TI - Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group. AB - BACKGROUND: The details of leukostasis in children and adolescents with chronic myeloid leukemia (CML) are unknown. This study determined the characteristics of leukostasis in children and adolescents with CML. PROCEDURE: A total of 256 cases from a retrospective study of patients with CML conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group from 1996 to 2011 were analyzed, and of these, 238 cases were evaluated in this study. RESULTS: Leukostasis was diagnosed in 23 patients (9.7%). The median leukocyte count and spleen size below the left costal margin in cases with leukostasis were significantly higher and larger when compared to those in cases without leukostasis (458.5 * 10(9) /l vs. 151.8 * 10(9) /l (P < 0.01), and 13 vs. 5 cm (P < 0.01), respectively). Leukostasis occurred with ocular symptoms in 14 cases, priapism in four cases, and dyspnea, syncope, headache, knee pain, difficulty hearing, and aseptic necrosis of the femoral head in one case each. One case had two leukostasis symptoms simultaneously. Three cases were diagnosed before imatinib became available. Five cases received special treatment, and in the remaining 15 cases, all of these symptoms resolved after treatment with imatinib. CONCLUSIONS: This retrospective study represents the largest series of children and adolescents in which leukostasis of CML has been reported. Our data provide useful insight into the characteristics of leukostasis in recent cases of children and adolescents with CML. PMID- 26485425 TI - Progressive Dopamine Transporter Binding Loss in Autopsy-Confirmed Corticobasal Degeneration. AB - BACKGROUND: Corticobasal degeneration (CBD) is characterized by neuronal and glial deposition of 4-repeat tau in the frontal and parietal cerebral cortex, white matter and striatum. There is neuronal loss in affected cortical regions and in the substantia nigra (SN). Recent single photon emission tomography (SPECT) studies have reported normal striatal dopamine transporter (DAT) binding in individual patients with CBD. OBJECTIVE: To study the pattern and course of DAT binding loss in CBD. METHODS: We retrospectively analyzed DAT SPECT studies in two patients presenting with a corticobasal syndrome in whom a diagnosis of CBD was later confirmed pathologically. RESULTS: Baseline scans at 1.5 years after symptom onset revealed only mild abnormalities (reduced uptake in one putamen). Follow up scans at 4.5 years (Case 1) and 5 years (Case 2) after symptom onset showed a marked decline of striatal DAT binding. In both cases, there was a 37% binding reduction from the age-expected striatal binding value. Asymmetry of striatal DAT binding had increased from mild in the first SPECT studies to moderate at the time of their final imaging. CONCLUSION: CBD patients can have delayed neuronal loss in the SN. Follow up DAT imaging may be of value in patients with possible CBD and a normal baseline scan. PMID- 26485426 TI - Non-Motor Correlates of Smoking Habits in de Novo Parkinson's Disease. AB - BACKGROUND: Parkinson's disease (PD) subjects are less likely to ever smoke and are more prone to quit smoking, as compared to controls. Therefore, smoking habits can be considered part of the non-motor phenotype, preceding the onset of motor PD by several years. OBJECTIVE: To explore non-motor symptom (NMS) correlates of smoking habits in de novo PD. METHODS: This cross-sectional study included 281 newly diagnosed, drug-naive PD subjects, recruited in Naples (Italy) and in Kassel (Germany). All subjects completed the NMS Questionnaire (NMSQ), and were investigated for smoking status (never, current and former smokers) and intensity (pack-years). RESULTS: 140 PD subjects never smoked, 20 currently smoked, and 121 had quit smoking before PD diagnosis. NMSQ total score did not associate with smoking status, but with smoking intensity (p = 0.028; coefficient = 0.088). A multinomial logistic regression stepwise model presenting never smoking as reference, selected as NMSQ correlates of current smoking: sex difficulties (p = 0.002; OR = 5.254), daytime sleepiness (p = 0.046; OR = 0.085), insomnia (p = 0.025; OR = 0.135), and vivid dreams (p = 0.040; OR = 3.110); and of former smoking: swallowing (p = 0.013; OR = 0.311), nausea (p = 0.027; OR = 7.157), unexplained pains (p = 0.002; OR = 3.409), forgetfulness (p = 0.005; OR = 2.592), sex interest (p = 0.007; OR = 0.221), sex difficulties (p = 0.038; OR = 4.215), and daytime sleepiness (p = 0.05; OR = 0.372). An ordinal logistic regression stepwise model selected as NMSQ correlates of smoking intensity: nocturnal restlessness (p = 0.027; coefficient = 0.974), and leg swelling (p = 0.004; coefficient = 1.305). CONCLUSIONS: Certain NMSs are associated with different smoking status and intensity, suggesting a variety of adaptive mechanisms to cigarette smoking. PMID- 26485427 TI - Audiovisual Processing is Abnormal in Parkinson's Disease and Correlates with Freezing of Gait and Disease Duration. AB - BACKGROUND: Sensory and perceptual disturbances progress with disease duration in Parkinson's disease (PD) and probably contribute to motor deficits such as bradykinesia and gait disturbances, including freezing of gait (FOG). Simple reaction time tests are ideal to explore sensory processing, as they require little cognitive processing. Multisensory integration is the ability of the brain to integrate sensory information from multiple modalities into a single coherent percept, which is crucial for complex motor tasks such as gait. OBJECTIVES: The aims of this study were to: 1. Assess differences in unisensory (auditory and visual) and multisensory processing speed in people with PD and age-matched healthy controls. 2. Compare relative differences in unisensory processing in people with PD with disease duration and freezing of gait status taking into account the motor delays, which are invariably present in PD. 3. Compare relative differences in multisensory (audiovisual) processing between the PD cohort and age-matched controls. METHODS: 39 people with PD (23 with FOG) and 17 age-matched healthy controls performed a reaction time task in response to unisensory (auditory-alone, visual-alone) and multisensory (audiovisual) stimuli. RESULTS: The PD group were significantly slower than controls for all conditions compared with healthy controls but auditory reaction times were significantly faster than visual for the PD group only. These relative unisensory differences are correlated with disease duration and divide the PD group by FOG status, but these factors are co-dependent. Although multisensory facilitation occurs in PD, it is significantly less enhanced than in healthy controls. CONCLUSION: There are significant unisensory and multisensory processing abnormalities in PD. The relative differences in unisensory processing are specific to PD progression, providing a link between these sensory abnormalities and a motor feature of PD. Sensory disturbances have previously been postulated to be central to FOG but this is the first study to predict audiovisual processing abnormalities using FOG status. The multisensory processing abnormalities are independent of disease duration and FOG status and may be a potential biomarker for the disease. PMID- 26485431 TI - Experimental Study of the Flexural and Compression Performance of an Innovative Pultruded Glass-Fiber-Reinforced Polymer-Wood Composite Profile. AB - The plate of a pultruded fiber-reinforced polymer or fiber-reinforced plastic (FRP) profile produced via a pultrusion process is likely to undergo local buckling and cracking along the fiber direction under an external load. In this study, we constructed a pultruded glass-fiber-reinforced polymer-light wood composite (PGWC) profile to explore its mechanical performance. A rectangular cross-sectional PGWC profile was fabricated with a paulownia wood core, alkali free glass fiber filaments, and unsaturated phthalate resin. Three-point bending and short column axial compression tests were conducted. Then, the stress calculation for the PGWC profile in the bending and axial compression tests was performed using the Timoshenko beam theory and the composite component analysis method to derive the flexural and axial compression rigidity of the profile during the elastic stress stage. The flexural capacity for this type of PGWC profile is 3.3-fold the sum of the flexural capacities of the wood core and the glass-fiber-reinforced polymer (GFRP) shell. The equivalent flexural rigidity is 1.5-fold the summed flexural rigidity of the wood core and GFRP shell. The maximum axial compressive bearing capacity for this type of PGWC profile can reach 1.79-fold the sum of those of the wood core and GFRP shell, and its elastic flexural rigidity is 1.2-fold the sum of their rigidities. These results indicate that in PGWC profiles, GFRP and wood materials have a positive combined effect. This study produced a pultruded composite material product with excellent mechanical performance for application in structures that require a large bearing capacity. PMID- 26485430 TI - Transforming Growth Factor-beta-Induced KDM4B Promotes Chondrogenic Differentiation of Human Mesenchymal Stem Cells. AB - The high prevalence of cartilage diseases and limited treatment options create a significant biomedical burden. Due to the inability of cartilage to regenerate itself, introducing chondrocyte progenitor cells to the affected site is of significant interest in cartilage regenerative therapies. Tissue engineering approaches using human mesenchymal stem cells (MSCs) are promising due to their chondrogenic potential, but a comprehensive understanding of the mechanisms governing the fate of MSCs is required for precise therapeutic applications in cartilage regeneration. TGF-beta is known to induce chondrogenesis by activating SMAD signaling pathway and upregulating chondrogenic genes such as SOX9; however, the epigenetic regulation of TGF-beta-mediated chondrogenesis is not understood. In this report, we found that TGF-beta dramatically induced the expression of KDM4B in MSCs. When KDM4B was overexpressed, chondrogenic differentiation was significantly enhanced while KDM4B depletion by shRNA led to a significant reduction in chondrogenic potential. Mechanistically, upon TGF-beta stimulation, KDM4B was recruited to the SOX9 promoter, removed the silencing H3K9me3 marks, and activated the transcription of SOX9. Furthermore, KDM4B depletion reduced the occupancy of SMAD3 in the SOX9 promoter, suggesting that KDM4B is required for SMAD-dependent coactivation of SOX9. Our results demonstrate the critical role of KDM4B in the epigenetic regulation of TGF-beta-mediated chondrogenic differentiation of MSCs. Since histone demethylases are chemically modifiable, KDM4B may be a novel therapeutic target in cartilage regenerative therapy. PMID- 26485429 TI - The Concept of Prodromal Parkinson's Disease. AB - Parkinson's disease (PD) is currently clinically defined by a set of cardinal motor features centred on the presence of bradykinesia and at least one additional motor symptom out of tremor, rigidity or postural instability. However, converging evidence from clinical, neuropathological, and imaging research suggests initiation of PD-specific pathology prior to appearance of these classical motor signs. This latent phase of neurodegeneration in PD is of particular relevance in relation to the development of disease-modifying or neuroprotective therapies which would require intervention at the earliest stages of disease. A key challenge in PD research, therefore, is to identify and validate markers for the preclinical and prodromal stages of the illness. Currently, several nonmotor symptoms have been associated with an increased risk to develop PD in otherwise healthy individuals and ongoing research is aimed at validating a variety of candidate PD biomarkers based on imaging, genetic, proteomic, or metabolomic signatures, supplemented by work on tissue markers accessible to minimally invasive biopsies. In fact, the recently defined MDS research criteria for prodromal PD have included combinations of risk and prodromal markers allowing to define target populations of future disease modification trials. PMID- 26485432 TI - Ecophysiological constraints of Aster tripolium under extreme thermal events impacts: Merging biophysical, biochemical and genetic insights. AB - Cold and heat waves are phenomenon that occurs in higher frequency and intensity due to global climate changes. Commonly cultivated crop species are crucially affected by extreme weather events, and therefore alternative crops - such as halophytes - gain in agricultural interest. While halophytes are potentially able to cope with temperature extremes on the long term exposure, effects of temporary events such as cold and heat waves are not yet described. In order to unveil the effects of these altered thermal environments, Aster tripolium plants were subjected to cold (9/5 degrees C) and heat (42/38 degrees C) waves regimes during 3 days and its photochemical and biochemical traits evaluated. In the potential cash crop A. tripolium cold waves induced the gene expression of dehydrins in order to counteract desiccation and thus to prevent oxidative stress. Regulatory proteins on the RNA maturation level (Maturase K) were highly expressed. Heat stress induced the gene expression of the cystein protease gene; most likely to degrade misfolded proteins temporary. Both thermal treatments decreased the photosynthetic efficiency and capacity, driven by a loss in the connectivity between PSII antennae. Nevertheless the light absorption capacity was unaffected due to an increased RC closure net rate. Cold wave-treated individuals showed a decrease in the carotenoid pigmentation, except auroxanthin. In cold wave treated individuals the overall peroxidase activity was significantly increased. Data suggest that exposure to both, cold and heat wave treatment decreased the ecophysiological capacity of A. tripolium. PMID- 26485428 TI - Tracking Parkinson's: Study Design and Baseline Patient Data. AB - BACKGROUND: There is wide variation in the phenotypic expression of Parkinson's disease (PD), which is driven by both genetic and epidemiological influences. OBJECTIVES: To define and explain variation in the clinical phenotype of PD, in relation to genotypic variation. METHODS: Tracking Parkinson's is a multicentre prospective longitudinal epidemiologic and biomarker study of PD. Patients attending specialist clinics in the United Kingdom with recent onset (<3.5 years) and young onset (diagnosed <50 years of age) PD were enrolled. Motor, non-motor and quality of life assessments were performed using validated scales. Cases are followed up 6 monthly up to 4.5 years for recent onset PD, and up to 1 year for young onset PD. We present here baseline clinical data from this large and demographically representative cohort. RESULTS: 2247 PD cases were recruited (1987 recent onset, 260 young onset). Recent onset cases had a mean (standard deviation, SD) age of 67.6 years (9.3) at study entry, 65.7% males, with disease duration 1.3 years (0.9), MDS-UPDRS 3 scores 22.9 (12.3), LEDD 295 mg/day (211) and PDQ-8 score 5.9 (4.8). Young onset cases were 53.5 years old (7.8) at study entry, 66.9% male, with disease duration 10.2 years (6.7), MDS-UPDRS 3 scores 27.4 (15.3), LEDD 926 mg/day (567) and PDQ-8 score 11.6 (6.1). CONCLUSIONS: We have established a large clinical PD cohort, consisting of young onset and recent onset cases, which is designed to evaluate variation in clinical expression, in relation to genetic influences, and which offers a platform for future imaging and biomarker research. PMID- 26485433 TI - 3,5 Diiodo-L-Thyronine (T2) Does Not Prevent Hepatic Steatosis or Insulin Resistance in Fat-Fed Sprague Dawley Rats. AB - Thyroid hormone mimetics are alluring potential therapies for diseases like dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and insulin resistance. Though diiodothyronines are thought inactive, pharmacologic treatment with 3,5- Diiodo-L-Thyronine (T2) reportedly reduces hepatic lipid content and improves glucose tolerance in fat-fed male rats. To test this, male Sprague Dawley rats fed a safflower-oil based high-fat diet were treated with T2 (0.25 mg/kg-d) or vehicle. Neither 10 nor 30 days of T2 treatment had an effect on weight, adiposity, plasma fatty acids, or hepatic steatosis. Insulin action was quantified in vivo by a hyperinsulinemic-euglycemic clamp. T2 did not alter fasting plasma glucose or insulin concentration. Basal endogenous glucose production (EGP) rate was unchanged. During the clamp, there was no difference in insulin stimulated whole body glucose disposal. Insulin suppressed EGP by 60% +/- 10 in T2-treated rats as compared with 47% +/- 4 suppression in the vehicle group (p = 0.32). This was associated with an improvement in hepatic insulin signaling; insulin stimulated Akt phosphorylation was ~2.5 fold greater in the T2-treated group as compared with the vehicle-treated group (p = 0.003). There was no change in expression of genes thought to mediate the effect of T2 on hepatic metabolism, including genes that regulate hepatic lipid oxidation (ppara, carnitine palmitoyltransferase 1a), genes that regulate hepatic fatty acid synthesis (srebp1c, acetyl coa carboxylase, fatty acid synthase), and genes involved in glycolysis and gluconeogenesis (L-pyruvate kinase, glucose 6 phosphatase). Therefore, in contrast with previous reports, in Sprague Dawley rats fed an unsaturated fat diet, T2 administration failed to improve NAFLD or whole body insulin sensitivity. Though there was a modest improvement in hepatic insulin signaling, this was not associated with significant differences in hepatic insulin action. Further study will be necessary before diiodothyronines can be considered an effective treatment for NAFLD and dyslipidemia. PMID- 26485434 TI - Hemispheric Asymmetries in Repetition Enhancement and Suppression Effects in the Newborn Brain. AB - BACKGROUND: The repeated presentation of stimuli typically attenuates neural responses (repetition suppression) or, less commonly, increases them (repetition enhancement) when stimuli are highly complex, degraded or presented under noisy conditions. In adult functional neuroimaging research, these repetition effects are considered as neural correlates of habituation. The development and respective functional significance of these effects in infancy remain largely unknown. OBJECTIVE: This study investigates repetition effects in newborns using functional near-infrared spectroscopy, and specifically the role of stimulus complexity in evoking a repetition enhancement vs. a repetition suppression response, following up on Gervain et al. (2008). In that study, abstract rule learning was found at birth in cortical areas specific to speech processing, as evidenced by a left-lateralized repetition enhancement of the hemodynamic response to highly variable speech sequences conforming to a repetition-based ABB artificial grammar, but not to a random ABC grammar. METHODS: Here, the same paradigm was used to investigate how simpler stimuli (12 different sequences per condition as opposed to 140), and simpler presentation conditions (blocked rather than interleaved) would influence repetition effects at birth. RESULTS: Results revealed that the two grammars elicited different dynamics in the two hemispheres. In left fronto-temporal areas, we reproduce the early perceptual discrimination of the two grammars, with ABB giving rise to a greater response at the beginning of the experiment than ABC. In addition, the ABC grammar evoked a repetition enhancement effect over time, whereas a stable response was found for the ABB grammar. Right fronto-temporal areas showed neither initial discrimination, nor change over time to either pattern. CONCLUSION: Taken together with Gervain et al. (2008), this is the first evidence that manipulating methodological factors influences the presence or absence of neural repetition enhancement effects in newborns and stimulus variability appears a particularly important factor. Further, this temporal modulation is restricted to the left hemisphere, confirming its specialization for learning linguistic regularities from birth. PMID- 26485435 TI - In Vivo Study of Dynamics and Stability of Dendritic Spines on Olfactory Bulb Interneurons in Xenopus laevis Tadpoles. AB - Dendritic spines undergo continuous remodeling during development of the nervous system. Their stability is essential for maintaining a functional neuronal circuit. Spine dynamics and stability of cortical excitatory pyramidal neurons have been explored extensively in mammalian animal models. However, little is known about spiny interneurons in non-mammalian vertebrate models. In the present study, neuronal morphology was visualized by single-cell electroporation. Spiny neurons were surveyed in the Xenopus tadpole brain and observed to be widely distributed in the olfactory bulb and telencephalon. DsRed- or PSD95-GFP expressing spiny interneurons in the olfactory bulb were selected for in vivo time-lapse imaging. Dendritic protrusions were classified as filopodia, thin, stubby, or mushroom spines based on morphology. Dendritic spines on the interneurons were highly dynamic, especially the filopodia and thin spines. The stubby and mushroom spines were relatively more stable, although their stability significantly decreased with longer observation intervals. The 4 spine types exhibited diverse preferences during morphological transitions from one spine type to others. Sensory deprivation induced by severing the olfactory nerve to block the input of mitral/tufted cells had no significant effects on interneuron spine stability. Hence, a new model was established in Xenopus laevis tadpoles to explore dendritic spine dynamics in vivo. PMID- 26485436 TI - First-Principles Prediction of Enthalpies of Formation for Polycyclic Aromatic Hydrocarbons and Derivatives. AB - In this article, the first-principles prediction of enthalpies of formation is demonstrated for 669 polycyclic aromatic hydrocarbon (PAH) compounds and a number of related functionalized molecules. It is shown that by extrapolating density functional theory calculations to a large basis set limit and then applying a group based correction scheme that good results may be obtained. Specifically, a mean unsigned deviation and root mean squared deviation from the experimental enthalpies of formation data of 5.0 and 6.4 kJ/mol, respectively, are obtained using this scheme. This computational scheme is economical to compute and straightforward to apply, while yielding results of reasonable reliability. The results are also compared for a smaller set of molecules to the predictions given by the G3B3 and G3MP2B3 variants of the Gaussian-3 model chemistry with a mean unsigned deviation and root mean squared deviation from the experimental enthalpies of formation of 4.5 and 4.8 kJ/mol, respectively. PMID- 26485437 TI - Within-Host and Population Transmission of blaOXA-48 in K. pneumoniae and E. coli. AB - During a large hospital outbreak of OXA-48 producing bacteria, most K. pneumoniaeOXA-48 isolates were phenotypically resistant to meropenem or imipenem, whereas most E. coliOXA-48 isolates were phenotypically susceptible to these antibiotics. In the absence of molecular gene-detection E. coliOXA-48 could remain undetected, facilitating cross-transmission and horizontal gene transfer of blaOXA-48. Based on 868 longitudinal molecular microbiological screening results from patients carrying K. pneumoniaeOXA-48 (n = 24), E. coliOXA-48 (n = 17), or both (n = 40) and mathematical modelling we determined mean durations of colonisation (278 and 225 days for K. pneumoniaeOXA-48 and E. coliOXA-48, respectively), and horizontal gene transfer rates (0.0091/day from K. pneumoniae to E. coli and 0.0015/day vice versa). Based on these findings the maximum effect of horizontal gene transfer of blaOXA-48 originating from E. coliOXA-48 on the basic reproduction number (R0) is 1.9%, and it is, therefore, unlikely that phenotypically susceptible E. coliOXA-48 will contribute significantly to the spread of blaOXA-48. PMID- 26485438 TI - Effects of Hydrodynamic Interactions on the Apparent 1D Mobility of a Nonspecifically Bound Protein Following a Helical Path around DNA. AB - We investigated effects of hydrodynamic interactions on diffusivities of proteins that undergo rotation-coupled sliding along DNA. For that, we applied numerical calculations of mobility and friction tensors to systems consisting of detailed bead-shell models of DNA and proteins of different size. Using tensors that result from these calculations along with an expression for the instantaneous energy dissipation rate due to motions of a nonspecifically bound protein that follows a helical track around DNA, we evaluated apparent one-dimensional friction and mobility coefficients for model proteins. The results that we obtained indicate that hydrodynamic interactions between DNA and proteins may substantially (even several-fold) reduce the apparent one-dimensional diffusivity of proteins, when compared with results of other theoretical analyses of the rotation-coupled sliding of proteins along DNA that neglect hydrodynamic effects. Moreover, accounting for hydrodynamic effects decreases the gap between values of diffusion coefficients of proteins on DNA measured experimentally and those estimated based on theoretical calculations and analyses applied to model systems. Altogether, the current study gives insights into the significance of hydrodynamic interactions in determination of the rate of finding target sites by DNA-binding proteins. PMID- 26485439 TI - Efficacy of continuous positive airway pressure on middle ear atelectasis: A double-blind placebo-controlled clinical trial. AB - OBJECTIVES/HYPOTHESIS: To investigate the effects of continuous positive airway pressure (CPAP) treatment on patients with middle ear atelectasis. STUDY DESIGN: Prospective, double-blind, randomized, placebo-controlled study. METHODS: Fifty four patients with middle ear atelectasis were randomized to receive CPAP treatment with a pressure level of either 14 cm H2 O (CPAP group) or 0 cm H2 O (placebo group) once per week for a period of 3 hours for 4 sessions. Outcome measures included otomicroscopic examination as well as tympanometric and audiometric evaluation. Patients were followed for 6 months. RESULTS: The CPAP group included 35 atelectatic ears, and the placebo group included 32 atelectatic ears. More ears recovered to normal tympanic membrane or regressed to grade 1 atelectasis in the CPAP group than in the placebo group during all follow-up visits (P < .05). There was a statistically significant increase in the middle ear pressure values of the patients in the CPAP group compared to the placebo group at week 5, month 3, and month 6 (P < .05). There was no significant difference in middle ear pressure values between follow-up visits in the CPAP group (P > .05). Significant improvement of pure-tone air-conduction threshold averages were found in the CPAP group compared to the placebo group at month 6 (P < .05). CONCLUSIONS: CPAP is a safe, well-tolerated way of applying positive pressure to the middle ear for patients with middle ear atelectasis. It contributes to significant improvement in middle ear pressure of these patients, also resulting in an improved degree of atelectasis. LEVEL OF EVIDENCE: 1b. Laryngoscope, 126:1649-1655, 2016. PMID- 26485440 TI - Polymeric Micelles as Carriers for Nerve-Highlighting Fluorescent Probe Delivery. AB - Nerve damage during surgery is a common morbidity experienced by patients that leaves them with chronic pain and/or loss of function. Currently, no clinically approved imaging technique exists to enhance nerve visualization in the operating room. Fluorescence image-guided surgery has gained in popularity and clinical acceptance over the past decade with a handful of imaging systems approved for clinical use. However, contrast agent development to complement these fluorescence-imaging systems has lagged behind with all currently approved fluorescent agents providing untargeted blood pool information. Nerve-specific fluorophores are known, however translations of these agents to the clinic has been complicated by their lipophilic nature, which necessitates specialized formulation strategies for successful systemic administration. To date the known nerve-specific fluorophores have only been demonstrated preclinically due to the necessity of a dimethyl sulfoxide containing formulation for solubilization. In the current study, a polymeric micellar (PM) formulation strategy was developed for a representative nerve-specific fluorophore from the distyrylbenzene family, BMB. The PM formulation strategy was able to solubilize BMB and demonstrated improved nerve-specific accumulation and fluorescence intensity when the same fluorophore dose was administered to mice utilizing the previous formulation strategy. The success of the PM formulation strategy will be important for moving toward clinical translation of these novel nerve-specific probes as it is nontoxic and biodegradable and has the potential to decrease the necessary dose for imaging while also improving the safety profile. PMID- 26485441 TI - Mycotic Infections Acquired outside Areas of Known Endemicity, United States. AB - In the United States, endemic mycoses--blastomycosis, coccidioidomycosis, and histoplasmosis--pose considerable clinical and public health challenges. Although the causative fungi typically exist within broadly defined geographic areas or ecologic niches, some evidence suggests that cases have occurred in humans and animals not exposed to these areas. We describe cases acquired outside regions of traditionally defined endemicity. These patients often have severe disease, but diagnosis may be delayed because of a low index of suspicion for mycotic disease, and many more cases probably go entirely undetected. Increased awareness of these diseases, with a specific focus on their potential occurrence in unusual areas, is needed. Continued interdisciplinary efforts to reevaluate and better describe areas of true endemicity are warranted, along with a more nuanced view of the notion of endemicity. The term "nonendemic" should be used with care; mycoses in such regions might more accurately be considered "not known to be endemic." PMID- 26485442 TI - Bis-corannulene Receptors for Fullerenes Based on Klarner's Tethers: Reaching the Affinity Limits. AB - Bis-corannulene receptors 4 and 5 with Klarner's tethers prepared by the Diels Alder cycloaddition form inclusion complexes with C60 and C70, as evidenced by (1)H NMR titration. While 4 exhibits affinity toward fullerenes comparable to the previously reported corannulene-based receptors, 5 exceeds the performance of the former systems by ca. 2 orders of magnitude and, in addition, shows an enhanced preference for C70 over C60. The X-ray crystal structure of C60@5 and DFT calculations indicate that the tether in 5 not only preorganizes the pincers into a proper topology of the host but also contributes to the dispersion-based binding with the fullerene guests. PMID- 26485443 TI - Microbial communities related to biodegradation of dispersed Macondo oil at low seawater temperature with Norwegian coastal seawater. AB - The Deepwater Horizon (DWH) accident in 2010 created a deepwater plume of small oil droplets from a deepwater well in the Mississippi Canyon lease block 252 ('Macondo oil'). A novel laboratory system was used in the current study to investigate biodegradation of Macondo oil dispersions (10 MUm or 30 MUm median droplet sizes) at low oil concentrations (2 mg l(-1)) in coastal Norwegian seawater at a temperature of 4-5 degrees C. Whole metagenome analyses showed that oil biodegradation was associated with the successive increased abundances of Gammaproteobacteria, while Alphaproteobacteria (Pelagibacter) became dominant at the end of the experiment. Colwellia and Oceanospirillales were related to n alkane biodegradation, while particularly Cycloclasticus and Marinobacter were associated with degradation of aromatic hydrocarbons (HCs). The larger oil droplet dispersions resulted in delayed sequential changes of Oceanospirillales and Cycloclasticus, related with slower degradation of alkanes and aromatic HCs. The bacterial successions associated with oil biodegradation showed both similarities and differences when compared with the results from DWH field samples and laboratory studies performed with deepwater from the Gulf of Mexico. PMID- 26485444 TI - Outcomes of Cord Blood Transplantation as Salvage Therapy after Graft Failure or Relapse after Prior Allogeneic Transplantation. AB - For patients with disease relapse or graft failure after allogeneic hematopoietic cell transplantation (HCT), there are few treatment options and survival rates are exceedingly low. Because of the unacceptably high risk of transplantation related mortality, second allogeneic HCTs are often not considered. Herein, we report the outcomes of 23 patients (median age, 33 years) undergoing a second allogeneic transplantation with unrelated cord blood donor grafts between 2006 and 2013. Indications for second HCT were relapse (n = 19), graft failure (n = 3), and donor-derived myelodysplastic syndrome (n = 1). Ten patients received reduced-intensity conditioning and 13 patients received either myeloablative (MAC) or middle-intensity (MIDI) conditioning. Twenty patients received a double cord blood transplantation. All patients engrafted at a median of 22 days (range, day 6 to 49). Death before day 100 occurred in 5 patients. Overall disease-free survival (DFS), treatment-related mortality, and relapse at 2 years were 31%, 33%, and 35%, respectively. Two-year DFS in the 13 patients receiving MAC or MIDI conditioning was slightly higher at 46%. Our results demonstrate that second allogeneic HCT using cord blood as the graft source should be considered in patients who have relapsed or experience graft failure after an allogeneic HCT. PMID- 26485446 TI - Trial of labour after previous caesarean section in sub-Saharan Africa. PMID- 26485445 TI - Fast Cars and No Brakes: Autologous Stem Cell Transplantation as a Platform for Novel Immunotherapies. AB - Autologous stem cell transplantation (ASCT) is indicated in a number of hematologic malignancies, including multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Relapse, however, remains 1 of the main causes of post-ASCT failure, and several strategies are being investigated to decrease the risk of relapse of progression. Recent advances in the treatment of hematological malignancies have included adoptive transfer of genetically modified T cells that express chimeric antigen receptors or T cell receptors, as well the use of checkpoint inhibitors. Early clinical results in nontransplantation patients have been very promising. This review will focus on the use of gene-modified T cells and checkpoint inhibitors in stem cell transplantation. PMID- 26485447 TI - Neuroprotective effects of levetiracetam target xCT in astrocytes in parkinsonian mice. AB - Astrocytes but not neurons express cystine/glutamate exchange transporter (xCT), which takes up cystine, and consequently supplies the substrate for GSH synthesis in neurons. It is recognized that GSH synthesis in neurons is dependent on the expression of xCT in astrocytes. Previous studies reported that levetiracetam (LEV), an anti-epileptic drug, increased xCT expression in vivo. The purpose of this study was to examine neuroprotective effects of LEV in parkinsonian models and demonstrate xCT in astrocytes as a target of neuroprotection against dopaminergic neurodegeneration. We identified striatal astrocytes cultured with LEV showed significant increase in xCT expression and GSH levels. Preincubation of primary cultured mesencephalic dopamine neurons with conditioned media from LEV-treated astrocytes protected against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. These protective effects were canceled by xCT inhibitor. Furthermore, reduction of nigrostriatal dopaminergic neurons in 6-OHDA-lesioned parkinsonian mice was significantly abrogated by repeated injections of LEV. Treatment with LEV significantly increased the expression of xCT in striatal astrocytes in the hemi-parkinsonian mice. In conclusion, LEV exerts neuroprotective effects against neurodegeneration via up-regulation of xCT and GSH in astrocytes. Thus, xCT in astrocytes could be a potential target in novel neuroprotective approaches to prevent degeneration of dopaminergic neurons. Glutathione (GSH) is the most potent intrinsic antioxidant. Since extracellular cysteine is readily oxidized to form cystine, cystine transport mechanisms are essential to provide cells with cysteine. Cystine uptake is mediated by cystine/glutamate exchange transporter (xCT), expressed primarily on astrocytes, but not on neurons. Astrocytes take up cystine via xCT and reduce it to cysteine to supply cysteine, the substrate for GSH synthesis in neurons. This study demonstrated that levetiracetam (LEV), an anti-epileptic drug, increased GSH in/from astrocytes via xCT up-regulation. GSH derived from astrocytes protects dopamine neurons against neurotoxicity induced by dopaminergic neurotoxin 6 hydroxydopamine (6-OHDA). Thus, xCT in astrocytes could be a potential target in novel neuroprotective approaches to prevent degeneration of dopaminergic neurons. PMID- 26485449 TI - Episodic adaptive diversification of classical swine fever virus RNA-dependent RNA polymerase NS5B. AB - Classical swine fever virus (CSFV) is the pathogen that causes a highly infectious disease of pigs and has led to disastrous losses to pig farms and related industries. The RNA-dependent RNA polymerase (RdRp) NS5B is a central component of the replicase complex (RC) in some single-stranded RNA viruses, including CSFV. On the basis of genetic variation, the CSFV RdRps could be clearly divided into 2 major groups and a minor group, which is consistent with the phylogenetic relationships and virulence diversification of the CSFV isolates. However, the adaptive signature underlying such an evolutionary profile of the polymerase and the virus is still an interesting open question. We analyzed the evolutionary trajectory of the CSFV RdRps over different timescales to evaluate the potential adaptation. We found that adaptive selection has driven the diversification of the RdRps between, but not within, CSFV major groups. Further, the major adaptive divergence-related sites are located in the surfaces relevant to the interaction with other component(s) of RC and the entrance and exit of the template-binding channel. These results might shed some light on the nature of the RdRp in virulence diversification of CSFV groups. PMID- 26485448 TI - Artemisinin-resistant Plasmodium falciparum clinical isolates can infect diverse mosquito vectors of Southeast Asia and Africa. AB - Artemisinin-resistant Plasmodium falciparum parasites are rapidly spreading in Southeast Asia, yet nothing is known about their transmission. This knowledge gap and the possibility that these parasites will spread to Africa endanger global efforts to eliminate malaria. Here we produce gametocytes from parasite clinical isolates that displayed artemisinin resistance in patients and in vitro, and use them to infect native and non-native mosquito vectors. We show that contemporary artemisinin-resistant isolates from Cambodia develop and produce sporozoites in two Southeast Asian vectors, Anopheles dirus and Anopheles minimus, and the major African vector, Anopheles coluzzii (formerly Anopheles gambiae M). The ability of artemisinin-resistant parasites to infect such highly diverse Anopheles species, combined with their higher gametocyte prevalence in patients, may explain the rapid expansion of these parasites in Cambodia and neighbouring countries, and further compromise efforts to prevent their global spread. PMID- 26485450 TI - Bacterial pathogens activate plasminogen to breach tissue barriers and escape from innate immunity. AB - Both coagulation and fibrinolysis are tightly connected with the innate immune system. Infection and inflammation cause profound alterations in the otherwise well-controlled balance between coagulation and fibrinolysis. Many pathogenic bacteria directly exploit the host's hemostatic system to increase their virulence. Here, we review the capacity of bacteria to activate plasminogen. The resulting proteolytic activity allows them to breach tissue barriers and evade innate immune defense, thus promoting bacterial spreading. Yersinia pestis, streptococci of group A, C and G and Staphylococcus aureus produce a specific bacterial plasminogen activator. Moreover, surface plasminogen receptors play an established role in pneumococcal, borrelial and group B streptococcal infections. This review summarizes the mechanisms of bacterial activation of host plasminogen and the role of the fibrinolytic system in infections caused by these pathogens. PMID- 26485451 TI - Atmospheric Visibility and PM10 as Indicators of New Particle Formation in an Urban Environment. AB - It is well-known that new particle formation (NPF) in the atmosphere is inhibited by pre-existing particles in the air that act as condensation sinks to decrease the concentration and, thus, the supersaturation of precursor gases. In this study, we investigate the effects of two parameters-atmospheric visibility, expressed as the particle backscatter coefficient (BSP), and PM10 particulate mass concentration-on the occurrences of NPF events in an urban environment where the majority of precursor gases originate from motor vehicle and industrial sources. This is the first attempt to derive direct relationships between these two parameters and the occurrence of NPF. NPF events were identified from data obtained with a neutral cluster and air ion spectrometer over 245 days within a calendar year. Bayesian logistic regression was used to determine the probability of observing NPF as functions of BSP and PM10. We show that the BSP at 08 h on a given day is a reliable indicator of an NPF event later that day. The posterior median probability of observing an NPF event was greater than 0.5 (95%) when the BSP at 08 h was less than 6.8 Mm(-1). PMID- 26485452 TI - Observation of Anion Order in Pb2Ti4O9F2. AB - The observation of anion order is indispensable for the investigation of oxyfluorides. However, the negligible contrast between O(2-) and F(-) in both X ray and neutron diffraction obscures the distinct anion sites for Rietveld refinement. Therefore, the difference in the chemical bonding of M-O(2-) and M-F( ) is the key to determining anion order. In this study, bond-valence-sum calculations and determination of the electron density distribution by the maximum entropy method illustrated anion order in the newly synthesized oxyfluoride Pb2Ti4O9F2. These results demonstrate a promising method to determine anion order in mixed anion systems. PMID- 26485453 TI - Comparison of rubidium-82 myocardial blood flow quantification with coronary calcium score for evaluation of coronary artery stenosis. AB - INTRODUCTION: PET myocardial perfusion imaging (MPI) is the standard technique for assessing myocardial function, but provides limited information on the anatomy of cardiac structures whereas the coronary artery calcium (CAC) score provides information on calcified plaque burden and the anatomical structure of the coronary arteries. The aim of this study was to determine the relationship between quantitative myocardial blood flow (MBF), CAC, and coronary artery disease (CAD). This work also aims to determine whether MBF quantification and/or CAC add value to relative MPI, and aid in the reclassification of patients with CAD. This way, a 'gatekeeper' study could be identified to predict coronary artery stenosis and improve our clinical service. MATERIALS AND METHODS: Rubidium 82 PET/CT MPI, calcium score, and computed tomographic coronary angiography imaging were performed in 128 patients with known or suspected CAD. The presence of ischemia was assessed from qualitative reporting of rubidium-82 MPI, and using the same data, quantitative values of MBF and coronary flow reserve (CFR) were derived. Calcium score images were quantitatively analyzed and categorized into three groups defined by CAC values of 0, 1-400, and >400. Significant stenosis was classified as stenosis of 50% or more on computed tomographic angiography. RESULTS: A total of 120 patients were included in the final analysis (77 men, 43 women). Our results showed an inverse correlation between stress MBF, CFR, and the percentage stenosis as well as an inverse correlation compared with CAC. A direct correlation between CAC and the percentage stenosis was observed, indicating that an increase in coronary calcification in individual coronary arteries is related to the severity of the coronary stenosis. These results proved that the addition of stress MBF to relative MPI (32%) resulted in a significantly higher sensitivity (48%, P=0.002), which increased significantly more with the addition of CFR (58%, P<=0.001). The further addition of CAC resulted in a significantly higher sensitivity (80%, P=0.001), with an even higher sensitivity with the addition of both CFR and CAC (95%, P<=0.001) to relative MPI. CONCLUSION: The addition of quantitative MBF conferred a substantial added diagnostic value to relative MPI for the diagnosis of CAD by highlighting compromised flow with the addition of CAC, increasing this added value even more. We recommend that this approach should be used to predict the presence of coronary artery stenosis at its earliest stage and guide physicians when making decisions on the management pathway of CAD without exposing patients to a high radiation dose during cardiac angiography. PMID- 26485454 TI - Chronic pelvic pain: how does noninvasive imaging compare with diagnostic laparoscopy? AB - PURPOSE OF REVIEW: Chronic pelvic pain (CPP) has an annual prevalence of 38/1000 in the UK, with coexisting pathologies often present. Diagnostic laparoscopy has long been the gold standard diagnostic test, but with up to 40% showing no abnormality, we explore the value of noninvasive imaging, such as pelvic ultrasound and MRI. RECENT FINDINGS: A literature review from inception until January 2015 of the following databases: PubMed, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Excerpta Medica database, and System for Information on Grey Literature in Europe were performed to identify published studies assessing the usefulness of ultrasound, MRI, and laparoscopy in the diagnosis of CPP. Three studies (194 women) addressed their comparative performance in patients with endometriosis, showing the sensitivity of ultrasound ranged between 58 and 88.5%; MRI was 56-91.5% and in the one study using histology as its reference standard, the sensitivity of laparoscopy was 85.7%. Noninvasive imaging has the additional benefit of being well tolerated, safer, and cheaper than surgery. SUMMARY: CPP, by nature of its multifactorial causation, can be difficult to manage and often requires a multidisciplinary team. Ultrasound and MRI may provide information about the presence or lack of abnormality, which would allow general practitioners or office gynaecologists to initiate treatment and think about surgery as a second-line investigative tool. PMID- 26485456 TI - Rotational vaginal delivery with Kielland's forceps: a systematic review and meta analysis of effectiveness and safety outcomes. AB - PURPOSE OF REVIEW: The use of Kielland's forceps has declined significantly in the last three decades. There is a lack of quality evidence on potential benefits and harms associated with using these forceps. We have performed a systematic review of the literature and meta-analysis to assess the safety and efficacy of using Kielland's forceps. RECENT FINDINGS: We have searched electronic databases for all clinical studies reporting primary data on using Kielland's forceps and assessed their risk of bias using the Newcastle-Ottawa Scale. We have pooled the event rate of adverse outcomes reported following the use of Kielland's forceps including a direct comparison to rotational ventouse. In total we included 23 studies. Direct comparison meta-analysis revealed higher failure rate with rotational ventouse compared with Kielland's. There was no statistically significant difference in the risk of adverse maternal outcomes between the two groups. There was higher risk of neonatal trauma in the ventouse group, but no significant difference in other neonatal outcomes. SUMMARY: Kielland's forceps have a high success rate with relatively low adverse outcomes despite their use being controversial. In comparison to rotational ventouse, Kielland's forceps have higher efficacy with less risk of neonatal trauma. PMID- 26485455 TI - Amniotic fluid embolism: despite progress, challenges remain. AB - PURPOSE OF REVIEW: This article reviews the incidence, pathophysiology, risk factors, diagnosis, and management of amniotic fluid embolism (AFE). RECENT FINDINGS: AFE is a leading cause of maternal morbidity and mortality despite an incidence of approximately 7 to 8 per 100,000 births. Recent reevaluation of AFE suggests that the presence of fetal tissue in maternal circulation alone is not sufficient to cause the clinical syndrome, but rather an individual's response to this fetal tissue. The 'anaphylactoid reaction' associated with AFE shares many clinical and metabolic aspects of septic shock. Acute dyspnea followed by cardiovascular collapse, coagulopathy, and neurological symptoms, such as coma and seizures may all be associated with the clinical AFE syndrome. Specific biochemical markers have been described, but are of limited clinical value because of the rapid progression of the disease process. Treatment is based on an interdisciplinary approach that consists of a combination of prompt, aggressive hemodynamic resuscitation, provision of end-organ support, correction of hemostatic disorders, and delivery. SUMMARY: Although AFE cannot be prevented, early diagnosis and intervention may lead to better outcomes for both the mother and the fetus. Clinical suspicion, traditional laboratory data, or intravascular cellular debris (demonstrated only in 50% of patients) are insufficient to make a definitive diagnosis of AFE. An evolving array of novel biomarkers may help differentiate AFE from other conditions, but none of them currently provide sufficient 'early warning' ability to make real-time impact on diagnosis and/or treatment of AFE. PMID- 26485457 TI - Management of uterine fibroids in pregnancy: recent trends. AB - PURPOSE OF REVIEW: The review analyzes how fibroids may influence pregnancy and how myomas may be modified by pregnancy. The most important clinical aspect concerns the impact of myoma on pregnancy and the possibility of a well tolerated surgical treatment for the mother and her fetus, preserving maternal reproductive capacity. RECENT FINDINGS: Fibroids significantly increase in size during early pregnancy and then decrease in the third trimester. Although most women with uterine fibroids have a regular pregnancy, data from the literature suggest that they may have a higher risk of fertility problems and pregnancy complications. SUMMARY: Myomectomy can increase the rate of pregnancy in women with infertility, attempting to restore a normal anatomy and reduce uterine contractility and local inflammation associated with the presence of fibroids, improving the blood supply. Current evidence does not suggest routine myomectomy during pregnancy or at the cesarean birth, as fibroids-related complications are rare and may be overcome by the risks of surgery. However, in selected cases, myomectomy is a feasible and safe technique and associated to a good outcome.The diagnosis of myomas in pregnancy may require attention for the adequate management to preserve maternal and fetal well-being. PMID- 26485458 TI - Thyroid disorders in pregnancy. AB - PURPOSE OF REVIEW: Recognition and management of thyroid disease during pregnancy is challenging with conflicting recommendations from various professional organizations. RECENT FINDINGS: We review the literature related to the diagnosis and management of gestational hypothyroidism and hyperthyroidism. We also discuss postpartum thyroiditis, thyroid nodules and thyroid cancer. The evidence clearly demonstrates that both overt hypothyroidism and hyperthyroidism should be treated, but controversy exists regarding the treatment of subclinical hypothyroidism and thyroid antibody positive euthyroidism, and whether pregnant women should be screened for thyroid disease. SUMMARY: Appropriate management of thyroid disease during pregnancy is important for maternal and fetal health, particularly the recognition and management of hypothyroidism and thyrotoxicosis. PMID- 26485459 TI - Target organ complications and prognostic significance of alerting reaction: analysis from the Dallas Heart Study. AB - OBJECTIVE: Noninvasive blood pressure (BP) measurement often triggers a transient rise in BP, known as an alerting reaction. However, the prevalence and prognostic significance of the alerting reaction has never been assessed in the general population. METHODS: We evaluated the association between the alerting reaction and left ventricular mass by MRI and urinary albumin-to-creatinine ratio in the Dallas Heart Study, a large population sample of 3069 individuals. Participants were categorized into four groups based on levels of consecutive BP: first, normal first BP and average third to fifth (avg3-5) BP of less than 140/90 mmHg (control group); second, high first BP of at least 140/90 mmHg and normal (avg3 5) BP (alerting reaction group); third, normal first BP and high (avg3-5) BP; and fourth, high first to fifth BP. Then, associations between BP categories with incident cardiovascular outcomes (coronary heart disease, stroke, atrial fibrillation, heart failure, and cardiovascular death) over a median follow-up period of 9.4 years were assessed. RESULTS: The sample-weighted prevalence of isolated hypertension during the first BP measurement was 9.6%. Presence of an alerting reaction was independently associated with increased left ventricular mass, urinary albumin-to-creatinine ratio, cardiovascular events after adjustment for traditional cardiovascular risk factors, and baseline BP (adjusted hazard ratio 1.24, 95% confidence interval 1.07-1.43). CONCLUSION: Our study indicated that the alerting reaction is independently associated with increased cardiovascular and renal complications. PMID- 26485460 TI - A randomized and controlled study of noninvasive hemodynamic monitoring as a guide to drug treatment of uncontrolled hypertensive patients. AB - BACKGROUND: In the BEtter control of BP in hypertensive pAtients monitored Using the HOTMAN sYstem study, we investigated whether utilizing noninvasive monitoring of hemodynamic parameters combined with a drug selection algorithm (integrated hemodynamic management - IHM) compared with conventional drug selection may improve uncontrolled hypertension in European Hypertension Excellence centers. METHOD: Uncontrolled (office SBP >140 mmHg and ambulatory daytime SBP >135 mmHg while taking >=2 antihypertensive drugs) essential hypertensive patients were referred to five European Hypertension Excellence centers and, if eligible, were randomized to IHM-guided (n = 83) vs. conventional (control, n = 84) treatment adjustment in an investigator-initiated multicenter prospective randomized parallel groups controlled study. RESULTS: The average number of antihypertensive drugs increased from 3.1 to 4.1 in both groups and differed only in a rise of the use of diuretics in the IHM groups (from 13 to 31%). Daytime SBP, defined as the primary endpoint, decreased markedly and to the same extent from baseline to 6 months in IHM (-15.8 +/- 14.8 mmHg) and control (-15.4 +/- 14.5 mmHg) groups (P = 0.87), with a similar behavior of office SBP (no between group differences, P = 0.18). Average number of adverse events was significantly lower in IHM than in controls (P = 0.008) but of the more general type and not necessarily related to drug treatment. CONCLUSION: Thus, noninvasive hemodynamic monitoring associated with a drug selection algorithm induced similar reductions in ambulatory daytime and office SBP compared with conventional drug selection in uncontrolled hypertensive patients referred to European Hypertension Excellence centers.Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01482364. PMID- 26485461 TI - Blood pressure variability after catheter-based renal sympathetic denervation in patients with resistant hypertension. AB - BACKGROUND: Renal denervation (RDN) reduces sympathetic activity and blood pressure (BP) in patients with resistant hypertension. Increased 24-h BP variability is associated with adverse cardiovascular outcomes and related to sympathetic activation. METHODS AND RESULTS: This multicenter study investigated the effect of RDN on BP variability in 84 patients with uncontrolled hypertension (office systolic BP >=140 mmHg) despite treatment with greater than three antihypertensive agents. BP variability was assessed by means of standard deviation, coefficient of variation (standard deviation/mean), and average real variability of 24-h ambulatory SBP at 3-month and 6-month follow-up. RDN significantly reduced office BP by 17/6 mmHg at 3-month and 19/7 mmHg at 6-month follow-up (P < 0.001 for all) and 24-h ambulatory BP by 9/5 mmHg (P < 0.001/P = 0.001) after 3 months and 12/7 mmHg (P < 0.001/P < 0.001) after 6 months. Standard deviation significantly decreased from 17.1 to 14.9 mmHg (P = 0.008) and 15.3 mmHg (P = 0.037), consistent with a reduction of coefficient of variation from 0.116 to 0.103 (P = 0.035) and 0.104 (P = 0.071) and average real variability from 12.3 to 10.9 (P = 0.029) and 11.0 (P = 0.054) after 3-month and 6-month, respectively. Interestingly, also BP nonresponders (change in office systolic BP < 10 mmHg after 6 months) showed a significant reduction of standard deviation after 3 months (P = 0.041, n = 26) and a borderline significant reduction at 6-month (P = 0.057, n = 28). CONCLUSIONS: RDN reduces office and ambulatory BP and BP variability in patients with resistant hypertension. Improvement in BP variability was also documented in patients characterized as office BP nonresponders after 6 months. PMID- 26485462 TI - Gamma-glutamyltransferase and risk of hypertension: a systematic review and dose response meta-analysis of prospective evidence. AB - The objective of this review was to obtain a reliable estimate of the magnitude of the prospective association between gamma-glutamyltransferase (GGT) and risk of hypertension, and to characterize the nature of the dose-response relationship. We conducted a systematic review and dose-response meta-analysis of published prospective studies. Relevant studies were identified in a literature search of MEDLINE, EMBASE, and Web of Science databases up to May 2015. Study specific relative risks (RRs) were meta-analyzed using random effects models. We examined a potential nonlinear relationship using restricted cubic splines. Of the 612 titles reviewed, we included 14 cohort studies with data on 44 582 participants and 5 270 hypertension cases. In a comparison of extreme thirds of baseline levels of GGT, RR for hypertension in pooled analysis of all 14 studies was 1.32 (95% confidence interval: 1.23-1.43). There was heterogeneity among the studies (P < 0.001), which was to a large part explained by average age of participants at baseline, average duration of follow-up, and the degree of confounder adjustment. In a pooled dose-response analysis of 10 studies with relevant data, there was evidence of a linear association between GGT and hypertension risk (P for nonlinearity = 0.37). The pooled RR of hypertension per 5 U/l increment in GGT levels was 1.08 (95% confidence interval: 1.04-1.13). Baseline circulating GGT level is associated with an increased risk of hypertension in the general population, consistent with a linear dose-response relationship. Further investigation of any potential relevance of GGT in hypertension prevention is warranted. PMID- 26485463 TI - Blood pressure changes after catheter-based renal denervation are related to reductions in total peripheral resistance. AB - BACKGROUND: Renal denervation (RDN) can reduce sympathetic activity and blood pressure (BP) in patients with uncontrolled hypertension. The exact mechanisms by which RDN results in BP reductions are yet not fully established. METHODS AND RESULTS: This study investigated the effects of RDN on office BP, 24-h ambulatory BP, noninvasive 10-min beat-to-beat digital pulse wave analysis, total peripheral resistance (TPR), cardiac output, and plasma renin and aldosterone serum concentrations in 30 patients with resistant hypertension. Adherence to antihypertensive drugs was assessed by liquid chromatography high-resolution tandem mass spectrometry analysis in plasma and urine at baseline and at 6 month. RDN significantly reduced office BP, beat-to-beat BP, and 24-h ambulatory BP by 19/6 (P = 0.021/P = 0.012), 12/7 (P = 0.005/P = 0.005), and 10/5 mmHg (P = 0.001/P = 0.049) at 6 months, respectively. TPR decreased from 1696 to 1377 dyn * s/cm (-19%; P = 0.027). This reduction was not associated with significant changes in cardiac output. The changes in office, ambulatory, and beat-to-beat BP correlated with the reductions of TPR. Adherence to antihypertensive treatment remained unchanged during the study period (84.7% at baseline, 83.6% at 6 months, P = 0.782). CONCLUSION: RDN reduced office BP, beat-to-beat BP, and 24-h ambulatory BP in patients with resistant hypertension after 6 months. The BP changes were associated with reductions in peripheral resistance, whereas cardiac output, plasma renin, and aldosterone levels remained unchanged. The observed effects were not explained by an increased intake of antihypertensive medications. PMID- 26485464 TI - Drug adherence monitoring in clinical trials: a necessity for a correct assessment of the efficacy and safety of antihypertensive therapies. PMID- 26485465 TI - Formulations of deoxycholic for therapy: a patent review (2011 - 2014). AB - INTRODUCTION: Deoxycholic acid (DOCA) is involved in many physiological functions and has been used in various fields of pharmaceutical formulations as a natural active solubilizing and permeation-enhancing agent. Although DOCA has been suggested to be a promoter of colon cancer, it has also been used extensively as a starting material to obtain new derivatives for potential therapeutic applications. AREA COVERED: In this review, we focus on patents and research reports from 2011 to 2014 related to pharmaceutical formulations and therapeutic applications using DOCA and its derivatives as surfactants or absorption enhancers, drug delivery carriers, and anti-cancer agents. EXPERT OPINION: In recent few years, DOCA and its derivatives have been used mostly as pharmaceutical excipients for solubilizing lipophilic compounds to improve their bioavailability. Other studies have expanded its applications to include enhanced drug permeability and have designed more effective drug carriers by conjugation with polymeric materials. Recently, a synthetic DOCA injection, ATX-101, has shown long-term efficacy in the non-surgical treatment of unwanted submental fat and acceptable tolerability in humans. Thus, it may be used for reducing specific localized fat accumulations. Additionally, DOCA has been a starting material for anti-cancer drugs, and some derivatives showed strong inhibitory activities against several carcinoma cells. PMID- 26485466 TI - Centromere and telomere sequence alterations reflect the rapid genome evolution within the carnivorous plant genus Genlisea. AB - Linear chromosomes of eukaryotic organisms invariably possess centromeres and telomeres to ensure proper chromosome segregation during nuclear divisions and to protect the chromosome ends from deterioration and fusion, respectively. While centromeric sequences may differ between species, with arrays of tandemly repeated sequences and retrotransposons being the most abundant sequence types in plant centromeres, telomeric sequences are usually highly conserved among plants and other organisms. The genome size of the carnivorous genus Genlisea (Lentibulariaceae) is highly variable. Here we study evolutionary sequence plasticity of these chromosomal domains at an intrageneric level. We show that Genlisea nigrocaulis (1C = 86 Mbp; 2n = 40) and G. hispidula (1C = 1550 Mbp; 2n = 40) differ as to their DNA composition at centromeres and telomeres. G. nigrocaulis and its close relative G. pygmaea revealed mainly 161 bp tandem repeats, while G. hispidula and its close relative G. subglabra displayed a combination of four retroelements at centromeric positions. G. nigrocaulis and G. pygmaea chromosome ends are characterized by the Arabidopsis-type telomeric repeats (TTTAGGG); G. hispidula and G. subglabra instead revealed two intermingled sequence variants (TTCAGG and TTTCAGG). These differences in centromeric and, surprisingly, also in telomeric DNA sequences, uncovered between groups with on average a > 9-fold genome size difference, emphasize the fast genome evolution within this genus. Such intrageneric evolutionary alteration of telomeric repeats with cytosine in the guanine-rich strand, not yet known for plants, might impact the epigenetic telomere chromatin modification. PMID- 26485467 TI - Electrolyte Imbalance in Patients with Sheehan's Syndrome. AB - BACKGROUND: We investigated the prevalence of electrolyte imbalance and the relationship between serum electrolyte and anterior pituitary hormone levels in patients with Sheehan's syndrome. METHODS: In a retrospective study, we investigated 78 patients with Sheehan's syndrome. We also included 95 normal control subjects who underwent a combined anterior pituitary hormone stimulation test and showed normal hormonal responses. RESULTS: In patients with Sheehan's syndrome, the serum levels of sodium, potassium, ionized calcium, magnesium, and inorganic phosphate were significantly lower than those in control subjects. The prevalence of hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia, and hypophosphatemia in patients with Sheehan's syndrome was 59.0% (n=46), 26.9% (n=21), 35.9% (n=28), 47.4% (n=37), and 23.1% (n=18), respectively. Levels of sodium and ionized calcium in serum were positively correlated with levels of all anterior pituitary hormones (all P<0.05). Levels of potassium in serum were positively correlated with adrenocorticotrophic hormone (ACTH) and growth hormone (GH) levels (all P<0.05). Levels of inorganic phosphate in serum were positively correlated with levels of thyroid-stimulating hormone, prolactin, and GH (all P<0.05), and levels of magnesium in serum were positively correlated with delta ACTH (P<0.01). CONCLUSION: Electrolyte imbalance was common in patients with Sheehan's syndrome. Furthermore, the degree of anterior pituitary hormone deficiency relates to the degree of electrolyte disturbance in patients with this disease. PMID- 26485468 TI - Thyroid Hormone Regulates the mRNA Expression of Small Heterodimer Partner through Liver Receptor Homolog-1. AB - BACKGROUND: Expression of hepatic cholesterol 7alpha-hydroxylase (CYP7A1) is negatively regulated by orphan nuclear receptor small heterodimer partner (SHP). In this study, we aimed to find whether thyroid hormone regulates SHP expression by modulating the transcriptional activities of liver receptor homolog-1 (LRH-1). METHODS: We injected thyroid hormone (triiodothyronine, T3) to C57BL/6J wild type. RNA was isolated from mouse liver and used for microarray analysis and quantitative real-time polymerase chain reaction (PCR). Human hepatoma cell and primary hepatocytes from mouse liver were used to confirm the effect of T3 in vitro. Promoter assay and electrophoretic mobility-shift assay (EMSA) were also performed using human hepatoma cell line. RESULTS: Initial microarray results indicated that SHP expression is markedly decreased in livers of T3 treated mice. We confirmed that T3 repressed SHP expression in the liver of mice as well as in mouse primary hepatocytes and human hepatoma cells by real-time PCR analysis. LRH 1 increased the promoter activity of SHP; however, this increased activity was markedly decreased after thyroid hormone receptor beta/retinoid X receptor alpha/T3 administration. EMSA revealed that T3 inhibits specific LRH-1 DNA binding. CONCLUSION: We found that thyroid hormone regulates the expression of SHP mRNA through interference with the transcription factor, LRH-1. PMID- 26485469 TI - Selective Mitochondrial Uptake of MKT-077 Can Suppress Medullary Thyroid Carcinoma Cell Survival In Vitro and In Vivo. AB - BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the rearranged during transfection (RET) proto-oncogene. Not all patients with progressive MTC respond to current therapy inhibiting RET, demanding additional therapeutic strategies. We recently demonstrated that disrupting mitochondrial metabolism using a mitochondria-targeted agent or by depleting a mitochondrial chaperone effectively suppressed human MTC cells in culture and in mouse xenografts by inducing apoptosis and RET downregulation. These observations led us to hypothesize that mitochondria are potential therapeutic targets for MTC. This study further tests this hypothesis using1 ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4-oxothiazolidin-2 ylidenemethyl] pyridinium chloride (MKT-077), a water-soluble rhodocyanine dye analogue, which can selectively accumulate in mitochondria. METHODS: The effects of MKT-077 on cell proliferation, survival, expression of RET and tumor protein 53 (TP53), and mitochondrial activity were determined in the human MTC lines in culture and in mouse xenografts. RESULTS: MKT-077 induced cell cycle arrest in TT and MZ-CRC-1. Intriguingly, MKT-077 also induced RET downregulation and strong cell death responses in TT cells, but not in MZ-CRC-1 cells. This discrepancy was mainly due to the difference between the capacities of these cell lines to retain MKT-077 in mitochondria. The cytotoxicity of MKT-077 in TT cells was mainly attributed to oxidative stress while being independent of TP53. MKT-077 also effectively suppressed tumor growth of TT xenografts. CONCLUSION: MKT-077 can suppress cell survival of certain MTC subtypes by accumulating in mitochondria and interfering with mitochondrial activity although it can also suppress cell proliferation via other mechanisms. These results consistently support the hypothesis that mitochondrial targeting has therapeutic potential for MTC. PMID- 26485470 TI - Risk Factors for Recurrence in Filipinos with Well-Differentiated Thyroid Cancer. AB - BACKGROUND: The incidence of well-differentiated thyroid cancer (WDTC) has increased in recent years. Despite its excellent prognosis, increasing morbidity from recurrent diseases continues to affect long-term outcomes. Among at-risk populations, Filipinos have the highest incidence of thyroid cancer worldwide, characterized by a highly aggressive and recurrent form of disease. Here, we sought to identify risk factors associated with disease recurrence among Filipinos with WDTC. METHODS: This retrospective cohort study examined 723 patients diagnosed with WDTC seen at Philippine General Hospital. Affected individuals were classified based on the presence or absence of disease recurrence. Multivariate logistic regression analyses were used to determine significant predictors of recurrence. RESULTS: Multiple risk factors, including age >45 years (odds ratio [OR], 1.44), multifocality of cancer (OR, 1.43), nodal involvement (OR, 4.0), and distant metastases at presentation (OR, 2.78), were significantly associated with a recurrence of papillary thyroid cancer (PTC). In contrast, follicular variant histology (OR, 0.60) and postsurgical radioactive iodine therapy (OR, 0.31) were protective for PTC recurrence. Distant metastases at presentation (OR, 19.4) and postsurgical radioactive iodine therapy (OR, 0.41) were associated with follicular thyroid cancer (FTC) recurrence. CONCLUSION: Lymph node metastases at presentation was the strongest predictor of recurrence in PTC, whereas distant metastases at presentation was the strongest for FTC recurrence. Among Filipinos, stratification of WDTC patients based on recurrence risk factors identified in this study will be helpful in guiding the intensity of treatment strategies and long-term thyroid cancer surveillance. PMID- 26485471 TI - Characteristics of Body Composition and Muscle Strength of North Korean Refugees during South Korean Stay. AB - BACKGROUND: The aim of this study was to investigate the changes of body composition and muscle strength of North Korean refugees (NKRs) according to their duration of stay in South Korea. METHODS: NKRs who volunteered and were living in South Korea, aged 20 to 75 years were recruited. Body compositions were analyzed by bioelectrical impedance analysis. Muscle strength was measured with the hand grip test. Demographic and migration information was obtained with a questionnaire. RESULTS: A total of 158 volunteers were recruited at a mean age of 48.3+/-11.4 years. The mean time from when they escaped from North Korea and arrived in South Korea was 5.8+/-4.3 years. Height, weight, and body surface area were significantly smaller in all NKRs compared to South Korean controls, except for women aged over 50 years. In females of younger ages (<50 years), NKRs with more than a 4-year stay in South Korea had a higher weight and fat mass than that of those who had a shorter stay (less than 4 years) in South Korea. All NKRs had a weaker grip strength than that of the age-matched controls from South Korea. CONCLUSION: The NKRs showed relatively smaller physiques and weaker muscle strength than that of the South Korean controls. In younger female NKRs, shorter South Korean stay group showed small body weight and fat mass than that of longer South Korean stay group. Specific health support programs might be needed. PMID- 26485472 TI - Network Consistent Data Association. AB - Existing data association techniques mostly focus on matching pairs of data-point sets and then repeating this process along space-time to achieve long term correspondences. However, in many problems such as person re-identification, a set of data-points may be observed at multiple spatio-temporal locations and/or by multiple agents in a network and simply combining the local pairwise association results between sets of data-points often leads to inconsistencies over the global space-time horizons. In this paper, we propose a Novel Network Consistent Data Association (NCDA) framework formulated as an optimization problem that not only maintains consistency in association results across the network, but also improves the pairwise data association accuracies. The proposed NCDA can be solved as a binary integer program leading to a globally optimal solution and is capable of handling the challenging data-association scenario where the number of data-points varies across different sets of instances in the network. We also present an online implementation of NCDA method that can dynamically associate new observations to already observed data-points in an iterative fashion, while maintaining network consistency. We have tested both the batch and the online NCDA in two application areas-person re-identification and spatio-temporal cell tracking and observed consistent and highly accurate data association results in all the cases. PMID- 26485473 TI - Structure-Preserving Binary Representations for RGB-D Action Recognition. AB - In this paper, we propose a novel binary local representation for RGB-D video data fusion with a structure-preserving projection. Our contribution consists of two aspects. Toacquire a general feature for the video data, we convert the problem to describing the gradient fields of RGB and depth information of video sequences. With the local fluxes of the gradient fields, which include the orientation and the magnitude of the neighborhood of each point, a new kind of continuous local descriptor called Local Flux Feature(LFF) is obtained. Then the LFFs from RGB and depth channels are fused into a Hamming space via the Structure Preserving Projection (SPP). Specifically, an orthogonal projection matrix is applied to preserve the pairwise structure with a shape constraint to avoid the collapse of data structure in the projected space. Furthermore, a bipartite graph structure of data is taken into consideration, which is regarded as a higher level connection between samples and classes than the pairwise structure of local features. Theextensive experiments show not only the high efficiency of binary codes and the effectiveness of combining LFFs from RGB-D channels via SPP on various action recognition benchmarks of RGB-D data, but also the potential power of LFF for general action recognition. PMID- 26485474 TI - Max-Margin Action Prediction Machine. AB - The speed with which intelligent systems can react to an action depends on how soon it can be recognized. The ability to recognize ongoing actions is critical in many applications, for example, spotting criminal activity. It is challenging, since decisions have to be made based on partial videos of temporally incomplete action executions. In this paper, we propose a novel discriminative multi-scale kernelized model for predicting the action class from a partially observed video. The proposed model captures temporal dynamics of human actions by explicitly considering all the history of observed features as well as features in smaller temporal segments. A compositional kernel is proposed to hierarchically capture the relationships between partial observations as well as the temporal segments, respectively. We develop a new learning formulation, which elegantly captures the temporal evolution over time, and enforces the label consistency between segments and corresponding partial videos. We prove that the proposed learning formulation minimizes the upper bound of the empirical risk. Experimental results on four public datasets show that the proposed approach outperforms state-of-the-art action prediction methods. PMID- 26485475 TI - Adherent Raindrop Modeling, Detectionand Removal in Video. AB - Raindrops adhered to a windscreen or window glass can significantly degrade the visibility of a scene. Modeling, detecting and removing raindrops will, therefore, benefit many computer vision applications, particularly outdoor surveillance systems and intelligent vehicle systems. In this paper, a method that automatically detects and removes adherent raindrops is introduced. The core idea is to exploit the local spatio-temporal derivatives of raindrops. To accomplish the idea, we first model adherent raindrops using law of physics, and detect raindrops based on these models in combination with motion and intensity temporal derivatives of the input video. Having detected the raindrops, we remove them and restore the images based on an analysis that some areas of raindrops completely occludes the scene, and some other areas occlude only partially. For partially occluding areas, we restore them by retrieving as much as possible information of the scene, namely, by solving a blending function on the detected partially occluding areas using the temporal intensity derivative. For completely occluding areas, we recover them by using a video completion technique. Experimental results using various real videos show the effectiveness of our method. PMID- 26485476 TI - A Global Hypothesis Verification Framework for 3D Object Recognition in Clutter. AB - Pipelines to recognize 3D objects despite clutter and occlusions usually end up with a final verification stage whereby recognition hypotheses are validated or dismissed based on how well they explain sensor measurements. Unlike previous work, we propose a Global Hypothesis Verification (GHV) approach which regards all hypotheses jointly so as to account for mutual interactions. GHV provides a principled framework to tackle the complexity of our visual world by leveraging on a plurality of recognition paradigms and cues. Accordingly, we present a 3D object recognition pipeline deploying both global and local 3D features as well as shape and color. Thereby, and facilitated by the robustness of the verification process, diverse object hypotheses can be gathered and weak hypotheses need not be suppressed too early to trade sensitivity for specificity. Experiments demonstrate the effectiveness of our proposal, which significantly improves over the state-of-art and attains ideal performance (no false negatives, no false positives) on three out of the six most relevant and challenging benchmark datasets. PMID- 26485477 TI - Glenohumeral posterior mobilization versus conventional physiotherapy for primary adhesive capsulitis: a randomized clinical trial. AB - OBJECTIVE: To compare the short-term efficacy of a glenohumeral posterior mobilization technique versus conventional physiotherapy for the improvement of the range of external rotation in patients with primary adhesive capsulitis of the shoulder. METHODS: This is a randomized clinical trial conducted at Hospital Clinico San Borja Arriaran in Chile. Fifty-seven patients with an age range of 50 to 58 years old were enrolled in two groups. Both groups were randomized to receive a treatment of 10 sessions: the experimental group (n=29) received a glenohumeral posterior mobilization technique after training with a cycle ergometer, and the control group (n=28) received conventional physiotherapy. The primary outcome measure was range of passive movement in external rotation; secondary outcomes were forward flexion and shoulder abduction, pain perception using the visual analogue scale and functionality test using the Constant-Murley Score. RESULTS: The study had the statistical power to detect a difference of four degrees between the groups in the improvement of the range of external rotation at the end of the treatment period. The experimental group showed a significant improvement with a mean difference of 46.3 degrees (SD=8.7) compared to 18.1 (SD=7.2) in the control group (p<0.0001). There was also a decrease in the perception of pain (p= 0.0002) and improved function (p< 0.0001) in the group treated with glenohumeral posterior mobilization technique. CONCLUSIONS: The glenohumeral posterior mobilization technique applied after training with cycle ergometer is an effective short-term technique to treat primary adhesive capsulitis decreasing the severity of pain and improving joint function compared with conventional physiotherapy treatment. The degree of increase in shoulder external rotation is more than 20 degrees beyond the increase achieved with conventional treatment. PMID- 26485478 TI - Nutritional Supplementation with Chlorella pyrenoidosa Lowers Serum Methylmalonic Acid in Vegans and Vegetarians with a Suspected Vitamin B12 Deficiency. AB - Since vitamin B12 occurs in substantial amounts only in foods derived from animals, vegetarians and particularly vegans are at risk of developing deficiencies of this essential vitamin. The chlorella used for this study is a commercially available whole-food supplement, which is believed to contain the physiologically active form of the vitamin. This exploratory open-label study was performed to determine if adding 9 g of Chlorella pyrenoidosa daily could help mitigate a vitamin B12 deficiency in vegetarians and vegans. Seventeen vegan or vegetarian adults (26-57 years of age) with a known vitamin B12 deficiency, as evidenced by a baseline serum methylmalonic acid (MMA) level above 270 nmol/L at screening, but who otherwise appeared healthy were enrolled in the study. Each participant added 9 g of C. pyrenoidosa to their daily diet for 60 +/- 5 days and their serum MMA, vitamin B12, homocysteine (Hcy) levels as well as mean corpuscular volume (MCV), hemoglobin (Hgb), and hematocrit (Hct) were measured at 30 and 60 days from baseline. After 30 and 60 days, the serum MMA level fell significantly (P < .05) by an average ~34%. Fifteen of the 17 (88%) subjects showed at least a 10% drop in MMA. At the same time, Hcy trended downward and serum vitamin B12 trended upward, while MCV, Hgb, and Hct appeared unchanged. The results of this work suggest that the vitamin B12 in chlorella is bioavailable and such dietary supplementation is a natural way for vegetarians and vegans to get the vitamin B12 they need. PMID- 26485479 TI - Stomatal responses to humidity: has the 'black box' finally been opened? PMID- 26485481 TI - Improved Crystallization of Perovskite Films by Optimized Solvent Annealing for High Efficiency Solar Cell. AB - Organic-inorganic halide perovskite-based thin film solar cells show excellent light-to-power conversion efficiency. The high performance for the devices requires the preparation of well-crystallized perovskite absorbers. In this paper, we used the postannealing process to treat the perovskite films under different solvent vapors and observed that the solvent vapors have a strong effect on the film growth. A model regarding the perovskite film growth was proposed as well. Intensive characterizations including scanning electron microscopy, electrochemical impedance spectroscopy, and admittance spectroscopy allowed us to attribute the improved performance to reduced recombination loss and defect density. Solar cell based on the DMSO-treated films delivered a power conversion efficiency of over 13% with negligible photocurrent hysteresis. PMID- 26485482 TI - Locations and Dislocations: Psychoanalysis in France. PMID- 26485480 TI - Substance use history in behavioral-variant frontotemporal dementia versus primary progressive aphasia. AB - As older adults are prone to cognitive disorders, the interaction of the fields of substance use and misuse and cognitive neuroscience is an emerging area of research. Substance use has been reported in some subtypes of frontotemporal dementia, such as behavioral variant frontotemporal dementia. However, characterization of substance use in other subtypes of frontotemporal dementia, such as primary progressive aphasia, is unknown. The objective of this baseline analysis was to explore whether any measures of substance use history differed significantly among behavioral variant frontotemporal dementia (n = 842) and primary progressive aphasia (n = 526) in a large national dataset. The National Alzheimer's Coordinating Center's Uniform Data Set study is a national dataset that collects data on patients with various cognitive disorders and includes some questions on substance use. Each substance use variable was used as the outcome and the frontotemporal dementia subtype as the predictor. Total years smoked cigarettes, age when last smoked cigarettes, average number of packs/day smoked when participants smoked, and any recent, remote, or combined recent/remote history of alcohol abuse or drug abuse did not significantly differ between the behavioral variant frontotemporal dementia and primary progressive aphasia subtypes (all p-values > .001). A significantly greater percentage of participants smoked in the last 30 days in the behavioral variant frontotemporal dementia subtype (10.4%, n = 834) compared to the primary progressive aphasia subtype (3.3%, n = 517; p < .001). Clinical providers in both the dementia and substance use fields are encouraged to screen for and monitor substance use in all frontotemporal dementia subtypes. PMID- 26485483 TI - The Analyst's Act and the Child's Desire: A Retrospective Case Study. AB - In this paper, I lay out a blueprint for a child analysis, stipulating the terms and ethics of the Lacanian field of psychoanalysis, the position of the analyst in that field, and the invitation to the child to discover a space for desire in the work of play. Drawing on the grounding work of Freud, Lacan, Dolto, Lefort, Mannoni, and Mathelin, I describe the mainsprings of the psychoanalytic clinic with the child. I then offer a child case and its trajectory from the development of a phobia to a symptom, and show how the primal scene fantasy and its articulation can open a space for desire in a child's play. What is particular to this work of playing is the emergence of signifiers that chain across generations, and move into new metaphors that foreground the Real of the child's experience and desire. PMID- 26485484 TI - My Session With Andre. AB - The author shares personal reminiscences of a therapy session with Andre Green, as well as impressions of professional meetings, readings, and clinical work. He describes personal help he received and aspects of Green's writings on dynamics of madness, as well as the latter's end-of-life discussion of therapeutic limits. PMID- 26485485 TI - Andre Green on the Theory and Treatment of "Non-Neurotic" Patients. AB - A pivotal turning point in contemporary psychoanalytic practice and conceptualization was the presentation by Andre Green at the 1975 meeting of the International Psychoanalytical Association. In his presentation Green opened new ways of thinking about non-neurotic patients based on a theory of psychosis that accounts for confusion of subject and object and a mode of symbolization derived from a dual organization of patient and analyst. Green proposed that analysts lend themselves to the fusional needs of their patients while the focus is on the force of the negative-destructive mental states where connection is superseded by disconnections that in turn lead to disorganization resulting in blank depression and negative hallucination. Green finds precedent for this viewpoint in his reading of Winnciott's work on transitional space as a developmental movement toward separation. Central to clinical work with non-neurotic patients is the analyst's use of their countertransference as a form of binding the inchoate into form built on interpreting in the transference as opposed to interpreting of the transference while titrating the degree of silence so as not to fuel the terror of too much absence. PMID- 26485486 TI - The Skin-Ego: Dyadic Sensuality, Trauma in Infancy, and Adult Narcissistic Issues. AB - The skin-ego is a metaphor created by the French psychoanalyst Didier Anzieu to describe the process by which the infant's emerging ego develops a container for psychic contents and achieves a secure feeling of well-being. The ego encloses the psychic apparatus as the skin encloses the body. The ego becomes able to fix barriers protecting the internal world and to screen exchanges with the id, the superego, and the outside world. The skin-ego is an envelope that contains thoughts and gives to thinking activity some limits, continuity, and a protection against the instincts. The functions of the skin-ego are to maintain thoughts, to contain ideas and affects, to provide a protective shield, to register traces of primary communication with the outside world, to manage inter-sensorial correspondences, to individuate, to support sexual excitation, and to recharge the libido. The skin-ego is the foundation of the container-contained relationship. An important part of psychoanalytic work with borderline patients is the reconstruction of the earliest phases of the skin-ego and their consequences for mental organization. PMID- 26485487 TI - Apres-Coup in French Psychoanalysis: The Long Afterlife of Nachtraglichkeit: The First Hundred Years, 1893 to 1993. AB - Apres-coup finds its origins in Freud's earliest psychoanalytic writings, but it was only half a century ago that French psychoanalysts rediscovered, clarified, and developed the concept and so brought it recognition as an essential Freudian concept. Because the history of apres-coup is embedded in the French reading of Freud, this article will give an account of that reading in relation to apres coup. PMID- 26485488 TI - Interview With Jean Laplanche. AB - The starting point for this interview with Jean Laplanche is a question regarding the place of infantile sexuality within psychoanalysis today. Laplanche begins by underscoring the audaciousness of Freud's characterization of infantile sexuality and the significance of the expansion of the field of "the sexual" that this characterization entails. He goes on to outline his celebrated "general theory of seduction." In doing so he explains key terms associated with it, such as the "enigmatic message" and the "fundamental anthropological situation," and clarifies how the theory seeks to account for sexuality in the expanded sense. In particular, Laplanche stresses the intersubjective origins of "drive" sexuality in infancy, its chaotic evolution, its unique economic mode of functioning, and its subsequent conflict with innate "instinctual" sexual impulses that surge forth at puberty. He also positions the general theory of seduction in relation to the important advances made by attachment theory in the field of the adult child relationship. Throughout the interview, the discussion touches on social contexts, and at points Laplanche outlines positions on topical concerns connected to education, media, and the law, and the importance of rethinking certain psychoanalytic paradigms in an age of new family structures that do not correspond to the nuclear unit. PMID- 26485489 TI - Jean Laplanche's Masochism. AB - This essay examines the theme of masochism in the metapsychological work of French psychoanalyst Jean Laplanche. One of the most distinctive aspects of Laplanche's work as a whole is its recursiveness: it advances by repeatedly retraversing the same themes and rereading the same Freudian texts, often after intervals of years and each time from a deepened critical perspective. The approach taken in this essay is therefore diachronic. That is, rather than seeking to present a reduced summation of Laplanche's position on masochism, it tracks the recursive evolution of his thinking about masochism, from the 1960s through to the development of his celebrated "general theory of seduction." The essay locates each of Laplanche's key interventions on masochism within the broader frameworks of his theoretical enterprise, and positions masochism as a point of orientation for understanding a number of the essential claims of his metapsychology, particularly the relationships among fantasy, pain and the drives; the economic dimensions of human desire; and the intersubjective origins of psychosexuality. Finally, the essay suggests that masochism might have a particular pertinence to psychoanalytic thinking as Laplanche conceives and practices it: that is, as a pains-taking labor whose very stimulus is the "wound" of the Freudian breakthrough. PMID- 26485490 TI - The Introjective Function of Dreaming and Its Impact on the Theory of Technique. AB - The author proposes for debate the thesis that the main function of the process of "dreaming" (Traumen) is a daily reactivation of the process of introjection. He itemizes and discusses the epistemological obstacles that apparently prevented Freud from taking this hypothesis under consideration. He goes on to examine the arguments and assumptions supporting the hypothesis that he discerns in Freud's development of the theory of the dream and in the posthumous publications of Ferenczi. After demonstrating the affinities between his own conception of the introjective function of dreaming and Jean Laplanche's "general theory of seduction," he evokes a few of the effects of his thesis on the practice and metapsychology of analytic technique. PMID- 26485492 TI - Priori mask guided image reconstruction (p-MGIR) for ultra-low dose cone-beam computed tomography. AB - Recently, the compressed sensing (CS) based iterative reconstruction method has received attention because of its ability to reconstruct cone beam computed tomography (CBCT) images with good quality using sparsely sampled or noisy projections, thus enabling dose reduction. However, some challenges remain. In particular, there is always a tradeoff between image resolution and noise/streak artifact reduction based on the amount of regularization weighting that is applied uniformly across the CBCT volume. The purpose of this study is to develop a novel low-dose CBCT reconstruction algorithm framework called priori mask guided image reconstruction (p-MGIR) that allows reconstruction of high-quality low-dose CBCT images while preserving the image resolution. In p-MGIR, the unknown CBCT volume was mathematically modeled as a combination of two regions: (1) where anatomical structures are complex, and (2) where intensities are relatively uniform. The priori mask, which is the key concept of the p-MGIR algorithm, was defined as the matrix that distinguishes between the two separate CBCT regions where the resolution needs to be preserved and where streak or noise needs to be suppressed. We then alternately updated each part of image by solving two sub-minimization problems iteratively, where one minimization was focused on preserving the edge information of the first part while the other concentrated on the removal of noise/artifacts from the latter part. To evaluate the performance of the p-MGIR algorithm, a numerical head-and-neck phantom, a Catphan 600 physical phantom, and a clinical head-and-neck cancer case were used for analysis. The results were compared with the standard Feldkamp-Davis-Kress as well as conventional CS-based algorithms. Examination of the p-MGIR algorithm showed that high-quality low-dose CBCT images can be reconstructed without compromising the image resolution. For both phantom and the patient cases, the p MGIR is able to achieve a clinically-reasonable image with 60 projections. Therefore, a clinically-viable, high-resolution head-and-neck CBCT image can be obtained while cutting the dose by 83%. Moreover, the image quality obtained using p-MGIR is better than the quality obtained using other algorithms. In this work, we propose a novel low-dose CBCT reconstruction algorithm called p-MGIR. It can be potentially used as a CBCT reconstruction algorithm with low dose scan requests. PMID- 26485494 TI - In vivo wideband multifrequency MR elastography of the human brain and liver. AB - PURPOSE: To demonstrate the feasibility of in vivo wideband MR elastography (wMRE) using continuous, time-harmonic shear vibrations in the frequency range of 10-50 Hz. THEORY AND METHODS: The method was tested in a gel phantom with marked mechanical loss. The brains and livers of eight volunteers were scanned by wMRE using multislice, single-shot MRE with optimized fractional encoding and synchronization of sequence acquisition to vibration. Multifrequency three dimensional inversion was used to reconstruct compound maps of magnitude |G*| and phase phi of the complex shear modulus. A new phase estimation, phi*, was developed to avoid systematic bias due to noise. RESULTS: In the phantom, G* dispersion measured by wMRE agreed well with oscillatory shear rheometry. |G*| and phi* measured at vibrations of 10-25 HZ, 25-35 HZ, and 40-50 HZ were 0.62 +/- 0.08, 1.56 +/- 0.16, 2.18 +/- 0.20 kPa and 0.09 +/- 0.17, 0.39 +/- 0.16, 0.20 +/- 0.13 rad in brain and 0.89 +/- 0.11, 1.67 +/- 0.20, 2.27 +/- 0.35 kPa and 0.15 +/ 0.10, 0.24 +/- 0.05, 0.26 +/- 0.05 rad in liver. Elastograms including all frequencies showed the best resolution of anatomical detail with |G*| = 1.38 +/- 0.12 kPa, phi* = 0.24 +/- 0.10 rad (brain) and |G*| = 1.79 +/- 0.23 kPa, phi* = 0.24 +/- 0.05 rad (liver). CONCLUSION: wMRE reveals highly dispersive G* properties of the brain and liver, and our results suggest that the influence of large-scale structures such as fluid-filled vessels and sulci on the MRE-measured parameters increases at low vibration frequencies. Magn Reson Med 76:1116-1126, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26485495 TI - Germ cell tumors: Treatment consensus across all age groups through MaGIC [Malignant Germ Cell International Collaborative]. PMID- 26485497 TI - Predictive Factors for the Uptake of Coping Strategies by Spousal Dementia Caregivers: A Systematic Review. AB - An understanding of spousal dementia caregivers' coping strategies and their predictive factors is imperative for caregivers' well-being. Although several reviews have explored the relationship between coping strategies and outcomes, no review has investigated factors that predict caregivers' use of one type of coping strategy over another. The current review aimed to identify factors that predict caregivers' coping strategies. Within this, we attempted to identify caregivers who are more likely to adopt dysfunctional coping strategies and be at risk of adverse outcomes. Several electronic databases were systematically searched. Twenty-one studies were eligible for review, describing 18 caregiver and care-recipient factors related to the 3 coping strategies. No factors were classified "predictive," however, 16 factors were "potentially predictive." Younger, more highly educated caregivers with greater emotional supports and knowledge of dementia were associated with solution-focused coping. Younger, less educated caregivers were associated with emotional support/acceptance-based coping strategies. Whereas nonwhite caregivers with less emotional supports caregiving for persons with more behavioral problems were associated with dysfunctional coping strategies. Enhancing caregiver self-efficacy, knowledge of dementia, improving social supports, linking to support groups, managing behavioral problems, as well as coaching adaptive coping strategies while flagging caregivers at risk for dysfunctional coping may improve outcomes for caregivers. PMID- 26485496 TI - Cross-validation of a Shortened Battery for the Assessment of Dysexecutive Disorders in Alzheimer Disease. AB - The frequency of executive disorders in mild-to-moderate Alzheimer disease (AD) has been demonstrated by the application of a comprehensive battery. The present study analyzed data from 2 recent multicenter studies based on the same executive battery. The objective was to derive a shortened battery by using the GREFEX population as a training dataset and by cross-validating the results in the REFLEX population. A total of 102 AD patients of the GREFEX study (MMSE=23.2+/ 2.9) and 72 patients of the REFLEX study (MMSE=20.8+/-3.5) were included. Tests were selected and receiver operating characteristic curves were generated relative to the performance of 780 controls from the GREFEX study. Stepwise logistic regression identified 3 cognitive tests (Six Elements Task, categorical fluency and Trail Making Test B error) and behavioral disorders globally referred as global hypoactivity (P=0.0001, all). This shortened battery was as accurate as the entire GREFEX battery in diagnosing dysexecutive disorders in both training group and the validation group. Bootstrap procedure confirmed the stability of AUC. A shortened battery based on 3 cognitive tests and 3 behavioral domains provides a high diagnosis accuracy of executive disorders in mild-to-moderate AD. PMID- 26485498 TI - Results From the NACC Uniform Data Set Neuropsychological Battery Crosswalk Study. AB - INTRODUCTION: Four new nonproprietary tests were recommended for use in the National Alzheimer's Coordinating Center's Uniform Data Set Neuropsychological Battery. These tests are similar to previous tests but also allow for continuity of longitudinal data collection and wide dissemination among research collaborators. METHODS: A Crosswalk Study was conducted in early 2014 to assess the correlation between each set of new and previous tests. Tests with good correlation were equated using equipercentile equating. The resulting conversion tables allow scores on the new tests to be converted to equivalent scores on the previous tests. RESULTS: All pairs of tests had good correlation (rho=0.68 to 0.78). Learning effects were detected for Logical Memory only. Confidence intervals were narrow at each point estimate, and prediction accuracy was high. DISCUSSION: The recommended new tests are well correlated with the previous tests. The equipercentile equating method produced conversion tables that provide a useful reference for clinicians and researchers. PMID- 26485499 TI - Improvement of Dream Enactment Behavior Associated With Levetiracetam Treatment in Dementia With Lewy Bodies. PMID- 26485500 TI - Consider the Source: The Implications of Informant Type on Outcome Assessments. PMID- 26485501 TI - CIED infection with either pocket or systemic infection presentation--complete device removal and long-term antibiotic treatment; long-term outcome. AB - OBJECTIVE: Cardiovascular implantable electronic device (CIED) infections are increasing in numbers. The objective was to review the clinical presentation and outcome in patients affected with CIED infections with either local pocket or systemic presentation. DESIGN: All device removals due to CIED infection during the period from 2005 to 2012 were retrospectively reviewed. CIED infections were categorized as systemic or pocket infections. Treatment included complete removal of the device, followed by antibiotic treatment of six weeks. RESULTS: Seventy one device removals due to infection (32 systemic and 39 pocket infections) were recorded during the study period. Median follow-up time was 26 (IQR 9-41) months, 30 day and 12 month mortality were 4% and 14%, respectively. There was no long term difference in mortality between patients with pocket vs. systemic infection (p = 0.48). During follow-up no relapses and two cases of new infections were noted (2.8%). CONCLUSIONS: CIED infection with systemic or pocket infection was difficult to distinguish in clinical presentation and outcome. Complete device removal and antibiotic treatment of long duration was safe and without relapses. PMID- 26485502 TI - Generation and stabilization of whey-based monodisperse nanoemulsions using ultra high-pressure homogenization and small amphipathic co-emulsifier combinations. AB - Ultra-high-pressure homogenization (UHPH) was used to generate monodisperse stable peanut oil nanoemulsions within a desired nanosize range (<100 nm) (DNR) stabilized using combinations of whey protein concentrate (WPC), sodium dodecyl sulfate, Triton X-100 (X100), and zwitterionic sulfobetaine-based surfactants differing in hydrophobicity. For WPC [2.0% (w/v)], the dispersed-phase fractions (phi) of 0.05 and 210 MPa significantly reduced the mean globule size (dvs) but the grouped frequency distribution was bimodal and larger than that of DNR. Addition of co-emulsifier sulfobetaine 3-10 (SB3-10) [7.5% (w/w) WPC] gave particles within DNR (dvs of 73 nm) though still in a bimodal distribution. Circular dichroism prior to UHPH showed little disruption of the secondary structure of proteins in WPC by SB3-10, whereas X100 obliterated it. A WPC/SB3-10 mixture retained some periodic structure even when mixed with X100 [10% (w/w) WPC] and remarkably gave a narrow monomodal distribution within DNR with the highest stability reflected by a lack of creaming after storage for 30 days (22 degrees C). PMID- 26485503 TI - Resveratrol abrogates lipopolysaccharide-induced depressive-like behavior, neuroinflammatory response, and CREB/BDNF signaling in mice. AB - Current evidence supports that depression is accompanied by the activation of the inflammatory-response system, and overproduction of pro-inflammatory cytokines may play a role in the pathophysiology of depressive disorders. Resveratrol has anti-inflammatory, antioxidant and anti-depressant-like properties. Using an animal model of depression induced by a single administration of lipopolysaccharide (LPS), the present study investigated the effects of resveratrol on LPS-induced depressive-like behavior and inflammatory-response in adult mice. Our results showed that pretreatment with resveratrol (80mg/kg, i.p.) for 7 consecutive days reversed LPS-increased the immobility time in the forced swimming test and tail suspension test, and LPS-reduced sucrose preference test. Moreover, the antidepressant action of resveratrol was paralleled by significantly reducing the expression levels of pro-inflammatory cytokines, and up-regulating phosphorylated cAMP response-element-binding protein (pCREB)/brain derived neurotrophic factor (BDNF) expression in prefrontal cortex (PFC) and hippocampus. In addition, resveratrol ameliorated LPS-induced NF-kappaB activation in the PFC and hippocampus. The results demonstrate that resveratrol may be an effective therapeutic agent for LPS-induced depressive-like behavior, partially due to its anti-inflammatory aptitude and by modulating pCREB and BDNF expression in the brain region of mice. PMID- 26485504 TI - Baicalin inhibiting cerebral ischemia/hypoxia-induced neuronal apoptosis via MRTF A-mediated transactivity. AB - Baicalin has been shown to provide the neuroprotective effect by alleviating cerebral ischemia injury. However, little's known about the underlying mechanism. Here, a cerebral artery occlusion (MACO)/reperfusion rat model and rat primary cortical neuron culture exposed to hydrogen peroxide (H2O2) were established to evaluate the effect of baicalin on ischemia-induced neuronal apoptosis. We found baicalin can significantly less neurological deficit and reduced infarct volume in vivo. And it efficiently inhibited neuronal apoptosis in vivo and vitro, which was especially characterized by the enhancing of transcription and expression of myeloid cell leukemia-1 (MCL-1) and B-cell lymphoma-2 (BCL-2) in a dose-dependent manner. Furthermore, Baicalin markedly increased myocardin-related transcription factor-A (MRTF-A) level either in ischemic hemisphere or in primary cortical neuron cultures, whiles the anti-apoptosis effect of baicalin was significantly inhibited by transfected with the small interfering RNA of MRTF-A (MRTF-A siRNA) in primary cortical neuron cultures. The luciferase assays also indicated baicalin enhanced the transactivity of MCL-1 and BCL-2 promoter by activating the key CArG box (CC [A/T] 6GG) element, which was reduced by MRTF-A siRNA, suggesting MRTF-A may participate the anti-apoptosis effect of baicalin, and MRTF A was involved in the transcriptional activity of MCL-1 and BCL-2 that was induced by baicalin. LY294002 (phosphatidylinositol-3 kinase (PI3K) inhibitor) and PD98059 (extracellular signal regulates kinase-1/2 (ERK1/2) inhibitor) obviously reduced baicalin-induced MRTF-A expression and transactivity and expression of MCL-1 and BCL-2, which further abolished the anti-apoptotic effect of baicalin on neuronal apoptosis. Taken together, our data provided the evidence demonstrating the neuroprotective effect of baicalin partially due to MRTF-A mediated transactivity and expression of MCL-1 and BCL-2 by triggering the CArG box, which might be controlled by the activation of PI3K and ERK1/2. PMID- 26485506 TI - Role of Oral Mucosal Fluid and Electrolyte Absorption and Secretion in Dry Mouth. AB - Dry mouth is induced by dehydration of the oral mucosa, resulting from an imbalance of fluid supply and clearance within the oral cavity. Saliva is the major source of oral mucosal fluid, whereas oral fluid clearance includes evaporation and swallowing. Oral mucosal fluid absorption has been suggested to play a critical role in oral fluid clearance; over-absorption of water and ions across the oral mucosa under certain conditions may be a major component for oral fluid imbalance, leading to mucosal dehydration. While numerous studies have confirmed that the oral mucosa absorbs fluid and electrolytes, the pathways and mechanisms mediating the absorption remain undefined. The transcellular pathway regulating oral mucosal epithelial absorption includes aquaporins, epithelial Na+ channel and/or Na+/H+ exchanger, whereas the paracellular transport is likely to be mediated by tight junctions. The regulatory mechanisms of these pathways require further elucidation. It remains unclear whether the oral mucosa also secretes fluid and ions into the oral cavity. Although intercellular lipids secreted by epithelial cells form the major barrier to paracellular water and ion transport, the role and regulation of these lipids in oral mucosal hydration in physiological and pathological conditions need further investigation. Delineation of these mechanisms will be conducive to the development of preventive and therapeutic interventions for dry mouth. PMID- 26485505 TI - Mice with Hepatic Loss of the Desmosomal Protein gamma-Catenin Are Prone to Cholestatic Injury and Chemical Carcinogenesis. AB - gamma-Catenin, an important component of desmosomes, may also participate in Wnt signaling. Herein, we dissect the role of gamma-catenin in liver by generating conditional gamma-catenin knockout (KO) mice and assessing their phenotype after bile duct ligation (BDL) and diethylnitrosamine-induced chemical carcinogenesis. At baseline, KO and wild-type littermates showed comparable serum biochemistry, liver histology, and global gene expression. beta-Catenin protein was modestly increased without any change in Wnt signaling. Desmosomes were maintained in KO, and despite no noticeable changes in gene expression, differential detergent fractionation revealed quantitative and qualitative changes in desmosomal cadherins, plaque proteins, and beta-catenin. Enhanced association of beta catenin to desmoglein-2 and plakophilin-3 was observed in KO. When subjected to BDL, wild-type littermates showed specific changes in desmosomal protein expression. In KO, BDL deteriorated baseline compensatory changes, which manifested as enhanced injury and fibrosis. KO also showed enhanced tumorigenesis to diethylnitrosamine treatment because of Wnt activation, as also verified in vitro. gamma-Catenin overexpression in hepatoma cells increased its binding to T cell factor 4 at the expense of beta-catenin-T-cell factor 4 association, induced unique target genes, affected Wnt targets, and reduced cell proliferation and viability. Thus, gamma-catenin loss in liver is basally well tolerated. However, after insults like BDL, these compensations at desmosomes fail, and KO show enhanced injury. Also, gamma-catenin negatively regulates tumor growth by affecting Wnt signaling. PMID- 26485507 TI - Comparison of Subgingival and Peri-implant Microbiome in Chronic Periodontitis. AB - OBJECTIVES: To analyse the microbia composition of 10 healthy dental implants and 10 chronic periodontitis patients. METHODS: Subgingival plaque and peri-implant biofilm were sampled at the first molar site before and after implant restoration. The analysis was conducted by 454-prosequencing of bacterial V1 to V3 regions of 16S rDNA. RESULTS: Chronic periodontitis subjects showed greater bacterial diversity compared with implant subjects. The relative abundance of sixteen genera and twelve species differed significantly between implant and chronic periodontitis subjects. The genera Catonella, Desulfovibrio, Mogibacterium, Peptostreptococcus and Propionibacterium were present in higher abundance in chronic periodontitis subjects, while implant subjects had higher proportions of Brevundimonas and Pseudomonas species. CONCLUSIONS: Our results demonstrate that implant restoration changes the oral microbiota. The analysis suggests that periodontal bacteria can remain for a prolonged period of time at non-dental sites, from where they can colonise the peri-implant. PMID- 26485508 TI - Prosthodontic Treatment for Severe Oligodontia with Long-term Follow-up. AB - OBJECTIVE: To express the early prosthodontic treatment strategies for severe oligodontia patients with or without a syndrome and to share details of their experiences of the long-term follow-up. METHODS: Patients with severe oligodontia (excluding the third molars, and with six or more congenitally missing permanent teeth) who had finished prosthetic rehabilitation between 2001 and 2014 and who had undergone at least 1-year follow-up at the Department of Prosthodontics, Peking University School of Stomatology were included in the study. The general and oral characteristics were determined and examined, interdisciplinary plans were provided, and the prosthodontic treatment conditions were described and evaluated. RESULTS: In total 26 subjects were included. Twenty males and six females, whose first dental visit occurred between the ages of 2 years and 9 months old, and 31 years old were recorded, of which, 12 (46.2%) subjects had non syndromic oligodontia and 14 (53.8%) had oligodontia with different syndromes. The number of congenitally missing teeth (excluding the third molars) was between 7 to 28 (mean = 18), with 14 and 21 teeth in the non-syndromic and syndromic oligodontia patients, respectively. Most of the patients accepted conventional prostheses and two had implant-supported crowns or bridges. The age of the first prosthesis delivery ranged from 3.5 to 31 years old. The follow-up period ranged from 15 months (1 year and 3 months) to 162 months (13.5 years), with a mean of 108 months (9 years). CONCLUSION: Early treatment for young patients and long term follow-up greatly benefits patients. Interdisciplinary treatment ensures more satisfactory results. PMID- 26485509 TI - Comparison of Measurements on Cone Beam Computed Tomography for Periodontal Intrabony Defect with Intra-surgical Measurements. AB - OBJECTIVE: To explore the relationship between cone beam computed tomography (CBCT) measurements and direct measurements during the surgery to correct intrabony defects. METHODS: Forty-four patients with 44 intrabony defects who finished initial periodontal therapy and were considered for periodontal surgery were recruited. Digital periapical radiography and CBCT was performed before the surgery. The distance from the bottom of the defect to the cementoenamel junction (CEJ-BD), the depth and mesio-distal width of the defect were measured on CBCT, periapical radiographs and during the surgery. The buccal-lingual width of the defect was only recorded on CBCT and during the surgery. Lastly, intra-surgical linear measurements were compared with measurements of radiographs and CBCT, respectively. RESULTS: The means of the intra-surgical CEJ to BD, the depth of the defect, the mesio-distal (M-D) width and the buccal-lingual (B-L) width of the defect were 8.90 mm, 5.52 mm, 3.35 mm and 7.40 mm, respectively. Between CBCT measurements and surgical measurements the differences for the CEJ to BD (0.76 +/ 1.40 mm) and the depth of the defect (0.63 +/- 1.67 mm) were statistically significant, but the differences for the M-D width (-0.17 +/- 0.67 mm) and the B L width (-0.16 +/- 0.65 mm) of the defect were not statistically significant. CONCLUSION: CBCT could provide relatively accurate measurements of the M-D width of the defect and additionally showed accurate measurements of the B-L width of the defect which periapical radiographs could not show. However, for vertical measurements of the intrabony defect (CEJ to BD and depth of the defect), when compared with measurements during the surgery, CBCT showed no advantages over periapical radiographs. A new method should be developed for accurately measuring the periodontal intrabony defects using CBCT in the future. PMID- 26485510 TI - Patterns and Risk Factors for White Spot Lesions in Orthodontic Patients with Fixed Appliances. AB - OBJECTIVE: To evaluate the development and risk factors of white spot lesions (WSLs) in orthodontic patients with fixed appliances in a Chinese population. METHODS: A total of 202 subjects participated in the cross-sectional study. Clinical examination of the state of the entire labial (buccal) enamel surface was conducted under artificial light using a clinical mirror and an explorer. A face-to-face interview was conducted through a structured questionnaire to collect a range of information, including demographic data, family income, level of education, toothbrushing frequency, fluoride toothpaste usage and the use of a professional toothbrush (V type). RESULTS: WSLs appeared on 57.9% of the subjects after orthodontic treatment with fixed appliances; the mean tooth number of WSLs was 4.8. A higher prevalence was observed in subjects whose time of therapy was 17 months or longer (OR = 3.2, P < 0.050), and who had modified their unhealthy dietary habits (OR = 3.7, P < 0.001). Younger individuals or individuals who consumed food with sugar at least once a day during the course of their orthodontic treatment also exhibited a higher likelihood of experiencing WSLs. CONCLUSION: The prevalence of WSLs after orthodontic treatment with fixed appliances was relatively high in China. Clinicians should be aware of the risk factors of WSLs that may occur during the treatment period. PMID- 26485511 TI - Urea Rinse effectively Neutralises Sucrose-induced Decrease in Plaque pH. AB - OBJECTIVES: To investigate the neutralising effects of subsequent urea rinse on sucrose-induced decrease in plaque pH with interdental plaque pH telemetry. METHOD: Six participants wearing partial lower prostheses which incorporated a miniature glass pH electrode were included. After 5 or 6 days of plaque accumulation on the tip of the electrode, the subjects rinsed with a 15 ml 10% sucrose solution, followed by no subsequent rinsing or rinsing with either 15 ml of water, 0.25%, 0.50% or 1.00% urea solution, for 2 min. The plaque pH was continuously recorded for 120 min. RESULTS: Without subsequent rinsing, the plaque pH decreased at 10 min to 4.39 and stayed below the critical pH of 5.7 for 80 min following a sucrose rinse. Subsequent water rinse showed little effects on the sucrose-induced decrease in plaque pH, whereas subsequent urea rinses all immediately and effectively neutralised sucrose-induced decrease in plaque pH, and remained above the critical pH of 5.7 until the end of data collection. CONCLUSION: Urea rinse could effectively counteract the pH fall following sucrose administration. These results strongly suggested that the regular use of low concentration urea rinse after carbohydrate consumption may help prevent caries. PMID- 26485512 TI - Evaluation by CBCT of Root and Canal Morphology in Mandibular Premolars in an Iranian Population. AB - OBJECTIVE: To compare the root canal morphology in the left and right mandibular premolars on cone beam computed tomography (CBCT) images. METHODS: In this analytical cross-sectional study, 457 CBCT images, including human left and right mandibular premolars were evaluated. CBCT scans were investigated in the three spatial planes and differences in the number of roots and canals were recorded. Data were analysed using chi-square test. The significance level was set at P < 0.05. RESULTS: From 914 mandibular first premolars, in the left side, 85.6% had one root and 14.4% had two roots; 69.6% had one canal and 30.4% had two canals. In the right side 87.3% had one root and 12.7% had two roots; 66.5% had one canal and 33.5% had two canals. There was no statistically significant difference in the number of roots (P = 0.440) and canals (P = 0.321) between left and right mandibular first premolars. From 914 mandibular second premolars, in the left side, 94.3% had one root and 5.7% had two roots; 77.9% had one canal and 22.1% had two canals. In the right side, 95.6% had one root and 4.4% had two roots; 83.4% had one canal and 16.6% had two canals. There was a significant difference in the number of canals between the left and right mandibular second premolars (P = 0.036). CONCLUSIONS: The root canal morphology in the mandibular left and right premolars was different, but there was a significant difference only in the number of canals in the mandibular second premolars. PMID- 26485513 TI - Whole Retinal Explants from Chicken Embryos for Electroporation and Chemical Reagent Treatments. AB - The retina is a good model for the developing central nervous system. The large size of the eye and most importantly the accessibility for experimental manipulations in ovo/in vivo makes the chicken embryonic retina a versatile and very efficient experimental model. Although the chicken retina is easy to target in ovo by intraocular injections or electroporation, the effective and exact concentration of the reagents within the retina may be difficult to fully control. This may be due to variations of the exact injection site, leakage from the eye or uneven diffusion of the substances. Furthermore, the frequency of malformations and mortality after invasive manipulations such as electroporation is rather high. This protocol describes an ex ovo technique for culturing whole retinal explants from chicken embryos and provides a method for controlled exposure of the retina to reagents. The protocol describes how to dissect, experimentally manipulate, and culture whole retinal explants from chicken embryos. The explants can be cultured for approximately 24 hr and be subjected to different manipulations such as electroporation. The major advantages are that the experiment is not dependent on the survival of the embryo and that the concentration of the introduced reagent can be varied and controlled in order to determine and optimize the effective concentration. Furthermore, the technique is rapid, cheap and together with its high experimental success rate, it ensures reproducible results. It should be emphasized that it serves as an excellent complement to experiments performed in ovo. PMID- 26485515 TI - Copper-Catalyzed Oxidative C-H Amination of Tetrahydrofuran with Indole/Carbazole Derivatives. AB - A simple alpha-C-H amination of cyclic ether with indole/carbazole derivatives has been accomplished by employing copper(II) chloride/bipy as the catalyst system. In the presence of the di-tert-butyl peroxide oxidant, cyclic ethers such as tetrahydrofuran, 1,4-dioxane, and tetrahydropyran successfully undergo C-H/N-H cross dehydrogenative coupling (CDC) with various carbazole or indole derivatives in good-to-excellent yields. PMID- 26485514 TI - NINL and DZANK1 Co-function in Vesicle Transport and Are Essential for Photoreceptor Development in Zebrafish. AB - Ciliopathies are Mendelian disorders caused by dysfunction of cilia, ubiquitous organelles involved in fluid propulsion (motile cilia) or signal transduction (primary cilia). Retinal dystrophy is a common phenotypic characteristic of ciliopathies since photoreceptor outer segments are specialized primary cilia. These ciliary structures heavily rely on intracellular minus-end directed transport of cargo, mediated at least in part by the cytoplasmic dynein 1 motor complex, for their formation, maintenance and function. Ninein-like protein (NINL) is known to associate with this motor complex and is an important interaction partner of the ciliopathy-associated proteins lebercilin, USH2A and CC2D2A. Here, we scrutinize the function of NINL with combined proteomic and zebrafish in vivo approaches. We identify Double Zinc Ribbon and Ankyrin Repeat domains 1 (DZANK1) as a novel interaction partner of NINL and show that loss of Ninl, Dzank1 or both synergistically leads to dysmorphic photoreceptor outer segments, accumulation of trans-Golgi-derived vesicles and mislocalization of Rhodopsin and Ush2a in zebrafish. In addition, retrograde melanosome transport is severely impaired in zebrafish lacking Ninl or Dzank1. We further demonstrate that NINL and DZANK1 are essential for intracellular dynein-based transport by associating with complementary subunits of the cytoplasmic dynein 1 motor complex, thus shedding light on the structure and stoichiometry of this important motor complex. Altogether, our results support a model in which the NINL-DZANK1 protein module is involved in the proper assembly and folding of the cytoplasmic dynein 1 motor complex in photoreceptor cells, a process essential for outer segment formation and function. PMID- 26485516 TI - Iron transport in the kidney: implications for physiology and cadmium nephrotoxicity. AB - The kidney has recently emerged as an organ with a significant role in systemic iron (Fe) homeostasis. Substantial amounts of Fe are filtered by the kidney, which have to be reabsorbed to prevent Fe deficiency. Accordingly Fe transporters and receptors for protein-bound Fe are expressed in the nephron that may also function as entry pathways for toxic metals, such as cadmium (Cd), by way of "ionic and molecular mimicry". Similarities, but also differences in handling of Cd by these transport routes offer rationales for the propensity of the kidney to develop Cd toxicity. This critical review provides a comprehensive update on Fe transport by the kidney and its relevance for physiology and Cd nephrotoxicity. Based on quantitative considerations, we have also estimated the in vivo relevance of the described transport pathways for physiology and toxicology. Under physiological conditions all segments of the kidney tubules are likely to utilize Fe for cellular Fe requiring processes for metabolic purposes and also to contribute to reabsorption of free and bound forms of Fe into the circulation. But Cd entering tubule cells disrupts metabolic pathways and is unable to exit. Furthermore, our quantitative analyses contest established models linking chronic Cd nephrotoxicity to proximal tubular uptake of metallothionein-bound Cd. Hence, Fe transport by the kidney may be beneficial by preventing losses from the body. But increased uptake of Fe or Cd that cannot exit tubule cells may lead to kidney injury, and Fe deficiency may facilitate renal Cd uptake. PMID- 26485517 TI - Identification of the critical attribute(s) of EBV gp350 antigen required for elicitation of a neutralizing antibody response in vivo. AB - Vaccine prophylaxis with EBV glycoprotein 350 (gp350) subunit plus adjuvant has been demonstrated clinically to protect individuals against infectious mononucleosis (IM), but the specifications of the antigen required to elicit this protection has remained largely theoretical. Previous studies have shown that antibodies to gp350 comprise the principle component of EBV-neutralizing sera. Further, a murine monoclonal antibody against gp350 (clone 72A1) is able to prevent infection by the virus both in vitro and in vivo. In the present study, we identify the 72A1 epitope on recombinant gp350 antigen as the site required for binding to CD21 on human B cells. We also identify the need for conformational-dependence of the antigen to generate EBV-neutralizing antibodies in vivo. Further, we have characterized the glycosylation status and antigenicity profiles of both native and denatured CHO-produced soluble gp350 as well as non glycosylated protein produced in Escherichia coli. Collectively our in vitro and in vivo data demonstrate the requirement for a conformationally accessible 72A1 epitope on gp350 to elicit EBV-neutralizing responses, and establish this as a critical attribute of this vaccine antigen. These data provide direction for commercial vaccine development, as the absence of this epitope on either E. coli expressed or denatured gp350, may limit production and purification options for the antigen. PMID- 26485518 TI - Connecting Age-Related Biological Decline to Frailty and Late-Life Vulnerability. AB - Frailty is an important construct in aging which allows for the identification of the most vulnerable subset of older adults. At least two conceptual models of frailty have been developed that have in turn facilitated the development of multiple frailty screening tools. This has enabled the study of populations of frail and nonfrail older adults, and facilitated the risk assessment for adverse health outcomes. In addition, using the syndromic approach to frailty, numerous biological hypotheses have been tested, which have identified chronic inflammatory pathway activation, hypothalamic-pituitary-adrenal axis activation, and sympathetic nervous system activity as important in the development of frailty. In addition, age-related molecular changes related to autophagy, mitochondrial decline, apoptosis, senescent cell development, and necroptosis likely contribute to the heterogeneous phenotype of frailty. The recent development of a frail mouse model with chronic inflammatory pathway activation has helped to facilitate further whole organism biological discoveries. The following article attempts to create an understanding of the connections between these age-related biological changes and frailty. PMID- 26485520 TI - Brucellosis and Coxiella burnetii Infection in Householders and Their Animals in Secure Villages in Herat Province, Afghanistan: A Cross-Sectional Study. AB - BACKGROUND: Brucellosis and coxiellosis are known to be endemic in ruminant populations throughout Afghanistan, but information about their prevalence and factors that affect prevalence in householders and livestock under diverse husbandry systems and pastoral settings is sparse. METHODS/PRINCIPAL FINDINGS: We conducted a cross-sectional survey to investigate the seroprevalence of brucellosis and Coxiella burnetii in humans and livestock in six secure districts in Herat from 26th December 2012-17th January 2013. A total of 204 households with livestock were surveyed in six Kuchi and five sedentary type villages. Blood samples from 1,017 humans, 1,143 sheep, 876 goats and 344 cattle were tested for brucellosis and Q fever. About one in six households (15.7%) had at least one Brucella seropositive person, about one in eight households (12.3%) had at least one Brucella seropositive animal and about one in four (24.5%) had either seropositive animals or humans. Ninety-seven percent of households had at least one C. burnetii seropositive person and 98.5% of households had one or more C. burnetii seropositive animals. Forty- seven householders had serological evidence of exposure to both C. burnetii and Brucella and eight animals were serologically positive for both diseases. Drinking unpasteurised milk (OR 1.6), treating animals for ticks (OR 1.4), milking sheep (OR 1.4), male gender (OR 1.4) and seropositivity to Brucella (OR 4.3) were identified as risk factors for seropositivity to C. burnetii in householders. Household factors associated with households having either Brucella seropositive animals or humans were Kuchi households (OR 2.5), having <= 4 rooms in the house (OR 2.9) and not owning land (OR 2.9). CONCLUSIONS: The results from this study provide baseline information for the planning and monitoring of future interventions against these diseases. The implementation of this study greatly improved collaboration, coordination and capability of veterinary and public health professionals from government, NGOs and donor funded projects. PMID- 26485519 TI - CD39 Expression Identifies Terminally Exhausted CD8+ T Cells. AB - Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. PMID- 26485521 TI - Experience with Thoracoscopic Repair of Long Gap Esophageal Atresia in Neonates. AB - INTRODUCTION: This report evaluates the results of a two-surgeon experience with thoracoscopic repair in patients with long gap esophageal atresia (EA). MATERIALS AND METHODS: From March 2000 to February 2015, 14 consecutive patients with pure EA were repaired thoracoscopically. The gap length was then evaluated by contrast gastrostomy tube study. Patients were operated on between 4 to 8 weeks of age. Patient weights ranged from 2.6 to 3.8 kg. The longest gap was 71/2 vertebral bodies. Dissection was carried well up into the thoracic inlet on the upper pouch and down to the esophageal hiatus on the lower pouch. A 15th patient was not referred until 3 months of age. RESULTS: All 15 procedures were completed successfully thoracoscopically. Operative times ranged from 60 to 135 minutes. There were two leaks; both resolved with conservative therapy. Feeds were started on Day 5 in all other patients. Six of 13 patients required dilations (one to nine), and 8 required a Nissen fundoplication for severe reflux. All patients are currently on full oral feeds. No patient has any evidence of chest wall asymmetry, winged scapula, or clinically significant scoliosis. CONCLUSIONS: Thoracoscopic repair of long gap EA has proven to be an effective and safe technique when performed in the first 2 months of life. The improved visualization and access to the upper pouch and lower pouches allow for maximal mobilization. The results are superior to those of documented open series and avoid the morbidity of repeated operations in the neonatal period. PMID- 26485522 TI - Microelectrode Guided Implantation of Electrodes into the Subthalamic Nucleus of Rats for Long-term Deep Brain Stimulation. AB - Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson's disease, dystonia or tremor. DBS is based on the delivery of electrical stimuli to specific deep anatomic structures of the central nervous system. However, the mechanisms underlying the effect of DBS remain enigmatic. This has led to an interest in investigating the impact of DBS in animal models, especially in rats. As DBS is a long-term therapy, research should be focused on molecular-genetic changes of neural circuits that occur several weeks after DBS. Long-term DBS in rats is challenging because the rats move around in their cage, which causes problems in keeping in place the wire leading from the head of the animal to the stimulator. Furthermore, target structures for stimulation in the rat brain are small and therefore electrodes cannot easily be placed at the required position. Thus, a set-up for long-lasting stimulation of rats using platinum/iridium electrodes with an impedance of about 1 MOmega was developed for this study. An electrode with these specifications allows for not only adequate stimulation but also recording of deep brain structures to identify the target area for DBS. In our set-up, an electrode with a plug for the wire was embedded in dental cement with four anchoring screws secured onto the skull. The wire from the plug to the stimulator was protected by a stainless-steel spring. A swivel was connected to the circuit to prevent the wire from becoming tangled. Overall, this stimulation set-up offers a high degree of free mobility for the rat and enables the head plug, as well as the wire connection between the plug and the stimulator, to retain long-lasting strength. PMID- 26485523 TI - The Impact of PNPLA3 rs738409 Genetic Polymorphism and Weight Gain >=10 kg after Age 20 on Non-Alcoholic Fatty Liver Disease in Non-Obese Japanese Individuals. AB - Non-alcoholic fatty liver disease (NAFLD) in non-obese individuals is inadequately elucidated. We aim to investigate the impact of known genetic polymorphisms on NAFLD and the interaction between genetic risks and weight gain on NAFLD in obese and non-obese Japanese individuals. A total of 1164 participants who received health checkups were included. Participants with excessive alcohol consumption, with viral hepatitis or other inappropriate cases were excluded. Fatty liver was diagnosed by ultrasonography. Participants with a body mass index (BMI) of <18.5 kg/m2, 18.5-22.9 kg/m2, 23.0-24.9 kg/m2 and >=25 kg/m2 were classified underweight, normal weight, overweight and obese, respectively. Self-administered questionnaire for lifestyle was assessed and a total of 8 previously reported genetic polymorphisms were chosen and examined. In all, 824 subjects were enrolled. The overall prevalence of NAFLD was 33.0%: 0% in underweight, 15.3% in normal weight, 41.1% in overweight and 71.7% in obese individuals. The prevalence of NAFLD is more affected by the G allele of patatin like phospholipase domain-containing protein 3 (PNPLA3) rs738409 in normal weight (odds ratio (OR) 3.52; 95%-CI: 1.42-8.71; P = 0.0063) and in overweight individuals (OR 2.60; 95%-CI: 1.14-5.91; P = 0.0225) than in obese individuals (not significant). Moreover, the G allele of PNPLA3 rs738409 and weight gain >=10 kg after age 20 had a joint effect on the risk of NAFLD in the normal weight (OR 12.00; 95% CI: 3.71-38.79; P = 3.3*10-5) and the overweight individuals (OR 13.40; 95% CI: 2.92-61.36; P = 0.0008). The G allele of PNPLA3 rs738409 is a prominent risk factor for NAFLD and the interaction between the PNPLA3 rs738409 and weight gain >=10 kg after age 20 plays a crucial role in the pathogenesis of NAFLD, especially in non-obese Japanese individuals. PMID- 26485524 TI - The Role of Quality Health Services and Discussion about Birth Spacing in Postpartum Contraceptive Use in Sindh, Pakistan: A Multilevel Analysis. AB - INTRODUCTION: Rapid population growth, stagnant contraceptive prevalence, and high unmet need for family planning present significant challenges for meeting Pakistan's national and international development goals. Although health behaviors are shaped by multiple social and environmental factors, research on contraceptive uptake in Pakistan has focused on individual and household determinants, and little attention has been given to community characteristics that may affect access to services and reproductive behavior. METHODS: Individual and community determinants of contraceptive use were identified using multivariable multilevel logistic regression to analyze data from a 2014 cross sectional survey of 6,200 mothers in 503 communities in Sindh, Pakistan. RESULTS: Only 27% of women who had given birth in the two years before the study reported using contraceptives. After adjusting for individual and community characteristics, there was no difference in the odds of contraceptive use between urban and rural women. Women who had delivered at a health facility had 1.4 times higher odds of contraceptive use than women who delivered at home. Those who received information about birth spacing from a doctor or relatives/friends had 1.81 and 1.38 times higher odds of contraceptive use, respectively, than those who did not. Living in a community where a higher proportion of women received quality antenatal care and where discussion of birth spacing was more common was significantly associated with contraceptive use. Community-wide poverty lowered contraceptive use. CONCLUSIONS: Quality of care at the community level has strong effects on contraceptive use, independent of the characteristics of individual households or women. These findings suggest that powerful gains in contraceptive use may be realized by improving the quality of antenatal care in Pakistan. Community health workers should focus on generating discussion of birth spacing in the community. Outreach efforts should target communities where the demand for contraception appears to be depressed due to high levels of poverty. PMID- 26485525 TI - Hybridization between Yellowstone Cutthroat Trout and Rainbow Trout Alters the Expression of Muscle Growth-Related Genes and Their Relationships with Growth Patterns. AB - Hybridization creates novel gene combinations that may generate important evolutionary novelty, but may also reduce existing adaptation by interrupting inherent biological processes, such as genotype-environment interactions. Hybridization often causes substantial change in patterns of gene expression, which, in turn, may cause phenotypic change. Rainbow trout (Oncorhynchus mykiss) and cutthroat trout (O. clarkii) produce viable hybrids in the wild, and introgressive hybridization with introduced rainbow trout is a major conservation concern for native cutthroat trout. The two species differ in body shape, which is likely an evolutionary adaptation to their native environments, and their hybrids tend to show intermediate morphology. The characterization of gene expression patterns may provide insights on the genetic basis of hybrid and parental morphologies, as well as on the ecological performance of hybrids in the wild. Here, we evaluated the expression of eight growth-related genes (MSTN-1a, MSTN-1b, MyoD1a, MyoD1b, MRF-4, IGF-1, IGF-2, and CAST-L) and the relationship of these genes with growth traits (length, weight, and condition factor) in six line crosses: both parental species, both reciprocal F1 hybrids, and both first generation backcrosses (F1 x rainbow trout and F1 x cutthroat trout). Four of these genes were differentially expressed among rainbow, cutthroat, and their hybrids. Transcript abundance was significantly correlated with growth traits across the parent species, but not across hybrids. Our findings suggest that rainbow and cutthroat trout exhibit differences in muscle growth regulation, that transcriptional networks may be modified by hybridization, and that hybridization disrupts intrinsic relationships between gene expression and growth patterns that may be functionally important for phenotypic adaptations. PMID- 26485526 TI - Correction: Spatial, Temporal, and Density-Dependent Components of Habitat Quality for a Desert Owl. PMID- 26485528 TI - Correction: Combining Cationic Liposomal Delivery with MPL-TDM for Cysteine Protease Cocktail Vaccination against Leishmania donovani: Evidence for Antigen Synergy and Protection. PMID- 26485527 TI - Evaluation of whole-mount in situ hybridization as a tool for pathway-based toxicological research with early-life stage fathead minnows. AB - Early-life stage fish can be more sensitive to toxicants than adults, so delineating mechanisms of perturbation of biological pathways by chemicals during this life stage is crucial. Whole-mount in situ hybridization (WISH) paired with quantitative real-time polymerase chain reaction (QPCR) assays can enhance pathway-based analyses through determination of specific tissues where changes in gene expression are occurring. While WISH has frequently been used in zebrafish (Danio rerio), this technology has not previously been applied to fathead minnows (Pimephales promelas), another well-established small fish model species. The objective of the present study was to adapt WISH to fathead minnow embryos and larvae, and use the approach to evaluate the effects of estrone, an environmentally-relevant estrogen receptor (ER) agonist. Embryos were exposed via the water to 0, 18 or 1800 ng estrone/L (0, 0.067 and 6.7nM) for 3 or 6 days in a solvent-free, flow-through test system. Relative transcript abundance of three estrogen-responsive genes, estrogen receptor-alpha (esr1), cytochrome P450 aromatase B (cyp19b), and vitellogenin (vtg) was examined in pooled whole embryos using QPCR, and the spatial distribution of up-regulated gene transcripts was examined in individual fish using WISH. After 3 days of exposure to 1800 ng estrone/L, esr1 and cyp19b were significantly up-regulated, while vtg mRNA expression was not affected. After 6 days of exposure to 1800 ng estrone/L, transcripts for all three genes were significantly up-regulated. Corresponding WISH assays revealed spatial distribution of esr1 and vtg in the liver region, an observation consistent with activation of the hepatic ER. This study clearly demonstrates the potential utility of WISH, in conjunction with QPCR, to examine the mechanistic basis of the effects of toxicants on early-life stage fathead minnows. PMID- 26485531 TI - General, Label-Free Method for Determining K(d) and Ligand Concentration Simultaneously. AB - Some of the most commonly used affinity reagents (e.g., antibodies) are often developed and used in conditions where their input concentrations ([L]0) and affinities (K(d)) are not known. Here, we have developed a general approach to determine both [L]0 and K(d) values simultaneously for affinity reagents (small molecules, proteins, and antibodies). To do this, we perform quantitative equilibrium exclusion immunoassays with two different concentrations of target and fit the data simultaneously to determine K(d) and [L]0. The results give accurate and reproducible measures of both values compared to established methods. By performing detailed error analysis, we demonstrate that our fitting gives unique solutions and indicates where K(d) and [L]0 measures are reliable. Furthermore, we found that a divalent model of antibody binding gives accurate K(d) and [L]0 values in both the forward (antibody immobilized) and the reverse (target immobilized) assays-addressing the long-term problem of obtaining quantitative data from reverse assays. PMID- 26485529 TI - An Orthologous Epigenetic Gene Expression Signature Derived from Differentiating Embryonic Stem Cells Identifies Regulators of Cardiogenesis. AB - Here we used predictive gene expression signatures within a multi-species framework to identify the genes that underlie cardiac cell fate decisions in differentiating embryonic stem cells. We show that the overlapping orthologous mouse and human genes are the most accurate candidate cardiogenic genes as these genes identified the most conserved developmental pathways that characterize the cardiac lineage. An RNAi-based screen of the candidate genes in Drosophila uncovered numerous novel cardiogenic genes. shRNA knockdown combined with transcriptome profiling of the newly-identified transcription factors zinc finger protein 503 and zinc finger E-box binding homeobox 2 and the well-known cardiac regulatory factor NK2 homeobox 5 revealed that zinc finger E-box binding homeobox 2 activates terminal differentiation genes required for cardiomyocyte structure and function whereas zinc finger protein 503 and NK2 homeobox 5 are required for specification of the cardiac lineage. We further demonstrated that an essential role of NK2 homeobox 5 and zinc finger protein 503 in specification of the cardiac lineage is the repression of gene expression programs characteristic of alternative cell fates. Collectively, these results show that orthologous gene expression signatures can be used to identify conserved cardiogenic pathways. PMID- 26485532 TI - The effectiveness of oral appliances for obstructive sleep apnea syndrome: A meta analysis. AB - OBJECTIVE: To evaluate the effectiveness of oral appliances (OAs) for managing patients with obstructive sleep apnea (OSA). METHODS: PubMed, Embase, Web of Science, CENTRAL and SIGLE were electronically searched from January 1980 to September 2015 for randomized or nonrandomized controlled trials that assessed the effectiveness of OAs on OSAS. The processes of study search, selection, data extraction, assessment of risk of bias and evaluation of evidence quality were conducted independently by two reviewer authors. Meta-analyses were performed in Review Manager 5, Stata11.0 and StatsDirect 2.7.9. RESULTS: Finally, we included 17 eligible studies which compared OAs and placebo or blank control. Six outcomes were assessed in this meta-analysis, i.e., apnea hypopnea index (AHI), respiratory arousal index (RAI), minimum oxygen saturation(MinSaO2), rapid eye movement (REM) sleep, sleep efficiency and Epworth Sleepiness Scale (ESS). Meta analysis revealed that the pooled mean differences were -10.26 [95% CI: (-12.59, 7.93)], -9.03 [95% CI: (-11.89, -6.17)], 3.08 [95% CI: (1.97, 4.19)], 0.36 [95% CI: (-0.30, 1.02)], 1.34 [95% CI: (-0.05, 2.73)] and -1.76 [95% CI: (-2.57, 0.94)], respectively. The sensitivity analysis and subgroup analysis displayed generally robust results except for MinSaO2, REM sleep and sleep efficiency. Furthermore, publication bias was detected in RAI and MinSaO2. CONCLUSIONS: The available evidence indicates benefits in respiration and sleep quality with oral appliances as compared to placebo devices or blank control, while we cannot determine its effectiveness in sleep efficiency and sleep architecture alterations. However, due to low evidence quality as revealed by GRADE, this finding should be interpreted with caution. CLINICAL SIGNIFICANCE: Through critical meta-analyses, we found that oral appliances are effective in respiration improving and sleep quality. The existing evidence supports the employment of OAs as a recommendable treatment option for OSA. This meta-analysis helps to direct clinical practice and future research, and promises to be of great interest for both practitioners and researchers. PMID- 26485533 TI - A Study on Mediation by Offspring BMI in the Association between Maternal Obesity and Child Respiratory Outcomes in the Amsterdam Born and Their Development Study Cohort. AB - BACKGROUND: A causal relationship between maternal obesity and offspring asthma is hypothesized to begin during early development, but no underlying mechanism for the found association is identified. We quantitatively examined mediation by offspring body mass index (BMI) in the association of maternal pre-pregnancy BMI on risk of asthma and wheezing during the first 7-8 years of life in a large Amsterdam born birth cohort. METHODS: For 3185 mother-child pairs, mothers reported maternal pre-pregnancy BMI and offspring outcomes "ever being diagnosed with asthma" and "wheezing in the past 12 months" on questionnaires. We measured offspring height and weight at age 5-6 years. We performed a multivariate log linear regression comparing outcomes in offspring of mothers with different BMI categories. For each category we quantified and tested mediation by offspring BMI and also investigated interaction by parental asthma. RESULTS: At the age of 7-8 years, 8% of the offspring ever had asthma and 7% had current wheezing. Maternal pre-pregnancy obesity was associated with higher risks of asthma (adjusted RR 2.32 (95% CI: 1.49-3.61) and wheezing (adjusted RR 2.16 (95% CI: 1.28-3.64). Offspring BMI was a mediator in the association between maternal BMI and offspring wheezing, but not for asthma. There was no interaction by parental asthma. CONCLUSIONS: Maternal pre-pregnancy obesity was associated with higher risks of offspring asthma and wheezing. The association between maternal obesity and offspring wheezing was both direct and indirect (mediated) through the child's own BMI. PMID- 26485535 TI - Toxic Takifugu pardalis eggs found in Takifugu niphobles gut: Implications for TTX accumulation in the pufferfish. AB - Pufferfish (Takifugu spp.) possess a potent neurotoxin, tetrodotoxin (TTX). TTX has been detected in various organisms including food animals of pufferfish, and TTX-producing bacteria have been isolated from these animals. TTX in marine pufferfish accumulates in the pufferfish via the food web starting with marine bacteria. However, such accumulation is unlikely to account for the amount of TTX in the pufferfish body because of the minute amounts of TTX produced by marine bacteria. Therefore, the toxification process in pufferfish still remains unclear. In this article we report the presence of numerous Takifugu pardalis eggs in the intestinal contents of another pufferfish, Takifugu niphobles. The identity of T. pardalis being determined by direct sequencing for mitochondrial DNA. LC-MS/MS analysis revealed that the peak detected in the egg samples corresponded to TTX. Toxification experiments in recirculating aquaria demonstrated that cultured Takifugu rubripes quickly became toxic upon being fed toxic (TTX-containing) T. rubripes eggs. These results suggest that T. niphobles ingested the toxic eggs of another pufferfish T. pardalis to toxify themselves more efficiently via a TTX loop consisting of TTX-bearing organisms at a higher trophic level in the food web. PMID- 26485534 TI - Changes in Cerebral Hemodynamics during Complex Motor Learning by Character Entry into Touch-Screen Terminals. AB - INTRODUCTION: Studies of cerebral hemodynamics during motor learning have mostly focused on neurorehabilitation interventions and their effectiveness. However, only a few imaging studies of motor learning and the underlying complex cognitive processes have been performed. METHODS: We measured cerebral hemodynamics using near-infrared spectroscopy (NIRS) in relation to acquisition patterns of motor skills in healthy subjects using character entry into a touch-screen terminal. Twenty healthy, right-handed subjects who had no previous experience with character entry using a touch-screen terminal participated in this study. They were asked to enter the characters of a randomly formed Japanese syllabary into the touch-screen terminal. All subjects performed the task with their right thumb for 15 s alternating with 25 s of rest for 30 repetitions. Performance was calculated by subtracting the number of incorrect answers from the number of correct answers, and gains in motor skills were evaluated according to the changes in performance across cycles. Behavioral and oxygenated hemoglobin concentration changes across task cycles were analyzed using Spearman's rank correlations. RESULTS: Performance correlated positively with task cycle, thus confirming motor learning. Hemodynamic activation over the left sensorimotor cortex (SMC) showed a positive correlation with task cycle, whereas activations over the right prefrontal cortex (PFC) and supplementary motor area (SMA) showed negative correlations. CONCLUSIONS: We suggest that increases in finger momentum with motor learning are reflected in the activity of the left SMC. We further speculate that the right PFC and SMA were activated during the early phases of motor learning, and that this activity was attenuated with learning progress. PMID- 26485536 TI - Development and in vitro characterisation of an oral self-emulsifying delivery system for daptomycin. AB - It was the aim of this study to develop an oral self-emulsifying drug delivery system (SEDDS) for the peptide drug daptomycin exhibiting an anionic net charge. Drug lipophilicity was increased by hydrophobic ion pairing with cationic surfactant dodecylamine hydrochloride in molar ratio of surfactant to peptide 5:1. Log P (octanol/water) of -5.0 was even raised to +4.8 due to complexation with dodecylamine hydrochloride. Various SEDDS formulations were developed and characterised regarding emulsification properties, droplet size, polydispersity index and zeta potential. When the daptomycin dodecylamine complex (DAP/DOA) was dissolved in a formulation containing 35% Dermofeel MCT, 30% Capmul MCM and 35% Cremophor RH40, a maximum payload of even 8.0% (w/w) corresponding to 5.5% pure daptomycin was achieved. The formulation was degraded by lipase within 90min. Release studies of daptomycin from this formulation emulsified in 50mM phosphate buffer pH6.8 demonstrated a sustained drug release for at least six hours. Moreover, SEDDS exhibited also mucus permeating properties as well as a protective effect towards drug degradation by alpha-chymotrypsin. According to these results, SEDDS containing 8% DAP/DOA complex may be considered as a new potential oral delivery system for daptomycin. PMID- 26485537 TI - Meiotic Spindle Assessment in Mouse Oocytes by siRNA-mediated Silencing. AB - Errors in chromosome segregation during meiotic division in gametes can lead to aneuploidy that is subsequently transmitted to the embryo upon fertilization. The resulting aneuploidy in developing embryos is recognized as a major cause of pregnancy loss and congenital birth defects such as Down's syndrome. Accurate chromosome segregation is critically dependent on the formation of the microtubule spindle apparatus, yet this process remains poorly understood in mammalian oocytes. Intriguingly, meiotic spindle assembly differs from mitosis and is regulated, at least in part, by unique microtubule organizing centers (MTOCs). Assessment of MTOC-associated proteins can provide valuable insight into the regulatory mechanisms that govern meiotic spindle formation and organization. Here, we describe methods to isolate mouse oocytes and deplete MTOC-associated proteins using a siRNA-mediated approach to test function. In addition, we describe oocyte fixation and immunofluorescence analysis conditions to evaluate meiotic spindle formation and organization. PMID- 26485538 TI - Temperature Tunable Self-Doping in Stable Diradicaloid Thin-Film Devices. AB - FDT and FDT-Br diradicaloids with stable coexisting close-shell and open-shell forms exhibit unconventional self-doping behavior in solid-state electronic devices that is temperature (T) tunable and reversible. The doping is strengthened by the increased T, leading to the absence of off-states (I(off)) in the transistors. PMID- 26485540 TI - Evaluation of novel Akt1 inhibitors as anticancer agents using virtual co crystallized pharmacophore generation. AB - The pharmacophoric features of the virtual co-crystallized protein of 17 Akt1 proteins were downloaded from the protein data bank, and explored to end up with 132 generated pharmacophores that had been evaluated using the decoy list composed of 1724 compounds. The areas under the curve of the Receiver-Operating Characteristic (ROC-AUC) were sorted, and the highest ranked pharmacophore 3MV5_2_01 was selected to be used as a searching tool in the National Cancer Institute (NCI) database. The captured hits were mapped based on successful hypotheses and the best fitted compounds were selected. The inhibition of Akt1 was measured and expressed as a percentage of inhibition. 24 out of the 40 compounds showed inhibition of Akt1, out of which 13 compounds showed more than 50% inhibition. Compound 1 showed 93.3% inhibition at 100 MUM concentration. To confirm the inhibition of Akt1 phosphorylation, MCF10A cell line was co-treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and 100 MUM of each of the most potent 13 Akt inhibitors (1-13). It was found that compounds 1 exert 91.6% inhibition of Akt1 phosphorylation in MCF10A cell line. PMID- 26485541 TI - Evaluation of Choroidal Vascular Changes in Patients with Multiple Sclerosis Using Enhanced Depth Imaging Optical Coherence Tomography. AB - OBJECTIVE: To evaluate the choroidal thickness in patients with multiple sclerosis (MS) using enhanced depth imaging optical coherence tomography (EDI OCT). METHODS: In this observational comparative study, 68 eyes of 34 MS patients and 60 eyes of 30 healthy subjects were evaluated. All participants underwent complete ophthalmologic examination and OCT scanning. Choroidal thickness measurements were performed at seven points. RESULTS: The mean subfoveal choroidal thickness was reduced significantly in MS patients (310.71 +/- 61.85 MUm) versus healthy controls (364.85 +/- 41.81 MUm) (p < 0.001). The difference was also significant at all six measurement points (p < 0.001 for all). Choroidal thickness measurements revealed no significant difference between MS eyes with a prior optic neuritis (ON) history (MS ON) and those without ON history (MS non ON). Subfoveal choroidal thickness did not correlate with retinal nerve fiber layer and Expanded Disability Status Scale score, but reduced choroidal thickness was associated with longer disease duration (r = -0.28, p = 0.019) in MS patients. CONCLUSION: In MS patients, choroidal structural changes occur both in MS ON and MS non-ON eyes. The decreased choroidal thickness might provide evidence to support a potential role of vascular dysregulation in the pathophysiology of MS. PMID- 26485542 TI - Azacitidine and Sorafenib Therapy in a Pediatric Patient With Refractory Acute Myeloid Leukemia With Monosomy 7 and Somatic PTPN11 Mutation. AB - Monosomy 7 is a well-documented cytogenetic aberration in pediatric acute myeloid leukemia (AML) and may occur in combinations with molecular abnormalities including PTPN11 mutation. PTPN11 mutations contribute to leukemogenesis through upregulation of Ras pathway signaling. We present the case of a 3-year-old female with AML with monosomy 7 and somatic PTPN11 mutation who was refractory to conventional AML chemotherapy but responded to a novel regimen of azacitidine and sorafenib followed by stem cell transplantation. Combination therapy with azacitidine and sorafenib may be an effective therapeutic strategy for patients with AML with Ras pathway abnormalities. PMID- 26485539 TI - Femoral Access and Delivery of Continuous Renal Replacement Therapy Dose. AB - AIMS: The study aims to describe the use of dialysis catheters in critically ill patients treated with continuous renal replacement therapy (CRRT) and to study the impact of femoral versus non-femoral access on CRRT dose. METHODS: Statistical analysis and predictive modelling of data from the Randomized Evaluation of Normal vs. Augmented Level renal replacement therapy trial. RESULTS: The femoral vein was the first access site in 937 (67%) of 1,399 patients. These patients had higher Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment scores (p = 0.009) and lower pH (p < 0.001) but similar mortality to patients with non-femoral access (44 vs. 45%; p = 0.63). Lower body weight was independently associated with femoral access placement (OR 0.97, 95% CI 0.96-0.98). Femoral access was associated with a 1.03% lower CRRT dose (p = 0.05), but a 4.20% higher dose was achieved with 13.5 Fr catheters (p = 0.03). CONCLUSIONS: Femoral access was preferred in lighter and sicker patients. Catheter gauge had greater impact than catheter site in CRRT dose delivery. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=439581. PMID- 26485543 TI - Course of hepatitis C virus (HCV) RNA and HCV core antigen testing are predictors for reaching sustained virologic response in liver transplant recipients undergoing sofosbuvir treatment in a real-life setting. AB - BACKGROUND: Hepatitis C virus (HCV) infection is associated with reduced graft survival in orthotopic liver transplant recipients. Treatment with the new direct acting antivirals (DAAs) is safe and efficient, but no reliable predictive factors for sustained virologic response (SVR) have been identified so far. The HCV core antigen assay (HCV-core-Ag) is a new, inexpensive, and efficient method to detect viral antigens, but the value of this technique to predict treatment response in orthotopic liver transplantation (OLT) patients is still unclear. METHODS: All OLT patients who were treated with a sofosbuvir-based antiviral regimen at our center between March 2014 and August 2014 were included in the analysis (n = 20). HCV-core-Ag and HCV RNA (polymerase chain reaction [PCR]) were determined at each visit. Primary endpoints of this study were SVR at 4 or 12 weeks after end of treatment (SVR 4 and SVR 12). RESULTS: HCV-core-Ag tested negative after a median of 2 weeks (range 1-16 weeks) while PCR tests became negative after a median of 4 weeks (range 2-12 weeks). Time until PCR negativity and until HCV-core-Ag negativity showed a good correlation (R = 0.711, P < 0.001, Fig. ). Seventeen of 20 patients (85%) achieved SVR 12. SVR 12 was associated with a short time interval between treatment start and HCV PCR negativity (P = 0.005) or HCV-core-Ag negativity (P = 0.003, Mann-Whitney test). No severe side effects were observed. CONCLUSIONS: DAA treatment is safe and well tolerated in OLT. The time points of HCV-core-Ag loss and PCR negativity were predictors of SVR 12. PMID- 26485544 TI - Genome-wide differential expression of synaptic long noncoding RNAs in autism spectrum disorder. AB - A genome-wide differential expression of long noncoding RNAs (lncRNAs) was identified in blood specimens of autism spectrum disorder (ASD). A total of 3929 lncRNAs were found to be differentially expressed in ASD peripheral leukocytes, including 2407 that were upregulated and 1522 that were downregulated. Simultaneously, 2591 messenger RNAs (mRNAs), including 1789 upregulated and 821 downregulated, were also identified in ASD leukocytes. Functional pathway analysis of these lncRNAs revealed neurological pathways of the synaptic vesicle cycling, long-term depression and long-term potentiation to be primarily involved. Thirteen synaptic lncRNAs, including nine upregulated and four downregulated, and 19 synaptic mRNAs, including 12 upregulated and seven downregulated, were identified as being differentially expressed in ASD. Our identification of differential expression of synaptic lncRNAs and mRNAs suggested that synaptic vesicle transportation and cycling are important for the delivery of synaptosomal protein(s) between presynaptic and postsynaptic membranes in ASD. Finding of 19 lncRNAs, which are the antisense, bi-directional and intergenic, of HOX genes may lead us to investigate the role of HOX genes involved in the development of ASD. Discovery of the lncRNAs of SHANK2-AS and BDNF-AS, the natural antisense of genes SHANK2 and BDNF, respectively, indicates that in addition to gene mutations, deregulation of lncRNAs on ASD-causing gene loci presents a new approach for exploring possible epigenetic mechanisms underlying ASD. Our study also opened a new avenue for exploring the use of lncRNA(s) as biomarker(s) for the early detection of ASD. PMID- 26485545 TI - A potential mechanism underlying atypical antipsychotics-induced lipid disturbances. AB - Previous findings suggested that a four-protein complex, including sterol regulatory element-binding protein (SREBP), SREBP-cleavage-activating protein (SCAP), insulin-induced gene (INSIG) and progesterone receptor membrane component 1 (PGRMC1), within the endoplasmic reticulum appears to be an important regulator responsible for atypical antipsychotic drug (AAPD)-induced lipid disturbances. In the present study, effects of typical antipsychotic drug and AAPDs as well as treatment outcome of steroid antagonist mifepristone (MIF) on the PGRMC1/INSIG/SCAP/SREBP pathway were investigated in rat liver using real-time quantitative polymerase chain reaction (qPCR) and western blot analysis. In addition, serum triacylglycerol, total cholesterol, free fatty acids and various hormones including progesterone, corticosterone and insulin were measured simultaneously. Following treatment with clozapine or risperidone, both lipogenesis and cholesterogenesis were enhanced via inhibition of PGRMC1/INSIG-2 and activation of SCAP/SREBP expressions. Such metabolic disturbances, however, were not demonstrated in rats treated with aripiprazole (ARI) or haloperidol (HAL). Moreover, the add-on treatment of MIF was effective in reversing the AAPD induced lipid disturbances by upregulating the expression of PGRMC1/INSIG-2 and subsequent downregulation of SCAP/SREBP. Taken together, our findings suggest that disturbances in lipid metabolism can occur at an early stage of AAPD treatment before the presence of weight gain. Such metabolic defects can be modified by an add-on treatment of steroid antagonist MIF enhancing the PGRMC1 pathway. Thus, it is likely that PGRMC1/INSIG-2 signaling may be a therapeutic target for AAPD-induced weight gain. PMID- 26485547 TI - Reduced protein synthesis in schizophrenia patient-derived olfactory cells. AB - Human olfactory neurosphere-derived (ONS) cells have the potential to provide novel insights into the cellular pathology of schizophrenia. We used discovery based proteomics and targeted functional analyses to reveal reductions in 17 ribosomal proteins, with an 18% decrease in the total ribosomal signal intensity in schizophrenia-patient-derived ONS cells. We quantified the rates of global protein synthesis in vitro and found a significant reduction in the rate of protein synthesis in schizophrenia patient-derived ONS cells compared with control-derived cells. Protein synthesis rates in fibroblast cell lines from the same patients did not differ, suggesting cell type-specific effects. Pathway analysis of dysregulated proteomic and transcriptomic data sets from these ONS cells converged to highlight perturbation of the eIF2alpha, eIF4 and mammalian target of rapamycin (mTOR) translational control pathways, and these pathways were also implicated in an independent induced pluripotent stem cell-derived neural stem model, and cohort, of schizophrenia patients. Analysis in schizophrenia genome-wide association data from the Psychiatric Genetics Consortium specifically implicated eIF2alpha regulatory kinase EIF2AK2, and confirmed the importance of the eIF2alpha, eIF4 and mTOR translational control pathways at the level of the genome. Thus, we integrated data from proteomic, transcriptomic, and functional assays from schizophrenia patient-derived ONS cells with genomics data to implicate dysregulated protein synthesis for the first time in schizophrenia. PMID- 26485548 TI - Massive pneumatosis without necrosis: A case report of Clostridium perfringens sepsis in an extremely low birth weight infant. AB - Pneumatosis intestinalis and free intraperitoneal air on abdominal radiographs are considered pathognomonic signs of necrotizing enterocolitis (NEC). We report a unique case of late-onset fulminant sepsis due to Clostridium perfringens presenting with shock, extensive pneumatosis intestinalis and free intraperitoneal air in an extremely low birth weight infant without histopathological evidence of bowel necrosis or NEC. PMID- 26485546 TI - Increased abundance of translation machinery in stem cell-derived neural progenitor cells from four schizophrenia patients. AB - The genetic and epigenetic factors contributing to risk for schizophrenia (SZ) remain unresolved. Here we demonstrate, for the first time, perturbed global protein translation in human-induced pluripotent stem cell (hiPSC)-derived forebrain neural progenitor cells (NPCs) from four SZ patients relative to six unaffected controls. We report increased total protein levels and protein synthesis, together with two independent sets of quantitative mass spectrometry evidence indicating markedly increased levels of ribosomal and translation initiation and elongation factor proteins, in SZ hiPSC NPCs. We posit that perturbed levels of global protein synthesis in SZ hiPSC NPCs represent a novel post-transcriptional mechanism that might contribute to disease progression. PMID- 26485549 TI - Use of melatonin as an adjuvant therapy in neonatal sepsis. AB - OBJECTIVE: The objective of this study is to evaluate the therapeutic efficacy of melatonin as an adjuvant therapy in treating neonatal sepsis. PATIENTS AND METHODS: A prospective clinical trial study was conducted on 50 infants with neonatal sepsis diagnosed on the basis of both clinical and laboratory criteria. Enrolled infants were divided into two groups. Intervention group (n = 25) received melatonin and antibiotics, while the control group (n = 25) was treated with antibiotics only. Melatonin was administered as a single oral dose of 20 mg and antibiotics were administered according to a standard protocol. Both groups were compared using a predefined sepsis score utilizing both clinical and laboratory parameters. RESULTS: There was no significant difference in sepsis score between both groups before starting melatonin (p-value = 0.99), while there was significant difference in sepsis score between groups after 24 hours, 48 hours and 72 hours of starting melatonin with (p-value = 0.008, 0.006 and 0.002, respectively). There was significant improvement sepsis score in both groups with more improvement of sepsis score in the intervention group. CONCLUSION: Administration of melatonin as an adjuvant therapy in the treatment of neonatal sepsis is associated with improvement of clinical and laboratory outcomes. PMID- 26485550 TI - Oxygen and parenteral nutrition two main oxidants for extremely preterm infants: 'It all adds up'. AB - OBJECTIVES: To assess the effect of early exposure to O2 and parenteral nutrition (PN) on oxidative stress at 36 weeks post-menstrual age (PMA) and on bronchopulmonary dysplasia (BPD) in extremely preterm infants. STUDY DESIGN: A prospective observational study including 116 infants <29 weeks of gestation. Baseline clinical characteristics, FiO2 on day 7, duration of PN and clinical outcomes data were collected. In 39 infants, whole blood glutathione (GSH) and oxidized glutathione (GSSG) at 36 weeks PMA were measured and the redox potential was calculated using Nernst equation. Student's t-test, Chi-square, Spearman correlation, ANOVA, and logistic regression analyses were used as appropriate. P < 0.05 was considered significant. RESULTS: FiO2 >=25% was associated with higher level of GSSG (0.29 +/- 0.04 versus 0.18 +/- 0.02 nmol/mg of protein), a more oxidized redox potential (-191 +/- 2 versus -198 +/- 2 mV) and more BPD (90% versus 45%). PN duration >14 days was also associated with higher level of GSSG (0.26 +/- 0.03 versus 0.13 +/- 0.02 nmol/mg of protein), a more oxidized redox potential (-193 +/- 5 versus -203 +/- 2 mV) and more BPD (89% versus 24%). In logistic regression model, each 1% increase in FiO2 and each day increase in PN duration resulted in an increase in the OR for BPD by 1.57 (1.09 -2.28) and 1.17 (1.03 -1.33) respectively. CONCLUSION: Early O2 supplement and PN have additive effects that were associated with prolonged oxidative stress and increased risk of BPD. Strategies targeting judicious use of O2 and decreasing the duration or developing a safer formulation of PN can be targeted to decrease BPD. PMID- 26485551 TI - Born early and born poor: An eco-bio-developmental model for poverty and preterm birth. AB - Poverty is associated with adverse long-term cognitive outcomes in children. Poverty is also linked with preterm delivery which, in turn, is associated with adverse cognitive outcomes. However, the extent of the effect of poverty on preterm delivery, as well as proposed mechanisms by which they occur, have not been well described. Further, the impact of poverty on preterm school readiness has not been reviewed. As the childhood poverty level continues to increase in the U.S., we examine the evidence around physiological, neurological, cognitive and learning outcomes associated with prematurity in the context of poverty. We use the evidence gathered to suggest an Eco-Bio-Developmental model, emphasizing poverty as a toxic stress which predisposes preterm birth and which, via epigenetic forces, can continue into the next generation. Continued postnatal social disadvantage for these developmentally high-risk preterm infants is strongly linked with poor neurodevelopmental outcomes, decreased school readiness, and decreased educational attainment which can perpetuate the poverty cycle. We suggest social remedies aimed at decreasing the impact of poverty on mothers, fathers, and children which may be effective in reducing the burden of preterm birth. PMID- 26485552 TI - Withholding feeding during transfusion: Standardization of practice and nutritional outcomes in premature infants. AB - OBJECTIVE: To evaluate the nutritional impact of a feed-holding guideline during transfusion for infants <32 weeks gestation. STUDY DESIGN: A pre-/post interventional study was conducted after introduction of a guideline to hold feeds during transfusion. Demographic variables in addition to nutritional outcomes were collected on all infants admitted within 48 hours of birth with gestational age <32 weeks. Data was collected during a 6 month period pre intervention and the 6 month period post-intervention. RESULTS: There were 145 eligible infants. Mean birth weight and gestational age were similar in both periods. In total, 98 infants received transfusions, and 82 of those had an active feeding order prior to at least one transfusion. Total transfusions per infant and transfusions ordered while an infant had active feeding orders were similar in both periods. Time to full feedings was decreased post-intervention (p < 0.001). Weight at 34 weeks, incidence of second IV placement, additional IV fluid use, and hypoglycemia were similar between groups.Of 593 total transfusions, 207 were ordered while an infant had an active order for enteral nutrition. Pre-intervention, 64% of transfusions had feeds held during transfusion. Post-intervention, 87% of transfusions had feeds held during transfusion. Feeds were held more often (p < 0.001) and for a shorter duration (p = 0.005) in the post-intervention group. CONCLUSION: Implementing a guideline standardizing feeding practices during transfusions in premature infants increases standardization of care and results in decreased variability in practice. Adverse nutritional consequences were not found after the introduction of the routine practice of holding feedings during transfusion in preterm infants. PMID- 26485553 TI - Test-retest reliability of the Capute scales for neurodevelopmental screening of a high risk sample: Impact of test-retest interval and degree of neonatal risk. AB - AIM: Reliable and valid screening and assessment tools are necessary to identify children at risk for neurodevelopmental disabilities who may require additional services. This study evaluated the test-retest reliability of the Capute Scales in a high-risk sample, hypothesizing adequate reliability across 6- and 12-month intervals. METHODS: Capute Scales scores (N = 66) were collected via retrospective chart review from a NICU follow-up clinic within a large urban medical center spanning three age-ranges: 12-18, 19-24, and 25-36 months. On average, participants were classified as very low birth weight and premature. Reliability of the Capute Scales was evaluated with intraclass correlation coefficients across length of test-retest interval, age at testing, and degree of neonatal complications. RESULTS: The Capute Scales demonstrated high reliability, regardless of length of test-retest interval (ranging from 6 to 14 months) or age of participant, for all index scores, including overall Developmental Quotient (DQ), language-based skill index (CLAMS) and nonverbal reasoning index (CAT). Linear regressions revealed that greater neonatal risk was related to poorer test retest reliability; however, reliability coefficients remained strong. CONCLUSIONS: The Capute Scales afford clinicians a reliable and valid means of screening and assessing for neurodevelopmental delay within high-risk infant populations. PMID- 26485554 TI - Retinopathy of prematurity: Risk factors and variability in Canadian neonatal intensive care units. AB - OBJECTIVE: To identify predictors of severe retinopathy of prematurity (ROP) in a large population-based cohort and to examine risk-adjusted variations across units. STUDY DESIGN: Retrospective analysis of Canadian Neonatal Network data on neonates with birth weight <1500 g who were screened for ROP between 2003 and 2010. Characteristics of infants with and without ROP were compared and a risk adjusted model for severe ROP was developed. Rates of severe ROP were compared between sites. RESULTS: 1163 of 9187 (12.7%) infants developed severe ROP. Lower gestational age, male sex, small for gestational age, patent ductus arteriosus, late onset sepsis, more than two blood transfusions, inotrope use, and outborn status were associated with an increased risk of severe ROP. Severe ROP rates varied significantly between units. CONCLUSION: Younger, smaller and sicker male infants had higher adjusted risks of severe ROP and rates varied significantly among sites. PMID- 26485556 TI - Does training improve compliance with hand hygiene and decrease infections in the neonatal intensive care unit? A prospective study. AB - INTRODUCTION: The most important tool in any infection control program is good hand hygiene. Despite recognizing that hand hygiene is crucial in reducing infection rates, hand hygiene compliance remains suboptimal. This study was designed to determine hand hygiene compliance, before and after an educational intervention and its impact on hospital infection rates. METHOD: The study was done in neonatal intensive care unit of an educational hospital. All healthcare providers working in the unit at the time of study were trained on importance of hand hygiene and methods of hand hygiene observation; after that hand washing compliance controlled by a physician during postintervention phase. Hand hygiene compliance, healthcare associated infection and mortality rates compared before and after educational intervention. RESULTS: Compliance of health-care workers for all hand hygiene opportunities combined was 30% before intervention and improved to 70% in postintervention. In postintervention phase, healthcare associated infection rates and mortality rates decreased significantly as the hand hygiene compliance improved. CONCLUSIONS: Good control of hand hygiene compliance by physician after an educational program may have good effect in healthcare associated infections control in neonatal intensive care unit. PMID- 26485555 TI - Outcome of oral sildenafil in neonatal persistent pulmonary hypertension of non cardiac causes. AB - BACKGROUND: Despite recent treatment modalities, mortality from persistent pulmonary hypertension (PPHN) remains significant. In instances where infants do not respond to inhaled nitric oxide (iNO), oral sildenafil could hold promise as a selective pulmonary vasodilator. Further studies are still needed to explore its efficacy and safety in newborns with PPHN. OBJECTIVES: To validate the efficacy of oral sildenafil on oxygenation and its short-term safety in newborns with persistent pulmonary hypertension. METHODS: A total of 27 newborns >=36 weeks gestational age were admitted to NICU with oxygenation index (OI) >=15 and confirmed diagnosis of PPHN with echocardiography. Oral sildenafil given at a dose of 1-2 mg/kg every 6 hours. We monitored improvement in oxygenation, safety and short-term outcomes. RESULTS: Among 27 newborns, oral sildenafil was efficacious in 21 patients (78%) with reduction of OI from 34.9 +/- 9.6 to 13 +/- 3.2 (p < 0.001), increase of PaO2 from 42.4 +/- 13.5 to 78 +/- 11.5 mmHg (<0.001), and reduction of FiO2 from 1.0 +/- 0 to 0.3 +/- 0.06 (<0.001). OI decreased by 6.3 % from baseline after the first dose of sildenafil and continued to decrease with subsequent doses. In 6 patients (22%) sildenafil did not work; 5/6 patients (18%) transferred to another tertiary NICU and one patient (4%) died of sepsis. None of the patients had significant systemic hypotension. CONCLUSION: Oral sildenafil is a promising pulmonary vasodilator in patients with PPHN, particularly in medical facilities with no available iNO and ECMO. It is well tolerated with no significant short term complications. PMID- 26485557 TI - A rare presentation of aplasia cutis congenita after feto-reduction in a trichorionic-triamniotic pregnancy. AB - Aplasia cutis congenita (ACC) is rare skin disorder of newborns that has been linked to both assisted reproductive technology (ART) and feto-reduction procedures. ACC is characterized by well-demarcated lesions that are devoid of all skin layers. Group-V ACC presents with a distinctive and symmetrical distribution pattern. It is thought to result from an insult to the fetus after concomitant twin demise and is almost exclusively reported in monochorionic gestations.A 41-year-old female with an in vitro fertilization (IVF) assisted tri chorionic gestation subsequently underwent selective feto-reduction of Fetus C. The patient delivered two pre-term neonates secondary to pre-eclampsia. The initial exam of Twin B showed extensive, well-demarcated, symmetrical areas devoid of any skin over the anterior and lateral trunk, extending up the lateral thoracic walls. Chest and abdominal viscera were visible through a thin fibrous membrane. The skin defects were managed conservatively with twice-daily dressings of Aquaphor, and Vaseline gauze. The areas of aplasia slowly contracted, though residual scarring was noted. After four weeks in the NICU, most of the areas were healed.ACC in multi-fetal pregnancies is a rare, but well-described complication. This is, to our knowledge, the first reported case in a tri-chorionic IVF gestation after feto-reduction. With increased incidence of ART-associated pregnancies and the use of feto-reduction for higher order gestations, this may become more common. Neonates often require specialized intensive care. Conservative management usually will suffice, although surgical grafting may be required. Physicians should be aware of this condition and counsel their feto reduction patients of the risk. PMID- 26485558 TI - Mounting evidence favoring single-family room neonatal intensive care. AB - Controversy regarding the optimal design for neonatal intensive care has existed for more than 20 years. Recent evidence confirms that in comparison with the traditional open-bay design, the single-room facility provides for improved control of excessive noise and light, improved staff and parental satisfaction with care and equal, or possibly reduced, cost of care. Single-room care was not associated with any increase in adverse outcomes. To optimize long term developmental outcomes, single-room care must be augmented with appropriate developmental therapy and programs to actively support parental involvement. PMID- 26485559 TI - Clinical associations to abnormal umbilical cord length in Latin American newborns. AB - INTRODUCTION: Umbilical cord is vital to fetal development and its alterations are related to fetal and neonatal deaths and to late neurological complications. Abnormal cord length has been recognized as the most important cord feature leading to unfavorable outcomes. We aimed to examine the relationship between fetal abnormalities and the length of umbilical cord using the ECLAMC (Estudio Colaborativo Latinoamericano de Malformaciones Congenitas/Latin American Collaborative Study on Congenital Malformations) database. METHODS: Using ECLAMC case-control registries, we conducted an observational study on the relationship between umbilical cord length and clinical variables such as chromosomal abnormalities and neonatal malformations. RESULTS: Birth registries totaled 61820; of them 3411 had complete cord data. Abnormal length was found in 427, with 174 short (5.10%) cords and 253 long (7.41%) cords. No relation was found between abnormal cord length and gender, parity or parents' age. More abnormal length cords were found than reported in other series; unexpectedly, more long cords were observed in twin gestations. It was observed that among short cords (174), 105 were from newborns with some type of malformation and 69 with no malformation (OR = 2.92, CI (95%) 2.15-3.98, p = 0.0001); of the 253 long cords, 168 had malformation and only 85 did not (OR = 3.80, CI (95%) 2.91-4.96, p = 0.0001). CONCLUSIONS: Abnormal cord length is associated with fetal malformation. Further studies are needed to determine the clinical applicability of using this parameter in counseling during prenatal visits. PMID- 26485560 TI - Mesenchymal Stromal Cells Disrupt mTOR-Signaling and Aerobic Glycolysis During T Cell Activation. AB - Mesenchymal stromal cells (MSCs) possess numerous regenerative and immune modulating functions. Transplantation across histocompatibility barriers is feasible due to their hypo-immunogenicity. MSCs have emerged as promising tools for treating graft-versus-host disease following allogeneic stem cell transplantation. It is well established that their clinical efficacy is substantially attributed to fine-tuning of T-cell responses. At the same time, increasing evidence suggests that metabolic processes control T-cell function and fate. Here, we investigated the MSCs' impact on the metabolic framework of activated T-cells. In fact, MSCs led to mitigated mTOR signaling. This phenomenon was accompanied by a weaker glycolytic response (including glucose uptake, glycolytic rate, and upregulation of glycolytic machinery) toward T-cell activating stimuli. Notably, MSCs express indoleamine-2,3-dioxygenase (IDO), which mediates T-cell suppressive tryptophan catabolism. Our observations suggest that IDO-induced tryptophan depletion interferes with a tryptophan-sufficiency signal that promotes cellular mTOR activation. Despite an immediate suppression of T-cell responses, MSCs foster a metabolically quiescent T-cell phenotype characterized by reduced mTOR signaling and glycolysis, increased autophagy, and lower oxidative stress levels. In fact, those features have previously been shown to promote generation of long-lived memory cells and it remains to be elucidated how MSC-induced metabolic effects shape in vivo T-cell immunity. PMID- 26485561 TI - A normal electrocardiogram and echocardiogram in a patient with a pericardial friction rub after delivery. PMID- 26485562 TI - Electrocardiographic characteristics of idiopathic premature ventricular contractions originating from the junction of the right ventricular outflow tract and tricuspid annulus. AB - AIMS: The right ventricular outflow tract (RVOT) and tricuspid annulus (TA) are common origins for idiopathic PVCs from the right ventricle. We sought to clarify the characteristics of a subgroup of idiopathic PVCs originating from the RVOT-TA junction. METHODS AND RESULTS: Surface ECG and intra-cardiac electrophysiological characteristics were analyzed in 101 patients with frequent PVCs who underwent successful RFCA in the right ventricle. Pacing was performed in the right ventricle in another 5 control subjects. The origin of PVCs determined by the successful ablation site was at the RVOT, the TA and the RVOT-TA junction in 78, 11 and 12 patients, respectively. The PVCs originating from RVOT-TA junction showed a monophasic R wave in leads I, II, III and aVF and a flat QRS complex in lead aVL. A flat QRS complex (rsr', qs, qr, rs or r pattern, mean r or qs amplitude, 0.3 +/- 0.1 mV) in lead aVL distinguished the RVOT-TA junction origin from the RVOT (deep negative, -0.7 +/- 0.4 mV) and the TA (tall positive, 0.8 +/- 0.3 mV) origins. Activation mapping and pace mapping strategies were successfully applied to localize this specific origin of the PVCs. Pacing at the RVOT-TA junction in the control subjects validated a flat QRS complex in lead aVL. CONCLUSION: We report for the first time that the RVOT-TA junction is a non-rare but distinct origin of right ventricular PVCs. The flat QRS complex in lead aVL distinguishes this origin from RVOT and TA. RFCA is highly effective for eliminating PVCs in this origin. PMID- 26485563 TI - Performance of a novel clinic score in differentiating Takotsubo cardiomyopathy from ST elevation myocardial infarction within the first 24h. PMID- 26485564 TI - Giant mitral blood cyst: Cardiovascular magnetic resonance imaging features. PMID- 26485565 TI - Molecular-Level Investigation of the Adsorption Mechanisms of Toluene and Aniline on Natural and Organically Modified Montmorillonite. AB - The present work reports the adsorption mechanisms of aniline and toluene in dry and hydrated montmorillonite (MMT-Na and MMT-Na-W) and tetramethylammonium-cation modified MMT (MMT-TMA) as determined through density functional theory. These theoretical investigations explicitly demonstrate that cation-pi interactions between Na(+)/TMA(+) cations and aromatics play the key role in adsorption of organics over MMT-Na and MMT-TMA. Weak hydrogen bonds between the H atoms of organics and basal O atoms of tetrahedral silicate also stabilize the location of organics. The combination of interactions between water and basal O atoms and between organics and water molecules in hydrated MMT complexes strengthens the adsorption of organics on MMT, resulting in higher formation energies in hydrated organically intercalated MMTs than in the corresponding dry complexes. The adsorption of organics also changes frontier orbital distributions and consequently promotes the preferential occurrence of reactions on the organics rather than on the MMT layers. These adsorption mechanisms predicted by theoretical investigation can be used to explicate the adsorption of aromatic organics on aluminosilicates with different external environment. PMID- 26485567 TI - Dynamics and Kinetics Study of "In-Water" Chemical Reactions by Enhanced Sampling of Reactive Trajectories. AB - High potential energy barriers and engagement of solvent coordinates set challenges for in silico studies of chemical reactions, and one is quite commonly limited to study reactions along predefined reaction coordinate(s). A systematic protocol, QM/MM MD simulations using enhanced sampling of reactive trajectories (ESoRT), is established to quantitatively study chemical transitions in complex systems. A number of trajectories for Claisen rearrangement in water and toluene were collected and analyzed, respectively. Evidence was found that the bond making and breaking during this reaction are concerted processes in solutions, preferentially through a chairlike configuration. Water plays an important dynamic role that helps stabilize the transition sate, and the dipole-dipole interaction between water and the solute also lowers the transition barrier. The calculated rate coefficient is consistent with the experimental measurement. Compared with water, the reaction pathway in toluene is "narrower" and the reaction rate is slower by almost three orders of magnitude due to the absence of proper interactions to stabilize the transition state. This study suggests that the "in-water" nature of the Claisen rearrangement in aqueous solution influences its thermodynamics, kinetics, as well as dynamics. PMID- 26485566 TI - Creation of Functional Viruses from Non-Functional cDNA Clones Obtained from an RNA Virus Population by the Use of Ancestral Reconstruction. AB - RNA viruses have the highest known mutation rates. Consequently it is likely that a high proportion of individual RNA virus genomes, isolated from an infected host, will contain lethal mutations and be non-functional. This is problematic if the aim is to clone and investigate high-fitness, functional cDNAs and may also pose problems for sequence-based analysis of viral evolution. To address these challenges we have performed a study of the evolution of classical swine fever virus (CSFV) using deep sequencing and analysis of 84 full-length cDNA clones, each representing individual genomes from a moderately virulent isolate. In addition to here being used as a model for RNA viruses generally, CSFV has high socioeconomic importance and remains a threat to animal welfare and pig production. We find that the majority of the investigated genomes are non functional and only 12% produced infectious RNA transcripts. Full length sequencing of cDNA clones and deep sequencing of the parental population identified substitutions important for the observed phenotypes. The investigated cDNA clones were furthermore used as the basis for inferring the sequence of functional viruses. Since each unique clone must necessarily be the descendant of a functional ancestor, we hypothesized that it should be possible to produce functional clones by reconstructing ancestral sequences. To test this we used phylogenetic methods to infer two ancestral sequences, which were then reconstructed as cDNA clones. Viruses rescued from the reconstructed cDNAs were tested in cell culture and pigs. Both reconstructed ancestral genomes proved functional, and displayed distinct phenotypes in vitro and in vivo. We suggest that reconstruction of ancestral viruses is a useful tool for experimental and computational investigations of virulence and viral evolution. Importantly, ancestral reconstruction can be done even on the basis of a set of sequences that all correspond to non-functional variants. PMID- 26485568 TI - Chemotherapy-Related Amenorrhea and Menopause in Young Chinese Breast Cancer Patients: Analysis on Incidence, Risk Factors and Serum Hormone Profiles. AB - PURPOSE: In this prospective cross-sectional study on young premenopausal breast cancer patients, the objectives were to: determine the incidences of chemotherapy related amenorrhea (CRA) and menopause (CRM); identify associated factors; and assess plasma levels of estradiol (E2) and follicular stimulating hormone (FSH) among patients who developed menopause. METHODS: Eligibility criteria include Chinese stage I-III breast cancer patients, premenopausal, age <=45 at breast cancer diagnosis, having received adjuvant chemotherapy, within 3-10 years after breast cancer diagnosis. Detailed menstrual history prior to and after adjuvant treatment was taken at study entry. Patients' background demographics, tumor characteristics and anti-cancer treatments were collected. The rates of CRA and CRM were determined. Analysis was conducted to identify factors associated with CRM. For postmenopausal patients, levels of E2 and FSH were analyzed. RESULTS: 286 patients were recruited; the median time from breast cancer diagnosis to study entry was 5.0 years. 255 patients (91.1%) developed CRA. Of these, 66.7% regained menstruation. At the time of study entry, 137 (48.9%) had developed CRM, amongst whom 84 were age <=45. On multivariate analysis, age was the only associated factor. Among patients with CRM, the median FSH was 41.0 IU/L; this was significantly lower in those who were taking tamoxifen compared to those who were not (20.1 vs. 59.7 IU/L, p<0.0001). The E2 level was <40 pmol/L; there was no difference between those who were still on tamoxifen or not. CONCLUSION: After adjuvant chemotherapy, the majority of young Chinese breast cancer patients developed CRA; ~50% developed CRM, with 61% at age <=45. Age at diagnosis is the only factor associated with CRM. FSH level may be affected by tamoxifen intake. PMID- 26485569 TI - MATtrack: A MATLAB-Based Quantitative Image Analysis Platform for Investigating Real-Time Photo-Converted Fluorescent Signals in Live Cells. AB - We introduce here MATtrack, an open source MATLAB-based computational platform developed to process multi-Tiff files produced by a photo-conversion time lapse protocol for live cell fluorescent microscopy. MATtrack automatically performs a series of steps required for image processing, including extraction and import of numerical values from Multi-Tiff files, red/green image classification using gating parameters, noise filtering, background extraction, contrast stretching and temporal smoothing. MATtrack also integrates a series of algorithms for quantitative image analysis enabling the construction of mean and standard deviation images, clustering and classification of subcellular regions and injection point approximation. In addition, MATtrack features a simple user interface, which enables monitoring of Fluorescent Signal Intensity in multiple Regions of Interest, over time. The latter encapsulates a region growing method to automatically delineate the contours of Regions of Interest selected by the user, and performs background and regional Average Fluorescence Tracking, and automatic plotting. Finally, MATtrack computes convenient visualization and exploration tools including a migration map, which provides an overview of the protein intracellular trajectories and accumulation areas. In conclusion, MATtrack is an open source MATLAB-based software package tailored to facilitate the analysis and visualization of large data files derived from real-time live cell fluorescent microscopy using photoconvertible proteins. It is flexible, user friendly, compatible with Windows, Mac, and Linux, and a wide range of data acquisition software. MATtrack is freely available for download at eleceng.dit.ie/courtney/MATtrack.zip. PMID- 26485571 TI - Atypical patterns of segregation of familial enlargement of the vestibular aqueduct. AB - OBJECTIVES/HYPOTHESIS: Hearing loss and enlarged vestibular aqueduct (EVA) can be inherited as an autosomal recessive trait caused by mutant alleles of the SLC26A4 gene. In some other families, EVA does not segregate in a typical autosomal recessive pattern. The goal of this study was to characterize the SLC26A4 genotypes and phenotypes of extended families with atypical segregation of EVA. STUDY DESIGN: Prospective study of cohort of families ascertained between 1998 and 2014 at the National Institutes of Health Clinical Center. METHODS: Study subjects were members of eight families segregating EVA in at least two members who were not related as siblings. Evaluations included pure-tone audiometry, temporal bone imaging, SLC26A4 nucleotide sequence analysis, SLC26A4-linked marker genotype and haplotype analysis, and pedigree analysis. RESULTS: One family had members with EVA caused by different etiologies, and two families had pseudodominant inheritance of recessive mutations of SLC26A4. In five families, the etiology remained unknown and could include inheritance of mutant alleles at another genetic locus, nongenetic influences, or a combination of these factors. CONCLUSIONS: Familial EVA can demonstrate a variety of atypical segregation patterns. Pseudodominant inheritance of SLC26A4 mutations or recessive alleles of other hearing loss genes may be more likely to occur in families in which deaf individuals have intermarried. The etiologic basis of atypical segregation of EVA without detectable SLC26A4 mutations remains unknown. Future studies of these families may reveal novel genes for EVA. LEVEL OF EVIDENCE: NA Laryngoscope, 126:E240-E247, 2016. PMID- 26485570 TI - Clinical and Molecular Epidemiology of Extended-Spectrum Beta-Lactamase-Producing Klebsiella spp.: A Systematic Review and Meta-Analyses. AB - Healthcare-related infections caused by extended-spectrum beta-lactamase (ESBL) producing Klebsiella spp. are of major concern. To control transmission, deep understanding of the transmission mechanisms is needed. This systematic review aimed to identify risk factors and sources, clonal relatedness using molecular techniques, and the most effective control strategies for ESBL-producing Klebsiella spp. A systematic search of PubMed, Embase, and Outbreak Database was performed. We identified 2771 articles from November 25th, 1960 until April 7th, 2014 of which 148 were included in the systematic review and 23 in a random effects meta-analysis study. The random-effects meta-analyses showed that underlying disease or condition (odds ratio [OR] = 6.25; 95% confidence interval [CI] = 2.85 to 13.66) generated the highest pooled estimate. ESBL-producing Klebsiella spp. were spread through person-to-person contact and via sources in the environment; we identified both monoclonal and polyclonal presence. Multi faceted interventions are needed to prevent transmission of ESBL-producing Klebsiella spp. PMID- 26485572 TI - Structure-Activity Relationship of PEGylated Polylysine Peptides as Scavenger Receptor Inhibitors for Non-Viral Gene Delivery. AB - PEGylated polylysine peptides of the general structure PEG30 kDa-Cys-Trp-LysN (N = 10 to 30) were used to form fully condensed plasmid DNA (pGL3) polyplexes at a ratio of 1 nmol of peptide per MUg of DNA (ranging from N:P 3:1 to 10:1 depending on Lys repeat). Co-administration of 5 to 80 nmols of excess PEG-peptide with fully formed polyplexes inhibited the liver uptake of (125)I-pGL3-polyplexes. The percent inhibition was dependent on the PEG-peptide dose and was saturable, consistent with inhibition of scavenger receptors. The scavenger receptor inhibition potency of PEG-peptides was dependent on the length of the Lys repeat, which increased 10-fold when comparing PEG30 kDa-Cys-Trp-Lys10 (IC50 of 20.2 MUM) with PEG30 kDa-Cys-Trp-Lys25 (IC50 of 2.1 MUM). We hypothesize that PEG-peptides inhibit scavenger receptors by spontaneously forming small 40 to 60 nm albumin nanoparticles that bind to and saturate the receptor. Scavenger receptor inhibition delayed the metabolism of pGL3-polyplexes, resulting in efficient gene expression in liver hepatocytes following delayed hydrodynamic dosing. PEG peptides represent a new class of scavenger inhibitors that will likely have broad utility in blocking unwanted liver uptake and metabolism of a variety of nanoparticles. PMID- 26485573 TI - Cep169, a Novel Microtubule Plus-End-Tracking Centrosomal Protein, Binds to CDK5RAP2 and Regulates Microtubule Stability. AB - The centrosomal protein, CDK5RAP2, is a microcephaly protein that regulates centrosomal maturation by recruitment of a gamma-tubulin ring complex (gamma TuRC) onto centrosomes. In this report, we identified a novel human centrosomal protein, Cep169, as a binding partner of CDK5RAP2, a member of microtubule plus end-tracking proteins (+TIPs). Cep169 interacts directly with CDK5RAP2 through CM1, an evolutionarily conserved domain, and colocalizes at the pericentriolar matrix (PCM) around centrioles with CDK5RAP2. In addition, Cep169 interacts with EB1 through SxIP-motif responsible for EB1 binding, and colocalizes with CDK5RAP2 at the microtubule plus-end. EB1-binding-deficient Cep169 abolishes EB1 interaction and microtubule plus-end attachment, indicating Cep169 as a novel member of +TIPs. We further show that ectopic expression of either Cep169 or CDK5RAP2 induces microtubule bundling and acetylation in U2OS cells, and depletion of Cep169 induces microtubule depolymerization in HeLa cells, although Cep169 is not required for assembly of gamma-tubulin onto centrosome by CDK5RAP2. These results show that Cep169 targets microtubule tips and regulates stability of microtubules with CDK5RAP2. PMID- 26485574 TI - Activity-dependent signaling: influence on plasticity in circuits controlling fear-related behavior. AB - Fear regulation is impaired in anxiety and trauma-related disorders. Patients experience heightened fear expression and reduced ability to extinguish fear memories. Because fear regulation is abnormal in these disorders and extinction recapitulates current treatment strategies, understanding the underlying mechanisms is vital for developing new treatments. This is critical because although extinction-based exposure therapy is a mainstay of treatment, relapse is common. We examine recent findings describing changes in network activity and functional connectivity within limbic circuits during fear regulation, and explore how activity-dependent signaling contributes to the neural activity patterns that control fear and anxiety. We review the role of the prototypical activity-dependent molecule, brain-derived neurotrophic factor (BDNF), whose signaling has been critically linked to regulation of fear behavior. PMID- 26485576 TI - Reversal of Diastereoselection in the Conjugate Addition of Cuprates to Unsaturated Lactams. AB - We report that the stereochemical outcome of the conjugate addition of organocopper reagents to bicyclic alpha,beta-unsaturated lactams derived from pyroglutaminol is determined by the nature of the aminal group. Bicyclic alpha,beta-unsaturated lactams in which the aminal is derived from a ketone have been found to afford products of syn conjugate addition. By contrast, bicyclic alpha,beta-unsaturated lactams in which the aminal is derived from an aldehyde afford products of anti conjugate addition. These remarkably different results obtained from very similar starting materials are unexpected. PMID- 26485575 TI - Maternal Effects of Respiratory Syncytial Virus Infection during Pregnancy. AB - Given the illness and deaths caused by respiratory syncytial virus (RSV) infection during the first year of life, preventing infant RSV infections through maternal vaccination is intriguing. However, little is known about the extent and maternal effects of RSV infection during pregnancy. We describe 3 cases of maternal RSV infection diagnosed at a US center during winter 2014. Case-patient 1 (26 years old, week 33 of gestation) received a diagnosis of RSV infection and required mechanical ventilation. Case-patient 2 (27 years old, week 34 of gestation) received a diagnosis of infection with influenza A(H1N1) virus and RSV and required mechanical ventilation. Case-patient 3 (21 years old, week 32 of gestation) received a diagnosis of group A streptococcus pharyngitis and RSV infection and was monitored as an outpatient. Clarifying the effects of maternal RSV infection could yield valuable insights into potential maternal and fetal benefits of an effective RSV vaccination program. PMID- 26485577 TI - Diagnosis of hepatitis C virus genotype 2k/1b needs NS5B sequencing. AB - Hepatitis C virus (HCV) is probably the most common cause of liver cirrhosis and hepatocellular carcinoma worldwide. The correct identification of HCV genotype has important clinical implications as a marker of responsiveness to antiviral therapy and serves as a guideline for the duration of treatment. The VERSANT HCV Genotype 2.0 Assay failed to detect HCV genotype 2k/1b. HCV genotype 2k/1b detection requires NS5B sequencing. PMID- 26485578 TI - Association between interpregnancy interval and future risk of maternal cardiovascular disease-a population-based record linkage study. AB - OBJECTIVE: To examine the associations between interpregnancy interval and later maternal cardiovascular disease (CVD) risk. DESIGN: Population-based record linkage study. SETTING: New South Wales, Australia, 1994-2011. POPULATION: 216 467 women having first and second liveborn singleton infants, excluding those with an existing or pregnancy-related CVD risk factor. METHODS: We linked birth records of mothers to the mothers' subsequent CVD (coronary heart disease, cerebrovascular events, and chronic heart failure) hospitalisation or death. Multivariable Cox proportional hazard regression was used to estimate adjusted hazard ratios (AHR) [95% confidence interval (CI)], accounting for maternal age, parity, socioeconomic status, and smoking during pregnancy. MAIN OUTCOME MEASURES: The first occurrence of a CVD hospitalisation or death after the second birth. RESULTS: In comparison with mothers with an interpregnancy interval of 18 23 months (reference category), the AHR among mothers with interpregnancy interval of <12 months was 1.56 (95% CI 1.18-2.07) and of 12-17 months was 1.13 (95% CI 0.84-1.51). The AHRs were 1.40 (95% CI 1.07-1.82), 1.87 (95% CI 1.21 2.89), and 3.41 (95% CI 1.07-10.91), corresponding to interpregnancy intervals of 24-59, 60-119, and >=120 months, respectively. AHRs of specific CVD categories showed a similar pattern. CONCLUSIONS: Interpregnancy interval is associated with the risk of subsequent maternal CVD in a J-shaped fashion. The association is independent of the existing and pregnancy-related CVD risk factors analysed. Both short and long interpregnancy intervals can be used as risk markers to identify women with an elevated CVD risk later in life. TWEETABLE ABSTRACT: Interpregnancy interval is associated with the risk of subsequent maternal cardiovascular disease in a J-shaped fashion. PMID- 26485580 TI - Electric eels use high-voltage to track fast-moving prey. AB - Electric eels (Electrophorus electricus) are legendary for their ability to incapacitate fish, humans, and horses with hundreds of volts of electricity. The function of this output as a weapon has been obvious for centuries but its potential role for electroreception has been overlooked. Here it is shown that electric eels use high-voltage simultaneously as a weapon and for precise and rapid electrolocation of fast-moving prey and conductors. Their speed, accuracy, and high-frequency pulse rate are reminiscent of bats using a 'terminal feeding buzz' to track insects. Eel's exhibit 'sensory conflict' when mechanosensory and electrosensory cues are separated, striking first toward mechanosensory cues and later toward conductors. Strikes initiated in the absence of conductors are aborted. In addition to providing new insights into the evolution of strongly electric fish and showing electric eels to be far more sophisticated than previously described, these findings reveal a trait with markedly dichotomous functions. PMID- 26485581 TI - Analyzing Evolutionary Optimization in Noisy Environments. AB - Many optimization tasks must be handled in noisy environments, where the exact evaluation of a solution cannot be obtained, only a noisy one. For optimization of noisy tasks, evolutionary algorithms (EAs), a type of stochastic metaheuristic search algorithm, have been widely and successfully applied. Previous work mainly focuses on the empirical study and design of EAs for optimization under noisy conditions, while the theoretical understandings are largely insufficient. In this study, we first investigate how noisy fitness can affect the running time of EAs. Two kinds of noise-helpful problems are identified, on which the EAs will run faster with the presence of noise, and thus the noise should not be handled. Second, on a representative noise-harmful problem in which the noise has a strong negative effect, we examine two commonly employed mechanisms dealing with noise in EAs: reevaluation and threshold selection. The analysis discloses that using these two strategies simultaneously is effective for the one-bit noise but ineffective for the asymmetric one-bit noise. Smooth threshold selection is then proposed, which can be proved to be an effective strategy to further improve the noise tolerance ability in the problem. We then complement the theoretical analysis by experiments on both synthetic problems as well as two combinatorial problems, the minimum spanning tree and the maximum matching. The experimental results agree with the theoretical findings and also show that the proposed smooth threshold selection can deal with the noise better. PMID- 26485582 TI - Social Stigma Toward Suicide: Effects of Group Categorization and Attributions in Korean Health News. AB - The purpose of this study is to examine the influence of health news content on the stigma of suicide. In particular, this study tested whether the onset controllability and group categorization had a causal effect on people's stigma toward suicide. The results indicated that stigma scores were lower for those who read an article explaining the causes of suicide as uncontrollable than for those who read an article explaining the causes as controllable. Also, lower stigma scores were observed for those who read an article depicting suicidal people as the in-group compared to those who read an article depicting suicidal people as the out-group. Furthermore, stigma scores were the highest for those exposed to an article with the out-group categorization combined with the controllable causes of suicide. PMID- 26485579 TI - The transcription factor Pax6 contributes to the induction of GLT-1 expression in astrocytes through an interaction with a distal enhancer element. AB - The Na(+) -dependent glutamate transporter GLT-1 (EAAT2) shows selective expression in astrocytes, and neurons induce the expression of GLT-1 in astrocytes. In an unpublished analysis of GLT-1 promoter reporter mice, we identified an evolutionarily conserved domain of 467 nucleotides ~ 8 kb upstream of the GLT-1 translation start site that is required for astrocytic expression. Using in silico approaches, we identified Pax6 as a transcription factor that could contribute to the control of GLT-1 expression by binding within this region. We demonstrated the expression of Pax6 protein in astrocytes in vivo. Lentiviral transduction of astrocytes with exogenous Pax6 increased the expression of enhanced green fluorescent protein (eGFP) in astrocytes prepared from transgenic mice that use a bacterial artificial chromosome containing a large genomic region surrounding the GLT-1 gene to control expression of eGFP. It also increased GLT-1 protein and GLT-1-mediated uptake, whereas there was no effect on the levels of the other astroglial glutamate transporter, glutamate aspartate transporter (GLAST). Transduction of astrocytes with an shRNA directed against Pax6 reduced neuron-dependent induction of GLT-1 or eGFP. Finally, we confirmed Pax6 interaction with the predicted DNA-binding site in electrophoretic mobility assays and chromatin immunoprecipitation (ChIP). Together, these studies show that Pax6 contributes to the regulation of GLT-1 through an interaction with these distal elements and identify a novel role of Pax6 in astrocyte biology. The astroglial glutamate transporter GLT-1 shows selective expression in astrocytes and its expression can be induced by neurons. In this study, we demonstrate that Pax6 is expressed in astrocytes and binds to the GLT-1 promoter in vitro and in vivo. Exogenous expression of Pax6 increases GLT-1 and enhanced green fluorescent protein (eGFP) expression in astrocytes from a transgenic mouse line that uses the GLT-1 gene to drive eGFP expression, and an shRNA directed against Pax6 attenuates neuron-dependent induction of GLT-1/eGFP. We therefore conclude that Pax6 contributes to the neuron-dependent induction of GLT-1. PMID- 26485583 TI - Fucoidan reduces inflammatory response in a rat model of hepatic ischemia reperfusion injury. AB - Ischemia-reperfusion (I/R) injury after a liver transplant is a major cause of severe complications that lead to graft dysfunction. Fucoidan, a complex of sulfated polysaccharides derived from marine brown algae, demonstrated antiapoptotic as well as potential anti-inflammatory properties in previous studies. Fucoidan has also shown protective effects on I/R-injured kidney and heart. However, whether fucoidan can attenuate hepatic I/R injury has not been examined. To clarify the role of fucoidan in hepatic I/R injury, Sprague-Dawley rats were subjected to sham operation or ischemia followed by reperfusion with treatment of saline or fucoidan (50, 100, or 200 mg.(kg body mass)(-1).d(-1)). The fucoidan-treated group showed decreased levels of alanine aminotransferase and aspartate aminotransferase compared with the control group. Myeloperoxidase and malondialdehyde activities and mRNA levels of CD11b in the fucoidan-treated group were significantly decreased. Hepatocellular swelling/necrosis, sinusoidal/vascular congestion, and inflammatory cell infiltration were also attenuated in the fucoidan group. The expression of TNF-alpha, IL-6, IL-1beta, CXCL-10, VCAM-1, and ICAM-1 were markedly decreased in the samples from the fucoidan-treated group. Fucoidan largely prevented activation of the inflammatory signaling pathway, compared with the control group. In summary, fucoidan can protect the liver from I/R injury through suppressing activation of the inflammatory signaling pathway, as well as the expression of inflammatory mediators, and inflammatory cell infiltration. PMID- 26485584 TI - Corneal-Reflection Eye-Tracking Technique for the Assessment of Horizontal Sound Localization Accuracy from 6 Months of Age. AB - OBJECTIVES: The evaluation of sound localization accuracy (SLA) requires precise behavioral responses from the listener. Such responses are not always possible to elicit in infants and young children, and procedures for the assessment of SLA are time consuming. The aim of this study was to develop a fast, valid, and objective method for the assessment of SLA from 6 months of age. To this end, pupil positions toward spatially distributed continuous auditory and visual stimuli were recorded. DESIGN: Twelve children (29 to 157 weeks of age) who passed the universal newborn hearing screening and eight adults (18 to 40 years of age) who had pure-tone thresholds <=20 dB HL in both ears participated in this study. Horizontal SLA was measured in a sound field with 12 loudspeaker/display (LD)-pairs placed in an audiological test room at 10 degrees intervals in the frontal horizontal plane (+/-55 degrees azimuth). An ongoing auditory-visual stimulus was presented at 63 dB SPL(A) and shifted to randomized loudspeakers simultaneously with pauses of the visual stimulus. The visual stimulus was automatically reintroduced at the azimuth of the sounding loudspeaker after a sound-only period of 1.6 sec. A corneal-reflection eye-tracking technique allowed the acquisition of the subjects' pupil positions relative to the LD-pairs. The perceived azimuth was defined as the median of the intersections between gaze and LD-pairs during the final 500 msec of the sound-only period. Overall SLA was quantified by an Error Index (EI), where EI = 0 corresponded to perfect match between perceived and presented azimuths, whereas EI = 1 corresponded to chance. RESULTS: SLA was rapidly measured in children (mean = 168 sec, n = 12) and adults (mean = 162 sec, n = 8). Visual inspection of gaze data indicated that gaze shifts occurred in sound-only periods. The medians of the perceived sound-source azimuths either coincided with the presenting sound-source azimuth or were offset by a maximum of 20 degrees in children. In contrast, adults revealed a perfect match from -55 to 55 degrees, except at 15 degrees azimuth (median = 20 degrees), with 9/12 of the quartile ranges = 0 degrees. Children showed a mean (SD) EI of 0.42 (0.17), which was significantly higher than that in adults (p < 0.0001). However, children revealed a distinct age-related EI improvement of 16 percentage points per year (r = -0.68, p = 0.015, n = 12), suggesting an ongoing maturation of SLA in the studied age range (29 to 157 weeks). The eight adults showed high SLA and high reliability as demonstrated by the low mean (SD) EI (0.054 [0.021]) and the low variability in test-retest differences (95% confidence interval = 0.020 to 0.046). CONCLUSIONS: Corneal-reflection eye-tracking provides an objective and fast assessment of horizontal SLA from about 6 months of age and may enable gaze to be used as an objective measure for sound localization in this age group. Infant SLA is immature and improvements are related to increasing age. Adults show high overall SLA and low intra- and intersubject variability in SLA. The technique may be used as a clinical tool for the evaluation of very early intervention in a young, preverbal population and throughout the life span. PMID- 26485585 TI - Forest Structure Affects Soil Mercury Losses in the Presence and Absence of Wildfire. AB - Soil is an important, dynamic component of regional and global mercury (Hg) cycles. This study evaluated how changes in forest soil Hg masses caused by atmospheric deposition and wildfire are affected by forest structure. Pre and postfire soil Hg measurements were made over two decades on replicate experimental units of three prefire forest structures (mature unthinned, mature thinned, clear-cut) in Douglas-fir dominated forest of southwestern Oregon. In the absence of wildfire, O-horizon Hg decreased by 60% during the 14 years after clearcutting, possibly the result of decreased atmospheric deposition due to the smaller-stature vegetative canopy; in contrast, no change was observed in mature unthinned and thinned forest. Wildfire decreased O-horizon Hg by >88% across all forest structures and decreased mineral-soil (0 to 66 mm depth) Hg by 50% in thinned forest and clear-cut. The wildfire-associated soil Hg loss was positively related to the amount of surface fine wood that burned during the fire, the proportion of area that burned at >700 degrees C, fire severity as indicated by tree mortality, and soil C loss. Loss of soil Hg due to the 200,000 ha wildfire was more than four times the annual atmospheric Hg emissions from human activities in Oregon. PMID- 26485586 TI - Efficacy and Safety of Transcanal Endoscopic Ear Surgery for Congenital Cholesteatomas: A Preliminary Report. AB - OBJECTIVE: Transcanal endoscopic ear surgery (TEES) can provide greater visual access during resection of middle ear disease than the operating microscope. The purpose of this study was to determine the safety and efficacy of TEES when used for the management of congenital cholesteatoma (CC) in children. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Twelve children with CC confined to the middle ear underwent TEES. Seven children were Potsic stage I, four were stage II, and one was stage III. The mean follow-up period was 23.1 months. INTERVENTION: Transcanal middle ear surgery using endoscopes. MAIN OUTCOME MEASURES: Incidence of surgical complications and cholesteatoma recurrence. RESULTS: Twelve patients underwent TEES and four patients underwent microscopic surgery during the same period. No surgical complications occurred. Postoperative audiograms were available for 7 of 12 patients who had puretone averages ranging from 3.3 to 23.9 dB HL (mean, 12.7 dB HL). One patient with a stage III CC was found to have residual disease during a second-look procedure, whose follow-up period was only 3 months. Other patients underwent one-stage operations and have developed no cholesteatoma recurrence. CONCLUSION: Although the follow-up period and number of patients were limited, early-stage CC can be safely removed using TEES. PMID- 26485587 TI - Conductive Hearing Loss in Association With Urate Deposits in the Middle Ear. PMID- 26485588 TI - Dexamethasone Protects Against Radiation-induced Loss of Auditory Hair Cells In Vitro. AB - HYPOTHESIS: Dexamethasone (DXM) protects against radiation-induced loss of auditory hair cells (HCs) in rat organ of Corti (OC) explants by reducing levels of oxidative stress and apoptosis. BACKGROUND: Radiation-induced sensorineural hearing loss (HL) is progressive, dose-dependent, and irreversible. Currently, there are no preventative therapeutic modalities for radiation-induced HL. DXM is a synthetic steroid that can potentially target many of the pathways involved in radiation-induced ototoxicity. METHODS: Whole OC explants were dissected from 3 day-old rat cochleae exposed to specific dosages of single-fraction radiation (0, 2, 5, 10, or 20 Gy), were either untreated or treated with DXM (75, 150, 300 MUg/mL), and then cultured for 48 or 96 hours. Confocal microscopy for oxidative stress (CellRox, 48 h) and apoptosis (TUNEL assay, 96 h) and fluorescent microscopy for viable HC counts (fluorescein isothiocyanate-phalloidin, 96 h) were performed. Analysis of variance and Tukey post hoc testing were used for statistical analysis. RESULTS: Radiation exposure initiated dose-dependent losses of inner and outer HCs, predominantly in the basal turns of the OC explants. DXM protected against radiation-induced HC losses in a dose-dependent manner. DXM significantly reduced levels of oxidative stress and apoptosis in radiation injured OC explants (p < 0.001). CONCLUSIONS: Radiation-initiated HC losses were dose-dependent in OC explants. DXM treatment protected explant HCs against radiation-initiated losses by decreasing the levels of oxidative stress and apoptosis. DXM may potentially be a therapeutic modality for preventing radiation induced HL; further in vivo studies are necessary. PMID- 26485589 TI - Evaluation of Magnetic Resonance Imaging Diagnostic Approaches for Vestibular Schwannoma Based on Hearing Threshold Differences Between Ears: Added Value of Auditory Brainstem Responses. AB - OBJECTIVE: This study investigates the most appropriate audiometric criterion in deciding which patients with asymmetric hearing loss should be referred to MRI to exclude a lesion in the cerebellopontine angle (CPA). Careful selection of patients could improve resource utilization while preventing unnecessary investigations with accompanying burden and costs. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Of all the patients who were referred to our clinic between 1997 and 2012, the records were reviewed of those who underwent pure-tone audiometry, auditory brainstem response (ABR) testing, and had a Gadolinium-enhanced MRI of the CPA. INTERVENTION: Regarding interaural pure-tone threshold differences at single or multiple (averaged) frequencies, we assigned multiple possible cut-off values (dB) defining an aberrant result, suggestive for CPA lesions. Results were compared with MRI to calculate sensitivity and specificity for every cut-off value. These were visualized as ROC curves enabling qualitative comparison. Added value of ABR was assessed as well. MAIN OUTCOME MEASURES: Sensitivity and specificity of various criteria to decide which patients with asymmetric hearing loss to send to MRI to exclude a CPA lesion. RESULTS: In total, 1016 records were reviewed. Two hundred ninety-four subjects (29%) were diagnosed with a CPA lesion on MRI. Sensitivity and specificity for audiometry results differed greatly depending on the predefined cut-off value for hearing threshold difference (40-95% sensitivity and 20-90% specificity). Best ROC curves were obtained when threshold differences at two or three higher frequencies were averaged. Adding results of ABR to the threshold criterion yielded a slightly better ROC curve, although sensitivity decreased. CONCLUSIONS: The best criterion to decide which patient with asymmetric hearing loss should be referred to MRI is based on the average bone conduction threshold difference at multiple (two or three) higher frequencies. The extent of the average threshold difference between ears that is used as a cutoff will mainly depend on treatment modality and (eventually) on resource costs and on the burden of Gadolinium-enhanced magnetic resonance imaging. Results of ABR can have little added value when only patients with a unilateral abnormal ABR at the worse hearing ear are referred to MRI. However, a lower sensitivity must then be accepted. PMID- 26485590 TI - Health Utility Improves After Surgery for Superior Canal Dehiscence Syndrome. AB - OBJECTIVE: Health utility value (HUV) is an outcome measure used to calculate quality adjusted life years (QALYs) and to determine cost-effectiveness of medical treatments. Herein, we measure HUV in patients with superior canal dehiscence syndrome (SCDS) before and after surgical repair. Health utility values of patients with SCDS are compared to normative data of the general United States population. STUDY DESIGN: Retrospective review of prospectively collected data. PATIENTS: Adult patients with SCDS. SETTING: Tertiary referral center. INTERVENTIONS: SCD repair via middle fossa craniotomy or transmastoid approaches. MAIN OUTCOME MEASURE: PRIMARY OUTCOME: change in HUV, as measured by the Short Form 6-Dimension questionnaire. SECONDARY OUTCOMES: autophony index (AI), dizziness handicap inventory (DHI), and hearing handicap inventory (HHI). RESULTS: Fifty-one patients with SCDS were enrolled, 23 underwent surgical repair. Mean HUV in patients with SCDS is significantly lower than the general U.S. POPULATION: 0.68 (SD = 0.13) versus 0.80 (0.29), p < 0.01, respectively. Patients electing to undergo surgical repair had similar values relative to nonoperated patients: 0.65 (0.13) versus 0.71 (0.14), p = 0.20, respectively. At mean follow-up of 12 months (range 3-39), postoperative HUV improved to 0.79 (0.12), p < 0.01. AI decreased (improved) after repair: 32.7 (28.0) to 4.8 (8.3), p < 0.001. DHI and HHI did not change significantly after surgery, p > 0.14. Nonoperated patients had no significant change in HUV during a mean follow-up period of 21 months (range 9-39), p = 0.33. CONCLUSIONS: SCDS patients have significantly lower HUV compared with the general U.S. POPULATION: HUV demonstrated improvement after surgery. Nonoperated patients have ongoing impaired quality of life. PMID- 26485591 TI - The Efficacy of Color-Mapped Diffusion-Weighted Images Combined With CT in the Diagnosis and Treatment of Cholesteatoma Using Transcanal Endoscopic Ear Surgery. AB - OBJECTIVE: To assess the efficacy of a color-mapped diffusion-weighted image combined with a computed tomography scan (CMDWI-CT) in preoperatively evaluating the anatomical location of cholesteatomas and determining whether a patient is indicated for transcanal endoscopic ear surgery (TEES) to reduce intraoperative switching to microscopic ear surgery (MES). STUDY DESIGN: Prospective case study. SETTING: A single university hospital. PATIENTS: Fifty-five patients scheduled for middle ear cholesteatoma surgery. INTERVENTION: The CMDWI-CT is produced in a multistep process. A color-mapped fusion image (CMFI) is created by performing MR cisternography on a 1-mm thin-slice nonecho planar diffusion-weighted imaging (non-EPI DWI) and then by performing color mapping on the resulting image to enhance cholesteatoma visualization. False positives are reduced by taking a T1 weighted image (T1WI), whereas false negatives are further reduced by preoperative endoscopic examination. As cholesteatomas are difficult to locate on a CMFI in the temporal bone region, we stripped out the MR cisternography data from the CMFI and then fused the CMFI to the initial computer tomography (CT) scan to create a CMDWI-CT. This CMDWI-CT better clarifies the cholesteatoma position within temporal bone. MAIN OUTCOME MEASURE(S): CMDWI-CT preoperative findings were compared with intraoperative findings. The positive predictive value and negative predictive value were also evaluated depending on the cholesteatoma location. RESULTS: CMDWI-CT facilitated accurate detection of the cholesteatoma anatomical location in the temporal bone region which was reflected in positive predictive and negative predictive values of over 90% for all areas of the middle ear. CONCLUSION: CMDWI-CT is a reliable diagnostic modality for evaluating the anatomical location of cholesteatomas that seem as high-signal regions on a CMFI and for determining whether TEES is indicated for treatment in such patients. PMID- 26485592 TI - Electro-Mechanical Stimulation of the Cochlea by Vibrating Cochlear Implant Electrodes. AB - INTRODUCTION: Electro-acoustic stimulation (EAS) of the cochlea uses the preserved residual low-frequency hearing for acoustic stimulation in combination with electrical stimulation. The acoustic low-frequency component is amplified and high-frequency hearing is enhanced by a cochlear implant (CI). In this work, the feasibility of EAS by the floating mass transducers (FMTs) firmly attached to the implanted electrode was investigated and the achieved stapes displacement was compared with sound stimulation. METHODS: Experiments were performed in eight fresh human temporal bones compliant to the ASTM standard (F2504-5). Four EAS custom-made prototypes (EAS-CMP) were tested, consisting of standard MED-EL CI electrodes with Vibrant Soundbridge (VSB) FMTs or a Bonebridge (BB) FMT tightly molded to the electrode in different orientations. The stapes footplate (SFP) response to EAS-CMP stimulation and sound stimulation was measured using a Laser Doppler Vibrometer (LDV). RESULTS: The SFP displacement amplitudes achieved by EAS-CMP stimulation were calculated to 1 VRMS FMT input and were pair-wise statistically compared between prototypes yielding no significant differences at frequencies <=1 kHz. At frequencies <=1 kHz stimulation by the BB FMT resulted in a flat and potentially highest SFP displacement amplitude of approximately -40 dB re MUm at 1 VRMS input voltage. Estimated equivalent sound pressure levels achieved by the BB FMT prototype were approximately 83-90 eq. dB SPL at frequencies <=1 kHz. CONCLUSION: The feasibility of cochlear stimulation by vibrating electrodes was shown although the achieved output level at frequencies <=1 kHz was too low for EAS applications. PMID- 26485594 TI - Asymptomatic Hydrops in a Case With Otosclerosis. PMID- 26485593 TI - Anti CD163+, Iba1+, and CD68+ Cells in the Adult Human Inner Ear: Normal Distribution of an Unappreciated Class of Macrophages/Microglia and Implications for Inflammatory Otopathology in Humans. AB - HYPOTHESIS: Identification, characterization, and location of cells involved in the innate immune defense system of the human inner ear may lead to a better understanding of many otologic diseases and new treatments for hearing and balance-related disorders. BACKGROUND: Many otologic disorders are thought to have, as part of their disease process, an immune component. Although resident macrophages are known to exist in the mouse inner ear, the innate immune cells in the human inner ear are, to date, unknown. METHODS: Primary antibodies against CD163, Iba1, and CD68 (markers known to be specific for macrophages/microglia) were used to immunohistochemically stain celloidin embedded archival temporal bone tissue of normal individuals with no known otologic disorders other than changes associated with age. RESULTS: Cells were positively stained throughout the temporal bone within the connective tissue and supporting cells with all three markers. They were often associated with neurons and on occasion entered the sensory cell areas of the auditory and vestibular epithelium. CONCLUSIONS: We have immunohistochemically identified an unappreciated class of cells in the normal adult inner ear consistent in staining characteristics and morphology with macrophages/microglia. As in other organ systems, it is likely these cells play an essential role in organ homeostasis that has not yet been elucidated within the ear. PMID- 26485595 TI - Systematic Review of Treatments for Autoimmune Inner Ear Disease. AB - OBJECTIVE: To systematically evaluate the evidence for treatment of autoimmune inner ear disease (AIED). DATA SOURCES: Medline/EMBASE, Cochrane Review. STUDY SELECTION: Studies reviewed were English language original articles reporting outcome data for subjects with AIED undergoing any treatment other than oral steroids alone with particular emphasis on prospectively collected data. DATA EXTRACTION: The full text of articles meeting selection criteria was reviewed for subject inclusion criteria, number of subjects, treatment type and duration, audiologic and vestibular evaluations, blinding, randomization, and follow-up. DATA SYNTHESIS: Twelve studies representing 272 subjects met selection criteria and presented prospective data, three of which were randomized and placebo controlled. Low numbers and heterogeneity between studies precluded meta analysis. CONCLUSIONS: Clear evidence of an effective treatment for AIED from high-quality prospective trials remains lacking. PMID- 26485596 TI - Progressively Recovering Auditory Brainstem Response in a Cochlear-implanted Child After Meningitis: A Case Report. AB - OBJECTIVE: I describe the case of an 8-year-old boy who developed meningitis several years after implantation and how electrically evoked auditory brainstem response (EABR) is used in the assessment of his hearing performance after recovery. PATIENT: An 8-year-old boy stopped using both his cochlear implants because of streptococcal meningitis accompanied with acute otitis media on the left ear. After recovery his hearing was quickly restored on the right ear, but he complained of not hearing well on the left ear. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURE: EABRs were measured on both ears 2 months after meningitis offset. Testing was repeated on the left ear 12 and 18 months after the first session. Responses were evoked by apical, mid-array, and basal electrodes. RESULTS: At initial testing EABRs were normal on the right ear. They were absent on the left ear for the apical electrode and present but with delayed wave latencies for the middle and basal electrodes. At the second and third sessions, EABRs were present for all electrodes and wave eV latencies were shorter. The stimulus level needed to evoke an EABR was considerably reduced on all electrodes from the first to the third session. There was good agreement between these findings and the subjective feedback from the patient. CONCLUSION: EABR provided valuable information throughout the patient's hearing recovery. Its use should be considered in difficult patients, especially those who cannot give feedback. PMID- 26485597 TI - Objective Measurements of Ossicular Chain Mobility Using a Palpating Instrument Intraoperatively. AB - BACKGROUND: The judgment of a normal or impaired mobility of middle ear ossicles is based on palpation and depends highly on the surgeon's subjective experience. The aim of this study was to develop and test a palpating instrument recording force and vector and allowing to support the surgeon's subjective impression with objective measurement results. STUDY DESIGN: Prospective recordings at surgery. SETTING: Tertiary referral center. PATIENTS AND METHODS: A fiberoptic force sensing element allowing force measures in three orthogonal directions was integrated into a handheld 45 degree hook and tested in temporal bones. Clinical data series from patients with a functionally normal chain (e.g., cochlear implants (CI)) and impaired ossicles (otosclerosis) were collected. The ossicles were palpated until their first movements out of the resting stage were visualized, the applied force, and vector were recorded by an independent observer. RESULTS: Four CI and 19 otosclerosis patients were further evaluated. The minimum detectable force change of the sensor was 0.2 gF (2 mN). In the otosclerosis patients the average force applied to move the malleus was 9.5 gF, on the incus 8.7 gF. These values were slightly lower after separation of the incudostapedial joint, reaching 8.5 gF and 6.9 gF, respectively. The fixed stapes showed a rigidity of 14.7 gF or higher. The values were lower in the CI group measuring 4.4 gF, 4.1 gF, and 3.3 gF on the three ossicles, respectively. CONCLUSIONS: We were able to produce a disposable, easy-to-handle palpating probe that enables the otologist to record continuously tip contact forces in three dimensions during his standard palpation of each ossicle. Normative values were reproduced for each ossicle, as well as increased rates for stapes fixation in otosclerosis. PMID- 26485598 TI - Utility of an Abbreviated Dizziness Questionnaire to Differentiate Between Causes of Vertigo and Guide Appropriate Referral: A Multicenter Prospective Blinded Study. AB - OBJECTIVE: Test performance of a focused dizziness questionnaire's ability to discriminate between peripheral and nonperipheral causes of vertigo. STUDY DESIGN: Prospective multicenter. SETTING: Four academic centers with experienced balance specialists. PATIENTS: New dizzy patients. INTERVENTIONS: A 32-question survey was given to participants. Balance specialists were blinded and a diagnosis was established for all participating patients within 6 months. MAIN OUTCOMES: Multinomial logistic regression was used to evaluate questionnaire performance in predicting final diagnosis and differentiating between peripheral and nonperipheral vertigo. Univariate and multivariable stepwise logistic regression were used to identify questions as significant predictors of the ultimate diagnosis. C-index was used to evaluate performance and discriminative power of the multivariable models. RESULTS: In total, 437 patients participated in the study. Eight participants without confirmed diagnoses were excluded and 429 were included in the analysis. Multinomial regression revealed that the model had good overall predictive accuracy of 78.5% for the final diagnosis and 75.5% for differentiating between peripheral and nonperipheral vertigo. Univariate logistic regression identified significant predictors of three main categories of vertigo: peripheral, central, and other. Predictors were entered into forward stepwise multivariable logistic regression. The discriminative power of the final models for peripheral, central, and other causes was considered good as measured by c-indices of 0.75, 0.7, and 0.78, respectively. CONCLUSION: This multicenter study demonstrates a focused dizziness questionnaire can accurately predict diagnosis for patients with chronic/relapsing dizziness referred to outpatient clinics. Additionally, this survey has significant capability to differentiate peripheral from nonperipheral causes of vertigo and may, in the future, serve as a screening tool for specialty referral. Clinical utility of this questionnaire to guide specialty referral is discussed. PMID- 26485599 TI - Hearing Loss Caused by Surgical Antiseptic in the Setting of an Unknown Tympanic Perforation. PMID- 26485600 TI - Efficacy of Concomitant Intratympanic Steroid Injection for Sudden Deafness According to Initial Hearing Loss. AB - OBJECTIVES/HYPOTHESIS: We identified the efficacy and appropriate target group for intratympanic steroid injections (ITS) in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). STUDY DESIGN: Retrospective case-control study. METHODS: Fifty-five ears treated with concomitant ITS and systemic steroids and 165 ears without ITS treatment were identified. Each case had three controls matched according to the age, sex, and the presence of vertigo. Patients were divided into subgroups according to pure tone audiometric configuration and the levels of initial hearing loss. Hearing results and frequency-related hearing gain were investigated. RESULTS: Additional ITS was effective for patients with an ascending type audiogram or patients with Grade 3 (60-90 dB) initial hearing loss. Concomitant ITS, however, resulted in a negative effect on hearing in patients with Grades 1 and 2 (<60 dB). ITS resulted in significant (p < 0.05) hearing improvement at 250 Hz in the Grade 3 (60-90 dB) and Grade 4 (>90 dB) ITS subgroups. CONCLUSIONS: The efficacy of additional ITS for ISSNHL was different among subgroups with various levels of initial hearing loss or audiogram configuration. PMID- 26485601 TI - Jugular Foramen Ganglioneuroma Presenting Radiographically as Schwannoma. PMID- 26485602 TI - Nitrogen-Doped Holey Graphene as an Anode for Lithium-Ion Batteries with High Volumetric Energy Density and Long Cycle Life. AB - Nitrogen-doped holey graphene (N-hG) as an anode material for lithium-ion batteries has delivered a maximum volumetric capacity of 384 mAh cm(-3) with an excellent long-term cycling life up to 6000 cycles, and as an electrochemical capacitor has delivered a maximum volumetric energy density of 171.2 Wh L(-1) and a volumetric capacitance of 201.6 F cm(-3) . PMID- 26485603 TI - Meaning, Resilience, and Traumatic Stress After the Deepwater Horizon Oil Spill: A Study of Mississippi Coastal Residents Seeking Mental Health Services. AB - The present study examines the relationship between resilience, perceived meaning in life, and traumatic stress symptoms among coastal residents of Mississippi directly affected by the Deepwater Horizon oil spill (also known as the Gulf oil spill). The study was conducted as part of a larger project that assessed the spill's effect on the mental health of individuals seeking therapeutic services. Multiple regression analyses were conducted to determine if resilience and perceived meaning are significant predictors of scores from a measure of posttraumatic stress. Descriptive data, reliability coefficients, and correlations were also calculated. Higher levels of resilience and meaning together were predictive of fewer posttraumatic stress symptoms after controlling for the effect of the spill. Resilience and meaning appeared to be similar predictors of lower posttraumatic stress scores, and meaning appears to be an important facet of what makes a person resilient. PMID- 26485604 TI - Fecal Incontinence in Adolescents Is Associated With Child Abuse, Somatization, and Poor Health-related Quality of Life. AB - BACKGROUND: The aim of this study was to evaluate the association between fecal incontinence (FI), child abuse, somatization, and health-related quality of life (HRQoL) in adolescents. METHODS: Adolescents (ages 13-18 years) were selected from 4 semi-urban schools in the Gampaha district, Sri Lanka. A validated, self administered questionnaire was used for data collection. FI was defined as at least 1 episode of leakage of feces per month. RESULTS: A total of 1807 adolescents were analyzed (boys 973 [53.8%], mean age 14.4 years, standard deviation [SD] 1.4 years). A total of 47 (2.6%) had FI. Prevalence of sexual abuse (17% vs 2.3% in controls, P < 0.0001), emotional abuse (40.4% vs 22.7%, P < 0.0001), and physical abuse (51% vs 24.3%, P < 0.0001) was significantly higher in children with FI. Adolescents with FI had higher mean somatization scores [mean 20.1, (SD 14.5) vs mean 9.3, (SD 9.2)] compared with those without FI (P < 0.0001). Those with FI also had lower HRQoL scores for physical functioning, social functioning, emotional functioning domains, and performances at school, together with a lower overall HRQoL score compared with those without FI (74.6 vs 87.1, P < 0.0001). CONCLUSIONS: There is a significant association between FI and physical, sexual, and emotional abuse. They also have a higher somatization score and a poor HRQoL score in physical, emotional, social, and school functioning domains compared with those without FI. PMID- 26485605 TI - Contrast-Based Real-Time Assessment of Microcirculatory Changes in a Fatty Liver After Ischemia Reperfusion Injury. AB - OBJECTIVES: A fatty liver is known to have impairment of microcirculation, which is worsened after ischemia reperfusion injury (IRI). This makes most fatty grafts unsuitable for transplantation, and in the absence of real time assessment of microcirculation this selection has been at best, random. The aim of this study was to demonstrate the utility of a contrast enhanced ultrasound model in quantitative assessment of the microcirculation of a fatty liver. METHODS: We subjected fatty mice to IRI, and blood flow dynamics were assessed before and after the injury. RESULTS: There was a significant increase in the resistive and pulsatility index of the extrahepatic artery and a significant decrease in velocity of the portal vein. There was also a quantifiable decrease in the intrahepatic blood volume, blood flow, time to peak flow, and perfusion index of mice with fatty liver, suggesting that a fatty liver develops hemodynamic abnormalities after IRI, leading to increased hepatocellular injury. CONCLUSIONS: Hemodynamic abnormalities in liver can be reliably quantified using a contrast, enhanced Doppler ultrasound, which is an inexpensive technique with multiple clinical applications. It can be used to assess the quality of the fatty liver donor graft before organ retrieval; for determining live donor candidacy, for making post-IRI recovery prognosis, and for assessing the effectiveness of therapeutic interventions. PMID- 26485606 TI - Prevalence and Natural History of Celiac Disease in a Cohort of At-risk Children. AB - OBJECTIVES: To assess the prevalence and clinical presentation of celiac disease (CD) in a cohort of children with HLA-DQ2 positive and evaluate the risk factors in the development of CD. METHODS: Between July 2004 and July 2005, parents of all healthy full-term newborns in our hospital were invited to participate. HLA DQ2 was tested in blood sample of the umbilical cord. A point of contact serological test was performed on children between 2 and 3 years of age. Positive results were confirmed by serum anti-transglutaminase 2 and endomysial antibodies. Children with high autoantibody titers underwent an intestinal biopsy. Children of the cohort diagnosed with CD before the screening study were included. Sex, mode of delivery, breast-feeding duration, and age of gluten introduction were studied. RESULTS: Of 1291 children, 362 were HLA-DQ2 positive and 262 participated in the study. CD was diagnosed in 4.1% (95% confidence interval (CI) 1.9-6.3). In the whole cohort, 60% had gastrointestinal symptoms, 7% poor weight gain, and 33% were asymptomatic. Five children with potential CD and 6 with CD autoimmunity became negative (42.3%) and are still negative after 5 to 7 years. Female sex was at-risk factor odds ratio 5.7 (95% CI 1.5-20.9), whereas breast-feeding during gluten introduction had a protective effect odds ratio 0.1 (95% CI 0.01-0.8). CONCLUSIONS: Prevalence of CD in this cohort was 4%, half of whom had digestive symptoms. Because a high proportion of children showed a spontaneous disappearance of antibodies, prevalence studies of CD in young children should be based on intestinal damage so as not to overestimate results. PMID- 26485607 TI - Eosinophilic Gastrointestinal Disorders Affect More Than Just the Esophagus. PMID- 26485608 TI - Transformation of the Paradigm in Intestinal Failure: Future Prognostication and Quality of Life, Not Just Survival. PMID- 26485609 TI - Visualizing the Tumor Microvasculature With a Nonlinear Plane-Wave Doppler Imaging Scheme Based on Amplitude Modulation. AB - Imaging with ultrasonic plane waves enables the combination of Doppler and microbubble contrast-enhanced imaging without compromising the Doppler ensemble length, as is the case for conventional line-by-line imaging, thus maintaining flow sensitivity. This permits the separation of conduit flow in large vessels from the perfusion background and the presentation of velocity estimates in real time. However, the ability to differentiate perfusion from the tissue signal is limited by the contrast-to-tissue (CTR) ratio achieved with the contrast-enhanced pulsing sequence, independently of the acquisition length. One way to improve the CTR is to use a Doppler sequence based on amplitude modulation instead of one based on pulse inversion. In this work, we discuss how amplitude modulation can be adapted to Doppler processing. We show that amplitude modulation Doppler, like pulse inversion Doppler, can separate the signal of moving tissue from that of moving microbubbles, while achieving a better contrast-to-tissue ratio than pulse inversion Doppler, both in vitro and in vivo. Both amplitude modulation Doppler and pulse inversion Doppler yield similar velocity estimates when the bandwidth of the RF echo is properly compensated. Finally, we demonstrate how amplitude modulation Doppler can be used to reveal both the conduit flow and the capillary perfusion at high frame rates in an in vivo tumor. PMID- 26485610 TI - Letter to the editor: anti-TNF therapy and radiation exposure in Crohn's disease: chicken or egg? PMID- 26485612 TI - Consensus-Based Palliative Care Competencies for Undergraduate Nurses and Physicians: A Demonstrative Process with Colombian Universities. AB - BACKGROUND: A World Health Assembly (WHA) resolution adopted in 2014 strongly encourages member states to integrate palliative care (PC) in undergraduate training for health professionals. OBJECTIVE: The study objective was to describe a consensus-based process workshop to develop PC competences for medical and nursing schools in Colombia and to present a summary of the findings. METHODS: The workshop included 36 participants representing 16 medical and 6 nursing schools from 18 universities in Colombia. Participants were distributed in four thematic groups. Using the International Association for Hospice and Palliative Care (IAHPC) List of Essential Practices (LEP) as guidance, they were asked to discuss and define PC competencies at the undergraduate level. Participants provided feedback and approved each recommendation, and then were asked to complete an evaluation. RESULTS: The resulting competences were separated into six categories: (1) Definition and Principles of PC, (2) Identification and Control of Symptoms, (3) End-of-Life Care, (4) Ethical and Legal Issues, (5) Psychosocial and Spiritual Issues, and (6) Teamwork. A comparative analysis revealed that treatment of several symptoms in the IAHPC LEP (pain, dyspnea, constipation, nausea, vomit, diarrhea, delirium, and insomnia) were included in the competencies. All of the IAHPC LEP related to psychological/emotional/spiritual care was included. The evaluation rate of return was 80%. The assessment was very positive: total score of 4.7/5.0; SD = 0.426), with 89% considering the workshop to be helpful. CONCLUSION: The workshop provided an opportunity for individuals from different disciplines to discuss competencies and achieve consensus. The resulting competencies will be helpful in the development of PC curricula for physicians and nurses throughout schools in Colombia and other countries. PMID- 26485611 TI - A refined genome-scale reconstruction of Chlamydomonas metabolism provides a platform for systems-level analyses. AB - Microalgae have reemerged as organisms of prime biotechnological interest due to their ability to synthesize a suite of valuable chemicals. To harness the capabilities of these organisms, we need a comprehensive systems-level understanding of their metabolism, which can be fundamentally achieved through large-scale mechanistic models of metabolism. In this study, we present a revised and significantly improved genome-scale metabolic model for the widely-studied microalga, Chlamydomonas reinhardtii. The model, iCre1355, represents a major advance over previous models, both in content and predictive power. iCre1355 encompasses a broad range of metabolic functions encoded across the nuclear, chloroplast and mitochondrial genomes accounting for 1355 genes (1460 transcripts), 2394 and 1133 metabolites. We found improved performance over the previous metabolic model based on comparisons of predictive accuracy across 306 phenotypes (from 81 mutants), lipid yield analysis and growth rates derived from chemostat-grown cells (under three conditions). Measurement of macronutrient uptake revealed carbon and phosphate to be good predictors of growth rate, while nitrogen consumption appeared to be in excess. We analyzed high-resolution time series transcriptomics data using iCre1355 to uncover dynamic pathway-level changes that occur in response to nitrogen starvation and changes in light intensity. This approach enabled accurate prediction of growth rates, the cessation of growth and accumulation of triacylglycerols during nitrogen starvation, and the temporal response of different growth-associated pathways to increased light intensity. Thus, iCre1355 represents an experimentally validated genome-scale reconstruction of C. reinhardtii metabolism that should serve as a useful resource for studying the metabolic processes of this and related microalgae. PMID- 26485613 TI - Estrogen Therapy Delays Autoimmune Diabetes and Promotes the Protective Efficiency of Natural Killer T-Cell Activation in Female Nonobese Diabetic Mice. AB - Therapeutic strategies focused on restoring immune tolerance remain the main avenue to prevent type 1 diabetes (T1D). Because estrogens potentiate FoxP3+ regulatory T cells (Treg) and invariant natural killer T (iNKT) cells, two regulatory lymphocyte populations that are functionally deficient in nonobese diabetic (NOD) mice, we investigated whether estradiol (E2) therapy influences the course of T1D in this model. To this end, female NOD mice were sc implanted with E2- or placebo-delivering pellets to explore the course of spontaneous and cyclophosphamide-induced diabetes. Treg-depleted and iNKT-cell-deficient (Jalpha18(-/-)) NOD mice were used to assess the respective involvement of these lymphocyte populations in E2 effects. Early E2 administration (from 4 wk of age) was found to preserve NOD mice from both spontaneous and cyclophosphamide-induced diabetes, and a complete protection was also observed throughout treatment when E2 treatment was initiated after the onset of insulitis (from 12 wk of age). This delayed E2 treatment remained fully effective in Treg-depleted mice but failed to entirely protect Jalpha18(-/-) mice. Accordingly, E2 administration was shown to restore the cytokine production of iNKT cells in response to in vivo challenge with the cognate ligand alpha-galactosylceramide. Finally, transient E2 administration potentiated the previously described protective action of alpha galactosylceramide treatment in NOD females. This study provides original evidence that E2 therapy strongly protects NOD mice from T1D and reveals the estrogen/iNKT cell axis as a new effective target to counteract diabetes onset at the stage of insulitis. Estrogen-based therapy should thus be considered for T1D prevention. PMID- 26485615 TI - The detection of simulated periapical lesions in human dry mandibles with cone beam computed tomography: a dose reduction study. AB - AIM: To assess in an ex vivo model the accuracy of detection of simulated periapical lesions using two cone-beam computed tomography (CBCT) dose modes and periapical radiography. METHODOLOGY: Small and large artificial periapical lesions were created with burs at the base of the socket of eleven mandibular molars, in seven human dry mandibles. Digital periapical radiographs, 360 degrees and 180 degrees rotations CBCT scans with standard dose and dose reduction (DR) modes were obtained before and after periapical lesions were prepared. Six blinded examiners scored the presence/absence of lesions. Inter- and intra examiner reliability were determined. Sensitivity, specificity, positive predictive values and negative predictive values and receiver operating characteristic (ROC) area under the curve (overall accuracy) were determined for each modality. RESULTS: The mean sensitivity and specificity of both CBCT rotations with dose reduction mode were higher compared to that of standard dose CBCT scans. The ROC Az mean values for periapical radiographs, 360 degrees scan with standard dose and dose reduction and 180 degrees scans with standard dose and dose reduction were 0.62, 0.94, 0.95, 0.95 and 0.97, respectively. No significant difference in the diagnostic accuracy of CBCT scans taken with standard and dose reduction modes, whilst their accuracy was significantly higher than periapical radiographs. CONCLUSIONS: Using dose reduction with 360 degrees and 180 degrees CBCT scans demonstrated good diagnostic accuracy in the detection of simulated periapical lesions whilst reducing the radiation dose by 54% and 51%, respectively, compared to conventional settings. Clinical evaluation is now needed to determine whether this is applicable to patients. PMID- 26485614 TI - The PGE2 EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice. AB - Mice carrying a targeted disruption of the prostaglandin E2 (PGE2) E-prostanoid receptor 3 (EP3) gene, Ptger3, were fed a high-fat diet (HFD), or a micronutrient matched control diet, to investigate the effects of disrupted PGE2-EP3 signaling on diabetes in a setting of diet-induced obesity. Although no differences in body weight were seen in mice fed the control diet, when fed a HFD, EP3(-/-) mice gained more weight relative to EP3(+/+) mice. Overall, EP3(-/-) mice had increased epididymal fat mass and adipocyte size; paradoxically, a relative decrease in both epididymal fat pad mass and adipocyte size was observed in the heaviest EP3(-/-) mice. The EP3(-/-) mice had increased macrophage infiltration, TNF-alpha, monocyte chemoattractant protein-1, IL-6 expression, and necrosis in their epididymal fat pads as compared with EP3(+/+) animals. Adipocytes isolated from EP3(+/+) or EP3(-/-) mice were assayed for the effect of PGE2-evoked inhibition of lipolysis. Adipocytes isolated from EP3(-/-) mice lacked PGE2 evoked inhibition of isoproterenol stimulated lipolysis compared with EP3(+/+). EP3(-/-) mice fed HFD had exaggerated ectopic lipid accumulation in skeletal muscle and liver, with evidence of hepatic steatosis. Both blood glucose and plasma insulin levels were similar between genotypes on a control diet, but when fed HFD, EP3(-/-) mice became hyperglycemic and hyperinsulinemic when compared with EP3(+/+) fed HFD, demonstrating a more severe insulin resistance phenotype in EP3(-/-). These results demonstrate that when fed a HFD, EP3(-/-) mice have abnormal lipid distribution, developing excessive ectopic lipid accumulation and associated insulin resistance. PMID- 26485618 TI - An advanced image processing method to improve the spatial resolution of ion radiographies. AB - We present an optimization method to improve the spatial resolution and the water equivalent thickness (WET) accuracy of ion radiographies. The method is designed for imaging systems measuring for each actively scanned beam spot the lateral position of the pencil beam and at the same time the Bragg curve (behind the target) in discrete steps without relying on tracker detectors to determine the ion trajectory before and after the irradiated volume. Specifically, the method was used for an imaging set-up consisting of a stack of 61 parallel-plate ionization chambers (PPIC) interleaved with absorber plates of polymethyl methacrylate (PMMA) working as a range telescope. The method uses not only the Bragg peak position, but approximates the entire measured Bragg curve as a superposition of differently shifted Bragg curves. Their relative weights allow to reconstruct the distribution of thickness around each scan spot of a heterogeneous phantom. The approach also allows merging the ion radiography with the geometric information of a co-registered x-ray radiography in order to increase its spatial resolution. The method was tested using Monte Carlo simulated and experimental proton radiographies of a PMMA step phantom and an anthropomorphic head phantom. For the step phantom, the effective spatial resolution was found to be 6 and 4 times higher than the nominal resolution for the simulated and experimental radiographies, respectively. For the head phantom, a gamma index was calculated to quantify the conformity of the simulated proton radiographies with a digitally reconstructed radiography (DRR) obtained from an x ray CT and properly converted into WET. For a distance-to-agreement (DTA) of 2.5 mm and a relative WET difference (RWET) of 2.5%, the passing ratio was 100%/85% for the optimized/non-optimized case, respectively. When the optimized proton radiography was merged with the co-registered DRR, the passing ratio was 100% at DTA = 1.3 mm and RWET = 1.3%. A special interpolation method allows to strongly reduce the dose by using a coarser grid of the measured beam spot position with a 5 times larger grid distance. We show that despite a dose reduction of 25 times (leading to a dose of 0.016 mGy for the current imaging set up), the image quality of the optimized radiographies remains fairly unaffected for both the simulated and experimental case. PMID- 26485616 TI - Intersectional Gene Expression in Zebrafish Using the Split KalTA4 System. AB - In this study, we describe the adaptation of the split Gal4 system for zebrafish. The Gal4-UAS system is widely used for expression of genes-of-interest by crossing driver lines expressing the transcription factor Gal4 (under the control of the promoter of interest) with reporter lines where upstream activating sequence (UAS) repeats (recognized by Gal4) drive expression of the genes-of interest. In the Split Gal4 system, hemi-drivers separately encode the DNA binding domain (DBD) and the activation domain (AD) of Gal4. When encoded under two different promoters, only those cells in the intersection of the promoters' expression pattern and in which both promoters are active reconstitute a functional Gal4 and activate expression from a UAS-driven transgene. We split the zebrafish-optimized version of Gal4, KalTA4, and generated a hemi-driver encoding the KalTA4 DBD and a hemi-driver encoding KalTA4's AD. We show that split KalTA4 domains can assemble in vivo and transactivate a UAS reporter transgene and that each hemi-driver alone cannot transactivate the reporter. Also, transactivation can happen in several cell types, with similar efficiency to intact KalTA4. Finally, in transient mosaic expression assays, we show that when hemi-drivers are preceded by two distinct promoters, they restrict the expression of an UAS driven reporter from a broader pattern (sox10) to its constituent smaller neuronal pattern. The Split KalTA4 system should be useful for expression of genes-of-interest in an intersectional manner, allowing for more refined manipulations of cell populations in zebrafish. PMID- 26485617 TI - Adverse Left Ventricular Remodeling and Age Assessed with Cardiac MR Imaging: The Multi-Ethnic Study of Atherosclerosis. AB - PURPOSE: To evaluate age-related left ventricular (LV) remodeling during longitudinal observation of a large cohort of asymptomatic individuals who were free of clinical cardiovascular disease at baseline. MATERIALS AND METHODS: The applicable institutional review boards approved this study, and all participants gave informed consent. Cardiac magnetic resonance (MR) imaging was used to identify longitudinal changes in LV structure and function in 2935 participants who underwent baseline and follow-up cardiac MR imaging in the Multi-Ethnic Study of Atherosclerosis. Participants were free of clinical cardiovascular disease at baseline. Participants who experienced an incident coronary heart disease event were excluded. Data were analyzed with multivariable mixed-effects regression models in which the outcome was cardiac MR imaging measurement, and the covariates included follow-up time and cardiac risk factors. RESULTS: Participants were aged 54-94 years at follow-up, and 53% of the participants were women. Median time between baseline and follow-up cardiac MR imaging was 9.4 years. Over this period, LV mass increased in men and decreased slightly in women (8.0 and -1.6 g per decade, respectively; P < .001). In both men and women, LV end-diastolic volume decreased (-9.8 and -13.3 mL per decade, respectively; P < .001), stroke volume decreased (-8.8 and -8.6 mL per decade, respectively; P < .001), and mass-to-volume ratio increased (0.14 and 0.11 g/mL per decade, respectively; P < .001). Change in LV mass was positively associated with systolic blood pressure and body mass index and negatively associated with treated hypertension and high-density lipoprotein cholesterol level. In men, the longitudinal LV mass increase was in contrast to a cross-sectional pattern of LV mass decrease. CONCLUSION: As patients age, the LV responds differently in its mass and volume between men and women, although both men and women experience increased concentric LV remodeling with age. In men, the opposition of longitudinal and cross-sectional changes in LV mass highlights the importance of longitudinal study. PMID- 26485619 TI - Kikuchi-Fujimoto disease: pediatric case report. AB - The Kikuchi-Fujimoto disease is a rare disease that occurs mostly in young adults, although some cases have been reported in children. It is usually characterized by fever and cervical lymphadenopathy. The etiology of the disease remains unknown. Its course is usually benign and self-limited. It has special histopathological features that allow the differential diagnosis with other entities, which from a clinical point of view can be very complicated. We report a 9 years 11 months old girl with lymphadenopathy and fever with five months evolution, which is the longest evolution among the cases reviewed by the authors in world literature. Given that the presentation of this disease in children is very rare, we estimate that the knowledge of this disease is relevant and pediatricians must consider it in the differential diagnosis of fever of unknown origin in children. PMID- 26485620 TI - Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High Risk Profiling. AB - RATIONALE: As of April 2015, participants in the Danish Lung Cancer Screening Trial had been followed for at least 5 years since their last screening. OBJECTIVES: Mortality, causes of death, and lung cancer findings are reported to explore the effect of computed tomography (CT) screening. METHODS: A total of 4,104 participants aged 50-70 years at the time of inclusion and with a minimum 20 pack-years of smoking were randomized to have five annual low-dose CT scans (study group) or no screening (control group). MEASUREMENTS AND MAIN RESULTS: Follow-up information regarding date and cause of death, lung cancer diagnosis, cancer stage, and histology was obtained from national registries. No differences between the two groups in lung cancer mortality (hazard ratio, 1.03; 95% confidence interval, 0.66-1.6; P = 0.888) or all-cause mortality (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27; P = 0.867) were observed. More cancers were found in the screening group than in the no-screening group (100 vs. 53, respectively; P < 0.001), particularly adenocarcinomas (58 vs. 18, respectively; P < 0.001). More early-stage cancers (stages I and II, 54 vs. 10, respectively; P < 0.001) and stage IIIa cancers (15 vs. 3, respectively; P = 0.009) were found in the screening group than in the control group. Stage IV cancers were nonsignificantly more frequent in the control group than in the screening group (32 vs. 23, respectively; P = 0.278). For the highest-stage cancers (T4N3M1, 21 vs. 8, respectively; P = 0.025), this difference was statistically significant, indicating an absolute stage shift. Older participants, those with chronic obstructive pulmonary disease, and those with more than 35 pack-years of smoking had a significantly increased risk of death due to lung cancer, with nonsignificantly fewer deaths in the screening group. CONCLUSIONS: No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial. Clinical trial registered with www.clinicaltrials.gov (NCT00496977). PMID- 26485621 TI - A case of insulin allergy successfully managed using multihexamer-forming insulin degludec combined with liraglutide. AB - BACKGROUND: Insulin allergy, one of insulin's adverse effects, is rare, especially in patients with Type 2 diabetes, but management is difficult and no effective strategy has yet been established. We experienced an insulin allergy case successfully managed with a novel combination of insulins. CASE REPORT: A 38 year-old woman started insulin therapy when diabetes was diagnosed at age 19 years. Despite poorly controlled diabetes because of poor adherence, she hoped to conceive a child and continuous subcutaneous insulin infusion was introduced using insulin aspart at age 32 years. One month thereafter, she developed skin reactions at the subcutaneous insulin infusion catheter insertion site. The patient was then tested for all rapid-acting insulin formulations, all of which triggered local reactions. She decided to continue the continuous subcutaneous infusion of human regular insulin, accompanied by oral cetirizine hydrochloride and betamethasone valerate ointment. The patient was admitted to our hospital at age 38 years with high HbA1c levels. She was tested for all long-acting insulin analogues. All results, except for insulin degludec, were positive. She discontinued continuous subcutaneous insulin infusion and switched to insulin degludec combined with liraglutide. The allergic reactions had completely disappeared and her blood glucose was well controlled by the time of discharge. CONCLUSION: Our patient was allergic to all insulin formulations except insulin degludec. Her allergic reactions completely disappeared after switching to insulin degludec. The crystallized structure of this insulin might mask its skin allergen antigenicity. Furthermore, her postprandial hyperglycaemia was successfully controlled with liraglutide. We propose multihexamer-forming ultra long-acting insulin plus glucagon-like peptide-1 analogues as a therapeutic option for patients with insulin allergy. PMID- 26485623 TI - Licorice-flavored Morphine for Babies: Winchell's Teething Syrup. PMID- 26485624 TI - "Fac-Simile" Confederate $10 Bill Advertising Odontunder by Dr. A. B. Cobb. PMID- 26485622 TI - Is adjuvant chemotherapy indicated in ovarian immature teratomas? A combined data analysis from the Malignant Germ Cell Tumor International Collaborative. AB - BACKGROUND: There is a debate regarding the management of ovarian immature teratomas (ITs). In adult women, postoperative chemotherapy is standard except for stage I, grade 1 disease, whereas surgery alone is standard in pediatric patients. To determine the role of chemotherapy, a pooled analysis of pediatric and adult clinical trials was conducted. METHODS: Data from 7 pediatric trials and 2 adult trials were merged in the Malignant Germ Cell International Collaborative data set. Four trials included patients with newly diagnosed pure ovarian ITs and were selected (Pediatric Oncology Group/Children's Cancer Group Intergroup Study (INT 0106), Second UKCCSG Germ Cell Tumor Study (GC2), Gynecologic Oncology Group (GOG 0078 and GOG 0090). Adult and pediatric trials were analyzed separately. The primary outcome measures were event-free survival (EFS) and overall survival (OS). RESULTS: One hundred seventy-nine patients were included (98 pediatric patients and 81 adult patients). Ninety pediatric patients were treated with surgery alone, whereas all adult patients received chemotherapy. The 5-year EFS and OS were 91% and 99%, respectively, for the pediatric cohort and 87% and 93%, respectively, for the adults. There were no relapses in grade 1 patients, regardless of the stage or age. Only 1 adult patient with a grade 2 IT relapsed. Among grade 3 patients, the 5-year EFS was 0.92 (0.72-0.98) for stage I/II and 0.52 (0.22-0.75) for stage III in the pediatric cohort (P = .005) and 0.91 (0.69-0.98) for stage I/II and 0.65 (0.39 0.83) for stage III/IV in the adult cohort (P = .01). Postoperative chemotherapy did not decrease relapses in the pediatric cohort. CONCLUSIONS: The grade was the most important risk factor for relapse in ovarian ITs. Among grade 3 patients, the stage was significantly associated with relapse. Adjuvant chemotherapy did not decrease relapses in the pediatric cohort; its role in adults remains unresolved. Cancer 2016;122:230-237. (c) 2015 American Cancer Society. PMID- 26485625 TI - Signed Simpson Stereoscopic Photoportrait, Blind-stamped Lennie. PMID- 26485626 TI - Bleeding Risk in Surgical Patients Receiving Sugammadex: Definitive Conclusions Are Not Yet Possible. PMID- 26485627 TI - In Reply. PMID- 26485628 TI - Incidence of Intraoperative Hypersensitivity Reactions: What's This About? PMID- 26485629 TI - In Reply. PMID- 26485635 TI - A Changing Anesthesiology Workforce: East and West, Males and Females, Then and Now. PMID- 26485636 TI - Erratum for: Lavandula angustifolia and Lavandula latifolia Essential Oils from Spain: Aromatic Profile and Bioactivities. PMID- 26485637 TI - Erratum for: Supercritical Fluid Chromatography as an Alternative Tool for the Qualitative and Quantitative Analysis of Metarhizium brunneum Metabolites from Culture Broth. PMID- 26485638 TI - Essential Oil from Myrica rubra Leaves Potentiated Antiproliferative and Prooxidative Effect of Doxorubicin and its Accumulation in Intestinal Cancer Cells. AB - Essential oil from the leaves of Myrica rubra, a subtropical Asian fruit tree traditionally used in folk medicines, has a significant antiproliferative effect in several intestinal cancer cell lines. Doxorubicin belongs to the most important cytostatics used in cancer therapy. The present study was designed to evaluate the effects of defined essential oil from M. rubra leaves on efficacy, prooxidative effect, and accumulation of doxorubicin in cancer cell lines and in non-cancerous cells. For this purpose, intestinal adenocarcinoma CaCo2 cells were used. Human fibroblasts (periodontal ligament) and a primary culture of rat hepatocytes served as models of non-cancerous cells. The results showed that the sole essential oil from M. rubra has a strong prooxidative effect in cancer cells while it acts as a mild antioxidant in hepatocytes. Combined with doxorubicin, the essential oil enhanced the antiproliferative and prooxidative effects of doxorubicin in cancer cells. At higher concentrations, synergism of doxorubicin and essential oil from M. rubra was proved. In non-cancerous cells, the essential oil did not affect the toxicity of doxorubicin and the doxorubicin-mediated reactive oxygen species formation. The essential oil increased the intracellular concentration of doxorubicin and enhanced selectively the doxorubicin accumulation in nuclei of cancer cells. Taken together, essential oil from M. rubra leaves could be able to improve the doxorubicin efficacy in cancer cells due to an increased reactive oxygen species production, and the doxorubicin accumulation in nuclei of cancer cells. PMID- 26485639 TI - Comparison of Ensemble Strategies in Online NIR for Monitoring the Extraction Process of Pericarpium Citri Reticulatae Based on Different Variable Selections. AB - Different ensemble strategies were compared in online near-infrared models for monitoring active pharmaceutical ingredients of Traditional Chinese Medicine. Bagging partial least square regression and boosting partial least square regression were adopted to near-infrared models, to determine hesperidin and nobiletin content during the extraction process of Pericarpium Citri Reticulatae in a pilot scale system. Different pretreatment methods were investigated, including Savitzky-Golay smoothing, derivatives, multiplicative scatter correction, standard normal variate, normalize, and combinations of them. Two different variable selection methods, including synergy interval partial least squares and backward interval partial least squares algorithms, were performed. Based on the result of the synergy interval partial least squares algorithm, bagging partial least square regression and boosting partial least square regression were adopted into the quantitative analysis. The results demonstrated that the established approach could be applied for rapid determination and real time monitoring of hesperidin and nobiletin in Pericarpium Citri Reticulatae (Citrus reticulata) during the extraction process. Comparing the results, the boosting partial least square regression provided a slightly better accuracy than the bagging partial least square regression. Finally, this paper provides a promising ensemble strategy on online near-infrared models in Chinese medicine. PMID- 26485640 TI - MicroRNA library screening identifies growth-suppressive microRNAs that regulate genes involved in cell cycle progression and apoptosis. AB - Micro(mi)RNAs play important and varied roles in tumorigenesis; however, the full repertoire of miRNAs that affect cancer cell growth is not known. In this study, an miRNA library was screened to identify those that affect the growth of A549 tumor cells. Among 300 miRNAs, miR-28-5p, -323-5p, -510-5p, -552-3p, and -608 were the most effective in inhibiting cell growth. More specifically, overexpressing miR-28-5p, -323-5p, and -510-5p induced G1 arrest, as determined by flow cytometry, whereas that of miR-608 induced cell death in a caspase dependent manner. Moreover, several genes involved in apoptosis and cell cycle progression were downregulated upon overexpression of each of the five miRNAs, with the functional targets of miR-552-3p and miR-608 confirmed by microarray, quantitative real-time PCR, and luciferase reporter assay. In miR-608-transfected cells, B cell lymphoma 2-like 1 (BCL2L1), D-type cyclin 1 (CCND1), CCND3, cytochrome b5 reductase 3 (CYB5R3), phosphoinositide 3-kinase regulatory subunit 2 (PIK3R2), specificity protein 1 (SP1), and phosphorylated Akt were all downregulated, while Bcl-2-interacting killer (BIK) was upregulated. Moreover, miR-608 was determined to have a suppressive function on tumor growth in an NCI H460 xenograft model. These findings provide insights into the roles of five miRNAs in growth inhibition and their potential function as cancer therapeutics. PMID- 26485641 TI - Bjorn J. Obrink (1943-2015). AB - Family members, friends and colleagues of Prof. Dr. Dr. h.c. Bjorn Obrink were deeply saddened to learn of his sudden death on August 21, 2015. Bjorn was one of the pioneers in cell adhesion research. Reading an article written by Bjorn, one quickly recognizes his outstanding qualities as a scientist: knowledgeable, innovative, precise and detailed in order to enable reproduction of his reported results. When meeting Bjorn, you were captured by his personality: warm-hearted, modest, and, above all, devoted to truth. PMID- 26485642 TI - Characterization of Leukocyte-platelet Rich Fibrin, A Novel Biomaterial. AB - Autologous platelet concentrates represent promising innovative tools in the field of regenerative medicine and have been extensively used in oral surgery. Unlike platelet rich plasma (PRP) that is a gel or a suspension, Leukocyte Platelet Rich Fibrin (L-PRF) is a solid 3D fibrin membrane generated chair-side from whole blood containing no anti-coagulant. The membrane has a dense three dimensional fibrin matrix with enriched platelets and abundant growth factors. L PRF is a popular adjunct in surgeries because of its superior handling characteristics as well as its suturability to the wound bed. The goal of the study is to demonstrate generation as well as provide detailed characterization of relevant properties of L-PRF that underlie its clinical success. PMID- 26485643 TI - Amino Catalytic Oxidative Thioesterification Approach to alpha-Ketothioesters. AB - An efficient metal-free method for the synthesis of alpha-ketothioesters is described for the first time. This reaction features the ability of pyrrolidine to fine-tune the reaction between 2-oxoaldehyde and thiols through iminium to the desired product in moderate to good yields. As an advantage, no external oxidants or metal catalysts are required in our method. Reactions performed under modified conditions lead to an apparent balance in reactivity of secondary amine and thiols toward 2-oxoaldehydes. PMID- 26485644 TI - Endoscopic-Assisted Surgery for Pyriform Sinus Fistula in Chinese Children: A 73 Consecutive-Case Study. AB - OBJECTIVE: Complete resection of the pyriform sinus fistula (PSF) tract is challenging due to repeated infection and inadequate procedures. We present our experiences with intraoperative endoscopic-assisted intubation or instillation of dye through the internal opening as a guide to identify the tract. MATERIALS AND METHODS: We retrospectively reviewed the charts of 73 consecutive patients diagnosed with PSF during 1999 until 2014 from two tertiary referral centers. Demographics, clinical presentation, imaging, treatment, and outcome were analyzed. RESULTS: The intraoperative endoscopy was successfully conducted in all 73 cases. No gender predominance was observed. Of the anomalies, 94.5% were left sided. Presenting symptoms consisted of neck abscess (n = 48), acute suppurative thyroiditis/thyroid abscess (n = 9), neck mass with or without dyspnea (n = 12), and thyroid nodule (n = 4). Barium esophagography and computed tomography scan with oral or intravenous contrast had a satisfactory positive predictive value. Partial thyroidectomy was performed on 25 cases (34.2%) if the ipsilateral thyroid was involved. Good outcome was achieved in all but 3 patients (70/73, 95.9%) during a median follow-up of 4 years (range, 8 months-14 years). Two patients developed postoperative complications: temporary vocal fold motion impairment and left-sided Horner's syndrome, respectively. PSF recurred in 1 case. CONCLUSIONS: A complete resection is essential for good outcomes. Intraoperative intubation or methylene blue injection by endoscopy can simplify the identification of the fistula tract during surgical exploration. PMID- 26485646 TI - A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection. AB - Tuberculosis (TB) still holds a major threat to the health of people worldwide, and there is a need for cost-efficient but reliable models to help us understand the disease mechanisms and advance the discoveries of new treatment options. In vitro cell cultures of monolayers or co-cultures lack the three-dimensional (3D) environment and tissue responses. Herein, we describe an innovative in vitro model of a human lung tissue, which holds promise to be an effective tool for studying the complex events that occur during infection with Mycobacterium tuberculosis (M. tuberculosis). The 3D tissue model consists of tissue-specific epithelial cells and fibroblasts, which are cultured in a matrix of collagen on top of a porous membrane. Upon air exposure, the epithelial cells stratify and secrete mucus at the apical side. By introducing human primary macrophages infected with M. tuberculosis to the tissue model, we have shown that immune cells migrate into the infected-tissue and form early stages of TB granuloma. These structures recapitulate the distinct feature of human TB, the granuloma, which is fundamentally different or not commonly observed in widely used experimental animal models. This organotypic culture method enables the 3D visualization and robust quantitative analysis that provides pivotal information on spatial and temporal features of host cell-pathogen interactions. Taken together, the lung tissue model provides a physiologically relevant tissue micro environment for studies on TB. Thus, the lung tissue model has potential implications for both basic mechanistic and applied studies. Importantly, the model allows addition or manipulation of individual cell types, which thereby widens its use for modelling a variety of infectious diseases that affect the lungs. PMID- 26485645 TI - The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3 Regulated Vesicle Trafficking. AB - Ciliopathies are a group of human disorders caused by dysfunction of primary cilia, ubiquitous microtubule-based organelles involved in transduction of extra cellular signals to the cell. This function requires the concentration of receptors and channels in the ciliary membrane, which is achieved by complex trafficking mechanisms, in part controlled by the small GTPase RAB8, and by sorting at the transition zone located at the entrance of the ciliary compartment. Mutations in the transition zone gene CC2D2A cause the related Joubert and Meckel syndromes, two typical ciliopathies characterized by central nervous system malformations, and result in loss of ciliary localization of multiple proteins in various models. The precise mechanisms by which CC2D2A and other transition zone proteins control protein entrance into the cilium and how they are linked to vesicular trafficking of incoming cargo remain largely unknown. In this work, we identify the centrosomal protein NINL as a physical interaction partner of CC2D2A. NINL partially co-localizes with CC2D2A at the base of cilia and ninl knockdown in zebrafish leads to photoreceptor outer segment loss, mislocalization of opsins and vesicle accumulation, similar to cc2d2a-/- phenotypes. Moreover, partial ninl knockdown in cc2d2a-/- embryos enhances the retinal phenotype of the mutants, indicating a genetic interaction in vivo, for which an illustration is found in patients from a Joubert Syndrome cohort. Similar to zebrafish cc2d2a mutants, ninl morphants display altered Rab8a localization. Further exploration of the NINL-associated interactome identifies MICAL3, a protein known to interact with Rab8 and to play an important role in vesicle docking and fusion. Together, these data support a model where CC2D2A associates with NINL to provide a docking point for cilia-directed cargo vesicles, suggesting a mechanism by which transition zone proteins can control the protein content of the ciliary compartment. PMID- 26485647 TI - Cellular Senescence and the Biology of Aging, Disease, and Frailty. AB - Population aging simultaneously highlights the remarkable advances in science, medicine, and public policy, and the formidable challenges facing society. Indeed, aging is the primary risk factor for many of the most common chronic diseases and frailty, which result in profound social and economic costs. Population aging also reveals an opportunity, i.e. interventions to disrupt the fundamental biology of aging could significantly delay the onset of age-related conditions as a group, and, as a result, extend the healthy life span, or health span. There is now considerable evidence that cellular senescence is an underlying mechanism of aging and age-related conditions. Cellular senescence is a process in which cells lose the ability to divide and damage neighboring cells by the factors they secrete, collectively referred to as the senescence associated secretory phenotype (SASP). Herein, we discuss the concept of cellular senescence, review the evidence that implicates cellular senescence and SASP in age-related deterioration, hyperproliferation, and inflammation, and propose that this underlying mechanism of aging may play a fundamental role in the biology of frailty. PMID- 26485648 TI - Carcinogenic Parasite Secretes Growth Factor That Accelerates Wound Healing and Potentially Promotes Neoplasia. AB - Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). Injury from feeding activities of this parasite within the human biliary tree causes extensive lesions, wounds that undergo protracted cycles of healing, and re-injury over years of chronic infection. We show that O. viverrini secreted proteins accelerated wound resolution in human cholangiocytes, an outcome that was compromised following silencing of expression of the fluke-derived gene encoding the granulin-like growth factor, Ov-GRN-1. Recombinant Ov-GRN-1 induced angiogenesis and accelerated mouse wound healing. Ov-GRN-1 was internalized by human cholangiocytes and induced gene and protein expression changes associated with wound healing and cancer pathways. Given the notable but seemingly paradoxical properties of liver fluke granulin in promoting not only wound healing but also a carcinogenic microenvironment, Ov-GRN-1 likely holds marked potential as a therapeutic wound-healing agent and as a vaccine against an infection-induced cancer of major public health significance in the developing world. PMID- 26485649 TI - Structural and Functional Characterization of the Enantiomers of the Antischistosomal Drug Oxamniquine. AB - BACKGROUND: For over two decades, a racemic mixture of oxamniquine (OXA) was administered to patients infected by Schistosoma mansoni, but whether one or both enantiomers exert antischistosomal activity was unknown. Recently, a ~30 kDa S. mansoni sulfotransferase (SmSULT) was identified as the target of OXA action. METHODOLOGY/PRINCIPAL FINDINGS: Here, we separate the OXA enantiomers using chromatographic methods and assign their optical activities as dextrorotary [(+) OXA] or levorotary [(-)-OXA]. Crystal structures of the parasite enzyme in complex with optically pure (+)-OXA and (-)-OXA) reveal their absolute configurations as S- and R-, respectively. When tested in vitro, S-OXA demonstrated the bulk of schistosomicidal activity, while R-OXA had antischistosomal effects when present at relatively high concentrations. Crystal structures R-OXA*SmSULT and S-OXA*SmSULT complexes reveal similarities in the modes of OXA binding, but only the S-OXA enantiomer is observed in the structure of the enzyme exposed to racemic OXA. CONCLUSIONS/SIGNIFICANCE: Together the data suggest the higher schistosomicidal activity of S-OXA is correlated with its ability to outcompete R-OXA binding the sulfotransferase active site. These findings have important implications for the design, syntheses, and dosing of new OXA-based antischistosomal compounds. PMID- 26485652 TI - Correction: Amelioration of Chemotherapy-Induced Intestinal Mucositis by Orally Administered Probiotics in a Mouse Model. PMID- 26485650 TI - Long-Term Effects of Botulinum Toxin Complex Type A Injection on Mechano- and Metabo-Sensitive Afferent Fibers Originating from Gastrocnemius Muscle. AB - The aim of the present study was to investigate long term effects of motor denervation by botulinum toxin complex type A (BoNT/A) from Clostridium Botulinum, on the afferent fibers originating from the gastrocnemius muscle of rats. Animals were divided in 2 experimental groups: 1) untreated animals acting as control and 2) treated animals in which the toxin was injected in the left muscle, the latter being itself divided into 3 subgroups according to their locomotor recovery with the help of a test based on footprint measurements of walking rats: i) no recovery (B0), ii) 50% recovery (B50) and iii) full recovery (B100). Then, muscle properties, metabosensitive afferent fiber responses to potassium chloride (KCl) and lactic acid injections and Electrically-Induced Fatigue (EIF), and mechanosensitive responses to tendon vibrations were measured. At the end of the experiment, rats were killed and the toxin injected muscles were weighted. After toxin injection, we observed a complete paralysis associated to a loss of force to muscle stimulation and a significant muscle atrophy, and a return to baseline when the animals recover. The response to fatigue was only decreased in the B0 group. The responses to KCl injections were only altered in the B100 groups while responses to lactic acid were altered in the 3 injected groups. Finally, our results indicated that neurotoxin altered the biphasic pattern of response of the mechanosensitive fiber to tendon vibrations in the B0 and B50 groups. These results indicated that neurotoxin injection induces muscle afferent activity alterations that persist and even worsen when the muscle has recovered his motor activity. PMID- 26485651 TI - Pulse Oximetry: A Non-Invasive, Novel Marker for the Quality of Chest Compressions in Porcine Models of Cardiac Arrest. AB - OBJECTIVE: Pulse oximetry, which noninvasively detects the blood flow of peripheral tissue, has achieved widespread clinical use. We have noticed that the better the quality of cardiopulmonary resuscitation (CPR), the better the appearance of pulse oximetry plethysmographic waveform (POP). We investigated whether the area under the curve (AUC) and/or the amplitude (Amp) of POP could be used to monitor the quality of CPR. DESIGN: Prospective, randomized controlled study. SETTING: Animal experimental center in Peking Union Medical Collage Hospital, Beijing, China. SUBJECTS: Healthy 3-month-old male domestic swine. INTERVENTIONS: 34 local pigs were enrolled in this study. After 4 minutes of untreated ventricular fibrillation, animals were randomly assigned into two resuscitation groups: a "low quality" group (with a compression depth of 3cm) and a "high quality" group (with a depth of 5cm). All treatments between the two groups were identical except for the depth of chest compressions. Hemodynamic parameters [coronary perfusion pressure (CPP), partial pressure of end-tidal carbon dioxide (PETCO2)] as well as AUC and Amp of POP were all collected and analyzed. MEASUREMENTS AND FINDINGS: There were statistical differences between the "high quality" group and the "low quality" group in AUC, Amp, CPP and PETCO2 during CPR (P<0.05). AUC, Amp and CPP were positively correlated with PETCO2, respectively (P<0.01). There was no statistical difference between the heart rate calculated according to the POP (FCPR) and the frequency of mechanical CPR at the 3rd minute of CPR. The FCPR was lower than the frequency of mechanical CPR at the 6th and the 9th minute of CPR. CONCLUSIONS: Both the AUC and Amp of POP correlated well with CPP and PETCO2 in animal models. The frequency of POP closely matched the CPR heart rate. AUC and Amp of POP might be potential noninvasive quality monitoring markers for CPR. PMID- 26485653 TI - Correction: Emergence of OXA-48-Producing Klebsiella pneumoniae in Taiwan. PMID- 26485654 TI - RNA Amplification Protocol Leads to Biased Polymerase Chain Reaction Results Especially for Low-Copy Transcripts of Human Bone Marrow-Derived Stromal Cells. AB - The amplification of RNA is becoming increasingly important, as often only limited amounts of cells are available for gene expression analysis. In this study, the gene expression profile of the 39 human homeobox (HOX) genes was analyzed in bone marrow-derived multipotent stromal cells (BM-MSCs) by reverse transcription (RT-) and quantitative polymerase chain reaction (qPCR). For further unlimited gene expression analysis, Whole Transcriptome Amplification (WTA) was used to amplify RNA from human BM-MSCs. However, WTA led to biased RT- and qPCR results, and even non-detectability of HOX transcripts compared to non amplified BM-MSC samples which instead revealed transcription. It is important to note that the same RNA of the respective human BM-MSC line was used for normal cDNA synthesis by standard reverse transcription (non-amplified RT samples) and for cDNA synthesis by WTA (amplified WTA samples). On this account, the different RT- and qPCR results were unexpected applying WTA. The significantly reduced detection of HOX transcripts after WTA has been demonstrated for numerous BM-MSC lines (n = 26) by RT-PCR analysis. Furthermore, undetectable HOX transcripts meaning HOX transcripts of human BM-MSCs that were detected after normal cDNA synthesis, but were no longer detectable after WTA, were consistently observed by qPCR analysis. Finally, qPCR experiments revealed a possible explanation for the differences between amplified and non-amplified BM-MSC samples: an inverse correlation between the biased qPCR results and the low expression level of the respective HOX gene. The PCR analysis of high-copy transcripts like GAPDH or RPL13A revealed unchanged qPCR results after WTA compared to corresponding non amplified BM-MSC samples. In contrast, WTA led to biased qPCR results for medium copy HOX transcripts, and even non-detectability of low-copy HOX transcripts of human BM-MSCs resulting in false negative RT- and qPCR data applying WTA. PMID- 26485655 TI - Reversible Electrochemical Sensor for Detection of High-Charge Density Polyanion Contaminants in Heparin. AB - We present a simple, rapid, and inexpensive electrochemical sensor based on a reversible pulsed chronopotentiometric polyanion-selective membrane electrode for the detection and quantification of oversulfated chondroitin sulfate (OSCS) and other high charge-density polyanions that could potentially be used to adulterate heparin. The membrane is free of ion exchanger and is formulated with plasticized poly(vinyl chloride) (PVC) and an inert lipophilic salt, tridodecylmethylammonium dinonylnaphthaline sulfonate (TDMA-DNNS). The neutral salt is used to reduce membrane resistance and to ensure reversibility of the sensor. More importantly, TDMA(+) is used as the recognition element for the polyanions. Here an anodic galvanostatic current pulse is applied across the membrane to cause the extraction of the polyanions from the sample into the membrane and potential is measured at the sample-membrane interface. The measured electromotive force (emf) is proportional to the concentration and the charge density of the polyanions. High charge-density polyanion contaminants and impurities in heparin can be detected using this method since the overall equilibrium potential response of polyions increases with increasing charge density of the polyions. Here, first the potential response of pure heparin is measured at a saturation concentration, the concentration beyond which further addition of heparin does not produce a change in potential response. Then the potential response of heparin tainted with different quantities of the high charge-density contaminant is measured at a fixed total polyion concentration (heparin concentration + contaminant concentration). The latter gives a greater negative potential response due to the presence of the high charge-density contaminant. The increase in the negative potential response can be used for detection and quantification of high charge density contaminants in heparin. We demonstrate here that 0.3% (w/w) OSCS as well as 0.1% (w/w) dextran sulfate can be detected in heparin at 20-mg/mL total polyion concentration. It has also been shown that 1% (w/w) of dextran sulfate can readily be detected in heparin at only 2-mg/mL total polyanion concentration with a linear response (R(2) = 0.994). PMID- 26485658 TI - Mild hypothermia preserves cerebral cortex microcirculation after resuscitation in a rat model of cardiac arrest. AB - OBJECTIVE: Mild hypothermia improves the outcomes of comatose patients after cardiac arrest. Its neuroprotective mechanism is not fully understood. We investigated the effects of mild hypothermia on cerebral cortex microcirculation and cerebral oxygen extraction ratio. METHODS: Twenty-five rats were randomized into the hypothermic group (HT), normothermic group (NT) or the sham control group. Ventricular fibrillation was electrically induced and untreated for 8 min, followed by 8 min of precordial compressions and mechanical ventilations. The core temperature in the HT group was reduced to 33+/-0.5 degrees C at 14 min after ROSC with a combination of ice packs, an electrical fan and a cooling blanket. The temperature was maintained at 33 degrees C for 8h. Hemodynamics, arterial and jugular venous blood gases and cerebral cortex microcirculation were measured at baseline, 2, 4 and 8h after ROSC. RESULTS: Microvascular flow index was significantly reduced in the NT and HT groups when compared with the SC group. A significant lesser reduction in microvascular flow index was observed in the HT group when compared with the NT group. Mild hypothermia reduced the cerebral oxygen extraction ratio after resuscitation when compared with the NT group. CONCLUSION: Mild hypothermia improves the cerebral cortex microcirculatory blood supply/oxygen uptake mismatching after resuscitation. This may provide an additional cerebral protection. PMID- 26485659 TI - PCI after out-of-hospital cardiac arrest: Does who, what or when matter? PMID- 26485657 TI - Potential Link between the Sphingosine-1-Phosphate (S1P) System and Defective Alveolar Macrophage Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD). AB - INTRODUCTION: We previously reported that alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD) are defective in their ability to phagocytose apoptotic cells, with a similar defect in response to cigarette smoke. The exact mechanisms for this defect are unknown. Sphingolipids including ceramide, sphingosine and sphingosine-1-phosphate (S1P) are involved in diverse cellular processes and we hypothesised that a comprehensive analysis of this system in alveolar macrophages in COPD may help to delineate the reasons for defective phagocytic function. METHODS: We compared mRNA expression of sphingosine kinases (SPHK1/2), S1P receptors (S1PR1-5) and S1P-degrading enzymes (SGPP1, SGPP2, SGPL1) in bronchoalveolar lavage-derived alveolar macrophages from 10 healthy controls, 7 healthy smokers and 20 COPD patients (10 current- and 10 ex-smokers) using Real-Time PCR. Phagocytosis of apoptotic cells was investigated using flow cytometry. Functional associations were assessed between sphingosine signalling system components and alveolar macrophage phagocytic ability in COPD. To elucidate functional effects of increased S1PR5 on macrophage phagocytic ability, we performed the phagocytosis assay in the presence of varying concentrations of suramin, an antagonist of S1PR3 and S1PR5. The effects of cigarette smoking on the S1P system were investigated using a THP-1 macrophage cell line model. RESULTS: We found significant increases in SPHK1/2 (3.4- and 2.1 fold increases respectively), S1PR2 and 5 (4.3- and 14.6-fold increases respectively), and SGPL1 (4.5-fold increase) in COPD vs. controls. S1PR5 and SGPL1 expression was unaffected by smoking status, suggesting a COPD "disease effect" rather than smoke effect per se. Significant associations were noted between S1PR5 and both lung function and phagocytosis. Cigarette smoke extract significantly increased mRNA expression of SPHK1, SPHK2, S1PR2 and S1PR5 by THP-1 macrophages, confirming the results in patient-derived macrophages. Antagonising SIPR5 significantly improved phagocytosis. CONCLUSION: Our results suggest a potential link between the S1P signalling system and defective macrophage phagocytic function in COPD and advise therapeutic targets. PMID- 26485660 TI - Online control of reaching and pointing to visual, auditory, and multimodal targets: Effects of target modality and method of determining correction latency. AB - Movements aimed towards objects occasionally have to be adjusted when the object moves. These online adjustments can be very rapid, occurring in as little as 100ms. More is known about the latency and neural basis of online control of movements to visual than to auditory target objects. We examined the latency of online corrections in reaching-to-point movements to visual and auditory targets that could change side and/or modality at movement onset. Visual or auditory targets were presented on the left or right sides, and participants were instructed to reach and point to them as quickly and as accurately as possible. On half of the trials, the targets changed side at movement onset, and participants had to correct their movements to point to the new target location as quickly as possible. Given different published approaches to measuring the latency for initiating movement corrections, we examined several different methods systematically. What we describe here as the optimal methods involved fitting a straight-line model to the velocity of the correction movement, rather than using a statistical criterion to determine correction onset. In the multimodal experiment, these model-fitting methods produced significantly lower latencies for correcting movements away from the auditory targets than away from the visual targets. Our results confirm that rapid online correction is possible for auditory targets, but further work is required to determine whether the underlying control system for reaching and pointing movements is the same for auditory and visual targets. PMID- 26485661 TI - Diffusion Tensor Imaging of the Auditory Neural Pathway for Clinical Outcome of Cochlear Implantation in Pediatric Congenital Sensorineural Hearing Loss Patients. AB - Although conventional structural MRI provides vital information in the evaluation of congenital sensorineural hearing loss (SNHL), it is relatively insensitive to white matter microstructure. Our objective was to evaluate possible changes in microstructure of the auditory pathway in children with congenital sensorineural hearing loss (SNHL), and the possible distinction between good and poor outcome of cochlear implantation (CI) patients by using diffusion tensor imaging (DTI). Twenty-four patients with congenital SNHL and 20 healthy controls underwent conventional MRI and DTI examination using a 1.5T MR scanner. The DTI metrics of fractional anisotropy (FA) and mean diffusivity (MD) of six regions of interest (ROIs) positioned along the auditory pathway-the trapezoid body, superior olivary nucleus, inferior colliculus, medial geniculate body, auditory radiation and white matter of Heschl's gyrus-was measured in all subjects. Among the 24 patients, 8 patients with a categorie of auditory performance (CAP) score over 6 were classified into the good outcome group, and 16 patients with a CAP score below 6 were classified into the poor outcome group. A significant decrease was observed in FA values while MD values remained unchanged at the six ROIs of SNHL patients compared with healthy controls. Compared to good outcome subjects, poor outcome subjects displayed decreased FA values at all of the ROIs. No changes were observed in MD values. Correlation analyses only revealed strong correlations between FA values and CAP scores, and strong correlations between CAP scores and age at implant were also found. No correlations of FA values with age at implant were observed. Our results show that preoperative DTI can be used to evaluate microstructural alterations in the auditory pathway that are not detectable by conventional MR imaging, and may play an important role in evaluating the outcome of CI. Early cochlear implantation might be more effectively to restore hearing in SNHL patients. PMID- 26485662 TI - Coordinated Behaviour in Pigeon Flocks. AB - We analysed pigeon flock flights using GPS trajectory data to reveal the most important kinematic aspects of flocking behaviour. We quantitatively investigated the internal motion of the flock based on pairwise statistics and found the following general relationships in all datasets: i) the temporal order of decisions characterised by the delay between directional changes is strictly related to the spatial order characterised by the longitudinal relative position within the flock; ii) during circling motion, pigeons use a mixture of two idealised and fundamentally different turning strategies, namely, parallel-path and equal-radius type turning. While pigeons tend to maintain their relative position within the flock on average, as in the parallel-path approximation, those who turn later also get behind as in the equal-radius case. Equal-radius type turning also tends to be expressed more during smaller radius turns. PMID- 26485663 TI - Identification of vitamin D3 target genes in human breast cancer tissue. AB - Multiple epidemiological studies have shown that high vitamin D3 status is strongly associated with improved breast cancer survival. To determine the molecular pathways influenced by 1 alpha, 25-dihydroxyvitamin D3 (1,25D) in breast epithelial cells we isolated RNA from normal human breast and cancer tissues treated with 1,25D in an ex vivo explant system. RNA-Seq revealed 523 genes that were differentially expressed in breast cancer tissues in response to 1,25D treatment, and 127 genes with altered expression in normal breast tissues. GoSeq KEGG pathway analysis revealed 1,25D down-regulated cellular metabolic pathways and enriched pathways involved with intercellular adhesion. The highly 1,25D up-regulated target genes CLMN, SERPINB1, EFTUD1, and KLK6were selected for further analysis and up-regulation by 1,25D was confirmed by qRT-PCR analysis in breast cancer cell lines and in a subset of human clinical samples from normal and cancer breast tissues. Ketoconazole potentiated 1,25D-mediated induction of CLMN, SERPINB1, and KLK6 mRNA through inhibition of 24-hydroxylase (CYP24A1) activity. Elevated expression levels of CLMN, SERPINB1, and KLK6 are associated with prolonged relapse-free survival for breast cancer patients. The major finding of the present study is that exposure of both normal and malignant breast tissue to 1,25D results in changes in cellular adhesion, metabolic pathways and tumor suppressor-like pathways, which support epidemiological data suggesting that adequate vitamin D3 levels may improve breast cancer outcome. PMID- 26485664 TI - Novel vitamin D analogues; cytotoxic and anti-proliferative activity against a diffuse large B-cell lymphoma cell line and B-cells from healthy donors. AB - Calcitriol (1,25-dihydroxyvitamin D3, 1,25D3) and vitamin D side-chain modified analogs (VDAs) have gained considerable attention as potential drugs in the treatment of acute myeloid leukemia (AML), yet studies of the impact of 1,25D3 and VDAs upon other haematological malignancies are more limited. To address this gap in knowledge, we have examined the action of 1,25D3 and VDAs on a human cell line (DOHH2, K422) typifying diffuse large B-cell lymphoma (DLBCL) and also peripheral blood B-cells isolated from healthy donors. 1,25D3 and certain VDAs displayed moderate cytotoxic and pro-apoptotic actions upon DLBCL cells. 1,25D3 and VDAs (100nM) caused the death of approximately 40% DOHH2 cells after 24h stimulation, similar to their impact on HL-60 cells (acute myeloid leukaemia cell line). In addition, 1,25D3 and VDAs displayed concentration and time-dependent anti-proliferative actions upon stimulated B-cells from healthy donors. The VDAs inhibited proliferation by approximately 30%. Hence VDAs may offer therapeutic potential for the treatment of DLBCL or conditions benefitted by B-cell depletion. PMID- 26485665 TI - The feto-placental unit, and potential roles of dehydroepiandrosterone (DHEA) in prenatal and postnatal brain development: A re-examination using the spiny mouse. AB - Synthesis of dehydroepiandrosterone (DHEA) by the fetal adrenal gland is important for placental oestrogen production, and may also be important for modulating the effects of glucocorticoids on the developing brain. We have preciously shown that the enzymes and accessory proteins needed for DHEA synthesis-cytochrome P450 enzyme 17alpha-hydroxylase/17,20 lyase (P450c17), cytochrome-b5 (Cytb5), 3beta-hydroxysteroid dehydrogenase (3betaHSD)-are expressed in the adrenal gland from 30 days gestation, and DHEA, cortisol and aldosterone are present in fetal plasma from this time. Explant culture of fetal adrenal tissue showed that the spiny mouse adrenal gland, can synthesize and secrete DHEA from at least 0.75 of gestation, and suggest that DHEA may have an important role(s) in placental biosynthesis of oestrogens and in modulating the actions of glucocorticoids in the developing brain in this species. Post-natally, increased immuno-expression of P450c17 and Cytb5 expression in the zona reticularis of the adrenal gland and a significant increase in the synthesis and secretion of DHEA in plasma from 8 to 20 days of age in the spiny mouse, are representative of a period of high adrenal androgen production consistent with the human phenomenon of adrenarche. The studies summarised in this review also show that DHEA is produced de novo in the developing brain of the spiny mouse. These results showed that the spiny mouse brain can indeed produce DHEA from pregnenolone in a time-dependant manner, and coupled with the identification of P450c17 and Cytb5 protein in several regions of the brain, support the idea that DHEA is an endogenous neuro-active steroid in this species. Together, the studies outlined in this review indicate that the androgen DHEA is an important hormone of adrenal and Central Nervous System (CNS) origin in the fetal and postnatal spiny mouse. Disturbance of the development of these fetal tissues, and/or of the relationship between the fetal adrenal gland and placenta during pregnancy, may have significant consequences for fetal development, placental function, and maturation of the brain. It is proposed that such disturbances of normal adrenal function could account for some of the neuropathologies that arise in juvenile and adult offspring following illness and stress experienced by the mother during pregnancy. PMID- 26485666 TI - Hierarchical Transition-Metal Dichalcogenide Nanosheets for Enhanced Electrocatalytic Hydrogen Evolution. AB - Hierarchical transition-metal dichalcogenide nanosheets are constructed through a versatile strategy, where the thermal polymerization of melamine and subsequent decomposition of carbon nitride successively guide the horizontal and vertical growths of transition-metal chalcogenides. Abundant edges and high surface areas endow the hierarchical MoS2 and WS2 nanosheets with excellent electrocatalytic performance for hydrogen evolution, including low onset potentials and high current densities. PMID- 26485667 TI - Endomembrane trafficking overarching cell plate formation. AB - By contrast to other eukaryotic kingdoms, plant cytokinesis is an inside-out process. A coordinated action of cytoskeletal transitions and endomembrane trafficking events builds a novel membrane compartment, the cell plate. Deposition of cell wall polymers transforms the lumen of this membrane compartment into a new cross wall, physically separating the daughter cells. The characterization of tethering complexes acting at discrete phases during cell plate formation and upstream of vesicle fusion events, the presence of modulators directing secretion and recycling during cytokinesis, as well as the identification and temporal recruitment of the endocytic machinery, provides a starting point to dissect the transitions in endomembrane trafficking which shape this process. This review aims to integrate recent findings on endomembrane trafficking events which spatio-temporally act to construct the cell plate. PMID- 26485668 TI - Changes in Japanese eyes after laser peripheral iridotomy: an anterior segment optical coherence tomography study. AB - BACKGROUND: The aim was to investigate the changes in anterior segment parameters, as assessed by anterior segment optical coherence tomography in Japanese subjects after laser peripheral iridotomy (LPI). DESIGN: This was a prospective observational study. PARTICIPANTS: The participants include 72 subjects with angle closure including primary angle closure suspect (PACS), primary angle closure (PAC), and primary angle closure glaucoma (PACG). METHODS: Anterior segment optical coherence tomography parameters was measured by customized software. Complete data of 51 subjects were available for final analysis. MAIN OUTCOME MEASURES: These were the following parameters: angle opening distance, trabecular-iris space area, anterior chamber depth, width, area and volume (iris thickness, curvature, and area, and lens vault (LV). RESULTS: A total of 25 PACS, 17 PAC and 9 PACG were included. Mean age was 74.7 +/- 6.7 years, and majority were women (80.4%). Following LPI, there was a significant increase in mean gonioscopic angle width (1.16 vs. 1.93, P < 0.001) and a corresponding increase in angle opening distance, trabecular-iris space area, and angle recess area (all P < 0.001). The anterior chamber area (P < 0.001), anterior chamber volume (P < 0.001) and anterior chamber depth (P = 0.003) increased significantly; and iris curvature (P < 0.001) was significantly reduced. There were no significant changes in anterior chamber width, LV, iris thickness and area. Age-adjusted and gender-adjusted analysis for predictors of percentage change in angle opening distance 750 showed significant association with greater baseline LV (beta = 0.32, P = 0.03). No significant differences were noted in the mean percentage change in parameters between the PACS and PAC-PACG. CONCLUSIONS: An increase in anterior chamber dimensions, angle widening and iris flattening; with a constant LV, iris thickness and iris area after LPI was demonstrated in Japanese eyes with angle closure. PMID- 26485669 TI - Hepatoblastoma in Rubinstein-Taybi Syndrome: A Case Report. PMID- 26485670 TI - Is Hypothermia Helpful in Severe Subarachnoid Hemorrhage? An Exploratory Study on Macro Vascular Spasm, Delayed Cerebral Infarction and Functional Outcome after Prolonged Hypothermia. AB - BACKGROUND: Therapeutic hypothermia (TH) is an established treatment after cardiac arrest and growing evidence supports its use as neuroprotective treatment in stroke. Only few and heterogeneous studies exist on the effect of hypothermia in subarachnoid hemorrhage (SAH). A novel approach of early and prolonged TH and its influence on key complications in poor-grade SAH, vasospasm and delayed cerebral ischemia (DCI) was evaluated. METHODS: This observational matched controlled study included 36 poor-grade (Hunt and Hess Scale >3 and World Federation of Neurosurgical Societies Scale >3) SAH patients. Twelve patients received early TH (<48 h after ictus), mild (35 degrees C), prolonged (7 +/- 1 days) and were matched to 24 patients from the prospective SAH database. Vasospasm was diagnosed by angiography, macrovascular spasm serially evaluated by Doppler sonography and DCI was defined as new infarction on follow-up CT. Functional outcome was assessed at 6 months by modified Rankin Scale (mRS) and categorized as favorable (mRS score 0-2) versus unfavorable (mRS score 3-6) outcome. RESULTS: Angiographic vasospasm was present in 71.0% of patients. TH neither influenced occurrence nor duration, but the degree of macrovascular spasm as well as peak spastic velocities were significantly reduced (p < 0.05). Frequency of DCI was 87.5% in non-TH vs. 50% in TH-treated patients, translating into a relative risk reduction of 43% and preventive risk ratio of 0.33 (95% CI 0.14-0.77, p = 0.036). Favorable functional outcome was twice as frequent in TH treated patients 66.7 vs. 33.3% of non-TH (p = 0.06). CONCLUSION: Early and prolonged TH was associated with a reduced degree of macrovascular spasm and significantly decreased occurrence of DCI, possibly ameliorating functional outcome. TH may represent a promising neuroprotective therapy possibly targeting multiple pathways of DCI development, notably macrovascular spasm, which strongly warrants further evaluation of its clinical impact. PMID- 26485671 TI - Application of the Mimic Valsalva Maneuver with the Help of a Saccule in Cerebrospinal Fluid Rhinorrhea Reconstruction Surgery. AB - OBJECTIVE: To explore the mimic Valsalva maneuver with the help of a saccule handled by an anesthesiologist in order to locate the leakage channel and repair the fistula during intranasal endoscopic reconstruction surgery of cerebrospinal fluid rhinorrhea. METHODS: From 2012 to 2014, 8 patients were diagnosed with cerebrospinal fluid rhinorrhea by medical histories, physical and biochemical examination. All patients were treated with intranasal endoscopic reconstruction surgery of cerebrospinal fluid rhinorrhea. During the surgery, the mimic Valsalva maneuver with the help of a saccule was carried out once or twice by an anesthetist during the operation. Intranasal endoscopy was used to accurately locate the leakage site as shown by the exact fistula. Temporal fascia, fascia lata, middle turbinate mucosa and nasal septum mucosa were all used to repair the fistula. RESULTS: After the surrounding mucosa was removed, the exact leakage sites were accurately found. Fascia materials were used in all 8 patients. All patients were successfully treated after their first operation, and 1 patient was successfully treated by two operations with no complications and recurrences. All the patients were followed up for 1 month to 2 years. CONCLUSION: The convenient method of the mimic Valsalva maneuver with the help of a saccule handled by an anesthesiologist has a good prospect in cerebrospinal fluid rhinorrhea reconstruction surgery. PMID- 26485672 TI - Viability and heat resistance of murine norovirus on bread. AB - Contaminated bread was the cause of a large-scale outbreak of norovirus disease in Japan in 2014. Contamination of seafood and uncooked food products by norovirus has been reported several times in the past; however the outbreak resulting from the contamination of bread products was unusual. A few reports on the presence of norovirus on bread products are available; however there have been no studies on the viability and heat resistance of norovirus on breads, which were investigated in this study. ce:italic>/ce:italic> strain 1 (MNV-1), a surrogate for human norovirus, was inoculated directly on 3 types of bread, but the infectivity of MNV-1 on bread samples was almost unchanged after 5days at 20 degrees C. MNV-1 was inoculated on white bread that was subsequently heated in a toaster for a maximum of 2min. The results showed that MNV-1 remained viable if the heating period was insufficient to inactivate. In addition, bread dough contaminated with MNV-1 was baked in the oven. Our results indicated that MNV-1 may remain viable on breads if the heating duration or temperature is insufficient. PMID- 26485673 TI - Ten Simple Rules for Experiments' Provenance. PMID- 26485674 TI - A comparison of outcomes in interventions for unilateral vocal fold paralysis: A systematic review. AB - OBJECTIVES/HYPOTHESIS: To critically review current literature comparing interventional approaches for unilateral vocal fold paralysis. STUDY DESIGN: Systematic review of the literature. METHODS: All English-language literature published in the PubMed database was eligible for inclusion. Inclusion criteria were: 1) the major topic must be a direct comparison of outcomes in interventions for unilateral vocal fold paralysis, 2) the subjects were 18 years or older, and 3) it was original research. Studies involving treatment of bilateral vocal fold paralysis and nonprocedural interventions were excluded. Included studies were categorized according to level of evidence. Outcomes analyzed were acoustic and aerodynamic measures, auditory perceptive evaluation, laryngoscopic findings, and complications. RESULTS: Of the 504 studies retrieved from the search strategy, 17 studies met inclusion and exclusion criteria. Overall, four interventional approaches were used for treatment of unilateral vocal fold paralysis: medialization thyroplasty, injection laryngoplasty, arytenoid adduction, and laryngeal reinnervation. Aside from some select improvements in single outcome parameters, overall, the majority of studies show no difference in improvement of outcomes between techniques. CONCLUSIONS: Four surgical interventions for unilateral vocal fold paralysis are available for treatment of unilateral vocal cord paralysis. Multiple studies show favorable outcomes, but no significant differences between treatment arms based on perceptual, acoustic, quality of life, and laryngoscopic outcomes. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1616 1624, 2016. PMID- 26485675 TI - Probability of detection of DNA deposited by habitual wearer and/or the second individual who touched the garment. AB - Available literature on the detection of transferred DNA does not address the interpretation issues in relation to who wore rather than touched the garment. To acquire a greater knowledge of the rate of detectable wearer, toucher and background DNA, 63 males wore their own underpants for 12h. The inside-waistband was handled by one of 11 female volunteers for 15s. The waist-band was mini-taped and subjected to DNA profiling with the AMPFlSTR((r)) NGM SElectTM kit. The findings show that on worn garments the probability of observing reportable DNA profiles is 61.9%. The wearer was detected as a single profile or part of a mixed profile in 50.8% of samples. When the wearer was present in a mixture, he was always observed as the major contributor. The toucher was detected on 11.1% of underpants. Reportable background DNA (non-wearer and non-toucher) occurs in 14.3% of samples and may affect the assessment of who wore the garment. Greater knowledge of the frequency of detection of reportable wearer DNA and/or toucher allows scientists to evaluate the likelihood of observing a matching profile if an individual wore a garment rather than touched it in disputed case scenarios. PMID- 26485676 TI - Degraded RNA transcript stable regions (StaRs) as targets for enhanced forensic RNA body fluid identification. AB - The detection of messenger RNA (mRNA) using reverse transcriptase PCR (RT-PCR) is becoming common practice for forensic body fluid identification. However, the degraded and scarce nature of RNA from forensic samples mean that mRNA transcripts are not consistently detected or remain undetected in practice. Conventional primer design for RT-PCR (and quantitative RT-PCR) includes targeting primers to span exon-exon boundaries or by having the primers on two separate exons, and satisfying common primer thermodynamic criteria. We have found that the conventional placement of primers is not always optimal for obtaining reproducible results from degraded samples. Using massively parallel sequencing data from degraded body fluids, we designed primers to amplify transcript regions of high read coverage, hence, higher stability, and compared these with primers designed using conventional methodology. Our findings are that primers designed for transcript regions of higher read coverage resulted in vastly improved detection of mRNA transcripts that were not previously detected or were not consistently detected in the same samples using conventional primers. We developed a new concept whereby primers targeted to transcript stable regions (StaRs) are able to consistently and specifically amplify a wide range of RNA biomarkers in various body fluids of varying degradation levels. PMID- 26485677 TI - HMGB1 Contributes to the Expression of P-Glycoprotein in Mouse Epileptic Brain through Toll-Like Receptor 4 and Receptor for Advanced Glycation End Products. AB - The objective of the present study was to investigate the role of high-mobility group box-1 (HMGB1) in the seizure-induced P-glycoprotein (P-gp) overexpression and the underlying mechanism. Kainic acid (KA)-induced mouse seizure model was used for in vivo experiments. Male C57BL/6 mice were divided into four groups: normal saline control (NS) group, KA-induced epileptic seizure (EP) group, and EP group pretreated with HMGB1 (EP+HMGB1 group) or BoxA (HMGB1 antagonist, EP+BoxA group). Compared to the NS group, increased levels of HMGB1 and P-gp in the brain were observed in the EP group. Injection of HMGB1 before the induction of KA further increased the expression of P-gp while pre-treatment with BoxA abolished this up-regulation. Next, the regulatory role of HMGB1 and its potential involved signal pathways were investigated in mouse microvascular endothelial bEnd.3 cells in vitro. Cells were treated with HMGB1, HMGB1 plus lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) [toll-like receptor 4 (TLR4) antagonist], HMGB1 plus FPS-ZM1 [receptor for advanced glycation end products (RAGE) inhibitor], HMGB1 plus SN50 [nuclear factor-kappa B (NF-kappaB) inhibitor], or vehicle. Treatment with HMGB1 increased the expression levels of P-gp, TLR4, RAGE and the activation of NF-kappaB in bEnd.3 cells. These effects were inhibited by the pre treatment with either LPS-RS or FPS-ZM1, and were abolished by the pre-treatment of SN50 or a combination treatment of both LPS-RS and FPS-ZM1. Luciferase reporter assays showed that exogenous expression of NF-kappaB p65 increased the promoter activity of multidrug resistance 1a (P-gp-encoding gene) in endothelial cells. These data indicate that HMGB1 contributes to the overexpression of P-gp in mouse epileptic brain tissues via activation of TLR4/RAGE receptors and the downstream transcription factor NF-kappaB in brain microvascular endothelial cells. PMID- 26485678 TI - Current status of deceased donor split liver transplantation in Japan. AB - BACKGROUND: The aim of this study was to analyze the outcomes of deceased donor split liver transplantation (LT) in Japan. METHODS: Among 257 deceased donor LTs, 36 recipients underwent split LT until the end of 2014. The clinical data of donors and recipients were collected from the national organ transplant network and 11 liver transplant institutions, and the outcomes of split LT were evaluated. RESULTS: Most of the whole livers were divided using the ex-situ splitting technique. Twelve livers were divided to left lateral segment/extended right lobe grafts and six livers to left lobe/right lobe grafts. The common underlying liver diseases consisted of graft failure in 11 patients, followed by acute liver failure in nine. Seventeen cases (48.6%) suffered from surgical complications, including biliary complications in six, all of which occurred in the cases receiving right-sided lobe grafts; intra-abdominal hemorrhage in five; and vascular complications in four. The overall graft 1-year and 3-year survival rates were 91.0% and 87.1%, respectively. CONCLUSIONS: An initial experience of deceased donor split LT in Japan shows acceptable outcomes despite the high incidence of surgical complications. Further advances in the development of the splitting technique are necessary to expand the application of split LT. PMID- 26485679 TI - Serotype Changes and Drug Resistance in Invasive Pneumococcal Diseases in Adults after Vaccinations in Children, Japan, 2010-2013. AB - After 7-valent pneumococcal conjugate vaccine (PCV) for children was introduced in Japan in November 2010, we examined changes in Streptococcus pneumoniae serotypes and in genetic antimicrobial drug resistance of isolates from adults with invasive pneumococcal diseases. During April 2010-March 2013, a total of 715 isolates were collected from adults with invasive pneumococcal diseases. Seven valent PCV serotypes in adults decreased from 43.3% to 23.8%, most noticeably for serotype 6B. Concomitantly, 23-valent pneumococcal polysaccharide vaccine (PPSV23) serotypes decreased from 82.2% to 72.2%; non-PPSV23 serotypes increased from 13.8% to 25.1%. Parallel with serotype changes, genotypic penicillin resistant S. pneumoniae decreased from 32.4% to 21.1%, and 6 non-PPSV23 serotypes emerged (6D, 15A, 15C, 16F, 23A, and 35B). Respective vaccine coverage rates for 13-valent PCV and PPSV23 differed by disease: 73.9% and 84.3% for patients with pneumonia, 56.4% and 69.2% for patients with bacteremia and sepsis, and 45.7% and 69.3% for patients with meningitis. PMID- 26485680 TI - Filtration of Macrophage Migration Inhibitory Factor (MIF) in Patients with End Stage Renal Disease Undergoing Hemodialysis. AB - BACKGROUND: End stage renal disease (ESRD) patients are characterized by increased morbidity and mortality due to highest prevalence of cardiovascular disease. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that controls cellular signaling in human physiology, pathophysiology, and diseases. Increased MIF plasma levels promote vascular inflammation and development of atherosclerosis. We have shown that MIF is associated with vascular dysfunction in ESRD patients. Whether hemodialysis (HD) affects circulating MIF plasma levels is unknown. We here aimed to investigate whether HD influences the circulating MIF pool in ESRD patients. METHODS AND RESULTS: An observational single-center study was conducted. MIF plasma levels in ESRD patients were assessed before, during, and after a HD session (n = 29). Healthy age-matched volunteers served as controls to compare correlations of MIF plasma levels with inflammatory plasma components (n = 20). MIF removed from the circulating blood pool could be detected in the dialysate and allowed for calculation of totally removed MIF (MIF content in dialysate 219+/-4 MUg/HD session). MIF plasma levels were markedly decreased 2 hour after initiation of HD (MIF plasma level pre-HD 84.8+/-6 ng/ml to intra-HD 61.2+/-5 ng/ml p<0.001) and were replenished already 20 min after termination of HD to basal levels (intra-HD 61.2+/-5 ng/ml to post-HD 79.8+/-5 ng/ml, p<0.001). CONCLUSION: MIF is a dialyzable plasma component that is effectively filtrated during HD from the patient blood pool in large amounts. After removal of remarkable amounts of MIF during a single HD session, MIF plasma pool is early reconstituted after termination of HD from unknown sources. PMID- 26485681 TI - Association of Cardiovascular Risk Factors with Carotid Intima Media Thickness in Patients with Rheumatoid Arthritis with Low Disease Activity Compared to Controls: A Cross-Sectional Study. AB - OBJECTIVES: Rheumatoid arthritis (RA) has been identified as an independent cardiovascular risk factor. The importance of risk factors such as hypertension and hyperlipidemia in the generation of atherosclerosis in RA patients is unclear. This study analyzed clinical parameters associated with carotid intima media thickness (cIMT) in patients with RA. METHODS: Subjects with RA and healthy controls without RA, both without known cardiovascular disease, were included. Participants underwent a standard physical examination and laboratory measurements including a lipid profile. cIMT was measured semi-automatically by ultrasound. RESULTS: In total 243 RA patients and 117 controls were included. The median RA disease duration was 7 years (IQR 2-14 years). The median DAS28 was 2.4 (IQR 1.6-3.2) and 114 (50.4%) of the RA patients were in remission. The presence of RA and cIMT were not associated (univariate analysis). Multivariable regression analysis showed that cIMT in RA patients was associated with age (B = 0.006, P<0.001) and systolic blood pressure (B = 0.003, P = 0.003). In controls, cIMT was associated with age (B = 0.006, P<0.001) and smoking (B = 0.097, P = 0.001). CONCLUSION: cIMT values were similar between RA patients and controls. Hypertension was strongly associated with cIMT in RA patients. After adjustment, no association between cIMT and specific RA disease characteristics was found in this well treated RA cohort. PMID- 26485682 TI - Neuronal and Endothelial Nitric Oxide Synthases in the Paraventricular Nucleus Modulate Sympathetic Overdrive in Insulin-Resistant Rats. AB - A central mechanism participates in sympathetic overdrive during insulin resistance (IR). Nitric oxide synthase (NOS) and nitric oxide (NO) modulate sympathetic nerve activity (SNA) in the paraventricular nucleus (PVN), which influences the autonomic regulation of cardiovascular responses. The aim of this study was to explore whether the NO system in the PVN is involved in the modulation of SNA in fructose-induced IR rats. Control rats received ordinary drinking water, whereas IR rats received 12.5% fructose-containing drinking water for 12 wks to induce IR. Basal SNA was assessed based on the changes in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in response to chemicals administered to the PVN. We found an increased plasma norepinephrine level but significantly reduced NO content and neuronal NOS (nNOS) and endothelial NOS (eNOS) protein expression levels in the PVN of IR rats compared to Control rats. No difference in inducible NOS (iNOS) protein expression was observed between the two groups. In anesthetized rats, the microinjection of sodium nitroprusside (SNP), an NO donor, or Nomega-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of NOS, into the PVN significantly decreased and increased basal SNA, respectively, in both normal and IR rats, but these responses to SNP and L-NAME in IR rats were smaller than those in normal rats. The administration of selective inhibitors of nNOS or eNOS, but not iNOS, to the PVN significantly increased basal SNA in both groups, but these responses were also smaller in IR rats. Moreover, IR rats exhibited reduced nNOS and eNOS activity in the PVN. In conclusion, these data indicate that the decreased protein expression and activity levels of nNOS and eNOS in the PVN lead to a reduction in the NO content in the PVN, thereby contributing to a subsequent enhancement in sympathoexcitation during IR. PMID- 26485683 TI - TLR2-MyD88-NF-kappaB pathway is involved in tubulointerstitial inflammation caused by proteinuria. AB - Proteinuria is an important risk factor for chronic kidney diseases (CKD). Several studies have suggested that proteinuria initiates tubulointerstitial inflammation, while the mechanisms have not been fully understood. In this study, we hypothesized whether the activation of the TLR2-MyD88-NF-kappaB pathway is involved in tubulointerstitial inflammation induced by proteinuria. We observed expression of TLR2, MyD88, NF-kappaB, as well as TNF-alpha and IL-6 detected by immunohistostaining, Western blotting and real-time PCR in albumin-overloaded (AO) nephropathy rats. In vitro, we observed these markers in HK-2 cells stimulated by albumin. We used TLR2 siRNA or the NF-kappaB inhibitor BAY 11-7082 to observe the influence of TNF-alpha and IL-6 expression caused by albumin overload. Finally, we studied these markers in non-IgA mesangioproliferative glomerulonephritis (MsPGN) patients with different levels of proteinuria. It was demonstrated that expression of TLR2, MyD88 and NF-kappaB were significantly increased in AO rats and in non-IgA MsPGN patients with high levels of proteinuria, and TNF-alpha and IL-6 expressions were increased after NF-kappaB activation. Furthermore, TNF-alpha and IL-6 expression was positively correlated with the level of proteinuria. Albumin-overload induced TNF-alpha and IL-6 secretions by the TLR2-MyD88-NF-kappaB pathway activation, which could be attenuated by the TLR2 siRNA or BAY 11-7082 in HK-2 cells. In summary, we demonstrated that proteinuria may exhibit an endogenous danger-associated molecular pattern (DAMP) that induces tubulointerstitial inflammation via the TLR2-MyD88-NF-kappaB pathway activation. PMID- 26485684 TI - Brain diseases and tumorigenesis: The good and bad cops of pentraxin3. AB - The prototype of long pentraxins, Pentraxin 3 (PTX3), is an evolutionarily conserved multifunctional, pattern-recognition protein constituted by a cyclic multimeric structure. PTX3 interacts with a variety of ligands, such as growth factors, extracellular matrix components, molecules of the complement cascade, pathogens recognition proteins, angiogenetic and adhesion molecules. PTX3 could be considered as a molecular link between innate and adaptive immunity as well as between focal and circulating responses during inflammation. In fact, it modulates the functions of resident dendritic cells and circulating lymphocytes. Recent evidence demonstrates that manipulation of PTX3 may produce even opposite effects depending on which target organ is considered and the physiopathological context. In the present review we discuss the good and bad cops of PTX3 concerning multifacted effects on inflammation, innate immunity, brain diseases and tumorigenesis. Finally, a perspective on PTX3 and autophagy is provided as a convergent pathway. PMID- 26485685 TI - Role of miR-497 in VEGF-A-mediated cancer cell growth and invasion in non-small cell lung cancer. AB - The malignancy of non-small cell lung cancer (NSCLC) is largely due to its invasion. Hence, prevention of the cancer cell invasion, which is essentially regulated by vascular endothelial growth factor A (VEGF-A), is substantially critical for a successful treatment for NSCLC. Here, we showed that compared to other cancers, NSCLC had a significant higher ratio of VEGF-A protein vs mRNA, and significantly lower levels of miR-497, suggesting presence of a post transcriptional control of VEGF-A in NSCLC different from other cancers. Compared with paired normal lung tissue, NSCLC expressed lower levels of miR-497 and higher levels of VEGF-A. Moreover, the levels of miR-497 and VEGF-A were inversely correlated in NSCLC specimen. Bioinformatics analyses showed that miR 497 bound to 3'-UTR of VEGF-A mRNA in NSCLC lines to inhibit its translation. Overexpression of miR-497 in NSCLC lines decreased VEGF-A protein, while depletion of miR-497 in NSCLC lines increased VEGF-A protein. However, modification of miR-497 levels in NSCLC lines did not alter VEGF-A mRNA levels. Overexpression of miR-497 in NSCLC lines inhibited cell growth and invasion, while depletion of miR-497 in NSCLC lines increased cell growth and invasion. Together, our data demonstrate a previously unappreciated role for miR-497 in suppression of VEGF-A-mediated NSCLC cancer cell growth and invasion. PMID- 26485686 TI - Clinical indication and timing of antenatal corticosteroid administration at a single centre. AB - OBJECTIVE: To determine how well antenatal corticosteroids (ACS) were timed, based on the indication for administration for women delivering preterm. DESIGN: Retrospective cohort study. SETTING: Tertiary medical centre. POPULATION: Six hundred and thirty women who had singleton preterm births between 24 and 34 weeks' gestational age. METHODS: Charts from 2006 to 2011 were reviewed for indications for ACS administration, which included premature rupture of membranes, threatened preterm labour, risk factors for spontaneous preterm birth such as short ultrasound cervical length, positive fetal fibronectin, and hypertensive disorders of pregnancy. Charts were reviewed for timing of ACS administration in relation to delivery. MAIN OUTCOME MEASURES: The primary outcome was optimal timing, defined as administration of ACS >= 24 hours to <= 7 days prior to delivery. RESULTS: Of 630 women who delivered preterm, 589 (93%) received ACS prior to delivery. ACS timing was optimal in 40% (238 of 589) of cases. Women with hypertensive disorders were most likely to have steroids optimally timed (62%). Asymptomatic women at increased risk for preterm delivery were less likely to receive optimally timed ACS (12%). The majority of women who received steroids >2 weeks prior to delivery (57%) received a second course. CONCLUSION: A majority of women who delivered preterm did not receive optimally timed ACS. Diagnostic tools that identified women at risk for preterm birth were not able to identify patients for appropriate steroid timing. Given the range of clinical scenarios in which patients are at increased risk for preterm delivery, further research is needed to assist clinicians in optimising steroid administration. TWEETABLE ABSTRACT: Optimal timing of antenatal steroids prior to delivery does not occur in most cases. PMID- 26485687 TI - Eukaryotic elongation factor 2 kinase regulates the synthesis of microtubule related proteins in neurons. AB - Modulation of the elongation phase of protein synthesis is important for numerous physiological processes in both neurons and other cell types. Elongation is primarily regulated via eukaryotic elongation factor 2 kinase (eEF2K). However, the consequence of altering eEF2K activity on the synthesis of specific proteins is largely unknown. Using both pharmacological and genetic manipulations of eEF2K combined with two protein-labeling techniques, stable isotope labeling of amino acids in cell culture and bio-orthogonal non-canonical amino acid tagging, we identified a subset of proteins whose synthesis is sensitive to inhibition of eEF2K in murine primary cortical neurons. Gene ontology (GO) analyses indicated that processes related to microtubules are particularly sensitive to eEF2K inhibition. Our findings suggest that eEF2K likely contributes to neuronal function by regulating the synthesis of microtubule-related proteins. Modulation of the elongation phase of protein synthesis is important for numerous physiological processes in neurons. Here, using labeling of new proteins coupled with proteomic techniques in primary cortical neurons, we find that the synthesis of microtubule-related proteins is up-regulated by inhibition of elongation. This suggests that translation elongation is a key regulator of cytoskeletal dynamics in neurons. PMID- 26485689 TI - Diabetes: Circulating factors implicated in diabetic enteropathy. PMID- 26485688 TI - Normal and Cystic Fibrosis Human Bronchial Epithelial Cells Infected with Pseudomonas aeruginosa Exhibit Distinct Gene Activation Patterns. AB - BACKGROUND AND AIMS: In cystic fibrosis (CF), Pseudomonas aeruginosa is not eradicated from the lower respiratory tract and is associated with epithelial inflammation that eventually causes tissue damage. To identify the molecular determinants of an effective response to P. aeruginosa infection, we performed a transcriptomic analysis of primary human bronchial epithelial cells from healthy donors (CTRL) 2, 4, and 6 h after induced P. aeruginosa infection. Compared to noninfected cells, infected cells showed changes in gene activity, which were most marked 6 h postinfection and usually consisted in upregulation. RESULTS: By comparing for each time point of infection, the transcriptomic response of epithelial cells from CF patients and healthy donors, we identified 851, 638, 667, and 980 differentially expressed genes 0, 2, 4, and 6 h postinfection, respectively. Gene selection followed by bioinformatic analysis showed that most of the differentially expressed genes, either up- or downregulated, were in the protein-binding and catalytic gene-ontology categories. Finally, we established that the protein products of the genes exhibiting the greatest differential upregulation (CSF2, CCL2, TNF, CSF3, MMP1, and MMP10) between CF patients and CTRL were produced in higher amounts by infected cells from CF patients versus CTRL. CONCLUSIONS: The differentially expressed genes in CF patients may constitute a signature for a detrimental inflammatory response and for an inefficient P. aeruginosa host-cell response. PMID- 26485690 TI - Thyroid hormone transporters-functions and clinical implications. PMID- 26485691 TI - Obesity: Adiponectin-good for the mother and her offspring? PMID- 26485692 TI - Chest compression using the foot or hand method: a prospective, randomized, controlled manikin study with school children. AB - OBJECTIVE: Maintaining a chest compression depth of 5 cm or more as specified by resuscitation guidelines is difficult. Historical studies have shown an advantage of the foot method (FM) over the hand method (HM) in participants weighing less than 50 kg. Because of the fact that the importance of chest compression is increasing from guideline to guideline, the FM technique had not been evaluated conclusively and worldwide resuscitation is taught to school children, we investigated whether school children achieved a higher quality of chest compression with the FM than with the HM. METHODS: A total of 105 school children, aged 12 to 15 years, were randomized to an FM or an HM resuscitation group. After a 3 min training video, 5 min of practice, and a 5 min latent time, the participants performed a 2 min sequence of chest compressions, which was recorded on a PC and evaluated later. RESULTS: The mean percentage of correct chest compression depth (primary endpoint) was low in both groups (HM 45%, FM 47%, P=0.76). This was also found for those weighing less than 50 kg and at least 50 kg in both groups (FM 23%, HM 34%, P=0.2; FM 62%, HM 56%, P=0.57). However, the HM group was better in frequency (98 vs. 86% in FM, P=0.03) and complete decompression (99 vs. 91% in FM, P<=0.001). CONCLUSION: The FM of applying chest compression did not result in a more accurately delivered compression depth compared with the HM for children and adolescents, irrespective of body weight. PMID- 26485693 TI - Interactive videoconferencing versus audio telephone calls for dispatcher assisted cardiopulmonary resuscitation using the ALERT algorithm: a randomized trial. AB - OBJECTIVES: The ALERT algorithm, a telephone cardiopulmonary resuscitation (CPR) protocol, has been shown to help bystanders initiate CPR. Mobile phone communications may play a role in emergency calls and improve dispatchers' understanding of the rescuer's situation. However, there is currently no validated protocol for videoconference-assisted CPR (v-CPR). We initiated this study to validate an original protocol of v-CPR and to evaluate the potential benefit in comparison with classical telephone-CPR (t-CPR). MATERIALS AND METHODS: We developed an algorithm for v-CPR, adapted from the ALERT t-CPR protocol. A total of 180 students were recruited from secondary school and assigned randomly either to t-CPR or to v-CPR. A manikin was used to evaluate CPR performance. RESULTS: The mean chest compression rate was higher in the v-CPR group (v-CPR: 110+/-16 vs. t-CPR: 86+/-28; P<0.0001), whereas depth was comparable between both groups (v-CPR: 48+/-13 vs. t-CPR: 47+/-16 mm; P=0.64). Hand positioning was correct in 91.7% with v-CPR, but only 68% with t-CPR (P=0.001). There was almost no 'hands-off' period in the v-CPR group [v-CPR: 0 (0 0.4) vs. t-CPR: 7 (0-25.5) s; P<0.0001], but the median no-flow time was increased in the v-CPR group [v-CPR: 146 (128-173.5) vs. t-CPR: 122 (105-143.5) s, P<0.0001]. The overall score of CPR performance was improved in the v-CPR group (P<0.001). CONCLUSION: The v-CPR protocol allows bystanders to reach compression rates and depths close to guidelines and to reduce 'hands-off' events during CPR. PMID- 26485694 TI - Ultrasonography for the diagnosis of patients with clinically suspected skin and soft tissue infections: a systematic review of the literature. AB - BACKGROUND: In patients presenting with skin and soft tissue infections (SSTI), the use of ultrasound may lead to a more accurate distinction between cellulitis and abscess compared with clinical assessment alone. OBJECTIVES: This systematic review aims to determine the diagnostic accuracy of ultrasound for detecting skin abscesses. In addition, it aims to assess the impact of using ultrasound on management decisions in patients with SSTI. METHODS: We searched relevant electronic databases for primary studies including MEDLINE, EMBASE, and CINAHL. We searched conference proceedings, checked references of retrieved articles, and contacted field experts. Two reviewers assessed the quality of each full-text publication using a modified QUADAS-2 tool. RESULTS: Five studies (n=710) fulfilled our inclusion criteria. Four studies compared the diagnostic accuracy of ultrasound with clinical examination alone (n=584). Most studies reported an improvement in diagnostic accuracy. The sensitivity of ultrasound ranged from 89 to 98% and the specificity ranged from 64 to 88%. However, the sensitivity of clinical assessment ranged from 75 to 90% and the specificity ranged from 55 to 83%; most of these results did not reach statistical significance. Sensitivity was further improved in cases of indeterminate clinical assessment. Two studies (n=176) examined the impact of ultrasound on management decisions. Use of ultrasound has led to significant and appropriate changes in management decisions in 16 to 39% of patients. CONCLUSION: The use of ultrasound could potentially improve diagnostic accuracy and lead to improved management decisions in patients with SSTI, especially in cases of indeterminate clinical assessment. Most of our findings did not achieve statistical significance. Further research is required to confirm these findings. PMID- 26485695 TI - An Integrated Glass Nanofluidic Device Enabling In-situ Electrokinetic Probing of Water Confined in a Single Nanochannel under Pressure-Driven Flow Conditions. AB - In-situ measurement of streaming currents in a single nanochannel with femtoliter scale volumes is achieved using an elaborately designed and fabricated glass nanofluidic chip with probe electrodes embedded within the nanochannel. The device and the method suggest a useful nanoscale tool enabling in situ understanding of the unique liquid properties observed in nanofluidic channels. PMID- 26485696 TI - Mindfulness as a Protective Factor for the Burden of Caregivers of Amyotrophic Lateral Sclerosis Patients. AB - OBJECTIVES: Caregivers of people with severe chronic conditions, such as amyotrophic lateral sclerosis (ALS), are at risk of developing depression and anxiety and reduced quality of life. Few studies have explored protective factors in this population and none investigated the role of mindfulness. The study aimed to examine the relationship between mindfulness and health-related outcomes in a population of ALS caregivers. METHODS: We conducted an online survey with ALS caregivers, and again at 4-month follow-up, to assess mindfulness, burden, quality of life, anxiety, and depression. The associations between mindfulness and the other outcomes were evaluated both cross-sectionally and longitudinally. RESULTS: Mindfulness correlated negatively with burden, depression, and anxiety and positively with quality of life, maintaining stability through time. CONCLUSION: Our results showed that mindfulness is positively related to quality of life and negatively related to level of burden. We suggest that this construct can represent a preventative factor toward the negative effects of caregiving. PMID- 26485697 TI - Evaluation of the Dissemination, Implementation, and Sustainability of the "Partnership for Health" Intervention. AB - Partnership for Health (PfH) is an evidence-based, clinician-delivered HIV prevention program conducted in the United States for HIV-positive patients. This intervention strives to reduce risky sexual behaviors through provider-patient discussions on safer sex and HIV status disclosure. A cross-sectional, mixed methods design was used to evaluate the dissemination and implementation of PfH, including training evaluations, an online trainee survey, and interviews with national trainers for PfH. Descriptive statistics were calculated with the categorical data, whereas thematic analysis was completed with the qualitative data. Between 2007 and 2013, PfH was disseminated to 776 individuals from 104 different organizations in 21 states/territories. The smallest proportion of trainees was physicians (6.9%). More than three-fourths of survey respondents (78.6%) reported using PfH, but less than one-third (31.8%) used the intervention with every patient. The PfH training supports the implementation of the intervention; however, challenges were experienced in clinician engagement. Tailored strategies to recruit and train clinicians providing care to HIV positive patients are required. PMID- 26485698 TI - Control of parental investment changes plastically over time with residual reproductive value. AB - Evolutionary conflict between parents and offspring over parental resource investment is a significant selective force on the traits of both parents and offspring. Empirical studies have shown that for some species, the amount of parental investment is controlled by the parents, whereas in other species, it is controlled by the offspring. The main difference between these two strategies is the residual reproductive value of the parents or opportunities for future reproduction. Therefore, this could explain the patterns of control of parental investment at the species level. However, the residual reproductive value of the parents will change during their lifetime; therefore, parental influence on the amount of investment can be expected to change plastically. Here, we investigated control of parental investment when parents were young and had a high residual reproductive value, compared to when they were old and had a low residual reproductive value using a cross-fostering experiment in the burying beetle Nicrophorus quadripunctatus. We found that parents exert greater control over parental investment when they are young, but parental control is weakened as the parents age. Our results demonstrate that control of parental investment is not fixed, but changes plastically during the parent's lifetime. PMID- 26485699 TI - Postprandial effects of the phosphodiesterase-5 inhibitor tadalafil in people with well-controlled Type 2 diabetes mellitus: a randomized controlled trial. PMID- 26485700 TI - Reduction of Advanced Breast Cancer Stages at Subsequent Participation in Mammography Screening. AB - PURPOSE: The decline in advanced breast cancer stages is presumably the most relevant surrogate parameter in mammography screening. It represents the last step in the causal cascade that is expected to affect breast cancer-related mortality. To assess the effectiveness of population-based screening, we analyzed the 2-year incidence rates of advanced breast cancers between women participating in the initial and in the first subsequent round. MATERIALS AND METHODS: The study included data from 19,563 initial and 18,034 subsequent examinations of one digital screening unit (2008 - 2010). Data on tumor stages, detected by screening or within the following interval of two years (2-year incidence), were provided by the epidemiological cancer registry. Rates of all and combined UICC stages 2, 3 and 4 (advanced stages) were reported for a two-year period. Proportions were tested for significance by using chi-square tests (p < 0.001). RESULTS: The 2 year incidence rate of all stages was significantly lower in participants in subsequent screening than in initial screening (0.85 vs. 1.29 per 100 women (%); p < 0.0001). A significantly lower 2-year incidence of advanced stages was observed for subsequent screening compared to initial screening (0.26 % vs. 0.48 %; p = 0.0007). Among women aged 50 to 59 years, the incidence of advanced stages was less clearly different (0.21 % vs. 0.35 %; p = 0.07) than in women aged 60 to 69 years (0.31 % vs. 0.70 %; p = 0.0008). CONCLUSION: During the change from prevalent to incident phase mammography screening, a program impact is seen by a lower 2-year incidence of advanced breast cancers within subsequent compared to initial participants, predominately in women aged 60 to 69 years. KEY POINTS: * The incidence of advanced tumor stages represents the most relevant surrogate parameter for screening effectiveness. * For the first time the 2-year incidence of advanced breast cancer stages after subsequent mammography screening was analyzed. * We observed a significant effect of screening on the 2-year incidence of advanced stages, predominately in the age group 60 to 69 years. PMID- 26485701 TI - Sex Bias and Maternal Contribution to Gene Expression Divergence in Drosophila Blastoderm Embryos. AB - Early embryogenesis is a unique developmental stage where genetic control of development is handed off from mother to zygote. Yet the contribution of this transition to the evolution of gene expression is poorly understood. Here we study two aspects of gene expression specific to early embryogenesis in Drosophila: sex-biased gene expression prior to the onset of canonical X chromosomal dosage compensation, and the contribution of maternally supplied mRNAs. We sequenced mRNAs from individual unfertilized eggs and precisely staged and sexed blastoderm embryos, and compared levels between D. melanogaster, D. yakuba, D. pseudoobscura and D. virilis. First, we find that mRNA content is highly conserved for a given stage and that studies relying on pooled embryos likely systematically overstate the degree of gene expression divergence. Unlike studies done on larvae and adults where most species show a larger proportion of genes with male-biased expression, we find that transcripts in Drosophila embryos are largely female-biased in all species, likely due to incomplete dosage compensation prior to the activation of the canonical dosage compensation mechanism. The divergence of sex-biased gene expression across species is observed to be often due to lineage-specific decrease of expression; the most drastic example of which is the overall reduction of male expression from the neo X chromosome in D. pseudoobscura, leading to a pervasive female-bias on this chromosome. We see no evidence for a faster evolution of expression on the X chromosome in embryos (no "faster-X" effect), unlike in adults, and contrary to a previous study on pooled non-sexed embryos. Finally, we find that most genes are conserved in regard to their maternal or zygotic origin of transcription, and present evidence that differences in maternal contribution to the blastoderm transcript pool may be due to species-specific divergence of transcript degradation rates. PMID- 26485702 TI - Determinants of Frailty and Longevity: Are They the Same Ones? AB - Older people are at risk of developing frailty with advancing age. The prevalence of frailty increases from 2.5-3% in adults aged 65 years to 30-35% in those older than 85 years. These results suggest that an association exists between longevity and frailty. However, at the same time, even at advanced age, the majority of older adults are free of frailty, suggesting that factors different from those contributing to or produced by the life length are involved in producing frailty. Genetic and epigenetic factors, nutrient-sensing systems, mainly the so-called insulin/insulin-like growth factor-1 signaling pathway, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, inflammation, and some hormonal systems are involved in longevity. However, factors involved in frailty are mainly inflammation and hormones, with an anecdotal role for genetic and other potential factors, but even these two common factors seem to regulate longevity and frailty in different ways. Moreover, their effect on frailty seems to change when they are acting in combination. PMID- 26485703 TI - Phenotypic and Functional Alterations in Circulating Memory CD8 T Cells with Time after Primary Infection. AB - Memory CD8 T cells confer increased protection to immune hosts upon secondary viral, bacterial, and parasitic infections. The level of protection provided depends on the numbers, quality (functional ability), and location of memory CD8 T cells present at the time of infection. While primary memory CD8 T cells can be maintained for the life of the host, the full extent of phenotypic and functional changes that occur over time after initial antigen encounter remains poorly characterized. Here we show that critical properties of circulating primary memory CD8 T cells, including location, phenotype, cytokine production, maintenance, secondary proliferation, secondary memory generation potential, and mitochondrial function change with time after infection. Interestingly, phenotypic and functional alterations in the memory population are not due solely to shifts in the ratio of effector (CD62Llo) and central memory (CD62Lhi) cells, but also occur within defined CD62Lhi memory CD8 T cell subsets. CD62Lhi memory cells retain the ability to efficiently produce cytokines with time after infection. However, while it is was not formally tested whether changes in CD62Lhi memory CD8 T cells over time occur in a cell intrinsic manner or are due to selective death and/or survival, the gene expression profiles of CD62Lhi memory CD8 T cells change, phenotypic heterogeneity decreases, and mitochondrial function and proliferative capacity in either a lymphopenic environment or in response to antigen re-encounter increase with time. Importantly, and in accordance with their enhanced proliferative and metabolic capabilities, protection provided against chronic LCMV clone-13 infection increases over time for both circulating memory CD8 T cell populations and for CD62Lhi memory cells. Taken together, the data in this study reveal that memory CD8 T cells continue to change with time after infection and suggest that the outcome of vaccination strategies designed to elicit protective memory CD8 T cells using single or prime boost immunizations depends upon the timing between antigen encounters. PMID- 26485704 TI - PKDL--A Silent Parasite Pool for Transmission of Leishmaniasis in Kala-azar Endemic Areas of Malda District, West Bengal, India. AB - Post Kala-azar Dermal Leishmaniasis (PKDL) is a chronic but not life-threatening disease; patients generally do not demand treatment, deserve much more attention because PKDL is highly relevant in the context of Visceral Leishmaniasis (VL) elimination. There is no standard guideline for diagnosis and treatment for PKDL. A species-specific PCR on slit skin smear demonstrated a sensitivity of 93.8%, but it has not been applied for routine diagnostic purpose. The study was conducted to determine the actual disease burden in an endemic area of Malda district, West Bengal, comparison of the three diagnostic tools for PKDL case detection and pattern of lesion regression after treatment. The prevalence of PKDL was determined by active surveillance and confirmed by PCR based diagnosis. Patients were treated with either sodium stibogluconate (SSG) or oral miltefosine and followed up for two years to observe lesion regression period. Twenty six PKDL cases were detected with a prevalence rate of 27.5% among the antileishmanial antibody positive cases. Among three diagnostic methods used, PCR is highly sensitive (88.46%) for case confirmation. In majority of the cases skin lesions persisted after treatment completion which gradually disappeared during 6 12 months post treatment period. Reappearance of lesions noted in two cases after 1.5 years of miltefosine treatment. A significant number of PKDL patients would remain undiagnosed without active mass surveys. Such surveys are required in other endemic areas to attain the ultimate goal of eliminating Kala-azar. PCR based method is helpful in confirming diagnosis of PKDL, referral laboratory at district or state level can achieve it. So a well-designed study with higher number of samples is essential to establish when/whether PKDL patients are free from parasite after treatment and to determine which PKDL patients need treatment for longer period. PMID- 26485705 TI - Testosterone-Induced Expression of Male Colour Morphs in Females of the Polymorphic Tawny Dragon Lizard, Ctenophorus decresii. AB - Many colour polymorphisms are present only in one sex, usually males, but proximate mechanisms controlling the expression of sex-limited colour polymorphisms have received little attention. Here, we test the hypothesis that artificial elevation of testosterone in females of the colour polymorphic tawny dragon lizard, Ctenophorus decresii, can induce them to express the same colour morphs, in similar frequencies, to those found in males. Male C. decresii, express four discrete throat colour morphs (orange, yellow, grey and an orange central patch surrounded by yellow). We used silastic implants to experimentally elevate testosterone levels in mature females to induce colour expression. Testosterone elevation resulted in a substantial increase in the proportion and intensity of orange but not yellow colouration, which was present in a subset of females prior to treatment. Consequently, females exhibited the same set of colour morphs as males, and we confirmed that these morphs are objectively classifiable, by using digital image analyses and spectral reflectance measurements, and occur in similar frequencies as in males. These results indicate that the influence of testosterone differs for different colours, suggesting that their expression may be governed by different proximate hormonal mechanisms. Thus, caution must be exercised when using artificial testosterone manipulation to induce female expression of sex-limited colour polymorphisms. Nevertheless, the ability to express sex-limited colours (in this case orange) to reveal the same, objectively classifiable morphs in similar frequencies to males suggests autosomal rather than sex-linked inheritance, and can facilitate further research on the genetic basis of colour polymorphism, including estimating heritability and selection on colour morphs from pedigree data. PMID- 26485707 TI - Correction: Lifestyle-Related Factors and Atopy in Seven Danish Population-Based Studies from Different Time Periods. PMID- 26485706 TI - Dietary Intervention for Overweight and Obese Adults: Comparison of Low Carbohydrate and Low-Fat Diets. A Meta-Analysis. AB - BACKGROUND: Reduced calorie, low fat diet is currently recommended diet for overweight and obese adults. Prior data suggest that low carbohydrate diets may also be a viable option for those who are overweight and obese. PURPOSE: Compare the effects of low carbohydrate versus low fats diet on weight and atherosclerotic cardiovascular disease risk in overweight and obese patients. DATA SOURCES: Systematic literature review via PubMed (1966-2014). STUDY SELECTION: Randomized controlled trials with >=8 weeks follow up, comparing low carbohydrate (<=120gm carbohydrates/day) and low fat diet (<=30% energy from fat/day). DATA EXTRACTION: Data were extracted and prepared for analysis using double data entry. Prior to identification of candidate publications, the outcomes of change in weight and metabolic factors were selected as defined by Cochrane Collaboration. Assessment of the effects of diets on predicted risk of atherosclerotic cardiovascular disease risk was added during the data collection phase. DATA SYNTHESIS: 1797 patients were included from 17 trials with <1 year follow up in 12. Compared with low fat diet, low carbohydrate was associated with significantly greater reduction in weight (Delta = -2.0 kg, 95% CI: -3.1, -0.9) and significantly lower predicted risk of atherosclerotic cardiovascular disease events (p<0.03). Frequentist and Bayesian results were concordant. The probability of greater weight loss associated with low carbohydrate was >99% while the reduction in predicted risk favoring low carbohydrate was >98%. LIMITATIONS: Lack of patient-level data and heterogeneity in dropout rates and outcomes reported. CONCLUSIONS: This trial-level meta-analysis of randomized controlled trials comparing LoCHO diets with LoFAT diets in strictly adherent populations demonstrates that each diet was associated with significant weight loss and reduction in predicted risk of ASCVD events. However, LoCHO diet was associated with modest but significantly greater improvements in weight loss and predicted ASCVD risk in studies from 8 weeks to 24 months in duration. These results suggest that future evaluations of dietary guidelines should consider low carbohydrate diets as effective and safe intervention for weight management in the overweight and obese, although long-term effects require further investigation. PMID- 26485708 TI - Identification and Characterization of Circular RNAs As a New Class of Putative Biomarkers in Human Blood. AB - Covalently closed circular RNA molecules (circRNAs) have recently emerged as a class of RNA isoforms with widespread and tissue specific expression across animals, oftentimes independent of the corresponding linear mRNAs. circRNAs are remarkably stable and sometimes highly expressed molecules. Here, we sequenced RNA in human peripheral whole blood to determine the potential of circRNAs as biomarkers in an easily accessible body fluid. We report the reproducible detection of thousands of circRNAs. Importantly, we observed that hundreds of circRNAs are much higher expressed than corresponding linear mRNAs. Thus, circRNA expression in human blood reveals and quantifies the activity of hundreds of coding genes not accessible by classical mRNA specific assays. Our findings suggest that circRNAs could be used as biomarker molecules in standard clinical blood samples. PMID- 26485709 TI - Enhanced G2/M Arrest, Caspase Related Apoptosis and Reduced E-Cadherin Dependent Intercellular Adhesion by Trabectedin in Prostate Cancer Stem Cells. AB - Trabectedin (Yondelis, ET-743) is a marine-derived tetrahydroisoquinoline alkaloid. It is originally derived from the Caribbean marine tunicate Ecteinascidia turbinata and currently produced synthetically. Trabectedin is active against a variety of tumor cell lines growing in culture. The present study focused on the effect of trabectedin in cell proliferation, cell cycle progression, apoptosis and spheroid formation in prostate cancer stem cells (CSCs). Cluster of differentiation (CD) 133+high/CD44+high prostate CSCs were isolated from the DU145 and PC-3 human prostate cancer cell line through flow cytometry. We studied the growth-inhibitory effects of trabectedin and its molecular mechanisms on human prostate CSCs and non-CSCs. DU-145 and PC-3 CSCs were treated with 0.1, 1, 10 and 100 nM trabectedin for 24, 48 and 72 h and the growth inhibition rates were examined using the sphere-forming assay. Annexin-V assay and immunofluorescence analyses were performed for the detection of the cell death. Concentration-dependent effects of trabectedin on the cell cycle were also evaluated. The cells were exposed to the different doses of trabectedin for 24, 48 and 72 h to evaluate the effect of trabectedin on the number and diameter of spheroids. According to the results, trabectedin induced cytotoxicity and apoptosis at the IC50 dose, resulting in a significant increase expression of caspase-3, caspase-8, caspase-9, p53 and decrease expression of bcl-2 in dose dependent manner. Cell cycle analyses revealed that trabectedin induces dose dependent G2/M-phase cell cycle arrest, particularly at high-dose treatments. Three-dimensional culture studies showed that trabectedin reduced the number and diameter of spheroids of DU145 and PC3 CSCs. Furthermore, we have found that trabectedin disrupted cell-cell interactions via E-cadherin in prostasphere of DU 145 and PC-3 CSCs. Our results showed that trabectedin inhibits cellular proliferation and accelerates apoptotic events in prostate CSCs; and may be a potential effective therapeutic agent against prostate cancer. PMID- 26485710 TI - Gray Matter Correlates of Cognitive Performance Differ between Relapsing Remitting and Primary-Progressive Multiple Sclerosis. AB - Multiple Sclerosis (MS) is a chronic inflammatory/demyelinating and neurodegenerative disease of the central nervous system (CNS). Most patients experience a relapsing-remitting (RR) course, while about 15-20% of patients experience a primary progressive (PP) course. Cognitive impairment affects approximately 40-70% of all MS patients and differences in cognitive impairment between RR-MS and PP-MS have been found. We aimed to compare RR-MS and PP-MS patients in terms of cognitive performance, and to investigate the MRI correlates of cognitive impairment in the two groups using measures of brain volumes and cortical thickness. Fifty-seven patients (42 RR-MS, 15 PP-MS) and thirty-eight matched controls underwent neuropsychological (NP) testing and MRI. PP-MS patients scored lower than RR-MS patients on most of the NP tests in absence of any specific pattern. PP-MS patients showed significantly lower caudate volume. There was no significant difference in MRI correlates of cognitive impairment between the two groups except for a prevalent association with MRI measures of cortical GM injury in RR-MS patients and with MRI measures of subcortical GM injury in PP-MS patients. This suggests that although cognitive impairment results from several factors, cortical and subcortical GM injury may play a different role depending on the disease course. PMID- 26485712 TI - High Levels of Nucleolar Spindle-Associated Protein and Reduced Levels of BRCA1 Expression Predict Poor Prognosis in Triple-Negative Breast Cancer. AB - PURPOSE: Nucleolar spindle-associated protein (NuSAP1) is an important mitosis related protein, and aberrant NuSAP1 expression is associated with abnormal spindles and mitosis. This study investigated the prognostic value of NuSAP1 in breast cancer. METHODS: Two sets of tissue microarrays (TMAs) that included samples from 450 breast cancer patients were constructed, of which 250 patients were training set and the other 200 patients were validation set. Immunohistochemical staining was performed to determine the NuSAP1 levels. A Kaplan-Meier analysis was used to estimate the prognostic value of NuSAP1 in breast cancer. A stepwise Cox analysis was performed to construct a risk prediction model for triple-negative breast cancer (TNBC). All statistical analysis was performed with SPSS software. RESULTS: There were 108 (43.5%) and 88 (44.0%) patients expressed NuSAP1 in the training set and validation set respectively. High levels of NuSAP1 expression were related to poor disease-free survival (DFS) in both training (P = 0.028) and validation (P = 0.006) cohorts, particularly in TNBC. With combination of two cohorts, both NuSAP1 (HR = 4.136, 95% CI: 1.956-8.747, P < 0.001) and BRCA1 (HR = 0.383, 95% CI: 0.160-0.915, P = 0.031) were independent prognostic indicators of DFS in TNBC. A receiver operating characteristic (ROC) analysis revealed that the combination of NuSAP1 and BRCA1 significantly improved the prognostic power compared with the traditional model (0.778 versus 0.612, P < 0.001). CONCLUSIONS: Our study confirms the prognostic value of NuSAP1 in breast cancer. The combination of NuSAP1 and BRCA1 could improve the DFS prediction accuracy in TNBC. PMID- 26485711 TI - Singlet Oxygen-Mediated Oxidation during UVA Radiation Alters the Dynamic of Genomic DNA Replication. AB - UVA radiation (320-400 nm) is a major environmental agent that can exert its deleterious action on living organisms through absorption of the UVA photons by endogenous or exogenous photosensitizers. This leads to the production of reactive oxygen species (ROS), such as singlet oxygen (1O2) and hydrogen peroxide (H2O2), which in turn can modify reversibly or irreversibly biomolecules, such as lipids, proteins and nucleic acids. We have previously reported that UVA-induced ROS strongly inhibit DNA replication in a dose-dependent manner, but independently of the cell cycle checkpoints activation. Here, we report that the production of 1O2 by UVA radiation leads to a transient inhibition of replication fork velocity, a transient decrease in the dNTP pool, a quickly reversible GSH dependent oxidation of the RRM1 subunit of ribonucleotide reductase and sustained inhibition of origin firing. The time of recovery post irradiation for each of these events can last from few minutes (reduction of oxidized RRM1) to several hours (replication fork velocity and origin firing). The quenching of 1O2 by sodium azide prevents the delay of DNA replication, the decrease in the dNTP pool and the oxidation of RRM1, while inhibition of Chk1 does not prevent the inhibition of origin firing. Although the molecular mechanism remains elusive, our data demonstrate that the dynamic of replication is altered by UVA photosensitization of vitamins via the production of singlet oxygen. PMID- 26485713 TI - Cancer Therapeutic Effects of Titanium Dioxide Nanoparticles Are Associated with Oxidative Stress and Cytokine Induction. AB - Nanoparticles (NPs) are considered to influence the inflammatory process; however, the precise mechanism and the significance in tumors are still not clear. In this study, when CT26 and LL2 mouse cancer cells were treated with 6-nm anatase titanium dioxide NPs (TDNPs) without ultraviolet irradiation, oxidative stress and induction of inflammatory cytokines were observed. Oxidative stress was further increased by disease-associated conditions such as high glucose concentrations and hypoxia. Inhaled or orally administered TDNPs generated granulomatous lesions in the lungs and colon of the rodent models tested, with increased oxidative stress and inflammatory cytokines. Oxidative stress and inflammatory cytokines were also found in cancer cells treated with gold or carbon black NPs. Treatment of CT26 cells with 10- to 70-nm rutile TDNPs showed that smaller NPs produced more oxidative stress and inflammatory cytokines than larger ones did. To avoid diffusion of TDNPs and to minimize toxicity, 10-nm TDNPs were suspended in a collagen gel inserted into a subcutaneous tumor in a CT26 mouse. A single TDNP treatment via this method inhibited tumor growth in a size- and dose-dependent manner, and resulted in lower levels of urinary 8-OHdG when compared to systemically administered TDNPs. These findings suggest that TDNPs might be useful for the local treatment of tumors. PMID- 26485714 TI - Role of Maternal Antibodies in Infants with Severe Diseases Related to Human Parechovirus Type 3. AB - Human parechovirus type 3 (HPeV3) is an emerging pathogen that causes sepsis and meningoencephalitis in young infants. To test the hypothesis that maternal antibodies can protect this population, we measured neutralizing antibody titers (NATs) to HPeV3 and other genotypes (HPeV1 and HPeV6) in 175 cord blood samples in Japan. The seropositivity rate (>=1:32) for HPeV3 was 61%, similar to that for the other genotypes, but decreased significantly as maternal age increased (p<0.001). Furthermore, during the 2014 HPeV3 epidemic, prospective measurement of NATs to HPeV3 in 45 patients with severe diseases caused by HPeV3 infection showed low NATs (<=1:16) at onset and persistently high NATs (>=1:512) until age 6 months. All intravenous immunoglobulin samples tested elicited high NATs to HPeV3. Our findings indicate that maternal antibodies to HPeV3 may help protect young infants from severe diseases related to HPeV3 and that antibody supplementation may benefit these patients. PMID- 26485715 TI - Spectrotemporal Modulation Detection and Speech Perception by Cochlear Implant Users. AB - Spectrotemporal modulation (STM) detection performance was examined for cochlear implant (CI) users. The test involved discriminating between an unmodulated steady noise and a modulated stimulus. The modulated stimulus presents frequency modulation patterns that change in frequency over time. In order to examine STM detection performance for different modulation conditions, two different temporal modulation rates (5 and 10 Hz) and three different spectral modulation densities (0.5, 1.0, and 2.0 cycles/octave) were employed, producing a total 6 different STM stimulus conditions. In order to explore how electric hearing constrains STM sensitivity for CI users differently from acoustic hearing, normal-hearing (NH) and hearing-impaired (HI) listeners were also tested on the same tasks. STM detection performance was best in NH subjects, followed by HI subjects. On average, CI subjects showed poorest performance, but some CI subjects showed high levels of STM detection performance that was comparable to acoustic hearing. Significant correlations were found between STM detection performance and speech identification performance in quiet and in noise. In order to understand the relative contribution of spectral and temporal modulation cues to speech perception abilities for CI users, spectral and temporal modulation detection was performed separately and related to STM detection and speech perception performance. The results suggest that that slow spectral modulation rather than slow temporal modulation may be important for determining speech perception capabilities for CI users. Lastly, test-retest reliability for STM detection was good with no learning. The present study demonstrates that STM detection may be a useful tool to evaluate the ability of CI sound processing strategies to deliver clinically pertinent acoustic modulation information. PMID- 26485716 TI - In Vivo Quantification of Inflammation in Experimental Autoimmune Encephalomyelitis Rats Using Fluorine-19 Magnetic Resonance Imaging Reveals Immune Cell Recruitment outside the Nervous System. AB - Progress in identifying new therapies for multiple sclerosis (MS) can be accelerated by using imaging biomarkers of disease progression or abatement in model systems. In this study, we evaluate the ability to noninvasively image and quantitate disease pathology using emerging "hot-spot" 19F MRI methods in an experimental autoimmune encephalomyelitis (EAE) rat, a model of MS. Rats with clinical symptoms of EAE were compared to control rats without EAE, as well as to EAE rats that received daily prophylactic treatments with cyclophosphamide. Perfluorocarbon (PFC) nanoemulsion was injected intravenously, which labels predominately monocytes and macrophages in situ. Analysis of the spin-density weighted 19F MRI data enabled quantification of the apparent macrophage burden in the central nervous system and other tissues. The in vivo MRI results were confirmed by extremely high-resolution 19F/1H magnetic resonance microscopy in excised tissue samples and histopathologic analyses. Additionally, 19F nuclear magnetic resonance spectroscopy of intact tissue samples was used to assay the PFC biodistribution in EAE and control rats. In vivo hot-spot 19F signals were detected predominantly in the EAE spinal cord, consistent with the presence of inflammatory infiltrates. Surprising, prominent 19F hot-spots were observed in bone-marrow cavities adjacent to spinal cord lesions; these were not observed in control animals. Quantitative evaluation of cohorts receiving cyclophosphamide treatment displayed significant reduction in 19F signal within the spinal cord and bone marrow of EAE rats. Overall, 19F MRI can be used to quantitatively monitored EAE disease burden, discover unexpected sites of inflammatory activity, and may serve as a sensitive biomarker for the discovery and preclinical assessment of novel MS therapeutic interventions. PMID- 26485717 TI - Zonation of Microbial Communities by a Hydrothermal Mound in the Atlantis II Deep (the Red Sea). AB - In deep-sea geothermal rift zones, the dispersal of hydrothermal fluids of moderately-high temperatures typically forms subseafloor mounds. Major mineral components of the crust covering the mound are barite and metal sulfides. As a result of the continental rifting along the Red Sea, metalliferous sediments accumulate on the seafloor of the Atlantis II Deep. In the present study, a barite crust was identified in a sediment core from the Atlantis II Deep, indicating the formation of a hydrothermal mound at the sampling site. Here, we examined how such a dense barite crust could affect the local environment and the distribution of microbial inhabitants. Our results demonstrate distinctive features of mineral components and microbial communities in the sediment layers separated by the barite crust. Within the mound, archaea accounted for 65% of the community. In contrast, the sediments above the barite boundary were overwhelmed by bacteria. The composition of microbial communities under the mound was similar to that in the sediments of the nearby Discovery Deep and marine cold seeps. This work reveals the zonation of microbial communities after the formation of the hydrothermal mound in the subsurface sediments of the rift basin. PMID- 26485718 TI - CD8 Memory Cells Develop Unique DNA Repair Mechanisms Favoring Productive Division. AB - Immune responses are efficient because the rare antigen-specific naive cells are able to proliferate extensively and accumulate upon antigen stimulation. Moreover, differentiation into memory cells actually increases T cell accumulation, indicating improved productive division in secondary immune responses. These properties raise an important paradox: how T cells may survive the DNA lesions necessarily induced during their extensive division without undergoing transformation. We here present the first data addressing the DNA damage responses (DDRs) of CD8 T cells in vivo during exponential expansion in primary and secondary responses in mice. We show that during exponential division CD8 T cells engage unique DDRs, which are not present in other exponentially dividing cells, in T lymphocytes after UV or X irradiation or in non-metastatic tumor cells. While in other cell types a single DDR pathway is affected, all DDR pathways and cell cycle checkpoints are affected in dividing CD8 T cells. All DDR pathways collapse in secondary responses in the absence of CD4 help. CD8 T cells are driven to compulsive suicidal divisions preventing the propagation of DNA lesions. In contrast, in the presence of CD4 help all the DDR pathways are up regulated, resembling those present in metastatic tumors. However, this up regulation is present only during the expansion phase; i.e., their dependence on antigen stimulation prevents CD8 transformation. These results explain how CD8 T cells maintain genome integrity in spite of their extensive division, and highlight the fundamental role of DDRs in the efficiency of CD8 immune responses. PMID- 26485720 TI - Assessing activities, participation, and quality of life in hemophilia: relevance, current limitations, and possible options. AB - The international classification of functioning (ICF) has provided a basic framework for the measurement of outcomes in any health condition. This includes the assessment of the level of activity, participation, and the quality of life of an individual with hemophilia. The measure of activity is an assessment of the individual's ability to perform daily tasks while participation assesses the social role of the individual. The health-related quality of life is an assessment of the perception of the individual's physical, mental, and social well-being. These functional outcomes are important to understand the impact of the broad spectrum of interventions in the management of hemophilia. The generic instruments used to measure these may be less sensitive than the disease-specific measures but are useful for the comparison between cohorts with different health conditions. Cross-cultural validity is essential for tools where the question can vary in the context of different cultures. PMID- 26485719 TI - Lesion Activity on Brain MRI in a Chinese Population with Unilateral Optic Neuritis. AB - Longitudinal studies have shown that brain white matter lesions are strong predictors of the conversion of unilateral optic neuritis to multiple sclerosis (MS) in Caucasian populations. Consequently brain MRI criteria have been developed to improve the prediction of the development of clinically definite multiple sclerosis (CDMS). In Asian populations, optic neuritis may be the first sign of classical or optic-spinal MS. These signs add to the uncertainty regarding brain MRI changes with respect to the course of unilateral optic neuritis. The aim of this study was to examine the association between brain lesion activity and conversion to CDMS in Chinese patients with unilateral optic neuritis. A small prospective cohort study of 40 consecutive Chinese patients who presented with unilateral optic neuritis was conducted. Brain lesion activity was recorded as the incidence of Gd-enhanced lesions and new T2 lesions. Brain lesions on MRI that were characteristic of MS were defined according to the 2010 revisions of the McDonald criteria. The primary endpoint was the development of CDMS. We found that nineteen patients (48%) had brain lesions that were characteristic of MS on the initial scan. One of these patients (3%) had Gd enhanced brain lesions. A significantly lower percentage of the patients (10%, p<0.001) presented with new T2 brain lesions on the second scan. During a median of 5 years of follow-up, seven patients (18%) developed CDMS. There was no significant difference in the conversion rate to CDMS between patients with and without brain lesions that were characteristic of MS (4/19 and 3/21, respectively; Fisher exact test, one-sided, p = 0.44). We conclude that brain lesions characteristic of MS are common in Chinese patients with unilateral optic neuritis; however, these patients exhibit low lesion activity. The predictive value of brain lesion activity for CDMS requires investigation in additional patients. PMID- 26485721 TI - Novel fibrinogen bbeta chain mutation as an underlying mechanism of afibrinogenemia? PMID- 26485722 TI - A Mutation Model from First Principles of the Genetic Code. AB - The paper presents a neutral Codons Probability Mutations (CPM) model of molecular evolution and genetic decay of an organism. The CPM model uses a Markov process with a 20-dimensional state space of probability distributions over amino acids. The transition matrix of the Markov process includes the mutation rate and those single point mutations compatible with the genetic code. This is an alternative to the standard Point Accepted Mutation (PAM) and BLOcks of amino acid SUbstitution Matrix (BLOSUM). Genetic decay is quantified as a similarity between the amino acid distribution of proteins from a (group of) species on one hand, and the equilibrium distribution of the Markov chain on the other. Amino acid data for the eukaryote, bacterium, and archaea families are used to illustrate how both the CPM and PAM models predict their genetic decay towards the equilibrium value of 1. A family of bacteria is studied in more detail. It is found that warm environment organisms on average have a higher degree of genetic decay compared to those species that live in cold environments. The paper addresses a new codon-based approach to quantify genetic decay due to single point mutations compatible with the genetic code. The present work may be seen as a first approach to use codon-based Markov models to study how genetic entropy increases with time in an effectively neutral biological regime. Various extensions of the model are also discussed. PMID- 26485723 TI - Exponential Synchronization of Coupled Stochastic Memristor-Based Neural Networks With Time-Varying Probabilistic Delay Coupling and Impulsive Delay. AB - This paper deals with the exponential synchronization of coupled stochastic memristor-based neural networks with probabilistic time-varying delay coupling and time-varying impulsive delay. There is one probabilistic transmittal delay in the delayed coupling that is translated by a Bernoulli stochastic variable satisfying a conditional probability distribution. The disturbance is described by a Wiener process. Based on Lyapunov functions, Halanay inequality, and linear matrix inequalities, sufficient conditions that depend on the probability distribution of the delay coupling and the impulsive delay were obtained. Numerical simulations are used to show the effectiveness of the theoretical results. PMID- 26485724 TI - Kohonen's Map Approach for the Belief Mass Modeling. AB - In the framework of the evidence theory, several approaches for estimating belief functions are proposed. However, they generally suffer from the problem of masses attribution in the case of compound hypotheses that lose much conceptual contribution of the theory. In this paper, an original method for estimating mass functions using Kohonen's map derived from the initial feature space and an initial classifier is proposed. Our approach allows a smart mass belief assignment, not only for simple hypotheses but also for disjunctions and conjunctions of hypotheses. Thus, it can model at the same time ignorance, imprecision, and paradox. The proposed method for a basic belief assignment (BBA) is of interest for solving estimation mass functions problems where a large quantity of multivariate data is available. Indeed, the use of Kohonen's map simplifies the process of assigning mass functions. The proposed method has been compared with the state-of-the-art BBA technique on benchmark database and applied on remote sensing data for image classification purpose. Experimentation shows that our approach gives similar or better results than other methods presented in the literature so far, with an ability to handle a large amount of data. PMID- 26485725 TI - Multi-AUV Target Search Based on Bioinspired Neurodynamics Model in 3-D Underwater Environments. AB - Target search in 3-D underwater environments is a challenge in multiple autonomous underwater vehicles (multi-AUVs) exploration. This paper focuses on an effective strategy for multi-AUV target search in the 3-D underwater environments with obstacles. First, the Dempster-Shafer theory of evidence is applied to extract information of environment from the sonar data to build a grid map of the underwater environments. Second, a topologically organized bioinspired neurodynamics model based on the grid map is constructed to represent the dynamic environment. The target globally attracts the AUVs through the dynamic neural activity landscape of the model, while the obstacles locally push the AUVs away to avoid collision. Finally, the AUVs plan their search path to the targets autonomously by a steepest gradient descent rule. The proposed algorithm deals with various situations, such as static targets search, dynamic targets search, and one or several AUVs break down in the 3-D underwater environments with obstacles. The simulation results show that the proposed algorithm is capable of guiding multi-AUV to achieve search task of multiple targets with higher efficiency and adaptability compared with other algorithms. PMID- 26485726 TI - Heart Sound Localization in Respiratory Sound Based on a New Computationally Efficient Entropy Bound. AB - A new entropy bound with low computational complexity for differential Shannon entropy estimation with kernel density approach is proposed in this study, which is based on defining a bound for the Kullback-Leibler divergence between two Gaussian mixture models. The proposed entropy bound is derived to provide computational efficiency without decreasing the accuracy in detecting heart sound segments in respiratory sound. It is shown both theoretically and experimentally that using the proposed bound in an adaptive threshold-based detection method gives very similar performance compared to that obtained by a nonparametric kernel based approach, while its computational cost is much lower. The performance of the proposed method is shown and compared with the three methods in the literature by means of experiments utilizing a database of 20 subjects. The results show that the false negative rate values for the proposed method are 1.45+/-1.50 % and 1.98+/-1.81 % for low and medium flow rates, respectively. These average values are similar to the results obtained by the alternative methods. Moreover, the average elapsed time of the proposed method for a piece of data with a length of 20 s is 0.05 s, which is significantly lower than that of the other methods. PMID- 26485727 TI - Canonical Polyadic Decomposition With Auxiliary Information for Brain-Computer Interface. AB - Physiological signals are often organized in the form of multiple dimensions (e.g., channel, time, task, and 3-D voxel), so it is better to preserve original organization structure when processing. Unlike vector-based methods that destroy data structure, canonical polyadic decomposition (CPD) aims to process physiological signals in the form of multiway array, which considers relationships between dimensions and preserves structure information contained by the physiological signal. Nowadays, CPD is utilized as an unsupervised method for feature extraction in a classification problem. After that, a classifier, such as support vector machine, is required to classify those features. In this manner, classification task is achieved in two isolated steps. We proposed supervised CPD by directly incorporating auxiliary label information during decomposition, by which a classification task can be achieved without an extra step of classifier training. The proposed method merges the decomposition and classifier learning together, so it reduces procedure of classification task compared with that of respective decomposition and classification. In order to evaluate the performance of the proposed method, three different kinds of signals, synthetic signal, EEG signal, and MEG signal, were used. The results based on evaluations of synthetic and real signals demonstrated that the proposed method is effective and efficient. PMID- 26485728 TI - Transfer Latent SVM for Joint Recognition and Localization of Actions in Videos. AB - In this paper, we develop a novel transfer latent support vector machine for joint recognition and localization of actions by using Web images and weakly annotated training videos. The model takes training videos which are only annotated with action labels as input for alleviating the laborious and time consuming manual annotations of action locations. Since the ground-truth of action locations in videos are not available, the locations are modeled as latent variables in our method and are inferred during both training and testing phrases. For the purpose of improving the localization accuracy with some prior information of action locations, we collect a number of Web images which are annotated with both action labels and action locations to learn a discriminative model by enforcing the local similarities between videos and Web images. A structural transformation based on randomized clustering forest is used to map the Web images to videos for handling the heterogeneous features of Web images and videos. Experiments on two public action datasets demonstrate the effectiveness of the proposed model for both action localization and action recognition. PMID- 26485729 TI - Hyperspectral Image Classification via Multitask Joint Sparse Representation and Stepwise MRF Optimization. AB - Hyperspectral image (HSI) classification is a crucial issue in remote sensing. Accurate classification benefits a large number of applications such as land use analysis and marine resource utilization. But high data correlation brings difficulty to reliable classification, especially for HSI with abundant spectral information. Furthermore, the traditional methods often fail to well consider the spatial coherency of HSI that also limits the classification performance. To address these inherent obstacles, a novel spectral-spatial classification scheme is proposed in this paper. The proposed method mainly focuses on multitask joint sparse representation (MJSR) and a stepwise Markov random filed framework, which are claimed to be two main contributions in this procedure. First, the MJSR not only reduces the spectral redundancy, but also retains necessary correlation in spectral field during classification. Second, the stepwise optimization further explores the spatial correlation that significantly enhances the classification accuracy and robustness. As far as several universal quality evaluation indexes are concerned, the experimental results on Indian Pines and Pavia University demonstrate the superiority of our method compared with the state-of-the-art competitors. PMID- 26485730 TI - Thyroid Hormones and Moderate Exposure to Perchlorate during Pregnancy in Women in Southern California. AB - BACKGROUND: Findings from national surveys suggest that everyone in the United States is exposed to perchlorate. At high doses, perchlorate, thiocyanate, and nitrate inhibit iodide uptake into the thyroid and decrease thyroid hormone production. Small changes in thyroid hormones during pregnancy, including changes within normal reference ranges, have been linked to cognitive function declines in the offspring. OBJECTIVES: We evaluated the potential effects of low environmental exposures to perchlorate on thyroid function. METHODS: Serum thyroid hormones and anti-thyroid antibodies and urinary perchlorate, thiocyanate, nitrate, and iodide concentrations were measured in 1,880 pregnant women from San Diego County, California, during 2000-2003, a period when much of the area's water supply was contaminated from an industrial plant with perchlorate at levels near the 2007 California regulatory standard of 6 MUg/L. Linear regression was used to evaluate associations between urinary perchlorate and serum thyroid hormone concentrations in models adjusted for urinary creatinine and thiocyanate, maternal age and education, ethnicity, and gestational age at serum collection. RESULTS: The median urinary perchlorate concentration was 6.5 MUg/L, about two times higher than in the general U.S. POPULATION: Adjusted associations were identified between increasing log10 perchlorate and decreasing total thyroxine (T4) [regression coefficient (beta) = 0.70; 95% CI: -1.06, -0.34], decreasing free thyroxine (fT4) (beta = -0.053; 95% CI: -0.092, -0.013), and increasing log10 thyroid-stimulating hormone (beta = 0.071; 95% CI: 0.008, 0.133). CONCLUSIONS: These results suggest that environmental perchlorate exposures may affect thyroid hormone production during pregnancy. This could have implications for public health given widespread perchlorate exposure and the importance of thyroid hormone in fetal neurodevelopment. CITATION: Steinmaus C, Pearl M, Kharrazi M, Blount BC, Miller MD, Pearce EN, Valentin-Blasini L, DeLorenze G, Hoofnagle AN, Liaw J. 2016. Thyroid hormones and moderate exposure to perchlorate during pregnancy in women in Southern California. Environ Health Perspect 124:861-867; http://dx.doi.org/10.1289/ehp.1409614. PMID- 26485731 TI - Air Pollution and Preterm Birth in the U.S. State of Georgia (2002-2006): Associations with Concentrations of 11 Ambient Air Pollutants Estimated by Combining Community Multiscale Air Quality Model (CMAQ) Simulations with Stationary Monitor Measurements. AB - BACKGROUND: Previous epidemiologic studies suggest associations between preterm birth and ambient air pollution. OBJECTIVE: We investigated associations between 11 ambient air pollutants, estimated by combining Community Multiscale Air Quality model (CMAQ) simulations with measurements from stationary monitors, and risk of preterm birth (< 37 weeks of gestation) in the U.S. state of Georgia. METHODS: Birth records for singleton births >= 27 weeks of gestation with complete covariate information and estimated dates of conception between 1 January 2002 and 28 February 2006 were obtained from the Office of Health Indicators for Planning, Georgia Department of Public Health (n = 511,658 births). Daily pollutant concentrations at 12-km resolution were estimated for 11 ambient air pollutants. We used logistic regression with county-level fixed effects to estimate associations between preterm birth and average pollutant concentrations during the first and second trimester. Discrete-time survival models were used to estimate third-trimester and total pregnancy associations. Effect modification was investigated by maternal education, race, census tract poverty level, and county-level urbanicity. RESULTS: Trimester-specific and total pregnancy associations (p < 0.05) were observed for several pollutants. All the traffic-related pollutants (carbon monoxide, nitrogen dioxide, PM2.5 elemental carbon) were associated with preterm birth [e.g., odds ratios for interquartile range increases in carbon monoxide during the first, second, and third trimesters and total pregnancy were 1.005 (95% CI: 1.001, 1.009), 1.007 (95% CI: 1.002, 1.011), 1.010 (95% CI: 1.006, 1.014), and 1.011 (95% CI: 1.006, 1.017)]. Associations tended to be higher for mothers with low educational attainment and African American mothers. CONCLUSION: Several ambient air pollutants were associated with preterm birth; associations were observed in all exposure windows. CITATION: Hao H, Chang HH, Holmes HA, Mulholland JA, Klein M, Darrow LA, Strickland MJ. 2016. Air pollution and preterm birth in the U.S. state of Georgia (2002-2006): associations with concentrations of 11 ambient air pollutants estimated by combining Community Multiscale Air Quality Model (CMAQ) simulations with stationary monitor measurements. Environ Health Perspect 124:875-880; http://dx.doi.org/10.1289/ehp.1409651. PMID- 26485732 TI - Outcome after percutaneous coronary intervention for different indications: long term results from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). AB - AIMS: The aim of this study was to evaluate clinical outcome for different indications for PCI in an unselected, nationwide PCI population at short- and long-term follow-up. METHODS AND RESULTS: We evaluated clinical outcome up to six years after PCI in all patients undergoing a PCI procedure for different indications in Sweden between 2006 and 2010. A total of 70,479 patients were treated for stable coronary artery disease (CAD) (21.0%), unstable angina (11.0%), non-ST-elevation myocardial infarction (NSTEMI) (36.6%) and ST-elevation myocardial infarction (STEMI) (31.4%). Mortality was higher in STEMI patients at one year after PCI (9.6%) compared to NSTEMI (4.7%), unstable angina (2.2%) and stable CAD (2.0%). At one year after PCI until the end of follow-up, the adjusted mortality risk (one to six years after PCI) and the risk of myocardial infarction were comparable between NSTEMI and STEMI patients and lower in patients with unstable angina and stable CAD. The adjusted risk of stent thrombosis and heart failure was highest in STEMI patients. CONCLUSIONS: The risk of short-term mortality, heart failure and stent thrombosis is highest for STEMI patients after PCI. Therapies to reduce stent thrombosis and heart failure appear to be most important in decreasing mortality in patients with STEMI or NSTEMI undergoing PCI. PMID- 26485733 TI - Four-year durability of clinical and haemodynamic outcomes of transcatheter aortic valve implantation with the self-expanding CoreValve. AB - AIMS: Long-term data on the durability of currently available transcatheter heart valves are limited. We sought to assess four-year clinical and echocardiographic outcomes in patients undergoing transcatheter aortic valve implantation (TAVI) with the CoreValve prosthesis. METHODS AND RESULTS: Between June 2007 and February 2014, 450 consecutive patients with symptomatic severe aortic stenosis underwent TAVI in our institution. For the purposes of this study, we included only those patients undergoing successful TAVI with the CoreValve prosthesis who had a minimum follow-up of four years (n=125). Survival rates at one, two, three and four years were 83.2, 76.8, 73.6 and 66.3%, respectively. Aortic regurgitation was a common finding after the procedure, especially due to paravalvular regurgitation (PVR), which was observed in the majority of patients (71.5%), mostly mild (52.0%). Progression from mild acute PVR to moderate PVR at four-year follow-up was reported in three patients. No cases of severe PVR were observed. Prosthetic valve failure was reported in four patients (3.2%). CONCLUSIONS: Our study demonstrates that favourable outcomes after successful TAVI are associated with sustained clinical and functional cardiovascular benefits up to four-year follow-up. Signs of moderate prosthetic valve failure are present only in a small percentage of patients. PMID- 26485734 TI - The Applied Behavior Analysis Research Paradigm and Single-Subject Designs in Adapted Physical Activity Research. AB - There are basic philosophical and paradigmatic assumptions that guide scholarly research endeavors, including the methods used and the types of questions asked. Through this article, kinesiology faculty and students with interests in adapted physical activity are encouraged to understand the basic assumptions of applied behavior analysis (ABA) methodology for conducting, analyzing, and presenting research of high quality in this paradigm. The purposes of this viewpoint paper are to present information fundamental to understanding the assumptions undergirding research methodology in ABA, describe key aspects of single-subject research designs, and discuss common research designs and data-analysis strategies used in single-subject studies. PMID- 26485736 TI - Gender-Based Correlation Profiles Among the Release Factors and Distance Thrown in Paralympic Seated Shot Put. AB - The purpose of this study was to investigate the relationships among release factors (speed, height, and angle) and distance thrown in Paralympic seated shot put. Forty-eight trials performed by 11 men and 5 women during the 2012 US Paralympic trials in track and field were analyzed. With both genders combined, release speed (r = .95, p < .01) and angle (r = .51, p < .01) showed significant correlations to distance thrown. Release speed (r = .94, p < .01) in men and all release factors (r = .60-.98, p < .02) in women showed significant correlations to distance. Release speed and angle were identified as important predictors of the distance, explaining over 89-96% of the variance in distance thrown. Unlike athletes without disability, seated shot-putters exhibited significant positive speed-angle correlations (combined: r = .37, p < .01; women: r = .57, p = .03). Application of these results should address a focus in training on generating speed through the release point with a consistent release angle. PMID- 26485737 TI - The Impact of Paralympic School Day on Student Attitudes Toward Inclusion in Physical Education. AB - The purpose of this study was to determine if Paralympic School Day (PSD), a published disability awareness program, would have a positive impact on the attitudes of students without disabilities toward the inclusion of students with disabilities in physical education classes. Participants were 143 sixth-grade students who were divided into 2 groups (experimental n = 71, control n = 72), with the experimental group receiving the PSD treatment. Participants responded 2 times to Siperstein's Adjective Checklist and Block's Children's Attitudes Toward Integrated Physical Education-Revised (CAIPE-R) questionnaire. Four ANCOVA tests were conducted. Results indicated a significant PSD treatment effect across all 4 measures: Adjective Checklist (p = .046, eta2 = .03), CAIPE-R (p = .002, eta2 = .04), inclusion subscale (p = .001, eta2 = .05), and sport-modification subscale (p = .027, eta2 = .02). PMID- 26485735 TI - Enjoyment, Barriers, and Beliefs About Physical Activity in Adolescents With and Without Autism Spectrum Disorder. AB - The authors compared physical activity enjoyment, perceived barriers, beliefs, and self-efficacy between adolescents with autism spectrum disorder (ASD) and typically developing (TD) adolescents. A questionnaire was verbally administered to 35 adolescents with ASD and 60 TD adolescents. Compared with TD adolescents, fewer adolescents with ASD enjoyed team sports (65% vs. 95%, p < .001) and physical education (84% vs. 98%, p = .02). A greater proportion of adolescents with ASD perceived that physical activities were too hard to learn (16% vs. 0%, p < .01), and fewer believed that physical activity was a way to make friends (68% vs. 97%, p < .001). Fewer adolescents with ASD preferred to do physical activity in their free time (25% vs. 58%, p < .01). Most adolescents with ASD felt that physical activity is fun (84%), but the proportion was lower than in TD adolescents (98%, p = .03). Some perceptions about physical activity were similar between the 2 groups, but differences identified may inform program development. PMID- 26485738 TI - CAN-flip: A Pilot Gymnastics Program for Children With Cerebral Palsy. AB - This pilot study examined whether an adapted gymnastics program, CAN-flip, could be a feasible activity for children with cerebral palsy (CP) leading to improvements in muscle fitness, motor performance, and physical self-perception. Four girls and 1 boy (9.8 +/- 1.3 yr) with CP participated in this multiple baseline across-subjects design and were randomly assigned to start either the 6 wk gymnastics or the 6-wk control period. Muscle strength, neuromuscular activation, range of motion, gross motor performance, balance, and physical self perception were assessed at baseline, after the first 6-wk period, and at the conclusion of the study. The gymnastics program comprised two 1-hr individualized classes per week. All participants were able to complete the gymnastics classes without injury and showed improvement in specific gymnastics skills. In addition, 3 of the 5 participants registered for regular gymnastics classes after the study, demonstrating the program's usability as a link to inclusive gymnastic classes. PMID- 26485741 TI - [30 years against suicide: a summary of our research on depression and suicide prevention between 1985 and 2015]. AB - In this paper we gather and discuss the results of our workgroup on depression and suicide prevention published between 1985 and 2015. We hope that this summary will focus the interest of the scientific community on suicidology and turn the attention of decision-makers on the fact that despite of its marked decrease in the past three decades, the suicide rate in Hungary is still the second highest in the EU. So, based on expert opinion, joint action is needed in order to achieve a further decrease of suicide rate in Hungary. PMID- 26485742 TI - [Psychedelics and quasi-psychedelics in the light of contemporary research: medical cannabis, MDMA, salvinorin A, ibogaine and ayahuasca]. AB - In lack of professional research and appropriate concepts our scientific knowledge of psychedelic agents is limited. According to the long-held official view these drugs are entirely harmful and have no medical use. However, a recent surge of clinical and pharmacological studies in the field indicates that many psychedelic-like agents have therapeutic potentials under proper circumstances. In this paper, from a biomedical and psychological perspective, we provide a brief review of the general effects and promising treatment uses of medical cannabis, 3,4-methylenedioxy-methamphetamine (MDMA), salvinorin A, ibogaine and the dimethyltryptamine-(DMT)-containing ayahuasca. In Hungary - similarly to many other countries - these compounds are classified as "narcotic drugs" and their research is difficult due to strict regulations. PMID- 26485743 TI - [The cognitive paradigm in the rehabilitation of schizophrenia - focusing on cognitive remediation]. AB - Neurocognitive deficits are core features of schizophrenia and well known to the specialists, concerning researches in Hungary as well. Significance of the topic derives from the fact that according to our present knowledge this is the prime symptom principally affecting everyday functioning and limits benefit of rehabilitation opportunities. The classic psychiatric rehabilitation toolset, either pharmacological or psychosocial, does not provide effective and specific assistance to alleviate the symptoms of the neurocognitive deficits. Despite the increasing presence of the neurocognitive-oriented rehabilitation in international publications and professional forums, cognitive development is rather neglected topic in the Hungarian literature; while the therapeutic practice - with the exception of one institution - is absent from the repertoire of the Hungarian rehabilitation. The purpose of this study is the multi-faceted presentation of recent results in the field of the cognitive remediation, describing the position of cognitive training and its place in the rehabilitation of schizophrenia, with the aim to gain reputation and promote clinical practice among the Hungarian experts. Cognitive remediation is a behavioral training, based on learning theory, with the aim of extensive and long-lasting improvement of cognitive functions of patients suffering from schizophrenia or other mental disorders. Despite the deceptively similar acronym it is important to distinguish this method from the cognitive behavioral therapy which shows similarity in its learning theory basis, but remediation involves much more educational features. Cognitive remediation is not a unified technique, different settings are known, but regardless of form factors it clearly has a specific and positive effect on the neurocognitive functions. It fits well into the rehabilitation methodology, in fact this embeddedness significantly increases its effectiveness and supports emergence of skills in everyday functioning, helping improving disorder outcomes. The generalizing process is partly related to the fact that with the improvement of patients' neurocognitive functions, they become "more accessible" in other therapeutic modalities, increasing their efficiency. Functional and structural changes in relevant cerebral fields correlating with improving neurocognitive performance is proven by growing number of imaging techniques. In addition cost efficiency considerations also support the applicability of the method, which adaptations - in terms of cognitive paradigm - were used in other psychiatric disorders with promising results. PMID- 26485744 TI - Reasons for acute psychiatric admission of patients with dementia. AB - INTRODUCTION: The estimated number of patients living with dementia in Hungary is between 150,000 and 300,000. Hungary's prevalence of vascular dementia is much higher than that of other countries. Patients with dementia can be admitted to psychiatric hospitals for several reasons, the least common of which is cognitive decline. Comorbid psychiatric disorders or dementia-related behavioral disturbances are much more common reasons. AIM: To examine the reasons for the acute psychiatric admission of patients suffering from dementia in a psychiatric center in Budapest. MATERIALS AND METHODS: In this retrospective survey the data of dementia patients who were referred to the Centre for Psychiatry and Addiction Medicine (CPAM) at Szent Istvan and Szent Laszlo Hospitals between August 1 and October 31, 2014 were analyzed with special attention paid to the reasons for hospitalization. RESULTS: Altogether 302 patients were admitted to the CPAM over the study period and 26.15% of them suffered from dementia. The distribution of dementia subtypes was as follows: 43% mixed type (vascular and neurodegenerative), 40.5% vascular type, 11.4% Alzheimer's disease, and 5.1% other types. A small percentage (12.7%) of patients had mild dementia, while 34.2% and 53.2% suffered from moderate and severe dementia, respectively. The major causes of hospitalization were aggressive behavior (34.2%), delirium (19%), and divagation and confusion 15.2% each. They were mainly associated with moderate and severe dementia. Suicide attempt was the reason for admission in 10.1% of cases, and delusions in 6.3%. With regard to admission outcome, 44.3% of patients were transferred to a medical ward, 12% within 3 days of psychiatric admission. Nearly 9% of patients required extended hospitalization, 21.5% were discharged home, 20.3% were transferred to a nursing home and 5.1% died while in hospital. More than half of the patients were rated on the CGI-C scale; 59% of them scored 2 points (much improved), 25% scored 1 point (very much improved) and 16% scored 3 points (moderate improvement). DISCUSSION: A high proportion of dementia patients acutely admitted to a psychiatric ward was medically compromised and either died soon after admission (5%) or was transferred to a medical ward for further treatment. This highlights the importance of a thorough medical work-up including physical examination and laboratory investigations for dementia patients requiring acute psychiatric admission. It is of note that only a small number of patients could be discharged home or to a nursing home. These figures underscore the need for more nursing home places and a better functioning social care system in this field. PMID- 26485745 TI - [Individual differences in sleep macrostructure: effects of anxiety, depression, aging and gender]. AB - OBJECTIVE: Anxiety is one of the most common psychiatric symptoms frequently associated with sleep disorders. Despite the intensive research, the role of sleep in the patomechanism of anxiety has remained unclear. The aim of the study was to investigate the anxiety-related changes in the sleep macrostructure and the impact of ageing, gender and the presence of depression. METHODS: 1083 patients with sleep symptoms were enrolled in the study. All patients have all night polysomnographies. The effect of anxiety, depression, aging and gender on the sleep initiation, maintenance and sleep stages respectively; were analysed in 4 different statistical approaches. RESULTS: Anxiety increased the latency of sleep and REM sleep; and decreased the length of REM sleep and slow-wave sleep; while depressive symptoms were associated with reduced REM latency, slow-wave sleep and increased REM duration. The length of slow-wave sleep, REM phase decreased with ageing and the sleep was fragmented. Women had more slow-wave sleep and less REM sleep than men. CONCLUSION: Normal order of sleep stages is essential in the cognitive processing of the brain. Changes in sleep macrostructure may have an impact in the impairment of cognitive functions of patients suffering from anxiety or depression. PMID- 26485746 TI - Hypermethylation of DLX4 predicts poor clinical outcome in patients with myelodysplastic syndrome. AB - BACKGROUND: Hypermethylation of DLX4 (distal-less homeobox 4) has been disclosed in a variety of cancers. Our work was aimed to examine the pattern of DLX4 methylation and further investigate its clinical relevance in patients with myelodysplastic syndrome (MDS). METHODS: Real-time quantitative methylation specific PCR and bisulfite sequencing PCR were carried out to detect the level of DLX4 methylation. Clinical significance of DLX4 methylation was analyzed between the DLX4 hypermethylated and non-hypermethylated patients. RESULTS: DLX4 was significantly hypermethylated in MDS patients than controls (p<0.001). No significant differences were observed between the hypermethylated and non hypermethylated MDS patients in white blood cells, platelets, age, WHO classifications, FAB classifications, IPSS risks, and common gene mutations (p>0.05). However, DLX4 hypermethylated patients tended to have higher hemoglobin (HB) than DLX4 non-hypermethylated patients (p=0.079). Moreover, there was a trend that male patients, poor karyotype patients, and IPSS Int-2/High patients had a higher frequency of DLX4 hypermethylation (p=0.067, 0.065, and 0.068). DLX4 hypermethylated patients had significantly shorter overall survival than DLX4 non hypermethylated patients (p=0.004). Multivariate analysis confirmed the prognostic value of DLX4 methylation in MDS patients (p<0.001). CONCLUSIONS: Our study indicated that DLX4 hypermethylation was a frequent event and acted as an independent prognostic biomarker in de novo MDS patients. PMID- 26485747 TI - Evaluating the use of procalcitonin in an asymptomatic, HIV-infected antiretroviral therapy-naive, South African cohort. AB - BACKGROUND: The chronic stage of human immunodeficiency virus (HIV) infection, although clinically asymptomatic, is characterized by activation of the immune system and persistent inflammation. Procalcitonin (PCT) has been studied in HIV infection as a marker of bacterial infection. Our aim was to assess the effect of persistent immune activation on PCT levels in asymptomatic treatment naive HIV infected subjects. METHODS: This was a cross-sectional study of 68 asymptomatic antiretroviral therapy-naive HIV infected participants and 42 uninfected controls. Stored serum samples were used to measure: PCT, interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP), high sensitivity C-reactive protein (hsCRP), immunoglobulin G (IgG) and albumin. PCT was correlated with markers of: disease progression (CD4 count and viral load), immune activation (CD 38 on CD8+ T cells, IgG and LBP), inflammation (IL-6, hsCRP and albumin). RESULTS: IL-6, IgG and CD8/38 were all significantly increased while albumin and CD4 counts were significantly lower in the HIV infected group. PCT levels were not significantly different between the two groups. There was no significant difference in LBP and hsCRP; however, their levels were increased in both groups. PCT correlated only with LBP (p=0.0001). IL-6 and LBP correlated positively with hsCRP and IgG. Albumin correlated inversely with IL-6 and viral load. Only IgG and CD8/38 correlated inversely with CD4 counts. CONCLUSIONS: We demonstrated the activation of the innate (raised LBP), humoral (raised IgG) and cellular immune systems (increased CD8/38 T cells). Despite a state of persistent inflammation, PCT levels are not elevated in asymptomatic untreated HIV infection. PMID- 26485748 TI - HB Puerta del Sol [HBA1:c.148A>C], HB Valdecilla [HBA2:c.3G>T], HB Gran Via [HBA2:c.98T>G], HB Macarena [HBA2:c.358C>T] and HB El Retiro [HBA2:c.364_366dupGTG]: description of five new hemoglobinopathies. AB - BACKGROUND: Structural hemoglobinopathies do not usually have a clinical impact, but they can interfere with the analytical determination of some parameters, such as the glycated hemoglobin in diabetic patients. Thalassemias represent a serious health problem in areas where their incidence is high. The defects in the post translational modifications produce hyper-unstable hemoglobin that is not detected by most of electrophoretic or chromatographic methods that are available so far. METHODS: We studied seven patients who belong to six unrelated families. The first two families were studied because they had peak abnormal hemoglobin (Hb) during routine analytical assays. The other four families were studied because they had microcytosis and hypochromia with normal HbA2 and HbF without iron deficiency. HbA2 and F quantification and abnormal Hb separation were performed by chromatographic and electrophoretic methods. The molecular characterization was performed using specific sequencing. RESULTS: The Hb Puerta del Sol presents electrophoretic mobility and elution in HPLC that is different from HbA and similar to HbS. The electrophoretic and chromatographic profiles of the four other variants are normal and do not show any anomalies, and their identification was only possible with sequencing. CONCLUSIONS: Some variants, such as Hb Valdecilla, Hb Gran Via, Hb Macarena and Hb El Retiro, have significant clinical impact when they are associated with other forms of alpha thalassemia, which could lead to more serious forms of this group of pathologies as for HbH disease. Therefore, it is important to maintain an adequate program for screening these diseases in countries where the prevalence is high to prevent the occurrence of severe forms. PMID- 26485749 TI - Quantification of beta-region IgA monoclonal proteins - should we include immunochemical Hevylite(r) measurements? Point. AB - Accurate measurement of IgA monoclonal proteins presents a significant challenge to laboratory staff. IgA heavy/light chain (Hevylite, HLC) analysis is an alternative methodology for monoclonal protein assessment, giving an independent measure of IgAkappa and IgAlambda concentrations. Clonality is assessed by calculating the ratio of involved immunoglobulin to background uninvolved immunoglobulin concentrations (e.g. IgAkappa/IgAlambda in an IgAkappa patient). Here we discuss the challenges faced by the laboratory in IgA monoclonal protein assessment, and compare the performance of Hevylite assays with electrophoresis and total IgA results. We present data which validates the use of Hevylite for response assessment: in most cases, Hevylite provides comparable response assignment to that provided by serum protein electrophoresis (SPE) and total IgA; in other cases Hevylite provides additional information, such as detection of residual disease or relapse. PMID- 26485750 TI - Impact of specimen mixing methods on presepsin point-of-care test results using whole blood. PMID- 26485751 TI - Role of the teneurins, teneurin C-terminal associated peptides (TCAP) in reproduction: clinical perspectives. AB - In humans, the teneurin gene family consists of four highly conserved paralogous genes that are the result of early vertebrate gene duplications arising from a gene introduced into multicellular organisms from a bacterial ancestor. In vertebrates and humans, the teneurins have become integrated into a number of critical physiological systems including several aspects of reproductive physiology. Structurally complex, these genes possess a sequence in their terminal exon that encodes for a bioactive peptide sequence termed the 'teneurin C-terminal associated peptide' (TCAP). The teneurin/TCAP protein forms an intercellular adhesive unit with its receptor, latrophilin, an Adhesion family G protein coupled receptor. It is present in numerous cell types and has been implicated in gamete migration and gonadal morphology. Moreover, TCAP is highly effective at reducing the corticotropin-releasing factor (CRF) stress response. As a result, TCAP may also play a role in regulating the stress-associated inhibition of reproduction. In addition, the teneurins and TCAP have been implicated in tumorigenesis associated with reproductive tissues. Therefore, the teneurin/TCAP system may offer clinicians a novel biomarker system upon which to diagnose some reproductive pathologies. PMID- 26485752 TI - Insulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle. AB - Skeletal muscle is the largest tissues in the human body and is considered the primary target for insulin-stimulated glucose disposal. In skeletal muscle, binding of the insulin to insulin receptor (IR) initiates a signaling cascade that results in the translocation of the insulin-sensitive glucose transporter protein 4 (GLUT4) to the plasma membrane which leads to facilitated diffusion of glucose into the cell. Understanding the precise signaling events guiding insulin stimulated glucose uptake is pivotal, because impairment in these signaling events leads to development of insulin resistance and type 2 diabetes. This review summarizes current understanding of insulin signaling pathways mediating glucose uptake in healthy and insulin-resistant skeletal muscle. PMID- 26485753 TI - High intensity focused ultrasound enhances anti-tumor immunity by inhibiting the negative regulatory effect of miR-134 on CD86 in a murine melanoma model. AB - HIFU has been demonstrated to enhance anti-tumor immunity, however, the mechanism of which has not been well elucidated. Emerging evidence indicates that miRNAs play important roles in immune response. In this study, we used the B16F10 melanoma allograft mouse model to investigate the role of miRNAs in HIFU-enhanced anti-tumor immunity. We found that HIFU treatment decreased circulating B16F10 cells and pulmonary metastasis nodules while increased IFN-gamma and TNF-alpha in the peripheral blood and cumulative mouse survival, which was associated with inhibition of miR-134 expression and activation of CD86 expression in tumor tissues. Further, we determined that miR-134 directly binds to the 3'UTR of CD86 mRNA to suppress its expression in B16F10 cells. When B16F10 cells transfected with miR-134 were co-cultured with normal splenic lymphocytes, the secretion of IFN-gamma and TNF-alpha from lymphocytes was reduced and B16F10 cell survival was increased. HIFU exposure efficiently decreased miR-134 while increased CD86 expression in B16F10 cells in vitro. CD86 knockdown with siRNA markedly rescued the viability of HIFU-treated B16F10 cells that co-cultured with lymphocytes. Altogether, our results suggest that HIFU down-regulates miR-134 to release the inhibition of miR-134 on CD86 in melanoma cells, thereby enhancing anti-tumor immune response. PMID- 26485754 TI - MiR-744 increases tumorigenicity of pancreatic cancer by activating Wnt/beta catenin pathway. AB - The Wnt/beta-catenin signaling pathway, commonly hyperactivated in pancreatic cancer, has been reported to play an important role in the maintenance of stemness of cancer stem cells (CSCs), which is closely related to the progression of pancreatic cancer. Therefore, exploring the regulatory mechanism in Wnt/beta catenin signaling may provide valuable clinical targets for cancer therapy. In the current study, we demonstrated that upregulation of miR-744 in pancreatic cancer promoted Wnt/beta-catenin signaling by directly targeting secreted frizzled-related protein 1 (SFRP1), glycogen synthase kinase 3beta (GSK3beta), and transducin-like enhancer of split 3 (TLE3), important negative modulators of Wnt/beta-catenin signaling. Expression of miR-744 was markedly upregulated in pancreatic cancer and positively correlated with poor patient survival. Furthermore, we found that overexpressing miR-744 enhanced, while inhibiting miR 744 reduced, the stem cell-like phenotype of pancreatic cancer cells in vitro. Importantly, in vivo model of human-derived pancreatic xenografts showed that miR 744 upregulation enhanced the tumorigenicity of pancreatic cancer cells. These findings suggest that miR-744 plays a vital role in promoting the stem cell-like phenotype of pancreatic cancer cells, and may represent a novel prognostic biomarker and therapeutic target. PMID- 26485755 TI - Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses. AB - AIMS: Tumor necrosis is associated with aggressive features of endometrial cancer and poor prognosis. Here, we investigated gene expression patterns and potential treatment targets related to presence of tumor necrosis in primary endometrial cancer lesions. METHODS AND RESULTS: By DNA microarray analysis, expression of genes related to tumor necrosis reflected multiple tumor-microenvironment interactions like tissue hypoxia, angiogenesis and inflammation pathways. A tumor necrosis signature of 38 genes and a related patient cluster (Cluster I, 67% of the cases) were associated with features of aggressive tumors such as type II cancers, estrogen receptor negative tumors and vascular invasion. Further, the tumor necrosis signature was increased in tumor cells grown in hypoxic conditions in vitro. Multiple genes with increased expression are known to be activated by HIF1A and NF-kB. CONCLUSIONS: Our findings indicate that the presence of tumor necrosis within primary tumors is associated with hypoxia, angiogenesis and inflammation responses. HIF1A, NF-kB and PI3K/mTOR might be potential treatment targets in aggressive endometrial cancers with presence of tumor necrosis. PMID- 26485756 TI - Prognostic impact of mismatch repair genes germline defects in colorectal cancer patients: are all mutations equal? AB - BACKGROUND: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by germline mutations in MisMatch Repair (MMR) genes, particularly in MLH1, MSH2 and MSH6. Patients with LS seem to have a more favourable prognosis than those with sporadic CRC, although the prognostic impact of different mutation types is unknown. Aim of our study is to compare survival outcomes of different types of MMR mutations in patients with LS-related CRC. METHODS: 302 CRC patients were prospectively selected on the basis of Amsterdam or Revised Bethesda criteria to undergo genetic testing: direct sequencing of DNA and MLPA were used to examine the entire MLH1, MSH2 and MSH6 coding sequence. Patients were classified as mutation-positive or negative according to the genetic testing result. RESULTS: A deleterious MMR mutation was found in 38/302 patients. Median overall survival (OS) was significantly higher in mutation positive vs mutation-negative patients (102.6 vs 77.7 months, HR:0.63, 95%CI:0.46 0.89, p = 0.0083). Different types of mutation were significantly related with OS: missense or splicing-site mutations were associated with better OS compared with rearrangement, frameshift or non-sense mutations (132.5 vs 82.5 months, HR:0.46, 95%CI:0.16-0.82, p = 0.0153). CONCLUSIONS: Our study confirms improved OS for LS-patients compared with mutation-negative CRC patients. In addition, not all mutations could be considered equal: the better prognosis in CRC patients with MMR pathogenic missense or splicing site mutation could be due to different functional activity of the encoded MMR protein. This matter should be investigated by use of functional assays in the future. PMID- 26485757 TI - Treatment outcomes and late toxicities of 869 patients with nasopharyngeal carcinoma treated with definitive intensity modulated radiation therapy: new insight into the value of total dose of cisplatin and radiation boost. AB - This study was to report the long-term outcomes and toxicities of nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). From 2009 to 2010, 869 non-metastatic NPC patients treated with IMRT were retrospectively enrolled. With a median follow-up of 54.3 months, the 5-year estimated local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were 89.7%, 94.5%, 85.6%, 76.3%, 84.0%, respectively. In locally advanced NPC, gender, T, N, total dose of cisplatin more than 300 mg/m(2) and radiation boost were independent prognostic factors for DMFS and DFS. Age, T, N and total dose of cisplatin were independent prognostic factors for OS. Radiation boost was an adverse factor for LRFS, RRFS, DMFS and DFS. Concurrent chemotherapy was not an independent prognostic factor for survival, despite marginally significant for DMFS in univariate analysis. Concurrent chemotherapy increased xerostomia and trismus, while higher total dose of cisplatin increased xerostomia and otologic toxicities. In conclusion, IMRT provided satisfactory long-term outcome for NPC, with acceptable late toxicities. Total dose of cisplatin was a prognostic factor for distant metastasis and overall survival. The role of concurrent chemotherapy and radiation boost in the setting of IMRT warrants further investigation. PMID- 26485758 TI - Arenobufagin intercalates with DNA leading to G2 cell cycle arrest via ATM/ATR pathway. AB - Arenobufagin, a representative bufadienolide, is the major active component in the traditional Chinese medicine Chan'su. It possesses significant antineoplastic activity in vitro. Although bufadienolide has been found to disrupt the cell cycle, the underlying mechanisms of this disruption are not defined. Here, we reported that arenobufagin blocked the transition from G2 to M phase of cell cycle through inhibiting the activation of CDK1-Cyclin B1 complex; The tumor suppressor p53 contributed to sustaining arrest at the G2 phase of the cell cycle in hepatocellular carcinoma (HCC) cells. Moreover, arenobufagin caused double strand DNA breaks (DSBs) and triggered the DNA damage response (DDR), partly via the ATM/ATR-Chk1/Chk2-Cdc25C signaling pathway. Importantly, we used a synthetic biotinylated arenobufagin-conjugated chemical probe in live cells to show that arenobufagin accumulated mainly in the nucleus. The microscopic thermodynamic parameters measured using isothermal titration calorimetry (ITC) also demonstrated that arenobufagin directly bound to DNA in vitro. The hypochromicity in the UV-visible absorption spectrum, the significant changes in the circular dichroism (CD) spectrum of DNA, and the distinct quenching in the fluorescence intensity of the ethidium bromide (EB)-DNA system before and after arenobufagin treatment indicated that arenobufagin bound to DNA in vitro by intercalation. Molecular modeling suggested arenobufagin intercalated with DNA via hydrogen bonds between arenobufagin and GT base pairs. Collectively, these data provide novel insights into arenobufagin-induced cell cycle disruption that are valuable for the further discussion and investigation of the use of arenobufagin in clinical anticancer chemotherapy. PMID- 26485759 TI - Systematic evaluation of underlying defects in DNA repair as an approach to case only assessment of familial prostate cancer. AB - Risk assessment for prostate cancer is challenging due to its genetic heterogeneity. In this study, our goal was to develop an operational framework to select and evaluate gene variants that may contribute to familial prostate cancer risk. Drawing on orthogonal sources, we developed a candidate list of genes relevant to prostate cancer, then analyzed germline exomes from 12 case-only prostate cancer patients from high-risk families to identify patterns of protein damaging gene variants. We described an average of 5 potentially disruptive variants in each individual and annotated them in the context of public databases representing human variation. Novel damaging variants were found in several genes of relevance to prostate cancer. Almost all patients had variants associated with defects in DNA damage response. Many also had variants linked to androgen signaling. Treatment of primary T-lymphocytes from these prostate cancer patients versus controls with DNA damaging agents showed elevated levels of the DNA double strand break (DSB) marker gammaH2AX (p < 0.05), supporting the idea of an underlying defect in DNA repair. This work suggests the value of focusing on underlying defects in DNA damage in familial prostate cancer risk assessment and demonstrates an operational framework for exome sequencing in case-only prostate cancer genetic evaluation. PMID- 26485760 TI - IDH1 mutation detection by droplet digital PCR in glioma. AB - Glioma is the most frequent central nervous system tumor in adults. The overall survival of glioma patients is disappointing, mostly due to the poor prognosis of glioblastoma (Grade IV glioma). Isocitrate dehydrogenase (IDH) is a key factor in metabolism and catalyzes the oxidative decarboxylation of isocitrate. Mutations in IDH genes are observed in over 70% of low-grade gliomas and some cases of glioblastoma. As the most frequent mutation, IDH1(R132H) has been served as a predictive marker of glioma patients. The recently developed droplet digital PCR (ddPCR) technique generates a large amount of nanoliter-sized droplets, each of which carries out a PCR reaction on one template. Therefore, ddPCR provides high precision and absolute quantification of the nucleic acid target, with wide applications for both research and clinical diagnosis. In the current study, we collected 62 glioma tissue samples (Grade II to IV) and detected IDH1 mutations by Sanger direct sequencing, ddPCR, and quantitative real-time PCR (qRT-PCR). With the results from Sanger direct sequencing as the standard, the characteristics of ddPCR were compared with qRT-PCR. The data indicated that ddPCR was much more sensitive and much easier to interpret than qRT-PCR. Thus, we demonstrated that ddPCR is a reliable and sensitive method for screening the IDH mutation. Therefore, ddPCR is able to applied clinically in predicting patient prognosis and selecting effective therapeutic strategies. Our data also supported that the prognosis of Grade II and III glioma was better in patients with an IDH mutation than in those without mutation. PMID- 26485761 TI - LncRNA ontology: inferring lncRNA functions based on chromatin states and expression patterns. AB - Accumulating evidences suggest that long non-coding RNAs (lncRNAs) perform important functions. Genome-wide chromatin-states area rich source of information about cellular state, yielding insights beyond what is typically obtained by transcriptome profiling. We propose an integrative method for genome-wide functional predictions of lncRNAs by combining chromatin states data with gene expression patterns. We first validated the method using protein-coding genes with known function annotations. Our validation results indicated that our integrative method performs better than co-expression analysis, and is accurate across different conditions. Next, by applying the integrative model genome-wide, we predicted the probable functions for more than 97% of human lncRNAs. The putative functions inferred by our method match with previously annotated by the targets of lncRNAs. Moreover, the linkage from the cellular processes influenced by cancer-associated lncRNAs to the cancer hallmarks provided a "lncRNA point-of view" on tumor biology. Our approach provides a functional annotation of the lncRNAs, which we developed into a web-based application, LncRNA Ontology, to provide visualization, analysis, and downloading of lncRNA putative functions. PMID- 26485763 TI - Age-dependent uncoupling of mitochondria from Ca2+ release units in skeletal muscle. AB - Calcium release units (CRUs) and mitochondria control myoplasmic [Ca2+] levels and ATP production in muscle, respectively. We recently reported that these two organelles are structurally connected by tethers, which promote proximity and proper Ca2+ signaling.Here we show that disposition, ultrastructure, and density of CRUs and mitochondria and their reciprocal association are compromised in muscle from aged mice. Specifically, the density of CRUs and mitochondria is decreased in muscle fibers from aged (>24 months) vs. adult (3-12 months), with an increased percentage of mitochondria being damaged and misplaced from their normal triadic position. A significant reduction in tether (13.8 +/- 0.4 vs. 5.5 +/- 0.3 tethers/100 um2) and CRU-mitochondrial pair density (37.4 +/- 0.8 vs. 27.0 +/- 0.7 pairs/100 um2) was also observed in aged mice. In addition, myoplasmic Ca2+ transient (1.68 +/- 0.08 vs 1.37 +/- 0.03) and mitochondrial Ca2+ uptake (9.6 +/- 0.050 vs 6.58 +/- 0.54) during repetitive high frequency tetanic stimulation were significantly decreased. Finally oxidative stress, assessed from levels of 3-nitrotyrosine (3-NT), Cu/Zn superoxide-dismutase (SOD1) and Mn superoxide dismutase (SOD2) expression, were significantly increased in aged mice. The reduced association between CRUs and mitochondria with aging may contribute to impaired cross-talk between the two organelles, possibly resulting in reduced efficiency in activity-dependent ATP production and, thus, to age dependent decline of skeletal muscle performance. PMID- 26485762 TI - SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells. AB - Targeting anti-apoptotic proteins can sensitize tumor cells to conventional chemotherapies or other targeted agents. Antagonizing the Inhibitor of Apoptosis Proteins (IAPs) with mimetics of the pro-apoptotic protein SMAC is one such approach. We used sensitization compound screening to uncover possible agents with the potential to further sensitize lung adenocarcinoma cells to the SMAC mimetic Debio 1143. Several compounds in combination with Debio 1143, including taxanes, topoisomerase inhibitors, and bromodomain inhibitors, super-additively inhibited growth and clonogenicity of lung adenocarcinoma cells. Co-treatment with Debio 1143 and the bromodomain inhibitor JQ1 suppresses the expression of c IAP1, c-IAP2, and XIAP. Non-canonical NF-kappaB signaling is also activated following Debio 1143 treatment, and Debio 1143 induces the formation of the ripoptosome in Debio 1143-sensitive cell lines. Sensitivity to Debio 1143 and JQ1 co-treatment was associated with baseline caspase-8 expression. In vivo treatment of lung adenocarcinoma xenografts with Debio 1143 in combination with JQ1 or docetaxel reduced tumor volume more than either single agent alone. As Debio 1143 containing combinations effectively inhibited both in vitro and in vivo growth of lung adenocarcinoma cells, these data provide a rationale for Debio 1143 combinations currently being evaluated in ongoing clinical trials and suggest potential utility of other combinations identified here. PMID- 26485764 TI - The quest for GAS vaccine. PMID- 26485765 TI - Identification of specific DNA methylation sites on the Y-chromosome as biomarker in prostate cancer. AB - As a diagnostic biomarker, prostate special antigen (PSA) tests always generate false positive results and lead to unnecessary and/or repeat biopsies. Therefore, there is an urgent need for developing more sensitive, specific diagnostic biomarkers. We epigenotyped methylated sites in cancer tissues and adjacent normal tissues from 66 patients. In comparison with normal adjacent tissues, we observed that there were 6 aberrant methylation sites in prostate cancer tissues on the Y-chromosome. We further performed pyrosequencing using urine of PCa patients and we identified one methylated site (cg05163709) as a potential biomarker. We evaluated the predictive capacity of the aberrant methylated sites using the area under receiver operating characteristic (ROC) curve (AUC). The ROC analysis showed a higher AUC for cg05163709 (0.915) than prostate-specific antigen (PSA, 0.769). These results indicated that aberrant DNA methylation of cg05163709 on the Y-chromosome could serve as a potential diagnostic biomarker with high sensitivity and specificity. PMID- 26485766 TI - Genetic variant of PRKAA1 and gastric cancer risk in an eastern Chinese population. AB - Published data on the association between PRKAA1 rs13361707 T > C polymorphism and gastric cancer (GCa) susceptibility were inconclusive. To derive a more precise estimation of the association, we conducted a large-scale GCa study of 1,124 cases and 1,194 controls to confirm this association in an eastern Chinese population. Our results showed that the C allele of PRKAA1 rs13361707 increased the GC risk in the study population [CT vs. TT, odds ratio (OR) = 1.72, 95% confidence interval (CI) = 1.40-2.12; CC vs. TT, OR = 2.15, 95%CI = 1.70-2.71; CT/CC vs. TT, OR = 1.86, 95%CI = 1.53-2.26; CC vs.TT/CT, OR = 1.49, 95%CI = 1.24 1.79]. In addition, the association of C allele with an increased GCa risk was still significant in subgroups, when stratified by age, sex, tumor site, drinking and smoking status. Moreover, the findings in the present study were validated by our further meta-analysis. In summary, these results indicated that the C allele of PRKAA1 rs13361707 was a low-penetrate risk factor for GCa. PMID- 26485767 TI - CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity. AB - Chemokines and chemokine receptors have critical roles in cancer metastasis and have emerged as one of the targeting options in cancer therapy. However, the treatment efficacy on both tumor and host compartments needs to be carefully evaluated. Here we report that targeting CXCR3 decreased tumor cell migration and at the same time improved host anti-tumor immunity. We observed an increased expression of CXCR3 in metastatic tumor cells compared to those from non metastatic tumor cells. Knockdown (KD) of CXCR3 in metastatic tumor cells suppressed tumor cell migration and metastasis. Importantly, CXCR3 expression in clinical breast cancer samples correlated with progression and metastasis. For the host compartment, deletion of CXCR3 in all host cells in 4T1 mammary tumor model significantly decreased metastasis. The underlying mechanisms involve a decreased expression of IL-4, IL-10, iNOs, and Arg-1 in myeloid cells and an increased T cell response. IFN-gamma neutralization diminished the metastasis inhibition in the CXCR3 knockout (KO) mice bearing 4T1 tumors, suggesting a critical role of host CXCR3 in immune suppression. Consistently, targeting CXCR3 using a small molecular inhibitor (AMG487) significantly suppressed metastasis and improved host anti-tumor immunity. Our findings demonstrate that targeting CXCR3 is effective in both tumor and host compartments, and suggest that CXCR3 inhibition is likely to avoid adverse effects on host cells. PMID- 26485769 TI - A single cut to pyroptosis. PMID- 26485768 TI - Akt inhibition improves irinotecan treatment and prevents cell emergence by switching the senescence response to apoptosis. AB - Activated in response to chemotherapy, senescence is a tumor suppressive mechanism that induces a permanent loss of proliferation. However, in response to treatment, it is not really known how cells can escape senescence and how irreversible or incomplete this pathway is. We have recently described that cells that escape senescence are more transformed than non-treated parental cells, they resist anoikis and rely on Mcl-1. In this study, we further characterize this emergence in response to irinotecan, a first line treatment used in colorectal cancer. Our results indicate that Akt was activated as a feedback pathway during the early step of senescence. The inhibition of the kinase prevented cell emergence and improved treatment efficacy, both in vitro and in vivo. This improvement was correlated with senescence inhibition, p21waf1 downregulation and a concomitant activation of apoptosis due to Noxa upregulation and Mcl-1 inactivation. The inactivation of Noxa prevented apoptosis and increased the number of emergent cells. Using either RNA interference or p21waf1-deficient cells, we further confirmed that an intact p53-p21-senescence pathway favored cell emergence and that its downregulation improved treatment efficacy through apoptosis induction. Therefore, although senescence is an efficient suppressive mechanism, it also generates more aggressive cells as a consequence of apoptosis inhibition. We therefore propose that senescence-inducing therapies should be used sequentially with drugs favoring cell death such as Akt inhibitors. This should reduce cell emergence and tumor relapse through a combined induction of senescence and apoptosis. PMID- 26485771 TI - [Bacteriological profile and antibiotic treatment of postoperative peritonitis]. AB - During the postoperative peritonitis (PPO) the main stay of treatment is the choice of probabilistic antibiotictherapy, it is also the main prognostic factor The aim of our study was to identify anappropriate antibiotic protocol to the current ecology of our unit. It was a retrospective study including 102 patients over a period of 09 years from 1 January 2003 to 3O November 2011. All of them are supported for the treatments off postoperative peritonitis in surgical intensive care unit of a service of general surgery a university hospital Charles Nicolle of Tunis. All bacteriological data (germs and sensitivity), and the terms of therapeutic modality for the empirical antibiotic therapy were listed. The incidence of PPO was Q90%.The average age of our patients was 57 +/- 18 years. The sex ratio was 1.08. One hundred and seven (107) microorganisms were isolated from 72 samples (44 microbial mono, 28 multi microbial). The frequency of gram positive cocci (GPC) was 16.82%, the Gram-negative bacilli (BGN) was 82.2%. The Enterobacteriaceae have proved particularity resistant. Thus, the ampicillin resistance was 87.14%, that the C3G was 33.80%, the Piperacillin to Tazobactam combination, was 36.5% and that the association Ticarcillin-clavulanic acid was 43.6%. For non-fermenting BGN, Pseudomonas aeruginosa was sensitive to ticarcillin in 80% of cases, to ceftazidime in 66.6% of cases, PiperacillinTazobactam--in 71.43% of cases, imipenem in 85 72% of cases, colimycin in 100% of cases and Amiklin in 71.43% of cases. For CGP, enterococci were resistant to ampicillin in 50% of cases and vancomycin in 0% of cases. The majority of patients received triple antibiotic therapy (59.8%) or combination therapy (34.3%). The main associations were: cefotaxime + Gentamycin + Metronidazole (35.2%), Amikacin Imipenem + + Metronidazole (12.7%), Imipenem + amikacin (9.8%), Piperacillin / Tazobactam + amikacin (9.8%) + amikacin and ertapenem (5.88%). Probabilitic antibiotic therapy was addapted in 69.4% of cases. The average duration of the prescribed antibiotic was 11 days +/- 6 days. The mortality rate was 39.2%, was 32.23 days. The isolated microorganisms are those of the intestinal flora which is generally changed and thus the bacteria are selected then are multidrug resistant. Prescribing antibiotics should consider probabilistic. Thus, Imipenem-Amiklin combination seems appropriate to our ecology. This empiric antibiotic therapy is secondarily adapted to the results of susceptibility testing to limit the selection of multi-resistant organisms. PMID- 26485772 TI - [Postoperative peritonitis: pronostic factors of mortality]. AB - The postoperative peritonitis (POP) remains formidable conditions due to a high mortality rate of between 20 and 80%. The purpose of this study is to identify risk factors for mortality. This study is a retrospective, descriptive analysis carried out over a period of 09 years (1/1/2003 - 30/11/2011) and interesting 102 patients supported for POP following general surgery. Achieved in department of General Surgery B Charles Nicolle hospital Tunis. The parameters measured included epidemiological data, data related to the Initial Surgical Intervention and reoperation for POP, terms of management and evolution. Bacteriological data were also seized. The incidence of POP was 0.90%. The average age of our patients was 58 +/- 19 years with a sex ratio of 1.08. Forty-seven percent of our patients belonged to the ASAII class. The initial operation was performed urgently in 49 patients (48%) with a majority belonging to the class II Altemeier (49.01%). Colorectal pathology (373%) and hepatobiliay (176%) were the most frequent reasons for the initial intervention. The frequency of clinical signs were fever (75.5%), hypothermia (6.9%), abdominal pain (725%), abdominal distension (46.1%), productive gastric aspiration (30.4%), abdominal defense (25.5%), externalizing the digestive fluid (25.5%), vomiting (19.6%), diarrhea (12.7%), tachycardia (569%), oliguria (42.2%), respiratory failure (40.2%), hypotension (35.3%), neuropsychiatric disorders ( 23.5%) and jaundice (69%). The treatment period was 2.95 +/- 3.16 days. The surgical recovery time was 78 days +/- 5.66. At the time of reoperation, the APACHE II score was 8.43 +/- 6.26 and 25.1 +/- MPI score 8.53. The POP was generalized in 52.9% of cases with purulent peritoneal fluid in 51% of cases. The most common cause was the dropping of the anastomosis (59.8%). Empirical antibiotic therapy was appropriate in 69.44 % of cases. The mortality rate was 39.2%. Multivariate analysis using multiple logistic regression identified the following factors as independent mortality factors: Age > or = 60 years (RR = 6.089), multiple organ failure (RR = 18.019), non-appropriate empiric antibiotic therapy (RR = 6.541), stercoral aspect of peritoneal fluid (RR 6.412). Despite a low frequency, the POP are burdened with a high mortality rate. The improved prognosis requires early diagnosis in order to allow a appropriate load medicosurgical support before the installation of multiorgan failure syndrome. Among the independent factors associated with mortality that we have identifed, the not adapted empiric antibiotic therapy is the main factor on which we can act. PMID- 26485773 TI - An unusual adenosine cyclic 3',5'-phosphate-dependent protein kinase from Dictyostelium discoideum. AB - The CAMP-dependent protein kinase from Dictyostelium discoideum was extracted from cells at the stage of culmination. Less than 50% of the enzyme remains as a CAMP-dependent holoenzyme in the extracts, and the rest is recovered in the form of dissociated regulatory and catalytic subunits that were purified. The regulatory subunit is a monomeric protein of M, 42 000 that carries only one cAMP binding site (Kd = 3 nM). The catalytic subunit is also a monomer of M, 40000 with a sedimentation coefficient of 3.3S. The CAMP-dependent holoenzyme is a dimer consisting of one regulatory and one catalytic subunit, and the same structure is found for the holoenzyme reconstituted from the isolated subunits. Whereas cAMP binding to the regulatory subunit is independent of pH, both the catalytic activity and its ability to be inhibited by addition of regulatory subunit are increased very strongly between pH 5.5 and 7. The differences in molecular and catalytic properties of this CAMP-dependent protein kinase with those from mammalian origin are discussed in relation with the possibility that the enzyme from Dictyostelium represents an early form of the molecule in the evolutionary process. PMID- 26485770 TI - Chromosome transplantation as a novel approach for correcting complex genomic disorders. AB - Genomic disorders resulting from large rearrangements of the genome remain an important unsolved issue in gene therapy. Chromosome transplantation, defined as the perfect replacement of an endogenous chromosome with a homologous one, has the potential of curing this kind of disorders. Here we report the first successful case of chromosome transplantation by replacement of an endogenous X chromosome carrying a mutation in the Hprt genewith a normal one in mouse embryonic stem cells (ESCs), correcting the genetic defect. The defect was also corrected by replacing the Y chromosome with an X chromosome. Chromosome transplanted clones maintained in vitro and in vivo features of stemness and contributed to chimera formation. Genome integrity was confirmed by cytogenetic and molecular genome analysis. The approach here proposed, with some modifications, might be used to cure various disorders due to other X chromosome aberrations in induced pluripotent stem (iPS) cells derived from affected patients. PMID- 26485774 TI - [The role of inherited thrombophilia and undifferentiated connective tissue dysplasia syndrome in the pathogenesis of female infertility: A clinical and morphological study]. AB - Impaired endometrial receptivity is a major cause of reproductive losses in in vitro fertilization (IVF) cycles given a normal embryo. Its causes may be associated with many diseases, including inherited thrombophilia (IT) and undifferentiated connective tissue dysplasia syndrome (uCTDS). However, endometrial receptivity remains little studied. OBJECTIVE: to investigate the morphological and immunohistochemical substrates of impaired endometrial receptivity in women with uCTDS, IT, and their concurrence. SUBJECTS AND METHODS: Antibodies against ER, PgR, LIF, VEGF, and PAI-1 were used to morphologically and immunohistochemically examine pipelle endometrial biopsy specimens taken from 141 women in the implantation window (on days 6-7 after ovulation). In accordance with their clinical diagnoses, the patients were divided into 4 groups: 1) 13 patients with uCTDS; 2) 100 with IT; 3) 19 with uCTDS and IT; 4) 9 healthy surrogate mothers (a control group). In the examined groups, a total of 145 (90.1%) out of all the IVF protocols were unsuccessful. In the remaining 16 (9.9%) patients without exception, miscarriage started at less than 10 weeks' gestation. RESULTS: In the implantation window, the endometrium was immature in 101 (83.1%) women and corresponded to late proliferation or early secretion phases; 102 (84.3%) women were also found to have no mature pinopodes, pointing to the fact that the endometrial receptivity was very low. Immunohistochemical examination revealed the lower expression of the receptivity marker LIF in the endometrial surface epithelium and its higher expression in the stroma in the study groups (p < 0.05 for the uCTDS and uCTDS+IT groups) and the higher expression of PAI-1 and VEGF in the epithelium, stroma, and endothelium in the study groups than in the control group (p < 0.05), suggesting the intensity of neoangiogenetic processes and impaired fibrinolysis in these patients. CONCLUSION: uCTDS and IT are risk factors of impaired endometrial receptivity in the pathogenesis of infertility. The manifestations of impaired endometrial receptivity in this case are a decrease in mature pinopodes in the surface epithelium; focal stromal sclerosis; and redistribution of the receptivity marker LIF from the surface epithelium to the stroma, which may be used for diagnosis, prediction, and the development of targeted therapy. PMID- 26485775 TI - [Histological and immunohistochemical examinations in the diagnosis of hepatic amyloidosis]. AB - OBJECTIVE: to investigate the histopathology of amyloid in liver biopsy specimens. MATERIAL AND METHODS. A total of 46 liver biopsy specimens were investigated in patients with histologically verified amyloidosis in 2006 to 2009 from the Amyloid Registry of the Charite University Hospital (Berlin). The liver biopsy specimens were fixed in formalin and embedded in paraffin. The paraffin sections were stained with hematoxylin and eosin and with Congo red. Amyloid was immunohistochemically classified using antibodies against amyloid P component, AA amyloid, apolipoprotein Al, lysozyme, fibrinogen, transthyretin, and kappa and lambda light chains. RESULTS: Amyloid deposits were diagnosed in the 46 liver biopsy specimens from 17 women and 29 men (mean age 60 years). Immunohistochemical subtyping was successful in 91% of the cases. AL amyloidosis was diagnosed in 87% of the biopsy specimens and further classified as AL lambda light chain amyloidosis (57%) and AL kappa-light chain amyloidosis (30%). The 46 liver biopsy specimens showed one case of AA amyloidosis (2%) and one case of transthyretin amyloidosis (2%). The type of amyloid could not be classified in 9% of the biopsy specimens. CONCLUSION: The investigation revealed that the most common types of hepatic amyloidosis are AL lambda- and AL kappa-light chain amyloidosis associated with the signs of parenchymal atrophy and steatosis. PMID- 26485776 TI - [Immunohistochemical and genetic profiles of melanomas with spindle cell morphology]. AB - OBJECTIVE: to comparatively study the immunohistochemical profile and to analyze mutations in the BRAF and N-RAS genes. MATERIAL AND METHODS: The spindle cell melanomas taken from the Institute's archives were divided into 6 groups according to the results of clinical and morphological analyses and follow-up studies. Immunohistochemical examination was conducted in 58 cases, including 19 nodular spindle cell melanomas, 10 superficial spreading melanomas, 4 combined melanomas, 8 sarcoma- toid melanomas, 13 mixed desmoplastic melanomas, and 4 pure desmoplastic melanomas. RESULTS: All tumors of the spectrum in question expressed S100, SOX10, KBA.62, nestin, and cyclin D1. The rate of positive staining was 80% for MITF, 69% for PNL2, 61% for HMB45, 58% for Melan A, 36% for CD117, and 35% for SMA. The expression of HMB45 and Melan A was diffuse and marked in the groups of nodular and superficial spreading melanomas; sarcomatoid and mixed desmoplastic melanomas showed only scattered stained cells; pure desmoplastic melanomas were negative to these markers. SMA immunoexpression was observed in only sarcomatoid and desmoplastic types. Dual S100 staining showed a separate actin-positive myofibroblast-like population disappearing in more cellular zones. EMA, claudin 1, and DOG1 were negative in all cases. BRAFV expression was detected in 14% (in 2 nodular and 1 superficial spreading melanomas) and correlated with the presence of mutation. NRAS mutation was found in 1 nodular spindle cell melanoma. Desmoplastic melanomas did not harbor the above mutations. CONCLUSION: This study indicates the variant heterogeneity of spindle cell melanomas, as confirmed by clinical, morphological, immunohistochemical, and molecular examinations. The findings may be useful in the differential diagnosis of these tumors. PMID- 26485777 TI - [Serrated lesions of the large intestine: Prevalence analysis and clinical and morphologic characteristics]. AB - OBJECTIVE: to retrospectively estimate the prevalence of serrated lesions of the large intestine and to reveal the features of dis- tribution of serrated lesions in the previously diagnosed classical adenomas and hyperplastic polyps. MATERIAL AND METHODS: A continuous sampling method was used to take biopsy specimens from the archive material of 440 polypoid lesions of the large intestine, which had entered in 2012-2013, and which were be morphologically reexamined by three experts. The mor- phological criteria for diagnosing different types of serrated lesions were taken according to the 2010 WHO classification of premalignant lesions of the large intestine and to the recommendations from an expert panel (Am J of Gastroenterology 2012). RESULTS: A group of serrated lesions included tubular (13.7%), tubulovillous adenomas (12.5%), and villous (50%) adenomas. The reexamination revealed 121 serrated lesions, including hyperplastic polyps (n = 55 (45.5%)), sessile serrated adenomas/ polyps (SSA/P) (n = 24 (19.8%)), out of which there were those with dysplasia (n=6 (5%)), traditional serrated adenomas (TSAs) (n = 20 (16.5%)), out of which there were those with dysplasia (n = 1 4 (11.6%)), and unclassified serrated polyps (n =22 (18.2%)). Most hyperplastic polyps (89%) and SSA/P (71%) were located distal to the splenic flexure of the colon; TSAs were equally distributed between the proximal and distal portions of the large intestine. The proportion of serrated lesions with dysplasia was 16.5%; that among SSA/P and TSAs was 25 and 70%, respectively. Serrated lesions with dysplasia were more often located proximally and were larger in size than those without dysplasia. CONCLUSION: Serrated lesions of the large intestine are its more common abnormalities than previously thought. The reexamination has revealed that serrated lesions occur in both the preexisting group of hyperplastic polyps and all groups of classical adenomas, suggesting the need for widespread introduction of the current classification intO everyday diagnostic practice. PMID- 26485778 TI - [Role of the skin expression of neuropeptides, neurotrophins and their receptors in the pathogenesis of dermatoses]. AB - OBJECTIVE: to define the role of neurotransmitters and their receptors in the development of itch and in the maintenance of a skin inflammatory response in patients with psoriasis and atopic dermatitis. MATERIAL AND METHODS: Skin biopsy specimens from 30 patients with psoriasis and 30 patients with atopic dermatitis were investigated by histological, immunoperoxidase, and indirect immunofluorescence assays. The investigators determined the expression of protein gene product 9.5 (PGP9.5), amphiregulin, semaphorin 3A, calcitonin gene-related peptide (CGRP) and its receptor (CGRP-R), nerve growth factor (NGF) and its receptor TrkA, and substance P (SP) and its receptor SP-R. The indirect immunofluorescence assay was used for quantitative analysis. The findings were statistically analyzed using a Statistica 10 program. RESULTS: Immunoperoxidase examination of the skin biopsy specimens from patients with atopic dermatitis and psoriasis revealed enhanced expression of amphiregulin, NGF, and PGP9.5, appearance of positively stained epidermal nerve fibers, and decreased expression of the nerve reduction factor semaphorin 3A in all cases. Some patients with atopic dermatitis and psoriasis showed increased expression of CGRP and CGRP-R, SP, SP-R, and TrkA. A pronounced inflammatory response was generally observed in these cases. CONCLUSION: The investigation performed suggests that atopic dermatitis and psoriasis are characterized by a larger number of epidermal nerve fibers and by a direct correlation between this indicator, disease severity, and itch intensity. The production of neuropeptides and neurotrophins is closely related to the development of a skin inflammatory response irrespective of its cause and dysregulation of these processes is likely to favor the body's sensitization and the chronic pattern the course of diseases. PMID- 26485779 TI - [A new classification of ovarian tumors]. AB - In 2014, the WHO published a new classification of ovarian tumors. Modifications refer to all nosological entities, touching on epithelial tumors to a greater extent. The performed studies and the accumulated experience could reveal new mechanisms for the pathogenesis of epithelial neoplasms, identify a new morphological group of seromucinous tumors, and make changes in the grading system for serous carcinomas. The paper discusses the changes made in the 2014 WHO classification of ovarian tumors, by describing their nosological entities and comparing it with the previous revision. PMID- 26485780 TI - [Morphological parameters of the heterogeneity of the substantia nigra in elderly men and women]. AB - OBJECTIVE: to define the quantitative characteristics of cell structures in the substantia nigra pars compacta of neurologically healthy elderly people (men and women). MATERIAL AND METHODS: Autopsy brain materials from neurologically healthy men and women who had died from intercurrent diseases at the age of 72 to 87 years were examined for quantitative characteristics of the substantia nigra pars compacta, by applying computed morphometric methods. RESULTS: In the elderly people (men and women), the compactness of arrangement of neurons, including those containing tyrosine hydroxylase (a marker of dopamine neurons), was much higher and the glial index was lower in the ventral area of the substantia nigra pars compacta than in the dorsal area. Comparing the structures in the substantia nigra pars compacta showed that the neurons were larger in the dorsal area and the variability of the compactness of their arrangement and the glial index were higher in the women than in the men. CONCLUSION: In the elderly people, the cell structures in the substantia nigra pars compacta are typified by high morphometric heterogeneity. PMID- 26485781 TI - [Lymphoepithelioma-like tumors: A review of literature and a clinical case of bladder carcinoma]. AB - The paper presents historical information and literature data on lymphoepitheliomas and lymphoepithelioma-like tumors at various sites. It considers the specific features of their histological structure, a differential diagnostic series, and immunohistochemical markers and gives brief information on treatment and prognosis. The paper depicts a clinical case of lymphoepithelioma like bladder carcinoma in an 80-year-old woman. PMID- 26485782 TI - Benign Fibro-Osseous Lesions of the Craniofacial Area in Children and Adolescents: A Review. AB - Benign fibro-osseous lesions (BFOL) of the craniofacial area are represented by a variety of morphologic processes that are characterized by pathologic ossifications and calcifications in association with a hypercellular fibroblastic marrow element. The current classification includes neoplasms, developmental dysplastic lesions and inflammatory/reactive processes [5]. The final diagnosis depends on-clinical, radiological and pathological features. The clinico pathologic features of this heterogeneous group of diseases are presented in this article. PMID- 26485783 TI - [Molecular and pathomorphological prognostic markers for melanoma: Current approaches and prospects]. AB - The incidence of melanoma demonstrates a persistent increasing tendency, which justifies the need to study and identify new prognostic markers for the development and course of this disease. The given paper shows current approaches to melanoma staging, including those to applying pathomorphological prognostic criteria, and discusses prospects for using the results of genomic and epigenomic studies of the carcinoma in clinical practice. PMID- 26485784 TI - [The Influence of the Functional State of Brain Regulatory Structures on the Programming, Selective Regulation and Control of Cognitive Activity in Children. Report I: Neuropsychological and EEG Analysis of Age-Related Changes in Brain Regulatory Functions in Children Aged 9-12 Years]. AB - Age-related changes in brain regulatory functions in children aged from 9 to 12 years with typical development were studied by means of neuropsychological and EEG analysis. The participants of the study were 107 children without learning difficulties and behavior deviations; they were devided into three groups (9-10, 10-11 and 11-12 years). The neuropsychological tests revealed nonlinear age related changes in different executive brain functions. The group of 10-11-year old children showed better results in programming, in- hibition of impulsive reactions and in the perception of socially relevant information than the group of 9-10- year-old children. At the same time, these children had more difficulties with selective activity regulation as compared with the younger group. The difficulties were mainly caused by switching from one element of the program to another and by retention of learned sequence of actions. These children also showed a lower level of motivation for task performance. The children aged 11-12 years had less difficulties with selective activity regulation; however, impulsive behavior was more frequent; these children also had a higher level of task performance motivation than in children aged 10-11 years. The analysis of resting state EEG revealed age-related differences in deviated EEG patterns associated with non-optimal functioning of fronto-thalamic system and hypothalamic structures. The incidence of these two types of EEG patterns was significantly higher in children aged 10-11 years as compared with children aged 9-10 years. The EEG of the groups of 10-11 and 11-12-years-old children did not show any significant differences. PMID- 26485785 TI - [Integrated Diagnostics Methods for the Treatment of the Individual Disorders of Cognitive Development]. AB - The article presents the results of integrated assessment of 500 children (300 males and 200 females aged from 4 to 12 years) cognitive disorders. The results include a list of the most important pre- and post-natal risk factors. It is shown that multifactor assessment of children with cognitive impairment (including history taking, psychological and neuropsychological examination, clinical, neurophysiological, ultrasonic, duplex and magnetic resonance scanning) allows to detect the main precursory signals of cognitive disorders, to deteremine strong and weak sides of developmental course of a particular child and, basing on that and to develop effective individual programs of intervention. PMID- 26485786 TI - [Neurophysiological Features of Perception of Emotional Stimuli in Health and in Patients with Paranoid Schizophrenia]. AB - Cognitive and emotional disorders, as far as is known, are the main syndromes of schizophrenia. Disorders of these functions are mainly determined by the clinical picture, as well as by psychophysiological correlates. The purpose of our study was to identify some psychophysiological factors which cause perceptual and emotional disturbances in patients with schizophrenia. These disorders of mental functions form the first rank (top) syndrome in patients with schizophrenia [1]. The studied patients had acute psychosis with a predominance of paranoid hallucinatory syndrome and did not receive antipsychotic therapy; i.e., the disturbances of sensory perception were most pronounced. The analysis of early component P100 and intermediate one N170 of event related potentials (ERPs) in the control group showed an increased level of excitation in response to emotionally threatening stimuli; the amplitude increased and the latency decreased in all leads. In contrast the analysis of components P100 and N170 in the group of patients with schizophrenia showed the increased latency and decreased amplitude. The obtained data provide evidence of pathological inhibition in the passive perception of emotionally significant stimuli. PMID- 26485787 TI - [The Features of Saccadic Reactions to a Consequent of Visual Stimuli in Healthy Subjects and Patients with Schizophrenia]. AB - We studied the features of cognitive functions of attention and decision making in 18 healthy subjects and 15 patients with schizophrenia with the use of pairs of two short visual stimuli (double step). In the group of patients with schizophrenia, we observed a higher number of errors and higher frequency of modified saccadic pattern--two saccades to each stimulus instead of only one saccade to the second stimulus. In these patients, the latency period of the first saccade was shorter, while the latency period of a single saccade to the second stimulus was longer as compared with healthy subjects. The lateral differences in the saccade latency in schizophrenic and healthy subjects are opposite. The data provide an evidence of disorders in the cognitive control and prognostic processes of saccade programming in schizophrenic patients. PMID- 26485788 TI - [The Effect of Social-Psychological Factors on the Development of Occupational Stress]. AB - The article presents data on social-psychological factors which cause the occupational stress. The results showed that there is a link between the level of work motivation and the physiological cost of work. We observed a number of peculiarities of occupational stress development caused by psychoemotional tension depending on the class of intensity of intellectual labor; we also studied biological age of the subjects. The speed of ageing of the employees who work under conditions of emotional stress (direct or indirect responsibility for the safety of other people) was found to increase. The study suggested promising directions of occupational stress prevention. PMID- 26485789 TI - [Stabilometry, Electromyography and Electroencephalography in Postmenopausal Women after Training of the Leg Support Sensation]. AB - Ageing, lack of physical activity and sedentary lifestyle cause disorders of the sensorimotor system of postural control. The role of support afferentation in the changes in cortical activity in balance impairments has not been studied yet. The purpose of this study was to investigate the changes in the stabilographic parameters of the body center of gravity, alpha activity indices of the electroencephalography (EEG) and electromyographic (EMG) measurements of forehead muscle tone in response to visual activation in standing and sitting positions in postmenopausal women after and without training of leg support sensation (LSS) The variables were compared between 3 groups: Group A (n = 12, age: 66 +/- 9 years)--women who have trained LSS with the help of Aikido techniques for 8 years; group F (n = 12, age: 65 +/- 6 years)--women who have attended Fitness training for 8 years; group N (n = 11, age: 66 +/- 7 years)--women who have not taken physical exercises for the last 8 years. It was found that in group N a change in body position from "sitting" to "standing" leads to a much greater increase in the area of stabilogram and in the energy expenditure needed to maintain the bal- ance than in groups A and F. Posture changes from sitting to standing position increases the tension of the forehead muscles and the suppression of alpha-1-amplitude, but decreases the power in high- and low frequency alpha-band of EEG and the width of alpha-band in group N. In women ofgroup F the posture change does not result in an increase in EMG and signs of activation or tension in EEG; in group A it leads to a decrease of visual activation indices and psychoemotional tension and to an increase in power in alpha-2-band which is a sign of neuronal efficiency. Basing on these data, we can conclude that training focused on support afferentation in postmenopausal women decreases the psychoemotional tension and increases neuronal efficiency ofsensorimotor integration of postural control system and can be used in the prevention of falls in elderly people. PMID- 26485790 TI - [General Features of the Formation of EEG Wave Structure in Children and Adolescents Living in Northern European Russia]. AB - The article presents the results of the analysis of EEG wave structure formation in children and adolescents aged 7-18 years living under severe conditions of the North. The approaches developed in discrete mathematics (the graph theory, the theory of network flows) were used to assess the time-frequency transformations of EEG patterns. We evaluated conditional probabilities of reciprocal transitions between the components of six frequency bands of E EG (delta, theta, alpha-1, alpha-2, beta-1, beta-2). We described age- and sex-related features as well as regional specificities of the EEG wave structure. We defined the age periods of reorganization of diffuse EEG activities into the main EEG rhythms; the role of distinct rhythms in the maintenance of the EEG wave structure and its dynamic rearrangements was also discussed. The age-related changes of the structure of EEG patterns form some general picture of the morphofunctional development of brain in children and adolescents at different stages of postnatal ontogenesis under severe climate and socio-economic conditions of the North. PMID- 26485791 TI - [Physiological Basis of the Improvement of Movement Accuracy with the Use of Stabilographic Training with Biological Feedback]. AB - We studied the physiological parameters of ball hitting by volleyball players in unsupported position and opportunities for their improvement by training with biological feedback. Physiological and biomechanical parameters of a direct attack hit from supported position correlate with biomechanical features ofjump shots. At the same time, the physiological basis of accuracy of shots consists of the improvement of trunk and arm movement coordination in the flight phase, the factors of intramuscular and intermuscular coordination of the hitting arm and the change in the displacement of the center of pressure. The use of computer stabilography training with biological feedback helps to optimize physiological and biomechanical parameters of physical actions in unsupported position, which ultimately causes an increase in the accuracy of jump hitting of the ball. The obtained results open the prospects for applying the method of computer stabilography to improve the performance of accuracy-targeted actions in unsupported position in various sports. PMID- 26485792 TI - [Relationship between the Parameters of Muscular and Cardiovascular Systems in Graded Exercise Testing in Subjects Doing Regular Exercises and Sports]. AB - We analyzed the relationship between EMG and ECG parameters during graded step dosed exercises with the use of bicycle ergometer in subjects doing regular exercises and sports. We observed the dynamics of EMG and ECG parameters in graded exercise testing. During physical activity of low intensity, muscular effort is mainly due to an increase in the heart rate; during activity of high intensity, the electrophysiological processes of the whole myocardium are involved. The interrelation of the parameters of muscular and cardiovascular systems was proved to increase with the intensity of physical activity. PMID- 26485793 TI - [Hemodynamic Status of Prepubertal and Pubertal Hockey Players]. AB - The hemodynamic status of 11-15-year-old hockey players depending on their age and puberty stage were studied and compared with hemodynamic parameters of the control group. It was found that regular muscle training has a dominant effect on the functional state of cardiovascular system (CVS) in prepuberty and puberty. It was proved that in hockey players a decrease in the heart rate (H R) and an increase in the stroke volume (SV) result in a significant increase in systolic blood pressure (SBP) at the age of 11-14 years and a progressive increase in total peripheral vascular resistance (PVR), in contrast to significantly lower values in the control group. The urgent adaptation of CVS to graduated physical activities at the age of 11-13 years leads to an enhancement of vascular spasmodic reactions while SV remains constant. It was found that in adolescent hockey players have consistently high SV and SBP; at the same time, maximal values of HR, cardiac output (CO) and diastolic blood pressure (DBP) were observed at the stages I and II of the puberty period; then, at the stage III, these parameters decrease. I n the control group, hymodinamic status changed in an opposite way. This may be an evidence of the stress effect of physical activities which results in the adaptive reactions of CVS rather than reactions typical of the puberty period. PMID- 26485794 TI - [The Effect of Repeated Local Ischemia on the Temperature and Skin Microcirculation in Human Hand]. AB - Thermal imaging and laser Doppler flowmetry were applied to study the effects of infrared (IR) radiation mediated by vascular response in healthy volunteers during regular unilateral arteriovenous occlusion of one of the fingers (4 times a day for 7 months with a gradual increase in exposure from 10 to 30 min). After repeated unilateral exposure, we observed consistent changes in temperature conditions and modes of thermoregulation of corresponding skin areas of both hands. We discovered a high level of positive correlation between the dynamics of IR emission from the experimental and control skin areas in the recovery phase after clamping, which indicates that systemic vascular response is involved. The possible mechanisms of post-occlusive changes in skin of the distal phalanges are discussed. These data suggest that multiple regular unilateral arteriovenous occlusions enhance the intradermal blood flow and can be used for the prevention of disorders of the peripheral microcirculation in various pathological conditions. PMID- 26485795 TI - [The Rheological Properties of Blood Depending on Age and Sex]. AB - The rheological properties of blood (viscosity, concentration of red blood cells, erythrocyte sedimantation rate, prothrombin index, and fibrinogen and blood lipid concentration) were studied in apparently healthy subjects of both sexes within the age range from 1 to 75 years. We observed an increase in blood viscosity from infancy to adulthood, followed by a decrease in older age in males. A progressive increase in viscosity is observed in females with aging. We determined three age periods during which the viscosity values remain constant: 1) from the period of early infancy to the second childhood (3.6 +/- 0.07 mPa s regardless of sex); 2) from adolescence to the second period of adulthood (5.1 +/- 0.06 in men; 4.3 +/- 0.05 mPa s in women); 3) elderly and senile age (4.7 +/- 0.13 in men; 4.4 +/- 0.09 mPa s in women). Sex-related differences in the absolute value of blood viscosity (p < 0.001) were discovered in the period of adulthood. Moreover, we observed sex-related differences in the values of determination coefficients of interrelation between viscosity and the level of red blood cells (R(M)2 = 0.41, p < 0.001; R(F)2 = 0.35, p < 0.001), and viscosity and cholesterol level (R(M)2 = 0.47, p < 0.001; R(F)2 = 0.68, p < 0.001) among men and women. The factor analysis showed that blood viscosity correlates with the concentration of red blood cells by 28%; with the level of fibrinogen, by 23%; with the cholesterol concentration, by 20%. PMID- 26485796 TI - [Characteristics of Membrane-Bound Pool of Leukocyte Lactate Dehydrogenase in Healthy Men of Different Age]. AB - The study of isoenzymes of leucocyte lactate dehydrogenase (LDH) in healthy men of different age showed a decrease in the membrane-bound pool of LDH-1 and LDH-4 in 40-year-old males as compared with 20-year-old males. The results indicate an age-related reduction of the reserve membrane-bound pool of several LDH isoforms. PMID- 26485797 TI - [Neurorehabilitation of Patients with Cerebral Palsy]. AB - Cerebral palsy is one of the common diseases that cause significant motor impairments. This review deals with new methods of motor rehabilitation of children with cerebral palsy in terms of modern physiology, as well as with summarized and analyzed results of experimental studies on the effectiveness of these methods. PMID- 26485799 TI - Productivity Commission is reviewing Australia's workplace relations framework. PMID- 26485798 TI - [The Status of Hemostasis System in Hypoxic Nitrogen-Oxygen and Argon-Oxygen Diving Gases]. AB - In this study the effect of factors of hermetic chamber with modified gas medium on the hemostasis system is analyzed in order to estimate and to compare different diving breathing gases. The parameters characterizing pro-, anticoagulant as well as fibrinolytic components of hemostasis were determined using clotting, chromogenic and immunological methods. The applied exposure did not affect the activity and regulatory potential of hemostasis significantly; however, the nitrogen-oxygen and argon-oxygen diving gases have a different effect on the hemostasis functioning, especially in the recovery period. PMID- 26485800 TI - Nurse and midwife to patient ratios victory for QLD. PMID- 26485801 TI - Nursing and Midwifery Health Program cares for the carers. PMID- 26485802 TI - Who really ever believed Tony Abbott's declaration that WorkChoices was dead, buried and cremated'? PMID- 26485803 TI - Exoskeletons to revolutionise rehabilitation. PMID- 26485804 TI - Indigenous health STEPPING INTO THE GAP. PMID- 26485805 TI - Where are the drug keys? PMID- 26485806 TI - Near death experience and nursing practice: lessons from the palliative care literature. PMID- 26485807 TI - Call for a convention on the rights of older people. PMID- 26485808 TI - Be like water. PMID- 26485809 TI - Is anxiety an issue for first year nursing students enrolled in bioscience units? PMID- 26485810 TI - Teaching from lived experience: a way to make mental health nursing more popular? PMID- 26485811 TI - Physical health focus at Wellness Clinic. PMID- 26485812 TI - Building clinical confidence and skills: a placement with a difference. PMID- 26485813 TI - Perinatal mental health nurse service at Flinders Medical Centre. PMID- 26485814 TI - A three dimensional view on mental health recovery. PMID- 26485815 TI - Holistic care approach. PMID- 26485816 TI - Finding my 'own beat' in a multi-disciplinary team. PMID- 26485818 TI - Managing aggression. PMID- 26485817 TI - The meaning of safety in an acute mental health inpatient services. PMID- 26485819 TI - Responding to youth suicide: a film for nurses and health workers. PMID- 26485820 TI - Adjusting to mental health nursing in Australia. PMID- 26485821 TI - Hearing voices. PMID- 26485822 TI - Mental health consumers' recovery in the emergency department. PMID- 26485823 TI - Security guards in mental health settings: starting the conversation. PMID- 26485824 TI - Introduction of restraint and seclusion reduction program in Margaret Tobin Centre 5J. PMID- 26485825 TI - 'Sicoko'. PMID- 26485826 TI - Revisiting Higher Hospital Weekend Mortality. PMID- 26485827 TI - Ebola Virus Disease--An Opportunity in Crisis? PMID- 26485828 TI - Expectations of General Practitioners for Patients Undergoing Elective Total Knee Arthroplasty. AB - Most patients undergoing total knee arthroplasty (TKA) in Ireland are referred to orthopaedic services by their general practitioners (GPs). We aimed to evaluate Irish GPs' expectations for their patients' perioperative experience and post operative return to function. A questionnaire was mailed to 350 GPs in all provinces. This included questions relating to GPs' expectations for their patients and their knowledge and sources of information on TKA. 111 completed questionnaires were returned (response rate 31.7%). Overall expectations for functional and psychological outcomes were high, especially regarding pain relief (108 (97.3%)) expected relief from most or all pre-operative pain), mobility (108 (97.3%)) expected patients to walk medium or long distances) and psychological wellbeing (95 (85.5%) considered this somewhat or very important). Only 22 (20.2%) reported receiving any relevant information or training within the previous year. Overall expectations for functional outcomes were high, however greater communication between surgeons and GPs may improve GP information, PMID- 26485829 TI - Pattern of Change in Renal Function Following Radical Nephrectomy for Renal Cell Carcinoma. AB - Radical nephrectomy (RN) is an independent risk factor for the development of chronic kidney disease (CKD) in those with renal cell carcinoma (RCC). We aimed to examine the pattern of change in post-operative renal function in patients who underwent RN for RCC over a 3 year period at our institution. We performed a retrospective review of histological and biochemical findings in patients undergoing RN for RCC over a 38 month period. Estimated glomerular filtration rate (eGFR) was recorded pre- and post-operatively and at follow-up. We analysed data on 131 patients (median follow-up 24 months). The proportion of patients with advanced CKD increased significantly at follow-up with 48 (85.7%) patients, classified as having stage 2 CKD pre-operatively, being re-classified as stage 3 5. Mean eGFR was significantly lower pre-operatively (76.6 mL/min/1.73 m2) compared to hospital discharge (61 mL/min/1.73 m2, p < 0.001) and follow-up (55.5 mL/min/1.73 m2, p < 0.001). Those with pT1 tumours sustained a significantly greater decline in eGFR compared to other stages. In conclusion, patients with pT1 a and pT1 b tumours sustain a disproportionate decline in renal function and may benefit the most from NSS. PMID- 26485830 TI - Evolution of Carotid Surgical Practice in the last Decade. AB - Stroke units provide immediate care and appropriate intervention in the evolving stroke. The aims of this study were to review the practice of carotid endarterectomy (CEA) before and after the establishment of a Stroke Unit in St. James's Hospital. Prior to the introduction of the Stroke Unit, 263 CEA's were performed over a five-year period. 139/263 (53%) of these were for symptomatic disease. 229 were performed in the five years since. 179/229 (78%) of these were for symptomatic disease. The 30-day stroke and death rates were < 2% before the introduction of the Stroke Unit, and have remained unchanged. Since the introduction of the Stroke Unit, there has been a slight decrease in the overall number of CEA's performed with a 25% increase in the proportion of endarterectomies performed for symptomatic disease. Despite the reduction in surgery for asymptomatic disease the overall 30-day stroke and death rate remains excellent at 2/229 (2%). PMID- 26485831 TI - Trauma Training and Workload: A National Survey. AB - Trauma is a major source of mortality and morbidity throughout Ireland. Training in trauma is dependant on experience gained by trainees within specific posts. Trauma services are a topical issue at present with much discussion about delivery and restructuring. With this in mind we conducted an online survey of trainees in emergency medicine, orthopaedic and general surgery to assess current experience and opinions with regard to trauma. The survey was vetted and distributed by the relevant training bodies. 59(98.33%) respondents believed smaller units should be bypassed for major trauma and 55 (91.67%) believed that larger hospitals receiving major trauma should have a trauma theatre available 24 hours a day. 55 (91.67%) also foresaw themselves covering major trauma as consultants, consequently these trainees will be the consultants developing, moulding and working in this restructured trauma service. PMID- 26485832 TI - Postnatal MRI Brain in Infants Treated for Twin-Twin Transfusion Syndrome. AB - Untreated twin-twin transfusion syndrome (TTTS) is associated with significant mortality and neurological impairment. Fetoscopic laser surgery (FLS) is the treatment of choice. We sought to assess intracranial abnormalities in TTTS twins following treatment. In this prospective, blinded study MRI scans were performed on 3 groups; (1) monochorionic diamniotic (MCDA) twins with TTTS who had undergone FLS (n = 10), (2) MCDA twins without TTTS (n = 8) and (3) dichorionic twins (n = 8). Scans were scored as either normal or abnormal. The primary outcome was a composite of abnormal MRI brain or intrauterine fetal demise. The primary outcome occurred in 6/10 (60%) of the TTTS group versus 3/8 (37.5%) in the MCDA group. The primary outcome was significantly different across all study groups [p = 0.029; X2 = 7.112]. We found that twins treated for TTTS are more likely to have abnormalities on MRI brain at term than other twin groups. This group merits term-corrected MRI as part of their postnatal assessment. PMID- 26485833 TI - Advanced Maternal Age and Assisted Reproductive Technologies in an Irish Population. AB - In recent decades the amount of women over 40 seeking assisted reproductive technology (ART) interventions in order to become pregnant has dramatically increased, both in Ireland and worldwide. This is due to an increase in the average age at which women are choosing to have their first child while additionally, many couples are choosing to have a second family later in life. However, as with natural conception, ART success rates decrease with maternal age. In the present study, we perform a 16 year retrospective analysis on our clinical data of women between 40 and 45 years of age, who have undergone ART at a tertiary referral ART clinic. The percentage of patients in this age group was analysed over time, in order to determine follicle recruitment, % oocyte yield, embryonic quality, positive hCG (pregnancy rate), clinical pregnancy rate and rate of preclinical pregnancy loss. Results from our clinic show that women greater than 43 years of age have a significantly reduced reproductive potential compared to women in the 40 to 42 years age group. Woman in the 43-45 age group showed reduced fertilization rates (53.73% versus 58.82%), reduced positive hCG rates (11.51%0/ versus 19.03%) and clinical pregnancy rates (5.04% versus 12.52%) and increased rates of preclinical pregnancy loss (56.23% versus 34.23%), compared to women in the 40-42 age group. With the age at which couples are choosing to have children constantly increasing, novel ART treatment strategies need to be developed. PMID- 26485834 TI - A Survey of Lung Health and COPD Awareness amongst Participants at a Mobile Spirometry Clinic. AB - Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of death in Ireland. It affects over 440,000 people 10%of Ireland's population), but awareness of COPD is low. COPD Support Ireland is a national charity established to advocate for and support those with COPD. For World COPD Day 2013, a mobile clinic visited 5 locations to provide information about COPD and free spirometry testing. In this study, we evaluated participants' level of knowledge about COPD and whether this was correlated with a number of variables. Participants completed a questionnaire (352). Questionnaires were analysed to ascertain this self-presenting population's characteristics. Most (247, 70.2%) were smokers/ex smokers, yet only 168 (47.7%) knew of COPD. Almost 18% (63, 17.9%) required referral to GPs with abnormal spirometry results. Our findings suggest the need for greater COPD education and awareness to increase earlier diagnosis, reduce health care costs and improve quality of life. PMID- 26485835 TI - Using Social Media to Increase Accessibility to Online Teaching Resources. AB - The key learning points of Surgical Grand Rounds (SGR) are often not accessible at times of exam revision for students. We sought to use Twitter as an online teaching repository. A SGR Twitter profile was created. 23 SGR presentations were made accessible on Twitter over a 3 month period. 93 students were invited to complete a questionnaire assessing usage of the repository. 84 (90%) in total responded, of these, 25 (80.6%) felt that the online provision of SGR through twitter was "useful". The majority (71%) felt that the online content was easily accessible. The novel use of social media is a useful adjunctive educational tool in accessing an online repository of SGR presentations. PMID- 26485836 TI - Congenital Arteriovenous Malformation of the Forearm and Hand. AB - We report the case of an asymptomatic arteriovenous malformation (AVM), extending from the forearm into the palm, in an 11-year-old boy. A debulking procedure was performed meticulously dissecting the lesion from the involved structures. The post-operative course was uncomplicated and no evidence of recurrence was noted at eighteen months follow-up. Extensive AVMs involving structures vital for hand function may be asymptomatic. Clinical follow-up is paramount, due to the inherent risk of recurrence. PMID- 26485837 TI - Therapeutic Hypothermia in ICUs. AB - Recent research on Therapeutic Hypothermia (TH) post cardiac arrest has raised questions about its implementation and benefits. TH to 32-34 degrees C is still included in international guidelines for post-cardiac arrest care. We investigated how Irish ICUs are utilising TH as part of their management of patients post cardiac arrest using a telephone survey of all Irish ICUs. All 25 ICUs in Ireland participated. As of quarter 2 2014, TH was part of post-cardiac arrest management in 20 ICUs (80%), which is similar to international figures. 2011 was the median year for units to start using TH in Ireland. Over half 13 (52%) of Irish ICUs have experience with cooling more than 10 patients. Despite lack of evidence for its benefit, 12 ICUs (48%) use TH for OHCA non VF-VT arrests. Lack of resources was cited by 2 ICUs (8%) as well as no local consensus by 1 ICU (4%) prevented a small minority adopting the protocol. Similar methods of inducing and maintaining TH were found in Ireland as with overseas. Interest was expressed in recent research on TH and in 2 ICUs local practice had changed because of it. An updated international resuscitation guideline is awaited. PMID- 26485838 TI - National Institutes of Health Stroke Scale (NIHSS): Are Hospital Doctors Up To Date? PMID- 26485839 TI - Maintaining Good Quality Clinical Data in Interhospital Transfer. PMID- 26485840 TI - CLINICAL SIGNIFICANCE OF SERUM N-TERMINAL PRO C-TYPE NATRIURETIC PEPTIDE IN HEPATITIS C-RELATED CHRONIC LIVER DISEASES. AB - To evaluate the clinical utility of serum levels of N-terminal pro C-type natruretic pep-tide (NT-pro CNP) in patients with hepatitis C related chronic liver disease (CLD), in prospective to disease complications and progression. This study included 66 hepatitis C-related CLD patients with and without ascites and 15 healthy individuals (control group). Serum NT-pro CNP was measured by ELISA. A stepwise progressive increase in NT-pro CNP levels was recorded through controls, patients without ascites and patients with ascites (p< 0.05). In addition, patients with hematemesis or encephalopathy had more than its double values than those without (p<0.01). Moreover, a significant difference was observed in the marker levels among esophageal varcies stages 1, 2, 3 (H=13.679, p=0.001), with highest levels in grade 3. NT-pro CNP correlated positively with alpha fetoprotein (rs =0.455, p=0.008) with no significant correlation neither with MELD nor Child scores (p>0.05). ROC curve analysis revealed the overall performance of the marker in discriminating CLD patients collectively from controls, the optimum cut-off level was 85 ng/L (AUC= 0. 803, sensitivity 84.8%& specificity 53.3%). An increased level of NT-pro CNP is a promising non-invasive marker of hepatitis C related CLD complications and disease progression. PMID- 26485841 TI - FINE STRUCTURAL STUDY ON EMERIA SP. INFECTING THE LIBYAN JIRDS (MERIONES LIBYCUS) IN SAUDI ARABIA: MEROGONY, MACROGAMETOGENESIS AND HOST-PARASITE RELATIONSHIP. AB - Ultrastructural characteristics of merogony and the development of mature merozoits and macrogametogensis of Eimeria sp. infecting the Libyan jird were investigated. Mono and binucleated schizonts were detected. Developed merozoites showed all the apicomplexan architecture (Pellicle, conoid, rhoptries, micronemes ... etc). Transformation into macrogametes were studied. Early macrogamonts characterized by the loss of all apicomblexan characters and the appearance of wall-forming bodies were the first indication for macrogametogenesis. As development precepded, two types of wall forming bodies (I, II) were clearly detected. Cell organelles including amylopectin granules and lipid globules were greatly increased in mature macrogametes. Young oocyst (zygote) with double-layer oocyst wall were also detected. Host cell reaction due to infection included hypertrophy of the infected host cell, enlargement, deformation and displacement of the host cell nucleus. Swollen and degeneration of mitochondria, endoplasmic reticulum and cytoplasmic vacuolation of the host cell. All parasite stages were enclosed in parasitophorous vacuole limited by unit membrane. Extended damage effect appeared in some neighboring host cell indicating the secretion of some toxins by the parasite. PMID- 26485842 TI - AN INITIAL INDICATION OF PREDISPOSING RISK OF SCHISTOSOMA MANSONI INFECTION FOR HEPATOCELLULAR CARCINOMA. AB - Estimated 500,000 - 1 million cases of hepatocellular carcinoma (HCC) are reported to occur yearly worldwide, with a mean annual incidence of around 3 - 4% of global population. HCC is rapidly fatal in most patients; that makes its incidence and mortality rates almost equal. In the last 5-10 years there were many alarming reports of sharply increased incidence of HCC. In Egypt, HCC reported to account for about 4.7% of chronic liver disease (CLD) patients, which has tremendous impact on socio-economic development in the country. Available data suggests indirect evidence of an association between Schistosoma mansoni and hepatocellular carcinoma, possibly through potentiation of hepatitis infections. The present study was conducted case control analysis of 60 HCC patients. Chronic schistosomiasis cases were confirmed by finding Anti-Schistosoma mansoni antibodies IgG by ELISA. Hepatitis C viral infection was proved by detection of viral load by quantitative Real time PCR. Among the study group 56.6% (34/60) were dweller in rural in Al-Fayoum governorate. Within hepatocellular carcinoma cases 26.7% (16/60) and 33.3% (20/60) suffered mono chronic schistosomiasis and mono hepatitis C (HCV) infections respectively, with no statistically significant differences (p=0.37), indicating comparable risk value of both infections in predisposing directly to HCC. Additionally; frequency of HCC patients with assumed potentiated HCV infection by chronic Schistosoma mansoni 6.7% (4/60) were statistically significant (p<0.05) less among total HCC patients included in this study, when compared to HCC patients preceded by either pure chronic schistosomiasis 26.7% (16/60) or pure HCV infection 33.3% (20/60). Our present study is one of few, addressing the possibility of direct relation between S. mansoni & hepatic carcinoma, concluding an initial indication of equal risk value of both human chronic S. mansoni infection and hepatitis C viral infections in precipitating hepatocellular carcinoma among Egyptian patients. PMID- 26485843 TI - REPELLENT EFFECT OF OCIMUM BASILICUM AND GLYCYRRHIZA GLABRA EXTRACTS AGAINST THE MOSQUITO VECTOR, CULEX PIPIENS (DIPTERA: CULICIDAE). AB - Essential or volatile oils of plants have been variously reported to have many medicinal applications. Methanol, acetone and petroleum ether extracts of Ocimum basilicum and Glycyrrhiza glabra were screened for their repellency effect against Culex pipiens mosquito. The repellent action of the present plants extracts were varied depending on the solvent used and dose of extract. Methanol extract of O. basilicum exhibited the lowest repellent activity as it recorded 77.4% at 6.7mg/cm2. The petroleum ether and acetone extract of 0. basilicum showed repellency of 98.1 & 84.6% respectively, at dose of 6.7mg/cm2, while methanolic extract of G. glabra recorded 73.8 & 50.3% at dose of 6.7 &1.7mg/cm2 respectively, the petroleum ether and acetone extract of G. glabra showed repellency of 76.3 & 81.6%, respectively at dose of 6.7mg/cm2, compared with the commercial formulation, N.N. diethyl toulamide (DEET) which exhibited 100% repellent action at dose of 1.8mg/cm2, respectively. The results may contribute to design an alternative way to control mosquitoes currently based on applications of synthetic insecticides. These extracts could be developed commercially as an effective personal protection meaure against mosquito bites and thus to control diseases caused by mosquito-borne pathogens. PMID- 26485844 TI - TRAINING PROGRAM FOR NURSING STAFF REGARDING VIRAL HEMORRHAGIC FEVERS IN A MILITARY HOSPITAL. AB - Viral hemorrhagic fevers (VHFs) refer to a group of illnesses caused by several distinct families of viruses. In general, the term "viral hemorrhagic fever" is used to describe a severe multisystem syndrome (multisystem in that multiple organ systems in the bpdy are affected). Characteristically, the overall vascular system is damaged, and the body's ability to regulate itself is impaired. These symptoms are often accompanied by hemorrhage (bleeding); however, the bleeding is it rarely life-threatening. While some types of hemorrhagic fever viruses can cause relatively mild illnesses, many of these viruses cause severe, life threatening disease. The selected disaster diseases for this study included: 1 Crimean-Congo hemorrhagic Fever, 2-Dengue Fever, 3-Ebola Fever, 4-Hem-orrhagic Fever with renal syndrome (HFRS), 5-Hantavirus Pulmonary Syndrome, 6-Lassa Fever, 7-Marburg Fever, 8-Rift Valley Fever and 9-Yellow Fever. The educational training program was given over ten sessions to a group of Staff Nurses. The results showed that the program succeeded in enhancing nurse' knowledge, awareness, responsibility, and obligations toward patients with the Viral Hemorrhagic Fevers The results showed a significant impact of training sessions illuminated in the follow-up test on the knowledge score of nurses in all types of diseases except for the Congo hemorrhagic fever, while, statistical significance varied in some diseases in the study when it comes to the comparison between pretest and post test. All results confirmed on the positive impact of the training program in enhancing the knowledge of nurses toward VHFs patients and their relevant. There was a significant positive impact of the training sessions on changing the attitude of nurses toward patients with VHFs. This result was confirmed on the collective level since the total scores on tests revealed significant positive impact of the study on changing the attitude of nurses toward relevant patients. The relationship included personal data (age, sex, level of education, & years of experiences) and main variables (knowledge scores & attitude change to patients) with the disease in question. This part revealed a significant relationship between all personal data and total knowledge score among nurses except for the level of education, while all results were insignificant for the relationship between the personal data and the nurses' attitude. Difference between the total nurses' attitude change and the total knowledge scores was significant on the three tests' levels; pre, post, and the follow-up. The overall evaluation showed that six criteria were adopted, regarding the educator, the length of presentations, the evaluation of the studied groups regarding the training facilities, the subject matters, the overall training program, and the importance of diseases in question to their practical working environment. The frequency distribution showed that the educator met nurses' expectations; the material tools were plausible enough to satisfy trainees and presentations were fairly short. But, the training facilities were just excellent by the vast majority of trainees. The entire material met specific needs of relevant health care organizations, but about 43% reported that it was difficult. The vast majority of trainees favored the program under almost all criteria studied in the final questionnaire. Above 50% of trainees were not confident enough toward their ability in applying their knowledge acquired practically. The final evaluation showed that the most important were Rift Valley fever, Ebola fever, Hanta virus pulmonary syndrome, Crimean Congo fever and lastly Dengue fever. Lassa and Marburg fevers were of less interest to nurses. PMID- 26485845 TI - DETECTION OF GIARDIA INTESTINALIS COPROANTIGENS IN DIARRHEIC SAMPLES BY IMMUNOCHROMATOGRAPHIC AND ELISATECHNIQUES. AB - Giardia intestinalis is one of the most common diarrhea-causing protozoa. The present study aimed to search for specific and sensitive diagnostic tests to avoid loss of infected cases with Giardia intestinalis by detection of G. intestinalis coproantigens in diarrheic samples through comparison between direct parasitological method, an enzyme linked immunosorbent assay (ELISA) and immunochromatographic test (ICT). A comparative cross-sectional study including 75 cases suffering from diarrhea and other gastrointestinal symptoms suggestive of intestinal giardiasis as abdominal distention, abdominal pain, anorexia, nausea, vomiting and weight loss, and 25 cases were without any clinical manifestations enrolled in this study. For every case, complete history taking and full clinical examination were done. Stool samples were collected from all cases and investigated by direct parasitological method, ELISA, and immunochromatographic techniques. The results showed that the sensitivity of immunochromatographic technique was 96% and specificity was 96% while sensitivity of ELISA was 98% and specificity was 96% on comparing their results to the microscopic examination of stool samples for Giardia intestinalis. PMID- 26485846 TI - COMPARISON OF PAIN CONTROL DURING TRUS GUIDED BIOPSIES BETWEEN BASAL PERI PROSTATIC LOCAL INFILTRATION ANESTHESIA VERSUS COMBINED TOPICAL ANAL LIGNOCAINE OINTMENT AND LOCAL INFILTRATION ANESTHESIA. AB - Control of pain associated with TRUS guided biopsies was the target of many researches that tried peri-prostatic local infiltration anesthesia (PLIA) either basal, apical, combined or topical anesthesia (TA). Thus, the efficacy of (PLIA) alone versus (PLIA) combined with (TA) in pain control during TRUS guided biopsies was compared. A total of 163 patients with a mean age+/-2stdev (61+/-1.4 years) and a mean PSA +/- 2stdev (8.5+/-1. lng/ml) 84 patients (Gl) were randomized to receive either PLIA alone (Gl) or 79 patients (G2) combined TA (using lignocaine 5% ointment of the anal ring, anal canal, and anterior rectal wall and basal PLIA via injecting 5 ml 2% xylocaine in both sides of the base), with cross-matched mean ages. Patients were asked to scale pain from 0-10 during probe insertion (P1), periprostatic infiltration (P2) and after taking biopsies in all patients (P3) using the visual analogue pain scale to complete a visual analogue scale questionnaire. The patients in G2 showed significantly less pain scores at all stages of the procedure (P1, P2 & P3) in comparison tp patients in G1 especially regarding P1 and P2. The mean reported pain score was 24, 4+/-5, 6 and 15, 8+/-3.8 for G1 & G2 respectively, with significant difference (p=0,022). PMID- 26485847 TI - A TRAINING PROGRAM FOR NURSING STAFF ON HEALTH HAZARDS OF CHEMICAL INSECTICIDES EXPOSURE IN A PRACTICAL FIELD. AB - An insecticide is an agent used against insects, ticks, mites and other animals affecting human welfare. Exposure to Insecticides is one of the most important occupational risks among staff worker in Military camp, veterinary medicine, industry and household as well as schools and hospitals. This study Aimed to improve nursing staff knowledge regarding adverse health effects of chemical insecticides exposure in a military field. SETTING: The study was conducted in one of the Main Military Hospital. RESEARCH DESIGN: was used a quasi-experimental research design to conduct this study. SUBJECT: all nursing staff who work in a Military Hospital (n=55) who accept to participate in the research study. RESULTS: A significant improvement in the Nurses' Total knowledge score was found in post-test as compared to that in pre-test. All nurses obtained a satisfactory level of knowledge after the 1st & 2nd post-tests; all of them evaluate the program in relation to trainees' exnectations as "excellent". PMID- 26485848 TI - LAPAROSCOPIC MANAGEMENT OF DISTAL URETERIC STONE IN BILHARZIAL URETER: RESULTS OF A SINGLE CENTER PROSPECTIVE STUDY. AB - No doubt, Bilharzial ureters are complicated by distal stricture due to precipitation of Bilharzial ova in distal ureter. These cases are associated with poorly functioning and grossly hydronephroic kidneys that hinder endoscopic manipulation of the coexistent distal, high burden, long standing impacted stones. Thus, laparoscopic uretrolithotomy was performed in 51 bilharzial patients with distal ureteric stones 4 trocars were used. The ureter was opened directly over the stone and the stone was extracted. A double-J stent was inserted into the ureter which was closed by 4-0 polyglactin running suture. The results showed that among 51 cases 33 males and 18 females; the mean age was 40.13 years. the mean stone size was 2.73 cm. Conversion to open surgery was in only one case; the mean operative time 92.05 (range 75-120 minutes); postoperative pain score ranged from 20 to 60, the mean number of PO analgesic request was 1.72 (range 1-3); it was once in 21, twice in 23 and thrice in 7 cases. Hospital stay ranged from 2 to 5 with a mean of 2.74 days; total duration of follow up ranged from 7 to 12 with a mean of 9.68. Stone recurrence reported in 4 cases; ureteric stricture reported in 2 cases. Stone free rate was reported to be 100%. PMID- 26485849 TI - ASSOCIATION BETWEEN PHLYCTENULAR CONJUNCTIVITIS AND INTESTINAL PARASITES. AB - This study was carred out on fifty children suffering from Phlyctenular keratoconjunctivitis and attending ophthalmology outpatient clinics of Sohag University Teaching Hospital and Sohag Ophthalmology Hospital, of them 30 (60%) male and 20 (40%) females with age range from 6months to 14 years. Fifty stool samples were collected and examined microscopically for detection of any parasitic infection. 12(24%) cases were infected with Hymenolepis nana, one (2%) case was infected with E. hyistolytica, one case was infected Enterobius vermicularis, one case was infected with Giardia lamblia and one case was infected Tenia spp., regarding to age and sex distribution of the disease, male gender and age ranged from 6-8years were more affected, rural children were more affected than urbans one. PMID- 26485850 TI - COMPUTED TOMOGRAPHY VERSUS PLAIN RADIOGRAM IN EVALUATION OF RESIDUAL STONES AFTER PERCUTANEOUS NEPHROLITHOTOMY OR PYELONEPHROLITHOTOMY FOR COMPLEX MULTIPLE AND BRANCHED KIDNEY STONES. AB - This study compared the efficacy of computed tomography of the urinary tract (CT urography) versus plain X-ray of the urinary tract (KUB) in detection and evaluation of the significance of residual stone after percutaneous nephrolithotripsy (PCNL) or surgical pyelonephrolithotomy (SPNL) for complex branching or multiple stones in the kidney. A retrospective prospective archival cohort of 168 patients underwent PCNL or SPNL for large stag horn or multiple stones in the kidney were evaluated, they were 113 patients who underwent SPNL, and 55 patients underwent PCNL. In all patients they had KUB second day of the operation, those who had multiple kidney punctures in the PCNL procedure for multiple stones, or multiple nephrotomies in the SPNL procedure, or had a radiolucent stones had an additional imaging with CT urography. Indications for the CT urography were cases of radiolucent stones and multiple small calyceal stones detected pre-operatively. The study was conducted between March 2010 and December 2014, data weie retrospectively analyzed. Preoperatively multiple or branching stones were diagnosed with intravenous urography and CT urography. Stone size and location were mapped pre-operatively on a real-size drawing, and three dimensional computed construction images in multiple planes. All patients were informed about the advantages, disadvantages and probable complications of both PCNL and SPNL before the selection of the procedure. Patients decided the type of the surgery type by themselves and written informed consent was obtained from all patients prior to the surgery. Patients were in two groups according to the patient's preference of surgery type. Group 1 consisted of 113 patients who underwent SPNL and Group 2 consisted of 55 patients treated with PCNL. Detection of residual stones stone postoperatively using KUB and CT urography was evaluated in both groups. There was statistical significance between the two imaging methodology in detection of residual stones after PCNL and/or SPNL. CT urography detected stones of 2 mm and up to 5mm which was not visualized with KUB. CT urography was statistically significant and precise in detecting the radiolucent stones of uric acid, urate, and phostate stones which were not detected by KUB. PMID- 26485851 TI - SODIUM DODECYL SULPHATE POLYACRILAMIDE GEL ELECTROPHORESIS (SDS-PAGE) FOR DIFFERENTIATION OF DIFFERENT SCHISTOSOME AND FASCIOLID SPECIES. AB - Fasciola and Schistosoma spp. are digenetic trematodes that have a major detrimental impact on human health worldwide. It is not unusual to find common molecules among parasites of different species, genera, or phyla. In this study Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) was used to identify the common proteins of adult Fasciola and Schistosoma spp. Adult Fasciola spp, were collected from the bile ducts of naturally infected cattle and sheep. Schistosoma mansoni and S. haematobium adults surface antigens were prepared in Theodor Bilharz Research Institute were used. Results showed sharing bands between all worms, which have the same molecular weight of 36 kDa. On the other hand, band with molecular weight 41 kDa was sharing between them except F. hepatica. Bands at 48 and 170 kDa were sharing between all species of Fasciola spp and Schistosoma mansoni. PMID- 26485852 TI - ULTRASTRUCTURAL STUDY OF TWO PARASITES INFECTING DOMESTICATED TURKEY MELEAGRIS GALLOPAVO LINNAEUS, 1758 (GALLIFORMES: MELEAGRIDINAE) QENA, EGYPT. AB - The work gave a detailed systematic morphology by optic and scan electron microscopy of two parasites; Raillietina echinobothriida Megnin, 1880 and Spirora meleagaris n. sp. infecting domesticated turkey, with some important description characters. SEM revealed that tegument of R. echinobothriida exhibits, filamentous, microtriches and sensory papillae densely covered the tegument of entire body, rostellum armed with two rows of hummer-shaped hooks and provide by 16-20 rows of small, rose thorn-shaped accessory spines. In addition, a number of taxonomic features in S. meleagaris n. sp. that differ from other species of the genus, mouth circular, bounded by a cuticular three circles plates, five pairs of cephalic papillae, an inner circle of two pairs situated on the wall of the buccal cavity, one pairs of larges sub-median amphids, and an outer circle of two pairs papillae. Buccal cavity supported by four chitinious cusped molar teeth anteriorly directed .Vulva near the end of the first third of the body, vulvular lips prominent. The male has unique rose like shaped pedunculated and unarranged numerous distributed sessile cervical papillae at the second third of the body that are distinguishable from other spirorid. PMID- 26485853 TI - ROLE OF T REGULATORY CELLS IN CHRONIC HCV INFECTED EGYPTIAN PATIENTS AND THEIR IMPACT ON THE RESPONSE TO PEGYLATED INTERFERON THERAPY. AB - Treatment of patients with chronic hepatitis C with the current standard pegylated interferon (PEG-IFN) and ribavirin achieves overall response (SVR) rates of ~55%. A role of CD4+ CD25+ regulatory T cells (Treg cells) has been proposed as they can suppress HCV-specific T cells in HCV-infected patients. Patients with chronic HCV legible for PEG-IFN plus ribavirin treatment, were classified according to their response to treatment into two groups (responders and non-responders, 32 and 27 patients respectively). Blood and plasma samples were collected at the start of treatment and at 12 and 24 weeks during treatment. Immunophenotyping by flow cytometry for Treg cells, the FOXP-3 expression using real-time PCR and measurement of IL-10, TGF-beta CXCL-9 and CXCL-10 were performed. Increased expression of Treg cells was detected in patients who didn't respond to treatment before and during treatment. Also, the levels of IL-10, TGF beta, CXCL-9 and CXCL-10 revealed significant increase.in non-responders all through compared to responders group. Evaluation of Treg cells, cytokines (IL-10 & TGF-beta) and chemokines (CXCL-9 & CXCL-10) before starting the treatment could be a predictor of response to treatment with PEG-IFN plus ribavirin. The optimum levels which would differentiate between responders and non-responders are needed to be defined before-hand. PMID- 26485854 TI - ROLE OF EPITHELIAL MESENCHYMAL TRANSITION IN HEPATIC FIBROGENESIS. AB - Liver fibrosis is a gradual process of increased secretion and decreased degradation of extra-cellular materials. Two cell types are now well recognized as being involved in liver fibrosis, i.e. hepatic stellate cells (HSCs) and portal mesenchymal cells. T iis process is initiated by the damage of hepatic cells, which leads to activation of hepatic stellate cells that differentiate into myofibroblasts leading to the formation of liver fibrosis. On the other hand, the epithelial-mesenchymal transition and mesenchymal-epithelial transition are crucial for the regulation of cellular plasticity during liver fibrosis. The EMT is a process in which molecular reprogramming leads epithelial cells to adopt a mesenchymal phenotype. During EMT, epithelial cells gain mesenchymal features which include changes in the expression of epithelial markers. The EMT process plays fundamental roles during embryogenesis, tissue fibrosis, and carcinogenesis. As multiple experimental studies of liver fibrosis have confirmed that established liver fibrosis is reversible upon cessation of the causative agent, modulation of the EMT markers could be promising as potential therapeutic agents. Better understanding of the molecular cascades of intracellular fibrogenic signaling and genetic factors that controlling the expression of EMT markers would be a powerful strategy for early diagnosis and treatment liver fibrosis at the genetic level. Activating or silencing of the responsible genes may be an efficient and more specific approach for treating liver fibrosis either through the arrest of EMT or the induction of MET. PMID- 26485855 TI - INTESTINAL PARASITES DETECTED DURING PRE-EMPLOYMENT STOOL EXAMINATION AT TERTIARY HEALTH CARE CENTER IN MAKKAH, KINGDOM OF SAUDI ARABIA. AB - This retrospective study determined the intestinal parasites discovered in 2490 new employees in a tertiary health care center in Makah as regards nationalities, age groups and sex over the period from January 2010 to January 2014 to decrease introduction of communicable diseases. All the data were provided through the electronic hospital information system. The overall positive cases were 16%, significantly higher in females 57.4% than males 42.6%. Differences in distribution of positive records among different geographical areas were highly significant being highest in East Asia 59.8 %. Blastocystis hominis was the most common parasite. It occurred in 78,9% of positive cases followed by Entamoeba coli 9.3%, Giardia lamblia 5.8% and Entamoeba histolytica/dispar 5.3%. These findings should motivate any other country importing expatriate employees to have effective screening programs for intestinal parasites. PMID- 26485856 TI - ULTRASTRUCURAL STUDY OF BEE LOUSE VARROA DESTRUCTOR ANDERSON & TRUEMAN 2000 (ACARI: VARROIDAE) WITH RESISTANCE MODELS FROM APIS MELLIFERA L. AB - The ectoparasitic mite Varroa destructor is the most dangerous pest of honeybee Egyptian race Apis mellifera L., as it causes many losses in apiculture worldwide. Adult female mites are flattened with a dome-shaped dorsal shield. The present SEM study revealed that the flat ventral surface is composed of series of plates. There are 5 rows of small, chemoreceptor papillae posterior to the genito ventro anal shield, and a unique respiratory structure (peritreme) is located laterally above Coxa III. Peritreme is a chitinized elongated area surrounding stigma opening, provided by a lid that looks like a rose with a curly thick inner membrane which has numerous teeth-like projections. Mite' legs appeared to be modified for parasitism and each is tipped by one distal empodium. The pretarsus of the first pair of legs becomes a concave sucker and the pretarsus of the 3 pairs of the posterior legs consists of membranous amblacral pad (the caruncle). The mouthparts appeared well modified for its diet on bee hernolymph with its' powerful pedipalp for host attachment. High magnification revealed different types of setae distributed on the body, the mechano-receptor pedipalp short. and long anal setae and dorsal shield sensory simple setae. PMID- 26485857 TI - LYMPHOEPITHELIOMA-LIKE CARCINOMA OF THE URINARY BLADDER ASSOCIATED WITH SCHISTOSOMIASIS: A CASE REPORT AND REVIEW OF LITERATURE. AB - Lymphoepithelioma-like carcinoma is an undifferentiated carcinoma with histological features similar to undifferentiated, non-keratinizing carcinoma of the nasopharynx. Lymphoepithelioma-like carcinoma of the urinary bladder is uncommon with a reported. incidence of 0.4% -1.3% of all bladder cancers. This case describes an 80 years old Egyptian male patient presented with recurrent hematuria and necroturia. Cystoscopy revealed a tumor involving the left lateral and the posterior wall of the urinary bladder. The patient underwent transurethral resection of the bladder tumor. Pathological examination showed muscle invasive lymphoepithelioma-like carcinoma associated with schistosomiasis of the urinary bladder. To the best of our knowledge the association of schistosomiasis with lymphoepithelioma-like bladder cancer was not described in the literature before this case report. PMID- 26485858 TI - INTESTINAL PARASITES IN PATIENTS WITH CHRONIC ABDOMINAL PAIN. AB - Information about intestinal parasites in Sohag (Upper Egypt) in patients with chronic abdominal pain is scarce. This study determined the intestinal parasites symptoms in 130 patients with chronic abdominal pain and cross-matched 20 healthy persons. Parasitic infection was confirmed by stool analysis.The most commonest clinical data with stool analysis was as following: 1-Entamoeba histolytica associated with nausea 20 (3 7.74%) followed by anorexia 19 (35.85%), 2-Entamoeba coli associated with diarrhea 3 (100%) followed by nausea 2 (66.67%) and vomiting 2 (66.67%), 3-Enetrobius vermicularis associated with nausea 2 (66.67%), diarrhea 2 (66.67%) followed by flatulence 1(33.33%), 4-Giardia lamblia associated with anorexia 3 (42.86%), vomiting 3 (42.86%) followed by diarrhea 2 (28.57%)., 6 Hymenolepis nana associated with anorexia 10 (40.00%) followed by flatulence 9 (36.00%), 7-Taenia saginata associated with dyspepsia 3 (60.00%) followed by flatulence 2 (40.00%), and 8-Ancylostoma duodenal associated with anorexia 2 (66.67%) and diarrhea 2 (66.67%). PMID- 26485859 TI - SCHISTOSOMIASIS IN NAG HAMMADY CITY, RELATIONSHIP BETWEEN INFECTION AND ANEMIA AMONG CHILDREN AND YOUTH, QENA GOVERNORATE, EGYPT. AB - The highest prevalence of schistosomiasis is usually found in school-age children and youth, where it represents the main cause of iron deficiency anemia. Study was done on 859 patients; their age from 5-18 years old at Nag Hammady at the period from July 2013 to July 2014 all of them had subjective history of contact or swimming in water canals. Urine was examined for urinary schistosomiasis by concentration and positive cases were subjected to urine analysis by Nucleopore filtration technique, S. haematobium was 30.96%, while stool samples were macroscopically examined mainly for enterobiasis and gravid segments and then were microscopically examined as stained direct smear and by sedimentation and Kato-Katz techniques. The intestinal parasites other than intestinal schistosomiasis were not encountered and the pure S. mansoni was 0.69% of examined patients. The overall pure schistosomiasis was 31.66%. Iron deficiency anemia was 27.7% in non-infected cases and in schistosomiasis patients iron deficiency anemia were found in 43.38% with statistically significant (P value=0.001). PMID- 26485860 TI - ALLERGIC REACTIONS CAUSED BY VENOM OF HYMENOPTEROUS STINGING INSECTS AND THE ROLE OF HEALTH CARE WORKERS. AB - The Hymenoptera are the third largest order of insects, comprising the sawflies, wasps, bees and ants. Worldwide, over 150,000 species are recognized, with many more remaining to be described. The name refers to the wings of the insects, but the original derivation is ambiguous. The Ancient Greek upsilonMUetanu (hymen) for membrane provides a pLusible etymology for the term because these insects have membranous wings. However, a key characteristic of this order is that the hind wings are connected to the fore wings by a series of hooks called hamuli. Thus, another plausible etymology involves, Hymen, the Ancient Greek god of marriage, as these insects have "married wings" in flight. Stinging insects and the medical risk associated with their venoms are complex topics, and presentation of information pertaining to them requires the use of technical terms. The most common reactions to these stings are transient pain and redness at the site lasting a few hours (local reaction), and exaggerated swelling lasting a few days (large local reaction). The most dangerous immediate reaction is anaphylaxis, which is potentially fatal. PMID- 26485861 TI - INTESTINAL PARASITIC INFECTIONS AND ATOPIC DISEASES IN CHILDREN: A HOSPITAL BASED STUDY. AB - Different helminth parasites may have different effects on allergy depending on the timing of the exposure. A meta-analysis of many of studies reported the association between the presence of geohelminth eggs in stool samples and asthma provided some evidence for parasite-specific effects. This study evaluated the occurrence of allergy among different intestinal parasitic infected patients. A cross sectional study was carried out from June, 2013 to October, 2013 in the Pediatric Outpatient Clinic of Al-Fayoum University Hospitals among 55 children aged 2 years to 13 years. The data were collected using ISSAC questionnaire of allergy (International Study of Asthma and Allergies in Childhood) also laboratory analysis of complete blood picture, stool analysis and measurement of total serum IgE were performed for the patients. Among the patients 27 suffered from allergy and 28 had no allergic complain. Stool examinations showed Entrobius vernicularis (15), Trichostrongylus species (9), Hymenolepis nana (8), Entameba histolytica (8), Giardia lamblia (6), and mixed infections (9). The allergic group by parasitological examination 7 children (25.9%) had Entrobius vermicularis; 6 children (22.2%) Entameba histolytica; and 2 children (7.4 %) Giardia lamblia, with eosinophilic count was higher in the enterobiasis infected children than in protozoa infected ones. There were significantly high IgE levels in mixed parasitic infection (P= 0.006) and with Entrobius vermicularis infections (P=0.04). Also statistically significant difference between allergic groups by ISAAC score and the non allergic group regarding Ig E levels (P= 0.03). There was no significant difference between numbers of children with allergy and those without allergy among different parasitic infections. However, a marked significant association between the allergy and parasitic infected children was not declaimed. PMID- 26485862 TI - NON-INVASIVE PREDICTORS FOR THE PRESENCE, GRADE AND RISK OF BLEEDING FROM ESOPHAGEAL VARICES IN PATIENTS WITH POST-HEPATITIC CIRRHOSIS. AB - Variceal bleeding is the last step of a chain of events initiatedby an increase in portal pressure, followed by the development and progressive dilation ofvarices until these finally rupture and bleed. The ideal method to diagnose portal hypertension should be accurate, noninvasive, objective, and reproducible. The study evaluated the predictive value of two non-invasive parameters for the diagnosis of esophageal varices (EV): 1-Right liver lobe diameter/serum albumin ratios (RLLD/S. albumin), and 2-Platelet count/splenic bipolar diameter ratios (Platelets count/SBPD). This study included eighty Egyptian patients with post hepatitic cirrhosis (45 males and 35 females). They underwent laboratory ultrasono-graphic and endoscopic examinations within one week. RLLD/S. albumin and Platelets count/SBPD ratios were calculated. The results showed that EV were not detected by upper digestive endoscopy in 25%, while grade I of EV was found in 17.5%, grade II in 17.5%, grade III in 20%, & grade IV in 20%. RLLD/S. albumin concentration ratio diagnosed the varices at cut off value of 3.43 with 95% sensitivity and 80% specificity. Also, it was positively correlated with grading of E.V, when this ratio increased the grading of E.V increases and vice versa. Besides, it predicted bleeding from E.V. at cut off value of 5.096 with 63% sensitivity and 73% specificity. Platelet count/SBPD ratio predicted the presence of varices at cut off value 1847 with 95% sensitivity and 93% specificity, and negatively correlated with grading of EV, when this ratio decreased grading of E.V increase and vice versa. It also predicted bleeding from E.V. at cut off value of 4809 with 50% sensitivity and 93% specificity. PMID- 26485863 TI - AMBULANT FLEXIBLE CYSTOSCOPY FOR FOLLOW-UP OF Ta-TI UROTHELIAL CARCINOMA OF THE URINARY BLADDER: PAIN PERCEPTION AND COST EFFECTIVE. AB - Ambulant flexible cystoscopy is the standard procedure in the urological practice for follow-up of Ta-T1 urothelial carcinoma (UC) due to its ability to survey the bladder for a variety of indications. It is the principal means of diagnosis and surveillance of bladder tumors. The follow-up of patients treated for Ta-T1 UC is of great importance because of the high incidence of recurrence and progression of the disease, whereby patients with Ta-T1 UC undergo cystoscopy every three months. The aim of this study to evaluate the procedure of ambulant flexible cystoscopy in proper diagnostic follow-up of Ta-T1 UC, patient's acceptance in regard to pain tolerance, non-hospital stay and expenses. Twenty one patients (18 male and 3 female) were diagnosed before as Ta-T1 UC by rigid cystoscopy and transuretheral resection of bladder (TURB) lesion scheduled for follow up by flexible cystoscopy under local anesthesia using 20 ml 2% lidocain gel on an ambulatory bases. Comparison was done using a cohort of 32 patients who underwent the procedure of follow-up of Ta-T1 cystoscopy and TURB using rigid cystoscopy and resectoscope. Seventeen patients 80.9% (16 male and 2 female) proved to be bladder free from recurrent lesion, 4 patients {19.1 %} (3 males and one female) which revealed recurrent lesions in spite of that the urinary bladder was free in pelvic ultrasonography. Cold cup biopsy from the lesions sent for histopathological examination which revealed recurrence of the tumor in 3 patients (two patients with Ta and one patient T1. TURB was done to have complete resection in 4 patients, the histopathological examination revealed ulcerating mucosa and free lamina propria in 3 specimens, and T2 in the fourth specimen. Comparison between the 2 groups revealed more patient's acceptance for the flexible cystoscopy group as regard pain tolerance, non-hospital stay and expenses. Ambulatory flexible cystoscopy with 20 ml of 2% lidocaine gel anesthesia is tolerated well by patients, with advantage of no hospital stay in the regular follow up of Ta-T1 tumors, pain perception was accepted by all patient provided delayed cystoscopy after lidocaine-gel instillation. PMID- 26485864 TI - PREVALENCE OF DICROCOELIUM DENDRITICUM INFECTION IN SHEEP AT TAIF PROVINCE, WEST SAUDI ARABIA. AB - Dicrocoelium dendriticum is a common zoonotic parasite of sheep in many Regions of Saudi Arabia. In chronic infections, this parasite causes biliary cirrhosis in livers of cattle, sheep, or goats and leads to economic losses. This study compared the prevalence of Dicrocoelium dendriticum in local sheep and imported sheep in Taif Province, West Saudi Arabia. This cross-sectional survey was carried out in slaughterhouses in Taif Province. A total 2230 local sheep and 21383 imported sheep were studied. The number of injury in imported sheep was observed as 99 representing 0.46% of the number of animals examined, while no record of any injury was observed in local sheep. PMID- 26485865 TI - INTESTINAL PARASITES IN DIABETIC PATIENTS IN SOHAG UNIVERSITY HOSPITALS, EGYPT. AB - Intestinal parasites usually create benign diseases, though they may induce complications with high morbidity and mortality to the immunocompromised, including diabetic patients. The study detected the prevalence of intestinal parasitic infections in diabetic patients, comparing to non-diabetic controls and other parameters. A total of 100 fecal samples were collected from diabetic patients at the outpatient clinic of Sohag University Hospitals and another 100 from cross matched controls. The samples were examined macroscopically and microscopically by direct smear and different concentration methods then stained by Modified Ziehl-Neelsen Acid fast stain. Glycated hemoglobin (Hb Alc) was measured to detect DM controlled patients. The data were organized, tabulated, and statistically analyzed. Intestinal parasites were found in 25 (25%) cases out of 100 patients in diabetic group and 7(7%) cases out of 100 controls with high significance (P<0.001)). In the diabetic group, Giardia lamblia was detected in 22 cases (22%) and 5 (5%) among controls, Entamoeba histolytica in 7 cases (7%) and 3 (3%) among controls, Hymenolypis nana in 5 cases (5%) and 3 (3%) among controls, Entamoeba coli in 8 patients (8%), Entamoeba hartmanni in 3 cases (3%), Dientamoeba fragilis in a case (1%), Cryptosporidium parvum in 5 cases (5%) and microsporidia in 3 cases (3%). But, E. coli, E. hartmanni, D. fragilis and C. parvum nor microsporidia were detected in controls. The rate of G. lamblia in DM patients compared to controls was high significant (P<0.001). Hymenolepis nana was 5% (5 cases) in diabetic patients compared to 3% (3 cases) in controls. Residence and sex differences were not significant, while age, >10 years showed the highest prevalence (P< 0.003), type I infection rate was significantly higher than type II (P<0.001). DM control was also significantly affected the infection rates (P<0.007 in type I and P< 0.01 in type II). PMID- 26485866 TI - LAPAROSCOPIC ASSISTED PER-CUTANEOUS RADIO-FREQUENCY ABLATION (LAPRFA) AS A NEW MODALITY FOR TREATMENT OF HCC IN CIRRHOTIC LIVER. AB - Laparoscopic assisted percutaneous radiofrequency ablation (LAPRFA) for hepatocellular carcinoma (HCC) under guidance of intra-operative laparoscopic ultrasound (IOLUS) is a new modality for obtaining additional assessment of the liver situation, better tumor staging and effective treatment for the hepatic focal lesion (HFL), in patients with a difficult percutaneous approach. Between September 2010 and July 2014, 1150 patients with HCC on top of liver cirrhosis were referred to HCC clinic (MDT clinic) at National Hepatology and Tropical Medicine Research Institute (NHTMRI). Fourty nine patients were submitted to LAPRFA under IOLUS guidanceby the Multidiscipplinary team decision. Operation time, hospital stay, post procedure complications were recorded. A routine spiral CT scan one month postoperative and laporatory investigations with AFP were mandatory during follow up. The results showed that LAPRFA was completed in all patients. The IOLUS examination identified new HFL in three patients. A total of 52 lesions were treated. The mean operative time was 92 minutes; eight procedures were associated in six patients: cholecystectomy (6) and adhesiolysis (2). A complete tumor ablation was observed in all patients during the procedure by the U/S assessment intra-operatively, and was documented via spiral computed tomography (CT scan) one mopth after treatment. PMID- 26485867 TI - [Elektropolis]. PMID- 26485868 TI - [In the end in service of humanity]. PMID- 26485869 TI - [Cooperation in practice, science and industry ]. PMID- 26485870 TI - [Anesthesia nursing in regional anesthesia]. PMID- 26485871 TI - ["The sleeping giant nursing must wake up"]. PMID- 26485872 TI - [Risk assessment of decubitus ulcer]. PMID- 26485873 TI - [Underestimated decubitus duration]. PMID- 26485874 TI - [Reacting to self-injury behavior]. PMID- 26485875 TI - [With instinct, expertise and patience]. PMID- 26485876 TI - [Source of criticism and identity?]. PMID- 26485877 TI - [Difficult times in Nepal]. PMID- 26485878 TI - [The motivating power of nursing colleagues]. PMID- 26485879 TI - [With perseverance and passion]. PMID- 26485880 TI - [Insidious epidemic]. PMID- 26485881 TI - [Are advance directives a facilitator?]. PMID- 26485882 TI - [An engagement at the Teddy Bear Hospital]. PMID- 26485883 TI - [George's clock]. PMID- 26485884 TI - [A recognition from patients and peers?]. PMID- 26485885 TI - [Good treatment of the elderly: an idea for improved care]. PMID- 26485886 TI - [Involvement of collaborators, key to success]. PMID- 26485887 TI - [What if all causes were not investigated?]. PMID- 26485889 TI - Lessons in decompression. PMID- 26485888 TI - [Hands up]. PMID- 26485890 TI - Utilization Management and ACR Select. AB - The ACR, published as ACR Select, provides an industry standard for imaging and through its experience with Appropriateness Criteria, is positioned to respond quickly to changing market demands. It has added hundreds of clinically relevant indications to ensure that even common scenarios have coverage. ACR Select is inclusive of numerous other credible content sources and actively receives vetted criteria from other medical specialty societies. ACR Select is well established in the market and available for integration into multiple physician access points. It also has support for the provisions and requirements of PL113-93. Healthcare providers have adopted ACR Select within their physician access points to deliver higher quality imaging services and understand the impact that imaging has on the overall care cycle. This better positions these providers to participate in risk-based contracts based on the value that appropriate imaging delivers. With the passage of PAMA, Congress has set a powerful precedent that has created the opportunity for every healthcare payer to transform the way imaging utilization is managed. Physicians will be required to consult Appropriateness Criteria delivered through CDS when placing orders for HTDI exams for Medicaid patients, and this can easily extend across the entire payer mix. PAMA has passed into public law (PLI113-93) and represents an opportunity for healthcare providers to develop risk based payment models across all imaging services, regardless of the payer of the claim or care setting. PMID- 26485891 TI - VNA: An Unavoidable Investment? PMID- 26485892 TI - Workplace Bullying in Healthcare: Part 2. AB - Bullying can occur in any work environment; however, it is especially prominent in healthcare. Although accrediting and professional organizations recognize the danger (to patients and staff) and have implemented standards and guidelines to curtail the behavior, organizations have been slow to adapt. Organizations that are beginning to address the problem encounter opposition, legal challenges, and lengthy battles. Laws that were originally created to protect employees unfortunately also protect the perpetrators. Oftentimes the victim(s) leave the organization long before any resolution. Part 2 of this series will describe the legal protection that is intended to protect staff, but unintentionally benefits the bully as well. PMID- 26485893 TI - The Promise. PMID- 26485894 TI - Clinical Decision Support Systems and Medical Imaging. AB - Clinical decision support systems (CDSS) can help clinicians make correct and timely decisions about patient care, reduce errors, comply with standard treatment and medication guidelines, reduce costs, and ultimately improve the quality of healthcare. An overview of various models is provided. This tool can apply to six areas of healthcare, all of which have a significant impact on improving care and provider performance: diagnosis, disease progress management, care and treatment, drug prescribing, evaluation, and prevention. Beginning in January 2017, referring physicians must use appropriateness criteria when ordering advanced imaging for Medicare patients. CDSS will be a critical part of this process. In the medical imaging chain, from ordered study to communicating results, such systems can help achieve best practices. PMID- 26485895 TI - CT Lung Cancer Screening Program Development: Part 1. AB - Emerging sources of reimbursement will stimulate the development of many new CT lung cancer screening programs. With reimbursement will come many requirements, however, necessitating that programs carefully manage quality and patient safety. A major consideration when developing a program is how to address the lack of consistency in payer and clinical guidelines for which patients to screen. Radiology administrators should employ basic project management and change management methods to organize the endeavor. PMID- 26485896 TI - It's People that Matter. PMID- 26485897 TI - Commit to Sit in Radiology. AB - At Houston Methodist Hospital, Commit to Sit is a program that encourages radiology professionals to communicate with patients in a way that demonstrates compassion, respect, empathy, and competence in order to foster a trusting relationship. Using active and empathic listening, dialogue is received and understood in the way it was intended, creating a patient centric environment resulting in high quality, safe patient care with improved outcomes. The implicit understanding derived from results and outcomes confirms the fact that patients prefer the radiology staff to sit while communicating with them. This understanding allows the voice of the patient to be heard and should be a consistent practice among all staff. PMID- 26485898 TI - E-Jail. PMID- 26485899 TI - Blessings and Challenges. PMID- 26485900 TI - Heroin: What's Next? PMID- 26485901 TI - The Changing Face of Heroin Addiction. PMID- 26485902 TI - Electrical Pulp Testing: Sources of Error. AB - INTRODUCTION: Accurate identification and assessment of an inflamed or necrotic tooth is essentialfor endodontic treatment. The purpose of this research was to investigate possible sources of error associated with the use of the electric pulp tester (EPT). METHODS: Forty-six intact teeth (23 tooth pairs) in 22 patients were evaluated in vivo. For the tooth pairs, one tooth had to have been previously endodontically treated and restored with a class II amalgam restoration. The restoration was required to have proximal contact with a class II amalgam of another vital posterior tooth. EPT was performed on pulpless and vital teeth for experimental groups (enamel, restoration, contacting, or isolated). RESULTS: The highest rate of false positive responses (82%) was found in the pulpless restored contacting group, suggesting that EPT impulses are able to travel through proximal metallic contacts and stimulate teeth distant from the EPT probe. All vital tooth groups had a high rate of positive responses with no significant diferences. CONCLUSIONS: If a tested tooth contains an interproximal restoration contacting adjacent restorations or the gingival, the teeth must be isolated (rubber dam) and the EPT probe should be placed in a region suspected to have uninterrupted tubule paths to the pulp. PMID- 26485903 TI - Using Multiple Bonding Strategies. AB - There are many ways to bond to tooth structure, some micro-mechanical some chemical, some a combination. Different dentin bonding materials have different bonding strengths to differently prepared surfaces, and because of differences in their nature, different areas of tooth structure present peculiar bonding challenges. This paper will review a variety of material types, elucidating their particular bonding strengths and commenting on improved bonding strategies to increase durability, strength, and favorable pulpal response. In this discussion, resin dentin bonding systems, glass ionomers, Gluma, resin cements, and newer combined products will br reviewed. PMID- 26485904 TI - Focus on Strengths for Greater Practice Health. PMID- 26485905 TI - [Methodology Guideline for Clinical Study Investigating Traditional Chinese Medicine and Integrative Medicine]. PMID- 26485906 TI - [Diagnosing and Treating Consensus of Integrative Medicine for Chronic Prostatitis]. PMID- 26485907 TI - [Zheng Classification in Chinese Medicine: from Its Integration with Disease Diagnosis to Clinical Effectiveness Assessment and Combinational New Drug Discovery]. AB - As the core of traditional Chinese medicine theory, Zheng (syndrome, or pattern) classification will promote personalized medicine by changing the clinical diagnosis into a more precise mode when integrating Zheng classification with disease diagnosis approaches. The author adopted rheumatoid arthritis (RA) as a disease model, to explore the scientific fundamentals of Zheng classification based on disease diagnosis using systemic biological approaches and evidence based medicine design, as well as developed novel approaches on the methodology of clinical effectiveness evaluation on Chinese medicine and R&D of combinational drugs design based on Fu Fang (Chinese herbal formula). Some unique research design and methods are herein introduced. PMID- 26485908 TI - [Study on Shen Is Progressing by Keeping Pace with the Time]. PMID- 26485909 TI - [Practical Diagnostic Criterion of Blood Stasis Syndrome: Introduction, Reliability, and Validity]. AB - OBJECTIVE: To introduce practical diagnostic criterion of blood stasis syndrome (BSS), and to evaluate its reliability and validity. METHODS: By referring to three diagnostic criteria of BSS [practical diagnostic criterion of BSS (criterion A), diagnostic criterion of BSS in 1986 (criterion B), Consensus of Integrative Medicine on BSS Diagnosis in 2011 (criterion C)], 712 patients from different departments of Xiyuan Hospital were recruited. The reliability of criterion A and its consistency with the other two criteria were assessed using Kappa coefficient. A Bayesian approach was also employed to assess the sensitivity and specificity of criterion A. RESULTS: According to the consistency check, criterion A presented good consistency when used by different researchers (the diagnostic accordance rate was 91. 96%, Kappa =0. 82, P <0.001). Meanwhile, there was an acceptable diagnostic consistency among the three diagnostic criteria. Bayesian estimation suggested that criterion A had higher sensitivity but similar specificity, as compared with criterion B or criterion C. Compared with criterion B [the median of sensitivity and specificity were 0. 762 (95% Cl: 0. 731 -0. 790) and 0. 902 (95% Cl: 0. 858 -0. 936) respectively, the median of sensitivity and specificity of criterion A were 0. 911 (95% CI: 0. 888 - 0. 930) and 0. 875 (95% CI: 0. 826 - 0. 915) respectively. Estimating the difference between criterion A and B, the median of sensitivity and specificity were 0. 149 (95% CI: 0. 112 -0.184) and -0. 026 (95% CI:-0. 085 -0. 033) respectively. Compared with criterion C [the median of sensitivity and specificity were 0. 831 (95% Cl: 0. 804 -0. 857) and 0. 892 (95% CI: 0. 848 - 0. 926) respectively], the median of sensitivity and specificity of criterion A were 0. 912 (95% CI: 0. 889 0. 932) and 0. 880 (95%CI: 0. 833 - 0.919) respectively. Estimating the difference between criterion A and C, the median of sensitivity and specificity were 0. 081 (95% CI: 0.047 - 0.114) and -0.011 (95%CI: -0.070 -0.046) respectively. CONCLUSION: Compared with criterion B and C, criterion A not only had better reliability, but also could significantly improve the sensitivity without obviously lowering the specificity. PMID- 26485910 TI - [Effect of Low Molecular Weight Heparin Calcium Combined Compound Danshen Injection on Perinatal Outcomes of Nephrotic Syndrome Patients with Early Onset Severe Pre-eclampsia]. AB - OBJECTIVE: To observe the effect of low molecular weight heparin calcium (LMWHC) combined Compound Danshen Injection (DI) on nephrotic syndrome patients with early onset severe preeclampsia. METHODS: Totally 80 nephrotic syndrome patients with early onset severe pre-eclampsia were randomly assigned to four groups voluntarily, i.e., Group A (22 cases, treated by magnesium sulfate), B (19 cases, treated by magnesium sulfate plus LMWHC), C (21 cases, magnesium sulfate plus DI), D (18 cases, magnesium sulfate plus LMWHC and DI). Umbilical arterial S/D ratios, amniotic fluid index (AFI), prolonged gestational age, placenta weight, neonatal weight, and Apgar score were compared among the four groups. RESULTS: Compared with before treatment in the same group, umbilical arterial S/D ratios decreased in the four groups (P <0. 05). AFI decreased in Group A, while it increased in Group B, C, and D (P<0. 05). Compared with Group A at the same time point, umbilical arterial S/D ratios decreased, and AFI increased in Group B, C, and D (P <0. 01 , P <0. 05). Prolonged gestational age and neonatal weight were increased in Group B, C, and D (P <0. 01, P <0. 05). Placenta weight were increased in Group B and D (P <0. 05). Apgar scores at 1 and 5 min were improved in Group D (P <0. 05). Compared with Group B and C at the same time point, umbilical arterial S/D ratios decreased, and AFI increased in Group D (P<0. 05). Compared with Group B, prolonged gestational age and placenta weight were decreased in Group C, but prolonged gestational age and placenta weight were increased in Group D (P <0.05). Compared with Group C, prolonged gestational age, placenta weight, and neonatal weight were increased in Group D (P <0. 05). CONCLUSION: Treatment of nephrotic syndrome patients with early onset severe pre eclampsia by LMWHC combined DI could prolong gestational ages, obviously improve prenatal outcomes, with better effect obtained than using any of them alone. PMID- 26485911 TI - [Effect of Magnesium Sulfate, Nifedipine Tablet Combined Salvia Injection on ET 1/NO, TXA2/PGI2 and Hemorheology of Preeclampsia Patients]. AB - OBJECTIVE: To observe the effect of magnesium sulfate, Nifedipine Tablet (NT) combined Salvia Injection (SI) on endothelin-1 (ET-1), nitric oxide (NO), thromboxane A2(TXA2), prostacyclin I2(PG2), and hemorheology of preeclampsia patients. METHODS: Totally 704 preeclampsia patients were randomly assigned to the treatment group and the control group, 352 cases in each group. All patients were treated with magnesium sulfate combined NT (on the first day: slow intravenous injection of magnesium sulfate 5 g + intravenous dripping of magnesium sulfate injection 10 g + oral administration of NT 30 mg; on the second and third day, intravenous dripping of magnesium sulfate injection 10 g + oral administration of NT 30 mg), while those in the treatment group were dripped with SI additionally at 20 mL per day for 3 consecutive days. Before and after treatment plasma levels of endothelin-1 (ET-1), nitric oxide (NO), TXA2, PGi2, and hemorheology indicators [such as high blood viscosity (HBV), low blood viscosity (LBV), plasma viscosity (PV), erythrocyte rigidity index (ERI), fibrinogen (FIB)] of two groups were detected. RESULTS: Compared with the same group before treatment, serum levels of ET-1, TXA2, HBV, LBV, PV, ERI, and FIB decreased in the two groups after treatment (P <0. 05), but levels of NO and PG2 increased (P <0. 05). Compared with the control group in the same period, levels of ET-1, TXA2, HBV, LBV, PV, ERI, and FIB decreased in the treatment group after treatment (P <0. 05), but levels of NO and PGI2 increased (P <0. 05). CONCLUSION: Magnesium sulfate, NT combined SI could effectively regulate the balance of ET 1/NO and TXA2/PGI2, and improve hemorheology of preeclampsia patients. PMID- 26485912 TI - [Effect of Modified Huanglian Jiedu Decoction Purgation Combined Electroacupuncture in Intervening Gastrointestinal Dysfunction of Critically Ill Patients Undergoing Abdominal Surgery]. AB - OBJECTIVE: To observe the effect of purgation and detoxification therapy on gastrointestinal dysfunction of critically ill patients undergoing abdominal surgery. METHODS: Totally 56 inpatients with severe gastrointestinal dysfunction after abdominal surgery at ICU of Guangdong Provincial Hospital of Traditional Chinese Medicine were assigned to the treatment group and the control group, 28 in each group. All patients received routine Western medical treatment. Patients in the treatment group additionally took Modified Huanglian Jiedu Decoction (MHJD) and received electroacupuncture (EA) for 7 days. The first exhaust time, defecation time, scores for gastrointestinal dysfunction, mechanical ventilation time, ICU hospitalization time, and 28-day fatality rate were observed. Furthermore, serum levels of diamine oxidase (DAO) and D-lactic acid were detected at day 1, 3, and 7 after treatment. RESULTS: The first exhaust time and the first defecation time in the treatment group were ahead of schedule, when compared with those of the control group (P <0. 05). Scores for gastrointestinal dysfunction, mechanical ventilation time, serum levels of DAO obviously decreased in the treatment group (P <0. 05). There was no statistical difference in serum levels of D-lactic acid, ICU stay time, the incidence of pulmonary infection, and 28-day mortality between the two groups (P >0. 05). Results of Logistic analysis showed that scores for gastrointestinal dysfunction were related with the incidence of pulmonary infection (P <0. 05). CONCLUSION: MHJD combined EA could promote the recovery of gastrointestinal function in critically ill patients after abdominal surgery via improving intestinal barrier function, which was benefit for shortening mechanical ventilation time. PMID- 26485913 TI - [Protection of Transcutaneous Acupoint Electrical Stimulation for Brain Injury Undergoing Intervention: a Clinical Observation]. AB - OBJECTIVE: To observe the effect of transcutaneous acupoint electrical stimulation (TAES) combined dexmedetomidine on hemodynamic of intracranial aneurysmal subarachnoid hemorrhage patients undergoing intervention, and their protection for brain Injury. METHODS: Totally 108 intracranial aneurysmal subarachnoid hemorrhage patients undergoing intervention were randomly assigned to the electroacupuncture (EA) group and the control group according to random digit table, 54 in each group. All patients were anesthetized with dexmedetomidine. Patients in the EA group were needled at bilateral Neiguan (PC6), Lieque (LU7), and Yunmen (LU2). Parameter setting was as follows: The dilatational wave at 1. 5 Hz, strength 2 - 4 mA, 30 min. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were compared between the two groups immediately after entry into the room (T0), after administration (T1), intubating (T2), resuscitation (T3), extubation (T4), and leaving the operating room (T5). Levels of S100beta protein (S100beta) and neuron specific enolase (NSE) were compared between the two groups at T0, immediately after surgery (T6), 6 h after operation (T7), 12 h after operation (T8), and 24 h after operation (T9). RESULTS: Compared with the same group at T0, SBP, DBP, MAP, and HR were significantly reduced in the two groups at T1-T5(P <0. 05), serum levels of S100beta and NSE in the two groups were significantly increased at T6-T9 (P<0. 05). Compared with the control group at T1 - T5, SBP, DBP, MAP, and HR decreased in the EA group (P <0. 05). Compared with the control group at T6-T9, serum levels of S100beta and NSE decreased in the EA group (P <0. 05). CONCLUSION: TAES combined dexmedetomidine could effectively maintain stable hemodynamics of intracranial aneurysmal subarachnoid hemorrhage patients undergoing intervention, and regulate their serum levels of S100beta and NSE. PMID- 26485914 TI - [Effect of Wenyang Huazhuo Tongluo Recipe on Peripheral Blood Thl7/Treg Cell Balance in Systemic Sclerosis Patients]. AB - OBJECTIVE: To observe the effect of Wenyang Huazhuo Tongluo Recipe (WYHZTLR) on the proportion of T helper 17 cells (Thl7)/regulatory T cells (Treg), and serum levels of IL-17 and IL-10 in peripheral blood of systemic sclerosis (SSc) patients with yang qi insufficiency and turbidity induced collaterals blockage syndrome (YQITICBS). METHODS: Totally 82 SSc patients were randomly assigned to the Western medicine group (as the control group) and the integrated Chinese and Western medicine group (as the treatment group), 41 cases in each group. All patients took methotrexate (MTX) tablet and prednisone tablet. Patients in the treatment group additionally took WYHZTLR. The treatment course for all was six consecutive months. Besides, another 70 healthy volunteers were recruited as a healthy control group (as the healthy group). Percentages of Th17 and Treg in peripheral blood were detected by flow cytometry. Serum levels of IL-17, IL-10, von Willebrand factor (vWF), aminoterminal propeptide of type l procollagen (PIIINP), and cross-linked carboxyterminal telopeptide of type I collagen ( I CTP) were measured by double antibody sandwich ELISA. The correlations between Th17/Treg and levels of vWF, PIIINP, I CTP, skin score, and disease activity index were observed by Pearson correlation analysis. RESULTS: The percentage of Th17 in peripheral blood, ratios of Th17/Treg, and the serum level of IL-17 were significantly higher, but the percentage of Treg and the serum level of IL-10 were significantly lower in SSc patients, when compared with those of the healthy group (P <0. 05, P <0. 01). Compared with the same group before treatment, the percentage of Thl7, ratios of Thl7/Treg, and levels of IL-17, vWF, and PIIINP all decreased in the two groups after treatment (P <0.05, P <0.01), but the percentage of Treg and the IL-10 level increased (P <0. 05, P <0. 01). Meanwhile,the level of I CTP was higher in the treatment group after treatment (P <0. 05). The improvement of all indices except the percentage of Th17 was more obvious in the treatment group than in the control group (P <0. 05, P <0. 01). The ratio of Th17/Treg was positively correlated with levels of vWF, PIIINP, skin score, and disease activity index before and after treatment respectively (P <0. 01), but with no obvious correlation with the level of I CTP (P >0. 05). CONCLUSION: WYHZTLR could achieve its therapeutic effect on SSc patients by regulating Th17/Treg imbalance, lowering levels of vWF and PIIINP, and elevating the level of I CTP. PMID- 26485915 TI - [Screening of Active Fractions from Huanglian Jiedu Decoction against Primary Neuron Injury after Oxygen-Glucose Deprivation]. AB - OBJECTIVE: To observe the protective effect of active fractions of Huanglian Jiedu Decoction (HJD) on primary cortical neuron injury after oxygen-glucose deprivation (OGD)/reperfusion (R) injury. Methods Using macroporous resin method, HJDFE30, HJDFE50, HJDFE75, and HJDFE95 with 30%, 50%, 75%, and 95% alcohol were respectively prepared. Then the content of active components in different HJD fractions was determined with reverse phase high-performance liquid chromatography (RP-HPLC). The OGD/R injury model was induced by sodium dithionite on primary cortical neurons in neonate rats. MTT assay was used to observe the effect of four fractions (HJDFE30, HJDFE50, HJDFE75, and HJDFE95) and seven index components of HJD on the neuron viability. RESULTS: RP-HPLC showed active component(s) contained in HJDFE30 was geniposide; baicalin, palmatine, berberine, and wogonside contained in HJDFE50; baicalin, berberine, baicalein, and wogonin contained in HJDFE75. The neuron viability was decreased after OGD for 20 min and reperfusion for 1 h, (P <0. 01), and significantly increased after administered with HJD, HJDFE30, HJDFE50, and HJDFE75 (P <0. 05, P <0. 01). Geniposide, baicalin, baicalein, palmatine, wogonside, and wogonin could increase the cortical neuron viability (P <0. 05, P <0. 01). CONCLUSIONS: HJDFE30, HJDFE50, and HJDFE75, as active fractions of HJD, had protective effect on primary cortical neuron injury after OGD/R. Furthermore, geniposide, baicalin, and baicalein were main active components of HJD. PMID- 26485916 TI - [Effect of Yinao Jieyu Recipe on Brain Derived Neurotrophic Factor of the Limbic System in Post-Stroke Model Rats]. AB - OBJECTIVE: To observe the evolutionary tendency of brain derived neurotrophic factor (BDNF) of the limbic system in post-stroke model rats and the intervention effect of Yinao Jieyu Recipe (YJR). METHODS: Male Wistar rats were randomly divided into the normal control group (n =6), the sham-operation group (n =7), the multiple cerebral infarction (MCI) group (n =10), the post-stroke depression (PSD) group (n =10), the Chinese medicine (CM) treatment group (n =10), and the Western medicine (WM) treatment group (n =10) according to random digit table after open-field testing. Rats in the normal control group were routinely fed. 0. 3 mL normal saline was intravenously pushing from the external carotid artery to rats in the sham-operation group, and distilled water administered to them by gastrogavage. Each dose allogenic microthrombi were in vitro pushed to rats in the rest groups from the external carotid artery. The PSD model was duplicated by 21-day chronic unpredictable mild stress (CUMS) and single cage feeding in the PSD group 7 days after surgery. After preparing models rats in the CM group and the WM group were administered with YJR and Nimodipine respectively for 4 successive weeks. Changes of BDNF and the intervention effect of YJR were observed at week 1, 2, and 4 after intervention. RESULTS: Immunohistochemical results of BDNF showed, compared with the normal control group, expression levels of BDNF in the hippocampus, hypothalamus, and amygdala decreased in the MCI group at week 2 and 4 (P <0. 01 , P <0. 05) ; expression levels of BDNF in each part decreased in the PSD group at week 1-4 (P <0.01). Compared with the MCI group, expression levels of BDNF in each part decreased in the PSD group at week 1-4 (P <0. 01). Compared with the PSD group, expression levels of BDNF in each part increased in the CM group at week 1-4 (P <0. 01). CONCLUSION: BDNF changes existed in post-stroke model rats, and YJR could slow down this progress. PMID- 26485917 TI - [Effect of Yifei Jianpi Recipe on Airway Inflammation and Airway Mucus Hypersecretion of Chronic Obstructive Pulmonary Disease Model Rats]. AB - OBJECTIVE: To observe preventive and therapeutic effect of Yifei Jianpi Recipe (YJR) on chronic obstructive pulmonary disease (COPD) model rats and to explore its mechanism from the way of airway inflammation and airway mucus hypersecretion. METHODS: The COPD rat model was established by using cigarette smoking combined with intratracheal injection of lipopolysaccharide (LPS). Male SD rats were randomly divided into the blank control group (control group), the model group, the YJR group, 6 in each group. Forced vital capacity (FVC), forced expiratory volume in 0. 1 second (FEV0. 1), FEVO. 1/FVC, peak expiratory flow (PEF) was tested by lung function device. Pathological changes of bronchi and lung tissues were observed by HE staining. Airway Goblet cells were observed using AB-PAS staining. Contents of IL-8, IL-17, and TNF-alpha in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). Protein expressions of intercellular cell adhesion molecule-1 (ICAM-1), nuclear factor KB (NF-KB), mucin 5AC (Muc5AC), and Toll-like receptor 4 (TLR4) in rat airway were detected by immunohistochemical assay. mRNA expressions of TLR4 and Muc5AC in bronchi and lung tissues were detected by real-time quantitative PCR (RT qPCR). RESULTS: Changes of bronchi and lung tissues in the model group rats were consistent with typical pathological manifestations of COPD. Compared with the model group, the degree of lung injury was significantly alleviated in the YJR group. Compared with the control group, FVC, FEV0. 1, FEVO. I/FVC, and PEF were decreased (P <0. 01), contents of IL-8, IL-17, and TNF-alpha in BALF were significantly increased (P <0. 01), protein expressions of ICAM-1, NF-KB, Muc5AC, and TLR4, mRNA expression levels of Muc5AC and TLR4 in bronchi and lung tissues were also significantly increased in the model group (P <0. 01). Compared with the model group, FVC, FEV0. 1, FEV0. 1/FVC, and PEF were significantly increased in the YJR group (P <0. 01, P <0. 05), but the rest indices were significantly lowered (P <0. 01, P <0. 05). CONCLUSION: YJR could decrease contents of IL-8, IL 17, and TNF-alpha in BALF of COPD model rats, inhibit protein expression levels of ICAM-1, NF-kappaB, Muc5AC, and TLR4.in airway and lung tissues, thus playing preventive and therapeutic roles by reducing airway inflammation and airway mucus hypersecretion. PMID- 26485918 TI - [Effect of Osteoking on Bone Mineral Density and Dickkopf-1 Protein Levels in Rabbits with Osteoporotic Fracture]. AB - OBJECTIVE: To explore the effect of Osteoking on bone mineral density (BMD) and serum Dickkopf-1 (DKK-1) protein levels in rabbits with osteoporotic fracture (OPF). METHODS: Totally 45 female Japanese big-ear rabbits were randomly divided into the treatment group, the model group, and the blank control group (as the control group), 15 in each group. Bilateral ovaries were ectomized for 24 weeks in the treatment group and the model group. Their left radial factures were induced after confirmed osteoporosis. Rabbits in the treatment group were administered with Osteoking by gastrogavage, once per two days. Equal volume of normal saline was given to rabbits in the model group. The general BMD and serum DKK-1 protein levels were detected before ovariectomy, at week 24 and 48 after ovariectomy. RESULTS: There was significant difference in the general BMD at week 24 after ovariectomy between the model group and the control group, and it was lower in the model group. Compared with the model group, the general BMD significantly increased and serum DKK-1 protein levels significantly decreased in the treatment group after intervention. Serum DKK-1 protein levels were significantly lower after intervention than before intervention in the treatment group. CONCLUSION: Osteoking could improve the BMD of OPF rabbits, and reduce their serum DKK-1 protein levels as well. PMID- 26485919 TI - [Effect of Herba Lycopodii Alcohol Extracted Granule Combined Methylprednisolone on Expression Levels of BDNF and NMDA and Behavior of Traumatic Spinal Cord Injury Rats]. AB - OBJECTIVE: To study different effects of Herba Lycopodii (HL) Alcohol Extracted Granule combined methylprednisolone on behavioral changes, brain derived neurotrophic factor (BDNF) expression levels, and N-methyl-D-aspartate (NMDA) receptor levels in rats with spinal cord injury (SCI). METHODS: Male adult SD rats were randomly divided into five groups, i.e., the sham-operation group, the model group, the HL treatment group, the methylprednisolone treatment group, the HL + methylprednisolone treatment group. Rats in the HL treatment group were intragastrically administered with HL at the daily dose of 50 mg/kg for 5 successive days. Rats in the methylprednisolone treatment group were intramuscularly injected with 50 mg/kg methylprednisolone within 8 h after spinal cord contusion, and then the dose of methylprednisolone was reduced for 10 mg/kg for 5 successive days. Rats in the HL + methylprednisolone treatment group received the two methods used for the aforesaid two groups. Basso Beattie and Bresnahan (BBB) score (for hindlimb motor functions) were assessed at day 0, 3, 7, and 28 after operation. At day 13 after SCI, injured spinal T8-10 was taken from 8 rats of each group and stored in liquid nitrogen. The N-methyl-D-aspartate (NMDA) receptor affinity (Kd) and the maximal binding capacity (Bmax) were determined using [3H]MK-801 radioactive ligand assay. Rats' injured spinal cords were taken for immunohistochemical assay at day 28 after SCI. Expression levels of BDNF in the ventral and dorsal horn of the spinal cord were observed. RESULTS: Compared with the sham-operation group, the number of BDNF positive neurons in the ventral and dorsal horn of the spinal cord increased in the model group, Bmax increased (470 +/- 34), Kd decreased, and BBB scores decreased at day 3 -28 (all P <0. 05). Compared with the SCI model group, the number of BDNF positive neurons and Kd increased, BBB scores at day 3 -28 increased (P <0. 05) in each medicated group. Bmax was (660 +/- 15) in the methylprednisolone treatment group, (646 +/- 25) in the HL treatment group, and (510 +/- 21) in the HL +methylprednisolone treatment group (P <0. 05). Compared with the methylprednisolone treatment group, the number of BDNF positive neurons and Kd increased, BBB scores at day 7 -28 increased, and Bmax decreased in the HL treatment group and the HL + methylprednisolone treatment group (all P <0. 05). Compard with the HL treatment group, the number of BDNF positive neurons and Kd increased, and Bmax decreased (all P < 0.05). CONCLUSIONS: HL could effectively improve motor functions of handlimbs, increase expression levels of BDNF in the spinal cord, and lessen secondary injury by affecting spinal levels of NMDA receptors. It showed certain therapeutic and protective roles in treating SCI. Its effect was better than that of methylprednisolone with synergism. PMID- 26485920 TI - [Exploration of the Essence of "Endogenous Turbidity" in Chinese Medicine]. AB - The essence of endogenous turbidity in Chinese medicine (CM) is different from cream, fat, phlegm, retention, damp, toxicity, and stasis. Along with the development of modern scientific technologies and biology, researches on the essence of endogenous turbidity should keep pace with the time. Its material bases should be defined and new connotation endowed at the microscopic level. The essence of turbidity lies in abnormal functions of zang-fu organs. Sugar, fat, protein, and other nutrient substances cannot be properly decomposed, but into semi-finished products or intermediate metabolites. They are inactive and cannot participate in normal material syntheses and decomposition. They cannot be transformed to energy metabolism, but also cannot be synthesized as executive functioning of active proteins. If they cannot be degraded by autophagy-lysosome or ubiquitin-prosome into glucose, fatty acids, amino acids, and other basic nutrients to be used again, they will accumulate inside the human body and become endogenous turbidity. Therefore, endogenous turbidity is different from final metabolites such as urea, carbon dioxide, etc., which can transform vital qi. How to improve the function of zang-fu organs, enhance its degradation by autophagy lysosome or ubiquitin-prosome is of great significance in normal operating of zang-fu organs and preventing the emergence and progress of related diseases. PMID- 26485921 TI - [Analysis of the National Natural Science Foundation of China during 2009 -2013 in the Discipline of Integrative Medicine]. PMID- 26485922 TI - [Peripheral Nerve Toxicity Caused by Oxaliplatin: Research Progress of Integrative Medicine]. PMID- 26485923 TI - Tendon Reconstruction with Tissue Engineering Approach--A Review. AB - Tendon injuries are a common and rising occurrence, associated with significant impairment to quality of life and financial burden to the healthcare system. Clinically, they represent an unresolved problem, due to poor natural tendon healing and the inability of current treatment strategies to restore the tendon to its native state. Tissue engineering offers a promising alternative, with the incorporation of scaffolds, cells and growth factors to support the complete regeneration of the tendon. The materials used in tendon engineering to date have provided significant advances in structural integrity and biological compatibility and in many cases the results obtained are superior to those observed in natural healing. However, grafts fail to reproduce the qualities of the pre-injured tendon and each has weaknesses subject to its constituent parts. Furthermore, many materials and cell types are being investigated concurrently, with seemingly little association or comparison between research results. In this review the properties of the most-investigated and effective components have been appraised in light of the surrounding literature, with research from early in vitro experiments to clinical trials being discussed. Extensive comparisons have been made between scaffolds, cell types and growth factors used, listing strengths and weaknesses to provide a stable platform for future research. Promising future endeavours are also described in the field of nanocomposite material science, stem cell sources and growth factors, which may bypass weaknesses found in individual elements. The future of tendon engineering looks bright, with growing understanding in material technology, cell and growth factor application and encouraging recent advances bringing us ever closer to regenerating the native tendon. PMID- 26485924 TI - An Anti-Adhesion Technique in Microfluidic Channel Using Dielectrophoresis for Particle Processing Microfluidic Chip Applications. AB - Particle adhesion to the walls of microfluidic channels is a prominent cause of deteriorating performance and reliability in miniaturized analytical devices; it can also cause unexpected changes in their structures and operating conditions. Therefore, the demand of anti-adhesion for wall loss reduction on particle processing chips is high. This paper demonstrates an anti-adhesion technique using dielectrophoresis. The proposed technique is applied to a distribution microchannel for a feasibility test and is then applied to a blood plasma filter, which is a human blood cell and plasma separation device. In the distribution microchannel, the application of electric potentials of 0-20 V(pp) at 3 MHz caused the wall loss of polystyrene latex (PSL) particles to decrease with decreasing particle diameter. When an electric potential of 20 V(pp) was applied in a distribution microchannel experiment using PSL particles, the wall loss decreased by 52.7 +/- 3% for 10-MUm-diameter particles. On the other hand, when a 20 V(pp) electric potential was applied in a distribution microchannel experiment using human blood cells, the wall loss decreased by 66.4 +/- 6%. In the blood plasma filter, the wall loss decreased by 54.89 +/- 5% at 20 V(pp) and 1 MHz. The purity efficiency of the blood plasma filter was 69.56% without the wall loss reduction technique and 95.14% when the applied electric potential was 20 V(pp). PMID- 26485925 TI - A Strategy to Develop Bioactive Nanoarchitecture Cellulose: Sustained Release and Multifarious Applications. AB - Cellulose membranes were engineered to produce hydrophobic surfaces via a simple and soft chemical process to introduce multifunctional properties of an otherwise hydrophilic cellulose surface with polymer-grafted nanosilver to form a core shell nanostructure. A superhydrophobic domain of the polymer on cellulose was created through the amide bond formation between the anhydride units of the polymer and the aminosiloxane-functionalized cellulose through layer-over-layer formulation. This formulation was confirmed through XPS, XRD, 29Si-NMR, and FTIR studies. Further, SEM and TEM analysis revealed that short linear silver nanowires were uniformly obtained with an average diameter of 60 nm and length of 288 nm, using a mild reducing agent at 60 degrees C, which resulted in a hierarchical cellulose surface. The nanosilver colloids released from the hierarchical cellulose surface were stabilized by the polymer matrix in solution, which led to a decrease in the rate of formation of Ag+ enhancing the material's killing efficacy against microbes. This biodegradable nanocomposite-based cellulose hierarchical surface development has potential for application as superhydrophobic membranes for oil-water separation, antimicrobial activity, and pH-triggered sustained release of colloidal silver for wound healing, which could possibly be applied for use as smart bandages. PMID- 26485926 TI - In Vitro and In Vivo Evaluation of Pectin/Copper Exchanged Faujasite Composite Membranes. AB - The biocompatibility and excellent ion exchange capacity make faujasites ideal candidates for tissue engineering applications. A novel pectin/copper exchanged faujasite hybrid membrane was synthesized by solvent casting technique, using calcium chloride as the crosslinking agent. AFM images revealed the egg-box model organization of calcium cross-linked pectin chains used as a matrix. The morphology of composite membranes was characterized by SEM and their elemental composition was determined using EDX. The higher contact angle of P (1%) when compared to that of native pectin figured out an enhanced hydrophobicity of hybrid material. The embedded faujasite particles maintained their crystalline structure as revealed by XRD and their interactions with the polymer matrix was evaluated by FTIR. The composite membrane with 1% (w/w) of copper exchanged faujasite, P(1%), exhibited better thermal stability, excellent antibacterial activity, controlled swelling and degradation. Finally, it displayed cell viability of 89% on NIH3T3 fibroblast cell lines and aided in improving wound healing and re-epithelialisation in Sprague Dawley rats. The obtained data suggested their potential as ideal matrices for efficient treatment of burn wounds. PMID- 26485927 TI - A Combination of Targeted Sunitinib Liposomes and Targeted Vinorelbine Liposomes for Treating Invasive Breast Cancer. AB - Regular chemotherapy cannot eradicate invasive breast cancer cells and the residual cancer cells will form vasculogenic mimicry (VM) channels under hypoxic conditions to provide nutrients for cancer masses prior to angiogenesis. This phenomenon is a major reason for the recurrence of invasive breast cancer after treatment. In this study, a novel type of targeted liposomes was developed by modifying a mitochondria-tropic material, D-a-tocopheryl polyethylene glycol 1000 succinate- triphenylphosphine conjugate (TPGS1000-TPP), to encapsulate sunitinib and vinorelbine separately and a combination of the two targeted drug liposomes was used to treat invasive breast cancer as well as VM channels. Evaluations were performed in breast cancer MCF-7 cells and highly invasive breast cancer MDA-MB 435S cells in vitro and in mice. The results determined that the functional material (TPGS1000-TPP) and suitable size of the liposomes (90-100 nm) resulted in prolonged blood circulation, an enhanced permeability retention (EPR) effect in cancer tissue, and a mitochondrial targeting effect. Targeted drug liposomes were internalized via cellular uptake and accumulated in the mitochondria of invasive breast cancer cells or VM channel-forming cancer cells to induce acute cytotoxic injury and apoptosis. Activated apoptotic enzymes caspase 9 and caspase 3 as well as down-regulated VM channel-forming indicators (MMP-9, EphA2, VE Cadherin, FAK and HIF-1alpha) contributed to significantly enhanced efficacy. Therefore, a combination of targeted sunitinib liposomes and targeted vinorelbine liposomes may provide an effective strategy for treating invasive breast cancer and prevent relapse arising from VM channels. PMID- 26485928 TI - Protecting Quantum Dot Fluorescence from Quenching to Achieve a Reliable Automated Multiplex Fluorescence In Situ Hybridization Assay. AB - Quantum dots (QD) are novel inorganic fluorochromes that are ultra-bright, photo stable, and available in multiple, highly-resolvable colors. QDs represent an ideal detection material for in situ hybridization (ISH) because they may provide unprecedented resolution and strong signal intensities that are not attainable with traditional fluorophores. Unfortunately, lack of reliability has been an impediment to widespread adoption of QD-based fluorescence in situ hybridization (QD FISH) technology. By optimizing QD-to-target accessibility, we have developed a QD FISH staining procedure that dramatically improves the reliability of an automated ERG/PTEN QD FISH assay (91% 1st pass rate). Here, we report improvements to the assay that protects QD fluorescence from quenching due to trace amounts of heavy metals and minimizes QD background signals. When using this method, highly-consistent staining was observed with the ERG/PTEN QD FISH assay in prostate tissue. Successful staining of several other clinically relevant genetic markers was also possible. We further demonstrated improved reliability for determining HER2 gene status in breast cancer, identifying anaplastic lymphoma kinase (ALK) gene break-apart in non-small cell lung cancer, and detecting human papillomavirus 16 (HPV16) in cervical intraepithelial neoplasia. The enhanced QD FISH assay allows for examining complicated genetic aberrances without use of enzymatic amplification. Our optimized methods now demonstrate reliability sufficient for QD FISH technology to be a diagnostic tool in a clinical setting. PMID- 26485929 TI - Bioconjugated Gold Nanoparticles Penetrate Into Spermatozoa Depending on Plasma Membrane Status. AB - Spermatozoa are not only essential for animal reproduction they also represent important tools for the manipulation of animal genetics. For instance, the genetic labeling and analysis of spermatozoa could provide a prospective complementation of pre-fertilization diagnosis and could help to prevent the inheritance of defective alleles during artificial insemination or to select beneficial traits in livestock. Spermatozoa feature extremely specialized membrane organization and restricted transport mechanisms making the labeling of genetically interesting DNA-sequences, e.g., with gold nanoparticles, a particular challenge. Here, we present a systematic study on the size-related internalization of ligand-free, monovalent and bivalent polydisperse gold nanoparticles, depending on spermatozoa membrane status. While monovalent conjugates were coupled solely to either negatively-charged oligonucleotides or positively-charged cell-penetrating peptides, bivalent conjugates were functionalized with both molecules simultaneously. The results clearly indicate that the cell membrane of acrosome-intact, bovine spermatozoa was neither permeable to ligand-free or oligonucleotide-conjugated nanoparticles, nor responsive to the mechanisms of cell-penetrating peptides. Interestingly, after acrosome reaction, which comprises major changes in sperm membrane composition, fluidity and charge, high numbers of monovalent and bivalent nanoparticles were found in the postequatorial segment, depicting a close and complex correlation between particle internalization and membrane organization. Additionally, depending on the applied peptide and for nanoparticle sizes < 10 nm even a successive nuclear penetration was observed, making the bivalent conjugates promising for future genetic delivery and sorting issues. PMID- 26485931 TI - Folate-Modified Poly(malic acid) Graft Polymeric Nanoparticles for Targeted Delivery of Doxorubicin: Synthesis, Characterization and Folate Receptor Expressed Cell Specificity. AB - A novel amphiphilic biodegradable cholesterol and poly(ethylene glycol)-folate grafted poly(alpha,beta-malic acid) (PMA-g-Chol/PEG-FA) was synthesized and characterized as self-assembled nanoparticles for targeted delivery of doxorubicin (DOX). The nanoparticles showed extremely low critical aggregation concentrations (CAC), appropriate zeta potential, narrow size distribution, good stability in serum conditions and negligible toxicity. After encapsulation'of DOX, PMA-g-Chol/PEG-FA nanoparticles showed significantly reduced cell viability (up to 30% for Hela and 27% for 4T1 cells) compared with the non-targeted ones on carcinoma cells with different levels of folate receptor (FR) expression. While no difference was detected on HEK293 cells (FR receptor negative) between the two nanoparticles. Addition of extra free folate obviously decreased the cellular mortality and inhibited the cellular uptake of targeted nanoparticles. In the Hela/HEK293 co-culture model, folate conjugated nanoparticles showed specific affiliation with Hela cells other than HEK293 cells, indicating good targeting property of the delivery system. As detected from ex vivo fluorescent imaging, PMA-g-Chol/PEG-FA nanoparticles could accumulate at tumor site with higher selectivity compared to PMA-g-Chol/PEG nanoparticles and DOX x HCl. In vivo antitumor studies confirmed the significant tumor inhibition efficacy of drug loaded PMA-g-Chol/PEG-FA nanoparticles with lower toxicity to normal tissues than DOX x HCI at the same dosage. PMID- 26485930 TI - Identification and Testing of Novel CARP-1 Functional Mimetic Compounds as Inhibitors of Non-Small Cell Lung and Triple Negative Breast Cancers. AB - The triple negative breast cancer (TNBCs) and non-small cell lung cancers (NSCLCs) often acquire mutations that contribute to failure of drugs in clinic and poor prognosis, thus presenting an urgent need to develop new and improved therapeutic modalities. Here we report that CARP-1 functional mimetic (CFMs) compounds 4 and 5, and 4.6, a structurally related analog of CFM-4, are potent inhibitors of TNBC and NSCLC cells in vitro. Cell growth suppression by CFM-4 and -4.6 involved interaction and elevated expression of CARP-1/CCAR1 and Death Effector Domain (DED) containing DNA binding (DEDD)2 proteins. Apoptosis by these compounds also involved activation of pro-apoptotic stress-activated kinases p38 and JNK1/2, cleavage of PARP and loss of mitotic cyclin B1. Both the CFMs inhibited abilities of NSCLC and TNBC cells to migrate, invade, and form colonies in suspension, while disrupting tubule formation by the human umbilical vein endothelial cells (HUVECs). Nano-lipid formulation of CFM-4 (CFM-4 NLF) enhanced its serum bioavailability when compared with the free CFM-4. Oral administration of CFM-4 NLF reduced weights and volume of the xenografted tumors derived from A549 NSCLC and MDA-MB-231 TNBC cells. Although no gross tissue or histological toxicities were noticed, the immuno-histochemical analysis revealed increased CARP-1 and DNA fragmentation in tumors of the CFM-4 NLF-treated animals. In conclusion, while stimulation of pro-apoptotic CARP-1 and DEDD2 expression and their binding underscore a novel mechanism of apoptosis transduction by CFM compounds, our proof-of-concept xenograft studies demonstrate therapeutic potential of CFM-4 for TNBC and NSCLC. PMID- 26485932 TI - Label-Free and Real-Time Detection of Avian Influenza Using Nanowire Field Effect Transistors. AB - Real-time and label-free detection of antibodies from avian influenza (anti-AI) in an aqueous solution is demonstrated with the use of a nanowire field effect transistor. A real-time measurement system is constructed without leakage paths through the solution medium. The current through the nanowire changes significantly after an injection of an anti-AI solution onto the device, which was previously functionalized by the antigen of AI as a probe of anti-AI. In contrast, no significant response arises when an anti-AI solution is injected onto a non-functionalized device. Therefore, the real-time detection of specific antibody-antigen interaction of the AI is successfully implemented for a chip based biosensor. PMID- 26485934 TI - Magnetic Multi-Walled Carbon Nanotubes for Tumor Theranostics. AB - Current diagnostic techniques do not reliably detect cancer at early stages, and traditional chemotherapy lacks specificity and causes systemic toxicity. To address these issues, multifunctional nanomaterials are becoming more widely studied as a means of cancer detection, therapy, and monitoring. Here, iron oxide (Fe3O4) nanoparticles were conjugated onto the surface of multi-walled carbon nanotubes (MWNTs), which were then modified with polyethylenimine (PEI) and polyethylene glycol (PEG) to improve their solubility and biocompatibility. Finally, human telomerase reverse transcriptase (hTERT) siRNA was loaded on the MWNT surface by electrostatic interaction to obtain a multifunctional delivery system (MWNT-Fe3O4-PEI-PEG/siRNA). This delivery system efficiently delivered siRNA, allowed targeting of certain sites by magnetic fields, facilitated photothermal heating by near infrared irradiation, and enabled magnetic resonance imaging, thereby indicating great potential for cancer theranostic applications. PMID- 26485935 TI - Novel IL-2-Poly(HPMA)Nanoconjugate Based Immunotherapy. AB - Interleukin-2 (IL-2) possesses a strong stimulatory activity for activated T and NK cells and it is an attractive molecule for immunotherapy. Nevertheless, extremely short half-life and severe toxicities associated with high-dose IL-2 treatment are serious and limiting drawbacks. In order to increase IL-2 half-life in vivo, we covalently conjugated synthetic semitelechelic polymeric carrier based on N-(2-hydroxypropyl)methacrylamide (HPMA) to IL-2. Thus, we synthesized IL-2-poly(HPMA) conjugate containing 2-3 polymer chains per IL-2 molecule in average. Such conjugate has lower biologic activity in comparison to IL-2 in vitro. However, it exerts much higher activity than IL-2 in vivo as shown by expansion of memory CD8+ T, NK, NKT, gammadeltaT and Treg cells. Moreover, IL-2 poly(HPMA) extremely effectively potentiates CD8+ T cell peptide-based vaccination. IL-2-poly(HPMA) shows also much longer half-time in circulation than IL-2 (-4 h versus -5 min). Collectively, modification of IL-2 with poly(HPMA) chains dramatically improves its potency and pharmacologic features in vivo, which have implications for immunotherapy. To our knowledge, this is the first proof-of-concept report of the use of polymer/protein modification of IL-2 to obtain more pronounced biological activity. PMID- 26485936 TI - [Supporting adherence to drug therapy in psychiatry]. AB - Maintenance therapy to reduce the risk of recurrence is an essential part of treatment of schizophrenia, bipolar disorder and major depressive disorder, but poor treatment adherence is common, impairing the treatment outcome. Improvement in the adherence to drug therapy requires a good therapeutic relationship. The patient and her/his family must be provided with information about the illness and its treatment. Drug therapy must be optimized on an individual basis. The use of long-acting antipsychotic injections should be encouraged. Regular contact with patients under long-term treatment must be maintained. The use of experts by experience is an effective supportive measure. PMID- 26485933 TI - UVB Dependence of Quantum Dot Reactive Oxygen Species Generation in Common Skin Cell Models. AB - Studies have shown that UVB can slightly increase the penetration of nanoparticles through skin and significantly alter skin cell biology, thus it is important to understand if and how UVB may impact subsequent nanoparticle skin cell interactions. The research presented herein evaluates the effect of UVB on quantum dot (QD) uptake and reactive oxygen species (ROS) generation in primary keratinocytes, primary melanocytes, and related cell lines. QD exposure induced cell type dependent ROS responses increased by pre-exposing cells to UVB and correlated with the level of QD uptake. Our results suggest that keratinocytes may be at greater risk for QD induced ROS generation than melanocytes, and raise awareness about the differential cellular effects that topically applied nanomaterials may have on UVB exposed skin. PMID- 26485937 TI - [Bullous pemphigoid--a cause of itching of the skin with increasing incidence]. AB - Bullous pemphigoid (BP) is an autoimmune bullous dermatosis of the elderly with increasing incidence. Autoantibodies against dermal collagen XVII cause severe pruritus and large, tense bullae that are clinically evident. Immunofluorescence analysis on perilesional skin is used in the diagnostics and serum BP1 80 levels parallel the disease activity. Topical or systemic steroids are mainly used as treatment, but adjuvant immunosuppressive medication may also be needed. Patients with bullous pemphigoid are more likely to have neurological diseases as comorbidity. In addition, mortality is significantly increased, possibly due to long-term use of systemic corticosteroids. PMID- 26485938 TI - [Complications in ankle fracture surgery]. AB - Ankle fractures are among the most frequently encountered surgically treated fractures. The operative treatment can be associated with several complications such as malreduction and infection. Reinforcing the surgical armamentarium with meticulous preoperative planning together with recognition of common surgical errors are valuable adjuncts in reducing these complications. Furthermore, it is crucial to recognize and address modifiable risk factors for infection so as to minimize this potentially devastating complication. When a deep infection does occur, it is best managed by a multidisciplinary musculosceletal infection team. PMID- 26485939 TI - [How do I write a scientific article--advice to a young researcher]. AB - Medical care should be based on the best available scientific evidence, and physicians are frequently engaged in research to contribute to the evidence base. Publishing is a prerequisite for science and publication record is an indicator of the merits of a scientist. The predominant format for publication of medical research is journal articles. Writing a journal article can be a daunting task for a neophyte, and the skill is usually adopted with learning by doing, with little formal training available. This review describes the general structure of an article and the essential contents of each section. PMID- 26485940 TI - [Are practice guidelines being followed in specialized care?]. AB - We surveyed to which extent the processes of examination and treatment in 2012 were based on guidelines based on evaluated scientific evidence within the Hospital District of Helsinki and Uusimaa. The survey was directed at the fulfillment of 31 Current Care guidelines and 19 HALO guidelines, four nursing science guidelines as well as one physiotherapeutic guideline in a total of 1,318 patients. Current Care guidelines were mainly fulfilled well. Poor fulfillment of drug recommendations after hospitalization was alarming. HALO guidelines were moderately well fulfilled, whereas there were defects in adherence to the nursing science and physiotherapeutic guidelines. PMID- 26485942 TI - [Vascular health of the ageing woman]. AB - Cardiovascular diseases are the leading cause of mortality in both men and women, but in women these diseases manifest at a later age. After menopause, the decline in estrogen levels accelerates key atherogenic processes, including dyslipidemia, endothelial dysfunction and arterial stiffening, increasing the risk for cardiovascular events. In the healthy vasculature, estrogen has several structural and functional protective effects. The primary indication for menopausal hormone therapy is the treatment of climacteric symptoms, in particular hot flashes. With appropriate timing of estrogen treatment, it is possible to improve the ageing women's vascular health. PMID- 26485941 TI - [Update on Current Care Guideline: Borderline personality disorder]. AB - Borderline personality disorder is a severe disorder that increases disability to a considerable extent. Emotional instability, difficulties in regulating behavior and interpersonal relationships are essential features of the disorder. Borderline personality disorder has a more favorable course than previously thought. Dialectic behavioral therapy, cognitive therapy, mentalization therapy and transference-focused psychotherapy seem to be effective. Hospital treatment should be carried out primarily in day hospital settings. Antipsychotics and mood stabilizers may be used for a range of symptoms. SSRIs may be useful in the treatment of impulsivity and aggression. Benzodiazepines should be avoided. PMID- 26485943 TI - [Will memory be lost with menopause--can an ageing woman be protected from memory disorder?]. AB - Approximately two out of three persons affected with Alzheimer's disease are women. Estrogen is known to have positive effects on the levels of brain-derived mediators and circulation. Along with menopause, decreasing female sex hormone levels have been assumed to promote the development of memory disorders. It is possible that timing of the start of hormone replacement therapy exactly to the menopause could provide the best benefit in respect of memory and information processing. Prevention and treatment of risk factors of cardiovascular diseases along with regular exercise and a healthy diet are more important than hormone therapy in the prevention of memory disorders. PMID- 26485944 TI - [Cancer in an elderly woman]. AB - The most common cancers in elderly women, i.e. over 70 years of age, are breast cancer, lung cancer, colorectal cancer, ovarian cancer and cancer of the uterine corpus. Breast, lung and pancreatic cancers are in turn the greatest causes of mortality. While age itself is not an obstacle to surgical or oncological treatments, implementation of the treatments in the elderly are often associated with challenges due to primary diseases and diminished function of organs. One of the greatest practical problems is the exclusion of elderly patients from clinical cancer trials. PMID- 26485945 TI - [Treatment of menopausal symptoms]. AB - Hormone therapy is the most effective treatment for sweating and hot flashes, which are the most common symptoms of the menopause. The initiation of therapy for a healthy female of 50 to 59 years usually entails more health benefits than adverse effects, and there is no absolute upper limit for the duration of the treatment. It remains to be evaluated yearly whether the need or prerequisites for continuation of the treatment still exist. If the use of hormone therapy is not desired, alleviation of hot flashes and sweating can be attempted with life style modifications and other remedies. PMID- 26485946 TI - Novel characterization of landscape-level variability in historical vegetation structure. AB - We analyzed historical timber inventory data collected systematically across a large mixed-conifer-dominated landscape to gain insight into the interaction between disturbances and vegetation structure and composition prior to 20th century land management practices. Using records from over 20 000 trees, we quantified historical vegetation structure and composition for nine distinct vegetation groups. Our findings highlight some key aspects of forest structure under an intact disturbance regime: (1) forests were low density, with mean live basal area and tree density ranging from 8-30 m2 /ha and 25-79 trees/ha, respectively; (2) understory and overstory structure and composition varied considerably across the landscape; and (3) elevational gradients largely explained variability in forest structure over the landscape. Furthermore, the presence of large trees across most of the surveyed area suggests that extensive stand-replacing disturbances were rare in these forests. The vegetation structure and composition characteristics we quantified, along with evidence of largely elevational control on these characteristics, can provide guidance for restoration efforts in similar forests. PMID- 26485947 TI - Evaluating the impact of gas extraction infrastructure on the occupancy of sagebrush-obligate songbirds. AB - Development associated with natural gas extraction may have negative effects on wildlife. Here we assessed the effects of natural gas development on the distributions of three sagebrush-obligate birds (Brewer's Sparrow, Spizella breweri; Sagebrush Sparrow, Amphispiza belli; and Sage Thrasher, Oreoscoptes montanus) at a natural gas extraction site in Wyoming, USA. Two drivers of habitat disturbance were investigated: natural gas well pads and roadways. Disturbances were quantified on a small scale (minimum distance to a disturbance) and a large scale (landscape density of a disturbance). Their effects on the study species' distributions were assessed using a multi-scale occupancy model. Minimum distances to wells and roadways were found to not have significant impacts on small-scale occupancy. However, roadway and well density at the landscape-scale significantly impacted the large-scale occupancy of Sagebrush Sparrows and Sage Thrashers. The results confirmed our hypotheses that increasing road density negatively affects the landscape-scale occupancy rates of Sagebrush Sparrow and Sage Thrasher, but did not confirm our hypothesis that increasing well density would negatively impact large-scale occupancy. We therefore suggest that linear features that affect patch size may be more important than point features in determining sagebrush-obligate songbird occupancy when compared to structural effects such as habitat fragmentation and increased predation. We recommend that future well construction be focused along existing roadways, that horizontal drilling be used to reduce the need for additional roads, and that deactivation and restoration of roadways be implemented upon the deactivation of wells, we also recommend a possible mitigation strategy when new roads are to be built. PMID- 26485948 TI - Large-scale expansion of no-take closures within the Great Barrier Reef has not enhanced fishery production. AB - A rare opportunity to test hypotheses about potential fishery benefits of large scale closures was initiated in July 2004 when an additional 28.4% of the 348 000 km2 Great Barrier Reef (GBR) region of Queensland, Australia was closed to all fishing. Advice to the Australian and Queensland governments that supported this initiative predicted these additional closures would generate minimal (10%) initial reductions in both catch and landed value within the GBR area, with recovery of catches becoming apparent after three years. To test these predictions, commercial fisheries data from the GBR area and from the two adjacent (non-GBR) areas of Queensland were compared for the periods immediately before and after the closures were implemented. The observed means for total annual catch and value within the GBR declined from preclosure (2000-2003) levels of 12780 Mg and Australian $160 million, to initial post-closure (2005-2008) levels of 8143 Mg and $102 million; decreases of 35% and 36% respectively. Because the reference areas in the non-GBR had minimal changes in catch and value, the beyond-BACI (before, after, control, impact) analyses estimated initial net reductions within the GBR of 35% for both total catch and value. There was no evidence of recovery in total catch levels or any comparative improvement in catch rates within the GBR nine years after implementation. These results are not consistent with the advice to governments that the closures would have minimal initial impacts and rapidly generate benefits to fisheries in the GBR through increased juvenile recruitment and adult spillovers. Instead, the absence of evidence of recovery in catches to date currently supports an alternative hypothesis that where there is already effective fisheries management, the closing of areas to all fishing will generate reductions in overall catches similar to the percentage of the fished area that is closed. PMID- 26485949 TI - Disturbance of wildlife by outdoor winter recreation: allostatic stress response and altered activity-energy budgets. AB - Anthropogenic disturbance of wildlife is of growing conservation concern, but we lack comprehensive approaches of its multiple negative effects. We investigated several effects of disturbance by winter outdoor sports on free-ranging alpine Black Grouse by simultaneously measuring their physiological and behavioral responses. We experimentally flushed radio-tagged Black Grouse from their snow burrows, once a day, during several successive days, and quantified their stress hormone levels (corticosterone metabolites in feces [FCM] collected. from individual snow burrows). We also measured feeding time allocation (activity budgets reconstructed from radio-emitted signals) in response to anthropogenic disturbance. Finally, we estimated the related extra energy expenditure that may be incurred: based on activity budgets, energy expenditure was modeled from measures of metabolism obtained from captive birds subjected to different ambient temperatures. The pattern of FCM excretion indicated the existence of a funneling effect as predicted by the allostatic theory of stress: initial stress hormone concentrations showed a wide inter-individual variation, which decreased during experimental flushing. Individuals with low initial pre-flushing FCM values augmented their concentration, while individuals with high initial FCM values lowered it. Experimental disturbance resulted in an extension of feeding duration during the following evening foraging bout, confirming the prediction that Black Grouse must compensate for the extra energy expenditure elicited by human disturbance. Birds with low initial baseline FCM concentrations were those that spent more time foraging. These FCM excretion and foraging patterns suggest that birds with high initial FCM concentrations might have been experiencing a situation of allostatic overload. The energetic model provides quantitative estimates of extra energy expenditure. A longer exposure to ambient temperatures outside the shelter of snow burrows, following disturbance, could increase the daily energy expenditure by > 10%, depending principally on ambient temperature and duration of exposure. This study confirms the predictions of allostatic theory and, to the best of our knowledge, constitutes the first demonstration of a funneling effect. It further establishes that winter recreation activities incur costly allostatic behavioral and energetic adjustments, which call for the creation of winter refuge areas together with the implementation of visitor steering measures for sensitive wildlife. PMID- 26485950 TI - Estimating wind-turbine-caused bird and bat fatality when zero carcasses are observed. AB - Many wind-power facilities in the United States have established effective monitoring programs to determine turbine-caused fatality rates of birds and bats, but estimating the number of fatalities of rare species poses special difficulties. The loss of even small numbers of individuals may adversely affect fragile populations, but typically, few (if any) carcasses are observed during monitoring. If monitoring design results in only a small proportion of carcasses detected, then finding zero carcasses may give little assurance that the number of actual fatalities is small. Fatality monitoring at wind-power facilities commonly involves conducting experiments to estimate the probability (g) an individual will be observed, accounting for the possibilities that it falls in an unsearched area, is scavenged prior to detection, or remains undetected even when present. When g < 1, the total carcass count (X) underestimates the total number of fatalities (M). Total counts can be 0 when M is small or when M is large and g << 1. Distinguishing these two cases is critical when estimating fatality of a rare species. Observing no individuals during searches may erroneously be interpreted as evidence of absence. We present an approach that uses Bayes' theorem to construct a posterior distribution for M, i.e., P(M ? X, g), reflecting the observed carcass count and previously estimated g. From this distribution, we calculate two values important to conservation: the probability that M is below a predetermined limit and the upper bound (M*) of the 100(1 - alpha)% credible interval for M. We investigate the dependence of M* on alpha, g, and the prior distribution of M, asking what value of g is required to attain a desired M for a given alpha. We found that when g < -0.15, M* was clearly influenced by the mean and variance of g and the choice of prior distribution for M, but the influence of these factors is minimal when g > -0.45. Further, we develop extensions for temporal replication that can inform prior distributions of M and methods for combining information across several areas or time periods. We apply the method to data collected at a wind-power facility where scheduled searches yielded X = 0 raptor carcasses. PMID- 26485951 TI - Iron-mediated stabilization of soil carbon amplifies the benefits of ecological restoration in degraded lands. AB - Recent observations across a 14-year restoration chronosequence have shown an unexpected accumulation of soil organic carbon in strip-mined areas of central Brazil. This was attributed to the rapid plant colonization that followed the incorporation of biosolids into exposed regoliths, but the specific mechanisms involved in the stabilization of carbon inputs from the vegetation remained unclear. Using isotopic and elemental analyses, we tested the hypothesis that plant-derived carbon accumulation was triggered by the formation of iron coordinated complexes, stabilized into physically protected (occluded) soil fractions. Confirming this hypothesis, we identified a fast formation of microaggregates shortly after the application of iron-rich biosolids, which was characterized by a strong association between pyrophosphate-extractable iron and plant-derived organic matter. The formation of microaggregates preceded the development of macroaggregates, which drastically increased soil carbon content ( 140 Mg C/ha) a few years after restoration. Consistent with previous theoretical work, iron-coordinated organic complexes served as nuclei for aggregate formation, reflecting the synergistic effect of biological, chemical, and physical mechanisms of carbon stabilization in developing soils. Nevertheless, iron was not the only factor affecting soil carbon content. The highest carbon accumulation was observed during the period of highest plant diversity (> 30 species; years 3-6), declining significantly with the exclusion of native species by invasive grasses (years 9-14). Furthermore, the increasing dominance of invasive grasses was associated with a steady decline in the concentration of soil nitrogen and phosphorus per unit of accumulated carbon. These results demonstrate the importance of interdependent ecological and biogeochemical processes, and the role of soil-plant interactions in determining the success of restoration efforts. In contrast with previous but unsuccessful attempts to restore mined areas through nutrient application alone, iron-mediated stabilization of vegetation inputs favored the regeneration of a barren stable state that had persisted for over five decades since disturbance. The effectiveness of coupled organic matter and iron "fertilization," combined with management of invasive species, has the possibility to enhance terrestrial carbon sequestration and accelerate the restoration of degraded lands, while addressing important challenges associated with urban waste disposal. PMID- 26485952 TI - Long-term oil contamination increases deterministic assembly processes in soil microbes. AB - The mechanisms that drive microbial turnover in time and space have received considerable attention but remain unclear, especially for situations with anthropogenic perturbation. To understand the impact of long-term oil contamination on microbial spatial turnover, 100 soil samples were taken from five oil exploration fields located in different geographic regions across China. The microbial functional diversity was analyzed with a high-throughput functional gene array, GeoChip. Our results indicated that soil microbial alpha-diversity (richness and Shannon diversity index) decreased significantly with contamination. All contaminated and uncontaminated samples exhibited significant spatial autocorrelation between microbial community similarity and spatial distance, as described by a distance-decay relationship (DDR). However, long-term oil exposure flattened the slopes of the DDRs of all of the functional genes and each functional group involved in C/N/P/S cycling, particularly of those involved in contaminant degradation. The relative importance of deterministic and stochastic processes in microbial assembly was determined. The decrease in microbial spatial turnover with long-term oil contamination was coupled with an increase in the proportion of deterministic processes that structured microbial assembly based on null model analysis. The results indicated long-term oil contamination significantly affects soil microbial community spatial structure by acting as an environmental filter to decrease the regional differences distinguishing soil microbial communities. PMID- 26485953 TI - Objective classification of latent behavioral states in bio-logging data using multivariate-normal hidden Markov models. AB - Analysis of complex time-series data from ecological system study requires quantitative tools for objective description and classification. These tools must take into account largely ignored problems of bias in manual classification, autocorrelation, and noise. Here we describe a method using existing estimation techniques for multivariate-normal hidden Markov models (HMMs) to develop such a classification. We use high-resolution behavioral data from bio-loggers attached to free-roaming pelagic tuna as an example. Observed patterns are assumed to be generated by an unseen Markov process that switches between several multivariate normal distributions. Our approach is assessed in two parts. The first uses simulation experiments, from which the ability of the HMM to estimate known parameter values is examined using artificial time series of data consistent with hypotheses about pelagic predator foraging ecology. The second is the application to time series of continuous vertical movement data from yellowfin and bigeye tuna taken from tuna tagging experiments. These data were compressed into summary metrics capturing the variation of patterns in diving behavior and formed into a multivariate time series used to estimate a HMM. Each observation was associated with covariate information incorporating the effect of day and night on behavioral switching. Known parameter values were well recovered by the HMMs in our simulation experiments, resulting in mean correct classification rates of 90 97%, although some variance-covariance parameters were estimated less accurately. HMMs with two distinct behavioral states were selected for every time series of real tuna data, predicting a shallow warm state, which was similar across all individuals, and a deep colder state, which was more variable. Marked diurnal behavioral switching was predicted, consistent with many previous empirical studies on tuna. HMMs provide easily interpretable models for the objective classification of many different types of noisy autocorrelated data, as typically found across a range of ecological systems. Summarizing time-series data into a multivariate assemblage of dimensions relevant to the desired classification provides a means to examine these data in an appropriate behavioral space. We discuss how outputs of these models can be applied to bio-logging and other imperfect behavioral data, providing easily interpretable models for hypothesis testing. PMID- 26485954 TI - Grazing maintains native plant diversity and promotes community stability in an annual grassland. AB - Maintaining native biodiversity in grasslands requires management and mitigation of anthropogenic changes that have altered resource availability, grazing regimes, and community composition. In California (USA), high levels of atmospheric nitrogen (N) deposition have facilitated the invasion of exotic grasses, posing a threat to the diverse plant and insect communities endemic to serpentine grasslands. Cattle grazing has been employed to mitigate the consequences of exotic grass invasion, but the ecological effects of grazing in this system are not fully understood. To characterize the effects of realistic N deposition on serpentine plant communities and to evaluate the efficacy of grazing as a management tool, we performed a factorial experiment adding N and excluding large herbivores in California's largest serpentine grassland. Although we observed significant interannual variation in community composition related to climate in our six-year study, exotic cover was consistently and negatively correlated with native plant richness. Sustained low-level N addition did not influence plant community composition, but grazing reduced grass abundance while maintaining greater native forb cover, native plant diversity, and species richness in comparison to plots excluding large herbivores. Furthermore, grazing increased the temporal stability of plant communities by decreasing year-to-year variation in native forb cover, native plant diversity, and native species richness. Taken together, our findings demonstrate that moderate-intensity cattle grazing can be used to restrict the invasive potential of exotic grasses and maintain native plant communities in serpentine grasslands. We hypothesize that the reduced temporal variability in serpentine plant communities managed by grazing may directly benefit populations of the threatened Edith's Bay checkerspot butterfly (Euphydryas editha bayensis). PMID- 26485955 TI - Recovery of arctic tundra from thermal erosion disturbance is constrained by nutrient accumulation: a modeling analysis. AB - Abstract. We calibrated the Multiple Element Limitation (MEL) model to Alaskan arctic tundra to simulate recovery of thermal erosion features (TEFs) caused by permafrost thaw and mass wasting. TEFs could significantly alter regional carbon (C) and nutrient budgets because permafrost soils contain large stocks of soil organic matter (SOM) and TEFs are expected to become more frequent as the climate warms. We simulated recovery following TEF stabilization and did not address initial, short-term losses of C and nutrients during TEF formation. To capture the variability among and within TEFs, we modeled a range of post-stabilization conditions by varying the initial size of SOM stocks and nutrient supply rates. Simulations indicate that nitrogen (N) losses after the TEF stabilizes are small, but phosphorus (P) losses continue. Vegetation biomass recovered 90% of its undisturbed C, N, and P stocks in 100 years using nutrients mineralized from SOM. Because of low litter inputs but continued decomposition, younger SOM continued to be lost for 10 years after the TEF began to recover, but recovered to about 84% of its undisturbed amount in 100 years. The older recalcitrant SOM in mineral soil continued to be lost throughout the 100-year simulation. Simulations suggest that biomass recovery depended on the amount of SOM remaining after disturbance. Recovery was initially limited by the photosynthetic capacity of vegetation but became co-limited by N and P once a plant canopy developed. Biomass and SOM recovery was enhanced by increasing nutrient supplies, but the magnitude, source, and controls on these supplies are poorly understood. Faster mineralization of nutrients from SOM (e.g., by warming) enhanced vegetation recovery but delayed recovery of SOM. Taken together, these results suggest that although vegetation and surface SOM on TEFs recovered quickly (25 and 100 years, respectively), the recovery of deep, mineral soil SOM took centuries and represented a major ecosystem C loss. PMID- 26485956 TI - Remote assessment of locally important ecological features across landscapes: how representative of reality? AB - The local ecological footprinting tool (LEFT) uses globally available databases, modeling, and algorithms to, remotely assess locally important ecological features across landscapes based on five criteria: biodiversity (beta-diversity), vulnerability (threatened species), fragmentation, connectivity, and resilience. This approach can be applied to terrestrial landscapes at a 300-m resolution within a given target area. Input is minimal (latitude and longitude) and output is a computer-generated report and series of maps that both individually and synthetically depict the relative value of each ecological criteria. A key question for any such tool, however, is how representative is the remotely obtained output compared to what is on the ground. Here, we present the results from comparing remotely- vs. field-generated outputs from the LEFT tool on two distinct study areas for beta-diversity and distribution of threatened species (vulnerability), the two fields computed by LEFT for which such an approach is feasible. The comparison method consists of a multivariate measure of similarity between two fields based on discrete wavelet transforms, and reveals consistent agreement across a wide range of spatial scales. These results suggest that remote assessment tools such as LEFT hold great potential for determining key ecological features across landscapes and for being utilized in preplanning biodiversity assessment tools. PMID- 26485957 TI - The agony of choice: different empirical mortality models lead to sharply different future forest dynamics. AB - Dynamic models are pivotal for projecting forest dynamics in a changing climate, from the local to the global scale. They encapsulate the processes of tree population dynamics with varying resolution. Yet, almost invariably, tree mortality is modeled based on simple, theoretical assumptions that lack a physiological and/or empirical basis. Although this has been widely criticized and a growing number of empirically derived alternatives are available, they have not been tested systematically in models of forest dynamics. We implemented an inventory-based and a tree-ring-based mortality routine in the forest gap model ForClim v3.0. We combined these routines with a stochastic and a deterministic approach for the determination of tree status (alive vs. dead). We tested the four new model versions for two Norway spruce forests in the Swiss Alps, one of which was managed (inventory time series spanning 72 years) and the other was unmanaged (41 years). Furthermore, we ran long-term simulations (-400 years) into the future under three climate scenarios to test model behavior under changing environmental conditions. The tests against inventory data showed an excellent match of simulated basal area and stem numbers at the managed site and a fair agreement at the unmanaged site for three of the four empirical mortality models, thus rendering the choice of one particular model difficult. However, long-term simulations under current climate revealed very different behavior of the mortality models in terms of simulated changes of basal area and stem numbers, both in timing and magnitude, thus indicating high sensitivity of simulated forest dynamics to assumptions on tree mortality. Our results underpin the potential of using empirical mortality routines in forest gap models. However, further tests are needed that span other climatic conditions and mixed forests. Short-term simulations to benchmark model behavior against empirical data are insufficient; long-term tests are needed that include both nonequilibrium and equilibrium conditions. Thus, there is the potential to greatly improve the robustness of future projections of forest dynamics via more reliable tree mortality submodels. PMID- 26485958 TI - Defoliation by pastoralists affects savanna tree seedling dynamics by limiting the facilitative role of canopy cover. AB - Recurrent tree defoliation by pastoralists, akin to herbivory, can negatively affect plant reproduction and population dynamics. However, our understanding of the indirect role of defoliation in seedling recruitment and tree-grass dynamics in tropical savanna is limited. In West African savanna, Fulani pastoralists frequently defoliate several fodder tree species to feed livestock in the dry season. We investigated the direct and indirect effects of recurrent defoliation of African mahogany (Khaya senegalensis) by Fulani people on seedling (< 2 cm basal diameter) and sapling dynamics in West Africa using four years of demographic data on seedling and sapling density, growth, and survival, coupled with fruit production and microhabitat data over the same time period. Tree canopy cover facilitated seedlings but had negative effects on sapling growth possibly via intraspecific competition with adult plants. Interspecific competition with grasses strongly reduced seedling survival but had a weak effect on sapling growth. Fire reduced seedling survival and weakly reduced growth of seedlings and saplings, but did not affect sapling survival. These results indicate that the effect of fire on seedlings and saplings is distinct, a mechanism suitable for an episodic recruitment of seedlings into the sapling stage and consistent with predictions from the demographic bottleneck model. Defoliation affected seedling density and sapling growth through changes in canopy cover, but had no effect on seedling growth and sapling survival. In the moist region, sapling density was higher in sites with low-intensity defoliation, indicating that defoliation may strengthen the tree recruitment bottleneck. Our study suggests that large-scale defoliation can alter the facilitative role of nurse trees on seedling dynamics and tree-sapling competition. Given that tree defoliation by local people is a widespread activity throughout savanna-forest systems in West Africa, it has the potential to affect tree-grass coexistence. Incorporating the influence of large tree defoliation into existing models of savanna dynamics can further our understanding of tree-grass coexistence and improve management. A rotating harvest system, which allows seedlings to recruit episodically, or a patchwork harvest, which maintains some nursery trees in the mosaic, could help sustain seedling recruitment and minimize the indirect effects of harvest. PMID- 26485959 TI - Are large macroalgal blooms necessarily bad? Nutrient impacts on seagrass in upwelling-influenced estuaries. AB - Knowledge of nutrient pathways and their resulting ecological interactions can alleviate numerous environmental problems associated with nutrient increases in both natural and managed systems. Although not unique, coastal systems are particularly prone to complex ecological interactions resulting from nutrient inputs from both the land and sea. Nutrient inputs to coastal systems often spur ulvoid macroalgal blooms, with negative consequences for seagrasses, primarily through shading, as well as through changes in local biogeochemistry. We conducted complementary field and mesocosm experiments in an upwelling-influenced estuary, where marine-derived nutrients dominate, to understand the direct and indirect effects of nutrients on the macroalgal-eelgrass (Zostera marina L.) interaction. In the field experiment, we found weak evidence that nutrients and/or macroalgal treatments had a negative effect on eelgrass. However, in the mesocosm experiment, we found that a combination of nutrient and macroalgal treatments led to strongly negative eelgrass responses, primarily via indirect effects associated with macroalgal additions. Together, increased total light attenuation and decreased sediment oxygen levels were associated with larger effects on eelgrass than shading alone, which was evaluated using mimic algae treatments that did not alter sediment redox potential. Nutrient addition in the mesocosms directly affected seagrass density; biomass, and morphology, but not as strongly as macroalgae. We hypothesize that the contrary results from these parallel experiments are a consequence of differences in the hydrodynamics between field and mesocosm settings. We suggest that the high rates of water movement and tidal submersion of our intertidal field experiments alleviated the light reduction and negative biogeochemical changes in the sediment associated with macroalgal canopies, as well as the nutrient effects observed in the mesocosm experiments. Furthermore, adaptation of ulvoids and eelgrass to high, but variable, background nutrient concentrations in upwelling-influenced estuaries may partly explain the venue-specific results reported here. In order to manage critical seagrass habitats, nutrient criteria and macroalgal indicators must consider variability in marine-based nutrient delivery and local physical conditions among estuaries. PMID- 26485960 TI - Population resilience to catastrophic mortality events during early life stages. AB - Catastrophic mortality events that drastically reduce the abundance of a population or a particular life stage can have long-term ecological and economic effects, and are of great concern in species conservation and management. Severe die-offs may be caused by natural catastrophes such as disease outbreaks and extreme climates, or human-caused disturbances such as toxic spills. Forecasting potential impacts of such disturbances is difficult and highly uncertain due to unknown future conditions, including population status and environmental conditions at the time of impact. Here, we present a framework for quantifying the range of potential, population-level effects of catastrophic events based on a hindcasting approach. A dynamic population model with Bayesian parameter estimation is used to simulate the impact of severe (50-99%) mortality events during the early life stages of Northeast Arctic cod (Gadus morhua), an abundant marine fish population of high economic value. We quantify the impact of such die offs in terms of subsequent changes in population biomass and harvest through direct comparison of simulated and historical trends, and estimate the duration of the impact as a measure of population resilience. Our results demonstrate strong resilience to catastrophic events that affect early life stages owing to density dependence in survival and a broad population age structure. Yet, while population recovery is. relatively fast, losses in harvest and economic value can be substantial. Future research efforts should focus on long-term and indirect effects via food web interactions in order to better understand the ecological and economic ramifications of catastrophic mortality events. PMID- 26485961 TI - Connectivity and conditional models of access and abundance of species in stream networks. AB - Barriers to passage of aquatic organisms at stream road crossings are a major cause of habitat fragmentation in stream networks. Accordingly, large investments have been made to restore passage at these crossings, but often without estimation of population-level benefits. Here, we describe a broad-scale approach to quantifying the effectiveness of passage restoration in terms interpretable at population levels, namely numbers of fish and length of stream gained through restoration, by sampling abundance in a study design that accounts for variable biogeographic species pools, variable stream and barrier configurations, and variable probabilities of capture and detectability for multiple species. We modified an existing zero-inflated negative-binomial model to estimate the probability of site access, abundance conditional on access, and capture probability of individual fish. Therein, we modeled probability of access as a function of gradient, stream road-crossing type, and downstream access by fish simultaneously with a predictive model for abundance at sites accessible to fish. Results indicated that replacement of barriers with new crossing designs intended to allow for greater movement was associated with dramatically higher probability of access for all fishes, including migratory Pacific salmon, trout, sculpin, and lamprey. Conversely, existing non-replaced crossings negatively impacted fish distributions. Assuming no downstream constraints on access, we estimated the potential length of stream restored by the program ranged between 7.33 (lamprey) and 15.28 km (small coastal cutthroat and rainbow trout). These contributions represented a fraction of the total length available upstream (187 km) of replaced crossings. When limited ranges of species were considered, the estimated contributions of culvert replacement were reduced (1.65-km range, for longnose dace to 12.31 km for small coastal cutthroat and rainbow trout). Numbers of fish contributed ranged from less than 500 (longnose dace) to greater than 100 000 (sculpin). Although our framework can address the question of effectiveness in a broad array of stream and crossing configurations, much stronger inferences would be possible if future restoration efforts were designed to address the limitations we encountered in this study, particularly the lack of available information on crossings and species presence prior to restoration, and nonrandom selection of crossings to be replaced. PMID- 26485962 TI - Time for recovery of riparian plants in restored northern Swedish streams: a chronosequence study. AB - A lack of ecological responses in stream restoration projects has been prevalent throughout recent literature with many studies reporting insufficient time for recovery. We assessed the relative importance of time, site variables, and landscape setting for understanding how plant species richness and understory productivity recover over time in riparian zones of northern Swedish streams. We used a space-for-time substitution consisting of 13 stream reaches restored 5-25 years ago, as well as five unrestored channelized reference reaches. We inventoried the riparian zone for all vascular plant species along 60-m study reaches and quantified cover and biomass in plots. We found that while species richness increased with time, understory biomass decreased. Forbs made up the majority of the species added, while the biomass of graminoids decreased the most over time, suggesting that the reduced dominance of graminoids favored less productive forbs. Species richness and density patterns could be attributed to dispersal limitation, with anemochorous species being more associated with time after restoration than hydrochorous, zoochorous, or vegetatively reproducing species. Using multiple linear regression, we found that time along with riparian slope and riparian buffer width (e.g., distance to logging activities) explained the most variability in species richness, but that variability in total understory biomass was explained primarily by time. The plant community composition of restored reaches differed from that of channelized references, but the difference did not increase over time. Rather, different time categories had different successional trajectories that seemed to converge on a unique climax community for that time period. Given our results, timelines for achieving species richness objectives should be extended to 25 years or longer if recovery is defined as a saturation of the accumulation of species over time. Other recommendations include making riparian slopes as gentle as possible given the landscape context and expanding riparian buffer width for restoration to have as much impact as possible. PMID- 26485963 TI - Trade-offs between objectives for ecosystem management of fisheries. AB - The strategic objectives for fisheries, which are enshrined in international conventions, are to maintain or restore stocks to produce maximum sustainable yield (MSY) and to implement the ecosystem approach, requiring that interactions between species be taken into account and conservation constraints be respected. While the yield and conservation aims are, to some extent, compatible when a fishery for a single species is considered, species interactions entail that MSY for a species depends on the species with which it interacts, and the yield and conservation objectives therefore conflict when an ecosystem approach to fisheries management is required. We applied a conceptual size- and trait-based model to clarify and resolve these issues by determining the fishing pattern that maximizes the total yield of an entire fish community in terms of catch biomass or economic rent under acceptable conservation constraints. Our results indicate that the eradication of large, predatory fish species results in a potential maximum catch at least twice as high as if conservation constraints are imposed. However, such a large catch could only be achieved at a cost of forgone rent; maximum rent extracts less than half of the potential maximum catch mass. When a conservation constraint is applied, catch can be maximized at negligible cost in forgone rent, compared with maximizing rent. Maximization of rent is the objective that comes closest to respecting conservation concerns. PMID- 26485964 TI - Accounting for groundwater in stream fish thermal habitat responses to climate change. AB - Forecasting climate change effects on aquatic fauna and their habitat requires an understanding of how water temperature responds to changing air temperature (i.e., thermal sensitivity). Previous efforts to forecast climate effects on brook trout (Salvelinus fontinalis) habitat have generally assumed uniform air water temperature relationships over large areas that cannot account for groundwater inputs and other processes that operate at finer spatial scales. We developed regression models that accounted for groundwater influences on thermal sensitivity from measured air-water temperature relationships within forested watersheds in eastern North America (Shenandoah National Park, Virginia, USA, 78 sites in nine watersheds). We used these reach-scale models to forecast climate change effects on stream temperature and brook trout thermal habitat, and compared our results to previous forecasts based upon large-scale models. Observed stream temperatures were generally less sensitive to air temperature than previously assumed, and we attribute this to the moderating effect of shallow groundwater inputs. Predicted groundwater temperatures from air-water regression models corresponded well to observed groundwater temperatures elsewhere in the study area. Predictions of brook trout future habitat loss derived from our fine-grained models. were far less pessimistic than those from prior models developed at coarser spatial resolutions. However, our models also revealed spatial variation in thermal sensitivity within and among catchments resulting in a patchy distribution of thermally suitable habitat. Habitat fragmentation due to thermal barriers therefore may have an increasingly important role for trout population viability in headwater streams. Our results demonstrate that simple adjustments to air-water temperature regression models can provide a powerful and cost-effective approach for predicting future stream temperatures while accounting for effects of groundwater. PMID- 26485965 TI - Trends and stability of inland fishery resources in Japanese lakes: introduction of exotic piscivores as a driver. AB - Although many studies have focused on marine resources, few studies have considered the resources of inland fisheries. Inland fishery resources are typically either monitored on the basis of catch data alone or are not assessed quantitatively at all, despite their social, economic, and ecological importance. Because freshwater ecosystems have been severely degraded by human activities, evaluating the trends and current status of fishery resources and assessing their drivers are urgent tasks. We compiled long-term data on the annual catch, fishing effort, and fishing power of 23 Japanese lakes, using two sets of government statistics that date back to the 1950s, which were previously neglected because of the large number of missing values. Using Bayesian state-space models, we examined the trajectories of the catch per unit effort (CPUE) of entire communities, considering changes in fishing effort and fishing power, and quantified both changes in the CPUE over the 10-, 20-, and 30-year periods preceding 2008 and the temporal detrended stability of the CPUE over the three periods. We also investigated the relationships among the CPUE changes and stability, anthropogenic drivers, and lake morphometric characteristics. The CPUE declined in 17, 19, and 15 of the 23 lakes over the past 10-, 20-, and 30-year periods, respectively. Our macroecological analyses demonstrate that the functional group richness of exotic piscivores was the most important predictor of changes in the CPUE among the drivers we considered. The stability of the CPUE was positively related to lake area; larger lakes have more stable CPUE. The functional group richness of exotic piscivores also negatively affected the stability of the CPUE. The effect of overfishing was considered to be small because both fishing effort and power declined in almost all of the lakes. Thus, our findings suggest that increasing exotic piscivore species may diminish the resources and their stability, particularly in Japanese lakes where native piscivores are rare. This might lead to a substantial decline in ecosystem services. Our study highlights the importance of assessing inland fishery resources in a comprehensive manner and the need for restoration strategies to mitigate the effects of exotic piscivores. PMID- 26485966 TI - Efficacy of generic allometric equations for estimating biomass: a test in Japanese natural forests. AB - Accurate estimation of tree and forest biomass is key to evaluating forest ecosystem functions and the global carbon cycle. Allometric equations that estimate tree biomass from a set of predictors, such as stem diameter and tree height, are commonly used. Most allometric equations are site specific, usually developed from a small number of trees harvested in a small area, and are either species specific or ignore interspecific differences in allometry. Due to lack of site-specific allometries, local equations are often applied to sites for which they were not originally developed (foreign sites), sometimes leading to large errors in biomass estimates. In this study, we developed generic allometric equations for aboveground biomass and component (stem, branch, leaf, and root) biomass using large, compiled data sets of 1203 harvested trees belonging to 102 species (60 deciduous angiosperm, 32 evergreen angiosperm, and 10 evergreen gymnosperm species) from 70 boreal, temperate, and subtropical natural forests in Japan. The best generic equations provided better biomass estimates than did local equations that were applied to foreign sites. The best generic equations included explanatory variables that represent interspecific differences in allometry in addition to stem diameter, reducing error by 4-12% compared to the generic equations that did not include the interspecific difference. Different explanatory variables were selected for different components. For aboveground and stem biomass, the best generic equations had species-specific wood specific gravity as an explanatory variable. For branch, leaf, and root biomass, the best equations had functional types (deciduous angiosperm, evergreen angiosperm, and evergreen gymnosperm) instead of functional traits (wood specific gravity or leaf mass per area), suggesting importance of other traits in addition to these traits, such as canopy and root architecture. Inclusion of tree height in addition to stem diameter improved the performance of the generic equation only for stem biomass and had no apparent effect on aboveground, branch, leaf, and root biomass at the site level. The development of a generic allometric equation taking account of interspecific differences is an effective approach for accurately estimating aboveground and component biomass in boreal, temperate, and subtropical natural forests. PMID- 26485968 TI - [Study on Sleep Staging Based on Support Vector Machines and Feature Selection in Single Channel Electroencephalogram]. AB - Sleep electroencephalogram (EEG) is an important index in diagnosing sleep disorders and related diseases. Manual sleep staging is time-consuming and often influenced by subjective factors. Existing automatic sleep staging methods have high complexity and a low accuracy rate. A sleep staging method based on support vector machines (SVM) and feature selection using single channel EEG single is proposed in this paper. Thirty-eight features were extracted from the single channel EEG signal. Then based on the feature selection method F-Score's definition, it was extended to multiclass with an added eliminate factor in order to find proper features, which were used as SVM classifier inputs. The eliminate factor was adopted to reduce the negative interaction of features to the result. Research on the F-Score with an added eliminate factor was further accomplished with the data from a standard open source database and the results were compared with none feature selection and standard F-Score feature selection. The results showed that the present method could effectively improve the sleep staging accuracy and reduce the computation time. PMID- 26485967 TI - [Research on Mental Fatigue Detecting Method Based on Sleep Deprivation Models]. AB - Mental fatigue is an important factor of human health and safety. It is important to achieve dynamic mental fatigue detection by using electroencephalogram (EEG) signals for fatigue prevention and job performance improvement. We in our study induced subjects' mental fatigue with 30 h sleep deprivation (SD) in the experiment. We extracted EEG features, including relative power, power ratio, center of gravity frequency (CGF), and basic relative power ratio. Then we built mental fatigue prediction model by using regression analysis. And we conducted lead optimization for prediction model. Result showed that R2 of prediction model could reach to 0.932. After lead optimization, 4 leads were used to build prediction model, in which R' could reach to 0.811. It can meet the daily applicatioi accuracy of mental fatigue prediction. PMID- 26485969 TI - [Study on Steady State Visual Evoked Potential Target Detection Based on Two dimensional Ensemble Empirical Mode Decomposition]. AB - Brain computer interface is a control system between brain and outside devices by transforming electroencephalogram (EEG) signal. The brain computer interface system does not depend on the normal output pathways, such as peripheral nerve and muscle tissue, so it can provide a new way of the communication control for paralysis or nerve muscle damaged disabled persons. Steady state visual evoked potential (SSVEP) is one of non-invasive EEG signals, and it has been widely used in research in recent years. SSVEP is a kind of rhythmic brain activity simulated by continuous visual stimuli. SSVEP frequency is composed of a fixed visual stimulation frequency and its harmonic frequencies. The two-dimensional ensemble empirical mode decomposition (2D-EEMD) is an improved algorithm of the classical empirical mode decomposition (EMD) algorithm which extended the decomposition to two-dimensional direction. 2D-EEMD has been widely used in ocean hurricane, nuclear magnetic resonance imaging (MRI), Lena image and other related image processing fields. The present study shown in this paper initiatively applies 2D EEMD to SSVEP. The decomposition, the 2-D picture of intrinsic mode function (IMF), can show the SSVEP frequency clearly. The SSVEP IMFs which had filtered noise and artifacts were mapped into the head picture to reflect the time changing trend of brain responding visual stimuli, and to reflect responding intension based on different brain regions. The results showed that the occipital region had the strongest response. Finally, this study used short-time Fourier transform (STFT) to detect SSVEP frequency of the 2D-EEMD reconstructed signal, and the accuracy rate increased by 16%. PMID- 26485970 TI - [Feature Extraction of Brainstem Auditory Evoked Potential Based on Wavelet Multi resolution Analysis]. AB - We proposed a multi-resolution-wavelet-transform based method to extract brainstem auditory evoked potential (BAEP) from the background noise and then to identify its characteristics correctly. Firstly we discussed the mother wavelet and wavelet transform algorithm and proved that bi-orthogonal wavelet bior5. 5 and stationary discrete wavelet transform (SWT) were more suitable for BAEP signals. The correlation analysis of D6 scale wavelet coefficients between single trails and the ensemble average of all trails showed that the trails with good correlation (> 0. 4) had higher signal-to-noise ratio, so that we could get a clear BAEP from a few trails by an average and wavelet filter method. Finally, we used this method to select desirable trails, extracted BAEP from every 10 trails and calculated the I-V inter-waves' latency. The results showed that this strategy of trail selection was efficient. This method can not only achieve better de-noising effect, but also greatly reduce the stimulation time needed as well. PMID- 26485971 TI - [Channel Selection for Multi-class Motor Imagery Based on Common Spatial Pattern]. AB - High-density channels are often used to acquire electroencephalogram (EEG) spatial information in different cortical regions of the brain in brain-computer interface (BCI) systems. However, applying excessive channels is inconvenient for signal acquisition, and it may bring artifacts. To avoid these defects, the common spatial pattern (CSP) algorithm was used for channel selection and a selection criteria based on norm-2 is proposed in this paper. The channels with the highest M scores were selected for the purpose of using fewer channels to acquire similar rate with high density channels. The Dataset III a from BCI competition 2005 were used for comparing the classification accuracies of three motor imagery between whole channels and the selected channels with the present proposed method. The experimental results showed that the classification accuracies of three subjects using the 20 channels selected with the present method were all higher than the classification accuracies using all 60 channels, which convinced that our method could be more effective and useful. PMID- 26485972 TI - [Tensor Feature Extraction Using Multi-linear Principal Component Analysis for Brain Computer Interface]. AB - The brain computer interface (BCI) can be used to control external devices directly through electroencephalogram (EEG) information. A multi-linear principal component analysis (MPCA) framework was used for the limitations of tensor form of multichannel EEG signals processing based on traditional principal component analysis (PCA) and two-dimensional principal component analysis (2DPCA). Based on MPCA, we used the projection of tensor-matrix to achieve the goal of dimensionality reduction and features exaction. Then we used the Fisher linear classifier to classify the features. Furthermore, we used this novel method on the BCI competition II dataset 4 and BCI competition N dataset 3 in the experiment. The second-order tensor representation of time-space EEG data and the third-order tensor representation of time-space-frequency BEG data were used. The best results that were superior to those from other dimensionality reduction methods were obtained by much debugging on parameter P and testQ. For two-order tensor, the highest accuracy rates could be achieved as 81.0% and 40.1%, and for three-order tensor, the highest accuracy rates were 76.0% and 43.5%, respectively. PMID- 26485973 TI - [Automatic Sleep Staging Method Based on Energy Features and Least Squares Support Vector Machine Classifier]. AB - The research of sleep staging is not only the basis of diagnosing sleep related diseases, but also the precondition of evaluating sleep quality, and has important clinical significance. In recent years, the research of automatic sleep staging based on computer has become a hotspot and made some achievements. Feature extraction and feature classification are two key technologies in automatic sleep staging system. In order to achieve effective automatic sleep staging, we proposed a new automatic sleep staging method which combines the energy features and least squares support vector machines (LS-SVM). Firstly, we used FIR band-pass filter to extract the energy features of Pz-Oz channel sleep electroencephalogram (EEG) signals, and compared them with those from wavelet packet transform method. Then we designed an LS-SVM classifier to realize the automatic sleep stage classification. The research showed that FIR band-pass filter (with the Kaiser window) performed better than wavelet packet transform (WPT) for energy feature extraction just in terms of the data from the Sleep-EDF Database and the LS-SVM classifier (with the RBF Kernel function) designed was good, and the automatic sleep staging method proposed in this paper was better than many similar methods from other studies with an average accuracy of 88.89% and had a very prosperous application future. PMID- 26485974 TI - [Research on Early Identification of Bipolar Disorder Based on Multi-layer Perceptron Neural Network]. AB - Multi-layer perceptron (MLP) neural network belongs to multi-layer feedforward neural network, and has the ability and characteristics of high intelligence. It can realize the complex nonlinear mapping by its own learning through the network. Bipolar disorder is a serious mental illness with high recurrence rate, high self-harm rate and high suicide rate. Most of the onset of the bipolar disorder starts with depressive episode, which can be easily misdiagnosed as unipolar depression and lead to a delayed treatment so as to influence the prognosis. The early identifica- tion of bipolar disorder is of great importance for patients with bipolar disorder. Due to the fact that the process of early identification of bipolar disorder is nonlinear, we in this paper discuss the MLP neural network application in early identification of bipolar disorder. This study covered 250 cases, including 143 cases with recurrent depression and 107 cases with bipolar disorder, and clinical features were statistically analyzed between the two groups. A total of 42 variables with significant differences were screened as the input variables of the neural network. Part of the samples were randomly selected as the learning sample, and the other as the test sample. By choosing different neu- ral network structures, all results of the identification of bipolar disorder were relatively good, which showed that MLP neural network could be used in the early identification of bipolar disorder. PMID- 26485975 TI - [Anomaly Detection of Multivariate Time Series Based on Riemannian Manifolds]. AB - Multivariate time series problems widely exist in production and life in the society. Anomaly detection has provided people with a lot of valuable information in financial, hydrological, meteorological fields, and the research areas of earthquake, video surveillance, medicine and others. In order to quickly and efficiently find exceptions in time sequence so that it can be presented in front of people in an intuitive way, we in this study combined the Riemannian manifold with statistical process control charts, based on sliding window, with a description of the covariance matrix as the time sequence, to achieve the multivariate time series of anomaly detection and its visualization. We made MA analog data flow and abnormal electrocardiogram data from MIT-BIH as experimental objects, and verified the anomaly detection method. The results showed that the method was reasonable and effective. PMID- 26485976 TI - [Development and Design of Portable Sleep Electroencephalogram Monitoring System]. AB - The growing rate of public health problem for increasing number of people afflicted with poor sleep quality suggests the importance of developing portable sleep electroencephalogram (EEG) monitoring systems. The system could record the overnight EEG signal, classify sleep stages automatically, and grade the sleep quality. We in our laboratory collected the signals in an easy way using a single channel with three electrodes which were placed in frontal position in case of the electrode drop-off during sleep. For a test, either silver disc electrodes or disposable medical electrocardiographic electrodes were used. Sleep EEG recorded by the two types of electrodes was compared to each other so as to find out which type was more suitable. Two algorithms were used for sleep EEG processing, i. e. amplitude-integrated EEG (aEEG) algorithm and sample entropy algorithm. Results showed that both algorithms could perform sleep stage classification and quality evaluation automatically. The present designed system could be used to monitor overnight sleep and provide quantitative evaluation. PMID- 26485977 TI - [Technical Research of Non-contact Electrocardiogram Based on Capacitive Coupling]. AB - Based on the capacitance coupling principle, we studied a capacitive way of non contact electrocardiogram (EGG) monitoring, making it possible to obtain ECG on the condition that a patient is habilimented. Conductive fabric with a good electrical conductivity was used as electrodes. The electrodes fixed on a bed sheet is presented in this paper. A capacitance comes into being as long as the body gets close to the surface of electrode, sandwiching the cotton cushion, which acts as dielectric. The surface potential generated by heart is coupled to electrodes through the capacitance. After being processed, the signal is suitable for monitoring. The test results show that 93.5% of R wave could be detected for 9 volunteers and ECG with good signal quality could be acquired for 2 burnt patients. Non-contact ECG is harmless to skin, and it has advantages for those patients to whom stickup electrodes are not suitable. On the other hand, it is convenient to use and good for permanent monitoring. PMID- 26485978 TI - [Research on Optical Parameter along Puncture Path in Spinal Surgery Navigation Based on Near Infrared Spectroscopy]. AB - Accurate placement of pedicle screws is a key factor of spinal surgery. Investigation of a new real-time intra-operative monitoring method is an important area of clinical application research which makes a contribution to planting pedicle screw accurately. Porcine spines were chosen as experimental objects. The changes of reduced scattering coefficient (MU'(s)) along normal puncture path, medial perforation path and lateral perforation path were measured and studied. A conclusion is drawn that there are two distinct peaks throughout the puncture process, appearing at the junction of cancellous bone and cortical bone, at the beginning and at the end, respectively. The reduced scattering coefficient is proved to be a good monitoring factor which can identify whether the screw is about to reach the critical position of the spine puncture. Moreover, the variation provides an important reference for spinal surgical navigation process. PMID- 26485979 TI - [Research and Development of A Kinect Based Virtual System for Upper Limb Rehabilitation]. AB - We developed a rehabilitation system by using the virtual reality technique and the Kinect in this paper. The system combines rehabilitation training with HMI and serious game organically, and provides a game and motion database to meet different patients' demands. Extended interface of game database is provided in two ways: personalized games can be developed by Virtools and Flash games which are suitable for patients' rehabilitation can be download from the Internet directly. In addition, the system provides patients with flexible interaction and easy control mode, and also presents real time data recording. An objective and subjective evaluation method is proposed to review the effectiveness of the rehabilitation training. According to the results of short questionnaires and the evaluation results of patients' rehabilitation training, the system compared with traditional rehabilitation can record and analyze the training data, which is useful to make rehabilitation plans. More entertainment and lower cost will increase patients' motivation, which helps to increase the rehabilitation effectiveness. PMID- 26485980 TI - [Experimental Detection Study on Cerebral Hemorrhage in Rabbits Based on Magnetic Induction Phase Shift Spectroscopy Under the Feature Band]. AB - This study was aimed to improve the sensitivity of magnetic induction phase shift detection system for cerebral hemorrhage. In the study, a cerebral hemorrhage model with 13 rabbits was established by injection of autologous blood and the cerebral hemorrhage was detected by utilizing magnetic induction phase shift spectroscopy (MIPSS) detection method under the feature band. Sixty five groups of phase shift spectroscopy data were obtained. According to the characteristics of cerebral hemorrhage phase shift spectroscopy under the feature hand, an effective method, B-F distribution, to diagnose the severity of cerebral hemorrhage was designed. The results showed that using MIPSS detection method under feature band, the phase shift obviously growed with increase of injection volume of autologous blood, and the phase shift induced by a 3-mL injection reached -7.750 3 degrees +/- 1.420 4 degrees. B-F distribution could effectively diagnose the severity of cerebral hemorrhage. It can be concluded that the sensitivity of the cerebral hemorrhage magnetic induction detection system is improved by one order of magnitude with the MIPSS detection method under the feature band. PMID- 26485981 TI - [A Digital System for Bioimpedance and Electrical Impedance Tomography Measurement System]. AB - A digital system for bioimpedance and electrical impedance tomography (EIT) measurement controlled by an ATmega16 microcontroller was constructed in our laboratory. There are eight digital electrodes using AD5933 to measure the impedance of the targets, and the data is transmitted to the computer wirelessly through nRF24L01. The structure of the system, circuit design, system testing, vitro measurements of animals' tissues and electrical impedance tomography are introduced specifically in this paper. The experimental results showed that the system relative error was 0.42%, and the signal noise ratio was 76.3 dB. The system not only can be used to measure the impedance by any two electrodes within the frequency of 1-100 kHz in a sweep scanning, but also can reconstruct the images of EIT. The animal experiments showed that the data was valid and plots were fitting with Cole-Cole theory. The testing verified the feasibility and effectiveness of the system. The images reconstructed of a salt-water tank are satisfactory and match with the actual distribution of the tank. The system improves the effectiveness of the front-end measuring signal and the stability of the system greatly. PMID- 26485982 TI - [Design and Implementation of a Mobile Operating Room Information Management System Based on Electronic Medical Record]. AB - A mobile operating room information management system with electronic medical record (EMR) is designed to improve work efficiency and to enhance the patient information sharing. In the operating room, this system acquires the information from various medical devices through the Client/Server (C/S) pattern, and automatically generates XML-based EMR. Outside the operating room, this system provides information access service by using the Browser/Server (B/S) pattern. Software test shows that this system can correctly collect medical information from equipment and clearly display the real-time waveform. By achieving surgery records with higher quality and sharing the information among mobile medical units, this system can effectively reduce doctors' workload and promote the information construction of the field hospital. PMID- 26485983 TI - [Image Feature Extraction and Discriminant Analysis of Xinjiang Uygur Medicine Based on Color Histogram]. AB - Image feature extraction is an important part of image processing and it is an important field of research and application of image processing technology. Uygur medicine is one of Chinese traditional medicine and researchers pay more attention to it. But large amounts of Uygur medicine data have not been fully utilized. In this study, we extracted the image color histogram feature of herbal and zooid medicine of Xinjiang Uygur. First, we did preprocessing, including image color enhancement, size normalizition and color space transformation. Then we extracted color histogram feature and analyzed them with statistical method. And finally, we evaluated the classification ability of features by Bayes discriminant analysis. Experimental results showed that high accuracy for Uygur medicine image classification was obtained by using color histogram feature. This study would have a certain help for the content-based medical image retrieval for Xinjiang Uygur medicine. PMID- 26485984 TI - [Anticoagulant Ability and Heparinization of Decellularized Biomaterial Scaffolds]. AB - In order to enhance the anticoagulant properties of decellularized biological materials as scaffolds for tissue engineering research via heparinized process, the decellularized porcine liver scaffolds were respectively immobilized with heparin through layer-by-layer self-assembly technique (LBL), multi-point attachment (MPA) or end-point attachment (EPA). The effects of heparinization and anticoagulant ability were tested. The results showed that the three different scaffolds had different contents of heparin. All the three kinds of heparinized scaffolds gained better performance of anticoagulant than that of the control scaffold. The thrombin time (TT), prothrombin time (PT) and activated partial thromboplastin time (APTT) of EPA scaffold group were longest in all the groups, and all the three times exceeded the measurement limit of the instrument. In addition, EPA scaffolds group showed the shortest prepared time, the slowest speed for heparin release and the longest recalcification time among all the groups. The decellularized biological materials for tissue engineering acquire the best effect of anticoagulant ability in vitro via EPA heparinized technique. PMID- 26485985 TI - [Three-dimensional Culture of Chondrocyte Using Methacrylic Alginate Gel Beads Cross-linked with Mixed Metal-cation]. AB - This study was to explore a better three-dimensional (3-D) culture method of chondrocyte. The interpenetrating network (IPN) gel beads were developed through a photo-cross linking reaction with mixed barium ions and calcium ions at the ratio of 5:5 with the methacrylic alginate (MA), which was a chemically conjugated alginate with methacrylic groups. The second generation of primary cartilage cells was encapsulated in the MA gel beads for three weeks. In the designated timing, HE stain, Alamar blue method and Scanning electron microscopic were used to determine the cartilage cells growth, proliferation and the cell distribution in the scaffolds, respectively. The expression of type II collagen was investigated by an immunohistochemistry assay and the glycosaminoglycan content was quantitatively evaluated with the spectrophotometry of 1, 9 dimethylene blue assay. Compared to the alginate control group, the deposition of glycosaminoglycan was significantly upregulated in IPN-MA gel beads with higher cell proliferation. The secretion of extracellular matrix and proliferation of chondrocyte in methacrylic alginate gel beads were higher than that in Alginate beads. Cells were able to attach, to grow well on the scaffolds under scanning electron microscopy. The result of immunohistochemistry staining of collagen type II was positive, confirming the maintenance of chondrocyte phenotype in methacrylic alginate gel beads. This study shows a great potential for three dimensional culture of cartilage. PMID- 26485986 TI - [Molecular Cloning, Recombinant Expression and Functional Characterization of the Soluble Tumor Necrosis Factor-related Apoptosis-inducing Ligand for the Macaca mulatta]. AB - Human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) might be developed as a novel anti-tumor drug due to its selective cytotoxicity in tumor cells. The predicted Macaca mulatta TRAIL (mmTRAIL) is highly homologous to hTRAIL in nucleotide acid as well as amino acid sequence, suggesting that mmTRAIL might induce apoptosis of human cancer cells. However, the cytotoxicity of mmTRAIL in human cancer cells has not been investigated. In this paper, it is reported that the gene encoding mmTRAIL has been cloned by using reverse transcriptase polymerase chain reaction (RT-PCR) from monkey peripheral blood mononuclear cells (PBMCs) in our laboratory. Subsequently, an expression plasmid was constructed by inserting mmTRAIL gene into pQE30 plasmid. After induction by addition of Isopropyl beta-D-1-Thiogalactopyranoside (IPTG), mmTRAIL was expressed. MmTRAIL was recovered from supernatant of sonicated bacteria by Ni-NTA agarose affinity chromatography. SDS-PAGE and gel filtration chromatography demonstrated that mmTRAIL forms trimer in solution. In vitro assays indicated that mmTRAIL was cytotoxic to human COLO205 tumor cells but not to normal cells at low concentration of nanomole. In addition, antitumor effect of mmTRAIL was evaluated in mice bearing human COLO205 tumor xenografts. Intratumorally injected mmTRAIL significantly inhibited growth of tumor grafts. These results suggested that mmTRAIL was valuable as candidate drug for cancer-targeted therapy. PMID- 26485987 TI - [Influence of Tumor Microenvironment of Hepatocellular Carcinoma on the Proliferation of Vascular Endothelial Cells and Vascular Angiogenesis Ability]. AB - To study the potential molecular mechanism of tumor angiogenesis in its microenvironment, we investigated the effects of HepG2 conditioned medium on the proliferation of vascular endothelial cell and vascular angiogenesis in our laboratory. Human umbilical vein endothelial EA. hy926 cells were co-cultured with HepG2 conditioned medium in vitro. The proliferation and the tubulogenesis of EA. hy926 cells were detected by teramethylazo salt azole (MTT) and tube formation assay, respectively. The results showed that the survival rate of the EA. hy926 cells was significantly increased under the co-culture condition. HepG2 conditioned medium also enhanced the angiogenesis ability of EA. hy926 cells. In addition, the expressions of intracellular VEGF and extracellular VEGFR (Flk-1) were regulated upward in a time-dependent manner. In conclusion, the proliferation of vascular endothelial cells and Vascula angiogenesis were improved under the condition of indirect co-culture. PMID- 26485988 TI - [Preliminary Study of Necroptosis in Cardiac Hypertrophy Induced by Pressure Overload]. AB - The aim of this study was to observe whether necroptosis is involved in the process of cardiac hypertrophy induced by pressure overload. SD rats underwent transverse abdominal aortic constriction (TAC) operation for establishing cardiac hypertrophy model. The structure and function of the left ventricle of rats were evaluated via echocardiography, left ventricular mass index, the expression of markers of cardiac hypertrophy and histological detection. Real-time PCR and Western blot were used to measure the gene and protein expression of receptor interacting protein kinase 1 and 3 (RIPK1 and RIPK3, the necroptosis markers) respectively. Four weeks after TAC operation, rat model for cardiac hypertrophy was established. The experimental data showed that the gene and protein expressions of RIPK1 and RIPK3 in the rat heart hypertrophic tissues after TAC for 4 weeks were increased significantly compared with those in the sham group. HE staining showed cardiomyocytes injury and hypertrophy in the hearts of TAC rat models. By transmission electron microscope, we observed that mitochondria of cardiomyocytes were damaged seriously in the TAC models. Treatment with losartan used, the selective antagonist of angiotensin II type I receptor could improve the cardiac function of TAC rats. Moreover, losartan treatment decreased the expression of RIPK1 and RIPK3 in heart tissues of TAC rats. The results suggest that necroptosis occurrs in the process of cardiac hypertrophy with pressure overload, and losartan could alleviate the cardiac hypertrophy and inhibit necroptosis. PMID- 26485989 TI - [Inhibition Function of Dominant-negative Mutant Gene Survivin-D53A to SPC-A1 Lung Adenocarcinoma Xenograft in Nude Mice Models]. AB - Survivin-D53A (SVV-D53A) is a dominant-negative mutant survivin, which represents a potential promising target for cancer gene therapy. The present study was designed to determine whether SVV-D53A plasmid encapsuled by DOTAP: Chol liposome would have the anti-tumor activity against SPC-A1 lung adenocarcinoma, and to detect the possible mechanisms. In our experiment, SPC-A1 cells were transfected in vitro with SVV-D53A plasmid and examined for protein expression by Western blot, then flow cytometric analysis was used to detect apoptosis. SPC-A1 lung adenocarcinoma xenografts were established in vivo in the nude mice, which received the i. v. administrations of SVV-D53A plasmid/liposome complexes. After mice were sacrificed, the paraffin-embedded tumor tissue sections were used for proliferating cell nuclear antigen (PCNA) expression and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Compared with the control group, the mice treated with SVV-D53A plasmid had an obviously reduced tumor volume, with high level of apoptosis and decreased cell proliferation in tumor tissue. The research results proved that the administration of SVV-D53A plasmid resulted in significant inhibition of SPC-A1 cells both in vitro and in vivo. The functional mechanism is that the anti-tumor response causes and induces tumor cell apoptosis. PMID- 26485991 TI - [Study of Functional Magnetic Resonance Imaging at Resting State for Patients in Sub-health Status]. AB - This study sought to reveal the difference of brain functions at resting-state between subjects with sub-health and normal controls by using the functional magnetic resonance imaging (fMRI) technology. Resting-state fMRI scans were performed on 24 subjects of sub-health and on 24 healthy controls with gender, age and education matched with the sub-health persons. Compared to the healthy controls, the sub-health group showed significantly higher regional homogeneity (ReHo) in the left post-central gyrus and the right post-central gyrus. On the other hand, the sub-health group showed significantly lower ReHo in the left superior frontal gyrus, in the right anterior cingulated cortex and ventra anterior cingulate gyrus, in the left dorsolateral frontal gyrus, and in the right middle temporal gyrus. The Significant difference in ReHo suggests that the sub-health persons have abnormalities in certain brain regions. It is proved that its specific action and meaning deserves further assessment. PMID- 26485990 TI - [Expression of Myocardial Specificity Markers MEF-2C and Cx43 in Rat Bone Marrow derived Mesenchymal Stem Cells Induced by Electrical Stimulation In Vitro]. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) for repairing damaged heart tissue are a new kind of important treatment options because of their potential to differentiate into cardiomyocytes. We in this experiment investigated the effect of different electrical stimulation time on the expression of myocardial specificity gene and protein in rat bone marrow mesenchymal stem cells (rBMSCs) in vitro. The rBMSCs of second or third generation were randomly divided into three groups, i.e, electrical stimulation (ES) group, 5-Azacytidine (5-Aza) group and the control group. The rBMSCs in the ES groups with complete medium were exposed to 2 V, 2 Hz, 5 ms electrical stimulation for 0. 5 h, 2 h, 4 h, and 6 h respectively every day for 10 days. Those in the 5-Aza group were induced by 5 Aza (10 MUmol/L) for 24 h, and then cultured with complete medium for 10 days. Those in the control group were only cultured with complete medium, without any treatment, for 10 days. The rBMSCs' morphological feature in each group was observed with inverted phase microscope. The mRNA expression of myocyte-specific enhancer factor 2C (MEF-2C) and connexin 43 (Cx43) were examined with Real-Time quantitative PCR and the protein expression of MEF-2C, Cx43 were detected with Western Blot method. The results showed that the mRNA expression level of the MEF 2C, Cx43 and the protein expression level of MEF-2C, Cx43 were significantly higher in the ES group and 5-Aza group than those in the relative control group (P < 0.05). It suggests that electrical stimulation could play a part of role in the induction of the rBMSCs to differentiate into the cariomyocyte-like cells in vitro and the effectiveness of the electrical stimulation with 2 h/d had the best in our experiment. But the mechanism how electrical stimulation promotes the differentiation of rBMSC into cardiomyocyte is still unclear. PMID- 26485992 TI - [Evaluation of Anterior Segment Parameters of Hyperopia of School-aged Children Using Anterior Segment Optical Coherence Tomography]. AB - The aim of this study was to investigate the feasibility of anterior segment optical coherence tomography to assess the anterior segment morphology of hyperopia in school-aged children. 320 eyes of 160 school-aged children, 6-12 years of age, were examined with anterior segment optical coherence tomography and were divided into four groups according to the cycloplegic spherical equivalence of refractive error. The mentioned four groups were: emmetropia group, low hyperopia group, moderate hyperopia group and high hyperopia group. The measurements of central corneal thickness, anterior chamber depth, angle opening distance, trabecular iris space area and scleral angle were compared in pairs among objects in the four groups. The results showed that high hyperopia and moderate hyperopia had shallower anterior chamber depth and narrower anterior chamber angle compared to those in emmetropia group. The study also showed that anterior segment optical coherence tomography as a non-contact technology could become a new technology for accessing the anterior segment morphology of hyperopia in school-aged children. PMID- 26485993 TI - [A Canine Portal Hypertension Model Induced by Intra-portal Administration of Polyurethane-Tetrahydrofuran Solutions]. AB - This study was to build a canine portal hypertension model by intra-portal administration of high polymer material polyurethane and organic solvent tetrahydrofuran mixed solutions in order to evaluate the effectiveness of the model. Twelve local crossbreed dogs were selected randomly, with intra-portal administration of 8% (weight/volume) polyurethane- tetrahydrofuran solutions through an incision in the upper abdomen to build the portal hypertension model. We measured the portal vein pressure before modeling, during modeling, and four-, eight-, and twelve- weeks after modeling, respectively. Then we evaluated the effectiveness of the model comparing values of data with those data obtained before modeling started, which were regarded as the normal values. The results showed that the portal vein pressure rose by 2. 5 times after the solution administrated instantly as much as that before modeling, and maintained at 1. 5 times after 4 weeks. This method presents an easy operation, low animal mortality and reliable model of portal hypertension. Its less abdominal adhesions and its ability in keeping normal anatomic structure specially make it suit for surgical research of portal hypertension. PMID- 26485994 TI - [Development of an Analgesia Therapy System for Delivery Based on Bio-feedback Transcuataneous Electrical Nerve Stimulation]. AB - Transcuataneous electrical nerve stimulation (TENS) analgesia as a non-drug method has received people's more and more attention recently. Considering problems of existing products, such as unstable performance and unsatisfied effectiveness, we developed a new analgesia therapy system for delivery based on bio-feedback TENS in our laboratory. We proposed a new idea for stimulation signal design, that is, we modulated a middle frequency signal by a traditional low frequency TENS wave in the new system. We designed different prescription waves for pain relief during a uterine contraction or massage between contractions. In the end, a bio-feedback TENS method was proposed, in which the waveforms of stimulation signals were selected and their parameters were modified automatically based on feedback from uterine pressure, etc. It was proved through quality tests and clinical trials that the system had good performance and satisfied analgesia effectiveness. PMID- 26485995 TI - [Arterial Plaques Identification Based on Intravascular Ultrasound Elasticity Imaging]. AB - Intravascular ultrasound (IVUS) is widely used in coronary artery examination. Ultrasonic elastography combined with IVUS is very conspicuous in identifying plaque component and in detecting plaque vulnerability degree. In this study, a simulation model of the blood vessel based on finite element analysis (FEA) was established. The vessel walls generally have radial changes caused by different intravascular pressure. The signals at lower pressures were used as the pre deformation data and the signals at higher pressure were used as the post deformation data. Displacement distribution was constructed using the time-domain cross-correlation method, and then strain images. By comparison of elastograms under different pressures, we obtained the optimal pressure step. Furthermore, on the basis of the obtained optimize pressure step, the simulation results showed that this method could effectively distinguish characteristics between different component plaques, and could guide the later experiments and clinical applications. PMID- 26485996 TI - [Assessment Method of Remnant alpha-1, 3-galactosyle Epitopes in Animal Tissue derived Biomaterials]. AB - The aim of this study was to establish an assessment method for determining alpha Gal (alpha-1, 3-galactosyle) epitopes contained in animal tissue or animal tissue derived biological materials with ELISA inhibition assay. Firstly, a 96 well plate was coated with Gal alpha-1, 3-Gal/bovine serum albumin (BSA) as a solid phase antigen and meanwhile, the anti-alpha-Gal M86 was used to react with alpha Gal antigens which contained in the test materials. Then, the residual antibodies (M86) in the supernatant of M86-Gal reaction mixture were measured using ELISA inhibition assay by the alpha-Gal coating plate. The inhibition curve of the ELISA inhibition assay, the R2 = 0.999, was well established. Checking using both alpha-Gal positive materials (rat liver tissues) and alpha-Gal negative materials (human placenta tissues) showed a good sensitivity and specificity. Based on the presently established method, the alpha-Gal expression profile of rat tissues, decellular animal tissue-derived biological materials and porcine dermal before and after decellular treatment were determined. The M86 ELISA inhibition assay method, which can quantitatively determine the alpha-Gal antigens contained in animal tissues or animal tissue-derived biomaterials, was refined. This M86 specific antibody based-ELISA inhibition assay established in the present study has good sensitivity and specificity, and could be a useful method for determining remnant alpha-1, 3Gal antigens in animal tissue-derived biomaterials. PMID- 26485997 TI - [Quantitative Analysis of Immuno-fluorescence of Nuclear Factor-kappaB Activation]. AB - Immuno-fluorescence technique can qualitatively determine certain nuclear translocation, of which NF-kappaB/ p65 implicates the activation of NF-kappaB signal pathways. Immuno-fluorescence analysis software with independent property rights is able to quantitatively analyze dynamic location of NF-kappaB/p65 by computing relative fluorescence units in nuclei and cytoplasm. We verified the quantitative analysis by Western Blot. When we applied the software to analysis of nuclear translocation in lipopolysaccharide (LPS) induced (0. 5 h, 1 h, 2 h, 4 h) primary human umbilical vein endothelial cells (HUVECs) , we found that nuclear translocation peak showed up at 2h as with calculated Western blot verification results, indicating that the inventive immuno-fluorescence analysis software can be applied to the quantitative analysis of immuno-fluorescence. PMID- 26485998 TI - [Design and Fabrication of a Device for Intraperitoneal Treatment of Pediatric Hernia]. AB - For treatment of pediatric inguinal hernia, we fabricated a device, i.e. so called "filling type pediatric hernia sac", which treats the problem from the abdominal cavity, through the abdominal and is a self-adaptive closer, using synthetic material. The device includes filling rack, self-adaptive umbrella support bar, bottom piece, outside pulling line and device fixing lines. The filling rack is composed of 2 concentric circles of 3.0 cm diameter with peripherally fixed together and can be pulled into the shapes of a ball or an olive. The supporting bar is structured of 3 pieces with 0.5 cm wide, 4.0 cm long, cross-fixed on top of the filling rack. The bottom piece is in a circular structure with a diameter of 3.0 cm, and it is connected to the filling rack bottom. Adjust positioning stay outside the fixed on the top of the device are connected at one end, and the other end free through filling the top frame connected with the bottom slice of central fixation. By using this device, we treated 37 pediatric inguinal hernia cases with 38 side-inguinal hernia successfully. The mean duration of post-operation follow-ups was 14.6 +/- 5.89 months, without hernia recurrence, obvious scar and hard sections of inguinal region. This device could provide a convenient, safe and effective plugging technology for children's pediatric hernia. PMID- 26485999 TI - [Research Progress of the Regulation Function of Epigenetics on Bone Marrow Mesenchymal Stem Cells]. AB - The regulation of epigenetics on bone marrow mesenchymal stem cells (BMSCs) has been a research hot spot in medical area. This paper mainly summarizes the progress of the regulation of DNA methylation, histone acetylation, small interfering RNA (siRNA) induced gene silence and microRNA (miRNA) on BMSCs. Our analysis shows that the regulation of epigenetics on BMSCs plays a significant role in the repair of bone tissue, nervous tissue and cardiac muscle. PMID- 26486000 TI - [Research Progress of Feasibility of Dendritic Cell Antifungal Vaccines]. AB - Fungal infection is an important clinical problem for patients with immune deficiency or immunosuppression. With deadly fungus infection case increasing, the development of antifungal vaccine attracts the attention of researchers. Dendritic cell (DC) is the unique antigen presenting cell (APC) to trigger the antifungal immune reaction, and recent studies indicate that the targeted vaccination strategy based on DC have prospective antifungal potentials. In this paper, we review the antifungal immunity mechanism and recent development of the targeted DC antifungal strategy. PMID- 26486001 TI - [Application Prospect of Stem Cell-derived Microvesicles in Regeneration of Injured Tissues]. AB - More and more evidence indicates that microvesicles (MVs) play a key role in cell to-cell communication. The MVs are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the cell surface membranes of most types. Components of donor cells are incorporated into MVs that contain bioactive lipids, proteins, genetic cargoes. MVs derived from stem cells may reprogram cells that survived in injury tissue and favor tissue regeneration by delivering their bioactive cargoes to influence the behaviors of recipient cells. Compared with mesenchymal stem cells (MSCs), MVs derived from MSCs were found to mimic the beneficial effects of these cells. These proregenerative effects mediated by MVs can be explained by the fact that MVs are enriched in bioactive lipids, anti-apoptotic and pro-stimulatory growth factors or cytokines, and deliver mRNAs, regulatory miRNAs and proteins that improve overall cell function. Therefore, it opens novel perspectives in exploiting these MVs in tissue regeneration and repair. In addition, the use of MVs instead of stem cells could represent a safe and potentially more advantageous alternative to cell-therapy approaches. PMID- 26486002 TI - [Present Status of Reliability Research on the Effects of Medical Instrument at the Instrument-tissue Interface]. AB - The interaction between medical instrument and target tissue during the surgery occurs in instrument-tissue interface. The reliability research on the interface is directly related to the safety and effectiveness of medical instrument in the clinical application. This paper illustrates the necessity of reliability research on instrument-tissue interface. Two main contents are synthetically reviewed the present paper: (1) reliability research on medical instruments; (2) biological tissue properties and its mechanical response. PMID- 26486003 TI - [Measuring Method of Cardiac Output and Its Progress]. AB - As one of the important indexes for the diagnosis and treatment of cardiovascular diseases, cardiac output can reflect the state of cardiovascular system timely, and can play a guiding role in the treatment of related diseases. In recent years detection technology of cardiac output has caused great attention, especially minimally invasive and non-invasive methods. In this paper, the principle of non invasive detection methods and their recent developments are described, and various detection methods are also analyzed. PMID- 26486004 TI - [Research Progress of Application of Microfluidics Techniques in Cryopreservation]. AB - Microfluidics technology may be an effective method to solve some problems in cryopreservation. This review presents the research progress of microfluidics technology in the field of cell membrane transport properties, cryoprotectant addition and washout and the vitrification for cryopreservation of biological materials. Existing problems of microfluidics technology in the application of cryopreservation are summarized and future research directions are indicated as well. PMID- 26486005 TI - [Advances in Diagnosis and Treatment of Differentiated Thyroid Cancer in Patients Showing Thyroglobulin Elevative and Iodine Scintigraphy Negative]. AB - Thyroglobulin (Tg) and radioiodine whole body scan (WBS) have been commonly used in follow-up of patients with differentiated thyroid carcinoma (DTC). Tg is associated with radioiodine uptake in local or distant metastases. In minority of patients, the follow-up scan shows no functioning thyroid tissue, but the serum thyroglobulin is still elevated. Therefore, we review recent developments of diagnosis and treatment of those patients with differentiated thyroid cancer and with thyroglobulin elevation but negative iodine scintigraphy. PMID- 26486006 TI - [Advances in Research on miR-21 and Breast Cancer]. AB - Breast cancer is a malignant tumor from normal breast epithelial. In recent years, many literature reports sought to determine the expression of predicted target genes of microRNA and their potential function, pathways and networks, which are involved in the tumorigenesis, metastasis and prognosis of breast cancer. The miR-21 has recently been found to be highly expressed in solid tumors than normal tissue, and it has exposed some layers of gene expression regulation that becomes a hot topic of breast cancer. This paper briefly reviews advances in research on miR-21 in breast cancer. PMID- 26486008 TI - ODA Member Spotlight: Trent Yadon, DDS, FAGD. Woodward, OK. PMID- 26486007 TI - ODA Cares: Crossings Community Clinic. PMID- 26486009 TI - Oklahoma Mission of Mercy: Getting to the Root of it All. PMID- 26486010 TI - OHCA Dental Focus Group. PMID- 26486011 TI - A comparative study of dydrogesterone and micronized progesterone for luteal phase support during in vitro fertilization (IVF) cycles. AB - The aim of the present study was to compare the efficacy, tolerability and patients' satisfaction after the use of oral dydrogesterone with vaginal micronized progesterone for luteal-phase support (LPS) among infertile women undergoing in vitro fertilization (IVF). A total of 210 women (aged 20-40 years old) with a history of infertility, who underwent controlled ovarian stimulation for fresh intra-cytoplasmic sperm injection-embryo transfer cycles, were included in the study. Consequently, they were randomized to receive LPS with dydrogesterone 20 mg twice daily (n = 96) or micronized progesterone 400 mg twice daily at the day of oocyte retrieval (n = 114). The clinical success rate (31% versus 33%; p = 0.888), miscarriage rate (5.0% versus 3.0%; p = 0.721), ongoing pregnancy rate (30.0% versus 30.0%; p = 1.000), implantation (22.0% versus 24.0%; p = 0.254) and multiple pregnancy rate (5.30% versus 7.20%; p = 0.394) were comparable among the two groups. Serum progesterone levels were significantly lower among the patients receiving dydrogesterone than the control group (13.62 +/- 13.83 ng/ml versus 20.66 +/- 18.09 ng/ml; p = 0.001). However, there was no statistically significant difference regarding the patients' satisfaction (p = 0.825) and tolerability (0.790) between the two groups. Our results showed that oral dydrogesterone (40 mg/day) is as effective as vaginal micronized progesterone considering its clinical outcomes and patients' satisfaction and tolerability, for LPS among women undergoing IVF. PMID- 26486012 TI - Morphometric variation and molecular characterization of snow trout species from Kashmir valley, India. AB - There is a significant taxonomic ambiguity among snow trout species due to their morphometric similarities. In view of this, a morphometric and molecular study was conducted on five different species of genus Schizothorax that have been reported from Kashmir valley. Morphometric data analyzed using multivariate statistics (Principal component analysis and cluster analysis) indicated the significant grouping of species to individual clusters. Mitochondrial DNA cytochrome oxidase I (COI) gene analysis revealed 0.2%-4.5% genetic divergence among the five species. This study confirms that utility of cytochrome oxidase I in species delineation along with morphometric data. Phylogenetic tree obtained using Neighbor-Joining method revealed that all the five species represented distinct species group. The Schizothorax genus formed two distinct clades; one containing S. niger, S. curvifrons and S. plagiostomus, while other clade containing S. esocinus and S. labiatus. This phlogeny trend was also supported by cluster analysis of morphometric characters. The phylogenetic analysis with other published COI sequences revealed distinct nature of these five species. The study may aid in the taxonomic identification of snow trout species in India. This may further increase the knowledge of the ichthyologists in planning conservation and management strategies for these important fish species along with their natural habitat. PMID- 26486013 TI - Ultrathin Hexagonal 2D Co2GeO4 Nanosheets: Excellent Li-Storage Performance and ex Situ Investigation of Electrochemical Mechanism. AB - Two-dimensional (2D) nanostructures are a desirable configuration for lithium ion battery (LIB) electrodes due to their large open surface and short pathway for lithium ions. Therefore, exploring new anode materials with 2D structure could be a promising direction to develop high-performance LIBs. Herein, we synthesized a new type of 2D Ge-based double metal oxides for lithium storage. Ultrathin hexagonal Co2GeO4 nanosheets with nanochannels are prepared by a simple hydrothermal method. When used as LIB anode, the sample delivers excellent cyclability and rate capability. A highly stable capacity of 1026 mAhg(-1) was recorded after 150 cycles. Detailed morphology and phase evolutions were detected by TEM and EELS measurements. It is found that Co2GeO4 decomposed into Ge NPs which are evenly dispersed in amorphous Co/Li2O matrix during the cycling process. Interestingly, the in situ formed Co matrix could serve as a conductive network for electrochemical process of Ge. Moreover, aggregations of Ge NPs could be restricted by the ultrathin configuration and Co/Li2O skeleton, leading to unique structure stability. Hence, the large surface areas, ultrathin thickness, and atomically metal matrix finally bring the superior electrochemical performance. PMID- 26486014 TI - Photoelectric detection of electron spin resonance of nitrogen-vacancy centres in diamond. AB - The readout of negatively charged nitrogen-vacancy centre electron spins is essential for applications in quantum computation, metrology and sensing. Conventional readout protocols are based on the detection of photons emitted from nitrogen-vacancy centres, a process limited by the efficiency of photon collection. We report on an alternative principle for detecting the magnetic resonance of nitrogen-vacancy centres, allowing the direct photoelectric readout of nitrogen-vacancy centres spin state in an all-diamond device. The photocurrent detection of magnetic resonance scheme is based on the detection of charge carriers promoted to the conduction band of diamond by two-photon ionization of nitrogen-vacancy centres. The optical and photoelectric detection of magnetic resonance are compared, by performing both types of measurements simultaneously. The minima detected in the measured photocurrent at resonant microwave frequencies are attributed to the spin-dependent ionization dynamics of nitrogen vacancy, originating from spin-selective non-radiative transitions to the metastable singlet state. PMID- 26486016 TI - A monocyte/granulocyte to lymphocyte ratio predicts survival in patients with hepatocellular carcinoma. AB - Conflict that the derived neutrophil lymphocyte (dNLR) has prognostic value in patients with a variety of cancers exists. The aim of the present study was to devise a monocyte/granulocyte to lymphocyte ratio (M/GLR) which counts as (white cell count - lymphocyte count) to lymphocyte count, and verify its prognostic value in patients with hepatocellular carcinoma (HCC). 1061 HCC patients were retrieved and the associations between M/GLR/NLR/dNLR and clinicopathological variables and survivals (OS and RFS) were analyzed. The area under the curve (AUC) was calculated to evaluate the discriminatory ability of M/GLR/NLR/dNLR. The median follow-up period was 947 days, the 1, 3, 5 year OS was 64%, 51%, and 46% respectively, and the median OS was 842 days. The cut-off values were determined by ROC as 2.8, 1.6, and 3.2 for NLR, dNLR, M/GLR respectively. Elevated M/GLR/NLR/dNLR was associated with poor prognosis (P = 0.001, P = 0.009 and P = 0.022 respectively). By time-dependent ROC, the AUC of M/GLR was higher than that of NLR or dNLR, either in whole group or in subgroups according to TNM stages or different treatments. We concluded that elevated M/GLR predicted poor prognosis for patients with HCC and the M/GLR can be used as an alternative to NLR and dNLR. PMID- 26486017 TI - Intermittent exotropia: Are we underminusing by not overminusing? PMID- 26486018 TI - Are things ever as they seem? PMID- 26486019 TI - Dichoptic movie viewing treats childhood amblyopia. AB - BACKGROUND: Contrast-balanced dichoptic experience with perceptual-learning tasks or simple games has been shown to improve visual acuity significantly in amblyopia. However, these tasks are intensive and repetitive, and up to 40% of unsupervised patients are noncompliant. We investigated the efficacy of a potentially more engaging movie method to provide contrast-balanced binocular experience via complementary dichoptic stimulation. METHODS: Eight amblyopic children 4-10 years of age were enrolled in a prospective cohort study to watch 3 dichoptic movies per week for 2 weeks on a passive 3D display. Dichoptic versions of 18 popular animated feature films were created. A patterned image mask of irregularly shaped blobs was multiplied with the movie images seen by the amblyopic eye and an inverse mask was multiplied with the images seen by the fellow eye. Fellow-eye contrast was initially set at a reduced level that allowed binocular vision and was then incremented by 10% at each visit. Best-corrected visual acuity, random dot stereoacuity, and interocular suppression were measured at baseline and 2 weeks. RESULTS: Mean amblyopic eye visual acuity (with standard error of the mean) improved from a logarithm of minimum angle of resolution of 0.72 +/- 0.08 at baseline to 0.52 +/- 0.09 (P = 0.003); that is, 2.0 lines of improvement at the 2-week outcome visit. No significant change in interocular suppression or stereoacuity was found. CONCLUSIONS: Passive viewing of dichoptic feature films is feasible and could be a promising new treatment for childhood amblyopia. The maximum improvement that may be achieved by watching dichoptic movies remains to be determined. No known side effects are associated with this new treatment. PMID- 26486020 TI - Surgical management of superior oblique paresis using inferior oblique anterior transposition. AB - BACKGROUND: Inferior oblique anterior transposition (IOAT) is an effective surgical procedure for weakening the inferior oblique muscle. The purpose of this study was to assess the effectiveness and complications of IOAT for superior oblique paresis at a single center over a period of 11 years. METHODS: The medical records of consecutive patients treated for congenital and acquired fourth nerve paresis with IOAT procedures at Addenbrookes Hospital, Cambridge, from 2001 to 2012 were retrospectively reviewed. All patients were examined before and after surgery: the vertical deviation in primary position and on contralateral gaze was measured, as were versions. The data collected included patient sex and age, presenting complaint, follow-up period, abnormal head position before and after surgery, postoperative complications, and further operative procedures. RESULTS: A total of 98 IOAT procedures were reviewed, with a mean follow-up of 5.8 months. The technique produced a mean correction of 9.5(Delta) in primary position and 17(Delta) in contralateral gaze. Inferior oblique overaction was reduced in all cases, with 20% having a residual overaction and 47% having an underaction. No patients had symptomatic antielevation syndrome. CONCLUSIONS: In this patient cohort, IOAT effectively managed appropriately selected patients with superior oblique paresis, improving the vertical deviation in primary position and contralateral gaze. The procedure induced limitation of elevation in some patients. No patient experienced major postoperative symptoms. PMID- 26486021 TI - Adjustable small-incision selective tenotomy and plication for correction of incomitant vertical strabismus and torsion. AB - PURPOSE: To evaluate the effectiveness of adjustable small-incision selective tenotomy and plication of vertical rectus muscles in correcting vertical strabismus incomitant in horizontal gaze positions and cyclotorsion. METHODS: The medical records of all patients who underwent adjustable small-incision selective tenotomy or plication of a vertical rectus muscle for correction of horizontally incomitant vertical strabismus or cyclotorsion by a single surgeon at a single eye institute from July 2013 to September 2014 were retrospectively reviewed. Selective tenotomy and plication were performed on either the nasal or temporal side of vertical rectus muscles, based on the direction of cyclotorsion and incomitance of vertical strabismus. RESULTS: Of 9 patients identified, 8 (89%) had successful correction of horizontally incomitant vertical strabismus, with postoperative vertical alignment within 4(Delta) of orthotropia in primary position, lateral gazes, and downgaze. Of the 8 patients with preoperative cyclotorsion, 4 (50%) were successfully corrected, with <5 degrees of cyclotorsion postoperatively. Of the 4 patients in whom cyclotorsion did not improve, 3 had undergone prior strabismus surgery, and 2 had restrictive strabismus. Eight of the 9 patients (89%) reported postoperative resolution of diplopia. CONCLUSIONS: Adjustable small-incision selective tenotomy and plication effectively treat horizontally incomitant vertical strabismus. These surgeries may be less effective for correcting cyclotorsion in patients with restriction or prior strabismus surgery. Advantages are that they may be performed in an adjustable manner and, in some cases, under topical anesthesia. PMID- 26486022 TI - Treatment of symptomatic convergence insufficiency with home-based computerized vergence system therapy in children. AB - PURPOSE: To evaluate the efficacy of a home-based computer orthoptic program for symptomatic convergence insufficiency (CI) in children. METHODS: The medical records of participants aged 5 to <18 years who were diagnosed with symptomatic CI and were treated with the Computerized Vergence System (CVS) program were retrospectively reviewed. All participants were prescribed 9 or 15 minutes of daily convergence exercises with the CVS program, 5 days per week, for the initial 6 weeks. Near point of convergence (NPC) and near convergence amplitude (NCA) were measured at baseline, 6 week, and final examinations. The presence or absence of diplopia and asthenopia with reading were recorded at baseline and final examinations. RESULTS: A total of 186 participants were included. At diagnosis, 72 participants (39%) reported diplopia and 182 (98%), reported asthenopia. At final examination, 172 participants (92%) were asymptomatic. Twelve participants (6%) subsequently received other treatment modalities. Mean NPC at baseline (5.9 cm) improved after 6 weeks of CVS therapy (3.3 cm) and at final examination (2.9 cm; P < 0.0005). Mean NCA at baseline (20.3(Delta)) improved after 6 weeks of CVS therapy (37.0(Delta)) and at the final examination (38.0(Delta); P < 0.0005). CONCLUSIONS: In this study, home-based CVS therapy reduced symptoms related to CI and improved the NPC and NCA of most children aged 5 to <18 years with symptomatic CI. PMID- 26486023 TI - Strabismus in patients with neurofibromatosis type 1-associated optic pathway glioma. AB - PURPOSE: To characterize the incidence, type, natural history, and treatment outcomes of strabismus in pediatric patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). METHODS: The medical records of consecutive patients diagnosed with NF1 and OPG at our neurofibromatosis clinic since 1985 were reviewed retrospectively. We noted age at diagnosis, reason for referral to our clinic, ophthalmologic examination results, presence or absence of strabismus, strabismus type and treatment, and final results of treatment. RESULTS: A total of 76 patients were included. Of these, 22 (28.9%) had strabismus: 5 (22.7%) had esotropia and 17 (77.2%) had exotropia; of those with exotropia, 10 (45%) also had hypotropia. In 12 patients (54.5%), strabismus was present at the first ophthalmologic examination. The development of strabismus preceded the diagnosis of both NF1 and OPG in 4 (5.3%) patients and the diagnosis of OPG in another 2 (2.6%) patients with known NF1. In 16 (76%) patients, the strabismus was sensory. Five patients (22.7%) underwent surgery, which resulted in a deviation angle of <10(Delta) in 1 patient, <20(Delta) in 2 patients, and >20(Delta) in 2 patients. CONCLUSIONS: Strabismus was the presenting symptom and led to the diagnosis of OPG in a subset of patients, including those who did not have a previous diagnosis of NF1. Exotropia, especially associated with a hypotropia, was the most common strabismic deviation seen in these patients. Sensory strabismus was the most common type seen in this population. Deviations of <10(Delta) may be difficult to achieve with strabismus surgery. PMID- 26486024 TI - Analysis of online patient education materials in pediatric ophthalmology. AB - BACKGROUND: Patients increasingly consult online resources for healthcare information. The American Medical Association (AMA) and National Institutes of Health (NIH) recommend that online education resources be written between a 3rd- and 7th-grade level. This study assesses whether online health information abides by these guidelines. METHODS: Ten pediatric ophthalmology conditions were entered into a commonly used search engine, Google.com, and analyzed using 10 validated readability scales. Scientific articles and articles written on patient forums were excluded. The 10 conditions--amblyopia, cataract, conjunctivitis, corneal abrasion, nystagmus, retinoblastoma, retinopathy of prematurity, strabismus, stye, and glaucoma--were also searched and analyzed separately from widely used websites, including Wikipedia and WebMD, as well as those of professional societies, including the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) and the American Optometric Association (AOA). RESULTS: The majority of articles were written above recommended guidelines. All scales showed that the 100 articles were written at a mean grade-level of 11.75 +/- 2.72. Only 12% of articles were written below a 9th-grade level and only 3% met recommended criteria. The articles accrued separately from Wikipedia, WebMD, AAPOS, and AOA also had average grade levels above the recommended guidelines. CONCLUSIONS: The readability of online patient education material exceeds NIH and AMA guidelines. This disparity can adversely affect caregiver comprehension of such resources and contribute to poor decision making. Pediatric ophthalmology online articles are generally written at a level too high for average caregiver comprehension. Revision of articles can increase satisfaction, improve outcomes, and facilitate the patient-ophthalmologist relationship. PMID- 26486025 TI - Accuracy of the Spot and Plusoptix photoscreeners for detection of astigmatism. AB - PURPOSE: To evaluate the accuracy of the Spot (V2.0.16) and Plusoptix S12 (ROC4, V6.1.4.0) photoscreeners in detecting astigmatism meeting AAPOS referral criteria in students from a population with high prevalence of astigmatism. METHODS: Students attending grades 3-8 on the Tohono O'odham reservation were examined. Screening was attempted with both the Spot and Plusoptix photoscreeners. Results were compared to cycloplegic refraction. Screening attempts providing no estimate of refractive error were considered fail/refer. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for detection of refractive errors were determined using AAPOS referral criteria and receiver operating characteristic area under the curve (ROC AUC) analysis was conducted for measures of astigmatism. Agreement between screening and cycloplegic refraction measurements of astigmatism, spherical equivalent, and anisometropia were assessed using t tests and correlation analyses. RESULTS: A total of 209 students were included. Of the total, 116 (55%) met examination positive criteria based on cycloplegic refraction, with 105 of those (90%) meeting the criterion for astigmatism. Measurements success rates were 97% for Spot and 54% for Plusoptix. Comparing the Spot and the Plusoptix, sensitivity was 96% versus 100%, specificity was 87% versus 61%, PPV was 90% versus 76%, and NPV was 94% versus 100% for detection of refractive error. Both screeners overestimated astigmatism by 1/3 D to 2/3 D. AUC for astigmatism was 0.97 for Spot and 0.83 for Plusoptix. CONCLUSIONS: In this highly astigmatic population, the Spot and the Plusoptix had similar sensitivity, but the Spot had better specificity and measurement success rates. Compared with results from study samples with lower rates of astigmatism, our results highlight the need to assess the ability of screening instruments to detect individual types of refractive errors. PMID- 26486026 TI - Evaluation of the Spot Vision Screener in young children in Costa Rica. AB - BACKGROUND: The Spot Vision Screener has demonstrated good sensitivity and specificity in the pediatric ophthalmology clinic setting. We sought to evaluate the updated Spot (version 2.0.16) in a general pediatric population through a collaboration of the Storm Eye Institute of the Medical University of South Carolina, the Clinica Dr Clorito Picado, and National Children's Hospital of Costa Rica. We compared results of screening with the Spot and pediatric ophthalmologic examination and determined sensitivity and specificity of the Spot in detecting amblyogenic risk factors (ARFs) according to the 2013 AAPOS Vision Screening Committee guidelines for automated vision screeners. METHODS: Children were screened with the Spot followed by a pediatric ophthalmologic examination. Cycloplegic refraction and motility findings were analyzed by age group to determine ARFs. RESULTS: A total of 219 subjects, averaging 60 months of age (range, 20-119 mo) were included. The prevalence of ARFs in our population was 12.3% (27/219). The most common risk factor was astigmatism, with a prevalence of 8.7% (19/219). The Spot referred 43 children (19.6%). Sensitivity of the Spot was 92.6%; specificity, 90.6%. The positive predictive value was 58.1%; the negative predictive value, 98.9%. CONCLUSIONS: The Spot demonstrated good sensitivity and specificity in detecting amblyopia risk factors in this general pediatric population. PMID- 26486027 TI - The use of irradiated corneal patch grafts in pediatric Ahmed drainage implant surgery. AB - PURPOSE: To describe the use of irradiated cornea for scleral reinforcement in Ahmed glaucoma valve drainage implant (AGV) devices in children. METHODS: The medical records of patients <18 years of age who underwent AGV surgery with irradiated cornea as scleral reinforcement were reviewed retrospectively. The primary outcome measure was erosion of the drainage tube through the corneal patch graft. Secondary outcome measures included other major complications: persistent inflammation, wound dehiscence, transmission of infectious disease, endophthalmitis, and tube/plate self-explantation. RESULTS: A total of 25 procedures (20 patients) met inclusion criteria. Average patient age was 70 months (range, 2 months to 17 years). Mean follow-up was 24.8 months (range, 6 months to 6.2 years). One tube experienced conjunctival exposure through two separate corneal grafts (2/25 cases [8%]), sequentially in the same eye. The first event occurred at month 3.5 after primary implantation of the tube shunt; the second erosion occurred following revision of the existing implant at month 1.5 postoperatively. There were 2 cases of auto-explantation, 2 cases of wound dehiscence, and 1 case of persistent inflammation. There were no cases of endophthalmitis or other infections. CONCLUSIONS: To our knowledge, this is the first report describing the use of corneal patch grafts in children. Irradiated cornea improves cosmesis and enhances visualization of the tube. The risk of tube exposure was found to be low and comparable to other materials used as a patch graft. PMID- 26486028 TI - Electroretinogram assessment of children with sensorineural hearing loss: implications for screening. AB - BACKGROUND: The guidelines of the National Deaf Children's Society recommend that children with sensorineural hearing loss (SNHL) be routinely screened for ophthalmological problems and suggest electroretinography (ERG) to exclude Usher syndrome. The present study reports the nature and prevalence of abnormal ERG findings in a cohort of children with SNHL undergoing ERG with the aim of identifying risk factors for the diagnosis of Usher syndrome. METHODS: The medical records of children (<18 years of age) with SNHL referred for ERG at Moorfields Eye Hospital, London, between January 2009 and December 2011 were retrospectively reviewed. Patients were included if they had been referred with SNHL by an audiological medicine consultant and the primary indication for electrodiagnostic testing was possible Usher syndrome. RESULTS: A total of 84 cases met inclusion criteria of which 13 (15%) had ERG findings showing rod-cone dysfunction consistent with a diagnosis of Usher syndrome. Two patients with retinal pigmentary changes had normal ERGs and were diagnosed with rubella retinopathy based on the clinical findings. Risk factor analysis showed that age of >=8 years at the time of ERG, sex, and bilateral hearing loss were not predictive of a diagnosis of Usher syndrome. However, the presence of or referral for cochlear implants, having relevant symptoms and/or clinical signs consistent with a retinal dystrophy, and profound hearing loss were all highly predictive. CONCLUSIONS: ERG is a useful diagnostic tool in children with SNHL and should be performed in children with SNHL who have cochlear implants and/or have signs or symptoms of retinal dystrophy. A focused approach could have potential cost saving benefit. PMID- 26486030 TI - Bilateral superior rectus transposition for congenital exotropia associated with anomalous medial rectus muscles. AB - Superior rectus transposition to the lateral rectus insertion without inferior rectus transposition has been used to correct esotropic deviations secondary to Duane syndrome and abducens nerve palsy. This is usually combined with an augmented posterior fixation suture of the superior rectus muscle to the lateral rectus muscle and ipsilateral medial rectus recession. We report a child with a large-angle congenital exotropia who was found to have anomalous medial rectus muscles bilaterally. Bilateral superior rectus transposition to the medial rectus insertion with bilateral lateral rectus recessions achieved good ocular alignment in primary position. PMID- 26486029 TI - In vitro characteristics of Tenon's fibroblast lines derived from pediatric and adult eyes do not fully explain pediatric glaucoma surgery failure: a preliminary report. AB - PURPOSE: To compare the in vitro characteristics of Tenon's capsule fibroblasts from children and adults that may be relevant to filtration surgery success. METHODS: Fibroblast cell lines derived from 5 young (median patient age, 2.4 years) and 7 old (median patient age, 71 years) discarded Tenon's capsule surgical specimens were used at early passage (P2-P3). Fibroblasts were plated at "high" (10(4)cells/cm(2)) or "low" density (10(3)cells/cm(2)) and harvested at days 0-14, for growth curve and doubling time comparisons. Migration was measured using a wound model (confluent monolayers +/- 5-fluorouracil [5-FU] over 1-96 hours). Collagen synthesis was measured as secreted hydroxyproline/24 hours from confluent monolayers. RESULTS: At low density, "young" fibroblasts achieved higher cell numbers at confluence (day 14) compared with "old": 158 +/- 35 versus 105 +/- 12 * 10(3)cells/cm(2) (P = 0.0034). Mean doubling time for young versus old was similar at low density plating: 20.95 +/- 1.55 versus 22.37 +/- 2.09 hours (P = 0.26). It was shorter, however, for young versus old at high-density plating: 42.11 +/- 6.01 versus 54.26 +/- 4.24 hours (P = 0.0051). Wound closure rates were similar for young versus old cells (4 lines for each group) with and without 5-FU. Collagen synthesis was similar for young and old (4 lines for each group). CONCLUSIONS: Although young fibroblasts reached higher density than old at confluence and had shorter doubling times at high-density plating, wound closure/migration and collagen synthesis rates were similar. Despite the preliminary nature of this study (few specimens, limited cell features explored), factors besides those intrinsic to the fibroblasts themselves likely mediate the more rapid healing/scarring after glaucoma filtration surgery in children. PMID- 26486031 TI - Recessive COL25A1 mutations cause isolated congenital ptosis or exotropic Duane syndrome with synergistic divergence. AB - Congenital cranial dysinnervation disorders are phenotypes of incomitant strabismus and/or ptosis. Recessive mutations in COL25A1 are a recently reported cause, but the associated ophthalmic phenotypes have not been detailed. We highlight phenotypes of the 4 affected children from the 2 reported families: isolated congenital ptosis (one unilateral, one bilateral) and Duane syndrome (one unilateral, one bilateral) with synergistic divergence. Further study is needed to understand how frequently recessive COL25A1 mutations underlie these specific ocular phenotypes. PMID- 26486032 TI - Medial rectus muscle anchoring in complete oculomotor nerve palsy. AB - The management of exotropia resulting from complete oculomotor nerve palsy is challenging. Conventional therapeutic interventions, including supramaximal resection and recession, superior oblique tendon resection and transposition, and several ocular anchoring procedures have yielded less-than-adequate results. Here we describe a novel surgical technique of anchoring the medial rectus muscle to the medial orbital wall in combination with lateral rectus disinsertion and reattachment to the lateral orbital wall. PMID- 26486034 TI - A child with rapidly progressive necrotizing group a streptococcal Tenon's capsule infection one day after strabismus surgery. AB - Periorbital infections after strabismus surgery are rare. We describe the first reported case of necrotizing group A streptococcal infection of the conjunctiva and Tenon's capsule complicating uneventful strabismus surgery in a 23-month-old boy, successfully managed with conservative intraoperative debridement and with targeted local and systemic antibiotics. PMID- 26486033 TI - A novel method for teaching key steps of strabismus surgery in the wet lab. AB - The surgical laboratory environment plays an important role in modern surgical education. Learning how to complete the key steps of strabismus surgery prior to actual surgery may enhance efficiency and sensitize the surgeon to potential complications. Cadaveric extraocular muscle is difficult to manipulate and specimens are not readily available; therefore, an alternative is needed to teach strabismus surgery techniques. We developed a wet lab to practice the key steps of strabismus surgery using commercially available bacon as an extraocular muscle substitute and cadaveric pig eyes for conjunctival and scleral tissue in a framework of peer teaching, expert supervision, and validated written feedback. PMID- 26486035 TI - Central retinal vein occlusion in an otherwise healthy child treated successfully with a single injection of bevacizumab. AB - We describe the case of an otherwise healthy 13-year-old boy who presented with blurred vision and deteriorating visual acuity in his left eye. Fundus examination showed left optic disk swelling, exudates, and hemorrhages. He was found to have an elevated left central retinal venous pressure to the level of arterial diastolic pressure, an elevated left central macular thickness and a prolonged disk-to-disk transit time on fluorescein angiography, which confirmed the diagnosis of unilateral central retinal vein occlusion (CRVO). The child was treated with one injection of bevacizumab. He has maintained visual acuity of 6/6 for 2 years following treatment, despite persistent elevated left central venous pressure and chronic optic disk edema. PMID- 26486036 TI - A 6-year-old boy with Cornelia de Lange syndrome and Coats disease: case report and review of the literature. AB - Cornelia de Lange syndrome (CdLS) can result in multiple congenital abnormalities and numerous ocular findings. We report the case of a 6-year-old boy with history of CdLS who presented with Coats disease. The findings in this case are compared to those found in the two previously reported cases of concomitant CdLS and Coats disease. The low incidence of these two disorders makes it highly unlikely that the connection is random in these 3 cases. The number of patients with both Cornelia de Lange syndrome and Coats disease is likely underestimated due to the difficulty in examining the peripheral retina in this patient population. PMID- 26486037 TI - Bilateral congenital corneal anesthesia in a patient with SCN9A mutation, confirmed primary erythromelalgia, and paroxysmal extreme pain disorder. AB - The SCN9A gene codes for the sodium voltage-gated channel NaV 1.7. Gain of function mutations cause pain disorders such as primary erythromelalgia, paroxysmal extreme pain disorder, and small fiber neuropathy. Loss of function mutations lead to congenital insensitivity to pain. We report the case of a 6 year-old girl with a SCN9A mutation who presented with both gain of function and loss of function phenotypes, including congenital corneal anesthesia. PMID- 26486038 TI - Combined orbital proptosis and exudative retinal detachment as initial manifestations of acute myeloid leukemia. AB - We report bilateral orbital and choroidal involvement as the presenting sign of acute myeloid leukemia in a 2-year-old white girl. The patient presented with painless proptosis and subconjunctival hemorrhage. Ophthalmic examination and magnetic resonance imaging revealed bilateral leukemic infiltrates of the orbits and choroid, with an exudative retinal detachment in the right eye. Bone marrow biopsy confirmed acute myeloid leukemia. Following radiation treatment, chemotherapy, and hematopoietic stem cell transplantation, the patient was doing well 12 months after presentation. Outcomes can be poor, even with treatment; prompt recognition of ophthalmic manifestations of leukemia, including proptosis, choroidal infiltration, and retinal detachment, is necessary. PMID- 26486039 TI - Acquired retinal pigmentary degeneration in a child with 13q deletion syndrome. AB - Orbeli syndrome, or 13q deletion syndrome, is a rare condition caused by a distal deletion in the long arm of chromosome 13. The syndrome is characterized by severe physical malformations and developmental delays and has been associated with numerous ocular manifestations. We report the case of a 10-year-old boy with 13q deletion syndrome, who was evaluated for impaired vision and found to have bilateral retinal pigmentary changes resembling those seen in retinitis pigmentosa. There has only been one other case of retinal pigment variation in association with 13q deletion syndrome; however, this represents the first case of bilateral symmetric retinal pigmentary changes with corresponding rod and cone dysfunction on electroretinography. PMID- 26486040 TI - Bilateral tractional retinal detachment in a patient with hemolytic-uremic syndrome. AB - Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by hemolytic anemia, acute kidney injury, and thrombocytopenia. Ophthalmic manifestations of HUS range from mild, including scattered intraretinal hemorrhages, to severe, including a Purtscher-like retinopathy and iris and optic disk neovascularization (NVD). We report the case of a 23-month-old girl with severe HUS who presented with bilateral dense vitreous hemorrhage. During vitrectomy, optic disk neovascularization and funnel-shaped, tractional detachments of both retinas were observed. To our knowledge, this is the first reported case of tractional retinal detachment in the context of HUS. PMID- 26486041 TI - Iron deficiency anemia presenting with macular star. AB - We report the case of 16-year-old girl who presented with sudden painless decreased vision in her right eye of 5 days' duration. Anterior segment examination in both eyes showed conjunctival pallor. Results of ophthalmoscopic examination and optical coherence tomography were consistent with macular preretinal hemorrhage in both eyes with macular star in the left eye. Hematologic investigation disclosed severe iron deficiency anaemia. After 2 months, with oral substitution therapy with ferrous ascorbate and improved iron levels, the patient's visual acuity improved and macular preretinal hemorrhage resolved in both eyes. PMID- 26486042 TI - Reply. PMID- 26486043 TI - Dilating distractions that work. PMID- 26486044 TI - The accuracy of anterior segment optical coherence tomography (AS-OCT) in localizing extraocular rectus muscles insertions. PMID- 26486045 TI - The accuracy of anterior segment optical coherence tomography (AS-OCT) in localizing extraocular rectus muscles insertions. PMID- 26486046 TI - Reply: To PMID 26059668. PMID- 26486047 TI - Rapid diagnosis of Mycoplasma pneumoniae in children with pneumonia by an immuno chromatographic antigen assay. AB - Mycoplasma pneumoniae is a particularly important pathogen that causes community acquired pneumonia in children. In this study, a rapid test was developed to diagnose M. pneumoniae by using a colloidal gold-based immuno-chromatographic assay which targets a region of the P1 gene. 302 specimens were analyzed by the colloidal gold assay in parallel with real-time PCR. Interestingly, the colloidal gold assay allowed M. pneumoniae identification, with a detection limit of 1 * 10(3) copies/ml. 76 samples were found to be positive in both real-time PCR and the colloidal gold assay; two specimens positive in real-time PCR were negative in the rapid colloidal gold assay. The specificity and sensitivity of the colloidal gold assay were 100% and 97.4%, respectively. These findings indicate that the newly developed immuno-chromatographic antigen assay is a rapid, sensitive and specific method for identifying M. pneumoniae, with potential clinical application in the early diagnosis of Mycoplasma pneumoniae infection. PMID- 26486049 TI - Fever following intracerebral and intraventricular hemorrhage. AB - Although it is a well-recognized sequela, the clinical course of fever following intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) with or without ICH has not been well-studied. Patients with fever following either ICH or IVH routinely undergo extensive testing only to conclude that the fever is "central" in origin. We performed a retrospective analysis of the clinical course of fever following isolated IVH, ICH, or IVH associated with ICH. Records of 49 patients with ICH and/or IVH who were admitted to the Cleveland Clinical Foundation from 1987 to 1991 were studied for the onset, duration and degree of temperature following the hemorrhage. The incidence of fever was 83.3% in 6 patients with isolated IVH, 52% in 25 patients with isolated ICH, and 88.8% in 18 patients with both ICH and IVH. The highest temperature reached was 40.6 degrees C in a patient with basal ganglia, third, and fourth ventricular hemorrhage. The fever lasted from 1 to 40 days. The fever could be attributed to infection in only 4 patients, and none of the patients with fever had proven deep vein thrombosis. PMID- 26486048 TI - Precise Delivery Into Chronic Spinal Cord Injury Syringomyelic Cysts with Magnetic Nanoparticles MRI Visualization. AB - BACKGROUND: Traumatic spinal cord injury (SCI) often results in the deficiency of glia and neurons in cystic cavities. These syringomyelic cysts can prevent axonal regeneration and sprouting. Details of the mechanism of syringomyelic cyst formation are unknown and an effective treatment for overcoming syringomyelic cysts is not available. MATERIAL AND METHODS: Ten adult female Wistar rats underwent contusion SCI modeling resulting in syringomyelic cyst formation. A novel method for locating the cysts was developed and employed. MRI safe silver needles were inserted through the erector spinae of anesthetized rats to create a stable reference point. MRI images of the rodent spine were taken with the needles in situ. This information was used to accurately locate the cyst and determine the 3-dimensional entry point coordinates for nanoparticle delivery. Nanoparticles were injected into the cyst during a primary injection of 8 ul and a secondary injection of 8 ul, to prove the procedure can be accurately repeated. RESULTS: None of the rats died intra- or post-operatively. The syringomyelic cysts were accurately located with the 3-dimensional entry point coordinates. After nanoparticle delivery twice into each rat, the visualized syringomyelic cyst volume significantly decreased from 5.71+/-0.21 mm3 to 3.23+/-0.364 mm3 and to 1.48+/-0.722 mm3. CONCLUSIONS: The present study describes a novel strategy for precise nanoparticle delivery into a syringomyelic cyst, using measurements obtained from MRI images. This strategy may aid in developing a new method for studying chronic spinal cord injury and a novel treatment for syringomyelic cysts. PMID- 26486050 TI - Preliminary experience using ticlopidine in clinical practice. AB - Although shown to be more effective than aspirin for secondary stroke prevention, the guidelines for utilizing ticlopidine in daily clinical practice are as yet undefined. We reviewed all entries into the Saint Louis University Stroke Registry for the period of January to December 1992 and identified individuals admitted with diagnosis of cerebral infarction or transient ischemic attack (TIA) and who, upon discharge, were prescribed ticlopidine. The etiologic diagnosis, event recurrence during follow-up, compliance with medication, and side effects of all these patients were documented following review of inpatient and outpatient records. A total of 32 patients, 19 (69%) with cerebral infarction and 10 (31%) with TIA were identified. The etiologic diagnoses included: 11 patients with atherothrom-boembolic events, three with lacunar strokes, seven with cardioembolic events, and 11 with stroke of uncertain etiology. None of the patients reported recurrent cerebrovascular events. Sixteen (50%) patients continued to take the drug up to their last visit, whereas 9 (28%) had it discontinued. Five patients were lost to follow-up, and two died from cardiac arrest. The reasons for drug discontinuation included high cost in two patients, allergic reactions in two, and gastrointestinal side effects in three. Two additional patients stopped taking ticlopidine on their own due to uncertain reasons. In spite of its potential usefulness, intolerance to ticlopidine and its high cost result in treatment discontinuation in a significant proportion of patients. These factors and their effect on patients' compliance must be taken into account when prescribing this medication. PMID- 26486051 TI - Gender difference in prognosis after transient cerebral ischemia or minor stroke. AB - The objective of this study was to determine if prognosis after transient cerebral ischemia or minor stroke is different for women and men. Eligible patients (n = 142), identified on a carotid ultrasound roster, had been hospitalized between 1984 and 1987 within 30 days of a first carotid transient ischemic attack or minor stroke. Participants were considered to have a study outcome if they had a stroke or died within 2 years. Gender differences were measured with crude and directly standardized relative risks for women compared with men. The crude 2-year risk of stroke or death was 35% for women and 20% for men. The crude relative risk for women compared with men was 1.74 (95% confidence interval = 1.01-3.00). The relative risk standardized for age was 1.39 (95% confidence interval = 0.84-2.29). The relative risk standardized for prognostic strata and comorbid illness was 1.38 (95% confidence interval = 0.75-2.53). This study does not confirm the hypothesis of a gender difference for risk of stroke or death after an initial transient ischemic attack or minor stroke. Although the crude relative risk for women was large and significant, the adjusted relative risk was smaller and nonsignificant. The effect of gender needs to be examined in a larger study that has adequate power to detect an important difference between men and women at an acceptable level of statistical significance. PMID- 26486052 TI - Functional electrical stimulation to the affected lower limb and recovery after cerebral infarction. AB - Functional electrical stimulation (FES) may improve recovery after stroke. We studied its effects in 38 postcerebral infarct patients. Twenty were randomly assigned to receive FES producing ankle dorsiflexion on the affected side and physical therapy. The remaining 18 received physical therapy only. Subjects were evaluated prior to commencing therapy, at its completion after 4 weeks, and again 4 weeks later using functional and electrophysiological measures. Functional deficit in most patients improved (p < 0.01). Although no significant differences were observed when those treated with FES and those not treated were compared at 4 and 8 weeks, there was significant improvement in the rate of recovery using an ambulation score (p < 0.05), and there was a similar trend in the Barthel Index for FES-treated patients (p < 0.1). Our results indicate that FES may confer additional benefit in acute stroke rehabilitation. Further studies are needed to delineate how best to use it. PMID- 26486053 TI - Transient ischemic attacks, risk factors, and precerebral color doppler angiosonography. AB - The aim of this study was to ascertain the importance of color-coded Doppler sonography (CCDS), a noninvasive examination technique, in early detection of atherosclerotic lesions in precerebral arteries. CCDS was utilized in a group of patients with one or several transient ischemic attacks (TIA) and in a group of non-TIA (NTIA) cases, so that the degree of atherosclerotic lesions of precerebral vessies in TIA and NTIA patients might be compared. The presence of risk factors for cerebrovascular disease (CVD) was compared in both groups as well. We examined 87 patients with TIA (38 women and 49 men), aged 19-86 years (mean, 60.97 +/- 11.97 years) and 48 NTIA patients (22 women and 26 men), aged 35 85 years (mean,60.04 +/- 9.37years). No statistically significant differences in age and gender were found between the groups. A significant difference was found between the common carotid artery intimal-medial thickness (CCA IMT) in TIA patients (CCA IMT right + left = 1.12 +/- 0.44 mm) and NTIA patients (CCA IMT right + left = 0.91 +/- 0.32 mm) (p < 0.0001). A positive significant association was found between both groups in the number of different plaques (p < 0.0001) and the number of stenoses (p < 0.0001). When risk factors were compared, the difference between TIA and NTIA groups was statistically significant in regard to high-density lipoproteins (p < 0.002), total cholesterol (p < 0.004), and blood glucose concentrations (p < 0.013), as well as systolic blood pressure (p < 0.011). In conclusion, Doppler sonographic changes in precerebral arteries were present in the TIA group in spite of the fact that both groups had identical risk factors for CVD. CCDS is a valuable aid for early detection of TIA patients who have a significant risk of developing brain infarction. PMID- 26486054 TI - Spontaneous internal carotid artery dissection presenting with headache and visual auras: Report of a case. AB - We describe a patient with a stroke in the territory of the right middle cerebral artery in whom the initial manifestation was unilateral pulsatile headache and positive visual symptoms. Doppler echography and cerebral angiography demonstrated dissection of the cervical internal carotid artery. Extracranial internal carotid artery dissection may present in a similar way to the migraine stroke syndrome. Appropriate imaging investigations are essential in order not to overlook the diagnosis. PMID- 26486055 TI - Changing trends in the etiologic diagnosis of ischemic stroke. AB - The evaluation of victims of ischemic stroke has evolved over the last few years, primarily as a result of the introduction of innovative, sensitive, and informative diagnostic procedures. The role of the neurologist appears to have been redefined as one in which the identification of the presumptive cause and mechanism of the stroke is one of the primary responsibilities. We compared the etiologic stroke subtypes of patients entered into the Saint Louis University Stroke Registry for the period January to June, 1986 (Group A), with analogous data collected in patients entered from January to June, 1992 (Group B). Group A included 57 patients whose stroke subtype distribution was as follows: 19% due to athero-thromboembolism, 18% cardiogenic, 5% lacunar, and 4% due to other causes. In addition, 54% of patients had strokes of unknown etiology. Group B comprised 137 patients with the following etiologic distribution: 35% cardiogenic, 26% atherothrombolic, 3% lacunar, and 6% from other causes. Only 29% had strokes of unknown etiology. The apparent increase in the proportion of cardiogenic strokes may be related to wider utilization of transesophageal echocardiography. There was also a significant drop in the proportion of strokes of unknown etiology. Finally, in comparison with other stroke registries, our data suggest that many small strokes may also result from cardiogenic embolism. These apparent changes in the proportion of stroke subtypes should be considered when patients are being evaluated for risk stratification. PMID- 26486056 TI - Recurrent pure sensory transient ischemic attacks: In vivo demonstration of associated thalamic infarction. AB - We present a case study and literature review to clarify the pathoanatomic substrate of recurrent pure sensory transient ischemic attacks (TIAs). A 60-year old woman had had over 50 transient episodes of left hemibody hypoesthesia over the previous 15 years. Interictal neurologic examination was normal. Magnetic resonance imaging (MRI) showed a small infarct in the ventroposterolateral (VPL) nucleus of the right thalamus. Symptoms resolved with warfarin therapy. Ischemia related pure sensory symptoms present as one of two clinical syndromes: (a) sudden onset of persistent unilateral face, arm, and/or leg hypoesthesia/paresthesias, preceded by no or few TIAs, or (b) frequent espisodes of transient unilateral hypoesthesia/paresthesias not progressing to permanent deficit. The first is widely recognized; recent computed tomography/MRI series have reported 105 cases associated with thalamic, brainstem, or thalamocortical projection sensory pathway infarction. Although equally common, the syndrome of recurrent transient hemihypoesthesia is under-recognized and has a less well described pathologic substrate. One previous case with postmortem documentation of a VPL thalamic infarction has been reported. We believe this is the first reported case of recurrent transient hemihypoesthesia associated with VPL thalamic infarction imaged in vivo. PMID- 26486057 TI - Results of a two-month follow-up after single heparin-induced extracorporeal LDL precipitation in vascular dementia. AB - A trial was undertaken with 44 patients with the diagnosis of cerebral multi infarct dementia. Of these, 24 had been exposed to single heparin-induced extracorporeal low-density lipoprotein (LDL) precipitation (HELP) whereby an immediate, safe, and statistically significant reduction of total cholesterol, LDL, triglycerides, fibrinogen (<0.0001 each), lipoprotein (a) (p < 0.003), whole blood viscosity (p < 0.005 at high shear and p < 0.007 at low shear rate), plasma viscosity (p < 0.0002) and red cell transit time (p < 0.0001) to between 17.9% and 58.8% could be obtained within 2 h. Even an amelioration in the neuropsychological state, objectified by the Mathew Scale (p < 0.01), the Mini Mental State Examination (p < 0.03), and the Activities-of-Daily-Living Test (p < 0.05) was observed. Despite the fact that the laboratory parameters had reached their pretreatment values within 10 days after the HELP procedure, the scores of the test battery remained stable during a follow-up period of 2 months. Within a control group (n = 20), no changes in laboratory data or in test scoring could be observed. PMID- 26486058 TI - Stroke units. AB - The medical complications that commonly occur following cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage are reviewed, and the available treatment options are outlined. A literature review is undertaken to assess the effect stroke units have on morbidity and mortality following stroke. PMID- 26486059 TI - Ischemic stroke in young adults: Results from the university of Wisconsin stroke registry. AB - We prospectively evaluated 128 consecutive young adults aged 18-50 years who suffered from at least one ischemic stroke. Men (92 of 128, 72%) predominated and had a mean age of 41 +/- 8 years. Women (36 of 128, 28%) had a mean age of 40 +/- 8 years (ns). Risk factors that separated male and female groups included previous stroke, which as seen overall in 34% (43 of 128; M/F = 38/5, p = 0.002), andstroke in thefamily, which was seen overall in21% (27 of 128;M/F = 22/5, p = 0.005). Thirty-day mortality was seen in 3% (4 of 128), all of whom were men. Stroke causes included atherosclerotic in 22% (28 of 128; M/F = 19/9, ns), cardioembolic in 17% (22 of 128, M/F = 17/5, ns), arteriopathic in 17% (22 of 128, M/F = 11/11, p < 0.002 for female preponderance), and coagulopathic in 15% (19 of 128, M/F = 18/1, p = 0.002 for male preponderance). Stroke causes remained "undetermined, " including small deep stroke and mixed causes, in 16%( 21 of 128; M/F = 17/4, ns), "uncertain, " including migraine-related and mitral valve prolapse, in 9% (11 of 128; M/F = 3/8, p = 0.002 for female preponderance), and "unknown" in 4% (5 of 128; M/F = 5/0, ns). These data, as part of the University of Wisconsin Stroke Registry, compare favorably to similar, previously published series from other institutions. Composite data from several of these series are also included. PMID- 26486060 TI - Neuropsychological improvements following endovascular embolization of arteriovenous malformation. AB - Two right-handed patients with large, left-hemisphere arteriovenous malformations (AVM) underwent serial endovascular embolization and neuropsychological testing procedures. One patient presented with hemorrhage, hemiplegia, and aphasia; the other patient presented with a seizure only with multiple cognitive impairments. Case 1 was assessed for motor-sensory skills in the left hand and for visual recall (nondominant hemisphere). Case 2 was administered a more global assessment of cognitive functions. Both patients demonstrated significant improvements in neuropsychological functions 1 month following endovascular embolization with >50% reduction in AVM volume. The nature and extent of these improvements are discussed with respect to intervention-related, reversed impairments. PMID- 26486061 TI - Genetic effects on serum testosterone and sex hormone-binding globulin in men: a Korean twin and family study. AB - We conducted a community-based cross-sectional study to evaluate the role of genetics in determining the individual difference in total testosterone and sex hormone-binding globulin levels. Study participants comprised 730 Korean men consisting of 142 pairs of monozygotic twins, 191 pairs of siblings, and 259 father-offspring pairs from 270 families who participated in the Healthy Twin study. Serum concentration of total testosterone and sex hormone-binding globulin were measured by chemiluminescence immunoassay, and free testosterone and bioavailable testosterone were calculated using Vermeulen's method. Quantitative genetic analysis based on a variance decomposition model showed that the heritability of total testosterone, free testosterone, bioavailable testosterone, and sex hormone-binding globulin were 0.56, 0.45, 0.44, and 0.69, respectively after accounting for age and body mass index. Proportions of variance explained by age and body mass index varied across different traits, from 8% for total testosterone to 31% for sex hormone-binding globulin. Bivariate analysis showed a high degree of additive genetic correlation (rhoG = 0.67) and a moderate degree of individual-specific environmental correlation (rhoE = 0.42) between total testosterone and sex hormone-binding globulin. The findings confirmed the important role of genetics in determining the individually different levels of testosterone and sex hormone-binding globulin during adulthood in Korean men as found in non-Asian populations, which may suggest that common biologic control for determining testosterone level directly or indirectly through binding protein are largely shared among different populations. PMID- 26486063 TI - The enhanced hydrogen storage of micro-nanostructured hybrids of Mg(BH4)2-carbon nanotubes. AB - We report the facile preparation of micro-nanostructured hybrids of Mg(BH4)2 carbon nanotubes (denoted as MBH-CNTs) and their enhanced hydrogen desorption/absorption performance. The hybrids with Mg(BH4)2 loadings of 25 wt%, 50 wt% and 75 wt% are synthesized through a one-step solvent method by adjusting the ratios of Mg(BH4)2 and CNTs. The optimized MBH-CNTs with 50 wt% Mg(BH4)2 exhibit a nanosized layer coating of Mg(BH4)2 with the thickness of 2-6 nm on the surface of CNTs. The MBH-CNTs with 50 wt% Mg(BH4)2 start to release hydrogen at 76 degrees C, which shows a significant decrease of about 200 degrees C compared with that of pure Mg(BH4)2 (about 292 degrees C). Furthermore, 3.79 wt% of H2 can be desorbed from this sample within 10 min at the peak release temperature of 117 degrees C. Meanwhile, the dehydrogenated MBH-CNTs could take up 2.5 wt% of H2 at 350 degrees C under the hydrogen pressure of 10 MPa. The high chemical activity of nanosized Mg(BH4)2 and the catalytic effect of CNTs synergistically promote reversible hydrogen storage. The simple synthesis process and enhanced hydrogen desorption/absorption of MBH-CNT hybrids shed light on the utilization of Mg(BH4)2 on CNTs as efficient hydrogen storage materials. PMID- 26486062 TI - Differences and similarities between extremely severe oligozoospermia and cryptozoospermia in intracytoplasmic sperm injection. AB - Patients with extremely severe oligozoospermia (ESO) and cryptozoospermia (CO) are suitable using intracytoplasmic sperm injection (ICSI) as an infertility treatment. However, some andrologists are confused to distinguish ESO and CO in clinic diagnose. This study was designed for the first time to evaluate and compare patients with ESO and CO to determine whether these are useful clinical distinctions. A total of 270 infertile men in our center were classified into four groups as Group nonobstruction azoospermia (NOA, n = 44), Group ESO (n = 78), Group CO (n = 40), and Group obstruction azoospermia (OA, n = 108). Comparisons of the volume of bilateral testes, the level of follicle stimulating hormone (FSH) and inhibin B were obtained in four groups. Then comparisons of fertilization rates, cleavage rate, and excellent embryos rate were obtained when couples performed ICSI. All indexes (volume of bilateral testis, level of FSH and inhibin B) in Groups ESO and CO were no difference, while Groups OA versus NOA, OA versus ESO, and OA versus CO were significant differences (P < 0.05). The rates of fertilization were no differences in Groups ESO and CO while Groups OA versus ESO, OA versus CO were significant differences (P < 0.05). Therefore, the spermatogenic functions in patients with CO and ESO were similar, better than NOA but worse than OA. However, it would be helpful to evaluate their spermatogenesis using testicular biopsies, especially accompanied azoospermia in clinical practice. PMID- 26486064 TI - Incidence of progression or rebleeding in hypertensive intracerebral hemorrhage. AB - The incidence of progression or rebleeding in hypertensive intracerebral hemorrhage (HICH) has not been clearly established. We review 56 cases of HICH involving the basal ganglia or thalamus and found four cases (one thalamic, three basal ganglia) in which progression or rebleeding occurred. These cases represent 7% (4/56) of the total number of cases and 13.8% (4/29) of the cases in which serial computer tomography (CT) was performed. In two cases, progression or rebleeding occurred during the first 24 h after onset of symptoms, whereas in the other two cases rebleeding appeared to be delayed (CT changes noted 5 and 6 days later). This study suggests that the incidence of progression or rebleeding in HICH occurs more commonly than had been believed and that rebleeding may occur early or late. PMID- 26486065 TI - Multivessel cervicocephalic and visceral arterial dissections: Pathogenic role of primary arterial disease in cervicocephalic arterial dissections. AB - The origin and pathogenesis of spontaneous internal carotid artery dissections in most cases remain unclear. It is presumed that in many cases an underlying arterial disease may predispose the artery to the mural dissection. In about 15% of cases, there is angiographic evidence of fibromuscular dysplasia in carotid, vertebral, or renal arteries. Uncommonly, cases of cystic medial necrosis and, rarely, other arterial diseases have been reported. However, in the majority of cases, no arterial disease can be documented. Multivessel spontaneous dissections strongly suggest the presence of underlying arterial disease despite absence of any angiographic or laboratory findings pointing to any specific arteriopathy. In this communication, three cases of multivessel cervicocephalic and visceral arterial dissections are reported. Angiographic and laboratory data gave no clues to the nature of the underlying arterial disease. Further clinical observations and histopathologic studies, when possible, as well as biochemical studies should provide more insight into the origin and pathogenesis of the spontaneous arterial dissections. PMID- 26486066 TI - Time course of platelet activation following acute ischemic stroke. AB - To assess the time course of platelet activation after acute ischemic stroke we measured the platelet protein beta-thromboglobulin (BTG) in 66 patients. Serial samples were obtained over a 3-month period. Mean values of BTG in patients with lacunar infarction were not significantly elevated at any time. In nonlacunar strokes, the mean BTG level during the first week after stroke was not significantly elevated. The mean BTG level rose in the second week and became statistically different from control (mean +/- SEM; 33.1 +/- 3.6 vs. 21.3 +/- 2.0 IU/ml, p = 0.01). Mean values then declined to normal. Significant differences were noted among stroke subtypes. During the first week, mean values of BTG were higher in cardioembolic stroke (36.9 +/- 6.2 IU/ml, p = 0.007 vs. controls) than in atherothrombotic stroke (22.1 +/- 2.8 IU/ml, p = 0.82). By the second week, mean BTG values were significantly elevated for both cardioembolic (44.4 +/- 8.3 IU/ml, p < 0.001) and atherothrombotic (33.8 +/- 5.0 IU/ml, p = 0.01) strokes. The rise of this marker following stroke suggests that at least some of the platelet activation associated with stroke is a secondary phenomenon. Cardioembolic stroke is associated with as much platelet activation as atherothrombotic stroke and may have greater platelet activation during the first week after stroke. PMID- 26486067 TI - Association of paretic lower extremity muscle strength and standing balance with stair-climbing ability in patients with stroke. AB - The purpose of this study was to investigate the relationship between stair climbing ability and standing balance and paretic lower extremity muscle strength in a sample of subjects following stroke. The subjects were 20 patients with hemiparesis and intact sensation who were a mean 67 years of age and 48 days post stroke. Stair-climbing ability was measured using a three-component (assistance, rail use, pattern) grading system from which a total score was derived. The strength of five muscle groups was measured with a hand-held dynamometer. The sum of the five muscle group strengths was calculated. Standing balance was measured using an ordinal grading scheme. Individual muscle group strengths as well as the sum of the muscle group strengths were correlated significantly with the total stair-climbing scores (rs = 0.734 - 0.860). Standing balance scores correlated significantly with the total stair-climbing scores (rs = 0.937). Multiple regression showed that standing balance alone explained stair-climbing ability as well as stair-climbing ability and muscle strength combined. The results reinforce that both paretic muscle strength and standing balance may be appropriate components of the assessment and potentially fruitful targets for treatment for patients with stroke. PMID- 26486068 TI - Clinical trials in acute ischemic stroke: Problems in design and interpretation. AB - When evaluating potential therapies for acute or progressing ischemic stroke, we should discard our preconceived notions about either efficacy or lack of efficacy of individual interventions. With carefully designed and performed clinical trials, we have the opportunity to change the present feeling of helplessness when it comes to the acute management of patients with ischemic stroke. The alternative to expensive, time-consuming, controlled clinical trials of promising therapies is to continue to treat on the basis of opinions or bias. PMID- 26486069 TI - Atrial-septal-aneurysm-associated thrombus and stroke: Demonstration with transesophageal echocardiography. AB - Atrial septal aneurysm is an increasingly recognized cardiac abnormality. It represents a marked bulging of the interatrial septum into one atrium or the other. A consistent association between this structure and embolic stroke has been demonstrated. Because of the high prevalence of patent foramen ovale or atrial septal defect associated with this structure, paradoxical embolism has been suggested as a mechanism for embolic events. An alternate explanation is the local association of the aneurysm with thrombus. Few data have been found to support this mechanism, however. We report a young woman with multiple strokes during pregnancy in whom transesophageal echocardiography allowed the in vivo demonstration of atrial-septal-aneurysm-associated thrombus. This observation lends further support to the "local thrombus" mechanism of embolie events. It also underscores the potential utility of transesophageal echocardiography in evaluating patients with stroke of uncertain etiology. PMID- 26486070 TI - Benign brainstem hemorrhage: A brief review. AB - Brainstem hemorrhage is usually associated with a poor prognosis. With the availability of cranial computed tomography (CT) in recent years, it has become apparent that some patients with hemorrhage in the brainstem may have milder symptoms and a better outcome. Although most such hemorrhages have been reported in the midbrain, benign hemorrhages have also been reported in the pons and medulla. This review summarizes reports in the literature with respect to the clinical features, diagnosis, and prognosis in patients with brainstem hemorrhage and a benign prognosis. My experience and review of the literature suggest that these hemorrhages are often missed until after cranial CT is performed, and etiology remains unknown in most cases. In patients with an arteriovenous malformation (AVM), angiographically visible or occult recurrences are frequent. In cases in which an etiology is not found, recovery is rapid and often complete or nearly complete, and recurrences are very rare. PMID- 26486071 TI - Hemostasis findings in headache and psychosocial stress associated with cerebral ischemia. AB - We assessed the prevalence of headache and psychosocial stress in a group of patients with cerebral ischemia and evaluated hemostatic function in these patients. Headache and preceding psychosocial stress were present in one-third and one-half, respectively, of patients capable of providing an adequate history and answering a standardized psychosocial questionnaire. There were no significant differences in hematocrit, white blood cell count and differential, fibrinogen, and platelet activation peptide beta-thromboglobulin, between patients with and without headache and between high- and low-stress patients. Fibrin D-dimer (a fragment of cross-linked fibrin) was significantly lower in high-stress compared to low-stress patients. There was no association between headache and stress level. These findings make unlikely the hypothesis that headache associated with cerebral ischemia is platelet-mediated and suggest that psychosocial stress on a chronic basis is not associated with procoagulant tendencies in this population. PMID- 26486072 TI - Size and distribution of lacunes defined by computed tomography: Correlation with blood pressure and possible stroke mechanisms. AB - To study the causes of lacunes (small cerebral infarcts) and the frequency of large brain infarcts in the same patients, the records of all patients admitted to the University of Utah Hospital between January 1983 and June 1986 with the diagnosis of acute cerebral or brainstem infarction were retrospectively reviewed. The neuroradiologist's interpretation of each patient's computed tomography (CT) scan was used to identify a cohort of 69 patients with lacunes. The medical records were examined for data pertaining to clinical events, and the CT scans were inspected to determine the dimensions and anatomic distribution of the infarcts. Patients who had larger infarcts or intracranial hemorrhages, in addition to one or more lacunes, were included. Twenty-seven patients (39%) were normotensive; 29 (42%) were hypertensive, and 13 (19%) had a history of hypertension but were normotensive at the time of the stroke. Ninety-five lacunes were distributed evenly among these three groups. The lacunes were larger in the normotensive patients. Twenty large infarcts were distributed evenly in the three groups. Diagnostic evaluation revealed significant abnormalities. The presence of cardiac and/or arterial disease places patients with lacunes at greater risk for more serious cerebral ischemic events and for recurrent small strokes. These observations are discussed as they relate to the causes and significance of lacunes. PMID- 26486073 TI - Collecting and registering sexual health information in the context of HIV risk in the electronic medical record of general practitioners: a qualitative exploration of the preference of general practitioners in urban communities in Flanders (Belgium). AB - Background and aim Current health-care delivery requires increasingly proactive and inter-professional work. Therefore, collecting patient information and knowledge management is of paramount importance. General practitioners (GPs) are well placed to lead these evolving models of care delivery. However, it is unclear how they are handling these changes. To gain an insight into this matter, the HIV epidemic was chosen as a test case. METHODS: Data were collected and analysed from 13 semi-structured interviews with GPs, working in urban communities in Flanders. Findings GPs use various types of patient information to estimate patients' risk of HIV. The way in which sexual health information is collected and registered, depends on the type of information under discussion. General patient information and medical history data are often automatically collected and registered. Proactively collecting sexual health information is uncommon. Moreover, the registration of the latter is not obvious, mostly owing to insufficient space in the electronic medical record (EMR). CONCLUSIONS: GPs seem willing to systematically collect and register sexual health information, in particular about HIV-risk factors. They expressed a need for guidance together with practical adjustments of the EMR to adequately capture and share this information. PMID- 26486074 TI - Catalytic Asymmetric Reactions of 4-Substituted Indoles with Nitroethene: A Direct Entry to Ergot Alkaloid Structures. AB - A domino Friedel-Crafts/nitro-Michael reaction between 4-substituted indoles and nitroethene is presented. The reaction is catalyzed by BINOL-derived phosphoric acid catalysts, and delivers the corresponding 3,4-ring-fused indoles with very good results in terms of yields and diastereo- and enantioselectivities. The tricyclic benzo[cd]indole products bear a nitro group at the right position to serve as precursors of ergot alkaloids, as demonstrated by the formal synthesis of 6,7-secoagroclavine from one of the adducts. DFT calculations suggest that the outcome of the reaction stems from the preferential evolution of a key nitronic acid intermediate through a nucleophilic addition pathway, rather than to the expected "quenching" through protonation. PMID- 26486075 TI - Geometries for the coherent control of four-wave mixing in graphene multilayers. AB - Deeply sub-wavelength two-dimensional films may exhibit extraordinarily strong nonlinear effects. Here we show that 2D films exhibit the remarkable property of a phase-controllable nonlinearity, i.e., the amplitude of the nonlinear polarisation wave in the medium can be controlled via the pump beam phase and determines whether a probe beam will "feel" or not the nonlinearity. This is in stark contrast to bulk nonlinearities where propagation in the medium averages out any such phase dependence. We perform a series of experiments in multilayer graphene that highlight some of the consequences of the optical nonlinearity phase-dependence, such as the coherent control of nonlinearly diffracted beams, single-pump-beam induced phase-conjugation and the demonstration of a nonlinear mirror characterised by negative reflection. The observed phase sensitivity is not specific to graphene but rather is solely a result of the dimensionality and is therefore expected in all 2D materials. PMID- 26486077 TI - Comprehensive investigation of oncogenic driver mutations in Chinese non-small cell lung cancer patients. AB - PURPOSE: To determine the frequency of driver mutations in Chinese non-small cell lung cancer (NSCLC) patients. METHODS: Comprehensive mutational analysis was performed in 1356 lung adenocarcinoma, 503 squamous cell carcinoma, 57 adenosquamous lung carcinoma, 19 large cell carcinoma and 8 sarcomatoid carcinoma. The effect of EGFR tyrosine kinase inhibitors (TKIs) on EGFR-mutated lung adenocarcinoma patients after disease recurrence was investigated. RESULTS: Mutations in EGFR kinase domain, HER2 kinase domain, KRAS, BRAF, ALK, ROS1 and RET were mutually exclusive. In lung adenocarcinoma cases "pan-negative" for the seven above-mentioned driver mutations, we also detected two oncogenic EGFR extracellular domain mutations (A289D and R324L), two HER2 extracellular and transmembrane domain mutations (S310Y and V659E), one ARAF S214C mutation and two CD74-NRG1 fusions. Six (1.2%) FGFR3 activating mutations were identified in lung squamous cell carcinoma (five S249C and one R248C). There were three (15.8%) EGFR mutations and four (21.1%) KRAS mutations in large cell carcinoma. Three (37.5%) KRAS mutations were detected in sarcomatoid carcinoma. In EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence, treatment with EGFR TKIs was an independent predictor of better overall survival (HR = 0.299, 95% CI: 0.172-0.519, P < 0.001). CONCLUSION: We determined the frequency of driver mutations in a large series of Chinese NSCLC patients. EGFR TKIs might improve the survival outcomes of EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence. PMID- 26486078 TI - VHL-dependent alterations in the secretome of renal cell carcinoma: Association with immune cell response? AB - Secreted proteins could modulate the interaction between tumor, stroma and immune cells within the tumor microenvironment thereby mounting an immunosuppressive tumor microenvironment. In order to determine the secretome-mediated, von Hippel Lindau (VHL)-regulated cross-talk between tumor cells and T lymphocytes peripheral blood mononuclear cells (PBMC) from healthy donors were either cultured in conditioned media obtained from normoxic and hypoxic human VHL deficient renal cell carcinoma (RCC) cell line (786-0VHL-) and its wild type (wt) VHL-transfected counterpart (786-0VHL+) or directly co-cultured with both cell lines. An increased T cell proliferation was detected in the presence of 786 0VHL+-conditioned medium. By applying a quantitative proteomic-based approach using differential gel electrophoresis followed by mass spectrometry fourteen proteins were identified to be differentially expressed within the secretome of 786-0VHL- cells when compared to that of 786-0VHL+ cells. All proteins identified were involved in multiple tumor-associated biological functions including immune responses. Functional studies on manganese superoxide dismutase 2 (MnSOD2) demonstrated that it was a regulator of T cell activation-induced oxidative signaling and cell death. Direct effects of soluble MnSOD2 on the growth properties and interleukin 2 (IL-2) secretion of T cells could be demonstrated underlining the critical role of extracellular MnSOD2 levels for T cell proliferation and activation. PMID- 26486079 TI - CGK733-induced LC3 II formation is positively associated with the expression of cyclin-dependent kinase inhibitor p21Waf1/Cip1 through modulation of the AMPK and PERK/CHOP signaling pathways. AB - Microtubule-associated protein 1A/1B-light chain 3 (LC3)-II is essential for autophagosome formation and is widely used to monitor autophagic activity. We show that CGK733 induces LC3 II and LC3-puncta accumulation, which are not involved in the activation of autophagy. The treatment of CGK733 did not alter the autophagic flux and was unrelated to p62 degradation. Treatment with CGK733 activated the AMP-activated protein kinase (AMPK) and protein kinase RNA-like endoplasmic reticulum kinase/CCAAT-enhancer-binding protein homologous protein (PERK/CHOP) pathways and elevated the expression of p21Waf1/Cip1. Inhibition of both AMPK and PERK/CHOP pathways by siRNA or chemical inhibitor could block CGK733-induced p21Waf1/Cip1 expression as well as caspase-3 cleavage. Knockdown of LC3 B (but not LC3 A) abolished CGK733-triggered LC3 II accumulation and consequently diminished AMPK and PERK/CHOP activity as well as p21Waf1/Cip1 expression. Our results demonstrate that CGK733-triggered LC3 II formation is an initial event upstream of the AMPK and PERK/CHOP pathways, both of which control p21Waf1/Cip1 expression. PMID- 26486080 TI - The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells. AB - Here we report that the PI3K/Akt1/IL-6/STAT3 signalling pathway regulates generation and stem cell-like properties of Non-Small Cell Lung Cancer (NSCLC) tumor initiating cells (TICs). Mutant Akt1, mutant PIK3CA or PTEN loss enhances formation of lung cancer spheroids (LCS), self-renewal, expression of stemness markers and tumorigenic potential of human immortalized bronchial cells (BEAS-2B) whereas Akt inhibition suppresses these activities in established (NCI-H460) and primary NSCLC cells. Matched microarray analysis of Akt1-interfered cells and LCSs identified IL-6 as a critical target of Akt signalling in NSCLC TICs. Accordingly, suppression of Akt in NSCLC cells decreases IL-6 levels, phosphorylation of IkK and IkB, NF-kB transcriptional activity, phosphorylation and transcriptional activity of STAT3 whereas active Akt1 up-regulates them. Exposure of LCSs isolated from NSCLC cells to blocking anti-IL-6 mAbs, shRNA to IL-6 receptor or to STAT3 markedly reduces the capability to generate LCSs, to self-renew and to form tumors, whereas administration of IL-6 to Akt-interfered cells restores the capability to generate LCSs. Finally, immunohistochemical studies in NSCLC patients demonstrated a positive correlative trend between activated Akt, IL-6 expression and STAT3 phosphorylation (n = 94; p < 0.05). In conclusion, our data indicate that aberrant Akt signalling contributes to maintaining stemness in lung cancer TICs through a NF-kB/IL-6/STAT3 pathway and provide novel potential therapeutic targets for eliminating these malignant cells in NSCLC. PMID- 26486081 TI - IDH1/2 but not DNMT3A mutations are suitable targets for minimal residual disease monitoring in acute myeloid leukemia patients: a study by the Acute Leukemia French Association. AB - Acute myeloid leukemia (AML) is a heterogeneous disease. Even within the same NPM1-mutated genetic subgroup, some patients harbor additional mutations in FLT3, IDH1/2, DNMT3A or TET2. Recent studies have shown the prognostic significance of minimal residual disease (MRD) in AML but it remains to be determined which molecular markers are the most suitable for MRD monitoring. Recent advances in next-generation sequencing (NGS) have provided the opportunity to use multiple molecular markers. In this study, we used NGS technology to assess MRD in 31 AML patients enrolled in the ALFA-0701 trial and harboring NPM1 mutations associated to IDH1/2 or DNMT3A mutations. NPM1 mutation-based MRD monitoring was performed by RTqPCR. IDH1/2 and DNMT3A mutations were quantified by NGS using an Ion Torrent Proton instrument with high coverage (2 million reads per sample). The monitoringof IDH1/2 mutations showed that these mutations were reliable MRD markers that allowed the prediction of relapse in the majority of patients. Moreover, IDH1/2 mutation status predicted relapse or disease evolution in 100% of cases if we included the patient who developed myelodysplastic syndrome. In contrast, DNMT3A mutations were not correlated to the disease status, as we found that a preleukemic clone with DNMT3A mutation persisted in 40% of the patients who were in complete remission, reflecting the persistence of clonal hematopoiesis. PMID- 26486082 TI - The potent tumor suppressor miR-497 inhibits cancer phenotypes in nasopharyngeal carcinoma by targeting ANLN and HSPA4L. AB - Nasopharyngeal carcinoma (NPC) is a malignancy with poor prognosis that is endemic to Southeast Asia. We profiled microRNAs (miRNAs) of NPCs using microarrays and confirmed the results by quantitative RT-PCR. The results revealed that seven miRNAs were significantly up-regulated, and six miRNAs were down-regulated, in NPC tissues relative to noncancerous nasopharyngeal epithelia (NNE). Expression of miR-497 was also significantly reduced in the plasma of NPC patients relative to the plasma of noncancerous control patients. The concordant down-regulation of miR-497 in tissues and plasma suggested that miR-497 could be used as a diagnostic biomarker for NPC. Functional analyses of the effect of miR 497 on cancer phenotypes revealed that transfection of miR-497 mimic into NPC cells suppressed cell growth and migration and induced apoptosis. Subcutaneous xenografts of transfected cells in nude mice demonstrated that miR-497 significantly inhibited tumor growth. Two potential targets of miR-497, ANLN (anillin, actin-binding protein) and HSPA4L (heat shock 70 kDa protein 4-like), both of which were overexpressed in NPC tissues, were negatively regulated by miR 497 mimic in NPC cell lines. Silencing of ANLN and HSPA4L suppressed cell proliferation and migration and induced apoptosis in NPC cells. Our findings indicate that miR-497 is a potent tumor suppressor that inhibits cancer phenotypes by targeting ANLN and HSPA4L in NPC. PMID- 26486083 TI - Molecular mechanisms of cisplatin cytotoxicity in acute promyelocytic leukemia cells. AB - Cis-diamminedichloroplatinum (II) (cisplatin) is a widely used anti-tumor drug for the treatment of a broad range of human malignancies with successful therapeutic outcomes for head and neck, ovarian, and testicular cancers. It has been found to inhibit cell cycle progression and to induce oxidative stress and apoptosis in acute promyelocytic leukemia (APL) cells. However, its molecular mechanisms of cytotoxic action are poorly understood. We hypothesized that cisplatin induces cytotoxicity through DNA adduct formation, oxidative stress, transcriptional factors (p53 and AP-1), cell cycle regulation, stress signaling and apoptosis in APL cells. We used the APL cell line as a model, and applied a variety of molecular tools to elucidate the cytotoxic mode of action of cisplatin. We found that cisplatin inhibited cell proliferation by a cytotoxicity, characterized by DNA damage and modulation of oxidative stress. Cisplatin also activated p53 and phosphorylated activator protein (AP-1) component, c-Jun at serine (63, 73) residue simultaneously leading to cell cycle arrest through stimulation of p21 and down regulation of cyclins and cyclin dependent kinases in APL cell lines. It strongly activated the intrinsic pathway of apoptosis through alteration of the mitochondrial membrane potential, release of cytochrome C, and up-regulation of caspase 3 activity. It also down regulated the p38MAPK pathway. Overall, this study highlights the molecular mechanisms that underline cisplatin toxicity to APL cells, and provides insights into selection of novel targets and/or design of therapeutic agents to treat APL. PMID- 26486084 TI - The activation of EGFR promotes myocardial tumor necrosis factor-alpha production and cardiac failure in endotoxemia. AB - To study the effect of EGFR activation on the generation of TNF-alpha and the occurrence of cardiac dysfuncetion during sepsis, PD168393 and erlotinib (both are EGFR inhibitors) were applied to decreased the production of TNF-alpha and phosphrylation of ERK1/2 and p38 induced by LPS in cardiomyocytes. These results were further proved by specifically knocked down the expression of EGFR in vitro. Both TAPI-1, a TNF-alpha converting enzyme (TACE) inhibitor, and TGF-alpha neutralizing antibody could inhibit the activation of EGFR and the generation of TNF-alpha mRNA after LPS treatment. The increase of TGF-alpha in response to LPS could also be suppressed by TAPI-1. On the other hand, exogenous TGF-alpha increased the expression of TNF-alpha mRNA and partially reversed the inhibitory effect of TAPI-1 on expression of TNF-alpha mRNA in response to LPS indicating that the transactivation of EGFR by LPS in cardiomyocytes needs the help of TACE and TGF-alpha. In endotoxemic mice, inhibition the activation of EGFR not only decreased TNF-alpha production in the myocardium but also improved left ventricular pump function and ameliorated cardiac dysfunction and ultimately improved survival rate. All these results provided a new insight of how EGFR regulation the production of TNF-alpha in cardiomyocytes and a potential new target for the treatment of cardiac dysfunction in sepsis. PMID- 26486086 TI - On representing the prognostic value of continuous gene expression biomarkers with the restricted mean survival curve. AB - MOTIVATION: Researchers developing biomarkers for cancer prognosis from quantitative gene expression data are often faced with an odd methodological discrepancy: while Cox's proportional hazards model, the appropriate and popular technique, produces a continuous and relative risk score, it is hard to cast the estimate in clear clinical terms like median months of survival and percent of patients affected. To produce a familiar Kaplan-Meier plot, researchers commonly make the decision to dichotomize a continuous (often unimodal and symmetric) score. It is well known in the statistical literature that this procedure induces significant bias. RESULTS: We illustrate the liabilities of common techniques for categorizing a risk score and discuss alternative approaches. We promote the use of the restricted mean survival (RMS) and the corresponding RMS curve that may be thought of as an analog to the best fit line from simple linear regression. CONCLUSIONS: Continuous biomarker workflows should be modified to include the more rigorous statistical techniques and descriptive plots described in this article. All statistics discussed can be computed via standard functions in the Survival package of the R statistical programming language. Example R language code for the RMS curve is presented in the appendix. PMID- 26486087 TI - AMPK potentiation by LKB1 isoforms. PMID- 26486085 TI - Concepts and mechanisms underlying chemotherapy induced immunogenic cell death: impact on clinical studies and considerations for combined therapies. AB - Chemotherapy has historically been thought to induce cancer cell death in an immunogenically silent manner. However, recent studies have demonstrated that therapeutic outcomes with specific chemotherapeutic agents (e.g. anthracyclines) correlate strongly with their ability to induce a process of immunogenic cell death (ICD) in cancer cells. This process generates a series of signals that stimulate the immune system to recognize and clear tumor cells. Extensive studies have revealed that chemotherapy-induced ICD occurs via the exposure/release of calreticulin (CALR), ATP, chemokine (C-X-C motif) ligand 10 (CXCL10) and high mobility group box 1 (HMGB1). This review provides an in-depth look into the concepts and mechanisms underlying CALR exposure, activation of the Toll-like receptor 3/IFN/CXCL10 axis, and the release of ATP and HMGB1 from dying cancer cells. Factors that influence the impact of ICD in clinical studies and the design of therapies combining chemotherapy with immunotherapy are also discussed. PMID- 26486088 TI - Detection of canonical A-to-G editing events at 3' UTRs and microRNA target sites in human lungs using next-generation sequencing. AB - RNA editing is a post-transcriptional modification of RNA. The majority of these changes result from adenosine deaminase acting on RNA (ADARs) catalyzing the conversion of adenosine residues to inosine in double-stranded RNAs (dsRNAs). Massively parallel sequencing has enabled the identification of RNA editing sites in human transcriptomes. In this study, we sequenced DNA and RNA from human lungs and identified RNA editing sites with high confidence via a computational pipeline utilizing stringent analysis thresholds. We identified a total of 3,447 editing sites that overlapped in three human lung samples, and with 50% of these sites having canonical A-to-G base changes. Approximately 27% of the edited sites overlapped with Alu repeats, and showed A-to-G clustering (>3 clusters in 100 bp). The majority of edited sites mapped to either 3' untranslated regions (UTRs) or introns close to splice sites; whereas, only few sites were in exons resulting in non-synonymous amino acid changes. Interestingly, we identified 652 A-to-G editing events in the 3' UTR of 205 target genes that mapped to 932 potential miRNA target binding sites. Several of these miRNA edited sites were validated in silico. Additionally, we validated several A-to-G edited sites by Sanger sequencing. Altogether, our study suggests a role for RNA editing in miRNA mediated gene regulation and splicing in human lungs. In this study, we have generated a RNA editome of human lung tissue that can be compared with other RNA editomes across different lung tissues to delineate a role for RNA editing in normal and diseased states. PMID- 26486089 TI - Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition. AB - ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance. Cell cycle arrest, DNA damage accumulation and repair were determined following VE-821 exposure.Defects in homologous recombination repair (HRR: ATM, BRCA2 and XRCC3) and base excision repair (BER: XRCC1) conferred sensitivity to VE-821. Surprisingly, the loss of different components of the trimeric non-homologous end-joining (NHEJ) protein DNA-PK had opposing effects. Loss of the DNA-binding component, Ku80, caused hypersensitivity to VE-821, but loss of its partner catalytic subunit, DNA-PKcs, did not. Unexpectedly, VE-821 was particularly cytotoxic to human and hamster cells expressing high levels of DNA-PKcs. High DNA-PKcs was associated with replicative stress and activation of the DDR. VE-821 suppressed HRR, determined by RAD51 focus formation, to a greater extent in cells with high DNA-PKcs.Defects in HRR and BER and high DNA-PKcs expression, that are common in cancer, confer sensitivity to ATR inhibitor monotherapy and may be developed as predictive biomarkers for personalised medicine. PMID- 26486090 TI - Aspirin might reduce the incidence of pancreatic cancer: A meta-analysis of observational studies. AB - Although there is evidence that non-steroidal anti-inflammatory drugs (NSAIDs) might be able to prevent pancreatic cancer, the findings from epidemiological studies have been inconsistent. In this paper, we conducted a meta-analysis of observational studies to examine this possibility. We searched PubMed and Embase for observational (cohort or case-control) studies examining the consumption of aspirin and other NSAIDs and the incidence of or mortality rates associated with pancreatic cancer. Twelve studies including approximately 258,000 participants in total were analysed. The administration of aspirin significantly reduced the incidence of pancreatic cancer (8 studies; odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.62 to 0.96; I(2) = 74.2%) but not the mortality associated with it (2 studies; OR = 0.94; 95% CI = 0.73 to 1.22). Specifically, frequent aspirin use was associated with reduced pancreatic cancer incidence (OR = 0.57; 95% CI = 0.39 to 0.83 for high frequency; OR = 0.57; 95% CI = 0.38 to 0.84 for medium frequency). The summary ORs regarding the incidence of pancreatic cancer and either non-aspirin NSAIDs use (OR = 1.08; 95% CI = 0.90 to 1.31) or overall NSAIDs use (OR = 0.97; 95% CI = 0.86 to 1.10) were not significant. In conclusion, aspirin use might reduce the incidence of pancreatic cancer; however, this finding should be interpreted with caution because of study heterogeneity. PMID- 26486091 TI - Branched isomeric 1,2,3-triazolium-based ionic liquids: new insight into structure-property relationships. AB - A series of four isomeric 1,2,3-triazolium-based ionic liquids (ILs) with vary degree of branching were synthesized and characterized to investigate the effect of ion branching on thermal and physical properties of the resulting IL. It was found that increased branching led to a higher ionicity and higher viscosity. The thermal properties were also altered significantly and spectral changes in the near edge X-ray absorption fine structure (NEXAFS) spectra show that branching affects intermolecular interaction. While the ionicity and viscosity varying linearly with branching, the MDSC and NEXAFS measurements show that the cation shape has a stronger influence on the melting temperature and absorptive properties than the number of branched alkyl substituents. PMID- 26486094 TI - Parents' and young people's involvement in designing a trial of ventilator weaning. AB - Consulting with users is considered best practice and is highly recommended in designing new trials. As part of our feasibility work, we undertook a consultation exercise with parents, ex-patients and young people prior to designing a trial of protocol-based ventilator weaning. Our aims were to (1) ascertain views on the relevance and importance of the trial; (2) determine the important parent/patient outcome measures; and (3) ascertain views on informed consent in a cluster randomized controlled trial. We conducted audio-recorded face-to-face, telephone and focus group interviews with parents and young people. Data were content analysed to generate information to address our specific consultation objectives. The setting was the north-western region of England. A total of 16 participants were interviewed: 2 parents of paediatric intensive care unit (PICU) survivors; 1 PICU survivor; and 13 young people from the former Medicines for Children Research Network. The trial objectives were deemed important and relevant, and participants considered the most important outcome measure to be the length of time on ventilation. Parents and young people did not consider written informed consent to be a necessary requirement in the context of this trial, rather awareness of unit participation in the trial was important with the opportunity of opting out of data collection. This consultation provided useful, pragmatic insights to inform trial design. We encountered significant challenges in recruiting parents and young people for this consultation exercise, and novel recruitment methods need to be considered for future work in this field. Patient and public involvement is essential to ensure that future trials answer parent-relevant questions and have meaningful outcome measures, as well as involving parents and young people in the general development of health care services. PMID- 26486092 TI - Thoracic Society of Australia and New Zealand oxygen guidelines for acute oxygen use in adults: 'Swimming between the flags'. AB - The purpose of the Thoracic Society of Australia and New Zealand guidelines is to provide simple, practical evidence-based recommendations for the acute use of oxygen in adults in clinical practice. The intended users are all health professionals responsible for the administration and/or monitoring of oxygen therapy in the management of acute medical patients in the community and hospital settings (excluding perioperative and intensive care patients), those responsible for the training of such health professionals, and both public and private health care organizations that deliver oxygen therapy. PMID- 26486095 TI - Variance and potential niche separation of microbial communities in subseafloor sediments off Shimokita Peninsula, Japan. AB - Subseafloor pelagic sediments with high concentrations of organic matter form habitats for diverse microorganisms. Here, we determined depth profiles of genes for SSU rRNA, mcrA, dsrA and amoA from just beneath the seafloor to 363.3 m below the seafloor (mbsf) using core samples obtained from the forearc basin off the Shimokita Peninsula. The molecular profiles were combined with data on lithostratigraphy, depositional age, sedimentation rate and pore-water chemistry. The SSU rRNA gene tag structure and diversity changed at around the sulfate methane transition zone (SMTZ), whereas the profiles varied further with depth below the SMTZ, probably in connection with the variation in pore-water chemistry. The depth profiles of diversity and abundance of dsrA, a key gene for sulfate reduction, suggested the possible niche separations of sulfate-reducing populations, even below the SMTZ. The diversity and abundance patterns of mcrA, a key gene for methanogenesis/anaerobic methanotrophy, suggested a stratified distribution and separation of anaerobic methanotrophy and hydrogenotrophic or methylotrophic methanogensis below the SMTZ. This study provides novel insights into the relationships between the composition and function of microbial communities and the chemical environment in the nutrient-rich continental margin subseafloor sediments, which may result in niche separation and variability in subseafloor microbial populations. PMID- 26486096 TI - Evolution of deuterostomy - and origin of the chordates. AB - The chordates are usually characterized as bilaterians showing deuterostomy, i.e. the mouth developing as a new opening between the archenteron and the ectoderm, serial gill pores/slits, and the complex of chorda and neural tube. Both numerous molecular studies and studies of morphology and embryology demonstrate that the neural tube must be considered homologous to the ventral nerve cord(s) of the protostomes, but the origin of the 'new' mouth of the deuterostomes has remained enigmatic. However, deuterostomy is known to occur in several protostomian groups, such as the chaetognaths and representatives of annelids, molluscs, arthropods and priapulans. This raises the question whether the deuterostomian mouth is in fact homologous with that of the protostomes, viz. the anterior opening of the ancestral blastopore divided through lateral blastopore fusion, i.e. amphistomy. A few studies of gene expression show identical expression patterns around mouth and anus in protostomes and deuterostomes. Closer studies of the embryology of ascidians and vertebrates show that the mouth/stomodaeum differentiates from the anterior edge of the neural plate. Together this indicates that the chordate mouth has moved to the anterior edge of the blastopore, so that the anterior loop of the ancestral circumblastoporal nerve cord, which is narrow in the protostomes, has become indistinguishable. In the vertebrates, the mouth has moved further around the anterior pole to the 'ventral' side. The conclusion must be that the chordate mouth (and that of the deuterostomes in general) is homologous to the protostomian mouth and that the latest common ancestor of protostomes and deuterostomes developed through amphistomy, as suggested by the trochaea theory. PMID- 26486097 TI - Video-assisted thoracoscopic surgery after renal transplantation: A single institution experience. AB - INTRODUCTION: The number of renal transplantations performed for patients with chronic kidney disease has increased in Japan, but little is known about the outcomes in those who subsequently undergo video-assisted thoracoscopic surgery (VATS). We therefore investigated the outcomes of consecutive patients requiring VATS after renal transplantation at our institute. METHODS: We retrospectively collected the clinical data for patients undergoing VATS after renal transplantation between January 2003 and September 2014. Specifically, we compared the serum creatinine level and estimated glomerular filtration rate preoperatively and postoperatively, and investigated the postoperative complications. RESULTS: In total, 12 patients underwent VATS after renal transplantation during the study period. All patients received two or three immunosuppressive agents. Operative methods used included VATS wedge resection (n = 4), segmentectomy (n = 4), lobectomy (n = 2), mediastinal tumor resection (n = 1), and chest wall tumor resection (n = 1). No patients required perioperative hemodialysis. There were no intraoperative complications, but one patient developed postoperative hemorrhagic cystitis and another developed pneumonia. One patient developed pneumocystis pneumonia 2 months after left lower lobectomy and required hemodialysis. No further hemodialysis was required by any patient. Of note, no statistically significant differences were observed between the preoperative and postoperative serum creatinine level (P = 0.666) and estimated glomerular filtration rate (P = 0.388). There were no in-hospital deaths. Univariate analysis revealed no significant risk factors for postoperative complications. CONCLUSION: This report showed favorable results for VATS after renal transplantation. However, clinicians must remain vigilant for complications because transplant recipients remain permanently immunocompromised. PMID- 26486100 TI - Betsy McClung 1942-2015. PMID- 26486099 TI - Selection of suitable reference genes for normalization of quantitative RT-PCR in peripheral blood samples of bottlenose dolphins (Tursiops truncatus). AB - Quantitative RT-PCR is often used as a research tool directed at gene transcription. Selection of optimal housekeeping genes (HKGs) as reference genes is critical to establishing sensitive and reproducible qRT-PCR-based assays. The current study was designed to identify the appropriate reference genes in blood leukocytes of bottlenose dolphins (Tursiops truncatus) for gene transcription research. Seventy-five blood samples collected from 7 bottlenose dolphins were used to analyze 15 candidate HKGs (ACTB, B2M, GAPDH, HPRT1, LDHB, PGK1, RPL4, RPL8, RPL18, RPS9, RPS18, TFRC, YWHAZ, LDHA, SDHA). HKG stability in qRT-PCR was determined using geNorm, NormFinder, BestKeeper and comparative delta Ct algorithms. Utilization of RefFinder, which combined all 4 algorithms, suggested that PGK1, HPRT1 and RPL4 were the most stable HKGs in bottlenose dolphin blood. Gene transcription perturbations in blood can serve as an indication of health status in cetaceans as it occurs prior to alterations in hematology and chemistry. This study identified HKGs that could be used in gene transcript studies, which may contribute to further mRNA relative quantification research in the peripheral blood leukocytes in captive cetaceans. PMID- 26486098 TI - Adolescents with or at ultra-high risk for bipolar disorder exhibit erythrocyte docosahexaenoic acid and eicosapentaenoic acid deficits: a candidate prodromal risk biomarker. AB - AIM: Mood disorders are associated with low levels of the long-chain omega-3 (LCn 3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This study investigated LCn-3 fatty acid biostatus in youth with or at varying risk for developing mania to assess its utility as a prodromal risk biomarker. METHOD: Erythrocyte fatty acid composition was determined in healthy adolescents (n = 28, HC), asymptomatic adolescents with a biological parent with bipolar I disorder (n = 30; 'high risk', HR), adolescents with a biological parent with bipolar I disorder and major depressive disorder, or depressive disorder not otherwise specified (n = 36; 'ultra-high risk', UHR), and first-episode adolescent bipolar manic patients (n = 35, BP). RESULTS: Group differences were observed for DHA (P <= 0.0001) and EPA (P = 0.03). Compared with HC, erythrocyte EPA + DHA ('omega-3 index') was significantly lower in BP (-24%, P <= 0.0001) and UHR (-19%, P = 0.0006) groups, and there was a trend in the HR group (-11%, P = 0.06). Compared with HC (61%), a greater percentage of HR (77%, P = 0.02), UHR (80%, P = 0.005) and BP (97%, P = 0.001) subjects exhibited EPA + DHA levels of <=4.0%. Among all subjects (n = 130), EPA + DHA was inversely correlated with manic (r = -0.29, P = 0.0008) and depressive (r = -0.28, P = 0.003) symptom severity. The AA/EPA + DHA ratio was significantly greater in BP (+22%, P = 0.0002) and UHR (+16%, P = 0.001) groups. CONCLUSIONS: Low EPA + DHA levels coincide with the initial onset of mania, and increasing risk for developing bipolar disorder is associated with graded erythrocyte EPA + DHA deficits. Low erythrocyte EPA + DHA biostatus may represent a promising prodromal risk biomarker warranting additional evaluation in future prospective studies. PMID- 26486101 TI - Visfatin serum level and expression in subcutaneous and visceral adipose tissue in prepubertal boys. AB - BACKGROUND: The biological role of visfatin in humans, especially in eutrophic and healthy children, is not understood yet, except for its link to obesity related disorders in adolescents and adults. OBJECTIVES: To determine the physiological values of serum visfatin concentrations, and visfatin mRNA expression in subcutaneous (SAT) and visceral adipose tissue (VAT), and to correlate them with anthropometric/metabolic data in prepubertal healthy boys. METHODS: The study included 59 healthy boys, age 1-10 years, hospitalized for elective surgery, divided according to age into group I (1-3 years old), group II (3-7 years old) and group III (7-10 years old). Anthropometric and biochemical measurements, and the visfatin serum and mRNA level in SAT and VAT were determined in all patients. RESULTS: Visfatin mRNA expression was higher in SAT compared with VAT in all three studied groups. Highest visfatin mRNA was found in SAT of group III compared with group II (P = 0.030). VAT visfatin mRNA expression negatively correlates with body weight (P = 0.039), waist circumference (P = 0.027) and morning glucose level (P = 0.007). CONCLUSION: Lack of changes in serum visfatin level despite the changes in visfatin mRNA expression of adipose tissue suggests paracrine effect of visfatin rather than endocrine. Negative correlation of visfatin VAT mRNA expression with anthropometric parameters indicates important role of VAT visfatin in maturation and in glucose metabolism. PMID- 26486103 TI - microRNA deregulation in keloids: an opportunity for clinical intervention? AB - Keloids are defined as benign dermal scars invading adjacent healthy tissue, characterized by aberrant fibroblast dynamics and overproduction of extracellular matrix. However, the aetiology and molecular mechanism of keloid production remain poorly understood. Recent discoveries have shed new light on the involvement of a class of non-coding RNAs known as microRNAs (miRNA), in keloid formation. A number of miRNAs have differential expression in keloid tissues and keloid-derived fibroblasts. These miRNAs have been characterized as novel regulators of cellular processes pertinent to wound healing, including extracellular matrix deposition and fibroblast proliferation. Delineating the functional significance of miRNA deregulation may help us better understand pathogenesis of keloids, and promote development of miRNA-directed therapeutics against this condition. PMID- 26486102 TI - Transmission of Clostridium difficile During Hospitalization for Allogeneic Stem Cell Transplant. AB - OBJECTIVE To determine the role of unit-based transmission that accounts for cases of early Clostridium difficile infection (CDI) during hospitalization for allogeneic stem cell transplant. SETTING Stem cell transplant unit at a tertiary care cancer center. METHODS Serially collected stool from patients admitted for transplant was screened for toxigenic C. difficile through the hospital stay and genotyping was performed by multilocus sequence typing. In addition, isolates retrieved from cases of CDI that occurred in other patients hospitalized on the same unit were similarly characterized. Transmission links were established by time-space clustering of cases and carriers of shared toxigenic C. difficile strains. RESULTS During the 27-month period, 1,099 samples from 264 patients were screened, 69 of which had evidence of toxigenic C. difficile; 52 patients developed CDI and 17 were nonsymptomatic carriers. For the 52 cases, 41 had evidence of toxigenic C. difficile on the first study sample obtained within a week of admission, among which 22 were positive within the first 48 hours. A total of 24 sequence types were isolated from this group; 1 patient had infection with the NAP1 strain. A total of 11 patients had microbiologic evidence of acquisition; donor source could be established in half of these cases. CONCLUSIONS Most cases of CDI after stem cell transplant represent delayed onset disease in nonsymptomatic carriers. Transmission on stem cell transplant unit was confirmed in 19% of early CDI cases in our cohort with a probable donor source established in half of the cases. PMID- 26486105 TI - Complete heart block and asystole following blunt cardiac trauma. AB - Cardiac contusion is a well-recognized complication of blunt chest trauma. Various conduction system disorders have been reported in association with this condition, the most common being right bundle branch block. Complete heart block (CHB) is seen rarely. Most cases of CHB are transient. We present the case of an 80-year-old woman who developed CHB and asystole following blunt cardiac trauma. Malignant cardiac arrhythmias such as CHB can be associated with blunt cardiac trauma. In most cases, CHB is transient resolving in days to weeks. In rare cases, however, CHB leads to asystole. Close monitoring and prompt intervention is thus required. PMID- 26486104 TI - PDZRN4 acts as a suppressor of cell proliferation in human liver cancer cell lines. AB - Recently, some reports show that Ligand of Numb Protein-X 1 (LNX1) could be a suppressor gene in gliomas, while our current research has firstly shown that PDZ domain containing ring finger 4 (PDZRN4), another member of LNX family, could also be a potential suppressor in hepatocellular carcinoma (HCC). PDZRN4, also named LNX4 (Ligand of Numb Protein-X 4), is a member of the LNX family. We recently found that PDZRN4, but not LNX1, was down-regulated in HCC samples, and the role of PDZRN4 in the progression of HCC had not been studied before. To address this question, firstly, we evaluated the expression of PDZRN4 in HCC samples and adjacent non-cancerous tissues. Semi-quantitative polymerase chain reaction showed that PDZRN4 was down-regulated in 24/36 (66.7%) HCC samples separately. In addition, our research shows that PDZRN4 is silenced in all of the 12 HCC cell lines tested. Subsequently, cell-based functional assay exhibited that ectopic expression of PDZRN4 inhibits the proliferation, plate colony formation and anchorage-independent colony formation of HCC cells. Collectively, our results showed that PDZRN4 might be a potential tumour suppressor gene and had anti-proliferative effect on HCC cell proliferation, which would be of great significance to the researches on HCC. PMID- 26486107 TI - Use of flexible bronchoscopy in an adult for removal of an aspirated foreign body at a community hospital. AB - Foreign body aspiration (FBA) is more common in children than adults with about 80% occurring in children aged less than 15 years. FBA in adults is often overlooked as a potential cause of airway obstruction especially if there is no asphyxiation. We present a case of a 45-year-old male with alcohol abuse who presented with post-obstructive pneumonia secondary to aspiration of tooth of unknown duration. The tooth was removed via flexible bronchoscopy (FBr) and we will discuss the use of FBr for foreign body (FB) removal, which FB can be easily removed by FBr, and the different techniques and devices used for FB removal via FBr. PMID- 26486106 TI - Cardiac lipoma. AB - Lipomas of the heart are encapsulated tumors that are composed primarily of mature fat cells. Cardiac lipomas can originate either from subendocardium (approximately 50%), subpericardium (25%), or from the myocardium (25%) and may be located more frequently in left ventricle or right atrium. We report a 74-year old female who presented with dyspnea on exertion and was found to have 5*5 cm mass occupying most of the right atrium on a transesophageal echocardiogram. PMID- 26486108 TI - Beware of Chilaiditi sign!! PMID- 26486109 TI - Spontaneous complete remission of type 1 diabetes mellitus in an adult - review and case report. AB - Type 1 diabetes mellitus (T1DM) is an autoimmune condition that results in low plasma insulin levels by destruction of beta cells of the pancreas. As part of the natural progression of this disease, some patients regain beta cell activity transiently. This period is often referred to as the 'honeymoon period' or remission of T1DM. During this period, patients manifest improved glycemic control with reduced or no use of insulin or anti-diabetic medications. The incidence rates of remission and duration of remission is extremely variable. Various factors seem to influence the remission rates and duration. These include but are not limited to C-peptide level, serum bicarbonate level at the time of diagnosis, duration of T1DM symptoms, haemoglobin A1C (HbA1C) levels at the time of diagnosis, sex, and age of the patient. Mechanism of remission is not clearly understood. Extensive research is ongoing in regard to the possible prevention and reversal of T1DM. However, most of the studies that showed positive results were small and uncontrolled. We present a 32-year-old newly diagnosed T1DM patient who presented with diabetic ketoacidosis (DKA) and HbA1C of 12.7%. She was on basal bolus insulin regimen for the first 4 months after diagnosis. Later, she stopped taking insulin and other anti-diabetic medications due to compliance and logistical issues. Eleven months after diagnosis, her HbA1C spontaneously improved to 5.6%. Currently (14 months after T1DM diagnosis), she is still in complete remission, not requiring insulin therapy. PMID- 26486110 TI - Heparin-induced thrombocytopenia following coronary artery bypass grafting: a diagnostic dilemma. AB - The diagnosis of heparin-induced thrombocytopenia (HIT) is a challenge in post cardiac surgery patients because of the high incidence of non-immune thrombocytopenia and heparin-platelet factor 4 antibodies in these groups. We present a case of HIT in a post coronary artery bypass surgery patient, which was successfully treated with prompt recognition and discontinuation of heparin products. PMID- 26486111 TI - Oral clindamycin causing acute cholestatic hepatitis without ductopenia: a brief review of idiosyncratic drug-induced liver injury and a case report. AB - Clindamycin is a lincosamide antibiotic active against most of the anaerobes, protozoans, and Gram-positive bacteria, including community-acquired methicillin resistant Staphylococcus aureus. Its use has increased greatly in the recent past due to wide spectrum of activity and good bioavailability in oral form. Close to 20% of the patients taking clindamycin experience diarrhea as the most common side effect. Hepatotoxicity is a rare side effect. Systemic clindamycin therapy has been linked to two forms of hepatotoxicity: transient serum aminotransferase elevation and an acute idiosyncratic liver injury that occurs 1-3 weeks after starting therapy. This article is a case report of oral clindamycin induced acute symptomatic cholestatic hepatitis and a brief review of the topic. PMID- 26486112 TI - Nosocomial keratitis caused by methicillin-resistant Staphylococcus aureus: case report and preventative measures. AB - A 47-year-old African-American woman was admitted to the intensive care unit of our community hospital for respiratory failure secondary to severe decompensated heart failure, requiring intubation. In the ensuing days, she developed a methicillin-resistant Staphylococcus aureus (MRSA) infection of the cornea, despite no growth of MRSA in multiple blood, sputum, and urine cultures. This unexpected corneal infection complicated her hospital stay, and increased morbidity and disease-related cost. Risk factors, warning signs, and preventative measures for MRSA keratitis secondary to lagophthalmos (inability to completely close one's eyelids) are outlined in this case report. Implementing simple precautions such as taping eyelids shut or using artificial lubrication may reduce patient morbidity and disease-related costs. These recommendations are directed to non-ophthalmic clinicians who provide care to patients in settings where MRSA colonization is widespread. PMID- 26486113 TI - Bow tie or no tie: a rule to reduce healthcare-acquired infections. PMID- 26486114 TI - Intrapulmonary arteriovenous malformation causing recurrent strokes. AB - This case reveals a left pulmonary arteriovenous malformation (PAVM) as a cause of recurrent cerebral and cerebellar emboli. Extensive workup excluded other etiologies of emboli formation, and the patient was transferred to a tertiary care center for percutaneous embolotherapy. In the absence of a clear etiology, PAVM should be considered as a potential cause of recurrent cerebral emboli, especially in the absence of carotid disease, intracardiac thrombus, atrial septal defect, and patent foramen ovale. Diagnostic work-up for the PAVM can be cost effective and expedited by utilization of agitated saline contrast echocardiography, as noted in our case. PMID- 26486115 TI - Spontaneous internal carotid dissection in a 38-year-old woman: a case report. AB - This case report describes a patient found to have amaurosis fugax as a result of non-traumatic internal carotid dissection. Monocular blindness can be due to multiple causes including keratitis, acute glaucoma, vitreous hemorrhage, uveitis, retinal vascular occlusion, retinal detachment, optic neuropathy, trauma, or vascular malformations. In the setting of headache, neck pain, and an otherwise normal ophthalmic examination, this case report highlights the importance of recognizing transient ischemic attack and carotid artery dissection in the differential diagnosis. To further clarify the diagnosis, carotid ultrasound may aid diagnosis as was seen in this case, where decreased internal carotid artery velocities were found and subsequent CT angiography of the neck confirmed a diagnosis of carotid dissection. If a dissection is present, progression of symptoms may indicate impending cerebral infarction and warrant immediate attention. Antiplatelet therapy is the first-line treatment with anticoagulation, thrombolysis, and surgery reserved for cases of recurrent, progressive symptomatic episodes. Surgical options include endovascular repair such as angioplasty, stent placement, embolization, surgical revascularization, and bypass. PMID- 26486116 TI - A diagnostic challenge in a young woman with intractable hiccups and vomiting: a case of neuromyelitis optica. AB - Intractable nausea and vomiting along with hiccups is a commonly encountered problem on any general medicine or gastroenterology service. These symptoms are usually not appreciated as the possible initial manifestation of neuromyelitis optica (NMO). Missing diagnosis at this early stage will lead to a delay in the treatment, and hence, irreversible complications including blindness and paraplegia could occur. We report a case of a 22-year-old young female who presented with intractable hiccups and vomiting. After extensive evaluation, she was found to have NMO which involved the area postrema, the vomiting center of the brain. Early diagnosis from the clinical picture aided by aquaporin-4 serologic testing is extremely important to allow early initiation of immunosuppressive therapy. Immunosuppression gives an opportunity to modify the disease at an earlier stage rather than waiting for evolution of disease to fulfill the diagnostic criteria of NMO. PMID- 26486117 TI - Central tendency and variability in biological systems: Part 2. AB - This is the second article of a series on fundamental concepts in biostatistics and research. In this article, the author reviews the manner in which researchers characterize data. Normality, standard deviation, mean, P value, and other concepts related to parametric statistics are discussed in common language, with a minimum of jargon and mathematics, and with clinical examples. Emphasis is given to conceptual understanding. PMID- 26486118 TI - Do all patients with acquired methemoglobinemia need treatment? A lesson learnt. AB - Acquired methemoglobinemia is a medical emergency, and its prompt recognition and treatment can avoid catastrophic complications including death. However, in mild asymptomatic cases without any comorbid conditions, it would be reasonable to simply observe and treat symptomatically to avoid severe treatment-related complications, especially in patients with suspected glucose-6-phosphate dehydrogenase (G6PD) deficiency. We present a case of mild methemoglobinemia in occult G6PD deficiency in which the patient developed hemolysis after treatment with intravenous methylene blue, requiring transfusion. PMID- 26486119 TI - Hereditary angioedema presenting as irritable bowel syndrome: a case of early closure. AB - Abdominal pain is one of the most common reasons for outpatient and emergency department visits. We present one such case of early closure in a 32-year-old male with recurrent abdominal pain who was diagnosed with irritable bowel syndrome (IBS). Family history was suspicious for hereditary angioedema (HAE). The HAE workup came back positive, and the patient was started on prophylactic therapy, which led to an improvement in symptoms and quality of life. The purpose of this case is to create awareness among physicians to test for HAE in patients diagnosed with IBS who, based on their history or physical examination, have clinical suspicion for HAE. PMID- 26486120 TI - Rapid assessment of health literacy on admission to the hospital. PMID- 26486121 TI - Post-polypectomy electrocoagulation syndrome: a rare cause of acute abdominal pain. AB - While generally safe, the most feared complication of colonoscopy is perforation of the colon, occurring in nearly 1 in 1,000 procedures, and is more common when polypectomy is performed and electrocautery is used. Less commonly known is the post-polypectomy electrocoagulation syndrome, a transmural burn of the colon which mimics the signs and symptoms of perforation as well as the time course, but follows a benign course and can be treated conservatively. PMID- 26486122 TI - Recognizing Wellens' syndrome, a warning sign of critical proximal LAD artery stenosis and impending anterior myocardial infarction. AB - Wellens' syndrome, also known as LAD coronary T-wave syndrome or the 'widow maker', is a pre-infarction syndrome with non-classical ischemic ECG changes and unremarkable cardiac biomarkers. This syndrome continues to be a 'can't miss' for the clinician as delay in urgent angiography and intervention can result in anterior myocardial infarction, left ventricular dysfunction, arrhythmias, and death. We describe a case followed by a discussion of identification criteria and clinical implications. PMID- 26486123 TI - Giant right atrial mass obliterating the right atrium. AB - A73-year-old man with past medical history of mechanical aortic valve replacement, metastatic melanoma of unknown primaries with liver metastasis, presented with progressive shortness of breath and dyspnea on exertion. Transthoracic echocardiography (TTE) showed a large homogenous mass completely occupying the right atrial cavity and extending to and nearly obstructing the inflow area of the tricuspid valve. He was treated with chemotherapy. PMID- 26486124 TI - Carbapenem-Resistant Enterobacteriaceae in Children, United States, 1999-2012. AB - The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) infections is increasing in the United States. However, few studies have addressed their epidemiology in children. To phenotypically identify CRE isolates cultured from patients 1-17 years of age, we used antimicrobial susceptibilities of Enterobacteriaceae reported to 300 laboratories participating in The Surveillance Network-USA database during January 1999-July 2012. Of 316,253 isolates analyzed, 266 (0.08%) were identified as CRE. CRE infection rate increases were highest for Enterobacter species, blood culture isolates, and isolates from intensive care units, increasing from 0.0% in 1999-2000 to 5.2%, 4.5%, and 3.2%, respectively, in 2011-2012. CRE occurrence in children is increasing but remains low and is less common than that for extended-spectrum beta-lactamase-producing Enterobacteriaceae. The molecular characterization of CRE isolates from children and clinical epidemiology of infection are essential for development of effective prevention strategies. PMID- 26486125 TI - Bone grafts utilized in dentistry: an analysis of patients' preferences. AB - BACKGROUND: Many procedures currently require the use of bone grafts to replace or recover bone volume that has been resorbed. However, the patient's opinion and preferences must be taken into account before implementing any treatment. Researchers have focused primarily on assessing the effectiveness of bone grafts rather than on patients' perceptions. Thus, the aim of this study was to explore patients' opinions regarding the different types of bone grafts used in dental treatments. METHODS: One hundred patients were randomly chosen participated in the study. A standardized survey of 10 questions was used to investigate their opinions regarding the different types of bone grafts used in dental treatments. Descriptive statistics were calculated for the different variables, and absolute frequencies and percentages were used as summary measures. A value of p <0.05 was selected as the threshold for statistical significance. RESULTS: The highest rate of refusal was observed for allografts and xenografts. The grafts with the lowest rates of refusal were autologous grafts (3 %) and alloplastics (2 %). No significant differences were found between the various types of bone grafts in the sociodemographic variables or the refusal/acceptance variable. Similarly, no significant relations were observed between a specific religious affiliation and the acceptance/refusal rates of the various types of graft. CONCLUSIONS: Allografts and xenografts elicited the highest refusal rates among the surveyed patients, and autologous bone and alloplastics were the most accepted bone grafts. Moreover, no differences were found in the sociodemographic variables or religious affiliations in terms of the acceptance/refusal rates of the different bone grafts. PMID- 26486126 TI - Lessons learned from England's Health Checks Programme: using qualitative research to identify and share best practice. AB - BACKGROUND: This study aimed to explore the challenges and barriers faced by staff involved in the delivery of the National Health Service (NHS) Health Check, a systematic cardiovascular disease (CVD) risk assessment and management program in primary care. METHODS: Data have been derived from three qualitative evaluations that were conducted in 25 General Practices and involved in depth interviews with 58 staff involved all levels of the delivery of the Health Checks. Analysis of the data was undertaken using the framework approach and findings are reported within the context of research and practice considerations. RESULTS: Findings indicated that there is no 'one size fits all' blueprint for maximising uptake although success factors were identified: evolution of the programme over time in response to local needs to suit the particular characteristics of the patient population; individual staff characteristics such as being proactive, enthusiastic and having specific responsibility; a supportive team. Training was clearly identified as an area that needed addressing and practitioners would benefit from CVD specific baseline training and refresher courses to keep them up to date with recent developments in the area. However there were other external factors that impinged on an individual's ability to provide an effective service, some of these were outside the control of individuals and included cutbacks in referral services, insufficient space to run clinics or general awareness of the Health Checks amongst patients. CONCLUSIONS: The everyday experiences of practitioners who participated in this study suggest that overall, Health Check is perceived as a worthwhile exercise. But, organisational and structural barriers need to be addressed. We also recommend that clear referral pathways be in place so staff can refer patients to appropriate services (healthy eating sessions, smoking cessation, and exercise referrals). Local authorities need to support initiatives that enable data sharing and linkage so that GP Practices are informed when patients take up services such as smoking cessation or alcohol harm reduction programmes run by social services. PMID- 26486127 TI - Alleviating central venous oxygen saturation (ScvO2): a new approach of kidney protection after cardiac surgery? PMID- 26486128 TI - [Thrombosis of the subclavian vein after conservative treatment of a clavicular fracture: A rare complication]. AB - We report the case of a 16-year-old male patient who presented with a clavicular fracture that was conservatively treated with a redressment bandage. After a few days the patient developed deep vein thrombosis of the subclavian, axillary and brachial veins, which was successfully treated with nadroparin. Conservative treatment of clavicular fractures is a common procedure in modern traumatology. Continuous, close monitoring and knowledge of rare but severe complications are necessary to avoid further complications. PMID- 26486129 TI - [Identification, diagnostics and guideline conform therapy of osteoporosis (DVO) in trauma patients : a treatment algorithm]. AB - Osteoporosis-associated fractures are of increasing importance in trauma surgery. The implementation of systematic diagnostics and treatment of osteoporosis during hospitalization, however, remains insufficient; therefore, a specific algorithm for the diagnosis and treatment of osteoporosis in trauma surgery patients was developed based on the German Osteology Society (Dachverband Osteologie, DVO) guidelines for osteoporosis from 2014. In a first step, the individual patient age and risk profile for osteoporosis are identified considering specific fractures indicative of osteoporosis. For these patients a questionnaire is completed which detects specific risk factors. In addition, the physical activity, risk of falls, dietary habits and the individual medication are collated as these can have a decisive influence on the subsequent therapy decisions. Prior to a specific treatment, laboratory osteoporosis tests, bone densitometry by dual energy X-ray absorptiometry (DXA) and if needed X-rays of the spine are carried out. For proximal femoral fractures the treatment of osteoporosis could already be indicated. With pre-existing glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted according to the table of T-scores detected by DXA. The treatment algorithm for diagnostics and treatment of osteoporosis in hospitalized trauma surgery patients can systematically and efficiently improve the identification of patients at risk. Thus, further fractures associated with osteoporosis or failure of internal fixation could be reduced in future. A prospective validation of the algorithm has already be initiated. PMID- 26486130 TI - Chemical contamination of soils in the New York City area following Hurricane Sandy. AB - This paper presents a unique data set of lead, arsenic, polychlorinated biphenyl (PCB), and polycyclic aromatic hydrocarbon (PAH) concentrations in soil samples collected from the metropolitan New York City area in the aftermath of Hurricane Sandy. Initial samples were collected by citizen scientists recruited via social media, a relatively unusual approach for a sample collection project. Participants in the affected areas collected 63 usable samples from basements, gardens, roads, and beaches. Results indicate high levels of arsenic, lead, PCBs, and PAHs in an area approximately 800 feet south of the United States Environmental Protection Agency (US EPA) Superfund site at Newtown Creek. A location adjacent to the Gowanus Canal, another Superfund site, was found to have high PCB concentrations. Areas of high PAH contamination tended to be near high traffic areas or next to sites of known contamination. While contamination as a direct result of Hurricane Sandy cannot be demonstrated conclusively, the presence of high levels of contamination close to known contamination sites, evidence for co-contamination, and decrease in number of samples containing measureable amounts of semi-volatile compounds from samples collected at similar locations 9 months after the storm suggest that contaminated particles may have migrated to residential areas as a result of flooding. PMID- 26486131 TI - Environmental impact of CO2, Rn, Hg degassing from the rupture zones produced by Wenchuan M s 8.0 earthquake in western Sichuan, China. AB - The concentrations and flux of CO2, (222)Radon (Rn), and gaseous elemental mercury (Hg) in soil gas were investigated based on the field measurements in June 2010 at ten sites along the seismic rupture zones produced by the May 12, 2008, Wenchuan M s 8.0 earthquake in order to assess the environmental impact of degassing of CO2, Rn and Hg. Soil gas concentrations of 344 sampling points were obtained. Seventy measurements of CO2, Rn and Hg flux by the static accumulation chamber method were performed. The results of risk assessment of CO2, Rn and Hg concentration in soil gas showed that (1) the concentration of CO2 in the epicenter of Wenchuan M s 8.0 earthquake and north end of seismic ruptures had low risk of asphyxia; (2) the concentrations of Rn in the north segment of seismic ruptures had high levels of radon, Maximum was up to level 4, according to Chinese code (GB 50325-2001); (3) the average geoaccumulation index I geo of soil Hg denoted the lack of soil contamination, and maximum values classified the soil gas as moderately to strongly polluted in the epicenter. The investigation of soil gas CO2, Rn and Hg degassing rate indicated that (1) the CO2 in soil gas was characterized by a mean [Formula: see text] of -20.4 0/00 and by a mean CO2 flux of 88.1 g m(-2) day(-1), which were in the range of the typical values for biologic CO2 degassing. The maximum of soil CO2 flux reached values of 399 g m( 2) day(-1) in the epicenter; (2) the soil Rn had higher exhalation in the north segment of seismic ruptures, the maximum reached value of 1976 m Bq m(-2) s(-1); (3) the soil Hg flux was lower, ranging from -2.5 to 18.7 n g m(-2) h(-1) and increased from south to north. The mean flux over the all profiles was 4.2 n g m( 2) h(-1). The total output of CO2 and Hg degassing estimated along seismic ruptures for a survey area of 18.17 km(2) were approximately 0.57 Mt year(-1) and 688.19 g year(-1). It is recommended that land-use planners should incorporate soil gas and/or gas flux measurements in the environmental assessment of areas of possible risk. A survey of all houses along seismic ruptures is advised as structural measures to prevent the ingress of soil gases, including CO2 and Rn, were needed in some houses. PMID- 26486132 TI - Oncological outcomes of sublobar resection for clinical-stage IA high-risk non small cell lung cancer patients with a radiologically solid appearance on computed tomography. AB - OBJECTIVES: Our study aim was to evaluate oncological outcomes after compromised sublobar resection for high-risk clinical-stage IA radiologically solid non-small cell lung cancer (NSCLC), and to investigate potential clinical predictors of improved survival. METHODS: Among 1109 resected clinical-stage IA NSCLC from 2008 to 2013, 115 (10 %) patients who presented radiologically solid, i.e., invasive appearances on thin-section computed tomography (CT) and were poor candidates for lobectomy underwent compromised sublobar resection. Radiologically solid lung cancer was defined as 0.5 <= consolidation/tumor ratio based on thin-section CT scan. RESULTS: The high-risk cohorts consisted of 65 men and 50 women, with an average age of 71.2 years. The 3-year overall survival (OS) and relapse-free survival were 82.2 and 72.2 % with 34 months of mean follow-up period. A multivariate analysis identified tumor size and carcinoembryonic antigen as significant, consolidation status as marginally significant clinical predictors of survival (p = 0.0141, 0.0426, 0.0623). When the patients were divided based on the number of negative predictors, the 3-year OS of the patients who met neither or one of these negative predictors (n = 64) was 98.4 % despite their anticipated risks, while that of the patients with 2 negative predictors was 71.5 % (n = 38), and the patients who met all of the poor conditions (n = 13) was 37.1 % even in clinical-stage IA disease (p < 0.0001). CONCLUSIONS: Among clinical-stage IA radiologically solid NSCLC patients who are not lobectomy candidates due to the anticipated risk, sublobar resection could provide acceptable oncological outcomes if patients show positive clinical predictors to improve their survival. PMID- 26486133 TI - Palatal rugae patterning in a modern Indonesian population. AB - BACKGROUND: Palatal rugae patterning has been suggested as useful complementary information for forensic purposes, when there are limitations in using the primary identifiers and when the individual patterning from e.g. a dental cast can be traced or the pattern can differentiate between alternative populations of origin. OBJECTIVES: The aim of this study was to identify the rugae patterns in a sample modern Indonesian population, to compare the patterns to previously reported observations, and to consider the requirements for possible forensic applications. MATERIAL AND METHODS: Archival dental casts were randomly selected to include 47 male and 53 female Indonesian patients of the Dental Hospital of the Faculty of Dentistry, University of Indonesia. The age and ethnic/geographic origin of the subjects were also recorded. The Trobo classification was applied to analyze the rugae shape patterns. RESULTS: The results showed the line, sinuous, and curve types of rugae as predominant shapes, representing together about 83% of the rugae of the study sample that for its size was considered reasonably representative of the Indonesian population. All recorded individual rugae patterns were unique, i.e. no similar patterns were found for any two individuals. The results are consistent with slow rugae loss at an average rate of one ruga in about 15 (+/-2) years after early adulthood. CONCLUSIONS: The palatal rugae patterns provide potentially useful supplementary information to establish the identity of an individual, but only when appropriate antemortem data are available. For this purpose, it is suggested that optical 3D oral/dental scanning is used to retain the data on the rugal and oropalatal patterns. Suitable pattern recognition methods may also reduce the potential effects of rugae modification in time. PMID- 26486134 TI - Ring-closing metathesis as key step in the synthesis of Luffarin I, 16-epi Luffarin I and Luffarin A. AB - Natural sesterterpenolides, luffarin I and luffarin A, from Luffariella geometrica have been synthesized, and this is the first reported synthesis of luffarin A. The Yamaguchi esterification of the nor-diterpenic fragment, obtained from 2.8-15MUM, with the appropriate furane alcohols yielded the necessary diene intermediates for the synthesis of the target molecules. The key strategic step in this synthesis was the ring-closing metathesis (RCM) reaction of the diene intermediates. This strategy allowed for the synthesis of 16-epi-luffarin I and analogues for structure-activity relationship (SAR) studies. The most active compound exhibited antiproliferative activity against a panel of six human solid tumour cell lines with [Formula: see text] values in the range 2.8-15 M. PMID- 26486136 TI - Platelet activating factor in allergies. AB - The platelet-activating factor (PAF) produced and released by mast cells, basophils, neutrophils, eosinophils, fibroblasts, platelets, endothelial cells, and even cardiac muscle cells plays an important role in inflammatory and thrombotic diseases. PAF has been shown to be an important mediator in anaphylaxis. Serum level of the factor correlates with the severity of systemic reactions. PAF is also involved in asthamatic patients' bronchoconstriction, mucus hypersecretion, and inflammation of bronchi. Furthermore, increased plasma levels of PAF have been reported in patients with urticarial. Studies have shown that PAF increases the permeability of skin's capillaries and indices the development of wheals, flare, and inflammatory reactions in the skin.This review focuses on the actions of the PAF on the eosinophiles and mast cells. Following that pathophysiological mechanism of the PAF in anaphylaxis bronchial asthma and urticaria was discussed. PMID- 26486137 TI - The first Rs of radiotherapy: or standing on the shoulders of giants. AB - The name of the Australian-born professor, Rodney H. Withers, is highly acknowledged among radiation biologists, radiation oncologists, medical physicists and other professionals. The list of his contributions towards knowledge enhancement and better understanding of the biological basis for radiotherapy is a long one. However, there are certain landmarks of Dr. Withers' research that are worth emphasizing, as they have marked several paths along the development of radiotherapy: the four Rs of radiotherapy, the accelerated tumour growth during treatment, the time-factor in radiotherapy, altered fractionation schemes and their corresponding isoeffect curves, normal tissue tolerance and organ architecture-just to name a few. This paper is a tribute to the work of Rodney Withers, which, far from being exhaustive, marks some of his greatest contributions to radiotherapy. PMID- 26486138 TI - Organocatalytic Site-Selective Acylation of Carbohydrates and Polyol Compounds. AB - Development and scope of conventionally difficult molecular transformation on site-selective acylation of carbohydrates and polyol compounds are described. A salient feature is that the site-selectivity can be controlled independently from the intrinsic reactivity of the substrate, i.e., catalyst-controlled selectivity. Therefore, some substrates undergo acylation with reversal of their intrinsic reactivity. The mechanistic aspects of catalyst-controlled site-selective acylation are discussed with the emphasis on the strategy relying on the accelerative reaction rather than the decelerative one. An unconventional retrosynthetic route based on catalyst-controlled site-selective acylation is proposed toward extremely short-step total synthesis of natural glycosides of an ellagitannin family. Application to the late-stage functionalization of the complex natural products of biological interest is also described. PMID- 26486135 TI - Quality of life and hormones after sex reassignment surgery. AB - BACKGROUND: Transpeople often look for sex reassignment surgery (SRS) to improve their quality of life (QoL). The hormonal therapy has many positive effects before and after SRS. There are no studies about correlation between hormonal status and QoL after SRS. AIM: To gather information on QoL, quality of sexual life and body image in transpeople at least 2 years after SRS,to compare these results with a control group and to evaluate the relations between the chosen items and hormonal status. SUBJECTS AND METHODS: Data from 60 transsexuals and from 60 healthy matched controls were collected. Testosterone,estradiol, LH and World Health Organization Quality of Life (WHOQOL-100) self-reported questionnaire were evaluated. Student's t test was applied to compare transsexuals and controls. Multiple regression model was applied to evaluate WHOQOL's chosen items and LH. RESULTS: The QoL and the quality of body image scores intranspeople were not statistically different from the matched control groups' ones. In the sexual life subscale,transwomen's scores were similar to biological women's ones, whereas transmen's scores were statistically lower than biological men's ones (P = 0.003). The quality of sexual life scored statistically lower in transmen than intranswomen (P = 0.048). A significant inverse relationship between LH and body image and between LH and quality of sexual life was found. CONCLUSIONS: This study highlights general satisfaction after SRS. In particular, transpeople's QoL turns out to be similar to Italian matched controls. LH resulted inversely correlated to body image and sexual life scores. PMID- 26486139 TI - A robust Bayesian dose-finding design for phase I/II clinical trials. AB - We propose a Bayesian phase I/II dose-finding trial design that simultaneously accounts for toxicity and efficacy. We model the toxicity and efficacy of investigational doses using a flexible Bayesian dynamic model, which borrows information across doses without imposing stringent parametric assumptions on the shape of the dose-toxicity and dose-efficacy curves. An intuitive utility function that reflects the desirability trade-offs between efficacy and toxicity is used to guide the dose assignment and selection. We also discuss the extension of this design to handle delayed toxicity and efficacy. We conduct extensive simulation studies to examine the operating characteristics of the proposed method under various practical scenarios. The results show that the proposed design possesses good operating characteristics and is robust to the shape of the dose-toxicity and dose-efficacy curves. PMID- 26486140 TI - Natural Carriers for siRNA Delivery. AB - This review is based on carriers of natural origin such as polysaccharides, proteins, and cell derived entities which have been used for delivery of siRNA. To realize the therapeutic potential of a delivery system, the role of the carrier is of utmost importance. Historical aspects of viral vectors, the first carriers of genes are briefly outlined. Chitosan, one of the extensively experimented carriers, alginates and other polysaccharides have shown success in siRNA delivery. Peptides of natural origin and mimics thereof have emerged as another versatile carrier. Exosomes and mini cells of cellular origin are the newest entrants to the area of siRNA delivery and probably the closest one can get to a natural carrier. In many of the carriers, modifications have provided better efficiency in delivery. The salient features of the carriers and their advantages and disadvantages are also reviewed. PMID- 26486141 TI - Liposomes and Lipid Envelope-Type Systems for Systemic siRNA Delivery. AB - The 'RNA interference' has emerged as a potential therapeutic strategy owing to its high specificity to silent any malfunctioned gene in diseases with genetic background. Currently intravenous delivery of siRNA has been a preferred way of administration due to high access of blood to the organs where direct delivery is not possible. Among non-viral delivery systems enabling systemic delivery of siRNA, liposomes and lipid envelope systems appear to be promising due to their biocompatibility over other systems. However, these systems are still challenged by toxicity issues, instability in blood, non-specific distribution and low transfection efficiency after intravenous administration. Therefore, to increase the success of lipid based siRNA delivery, it is essential to understand the importance of various factors affecting the efficiency of siRNA delivery. The current review focuses on the formulation of lipid based siRNA formulations, the challenges posed in systemic delivery and various aspects affecting the transfection efficiency of such formulations. The review also focuses on emerging strategies for lipid based siRNA delivery and overviews clinical prospects for better development of siRNA delivery systems in future. Considering the current trends, it seems that liposomes and lipid based envelope systems for systemic delivery of siRNA will translate into extensive clinical application overcoming the associated challenges in near future. PMID- 26486142 TI - Exosomes: Natural Carriers for siRNA Delivery. AB - Various cells of the human physiological system have the capability to release extracellular vesicles (EVs) involved in intercellular transport of proteins and nucleic acids. Exosomes are a subtype of extracellular vesicles having their origin through endocytic pathway. While being involved in intercellular transport of macromolecules, exosomes, due to their presence in several body fluids, can also be utilized as a system to commute RNA molecules and proteins in the body. Recent advances in gene therapy have provided a new outlook in disease therapeutics by modulation of gene expression using oligonucleotide based approach and exosomes have been reported a potential carrier for nucleic acid based therapeutic moieties. In recent years, small interfering RNA (siRNA) has emerged as promising therapeutic alternative for diseases with gene-based pathophysiology, however poor bioavailability limits its therapeutic potential. For effective delivery and enhancement of bioavailability of siRNA, several carriers including dendrimers, liposomes, siRNA conjugates, and siRNA aptamer chimeras, to name a few, have been explored. Exosomes can be considered a promising carrier for effective delivery of siRNA due to their existence in body's endogenous system and high tolerance. The present review focuses on delivering knowledge about exosomes, siRNA, and capability of exosomes to act as natural carriers for siRNA delivery. PMID- 26486144 TI - RNA Interference as a Therapeutic Strategy for the Treatment of Liver Diseases. AB - RNA interference has emerged as an innovative technology for gene silencing that degrades mRNAs complementary to the antisense strands of double-stranded, short interfering RNAs (siRNAs). Its therapeutic application has important advantages over small-molecule drugs since offers the possibility of targeting virtually all genes and allows selective silencing of one or several genes. So far, a relative small proportion of cellular proteins can bind and respond to chemical drugs. Based on that, RNA interference-mediated gene silencing is widely considered as a crucial breakthrough in molecular biology with a direct translation to medicine. The liver has been widely chosen as a model system for the development of RNA interference therapy due to the convenience and availability of effective delivery into this tissue. Numerous preclinical models have revealed promising results, but the safety of this technology remains the primary challenge in developing siRNA based treatments. Liver diseases comprise a broad spectrum of genetic and non-genetic pathologies including acute fulminant liver injury that demands urgent medical care, or chronic pathologies such as nonalcoholic fatty liver (NAFLD), alcoholic liver disease, liver cirrhosis, viral hepatitis and hepatocellular carcinoma (HCC). In some cases restoration of liver function is not possible and alternatives to liver transplantation offering novel and efficient therapeutic approaches are urgently needed. In this review, we describe recent insights on the advantages of using RNA interference in preclinical settings as a targeted strategy with potential to markedly improve the treatment of liver diseases. PMID- 26486143 TI - siRNA Delivery by Stimuli-Sensitive Nanocarriers. AB - Since its discovery in the late 1990, small interfering RNA (siRNA) have quickly crept into the biopharmaceutical research as a new and powerful tool for the treatment of different human diseases based on altered gene-expression. Despite promising data from many pre-clinical studies, concrete hurdles still need to be overcome to bring therapeutic siRNAs in clinic. The design of stimuli-sensitive nanopreparations for gene therapy is a lively area of the current research. Compared to conventional systems for siRNA delivery, this type of platform can respond to local stimuli that are characteristics of the pathological area of interest, allowing the release of nucleic acids at the desired site. Acidic pH, de-regulated levels of enzymes, altered redox potential and magnetic field are examples of stimuli exploit to design stimuli-sensitive nanoparticles. In this review, we discuss on recent stimulisensitive strategies for siRNA delivery and we highlight on the potential of combining multiple stimuli-sensitive strategies in the same nano-platform for a better therapeutic outcome. PMID- 26486145 TI - Nanoplatforms for Delivery of siRNA to the Eye. AB - Drug delivery to the eye is challenging for formulation scientists due to physiological barriers that separate the eye from the rest of the body. A variety of ocular disorders demand the development of optimal drug delivery systems for the administration of drugs and therapeutic agents that can overcome barriers that restrict drug bioavailability. SiRNA inhibits the expression of target genes and has immense potential as a biological tool for the therapeutic inhibition of disease causing genes; however, delivery of siRNA to ocular tissue is a challenge. Recent literature suggests that nanoplatforms show great promise in enhancing ophthalmic drug delivery. A drug delivery system involving nanoparticles and siRNA could surpass problems faced in ocular delivery with improved biodistribution and lower toxicity. This review covers recent research in the area of nanocarrier siRNA drug delivery for various ocular disorders. PMID- 26486146 TI - Brain Targeting of siRNA via Intranasal Pathway. AB - Brain diseases are the most serious health problems; represent a significant and worldwide public health problem. Small interfering RNAs (siRNAs) can initiate specific silencing of genes and are potential therapeutic agents for many genetically influenced diseases including brain disease. However, on systemic administration the blood-brain barrier (BBB) poses most significant obstacle for the therapeutic siRNAs delivery to the brain. Therefore, the development of successful approaches to enhance siRNA delivery to the brain is of immense interest in clinical and pharmaceutical research. At present, intranasal delivery approach serves as an effective mode of direct delivery of siRNAs to brain by bypassing BBB. In this review, we describe the principles of RNA interference (RNAi) machinery; challenges associated with siRNAs in therapeutics brain targeting and summarize the recent progress made in the use of vector based siRNA technology. Further, it is anticipated that intranasal delivery approach will have a very important role to play in the future for the translation of siRNAs therapeutics from bench to bedside for different brain diseases. PMID- 26486147 TI - siRNA Therapy, Challenges and Underlying Perspectives of Dendrimer as Delivery Vector. AB - siRNA technology presents a helpful means of gene silencing in mammalian cells. Advancement in the field includes enhanced attentiveness in the characterization of target and off-target effects employing suitable controls and gene expression microarrays. These will permit expansion in the measurement of single and multiple target combinations and also permit comprehensive efforts to understand mammalian cell processes. Another fact is that the delivery of siRNA requires the creation of a nanoparticulate vector with controlled structural geometry and surface modalities inside the targeted cells. On the other hand, dendrimers represent the class of carrier system where massive control over size, shape and physicochemical properties makes this delivery vector exceptional and favorable in genetic transfection applications. The siRNA therapeutics may be incorporated inside the geometry of the density controlled dendrimers with the option of engineering the structure to the specific needs of the genetic material and its indication. The existing reports on the siRNA carrying and deliverance potential of dendrimers clearly suggest the significance of this novel class of polymeric architecture and certainly elevate the futuristic use of this highly branched vector as genetic material delivery system. PMID- 26486148 TI - Image-Guided Nanoparticle-Based siRNA Delivery for Cancer Therapy. AB - With the discovery of RNA interference technology, small-interfering RNA (siRNA) has emerged as new powerful tool for gene therapy because of its high targeting specificity and selectivity. However, one of the limitations to successful gene therapy is the inability to monitor delivery of genes and therapeutic responses at the targeted site. Hence, a combinatorial approach of gene therapy with molecular imaging has been crucial in optimizing gene therapy. Recent advances in nanotechnology have made tremendous efforts to develop multifunctional nanoparticles that contain imaging and therapeutic agents together for image guided therapy. The nanoparticles serve as contrast agents in imaging for disease detection with simultaneous delivery of therapeutics to cure the diseases. The therapy also helps to monitor the drug accumulation and assimilation in the body, thereby facilitating the evaluation of treatment effects. Here, we present an overview of polymer and lipid-based carriers for siRNA delivery, along with imaging agents as image guided therapy, in the treatment of breast, lung, liver, ovarian, cervical, and prostate cancers. PMID- 26486149 TI - Development and Validation of Stability-Indicating Method for the Simultaneous Determination of Ketoconazole and Beauvericin in Pharmaceutical Tablets. AB - In this work, a stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated for the simultaneous analysis of ketoconazole (KCZ) and beauvericin (BEA) as well as their degradation products in the combination tablets. KCZ is a synthetic broad-spectrum antifungal agent with the risk of hepatoxicity. However, it was found that the combined use of KCZ and BEA in their low dose had not only maintained the antifungal activity of KCZ but also significantly reduced the liver toxicity. The method development was started from forced degradation studies including acidic, basic, oxidative, thermal and photolytic degradations in the solution mixtures of KCZ and BEA. The forced degradation study results indicate that hydrolysis and oxidation were the major degradation pathways for KCZ while BEA mainly decomposed under basic hydrolytic condition. The newly developed HPLC method was validated according to the International Conference on Harmonization (ICH) guidelines with respect to specificity, linearity, precision, accuracy, limits of detection and quantification and robustness. The method validation results indicate that the new HPLC method could be successfully applied in the simultaneous detection and quantitation of KCZ and BEA and their degradation products. For example, the accuracy and the precision of the method were determined by a recovery study at 80, 100 and 120% of the tablet dosage levels. The recovery was found to be 99.6 100.2 for both analytes with a relative standard deviation of no more than 1.2% (n = 5) at any concentration level. This new method can be used for further development of various KCZ and BEA combination drug products. PMID- 26486150 TI - A new diagnostic accuracy measure and cut-point selection criterion. AB - Most diagnostic accuracy measures and criteria for selecting optimal cut-points are only applicable to diseases with binary or three stages. Currently, there exist two diagnostic measures for diseases with general k stages: the hypervolume under the manifold and the generalized Youden index. While hypervolume under the manifold cannot be used for cut-points selection, generalized Youden index is only defined upon correct classification rates. This paper proposes a new measure named maximum absolute determinant for diseases with k stages ([Formula: see text]). This comprehensive new measure utilizes all the available classification information and serves as a cut-points selection criterion as well. Both the geometric and probabilistic interpretations for the new measure are examined. Power and simulation studies are carried out to investigate its performance as a measure of diagnostic accuracy as well as cut-points selection criterion. A real data set from Alzheimer's Disease Neuroimaging Initiative is analyzed using the proposed maximum absolute determinant. PMID- 26486151 TI - Relationship between the image quality and noise-equivalent count in time-of flight positron emission tomography. AB - OBJECTIVE: The aim of this study was to investigate the relationship between the NEC and TOF-PET image quality. METHODS: The National Electrical Manufactures Association and International Electrical Commission (NEMA IEC) body phantom with a 10-mm diameter sphere was filled with an 18F-FDG solution with a 4:1 radioactivity ratio. The PET data were acquired in the three-dimensional list mode for 20 min. We created frame data ranging from 1 to 5 min acquisition time, which were then reconstructed using the baseline ordered-subsets expectation maximization (OSEM), the OSEM + point spread function (PSF) algorithm, OSEM + time-of-flight (TOF) algorithm and OSEM + PSF + TOF algorithm. The PET images were analyzed according to the noise-equivalent count (NEC), the coefficients of variance of the background (CVBG), the maximum count (CVmax) and the contrast (CVCONT). The results were compared with the recommended value according to the guidelines for the oncology FDG-PET/CT protocol. RESULTS: The NEC was higher than the recommended value at 3 min or longer acquisition time. The CVBG lower than 15% were obtained at 3 min acquisition time without TOF and at 2 min acquisition time with TOF. The CVBG of 10% or lower were obtained at 5 min or longer acquisition time without TOF and at 4 min or longer acquisition time with TOF. Both the CVmax and CVCONT lower than 10% were obtained at 3 min or longer acquisition time without TOF and at 1 min acquisition or longer with TOF. No particular relationships were observed between the frame number and degree of the variation in the image quality. The CVCONT significantly correlated with the NEC for the data reconstructed without TOF information, while there were no significant correlations between these useful metrics for the data reconstructed with TOF. CONCLUSION: This study demonstrated that the NEC is not a useful metric for the evaluation of the image quality on TOF-PET images. PMID- 26486152 TI - Percutaneous Retrieval of Permanent Inferior Vena Cava Filters. AB - PURPOSE: To evaluate the feasibility, risks, and techniques of percutaneous removal of permanent TrapEase and Simon Nitinol IVC filters. MATERIALS AND METHODS: Between August 2011 and August 2015, 12 patients (5 women, 7 men; age range, 26-75 years) underwent an attempt at percutaneous removal of permanent TrapEase (10) and Simon Nitinol (2) IVC filters due to a history of IVC filter complications or need for lifelong anticoagulation due to the filter. Medical records were reviewed for filter dwell time, presence of iliocaval deep venous thrombosis, procedural technique, and complications. RESULTS: Filter dwell times ranged from 7 days to 15 years (mean 5.1 years). Successful removal of permanent IVC filters was possible in 11 of 12 patients (91.6%). In 1 patient, a chronically thrombosed IVC filter could not be removed despite laser sheath assistance, but was successfully recanalized with the PowerWire RF guidewire. In the failed retrieval attempt, a stent was placed through the chronically thrombosed IVC filter with restoration of in-line flow. One major complication of large venous groin hematoma was encountered. CONCLUSIONS: In carefully selected patients, percutaneous removal of permanent IVC filters can be performed safely despite prolonged filter dwell times. Extraction of chronically embedded permanent IVC filters may be facilitated by jugular and femoral approaches, often with laser sheath assistance. Chronic filter thrombosis and caval scarring may increase the risk of retrieval failure. PMID- 26486153 TI - Ex Vivo Liver Experiment of Hydrochloric Acid-Infused and Saline-Infused Monopolar Radiofrequency Ablation: Better Outcomes in Temperature, Energy, and Coagulation. AB - OBJECTIVE: To compare temperature, energy, and coagulation between hydrochloric acid-infused radiofrequency ablation (HAIRFA) and normal saline-infused radiofrequency ablation (NSIRFA) in ex vivo porcine liver model. MATERIALS AND METHODS: 30 fresh porcine livers were excised in 60 lesions, 30 with HAIRFA and the other 30 with NSIRFA. Both modalities used monopolar perfusion electrode connected to a RF generator set at 103 degrees C and 30 W. In each group, ablation time was set at 10, 20, or 30 min (10 lesions from each group at each time). We compared tissue temperatures (at 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 cm away from the electrode tip), average power, deposited energy, deposited energy per coagulation volume (DEV), coagulation diameters, coagulative volume, and spherical ratio between the two groups. RESULTS: Temperature-time curves showed that HAIRFA provided progressively greater heating than that of NSIRFA. At 30 min, mean average power, deposited energy, coagulation volumes (113.67 vs. 12.28 cm(3)) and diameters, and increasing in tissue temperature were much greater with HAIRFA (P < 0.001 for all), except DEV was lower (456 vs. 1396 J/cm(3), P < 0.001). The spherical ratio was closer to 1 with HAIRFA (1.23 vs. 1.46). Coagulation diameters, volume, and average power of HAIRFA increased significantly with longer ablation times. While with NSIRFA, these characteristics were stable till later 20 min, except the power decreased with longer ablation times. CONCLUSIONS: HAIRFA creates much larger and more spherical lesions by increasing overall energy deposition, modulating thermal conductivity, and transferring heat during ablation. PMID- 26486154 TI - Guide Needle-Assisted Ablation of Subcapsular Hepatoma with Colonic Interposition (Chilaiditi's Sign). PMID- 26486155 TI - Usefulness of Cone-Beam Computed Tomography and Automatic Vessel Detection Software in Emergency Transarterial Embolization. AB - BACKGROUND: This study was designed to evaluate the utility of dual phase cone beam computed tomography (DP-CBCT) and automatic vessel detection (AVD) software to guide transarterial embolization (TAE) of angiographically challenging arterial bleedings in emergency settings. METHODS: Twenty patients with an arterial bleeding at computed tomography angiography and an inconclusive identification of the bleeding vessel at the initial 2D angiographic series were included. Accuracy of DP-CBCT and AVD software were defined as the ability to detect the bleeding site and the culprit arterial bleeder, respectively. Technical success was defined as the correct positioning of the microcatheter using AVD software. Clinical success was defined as the successful embolization. Total volume of iodinated contrast medium and overall procedure time were registered. RESULTS: The bleeding site was not detected by initial angiogram in 20% of cases, while impossibility to identify the bleeding vessel was the reason for inclusion in the remaining cases. The bleeding site was detected by DP-CBCT in 19 of 20 (95%) patients; in one case CBCT-CT fusion was required. AVD software identified the culprit arterial branch in 18 of 20 (90%) cases. In two cases, vessel tracking required manual marking of the candidate arterial bleeder. Technical success was 95%. Successful embolization was achieved in all patients. Mean contrast volume injected for each patient was 77.5 ml, and mean overall procedural time was 50 min. CONCLUSIONS: C-arm CBCT and AVD software during TAE of angiographically challenging arterial bleedings is feasible and may facilitate successful embolization. Staff training in CBCT imaging and software manipulation is necessary. PMID- 26486156 TI - CT-Guided Superior Vena Cava Puncture: A Solution to Re-Establishing Access in Haemodialysis-Related Central Venous Occlusion Refractory to Conventional Endovascular Techniques. AB - PURPOSE: The purpose of this technical note is to demonstrate the novel use of CT guided superior vena cava (SVC) puncture and subsequent tunnelled haemodialysis (HD) line placement in end-stage renal failure (ESRF) patients with central venous obstruction refractory to conventional percutaneous venoplasty (PTV) and wire transgression, thereby allowing resumption of HD. METHODS: Three successive ESRF patients underwent CT-guided SVC puncture with subsequent tract recanalisation. Ultrasound-guided puncture of the right internal jugular vein was performed, the needle advanced to the patent SVC under CT guidance, with subsequent insertion of a stabilisation guidewire. Following appropriate tract angioplasty, twin-tunnelled HD catheters were inserted and HD resumed. RESULTS: No immediate complications were identified. There was resumption of HD in all three patients with a 100% success rate. One patient's HD catheter remained in use for 2 years post-procedure, and another remains functional 1 year to the present day. One patient died 2 weeks after the procedure due to pancreatitis related abdominal sepsis unrelated to the Tesio lines. CONCLUSION: CT-guided SVC puncture and tunnelled HD line insertion in HD-related central venous occlusion (CVO) refractory to conventional recanalisation options can be performed safely, requires no extra equipment and lies within the skill set and resources of most interventional radiology departments involved in the management of HD patients. PMID- 26486157 TI - Unilateral vocal cord palsy and dysphagia: an unusual presentation of cerebellopontine angle meningioma. AB - Cerebellopontine angle (CPA) tumours are the most common neoplasms in the posterior fossa, accounting for 5-10% of intracranial tumours. Most CPA tumours are benign, with most being vestibular schwannomas. Meningiomas arising from the jugular foramen are among the rarest of all with very few being described in the literature. Treatment options vary considerably as experience with these tumours is limited. One option is a skull base approach, but this depends on size, location and ability to preserve lower cranial nerve function. This can be extremely challenging and is accompanied by high mortality risk; therefore, a more conservative option must be considered. This case report highlights the difficulty in management of patients with jugular fossa meningiomas, including appropriate investigations, analysis of surgical versus conservative treatment and associated complications. Furthermore, we elaborate the decision-making process pertaining to the tailoring of the surgical route used for the resection of jugular foramen meningiomas. (Jugular Foramen Meningioma, cerebellopontine angle). PMID- 26486158 TI - Doing the right thing. PMID- 26486159 TI - Editorial: on artemisinin, avermectins and Nobel Prizes. PMID- 26486160 TI - Acute aerobic exercise increases exogenously infused bone marrow cell retention in the heart. AB - Stem cell therapy for myocardial infarction (MI) has been shown to improve cardiac function and reduce infarct size. Exercise training, in the form of cardiac rehabilitation, is an essential part of patient care post-MI. Hence, we tested the effects of acute and chronic aerobic exercise on stem cell retention and cardiac remodeling post-MI. Small epicardial MI's were induced in 12-month old C57BL/6 mice via cryoinjury. Two weeks post-MI, vehicle infusion (N = 4) or GFP(+) bone marrow-derived cells (BMC) were injected (tail vein I.V.) immediately after acute exercise (N = 14) or sedentary conditions (N = 14). A subset of mice continued a 5-week intervention of chronic treadmill exercise (10-13 m/min; 45 min/day; 4 days/week; N = 7) or remained sedentary (N = 6). Exercise tolerance was assessed using a graded exercise test, and cardiac function was assessed with echocardiography. Acute exercise increased GFP(+) BMC retention in the infarcted zone of the heart by 30% versus sedentary (P < 0.05). This was not associated with alterations in myocardial function or gene expression of key cell adhesion molecules. Animals treated with chronic exercise increased exercise capacity (P < 0.05) and cardiac mass (P < 0.05) without change in left ventricular ejection fraction (LVEF), infarct size, or regional wall thickness (P = NS) compared with sedentary. While BMC's alone did not affect exercise capacity, they increased LVEF (P < 0.05) and Ki67(+) nuclei number in the border zone of the heart (P < 0.05), which was potentiated with chronic exercise training (P < 0.05). We conclude that acute exercise increases BMC retention in infarcted hearts and chronic training increases exogenous BMC-mediated effects on stimulating the cardiomyocyte cell cycle. These preclinical results suggest that exercise may help to optimize stem cell therapeutics following MI. PMID- 26486161 TI - The role of IL-6 in the physiologic versus hypertensive blood pressure actions of angiotensin II. AB - Angiotensin II (AngII) is a critical physiologic regulator of volume homeostasis and mean arterial pressure (MAP), yet it also is known to induce immune mechanisms that contribute to hypertension. This study determined the role of interleukin-6 (IL-6) in the physiologic effect of AngII to maintain normal MAP during low-salt (LS) intake, and whether hypertension induced by plasma AngII concentrations measured during LS diet required IL-6. IL-6 knockout (KO) and wild type (WT) mice were placed on LS diet for 7 days, and MAP was measured 19 h/day with telemetry. MAP was not affected by LS in either group, averaging 101 +/- 4 and 100 +/- 4 mmHg in WT and KO mice, respectively, over the last 3 days. Seven days of ACEI decreased MAP ~25 mmHg in both groups. In other KO and WT mice, AngII was infused at 200 ng/kg per minute to approximate plasma AngII levels during LS. Surgical reduction of kidney mass and high-salt diet were used to amplify the blood pressure effect. The increase in MAP after 7 days was not different, averaging 20 +/- 5 and 22 +/- 6 mmHg in WT and KO mice, respectively. Janus Kinase 2 (JAK2)/signal transducer of activated transcription (STAT3) phosphorylation were not affected by LS, but were increased by AngII infusion at 200 and 800 ng/kg per minute. These data suggest that physiologic levels of AngII do not activate or require IL-6 to affect blood pressure significantly, whether AngII is maintaining blood pressure on LS diet or causing blood pressure to increase. JAK2/STAT3 activation, however, is tightly associated with AngII hypertension, even when caused by physiologic levels of AngII. PMID- 26486162 TI - Analysis of Cervical Sagittal Balance Parameters in MRIs of Patients with Disc Degenerative Disease. AB - BACKGROUND: The aim of this study was to explore the correlations between the different parameters of the cervical sagittal balance in magnetic resonance images (MRI) and evaluate the criteria for their clinical application in disc degenerative diseases. MATERIAL AND METHODS: We conducted a retrospective review of the MRIs of 125 adult outpatients with disc-degenerative diseases of the cervical spine; the images were obtained between May and July 2014 at our institute. The control group comprised 50 volunteers whose MRIs were also obtained. The parameters measured in the MRIs were: neck tilt (NT), T1 slope (T1S), thoracic inlet angle (TIA), and Cobb's angle (C2-7). The correlation between the various parameters was analyzed using the Pearson correlation coefficient. RESULTS: The outpatients group showed moderate correlation between TIA and T1S, a significant correlation between TIA and NT, a weak correlation between T1S and Cobb's angle, and a weakly negative correlation between T1S and NT. Further, the TIA showed no significant difference between the outpatient group and the control group, as per the sample t test. CONCLUSIONS: Our findings indicate that TIA, T1S, and NT could be used as indices for the evaluation of cervical sagittal balance and that the TIA could be used as a reference to assess the cervical compensation. Restoration of the NT and T1S should be considered as a goal of surgical treatment during the preoperative planning in patients with disc-degenerative diseases. PMID- 26486163 TI - Cell Type-Specific and Inducible PTEN Gene Silencing by a Tetracycline Transcriptional Activator-Regulated Short Hairpin RNA. AB - Inducible and reversible gene silencing in desired types of cells is instrumental for deciphering gene functions using cultured cells or in vivo models. However, efficient conditional gene knockdown systems remain to be established. Here, we report the generation of an inducible expression system for short hairpin RNA (shRNA) targeted to PTEN, a well-documented dual-specificity phosphatase involved in tumor suppression and ontogenesis. Upon induction by doxycycline (DOX), the reverse tetracycline transcriptional activator (rtTA) switched on the concomitant expression of GFP and a miR-30 precursor, the subsequent processing of which released the embedded PTEN-targeted shRNA. The efficacy and reversibility of PTEN knockdown by this construct was validated in normal and neoplastic cells, in which PTEN deficiency resulted in accelerated cell proliferation, suppressed apoptosis, and increased invasiveness. Transgenic mice harboring the conditional shRNA-expression cassette were obtained; GFP expression and concurrent PTEN silencing were observed upon ectopic expression of rtTA and induction with Dox. Therefore, this study provides novel tools for the precise dissection of PTEN functions and the generation of PTEN loss of function models in specific subsets of cells during carcinogenesis and ontogenesis. PMID- 26486164 TI - Repeated Superovulation via PMSG/hCG Administration Induces 2-Cys Peroxiredoxins Expression and Overoxidation in the Reproductive Tracts of Female Mice. AB - Superovulation induced by exogenous gonadotropin treatment (PMSG/hCG) increases the number of available oocytes in humans and animals. However, Superovulatory PMSG/hCG treatment is known to affect maternal environment, and these effects may result from PMSG/hCG treatment-induced oxidative stress. 2-Cys peroxiredoxins (2 Cys Prxs) act as antioxidant enzymes that protect cells from oxidative stress induced by various exogenous stimuli. Therefore, the objective of this study was to test the hypothesis that repeated PMSG/hCG treatment induces 2-Cys Prx expression and overoxidation in the reproductive tracts of female mice. Immunohistochemistry and western blotting analyses further demonstrated that, after PMSG/hCG treatment, the protein expression levels of 2-Cys Prxs increased most significantly in the ovaries, while that of Prx1 was most affected by PMSG/hCG stimulation in all tissues of the female reproductive tract. Repeated PMSG/hCG treatment eventually leads to 2-Cys Prxs overoxidation in all reproductive organs of female mice, and the abundance of the 2-Cys Prxs-SO2/3 proteins reported here supports the hypothesis that repeated superovulation induces strong oxidative stress and damage to the female reproductive tract. Our data suggest that excessive oxidative stress caused by repeated PMSG/hCG stimulation increases 2-Cys Prxs expression and overoxidation in the female reproductive organs. Intracellular 2-Cys Prx therefore plays an important role in maintaining the reproductive organ environment of female mice upon exogenous gonadotropin treatment. PMID- 26486165 TI - Ifosfamide-loaded poly (lactic-co-glycolic acid) PLGA-dextran polymeric nanoparticles to improve the antitumor efficacy in Osteosarcoma. AB - BACKGROUND: Osteosarcoma is a typical bone cancer that primarily affects adolescents. The therapeutic activity of drugs is limited by their severe drug related toxicities, therefore, a therapeutic approach which is less toxic and highly effective in tumor is of utmost importance. METHOD: In this study, ifosfamide-loaded poly (lactic-co-glycolic acid) (PLGA)-dextran polymeric nanoparticles (PD/IFS) was developed and studied its anticancer efficacy against multiple osteosarcoma cancer cells. The drug-loaded nanoparticle was characterized for physical and biological characterizations. RESULTS: The formulated PD/IFS showed a high drug loading capacity and displayed a pH sensitive release pattern, with a sustained release profile of the IFS. PD/IFS nanoparticles exhibited remarkable in vitro anticancer activity comparable to that of free IFS solution in a concentration dependent manner in MG63 and Saos-2 cancer cells. PLGA-dextran by itself did not affect cell viability of cancer cells indicating its excellent biocompatibility. The formulation exhibited significantly higher PARP and caspase-3/7 expression in both the cancer cells. CONCLUSION: Our study successfully demonstrated that nanoparticulate encapsulation of antitumor agent will increase the therapeutic efficacy and exhibit a greater induction of apoptosis and cell death. PMID- 26486168 TI - Population-Based Study of Incidence of Acute Abdominal Aortic Aneurysms With Projected Impact of Screening Strategy. PMID- 26486166 TI - Effect of Switching From Statin Monotherapy to Ezetimibe/Simvastatin Combination Therapy Compared With Other Intensified Lipid-Lowering Strategies on Lipoprotein Subclasses in Diabetic Patients With Symptomatic Cardiovascular Disease. AB - BACKGROUND: Patients with diabetes mellitus and cardiovascular disease may not achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on statin monotherapy, attributed partly to atherogenic dyslipidemia. More intensive LDL-C lowering therapy can be considered for these patients. A previous randomized, controlled study demonstrated greater LDL-C lowering in diabetic patients with symptomatic cardiovascular disease who switched from simvastatin 20 mg (S20) or atorvastatin 10 mg (A10) to combination ezetimibe/simvastatin 10/20 mg (ES10/20) therapy, compared with statin dose-doubling (to S40 or A20) or switching to rosuvastatin 10 mg (R10). The effect of these regimens on novel biomarkers of atherogenic dyslipidemia (low- and high-density lipoprotein particle number and lipoprotein-associated phospholipase A2 [Lp-PLA2]) was assessed. METHODS AND RESULTS: Treatment effects on low- and high-density lipoprotein particle number (by NMR) and Lp-PLA2 (by ELISA) were evaluated using plasma samples available from 358 subjects in the study. Switching to ES10/20 reduced low-density lipoprotein-particle number numerically more than did statin dose-doubling and was comparable with R10 (-133.3, -94.4, and -56.3 nmol/L, respectively; P>0.05). Increases in high-density lipoprotein particle number were significantly greater with switches to ES10/20 versus statin dose-doubling (1.5 and -0.5 MUmol/L; P<0.05) and comparable with R10 (0.7 MUmol/L; P>0.05). Percentages of patients attaining low-density lipoprotein particle number levels <990 nmol/L were 62.4% for ES10/20, 54.1% for statin dose-doubling, and 57.0% for R10. Switching to ES10/20 reduced Lp-PLA2 activity significantly more than did statin dose-doubling (-28.0 versus -3.8 nmol/min per mL, P<0.05) and was comparable with R10 (-28.0 versus -18.6 nmol/min per mL; P>0.05); effects on Lp-PLA2 concentration were modest. CONCLUSIONS: In diabetic patients with dyslipidemia, switching from statins to combination ES10/20 therapy generally improved lipoprotein subclass profile and Lp-PLA2 activity more than did statin dose-doubling and was comparable with R10, consistent with its lipid effects. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00862251. PMID- 26486167 TI - Choice and Selection of Treatment Modalities for Cardiac Patients: An Interventional Cardiology Perspective. PMID- 26486169 TI - Complete mitochondrial genome of banjofish (Banjos banjos): genome characterization and phylogenetic analysis. AB - The banjofish (Banjos banjos) is the only species in the monotypic genus Banjos and in the family Banjosidae. To understand the phylogenetic relationship of banjofish in teleost, we firstly determined the complete mitochondrial genome of banjofish. The entire mitochondrial genome of banjofish is 16 485 bp in length, including 13 protein-coding genes and 2 ribosomal RNA genes (rRNA), 22 transfer RNA genes (tRNA) and a control region (CR). The overall base composition is T, 26.2%; C, 29.2%; A, 28.6% and G, 16.0%. The central conserved sequence blocks (CSB) were identified and the core sequence (ACATATATGT) of terminal-associated sequences was recognized in the control region. The gene arrangement, base composition, and tRNA structures of the complete mitochondrial genome of banjofish is consistent with those of other teleost. The complete mitochondrial genome of banjofish was used to construct phylogenetic tree, which shows that banjofish is clustered with the fishes of the family Histiopteridae. We expect that the availability of mitochondrial genome of banjofish will facilitate the further investigations of the taxonomic resolution, biogeography and molecular systematic. PMID- 26486170 TI - Protective effects of beta glucan in brain tissues of post-menopausal rats: a histochemical and ultra-structural study. AB - Decline of estrogen during menopause has been associated with numerous significant changes that have been linked to many pathophysiological complications. In addition, ovarian hormone deficiency increases the production of reactive oxygen radicals which could result in oxidative stress and cell damage. While estrogen therapy is often considered to overcome the behavioral and physiological shortcomings, antioxidants are gaining popularity for their beneficial property. For this purpose, in the present study, utilizing the antioxidant properties of beta glucan has been examined in treatment of menopause induced oxidative stress in cerebral neurons. Four groups of female Wistar rats were used: control, ovariectomy, ovariectomy + estrogen treated and ovariectomy + beta glucan treated. We observed a significant increase in neural degeneration in ovariectomized rats as compared to controls. Moreover, increased oxidative stress in the brains of the ovariectomized rats has been detected by performing immunohistochemical analysis. A large number of immuno-positive cerebral neurons have been observed in ovariectomy group rat brains. Interestingly, providing beta glucan treatment to ovariectomized rats reduced the number of degenerated neurons. Our study is the first to examine light and electron microscopic examination and immunohistochemical and stereological analysis of estrogen depletion in rats and to test protective role of beta glucan in the experimental study. PMID- 26486171 TI - Voyaging in Strange Seas: The Great Revolution in Science. PMID- 26486172 TI - Essential roles for Cavbeta2 and Cav1 channels in thymocyte development and T cell homeostasis. AB - Calcium ions (Ca(2+)) are important in numerous signal transduction processes, including the development and differentiation of T cells in the thymus. We report that thymocytes have multiple types of pore-forming alpha subunits and regulatory beta subunits that constitute voltage-gated Ca(2+) (Cav) channels. In mice, T cell-specific deletion of the gene encoding the beta2 regulatory subunit of Cav channels (Cacnb2) reduced the abundances of the channels Cav1.2 and Cav1.3 (both of which contain pore-forming alpha1 subunits) and impaired T cell development, which led to a substantial decrease in the numbers of thymocytes and peripheral T cells. Similar to the effect of Cacnb2 deficiency, pharmacological blockade of pore-forming Cav1alpha subunits reduced the sustained Ca(2+) influx in thymocytes upon stimulation of the T cell receptor, decreased the abundance of the transcription factor NFATc3, inhibited the proliferation of thymocytes in vitro, and led to lymphopenia in mice. Together, our data suggest that Cav1 channels are conduits for the sustained Ca(2+) influx that is required for the development of T cells. PMID- 26486173 TI - CD4+ T cell-dependent and CD4+ T cell-independent cytokine-chemokine network changes in the immune responses of HIV-infected individuals. AB - A vital defect in the immune systems of HIV-infected individuals is the loss of CD4(+) T cells, resulting in impaired immune responses. We hypothesized that there were CD4(+) T cell-dependent and CD4(+) T cell-independent alterations in the immune responses of HIV-1(+) individuals. To test this, we analyzed the secretion of cytokines and chemokines from stimulated peripheral blood mononuclear cell (PBMC) populations from HIV(+) donors, healthy donors, and healthy donors with CD4(+) T cells experimentally depleted. Multivariate analyses of 16 cytokines and chemokines at 6 and 72 hours after three stimuli (antibody coated beads to stimulate T cells and R848 or lipopolysaccharide to stimulate innate immune cells) enabled integrative analysis of secreted profiles. Two major effects in HIV(+) PBMCs were not reproduced upon depletion of CD4(+) T cells in healthy PBMCs: (i) HIV(+) PBMCs maintained T cell-associated secreted profiles after T cell stimulation; (ii) HIV(+) PBMCs showed impaired interferon-gamma (IFN gamma) secretion early after innate stimulation. These changes arose from hyperactive T cells and debilitated natural killer (NK) cell, respectively. Modeling and experiments showed that early IFN-gamma secretion predicted later differences in secreted profiles in vitro. This effect was recapitulated in healthy PBMCs by blocking the IFN-gamma receptor. Thus, we identified a critical deficiency in NK cell responses of HIV-infected individuals, independent of CD4(+) T cell depletion, which directs secreted profiles. Our findings illustrate a broad approach for identifying key disease-associated nodes in a multicellular, multivariate signaling network. PMID- 26486175 TI - Matters of context guide future research in TGFbeta superfamily signaling. AB - The highly conserved wiring of the SMAD-dependent transforming growth factor beta (TGFbeta) superfamily signaling pathway has been mapped over the last 20 years after molecular discovery of its component parts. Numerous alternative TGFbeta activated signaling pathways that elicit SMAD-independent biological responses also exist. However, the molecular mechanisms responsible for the renowned context dependency of TGFbeta signaling output remains an active and often confounding area of research, providing a prototype relevant to regulation of other signaling pathways. Highlighting discoveries presented at the 9th FASEB meeting, The TGFbeta Superfamily: Signaling in Development and Disease (July 12 17th 2015 in Snowmass, Colorado), this Review outlines research into the rich contextual nature of TGFbeta signaling output and offers clues for therapeutic advances. PMID- 26486176 TI - Functional p-Type, Polymerized Organic Electrode Interlayer in CH3NH3PbI3 Perovskite/Fullerene Planar Heterojunction Hybrid Solar Cells. AB - Thermal curing of the styrene-functionalized 9,9-diarylfluorene-based triaryldiamine monomer (VB-DAAF) forms an ideal p-type organic electrode interlayer capable of resisting solvation of the polar precursor solution in fabricating methylammonium lead iodide (CH3NH3PbI3) perovskite/fullerene (C60) planar heterojunction hybrid solar cells. The polymerized VB-DAAF film exhibits a good energy level alignment with the valence-band-edge level of the CH3NH3PbI3 perovskite to facilitate the transport of holes. The large energy barrier to the conduction-band-edge level of the CH3NH3PbI3 perovskite effectively blocks electrons from reaching the positive electrode and reduces the photon energy loss due to recombination. The best-performing cell with the configuration of glass/indium-tin oxide/polymerized VB-DAAF/CH3NH3PbI3 perovskite/C60/bathocuproine/aluminum is free of a poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) layer to achieve an open-circuit voltage (VOC) = 1.02 V, a short-circuit current (JSC) = 18.92 mA/cm(2), and a fill factor (FF) = 0.78, corresponding to a power conversion efficiency (PCE) of 15.17% under standard 1 sun AM 1.5G simulated solar irradiation. The performance is much superior to the device applying the PEDOT: PSS interlayer with photovoltaic parameters of VOC = 0.85 V, JSC = 16.37 mA/cm(2), and FF = 0.74, corresponding to a PCE of 10.27%. Additionally, we had applied a UV-assisted process to polymerize the VB-DAAF film at relatively lower temperature and fabricate decent perovskite-based solar cells on the flexible substrate for real applications. PMID- 26486174 TI - Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice. AB - Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4(SMKO) mice with an SMC-specific deletion of the Fbln4 gene, which encodes the vascular ECM component fibulin-4, develop ascending aortic aneurysms that have increased abundance of angiotensin converting enzyme (ACE); inhibiting angiotensin II signaling within the first month of life prevents aneurysm development. We used comparative proteomics analysis of Fbln4(SMKO) aortas from postnatal day (P) 1 to P30 mice to identify key molecules involved in aneurysm initiation and expansion. At P14, the actin depolymerizing factor cofilin was dephosphorylated and thus activated, and at P7, the abundance of slingshot-1 (SSH1) phosphatase, an activator of cofilin, was increased, leading to actin cytoskeletal remodeling. Also, by P7, biomechanical changes and underdeveloped elastic lamina-SMC connections were evident, and the abundance of early growth response 1 (Egr1), a mechanosensitive transcription factor that stimulates ACE expression, was increased, which was before the increases in ACE abundance and cofilin activation. Postnatal deletion of Fbln4 in SMCs at P7 prevented cofilin activation and aneurysm formation, suggesting that these processes required disruption of elastic lamina-SMC connections. Phosphoinositide 3-kinase (PI3K) is involved in the angiotensin II-mediated activation of SSH1, and administration of PI3K inhibitors from P7 to P30 decreased SSH1 abundance and prevented aneurysms. These results suggest that aneurysm formation arises from abnormal mechanosensing of SMCs resulting from the loss of elastic lamina-SMC connections and from increased SSH1 and cofilin activity, which may be potential therapeutic targets for treating ascending aortic aneurysms. PMID- 26486177 TI - Three Gaseous Neurotransmitters, Nitric oxide, Carbon Monoxide, and Hydrogen Sulfide, Are Involved in the Neurogenic Relaxation Responses of the Porcine Internal Anal Sphincter. AB - BACKGROUND/AIMS: The internal anal sphincter (IAS) plays an important role in maintaining continence and a number of neurotransmitters are known to regulate IAS tone. The aim of this study was to determine the relative importance of the neurotransmitters involved in the relaxant and contractile responses of the porcine IAS. METHODS: Responses of isolated strips of IAS to electrical field stimulation (EFS) were obtained in the absence and presence of inhibitors of neurotransmitter systems. RESULTS: Contractile responses of the sphincter to EFS were unaffected by the muscarinic receptor antagonist, atropine (1 MUM), but were almost completely abolished by the adrenergic neuron blocker guanethidine (10 MUM). Contractile responses were also reduced (by 45% at 5 Hz, P < 0.01) following desensitisation of purinergic receptors with alpha,beta-methylene-ATP (10 MUM). In the presence of guanethidine, atropine, and alpha,beta-methylene ATP, the remaining relaxatory responses to EFS were examined. These responses were not altered by the cyclooxygenase inhibitor, indomethacin (5 MUM), the vasoactive intestinal polypeptide receptor antagonist, [D-p-Cl-Phe(6),Leu(17)] vasoactive intestinal peptide (PheLeu-VIP; 100 nM), or the purinoceptor antagonists, 8-phenyltheophyline (P1 receptors) or suramin (P2 receptors). However, relaxation responses were reduced by Nomega-nitro-L-arginine (L-NNA; 100 MUM), an inhibitor of nitric oxide synthesis (40-50% reduction), zinc protoprophyrin IX (10 MUM), an inhibitor of carbon monoxide synthesis (20-40% reduction), and also propargylglycine (30 MUM) and aminooxyacetic acid (30 MUM), inhibitors of hydrogen sulphide synthesis (15-20% reduction). CONCLUSIONS: Stimulation of IAS efferent nerves releases excitatory and inhibitory neurotransmitters: noradrenaline is the predominant contractile transmitter with a smaller component from ATP, whilst 3 gases mediate relaxation responses to EFS, with the combined contributions being nitric oxide > carbon monoxide > hydrogen sulfide. PMID- 26486178 TI - Response to Comment on "Intimate Coupling of Photocatalysis and Biodegradation for Degrading Phenol Using Different Light Types: Visible Light vs UV Light". PMID- 26486179 TI - Identification of differentially expressed microRNAs between Bacillus thuringiensis Cry1Ab-resistant and -susceptible strains of Ostrinia furnacalis. AB - The Asian corn borer (ACB), Ostrinia furnacalis (Guenee), can develop strong resistance to Cry1Ab, the most widely commercialized Cry toxin for Bt maize worldwide. It is essential to understand the mechanism of resistance for management of this species, but information on the post-transcriptional regulation of Bt resistance in this target insect is limited. In the present study, RNA was extracted from the ACB in various larval stages (1-5 instar) from Cry1Ab-sensitive (ACB-BtS) and -resistant (ACB-AbR) strains, each of which included two biological replicates. Using Illumina sequencing, a total of 23,809,890 high-quality reads were collected from the four ACB libraries. The numbers of known microRNAs (miRNAs) were 302 and 395 for ACB-BtS and 268 and 287 for ACB-AbR. Using Mireap software, we identified 32 and 16 potential novel miRNAs for ACB-BtS and 18 and 22 for ACB-AbR. Among them, 21 known and 1 novel miRNAs had significantly different expression between ACB-BtS and ACB-AbR. Several miRNAs were observed to target potential Bt receptor genes, such as aminopeptidase N and cadherin-like protein. The glycosylphosphatidylinositol anchor biosynthetic process and ABC transporters pathway were identified through Gene Ontology and KEGG pathway analysis of target genes of the differentially expressed miRNAs. PMID- 26486180 TI - A single design strategy for dual sensitive pH probe with a suitable range to map pH in living cells. AB - Due to the lack of a proper imaging approach, a veracious pH map of normal and abnormal cell is still rare. In this work, we presented a rhodamine salicylaldehyde combination (Rh-SA2) as a novel pH probe, which has dual sensitive units for both acidic and basic environment. This dual sensitive probe acts like a chameleon in living cells and offers the doubling guarantees for endocellular pH mapping. Moreover, a quantitative measurement of cellular pH changes was allowed and the endocellular pH values under drug-associated stimuli were also investigated. PMID- 26486181 TI - Genetically-reduced serum ACE activity might be a causal risk factor for obstructive sleep apnea syndrome: A meta-analysis. AB - We meta-analytically summarized the associations of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with ACE activity and obstructive sleep apnea syndrome (OSAS) to see whether ACE activity is causally associated with OSAS. Literature search and data abstraction were done in duplicate. Sixteen articles including 2060 OSAS patients and 1878 controls were summarized. Overall, no significance was observed for the association of I/D polymorphism with OSAS, whereas carriers of II genotype (weighted mean difference or WMD, 95% confidence interval or CI, P: -11.976, -17.168 to -6.783, <0.001) or I allele (-9.842, -14.766 to -4.918, <0.001) had a lower level of serum ACE activity compared with DD genotype carriers, respectively. In subgroup analyses, carriers of II genotype were 3.806 times more likely to develop OSAS (95% CI, P: 1.865 to 7.765, <0.001) in OSAS patients with hypertension, without heterogeneity. Mendelian randomization analysis indicated there was 37.4% (95% CI: 1.115 to 3.142) and 32.4% (1.106 to 2.845) increased risk of OSAS by a reduction of 1 U/L in ACE activity for the II genotype and I allele carriers versus DD genotype carriers, respectively. There was no observable publication bias. Collectively, genetically-reduced serum ACE activity might be a causal risk factor for OSAS. PMID- 26486182 TI - Reversed reactivity of anilines with alkynes in the rhodium-catalysed C-H activation/carbonylation tandem. AB - Development of multicatalytic approach consisting of two or more mechanistically distinct catalytic steps using a single-site catalyst for rapid and straightforward access of structurally complex molecules under eco-benign conditions has significance in contemporary science. We have developed herein a rhodium-catalysed C-H activation strategy which uses an unprotected anilines and an electron-deficient alkynes to C-C bonded products as a potential intermediate in contrast to the archetypical C-N bonded products with high levels of regioselectivity. This is followed by carbonylation of C-H bond activated intermediate and subsequent annulation into quinolines has been described. This rhodium-catalysed auto-tandem reaction operates under mild, environmentally benign conditions using water as the solvent and CO surrogates as the carbonyl source with the concomitant generation of hydrogen gas. The strategy may facilitate the development of new synthetic protocols for the efficient and sustainable production of chemicals in an atom-economic way from simple, abundant starting materials. PMID- 26486183 TI - Simultaneous shaping of amplitude and phase of light in the entire output plane with a phase-only hologram. AB - An iterative beam shaping algorithm is proposed to simultaneously shape the amplitude and phase of an optical beam. The proposed algorithm consists of one input plane and two completely overlapped output planes which refer to the output plane in real space. The two output planes are imposed with both amplitude and phase constraints, and the constrained areas in the two output planes are complementary. As a result, both the amplitude and phase in the entire output plane are controllable and arbitrary target complex amplitudes can be achieved with the proposed algorithm. The computing result of the proposed algorithm is a phase-only distribution which can be conveniently realized with a spatial light modulator or a fabricated diffractive optical element. Both simulations and experiments have verified the high performance of the proposed algorithm. PMID- 26486184 TI - Direct and high throughput (HT) interactions on the ribosomal surface by iRIA. AB - Ribosomes function as platforms for binding of other molecules, but technologies for studying this process are lacking. Therefore we developed iRIA (in vitro Ribosomes Interaction Assay). In approach I, Artemia salina ribosomes spotted on solid phase are used for binding picomoles of analytes; in approach II, cellular extracts allow the measurement of ribosome activity in different conditions. We apply the method to analyze several features of eIF6 binding to 60S subunits. By approach I, we show that the off-rate of eIF6 from preribosomes is slower than from mature ribosomes and that its binding to mature 60S occurs in the nM affinity range. By approach II we show that eIF6 binding sites on 60S are increased with mild eIF6 depletion and decreased in cells that are devoid of SBDS, a ribosomal factor necessary for 60S maturation and involved in Swachman Diamond syndrome. We show binding conditions to immobilized ribosomes adaptable to HT and quantify free ribosomes in cell extracts. In conclusion, we suggest that iRIA will greatly facilitate the study of interactions on the ribosomal surface. PMID- 26486185 TI - On testing neural network models. PMID- 26486186 TI - Neural networks in the future of neuroscience research. PMID- 26486187 TI - Prevalence and Timing of Screening and Diagnostic Testing for Gestational Diabetes Mellitus: A Population-Based Study in Alberta, Canada. AB - OBJECTIVE: The extent to which pregnant women are screened for gestational diabetes mellitus (GDM) at the population level is not known. We examined the rate, type, and timing of GDM screening and diagnostic testing in the province of Alberta, Canada. Geographic and temporal differences in screening rates, and maternal risk factors associated with lower likelihood of screening, were also determined. RESEARCH DESIGN AND METHODS: Our retrospective linked-database cohort study included 86,842 primiparous women with deliveries between 1 October 2008 and 31 December 2012. Multivariable logistic regression analysis was used to examine maternal factors associated with lower likelihood of GDM screening. RESULTS: Overall, 94% (n = 81,304) of women underwent some form of glycemic assessment in the 270 days prior to delivery. The majority (91%) received a 50-g glucose screen (GDS). Women not screened were younger and more likely to smoke and had lower maternal weight and median household income. When a diagnostic 75-g oral glucose tolerance test (OGTT) was indicated, it occurred a median of 10 (interquartile range 7, 15) days after the screen. CONCLUSIONS: GDS occurred widely in a system where it was universally recommended and paid for publicly. When indicated, a 75-g OGTT was completed within 15 days in 75% of cases. Our finding that this two-step approach was widely implemented in a timely fashion supports continued endorsement of a two-step approach to screening and diagnosis of GDM. Further research is merited to assess whether the one-step GDM diagnostic approach results in different rates and timing of the 75-g OGTT and affects pregnancy outcomes. PMID- 26486188 TI - Association Between Handedness and Type 2 Diabetes: The E3N Study. PMID- 26486189 TI - Associations Between Prediabetes, by Three Different Diagnostic Criteria, and Incident CVD Differ in South Asians and Europeans. AB - OBJECTIVE: We examined longitudinal associations between prediabetes and cardiovascular disease (CVD) (coronary heart disease [CHD] and stroke) in Europeans and South Asians. RESEARCH DESIGN AND METHODS: This was a U.K. cohort study of 1,336 Europeans and 1,139 South Asians, aged 40-69 years at baseline (1988-1991). Assessment included blood pressure, blood tests, anthropometry, and questionnaires. Prediabetes was determined by OGTT or HbA1c, using either International Expert Committee (IEC) (HbA1c 6.0-6.5% [42-48 mmol/mol]) or American Diabetes Association (ADA) (HbA1c 5.7-6.5% [39-48 mmol/mol]) cut points. Incident CHD and stroke were established at 20 years from death certification, hospital admission, primary care record review, and participant report. RESULTS: Compared with normoglycemic individuals, IEC-defined prediabetes was related to both CHD and CVD risk in Europeans but not South Asians (subhazard ratio for CHD 1.68 [95% CI 1.19, 2.38] vs. 1.00 [0.75, 1.33], ethnicity interaction P = 0.008, and for CVD 1.49 [1.08, 2.07] vs. 1.03 [0.78, 1.36], ethnicity interaction P = 0.04). Conversely, IEC-defined prediabetes was associated with stroke risk in South Asians but not Europeans (1.73 [1.03, 2.90] vs. 0.85 [0.44, 1.64], ethnicity interaction P = 0.11). Risks were adjusted for age, sex, smoking, total to-HDL cholesterol ratio, waist-to-hip ratio, systolic blood pressure, and antihypertensive use. Associations were weaker for OGTT or ADA-defined prediabetes. Conversion from prediabetes to diabetes was greater in South Asians, but accounting for time to conversion did not account for these ethnic differences. CONCLUSIONS: Associations between prediabetes and CVD differed by prediabetes diagnostic criterion, type of CVD, and ethnicity, with associations being present for overall CVD in Europeans but not South Asians. Substantiation of these findings and investigation of potential explanations are required. PMID- 26486191 TI - Twelve-Week Treatment With Liraglutide as Add-on to Insulin in Normal-Weight Patients With Poorly Controlled Type 1 Diabetes: A Randomized, Placebo Controlled, Double-Blind Parallel Study. AB - OBJECTIVE: This study investigated the efficacy and safety of once-daily liraglutide 1.2 mg versus placebo as add-on to insulin treatment in normal-weight patients with poorly controlled type 1 diabetes. RESEARCH DESIGN AND METHODS: In a randomized (1:1), double-blind, placebo-controlled design, 40 patients with type 1 diabetes (HbA1c >=8% [64 mmol/mol]) received once-daily liraglutide 1.2 mg or placebo for 12 weeks. Continuous glucose monitoring was performed before and at the end of treatment. The primary end point was change in HbA1c. Secondary end points included change in insulin dose, weight, glycemic excursions, heart rate, and blood pressure. RESULTS: Baseline HbA1c was similar in the liraglutide and placebo group (8.8 +/- 0.2 and 8.7 +/- 0.1% [72.5 +/- 2.2 and 71.8 +/- 1.5 mmol/mol]). Change in HbA1c from baseline was -0.6 +/- 0.2% (-6.22 +/- 1.71 mmol/mol) with liraglutide and -0.5 +/- 0.2% (-5.56 +/- 1.67 mmol/mol) with placebo (P = 0.62). Variation in glycemic excursions did not change in either group. Change in body weight was -3.13 +/- 0.58 and +1.12 +/- 0.42 kg (P < 0.0001) with liraglutide and placebo, respectively. The bolus insulin dose decreased in liraglutide-treated patients and did not change with placebo treatment (4.0 +/- 1.3 vs. 0.0 +/- 1.0 IU, P = 0.02). Heart rate increased within the liraglutide group (P = 0.04) but not compared with placebo, whereas mean systolic blood pressure decreased compared with placebo (between-group difference 3.21 mmHg [95% CI -8.31 to 1.90], P = 0.04). Liraglutide was more frequently associated with gastrointestinal adverse effects. The incidence of hypoglycemia did not differ between groups. CONCLUSIONS: Liraglutide significantly reduces body weight and insulin requirements but has no additional effect on HbA1c in normal-weight patients with type 1 diabetes inadequately controlled on insulin alone. PMID- 26486193 TI - The power laws of nanoscale forces under ambient conditions. AB - We report a power law derived from experimental atomic force microscopy (AFM) data suggesting a nano to mesoscale transition in force-distance dependencies. Our results are in relative agreement with the Hamaker and Lifshitz theories for van der Waals forces for the larger tip radii only. PMID- 26486192 TI - Efficacy and Safety of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes. AB - OBJECTIVE: This study assessed the efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor, as add-on to insulin in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: This 18-week, double-blind, phase 2 study randomized 351 patients (HbA1c 7.0-9.0% [53-75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion to canagliflozin 100 or 300 mg or placebo. The primary end point was the proportion of patients achieving at week 18 both HbA1c reduction from baseline of >=0.4% (>=4.4 mmol/mol) and no increase in body weight. Other end points included changes in HbA1c, body weight, and insulin dose, as well as hypoglycemia incidence. Safety was assessed by adverse event (AE) reports. RESULTS: More patients had both HbA1c reduction >=0.4% and no increase in body weight with canagliflozin 100 and 300 mg versus placebo at week 18 (36.9%, 41.4%, 14.5%, respectively; P < 0.001). Both canagliflozin doses provided reductions in HbA1c, body weight, and insulin dose versus placebo over 18 weeks. The incidence of hypoglycemia was similar across groups; severe hypoglycemia rates were low (1.7-6.8%). Overall incidence of AEs was 55.6%, 67.5%, and 54.7% with canagliflozin 100 and 300 mg and placebo; discontinuation rates were low (0.9-1.3%). Increased incidence of ketone-related AEs (5.1%, 9.4%, 0%), including the specific AE of diabetic ketoacidosis (DKA) (4.3%, 6.0%, 0%), was seen with canagliflozin 100 and 300 mg versus placebo. CONCLUSIONS: Canagliflozin provided reductions in HbA1c, body weight, and insulin dose with no increase in hypoglycemia, but increased rates of ketone-related AEs, including DKA, in adults with type 1 diabetes inadequately controlled with insulin. PMID- 26486194 TI - X-Ray crystal structure, and optical and electrochemical properties of the Au15Ag3(SC6H11)14 nanocluster with a core-shell structure. AB - We report the X-ray crystallographic structure of an 18-metal atom Au-Ag bimetallic nanocluster (NC) formulated as [Au15Ag3(SC6H11)14]. This NC consists of a Au6Ag3 bi-octahedral kernel, which is built up by two octahedral Au3Ag3 units through sharing one Ag3 triangular face. The [Au15Ag3(SC6H11)14] can be viewed as a core-shell structure with the doped Ag atoms as the core and Au atoms as the shell. Detailed analyses by UV-vis spectroscopy, X-ray photoelectron spectroscopy (XPS), and electrochemical measurements clearly show distinct differences in the electronic structure between [Au15Ag3(SC6H11)14] and the homometal [Au18(SC6H11)14] NC. This study contributes to the deep understanding on bimetallic nanoclusters. PMID- 26486190 TI - Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women. AB - OBJECTIVE: In older women, higher levels of estrogen may exacerbate the increased risk for cognitive impairment conveyed by diabetes. We examined whether the effect of postmenopausal hormone therapy (HT) on cognitive impairment incidence differs depending on type 2 diabetes. RESEARCH DESIGN AND METHODS: The Women's Health Initiative (WHI) randomized clinical trials assigned women to HT (0.625 mg/day conjugated equine estrogens with or without [i.e., unopposed] 2.5 mg/day medroxyprogesterone acetate) or matching placebo for an average of 4.7-5.9 years. A total of 7,233 women, aged 65-80 years, were classified according to type 2 diabetes status and followed for probable dementia and cognitive impairment (mild cognitive impairment or dementia). RESULTS: Through a maximum of 18 years of follow-up, women with diabetes had increased risk of probable dementia (hazard ratio [HR] 1.54 [95% CI 1.16-2.06]) and cognitive impairment (HR 1.83 [1.50 2.23]). The combination of diabetes and random assignment to HT increased their risk of dementia (HR 2.12 [1.47-3.06]) and cognitive impairment (HR 2.20 [1.70 2.87]) compared with women without these conditions, interaction P = 0.09 and P = 0.08. These interactions appeared to be limited to women assigned to unopposed conjugated equine estrogens. CONCLUSIONS: These analyses provide additional support to a prior report that higher levels of estrogen may exacerbate risks that type 2 diabetes poses for cognitive function in older women. The role estrogen plays in suppressing non-glucose-based energy sources in the brain may explain this interaction. PMID- 26486195 TI - Hierarchical core/shell structure of MnO2@polyaniline composites grown on carbon fiber paper for application in pseudocapacitors. AB - Hierarchical core/shell structured arrays of MnO2@polyaniline (PANI) nanosheets are successfully deposited on the surface of carbon fiber paper (CFP) by a two step method of a redox reaction-assisted deposition of MnO2 and post electrodeposition of PANI. The CFP is used as a three-dimensional (3D) current collector to ensure 3D transport of ions and electrons with a large surface area. In addition, the electrodeposition technique enables conformal and thin coating of a layer of PANI across the entire MnO2 nanosheet. The MnO2@PANI on the CFP shows a unique architecture for efficient ion diffusion pathways in hierarchical porous structures and rapid electron transfer through PANI coated layers. The MnO2@PANI/CFP can be applied as a binder- and carbon-free electrode for supercapacitors. Evaluation of the electrochemical performance revealed that the as-prepared electrodes have a high value of specific capacitance (437 F g(-1) at 1 A g(-1)), high rate capability (62.4% retention at 15 A g(-1)), and good cycle life (~100% at sequential current densities of 1 and 5 A g(-1) over 3000 cycles). PMID- 26486196 TI - Cluster of Puerperal Fever in an Obstetric Ward: A Reminder of Ignaz Semmelweis. PMID- 26486198 TI - Global microRNA profiling of peripheral blood mononuclear cells in patients with Behcet's disease. AB - OBJECTIVES: To explore the post-transcriptional regulation of the peripheral blood mononuclear cells (PBMCs) transcriptome by microRNAs in Behcet's disease (BD). METHODS: Using TaqMan Low Density Array-based microRNAs expression profiling, the expression of 750 mature human microRNAs in PBMCs from 5 BD patients and 3 healthy controls (HC) was compared. The expression of deregulated microRNAs was then validated by quantitative real time-polymerase chain reaction (qRT-PCR), in 42 BD patients and 8 HC. RESULTS: In the initial screening, 13 microRNAs appeared deregulated in BD vs HC. Among them, the differential expression of miR-720 and miR-139-3p was confirmed by qRT-PCR, (p<0.05 and FDR<5%). Areas under the receiver operating characteristic curve for miR-139-3p, miR-720 and miR-139-3p+miR-720 in the validation cohort were 0.84, 0.87 and 0.92 respectively, indicating good discrimination between BD patients and HC. Post-hoc analysis showed that 9 out of 13 microRNAs from the discovery phase were significantly upregulated in active vs. quiescent BD, suggesting inflammation as a key regulator of microRNAs machinery in BD. In silico analysis revealed that several BD candidate susceptibility genes are predicted target of significantly deregulated microRNAs in active BD. A significant enrichment in microRNAs targeting elements of the Toll-like receptor (TLR) and T-cell receptor signalling pathways was also assumed. CONCLUSIONS: miR199-3p and miR720 deserve further confirmation as biomarkers of BD in larger studies. PBMCs from active BD displayed a unique signature of microRNAs which may be implicated in regulation of innate immunity activation and T-cell function. PMID- 26486199 TI - If it looks like a duck, swims like a duck, and quacks like a duck, it probably is a duck: black market medicine and privatization in Israel. PMID- 26486200 TI - Tim-3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients. AB - INTRODUCTION: T cell immunoglobulin and mucin domain (Tim) 3 and programmed death 1 (PD-1) are co-inhibitory receptors involved in the so-called T cell exhaustion, and in vivo blockade of these molecules restores T cell dysfunction. High expression of Tim-3 and PD-1 is induced after chronic antigen-specific stimulation of T cells during HIV infection. We have previously demonstrated that the interaction of Tim-3 with its ligand galectin-9 induces macrophage activation and killing of Mycobacterium tuberculosis. Our aim in this study was to analyze the Tim-3 expression profile before and after six months of antiretroviral therapy and the impact of Tim-3 and PD-1 blocking on immunity against M. tuberculosis. MATERIALS AND METHODS: HIV+ patients naive to anti-retroviral therapy (ART) were followed up for six months. Peripheral immune-cell phenotype (CD38/HLA-DR/galectin-9/Tim-3 and PD-1) was assessed by flow cytometry. Supernatants were analyzed with a multiplex cytokine detection system (human Th1/Th2 cytokine Cytometric Bead Array) by flow cytometry. Control of bacterial growth was evaluated by using an in vitro experimental model in which virulent M. tuberculosis-infected macrophages were cultured with T cells in the presence or absence of Tim-3 and PD-1 blocking antibodies. Interleukin-1 beta treatment of infected macrophages was evaluated by enumerating colony-forming units. RESULTS: We showed that HIV+ patients had an increased expression of Tim-3 in T cells and were able to control bacterial growth before ART administration. By blocking Tim 3 and PD-1, macrophages and T cells recovered their functionality and had a higher ability to control bacterial growth; this result was partially dependent on the restitution of cytokine production. CONCLUSIONS: In this study, we demonstrated that increased Tim-3 expression can limit the ability of the immune system to control the infection of intracellular bacteria such as M. tuberculosis. The use of ART and the in vitro manipulation of the Tim-3 and PD-1 molecules restored the functionality of T cells and macrophages to restrict bacterial growth. Our results provide a novel immune strategy that may be implemented in the near future in order to improve the immune responses in HIV+ patients. PMID- 26486201 TI - Elderly patient's knowledge, attitudes and behaviors regarding care and maintenance of the removable prosthesis: a qualitative study. AB - AIM: Regular care and efficient hygiene procedures play a major role in the maintenance of oral health and long-term success of removable prosthodontic treatment. The aim of this study was to assess the knowledge, attitude and behavior of the elderly patients towards care and maintenance of their removable prosthesis. METHODS: One-hundred and forty elderly patients, who visited the Department of Prosthodontics and Dental Surgery, VMMC and Safdarjung Hospital, Delhi, India for dental treatment were recruited into this study and completed a single interviewer-administered questionnaire. The questionnaire included information on gender, age, socioeconomic status, medical status, length of use of the prosthesis, cleaning material and technique, etc. RESULTS: It was revealed that the lack of knowledge and awareness of importance of the denture hygiene; poor socioeconomic and compromised medical status of the patients, created barriers to regular and preventive dental care of denture wearers. The oral hygiene and care practices were found to be disappointing and the knowledge about the denture's duration of use, dietary limitations, maintenance, storage methods and follow-up visits was found to be limited. CONCLUSION: The results of this study indicate that patients' knowledge, attitudes and behavior about the importance of the dental prosthesis need to be improved. Coordinated efforts by prosthodontists, community dentists and other health professionals are required to impart dental health education about oral prosthesis hygiene, care habits, importance of the regular recalls and to promote preventive dental programmes. PMID- 26486202 TI - Antibacterial efficacy of polymer containing nanoparticles in comparison with sodium hypochlorite in infected root canals. AB - AIM: The aim of the present study was to compare the antibacterial properties of PLGA polymer containing ZnO, Ag and ZnO/Ag nanoparticles with those of 2.5% NaOCl in root canals contaminated with Enterococcus faecalis. METHODS: A total of 100 maxillary central incisors were selected. After the crowns were removed to achieve 12-mm-length roots, the root canals were prepared with RaCe rotary system. The samples were sterilized; then 200 uL of E. faecalis suspension (ATCC 29212) was placed in each root canal. The samples were divided into 5 groups based on the antibacterial agent used. Group 1 served as the control group. In group 2 the polymer suspension containing ZnO nanoparticles, in group 3 the polymer solution containing ZnO/Ag nanoparticles, in group 4 the polymer solution containing Ag nanoparticles and in group 5, 2.5% NaOCl were used. After 24 hours, a solution was prepared using dentin chips from each root canal and placed on agar plates, followed by colony-forming units (CFU) count determination. Means +/ standard deviations were calculated and Kruskal-Wallis test was used to evaluate the antibacterial properties of different irrigation agents. Mann-Whitney U test was used for two-by-two comparisons of the groups, with the level of significance being set at 0.05. RESULTS: The maximum and minimum CFU counts were observed in the control and NaOCl groups, respectively. In the polymer groups, the maximum and minimum CFU counts were observed in the Ag and ZnO/Ag groups, respectively. There were significant differences in CFU counts between the study groups after application of irrigation solutions (P<0.05). Two-by-two comparisons of the groups using Mann-Whitney U test showed significant differences between all the study groups (P<0.05), except for groups ZnO and Ag (P=0.7). CONCLUSION: Sodium hypochlorite solution was more effective than copolymer containing nanoparticles and of all the tested nanoparticles; ZnO/Ag nanoparticles exhibited the highest antibacterial activity. PMID- 26486203 TI - The pedicled buccal fat pad in oral reconstruction. AB - AIM: Aim of the study was to present a follow-up on 46 cases in which pedical buccal fat pad (BFP) flaps were used to repair oral defects without any additional local flaps or skin grafts. METHODS: The study comprised 46 patients, 31 men and 15 women, with an age range of 30-78 years (mean age 57.3 years). They were treated with a pedicled flap to repair defects of the ipsilateral maxilla (anterior or posterior), soft palate or retromolar mandibular area following tumor resection, osteonecrosis or the closure of oro-antral fistulae. The defects ranged from 2 * 2.5 cm to 4.5 * 5 cm. All patients were treated under general anesthesia. RESULTS: The flap fully covered the intraoral defect with any aesthetic deficits. After one month, the flap was fully epithelialized and of adequate thickness in all cases. Three postoperative complications were reported: one superficial necrosis and two small fistulae. CONCLUSION: Although the BFP has long been recognized and despite the simplicity of preparing the flap itself, numerically significant reports concerning the use of this technique in reconstructive facial surgery have only recently been published. The pedicled buccal fat flap is convenient and reliably repairs oral defects up to 4.5 cm in diameter on the ipsilateral side of the soft and hard palate, posterior alveolar region of the maxilla and the retromolar mandibular area. The surgical procedure is simple and morbidity at the donor site in not significant. PMID- 26486204 TI - Modified Dental Anxiety Scale: validation of the Italian version. AB - AIM: Anxiety is a relevant problem in dental practice. The Modified Dental Anxiety Scale (MDAS) is a brief, simple questionnaire consisting of five questions with a total score ranging from 5 to 25, the Italian version of which is not available yet. The aim of the study was to provide an Italian version of the MDAS and check its reliability in oral surgery, which is a major cause of dental anxiety due to the expected perception of pain and suffering. METHODS: The Italian version of the test was administered to 230 patients (98 male and 132 female patients, ages 14-88 years) undergoing oral surgery. Further recorded data were: American Society of Anaesthesiologists physical status classification (ASA PS), frequency of visiting the dentist and any previous distressing experiences in dental or medical setting. RESULTS: The internal consistency of the test was high, with a Cronbach's alpha=0.92. The MDAS score was significantly higher in females (P<0.0001) and in patients with previous distressing experiences in medical and/or dental settings (P<0.0001); the correlation with age (P=0.01) and frequency on visiting the dentist (P=0.02) were also significant. CONCLUSIONS: The patients' selection (oral surgery only) may be a limit of the study, which might not provide an estimation of anxiety prevalence in the general dental population; however our result agree with those of studies performed in other Countries in the generic population, suggesting the absence of major differences with respect to the surgical setting and show the reliability and manageability of the Italian version of MDAS. PMID- 26486205 TI - Edentulous mandible: clinical results of reconstruction with fresh frozen bone. AB - AIM: The aim of this study was the clinical and radiological evaluation in severe mandibular atrophy (class V-VI Cadwood-Howell) of bone grafts with homologous fresh frozen bone (FFB) in patients with dysesthesia of the inferior alveolar nerve with or without transposition of the NAI in order to perform a proper implant-prosthetic rehabilitation. METHODS: This article presents our experience in mandibular reconstructions performed in 12 patients with severe mandibular atrophy and dysesthesia performing onlay grafts with FFB and subsequent implant prosthetic rehabilitation. RESULTS: The surgical protocol of homologous bone graft in symptomatic patients with severe mandibular atrophy presented an excellent clinical outcome with disappearance of dysesthesia in all patients treated, good graft integration and a complete implant-prosthetic rehabilitation with loss of only 3 implants at the 24-36 month follow up visit. CONCLUSION: Homologous bone grafting in patients with severe mandibular atrophy may be a viable therapeutic option in cases of prosthetic reconstruction in those symptomatic patients who cannot tolerate removable dentures, reducing intraoperative time, patient morbidity and the complications in common sites of autologous bone graft removal. PMID- 26486206 TI - Fiber reinforced composites orthodontic retainers. AB - AIM: Retention is the phase of orthodontic treatment that attempts to hold teeth in their corrected positions after orthodontic therapy is completed. The aim of this study was to consider fiber-reinforced composites (FRC) as a possible alternative to conventional multistranded stainless steel wire for retention through SEM analysis. METHODS: Two different FRC orthodontic retainers were investigated, i.e. Everstick(r) (Stick Tech Ltd, Turku, Finland) (type A, 24 samples), with a diameter of 0.76 mm made of glass fibers and a Young's modulus of elasticity of 28 gpa, and Ribbond(r) (Ribbond, Inc., Seattle, Washington, WA, USA) (type B, 24 samples), with ultra high molecular weight and with an high Young's modulus of elasticity by polyethylene fibers cold treated with plasma gas. Six groups were created: control groups A1 and B1, composed by 8 type A and 8 type B samples without impregnation and only with fluid resin before curing; groups A2 and B2, composed respectively by 8 type A and 8 type B samples impregnated with fluid resin Heliobond for 6 seconds; groups A3 and B3, composed respectively by 8 type A and 8 type B samples impregnated with fluid resin Heliobond for 6 minutes before curing. RESULTS: Cross- and lengthwise SEM analysis of the sectioned samples made showed that fiber without impregnation with fluid resin, before curing, showed interwoven and straight directed cylindrical fibers. The SEM analysis denoted that the two types of fiber shows structural characteristics differing in dimension, number, diameter and orientation of FRC without a preliminary treatment through impregnation of the fibers with fluid resin. CONCLUSION: An impregnation time of 6 seconds could considerably reduced voids, crazes and microcracks of the fibers, making them more resistant to the other oral and bacterial agents. A larger time of impregnation (6 minutes), with fluid resin before hardening, further enhances the morphological characteristics of the FRC. PMID- 26486207 TI - The adolescent patient: parental responsibility, the right to be informed and the right to be heard. AB - The increasing emphasis placed on patients' rights, in dentistry as well as in other areas, is also having repercussions on the structure of the relationship between health care staff, the under-age patient and his /her parents. The authors reflect about the decision-making process when the patient is a minor in the field of dentistry and underline the role of the parties involved (dentist, parents, under-age patient) in different circumstances (e.g. ordinary care or non routine care; urgent situations; conflict between parents; refusal of the parents; disagreement between the parents and the child, refusal of the under-age patient; etc.). The Law must first ensure that the minors' needs for protection are met by awarding their parents the power and duty to care for them and, thus, also to take health care decisions in their interest. At the same time, domestic legislation and international legislation supports the need to give greater weight to minors' opinions as they approach the age of majority and, therefore, as they acquire a certain degree of maturity. The rights of under-age patients are safeguarded by actively involving them in the decision-making process, with particular reference to their right to information and right to be heard, to the extent that their age and understanding allow, with due consideration to the specific situation. PMID- 26486208 TI - Predictive Factors of Febrile Neutropenia Induced by Anticancer Chemotherapy in the South of Tunisia. AB - INTRODUCTION: Febrile Neutropenia (FN) secondary to chemotherapy is the most common and the earliest hematological complication. The aim of this work is to study the predictive factors of FN. Materiel and Methods: This is a retrospective study including 186 episodes of FN induced by chemotherapy treated in the department of oncology at Sfax in southern Tunisia during the period between 1 January 2006 and 31 December 2010. RESULT: The mean age of patients was 40 years. One hundred and seventeen patients had solid tumors (86.02%), 18 patients (13.23%) had hematological malignancies and one patient was treated for hypo pharyngeal cancer and aplastic Anemia. Chemotherapy was indicated for curative purpose in 94 cases and palliative purpose in 92 cases. One hundred and four patients (76.5%) had a single episode of FN and 32 (23.5%) had at least two episodes. The average time of febrile neutropenia was 11 days. CONCLUSION: Personal history of FN, poor performance status, chemotherapy regimen and the stage of the disease increased the risk of FN, with a statistically significant difference. Other factors such as hematological malignancies, the age over 65 years and concurrent chemo radiotherapy were not retained in our series. PMID- 26486210 TI - Regulation Policy on Tissue Engineering and Regenerative Medicine in Asian Pacific Region. PMID- 26486209 TI - Characteristics and phylogenetic analysis of the complete mitochondrial genome of Cheilodactylus quadricornis (Perciformes, Cheilodactylidae). AB - The complete mitochondrial genome of the Cheilodactylus quadricornis was firstly determined in the present study. The mitochondrial genome of C. quadricornis is 16 521 nucleotides, comprising 13 protein-coding genes and 2 ribosomal RNA genes, 22 tRNA genes and 2 main non-coding regions (the control region and the origin of the light-strand replication). The overall base composition was T, 26.3%; C, 29.6%; A, 27.8% and G, 16.3%. The gene arrangement, base composition, and tRNA structures of the complete mitochondrial genome of C. quadricornis is similar to other teleosts. Only two central conserved sequence blocks (CSB-2 and CSB-3) were identified in the control region. In addition, the conserved motif 5'-GCCGG-3' was identified in the origin of light-strand replication of C. quadricornis. The complete mitochondrial genome of C. quadricornis was used to construct phylogenetic tree, which shows that C. quadricornis and C. variegatus clustered in a clade and formed a sister relationship. This mitogenome sequence data would play an important role in population genetics and phylogenetic analysis of the Cheilodactylidae. PMID- 26486212 TI - A Translocal Perspective: Mustang Images in the Cultural, Economic and Political Landscape. AB - Translocal spaces are created out of the process of globalization whereby interventions such as electronic media and migration radically change social relations and breakdown the isomorphism of space, place, and culture [1]. This approach is useful in examining the controversy surrounding the mustang. This paper explores how different social constructions influence the management of mustangs as they move between the local and national level. At each cultural level, political, economic, and environmental issues converge encouraging the emphasis of some cultural constructions over others. These socially constructed images give insight into what the mustang means to a post-industrial culture and it may simultaneously contribute to the animal's eventual demise. PMID- 26486211 TI - An International Comparison of Female and Male Students' Attitudes to the Use of Animals. AB - Previous research has demonstrated that in households where the male partner is more dominant, there is convergence in male and female attitudes towards animals, whereas if the female partner is empowered they exhibit greater empathy towards animals than the male partner. We tested this theory of 'female empowered empathy' internationally in a survey of female and male students' attitudes towards use of animals, conducted in 11 Eurasian countries: China, Czech Republic, Great Britain, Iran, Ireland, South Korea, Macedonia, Norway, Serbia, Spain and Sweden. Gender empowerment was estimated for each country using the Gender Empowerment Measure designed by the United Nations. The survey was administered via the internet in universities within countries, and 1,902 female and 1,530 male student responses from 102 universities were received. Respondents rated the acceptability of 43 major concerns about human use of animals, and the importance of 13 world social issues, including animal protection, environmental protection and sustainable development. Females had greater concern for animal welfare and rights than males. There was a positive correlation between the Gender Empowerment Measure and the ratio of female to male concern for animal welfare and rights, but not for other world issues. Thus in countries where females were more empowered, principally Sweden, Norway and Great Britain, females had much greater concern than males for animal issues, whereas in other countries the responses of males and females were more similar. Across countries female students were more likely to avoid meat and less likely to avoid eggs, milk and seafood than male students, and were more likely to have kept pets than males. Females rated cats as more sentient than males did. The results demonstrate that females have greater concern for animal welfare and rights than males, and that this is more likely to be expressed in countries where females are relatively empowered, suggesting that 'emancipated female empathy' operates across countries as well as at a local level. PMID- 26486213 TI - An Inclusive Re-Engagement with our Nonhuman Animal Kin: Considering Human Interrelationships with Nonhuman Animals. AB - As humans increasingly acknowledge the effects that they are having on the planet, there is a realisation implicit in these effects that human interrelationships with nature are actually arbitrated and expedited exploitatively. Understanding how the different discourses and histories through which the interrelationships with nature are mediated and actually told and then retold is fundamental to appreciating how humans may relate with nature less exploitatively and in ways that are more inclusionary, particularly with nonhuman animals. Humans perceive nature and individual nonhuman animals in various ways. This paper provides an investigation of how humans have socially constructed nature and their place as either within or outside of it. Such constructions are elaborated conceptually and through narrative. More pertinently, this paper examines how nature and nonhuman animals are perceived and placed within those narratives that humans construct from reality. It is stressed here that such constructions have, and may continue, to lead to a worsening of the effects that humans have on the planet if there is no acceptance or recognition that certain realities exist beyond the exploitative bounds of any human-inspired concept or narrative. This paper therefore provides the groundwork for the foundations of an ethic that is both socially and ecologically inclusive and is based on a soft realist approach. PMID- 26486214 TI - The Mirror Has Two Faces: Contradictory Reflections of Donkeys in Western Literature from Lucius to Balthazar. AB - How we represent animals both reflects our attitudes towards them and affects our treatment of them. The donkey has lived alongside humans, bearing their burdens since the time of their domestication over 10,000 years ago. Despite this, they have invariably enjoyed a low status in human cultures, received little appreciation and been treated harshly. We view some animals as being more worthy than others and represent them accordingly: donkeys have been ridiculed and derided. Literary representations of donkeys from the fables of Ancient Greece to contemporary iconic texts are explored to follow the donkey through the human imaginary. These representations derive from two main, conflicting sources, Greek literature and the Bible. Examining these cultural representations may lead towards a greater understanding of the way they affect the actual animal and lead to a greater understanding of that animal and, ultimately, to better treatment of them. PMID- 26486215 TI - Challenges to the Development and Implementation of Public Policies to Achieve Animal Welfare Outcomes. AB - Although there is a long-established tradition of concern for the welfare of animals, it was not until the mid 1800's that governments sought to enact legislation to protect animals from cruelty. In the 1950's, questions concerning animal welfare re-emerged and in the ensuing years have been an on-going focus of government activities. These developments occurred against a backdrop of significant social change but there are important differences in what now underpins and informs these considerations. In the formulation and implementation of public policies, governments look for a course of action that represents and protects the interests of the community; the process may be challenging with competing interests but the final determination seeks a middle ground that best meets the needs and interests of the community as a whole. When policy development concerns our relationship with other animals, the complexity of this relationship presents particular challenges not only to the formulation of policies but also to the evaluation of outcomes. Notably, the depth of feelings and diversity of views in our community reflect the complex social, cultural and personal dimensions of this relationship. The use of animals for scientific purposes remains one of the most contentious animal welfare issues primarily because when animals are used for these purposes, accepted animal welfare benchmarks cannot always be met. Based on the Australian experience, this paper will discuss the influences in and on-going challenges to the development and implementation of public policy when animals are used for these purposes. PMID- 26486216 TI - From "Animal Machines" to "Happy Meat"? Foucault's Ideas of Disciplinary and Pastoral Power Applied to 'Animal-Centred' Welfare Discourse. AB - Michel Foucault's work traces shifting techniques in the governance of humans, from the production of 'docile bodies' subjected to the knowledge formations of the human sciences (disciplinary power), to the facilitation of self-governing agents directed towards specified forms of self-knowledge by quasi-therapeutic authorities (pastoral power). While mindful of the important differences between the governance of human subjects and the oppression of nonhuman animals, exemplified in nonhuman animals' legal status as property, this paper explores parallel shifts from disciplinary to pastoral regimes of human-'farmed' animal relations. Recent innovations in 'animal-centred' welfare science represent a trend away from the 'disciplinary' techniques of confinement and torture associated with 'factory farms' and towards quasi-therapeutic ways of claiming to know 'farmed' animals, in which the animals themselves are co-opted into the processes by which knowledge about them is generated. The new pastoral turn in 'animal-centred' welfare finds popular expression in 'happy meat' discourses that invite 'consumers' to adopt a position of vicarious carer for the 'farmed' animals who they eat. The paper concludes that while 'animal-centred' welfare reform and 'happy meat' discourses promise a possibility of a somewhat less degraded life for some 'farmed' animals, they do so by perpetuating exploitation and oppression and entrenching speciesist privilege by making it less vulnerable to critical scrutiny. PMID- 26486217 TI - Animal Rights as a Mainstream Phenomenon. AB - Businesses and professions must stay in accord with social ethics, or risk losing their autonomy.A major social ethical issue that has emerged in the past four decades is the treatment of animals in various areas of human use. Society's moral concern has outgrown the traditional ethic of animal cruelty that began in biblical times and is encoded in the laws of all civilized societies. There are five major reasons for this new social concern, most importantly, the replacement of husbandry-based agriculture with industrial agriculture. This loss of husbandry to industry has threatened the traditional fair contract between humans and animals, and resulted in significant amounts of animal suffering arising on four different fronts. Because such suffering is not occasioned by cruelty, a new ethic for animals was required to express social concerns. Since ethics proceed from preexisting ethics rather than ex nihilo, society has looked to its ethic for humans, appropriately modified, to find moral categories applicable to animals. This concept of legally encoded rights for animals has emerged as a plausible vehicle for reform. PMID- 26486218 TI - What's in a Name?-Consequences of Naming Non-Human Animals. AB - The act of naming is among the most basic actions of language. Indeed, it is naming something that enables us to communicate about it in specific terms, whether the object named is human or non-human, animate or inanimate. However, naming is not as uncomplicated as we may usually think and names have consequences for the way we think about animals (human and non-human), peoples, species, places, things etc. Through a blend of history, philosophy and representational theory-and using examples from, among other things, the Bible, Martin Luther, colonialism/imperialism and contemporary ways of keeping and regarding non-human animals-this paper attempts to trace the importance of (both specific and generic) naming to our relationships with the non-human. It explores this topic from the naming of the animals in Genesis to the names given and used by scientists, keepers of companion animals, media etc. in our societies today, and asks the question of what the consequences of naming non-human animals are for us, for the beings named and for the power relations between our species and the non-human species and individuals we name. PMID- 26486219 TI - Integrating Values and Ethics into Wildlife Policy and Management-Lessons from North America. AB - Few animals provoke as wide a range of emotions as wolves. Some see wolves as icons of a lost wilderness; others see them as intruders. As the battle continues between wolf proponents and opponents, finding solutions that resolve conflicts while supporting the integrity of nature is challenging. In this essay we argue that we need to make room for wolves and other native carnivores who are re colonizing areas from which they were extirpated. Strategies that foster coexistence are necessary and wildlife agencies must consider all stakeholders and invest adequate resources to inform the public about how to mitigate conflicts between people/domestic animals, and predators. Values and ethics must be woven into wildlife policy and management and we must be willing to ask difficult ethical questions and learn from past mistakes. PMID- 26486220 TI - Conceptualising Animal Abuse with an Antisocial Behaviour Framework. AB - This paper reviews current findings in the human aggression and antisocial behaviour literature and those in the animal abuse literature with the aim of highlighting the overlap in conceptualisation. The major aim of this review is to highlight that the co-occurrence between animal abuse behaviours and aggression and violence toward humans can be logically understood through examination of the research evidence for antisocial and aggressive behaviour. From examination through this framework, it is not at all surprising that the two co-occur. Indeed, it would be surprising if they did not. Animal abuse is one expression of antisocial behaviour. What is also known from the extensive antisocial behaviour literature is that antisocial behaviours co-occur such that the presence of one form of antisocial behaviour is highly predictive of the presence of other antisocial behaviours. From such a framework, it becomes evident that animal abuse should be considered an important indicator of antisocial behaviour and violence as are other aggressive and antisocial behaviours. The implications of such a stance are that law enforcement, health and other professionals should not minimize the presence of animal abuse in their law enforcement, prevention, and treatment decisions. PMID- 26486221 TI - Countering Brutality to Wildlife, Relationism and Ethics: Conservation, Welfare and the 'Ecoversity'. AB - Wildlife objectification and cruelty are everyday aspects of Australian society that eschew values of human kindness, empathy, and an understanding of the uniqueness and importance of non-human life in the natural world. Fostered by institutional failure, greed and selfishness, and the worst aspects of human disregard, the objectification of animals has its roots in longstanding Western anthropocentric philosophical perspectives, post colonialism, and a global uptake of neoliberal capitalism. Conservation, animal rights and welfare movements have been unable to stem the ever-growing abuse of wildlife, while 'greenwash' language such as 'resource use', 'management', 'pests', 'over-abundance', 'conservation hunting' and 'ecology' coat this violence with a respectable public veneer. We propose an engaged learning approach to address the burgeoning culture of wildlife cruelty and objectification that comprises three elements: a relational ethic based on intrinsic understanding of the way wildlife and humans might view each other [1-3]; geography of place and space [4], where there are implications for how we ascribe contextual meaning and practice in human-animal relations; and, following [5], engaged learning designed around our ethical relations with others, beyond the biophysical and novel and towards the reflective metaphysical. We propose the 'ecoversity' [6], as a scholarly and practical tool for focusing on the intersection of these three elements as an ethical place-based learning approach to wildlife relationism. We believe it provides a mechanism to help bridge the gap between human and non-human animals, conservation and welfare, science and understanding, and between objectification and relationism as a means of addressing entrenched cruelty to wildlife. PMID- 26486222 TI - A Conservation Ethic and the Collecting of Animals by Institutions of Natural Heritage in the Twenty-First Century: Case Study of the Australian Museum. AB - Collecting of animals from their habitats for preservation by museums and related bodies is a core operation of such institutions. Conservation of biodiversity in the current era is a priority in the scientific agendas of museums of natural heritage in Australia and the world. Intuitively, to take animals from the wild, while engaged in scientific or other practices that are supposed to promote their ongoing survival, may appear be incompatible. The Australian Museum presents an interesting ground to consider zoological collecting by museums in the twenty first century. Anderson and Reeves in 1994 argued that a milieu existed that undervalued native species, and that the role of natural history museums, up to as late as the mid-twentieth century, was only to make a record the faunal diversity of Australia, which would inevitably be extinct. Despite the latter, conservation of Australia's faunal diversity is a key aspect of research programmes in Australia's institutions of natural heritage in the current era. This paper analyses collecting of animals, a core task for institutions of natural heritage, and how this interacts with a professed "conservation ethic" in a twenty-first century Australian setting. PMID- 26486223 TI - Silence and Denial in Everyday Life-The Case of Animal Suffering. AB - How can we make sense of the fact that we live in a world where good people co exist in silence about widespread animal suffering. How is it that sites of suffering such as laboratories, factory farms, abattoirs and animal transportation are all around us and yet we 'do not, in a certain sense, know about them' [1]. This 'not knowing' is one of the most difficult barriers for animal activists who must constantly develop new strategies in an attempt to catch public attention and translate it into action. Recent contributions from the 'sociology of denial' have elucidated many of the mechanisms involved in 'not knowing' in relation to human atrocities and genocide. In this context, 'denial' refers to the maintenance of social worlds in which an undesirable situation is unrecognized, ignored or made to seem normal [2]. These include different types of denial: personal, official and cultural, as well as the process of normalization whereby suffering becomes invisible through routinization, tolerance, accommodation, collusion and cover up. Denial and normalization reflect both personal and collective states where suffering is not acknowledged [3]. In this paper, I will examine insights from the sociology of denial and apply them to human denial and normalization of animal suffering. This will include an examination of denial which is both individual and social and the implications of these insights for theory and practice in the human/animal relationship. PMID- 26486224 TI - The effect of medical versus surgical treatment of spontaneous miscarriage on subsequent in vitro fertilization cycles. AB - OBJECTIVE: To evaluate the effect of dilation and curettage (D&C) and misoprostol as treatments for spontaneous miscarriage (SM) on in vitro fertilization (IVF) parameters in the subsequent IVF cycle. DESIGN: Multicenter, retrospective, cohort study. Women treated for SM after IVF treatment with D&C or misoprostol and underwent a subsequent IVF cycle was included. The main outcome measures were ovarian response, endometrial thickness and pregnancy rate in the subsequent IVF cycle after MA. RESULTS: Among 73 patients with miscarriage, 41 had D&C and 32 were given misoprostol. Baseline serum follicle stimulating hormone (FSH) levels and ovarian responses before and after treatment of miscarriage were comparable. No significant differences were observed between the D&C and the misoprostol groups in basal FSH levels, endometrial thickness and parameters of ovarian response in the subsequent IVF cycle. CONCLUSION: D&C and misoprostol are both effective treatments for IVF patients with miscarriage, without an adverse effect on subsequent IVF treatment outcome. PMID- 26486225 TI - Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential. AB - Rho kinases (ROCKs) belong to the serine-threonine family, the inhibition of which affects the function of many downstream substrates. As such, ROCK inhibitors have potential therapeutic applicability in a wide variety of pathological conditions including asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, kidney failure, neuronal degeneration, and osteoporosis. To date, two ROCK inhibitors have been approved for clinical use in Japan (fasudil and ripasudil) and one in China (fasudil). In 1995 fasudil was approved for the treatment of cerebral vasospasm, and more recently, ripasudil was approved for the treatment of glaucoma in 2014. In this Perspective, we present a comprehensive review of the physiological and biological functions for ROCK, the properties and development of over 170 ROCK inhibitors as well as their therapeutic potential, the current status, and future considerations. PMID- 26486226 TI - De Novo Fragment Design for Drug Discovery and Chemical Biology. AB - Automated molecular de novo design led to the discovery of an innovative inhibitor of death-associated protein kinase 3 (DAPK3). An unprecedented crystal structure of the inactive DAPK3 homodimer shows the fragment-like hit bound to the ATP pocket. Target prediction software based on machine learning models correctly identified additional macromolecular targets of the computationally designed compound and the structurally related marketed drug azosemide. The study validates computational de novo design as a prime method for generating chemical probes and starting points for drug discovery. PMID- 26486227 TI - A Convenient Palladium-Catalyzed Carbonylative Suzuki Coupling of Aryl Halides with Formic Acid as the Carbon Monoxide Source. AB - A practical palladium-catalyzed carbonylative Suzuki coupling of aryl halides under carbon monoxide gas-free conditions has been developed. Here, formic acid was utilized as the carbon monoxide source for the first time with acetic anhydride as the additive. A variety of diarylketones were produced in moderate to excellent yields from the corresponding aryl halides and arylboronic acids. PMID- 26486228 TI - Visual selective attention biases contribute to the other-race effect among 9 month-old infants. AB - During the first year of life, infants maintain their ability to discriminate faces from their own race but become less able to differentiate other-race faces. Though this is likely due to daily experience with own-race faces, the mechanisms linking repeated exposure to optimal face processing remain unclear. One possibility is that frequent experience with own-race faces generates a selective attention bias to these faces. Selective attention elicits enhancement of attended information and suppression of distraction to improve visual processing of attended objects. Thus attention biases to own-race faces may boost processing and discrimination of these faces relative to other-race faces. We used a spatial cueing task to bias attention to own- or other-race faces among Caucasian 9-month old infants. Infants discriminated faces in the focus of the attention bias, regardless of race, indicating that infants remained sensitive to differences among other-race faces. Instead, efficacy of face discrimination reflected the extent of attention engagement. PMID- 26486229 TI - Recurrence and Its Impact on the Health-related Quality of Life in Patients with Gastroesophageal Reflux Disease: A Prospective Follow-up Analysis. AB - BACKGROUND/AIMS: Limited data exist on the outcome of gastroesophageal reflux disease (GERD) treatment and its impact on the health-related quality of life (HRQoL) in the Asian population. This study aims to evaluate the treatment outcomes, to investigate the factors associated with recurrence, and to evaluate the impact of the treatment outcome on the HRQoL in a Korean GERD population. METHODS: This was a prospective, multicenter study involving a total of 824 GERD patients. The response to treatment was assessed at week 4 (or week 8 for the patients who did not achieve complete resolution [CR] at week 4). The EQ-5D questionnaire was used at baseline, end of treatment, and first recurrence to assess the HRQoL. To assess GERD symptoms, contact of patients by phone at 1, 6, and 12 months following treatment was carried out. RESULTS: CR was achieved in 65.6% and recurrence was observed in 47.8% following treatment. CR and recurrence rates did not differ by the presence of esophagitis. Multivariate analysis revealed that acid regurgitation (odds ratio 2.249; 95% confidence interval 1.293 3.912; P= 0.004) and both acid regurgitation and heartburn (odds ratio 2.330; 95% confidence interval 1.392-3.901; P= 0.001) were independent risk factors for GERD recurrence. EQ-5D scores were more improved in patients with CR than in those without CR, and worsened more during follow-up in patients with recurrence than in those without recurrence. CONCLUSIONS: We should achieve complete symptom relief and attempt to prevent recurrence in GERD patients to improve their HRQoL. PMID- 26486231 TI - Implementation of Complete Boolean Logic Functions in Single Complementary Resistive Switch. AB - The unique complementary switching behaviour of complementary resistive switches (CRSs) makes them very attractive for logic applications. The implementation of complete Boolean logic functions in a single CRS cell is certainly an extremely important step towards the commercialisation of related logic circuits, but it has not been accomplished to date. Here, we report two methods for the implementation of complete Boolean logic functions in a single CRS cell. The first method is based on the intrinsic switchable diode of a peculiar CRS cell that is composed of two anti-serial bipolar resistive switches with a rectifying high resistance state, while the second method is based directly on the complementary switching behaviour itself of any single CRS cell. The feasibilities of both methods have been theoretically predicted and then experimentally demonstrated on the basis of a Ta/Ta2O5/Pt/Ta2O5/Ta CRS cell. Therefore, these two methods-in particular the complementary switching behaviour itself-based method, which has natural immunity to the sneak-path issue of crossbar logic circuits-are believed to be capable of significantly advancing both our understanding and commercialization of related logic circuits. Moreover, peculiar CRS cells have been demonstrated to be feasible for tri-level storage, which can serve as an alternative method of realising ultra-high-density data storage. PMID- 26486230 TI - Systematic review of cross-national drug utilization studies in Latin America: methods and comparability. AB - PURPOSE: We systematically review the cross-national drug utilization studies performed in Latin America (LA) in order to analyze the methods applied and assess the validity of the data to ensure the comparability. METHODS: A systematic search in Medline, Embase, and BIREME was performed. Drug utilization studies including LA countries and comparing drug exposure data on volume were included. The data validity was judged independently by two authors as having low, medium, high, or unclear risk of bias. RESULTS: Out of 1191 articles, 25 were kept for full text reading. Finally, five studies were selected. Eight different Latin American countries were involved in the comparisons. The selected studies analyzed wholesale data from a private research company collecting information from the private healthcare sector. In three studies, a high risk of bias in the extrapolation method applied was identified. In one study, a risk of data collection bias was detected. The most frequent limitation detected by the original authors was related to the unavailability of information from the public sector in LA. CONCLUSION: Drug utilization studies comparing data cross nationally are scarce in LA. In general, validity of the comparisons is hampered by a potential risk of extrapolation bias given the lack of available data on drug consumption from the public healthcare sector. Setting up systems to remediate this situation is a future challenge for researchers and (supra)national authorities in the region. PMID- 26486232 TI - Reorganization of sea urchin gene regulatory networks at least 268 million years ago as revealed by oldest fossil cidaroid echinoid. AB - Echinoids, or sea urchins, are rare in the Palaeozoic fossil record, and thus the details regarding the early diversification of crown group echinoids are unclear. Here we report on the earliest probable crown group echinoid from the fossil record, recovered from Permian (Roadian-Capitanian) rocks of west Texas, which has important implications for the timing of the divergence of crown group echinoids. The presence of apophyses and rigidly sutured interambulacral areas with two columns of plates indicates this species is a cidaroid echinoid. The species, Eotiaris guadalupensis, n. sp. is therefore the earliest stem group cidaroid. The occurrence of this species in Roadian strata pushes back the divergence of cidaroids and euechinoids, the clades that comprise all living echinoids, to at least 268.8 Ma, ten million years older than the previously oldest known cidaroid. Furthermore, the genomic regulation of development in echinoids is amongst the best known, and this new species informs the timing of large-scale reorganization in echinoid gene regulatory networks that occurred at the cidaroid-euechinoid divergence, indicating that these changes took place by the Roadian stage of the Permian. PMID- 26486233 TI - Vascular endothelial growth factor (VEGF)-634G/C polymorphism was associated with severe pre-eclampsia and lower serum VEGF level. AB - AIM: Vascular endothelial growth factor (VEGF) is an angiogenic factor whose production is increased in pre-eclampsia (PE). Therefore, the present study was conducted aiming at assessing the possible association of VEGF polymorphisms with PE susceptibility in the southeast of Iran. MATERIAL AND METHODS: Overall, 192 PE women and 186 unrelated age-matched normotensive pregnant women were genotyped for the VEGF-2578C/A (rs699947), -1154G/A (rs1570360), and -634G/C (rs2010963) polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism method. Serum VEGF levels were determined by the enzyme-linked immunosorbent assay method. RESULTS: There was no significant difference in VEGF 2578C/A, -1154G/A and -634G/C polymorphisms between PE women and controls. However, the frequency of VEGF-634GC and CC genotypes was significantly higher in women with severe PE compared to mild PE and controls. In addition, serum VEGF levels were significantly lower in PE women. The VEGF-634CC genotype was associated with lower serum VEGF levels compared to the VEGF-634GG genotype. Moreover, serum VEGF levels were significantly lower in individuals with the VEGF 634CC genotype compared to VEGF-634GC genotype only in the control group. The mean serum VEGF levels did not differ significantly between genotypes of VEGF 2587C/A and -1154G/A polymorphisms. CONCLUSION: Our findings suggest that the association of VEGF-634G/C polymorphisms with severe PE and the VEGF-634CC genotype was correlated with lower serum VEGF levels. PMID- 26486235 TI - Mercury Vapor Sorption and Amalgamation with a Thin Gold Film. AB - Understanding the amalgamation mechanisms between mercury and gold is of fundamental interest and importance to many mercury sensing applications. However, there is only limited and piecemeal discussion in the literature of the mechanisms by which Au-Hg amalgams are formed on thin Au films. Here, we present a comprehensive description of a series of morphological changes occurring in a thin polycrystalline Au film during Au-Hg amalgamation investigated by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and atomic force microscopy (AFM). These microscopic investigations enable us to offer a coherent explanation for the features and the mechanisms of amalgamation of Hg with Au in the film. We also use an optical technique (fringes of equal chromatic order, FECO) to observe changes in optical thickness and reflectivity of the film. Amalgamation reactions in the film render it inhomogeneous, thus making optical techniques unsuitable as a method for quantitative monitoring of Hg vapor using Au films of this type. PMID- 26486236 TI - Contralateral reperfusion injury after carotid endarterectomy. AB - Reperfusion brain edema occurs infrequently after carotid endarterectomy and has been reported only ipsilateral to the side of surgery. We report a 51-year-old woman who presented with transient right arm weakness followed by left hemiparesis. Angiography showed occlusion of the left internal carotid artery, 90% stenosis of the right internal carotid artery, filling of the left anterior cerebral artery from the right carotid circulation only, and filling of the left middle cerebral artery branches by pial collaterals from the left anterior cerebral and posterior cerebral arteries. The patient had a right carotid endarterectomy and 1 day postoperatively developed a severe headache but had no new focal neurologic findings. Computed tomography showed effacement of sulci and scattered areas of high attenuation in the left parietal lobe, consistent with cerebral edema and petechial hemorrhage or vascular engorgement. Magnetic resonance imaging 2 days later did not show a lesion in the left hemisphere, suggesting resolution of the edema. This report suggests that reperfusion brain edema can occur contralateral to carotid endarterectomy. PMID- 26486234 TI - Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. AB - Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer-amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derived from peripheral monocytes from patients with type 1 Gaucher disease with genotype N370S/N370S, we confirmed an increased secretion of interleukins IL-1beta and IL-6. In addition, we found that activation of the inflammasome, a multiprotein complex that activates caspase-1, led to the maturation of IL-1beta in Gaucher macrophages. We show that inflammasome activation in these cells is the result of impaired autophagy. Treatment with the small-molecule glucocerebrosidase chaperone NCGC758 reversed these defects, inducing autophagy and reducing IL-1beta secretion, confirming the role of the deficiency of lysosomal glucocerebrosidase in these processes. We found that in Gaucher macrophages elevated levels of the autophagic adaptor p62 prevented the delivery of inflammasomes to autophagosomes. This increase in p62 led to activation of p65-NF-kB in the nucleus, promoting the expression of inflammatory cytokines and the secretion of IL-1beta. This newly elucidated mechanism ties lysosomal dysfunction to inflammasome activation, and may contribute to the massive organomegaly, bone involvement and increased susceptibility to certain malignancies seen in Gaucher disease. Moreover, this link between lysosomal storage, impaired autophagy, and inflammation may have implications relevant to both Parkinson disease and the aging process. Defects in these basic cellular processes may also provide new therapeutic targets. PMID- 26486237 TI - Update on stroke risk factors. AB - As medicine moves into the 21st century, with the added pressures of increasing costs and limited resources, successful diminution of the impact of stroke on the population will require shifting our emphasis away from treating end stages of generalized atherosclerosis and other underlying diseases to preventing underlying diseases and stroke. This approach will require more sophisticated and more definitive studies to identify, verify, and explain better the relative importance of known risk factors, the interactions of various risk factors with one another, and the existence of currently unknown or unverified risk factors. In this article, we review the current state of knowledge about certain stroke risk factors in light of new epidemiologic studies conducted in the last decade with emphasis on modifiable risk factors, now and in the future. PMID- 26486238 TI - Mental status changes and stroke. AB - A retrospective analysis at a tertiary referred center was done to determine the frequency with which an acute confusional state is caused by a stroke and to evaluate the usefulness of performing computed tomography in this setting. We reviewed 127 neurology consultations requested for patients presenting with acute and apparently isolated mental status changes. The mean age was 62. Nine of 127 (7%) were thought to have suffered mental status changes as a result of an acute stroke: one subarachnoid hemorrhage and eight ischemic strokes. There was no intracerebral hemorrhage. The locations of the infarcts were right frontoparietal (four patients), bilateral occipital (two patients), bilateral frontal (two patients), and right pontine (one patient, in whom the causality of the stroke was uncertain). Of those nine strokes presenting with isolated mental symptoms, six (66%) had some focal abnormality on neurological examination. Only three of the 109 patients (2.7%) with no focal findings were ultimately diagnosed as strokes, and one of these had a subarachnoid hemorrhage. Stroke was a relatively rare cause of acute confusional syndrome. The neurological examination had a very high negative predictive value (97%) and was reliable in selecting patients who should undergo an imaging study. PMID- 26486239 TI - Hemodynamic considerations during carotid endarterectomy. AB - To evaluate the hemodynamic and angiographic characteristics of patients undergoing carotid endarterectomy, we reviewed the medical records, angiograms, transcranial Doppler ultrasound data, and EEGs of 42 consecutive patients having 44 carotid endarterectomies. Significant (p < 0.0002) changes in the peak systolic velocity of the middle cerebral artery ipsilateral to the side of surgery (iMCAFV) occurred with anesthesia, carotid clamping, shunting, and the release of clamps. Thirteen percent of patients with collateral flow toward the side of surgery and 57% of those with flow away from the operated side had a drop in iMCAFV exceeding 50% of the baseline value (p = 0.054); the presence of a <70% ipsilateral internal carotid artery stenosis was also correlated with a similar decrease in iMCAFV (p = 0.01). There was no correlation between systolic blood pressure changes and iMCAFV in patients who were not shunted. This information may be useful in guiding intraoperative decision-making. PMID- 26486240 TI - White matter lesions on magnetic resonance imaging in a healthy elderly population: Correlations to vascular risk factors and carotid atherosclerosis. AB - We performed magnetic resonance imaging (MRI) and extensive risk factor evaluation on 196 randomly selected, clinically asymptomatic participants of the Austrian Stroke Prevention Study to determine the clinical correlates of MRI white matter lesions (WML) in normals. WML were present in 103 (52.6%) individuals. There were 69 (35.2%) subjects with Grade 1 (punctate), 26 (13.3%) with Grade 2 (beginning confluent), and 8 (4.1%) with Grade 3 (confluent) WML Multivariate stepwise forward regression analysis created a model of independent predictors of the WML score including arterial hypertension (p = 0.001) and age (p = 0.04). Only 24.7% of WML score variance could be explained by the two variables, however. No other demographic or clinical factors, such as cardiac disease, diabetes mellitus, smoking, lipid status, serum fibrinogen, hematocrit, antiphospholipid antibody titer, or ultrasound results of the carotid arteries entered the model. These data imply the presence of yet undetermined factors in the pathogenesis of WML, probably independent of those known to be associated with atherothrombotic brain infarction. PMID- 26486241 TI - "Silent cerebrovascular lesions" occur among elderly "normal" volunteers besides patients with previous symptomatic strokes. AB - "Silent cerebral infarctions" are a common finding on neuroimaging of neurologically normal elderly patients without any history of stroke. The precise incidence is unknown but increases with advancing age and associated risk factors for stroke and arteriosclerosis. Among a group of 86 neurologically and cognitively "normal" volunteers without a history of stroke, 9 were found to have "silent cerebrovascular lesions" on computed tomography. Thus, there was a 10.5% incidence in the group of 86 "normal" volunteers. It was also found that additional "silent strokes" occurred among 38 patients with a documented history of prior stroke at a rate of 3.4% per year. PMID- 26486242 TI - Admission function portends discharge function and length of stay after stroke. AB - This retrospective study of 51 patients with stroke examined the relationship between functional independence and length of stay in a hospital-based acute rehabilitation unit. Functional independence increased significantly over the course of rehabilitation. The patients' functional independence at discharge and length of stay both correlated significantly with admission function. Self-care, mobility, and locomotion items and categories provided the best prediction of length of stay. Such variables, therefore, may prove most useful in program planning. PMID- 26486243 TI - Cardiac chiari network as an etiology for embolic stroke. AB - The Chiari network is a congenital remnant in the right atrium. It is not commonly associated wtih clinical complications. We report the first case of medically treated embolic stroke in a patient with a cardiac Chiari network and a patent foramen ovale. A 59-year-old woman without cardiac history or signs presented with multiple cerebral infarctions in both the anterior and posterior cerebral circulations. Standard evaluation for cerebral infarction was unrevealing. Transesophageal echocardiography demonstrated a Chiari network in the right atrium and a right-to-left shunt. The Chiari network appeared thickened. After anticoagulation with warfarin, the patient developed no new symptoms of stroke, and repeat transesophageal echocardiography showed resolution of the presumed thrombus on the Chiari network. In workup of patients with ischemic strokes of unknown etiology, transesophageal echocardiography should be considered as an important method for comprehensive evaluation of the right atrium. PMID- 26486244 TI - Silent cerebral infarcts in patients with ischemic infarction. AB - Silent cerebral infarcts occur in patients with chronic nonvalvular atrial fibrillation and asymptomatic or symptomatic carotid stenosis. There is not a well-defined prevalence of asymptomatic lesions in patients with transient ischemic attack or completed strokes. We attempted to determine the occurrence rate of silent brain infarction in a hospital population, including a comparison of the risk factors with those of symptomatic infarction and an evaluation of the relevance of infarction size and location. PMID- 26486245 TI - White matter changes and ventricular enlargement on magnetic resonance imaging: Comparison between normal elderly subjects and patients with cerebrovascular disorders. AB - T2-weighted magnetic resonance imaging has been shown to be effective in detecting changes in cerebral white matter. High signal intensity in cerebral white matter regions has been suggested to be indicative of the presence of a disease state. In normal aging, white matter changes, known as leuko-araiosis, have been reported to be widespread. Some studies have linked leuko-araiosis to aging and risk factors for stroke. There is also evidence that changes in cerebral white matter occur in hydrocephalus and that enlargement of the lateral ventricles is a byproduct of severe white matter changes. This study reports data on the frequency and severity of leuko-araiosis in normal subjects and patients with cerebrovascular disease and explores the relationship between white matter changes and ventricular dilatation. PMID- 26486246 TI - Detection of prothrombotic state in ischemic stroke by monitoring plasma molecular markers. AB - The feasibility of using recently developed coagulation-fibrinolysis markers to detect hemostatic alteration in acute ischemic stroke was examined to see whether they may be employed as predictors of recurrence. We measured serially the plasma thrombin-antithrombin III complex (TAT), plasmin-alpha2 plasmin inhibitor complex (PIC) and D-dimer in patients with ischemic stroke (53 acute, 102 chronic) and 37 normal control subjects. In the acute stage, TAT and D-dimer were significantly increased in both atherothrombotic and lacunar stroke. In cardioembolic stroke, TAT, PIC, and cross-linked D-dimer (D-dimer) were more significantly increased and reached a peak within 3 days (TAT) or at around the second week (PIC, D dimer) poststroke. TAT, PIC, and D-dimer correlated with infarct size, but TAT and D-dimer were significantly increased even in patients with small infarcts. In the chronic stage, TAT was increased above the mean + 2 SD in 7 patients with cardioembolic stroke (n = 17), in 13 with atherothrombotic stroke (n = 37), and in 11 with lacunar stroke (n = 48). In those we had examined within 4 months before recurrence, TAT was increased above the mean + 2 SD in 7 patients (n = 8). We demonstrated TAT and D-dimer to be highly sensitive detectors of hemostatic alteration in small ischemic stroke, contrary to previous reports, and also showed that TAT can detect the prothrombotic state before recurrence. PMID- 26486247 TI - Aggravated ischemic magnetic resonance imaging findings in patients with chronic cerebrovascular disease without apparent clinical worsening. AB - The detection by magnetic resonance imaging (MRI) of cerebral ischemic pathology in patients with cerebral infarction (chronic stage) was investigated. The purpose of the study was to determine whether or not there was exacerbation of hypertense foci on MRI during the observation period without worsening of clinical and neurological symptoms and to consider what risk factors play a role in the aggravation of new ischemic foci on MRI. PMID- 26486248 TI - Clinical applicability of methods to measure carotid stenosis. AB - The North American (NASCET) and European (ECST) trials of carotid endarterectomy used discrepant methods to measure carotid stenosis on angiography. The aim of this study was to evaluate clinical applicability of currently available angiographic methods to measure carotid stenosis. Consecutive patients undergoing carotid angiography were evaluated. To estimate the normal internal carotid artery (ICA) bulb diameter on angiography, the common carotid artery (CCA) was used (ICA bulb diameter = 1.2 X CCA diameter measured 3-5 cm below the bifurcation) and the ICA diameter reduction was calculated: 1 - (d/1.2 X CCA) X 100%. We validated this against the planimetry of the intact removed plaque and termed it the Carotid Stenosis Index (CSI). The clinical applicability of NASCET, ECST, and CSI methods was then compared. Four observers evaluated 165 consecutive carotid angiograms performed over a 1-year period; 20% of arteries were normal, and 10% of ICAs were occluded. After these were excluded, the NASCET method was inapplicable in 30% of angiograms because of "negative stenosis" with minor degrees of atherosclerosis, inadequate views of the distal ICA, and two or more segments of distal ICA with parallel walls in which the diameters differed significantly. The ECST method gave an equivocal outline of the bulb in 10% of all angiograms. The CSI method was applicable in 97% of all angiograms, the major limitation being the presence of severe CCA atheroma (3%). The normal ICA bulb has -84% stenosis according to NASCET, whereas NASCET 0% stenosis equals 45-50% diameter reduction of ICA bulb and NASCET-positive stenoses cover only the last 50% of ICA stenoses. Although NASCET and ECST data are singularly irreplacable for surgical decisions, the angiographic methods used are discrepant from each other and of limited clinical applicability. This may affect the generalizibility of the results of these trials. CSI provides a firm scientific basis to make the results of the trials compatible. PMID- 26486250 TI - Recurrent intracranial hemorrhage in an adult with moyamoya vasculopathy and a basilar artery aneurysm. AB - Moyamoya disease is an unusual disorder of the cerebral vasculature, characterized by internal carotid artery occlusions and formation of a collateral network of the intracranial vessels, which resembles a "puff of smoke" ("moyamoya" in Japanese) on cerebral angiography. This condition has a higher than-usual association with intracranial aneurysms. We present a case of recurrent intracranial hemorrhage in an adult with moyamoya-like vasculopathy and a basilar tip aneurysm. PMID- 26486249 TI - Positron emission tomographic study of postinfarction seizures. AB - Positron emission tomography (PET), using the steady-state technique with (15)O, was performed in 18 patients 4-14 months after a thromboembolic stroke in the territory of the middle cerebral artery. Eight patients developed seizures 2-12 months after infarction. The patients with and without late-onset epilepsy were comparable according to age, etiology, and location of the stroke, and the degree of neurological deficit. PET examination showed a more pronounced decrease in regional cerebral blood flow (rCBF) and oxygen consumption (rCMRO2) in the infarcted area in the group with postapoplectic seizures compared to the nonepileptic stroke group. The PET findings were similar in the border areas of the infarcts and in the contralateral hemispheres of both groups. It cannot be determined if the more decreased rCBF and rCMRO2 in the infarcted zone of the group of patients with postinfarction epilepsy is the cause or the consequence of the seizures. PMID- 26486251 TI - Evidence of "regional hyperemia" in patients with severe closed head injury using single-photon emission computed tomography. AB - Regional cerebral blood flow (rCBF) was assessed in 32 patients with acute/subacute (n = 18) or chronic (n = 14) head injury using single-photon emission computed tomography (SPECT) and (99m)Tc-hexamethylpropylenenamine oxime (HMPAO) (n = 20) or (123)I-IMP (n = 12). Twelve of the 18 patients with acute/subacute head injury were studied with a high-resolution three-head camera and (99m)Tc-HMPAO. Twenty-eight SPECT studies showed regional abnormalities of tracer uptake. In all cases in which computed tomography (CT) and/or magnetic resonance imaging (MRI) (n = 30) were available for comparison, SPECT showed similar or more extensive abnormalities with high agreement on the laterality of the lesions. Particularly in the 18 patients with acute/subacute head injury, SPECT revealed more and larger lesions than the anatomical scans. In 9 of the 12 patients, at least one region with increase in HMPAO uptake reflecting "hyperemia" was detected (mean study time after injury, 6.3 +/- 2.7 days). Follow up SPECT scans in two patients showed decreased tracer uptake in the previous hyperemic regions and encephalomalacia in the anatomical scan. Thus, hyperemia may reflect "luxury perfusion" in early phases of head injury. In three patients with diffuse axonal injury, a generalized reduction in cortical tracer activity, especially in occipital/parietal regions, was observed. The typical finding in chronic head injury was observation of lesions of similar sizes and high agreement in focal abnormalities between SPECT and CT and/or MRI. However, in nine patients with behavioral disturbances, a decrease in the cortical/basal ganglia was detected. Thus, our study confirms the presence of hyperemia in acute/subacute head injury and demonstrates the value of SPECT for assessing functional impairment in these patients. PMID- 26486252 TI - Computed tomography and magnetic resonance observations in asymptomatic cerebral ischemic lesions. AB - We compared the results of computed tomography and magnetic resonance imaging in the evaluation of silent cerebral ischemic lesions in patients without a history of cerebrovascular events and those who present an initial cerebral ischemic episode. PMID- 26486253 TI - Maximizing the photo catalytic and photo response properties of multimodal plasmonic Ag/WO(3-x) heterostructure nanorods by variation of the Ag size. AB - High quality nearly monodisperse colloidal WO3-x nanorods with an aspect ratio ~18 were synthesized using the thermal decomposition technique. The effects of a capping agent and an activating agent on the nanorod aspect ratio have been studied. Excess carrier concentration due to large oxygen vacancy and smaller width of the nanorods compared to the Bohr exciton radius gives rise to an increase of the band gap. Shape anisotropy in nanorods results in two plasmonic absorbance bands at about 890 nm and 5900 nm corresponding to short axis and long axis plasmon modes. The short axis mode reveals an excellent plasmonic sensitivity of ~345 nm per refractive index. A plasmonic photocatalysis process based on WO3-x nanorods has been developed to synthesize Ag/WO3-x heterostructures consisting of multiple Ag dots with ~2 nm size, randomly decorated on the surface of the WO3-x nanorods. Long time irradiation leads to an increase in the size (5 nm) of Ag nanocrystals concomitant with decrease in the number of Ag nanocrystals attached per WO3-x nanorod. Plasmonic photocatalysis followed by thermal annealing produces only one Ag nanocrystal of size ~10 nm on each WO3-x nanorod. Red shifting and broadening of plasmon bands of Ag nanocrystals and WO3-x nanorods confirm the formation of heterostructures between the metal and semiconductor. Detailed transmission electron micrograph analysis indicates the epitaxial growth of Ag nanocrystals onto WO3-x nanorods. A high photocurrent gain of about 4000 is observed for Ag (10 nm)/WO3-x heterostructures. The photodegradation rate for Rhodamine-B and methylene blue is maximum for Ag (10 nm)/WO3-x heterostructures due to efficient electron transfer from WO3-x nanorods to Ag nanocrystals. Metal plasmon-semiconductor exciton coupling, prominent plasmon absorbance of metal nanoparticles, and formation of an epitaxial interface are found to be the important factors to achieve the maximum photocatalytic activity and fabrication of a high speed photodetector device by employing the heterostructures. PMID- 26486254 TI - Soil-borne reservoirs of antibiotic-resistant bacteria are established following therapeutic treatment of dairy calves. AB - We determined if antibiotics residues that are excreted from treated animals can contribute to persistence of resistant bacteria in agricultural environments. Administration of ceftiofur, a third-generation cephalosporin, resulted in a ~ 3 log increase in ceftiofur-resistant Escherichia coli found in the faeces and pen soils by day 10 (P = 0.005). This resistant population quickly subsided in faeces, but was sustained in the pen soil (~ 4.5 log bacteria g(-1)) throughout the trial (1 month). Florfenicol treatment resulted in a similar pattern although the loss of florfenicol-resistant E. coli was slower for faeces and remained stable at ~ 6 log bacteria g(-1) in the soil. Calves were treated in pens where eGFP-labelled E. coli were present in the bedding (~ 2 log g(-1)) resulting in amplification of the eGFP E. coli population ~ 2.1 log more than eGFP E. coli populations in pens with untreated calves (day 4; P < 0.005). Excreted residues accounted for > 10-fold greater contribution to the bedding reservoir compared with shedding of resistant bacteria in faeces. Treatment with therapeutic doses of ceftiofur or florfenicol resulted in 2-3 log g(-1) more bacteria than the estimated ID50 (2.83 CFU g(-1)), consistent with a soil-borne reservoir emerging after antibiotic treatment that can contribute to the long-term persistence of antibiotic resistance in animal agriculture. PMID- 26486255 TI - Comment on "Intimate Coupling of Photocatalysis and Biodegradation for Degrading Phenol Using Different Light Types: Visible Light vs UV Light". PMID- 26486257 TI - The Common Elements of treatment engagement for clinically high-risk youth and youth with first-episode psychosis. AB - AIM: Without treatment, clinically high-risk (CHR) youth or youth with first episode psychosis (FEP) have increased risk for significant complications from their illness; yet, treatment engagement among these youth is critically low. The purpose of this study was to examine engagement efforts with CHR/FEP youth to stimulate new ideas that might facilitate participation in services for this population. METHODS: A literature review using distillation methods identified engagement practices reported in two bodies of literature. The first body of literature (i.e. 'CHR/FEP engagement') included 13 studies employing qualitative designs to explore consumer perspectives about treatment engagement practices in samples of CHR/FEP youth and their families. The second body of research (i.e. 'CHR/FEP RCTs') included 18 randomized controlled trials (RCTs) testing treatments for CHR/FEP youth and their families. Engagement practice frequencies were compared with the frequency of these practices within effective engagement interventions, as tested in 40 RCTs within the broader child and adolescent mental health literature (i.e. 'CAMH engagement'). RESULTS: Treatment attrition and attendance were the most frequent engagement outcomes measured in the CHR/FEP RCTs. There were notable efforts described in the CHR/FEP RCTs towards engaging youth and families, yet CHR/FEP RCTs reportedly included only a small proportion of engagement practices described in either the CHR/FEP or CAMH engagement literatures. CONCLUSION: Results suggest there might be practices available to complement current efforts at engaging CHR/FEP youth in treatment, and that increased attention to the measurement of engagement outcomes could provide important information regarding engagement in a population with low treatment engagement rates. PMID- 26486256 TI - Psychosocial predictors of weight loss by race and sex. AB - This paper examined the psychosocial predictors of weight loss among race and sex subgroups. Analyses included overweight and obese participants from the PREMIER study, a previously published randomized trial that examined the effects of two multi-component lifestyle interventions on blood pressure among pre-hypertensive and stage 1 hypertensive adults. Both intervention conditions received behavioural recommendations for weight loss and group sessions. Weight and psychosocial measures of self-efficacy and social support for diet and exercise were assessed at baseline and at 6 months. There were 157 African-American (AA) women, 46 AA men, 203 non-AA women and 182 non-AA men with an average age of 50 years and average body mass index of 34 at baseline. Multiple predictor regression models were performed individually by race and sex subgroup. Among AA women, increases in diet self-efficacy were associated with weight loss. Among AA men, increases in diet-related social support and self-efficacy, along with increases in family support to exercise, were associated with weight loss (all Ps <0.05). Among non-AA women, increases in friends' support to exercise and exercise-related self-efficacy were associated with weight loss, and among non-AA men only increases in diet self-efficacy were associated with weight loss (all Ps <0.05). These results emphasize the need for targeted interventions based on race and sex to optimize the impact of lifestyle-based weight loss programmes. PMID- 26486259 TI - Trapping of Oxygen Vacancies at Crystallographic Shear Planes in Acceptor-Doped Pb-Based Ferroelectrics. AB - The defect chemistry of the ferroelectric material PbTiO3 after doping with Fe(III) acceptor ions is reported. Using advanced transmission electron microscopy and powder X-ray and neutron diffraction, we demonstrate that even at concentrations as low as circa 1.7% (material composition approximately ABO2.95), the oxygen vacancies are trapped into extended planar defects, specifically crystallographic shear planes. We investigate the evolution of these defects upon doping and unravel their detailed atomic structure using the formalism of superspace crystallography, thus unveiling their role in nonstoichiometry in the Pb-based perovskites. PMID- 26486260 TI - Editorial: Another aspirin study. PMID- 26486258 TI - Evaluation of selected interleukins in patients with different gastric neoplasms: a preliminary report. AB - Abnormal interactions between cytokines may be an overlooked mechanism linking the development of different types of gastric neoplasms. In this study a comprehensive analysis of the systemic levels of interleukins (IL-1,IL-6, IL-8,IL 10 and IL-12) was performed in 75 patients with different gastric neoplasms (cancer, gastrointestinal stromal tumors, neuroendocrine neoplasms, lymphomas) and 40 healthy volunteers. Patients with gastric cancer (GC) have significantly higher IL-6 levels, and lower IL-8 and IL-10 concentrations, in comparison to controls and patients with other gastric neoplasms. Analogous results were observed in terms of IL-6/IL-8 and IL-6/IL-10 ratios, whose values were also higher in GC patients. In GC patients no associations were detected between the systemic levels/values of interleukins (ratios) and TNM staging. IL-6, IL-10, IL 6/IL-8 and IL-6/IL-10 ratios appeared to hold diagnostic potential in confirming/excluding the presence of GC. Their sensitivity/specificity in GC detection/exclusion was approximately 54-72%. In conclusion, disturbed systemic biochemical balance in multiple interleukins exists at the earliest stages of and appears to be specific to GC. The interleukin ratios proposed here seem to be more promising indicators of GC in humans than direct systemic levels of interleukins, and probably possess the potential to be applied as a supporting factor for techniques routinely used. PMID- 26486262 TI - Management of unruptured intracranial aneurysms: A decision analysis. AB - Decision analysis was carried out to gain insight into the optimal management of patients aged 20-80 years with unruptured intracranial aneurysms between 10 and 25 mm in diameter. Baseline probabilities for outcomes resulting from either elective repair of the aneurysm or nonintervention were obtained from studies of patients with intracranial aneurysms seen at the Mayo Clinic. The utility of each outcome was based on the mean life expectancy for otherwise normal people of the same age and sex, with an adjustment made for quality of life. If these baseline probabilities and utilities are used in the calculations, elective surgical repair of unruptured aneurysms of this size is preferable to nonintervention in men under age 69 and in women under age 75 if they are otherwise in good health. PMID- 26486261 TI - A multicenter validation study of Doppler ultrasound versus angiography. AB - The establishment of 60% or greater diameter stenosis by Doppler ultrasound is an eligibility requirement of the Asymptomatic Carotid Atherosclerosis Study (ACAS). We used a uniform statistical approach for each of 30 Doppler devices to establish a cutpoint for the peak systolic flow to insure a positive predictive value of 90% in predicting a 60%+ stenosis by angiography. Data were analyzed by device; however, performance relates to the device-sonographer-reader system. For those devices reporting in peak systolic velocity, cutpoints ranged from 151 to 390 cm/s, and for those reporting a peak systolic frequency from 5,400 to 11,250 Hz. Eighteen devices had a sensitivity above 60%, and nine devices had a sensitivity above 80%. However, for six instruments, the relationship between Doppler and angiography was too weak to establish any cutpoint. In addition, for one instrument a value could be established, but the associated sensitivity was only 18%. This remarkable variability in the performance is at odds with the high sensitivity uniformly published in the literature, suggesting (a) that the high reported sensitivity for Doppler may represent an overestimate of average performance, perhaps due to publication bias, (b) the paramount need for documented quality control measures within local laboratories to insure that Doppler examinations are performed reliably, and (c) the need for caution in the generalization of results among laboratories. PMID- 26486263 TI - Acute stroke trials: Reasons for patient withdrawal. AB - Knowing why patients fail to complete a clinical trial should help in planning such trials and in estimating their costs. We analyzed reasons why subjects failed to complete two similar acute stroke trials of calcium-channel antagonists. The trials were double-blind, placebo-controlled, and lasted 2 and 3 weeks, respectively. We enrolled 43 patients in the first trial and 37% were withdrawn; 30 patients were enrolled in the second trial and 47% were withdrawn. Reasons for withdrawal were similar in the two trials. When data from the two trials were combined, reasons for withdrawal were errors in administering medication (11%), use of a proscribed drug (7%), early death (7%), a disqualifying illness discovered after enrollment (8%), withdrawal of consent (4%), and enrollment beyond the time limit (<1%). Presence of stroke risk factors, age, sex, and even stroke severity did not significantly increase withdrawal frequency. Since most patients were lost early in the trial, its length did not contribute substantially to premature withdrawal. PMID- 26486264 TI - Recovery and outcome of patients with stroke treated in an acute care hospital. AB - This retrospective study of patients with stroke was performed to describe the patients' functional independence on admission to and discharge from physical therapy treatment, determine whether significant functional recovery occurred during the treatment period, and identify independent variables correlating with recovery and outcome at discharge. The Functional Independence Measurement (FIM) system was used to score performance in bed mobility, transfers, locomotion, and stairs. Outcome was indicated by the discharge FIM scores and discharge habitat. The 105 patients whose acute care records were reviewed demonstrated significant improvements between admission and discharge in all functions. Among the variables that correlated significantly with recovery were number of treatments and admission FIM scores. Age and number of treatments correlated significantly with discharge habitat. All FIM scores (admission and discharge) correlated significantly with discharge habitat. Results suggest that FIM scores can be used to document the functional status of patients with stroke in an acute care setting and that the scores have value as predictors of recovery and outcome. PMID- 26486265 TI - Longitudinal measurement of cerebral perfusion in patients with multi-infarct dementia. AB - Longitudinal measurements of local cerebral blood flow (LCBF) were performed in 13 patients with multi-infarct dementia (MID) utilizing the xenon-enhanced computed tomography-CBF method. Subjects were divided into two groups: a group consisting of five patients with MID who deteriorated (aged 60.6 +/- 5.3 years) and whose CCSE scores decreased and a stable group comprised of eight patients (aged 64.5 +/- 4.5 years) whose CCSE scores did not change. Mean intervals between first and second LCBF measurements were 663 +/- 182 days for the deteriorated group and 795 +/- 495 days for the stable group. In the deteriorated group, LCBF values for frontal cortex, thalamus, and frontal white matter had declined further at the second measurement. In the stable group, LCBF values were not uniformly stable, but there were no overall mean decreases. The annual rate of decline among patients who deteriorated for frontal cortex, thalamus, and frontal white matter exceeded annual declines measured in elderly normal volunteers. Results suggest that progressive cerebral hypoperfusion contributes to cognitive declines in mild MID, but, if cerebral perfusion of frontal lobes and basal ganglia can become stabilized, further cognitive deterioration can be prevented. PMID- 26486267 TI - Aspirin in stroke prevention. PMID- 26486266 TI - Releasable tissue plasminogen activators in ischemic stroke. AB - To determine if patients who suffer atherothrombotic ischemic stroke have altered release of tissue plasminogen activator (t-PA), we measured levels in 22 patients within 24 h of onset of symptoms and 1-2 months later. t-PA levels were measured in blood samples by using a colorimetric method after subjecting the plasma to euglobulin fractionation and reacting it with plasminogen and plasmin substrate. Values from a group of normal volunteers previously studied were used as controls. Individual variability in t-PA levels was found acutely and in the recovery phase. During the latter, patients' levels were significantly higher than controls, which was not the case in the acute phase. There was no correlation among t-PA levels, size of cerebral infarct, and patients' clinical status. We propose that endothelial repair and a rebound in endogenous fibrinolytic activity in the absence of peripheral venous disease are responsible for the late (recovery phase) elevation in t-PA. PMID- 26486268 TI - Early treatment of acute ischemic stroke. PMID- 26486269 TI - Iron-based inorganic-organic hybrid and superlattice thin films by ALD/MLD. AB - Here we present novel layer-by-layer deposition processes for the fabrication of inorganic-organic hybrid thin films of the (-Fe-O-C6H4-O-)n type and also superlattices where thicker iron oxide layers alternate with monomolecular-thin organic layers. The processes are based on a combination of atomic layer deposition (ALD) and molecular layer deposition (MLD) techniques where the cyclopentadienyl iron dicarbonyl dimer (Cp2Fe2(CO)4) is used as the iron source and hydroquinone (HQ) as the organic precursor. For the (-Fe-O-C6H4-O-)n hybrid films a growth rate value as high as 3.7 A per cycle was achieved at 180 degrees C. Superlattices where thin crystalline iron oxide layers of the magnetite structure alternate with single organic layers consisting of benzene rings were moreover successfully fabricated from the same precursors at 160 degrees C using water as the source of oxygen in the ALD cycles for the magnetite layers. We foresee that our new ALD/MLD processes offer a valuable novel tool to modify the properties of magnetite thin films and even more widely possess the potential to boost the ALD/MLD research frontier on functional transition metal oxide based thin films. PMID- 26486270 TI - Role of Spm-Cer-S1P signalling pathway in MMP-2 mediated U46619-induced proliferation of pulmonary artery smooth muscle cells: protective role of epigallocatechin-3-gallate. AB - During remodelling of pulmonary artery, marked proliferation of pulmonary artery smooth muscle cells (PASMCs) occurs, which contributes to pulmonary hypertension. Thromboxane A2 (TxA2) has been shown to produce pulmonary hypertension. The present study investigates the inhibitory effect of epigallocatechin-3-gallate (EGCG) on the TxA2 mimetic, U46619-induced proliferation of PASMCs. U46619 at a concentration of 10 nM induces maximum proliferation of bovine PASMCs. Both pharmacological and genetic inhibitors of p(38)MAPK, NF-kappaB and MMP-2 significantly inhibit U46619-induced cell proliferation. EGCG markedly abrogate U46619-induced p(38)MAPK phosphorylation, NF-kappaB activation, proMMP-2 expression and activation, and also the cell proliferation. U46619 causes an increase in the activation of sphingomyelinase (SMase) and sphingosine kinase (SPHK) and also increase sphingosine 1 phosphate (S1P) level. U46619 also induces phosphorylation of ERK1/2, which phosphorylates SPHK leading to an increase in S1P level. Both pharmacological and genetic inhibitors of SMase and SPHK markedly inhibit U46619-induced cell proliferation. Additionally, pharmacological and genetic inhibitors of MMP-2 markedly abrogate U46619-induced SMase activity and S1P level. EGCG markedly inhibit U46619-induced SMase activity, ERK1/2 and SPHK phosphorylation and S1P level in the cells. Overall, Sphingomyeline-Ceramide Sphingosine-1-phosphate (Spm-Cer-S1P) signalling axis plays an important role in MMP-2 mediated U46619-induced proliferation of PASMCs. Importantly, EGCG inhibits U46619 induced increase in MMP-2 activation by modulating p(38)MAPK-NFkappaB pathway and subsequently prevents the cell proliferation. PMID- 26486272 TI - Routine Use of Contact Precautions for Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus: Which Way Is the Pendulum Swinging? AB - BACKGROUND Studies have suggested that contact precautions (CP) for methicillin resistant Staphylococcus aureus and vancomycin-resistant enterococcus may have risks that outweigh the benefits. These risks, coupled with more widespread use of horizontal interventions such as daily bathing with chlorhexidine gluconate, have brought into question the value of routine CP for these organisms. OBJECTIVE To assess the state of utilization of CP as well as adjunctive measures to reduce the risk of transmission in US hospitals. DESIGN Cross-sectional survey. PARTICIPANTS Total of 751 physician members of the Emerging Infections Network. METHODS An 8-question electronic survey distributed by email. RESULTS A total of 426/751 (57%) responded to the survey; 337/364 (93%) of respondents use routine CP for methicillin-resistant S. aureus and 335/364 (92%) use routine CP for vancomycin-resistant enterococcus. The most widely used trigger for initiation of CP for both pathogens was positive clinical culture. Practices for discontinuation of isolation varied widely. We found that 325/354 (92%) perform routine chlorhexidine gluconate bathing and 236/353 (67%) perform S. aureus decolonization with mupirocin for 1 or more subsets of inpatients, and 82/356 (23%) reported using either hydrogen peroxide vapor or ultraviolet-C room disinfection at discharge. Free text responses noted frustration and variation in the application, practice, and process for initiation and discontinuation of CP. CONCLUSIONS Use of CP for methicillin-resistant S. aureus and vancomycin resistant enterococcus remains commonplace, although horizontal interventions such as chlorhexidine gluconate bathing are increasingly used. The heterogeneity of practices and policies was striking. Evidence-based guidelines regarding CP and horizontal interventions are needed. Infect. Control Hosp. Epidemiol. 2015;37(1):36-40. PMID- 26486271 TI - Orphan nuclear receptor Nur77 affects cardiomyocyte calcium homeostasis and adverse cardiac remodelling. AB - Distinct stressors may induce heart failure. As compensation, beta-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca(2+) ([Ca(2+)]i). However, chronic beta-adrenergic stimulation promotes adverse cardiac remodelling. Cardiac expression of nuclear receptor Nur77 is enhanced by beta-adrenergic stimulation, but its role in cardiac remodelling is still unclear. We show high and rapid Nur77 upregulation in cardiomyocytes stimulated with beta-adrenergic agonist isoproterenol. Nur77 knockdown in culture resulted in hypertrophic cardiomyocytes. Ventricular cardiomyocytes from Nur77-deficient (Nur77-KO) mice exhibited elevated diastolic and systolic [Ca(2+)]i and prolonged action potentials compared to wild type (WT). In vivo, these differences resulted in larger cardiomyocytes, increased expression of hypertrophic genes, and more cardiac fibrosis in Nur77-KO mice upon chronic isoproterenol stimulation. In line with the observed elevated [Ca(2+)]i, Ca(2+)-activated phosphatase calcineurin was more active in Nur77-KO mice compared to WT. In contrast, after cardiac pressure overload by aortic constriction, Nur77-KO mice exhibited attenuated remodelling compared to WT. Concluding, Nur77-deficiency results in significantly altered cardiac Ca(2+) homeostasis and distinct remodelling outcome depending on the type of insult. Detailed knowledge on the role of Nur77 in maintaining cardiomyocyte Ca(2+) homeostasis and the dual role Nur77 plays in cardiac remodelling will aid in developing personalized therapies against heart failure. PMID- 26486274 TI - Fast microwave treatments of single source alkoxides for nanostructured Li-ion battery electrodes. AB - Microwave or ultrasonic treatment of metal alkoxides presents a fast, low cost route to both anode and cathode nanomaterials for Li-ion battery applications. Here, we demonstrate the formation of LiMPO4 (M = Fe, Mn) and Mn3O4 nanostructures via this simple route which exhibit excellent electrochemical performances. This approach opens up a new avenue for the targeted design of nanostructured materials, where co-location of the desired metals in a single starting material shortens reaction times and temperatures since there is a decrease in diffusional energy requirements usually needed for these reactions to proceed. PMID- 26486273 TI - Microphthalmia-associated transcription factor/T-box factor-2 axis acts through Cyclin D1 to regulate melanocyte proliferation. AB - OBJECTIVES: Control of cell proliferation is critical for accurate cell differentiation and tissue formation, during development and regeneration. Here, we have analysed the role of microphthalmia-associated transcription factor MITF and its direct target, T-box factor TBX2, in regulating proliferation of mammalian neural crest-derived melanocytes. MATERIALS AND METHODS: Immunohistochemistry was used to examine spatial and temporal expression of TBX2 in melanocytes in vivo. RNAi and cell proliferation analysis were used to investigate functional roles of TBX2. Furthermore, quantitative RT-PCR, western blot analysis and flow cytometry were used to further scrutinize molecular mechanisms underlying TBX2-dependent cell proliferation. RESULTS: TBX2 was found to be co-expressed with MITF in melanocytes of mouse hair follicles. Specific Tbx2 knockdown in primary neural crest cells led to inhibition MITF-positive melanoblast proliferation. Tbx2 knockdown in melan-a cells led to reduction in Cyclin D1 expression and G1-phase cell cycle arrest. TBX2 directly activated Ccnd1 transcription by binding to a specific sequence in the Ccnd1 promoter, and the defect in cell proliferation could be rescued partially by overexpression of Cyclin D1 in Tbx2 knockdown melanocytes. CONCLUSIONS: Results suggest that the Mitf-Tbx2-Cyclin D1 pathway played an important role in regulation of melanocyte proliferation, and provided novel insights into the complex physiology of melanocytes. PMID- 26486275 TI - Turning bubbles on and off during boiling using charged surfactants. AB - Boiling--a process that has powered industries since the steam age--is governed by bubble formation. State-of-the-art boiling surfaces often increase bubble nucleation via roughness and/or wettability modification to increase performance. However, without active in situ control of bubbles, temperature or steam generation cannot be adjusted for a given heat input. Here we report the ability to turn bubbles 'on and off' independent of heat input during boiling both temporally and spatially via molecular manipulation of the boiling surface. As a result, we can rapidly and reversibly alter heat transfer performance up to an order of magnitude. Our experiments show that this active control is achieved by electrostatically adsorbing and desorbing charged surfactants to alter the wettability of the surface, thereby affecting nucleation. This approach can improve performance and flexibility in existing boiling technologies as well as enable emerging or unprecedented energy applications. PMID- 26486276 TI - Ferroelectricity in underdoped La-based cuprates. AB - Doping a "parent" antiferromagnetic Mott insulator in cuprates leads to short range electronic correlations and eventually to high-Tc superconductivity. However, the nature of charge correlations in the lightly doped cuprates remains unclear. Understanding the intermediate electronic phase in the phase diagram (between the parent insulator and the high-Tc superconductor) is expected to elucidate the complexity both inside and outside the superconducting dome, and in particular in the underdoped region. One such phase is ferroelectricity whose origin and relation to the properties of high-Tc superconductors is subject of current research. Here we demonstrate that ferroelectricity and the associated magnetoelectric coupling are in fact common in La-214 cuprates namely, La2 xSrxCuO4, La2LixCu1-xO4 and La2CuO4+x. It is proposed that ferroelectricity may result from local CuO6 octahedral distortions, associated with the dopant atoms and clustering of the doped charge carriers, which break spatial inversion symmetry at the local scale whereas magnetoelectric coupling can be tuned through Dzyaloshinskii-Moriya interaction. PMID- 26486277 TI - Self-assembly via microfluidics. AB - The self-assembly of amphiphilic building blocks has attracted extensive interest in myriad fields in recent years, due to their great potential in the nanoscale design of functional hybrid materials. Microfluidic techniques provide an intriguing method to control kinetic aspects of the self-assembly of molecular amphiphiles by the facile adjustment of the hydrodynamics of the fluids. Up to now, there have been several reports about one-step direct self-assembly of different building blocks with versatile and multi-shape products without templates, which demonstrated the advantages of microfluidics. These assemblies with different morphologies have great applications in various areas such as cancer therapy, micromotor fabrication, and controlled drug delivery. PMID- 26486278 TI - Adhesion of voids to bimetal interfaces with non-uniform energies. AB - Interface engineering has become an important strategy for designing radiation resistant materials. Critical to its success is fundamental understanding of the interactions between interfaces and radiation-induced defects, such as voids. Using transmission electron microscopy, here we report an interesting phenomenon in their interaction, wherein voids adhere to only one side of the bimetal interfaces rather than overlapping them. We show that this asymmetrical void interface interaction is a consequence of differing surface energies of the two metals and non-uniformity in their interface formation energy. Specifically, voids grow within the phase of lower surface energy and wet only the high interface energy regions. Furthermore, because this outcome cannot be accounted for by wetting of interfaces with uniform internal energy, our report provides experimental evidence that bimetal interfaces contain non-uniform internal energy distributions. This work also indicates that to design irradiation-resistant materials, we can avoid void-interface overlap via tuning the configurations of interfaces. PMID- 26486279 TI - CELIAC DISEASE OR GLUTEN RELATED DISORDERS? WHO WOULD BE THE DISEASE OF THE TIME? PMID- 26486280 TI - THE NEUROLOGICAL FACE OF CELIAC DISEASE. AB - BACKGROUND: Several neurological disorders have also been widely described in celiac disease patients. OBJECTIVE: The aim of this study was to determine the incidence of accompanying different neurologic manifestations in children with celiac disease at the time of diagnosis and to discuss these manifestations in the light of the recent literature. METHODS: This prospective cross sectional study included 297 children diagnosed with celiac disease. The medical records of all patients were reviewed. RESULTS: In neurological evaluation, totally 40 (13. 5%) of the 297 celiac patients had a neurological finding including headache, epilepsy, migraine, mental retardation, breath holding spells, ataxia, cerebral palsy, attention deficit hyperactivity disorder, Down syndrome and Turner syndrome in order of frequency. There was not any significant difference between the laboratory data of the patients with and without neurological manifestations. However; type 3a biopsy was statistically significantly more common among patients without neurological manifestations, while type 3b biopsy was statistically significantly more common among patients with neurological manifestations. CONCLUSION: It is important to keep in mind that in clinical course of celiac disease different neurological manifestations may be reported. PMID- 26486281 TI - QUALITY OF LIFE EVALUATION IN CELIAC PATIENTS FROM SOUTHERN BRAZIL. AB - BACKGROUND: Restrictions imposed by the gluten-free diet generate large changes in the daily habits of the celiac patient, causing a negative impact on quality of life. OBJECTIVE: This study aimed to evaluate the quality of life of patients with celiac disease on a capital in Southern Brazil. METHODS: Patients older than 18 years were included, with confirmed celiac disease for at least 60 days in the period from June to October 2013. A validated questionnaire, with specific questions to assess the patient's quality of life celiac was applied. A total score ranged from 20 to 100 points; the higher the score, worse quality of life. RESULTS: A total of 103 questionnaires were evaluated, 96 (93.2%) female, with average score 56.6+/-12.35 (28 to 88 points). The comparison between the questionnaire scores and family income was not significant (P=0.139). Patients diagnosed less than 1 year have poorer quality of life than those with more than 10 years (P=0.063). Patients older than 60 years had better quality of life compared with the younger ones (P=0.04). CONCLUSION: There was no association between quality of life and factors such as family income, length of diet and age at diagnosis. Chronological age greater than 60 years has positively influenced the quality of life of celiac patients. PMID- 26486282 TI - LOW BONE MINERAL DENSITY IN BRAZILIAN PATIENTS AT DIAGNOSIS OF CELIAC DISEASE. AB - BACKGROUND: Low bone mineral density is considered an extra-intestinal manifestation of celiac disease with reduced bone mass, increased bone fragility, and risk of fractures. Celiac disease is considered a condition at high risk for secondary osteoporosis and the evaluation of bone density is very important in the clinical management of these patients. OBJECTIVE: The present study aimed to investigate bone alterations in celiac patients from Curitiba, South Region of Brazil at diagnosis, correlating the findings with age and gender. METHODS: Patients who were included in the study were attended to in a private office of the same physician from January 2009 to December 2013. The diagnosis of celiac disease was done through clinical, serological and histological findings. All data were collected from the medical charts of the patients. After the diagnosis of celiac disease, evaluation for low bone mineral density was requested by dual energy X-ray absorptiometry (DEXA). DEXA bone densitometer was used to estimate low bone mineral density at the lumbar spine and femur. RESULTS: A total of 101 patients, 82 (81.2%) female and 19 (18.8%) male subjects, with mean age of 39.0+/ 3.03 years were included. At celiac disease diagnosis, 36 (35.6%) were younger than 30 years, 41 (40.6%) were between 31 and 50 years, and 24 (23.8%) were older than 50 years. Among the evaluated patients, 69 (68.3%) presented low bone mineral density, being 47% with osteopenia and 32% with osteoporosis. Patients who were older than 51 years and diagnosed with celiac disease presented low bone mineral density in 83.3% (20/24) of the cases. As expected, age influenced significantly the low bone mineral density findings. Among women, low bone mineral density was present with high frequency (60%) from 30 to 50 years. In patients diagnosed older than 60 years (n=8), all the women (n=5) and two of the three men had osteoporosis. CONCLUSION: This study demonstrated that 69% of Brazilian patients with celiac disease at diagnosis had low bone mineral density, being more frequent in women older than 50 years. PMID- 26486283 TI - URINARY DYSFUNCTION AFTER SURGICAL TREATMENT FOR RECTAL CANCER. AB - BACKGROUND: The impact on quality of life attributed to treatment for rectal cancer remains high. Deterioration of the urinary function is a relevant complication within that context. OBJECTIVE: To detect the presence of urinary dysfunction and its risk factors among individuals underwent surgical treatment for rectal cancer. METHODS: The present prospective study analyzed 42 patients from both genders underwent surgical treatment for rectal adenocarcinoma with curative intent. The version of the International Prostatic Symptom Score (IPSS) questionnaire validated for the Portuguese language was applied at two time points: immediately before and 6 months after surgery. Risk factors for urinary dysfunction were analysed by means of logistic regression and Student's t-test. RESULTS: Eight (19%) participants exhibited moderate-to-severe urinary dysfunction 6 months after surgery; the average IPSS increased from 1.43 at baseline to 4.62 six months after surgery (P<0.001). None of the variables assessed as potential risk factors exhibited statistical significance, i.e., age, gender, distance from tumour to anal margin, neoadjuvant therapy, adjuvant therapy, type of surgery, surgical approach (laparoscopy or laparotomy), and duration of surgery. CONCLUSION: This study identified an incidence of 19% of moderate to severe urinary dysfunction after 6 months surveillance. No risk factor for urinary dysfunction was identified in this population. PMID- 26486284 TI - ENDOSCOPIC ULTRASOUND IN THE EVALUATION OF UPPER SUBEPITHELIAL LESIONS. AB - BACKGROUND: Endoscopic ultrasound is considered the best imaging test for the diagnosis and evaluation of subepithelial lesions of the gastrointestinal tract. OBJECTIVE: The present study aims to describe the endosonographic characteristics of upper gastric subepithelial lesions and our experience using endoscopic ultrasound for evaluation of such lesions. METHODS: Retrospective data study of 342 patients who underwent endoscopic ultrasound evaluation of subepithelial lesions. RESULTS: Lesions of the fourth layer were more common in the stomach (63.72%) than in the esophagus (44.68%) and duodenum (29.03%). In stomach, 81.1% of the lesions >=2 cm, and 96.5% >=3 cm, were from the fourth layer. Endosonographic signs that could be related to malignant behavior, such as irregular borders, echogenic foci, cystic spaces and/or size greater than 3 cm were identified in 34 (15.81%) lesions at the first endoscopic ultrasound evaluation. Endoscopic ultrasound-fine needle aspiration did the diagnosis in 21 (61.76%) patients who were submitted a puncture. Three (12.0%) lesions of 25 who were submitted to regular endoscopic ultrasound surveillance increased the size. CONCLUSION: Stomach is the organ most affected with subepithelial lesions of the gastrointestinal tract and the fourth layer was the most common layer of origin. More than 80% of gastric subepithelial lesions from the fourth layer are >=2 cm. Endoscopic ultrasound evaluation of subepithelial lesions has been very important for stratification into risk groups and to determine the best management. PMID- 26486285 TI - EFFECT OF GUM CHEWING ON AIR SWALLOWING, SALIVA SWALLOWING AND BELCHING. AB - BACKGROUND: Eructation is a physiologic event which allows gastric venting of swallowed air and most of the time is not perceived as a symptom. This is called gastric belching. Supragastric belching occurs when swallowed air does not reach the stomach and returns by mouth a short time after swallowing. This situation may cause discomfort, life limitations and problems in daily life. OBJECTIVE: Our objective in this investigation was to evaluate if gum chewing increases the frequency of gastric and/or supragastric belches. METHODS: Esophageal transit of liquid and gas was evaluated by impedance measurement in 16 patients with complaint of troublesome belching and in 15 controls. The Rome III criteria were used in the diagnosis of troublesome belching. The esophageal transit of liquid and gas was measured at 5 cm, 10 cm, 15 cm and 20 cm from the lower esophageal sphincter. The subjects were evaluated for 1 hour which was divided into three 20 minute periods: (1) while sitting for a 20-minute base period; (2) after the ingestion of yogurt (200 mL, 190 kcal), in which the subjects were evaluated while chewing or not chewing gum; (3) final 20-minute period in which the subjects then inverted the task of chewing or not chewing gum. In gastric belch, the air flowed from the stomach through the esophagus in oral direction and in supragastric belch the air entered the esophagus rapidly from proximal and was expulsed almost immediately in oral direction. Air swallows were characterized by an increase of at least 50% of basal impedance and saliva swallow by a decrease of at least 50% of basal impedance, that progress from proximal to distal esophagus. RESULTS: In base period, air swallowing was more frequent in patients than in controls and saliva swallowing was more frequent in controls than in patients. There was no difference between the medians of controls and patients in the number of gastric belches and supragastric belches. In six patients, supragastric belches were seen at least once during the 20-minute base period. None of the controls had supragastric belches. In the control group, the ingestion of yogurt caused no significant alteration in the number of air swallows, saliva swallows, gastric belches and supragastric belches. In the patient group, there was an increase in the number of air swallows. If the subjects were chewing gum during this 20-minute period, there was an increase in the number of saliva swallows in both groups, without alterations of the number of air swallow, gastric belches and supragastric belches. There was no alteration in the number of the saliva swallows, air swallows, gastric belches and supragastric belches in both groups for subjects who did not chew gum in the 20 40 minute period after yogurt ingestion. When the subjects were chewing the gum, there was an increase in saliva swallows in the control and patients groups and in air swallows in the patients group. CONCLUSION: Gum chewing causes an increase in saliva swallowing in both patients with excessive belching and in controls, and an increase in air swallowing in patients with excessive belching 20 minutes after yogurt ingestion. Gum chewing did not increase or decrease the frequency of gastric or supragastric belches. PMID- 26486286 TI - EVALUATION OF LEUKOCYTE ESTERASE REAGENT STRIPS TEST IN THE DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS IN CHILDREN WITH CIRRHOSIS. AB - BACKGROUND: Spontaneous bacterial peritonitis is defined as an ascetic fluid infection without an evident intra-abdominal surgically treatable source. Spontaneous bacterial peritonitis is one of the severe complications in patients with cirrhosis and ascites. Without early antibiotic treatment, this complication is associated with high mortality rate; therefore, early diagnosis and treatment of spontaneous bacterial peritonitis is necessary for survival. Leukocyte esterase reagent can rapidly diagnose the spontaneous bacterial peritonitis. OBJECTIVE: This study aimed to find out the diagnostic accuracy of leukocyte esterase dipstick test for the diagnosis of spontaneous bacterial peritonitis. METHODS: A single centered hospital-based cross-sectional study was conducted during July 2013 to August 2014 on children with cirrhotic liver disease and ascites who were admitted in the Department of Pediatric Gastroenterology in Nemazee Hospital affiliated to Shiraz University of Medical Sciences (Iran). All patients underwent abdominal paracentesis, and the ascitic fluid was processed for cell count, leukocyte esterase reagent strip test (Combiscreen SL10) and culture. Spontaneous bacterial peritonitis was defined as having a polymorphonuclear count (PMN >=250/m3) in ascitic fluid. Sensitivity, specificity, positive predictive value and negative predictive value of leukocyte esterase test were calculated according to the formula. RESULTS: Totally, 150 ascitic fluid sample of cirrhotic male patients (53.2%) and their mean age (4.33+/-1.88 years) were analyzed. Biliary atresia (n=44, 29.4%) and idiopathic neonatal hepatitis (n=29, 19.3%) were the most frequent etiology of cirrhosis. Also, abdominal pain (68.6%) and distension (64%) were the most common presenting complaint. Of all cases, 41 patients (27.35%) were diagnosed to have spontaneous bacterial peritonitis (PMN >=250/mm3). Sensitivity and specificity of leukocyte esterase reagent test according to PMNs >=250 mm3 were 87.80% and 91.74%, also on ascitic fluid culture results were 88.23% and 77.44%. Positive predictive value and negative predictive value of this test in PMNs >=250 mm3 were 80% and 95.23% and in cases with positive culture 33.33% and 98.09% were obtained, respectively. Efficiency of leukocyte esterase reagent test in diagnosing spontaneous bacterial peritonitis, according to PMNs >=250 mm3 and culture results were 90.66% and 78.66%. CONCLUSION: The leukocyte esterase strip test may be used as rapid test for diagnosis of spontaneous bacterial peritonitis due to its high diagnostic validity. PMID- 26486287 TI - INTERMEDIATE ENDEMICITY OF HEPATITIS A VIRUS INFECTION IN RURAL SETTLEMENT PROJECTS OF SOUTHWEST GOIAS, BRAZIL. AB - BACKGROUND: Rural populations present an elevated risk of exposure to hepatitis A virus. OBJECTIVE: The objective of this study was to estimate the prevalence and risk factors associated with hepatitis A virus infection among residents of rural settlement projects of southwest Goias, Central Brazil. METHODS: A total of 466 residents were interviewed and tested for the detection of anti- hepatitis A virus antibodies by ELISA. RESULTS: The global prevalence of anti- hepatitis A virus was 82.2%. In individuals aged 5-9 years and 10-19 years, the prevalence was 15% and 58.8%, respectively. Persons in the 10-19 age group, with a history of life in encampments, with more than five people per residence consuming well water, were predictors for exposure to hepatitis A virus. CONCLUSION: Our results suggest that the hepatitis A virus endemicity in rural settlements in southwest Goias similar to that found in the urban population of the Midwest Region, confirming the implementation of universal hepatitis A vaccination in children. PMID- 26486288 TI - NUTRITIONAL STATUS AND DIETARY INTAKE IN NON-CIRRHOTIC ADULT CHRONIC HEPATITIS C PATIENTS. AB - BACKGROUND: The hepatitis C virus is one of the main causes of liver disease worldwide and may develop nutritional deficiencies. OBJECTIVE: The objective of this study was to assess and compare different nutritional status methods of adult patients with chronic hepatitis C virus, and to describe inadequacies in dietary intake. METHODS: A cross-sectional study was conducted with adult outpatients with hepatitis C virus at a Brazilian hospital. Nutritional assessment included the 24-hour dietary recall, anthropometry (body weight, height, body mass index, triceps skinfold, mid-upper arm circumference, mid-arm muscle circumference, mid-upper arm muscle area, adductor policis muscle), Subjective Global Assessment, Royal Free Hospital Global Assessment and handgrip strength. RESULTS: A total of 94 outpatients (ages 30 to 76 years), was included, 46 were men. The prevalence of malnutrition as measured by the different methods was 6.4% (body mass index); 60.6% (handgrip strength), and 53.2% (Royal Free Hospital Global Assessment). There was correlation between mid-upper arm circumference and mid-arm muscle circumference (r=0.821), mid-upper arm circumference and triceps skinfold (r=0.575) and mid-upper arm circumference and mid-upper arm muscle area (r=0.781). Energy and protein intakes were below recommended levels in 49 (52.1%) and 44 (46.8%) of patients, respectively. Inadequate calcium, potassium, zinc and vitamin C intakes occurred in 92.6%, 97.9%, 63.8% and 60.6% of patients. There was an association between dietary energy and protein intake with Royal Free Hospital Global Assessment (P<0.001) and a tendency for them to be associated with handgrip strength (P=0.076 and P=0.054). CONCLUSION: Malnutrition is frequently in hepatitis C virus patients. They have high prevalence of inadequate energy, protein and micronutrients intake, even in the absence of cirrhosis. PMID- 26486289 TI - LIPID PROFILE OF CIRRHOTIC PATIENTS AND ITS ASSOCIATION WITH PROGNOSTIC SCORES: a cross-sectional study. AB - BACKGROUND: In cirrhosis the production of cholesterol and lipoproteins is altered. OBJECTIVE: Evaluate the lipid profile by measuring total cholesterol, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein and triglyceride levels in patients with cirrhosis caused by alcoholism and/or hepatitis C virus infection and determine its association with Child-Pugh and MELD scores. METHODS: Cross-sectional retrospective study of patients treated at the outpatient clinic in Porto Alegre, Brazil, from 2006 to 2010. RESULTS: In total, 314 records were reviewed, and 153 (48.7%) met the inclusion criteria, of which 82 (53.6%) had cirrhosis that was due to hepatitis C virus infection, 50 (32.7%) were due to alcoholism, and 21 (13.7%) were due to alcoholism and hepatitis C virus infection. The total cholesterol levels diminished with a Child Pugh progression (P<0.001). Child-Pugh C was significantly associated with lover levels of low-density lipoprotein (<70 mg/dL; P<0.001), high-density lipoprotein (<40 mg/dL; P<0.001) and triglyceride (<70 mg/dL; P=0.003). MELD>20 was associated with lower total cholesterol levels (<100mg/dL; P<0.001), very low density lipoprotein (<16 mg/dL; P=0.006), and low-density lipoprotein (<70 mg/dL; P=0.003). Inverse and statistically significant correlations were observed between Child-Pugh and all the lipid fractions analyzed (P<0.001). The increase in MELD was inversely correlated with reduced levels in total cholesterol (P<0.001), high-density lipoprotein (P<0.001), low-density lipoprotein (P<0.001), very low-density lipoprotein (P=0.030) and triglyceride (P=0.003). CONCLUSION: A reduction in the lipid profile in patients with cirrhosis due to hepatitis C virus infection and/or alcoholism was significantly associated with the Child Pugh and MELD prognostic markers. These results suggest that the lipid profile may be used as a tool to assist in evaluating liver disease. PMID- 26486290 TI - PEGYLATED INTERFERON AND RIBAVIRIN FOR TREATMENT OF RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION: a single-liver transplant center experience in Brazil. AB - BACKGROUND: Treatment of hepatitis C virus infection in post-transplantation patients is a challenge due to poor tolerance and low success rates. OBJECTIVE: To determine the response rate to pegylated interferon and ribavirin in post liver transplant patients with hepatitis C recurrence. METHODS: Between 18 May 2002 and 18 December 2011, 601 patients underwent liver transplantation at our service (Hospital Universitario Walter Cantidio, University of Ceara), 176 (29.2%) of whom were hepatitis C virus positive. Forty received antiviral therapy and were included in this cohort study. Twenty-eight (70%) completed the treatment protocol, which consisted of pegylated interferon and ribavirin for 48 weeks. RESULTS: The sustained virological response rate was 55% according to intention-to-treat analysis. Recipient age and exposure to antiviral drugs prior to liver transplantation were associated with sustained virological response in the multivariate analysis. Patients were followed for 57 months on the average. Survival at 1 and 5 years was 100% in responders, versus 100% and 78%, respectively, in non-responders. CONCLUSION: Sustained virological response rates were satisfactory in our series of liver transplantation patients, and decreased with increasing recipient age. Non-exposure to antiviral drugs prior to liver transplantation was positively associated with sustained virological response. The overall survival of responders and non-responders was similar. PMID- 26486291 TI - ANALYSIS OF POLYMORPHISMS IN THE INTERLEUKIN 18 GENE PROMOTOR (-137 G/C AND -607 C/A) IN PATIENTS INFECTED WITH HEPATITIS C VIRUS FROM THE BRAZILIAN AMAZON. AB - BACKGROUND: The hepatitis C virus has been recognized as the leading cause of chronic liver disease in the world. Host genetic factors have been implicated in the persistence of hepatitis C virus infection. Single nucleotide polymorphisms at positions -607 C/A (rs1946518) and -137 G/C (rs187238) in the IL-18 gene promoter have been suggested to be associated with delayed hepatitis C virus clearance and persistence of the disease. OBJECTIVE: Identify these polymorphisms in a population infected with hepatitis C virus from the Brazilian Amazon region. METHODS: In a cross-sectional analytical study conducted in Belem, Para, Brazil, 304 patients infected with hepatitis C virus were divided into two groups: group A, patients with persistent infection; group B, patients with spontaneous clearance. The control group consisted of 376 volunteers not infected with hepatitis C virus. Samples were analyzed by RT-PCR for the detection of viral RNA and by RFLP-PCR to evaluate the presence of the -137 G/C and -607 C/A IL-18 gene promoter polymorphisms. RESULTS: Comparison of polymorphism allele frequencies between the patient and control groups showed a higher frequency of allele C at position -607 among patients (P=0.02). When the association between the polymorphisms and viral infection was analyzed, patients carrying genotype C/A at position -607 were found to be at higher risk of persistent hepatitis C virus infection (P=0.03). CONCLUSION: The present results suggest a possible role of the -607 IL-18 gene promoter polymorphism in the pathogenesis of hepatitis C virus infection. PMID- 26486292 TI - INFLUENCE OF OXIDATIVE STRESS AND OBESITY IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS. AB - BACKGROUND: Nonalcoholic steatohepatitis is considered the hepatic manifestation of metabolic syndrome and it is particularly associated to the insulin resistance, hypertension, obesity and abnormalities in lipid and glucose metabolism. OBJECTIVE: Considering the importance of obesity and oxidative stress in the pathophysiology of nonalcoholic steatohepatitis, this study aimed to evaluate the presence and association of the obesity and oxidative stress in this pathology. METHODS: Fifteen outpatients with nonalcoholic steatohepatitis (nonalcoholic steatohepatitis group), diagnosed according to the histopathological findings from the liver biopsy, and 15 body mass index-matched subjects (non nonalcoholic steatohepatitis group) without nonalcoholic steatohepatitis were included. All volunteers were registered in a Brazilian University Hospital. Nutritional assessment (weight, height, body mass index and waist circumference) and biochemical analysis (fasting glucose, liver enzymes, lipid profile, leptin, superoxide dismutase, glutathione peroxidase, vitamins C and E, catalase and 8-isoprostane) were performed for all the participants. The student t test was used for statistical analysis, with P<0.05 as the significant factor. RESULTS: Nonalcoholic steatohepatitis patients had higher fasting glucose, hepatic enzymes (serum aspartate aminotransaminase, alanine aminotransaminase, gamma glutamyl transferase, alkaline phosphatase), triglycerides and superoxide dismutase and lower glutathione peroxidase values than non nonalcoholic steatohepatitis individuals. CONCLUSION: This paper demonstrates that only the presence of obesity is not enough to trigger alterations in all the studied biomarkers. Despite the majority of oxidative stress markers being found to be similar in both conditions, the nonalcoholic steatohepatitis subjects could be slightly more affected than the non nonalcoholic steatohepatitis individuals. PMID- 26486293 TI - ACOUSTIC RADIATION FORCE IMPULSE IS EQUIVALENT TO LIVER BIOPSY TO EVALUATE LIVER FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS C AND NONALCOHOLIC FATTY LIVER DISEASE. AB - BACKGROUND: Liver biopsy is recommended as the gold standard method for assessing the stage of liver fibrosis in patients with chronic liver disease. However, it is invasive, with potential risks and complications. Elastography is an ultrasound technique that provides information of changes in the liver tissue, evaluating tissue elasticity and acoustic radiation force impulse is one of the available techniques. OBJECTIVE: The main objective of this study was to evaluate the sensitivity and specificity of acoustic radiation force impulse comparing to liver biopsy to evaluate fibrosis in patients with chronic hepatitis C virus and nonalcoholic fatty liver disease. METHODS: Twenty four patients were included, everyone underwent liver biopsy and acoustic radiation force impulse, and the results were compared with values described in the literature by several authors. RESULTS: In the population of patients with chronic hepatitis C, our data were better correlated with data published by Carmen Fierbinteanu-Braticevici et al., with an accuracy of 82.4%, sensitivity of 71.4% and specificity of 90%. For nonalcoholic fatty liver disease, our data were better correlated with data published by Masato Yoneda et al., with an accuracy of 85.7%, sensitivity 80% and specificity of 100%. CONCLUSION: Acoustic radiation force impulse is a method with good accuracy to distinguish initial fibrosis from advanced fibrosis in hepatitis C virus and nonalcoholic fatty liver disease and can replace biopsy in most cases. PMID- 26486294 TI - GAMMA GLUTAMYLTRANSFERASE IMPACT IN THERAPEUTIC RESPONSE OF CHRONIC HEPATITIS C: a systematic review of the literature. AB - BACKGROUND: The standard treatment of chronic hepatitis C is the administration of pegylated interferon alpha2a or alpha2b in combination with ribavirin, but adverse effects can be observed, as well as the high cost of this therapy. Therefore, there is interest in understanding the predictors of sustained virologic response, as the gamma glutamyltransferase. OBJECTIVE: To evaluate the serum levels of gamma glutamyltransferase as a predictor of response to treatment with pegylated interferon alpha and ribavirin in chronic hepatitis C. METHODS: This is a systematic review of literature, conducted by consulting PUBMED, LILACS, MEDLINE, SCOPUS, Cochrane electronic databases, and active search of articles selected between January 2000 and April 2013. RESULTS: A total of 4,785 titles were identified. Out of those material, following inclusion and exclusion criteria, 273 abstracts were selected, by two independent researchers. After reading those texts, the reviewers consensually included ten studies for systematization and classification, according to the criteria of the Oxford Scale. 1B studies are predominant (prospective cohort study - six studies). Rapid virologic response and early virological response were considered as estimates for the sustained virological response. The frequency of virologic response was identified in three studies and early virological response in two, with a total of 392 and 413 patients, respectively; sustained virologic response was reported in nine articles corresponding to 3,787 patients (76.5 %). CONCLUSION: Gamma glutamyltransferase is a predictor of sustained virologic response in the treatment of chronic hepatitis C with pegylated interferon alpha2a or alpha2b associated with ribavirin. PMID- 26486295 TI - PREVALENCE OF INCIDENTAL GALLBLADDER CANCER IN A TERTIARY-CARE HOSPITAL FROM PERNAMBUCO, BRAZIL. AB - BACKGROUND: Gallbladder cancer is sometimes incidentally uncovered following cholecystectomy for gallstones diseases. The supposed highly variable prevalence of incidental gallbladder cancer through our country is unknown. OBJECTIVE: To explore the prevalence of incidental gallbladder cancer in our tertiary-care hospital. METHODS: A cross-sectional study was carried out on patients who consecutively underwent cholecystectomy due to gallstones disease at Faculdade Pernambucana de Saude, Instituto de Medicina Integral Professor Fernando Figueira - FPS/IMIP, from January, 2007 to December, 2010. Data on incidental gallbladder cancer patients were explored for prevalence estimation and description of our experience with the management of this malignancy. RESULTS: Our analysis involved 2018 patients with a marked predominance of women (n=1.697; 84.1%) over men (n=321; 15.9%). The 3-year prevalence estimate of 0.34% was recorded for incidental gallbladder cancer in our sample. Regarding tumor staging, there were 1 T1a, 1 T1b, and 5 T2 adenocarcinoma tumors. Laparoscopic cholecystectomy alone was performed for the T1a tumor, and additional radical surgery was performed in five others. One patient presented metastatic disease at the time of repeat surgery. The final pathology revealed residual/additional disease in all T2 tumors after radical surgery whereas the T1b patient underwent a salvage Whipple's procedure due to a secondary distal cholangiocarcinoma. The patient with T1a tumor is alive after 3-year follow-up but all of the others died because of disease recurrence/progression up to 12 months. CONCLUSION: This study confirms the poor prognosis of Gallbladder cancer even when incidentally diagnosed following cholecystectomy and supposes a 3-year prevalence estimate of 0.34% for incidental gallbladder cancer in our Center from Pernambuco State, Brazil. PMID- 26486296 TI - PLUMMER VINSON SYNDROME--is it common in males? AB - BACKGROUND: Plummer-Vinson syndrome is characterized by a triad of dysphagia, iron deficiency anemia and esophageal web. Most of the patients are middle aged women in the fourth to seventh decade of life. OBJECTIVE: Very few cases of Plummer-Vinson syndrome affecting males have been reported. Here we report a series of male patients found to be suffering from Plummer-Vinson syndrome. METHODS: Five males presented to us with dysphagia and fatigue of various durations, from April to August, 2012. RESULTS: These patients were found to have iron deficiency anemia and esophageal web on subsequent investigations and were treated successfully with oral iron therapy. CONCLUSION: Plummer-Vinson syndrome is common in both males and females and can be successfully treated with oral iron therapy. The patients have an increased risk of developing gastrointestinal malignancies and should be thoroughly evaluated for the same. PMID- 26486297 TI - Interfacial charge-transfer transitions in a TiO2-benzenedithiol complex with Ti S-C linkages. AB - Interfacial charge-transfer (ICT) transitions between organic materials and inorganic semiconductors are a new mechanism for light absorption at organic semiconductor interfaces. ICT transitions cause one-step interfacial charge separation without loss of energy. This feature is potentially useful to realize efficient organic-inorganic hybrid solar cells. ICT transitions have been examined by employing titanium dioxide (TiO2) nanoparticles chemisorbed with pi conjugated molecules via Ti-O-C linkages. Here, we report ICT transitions in a TiO2 and 1,2-benzenedithiol (BDT) complex with Ti-S-C linkages. BDT adsorbs on TiO2 by the bridging bidentate coordination of the sulfur atoms to surface titanium atoms. The TiO2-BDT complex shows ICT transitions from the BDT moiety to the conduction band of TiO2 in the visible region. The ICT transitions occur by orbital overlaps between the d orbitals of the surface titanium atoms and the pi orbitals of the benzene ring. Our density-functional-theory (DFT) analysis reveals that the 3p valence orbitals of the sulfur bridging atoms contribute to more than 50% of the highest occupied molecular orbital (HOMO) and the 3d 3p(sulfur)-pi interaction via the Ti-S-C linkage enhances the electronic mixing between the titanium atoms and the benzene moiety as compared to the 3d 2p(oxygen)-pivia the Ti-O-C linkage. This result indicates the important role of the heavier-atom linkers for strong organic-inorganic electronic couplings. PMID- 26486298 TI - Behcet's disease patients with multiple sclerosis-like features: discriminative value of Barkhof criteria. AB - OBJECTIVES: Behcet's disease (BD) is a systemic auto-inflammatory disorder of unknown cause, which may affect the central nervous system in around 5% of the patients [neuro-BD (NBD)], usually causing large lesions encompassing brainstem, diencephalon and basal ganglia regions. Occasionally NBD patients present with white matter lesions necessitating differential diagnosis from multiple sclerosis (MS). In this study, the efficacy of Barkhof criteria was tested in diagnostic differentiation of NBD and MS. METHODS: Charts and MRIs of 84 NBD patients were retrospectively evaluated. Clinical and radiological features of NBD patients fulfilling (Barkhof+) and not fulfilling Barkhof criteria (Barkhof-) were compared. RESULTS: While the Barkhof- patients (n=73) mostly displayed typical large lesions covering brainstem, diencephalon and basal ganglia regions and neurological findings consistent with brainstem involvement, all Barkhof+ (n=11) patients demonstrated MS-like white matter lesions, fulfilled McDonald's criteria and showed reduced frequency of brainstem symptoms and increased frequency of hemiparesis, hemihypesthesia and spinal cord symptoms. Moreover, the Barkhof+ group had more female patients, increased number of attacks, higher rate of oligoclonal band positivity and less patients with cerebrospinal fluid pleocytosis. CONCLUSIONS: A subgroup of BD patients with neurological complaints displays MS-like lesions, fulfills the clinical and radiological criteria of MS and presents with clinical and laboratory features resembling those of MS rather than NBD. These results suggest that Barkhof+ patients are either an overlapping group between NBD and MS, or they represent MS patients with concomitant systemic findings of BD, rather than NBD. Barkhof criteria appear to be effective in discriminating these patients. PMID- 26486299 TI - Validating self-reported food expenditures against food store and eating-out receipts. AB - BACKGROUND/OBJECTIVES: To compare objective food store and eating-out receipts with self-reported household food expenditures. SUBJECTS/METHODS: The Seattle Obesity Study II was based on a representative sample of King County adults, Washington, USA. Self-reported household food expenditures were modeled on the Flexible Consumer Behavior Survey (FCBS) Module from 2007 to 2009 National Health and Nutrition Examination Survey (NHANES). Objective food expenditure data were collected using receipts. Self-reported food expenditures for 447 participants were compared with receipts using paired t-tests, Bland-Altman plots and kappa statistics. Bias by sociodemographics was also examined. RESULTS: Self-reported expenditures closely matched with objective receipt data. Paired t-tests showed no significant differences between receipts and self-reported data on total food expenditures, expenditures at food stores or eating out. However, the highest income strata showed weaker agreement. Bland-Altman plots confirmed no significant bias across both methods-mean difference: 6.4; agreement limits: 123.5 to 143.4 for total food expenditures, mean difference 5.7 for food stores and mean difference 1.7 for eating out. The kappa-statistics showed good agreement for each (kappa 0.51, 0.41 and 0.49 respectively. Households with higher education and income had significantly more number of receipts and higher food expenditures. CONCLUSIONS: Self-reported food expenditures using NHANES questions, both for food stores and eating out, serve as a decent proxy for objective household food expenditures from receipts. This method should be used with caution among high-income populations, or with high food expenditures. This is the first validation of the FCBS food expenditures question using food store and eating-out receipts. PMID- 26486300 TI - Adherence to the Dutch dietary guidelines is inversely associated with 20-year mortality in a large prospective cohort study. AB - BACKGROUND/OBJECTIVES: The Dutch guidelines for a healthy diet aim to reduce major chronic diseases. However, supporting evidence on their overall association with all-cause and cause-specific mortality is limited. Recently, the Dutch Healthy Diet-index (DHD-index) has been developed to assess adherence to these guidelines. The aim was to examine the association between the DHD-index and all cause mortality and deaths from cardiovascular disease (CVD), coronary heart disease (CHD), stroke and cancer. SUBJECTS/METHODS: We followed 3593 men and women aged 55 years and older enrolled in the Rotterdam Study, a population-based prospective cohort study, from baseline in 1990-1993 to 2011. A validated 170 item food frequency questionnaire at baseline was used to calculate the DHD-index score (maximum 90 points). Cox proportional hazard models were used to estimate hazard ratios (HRs) adjusting for age, sex, total energy intake, smoking and educational level. RESULTS: During the 20-year follow-up, 1831 (51%) deaths were reported. Mean DHD-index score was 60.6 (s.d. 10.6). The score was inversely associated with all-cause mortality (highest vs lowest quartile HR 0.77; 95% confidence interval (CI) 0.67, 0.89). Inverse but non-significant associations were observed for mortality due to CVD (HR 0.74; 95% CI 0.55, 1.01), CHD (HR 0.60; 95% CI 0.34, 1.06) and stroke (HR 0.67; 95% CI 0.36, 1.22), whereas no association was observed with cancer mortality (HR 0.99; 95% CI 0.90, 1.11). CONCLUSIONS: A higher level of adherence to the Dutch dietary guidelines, as assessed with the DHD-index, was associated with a lower risk of all-cause mortality, probably due to an inverse association with cardiovascular causes of death. PMID- 26486301 TI - Measuring practical knowledge about balanced meals: development and validation of the brief PKB-7 scale. AB - BACKGROUND/OBJECTIVES: As a high-quality diet is associated with a lower risk for several diseases and all-cause mortality, current nutrition education tools provide people with information regarding how to build a healthy and a balanced meal. To assess this basic nutrition knowledge, the research aim was to develop and validate a brief scale to measure the Practical Knowledge about Balanced meals (PKB-7). SUBJECTS/METHODS: A pool of 25 items was pretested with experts and laypeople before being tested on a random sample in Switzerland (n=517). For item selection, a Rasch model analysis was applied. The validity and reliability of the new scale were assessed by three additional studies including laypeople (n=597; n=145) and nutrition experts (n=59). RESULTS: The final scale consists of seven multiple-choice items, which met the assumptions of the Rasch model. The validity of the new scale was shown by several aspects: the Rasch model was replicated in a second study, and nutrition experts achieved significantly higher scores than laypeople (t(148)=20.27, P<0.001, d=1.78). In addition, the PKB-7 scale was correlated with other nutrition-related constructs and associated with reported vegetable consumption. Test-retest reliability (r=0.68, P<0.001) was acceptable. CONCLUSIONS: The PKB-7 scale is a reliable and a valid Rasch-based instrument in Swiss citizens aged between 18 and 80 years for measuring the practical knowledge about balanced meals based on current dietary guidelines. This brief and easy-to-use scale is intended for application in both research and practice. PMID- 26486302 TI - Effects of calorie labelling on macro- and micro-nutrients in main-meal choices made by young adults. AB - BACKGROUND/OBJECTIVES: There is limited evidence that prominent calorie labelling on out-of-home meals helps consumers reduce calorie intakes and avoid weight gain, but no evidence on its effects on macro- and micro-nutrients. The objective of this study was to assess the impact of prominent calorie labelling on energy, macro- and micro-nutrients. SUBJECTS/METHODS: Young adults in a catered residential setting were observed when choosing main meals over three study periods in fixed order in this observational study. Period 1: with calorie labels (20 weeks); period 2: without calorie labels (10 weeks); period 3: with calorie labels plus information on estimated energy requirements (10 weeks). Nutrient contents of meal choices were analysed from food composition tables. RESULTS: Energy, 4 macronutrients and 19 micronutrients levels were derived from 4200 meals chosen by 120 subjects over 40 weeks. Means (s.d. or Median) for key macro- and micro-nutrients were for period 1: energy=658 (94) kcal, fat=31 (8.6) g, saturated fat=10.5 (2.7) g, B12=2.5 (1.7) MUg, folate=119 (46.8) MUg, vitamin C=80.0 (42) mg, Ca=278 (129) mg, Na=1230 (119) mg, Fe=22 (10) g, Se=19 (10.1) MUg, I=34 (10.1) MUg, period 2: energy=723 (87) kcal, fat=35 (7.6) g, saturated fat=12 (2.7) g, B12=3.4 (1.7) MUg, Folate=182 (13.3) MUg, vitamin C=87.0 (49.7) mg, Ca=379 (149) mg, Na=1352 (114) mg, Fe=41.6 (14) g, Se=26 (10.3) MUg, I=38.0 (18.4) MUg, period 3: energy=578 (109) kcal, fat=27.3 (9.1) g, saturated fat=8.5 (2.7) g, B12=2.2 (0.5) MUg, Folate=90 (50.8) MUg, vitamin C=75.0 (34) mg, Ca=277 (119) mg, Na=1205 (99) mg, Fe=14.5 (10.9) g, Se=15.0 (10) MUg, I=32.0 (18.4) MUg. All macro- and micro-nutrients, except for B1, vitamin C, vitamin E and Ca were significantly different between the three periods (P<0.001), but all mean intakes remained above recommended levels. CONCLUSIONS: Calorie labelling resulted in reductions in calories, fat and saturated fat contents of the meals chosen, without compromising micronutrient consumptions. PMID- 26486303 TI - The levels of human milk microRNAs and their association with maternal weight characteristics. AB - BACKGROUND/OBJECTIVES: Specific microRNAs (miRNAs) that are known to have roles in various physiological and pathological processes in mammals are found in human breast milk, but the impact of maternal status on miRNA levels in milk is not fully understood. The objective of this study was to explore maternal and infant factors that can potentially influence the levels of let-7a (MIMAT0000062), miRNA 30B (MIMAT0000420) and miRNA-378 (MIMAT0000732) in human milk, all of which are known to participate in adipogenesis. SUBJECTS/METHODS: Colostrum from 86 mothers and mature milk from 33 mothers were collected. The miRNA levels in these samples were determined using real-time PCR. Correlations between the levels of these miRNAs and lactation duration, maternal weight/BMI before and late in the pregnancy, maternal age, gestational weeks and infant gender were analysed. RESULTS: The levels of let-7a (2.58+/-0.67) and miRNA-378 (4.64+/-0.69) in colostrum were higher than those in mature milk (2.39+/-0.62, 3.62+/-0.77, P<0.01). Conversely, the level of miRNA-30B was higher in mature milk (4.92+/ 0.57) than in colostrum (4.05+/-0.61, P<0.01). The levels of miRNA-30B, let-7a and miRNA-378 in colostrum were negatively correlated with maternal pre-pregnancy BMI (P<0.01), and, in mature milk, let-7a was negatively correlated with maternal weight late in the pregnancy (P<0.05). Moreover, miRNA-30B and miRNA-378 were higher in the colostrum received by girls than in that received by boys (P<0.01). This pattern held for miRNA-378 when controlling for maternal pre-pregnancy BMI. CONCLUSIONS: Adipogenesis miRNAs were expressed in both colostrum and mature milk and were related to maternal weight and infant gender. The miRNAs in human milk determined in this study provide a basis for future studies of their biological functions in infants. PMID- 26486305 TI - The chloroplast genome hidden in plain sight, open access publishing and anti fragile distributed data sources. AB - We sequenced several cannabis genomes in 2011 of June and the first and the longest contigs to emerge were the chloroplast and mitochondrial genomes. Having been a contributor to the Human Genome Project and an eye-witness to the real benefits of immediate data release, I have first hand experience with the potential mal-investment of millions of dollars of tax payer money narrowly averted due to the adopted global rapid data release policy. The policy was vital in reducing duplication of effort and economic waste. As a result, we felt obligated to publish the Cannabis genome data in a similar spirit and placed them immediately on a cloud based Amazon server in August of 2011. While these rapid data release practices were heralded by many in the media, we still find some authors fail to find or reference said work and hope to compel the readership that this omission has more pervasive repercussions than bruised egos and is a regression for our community. PMID- 26486304 TI - Association of nutritional status as measured by the Mini-Nutritional Assessment Short Form with changes in mobility, institutionalization and death after hip fracture. AB - BACKGROUND/OBJECTIVES: We examined the association of nutritional status as measured by the Mini-Nutritional Assessment Short Form (MNA-SF) with changes in mobility, institutionalization and death after hip fracture. SUBJECTS/METHODS: Population-based prospective data were collected on 472 out of 693 consecutive hip fracture patients aged 65 years and over between January 2010 and December 2012. Declined vs same or improved mobility level, institutionalization and death during the 4-month follow-up were the outcomes. Age, gender, American Society of Anesthesiologists scores, pre-fracture diagnosis of a memory disorder, mobility level, living arrangements and MNA-SF scores at baseline were the independent variables. Age-adjusted and multivariate logistic regression and Cox proportional hazards models were conducted. RESULTS: At baseline, 41 (9%) patients were malnourished and 200 (42%) patients at risk of malnutrition according to the MNA SF. During the follow-up, 90 (19%) had died. In the multivariate Cox proportional hazards model, malnutrition (hazard ratio 2.16; 95% confidence interval (CI) 1.07 4.34) was associated with mortality. In the multivariate binary logistic regression analyses, risk of malnutrition (odds ratios (OR) 2.42; 95% CI 1.25 4.66) and malnutrition (OR 6.10;95% CI 2.01-18.5) predicted institutionalization. Risk of malnutrition (OR 2.03; 95% CI 1.24-3.31) was associated with decline in the mobility level. CONCLUSIONS: Malnutrition or risk of malnutrition as measured by the MNA-SF were independent predictors of negative outcomes after hip fracture. Patients classified as being at risk of malnutrition by the MNA-SF may constitute a patient population with mild-to-moderate malnutrition and may require specific attention when nutritional interventions are designed after hip fracture. PMID- 26486306 TI - Older patients' participation in hospital admissions through the emergency department: an interview study of healthcare professionals. AB - BACKGROUND: Patient participation is an important aspect of healthcare quality and may be one way to improve the quality of transitional care for older patients. Research reveals minimal awareness about patient participation in hospital admissions. Hospital admissions require attention to individuals' specific needs beyond patient frailty, and to involve patients and their families in shared decision-making. The aim of this study was to identify factors influencing patient participation by exploring healthcare professionals' views on patient participation during the hospital admission of older patients through the emergency department (ED). METHODS: The study used a qualitative and descriptive design with face-to-face interviews. A total of 27 interviews were conducted with 15 healthcare professionals from one hospital and 12 from another. The data were analyzed using systematic text condensation. RESULTS: Healthcare professionals thought that patient participation in hospital admissions was influenced by five main factors: 1) routine treatment and care during hospital admission, and in particular certain procedures such as medical examinations; 2) the frail and thankful older patients, and the overall picture of their medical needs; 3) hospital resources, such as available staff and beds; 4) healthcare professionals' attitude towards finding out about older patients' experiences; and 5) the presence of a supportive and demanding next of kin acting as an advocate for the patient. CONCLUSIONS: Patient participation in hospital admissions of older patients is dependent on the way the service is organized, the patients' condition, hospital resources, healthcare professionals' attitudes, and support from patients' next of kin. Some of the participants had high expectations of themselves and actively involved patients, but others did not find patient participation relevant in the emergency department. Some used crowded wards as a reason not to engage older patients in their own care. PMID- 26486307 TI - Treatment of Large Bone Defects with a Vascularized Periosteal Flap in Combination with Biodegradable Scaffold Seeded with Bone Marrow-Derived Mononuclear Cells: An Experimental Study in Rats. AB - INTRODUCTION: The surgical treatment of large bone defects continues to pose a major challenge in modern trauma and orthopedic surgery. In this study we test the effectiveness of a tissue engineering approach, using three-dimensional (3D) beta-tricalcium phosphate (beta-TCP) scaffolding plus bone marrow-derived mononuclear cells (BM-MNCs), combined with a vascularized periosteal flap, in a rat femur critical size defect model. METHODS: Eighty rats were randomly allocated into four equal groups. Under general anesthesia, critical size defects were created on their femurs and were treated with (1) Vascularized periosteal flap alone, (2) Vascularized periosteal flap+beta-TCP scaffolding, (3) Vascularized periosteal flap+beta-TCP scaffolding+ligated vascular pedicle, and (4) Vascularized periosteal flap+beta-TCP scaffolding+BM-MNCs. After 4 and 8 weeks animals were euthanized and the bone defects were harvested for analysis of new bone formation, vascularization, and strength using histology, immunohistology, micro-CT, and biomechanical testing, respectively. RESULTS: Group 1: (P. flap) Increase in new bone formation and vascularization. Group 2: (P. flap+scaffold) Increase in new bone formation and vascularization. Group 3: (P. flap+scaffold+ligated vascular pedicle) No new bone formation and no vascularization. Group 4: (P. flap+scaffold+BM-MNCs) A significant (p < 0.05) increase was seen in new bone formation, vascularization, and strength in bones treated with flaps, scaffold, and BM-MNCs, when compared with the other treatment groups. CONCLUSION: Combining a vascularized periosteal flap with tissue engineering approach (beta-TCP scaffolding and BM-MNC) results in significantly improved bone healing in our rat femur critical size bone defect model. PMID- 26486309 TI - Association of serum glypican-4 levels with cardiovascular risk predictors in women with polycystic ovary syndrome - a pilot study. AB - OBJECTIVE: Glypican-4 (Gpc4) is an adipokine which interacts with the insulin receptor and affects insulin sensitivity in proteoglycans. Insulin resistance plays a crucial role in the etiology of polycystic ovary syndrome (PCOS). PCOS is associated with metabolic disturbances such as abdominal obesity, dyslipidemia and type 2 diabetes. Thus, higher levels of Gpc4 released from visceral adipose tissue in women with PCOS may suggest an increased risk of cardiovascular disease (CVD). DESIGN: The aim of this pilot study was to determine whether the serum Gpc4 level is associated with cardiovascular risk predictors in women with PCOS. METHODS: Sixty-two women with PCOS according to the Rotterdam criteria (20-35 years old) and 43 healthy controls were studied. Cardiovascular risk predictors such as obesity indices, fat deposits according to dual-energy X-ray absorptiometry, biochemical lipid profile parameters and Homeostasis Model Assessment were estimated. RESULTS: The serum Gpc4 level in PCOS women was significantly higher (2.61 +/- 1.17 ng/ml) than in the control group (1.55 +/- 0.47 ng/ml) and correlated with waist circumference, waist-to-hip ratio, total fat and android fat deposit to gynoid fat deposit ratio only in the PCOS group. CONCLUSION: The Gpc4 level was higher in the PCOS group and correlated with CVD risk predictors, especially fat distribution. PMID- 26486308 TI - Accelerated bone ingrowth by local delivery of Zinc from bioactive glass: oxidative stress status, mechanical property, and microarchitectural characterization in an ovariectomized rat model. AB - BACKGROUND: Synthetic bone graft substitutes such as bioactive glass (BG) material are developed in order to achieve successful bone regeneration. Zn plays an important role in the proper bone growth, development, and maintenance of healthy bones. AIMS: This study aims to evaluate in vivo the performance therapy of zinc-doped bioactive glass (BG-Zn) and its applications in biomedicine. METHODS: Female Wistar rats were ovariectomized. BG and BG-Zn were implanted in the femoral condyles of Wistar rats and compared to that of control group. Grafted bone tissues were carefully removed to evaluate the oxidative stress status, histomorphometric profile, mechanical property, and mineral bone distribution by using inductively coupled plasma optical emission spectrometry. RESULTS: A significant decrease of thiobarbituric acid-reactive substances was observed after BG-Zn implantation. Superoxide dismutase, catalase (CAT), and glutathione peroxidase (GPx) activities significantly increased in ovariectomized group implanted with Zinc-doped bioactive glass (OVX-BG-Zn) as compared to ovariectomized group implanted with bioactive glass (OVX-BG). An improved mechanical property was noticed in contact of OVX-BG-Zn (39+/-6 HV) when compared with that of OVX-BG group (26+/-9 HV). After 90 days of implantation, the histomorphometric analysis showed that trabecular thickness (Tb.Th) and trabecular number (Tb.N) were significantly increased with 28 and 24%, respectively, in treated rats of OVX-BG-Zn group as compared to those of OVX-BG groups. Trabecular separation (Tb.Sp) and trabecular bone pattern factor (TBPf) were significantly decreased in OVX-BG-Zn group with 29.5 and 54% when compared with those of OVX-BG rat groups. On the other hand, a rise in Ca and P ion concentrations in the implanted microenvironment was shown and lead to the formation/deposition of Ca-P phases. The ratio of pyridinoline [Pyr] to dihydroxylysinonorleucine [DHLNL] cross-links was normalized to the control level. CONCLUSION: Our findings suggested that BG-Zn might have promising potential applications for osteoporosis therapy. PMID- 26486310 TI - The first whole genome and transcriptome of the cinereous vulture reveals adaptation in the gastric and immune defense systems and possible convergent evolution between the Old and New World vultures. AB - BACKGROUND: The cinereous vulture, Aegypius monachus, is the largest bird of prey and plays a key role in the ecosystem by removing carcasses, thus preventing the spread of diseases. Its feeding habits force it to cope with constant exposure to pathogens, making this species an interesting target for discovering functionally selected genetic variants. Furthermore, the presence of two independently evolved vulture groups, Old World and New World vultures, provides a natural experiment in which to investigate convergent evolution due to obligate scavenging. RESULTS: We sequenced the genome of a cinereous vulture, and mapped it to the bald eagle reference genome, a close relative with a divergence time of 18 million years. By comparing the cinereous vulture to other avian genomes, we find positively selected genetic variations in this species associated with respiration, likely linked to their ability of immune defense responses and gastric acid secretion, consistent with their ability to digest carcasses. Comparisons between the Old World and New World vulture groups suggest convergent gene evolution. We assemble the cinereous vulture blood transcriptome from a second individual, and annotate genes. Finally, we infer the demographic history of the cinereous vulture which shows marked fluctuations in effective population size during the late Pleistocene. CONCLUSIONS: We present the first genome and transcriptome analyses of the cinereous vulture compared to other avian genomes and transcriptomes, revealing genetic signatures of dietary and environmental adaptations accompanied by possible convergent evolution between the Old World and New World vultures. PMID- 26486311 TI - Cancer survivors' perspectives on delivery of survivorship care by primary care physicians: an internet-based survey. AB - BACKGROUND: Helping cancer survivors to transition from active treatment to long term survivorship requires coordinated efforts by both oncologists and primary care physicians (PCPs). This study aims to evaluate cancer survivors' perspectives on PCP-delivered survivorship care. METHODS: We conducted an Internet-based cross-sectional survey of cancer survivors via www.OncoLink.org . Regression analyses were used to identify factors associated with perception of PCP-delivered survivorship care. RESULTS: The 352 respondents rated overall PCP delivered survivorship care as 60 out of 100 (SD = 23). The areas of care most strongly endorsed were general care (62 %), psychosocial support (65 %), and holistic care (68 %). Survivors were less likely to perceive their PCPs as knowledgeable about cancer follow-up (43 %), late or long-term effects of cancer therapy (45 %), and diagnosis and treatment of symptoms related to cancer or cancer therapy (42 %). While 72 % of survivors reported satisfaction with their PCP's care overall, only 41 % felt that their PCPs and oncologists communicated well with one another. In a multivariate regression analysis, higher trust in PCP (p < 0.001), non-white race (p = 0.001), living in the United States (p = 0.007), and visiting a PCP two or more times per year (p = 0.009) were significantly associated with higher ratings of PCP-delivered survivorship care. CONCLUSIONS: While cancer survivors in general are satisfied with care delivery by PCPs, they perceived that their PCPs have limited abilities in performing cancer-specific follow-up and late effect monitoring and treatment. Better education of family physicians about survivorship issues and improved communication between PCPs and oncologists are needed to improve PCPs' delivery of survivorship care. PMID- 26486312 TI - Factors that influence persistence or recurrence of high-grade squamous intraepithelial lesion with positive margins after the loop electrosurgical excision procedure: a retrospective study. AB - BACKGROUND: In 5-20 % of patients with cervical high-grade squamous intraepithelial lesion (HSIL), a positive margin after the loop electrosurgical excision procedure (LEEP) is associated with persistence/recurrence, but the prognostic value of other clinico-pathological factors is less clear. METHODS: Among 4336 patients with HSIL who underwent an initial LEEP, 275 (6 %) had HSIL positive margins, 37 of whom were lost to follow-up. We evaluated the remaining 238 patients. Persistence/recurrence was defined as histopathological HSIL during follow-up. RESULTS: The age of the patients ranged from 21 to 69 years (median: 40). The median follow-up period was 25 months (range: 6-43). Of the 238 patients, 211 (88.7 %) patients remained free of persistence/recurrence, while 27 (11.3 %) experienced persistence/recurrence. According to a univariate analysis, age (P = 0.03) and maximum specimen diameter (P = 0.043) were associated with persistence/recurrence, but number/location of involved margin sections and the pathology of the endocervical curettage were not (P > 0.10). The relative risk of the subjects (greater than or equal to 35 years ages) was 4.6 times of the subject less than 35 years, the difference was statistically significant (14 % vs. 3 %, P < 0.05). A multivariate analysis indicated that an age of 35 years or older was the only independent risk factor (OR 4.97, 95 % CI 1.14-21.62, P = 0.03). CONCLUSION: In patients with HSIL and HSIL-involved margins after an initial LEEP, age is a strong independent predictor of persistence/recurrence. Follow-up with screening cytology and/or biopsy may be considered in younger patients, whereas a secondary LEEP/hysterectomy may be considered in older patients. PMID- 26486313 TI - Aquatic Biodiversity in the Amazon: Habitat Specialization and Geographic Isolation Promote Species Richness. AB - The Neotropical freshwater ichthyofauna has among the highest species richness and density of any vertebrate fauna on Earth, with more than 5,600 species compressed into less than 12% of the world's land surface area, and less than 0.002% of the world's total liquid water supply. How have so many species come to co-exist in such a small amount of total habitat space? Here we report results of an aquatic faunal survey of the Fitzcarrald region in southeastern Peru, an area of low-elevation upland (200-500 m above sea level) rainforest in the Western Amazon, that straddles the headwaters of four large Amazonian tributaries; the Jurua (Yurua), Ucayali, Purus, and Madre de Dios rivers. All measures of fish species diversity in this region are high; there is high alpha diversity with many species coexisting in the same locality, high beta diversity with high turnover between habitats, and high gamma diversity with high turnover between adjacent tributary basins. Current data show little species endemism, and no known examples of sympatric sister species, within the Fitzcarrald region, suggesting a lack of localized or recent adaptive divergences. These results support the hypothesis that the fish species of the Fitzcarrald region are relatively ancient, predating the Late Miocene-Pliocene (c. 4 Ma) uplift that isolated its several headwater basins. The results also suggest that habitat specialization (phylogenetic niche conservatism) and geographic isolation (dispersal limitation) have contributed to the maintenance of high species richness in this region of the Amazon Basin. PMID- 26486315 TI - Erratum to: Sail or sink: novel behavioural adaptations on water in aerially dispersing species. PMID- 26486314 TI - Plague: Infections of Companion Animals and Opportunities for Intervention. AB - Plague is a zoonotic disease, normally circulating in rodent populations, transmitted to humans most commonly through the bite of an infected flea vector. Secondary infection of the lungs results in generation of infectious aerosols, which pose a significant hazard to close contacts. In enzootic areas, plague infections have been reported in owners and veterinarians who come into contact with infected pets. Dogs are relatively resistant, but can import infected fleas into the home. Cats are acutely susceptible, and can present a direct hazard to health. Reducing roaming and hunting behaviours, combined with flea control measures go some way to reducing the risk to humans. Various vaccine formulations have been developed which may be suitable to protect companion animals from contracting plague, and thus preventing onward transmission to man. Since transmission has resulted in a number of fatal cases of plague, the vaccination of domestic animals such as cats would seem a low cost strategy for reducing the risk of infection by this serious disease in enzootic regions. PMID- 26486316 TI - Age-related neuromuscular changes affecting human vastus lateralis. AB - KEY POINTS: Skeletal muscle size and strength decline in older age. The vastus lateralis, a large thigh muscle, undergoes extensive neuromuscular remodelling in healthy ageing, as characterized by a loss of motor neurons, enlargement of surviving motor units and instability of neuromuscular junction transmission. The loss of motor axons and changes to motor unit potential transmission precede a clinically-relevant loss of muscle mass and function. ABSTRACT: The anterior thigh muscles are particularly susceptible to muscle loss and weakness during ageing, although how this is associated with changes to neuromuscular structure and function in terms of motor unit (MU) number, size and MU potential (MUP) stability remains unclear. Intramuscular (I.M.) and surface electromyographic signals were recorded from the vastus lateralis (VL) during voluntary contractions held at 25% maximal knee extensor strength in 22 young (mean +/- SD, 25.3 +/- 4.8 years) and 20 physically active older men (71.4 +/- 6.2 years). MUP size, firing rates, phases, turns and near fibre (NF) jiggle were determined and MU number estimates (MUNEs) were made by comparing average surface MUP with maximal electrically-evoked compound muscle action potentials. Quadriceps cross sectional area was measured by magnetic resonance imaging. In total, 379 individual MUs were sampled in younger men and 346 in older men. Compared to the MU in younger participants, those in older participants had 8% lower firing rates and larger MUP size (+25%), as well as increased complexity, as indicated by phases (+13%), turns (+20%) and NF jiggle (+11%) (all P < 0.0005). The MUNE values (derived from the area of muscle in range of the surface-electrode) in older participants were ~70% of those in the young (P < 0.05). Taking into consideration the 30% smaller cross-sectional area of the VL, the total number of MUs in the older muscles was between 50% and 60% lower compared to in young muscles (P < 0.0005). A large portion of the VL MU pool is lost in older men and those recruited during moderate intensity contractions were enlarged and less stable. These MU changes were evident before clinically relevant changes to muscle function were apparent; nevertheless, the changes in MU number and size are probably a prelude to future movement problems. PMID- 26486317 TI - Hit Optimization of 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3 carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood Disorders. AB - Novel treatments for bipolar disorder with improved efficacy and broader spectrum of activity are urgently needed. Glycogen synthase kinase 3beta (GSK-3beta) has been suggested to be a key player in the pathophysiology of bipolar disorder. A series of novel GSK-3beta inhibitors having the common N-[(1-alkylpiperidin-4 yl)methyl]-1H-indazole-3-carboxamide scaffold were prepared taking advantage of an X-ray cocrystal structure of compound 5 with GSK-3beta. We probed different substitutions at the indazole 5-position and at the piperidine-nitrogen to obtain potent ATP-competitive GSK-3beta inhibitors with good cell activity. Among the compounds assessed in the in vivo PK experiments, 14i showed, after i.p. dosing, encouraging plasma PK profile and brain exposure, as well as efficacy in a mouse model of mania. Compound 14i was selected for further in vitro/in vivo pharmacological evaluation, in order to elucidate the use of ATP-competitive GSK 3beta inhibitors as new tools in the development of new treatments for mood disorders. PMID- 26486319 TI - Formation of Highly Strained N-Heterocycles via Decomposition of Iron N Heterocyclic Carbene Complexes: The Value of Labile Fe-C Bonds. AB - An unusual, highly-strained annulated 2,2'-biimdazole was isolated as decomposition product of the outer-sphere one-electron oxidation of an iron(II) N heterocyclic carbene (NHC) complex bearing a tetradentate bis(NHC)-bis- (pyridine) ligand (NCCN). Reductive elimination leading to the 2,2'-biimdazole is a consequence of the lability of the Fe?C bonds in the transient species and also extends to complexes with modified ligands but the same coordination geometry. Closely related by a two-electron redox step to a family of less-strained tetraazafulvalenes, the obtained 2,2'-biimidazolium salts were studied electrochemically. Introduction of methyl substituents at the methylene tether significantly increased the reversibility of the electrochemical reduction. Furthermore, the reactivity of the 2,2'-biimidazolium salt was examined by oxidative addition of [Ni(cod)2 ] to the central C?C bond, providing a previously unknown way for the formation of NHC transition metal complexes. PMID- 26486318 TI - Topical management of striae distensae (stretch marks): prevention and therapy of striae rubrae and albae. AB - Striae distensae (SD) are common dermal lesions, with significant physical and psychological impact. Many therapeutic modalities are available but none can completely eradicate SD. The most common therapy is the application of topicals used both therapeutically and prophylactically. Even though there are many commercially available topical products, not all have sufficient level of evidence to support their continued use in SD. The aim here was to assess the evidence for the use of topicals in SD and to propose a structured approach in managing SD. A systematic search of published literature and manufacturer website information for topicals in SD was carried out. The results showed that there are few studies (n = 11) which investigate the efficacy of topicals in management of SD. Trofolastin and Alphastria creams demonstrated level-2 evidence of positive results for their prophylactic use in SD. Additionally, tretinoin used therapeutically showed varying results whilst cocoa butter and olive oil did not demonstrate any effect. Overall, there is a distinct lack of evidence for each topical formulation. The majority of topicals failed to mention their effect on early vs. later stages of SD (striae rubrae compared to striae albae) and their role in both prevention and treatment. In conclusion, there is no topical formulation, which is shown to be most effective in eradicating or improving SD. A structured approach in identification and targeted management of symptoms and signs with the appropriate topical is required. Randomized controlled trials are necessary to assess the efficacy of topical products for treatment and prevention of different stages of SD. PMID- 26486320 TI - A Single Biosensor for Evaluating the Levels of Copper Ion and L-Cysteine in a Live Rat Brain with Alzheimer's Disease. AB - Copper ion (Cu(2+)) and L-cysteine (CySH) are closely correlated with physiological and pathological events of Alzheimer's Disease (AD), however the detailed mechanism is still unclear, mainly owing to a lack of accurate analytical methods in live brains. Herein, we report a single biosensor for electrochemical ratiometric detection of Cu(2+) and CySH in live rat brains with AD. N,N-di-(2-picoly)ethylenediamine (DPEA) is first synthesized for specific recognition of Cu(2+) to form a DPEA-Cu(2+) complex. This complex shows high selectivity for CySH owing to the release of Cu(2+) from the complex through CySH binding to Cu(2+) center. In parallel, 5'-MB-GGCGCGATTTTTTTTTTTTT-SH-3' (HS-DNA MB, MB=Methylene Blue) is designed as an inner-reference for providing a built-in correction to improve the accuracy. As a result, combined with the amplified effect of Au nanoleaves, our single ratiometric biosensor can be successfully applied in real-time detection of Cu(2+) and CySH in the live rat brains with AD. To our knowledge, this is the first report on the accurate concentrations of Cu(2+) and CySH in live rat brains with AD. PMID- 26486321 TI - What is "homology thinking" and what is it for? AB - In this paper I examine the thesis by Marc Ereshefsky that, in evolutionary biology, there is a third style of thinking, besides the well-known "population thinking" and "tree thinking." Ereshefsky proposes "homology thinking" as a third approach, focused on the transformation of organismal phenotypes. In this short commentary, I aim at identifying the underlying biological assumptions for homology thinking and how they can be put to work in a research program within evolutionary biology. I propose that homology thinking is based on three insights: 1) multicellular organisms consist of developmentally individualized parts (sub-systems); 2) that developmental individuation entails evolutionary individuation, that is, variational quasi-independence; and 3) these individuated body parts are inherited, though indirectly, and form lineages that are recognized as homologies. These facts support a research program focused on the modification and origination of individuated body parts that supplements and puts into perspective the population genetic and phylogenetic approaches to the study of evolution. PMID- 26486323 TI - Guest editorial: pre-leukemia/pre-lymphoma-what is old, what is new? PMID- 26486322 TI - Comparison of peritoneal closure techniques in laparoscopic transabdominal preperitoneal inguinal hernia repair: a prospective randomized study. AB - PURPOSE: We aimed to compare tacker and suture techniques for peritoneal closure with respect to patient outcomes. METHODS: A total of 64 patients were included in the study, 32 being in the tacker group and 32 in the suture group. All patients underwent laparoscopic TAPP inguinal hernia repair. Both groups were compared with respect to age, sex, duration of peritoneal closure and the operation, hernia type, the number of tackers used for mesh fixation, postoperative complication rate, visual analogue scale (VAS) scores on 1st, 7th, and 30th days, duration of follow-up, and recurrence rates. RESULTS: Duration of peritoneal closure and the operation was significantly shorter in the tacker group compared to the suture group (p < 0.001, p = 0.008, respectively). Statistical analysis with the two-way analysis of variance method revealed that mesh fixation with one or two tackers did not influence postoperative pain. VAS 1 was significantly lower in patients with peritoneal closure with suture compared to the patients undergoing peritoneal closure with tacker (p = 0.027). VAS 7 and VAS 30 were lower for peritoneal closure with suture versus tacker, although the difference did not reach statistical significance (p = 0.064, p = 0.294, respectively). We observed no recurrence at an average of 21-month follow-up. CONCLUSIONS: Tacker and suture appeared to have a comparable safety for peritoneal closure in laparoscopic TAPP inguinal hernia operation. It can be suggested that peritoneal closure with tacker increased short-term pain, independent of the number of tackers used for mesh fixation. Long-term pain was similar in both groups. PMID- 26486324 TI - A review of consanguinity in Ireland--estimation of frequency and approaches to mitigate risks. AB - INTRODUCTION: Over half of marriages are consanguineous in some countries, and about 10 % of children worldwide have consanguineous parents. Perceived benefits of consanguineous marriage (CM) include preservation of tradition, stronger family ties, financial advantages, and bride protection. Potential harms include autosomal recessive disorders, complex congenital malformations, stillbirths, postnatal mortality. There have been no population-based data published on frequency of CM in Ireland since 1970. METHODS: International prevalence figures and published estimates of CM were applied to 2011 Irish Census data to calculate the frequency of CM in at-risk groups. Searches of the published and grey literature were conducted to review evidence-based approaches to mitigate risks of CM and apply findings to the Irish context. RESULTS: The estimated number of consanguineous couples has grown in subpopulations in Ireland in the past decade, particularly among Pakistanis (>967 couples), Nigerians (418-794 couples) and Indians (54-2099 couples). There are up to 3000 consanguineous couples in the Traveller community. Evidence for approaches to mitigate associated risks supports a three-stranded approach: family-centred genetics services, training and education of healthcare professionals (HCPs), community education programmes. DISCUSSION: Consanguineous couples desire accurate information for reproductive decisions, but may avoid hospital-based services due to language barriers, poor understanding, stigma. Uptake of genetic counselling and carrier testing is higher if a family-centred approach is provided, ideally through home visits in the couple's preferred language. Targeted education programmes enhance community awareness and have led to declines in CM elsewhere. Education of HCPs is necessary to clarify referral pathways, as many have exaggerated impressions of the genetic risks. PMID- 26486325 TI - The role of TARBP2 in the development and progression of cancers. AB - TARBP2 is a RNA-binding protein (RBP) involved in miRNA processing and maturation. TARBP2 plays significant roles in many biological and pathological conditions, including viral expression of HIV-1, microsatellite instability, cancer stem cell properties, and tumor progression. Overexpression of TARBP2 was observed in many cancers such as prostate cancer, cutaneous malignant melanoma, and adrenocortical carcinoma. In addition, TARBP2 was also found to be downregulated in some cancers including colorectal cancer, gastric cancer, Ewing sarcoma, and upper urinary tract urothelial carcinoma. Therefore, whether TARBP2 functions as the tumor suppressor or tumor promoter is conflicting. In the present review, we provide an overview of current knowledge concerning the role of TARBP2 in tumor development and progression. PMID- 26486326 TI - Establishment and characterization of a human intrahepatic cholangiocarcinoma cell line derived from an Italian patient. AB - Biliary tract carcinoma is a rare malignancy with multiple causes, which underlie the different genetic and molecular profiles. Cancer cell lines are affordable models, reflecting the characteristics of the tumor of origin. They represent useful tools to identify molecular targets for treatment. Here, we established and characterized from biological, molecular, and genetic point of view, an Italian intrahepatic cholangiocarcinoma cell line (ICC), the MT-CHC01. MT-CHC01 cells were isolated from a tumor-derived xenograft. Immunophenotypical characterization was evaluated both at early and after stabilization passages. In vitro biological, genetic, and molecular features were also investigated. In vivo tumorigenicity was assessed in NOD/SCID mice. MT-CHC01cells retain epithelial cell markers, EPCAM, CK7, and CK19, and some stemness and pluripotency markers, i.e., SOX2, Nanog, CD49f/integrin-alpha6, CD24, PDX1, FOXA2, and CD133. They grow as a monolayer, with a population double time of about 40 h; they show a low migration and invasion potential. In low attachment conditions, they are able to form spheres and to growth in anchorage-independent manner. After subcutaneous injection, they retain in vivo tumorigenicity; the expression of biliary markers as CA19-9 and CEA were maintained from primary tumor. The karyotype is highly complex, with a hypotriploid to hypertriploid modal number (3n+/-) (52 to 77 chromosomes); low level of HER2 gene amplification, TP53 deletion, gain of AURKA were identified; K-RAS G12D mutation were maintained from primary tumor to MT CHC01 cells. We established the first ICC cell line derived from an Italian patient. It will help to study either the biology of this tumor or to test drugs both in vitro and in vivo. PMID- 26486327 TI - St Gallen molecular subtypes in feline mammary carcinoma and paired metastases disease progression and clinical implications from a 3-year follow-up study. AB - Considering that scarce data are available on disease progression of feline mammary carcinoma (FMC), this study aimed to analyze the clinical, pathological, and immunophenotypic features collected from 61 queens with FMC and to compare the concordance ratios of the expression levels of five molecular markers (ER, PR, fHER2, CK5/6, and Ki-67) between primary tumors (PT) and metastatic lesions. The results showed that cats with luminal A mammary carcinomas (MC) had higher overall survival (924.6 days, p = 0.001) and longer disease-free period (385.4 days, p = 0.005) compared to the ones with other MC subtypes. In fact, queens with triple negative/basal-like MC showed the lowest survival (mean 156.2 days) and the shortest disease-free survival (mean 28 days) among the molecular subtypes of MC. The lung was the organ most frequently affected by metastases, and animals with lung and/or pleural metastases were more likely to display metastases at three or more locations (p = 0.039). A large heterogeneity in protein expression levels was found between PT and paired metastases, with both estrogen and progesterone receptors more likely to be downregulated in metastases. Paired metastases frequently had higher Ki-67 index than PT, whereas fHER2 overexpression was seen in 46 samples (30 %) and CK5/6 expression was found in 50.7 % of metastases (36/71). Results also revealed that disease progression leads to a high percentage of triple negative/basal-like metastases (9/23; 39.1 %) associated with the absence of luminal A subtype in distant metastases (0/23). This study highlights the prognostic importance of immunophenotyping of MC in cats, although the modified protein expression identified in metastases contributes to justify why possible targeted therapies may fail in some animals with metastatic disease. Altogether, the results obtained also demonstrate that FMC can be used as a model to study human breast cancer. PMID- 26486329 TI - HIFU Tissue Ablation: Concept and Devices. AB - High intensity focused ultrasound (HIFU) is rapidly gaining clinical acceptance as a technique capable of providing non-invasive heating and ablation for a wide range of applications. Usually requiring only a single session, treatments are often conducted as day case procedures, with the patient either fully conscious, lightly sedated or under light general anesthesia. HIFU scores over other thermal ablation techniques because of the lack of necessity for the transcutaneous insertion of probes into the target tissue. Sources placed either outside the body (for treatment of tumors or abnormalities of the liver, kidney, breast, uterus, pancreas brain and bone), or in the rectum (for treatment of the prostate), provide rapid heating of a target tissue volume, the highly focused nature of the field leaving tissue in the ultrasound propagation path relatively unaffected. Numerous extra-corporeal, transrectal and interstitial devices have been designed to optimize application-specific treatment delivery for the wide ranging areas of application that are now being explored with HIFU. Their principle of operation is described here, and an overview of their design principles is given. PMID- 26486328 TI - Long non-coding RNA small nucleolar RNA host gene 12 (SNHG12) promotes cell proliferation and migration by upregulating angiomotin gene expression in human osteosarcoma cells. AB - The long non-coding RNA (lncRNA) small nucleolar RNA host gene 12 (SNHG12) has a role in cell proliferation and migration. Angiomotin, encoded by the AMOT gene, is a protein that regulates the migration and organization of endothelial cells. SNHG12 and AMOT have been shown to play a role in a variety of human cancers but have yet to be studied in detail in human osteosarcoma. Tissue samples from primary osteosarcoma (n = 20) and adjacent normal tissues (n = 20), the osteosarcoma cell lines, SAOS-2, MG-63, U-2 OS, and the human osteoblast cell line hFOB (OB3) were studied using Western blot for angiomotin, and quantitative real-time polymerase chain reaction for the expression of SNHG12 and AMOT. The expression of SNHG12 was knocked down using RNA interference. Cell migration assays were performed. Cell apoptosis was studied using flow cytometry. SNHG12 and AMOT messenger RNA (mRNA) expression was upregulated in osteosarcoma tissues and cell lines when compared with normal tissues and cells. Upregulation of AMOT mRNA was associated with upregulation of SNHG12. Knockdown of SNHG12 reduced the expression of angiomotin in osteosarcoma cells and suppressed cell proliferation and migration but did not affect cell apoptosis. This preliminary study has shown that the lncRNA SNHG12 promotes cell proliferation and migration by upregulating AMOT gene expression in osteosarcoma cells in vivo and in vitro. Further studies are recommended to investigate the role of SNHG12 and AMOT expression in tumor cell proliferation and migration and angiogenesis in osteosarcoma and a range of malignant mesenchymal tumors. PMID- 26486330 TI - Prostate Focused Ultrasound Therapy. AB - The tremendous progress in engineering and computing power coupled with ultrasound transducer technology and imaging modalities over the past 20 years have encouraged a revival of clinical interest in ultrasound therapy, mainly in High-Intensity Focused Ultrasound (HIFU). So far, the most extensive results from HIFU obtained in urology involve transrectal prostate ablation, which appears to be an effective therapeutic alternative for patients with malignant prostate tumors. Prostate cancer (PCa) is one of the most frequently diagnosed cancers in men. Several treatment options with different therapeutic approaches exist, including HIFU for localized PCa that has been in use for over 15 years. Since the early 2000s, two systems have been marketed for this application, and other devices are currently in clinical trials. HIFU treatment can be used either alone or in combination with (before- or after-) external beam radiotherapy (EBRT) (before or after HIFU) and can be repeated multiple times. HIFU treatment is performed under real-time monitoring with ultrasound or guided by MRI. Two indications are validated today: Primary care treatment and EBRT failure. The results of HIFU for primary care treatment are similar to standard conformal EBRT, even though no randomized comparative studies have been performed and no 10 year follow up data is yet available for HIFU. Salvage HIFU after EBRT failure is increasing with oncological outcomes, similar to those achieved with surgery but with the advantage of fewer adverse effects. HIFU is an evolving technology perfectly adapted for focal treatment. Thus, HIFU focal therapy is another pathway that must be explored when considering the accuracy and reliability for PCa mapping techniques. HIFU would be particularly suited for such a therapy since it is clear that HIFU outcomes and toxicity are relative to the volume of prostate treated. PMID- 26486331 TI - MRI-Guided HIFU Methods for the Ablation of Liver and Renal Cancers. AB - MRI-guided High Intensity Focused Ultrasound (MRI-HIFU) is a promising method for the non-invasive ablation of pathological tissue in many organs, including mobile organs such as liver and kidney. The possibility to locally deposit thermal energy in a non-invasive way opens a path towards new therapeutic strategies with improved reliability and reduced associated trauma, leading to improved efficacy, reduced hospitalization and costs. Liver and kidney tumors represent a major health problem because not all patients are suitable for curative treatment with surgery. Currently, radio-frequency is the most used method for percutaneous ablation. The development of a completely non-invasive method based on MR guided high intensity focused ultrasound (HIFU) treatments is of particular interest due to the associated reduced burden for the patient, treatment related patient morbidity and complication rate. The objective of MR-guidance is hereby to control heat deposition with HIFU within the targeted pathological area, despite the physiological motion of these organs, in order to provide an effective treatment with a reduced duration and an increased level of patient safety. Regarding this, several technological challenges have to be addressed: Firstly, the anatomical location of both organs within the thoracic cage requires inter costal ablation strategies, which preserve the therapeutic efficiency, but prevent undesired tissue damage to the ribs and the intercostal muscle. Secondly, both therapy guidance and energy deposition have to be rendered compatible with the continuous physiological motion of the abdomen. PMID- 26486332 TI - Magnetic Resonance-Guided High Intensity Focused Ultrasound Ablation of Breast Cancer. AB - This chapter describes several aspects of MR-HIFU treatment for breast cancer. The current and future applications, technical developments and clinical results are discussed. MR-HIFU ablation is under investigation for the treatment of breast cancer, but is not yet ready for clinical implementation. Firstly, the efficacy of MR-HIFU ablation should be investigated in large trials. The existing literature shows that results of initial, small studies are moderate, but opportunities for improvement are available. Careful patient selection, taking treatment margins into account and using a dedicated breast system might improve treatment outcomes. MRI-guidance has proven to be beneficial for the accuracy and safety of HIFU treatments because of its usefulness before, during and after treatments. In conclusion, MR-HIFU is promising for the treatment of breast cancer and might lead to a change in breast cancer care in the future. PMID- 26486333 TI - HIFU for Palliative Treatment of Pancreatic Cancer. AB - Pancreatic cancer is one of the deadliest malignancies, with only a 6 % 5-year survival rate and over 50 % of patients being diagnosed at the advanced stage. Current therapies are ineffective, and the treatment of patients with advanced disease is palliative. In the past decade, HIFU ablation has emerged as a modality for palliative treatment of pancreatic tumors. Multiple preclinical and non-randomized clinical trials have been performed to evaluate the safety and efficacy of this procedure. Substantial tumor-related pain reduction was achieved in most cases after HIFU treatment and few significant side effects were observed. In addition, some studies indicate that combination of HIFU ablation with chemotherapy may provide a survival benefit. This chapter summarizes the pre clinical and clinical experience obtained to date in HIFU treatment of pancreatic tumors and discusses the challenges, limitations and new approaches in this modality. PMID- 26486334 TI - MR-Guided Transcranial Focused Ultrasound. AB - Previous chapters introduced the ability of using focused ultrasound to ablate tissues. It has led to various clinical applications in the treatment of uterine fibroid, prostate or liver cancers. Nevertheless, treating the brain non invasively with focused ultrasound has been considered beyond reach for almost a century: The skull bone protects the brain from mechanical injuries, but it also reflects and refracts ultrasound, making it difficult to target the brain with focused ultrasound. Fortunately, aberration correction techniques have been developed recently and thermal lesioning in the thalamus has been achieved clinically. This chapter introduces the aberration effect of the skull bone and how it can be corrected non-invasively. It also presents the latest clinical results obtained with thermal ablation and introduces novel non-thermal approaches that could revolutionize brain therapy in the future. PMID- 26486335 TI - Focused Ultrasound and Lithotripsy. AB - Shock wave lithotripsy has generally been a first choice for kidney stone removal. The shock wave lithotripter uses an order of microsecond pulse durations and up to a 100 MPa pressure spike triggered at approximately 0.5-2 Hz to fragment kidney stones through mechanical mechanisms. One important mechanism is cavitation. We proposed an alternative type of lithotripsy method that maximizes cavitation activity to disintegrate kidney stones using high-intensity focused ultrasound (HIFU). Here we outline the method according to the previously published literature (Matsumoto et al., Dynamics of bubble cloud in focused ultrasound. Proceedings of the second international symposium on therapeutic ultrasound, pp 290-299, 2002; Ikeda et al., Ultrasound Med Biol 32:1383-1397, 2006; Yoshizawa et al., Med Biol Eng Comput 47:851-860, 2009; Koizumi et al., A control framework for the non-invasive ultrasound the ragnostic system. Proceedings of 2009 IEEE/RSJ International Conference on Intelligent Robotics and Systems (IROS), pp 4511-4516, 2009; Koizumi et al., IEEE Trans Robot 25:522-538, 2009). Cavitation activity is highly unpredictable; thus, a precise control system is needed. The proposed method comprises three steps of control in kidney stone treatment. The first step is control of localized high pressure fluctuation on the stone. The second step is monitoring of cavitation activity and giving feedback on the optimized ultrasound conditions. The third step is stone tracking and precise ultrasound focusing on the stone. For the high pressure control we designed a two-frequency wave (cavitation control (C-C) waveform); a high frequency ultrasound pulse (1-4 MHz) to create a cavitation cloud, and a low frequency trailing pulse (0.5 MHz) following the high frequency pulse to force the cloud into collapse. High speed photography showed cavitation collapse on a kidney stone and shock wave emission from the cloud. We also conducted in-vitro erosion tests of model and natural kidney stones. For the model stones, the erosion rate of the C-C waveform showed a distinct advantage with the combined high and low frequency waves over either wave alone. For optimization of the high frequency ultrasound intensity, we investigated the relationship between subharmonic emission from cavitation bubbles and stone erosion volume. For stone tracking we have also developed a non-invasive ultrasound theragnostic system (NIUTS) that compensates for kidney motion. Natural stones were eroded and most of the resulting fragments were less than 1 mm in diameter. The small fragments were small enough to pass through the urethra. The results demonstrate that, with the precise control of cavitation activity, focused ultrasound has the potential to be used to develop a less invasive and more controllable lithotripsy system. PMID- 26486336 TI - Heat-Based Tumor Ablation: Role of the Immune Response. AB - The ideal cancer therapy not only induces the death of all localized tumor cells with less damage to surrounding normal tissue, but also activates a systemic antitumor immunity. Heat-based tumor ablation has the potential to be such a treatment as it can minimal-invasively ablate a targeted tumor below the skin surface, and may subsequently augment host antitumor immunity. This chapter primarily introduces increasing pre-clinical and clinical evidence linking antitumor immune response to thermal tumor ablation, and then discusses the potential mechanisms involved in ablation-enhanced host antitumor immunity. The seminal studies performed so far indicate that although it is not possible to make definite conclusions on the connection between thermal ablation and antitumor immune response, it is nonetheless important to conduct extensive studies on the subject in order to elucidate the processes involved. PMID- 26486337 TI - Droplets, Bubbles and Ultrasound Interactions. AB - The interaction of droplets and bubbles with ultrasound has been studied extensively in the last 25 years. Microbubbles are broadly used in diagnostic and therapeutic medical applications, for instance, as ultrasound contrast agents. They have a similar size as red blood cells, and thus are able to circulate within blood vessels. Perfluorocarbon liquid droplets can be a potential new generation of microbubble agents as ultrasound can trigger their conversion into gas bubbles. Prior to activation, they are at least five times smaller in diameter than the resulting bubbles. Together with the violent nature of the phase-transition, the droplets can be used for local drug delivery, embolotherapy, HIFU enhancement and tumor imaging. Here we explain the basics of bubble dynamics, described by the Rayleigh-Plesset equation, bubble resonance frequency, damping and quality factor. We show the elegant calculation of the above characteristics for the case of small amplitude oscillations by linearizing the equations. The effect and importance of a bubble coating and effective surface tension are also discussed. We give the main characteristics of the power spectrum of bubble oscillations. Preceding bubble dynamics, ultrasound propagation is introduced. We explain the speed of sound, nonlinearity and attenuation terms. We examine bubble ultrasound scattering and how it depends on the wave-shape of the incident wave. Finally, we introduce droplet interaction with ultrasound. We elucidate the ultrasound-focusing concept within a droplets sphere, droplet shaking due to media compressibility and droplet phase-conversion dynamics. PMID- 26486338 TI - Sonoporation: Concept and Mechanisms. AB - Contrast agents for ultrasound are now routinely used for diagnosis and imaging. In recent years, new promising possibilities for targeted drug delivery have been proposed that can be realized by using the microbubble composing ultrasound contrast agents (UCAs). The microbubbles can carry drugs and selectively adhere to specific sites in the human body. This capability, in combination with the effect known as sonoporation, provides great possibilities for localized drug delivery. Sonoporation is a process in which ultrasonically activated UCAs, pulsating nearby biological barriers (cell membrane or endothelial layer), increase their permeability and thereby enhance the extravasation of external substances. In this way drugs and genes can be delivered inside individual cells without serious consequences for the cell viability. Sonoporation has been validated both in-vitro using cell cultures and in-vivo in preclinical studies. However, today, the mechanisms by which molecules cross the biological barriers remain unrevealed despite a number of proposed theories. This chapter will provide a survey of the current studies on various hypotheses regarding the routes by which drugs are incorporated into cells or across the endothelial layer and possible associated microbubble acoustic phenomena. PMID- 26486339 TI - Design of Microbubbles for Gene/Drug Delivery. AB - The role of ultrasound contrast agents (UCA) initially designed for diagnosis has evolved towards a therapeutic use. Ultrasound (US) for triggered drug delivery has many advantages. In particular, it enables a high spatial control of drug release, thus potentially allowing activation of drug delivery only in the targeted region, and not in surrounding healthy tissue. Moreover, UCA imaging can also be used firstly to precisely locate the target region to, and then used to monitor the drug delivery process by tracking the location of release occurrence. All these features make UCA and ultrasound attractive means to mediate drug delivery. The three main potential clinical indications for drug/gene US delivery are (i) the cardiovascular system, (ii) the central nervous system for small molecule delivery, and (iii) tumor therapy using cytotoxic drugs. Although promising results have been achieved in preclinical studies in various animal models, still very few examples of clinical use have been reported. In this chapter will be addressed the aspects pertaining to UCA formulation (chemical composition, mode of preparation, analytical methods...) and the requirement for a potential translation into the clinic following approval by regulatory authorities. PMID- 26486340 TI - Co-administration of Microbubbles and Drugs in Ultrasound-Assisted Drug Delivery: Comparison with Drug-Carrying Particles. AB - There are two alternative approaches to ultrasound-assisted drug delivery. First, the drug can be entrapped into or attached onto the ultrasound-responsive particles and administered in the vasculature, to achieve ultrasound-triggered drug release from the particles and localized tissue deposition in response to ultrasound treatment of the target zone. Second, the drug can be co-administered with the microbubbles or other sonosensitive particles. In this case, the action of ultrasound on the particles (which act as cavitation nuclei) results in the transient improvement of permeability of the physiological barriers, so that the circulating drug can exit the bloodstream and get into the target tissues and cells. We discuss and compare both of these approaches, their characteristic advantages and disadvantages for the specific drug delivery scenarios. Clearly, the system based on the off-label use of the existing approved microbubbles and drugs (or drug carriers) will have a chance of getting to clinical trials faster and with lesser resources spent. However, if a superior curative potential of a sonosensitive drug carrier is proven, and formulation stability problems are addressed properly, this approach may find its way to practical use, especially for nucleic acid delivery scenarios. PMID- 26486341 TI - Drug-Loaded Perfluorocarbon Nanodroplets for Ultrasound-Mediated Drug Delivery. AB - The interaction of nanoparticles with directed energy is a novel application in targeted drug delivery. This chapter focuses on perfluorocarbon nanoemulsions, whose action in drug delivery depends on the ultrasound-triggered phase shift from liquid to gaseous state. These nanoemulsions have great potential for unloading encapsulated drugs at a desired time and location in the body in response to directed ultrasound. In addition, they actively alter their nano environment for enhancing drug transport through various biological barriers to sites of action, which significantly enhances therapeutic outcome. PMID- 26486342 TI - Bubble-Assisted Ultrasound: Application in Immunotherapy and Vaccination. AB - Bubble-assisted ultrasound is a versatile technology with great potential in immunotherapy and vaccination. This technology involves the exposure of immune cells (i.e., dendritic cells, lymphocytes) in-vitro or diseased tissues (i.e., brain, tumor) in-vivo to ultrasound treatment with gas bubbles. Bubble destruction leads to physical forces that induce the direct delivery of weakly permeant immuno-stimulatory molecules either into the cytoplasm of immune cells, or through the endothelial barrier of diseased tissues. Hence, therapeutic antibodies (i.e., antibody-based immunotherapy) and cytokine-encoding nucleic acids (i.e., cytokine gene therapy) can be successfully delivered into diseased tissues, thus improving immune responses. In addition, protein antigens, as well as antigen-encoding nucleic acids (pDNA, mRNA), can be delivered into dendritic cells (i.e., dendritic cell-based vaccines), thus leading to a long-lasting prophylactic or therapeutic immunization. This chapter focuses on the state-of the-art of bubble-assisted ultrasound in the field of immunotherapy and vaccination. PMID- 26486343 TI - Sonoporation: Applications for Cancer Therapy. AB - Therapeutic efficacy of both traditional chemotherapy and gene therapy in cancer is highly dependent on the ability to deliver drugs across natural barriers, such as the vessel wall or tumor cell membranes. In this regard, sonoporation induced by ultrasound-guided microbubble (USMB) destruction has been widely investigated in the enhancement of therapeutic drug delivery given it can help overcome these natural barriers, thereby increasing drug delivery into cancer. In this chapter we discuss challenges in current cancer therapy and how some of these challenges could be overcome using USMB-mediated drug delivery. We particularly focus on recent advances in delivery approaches that have been developed to further improve therapeutic efficiency and specificity of various cancer treatments. An example of clinical translation of USMB-mediated drug delivery is also shown. PMID- 26486344 TI - Microbubble-Assisted Ultrasound for Drug Delivery in the Brain and Central Nervous System. AB - The blood-brain barrier is a serious impediment to the delivery of pharmaceutical treatments for brain diseases, including cancer, neurodegenerative and neuropsychatric diseases. Focused ultrasound, when combined with microbubbles, has emerged as an effective method to transiently and locally open the blood brain barrier to promote drug delivery to the brain. Focused ultrasound has been used to successfully deliver a wide variety of therapeutic agents to pre-clinical disease models. The requirement for clinical translation of focused ultrasound technology is considered. PMID- 26486345 TI - Microbubbles and Ultrasound: Therapeutic Applications in Diabetic Nephropathy. AB - Diabetic nephropathy (DN) remains one of the most common causes of end-stage renal disease. Current therapeutic strategies aiming at optimization of serum glucose and blood pressure are beneficial in early stage DN, but are unable to fully prevent disease progression. With the limitations of current medical therapies and the shortage of available donor organs for kidney transplantation, the need for novel therapies to address DN complications and prevent progression towards end-stage renal failure is crucial. The development of ultrasound technology for non-invasive and targeted in-vivo gene delivery using high power ultrasound and carrier microbubbles offers great therapeutic potential for the prevention and treatment of DN. The promising results from preclinical studies of ultrasound-mediated gene delivery (UMGD) in several DN animal models suggest that UMGD offers a unique, non-invasive platform for gene- and cell-based therapies targeted against DN with strong clinical translation potential. PMID- 26486346 TI - Drug and Gene Delivery using Sonoporation for Cardiovascular Disease. AB - Using the improvements made in diagnostic contrast enhanced ultrasound, researchers have made significant progress in the field of ultrasound-mediated sonoporation for drug delivery. Many programs take advantage of commercial products; both ultrasound imaging systems and contrast agents to better enable translation from preclinical to first-in-man studies (Kotopoulis et al., Med Phys 40:072902, 2013). Particularly well-suited targets for this novel therapy are diseases of the cardiovascular system. This chapter will highlight several recent studies addressing treatment of both acute and chronic conditions. PMID- 26486348 TI - Ultrasound-Mediated Polymeric Micelle Drug Delivery. AB - The synthesis of multi-functional nanocarriers and the design of new stimuli responsive means are equally important for drug delivery. Ultrasound can be used as a remote, non-invasive and controllable trigger for the stimuli-responsive release of nanocarriers. Polymeric micelles are one kind of potential drug nanocarrier. By combining ultrasound and polymeric micelles, a new modality (i.e., ultrasound-mediated polymeric micelle drug delivery) has been developed and has recently received increasing attention. A major challenge remaining in developing ultrasound-responsive polymeric micelles is the improvement of the sensitivity or responsiveness of polymeric micelles to ultrasound. This chapter reviews the recent advance in this field. In order to understand the interaction mechanism between ultrasound stimulus and polymeric micelles, ultrasound effects, such as thermal effect, cavitation effect, ultrasound sonochemistry (including ultrasonic degradation, ultrasound-initiated polymerization, ultrasonic in-situ polymerization and ultrasound site-specific degradation), as well as basic micellar knowledge are introduced. Ultrasound-mediated polymeric micelle drug delivery has been classified into two main streams based on the different interaction mechanism between ultrasound and polymeric micelles; one is based on the ultrasound-induced physical disruption of the micelle and reversible release of payload. The other is based on micellar ultrasound mechanochemical disruption and irreversible release of payload. PMID- 26486349 TI - Stimulation of Bone Repair with Ultrasound. AB - This chapter reviews the different options available for the use of ultrasound in the enhancement of fracture healing or in the reactivation of a failed healing process: LIPUS, shock waves and ultrasound-mediated delivery of bioactive molecules, such as growth factors or plasmids. The main emphasis is on LIPUS, or Low Intensity Pulsed Ultrasound, the most widespread and studied technique. LIPUS has pronounced bioeffects on tissue regeneration, while employing intensities within a diagnostic range. The biological response to LIPUS is complex as the response of numerous cell types to this stimulus involves several pathways. Known to-date mechanotransduction pathways involved in cell responses include MAPK and other kinases signaling pathways, gap-junctional intercellular communication, up regulation and clustering of integrins, involvement of the COX-2/PGE2 and iNOS/NO pathways, and activation of the ATI mechanoreceptor. Mechanisms at the origin of LIPUS biological effects remain intriguing, and analysis is hampered by the diversity of experimental systems used in-vitro. Data point to clear evidence that bioeffects can be modulated by direct and indirect mechanical effects, like acoustic radiation force, acoustic streaming, propagation of surface waves, heat, fluid-flow induced circulation and redistribution of nutrients, oxygen and signaling molecules. One of the future engineering challenge is therefore the design of dedicated experimental set-ups allowing control of these different mechanical phenomena, and to relate them to biological responses. Then, the derivation of an 'acoustic dose' and the cross-calibration of the different experimental systems will be possible. Despite this imperfect knowledge of LIPUS biophysics, the clinical evidence, although most often of low quality, speaks in favor of the clinical use of LIPUS, when the economics of nonunion and the absence of toxicity of this ultrasound technology are taken into account. PMID- 26486350 TI - Sonodynamic Therapy: Concept, Mechanism and Application to Cancer Treatment. AB - Sonodynamic therapy (SDT) represents an emerging approach that offers the possibility of non-invasively eradicating solid tumors in a site-directed manner. It involves the sensitization of target tissues with a non-toxic sensitizing chemical agent and subsequent exposure of the sensitized tissues to relatively low-intensity ultrasound. Essentially, both aspects (the sensitization and ultrasound exposure) are harmless, and cytotoxic events occur when both are combined. Due to the significant depth that ultrasound penetrates tissue, the approach provides an advantage over similar alternative approaches, such as photodynamic therapy (PDT), in which less penetrating light is employed to provide the cytotoxic effect in sensitized tissues. This suggests that sonodynamic therapy may find wider clinical application, particularly for the non invasive treatment of less accessible lesions. Early SDT-based approaches employed many of the sensitizers used in PDT, although the manner in which ultrasound activates the sensitizer differs from activation events in PDT. Here we will review the currently accepted mechanisms by which ultrasound activates sensitizers to elicit cytotoxic effects. In addition, we will explore the breath of evidence from in-vitro and in-vivo SDT-based studies, providing the reader with an insight into the therapeutic potential offered by SDT in the treatment of cancer. PMID- 26486351 TI - World Health Organization-defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management. AB - DISEASE OVERVIEW: The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. DIAGNOSIS: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semi molecular classification scheme of disease subtypes including 'myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1', chronic eosinophilic leukemia, not otherwise specified, (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of the therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established. PMID- 26486347 TI - Sonothrombolysis. AB - Thrombo-occlusive disease is a leading cause of morbidity and mortality. In this chapter, the use of ultrasound to accelerate clot breakdown alone or in combination with thrombolytic drugs will be reported. Primary thrombus formation during cardiovascular disease and standard treatment methods will be discussed. Mechanisms for ultrasound enhancement of thrombolysis, including thermal heating, radiation force, and cavitation, will be reviewed. Finally, in-vitro, in-vivo and clinical evidence of enhanced thrombolytic efficacy with ultrasound will be presented and discussed. PMID- 26486352 TI - Long-term effect on dystonia after pallidal deep brain stimulation (DBS) in three members of a family with a THAP1 mutation. AB - Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an established treatment in patients with severe dystonia. However, factors predicting outcome are largely unknown and motor improvement in DYT6 patients after DBS has been reported to be poorer as compared to, e.g., DYT1 patients. Here, we report the course of clinical improvement for up to 11 years of pallidal DBS in three male patients belonging to the same family with early-onset generalized or segmental dystonia due to a heterozygous THAP1 gene mutation (DYT6). All patients showed an initial effective response to pallidal DBS with a mean of 56.9 +/- 11.7% improvement in the Burke-Fahn-Marsden Dystonia motor and 45.5 +/- 22.4% in the disability score at 1-year follow-up. The long-term outcome of pallidal DBS was favorable in two patients (39, 67% motor improvement, respectively). Our findings demonstrate that motor improvement is variable and may depend on disease severity, disease duration, and clinical presentation. Overall, our observation supports pallidal DBS as an important treatment option in patients with DYT6 dystonia. PMID- 26486353 TI - Giovanni Battista Morgagni (1682-1771). AB - Giovanni Battista Morgagni (1682-1771) is considered the father of neuropathology and one of the most important innovators in the history of medicine. In his "opus magnum" De sedibus et causis morborum per anatomen indagatis (The Seats and causes of diseases investigated by anatomy), he established pathological anatomy as a science by correlating clinical histories with autopsy findings. PMID- 26486354 TI - The pattern of gray matter atrophy in Parkinson's disease differs in cortical and subcortical regions. AB - Cortical and subcortical gray matter (GM) atrophy may progress differently during the course of Parkinson's disease (PD). We delineated and compared the longitudinal pattern of these PD-related changes. Structural MRIs and clinical measures were obtained from 76 PD with different disease durations and 70 Controls at baseline, 18-, and 36 months. Both cortical and subcortical (putamen, caudate, and globus pallidus) GM volumes were obtained, compared, and associated with PD clinical measures at baseline. Their volumes and rates of change also were compared among Controls, PDs, and PD subgroups based on duration of illness [<=1 year (PD(E)), 1-5 years (PD(M)), and >5 years (PD(L))]. Compared to Controls, PD subjects displayed smaller cortical GM and striatal(putamen, caudate, ps <=0.001), volumes at baseline. Cortical GM volumes were negatively associated with disease duration at baseline, whereas striatal volumes were not. PD subjects demonstrated accelerated volume loss in cortical GM (p = 0.006), putamen (p = 0.034), and caudate (p = 0.008) compared to Controls. Subgroup analyses demonstrated that accelerated cortical atrophy reached statistical significance in PD subjects with duration of illness 1-5 years (PD(M), ps<0.001) and the trend of accelerated atrophy seemed to persist until later stages, whereas striatal atrophy occurred in PD subjects with PD(E) (p = 0.021 for putamen, p = 0.005 for caudate) and PD(M) (p = 0.002 for putamen, p = 0.001 for caudate) that significantly slowed down in PD(L) (ps for PD(L) vs PD(E) or PD(M): <0.01). The pattern of GM loss in PD differs in cortical and subcortical regions, with striatal atrophy occurring earlier and extra-striatal cortical atrophy later. PMID- 26486355 TI - Death, end-stage renal disease and renal function decline in patients with diabetic nephropathy in French cohorts of type 1 and type 2 diabetes. AB - AIMS/HYPOTHESIS: Microvascular complications are a common feature of diabetes but additional research is needed regarding diabetic nephropathy endpoints in type 1 and type 2 diabetes. METHODS: We compared 277 type 1 diabetes patients with 942 type 2 diabetes patients, with clinical proteinuria and no endstage renal disease (ESRD) at baseline, prospectively followed for death, ESRD and decline in estimated glomerular filtration rate (eGFR, all available measures). RESULTS: The incidence rate of death was 67.0 (95% CI 59.2, 74.8) vs. 24.6 (95% CI, 19.0, 30.2) per 1,000 patient-years, in type 2 diabetes and type 1 diabetes, respectively. Unadjusted risk for death was greater for type 2 diabetes patients (HR 3.423; 95% CI, 2.501, 4.683; p<0.0001), but the difference did not persist after adjustment for age (HRage-adj 0.859; 95% CI 0.581, 1.269; p=0.445). The incidence rate of ESRD was 18.4 (95% CI 14.2, 22.5) vs. 47.1 (95%CI 38.4, 55.9) per 1,000 patient-years, in type 2 diabetes and type 1 diabetes, respectively. Unadjusted risk for ESRD was lower in type 2 diabetes (HR 0.399; 95% CI 0.287, 0.554; p<0.0001), but the difference did not persist after adjustment for sex, age and baseline serum creatinine (HRadj 0.989; 95% CI 0.597, 1.639; p=0.965). In a mixed linear model, eGFR decline was not significantly different in type 2 vs. type 1 diabetes (difference in slope -0.19 [0.28] ml min(-1) 1.73 m(-2) year(-1); p=0.512). CONCLUSIONS/INTERPRETATION: In diabetic nephropathy, once baseline risk factors were taken into account the risk for death, ESRD and renal function decline did not significantly differ between type 1 diabetes and type 2 diabetes. PMID- 26486357 TI - Mapping forested wetlands in the Great Zhan River Basin through integrating optical, radar, and topographical data classification techniques. AB - Knowledge of the spatial extent of forested wetlands is essential to many studies including wetland functioning assessment, greenhouse gas flux estimation, and wildlife suitable habitat identification. For discriminating forested wetlands from their adjacent land cover types, researchers have resorted to image analysis techniques applied to numerous remotely sensed data. While with some success, there is still no consensus on the optimal approaches for mapping forested wetlands. To address this problem, we examined two machine learning approaches, random forest (RF) and K-nearest neighbor (KNN) algorithms, and applied these two approaches to the framework of pixel-based and object-based classifications. The RF and KNN algorithms were constructed using predictors derived from Landsat 8 imagery, Radarsat-2 advanced synthetic aperture radar (SAR), and topographical indices. The results show that the objected-based classifications performed better than per-pixel classifications using the same algorithm (RF) in terms of overall accuracy and the difference of their kappa coefficients are statistically significant (p<0.01). There were noticeably omissions for forested and herbaceous wetlands based on the per-pixel classifications using the RF algorithm. As for the object-based image analysis, there were also statistically significant differences (p<0.01) of Kappa coefficient between results performed based on RF and KNN algorithms. The object-based classification using RF provided a more visually adequate distribution of interested land cover types, while the object classifications based on the KNN algorithm showed noticeably commissions for forested wetlands and omissions for agriculture land. This research proves that the object-based classification with RF using optical, radar, and topographical data improved the mapping accuracy of land covers and provided a feasible approach to discriminate the forested wetlands from the other land cover types in forestry area. PMID- 26486356 TI - Resistance training improves skeletal muscle insulin sensitivity in elderly offspring of overweight and obese mothers. AB - AIMS/HYPOTHESIS: Maternal obesity predisposes offspring to adulthood morbidities, including type 2 diabetes. Type 2 diabetes and insulin resistance have been associated with shortened telomere length. First, we aimed to investigate whether or not maternal obesity influences insulin sensitivity and its relationship with leucocyte telomere length (LTL) in elderly women. Second, we tested whether or not resistance exercise training improves insulin sensitivity in elderly frail women. METHODS: Forty-six elderly women, of whom 20 were frail offspring of lean/normal weight mothers (OLM, BMI <=26.3 kg/m2) and 17 were frail offspring of overweight/obese mothers (OOM,BMI >=28.1 kg/m2), were studied before and after a 4 month resistance training (RT) intervention. Muscle insulin sensitivity of glucose uptake was measured using 18F-fluoro-2-deoxyglucose and positron emission tomography with computed tomography during a hyperinsulinaemic-euglycaemic clamp. Muscle mass and lipid content were measured using magnetic resonance and LTL was measured using real-time PCR. RESULTS: The OOM group had lower thigh muscle insulin sensitivity compared with the OLM group (p=0.048) but similar whole body insulin sensitivity. RT improved whole body and skeletal muscle insulin sensitivity in the OOM group only (p=0.004 and p=0.013, respectively), and increased muscle mass in both groups (p <0 .01). In addition, in the OOM group, LTL correlated with different thigh muscle groups insulin sensitivity (rho >= 0.53; p <= 0.05). Individuals with shorter LTL showed a higher increase in skeletal muscle insulin sensitivity after training (rho >= -0.61; p <= 0.05). CONCLUSIONS/INTERPRETATION: Maternal obesity and having telomere shortening were associated with insulin resistance in adult offspring. A resistance exercise training programme may reverse this disadvantage among offspring of obese mothers. Trial registration: ClinicalTrials.gov NCT01931540. PMID- 26486358 TI - Cryptococcal meningoencephalitis associated with the long-term use of ruxolitinib. PMID- 26486359 TI - Among-species variation in the energy budgets of reef-building corals: scaling from coral polyps to communities. AB - The symbiosis between corals and dinoflagellates promotes the rapid growth of corals in shallow tropical oceans, and the high overall productivity of coral reefs. The aim of this study was to quantify and understand variation in carbon acquisition and allocation among coral species. We measured multiple physiological traits (including symbiont density, calcification, photosynthesis and tissue composition) for the same coral fragments to facilitate direct comparisons between species (Stylophora pistillata, Pocillopora damicornis, Galaxea fascicularis, Turbinaria reniformis and Acropora sp.). Tissue protein content was highly sensitive to the availability of particulate food, increasing in fed colonies of all species. Despite among-species variation in physiology, and consistent effects of feeding on some traits, overall energy allocation to tissue compared with skeleton growth did not depend on food availability. Extrapolating from our results, estimated whole-assemblage carbon uptake varied >20-fold across different coral assemblages, but this variation was largely driven by differences in the tissue surface area of different colony morphologies, rather than by differences in surface-area-specific physiological rates. Our results caution against drawing conclusions about reef productivity based solely on physiological rates measured per unit tissue surface area. Understanding the causes and consequences of among-species variation in physiological energetics provides insight into the mechanisms that underlie the fluxes of organic matter within reefs, and between reefs and the open ocean. PMID- 26486360 TI - The sexually dimorphic behaviour of adult Drosophila suzukii: elevated female locomotor activity and loss of siesta is a post-mating response. AB - The polyphagous Drosophila suzukii is a highly invasive species that causes extensive damage to a wide range of berry and stone fruit crops. A better understanding of its biology and especially its behaviour will aid the development of new control strategies. We investigated the locomotor behaviour of D. suzukii in a semi-natural environment resembling a typical summer in northern England and show that adult female D. suzukii are at least 4-fold more active during daylight hours than adult males. This result was reproduced in several laboratory environments and was shown to be a robust feature of mated, but not virgin, female flies. Both males and virgin females kept on a 12 h light:12 h dark (12LD) cycle and constant temperature displayed night-time inactivity (sleep) followed by weak activity in the morning, an afternoon period of quiescence (siesta) and then a prominent evening peak of activity. Both the siesta and the sharp evening peak at lights off were severely reduced in females after mating. Flies of either sex entrained in 12LD displayed a circadian pattern of activity in constant darkness confirming the importance of an endogenous clock in regulating adult activity. This response of females to mating is similar to that elicited in female Drosophila melanogaster by the male sex peptide (SP). We used mass spectrometry to identify a molecular ion (m/z, 5145) corresponding to the poly-hydroxylated SP of D. suzukii and to show that this molecule is transferred to the female reproductive tract during copulation. We propose that the siesta experienced by male and virgin female D. suzukii is an adaptation to avoid unnecessary exposure to the afternoon sun, but that mated females faced with the challenge of obtaining resources for egg production and finding oviposition sites take greater risks, and we suggest that the change in female behaviour is induced by the male SP. PMID- 26486361 TI - A simple behaviour provides accuracy and flexibility in odour plume tracking--the robotic control of sensory-motor coupling in silkmoths. AB - Odour plume tracking is an essential behaviour for animal survival. A fundamental strategy for this is to move upstream and then across-stream. Male silkmoths, Bombyx mori, display this strategy as a pre-programmed sequential behaviour. They walk forward (surge) in response to the female sex pheromone and perform a zigzagging 'mating dance'. Though pre-programmed, the surge direction is modulated by bilateral olfactory input and optic flow. However, the nature of the interaction between these two sensory modalities and contribution of the resultant motor command to localizing an odour source are still unknown. We evaluated the ability of the silkmoth to localize an odour source under conditions of disturbed sensory-motor coupling, using a silkmoth-driven mobile robot. The significance of the bilateral olfaction of the moth was confirmed by inverting the olfactory input to the antennae, or its motor output. Inversion of the motor output induced consecutive circling, which was inhibited by covering the visual field of the moth. This suggests that the corollary discharge from the motor command and the reafference of self-generated optic flow generate compensatory signals to guide the surge accurately. Additionally, after inverting the olfactory input, the robot successfully tracked the odour plume by using a combination of behaviours. These results indicate that accurate guidance of the reflexive surge by integrating bilateral olfactory and visual information with innate pre-programmed behaviours increases the flexibility to track an odour plume even under disturbed circumstances. PMID- 26486362 TI - Fishing for drifts: detecting buoyancy changes of a top marine predator using a step-wise filtering method. AB - In southern elephant seals (Mirounga leonina), fasting- and foraging-related fluctuations in body composition are reflected by buoyancy changes. Such buoyancy changes can be monitored by measuring changes in the rate at which a seal drifts passively through the water column, i.e. when all active swimming motion ceases. Here, we present an improved knowledge-based method for detecting buoyancy changes from compressed and abstracted dive profiles received through telemetry. By step-wise filtering of the dive data, the developed algorithm identifies fragments of dives that correspond to times when animals drift. In the dive records of 11 southern elephant seals from South Georgia, this filtering method identified 0.8-2.2% of all dives as drift dives, indicating large individual variation in drift diving behaviour. The obtained drift rate time series exhibit that, at the beginning of each migration, all individuals were strongly negatively buoyant. Over the following 75-150 days, the buoyancy of all individuals peaked close to or at neutral buoyancy, indicative of a seal's foraging success. Independent verification with visually inspected detailed high resolution dive data confirmed that this method is capable of reliably detecting buoyancy changes in the dive records of drift diving species using abstracted data. This also affirms that abstracted dive profiles convey the geometric shape of drift dives in sufficient detail for them to be identified. Further, it suggests that, using this step-wise filtering method, buoyancy changes could be detected even in old datasets with compressed dive information, for which conventional drift dive classification previously failed. PMID- 26486363 TI - Eye and head movements shape gaze shifts in Indian peafowl. AB - Animals selectively direct their visual attention toward relevant aspects of their environments. They can shift their attention using a combination of eye, head and body movements. While we have a growing understanding of eye and head movements in mammals, we know little about these processes in birds. We therefore measured the eye and head movements of freely behaving Indian peafowl (Pavo cristatus) using a telemetric eye-tracker. Both eye and head movements contributed to gaze changes in peafowl. When gaze shifts were smaller, eye movements played a larger role than when gaze shifts were larger. The duration and velocity of eye and head movements were positively related to the size of the eye and head movements, respectively. In addition, the coordination of eye and head movements in peafowl differed from that in mammals; peafowl exhibited a near absence of the vestibulo-ocular reflex, which may partly result from the peafowl's ability to move their heads as quickly as their eyes. PMID- 26486364 TI - Simultaneous measurement of 3D zooplankton trajectories and surrounding fluid velocity field in complex flows. AB - We describe an automated, volumetric particle image velocimetry (PIV) and tracking method that measures time-resolved, 3D zooplankton trajectories and surrounding volumetric fluid velocity fields simultaneously and non-intrusively. The method is demonstrated for groups of copepods flowing past a wall-mounted cylinder. We show that copepods execute escape responses when subjected to a strain rate threshold upstream of a cylinder, but the same threshold range elicits no escape responses in the turbulent wake downstream. The method was also used to document the instantaneous slip velocity of zooplankton and the resulting differences in trajectory between zooplankton and non-inertial fluid particles in the unsteady wake flow, showing the method's capability to quantify drift for both passive and motile organisms in turbulent environments. Applications of the method extend to any group of organisms interacting with the surrounding fluid environment, where organism location, larger-scale eddies and smaller-scale fluid deformation rates can all be tracked and analyzed. PMID- 26486365 TI - Discontinuous gas-exchange cycle characteristics are differentially affected by hydration state and energy metabolism in gregarious and solitary desert locusts. AB - The termination of discontinuous gas exchange cycles (DGCs) in severely dehydrated insects casts doubt on the generality of the hygric hypothesis, which posits that DGCs evolved as a water conservation mechanism. We followed DGC characteristics in the two density-dependent phases of the desert locust Schistocerca gregaria throughout exposure to an experimental treatment of combined dehydration and starvation stress, and subsequent rehydration. We hypothesized that, under stressful conditions, the more stress-resistant gregarious locusts would maintain DGCs longer than solitary locusts. However, we found no phase-specific variations in body water content, water loss rates (total and respiratory) or timing of stress-induced abolishment of DGCs. Likewise, locusts of both phases re-employed DGCs after ingesting comparable volumes of water when rehydrated. Despite comparable water management performances, the effect of exposure to stressful experimental conditions on DGC characteristics varied significantly between gregarious and solitary locusts. Interburst duration, which is affected by the ability to buffer CO2, was significantly reduced in dehydrated solitary locusts compared with gregarious locusts. Moreover, despite similar rehydration levels, only gregarious locusts recovered their initial CO2 accumulation capacity, indicating that cycle characteristics are affected by factors other than haemolymph volume. Haemolymph protein measurements and calculated respiratory exchange ratios suggest that catabolism of haemolymph proteins may contribute to a reduced haemolymph buffering capacity, and thus a compromised ability for CO2 accumulation, in solitary locusts. Nevertheless, DGC was lost at similar hydration states in the two phases, suggesting that DGCs are terminated as a result of inadequate oxygen supply to the tissues. PMID- 26486366 TI - Characterizing the metabolic capacity of the anoxic hagfish heart. AB - Pacific hagfish, Eptatretus stoutii, can recover from 36 h of anoxia at 10 degrees C. Such anoxia tolerance demands the mobilization of anaerobic fuels and the removal of metabolic wastes--processes that require a functional heart. The purpose of this study was to measure the metabolic response of the excised, cannulated hagfish heart to anoxia using direct calorimetry. These experiments were coupled with measurements of cardiac pH and metabolite concentrations, at multiple time points, to monitor acid-base balance and anaerobic ATP production. We also exposed hagfish to anoxia to compare the in vitro responses of the excised hearts with the in vivo responses. The calorimetry results revealed a significant reduction in the rate of metabolic heat production over the first hour of anoxia exposure, and a recovery over the subsequent 6 h. This response is likely attributable to a rapid anoxia-induced depression of aerobic ATP production pathways followed by an upregulation of anaerobic ATP-production pathways such that the ATP production rate was restored to that measured in normoxia. Glycogen-depletion measurements suggest that metabolic processes were initially supported by glycolysis but that an alternative fuel source was used to support the sustained rates of ATP production. The maintenance of intracellular pH during anoxia indicates a remarkable ability of the myocytes to buffer/regulate protons and thus protect cardiac function. Altogether, these results illustrate that the low metabolic demand of the hagfish heart allows for near-routine levels of cardiac metabolism to be supported anaerobically. This is probably a significant contributor to the hagfish's exceptional anoxia tolerance. PMID- 26486367 TI - A role for nitric oxide in the control of breathing in zebrafish (Danio rerio). AB - Nitric oxide (NO) is a gaseous neurotransmitter, which, in adult mammals, modulates the acute hypoxic ventilatory response; its role in the control of breathing in fish during development is unknown. We addressed the interactive effects of developmental age and NO in the control of piscine breathing by measuring the ventilatory response of zebrafish (Danio rerio) adults and larvae to NO donors and by inhibiting endogenous production of NO. In adults, sodium nitroprusside (SNP), a NO donor, inhibited ventilation; the extent of the ventilatory inhibition was related to the pre-existing ventilatory drive, with the greatest inhibition exhibited during exposure to hypoxia (PO2=5.6 kPa). Inhibition of endogenous NO production using L-NAME suppressed the hypoventilatory response to hyperoxia, supporting an inhibitory role of NO in adult zebrafish. Neuroepithelial cells (NECs), the putative oxygen chemoreceptors of fish, contain neuronal nitric oxide synthase (nNOS). In zebrafish larvae at 4 days post-fertilization, SNP increased ventilation in a concentration-dependent manner. Inhibition of NOS activity with L-NAME or knockdown of nNOS inhibited the hypoxic (PO2=3.5 kPa) ventilatory response. Immunohistochemistry revealed the presence of nNOS in the NECs of larvae. Taken together, these data suggest that NO plays an inhibitory role in the control of ventilation in adult zebrafish, but an excitatory role in larvae. PMID- 26486369 TI - CaMKII knockdown affects both early and late phases of olfactory long-term memory in the honeybee. AB - Honeybees are able to solve complex learning tasks and memorize learned information for long time periods. The molecular mechanisms mediating long-term memory (LTM) in the honeybee Apis mellifera are, to a large part, still unknown. We approached this question by investigating the potential function of the calcium/calmodulin-dependent protein kinase II (CaMKII), an enzyme known as a 'molecular memory switch' in vertebrates. CaMKII is able to switch to a calcium independent constitutively active state, providing a mechanism for a molecular memory and has further been shown to play an essential role in structural synaptic plasticity. Using a combination of knockdown by RNA interference and pharmacological manipulation, we disrupted the function of CaMKII during olfactory learning and memory formation. We found that learning, memory acquisition and mid-term memory were not affected, but all manipulations consistently resulted in an impaired LTM. Both early LTM (24 h after learning) and late LTM (72 h after learning) were significantly disrupted, indicating the necessity of CaMKII in two successive stages of LTM formation in the honeybee. PMID- 26486368 TI - Acute cold and exercise training up-regulate similar aspects of fatty acid transport and catabolism in house sparrows (Passer domesticus). AB - Summit maximum thermoregulatory metabolic rate (Msum) and maximum exercise metabolic rate (MMR) both increase in response to acute cold or exercise training in birds. Because lipids are the main fuel supporting both thermogenesis and exercise in birds, adjustments to lipid transport and catabolic capacities may support elevated energy demands from cold and exercise training. To examine a potential mechanistic role for lipid transport and catabolism in organismal cross training effects (exercise effects on both exercise and thermogenesis, and vice versa), we measured enzyme activities and mRNA and protein expression in pectoralis muscle for several key steps of lipid transport and catabolism pathways in house sparrows (Passer domesticus) during acute exercise and cold training. Both training protocols elevated pectoralis protein levels of fatty acid translocase (FAT/CD36), cytosolic fatty acid-binding protein, and citrate synthase (CS) activity. However, mRNA expression of FAT/CD36 and both mRNA and protein expression of plasma membrane fatty acid-binding protein did not change for either training group. CS activities in supracoracoideus, leg and heart, and carnitine palmitoyl transferase (CPT) and beta-hydroxyacyl CoA-dehydrogenase activities in all muscles did not vary significantly with either training protocol. Both Msum and MMR were significantly positively correlated with CPT and CS activities. These data suggest that up-regulation of trans-sarcolemmal and intramyocyte lipid transport capacities and cellular metabolic intensities, along with previously documented increases in body and pectoralis muscle masses and pectoralis myostatin (a muscle growth inhibitor) levels, are common mechanisms underlying the training effects of both exercise and shivering in birds. PMID- 26486370 TI - Behavioural evidence for a visual and proprioceptive control of head roll in hoverflies (Episyrphus balteatus). AB - The ability of hoverflies to control their head orientation with respect to their body contributes importantly to their agility and their autonomous navigation abilities. Many tasks performed by this insect during flight, especially while hovering, involve a head stabilization reflex. This reflex, which is mediated by multisensory channels, prevents the visual processing from being disturbed by motion blur and maintains a consistent perception of the visual environment. The so-called dorsal light response (DLR) is another head control reflex, which makes insects sensitive to the brightest part of the visual field. In this study, we experimentally validate and quantify the control loop driving the head roll with respect to the horizon in hoverflies. The new approach developed here consisted of using an upside-down horizon in a body roll paradigm. In this unusual configuration, tethered flying hoverflies surprisingly no longer use purely vision-based control for head stabilization. These results shed new light on the role of neck proprioceptor organs in head and body stabilization with respect to the horizon. Based on the responses obtained with male and female hoverflies, an improved model was then developed in which the output signals delivered by the neck proprioceptor organs are combined with the visual error in the estimated position of the body roll. An internal estimation of the body roll angle with respect to the horizon might explain the extremely accurate flight performances achieved by some hovering insects. PMID- 26486371 TI - Trajectories of self-reported cognitive function in postmenopausal women during adjuvant systemic therapy for breast cancer. AB - OBJECTIVE: In a sample of 368 postmenopausal women, we (1) determined within cohort and between-cohort relationships between adjuvant systemic therapy for breast cancer and self-reported cognitive function during the first 18 months of therapy and (2) evaluated the influence of co-occurring symptoms, neuropsychological function, and other covariates on relationships. METHODS: We evaluated self-reported cognitive function, using the Patient Assessment of Own Functioning Inventory (PAOFI), and potential covariates (e.g., co-occurring symptom scores and neuropsychological function z-scores) in 158 women receiving aromatase inhibitor (AI) therapy alone, 104 women receiving chemotherapy followed by AI therapy, and 106 non-cancer controls. Patients were assessed before systemic therapy and then every 6 months, for a total of four assessments over 18 months. Controls were assessed at matched time points. Mixed-effects modeling was used to determine longitudinal relationships. RESULTS: Controlling for covariates, patients enrolled before chemotherapy reported poorer global cognitive function (p < 0.001), memory (p < 0.001), language and communication (p < 0.001), and sensorimotor function (p = 0.002) after chemotherapy. These patients reported poorer higher-level cognitive and intellectual functions from before chemotherapy to 12 months after initiation of AI therapy (p < 0.001). Higher levels of depressive symptoms (p < 0.001), anxiety (p < 0.001), and fatigue (p = 0.040) at enrollment were predictors of poorer cognitive function over time. PAOFI total score was a predictor of executive function (p = 0.048) and visual working memory (p = 0.005) z-scores, controlling for covariates. CONCLUSIONS: Findings provide further evidence of poorer self-reported cognitive function after chemotherapy and of relationships between co-occurring symptoms and cognitive changes. AI therapy alone does not have an impact on self-reported cognitive function. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26486373 TI - Cellular economy in fission yeast cells continuously cultured with limited nitrogen resources. AB - In ribosome biogenesis, a large fraction of ribosomes is used for producing ribosomal proteins themselves. Here, we applied simulation and experimentation to determine what fraction of ribosomes should be allocated for the synthesis of ribosomal proteins to optimize cellular economy for growth. We define the "r fraction" as the fraction of mRNA of the ribosomal protein genes out of the total mRNA, and we simulated the effect of the r-fraction on the number of ribosomes. We then empirically measured the amount of protein and RNA in fission yeast cells cultured with high and low nitrogen sources. In the cells cultured with a low nitrogen source, the r-fraction decreased from 0.46 to 0.42 with a 40% reduction of rRNA, but the reduction of the total protein was smaller at 30%. These results indicate that the r-fraction is internally controlled to optimize the efficiency of protein synthesis at a limited cellular cost. PMID- 26486374 TI - A Pilot Study of the Effect of Daikenchuto on Rectal Sensation in Patients with Irritable Bowel Syndrome. AB - BACKGROUND/AIMS: Daikenchuto (TU 100), a botanical agent that modulates gastrointestinal nerves, is used in the treatment of motility and functional disorders. Our aim was to study the effects of TU-100 on rectal compliance and sensation in patients with irritable bowel syndrome (IBS). METHODS: In 20 patients per treatment arm, we conducted a single-center, randomized, parallel group, double-blind, placebo-controlled, single-dose pharmacodynamics study evaluating the effects of TU-100, 15 g (5 g t.i.d. [means 3 times a day]), for 14 16 consecutive days on rectal compliance and rectal sensation (thresholds and sensation ratings), all measured at baseline and on the last day of medication treatment. The primary endpoint was rectal sensation thresholds and sensation ratings in response to balloon distension at 32 mmHg. Secondary endpoints were rectal compliance, sensation thresholds, ratings and tone (fasting and postprandial), bowel pattern, abdominal pain (average and worst severity) and bloating scores, IBS quality of life and safety profile. RESULTS: Rectal sensation ratings post-treatment were significantly associated with baseline (pre treatment) ratings and with level of anxiety or stress recorded at the time of the sensation testing. There were no effects of TU-100 treatment on rectal sensation ratings, sensation thresholds, rectal fasting or postprandial tone, rectal compliance, bowel function, abdominal pain or bloating scores, or IBS quality of life. CONCLUSIONS: TU-100 did not significantly affect rectal compliance and sensation in patients with IBS in this study. PMID- 26486372 TI - Genome of the facultative scuticociliatosis pathogen Pseudocohnilembus persalinus provides insight into its virulence through horizontal gene transfer. AB - Certain ciliates of the subclass Scuticociliatia (scuticociliates) are facultative parasites of fishes in which they cause a suite of diseases collectively termed scuticociliatosis. Hitherto, comparatively little was known about genetics and genomics of scuticociliates or the mechanism of scuticociliatosis. In this study, a laboratory culture of the facultatively pathogenic scuticociliate Pseudocohnilembus persalinus was established and its genome sequenced, giving the first genome of a marine ciliate. Genome-wide horizontal gene transfer (HGT) analysis showed P. persalinus has acquired many unique prokaryote-derived genes that potentially contribute to the virulence of this organism, including cell adhesion, hemolysis and heme utilization genes. These findings give new insights into our understanding of the pathology of scuticociliates. PMID- 26486375 TI - Quality of Life Differences in Female and Male Patients with Fecal Incontinence. AB - BACKGROUND/AIMS: To explore and compare quality of life (QoL) differences in female and male patients with fecal incontinence. METHODS: Ninety-one patients with fecal incontinence (60 women, mean (SD) age 64.13 (9.72) years; 31 men, mean (SD) age 63.61 (13.33) years) were assessed for pathophysiology (anorectal manometry and ultrasound), clinical severity (Wexner and Vaizey scales), QoL (Fecal Incontinence Quality of Life Score [FIQL]) and health status (EQ-5D). RESULTS: External and internal anal sphincter impairment rates were 96.5% and 70.2%, respectively, in women, compared to 30% and 43.3% respectively in men (P< 0.05). Clinical severity was similar in both sexes, with mean (SD) Wexner scores of 10.95 (4.35) for women and 9.81 (4.30) for men, and mean (SD) Vaizey scores of 13.27 (4.66) for women and 11.90 (5.22) for men. Scores for women were significantly lower for all FIQL depression and coping subscales (P< 0.001) and the EQ-5D depression subscale (P< 0.01). EQ-5D index was 0.687 (0.20) for women and 0.835 (0.15) for men (P< 0.001). QoL was negatively affected by female gender (?1.336), anxiety/depression (?1.324) and clinical severity (?0.302), whereas age had a positive impact (0.055 per year) (P< 0.01). CONCLUSIONS: The pathophysiology of fecal incontinence differed between the sexes. For similar severity scores, impact on QoL was higher in women. Gender had the highest impact on QoL compared to other factors. QoL measurements should be part of assessment and treatment protocols. PMID- 26486376 TI - Utility of indocyanine-green fluorescent imaging during robot-assisted sphincter saving surgery on rectal cancer patients. AB - BACKGROUND: There have been few studies describing the use of indocyanine green (ICG) fluorescent imaging during robot-assisted (RA) sphincter-saving operations (SSOs) and assessing its potential role in reducing anastomotic leak (AL). METHODS: A consecutive cohort of 436 rectal cancer patients who underwent curative RA SSOs were prospectively enrolled during 2010-2014, including 123 patients with ICG imaging (ICG+ group) and 313 patients without ICG imaging (ICG- group). RESULTS: ICG imaging appeared to be helpful in identifying competent perfusion of the bowel adjacent to the anastomosis in 13 patients (10.6%) who might be susceptible to bowel ischaemia, including restrictive mesocolon. AL was remarkably greater in the ICG- group compared with the ICG+ group (5.4% vs 0.8%; p = 0.031). CONCLUSIONS: ICG imaging during RA SSO provides accurate real-time knowledge of the perfusion status at or near the anastomosis, specifically reducing AL in patients who may incur bowel ischaemia. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26486378 TI - The rise and rise of generic prescribing. PMID- 26486379 TI - Introductory remarks. PMID- 26486377 TI - Early experience with the new endovascular aneurysm sealing system Nellix: First clinical results after 50 implantations. AB - OBJECTIVE: In the present study, 50 EVAS procedures were evaluated in regard to primary (survival and technical success) and secondary (device-related complications) events of interest. METHODS: The single center study was conducted from July 2013 to August 2014 with prospective collection of the clinical data. The clinical results were controlled by CT angiography and contrast-enhanced ultrasound. RESULTS: The technical success was 98% and the 30-day mortality 4%. One (2%) patient died from multisystem organ failure and another patient from an intracranial bleeding, respectively. One patient (2%) suffered from a device related aneurysm rupture. During early follow-up, one (2%) patient developed an endoleak type II, while three (6%) patients suffered from a partial endograft limb thrombosis. Overall, a secondary intervention was necessary in six (12%) patients. CONCLUSIONS: With the Nellix EVAS system, a high primary technical success of 98% was achieved; one (2%) patient developed an endoleak type II which did not require secondary intervention. Those promising results are contrasted by a substantial rate of endograft limb thromboses (8%) and one (2%) intraoperative aneurysm rupture. Further studies are needed to assess the durability of the Nellix stentgraft and the occurrence of device-related complications. PMID- 26486381 TI - Discussion. PMID- 26486380 TI - Diaschisis in stroke. PMID- 26486382 TI - Stroke units. PMID- 26486384 TI - Essential investigations for patients with transient ischemic attacks and evolving stroke. PMID- 26486383 TI - Discussion. PMID- 26486385 TI - The brain and cardiac surgery: Design and implementation of a research program. PMID- 26486387 TI - Discussion. PMID- 26486386 TI - Discussion. PMID- 26486388 TI - Transient ischemic attack: Is it a relevant concept? PMID- 26486389 TI - Aspirin for stroke prevention: An update. PMID- 26486390 TI - Discussion. PMID- 26486391 TI - Introductory remarks. PMID- 26486392 TI - Discussion. PMID- 26486393 TI - Ultrasound and magnetic resonance angiography. PMID- 26486394 TI - Magnetic resonance angiography in cerebrovascular disease: A clinical update. PMID- 26486395 TI - Discussion. PMID- 26486396 TI - Introductory remarks. PMID- 26486397 TI - Silent cerebral infarction/lacunes. PMID- 26486398 TI - Silent cerebral infarctions in transient ischemic attack populations: Implications of advancing technology. PMID- 26486399 TI - Discussion. PMID- 26486401 TI - The semantics of brain hemorrhage: Some practical problems of risk and benefit assessment in fibrinolytic therapy. PMID- 26486400 TI - Thrombolytic therapy in acute ischemic stroke. PMID- 26486402 TI - Discussion. PMID- 26486403 TI - Neuronal protection and hemorheology. PMID- 26486405 TI - Discussion. PMID- 26486404 TI - Heparin-induced extracorporeal low-density-lipoprotein precipitation (HELP). PMID- 26486406 TI - Blood pressure regulation in ischemic cerebral vascular disease. PMID- 26486407 TI - Management of blood pressure in acute and chronic cerebrovascular disease from the viewpoint of cerebral blood flow. PMID- 26486409 TI - Discussion. PMID- 26486408 TI - Influence of hyperglycemia on outcome of ischemic stroke. PMID- 26486410 TI - Brain edema in acute ischemic stroke. PMID- 26486411 TI - Discussion. PMID- 26486412 TI - Diaschisis: Epiphenomenon or clinical entity? PMID- 26486413 TI - Metallated porphyrin based porous organic polymers as efficient electrocatalysts. AB - Developing efficient, stable and low-cost catalysts for Oxygen Reduction Reaction (ORR) is of great significance to many emerging technologies including fuel cells and metal-air batteries. Herein, we report the development of a cobalt(II) porphyrin based porous organic polymer (CoPOP) and its pyrolyzed derivatives as highly active ORR catalysts. The as-synthesized CoPOP exhibits high porosity and excellent catalytic performance stability, retaining ~100% constant ORR current over 50,000 s in both alkaline and acidic media. Pyrolysis of CoPOP at various temperatures (600 degrees C, 800 degrees C, and 1000 degrees C) yields the materials consisting of graphitic carbon layers and cobalt nanoparticles, which show greatly enhanced catalytic activity compared to the as-synthesized CoPOP. Among them, CoPOP-800/C pyrolyzed at 800 degrees C shows the highest specific surface area and ORR activity, displaying the most positive half-wave potential (0.825 V vs. RHE) and the largest limited diffusion current density (5.35 mA cm( 2)) in an alkaline medium, which are comparable to those of commercial Pt/C (20 wt%) (half-wave potential 0.829 V vs. RHE, limited diffusion current density 5.10 mA cm(-2)). RDE and RRDE experiments indicate that CoPOP-800/C directly reduces molecular oxygen to water through a 4-e(-) pathway in both alkaline and acidic media. More importantly, CoPOP-800/C exhibits excellent durability and methanol tolerance under acidic and alkaline conditions, which surpass the Pt/C (20 wt%) system. PMID- 26486414 TI - Significant alteration of soil bacterial communities and organic carbon decomposition by different long-term fertilization management conditions of extremely low-productivity arable soil in South China. AB - Different fertilization managements of red soil, a kind of Ferralic Cambisol, strongly affected the soil properties and associated microbial communities. The association of the soil microbial community and functionality with long-term fertilization management in the unique low-productivity red soil ecosystem is important for both soil microbial ecology and agricultural production. Here, 454 pyrosequencing analysis of 16S recombinant ribonucleic acid genes and GeoChip4 NimbleGen-based functional gene analysis were used to study the soil bacterial community composition and functional genes involved in soil organic carbon degradation. Long-term nitrogen-containing chemical fertilization-induced soil acidification and fertility decline and significantly altered the soil bacterial community, whereas long-term organic fertilization and fallow management improved the soil quality and maintained the bacterial diversity. Short-term quicklime remediation of the acidified soils did not change the bacterial communities. Organic fertilization and fallow management supported eutrophic ecosystems, in which copiotrophic taxa increased in relative abundance and have a higher intensity of labile-C-degrading genes. However, long-term nitrogen-containing chemical fertilization treatments supported oligotrophic ecosystems, in which oligotrophic taxa increased in relative abundance and have a higher intensity of recalcitrant-C-degrading genes but a lower intensity of labile-C-degrading genes. Quicklime application increased the relative abundance of copiotrophic taxa and crop production, although these effects were utterly inadequate. This study provides insights into the interaction of soil bacterial communities, soil functionality and long-term fertilization management in the red soil ecosystem; these insights are important for improving the fertility of unique low productivity red soil. PMID- 26486415 TI - Elucidating the use of enoxaparin in non-ST-elevation acute coronary syndromes (NSTE-ACS). PMID- 26486416 TI - A higher overall diet quality is inversely associated with the risk of chronic obstructive pulmonary disease (COPD) in men and women. PMID- 26486417 TI - Novel morphological macular findings in juvenile CLN3 disease. AB - AIMS: Juvenile CLN3 disease, one of the most common forms of a group of lysosomal storage diseases called neuronal ceroid lipofuscinoses (NCLs), is a progressive neurodegenerative disorder with initial visual deterioration. The objective of this study was to analyse the retinal phenotype of patients with CLN3 disease with the help of recent ophthalmic imaging modalities to distinguish CLN3 disease from other inherited retinal dystrophies. METHODS: Patients underwent ophthalmic evaluations, including anterior and posterior segment examinations, optical coherence tomography, fundus autofluorescence, near infrared imaging and fundus photography. Patients were also assessed according to the Hamburg juvenile NCL (JNCL) score. Each ophthalmic finding was assessed by three independent examiners and assigned to a clinical severity score. RESULTS: 22 eyes of 11 patients were included. The mean age at examination was 14.4 years (range 11.8-26.4 years), with an average age at initial diagnosis of 8 years (range 4.5-11 years). The mean Hamburg JNCL score was 7.3 (range 0-13). All patients showed a specific macular striation pattern on optical coherence tomography that was independent of age and progression of the disease. Other previously described retinal features of CLN3 disease were classified into four severity grades. CONCLUSIONS: This study represents the first prospective observational case series documenting retinal abnormalities in CLN3 disease with the aid of the spectral domain optical coherence tomography. The major finding was a characteristic, striated macular pattern in all patients studied. Particularly in early disease cases, macular striae can potentially help to discriminate CLN3 disease from other inherited forms of retinitis pigmentosa. PMID- 26486418 TI - Diabetes and diabetic retinopathy in people aged 50 years and older in the Republic of Suriname. AB - BACKGROUND/AIMS: Population-based surveys on diabetes and diabetic retinopathy (DR) are necessary to increase awareness and develop screening and therapeutic programmes. The aim was to estimate the prevalence of DR in older adults of different ethnic backgrounds in Suriname. METHODS: Fifty clusters of 60 people aged >=50 years were randomly selected with a probability proportional to the size of the population unit. Eligible people were randomly selected through compact segment sampling and examined using the Rapid Assessment of Avoidable Blindness plus Diabetic Retinopathy (RAAB + DR) protocol. Participants were classified as having diabetes if they: were previously diagnosed with diabetes; were receiving treatment for glucose control; had a random blood glucose level >200 mg/dL. These participants were dilated for funduscopy, assessed for DR following the Scottish DR grading protocol and evaluated for ethnicity and DR ophthalmic screening frequencies. RESULTS: A total of 2806 individuals was examined (response 93.6%). The prevalence of diabetes was 24.6%. In these patients any type of DR and/or maculopathy occurred in 21.6% and sight threatening DR in 8.0%. Of the known diabetics, 34.2% never had an eye examination for DR and in 13.0% the last examination was >24 months ago. The prevalence of diabetes was significantly higher in Hindustani people compared with other major ethnic groups. CONCLUSIONS: The prevalence of diabetes and diabetics without regular DR control in people aged >=50 years in Suriname was higher than expected. The uptake for special services for DR has to be expanded to decrease patient delay and DR-induced blindness. PMID- 26486421 TI - Tin(II)-functionalization of the archetypal {P8W48} polyoxotungstate. AB - The synthesis of [K(4.5) ? (ClSn(II))8P8W48O184](17.5-), featuring Sn(II) ions in trigonal-pyramidal SnO2Cl environment coordinating to the two inner rims of the wheel-shaped {P8W48}-type polyoxotungstate(vi) archetype, showcases how high chloride ligand concentrations as well as the control of the polyanion solubility via electrolytes and evaporation rates are essential to prevent numerous competing reactions that can hamper the Sn(ii) functionalization of polyoxometalates. PMID- 26486420 TI - The Extracellular Vesicles of the Helminth Pathogen, Fasciola hepatica: Biogenesis Pathways and Cargo Molecules Involved in Parasite Pathogenesis. AB - Extracellular vesicles (EVs) released by parasites have important roles in establishing and maintaining infection. Analysis of the soluble and vesicular secretions of adult Fasciola hepatica has established a definitive characterization of the total secretome of this zoonotic parasite. Fasciola secretes at least two subpopulations of EVs that differ according to size, cargo molecules and site of release from the parasite. The larger EVs are released from the specialized cells that line the parasite gastrodermus and contain the zymogen of the 37 kDa cathepsin L peptidase that performs a digestive function. The smaller exosome-like vesicle population originate from multivesicular bodies within the tegumental syncytium and carry many previously described immunomodulatory molecules that could be delivered into host cells. By integrating our proteomics data with recently available transcriptomic data sets we have detailed the pathways involved with EV biogenesis in F. hepatica and propose that the small exosome biogenesis occurs via ESCRT-dependent MVB formation in the tegumental syncytium before being shed from the apical plasma membrane. Furthermore, we found that the molecular "machinery" required for EV biogenesis is constitutively expressed across the intramammalian development stages of the parasite. By contrast, the cargo molecules packaged within the EVs are developmentally regulated, most likely to facilitate the parasites migration through host tissue and to counteract host immune attack. PMID- 26486419 TI - Changes in Protein Expression and Lysine Acetylation Induced by Decreased Glutathione Levels in Astrocytes. AB - Astrocytes and neurons form a highly specialized functional unit, and the loss or gain of astrocytic functions can influence the initiation and progression of different neurodegenerative diseases. Neurons depend on the antioxidant protection provided by neighboring astrocytes. Glutathione (gamma-l-glutamyl-l cysteinyl-glycine) is a major component of the antioxidant system that defends cells against the toxic effects of reactive oxygen/nitrogen species. A decline in glutathione levels has been observed in aging and neurodegenerative diseases, and it aggravates the pathology in an amyotrophic lateral sclerosis-mouse model. Using a SILAC-based quantitative proteomic approach, we analyzed changes in global protein expression and lysine acetylation in primary astrocyte cultures obtained from wild-type mice or those deficient in the glutamate-cysteine ligase modifier subunit (GCLM). GCLM knockout astrocytes display an ~80% reduction in total glutathione levels. We identified potential molecular targets and novel sites of acetylation that are affected by the chronic decrease in glutathione levels and observed a response mediated by Nrf2 activation. In addition, sequence analysis of peptides displaying increased acetylation in GCLM knockout astrocytes revealed an enrichment of cysteine residues in the vicinity of the acetylation site, which suggests potential crosstalk between lysine-acetylation and cysteine modification. Regulation of several metabolic and antioxidant pathways was observed at the level of protein expression and lysine acetylation, revealing a coordinated response involving transcriptional and posttranslational regulation. PMID- 26486423 TI - Selecting a Method of Case Identification to Estimate the Involvement of People With Mental Illnesses in the Criminal Justice System: A Research Note. AB - Arrest and incarceration are a pervasive reality for people with mental illnesses. Wide variation, however, exists in the estimates of the percentage of people with mental illnesses who become involved in the criminal justice system. Researchers and practitioners need a variety of methods in their toolbox to maximize their ability to identify mental illness depending on available resources and needs. Yet, the benefits and costs of utilizing these different approaches have yet to be explored in the criminal justice literature. To begin exploring the utility of the different methods of case identification, we review the most commonly used approaches to identifying people with mental illnesses and end with a detailed examination of the use of behavior health records. The use of behavioral health records is a case identification method that has gained emerging support in criminal justice research in recent years. PMID- 26486422 TI - Examination of the "CSI Effect" on Perceptions of Scientific and Testimonial Evidence in a Hong Kong Chinese Sample. AB - Television is a powerful medium through which to convey information and messages to the public. The recent proliferation of forensic science and criminal justice information throughout all forms of media, coupled with raised expectations toward forensic evidence, has led some to suspect that a "CSI effect" ( Crime Scene Investigation effect) is taking place. The present study contributes to the literature addressing the CSI effect in two ways. First, it examines whether the CSI effect exists in the Chinese population of Hong Kong. Second, using a mock jury paradigm, it empirically examines a more integrative perspective of the CSI effect. It was found that, although the amount of media coverage involving forensic evidence does influence participants' perception of legal evidence to some degree, such a perception does not affect participants' legal decision making. Viewers of forensic dramas were not more likely to convict the defendant when forensic evidence was presented and not less likely to convict when only testimonial evidence was presented. The only significant predictor of the defendant's culpability when scientific evidence was presented was participants' ratings of the reliability of scientific evidence. Results from the present study lend no support to the existence of the CSI effect in Hong Kong. PMID- 26486425 TI - Early exposure to parental bipolar disorder and risk of mood disorder: the Flourish Canadian prospective offspring cohort study. AB - AIM: Exposure to postnatal parental depression is associated with offspring mood disorder later in life; however, little is known about exposure to parental bipolar disorder (BD) and subsequent risk of psychopathology. The aim of this study was to determine the association between the duration, severity and timing of exposure to parental BD in early childhood and subsequent risk of mood disorder. METHODS: 189 offspring of a parent with BD completed annual assessments following Kiddie Schedule for Affective Disorders (KSADS) format semistructured interviews as part of an ongoing 16-year prospective cohort study. Clinical data from the affected parents were collected over the first decade of their offspring's life using SADS-L format semistructured interviews and coded using the Affective Morbidity Index (AMI). RESULTS: A longer duration of exposure to parental BD was associated with a 1.5-fold risk of any psychopathology (95% confidence interval (CI): 1.0-2.3) and a 2.5-fold increased risk of substance use disorders (95% CI: 1.2-5.3). Exposure during the first 2 years of life was significantly associated with the risk of mood disorder (hazard ratio (HR): 1.1, 95% CI: 1.0-1.2), whereas exposure later in childhood was not. CONCLUSIONS: The duration of exposure to active parental BD in childhood is an important risk factor for the subsequent development of mood and non-mood psychopathology risk in offspring. These findings emphasize the importance of effective treatment of parents with BD to help both themselves and their children, especially early in development. PMID- 26486427 TI - Immunohistochemistry of carotid plaque neovascularization and vasa vasorum. AB - Carotid artery surgical specimens from 15 consecutive patients undergoing carotid endarterectomy were studied in an attempt to identify morphologic differences between carotid artery plaque neovascularization (NV) and normal vasa vasorum (VV). The patients included 12 men and 3 women with an age range of 55-81 years (mean, 67). Nine of them had ischemic symptoms directly related to the plaque being removed. The specimens were stained with hematoxylin-eosin, Verhoef-Van Gieson, and factor VIII-related antigen techniques. In addition, normal carotid arteries were obtained for comparison from two autopsies of young individuals, victims of traumatic death. The severity of NV within the plaque was graded based on the appearance and location of new vessels, as they compared to W. Mild NV (Grade I) was found in 3/15, whereas moderate and severe (Grades II and III) were each found in 6/15 cases. Increasing severity of NV was associated with more tortuosity, thicker walls, and location closer to the carotid lumen. The presence and severity of NV did not correlate with plaque thickness (p = 0.2), the presence of symptoms (p = 0.5), or any other risk factors for stroke. Carotid plaque NV seems independent of the degree of atheroma and morphologically different than VV. Its origin, true incidence, and role in the production of carotid intraplaque hemorrhage and increased stroke risk are still uncertain. This is the first immunohistochemical study of carotid plaque neovascularization. PMID- 26486426 TI - One-step resonant controlled-phase gate on distant transmon qutrits in different 1D superconducting resonators. AB - We propose a scheme to construct the controlled-phase (c-phase) gate on distant transmon qutrits hosted in different resonators inter-coupled by a connected transmon qutrit. Different from previous works for entanglement generation and information transfer on two distant qubits in a dispersive regime in the similar systems, our gate is constructed in the resonant regime with one step. The numerical simulation shows that the fidelity of our c-phase gate is 99.5% within 86.3 ns. As an interesting application of our c-phase gate, we propose an effective scheme to complete a conventional square lattice of two-dimensional surface code layout for fault-tolerant quantum computing on the distant transmon qutrits. The four-step coupling between the nearest distant transmon qutrits, small coupling strengths of the distant transmon qutrits, and the non-population on the connection transmon qutrit can reduce the interactions among different parts of the layout effectively, which makes the layout be integrated with a large scale in an easier way. PMID- 26486428 TI - Prevalence of patent foramen ovale in young patients with stroke: Role of color flow echocardiography. AB - Thirty-five young patients with ischemic stroke were studied via color-flow echocardiography in order to detect patent foramen ovale. The stroke patients were divided into two groups: those with undetermined stroke etiology (Group I) and those with determined stroke etiology (Group II). The prevalence of patent foramen ovale was 67% in Group I and 43% in Group II. Our results suggest that patent foramen ovale is more frequent in stroke patients, especially in patients without defined etiology. We also suggest that paradoxical embolism is more frequent than previously thought. PMID- 26486424 TI - A Double Whammy: Targeting Both Fatty Acid Amide Hydrolase (FAAH) and Cyclooxygenase (COX) To Treat Pain and Inflammation. AB - Pain states that arise from non-resolving inflammation, such as inflammatory bowel disease or arthritis, pose an unusually difficult challenge for therapy because of the complexity and heterogeneity of their underlying mechanisms. It has been suggested that key nodes linking interactive pathogenic pathways of non resolving inflammation might offer novel targets for the treatment of inflammatory pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the cyclooxygenase (COX)-mediated production of pain- and inflammation-inducing prostanoids, are a common first-line treatment for this condition, but their use is limited by mechanism-based side effects. The endogenous levels of anandamide, an endocannabinoid mediator with analgesic and tissue-protective functions, are regulated by fatty acid amide hydrolase (FAAH). This review outlines the pharmacological and chemical rationale for the simultaneous inhibition of COX and FAAH activities with designed multitarget agents. Preclinical studies indicate that such agents may combine superior anti-inflammatory efficacy with reduced toxicity. PMID- 26486429 TI - Brain SPECT and transcranial doppler ultrasound in vasospasm-induced delayed cerebral ischemia after subarachnoid hemorrhage. AB - Clinical vasospasm, or delayed ischemia-related neurologic deficits, is the prime determinant of morbidity and mortality after subarachnoid hemorrhage. The diagnosis of clinical vasospasm has been based mainly on clinical observations. Noninvasive techniques for evaluating vasospasm have great promise in supplementing the detailed neurologic examination and assessing the effects of therapy. The clinical utility of single-photon emission computed tomography (SPECT) of regional cerebral blood flow and transcranial Doppler ultrasound (TCD) in the evaluation of cerebral vasospasm after subarachnoid hemorrhage was reviewed in 40 patients. The combination of these noninvasive tests was valuable for the investigation of the dynamic anatomic and functional aspects of vasospasm. TCD proved helpful in monitoring for vascular narrowing by measurements of blood flow velocity. Brain SPECT ascertained the effects of vasospasm on regional cerebral blood flow. In the diagnosis of clinical vasospasm, or delayed ischemic deficits, brain SPECT was more sensitive and specific than TCD. The combination of SPECT and TCD was useful in the assessment of the effect of cerebral angioplasty on hemodynamics and perfusion in the attempt to avert infarction. PMID- 26486430 TI - Nimodipine and the evolution of hemorheological variables after acute ischemic stroke. AB - We studied the effects of the calcium channel antagonist nimodipine on the evolution of hemorheological variables during the first 3 weeks following ischemic stroke. We studied 13 patients and found that, compared to baseline levels, plasma fibrinogen concentration and low-shear whole-blood viscosity rose significantly in patients receiving placebo but not in those receiving nimodipine. Red blood cell aggregation rose in both groups but less so in nimodipine-treated patients. Hematocrit, high-shear whole-blood viscosity, and red blood cell deformability did not change significantly in either group. In conclusion, the use of nimodipine appears to alter the evolution of some hemorheological variables following acute ischemic stroke. PMID- 26486431 TI - Stroke secondary to carotid occlusion in a young man with nephrotic syndrome: Case description and review of the literature. AB - We report a case of hemispheric stroke and death secondary to thrombosis of the internal carotid artery in a young adult with minimal-change nephrotic syndrome. Thrombotic complications are common in patients with nephrotic syndrome and may be due to a hypercoagulable state. To our knowledge, this is the first report of cerebral infarction due to thrombosis in the extracranial vasculature in a patient with nephrotic syndrome. We review previous reports of cerebral infarction in association with nephrotic syndrome and discuss possible mechanisms of hypercoagulability in this setting. PMID- 26486433 TI - AIREN-NINDS 1991 workshop on stroke prevention and therapy in technically advanced societies. PMID- 26486432 TI - Aseptic cerebral venous thrombosis: Proposed prognostic scale. AB - Seventy-eight patients with aseptic cerebral venous thrombosis between 1966 and 1990 were reviewed in order to determine prognostic factors for this condition. Sixty-eight patients were women. The average age of the patients was 30.5 years. Fifty-two percent of patients developed the thrombosis during the postpartum or puerperal stage. The clinical manifestations that were associated with a poor prognosis were: stupor or coma, bilateral pyramidal tract signs, generalized seizures, meningeal signs, bilateral lesions on computed tomography, and hemorrhagic cerebrospinal fluid. Using these clinical features, a prognostic scale is proposed with a positive predictive value of 0.98 for a good prognosis and 0.96 for a poor prognosis. PMID- 26486434 TI - Changing incidence and mortality rates for stroke. PMID- 26486435 TI - Stroke risk factors and stroke prevention. PMID- 26486436 TI - Evaluation of medical therapies of acute ischemic stroke. PMID- 26486437 TI - Pros and cons of intensive care units for acute stroke. PMID- 26486438 TI - Evaluation of and controversies in surgical therapies. PMID- 26486439 TI - Evaluation of and controversies in stroke rehabilitation. PMID- 26486440 TI - Internal quality control in point-of-care testing: where's the evidence? AB - ISO 22870 standards require protocols for performance of internal quality control for all point-of-care testing devices and training of users in its theory and practice. However, the unique setting of point-of-care testing (i.e. processes conducted by non-scientific users) means that laboratory internal quality control programmes do not easily translate to point-of-care testing. In addition, while the evidence base for internal quality control within the laboratory has been increasing, the equivalent literature surrounding point-of-care testing is very limited. This has led to wide variation in what is considered acceptable practice for internal quality control at the point of care. Indeed, it has been demonstrated that internal quality control is an area of deficiency in point-of care testing. Internal quality control protocols used at point-of-care testing should be defined based on risk management. The protocol will therefore be dependent on analyser complexity and availability of inbuilt system checks, the risk associated with release of an incorrect patient result as well as frequency of use. The emphasis should be on designing an effective internal quality control protocol as opposed to the inherent tendency of introducing high-frequency quality control. Typically a simple pass or fail criterion is used for internal quality control in point-of-care testing based on whether internal quality control results fall within assigned ranges. While simply taught, such criteria can require broad internal quality control ranges to decrease the probability of false rejection (also reducing the probability of error detection). Customized internal quality control ranges, two-tier acceptance systems and assay-specific internal quality control can be used to improve error detection rates. PMID- 26486441 TI - Comparison of the performance of Anyplex II HPV HR, the Cobas 4800 human papillomavirus test and Hybrid Capture 2. AB - BACKGROUND: Anyplex II HPV HR (Anyplex_HR; Seegene, Seoul, Korea) is a new multiplex real-time polymerase chain reaction assay for screening cervical cancer, and it is designed to detect 14 high-risk human papillomaviruses along with all the genotype information in a single tube. The aim of this study was to evaluate the performance of the Anyplex_HR in comparison to that of the Cobas 4800 HPV (Cobas_4800; Roche Molecular Diagnostics, Pleasanton, CA, USA) and the Hybrid capture 2 (HC2; Qiagen GmbH, Hilden, Germany). METHODS: The performance of the Anyplex_HR for high-risk human papillomavirus genotype detection was prospectively evaluated against that of the HC2 and the Cobas_4800 at the National Cancer Center using 400 cervical samples. All discrepant samples were confirmed by polymerase chain reaction with type-specific primers followed by sequencing. RESULTS: The overall agreement and kappa value of the Anyplex_HR with the Cobas_4800 were 98.0% and 0.96, respectively. The level of agreement between the two assays and the corresponding kappa values for human papillomavirus16, human papillomavirus18 and other high-risk human papillomaviruses were 99.5%, 99.8% and 98.8%, and 0.98, 0.96 and 0.97, respectively. The agreement and kappa value of the HC2 with the Cobas_4800 were 95.3% and 0.91. The human papillomavirus positivity of the Anyplex_HR and the Cobas_4800 in low-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion samples demonstrated 100% concordance. Both the Anyplex_HR and the Cobas_4800 showed excellent results in the precision test. CONCLUSIONS: The Anyplex_HR is comparable with the Cobas_4800 and the HC2 for human papillomavirus DNA testing, and it may prove more useful for follow-up testing and patient management by providing genotyping information additional to human papillomavirus16 and human papillomavirus18. PMID- 26486442 TI - Streptococcus caprae sp. nov., isolated from Iberian ibex (Capra pyrenaica hispanica). AB - Biochemical and molecular genetic studies were performed on a novel Gram-stain positive, catalase-negative, coccus-shaped organism isolated from tonsil samples of two Iberian ibexes. The micro-organism was identified as a streptococcal species based on its cellular, morphological and biochemical characteristics. 16S rRNA gene sequence comparison studies confirmed its identification as a member of the genus Streptococcus, but the organism did not correspond to any species of this genus. The nearest phylogenetic relative of the unknown coccus from ibex was Streptococcus porci 2923-03T (96.6 % 16S rRNA gene sequence similarity). Analysis based on rpoB and sodA gene sequences revealed sequence similarity values lower than 86.0 and 83.8 %, respectively, from the type strains of recognized Streptococcus species. The novel bacterial isolate was distinguished from Streptococcus porci and other Streptococcus species using biochemical tests. Based on both phenotypic and phylogenetic findings, it is proposed that the unknown bacterium be classified as representing a novel species of the genus Streptococcus, for which the name Streptococcus caprae sp. nov. is proposed. The type strain is DICM07-02790-1CT ( = CECT 8872T = CCUG 67170T). PMID- 26486443 TI - Stat3-siRNA inhibits the growth of gastric cancer in vitro and in vivo. AB - Gastric cancer remains one of the most prevalent and lethal malignancies in the world. Despite new advances in treatment and diagnosis, patients with advanced gastric cancer are still difficult to cure resulting in a high mortality rate and poor prognosis. Signal transducer and activator of transcription 3 (Stat3) is observed aberrant in multiple tumours, including gastric cancer. Stat3 overexpression was confirmed performing a vital role in tumorigenesis. In the present study, we constructed a pSi-Stat3 plasmid to silence Stat3 and investigated the effect of pSi-Stat3 on cell proliferation, apoptosis and cell cycle progression in gastric cancer cell line SGC-7901 and mice xenograft model. Downstream proteins of Stat3, including Cyclin-D1, Survivin and Bcl-2, were detected as well for the underlying mechanism exploration. It showed that pSi Stat3 can effectively silence the expression of Stat3 and inhibits the growth of gastric tumour both in vitro and in vivo significantly via cell apoptosis and cell cycle shift induction. The findings suggest that Stat3 signal pathway might be a promising therapeutic target for tumour treatment, including gastric cancer. PMID- 26486444 TI - VILLIN2 Emerges as a Master Builder in Rice. PMID- 26486448 TI - Correction. PMID- 26486445 TI - VLN2 Regulates Plant Architecture by Affecting Microfilament Dynamics and Polar Auxin Transport in Rice. AB - As a fundamental and dynamic cytoskeleton network, microfilaments (MFs) are regulated by diverse actin binding proteins (ABPs). Villins are one type of ABPs belonging to the villin/gelsolin superfamily, and their function is poorly understood in monocotyledonous plants. Here, we report the isolation and characterization of a rice (Oryza sativa) mutant defective in VILLIN2 (VLN2), which exhibits malformed organs, including twisted roots and shoots at the seedling stage. Cellular examination revealed that the twisted phenotype of the vln2 mutant is mainly caused by asymmetrical expansion of cells on the opposite sides of an organ. VLN2 is preferentially expressed in growing tissues, consistent with a role in regulating cell expansion in developing organs. Biochemically, VLN2 exhibits conserved actin filament bundling, severing and capping activities in vitro, with bundling and stabilizing activity being confirmed in vivo. In line with these findings, the vln2 mutant plants exhibit a more dynamic actin cytoskeleton network than the wild type. We show that vln2 mutant plants exhibit a hypersensitive gravitropic response, faster recycling of PIN2 (an auxin efflux carrier), and altered auxin distribution. Together, our results demonstrate that VLN2 plays an important role in regulating plant architecture by modulating MF dynamics, recycling of PIN2, and polar auxin transport. PMID- 26486447 TI - GLABRA2 Directly Suppresses Basic Helix-Loop-Helix Transcription Factor Genes with Diverse Functions in Root Hair Development. AB - The Arabidopsis thaliana GLABRA2 (GL2) gene encodes a transcription factor involved in the cell differentiation of various epidermal tissues. During root hair pattern formation, GL2 suppresses root hair development in non-hair cells, acting as a node between the gene regulatory networks for cell fate determination and cell differentiation. Despite the importance of GL2 function, its molecular basis remains obscure because the GL2 target genes leading to the network for cell differentiation are unknown. We identified five basic helix-loop-helix (bHLH) transcription factor genes (ROOT HAIR DEFECTIVE6 [RHD6], RHD6-LIKE1 [RSL1], RSL2, Lj-RHL1-LIKE1 [LRL1], and LRL2) as GL2 direct targets using transcriptional and posttranslational induction systems. Chromatin immunoprecipitation analysis confirmed GL2 binding to upstream regions of these genes in planta. Reporter gene analyses showed that these genes are expressed in various stages of root hair development and are suppressed by GL2 in non-hair cells. GL2 promoter-driven GFP fusions of LRL1 and LRL2, but not those of the other bHLH proteins, conferred root hair development on non-hair cells. These results indicate that GL2 directly suppresses bHLH genes with diverse functions in root hair development. PMID- 26486449 TI - Heavy metal removal from MSWI fly ash by electrokinetic remediation coupled with a permeable activated charcoal reactive barrier. AB - This paper presents the investigations into the feasibility of the application of a remediation system that couples electrokinetic remediation (EKR) with the permeable reactive barrier (PRB) concept for municipal solid waste incineration (MSWI) fly ash with activated charcoal as the PRB material. The experimental results of this study showed that the proposed combined method can effectively improve the remediation efficiency and that the addition of the oxalic acid to the PRB media before the coupled system can further enhance the remediation process. In the optimization tests, the maximum removals of Zn, Pb, Cu and Cd were achieved under different experimental conditions. The voltage gradient and processing time were shown to have significant effects on the removal of Cu and Cd, whereas the addition of the oxalic acid had a more significant influence on the removal of Pb. Generally, the processing time is the most significant factor in changing the removal rates of HMs in the enhanced coupled system. In terms of the leaching toxicity, the specimen remediated by ENEKR + PRB showed the lowest leaching value for each HM in the S2 and S3 regions. PMID- 26486450 TI - A multivariate model exploring the predictive value of demographic, adolescent, and family factors on glycemic control in adolescents with type 1 diabetes. AB - OBJECTIVE: The current study examined how a comprehensive set of variables from multiple domains, including at the adolescent and family level, were predictive of glycemic control in adolescents with type 1 diabetes (T1D). METHODS: Participants included 100 adolescents with T1D ages 10-16 yrs and their parents. Participants were enrolled in a longitudinal study about youth decision-making involvement in chronic illness management of which the baseline data were available for analysis. Bivariate associations with glycemic control (HbA1C) were tested. Hierarchical linear regression was implemented to inform the predictive model. RESULTS: In bivariate analyses, race, family structure, household income, insulin regimen, adolescent-reported adherence to diabetes self-management, cognitive development, adolescent responsibility for T1D management, and parent behavior during the illness management discussion were associated with HbA1c. In the multivariate model, the only significant predictors of HbA1c were race and insulin regimen, accounting for 17% of the variance. Caucasians had better glycemic control than other racial groups. Participants using pre-mixed insulin therapy and basal-bolus insulin had worse glycemic control than those on insulin pumps. CONCLUSIONS: This study shows that despite associations of adolescent and family-level variables with glycemic control at the bivariate level, only race and insulin regimen are predictive of glycemic control in hierarchical multivariate analyses. This model offers an alternative way to examine the relationship of demographic and psychosocial factors on glycemic control in adolescents with T1D. PMID- 26486452 TI - Corrigendum: An indica rice genotype showed a similar yield enhancement to that of hybrid rice under free air carbon dioxide enrichment. PMID- 26486453 TI - Does the Tokyo guidelines predict the extent of gallbladder inflammation in patients with acute cholecystitis? A single center retrospective analysis. AB - BACKGROUND: The Tokyo guidelines provide criteria for the diagnosis and classification of acute cholecystitis in three severity grades. However, no data exists on the predictive value of these guidelines. The aim of this study was to analyze the accuracy of the Tokyo guidelines as a predicting parameter for the severity of acute cholecystitis in patients undergoing laparoscopic cholecystectomy. METHODS: A retrospective analysis of the charts of patients undergoing laparoscopic cholecystectomy for acute cholecystitis in a primary care hospital within a five-year period was performed. The preoperative severity grades were compared with the histological extent of inflammation. RESULTS: One hundred thirty-eight patients; 79 with severity grade I, 33 with grade II and 26 with grade III were analyzed. The incidence of uncomplicated cholecystitis decreased with increasing severity grade, while the incidence of complicated cholecystitis increased with increasing severity. However, complicated cholecystitis was evident in an unexpectedly high number of cases with severity grade I. There was a significant correlation (chi (2)(1) = 10. 43, p = 0.01) between the preoperative severity grade and the extent of gallbladder inflammation on histopathology. Conversion to open surgery (14 vs. 5, p = 0.002) and complications (17 vs. 7, p = 0.001) were significantly higher in patients with preoperative severity grade II/III compared to patients with severity grade I. CONCLUSION: Worsening clinical severity correlated significantly with worseing pathology, findings from blood test and clinical outcomes; rates of conversion and morbidity. However, the Tokyo guidelines may have a tendency to underestimate the extent of inflammation in male patients with severity grade I and over estimate the difficulty of dissection in severity grade II. PMID- 26486454 TI - Research highlights: enhancing whole genome amplification using compartmentalization. AB - The ability to break up a larger liquid volume into an array of smaller confined volumes that do not chemically communicate is a key enabling technology driving microfluidic innovations. We highlight recent work using drop-based confinement to improve on whole genome amplification, reducing amplification bias and contaminant amplification by bringing reactions to saturation within each confined drop. We also highlight a complementary technique to target whole genome amplification to a subset of nucleic acids within a sample by combining drop based PCR with sorting and downstream sequencing. These new approaches have the potential to enhance our ability to categorize the diversity of microorganisms (especially difficult to culture species) that contribute to complex microbial communities, and in particular assemble the individual genomes of the species involved in biologically and environmentally important microbiomes. PMID- 26486451 TI - Mechanisms of blood homeostasis: lineage tracking and a neutral model of cell populations in rhesus macaques. AB - BACKGROUND: How a potentially diverse population of hematopoietic stem cells (HSCs) differentiates and proliferates to supply more than 10(11) mature blood cells every day in humans remains a key biological question. We investigated this process by quantitatively analyzing the clonal structure of peripheral blood that is generated by a population of transplanted lentivirus-marked HSCs in myeloablated rhesus macaques. Each transplanted HSC generates a clonal lineage of cells in the peripheral blood that is then detected and quantified through deep sequencing of the viral vector integration sites (VIS) common within each lineage. This approach allowed us to observe, over a period of 4-12 years, hundreds of distinct clonal lineages. RESULTS: While the distinct clone sizes varied by three orders of magnitude, we found that collectively, they form a steady-state clone size-distribution with a distinctive shape. Steady-state solutions of our model show that the predicted clone size-distribution is sensitive to only two combinations of parameters. By fitting the measured clone size-distributions to our mechanistic model, we estimate both the effective HSC differentiation rate and the number of active HSCs. CONCLUSIONS: Our concise mathematical model shows how slow HSC differentiation followed by fast progenitor growth can be responsible for the observed broad clone size-distribution. Although all cells are assumed to be statistically identical, analogous to a neutral theory for the different clone lineages, our mathematical approach captures the intrinsic variability in the times to HSC differentiation after transplantation. PMID- 26486457 TI - Periodic harvesting of embryonic stem cells from a hollow-fiber membrane based four-compartment bioreactor. AB - Different types of stem cells have been investigated for applications in drug screening and toxicity testing. In order to provide sufficient numbers of cells for such in vitro applications a scale-up of stem cell culture is necessary. Bioreactors for dynamic three-dimensional (3D) culture of growing cells offer the option for culturing large amounts of stem cells at high densities in a closed system. We describe a method for periodic harvesting of pluripotent stem cells (PSC) during expansion in a perfused 3D hollow-fiber membrane bioreactor, using mouse embryonic stem cells (mESC) as a model cell line. A number of 100 * 10(6) mESC were seeded in bioreactors in the presence of mouse embryonic fibroblasts (MEF) as feeder cells. Over a cultivation interval of nine days cells were harvested by trypsin perfusion and mechanical agitation every second to third culture day. A mean of 380 * 10(6) mESC could be removed with every harvest. Subsequent to harvesting, cells continued growing in the bioreactor, as determined by increasing glucose consumption and lactate production. Immunocytochemical staining and mRNA expression analysis of markers for pluripotency and the three germ layers showed a similar expression of most markers in the harvested cells and in mESC control cultures. In conclusion, successful expansion and harvesting of viable mESC from bioreactor cultures with preservation of sterility was shown. The present study is the first one showing the feasibility of periodic harvesting of adherent cells from a continuously perfused four-compartment bioreactor including further cultivation of remaining cells. PMID- 26486456 TI - A Successful Vancomycin-Resistant Enterococci Reduction Bundle at a Singapore Hospital. AB - We report a reduction in the vancomycin-resistant enterococci (VRE) rate from a peak of 1.5 cases per 1,000 admissions (95% confidence interval [CI], 1.0-2.1) in August 2012 to 0.5 per 1,000 admissions (95% CI: 0.3-1.0) by January 2015, associated with a bundle of interventions. Infect. Control Hosp. Epidemiol. 2015;37(1):107-109. PMID- 26486455 TI - Exploratory biomarker analysis for treatment response in KRAS wild type metastatic colorectal cancer patients who received cetuximab plus irinotecan. AB - BACKGROUND: More than half of the patients selected based on KRAS mutation status fail to respond to the treatment with cetuximab in metastatic colorectal cancer (mCRC). We designed a study to identify additional biomarkers that could act as indicators for cetuximab treatment in mCRC. METHODS: We investigated 58 tumor samples from wild type KRAS CRC patients treated with cetuximab plus irinotecan (CI). We conducted the genotyping for mutations in either BRAF or PIK3CA and profiled comprehensively the expression of 522 kinase genes. RESULTS: BRAF mutation was detected in 5.1 % (3/58) of patients. All 50 patients showed wild type PIK3CA. Gene expression patterns that categorized patients with or without the disease control to CI were compared by supervised classification analysis. PSKH1, TLK2 and PHKG2 were overexpressed significantly in patients with the disease control to IC. The higher expression value of PSKH1 (r = 0.462, p < 0.001) and TLK2 (r = 0.361, p = 0.005) had the significant correlation to prolonged PFS. CONCLUSION: The result of this work demonstrated that expression nature of kinase genes such as PSKH1, TLK2 and PHKG2 may be informative to predict the efficacy of CI in wild type KRAS CRC. Mutations in either BRAF or PIK3CA were rare subsets in wild type KRAS CRC. PMID- 26486458 TI - [Which Psychoactives Substances are Found in Used Syringes?] AB - OBJECTIVE: The aim of this study is to analyze the residual content of used syringes. METHODS: Used syringes were collected in March 2014 at 9 sites in Marseille (automatic injection kit dispensers, streets, drug-user risk reduction centers [Centres d'Accueil et d'Accompagnement a la Reduction de Risques pour Usagers de Drogues, CAARUD]). Several substances (n = 28) were investigated using liquid chromatography and mass spectrometry method. RESULTS: On average 2 +/- 1 substances in each syringe were found among 254 syringes analyzed. The most detected substances were cocaine, buprenorphine, methylphenidate and cathinones (in 57%, 56%, 39% and 19% of the syringes respectively). Heroin and morphine were found in 10% of the syringes. DISCUSSION-CONCLUSION: This study helps define the main substances consumed by injection drugs users. It highlighted differencies in used substances according to neighbourhood and site of collection and thus help to adjust prevention and harm reduction strategies. PMID- 26486460 TI - [Hyperuricemia and cardiovascular risk: myth or fact?]. PMID- 26486459 TI - Genetic variants in the upstream region of activin receptor IIA are associated with female fertility in Japanese Black cattle. AB - BACKGROUND: Female fertility, a fundamental trait required for animal reproduction, has gradually declined in the last 2 decades in Japanese Black cattle. To identify associated genetic variants in Japanese Black cattle, we evaluated female fertility as a metric to describe the average inverse of the number of artificial inseminations required for conception from the first through the fourth parity (ANAI4) and conducted a genome-wide association study (GWAS) using 430 animals with extreme ANAI4 values from 10,399 animals. RESULTS: We found that 2 variants, namely a single-nucleotide polymorphisms (SNP; g.48476925C > T) and a 3-bp indel (g.48476943_48476946insGGC), in the upstream region of the activin receptor IIA gene (ACVR2A) were associated with ANAI4. ACVR2A transcripts from Japanese Black cattle of the Q haplotype, defined by the SNP and the 3-bp indel, with increased ANAI4 were 1.29-1.32-fold more abundant than q-derived transcripts. In agreement, reporter assay results revealed that the activity of the ACVR2A promoter was higher in reporter constructs with the Q haplotype than in those with the q haplotype by approximately 1.2 fold. Expression of exogenous ACVR2A induced dose-dependent increases of reporter activity from the follicle stimulating hormone, beta polypeptide (FSHB) promoter in response to activin A in a pituitary gonadotrophic cell line. The findings suggested that sequence variations in the upstream region of ACVR2A with the Q haplotype increased ACVR2A transcription, which in turn induced FSHB expression. This association was replicated using a sample population size of 1,433 animals; the frequency of the Q haplotype was 0.39, and Q-to-q haplotype substitution resulted in an increase of 0.02 in terms of ANAI4. CONCLUSIONS: This GWAS identified variants in the upstream region of ACVR2A, which were associated with female fertility in Japanese Black cattle. The variants affected the level of ACVR2A mRNA expression, which could lead to an allelic imbalance. This association was replicated with a sample population of 1,433 animals. Thus, the results suggest that the Q haplotype could serve as a useful marker to select Japanese Black cattle with superior female fertility. PMID- 26486461 TI - Correlation of serum uric acid with heart rate variability in hypertension. AB - BACKGROUND: Autonomic dysfunction with dominant sympathetic tone is a common finding among hypertensives and prehypertensives. Uric acid is one of the independent predictors of hypertension. There are very few studies which have shown a relationship between the autonomic tone and uric acid generation pathway among prehypertensives and hypertensives. Aim of the study was to estimate and correlate serum uric acid levels with autonomic function as measured by heart rate variability (HRV) among prehypertensives and hypertensives. METHODS: Cross sectional study of three groups, prehypertensives, hypertensives and normotensives, classified according to Joint National Committee VII criteria, with 35 subjects in each group were included in this study. Serum uric acid levels were estimated by using colorimetric assay kit. HRV was analyzed after recording lead II Electrocardiogram using RMS Vagus HRV software (RMS, India). One-way ANOVA and Pearson's correlation was done using SPSS 18.0 software. RESULTS: Mean uric acid levels were 5.62+/-2.21mg/dL in normal subjects, 7.06+/ 2.87mg/dL in prehypertensives and 9.77+/-2.04mg/dL in hypertensives. There was statistically significant negative correlation between uric acid and time domain parameters of HRV in the whole sample and among prehypertensives and positive correlation with low frequency power (LF) in ms(2) and n.u. CONCLUSIONS: Serum uric acid levels were high in prehypertensives and hypertensives as compared to normal subjects. Further, there was statistically significant correlation seen between uric acid levels and sympathetic domain parameters particularly among prehypertensives. PMID- 26486462 TI - [Circulating endothelial progenitor cell levels in treated hypertensive patients]. AB - INTRODUCTION: Most optimally treated hypertensive patients still have an around 50% increased risk of any cardiovascular event, suggesting the possible existence of unidentified risk factors. In the last years there has been evidence of the essential role of circulating endothelial progenitor cells (EPCs) in the maintenance of endothelial integrity and function, increasing the interest in their involvement in cardiovascular disease. In this study, the circulating levels of EPCs and vascular endothelial growth factor (VEGF) are investigated in treated hypertensive patients with adequate control of blood pressure (BP). MATERIAL AND METHODS: Blood samples were collected from treated hypertensive patients with controlled BP. Plasma levels of EPCs CD34+/KDR+ and CD34+/VE cadherin+ were quantified by flow cytometry. Plasma concentration of VEGF was determined by ELISA. A group of healthy subjects without cardiovascular risk factors was included as controls. RESULTS: A total of 108 hypertensive patients were included (61+/-12 years, 47.2% men) of which 82.4% showed BP<140/90 mmHg, 91.7% and 81.5% controlled diabetes (HbA1c <7%) and cLDL (<130 or 100 mg/dL), respectively, and 85.2% were non-smokers. Around 45% of them were obese. Although patients had cardiovascular parameters within normal ranges, they showed significantly lower levels of CD34+/KDR+ and CD34+/VE-cadherin+ compared with healthy control group, although plasma VEGF concentration was higher in patients than in controls. CONCLUSIONS: Despite an optimal treatment, hypertensive patients show a decreased number of circulating EPCs that could be, at least in part, responsible for their residual cardiovascular risk, suggesting that these cells could be a therapeutic target. PMID- 26486463 TI - [Is blood pressure control different in women than in men?]. AB - Blood pressure (BP) evolves with age; until the 50's it is higher in men than in women, equaling and even then increasing in women. The prevalence of controlled BP appears to be similar between the sexes, but the prevalence of cardiovascular disease is higher in women than in men. The possibility that BP influences the cardiovascular risk differently according to sex must therefore be considered. While some studies suggest no difference exists, others have shown evidence of an increased risk in women with respect to men despite equal BP. In this way, it seems that the measurement of ambulatory BP, but not office BP, would mark the differences in the association between BP-gender and cardiovascular risk. It should therefore be investigated the possibility of a different BP goal for women and men, especially by evaluating ambulatory BP. PMID- 26486464 TI - [Seasonal variation in weight in a working population]. PMID- 26486465 TI - Quantifying the density and utilization of active sites in non-precious metal oxygen electroreduction catalysts. AB - Carbon materials doped with transition metal and nitrogen are highly active, non precious metal catalysts for the electrochemical conversion of molecular oxygen in fuel cells, metal air batteries, and electrolytic processes. However, accurate measurement of their intrinsic turn-over frequency and active-site density based on metal centres in bulk and surface has remained difficult to date, which has hampered a more rational catalyst design. Here we report a successful quantification of bulk and surface-based active-site density and associated turn over frequency values of mono- and bimetallic Fe/N-doped carbons using a combination of chemisorption, desorption and (57)Fe Mossbauer spectroscopy techniques. Our general approach yields an experimental descriptor for the intrinsic activity and the active-site utilization, aiding in the catalyst development process and enabling a previously unachieved level of understanding of reactivity trends owing to a deconvolution of site density and intrinsic activity. PMID- 26486466 TI - Talker- and language-specific effects on speech intelligibility in noise assessed with bilingual talkers: Which language is more robust against noise and reverberation? AB - OBJECTIVE: Investigate talker- and language-specific aspects of speech intelligibility in noise and reverberation using highly comparable matrix sentence tests across languages. DESIGN: Matrix sentences spoken by German/Russian and German/Spanish bilingual talkers were recorded. These sentences were used to measure speech reception thresholds (SRTs) with native listeners in the respective languages in different listening conditions (stationary and fluctuating noise, multi-talker babble, reverberated speech-in noise condition). STUDY SAMPLE: Four German/Russian and four German/Spanish bilingual talkers; 20 native German-speaking, 10 native Russian-speaking, and 10 native Spanish-speaking listeners. RESULTS: Across-talker SRT differences of up to 6 dB were found for both groups of bilinguals. SRTs of German/Russian bilingual talkers were the same in both languages. SRTs of German/Spanish bilingual talkers were higher when they talked in Spanish than when they talked in German. The benefit from listening in the gaps was similar across all languages. The detrimental effect of reverberation was larger for Spanish than for German and Russian. CONCLUSIONS: Within the limitations set by the number and slight accentedness of talkers and other possible confounding factors, talker- and test-condition-dependent differences were isolated from the language effect: Russian and German exhibited similar intelligibility in noise and reverberation, whereas Spanish was more impaired in these situations. PMID- 26486467 TI - Zwint-1 is required for spindle assembly checkpoint function and kinetochore microtubule attachment during oocyte meiosis. AB - The key step for faithful chromosome segregation during meiosis is kinetochore assembly. Defects in this process result in aneuploidy, leading to miscarriages, infertility and various birth defects. However, the roles of kinetochores in homologous chromosome segregation during meiosis are ill-defined. Here we found that Zwint-1 is required for homologous chromosome segregation during meiosis. Knockdown of Zwint-1 accelerated the first meiosis by abrogating the kinetochore recruitment of Mad2, leading to chromosome misalignment and a high incidence of aneuploidy. Although Zwint-1 knockdown did not affect Aurora C kinase activity, the meiotic defects following Zwint-1 knockdown were similar to those observed with ZM447439 treatment. Importantly, the chromosome misalignment following Aurora C kinase inhibition was not restored after removing the inhibitor in Zwint 1-knockdown oocytes, whereas the defect was rescued after the inhibitor washout in the control oocytes. These results suggest that Aurora C kinase-mediated correction of erroneous kinetochore-microtubule attachment is primarily regulated by Zwint-1. Our results provide the first evidence that Zwint-1 is required to correct erroneous kinetochore-microtubule attachment and regulate spindle checkpoint function during meiosis. PMID- 26486468 TI - Near-IR mediated intracellular uncaging of NO from cell targeted hollow gold nanoparticles. AB - We demonstrate modulation of nitric oxide release in solution and in human prostate cancer cells from a thiol functionalized cupferron (TCF) absorbed on hollow gold nanoshells (HGNs) using near-infrared (NIR) light. NO release from the TCF-HGN conjugates occurs through localized surface heating due to NIR excitation of the surface plasmon. Specific HGN targeting is achieved through cell surface directed peptides, and excitation with tissue penetrating NIR light provides unprecedented spatio-temporal control of NO delivery to biological targets. PMID- 26486469 TI - A canine orthologue of the human GFAP c.716G>A (p.Arg239His) variant causes Alexander disease in a Labrador retriever. AB - Alexander disease (AxD) is a fatal neurodegenerative disorder of astrocyte dysfunction in man, for which already a number of causal variants are described, mostly de novo dominant missense variants in the glial fibrillary acidic protein (GFAP). A similar disorder was already phenotypically described in animals but without the identification of causal variants. We diagnosed a Labrador retriever with a juvenile form of AxD based on clinical (tetraparesis with spastic front limbs mimicking 'swimming puppy syndrome') and pathological (the detection of GFAP containing Rosenthal fibers in astrocytes) features. In order to identify a causal variant, the coding sequences of the four detected GFAP transcript variants (orthologues from human transcript variants alpha, gamma, delta/E and kappa) were sequenced. From the five detected variants, a heterozygous c.719G>A nucleotide substitution resulting in a p.Arg240His substitution was considered to be causal, because it is orthologous to the heterozygous de novo dominant c.716G>A (p.Arg239His) hotspot variant in man, proven to cause a severe phenotype. In addition, the variant was not found in 50 unrelated healthy Labrador retrievers. Because the condition in dogs is morphologically similar to man, it could be a promising animal model for further elucidating the genotype/phenotype correlation in order to treat or prevent this disease. PMID- 26486470 TI - Genetic evidence for an origin of the Armenians from Bronze Age mixing of multiple populations. AB - The Armenians are a culturally isolated population who historically inhabited a region in the Near East bounded by the Mediterranean and Black seas and the Caucasus, but remain under-represented in genetic studies and have a complex history including a major geographic displacement during World War I. Here, we analyse genome-wide variation in 173 Armenians and compare them with 78 other worldwide populations. We find that Armenians form a distinctive cluster linking the Near East, Europe, and the Caucasus. We show that Armenian diversity can be explained by several mixtures of Eurasian populations that occurred between ~3000 and ~2000 bce, a period characterized by major population migrations after the domestication of the horse, appearance of chariots, and the rise of advanced civilizations in the Near East. However, genetic signals of population mixture cease after ~1200 bce when Bronze Age civilizations in the Eastern Mediterranean world suddenly and violently collapsed. Armenians have since remained isolated and genetic structure within the population developed ~500 years ago when Armenia was divided between the Ottomans and the Safavid Empire in Iran. Finally, we show that Armenians have higher genetic affinity to Neolithic Europeans than other present-day Near Easterners, and that 29% of Armenian ancestry may originate from an ancestral population that is best represented by Neolithic Europeans. PMID- 26486471 TI - Genome-wide association studies identify genetic loci for low von Willebrand factor levels. AB - Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available. Each study conducted analyses using logistic regression of SNPs on dichotomized VWF:Ag measures (lowest 5% for blood group O and non-O) with an additive genetic model adjusted for age and sex. An inverse-variance weighted meta-analysis was performed for VWF:Ag levels. A total of 97 SNPs exceeded the genome-wide significance threshold of 5 * 10(-8) and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 * 10(-10)), 9q34 (2.4 * 10(-64)), 12p13 (5.3 * 10(-22)), 12q23 (1.2 * 10(-8)) and 13q13 (2.6 * 10(-8)). All loci were within or close to genes, including STXBP5 (Syntaxin Binding Protein 5) (6q24), STAB5 (stabilin-5) (12q23), ABO (9q34), VWF (12p13) and UFM1 (ubiquitin-fold modifier 1) (13q13). Of these, UFM1 has not been previously associated with VWF:Ag levels. Four genes that were previously associated with VWF levels (VWF, ABO, STXBP5 and STAB2) were also associated with low VWF levels, and, in addition, we identified a new gene, UFM1, that is associated with low VWF levels. These findings point to novel mechanisms for the occurrence of low VWF levels. PMID- 26486472 TI - West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1. AB - West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births. To get better insights on the genetic of this pathology, we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings. GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis. The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor. Yeast complementation assays show that the activity of GUF1(A609S) is modified in suboptimal environments. We suggest a new link between improper assembly of respiratory chain complexes and WS. PMID- 26486475 TI - Femtosecond 2DIR spectroscopy of the nitrile stretching vibration of thiocyanate anions in liquid-to-supercritical heavy water. Spectral diffusion and libration induced hydrogen-bond dynamics. AB - Femtosecond two-dimensional infrared (2DIR) spectroscopy was carried out to study the dynamics of vibrational spectral diffusion of the nitrile stretching vibration of thiocyanate anions (S-C=N(-)) dissolved in liquid-to-supercritical heavy water (D2O). The 2DIR line shapes were used to extract through a nodal slope analysis quantitative information about the correlation function for temporal fluctuations of the CN-stretching frequency. The inverse nodal slope could be fitted phenomenologically by a simple double-exponential decay whose predominant component had a time constant ranging between 300 fs and 1 ps depending on the temperature. The temperature dependence is interpreted in terms of solvent structural fluctuations that are driven by the librational motions of the D2O molecules located in the first solvation shell of the anion. Complementary molecular dynamics simulations of the SCN(-)/D2O system indicate that the breaking and making of hydrogen-bonds between the terminal N-atom of the anion and the D2O molecules are induced by the same solvent-shell librational degrees of freedom that drive the vibrational line broadening dynamics seen in the 2DIR experiment. PMID- 26486474 TI - De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome. AB - PEHO syndrome (OMIM no. 260565) is characterized by myoclonic jerking and infantile spasms, profound psychomotor retardation with the absence of motor milestones and speech, absence or early loss of visual fixation with atrophy of optic discs by 2 years of age and progressive brain atrophy on neuroimaging. We describe the results of a genomic study of a girl with PEHO syndrome and review the literature on cases with a disease-causing variant in the same gene. Exome sequencing of the index and unaffected parents followed by Sanger confirmation identified nine candidate genes harboring nonsynonymous rare variants identified by trio whole-exome sequencing. The de novo variant, a missense variant (c.296C>T, p.(T99M)), affecting the motor domain of KIF1A was considered the pathogenic mutation. The literature review revealed 24 cases with disease-causing variants in the motor domain of KIF1A, of which three met all the criteria for PEHO syndrome and an additional patient with incomplete clinical data met four of the five criteria. If the criteria were modified to include cases with any convulsive disorder and less profound intellectual disability, a total of six patients met all five of the criteria, three patients met four of the criteria and six met three of the criteria. Our results indicate that the molecular basis for PEHO syndrome, in at least a subset of patients, is a dominant KIF1A variant affecting the motor domain of the protein. Variable expressivity is seen with recurrent variants causing the full phenotype of PEHO syndrome in some patients and in other patients, a partial or milder PEHO phenotype. PMID- 26486473 TI - Heterozygous deletion of the LRFN2 gene is associated with working memory deficits. AB - Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families. PMID- 26486476 TI - [Adrenal incidentaloma]. AB - Incidentaloma is an adrenal mass discovered serendipitously. Because of increasing use of imaging techniques it is a common finding, being present in more than 1 % of adults. During work-up malignancy has to be ruled out. Classically imaging using CT or MRI is used. Recently PET-CT with FDG has been used more often as its sensitivity for diagnosis of malignancy is about 97 % and specificity 91 %. Hormonal evaluation should diagnose subclinical hypercortisolism. (Dexamethasone Suppression Test is the method of choice). Aldosterone and Renin should be measured only in patients with hypertension and catecholamines in tumours with higher native density than 10 HU. During follow-up repeated CT scan are needed only in selected patients and the need of routine biochemical follow-up has been questioned as well. PMID- 26486477 TI - [Adrenal insufficiency]. AB - Adrenal insufficiency is a potentially life threatening condition. The paper deals with differential diagnostics and limits of dynamic testing, possibilities of de-escalation of corticosteroid therapy and substitution therapy with glucocorticoids, mineralocorticoids and androgens. New replacement possibilities are mentioned including those in development. PMID- 26486478 TI - [Thyroid gland and pregnancy - summary of important findings]. AB - Thyroid hormones play fundamental role in conception and pregnancy and are essential for normal adult health, fetus and childhood development. Many studies have shown an association between maternal thyroid diseases esp. hypothyroidism with obstetric problems and/or psychomotoric impairment in the offspring. The prevalence of undiagnosed lower thyroid function in pregnancy is present in about 4-8 % of pregnant women, and euthyroid women with thyroid autoimmunity (6-8 %) are further candidates for thyroid disorders in pregnancy. The thyroid gland needs to produce 50 % more thyroxine in pregnancy to maintain an euthyroid state to keep TSH ideally 2.5 mIU/l in the first trimester of pregnancy and TSH 3.0 mIU/l in the second and third trimester. Consequently, there is a need to start the substitution therapy as soon as diagnosis of subclinical and /or overt hypotyroidism is established, and in majority of euthyroid women with autoimmune thyroid disease there is a need to start therapy as well. Most women on levothyroxine therapy before pregnancy require an increase in dose when pregnant. As maternal thyroid disease is a quite prevalent condition and often asymptomatic, but easily diagnosed and for which an effective, safe and cheap treatment is available, endocrinological societies including CES CLS JEP worldwide are suggesting the need of thyroid dysfunction screening as a simple prevention attitude. Hormone determination of TSH and TPOab antibodies should be performed early during the first trimester, using trimester-specific reference values. Furthermore, adequate iodine supplementation during pregnancy is critical and if feasible it should be initiated before the woman attempts to conceive. PMID- 26486479 TI - [Management of hypothyroidism and hyperthyroidism]. AB - Functional thyropathies present significant health risks for patients. Advanced functional thyropathies are always treated while indications for therapy of subclinical thyropathies are individual and often controversial. It is widely agreed that these disorders should be diagnosed and individuals should be followed. The drug of choice in substitution therapy of hypothyroidism is levothyroxine, in the treatment of hyperthyroidism it is methimazole. Administration of propylthiouracil should be limited to the first trimester of pregnancy, because its serious hepatotoxicity has been described. Hyperthyroidism based on thyroid nodules and immunogenic hyperthyroidism not reaching long-term remission, need to be treated radically: by surgery or radioiodine treatment. When radiation protection requirements are met, radioiodine can also be administered on an outpatient basis. Exceptionally, small doses of methimazole can be administered over an extended period of time in individual cases. PMID- 26486480 TI - [Subclinical thyroid disease]. AB - Importance of subclinical thyroid disease (STh) is now a matter of discussion. Definition of this unit is laboratory: in presence of normal level of thyroxine (T4) TSH value is changed: in lower TSH level the subclinical hyperthyroidism (STx) in increase TSH levels subclinical hypothyroidism (SH) is present. Risk of clinical manifestation is two three times highter in comparison with persons with normal TSH level. Clinical importance STh is still not evaluated definitively. SH caused disturbance of lipid metabolism, elasticity of vessels and endothelial function and therefore increases risk of atherosclerosis. STx causes electrical instability of myocardium with increased risk of arythmias, increases risk of osteoporosis and other changes. Most important are effects of STh in cardiology, reproductive medicine and gynecology. Clinical significance of these effects is not definitively evaluated. PMID- 26486481 TI - [Autoimmune thyroiditis and thyroid cancer]. AB - Association between autoimmune thyroiditis (CLT) and thyroid cancer remains not clear. Although both diseases often occur simultaneously in histological samples, it is not yet clear whether CLT can be regarded as a risk factor for thyroid malignancy. This review focus on the known epidemiological and molecular genetics links between both diseases. Most studies have shown a significant association between thyroid cancer and positive antibodies to thyroglobulin and histological evidence of CLT, as well. Both disorders share some risk factors (greater incidence in women, in areas with adequate supply of iodine and in patients after radiotherapy of the neck) and molecular genetics linkage. For example: RET/PTC rearrangements could be more often found in carcinomas associated with CLT, but this mutation could be found in benign lesions such as CLT, as well. CLT seems to be a positive prognostic factor in patients with differentiated thyroid cancer. It is associated with less invasive forms of tumor, lower occurrence of infiltrated lymphatic nodes and a lower risk of recurrence. PMID- 26486482 TI - [Functional hypothalamic amenorrhea]. AB - Functional hypothalamic amenorrhea (FHA) besides pregnancy and syndrome of polycystic ovary is one of the most common causes of secondary amenorrhea. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle stimulating hormone and luteinizing hormone). FHA is a form of the defence of organism in situations where life functions are more important than reproductive function. FHA is reversible; it can be normalized after ceasing the stress situation. There are three types of FHA: weight loss related, stress-related, and exercise-related amenorrhea. The final consequences are complex hormonal changes manifested by profound hypoestrogenism. Additionally, these patients present mild hypercortisolemia, low serum insulin levels, low insulin-like growth factor 1 (IGF-1) and low total triiodothyronine. Women health in this disorder is disturbed in several aspects including the skeletal system, cardiovascular system, and mental problems. Patients manifest a decrease in bone mass density, which is related to an increase in fracture risk. Therefore, osteopenia and osteoporosis are the main long-term complications of FHA. Cardiovascular complications include endothelial dysfunction and abnormal changes in the lipid profile. FHA patients present significantly higher depression and anxiety and also sexual problems compared to healthy subjects. PMID- 26486483 TI - [Polycystic ovary syndrome]. AB - For diagnosing of polycystic ovary syndrome (PCOS) it is currently recommended to follow the ESHRE criteria. For diagnosis according to them two of the following three symptoms are sufficient: 1. morphology of polycystic ovaria, 2. clinical manifestations of hyperandrogenism or laboratory proof of hyperandrogenemia, and 3. oligo-anovulation. PCOS is a complex disorder in whose pathogenesis genetic and environmental effects interact. It is not a gynecological disorder alone, the syndrome is accompanied by insulin resistance which leads to increased incidence of type 2 diabetes mellitus and impaired glucose tolerance (4 times and twice, independently of BMI). Also gestational DM occurs more frequently. Dyslipidemia, arterial hypertension, elevated CRP and homocysteine levels, endothelial dysfunction and greater intima-media thickness are also more frequent. It is not quite clear, however, whether women with PCOS suffer cardiovascular events more frequently as well. More often than is accidental PCOS is associated with depression, anxiety and eating disorders, further with nonalcoholic steatohepatitis and with the sleep apnoea syndrome - especially in obese women. Therapeutic measures include non-pharmacological methods - lifestyle adjustments focused on weight reduction in obese individuals, cosmetic measures for dermatologic manifestation of hyperandrogenism, in particular laser and pharmacotherapy (combined hormonal contraceptives and antiandrogens). Menstrual irregularities can be treated with contraceptives or cyclical administration of gestagens, also metformin can be used. PMID- 26486484 TI - [News in diagnostics and therapy of multiple endocrine neoplasia type 1]. AB - MEN1 syndrome is an autosomal dominant disorder caused by mutation in the men in gene located on the 11th chromosome. It is a rare disorder with incidence of 1 : 30 000. It involves functional or cancerous diseases of parathyroid glands, hypophysis, endocrine pancreas, adrenal glands, or other tumors. The diagnosis of MEN1 is suspected if at least 2 components of this multiple tumor syndrome occur simultaneously. The increase in diagnostic precision enables detection of MEN1 in its early stages. Currently, the most frequently discussed topics include the use of biomarkers for diagnostics and new approaches in surgical treatment of MEN1. PMID- 26486485 TI - [Acromegaly: current view]. AB - Acromegaly is a rare disorder caused by autonomous oversecretion of growth hormone mostly by pituitary adenoma. Untreated acromegaly leads to significantly increased morbidity and mortality and impaired quality of life. Early diagnosis and treatment is therefore essential for improvement of patients prognosis and management of acromegaly should be concentrated in specialized centres. Present article summarizes current view on diagnosis and treatment of acromegaly. PMID- 26486486 TI - [Systemic glucocorticoids treatment: practical view]. AB - Glucocorticoids are derivatives of natural human glucocorticoid cortisol. There are used for treatment of a number of diseases and disorders for more than 65 years mainly because of their immunosuppressive properties. However, their use is accompanied by various side effects that have to be considered when treating patients. The article summarizes biological effects of glucocorticoids, main indications for their use, their side effects and precautions necessary to bear in mind during treatment. PMID- 26486487 TI - The complete mitochondrial genome of Anguilla japonica (Anguilliformes, Anguillidae) collected from Yangtze estuary and the phylogenetic relationship in genus Anguilla. AB - The complete mitochondrial genome of Anguilla japonica collected from Yangtze estuary was determined by next-generation sequencing. The mitogenome is a circular molecule 16 715 bp in length, including the typical structure of 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, and a control region. The TAS, central CSB and CSB were detected in the control region. The gene contents of the mitogenome are identical to those observed in most bony fishes. The phylogenetic tree in the genus Anguilla showed that A. japonica clustered in a separate branch. PMID- 26486488 TI - Lewis Acid Catalyzed Asymmetric Three-Component Coupling Reaction: Facile Synthesis of alpha-Fluoromethylated Tertiary Alcohols. AB - A chiral dicationic palladium complex is found to be an efficient Lewis acid catalyst for the synthesis of alpha-fluoromethyl-substituted tertiary alcohols using a three-component coupling reaction. The reaction transforms three simple and readily available components (terminal alkyne, arene, and fluoromethylpyruvate) to valuable chiral organofluorine compounds. This strategy is completely atom-economical and results in perfect regioselectivities and high enantioselectivities of the corresponding tertiary allylic alcohols in good to excellent yields. PMID- 26486489 TI - Behcet's disease and cerebral sinus vein thrombosis in children: a case study and review of the literature. AB - OBJECTIVES: Central nervous system (CNS) involvement, one of the most severe manifestations of Behcet's disease (BD), is uncommon in children. Because it is rare, the clinical features of this disease in children are not well characterised. Here we describe a teenager with BD which was disclosed following an episode of cerebral sinus vein thrombosis (CSVT) and review the available literature on children with CSVT associated with BD. METHODS: A 12-year-old boy who presented with CSVT is described and the relevant literature, based on a Medline search from 1966 to January 2015 is reviewed. RESULTS: Twenty-three well documented reports of children with CSVT and BD are described. This manifestation affected mainly males (61%) with a mean age of 12 years (range 4-18). BD was first diagnosed simultaneously or following CSVT in the majority of cases (75%). Multiple sinuses were involved in 30% of the cases. Thrombosis of additional large vessel was identified in 5 of the 23 children. The most common presenting symptom and signs were headache (91%), lasting more than 3 days in most cases (75%), followed by papilledema (43%), seizures (17%), and personality changes (9%). A mixed pattern of CNS involvement including both parenchymal involvement and CSVT, was demonstrated in only two patients (9%). Management of CSVT differed between reports. CONCLUSIONS: CSVT in children is a rarely reported manifestation of BD and has a characteristic clinical picture of a teenage boy presenting with prolonged headache, with no previous diagnosis of BD. A therapeutic approach has not been established yet. PMID- 26486490 TI - Influence of wearing a scuba diving mouthpiece on the stomatognathic system - considerations for mouthpiece design. AB - Although diver's mouth syndrome (DMS) has long been recognized by scuba divers, little attention has been paid to the influence of wearing a scuba diving mouthpiece on the stomatognathic system. In this review, DMS-related stomatognathic events (DMS-SE) while wearing a mouthpiece, the relationship between components of the mouthpiece and those events, and design considerations to reduce the risk of those events are discussed based on evidence from 32 articles concerning scuba diving mouthpieces. Forward movement of the mandible, loss of molar occlusal support, and continuous jaw clenching while wearing a mouthpiece are considered to be pathogenic for DMS-SE. Several experimental studies have suggested a relationship between incidence of those events and the design of mouthpiece components such as the connector, labial flange, platform, and occlusal rug, and the possibility of reducing risk of those events through design customization of these components. Improvement of the shape of commercially available mouthpieces and creation of custom-made mouthpieces may thus contribute to the prevention and treatment of DMS-SE and the provision of a comfortable diving environment. PMID- 26486491 TI - Sneddon syndrome--imaging findings. PMID- 26486493 TI - Early occurrence of brief potentially ictal rhythmic discharges [B(I)RDs], and subsequent emergence of asymmetric extreme delta brush (EDB) in Anti-NMDA receptors encephalitis. PMID- 26486492 TI - Intracranial dural arteriovenous fistula with perimedullary drainage treated by endovascular embolization. PMID- 26486494 TI - Persistent Sydenham's chorea is not associated with sustained lymphocyte dysfunction. AB - The mechanisms involved in the symptoms of Sydenham's chorea (SC) remain obscure. Taking into account the autoreactive antibody-mediated hypothesis of SC pathogenesis, the persistence of chorea may be associated with increased levels of B1 lymphocytes and other lymphocyte subsets. We evaluated lymphocyte subsets, including B1 and T cells, in patients with remitted (RSC) and persistent (PSC) SC by flow cytometry. Our results showed neither difference in the frequency of T and B lymphocytes subpopulations nor in their activation and functional states. These findings undermine the view of PSC as a sustained cytotoxic cellular mediated condition. Alternative mechanisms may explain the pathogenesis of PSC. PMID- 26486496 TI - Marchiafava-Bignami disease in an AIDS patient. PMID- 26486495 TI - Pelizaeus Merzbacher disease: dysmyelination versus demyelination. PMID- 26486497 TI - Migraine patients consistently show abnormal vestibular bedside tests. AB - Migraine and vertigo are common disorders, with lifetime prevalences of 16% and 7% respectively, and co-morbidity around 3.2%. Vestibular syndromes and dizziness occur more frequently in migraine patients. We investigated bedside clinical signs indicative of vestibular dysfunction in migraineurs. OBJECTIVE: To test the hypothesis that vestibulo-ocular reflex, vestibulo-spinal reflex and fall risk (FR) responses as measured by 14 bedside tests are abnormal in migraineurs without vertigo, as compared with controls. METHOD: Cross-sectional study including sixty individuals - thirty migraineurs, 25 women, 19-60 y-o; and 30 gender/age healthy paired controls. RESULTS: Migraineurs showed a tendency to perform worse in almost all tests, albeit only the Romberg tandem test was statistically different from controls. A combination of four abnormal tests better discriminated the two groups (93.3% specificity). CONCLUSION: Migraine patients consistently showed abnormal vestibular bedside tests when compared with controls. PMID- 26486498 TI - Hydroxylated Daphniphyllum Alkaloids from Daphniphyllum himalense. AB - Thirteen new hydroxylated calyciphylline A-type Daphniphyllum alkaloids (1-13) were isolated from an ethanolic extract of Daphniphyllum himalense. These structures were characterized on the basis of spectroscopic data analysis, especially from their 2D NMR spectra. Oxidation at the C-3, C-9, C-11, and C-12 positions is reported for the first time for this class of compounds. Selective compounds showed low inhibitory rates against three kinase enzymes, PTP1B, aurora A, and IKK-beta, at a concentration of 20 MUg/mL. PMID- 26486499 TI - The Same but Different: Regulation of Tissue Engineering and Regenerative Medicine in the Context of Regional and International Standards and Expectations. AB - This commentary places the contributions from several Asian-Pacific countries that constitute this Special Issue in the context of trends in global regulation of tissue engineering and regenerative medicine products and services. It concentrates on the generic issues that face regulation in each jurisdiction and the manner how these issues have to be faced in the light of cultural, political, and economic regional differences. PMID- 26486500 TI - Bats of the Western Indian Ocean Islands. AB - The natural colonisation of many remote oceanic islands by bats, including those of the western Indian Ocean, has been facilitated by their unique capability among mammals for powered flight. In the western Indian Ocean region, only the Malagasy islands of Madagascar and the Comoros archipelago have been naturally colonised by non-volant mammals. Despite their greater potential for inter-island dispersal, and thus gene transfer, endemicity of Chiroptera in the western Indian Ocean islands is high. Given their vulnerability to stochastic and anthropogenic disturbances, greater focus needs to be placed on investigating the demographic and ecological history of bats on Western Indian Ocean islands to safeguard not only their future, but also the ecosystem functioning on these islands, for which they are undoubtedly such an integral part. Here, I summarise the taxonomic and life history information available on bats from Western Indian Ocean islands and highlight knowledge gaps and conservation issues that threaten the continued persistence of some species. PMID- 26486501 TI - Cosmopolitanism and Biogeography of the Genus Manganonema (Nematoda: Monhysterida) in the Deep Sea. AB - Spatial patterns of species diversity provide information about the mechanisms that regulate biodiversity and are important for setting conservation priorities. Present knowledge of the biogeography of meiofauna in the deep sea is scarce. This investigation focuses on the distribution of the deep-sea nematode genus Manganonema, which is typically extremely rare in deep-sea sediment samples. Forty-four specimens of eight different species of this genus were recorded from different Atlantic and Mediterranean regions. Four out of the eight species encountered are new to science. We report here that this genus is widespread both in the Atlantic and in the Mediterranean Sea. These new findings together with literature information indicate that Manganonema is a cosmopolitan genus, inhabiting a variety of deep-sea habitats and oceans. Manganonema shows the highest diversity at water depths >4,000 m. Our data, therefore, indicate that this is preferentially an abyssal genus that is able, at the same time, to colonize specific habitats at depths shallower than 1,000 m. The analysis of the distribution of the genus Manganonema indicates the presence of large differences in dispersal strategies among different species, ranging from locally endemic to cosmopolitan. Lacking meroplanktonic larvae and having limited dispersal ability due to their small size, it has been hypothesized that nematodes have limited dispersal potential. However, the investigated deep-sea nematodes were present across different oceans covering macro-scale distances. Among the possible explanations (hydrological conditions, geographical and geological pathways, long term processes, specific historical events), their apparent preference of colonizing highly hydrodynamic systems, could suggest that these infaunal organisms are transported by means of deep-sea benthic storms and turbidity currents over long distances. PMID- 26486503 TI - beta,beta'-Bipyrrole Fusion-Driven cis-Bimetallic Complexation in Isomeric Porphyrin. AB - An unprecedented cis-bimetallic complex of dinaphthoporphycene (DNP), namely [Pd2(MU-DNP)(MU-OAc)2], is reported. The most striking feature of this complex is that two palladiums coordinate to the macrocycle on the same side and are closely held together (Pd-Pd: 2.67 A) by two bridging acetate ligands exhibiting significant metal-metal bonding interaction (bond order 0.18 evaluated by NBO analysis). Interestingly, replacing acetate with acetylacetonate (acac) could stabilize an unusual mono-palladium complex of DNP, where Pd coordinates unsymmetrically to two ring Ns above the macrocyclic plane, as well as coordinating with two Os of the acac ligand. Remarkably, the rigid DNP core displays enhanced complexation induced aromaticity (as per NICS and HOMA analysis), despite undergoing severe core deformation during complexation with metal ion(s) as noticed from their solid-state structures. PMID- 26486502 TI - Vaccines against a Major Cause of Abortion in Cattle, Neospora caninum Infection. AB - Neosporosis, caused by the apicomplexan parasite Neospora caninum, represents one of the economically most important causes of abortion in cattle. During pregnancy, the parasite infects the placental tissue and the fetus, which can lead to stillbirth, abortion, or birth of weak calves. Alternatively, calves are born without clinical symptoms, but they can carry over the parasite to the next generation. In addition, N. caninum causes neuromuscular disease in dogs. The economic importance of neosporosis has prompted researchers to invest in the development of measures to prevent infection of cattle by vaccination. A good vaccine must stimulate protective cellular immune responses as well as antibody responses at mucosal sites and, systemically, must activate T-helper cells to produce relevant cytokines, and must elicit specific antibodies that aid in limiting parasite proliferation, e.g., by interference with host cell invasion, activation of complement, and/or opsonization of parasites to have them killed by macrophages. Different types of vaccines have been investigated, either in bovines or in the mouse model. These include live vaccines such as naturally less virulent isolates of N. caninum, attenuated strains generated by irradiation or chemical means, or genetically modified transgenic strains. Live vaccines were shown to be very effective; however, there are serious disadvantages in terms of safety, costs of production, and stability of the final product. Subunit vaccines have been intensively studied, as they would have clear advantages such as reduced costs in production, processing and storage, increased stability and shelf life. The parasite antigens involved in adhesion and invasion of host cells, such as surface constituents, microneme-, rhoptry- and dense granule components represent interesting targets. Subunit vaccines have been applied as bacterially expressed recombinant antigens or as DNA vaccines. Besides monovalent vaccines also polyvalent combinations of different antigens have been used, providing increased protection. Vaccines have been combined with immunostimulating carriers and, more recently, chimeric vaccines, incorporating immuno-relevant domains of several antigens into a single protein, have been developed. PMID- 26486504 TI - From synaptically localized to volume transmission by nitric oxide. AB - Nitric oxide (NO) functions widely as a transmitter/diffusible second messenger in the central nervous system, exerting physiological effects in target cells by binding to specialized guanylyl cyclase-coupled receptors, resulting in cGMP generation. Despite having many context-dependent physiological roles and being implicated in numerous disease states, there has been a lack of clarity about the ways that NO operates at the cellular and subcellular levels. Recently, several approaches have been used to try to gain a more concrete, quantitative understanding of this unique signalling pathway. These approaches have included analysing the kinetics of NO receptor function, real-time imaging of cellular NO signal transduction in target cells, and the use of ultrasensitive detector cells to record NO as it is being generated from native sources in brain tissue. The current picture is that, when formed in a synapse, NO is likely to act only very locally, probably mostly within the confines of that synapse, and to exist only in picomolar concentrations. Nevertheless, closely neighbouring synapses may also be within reach, raising the possibility of synaptic crosstalk. By engaging its enzyme-coupled receptors, the low NO concentrations are able to stimulate physiological (submicromolar) increases in cGMP concentration in an activity dependent manner. When many NO-emitting neurones or synapses are active simultaneously in a tissue region, NO can act more like a volume transmitter to influence, and perhaps coordinate, the behaviour of cells within that region, irrespective of their identity and anatomical connectivity. PMID- 26486505 TI - Antitumor effect of antiplatelet agents in gastric cancer cells: an in vivo and in vitro study. AB - BACKGROUND: The antitumor effects of antiplatelet agents in gastric cancer cells are not well known. In this study, the possibility of gastric cancer treatment with an antiplatelet agent, mainly aspirin, was examined both in vivo and in vitro. METHODS: For in vivo experiments, tumor-bearing mice were treated by an antiplatelet antibody or aspirin, and the tumor growth was compared. For in vitro experiments, human gastric cancer cell lines were used to confirm the cancer cell growth and inhibition by reducing the platelet count or using aspirin. We also examined several cytokines by using an ELISA assay and conducted microRNA microarray analysis of MKN-45 tumor cells to determine the influence of platelets or aspirin. RESULTS: In vivo experiments showed that tumor growth was inhibited by halving the circulating platelet count by using an antiplatelet antibody or peroral daily aspirin. In vitro experiments showed that the proliferation rates of gastric cancer cell lines were increased after coincubation with platelets and that the effect was inhibited by aspirin. Although the expression of interleukin 6, platelet-derived growth factor, transforming growth factor-beta, and prostaglandin E2 did not correlate with tumor growth inhibition by aspirin, seven microRNAs showed altered expression in cancer cells in response to coincubation with platelets or addition of aspirin. Cells transfected with mir-4670-5p showed a significant increase in proliferation compared to negative control cells. CONCLUSIONS: Our study showed that platelets increased the proliferation of gastric cancer cells and that this increase was inhibited by antiplatelet antibody or aspirin. Mir-4670-5p may play an important role in these responses. PMID- 26486506 TI - BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer. AB - BACKGROUND: Preoperative chemotherapy is a promising strategy for downstaging advanced gastric cancer before radical resection, although severe adverse events can occur and clinical outcomes are often unsatisfactory. To identify predictive biomarkers of drug sensitivity, we used a well-designed functional apoptosis assay and assessed the correlations between chemosensitivity and clinical outcomes. METHODS: Drug sensitivity to docetaxel, cisplatin, and 5-fluorouracil was examined in 11 gastric cancer cell lines. BCL2-homology domain 3 (BH3) profiling was performed and assessed for correlations with drug sensitivity. Immunohistochemical staining of clinical gastric cancer specimens was performed before preoperative chemotherapy, and correlations with histopathological responses and clinical outcomes were assessed. RESULTS: BIM (BCL2L11)-BH3 profiling results correlated with docetaxel sensitivity and BAK protein expression, whose knockdown caused docetaxel resistance. The BAK expression indexes of 69 gastric cancer specimens before preoperative chemotherapy (including docetaxel treatment) were determined by multiplying numerical values describing the degrees of BAK positivity and staining intensity observed. Patients whose specimens showed good chemotherapeutic histopathological responses had higher BAK indexes than those with poor responses. Patients with BAK index values >=3 showed improved progression-free survival (HR, 2.664; 95 % CI, 1.352 5.248; P = 0.005) and overall survival (HR, 3.390; 95 % CI, 1.549-7.422; P = 0.002). CONCLUSIONS: BH3 profiling clearly showed that BIM expression, which depends on BAK expression, correlated with docetaxel sensitivity. BAK expression in gastric cancer is thus predictive of chemotherapeutic responses to docetaxel and clinical prognosis in patients treated with preoperative chemotherapy. PMID- 26486507 TI - Pepsinogen-II 100 bp ins/del gene polymorphism and its elevated circulating levels are associated with gastric cancer, particularly with Helicobacter pylori infection and intestinal metaplasia. AB - BACKGROUND: Polymorphism in the gene of pepsinogen-II (PG-II) and its serum level are effective biomarkers for terminal differentiation of gastric mucosa into gastritis, intestinal metaplasia (IM), and gastric cancer (GC) in relationship to Helicobacter pylori infection. METHODS: Genotyping of the PG-II 100 bp insertion/deletion (ins/del) polymorphism was performed in patients with GC (n = 192) and age- and gender-matched H. pylori-associated dyspepsia (n = 180) and healthy subjects (HS, n = 240) by PCR. IgG anti-H. pylori (in all subjects) and serum PG-II levels were estimated in 145 patients each with GC and dyspepsia and in 65 healthy controls (HC) using ELISA (Biohit Oyj, Finland). RESULTS: Five alleles were amplified by PCR: allele 5 (510 bp), allele 4 (480 bp), allele 3 (450 bp), allele 2 (400 bp), and allele 1 (shorter allele, 310 bp). Allele 1 carriage was infrequent, and serum PG-II level was higher among patients with GC than in HC [OR 0.43 (95 % CI, 0.29-0.85), p < 0.001 and mean +/- SD; 17.53 +/- 12.60 vs. 12.77 +/- 7.53 ug/l, p = 0.005, respectively], particularly in the presence of H. pylori [OR 0.42 (0.25-0.71), p = 0.001 and 18.78 +/- 12.63 vs. 13.97 +/- 8.14, p = 0.034]. However, allele 1 carriage and PG-II levels were comparable among patients with GC and dyspepsia. Patients with IM also carried allele 1 infrequently and had higher levels of PG-II than those without [OR 0.5 (0.29-0.85), p = 0.011 and 20.07 +/- 14.22 vs. 16.61 +/- 12.08, p = 0.048]. CONCLUSIONS: Carriage of the shorter allele of the PG-II 100 bp ins/del polymorphism and elevated levels of PG-II are associated with GC, particularly with H. pylori infection and IM. PMID- 26486509 TI - Erratum to: Expression of hsromega-RNAi transgene prior to heat shock specifically compromises accumulation of heat shock-induced Hsp70 in Drosophila melanogaster. PMID- 26486508 TI - Atrophic gastritis and enlarged gastric folds diagnosed by double-contrast upper gastrointestinal barium X-ray radiography are useful to predict future gastric cancer development based on the 3-year prospective observation. AB - BACKGROUND: Double-contrast upper gastrointestinal barium X-ray radiography (UGI XR) is the standard gastric cancer screening method in Japan. Atrophic gastritis and enlarged gastric folds are considered the two major features of Helicobacter pylori-induced chronic gastritis, but the clinical meaning of evaluating them by UGI-XR has not been elucidated. METHODS: We analyzed healthy UGI-XR examinees without a history of gastrectomy, previous Helicobacter pylori eradication and usage of gastric acid suppressants. RESULTS AND CONCLUSIONS: Of the 6433 subjects, 1936 (30.1 %) had atrophic gastritis and 1253 (19.5 %) had enlarged gastric folds. During the 3-year prospective observational follow-up, gastric cancer developed in seven subjects, six of whom (85.7 %) had atrophic gastritis with H. pylori infection and five of whom (71.4 %) had enlarged gastric folds with H. pylori infection. The Kaplan-Meier method with log-rank testing revealed that both UGI-XR-based atrophic gastritis (p = 0.0011) and enlarged gastric folds (p = 0.0003) are significant predictors for future gastric cancer incidence. PMID- 26486510 TI - Paroxysmal Atrial Fibrillation in Cryptogenic Stroke: an Overlooked Explanation? AB - Approximately one third of ischemic strokes are labeled cryptogenic because the etiology is unknown despite a thorough evaluation. Paroxysmal atrial fibrillation carries the same risk of ischemic stroke as persistent atrial fibrillation and has increasingly gained attention as a potential source of cryptogenic stroke. Recent trials utilizing long-term cardiac monitoring devices have demonstrated high rates of previously undetected paroxysmal atrial fibrillation in patients with cryptogenic stroke. Newly detected atrial fibrillation has subsequently changed treatment and increased the use of oral anticoagulation in these studies. Other trials have shown an increased risk of stroke and thromboembolism in patients with device-detected subclinical tachyarrhythmias. Together, these studies suggest an important relationship between episodes of paroxysmal atrial fibrillation and the risk of cryptogenic stroke, but further investigations are needed to guide diagnostic and therapeutic decisions. PMID- 26486511 TI - Surgical Strategies for Management of Mitral Regurgitation: Recent Evidence from Randomized Controlled Trials. AB - In contrast to mitral regurgitation (MR) caused by structural abnormality of the valve ("primary" MR), about which there is increasing consensus regarding treatment, there is increasing controversy around the management of functional or "secondary" MR, of which "ischemic mitral regurgitation" (IMR) is a common cause. While the trend in the management of primary MR is increasingly aggressive, with wide agreement on the preference for repair over replacement such that debate centers on earlier and earlier repair even among asymptomatic patients, the situation is reversed in the setting of secondary MR with uncertainly beyond the mode of management (repair or replacement) to the value of intervening at all. This is, in part, because the term IMR has been somewhat loosely applied by the medical and surgical communities to include regurgitation secondary to active myocardial ischemia, as well as that resulting from a completed myocardial infarct. As a result, there is considerable variability in reported outcomes of surgical interventions for IMR. In addition, the natural history of IMR is quite adverse-more so than that of many solid organ malignancies-and its surgical treatment has traditionally carried a higher operative mortality than many cardiac surgical procedures, including similar operations for primary MR and incidental coronary artery disease. Added to this, with recent advances in both the medical and surgical treatment of heart failure improving nonoperative outcomes and simultaneously reducing operative risk compared to reports from previous decades, the landscape has been quite dynamic. Here, we review the issues surrounding surgical treatment for IMR, along with available evidence supporting different approaches, to lend an informed perspective on the divergent opinions among experts in this field and guide the appropriate management of the individual patient. PMID- 26486512 TI - Fibrinolysis for Acute Care of Pulmonary Embolism in the Intermediate Risk Patient. AB - Controversy over the role of fibrinolysis in patients with intermediate-risk pulmonary embolism (PE) has persisted because of the lack of adequately sized trials. The PEITHO study now allows a more precise estimate of the risk to benefit ratio of fibrinolysis in these patients. This trial enrolled patients with intermediate-risk PE who were randomized to receive heparin with either tenecteplase or placebo. Fibrinolysis was associated with a significant reduction in the combined end-point of death or hemodynamic decompensation, but also with a significant increase in the risk of major bleeding. The primary efficacy end point occurred in 2.6 % of the patients in the tenecteplase group and in 5.6 % of the patients in the placebo group (OR, 0.44; 95 % CI, 0.23 to 0.87), conversely, major extracranial bleeding occurred in 6.3 % and 1.2 % in the tenecteplase and placebo groups, respectively (OR, 5.55; 95 % CI, 2.3 to 13.39) and stroke occurred in 2.4 % and in 0.2 % of the patients in the tenecteplase group and in the placebo group, respectively (OR, 12.10; 95 % CI, 1.57 to 93.39). No difference was observed for the risk of death alone and the risk of full-dose thrombolytic therapy outweighs its benefit in patients with intermediate-risk PE. Recent meta-analyses suggest that fibrinolysis may be associated with a slight reduction in overall mortality offset by an increase in major bleeding. Two pilot studies suggest that a reduced dose of fibrinolysis may produce significant hemodynamic improvement with a low risk of major bleeding. These options need to be evaluated in larger studies including patients with a higher risk of adverse outcome than those included in the PEITHO study. PMID- 26486513 TI - A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep. AB - PURPOSE: Cancer metastasis to pulmonary lymph nodes dictates the need to deliver chemotherapeutic and diagnostic agents to the lung and associated lymph nodes. Drug conjugation to dendrimer-based delivery systems has the potential to reduce toxicity, enhance lung retention and promote lymphatic distribution in rats. The current study therefore evaluated the pharmacokinetics and lung lymphatic exposure of a PEGylated dendrimer following inhaled administration. METHODS: Plasma pharmacokinetics and disposition of a 22 kDa PEGylated dendrimer were compared after aerosol administration to rats and sheep. Lung-derived lymph could not be sampled in rats and so lymphatic transport of the dendrimer from the lung was assessed in sheep. RESULTS: Higher plasma concentrations were achieved when dendrimer was administered to the lungs of rats as a liquid instillation when compared to an aerosol. Plasma pharmacokinetics were similar between sheep and rats, although some differences in disposition patterns were evident. Unexpectedly, less than 0.5% of the aerosol dose was recovered in pulmonary lymph. CONCLUSIONS: The data suggest that rats provide a relevant model for assessing the pharmacokinetics of inhaled macromolecules prior to evaluation in larger animals, but that the pulmonary lymphatics are unlikely to play a major role in the absorption of nanocarriers from the lungs. PMID- 26486514 TI - "Magic" Ionization Mass Spectrometry. AB - The systematic study of the temperature and pressure dependence of matrix assisted ionization (MAI) led us to the discovery of the seemingly impossible, initially explained by some reviewers as either sleight of hand or the misinterpretation by an overzealous young scientist of results reported many years before and having little utility. The "magic" that we were attempting to report was that with matrix assistance, molecules, at least as large as bovine serum albumin (66 kDa), are lifted into the gas phase as multiply charged ions simply by exposure of the matrix:analyte sample to the vacuum of a mass spectrometer. Applied heat, a laser, or voltages are not necessary to achieve charge states and ion abundances only previously observed with electrospray ionization (ESI). The fundamentals of how solid phase volatile or nonvolatile compounds are converted to gas-phase ions without added energy currently involves speculation providing a great opportunity to rethink mechanistic understanding of ionization processes used in mass spectrometry. Improved understanding of the mechanism(s) of these processes and their connection to ESI and matrix-assisted laser desorption/ionization may provide opportunities to further develop new ionization strategies for traditional and yet unforeseen applications of mass spectrometry. This Critical Insights article covers developments leading to the discovery of a seemingly magic ionization process that is simple to use, fast, sensitive, robust, and can be directly applied to surface characterization using portable or high performance mass spectrometers. PMID- 26486515 TI - Insulin-like growth factor 1 (IGF-1) regulates prolactin, growth hormone, and IGF-1 receptor expression in the pituitary gland of the gilthead sea bream Sparus aurata. AB - The role of insulin-like growth factor 1 (IGF-1) on regulation of growth hormone (GH) and prolactin (PRL) as well as the possible involvement of IGF-1 receptor subtype a (IGF-1Ra) mRNA was assessed in juvenile specimens of Sparus aurata. IGF 1Ra was successfully cloned, and active receptor domains were localized in its mRNA precursor. Also, phylogenetic analysis of the protein sequence indicated a closer proximity to IGF-1Ra isoform found in zebrafish and other teleosts, than to the isoform IGF-1Rb. The most abundant presence of IGF-1Ra mRNA was detected in white muscle, whereas head kidney showed the lowest gene expression among 24 different studied tissues. Pituitaries of juvenile specimens of S. aurata were incubated in vitro with different doses of IGF-1 (0, 1, 100, and 1000 ng mL(-1)) during a period of 10 h. Total RNA with a high quality could be obtained from these pituitaries. PRL mRNA expression significantly increased with increasing IGF-1 doses. Similarly, IGF-1Ra mRNA increased its expression in response to IGF 1. However, GH mRNA levels decreased in a dose-dependent manner after IGF-1 treatment. The contradictory responses of GH and PRL expressions to IGF-1 in our experiment are possibly mediated by IGF-1Ra presence on the somatotrophs and prolactotrophs. The increase in IGF-1Ra mRNA levels may be related to the proper activation of the PI3-K/Akt signal transduction pathways which are normally involved in GH and PRL regulation. PMID- 26486516 TI - Progress in controlling starch structure by modifying starch-branching enzymes. AB - MAIN CONCLUSION: This paper reviews the progress of development of plants with desirable starch structure by modifying starch branching enzymes. Starch branching enzyme (SBE) is responsible for the creation of branches during starch biosynthesis in plastids, and is a major determinant of the final fine structure and physical properties of the starch. Multiple isoforms of SBE have been found in plants, with each playing a different role in amylopectin synthesis. Different methods have been used to develop desirable starch structures by modifying the SBE activity. These can involve changing its expression level (either up regulation or down-regulation), genetically modifying the activity of the SBE itself, and varying the length of its transferred chains. Changing the activity and the transferred chain length of SBE has been less studied than changing the expression level of SBE in vivo. This article reviews and summarizes new tools for developing plants producing the next generation of starches. PMID- 26486517 TI - Pharmacokinetic and pharmacodynamic study of tariquidar (XR9576), a P glycoprotein inhibitor, in combination with doxorubicin, vinorelbine, or docetaxel in children and adolescents with refractory solid tumors. AB - PURPOSE: P-glycoprotein (Pgp), an ATP-dependent transport protein, confers multidrug resistance in cancer cells. Tariquidar binds and inhibits Pgp. To assess the toxicity, pharmacokinetics (PK), and pharmacodynamics of tariquidar, we conducted a phase I trial of tariquidar in combination with doxorubicin, docetaxel, or vinorelbine in children and adolescents with recurrent or refractory solid tumors. METHODS: Patients less than 19 years of age with refractory or recurrent solid tumors were eligible. Tariquidar (1, 1.5, or 2 mg/kg) was administered alone and in combination with doxorubicin, docetaxel, or vinorelbine. PK of tariquidar and cytotoxic drugs was performed. Pgp function was assessed by a rhodamine efflux assay and (99m)Tc-sestamibi scintigraphy. Tumor Pgp expression was assessed by immunohistochemistry. Response was assessed using Response Evaluation Criteria in Solid Tumors. RESULTS: Twenty-nine subjects were enrolled. No tariquidar-related dose-limiting toxicity (DLT) was observed. DLT related to cytotoxic drugs occurred in 12 % of subjects receiving tariquidar 2 mg/kg. When administered in combination with tariquidar, the clearance of docetaxel and vinorelbine was reduced compared to prior studies. Inhibition of rhodamine efflux was dose dependent. After tariquidar administration, (99m)Tc sestamibi accumulation in tumor increased by 22 %. Objective responses (1 complete, 2 partial) were observed. There was no association between tumor Pgp expression and response. CONCLUSION: A tolerable and biologically active dose of tariquidar was established in children and adolescents. This trial demonstrates that modulators of resistance can be evaluated in combination with chemotherapy, and pharmacokinetic and pharmacodynamic endpoints can be useful in determination of recommended dose in children and adolescents. PMID- 26486518 TI - Correlation between biofilm production, antibiotic susceptibility and exopolysaccharide composition in Burkholderia pseudomallei bpsI, ppk, and rpoS mutant strains. AB - Burkholderia pseudomallei is the cause of melioidosis, a fatal tropical infectious disease, which has been reported to have a high rate of recurrence, even when an intensive dose of antibiotics is used. Biofilm formation is believed to be one of the possible causes of relapse because of its ability to increase drug resistance. EPS in biofilms have been reported to be related to the limitation of antibiotic penetration in B. pseudomallei. However, the mechanisms by which biofilms restrict the diffusion of antibiotics remain unclear. The present study presents a correlation between exopolysaccharide production in biofilm matrix and antibiotic resistance in B. pseudomallei using bpsI, ppk, and rpoS mutant strains. CLSM revealed a reduction in exopolysaccharide production and disabled micro-colony formation in B. pseudomallei mutants, which paralleled the antibiotic resistance. Different ratios of carbohydrate contents in the exopolysaccharides of the mutants were detected, although they have the same components, including glucose, galactose, mannose, and rhamnose, with the exception being that no detectable rhamnose peak was observed in the bpsI mutant. These results indicate that the correlation between these phenomena in the B. pseudomallei biofilm at least results from the exopolysaccharide, which may be under the regulation of bpsI, ppk, or rpoS genes. PMID- 26486519 TI - Evaluation of Death Cases Connected to Electric Current in Aydin Province, Western Turkey. AB - In this article, the authors discuss electric shock fatalities in Aydin province and compare these findings with the findings of other studies conducted in Turkey and worldwide. Data were gathered from 2001-2013 autopsy reports retrospectively. A total of 34 cases were reviewed in terms of age and gender, scene and time of event, number of lesions and their locations, organ injuries, origin of electricity, and degree of burns. In all cases, electrical death was accidental. Electrical shock fatalities were most common in the 30 to 39 age group. Fourteen cases (41.2%) involved workers: 7 cases (2.6%) were agricultural workers, 4 cases (11.8%) were housewives, 2 (5.9%) were electrical workers, and 7 (20.6%) were unemployed or in other occupations. The authors are addressing this public health problem to minimize the number of electrical deaths. PMID- 26486521 TI - Bioprinting of human pluripotent stem cells and their directed differentiation into hepatocyte-like cells for the generation of mini-livers in 3D. AB - We report the first investigation into the bioprinting of human induced pluripotent stem cells (hiPSCs), their response to a valve-based printing process as well as their post-printing differentiation into hepatocyte-like cells (HLCs). HLCs differentiated from both hiPSCs and human embryonic stem cells (hESCs) sources were bioprinted and examined for the presence of hepatic markers to further validate the compatibility of the valve-based bioprinting process with fragile cell transfer. Examined cells were positive for nuclear factor 4 alpha and were demonstrated to secrete albumin and have morphology that was also found to be similar to that of hepatocytes. Both hESC and hiPSC lines were tested for post-printing viability and pluripotency and were found to have negligible difference in terms of viability and pluripotency between the printed and non printed cells. hESC-derived HLCs were 3D printed using alginate hydrogel matrix and tested for viability and albumin secretion during the remaining differentiation and were found to be hepatic in nature. 3D printed with 40-layer of HLC-containing alginate structures reached peak albumin secretion at day 21 of the differentiation protocol. This work demonstrates that the valve-based printing process is gentle enough to print human pluripotent stem cells (hPSCs) (both hESCs and hiPSCs) while either maintaining their pluripotency or directing their differentiation into specific lineages. The ability to bioprint hPSCs will pave the way for producing organs or tissues on demand from patient specific cells which could be used for animal-free drug development and personalized medicine. PMID- 26486520 TI - An evidence-based knowledgebase of metastasis suppressors to identify key pathways relevant to cancer metastasis. AB - Metastasis suppressor genes (MS genes) are genes that play important roles in inhibiting the process of cancer metastasis without preventing growth of the primary tumor. Identification of these genes and understanding their functions are critical for investigation of cancer metastasis. Recent studies on cancer metastasis have identified many new susceptibility MS genes. However, the comprehensive illustration of diverse cellular processes regulated by metastasis suppressors during the metastasis cascade is lacking. Thus, the relationship between MS genes and cancer risk is still unclear. To unveil the cellular complexity of MS genes, we have constructed MSGene (http://MSGene.bioinfo minzhao.org/), the first literature-based gene resource for exploring human MS genes. In total, we manually curated 194 experimentally verified MS genes and mapped to 1448 homologous genes from 17 model species. Follow-up functional analyses associated 194 human MS genes with epithelium/tissue morphogenesis and epithelia cell proliferation. In addition, pathway analysis highlights the prominent role of MS genes in activation of platelets and coagulation system in tumor metastatic cascade. Moreover, global mutation pattern of MS genes across multiple cancers may reveal common cancer metastasis mechanisms. All these results illustrate the importance of MSGene to our understanding on cell development and cancer metastasis. PMID- 26486523 TI - [Diffusion of hospital health outcomes]. PMID- 26486522 TI - Auricular vagal nerve stimulation ameliorates burn-induced gastric dysmotility via sympathetic-COX-2 pathways in rats. AB - BACKGROUND: Severe burn injury has been demonstrated to delay gastric emptying. The aim of this study was to investigate effects and cellular mechanisms of auricular electroacupuncture (AEA) at the acupoints innervated by the auricular branch of vagus nerve on burn-induced gastric dysmotility in rats. METHODS: Propranolol (beta-adrenoceptor antagonist) was injected intraperitoneally after the rats underwent burn injury. All experiments were performed 6 h following burn/sham burn injury. AEA was performed at bilateral auricular acupoints for 45 min. Electrocardiogram was recorded for 30 min. Plasma hormones were measured; cyclooxygenase (COX)-2 expressions in gastric tissue were measured using western blotting and real-time RT-PCR. KEY RESULTS: (i) Burn injury delayed gastric emptying (p = 0.006) and AEA increased gastric emptying by 49% (p = 0.045). (ii) Burn injury evoked a significant elevation in plasma noradrenaline, which was suppressed by AEA. (iii) Burn injury significantly increased protein and mRNA expressions of COX-2 in gastric fundus and antrum. AEA suppressed burn-induced increase in protein expressions, but not mRNA expressions of COX-2. CONCLUSIONS & INFERENCES: Burn injury delays gastric emptying by up-regulating COX-2 attributed to sympathetic overactivity. AEA improves burn-induced delay in gastric emptying, possibly mediated via the sympathetic-COX-2 pathway. PMID- 26486524 TI - [Disclosure of sources of funding in biomedical journals. Descriptive study of four Spanish publications]. AB - BACKGROUND: The source of research funding can result in bias, and its disclosure is essential in the publication of results. The aim of the study is to identify the frequency and type of sources of funding in the articles published by four Spanish biomedical journals published in Spanish. MATERIAL AND METHODS: The frequency and type of financial disclosures in the articles published during 2012 in the ordinary numbers of Atencion Primaria, Medicina Clinica, Revista Clinica Espanola and Revista Espanola de Cardiologia were analyzed. Articles described as "Editorial", "Original article", "Consensus Document", "Review" and "Special Article" were considered. It was decided in each case whether or not the article included any funding disclosure and the type of the declared funding (public or private). RESULTS: Four hundred and twelve publications were analyzed. In 32.5% there was disclosure of funding: 38% in Atencion Primaria, 27% in Medicina Clinica, 15% in Revista Clinica Espanola and 45% in Revista Espanola de Cardiologia. By type of articles, 47% of original articles, 44% of consensus documents, 21% of reviews, 14% of special articles and 8% of editorials had a funding source. In 51.5% of the cases, funding was exclusively public, in 36.5% exclusively private and in 10% mixed. CONCLUSIONS: There is considerable variability in the disclosure of funding sources in articles appearing in these four Spanish biomedical journals. It would be necessary to improve the disclosure requirements of sources of funding, making them uniform, clear and transparent. PMID- 26486525 TI - [Quality of life in patients diagnosed of prostate cancer treated with continuous androgen deprivation therapy vs. intermittent therapy]. AB - BACKGROUND: Treatment with intermittent androgen deprivation (IAD) seeks to improve the quality of life of patients with prosta-te cancer, with the same oncologic results as continuous androgen deprivation (CAD). The aim of this paper is to compare, using the CAVIPRES questionnaire, the quality of life between two groups of patients, one treated with CAD and the other with IAD. MATERIALS AND METHODS: A longitudinal study was performed for 24 months involving 114 patients. After 6 months, patients were randomized to two treatment groups (49 patients in CAD and 51 patients in IAD), controlled at 6, 12 and 18 months from randomisation. The score of the items and the overall score of the CAVIPRES questionnaire between the two groups was compared and their variation over time was studied. RESULTS: Patients with IAD had a better overall score than patients with CAD (p=0.002). Of the 5 blocks of items into which the questionnaire was divided, the IAD group had a better score than CAD in "Psychological aspects" (p=0.009) and "Social and partner support" (p=0.008). At 18 months, IAD improved the overall quality of life of patients relative to the time of randomization (p=0.000), as well as the score for "Sexual Life" (p=0.000) and "Social and partner support" (p=0.002). CAD did not improve overall quality of life or the score for the different blocks throughout the study (p>0.05). CONCLUSIONS: IAD improves overall quality of life of patients at 18 months of stopping treatment. PMID- 26486526 TI - [Adverse events caused by activated charcoal in an emergency services survey]. AB - BACKGROUND: There are few studies in Spain on the use of activated charcoal (AC) in acute poisoning via the digestive tract, and more specifically on its protocol and adverse events following its administration. The aim of this article is to know the experience in the use of AC by doctors and nurses of the Spanish emergency services. METHOD: Survey developed using Google Docs to health professionals in emergency services. RESULTS: Three hundred and sixty-four questionnaires were received, 52% of them from doctors. Catheterization prior to the use of AC in 74.5% of patients was performed, and did not use a catheter in 13%. The application of AC was considered correct in 37.4%, and overall it was used in 92.4% of cases. The lateral safety position was used in 46.2%, antiemetics in 86.5% and isolation of the airway in case of coma (GCS<8) in 60%. The most described adverse events were vomiting of AC (61%), epixtasis when the catheter was positioned (51.1%), and its incorrect positioning (36%). Inhaling vomit occurred in 11.8% and inhaling carbon in 4.7%. Seven point one percent stated that the adverse events had been life-threatening to patients. No relation was found between the protocol and serious or life-threatening adverse events, nor between these latter and clinical safety measures. CONCLUSIONS: The incidence of adverse events according to the information provided by professionals in this survey of clinical practice might be higher than the incidence found in the literature. PMID- 26486527 TI - [Communication skills: a preventive factor in Burnout syndrome in health professionals]. AB - BACKGROUND: Health professionals are a group that suffers high levels of job stress and burnout. The aim of this study is to demonstrate empirically that the healthcare count on communication skills helps prevent Burnout Syndrome. METHOD: An observational, analytical, cross-sectional study was proposed, involving a sample of 927 health professionals (197 doctors, 450 nurses and 280 auxiliary nurses). Participants completed questionnaires measuring communication skills in health care (EHC-PS) and the Maslach Burnout Inventory Human Services Survey (MBI HSS). RESULTS: A negative and statistically significant correlation between the different dimensions of communication skills and emotional exhaustion and depersonalization dimensions of burnout was obtained. On the other hand, a positive and statistically significant correlation between the dimensions of communication skills and the personal accomplishment dimension of burnout was observed. CONCLUSIONS: It was shown that the communication skills of health professionals provide protection from and cushion Burnout Syndrome. PMID- 26486528 TI - [Validity and reliability of the Spanish version of the oral assessment guide (OAG) in cancer patients]. AB - BACKGROUND: The Oral Assessment Guide (OAG) is a widely used tool designed for evaluating problems of oral mucous in cancer patients, but it has not been validated in Spanish. The aim of this work is to translate and validate into Spanish the scale of the OAG designed by Eilers. METHOD: The translation process was carried out using the method of back-translation by bilingual translators. The study was carried out with cancer patients, both outpatient and inpatients, of the Hematology/Oncology Department and with oncology nurses. The following psychometric properties of the OAG were evaluated: internal consistency, concurrent validity with WHO's mucositis scale, interjudge agreement between two different nurses. The perception of patients and nurses on the use of the OAG was also assessed. RESULTS: An adequate Spanish version of the OAG was obtained. All the participants (n=40) completed the study. Internal consistency measured by Cronbach's alpha was 0.71 and interjudge agreement obtained a moderate to good Kappa index in the majority of items (k=0.4-0.81), except in "tongue and gums" (k=0.33-0.37). Concurrent validity with WHO mucositis scale was acceptable (r=0.458). All the nurses (n=6) considered that the scale was easy to understand and useful in clinical practice. The patients said that oral evaluation with the scale did not cause them discomfort. CONCLUSIONS: The Spanish version of the OAG is a valid and reliable instrument in cancer patients. It is a scale that is easy to use in clinical practice and is well accepted by patients. PMID- 26486529 TI - [Determinants and economic cost of patient absenteeism in outpatient departments of the Costa del Sol Health Agency]. AB - BACKGROUND: To identify factors related to the people, the process and the context that determine patient compliance with their appointments in the ambulatory outpatient services in the Costa del Sol Health Care Agency; and to obtain the profile of patients who fail to keep their appointments, the reasons for this failure and an estimation of its economic cost. METHODS: Observational multicenter case-control study, through a survey carried out on patients with an appointment in the ambulatory outpatient services during 2013 and 2014, and analysis of the cost per appointment. RESULTS: In total, 882 patients participated in the study (294 cases and 588 controls). The main reasons for missing an appointment were forgetting about it (29, 6%; n=87), and failure in communication (16%; n=47). A shorter time period before the appointment and older age were significantly associated with fewer absences, as well as the fact of having attended more consultations in the past year. The economic cost was more than 3 million euros for a non-attendance rate of 13.8%. CONCLUSIONS: Young patients who usually do not visit outpatient clinics are at greatest risk of absence from scheduled appointments in our health area. The main reasons for absenteeism are preventable and interventions such as improved communication procedures or appointment reminder systems could be beneficial. PMID- 26486530 TI - [The reputation of Spanish hospitals. Basis for developing a reputation index of hospitals]. AB - BACKGROUND: The reputation of the health centers is associated with: greater user preference in obtaining their services, better clinical outcomes and higher care quality and potential for attracting talented professionals. Reputation was evaluated using indexes and scales. The aim of this study is to analyze the attributes that should be gathered in a reputation index for Spanish hospitals. MATERIAL AND METHODS: Study based on qualitative techniques of consensus (nominal group technique + Delphi technique). RESULTS: Four dimensions were identified that form the reputation index: care quality, ethical behavior, credibility/confidence and biomedical innovation and research, which in turn are subdivided into 12 components in total. CONCLUSIONS: In building a reputation index consideration must be given to the combination of objective data (e.g. quality and safety outcomes) with other data that are subjective in nature (e.g., patient satisfaction). Future studies should go online to validate the reference standards in building a reputation index for hospitals. PMID- 26486531 TI - [Readability and internet accessibility of informative documents for spinal cord injury patients in Spanish]. AB - BACKGROUND: Patients with spinal cord injuries and their carers have access to leaflets on Internet that they can use as educational material to complement traditional forms of education. The aim of this study is to evaluate the readability of informative documents in Spanish, obtained from Internet and aimed at patients with spinal cord injuries. METHODS: A search was made with the Google search engine using the following key words: recommendation, advice, guide, manual, self-care, education and information, adding spinal cord injury, paraplegia and tetraplegia to each of the terms. We analyzed the first 50 results of each search. The readability of the leaflets was studied with the Flesch Szigriszt index and the INFLESZ scale, both available on the INFLESZ program. Also indicated were year of publication, country and number of authors of the documents obtained. RESULTS: We obtained 16 documents, developed between 2001 and 2011. Readability oscillated between 43.34 (some-what difficult) and 62 (normal), with an average value of 51.56 (somewhat difficult). Only 4 pamphlets (25%) showed a Flesch-Szigriszt index of >= 55 (normal). There was no difference in readability by year, authors or country of publication. CONCLUSIONS: The readability of 75% of the documents studied was "somewhat difficult" according to the INFLESZ scale. These results coincide with previous studies, in both Spanish and English. If the readability of this type of documents is improved, it will be easier to achieve their educational goal. PMID- 26486532 TI - Cause of death in hospitalized patients with laboratory-confirmed influenza. AB - BACKGROUND: We analyzed the underlying cause of death recorded in hospitalized patients with laboratory-confirmed influenza. METHODS: The present study included all patients with a laboratory-confirmed diagnosis of influenza during the influenza seasons 2009-2010 to 2013-2014 who were attended to in hospital and died. Their underlying cause of death according to the International Classification of Diseases 10th Revision was obtained from the Navarre Mortality Registry. RESULTS: Among 49 patients studied, the underlying causes of death were 35% influenza, 4% pneumonia, 14% other respiratory diseases, 10% circulatory disease and 37% other causes. CONCLUSIONS: Non-cardiorespiratory causes accounted for a third of deaths in patients with confirmed influenza, thus all-cause mortality should be considered in estimating the full burden of influenza mortality. PMID- 26486533 TI - [Influence of prehospital response times in the survival of trauma patients in Navarre]. AB - The relation between response times and mortality of polytrauma patients in the so-called "golden hour" continues to be a subject of debate. The purpose of this study is to determine the variables related to mortality in these patients and the influence of response times of the Emergency Medical Services in this mortality. To this end, the data in the "Major Trauma of Navarre" Register (retrospective cohort of polytrauma patients attended to by the Navarre Health Service) were analyzed for the four year period between 2010 and 2013. Of the 217 trauma cases available for the analysis, 42 (19%) died. No significant association was found in the multi-variate analysis between the different response times and mortality: arrival at the scene (odds ratio (OR) 1.0; 95% confidence interval (CI) from 0.99 to 1.01), in the scenario (OR 1.00; 95% CI from 0.98 to 1.02) and total time (OR 1.00; 95% CI from 0.99 to 1.01). The variables that influenced mortality are patient age and severity of injuries measured by the prehospital Triage-Revised Trauma Score (T-RTS) and the New Injury Severity Score (NISS). The mortality of polytrauma patients attended to by the emergency system in our region is influenced by age and by the intensity of the aggression suffered, determined by the prehospital T-RTS and by the NISS. The response times of the hospital do not have a significant influence. PMID- 26486534 TI - [Dendritic cells in cancer immunotherapy]. AB - Since the beginning of the 20th century, biomedical scientists have tried to take advantage of the natural anti-cancer activities of the immune system. However, all the scientific and medical efforts dedicated to this have not resulted in the expected success. In fact, classical antineoplastic treatments such as surgery, radio and chemotherapy are still first line treatments. Even so, there is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anti-cancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen presenting cells such as DC. Although there are a number of strategies to strengthen antigen presentation by DC, anti-cancer immunotherapy is not as effective as we would expect according to preclinical data accumulated in recent decades. We do not aim to make an exhaustive review of DC immunotherapy here, which is an extensive research subject already dealt with in many specialised reviews. Instead, we present the experimental approaches undertaken by our group over the last decade, by modifying DC to improve their anti-tumour capacities. PMID- 26486535 TI - [Guidelines for cochlear implant indication in Navarre]. AB - Cochlear implants are indicated in severe to profound hearing loss with no benefit with hearing aids. Since the beginning of cochlear implants 30 years ago, auditory outcomes have been improving due to changes introduced in differ-ent areas: electrode design, strategy, surgical technique... Given good results within this period of time, cochlear implant indication has varied too. The aim of this paper is to show an update on indication criteria for cochlear implantation in Navarre, for application in daily practice. The indications are established by consensus amongst the hospitals of the region. PMID- 26486536 TI - [Recovery from total knee arthroplasty through continuous passive motion]. AB - The purpose of this study was to know the effects of continuous passive mobilization in patients who underwent total knee arthroplasty. A search strategy was developed to retrieve all clinical trials, written in English and/or Spanish, published in the electronic search databases PubMed, Cochrane Library Plus, Dialnet, CSIC and PEDro. The inclusion criteria were: clinical trials published from January 2000 until November 2014 in English or Spanish. Out of 537 clinical trials that were potentially relevant, a total of 12 were included in this review. The evaluation of 1,153 patients shows that there is no significant difference in improving the range of the joint, pain, balance, motion, healing and hospital stay using continuous passive mobilization against the regular physiotherapy treatment for total knee arthroplasty. The application of continuous passive mobilization in the long-term does not provide any benefit in terms of the breadth of the range of the joint, pain and improvement of standing and motion in comparison with conventional postoperative physiotherapy treatment in total knee arthroplasty. In the short term an improvement is obtained in the range of joint motion in knee flexion. PMID- 26486537 TI - [Gender differences in the treatment and outcome of patients with acute coronary syndrome]. PMID- 26486538 TI - [Author's reply. Gender differences in the treatment and outcome of patients with acute coronary syndrome]. PMID- 26486539 TI - [Programs of type 1 diabetes education and incidence of type 1 diabetes in Navarre]. PMID- 26486540 TI - [Author's reply. Programs of type 1 diabetes education and incidence of type 1 diabetes in Navarre]. PMID- 26486541 TI - [Allergology in the public health service of the Community of Madrid]. PMID- 26486542 TI - [The spirometry in pre-school children]. PMID- 26486543 TI - [Slipping rib syndrome. An aggressive but effective treatment]. AB - Slipping rib syndrome (SRS) is an unusual cause of recurrent chest or abdominal pain in children. The diagnosis is elusive, including gastroenterological, cardiac, respiratory, infectious and chest or abdominal muscular pathologies. Two paediatric patients were diagnosed with SRS, both of them were female teenagers with a similar clinical pattern: crippling unilateral chest pain without a traumatic event. On physical examination, all patients had reproducible pain with the "hooking maneuver". Surgical excision of the costal cartilages was done, preserving the perichondrium. No complications were reported. In both cases we achieve an excellent outcome after one and four years of follow-up, resolving the symptoms completely. The surgical excision of the costal cartilages seems to be an aggressive option but with an excellent outcome. A minimum invasive approach could be a better option in the future. PMID- 26486544 TI - [Epithelioid angiosarcoma of the gallbladder. Case report and review of the literature]. AB - Angiosarcoma of the gallbladder is an infrequent pathology but has a high morbidity and mortality. There are only 10 references in the international literature. We present a case treated in our center and we review the cases published since 1956. An 81 year-old male patient with abdominal pain, asthenia and dyspnea. Analytically anemia and leukocytosis. Exploration found a distended abdomen, right hypochondrium pain, with defense. Abdominal echography and a CT were requested with a diagnosis of acute cholecystitis and he was admitted for antibiotic treatment. The patient did not evolve favorably and was subjected to emergency surgery, which found a haemoperitoneum and a gallbladder with a tumoral appearance that could not be totally extirpated. He died 20 days after the operation. The report from pathological anatomy was compatible with epithelioid angiosarcoma of the biliary gallbladder. Gallbladder angiosarcoma is a neoplasia with a bad prognosis, whose clinical presentation can be mistaken for acute cholecystitis. Improving the prognosis of this disease involves carrying out early diagnosis and surgical treatment. PMID- 26486545 TI - [Microvascular pulmonary tumor embolism in a patient with urothelial tumor]. AB - Pulmonary tumor embolisms (PTE) are an infrequent cause of dyspnea in oncological patients. The majority are diagnosed in patients with advanced tumors, above all localized in the breast, lung or stomach. There are few published cases involving patients with urothelial tumors. We present the case of a 69 year-old male, without a previous diagnosis of cancer, who was admitted due to subacute dyspnea, with clinical suspicion of pulmonary thromboembolism (PT). The patient died on the fifth day of admission. The autopsy confirmed the existence of a tumor in the left renal pelvis with hepatic and lymphoganglionary metastasis and an extensive microvascular pulmonary embolism that affected a large part of the capillaries and medium-caliber blood vessels of both lungs. PTE were considered responsible for the progressive respiratory failure and as the final cause of death. The most frequent clinical presentation of PTE is dyspnea. They are often mistaken for PT and diagnosis is not easy. Their prognosis is very bad, with extremely high mortality and confirmation is usually post-mortem. PMID- 26486546 TI - [Small bowel intussusception in the adult caused by ileal submucous lipoma]. AB - We present the case of a 68 year-old male patient with secondary intestinal intussuspection due to a submucous li-poma of the ileum. This is a rare entity in adults and is usually due to an organic lesion. The clinical manifestation is characterized by vomiting, abdominal pain and melenas. In our case the patient, following a colonoscopy and an abdominal CT-scan, was subjected to an extended resection of caecum and terminal ilium. At present, the precision of the etiological diagnosis of intussuspections has increased thanks to the development of image tests, like CT-scan. Early surgical treatment is recommended, without intraoperative deintussuspection given the high risk of presenting a malign or ischemic lesion in the adult. PMID- 26486547 TI - Delayed renal dysfunction and flash pulmonary edema post endovascular abdominal aneurysm repair. AB - After endovascular aortic repair (EVAR), the deterioration in long-term renal function is probably multifactorial. Preoperative renal failure is an independent risk factor. Postoperative renal dysfunction can be associated with inadvertent renal artery occlusion, renal artery complications as stenosis, plaque dislodgement, or dissection. Ischemic nephropathy can accelerate hypertension and circulatory congestion. We report a case of coverage of the renal arteries symptomatic with flash pulmonary edema and renal failure 15 months after EVAR, suggesting a delayed endograft migration. The patient had complete resolution of symptoms and renal function after renal artery stenting with placement between endograft and aneurysm to the left renal artery. PMID- 26486548 TI - Migration of a Metallic Foreign Body Into the Heart. PMID- 26486549 TI - A versatile and highly efficient post-functionalization method for grafting organic molecules onto Anderson-type polyoxometalates. AB - A new azide functionalized Anderson polyoxometalate was synthesized, fully characterized and subsequently used as a building block for further POM post functionalization with organic compounds through a copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Optimization of the reaction conditions led to an efficient, fast, convenient and versatile POM coupling method. PMID- 26486550 TI - Acute ischemic stroke and transient ischemic attack: A costly business and a strategy to reduce costs (the "Time-Zero" plan). AB - Managed health care systems and other insurers in the United States are scrutinizing cost-containment measures for acute stroke care. Stroke remains a costly inpatient neurologic disease. Diagnostic technology for stroke has become extremely sophisticated, and the clinician must choose from a broad range of expensive tests. Conflict may arise as stroke patients and caregivers expect a full range of diagnostic tests, whereas primary care physicians strive for the most efficient diagnostic battery and cost containment. The neurologic specialist may find himself or herself caught in the middle of this conflict, frustrated by the apparent failure of the system to satisfy the expectations of providing the highest quality of patient care within cost-containment needs. The "Time-Zero" proposal is a plan to capture both high-quality stroke care and cost containment because common sense must prevail in these times of medical economic uncertainty. Physicians and stroke diagnostic providers must modify their behavior and maintain a flexible approach regarding availability of diagnostic services, whereas insurers must be willing to maintain quality standards to achieve rapid stroke diagnosis and treatment. There is a common ground where patients, physicians, and insurers can 'meet to tackle this challenge. The cost-containment "bottom line" will not mysteriously disappear; thus, we must have a rational plan for stroke diagnosis and treatment that lessens patient, physician, and insurer dissatisfaction. PMID- 26486551 TI - The significance of basal ganglia infarction. AB - The striatum is a selectively vulnerable region of brain in animal models of ischemic stroke. We performed cerebral blood flow with single-photon emission computed tomography (SPECT) on six patients with focal basal ganglia infarction and five patients with hemispheric infarction to determine whether the striatum is selectively vulnerable to ischemia in human stroke. SPECT was performed with a Toshiba model 602A digital scintillation camera using 30 mCi (99m)Tc Ceretec. One hour after injection, scans were performed at 5 degrees intervals to a complete 360 degrees over 40 min. Data were processed into sagittal, axial, and coronal views. Groups were compared by Fischer's exact test. Five of the six patients with basal ganglia infarction had diffuse hemispheric ischemia. All five patients with focal hemispheric infarction had ischemia confined to that region (p = 0.01). Focal infarction of the striatum occurs in diffuse cerebral ischemia because the striatum is a selectively vulnerable brain region. PMID- 26486552 TI - Physician attitudes toward treatment options for cerebrovascular disease. AB - One-hundred physicians older than 50 and 100 physicians younger than 50 were surveyed concerning treatment preferences for patients with transient ischemic attacks (TIAs) or completed stroke. These attitudes were compared to cardiovascular disease prevention strategies for patients with angina pectoris and myocardial infarction. Physicians younger than 50 were therapeutically aggressive for cerebrovascular and cardiovascular disease; physicians older than 50 were aggressive for cardiovascular disease but therapeutically nihilistic for cerebrovascular disease. Physicians younger than 50 were more likely to be aggressive for TIA than for completed stroke patients, and these physicians were more likely to utilize ticlopidine and oral anticoagulants for both TIA and completed stroke patients. PMID- 26486553 TI - Paradoxical embolism after cardiac catheterization. AB - Paradoxical embolism is seen in fewer than 2% of all arterial emboli. It occurs most often through a patent foramen ovale (PFO), which is present in up to one third of patients with strokes of unknown etiology. We report a 69-year-old woman in whom a thrombus traveled from the lower extremity venous system to her right middle cerebral artery through an unsuspected atrial septal defect. Following right femoral artery catheterization for coronary angiography, she developed a femoral artery pseudoaneurysm and groin hematoma causing compression of the right femoral vein and venous thrombosis. Before she could undergo surgical evacuation and repair, she developed a right brain stroke with cognitive deficits, left field cut, left hemiparesis, and sensory loss. Transthoracic echocardiography with bubble contrast showed a small PFO with right-to-left interatrial shunting. A Greenfield filter was placed in the inferior vena cava, and the patient was anticoagulated before she underwent inpatient rehabilitation. This case illustrates the importance of considering paradoxical emboli in unexplained strokes. The literature is reviewed, and treatment and prevention of paradoxical emboli are discussed. PMID- 26486554 TI - Effect of intra-arterial papaverine on cerebral blood flow in vasospasm after subarachnoid hemorrhage: A study using single-photon emission computed tomography. AB - Cerebral vasospasm is an important cause of delayed stroke after subarachnoid hemorrhage. Single-photon emission computed tomography (SPECT) of regional cerebral blood flow with (99m)Tc-hexamethyl propylenenamine oxime (HMPAO) was performed before and after intra-arterial papaverine treatment in 10 patients with symptomatic cerebral vasospasm. Two patients were treated twice. The ultimate clinical outcome was improved due to papaverine in 5 of the 10 patients. SPECT imaging correlated with clinical course in 10 of 12 treatments. One of the discordant cases had significant residual mesial frontal lobe perfusion defects on SPECT despite improvement in blood flow in the lateral aspects of the frontal lobes and did not improve clinically. The other was stable but required definitive treatment with balloon angioplasty on the following day before clinical improvement was noted. Papaverine has effectiveness in pharmacologically dilating constricted cerebral arteries and is preferred for distal vasospasm and in vessels that may be difficult to dilate via balloon angioplasty. Technetium 99m-HMPAO SPECT imaging detects cerebral perfusion deficits associated with vasospasm and monitors the effect of intra-arterial papaverine on regional cerebral blood flow. PMID- 26486555 TI - Magnetic resonance angiography in the diagnosis of deep cerebral venous thrombosis. AB - Given the nonspecific and conflicting "indirect" signs and rare occurrence of the true "direct" signs on computed tomography (CT) and magnetic resonance imaging (MRI), conventional angiography has been the "gold standard" in the diagnosis of cerebral venous thrombosis. Visualization of the deep venous system by magnetic resonance angiography (MRA) suggests this modality may accurately demonstrate thrombosis at this level. We present a 34-year-old Down syndrome patient with deep cerebral venous thrombosis demonstrated by MRA who was initially misdiagnosed as a bithalamic glioma due to the similarity in the imaging characteristics of the two conditions. No direct evidence of venous thrombosis was present on CT or MRI. MRA was the sole noninvasive imaging modality to "directly" demonstrate venous thrombosis and is suggested in the evaluation of unexplained or atypical cerebral events that may represent deep cerebral venous thrombosis. PMID- 26486556 TI - Predicting discharge functional status and rehabilitation efficiency from preadmission functional assessments. AB - Various indicators have been used to predict functional change and outcome in stroke rehabilitation. One previous study indicated that functional assessments performed prior to rehabilitation admission correlated well with functional status at discharge and also were indicative of rehabilitation efficiency scores. The present study attempted to replicate these findings in a study of 14 additional stroke patients admitted to an inpatient unit; data collection on additional patients is ongoing. Patients' weekly Functional Independence Measure (FIM) scores were assessed, together with their preadmission FIM score (PFM) and other clinical data. As in the previous study, PFM scores correlated well with functional ratings made by the team following admission (r = 0.78), and with discharge FIM scores (r = 0.68). Patients with PFM scores of 30 or less had much lower rehabilitation efficiency ratios (0.62) than those with PFM scores greater than 30 (0.97). Finally, in a multiple regression equation with discharge functional status as the dependent variable, PFM scores accounted for almost as much of the variance (47%) as FIM scores obtained during the first week of admission (63%). Overall, the results obtained were remarkably consistent with the previous study cited. The current results imply that the use of preadmission functional ratings may be a valid and useful way to predict functional change and efficiency of inpatient rehabilitation admission. PMID- 26486557 TI - Low yield of clinically significant transesophageal echocardiographic findings in patients with lacunar stroke. AB - Transesophageal echocardiography (TEE) is a sensitive technique for the detection of cardioembolic sources of stroke in patients with cryptogenic stroke. However, the yield of clinically significant TEE-detected abnormalities in other stroke subtypes such as lacunar stroke is unknown. We prospectively followed 145 consecutive stroke patients, including 26 patients with typical lacunar syndromes, to determine the relative risk of recurrent brain ischemia associated with TEE findings. The yield of TEE in patients with lacunar stroke syndromes was extremely low, except for a very high rate of atrial septal aneurysm (ASA). Although ASA was associated with a high risk of recurrent stroke or transient ischemic attack in patients with nonlacunar stroke, ASA was not associated with stroke recurrence in patients with lacunar stroke (p = 0.02, Cox's proportional hazard regression model). We conclude that TEE is unlikely to provide clinically relevant information in patients with typical lacunar syndromes. PMID- 26486558 TI - Retrospective analysis of aspirin and ticlopidine in preventing recurrent stroke following an initial lacunar infarct. AB - Of 73 patients with initial lacunar stroke subsequently treated with aspirin, 13 (18%) developed recurrent stroke (11 lacunar infarcts and 2 nonlacunar infarcts), and 4 (5%) died within 1 year. Of the aspirin-treated lacunar infarct patients, 58 received 325 mg or lower-dose aspirin, and 15 received 600-1,300 mg of aspirin. Thirteen aspirin-treated patients who developed recurrent ischemic stroke received 80 mg or 325 mg of aspirin, whereas recurrent stroke did not occur in 15 patients treated with 600-1,300 mg of aspirin daily. Of 25 patients with lacunar stroke who were subsequently treated with 250 mg of ticlopidine twice daily, 1 patient (4%) developed recurrent lacunar infarct, and none died within 1 year. Of 10 patients who had an initial lacunar stroke and subsequently received no antiplatelet medication, 4 (40%) developed recurrent lacunar stroke, and 1 (10%) died within 1 year. PMID- 26486559 TI - Upper motor neuron signs in acute stroke: Prevalence, interobserver reliability, and timing of initial examination. AB - There is little documentation in the neurologic literature of the prevalence or reliability of upper motor neuron (UMN) signs in acute stroke. This knowledge is important for those conducting neurologic surveys and clinical trials among stroke patients because it may aid in the design of data collection instruments. One-hundred stroke patients admitted to the Columbia-Presbyterian Medical Center Neurovascular Unit were independently examined by two neurologists who were blinded to the patient's clinical history and neuroimaging studies. Kappa values ranges from -0.09 to 0.57, and concordance rates ranged from 0.55 to 1.0. The prevalence of 13 UMN signs varied considerably (3-94%). More prevalent UMN signs such as pronator drift, diminished fine coordination, hyperreflexia, Babinski and Chaddock signs were also reasonably reliable. There were differences between the early-acute and late-acute motor stroke groups; however, these were not significant. Prevalence, reliability, and, possibly, the time of initial examination were inter-related. The clinical utility of each UMN sign is a function of three inter-related factors: prevalence, reliability, and time of examination. Hence, the time of initial neurologic assessment may have some impact on the prevalence and reliability of UMN signs. PMID- 26486560 TI - Carotid endarterectomy for patients with asymptomatic internal carotid artery stenosis. AB - The investigators of the Asymptomatic Carotid Atherosclerosis Study are reporting the interim results of a randomized controlled clinical trial of carotid endarterectomy in patients who have asymptomatic carotid stenosis of greater than 60% reduction in diameter. In addition to aspirin and aggressive management of modifiable risk factors, one-half of the patients were randomly assigned to receive surgery after angiograhic confirmation of the lesion. Carotid endarterectomy is beneficial with a statistically significant absolute reduction of 5.8% in the risk of the primary end point of stroke within 5 years and a relative risk reduction of 55%. As a consequence of the trial reaching statistical significance in favor of endarterectomy, and on the recommendation of the study's data monitoring committee, physicians participating in the study were immediately notified and advised to reevaluate patients who did not receive surgery. It is important to note that the success of the operation depends on medical centers and surgeons who have a documented perioperative morbidity and mortality of less than 3%, careful selection of patients, and postoperative management of modifiable risk factors. PMID- 26486561 TI - Ionising radiation in the workplace. PMID- 26486562 TI - Atom precise platinum-thiol crowns. AB - Ligand stabilized water soluble Pt nanoclusters were synthesized and characterized through electrospray ionization mass spectrometry. Glutathione was used as the ligand, and Pt5(SG)10, and Pt6(SG)12 clusters were synthesized. Theoretical investigations found that these clusters do not possess a metal core, but rather are most stable in a ring structure. The clusters are stabilized through the thiol ligands forming a square planar structure around each Pt atom to form a ring. The structural elucidation was confirmed through UV/Vis and IR spectroscopy. PMID- 26486565 TI - Microplastic Pollution in Table Salts from China. AB - Microplastics have been found in seas all over the world. We hypothesize that sea salts might contain microplastics, because they are directly supplied by seawater. To test our hypothesis, we collected 15 brands of sea salts, lake salts, and rock/well salts from supermarkets throughout China. The microplastics content was 550-681 particles/kg in sea salts, 43-364 particles/kg in lake salts, and 7-204 particles/kg in rock/well salts. In sea salts, fragments and fibers were the prevalent types of particles compared with pellets and sheets. Microplastics measuring less than 200 MUm represented the majority of the particles, accounting for 55% of the total microplastics, and the most common microplastics were polyethylene terephthalate, followed by polyethylene and cellophane in sea salts. The abundance of microplastics in sea salts was significantly higher than that in lake salts and rock/well salts. This result indicates that sea products, such as sea salts, are contaminated by microplastics. To the best of our knowledge, this is the first report on microplastic pollution in abiotic sea products. PMID- 26486566 TI - Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis. AB - Ligand efficiency has proven to be a valuable concept for optimization of leads in the early stages of drug design. Taking this one step further, group efficiency (GE) evaluates the binding efficiency of each appendage of a molecule, further fine-tuning the drug design process. Here, GE analysis is used to systematically improve the potency of inhibitors of Mycobacterium tuberculosis pantothenate synthetase, an important target in tuberculosis therapy. Binding efficiencies were found to be distributed unevenly within a lead molecule derived using a fragment-based approach. Substitution of the less efficient parts of the molecule allowed systematic development of more potent compounds. This method of dissecting and analyzing different groups within a molecule offers a rational and general way of carrying out lead optimization, with potential broad application within drug discovery. PMID- 26486567 TI - Expression of p53 predicts risk of prevalent and incident advanced neoplasia in patients with Barrett's esophagus and epithelial changes indefinite for dysplasia. AB - BACKGROUND AND AIMS: Patients with Barrett's esophagus (BE) are at an increased risk for developing esophageal adenocarcinoma (EAC); thus they may undergo regular endoscopic surveillance. If epithelial changes cannot be unequivocally classified as negative or positive for dysplasia, a diagnosis of indefinite for dysplasia (IND) is recommended. Several biomarkers have been proposed as markers or predictors of neoplasia in the general BE population; however, their significance is not clear in patients with BE-IND. We therefore performed a retrospective study to determine whether expression of these biomarkers was associated with the development of neoplasia in BE-IND patients. METHODS: We searched our archives to identify all cases of BE-IND diagnosed between January 1992 and December 2007. Immunohistochemical analyses were used to semi-quantify the expression of p53, alpha-methylacyl-CoA racemase (AMACR), and cyclin D1. A univariate analysis was used to identify predictors for prevalent and incident neoplasia and advanced neoplasia. RESULTS: Among the 103 patients with an index diagnosis of BE-IND who were included in this study, 81 (78.6%) underwent a follow-up biopsy within 12 months of diagnosis; 10 (12.3%) had neoplasia, including four (4.9%) with advanced neoplasia. Among 79 patients without prevalent neoplasia who underwent more than 1 year of follow-up, 18 (22.8%) had developed neoplasia, including four (5.1%) with advanced neoplasia. AMACR and cyclin D1 expression levels were not correlated with prevalent or incident neoplasia; however, high p53 expression (>5%) was associated with prevalent advanced neoplasia on surveillance biopsy (P = 0.04) and with an increased risk of progression to advanced neoplasia (HR = 12; P = 0.03). CONCLUSION: In this study, p53 expression was found to be predictive of prevalent advanced neoplasia and progression to advanced neoplasia in patients with BE-IND. PMID- 26486569 TI - Catalytic Intramolecular Ketone Alkylation with Olefins by Dual Activation. AB - Two complementary methods for catalytic intramolecular ketone alkylation reactions with unactivated olefins, resulting in Conia-ene-type reactions, are reported. The transformations are enabled by dual activation of both the ketone and the olefin and are atom-economical as stoichiometric oxidants or reductants are not required. Assisted by Kool's aniline catalyst, the reaction conditions can be both pH- and redox-neutral. A broad range of functional groups are thus tolerated. Whereas the rhodium catalysts are effective for the formation of five membered rings, a ruthenium-based system that affords the six-membered ring products was also developed. PMID- 26486572 TI - Editorial: Athrogenic embolism causing cerebral infarction. PMID- 26486570 TI - Integrative metabonomics as potential method for diagnosis of thyroid malignancy. AB - Thyroid nodules can be classified into benign and malignant tumors. However, distinguishing between these two types of tumors can be challenging in clinics. Since malignant nodules require surgical intervention whereas asymptomatic benign tumors do not, there is an urgent need for new techniques that enable accurate diagnosis of malignant thyroid nodules. Here, we used (1)H NMR spectroscopy coupled with pattern recognition techniques to analyze the metabonomes of thyroid tissues and their extracts from thyroid lesion patients (n = 53) and their adjacent healthy thyroid tissues (n = 46). We also measured fatty acid compositions using GC-FID/MS techniques as complementary information. We demonstrate that thyroid lesion tissues can be clearly distinguishable from healthy tissues, and malignant tumors can also be distinguished from the benign tumors based on the metabolic profiles, both with high sensitivity and specificity. In addition, we show that thyroid lesions are accompanied with disturbances of multiple metabolic pathways, including alterations in energy metabolism (glycolysis, lipid and TCA cycle), promotions in protein turnover, nucleotide biosynthesis as well as phosphatidylcholine biosynthesis. These findings provide essential information on the metabolic features of thyroid lesions and demonstrate that metabonomics technology can be potentially useful in the rapid and accurate preoperative diagnosis of malignant thyroid nodules. PMID- 26486568 TI - Advances in the management of Barrett's esophagus and early esophageal adenocarcinoma. AB - The incidence of esophageal adenocarcinoma (EAC) has markedly increased in the United States over the last few decades. Barrett's esophagus (BE) is the most significant known risk factor for this malignancy. Theoretically, screening and treating early BE should help prevent EAC but the exact incidence of BE and its progression to EAC is not entirely known and cost-effectiveness studies for Barrett's screening are lacking. Over the last few years, there have been major advances in our understanding of the epidemiology, pathogenesis and endoscopic management of BE. These developments focus on early recognition of advanced histology and endoscopic treatment of high-grade dysplasia. Advanced resection techniques now enable us to endoscopically treat early esophageal cancer. In this review, we will discuss these recent advances in diagnosis and treatment of Barrett's esophagus and early esophageal adenocarcinoma. PMID- 26486573 TI - The course of necrotizing arteritis: Imaging with real-time B-mode ultrasonography. AB - The morphology of the acute and chronic phases of necrotizing ateritis was demonstrated by real-time B-mode ultrasonography of the external carotid artery in a 52-year-old woman with documented arteritis. The morphological changes correlated with the clinical exacerbation and remission of the symptoms. PMID- 26486571 TI - Court applications for withdrawal of artificial nutrition and hydration from patients in a permanent vegetative state: family experiences. AB - Withdrawal of artificially delivered nutrition and hydration (ANH) from patients in a permanent vegetative state (PVS) requires judicial approval in England and Wales, even when families and healthcare professionals agree that withdrawal is in the patient's best interests. Part of the rationale underpinning the original recommendation for such court approval was the reassurance of patients' families, but there has been no research as to whether or not family members are reassured by the requirement for court proceedings or how they experience the process. The research reported here draws on in-depth narrative interviews with 10 family members (from five different families) of PVS patients who have been the subject of court proceedings for ANH-withdrawal. We analyse the empirical evidence to understand how family members perceive and experience the process of applying to the courts for ANH-withdrawal and consider the ethical and practice implications of our findings. Our analysis of family experience supports arguments grounded in economic and legal analysis that court approval should no longer be required. We conclude with some suggestions for how we might develop other more efficient, just and humane mechanisms for reviewing best interests decisions about ANH withdrawal from these patients. PMID- 26486574 TI - Occipital infarction: Carotid artery and cardiac findings. AB - Extracranial carotid artery disease can cause occipital infarction when the posterior cerebral artery originates from the carotid artery. To determine the prevalence of serious extracranial carotid artery stenosis (>=50%) and potential stroke mechanisms in patients with posterior cerebral artery territory occipital infarcts, we studied 24 consecutive patients with recent infarcts documented on computed tomography or magnetic resonance imaging. All patients presented with a homonymous visual field defect, and eight also had other cerebral dysfunctions. Eighteen patients had carotid studies: duplex ultrasound in 17 and arteriography in 1. Twenty patients had echocardiography. Presumed mechanisms of infarction were cardiac embolism in 10 patients (42%), hypercoagulability in 2 (8%), artery to-artery embolism in 1 (4%), migraine in 1 (4%), multiple potential mechanisms (cardiac embolism, hypercoagulability, and migraine) in 1 (4%), and undetermined in the remaining 9 (38%). None of the patients had extracranial carotid artery stenosis >=50%. Extracranial carotid artery disease appears to be a rare cause of occipital infarction. Our findings support conclusions reached in previous studies, that cardiac embolism is the principal cause of occipital infarction. PMID- 26486575 TI - Deep vein thrombosis in stroke patients: An overview. AB - Deep vein thrombosis (DVT) is prevalent both in the acute and the later phases of stroke. From previous studies using (125)I fibrinogen uptake, its peak incidence appears to occur during the first 10 days of stroke. Using venography and impedance plethymography, its prevalence is still high (between 30% and 40%) 1 1/2 to 6 months after stroke. The incidence of pulmonary embolism appear to diminish after the acute phase of stroke. Venous stasis is a widely accepted factor in the cause of DVT. More recently, venous injury as endothelial damage from excessive venodilation has been postulated. Increased venous size in hemiplegic limb has been reported. Further studies as to the role of decreased venous velocity and increased venous size and the effect of various modalities influencing these effects are needed. Routine screening of stroke patients appears indicated, but what protocol should be followed has yet to be determined. Selective screening by stratifying patients as to their clinical risk may be appropriate if found safe and cost-effective. Prophylactic treatment should be initiated in patients who are at increased risk of DVT. The prophylaxis of venous thrombosis in stroke patients remains uncertain. The use of low-molecular heparin may be a promising option if it is proven safe, efficacious, and causes less bleeding. Other prophylactic methods remain to be investigated. PMID- 26486576 TI - Role of leukocyte adhesion in clinical stroke. AB - Activated neutrophils appear to be directly involved in potentiating central nervous system ischemic injury. After initial endothelial adherence, neutrophils can produce capillary plugging with subsequent parenchymal infiltration and resulting cytotoxic neuronal injury. We used an in vitro leukocyte adherence assay to determine if adhesion is increased in acute stroke (within 72 h) or in patients at high risk for stroke (two or more risk factors) compared to matched controls. Neutrophils were isolated using density gradient centrifugation, and adherence to laminin or fibronectin was determined using a myeloperoxidase assay. The adhesion to laminin was significantly higher (p < 0.05) in the stroke group (23.6 +/- 4.3; n = 14) compared to controls (9.7 +/- 2.3; n = 12), with the risk group being intermediate (16.3 +/- 4.3; n = 14). Total WBC counts were significantly higher in the stroke 8.0 +/- 0.72 and risk 7.8 +/- 0.41 groups (p < 0.05), compared to controls 5.3 +/- 0.27. These data indicate that neutrophil adherence is increased in acute stroke and suggests that the total number of potentially adherent cells (total neutrophils times percent adherent cells) is greatly increased. PMID- 26486577 TI - Avicenna on the causes and signs of stroke. AB - Ancient and medieval theories on the causes and signs of stroke are presented in a translation of the relevant chapters of the Canon of Medicine by Avicenna (908 1037 A.D.), which was one of the main books studied by doctors for nearly 500 years. Recognised aetiologic factors included vascular occlusion, cerebral abscess, trauma, and repeated blood-letting. Motor and sensory deficits were described, as was the occasional association with facial palsy, respiratory difficulty, and coma. Warning symptoms such as severe headache and blackout were known, as was the poor prognosis associated with stroke that follows severe headache. Obesity as a risk factor was identified. PMID- 26486578 TI - Physostigmine improves cerebral blood flow in human focal cerebral ischemia. AB - The effect of intravenous physostigmine on cerebral perfusion of patients with cortical stroke was investigated using hexamethyl-propyleneamine oxime (HMPAO) single-photon emission computed tomography. Each patient was studied twice, afteran intravenous infusion of either 1 mg of physostigmine salicylate or saline. A marked increase in HMPAO activity was observed in all regions of post physostigmine scans when compared to the corresponding post-saline scans, except for the area of infarction and its mirror area in the contralateral hemisphere. In conclusion, physostigmine improves perfusion in the area of penumbra of patients with cortical infarction. PMID- 26486579 TI - A pilot study of the end point verification system in the asymptomatic carotid atherosclerosis study. AB - Ipsilateral transient ischemic attack (TIA) and cerebral infarction (CI) are primary end points of the Asymptomatic Carotid Atherosclerosis Study (ACAS), an ongoing multicenter, prospective, randomized trial designed to assess the effectiveness of carotid endarterectomy for patients with asymptomatic, hemodynamically significant stenosis of the internal or common carotid artery. The evanescent nature and absence of residual physical findings in TIAs pose special difficulties that contribute to interobserver disagreement. A standardized definition was established to be applied accurately and uniformly at the participating centers, including a questionnaire on six cardinal neurological symptoms, a computerized algorithm for characterization of events, and a verification system involving the independent evaluations of three reviewers. Modifications to the end point verification protocol after pilot testing in 115 patients with one or more symptoms enabled the algorithm to distinguish vascular from nonvascular events with a sensitivity of 83%, a specificity of 69%, positive predictive value of 71%, and negative predictive value of 82%. ACAS has developed a system for detecting and diagnosing end points. Using the algorithm as a guideline, consensus between two institutional physicians and a blinded independent reviewer must be made for an end point to be declared. If no consensus can be reached, a panel of two blinded external reviewers confers to arrive at an adjudication of the case. All potential end points are reviewed retrospectively by an end points committee for final adjudication. PMID- 26486580 TI - Cystic medial necrosis and internal carotid artery dissection in a marfan sibling: Partial expression of marfan syndrome. AB - Only rare cases of primary extra-aortic cystic medial necrosis and cervicocephalic arterial dissections have been reported in Marfan syndrome. We report an apparently traumatic dissection of the internal carotid artery in a woman whose brother had classic Marfan syndrome. The patient herself had no apparent manifestations of the syndrome, but she had cystic medial necrosis and significant loss of elastic fibers of the media. In Marfan syndrome, the penetrance of the gene can be quite variable, such that some members of the same family may show the full syndrome, whereas others reveal only the rudiments of the syndrome or, perhaps as exemplified by the case reported here, only manifest microscopic arterial abnormalities. PMID- 26486581 TI - Thalamic ependymoma presenting as recurrent subarachnoid hemorrhage. AB - We describe a 65-year-old woman who presented with recurrent subarachnoid hemorrhage due to a pathologically proven thalamic ependymoma. This is the first report of such a case. Cerebral angiography and initial imaging studies did not reveal a source of bleeding. Our case emphasizes the importance of periodically following patients with subarachnoid hemorrhage of undetermined etiology. PMID- 26486582 TI - Problems in identifying paradoxical cerebral embolism: Case report with discussion. AB - We report a case of paradoxical cerebral embolism in a 63-year-old man with newly diagnosed rectal cancer. The onset was heralded by nearly simultaneous pulmonary embolism and left hemiplegia. He was subsequently found to have deep venous thrombosis. Despite placement of a vena caval filter, a second cerebral infarction occurred in the opposite hemisphere. Air contrast transthoracic echocardiography was negative, but autopsy revealed a patent foramen ovale. Problems in the identification of paradoxical embolism are discussed. PMID- 26486583 TI - Reply. PMID- 26486584 TI - Controllable Growth of Perovskite Films by Room-Temperature Air Exposure for Efficient Planar Heterojunction Photovoltaic Cells. AB - A two-step solution processing approach has been established to grow void-free perovskite films for low-cost high-performance planar heterojunction photovoltaic devices. A high-temperature thermal annealing treatment was applied to drive the diffusion of CH3NH3I precursor molecules into a compact PbI2 layer to form perovskite films. However, thermal annealing for extended periods led to degraded device performance owing to the defects generated by decomposition of perovskite into PbI2. A controllable layer-by-layer spin-coating method was used to grow "bilayer" CH3NH3I/PbI2 films, and then drive the interdiffusion between PbI2 and CH3NH3I layers by a simple air exposure at room temperature for making well oriented, highly crystalline perovskite films without thermal annealing. This high degree of crystallinity resulted in a carrier diffusion length of ca. 800 nm and a high device efficiency of 15.6%, which is comparable to values reported for thermally annealed perovskite films. PMID- 26486586 TI - What causes cam deformity and femoroacetabular impingement: still too many questions to provide clear answers. PMID- 26486585 TI - Individualised physiotherapy as an adjunct to guideline-based advice for low back disorders in primary care: a randomised controlled trial. AB - BACKGROUND: Many patients with low-back disorders persisting beyond 6 weeks do not recover. This study investigates whether individualised physiotherapy plus guideline-based advice results in superior outcomes to advice alone in participants with low-back disorders. METHODS: This prospective parallel group multicentre randomised controlled trial was set in 16 primary care physiotherapy practices in Melbourne, Australia. Random assignment resulted in 156 participants receiving 10 sessions of physiotherapy that was individualised based on pathoanatomical, psychosocial and neurophysiological barriers to recovery combined with guideline-based advice, and 144 participants receiving 2 sessions of physiotherapist-delivered advice alone. Primary outcomes were activity limitation (Oswestry Disability Index) and numerical rating scales for back and leg pain at 5, 10, 26 and 52 weeks postbaseline. Analyses were by intention-to treat using linear mixed models. RESULTS: Between-group differences showed significant effects favouring individualised physiotherapy for back and leg pain at 10 weeks (back: 1.3, 95% CI 0.8 to 1.8; leg: 1.1, 95% CI 0.5 to 1.7) and 26 weeks (back: 0.9, 95% CI 0.4 to 1.4; leg: 1.0, 95% CI 0.4 to 1.6). Oswestry favoured individualised physiotherapy at 10 weeks (4.7; 95% CI 2.0 to 7.5), 26 weeks (5.4; 95% CI 2.6 to 8.2) and 52 weeks (4.3; 95% CI 1.4 to 7.1). Responder analysis at 52 weeks showed participants receiving individualised physiotherapy were more likely to improve by a clinically important amount of 50% from baseline for Oswestry (relative risk (RR=1.3) 1.5; 95% CI 1.2 to 1.8) and back pain (RR 1.3; 95% CI 1.2 to 1.8) than participants receiving advice alone. CONCLUSIONS: 10 sessions of individualised physiotherapy was more effective than 2 sessions of advice alone in participants with low-back disorders of >=6 weeks and <=6 months duration. Between-group changes were sustained at 12 months for activity limitation and 6 months for back and leg pain and were likely to be clinically significant. CLINICAL TRIAL REGISTRATION: ACTRN12609000834257. PMID- 26486588 TI - Support for presence during cardiopulmonary resuscitation if it is a child or relative, though views differ by gender. PMID- 26486589 TI - Fever during pregnancy linked to child motor development. PMID- 26486587 TI - Ablation of CD8alpha(+) dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice. AB - Clinical complications of atherosclerosis are almost exclusively linked to destabilization of the atherosclerotic plaque. Batf3-dependent dendritic cells specialize in cross-presentation of necrotic tissue-derived epitopes to directly activate cytolytic CD8 Tcells. The mature plaque (necrotic, containing dendritic cells and CD8 Tcells) could offer the ideal environment for cross-presentation, resulting in cytotoxic immunity and plaque destabilization. Ldlr(-/-) mice were transplanted with batf3(-/-) or wt bone marrow and put on a western type diet. Hematopoietic batf3 deficiency sharply decreased CD8alpha(+) DC numbers in spleen and lymph nodes (>80%; P < 0,001). Concordantly, batf3(-/-) chimeras had a 75% reduction in OT-I cross-priming capacity in vivo. Batf3(-/-) chimeric mice did not show lower Tcell or other leukocyte subset numbers. Despite dampened cross presentation capacity, batf3(-/-) chimeras had equal atherosclerosis burden in aortic arch and root. Likewise, batf3(-/-) chimeras and wt mice revealed no differences in parameters of plaque stability: plaque Tcell infiltration, cell death, collagen composition, and macrophage and vascular smooth muscle cell content were unchanged. These results show that CD8alpha(+) DC loss in hyperlipidemic mice profoundly reduces cross-priming ability, nevertheless it does not influence lesion development. Taken together, we clearly demonstrate that CD8alpha(+) DC-mediated cross-presentation does not significantly contribute to atherosclerotic plaque formation and stability. PMID- 26486590 TI - Occallatibacter riparius gen. nov., sp. nov. and Occallatibacter savannae sp. nov., acidobacteria isolated from Namibian soils, and emended description of the family Acidobacteriaceae. AB - Three Gram-negative, non-spore-forming, encapsulated bacteria were isolated from a Namibian river-bank soil (strains 277T and 307) and a semiarid savannah soil (strain A2-1cT). 16S rRNA gene sequence analyses placed them within subdivision 1 of the Acidobacteria and revealed 100 % similarity between strains 277T and 307 and 98.2 % similarity between A2-1cT and the former two strains. The closest relatives with validly published names were Telmatobacter bradus, Acidicapsa borealis and Acidicapsa ligni (94.7-95.9 % similarity to the type strains). Cells of all three strains were rod-shaped and motile and divided by binary fission. Ultrastructural analyses revealed a thick cell envelope, resulting mainly from a thick periplasmic space. Colonies of strains 277T and 307 were white to cream and light pink, respectively, while strain A2-1cT displayed a bright pink colour. All three strains were aerobic, chemoheterotrophic mesophiles with a broad temperature range for growth and a moderately acidic pH optimum. Sugars and complex proteinaceous substrates were the preferred carbon and energy sources. A few polysaccharides were degraded. The major quinone in all three strains was MK 8; MK-7 occurred in strain A2-1cT as a minor compound. Major fatty acids were iso C15 : 0 and iso-C17 : 1omega7c. In addition, iso-C17 : 0 occurred in significant amounts. The DNA G+C contents of strains 277T, 307 and A2-1cT were 59.6, 59.9 and 58.5 mol%, respectively. Based on these characteristics, the three isolates are assigned to two novel species of the novel genus Occallatibacter gen. nov., Occallatibacter riparius sp. nov. [type strain 277T ( = DSM 25168T = LMG 26948T) and reference strain 307 ( = DSM 25169 = LMG 26947)] and Occallatibacter savannae sp. nov. [type strain A2-1cT ( = DSM 25170T = LMG 26946T)]. Together with several other recently described taxa, the novel isolates provide the basis for an emended description of the established family Acidobacteriaceae. PMID- 26486591 TI - The role of influenza in the epidemiology of pneumonia. AB - Interactions arising from sequential viral and bacterial infections play important roles in the epidemiological outcome of many respiratory pathogens. Influenza virus has been implicated in the pathogenesis of several respiratory bacterial pathogens commonly associated with pneumonia. Though clinical evidence supporting this interaction is unambiguous, its population-level effects magnitude, epidemiological impact and variation during pandemic and seasonal outbreaks-remain unclear. To address these unknowns, we used longitudinal influenza and pneumonia incidence data, at different spatial resolutions and across different epidemiological periods, to infer the nature, timing and the intensity of influenza-pneumonia interaction. We used a mechanistic transmission model within a likelihood-based inference framework to carry out formal hypothesis testing. Irrespective of the source of data examined, we found that influenza infection increases the risk of pneumonia by ~100-fold. We found no support for enhanced transmission or severity impact of the interaction. For model-validation, we challenged our fitted model to make out-of-sample pneumonia predictions during pandemic and non-pandemic periods. The consistency in our inference tests carried out on several distinct datasets, and the predictive skill of our model increase confidence in our overall conclusion that influenza infection substantially enhances the risk of pneumonia, though only for a short period. PMID- 26486593 TI - Erratum to: Health information priorities for more effective implementation and monitoring of non-communicable disease programs in low- and middle-income countries: lessons from the Pacific. PMID- 26486594 TI - A novel robust quantitative Forster resonance energy transfer assay for protease SENP2 kinetics determination against its all natural substrates. AB - SUMOylation (the process of adding the SUMO [small ubiquitin-like modifier] to substrates) is an important post-translational modification of critical proteins in multiple processes. Sentrin/SUMO-specific proteases (SENPs) act as endopeptidases to process the pre-SUMO or as isopeptidases to deconjugate the SUMO from its substrate. Determining the kinetics of SENPs is important for understanding their activities. Forster resonance energy transfer (FRET) technology has been widely used in biomedical research and is a powerful tool for elucidating protein interactions. In this paper we report a novel quantitative FRET-based protease assay for SENP2 endopeptidase activity that accounts for the self-fluorescent emissions of the donor (CyPet) and the acceptor (YPet). The kinetic parameters, k(cat), K(M), and catalytic efficiency (k(cat)/K(M)) of catalytic domain SENP2 toward pre-SUMO1/2/3, were obtained by this novel design. Although we use SENP2 to demonstrate our method, the general principles of this quantitative FRET-based protease kinetic determination can be readily applied to other proteases. PMID- 26486592 TI - Genomic Foundation of Starch-to-Lipid Switch in Oleaginous Chlorella spp. AB - The ability to rapidly switch the intracellular energy storage form from starch to lipids is an advantageous trait for microalgae feedstock. To probe this mechanism, we sequenced the 56.8-Mbp genome of Chlorella pyrenoidosa FACHB-9, an industrial production strain for protein, starch, and lipids. The genome exhibits positive selection and gene family expansion in lipid and carbohydrate metabolism and genes related to cell cycle and stress response. Moreover, 10 lipid metabolism genes might be originated from bacteria via horizontal gene transfer. Transcriptomic dynamics tracked via messenger RNA sequencing over six time points during metabolic switch from starch-rich heterotrophy to lipid-rich photoautotrophy revealed that under heterotrophy, genes most strongly expressed were from the tricarboxylic acid cycle, respiratory chain, oxidative phosphorylation, gluconeogenesis, glyoxylate cycle, and amino acid metabolisms, whereas those most down-regulated were from fatty acid and oxidative pentose phosphate metabolism. The shift from heterotrophy into photoautotrophy highlights up-regulation of genes from carbon fixation, photosynthesis, fatty acid biosynthesis, the oxidative pentose phosphate pathway, and starch catabolism, which resulted in a marked redirection of metabolism, where the primary carbon source of glycine is no longer supplied to cell building blocks by the tricarboxylic acid cycle and gluconeogenesis, whereas carbon skeletons from photosynthesis and starch degradation may be directly channeled into fatty acid and protein biosynthesis. By establishing the first genetic transformation in industrial oleaginous C. pyrenoidosa, we further showed that overexpression of an NAD(H) kinase from Arabidopsis (Arabidopsis thaliana) increased cellular lipid content by 110.4%, yet without reducing growth rate. These findings provide a foundation for exploiting the metabolic switch in microalgae for improved photosynthetic production of food and fuels. PMID- 26486595 TI - Gastric cancer diagnosed after Helicobacter pylori eradication in diabetes mellitus patients. AB - BACKGROUND: Helicobacter pylori infection is the most important risk factor for gastric cancer, for which eradication therapy is commonly performed. However, gastric cancer is sometimes discovered after successful eradication of H. pylori. Much evidence indicates that diabetes mellitus (DM) is a risk factor for gastric cancer. The incidence and characteristics of gastric cancer diagnosed after H. pylori eradication in DM patients remain to be determined. METHODS: We followed the clinical course of patients who underwent H. pylori eradication therapy at our institution. Endoscopy was performed before and after eradication. We compared the incidence and clinical characteristics of gastric cancer arising in DM and non-DM patients. RESULTS: In total, 965 patients who underwent successful eradication (518 DM and 447 non-DM patients) were followed-up for an average of 4.5 years. During the follow-up period, 21 gastric cancers were diagnosed (12 in DM patients and 9 in non-DM patients). The incidence of gastric cancer after eradication was not significantly different between DM and non-DM patients (0.485 and 0.482 %/year, respectively). There was no significant difference in the pathology, diameter, depth, location, or treatment of gastric cancer between patients with and without DM. CONCLUSION: The incidence and characteristics of gastric cancer occurring after H. pylori eradication were comparable between DM and non-DM patients. PMID- 26486597 TI - Evaluating the Use of the Case Mix Index for Risk Adjustment of Healthcare Associated Infection Data: An Illustration using Clostridium difficile Infection Data from the National Healthcare Safety Network. AB - BACKGROUND Case mix index (CMI) has been used as a facility-level indicator of patient disease severity. We sought to evaluate the potential for CMI to be used for risk adjustment of National Healthcare Safety Network (NHSN) healthcare associated infection (HAI) data. METHODS NHSN facility-wide laboratory-identified Clostridium difficile infection event data from 2012 were merged with the fiscal year 2012 Inpatient Prospective Payment System (IPPS) Impact file by CMS certification number (CCN) to obtain a CMI value for hospitals reporting to NHSN. Negative binomial regression was used to evaluate whether CMI was significantly associated with healthcare facility-onset (HO) CDI in univariate and multivariate analysis. RESULTS Among 1,468 acute care hospitals reporting CDI data to NHSN in 2012, 1,429 matched by CCN to a CMI value in the Impact file. CMI (median, 1.49; interquartile range, 1.36-1.66) was a significant predictor of HO CDI in univariate analysis (P<.0001). After controlling for community onset CDI prevalence rate, medical school affiliation, hospital size, and CDI test type use, CMI remained highly significant (P<.0001), with an increase of 0.1 point in CMI associated with a 3.4% increase in the HO CDI incidence rate. CONCLUSIONS CMI was a significant predictor of NHSN HO CDI incidence. Additional work to explore the feasibility of using CMI for risk adjustment of NHSN data is necessary. Infect. Control Hosp. Epidemiol. 2015;37(1):19-25. PMID- 26486596 TI - Angiotensin II status and sympathetic activation among hypertensive patients in Uganda: a cross-sectional study. AB - BACKGROUND: Sympathetic activation and renin-angiotensin system are essential for development and sustenance of hypertension. However, the status of these systems has not been well evaluated among patients in an African setting. This study therefore set out to assess the angiotensin II status and sympathetic activation among hypertensive patients in Uganda. METHODS: In this cross sectional study conducted at Mulago, the national referral hospital, blood samples were taken to measure angiotensin II, metanephrines and normetanephrines. Urine samples were also taken for measuring urine creatinine and sodium. The angiotensin II categories were defined using the Mosby's Diagnostic and Laboratory Test References. 9th ed while the metanephrines and normetanephrine categories were defined using the Makerere University Biosafety II Immunology Laboratory reference values. RESULTS: 162 patients were consented and enrolled into the study, of these 136 (84 %) had low, 15 (9 %) had normal, while, 11 (7 %) had high angiotensin II levels. 142 (88 %) participants had normal levels of metanephrine, while 20 (12 %) had high levels. Only 88 were assessed for metanephrines and of these 85 (97 %) had normal, while 3 (3 %) had raised levels. Urine sodium was associated with low and normal angiotensin II levels (P value 0.007). Female gender and diastolic blood pressure were associated with a protective effect against high normetanephrines (OR 0.29, P value 0.015), 80-89 mmHg (OR 0.19, p value 0.053), above 100 mmHg (OR 0.27, p value 0.022). Current smoking status was associated with high risk for abnormal normetanephrines (OR 17.6, P value -0.022) while former smoking was associated with high risk for abnormal metanephrines (OR 18.7, p value 0.022). After multivariate analysis, all the significant variables at bivariate analysis were still significant except those who stopped smoking and those with a BP at 80-89 which were not significant. CONCLUSIONS: Hypertensive patients in this setting have predominantly low angiotensin II hypertension as a result of high salt intake. Sympathetic activation is not a significant mechanism of hypertension in this study population, more so in the females, with the exception of smokers who have a highly activated sympathetic system. Therefore, the use of agents targeting renin angiotensin and sympathetic systems as single first line antihypertensive agents in this setting should be re-evaluated if such patients are to be treated effectively. PMID- 26486599 TI - Inter-observer variation and diagnostic efficacy of apparent diffusion coefficient (ADC) measurements obtained by diffusion-weighted imaging (DWI) in small renal masses. AB - BACKGROUND: Diffusion-weighted imaging (DWI) is increasingly used to diagnose renal lesion subtypes. Especially in small renal masses, identification of less aggressive tumor types is of clinical interest, as active surveillance strategies can be applied. PURPOSE: To evaluate the inter-observer variation and diagnostic efficacy of apparent diffusion coefficient (ADC) measurements obtained by DWI in small renal masses <=4 cm (SRM). MATERIAL AND METHODS: This retrospective IRB approved study included 39 patients (46 SRM: 12 benign, 34 malignant). All underwent a 3 T DWI of SRM prior to surgery. Two radiologists independently analyzed all imaging data by three measurements. Limits of agreement, intraclass correlation coefficients (ICC), group comparisons by t-tests, and ROC analysis were performed. RESULTS: Reliability of ADC measurements was very high with an ICC of >0.9 for both observers. Inter-rater reliability was high with an ICC of 0.82. Limits of agreement for average ADC values between both observers were 23.5% to 38.3% with a mean difference of 7.5% between both observers. No significant differences were found between benign and malignant lesions (P value Observer 1: 0.362, Observer 2: 0.622). Papillary carcinoma showed lower ADC values compared to non-papillary carcinoma (P value Observer 1: 0.008, Observer 2: 0.012). Consequently, ROC analysis revealed a significant (P < 0.001, respectively) area under the ROC curve of 0.853 (Observer 1) and 0.837 (Observer 2) without significant differences between both readers (P = 0.772). CONCLUSION: ADC measurements of SRM at 3 T show a high reproducibility and differentiate papillary from non-papillary carcinoma subtypes. However, measurement variability may limit the application of fixed ADC thresholds for lesion diagnosis. PMID- 26486598 TI - Incidence of prostate and urological cancers in England by ethnic group, 2001 2007: a descriptive study. AB - BACKGROUND: The aetiology of urological cancers is poorly understood and variations in incidence by ethnic group may provide insights into the relative importance of genetic and environmental risk factors. Our objective was to compare the incidence of four urological cancers (kidney, bladder, prostate and testicular) among six 'non-White' ethnic groups in England (Indian, Pakistani, Bangladeshi, Black African, Black Caribbean and Chinese) to each other and to Whites. METHODS: We obtained Information on ethnicity for all urological cancer registrations from 2001 to 2007 (n = 329,524) by linkage to the Hospital Episodes Statistics database. We calculated incidence rate ratios adjusted for age, sex and income, comparing the six ethnic groups (and combined 'South Asian' and 'Black' groups) to Whites and to each other. RESULTS: There were significant differences in the incidence of all four cancers between the ethnic groups (all p < 0.001). In general, 'non-White' groups had a lower incidence of urological cancers compared to Whites, except prostate cancer, which displayed a higher incidence in Blacks. (IRR 2.55) There was strong evidence of differences in risk between Indians, Pakistanis and Bangladeshis for kidney, bladder and prostate cancer (p < 0.001), and between Black Africans and Black Caribbeans for all four cancers (p < 0.001). CONCLUSIONS: The risk of urological cancers in England varies greatly by ethnicity, including within groups that have traditionally been analysed together (South Asians and Blacks). In general, these differences are not readily explained by known risk factors, although the very high incidence of prostate cancer in both black Africans and Caribbeans suggests increased genetic susceptibility. g. PMID- 26486600 TI - Endometrial cancer: correlation of apparent diffusion coefficient (ADC) with tumor cellularity and tumor grade. AB - BACKGROUND: Diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) are widely used for detecting uterine endometrial cancer. The relationships between ADC values and pathological features of endometrial cancer have not yet been established. PURPOSE: To investigate whether ADC values of endometrial cancer vary according to histologic tumor cellularity and tumor grade. MATERIAL AND METHODS: We retrospectively reviewed 30 pathologically confirmed endometrial cancers. All patients underwent conventional non-enhanced magnetic resonance imaging (MRI) and DWI procedures, and ADC values were calculated. Tumor cellularity was evaluated by counting cancer cells in three high-power ( * 400) fields. The correlation between ADC values and tumor cellularity was assessed using Pearson's correlation coefficient test for statistical analysis. RESULTS: The mean +/- standard deviation (SD) ADC value ( *10(-3) mm(2)/s) of endometrial cancer was 0.85 +/- 0.22 (range, 0.55-1.71). The mean +/- SD tumor cellularity was 528.36 +/- 16.89 (range, 298.0-763.6). ADC values were significantly inversely correlated with tumor cellularity. No significant relationship was observed between ADC values and tumor grade (mean ADC values: G1, 0.88 +/- 0.265 * 10(-3) mm(2)/s; G2, 0.80 +/- 0.178 * 10(-3) mm(2)/s; G3, 0.81 +/- 0.117 * 10(-3) mm(2)/s). CONCLUSION: There is a significant inverse relationship between ADC values and tumor cellularity in endometrial cancer. No significant differences in average ADC value were observed between G1, G2, and G3 tumors. However, the lower the tumor grade, the wider the SD. PMID- 26486601 TI - Interaction Between Season of Birth and COMT Val158Met (rs4680) in ADHD in a Large Sample of Chinese Han Participants. AB - OBJECTIVE: To investigate the interaction between catechol-O-methyltransferase gene (COMT) Val108/158Met (rs4680) and season of birth (SOB) on ADHD and its symptoms. METHOD: We conducted transmission disequilibrium tests (TDTs) in 976 trios, then further performed the above analyses in subgroups according to SOB. Quantitative analyses were performed for ADHD symptoms evaluated by ADHD Rating Scale-IV in 1,530 ADHD cases. RESULTS: Overall, there was no association between COMT and ADHD. After stratification, we found an increased transmission of the Val allele in the trios born in spring, while a decreased transmission was observed in the autumn months. We also observed a significant interaction between Val108/158Met and SOB on ADHD symptoms. Among those born in spring, Met carriers had milder ADHD symptoms compared with Val homozygotes, whereas opposite association was found in those born in autumn. CONCLUSION: Our study provided evidence for the modifying effect of SOB on the association between COMT and ADHD along with its symptoms. PMID- 26486602 TI - Neurocognitive Deficits in Attention-Deficit/Hyperactivity Disorder With and Without Comorbid Oppositional Defiant Disorder. AB - OBJECTIVE: Oppositional Defiant Disorder (ODD) is highly prevalent in Attention Deficit/Hyperactivity Disorder (ADHD) and may account for inconsistencies in findings on neurocognitive functioning in ADHD. Our aim was to assess cool and hot executive functioning (EF) and temporal processing in ADHD with and without comorbid ODD to elucidate the effects of comorbid ODD. METHOD: ADHD-only (n = 82), ADHD + ODD (n = 82), and controls (n = 82), with mean age 16 years (SD = 3.1), matched for age, gender, IQ, and ADHD type (clinical groups) were assessed on cool EF (inhibition, working memory), hot EF (reinforcement processing, emotion recognition), and temporal processing (time production and reproduction). RESULTS: Individuals with ADHD + ODD showed abnormalities in inhibition, working memory, facial emotion recognition, and temporal processing, whereas individuals with ADHD-only were solely impaired in working memory and time production. CONCLUSION: Findings suggest that ODD carries a substantial part of the EF deficits observed in ADHD and contrast with current theories of neurocognitive impairments in ADHD. PMID- 26486603 TI - Recent Trends in Stimulant Usage. AB - OBJECTIVE: In the last decade, dramatic changes have occurred in stimulant medication prevalence and in patterns of stimulant treatment. The resultant trends merit analysis. METHOD: Usage patterns of stimulant medication, specifically amphetamine and methylphenidate, were analyzed for trends. The data were obtained from datasets including pharmacy claims, aggregate production quotas, bulk distribution to counties, pharmacy prescription sales, parent surveys, and physician visit surveys. Stimulant medication trends were organized by drug subclass, year, age group, gender, country, prescriber specialty, diagnosis, and expenditures. RESULTS: Major recent trends are as follows: amphetamine medication usage has prominently surpassed methylphenidate, total stimulant prescription sales to adults have surpassed those for youth, and more adult women are prescribed stimulants than adult men. CONCLUSION: Stimulant medication treatment-particularly of amphetamines-is rapidly expanding in the United States. Off-label use is reported to be at least 40% of total use and appears to be more common in adults. (J. of Att. Dis. 2016; 20(6) 471-477). PMID- 26486604 TI - Ultrahigh sensitivity and layer-dependent sensing performance of phosphorene based gas sensors. AB - Two-dimensional (2D) layered materials have attracted significant attention for device applications because of their unique structures and outstanding properties. Here, a field-effect transistor (FET) sensor device is fabricated based on 2D phosphorene nanosheets (PNSs). The PNS sensor exhibits an ultrahigh sensitivity to NO2 in dry air and the sensitivity is dependent on its thickness. A maximum response is observed for 4.8-nm-thick PNS, with a sensitivity up to 190% at 20 parts per billion (p.p.b.) at room temperature. First-principles calculations combined with the statistical thermodynamics modelling predict that the adsorption density is ~10(15) cm(-2) for the 4.8-nm-thick PNS when exposed to 20 p.p.b. NO2 at 300 K. Our sensitivity modelling further suggests that the dependence of sensitivity on the PNS thickness is dictated by the band gap for thinner sheets (<10 nm) and by the effective thickness on gas adsorption for thicker sheets (>10 nm). PMID- 26486605 TI - The complete chloroplast genome of an irreplaceable dietary and model crop, foxtail millet (Setaria italica). AB - The complete chloroplast genome sequence of foxtail millet (Setaria italica), an important food and fodder crop in the family Poaceae, is first reported in this study. The genome consists of 1 35 516 bp containing a pair of inverted repeats (IRs) of 21 804 bp separated by a large single-copy (LSC) region and a small single-copy (SSC) region of 79 896 bp and 12 012 bp, respectively. Coding sequences constitute 58.8% of the genome harboring 111 unique genes, 71 of which are protein-coding genes, 4 are rRNA genes, and 36 are tRNA genes. Phylogenetic analysis indicated foxtail millet clustered with Panicum virgatum and Echinochloa crus-galli belonging to the tribe Paniceae of the subfamily Panicoideae. This newly determined chloroplast genome will provide valuable information for the future breeding programs of valuable cereal crops in the family Poaceae. PMID- 26486606 TI - Comparison of transmission of Papaya leaf curl China virus among four cryptic species of the whitefly Bemisia tabaci complex. AB - Begomoviruses are transmitted by cryptic species of the whitefly Bemisia tabaci complex, often in a species-specific manner. Papaya leaf curl China virus (PaLCuCNV) has been recorded to infect several crops including papaya, tomato and tobacco in China. To help assess the risks of spread of this virus, we compared the acquisition, retention and transmission of PaLCuCNV among four species of whiteflies, Middle East-Asia Minor 1 (MEAM1), Mediterranean (MED), Asia 1 and Asia II 7. All four species of whiteflies are able to acquire, retain and transmit the virus, but with different levels of efficiency. Transmission tests using tomato as the host plant showed that MEAM1 transmitted PaLCuCNV with substantially higher efficiency than did MED, Asia 1 and Asia II 7. Furthermore, accumulation of PaLCuCNV in the whiteflies was positively associated with its efficiency of transmitting the virus. Altogether, these findings indicate that MEAM1 is the most efficient vector for PaLCuCNV in the four species of whiteflies, and suggest that risks of PaLCuCNV pandemics are high in regions where MEAM1 occurs. PMID- 26486608 TI - Chemical control of dissolution-driven convection in partially miscible systems: theoretical classification. AB - Dissolution-driven convection occurs in the host phase of a partially miscible system when a buoyantly unstable density stratification develops upon dissolution. Reactions can impact such convection by changing the composition and thus the density of the host phase. Here we study the influence of A + B -> C reactions on such convective dissolution when A is the dissolving species and B a reactant initially in solution in the host phase. We perform a linear stability analysis of related reaction-diffusion density profiles to compare the growth rate of the instability in the reactive case to its non reactive counterpart when all species diffuse at the same rate. We classify the stabilizing or destabilizing influence of reactions on the buoyancy-driven convection in a parameter space spanned by the solutal Rayleigh numbers RA,B,C of chemical species A, B, C and by the ratio beta of initial concentrations of the reactants. For RA > 0, the non reactive dissolution of A in the host phase is buoyantly unstable. In that case, we show that the reaction is enhancing convection provided C is sufficiently denser than B. Increasing the ratio beta of initial reactant concentrations increases the effect of chemistry but does not significantly impact the stabilizing/destabilizing classification. When the non reactive case is buoyantly stable (RA<= 0), reactions can create in time an unstable density stratification and trigger convection if RC > RB. Our theoretical approach allows classifying previous results in a unifying picture and developing strategies for the chemical control of convective dissolution. PMID- 26486607 TI - Comparative RNA seq analysis of the New Zealand glowworm Arachnocampa luminosa reveals bioluminescence-related genes. AB - BACKGROUND: The New Zealand glowworm is the larva of a carnivorous fungus gnat that produces bioluminescence to attract prey. The bioluminescent system of the glowworm is evolutionarily distinct from other well-characterised systems, especially that of the fireflies, and the molecules involved have not yet been identified. We have used high throughput sequencing technology to produce a transcriptome for the glowworm and identify transcripts encoding proteins that are likely to be involved in glowworm bioluminescence. RESULTS: Here we report the sequencing and annotation of the first transcriptome of the glowworm, and a differential analysis of expression from the glowworm light organ compared with non-light organ tissue. The analysis identified six transcripts encoding proteins that are potentially involved in glowworm bioluminescence. Three of these proteins are members of the ANL superfamily of adenylating enzymes, with similar amino acid sequences to that of the luciferase enzyme found in fireflies (31 to 37 % identical), and are candidate luciferases for the glowworm bioluminescent system. The remaining three transcripts encode putative aminoacylase, phosphatidylethanolamine-binding and glutathione S-transferase proteins. CONCLUSIONS: This research provides a basis for further biochemical studies into how the glowworm produces light, and a source of genetic information to aid future ecological and evolutionary studies of the glowworm. PMID- 26486609 TI - Adaptive selection and coevolution at the proteins of the Polycomb repressive complexes in Drosophila. AB - Polycomb group (PcG) proteins are important epigenetic regulatory proteins that modulate the chromatin state through posttranslational histone modifications. These interacting proteins form multimeric complexes that repress gene expression. Thus, PcG proteins are expected to evolve coordinately, which might be reflected in their phylogenetic trees by concordant episodes of positive selection and by a correlation in evolutionary rates. In order to detect these signals of coevolution, the molecular evolution of 17 genes encoding the subunits of five Polycomb repressive complexes has been analyzed in the Drosophila genus. The observed distribution of divergence differs substantially among and along proteins. Indeed, CAF1 is uniformly conserved, whereas only the established protein domains are conserved in other proteins, such as PHO, PHOL, PSC, PH-P and ASX. Moreover, regions with a low divergence not yet described as protein domains are present, for instance, in SFMBT and SU(Z)12. Maximum likelihood methods indicate an acceleration in the nonsynonymous substitution rate at the lineage ancestral to the obscura group species in most genes encoding subunits of the Pcl PRC2 complex and in genes Sfmbt, Psc and Kdm2. These methods also allow inferring the action of positive selection in this lineage at genes E(z) and Sfmbt. Finally, the protein interaction network predicted from the complete proteomes of 12 Drosophila species using a coevolutionary approach shows two tight PcG clusters. These clusters include well-established binary interactions among PcG proteins as well as new putative interactions. PMID- 26486610 TI - Common garden experiments in the genomic era: new perspectives and opportunities. AB - The study of local adaptation is rendered difficult by many evolutionary confounding phenomena (for example, genetic drift and demographic history). When complex traits are involved in local adaptation, phenomena such as phenotypic plasticity further hamper evolutionary biologists to study the complex relationships between phenotype, genotype and environment. In this perspective paper, we suggest that the common garden experiment, specifically designed to deal with phenotypic plasticity, has a clear role to play in the study of local adaptation, even (if not specifically) in the genomic era. After a quick review of some high-throughput genotyping protocols relevant in the context of a common garden, we explore how to improve common garden analyses with dense marker panel data and recent statistical methods. We then show how combining approaches from population genomics and genome-wide association studies with the settings of a common garden can yield to a very efficient, thorough and integrative study of local adaptation. Especially, evidence from genomic (for example, genome scan) and phenotypic origins constitute independent insights into the possibility of local adaptation scenarios, and genome-wide association studies in the context of a common garden experiment allow to decipher the genetic bases of adaptive traits. PMID- 26486612 TI - Effect of pi-pi interaction in Bergman cyclisation. AB - The role of pi-pi interactions in controlling the reactivity and selectivity of a chemical reaction is only recently being explored, even though their ubiquitous role in the structural aspects is well known. We have studied Bergman cyclisation focusing on the effect of pi-pi interactions on the activation barrier and the variation of pi-pi interactions along the reaction coordinate. We used enediyne substrates that contain phenyl groups connected to the reaction centres (C1 and C6 atoms), separated by 0, 1 and 2 linker groups. The main difference between the substrates is that the Ph groups enjoy different flexibility to accommodate the changes occurring during the progress of the reaction. The path length of the minimum energy path is increased - shortest in the least flexible substrate (a) and longer in the more flexible ones (c, d and e). We calculated the interaction between the Ph groups, the pi-pi interaction, using BP86-D3BJ, B3LYP-D3BJ, M06 2X, B2PLYP-D3BJ, SCS-MP2, and SAPT. The BP86-D3BJ was found to be sufficiently accurate with a mean absolute deviation of 0.26 kcal mol(-1) with respect to the SAPT2+3 values. The variation in the pi-pi interaction shows different behaviour in a-e, and this can be correlated with the flexibility of the Ph groups to orient themselves to maintain the optimal relative orientation while conforming to the changes in the reaction coordinate. We analysed the relative orientation of the phenyl groups using certain geometric parameters that showed that when Ph groups can attain a relative orientation close to that of the free dimer, the interaction is maximum. Energy decomposition analysis using SAPT showed that the dispersive interaction is the major contributor (50-60%) to the attractive forces. The pi-pi interactions influenced the overall activation energy, either by destabilising the substrates or by stabilising the TS - resulting in a variation of about 3.5 kcal mol(-1) in activation energies in a-e. The effect of substituents of different electronic nature was assessed which showed that electron donating and electron withdrawing substituents increase the pi-pi interactions; however, the TS is more stabilised and hence activation energies are increased. PMID- 26486611 TI - Ditch network sustains functional connectivity and influences patterns of gene flow in an intensive agricultural landscape. AB - In intensive agricultural landscapes, plant species previously relying on semi natural habitats may persist as metapopulations within landscape linear elements. Maintenance of populations' connectivity through pollen and seed dispersal is a key factor in species persistence in the face of substantial habitat loss. The goals of this study were to investigate the potential corridor role of ditches and to identify the landscape components that significantly impact patterns of gene flow among remnant populations. Using microsatellite loci, we explored the spatial genetic structure of two hydrochorous wetland plants exhibiting contrasting local abundance and different habitat requirements: the rare and regionally protected Oenanthe aquatica and the more commonly distributed Lycopus europaeus, in an 83 km(2) agricultural lowland located in northern France. Both species exhibited a significant spatial genetic structure, along with substantial levels of genetic differentiation, especially for L. europaeus, which also expressed high levels of inbreeding. Isolation-by-distance analysis revealed enhanced gene flow along ditches, indicating their key role in effective seed and pollen dispersal. Our data also suggested that the configuration of the ditch network and the landscape elements significantly affected population genetic structure, with (i) species-specific scale effects on the genetic neighborhood and (ii) detrimental impact of human ditch management on genetic diversity, especially for O. aquatica. Altogether, these findings highlighted the key role of ditches in the maintenance of plant biodiversity in intensive agricultural landscapes with few remnant wetland habitats. PMID- 26486613 TI - A Shot in the Arm for HIV Prevention? Recent Successes and Critical Thresholds. AB - Efforts to decrease the spread of HIV worldwide continue at a rapid pace. With the development of new biomedical interventions and findings from pivotal clinical trials, a new framework for short-term and long-term prevention strategies is emerging. It is clear that biomedical-based approaches targeted at the highest risk populations have the greatest potential to have a short-term impact. Unfortunately, challenges with adherence in healthy populations at risk are now well-recognized, and competing health care priorities in the context of fragile delivery infrastructures pose formidable obstacles to implementation. We need better ways to identify high-risk populations, sophisticated understanding of the behavioral parameters that can ensure adherence, and the development of better strategies to provide sustained delivery of preexposure prophylaxis (PrEP). In the long term, we need an effective vaccine--a path that has proven to be rocky. Research facilitating an increased understanding of immune responses and what represents effective responses to prevent HIV acquisition should facilitate progress. While we wait for that time, PrEP offers the best strategy for short-term impact. PMID- 26486615 TI - Increased serum concentrations of neutrophil-derived protein S100A12 in heterozygous carriers of MEFV mutations. AB - OBJECTIVES: To assess subclinical inflammation in heterozygous carriers of Mediterranean fever (MEFV) gene mutations, analysis of classical inflammation markers and S100A12 was performed. METHODS: Exons 2, 3, and 10 of the MEFV gene, C-reactive protein (CRP), serum amyloid A protein (SAA), procalcitonin (PCT), and S100A12 concentrations, erythrocyte sedimentation rate (ESR), and differential blood count were analysed in apparently healthy parents (n=26) of homozygous children with familial Mediterranean fever (FMF). Their general health condition was assessed by a standardised questionnaire. In order to collect data on the disease course, subjects were reevaluated after 5 years by means of telephone interview and/or questionnaire. RESULTS: Twenty-two individuals with one typical mutation in the MEFV gene were included. Mean values (mean+/-SEM) of classical inflammation markers were within the normal range (ESR of 11.7+/-1.9 mm/h, SAA 4.7+/-0.4 mg/l, CRP 0.26+/-0.04 mg/dl), while PCT was non-detectable in all cases (<0.1 MUg/l). Eleven subjects showed elevated S100A12 levels [>140 ng/ml] with a mean concentration of 205+/-43 ng/ml. Thus, the mean value of S100A12 was 1.5 fold higher than the regular cut-off. CONCLUSIONS: 50% of the heterozygous MEFV mutation carriers exhibited elevated S100A12 levels, supporting previous observations that S100 molecules are very sensitive biomarkers of subclinical inflammation. Possibly, S100A12 could be a prognostic biomarker to detect individuals at risk of FMF manifestation who might benefit from colchicine therapy. PMID- 26486616 TI - Solvation of Calcium-Phosphate Headgroup Complexes at the DPPC/Aqueous Interface. AB - The effects of sodium (Na(+) ) and calcium (Ca(2+) ) cations on model zwitterionic dipalmitoylphosphatidylcholine (DPPC) monolayers spread on metal chloride salt solutions are investigated by means of vibrational sum frequency generation (VSFG) and heterodyne-detected (HD)-VSFG spectroscopy. VSFG and HD VSFG spectra in the OH stretching region reveal cation-specific effects on the interfacial water's H-bonding network, knowledge of which has been limited to date. It is found that low-concentrated Ca(2+) more strongly perturbs interfacial water organization relative to highly concentrated Na(+) . At higher Ca(2+) concentrations, the water H-bonding network at the DPPC/CaCl2 interface reorganizes and the resulting spectrum closely follows that of the bare air/CaCl2 interface up to ~3400 cm(-1) . Most interesting is the appearance of a negative band at ~3450 cm(-1) in the DPPC/CaCl2 Im chis ((2)) spectra, likely arising from an asymmetric solvation of Ca(2+) -phosphate headgroup complexes. This gives rise to an electric field that orients the net OH transition moments of a subset of OH dipoles toward the bulk solution. PMID- 26486618 TI - Pathogenicity of POFUT1 mutations in two Chinese families with Dowling-Degos disease. PMID- 26486617 TI - Surveillance of Stem Cell Fate and Function: A System for Assessing Cell Survival and Collagen Expression In Situ. AB - Cell-based therapy is an emerging paradigm in skeletal regenerative medicine. However, the primary means by which transplanted cells contribute to bone repair and regeneration remain controversial. To gain an insight into the mechanisms of how both transplanted and endogenous cells mediate skeletal healing, we used a transgenic mouse strain expressing both the topaz variant of green fluorescent protein under the control of the collagen, type I, alpha 1 promoter/enhancer sequence (Col1a1(GFP)) and membrane-bound tomato red fluorescent protein constitutively in all cell types (R26(mTmG)). A comparison of healing in parietal versus frontal calvarial defects in these mice revealed that frontal osteoblasts express Col1a1 to a greater degree than parietal osteoblasts. Furthermore, the scaffold-based application of adipose-derived stromal cells (ASCs), bone marrow derived mesenchymal stem cells (BM-MSCs), and osteoblasts derived from these mice to critical-sized calvarial defects allowed for investigation of cell survival and function following transplantation. We found that ASCs led to significantly faster rates of bone healing in comparison to BM-MSCs and osteoblasts. ASCs displayed both increased survival and increased Col1a1 expression compared to BM MSCs and osteoblasts following calvarial defect transplantation, which may explain their superior regenerative capacity in the context of bone healing. Using this novel reporter system, we were able to elucidate how cell-based therapies impact bone healing and identify ASCs as an attractive candidate for cell-based skeletal regenerative therapy. These insights potentially influence stem cell selection in translational clinical trials evaluating cell-based therapeutics for osseous repair and regeneration. PMID- 26486620 TI - Managing Livestock Species under Climate Change in Australia. AB - This paper examines the vulnerabilities of major livestock species raised in Australia to climate change using the regional livestock profile of Australia of around 1,400 regions. The number of each species owned, the number of each species sold, and the aggregate livestock revenue across all species are examined. The four major species analyzed are sheep, beef cattle, dairy cattle, and pigs. The analysis also includes livestock products such as wool and milk. These livestock production statistics are regressed against climate, geophysical, market and household characteristics. In contrast to crop studies, the analysis finds that livestock species are resilient to a hotter and more arid climate. Under the CSIRO climate scenario in which temperature increases by 3.4 degrees C, livestock revenue per farm increases significantly while the number of each species owned increases by large percentages except for dairy cattle. The precipitation reduction by about 8% in 2060 also increases the numbers of livestock species per farm household. Under both UKMO and GISS scenarios, livestock revenue is expected to increase by around 47% while the livestock population increases by large percentage. Livestock management may play a key role in adapting to a hot and arid climate in Australia. However, critical values of the climatic variables for the species analyzed in this paper are not obvious from the regional data. PMID- 26486619 TI - Canine Rabies: A Looming Threat to Public Health. AB - Rabies is an acute, fatal viral disease that infects domestic and wild animals and is transmissible to humans. Worldwide, rabies kills over 55,000 people every year. The domestic dog plays a pivotal role in rabies transmission. Domestic dogs are not only part of our daily lives but also of our immediate surroundings, and this is reflected in the rise in pet dog ownership in developed and developing countries. This is important given that more frequent exposures and interactions at the animal-human interface increases the likelihood of contracting zoonotic diseases of companion animals. Despite existing vaccines and post-exposure prophylactic treatment, rabies remains a neglected disease that is poorly controlled throughout much of the developing world, particularly Africa and Asia, where most human rabies deaths occur. It is believed that with sustained international commitments, global elimination of rabies from domestic dog populations, the most dangerous vector to humans, is a realistic goal. PMID- 26486621 TI - Welfare of Aged Horses. AB - Horses form a unique and special part of their owners' lives and aged horses are no exception. This review considers the health and management of aged horses, including the role of the owner and their perceptions of aged horses, potential threats or risks to their welfare and finally, factors affecting quality of life and euthanasia of aged horses. Owners of aged horses are concerned about the health, welfare and quality of life of their aged animals. Yet surveys of management and preventive healthcare reflect that there may be some limitations to what owners are actually achieving in practice. They show declining management as horses age, particularly for the retired horse and insufficient appropriate preventive healthcare via veterinary surgeons. The veterinary surgeon plays an essential and influential role in preventive healthcare, management of diseases and disorders and ultimately in the decision making process for euthanasia of aged horses at the end of their lives. The value of aged horses should not be underestimated by veterinarians and others working with them and the continuing care of aged horses should be regarded with the same importance as the care of younger horses with more obvious monetary value. PMID- 26486623 TI - Signs Observed Among Animal Species Infected with Raccoon Rabies Variant Virus, Massachusetts, USA, 1992-2010. AB - We analyzed signs occurring among domestic and wild terrestrial animal species infected with raccoon rabies variant virus (RRV) in Massachusetts, 1992-2010. The clinical sign of aggression was significantly associated with rabid stray cats (odds ratio, OR = 2.3) and RRV affected major wild terrestrial animal species individually, which included raccoons (OR = 2.8), skunks (OR = 8.0), gray foxes (OR = 21.3), red foxes (OR = 10.4), woodchucks (OR = 4.7) and coyotes (OR = 27.6). While aggression is a useful predictor of rabies among wild animals, combinations of other signs such as ataxia, disorientation, and salivation are useful predictors of rabies among domestic animals. Pets reported with multiple clinical signs had significantly higher rabies positive testing result than those reported with single clinical sign (p < 0.001). The result suggested the importance of avoiding aggressive terrestrial wild animals and giving additional attention to pets with multiple clinical signs. PMID- 26486622 TI - Zoonotic Poxviruses Associated with Companion Animals. AB - Understanding the zoonotic risk posed by poxviruses in companion animals is important for protecting both human and animal health. The outbreak of monkeypox in the United States, as well as current reports of cowpox in Europe, point to the fact that companion animals are increasingly serving as sources of poxvirus transmission to people. In addition, the trend among hobbyists to keep livestock (such as goats) in urban and semi-urban areas has contributed to increased parapoxvirus exposures among people not traditionally considered at high risk. Despite the historic notoriety of poxviruses and the diseases they cause, poxvirus infections are often missed. Delays in diagnosing poxvirus-associated infections in companion animals can lead to inadvertent human exposures. Delays in confirming human infections can result in inappropriate treatment or prolonged recovery. Early recognition of poxvirus-associated infections and application of appropriate preventive measures can reduce the spread of virus between companion animals and their owners. This review will discuss the epidemiology and clinical features associated with the zoonotic poxvirus infections most commonly associated with companion animals. PMID- 26486624 TI - Investigation of an Imported Case of Rabies in a Juvenile Dog with Atypical Presentation. AB - Movement of dogs between rabies-endemic and rabies-free countries carries the inherent risk of introducing the disease. In April of 2008, a juvenile dog was imported to the UK from Sri Lanka. It died shortly after transfer to a quarantine facility in the south-east of England following a short history of diarrhoea and convulsions but no overt signs of aggression. Subsequent investigation confirmed that rabies was the cause of death. Rabies virus was isolated from brain samples taken from the dog and the subsequent phylogenetic investigation confirmed that the genomic sequence from this virus shared over 99% homology with endemic rabies viruses from Sri Lanka. Histological examination of the brain demonstrated clear signs of encephalitis and rabies antigenic labeling in numerous neurons. In this particular case, Negri bodies were absent. As this case was diagnosed in a quarantine facility, the 'rabies-free' status of the UK was un-affected. PMID- 26486625 TI - Bridging the Gap Between Validation and Implementation of Non-Animal Veterinary Vaccine Potency Testing Methods. AB - In recent years, technologically advanced high-throughput techniques have been developed that replace, reduce or refine animal use in vaccine quality control tests. Following validation, these tests are slowly being accepted for use by international regulatory authorities. Because regulatory acceptance itself has not guaranteed that approved humane methods are adopted by manufacturers, various organizations have sought to foster the preferential use of validated non-animal methods by interfacing with industry and regulatory authorities. After noticing this gap between regulation and uptake by industry, we began developing a paradigm that seeks to narrow the gap and quicken implementation of new replacement, refinement or reduction guidance. A systematic analysis of our experience in promoting the transparent implementation of validated non-animal vaccine potency assays has led to the refinement of our paradigmatic process, presented here, by which interested parties can assess the local regulatory acceptance of methods that reduce animal use and integrate them into quality control testing protocols, or ensure the elimination of peripheral barriers to their use, particularly for potency and other tests carried out on production batches. PMID- 26486626 TI - Construction and Operation of a Ventilated Hood System for Measuring Greenhouse Gas and Volatile Organic Compound Emissions from Cattle. AB - Recent interest in greenhouse gas emissions from ruminants, such as cattle, has spawned a need for affordable, precise, and accurate methods for the measurement of gaseous emissions arising from enteric fermentation. A new head hood system for cattle designed to capture and quantify emissions was recently developed at the University of California, Davis. The system consists of two head hoods, two vacuum pumps, and an instrumentation cabinet housing the required data collection equipment. This system has the capability of measuring carbon dioxide, methane, ethanol, methanol, water vapor, nitrous oxide, acetic acid emissions and oxygen consumption in real-time. A unique aspect of the hoods is the front, back, and sides are made of clear polycarbonate sheeting allowing the cattle a full range of vision during gas sampling. Recovery rates for these slightly negative pressure chambers were measured ranging from 97.6 to 99.3 percent. This system can capture high quality data for use in improving emission inventories and evaluating gaseous emission mitigation strategies. PMID- 26486628 TI - Emergency Radiology goes international. PMID- 26486629 TI - Development of a single-photon-counting camera with use of a triple-stacked micro-channel plate. AB - At the quantum-mechanical level, all substances (not merely electromagnetic waves such as light and X-rays) exhibit wave-particle duality. Whereas students of radiation science can easily understand the wave nature of electromagnetic waves, the particle (photon) nature may elude them. Therefore, to assist students in understanding the wave-particle duality of electromagnetic waves, we have developed a photon-counting camera that captures single photons in two dimensional images. As an image intensifier, this camera has a triple-stacked micro-channel plate (MCP) with an amplification factor of 10(6). The ultra-low light of a single photon entering the camera is first converted to an electron through the photoelectric effect on the photocathode. The electron is intensified by the triple-stacked MCP and then converted to a visible light distribution, which is measured by a high-sensitivity complementary metal oxide semiconductor image sensor. Because it detects individual photons, the photon-counting camera is expected to provide students with a complete understanding of the particle nature of electromagnetic waves. Moreover, it measures ultra-weak light that cannot be detected by ordinary low-sensitivity cameras. Therefore, it is suitable for experimental research on scintillator luminescence, biophoton detection, and similar topics. PMID- 26486627 TI - Intrinsic muscle clock is necessary for musculoskeletal health. AB - KEY POINTS: The endogenous molecular clock in skeletal muscle is necessary for maintenance of phenotype and function. Loss of Bmal1 solely from adult skeletal muscle (iMSBmal1(-/-) ) results in reductions in specific tension, increased oxidative fibre type and increased muscle fibrosis with no change in feeding or activity. Disruption of the molecular clock in adult skeletal muscle is sufficient to induce changes in skeletal muscle similar to those seen in the Bmal1 knockout mouse (Bmal1(-/-) ), a model of advanced ageing. iMSBmal1(-/-) mice develop increased bone calcification and decreased joint collagen, which in combination with the functional changes in skeletal muscle results in altered gait. This study uncovers a fundamental role for the skeletal muscle clock in musculoskeletal homeostasis with potential implications for ageing. ABSTRACT: Disruption of circadian rhythms in humans and rodents has implicated a fundamental role for circadian rhythms in ageing and the development of many chronic diseases including diabetes, cardiovascular disease, depression and cancer. The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop with Bmal1 encoding a core molecular clock transcription factor. Germline Bmal1 knockout (Bmal1 KO) mice have a shortened lifespan, show features of advanced ageing and exhibit significant weakness with decreased maximum specific tension at the whole muscle and single fibre levels. We tested the role of the molecular clock in adult skeletal muscle by generating mice that allow for the inducible skeletal muscle-specific deletion of Bmal1 (iMSBmal1). Here we show that disruption of the molecular clock, specifically in adult skeletal muscle, is associated with a muscle phenotype including reductions in specific tension, increased oxidative fibre type, and increased muscle fibrosis similar to that seen in the Bmal1 KO mouse. Remarkably, the phenotype observed in the iMSBmal1(-/-) mice was not limited to changes in muscle. Similar to the germline Bmal1 KO mice, we observed significant bone and cartilage changes throughout the body suggesting a role for the skeletal muscle molecular clock in both the skeletal muscle niche and the systemic milieu. This emerging area of circadian rhythms and the molecular clock in skeletal muscle holds the potential to provide significant insight into intrinsic mechanisms of the maintenance of muscle quality and function as well as identifying a novel crosstalk between skeletal muscle, cartilage and bone. PMID- 26486630 TI - Epidemiology of "Heart Failure with Recovered Ejection Fraction": What do we do After Recovery? AB - Improvement in functional status, long-term survival, and quality of life has always been the goal of therapy in patients with heart failure with reduced ejection fraction. Neurohormonal modulating medications help patients achieve these goals and, in a subgroup of patients, can promote "reverse remodeling" resulting in the recovery of left ventricular systolic function. In the era of durable mechanical support, myocardial recovery that leads to explantation of the ventricular assist device occurs in a minority of cases. Optimal medical therapy appears to be a key component of achieving myocardial recovery, with recovery more likely in patients with a shorter duration of heart failure and a non ischemic etiology. However, little is known about future management of patients who attain myocardial recovery, either with or without mechanical support. This review explores the epidemiology, physiology, cellular biology, and long-term outcomes for this subgroup of heart failure patients and outlines areas for future study. PMID- 26486631 TI - Current Approach to Decongestive Therapy in Acute Heart Failure. AB - Congestion, defined by elevated cardiac filling pressures, is the major driver of hospitalization in acute decompensated heart failure. Careful clinical assessment should allow to determine whether volume overload or volume misdistribution is the predominating mechanism of congestion. Differentiation is imperative because therapy differs. If volume overloads prevails, loop diuretics are considered the mainstay therapy. However, early use of combinational therapy with diuretics acting more proximal or distal in the nephron could allow for a more profound natriuresis and diuresis. A stepped guided pharmacological treatment should focus on achieving complete decongestion, because persistent congestion is a major driver of readmission. If diuretic strategies remain unsuccessful, ultrafiltration should be considered. Ultrafiltration should be used with caution in the setting of worsening of renal function. When volume misdistribution and impaired venous capacitance predominate the picture of congestion, unloading-more than diuretics-with arteriolar and venous vasodilators might mitigate the clinical picture of congestion. This review offers a thorough overview and practical insight in the use of current and potential decongestive therapies. PMID- 26486632 TI - Twelve-Month Outcomes of a Randomized Trial of the Positive Thoughts and Action Program for Depression Among Early Adolescents. AB - This study was conducted to examine the 12-month effects on depression and depressive symptoms of a group-based cognitive-behavioral preventive intervention for middle school students (Positive Thoughts and Actions, or PTA), relative to a brief, individually administered supportive intervention (Individual Support Program, or ISP). A randomized clinical trial was conducted with 120 early adolescents (73 girls and 47 boys; age 12-14 years) drawn from a school-based population who had elevated depressive symptoms. Youths completed measures of depressive symptoms at baseline, post-intervention, and 6 and 12 months into the follow-up phase. Measures of internalizing problems, externalizing problems, school adjustment, interpersonal relationships, and health behavior were obtained from parents and/or youth. Multilevel models indicated that the effect of PTA on youth-reported depressive symptoms persisted until 12-month follow-up; d = 0.36 at post-intervention, d = 0.24 at 6-month follow-up, and d = 0.21 at 12-month follow-up. PTA youths also reported lower internalizing symptoms at post intervention, d = 0.44, and at 12-month follow-up, d = 0.39. Time-limited effects were found for parent-reported internalizing symptoms and health behavior. Onset of new depressive episodes did not differ based on intervention group (21 % ISP; 17 % PTA). Results demonstrate support for the long-term efficacy of PTA, a cognitive-behavioral preventive intervention in which youths engage in personal goal-setting and practice social-emotional skills. PMID- 26486633 TI - Genital Herpes Simplex Virus Type 2 Shedding Among Adults With and Without HIV Infection in Uganda. AB - BACKGROUND: Despite the high prevalence of herpes simplex virus type 2 (HSV-2) in sub-Saharan Africa, the natural history of infection among Africans is not well characterized. We evaluated the frequency of genital HSV shedding in HIV seropositive and HIV-seronegative men and women in Uganda. METHODS: Ninety-three HSV-2-seropositive Ugandan adults collected anogenital swab specimens for HSV DNA quantification by polymerase chain reaction 3 times daily for 6 weeks. RESULTS: HSV-2 was detected from 2484 of 11 283 swab specimens collected (22%), with a median quantity of 4.3 log10 HSV copies/mL (range, 2.2-8.9 log10 HSV copies/mL). Genital lesions were reported on 749 of 3875 days (19%), and subclinical HSV shedding was detected from 1480 of 9113 swab specimens (16%) collected on days without lesions. Men had higher rates of total HSV shedding (relative risk [RR], 2.0 [95% confidence interval {CI}, 1.3-2.9]; P < .001); subclinical shedding (RR, 1.7 [95% CI, 1.1-2.7]; P = .01), and genital lesions (RR, 2.1 [95% CI, 1.2-3.4]; P = .005), compared with women. No differences in shedding rates or lesion frequency were observed based on HIV serostatus. CONCLUSIONS: HSV-2 shedding frequency and quantity are high among HSV-2-seropositive adults in sub-Saharan Africa, including persons with and those without HIV infection. Shedding rates were particularly high among men, which may contribute to the high prevalence of HSV-2 and early acquisition among African women. PMID- 26486635 TI - Impaired Cytokine but Enhanced Cytotoxic Marker Expression in Mycobacterium tuberculosis-Induced CD8+ T Cells in Individuals With Type 2 Diabetes and Latent Mycobacterium tuberculosis Infection. AB - Type 2 diabetes mellitus (DM) is a risk factor for tuberculosis among individuals with latent Mycobacterium tuberculosis infection. To explore the influence of DM on CD8(+) T-cell responses during latent M. tuberculosis infection, we estimated the cytokine and cytotoxic marker expression pattern in individuals with latent M. tuberculosis infection with DM and those with latent M. tuberculosis infection without DM. Among individuals with latent M. tuberculosis infection, those with DM had diminished frequencies of CD8(+) T-helper type 1 (Th1), Th2, and Th17 cells following stimulation by M. tuberculosis antigen and enhanced frequencies of CD8(+) T cells expressing cytotoxic markers, compared with those without DM. Thus, our results suggest that coincident DM modulates CD8(+) T-cell function during latent M. tuberculosis infection. PMID- 26486634 TI - Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) causes life-threatening disease. Dipeptidyl peptidase 4 (DPP4) is the receptor for cell binding and entry. There is a need for small-animal models of MERS, but mice are not susceptible to MERS because murine dpp4 does not serve as a receptor. We developed transgenic mice expressing human DPP4 (hDPP4) under the control of the surfactant protein C promoter or cytokeratin 18 promoter that are susceptible to infection with MERS-CoV. Notably, mice expressing hDPP4 with the cytokeratin 18 promoter developed progressive, uniformly fatal disease following intranasal inoculation. High virus titers were present in lung and brain tissues 2 and 6 days after infection, respectively. MERS-CoV-infected lungs revealed mononuclear cell infiltration, alveolar edema, and microvascular thrombosis, with airways generally unaffected. Brain disease was observed, with the greatest involvement noted in the thalamus and brain stem. Animals immunized with a vaccine candidate were uniformly protected from lethal infection. These new mouse models of MERS CoV should be useful for investigation of early disease mechanisms and therapeutic interventions. PMID- 26486636 TI - Modulation of CD4+ and CD8+ T-Cell Function by Interleukin 19 and Interleukin 24 During Filarial Infections. AB - Interleukin 19 (IL-19) and interleukin 24 (IL-24) are cytokines that are highly expressed in filarial infections. To study the role of IL-19 and IL-24 in regulating T-cell responses, we examined the frequency of T-helper type 1 (Th1)/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, Th22/Tc22, and Tr1 cells in 26 filariae infected individuals stimulated with filarial antigen following IL-19 or IL-24 neutralization. IL-19 or IL-24 neutralization resulted in significantly enhanced frequencies of Th1/Tc1 and/or Th17/Tc17 cells and significantly reduced frequencies of Th2/Tc2, Tr1, and/or Th9/Tc9 cells. Thus, we demonstrate that IL 19 and IL-24 are associated with the modulation of T-cell responses in filarial infections. PMID- 26486639 TI - Titchener's ? in context 1--delimited, discrete monomotif patterns, line arrangements, and branching patterns. AB - Three experiments tested the effects of the presence of nontarget ?s on Titchener's (1901) ?-illusion. Experiment 1 used patterns of four separate ?s, Experiment 2 used branching patterns in which four ?s were stuck together, and Experiment 3 used patterns of four triangles or four beehive forms for which the ? could be seen as a skeleton. Three independent samples of 12 observers each had to haptically indicate the lengths of target lines and verbally judge the relative lengths of the two lines of target ?s. The illusion to judge or indicate the ?'s undivided line as longer than its divided line survived throughout except for the branching patterns: here, haptic indications did not differ between the two types of lines. Specific features of these patterns and of the ? itself may be responsible for these effects. PMID- 26486640 TI - Joint Simon effects for non-human co-actors. AB - Social interactions with non-biological agents and interactions with technical devices have become increasingly important over the last years. Recent studies investigating the interactions between humans and non-human agents showed rather inconsistent results. While the joint Simon effect (cSE) was found to be absent for non-human co-actors like virtual wooden hands, other studies showed pronounced cSEs when the co-actor was a real event-producing object. However, an often overlooked difference between these studies is the way these co-actors delivered response events. Studies replacing the co-actor by event-producing objects used a continuous response mode, while in studies using wooden hands, the co-actor always produced action effects in a task-related, turn-taking mode. In a series of four experiments, we systematically tested the effects of the response mode on the size of the cSE. The cSE was larger when the co-actor produced events in a turn-taking response mode than in a continuous response mode. Furthermore, we consistently found reliable cSEs for different kinds of virtual non-human co actors (including a Japanese waving cat, scrambled patterns, and a wooden hand), and found no difference in the size of the cSE between human and non-human co actors. We discuss possible mechanisms explaining why a cSE might be present or absent when sharing tasks with virtual non-human co-actors. PMID- 26486638 TI - Soil-Transmitted Helminth Infections Are Associated With an Increase in Human Papillomavirus Prevalence and a T-Helper Type 2 Cytokine Signature in Cervical Fluids. AB - BACKGROUND: An ecological correlation between invasive cervical cancer incidence and burden of soil-transmitted helminths (STH) is hypothesized to explain the excess in detectable human papillomavirus (HPV) infection in Latin America, via a global T-helper type 2 (Th2)-biased mucosal immune response secondary to STH infection. METHODS: The association between current STH infection and HPV prevalence was compared in regions of Peru where STH is or is not endemic. Adjusted prevalence ratios (PRs) with robust variance were estimated as an effect measure of STH infection on HPV prevalence in each study site. Soluble immune marker profiles in STH-infected and STH-uninfected women were compared using Spearman rank correlation with the Sidak correction. RESULTS: Among women in the helminth-endemic region of the Peruvian Amazon, those with STH infection women had a 60% higher prevalence of HPV, compared with those without STH infection (PR, 1.6; 95% confidence interval, 1.0-2.7). Non-STH parasitic/protozoal infections in the non-STH-endemic population of Peru were not associated with HPV prevalence. In Iquitos, A Th2 immune profile was observed in cervical fluid from helminth-infected women but not helminth-uninfected women. CONCLUSIONS: A proportion of the increased HPV prevalence at older ages observed in Latin America may be due to a population-level difference in the efficiency of immunological control of HPV across the lifespan due to endemic STH infection. PMID- 26486637 TI - Age-Specific Race and Ethnicity Disparities in HIV Infection and Awareness Among Men Who Have Sex With Men--20 US Cities, 2008-2014. AB - BACKGROUND: Over half of human immunodeficiency virus (HIV) infections in the United States occur among men who have sex with men (MSM). Among MSM, 16% of estimated new infections in 2010 occurred among black MSM <25 years old. METHODOLOGY: We analyzed National HIV Behavioral Surveillance data on MSM from 20 cities. Poisson models were used to test racial disparities, by age, in HIV prevalence, HIV awareness, and sex behaviors among MSM in 2014. Data from 2008, 2011, and 2014 were used to examine how racial/ethnic disparities changed across time. RESULTS: While black MSM did not report greater sexual risk than other MSM, they were most likely to be infected with HIV and least likely to know it. Among black MSM aged 18-24 years tested in 2014, 26% were HIV positive. Among white MSM aged 18-24 years tested in 2014, 3% were HIV positive. The disparity in HIV prevalence between black and white MSM increased from 2008 to 2014, especially among young MSM. CONCLUSIONS: Disparities in HIV prevalence between black and white MSM continue to increase. Black MSM may be infected with HIV at younger ages than other MSM and may benefit from prevention efforts that address the needs of younger men. PMID- 26486641 TI - Spatial action-effect binding. AB - The temporal interval between an action and its ensuing effect is perceptually compressed. Specifically, the perceived onset of actions is shifted towards their effects in time and, vice versa, the perceived onset of effects is shifted towards their causing actions. In four experiments, we report evidence showing that action-effect binding also occurs in the spatial domain. Participants controlled the location of a visual stimulus by performing stylus movements before they judged either the position of the stylus or the position of the visual stimulus. The results yielded spatial binding between the perceived stylus position and the perceived stimulus position when the stimulus was under full control of the hand movement compared to control conditions without direct control. PMID- 26486642 TI - The scope of no return: Openness predicts the spatial distribution of Inhibition of Return. AB - How and what we attend to is foundational in determining the content of our experience, thus differences in attention contribute significantly to how we perceive the world, learn, and develop. Personality also plays a role in constraining how we learn to perceive the world and it is conceivable that some facets of personality interact with visual attention; however, the relationship between these two constitutional aspects of psychology remains unclear. To address this interplay between cognition and personality, we looked at how the Big Five personality traits relate to the spatial scope of attention, as indexed by the spatial distribution of Inhibition of Return (IOR). IOR is marked by a decrement in reaction time when a target appears at a cued location, more than 200 ms after that cue. As the cue/target distance increases there is a release from inhibition, providing a measure of the spatial distribution of IOR and reflecting the spatial scope of attention. The results presented here show personality does predict the distribution of IOR. Specifically, higher trait Openness is associated with a broader distribution of IOR and attention. This finding suggests there is an intimate connection between personality, particularly Openness, and the spatial allocation of attention. PMID- 26486643 TI - Novelty biases attention and gaze in a surprise trial. AB - While the classical distinction between task-driven and stimulus-driven biasing of attention appears to be a dichotomy at first sight, there seems to be a third category that depends on the contrast or discrepancy between active representations and the upcoming stimulus, and may be termed novelty, surprise, or prediction failure. For previous demonstrations of the discrepancy-attention link, stimulus-driven components (saliency) may have played a decisive role. The present study was conducted to evaluate the discrepancy-attention link in a display where novel and familiar stimuli are equated for saliency. Eye tracking was used to determine fixations on novel and familiar stimuli as a proxy for attention. Results show a prioritization of attention by the novel color, and a de-prioritization of the familiar color, which is clearly present at the second fixation, and spans over the next couple of fixations. Saliency, on the other hand, did not prioritize items in the display. The results thus reinforce the notion that novelty captures and binds attention. PMID- 26486644 TI - [Complications of knee arthroscopy]. AB - BACKGROUND: Today, knee arthroscopy is one of the standard interventions performed by an orthopaedist and usually has a low potential for complications. PURPOSE: The surgeon should still be aware of possible problems, and be able to control and explain them to the patient in detail before surgery. MATERIALS AND METHODS: The possible relevant peri-, intra- and postoperative complications of knee arthroscopy are discussed. RESULTS: Evaluation of the patient's medical history and comorbidities is crucial to successful treatment, in addition to a correct diagnosis and indications with the assistance of appropriate imaging procedures. Nervous and vascular injuries, malplacement of arthroscopy portals, thrombosis, air embolism, material breakage and a possible compartment syndrome constitute the peri-and intraoperative complications. Postoperatively, the most frequent negative events are haemarthrosis, thrombosis, embolism and infection, and the appearance of synovial fistulas. In the case of a joint infection, consistent and immediate diagnosis and therapy are vital for joint preservation. Late complications after arthroscopic interventions include Ahlback's disease, arthrofibrosis and complex regional pain syndrome (CRPS). DISCUSSION: Nowadays, the systematic education of arthroscopic surgeons using simulators, models, and cadavers, in addition to shadowing experienced arthroscopists, is required to offer patients the best therapeutic options. PMID- 26486645 TI - Garland Allen, Thomas Hunt Morgan, and Development. AB - Garland E. Allen's 1978 biography of the Nobel Prize winning biologist Thomas Hunt Morgan provides an excellent study of the man and his science. Allen presents Morgan as an opportunistic scientist who follows where his observations take him, leading him to his foundational work in Drosophila genetics. The book was rightfully hailed as an important achievement and it introduced generations of readers to Morgan. Yet, in hindsight, Allen's book largely misses an equally important part of Morgan's work - his study of development and regeneration. It is worth returning to this part of Morgan, exploring what Morgan contributed and also why he has been seen by contemporaries and historians such as Allen as having set aside some of the most important developmental problems. A closer look shows how Morgan's view of cells and development that was different from that of his most noted contemporaries led to interpretation of his important contributions in favor of genetics. This essay is part of a special issue, revisiting Garland Allen's views on the history of life sciences in the twentieth century. PMID- 26486646 TI - Membrane filter method to study the effects of Lactobacillus acidophilus and Bifidobacterium longum on fecal microbiota. AB - A large number of commensal bacteria inhabit the intestinal tract, and interbacterial communication among gut microbiota is thought to occur. In order to analyze symbiotic relationships between probiotic strains and the gut microbiota, a ring with a membrane filter fitted to the bottom was used for in vitro investigations. Test strains comprising probiotic nitto strains (Lactobacillus acidophilus NT and Bifidobacterium longum NT) and type strains (L. acidophilus JCM1132(T) and B. longum JCM1217(T) ) were obtained from diluted fecal samples using the membrane filter to simulate interbacterial communication. Bifidobacterium spp., Streptococcus pasteurianus, Collinsella aerofaciens, and Clostridium spp. were the most abundant gut bacteria detected before coculture with the test strains. Results of the coculture experiments indicated that the test strains significantly promote the growth of Ruminococcus gnavus, Ruminococcus torques, and Veillonella spp. and inhibit the growth of Sutterella wadsworthensis. Differences in the relative abundances of gut bacterial strains were furthermore observed after coculture of the fecal samples with each test strain. Bifidobacterium spp., which was detected as the dominant strain in the fecal samples, was found to be unaffected by coculture with the test strains. In the present study, interbacterial communication using bacterial metabolites between the test strains and the gut microbiota was demonstrated by the coculture technique. The detailed mechanisms and effects of the complex interbacterial communications that occur among the gut microbiota are, however, still unclear. Further investigation of these relationships by coculture of several fecal samples with probiotic strains is urgently required. PMID- 26486647 TI - Age-related emotional bias in processing two emotionally valenced tasks. AB - Previous studies suggest that older adults process positive emotions more efficiently than negative emotions, whereas younger adults show the reverse effect. We examined whether this age-related difference in emotional bias still occurs when attention is engaged in two emotional tasks. We used a psychological refractory period paradigm and varied the emotional valence of Task 1 and Task 2. In both experiments, Task 1 was emotional face discrimination (happy vs. angry faces) and Task 2 was sound discrimination (laugh, punch, vs. cork pop in Experiment 1 and laugh vs. scream in Experiment 2). The backward emotional correspondence effect for positively and negatively valenced Task 2 on Task 1 was measured. In both experiments, younger adults showed a backward correspondence effect from a negatively valenced Task 2, suggesting parallel processing of negatively valenced stimuli. Older adults showed similar negativity bias in Experiment 2 with a more salient negative sound ("scream" relative to "punch"). These results are consistent with an arousal-bias competition model [Mather and Sutherland (Perspectives in Psychological Sciences 6:114-133, 2011)], suggesting that emotional arousal modulates top-down attentional control settings (emotional regulation) with age. PMID- 26486648 TI - Working memory updating occurs independently of the need to maintain task context: accounting for triggering updating in the AX-CPT paradigm. AB - Theoretical models suggest that maintenance and updating are two functional states of working memory (WM), which are controlled by a gate between perceptual information and WM representations. Opening the gate enables updating WM with input, while closing it enables keeping the maintained information shielded from interference. However, it is still unclear when gate opening takes place, and what is the external signal that triggers it. A version of the AX-CPT paradigm was used to examine a recent proposal in the literature, suggesting that updating is triggered whenever the maintenance of the context is necessary for task performance (context-dependent tasks). In four experiments using this paradigm, we show that (1) a task-switching cost takes place in both context-dependent and context-independent trials; (2) task-switching is additive to the dependency effect, and (3) unlike switching cost, the dependency effect is not affected by preparation and, therefore, does not reflect context-updating. We suggest that WM updating is likely to be triggered by a simple mechanism that occurs in each trial of the task regardless of whether maintaining the context is needed or not. The implications for WM updating and its relationship to task-switching are discussed. PMID- 26486649 TI - Dog owners show experience-based viewing behaviour in judging dog face approachability. AB - Our prior visual experience plays a critical role in face perception. We show superior perceptual performance for differentiating conspecific (vs non conspecific), own-race (vs other-race) and familiar (vs unfamiliar) faces. However, it remains unclear whether our experience with faces of other species would influence our gaze allocation for extracting salient facial information. In this eye-tracking study, we asked both dog owners and non-owners to judge the approachability of human, monkey and dog faces, and systematically compared their behavioural performance and gaze pattern associated with the task. Compared to non-owners, dog owners assessed dog faces with shorter time and fewer fixations, but gave higher approachability ratings. The gaze allocation within local facial features was also modulated by the ownership. The averaged proportion of the fixations and viewing time directed at the dog mouth region were significantly less for the dog owners, and more experienced dog owners tended to look more at the dog eyes, suggesting the adoption of a prior experience-based viewing behaviour for assessing dog approachability. No differences in behavioural performance and gaze pattern were observed between dog owners and non-owners when judging human and monkey faces, implying that the dog owner's experience-based gaze strategy for viewing dog faces was not transferable across faces of other species. PMID- 26486650 TI - Conflict resolution in two-digit number processing: evidence of an inhibitory mechanism. AB - We investigated the mechanism involved in conflict resolution when individuals processed two-digit numbers. Participants performed a comparison task in blocks of two trials. In the first trial, between-decade two-digit numbers were used in a compatible condition where the decade and the unit of one number were larger than those of the other number (i.e., 21-73) and an incompatible condition where the decade of one number was larger but the unit was smaller than those of the other number (i.e., 61-53). In the second trial, within-decade two-digit numbers were presented in a related condition where the numbers contained the units presented previously (i.e., 41-43) and an unrelated condition with units that did not appear before (i.e., 48-49). In the first trial, participants responded more slowly in incompatible trials relative to compatible trials. In the second trial, participants were slower in the related condition relative to unrelated trials only after incompatible trials. These results suggest that participants experienced conflict in the incompatible condition of first trial and that they inhibited irrelevant units to resolve conflict. PMID- 26486651 TI - Implicit learning is order dependent. AB - We report two experiments using the artificial-grammar task that demonstrate order dependence in implicit learning. Studying grammatical training strings in different orders did not affect participants' discrimination of grammatical from ungrammatical test strings, but it did affect their judgments about specific test strings. Current accounts of learning in the artificial-grammar task focus on category-level discrimination and largely ignore item-level discrimination. Hence, the results highlight the importance of moving theory from a category- to an item-level of analysis and point to a new way to evaluate and to refine accounts of implicit learning. PMID- 26486653 TI - Walk the Talk: The Nurses' Role in Increasing Physical Activity. PMID- 26486652 TI - A proteomic analysis of seeds from Bt-transgenic Brassica napus and hybrids with wild B. juncea. AB - Transgene insertions might have unintended side effects on the transgenic host, both crop and hybrids with wild relatives that harbor transgenes. We employed proteomic approaches to assess protein abundance changes in seeds from Bt transgenic oilseed rape (Brassica napus) and its hybrids with wild mustard (B. juncea). A total of 24, 15 and 34 protein spots matching to 23, 13 and 31 unique genes were identified that changed at least 1.5 fold (p < 0.05, Student's t-test) in abundance between transgenic (tBN) and non-transgenic (BN) oilseed rape, between hybrids of B. juncea (BJ) * tBN (BJtBN) and BJ * BN (BJBN) and between BJBN and BJ, respectively. Eight proteins had higher abundance in tBN than in BN. None of these proteins was toxic or nutritionally harmful to human health, which is not surprising since the seeds are not known to produce toxic proteins. Protein spots varying in abundance between BJtBN and BJBN seeds were the same or homologous to those in the respective parents. None of the differentially accumulated proteins between BJtBN and BJBN were identical to those between tBN and BN. Results indicated that unintended effects resulted from transgene flow fell within the range of natural variability of hybridization and those found in the native host proteomes. PMID- 26486654 TI - X-ray analysis of gastrointestinal motility in conscious mice. Effects of morphine and comparison with rats. AB - BACKGROUND: Non-invasive methods to study gastrointestinal (GI) motility are of high interest, particularly in chronic studies. Amongst these, radiographic techniques after contrast intragastric administration may offer many advantages. In previous studies, we have successfully and reproducibly applied these techniques together with a semiquantitative analysis method to characterize the effect of different drugs, acutely or repeatedly administered in rat models, but we have never before used these techniques in mice. These are very convenient in basic research. Our aim was to determine if our method is also valid in mice. Additionally, we determined the effect of morphine on GI motor function in both species. METHODS: Animals received an intraperitoneal administration of morphine (at 10 and 5 mg/kg for rats and mice, respectively). Twenty min later, barium contrast (at 2 g/mL) was gavaged (2.5 and 0.4 mL for rats and mice respectively) and serial X-rays were obtained 0-8 h after contrast. X-rays were analyzed as previously described, using a semiquantitative score to build motility curves for each GI region. KEY RESULTS: Motility was much faster in mice than in rats for all GI regions. Morphine at the doses used significantly depressed motility in both species to a similar extent if the whole gut or the upper GI regions (stomach, small intestine) were considered, although its effect seemed to be more intense in the lower GI regions (caecum, colorectum) in rats than in mice. CONCLUSIONS & INFERENCES: We have validated our X-rays method for its use in mice. PMID- 26486655 TI - A facile method for high-performance multicolor upconversion microrods for biological encoding. AB - In this paper, we demonstrate a facile method for preparing high-performance multicolor upconversion (UC) microrods for biological encoding. Multicolor UC microrods were prepared through a one-step facile hydrothermal method. The as prepared UC microrods were uniform in shape and size (about 2 MUm in length). For bioconjugation, the UC microrods were functionalized by coating with an amino terminated silica shell. In order to magnify the bioactive sites, poly (acrylic acid) was introduced to the surface of UC microrods. The optical micrographs displayed that the carboxylated UC microrods were bright enough for observation of single crystals by a conventional microscope. They also exhibited excellent fluorescence stability against time expansion and pH change. Furthermore, a conventional optical microscope can readout the results of a sandwich immunoassay that was conducted by the UC microrods. All the results indicated that the UC microrods exhibited great potential to be new encoding particles for biological molecules. PMID- 26486656 TI - Who wants to be a researcher? PMID- 26486657 TI - [Re: Criteria-based diagnostics generate excessive and incorrect diagnoses]. PMID- 26486658 TI - [P. Gjerden replies]. PMID- 26486659 TI - [Re: Where is the boundary between diagnostics and research?]. PMID- 26486660 TI - [Re: Emergency hospitalisation in six municipalities in the Sunnmore district]. PMID- 26486661 TI - [T. Hole and colleagues reply]. PMID- 26486662 TI - [Re: First generalized tonic-clonic seizure]. PMID- 26486663 TI - Telemedicine brings specialist healthcare services to patients' homes. PMID- 26486664 TI - Dogs as the source of Giardia in Bergen in 2004 - barking up the wrong tree? PMID- 26486665 TI - [In Process Citation]. PMID- 26486666 TI - [In Process Citation]. PMID- 26486667 TI - Obese, fat, or just overweight? AB - BACKGROUND: Discussing obesity with the patient without this being perceived as offensive may represent a challenge. Prevention of lifestyle diseases requires that this topic be addressed with those concerned. In this study, we investigate the patients' sensitivity to expressions, i.e. their notions of appropriateness or inappropriateness regarding various terms for obesity, and what patient characteristics are associated with such sensitivity to expressions. MATERIAL AND METHOD: The investigation is part of a five-year study of patients in Central Norway who were treated for morbid obesity. The terms used in the study had been suggested by the Overweight Patients' Association. Data on sensitivity to expressions were collected with the aid of a questionnaire one year after completion of the treatment. RESULTS: Altogether 157 out of 206 participants completed the questionnaire. Their average body mass index (BMI) (SD) amounted to 37.6 kg/m2 (7.3 kg/m2). Their sensitivity to 14 different designations varied. "Weight", "overweight" and "weight problem" returned the best scores, whereas "obesitas", "obese" and "fat" were deemed least appropriate. The highest sensitivity to expressions was found among women, those who developed overweight early in life, those who had higher education and those who were dissatisfied with their weight. INTERPRETATION: The perceptions of various expressions for overweight and obesity varied considerably. Knowledge about this topic may be relevant for doctors and other health personnel in prevention and treatment of obesity. PMID- 26486668 TI - [Diagnostic accuracy for heart failure - data from the Akershus Cardiac Examination 2 Study]. AB - BACKGROUND: Diagnosing heart failure in an on-call setting can be difficult, and international studies report diagnostic accuracy among duty doctors, as measured using area under the ROC curve (AUC), to be 0.76-0.90. This study has examined the accuracy with which doctors in the internal medicine out-of-hours service in a Norwegian university hospital distinguish heart failure from no heart failure in patients with dyspnoea. MATERIAL AND METHOD: Information was gathered on 468 patients admitted to Akershus University Hospital with dyspnoea between June 2009 and November 2010, and 314 patients were included in the study. The duty doctors estimated the probability of heart failure (0-100%) before N-terminal pro-B-type natriuretic peptide (NTproBNP) concentrations were known. The final diagnosis for the hospital admission was made retrospectively by two independent doctors after review of the medical records, including supplementary tests and the patient outcome. RESULTS: Heart failure was considered the cause of hospitalisation in 143 patients (46%). Patients with heart failure were older, more often men, had a higher prevalence of heart disease, reduced/impaired renal function, and higher NTproBNP concentrations than patients with non-heart failure dyspnoea. The diagnostic accuracy among duty doctors for heart failure (AUC) was 0.86 (95% confidence interval 0.82-0.90). The doctors' diagnostic accuracy was lower when the patient had heart failure with left ventricular ejection fraction [LVEF] >= 50% (n=52): AUC 0.83 (0.77-0.87). INTERPRETATION: The duty doctors at Akershus University Hospital from 2009-2010 demonstrated similar diagnostic accuracy for heart failure as previously reported from international centres. Diagnostic accuracy was lower for heart failure patients with LVEF >= 50%. PMID- 26486669 TI - Therapeutic complement inhibition - from experimental to clinical medicine. AB - Internationally, the use of the C5-inhibiting monoclonal antibody eculizumab has in the course of just a few years become the first choice of treatment of atypical haemolytic uraemic syndrome and the most severe phenotypes of paroxysmal nocturnal haemoglobinuria. At present eculizumab is the only complement inhibitor in ordinary clinical use. This despite the fact that there only exists one randomised, placebo-controlled trial of eculizumab for paroxysmal nocturnal haemoglobinuria and none for atypical haemolytic uraemic syndrome, and that the therapy is very costly. There is reason to believe that complement inhibition as therapy will increase in the future, and that other drugs will also prove to be effective. PMID- 26486670 TI - Cerebral venous thrombectomy. PMID- 26486671 TI - A woman in her 70s with chronic walking difficulties. PMID- 26486672 TI - What exactly is myalgic encephalomyelitis? PMID- 26486673 TI - [Norwegian National Unity party physicians and their relationship with euthanasia]. PMID- 26486675 TI - [In Process Citation]. PMID- 26486674 TI - [Senile and demented]. PMID- 26486677 TI - [Are physicians leisure time more important than others?]. PMID- 26486678 TI - [Pelvic pain brought to light]. PMID- 26486679 TI - [Local ischemia can be detected by internal organ CO2 measurement]. PMID- 26486680 TI - [Random depression treatment in nursing homes]. PMID- 26486683 TI - Bolder science needed now for protected areas. AB - Recognizing that protected areas (PAs) are essential for effective biodiversity conservation action, the Convention on Biological Diversity established ambitious PA targets as part of the 2020 Strategic Plan for Biodiversity. Under the strategic goal to "improve the status of biodiversity by safeguarding ecosystems, species, and genetic diversity," Target 11 aims to put 17% of terrestrial and 10% of marine regions under PA status by 2020. Additionally and crucially, these areas are required to be of particular importance for biodiversity and ecosystem services, effectively and equitably managed, ecologically representative, and well-connected and to include "other effective area-based conservation measures" (OECMs). Whereas the area-based targets are explicit and measurable, the lack of guidance for what constitutes important and representative; effective; and OECMs is affecting how nations are implementing the target. There is a real risk that Target 11 may be achieved in terms of area while failing the overall strategic goal for which it is established because the areas are poorly located, inadequately managed, or based on unjustifiable inclusion of OECMs. We argue that the conservation science community can help establish ecologically sensible PA targets to help prioritize important biodiversity areas and achieve ecological representation; identify clear, comparable performance metrics of ecological effectiveness so progress toward these targets can be assessed; and identify metrics and report on the contribution OECMs make toward the target. By providing ecologically sensible targets and new performance metrics for measuring the effectiveness of both PAs and OECMs, the science community can actively ensure that the achievement of the required area in Target 11 is not simply an end in itself but generates genuine benefits for biodiversity. PMID- 26486684 TI - Respiratory failure with cervicomedullary infarctions. AB - Respiratory failure from brainstem and spinal cord infarction has been described without attention to ventilatory characteristics and prognosis. We describe two patients who suffered from complete aventilation with cervicomedullary infarctions. One achieved full recovery of spontaneous breathing, and the other had persistent aventilation until her death 4 months after her stroke from sepsis. The anatomical extent of the infarction as identified by magnetic resonance imaging was predictive of the recoverability of spontaneous breathing, and important clinical considerations are emphasized when considering weaning a patient from mechanical ventilation after respiratory failure from cervicomedullary infarction. PMID- 26486682 TI - Effect of a postoperative exercise program on arteriovenous fistula maturation: A randomized controlled trial. AB - Exercises after arteriovenous fistula (AVF) creation may help to improve maturation; however, their usefulness has only been examined in indirect, non comparative studies or small trials. Between June 2013 and November 2014, we included all ambulatory patients with stages 5-5D chronic kidney disease who were candidates for the creation of a native AVF in our center. After surgery, all patients were randomized to an exercise group or a control group with single blind control. At 1 month postoperatively, clinical maturation (expert nurse inspection) and ultrasonographic maturation (flow >500 mL/min, venous diameter >5 mm and depth <6 mm) were assessed in all patients. A total of 72 patients were randomized, 3 were lost to follow-up, and 69 were finally analyzed. The mean age was 66.8 years (standard deviation 13.8), 70.0% were men, and 65.2% were in pre dialysis. After surgery (42.0% had distal AVF), the patients were randomized (31 controls, 38 exercise group). At 1 month after surgery, global clinical and ultrasonographic maturation was assessed in 88.4% and 78.3% of AVF, respectively (kappa = 0.539). Non-significant differences in clinical or ultrasonographic maturation were seen between exercise and control group (94.7% vs. 80.6%, P = 0.069; 81.6% vs. 74.2%, P = 0.459). A stepwise logistic regression was performed to control previously analyzed asymmetrically distributed confounding factors (AVF localization), revealing that the exercise group showed greater clinical, but not ultrasonographic, maturation (odds ratio [OR] 5.861, 95% confidence interval: 1.006-34.146 and OR 2.403, 0.66-8.754). A postoperative controlled exercise program after AVF creation seems to increase 1-month clinical AVF maturation in distal accesses. Furthermore, exercise programs should be taken into account, especially in distal accesses. PMID- 26486685 TI - Cerebral infarction during hypertensive encephalopathy: Case report with pathologic and atypical radiographic findings. AB - Neuroimaging of patients with hypertensive encephalopathy frequently reveals white matter changes that reverse with control of blood pressure. We report a young woman who presented with hypertensive encephalopathy but with unusual radiographic findings. Her course and atypical appearance on magnetic resonance imaging raised suspicion for encephalitis, but autopsy disclosed a large cerebral infarction, an uncommon complication during this clinical syndrome. The discovery of a pheochromocytoma at autopsy was also unexpected and may be associated with the unusual features of this case. The clinical, pathologic, and radiographic descriptions of this case may offer further insight into the pathophysiology of hypertensive encephalopathy. PMID- 26486686 TI - Factors predicting 30-day mortality in the Warsaw stroke registry. AB - Poland has high mortality and morbidity due to stroke. Our prospective population based study conducted in Warsaw in 1991-1992 showed a stroke incidence similar to other European countries. However, 30-day case mortality rates were much higher. Our aim was to explore factors predicting 30-day mortality in Warsaw. The study population consisted of all patients with first-ever-in-a-lifetime strokes admitted to the Department of Cerebrovascular Diseases during the 2-year prospective population-based stroke registry. Cases with uncertain stroke type were excluded from analysis. During the 2-year study period, 633 patients with stroke were registered (462 with first-ever-in-a-lifetime stroke); 351 of them completed full diagnostic procedures, and 297 were diagnosed with ischemic stroke (IS) and 54 with intracerebral hemorrhage (ICH). A logistic regression model for IS identified 7 independent variables predicting 30-day mortality: increasing age, decreased consciousness at the onset of stroke, extraocular movement disorder, severity of motor weakness, congestive heart failure, kidney diseases, and chronic obstructive pulmonary diseases (COPD). A logistic regression model for ICH identified two independent predictor variables: extraocular movement disorders and decreased consciousness. Comparison of the Warsaw Stroke Registry with the Stroke Data Bank (SDB) revealed higher prevalences of heart disease (angina and atrial fibrillation) and COPD in the Warsaw population. Comorbidity of medical diseases with stroke probably contributed to higher mortality in the Warsaw as opposed to U.S. PATIENT SAMPLE: Disorders of consciousness at the onset of stroke were more severe in Warsaw than in the U.S. SAMPLE: Stroke type, severity of weakness score, and severity of stroke scale were similar for the SDB and Warsaw populations. In Poland, high levels of medical comorbidity rather than stroke severity probably account for poor short-term prognosis in stroke. PMID- 26486687 TI - Beneficial effect of clonidine on spasticity antagonized by baclofen in a stroke patient. AB - Although Clonidine has recently been described as a useful antispasticity agent, to our knowledge there has not been a previous report of clonidine's antispasticity effect antagonized by baclofen. Using a 0-5 Modified Ashworth Scale to evaluate the right knee extensor tone in a 74-year-old man 5 months following a left middle cerebral artery stroke, tone improved from 3 to 1 on Clonidine 0.6 mg daily in divided doses. The day after addition of baclofen at 15 mg daily in divided doses, tone increased to 4. Baclofen was withdrawn with a decrease in tone to 2. Baclofen alone at the above dose resulted in tone comparable to the clonidine-free baseline. Treatment with Clonidine alone was resumed, and the expected reduction in hypertonicity was again observed. Possible mechanisms of action for baclofen antagonizing the beneficial effect of Clonidine on spasticity after stroke are presented and discussed. PMID- 26486688 TI - Utility of magnetic resonance angiography and carotid ultrasound in the evaluation of carotid stenosis. AB - We assessed the utility of noninvasive methods for clinical decision-making in carotid stenosis. We compared the results from magnetic resonance angiography (MRA), carotid ultrasound (CUS), and conventional carotid angiography (CCA) for 39 arteries. Noninvasive studies were graded by a 5-point diameter scale. Conventional angiograms were evaluated for percent stenosis using the North American Symptomatic Carotid Endarterectomy Trial criteria and diameter of residual lumen by caliper. Agreement was 64% between MRA and CCA, 72% between CUS and CCA, and 77% between MRA and CUS. For vessels measuring greater than 60% stenosis by CCA, sensitivity was 100% for both MRA and CUS. Specificities were 65% (MRA) and 71% (CUS), reflecting the tendency for MRA and CUS to overestimate stenosis. MRA and CUS correlated with residual lumen, even in some cases where they disagreed with the percent stenosis. We conclude that patients with normal arteries or mild stenosis as determined by MRA and CUS may be excluded from further evaluation, whereas patients with highergrade lesions should be evaluated with CCA prior to consideration for surgery. Close correlation between the results of MRA and CUS, as well as their apparent correlation with residual lumen, suggests that MRA and CUS may more accurately reflect carotid flow than does calculated percent stenosis. PMID- 26486689 TI - Stroke causing pure brachial monoparesis. AB - We studied 15 consecutive patients with acute brachial monoparesis due to stroke. There were 12 men and 3 women aged 45-78 years (mean, 61). Stroke workup included brain imaging, carotid duplex, echocardiography, and blood tests. In nine patients, the arm weakness was mainly distal, and in six it was equal distally and proximally. Tendon reflexes in the affected arm compared to the contralateral arm were symmetrical in 10, increased in 3, and decreased in 2 patients. In 14 patients, brain imaging showed a stroke in the middle cerebral artery branch territory superficially corresponding to the symptoms; and magnetic resonance imaging was negative in 1. Fourteen strokes were ischemic, and 1 was hemorrhagic. Of the 14 patients with ischemic stroke, 6 had > 50% ipsilateral extracranial cartoid artery stenosis, 4 had a serious source of cardiac emboli, and in 4 the cause of stroke was not identified. Our findings suggest that sudden brachial monoparesis should be considered a middle cerebral artery branch territory nonlacunar stroke syndrome. The etiologies of stroke causing pure brachial monoparesis are varied and include carotid artery disease, cardiac embolism, and intracerebral hemorrhage. PMID- 26486690 TI - Problems in the recognition of aortoembolic stroke. AB - Recent reports suggest aortoembolism is an important cause of stroke. Although transesophageal echocardiography visualizes the aortic arch, diagnosis of aortoembolism stroke is not common. We investigated reasons for this discrepancy at our institution. We reviewed charts and transesophageal echocardiography videotapes of 16 patients with recent ischemic stroke or transient ischemic attack who had undergone transesophageal echocardiography. For each patient, we determined the most likely cause of cerebral ischemia, and we compared the official transesophageal echocardiography report to our interpretation of the videotape. In our videotape review, 13 patients had good visualization of the aortic arch. Of 6 patients with atherosclerosis in the arch, 1 had high-grade carotid stenosis, 1 had atrial fibrillation, 1 had "small-vessel disease," and 3 had cerebral ischemia of unknown cause. The official reports did not mention aortic arch disease in 4 of 6 patients. A possible cause of cerebral ischemia was identified in 6 of 7 patients with normal aortic arches. Of 3 patients who had poor visualization of the aortic arch, one had "small-vessel disease," and 2 had ischemic stroke of unknown cause despite extensive workups. We conclude that aortic arch disease is common in patients with ischemic stroke and transient ischemic attack and may be a cause of cerebral ischemia, especially in patients with stroke or transient ischemic attack due to small-vessel occlusion or of unknown cause. Aortic arch disease may not be identified as the cause of stroke or transient ischemic attack because (a) transesophageal echocardiography is not done, (b) transesophageal echocardiography is done but the aortic arch is not visualized, (c) transesophageal echocardiography is done, the aortic arch is visualized, but the examiner does not comment on aortic arch disease, or (d) despite transesophageal echocardiography identification of arotic arch disease, the treating physician does not consider the aorta to be a potential source of embolization. PMID- 26486691 TI - A computational study of the chlorination and hydroxylation of amines by hypochlorous acid. AB - The reactions of hypochlorous acid (HOCl) with ammonia, (di)methylamine, and heterocyclic amines have been studied computationally using double-hybrid DFT methods (B2PLYP-D and BK-PLYP) and a G3B3 composite scheme. In the gas phase the calculated energy barriers for N- and/or C-hydroxylation are ca. 100 kJ mol(-1) lower than the barrier for N-chlorination of amines. In the model solvent, however, the latter process becomes kinetically more favored. The explicit solvent effects are crucial for determination of the reaction mechanism. The N chlorination is extremely susceptible to the presence of explicit water molecules, while no beneficial solvation effect has been found for the N- or C hydroxylation of amines. The origin of the observed solvent effects arises from differential solvation of the respective transition states for chlorine- and oxygen-transfers, respectively. The nature of solvation of the transition state structures has been explored in more detail by classical molecular dynamics (MD) simulation. In agreement with the quantum mechanical approach, the most stable structural motif, which includes the amine, HOCl, and two reactive waters, has been identified during the MD simulation. The inclusion of 5 or 6 explicit water molecules is required to reproduce the experimental barriers for HOCl-induced formation of N-chloramines in an aqueous environment. PMID- 26486692 TI - Public Health England denies conspiracy over obesity report's timing. PMID- 26486693 TI - Trends in incidence and survival for upper tract urothelial cancer (UTUC) in the state of Victoria--Australia. AB - OBJECTIVE: To investigate the incidence and mortality trends of upper tract urothelial cancers (UTUC) in Victoria over the last decade. PATIENTS AND METHODS: Age-adjusted incidence and mortality rates were calculated for UTUC. These were identified using data from the Victorian Cancer Registry from 2001 until 2011 based on histological diagnoses. Age at diagnosis, sex and demographical location were compared. RESULTS: The age-standardised incidence of UTUC remained stable from 2001 to 2011. There were 278 deaths from UTUC over this period with an overall 5-year survival rate of 32%. There was no significant difference in survival between 2001-06 and 2007-11 (30% vs 36%, respectively). Lower age at diagnosis was associated with a significant improvement in survival (P = 0.01). Sex and geographical location appeared to have no effect on survival. CONCLUSION: The 5-year survival rates for UTUC in Victoria are poor, particularly in comparison to worldwide data. In contrast to worldwide trends, the incidence of UTUC appears to be stable. No significant improvement in 5-year survival rates over the short study period was identified. These findings highlight the difficulties in managing this rare yet deadly malignancy. PMID- 26486695 TI - Modular solid-phase synthesis, catalytic application and efficient recycling of supported phosphine-phosphite ligand libraries. AB - In spite of decades of research in the field of homogeneous asymmetric catalysis the discovery of new high performance catalysts still relies heavily on trial-and error. There is still a lack of efficient combinatorial methods which enable the synthesis and screening of vast ligand libraries, especially for bidentate phosphorus ligands. Here we present a highly modular solid-phase synthetic approach which provides facile access to libraries of phosphine-phosphite ligands in quantitative yield requiring only minimal work-up. The obtained library of supported phosphine-phosphites was successfully applied in rhodium catalyzed asymmetric hydrogenation obtaining high enantioselectivities up to 98%. Also, these polymer supported ligands could be successfully recycled under batch conditions exhibiting only a small decline of activity and no loss of selectivity. PMID- 26486694 TI - Rates of As and Trace-Element Mobilization Caused by Fe Reduction in Mixed BTEX Ethanol Experimental Plumes. AB - Biodegradation of organic matter, including petroleum-based fuels and biofuels, can create undesired secondary water-quality effects. Trace elements, especially arsenic (As), have strong adsorption affinities for Fe(III) (oxyhydr)-oxides and can be released to groundwater during Fe-reducing biodegradation. We investigated the mobilization of naturally occurring As, cobalt (Co), chromium (Cr), and nickel (Ni) from wetland sediments caused by the introduction of benzene, toluene, ethylbenzene, and xylenes (BTEX) and ethanol mixtures under iron- and nitrate-reducing conditions, using in situ push-pull tests. When BTEX alone was added, results showed simultaneous onset and similar rates of Fe reduction and As mobilization. In the presence of ethanol, the maximum rates of As release and Fe reduction were higher, the time to onset of reaction was decreased, and the rates occurred in multiple stages that reflected additional processes. The concentration of As increased from <1 MUg/L to a maximum of 99 MUg/L, exceeding the 10 MUg/L limit for drinking water. Mobilization of Co, Cr, and Ni was observed in association with ethanol biodegradation but not with BTEX. These results demonstrate the potential for trace-element contamination of drinking water during biodegradation and highlight the importance of monitoring trace elements at natural and enhanced attenuation sites. PMID- 26486697 TI - Toward a terahertz-driven electron gun. AB - Femtosecond electron bunches with keV energies and eV energy spread are needed by condensed matter physicists to resolve state transitions in carbon nanotubes, molecular structures, organic salts, and charge density wave materials. These semirelativistic electron sources are not only of interest for ultrafast electron diffraction, but also for electron energy-loss spectroscopy and as a seed for x ray FELs. Thus far, the output energy spread (hence pulse duration) of ultrafast electron guns has been limited by the achievable electric field at the surface of the emitter, which is 10 MV/m for DC guns and 200 MV/m for RF guns. A single cycle THz electron gun provides a unique opportunity to not only achieve GV/m surface electric fields but also with relatively low THz pulse energies, since a single-cycle transform-limited waveform is the most efficient way to achieve intense electric fields. Here, electron bunches of 50 fC from a flat copper photocathode are accelerated from rest to tens of eV by a microjoule THz pulse with peak electric field of 72 MV/m at 1 kHz repetition rate. We show that scaling to the readily-available GV/m THz field regime would translate to monoenergetic electron beams of ~100 keV. PMID- 26486698 TI - Local Heat Application for the Treatment of Buruli Ulcer: Results of a Phase II Open Label Single Center Non Comparative Clinical Trial. AB - BACKGROUND: Buruli ulcer (BU) is a necrotizing skin disease most prevalent among West African children. The causative organism, Mycobacterium ulcerans, is sensitive to temperatures above 37 degrees C. We investigated the safety and efficacy of a local heat application device based on phase change material. METHODS: In a phase II open label single center noncomparative clinical trial (ISRCTN 72102977) under GCP standards in Cameroon, laboratory confirmed BU patients received up to 8 weeks of heat treatment. We assessed efficacy based on the endpoints 'absence of clinical BU specific features' or 'wound closure' within 6 months ("primary cure"), and 'absence of clinical recurrence within 24 month' ("definite cure"). RESULTS: Of 53 patients 51 (96%) had ulcerative disease. 62% were classified as World Health Organization category II, 19% each as category I and III. The average lesion size was 45 cm(2). Within 6 months after completion of heat treatment 92.4% (49 of 53, 95% confidence interval [CI], 81.8% to 98.0%) achieved cure of their primary lesion. At 24 months follow-up 83.7% (41 of 49, 95% CI, 70.3% to 92.7%) of patients with primary cure remained free of recurrence. Heat treatment was well tolerated; adverse effects were occasional mild local skin reactions. CONCLUSIONS: Local thermotherapy is a highly effective, simple, cheap and safe treatment for M. ulcerans disease. It has in particular potential as home-based remedy for BU suspicious lesions at community level where laboratory confirmation is not available. CLINICAL TRIALS REGISTRATION: ISRCT 72102977. PMID- 26486700 TI - Reply to Ressner et al. PMID- 26486701 TI - Significant Reduction of External Ventricular Drainage-Associated Meningoventriculitis by Chlorhexidine-Containing Dressings: A Before-After Trial. PMID- 26486699 TI - Impact of Sulfadoxine-Pyrimethamine Resistance on Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy at Clearing Infections and Preventing Low Birth Weight. AB - BACKGROUND: Owing to increasing sulfadoxine-pyrimethamine (SP) resistance in sub Saharan Africa, monitoring the effectiveness of intermittent preventive therapy in pregnancy (IPTp) with SP is crucial. METHODS: Between 2009 and 2013, both the efficacy of IPTp-SP at clearing existing peripheral malaria infections and the effectiveness of IPTp-SP at reducing low birth weight (LBW) were assessed among human immunodeficiency virus-uninfected participants in 8 sites in 6 countries. Sites were classified as high, medium, or low resistance after measuring parasite mutations conferring SP resistance. An individual-level prospective pooled analysis was conducted. RESULTS: Among 1222 parasitemic pregnant women, overall polymerase chain reaction-uncorrected and -corrected failure rates by day 42 were 21.3% and 10.0%, respectively (39.7% and 21.1% in high-resistance areas; 4.9% and 1.1% in low-resistance areas). Median time to recurrence decreased with increasing prevalence of Pfdhps-K540E. Among 6099 women at delivery, IPTp-SP was associated with a 22% reduction in the risk of LBW (prevalence ratio [PR], 0.78; 95% confidence interval [CI], .69-.88; P < .001). This association was not modified by insecticide-treated net use or gravidity, and remained significant in areas with high SP resistance (PR, 0.81; 95% CI, .67-.97; P = .02). CONCLUSIONS: The efficacy of SP to clear peripheral parasites and prevent new infections during pregnancy is compromised in areas with >90% prevalence of Pfdhps-K540E. Nevertheless, in these high-resistance areas, IPTp-SP use remains associated with increases in birth weight and maternal hemoglobin. The effectiveness of IPTp in eastern and southern Africa is threatened by further increases in SP resistance and reinforces the need to evaluate alternative drugs and strategies for the control of malaria in pregnancy. PMID- 26486703 TI - Noninferiority Doesn't Mean Not Inferior. PMID- 26486704 TI - Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis. AB - BACKGROUND: Available treatments for lymphatic filariasis (LF) are limited in their longterm clearance of microfilaria from the blood. The safety and efficacy of a single-dose triple-drug therapy of the antifilarial drugs diethylcarbamazine (DEC), ivermectin (IVM), and albendazole (ALB) for LF are unknown. METHODS: We performed a pilot study to test the efficacy, safety, and pharmacokinetics of single-dose DEC, IVM, and ALB in Wuchereria bancrofti-infected Papua New Guineans. Adults were randomized into 2 treatment arms, DEC 6 mg/kg + ALB 400 mg (N = 12) or DEC 6 mg/kg + ALB 400 mg + IVM 200 MUg/kg (N = 12), and monitored for microfilaria, parasite antigenemia, adverse events (AEs), and serum drug levels. RESULTS: Triple-drug therapy induced >2-log reductions in microfilaria levels at 36 and 168 hours after treatment compared with approximately 1-log reduction with 2 drugs. All 12 individuals who received 3 drugs were microfilaria negative 1 year after treatment, whereas 11 of 12 individuals in the 2-drug regimen were microfilaria positive. In 6 participants followed 2 years after treatment, those who received 3 drugs remained microfilaria negative. AEs, particularly fever, myalgias, pruritus, and proteinuria/hematuria, occurred in 83% vs 50% of those receiving triple-drug compared to 2-drug treatment respectively (P = .021); all resolved within 7 days after treatment. No serious AEs were observed in either group. There was no significant effect of IVM on DEC or ALB drug levels. CONCLUSIONS: Triple-drug therapy is safe and more effective than DEC + ALB for Bancroftian filariasis and has the potential to accelerate elimination of lymphatic filariasis. CLINICAL TRIALS REGISTRATION: NCT01975441. PMID- 26486702 TI - Randomized Controlled Trial to Compare Immunogenicity of Standard-Dose Intramuscular Versus Intradermal Trivalent Inactivated Influenza Vaccine in HIV Infected Men Who Have Sex With Men in Bangkok, Thailand. AB - BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) are at increased risk for severe influenza, yet immune responses to standard-dose intramuscular (IM) influenza vaccine are suboptimal in this population. Intradermal (ID) delivery of influenza vaccine might improve immune response through enhanced stimulation of dendritic cells. METHODS: We conducted a randomized, double-blind, controlled trial to compare the immunogenicity of off label standard-dose (15 ug) ID vs standard-dose (15 ug) IM inactive influenza vaccine in HIV-infected men in Bangkok, Thailand. The primary study outcome was seroconversion (minimum titer of 1:40 and >=4-fold rise in antibody titer) at 1 month postvaccination based on serum hemagglutination inhibition antibody titers against each vaccine strain. Adverse events (AEs) in the 7 days following vaccination were also assessed. RESULTS: We enrolled 400 HIV-infected participants; 200 were randomly assigned to receive IM and 200 ID vaccine. Vaccine arms were well-balanced with respect to age, CD4 cell count, HIV RNA load, and antiretroviral treatment. Percentage of seroconversion to all (ID 14% vs IM 15%; P = .8) or at least 1 (ID 69% vs IM 68%; P = .7) of the 3 vaccine strains did not differ significantly between ID vs IM vaccine recipients. A higher proportion of participants who received ID vaccine had mild injection-site AEs compared with participants who received IM vaccine (77% vs 27%). CONCLUSIONS: There were no significant differences in the immunogenicity of standard-dose ID vs IM influenza vaccine in this HIV-infected population in Thailand. Additional strategies to enhance immune responses to influenza vaccine among HIV-infected persons are needed. CLINICAL TRIALS REGISTRATION: NCT01538940. PMID- 26486706 TI - PrEP Continuum of Care for MSM in Atlanta and Los Angeles County. PMID- 26486705 TI - Azole Resistance in Aspergillus fumigatus: Can We Retain the Clinical Use of Mold Active Antifungal Azoles? AB - Azole resistance in Aspergillus fumigatus has emerged as a global health problem. Although the number of cases of azole-resistant aspergillosis is still limited, resistance mechanisms continue to emerge, thereby threatening the role of the azole class in the management of diseases caused by Aspergillus. The majority of cases of azole-resistant disease are due to resistant A. fumigatus originating from the environment. Patient management is difficult due to the absence of patient risk factors, delayed diagnosis, and limited treatment options, resulting in poor treatment outcome. International and collaborative efforts are required to understand how resistance develops in the environment to allow effective measures to be implemented aimed at retaining the use of azoles both for food production and human medicine. PMID- 26486707 TI - Antimicrobial Stewardship and the Allergist: Reclaiming our Antibiotic Armamentarium. PMID- 26486708 TI - Response to Spellberg and Brass. PMID- 26486709 TI - Lipid profile in acute stroke: A prospective study. AB - The dramatic decline in the risk of stroke is most likely secondary to a better control of risk factors, especially hypertension. An increase in low-density lipoprotein (LDL) cholesterol or a decrease in high-density lipoprotein (HDL) cholesterol may be additional risk factors for cerebrovascular diseases. In this study, we prospectively evaluated patients with ischemic stroke (except for cardioembolic) and age-matched controls for serum cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, very low-density lipoprotein cholesterol, and apoprotein A and B. Blood levels were determined at least 8 weeks after the acute stroke or transient ischemic attack. Between September 1989 and September 1990,59 patients and 60 controls were investigated. There were no differences among total cholesterol, triglycerides, LDL cholesterol, and apoproteins in the two groups. HDL cholesterol, however, was significantly higher in patients with stroke. In stroke patients, total cholesterol (p < 0.05), LDL cholesterol (p < 0.05), and apolipoprotein B (p < 0.05) were significantly higher in female patients compared to male patients. This study confirms that low HDL cholesterol may be a risk factor for stroke. Additionally, ally, we show that lipid abnormalities may appear to be more significant in women. PMID- 26486710 TI - Behavioral problems in stroke rehabilitation patients: A prospective pilot study. AB - Thirty-two patients undergoing rehabilitation after stroke were prospectively evaluated in a pilot study to determine the frequency and significance of behavioral problems interfering with rehabilitation. Based on prior experience within the rehabilitation unit, we studied depression, as well as somnolence, irritability, anxiety, confusion, delusions, denial of deficit, impulsivity, inappropriate sexual behavior, and pain. Depression was present in 31% of patients, and other behavioral problems occurred in up to 41% of patients. Although the sample size was small, significant associations were noted between somnolence and left hemisphere infarct, between the number of behavioral problems and rehabilitation outcome, and between certain behavioral problems and neurologic variables. Behavioral problems other than depression are common after stroke, and such problems correlate with specific neurologic variables. Rehabilitation outcome can be hindered by these identified behavior problems. PMID- 26486711 TI - Hemodilution therapy for lacunar stroke: Treatment results in 10 consecutive cases. AB - Because precipitous neurological deterioration occurred during blood pressure reduction in a seminal case of lacunar infarction, nine subsequent patients with acute partial or evolving lacunar deficits were treated with hemodilution and blood pressure nonintervention to test the hypothesis that lacunar infarction represents perfusion failure. Isovolemic hemodilution was performed using hetastarch with target hematocrit of 30-33. Pretreatment brain computed tomography, carotid ultrasound, and echocardiography were normal. Nine patients recovered normal neurological function, and two regained complete functional independence in close temporal correlation with hemodilution and within 7 days of symptom onset. Magnetic resonance imaging of the brain demonstrated appropriate single white matter lesions in nine cases. No specific risk factor combination could be identified. No patient has had recurrent stroke in follow-up from 18 to 36 months. Response to hemodilution suggests the possibility of a hemodynamic pathophysiology. Successful treatment requires (a) blood pressure nonintervention and (b) hemodilution prior to severe clinical deterioration. A controlled trial seems indicated. PMID- 26486712 TI - Early computed tomography demonstration of cerebral infarction does not correlate with clinical outcome. AB - The results of unenhanced computed tomography (CT) obtained in 105 consecutive patients admitted with cerebral infarction were compared with the patients' clinical outcome and their Glasgow Outcome Scores upon discharge. Specific analysis of the findings in patients with early admission CT (within 12 h of onset) was carried out. The size of the infarction was calculated from delayed CT images (small if less than 50 mm(3); moderate if 50-250 mm(3); large if greater than 250 mm(3)). Initial CT demonstration of the cerebral infarction was accomplished in 57 (54.3%) patients. Forty patients were studied early (<12h) and, of these, 20 (50%) showed abnormal admission CT. The size of the infarction correlated with its demonstration by admission CT. This correlation was found in all patients (p < 0.0001), as well as in those who had early CT (p = 0.015). Also, the size of the infarction correlated with the outcome of the patient (p < 0.001). The demonstration of the lesion by early CT, however, failed to correlate with the outcome of the patients. This finding, although at first surprising, is analogous to reports addressing the predictive value of other CT parameters. PMID- 26486713 TI - Postpartum eclampsia and subarachnoid hemorrhage. AB - In the clinical setting of ankle edema, headache, proteinuria, and elevated blood pressure, a 33-year-old woman developed a postpartum subarachnoid hemorrhage that was seen on computed tomography and magnetic resonance imaging. Angiography demonstrated diffuse cerebral vasospasm without other underlying pathology. Subarachnoid hemorrhage with vasospasm in pre-eclampsia, not previously documented in the absence of associated systemic or cerebral abnormality, is described. PMID- 26486714 TI - Patent foramen ovale causing stroke in an elderly woman. AB - A patent foramen ovale (PFO) was fully documented as the cause of a cerebral infarction in a 78-year-old woman, with asymptomatic deep venous thrombosis and pulmonary embolism as secondary causes. The report is unique in view of the patient's age and lack of history or clinical evidence of cardiac or pulmonary disease, thromboembolic disease, or systemic embolism at or before the stroke. This case emphasizes the etiologic role of PFO in cryptogenic strokes even in elderly patients with no obvious clinical risk factors for paradoxical embolism. PMID- 26486715 TI - Journals publishing research relevant to stroke rehabilitation. AB - The purpose of this brief article is to provide a list of core journals relevant to stroke rehabilitation and to indicate the adequacy of five bibliographic indexing services in covering them. Citation analysis yielded a list of 30 core journals. No indexing service's data base included all of the 28 journals used in evaluating comprehensiveness. All services except the Cumulative Index of Nursing and Allied Health, however, included over 71% of the journals. To be completely comprehensive in journal coverage, any pair of indexes had to include AMED/ CATS. The all too common reliance on Index Medicus/Medline will result in a relatively thorough but clearly incomplete search. PMID- 26486716 TI - "Lacunar Infarcts" do not invariably result in "Lacunes". AB - We report two cases of acute cerebral infarcts interpreted radiographically as "lacunes." Although the neurological deficits persisted, the "lacunes" seen on computed tomography and magnetic resonance imaging did not persist. These two cases suggest that the radiographic diagnosis of acute "lacunar infarcts" may not be a reliable predictor of lacune formation. PMID- 26486717 TI - Large-vessel thrombotic stroke in a patient with rheumatoid arthritis and lupus anticoagulant. AB - The association of ischemic stroke and antiphospholipid antibodies (APA) has now been reported in a large number of patients. Most such patients had systemic lupus erythematosus or no underlying disease. We now report a patient with rheumatoid arthritis (RA) and APA who developed an acute stroke. Although the association of APA with RA is not uncommon, acute stroke has very rarely been reported. The paucity of strokes in such patients may possibly be secondary to the common practice of using aspirin in such patients. PMID- 26486718 TI - Cerebrospinal fluid cellular response in uncomplicated acute ischemic stroke. AB - Because information regarding cerebrospinal fluid (CSF) cellular response in acute ischemic stroke (AIS) is inconclusive, we conducted the following investigation. Cell counts were performed in CSF obtained within 24 h of onset of symptoms in 118 adult patients 86 years or younger with uncomplicated AIS, after hemorrhage and mass effect were ruled out by computed tomography. In 98, CSF examination was repeated on day 7. None of the patients had evidence for systemic infection, inflammatory disease, vasculitis, leukocytosis, anemia or coagulopathy. CSF pleocytosis was defined as white blood cell (WBC) count of five or more mononuclear leukocytes (MNLs) and/or one or more polymorphonuclear leukocytes per cubic milliliter. No cells were found in 78 (66.1%) patients, 25 (21.2%) had one to four MNLs, and 15 (12.7%) had pleocytosis; none had hypoglycorrhachia. Nine patients had traumatic lumbar puncture (LP); in five of them, pleocytosis persisted after correction for red blood cell count. The highest WBC count was 15 cells per cubic milliliter. Only two patients had CSF pleocytosis on day 7; both had had traumatic LP and pleocytosis acutely. We found no correlation between CSF pleocytosis and cardiac source of embolus or type of ischemic stroke. From our data, we conclude that in uncomplicated AIS, CSF pleocytosis is rare and, when present, is mild; it has no correlation with type of stroke and is of no diagnostic value. PMID- 26486719 TI - Severe extracranial carotid atherosclerosis in young adults. AB - Studies of stroke in adults under age 50 emphasize nonatherosclerotic causes. We examined the risk factor profile in 41 patients under age 45 who underwent carotid endarterectomy for severe atherosclerotic stenosis at the Cleveland Clinic Foundation from 1975 to 1990. Smoking was the strongest risk factor. Hyperlipidemia, family history, and associated coronary atherosclerosis were also major risk factors. In contradistinction to older patients with carotid disease, hypertension was a less important risk factor. PMID- 26486720 TI - Nonalcoholic fatty liver disease, cardiovascular outcomes, and mortality in patients undergoing a coronary angiogram. PMID- 26486721 TI - Unconventional interplay between heterovalent dopant elements: Switch-and modulator band-gap engineering in (Y, Co)-Codoped CeO2 nanocrystals. AB - We report the experimental observation and theoretical explanation of an unconventional interplay between divalent Co and trivalent Y dopants, both of which incur oxygen vacancies in the CeO2 host that has predominantly tetravalent Ce cations. The Co dopant atoms were experimentally found to act as a switch that turns on the dormant effect of Y-modulated band-gap reduction. As revealed by density functional theory (DFT) calculations with structures verified by synchrotron-radiation x-ray measurements, a Co 3d band that hybridizes with Ce 4f band was lowered due to reduced O 2p repulsion arising from oxygen vacancies incurred by Y doping and therefore gave rise to the observed band-gap narrowing effect. Such switch-and-modulator scheme for band-gap engineering in nanocrystal materials can lead to important applications in environmental protection and solar energy harvesting technologies. PMID- 26486722 TI - Semi-automated repetitive sequence-based PCR amplification for species of the Scedosporium apiospermum complex. AB - PURPOSE: The Scedosporium apiospermum species complex usually ranks second among the filamentous fungi colonizing the airways of patients with cystic fibrosis (CF), but little is known about the molecular epidemiology of the airway colonization. METHODS: Polymerase chain reaction (PCR) amplification of repetitive sequences (rep-PCR) was applied to the retrospective analysis of a panel of isolates already studied by random amplification of polymorphic DNA (RAPD) and comprising 63 isolates recovered from sputa from 9 CF patients. Results were compared to those obtained previously by RAPD, and herein by beta tubulin (TUB) gene sequencing and Multilocus Sequence Typing (MLST). RESULTS: Within the panel of isolates studied,S. apiospermum sensu stricto and Scedosporium boydii, as expected, were the predominant species with 21 and 36 isolates, respectively. Four isolates from one patient were identified as Scedosporium aurantiacum, whereas two isolates belonged to the Pseudallescheria ellipsoidea subgroup of S. boydii rep-PCR analysis of these isolates clearly differentiated the three species and P. ellipsoidea isolates, whatever the rep PCR kit used, and also permitted strain differentiation. When using the mold primer kit, results from rep-PCR were in close agreement with those obtained by MLST. For both S. apiospermum and S. boydii, 8 genotypes were differentiated by rep-PCR and MLST compared to 10 by RAPD. All S. aurantiacum isolates shared the same RAPD genotype and exhibited the same rep-PCR profile and sequence type. CONCLUSIONS: These results illustrate the efficacy of rep-PCR for both species identification within the S. apiospermum complex and genotyping for the two major species of this complex.Abstract presentation: Part of this work was presented during the 18th Congress of the International Society for Human and Animal Mycology, Berlin (Germany), June 2012.S. Giraud, C. Godon, A. Rougeron, J.P. Bouchara and L. Favennec are members of the ECMM/ISHAM working group on Fungal respiratory infections in Cystic Fibrosis(Fri-CF). PMID- 26486723 TI - Computational evidence that fast translation speed can increase the probability of cotranslational protein folding. AB - Translation speed can affect the cotranslational folding of nascent peptide. Experimental observations have indicated that slowing down translation rates of codons can increase the probability of protein cotranslational folding. Recently, a kinetic modeling indicates that fast translation can also increase the probability of cotranslational protein folding by avoiding misfolded intermediates. We show that the villin headpiece subdomain HP35 is an ideal model to demonstrate this phenomenon. We studied cotranslational folding of HP35 with different fast translation speeds by all-atom molecular dynamics simulations and found that HP35 can fold along a well-defined pathway that passes the on-pathway intermediate but avoids the misfolded off-pathway intermediate in certain case. This greatly increases the probability of HP35 cotranslational folding and the approximate mean first passage time of folding into native state is about 1.67MUs. Since we also considered the space-confined effect of the ribosomal exit tunnel on the cotranslational folding, our simulation results suggested alternative mechanism for the increasing of cotranslational folding probability by fast translation speed. PMID- 26486724 TI - Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames. AB - Mammalian gene expression displays widespread circadian oscillations. Rhythmic transcription underlies the core clock mechanism, but it cannot explain numerous observations made at the level of protein rhythmicity. We have used ribosome profiling in mouse liver to measure the translation of mRNAs into protein around the clock and at high temporal and nucleotide resolution. We discovered, transcriptome-wide, extensive rhythms in ribosome occupancy and identified a core set of approximately 150 mRNAs subject to particularly robust daily changes in translation efficiency. Cycling proteins produced from nonoscillating transcripts revealed thus-far-unknown rhythmic regulation associated with specific pathways (notably in iron metabolism, through the rhythmic translation of transcripts containing iron responsive elements), and indicated feedback to the rhythmic transcriptome through novel rhythmic transcription factors. Moreover, estimates of relative levels of core clock protein biosynthesis that we deduced from the data explained known features of the circadian clock better than did mRNA expression alone. Finally, we identified uORF translation as a novel regulatory mechanism within the clock circuitry. Consistent with the occurrence of translated uORFs in several core clock transcripts, loss-of-function of Denr, a known regulator of reinitiation after uORF usage and of ribosome recycling, led to circadian period shortening in cells. In summary, our data offer a framework for understanding the dynamics of translational regulation, circadian gene expression, and metabolic control in a solid mammalian organ. PMID- 26486726 TI - Review of the taxonomy of the genus Arthrobacter, emendation of the genus Arthrobacter sensu lato, proposal to reclassify selected species of the genus Arthrobacter in the novel genera Glutamicibacter gen. nov., Paeniglutamicibacter gen. nov., Pseudoglutamicibacter gen. nov., Paenarthrobacter gen. nov. and Pseudarthrobacter gen. nov., and emended description of Arthrobacter roseus. AB - In this paper, the taxonomy of the genus Arthrobacter is discussed, from its first description in 1947 to the present state. Emphasis is given to intrageneric phylogeny and chemotaxonomic characteristics, concentrating on quinone systems, peptidoglycan compositions and polar lipid profiles. Internal groups within the genus Arthrobacter indicated from homogeneous chemotaxonomic traits and corresponding to phylogenetic grouping and/or high 16S rRNA gene sequence similarities are highlighted. Furthermore, polar lipid profiles and quinone systems of selected species are shown, filling some gaps concerning these chemotaxonomic traits. Based on phylogenetic groupings, 16S rRNA gene sequence similarities and homogeneity in peptidoglycan types, quinone systems and polar lipid profiles, a description of the genus Arthrobacter sensu lato and an emended description of Arthrobacter roseus are provided. Furthermore, reclassifications of selected species of the genus Arthrobacter into novel genera are proposed, namely Glutamicibacter gen. nov. (nine species), Paeniglutamicibacter gen. nov. (six species), Pseudoglutamicibacter gen. nov. (two species), Paenarthrobacter gen. nov. (six species) and Pseudarthrobacter gen. nov. (ten species). PMID- 26486725 TI - Promoter-distal RNA polymerase II binding discriminates active from inactive CCAAT/ enhancer-binding protein beta binding sites. AB - Transcription factors (TFs) bind to thousands of DNA sequences in mammalian genomes, but most of these binding events appear to have no direct effect on gene expression. It is unclear why only a subset of TF bound sites are actively involved in transcriptional regulation. Moreover, the key genomic features that accurately discriminate between active and inactive TF binding events remain ambiguous. Recent studies have identified promoter-distal RNA polymerase II (RNAP2) binding at enhancer elements, suggesting that these interactions may serve as a marker for active regulatory sequences. Despite these correlative analyses, a thorough functional validation of these genomic co-occupancies is still lacking. To characterize the gene regulatory activity of DNA sequences underlying promoter-distal TF binding events that co-occur with RNAP2 and TF sites devoid of RNAP2 occupancy using a functional reporter assay, we performed cis-regulatory element sequencing (CRE-seq). We tested more than 1000 promoter distal CCAAT/enhancer-binding protein beta (CEBPB)-bound sites in HepG2 and K562 cells, and found that CEBPB-bound sites co-occurring with RNAP2 were more likely to exhibit enhancer activity. CEBPB-bound sites further maintained substantial cell-type specificity, indicating that local DNA sequence can accurately convey cell-type-specific regulatory information. By comparing our CRE-seq results to a comprehensive set of genome annotations, we identified a variety of genomic features that are strong predictors of regulatory element activity and cell-type specific activity. Collectively, our functional assay results indicate that RNAP2 occupancy can be used as a key genomic marker that can distinguish active from inactive TF bound sites. PMID- 26486727 TI - De-adoption and its 43 related terms: harmonizing low-value care terminology. AB - Research into the prevalence and impact of low-value medical practices has evolved substantially over the past two decades. However, despite international efforts, many challenges still remain with regards to progress in this field, including limits in the capacity to identify and prioritize low-value care practices and to systematically appraise clinical and policy attempts at redressing low-value care. A recent article by Niven et al. in BMC Medicine consolidates the current literature and terminology on the de-adoption of clinical practices, advocating the use of de-adoption as an appropriate term to label low-value care and proposes a new synthesis model to facilitate efforts to reverse ineffective and harmful medical practices. We hope that this work will facilitate advances in low-value care research and policy, and shift focus towards establishing evidence for de-adopting low-value interventions, which is crucial since attempts to reduce low-value care interventions have shown mixed results. Please see related article: http://www.biomedcentral.com/1741 7015/13/255. PMID- 26486729 TI - Identification, characterization and target gene analysis of testicular microRNAs in the oriental fruit fly Bactrocera dorsalis. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate various diverse biological processes including insect spermatogenesis. The oriental fruit fly, Bactrocera dorsalis, is one of the most destructive horticultural pests in East Asia and the Pacific region. Although developmental miRNA profiles of B. dorsalis have enriched our knowledge, specific testicular miRNAs in this dipteran species are unexplored. In this study, we identified miRNAs from B. dorsalis testes by deep sequencing, which provided an overview of miRNA expression during spermatogenesis. Small RNA libraries were constructed from the testes of fully mature (FM), immature (IM) and middle-aged (MA) adult flies of B. dorsalis. Small RNA sequencing and data analysis revealed 172 known and 78 novel miRNAs amongst these libraries. Pairwise comparisons of libraries led to the identification of 24, 15 and 14 differentially expressed miRNAs in FM vs. IM, FM vs. MA and IM vs. MA insects, respectively. Using a bioinformatic approach, we predicted 124 target genes against the 13 most differentially expressed miRNAs. Furthermore, the expression patterns of six randomly selected miRNAs (from the 13 most differentially expressed miRNAs) and their putative target genes (from the 124 predicted target genes) were analysed in the testis of B. dorsalis by quantitative real-time PCR, which showed that out of six, four tested miRNAs mRNAs had an inverse expression pattern and are probably co-regulated. This study is the first comparative profile of the miRNA transcriptome in three developmental stages of the testis, and provides a useful resource for further studies on the role of miRNAs in spermatogenesis in B. dorsalis. PMID- 26486728 TI - A pilot cohort study of cerebral autoregulation and 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy who received therapeutic hypothermia. AB - BACKGROUND: Neurodevelopmental disabilities persist in survivors of neonatal hypoxic-ischemic encephalopathy (HIE) despite treatment with therapeutic hypothermia. Cerebrovascular autoregulation, the mechanism that maintains cerebral perfusion during changes in blood pressure, may influence outcomes. Our objective was to describe the relationship between acute autoregulatory vasoreactivity during treatment and neurodevelopmental outcomes at 2 years of age. METHODS: In a pilot study of 28 neonates with HIE, we measured cerebral autoregulatory vasoreactivity with the hemoglobin volume index (HVx) during therapeutic hypothermia, rewarming, and the first 6 h of normothermia. The HVx, which is derived from near-infrared spectroscopy, was used to identify the individual optimal mean arterial blood pressure (MAPOPT) at which autoregulatory vasoreactivity is greatest. Cognitive and motor neurodevelopmental evaluations were completed in 19 children at 21-32 months of age. MAPOPT, blood pressure in relation to MAPOPT, blood pressure below gestational age + 5 (ga + 5), and regional cerebral oximetry (rSO2) were compared to the neurodevelopmental outcomes. RESULTS: Nineteen children who had HIE and were treated with therapeutic hypothermia performed in the average range on cognitive and motor evaluations at 21-32 months of age, although the mean performance was lower than that of published normative samples. Children with impairments at the 2-year evaluation had higher MAPOPT values, spent more time with blood pressure below MAPOPT, and had greater blood pressure deviation below MAPOPT during rewarming in the neonatal period than those without impairments. Greater blood pressure deviation above MAPOPT during rewarming was associated with less disability and higher cognitive scores. No association was observed between rSO2 or blood pressure below ga + 5 and neurodevelopmental outcomes. CONCLUSION: In this pilot cohort, motor and cognitive impairments at 21-32 months of age were associated with greater blood pressure deviation below MAPOPT during rewarming following therapeutic hypothermia, but not with rSO2 or blood pressure below ga + 5. This suggests that identifying individual neonates' MAPOPT is superior to using hemodynamic goals based on gestational age or rSO2 in the acute management of neonatal HIE. PMID- 26486730 TI - Planning oral health care using the sociodental approach and the index of family living conditions: a cross-sectional study in Brazilian adolescents. AB - BACKGROUND: Oral health care needs assessment is frequently restricted to clinical measures. Combining normative assessment, behavioural propensity, oral health-related quality of life and information of family living conditions may provide a better comprehensive approach of adolescent's oral health needs assessment. The aim of this study was to compare normative methods of dental caries need with the sociodental approach in 12-year-old adolescents according to family's living conditions in a deprived community in Brazil. In addition, dental caries need assessment using the normative method and the sociodental approach was compared between adolescents living in different living conditions. METHODS: A cross-sectional survey was conducted in the Manguinhos community in the city of Rio de Janeiro, Brazil. A weighted sample of 159 participants was randomly selected to represent the population of 2004 12-year-old adolescents. Socioeconomic characteristics and living conditions of the family were assessed using the Family Development Index (FDI). Oral health-related quality of life (OHRQoL) was assessed using the generic and CS-Child-OIDP, and adolescent's propensity to adopt oral health promoting behaviours was verified through interviews. Dental caries and treatment need were assessed normatively by clinical oral examinations (DMFT Index) and adolescents were classified into two groups (non severe or severe caries). The sociodental approach included clinical measures of caries, propensity to adopt oral health promoting behaviors and OHRQoL. Families were classified based on the FDI as 'not severe', 'severe' and 'very severe'. Measures of caries, OHRQoL and propensity outcomes were compared between FDI groups using Chi-square and Kruskal-Wallis tests. In addition, dental treatment needs using normative method and sociodental approach were compared for the whole sample and according to FDI groups. RESULTS: Dental caries, OHRQoL and lower propensity needs were positively associated with FDI severity. The percentages of adolescents with normative dental needs from families with 'very severe', 'severe' and 'not severe' FDI were 59.3, 48.4 and 17.2 % (P < 0.05). Using the sociodental approach, the treatment needs for the three FDI groups decreased to 8.8, 13.6 and 8.6 %, respectively (P < 0.05). CONCLUSIONS: Using a combination of sociodental approach and the index of family living conditions was useful for defining dental care priorities in adolescents living in deprived communities and can optimise the use of resources in dental services. PMID- 26486731 TI - Diagnostic efficiency. PMID- 26486732 TI - Advantages and disadvantages of technologies for HER2 testing in breast cancer specimens. AB - OBJECTIVES: Human epidermal growth factor receptor 2 (HER2) plays a central role as a prognostic and predictive marker in breast cancer specimens. Reliable HER2 evaluation is central to determine the eligibility of patients with breast cancer to targeted anti-HER2 therapies such as trastuzumab and lapatinib. Presently, several methods exist for the determination of HER2 status at different levels (protein, RNA, and DNA level). METHODS: In this review, we discuss the main advantages and disadvantages of the techniques developed so far for the evaluation of HER2 status in breast cancer specimens. RESULTS: Each technique has its own advantages and disadvantages. It is therefore not surprising that no consensus has been reached so far on which technique is the best for the determination of HER2 status. CONCLUSIONS: Currently, emphasis must be put on standardization of procedures, internal and external quality control assessment, and competency evaluation of already existing methods to ensure accurate, reliable, and clinically meaningful test results. Development of new robust and accurate diagnostic assays should also be encouraged. In addition, large clinical trials are warranted to identify the technique that most reliably predicts a positive response to anti-HER2 drugs. PMID- 26486733 TI - Inappropriate repeats of six common tests in a Canadian city: a population cohort study within a laboratory informatics framework. AB - OBJECTIVES: To identify inappropriate repeats of six common laboratory tests in a population sample of patients, using highly specific criteria based only on repeat time and test value. METHODS: We used a laboratory informatics database to conduct a retrospective cohort study using a population sample of 103,000 patients in the city of Calgary with an index test in 2010 and uniform follow-up of 1 year. We examined six tests (cholesterol, hemoglobin A1c, thyroid stimulating hormone, vitamin B12, vitamin D, and ferritin) with consensus-based or easily justified criteria for inappropriate repeats based solely on time to repeat and the index test value. RESULTS: The percentages of tests repeated at 3, 6, and 12 months were 11%, 23%, and 41%, respectively. In total, 16% of these six tests were inappropriately repeated, representing an annual internal cost of $0.6 to $2.2 million Canadian dollars and corresponding to population-scaled national estimates for Canada and the United States of $160 million and $2.4 billion, respectively. CONCLUSIONS: Objective definitions based on repeated testing identified 16% of six studied tests as inappropriate, delineating a subset of inappropriate testing that is well suited to automated identification and intervention and that provides a likely lower bound on the true burden of inappropriate testing. PMID- 26486734 TI - Multigene clinical mutational profiling of breast carcinoma using next-generation sequencing. AB - OBJECTIVES: The advent of next-generation sequencing (NGS) platforms in the realm of clinical molecular diagnostics provides multigene mutational profiling through massively parallel sequencing. METHODS: We analyzed 415 breast carcinoma samples from 354 patients using NGS in known hotspots of 46 commonly known cancer-causing genes. RESULTS: A total of 281 somatic nonsynonymous mutations were detected in 62.1% of patients. TP53 was most frequently mutated (38.8%), followed by PIK3CA (31.7%), AKT1 (6%), and ATM (3.9%), with other mutations detected at a lower frequency. When stratified into clinically relevant therapeutic groups (estrogen receptor [ER]/progesterone receptor [PR]+ human epidermal growth factor receptor 2 [HER2]-, ER/PR+HER2+, ER/PR-HER2+, ER/PR/HER2-), each group showed distinct mutational profiles. The ER/PR+HER2- tumors (n = 132) showed the highest frequency of PIK3CA mutations (38%), while the triple-negative tumors (n = 64) had a significantly higher number of TP53 mutations (62%). Of the 61 patients tested for both primary and metastatic tumors, concordant results were seen in 47 (77%) patients, while 13 patients showed additional mutations in the metastasis. CONCLUSIONS: Our results indicate that breast cancers may harbor potentially actionable mutations for targeted therapeutics. Therefore, NGS-based mutational profiling can provide useful information that can guide targeted cancer therapy. PMID- 26486735 TI - Multinucleation is an objective feature useful in the diagnosis of pleomorphic lobular carcinoma in situ. AB - OBJECTIVES: Bi- and multinucleated (B/M) cells are present in a variety of tumors. We evaluated lobular carcinoma in situ (classic and pleomorphic types) and ductal carcinoma in situ (DCIS) to determine if this objective morphologic feature aids the differential diagnosis. METHODS: The number of B/M cells was recorded in pleomorphic lobular carcinoma in situ (PLCIS) (n = 20), classic lobular carcinoma in situ (CLCIS) (n = 26), and DCIS (n = 37). RESULTS: Binucleated cells were significantly more frequent in PLCIS (100%) vs DCIS (43%; P < .0001) and CLCIS (54%; P = .0004). Multinucleated cells were present in 25% of PLCIS cases and 8% of DCIS cases, and they were absent in CLCIS. The quantity of B/M per high-power field (hpf) was less in DCIS (mean, 1.1) and CLCIS (mean, 2.5) compared with PLCIS (mean, 5.8). Thirty-five percent of PLCIS cases had more than five B/M per hpf. CONCLUSIONS: Binucleated cells are significantly more frequent in PLCIS vs CLCIS and DCIS. Multinucleated cells were never identified in CLCIS. PLCIS should be considered as a diagnosis when B/M is noted. PMID- 26486736 TI - Use of geospatial mapping to determine suitable locations for patient service centers for phlebotomy services. AB - OBJECTIVES: Approaches to determining optimal locations for patient service centers (phlebotomy clinics) have not been addressed in the published literature. Using the city of Calgary, Alberta, Canada, as a test case, our objective is to present a novel method for determining underserviced geographic areas within a city to guide the choice of potential new patient service center locations. METHODS: Data on travel distances for 198,883 phlebotomy visits as well as population data from the 2011 Canada Census were used for this study. Using geospatial mapping techniques, we produced maps of the city showing actual relative travel distances for patients as well as the geographic distribution of population density of patients undergoing phlebotomies. RESULTS: There was a striking pattern of increased travel distances in certain parts of the city. These also corresponded to geographic areas with greater density of patients seeking phlebotomies. CONCLUSIONS: This analysis provided clear, objective evidence of communities that are currently relatively underserved by patient service centers. This approach could be used by other laboratories to plan the location of new patient service centers. PMID- 26486737 TI - Clinical utility of concurrent single-nucleotide polymorphism microarray on fresh tissue as a supplementary test in the diagnosis of renal epithelial neoplasms. AB - OBJECTIVES: The histologic and immunohistochemical variability of renal epithelial tumors makes classification difficult; with significant clinical implications, efforts to make the proper diagnoses are necessary. Single nucleotide polymorphism (SNP) microarray analysis has been proposed as a supplementary study for the classification of renal epithelial neoplasms; however, its practical use in the routine clinical setting has not been explored. METHODS: Surgical pathology cases that were classified histologically as renal epithelial tumor subtypes and had concurrent SNP microarray were retrospectively reviewed to correlate tumor morphology and SNP microarray results. RESULTS: Of the 99 cases reviewed, 88 (89%) had concordant histologic and microarray results. Four (4%) cases were unclassifiable by microarray due to uncharacteristic chromosomal abnormalities. Seven (7%) of the 99 cases had discordant microarray and histologic diagnoses, and following review of the histology, the diagnoses in two of these cases were subsequently changed. CONCLUSIONS: For most cases, concurrent SNP microarray confirmed the histologic diagnosis. However, discrepant microarray results prompted review of morphology and further ancillary studies, resulting in amendment of the final diagnosis in 29% of discrepant cases. SNP microarray analysis can be used to assist with the diagnosis of renal epithelial tumors, particularly those with atypical morphologic features. PMID- 26486738 TI - Development and validation of CALR mutation testing for clinical diagnosis. AB - OBJECTIVES: To validate a diagnostic assay for detecting CALR mutations in the clinical setting. METHODS: Traditional polymerase chain reaction (PCR) was performed on DNA previously extracted from 60 specimens (30 bone marrow aspirates [BMAs] and 30 peripheral blood [PB] samples) from 55 patients. Nearly all reported CALR mutations are insertions or deletions in exon 9. Therefore, we performed amplicon sizing by capillary electrophoresis and fragment length analysis (FLA) to determine mutation status. Mutations were confirmed by Sanger sequencing. RESULTS: Fourteen samples from 10 patients with JAK2 and MPL wild type myeloproliferative neoplasms were positive for CALR mutation. Detected mutations included a 52-base pair (bp) deletion (n = 6), a 5-bp insertion (n = 2), a 31-bp deletion (n = 1), and a 61-bp deletion (n = 1). Sanger sequencing of 15 samples showed 100% concordance. Matched patient PB and BMA samples (n = 5) harbored identical mutations, and samples run multiple times (n = 8) showed 100% reproducibility. CONCLUSIONS: We conclude that CALR mutations may be quickly and accurately detected by FLA of PCR amplicons by capillary electrophoresis. These methods are routine procedures for most molecular laboratories and should allow for straightforward incorporation of the CALR assay into the clinical diagnostic testing menu. PMID- 26486739 TI - Clinical validation of a multipurpose assay for detection and genotyping of CALR mutations in myeloproliferative neoplasms. AB - OBJECTIVES: To develop a polymerase chain reaction (PCR)-based approach to detect CALR mutations in myeloproliferative neoplasms (MPNs) in a clinical laboratory. METHODS: DNA was extracted from bone marrow aspirate samples of 67 JAK2 wild-type MPNs (22 with matched peripheral blood), 54 cases of unclassifiable myelodysplastic syndrome/MPN, and 16 cases of atypical chronic myeloid leukemia. We used genomic DNA to detect somatic mutations in exon 9 of CALR and PCR with fluorescently labeled and M13-tagged primers and subjected the products to capillary electrophoresis (CE) followed by Sanger sequencing. Detailed assay performance characteristics were established. RESULTS: We identified CALR mutations in 19 (28.4%) of 67 JAK2-negative MPNs, including 14 type I (52-base pair [bp] deletion), four type II (5-bp insertions), and one type III (18-bp deletion). All mutations were confirmed by Sanger sequencing. Sensitivity studies showed 2.5% and 5% mutation detection levels by CE and Sanger sequencing, respectively, with high reproducibility. CONCLUSIONS: This assay allows for rapid, convenient screening for CALR mutations in MPNs, thereby reducing the number of cases that require assessment by Sanger sequencing, reducing labor and improving turnaround time. PMID- 26486741 TI - FLOCK cluster analysis of mast cell event clustering by high-sensitivity flow cytometry predicts systemic mastocytosis. AB - OBJECTIVES: In our high-sensitivity flow cytometric approach for systemic mastocytosis (SM), we identified mast cell event clustering as a new diagnostic criterion for the disease. METHODS: To objectively characterize mast cell gated event distributions, we performed cluster analysis using FLOCK, a computational approach to identify cell subsets in multidimensional flow cytometry data in an unbiased, automated fashion. RESULTS: FLOCK identified discrete mast cell populations in most cases of SM (56/75 [75%]) but only a minority of non-SM cases (17/124 [14%]). FLOCK-identified mast cell populations accounted for 2.46% of total cells on average in SM cases and 0.09% of total cells on average in non-SM cases (P < .0001) and were predictive of SM, with a sensitivity of 75%, a specificity of 86%, a positive predictive value of 76%, and a negative predictive value of 85%. CONCLUSIONS: FLOCK analysis provides useful diagnostic information for evaluating patients with suspected SM, and may be useful for the analysis of other hematopoietic neoplasms. PMID- 26486740 TI - GATA3 expression in advanced breast cancer: prognostic value and organ-specific relapse. AB - OBJECTIVES: GATA3 is a transcription factor regulating luminal cell differentiation in the mammary glands and has been implicated in the luminal types of breast carcinoma. The prognostic significance of GATA3 in breast cancer remains controversial. METHODS: In this study, we assessed the prognostic value of the molecule in a subset of 62 advanced breast cancers and 10 control breast cancers (no metastasis after follow-up). RESULTS: GATA3 expression levels in luminal tumors of advanced stage were significantly higher than that of the human epidermal growth factor receptor 2 (HER2) subtype and triple-negative carcinomas, as expected, but were similar to those of the luminal controls. Furthermore, 88% of nonluminal tumors showed variable GATA3 expression, for which the HER2 subtype had significantly higher GATA3 expression than that of the triple-negative carcinomas. Interestingly, GATA3 levels were significantly lower in carcinomas with lung relapse compared to those with metastatic recurrence to other organs, thus reflecting the findings in animal models. No significant difference was observed between tumors with bone relapse and those metastasized to nonskeletal sites. Moreover, high GATA3 expression was significantly associated with favorable relapse-free survival and overall survival. CONCLUSIONS: These findings suggest that GATA3 may not act solely as a luminal differentiation marker, and further uncovering the molecular pathways by which GATA3 regulates the downstream targets will be crucial to our understanding of breast cancer dissemination. PMID- 26486742 TI - Sexually transmitted infectious colitis vs inflammatory bowel disease: distinguishing features from a case-controlled study. AB - OBJECTIVES: Sexually transmitted infectious (STI) colitis often raises concern for inflammatory bowel disease (IBD). In this study, we compare histologic features of IBD with STI colitis caused by syphilis and lymphogranuloma venereum. METHODS: The STI colitis group included 10 unique colorectal biopsy specimens in patients with clinically confirmed syphilis and/or lymphogranuloma venereum. The STI biopsy specimens were compared with patients matched for age, sex, and site with Crohn disease (n = 10) or ulcerative colitis (n = 10). All IBD controls had an established history of IBD (up to 276 months of follow-up, mean follow-up = 102 months). RESULTS: Discriminating features (P < .05) of STI colitis included its exclusive identification in human immunodeficiency virus-positive men who have sex with men, anal pain, and anal discharge. STI colitis contained the triad of (1) minimal active chronic crypt centric damage, (2) a lack of mucosal eosinophilia, and (3) submucosal plasma cells, endothelial swelling, and perivascular plasma cells. Nondiscriminating features (P > .05) included rectal bleeding, endoscopic appearance, skip lesions, ulcerations, aphthoid lesions, granulomata, foreign body giant cells, neural hyperplasia, fibrosis, and lymphoid aggregates. CONCLUSIONS: While STI colitis shares many overlapping features with IBD, histologic and clinical discriminating features may be helpful when confronted with that differential diagnosis. PMID- 26486743 TI - Utility of BRAF V600E mutation-specific immunohistochemistry in detecting BRAF V600E-mutated gastrointestinal stromal tumors. AB - OBJECTIVES: As patients with BRAF V600E mutation respond to BRAF inhibitors, it is important to identify these mutations to stratify patients for the appropriate therapy. In this study, we evaluated the utility of a BRAF V600E allele-specific antibody in gastrointestinal stromal tumors (GISTs). METHODS: BRAF V600E mutation specific immunohistochemistry (negative, weak, or moderate/strong expression) and BRAF sequencing were performed on 38 consecutive GISTs diagnosed between January 2013 and April 2014. RESULTS: GISTs from a cohort of 25 men and 13 women (mean age, 61 years; range, 39-88 years) were localized to the stomach (18), small bowel (10), colon (three), rectum (two), and pelvis/omentum (five). Strong and diffuse cytoplasmic BRAF expression was noted in two (5%) of 38 cases, while eight (21%) of 38 cases showed weak staining, and 28 (74%) of 38 cases were negative. Both of the strongly positive cases arose in the stomach, occurring in a 42-year-old and a 47-year-old woman, respectively. The lesions measured 0.8 and 1 cm, showed spindle cell morphology, and had no risk of progressive disease by Miettinen criteria. Both cases showed heterozygous BRAF V600E, while no BRAF mutations were detected in cases with weak or negative BRAF expression. CONCLUSIONS: BRAF V600E mutation-specific immunohistochemistry is a highly sensitive and specific method for detecting BRAF-mutated GISTs. PMID- 26486744 TI - Primary vaginal mucinous adenocarcinoma of intestinal type, associated with intestinal metaplasia of Skene ducts in a diethylstilbestrol-exposed woman. AB - OBJECTIVES: Primary mucinous vaginal adenocarcinoma of intestinal type is an extremely rare malignancy of uncertain histogenesis, which makes for a diagnostic challenge. We report a case and describe the histopathologic features and the unusual immunoprofile of this rare entity. METHODS: We report a case of vaginal mucinous adenocarcinoma of intestinal type in a diethylstilbestrol-exposed woman in which intestinal metaplasia of the Skene duct was found at the time of recurrence. RESULTS: As the histogenesis of primary vaginal intestinaltype adenocarcinomas remains uncertain, the finding of Skene duct metaplasia in association with invasive adenocarcinoma lends support to the origin of vaginal mucinous adenocarcinomas of intestinal type to be metaplasia, at least in some cases. Such an origin accounts for the unusual immunohistochemical profile, which raises concern for a metastatic adenocarcinoma of gastrointestinal origin. CONCLUSIONS: Recognition of this rare entity is important, particularly to avoid the pitfall of misdiagnosing metastatic disease. PMID- 26486745 TI - Thyroid-like follicular carcinoma of the kidney: one case report and review of the literature. AB - OBJECTIVES: Thyroid-like follicular carcinoma of the kidney continues to confound the practicing pathologist with its close resemblance to the follicular variant of thyroid carcinoma, as well as other benign and malignant entities. Our goal is to expand the knowledge of this rare renal cell carcinoma subtype, which is morphologically similar to follicular carcinoma of the thyroid but lacks expression of characteristic thyroid immunohistochemical markers such as TTF-1 and thyroglobulin. METHODS: We evaluated the gross, histologic, immunohistochemical, and fluorescence in situ hybridization (FISH) studies of a new case and performed a comprehensive review of the literature. RESULTS: The lesion was spongy and well-circumscribed. Microscopically it showed variably sized follicular structures, filled with abundant, deeply eosinophilic, colloid like material. At the periphery, it displayed areas resembling metanephric adenoma and early stages of nephrogenesis. The tumor cells strongly expressed CK7, PAX-8, PAX-2, vimentin, EMA, and CK19 immunostains. Other markers, such as CD10, RCC, HBME-1, thyroglobulin, and TTF-1, were not immunoreactive. The tumor was negative for trisomy of both 7 and 17 and showed borderline monosomies (losses) of both chromosomes in FISH studies. CONCLUSIONS: Five years of preoperative observation and lack of recurrence bring further insight into the slow progressive nature of this neoplasm and support a low malignant potential. Proper identification is important to secure adequate treatment and follow-up. PMID- 26486746 TI - Primary cutaneous follicle center lymphoma associated with an extracutaneous dissemination: a cytogenetic finding of potential prognostic value. AB - OBJECTIVES: Cytogenetic studies on cutaneous lymphomas are rare, and very little is known about their prognostic value. We present a rare case of primary cutaneous follicle center lymphoma (PCFCL) with a complex translocation presenting with cutaneous and extracutaneous dissemination in the lymph node. METHODS: Morphologic, immunohistochemical, conventional cytogenetic, and fluorescence in situ hybridization (FISH) studies were performed on this patient. RESULTS: A combination of cytogenetic and FISH analysis identified a complex novel four-way t(2;14;9;3) (p11.2;q32;p13;q27) translocation involving rearrangements of BCL6, immunoglobulin light and heavy chain genes, and an unknown gene on 9p. CONCLUSIONS: Our report elaborates the morphologic and immunohistochemical features in combination with cytogenetic and molecular cytogenetic analysis of PCFCL, which provide additional insight into the clinical and biologic behavior of this lesion. PMID- 26486747 TI - A collision tumor of papillary renal cell carcinoma and oncocytoma: case report and literature review. AB - OBJECTIVES: The most common renal neoplasms include clear cell, chromophobe, and papillary renal cell carcinomas (PRCCs) and oncocytomas. While lesions containing hybrid features of different tumor types, such as hybrid oncocytic tumors, have been well documented in the literature, the finding of a collision tumor of two distinct tumor types- PRCC and oncocytoma-is extremely rare. METHODS: We present a case of PRCC associated with an oncocytoma. Our discussion includes a review of the available literature on this rare type of collision tumor. RESULTS: Prosection of a partial nephrectomy performed in a 78-year-old man for painless gross hematuria and nocturia revealed a 6.4 * 5 * 3.6-cm well-delineated orange to yellow-tan mass harboring a white-tan 1 * 0.9 * 0.9-cm mass. Histologic diagnosis of PRCC associated with an oncocytoma was rendered. By immunohistochemistry, focal CK7 expression was present in the oncocytoma, while strong diffuse positive CK7 expression was present in the PRCC component. Fluorescence in situ hybridization (FISH) revealed trisomy 17 in 39.3% of PRCC tumor nuclei but no significant chromosomal aberration in oncocytoma. CONCLUSIONS: In view of this and previously reported cases, thorough sectioning and examination, especially in large oncocytomas, is recommended to exclude the presence of an associated malignancy. To our knowledge, trisomy 17 by FISH has not been previously reported in these extremely rare tumors. PMID- 26486749 TI - Correction. PMID- 26486748 TI - A look into the evolution of Epstein-Barr virus-induced lymphoproliferative disorders: a case study. AB - OBJECTIVES: Epstein-Barr virus (EBV)-induced lymphoproliferative disorders (LPDs) are lymphoid proliferations arising as a result of the loss of an effective EBV specific cytotoxic T-cell response. LPDs may occur for primary or acquired impairment of the immune system, as well as in some persons without documented immunodeficiency. METHODS: In this article, we describe the case of a human immunodeficiency virus-positive patient affected by an EBV-LPD of the stomach who developed a nodal diffuse large B-cell lymphoma with complex morphologic and molecular features. RESULTS: GeneScan analysis of the gastric specimen identified two different heavy-chain immunoglobulin gene (IGH) rearrangements characterized by a dominant peak of 285 base pairs (bp) in length and a smaller peak of 266 bp in length. In the lymph node sample, IGH evaluation also demonstrated two different peaks; however, the main peak corresponded to the minor peak detected in the EBV-LPD specimen at the diagnosis. In addition, a monoclonal immunoglobulin light chain gene (IGL) rearrangement was also found. We also demonstrated that the major peak in the stomach corresponded to the EBV-positive population observed in the histologic sections. CONCLUSIONS: This case may provide additional insights to better understanding the "hit-and-run" role for EBV in lymphomagenesis. However, we could not exclude that our findings represent the co-occurrence of two unrelated B-cell neoplasms rather than a progression from an EBV-positive neoplasm to an EBV-negative one. PMID- 26486750 TI - Point-of-care pleural and lung ultrasound in a newborn suffering from cardiac arrest due to tension pneumothorax after cardiac surgery. AB - We report the case of a 12-day-old newborn affected by coarctation of the aorta and intraventricular defect who underwent coarctectomy and pulmonary artery banding. On post-operative day 7, the patient suffered from pulseless electric activity due to tension pneumothorax. Point-of-care ultrasound was performed during cardiopulmonary resuscitation in an attempt to diagnose pneumothorax. The diagnosis was made without delaying or interrupting chest compressions, and the pneumothorax was promptly treated. PMID- 26486751 TI - Zeolite-like liquid crystals. AB - Zeolites represent inorganic solid-state materials with porous structures of fascinating complexity. Recently, significant progress was made by reticular synthesis of related organic solid-state materials, such as metal-organic or covalent organic frameworks. Herein we go a step further and report the first example of a fluid honeycomb mimicking a zeolitic framework. In this unique self assembled liquid crystalline structure, transverse-lying pi-conjugated rod-like molecules form pentagonal channels, encircling larger octagonal channels, a structural motif also found in some zeolites. Additional bundles of coaxial molecules penetrate the centres of the larger channels, unreachable by chains attached to the honeycomb framework. This creates a unique fluid hybrid structure combining positive and negative anisotropies, providing the potential for tuning the directionality of anisotropic optical, electrical and magnetic properties. This work also demonstrates a new approach to complex soft-matter self-assembly, by using frustration between space filling and the entropic penalty of chain extension. PMID- 26486752 TI - Nano-scale, planar and multi-tiered current pathways from a carbon nanotube copper composite with high conductivity, ampacity and stability. AB - New lithographically processable materials with high ampacity are in demand to meet the increasing requirement for high operational current density at high temperatures existing in current pathways within electronic devices. To meet this demand, we report an approach to fabricate a high ampacity (~100 times higher than Cu) carbon nanotube-copper (CNT-Cu) composite into a variety of complex nano scale, planar and multi-tiered current pathways. The approach involved the use of a two-stage electrodeposition of copper into a pre-patterned template of porous, thin CNT sheets acting as the electrode. The versatility of this approach enabled the realization of completely suspended multi-tier, dielectric-less 'air-gap' CNT Cu circuits that could be electrically isolated from each other and are challenging to fabricate with pure Cu or any metal. Importantly, all such complex structures, ranging from 500 nm to 20 MUm in width, exhibited ~100-times higher ampacity than any known metal, with comparable electrical conductivity as Cu. In addition, CNT-Cu structures also exhibited a superior temperature stability compared to the ~10-times wider Cu counterparts. We believe that the combination of our approach and the properties demonstrated here are vital achievements for the future development of efficient and powerful electrical devices. PMID- 26486753 TI - The complete mitochondrial genome of the Dipodomys ordii (Ord's kangaroo rat). AB - Ord's kangaroo rat is a kangaroo rat native to western North America. In this study, we first reported the complete mitochondrial genome of Dipodomys ordii that the first has the complete mitochondrial genome in the genus of Heteromyidae. The mitogenome is a circular molecule of 16 257 bp in length, containing 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs and a putative displacement loop region. All protein-coding genes started with a traditional ATN codon and terminated with the mitochondria stop codon (TAA/TAG/AGA) or a single T base. The gene order and composition of mitogenome was similar to that of most other Sciurognathi species and its GC content was 36.73%. Thirteen protein-coding genes of D. ordii together with eight other closely species were used to construct the species phylogenetic tree for verification of the accuracy of new determined mitogenome sequences. PMID- 26486754 TI - The influence of orthopedic corsets on the incidence of pathological fractures in patients with spinal bone metastases after radiotherapy. AB - BACKGROUND: Clinical care of unstable spinal bone metastases in many centers often includes patient immobilization by means of an orthopedic corset in order to prevent pathological fractures. The aim of this retrospective analysis was to evaluate the incidence of pathological fractures after radiotherapy (RT) in patients with and without orthopedic corsets and to assess prognostic factors for pathological fractures in patients with spinal bone metastases. METHODS: The incidence of pathological fractures in 915 patients with 2.195 osteolytic metastases in the thoracic and lumbar spine was evaluated retrospectively on the basis of computed tomography (CT) scans between January 2000 and January 2012 depending on prescription and wearing of patient-customized orthopedic corsets. RESULTS: In the corset group, 6.8 and 8.0 % in no-corset group showed pathological fractures prior to RT, no significant difference between groups was detected (p = 0.473). After 6 months, patients in the corset group showed pathological fractures in 8.6 % and in no-corset group in 9.3 % (p = 0.709). The univariate and bivariate analyses demonstrated no significant prognostic factor for incidence of pathological fractures in both groups. CONCLUSIONS: In this analysis, we could show for the first time in more than 900 patients, that abandoning a general corset supply in patients with spinal metastases does not significantly cause increased rates of pathological fractures. Importantly, the incidence of pathological fracture after RT was small. PMID- 26486755 TI - Topotecan for Relapsed Small-cell Lung Cancer: Systematic Review and Meta Analysis of 1347 Patients. AB - Topotecan is the most reliable chemotherapy regimen for relapsed small-cell lung carcinoma (SCLC). The efficacy and adverse effects of topotecan as reported by previous studies varied greatly. The inclusion criterion was a prospective study that was able to provide data for 6-month over-all survival (OS) rate, 1-year OS rate, objective responses, and/or adverse effects of single agent topotecan as a second line chemotherapy for SCLC, written in English language as a full article. Any topotecan regimen were allowed. Binary data were meta-analyzed with the random-model generic inverse variance method. We included 14 articles consisted of 1347 patients. Pooled values were estimated as follows. Six-month OS rate: 37% (95% CI: 28-46%). One-year OS rate: 9% (95% CI: 5-13%). Response rate: 5% (95% CI: 1-8%). Six-month OS rate: 57% (95% CI: 50-64%). One-year OS rate: 27% (95% CI: 22-32%). Response rate: 17% (95% CI: 11-23%). Grade III/IV neutropenia 69% (95% CI: 58-80%). Grade III/IV thrombopenia 41% (95% CI: 34-48%). Grade III/IV anemia 24% (95% CI: 17 30%). Non-hematorogical events were rare. Chemotherapy-related death 2% (95% CI: 1-3%). In conclusion, Topotecan provided a possibly promising outcome for sensitive-relapse SCLC and poor outcome for refractory relapse SCLC. Adverse events were mainly hematological. PMID- 26486757 TI - One-pot synthesis of etched Cu2O cubes with exposed {110} facets with enhanced visible-light-driven photocatalytic activity. AB - Novel etched Cu2O cubes with exposed {110} facets are synthesized via an oxidative etching method at room temperature. The photocatalytic performance indicates that these architectures show higher photocatalytic activity than that of the normal Cu2O cubes in the degradation of methylene orange. PMID- 26486756 TI - Antibiotic use and childhood body mass index trajectory. AB - BACKGROUND/OBJECTIVES: Antibiotics are commonly prescribed for children. Use of antibiotics early in life has been linked to weight gain but there are no large scale, population-based, longitudinal studies of the full age range among mainly healthy children. SUBJECTS/METHODS: We used electronic health record data on 163 820 children aged 3-18 years and mixed effects linear regression to model associations of antibiotic orders with growth curve trajectories of annual body mass index (BMI) controlling for confounders. Models evaluated three kinds of antibiotic associations-reversible (time-varying indicator for an order in year before each BMI), persistent (time-varying cumulative orders up to BMIj) and progressive (cumulative orders up to prior BMI (BMIj-1))-and whether these varied by age. RESULTS: Among 142 824 children under care in the prior year, a reversible association was observed and this short-term BMI gain was modified by age (P<0.001); effect size peaked in mid-teen years. A persistent association was observed and this association was stronger with increasing age (P<0.001). The addition of the progressive association among children with at least three BMIs (n=79 752) revealed that higher cumulative orders were associated with progressive weight gain; this did not vary by age. Among children with an antibiotic order in the prior year and at least seven lifetime orders, antibiotics (all classes combined) were associated with an average weight gain of approximately 1.4 kg at age 15 years. When antibiotic classes were evaluated separately, the largest weight gain at 15 years was associated with macrolide use. CONCLUSIONS: We found evidence of reversible, persistent and progressive effects of antibiotic use on BMI trajectories, with different effects by age, among mainly healthy children. The results suggest that antibiotic use may influence weight gain throughout childhood and not just during the earliest years as has been the primary focus of most prior studies. PMID- 26486758 TI - Laparoendoscopic Single-Site Retroperitoneoscopic Adrenalectomy Versus Conventional Retroperitoneoscopic Adrenalectomy in Obese Patients. AB - OBJECTIVE: To compare the operative outcomes of obese patients undergoing laparoendoscopic single-site (LESS) retroperitoneoscopic adrenalectomy or standard laparoscopic (LAP) retroperitoneoscopic adrenalectomy. METHODS: Between September 2011 and April 2015, 51 obese patients underwent LESS retroperitoneoscopic adrenalectomy and their operative outcomes were compared with 65 obese patients who underwent standard retroperitoneoscopic adrenalectomy by the same surgeon. In the LESS group, a single-port access was positioned in the lumbar incision. The standard retroperitoneal adrenalectomy technique was performed with a combination of conventional and curved LAP instruments. The following parameters were adopted: patient demographics, surgical details, perioperative complications, postoperative outcome data, and short-term outcomes. RESULTS: The LESS group was comparable with the LAP group in terms of total operative time (70.4 +/- 21.3 vs 65.5 +/- 24.8 minutes, p = 0.26), hospital length of stay (5.7 +/- 1.2 vs 6.1 +/- 1.5 days, p = 0.12), and incidence of complications (4/51 vs 5/65, p = 0.98) for patients with similar baseline demographics. The LESS group had significantly shorter surgical incisions (2.8 +/ 0.3 vs 5.3 +/- 0.6 cm, p < 0.0001), lower in-hospital analgesic requirement (7.6 +/- 3.3 mg morphine equivalent vs 10.5 +/- 6.2 mg, p = 0.003), and significantly superior scar satisfaction score (9.3 +/- 0.7 vs 7.6 +/- 1.4, p < 0.0001) than the LAP group. Although estimated blood loss was greater in the LESS group (28.1 +/- 10.6 vs 16.9 +/- 7.2 mL in the LAP group, p < 0.0001), <50 mL overall blood loss was not clinically significant. During a mean follow-up of 20.2 months, no recurrences or deaths were documented in either group. CONCLUSIONS: In properly selected patients, LESS retroperitoneoscopic adrenalectomy for obese individuals is technically feasible and safe in experienced hands, offering perioperative outcomes comparable with those of the conventional multiport approach, but with a superior cosmetic outcome. PMID- 26486759 TI - Genome-wide identification and characterization of the superoxide dismutase gene family in Musa acuminata cv. Tianbaojiao (AAA group). AB - BACKGROUND: Superoxide dismutase (SOD) is an essential enzyme of the plant antioxidant system that responds to oxidative stresses caused by adverse conditions. Banana is an important staple and economic crop in tropical and subtropical regions. However, its growth and yield are constantly affected by various abiotic stresses. To analyze the roles of distinct SOD genes under various stresses, a detailed characterization and analysis of the SOD gene family in Cavendish banana is indispensable. METHODS: The presence and structure of the SOD family genes were experimentally verified using 5'/3' RACE-PCR, reverse transcription PCR and PCR. Then, their syntenic relationships, conserved motifs and phylogenetic relationships were analyzed using software. Cis-elements present in the promoters were predicted via PlantCARE. And the expression levels under abiotic and hormonal stresses were determined using real-time quantitative polymerase chain reaction. RESULTS: In total, 25 'Tianbaojiao' SOD cDNAs (MaSODs), which encoded six Cu/ZnSODs, four MnSODs and two FeSODs, were cloned. The 12 MaSOD genes were divided into four groups based on their conserved motifs, which corroborated their classifications based on gene-structure patterns and subcellular localizations. Eleven MaSOD promoters were isolated and found to contain many cis-acting elements involved in stress responses. Gene expression analysis showed that 11 out of the 12 MaSODs were expressed in all tested tissues (leaf, pseudostem and root), whereas MaCSD2B was expressed only in leaves and roots. Specific MaSOD members exhibited different expression patterns under abiotic and hormonal treatments. Among the 12 MaSOD genes, MaCSD1D was the only one that responded to all eight treatments, suggesting that this gene plays a predominant role in reactive oxygen species scavenging caused by various stresses in banana. CONCLUSIONS: A genome-wide analysis showed that the 'Tianbaojiao' banana harbored an expanded SOD gene family. Whole genome duplication, segmental duplication and complex transcriptional regulation contributed to the gene expansion and mRNA diversity of the MaSODs. The expression patterns of distinct MaSOD genes showed that they are important responses to different abiotic and hormonal stresses in banana. PMID- 26486761 TI - Copper-Catalyzed Aerobic Decarboxylation/Ketooxygenation of Electron-Deficient Alkenes. AB - A copper-catalyzed ketooxygenation of electron-deficient alkenes was developed. This approach combines O-H alkylation, aerobic decarboxylation, and oxygenation in one transformation. Mechanistic investigation of this reaction showed that the copper salt is responsible for both generating the amidoxyl radical and promoting aerobic decarboxylation. PMID- 26486762 TI - Daclatasvir: A NS5A Replication Complex Inhibitor for Hepatitis C Infection. AB - OBJECTIVES: To review the pharmacology, efficacy, and safety of daclatasvir in the treatment of patients with chronic hepatitis C virus (HCV) infection. DATA SOURCES: A literature search through EMBASE and PubMed was conducted (January 1966 to August 2015) using the terms BMS-790052, daclatasvir, and hepatitis C. References from retrieved articles were reviewed for any additional material. Additionally, the new drug application and prescribing information were retrieved. STUDY SELECTION/DATA EXTRACTION: The literature search was limited to human studies published in English. Phase 1, 2, and 3 studies describing the pharmacology, pharmacokinetics, efficacy, and safety of daclatasvir for HCV were identified. DATA SYNTHESIS: Daclatasvir, a nonstructural 5A protein inhibitor, combined with sofosbuvir, is indicated for adult patients with chronic HCV genotype 3 regardless of treatment or cirrhosis status. The phase III ALLY-3 trial (n = 152) demonstrated that daclatasvir taken once daily with sofosbuvir for 12 weeks was effective at achieving sustained virological response (SVR) rates in treatment-naive (97%) and treatment-experienced (94%) patients without cirrhosis. Patients with cirrhosis had significantly lower SVR rates (58 and 69%, respectively). The most common adverse drug events associated with daclatasvir and sofosbuvir in ALLY-3 were headache (20%), fatigue (19%), and nausea (12%). CONCLUSIONS: Daclatasvir, when combined with sofosbuvir, is an effective agent to treat HCV genotype 3, with SVR rates above 90% for patients without cirrhosis who are treatment naive or experienced. SVR rates for treatment-naive or -experienced patients with cirrhosis are not as robust (58%-69%). PMID- 26486763 TI - Azithromycin Pharmacokinetics in Adults With Acute Respiratory Distress Syndrome Undergoing Treatment With Extracorporeal-Membrane Oxygenation. PMID- 26486760 TI - Subacute Pain after Traumatic Brain Injury Is Associated with Lower Insular N Acetylaspartate Concentrations. AB - Persistent pain is experienced by more than 50% of persons who sustain a traumatic brain injury (TBI), and more than 30% experience significant pain as early as 6 weeks after injury. Although neuropathic pain is a common consequence after CNS injuries, little attention has been given to neuropathic pain symptoms after TBI. Magnetic resonance spectroscopy (MRS) studies in subjects with TBI show decreased brain concentrations of N-acetylaspartate (NAA), a marker of neuronal density and viability. Although decreased brain NAA has been associated with neuropathic pain associated with spinal cord injury (SCI) and diabetes, this relationship has not been examined after TBI. The primary purpose of this study was to test the hypothesis that lower NAA concentrations in brain areas involved in pain perception and modulation would be associated with greater severity of neuropathic pain symptoms. Participants with TBI underwent volumetric MRS, pain and psychosocial interviews. Cluster analysis of the Neuropathic Pain Symptom Inventory subscores resulted in two TBI subgroups: The Moderate Neuropathic Pain (n = 17; 37.8%), with significantly (p = 0.038) lower insular NAA than the Low or no Neuropathic Pain group (n = 28; 62.2%), or age- and sex-matched controls (n = 45; p < 0.001). A hierarchical linear regression analysis controlling for age, sex, and time post-TBI showed that pain severity was significantly (F = 11.0; p < 0.001) predicted by a combination of lower insular NAA/Creatine (p < 0.001), lower right insular gray matter fractional volume (p < 0.001), female sex (p = 0.005), and older age (p = 0.039). These findings suggest that neuronal dysfunction in brain areas involved in pain processing is associated with pain after TBI. PMID- 26486765 TI - Molecular Solution Behaviour of an Intermediate Biofuel Feedstock: Acetone Butanol-Ethanol (ABE). AB - Mixtures of acetone, butanol, and ethanol (ABE) are common intermediate products in the production of biofuels via biomass fermentation. Their separation to yield, for example, bio-butanol, is still difficult due to the lack of a fundamental understanding of these mixtures at the molecular level. In order to bridge this gap, a detailed analysis of characteristic features of the vibrational spectrum is carried out. A systematic study of the binary solutions of acetone with ethanol and butanol does not only reveal a universal behaviour at the molecular level when acetone is mixed with short-chain alcohols, it also shows that the phenomena at a length scale between the molecules and in the macroscopic solution need to be taken into account to understand the structure property relationships. The size of self-associated molecule clusters seems to determine whether or not a system exhibits an azeotrope. When a second alcohol is added to an acetone/alcohol solution, no additional non-idealities are induced, which is advantageous for modelling ternary ABE mixtures and for improving their processing in the production of biofuels. PMID- 26486766 TI - Multicomponent/Palladium-Catalyzed Cascade Entry to Benzopyrrolizidine Derivatives: Synthesis and Antioxidant Evaluation. AB - A versatile and efficient protocol for the synthesis of highly substituted benzopyrrolizidines (tetrahydro-3H-pyrrolo[2,1-a]isoindol-3-ones) is reported. The strategy consisted of an Ugi four-component reaction/elimination methodology to afford dehydroalanines containing trans-cinnamic acid derivatives and different substituted 2-bromobenzylamines, followed by a palladium-catalyzed 5 exo-trig/5-exo-trig cascade carbocyclization process. Gratifyingly, benzopyrrolizidines were obtained in moderate to good yields (42-77%) with a Z geometry due to the structural requirements for syn-beta-hydride elimination. The prepared heterocyclic scaffolds are decorated with several substituents and incorporate a benzopyrrolizidine-fused system, along with an embedded cinnamic acid derivative, two privileged medicinal chemistry scaffolds. Additionally, since some of the compounds are derived from the well-known antioxidants ferulic and sinapinic acids, they were tested for their in vitro antioxidant capacity. The data suggested that compounds having a p-hydroxyl group showed moderate 2,2 diphenyl-1-picrylhydrazyl-radical-scavenging activity and were effective antioxidants in preventing lipoperoxidation in a thiobarbituric acid reactive substances assay. PMID- 26486764 TI - Association of haplotypes of the TLR8 locus with susceptibility to Crohn's and Behcet's diseases. AB - OBJECTIVES: The aim of this study was to investigate the role of the TLR8, a mediator of innate inflammatory response, in susceptibility to two immune mediated disorders characterised by dysregulation of the immune response, Crohn's and Behcet's diseases (CD and BD). METHODS: A total of 844 CD, 371 BD patients and 1385 controls were genotyped in 8 tag single nucleotide polymorphisms (tSNPs) in the locus TLR8 (chromosome X). All these tSNPs have a minor allele frequency greater than 0.05 in the Caucasian population. RESULTS: The rs2407992 and the rs5744067 were associated with susceptibility to BD and CD, respectively (OR=1.34, 95%CI=1.10-1.62, p=0.0025 and OR=0.82, 95%CI=0.68-0.99, p=0.045, respectively). Although after stratification by gender, statistically significant differences in the distribution of the aforementioned SNPs were only observed in the females groups (BD OR=1.31, 95%CI=1.06-1.64, p=0.012 and CD OR=0.84, 95%CI=0.72-0.98, p=0.044) the trend was similar among males. Since the rs5744067 and rs2407992 are located in the same linkage disequilibrium block, we performed a haplotypic analysis by combination of the tSNPs. One haplotype (H1) was identified as a protective factor in BD (OR=0.75, 95%CI=0.62-0.90, p=0.0027) and another (H2) as a protective factor in CD (OR=0.78, 95%CI=0.64-094, p=0.0102). No statistically significant differences in the mean of the levels of expression attributable to the haplotype variants were found in the in silico analysis performed. CONCLUSIONS: Our results suggest a relationship between the TLR8 and the susceptibility to CD and BD. Nevertheless, these differences could not be imputed to the levels of expression. PMID- 26486767 TI - Chemomechanical versus drilling methods for caries removal: an in vitro study. AB - The purpose of this study was to compare the performance of chemomechanical caries removal (CMCR) with that of conventional drilling for efficacy of caries removal, time spent, morphological changes and microhardness of surface dentin, and microleakage of subsequent restorations. Forty-six carious deciduous molars were randomly divided into two groups: one each for caries removal by (1) CMCR and by (2) drilling. The completeness of caries removal was evaluated by visual and tactile criteria and a caries detector device. Twenty teeth in each group were restored with glass ionomer (GI) and subjected to thermocycling before undergoing microleakage and microhardness tests. In each group, three restored teeth were used for polarized light microscopic analysis, and three unrestored teeth for scanning electron microscopy (SEM). There was no significant difference in the completeness of caries removal between groups. However, time spent for caries removal by CMCR was significantly longer than that required for drilling. Restorations in the CMCR group had significantly more microleakage than those in the drilling group. Dentin hardness of the cavity floor after CMCR was also significantly lower. Microscopic analyses showed roughened and irregular dentin surfaces in the CMCR group, unlike the smooth surfaces observed in the drilling group. In conclusion, CMCR was as efficacious as drilling in term of completeness of caries removal, but required longer excavation times and resulted in lower microhardness of residual dentin as well as more microleakage after restorations with GI. Further laboratory and clinical evaluations on the efficiency and performance of CMCR for the durability of subsequent restorations are required. PMID- 26486768 TI - A comparison of two reciprocating instruments using bending stress and cyclic fatigue tests. AB - The aim of this study was to comparatively evaluate the bending resistance at 45o, the static and dynamic cyclic fatigue life, and the fracture type of the WaveOne (Dentsply Maillefer, Ballaigues, Switzerland) 25-08 and Reciproc (VDW, Munich, Germany) 25-08 instruments. A total of 60 nickel-titanium (NiTi) instruments (30 Reciproc and 30 WaveOne) from three different lots, each of which was 25 mm in length, were tested. The bending resistance was evaluated through the results of a cantilever-bending test conducted using a universal testing machine. Static and dynamic cyclic fatigue testing was conducted using a custom made device. For the static and dynamic tests, a cast Ni-Cr-Mo-Ti alloy metal block with an artificial canal measuring 1.77 mm in diameter and 20.00 mm in total length was used. A scanning electron microscope was used to determine the type of fracture. Statistical analyses were performed on the results. The WaveOne instrument was less flexible than the Reciproc (p < 0.05). The Reciproc instrument showed better resistance in the static and dynamic cyclic fatigue tests (p < 0.05). The transverse cross-section and geometry of the instruments were important factors in their resistance to bending and cyclic fracture. Both of the instruments showed ductile-type fracture characteristics. It can be concluded that the Reciproc 25-08 instrument was more resistant to static and dynamic cyclic fatigue than the WaveOne 25-08 instrument, while the WaveOne 25-08 instrument was less flexible. Bending and resistance to cyclic fracture were influenced by the instruments' geometries and transverse cross-sections. Both of the instruments showed ductile-type fracture characteristics. PMID- 26486769 TI - Association between Bolton discrepancy and Angle malocclusions. AB - This study aimed to assess and compare the overall and anterior ratios of tooth size discrepancies in all Angle malocclusion groups. The following null hypothesis (H0) was tested: no difference between tooth size discrepancies (overall and anterior) would be observed among Angle malocclusion groups. The sample comprised of 711 pre-orthodontic treatment study casts of Brazilian patients with a mean age of 17.42 years selected from private practices in Brazil. The casts were divided into 3 groups according to the type of malocclusion: Class I (n = 321), Class II (n = 324), and Class III patients (n = 66). The measurement of the greatest mesiodistal width of the teeth was performed using a centesimal precision digital caliper directly on the study casts, from the distal surface of the left first molar to the distal surface of the right first molar. The overall and anterior ratios between the maxillary and mandibular teeth were evaluated using Bolton's method. The following statistical tests were applied: chi-square, independent t-test, and one-way ANOVA. Results showed that all Angle malocclusions groups exhibited a ratio compatible with those recommended by Bolton. With respect to the overall and anterior ratios among the malocclusion groups, no statistically significant differences were found. The null hypothesis was accepted because the results showed no differences in the overall and anterior ratios of tooth size discrepancies among different Angle malocclusion groups. PMID- 26486770 TI - Cyclic fatigue resistance of two nickel-titanium instruments in different curving angles: a comparative study. AB - The cyclic resistance of ProTaper Universal (size 25/08) and ProTaper Next (size 25/06) instruments was compared in artificial canals with different curvatures in this study. A total of 30 ProTaper Universal and 30 ProTaper Next instruments were divided into 6 groups (n = 10) and were operated into artificial canals with 3 different angles of curvature (45 degrees , 60 degrees , 90 degrees ). The canal length was kept consistent in this study. The number of cycles to fracture (NCF) was counted until file fracture occurred, at which point, the length of the fragment was measured. The data were analyzed statistically using ANOVA complemented by the Tukey test (p < 0.05). Cross sections of the fractured files were scanned by an electron microscope. In the fatigue test, the ProTaper Next displayed more resistance in 45 degrees and 60 degrees canals (p < 0.05), whereas ProTaper Universal exhibited a better operability in 90 degrees canals (p < 0.05). The average length of the fragments from ProTaper Next was significantly shorter than that from ProTaper Universal in 90 degrees canals (p < 0.05). The cross sections of the fractured surfaces became flatter when the curvature angles decreased from 90 degrees to 45 degrees . ProTaper Next was more reliable when shaping in curved canals, whereas ProTaper Universal was more sui for the preparation of root canals with severe curvatures. PMID- 26486771 TI - Cell phone radiation effects on cytogenetic abnormalities of oral mucosal cells. AB - The aim of this study was to evaluate the effects of exposure to cell phone electromagnetic radiation on the frequency of micronuclei, broken eggs cells, binucleated cells, and karyorrhexis in epithelial cells of the oral mucosa. The sample was composed of 60 cell phone users, who were non-smokers and non drinkers, and had no clinically visible oral lesions. Cells were obtained from anatomical sites with the highest incidence of oral cancer: lower lip, border of the tongue, and floor of the mouth. The Feulgen reaction was used for quantification of nuclear anomalies in 1,000 cells/slide. A slightly increase in the number of micronucleated cells in the lower lip and in binucleated cells on the floor of the mouth was observed in individuals who used their phones > 60 minutes/week. The analysis also revealed an increased number of broken eggs in the tongue of individuals owning a cell phone for over eight years. Results suggest that exposure to electromagnetic waves emitted by cell phones can increase nuclear abnormalities in individuals who use a cell phone for more than 60 minutes per week and for over eight years. Based on the present findings, we suggest that exposure to electromagnetic radiation emitted by cell phones may interfere with the development of metanuclear anomalies. Therefore, it is demonstrated that, despite a significant increase in these anomalies, the radiation emitted by cell phones among frequent users is within acceptable physiological limits. PMID- 26486772 TI - Greenhouse Gas Emissions from Three Cage Layer Housing Systems. AB - Agriculture accounts for 10 to 12% of the World's total greenhouse gas (GHG) emissions. Manure management alone is responsible for 13% of GHG emissions from the agricultural sector. During the last decade, Quebec's egg production systems have shifted from deep-pit housing systems to manure belt housing systems. The objective of this study was to measure and compare carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) emissions from three different cage layer housing systems: a deep liquid manure pit and a manure belt with natural or forced air drying. Deep liquid manure pit housing systems consist of "A" frame layer cages located over a closed pit containing the hens' droppings to which water is added to facilitate removal by pumping. Manure belt techniques imply that manure drops on a belt beneath each row of battery cages where it is either dried naturally or by forced air until it is removed. The experiment was replicated with 360 hens reared into twelve independent bench-scale rooms during eight weeks (19-27 weeks of age). The natural and forced air manure belt systems reduced CO2 (28.2 and 28.7 kg yr(-1) hen(-1), respectively), CH4 (25.3 and 27.7 g yr(-1) hen(-1), respectively) and N2O (2.60 and 2.48 g yr(-1) hen(-1), respectively) emissions by about 21, 16 and 9% in comparison with the deep-pit technique (36.0 kg CO2 yr(-1) hen(-1), 31.6 g CH4 yr(-1) hen(-1) and 2.78 g N2O yr(-1) hen(-1)). The shift to manure belt systems needs to be encouraged since this housing system significantly decreases the production of GHG. PMID- 26486773 TI - Effects of Dietary Yeast (Saccharomyces cerevisia) Supplementation in Practical Diets of Tilapia (Oreochromis niloticus). AB - A 51-day feeding trial was carried out to determine the effects of various dietary levels of brewer's yeast, Saccharomyces cerevisiae, in the growth performance, body composition and nutrient utilization in Nile tilapia, Oreochromis niloticus, juveniles. Fish (7.6 +/- 0.3 g) were stocked into eighteen 1,000-L tanks (100 fish per tank; n = 3) and fed to apparent satiation six isonitrogenous (27% crude protein) and isoenergetic (19 kJ/g) diets, formulated to contain different dried yeast levels (0%, 10%, 15%, 20%, 30% or 40% diet) in substitution to fishmeal. Body weight tripled at the end of the feeding trial for fish fed up to 20% dietary yeast incorporation. Daily growth coefficient (DGC, % body weight/day) decreased with increasing dietary yeast level (P < 0.0001). Voluntary feed intake (VFI, %BW/day) did not vary significantly with increasing yeast level. Fish fed 40% yeast showed significant reduction in protein efficiency rate, protein retention and nitrogen gain. Increasing levels of dietary yeast did not significantly affect protein or lipid digestibility. Dietary dried yeast was seemingly palatable to tilapia juveniles and was suitable up to 15% inclusion to promote growth and efficient diet utilization, without affecting body composition. PMID- 26486774 TI - Prevalence and Incidence of Abnormal Behaviours in Individually Housed Sheep. AB - This study examined the prevalence and incidence of abnormal behaviour in sheep housed individually indoors. Ninety-six castrated Merino sheep were observed using 15-min instantaneous sampling between 08:15 and 18:15 h for two consecutive days over a 3-week period. Sheep on average spent 62% of their time idle, 17% feeding, 1% drinking, 5% pacing, 10% chewing pen fixtures and 4% nosing pen fixtures. Pacing behaviour was predominantly seen in the morning with sheep on average spending 14% of their time pacing. Sheep on average spent 4% of their time in the morning and 13% of their time in the afternoon chewing pen fixtures. In the afternoon, the predominant behaviour was idle with sheep on average spending 71% of their time idle. Seventy-one percent of the sheep displayed one or more of the behaviours of pacing, and chewing and nosing pen fixtures for more than 10% of the day and 47% displayed one or more of these behaviours for more than 20% of the day. The prevalence and incidence of these 'abnormal' behaviours appears high, especially in relation to that of sheep grazed outdoors on pasture, and raises the question of the welfare risk to these animals. However, without a more comprehensive appreciation of other aspects of the animal's biology, such as stress physiology and fitness characteristics, it is difficult to understand the welfare implications of these behaviours. PMID- 26486775 TI - Social Environment and Control Status of Companion Animal-Borne Zoonoses in Japan. AB - Changing social and environmental factors have been the cause of an increase in the number and variety of animals are being imported into Japan. Moreover, the number of Japanese households are keeping companion animals has also risen. These factors, along with the high density of the Japanese population and the low percentage of registered dogs, have increased the risk of animal-to-human transmission of zoonoses. To control zoonosis outbreaks, the Japanese government has implemented a three-stage approach for the border control of zoonoses and has stipulated the monitoring and reporting of eight companion animal-borne zoonoses under the Rabies Prevention Law and the Infectious Diseases Control Law. The fact that no case of human and animal rabies has been reported over the past 50 years indicates that these measures are highly effective in preventing rabies transmission. Although it is known that the total number of possible companion animal-borne zoonosis outbreaks decreased between 2005 and 2009 when compared with numbers between 2001 and 2004, the number of zoonosis cases that can be attributed to transmission by companion animals remains unclear. Active surveillance should be conducted on a national level to collect the data necessary to determine this number and identify trends in companion-animal transmitted diseases. Using the data collected, regulation systems should be evaluated to determine whether they have met reasonable goals and policy planning conducted for the control of emerging diseases. PMID- 26486776 TI - Effects of Dietary Fatty Acids on Lipid Traits in the Muscle and Perirenal Fat of Growing Rabbits Fed Mixed Diets. AB - The aim of this study was to evaluate the effects of various raw materials (spirulina, curcuma, tomato pomace, false flax, linseed, chia, perilla seeds) as suitable polyunsaturated fatty acid n-3 (n-3 PUFA) sources, on the lipid traits in the longissimus dorsi muscle and perirenal fat of growing rabbits. The fatty acid (FA) analyses of the diets, carried out by gas chromatography, differed over a wide range on the basis of the highly varied ingredients in 27 experimental formulations. Among the 29 identified FAs, three from feeds were catabolized in the rabbits, five were de novo synthesized and stored chiefly in the muscle. It was possible to linearly characterize the incorporation from the feed to the muscle of 16 FAs. This study has confirmed that the dietary inclusion of various raw materials could be considered as a way of enriching the n-3 PUFA of rabbit meat. A proposal for the prediction of n-3 PUFA from dietary alpha-linolenic acid (C18:3 n-3) and a panel of another 10 FAs has been made for intramuscular fat (R2 = 0.94) and perirenal fat (R2 = 0.96). PMID- 26486777 TI - Analysis of Animal Research Ethics Committee Membership at American Institutions. AB - Institutional Animal Care and Use Committees (IACUCs) were created to review, approve and oversee animal experiments and to balance the interests of researchers, animals, institutions and the general public. This study analyzed the overall membership of IACUCs at leading U.S. research institutions. We found that these committees and their leadership are comprised of a preponderance of animal researchers, as well as other members who are affiliated with each institution; some of whom also work in animal laboratories. This overwhelming presence of animal research and institutional interests may dilute input from the few IACUC members representing animal welfare and the general public, contribute to previously-documented committee bias in favor of approving animal experiments and reduce the overall objectivity and effectiveness of the oversight system. PMID- 26486778 TI - The Interaction Between Dietary Valine and Tryptophan Content and Their Effect on the Performance of Piglets. AB - Four experimental diets for newly weaned pigs were formulated: (1) low valine and low tryptophan; (2) low valine and high tryptophan; (3) high valine and low tryptophan and (4) high valine and high tryptophan. Dietary standardized ileal digestible (SID) lysine content was 1.06 g/kg. The SID valine to SID lysine ratio was 0.58 and 0.67 for the low and high valine diets, respectively, and SID tryptophan to SID lysine ratios were 0.19 and 0.22 for the low and high tryptophan diets, respectively. In total, 64 pens of 6 pigs (3 barrows and 3 gilts) were divided over the four experimental treatments. No interaction between dietary supply of valine and tryptophan was observed (P > 0.1 for all parameters). Increasing the dietary valine content increased the daily feed intake, daily gain and gain:feed (P < 0.001 for all three parameters). Increasing the dietary tryptophan content improved gain:feed during the first 2 weeks (P < 0.05) and overall (P < 0.05). Valine supply had a greater effect on performance results than tryptophan supply. It may thus be beneficial to provide a diet with an optimal dietary concentration of valine even if other amino acids are at suboptimal dietary levels. PMID- 26486779 TI - Bias During the Evaluation of Animal Studies? AB - My recent book entitled The Costs and Benefits of Animal Experiments seeks to answer a key question within animal ethics, namely: is animal experimentation ethically justifiable? Or, more precisely, is it justifiable within the utilitarian cost:benefit framework that fundamentally underpins most regulations governing animal experimentation? To answer this question I reviewed more than 500 scientific publications describing animal studies, animal welfare impacts, and alternative research, toxicity testing and educational methodologies. To minimise bias I focused primarily on large-scale systematic reviews that had examined the human clinical and toxicological utility of animal studies. Despite this, Dr. Susanne Prankel recently reviewed my book in this journal, essentially accusing me of bias. However, she failed to provide any substantive evidence to refute my conclusions, let alone evidence of similar weight to that on which they are based. Those conclusions are, in fact, firmly based on utilitarian ethical reasoning, informed by scientific evidence of considerable strength, and I believe they are robust. PMID- 26486780 TI - Livestock Helminths in a Changing Climate: Approaches and Restrictions to Meaningful Predictions. AB - Climate change is a driving force for livestock parasite risk. This is especially true for helminths including the nematodes Haemonchus contortus, Teladorsagia circumcincta, Nematodirus battus, and the trematode Fasciola hepatica, since survival and development of free-living stages is chiefly affected by temperature and moisture. The paucity of long term predictions of helminth risk under climate change has driven us to explore optimal modelling approaches and identify current bottlenecks to generating meaningful predictions. We classify approaches as correlative or mechanistic, exploring their strengths and limitations. Climate is one aspect of a complex system and, at the farm level, husbandry has a dominant influence on helminth transmission. Continuing environmental change will necessitate the adoption of mitigation and adaptation strategies in husbandry. Long term predictive models need to have the architecture to incorporate these changes. Ultimately, an optimal modelling approach is likely to combine mechanistic processes and physiological thresholds with correlative bioclimatic modelling, incorporating changes in livestock husbandry and disease control. Irrespective of approach, the principal limitation to parasite predictions is the availability of active surveillance data and empirical data on physiological responses to climate variables. By combining improved empirical data and refined models with a broad view of the livestock system, robust projections of helminth risk can be developed. PMID- 26486781 TI - Tourism Experiences and Self-Rated Health Among Older Adults in China. AB - OBJECTIVE: To investigate factors associated with tourism experiences, and the association between tourism experiences and subsequent self-rated health. METHOD: Multilevel logistic regression models and four waves of panel data from a large nationally representative survey of older adults in China were employed. RESULTS: Those who had a tourism experience tended to be younger, men, urban residents, have a higher socioeconomic status (SES), and frequently participate in leisure activities and exercise. However, controlling for SES, women were more likely than men to have a tourism experience. Notably, tourism was negatively associated with poor self-rated health and the association was robust to adjustments for a wide range of confounders. DISCUSSION: The net beneficial impact of tourism on self-rated health may operate through several mechanisms such as improvements in tourists' cognitive functioning, healthy lifestyles, self-esteen, family and social relations, and psychological and spirtual well-being. Tourism participation is an effective way to promote healthy aging. PMID- 26486782 TI - Trajectories of Outdoor Mobility in Vulnerable Community-Dwelling Elderly: The Role of Individual and Environmental Factors. AB - OBJECTIVE: Outdoor mobility is critical for healthy aging, yet little is known about the factors influencing mobility in the frail elderly. We investigated the role of individual and community risk factors on trajectories of mobility in a population of vulnerable community-dwelling elderly. METHOD: Using data from 1,188 older adults in Detroit, MI, who qualify for federally funded home care, a latent class growth analysis was used to model the frequency of going outside over a 15-month period. RESULTS: Four latent trajectories were found: those with a low, high, and declining frequency of going outdoors over time, and those who do not go outdoors on a regular basis. Risk factors for membership in the homebound and infrequent mobility groups were older age, more severe mobility impairment, and fear of falling. Barriers at the entry to the home were associated with being homebound. DISCUSSION: Declining health status and functional limitations are risk factors that pose a threat to outdoor mobility in the frail elderly, while housing barriers and community accessibility also merit attention. PMID- 26486783 TI - Associations of Daily Pedometer Steps and Self-Reported Physical Activity With Health-Related Quality of Life: Results From the Alberta Older Adult Health Survey. AB - OBJECTIVE: The aim of this article is to examine associations of self-reported physical activity (PA) and pedometer steps with health-related quality of life (HRQoL) among a population-based sample of older adults. METHOD: Adults >=55 years (N = 1,296) were recruited through random-digit dialing and responded to a questionnaire via computer-assisted telephone interviewing methods. Questionnaires assessed demographic variables and validated measures of PA and HRQoL. Participants received a step pedometer and waist circumference tape measure via post. RESULTS: Compared with participants in the low-step group (0 6,999 steps/day), participants in the high-step group (>10,000 steps/day) had significantly higher scores on mental health (Mdiff = 3.1, p < .001, confidence intervals [CI] = [1.8, 4.3]), physical health (Mdiff = 3.5, p < .001, CI = [2.2, 4.7]), and global health (Mdiff = 3.5, p < .001, CI = [2.3, 4.7]). Waist circumference and body mass index did not moderate any associations of pedometer steps and PA with HRQoL. CONCLUSION: Older adults exceeding established step thresholds reported significantly higher HRQoL indices compared with those achieving lower thresholds. PMID- 26486784 TI - Supramolecular Porphyrin Copolymer Assembled through Host-Guest Interactions and Metal-Ligand Coordination. AB - Bisporphyrin cleft molecule 1 Zn possessing a guest moiety assembled to form supramolecular polymers through host-guest interactions. Bispyridine cross linkers created interchain connections among the supramolecular polymers to form networked polymers in solution. Solution viscometry confirmed that the cross linked supramolecular polymers were highly entangled. Frequency-dependent linear viscoelastic spectroscopy revealed that the supramolecular polymers generated well-entangled solutions with associating and networking polymers, whereas the solid-like aggregates moved individually without breaking and reforming structures below the transition temperature of 9.6 degrees C. Morphological transition of the supramolecular polymers was evidenced by AFM images; the non cross-linked polymer resulted in wide-spread thin networks, while the cross linked networks produced thicker worm-like nanostructures. The supramolecular networks gelled in 1,1,2,2-tetrachloroethane, and an elastic free-standing film was fabricated with a Young's modulus of 1 GPa. PMID- 26486785 TI - Proteolytic fragmentation of inositol 1,4,5-trisphosphate receptors: a novel mechanism regulating channel activity? AB - Inositol 1,4,5-trisphosphate receptors (IP3 Rs) are a family of ubiquitously expressed intracellular Ca(2+) release channels. Regulation of channel activity by Ca(2+) , nucleotides, phosphorylation, protein binding partners and other cellular factors is thought to play a major role in defining the specific spatiotemporal characteristics of intracellular Ca(2+) signals. These properties are, in turn, believed pivotal for the selective and specific physiological activation of Ca(2+) -dependent effectors. IP3 Rs are also substrates for the intracellular cysteine proteases, calpain and caspase. Cleavage of the IP3 R has been proposed to play a role in apoptotic cell death by uncoupling regions important for IP3 binding from the channel domain, leaving an unregulated leaky Ca(2+) pore. Contrary to this hypothesis, we demonstrate following proteolysis that N- and C-termini of IP3 R1 remain associated, presumably through non covalent interactions. Further, we show that complementary fragments of IP3 R1 assemble into tetrameric structures and retain their ability to be regulated robustly by IP3 . While peptide continuity is clearly not necessary for IP3 gating of the channel, we propose that cleavage of the IP3 R peptide chain may alter other important regulatory events to modulate channel activity. In this scenario, stimulation of the cleaved IP3 R may support distinct spatiotemporal Ca(2+) signals and activation of specific effectors. Notably, in many adaptive physiological events, the non-apoptotic activities of caspase and calpain are demonstrated to be important, but the substrates of the proteases are poorly defined. We speculate that proteolytic fragmentation may represent a novel form of IP3 R regulation, which plays a role in varied adaptive physiological processes. PMID- 26486786 TI - Clinical and molecular response to interferon-alpha therapy in essential thrombocythemia patients with CALR mutations. AB - Myeloproliferative neoplasms are clonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters, clinical evolution, and prognosis. Few therapeutic options are available, among which interferon alpha (IFNalpha) presents interesting properties like the ability to induce hematologic responses (HRs) and molecular responses (MRs) in patients with JAK2 mutation. We report on the response to IFNalpha therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). HR was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and 2 patients even achieved complete MR. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next-generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2, and TP53 genes). The presence of additional mutations was associated with poorer MR on CALR mutant clones, with only minor or no MRs in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNalpha in a given patient, but no new mutation emerged during treatment. In all, this study shows that IFNalpha induces high rates of HRs and MRs in CALR-mutated ET, and that the presence of additional nondriver mutations may influence the MR to therapy. PMID- 26486788 TI - Telomere shortening in enterocytes of patients with uncontrolled acute intestinal graft-versus-host disease. AB - Acute intestinal graft-versus-host disease (aGVHD) refractory to immunosuppressive treatment is a serious complication after allogenic hematopoietic stem cell transplantation (HSCT). The underlying mechanisms of refractory aGVHD of the gut are not fully understood. Although telomere length (TL) reflects the replicative history of a cell, critically short telomeres have been associated with replicative exhaustion and tissue failure. In this study, we demonstrate that enterocytes of patients with refractory intestinal aGVHD show significantly increased proliferation, which translates into significant and critical telomere attrition following HSCT as compared with unaffected patients undergoing HSCT. Calculated telomere loss in aGVHD patients is 190 bp/wk, thereby massively exceeding physiological steady-state TL shortening rates such as in lymphocytes (~50 bp/y). Our data support the hypothesis that increased compensatory proliferation following continued tissue damage can result in massive telomere loss in enterocytes of aGVHD patients. The present study introduces aGVHD-triggered increased cellular turnover and telomere loss with subsequent replicative exhaustion as a mechanism for refractory gut GVHD that is compatible with the long-term clinical aspect of the disease and provides a basis for stem cell protective therapies in the treatment of aGVHD. PMID- 26486787 TI - Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis. AB - The Ki-1 antigen (CD30) is an established therapeutic target in patients with Hodgkin lymphoma and anaplastic large-cell lymphoma. We have recently shown that CD30 is expressed abundantly in the cytoplasm of neoplastic mast cells (MCs) in patients with advanced systemic mastocytosis (SM). In the current study, we asked whether CD30 is expressed on the surface of neoplastic MCs in advanced SM, and whether this surface structure may serve as therapeutic target in SM. As assessed by flow cytometry, CD30 was found to be expressed on the surface of neoplastic MCs in 3 of 25 patients (12%) with indolent SM, 4 of 7 patients (57%) with aggressive SM, and 4 of 7 patients (57%) with MC leukemia. The immature RAS transformed human MC line MCPV-1.1 also expressed cell surface CD30, whereas the KIT-transformed MC line HMC-1.2 expressed no detectable CD30. The CD30-targeting antibody-conjugate brentuximab-vedotin inhibited proliferation in neoplastic MCs, with lower IC50 values obtained in CD30(+) MCPV-1.1 cells (10 ug/mL) compared with CD30(-) HMC-1.2 cells (>50 ug/mL). In addition, brentuximab-vedotin suppressed the engraftment of MCPV-1.1 cells in NSG mice. Moreover, brentuximab vedotin produced apoptosis in all CD30(+) MC lines tested as well as in primary neoplastic MCs in patients with CD30(+) SM, but did not induce apoptosis in neoplastic MCs in patients with CD30(-) SM. Furthermore, brentuximab-vedotin was found to downregulate anti-IgE-induced histamine release in CD30(+) MCs. Finally, brentuximab-vedotin and the KIT D816V-targeting drug PKC412 produced synergistic growth-inhibitory effects in MCPV-1.1 cells. Together, CD30 is a promising new drug target for patients with CD30(+) advanced SM. PMID- 26486789 TI - Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. AB - Despite promising results with targeted drugs, chemoimmunotherapy with fludarabine, cyclophosphamide (FC), and rituximab (R) remains the standard therapy for fit patients with untreated chronic lymphocytic leukemia (CLL). Herein, we present the long-term follow-up of the randomized CLL8 trial reporting safety and efficacy of FC and FCR treatment of 817 treatment-naive patients with CLL. The primary end point was progression-free survival (PFS). With a median follow-up of 5.9 years, median PFS were 56.8 and 32.9 months for the FCR and FC group (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.50-0.69, P < .001). Median overall survival (OS) was not reached for the FCR group and was 86.0 months for the FC group (HR, 0.68; 95% CI, 0.54-0.89, P = .001). In patients with mutated IGHV (IGHV MUT), FCR improved PFS and OS compared with FC (PFS: HR, 0.47; 95% CI, 0.33-0.68, P < .001; OS: HR, 0.62; 95% CI, 0.34-1.11, P = .1). This improvement remained applicable for all cytogenetic subgroups other than del(17p). Long-term safety analyses showed that FCR had a higher rate of prolonged neutropenia during the first year after treatment (16.6% vs 8.8%; P = .007). Secondary malignancies including Richter's transformation occurred in 13.1% in the FCR group and in 17.4% in the FC group (P = .1). First-line chemoimmunotherapy with FCR induces long-term remissions and highly relevant improvement in OS in specific genetic subgroups of fit patients with CLL, in particular those with IGHV MUT. This trial was registered at www.clinicaltrials.gov as #NCT00281918. PMID- 26486790 TI - The Effect of Digestion and Drug Load on Halofantrine Absorption from Self nanoemulsifying Drug Delivery System (SNEDDS). AB - A super-saturated self-nanoemulsifying drug delivery system (super-SNEDDS), containing the poorly water-soluble drug halofantrine (Hf) at 150% of equilibrium solubility (S eq), was compared in vitro and in vivo with a conventional SNEDDS (75% of S eq) with respect to bioavailability and digestibility. Further, the effect of digestion on oral absorption of Hf from SNEDDS and super-SNEDDS was assessed by incorporation of the lipase inhibitor tetrahydrolipstatin (orlistat) into the SNEDDS. The SNEDDS contained soybean oil/Maisine 34-I (1:1), Kolliphor RH40, and ethanol at a ratio of 55:35:10, w/w percent. For the dynamic in vitro lipolysis, the precipitation of Hf at 60 min was significantly larger for the super-SNEDDS (66.8 +/- 16.4%) than for the SNEDDS (18.5 +/- 9.2%). The inhibition of the in vitro digestion by orlistat (1% (w/w)) lowered drug precipitation significantly for both the super-SNEDDS (36.8 +/- 1.7%) and the SNEDDS (3.9 +/- 0.7%). In the in vivo studies, the super-SNEDDS concept proved valid in a rat model with a significantly larger C max for the super-SNEDDS (964 +/- 167 ng/mL) than for the SNEDDS (506 +/- 112 ng/mL). The bioavailability of Hf dosed in super SNEDDS (32.9 +/- 3.6%) and SNEDDS (22.5 +/- 6.3%) did not change significantly with co-administration of orlistat (45.5 +/- 7.3% and 21.9 +/- 6.5%, respectively). However, the pharmacokinetic parameters changed; the t max of the super-SNEDDS (1.3 +/- 0.1 h) and SNEDDS (2.8 +/- 1.2 h) were significantly lower when dosed with orlistat (6.0 +/- 1.3 and 6.3 +/- 1.2 h, respectively). These findings suggest that the role of lipid digestion for the absorption of drugs from SNEDDS may be less important than previously thought. PMID- 26486791 TI - Prevention of Stroke in Rheumatoid Arthritis. AB - The risk of cerebrovascular disease is increased among rheumatoid arthritis (RA) patients and remains an underserved area of medical need. Only a minor proportion of RA patients achieve suitable stroke prevention. Classical cardiovascular risk factors appear to be under-diagnosed and undertreated among patients with RA. Reducing the inflammatory burden is also necessary to lower the cardiovascular risk. An adequate control of disease activity and cerebrovascular risk assessment using national guidelines should be recommended for all patients with RA. For patients with a documented history of cerebrovascular or cardiovascular risk factors, smoking cessation and corticosteroids and non-steroidal anti inflammatory drugs at the lowest dose possible are crucial. Risk score models should be adapted for patients with RA by introducing a 1.5 multiplication factor, and their results interpreted to appropriately direct clinical care. Statins, angiotensin-converting enzyme inhibitors, and angiotensin-II receptor blockers are preferred treatment options. Biologic and non-biologic disease modifying anti-rheumatic drugs should be initiated early to mitigate the necessity of symptom control drugs and to achieve early alleviation of the inflammatory state. Early control can improve vascular compliance, decrease atherosclerosis, improve overall lipid and metabolic profiles, and reduce the incidence of heart disease that may lead to atrial fibrillation. In patients with significant cervical spine involvement, early intervention and improved disease control are necessary and may prevent further mechanical vascular injury. PMID- 26486792 TI - Clinical Relevance of Orthostatic Hypotension in Neurodegenerative Disease. AB - The autonomic nervous system appears to be uniquely susceptible to degeneration in disorders of alpha-synuclein pathology. Clinically, autonomic dysfunction in these disorders manifests as neurogenic orthostatic hypotension (nOH), a condition that results in substantial morbidity and mortality. nOH results from pathology affecting either the central autonomic pathways or peripheral autonomic nerve fibers. Determining the localization and pathophysiology of nOH is critical in effectively managing this disorder and selecting appropriate treatment options. In this review, we discuss the pathophysiology of nOH with respect to the various alpha-synuclein-related neurodegenerative conditions. We highlight the associated clinical features, including gait instability, rapid eye movement behavior disorder, and hyposmia. We also review the current pharmacologic treatment options for nOH. Overall, the goals of therapy are to improve symptoms and prevent syncope and falls. Non-pharmacologic interventions should be introduced first, followed by carefully selected pharmacologic therapies. Treatment decisions should be directed by an understanding of the underlying pathophysiology, as well as the comorbidities and potential contributing factors present in each individual patient. PMID- 26486793 TI - Magnetic Targeting and Delivery of Drug-Loaded SWCNTs Theranostic Nanoprobes to Lung Metastasis in Breast Cancer Animal Model: Noninvasive Monitoring Using Magnetic Resonance Imaging. AB - PURPOSE: In this study, we aimed to develop novel therapeutic and diagnostic approaches by improving the targeting of doxorubicin-loaded single-walled carbon nanotubes (SWCNTs) to metastatic regions, and monitor their preferential homing and enhanced therapeutic effect using noninvasive free-breathing magnetic resonance imaging (MRI) and bioluminescence imaging. PROCEDURES: High-energy flexible magnets were specifically positioned over the metastatic tumor sites in the lungs. SWCNTs biodistribution, tumor progression, and subsequent treatment efficiency were assessed following administration of the magnetically attracted doxorubicin-loaded anti-CD105 conjugated nanocarriers. RESULTS: The use of high energy magnets offered improved theranostic effect of doxorubicin-loaded nanocarriers, by magnetically targeting them towards metastatic tumor sites in the lungs. MRI allowed sensitive monitoring of nanocarriers biodistribution in the abdominal organs, their preferential homing towards the metastatic sites, and their enhanced therapeutic effect. CONCLUSIONS: Combination of noninvasive MRI to localize sensitively the tumor sites, with specific positioning of magnets that can enhance the magnetic targeting of nanocarriers, allowed increasing the treatment efficiency. PMID- 26486794 TI - Perceiving and expressing feelings through actions in relation to individual differences in empathic traits: the Action and Feelings Questionnaire (AFQ). AB - Empathy is usually conceived of as independent of the non-verbal behaviors which mediate its experience, though embodied cognition theory predicts that individual differences in action representation will affect empathic traits. The "Actions and Feelings Questionnaire" (AFQ) was designed to capture individual differences in self-awareness of own and others' actions, particularly those associated with feelings, which we predicted would correlate with levels of empathic traits. A pilot 30-item questionnaire included items on perceptual sensitivity to action, imitation, action imagery, and gestural and facial expression. It was completed by a sample of 278 adults (mean age 21.2 years; 189 females, 89 males) along with the 15-item Empathic Quotient (EQ) Questionnaire. Total scores on the final 18 item questionnaire showed strong internal coherence (Cronbach's alpha of 0.81) and test-retest reliability (ICC=0.88), marked effect of sex and highly significant correlation with EQ. The questionnaire was administered to participants in an fMRI study investigating the neural correlates of facial imitation. Total AFQ score correlated with activity in somatosensory cortex, insula, anterior cingulate, and visual cortex. The AFQ shows promise as a brief and simple self-report measure sensitive to variability in the self-awareness of actions associated with feelings. It suggests that much of the variability of empathic traits in typical populations is accounted for by variance in this capacity. We suggest that being more empathic really is about being "touchy feely," and this questionnaire provides a novel measure of action-based empathy. PMID- 26486795 TI - Impact of a Pediatric Dermatology Service on Emergency Department Utilization for Children with Dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is the most common chronic pediatric skin disease, and it can profoundly affect a family's quality of life. Children with flaring AD often seek treatment in emergency departments (EDs), which leads to expensive care and ineffective long-term disease control. OBJECTIVES: The objective of the current study was to determine the effect of a pediatric dermatology service (PDS) on ED use and charges and of disease outcomes for patients diagnosed with AD before and after establishing an intramural PDS. METHODS: This retrospective study reviewed electronic medical records of patients presenting to an urban children's hospital ED with diagnoses encompassing the terms AD, eczema, dermatitis and International Classification of Diseases, Ninth Revision (ICD-9) codes 691.8 and 692.9 during the year before (pre-PDS period) and 3 years after establishing a PDS. RESULTS: There were 205 ED visits for dermatitis in the pre-PDS period and 130 in the with-PDS period, a 36.6% decrease (p < 0.001). In the pre-PDS period, 53.7% (n = 110/205) of patients presenting to the ED had moderate dermatitis, compared with 26.2% (n = 34/130) in the with-PDS period, a 69.1% decrease (p < 0.001). Total ED charges were $142,885 for the pre PDS period and $90,610 for the with-PDS period, a $52,275 decrease. CONCLUSIONS: This study provides a salient example of achieving the triple aim of health care reform: improving health outcomes (decreased ED visits) improving the patient experience (transitioning care from the ED to the more appropriate ambulatory clinical setting), and decreasing the cost of care (decreased ED charges). PMID- 26486796 TI - Application of omics data in regulatory toxicology: report of an international BfR expert workshop. AB - Advances in omics techniques and molecular toxicology are necessary to provide new perspectives for regulatory toxicology. By the application of modern molecular techniques, more mechanistic information should be gained to support standard toxicity studies and to contribute to a reduction and refinement of animal experiments required for certain regulatory purposes. The relevance and applicability of data obtained by omics methods to regulatory purposes such as grouping of chemicals, mode of action analysis or classification and labelling needs further improvement, defined validation and cautious expert judgment. Based on the results of an international expert workshop organized 2014 by the Federal Institute for Risk Assessment in Berlin, this paper is aimed to provide a critical overview of the regulatory relevance and reliability of omics methods, basic requirements on data quality and validation, as well as regulatory criteria to decide which effects observed by omics methods should be considered adverse or non-adverse. As a way forward, it was concluded that the inclusion of omics data can facilitate a more flexible approach for regulatory risk assessment and may help to reduce or refine animal testing. PMID- 26486797 TI - Progression and inflammation of human myeloid leukemia induced by ambient PM2.5 exposure. AB - PM2.5 (aerodynamic diameter <=2.5 MUm) has been a dominating and ubiquitous air pollutant and has become a global concern. Emerging evidences suggest a positive correlation between PM2.5 and leukemia, but the underlying molecular mechanisms remain unclear and need to be elucidated. Here, we assessed the impacts of PM2.5 on the progression and inflammation of human myeloid leukemia at lower environmental doses and explored the possible pathway. We showed that PM2.5 exposure significantly induced the leukemia cell growth and enhanced the release of inflammatory mediators in both in vitro and in vivo models. Additionally, NF kappaB p65 and p-STAT3 were activated in PM2.5-treated leukemia cells, with a concomitant increase in both ROS formation and NADPH oxidase expressions. Strikingly, the supplement of inhibitors, including NAC (ROS), PDTC (NF-kappaB), or WP1066 (STAT3), contributed to a decline in leukemia cell growth. Furthermore, enhanced expressions of inflammatory cytokines were attenuated by the addition of NAC or PDTC, but not affected by WP1066. This study demonstrates that PM2.5 promotes leukemia progression, identifies a potential intervention target, and provides further understanding of the detrimental effect of PM2.5 exposure on human health. PMID- 26486800 TI - Management of Pediatric Migraine Headache in the Emergency Room and Infusion Center. AB - Migraine is a common disorder that starts at an early age and takes a variable pattern from intermittent to chronic headache with several exacerbations throughout a lifetime. Children and adolescents are significantly affected. If an acute headache is not aborted by outpatient migraine therapy, it often causes severe disability, preventing the child from attending school and social events. Treating the acute severe headache aggressively helps prevent prolonged disability as well as possible chronification. Multiple medications are available, mostly for the outpatient management of an attack and include the use of over-the-counter anti-inflammatory medications as well as prescribed medications in the triptan group. These therapies do sometime fail and the exacerbation can last from days to weeks. If the headache lasts 72 hours or longer it will fall in the category of status migrainosus. Status migrainosus is described as a severe disabling headache lasting 72 hours or more by the ICHD3 criteria. Disability is a major issue in children and adolescents and aggressive acute measures are to be taken to control it as soon as possible. Early aggressive intravenous therapy can be very effective in breaking the attack and allowing the child to be quickly back to normal functioning. This article reviews what is available for the treatment of pediatric primary headaches in the emergency room. PMID- 26486801 TI - Alternative Splicing in the Human PMP22 Gene: Implications in CMT1A Neuropathy. AB - CMT1A patients commonly share PMP22 genetic overloading but they show phenotypic heterogeneity and variability in PMP22 mRNA and protein expression. Moreover, PMP22 mRNA levels do not correlate with clinical outcome measures in these patients, suggesting their uselessness as a disease biomarker. Thus, in-depth analysis of PMP22 transcription and translation might help to define its pathogenic role in CMT1A. We focused on the alternative splicing of PMP22 gene to verify whether mRNA processing is altered in CMT1A. We identified three new PMP22 transcripts enriched in human sural nerve biopsies. One of them was an untranslated variant, whereas the other two originated from a PMP22 undescribed exon and encoded for a new putative protein localized in the endoplasmic reticulum. As splicing events in the PMP22 gene are differently regulated in tissues and during development, we analyzed the levels of PMP22 transcripts and their splicing pattern in human and experimental CMT1A. We found an altered PMP22 splicing ratio in the CMT1A rat. In addition, we showed a remarkable derangement in rat QKI expression, which is a critical regulator of splicing during myelination. Overall, our data suggest that an alteration of mRNA processing could be a pathogenic mechanism in CMT1A. PMID- 26486802 TI - Evolutionary dynamics of collective index insurance. AB - Index-based insurances offer promising opportunities for climate-risk investments in developing countries. Indeed, contracts conditional on, e.g., weather or livestock indexes can be cheaper to set up than conventional indemnity-based insurances, while offering a safety net to vulnerable households, allowing them to eventually escape poverty traps. Moreover, transaction costs by insurance companies may be additionally reduced if contracts, instead of arranged with single households, are endorsed by collectives of households that bear the responsibility of managing the division of the insurance coverage by its members whenever the index is surpassed, allowing for additional flexibility in what concerns risk-sharing and also allowing insurance companies to avoid the costs associated with moral hazard. Here we resort to a population dynamics framework to investigate under which conditions household collectives may find collective index insurances attractive, when compared with individual index insurances. We assume risk sharing among the participants of each collective, and model collective action in terms of an N-person threshold game. Compared to less affordable individual index insurances, we show how collective index insurances lead to a coordination problem in which the adoption of index insurances may become the optimal decision, spreading index insurance coverage to the entire population. We further investigate the role of risk-averse and risk-prone behaviors, as well as the role of partial correlation between insurance coverage and actual loss of crops, and in which way these affect the original coordination thresholds. PMID- 26486803 TI - Influences of carbon concentration on crystal structures and ideal strengths of B2CxO compounds in the B-C-O system. AB - The search for novel superhard materials with special structures and improved thermal stability and hardness remains considerably experimental and theoretical challenges. Recent reports proposed that higher carbon content in ternary B2CxO compounds, which are isoelectronic with diamond, would lead to increased strength and hardness. This notion was derived from the calculated elastic parameters and empirical hardness formulas based on structural and electronic properties of the equilibrium structures. In present work, we introduce three potential ultra incompressible and thermodynamically stable B2CxO (x >= 2) phases via a systematic particle swarm optimization algorithm structure searches. By evaluating the trends of the crystal configuration, electronic structure, and mechanical properties as a function of the C concentration, it is found that the high carbon concentration benefits the formation of the sp(3) C-C covalent bonds and leads to the enhanced elastic moduli and ideal strengths in these B2CxO compounds. Studies of strain-stress behavior at large deformation, however, indicate that all these B2CxO compounds possess substantially lower ideal shear strengths than those of diamond and c-BN, suggesting that they may not be intrinsically superhard. PMID- 26486804 TI - Continent-scale global change attribution in European birds - combining annual and decadal time scales. AB - Species attributes are commonly used to infer impacts of environmental change on multiyear species trends, e.g. decadal changes in population size. However, by themselves attributes are of limited value in global change attribution since they do not measure the changing environment. A broader foundation for attributing species responses to global change may be achieved by complementing an attributes-based approach by one estimating the relationship between repeated measures of organismal and environmental changes over short time scales. To assess the benefit of this multiscale perspective, we investigate the recent impact of multiple environmental changes on European farmland birds, here focusing on climate change and land use change. We analyze more than 800 time series from 18 countries spanning the past two decades. Analysis of long-term population growth rates documents simultaneous responses that can be attributed to both climate change and land-use change, including long-term increases in populations of hot-dwelling species and declines in long-distance migrants and farmland specialists. In contrast, analysis of annual growth rates yield novel insights into the potential mechanisms driving long-term climate induced change. In particular, we find that birds are affected by winter, spring, and summer conditions depending on the distinct breeding phenology that corresponds to their migratory strategy. Birds in general benefit from higher temperatures or higher primary productivity early on or in the peak of the breeding season with the largest effect sizes observed in cooler parts of species' climatic ranges. Our results document the potential of combining time scales and integrating both species attributes and environmental variables for global change attribution. We suggest such an approach will be of general use when high-resolution time series are available in large-scale biodiversity surveys. PMID- 26486805 TI - Photogalvanic effect in monolayer black phosphorus. AB - We report a first-principles theoretical approach for analyzing linear and circular photogalvanic effects (PGEs) based on density functional theory within the nonequilibrium Green's function formalism. Using this approach we investigate the PGE phenomena in monolayer black phosphorus (MBP) doped with sulfur atoms. The impurity doping breaks the space inversion symmetry of pristine MBP, leading to a C s symmetry with a mirror reflection plane normal to the zigzag direction of the MBP lattice. Governed by this symmetry, a linear PGE is induced in both zigzag and armchair directions, and a circular PGE is induced along the zigzag direction. A robust broadband photoresponse is found from the near-infrared to the visible range for the MBP device. There is a strong anisotropy in PGE: photoresponse in the zigzag direction can be larger by an order of magnitude than that in the armchair direction. We identify the origin of the observed PGE as the inter-band transitions from the impurity and valence bands to the conduction bands, which involves a transfer of angular momentum from photons to electrons. PMID- 26486799 TI - Hospital and intensive care unit management of decompensated pulmonary hypertension and right ventricular failure. AB - Pulmonary hypertension and concomitant right ventricular failure present a diagnostic and therapeutic challenge in the intensive care unit and have been associated with a high mortality. Significant co-morbidities and hemodynamic instability are often present, and routine critical care unit resuscitation may worsen hemodynamics and limit the chances of survival in patients with an already underlying poor prognosis. Right ventricular failure results from structural or functional processes that limit the right ventricle's ability to maintain adequate cardiac output. It is commonly seen as the result of left heart failure, acute pulmonary embolism, progression or decompensation of pulmonary hypertension, sepsis, acute lung injury, or in the perioperative setting. Prompt recognition of the underlying cause and institution of treatment with a thorough understanding of the elements necessary to optimize preload, cardiac contractility, enhance systemic arterial perfusion, and reduce right ventricular afterload are of paramount importance. Moreover, the emergence of previously uncommon entities in patients with pulmonary hypertension (pregnancy, sepsis, liver disease, etc.) and the availability of modern devices to provide support pose additional challenges that must be addressed with an in-depth knowledge of this disease. PMID- 26486806 TI - Post-hemodialysis dosing of 1 vs. 2 g of ceftazidime in anuric end-stage renal disease patients on low-flux dialysis and its pharmacodynamic implications on clinical use. AB - Ceftazidime is a cost-effective antimicrobial against Gram-negative pathogens associated with sepsis in end-stage renal disease (ESRD) hemodialysis patients with potential for wider use with the advent of ceftazidime-avibactam. Dosing ceftazidime post-hemodialysis appears attractive and convenient, but limited in vivo data on pharmacodynamic efficacy (PE) attainment, defined as >70% of the interdialytic period drug concentrations exceed susceptible pathogens minimal inhibitory concentrations (MICs) (%TMIC), warrants further assessment. We therefore evaluated PE and tolerability of 1 against 2 g regime in anuric ESRD patients on low-flux hemodialysis. Two doses of 1 or 2 g ceftazidime were administered post-hemodialysis prior to 48- and 72-hour interdialytic intervals in ESRD inpatients without active infections. Peak and trough concentrations (mg/L) were assayed using a validated liquid chromatography-tandem mass spectrometry method. Proportion of patients achieving PE for known pathogens with MICs <= 8 mg/L and adverse effects were assessed. Six (43%) and eight (57%) adult patients received 1 and 2 g dose, respectively. Median (25th-75th percentile), peak, 48- and 72-hour trough ceftazidime concentrations were 78 (60-98) vs. 158 (128-196), 37 (23-37) vs. 49 (39-71), and 13 (12-20) vs. 26 (21-41) mg/L, respectively, resulting in 100% TMIC for both doses. One patient on the 1-g dose experienced mild pruritus. Reliable and safe PE attainment over both 48- and 72 hour interdialytic interval was achievable with 1 g of ceftazidime dosed post hemodialysis. The 2 g dose was equally effective and well tolerated but may not be necessary. These findings need validation in non-anuric patients, high-flux hemodialysis, and during avibactam co-administration. PMID- 26486809 TI - Prospective measures of cerebral atrophy and perfusion among cognitively intact stroke patients. AB - Cerebral atrophy, tissue densities, and local perfusions were measured prospectively utilizing computed tomography among 19 cognitively intact stroke patients and 24 age-matched cognitively and neurologically normal controls. Mean follow-up intervals were 27.0 months for stroke patients and 31.0 months for controls. Stroke patients were treated by controlling risk factors and antiplatelet drugs. Cognitive testing remained normal among patients and controls. Among stroke patients, annual rates for cerebral atrophic indices were +3.4%, for ventricular enlargement +6.9%, for subarachnoid space enlargement +0.1%, and for cortical atrophy -2.5%. Annual reductions in cerebral perfusion, per 100 g brain/min, for cortex were total, -2.3 ml; frontal -3.8 ml; temporal, 2.4 ml; occipital, 2.0 ml; basal ganglia, -2.3 ml; and thalamus -3.8 ml. Annual decreases in local Hounsfield unit (LHU) densities for cortex were total, -0.6 HU; frontal, -0.8 HU; and temporal, -0.4 HU. Among controls, annual rates for cortical atrophy were -1.0% and for declines in cerebral perfusion were -0.7 ml for total cortex, and -1.4 ml for temporal cortex. Annual decreases in HU densities were total cortex, -0.6 HU; frontal, -0.9 HU; and temporal -0.4 HU. Among cognitively intact stroke patients, annual rates for cerebral atrophy and reductions in cerebral cortical perfusion were accelerated by more than three times those seen among agematched controls but were significantly less than similar measures among stroke patients with dementia. PMID- 26486807 TI - Evaluation of an Electrochemical Point-of-Care Meter for Measuring Glucose Concentration in Blood from Periparturient Dairy Cattle. AB - BACKGROUND: The Precision Xtra((r)) meter is a promising low cost electrochemical point-of-care unit for measuring blood glucose concentration ([gluc]) in cattle blood. The meter uses an algorithm that assumes the intra-erythrocyte [gluc] equals the plasma [gluc] on a molal basis, and that the hematocrit is similar in humans and cattle. OBJECTIVES: The primary objective was to determine the accuracy of the meter for measuring plasma [gluc] in dairy cattle. Secondary objectives were to characterize the influence of hematocrit and sample temperature on the measured value for [gluc]. ANIMALS: A total of 106 periparturient Holstein-Friesian cattle. METHODS: Blood and plasma samples (1,109) were obtained and Deming regression and Bland-Altman plots were used to determine the accuracy of the meter against the reference method (plasma hexokinase assay). Multivariable regression and linear regression were used to determine the effect of hematocrit and sample temperature on the plasma [gluc] measured by the meter. RESULTS: Intra-erythrocyte [gluc] was 18% of plasma [gluc] on a molar basis. Sample temperature had a significant linear effect on plasma [gluc] as measured by the meter for 3/5 plasma samples when measured [gluc] > 160 mg/dL. CONCLUSIONS AND CLINICAL IMPORTANCE: The meter utilizes an algorithm that is optimized for human blood and is inaccurate when applied to bovine blood. Until a cattle-specific algorithm is developed, we recommend using plasma as the analyte instead of blood and calculating plasma [gluc] using the equation: [gluc] = 0.66 * [gluc]p-meter + 15, where [gluc]p-meter is the value reported by the meter. If blood is measured, then we recommend using the equation: [gluc] = 0.90 * [gluc]b-meter + 15. PMID- 26486810 TI - Transcranial Doppler "High Intensity Transient Signals" in the acute phase and long-term follow-up of mechanical heart valve implantation. AB - Patients have a significant risk for suffering from stroke caused by cardiac emboli following prosthetic valve implantation. It is known that cerebral emboli present with "high intensity transient signals" (HITS) in transcranial Doppler (TCD) spectral curves. The purpose of this research was to look for possible HITS in the acute phase and long-term follow-up of mechanical heart valve implantation with TCD to correlate the number of HITS with clinical symptoms and to find parameters associated with an increase or decrease in HITS in patients with prosthetic heart valves. We examined the frequency of HITS after mechanical valve replacement with TCD in the left middle cerebral artery (MCA) for a period of 15 min. A total of 179 patients were investigated. One-hundred patients were examined at intervals between 1 and 33 days (Group 1) and 79 patients between 10 and 13 months (Group 2) after valve replacement. These data were correlated with neurological deficits and hematological parameters. In Group 1, at least one HITS could be detected by TCD in 65 patients (65%). There were no differences between sexes or in valve location, heart rhythm, and thromboplastin time between patients with and without HITS. The prevalence of HITS in valve types other than St. Jude and Medtronic Hall was significantly higher (p = 0.004). Ninety-three of the patients in Group 1 were neurologically asymptomatic; seven patients suffered from a hemispheric deficit after valve implantation. The neurologically symptomatic patients presented with a significantly higher HITS rate (10.9 +/- 8.3; mean +/- SD) than the neurologically asymptomatic patients (4.4 +/- 12.3). One year after surgery (Group 2), the prevalence of HITS was 77%. The number of HITS in Group 2 was significantly higher than in Group 1 (p = 0.003). Following valve replacement, patients present with a high frequency of HITS. Symptomatic patients have a significantly higher rate of HITS than asymptomatic patients in the acute postoperative period. Thus, TCD examination may be used as an additional method to evaluate the individual risk for cerebral ischemia in the acute phase of heart valve implantation. PMID- 26486811 TI - Risk factors for thromboembolism during aspirin therapy in patients with atrial fibrillation: The stroke prevention in atrial fibrillation study. AB - Although atrial fibrillation (AF) is associated with ischemic stroke, some AF patients have an inherently low rate of thromboembolism. Additional AF patients might have a low thromboembolic rate when given aspirin. We undertook exploratory analyses to identify patient features related to thromboembolism during aspirin therapy, as the basis for the design of a clinical trial. A cohort of 854 patients given aspirin 325 mg/day and followed for a mean of 2.3 years in a clinical trial was analyzed. Clinical and echocardiographic features at study entry were correlated with subsequent arterial thromboembolism by multivariate analysis. AF patients given aspirin who had high thromboembolic rates were women over age 75 years (10.4%/year) and those of either gender with systolic blood pressure > 160 T (7.6%/year), prior thromboembolism (6.4%/year), and impaired left ventricular function (5.5%/year). AF patients with one or more of these features had a thromboembolic rate of 5.9%/year (95% CI 4.5-7.8) during aspirin therapy. Patients without these features comprised 52% of the cohort and had a thromboembolic rate of 1.9% per year (95% CI, 1.2-2.9). Most strokes in all subgroups were classified as cardioembolic; the highest rate of cardioembolic stroke occurred in elderly women (6.1%/year). These exploratory analyses suggest that many AF patients may have a relatively low thromboembolic rate when given aspirin, but the findings must be independently confirmed before being applied to clinical management. Pathogenic mediators of high-risk features and aspirin responsiveness are unclear. PMID- 26486812 TI - Evident risk factors for younger stroke patients in Taiwan. AB - Risk factors for stroke in the young are often different from those in older patients. Since a rather high incidence of stroke exists in Taiwan, we prospectively studied risk factors in 208 stroke patients aged between 15 and 45 years seen in four main hospitals in Taiwan from 1986 to 1993. Of the 116 patients with cerebral infarction, 48 (41.4%) had related premature atherosclerosis mainly caused by hypertension (18.1%), hyperlipidemia (4.3%), and diabetes mellitus (3.4%). Thirty-four patients (29.3%) had an identifiable predisposing factor of cardiac origin including valvular diseases. In 92 patients with cerebral hemorrhage, hypertension was present in 30 patients (32.6%) and a vascular malformation of brain in 21 patients (22.8%). For a specific district in Taiwan, the major risk factors for strokes in younger patients were hypertension, rheumatic heart disease, and vascular malformation of brain. Cardiac and neuroradiologic investigations are particularly indicative, and clinical effort in the management of these treatable causes needs emphasis. PMID- 26486813 TI - Loss of autoregulation in patients with intracerebral hemorrhage. AB - We evaluated cerebral vasomotor reactivity to acetazolamide in seven consecutive patients with intracerebral hemorrhage (ICH) with transcranial Doppler to evaluate autoregulation of cerebral blood flow in acute ICH. Two patients had prominent loss of vasoreactivity to acetazolamide stimulation. This suggests that autoregulation may be impaired in some patients with acute ICH. Further studies are required to determine the clinical implications of loss of autoregulation in acute phase of ICH. PMID- 26486814 TI - Cytokine and superoxide production in clinical stroke. AB - Cytokines appear to play an important role in a variety of central nervous system (CNS) diseases and may be involved in ischemia. Activated leukocytes are a major source of cytokines and other inflammatory mediators that may directly injure ischemic CNS tissue. To investigate the importance of these substances in clinical stroke, we compared spontaneous secretion of IL-lbeta, IL-6, IL-8, and superoxide production from neutrophils (PMN) and mononuclear cells (MNC) isolated from either acute stroke patients (n = 10) or matched controls (n = 10). Cytokine production from 5 * 10(6) cells incubated for 24 h was determined by ELISA. MNC from acute stroke patients secreted significantly less IL-1beta, IL-6, and IL-8 than MNC from control patients. No significant cytokine production was detected from PMN. Superoxide production from 1.25 * 10(5) cells was determined over 1 h measuring cytochrome C reduction. There was a trend toward higher superoxide production in PMN from acute stroke patients, whereas the superoxide production in MNC from acute stroke patients was significantly higher than that of control MNC. This difference persisted even when various agonists were added preincubation. This study suggests that MNC spontaneous cytokine secretion is reduced in acute stroke patients, whereas superoxide production is increased. This decreased cytokine production may be secondary to the effects of a cytokine inhibitory factor. PMID- 26486815 TI - Unilateral oval pupil with good outcome: Report of two cases. AB - Unilateral oval pupil has numerous causes, and several pathophysiologic mechanisms have been proposed. Prognosis is nearly universally poor. We present two patients, an 86-year-old woman and a 61-year-old woman, who developed coma and unilateral oval pupil due to ischemia and hypoglycemia, respectively. In the second case, a discrete area of ipsilateral brainstem ischemia was demonstrated by magnetic resonance imaging. Both patients recovered. The prognosis for comatose patients with unilateral oval pupil is not universally poor. PMID- 26486816 TI - Thrombotic thrombocytopenic purpura: A neurological perspective. AB - We report 17 cases of thrombotic thrombocytopenic purpura (TTP) admitted to Indiana University Medical Center (IUMC) between January 1985 and December 1994. There were 11 women and 6 men ranging in age from 17 to 70 years. Fifteen patients had impaired mental status during hospitalization, and seven had seizures. Patients were treated with different therapeutic modalities including corticosteroids, aspirin, plasma transfusions, splenectomy, and plasma exchange. Neither neurological status on admission nor seizures was predictive of outcome. Presence of underlying disorders did not alter outcome or treatment response. Three patients died during hospitalization, and three developed end-stage renal disease. The presence of confusion, seizures, thrombocytopenia, microangiopathic hemolytic anemia, and renal failure should alert the clinician to the possibility of TTP and the need for prompt administration of plasma exchange. PMID- 26486817 TI - Prognostic significance of ST-segment depression on continuous electrocardiography in patients with acute ischemic neurologic events. AB - Patients with a history of ischemic stroke or transient ischemic attack (TIA) are at significant risk of cardiac death. This study reports the prognostic significance of ST-segment depression and ventricular tachycardia on continuous electrocardiography in 48 consecutive patients hospitalized with an acute ischemic stroke or TIA. Thirty-one percent of patients had episodes of asymptomatic ST-segment depression and 6% had transient ventricular tachycardia on continuous electrocardiographic monitoring. At a mean follow-up of 13 months, 19% had experienced a cardiac outcome, and 19% met criteria for a neurologic outcome. Cardiac and neurologic outcomes, including death, were not significantly different in patients with and without ST-segment depression on continuous electrocardiography. Cardiac outcomes occurred in 13% of patients with ST-segment depression and in 21% of patient without ST-segment depression (p = 0.52). However, ventricular tachycardia was associated with a higher rate of cardiac death (33% vs. 2%, p < 0.01). Only 27% of patients subsequently found to have coronary artery disease had ST-segment depression by continuous electrocardiography. In contrast to patients with coronary artery disease, ST segment depression on continuous electrocardiography is not associated with poorer outcome among patients with acute ischemic stroke or TIA. PMID- 26486818 TI - Incidence and risk factors of venous thromboembolism after pelvic uro-oncologic surgery--a single center experience. AB - OBJECTIVE: To determine the incidence and assess risk factors for the development of VTE among patients undergoing major pelvic surgery for prostate and bladder cancer in an Australian tertiary referral center. PATIENTS AND METHODS: Consecutive patients undergoing major pelvic uro-oncologic surgery, namely radical cystectomy and radical prostatectomy over a five-year period (2009-2013) were identified. Patient variables and types of thromboprophylaxis (pharmacological and/or mechanical) used in this patient cohort were collected for analyses as predictive factors. RESULTS: The overall incidence of VTE was 1.8%. Patients undergoing radical cystectomy were more likely to suffer a VTE event compared to patients having radical prostatectomy. In this cohort, the risk factors for VTE include, prolonged operative time of greater than 4 hours (h), lymph node dissection (LND) and patients requiring blood transfusions. CONCLUSION: Patients undergoing major pelvic uro-oncologic surgery have an approximately 1.8% risk of developing VTE. Risk factors identified in this study should be used to guide the use of early and prolonged thromboprophylaxis. PMID- 26486819 TI - Tuning the Reactivity of Chromium(III)-Superoxo Species by Coordinating Axial Ligands. AB - Metal-superoxo species have attracted much attention recently as key intermediates in enzymatic and biomimetic oxidation reactions. The effect(s) of axial ligands on the chemical properties of metal-superoxo complexes has never been explored previously. In this study, we synthesized and characterized chromium(III)-superoxo complexes bearing TMC derivatives with pendant pyridine and imidazole donors, such as [Cr(III)(O2)(TMC-Py)](2+) (1, TMC-Py = 4,8,11 trimethyl-1-(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane) and [Cr(III)(O2)(TMC-Im)](2+) (2, TMC-Im = 4,8,11-trimethyl-1-(2 methylimidazolmethyl)-1,4,8,11-tetraazacyclotetradecane). The reactivity of chromium(III)-superoxo complexes binding different axial ligands, such as 1, 2, and [Cr(III)(O2)(TMC)(Cl)](+) (3, TMC = 1,4,8,11-tetramethyl-1,4,8,11 tetraazacyclotetradecane), was then investigated in C-H bond activation and oxygen atom transfer reactions. Kinetic studies revealed that the reactivity of the Cr(III)-superoxo complexes depends on the axial ligands, showing the reactivity order of 1 > 2 > 3 in those electrophilic oxidation reactions. It was also shown that there is a good correlation between the reactivity of the chromium(III)-superoxo complexes and their redox potentials, in which the redox potentials of the chromium(III)-superoxo complexes are in the order 1 > 2 > 3. DFT calculations reproduced the reactivity order between 1 and 3 in both C-H bond activation and oxygen atom transfer reactions, and the latter reaction is described using orbital interactions. The calculations are also in agreement with the experimentally obtained redox potentials. The present results provide the first example showing that the reactivity of metal-superoxo species can be tuned by the electron-donating ability of axial ligands bound trans to the metal superoxo moiety. PMID- 26486820 TI - Poor countries press for extension of exemption from drug patents. PMID- 26486821 TI - Eco-exergy and emergy based self-organization of three forest plantations in lower subtropical China. AB - The bio-thermodynamic structures of a mixed native species plantation, a conifer plantation and an Acacia mangium plantation in Southern China were quantified over a period of 15 years based on eco-exergy methods. The efficiencies of structural development and maintenance were quantified through an integrated application of eco-exergy and emergy methods. The results showed that the storage of eco-exergy increased over 3 times in all three plantations, as predicted by the maximum eco-exergy principle. This trend was primarily seen due to the accumulation of biomass, instead of an increase in the specific eco-exergy (eco exergy per unit biomass), although species richness did increase. The eco-exergy to emergy and eco-exergy to empower ratios of the three plantations generally increased during the study period, but the rate of increase slowed down after 20 years. The dominant trees are the largest contributors to the eco-exergy stored in the plantations, and thus, the introduction of suitable indigenous tree species should be considered after the existing trees pass through their period of most rapid growth or around 20 years after planting. The combined application of C-values and suggested weighting factors in the eco-exergy calculation can imply opposite results, but may also supply useful information for forest management. PMID- 26486822 TI - Surface functionalization allowing repetitive use of optical sensors for real time detection of antibody-bacteria interaction. AB - In this study, sensor surface functionalization allowing the repetitive use of a sensing device was evaluated for antibody-based detection of living bacteria using an optical planar Bragg grating sensor. To achieve regenerable immobilization of bacteria specific antibodies, the heterobifunctional cross linker N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) was linked to an aminosilanized sensor surface and subsequently reduced to expose sulfhydryl groups enabling the covalent conjugation of SPDP-activated antibodies via disulfide bonds. The immobilization of a capture antibody specific for Staphylococcus aureus on the sensor surface as well as specific binding of S. aureus could be monitored, highlighting the applicability of optical sensors for the specific detection of large biological structures. Reusability of bacteria saturated sensors was successfully demonstrated by cleaving the antibody along with bound bacteria through reduction of disulfide bonds and subsequent re functionalization with activated antibody, resulting in comparable sensitivity towards S. aureus. PMID- 26486823 TI - Development of cell-cycle checkpoint therapy for solid tumors. AB - Cellular proliferation is tightly controlled by several cell-cycle checkpoint proteins. In cancer, the genes encoding these proteins are often disrupted and cause unrestrained cancer growth. The proteins are over-expressed in many malignancies; thus, they are potential targets for anti-cancer therapies. These proteins include cyclin-dependent kinase, checkpoint kinase, WEE1 kinase, aurora kinase and polo-like kinase. Cyclin-dependent kinase inhibitors are the most advanced cell-cycle checkpoint therapeutics available. For instance, palbociclib (PD0332991) is a first-in-class, oral, highly selective inhibitor of CDK4/6 and, in combination with letrozole (Phase II; PALOMA-1) or with fulvestrant (Phase III; PALOMA-3), it has significantly prolonged progression-free survival, in patients with metastatic estrogen receptor-positive, HER2-negative breast cancer, in comparison with that observed in patients using letrozole, or fulvestrant alone, respectively. In this review, we provide an overview of the current compounds available for cell-cycle checkpoint protein-directed therapy for solid tumors. PMID- 26486825 TI - Intra-arterial chemoradiotherapy for head and neck cancer. AB - Intra-arterial chemotherapy has been used to treat localized malignant neoplasms in patients with head and neck cancer for over 50 years as the head and neck region is particularly well suited to regional chemotherapy. Early intra-arterial chemotherapy did not prove its efficacy. In addition, the additional complications associated with establishing and maintaining arterial access have further dampened enthusiasm for this approach. Subsequent significant advances in vascular radiology techniques and the development of new devices, such as fluoroscopy units and angiographic catheters, have made possible safe, accurate and repeated superselective intra-arterial chemotherapy. Intra-arterial infusion of high-dose cisplatin with systemic neutralization by intravenous sodium thiosulfate (RADPLAT) is a theoretically attractive approach to the treatment of advanced head and neck cancer. However, a Dutch trial comparing intra-arterial and intravenous chemoradiotherapy for advanced head and neck cancer showed that RADPLAT was not superior to intravenous chemoradiotherapy. Therefore, further investigation of RADPLAT, including the refinement of the indications for its application, is needed. PMID- 26486824 TI - Efficacy and safety of leuprorelin acetate 6-month depot in prostate cancer patients: a Phase III, randomized, open-label, parallel-group, comparative study in Japan. AB - OBJECTIVE: Leuprorelin acetate (TAP-144-SR) is commonly used worldwide in prostate cancer patients. This study was conducted to assess the non-inferiority of a 6-month depot formulation of TAP-144-SR (TAP-144-SR [6M]) 22.5 mg to a 3 month depot formulation of TAP-144-SR (TAP-144-SR [3M]) 11.25 mg in prostate cancer patients in Japan. METHODS: This was a 48-week Phase III, open-label, parallel-group comparative study. TAP-144-SR (6M) 22.5 mg (6M group) and TAP-144 SR (3M) 11.25 mg (3M group) were administered to 81 and 79 subjects, respectively. The primary endpoint was the rate of serum testosterone suppression to the castrate level (<=100 ng/dl). RESULTS: Serum testosterone of all subjects excluding one subject in the 3M group was suppressed to the castrate level throughout 48 weeks. The estimated between-group difference (6M group - 3M group) in suppression rate was 1.3% (95% confidence interval: -3.4, 6.8), and its lower confidence interval was more than -10% of the pre-determined allowable limit value to judge the non-inferiority. The prostate-specific antigen concentrations were stable throughout the study in both groups. Progressive disease in the best overall response based on the Response Evaluation Criteria In Solid Tumors was 0.0% for the 6M group and 2.6% for the 3M group. Adverse events occurred in 92.6% in the 6M group and 89.9% in the 3M group. Adverse events leading to discontinuation were reported in 2.5% in the 6M group and 3.8% in the 3M group. CONCLUSIONS: TAP-144-SR (6M) was not inferior to TAP-144-SR (3M) for the suppressive effect on serum testosterone level. TAP-144-SR (6M) was also as well tolerated as TAP-144-SR (3M). PMID- 26486827 TI - Editorial announcement. PMID- 26486826 TI - Biological markers of invasive breast cancer. AB - Biological markers for breast cancer are biomolecules that result from cancer related processes and are associated with particular clinical outcomes; they thus help predict responses to therapy. In recent years, gene expression profiling has made the molecular classification of breast cancer possible. Classification of breast cancer by immunohistochemical expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 and Ki-67 is standard practice for clinical decision-making. Assessments of hormone receptor expression and human epidermal growth factor receptor 2 overexpression help estimate benefits from targeted therapies and have greatly improved prognoses for women with these breast cancer types. Although Ki-67 positivity is associated with an adverse outcome, its clear identification is an aid to optimal disease management. Standardization of testing methodology to minimize inter-laboratory measurement variations is a remaining issue. Multi-gene assays provide prognostic information and identify those most likely to benefit from systemic chemotherapy. Incorporating molecular profiles with conventional pathological classification would be more precise, and could enhance the clinical development of personalized therapy in breast cancer. PMID- 26486828 TI - Leuko-Araiosis and cerebral hypoperfusion compared between patients with ischemic vascular dementia and normal elderly volunteers. AB - Lesions in white matter of unknown origin among the elderly have been of interest for many years, and their pathogenesis and clinical significance need clarification. Local cerebral blood flow was measured among patients with ichemic vascular dementia (IVD, n = 38) and compared with age-matched normal volunteers (n = 18) utilizing xenon-enhanced computed tomography (CT). Volume ratios for total leuko-araiosis, as well as volume ratios for apparently normal white and gray matter, were determined by plain, noncontrasted CT densitometry throughout slices of brain examined later during stable xenon inhalation enabling perfusion values for each compartment to be compared. Volume ratios for total leuko araiosis to total brain parenchyma were twice as large among patients with IVD (12.0 +/- 5.6%) compared with elderly normal volunteers (6.0 +/- 2.7%). However, cerebral perfusion values within regions of leuko-araiosis compared to"normal" white matter were decreased to the same degree among patients with IVD (14 +/- 6 ml/100 g brain/min) and among elderly normal volunteers with leuko-araiosis (13 +/- 5). Local cerebral blood flow values were reduced for all regions of brain examined among IVD patients compared with age-matched normals. Among patients with IVD, multiple regression analyses correlated increased volumes of leuko araiosis with (a) advancing age, (b) hypertension, and (c) reduced perfusion in vascular territories supplying the putamen. Hypoperfusion within deep cerebral territories correlates with pathogenesis of leuko-araiosis among patients with ischemic vascular dementia. PMID- 26486829 TI - Cryptococcal meningitis/acquired immune deficiency syndrome presenting as a transient neurologic deficit. AB - A previously healthy man presented with a transient neurologic deficit and neck pain. Lumbar puncture revealed cryptococcal meningitis. He was subsequently found to have acquired immune deficiency syndrome (AIDS). Transient neurologic deficit is an uncommon initial manifestation of cryptococcal meningitis. We suggest AIDS related infections be considered in the differential diagnosis of transient neurologic deficits. PMID- 26486830 TI - Anti-VDRL antibodies by ELISA in cerebrospinal fluid and its value in the differential diagnosis of abnormalities of the cerebrospinal fluid. AB - Enzyme-linked immunoabsorbent assay (ELISA) techniques for the detection of antibodies to the Venereal Disease Research Laboratories (VDRL) antigen as well as for the estimation of antibodies to cardiolipin (aCL) in cerebrospinal fluid (CSF) were performed in several groups of patients, including those with definite paretic neurosyphilis (DPNS, 10 patients), probable paretic neurosyphilis (PPNS, 19 patients), systemic lupus erythematosus (SLE, 71 patients), and miscellaneous neurologic disorders (30 patients), and normal subjects (11 patients). In the DPNS group, all demonstrated positive VDRL by ELISA, and 7 also had positive aCL tests, whereas only 7 of the 10 had positive CSF fluorescent treponemal antibody absorption (FTA-ABS) and Treponema pallidum hemagglutination assay (TPH A) tests. Three had positive VDRL tests by flocculation. In the PPNS group, no patients had positive FTA-ABS, TPH A, or VDRL flocculation tests in CSF. However, 18 of the 19 had positive CSF VDRL by ELISA; two of these also had positive aCL tests. Four SLE patients had positive CSF aCL tests (three with positive ELISA VDRL). Only one patient in the miscellaneous group had positive CSF aCL (Guillain-Barre syndrome), and one had positive IgM VDRL tests (bacterial meningitis). The value of VDRL ELISA in the diagnosis of neurosyphilis in the face of other negative conventional tests is established by our study and had important therapeutic consequences in patients with possible/probable neurosyphilis. The aCL test often may be positive in patients with DPNS but is less useful in the PPNS group. PMID- 26486831 TI - Effect of elastic compression stockings on venous hemodynamics in hemiplegic patients. AB - Unilateral lower extremity edema and an increased risk of thromboembolism have been associated with hemiplegia following stroke. This study was undertaken to determine the effect of knee-high, graded elastic stockings on venous hemodynamics in hemiplegic patients. Thirty-six patients with recent cerebral infarcts were studied. The presence of underlying venous or arterial occlusive disease was excluded in all patients. Duplex scanning techniques were used to measure femoral and popliteal venous circumference, cross-sectional area, and peak flow velocity in the normal and paralyzed extremities both with and without stockings. All patients were examined and assessed for the degree of motor weakness and Brunnstrom stage of recovery. Associated medical illnesses were also reviewed. These patients were found to have a decreased flow in the femoral (p = 0.0002) and popliteal (p = 0.006) veins and an increase in the femoral vein size. The application of compression stockings resulted in a significant increase in venous size and flow velocity in both areas. The femoral and popliteal velocity correlated inversely with the degree of motor impairment and Brunnstrom stage, suggesting that factors other than the muscle pump may be responsible for the augmentation of femoral flow velocity in the paralyzed leg. There was no correlation demonstrated with other variables such as age, gender, cardiovascular disease, or diabetes. These results would indicate a potential benefit of graded knee-high elastic compression stockings in reducing venous flow stasis in hemi paretic patients. PMID- 26486832 TI - Population-Based in-hospital stroke morbidity and mortality. AB - To investigate the risk and prognostic factors for in-hospital incident stroke and stroke mortality, surveillance was conducted on Rochester, MN, residents free of stroke when admitted to the hospital in the years 1950 through 1984. The in hospital first stroke attack rates remained stable for the calendar years 1970,1976, and 1980. Of the first strokes that occurred in the hospital, 42% were adventitious. In approximately 60% of patients with adventitious strokes, the strokes developed within 2 days after a hospital procedure. Patients with cardiovascular problems were the majority among the patients who had nonadventitious strokes. Four independently significant prognostic factors associated with stroke 30-day mortality included age (relative risk, 1.6 per 10 years), calendar year (relative risk, 0.7 per 10 years), atrial fibrillation or flutter (relative risk, 2.3), and intracranial hemorrhage compared with cerebral infarction (relative risk, 12.4). These findings emphasize the heterogeneity of the pathophysiologic mechanisms for in-hospital stroke. PMID- 26486833 TI - Identification of stenosis of the opercular segment of the middle cerebral artery trunk by transcranial color flow duplex doppler. AB - Transcranial color flow duplex Doppler sonography was able to identify a stenosis of the middle cerebral artery documented by angiography to be just proximal to the start of the sylvian triangle in a 50-year-old woman with progressive aphasia. The lesion was too distal to be detected by traditional transcranial Doppler sonography. Transverse and longitudinal color flow images of the opercular segment of the middle cerebral artery are shown with identification of the branches of the middle cerebral artery trifurcation. PMID- 26486834 TI - Magnetic resonance imaging cinecisternography in patients with white matter lesions. AB - 1. The dynamic changes in ventricular size were computed by MRI cinecisternography. 2. The data analyzed showed that the phasic changes in size of the third ventricle and/or fourth ventricle were reduced in patients with the small multiple infarcts, with dementia, and with enlarged lateral ventricles when compared to subjects without these findings. 3. The derangement in CSF flow dynamics may be involved in the pathogenesis of vascular dementia. PMID- 26486835 TI - Dementia associated with lacunar infarctions. PMID- 26486836 TI - Vascular dementia: Problems with definition, nomenclature, and classification. PMID- 26486837 TI - Comparison of quantitative magnetic resonance imaging and positron emission tomography between patients with dementia of the alzheimer type and multi-infarct dementia. PMID- 26486838 TI - Cerebral lesions on magnetic resonance imaging in vascular dementia. PMID- 26486839 TI - Is the Leuko-Araiosis-Dementia syndrome different from Binswanger's subcortical atherosclerotic encephalopathy? PMID- 26486840 TI - HELP application in multi-infarct dementia. AB - HELP is capable of lowering LDL, cholesterol, triglycerides, and fibrinogen. It has been proven that HELP application has an impact on MID by decreasing plasma fibrinogen, cholesterol, LDL, triglycerides, thus also reducing whole-blood plasma viscosity, plasma fibrinogen, and red cell transit time. It has been shown that a single HELP treatment in MID is followed by an improvement of the scores obtained from the rating scales employed (Mathew, Mini Mental State Examination, Activities of Daily Living) for as long as 10 days, which was supported by comparison with the scores of a control group. Repeated HELP application (up to five) within 40 days led to an improvement of the test battery values in comparison with base values and those of the respective control group. Further applications (up to 10) of plasmapheresis, however, remained without any remarkable effect on the rating scales employed, with the difference from the corresponding control groups remaining the same. PMID- 26486841 TI - Treatment of multi-infarct dementia with citicholine. AB - A double-blind placebo controlled trial was conducted in 146 patients with MID who were allocated randomly into two groups, one receiving 250 mg citi-choline three times day and the other receiving isotonic saline three times a day for 2 months. The group treated with citicholine showed a marked improvement on the MMSE compared with the placebo group. No significant side effects were noted. PMID- 26486842 TI - Can measurement of CSF alpha 1-Antichymotrypsin be a useful tool for differential diagnosis of vascular dementia and Alzheimer's disease? PMID- 26486843 TI - Disturbance in cerebrovascular CO2 reactivity in multi-infarct dementia. PMID- 26486844 TI - Recovery of cortical blood flow and dementia after superficial temporal-middle cerebral artery bypass in a patient with severe carotid occlusive lesions: A two year follow-up study. PMID- 26486845 TI - Long-term follow-up of patients with vascular dementia: Bertha memorial lecture, 1992. PMID- 26486846 TI - Erratum. AB - Mayor P, Bowler M, Lopez-Plana C. 2013. Functional morphology of the female genital organs in the Peruvian red uakari monkey (Cacajao calvus ucayalii). Am J Primatol 75: 545-554. In the article cited above, there was an error in calculating the ovarian volume. The corrected values are indicated in the revised Table I below. PMID- 26486847 TI - Fabrication of three dimensional patterns of wide dimensional range using microbes and their applications. AB - Inspired by the wound healing property of certain trees, we report a novel microbes based additive process for producing three dimensional patterns, which has a potential of engineering applications in a variety of fields. Imposing a two dimensional pattern of microbes on a gel media and allowing them to grow in the third dimension is known from its use in biological studies. Instead, we have introduced an intermediate porous substrate between the gel media and the microbial growth, which enables three dimensional patterns in specific forms that can be lifted off and used in engineering applications. In order to demonstrate the applicability of this idea in a diverse set of areas, two applications are selected. In one, using this method of microbial growth, we have fabricated microlenses for enhanced light extraction in organic light emitting diodes, where densely packed microlenses of the diameters of hundreds of microns lead to luminance increase by a factor of 1.24X. In another entirely different type of application, braille text patterns are prepared on a normal office paper where the grown microbial colonies serve as braille tactile dots. Braille dot patterns thus prepared meet the standard specifications (size and spacing) for braille books. PMID- 26486849 TI - Do repeated rumble strip hits improve driver alertness? AB - Driving while sleepy is associated with increased crash risk. Rumble strips are designed to alert a sleepy or inattentive driver when they deviate outside their driving lane. The current study sought to examine the effects of repeated rumble strip hits on levels of physiological and subjective sleepiness as well as simulated driving performance. In total, 36 regular shift workers drove a high fidelity moving base simulator on a simulated road with rumble strips installed at the shoulder and centre line after a working a full night shift. The results show that, on average, the first rumble strip occurred after 20 min of driving, with subsequent hits occurring 10 min later, with the last three occurring approximately every 5 min thereafter. Specifically, it was found that the first rumble strip hit reduced physiological sleepiness; however, subsequent hits did not increase alertness. Moreover, the results also demonstrate that increased subjective sleepiness levels, via the Karolinska Sleepiness Scale, were associated with a greater probability of hitting a rumble strip. The present results suggest that sleepiness is very resilient to even strongly arousing stimuli, with physiological and subjective sleepiness increasing over the duration of the drive, despite the interference caused by rumble strips. PMID- 26486848 TI - Computer-assisted quantification of motile and invasive capabilities of cancer cells. AB - High-throughput analysis of cancer cell dissemination and its control by extrinsic and intrinsic cellular factors is hampered by the lack of adequate and efficient analytical tools for quantifying cell motility. Oncology research would greatly benefit from such a methodology that allows to rapidly determine the motile behaviour of cancer cells under different environmental conditions, including inside three-dimensional matrices. We combined automated microscopy imaging of two- and three-dimensional cell cultures with computational image analysis into a single assay platform for studying cell dissemination in high throughput. We have validated this new approach for medulloblastoma, a metastatic paediatric brain tumour, in combination with the activation of growth factor signalling pathways with established pro-migratory functions. The platform enabled the detection of primary tumour and patient-derived xenograft cell sensitivity to growth factor-dependent motility and dissemination and identified tumour subgroup-specific responses to selected growth factors of excellent diagnostic value. PMID- 26486850 TI - Nocardiopsis ansamitocini sp. nov., a new producer of ansamitocin P-3 of the genus Nocardiopsis. AB - An alkalitolerant actinomycete strain, designated EGI 80425T, capable of producing ansamitocin P-3, was isolated from a saline-alkali soil sample of Xinjiang province, north-west China, and subjected to a polyphasic taxonomic characterization. Strain EGI 80425T formed non-fragmented substrate mycelia and white aerial hyphae with long spore chains. Whole-cell hydrolysates of the isolate contained meso-diaminopimelic acid as the diagnostic diamino acid and rhamnose as the major sugar. The major fatty acids were anteiso-C17 : 0, iso-C16 : 0 and C18 : 1omega9c. The predominant menaquinones were MK-10(H4), MK-10(H6), MK-10(H8) and MK-9(H4). The G+C content of the genomic DNA of strain EGI 80425T was 70.2 mol%. Strain EGI 80425T showed highest 16S rRNA gene sequence similarity to Nocardiopsis dassonvillei subsp. dassonvillei DSM 43111T (96.44 %). Phylogenetic analysis showed that strain EGI 80425T clustered with the members of the genus Nocardiopsis. Based on phenotypic, chemotaxonomic and phylogenetic characteristics, strain EGI 80425T represents a novel species of the genus Nocardiopsis, for which the name Nocardiopsis ansamitocini sp. nov. is proposed. The type strain is EGI 80425T ( = CGMCC 9969T = KCTC 39605T). PMID- 26486851 TI - Six-month Calorie Restriction in Overweight Individuals Elicits Transcriptomic Response in Subcutaneous Adipose Tissue That is Distinct From Effects of Energy Deficit. AB - Calorie restriction confers health benefits distinct from energy deficit by exercise. We characterized the adipose-transcriptome to investigate the molecular basis of the differential phenotypic responses. Abdominal subcutaneous fat was collected from 24 overweight participants randomized in three groups (N = 8/group): weight maintenance (control), 25% energy deficit by calorie restriction alone (CR), and 25% energy deficit by calorie restriction with structured exercise (CREX). Within each group, gene expression was compared between 6 months and baseline with cutoffs at nominal p <= .01 and absolute fold-change >= 1.5. Gene-set enrichment analysis (false discovery rate < 5%) was used to identify significantly regulated biological pathways. CR and CREX elicited similar overall clinical response to energy deficit and a comparable reduction in gene transcription specific to oxidative phosphorylation and proteasome function. CR vastly outweighed CREX in the number of differentially regulated genes (88 vs 39) and pathways (28 vs 6). CR specifically downregulated the chemokine signaling related pathways. Among the CR-regulated genes, 27 functioned as transcription/translation regulators (eg, mRNA processing or transcription/translation initiation), whereas CREX regulated only one gene in this category. Our data suggest that CR has a broader effect on the transcriptome compared with CREX which may mediate its specific impact on delaying primary aging. PMID- 26486852 TI - Prevalence and distribution of exposure to Schmallenberg virus in Irish cattle during October 2012 to November 2013. AB - BACKGROUND: Schmallenberg virus (SBV) was first identified in November 2011. It is a novel Orthobunyavirus (family Bunyaviridae) whose main ill effect is congenital malformation of the musculoskeletal and central nervous systems. It is borne by Culicoides spp., and has spread extensively in western Europe. The first case of SBV in Ireland was diagnosed in October 2012. It was anticipated that once the virus emerged in Ireland that there would be wide scale or nationwide spread over the course of the 2013 vector season. The objectives of this study were to determine the seroprevalence and distribution of exposure to Schmallenberg virus in Irish cattle from November 2012 to November 2013. METHODS: Samples of brain for the pathology based surveillance were collected from malformed bovine and ovine foetuses submitted for post mortem examination. These samples were tested for SBV using RT-qPCR. Three serological surveys were carried out on sera submitted for the national brucellosis eradicartion programme. A spatial analysis of both sets of data was carried out. RESULTS: Between October 2012 and 10th May 2013, SBV was confirmed by RT-qPCR in brain tissues from malformed foetuses obtained from 49 cattle herds and 30 sheep flocks in Ireland. In national serosurveys conducted between November 2012 until November 2013 the herd-level and animal-level SBV seroprevalences in cattle were 53 and 36 % respectively for the first survey, 51 and 35 % for the second survey and 53 and 33 % for the third survey. The herd level seroprevalence in counties ranged from 0 to 100 %, with the counties in the south and southeast having the highest seroprevalence (>50 %), the midlands a moderate herd level seroprevalence (10-50 %) while northern and north western counties had a low herd level seroprevalence (0-10 %). There was close spatial agreement between the results of the two different targeted surveillance strategies. CONCLUSIONS: At the end of the 2012 vector season, there was widespread exposure to SBV among herds in southern and south eastern Ireland. During 2013, there was little or no evidence of further outward spread, unlike the situation in several other European countries. Given the lack of evidence for circulation of the virus since 2012, it is likely that the younger age cohort in herds previously exposed to SBV and substantial proportions of animals of all ages on the margins of affected areas are immunologically naive to SBV, and would be susceptible to infection if the virus were to re-emerge. PMID- 26486853 TI - Annual review of children with neurofibromatosis type 1. AB - We aim to provide a concise, evidence-based framework to assist secondary level, community and acute paediatricians during a 20-60 min annual review of children with neurofibromatosis type 1. This review does not cover all aspects of the disorder. We recognise the importance of an overview of the pathogenesis, molecular genetic testing, clinical manifestations and management; we shall cover some of this briefly, but this is not our focus here. We focus instead on the following areas: (A) what questions should be asked during annual review, (B) what should be included in a focused examination, (C) when to request further investigations and (D) when should a referral be made to tertiary specialists and other members of the multidisciplinary team. Ongoing debates regarding screening remain in certain areas, particularly regarding imaging and ophthalmology follow up; here we summarise the differing opinions and make a recommendation based on the currently available evidence. PMID- 26486854 TI - Successful surgical palliation of a triple-outlet right ventricle: a rare congenital cardiac malformation. AB - Most commonly, hearts have either a single arterial trunk or two arterial trunks; however, rare reports exist of a "tritruncal" heart, a heart with three outflow tracts. Here, we present one of the first reports of successful surgical palliation of a triple-outlet right ventricle. PMID- 26486855 TI - Long-Term Suppression of Atrial Fibrillation by Botulinum Toxin Injection Into Epicardial Fat Pads in Patients Undergoing Cardiac Surgery: One-Year Follow-Up of a Randomized Pilot Study. AB - BACKGROUND: Animal models suggest that the neurotransmitter inhibitor, botulinum toxin, when injected into the epicardial fat pads can suppress atrial fibrillation inducibility. The aim of this prospective randomized double-blind study was to compare the efficacy and safety of botulinum toxin injection into epicardial fat pads for preventing atrial tachyarrhythmias. METHODS AND RESULTS: Patients with history of paroxysmal atrial fibrillation and indication for coronary artery bypass graft surgery were randomized to botulinum toxin (Xeomin, Merz, Germany; 50 U/1 mL at each fat pad; n=30) or placebo (0.9% normal saline, 1 mL at each fat pad; n=30) injection into epicardial fat pads during surgery. Patients were followed for 1 year to assess maintenance of sinus rhythm using an implantable loop recorder. All patients in both groups had successful epicardial fat pad injections without complications. The incidence of early postoperative atrial fibrillation within 30 days after coronary artery bypass graft was 2 of 30 patients (7%) in the botulinum toxin group and 9 of 30 patients (30%) in the placebo group (P=0.024). Between 30 days and up to the 12-month follow-up examination, 7 of the 30 patients in the placebo group (27%) and none of the 30 patients in the botulinum toxin group (0%) had recurrent atrial fibrillation (P=0.002). There were no complications observed during the 1-year follow-up. CONCLUSIONS: Botulinum toxin injection into epicardial fat pads during coronary artery bypass graft provided substantial atrial tachyarrhythmia suppression both early as well as during 1-year follow-up, without any serious adverse events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01842529. PMID- 26486856 TI - Left Atrial Appendage Remodeling After Lariat Left Atrial Appendage Ligation. AB - BACKGROUND: Left atrial appendage (LAA) ligation with the Lariat device is being used for stroke prevention in atrial fibrillation. Residual leaks into the LAA are commonly reported after the procedure. Little is known about the anatomic LAA remodeling after Lariat ligation. METHODS AND RESULTS: In an exploratory study, we evaluated LAA 3-dimensional geometry via computed tomographic scan in 31 consecutive patients before Lariat closure and after a minimum of 30 days post procedure. Thirteen patients were classified as unfavorable cases based on anatomic criteria. Our population had an average age of 70+/-12 years, a mean CHADS2 (congestive heart failure, hypertension, age>75, diabetes mellitus, history of stroke) score of 3.2+/-1.2, a mean CHADS2VASC (CHADS2 in addition to female sex, ages 65-75, as well as double impact of age >75, vascular disease) of 4.2+/-1.5, and a mean HASBLED (hypertension, abnormal renal/liver function, stroke, bleeding predisposition/history, labile international normalized ratio, elderly, drugs/alcohol) bleeding score of 4.0+/-1.1. Successful suture deployment was achieved in all cases, but 3 patients had intraprocedural residual flow into the LAA (leak). On follow-up, 10 patients (32%) had recanalized residual LAA cavities, which were morphologically similar to the original LAA, albeit significantly smaller in volume (22.5+/-13.3% of the original volume). Recanalization was not associated with age, sex, comorbid conditions, stroke or bleeding risk scores, follow-up interval, baseline LAA volume, or morphology. Unfavorable cases had anatomic outcomes comparable with those of the anatomically favorable population. No patients have exhibited thromboembolism after 842+/-338 days post ligation. CONCLUSIONS: Incomplete LAA ligation after Lariat is common. However, the remodeled LAA cavity is dramatically reduced. Diminished cavity size and tightening of the LAA orifice may play a role in the reduction of thrombus formation. PMID- 26486858 TI - Acute renal failure during immediate post transplant period due to a pericardial effusion. AB - BACKGROUND: Pericardial effusions and acute renal failure are common findings in clinical practice. However, acute renal failure resulting from pericardial effusions (without tamponade) is a rare finding. We report the first such case to occur in a transplanted kidney. CASE PRESENTATION: A 20-year-old Sri Lankan male presented with hypertensive crisis in the background of end stage renal failure. He was thoroughly investigated for secondary causes of hypertension to no avail. He was hemodialysed adequately for 6 months, while being worked up for transplantation. He received an ABO matched, living donor transplant. Immediate post-operative period his urine outputs were poor, soon to became anuric by 6 h post-transplant. Elevated liver enzymes and non-specific increase of resistivity indexes (0.84-0.88) at the Doppler scan raised the possibility of venous hypertension. An echocardiogram showed a moderately large pericardial effusion which was tapped, and found to be a transudate. He started producing urine within 6 h, entered polyuric phase by day 3, and by day 7 his creatinine dropped to reference levels. Vasculitis screen, anti nuclear factor, viral screen, and rickettsia serology were negative. Albumin levels on day 2 were 27 g/l and were replaced using human albumin. The exact cause of pericardial effusion is unclear but hypoalbuminemia, drug-induced and idiopathic are possible causes. He has excellent graft function, no recurrences or constrictive pericarditis after 2 years follow. CONCLUSION: We recommend any patient who has delayed graft function and raised central venous pressures to have an echocardiogram to exclude pericardial effusions. The response to pericardiocentesis had been universally good in reported cases. PMID- 26486857 TI - A randomized controlled behavioral intervention trial to improve medication adherence in adult stroke patients with prescription tailored Short Messaging Service (SMS)-SMS4Stroke study. AB - BACKGROUND: The effectiveness of mobile technology to improve medication adherence via customized Short Messaging Service (SMS) reminders for stroke has not been tested in resource poor areas. We designed a randomized controlled trial to test the effectiveness of SMS on improving medication adherence in stroke survivors in Pakistan. METHODS: This was a parallel group, assessor-blinded, randomized, controlled, superiority trial. Participants were centrally randomized in fixed block sizes. Adult participants on multiple medications with access to a cell phone and stroke at least 4 weeks from onset (Onset as defined by last seen normal) were eligible. The intervention group, in addition to usual care, received reminder SMS for 2 months that contained a) Personalized, prescription tailored daily medication reminder(s) b) Twice weekly health information SMS. The Health Belief Model and Social Cognitive theory were used to design the language and content of messages. Frontline SMS software was used for SMS delivery. Medication adherence was self-reported and measured on the validated Urdu version of Morisky Medication Adherence Questionnaire. Multiple linear regression was used to model the outcome against intervention and other covariates. Analysis was conducted by intention-to-treat principle. RESULTS: Two hundred participants were enrolled. 38 participants were lost to follow-up. After 2 months, the mean medication score was 7.4 (95 % CI: 7.2-7.6) in the intervention group while 6.7 (95 % CI: 6.4-7.02) in the control group. The adjusted mean difference (Delta) was 0.54 (95 % CI: 0.22-0.85). The mean diastolic blood pressure in the intervention group was 2.6 mmHg (95 % CI; -5.5 to 0.15) lower compared to the usual care group. CONCLUSION: A short intervention of customized SMS can improve medication adherence and effect stroke risk factors like diastolic blood pressure in stroke survivors with complex medication regimens living in resource poor areas. TRIAL REGISTRATION: Clinicaltrials.gov NCT01986023 last accessed at https://clinicaltrials.gov/ct2/show/NCT01986023. PMID- 26486859 TI - Impact of liver cirrhosis due to chronic hepatitis C viral infection on the outcome of ovarian cancer: a prospective study. AB - BACKGROUND: This study was designed to investigate the impact of liver cirrhosis due to chronic hepatitis C virus (HCV) infection on the disease-free and overall survival of ovarian cancer patients undergoing a standard primary operation followed by standard chemotherapy. Attainment of the operative goals, intra- and postoperative events, possible complications under chemotherapy necessitating the termination of treatment, and the impact of ovarian cancer treatment on liver function were assessed. METHODS: This was a prospective observational study that included only patients with primary epithelial ovarian cancer. Only patients with Child-Turcotte-Pugh classification class A disease were recruited. Patients were divided into two groups according to whether they had liver cirrhosis. All the patients underwent primary debulking surgery followed by 6 cycles of chemotherapy, and were followed-up for 24 months after chemotherapy was completed. RESULTS: We recruited 77 patients, 19 of whom had liver cirrhosis. There were no significant differences between patients with or without liver cirrhosis with respect to tumor stage, histopathological type, tumor grade, or optimal operative debulking. There was no registered liver dysfunction-related mortality in the follow-up period, and there were no statistically significant differences between the groups with respect to disease-free or overall survival (p = 0.719 and p = 0.524, respectively). CONCLUSION: From the results of this study, we conclude that compensated liver cirrhosis (Child-Turcotte-Pugh class A) due to chronic HCV infection affects neither the disease-free nor the overall survival of ovarian cancer patients, regardless of their stage. This study shows that it is possible to treat ovarian cancer patients with cirrhosis caused by HCV infection the same as any other patient; treatment does not have to be adjusted as long as the patients have Class A disease. PMID- 26486860 TI - Listening in. AB - Zebra finches communicate with each other in ways that are more complex than previously thought. PMID- 26486862 TI - Correction: Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion. PMID- 26486863 TI - Molecular co-catalyst accelerating hole transfer for enhanced photocatalytic H2 evolution. AB - In artificial photocatalysis, sluggish kinetics of hole transfer and the resulting high-charge recombination rate have been the Achilles' heel of photocatalytic conversion efficiency. Here we demonstrate water-soluble molecules as co-catalysts to accelerate hole transfer for improved photocatalytic H2 evolution activity. Trifluoroacetic acid (TFA), by virtue of its reversible redox couple TFA./TFA(-), serves as a homogeneous co-catalyst that not only maximizes the contact areas between co-catalysts and reactants but also greatly promotes hole transfer. Thus K4Nb6O17 nanosheet catalysts achieve drastically increased photocatalytic H2 production rate in the presence of TFA, up to 32 times with respect to the blank experiment. The molecular co-catalyst represents a new, simple and highly effective approach to suppress recombination of photogenerated charges, and has provided fertile new ground for creating high-efficiency photosynthesis systems, avoiding use of noble-metal co-catalysts. PMID- 26486864 TI - Letter by Gutierrez et al Regarding Article, "Differential Vascular Pathophysiologic Types of Intracranial Atherosclerotic Stroke: A High-Resolution Wall Magnetic Resonance Imaging Study". PMID- 26486861 TI - Assembly and positioning of actomyosin rings by contractility and planar cell polarity. AB - The actomyosin cytoskeleton is a primary force-generating mechanism in morphogenesis, thus a robust spatial control of cytoskeletal positioning is essential. In this report, we demonstrate that actomyosin contractility and planar cell polarity (PCP) interact in post-mitotic Ciona notochord cells to self assemble and reposition actomyosin rings, which play an essential role for cell elongation. Intriguingly, rings always form at the cells' anterior edge before migrating towards the center as contractility increases, reflecting a novel dynamical property of the cortex. Our drug and genetic manipulations uncover a tug-of-war between contractility, which localizes cortical flows toward the equator and PCP, which tries to reposition them. We develop a simple model of the physical forces underlying this tug-of-war, which quantitatively reproduces our results. We thus propose a quantitative framework for dissecting the relative contribution of contractility and PCP to the self-assembly and repositioning of cytoskeletal structures, which should be applicable to other morphogenetic events. PMID- 26486866 TI - Efficacy and Safety of Platelet Glycoprotein Receptor Blockade in Aged and Comorbid Mice With Acute Experimental Stroke. AB - BACKGROUND AND PURPOSE: Despite the medical and socioeconomic effect of ischemic stroke and extensive preclinical research, treatment options for ischemic stroke are limited. We recently identified and characterized essential steps of thrombus formation in stroke and demonstrated that inhibition of the platelet glycoprotein (GP) receptors Ib and VI, but not IIb/IIIa, protects young and healthy mice from ischemic neurodegeneration. Whether these findings translate to the clinic remains unclear. Considering that the typical stroke patient is elderly with comorbidity, we aimed to analyze the efficacy and safety of novel preclinical antithrombotics in adult and comorbid mice with acute experimental stroke. METHODS: We subjected adult, healthy, atherosclerotic (Ldlr(-/-)), diabetic (streptozotocin treated), and hypertensive (RenTgMK) mice to a 60-minute transient middle cerebral artery occlusion. Animals were pretreated with anti GPVI antibodies or treated 1 hour after stroke induction with anti-GPIb or anti GPIIb/IIIa antigen-binding fragments, respectively. Isotype treatment served as control. Twenty-four hours after transient middle cerebral artery occlusion, we visually assessed the intracerebral hemorrhage rate and measured infarct volumes (using 2,3,5-triphenyltetrazolium chloride-stained brain slices) and functional outcome (using Bederson and grip-test scores). RESULTS: GPIb and GPVI inhibition protected the mice from ischemic stroke without increasing bleeding complications. In contrast, GPIIb/IIIa inhibition was not protective but increased the intracerebral hemorrhage rate. CONCLUSIONS: Inhibition of early steps of thrombus formation protects adult and comorbid mice from ischemic stroke. The use of clinically meaningful mouse strains might improve the translation of preclinical stroke research to the clinic. PMID- 26486867 TI - Global Stroke Belt: Geographic Variation in Stroke Burden Worldwide. PMID- 26486868 TI - Effects of Blood Pressure and Blood Pressure-Lowering Treatment During the First 24 Hours Among Patients in the Third International Stroke Trial of Thrombolytic Treatment for Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: In patients with acute ischemic stroke, a high blood pressure or a highly variable blood pressure is a common reason for withholding thrombolytic treatment, but guidelines recommend a conservative approach to active blood pressure lowering in this setting. We have performed exploratory analyses to study the clinical effects of blood pressure and early blood pressure lowering treatment in patients included in a randomized-controlled trial of thrombolytic treatment for acute ischemic stroke. METHODS: The Third International Stroke Trial (IST-3) randomized 3035 patients with ischemic stroke to recombinant tissue-type plasminogen activator 0.9 mg/kg or open control within 6 hours of symptom onset. Blood pressure was measured at randomization, at start of treatment, and at 30 minutes and 1 and 24 hours after start of treatment, and the use of blood pressure-lowering treatment during the first 24 hours was recorded. We have characterized blood pressure by mean systolic blood pressure at baseline, by variability of systolic blood pressure (expressed by the standard deviation and the range between the lowest and the highest pressure), and by the change in systolic blood pressure from baseline to 24 hours. We used logistic regression analysis to explore the associations of blood pressure characteristics or blood pressure-lowering treatment with early adverse events, early death, and functional outcome at 6 months, after adjustment for key prognostic variables. RESULTS: High baseline blood pressure and high blood pressure variability during the first 24 hours were associated with higher numbers of early adverse events and early deaths, and for several analyses, the differences were statistically significant. A larger decline in blood pressure and the use of blood pressure lowering treatment during the first 24 hours were associated with a reduced risk of poor outcome at 6 months (odds ratio, 0.93; 95% confidence interval, 0.89 0.97; P=0.001 and odds ratio, 0.78; 95% confidence interval, 0.65-0.93; P=0.007, respectively), irrespective of whether the patient was given recombinant tissue type plasminogen activator (P values for interaction >0.05). CONCLUSIONS: Among patients with ischemic stroke who are candidates for thrombolytic treatment, high baseline blood pressure and a large pressure variability during the first 24 hours may be associated with a poor prognosis, whereas a large reduction in blood pressure and the use of blood pressure-lowering treatment during the first 24 hours may be associated with a favorable prognosis. These data support the rationale for further trials of agents that lower blood pressure or reduce blood pressure variability in the acute phase of ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00120003. PMID- 26486865 TI - Endovascular Therapy Is Effective and Safe for Patients With Severe Ischemic Stroke: Pooled Analysis of Interventional Management of Stroke III and Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands Data. AB - BACKGROUND AND PURPOSE: We assessed the effect of endovascular treatment in acute ischemic stroke patients with severe neurological deficit (National Institutes of Health Stroke Scale score, >=20) after a prespecified analysis plan. METHODS: The pooled analysis of the Interventional Management of Stroke III (IMS III) and Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trials included participants with an National Institutes of Health Stroke Scale score of >=20 before intravenous tissue-type plasminogen activator (tPA) treatment (IMS III) or randomization (MR CLEAN) who were treated with intravenous tPA <=3 hours of stroke onset. Our hypothesis was that participants with severe stroke randomized to endovascular therapy after intravenous tPA would have improved 90-day outcome (distribution of modified Rankin Scale scores), when compared with those who received intravenous tPA alone. RESULTS: Among 342 participants in the pooled analysis (194 from IMS III and 148 from MR CLEAN), an ordinal logistic regression model showed that the endovascular group had superior 90-day outcome compared with the intravenous tPA group (adjusted odds ratio, 1.78; 95% confidence interval, 1.20-2.66). In the logistic regression model of the dichotomous outcome (modified Rankin Scale score, 0-2, or functional independence), the endovascular group had superior outcomes (adjusted odds ratio, 1.97; 95% confidence interval, 1.09-3.56). Functional independence (modified Rankin Scale score, <=2) at 90 days was 25% in the endovascular group when compared with 14% in the intravenous tPA group. CONCLUSIONS: Endovascular therapy after intravenous tPA within 3 hours of symptom onset improves functional outcome at 90 days after severe ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424 (IMS III) and ISRCTN10888758 (MR CLEAN). PMID- 26486869 TI - Dialysis Requiring Acute Kidney Injury in Acute Cerebrovascular Accident Hospitalizations. AB - BACKGROUND AND PURPOSE: The epidemiology of dialysis requiring acute kidney injury (AKI-D) in acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) admissions is poorly understood with previous studies being from a single center or year. METHODS: We used the Nationwide Inpatient Sample to evaluate the yearly incidence trends of AKI-D in hospitalizations with AIS and ICH from 2002 to 2011. We also evaluated the trend of impact of AKI-D on in-hospital mortality and adverse discharge using adjusted odds ratios (aOR) after adjusting for demographics and comorbidity indices. RESULTS: We extracted a total of 3,937,928 and 696,754 hospitalizations with AIS and ICH, respectively. AKI-D occurred in 1.5 and 3.5 per 1000 in AIS and ICH admissions, respectively. Incidence of admissions complicated by AKI-D doubled from 0.9/1000 to 1.7/1000 in AIS and from 2.1/1000 to 4.3/1000 in ICH admissions. In AIS admissions, AKI-D was associated with 30% higher odds of mortality (aOR, 1.30; 95% confidence interval, 1.12-1.48; P<0.001) and 18% higher odds of adverse discharge (aOR, 1.18; 95% confidence interval, 1.02-1.37; P<0.001). Similarly, in ICH admissions, AKI-D was associated with twice the odds of mortality (aOR, 1.95; 95% confidence interval, 1.61-2.36; P<0.01) and 74% higher odds of adverse discharge (aOR, 1.74; 95% confidence interval, 1.34-2.24; P<0.01). Attributable risk percent of mortality was high with AKI-D (98%-99%) and did not change significantly over the study period. CONCLUSIONS: Incidence of AKI-D complicating hospitalizations with cerebrovascular accident continues to grow and is associated with increased mortality and adverse discharge. This highlights the need for early diagnosis, better risk stratification, and preparedness for need for complex long-term care in this vulnerable population. PMID- 26486870 TI - Phylogenetic patterns of gene rearrangements in four mitochondrial genomes from the green algal family Hydrodictyaceae (Sphaeropleales, Chlorophyceae). AB - BACKGROUND: The variability in gene organization and architecture of green algal mitochondrial genomes is only recently being studied on a finer taxonomic scale. Sequenced mt genomes from the chlorophycean orders Volvocales and Sphaeropleales exhibit considerable variation in size, content, and structure, even among closely related genera. However, sampling of mt genomes on a within-family scale is still poor and the sparsity of information precludes a thorough understanding of genome evolution in the green algae. METHODS: Genomic DNA of representative taxa were sequenced on an Illumina HiSeq2500 to produce 2x100 bp paired reads, and mitochondrial genomes were assembled and annotated using Geneious v.6.1.5. Phylogenetic analysis of 13 protein-coding mitochondrial genes spanning the Sphaeropleales was performed. RESULTS: This study presents one of the first within-family comparisons of mt genome diversity, and is the first to report complete mt genomes for the family Hydrodictyaceae (order Sphaeropleales). Four complete mt genomes representing three taxa and four phylogenetic groups, Stauridium tetras, Pseudopediastrum boryanum, and Pediastrum duplex, range in size from 37,723 to 53,560 bp. The size variability is primarily due to intergenic region expansion, and intron content is generally low compared with other mt genomes of Sphaeropleales. CONCLUSIONS: Certain gene rearrangements appear to follow a phylogenetic pattern, and with a more thorough taxon sampling genome-level sequence may be useful in resolving systematic conundrums that plague this morphologically diverse family. PMID- 26486871 TI - Spectral Tuning of Killer Whale (Orcinus orca) Rhodopsin: Evidence for Positive Selection and Functional Adaptation in a Cetacean Visual Pigment. AB - Cetaceans have undergone a remarkable evolutionary transition that was accompanied by many sensory adaptations, including modification of the visual system for underwater environments. Recent sequencing of cetacean genomes has made it possible to begin exploring the molecular basis of these adaptations. In this study we use in vitro expression methods to experimentally characterize the first step of the visual transduction cascade, the light activation of rhodopsin, for the killer whale. To investigate the spectral effects of amino acid substitutions thought to correspond with absorbance shifts relative to terrestrial mammals, we used the orca gene as a background for the first site directed mutagenesis experiments in a cetacean rhodopsin. The S292A mutation had the largest effect, and was responsible for the majority of the spectral difference between killer whale and bovine (terrestrial) rhodopsin. Using codon based likelihood models, we also found significant evidence for positive selection in cetacean rhodopsin sequences, including on spectral tuning sites we experimentally mutated. We then investigated patterns of ecological divergence that may be correlated with rhodopsin functional variation by using a series of clade models that partitioned the data set according to phylogeny, habitat, and foraging depth zone. Only the model partitioning according to depth was significant. This suggests that foraging dives might be a selective regime influencing cetacean rhodopsin divergence, and our experimental results indicate that spectral tuning may be playing an adaptive role in this process. Our study demonstrates that combining computational and experimental methods is crucial for gaining insight into the selection pressures underlying molecular evolution. PMID- 26486872 TI - A Distinct Mitochondrial Genome with DUI-Like Inheritance in the Ocean Quahog Arctica islandica. AB - Mitochondrial DNA (mtDNA) is strictly maternally inherited in metazoans. The major exception to this rule has been found in many bivalve species which allow the presence of different sex-linked mtDNA molecules. This mechanism, named doubly uniparental inheritance (DUI), is characterized by the presence of two mtDNAs: The female mtDNA is found in somatic tissue and female gonads, whereas the male mtDNA is usually found in male gonads and sperm. In this study we highlight the existence of two divergent mitochondrial haplotypes with a low genetic difference around 6-8% in Arctica islandica, a long-lived clam belonging to the Arcticidae, a sister group to the Veneridae in which DUI has been found. Phylogenetic analysis on cytochrome b and 16S sequences from somatic and gonadic tissues of clams belonging to different populations reveals the presence of the "divergent" type in male gonads only and the "normal" type in somatic tissues and female gonads. This peculiar segregation of divergent mtDNA types speaks for the occurrence of the DUI mechanism in A. islandica. This example also highlights the difficulties to assess the presence of such particular mitochondrial inheritance system and underlines the possible misinterpretations in phylogeographic and phylogenetic studies of bivalve species linked to the presence of two poorly differentiated mitochondrial genomes. PMID- 26486873 TI - Drosophila X-Linked Genes Have Lower Translation Rates than Autosomal Genes. AB - In Drosophila, X-linked and autosomal genes achieve comparable expression at the mRNA level. Whether comparable X-autosome gene expression is realized at the translational and, ultimately, the protein levels is, however, unknown. Previous studies suggest the possibility of higher translation rates for X-linked genes owing to stronger usage of preferred codons. In this study, we use public ribosome profiling data from Drosophila melanogaster to infer translation rates on the X chromosome versus the autosomes. We find that X-linked genes have consistently lower ribosome densities than autosomal genes in S2 cells, early embryos, eggs, and mature oocytes. Surprisingly, the lower ribosome densities of X-linked genes are not consistent with faster translation elongation but instead imply slower translation initiation. In particular, X-linked genes have sequence features known to slow translation initiation such as stronger mRNA structure near start codons and longer 5'-UTRs. Comparison to outgroup species suggests that stronger mRNA structure is an evolved feature of Drosophila X chromosomes. Finally, we find that the magnitude of the X-autosome difference in ribosome densities is smaller for genes encoding members of protein complexes, suggesting that stoichiometry constrains the evolution of translation rates. In sum, our analyses suggest that Drosophila X-linked genes have evolved lower translation rates than autosomal genes despite stronger usage of preferred codons. PMID- 26486874 TI - Functionalized nanomaterials: are they effective to perform gene delivery to difficult-to-transfect cells with no cytotoxicity? AB - Nanodiamonds (NDs), multiwalled carbon nanotubes (MWCNTs) and gold nanorods (NRs) can be functionalized to promote gene delivery to hard-to-transfect cells with higher transfection efficiency than cationic lipids, and inducing less cell death. PMID- 26486875 TI - Cooperativity flows and shear-bandings: a statistical field theory approach. AB - Cooperativity effects have been proposed to explain the non-local rheology in the dynamics of soft jammed systems. Based on the analysis of the free-energy model proposed by L. Bocquet, A. Colin and A. Ajdari, Phys. Rev. Lett., 2009, 103, 036001, we show that cooperativity effects resulting from the non-local nature of the fluidity (inverse viscosity) are intimately related to the emergence of shear banding configurations. This connection materializes through the onset of inhomogeneous compact solutions (compactons), wherein the fluidity is confined to finite-support subregions of the flow and strictly zero elsewhere. The compacton coexistence with regions of zero fluidity ("non-flowing vacuum") is shown to be stabilized by the presence of mechanical noise, which ultimately shapes up the equilibrium distribution of the fluidity field, the latter acting as an order parameter for the flow-noflow transitions occurring in the material. PMID- 26486876 TI - Complete mitochondrial genome of the Loligo beka. AB - In this study, we determined the complete mitochondrial genome of Loligo beka. The genome was 17 483 bp in length and contained 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and three main non-coding regions. The overall base composition of L.beka is A 40.35%, T 32.53%, C 18.53%, and G 8.58%, with a highly A + T bias of 72.89%. All the three control regions (CR) contain termination-associated sequences and conserved sequence blocks. Here we describe a phylogenetic analysis of 11 species cephalopoda based on the complete mitochondrial genome, the result showed that the Loliolus uyii is most closely related to L. beka. This mitogenome sequence data would play an important role in the investigation of phylogenetic relationship, taxonomic resolution and phylogeography of the cephalopoda. PMID- 26486877 TI - Anisotropic thermoelectric properties of layered compounds in SnX2 (X = S, Se): a promising thermoelectric material. AB - Thermoelectrics interconvert heat to electricity and are of great interest in waste heat recovery, solid-state cooling and so on. Here we assessed the potential of SnS2 and SnSe2 as thermoelectric materials at the temperature gradient from 300 to 800 K. Reflecting the crystal structure, the transport coefficients are highly anisotropic between a and c directions, in particular for the electrical conductivity. The preferred direction for both materials is the a direction in TE application. Most strikingly, when 800 K is reached, SnS2 can show a peak power factor (PF) of 15.50 MUW cm(-1) K(-2) along the a direction, while a relatively low value (11.72 MUW cm(-1) K(-2)) is obtained in the same direction of SnSe2. These values are comparable to those observed in thermoelectrics such as SnSe and SnS. At 300 K, the minimum lattice thermal conductivity (kappamin) along the a direction is estimated to be about 0.67 and 0.55 W m(-1) K(-1) for SnS2 and SnSe2, respectively, even lower than the measured lattice thermal conductivity of Bi2Te3 (1.28 W m(-1) K(-1) at 300 K). The reasonable PF and kappamin suggest that both SnS2 and SnSe2 are potential thermoelectric materials. Indeed, the estimated peak ZT can approach 0.88 for SnSe2 and a higher value of 0.96 for SnS2 along the a direction at a carrier concentration of 1.94 * 10(19) (SnSe2) vs. 2.87 * 10(19) cm(-3) (SnS2). The best ZT values in SnX2 (X = S, Se) are comparable to that in Bi2Te3 (0.8), a typical thermoelectric material. We hope that this theoretical investigation will provide useful information for further experimental and theoretical studies on optimizing the thermoelectric properties of SnX2 materials. PMID- 26486878 TI - Celebrating the 2015 Nobel Prize in Physiology or Medicine of Dr Satoshi Omura. PMID- 26486880 TI - Large-size nanosheets of 9,10-bis(phenylethynyl)anthracene with high photoresponse and light emission anisotropy. AB - Large-size single crystalline nanosheets of 9,10-bis(phenylethynyl)-anthracene were prepared by a facile solution process and were fully characterized. The prototype photodetector was then fabricated on the basis of a single nanosheet and exhibited superior performance with the largest photoresponse ratio up to ca. 10(5). Moreover, the nanosheets show obvious light emission anisotropy. PMID- 26486879 TI - Prevalence of mutations conferring resistance among multi- and extensively drug resistant Mycobacterium tuberculosis isolates in China. AB - To identify the mutations in multi- and extensively drug-resistant tuberculosis isolates and to evaluate the use of molecular markers of resistance, we analyzed 257 multi- and extensively drug-resistant isolates and 64 pan-sensitive isolates from 23 provinces in China. Seven loci associated with drug resistance, including rpoB for rifampin (RIF), katG, inhA and oxyR-ahpC for isoniazid (INH), gyrA and gyrB for ofloxacin (OFX), and rrs for kanmycin (KAN), were examined by DNA sequencing. Compared with the phenotypic data, the sensitivity and specificity for DNA sequencing were 91.1% and 98.4% for RIF, 80.2% and 98.4% for INH, 72.2% and 98.3% for OFX and 40% and 98.2% for KAN, respectively. The most common mutations found in RIF, INH, OFX and KAN resistance were Ser531Leu (48.2%) in rpoB, Ser315Thr (49.8%) in katG, C(-15)T (10.5%) in inhA, Asp94Gly (20.3%), Asp94Ala (12.7%) and Ala90Val (21.5%) in gyrA, and A1401G (40%) in rrs. This molecular information will be helpful to establish new molecular biology-based methods for diagnosing multi- and extensively drug-resistant tuberculosis in China. PMID- 26486881 TI - Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury. AB - Activated microglia and macrophages exert dual beneficial and detrimental roles after central nervous system injury, which are thought to be due to their polarization along a continuum from a classical pro-inflammatory M1-like state to an alternative anti-inflammatory M2-like state. The goal of the present study was to analyze the temporal dynamics of microglia/macrophage polarization within the lesion micro-environment following traumatic brain injury (TBI) using a moderate level controlled cortical impact (CCI) model in mice. We performed a detailed phenotypic analysis of M1- and M2-like polarized microglia/macrophages, as well as nicotinamide adenine dinucleotide phosphate oxidase (NOX2) expression, through 7 days post-injury using real-time polymerase chain reaction (qPCR), flow cytometry and image analyses. We demonstrated that microglia/macrophages express both M1- and M2-like phenotypic markers early after TBI, but the transient up regulation of the M2-like phenotype was replaced by a predominant M1- or mixed transitional (Mtran) phenotype that expressed high levels of NOX2 at 7 days post injury. The shift towards the M1-like and Mtran phenotype was associated with increased cortical and hippocampal neurodegeneration. In a follow up study, we administered a selective NOX2 inhibitor, gp91ds-tat, to CCI mice starting at 24 h post-injury to investigate the relationship between NOX2 and M1-like/Mtran phenotypes. Delayed gp91ds-tat treatment altered M1-/M2-like balance in favor of the anti-inflammatory M2-like phenotype, and significantly reduced oxidative damage in neurons at 7 days post-injury. Therefore, our data suggest that despite M1-like and M2-like polarized microglia/macrophages being activated after TBI, the early M2-like response becomes dysfunctional over time, resulting in development of pathological M1-like and Mtran phenotypes driven by increased NOX2 activity. PMID- 26486882 TI - Badiranji Buya Keli, a Traditional Uyghur Medicine, Induces Vasodilation in Rat Artery: Signaling Mediated by Nitric Oxide Production in Endothelial Cells. AB - Badiranji Buya Keli (BBK) is a traditional Uyghur medicine derived from Dracocephalum Moldavica Herba (DMH, the aerial part of Dracocephalum moldavica L.). BBK has been widely used in treating cardiovascular and cerebrovascular diseases. Here, the quality control of BBK was established by using HPLC analysis of rosmarinic acid and tilianin. After chemical standardization, the biological effects of BBK was tested. First, BBK inhibited platelet aggregation of rabbit plasma. Second, BBK induced vasodilation in rat aortic ring, and this effect was partially mediated by nitric oxide (NO) production in endothelial cells. Third, BBK induced NO production in cultured human umbilical vein endothelial cells (HUVECs). In HUVECs, the phosphorylation of endothelial NO synthase (eNOS) was markedly increased after application of BBK. Pre-treatment with the eNOS blocker N(omega) -nitro-l-arginine methyl ester hydrochloride could abolish BBK-induced NO production and eNOS phosphorylation. Taken together, these results suggest that BBK could exert beneficial effects in cardiovascular system, which may provide parts of molecular explanation to account for its traditional usage in Uyghur medicine. PMID- 26486883 TI - Sustained suppression of viral replication in improving vitamin D serum concentrations in patients with chronic hepatitis B. AB - Recently, the role of vitamin D in chronic hepatitis B (CHB) has attracted a lot attention. In this study, 128 naive CHB patients (91 with positive HBeAg, 37 with negative-HBeAg) were enrolled, and 128 volunteers without liver diseases were enrolled as controls. Compared to that of healthy controls, the mean level of 25(OH)D3 in CHB patients was significantly lower; and the percent of patients with sufficient 25(OH)D3 (>=20 ng/mL) was also significantly lower than that of healthy controls. Among those CHB patients, the level of 25(OH)D3 was negatively correlated with the serum HBV-DNA level. Additionally, the level of 25(OH)D3 was significantly lower in HBeAg-positive patients than that in HBeAg-negative patients. After the patients went through the long-term antiviral treatments, both the mean level of 25(OH)D3 and the percent of patients with sufficient 25(OH)D3 increased significantly. Additionally, patients who were HBeAg free after the treatment also had much higher 25(OH)D3 level than those with persistent positive HBeAg. All those data suggested that the low vitamin D serum level was dangerous for CHB patients, and the level of 25(OH)D3 was highly negatively correlated with HBV-DNA levels. Effective antiviral therapy might increase the level of vitamin D in CHB patients. PMID- 26486884 TI - Nonprosthetic Direct Inguinal Hernia Repair During Robotic Radical Prostatectomy. AB - OBJECTIVE: To report our experience with concomitant hernia repair during robot assisted radical prostatectomy (RARP) with a nonprosthetic and tissue-based technique. METHODS: We conducted a retrospective review on 1005 consecutive patients who underwent RARP between the years 2005 and 2015. Twenty-nine patients, who underwent 37, concurrent, direct, inguinal hernia repairs, were identified (group 1) and compared to a match control group of 29 patients who underwent RARP without hernia repair (group 2). Cases were matched 1:1 for age, body-mass index, and pathologic stage. The reinforcement of the floor was achieved with a modified posterior wall darn repair. The repair consisted of suturing the lateral edge of the rectus abdominis muscle sheath to the ileopectineal ligament (Cooper's ligament) with continuous prolene loose suture. This technique provided a tissue-based repair and the final reinforcement of the floor was expected to ensue by the secondary fibrotic tissue development and maturing between the sutures. RESULTS: From a total of 1005 patients who underwent RARP, 29 (2.8%) were preoperatively identified with a primary, direct inguinal hernia and underwent concomitant inguinal herniorrhaphy. The operative time was 147 minutes for group 1 vs 143 minutes for group 2 (p = 0.8). Estimated blood loss was 175 mL for the group with the hernia repair vs 200 mL for the group without repair (p = 0.3). There were no Clavien-Dindo grade >1 complications observed in either of the groups. Mean follow-up period was 32.1 months for group 1 vs 33.3 for group 2 (p = 0.8). Importantly, no hernia recurrences were observed. CONCLUSIONS: Inguinal hernias represent an important surgical issue and may be repaired concurrently during radical prostatectomy to minimize the risks of postoperative complications. The concomitant repair of inguinal hernias during robotic radical prostatectomy utilizing a nonprosthetic is a safe and feasible alternative for primary direct hernia repair during prostatectomy. PMID- 26486886 TI - CT screening in current moderate smokers may be justified as study finds similar lung cancer risk to heavier smokers. PMID- 26486885 TI - "Chameleonic" backbone hydrogen bonds in protein binding and as drug targets. AB - We carry out a time-averaged contact matrix study to reveal the existence of protein backbone hydrogen bonds (BHBs) whose net persistence in time differs markedly form their corresponding PDB-reported state. We term such interactions as "chameleonic" BHBs, CBHBs, precisely to account for their tendency to change the structural prescription of the PDB for the opposite bonding propensity in solution. We also find a significant enrichment of protein binding sites in CBHBs, relate them to local water exposure and analyze their behavior as ligand/drug targets. Thus, the dynamic analysis of hydrogen bond propensity might lay the foundations for new tools of interest in protein binding-site prediction and in lead optimization for drug design. PMID- 26486890 TI - Label-Free (XIC) Quantification of Venom Procoagulant and Neurotoxin Expression in Related Australian Elapid Snakes Gives Insight into Venom Toxicity Evolution. AB - This study demonstrates a direct role of venom protein expression alteration in the evolution of snake venom toxicity. Avian skeletal muscle contractile response to exogenously administered acetylcholine is completely inhibited upon exposure to South Australian and largely preserved following exposure to Queensland eastern brown snake Pseudonaja textilis venom, indicating potent postsynaptic neurotoxicity of the former and lack thereof of the latter venom. Label-free quantitative proteomics reveals extremely large differences in the expression of postsynaptic three-finger alpha-neurotoxins in these venoms, explaining the difference in the muscle contractile response and suggesting that the type of toxicity induced by venom can be modified by altered expression of venom proteins. Furthermore, the onset of neuromuscular paralysis in the rat phrenic nerve-diaphragm preparation occurs sooner upon exposure to the venom (10 MUg/mL) with high expression of alpha-neurotoxins than the venoms containing predominately presynaptic beta-neurotoxins. The study also finds that the onset of rat plasma coagulation is faster following exposure to the venoms with higher expression of venom prothrombin activator subunits. This is the first quantitative proteomic study that uses extracted ion chromatogram peak areas (MS1 XIC) of distinct homologous tryptic peptides to directly show the differences in the expression of venom proteins. PMID- 26486893 TI - Scientific communication in nursing. PMID- 26486891 TI - Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3 (-) secretion revealed by disease causing human mutation. AB - KEY POINTS: Fluid and HCO3 (-) secretion is essential for all epithelia; aberrant secretion is associated with several diseases. Carbonic anhydrase XII (CA12) is the key carbonic anhydrase in epithelial fluid and HCO3 (-) secretion and works by activating the ductal Cl(-) -HCO3 (-) exchanger AE2. Delivery of CA12 to salivary glands increases salivation in mice and of the human mutation CA12(E143K) markedly inhibits it. The human mutation CA12(E143K) causes disease due to aberrant CA12 glycosylation, and misfolding resulting in loss of AE2 activity. ABSTRACT: Aberrant epithelial fluid and HCO3 (-) secretion is associated with many diseases. The activity of HCO3 (-) transporters depends of HCO3 (-) availability that is determined by carbonic anhydrases (CAs). Which CAs are essential for epithelial function is unknown. CA12 stands out since the CA12(E143K) mutation causes salt wasting in sweat and dehydration in humans. Here, we report that expression of CA12 and of CA12(E143K) in mice salivary glands respectively increased and prominently inhibited ductal fluid secretion and salivation in vivo. CA12 markedly increases the activity and is the major HCO3 (-) supplier of ductal Cl(-) -HCO3 (-) exchanger AE2, but not of NBCe1-B. The E143K mutation alters CA12 glycosylation at N28 and N80, resulting in retention of the basolateral CA12 in the ER. Knockdown of AE2 and of CA12 inhibited pancreatic and salivary gland ductal AE2 activity and fluid secretion. Accordingly, patients homozygous for the CA12(E143K) mutation have a dry mouth, dry tongue phenotype. These findings reveal an unsuspected prominent role of CA12 in epithelial function, explain the disease and call for caution in the use of CA12 inhibitors in cancer treatment. PMID- 26486892 TI - Perceived age is associated with bone status in women aged 25-93 years. AB - Higher perceived age (PA) is reported to be associated with age-related diseases. Because osteoporosis is considered an age-related disease, we hypothesized that age perceived from photographs is associated with bone mineral density (BMD)/trabecular bone score (TBS) when controlled for chronological age. This is a cross-sectional study of 460 women aged 25-93 years. BMD/TBS was measured. Twenty physicians assessed age from facial and whole-body photographs. Residual PA (R(PACA)) was calculated from the regression of PA on chronological age. Participants were divided into "looking old" (LO) or "looking young" (LY). Linear mixed models and general linear models fitted with BMD/TBS as outcome and either R(PACA) or LO/LY as an independent variable, considering chronological age. Estimates of R(PACA) were all negative; i.e., an increase in R(PAC) is associated with lower BMD, consistent with the hypothesis (e.g., beta -0.29%; 95% confidence interval (CI) 0.55, 0.03). Statistical significance of the association of age adjusted facial R(PACA) with BMD was found. Adjusted for body mass index (BMI), menopause, and hormone replacement therapy, higher R(PACA) from all photographic presentations were significantly associated with lower BMD based on statistical significance. BMD/TBS was in all analyses higher in the group LY compared with LO, when adjusted for age and BMI (e.g., beta 4.37%; 95 CI 0.62, 8.26), but statistical significance was obtained only from the BMD analyses. A higher PA was significantly associated with a lower BMD/TBD, and the size of association in older women indicates that it might have value as part of the clinical assessment of osteoporotic risk. PMID- 26486894 TI - [Embracement with risk classification in the emergency department from the perspective of older adults]. AB - OBJECTIVE: To assess practices of embracement at the patient intake area of the emergency department of Porto Alegre Clinicas Hospital from the perspective of the older adults. METHODS: Qualitative investigation using the case study approach with 30 older adults trough semi-structured interview between July by November 2010. Data were assessed by thematic analysis with the Nvivo software suite. RESULTS: Responses focused on wait times and on the role of nurses in patient classification. User embracement practices enhanced the work process and highlighted the direct contact between nurses and users. CONCLUSIONS: The care needs of the older adults, the respect for the assessment protocol intervals and work on internal and external network can be improved in order to qualify attention to these patients. PMID- 26486895 TI - [Socioeconomic characteristics and quality of life of urban and rural elderly people with heart disease]. AB - OBJECTIVE: To compare the socioeconomic variables and quality of life scores (QOL) of elderly residents with heart diseases in urban and rural areas. METHOD: household survey with 829 urban and 220 rural elderlies. The data were collected using: Brazilian Questionnaire for Functional and Multidimensional Assessment, WHOQOL-BREF and WHOQOL-OLD. The collection in the urban area was from June to December of 2008 and, in the rural area, from June 2010 to March 2011. Chi square, t-student and multiple linear regression (p <0.05) tests were used. RESULTS: The proportion of women and elderlies with 75 years of age and over was higher in urban areas. Lower scores among urban elderlies physical and social relations were observed, and; facets autonomy, past, present and future activities and intimacy; for the rural elderlies, the environment, sensory abilities, death and dying. CONCLUSION: the urban elderlies showed a lower QOL score in most areas and facets compared to rural elderlies. PMID- 26486896 TI - [Nursing workload in a coronary unit according to the Nursing Activities Score]. AB - OBJECTIVE: this study aimed to using the Nursing Activities Score to assess nursing workload in a coronary care unit, to assess the distribution of workload between shifts, and to compare the current staff of the care unit with that recommended by the instrument. METHOD: this was a longitudinal study, conducted in a teaching hospital in Southern Brazil, between April to June 2012. RESULTS: A total of 604 NAS measures were obtained from the 61 patients included. The mean workload per shift was 47% (+/-12), with the greatest workload being reported in the afternoon shifts. CONCLUSION: according to the NAS, a mean of two and a maximum of 2.4 nursing professionals would be required per shift to meet all patient demands, suggesting that the current staff size in the CCU is adequate. The NAS was successful in assessing nursing workload and changes in patient demands over time. PMID- 26486897 TI - [Comprehension of community healthcare agents on the National Humanization Policy]. AB - OBJECTIVE: To identify the comprehension of Community Healthcare Agents on the National Humanization Policy (NHP), as well as to analyze whether they recognize healthcare actions developed in their daily lives, as those established by the NHP. METHOD: Exploratory and descriptive qualitative research, conducted between June and September 2013, with 15 Community Healthcare Agents of the Family Health Strategy Program in a city located in the West of Sao Paulo state. The data collection was conducted through individual interviews, using a semi-structured script and submitted to content analysis. RESULTS: Two categories emerged: "Superficial knowledge: an obstacle to the construction of humanized care" and "Actions of humanized health: trying to get closer". CONCLUSION: The basic concepts of NHP are part of the knowledge of these professionals, but the understanding they possess is superficial, which directly affects the actions provided to the community. PMID- 26486898 TI - [Living and health conditions of elderly people over 80]. AB - OBJECTIVE: This article proposes to describe demographic data and health conditions of elderly people at age 80 or more. METHOD: Quantitative-descriptive study of 95 elderlies from five units of the Family Health Strategy in the period from September to December 2013, using script with general data of the living conditions and health, including validated scales in geriatrics and gerontology. RESULTS: The average age was 85.4 years. There was a predominance of women. Most were widowers with family income, more frequently between 2 or 3 minimum wages and economic participation is for means of sharing responsibility. They present dependency for many of Daily Living Instrumental Activities and, on average, reported 2.2 diseases. Fear of falling, decreased vision and hearing as well as pain in different body regions are reported. CONCLUSION: It appears that they have more intense needs than the elderly in general, requiring new ways of organizing their health care. PMID- 26486899 TI - [Pre hospital indicators in assessing the quality of care for patients with acute coronary syndrome]. AB - OBJECTIVE: to assess quality indicators related to the pre-hospital time for patients with acute coronary syndrome. METHOD: collection took place at a tertiary hospital in Parana between 2012 and 2013, through interviews and a medical record review. 94 patients participated, 52.1% male, 78.7% who were over 50 years old, 46.9% studied until the fourth grade, 60.6% were diagnosed with acute myocardial infarction. RESULTS: the outcomes were the time between the onset of symptoms and the decision to seek help with an average of 1022 min+/ 343.13, door-to-door 805 min+/-181.78; and reperfusion, 455 min+/-364.8. The choice to seek out care within 60 min occurred in patients who were having a heart attack, and longer than 60 min in those with a history of heart attack or prior catheterization. CONCLUSION: We concluded that the pre-hospital indicators studied interfered with the quality of care. PMID- 26486900 TI - [Control mechanisms for the integration of teaching and service in the Pro-Saude nursing programme]. AB - OBJECTIVE: To characterize and analyze the control mechanisms of institutional relations for the integration of health education and services linked to the Pro Saude programme, according to the professors and nurses of health centres in Florianopolis. METHOD: A qualitative approach based on a single case study. Sixteen semi-structured interviews were conducted in the second semester of 2012 at eight health centres where nursing students carry out practical activities and internships in primary health care. The data were subjected to content analysis with the comparison of responses from both segments. RESULTS: Three categories were created: Characterization of control mechanisms; Influences of control mechanisms; and, Suggestions for the improvement of control mechanisms for the integration of teaching and services. CONCLUSION: A greater understanding of the control mechanisms for the integration of teaching and services proportionally leads to better management of inter-organizational cooperation and the subsequent improvement of the care provided to users. PMID- 26486902 TI - [Nurses' perceptions of the vulnerabilities to STD/AIDS in light of the process of adolescence]. AB - OBJECTIVE: to understand the perception of nurses on the vulnerabilities to STD/AIDS in light of the process of adolescence. METHOD: qualitative research conducted with 15 nurses in a centre for the studies of adolescent healthcare of a university hospital in Rio de Janeiro/Brazil. The adopted theoretical and methodological frameworks were the Complexity Theory and the Grounded Theory, respectively. The semi-structured interview was used to collect data from January to August 2012. RESULTS: this research presents the category: Nurses' perceptions of the vulnerabilities to STD/AIDS in light of the process of adolescence, and the subcategories: Risks and uncertainties of the process of adolescence: paths to STD/AIDS; Age-adolescence complex: expanding knowledge from the perception of nurses. CONCLUSION: once the nurses understand the complexity of adolescence, they create strategies to reduce the vulnerability of adolescents to STD/AIDS. This signals the need to invest in education, assistance and the management of nursing care for adolescents. PMID- 26486901 TI - [The challenge of tobacco control at a university hospital]. AB - OBJECTIVE: To identify the actions taken by the Commission of Tobacco Control (CTC) to control smoking in the hospital environment. METHODS: Descriptive and exploratory retrospective documentary research conducted at a university hospital in southern Brazil, in 2014. The content of the minutes of CTC meetings was used to create a database, and the rounds reports were descriptively analyzed. We sought to identify the most relevant actions from 2005 to 2014. RESULTS: The CTC implemented the Tobacco-Free Environment programme restricted cigarette smoking to designated areas and subsequently deactivated these areas. The only remaining outdoor smoking area in 2014 was deactivated. CONCLUSION: CTC actions have contributed to tobacco control in the hospital environment. This study will hopefully serve as a model to encourage other institutions to implement similar actions. PMID- 26486903 TI - [Profile of nursing diagnoses of hospitalized patients in an infectious disease unit]. AB - OBJECTIVE: To define the profile of nursing diagnoses of hospitalized patients at an infectious diseases unit. METHODS: This is a descriptive study based on the quantitative approach conducted at an infectious diseases unit in Paraiba, Brazil, from January to February 2014. The data collection instrument was based on the Theory of Basic Human Needs by Wanda de Aguiar Horta, followed by the classification system CIPER version 2.0 to construct the diagnoses. RESULTS: Data analysis resulted in 36 nursing diagnoses statements, with a higher prevalence of impaired food intake, cachexia, impaired spontaneous bladder elimination, impaired oral cavity hygiene, exposure to contamination, rapid heart rate, insomnia, drug abuse, alcohol and tobacco abuse, social isolation, acceptance and fear. CONCLUSIONS: The identification of a diagnostics profile is critical to guide nursing interventions. PMID- 26486904 TI - [Preference and factors associated with the type of delivery among new mothers in a public maternity hospital]. AB - OBJECTIVE: To identify reproductive and socioeconomic factors that influence the preference for a method of childbirth. METHOD: Data were collected using semi structured interviews with 233 women in postpartum care. Data were analyzed using association tests, namely the Chi-square test and multiple logistic regression. RESULTS: The preference for vaginal childbirth was cited by 58% of women. The main reasons for this preference were quick postpartum recovery, a negative experience in Caesarean childbirth and fulfilment through motherhood. Analysis of the logistic models of preference for vaginal delivery according to the independent variables revealed a greater occurrence in women who had previous experience of this type of delivery (PR: 1.91; CI: 1.15-3.17) and had received prior guidance (PR: 1.76; CI: 1.06-2.90). CONCLUSION: Findings highlight the need to transform the model of care provided during pregnancy and childbirth. PMID- 26486905 TI - [Teaching in higher education in nursing: an integrative literature review]. AB - OBJECTIVE: To analyze the knowledge produced about teaching in higher education in nursing. METHOD: Integrative literature review of full articles available on the LILACS, SciELO, BDENF and ERIC databases, through the descriptors "nursing faculty"and "practices of nursing faculty" and keywords "Teaching in nursing" or "Education in nursing"and "Nursing professors" and "Teaching knowledge" in Portuguese, English or Spanish, published from January 2008 to November 2013. RESULTS: 31 articles were identified. The data led to the following thematic categories: Training for faculty, Conflict of roles: being a nurse and being a teacher and Organization of the teaching work. CONCLUSIONS: It was found that there are numerous gaps in understanding the teaching activity in nursing. The concerns identified may offer help for understanding the teaching world and conceptions about being a teacher in nursing. PMID- 26486906 TI - [Acute pain in myocardial infarction: analysis of concept]. AB - OBJECTIVE: To analyze the concept "sharp pain" in the context of acute myocardial infarction. METHODS: Conceptual analysis method proposed by Walker and Avant. This makes it possible to clarify the concept of attributes. We conducted an integrative review to assist the search of studies published in 2006 and 2012, using the descriptors 'Acute Pain' and 'myocardial infarction', through consultation to Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus and Public/Publish Medline (PubMed) data. RESULTS: A sample of 29 studies was selected in which the background identified was: reduction of myocardial perfusion and/or death of myocardial tissue; attributes: quality, location, time, duration and irradiation; and consequent: report of pain, dyspnea, high heart rate, nausea, vomiting, high blood pressure, high respiratory rate, sleep disturbance, diaphoresis, fatigue, paleness, weakness, anxiety and fear. CONCLUSION: The findings have clarified the attributes of the concept sharp pain in myocardial infarction. PMID- 26486907 TI - [Theory of unpleasant symptoms: support for the management of symptoms in children and adolescents with cancer]. AB - OBJECTIVE: To present an overview of the clusters of neuropsychological symptoms in children and adolescents with cancer from the perspective of the Theory of Unpleasant Symptoms. METHODS: A theoretical and reflective study based on international literature and the critical analysis of the authors. RESULTS: In scientific literature, there is scarcity of international studies and an absence of studies in Brazil regarding the neuropsychological symptom clusters in children and adolescents with cancer. The theory of unpleasant symptoms is consistent because it emphasizes the complexity and interaction of the symptoms, the interrelationship between symptoms, the factors that influence symptoms, and the results and consequences of symptoms, thus supporting the planning of nursing interventions in paediatric oncology. CONCLUSION: It is essential to update knowledge on this subject and discuss the theories that support research and the clinical practice of symptom management in order to better qualify nursing care. PMID- 26486908 TI - [Knowledge translation: translating research into policy and practice]. AB - OBJECTIVE: This paper provides a theoretical-reflective study of knowledge translation concepts and their implementation processes for using research evidence in policy and practice. RESULTS: The process of translating research into practice is iterative and dynamic, with fluid boundaries between knowledge creation and action development. Knowledge translation focuses on co-creating knowledge with stakeholders and sharing that knowledge to ensure uptake of relevant research to facilitate informed decisions and changes in policy, practice, and health services delivery. In Brazil, many challenges exist in implementing knowledge translation: lack of awareness, lack of partnerships between researchers and knowledge-users, and low research budgets. CONCLUSIONS: An emphasis on knowledge translation has the potential to positively impact health outcomes. Future research in Brazil is needed to study approaches to improve the uptake of research results in the Brazilian context. PMID- 26486909 TI - Editorial. International Inaugural Address. PMID- 26486911 TI - Fine mapping of a calving QTL on Bos taurus autosome 18 in Holstein cattle. AB - Decreased calving performance not only directly impacts the economic efficiency of dairy cattle farming but also influences public concern for animal welfare. Previous studies have revealed a QTL on Bos taurus autosome (BTA) 18 that has a large effect on calving traits in Holstein cattle. In this study, fine mapping of this QTL was performed using imputed high-density SNP chip (HD) genotypes followed by imputed next-generation sequencing (NGS) variants. BTA18 was scanned for seven direct calving traits in 6113 bulls with imputed HD genotypes. SNP rs136283363 (BTA18: 57 548 213) was consistently the most significantly associated SNP across all seven traits [e.g. p-value = 2.04 * 10(-59) for birth index (BI)]. To finely map the QTL region and to explore pleiotropic effects, we studied NGS variants within the targeted region (BTA18: 57 321 450-57 625 355) for associations with direct calving traits and with three conformation traits. Significant variants were prioritized, and their biological relevance to the traits was interpreted. Considering their functional relationships with direct calving traits, SIGLEC12, CD33 and CEACAM18 were proposed as candidate genes. In addition, pleiotropic effects of this QTL region on direct calving traits and conformation traits were observed. However, the extent of linkage disequilibrium combined with the lack of complete annotation and potential errors in the Bos taurus genome assembly hampered our efforts to pinpoint the causal mutation. PMID- 26486912 TI - Carbon Footprints for Food of Animal Origin: What are the Most Preferable Criteria to Measure Animal Yields? AB - There are increasing efforts to determine the origin of greenhouse gas emissions caused by human activities (including food consumption) and to identify, apply and exploit reduction potentials. Low emissions are generally the result of increased efficiency in resource utilization. Considering climate related factors, the emissions of carbon dioxide, methane and laughing gas are summarized to so-called carbon footprints (CF). The CF for food of animal origin such as milk, eggs, meat and fish depend on a number of influencing factors such as animal species, type of production, feeding of animals, animal performance, system boundaries and outputs of production. Milk and egg yields are more clearly defined animal yields or outcomes of production than food from the carcasses of animals. Possible endpoints of growing/slaughter animals are body weight gain, carcass weight gain (warm or cold), meat, edible fractions or edible protein. The production of edible protein of animal origin may be considered as one of the main objectives of animal husbandry in many countries. On the other hand, the efficiency of various lines of production and the CF per product can also be easily compared on the basis of edible protein. The pros and contras of various outputs of animal production under special consideration of edible protein are discussed in the paper. PMID- 26486913 TI - Is the Grass Always Greener? Comparing the Environmental Impact of Conventional, Natural and Grass-Fed Beef Production Systems. AB - This study compared the environmental impact of conventional, natural and grass fed beef production systems. A deterministic model based on the metabolism and nutrient requirements of the beef population was used to quantify resource inputs and waste outputs per 1.0 * 108 kg of hot carcass weight beef in conventional (CON), natural (NAT) and grass-fed (GFD) production systems. Production systems were modeled using characteristic management practices, population dynamics and production data from U.S. beef production systems. Increased productivity (slaughter weight and growth rate) in the CON system reduced the cattle population size required to produce 1.0 * 108 kg of beef compared to the NAT or GFD system. The CON system required 56.3% of the animals, 24.8% of the water, 55.3% of the land and 71.4% of the fossil fuel energy required to produce 1.0 * 108 kg of beef compared to the GFD system. The carbon footprint per 1.0 * 108 kg of beef was lowest in the CON system (15,989 * 103 t), intermediate in the NAT system (18,772 * 103 t) and highest in the GFD system (26,785 * 103 t). The challenge to the U.S beef industry is to communicate differences in system environmental impacts to facilitate informed dietary choice. PMID- 26486914 TI - Why Did You Choose This Pet?: Adopters and Pet Selection Preferences in Five Animal Shelters in the United States. AB - Responses from an adopter survey (n = 1,491) determined reasons for pet selection, type of information received by the adopter, and the context in which the animal's behavior was observed. Appearance of the animal, social behavior with adopter, and personality were the top reasons for adoption across species and age groups. Most adopters stated that information about the animal from a staff member or volunteer was more important than information on cage cards, and health and behavior information was particularly important. Adopters found greater importance in interacting with the animal rather than viewing it in its kennel. The results of this study can be used by shelters to create better adoption matches, prioritize shelter resources and staff training, and potentially increase adoptions. Additionally, some simple training techniques are suggested to facilitate adopter-friendly behaviors from sheltered dogs and cats. PMID- 26486915 TI - Methods for Measuring and Estimating Methane Emission from Ruminants. AB - This paper is a brief introduction to the different methods used to quantify the enteric methane emission from ruminants. A thorough knowledge of the advantages and disadvantages of these methods is very important in order to plan experiments, understand and interpret experimental results, and compare them with other studies. The aim of the paper is to describe the principles, advantages and disadvantages of different methods used to quantify the enteric methane emission from ruminants. The best-known methods: Chambers/respiration chambers, SF6 technique and in vitro gas production technique and the newer CO2 methods are described. Model estimations, which are used to calculate national budget and single cow enteric emission from intake and diet composition, are also discussed. Other methods under development such as the micrometeorological technique, combined feeder and CH4 analyzer and proxy methods are briefly mentioned. Methods of choice for estimating enteric methane emission depend on aim, equipment, knowledge, time and money available, but interpretation of results obtained with a given method can be improved if knowledge about the disadvantages and advantages are used in the planning of experiments. PMID- 26486916 TI - Supplementation of Ascorbic Acid in Weanling Horses Following Prolonged Transportation. AB - Though horses synthesize ascorbic acid in their liver in amounts that meet their needs under normal circumstances, prolonged stress results in low plasma concentrations due to enhanced utilization and renal excretion and can reduce immune function. It was hypothesized that plasma ascorbic acid could be maintained in weanling horses by oral supplementation following prolonged transportation. Weanlings were supplemented with no ascorbic acid (Tx 0: n = 4), 5 grams ascorbic acid twice daily for 5 days (Tx 1: n = 4) or for 10 days (Tx 2: n = 4) following >50 hours of transportation. Supplementation caused slight (P < 0.2) increases in plasma ascorbic acid concentrations. Both supplemented groups had decreased (P < 0.05) plasma concentrations for 1 to 3 weeks following cessation of supplementation, possibly due to increased renal excretion or suppressed hepatic synthesis. Supplementation of ascorbic acid following prolonged stress will increase plasma concentrations, but prolonged supplementation should be avoided. PMID- 26486917 TI - Greenhouse Gas Emissions from Calf- and Yearling-Fed Beef Production Systems, With and Without the Use of Growth Promotants. AB - A spring calving herd consisting of about 350 beef cows, 14-16 breeding bulls, 60 replacement heifers and 112 steers were used to compare the whole-farm GHG emissions among calf-fed vs. yearling-fed production systems with and without growth implants. Carbon footprint ranged from 11.63 to 13.22 kg CO2e per kg live weight (19.87-22.52 kg CO2e per kg carcass weight). Enteric CH4 was the largest source of GHG emissions (53-54%), followed by manure N2O (20-22%), cropping N2O (11%), energy use CO2 (9-9.5%), and manure CH4 (4-6%). Beef cow accounted for 77% and 58% of the GHG emissions in the calf-fed and yearling-fed. Feeders accounted for the second highest GHG emissions (15% calf-fed; 35-36% yearling-fed). Implants reduced the carbon footprint by 4.9-5.1% compared with hormone-free. Calf-fed reduced the carbon footprint by 6.3-7.5% compared with yearling-fed. When expressed as kg CO2e per kg carcass weight per year the carbon footprint of calf-fed production was 73.9-76.1% lower than yearling-fed production, and calf fed implanted was 85% lower than hormone-free yearling-fed. Reducing GHG emissions from beef production may be accomplished by improving the feed efficiency of the cow herd, decreasing the days on low quality feeds, and reducing the age at harvest of youthful cattle. PMID- 26486918 TI - Nutritional Influences on Skatole Formation and Skatole Metabolism in the Pig. AB - Skatole is a tryptophan (TRP) metabolite with fecal odor. Together with the testicular steroid androstenone it is regarded as a main determinant of boar taint, even if elevated concentrations of skatole occur occasionally in gilts and barrows. Skatole concentrations in adipose tissue result from a complex process, which includes the availability of TRP and the presence of specialized bacteria in the gut in need of TRP for energy production, as well as absorption, transport and accumulation of skatole in adipose tissue. Several steps of this process are influenced by diet and specific feed compounds. In the present paper the current knowledge about physiological mechanisms of skatole dynamics is summarized. Additionally mechanisms are discussed, by which effective feeding strategies and feed additives exert their influence in the prevention of high skatole concentrations in adipose pig tissue. It was concluded that the most effective measures are those which influence several steps of skatole formation. Despite the numerous studies carried out in the field of skatole physiology, interesting aspects still need clarification, such as the effect of adipose tissue turnover. Reliable control of skatole accretion in fat of boars is one of the main prerequisites for pork production with entire males. PMID- 26486920 TI - Mannan Oligosaccharides in Nursery Pig Nutrition and Their Potential Mode of Action. AB - Mannan oligosaccharides (MOSs) are often referred to as one of the potential alternatives for antimicrobial growth promoters. The aim of the paper is to provide a review of mannan oligosaccharide products in relation to their growth promoting effect and mode of action based on the latest publications. We discuss the dietary impact of MOSs on (1) microbial changes, (2) morphological changes of gut tissue and digestibility of nutrients, and (3) immune response of pigs after weaning. Dietary MOSs maintain the intestinal integrity and the digestive and absorptive function of the gut in the post-weaning period. Recent results suggest that MOS enhances the disease resistance in swine by promoting antigen presentation facilitating thereby the shift from an innate to an adaptive immune response. Accordingly, dietary MOS supplementation has a potential growth promoting effect in pigs kept in a poor hygienic environment, while the positive effect of MOS is not observed in healthy pig herds with high hygienic standards that are able to maintain a high growth rate after weaning. PMID- 26486921 TI - Extending the Collection Duration of Breath Samples for Enteric Methane Emission Estimation Using the SF6 Tracer Technique. AB - The daily sample collection protocol of the sulphur hexafluoride (SF6) tracer technique for the estimation of methane (CH4) emissions from ruminants may not be practical under extensive grazing systems. Here, under controlled conditions, we evaluated extended periods of sampling as an alternative to daily sample collections. Eight rumen-fistulated cows were housed and fed lucerne silage to achieve common daily feed intakes of 6.4 kg dry matter per cow. Following SF6 permeation tube dosing, eight sampling lines were fitted to the breath collection harness, so that a common gas mix was available to each line. Half of the lines collected samples into PVC yokes using a modified capillary system as commonly used in New Zealand (NZL), and half collected samples into stainless steel cylinders using a ball-bearing flow restrictor as used in Argentina (ARG), all within a 10-day time frame, either daily, across two consecutive 5-day periods or across one 10-day period (in duplicate). The NZL system had greater sampling success (97.3 vs. 79.5%) and yielded more consistent CH4 emission estimates than the ARG system. Emission estimates from NZL daily, NZL 5-day and NZL 10-day samplings were 114, 110 and 111 g d(-1), respectively. Extended sample collection protocol may be feasible, but definitive evaluation of this alternative as well as sample collection systems is required under grazing situations before a decision on recommendation can be made. PMID- 26486919 TI - A Potential Role for Pro-Inflammatory Cytokines in the Development of Insulin Resistance in Horses. AB - Understanding the mechanisms involved in the development of insulin resistance in horses should enable development of effective treatment and prevention strategies. Current knowledge of these mechanisms is based upon research in obese humans and rodents, in which there is evidence that the increased production of pro-inflammatory cytokines by adipose tissue negatively influences insulin signaling in insulin-responsive tissues. In horses, plasma concentrations of the cytokine, tumor necrosis factor-alpha, have been positively correlated with body fatness and insulin resistance, leading to the hypothesis that inflammation may reduce insulin sensitivity in horses. However, little evidence has documented a tissue site of production and a direct link between inflammation and induction of insulin resistance has not been established. Several mechanisms are reviewed in this article, including the potential for macrophage infiltration, hyperinsulinemia, hypoxia, and lipopolysaccharide to increase pro-inflammatory cytokine production by adipose tissue of obese horses. Clearly defining the role of cytokines in reduced insulin sensitivity of horses will be a very important step in determining how obesity and insulin resistance are related. PMID- 26486922 TI - Methane Emission and Milk Production of Dairy Cows Grazing Pastures Rich in Legumes or Rich in Grasses in Uruguay. AB - Understanding the impact of changing pasture composition on reducing emissions of GHGs in dairy grazing systems is an important issue to mitigate climate change. The aim of this study was to estimate daily CH4 emissions of dairy cows grazing two mixed pastures with contrasting composition of grasses and legumes: L pasture with 60% legumes on Dry Matter (DM) basis and G pasture with 75% grasses on DM basis. Milk production and CH4 emissions were compared over two periods of two weeks during spring using eight lactating Holstein cows in a 2 * 2 Latin square design. Herbage organic matter intake (HOMI) was estimated by chromic oxide dilution and herbage organic matter digestibility (OMD) was estimated by faecal index. Methane emission was estimated by using the sulfur hexafluoride (SF6) tracer technique adapted to collect breath samples over 5-day periods. OMD (0.71) and HOMI (15.7 kg OM) were not affected by pasture composition. Milk production (20.3 kg/d), milk fat yield (742 g/d) and milk protein yield (667 g/d) were similar for both pastures. This may be explained by the high herbage allowance (30 kg DM above 5 cm/cow) which allowed the cows to graze selectively, in particular in grass sward. Similarly, methane emission expressed as absolute value (368 g/d or 516 L/d) or expressed as methane yield (6.6% of Gross Energy Intake (GEI)) was not affected by treatments. In conclusion, at high herbage allowance, the quality of the diet selected by grazing cows did not differ between pastures rich in legumes or rich in grasses, and therefore there was no effect on milk or methane production. PMID- 26486923 TI - Frequency of Lost Dogs and Cats in the United States and the Methods Used to Locate Them. AB - A cross-sectional national random digit dial telephone interview was conducted between September and November 2010. There were 1,015 households that had owned a dog or cat within the past five years. Of these 817 households owned dogs and 506 owned cats. Fourteen percent of dogs (95% Confidence Interval (CI): 11-16%) and 15% (95% CI: 12-18%) of cats were lost in the past five years. No owner demographic variables were associated with losing a pet. Ninety three percent (95% CI: 86-97%) of dogs and 75% (95% CI: 64-85%) of cats were recovered. For dogs, searching the neighborhood and returning on their own were the most common methods of finding the dog; 14% were found through an identification tag. For cats, returning on their own was most common. Dogs were more likely than cats to be lost more than once. Cats were less likely than dogs to have any type of identification. Knowledge of the successful methods of finding dogs and cats can provide invaluable help for owners of lost pets. Since 25% of lost cats were not found, other methods of reuniting cats and their owners are needed. Collars and ID tags or humane trapping could be valuable approaches. PMID- 26486924 TI - Elucidating Interactions between DMSO and Chelate-Based Ionic Liquids. AB - The C-D bond stretching vibrations of deuterated dimethyl sulfoxide ([D6 ]DMSO) and the C2 -H bond stretching vibrations of 1,1,1,5,5,5-hexafluoropentane-2,4 dione (hfac) ligand in anion are chosen as probes to elucidate the solvent-solute interaction between chelate-based ionic liquids (ILs) and DMSO by vibrational spectroscopic studies. The indirect effect from the interaction of the adjacent S=O functional group of DMSO with the cation [C10 mim](+) and anion [Mn(hfac)3 ]( ) of the ILs leads to the blue-shift of the C-D stretching vibrations of DMSO. The C2 -H bond stretching vibrations in hfac ligand is closely related to the ionic hydrogen bond strength between the cation and anion of chelate-based ILs. EPR studies reveal that the crystal field of the central metal is kept when the chelate-based ILs are in different microstructure environment in the solution. PMID- 26486925 TI - TNF-alpha antagonists and thalidomide for the management of gastrointestinal Behcet's syndrome refractory to the conventional treatment modalities: a case series and review of the literature. AB - OBJECTIVES: Gastrointestinal involvement of Behcet's syndrome is usually treated with glucocorticoids, 5-aminosalicylic acid compounds and azathioprine. However, some patients are refractory to these conventional therapy modalities. In this paper we report our experience on 13 patients with gastrointestinal involvement of Behcet's syndrome who were refractory to the conventional therapy and who were treated with TNF-alpha antagonists and/or thalidomide. METHODS: We reviewed the charts of our Behcet's syndrome patients with gastrointestinal involvement and identified those who were treated with TNF-alpha antagonists and/or thalidomide. Demographic features, previous and concomitant drugs, previous surgery, time to remission and duration of remission were tabulated. We also performed a systematic review of publications on gastrointestinal involvement of Behcet's syndrome patients treated with TNF-alpha antagonists and/or thalidomide. RESULTS: Among our 64 patients with gastrointestinal involvement of Behcet's syndrome, we identified 13 (20%) (7 women, 6 men, mean age 27.4+/-9.4) who had been treated with TNF-alpha antagonists and/or thalidomide. Their previous medications were glucocorticoids (13/13), azathioprine (13/13), 5-aminosalicylic acid derivatives (3/13) and budesonide (1/13). Clinical and endoscopic remission was obtained in 10 patients. One patient died with sepsis. The systematic literature search revealed 91 cases who had used TNF-alpha antagonists and 15 who had used thalidomide. Among the patients who had received TNF-alpha antagonists, clinical remission was obtained in 47/91 patients (51%), while endoscopic remission was observed in 21/46 (45%) who had a control colonoscopy. CONCLUSIONS: One fifth of our Behcet's syndrome patients with gastrointestinal involvement were refractory to conventional treatment modalities. Remission was obtained with TNF-alpha antagonists and/or thalidomide in about 75% of the cases. PMID- 26486926 TI - From bedside to bench--meeting report of the 7th International Conference on cGMP "cGMP: generators, effectors and therapeutic implications" in Trier, Germany, from June 19th to 21st 2015. AB - During the past decade, our knowledge on the physiology, pathophysiology, basic pharmacology, and clinical pharmacology of the second messenger (cGMP) has increased tremendously. It is now well-established that cGMP, generated by soluble and particulate guanylate cyclases, is highly compartmentalized in cells and regulates numerous body functions. New cGMP-regulated physiological functions include meiosis and temperature perception. cGMP is involved in the genesis of numerous pathologies including cardiovascular, pulmonary, endocrine, metabolic, neuropsychiatric, eye, and tumor diseases. Several new clinical uses of stimulators and activators of soluble guanylate cyclase and of phosphodiesterase inhibitors such as heart failure, kidney failure, cognitive disorders, obesity bronchial asthma, and osteoporosis are emerging. The combination of neprilysin inhibitors-enhancing stimulation of the particulate guanylate cyclase pathway by preventing natriuretic peptide degradation-with angiotensin AT1 receptor antagonists constitutes a novel promising strategy for heart failure treatment. The role of oxidative stress in cGMP signaling, application of cGMP sensors, and gene therapy for degenerative eye diseases are emerging topics. It is anticipated that cGMP research will further prosper over the next years and reach out into more and more basic and clinical disciplines. PMID- 26486927 TI - From Whole Gene Deletion to Point Mutations of EP300-Positive Rubinstein-Taybi Patients: New Insights into the Mutational Spectrum and Peculiar Clinical Hallmarks. AB - Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by growth deficiency, skeletal abnormalities, dysmorphic features, and intellectual disability. Causative mutations in CREBBP and EP300 genes have been identified in ~55% and ~8% of affected individuals. To date, only 28 EP300 alterations in 29 RSTS clinically described patients have been reported. EP300 analysis of 22 CREBBP-negative RSTS patients from our cohort led us to identify six novel mutations: a 376-kb deletion depleting EP300 gene; an exons 17-19 deletion (c.(3141+1_3142-1)_(3590+1_3591-1)del/p.(Ile1047Serfs*30)); two stop mutations, (c.3829A>T/p.(Lys1277*) and c.4585C>T/p.(Arg1529*)); a splicing mutation (c.1878-12A>G/p.(Ala627Glnfs*11)), and a duplication (c.4640dupA/p.(Asn1547Lysfs*3)). All EP300-mutated individuals show a mild RSTS phenotype and peculiar findings including maternal gestosis, skin manifestation, especially nevi or keloids, back malformations, and a behavior predisposing to anxiety. Furthermore, the patient carrying the complete EP300 deletion does not show a markedly severe clinical picture, even if a more composite phenotype was noticed. By characterizing six novel EP300-mutated patients, this study provides further insights into the EP300-specific clinical presentation and expands the mutational repertoire including the first case of a whole gene deletion. These new data will enhance EP300-mutated cases identification highlighting distinctive features and will improve the clinical practice allowing a better genotype phenotype correlation. PMID- 26486928 TI - Age But Not Sex Is Associated With Efficacy and Adverse Events Following Administration of Intravenous Migraine Medication: An Analysis of a Clinical Trial Database. AB - BACKGROUND: Migraine prevalence is associated with both sex and age. Differences in efficacy of parenteral migraine medication administration based on the sex and age of the patient have not been explored in the published literature. OBJECTIVE: The objective was to determine whether sex and age are associated with short-term headache relief, sustained headache freedom, or adverse medication effects in data collected during 3 emergency department (ED)-based acute migraine comparative efficacy trials. METHODS: Data were combined from 3 studies in which patients who presented to an ED with acute migraine were randomized to one of the following intravenous medication regimens: (1) metoclopramide combined with diphenhydramine; (2) metoclopramide combined with diphenhydramine and dexamethasone; (3) metoclopramide alone; (4) ketorolac; or (5) valproate. In each of these studies, (1) short-term efficacy (patient description of the headache as "mild" or "none" 1 hour after medication administration); (2) sustained efficacy (patient description of the headache as "none" within 2 hours of medication administration and no headache recurrence for 24 hours post ED discharge); and (3) the frequency of any adverse medication effects within 24 hours of medication administration was determined. For each of the medication regimens studied, efficacy and adverse event rates were compared between men vs women and the older vs the younger half of patients. Multivariate logistic regression models were constructed in which sex and age were maintained in the model as well as variables representing each of the medication regimens patients received. RESULTS: A total of 884 patients were included in this analysis (140 men and 744 women). The median age was 35 years. After controlling for age and medication received, female sex was not associated with short-term efficacy (OR 0.98 [95% confidence interval (CI): 0.66, 1.46]), sustained efficacy (OR 0.72 [95%CI: 0.45, 1.15]), or adverse events (OR 1.14 [95%CI: 0.77, 1.71]). Age >36 years, however, was associated with short-term efficacy (OR 0.66 [95%CI: 0.49, 0.88]), sustained efficacy (OR 0.50 [95%CI: 0.34, 0.73]), and adverse events (OR 1.36 [95%CI: 1.02, 1.82]). CONCLUSION: Sex was not associated with response to parenteral acute migraine medication. Age was associated with both efficacy and adverse events. PMID- 26486929 TI - Sodium channel blockers for neuroprotection in multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating disease of the central nervous system (CNS), which can occur in many parts of the CNS and result in a wide range of symptoms including sensory impairment, fatigue, walking or balance problems, visual impairment, vertigo and cognitive disabilities. At present, the most commonly used MS treatments are immunomodulating agents, but they have little effect on the disability. Experimental studies show that sodium (Na(+)) accumulation leads to intracellular calcium (Ca(2+)) release, and the increased calcium levels can activate nitric oxide synthase and harmful proteases and lipases. These factors contribute to axonal injury in people with MS. If partial blockade of voltage-gated sodium channels could result in neuroprotection, this would be of benefit for preventing disability progression in these people. Neuroprotection is emerging as a potentially important strategy for preventing disability progression in people with MS. OBJECTIVES: To assess the efficacy and safety of sodium channel blockers for neuroprotection in people with MS to prevent the occurrence of disability and alleviate the burden of the disease. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (27 August 2015) which, among other sources, contains references from the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue (8), MEDLINE (1966 to August 2015), EMBASE (1974 to August 2015), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1981 to August 2015), Latin American and Caribbean Health Science Information Database (LILACS) (1982 to August 2015), ClinicalTrials.gov (http://clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Portal (ICTRP) search portal (http://apps.who.int/trialsearch). In addition, we searched four Chinese databases, ongoing trials registers and relevant reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) that examined sodium channel blockers used alone or as an add-on to any approved treatments for MS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality and extracted the data. MAIN RESULTS: Only one study evaluating lamotrigine in secondary progressive MS was eligible. One hundred and twenty people were included, 61 randomly assigned to lamotrigine treatment and 59 to placebo treatment. The average age of participants in the two groups was 51.9 years and 50.1 years, respectively. The proportion of male participants was 27.5%. The period of follow-up was 2 years. No data were found on disability progression and people who experienced relapses. No significant differences were found for serious adverse events between the two groups. Treatment with lamotrigine was associated with more rashes (20% vs 5%, P value 0.03) and transient, dose-related deterioration of mobility (66% vs 34%, P value 0.001) than placebo. Furthermore, no significant difference between the two groups was found in the magnetic resonance imaging (MRI) measurements of cerebral atrophy, Expanded Disability Status Score changes, Multiple Sclerosis Functional Composite score changes. This study was judged to be at high risk of bias. This review will be updated when the three ongoing studies we identified are completed. AUTHORS' CONCLUSIONS: The quality of evidence was judged to be very low due to the low number of available studies and included participants. There is a lack of evidence to address the review question on the efficacy of sodium channel blockers for people with MS. Assessment of the three ongoing trials might change this conclusion. Further high-quality large scale studies are needed. PMID- 26486930 TI - Expectant Management of Low-Risk Bladder Cancer. AB - Patients with one or more low-grade bladder tumors of the urinary bladder will often develop a subsequent tumor but these so called "recurrences" are almost always of similar grade and rarely invade beyond the basement membrane. Therefore, the clinician should try to minimize the morbidity associated with treating these new tumors. Since many of these patients are elderly or have comorbidities, active surveillance is a very reasonable initial approach if these tumors are very small and appear low-grade. Another alternative is fulguration in the outpatient setting using a flexible cystoscope and electrode. The goal is to try to avoid the hospital and performing a formal transurethral resection. This adds potential morbidity, inconvenience, and cost. PMID- 26486931 TI - Tunnelling anisotropic magnetoresistance due to antiferromagnetic CoO tunnel barriers. AB - A new approach in spintronics is based on spin-polarized charge transport phenomena governed by antiferromagnetic (AFM) materials. Recent studies have demonstrated the feasibility of this approach for AFM metals and semiconductors. We report tunneling anisotropic magnetoresistance (TAMR) due to the rotation of antiferromagnetic moments of an insulating CoO layer, incorporated into a tunnel junction consisting of sapphire(substrate)/fcc-Co/CoO/AlOx/Al. The ferromagnetic Co layer is exchange coupled to the AFM CoO layer and drives rotation of the AFM moments in an external magnetic field. The results may help pave the way towards the development of spintronic devices based on AFM insulators. PMID- 26486932 TI - Role of the discriminative properties of the reinforcer in resurgence. AB - In three experiments with rat subjects, we examined the effects of the discriminative effects of reinforcers that were presented during or after operant extinction. Experiments 1 and 2 examined resurgence, in which an extinguished operant response (R1) recovers when a second behavior (R2) that has been reinforced to replace it is also placed in extinction. The results of Experiment 1 suggest that the amount of R1's resurgence is a decreasing linear function of the interreinforcement interval used during the reinforcement of R2. In Experiment 2, R1 was reinforced with one outcome (O1), and R2 was then reinforced with a second outcome (O2) while R1 was extinguished. In resurgence tests, response-independent (noncontingent) presentations of O2 prevented resurgence of R1, which otherwise occurred when testing was conducted with either no reinforcers or noncontingent presentations of O1. In Experiment 3, we then examined the effects of noncontingent O1 and O2 presentations after simple extinction in either the presence or the absence of noncontingent presentations of O2. Overall, the results are consistent with a role for the discriminative properties of the reinforcer in controlling operant behavior. In resurgence, the reinforcer used during response elimination provides a distinct context that controls the inhibition of R1. The results are less consistent with an alternative view emphasizing the disrupting effects of alternative reinforcement. PMID- 26486933 TI - Central amygdala lesions inhibit pontine nuclei acoustic reactivity and retard delay eyeblink conditioning acquisition in adult rats. AB - In delay eyeblink conditioning (EBC) a neutral conditioned stimulus (CS; tone) is repeatedly paired with a mildly aversive unconditioned stimulus (US; periorbital electrical shock). Over training, subjects learn to produce an anticipatory eyeblink conditioned response (CR) during the CS, prior to US onset. While cerebellar synaptic plasticity is necessary for successful EBC, the amygdala is proposed to enhance eyeblink CR acquisition. In the current study, adult Long Evans rats received bilateral sham or neurotoxic lesions of the central nucleus of the amygdala (CEA) followed by 1 or 4 EBC sessions. Fear-evoked freezing behavior, CS-mediated enhancement of the unconditioned response (UR), and eyeblink CR acquisition were all impaired in the CEA lesion rats relative to sham controls. There were also significantly fewer c-Fos immunoreactive cells in the pontine nuclei (PN)-major relays of acoustic information to the cerebellum following the first and fourth EBC session in lesion rats. In sham rats, freezing behavior decreased from session 1 to 4, commensurate with nucleus-specific reductions in amygdala Fos+ cell counts. Results suggest delay EBC proceeds through three stages: in stage one the amygdala rapidly excites diffuse fear responses and PN acoustic reactivity, facilitating cerebellar synaptic plasticity and the development of eyeblink CRs in stage two, leading, in stage three, to a diminution or stabilization of conditioned fear responding. PMID- 26486934 TI - Reciprocal altruism in rats: Why does it occur? AB - The finding of reciprocal altruism in rats does not explain how such behavior came to be. Attributing it to a genetic predisposition or basic learning processes may not be what the authors had in mind, but the alternative, cultural learning, seems even less plausible for rats and perhaps is not even the primary basis for reciprocal altruism in humans. PMID- 26486935 TI - Impaired Social Decision-Making Mediates the Association Between ADHD and Social Problems. AB - Attention-deficit/hyperactivity disorder (ADHD) reliably predicts social dysfunction, ranging from poor social competence and elevated peer rejection to inadequate social skills. Yet, the factors mediating predictions of social problems from childhood ADHD are not well understood. In the present study, we investigated social functioning in 186 (69 % male) 6 to 10 year-old (M = 7.88, SD = 1.17) children with (n = 98) and without (n = 87) ADHD who were followed prospectively for two years. We implemented a well-validated measure of social problems as well as a novel social decision-making task assessing dynamic response to changing affective cues at the two-year follow-up. According to separate parent and teacher report, baseline ADHD symptoms positively predicted social problems at the two-year follow-up; individual differences on the social decision-making task mediated this association. This finding was replicated when ADHD dimensions (i.e., inattention and hyperactivity/impulsivity) were separately examined. These findings suggest that the deficient use of affective cues to effectively guide behavior may partially underlie poor social functioning among children with ADHD. If replicated, these preliminary findings suggest that social skills interventions that target interpretation of affective cues to aid in social decision-making behavior may improve social outcomes negatively affected by early ADHD symptoms. PMID- 26486937 TI - Assessment of liver fibrosis in chronic hepatitis B using acoustic structure quantification: quantitative morphological ultrasound. AB - OBJECTIVES: To prospectively investigate the usefulness of acoustic structure quantification (ASQ) for noninvasive assessment of liver fibrosis in patients with chronic hepatitis B (CHB). METHODS: Consecutive patients with CHB scheduled for liver biopsy or partial liver resection underwent standardized ASQ examinations. The ASQ parameter, named focal disturbance (FD) ratio, were compared with METAVIR scores. The analysis was based on receiver operating characteristic (ROC) curves and multiple regression analysis. RESULTS: A total of 114 patients were enrolled in the final analysis. The area under the ROC curve for the FD ratio was 0.84 for significant fibrosis (>= F2), 0.86 for severe fibrosis (>= F3), and 0.83 for cirrhosis (= F4). The optimal cutoff values for the FD ratio were 0.25, 0.30 and 0.50 for fibrosis stages >= F2, >= F3 and = F4, respectively. The prevalence of a difference of at least two stages between the FD ratio and the histological stage was 12.3 % (14 of 114). The fibrosis stage (P < 0.001), degree of steatosis (P < 0.001) were independent factors associated with the FD ratio. CONCLUSIONS: FD ratio should be an effective noninvasive imaging biomarker for the assessment of liver fibrosis in patients with CHB. KEY POINTS: * Focal disturbance (FD) ratio increased with the increasing histological fibrosis stages. * FD ratio showed promising diagnostic accuracy in assessing liver fibrosis. * Degree of fibrosis and steatosis were independent factors associated with FD ratio. PMID- 26486936 TI - MRI evaluation of small (<4cm) solid renal masses: multivariate modeling improves diagnostic accuracy for angiomyolipoma without visible fat compared to univariate analysis. AB - OBJECTIVE: To assess MRI for diagnosis of angiomyolipoma without visible fat (AMLwvf). MATERIAL AND METHODS: With IRB approval, a retrospective study in consecutive patients with contrast-enhanced (CE)-MRI and <4 cm solid renal masses from 2002-2013 was performed. Ten AMLwvf were compared to 77 RCC; 33 clear cell (cc), 35 papillary (p), 9 chromophobe (ch). A blinded radiologist measured T2W signal-intensity ratio (SIR), chemical-shift (CS) SI-index and area under CE-MRI curve (CE-AUC). Regression modeling and ROC analysis was performed. RESULTS: T2W SIR was lower in AMLwvf (0.64 +/- 0.12) compared to cc-RCC (1.37 +/- 0.30, p < 0.001), ch-RCC (0.94 +/- 0.19, p = 0.005) but not p-RCC (0.74 +/- 0.17, p = 0.2). CS-SI index was higher in AMLwvf (16.1 +/- 31.5 %) compared to p-RCC (-5.2 +/- 26.1 %, p = 0.02) but not ch-RCC (3.0 +/- 12.5 %, p = 0.1) or cc-RCC (7.7 +/- 17.9 %,p = 0.1). CE-AUC was higher in AMLwvf (515.7 +/- 144.7) compared to p-RCC (154.5 +/- 92.8, p < 0.001) but not ch-RCC (341.5 +/- 202.7, p = 0.07) or cc-RCC (520.9 +/- 276.9, p = 0.95). Univariate ROC-AUC were: T2SIR = 0.86 (CI 0.77 0.96); CE-AUC = 0.76 (CI 0.65-0.87); CS-SI index = 0.66 (CI 0.4.3-0.85). Logistic regression models improved ROC-AUC, A) T2 SIR + CE-AUC = 0.97 (CI 0.93-1.0) and T2 SIR + CS-SI index = 0.92 (CI 0.84-0.99) compared to univariate analyses (p < 0.05). The optimal sensitivity/specificity of T2SIR + CE-AUC and T2SIR + CS-SI index were 100/88.8 % and 60/97.4 %. CONCLUSION: MRI, using multi-variate modelling, is accurate for diagnosis of AMLwvf. KEY POINTS: * AMLwvf are difficult to prospectively diagnose with imaging. * MRI findings associated with AMLwvf overlap with various RCC subtypes. * T2W-SI combined with chemical-shift SI-index is specific for AMLwvf but lacks sensitivity. * T2W-SI combined with AUC CE-MRI is sensitive and specific for AMLwvf. * Models incorporating two or more findings are more accurate than univariate analysis. PMID- 26486939 TI - Non-degenerate n-type doping by hydrazine treatment in metal work function engineered WSe2 field-effect transistor. AB - We report a facile and highly effective n-doping method using hydrazine solution to realize enhanced electron conduction in a WSe2 field-effect transistor (FET) with three different metal contacts of varying work functions-namely, Ti, Co, and Pt. Before hydrazine treatment, the Ti- and Co-contacted WSe2 FETs show weak ambipolar behaviour with electron dominant transport, whereas in the Pt-contacted WSe2 FETs, the p-type unipolar behaviour was observed with the transport dominated by holes. In the hydrazine treatment, a p-type WSe2 FET (Pt contacted) was converted to n-type with enhanced electron conduction, whereas highly n-doped properties were achieved for both Ti- and Co-contacted WSe2 FETs with on-current increasing by three orders of magnitude for Ti. All n-doped WSe2 FETs exhibited enhanced hysteresis in their transfer characteristics, which opens up the possibility of developing memories using transition metal dichalcogenides. PMID- 26486938 TI - Comparison of the image qualities of filtered back-projection, adaptive statistical iterative reconstruction, and model-based iterative reconstruction for CT venography at 80 kVp. AB - PURPOSE: To evaluate the subjective and objective qualities of computed tomography (CT) venography images at 80 kVp using model-based iterative reconstruction (MBIR) and to compare these with those of filtered back projection (FBP) and adaptive statistical iterative reconstruction (ASIR) using the same CT data sets. MATERIALS AND METHODS: Forty-four patients (mean age: 56.1 +/- 18.1) who underwent 80 kVp CT venography (CTV) for the evaluation of deep vein thrombosis (DVT) during 4 months were enrolled in this retrospective study. The same raw data were reconstructed using FBP, ASIR, and MBIR. Objective and subjective image analysis were performed at the inferior vena cava (IVC), femoral vein, and popliteal vein. RESULTS: The mean CNR of MBIR was significantly greater than those of FBP and ASIR and images reconstructed using MBIR had significantly lower objective image noise (p < .001). Subjective image quality and confidence of detecting DVT by MBIR group were significantly greater than those of FBP and ASIR (p < .005), and MBIR had the lowest score for subjective image noise (p < .001). CONCLUSION: CTV at 80 kVp with MBIR was superior to FBP and ASIR regarding subjective and objective image qualities. KEY POINTS: * MBIR provides superior image quality compared with FBP and ASIR * CTV at 80kVp with MBIR improves diagnostic confidence in diagnosing DVT * CTV at 80kVp with MBIR presents better image quality with low radiation. PMID- 26486940 TI - How the cladoceran heterogonic life cycle evolved--insights from gamogenetic reproduction and direct development in Cyclestherida. AB - Here we document the early gamogenetic development of Cyclestherida, including a characterization of the nervous system. Resting eggs in Cyclestheria are protected by an ephippium, built by the major part of the carapace. The first stages of development are enclosed in an outer chorion and an inner vitelline membrane. After shedding of the chorion, the vitelline membrane inflates and later stages are free-floating within the vitelline membrane. Only the juveniles are released from the vitelline membrane. Developmental stages of the gamogenetic direct development and of the parthenogenetic pseudo-direct development are remarkably similar in Cyclestheria, both regarding external and nervous system development. Because of this high degree of correspondence, as well as the important differences to the anamorphic development in Spinicaudata, we suggest that the developmental stages from the gamogenetic life cycle evolved directly from the parthenogenetic life cycle. This implies that resting egg development in Cladoceromorpha does not correspond directly to the resting egg development in large branchiopods. This leads us to the conclusion that the entire heterogonous life cycle in Cladoceromorpha probably evolved anew. PMID- 26486941 TI - A Bayesian perspective on constructing a written assessment of probabilistic clinical reasoning in experienced clinicians. AB - RATIONALE: Decision-making performance assessments have proven problematic for assessing clinical reasoning. AIMS AND OBJECTIVES: A Bayesian approach to designing an advanced clinical reasoning assessment is well grounded in mathematical and cognitive theory and may offer significant psychometric advantages. Probabilistic logic plays an important role in medical problem solving, and performances on Bayesian-type tasks appear to be causally-related to the ability to make sound clinical decisions. METHODS: A validity argument is used to guide the design of an assessment of medical reasoning using clinical probabilities. RESULTS/CONCLUSIONS: The practical advantage of using a Bayesian approach to item design relates to the fact that probability theory provides a rationally optimal method for managing uncertain information and provides the criteria for objective correct answer scoring. Potential item formats are discussed. PMID- 26486942 TI - Clonorchis sinensis lysophospholipase inhibits TGF-beta1-induced expression of pro-fibrogenic genes through attenuating the activations of Smad3, JNK2, and ERK1/2 in hepatic stellate cell line LX-2. AB - Liver fibrosis is a wound healing response associated with chronic liver injury. Hepatic stellate cells (HSCs) activation is a key event in the development of liver fibrosis. Since helminths have the ability to live for decades in the host by establishing an adaptive relationship in the interplay with its hosts, we hypothesize that whether Clonochis sinensis LysophospholipaseA (CsLysoPLA), a component of excretory/secretory proteins, can attenuate the fibrogenic response by inhibiting activation of LX-2 cells, thereby balancing the pro-fibrotic and anti-fibrotic response during the Clonochis sinensis (C. sinensis) infection. In the present study, LX-2 cells were stimulated with CsLysoPLA in the presence of TGF-beta1, and the expressions of collagen type I (COL1A1), alpha-smooth muscle actin (alpha-SMA), and matrix metalloproteinase 2 (MMP2) were decreased. In addition, CsLysoPLA significantly inhibited the proliferation and migration of LX 2 cells stimulated by TGF-beta1. Pretreatment of LX-2 cells with CsLysoPLA attenuated the phosphorylation of Smad3 as well as JNK2 and ERK1/2 in response to the stimulation of TGF-beta1. For the first time, our results showed an anti fibrogenic effect of CsLysoPLA by attenuating the response of LX-2 cells to TGF beta1 through inhibiting the activations of Smad3, ERK1/2, and JNK2. PMID- 26486943 TI - Increased Gal-9 and Tim-3 expressions during liver damage in a murine malarial model. AB - Malaria has been one of the most devastating tropical parasite infectious diseases popular around the world. Severe malaria is characterized by multiple organ dysfunctions, especially liver damage. However, the mechanisms of malarial liver injury remain to be better clarified. In this study, Kunming mice inoculated intraperitoneally (i.p.) with 10(6) Plasmodium berghei ANKA (PbANKA) infected red blood cells (iRBCs) were investigated at days 5, 10, 15, and 20 post infection (p.i.) to elucidate the profiles of T-cell immunoglobulin and mucin domain-3 (Tim-3) and its ligand galecin-9 (Gal-9) in the development of liver injury. The histopathology of livers and spleens from PbANKA-infected mice were observed, the parasite burdens of the livers and spleens using quantitative real time PCR (qRT-PCR), Tim-3- and Gal-9-positive cells in the livers and spleens using immunohistochemical staining, and the mRNA levels of Tim-3, Gal-9, and cytokines in both the livers and spleens using qRT-PCR were examined. Our results showed that parasite burdens in the livers and spleens were significantly increased with time after PbANKA infection. Histological scores of both the liver and spleen tissues were significantly increased with time; the numbers of Tim-3- and Gal-9-positive cells were significantly increased in both the livers and spleens using immunohistochemical staining, and the mRNA levels of Tim-3 and Gal 9 in the livers and spleens were also significantly increased after infection. Our data suggests that the increase of Tim-3/Gal-9 expressions may play an important role in the liver damage during P. berghei infection. PMID- 26486946 TI - Transcranial Doppler signals during cerebral angiography and cardiac catheterization. AB - Cerebral angiography is associated with a 0.45-4% risk of neurological complications and a less than 1% risk of permanent neurological deficit. Recently, air embolism has been implicated as a major cause of these complications. Cardiac catheterization is associated with a neurological complication rate of less than 1%; the predominant mechanism appears to be embolic. We used transcranial Doppler ultrasonography to detect high-intensity signals suspected to be related to air emboli, a potential cause of neurological complications in patients undergoing coronary and carotid angiography. We prospectively examined a total of 42 consecutive patients with transcranial Doppler ultrasound. Twenty-one patients underwent cerebral angiography, and 21 patients underwent cardiac catheterization. In both groups of patients, high intensity bidirectional Doppler signals were recorded during different phases of angiography. High-intensity, longduration Doppler signals completely masking the background cardiac cycle signals were observed during machine-powered rapid injection of contrast medium with good correlation between the duration of Doppler signals and the duration of automated injection. In addition, high intensity signals of much shorter duration were also observed during manual injection of saline or contrast medium and during catheter manipulation. In our study, the high-intensity Doppler signals recorded were identical in all patients who underwent cerebral and coronary angiography. No spontaneous emboli were seen. None of our 42 patients developed any type of neurological symptoms during or after the procedure. These high-intensity signatures do not represent air embolism exclusively; rather, they are likely a combination of turbulence in the bloodstream created during rapid injection, air emboli, and, perhaps, echogenicity of the contrast medium. PMID- 26486944 TI - Detection of Dirofilaria repens microfilariae in a dog from Portugal. AB - Dirofilaria repens causes subcutaneous infection in dogs and cats, and is the main agent of human dirofilariosis in Europe. Detection of D. repens is described in a dog from Portugal, a finding that simultaneously represents the first presumable case of autochthonous infection with the parasite in any animal host species in the country. A mixed D. repens/Dirofilaria immitis infection (20:1 ratio) was found, with an overall density of 1267 microfilariae per millilitre of blood. Morphological features, including morphometry, and acid phosphatase histochemical staining confirmed identity of the two filarioids. Distribution of D. repens in Portugal should be further assessed at the population level both in vertebrate hosts and in vectors. Due to the zoonotic potential of the parasite, preventive measures such as the administration of microfilaricides and insect repellents should be put into practice to protect animals and public health. PMID- 26486947 TI - FV-ARG-506-GLN-Mutation-associated resistance to activated protein C in ischemic stroke. AB - A recently described coagulation disorder [FV-Arg-506-Gln-mutation-associated resistance to activated protein C (APC-resistance)] leads to a five- to tenfold increased risk for venous thromboembolism. The aim of the study was to determine if this disorder also predisposes to ischemic stroke. Ninety-nine consecutive patients with ischemic stroke of noncardiac origin were screened for APC resistance and tested for the FV-Arg-506-Gln mutation. The FV-Arg-506-Gln mutation was found in 5 of the 99 stroke patients and in 6% of a pool of blood donors. FV-Arg-506-Gln mutation is not a major cause of ischemic stroke. However, a minor predisposing effect cannot be excluded. Further studies with larger stroke populations and subpopulations are indicated to determine the exact impact of this condition on ischemic stroke. PMID- 26486948 TI - Effect of screening for syphilis on the management of patients with cerebrovascular disease. AB - Although meningovascular syphilis may result in cerebral ischemia, the effect of syphilis screening on the management of patients with ischemic stroke is unclear. This is due to the variability in syphilis incidence and prevalence, as well as the diverse manifestations that vary with stage of infection. We prospectively screened patients with cerebrovascular disease (CVD) for syphilis and analyzed seropositivity rates as well as assessed the impact of screening on patient management. There were relatively high rates of seropositivity in both CVD (12.5%, n = 104) and control (9.9%, n = 211) populations without a significant difference between groups. Overall, syphilis screening had little impact on the management of the patients with CVD. No cerebral event was attributed to meningovascular syphilis, and there was no identifiable group in which syphilis screening was more likely to result in treatment for meningovascular syphilis, although there were significantly (p < 0.001) higher rates of seropositivity in black patients than whites. The relatively high incidence of seropositivity in both groups is representative of local syphilis prevalence and suggests that screening is warranted in patients with neurological disease, but not necessarily as part of the evaluation for cerebral ischemia. PMID- 26486949 TI - An inquiry into the seasonal nature of cerebrovascular disease. AB - An overview of the stroke literature indicates that cerebrovascular accidents (C VA) occur more often during the winter months relative to any other time of the year. Part I of this review presents a retrospection of previous research attempting to link CVA occurrence with the seasons. Part II discusses circadian and circannual rhythms in relation to health and general physiology, and in particular the relation of serotoninergic systems to these rhythms. Part III presents a discussion of how seasonal CVAs may be interpreted in terms of the current knowledge concerning circannual and circadian rhythms. These underlying rhythms may help to better understand research dealing with stroke and stroke pathologies, as well as aid in the design of more realistic protocols. PMID- 26486950 TI - Anticardiolipin antibodies in a university hospital population. AB - We have retrospectively reviewed data on our university hospital patients who had had at least one anticardiolipin antibody (aCL) titer performed (n = 781) during a 32-month study period between January 1991 and September 1993. We were able to locate clinical data on 95% (741 of 781) of these patients. Women (W) predominated at 70% (513 of 741), with men (M) at 30% (228 of 741). Reasons for ordering this test included brain infarct (M, 16%; W, 9%), multiple brain infarcts (M, 5%; W, 5%), migraine (M, 5%; W, 19%), and excessive clotting tendencies (M, 19%; W, 10%). Overall, aCL positivity was found in 10% of patients (73 of 741), with second-titer-confirmed positivity at 82% (60 of 73), men positive at 8% (18 of 228), and women positive at 11% (55 of 513; M versus W NS). For men, brain infarct (16% of aCL-positive in M versus 5% in W, p = 0.02), and for women, multiple brain infarcts (32% versus 0%, p = 0.01), migraine (10% versus 0%, p = 0.01), and systemic lupus erythematosus (30% versus 14%, p = 0.07) were the evident men-versus-women differences. We further studied stroke risk factors, associated conditions, family history, and laboratory findings relative to both sexes. aCL positivity continues to present differently, based on sex, at our university hospital. PMID- 26486951 TI - "Top of the basilar artery" syndrome and thalamic aphasia: A case report. AB - Patients with midbrain infarction are usually comatose and have a poor prognosis. We report a case of "top of the basilar artery" syndrome in an 84-year-old right handed man with infarction of medial basal thalamus, superior colliculus, pretectal area, medial longitudinal fasciculus, oculomotor nucleus, and left occipital lobe documented by magnetic resonance imaging. The clinical manifestations included right homonymous hemianopsia, bilateral oculomotor palsy, spastic dysarthria, and thalamic aphasia, which correlated with radiological findings. The presentation is unusual because of the extent of involvement in a fairly alert patient with a "pseudo-coma" pattern due to bilateral ptosis and thalamic aphasia. PMID- 26486952 TI - Limb-shaking transient ischemic attacks: Two case reports with unusual pathogenesis. AB - Limb-shaking transient ischemic attacks are associated with transient regional cerebral hypoperfusion and severe carotid stenosis. We report two patients with unusual pathogenesis of limb-shaking attacks, one a 73-year-old woman with right sided limb-shaking attacks and normal carotid angiography (recently diagnosed with essential thrombocytosis, antiplatelet agents eliminated her attacks) and the other a 56-year-old woman with peptic ulcer disease and multiple episodes of left-sided limb-shaking. Severe anemia was found along with bilateral carotid stenoses >70%. Correction of her anemia abolished her limb-shaking episodes. The presumed pathogenesis of limb-shaking transient ischemic attacks is transient focal cerebral ischemia from severe occlusive disease. Our two patients demonstrate that the mechanisms of ischemia may include other factors that affect oxygen delivery such as anemia or platelet disorders. PMID- 26486953 TI - An unusual case of postpartum stroke. AB - Intracranial hemorrhage is a rare peripartum complication. We report a 28-year old woman, 24 h postpartum, with acute onset of aphasia, right lower facial paresis, and spastic right hemiplegia secondary to hemorrhage into a previously undiagnosed large left parasagittal meningioma. Prompt diagnosis and surgical intervention led to an excellent outcome. Intrameningiomal hemorrhage as a treatable cause of peripartum stroke is discussed. PMID- 26486954 TI - A case of intracerebral air embolism following acupuncture. AB - Recently, the reported causes of cerebral air embolism are more from invasive medical procedures than decompressive sickness. We report a patient with homolateral cerebral air embolism probably due to acupuncture to the anterior neck. A 64-year-old man was admitted with early seizure followed by unconsciousness and focal neurologic deficits. He had subcutaneous emphysema into the left anterior neck and chest wall. Several hours before admission, he underwent the acupuncture in the area of left anterior neck for the treatment of previous hemiplegia. Initial brain computed tomography (CT) showed multiple, small (2-8 mm in diameter) air bubbles in the corticomedullary junction area of the left cerebral hemisphere. He regained consciousness 2 days later. A delayed CT scan, taken 6 days after the event, showed no air bubbles in the cerebral hemisphere but massive cerebral edema. The patient's condition continued to improve during his hospital stay. He was discharged 3 weeks later with minimal neurologic deficits. Unilateral cerebral artery air embolism in this patient is thought to be caused by direct infiltration of air to the common carotid artery following acupuncture. PMID- 26486955 TI - A new form of management of stroke. AB - The effects of nimodipine administration intravenously and orally are compared in a double-blind study of 143 patients with stroke, who were admitted to the hospital within 6 h after the onset of symptoms. In both the infarct group and the hemorrhagic stroke group, there was significant improvement as evaluated by the Matthew Scale and Barthel Index, especially in the nimodipine infusion group. For the group receiving nimodipine orally, the results were less evident. The data suggest that nimodipine should be given as an infusion as early as possible. PMID- 26486956 TI - Cost of stroke in Mexico. AB - We report the estimated costs of stroke management in Mexico. The cost of stroke in our country has not been formerly described previously. The costs were estimated from population-based studies: the national survey on stroke and those performed by the Health Mexican Foundation. Other sources were the administration of private hospitals and official statistics obtained from the National Institute of Informatic, Statistic and Geography. Of 89 million Mexicans, 6.1% are older than 60 years. Based on the national stroke survey, it was calculated that 32,000 people suffer from stroke each year. Their mean age is 63 years. The estimated cost of acute stroke care in 1994 was $7,700 (U.S. dollars) per patient in private hospitals and $6,600 in institutions of the health sector. The major portion of the costs were spent in diagnostic procedures (40%). Physician costs ranged from 12% to 19%. The average in-hospital stay was 9 days with 18% in hospital mortality rate. About 20% of the total population are not covered by health care institutions. The cost of stroke care in Mexico is lower than in industrialized countries because of a shorter hospital stay and lower personnel wages. Indirect costs for chronic care are unknown in our country. The number of people older than 60 years will increase in the next century; hence, the number of persons with stroke will rise. PMID- 26486957 TI - The strange story of aspirin and the prevention of stroke. PMID- 26486959 TI - Graphene quantum dot sensitized leaf-like InVO4/BiVO4 nanostructure: a novel ternary heterostructured QD-RGO/InVO4/BiVO4 composite with enhanced visible-light photocatalytic activity. AB - Leaf-like InVO4/BiVO4 nanostructures with sizes of 2-5 MUm were synthesized by a simple hydrothermal method. Graphene quantum dots (QD-RGO) were then deposited onto the surfaces of the leaf-like InVO4/BiVO4 crystals through a facile deposition-precipitation technique. Under visible light irradiation (lambda > 420 nm), the QD-RGO/InVO4/BiVO4 photocatalyst degraded rhodamine B (Rh B) efficiently and displayed a much higher photocatalytic activity than pure BiVO4, InVO4, RGO/InVO4, RGO/BiVO4 or an InVO4/BiVO4 hybrid. The InVO4/BiVO4 photocatalyst with 3 wt% of QD-RGO exhibited the highest photocatalytic efficiency. The quenching effects of different scavengers demonstrated that O2(-) played a major role in Rh B degradation. It was elucidated that the excellent photocatalytic activity of QD RGO/InVO4/BiVO4 for the degradation of Rh B under visible light (lambda > 420 nm) can be ascribed to the extended absorption in the visible light region resulting from the QD-RGO loading, the high specific surface area, and the efficient separation of photogenerated electrons and holes through the QD-RGO/InVO4/BiVO4 heterostructure. PMID- 26486958 TI - Tristetraprolin regulation of interleukin-22 production. AB - Interleukin (IL)-22 is a STAT3-activating cytokine displaying characteristic AU rich elements (ARE) in the 3'-untranslated region (3'-UTR) of its mRNA. This architecture suggests gene regulation by modulation of mRNA stability. Since related cytokines undergo post-transcriptional regulation by ARE-binding tristetraprolin (TTP), the role of this destabilizing protein in IL-22 production was investigated. Herein, we demonstrate that TTP-deficient mice display augmented serum IL-22. Likewise, IL-22 mRNA was enhanced in TTP-deficient splenocytes and isolated primary T cells. A pivotal role for TTP is underscored by an extended IL-22 mRNA half-life detectable in TTP-deficient T cells. Luciferase-reporter assays performed in human Jurkat T cells proved the destabilizing potential of the human IL-22-3'-UTR. Furthermore, overexpression of TTP in HEK293 cells substantially decreased luciferase activity directed by the IL-22-3'-UTR. Transcript destabilization by TTP was nullified upon cellular activation by TPA/A23187, an effect dependent on MEK1/2 activity. Accordingly, IL 22 mRNA half-life as determined in TPA/A23187-stimulated Jurkat T cells decreased under the influence of the MEK1/2 inhibitor U0126. Altogether, data indicate that TTP directly controls IL-22 production, a process counteracted by MEK1/2. The TTP dependent regulatory pathway described herein likely contributes to the role of IL-22 in inflammation and cancer and may evolve as novel target for pharmacological IL-22 modulation. PMID- 26486960 TI - Free-Standing Bilayered Nanoparticle Superlattice Nanosheets with Asymmetric Ionic Transport Behaviors. AB - Natural cell membranes can directionally and selectively regulate the ion transport, which is critical for the functioning of living cells. Here, we report on the fabrication of an artificial membrane based on an asymmetric nanoparticle superlattice bilayered nanosheet, which exhibits similar ion transport characteristics. The superlattice nanosheets were fabricated via a drying mediated self-assembly of polystyrene-capped gold nanoparticles at the liquid-air interface. By adopting a layer-by-layer assembly process, an asymmetric nanomembrane could be obtained consisting of two nanosheets with different nanoparticle size. The resulting nanomembranes exhibit an asymmetric ion transport behavior, and diode-like current-voltage curves were observed. The asymmetric ion transport is attributed to the cone-like nanochannels formed within the membranes, upon which a simulation map was established to illustrate the relationship between the channel structure and the ionic selectivity, in consistency with our experimental results. Our superlattice nanosheet-based design presents a promising strategy for the fabrication of next-generation smart nanomembranes for rationally and selectively regulating the ion transport even at a large ion flux, with potential applications in a wide range of fields, including biosensor devices, energy conversion, biophotonics, and bioelectronics. PMID- 26486964 TI - Characteristics of prisoners with neurodevelopmental disorders and difficulties. AB - BACKGROUND: Previous studies have found high rates of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and intellectual disability (ID) within the criminal justice system (CJS). However, little is understood about prisoners with neurodevelopmental disorders and difficulties (NDD) or their needs. This study aimed to identify prisoners with NDD and compare their characteristics with prisoners without NDD on a range of socio-demographic and social functioning measures. METHOD: This was a descriptive, cross-sectional study carried out using face-to-face interviews with 240 participants in a London Category C prison. Standardised tools were used to assess prisoners for ADHD, ASD and ID. RESULTS: The study identified 87 prisoners who screened positive for one or more type of NDD. Participants with NDD were significantly younger and more likely to be single [(odds ratio) OR = 2.1], homeless (OR = 3.4) or unemployed (OR = 2.6) before they came into prison. They also had poorer educational achievements that those without NDD. Over 80% of those with NDD had a previous conviction or imprisonment. CONCLUSIONS: The findings confirm the presence of significant numbers of people with NDD in a male prison. Services across the CJS are required for this group; specifically, there is a need for raised awareness among those working in the CJS to improve the recognition of offenders with NDD. Services in the community need to work with individuals with NDD who are at risk of offending, targeting those who are homeless, unemployed and have poor employment opportunities. PMID- 26486965 TI - Epoxides Derived from Dietary Dihomo-Gamma-Linolenic Acid Induce Germ Cell Death in C. elegans. AB - Dietary fats are not created equally, slight differences in structure lead to crucial differences in function. Muticellular organisms use polyunsaturated fatty acid as substrates to produce potent signaling molecules crucial for many physiological processes, including reproduction. Here we explored the mechanism responsible for germ cell loss induced by dietary supplementation of dihomo-gamma linolenic acid (DGLA, 20:3n-6) in the roundworm Caenorhabditis elegans. In this study we found that C. elegans CYP-33E2 activity produces a range of epoxy and hydroxy metabolites from dietary DGLA. Knockdown of cyp-33E2 suppressed the DGLA induced sterility phenotype. Additionally, direct exposure of two specific DGLA derived epoxy products, 8,9- and 14,15-epoxyeicosadienoic acids, produced germ cell abnormalities in the C. elegans gonad. We propose that sterility is mediated by the production of toxic DGLA-derived epoxides that trigger germ cell destruction. These studies are the first to establish a biological activity for a CYP-produced metabolite of DGLA. PMID- 26486966 TI - Selective Area Band Engineering of Graphene using Cobalt-Mediated Oxidation. AB - This study reports a scalable and economical method to open a band gap in single layer graphene by deposition of cobalt metal on its surface using physical vapor deposition in high vacuum. At low cobalt thickness, clusters form at impurity sites on the graphene without etching or damaging the graphene. When exposed to oxygen at room temperature, oxygen functional groups form in proportion to the cobalt thickness that modify the graphene band structure. Cobalt/Graphene resulting from this treatment can support a band gap of 0.30 eV, while remaining largely undamaged to preserve its structural and electrical properties. A mechanism of cobalt-mediated band opening is proposed as a two-step process starting with charge transfer from metal to graphene, followed by formation of oxides where cobalt has been deposited. Contributions from the formation of both CoO and oxygen functional groups on graphene affect the electronic structure to open a band gap. This study demonstrates that cobalt-mediated oxidation is a viable method to introduce a band gap into graphene at room temperature that could be applicable in electronics applications. PMID- 26486967 TI - Lactobacillus insicii sp. nov., isolated from fermented raw meat. AB - The analysis of the bacterial microbiota of retain samples of pork salami revealed an isolate (strain TMW 1.2011T) that could neither be assigned to typical genera of starter organisms nor to any other known meat-associated species. Cells were Gram-stain-positive, short, straight rods occurring singly, in pairs or short chains. Phylogenetic analysis of the 16S rRNA gene sequence and specific phenotypic characteristics showed that strain TMW 1.2011T belonged to the phylogenetic Lactobacillus alimentarius group, and the closest neighbours were Lactobacillus nodensis JCM 14932T (97.8 % 16S rRNA gene sequence similarity), Lactobacillus tucceti DSM 20183T (97.4 %), 'Lactobacillus ginsenosidimutans' EMML 3041 (97.3 %), Lactobacillus versmoldensis DSM 14857T (96.9 %) and Lactobacillus furfuricola JCM 18764T (97.2 %). Similarities using partial gene sequences of the alternative chronometers pheS, dnaK and rpoA also support these relationships. DNA-DNA relatedness between the novel isolate and L. nodensis JCM 14932T, L. versmoldensis DSM 14857T and L. tucceti DSM 20183T, L. furfuricola JCM 18764T and 'L. ginsenosidimutans' EMML 3041 were below 70 % and the DNA G+C content was 36.3 mol%. The cell-wall peptidoglycan type is l-Lys-Gly d-Asp. Based on phylogenetic, chemotaxonomic and physiological evidence, strain TMW 1.2011T represents a novel species of the genus Lactobacillus, for which the name Lactobacillus insicii sp. nov. is proposed. The type strain is TMW 1.2011T ( = CECT 8802T = DSM 29801T). PMID- 26486968 TI - Repeat transurethral resection for non-muscle-invasive bladder cancer: a contemporary series. AB - OBJECTIVES: To evaluate the depth of transurethral resections of bladder tumour (TURBT), residual cancer rates and up-staging rates in a contemporary Australian series. MATERIALS AND METHODS: Specimen reports from a single, major reporting pathology centre, servicing a group of urological oncologists in Sydney were obtained for TURBTs performed between October 2008 and February 2013. We examined the depth of TURBT, rates of repeat-TURBT (re-TUR) and residual cancer rates at the 3-6 month check cystoscopy. RESULTS: One thousand and two hundred and nine transurethral resection specimens retrieved during this period were analysed. There were 162 (13.4%) T1 specimens and 631 (52.2%) Ta specimens, 218 (34.5%) of which were high grade. Muscularis propria was present in 506 (41.9%) specimens in total and in 151 (39.7%) of 380 high-risk specimens (high grade Ta, T1). Of the 380 high-risk non-muscle-invasive tumours, 85 (22.4%) proceeded to re-TUR. Of the 48 T1 specimens and 37 Ta high grade specimens that proceeded to re-TUR, 7 (14.6%) and 1 (2.7%) respectively were upstaged to muscle-invasive disease. Rates of residual disease/early recurrence at 3-6 months was significantly better for those with re-TUR compared to those without 56.8% vs 82.5% (P < 0.001) for Ta high grade and 39.6% vs 84% (P = 0.028) for T1 tumours respectively. CONCLUSION: Re-TUR rates in high-risk non-muscle-invasive bladder cancer are low. However in a contemporary series, the upstaging rates are low, but residual cancer rates high, supporting the need for re-TUR in this population. PMID- 26486969 TI - Importance of Time Scale and Local Environment in Electron-Driven Proton Transfer. The Anion of Acetoacetic Acid. AB - Anion photoelectron spectroscopy (PES) and electron energy-loss spectroscopy (EELS) probe different regions of the anionic potential energy surface. These complementary techniques provided information about anionic states of acetoacetic acid (AA). Electronic structure calculations facilitated the identification of the most stable tautomers and conformers for both neutral and anionic AA and determined their relative stabilities and excess electron binding energies. The most stable conformers of the neutral keto and enol tautomers differ by less than 1 kcal/mol in terms of electronic energies corrected for zero-point vibrations. Thermal effects favor these conformers of the keto tautomer, which do not support an intramolecular hydrogen bond between the keto and the carboxylic groups. The valence anion displays a distinct minimum which results from proton transfer from the carboxylic to the keto group; thus, we name it an ol structure. The minimum is characterized by a short intramolecular hydrogen bond, a significant electron vertical detachment energy of 2.38 eV, but a modest adiabatic electron affinity of 0.33 eV. The valence anion was identified in the anion PES experiments, and the measured electron vertical detachment energy of 2.30 eV is in good agreement with our computational prediction. We conclude that binding an excess electron in a pi* valence orbital changes the localization of a proton in the fully relaxed structure of the AA(-) anion. The results of EELS experiments do not provide evidence for an ultrarapid proton transfer in the lowest pi* resonance of AA(-), which would be capable of competing with electron autodetachment. This observation is consistent with our computational results, indicating that major gas-phase conformers and tautomers of neutral AA do not support the intramolecular hydrogen bond that would facilitate ultrarapid proton transfer and formation of the ol valence anion. This is confirmed by our vibrational EELS spectrum. Anions formed by vertical electron attachment to dominant neutrals undergo electron autodetachment with or without vibrational excitations but are unable to relax to the ol structure on a time scale fast enough to compete with autodetachment. PMID- 26486971 TI - Disaster Management and General Dental Practitioners in India: An Overlooked Resource. AB - OBJECTIVE: To assess General Dental Practitioners' (GDPs) in India willingness to participate in disaster management and their previous training pertaining to disaster management, and to assess GDP objective knowledge, attitude, and behavior regarding disaster management. MATERIALS AND METHODS: This study was a cross-sectional survey conducted on all GDPs of Jodhpur, Rajasthan, India. Willingness to participate, perceived knowledge, perceived effectiveness, objective knowledge, attitude, and behavior regarding disaster management were assessed through questionnaire method. Information also was collected regarding age, gender, religion, and residence. RESULTS: A total of 142 out of 180 GDPs participated in the study, representing a response rate of 79%. A majority (85%) of respondents were willing to participate in disaster management. Mean score for knowledge was 12.21%, for attitude was 33.56%, for behavior was 14.50%, and for perceived effectiveness was 9.08%. Significant correlations were observed between qualification and perceived effectiveness (P=.003), and between attitude and years of practice (P=.04). Willingness to participate in disaster management and age showed significant association (P=.000). CONCLUSIONS: High willingness and attitude to participate in disaster management was observed among respondents. Low knowledge and behavior scores were observed among GDPs. PMID- 26486970 TI - An approach to the immunophenotypic features of circulating CD4+NKG2D+ T cells in invasive cervical carcinoma. AB - BACKGROUND: NKG2D, an activating immunoreceptor, is primarily restricted to NK cells and CD8(+) T cells. The existence of an atypical cytotoxic CD4(+)NKG2D(+) T cell population has also been found in patients with autoimmune dysfunctions. Nonetheless, contradictory evidence has categorized this population with a regulatory rather than cytotoxic role in other situations. These confounding data have led to the proposal that two distinct CD4(+)NKG2D(+) T cell subsets might exist. The immune response elicited in cervical cancer has been characterized by apparent contradictions concerning the role that T cells, in particular T-helper cells, might be playing in the control of the tumor growth. Interestingly, we recently reported a substantial increase in the frequency of CD4(+)NKG2D(+) T cells in patients with cervical intraepithelial neoplasia grade-1. However, whether this particular population is also found in patients with more advanced cervical lesions or whether they express a distinctive phenotype remains still to be clarified. In this urgent study, we focused our attention on the immunophenotypic characterization of CD4(+)NKG2D(+) T cells in patients with well established cervical carcinoma and revealed the existence of at least two separate CD4(+)NKG2D(+) T cell subsets defined by the co-expression or absence of CD28. RESULTS: Patients with diagnosis of invasive cervical carcinoma were enrolled in the study. A group of healthy individuals was also included. Multicolor flow cytometry was used for exploration of TCR alpha/beta, CD28, CD158b, CD45RO, HLA-DR, CD161, and CD107a. A Luminex-based cytokine kit was used to quantify the levels of pro- and anti-inflammatory cytokines. We found an increased percentage of CD4(+)NKG2D(+) T cells in patients with cervical cancer when compared with controls. Accordingly with an increase of CD4(+)NKG2D(+) T cells, we found decreased CD28 expression. The activating or degranulation markers HLA-DR, CD161, and CD107a were heterogeneously expressed. The levels of IL-1beta, IL-2, TNF-alpha, and IL-10 were negatively correlated with the percentages of CD4(+)NKG2D(+) T cells in patients with cervical carcinoma. CONCLUSIONS: Taken together, our results reveal the existence of two separate CD4(+)NKG2D(+) T cell subsets defined by the co-expression or absence of CD28, the latter more likely to be present in patients with cervical cancer. PMID- 26486972 TI - Risk stratification in acute myocardial infarction with multiparametric cardiac magnetic resonance imaging: getting to the core of the matter. PMID- 26486973 TI - Sources of heterogeneous variability and trends in Antarctic sea-ice. AB - While the Northern Hemisphere sea-ice has uniformly declined over the past several decades, the observed sea-ice in the Southern Hemisphere has exhibited regions of increase and decrease. Here we use a comprehensive set of ocean-sea ice simulations (1990-2007) to elucidate the drivers of the observed heterogeneous sea-ice trends. We show wind variability is an important determinant of the heterogeneous pattern of the variability and trends in Southern Hemisphere sea-ice. Only in the West Pacific region does Southern Annular Mode wind forcing contribute significantly to the trend in sea-ice duration. El Nino Southern Oscillation wind forcing contribution to the sea-ice duration trend is confined to the Atlantic and Pacific. In the Indian Ocean, weather is a significant driver of the sea-ice duration trend. Only in the East Pacific region is wind forcing alone insufficient to give rise to the observed sea-ice decline and must be augmented by warming to reproduce the observations. PMID- 26486975 TI - Molecular mechanism of substrate specificity for delta 6 desaturase from Mortierella alpina and Micromonas pusilla. AB - The omega6 and omega3 pathways are two major pathways in the biosynthesis of PUFAs. In both of these, delta 6 desaturase (FADS6) is a key bifunctional enzyme desaturating linoleic acid or alpha-linolenic acid. Microbial species have different propensity for accumulating omega6- or omega3-series PUFAs, which may be determined by the substrate preference of FADS6 enzyme. In the present study, we analyzed the molecular mechanism of FADS6 substrate specificity. FADS6 cDNAs were cloned from Mortierella alpina (ATCC 32222) and Micromonas pusilla (CCMP1545) that synthesized high levels of arachidonic acid and EPA, respectively. M. alpina FADS6 (MaFADS6-I) showed substrate preference for LA; whereas, M. pusilla FADS6 (MpFADS6) preferred ALA. To understand the structural basis of substrate specificity, MaFADS6-I and MpFADS6 sequences were divided into five sections and a domain swapping approach was used to examine the role of each section in substrate preference. Our results showed that sequences between the histidine boxes I and II played a pivotal role in substrate preference. Based on our domain swapping results, nine amino acid (aa) residues were targeted for further analysis by site-directed mutagenesis. G194L, E222S, M227K, and V399I/I400E substitutions interfered with substrate recognition, which suggests that the corresponding aa residues play an important role in this process. PMID- 26486974 TI - Statin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia. AB - The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride ( 41%), remnant cholesterol (-55%), and LDL-cholesterol (-39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D. PMID- 26486976 TI - Exploring strategies used following a group-based fatigue management programme for people with multiple sclerosis (FACETS) via the Fatigue Management Strategies Questionnaire (FMSQ). AB - OBJECTIVES: To explore cross-sectional patterns of use of fatigue management strategies in people with multiple sclerosis (MS) who had attended a group-based fatigue management programme, Fatigue: Applying Cognitive behavioural and Energy effectiveness Techniques to lifeStyle ('FACETS'). In a multicentre randomised controlled trial (RCT) the FACETS programme was shown to reduce fatigue severity and improve self-efficacy and quality of life. DESIGN: A questionnaire substudy within a RCT involving the self-completed Fatigue Management Strategies Questionnaire (FMSQ). The FMSQ includes: (1) closed questions about the use and helpfulness of fatigue management strategies taught in FACETS and (2) open items about changes to lifestyle, attitudes or expectations, barriers or difficulties encountered and helpful strategies not covered in FACETS. PARTICIPANTS: All had a clinical diagnosis of MS, significant fatigue, were ambulatory and had attended at least 4 of 6 scheduled FACETS sessions. METHODS: Participants (n=72) were posted the FMSQ with a prepaid return envelope 4 months after the end of the FACETS programme. RESULTS: 82% (59/72) of participants returned the FMSQ. The fatigue management strategies most frequently used since attending FACETS were prioritisation (80%), pacing (78%), saying no to others (78%), grading tasks (75%) and challenging unhelpful thoughts (71%). Adding in those participants who were already using the respective strategies prior to FACETS, the three most used strategies at 4 months were prioritisation (55/59), grading (54/59) and pacing (53/58). Free-text comments illustrated the complex interplay between attitudes/expectations, behaviours, emotions and the environment. Issues related to expectations featured strongly in participants' comments. Expectations (from self and others) were both facilitators and barriers to effective fatigue management. CONCLUSIONS: Individuals' comments highlighted the complex, multifaceted nature of fatigue management. Revising expectations and a greater acceptance of fatigue were important shifts following the programme. Findings support the relevance of a cognitive behavioural approach for fatigue management. Booster sessions might be a useful addition to the FACETS programme. TRIAL REGISTRATION NUMBER: Current controlled trials ISRCTN76517470; Results. PMID- 26486978 TI - What is 'healthy'? Establishing reference intervals in feline medicine. PMID- 26486977 TI - Diagnostic accuracy of the Edinburgh Postnatal Depression Scale (EPDS) for detecting major depression in pregnant and postnatal women: protocol for a systematic review and individual patient data meta-analyses. AB - INTRODUCTION: Studies of the diagnostic accuracy of depression screening tools often used data-driven methods to select optimal cut-offs. Typically, these studies report results from a small range of cut-off points around whatever cut off score is identified as most accurate. When published data are combined in meta-analyses, estimates of accuracy for different cut-off points may be based on data from different studies, rather than data from all studies for each cut-off point. Thus, traditional meta-analyses may exaggerate accuracy estimates. Individual patient data (IPD) meta-analyses synthesise data from all studies for each cut-off score to obtain accuracy estimates. The 10-item Edinburgh Postnatal Depression Scale (EPDS) is commonly recommended for depression screening in the perinatal period. The primary objective of this IPD meta-analysis is to determine the diagnostic accuracy of the EPDS to detect major depression among women during pregnancy and in the postpartum period across all potentially relevant cut-off scores, accounting for patient factors that may influence accuracy (age, pregnancy vs postpartum). METHODS AND ANALYSIS: Data sources will include Medline, Medline In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science. Studies that include a diagnosis of major depression based on a validated structured or semistructured clinical interview administered within 2 weeks of (before or after) the administration of the EPDS will be included. Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects meta-analysis will be conducted for the full range of plausible cut-off values. Analyses will evaluate data from pregnancy and the postpartum period separately, as well as combining data from all women in a single model. ETHICS AND DISSEMINATION: This study does not require ethics approval. Dissemination will include journal articles and presentations to policymakers, healthcare providers and researchers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2015:CRD42015024785. PMID- 26486979 TI - Efficacy of antiviral chemotherapy for retrovirus-infected cats: What does the current literature tell us? AB - GLOBAL IMPORTANCE: The two feline retroviruses, feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV), are global and widespread, but differ in their potential to cause disease. VIRAL INFECTION - FIV: FIV, a lentivirus that shares many properties with human immunodeficiency virus (HIV), can cause an acquired immune deficiency syndrome, which predisposes cats to other infections, stomatitis, neurological disorders and tumours. Although secondary infections are common, specific opportunistic infections or acquired immunodeficiency virus defining infections, such as those that occur with HIV, are not commonly reported in FIV-infected cats. In most naturally infected cats, FIV does not cause a severe clinical syndrome; with appropriate care, FIV-infected cats can live many years before succumbing to conditions unrelated to their FIV infection. Thus, overall survival time is not necessarily shorter than in uninfected cats, and quality of life is usually high over many years or lifelong. VIRAL INFECTION - FELV: FeLV, an oncornavirus, is more pathogenic than FIV. Historically, it was considered to account for more disease-related deaths and clinical syndromes in cats than any other infectious agent. Recently, the prevalence and importance of FeLV have been decreasing, mainly because of testing and eradication programmes and the use of FeLV vaccines. Progressive FeLV infection can cause tumours, bone marrow suppression and immunosuppression, as well as neurological and other disorders, and leads to a decrease in life expectancy. However, with appropriate care, many FeLV-infected cats can also live several years with a good quality of life. PRACTICAL RELEVANCE: A decision regarding treatment or euthanasia should never be based solely on the presence or absence of a retrovirus infection. Antiviral chemotherapy is of increasing interest in veterinary medicine, but is still not used commonly. EVIDENCE BASE: This article reviews the current literature on antiviral chemotherapy in retrovirus-infected cats, focusing on drugs that are currently available on the market and, thus, could potentially be used in cats. PMID- 26486980 TI - Cytauxzoonosis: Diagnosis and treatment of an emerging disease. AB - PRACTICAL RELEVANCE: Cytauxzoonosis is a life-threatening hematoprotozoal disease with a rapidly progressive clinical course. Once considered a rare disease only relevant to a small geographic area, it is now recognized in more than about a third of the United States. The geographic range seems likely to increase with expansion of the range of the vector tick. CLINICAL CHALLENGES: Both disease diagnosis and treatment offer challenges. The acute illness is often recognized by characteristic parasitic cellular inclusions, but illness may occur before parasites can be identified, and parasitic inclusions may persist long after illness has resolved. Also, while infection was once considered nearly uniformly fatal, subclinical infections are now recognized. Disease prognosis has improved for many cats through implementation of new therapies, but some pathogens are resistant to these therapies and death from disease is still common. Currently, prevention strategies are limited to ectoparasite control. GLOBAL IMPORTANCE: Cytauxzoonosis caused by Cytauxzoon felis is limited to the Americas, and is especially problematic in southeastern and south central USA. However, other Cytauxzoon species have been recognized in Europe and Asia. AUDIENCE: This review is aimed at veterinary practitioners and focuses on the diagnosis and treatment of cytauxzoonosis. Disease management is of crucial importance in endemic regions. Furthermore, the expanding geographic range of infection, and the possibility of parasite identification in chronically infected cats with a travel history, make understanding cytauxzoonosis relevant in non-endemic regions as well. EVIDENCE BASE: The authors draw on evidence from prospective clinical trials, experimental infections, retrospective clinical studies and case reports, as well as their own personal experience with the diagnosis and treatment of cytauxzoonosis. PMID- 26486981 TI - Reference interval for rectal temperature in healthy confined adult cats. AB - OBJECTIVES: Despite the common use of rectal temperature for assessing health and identifying infectious diseases in cats, there is little evidence to support frequently cited feline reference intervals for rectal temperature. Body temperature measurements are most commonly performed indoors in animal shelters and veterinary clinics. In these facilities, cats are often inactive and housed in small enclosures in a climate-controlled environment. The purpose of this study was to establish a new reference interval for rectal temperature in healthy confined adult cats. METHODS: Rectal temperatures were measured in 200 healthy adult indoor cats in animal shelters, veterinary clinics and private homes. The reference interval was established using the method of the Clinical and Laboratory Standards Institute. RESULTS: The reference interval for healthy adult cat rectal temperature was determined to range from 36.7 degrees C (confidence interval [CI] = 36.6-36.8 degrees C; 98.1 degrees F [CI = 97.9-98.3 degrees F]) at the lower limit to 38.9 degrees C (CI = 38.8-39.1 degrees C; 102.1 degrees F [CI = 101.9-102.3 degrees F]) at the upper limit. The ambient temperature ranged from 20.3-30.8 degrees C (68.5-87.5 degrees F). Rectal temperature was not significantly correlated with ambient temperature. CONCLUSIONS AND RELEVANCE: A range of 36.7-38.9 degrees C (98.1-102.1 degrees F) should be considered the new reference interval for healthy adult cats for rectal temperature measured indoors in climate-controlled conditions. This range is lower than commonly reported. Use of previously published ranges could lead to overdiagnosis of hypothermia or underdiagnosis of mild pyrexia. PMID- 26486982 TI - Cutaneous asthenia (Ehlers-Danlos-like syndrome) of Burmese cats. AB - OF CASES: A 6-month-old Burmese kitten developed focal skin lesions following a routine ovariohysterectomy. These were eventually attributed to the patient struggling during catheter placement and induction of anaesthesia. The lesions were caused by fluid extravasation in the subcutis and ischaemic necrosis of the overlying dermis, giving rise to an eschar-like appearance. Such lesions have been seen previously in Burmese cats with cutaneous asthenia and it is thought that they arise due to poor collagenous support for dermal blood vessels. An increased skin extensibility index (>23%) supported a diagnosis of cutaneous asthenia (Ehlers-Danlos-like syndrome), which has been reported as an inherited condition of Burmese cats in Australia, New Zealand and Europe. An additional Burmese cat with cutaneous asthenia is presented in detail, with lifetime follow up and further salient observations by the owner, a veterinarian. Photographs of three other affected Burmese cats are provided to illustrate the range of presentations encountered with this condition. All five affected cats were presented with eschars, atrophic alopecia and increased skin extensibility, while one cat also had skin ulcers. Routine histopathological examination, including use of special stains such as trichrome, was unhelpful in establishing the diagnosis. CLINICAL REVIEW: The clinical features of this genetic disease of Burmese cats are reviewed, especially in relation to the postulated 'vasculopathy' that gives rise to characteristic skin lesions. Long term management of this condition is discussed briefly. PMID- 26486983 TI - Management of diabetic cats in primary care practices: ABVP roundtable report. PMID- 26486984 TI - Spontaneous and specific myogenic differentiation of human mesenchymal stem cells on polyethylene glycol-linked multi-walled carbon nanotube films for skeletal muscle engineering. AB - This study explored the influence of polyethylene glycol-linked multi-walled carbon nanotube (PEG-CNT) films on skeletal myogenic differentiation of human mesenchymal stem cells (hMSCs). PEG-CNT films were prepared with nanoscale surface roughness, orderly arrangement of PEG-CNTs, high hydrophilicity and high mechanical strength. Notably, PEG-CNT films alone could direct the skeletal myogenic differentiation of hMSCs in the absence of myogenic induction factors. The quantitative real-time polymerase chain reaction (RT-PCR) showed that the non induced hMSCs plated on the PEG-CNT films, compared to the negative control, presented significant up-regulation of general myogenic markers including early commitment markers of myoblast differentiation protein-1 (MyoD) and desmin, as well as a late phase marker of myosin heavy chain-2 (MHC). Corresponding protein analysis by immunoblot assays corroborated these results. Skeletal muscle specific markers, fast skeletal troponin-C (TnC) and ryanodine receptor-1 (Ryr) were also significantly increased in the non-induced hMSCs on PEG-CNT films by RT PCR. For these cells, the commitment to specific skeletal myoblasts was further proved by the absence of enhanced adipogenic, chondrogenic and osteogenic markers. This study elucidated that PEG-CNT films supported a dedicated differentiation of hMSCs into a skeletal myogenic lineage and can work as a promising material towards skeletal muscle injury repair. PMID- 26486985 TI - Increased cortical activation upon painful stimulation in fibromyalgia syndrome. AB - BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic condition characterized by widespread pain and associated symptoms. We investigated cerebral activation in FMS patients by functional near-infrared spectroscopy (fNIRS). METHODS: Two stimulation paradigms were applied: a) painful pressure stimulation at the dorsal forearm; b) verbal fluency test (VFT). We prospectively recruited 25 FMS patients, ten patients with unipolar major depression (MD) without pain, and 35 healthy controls. All patients underwent neurological examination and all subjects were investigated with questionnaires (pain, depression, FMS, empathy). RESULTS: FMS patients had lower pressure pain thresholds than patients with MD and controls (p < .001) and reported higher pain intensity (p < 0.001). Upon unilateral pressure pain stimulation fNIRS recordings revealed increased bilateral cortical activation in FMS patients compared to controls (p < 0.05). FMS patients also displayed a stronger contralateral activity over the dorsolateral prefrontal cortex in direct comparison to patients with MD (p < 0.05). While all three groups performed equally well in the VFT, a frontal deficit in cortical activation was only found in patients with depression (p < 0.05). Performance and cortical activation correlated negatively in FMS patients (p < 0.05) and positively in patients with MD (p < 0.05). CONCLUSION: Our data give further evidence for altered central nervous processing in patients with FMS and the distinction between FMS and MD. TRIAL REGISTRATION: ISRCTN registry ID ISRCTN15015327 (24.09.2015). PMID- 26486986 TI - Reduced toxicity in the treatment of locally advanced rectal cancer: a comparison of volumetric modulated arc therapy and 3D conformal radiotherapy. AB - BACKGROUND: Excellent dosimetric characteristics were demonstrated for volumetric modulated arc therapy (VMAT) in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). In a single-center retrospective analysis, we tested whether these advantages may translate into significant clinical benefits. We compared VMAT to conventional 3D conformal radiotherapy (3DCRT) in patients, homogeneously treated according to the control arm of the CAO/ARO/AIO-04 trial. METHODS: CRT consisted of pelvic irradiation with 50.4/1.8Gy by VMAT (n = 81) or 3DCRT (n = 107) and two cycles of 5-fluorouracil. Standardized total mesorectal excision surgery was performed within 4-6 weeks. The tumor regression grading (TRG) was assessed by the Dworak score. Acute and late toxicity were evaluated via the Common Terminology Criteria for Adverse Events and the Late effects of normal tissues scale, respectively. Side effects greater than or equal to grade 3 were considered high-grade. RESULTS: Median follow-up was 18.3 months in the VMAT group and 61.5 months in the 3DCRT group with no differences in TRG between them (p = 0.1727). VMAT treatment substantially reduced high-grade acute and late toxicity, with 5 % versus 20 % (p = 0.0081) and 6 % vs. 22 % (p = 0.0039), respectively. With regard to specific organs, differences were found in skin reaction (p = 0.019) and proctitis (p = 0.0153). CONCLUSIONS: VMAT treatment in preoperative CRT for LARC showed the potential to substantially reduce high-grade acute and late toxicity. Importantly, we could demonstrate that VMAT irradiation did not impair short-term oncological results. We conclude, that the reduced toxicity after VMAT irradiation may pave the way for more efficient systemic therapies, and hopefully improved patient survival in the multimodal treatment of LARC. PMID- 26486987 TI - In vivo antimalarial evaluation of some 2,3-disubstituted-4(3H)-quinazolinone derivatives. AB - BACKGROUND: Malaria is a neglected tropical parasitic disease affecting billons of people around the globe. Though the number of cases and deaths associated with malaria are decreasing in recent years, it is the most deadly disease in the world. This study aimed at investigating the in vivo antimalarial activities of some 2,3-disubstituted-4(3H)-quinazolinone derivatives. RESULTS: The in vivo antimalarial activities of the test compounds (6-9 and 11-13) were investigated using the 4-day suppressive standard test in mice infected with chloroquine sensitive Plasmodium berghei ANKA strain. The tested compounds showed significant antimalarial activities with mean percentage suppression of 43.71-72.86 % which is significantly higher than the negative control group (p < 0.05). Compounds 12 and 13 displayed better antimalarial activities from the group with mean percentage suppression of 67.60 and 72.86 % respectively. CONCLUSION: The tested compounds showed significant in vivo antimalarial activities in mice infected with P. berghi ANKA strain. Thus, 3-aryl-2-(substitutedstyryl)-4(3H) quinazolinones represent a possible scaffold for the development of antimalarial agents. PMID- 26486988 TI - The complete mitochondrial genome of Chirolophis japonicus (Perciformes: Stichaeidae). AB - The complete mitochondrial genome of Chirolophis japonicus was sequenced for the first time in this study. It is a closed-circular molecule of 16 521 bp in length and contains 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, an origin of light strand replication (OL), and a control region (CR). The overall base composition of the heavy-strand is 25.5% A, 28.6% T, 18.3% G, and 27.6% C, and the lengths of 2 rRNA genes are 946 and 1692 bp, respectively. Maximum likelihood tree based on all the amino acid sequences of 13 mitochondrial PCGs was constructed, in which C. japonicus is close to three species of infraorder Zoarcales. These results are expected to provide useful molecular data for species identification and further phylogenetic studies of genus Chirolophis. PMID- 26486989 TI - Comparison among three variant callers and assessment of the accuracy of imputation from SNP array data to whole-genome sequence level in chicken. AB - BACKGROUND: The technical progress in the last decade has made it possible to sequence millions of DNA reads in a relatively short time frame. Several variant callers based on different algorithms have emerged and have made it possible to extract single nucleotide polymorphisms (SNPs) out of the whole-genome sequence. Often, only a few individuals of a population are sequenced completely and imputation is used to obtain genotypes for all sequence-based SNP loci for other individuals, which have been genotyped for a subset of SNPs using a genotyping array. METHODS: First, we compared the sets of variants detected with different variant callers, namely GATK, freebayes and SAMtools, and checked the quality of genotypes of the called variants in a set of 50 fully sequenced white and brown layers. Second, we assessed the imputation accuracy (measured as the correlation between imputed and true genotype per SNP and per individual, and genotype conflict between father-progeny pairs) when imputing from high density SNP array data to whole-genome sequence using data from around 1000 individuals from six different generations. Three different imputation programs (Minimac, FImpute and IMPUTE2) were checked in different validation scenarios. RESULTS: There were 1,741,573 SNPs detected by all three callers on the studied chromosomes 3, 6, and 28, which was 71.6 % (81.6 %, 88.0 %) of SNPs detected by GATK (SAMtools, freebayes) in total. Genotype concordance (GC) defined as the proportion of individuals whose array-derived genotypes are the same as the sequence-derived genotypes over all non-missing SNPs on the array were 0.98 (GATK), 0.97 (freebayes) and 0.98 (SAMtools). Furthermore, the percentage of variants that had high values (>0.9) for another three measures (non-reference sensitivity, non reference genotype concordance and precision) were 90 (88, 75) for GATK (SAMtools, freebayes). With all imputation programs, correlation between original and imputed genotypes was >0.95 on average with randomly masked 1000 SNPs from the SNP array and >0.85 for a leave-one-out cross-validation within sequenced individuals. CONCLUSIONS: Performance of all variant callers studied was very good in general, particularly for GATK and SAMtools. FImpute performed slightly worse than Minimac and IMPUTE2 in terms of genotype correlation, especially for SNPs with low minor allele frequency, while it had lowest numbers in Mendelian conflicts in available father-progeny pairs. Correlations of real and imputed genotypes remained constantly high even if individuals to be imputed were several generations away from the sequenced individuals. PMID- 26486991 TI - Formation of Li3O4 nano particles in the discharge products of non-aqueous lithium-oxygen batteries leads to lower charge overvoltage. AB - Density functional theory calculations are made for bulk thermodynamic properties and surface energies of Li2O2, a primary discharge product, and Li3O4, a possible byproduct in the discharge products, of the non-aqueous lithium-oxygen batteries. Results show that the standard formation Gibbs free energy of bulk Li3O4 is marginally higher than that of Li2O2, but the surface energy of Li3O4 is much lower. Low surface energy results in both lowered nucleation energy and formation Gibbs free energy in the nanometer regime, allowing the Li3O4 nano particles to nucleate ahead of Li2O2 during the discharge process and to exist stably when particle sizes are smaller than about 40 nm. The scanning transmission electron microscopy (STEM) image of Li3O4 crystals is simulated and compared with the measured STEM image of the discharge product particles. The consistency between the simulated and measured STEM images suggests that the Li3O4 phase can exist stably as a discharge product. The energy profile of the oxygen evolution reaction (OER) occurring on the most abundant surfaces of Li3O4 is also calculated. The predicted overpotential for the OER on the {0001} surface (0.30 V) shows a good agreement with experimental data. The presence of more electronically conductive Li3O4 nano particles in the primary discharge product Li2O2 tends to decrease the charge overvoltage of the batteries, explaining why the lower voltage area (<3.5 V) was widely observed during the charging of the batteries. An increase in the oxygen pressure or a decrease in temperature enhances the stability of the Li3O4 phase and increase the proportion of the Li3O4 phase in the discharge products, consequently leading to a lower overall charge overvoltage. PMID- 26486990 TI - Impact of traffic-related air pollution on acute changes in cardiac autonomic modulation during rest and physical activity: a cross-over study. AB - People are often exposed to traffic-related air pollution (TRAP) during physical activity (PA), but it is not clear if PA modifies the impact of TRAP on cardiac autonomic modulation. We conducted a panel study among 28 healthy adults in Barcelona, Spain to examine how PA may modify the impact of TRAP on cardiac autonomic regulation. Participants completed four 2-h exposure scenarios that included either rest or intermittent exercise in high- and low-traffic environments. Time- and frequency-domain measures of heart rate variability (HRV) were monitored during each exposure period along with continuous measures of TRAP. Linear mixed-effects models were used to estimate the impact of TRAP on HRV as well as potential effect modification by PA. Exposure to TRAP was associated with consistent decreases in HRV; however, exposure-response relationships were not always linear over the broad range of exposures. For example, each 10 MUg/m(3) increase in black carbon was associated with a 23% (95% CI: -31, -13) decrease in high frequency power at the low-traffic site, whereas no association was observed at the high-traffic site. PA modified the impact of TRAP on HRV at the high-traffic site and tended to weaken inverse associations with measures reflecting parasympathetic modulation (P <= 0.001). Evidence of effect modification at the low-traffic site was less consistent. The strength and direction of the relationship between TRAP and HRV may vary across exposure gradients. PA may modify the impact of TRAP on HRV, particularly at higher concentrations. PMID- 26486992 TI - The influence of M. P. Bryden's work on lateralization of motor skill: Is the preferred hand selected for and better at tasks requiring a high degree of skill? AB - One question of interest to Dr M. P. Bryden was how skilled motor behaviour, task complexity, and the degree of handedness are linked. His research suggested that there would be dissociation between hand preference and performance for skilled versus unskilled actions. The thought was that "simple" or unskilled tasks such reaching or grasping could be performed equally well by either hand, and thus either could be selected. Skilled tasks such as fine manipulation would be performed best by the preferred hand and thus it would be selected more frequently. Over the past two decades, researchers have attempted to determine whether such a definition of skilled action best encapsulates the specialization of the preferred hand. The current paper will review M. P. Bryden's research on skilled motor behaviour, as well as more recent work, and explore the question of whether the preferred hand is actually superior and preferred for actions requiring manipulation. PMID- 26486993 TI - Ferrocifen type anti cancer drugs. AB - Despite current developments in therapeutics focusing on biotechnologically oriented species, the unflagging utility of small molecules or peptides in medicine is still producing strong results. In 2014 for example, of the 41 new medicines authorized for sale, 33 belonged to the category of small molecules, while in 2013 they represented 24 of 27, according to the FDA. This can be explained as the result of recent forays into new or long-neglected areas of chemistry. Medicinal organometallic chemistry can provide us with an antimalarial against resistant parasitic strains, as attested by the phase II clinical development of ferroquine, with a new framework for conceptual advances based on three-dimensional space-filling, and with redox or indeed catalytic intracellular properties. In this context, bioferrocene species with antiproliferative potential have for several years been the subject of sustained effort, based on some initial successes and on the nature of ferrocene as a stable aromatic, with low toxicity, low cost, and possessing reversible redox properties. We show here the different antitumoral approaches offered by ferrocifen derivatives, originally simple derivatives of tamoxifen, which over the course of their development have proved to possess remarkable structural and mechanistic diversity. These entities act via various targets, some of which have been identified, that are triggered according to the concentration of the products. They also act according to the nature of the cancer cells and their functionality, by mechanistic pathways that can operate either synergistically or not, in successive, concomitant or sequential ways, depending for example on newly identified signaling pathways inducing senescence or apoptosis. Here we present a first attempt to rationalize the behavior of these entities with various anticancer targets. PMID- 26486994 TI - Ag Nanorods Coated with Ultrathin TiO2 Shells as Stable and Recyclable SERS Substrates. AB - TiO2-coated Ag nanorods (Ag@TiO2 NRs) have been fabricated as multifunctional surface-enhanced Raman scattering (SERS) substrates. Uniform TiO2 shells could sufficiently protect the internal Ag NRs against oxidation and sulfuration, thus the temporal stability of SERS substrates was markedly improved. Meanwhile, due to the synergetic effect between crystalline TiO2 and Ag, the nanocomposites could clean themselves via photocatalytic degradation of the adsorbed molecules under ultraviolet irradiation and water dilution, making the SERS substrates renewable. Such Ag@TiO2 NRs were shown to serve as outstanding SERS sensors featuring high sensitivity, superior stability and recyclability. PMID- 26486995 TI - Is Extensive Parenchymal Resection During Robotic Partial Nephrectomy Justified? A Match-Paired Comparison of Two Extirpative Surgical Modalities for Treatment of a Complex Renal Neoplasm. AB - OBJECTIVE: To analyze the outcomes of robotic partial nephrectomy (RPN) in patients where nephron-sparing surgery would have mandated a large amount of renal volume resection. METHODS: Patients undergoing RPN with extensive volume resection (>=30%), from 2006 to 2014, were identified. Pre- and postoperative CT/MRI-based volumetric assessment of the operated kidney was performed. To address the possible benefits of RPN, we matched this cohort to patients undergoing laparoscopic radical nephrectomy (LRN). The groups were matched for tumor size, R.E.N.A.L. nephrometry score, age-adjusted Charlson comorbidity index (ACCI), and preoperative estimated glomerular filtration rate (eGFR). Demographics, perioperative, functional, and oncologic outcomes were compared between the groups. Multivariable analysis of factors predicting chronic kidney disease (CKD) upstaging (type of surgery, R.E.N.A.L. score, ACCI, and baseline eGFR) was performed. RESULTS: In total, 52 patients undergoing RPN were matched to 52 LRN patients. The median R.E.N.A.L. score (interquartile range) was 9 (9 10) for both groups. Demographic variables were comparable between the groups. The median renal volume preservation in the RPN group was 57.0% (47.2-67.2). The rates of overall and major complications were comparable between RPN and LRN. The RPN group had higher overall eGFR preservation (75.8% vs 68.5%; p = 0.01) and a lower rate of CKD upstaging (26.9% vs 50.6%; p = 0.001). On multivariable analysis, LRN and baseline eGFR were significant predictors of CKD upstaging (odds ratio [OR] 4.26; 95% CI [1.80-10.12]; p = 0.001 and OR 0.98; 95% CI [0.96 0.99]; p = 0.03, respectively). During the median follow-up time of 21 (9-36) months, local recurrence, metastasis, and cancer-specific and overall survival were comparable between RPN and LRN. CONCLUSION: RPN requiring extensive volume resection provides renal functional preservation without significant increase in surgical complications or compromising short-term oncologic outcomes. PMID- 26486997 TI - Managing hindering self-focused attention in counseling sessions. AB - OBJECTIVE: This study examined the moderation effects of management strategies on the association between hindering self-focused attention and counseling self efficacy. METHOD: Participants were 160 counselor trainees. A hierarchical regression was used to analyze the data, and a simple effect analysis was used to explore the nature of the interaction. RESULTS: Results indicated that, for trainees who used more basic counseling techniques, counseling self-efficacy remained the same no matter their hindering self-focused attention experiences. However, for those who used less basic counseling techniques, their counseling self-efficacy dropped when they had more experiences of hindering self-focused attention. Similarly, for trainees who used more self-awareness to understand clients, these trainees reported a similar level of counseling self-efficacy no matter their hindering self-focused attention experiences. Conversely, for those who used less self-awareness as a tool to understand their clients during their sessions, their counseling self-efficacy decreased when they had more experiences of hindering self-focused attention. CONCLUSION: This is the first study that extends the literature on direct, linear relationships between hindering self focused attention and counseling self-efficacy. Results suggested two strategies (i.e., use of basic counseling techniques and use of self-awareness to understand clients) significantly moderate the above association. PMID- 26486996 TI - The pleiotropic ABNORMAL FLOWER AND DWARF1 affects plant height, floral development and grain yield in rice. AB - Moderate plant height and successful establishment of reproductive organs play pivotal roles in rice grain production. The molecular mechanism that controls the two aspects remains unclear in rice. In the present study, we characterized a rice gene, ABNORMAL FLOWER AND DWARF1 (AFD1) that determined plant height, floral development and grain yield. The afd1 mutant showed variable defects including the dwarfism, long panicle, low seed setting and reduced grain yield. In addition, abnormal floral organs were also observed in the afd1 mutant including slender and thick hulls, and hull-like lodicules. AFD1 encoded a DUF640 domain protein and was expressed in all tested tissues and organs. Subcellular localization showed AFD1-green fluorescent fusion protein (GFP) was localized in the nucleus. Meantime, our results suggested that AFD1 regulated the expression of cell division and expansion related genes. PMID- 26486998 TI - Increased utilization of postmastectomy radiotherapy in the United States from 2003 to 2011 in patients with one to three tumor positive nodes. AB - BACKGROUND AND OBJECTIVES: There have been few recent studies that have examined the use of postmastectomy radiotherapy (PMRT) for patients with 1-3 positive nodes. METHODS: We utilized the National Cancer Data Base to examine trends in PMRT for 346,218 patients with Stage I-III breast cancer from 2003 to 2011. Neoadjuvant therapy cases were excluded. Log linear models examined trends in PMRT and logistic regressions were used to examine factors related to PMRT. RESULTS: The proportion of pT1-2N1 patients receiving PMRT increased from 23.9% in 2003 to 36.4% in 2011 with an annual percent change (APC) of 6.2% (P < 0.001). There were significant increases in the use of PMRT amongst patients with one (APC = 7.7%), two (APC = 6.7%), and three (APC = 4.2%) positive nodes. In 2011, 27.8%, 43.8%, and 57.8% of patients with one, two or three positive nodes underwent PMRT, respectively. The number of positive nodes and tumor size were the strongest independent predictors of PMRT in the 1-3 node group; lymphovascular invasion, invasive lobular histology, and triple negative phenotypes were also associated with PMRT use. CONCLUSION: PMRT for patients with pT1-2N1 disease has increased with the greatest increase seen in those with one tumor positive node. Tumor factors remain strong independent predictors of PMRT. PMID- 26487000 TI - Surgical Resection is Better than Transarterial Chemoembolization for Patients with Hepatocellular Carcinoma Beyond the Milan Criteria: A Prognostic Nomogram Study. AB - BACKGROUND: The clinical outcomes in hepatocellular carcinoma (HCC) patients receiving surgical resection (SR) or transarterial chemoembolization (TACE) are diverse. This study aimed to develop a nomogram to predict individualized survival risk in patients with HCC beyond the Milan criteria undergoing aggressive treatments (SR and TACE). METHODS: A total of 1009 patients were enrolled in the study and randomly grouped into derivation (n = 505) and validation sets (n = 504). The multivariate Cox proportional hazards model was used to select significant prognostic predictors from the derivation set to generate the nomogram. The performance of the nomogram was evaluated by discrimination (concordance index) and calibration tests. RESULTS: Serum albumin <3.8 g/dL, alpha-fetoprotein >=400 ng/mL, TACE, vascular invasion, multiple tumors, and tumor volume >=200 cm(3) were associated with poor survival in the multivariate Cox model (all p < 0.05). A nomogram with a scale of 0-47 was developed with these six variables, and the predicted survival rates at 1 and 3 years were calculated. The derivation set with bootstrapping (B = 100) had a good concordance index of 0.694 [95% confidence interval (CI) 0.68-0.708]. Discrimination test in the validation set provided a concordance index of 0.71 (95 % CI 0.697-0.722), and the calibration plots well-matched the 45-degree line for 1- and 3-year survival prediction. The respective survival for patients undergoing SR or TACE could be predicted based on the nomogram across different risk scores. CONCLUSIONS: This easy-to-use nomogram may accurately predict survival at 1 and 3 years for individual HCC patients beyond the Milan criteria, and provide quantitative survival advantage of SR over TACE. PMID- 26486999 TI - Intraoperative Ultrasound Guidance in Breast-Conserving Surgery Improves Cosmetic Outcomes and Patient Satisfaction: Results of a Multicenter Randomized Controlled Trial (COBALT). AB - BACKGROUND: Ultrasound-guided breast-conserving surgery (USS) results in a significant reduction in both margin involvement and excision volumes (COBALT trial). Objective. The aim of the present study was to determine whether USS also leads to improvements in cosmetic outcome and patient satisfaction when compared with standard palpation-guided surgery (PGS). METHODS: A total of 134 patients with T1-T2 invasive breast cancer were included in the COBALT trial (NTR2579) and randomized to either USS (65 patients) or PGS (69 patients). Cosmetic outcomes were assessed by a three-member panel using computerized software Breast Cancer Conservative Treatment cosmetic results (BCCT.- core) and by patient self evaluation, including patient satisfaction. Time points for follow-up were 3, 6, and 12 months after surgery. Overall cosmetic outcome and patient satisfaction were scored on a 4-point Likert scale (excellent, good, fair, or poor), and outcomes were analyzed using a multilevel, mixed effect, proportional odds model for ordinal responses. RESULTS: Ultrasound-guided breast-conserving surgery achieved better cosmetic outcomes, with 20 % excellence overall and only 6 % rated as poor, whereas 14 % of PGS outcomes were rated excellent and 13 % as poor. USS also had consistently lower odds for worse cosmetic outcomes (odds ratio 0.55, p = 0.067) than PGS. The chance of having a worse outcome was significantly increased by a larger lumpectomy volume (ptrend = 0.002); a volume [40 cc showed odds 2.78-fold higher for a worse outcome than a volume B40 cc. USS resulted in higher patient satisfaction compared with PGS. CONCLUSION: Ultrasound guided breast-conserving surgery achieved better overall cosmetic outcomes and patient satisfaction than PGS. Lumpectomy volumes[40 cc resulted in significantly worse cosmetic outcomes. PMID- 26487001 TI - Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet. AB - The accumulation of intramyocellular lipid (IMCL) is recognized as an important determinant of insulin resistance, and is increased by a high-fat diet (HFD). However, the effects of HFD on IMCL and insulin sensitivity are highly variable. The aim of this study was to identify the genes in muscle that are related to this inter-individual variation. Fifty healthy men were recruited for this study. Before and after HFD for 3 days, IMCL levels in the tibialis anterior were measured by (1)H magnetic resonance spectroscopy, and peripheral insulin sensitivity was evaluated by glucose infusion rate (GIR) during the euglycemic hyperinsulinemic clamp. Subjects who showed a large increase in IMCL and a large decrease in GIR by HFD were classified as high responders (HRs), and subjects who showed a small increase in IMCL and a small decrease in GIR were classified as low responders (LRs). In five subjects from each group, the gene expression profile of the vastus lateralis muscle was analyzed by DNA microarray analysis. Before HFD, gene expression profiles related to lipid metabolism were comparable between the two groups. Gene Set Enrichment Analysis demonstrated that five gene sets related to lipid metabolism were upregulated by HFD in the HR group but not in the LR group. Changes in gene expression patterns were confirmed by qRT-PCR using more samples (LR, n = 9; HR, n = 11). These results suggest that IMCL accumulation/impaired insulin sensitivity after HFD is closely associated with changes in the expression of genes related to lipid metabolism in muscle. PMID- 26487004 TI - Bone microstructural defects and osteopenia in hemizygous betaIVSII-654 knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function. AB - beta-Thalassemia, a hereditary anemic disorder, is often associated with skeletal complications that can be found in both males and females. The present study aimed to investigate the age- and sex-dependent changes in bone mineral density (BMD) and trabecular microstructure in beta(IVSII-654) knockin thalassemic mice. Dual-energy X-ray absorptiometry and computer-assisted bone histomorphometry were employed to investigate temporal changes in BMD and histomorphometric parameters in male and female mice of a beta(IVSII-654) knockin mouse model of human beta thalassemia, in which impaired splicing of beta-globin transcript was caused by hemizygous C->T mutation at nucleotide 654 of intron 2. Young, growing beta(IVSII 654) mice (1 mo old) manifested shorter bone length and lower BMD than their wild type littermates, indicating possible growth retardation and osteopenia, the latter of which persisted until 8 mo of age (adult mice). Interestingly, two-way analysis of variance suggested an interaction between sex and beta(IVSII-654) genotype, i.e., more severe osteopenia in adult female mice. Bone histomorphometry further suggested that low trabecular bone volume in male beta(IVSII-654) mice, particularly during a growing period (1-2 mo), was primarily due to suppression of bone formation, whereas both a low bone formation rate and a marked increase in osteoclast surface were observed in female beta(IVSII-654) mice. In conclusion, osteopenia and trabecular microstructural defects were present in both male and female beta(IVSII-654) knockin thalassemic mice, but the severity, disease progression, and cellular mechanism differed between the sexes. PMID- 26487003 TI - 2-Methoxyestradiol blocks the RhoA/ROCK1 pathway in human aortic smooth muscle cells. AB - 2-Methoxyestradiol (2-ME), a metabolite of estradiol with little affinity for estrogen receptors, inhibits proliferation of vascular smooth muscle cells; however, the molecular mechanisms underlying this effect are incompletely understood. Our previous work shows that 2-ME inhibits initiation (blocks phosphorylation of ERK and Akt) and progression (reduces cyclin expression and increases expression of cyclin inhibitors) of the mitogenic pathway and interferes with mitosis (disrupts tubulin organization). Because the RhoA/ROCK1 pathway (RhoA -> ROCK1 -> myosin phosphatase targeting subunit -> myosin light chain) is involved in cytokinesis, herein we tested the concept that 2-ME also blocks the RhoA/ROCK1 pathway. Because of the potential importance of 2-ME for preventing/treating vascular diseases, experiments were conducted in female human aortic vascular smooth muscle cells. Microarray transcriptional profiling suggested an effect of 2-ME on the RhoA/ROCK1 pathway. Indeed, 2-ME blocked mitogen-induced GTP-bound RhoABC expression and membrane-bound RhoA, suggesting interference with the activation of RhoA. 2-ME also reduced ROCK1 expression, suggesting reduced production of the primary downstream signaling kinase of the RhoA pathway. Moreover, 2-ME inhibited RhoA/ROCK1 pathway downstream signaling, including phosphorylated myosin phosphatase targeting subunit and myosin light chain; the ROCK1 inhibitor H-1152 mimicked these effects of 2-ME; both 2-ME and H 1152 blocked cytokinesis. 2-ME also reduced the expression of tissue factor, yet another downstream signaling component of the RhoA/ROCK1 pathway. We conclude that 2-ME inhibits the pathway RhoA -> ROCK1 -> myosin phosphatase targeting subunit -> myosin light chain, and this likely contributes to the reduced cytokinesis in 2-ME treated HASMCs. PMID- 26487002 TI - Disruption of REDD1 gene ameliorates sepsis-induced decrease in mTORC1 signaling but has divergent effects on proteolytic signaling in skeletal muscle. AB - Sepsis-induced skeletal muscle atrophy and weakness are due in part to decreased mTORC1-mediated protein synthesis and increased proteolysis via the autophagy lysosomal system and ubiquitin-proteasome pathway. The REDD1 (regulated in development and DNA damage-1) protein is increased in sepsis and can negatively regulate mTORC1 activity. However, the contribution of REDD1 to the sepsis induced change in muscle protein synthesis and degradation has not been determined. Sepsis was produced by cecal ligation and puncture in female REDD1(-/ ) or wild-type (WT) mice, and end points were assessed 24 h later in gastrocnemius; time-matched, pair-fed controls of each genotype were included. Sepsis increased REDD1 protein 300% in WT mice, whereas REDD1 was absent in REDD1(-/-) muscle. Sepsis decreased protein synthesis and phosphorylation of downstream targets of mTORC1 (S6K1 Thr(389), rpS6 Ser(240/244), 4E-BP1 Ser(65)) in WT but not REDD1(-/-) mice. However, Akt and PRAS40 phosphorylation was suppressed in both sham and septic muscle from REDD1(-/-) mice despite unaltered PDK1, PP2A, or TSC2 expression. Sepsis increased autophagy as indicated by decreased ULK1 Ser(757) phosphorylation and p62 abundance and increased LC3B-II/I in WT mice, whereas these changes were absent in septic REDD1(-/-) mice. Conversely, REDD1 deletion did not prevent the sepsis-induced decrease in IGF-I mRNA or the concomitant increase in IL-6, TNFalpha, MuRF1, and atrogin1 mRNA expression. Lastly, 5-day survival in a separate set of septic mice did not differ between WT and REDD1(-/-) mice. These data highlight the central role of REDD1 in regulating both protein synthesis and autophagy in skeletal muscle during sepsis. PMID- 26487005 TI - Diabetes prevalence in NZO females depends on estrogen action on liver fat content. AB - In humans and rodents, risk of metabolic syndrome is sexually dimorphic, with an increased incidence in males. Additionally, the protective role of female gonadal hormones is ostensible, as prevalence of type 2 diabetes mellitus (T2DM) increases after menopause. Here, we investigated the influence of estrogen (E2) on the onset of T2DM in female New Zealand obese (NZO) mice. Diabetes prevalence (defined as blood glucose levels >16.6 mmol/l) of NZO females on high-fat diet (60 kcal% fat) in week 22 was 43%. This was markedly dependent on liver fat content in week 10, as detected by computed tomography. Only mice with a liver fat content >9% in week 10 plus glucose levels >10 mmol/l in week 9 developed hyperglycemia by week 22. In addition, at 11 wk, diacylglycerols were elevated in livers of diabetes-prone mice compared with controls. Hepatic expression profiles obtained from diabetes-prone and -resistant mice at 11 wk revealed increased abundance of two transcripts in diabetes-prone mice: Mogat1, which catalyzes the synthesis of diacylglycerols from monoacylglycerol and fatty acyl-CoA, and the fatty acid transporter Cd36. E2 treatment of diabetes-prone mice for 10 wk prevented any further increase in liver fat content and reduced diacylglycerols and the abundance of Mogat1 and Cd36, leading to a reduction of diabetes prevalence and an improved glucose tolerance compared with untreated mice. Our data indicate that early elevation of hepatic Cd36 and Mogat1 associates with increased production and accumulation of triglycerides and diacylglycerols, presumably resulting in reduced hepatic insulin sensitivity and leading to later onset of T2DM. PMID- 26487006 TI - Gastric inhibitory polypeptide immunoneutralization attenuates development of obesity in mice. AB - Previous reports have suggested that the abrogation of gastric inhibitory polypeptide (GIP) signaling could be exploited to prevent and treat obesity and obesity-related disorders in humans. This study was designed to determine whether immunoneutralization of GIP, using a newly developed specific monoclonal antibody (mAb), would prevent the development of obesity. Specific mAb directed against the carboxy terminus of mouse GIP was identified, and its effects on the insulin response to oral and to intraperitoneal (ip) glucose and on weight gain were evaluated. Administration of mAb (30 mg/kg body wt, BW) to mice attenuated the insulin response to oral glucose by 70% and completely eliminated the response to ip glucose coadministered with human GIP. Nine-week-old C57BL/6 mice injected with GIP mAbs (60 mg.kg BW(-1).wk(-1)) for 17 wk gained 46.5% less weight than control mice fed an identical high-fat diet (P < 0.001). No significant differences in the quantity of food consumed were detected between the two treatment groups. Furthermore, magnetic resonance imaging demonstrated that subcutaneous, omental, and hepatic fat were 1.97-, 3.46-, and 2.15-fold, respectively, lower in mAb-treated animals than in controls. Moreover, serum insulin, leptin, total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides were significantly reduced, whereas the high-density lipoprotein (HDL)/TC ratio was 1.25-fold higher in treated animals than in controls. These studies support the hypothesis that a reduction in GIP signaling using a GIP neutralizing mAb might provide a useful method for the treatment and prevention of obesity and related disorders. PMID- 26487007 TI - Multifaceted interplay among mediators and regulators of intestinal glucose absorption: potential impacts on diabetes research and treatment. AB - Glucose is the prominent molecule that characterizes diabetes and, like the vast majority of nutrients in our diet, it is absorbed and enters the bloodstream directly through the small intestine; hence, small intestine physiology impacts blood glucose levels directly. Accordingly, intestinal regulatory modulators represent a promising avenue through which diabetic blood glucose levels might be moderated clinically. Despite the critical role of small intestine in blood glucose homeostasis, most physiological diabetes research has focused on other organs, such as the pancreas, kidney, and liver. We contend that an improved understanding of intestinal regulatory mediators may be fundamental for the development of first-line preventive and therapeutic interventions in patients with diabetes and diabetes-related diseases. This review summarizes the major important intestinal regulatory mediators, discusses how they influence intestinal glucose absorption, and suggests possible candidates for future diabetes research and the development of antidiabetic therapeutic agents. PMID- 26487008 TI - Ingestion of glucose or sucrose prevents liver but not muscle glycogen depletion during prolonged endurance-type exercise in trained cyclists. AB - The purpose of this study was to define the effect of glucose ingestion compared with sucrose ingestion on liver and muscle glycogen depletion during prolonged endurance-type exercise. Fourteen cyclists completed two 3-h bouts of cycling at 50% of peak power output while ingesting either glucose or sucrose at a rate of 1.7 g/min (102 g/h). Four cyclists performed an additional third test for reference in which only water was consumed. We employed (13)C magnetic resonance spectroscopy to determine liver and muscle glycogen concentrations before and after exercise. Expired breath was sampled during exercise to estimate whole body substrate use. After glucose and sucrose ingestion, liver glycogen levels did not show a significant decline after exercise (from 325 +/- 168 to 345 +/- 205 and 321 +/- 177 to 348 +/- 170 mmol/l, respectively; P > 0.05), with no differences between treatments. Muscle glycogen concentrations declined (from 101 +/- 49 to 60 +/- 34 and 114 +/- 48 to 67 +/- 34 mmol/l, respectively; P < 0.05), with no differences between treatments. Whole body carbohydrate utilization was greater with sucrose (2.03 +/- 0.43 g/min) vs. glucose (1.66 +/- 0.36 g/min; P < 0.05) ingestion. Both liver (from 454 +/- 33 to 283 +/- 82 mmol/l; P < 0.05) and muscle (from 111 +/- 46 to 67 +/- 31 mmol/l; P < 0.01) glycogen concentrations declined during exercise when only water was ingested. Both glucose and sucrose ingestion prevent liver glycogen depletion during prolonged endurance-type exercise. Sucrose ingestion does not preserve liver glycogen concentrations more than glucose ingestion. However, sucrose ingestion does increase whole body carbohydrate utilization compared with glucose ingestion. This trial was registered at https://www.clinicaltrials.gov as NCT02110836. PMID- 26487012 TI - Global deaths from road incidents plateau. PMID- 26487010 TI - Impact of maternal undernutrition around the time of conception on factors regulating hepatic lipid metabolism and microRNAs in singleton and twin fetuses. AB - We have investigated the effects of embryo number and maternal undernutrition imposed either around the time of conception or before implantation on hepatic lipid metabolism in the sheep fetus. We have demonstrated that periconceptional undernutrition and preimplantation undernutrition each resulted in decreased hepatic fatty acid beta-oxidation regulators, PGC-1alpha (P < 0.05), PDK2 (P < 0.01), and PDK4 (P < 0.01) mRNA expression in singleton and twin fetuses at 135 138 days gestation. In singletons, there was also lower hepatic PDK4 (P < 0.01), CPT-1 (P < 0.01), and PKCzeta (P < 0.01) protein abundance in the PCUN and PIUN groups and a lower protein abundance of PDPK-1 (P < 0.05) in the PCUN group. Interestingly, in twins, the hepatic protein abundance of p-AMPK (Ser(485)) (P < 0.01), p-PDPK-1 (Ser(41)) (P < 0.05), and PKCzeta (P < 0.05) was higher in the PCUN and PIUN groups, and hepatic PDK4 (P < 0.001) and CPT-1 (P < 0.05) protein abundance was also higher in the PIUN twin fetus. We also found that the expression of a number of microRNAs was altered in response to PCUN or PIUN and that there is evidence that these changes may underlie the changes in the protein abundance of key regulators of hepatic fatty acid beta-oxidation in the PCUN and PIUN groups. Therefore, embryo number and the timing of maternal undernutrition in early pregnancy have a differential impact on hepatic microRNA expression and on the factors that regulate hepatic fatty acid oxidation and lipid synthesis. PMID- 26487009 TI - Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin resistant skeletal muscle after acute exercise. AB - Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24-48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise. PMID- 26487013 TI - Reanalysis of the Aqueous Spectrum of the Neptunyl(V) [NpO2(+)] Ion. AB - The actinyl ions, consisting of the dioxoactinde(VI) and dioxoactinide(V) ions, are unique in the periodic table. However, very few quantitative studies of the spectra of these ions have been performed. In this paper the analysis of the optical spectrum of the aqueous neptunyl(V) [NpO2(+)] ion in 1 M HClO4 is reexamined. The species in solution is assumed to be the linear NpO2(+) ion surrounded in the equatorial plane by five oxygen atoms from five H2O molecules. The neptunyl(V) ion has the 5f(2) open-shell configuration, and the low-lying optical transitions (up to ~20 000 cm(-1)) observed are primarily from the two 5f electrons occupying the 5fphi and 5fdelta orbitals. The conventional parametric theory used for f(n) systems is applied to these low-lying transitions utilizing the intensity calculations that Matiska et al.1 have performed for this ion and the data reported by Eisenstein and Pryce.2 Possible ratios for the Slater electrostatic repulsion parameters are obtained from the data for the isoelectronic ion U(4+) (5f(2)) in various host crystals. The results are consistent with earlier crystal field analyses of the 5f(1) neptunyl(VI) [NpO2(2+)] ion. PMID- 26487011 TI - Left main coronary artery disease: A review of the spectrum of noninvasive diagnostic modalities. AB - Medically managed significant left main (LM) stem disease has been considered a determinant of increased cardiac mortality approaching 50% at 3-year follow-up. Despite the clinical significance of LM disease, studies comparing the various diagnostic modalities, especially noninvasive, are sparse. Clinicians, particularly imagers, should be aware of the strengths and weaknesses of existing modalities to diagnose LM disease as integrating many clues (history, symptoms, electrocardiogram, and stress hemodynamics are essential to suspect this diagnosis and proceed to the next step). Here we review the existing data on the current role of electrocardiography, nuclear myocardial perfusion imaging (single photon emission computed tomography and positron emission tomography), stress echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging in diagnostic evaluation of LM disease. Wherever applicable we have extended our discussion to multivessel coronary artery disease encompassing scenarios where LMS can present as LM equivalent with or without extensive multivessel coronary artery disease. PMID- 26487014 TI - Universal Access to Health and Universal Health Coverage: identification of nursing research priorities in Latin America. AB - OBJECTIVE: To estabilish a regional list for nursing research priorities in health systems and services in the Region of the Americas based on the concepts of Universal Access to Health and Universal Health Coverage. METHOD: Five-stage consensus process: systematic review of literature; appraisal of resulting questions and topics; ranking of the items by graduate program coordinators; discussion and ranking amongst a forum of researchers and public health leaders; and consultation with the Ministries of Health of the Pan American Health Organization's member states. RESULTS: The resulting list of nursing research priorities consists of 276 study questions/ topics, which are sorted into 14 subcategories distributed into six major categories: 1. Policies and education of nursing human resources; 2. Structure, organization and dynamics of health systems and services; 3. Science, technology, innovation, and information systems in public health; 4. Financing of health systems and services; 5. Health policies, governance, and social control; and 6. Social studies in the health field. CONCLUSION: The list of nursing research priorities is expected to serve as guidance and support for nursing research on health systems and services across Latin America. Not only researchers, but also Ministries of Health, leaders in public health, and research funding agencies are encouraged to use the results of this list to help inform research-funding decisions. PMID- 26487015 TI - Auxin response factors. AB - Auxin signalling involves the activation or repression of gene expression by a class of auxin response factor (ARF) proteins that bind to auxin response elements in auxin-responsive gene promoters. The release of ARF repression in the presence of auxin by the degradation of their cognate auxin/indole-3-acetic acid repressors forms a paradigm of transcriptional response to auxin. However, this mechanism only applies to activating ARFs, and further layers of complexity of ARF function and regulation are being revealed, which partly reflect their highly modular domain structure. This review summarizes our knowledge concerning ARF binding site specificity, homodimer and heterodimer multimeric ARF association and cooperative function and how activator ARFs activate target genes via chromatin remodelling and evolutionary information derived from phylogenetic comparisons from ARFs from diverse species. ARFs are regulated in diverse ways, and their importance in non-auxin-regulated pathways is becoming evident. They are also embedded within higher-order transcription factor complexes that integrate signalling pathways from other hormones and in response to the environment. The ways in which new information concerning ARFs on many levels is causing a revision of existing paradigms of auxin response are discussed. PMID- 26487018 TI - Artificial Protection Film on Lithium Metal Anode toward Long-Cycle-Life Lithium Oxygen Batteries. PMID- 26487019 TI - Aerogels: Aerogels from CdSe/CdS Nanorods with Ultra-long Exciton Lifetimes and High Fluorescence Quantum Yields (Adv. Mater. 40/2015). AB - The fabrication of gels from semiconductor nanoparticles by means of a controlled and optimized destabilization process is investigated by N. C. Bigall and co workers on page 6152. Aerogels with high photoluminescence quantum yield and ultra-long radiative lifetimes are fabricated from CdSe/CdS seeded nanorods. It is shown that excited electrons can be delocalized within the aerogel monolith while, at the same time, holes stay confined in the CdSe cores. This type of assembly of nanoparticles shows novel properties in comparison to those of the nanoparticle building blocks and of the bulk material. PMID- 26487024 TI - Whole Farm Net Greenhouse Gas Abatement from Establishing Kikuyu-Based Perennial Pastures in South-Western Australia. AB - On-farm activities that reduce GHG emissions or sequester carbon from the atmosphere to compensate for anthropogenic emissions are currently being evaluated by the Australian Government as carbon offset opportunities. The aim of this study was to examine the implications of establishing and grazing Kikuyu pastures, integrated as part of a mixed Merino sheep and cropping system, as a carbon offset mechanism. For the assessment of changes in net greenhouse gas emissions, results from a combination of whole farm economic and livestock models were used (MIDAS and GrassGro). Net GHG emissions were determined by deducting increased emissions from introducing this practice change (increased methane and nitrous oxide emissions due to higher stocking rates) from the soil carbon sequestered from growing the Kikuyu pasture. Our results indicate that livestock systems using perennial pastures may have substantially lower net GHG emissions, and reduced GHG intensity of production, compared with annual plant-based production systems. Soil carbon accumulation by converting 45% of arable land within a farm enterprise to Kikuyu-based pasture was determined to be 0.80 t CO2 e farm ha(-1) yr(-1) and increased GHG emissions (leakage) was 0.19 t CO2-e farm ha(-1) yr(-1). The net benefit of this practice change was 0.61 t CO2-e farm ha( 1) yr(-1) while the rate of soil carbon accumulation remains constant. The use of perennial pastures improved the efficiency of animal production almost eight fold when expressed as carbon dioxide equivalent emissions per unit of animal product. The strategy of using perennial pasture to improve production levels and store additional carbon in the soil demonstrates how livestock should be considered in farming systems as both sources and sinks for GHG abatement. PMID- 26487025 TI - Preliminary Investigation of Food Guarding Behavior in Shelter Dogs in the United States. AB - A survey given to animal shelters across the US reported food bowl guarding as one of the most common reasons for euthanasia and only 34% attempted to modify this guarding behavior. This study identified 96 dogs that guarded their food bowl during an assessment, and then placed them into a home on a modification program. Food guarding behavior was identified as stiffening, gulping, growling, freezing, and/or biting a fake hand during the SAFER((r)) food bowl assessment. Dogs that exhibited guarding behavior over toys were excluded. Follow-up was done at 3 days, 3 weeks, and 3 months post adoption to measure all guarding behavior in the home. Six adopters reported at least one incident involving guarding in the first three weeks, of which only one was around the food bowl. By three months, those adopters reported no guarding behavior except one new occurrence of a dog guarding a rawhide was reported in the third month. For dog identified with food guarding, the return rate to the shelter was 5% and 9% for adult dogs not identified with guarding behavior. Adopters did not comply with at least one aspect of the program, so it is unclear why so little guarding was reported. The key finding is that dogs that guarded their food bowl in the shelter were not guarding their food in their new homes. PMID- 26487026 TI - Changes in Habitat Structure May Explain Decrease in Reintroduced Mohor Gazelle Population in the Guembeul Fauna Reserve, Senegal. AB - Reintroduction is a widespread method for saving populations of endangered species from extinction. In spite of recent reviews, it is difficult to reach general conclusions about its value as a conservation tool, as authors are reluctant to publish unsuccessful results. The Mohor gazelle is a North African gazelle, extinct in the wild. Eight individuals were reintroduced in Senegal in 1984. The population grew progressively, albeit slowly, during the first 20 years after release, but then declined dramatically, until the population in 2009 was estimated at no more than 13-15 individuals. This study attempts to determine the likelihood of gazelle-habitat relationships to explain why the size of the gazelle population has diminished. Our results show that the Mohor gazelle in Guembeul is found in open habitats with less developed canopy where the grass is shorter, suggesting the possibility that changes in habitat structure have taken place during the time the gazelles have been in the Reserve, reducing the amount of suitable habitat. Reintroduction design usually concentrates on short-term factors that may affect survival of the released animals and their descendants (short-term achievement), while the key factors for assessing its success may be those that affect the long-term evolution of the population. PMID- 26487027 TI - Hunting Activity Among Naturalistically Housed Chimpanzees (Pan troglodytes) at the Fundacio Mona (Girona, Spain). Predation, Occasional Consumption and Strategies in Rehabilitated Animals. AB - Predatory behavior in wild chimpanzees and other primates has been well documented over the last 30 years. However, as it is an opportunistic behavior, conditions which may promote such behavior are left up to chance. Until now, predatory behavior among captive chimpanzees has been poorly documented. In this paper, we present five instances providing evidence of predatory behavior: four performed by isolated individuals and one carried out in cooperation. The evidence of group predation involved the chimpanzees adopting different roles as pursuers and ambushers. Prey was partially eaten in some cases, but not in the social episode. This study confirms that naturalistic environments allow chimpanzees to enhance species-typical behavioral patterns. PMID- 26487028 TI - Companion Animals, Natural Disasters and the Law: An Australian Perspective. AB - This article examines the regulation of companion animal welfare during disasters, with some context provided by two recent major disaster events in Australia. Important general lessons for improved disaster management were identified in subsequent inquiries. However, the interests of companion animals continue to be inadequately addressed. This is because key assumptions underpinning disaster planning for companion animals-the primacy of human interests over animal interests and that individuals will properly address companion animal needs during times of disaster-are open to question. In particular these assumptions fail to recognise the inherent value of companion animals, underestimate the strong bond shared by some owners and their animals and, at the same time, overestimate the capacity of some owners to adequately meet the needs of their animals. PMID- 26487029 TI - One Medicine, One Acupuncture. AB - "One Acupuncture", like "One Medicine", has the potential to improve research quality and clinical outcomes. However, while human acupuncture point locations have remained largely consistent over time, the veterinary versions remain imprecise and variable. Establishing anatomical criteria for veterinary acupuncture atlases in keeping with the human template will create congruence across species, benefiting both research and practice. Anatomic criteria for points based on objectively verifiable structures will facilitate translational research. Functionally comparative innervation, in particular, should be similar between species, as the nerves initiate and mediate physiologic changes that result from point stimulation. If researchers choose points that activate different nerves in one species than in another, unpredictable outcomes may occur. Variability in point placement will impede progress and hamper the ability of researchers and clinicians to make meaningful comparisons across species. This paper reveals incongruities that remain between human and veterinary acupuncture points, illustrating the need to analyze anatomical characteristics of each point to assure accuracy in selecting transpositional acupuncture locations. PMID- 26487030 TI - Effect of Time (Within and Between Days), and Dairy Production Factors on the Impedance Value at 24 Acupuncture Points in Dairy Cows. AB - This study evaluated the effect of hour and day of measurement, and of production factors on the impedance values (IVs) at 24 acupuncture points (APs). This is a first step in assessing whether electro-acupuncture can contribute to reduced antibiotic use in dairy farming. The APs studied were left (L) and right (R) points of the bladder (BL) and stomach (ST) meridians. The effect of time was measured in a 3x3 Latin square on six cows in one herd. The effect of production factors was analyzed using 108 cows from three herds for two months. The effect of time excludes BL 14R, 16R, 21R, 22R, 30R, 46-02R, 43-01L and 30L, and ST18 bilaterally for diagnostic use. The contribution of parity, age or lactation period to monthly models of BL21R, 18R and 15R, and ST18R exclude these for diagnostic use. Of the remaining APs, BL19R, BL20R and BL46-02L showed stable IVs and are recommended for reference measurements. APs BL14L, BL16L and BL17L are recommended for diagnostics, and BL 16R, 17R, 18R, 23R, 30R, 15L, 20L, 22L and 29L need further study. Factors contributing to the variation in the IV of several APs were: milk robot, number of inseminations, body condition score, days of the preceding lactation, kg milk and kg milk fat of current and preceding month and preceding year, and milk cell count and urea content. PMID- 26487031 TI - Gold Bead Implantation in Acupoints for Coxofemoral Arthrosis in Dogs: Method Description and Adverse Effects. AB - Gold bead implantation has been used for years as an alternative method to improve function in chronic joint disease both in humans and dogs. The aims of the present study were to describe the technique of implanting 24-karat gold beads around the hip joints of dogs with chronic hip dysplasia, and to record any side effects or complications of such treatment. A prospective placebo-controlled double-blinded clinical trial was performed. Eighty dogs were randomly allocated to treatment or placebo, with 38 in the gold implantation group and 42 in the placebo group, and followed intensely for six months. The implantation technique was simple to perform, using fluoroscopy and with the dogs under inhalation anesthesia for about 30 minutes. Adverse effects, measured as pain or discomfort, were seen for a period of up to four weeks in 15 of the dogs in the gold implantation group, compared to six dogs in the placebo group. During implantation, a technical difficulty occurred as 82% of the dogs showed leakage of blood and/or synovia from the needles. The dogs in the gold implantation group were radiographed 18 months later. Of the 30 dogs that were radiographed at both inclusion and 24 months, 80% (24 dogs) showed a deterioration of the coxofemoral arthrosis, the other six had stable disease evaluated by radiography. Migration of gold beads was only observed in one dog. PMID- 26487032 TI - A Greenhouse Gas and Soil Carbon Model for Estimating the Carbon Footprint of Livestock Production in Canada. AB - To assess tradeoffs between environmental sustainability and changes in food production on agricultural land in Canada the Unified Livestock Industry and Crop Emissions Estimation System (ULICEES) was developed. It incorporates four livestock specific GHG assessments in a single model. To demonstrate the application of ULICEES, 10% of beef cattle protein production was assumed to be displaced with an equivalent amount of pork protein. Without accounting for the loss of soil carbon, this 10% shift reduced GHG emissions by 2.5 TgCO2e y(-1). The payback period was defined as the number of years required for a GHG reduction to equal soil carbon lost from the associated land use shift. A payback period that is shorter than 40 years represents a net long term decrease in GHG emissions. Displacing beef cattle with hogs resulted in a surplus area of forage. When this residual land was left in ungrazed perennial forage, the payback periods were less than 4 years and when it was reseeded to annual crops, they were equal to or less than 40 years. They were generally greater than 40 years when this land was used to raise cattle. Agricultural GHG mitigation policies will inevitably involve a trade-off between production, land use and GHG emission reduction. ULICEES is a model that can objectively assess these trade-offs for Canadian agriculture. PMID- 26487033 TI - Acupuncture Points of the Horse's Distal Thoracic Limb: A Neuroanatomic Approach to the Transposition of Traditional Points. AB - Veterinary acupuncture charts were developed based on the concept of transpositional points whereby human acupuncture maps were adapted to animal anatomy. Transpositional acupuncture points have traditionally been placed in specific locations around the horse's coronet and distal limb believed to be the closest approximation to the human distal limb points. Because the horse has a single digit and lacks several structures analogous to the human hand and foot, precisely transposing all of the human digital points is not anatomically possible. To date there is no published research on the effect of acupuncture treatment of the equine distal limb points. This paper presents a modified approach to equine distal limb point selection based on what is known from research on other species about the neuroanatomic method of acupuncture. A rationale is presented for modification of traditional equine ting points as well as additional points around the hoof and distal limb that do not appear in the standard textbooks of equine acupuncture. The anatomy and physiology of the equine foot likely to be affected by acupuncture are briefly reviewed. Modified neuroanatomic points are proposed that may be more accurate as transpositional points. As an example of clinical application, a neuroanatomic approach to acupuncture treatment of equine laminitis is presented. PMID- 26487035 TI - Intermediate uveitis associated with familial Mediterranean fever. PMID- 26487034 TI - Double Muscling in Cattle: Genes, Husbandry, Carcasses and Meat. AB - Molecular biology has enabled the identification of the mechanisms whereby inactive myostatin increases skeletal muscle growth in double-muscled (DM) animals. Myostatin is a secreted growth differentiation factor belonging to the transforming growth factor-beta superfamily. Mutations make the myostatin gene inactive, resulting in muscle hypertrophy. The relationship between the different characteristics of DM cattle are defined with possible consequences for livestock husbandry. The extremely high carcass yield of DM animals coincides with a reduction in the size of most vital organs. As a consequence, DM animals may be more susceptible to respiratory disease, urolithiasis, lameness, nutritional stress, heat stress and dystocia, resulting in a lower robustness. Their feed intake capacity is reduced, necessitating a diet with a greater nutrient density. The modified myofiber type is responsible for a lower capillary density, and it induces a more glycolytic metabolism. There are associated changes for the living animal and post-mortem metabolism alterations, requiring appropriate slaughter conditions to maintain a high meat quality. Intramuscular fat content is low, and it is characterized by more unsaturated fatty acids, providing healthier meat for the consumer. It may not always be easy to find a balance between the different disciplines underlying the livestock husbandry of DM animals to realize a good performance and health and meat quality. PMID- 26487037 TI - White matter alterations of the corticospinal tract in adults born very preterm and/or with very low birth weight. AB - White matter (WM) injury, either visible on conventional magnetic resonance images (MRI) or measurable by diffusion tensor imaging (DTI), is frequent in preterm born individuals and often affects the corticospinal tract (CST). The relation between visible and invisible white mater alterations in the reconstructed CST of preterm subjects has so far been studied in infants, children and up to adolescence. Therefore, we probabilistically tracked the CST in 53 term-born and 56 very preterm and/or low birth weight (VP/VLBW, < 32 weeks of gestation and/or birth weight < 1,500 g) adults (mean age 26 years) and compared their DTI parameters (axial, radial, mean diffusivity--AD, RD, MD, fractional anisotropy--FA) in the whole CST and slice-wise along the CST. Additionally, we used the automatic, tract-based-spatial-statistics (TBSS) as an alternative to tractography. We compared control and VP/VLBW and subgroups with and without CST WM lesions visible on conventional MRI. Compared to controls, VP/VLBW subjects had significantly higher diffusivity (AD, RD, MD) in the whole CST, slice-wise along the CST, and in multiple regions along the TBSS skeleton. VP/VLBW subjects also had significantly lower (TBSS) and higher (tractography) FA in regions along the CST, but no different mean FA in the tracked CST as a whole. Diffusion changes were weaker, but remained significant for both, tractography and TBSS, when excluding subjects with visible CST lesions. Chronic CST injury persists in VP/VLBW adults even in the absence of visible WM lesions, indicating long-term structural WM changes induced by premature birth. PMID- 26487038 TI - Impact of Medicare Age Eligibility on Health Spending among U.S. and Foreign-Born Adults. AB - OBJECTIVE: Examine differences in health care expenditures between foreign-born and U.S.-born adults in late mid-life, and how these differences change after age 65, when Medicare is near-universal. DATA: Medical Expenditures Panel Survey data (2000-2010) on adults ages 55-75 years (n = 46,132) to examine annual total and payer-specific expenditures. STUDY DESIGN: We use (1) propensity score matching to generate quasi-experimental samples with equivalent health needs and health care preferences, (2) generalized linear modeling to estimate group differences in expenditures, and (3) bootstrapping methods to obtain variance estimates for significance testing. PRINCIPAL FINDINGS: Among adults ages 55-64, the foreign born spend $3,314 (p < .001) less on health care, even when they have equivalent health needs and health care preferences. This difference is due mainly to lower spending through private insurance. After age 65, differences in total spending disappear but not differences in payer-specific spending. The foreign-born continue to spend significantly less through private insurance and begin to spend significantly more through Medicare and Medicaid. CONCLUSION: Foreign-born adults in late mid-life spend significantly less on health care than U.S.-born adults. After age 65, with near-universal Medicare coverage, differences in total spending disappear between the groups, although differences in spending by payer persist. PMID- 26487040 TI - Network structure of multivariate time series. AB - Our understanding of a variety of phenomena in physics, biology and economics crucially depends on the analysis of multivariate time series. While a wide range tools and techniques for time series analysis already exist, the increasing availability of massive data structures calls for new approaches for multidimensional signal processing. We present here a non-parametric method to analyse multivariate time series, based on the mapping of a multidimensional time series into a multilayer network, which allows to extract information on a high dimensional dynamical system through the analysis of the structure of the associated multiplex network. The method is simple to implement, general, scalable, does not require ad hoc phase space partitioning, and is thus suitable for the analysis of large, heterogeneous and non-stationary time series. We show that simple structural descriptors of the associated multiplex networks allow to extract and quantify nontrivial properties of coupled chaotic maps, including the transition between different dynamical phases and the onset of various types of synchronization. As a concrete example we then study financial time series, showing that a multiplex network analysis can efficiently discriminate crises from periods of financial stability, where standard methods based on time-series symbolization often fail. PMID- 26487041 TI - Pattern formation on silicon by laser-initiated liquid-assisted colloidal lithography. AB - We report sub-diffraction limited patterning of Si substrate surfaces by laser initiated liquid-assisted colloidal lithography. The technique involves exposing a two-dimensional lattice of transparent colloidal particles spin coated on the substrate of interest (here Si) immersed in a liquid (e.g. methanol, acetone, carbon tetrachloride, toluene) to a single picosecond pulse of ultraviolet laser radiation. Surface patterns formed using colloidal particles with different radii in the range 195 nm <= R <= 1.5 MUm and liquids with differing indices of refraction (n(liquid)) are demonstrated, the detailed topographies of which are sensitively dependent upon whether the index of refraction of the colloidal particle (n(colloid)) is greater or smaller than n liquid (i.e. upon whether the incident light converges or diverges upon interaction with the particle). The spatial intensity modulation formed by diffraction of the single laser pulse by the colloidal particles is imprinted into the Si substrate. PMID- 26487039 TI - Adolescent binge-like alcohol alters sensitivity to acute alcohol effects on dopamine release in the nucleus accumbens of adult rats. AB - Rationale: Early onset of alcohol drinking has been associated with alcohol abuse in adulthood. The neurobiology of this phenomenon is unclear, but mesolimbic dopamine pathways, which are dynamic during adolescence, may play a role. OBJECTIVES: We investigated the impact of adolescent binge-like alcohol on phasic dopaminergic neurotransmission during adulthood. METHODS: Rats received intermittent intragastric ethanol, water, or nothing during adolescence. In adulthood, electrically evoked dopamine release and subsequent uptake were measured in the nucleus accumbens core at baseline and after acute challenge of ethanol or saline. RESULTS: Adolescent ethanol exposure did not alter basal measures of evoked dopamine release or uptake. Ethanol challenge dose-dependently decreased the amplitude of evoked dopamine release in rats by 30-50 % in control groups, as previously reported, but did not alter evoked release in ethanol exposed animals. To address the mechanism by which ethanol altered dopamine signaling, the evoked signals were modeled to estimate dopamine efflux per impulse and the velocity of the dopamine transporter. Dopamine uptake was slower in all exposure groups after ethanol challenge compared to saline, while dopamine efflux per pulse of electrical stimulation was reduced by ethanol only in ethanol naive rats. CONCLUSIONS: The results demonstrate that exposure to binge levels of ethanol during adolescence blunts the effect of ethanol challenge to reduce the amplitude of phasic dopamine release in adulthood. Large dopamine transients may result in more extracellular dopamine after alcohol challenge in adolescent exposed rats and may be one mechanism by which alcohol is more reinforcing in people who initiated drinking at an early age. PMID- 26487042 TI - A neurophylogenetic approach provides new insight to the evolution of Scaphopoda. AB - The position of scaphopods in molluscan phylogeny remains singularly contentious, with several sister relationships supported by morphological and phylogenomic data: Scaphopoda + Bivalvia (Diasoma), Scaphopoda + Cephalopoda (Variopoda), and Scaphopoda + Gastropoda. Nervous system architecture has contributed significant insights to reconstructing phylogeny in the Mollusca and other invertebrate groups, but a modern neurophylogenetic approach has not been applied to molluscs, hampered by a lack of clearly defined homologous characters that can be unequivocally compared across the radical body plan disparity among the living clades. We present the first three-dimensional reconstruction of the anterior nervous system of a scaphopod, Rhabdus rectius, using histological tomography. We also describe a new putative sensory organ, a paired and pigmented sensory mantle slit. This structure is restricted to our study species and not a general feature of scaphopods, but it forms an integral part of the description of the nervous system in R. rectius. It also highlights the potential utility of neuro anatomical characters for multiple levels of phylogenetic inference beyond this study. This potential has not previously been exploited for the thorny problem of molluscan phylogeny. The neuroanatomy of scaphopods demonstrates a highly derived architecture that shares a number of key characters with the cephalopod nervous system, and supports a Scaphopoda + Cephalopoda grouping. PMID- 26487044 TI - CORR Insights(r): Does Strict Adherence to the Ponseti Method Improve Isolated Clubfoot Treatment Outcomes? A Two-institution Review. PMID- 26487043 TI - Cochrane in CORR1: Steroids for Acute Spinal Cord Injury (Review). PMID- 26487046 TI - Digital LED Pixels: Instructions for use and a characterization of their properties. AB - This article details how to control light emitting diodes (LEDs) using an ordinary desktop computer. By combining digitally addressable LEDs with an off the-shelf microcontroller (Arduino), multiple LEDs can be controlled independently and with a high degree of temporal, chromatic, and luminance precision. The proposed solution is safe (can be powered by a 5-V battery), tested (has been used in published research), inexpensive (~ $60 + $2 per LED), highly interoperable (can be controlled by any type of computer/operating system via a USB or Bluetooth connection), requires no prior knowledge of electrical engineering (components simply require plugging together), and uses widely available components for which established help forums already exist. Matlab code is provided, including a 'minimal working example' of use suitable for use by beginners. Properties of the recommended LEDs are also characterized, including their response time, luminance profile, and color gamut. Based on these, it is shown that the LEDs are highly stable in terms of both luminance and chromaticity, and do not suffer from issues of warm-up, chromatic shift, and slow response times associated with traditional CRT and LCD monitor technology. PMID- 26487045 TI - How Does Bony Surgery Affect Results of Anterior Open Reduction in Walking-age Children With Developmental Hip Dysplasia? AB - BACKGROUND: Anterior open reduction is commonly used to treat hip subluxation or dislocation in developmental dysplasia of the hip (DDH) in walking-age children. Pelvic and/or femoral osteotomy may be used in addition, but it is unclear how this affects avascular necrosis (AVN) risk and radiological and clinical results. QUESTIONS/PURPOSES: The purpose of this study was to review studies of walking age patients treated either with an open reduction alone or combined with pelvic and/or femoral osteotomies and determine whether there is a difference between groups in the proportion of patients: (1) developing clinically relevant femoral head AVN (Kalamchi & MacEwen Types II to IV or equivalent); (2) achieving a satisfactory radiological result (Severin Grade I/II or equivalent); (3) achieving a satisfactory clinical result (McKay excellent or good rating or equivalent); and (4) requiring further nonsalvage surgery. METHODS: MEDLINE, Embase, the Cochrane Centre Register of Controlled Trials, and ClinicalTrials.gov were searched for studies of anterior open reduction for DDH in children aged 12 months to 6 years old. We assessed AVN, clinical and radiological results, and requirement for further procedures. The effect of failed conservative management, traction, age at operation, and followup duration was also assessed. Eighteen studies met the review eligibility criteria. RESULTS: Open reduction alone had a lower risk of AVN than open reduction combined with pelvic and femoral osteotomy (4% versus 24%), but there was no significant difference compared with open reduction with either pelvic (17%) or femoral osteotomy (18%). More hips treated with open reduction alone had satisfactory radiological results than open reduction combined with pelvic and femoral osteotomy (97% versus 83%) and satisfactory clinical results than all other interventions. More hips treated with open reduction alone required further surgical management (56%) compared with open reduction and pelvic osteotomy (11%) and combined pelvic and femoral osteotomies (8%). CONCLUSIONS: Open reduction with concomitant pelvic osteotomy is the most appropriate option to provide durable results with the lowest risk of AVN and best radiological and clinical results. There is no evidence that addition of a femoral osteotomy provides any additional benefit to the patient, although it may be necessary to achieve reduction. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26487047 TI - A novel approach to investigate recursion and iteration in visual hierarchical processing. AB - We describe a new method to explore recursive cognition in the visual domain. We define recursion as the ability to represent multiple hierarchical levels using the same rule, entailing the ability to generate new levels beyond those previously encountered. With this definition recursion can be distinguished from general hierarchical embedding. To investigate this recursion/hierarchy distinction in the visual domain, we developed two novel methods: The Visual Recursion Task (VRT), in which an inferred rule is used to represent new hierarchical levels, and the Embedded Iteration Task (EIT), in which additional elements are added to an existing hierarchical level. We found that adult humans can represent recursion in the visuo-spatial domain, and that this ability is distinct from both general intelligence and the ability to represent iterative processes embedded within hierarchical structures. Compared with embedded iteration, visual recursion correlated positively with other recursive planning tasks (Tower of Hanoi), but not with specific visuo-spatial resources (spatial short-term memory and working memory). We conclude that humans are able to use recursive representations to process complex visuo-spatial hierarchies and that our visual recursion task taps into specific cognitive resources. This method opens exciting opportunities to explore the relationship between visual recursion and language. PMID- 26487048 TI - The relative accuracy and interpretability of five sequential analysis methods: A simulation study. AB - A variety of sequential analysis methods exist to quantify close temporal associations between events from direct observation data. In the present study, we compared the relative accuracy and interpretability of five sequential analysis methods using simulated data. The methods included three existing approaches (event lag, concurrent interval, and time window) and two proposed modifications of the event lag approach (event lag with contiguous pauses and event lag with noncontiguous pauses) designed to address limitations of the existing approaches. We evaluated accuracy on the basis of the extent to which the mean contingency estimates produced by each method approximated a known mean (i.e., zero). We evaluated interpretability on the basis of the extent to which the contingency estimates produced by each method were independent from chance estimates of the two-event sequence. The results indicated that the event lag with contiguous pauses method produced the most accurate and interpretable estimates of contingency. This modified method prevents the total number of event types from influencing contingency estimates, thus solving a problem associated with the traditional event lag method. PMID- 26487049 TI - Filling the gaps: A speeded word fragment completion megastudy. AB - In the speeded word fragment completion task, participants have to complete fragments such as tom_to as quickly and accurately as possible. Previous work has shown that this paradigm can successfully capture subtle priming effects (Heyman, De Deyne, Hutchison, & Storms Behavior Research Methods, 47, 580-606, 2015). In addition, it has several advantages over the widely used lexical decision task. That is, the speeded word fragment completion task is more efficient, more engaging, and easier. Given its potential, we conducted a study to gather speeded word fragment completion norms. The goal of this megastudy was twofold. On the one hand, it provides a rich database of over 8,000 stimuli, which can, for instance, be used in future research to equate stimuli on baseline response times. On the other hand, the aim was to gain insight into the underlying processes of the speeded word fragment completion task. To this end, item-level regression and mixed-effects analyses were performed on the response latencies using 23 predictor variables. Since all items were selected from the Dutch Lexicon Project (Keuleers, Diependaele, & Brysbaert Frontiers in Psychology, 1, 174, 2010), we ran the same analyses on lexical decision latencies to compare the two tasks. Overall, the results revealed many similarities, but also some remarkable differences, which are discussed. We propose that both tasks are complementary when examining visual word recognition. The article ends with a discussion of potential process models of the speeded word fragment completion task. PMID- 26487050 TI - Improving impulsivity assessment using movement recognition: A pilot study. AB - The Continuous Performance Test (CPT) is a widely used computerized test to assess impulsivity. This article proposes the use of a CPT variant based on movement recognition to obtain more accurate measurements of impulsivity. In this pilot study, 22 volunteers participated in a CPT experiment responding to the stimuli by raising his or her dominant hand instead of pressing the space bar in a keyboard. Using this method, correlations of self-reported impulsivity with number of commission errors and average reaction time improved those obtained with standard CPT. PMID- 26487051 TI - Effect size measures in a two-independent-samples case with nonnormal and nonhomogeneous data. AB - In psychological science, the "new statistics" refer to the new statistical practices that focus on effect size (ES) evaluation instead of conventional null hypothesis significance testing (Cumming, Psychological Science, 25, 7-29, 2014). In a two-independent-samples scenario, Cohen's (1988) standardized mean difference (d) is the most popular ES, but its accuracy relies on two assumptions: normality and homogeneity of variances. Five other ESs-the unscaled robust d (d r* ; Hogarty & Kromrey, 2001), scaled robust d (d r ; Algina, Keselman, & Penfield, Psychological Methods, 10, 317-328, 2005), point-biserial correlation (r pb ; McGrath & Meyer, Psychological Methods, 11, 386-401, 2006), common-language ES (CL; Cliff, Psychological Bulletin, 114, 494-509, 1993), and nonparametric estimator for CL (A w ; Ruscio, Psychological Methods, 13, 19-30, 2008)-may be robust to violations of these assumptions, but no study has systematically evaluated their performance. Thus, in this simulation study the performance of these six ESs was examined across five factors: data distribution, sample, base rate, variance ratio, and sample size. The results showed that A w and d r were generally robust to these violations, and A w slightly outperformed d r . Implications for the use of A w and d r in real-world research are discussed. PMID- 26487052 TI - MultiLog: a tool for the control and output merging of multiple logging applications. AB - MultiLog is a logging tool that controls, gathers, and combines the output, on the-fly, from existing research and commercial logging applications or "loggers." Loggers record a specific set of user actions on a computing device, helping researchers to better understand environments or interactions, guiding the design of new or improved interfaces and applications. MultiLog reduces researchers' required implementation effort by simplifying the set-up of multiple loggers and seamlessly combining their output. This in turn increases the availability of logging systems to non-technical experimenters for both short-term and longitudinal observation studies. MultiLog supports two operating modes: "researcher mode" where experimenters configure multiple logging systems, and "deployment mode" where the system is deployed to user-study participants' systems. Researcher mode allows researchers to install, configure log filtering and obfuscation, observe near real-time event streams, and save configuration files ready for deployment. Deployment mode simplifies data collection from multiple loggers by running in the system tray at user log-in, starting loggers, combining their output, and securely uploading the data to a web-server. It also supports real-time browsing of log data, pausing of logging, and removal of log lines. Performance evaluations show that MultiLog does not adversely affect system performance, even when simultaneously running several logging systems. Initial studies show the system runs reliably over a period of 10 weeks. PMID- 26487053 TI - Item exposure control for multidimensional computer adaptive testing under maximum likelihood and expected a posteriori estimation. AB - Item bank stratification has been shown to be an effective method for combating item overexposure in both uni- and multidimensional computer adaptive testing. However, item bank stratification cannot guarantee that items will not be overexposed-that is, exposed at a rate exceeding some prespecified threshold. In this article, we propose enhancing stratification for multidimensional computer adaptive tests by combining it with the item eligibility method, a technique for controlling the maximum exposure rate in computerized tests. The performance of the method was examined via a simulation study and compared to existing methods of item selection and exposure control. Also, for the first time, maximum likelihood (MLE) and expected a posteriori (EAP) estimation of examinee ability were compared side by side in a multidimensional computer adaptive test. The simulation suggested that the proposed method is effective in suppressing the maximum item exposure rate with very little loss of measurement accuracy and precision. As compared to MLE, EAP generates smaller mean squared errors of the ability estimates in all simulation conditions. PMID- 26487054 TI - Communicative interactions in point-light displays: Choosing among multiple response alternatives. AB - Vision scientists are increasingly relying on the point-light technique as a way to investigate the perception of human motion. Unfortunately, the lack of standardized stimulus sets has so far limited the use of this technique for studying social interaction. Here, we describe a new tool to study the interaction between two agents starting from point-light displays: the Communicative Interaction Database - 5AFC format (CID-5). The CID-5 consists of 14 communicative and seven non-communicative individual actions performed by two agents. Stimuli were constructed by combining motion capture techniques and 3-D animation software to provide precise control over the computer-generated actions. For each action stimulus, we provide coordinate files and movie files depicting the action as seen from four different perspectives. Furthermore, the archive contains a text file with a list of five alternative action descriptions to construct forced-choice paradigms. In order to validate the CID-5 format, we provide normative data collected to assess action identification within a 5AFC tasks. The CID-5 archive is freely downloadable from http://bsb-lab.org/research/ and from the supplementary materials of this article. PMID- 26487055 TI - Immune checkpoint inhibitors: a new frontier in bladder cancer. AB - Immunotherapy is rapidly changing the field of urologic oncology. In this review, we discuss the role of the immune system in general and place a particular emphasis on the biology of the immune checkpoint and its role in cancer. Bladder cancer, as one of the most immunogenic neoplasms, is an exciting target for immune checkpoint inhibition. Early preclinical data and human trial experience suggest that this new drug class may shape bladder cancer therapy for years to come. PMID- 26487062 TI - Electromyography of Swallowing with Fine Wire Intramuscular Electrodes in Healthy Human: Amplitude Difference of Selected Hyoid Muscles. AB - Few studies have examined the intensity of muscle activity during swallowing in healthy humans. We examined selected hyoid muscles using fine wire intramuscular electromyography (EMG) during swallowing of four food consistencies. Thirteen healthy adults were studied using videofluorography and EMG of the anterior belly of digastric (ABD), geniohyoid (GH), sternohyoid (SH), and masseter (MA; surface electrodes) while ingesting thin liquid (three trials) and solid food of three consistencies (banana, tofu, and cookie, three trials each). After rectification, integration, and normalization, peak EMG amplitudes for each muscle in each trial were measured. Hyoid displacements were measured in two dimensions. Data were analyzed using repeated measures ANOVA with Bonferroni correction. GH had the highest adjusted amplitude for both solids and liquid. For MA and ABD, amplitude was highest with triturated cookie. For ABD, amplitude was lowest with liquid. There were no significant food consistency effects for GH or SH. Hyoid displacements were greatest for cookie and the lowest for liquid. EMG amplitude varied with initial food consistency. The high peak EMG amplitude of GH is consistent with its essential role in opening the upper esophageal sphincter. High MA amplitude with hard solid foods is likely due to the higher tongue-palate pressure with triturated solids. The higher ABD amplitude with solid food is associated with greater hyoid displacement. These findings support the existence of a central pattern generator that modifies the level of muscle activity during pharyngeal swallowing in response to input from mechanoreceptors in the oral cavity. PMID- 26487063 TI - Usefulness of Prophylactic Percutaneous Gastrostomy Placement in Patients with Head and Neck Cancer Treated with Chemoradiotherapy. AB - Chemoradiotherapy (CRT) has evolved as the preferred organ preservation strategy in the treatment of locally advanced head and neck cancer (HNC). This approach increases malnutrition, and thus, establishing a direct enteral feeding route is essential. To evaluate the usefulness of prophylactic percutaneous endoscopic gastrostomy (PEG) in HNC patients receiving definitive CRT, we performed a prospective evaluation of HNC patients over a 6-month period. Patients and tumor characteristics, nutritional status 30 days after PEG insertion and technique complications were evaluated. We also assessed the long-term PEG usage. Forty seven PEGs were placed and only 2 patients did not use it. The mean time of PEG use was 131 days (4-255) and mean duration of exclusive utilization was 71 days (4-180). On 30th day after procedure, 34/45 (76 %) patients had lost weight, but only 10/45 (22 %) patients had lost more than 10 % of their initial weight. The most frequent complications were minor peristomal infections, which were correlated with proton-pump inhibitor use before PEG placement (OR 3.91, 95 % CI 1.01-15.2, and p = 0.049). One year later, 19 % of patients in remission continue needing PEG. Enteric nutritional support is essential during and after CRT in HNC patients. Most patients lost weight even with PEG. One-fifth of patients in remission required long-term PEG utilization. PMID- 26487064 TI - Compensatory Mechanisms in Patients After a Partial or Total Glossectomy due to Oral Cancer. AB - Excision of a part or the whole of tongue due to oral cancer disturbs swallowing and speech. Lower airways aspiration of the swallowed bolus in patients after such oral structures excision is a symptom of major swallowing disorder and may be the cause of aspiration pneumonia. Restoration of oral nutrition is possible after exclusion or reduction of aspiration threat in the patients. Video fluoroscopic evaluation of the swallowing performed at the beginning of the swallowing rehabilitation in 95 patients after a total or partial glossectomy due to oral cancer, who assessed their saliva swallowing as efficient on the day of examination, showed disturbances of all of the swallowing stages. The most common disturbances involved the oral stage: limited mobility of the oral tongue, impaired glossopalatal seal, and weak glossopharyngeal seal. The most serious among them involved pharyngeal stage of swallowing, as leakage into the larynx and aspiration. The patients used their own methods during barium suspension swallowing to facilitate the swallowing act. They used such methods as: changing the position of the head to the body, additional swallows, engaging the adjacent structures into sealing the oral fissure. We assumed that the compensatory mechanisms (CM) worked out by the patients before the swallowing examination will enable them efficient barium suspension swallowing. The CM were applied by 71 of 95 patients; 51 of the patients used more than one compensatory mechanism. Swallowing in 61 of the compensating patients was at least functional; swallowing in 10 of the compensating patients was non-efficient and caused recurrent aspiration. The results of our research negate the validity of multiple swallows (more than three) without apnea elongation because it may lead to aspiration. Aspiration was also recorded in patients with weak airways closure and immovable epiglottis, who complemented the impaired oral transport with gravitational oral transport by moving chin up during a swallow. The hypothesis that CM applied by the patients after oral cancer excision during saliva swallowing will be helpful in swallowing of the barium suspension was not proved. In 10 of all the patients recurring aspiration was found despite CM application. Determination of aspiration risk is the key to efficient swallowing rehabilitation. The assessment of CM applied spontaneously by the patients' maintenance validity is particularly important. Video fluoroscopic examination of swallowing allows to assess the aforementioned issue and is crucial for better comprehension of CM applied by the patients in creating a new swallowing pattern after oral cancer excision. PMID- 26487065 TI - New Swallowing Evaluation Using Piezoelectricity in Normal Individuals. AB - This study aimed to elucidate the relationship between the piezoelectric waveform latency, hyoid bone movement, surface electromyogram (sEMG), and the pharyngeal transit time (PTT) during swallowing. Forty-one healthy subjects were divided into three age groups: younger (20-39 years, n = 8), middle-aged (40-59 years, n = 9), and older (60-79 years, n = 24). Motion analysis of the hyoid bone using videofluorography (VF), waveform analysis of the front neck using piezoelectric films, and sEMG of the suprahyoid muscle group were performed simultaneously. Latencies of the three movement phases were defined as upward (VFS1), forward (VFS2), and returning to starting position (VFS3). The three phases of the piezoelectric waveform-from wave initiation of the negative wave to the start of the second deep negative wave; from the start of the second deep negative wave to the start of the last positive wave (SLPW); and from the SLPW to the end of the last positive wave-were defined as PS1, PS2, and PS3, respectively. VFS1-3 and PS1-3 were significantly correlated. VFS1 and PS1 latencies were significantly longer with thick liquid than with thin liquid. VFS2, PS1, and PS2 latencies were longer in the older group than in the other two groups. The start of PS1 was nearly equal to those of sEMG and VFS1. Bolus arrival time in the valleculae was statistically equal to the end of the PS1 with both thin and thick liquids. To establish the swallowing screening using Piezoelectric film, further investigation is necessary in the dysphagia patients. PMID- 26487067 TI - High Electron Mobility of Nb-Doped SrTiO3 Films Stemming from Rod-Type Sr Vacancy Clusters. AB - Achieving high electron mobility in SrTiO3 films is of significant interest, particularly in relation to technological applications such as oxide semiconductors, field-induced superconductors, and thermoelectric generators. One route to achieving high electron mobility is growth of high quality SrTiO3 films with low defect concentrations. Another approach for mobility enhancement is applying a strain to the crystal. However, the maximum mobilities obtainable by these approaches are limited both by external and internal factors (currently available fabrication techniques, and maximum crystal strain, for example). In this paper, we demonstrate a unique crystal engineering approach to alter the strain in Nb-doped SrTiO3 films based on the deliberate introduction of Sr vacancy clusters. Nb-doped SrTiO3 films produced in this manner are found to exhibit remarkably enhanced electron mobilities (exceeding 53,000 cm(2) V(-1) s( 1)). This method of defect engineering is expected to enable tuning and enhancement of electron mobilities not only in SrTiO3 films, but also in thin films and bulk crystals of other perovskite-type materials. PMID- 26487066 TI - Constitutively Active Acetylcholine-Dependent Potassium Current Increases Atrial Defibrillation Threshold by Favoring Post-Shock Re-Initiation. AB - Electrical cardioversion (ECV), a mainstay in atrial fibrillation (AF) treatment, is unsuccessful in up to 10-20% of patients. An important aspect of the remodeling process caused by AF is the constitutive activition of the atrium specific acetylcholine-dependent potassium current (IK,ACh -> IK,ACh-c), which is associated with ECV failure. This study investigated the role of IK,ACh-c in ECV failure and setting the atrial defibrillation threshold (aDFT) in optically mapped neonatal rat cardiomyocyte monolayers. AF was induced by burst pacing followed by application of biphasic shocks of 25-100 V to determine aDFT. Blocking IK,ACh-c by tertiapin significantly decreased DFT, which correlated with a significant increase in wavelength during reentry. Genetic knockdown experiments, using lentiviral vectors encoding a Kcnj5-specific shRNA to modulate IK,ACh-c, yielded similar results. Mechanistically, failed ECV was attributed to incomplete phase singularity (PS) removal or reemergence of PSs (i.e. re initiation) through unidirectional propagation of shock-induced action potentials. Re-initiation occurred at significantly higher voltages than incomplete PS-removal and was inhibited by IK,ACh-c blockade. Whole-heart mapping confirmed our findings showing a 60% increase in ECV success rate after IK,ACh-c blockade. This study provides new mechanistic insight into failing ECV of AF and identifies IK,ACh-c as possible atrium-specific target to increase ECV effectiveness, while decreasing its harmfulness. PMID- 26487068 TI - Nonparametric estimation of time-dependent ROC curves conditional on a continuous covariate. AB - The receiver-operating characteristic (ROC) curve is the most widely used measure for evaluating the performance of a diagnostic biomarker when predicting a binary disease outcome. The ROC curve displays the true positive rate (or sensitivity) and the false positive rate (or 1-specificity) for different cut-off values used to classify an individual as healthy or diseased. In time-to-event studies, however, the disease status (e.g. death or alive) of an individual is not a fixed characteristic, and it varies along the study. In such cases, when evaluating the performance of the biomarker, several issues should be taken into account: first, the time-dependent nature of the disease status; and second, the presence of incomplete data (e.g. censored data typically present in survival studies). Accordingly, to assess the discrimination power of continuous biomarkers for time dependent disease outcomes, time-dependent extensions of true positive rate, false positive rate, and ROC curve have been recently proposed. In this work, we present new nonparametric estimators of the cumulative/dynamic time-dependent ROC curve that allow accounting for the possible modifying effect of current or past covariate measures on the discriminatory power of the biomarker. The proposed estimators can accommodate right-censored data, as well as covariate-dependent censoring. The behavior of the estimators proposed in this study will be explored through simulations and illustrated using data from a cohort of patients who suffered from acute coronary syndrome. PMID- 26487069 TI - [Quality, accesibility and sustainability: Keys for Advanced Nursing Practice in Spain]. PMID- 26487070 TI - [Is it necessary to measure gastric residuals in very low birth weight infants?]. PMID- 26487071 TI - Editorial: Time is brain! PMID- 26487072 TI - Outcome and pathogenesis of stroke is conditioned by place of stroke occurrence. AB - To investigate whether stroke pathogenesis and sequelae are conditional on place of initial stroke occurrence, 2,238 incident stroke cases among Rochester, Minnesota, residents in the period from 1950 to 1984 were evaluated. Virtually compete case ascertainment of first strokes in Rochester nursing homes (153 strokes), hospitals (194), and homes (1,891) was possible through a medical record linkage system. Stroke cases were reviewed by a neurologist applying uniform criteria. Although most patients had the first stroke at home (84%), there was an increasing trend over the study period of first strokes occurring while patients were hospitalized. For nursing home incident strokes, there was a linear increase over calendar time of patients being hospitalized. This paralleled an overall increase in patients being hospitalized for the first stroke. Persons with initial stroke in the home who were hospitalized had lower 5 year observed survival than those who were not hospitalized (p 0.0067), an indication that those with more severe stroke were more likely to be hospitalized. The 5-year relative survival was highest for initial stroke occurrence in the home (57%), intermediate for in-hospital strokes (35%), and lowest for nursing home strokes (11%). Comorbid conditions undoubtedly contributed to the difference in survival patterns. A cardiac source of embolus was present in more than 40% of strokes occurring in the nursing home and in over half the strokes that occurred in the hospital. PMID- 26487073 TI - Transcranial doppler findings during spontaneous recanalization of vertebrobasilar occlusions. AB - Transcranial Doppler sonography (TCD) is of recognized value in the noninvasive detection of intracranial stenosis and occlusion. Serial TCD studies can detect recanalization of middle cerebral artery occlusion. Little information exists on TCD findings during vertebrobasilar recanalization. We report a 25-year-old woman with chronic meningitis who developed severe pontine and cerebellar infarctions due to bilateral distal vertebral and proximal basilar artery occlusion. Initial TCD showed a high-resistance signal from the distal right vertebral artery and no signal from the basilar artery. Evolutionary changes in flow velocities detected by seven TCD studies over a 5-week period suggested spontaneous recanalization of the distal vertebral and proximal basilar artery occlusion. These findings were accompanied by dramatic clinical improvement. Recurrent symptoms and TCD on day 73 suggested reocclusion, confirmed by repeat angiography. TCD may be useful for monitoring posterior circulation hemodynamics during recanalization of vertebrobasilar occlusions in selected patients. PMID- 26487074 TI - Artery-to-Artery cerebral emboli detection with transcranial doppler: Analysis of eight cases. AB - We present eight cases in which intracranial arterial emboli were detected with transcranial Doppler (TCD). In all patients, the putative arterial source of emboli was demonstrated by angiography. The presumed lesion representing the source of emboli was atherosclerosis (three), radiation-induced atherosclerosis/dissection (one), fibromuscular dysplasia (one), and traumatic dissection (three). TCD was effective in detecting microemboli, localizing the potential source of emboli, and monitoring the effectiveness of treatment. PMID- 26487075 TI - Predictors of cerebral infarction following transient ischemic attack. AB - Transient ischemic attack (TIA) is a warning sign for impending cerebral infarction, mainly within several months following the attack. To determine if any clinical characteristics could prognosticate cerebral infarction following a TIA, we studied and followed 68 consecutive patients who presented with a TIA. We determined the vascular risk factors, frequency, duration, vascular territory involved, and presumed etiology of the attacks. Diagnostic tests and treatment were individualized. Follow-up ranged from 1 day to 36 months (mean, 19 months). Four patients died from non-neurologic causes without having had a stroke. Cerebral infarction occurred in five patients (7%), 6 hours, 1 day, 10 days, 5 months, and 14 months after the presenting TIA. Two clinical characteristics were associated with a significantly increased risk of cerebral infarction: diabetes mellitus (p < 0.001) and history of multiple TIAs > 1/month at the time of presentation (p = 0.005). Patients presenting with a recent TIA and these risk factors may benefit from more aggressive treatment. PMID- 26487076 TI - Comprehensive outpatient approach to stroke rehabilitation. AB - The purpose of this study was to describe the outcome of stroke rehabilitation in a comprehensive outpatient rehabilitation facility. The study consisted of 115 stroke patients, seen during a 3-year period, who were treated with outpatient Physiatric services, physical, occupational, and speech therapies, and social work services. Patient progress was measured by an Individual Functional Profile in the areas of mobility, self-care, communication, and social function. Improvements were shown from admission to discharge, in mobility by 73% of the patients, in activities of daily living (ADL) by 81%, in communication by 82%, and in social function by 58% of the patients. Maintenance of function was reported by telephone 3 months post-discharge, in mobility by 75% of the patients, in ADL by 75%, in communication by 88%, and in social function by 73%. In addition, improvements were shown by 4% in mobility, 12% in ADL, 7% in communication, and 14% in social function at 3 months. The study suggests that a comprehensive team approach in an outpatient setting for stroke rehabilitation is beneficial for a majority of the patients. PMID- 26487077 TI - Ticlopidine aspirin stroke study: Outcome by vascular distribution of the qualifying event. AB - Outcomes from the Ticlopidine Aspirin Stroke Study (TASS) population stratified by the vascular distribution of the qualifying ischemic event are described. Among patients having a qualifying event in the carotid circulation, the 1-year risk reduction for death or nonfatal stroke was 49% and for fatal or nonfatal stroke was 49.7% for ticlopidine versus aspirin. For those with a vertebrobasilar distribution, the 1-year risk reductions for death or nonfatal stroke and fatal or nonfatal stroke were 22% and 46% (NS), respectively, for ticlopidine relative to aspirin. The overall risk reduction for fatal or nonfatal stroke was 24.6% (1.35, 42.4; p = 0.039) for an event in the carotid distribution and 28.0% ( 20.6, 57.0; p = 0.211) for one in the vertebrobasilar distribution. The incidence of adverse events was greater in the ticlopidine group (40% versus 28%); however, the incidence of serious or life-threatening adverse events was similar (1.4% with ticlopidine and 1.5% with aspirin. PMID- 26487078 TI - Impact of transesophageal echocardiogram on the management of acute stroke. AB - The etiology of cardioembolism is established in only a small percentage of patients. With the recent availability of transesophageal echocardiography (TEE), the detection of a cardiac source has increased, but the usefulness of this added sensitivity is not well established. We recently reported that TEE may show a potential cardiacsource in41% of patients with stroke. This resulted in a change in therapy in only 5% of patients. We now report the reasons for this low impact of the use of TEE in patients with acute stroke. Patients already on anticoagulants, poor risk for anticoagulant therapy, and another more obvious etiology for the stroke were the most common reasons for not changing therapy. Our study suggests that TEE should be reserved for patients with acute stroke in whom an etiology is not evident and in whom detecting a cardiac source would lead to a change in therapy. PMID- 26487079 TI - Smoothly progressive cerebral infarction over three weeks: Clinicopathological study in a patient with carotid occlusion. AB - We report an 80-year-old patient with internal carotid artery (ICA) occlusion and smoothly progressive worsening of neurological and neuropsychological dysfunction over 3 weeks despite intravenous heparin anticoagulation. At autopsy, there were multiple small [nonvisible on computed tomography (CT)] and large (seen on CT) infarcts distal to the occluded ICA. They corresponded to multiple embolic arterial occlusions throughout the hemisphere. These findings show that smoothly progressing stroke associated with ipsilateral ICA occlusion may be due to relentless, iterative artery-to-artery embolism rather than to hemodynamic compromise. They also cast doubts on the potential usefulness of anticoagulation in this situation. PMID- 26487080 TI - Influence of site on course of intracerebral hemorrhage. AB - The influence of site of hemorrhage on presentation, clinical profile, hospital course, and outcome was examined in 225 patients with intracerebral hemorrhage in the NINDS Stroke Data Bank. Mode of presentation differed by hemorrhage site (coma at onset was most typical of pontine hemorrhage and headache with vomiting was most typical of cerebellar hemorrhage, whereas onset of focal deficit sometimes with headache was typical of lobar and and basal ganglionic hemorrhages). Distinct clinical profiles were found for cerebellar (ataxia, drowsiness, and horizontal gaze paresis), pontine (quadriparesis, coma, vertical and horizontal gaze paresis), and caudate hemorrhages (drowsiness and hemiparesis). Putaminal, thalamic, and lobar hemorrhages presented similarly with hemiparesis, sensory loss, and higher cortical function deficits. However, thalamic hemorrhages had more sensory loss, putaminal hemorrhages had more weakness, and lobar hemorrhages had more higher cortical function deficits. Hemorrhage volume was greatest for the lobar and putaminal hemorrhages and smallest for the pontine and cerebellar hemorrhages. Clot evacuations were performed for 28.9% of the lobar hemorrhages and 48.2% of the cerebellar hemorrhages. Few basal ganglionic hemorrhages or pontine hemorrhages had clot evacuations. Thirty-day survival was lowest for caudate hemorrhage (46.2%) and highest for cerebellar hemorrhage (81.5%). Hydrocephalus, intraventricular blood, larger size, and mass effect were adverse predictors of survival at most but not all hemorrhage sites. History of hypertension was the most prevalent risk factor for hemorrhage (64.0% of the patients). Other risk factors for hemorrhage included anticoagulants, platelet antiaggregating drugs, aneurysms, arteriovenous malformations, pregnancy, alcohol use, amyloid angiopathy, thrombocytopenia, renal and liver failure, and cocaine use. The most common medical complications were pneumonia (15.5%), urinary tract infection (15.0%), arrhythmias (8.4%), and seizures (8.0%). PMID- 26487081 TI - Using Bayesian analysis for hypothesis testing in addiction science. PMID- 26487082 TI - GABAergic neurons of the medial septum play a nodal role in facilitation of nociception-induced affect. AB - The present study explored the functional details of the influence of medial septal region (MSDB) on spectrum of nociceptive behaviours by manipulating intraseptal GABAergic mechanisms. Results showed that formalin-induced acute nociception was not affected by intraseptal microinjection of bicuculline, a GABAA receptor antagonist, or on selective lesion of septal GABAergic neurons. Indeed, the acute nociceptive responses were dissociated from the regulation of sensorimotor behaviour and generation of theta-rhythm by the GABAergic mechanisms in MSDB. The GABAergic lesion attenuated formalin-induced unconditioned cellular response in the anterior cingulate cortex (ACC) and blocked formalin-induced conditioned place avoidance (F-CPA), and as well as the contextual fear induced on conditioning with brief footshock. The effects of lesion on nociceptive conditioned cellular responses were, however, variable. Interestingly, the lesion attenuated the conditioned representation of experimental context in dorsal hippocampus field CA1 in the F-CPA task. Collectively, the preceding suggests that the MSDB is a nodal centre wherein the GABAergic neurons mediate nociceptive affect-motivation by regulating cellular mechanisms in ACC that confer an aversive value to the noxious stimulus. Further, in conjunction with a modulatory influence on hippocampal contextual processing, MSDB may integrate affect with context as part of associative learning in the F-CPA task. PMID- 26487083 TI - Experimental demonstration of high fidelity entanglement distribution over decoherence channels via qubit transduction. AB - Quantum coherence and entanglement, which are essential resources for quantum information, are often degraded and lost due to decoherence. Here, we report a proof-of-principle experimental demonstration of high fidelity entanglement distribution over decoherence channels via qubit transduction. By unitarily switching the initial qubit encoding to another, which is insensitive to particular forms of decoherence, we have demonstrated that it is possible to avoid the effect of decoherence completely. In particular, we demonstrate high fidelity distribution of photonic polarization entanglement over quantum channels with two types of decoherence, amplitude damping and polarization-mode dispersion, via qubit transduction between polarization qubits and dual-rail qubits. These results represent a significant breakthrough in quantum communication over decoherence channels as the protocol is input-state independent, requires no ancillary photons and symmetries, and has near-unity success probability. PMID- 26487084 TI - Rapid additive-free selenocystine-selenoester peptide ligation. AB - We describe an unprecedented reaction between peptide selenoesters and peptide dimers bearing N-terminal selenocystine that proceeds in aqueous buffer to afford native amide bonds without the use of additives. The selenocystine-selenoester ligations are complete in minutes, even at sterically hindered junctions, and can be used in concert with one-pot deselenization chemistry. Various pathways for the transformation are proposed and probed through a combination of experimental and computational studies. Our new reaction manifold is also showcased in the total synthesis of two proteins. PMID- 26487085 TI - Amino acid residues Ala283 and His421 in the RNA-dependent RNA polymerase of porcine reproductive and respiratory syndrome virus play important roles in viral ribavirin sensitivity and quasispecies diversity. AB - The quasispecies diversity of RNA viruses is mainly determined by the fidelity of RNA-dependent RNA polymerase (RdRp) during viral RNA replication. Certain amino acid residues play an important role in determining the fidelity, and such residues can be substituted with other amino acids to produce virus strains with higher fidelity. In this study, two amino acid substitutions (A283T and H421Y) in the RdRp of porcine reproductive and respiratory syndrome virus (PRRSV) were identified under the selection of ribavirin. Preliminary data showed that two substitutions were involved in conferring PRRSV with the properties of increased ribavirin resistance and restricted quasispecies diversity. The results indicated that these two amino acid residues (Ala283 and His421) play a crucial role in PRRSV replication by affecting the fidelity of its RdRp. The results have important implications for understanding the molecular mechanism of PRRSV evolution and pathogenicity, and developing a safer modified live-attenuated vaccine (MLV) against PRRSV. PMID- 26487086 TI - Hospital Nurses' Competencies in Disaster Situations: A Qualitative Study in the South of Brazil. AB - Introduction Hospital nurses play a key role in the aftermath of the occurrence of disasters and need specific competencies to work in these situations. From a global perspective, few models exist that focus on disaster nursing. PROBLEM: This study aimed to identify hospital nurses' competencies in disaster situations. METHOD: A qualitative, descriptive, exploratory study was developed using focus groups as a method of data collection. Three meetings were held from June through September 2012 with nurses who worked at a hospital used as reference for disaster situations in the South of Brazil. Thematic analysis of collected data generated the competencies. For statement standardization, a format consistent with a verb, a noun, and a complement was adopted. RESULTS: The group validated 17 competencies, which were organized according to the phases of emergency management described by the World Health Organization (WHO) and classified in domain areas of management, health care, communication, and education. CONCLUSIONS: The competencies identified in this study can contribute to the education and practice of nurses in the hospital ambience, strengthening its capacity to face disaster situations. PMID- 26487088 TI - Increasing water cycle extremes in California and in relation to ENSO cycle under global warming. AB - Since the winter of 2013-2014, California has experienced its most severe drought in recorded history, causing statewide water stress, severe economic loss and an extraordinary increase in wildfires. Identifying the effects of global warming on regional water cycle extremes, such as the ongoing drought in California, remains a challenge. Here we analyse large-ensemble and multi-model simulations that project the future of water cycle extremes in California as well as to understand those associations that pertain to changing climate oscillations under global warming. Both intense drought and excessive flooding are projected to increase by at least 50% towards the end of the twenty-first century; this projected increase in water cycle extremes is associated with a strengthened relation to El Nino and the Southern Oscillation (ENSO)--in particular, extreme El Nino and La Nina events that modulate California's climate not only through its warm and cold phases but also its precursor patterns. PMID- 26487087 TI - Natural history of chronic hepatitis B virus infection from infancy to adult life - the mechanism of inflammation triggering and long-term impacts. AB - Chronic hepatitis B virus (HBV) infection in endemic areas usually starts since infancy and early childhood and persists lifelong. The clinical course varies among different chronic infected subjects. Majority of chronic HBV infected children present with immune-tolerant status initially, experience the immune clearance phase with various degree of liver injury during or beyond puberty, and then enter the inactive phase after hepatitis B e antigen (HBeAg) seroconversion. Part of them may have HBV DNA titers elevation with hepatitis flare after HBeAg seroconversion, the so call HBeAg-negative hepatitis flare. Liver cirrhosis, and even hepatocellular carcinoma may develop afterward.The complex course of chronic HBV infection is associated with the age/route of viral acquisition, host factors such as immune and endocrine factors, viral factors, and host-viral interactions. The adrenarche and puberty onset modulate the start of immune clearance and the severity of liver inflammation in chronic HBV infected children. The genotype and phenotype of human cytokines, innate immunity, and human leukocyte antigens are also associated with the onset of immune clearance of HBV and severity of inflammation. Immune escape HBV mutant strains, emerged during the immune clearance phase under host immune surveillance, may cause different impacts on viral biosynthesis, host immune responses, and clinical course.Early events in childhood during chronic HBV infection may serve as important predictors for the later outcome in adulthood. Understanding the mechanisms triggering liver inflammation and their long-term impacts may enhance the development of better and earlier therapeutic strategies for patients with chronic HBV infection. PMID- 26487089 TI - A multifunctional hemin@metal-organic framework and its application to construct an electrochemical aptasensor for thrombin detection. AB - A new type of multifunctional metal-organic framework (MOF) has been synthesized by encapsulating hemin into the nano-sized Fe-MIL-88 MOFs (hemin@MOFs) and first applied in an electrochemical aptasensor to detect thrombin (TB) with the aid of an enzyme for signal amplification. The gold nanoparticle functionalized hemin@MOFs (Au/hemin@MOFs) have not only simultaneously served as redox mediators and solid electrocatalysts, but have also been utilized as an ideal loading platform to immobilize a large number of biomolecules. In this aptasensor, Au/hemin@MOFs conjugated with glucose oxidase (GOD) and thrombin binding aptamer (TBA II) were used as the secondary aptamer bioconjugates (Au/hemin@MOF-TBA II GOD bioconjugates), and TB was sandwiched between Au/hemin@MOF-TBA II-GOD bioconjugates and the amino-terminated TBA I which was self-assembled on the gold nanoparticle (AuNP) modified electrode. The GOD could oxidize glucose into gluconic acid accompanied by the generation of H2O2. The generated H2O2 on the electrode surface was further electrocatalyzed by hemin@MOFs to amplify the electrochemical signal of hemin contained in hemin@MOFs. Therefore, the synthesized hemin@MOFs represented a new paradigm for multifunctional materials since it combined three different functions including serving as catalysts, redox mediators and loading platforms within a single material. With such an ingenious design, a wide linear range of 0.0001 nM to 30 nM was acquired with a relatively low detection limit of 0.068 pM for TB detection. PMID- 26487090 TI - The complete mitochondrial genome of the Symphysodon aequifasciatus (Pellegrin, 1904). AB - In this study, the complete mitogenome sequence of the Symphysodon aequifasciatus has been sequenced by next-generation sequencing method. The mitogenome consists of 16 545 bp, including 13 protein-coding genes, 22 transfer RNAs and 2 ribosomal RNAs genes. The overall base composition of the fish is 28.8% for A, 30.1% for C, 15.0% for G, and 26.1% for T, suggesting a 99% identity to S. discus Heckel and a 98% identity to S. haraldi. It provides essential and important DNA molecular data for further phylogeography and evolutionary analysis for Symphysodon phylogeny. PMID- 26487092 TI - WFPHA: World Federation of Public Health Associations. PMID- 26487093 TI - Multi-slice nanostructured WS2@rGO with enhanced Li-ion battery performance and a comprehensive mechanistic investigation. AB - A thin nanoslice structured WS2@reduced graphene oxide (rGO) composite was successfully fabricated by a facile hydrothermal synthesis method. The layered structure and morphology of the composite were investigated by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM). The WS2@rGO composite structure demonstrated significantly enhanced rate capability performance in comparison with pristine WS2 when used as an anode material for lithium-ion batteries (LIBs). The composite demonstrated a capacity of 565 mA h g(-1) after 100 cycles when cycled at 0.1 A g(-1) and it could still deliver a stable capacity of about 337 mA h g( 1) at 2 A g(-1). Electrochemical impedance spectroscopy (EIS) measurement showed that the synergistic effect between WS2 and rGO could remarkably reduce the contact resistance and improve the corresponding electrochemical performances. In order to analyze and interpret the corresponding results from a theoretically sound perspective, first principles calculations was further performed to investigate the corresponding inner mechanisms of pristine WS2 and WS2@graphene composite. The nudged elastic band (NEB) method was used to investigate the diffusion properties of Li in the different structures. Molecular dynamics (MD) simulation and Young's modulus calculation were further employed to explore the stability and mechanical properties of the two structures for the first time. These new perspectives pave the way for the design and fabrication of graphene TMDs based composites as the next generation of LIB anode materials with high power density and cycling stability. PMID- 26487091 TI - Intraoperative neuromonitoring for function-guided resection differs for supratentorial motor eloquent gliomas and metastases. AB - BACKGROUND: Recent data show differences in intraoperative neuromonitoring (IOM) in relation to the operated brain lesion. Due to the recently shown infiltrative nature of cerebral metastases, this work investigates the differences of IOM for cerebral metastases and glioma resection concerning sensitivity, specificity, and predictive values when aiming on preservation of motor function. METHODS: Between 2006 and 2011 we resected 171 eloquently located tumors (56 metastases, 115 gliomas) associated with the rolandic cortex or the pyramidal tract using IOM via direct cortical motor evoked potentials (MEPs). Postoperatively, MEP data were re analyzed with respect to surgery-related paresis, residual tumor, and postoperative MRI with two different thresholds for MEP decline (50 and 80 % below baseline). RESULTS: MEP monitoring was successful in 158 cases (92.4 %). MEPs were stable in 54.7 % of all metastases cases and in 65.2 % of all glioma cases (p < 0.0001). After metastases resection, 21.4 % of patients improved and 21.9 % deteriorated in motor function. Glioma patients improved in only 5.4 % and worsened in 31.3 % of cases (p < 0.05). Resection was stopped due to MEP decline in 8.0 % (metastases) and 34.8 % of cases (gliomas) (p < 0.0002). CONCLUSION: There is significant difference between glioma and metastases resection. Post hoc, metastases show more stable MEPs but a surprisingly high rate of surgery related paresis and therefore a higher rate of false negative IOM. PMID- 26487095 TI - Using dual task walking as an aid to assess executive dysfunction ecologically in neurological populations: A narrative review. AB - Within rehabilitation, clinical assessment plays a crucial role in diagnosis, prognostication and making decisions about return to function. The ecological validity of the assessment of executive dysfunction has become a particular focus in neuropsychology and is gaining interest in mobility research and neurological rehabilitation of acquired brain injury or degenerative neurological diseases. In this narrative review, we look at how the task of walking and the inseparable cognitive demands and interference of the surrounding environment are exploited in dual task walking (DTW) paradigms to expose executive dysfunction. While quite a number of studies and reviews have recently focused on the utility of DTW for gait assessment, particularly to assess fall risk, very little consideration has been given to the level of ecological validity required. This paper directly addresses this issue with discussion of evidence and lacunas related to task, personal and technological factors that should be addressed in order to exploit fully DTW paradigms as an ecological assessment tool. PMID- 26487094 TI - Endometriosis as a risk factor for ovarian or endometrial cancer - results of a hospital-based case-control study. AB - BACKGROUND: No screening programs are available for ovarian or endometrial cancer. One reason for this is the low incidence of the conditions, resulting in low positive predictive values for tests, which are not very specific. One way of addressing this problem might be to use risk factors to define subpopulations with a higher incidence. The aim of this study was to investigate the extent to which a medical history of endometriosis can serve as a risk factor for ovarian or endometrial cancer. METHODS: In a hospital-based case-control analysis, the cases represented patients with endometrial or ovarian cancer who were participating in studies aimed at assessing the risk for these diseases. The controls were women between the age of 40 and 85 who were invited to take part via a newspaper advertisement. A total of 289 cases and 1016 controls were included. Using logistic regression models, it was tested whether self-reported endometriosis is a predictor of case-control status in addition to age, body mass index (BMI), number of pregnancies and previous oral contraceptive (OC) use. RESULTS: Endometriosis was reported in 2.1 % of the controls (n = 21) and 4.8 % of the cases (n = 14). Endometriosis was a relevant predictor for case-control status in addition to other predictive factors (OR 2.63; 95 % CI, 1.28 to 5.41). CONCLUSION: This case-control study found that self-reported endometriosis may be a risk factor for endometrial or ovarian cancer in women between 40 and 85 years. There have been very few studies addressing this issue, and incorporating it into a clinical prediction model would require a more precise characterization of the risk factor of endometriosis. PMID- 26487096 TI - Options for surgical treatment of cervical fractures in patients with spondylotic spine: a case series and review of the literature. AB - INTRODUCTION: The surgical treatment of unstable cervical fractures is challenging for spinal surgeons. Unstable cervical fractures associated with spondyloarthropathy and deformities that alter function, form and stability present a greater challenge. Having multiple options to manage this difficult situation is important to all spine surgeons and the results of each case depends on the singular characteristics of patients. The purpose of this case report is to describe the main forms of presentation of unstable cervical subaxial fractures in the spondylotic spine and their surgical treatments. CASE PRESENTATION: We present three cases of Caucasian men aged 30, 53 and 59 years with spondylosis with unstable cervical fractures and alternatives choices for surgical treatment, and a review of the literature. Each patient underwent a different surgical procedure of the cervical subaxial spine using an isolated anterior, posterior or combined approach demonstrating good outcomes in all cases. CONCLUSIONS: The treatment of subaxial cervical spinal fractures is complex, and when these fractures are associated with the deformities caused by spondyloarthropathies they can be thought provoking for spine surgeons such as orthopedists or neurosurgeons. The isolated anterior, posterior and combined approaches are safe and effective for treating these pathologies. PMID- 26487097 TI - New approaches from nanomedicine for treating leishmaniasis. AB - Leishmaniasis, a vector-borne disease caused by obligate intramacrophage protozoa, threatens 350 million people in 98 countries around the world. There are already 12 million infected people worldwide and two million new cases occur annually. Leishmaniasis has three main clinical presentations: cutaneous (CL), mucosal (ML), and visceral (VL). It is considered an opportunistic, infectious disease and the HIV-leishmaniasis correlation is well known. Antimonial compounds are used as first-line treatment drugs, but their toxicity, which can be extremely high, leads to a number of undesirable side effects and resultant failure of the patients to adhere to treatment. There is also a reported increase in Leishmania sp. resistance to these drugs. Nanotechnology has emerged as an attractive alternative because of its improved bioavailability and lower toxicity, and other characteristics that help to relieve the burden of this disease. In this review we will present some of the recent advances in the nanotechnological research regarding the treatment of leishmaniasis. The preclinical results regarding the approaches for a biomedical treatment of the disease have been encouraging, but further efforts will still be necessary for this therapy to have greater clinical applicability in humans. PMID- 26487100 TI - Resuscitating heart transplantation: the donation after circulatory determined death donor. PMID- 26487098 TI - Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations. AB - Although Bacillus Calmette-Guerin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor contributing to this variability may be the diversity of the BCG strains that are used around the world, in part from genomic changes accumulated during vaccine production and their resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression of proteins across five representative BCG strains of the four tandem duplication (DU) groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and insertions and deletions (indels) across fourteen BCG strains. Genome-wide SNP characterization allowed the construction of a new and robust phylogenic genealogy of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may be reflected by altered immunogenicity and possibly vaccine efficacy. Together, these integrated omic data represent the most comprehensive catalogue of genetic variation across a global collection of BCG strains. PMID- 26487101 TI - Clinical features and prognostic value of stent-graft-induced post-implantation syndrome after thoracic endovascular aortic repair in patients with type B acute aortic syndromes. AB - OBJECTIVES: The aim of this study was to investigate the incidence, the biomarker profile and the clinical impact of post-implantation syndrome (PIS) after thoracic endovascular aortic repair (TEVAR) for type B acute aortic syndromes (AASs). METHODS: This retrospective study included 133 patients with type B AASs undergoing TEVAR; PIS was defined as fever >38 degrees C, white blood cells (WBCs) >12.0/nl and C-reactive protein (CRP) >10 mg/dl within 72 h after TEVAR, despite negative blood cultures. Fibrinogen (FBG), D-dimer (D-d) and interleukin 6 (IL-6) were also determined. The clinical endpoints were all-cause mortality and a composite of major adverse events (MAEs such as aortic rupture, need for reintervention and all-cause mortality) at follow-up. RESULTS: PIS was diagnosed in 15.8% of patients and was associated with higher peak values of WBC (17.0 +/- 5.1 vs 10.6 +/- 3.7/nl, P = 0.002), CRP (22.0 +/- 5.4 vs 16.8 +/- 8.2 mg/dl, P = 0.03), FBG (779 +/- 246 vs 639 +/- 225 mg/dl, P = 0.046), D-d (1675 +/- 605 vs 1048 +/- 639 ug/l, P = 0.003) and IL-6 (192 +/- 101 vs 84 +/- 34 pg/ml, P = 0.03) than non-PIS patients. All-cause mortality did not significantly differ between PIS and non-PIS patients during the index hospitalization (0.0 vs 6.3%; P = 0.60) and at follow-up (18.8 vs 4.9%; P = 0.086). MAEs were more frequent in the PIS than in the non-PIS group (62.5 vs 25.9%; P = 0.004). PIS (hazard ratio [HR] 3.26, P = 0.022), stroke (HR 3.41, P = 0.004), aortic enlargement (HR 6.88, P = 0.001) and partial thrombosis of the false lumen (HR 6.20, P = 0.003) were independent predictors of MAEs. CONCLUSIONS: PIS occurred in 15.8% of patients with AASs without affecting in-hospital outcome. At follow-up, PIS was associated with increased rates of MAEs, but not mortality. PMID- 26487099 TI - The transcriptome of Candida albicans mitochondria and the evolution of organellar transcription units in yeasts. AB - BACKGROUND: Yeasts show remarkable variation in the organization of their mitochondrial genomes, yet there is little experimental data on organellar gene expression outside few model species. Candida albicans is interesting as a human pathogen, and as a representative of a clade that is distant from the model yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. Unlike them, it encodes seven Complex I subunits in its mtDNA. No experimental data regarding organellar expression were available prior to this study. METHODS: We used high throughput RNA sequencing and traditional RNA biology techniques to study the mitochondrial transcriptome of C. albicans strains BWP17 and SN148. RESULTS: The 14 protein-coding genes, two ribosomal RNA genes, and 24 tRNA genes are expressed as eight primary polycistronic transcription units. We also found transcriptional activity in the noncoding regions, and antisense transcripts that could be a part of a regulatory mechanism. The promoter sequence is a variant of the nonanucleotide identified in other yeast mtDNAs, but some of the active promoters show significant departures from the consensus. The primary transcripts are processed by a tRNA punctuation mechanism into the monocistronic and bicistronic mature RNAs. The steady state levels of various mature transcripts exhibit large differences that are a result of posttranscriptional regulation. Transcriptome analysis allowed to precisely annotate the positions of introns in the RNL (2), COB (2) and COX1 (4) genes, as well as to refine the annotation of tRNAs and rRNAs. Comparative study of the mitochondrial genome organization in various Candida species indicates that they undergo shuffling in blocks usually containing 2-3 genes, and that their arrangement in primary transcripts is not conserved. tRNA genes with their associated promoters, as well as GC-rich sequence elements play an important role in these evolutionary events. CONCLUSIONS: The main evolutionary force shaping the mitochondrial genomes of yeasts is the frequent recombination, constantly breaking apart and joining genes into novel primary transcription units. The mitochondrial transcription units are constantly rearranged in evolution shaping the features of gene expression, such as the presence of secondary promoter sites that are inactive, or act as "booster" promoters, simplified transcriptional regulation and reliance on posttranscriptional mechanisms. PMID- 26487102 TI - Collagen nanofiber containing silver nanoparticles for improved wound-healing applications. AB - Electrospun nanofibers showing great promise for fabricating nanostructured materials might help to improve the quality of wound care. The present study aimed to investigate the wound-healing potential of collagen nanofiber mats containing silver nanoparticles. Silver nanoparticles (AgNPs) synthesized by the chemical reduction method were incorporated in collagen nanofibers during the electrospinning process. Characterization of electrospun nanofiber mats revealed a mean fiber diameters in the range of 300-700 nm with a sustained release of silver ions shown to follow pseudo-order kinetics. MIC of AgNPs against Staphylococcus aureus and Pseudomonas aeruginosa were evaluated using micro dilution assay and further antimicrobial activity of fabricated nanofibers was performed. Finally, in vivo studies were performed to demonstrate the wound healing efficacy of composite nanofibers. In vitro results confirmed the potential antimicrobial efficacy provided by AgNPs and AgNPs composite nanofibers, essential to provide an aseptic environment at the wound site. In vivo study revealed that the rate of wound healing of the composite nanofiber mats was found to be accelerated compared with plain collagen nanofibers. Histology analysis revealed an accelerated re-epithelization, collagen production, and better wound contraction with AgNPs composite collagen nanofibers. PMID- 26487103 TI - Vaginal delivery simulation in the Obstetrics and Gynaecology clerkship. AB - BACKGROUND: Although simulation is now used in other areas of obstetrics and gynaecology, its utility in the training of an uncomplicated vaginal delivery is surprisingly under-explored. Here we describe our experience integrating simulation into the third-year Obstetrics and Gynaecology (OB/GYN) clerkship. METHODS: In 2013/14, at the start of each 4-week OB/GYN clerkship, each third year student participated in a 90-minute vaginal delivery simulation session using the Noelle((r)) simulator. Upon completion of the clerkship, they were surveyed using a five-point Likert scale questionnaire (1, inferior; 5, superior) to assess self-perceived training adequacy, clinical preparedness and number of deliveries performed during the clerkship. Students who completed the clerkship in 2012/13, before the introduction of the simulation, were also surveyed to serve as a comparison group. Survey scores and number of deliveries performed were compared between the two cohorts of students. RESULTS: The 2013/14 cohort (n = 98) who received simulation training gave their training in vaginal deliveries an average rating of 4.1, versus 2.7 for the 2012/13 cohort that did not receive the simulation (n = 80; p < 0.001). Self-perceived preparedness to perform a vaginal delivery was 4.0 in the 2013/14 cohort, versus 3.0 in the 2012/13 cohort (p < 0.001). There was no difference in the number of deliveries performed between the cohorts. DISCUSSION: Students that received simulation rated their training adequacy and readiness to perform a vaginal delivery higher than students that did not receive training. Simulation did not increase participation in real-life deliveries. The utility of simulation in the training of an uncomplicated vaginal delivery is under-explored. PMID- 26487104 TI - Patent foramen ovale: the current state of play. PMID- 26487106 TI - For the Love of Death: Somnophilic and Necrophilic Acts and Fantasies. AB - The psychoanalytic literature on somnophilic and necrophilic fantasies and acts is indeed sparse. It is argued here that one must distinguish the forms of fantasy, playacting, and actual behavior that lie along a spectrum of romantic or sexual behavior involving people who are sleeping, drugged, immobile, inanimate, comatose, or dead. Regardless of these distinctions, however, the underlying dynamics commonly involve reunion with the mother, an inability to mourn, fear of the female, and an attempt at mastering and transcending the fear of death. To highlight these psychodynamics, a clinical case of somnophilia, Pedro Almodovar's Talk to Her (a film about romantic relationships with comatose women), and the case of Count von Cosel, a quixotic necrophiliac, are presented. Gender differences are emphasized in the analysis of case material and cultural tropes. PMID- 26487105 TI - Comprehensive Analysis of in Vivo Phosphoproteome of Mouse Liver Microsomes. AB - Protein phosphorylation at serine, threonine, and tyrosine residues are some of the most widespread reversible post-translational modifications. Microsomes are vesicle-like bodies, not ordinarily present within living cells, which form from pieces of the endoplasmic reticulum (ER), plasma membrane, mitochondria, or Golgi apparatus of broken eukaryotic cells. Here we investigated the total phosphoproteome of mouse liver microsomes (MLMs) using TiO2 enrichment of phosphopeptides coupled to on-line 2D-LC-MS/MS. In total, 699 phosphorylation sites in 527 proteins were identified in MLMs. When compared with the current phosphoSitePlus database, 155 novel phosphoproteins were identified in MLM. The distributions of phosphosites were 89.4, 8.0, and 2.6% for phosphoserine, phosphotheronine, and phosphotyrosine, respectively. By Motif-X analysis, eight Ser motifs and one Thr motif were found, and five acidic, two basophilic-, and two proline-directed motifs were assigned. The potential functions of phosphoproteins in MLM were assigned by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In GO annotation, phosphorylated microsomal proteins were involved in mRNA processing, mRNA metabolic processes, and RNA splicing. In the KEGG pathway analysis, phosphorylated microsomal proteins were highly enriched in ribosome protein processing in ER and ribosomes and in RNA transport. Furthermore, we determined that 52 and 23 phosphoproteins were potential substrates of cAMP-dependent protein kinase A and casein kinase II, respectively, many of which are 40S/60S ribosomal proteins. Overall, our results provide an overview of features of protein phosphorylation in MLMs that should be a valuable resource for the future understanding of protein synthesis or translation involving phosphorylation. PMID- 26487107 TI - Introduction: In Memory of Robert S. Wallerstein. PMID- 26487108 TI - Psychodynamic Treatment for Separation Anxiety in a Treatment Nonresponder. AB - Separation anxiety, long an area of interest for psychoanalysts, has been included in DSM-5 among general "anxiety disorders" that span across age groups. The syndrome of separation anxiety has been shown to correlate with nonresponse to treatments for anxiety and mood disorders (Milrod et al. 2014). It is therefore of public health importance to develop targeted treatments for this syndrome. Some psychoanalysts have suggested that brief psychoanalytic interventions may be of particular value in addressing separation anxiety. Our clinical work with patients with anxiety disorders with high levels of separation anxiety indicates that they have such intense anger and ambivalence in fraught intimate relationships that they feel stuck and helpless, almost eliminating more positive feelings. This ambivalence and associated unconscious conflicts inevitably emerge in the therapeutic relationship and can threaten to disrupt treatment efforts. We propose a set of focused psychodynamic psychotherapeutic interventions to address separation anxiety, developed as part of Panic-Focused Psychodynamic Psychotherapy-eXtended Range (PFPP-XR; Busch et al. 2012). We present a case from our research study of treatment nonresponders with anxiety disorders and separation anxiety. The patient was successfully treated with PFPP XR in a 21-session treatment. PMID- 26487109 TI - Explanatory Understanding in a Single Case of Separation Anxiety Syndrome: Commentary on Busch and Milrod. PMID- 26487110 TI - An Innovative Brief Psychodynamic Psychotherapy: Commentary on Busch and Milrod. PMID- 26487111 TI - Overcoming O: Dewey and the Problem of Bion's Metaphysics. AB - Bion guides us to eschew memory, desire, and understanding in order to become one with O-the ultimate reality of the analytic moment. However, his directions are valid only to the extent that such a meta-reality actually exists. Otherwise there is nothing to unite with and no reason to shun memory or desire. The present work inquires whether we may provide Bion's technique with a less speculative philosophy, specifically Dewey's pragmatist theory of aesthetics. It begins with reviewing the similarities between the two writers' methods, highlighting their shared emphasis on openness to the unknown. Yet listening to their intonations reveals that they actually convey opposite ideas as to what this "unknown" may be. Whereas Dewey sanguinely portrays the possibilities of the "yet-unknown," Bion emphasizes the dread of our inescapable encounter with the unknowable. This dread is embodied in his concept of O. Thus, rather than being merely a metaphysical speculation, O communicates Bion's conviction that fear forms the core of our existence. Banishing O from the counseling room may indeed aid his method in becoming accessible to a wider audience; at the same time, however, doing so might also deprive it of the very context that gives it meaning. PMID- 26487112 TI - A Pragmatic Approach to Bion's Late Work: A Response to Soffer-Dudek. PMID- 26487113 TI - Of Losing Oneself: Bion's Traumatic War Experiences as a Foundation for his Outlook on Psychoanalysis. PMID- 26487114 TI - The Unseen and the Unheard: South African and Indian Responses to Social Invisibility and Psychic Pain. PMID- 26487115 TI - Three Analysts on Freud's "Observations on Transference-Love". Panel Report. PMID- 26487116 TI - Hans Loewald's Psychoanalysis and the History of the Individual. PMID- 26487117 TI - The Omnipotence of the Psychoanalyst: Thoughts on the Need to Consider Retirement. PMID- 26487118 TI - Convergent and Clinical Validity of the Pathological Narcissism Inventory. PMID- 26487120 TI - The Dynamic Family Functioning Instrument: A Preliminary Exploration. PMID- 26487121 TI - What we Talk about when we Talk about Supervision: The Clear and the Confusing in Graduate Psychiatric Education. PMID- 26487122 TI - Webbing and Delamination of Drug Eluting Stent Coatings. AB - The advancement of the drug-eluting stent technology raises the significant challenge of safe mechanical design of polymer coated stent systems. Experimental images of stent coatings undergoing significant damage during deployment have been reported; such coating damage and delamination can lead to complications such as restenosis and increased thrombogenicity. In the current study a cohesive zone modeling framework is developed to predict coating delamination and buckling due to hinge deformation during stent deployment. Models are then extended to analyze, for the first time, stent-coating damage due to webbing defects. Webbing defects occur when a bond forms between coating layers on adjacent struts, resulting in extensive delamination of the coating from the strut surfaces. The analyzes presented in this paper uncover the mechanical factors that govern webbing induced coating damage. Finally, an experimental fracture test of a commercially available stent coating material is performed and results demonstrate that the high cohesive strength of the coating material will prevent web fracture, resulting in significant coating delamination during stent deployment. PMID- 26487125 TI - Advanced nursing practice: strategies for training and knowledge building. PMID- 26487123 TI - X-ray Phase Contrast Allows Three Dimensional, Quantitative Imaging of Hydrogel Implants. AB - Three dimensional imaging techniques are needed for the evaluation and assessment of biomaterials used for tissue engineering and drug delivery applications. Hydrogels are a particularly popular class of materials for medical applications but are difficult to image in tissue using most available imaging modalities. Imaging techniques based on X-ray Phase Contrast (XPC) have shown promise for tissue engineering applications due to their ability to provide image contrast based on multiple X-ray properties. In this manuscript, we investigate the use of XPC for imaging a model hydrogel and soft tissue structure. Porous fibrin loaded poly(ethylene glycol) hydrogels were synthesized and implanted in a rodent subcutaneous model. Samples were explanted and imaged with an analyzer-based XPC technique and processed and stained for histology for comparison. Both hydrogel and soft tissues structures could be identified in XPC images. Structure in skeletal muscle adjacent could be visualized and invading fibrovascular tissue could be quantified. There were no differences between invading tissue measurements from XPC and the gold-standard histology. These results provide evidence of the significant potential of techniques based on XPC for 3D imaging of hydrogel structure and local tissue response. PMID- 26487124 TI - Robotic gastrectomy and esophagogastrectomy: A single center experience of 105 cases. AB - BACKGROUND: A robotic approach to general surgery procedures may provide improved postoperative outcomes compared to either open or laparoscopic approaches. The role of robotics for gastroesophageal surgery, however, is still being evaluated. STUDY DESIGN: A review of the prospective database for robotic surgery at Valley Hospital between January 2002 and March 2014 identified 105 patients who underwent robotic gastric and esophageal resection. Patient demographics and perioperative factors were studied. RESULTS: Over a 12 years period, 105 patients underwent robotic gastroesophageal resection. The median operative time for distal gastrectomy (230 min [112-327]) was significantly less compared to either total gastrectomy (302 min [214-364]) or esophagogastrectomy (309 min [190-682]). The length of stay for patients undergoing distal gastrectomy (6 days [4-32]) was also significantly less than patients undergoing total gastrectomy (11 days [7 43]), as well as esophagogastrectomy (9 days [5-64]). In regard to the learning curve to perform robotic gastroesophageal surgery, there was a significant correlation between operative time and overall experience. CONCLUSIONS: This study demonstrated that robotic gastroesophageal surgery is feasible and can be safely performed. Assuming familiarity with the open procedures and acquisition of basic robotic skills, the learning curve for robotic gastroesophageal surgery requires approximately 20 cases. PMID- 26487126 TI - Use of the nursing intervention classification for identifying the workload of a nursing team in a surgical center. AB - OBJECTIVE: to analyze the distribution of nursing professionals' workloads, according to the Nursing Intervention Classification (NIC), during the transoperative period at a surgical center specializing in oncology. METHODS: this was an observational and descriptive cross-sectional study. The sample consisted of 11 nurses, 25 nursing technicians who performed a variety of roles within the operating room, 16 nursing technicians who worked with the surgical instrumentation and two nursing technicians from patient reception who worked in the surgical center during the transoperative period. An instrument was developed to collect data and the interventions were validated according to NIC taxonomy. RESULTS: a total of 266 activities were identified and mapped into 49 nursing interventions, seven domains and 20 classes of the NIC. The most representative domains were Physiological-Complex (61.68%) and Health System (22.12%), while the most frequent interventions were Surgical Care (30.62%) and Documentation (11.47%), respectively. The productivity of the nursing team reached 95.34%. CONCLUSIONS: use of the Nursing Intervention Classification contributes towards the discussion regarding adequate, professional nursing staffing levels, because it shows the distribution of the work load. PMID- 26487127 TI - The influence of care interventions on the continuity of sleep of intensive care unit patients. AB - OBJECTIVE: to identify care interventions, performed by the health team, and their influence on the continuity of sleep of patients hospitalized in the Intensive Care Unit. METHOD: descriptive study with a sample of 12 patients. A filming technique was used for the data collection. The awakenings from sleep were measured using the actigraphy method. The analysis of the data was descriptive, processed using the Statistical Package for the Social Sciences software. RESULTS: 529 care interventions were identified, grouped into 28 different types, of which 12 (42.8%) caused awakening from sleep for the patients. A mean of 44.1 interventions/patient/day was observed, with 1.8 interventions/patient/hour. The administration of oral medicine and food were the interventions that caused higher frequencies of awakenings in the patients. CONCLUSION: it was identified that the health care interventions can harm the sleep of ICU patients. It is recommended that health professionals rethink the planning of interventions according to the individual demand of the patients, with the diversification of schedules and introduction of new practices to improve the quality of sleep of Intensive Care Unit patients. PMID- 26487128 TI - High risk for obstructive sleep apnea in patients with acute myocardial infarction. AB - OBJECTIVES: to stratify the risk for obstructive sleep apnea in patients with acute myocardial infarction, treated at a public, tertiary, teaching hospital of the state of Sao Paulo, Brazil, and to identify related sociodemographic and clinical factors. METHOD: cross-sectional analytical study with 113 patients (mean age 59.57 years, 70.8% male). A specific questionnaire was used for the sociodemographic and clinical characterization and the Berlin Questionnaire for the stratification of the risk of obstructive sleep apnea syndrome. RESULTS: the prevalence of high risk was 60.2% and the outcome of clinical worsening during hospitalization was more frequent among these patients. The factors related to high risk were body mass index over 30 kg/m2, arterial hypertension and waist circumference indicative of cardiovascular risk, while older age (60 years and over) constituted a protective factor. CONCLUSION: considering the high prevalence of obstructive sleep apnea and its relation to clinical worsening, it is suggested that nurses should monitor, in their clinical practice, people at high risk for this syndrome, guiding control measures of modifiable factors and aiming to prevent the associated complications, including worsening of cardiovascular diseases. PMID- 26487129 TI - Postoperative self-efficacy and psychological morbidity in radical prostatectomy. AB - OBJECTIVE: evaluate the general and perceived self-efficacy, psychological morbidity, and knowledge about postoperative care of patients submitted to radical prostatectomy. Identify the relationships between the variables and know the predictors of self-efficacy. METHOD: descriptive, cross-sectional study, conducted with 76 hospitalized men. The scales used were the General and Perceived Self-efficacy Scale and the Hospital Anxiety and Depression Scale, in addition to sociodemographic, clinical and knowledge questionnaires. RESULTS: a negative relationship was found for self-efficacy in relation to anxiety and depression. Psychological morbidity was a significant predictor variable for self efficacy. An active professional situation and the waiting time for surgery also proved to be relevant variables for anxiety and knowledge, respectively. CONCLUSION: participants had a good level of general and perceived self-efficacy and small percentage of depression. With these findings, it is possible to produce the profile of patients about their psychological needs after radical prostatectomy and, thus, allow the nursing professionals to act holistically, considering not only the need for care of physical nature, but also of psychosocial nature. PMID- 26487130 TI - Validation of the self-confidence scale of nursing care in urinary retention. AB - OBJECTIVE: to validate an instrument to measure self-confidence of nursing care in urinary retention. METHODS: methodological research study, carried out after ethical approval. A Likert-like scale of 32 items related to nursing care in urinary retention was applied to students of the graduate nursing course. For instrument validation, analysis of the sample adequacy and main components, Varimax orthogonal rotation and internal consistency analyses were developed. RESULTS: in a sample of 305 students, there was high correlation of all items with the total scale and Cronbach's alpha of 0.949. The scale items were divided into five factors with internal consistency: Factor 1 (0.890), Factor 2 (0.874), Factor 3 (0.868), Factor 4 (0.814) and Factor 5 (0.773), respectively. CONCLUSION: the scale meets the validity requirements, demonstrating potential for use in evaluation and research. PMID- 26487131 TI - The cultural dialogue on the domestic dimension of care to immigrant caregivers in Spain. AB - OBJECTIVES: to determine how the immigration phenomenon influences the response to informal care in the domestic level through the caregiver activity, and to analyze the cultural dialogue established in the residential area of Murcia (Spain). METHOD: This is an ethnographic study, conducted in 26 informal immigrant caregivers. As data collection instruments, semi-structured interviews and participant observation were employed. MAXQDA-2 assisted content analysis was also applied. RESULTS: the immigrant caregiver is the main consumer of traditional medicines, extending these health practices to her home group. A cultural dialogue is established on informal care, characterized by interculturalism and mutual adaptation. CONCLUSIONS: cultural hybridization was identified for informal caregivers, immigrants and cultural integration: new health care practices and cultural behaviors in informal systems. There is a transformation in the roles of family members attended in domestic environments, increasing quality of life and self care. They represent an alternative to medicalization, promoting self-management of health. PMID- 26487132 TI - Obstetric profile of pregnant adolescents in a public hospital: risk at beginning of labor, at delivery, postpartum, and in puerperium. AB - OBJECTIVE: describe the obstetric profile of adolescents at beginning of labor, at delivery, postpartum, and in puerperium. METHOD: Cross-sectional descriptive study with 85 pregnant adolescents, selected by convenience, referred by health centers to a public hospital in Mexico City. Risks were evaluated before, during and after delivery and in puerperium, and measured respectively with the "Previgenes" that compose the Reproductive and Perinatal Risk Assessment System. RESULTS: socioeconomic status, occupation and education level had influence on the emotionality of adolescents in relation to labor, whose obstetric risk was low for 55%, medium for 35%, and high for 10%. Risk in labor was low for 55%, medium for 18%, and high for 27%. Risk postpartum was low for 50%, medium for 25%, and high for 25%. In puerperium, most adolescents (90%) had low risk. CONCLUSION: most adolescents had low risk in the stages evaluated. The study contributed to identify strategies to approach risk considering the vulnerability inherent in this type of population and favored the conduct of appropriate interventions for the respective needs. PMID- 26487133 TI - A conceptual framework of clinical nursing care in intensive care. AB - OBJECTIVE: to propose a conceptual framework for clinical nursing care in intensive care. METHOD: descriptive and qualitative field research, carried out with 21 nurses from an intensive care unit of a federal public hospital. We conducted semi-structured interviews and thematic and lexical content analysis, supported by Alceste software. RESULTS: the characteristics of clinical intensive care emerge from the specialized knowledge of the interaction, the work context, types of patients and nurses characteristic of the intensive care and care frameworks. CONCLUSION: the conceptual framework of the clinic's intensive care articulates elements characteristic of the dynamics of this scenario: objective elements regarding technology and attention to equipment and subjective elements related to human interaction, specific of nursing care, countering criticism based on dehumanization. PMID- 26487134 TI - Comparative study: TQ and Lean Production ownership models in health services. AB - OBJECTIVE: compare the application of Total Quality (TQ) models used in processes of a health service, cases of lean healthcare and literature from another institution that has also applied this model. METHOD: this is a qualitative research that was conducted through a descriptive case study. RESULTS: through critical analysis of the institutions studied it was possible to make a comparison between the traditional quality approach checked in one case and the theoretical and practice lean production approach used in another case and the specifications are described below. CONCLUSION: the research identified that the lean model was better suited for people that work systemically and generate the flow. It also pointed towards some potential challenges in the introduction and implementation of lean methods in health. PMID- 26487135 TI - Intimate partner violence and anxiety disorders in pregnancy: the importance of vocational training of the nursing staff in facing them. AB - OBJECTIVE: to identify the relationship between posttraumatic stress disorder, trait and state anxiety, and intimate partner violence during pregnancy. METHOD: observational, cross-sectional study developed with 358 pregnant women. The Posttraumatic Stress Disorder Checklist - Civilian Version was used, as well as the State-Trait Anxiety Inventory and an adapted version of the instrument used in the World Health Organization Multi-country Study on Women's Health and Domestic Violence. RESULTS: after adjusting to the multiple logistic regression model, intimate partner violence, occurred during pregnancy, was associated with the indication of posttraumatic stress disorder. The adjusted multiple linear regression models showed that the victims of violence, in the current pregnancy, had higher symptom scores of trait and state anxiety than non-victims. CONCLUSION: recognizing the intimate partner violence as a clinically relevant and identifiable risk factor for the occurrence of anxiety disorders during pregnancy can be a first step in the prevention thereof. PMID- 26487136 TI - Support to women who denounce experiences of violence based on her social network. AB - OBJECTIVE: to analyze the possibilities of help/support through the mapping and acknowledgement of the social network of women who denounce experiences of violence at a Police Precinct for Women. METHOD: qualitative study based on the theoretical-methodological framework of Lia Sanicola's Social Network, through interviews with 19 women. RESULTS: the analysis of the network maps evidenced that the primary social network was more present than the secondary on and, despite consisting of significant relations, it demonstrates limitations. The women access the secondary network occasionally in the violence problem and/or its repercussions in their life and health. The discrete presence of the health network in the composition of the social network was revealed and, when mentioned, the relation between the health professional and the woman was characterized as fragile. CONCLUSION: the importance of the social network relates to the creation of spaces of help/support for the women beyond the moment of the aggression, which accompany them throughout their process of emancipation from an experience annulled by violence, considering that each woman acts and makes decisions in the relational context when she is ready for it. PMID- 26487137 TI - Women experiencing the intergenerationality of conjugal violence. AB - OBJECTIVE: to analyze the family relationship, in childhood and adolescence, of women who experience conjugal violence. METHOD: qualitative study. Interviews were held with 19 women, who were experiencing conjugal violence, and who were resident in a community in Salvador, Bahia, Brazil. The project was approved by the Research Ethics Committee (N. 42/2011). RESULTS: the data was organized using the Discourse of the Collective Subject, identifying the summary central ideas: they witnessed violence between their parents; they suffered repercussions from the violence between their parents: they were angry about the mother's submission to her partner; and they reproduced the conjugal violence. The discourse showed that the women witnessed, in childhood and adolescence, violence between their parents, and were injured both physically and psychologically. As a result of the mother's submission, feelings of anger arose in the children. However, in the adult phase of their own lives, they noticed that their conjugal life resembled that of their parents, reproducing the violence. CONCLUSION: investment is necessary in strategies designed to break inter-generational violence, and the health professionals are important in this process, as it is a phenomenon with repercussions in health. Because they work in the Family Health Strategy, which focuses on the prevention of harm and illness, health promotion and interdepartmentality, the nurses are essential in the process of preventing and confronting this phenomenon. PMID- 26487138 TI - Factors associated with the patient safety climate at a teaching hospital. AB - OBJECTIVES: to investigate the association between the scores of the patient safety climate and socio-demographic and professional variables. METHODS: an observational, sectional and quantitative study, conducted at a large public teaching hospital. The Safety Attitudes Questionnaire was used, translated and validated for Brazil. Data analysis used the software Statistical Package for Social Sciences. In the bivariate analysis, we used Student's t-test, analysis of variance and Spearman's correlation of (alpha=0.05). To identify predictors for the safety climate scores, multiple linear regression was used, having the safety climate domain as the main outcome (alpha=0.01). RESULTS: most participants were women, nursing staff, who worked in direct care to adult patients in critical areas, without a graduate degree and without any other employment. The average and median total score of the instrument corresponded to 61.8 (SD=13.7) and 63.3, respectively. The variable professional performance was found as a factor associated with the safety environment for the domain perception of service management and hospital management (p=0.01). CONCLUSION: the identification of factors associated with the safety environment permits the construction of strategies for safe practices in the hospitals. PMID- 26487139 TI - Treatment adherence in heart failure patients followed up by nurses in two specialized clinics. AB - OBJECTIVES: to analyze treatment adherence in heart failure (HF) patients followed up by the nursing staff at specialized clinics and its association with patients' characteristics such as number of previous appointments, family structure, and comorbidities. METHODS: a cross-sectional study was conducted at two reference clinics for the treatment of HF patients (center 1 and center 2). Data were obtained using a 10-item questionnaire with scores ranging from 0 to 26 points; adherence was considered adequate if the score was >= 18 points, or 70% of adherence. RESULTS: a total of 340 patients were included. Mean adherence score was 16 (+/-4) points. Additionally, 124 (36.5%) patients showed an adherence rate >= 70%. It was demonstrated that patients who lived with their family had higher adherence scores, that three or more previous nursing appointments was significantly associated with higher adherence (p<0.001), and that hypertension was associated with low adherence (p=0.023). CONCLUSIONS: treatment adherence was considered satisfactory in less than a half of the patients followed up at the two clinics specialized in HF. Living with the family and attending to a great number of nursing appointments improved adherence, while the presence of hypertension led to worse adherence. PMID- 26487140 TI - Experiencing organ donation: feelings of relatives after consent. AB - OBJECTIVE: to identify experiences and feelings on the organ donation process, from the perspective of a relative of an organ donor in a transplant unit. METHOD: this was exploratory research using a qualitative approach, performed with seven family members of different organ donors, selected by a lottery. Sociodemographic data and the experiences regarding the donation process were collected through semi-structured interviews. The language material was transcribed and submitted to content analysis. RESULTS: poor sensitivity of the medical staff communicating the relative's brain death--the potential donor--and the lack of socio-emotional support prior to the situation experienced by the family was highlighted by participants. CONCLUSIONS: the study identified the need to provide social-emotional support for families facing the experience of the organ donation process. From these findings, other care and management practices in health must be discussed to impact the strengthening of the family ties, post-donation, as well as the organ procurement indexes. PMID- 26487141 TI - Peritonitis and catheter exit-site infection in patients on peritoneal dialysis at home. AB - OBJECTIVE: to analyze the complications related to peritonitis and catheter exit site infections, in patients on peritoneal dialysis at home. METHOD: quantitative and cross-sectional study, carried out with 90 patients on peritoneal dialysis at home, in a municipality in the Northeast region of Brazil. For data collection, it was used two structured scripts and consultation on medical records. Descriptive analysis and comparison tests among independent groups were used, considering p<0.05 as level of statistical significance. RESULTS: by comparing the frequency of peritonitis and the length of treatment, it was found that patients over two years of peritoneal dialysis were more likely to develop peritonitis (X2=6.39; p=0.01). The number of episodes of peritoneal catheter exit site infection showed association with the length of treatment (U=224,000; p=0.015). CONCLUSION: peritonitis and catheter exit-site infection are associated with the length of treatment. PMID- 26487142 TI - Epidemiological characteristics of cases of death from tuberculosis and vulnerable territories. AB - OBJECTIVE: to characterize the differences in the clinical and epidemiological profile of cases of death that had tuberculosis as an immediate or associated cause, and to analyze the spatial distribution of the cases of death from tuberculosis within the territories of Ribeirao Preto, Brazil. METHOD: an ecological study, in which the population consisted of 114 cases of death from tuberculosis. Bivariate analysis was carried out, as well as point density analysis, defined with the Kernel estimate. RESULTS: of the cases of death from tuberculosis, 50 were the immediate cause and 64 an associated cause. Age (p=.008) and sector responsible for the death certificate (p=.003) were the variables that presented statistically significant associations with the cause of death. The spatial distribution, in both events, did not occur randomly, forming clusters in areas of the municipality. CONCLUSION: the difference in the profiles of the cases of death from tuberculosis, as a basic cause and as an associated cause, was governed by the age and the sector responsible for the completion of the death certificate. The non-randomness of the spatial distribution of the cases suggests areas that are vulnerable to these events. Knowing these areas can contribute to the choice of disease control strategies. PMID- 26487143 TI - Prevalence of Brucella spp in humans. AB - OBJECTIVE: to determine the seroprevalence of Brucella spp in humans. METHOD: this is an observational study, developed with 455 individuals between 18 and 64 years old, who use the Estrategia de Saude da Familia (Brazil's family health strategy). The serum samples of volunteers underwent buffered acid antigen tests, such as screening, agar gel immunodiffusion and slow seroagglutination test in tubes and 2-Mercaptoethanol. RESULTS: among the samples, 1.98% has responded to buffered-acid antigen, 2.85% to agar gel immunodiffusion test and 1.54% to the slow seroagglutination tests on tubes/2-Mercaptoethanol. The prevalence of Brucella spp was 4.4%, represented by the last two tests. CONCLUSION: the results of this research suggest that the studied population is exposed to Brucella spp infection. PMID- 26487144 TI - Software development to support decision making in the selection of nursing diagnoses and interventions for children and adolescents. AB - OBJECTIVE: to report the development of a software to support decision-making for the selection of nursing diagnoses and interventions for children and adolescents, based on the nomenclature of nursing diagnoses, outcomes and interventions of a university hospital in Paraiba. METHOD: a methodological applied study based on software engineering, as proposed by Pressman, developed in three cycles, namely: flow chart construction, development of the navigation interface, and construction of functional expressions and programming development. RESULT: the software consists of administrative and nursing process screens. The assessment is automatically selected according to age group, the nursing diagnoses are suggested by the system after information is inserted, and can be indicated by the nurse. The interventions for the chosen diagnosis are selected by structuring the care plan. CONCLUSION: the development of this tool used to document the nursing actions will contribute to decision-making and quality of care. PMID- 26487145 TI - The discursive production of professionals about humanizing health: singularity, rights and ethics. AB - OBJECTIVE: to describe the discursive production of professionals about the humanization of health. METHOD: qualitative study of descriptive approach, inspired by the social representation theory, with 24 professionals in the healthcare field, working in a university hospital with the established humanization policy. The selection of participants was conducted according to criteria of adequacy and diversity for an intentional sample. Data collection was conducted by semi-structured interviews. RESULTS: through content analysis, three categories emerged, around which the analyses were conducted: "humanizing health as an act of accepting the other as unique", "humanizing health as a matter of right" and "humanizing health as an ethical issue". The discursive production of professionals is based on a perspective which is based on the humanist prospect with socio-historical bias. CONCLUSION: healthcare professionals must know the National Humanization Policy in order to provide quality care, promoting the meeting, welcoming and recognition of oneself, others and their profession in the political and socio-historical scenario of their country as a citizen, not only of rights, but also of obligations. PMID- 26487146 TI - Nurses' daily life: gender relations from the time spent in hospital. AB - OBJECTIVE: to analyze the everyday life of nurses through the sexual work division as well as through interdependence relations and the time in hospital. METHOD: quanti-qualitative study, based on the Time Use Survey and in Norbert Elias's Configuration Theory of Interdependencies. Daily shifts distribution record, directed by 42 participants--with self-confrontation--by interviews which drew dialogues on subjective aspects of the everyday experiences related to use of time, based on a job at a university hospital. The theoretical intake that founded data analysis was based on concepts of conflicts of interest, power struggles, sexual work division and polychronic-monochronic concepts--whether the work environment demands multitasking nurses or not. RESULTS: time records allowed to observe differences between the groups studied, useful to identify conflicts, tensions, power struggles and gender inequalities in interviewees' everyday affairs that do not only affect physical and mental health, but also their way of life. CONCLUSION: the analytical path pointed out the need for public policies that promote equity in gender relations, keeping at sight the exercise of plural discourses and tolerant stances capable to respect differences between individual and collective time. PMID- 26487147 TI - Child development surveillance: intervention study with nurses of the Family Health Strategy. AB - OBJECTIVE: to evaluate the effectiveness of an educational action in child development surveillance performed by nurses working in primary health care. METHODS: interventional study with a before-and-after type of design, carried out with 45 nurses and 450 mothers of children under 2 years of age. Initially, it was evaluated the practices and knowledge of nurses on child development surveillance and the mothers were interviewed about these practices. Subsequently, workshops were carried out with nurses and four months later, the knowledge of nurses and the maternal information were reevaluated. RESULTS: after intervention there was significant increase in the frequency of the following aspects: from 73% to 100%, in relation to the practice of nurses of asking the opinion of mothers about their children's development; from 42% to 91%, regarding the use of the systematized instrument of evaluation; from 91% to 100% with respect to guidance to mothers on how to stimulate child development. CONCLUSIONS: the intervention contributed to the increase of knowledge of nurses and implementation of child development surveillance, showing the importance of this initiative to improve the quality of child health care. PMID- 26487148 TI - Anxiety in children following hospitalization: a proposal for a nursing diagnosis. AB - OBJECTIVE: to describe the process of developing a nursing diagnosis regarding child anxiety following hospitalization, which is to be submitted to the international classification for nursing practice, in accordance with the guidelines set out by the International Council of Nurses and the ISO standard 18104:2014. METHOD: this methodological study includes a conceptual analysis that bases itself on analyzing the phenomena of anxiety and hospitalization, while identifying the critical attributes of the concept and developing an operational definition. RESULTS: all the criteria for including a new nursing concept were followed and there was no violation of the framework of the International Classification for Nursing Practice with the proposed inclusion, since the concept of anxiety already exists in this classification system and the concept of anxiety from hospitalization would be considered a species or subclass of this concept. CONCLUSION: this analysis of the concept of hospitalization anxiety in children allowed its meaning to be clarified and, consequently, understanding to be constructed regarding its practical applicability. This achievement contributed in terms of providing incentive to develop new proposals for nursing diagnoses to be included in the International Classification for Nursing Practice. PMID- 26487149 TI - Validation of the Adherence Determinants Questionnaire scale among women with breast and cervical cancer. AB - OBJECTIVES: the aim was to translate and culturally adapt the Adherence Determinants Questionnaire scale for the Portuguese language in the Brazilian context, and to check its reliability and validity to analyze the elements of the adherence of patients to the clinical treatment for breast and cervical cancer. METHOD: this was a methodological study, carried out in two oncology reference centers. The sample consisted of 198 participants, with 152 being treated for breast cancer and 46 being treated for cervical cancer. The content validation was performed by a committee of experts. The construct validation was demonstrated through factor analysis and the reliability was analyzed using Cronbach's alpha. RESULTS: the committee of experts made the necessary adjustments so that the scale was adapted to the Brazilian context. The factor analysis suggested a reduction from seven to five factors and the maintenance of 38 items similar to those of the original scale. The reliability, investigated through Cronbach's alpha, was .829, showing high internal consistency. CONCLUSION: it was concluded that the Brazilian version of the Adherence Determinants Questionnaire scale is a valid and reliable instrument that is able to measure the elements of adherence to the treatment for breast and cervical cancer. PMID- 26487150 TI - Primary Health Care Evaluation: the view of clients and professionals about the Family Health Strategy. AB - OBJECTIVE: to evaluate the attributes of primary health care as for access; longitudinality; comprehensiveness; coordination; family counseling and community counseling in the Family Health Strategy, triangulating and comparing the views of stakeholders involved in the care process. METHOD: evaluative research with a quantitative approach and cross-sectional design. Data collected using the Primary Care Assessment Tool for interviews with 527 adult clients, 34 health professionals, and 330 parents of children up to two years old, related to 33 family health teams, in eleven municipalities. Analysis conducted in the Statistical Package for Social Sciences software, with a confidence interval of 95% and error of 0.1. RESULTS: the three groups assessed the first contact access - accessibility with low scores. Professionals evaluated with a high score the other attributes. Clients assigned low score evaluations for the attributes: community counseling; family counseling; comprehensiveness - services rendered; comprehensiveness - available services. CONCLUSIONS: the quality of performance self-reported by the professionals of the Family Health Strategy is not perceived or valued by clients, and the actions and services may have been developed inappropriately or insufficiently to be apprehended by the experience of clients. PMID- 26487151 TI - Time-Resolved Gas-Phase Kinetic, Quantum Chemical, and RRKM Studies of the Reaction of Silylene with 2,5-Dihydrofuran. AB - Time-resolved kinetics studies of silylene, SiH2, generated by laser flash photolysis of phenylsilane, were performed to obtain rate coefficients for its bimolecular reaction with 2,5-dihydrofuran (2,5-DHF). The reaction was studied in the gas phase over the pressure range of 1-100 Torr in SF6 bath gas, at five temperatures in the range of 296-598 K. The reaction showed pressure dependences characteristic of a third body assisted association. The second-order rate coefficients obtained by Rice-Ramsperger-Kassel-Marcus (RRKM)-assisted extrapolation to the high-pressure limit at each temperature fitted the following Arrhenius equation where the error limits are single standard deviations: log(k/cm(3) molecule(-1) s(-1)) = (-9.96 +/- 0.08) + (3.38 +/- 0.62 kJ mol( 1))/RT ln 10. End-product analysis revealed no GC-identifiable product. Quantum chemical (ab initio) calculations indicate that reaction of SiH2 with 2,5-DHF can occur at both the double bond (to form a silirane) and the O atom (to form a donor-acceptor, zwitterionic complex) via barrierless processes. Further possible reaction steps were explored, of which the only viable one appears to be decomposition of the O-complex to give 1,3-butadiene + silanone, although isomerization of the silirane cannot be completely ruled out. The potential energy surface for SiH2 + 2,5-DHF is consistent with that of SiH2 with Me2O, and with that of SiH2 with cis-but-2-ene, the simplest reference reactions. RRKM calculations incorporating reaction at both pi- and O atom sites, can be made to fit the experimental rate coefficient pressure dependence curves at 296-476 K, giving values for k(infinity)(pi) and k(infinity)(O) that indicate the latter is larger in magnitude at all temperatures, in contrast to values from individual model reactions. This unexpected result suggests that, in 2,5-DHF with its two different reaction sites, the O atom exerts the more pronounced electrophilic attraction on the approaching silylene. Arrhenius parameters for the individual pathways were obtained. The lack of a fit at 598 K is consistent with decomposition of the O-complex to give 1,3-butadiene + silanone. PMID- 26487152 TI - Is consciousness fragile? PMID- 26487153 TI - Influence of arm position on catheter placement during real-time ultrasound guided right infraclavicular proximal axillary venous catheterization. AB - BACKGROUND: Real-time ultrasound-guided infraclavicular proximal axillary venous catheterization is used in many clinical situations and provides the advantages of catheter stabilization, a reduced risk of catheter-related infection, and comfort for the patient without limitation of movement. However, unintended catheter tip dislocation and accidental arterial puncture occur occasionally. This study was designed to investigate the influence of arm position on catheter placement and complications. METHODS: Patients were randomized to either the neutral group (n=240) or the abduction group (n=241). In the neutral group, patients were positioned with the head and shoulders placed in an anatomically neutral position and the arms kept by the side during catheterization. In the abduction group, the right upper arm was abducted at 90 degrees from the trunk during catheterization. After real-time ultrasound-guided catheterization was carried out in the right infraclavicular proximal axillary vein, misplacement of the catheter and all complications were evaluated with ultrasound and chest radiography. RESULTS: The success rate of complete catheterization before evaluating the placement of the catheter was high in both groups (97.1 vs 98.8%, P=not significant). The incidence of accidental arterial puncture was not different (1.7 vs 0%, P=not significant). The incidence of misplacement of the catheter was higher in the neutral group than in the abduction group (3.9 vs 0.4%, P=0.01). There were no complications, such as haemothorax, pneumothorax, or injury to the brachial plexus and phrenic nerve, in either group. CONCLUSIONS: Upper arm abduction may minimize the risk of misplacement of the catheter during real-time ultrasound-guided infraclavicular proximal axillary venous catheterization. CLINICAL TRIAL REGISTRATION: The trial was registered with the Clinical Trial Registry of Korea: https://cris.nih.go.kr/cris/index.jsp. Identifier: KCT0001417. PMID- 26487154 TI - Understanding outcomes after neuraxial anaesthesia: time to turn the page. PMID- 26487155 TI - The Link between Alzheimer's Disease and Down Syndrome. A Historical Perspective. PMID- 26487156 TI - Demographic, developmental and psychosocial predictors of the development of anxiety in adults with ADHD. AB - The purpose of this research was to investigate potential demographic, developmental and psychosocial predictors of anxiety in the context of ADHD. Participants included 267 adults with a diagnosis of ADHD (168 males:99 females) and an age range of 18-70 years (M = 31 years; SD = 10.03 years). A background interview, parent questionnaire and rating scales were used to gather participant information. Correlations, independent t tests and one-way analysis of variances were used to identify variables associated with anxiety, and a stepwise multiple regression was used to identify potential predictors of anxiety. Variables associated with anxiety included childhood aggression, employment status, difficulties making friends, number of children and caffeine intake. Childhood aggression and caffeine intake were the potential predictors. Clinicians should be aware of these potential predictors of anxiety in the context of ADHD in order to minimise the likelihood of the development or maintenance of comorbid anxiety. Future research is needed in order to draw any conclusions on cause and effect. PMID- 26487157 TI - Association Between Young Australian's Drinking Behaviours and Their Interactions With Alcohol Brands on Facebook: Results of an Online Survey. AB - AIMS: To examine the association of alcohol-brand social networking pages and Facebook users' drinking attitudes and behaviours. METHODS: Cross-sectional, self report data were obtained from a convenience sample of 283 Australian Facebook users aged 16-24 years via an online survey. RESULTS: More than half of the respondents reported using Facebook for more than an hour daily. While only 20% had actively interacted with an alcohol brand on Facebook, we found a significant association between this active interaction and alcohol consumption, and a strong association between engagement with alcohol brands on Facebook and problematic drinking. CONCLUSIONS: The findings of this study demonstrate the need for further research into the complex interaction between social networking and alcohol consumption, and add support to calls for effective regulation of alcohol marketing on social network platforms. PMID- 26487158 TI - New predictive model of rebleeding during follow-up of patents with obscure gastrointestinal bleeding: A multicenter cohort study. AB - BACKGROUND AND AIM: The long-term recurrence rate of patients with obscure gastrointestinal bleeding (OGIB) who underwent video capsule endoscopy (VCE) remains unknown. Our study aimed to identify the cumulative incidence of rebleeding, develop a predictive model of rebleeding, and evaluate whether the model can be applied in other outcomes among patients with OGIB. METHODS: We conducted a multicenter retrospective cohort study of 320 patients with OGIB who underwent VCE between 2009 and 2014. A rebleeding model was developed using multivariate Cox proportional hazards analysis and evaluated using Harrell's c index. RESULTS: Rebleeding occurred in 43 patients (13.4%) during a mean follow up period of 18.3 (standard error, 0.9) months. The rebleeding sources were the small intestine (n = 17), extra-small intestine (n = 13), and unknown (n = 13). The cumulative incidence of rebleeding was 11.0% at 12 months and 35.3% at 60 months. Multivariate analysis revealed that female gender, liver cirrhosis, warfarin use, overt bleeding, and positive VCE findings were significant predictors of rebleeding. The rebleeding rate was 0% in patients with no predictors and 40% in patients with full predictors (P < 0.01). The model presented a high predictive accuracy (c-statistic, 0.733). Patients with higher predictors exhibited higher transfusion requirements, longer length of stay, and higher mortality (P < 0.01). CONCLUSION: The cumulative incidence of rebleeding at 12 and 60 months was 11.0% and 35.3%, respectively. Five factors enable prediction of not only rebleeding but also transfusion requirements, length of stay, and death in OGIB patients. PMID- 26487159 TI - Acute coronary syndromes. PMID- 26487160 TI - Toward Low-Frequency Mechanical Energy Harvesting Using Energy-Dense Piezoelectrochemical Materials. AB - The piezoelectrochemical coupling between mechanical stress and electrochemical potential is explored in the context of mechanical energy harvesting and shown to have promise in developing high-energy-density harvesters for low-frequency applications (e.g., human locomotion). This novel concept is demonstrated experimentally by cyclically compressing an off-the-shelf lithium-ion battery and measuring the generated electric power output. PMID- 26487161 TI - The Assessment of Animal Welfare in British Zoos by Government-Appointed Inspectors. AB - We analysed the reports of government-appointed inspectors from 192 zoos between 2005-2008 to provide the first review of how animal welfare was assessed in British zoos since the enactment of the Zoo Licensing Act 1981. We examined the effects of whether or not a veterinarian was included in the inspection team, type of inspection, licence status of the zoo and membership of a zoo association on the inspectors' assessments of animal welfare standards in five areas that approximate to the Five Freedoms. At least 11% of full licence inspections did not comply with the legal requirement for two inspectors. The inspectors' reports were unclear as to how animal welfare was assessed, whether all animals or only a sub-sample had been inspected, and were based predominantly on welfare inputs rather than outcomes. Of 9,024 animal welfare assessments across the 192 zoos, 7,511 (83%) were graded as meeting the standards, 782 (9%) as substandard and the rest were not graded. Of the 192 zoos, 47 (24%) were assessed as meeting all the animal welfare standards. Membership of a zoo association was not associated with a higher overall assessment of animal welfare standards, and specialist collections such as Farm Parks and Other Bird collections performed least well. We recommend a number of changes to the inspection process that should lead to greater clarity in the assessment of animal welfare in British zoos. PMID- 26487162 TI - Pet Ownership and Evacuation Prior to Hurricane Irene. AB - Pet ownership has historically been one of the biggest risk factors for evacuation failure prior to natural disasters. The forced abandonment of pets during Hurricane Katrina in 2005 made national headlines and led to the passage of the Pet Evacuation and Transportation Standards Act (PETS, 2006) which mandated local authorities to plan for companion animal evacuation. Hurricane Irene hit the East Coast of the United States in 2011, providing an excellent opportunity to examine the impact of the PETS legislation on frequency and ease of evacuation among pet owners and non-pet owners. Ninety pet owners and 27 non pet owners who lived in mandatory evacuation zones completed questionnaires assessing their experiences during the hurricane and symptoms of depression, PTSD, dissociative experiences, and acute stress. Pet ownership was not found to be a statistical risk factor for evacuation failure. However, many pet owners who failed to evacuate continue to cite pet related reasons. PMID- 26487163 TI - The Influence of Climate, Soil and Pasture Type on Productivity and Greenhouse Gas Emissions Intensity of Modeled Beef Cow-Calf Grazing Systems in Southern Australia. AB - A biophysical whole farm system model was used to simulate the interaction between the historical climate, soil and pasture type at sites in southern Australia and assess the balance between productivity and greenhouse gas emissions (expressed in carbon dioxide equivalents, CO2-eq.) intensity of beef cow-calf grazing systems. Four sites were chosen to represent a range of climatic zones, soil and pasture types. Poorer feed quality and supply limited the annual carrying capacity of the kikuyu pasture compared to phalaris pastures, with an average long-term carrying capacity across sites estimated to be 0.6 to 0.9 cows/ha. A relative reduction in level of feed intake to productivity of calf live weight/ha at weaning by feeding supplementary feed reduced the average CO2 eq. emissions/kg calf live weight at weaning of cows on the kikuyu pasture (18.4 and 18.9 kg/kg with and without supplementation, respectively), whereas at the other sites studied an increase in intake level to productivity and emission intensity was seen (between 10.4 to 12.5 kg/kg without and with supplementary feed, respectively). Enteric fermentation and nitrous oxide emissions from denitrification were the main sources of annual variability in emissions intensity, particularly at the lower rainfall sites. Emissions per unit product of low input systems can be minimized by efficient utilization of pasture to maximize the annual turnoff of weaned calves and diluting resource input per unit product. PMID- 26487164 TI - Adaptations and Predispositions of Different Middle European Arthropod Taxa (Collembola, Araneae, Chilopoda, Diplopoda) to Flooding and Drought Conditions. AB - Floodplain forests and wetlands are amongst the most diverse and species rich habitats on earth. Arthropods are a key group for the high diversity pattern of these landscapes, due to the fact that the change between flooding and drought causes in different life cycles and in a variety of adaptations in the different taxa. The floodplain forests and wetlands of Central Amazonia are well investigated and over the last 50 years many adaptations of several hexapod, myriapod and arachnid orders were described. In contrast to Amazonia the Middle European floodplains were less investigated concerning the adaptations of arthropods to flood and drought conditions. This review summarizes the adaptations and predispositions of springtails, web spiders, millipedes and centipedes to the changeable flood and drought conditions of Middle European floodplain forests and wetlands. Furthermore the impact of regional climate change predictions like increasing aperiodic summer floods and the decrease of typical winter and spring floods are discussed in this article. PMID- 26487165 TI - Effects of Severe Floods and Droughts on Wildlife of the Pantanal Wetland (Brazil)-A Review. AB - Flooding throughout the Pantanal is seasonal. The complex vegetative cover and high seasonal productivity support a diverse and abundant fauna. A gradient in flood level supports a range of major habitats in a complex mosaic with annual seasonality. The rivers and streams are lined with gallery forests, and other arboreal habitats exist in the more elevated areas. The remainder is either grasslands or seasonally flooded grasslands. The regional flora and fauna are adapted to annual water fluctuation. However, an inter-annual series of higher or lower rainfalls has caused either severe floods or drastic dry seasons. Large scale climate phenomena such as greenhouse gases, El Nino and La Nina influence the seasonality of floods and droughts in the Pantanal. Knowledge of severe floods and droughts, which characterize natural disasters, is fundamental for wildlife management and nature conservation of the Pantanal. Plants and wild animals, for example, are affected by tree mortality in riparian forest after extreme flooding, with consequent habitat modification for wild animals. In addition, human activities are also affected since cattle ranching and ecotourism are economically important in the region, and when seasons with unusual floods or droughts occur, areas with human settlements are impacted. PMID- 26487166 TI - Semi-Ownership and Sterilisation of Cats and Dogs in Thailand. AB - The aim of this study was to identify the prevalence of cat and dog semi ownership in Thailand and factors that predict sterilisation. Semi-ownership was defined as interacting/caring for a companion animal that the respondent does not own, such as a stray cat or dog. A randomised telephone survey recruited 494 Thai nationals residing in Thailand. The findings revealed that 14% of respondents (n = 71) engaged in dog semi-ownership and only 17% of these dogs had been sterilised. Similarly, 11% of respondents (n = 55) engaged in cat semi-ownership and only 7% were known to be sterilised. Using Hierarchical Multiple Regression, the findings showed that 62% and 75% of the variance in intentions to sterilise semi-owned dogs and cats, respectively, was predicted by religious beliefs, and psychosocial factors such as attitudes, perceived pressure from others, and perceived behavioural control. Community awareness campaigns that approach the issue of sterilisation in a way that is consistent with cultural and religious traditions using Thai role models, such as veterinarians, may go some way in reducing stray animal population growth. PMID- 26487167 TI - Animal Sentience: Where Are We and Where Are We Heading? AB - The science of animal sentience underpins the entire animal welfare movement. Demonstrating objectively what animals are capable of is key to achieving a positive change in attitudes and actions towards animals, and a real, sustainable difference for animal welfare. This paper briefly summarises understanding and acceptance of animal sentience through the ages. Although not an exhaustive history, it highlights some of the leading figures whose opinions and work have most affected perspectives of animal sentience. There follows a review of the current state of animal sentience, what is known, and what the main limitations have been for the development of the study of sentience. The paper concludes with some thoughts for the future of the science, and where it should be going in order to most benefit animal welfare. PMID- 26487169 TI - Fatigue is correlated with disease activity but not with the type of organ involvement in Behcet's syndrome: a comparative clinical survey. AB - OBJECTIVES: Fatigue is an important problem in inflammatory diseases and affects the quality of life (QoL). We aimed to evaluate the severity and impact of fatigue in Behcet's syndrome (BS) and to determine its association with type of organ involvement and gender. METHODS: One hundred and fifty-two BS, 51 rheumatoid arthritis (RA), 51 systemic lupus erythematosus (SLE), 51 ankylosing spondylitis (AS) patients and 65 healthy controls were evaluated by the fatigue severity scale, fatigue impact scale, fibromyalgia impact questionnaire (FIQ), RAPID3, SF-36 and Behcet's syndrome activity scale (the latter only in BS patients). We also analysed subgroups of BS patients with predominantly eye, vascular, joint and mucocutaneous involvement and did an additional gender analysis. RESULTS: Fatigue severity and fatigue impact scores were similar among BS, RA, SLE and AS patients and significantly higher than that in healthy controls (F4df=8.51; p<0.001 and F4df=8.67; p<0.001, respectively). The fatigue severity and fatigue impact scores were similarly high in BS subgroups with different types of organ involvement, and in both genders. CONCLUSIONS: Fatigue is an important problem in BS, as it is in other inflammatory conditions. It is similarly severe in subgroups of patients with eye, vascular, joint and mucocutaneous involvement and in either gender. Fatigue is a candidate outcome measure for clinical trials, to assess the life impact of Behcet's syndrome. PMID- 26487168 TI - Proactive Management of the Equine Athlete. AB - Across many equestrian disciplines the median competition career of a horse is relatively short. One of the major reasons for short career length is musculoskeletal injury and a consistent variable is the trainer effect. There are significant opportunities within equestrian sport for a holistic approach to horse health to attenuate musculoskeletal injury. Proactive integration of care by health professionals could provide a mechanism to attenuate injury risk and the trainer effect. However, the limited data available on current exercise regimens for sport horses restricts interpretation of how management and exercise volume could be modified to reduce injury risk. Early exercise in the juvenile horse (i.e., pre weaning) has a positive effect on stimulating the musculoskeletal system and primes the horse for an athletic career. The early introduction to sport competition has also been identified to have a positive effect on career length. These data indicate that management systems reflecting the cursorial evolution of the horse may aid in attenuating loss from sport due to musculoskeletal injury. PMID- 26487170 TI - Negative pressure wound therapy limits downgrowth in percutaneous devices. AB - Maintenance of a soft tissue seal around percutaneous devices is challenged by the downgrowth of periprosthetic tissues-a gateway to potential infection. As negative pressure wound therapy (NPWT) is used clinically to facilitate healing of complex soft tissue pathologies, it was hypothesized that NPWT could limit downgrowth of periprosthetic tissues. To test this hypothesis, 20 hairless guinea pigs were randomly assigned into four groups (n = 5/group). Using a One-Stage (Groups 1 and 3) or a Two-Stage (Groups 2 and 4) surgical procedure, each animal was implanted with a titanium-alloy subdermal device porous-coated with commercially pure, medical grade titanium. Each subdermal device had a smooth titanium-alloy percutaneous post. The One-Stage procedure encompassed insertion of a fully assembled device during a single surgery. The Two-Stage procedure involved the implantation of a subdermal device during the first surgery, and then three weeks later, insertion of a percutaneous post. Groups 1 and 2 served as untreated controls and Groups 3 and 4 received NPWT. Four weeks postimplantation of the post, the devices and surrounding tissues were harvested, and histologically evaluated for downgrowth. Within the untreated control groups, the Two-Stage surgical procedure significantly decreased downgrowth (p = 0.027) when compared with the One-Stage procedure. Independent of the surgical procedures performed, NPWT significantly limited downgrowth (p <= 0.05) when compared with the untreated controls. PMID- 26487171 TI - The Impact of Improved Population Life Expectancy in Survival Trend Analyses of Specific Diseases. AB - BACKGROUND: Survival trend analyses examine mortality outcomes over time. The impact of conducting survival trend analyses without accounting for improved population survival has not been systematically studied. METHODS: The 1-year risk of death in the 100 most common hospital admissions for Ontario adults in 1994, 1999, 2004, and 2009 was determined. Generalized linear models were used to determine if adjusted death risk changed significantly over time with and without accounting for population survival. RESULTS: The statistical significance of temporal trends in survival changed after accounting for population life expectancy in 16 diagnoses (16 percent) (in 13 of 55 diagnoses, statistically significant decreasing mortality trends became insignificant; in 3 of 15 diagnoses, insignificant trends changed to a significant increase in mortality risk over time). CONCLUSIONS: These results highlight the importance of accounting for population life-expectancy changes in survival trend analyses. PMID- 26487172 TI - Shape-based acetabular cartilage segmentation: application to CT and MRI datasets. AB - PURPOSE: A new method for acetabular cartilage segmentation in both computed tomography (CT) arthrography and magnetic resonance imaging (MRI) datasets with leg tension is developed and tested. METHODS: The new segmentation method is based on the combination of shape and intensity information. Shape information is acquired according to the predictable nonlinear relationship between the U-shaped acetabulum region and acetabular cartilage. Intensity information is obtained from the acetabular cartilage region automatically to complete the segmentation procedures. This method is evaluated using 54 CT arthrography datasets with two different radiation doses and 20 MRI datasets. Additionally, the performance of this method in identifying acetabular cartilage is compared with four other acetabular cartilage segmentation methods. RESULTS: This method performed better than the comparison methods. Indeed, this method maintained good accuracy level for 74 datasets independent of the cartilage modality and with minimum user interaction in the bone segmentation procedures. In addition, this method was efficient in noisy conditions and in detection of the damaged cartilages with zero thickness, which confirmed its potential clinical usefulness. CONCLUSIONS: Our new method proposes acetabular cartilage segmentation in three different datasets based on the combination of the shape and intensity information. This method executes well in situations where there are clear boundaries between the acetabular and femoral cartilages. However, the acetabular cartilage and pelvic bone information should be obtained from one dataset such as CT arthrography or MRI datasets with leg traction. PMID- 26487173 TI - Wound drainage after plastic and reconstructive surgery of the breast. AB - BACKGROUND: Wound drains are often used after plastic and reconstructive surgery of the breast, in order to reduce potential complications. It is unclear whether there is any evidence to support this practice and we therefore undertook a systematic review of the best evidence available. OBJECTIVES: To compare the safety and efficacy of the use of wound drains following elective plastic and reconstructive surgery procedures of the breast. SEARCH METHODS: For the first update of this review we searched the Cochrane Wounds Group Specialised Register (searched 4 March 2015); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 2); Ovid MEDLINE (2012 to March 3 2015); Ovid MEDLINE (In-Process & Other Non-Indexed Citations March 3 2015); Ovid EMBASE (2012 to March 3 2015); and EBSCO CINAHL (2012 to March 4 2015). There were no restrictions on the basis of date or language of publication. SELECTION CRITERIA: Three review authors undertook independent screening of the search results. All randomised trials (RCTs) that compared the use of a wound drain with no wound drain following plastic and reconstructive surgery of the breast (breast augmentation, breast reduction and breast reconstruction) in women were eligible. DATA COLLECTION AND ANALYSIS: Two review authors undertook independent data extraction of study characteristics, methodological quality and outcomes (e.g. infection, other wound complications, pain, and length of hospital stay). Risk of bias was assessed independently by two review authors. We calculated the risk ratio (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals. Analysis was on an intention-to-treat basis. MAIN RESULTS: Three randomised trials were identified and included in the review out of 190 studies that were initially screened; all evaluated wound drainage after breast reduction surgery. No new trials were identified for this first update. In total there were 306 women in the three trials, and 505 breasts were studied (254 drained, and 251 who were not drained). Apart from a significantly shorter duration of hospital stay for those participants who did not have drains (MD 0.77; 95% CI 0.40 to 1.14), there was no statistically significant impact of the use of drains on outcomes. AUTHORS' CONCLUSIONS: The limited evidence available shows no significant benefit of using post-operative wound drains in reduction mammoplasty, though hospital stay may be shorter when drains are not used. No data are available for breast augmentation or breast reconstruction, and this requires investigation. PMID- 26487175 TI - Electrodeposition of spinel MnCo2O4 nanosheets for supercapacitor applications. AB - Herein, we report a facile, low-cost and one-step electrodeposition approach for the synthesis MnCo2O4 (MCO) nanosheet arrays on indium doped tin oxide (ITO) coated glass substrates. The crystalline phase and morphology of the materials are studied by x-ray diffraction, energy dispersive x-ray analysis and field emission scanning electron microscopy. The supercapacitor performance of the MCO nanosheets are studied in a three-electrode configuration in 2 M KOH electrolyte. The as-prepared binder-free electrode shows a high specific capacitance of 290 F g(-1) at 1 mV s(-1) with excellent cyclic stability even after 1000 charge/discharge cycles. The obtained energy density and power density of the MCO nanosheets are 10.04 Wh kg(-1) and 5.2 kW kg(-1) respectively. The superior electrochemical performances are mainly attributed to its nanosheet like structure which provides a large reaction surface area, and fast ion and electron transfer rate. PMID- 26487174 TI - Ca(2+)/calmodulin regulates Kvbeta1.1-mediated inactivation of voltage-gated K(+) channels. AB - A-type K(+) channels open on membrane depolarization and undergo subsequent rapid inactivation such that they are ideally suited for fine-tuning the electrical signaling in neurons and muscle cells. Channel inactivation mostly follows the so called ball-and-chain mechanism, in which the N-terminal structures of either the K(+) channel's alpha or beta subunits occlude the channel pore entry facing the cytosol. Inactivation of Kv1.1 and Kv1.4 channels induced by Kvbeta1.1 subunits is profoundly decelerated in response to a rise in the intracellular Ca(2+) concentration, thus making the affected channel complexes negative feedback regulators to limit neuronal overexcitation. With electrophysiological and biochemical experiments we show that the Ca(2+) dependence is gained by binding of calmodulin to the "chain" segment of Kvbeta1.1 thereby compromising the mobility of the inactivation particle. Furthermore, inactivation regulation via Ca(2+)/calmodulin does not interfere with the beta subunit's enzymatic activity as an NADPH-dependent oxidoreductase, thus rendering the Kvbeta1.1 subunit a multifunctional receptor that integrates cytosolic signals to be transduced to altered electrical cellular activity. PMID- 26487176 TI - The presence of a single-nucleotide polymorphism in the BDNF gene affects the rate of locomotor adaptation after stroke. AB - Induction of neural plasticity through motor learning has been demonstrated in animals and humans. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, is thought to play an integral role in modulation of central nervous system plasticity during learning and motor skill recovery. Thirty percent of humans possess a single-nucleotide polymorphism on the BDNF gene (Val66Met), which has been linked to decreased activity-dependent release of BDNF. Presence of the polymorphism has been associated with altered cortical activation, short-term plasticity and altered skill acquisition, and learning in healthy humans. The impact of the Val66Met polymorphism on motor learning post-stroke has not been explored. The purpose of this study was to examine the impact of the Val66Met polymorphism in learning of a novel locomotor task in subjects with chronic stroke. It was hypothesized that subjects with the polymorphism would have an altered rate and magnitude of adaptation to a novel locomotor walking paradigm (the split-belt treadmill), compared to those without the polymorphism. The rate of adaptation was evaluated as the reduction in gait asymmetry during the first 30 (early adaptation) and last 100 (late adaptation) strides. Twenty-seven individuals with chronic stroke participated in a single session of split-belt treadmill walking and tested for the polymorphism. Step length and limb phase were measured to assess adaptation of spatial and temporal parameters of walking. The rate of adaptation of step length asymmetry differed significantly between those with and without the polymorphism, while the amount of total adaptation did not. These results suggest that chronic stroke survivors, regardless of presence or absence of the polymorphism, are able to adapt their walking pattern over a period of trial-and-error practice; however, the presence of the polymorphism influences the rate at which this is achieved. PMID- 26487178 TI - Postural responses to anterior and posterior perturbations applied to the upper trunk of standing human subjects. AB - This study concerned the effects of brisk perturbations applied to the shoulders of standing subjects to displace them either forwards or backwards, our aim being to characterise the responses to these disturbances. Subjects stood on a force platform, and acceleration was measured at the level of C7, the sacrum and both tibial tuberosities. Surface EMG was measured from soleus (SOL), tibialis anterior (TA), the hamstrings (HS), quadriceps (QUAD), rectus abdominis (RA) and lumbar paraspinal (PS) muscles. Trials were recorded for each of four conditions: subjects' eyes open (reference) or closed and on a firm (reference) or compliant surface. Observations were also made of voluntary postural reactions to a tap over the deltoid. Anterior perturbations (mean C7 acceleration 251.7 mg) evoked activity within the dorsal muscles (SOL, HS, PS) with a similar latency to voluntary responses to shoulder tapping. Responses to posterior perturbations (mean C7 acceleration -240.4 mg) were more complex beginning, on average, at shorter latency than voluntary activity (median TA 78.0 ms). There was activation of TA, QUAD and SOL associated with initial forward acceleration of the lower legs. The EMG responses consisted of an initial phasic discharge followed by a more prolonged one. These responses differ from the pattern of automatic postural responses that follow displacements at the level of the ankles, and it is unlikely that proprioceptive afferents excited by ankle movement had a role in the initial responses. Vision and surface properties had only minor effects. Perturbations of the upper trunk evoke stereotyped compensatory postural responses for each direction of perturbation. For posterior perturbations, EMG onset occurs earlier than for voluntary responses. PMID- 26487177 TI - The stuff that motor chunks are made of: Spatial instead of motor representations? AB - In order to determine how participants represent practiced, discrete keying sequences in the discrete sequence production task, we had 24 participants practice two six-key sequences on the basis of two pre-learned six-digit numbers. These sequences were carried out by fingers of the left (L) and right (R) hand with between-hand transitions always occurring between the second and third, and the fifth and sixth responses. This yielded the so-called LLRRRL and RRLLLR sequences. Early and late in practice, the keypad used for the right hand was briefly relocated from the front of the participants to 90 degrees at their right side. The results indicate that after 600 practice trials, executing a keying sequence relies heavily on a spatial cross-hand representation in a trunk- or head-based reference frame that after about only 15 trials is fully adjusted to the changed hand location. The hand location effect was not found with the last sequence element. This is attributed to the application of explicit knowledge. The between-hand transitions appeared to induce initial segmentation in some of the participants, but this did not consolidate into a concatenation point of successive motor chunks. PMID- 26487179 TI - Effects of anodal tDCS of the lower limb M1 on ankle reaction time in young adults. AB - Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that modulates cortical excitability and influences motor behavior. There is limited information available regarding the effects of anodal tDCS on lower limb reaction time. In this study, we aimed to investigate the effects of anodal tDCS on lower limb simple reaction time (SRT) and choice reaction time (CRT). We probed this question further by examining the effects of anodal tDCS of the lower limb M1 on an upper limb RT task and a cognitive measure. Fourteen healthy young adults received anodal tDCS and sham tDCS to the lower limb M1 on two separate testing days in a counterbalanced order. After stimulation, we assessed the effects of tDCS on ankle dorsiflexion SRT and CRT, ankle plantarflexion SRT and CRT, wrist extension SRT and CRT and the symbol digit modality test (SDMT). Anodal tDCS significantly improved response times from baseline for ankle CRT but not for ankle SRT or wrist SRT or CRT. A significant decrement (i.e., longer response time) was noted for the sham tDCS conditions. There was a significant difference between anodal and sham conditions for all RT tasks, suggesting that anodal tDCS improved RT compared to sham. No change in SDMT scores was observed for both conditions. Anodal tDCS appeared to differentially modulate ankle SRT and CRT, suggesting an influence of anodal tDCS on complex motor processes and/or the supplementary motor area. Absence of effects on wrist CRT or SDMT suggests a spatial specificity of the influence of tDCS. Anodal tDCS also appears to potentially negate the effects of fatigue or task switching that was detrimental to RT in the sham condition. PMID- 26487180 TI - Stability control during the performance of a simultaneous obstacle avoidance and auditory Stroop task. AB - Navigation through complex environments requires a greater degree of control and attentional resources from the central nervous system to ensure postural stability and efficient goal completion as compared to quiet standing or unobstructed walking. Furthermore, when a cognitive task is also performed in a dual-task scenario, additional resources may be required. The purpose of the current study was to examine the effects of performing a concurrent cognitive (auditory Stroop task) and complex locomotor task (with a stationary or dynamic obstacle) on frontal plane stability control quantified using a margin of stability (MOS) measure. Fourteen healthy young adults performed 40 dual-task trials (randomized in a balanced design for auditory Stroop congruency and obstacle movement). Results indicated that frontal plane MOS was greatest for the obstacle crossing step and was greater for the dynamic obstacle as compared to the stationary obstacle. Conversely, frontal plane MOS was the smallest for the pre-crossing step, indicating that this point in the obstacle stepping strategy may be the least stable. No effect of cognitive task difficulty was observed for any of the experimental conditions, providing support for a 'posture-first' strategy. These findings suggest that an increase in stability is prioritized for the obstacle crossing step, potentially at the expense of reduced stability in the step immediately preceding the obstacle. These results have implications for better understanding how the CNS controls stability at different events during the obstacle crossing strategy in a complex environment. PMID- 26487181 TI - Motor imagery-based skill acquisition disrupted following rTMS of the inferior parietal lobule. AB - Motor imagery (MI), the mental rehearsal of motor tasks, has promise as a therapy in post-stroke rehabilitation. The potential effectiveness of MI is attributed to the facilitation of plasticity in numerous brain regions akin to those recruited for physical practice. It is suggested, however, that MI relies more heavily on regions commonly affected post-stroke, including left hemisphere parietal regions involved in visuospatial processes. However, the impact of parietal damage on MI based skill acquisition that underlies rehabilitation remains unclear. Here, we examine the contribution of the left inferior parietal lobule (IPL) to MI using inhibitory transcranial magnetic stimulation (TMS) and an MI-based implicit sequence learning (ISL) paradigm. Participants (N = 27) completed the MI-based ISL paradigm after receiving continuous theta burst stimulation to the left IPL (TMS), or with the coil angled away from the scalp (sham). Reaction time differences (dRT) and effect sizes between implicit and random sequences assessed success of MI-based learning. Mean dRT for the sham group was 36.1 +/- 28.2 ms (d = 0.71). Mean dRT in the TMS group was 7.7 +/- 38.5 ms (d = 0.11). These results indicate that inhibition of the left IPL impaired MI-based learning. We conclude that the IPL and likely the visuospatial processes it mediates are critical for MI performance and thus MI-based skill acquisition or learning. Ultimately, these findings have implications for the use of MI in post-stroke rehabilitation. PMID- 26487183 TI - Patterns of Wnt signaling in the life cycle of Podocoryna carnea and its implications for medusae evolution in Hydrozoa (Cnidaria). AB - Hydrozoans are known for their complex life cycles, alternating between benthic, asexually reproducing polyps and pelagic, sexually reproducing medusae. Although patterning in hydrozoan polyps has been well studied, little is known about the signaling mechanisms governing medusa development. In order to investigate the role of Wnt signaling in medusa development, we use RNA-Seq data collected from three discrete life cycle stages of Podocoryna carnea to assemble, annotate, and assess enrichment and differential expression (DE) of Wnt pathway elements in P. carnea's transcriptome. Enrichment analyses revealed a statistically significant enrichment of DE Wnt signaling transcripts in the transcriptome of P. carnea, of which, the vast majority of these were significantly up-regulated in developing and adult medusae stages. Whole mount in situ hybridization (ISH) reveals co expression of the Wnt ligand, Wnt3, and a membrane bound Wnt receptor, frizzled3, at the distal and oral ends of the developmental axes of medusae and polyps in P. carnea. DE and ISH results presented here reveal expression of Wnt signaling components consistent with it playing a role in medusa development. Specifically, Wnt ligand expression in the oral region suggests that the Wnt pathway may play a role in medusa patterning, similar to that of polyps. Previous Wnt expression studies in hydrozoan taxa with reduced medusa have failed to detect co-expression of Wnt3 and a frizzled receptor at their truncated developmental axes, suggesting that down regulation of Wnt pathway elements may play a key role in the loss of the medusa life cycle stage in hydrozoan evolution. PMID- 26487182 TI - Decreased face primary motor cortex (face-M1) excitability induced by noxious stimulation of the rat molar tooth pulp is dependent on the functional integrity of medullary astrocytes. AB - We have recently shown that application of the small-fiber excitant and inflammatory irritant mustard oil (MO) to the rat molar tooth pulp can decrease face-M1 excitability, but increase the excitability of trigeminal medullary dorsal horn (MDH) nociceptive neurons and that application of the astrocytic inhibitor methionine sulfoximine (MSO) to the face-M1 or MDH can attenuate the MO induced changes. The present study aimed to determine whether medullary MSO application could modulate the MO-induced decreased face-M1 excitability. Under ketamine general anesthesia, electromyographic (EMG) electrodes were implanted into the right anterior digastric (RAD, jaw-opening muscle) of adult male Sprague Dawley rats. A microelectrode was positioned at a low-threshold (<=30 MUA) site in the left face-M1. Then MO (n = 16) or control-solution (n = 16) was applied to the previously exposed molar tooth pulp, and intracortical microstimulation threshold intensities for evoking RAD EMG activities were monitored for 15 min. MSO (0.1 mM, n = 8) or phosphate-buffered saline (PBS, n = 8) was then applied to the MDH and RAD thresholds monitored every 15 min for 120 min. Statistics used ANOVA followed by post hoc Bonferroni as appropriate (p < 0.05). As compared to baseline, RAD thresholds significantly increased (i.e., decreased excitability) within 1 min (26.3 +/- 7.9%, p = 0.007) and peaked at 15 min following pulpal MO application (49.9 +/- 5.7%, p < 0.001) but not following control-solution. Following MSO (but not PBS) application to the medulla, RAD thresholds significantly decreased within 15 min (26.5 +/- 3.0%, p = 0.05) and at 60 min approached 6.3 +/- 2.4%, of baseline values (p = 0.1). These novel findings suggest that clinically related motor disturbances arising from dental pain may involve decreased face-M1 excitability that is modulated by medullary astrocytes. PMID- 26487184 TI - Enhanced Expression of Fibroblast Growth Factor Receptor 3 IIIc Promotes Human Esophageal Carcinoma Cell Proliferation. AB - Deregulated expression of fibroblast growth factor receptors (FGFRs) and their ligands plays critical roles in tumorigenesis. The gene expression of an alternatively spliced isoforms of FGFR3, FGFR3IIIc, was analyzed by RT-PCR in samples from patients with esophageal carcinoma (EC), including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). The incidence of FGFR3IIIc was higher in EC [12/16 (75%); p=0.073] than in non-cancerous mucosa (NCM) [6/16 (38%)]. Indeed, an immunohistochemical analysis of early-stage ESCC showed that carcinoma cells expressing FGFR3IIIc stained positively with SCC-112, a tumor marker, and Ki67, a cell proliferation marker, suggesting that the expression of FGFR3IIIc promotes cell proliferation. We used EC-GI-10 cells endogenously expressing FGFR3IIIc as a model of ESCC to provide mechanistic insight into the role of FGFR3IIIc in ESCC. The knockdown of endogenous FGFR3 using siRNA treatment significantly abrogated cell proliferation and the overexpression of FGFR3IIIc in cells with enhanced cell proliferation. EC-GI-10 cells and ESCC from patients with EC showed endogenous expression of FGF2, a specific ligand for FGFR3IIIc, suggesting that the upregulated expression of FGFR3IIIc may create autocrine FGF signaling in ESCC. Taken together, FGFR3IIIc may have the potential to be an early-stage tumor marker and a molecular target for ESCC therapy. PMID- 26487187 TI - Effect of Statin Therapy on Fibrous Cap Thickness in Coronary Plaques Using Optical Coherence Tomography: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate the effect of statin therapy on coronary fibrous cap thickness (FCT) as assessed by optical coherence tomography (OCT) and the relationship between FCT and traditional coronary risk factors. BACKGROUND: Increasing evidence has shown that statin therapy results in a marked increase in coronary FCT. However, the relationship between this increase in FCT and the lipid profile has not been clearly elucidated. METHODS: A literature search of PubMed, Embase, the Cochrane Library, and Web of Science up to March 17, 2015 was performed. Studies providing data on FCT using OCT at baseline and follow-up in patients receiving statin therapy were included. Weighted mean difference (WMD) with a random-effects model was used. RESULTS: Six OCT studies were included. The FCT in coronary plaques was significantly increased after statin therapy (WMD: 58.79 MUm, 95% CI 33.82-83.76 MUm, P < 0.001). When compared with the placebo group, the increase in FCT was also greater in the statin group (WMD: 72.28 MUm, 95% CI 44.97-99.58 MUm, P < 0.001). Meta regression analysis demonstrated no significant correlations between the increase in FTC and the changes in total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels during follow-up. Similarly, there were no significant correlations between the increase in FCT and age, male gender, hypertension, diabetes, and smoking. CONCLUSIONS: Statin therapy induced a significant increase in coronary FCT evaluated by OCT. This increase in FCT was independent of traditional coronary risk factors including the lipid profile. PMID- 26487185 TI - Disaccharides Protect Antigens from Drying-Induced Damage in Routinely Processed Tissue Sections. AB - Drying of the tissue section, partial or total, during immunostaining negatively affects both the staining of tissue antigens and the ability to remove previously deposited antibody layers, particularly during sequential rounds of de-staining and re-staining for multiple antigens. The cause is a progressive loss of the protein-associated water up to the removal of the non-freezable water, a step which abolishes the immunoavailability of the epitope. In order to describe and prevent these adverse effects, we tested, among other substances, sugars, which are known to protect unicellular organisms from freezing and dehydration, and stabilize drugs and reagents in solid state form in medical devices. Disaccharides (lactose, sucrose) prevented the air drying-induced antigen masking and protected tissue-bound antigens and antibodies from air drying-induced damage. Complete removal of the bound antibody layers by chemical stripping was permitted if lactose was present during air drying. Lactose, sucrose and other disaccharides prevent air drying artifacts, allow homogeneous, consistent staining and the reuse of formalin-fixed, paraffin-embedded tissue sections for repeated immunostaining rounds by guaranteeing constant staining quality in suboptimal hydration conditions. PMID- 26487188 TI - Expression of Mx Gene in Cirrhinus mrigala (Hamilton, 1822) to OmpC Protein of Aeromonas hydrophila and Bacterial Infection. AB - The aims of this study were to identify alternative myxovirus (Mx) stimulatory compounds in Cirrhinus mrigala and to characterize the kinetics and intensity of their stimulated responses by semi-quantitative RT-PCR. Mx transcripts were measured in C. mrigala injected with Aeromonas OmpC (outer membrane protein) at a dose 0.4 mg/fish. At day 1, day 2, day 3, day 5, day 10, day 20 and day 30, samples were collected from kidney, spleen, liver, heart brain, gill, intestine and muscle for the study of Mx transcript and housekeeping gene beta-actin. Similarly, Mx gene expression was also studied in Aeromonas hydrophila-infected fish for a period of 10 days. Mx/beta-actin ratio was constitutively expressed from all the organs of OmpC-vaccinated fish. The expression was significantly highest (P <= 0.05) in spleen, followed by liver, kidney, intestine, gill, heart, muscle and brain. The expression was highest in day 2 except spleen (on day 3) and subsequently reduced up to day 30. Control fish also showed Mx expression. Similarly, A. hydrophila-infected fish showed Mx/beta-actin ratio upregulated significantly in the spleen and kidney on day 5, liver on day 2 and intestine on day 3. This study revealed that OmpC of A. hydrophila and its infection could stimulate the antiviral Mx gene of C. mrigala. PMID- 26487189 TI - A Python tool to set up relative free energy calculations in GROMACS. AB - Free energy calculations based on molecular dynamics (MD) simulations have seen a tremendous growth in the last decade. However, it is still difficult and tedious to set them up in an automated manner, as the majority of the present-day MD simulation packages lack that functionality. Relative free energy calculations are a particular challenge for several reasons, including the problem of finding a common substructure and mapping the transformation to be applied. Here we present a tool, alchemical-setup.py, that automatically generates all the input files needed to perform relative solvation and binding free energy calculations with the MD package GROMACS. When combined with Lead Optimization Mapper (LOMAP; Liu et al. in J Comput Aided Mol Des 27(9):755-770, 2013), recently developed in our group, alchemical-setup.py allows fully automated setup of relative free energy calculations in GROMACS. Taking a graph of the planned calculations and a mapping, both computed by LOMAP, our tool generates the topology and coordinate files needed to perform relative free energy calculations for a given set of molecules, and provides a set of simulation input parameters. The tool was validated by performing relative hydration free energy calculations for a handful of molecules from the SAMPL4 challenge (Mobley et al. in J Comput Aided Mol Des 28(4):135-150, 2014). Good agreement with previously published results and the straightforward way in which free energy calculations can be conducted make alchemical-setup.py a promising tool for automated setup of relative solvation and binding free energy calculations. PMID- 26487190 TI - Ethnic Residential Segregation: A Multilevel, Multigroup, Multiscale Approach Exemplified by London in 2011. AB - We develop and apply a multilevel modeling approach that is simultaneously capable of assessing multigroup and multiscale segregation in the presence of substantial stochastic variation that accompanies ethnicity rates based on small absolute counts. Bayesian MCMC estimation of a log-normal Poisson model allows the calculation of the variance estimates of the degree of segregation in a single overall model, and credible intervals are obtained to provide a measure of uncertainty around those estimates. The procedure partitions the variance at different levels and implicitly models the dependency (or autocorrelation) at each spatial scale below the topmost one. Substantively, we apply the model to 2011 census data for London, one of the world's most ethnically diverse cities. We find that the degree of segregation depends both on scale and group. PMID- 26487191 TI - Like Father, Like Son? Intergenerational Educational Mobility in India. AB - Using the nationally representative India Human Development Survey (IHDS), we create a unique son-father matched data set that is representative of the entire adult male population (aged 20-65) in India. We use these data to document the evolution of intergenerational transmission of educational attainment in India over time, among different castes and states for the birth cohorts of 1940-1985. We find that educational persistence, as measured by the regression coefficient of father's education as a predictor of son's education, has declined over time. This implies that increases in average educational attainment are driven primarily by increases among children of less-educated fathers. However, we do not find such a declining trend in the correlation between educational attainment of sons and fathers, which is another commonly used measure of persistence. To understand the source of such a discrepancy between the two measures of educational persistence, we decompose the intergenerational correlation and find that although persistence has declined at the lower end of the fathers' educational distribution, it has increased at the top end of that distribution. PMID- 26487192 TI - [Results of Cutler-Beard procedure for reconstruction of extensive full thickness upper eyelid defects following tumor resection]. AB - BACKGROUND: The Cutler-Beard bridge flap technique is an established method for reconstruction of large full thickness upper eyelid defects. The purpose of the present study was to report experiences with the surgical technique, complications and results of this cutaneoconjunctival flap procedure following tumor resection. PATIENTS AND METHODS: A total of 18 patients with extensive full thickness upper eyelid defects after tumor excision underwent a Cutler-Beard procedure. Of the patients four received an additional eye bank scleral implant and one received an additional free tarsal graft from the fellow upper eyelid to enhance eyelid stability. RESULTS: The Cutler-Beard bridge flap technique was surgically feasible in all patients without causing damage to the lower eyelid bridge or resulting in any infections. Out of the 13 reconstructions without additional stabilizing tissue 3 (23%) developed an upper eyelid entropion that was successfully managed using a secondary scleral implant. None of the five reconstructions using additional scleral or tarsal tissue showed an entropion of the upper eyelid. CONCLUSION: The Cutler-Beard bridge flap technique, which can be combined with grafting additional stabilization tissue in defects exceeding 75% of the upper eyelid length, is a reliable method for reconstruction of large full thickness upper eyelid defects following tumor excision. PMID- 26487193 TI - One-to-one encapsulation based on alternating droplet generation. AB - This paper reports the preparation of encapsulated particles as models of cells using an alternating droplet generation encapsulation method in which the number of particles in a droplet is controlled by a microchannel to achieve one-to-one encapsulation. Using a microchannel in which wettability is treated locally, the fluorescent particles used as models of cells were successfully encapsulated in uniform water-in-oil-in-water (W/O/W) emulsion droplets. Furthermore, 20% of the particle-containing droplets contained one particle. Additionally, when a surfactant with the appropriate properties was used, the fluorescent particles within each inner aqueous droplet were enclosed in the merged droplet by spontaneous droplet coalescence. This one-to-one encapsulation method based on alternating droplet generation could be used for a variety of applications, such as high-throughput single-cell assays, gene transfection into cells or one-to-one cell fusion. PMID- 26487194 TI - Two-Dimensional Tin Disulfide Nanosheets for Enhanced Sodium Storage. AB - Sodium-ion batteries (SIBs) are considered as complementary alternatives to lithium-ion batteries for grid energy storage due to the abundance of sodium. However, low capacity, poor rate capability, and cycling stability of existing anodes significantly hinder the practical applications of SIBs. Herein, ultrathin two-dimensional SnS2 nanosheets (3-4 nm in thickness) are synthesized via a facile refluxing process toward enhanced sodium storage. The SnS2 nanosheets exhibit a high apparent diffusion coefficient of Na(+) and fast sodiation/desodiation reaction kinetics. In half-cells, the nanosheets deliver a high reversible capacity of 733 mAh g(-1) at 0.1 A g(-1), which still remains up to 435 mAh g(-1) at 2 A g(-1). The cell has a high capacity retention of 647 mA h g(-1) during the 50th cycle at 0.1 A g(-1), which is by far the best for SnS2, suggesting that nanosheet morphology is beneficial to improve cycling stability in addition to rate capability. The SnS2 nanosheets also show encouraging performance in a full cell with a Na3V2(PO4)3 cathode. In addition, the sodium storage mechanism is investigated by ex situ XRD coupled with high-resolution TEM. The high specific capacity, good rate capability, and cycling durability suggest that SnS2 nanosheets have great potential working as anodes for high performance SIBs. PMID- 26487195 TI - Intraluminal lavage to remove exfoliated tumor cells after colorectal endoscopic submucosal dissection. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) involves dissection of tumors and manipulation of them in an exposed condition for prolonged periods. A large number of tumor cells are exfoliated into the intestinal lumen after colorectal ESD. The aim of this study was to determine whether lavage volume has an influence on tumor cell clearance after colorectal ESD. METHODS: Twenty patients who underwent colorectal ESD at our hospital between July 2013 and December 2014 were studied. Cytological examination of intraluminal lavage samples associated incremental increases in lavage volume was collected. This prospective study was approved by the ethics committee of our hospital. RESULTS: No patients had exfoliated tumor cells in their samples before ESD. Four patients (20 %) had exfoliated tumor cells in their samples after lavage with 500 ml, while one patient (5 %) had exfoliated tumor cells after lavage with 1000 or 1500 ml. CONCLUSION: Tumor cells are exfoliated into the intestinal lumen by tumor manipulation during colorectal ESD. There seems to be a risk for implantation after ESD, as well as rectal surgery. Sufficient intraluminal lavage of more than 1000 ml may be desirable to remove exfoliated tumor cells after colorectal ESD. PMID- 26487196 TI - Comparison of open, laparoscopic, and robotic approaches for total abdominal colectomy. AB - BACKGROUND: The utilization of minimally invasive surgery is increasing in colorectal surgery. We sought to compare the outcomes of patients who underwent elective open, laparoscopic, and robotic total abdominal colectomy. METHODS: The NIS database was used to examine the clinical data of patients who underwent an elective total colectomy procedure during 2009-2012. Multivariate regression analysis was performed to compare the three surgical approaches. RESULTS: We sampled a total of 26,721 patients who underwent elective total colectomy. Of these, 16,780 (62.8 %) had an open operation, while 9934 (37.2 %) had a minimally invasive approach (9614 laparoscopic surgery, and 326 robotic surgery). The most common indication for an operation was ulcerative colitis (31 %). Patients who underwent open surgery had significantly higher mortality and morbidity compared to laparoscopic (AOR 2.48, 1.30, P < 0.01) and robotic approaches (AOR 1.04, 1.30, P < 0.01 and P = 0.04, respectively). There was no significant difference in mortality and morbidity between the laparoscopic and robotic approaches (AOR 0.96, 1.03, P = 0.10, P = 0.78). However, conversion rate of laparoscopic surgery to open was significantly higher than that of robotic approach (13.3 vs. 1.5 %, P < 0.01). Patients who underwent laparoscopic surgery had significantly lower total hospital charges compared to patients who underwent open surgery (mean difference = $21,489, P < 0.01). Also, total hospital charges for a robotic approach were significantly higher than for a laparoscopic approach (mean difference = $15,595, P < 0.01). CONCLUSION: Minimally invasive approaches to total colectomy are safe, with the advantage of lower mortality and morbidity compared to an open approach. Although there was no significant difference in the morbidity between minimally invasive approaches, robotic surgery had a significantly lower conversion rate compared to laparoscopic approach. Total hospital charges are significantly higher in robotic surgery compared to laparoscopic approach. PMID- 26487197 TI - Prevention of esophageal stricture after endoscopic submucosal dissection: a systematic review and meta-analysis. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) of extensive superficial cancers of the esophagus may progress with high rates of postoperative stenosis, resulting in significantly decreased quality of life. Several therapies are performed to prevent this, but have not yet been compared in a systematic review. METHODS: A systematic review of the literature and meta-analysis were performed using the MEDLINE, Embase, Cochrane, LILACS, Scopus, and CINAHL databases. Clinical trials and observational studies were searched from March 2014 to February 2015. Search terms included: endoscopy, ESD, esophageal stenosis, and esophageal stricture. Three retrospective and four prospective (three randomized) cohort studies were selected and involved 249 patients with superficial esophageal neoplasia who underwent ESD, at least two-thirds of the circumference. We grouped trials comparing different techniques to prevent esophagus stenosis post-ESD. RESULTS: We conducted different meta-analyses on randomized clinical trials (RCT), non-RCT, and global analysis. In RCT (three studies, n = 85), the preventive therapy decreased the risk of stenosis (risk difference = -0.36, 95 % CI -0.55 to -0.18, P = 0.0001). Two studies (one randomized and one non randomized, n = 55) showed that preventative therapy lowered the average number of endoscopy dilatations (mean difference = -8.57, 95 % CI -13.88 to -3.25, P < 0.002). There were no significant differences in the three RCT studies (n = 85) in complication rates between patients with preventative therapy and those without (risk difference = 0.02, 95 % CI -0.09 to 0.14, P = 0.68). CONCLUSIONS: The use of preventive therapy after extensive ESD of the esophagus reduces the risk of stenosis and the number of endoscopic dilatations for resolution of stenosis without increasing the number of complications. PMID- 26487198 TI - Metabolic consequences of the incorporation of a Roux limb in an omega loop (mini) gastric bypass: evaluation by a glucose tolerance test at mid-term follow up. AB - BACKGROUND: In the technique used in our department, Roux-en-Y gastric bypass (RYGB) anatomically only differs from the mini- or omega loop gastric bypass (OLGB) by the incorporation of an isolated alimentary limb, called the Roux limb. The metabolic consequences of the incorporation of a Roux limb are unknown. OBJECTIVES: To evaluate differences in glucose and insulin dynamics between RYGB and OLGB in normoglycemic patients, by submitting them to a glucose challenge after stabilization of their weight. METHODS: Nondiabetic patients who had undergone OLGB 4 years earlier were matched with nondiabetic patients who had undergone RYGB around the same time and with healthy controls. Participants underwent oral (OGTT) and intravenous glucose tolerance test (IVGTT). Endpoints of the study were: progression of plasma glucose and insulin, changes in their concentration [calculated by area under the curve (AUC)] at OGTT and IVGTT, incretin effect and incidence of hypoglycemia. RESULTS: Each of the three groups comprised 14 participants. At OGTT, plasma glucose and insulin incremental values were comparable after OLGB and RYGB, and substantially higher than in controls. Overall glucose concentration, however, did not vary across the three groups. Thirty-minute and overall insulin plasma concentration, indicators of early and total insulin secretion, respectively, was significantly higher in both bypass groups than in controls, and was greatest in OLGB. Severe hypoglycemia occurred in one out of two patients in both bypass groups. At IVGTT, no differences were registered across the three groups and no participant experienced hypoglycemia. The incretin effect was higher after OLGB than after RYGB, but the difference was not statistically significant. CONCLUSIONS: The incorporation of a Roux limb in a loop gastric bypass appears to create a statistically nonsignificant tendency toward reducing insulin hypersecretion observed at OGTT after OLGB, and consequently toward tapering the incretin effect. PMID- 26487199 TI - Endoscopic hemostasis for peptic ulcer bleeding: systematic review and meta analyses of randomized controlled trials. AB - BACKGROUND: Peptic ulcer represents the most common cause of upper gastrointestinal bleeding. Endoscopic therapy can reduce the risks of rebleeding, continued bleeding, need for surgery, and mortality. The objective of this review is to compare the different modalities of endoscopic therapy. METHODS: Studies were identified by searching electronic databases MEDLINE, Embase, Cochrane, LILACS, DARE, and CINAHL. We selected randomized clinical trials that assessed contemporary endoscopic hemostatic techniques. The outcomes evaluated were: initial hemostasis, rebleeding rate, need for surgery, and mortality. The possibility of publication bias was evaluated by funnel plots. An additional analysis was made, including only the higher-quality trials. RESULTS: Twenty eight trials involving 2988 patients were evaluated. Injection therapy alone was inferior to injection therapy with hemoclip and with thermal coagulation when evaluating rebleeding and the need for emergency surgery. Hemoclip was superior to injection therapy in terms of rebleeding; there were no statistically significant differences between hemoclip alone and hemoclip with injection therapy. There was considerable heterogeneity in the comparisons between hemoclip and thermal coagulation. There were no statistically significant differences between thermal coagulation and injection therapy, though their combination was superior, in terms of rebleeding, to thermal coagulation alone. CONCLUSIONS: Injection therapy should not be used alone. Hemoclip is superior to injection therapy, and combining hemoclip with an injectate does not improve hemostatic efficacy above hemoclip alone. Thermal coagulation has similar efficacy as injection therapy; combining these appears to be superior to thermal coagulation alone. Therefore, we recommend the application of hemoclips or the combined use of injection therapy with thermal coagulation for the treatment of peptic ulcer bleeding. PMID- 26487200 TI - Electrical stimulation therapy of the lower esophageal sphincter is successful in treating GERD: long-term 3-year results. AB - BACKGROUND: Electrical stimulation of the lower esophageal sphincter (LES) has been shown to improve outcomes in patients with gastroesophageal reflux disease (GERD) at 2 years. The aim of the study was to evaluate the safety and efficacy of LES stimulation in the same cohort at 3 years. METHODS: GERD patients with partial response to PPI, with % 24-h esophageal pH < 4.0 for >5 %, with hiatal hernia <3 cm and with esophagitis <=LA grade C were treated with LES stimulation in an open-label 2-year trial. All patients were on fixed stimulation parameter of 20 Hz, 220 MUs, 5 mA delivered in twelve, 30-min sessions. After completing the 2-year open-label study, they were offered enrollment into a multicenter registry trial and were evaluated using GERD-HRQL, symptom diaries and pH testing at their 3-year follow-up. RESULTS: Fifteen patients completed their 3-year evaluation [mean (SD) age = 56.1 (9.7) years; men = 8] on LES stimulation. At 3 years, there was a significant improvement in their median (IQR) GERD-HRQL on electrical stimulation compared to both their on PPI [9 (6-10) vs. 1 (0-2), p = 0.001] and off PPI [22 (21-24) vs. 1 (0-2), p < 0.001]. Median 24-h distal esophageal acid exposure was significantly reduced from [10.3 (7.5-11.6) % at baseline vs. 3 (1.9-4.5) %, p < 0.001] at 3 years. Seventy-three % (11/15) patients had normalized their distal esophageal acid exposure at 3 years. Remaining four patients had improved their distal esophageal acid exposure by 39 48 % from baseline. All but four patients reported cessation of regular PPI use (>50 % of days with PPI use); three had normal esophageal pH at 3 years. There were no unanticipated device- or stimulation-related adverse events or untoward sensation reported during the 2- to 3-year follow-up. CONCLUSION: LES-EST is safe and effective for treating patients with GERD over long-term, 3-year duration. There was a significant and sustained improvement in esophageal acid exposure and reduction in GERD symptoms and PPI use. Further, no new GI side effects or adverse events were reported. PMID- 26487201 TI - Endolumenal colon occlusion reduces peritoneal contamination during a transrectal NOTES procedure: a controlled porcine survival study. AB - BACKGROUND: To enable an efficient and enduring decontamination of the rectal mucosa during transanal endosocopic procedures, we developed a device for reversible endolumenal colon occlusion (ColoShield). The aim of this study was to assess the value of ColoShield in reducing peritoneal contamination during a transrectal procedure. METHODS: Sixteen pigs underwent transrectal hybrid NOTES cholecystectomy after standardized disinfective rectal washout either with endolumenal colon occlusion using ColoShield (N = 8) or without colon occlusion (N = 8). Rectal swab samples were taken before and after rectal washout and at the end of the procedure. Peritoneal biopsies for microbiological evaluation were obtained at the end of the procedure and at necropsy 7 days after surgery. RESULTS: Peritoneal contamination at the end of surgery was significantly lower using ColoShield compared to not using colon occlusion [13 (1/8) vs. 75 % (6/8); P = 0.012]. No significant differences were found regarding contamination of rectal swabs and peritoneal contamination at necropsy. CONCLUSION: The application of ColoShield may increase the safety of transrectal NOTES and transanal endoscopic procedures by reducing peritoneal contamination and consecutive infectious complications. PMID- 26487202 TI - Robotic-assisted outcomes are not tied to surgeon volume and experience. AB - INTRODUCTION: There are little data regarding whether hospital and surgeon factors affect outcomes following robotic-assisted surgery (RAS). The purpose of this study was to investigate whether any such factor was associated with hospital length of stay (HLOS) and complications following common RAS procedures in the State of New York. METHODS: Following IRB approval, The New York Statewide Planning and Research Cooperative System administrative dataset was used to identify eight common RAS procedures through ICD-9 codes: cholecystectomy, colectomy, Roux-en-Y gastric bypass, sleeve gastrectomy, esophageal fundoplication, pancreatectomy, splenectomy, and gastrectomy between 2008 and 2012. Physician factors evaluated included time since graduation, fellowship status, and number of procedures performed; hospital-level factors included urban versus rural setting, teaching status, hospital size, and the presence of a fellowship. All these factors were further evaluated in multivariable regression models to evaluate for effect on overall complication and HLOS after adjusting for covariates such as patients' characteristics and comorbidities. RESULTS: There were 1670 patients who underwent RAS with average HLOS of 4.433 days and overall complication rate of 18.8 %. Univariate analysis showed that patients of physicians having fellowship training tended to have higher rate of complication 22.82 versus 13.49 % (P = 0.0055), but these were also sicker patients. In addition, physicians with higher number of procedures had lower complications (P = 0.0138). However, these two factors were not significant after controlling for other covariates. Neither physician- nor hospital-related factors were significantly related to HLOS with or without adjusting for other covariates. CONCLUSIONS: Robotic assistance may eliminate the differences between hospitals and physicians. PMID- 26487203 TI - The learning curve of laparoscopic liver resection after the Louisville statement 2008: Will it be more effective and smooth? AB - BACKGROUND: Laparoscopic liver resection (LLR) has been proven to be feasible and safe. However, it is a difficult and complex procedure with a steep learning curve. The aim of this study was to evaluate the learning curve of LLR at our institutions since 2008. METHODS: One hundred and twenty-six consecutive LLRs were included from May 2008 to December 2014. Patient characteristics, operative data, and surgical outcomes were collected prospectively and analyzed. RESULTS: The median tumor size was 25 mm (range 5-90 mm), and 96 % of the resected tumors were malignant. 41.3 % (52/126) of patients had pathologically proven liver cirrhosis. The median operation time was 216 min (range 40-602 min) with a median blood loss of 100 ml (range 20-2300 ml). The median length of hospital stay was 4 days (range 2-10 days). Six major postoperative complications occurred in this series, and there was no 90-day postoperative mortality. Regarding the incidence of major operative events including operation time longer than 300 min, perioperative blood loss above 500 ml, and major postoperative complications, the learning curve [as evaluated by the cumulative sum (CUSUM) technique] showed its first reverse after 22 cases. The indication of laparoscopic resection in this series extended after 60 cases to include tumors located in difficult locations (segments 4a, 7, 8) and major hepatectomy. CUSUM showed that the incidence of major operative events proceeded to increase again, and the second reverse was noted after an additional 40 cases of experience. Location of the tumor in a difficult area emerged as a significant predictor of major operative events. CONCLUSIONS: In carefully selected patients, CUSUM analysis showed 22 cases were needed to overcome the learning curve for minor LLR. PMID- 26487204 TI - The role of tumor size in surgical decision making after endoscopic resection for early gastric cancer. AB - BACKGROUND: Endoscopic resection (ER) is curative treatment option for early gastric cancer (EGC). Additional surgery is required when the tumor pathology is beyond ER indication. It is unclear whether tumor size can be correlated with indications for surgery after ER. Therefore, we aimed to access the role of tumor size for surgical decision making after ER. METHODS: We reviewed clinicopathological data from 3246 patients underwent gastrectomy for EGC. The patients were classified into three groups as follows: the ulcer-negative intramucosal cancer with undifferentiated histology, ulcerative intramucosal cancer with differentiated histology, and minute submucosal (SM1) cancer with differentiated histology. The probability of additional surgery after ER was defined as at least one positive result for lymph node metastasis, lymphovascular invasion or perineural invasion. The probability was compared between individual tumor size and ER size criteria in each group using area under receiver operating characteristic curves. RESULTS: The probabilities of ulcer-negative intramucosal cancer with undifferentiated histology, SM1 cancer with differentiated histology and ulcerative intramucosal cancer with differentiated histology were 4.2, 22.1 and 2.5 %. In the ulcerative intramucosal cancer with differentiated histology group, these probabilities increased when the difference in tumor size was >1 mm compared with ER size criteria. The probability was not increased when there was a >10-mm tumor size difference compared with ER size criteria in the other two groups. CONCLUSIONS: Tumor size was correlated with ER criteria in patients with ulcerative intramucosal cancer with differentiated histology after ER but was not strictly correlated with ER criteria in the other two patient groups. However, further study may be necessary to validate our results in the future. PMID- 26487205 TI - Where are my instruments? Hazards in delivery of surgical instruments. AB - BACKGROUND: Unavailability of instruments is recognised to cause delays and stress in the operating room, which can lead to additional risks for the patients. The aim was to provide an overview of the hazards in the entire delivery process of surgical instruments and to provide insight into how Information Technology (IT) could support this process in terms of information availability and exchange. METHODS: The process of delivery was described according to the Healthcare Failure Mode and Effects Analysis methodology for two hospitals. The different means of information exchange and availability were listed. Then, hazards were identified and further analysed for each step of the process. RESULTS: For the first hospital, 172 hazards were identified, and 23 of hazards were classified as high risk. Only one hazard was considered as 'controlled' (when actions were taken to remove the hazard later in the process). Twenty-two hazards were 'tolerated' (when no actions were taken, and it was therefore accepted that adverse events may occur). For the second hospital, 158 hazards were identified, and 49 of hazards were classified as high risk. Eight hazards were 'controlled' and 41 were 'tolerated'. The means for information exchange and information systems were numerous for both cases, while there was not one system that provided an overview of all relevant information. CONCLUSIONS: The majority of the high-risk hazards are expected to be controlled by the use of IT support. Centralised information and information availability for different parties reduce risks related to unavailability of instruments in the operating room. PMID- 26487206 TI - Discordant findings between preoperative endoscopy and postoperative pathology as an independent prognostic factor in gastric cancer patients. AB - BACKGROUND: Endoscopically diagnosed early gastric cancers (EGCs) are sometimes revealed to be advanced gastric cancers (AGCs) on pathologic examination of the resected specimen, and also endoscopically diagnosed AGCs are often determined to be EGCs. This study was designed to determine the impact on prognosis of the discordant finding between preoperative endoscopy and postoperative pathology in gastric cancer patients. METHODS: Patients with gastric cancer stages pT1a-T4a who underwent curative gastrectomy between 2004 and 2010 were included in the study. The preoperative endoscopic findings and clinicopathologic features were analyzed. The prognostic impact on recurrence-free survival of discordance between endoscopic and pathologic examinations was analyzed using multivariate analysis. RESULTS: Among 367 patients diagnosed with EGC on preoperative endoscopy, 40 (11 %) had AGC on final pathologic examination; this was more common in female patients, upper one-third location of the cancer, poorly differentiated tumor, combined gross type (elevated and depressed), lymphovascular invasion and lymph node metastasis. Among 350 patients diagnosed with AGC on preoperative endoscopy, 66 (19 %) had EGC pathologically; this was more frequent in patients with tumor in the lower and/or middle third of the stomach, differentiated tumor, Borrmann type 1 and absence of lymph node metastasis. The endoscopic appearance of AGC was identified as a poor prognostic factor related to recurrence-free survival in patients with EGC, whereas discordance did not influence recurrence-free survival in patients with AGC. CONCLUSIONS: Discordant preoperative endoscopic appearance may be an indicator of biologic aggressiveness and a reliable prognostic factor in EGC, but not in AGC. PMID- 26487207 TI - Novel laparoscopic narrow band imaging for real-time detection of bile leak during hepatectomy: proof of the concept in a porcine model. AB - INTRODUCTION: Bile leakage is a serious complication occurring in up to 10 % of hepatic resections. Intraoperative detection of bile leakage is challenging, and concomitant blood oozing can mask the presence of bile. Intraductal dye injection [methylene blue or indocyanine green (ICG)] is a validated technique to detect bile leakage. However, this method is time-consuming, particularly in the laparoscopic setting. A novel narrow band imaging (NBI) modality (SPECTRA-A; Karl Storz, Tuttlingen, Germany) allows easy discrimination of the presence of bile, which appears in clear orange, by image processing. The aim of this experimental study was to evaluate SPECTRA-A ability to detect bile leakage. METHODS: Twelve laparoscopic partial hepatectomies were performed in seven pigs. The common bile duct was clipped distally and dissected, and a catheter was inserted and secured with a suture or a clip. Liver dissection was achieved with an ultrasonic cutting device. Dissection surfaces were checked by frequently switching on the SPECTRA filter to identify the presence of bile leakage. Intraductal ICG injection through the catheter was performed to confirm SPECTRA findings. RESULTS: Three active bile leakages were obtained out of 12 hepatectomies and successfully detected intraoperatively by the SPECTRA. There was complete concordance between NBI and ICG fluorescence detection. No active leaks were found in the remaining cases with both techniques. The leaking area identified was sutured, and SPECTRA was used to assess the success of the repair. CONCLUSIONS: The SPECTRA laparoscopic image processing system allows for rapid detection of bile leaks following hepatectomy without any contrast injection. PMID- 26487208 TI - Efficacy of endoscopic submucosal dissection with dental floss clip traction for gastric epithelial neoplasia: a pilot study (with video). AB - BACKGROUND: Providing appropriate tension to the lesion and securing a stable view of the submucosal layer is important for accomplishing successful endoscopic submucosal dissection (ESD) in gastric cancer. Dental floss clip traction (DFC), a new traction method, is proposed to reduce the difficulty of ESD. The objective of this pilot study was to investigate the efficacy of DFC for gastric ESD. METHODS: From August to November 2014, a total of 95 patients with 104 gastric epithelial neoplasms underwent DFC-ESD (DFC group). Historical controls treated by conventional ESD (control group) were individually matched to cases at a 1:1 ratio by lesion location, ulcer findings, resected specimen size, and the proficiency of the operator (trainee/expert). The outcomes of the procedure in the two groups were then compared. RESULTS: The mean +/- SD procedure time was 43 +/- 24 min in the DFC group and 52 +/- 30 min in the control group (P < 0.01). Fewer lesions in the DFC group needed >80 min compared with the control group (3 vs-16 cases, P = 0.01). There were no significant differences in adverse events between the groups. Perforation and delayed bleeding occurred in one and four lesions, respectively, in the DFC group, and three and nine in the control group. En bloc resection was achieved in all cases. No significant differences were found regarding curability of ESD between the groups. CONCLUSIONS: DFC effectively reduced ESD procedure time without increasing adverse events. DFC is helpful for rapid, safe ESD. PMID- 26487209 TI - Indocyanine green-enhanced fluorescence to assess bowel perfusion during laparoscopic colorectal resection. AB - AIMS: Anastomotic leakage after colorectal surgery is a severe complication. One possible cause of anastomotic leakage is insufficient vascular supply. The aim of this study was to evaluate the feasibility and the usefulness of intraoperative assessment of vascular anastomotic perfusion in colorectal surgery using indocyanine green (ICG)-enhanced fluorescence. METHODS: Between May 2013 and October 2014, all anastomosis and resection margins in colorectal surgery were investigated using fluorescence angiography (KARL STORZ GmbH & Co. KG, Tuttlingen, Germany) intraoperatively to assess colonic perfusion prior to and after completion of the anastomosis, both in right and left colectomies. RESULTS: A total of 107 patients undergoing colorectal laparoscopic resections were enrolled: 40 right colectomies, 10 splenic flexure segmental resections, 35 left colectomies, and 22 anterior resections. In 90 % of cases, the indication for surgery was cancer and high ligation of vessels was performed. Based on the fluorescence intensity, the surgical team judged the distal part of the proximal bowel to be anastomosed insufficiently perfused in 4/107 patients (two anterior, one sigmoid and one segmental splenic flexure resections for cancer), and consequently, further proximal "re-resection" up to a "fluorescent" portion was performed. None of these patients had a clinical leak. The overall morbidity rate was 30 %; one patient undergoing right colectomy had an anastomotic leakage, apparently unrelated to ischemia; there were no clinical evident anastomotic leakages in colorectal resections including all low anterior resections. CONCLUSIONS: ICG-enhanced fluorescent angiography provides useful intraoperative information about the vascular perfusion during colorectal surgery and may lead to change the site of resection and/or anastomosis, possibly affecting the anastomotic leak rate. Larger further randomized prospective trials are needed to validate this new technique. PMID- 26487210 TI - Examining variation in cost based on surgeon choices for elective laparoscopic cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is the standard of care for treatment of benign biliary disease. Declining reimbursements and increasing medical costs require physicians to examine closely their choices for equipment to decrease overall costs, particularly looking at key steps of cholecystectomy. The objective of this study was to examine variations between surgeons in equipment and operating room costs for elective LC. METHODS: Elective LC performed at IUH West Hospital in 2013 was analyzed. Patient demographics, preoperative diagnosis, operative time, surgical equipment, and resident participation were tracked. Exclusion criteria included acute cholecystitis and cases with additional procedures. Electronic medical records for clinical data and administrative records for reimbursement data were reviewed. Total supply costs and disposable costs for key portions of the LC were analyzed. Reimbursements were obtained from all payers for LC. RESULTS: All LC were examined (n = 362) and 272 met inclusion criteria. Demographics and pathology were similar between surgeons. Operative time varied significantly (range 53-98 min) with the lowest cost surgeon taking the longest overall time. Times were significantly affected by resident participation. The total morbidity was 4 %, with no mortalities. Total supply costs by surgeon ranged from $412-$924. The most costeffective technique included the use of plastic locking clips and hook electrocautery. Hospital and surgeon reimbursements were $336-$11,554 and $669 $1500 respectively. CONCLUSION: This study highlights effects of surgeon choice as it relates to variable costs for surgical technique during elective LC without compromising safety. With healthcare reform emphasizing reduced healthcare expenditures, it is vital for surgeons to identify areas of unnecessary cost. Operating room time also contributes to cost, thus surgeons should implement techniques to complete procedures in a safe yet efficient fashion. Transparency by surgeons can lead to data that may support standardization of technique across a healthcare system to lower total supply costs. PMID- 26487211 TI - Laparoscopic versus open enucleation for pancreatic neoplasms: clinical outcomes and pancreatic function analysis. AB - BACKGROUND: The studies comparing laparoscopic enucleation (LE) with open enucleation (OE) are limited. This study aimed to compare perioperative outcomes of patients undergoing LE and OE and to assess the pancreatic function after LE. METHODS: Between February 2001 and July 2014, patients who underwent enucleation were reviewed. Patients were divided into two groups as LE and OE. Data considered for comparison analysis were patient demographics, intraoperative variables, morbidity, postoperative hospital stay, mortality, pathologic findings, and long-term follow-up (including pancreatic function). RESULTS: Thirty-seven patients (15 LE and 22 OE) were included in the final analysis. Baseline characteristics were similar in the two groups. LE group showed significantly shorter operating time (118.2 +/- 33.1 vs. 155.2 +/- 44.3 min, p = 0.009), lower estimated blood loss (80.0 +/- 71.2 vs. 195.5 +/- 103.4 ml, p = 0.001), shorter first flatus time (1.8 +/- 1.0 vs. 3.4 +/- 1.8 days, p = 0.004), shorter diet start time (2.4 +/- 1.0 vs. 4.4 +/- 2.0 days, p = 0.001), shorter postoperative hospital stay (7.9 +/- 3.4 vs. 11.2 +/- 5.7 days, p = 0.046). Postoperative outcomes, including morbidity (40.0 vs. 45.5 %, p = 1.000), grade B/C pancreatic fistula rates (20.0 vs. 13.6 %, p = 0.874), and mortality, were similar in the two groups. The median follow-up period was 47 months (range 7-163 months). No local recurrence or distant metastasis was detected in either group. Only one patient (4.8 %) underwent OE developed new-onset diabetes, in comparison with none in the LE group. One patient (7.1 %) had weight loss and received pancreatic enzyme supplementation in the LE group, in comparison with two patients (9.5 %) in the OE group. CONCLUSIONS: LE is a safe and feasible technique for the benign or low malignant-potential pancreatic neoplasms. Compared to OE, LE had shorter operating time, lower estimated blood loss, and faster recovery. LE could preserve the pancreatic function as the OE. PMID- 26487212 TI - Predictive factors for successful ultrasound-guided percutaneous drainage in necrotizing pancreatitis. AB - BACKGROUND: Percutaneous catheter drainage (PCD) is now regarded as an initial minimal access technique of step-up approach for necrotizing pancreatitis. Factors that led to surgical intervention after initial management with PCD have rarely been reported. This study was to evaluate the safety and efficacy of ultrasound-guided PCD in patients with necrotizing pancreatitis and identify a subgroup of patients where PCD alone would be effective. METHODS: We performed a retrospective review of patients with necrotizing pancreatitis who underwent intervention in West China Hospital from January 1, 2009, to March 31, 2013. RESULTS: Patients who underwent initial PCD therapy had lower intra-abdominal bleeding rate (41/235 vs. 1/51, P = 0.002), lower enterocutaneous fistula rate (28/235 vs. 0/51, P = 0.004), and lower mortality rate (46/235 vs. 3/51, P = 0.001) when compared with the patients who underwent operative intervention. The successful PCD group had lower computed tomography (CT) mean density of necrotic fluid collection (18 HU vs. 25 HU, P = 0.01) and higher prevalence of walled-off necrosis (20/35 vs. 5/16, P = 0.04) when compared with failed PCD group. Multivariate analysis of the predictors of surgery showed that only CT mean density of necrotic fluid collection [odd ratio (OR) 1.63, 95 % confidence interval (CI) 1.04-2.94, P = 0.006] was identified as significant factor. CONCLUSION: CT mean density of necrotic fluid collection and the existence of acute necrotic collection could influence the success rate of PCD. PMID- 26487213 TI - Evaluation of the need for routine esophagram after peroral endoscopic myotomy (POEM). AB - BACKGROUND: Peroral endoscopic myotomy (POEM) is a novel surgical option for the treatment of achalasia. Most centers perform a routine esophagram on postoperative day (POD) #1 to rule esophageal perforation and leaks. In this study, we sought to determine the clinical utility of routine contrast studies post-POEM. METHODS: POEM was performed using an anterior submucosal tunnel and selective myotomy of the circular muscle layer. A routine contrast esophagram was obtained on POD #1. We conducted a retrospective review of the radiologists' interpretations of these studies and compared them to patient's clinical course. RESULTS: Seventy-eight patients were included. Among these, two complications occurred. One patient was non-compliant with postoperative nil per os orders and developed epigastric pain suspicious for a leak that was demonstrated on esophagram. Another patient had subcutaneous emphysema on POD #1 esophagram, a finding that was also present on physical examination, without esophageal leakage. Another esophagram in an asymptomatic patient was suspicious for submucosal tunnel hematoma which prompted a return to the operating room with negative results. Overall, 56 patients had abnormal studies. POD #1 esophagram demonstrated a sensitivity of 100 % and specificity of 45 % in identifying clinically significant complications. CONCLUSIONS: In this series, we found routine esophagram to have a high sensitivity but a very low specificity in detecting clinically significant complications. Routine esophagram after POEM may not be necessary. PMID- 26487214 TI - A scoring system to predict the risk of organ/space surgical site infections after laparoscopic gastrectomy for gastric cancer based on a large-scale retrospective study. AB - BACKGROUND: A scoring system allows risk stratification of morbidity might be helpful for selecting risk-adapted interventions to improve surgical safety. Few studies have been designed to develop scoring systems to predict SSIs after laparoscopic gastrectomy for gastric cancer. METHODS: We analyzed the records of 2364 patients who underwent laparoscopic gastrectomy for gastric cancer. A logistic regression model was used to identify the determinant variables and develop a predictive score. RESULTS: There were 2364 patients, of whom 131 (5.5 %) developed overall SSIs, 33 (1.4 %) developed incisional SSIs, and 98 (4.1 %) developed organ/space SSIs. No significant risk factor was associated with incisional SSIs. A multivariate analysis showed the following adverse risk factors for organ/space SSIs: BMI >= 25 kg/m(2), intraoperative blood loss >=75 ml, operation time >=240 min, and perioperative transfusion. Each of these factors contributed 1 point to the risk score. The organ/space SSIs rates were 1.8, 3.9, 9.9, and 39.0 % for the low-, intermediate-, high-, and extremely high risk categories, respectively (p < 0.001). The area under the receiver operating characteristic curve for the score of organ/space SSIs was 0.734. There were no statistically significant differences between the observed and predicted incidence rates for organ/space SSIs in the validation set. CONCLUSIONS: This validated and simple scoring system could accurately predict the risk of organ/space SSIs after laparoscopic gastrectomy for gastric cancer. The score might be helpful in the selection of risk-adapted interventions to decrease the incidence rates of organ/space SSIs. PMID- 26487217 TI - Laparoscopic translevator approach to abdominoperineal resection for rectal adenocarcinoma: feasibility and short-term oncologic outcomes. AB - BACKGROUND: The extra-levator approach to abdominal perineal resection (APR) was developed in order to reduce the rates of positive circumferential resection margin. This approach, however, is associated with significant morbidity. We postulate that a less radical resection of the levators done laparoscopically could significantly decrease the rate of perineal complications while ensuring an oncologically adequate specimen. To date, to our knowledge, there are no reports in the literature describing a laparoscopic translevator approach for APR. The purpose of this study is to describe our initial experience with this approach and assess our short-term oncologic and clinical outcomes. METHODS: This is a retrospective study of patients who underwent laparoscopic APR with intra abdominal levator transection for rectal cancer from 2012 to 2014 at a single tertiary care institution. Main outcome measures include: perineal flap rates, post-operative complications, length of stay, distance from tumour to circumferential resection margin, R0 status, and disease recurrence. Data are presented as median (interquartile range) unless otherwise noted. RESULTS: Seventeen cases were identified. Patient age was 61 (range 34-75), and 59 % were male. Pre-operative distance of the tumour from the anal verge was 2.6 cm (0.4 3.9). Post-operative length of stay was 4 (4-6) days. One patient required a perineal flap for reconstruction. Four patients (22 %) had perineal complications (three wound infections and one hernia). No patients reported sexual dysfunction, and one (5 %) developed urinary retention. Five (29 %) patients had a complete pathological response. The circumferential resection margin was 1.5 (0.8-2.5) cm, with no positive margins reported. The number of retrieved lymph nodes was 12 (range 2-30). Follow-up was 9.7 months (range 20 days-23 months), during which one patient developed recurrent disease. CONCLUSIONS: This study describes a novel surgical approach to APR that has the potential to both decrease perineal complications and provide excellent oncologic results. PMID- 26487215 TI - Expanding indications and regional diversity in laparoscopic liver resection unveiled by the International Survey on Technical Aspects of Laparoscopic Liver Resection (INSTALL) study. AB - BACKGROUND: Laparoscopic liver resection (LLR) has undergone widespread dissemination after the first international consensus conference in 2008, and specialized centers continue to report remarkable achievements. However, little is known about the global adoption of LLR. This study aimed to illuminate geographical variances in the indications and technical aspects of LLR and to delineate the evolution of this approach worldwide. METHODS: In advance of the Second International Consensus Conference in Morioka, Japan, a web-based, anonymous questionnaire comprising 46 questions, named the International Survey on Technical Aspects of Laparoscopic Liver Resection study, was sent via e-mail to the members of regional and International Hepato-Pancreato-Biliary Association offices. The results of the 13 questions concerning the global diffusion of LLR have been reported previously. Responses to the remaining 33 questions that corresponded to indications and surgical techniques used in LLR were collected and analyzed. RESULTS: Survey responses were received from 412 LLR surgeons in 42 countries on five continents. The majority of surgeons in North America had no restrictions on the maximum size or number of tumors to be resected laparoscopically. Likewise, >50 % of surgeons in East Asia and North America performed LLR for the postero-superior 'difficult' segments. Major resection was performed in 40 to >60 % of centers in North America, Europe, and East Asia. Donor hepatectomy was performed only in specialized centers. More than 75 % of respondents had adopted a pure laparoscopic approach. A flexible laparoscope was most commonly used in East Asia. Most surgeons used pneumoperitoneal pressure at around 9-16 mmHg. Other techniques and devices were used at the discretion of each surgeon. CONCLUSIONS: Indications for LLR continue to expand with some regional diversity. Surgical approaches and devices used in LLR are a matter of preference and availability, as in open liver resection. PMID- 26487216 TI - Comparison of single-stapling and hemi-double-stapling methods for intracorporeal esophagojejunostomy using a circular stapler after totally laparoscopic total gastrectomy. AB - BACKGROUND: Laparoscopic total gastrectomy is not widely performed because of the difficulty of esophagojejunal reconstruction. This study analyzed complication rates of two different methods for reconstruction by a circular stapler after totally laparoscopic total gastrectomy (TLTG). METHODS: Between 2010 and 2014, clinical data of 19 patients who underwent TLTG for gastric adenocarcinoma were collected retrospectively. There were two methods to fix the anvil of a circular stapler into the distal esophagus: In the single-stapling technique (SST) group, Endo-PSI(II) was used for purse-suturing on the distal esophagus for reconstruction, and in the hemi-double-stapling technique (hemi-DST) group, the esophagus was cut by linear stapler with the entry hole of the anvil shaft opened after inserting the anvil tail. In both groups, surgical procedures were the same, except for the reconstruction. RESULTS: All TLTGs were performed securely without mortality. Intracorporeal laparoscopic esophagojejunal anastomosis was performed successfully for all the patients. In the hemi-DST group, four patients experienced anastomotic stenosis, three of whom required endoscopic balloon dilation. In contrast, no stenosis was seen in the SST group (p = 0.033). CONCLUSIONS: Anastomosis with SST is preferred to that with hemi-DST to minimize postoperative complications. PMID- 26487218 TI - Acetazolamide reduces postoperative pain following laparoscopic inguinal herniorrhaphy. AB - BACKGROUND: Carbonic acid accumulation, which results from CO2 insufflation, can produce visceral and referred pain in the postoperative setting. Acetazolamide inhibits carbonic anhydrase, an enzyme that accelerates carbonic acid formation. We hypothesized that preoperative administration of acetazolamide would decrease postoperative pain in patients undergoing laparoscopic inguinal herniorrhaphy. METHODS: A retrospective review was conducted of patients who underwent laparoscopic preperitoneal inguinal herniorrhaphy at the Medical College of Wisconsin between October 2012 and September 2014. Beginning in January 2014, patients began receiving 250 mg of acetazolamide preoperatively; patients prior to that time did not. The visual analog scale (range 0-10) was used to assess both preoperative pain and postoperative pain. RESULTS: A total of 66 patients underwent laparoscopic inguinal herniorrhaphy during the study interval. Of these, 22 (33 %) patients received acetazolamide preoperatively, and 44 (67 %) were included as controls. Overall mean pain scores were lower in the acetazolamide group (1.9 +/- 1.45 vs 2.9 +/- 1.5, p = 0.04). Specifically, patients who received acetazolamide reported lower pain scores immediately after surgery (0.6 +/- 1.2 vs 1.9 +/- 2.3, p = 0.01) and on post-op day one (2.3 +/- 0.9 vs 4.0 +/- 2.1, p = 0.04). Total morphine equivalents administered to manage postoperative pain were significantly less for the acetazolamide group (4.3 +/- 4.8 mg) when compared to the control group (8.9 +/- 8.4 mg), p = 0.04. Perioperative complications did not differ between the groups (p = 0.16). CONCLUSIONS: Acetazolamide appears to reduce pain in the immediate postoperative setting. Patients who received acetazolamide had lower pain scores postoperatively and required fewer narcotics for pain management prior to discharge. PMID- 26487219 TI - Comparison of laparoscopic subtotal colectomy with posterior vaginal suspension and laparoscopic subtotal colectomy with transvaginal repair for patients with slow-transit constipation complicated with rectocele: a non-randomized comparative study in a single center. AB - BACKGROUND: Slow-transit constipation complicated with rectocele is a mixed constipation difficult to treat by surgery. Different hospitals and surgeons may employ different surgical procedures. The present study aims to compare the efficacy of laparoscopic subtotal colectomy (LSC) with posterior vaginal suspension and LSC with transvaginal repair for patients having refractory slow transit constipation complicated with rectocele. METHODS: This paper is a retrospective study of 64 patients having refractory slow-transit constipation complicated with rectocele. Admitted from January 2002 to December 2012, the 64 patients were non-randomly divided into two groups: patients who underwent LSC with posterior vaginal suspension (Group A, 36 patients) and patients who underwent LSC with transvaginal repair (Group B, 28 patients). RESULTS: There was no statistically significant difference (P > 0.05) in preoperative general characteristics and Wexner constipation score between Group A and Group B. There was no statistically significant difference (P > 0.05) in operative time and intraoperative blood loss between the two groups. One month after the surgery, there was no statistically significant difference (P > 0.05) in early postoperative complications, constipation recurrence rate, degree of improvement in constipation symptoms, and Wexner constipation score between the two groups. But 1-year follow-up results show that there was statistically significant difference (P < 0.05) in constipation recurrence rate, gastrointestinal quality of life index, the degree of improvement in constipation symptoms, and Wexner constipation score between the two groups. CONCLUSION: Compared with the LSC with transvaginal repair, the LSC with posterior vaginal suspension demonstrated better efficacy in treating refractory slow-transit constipation complicated with rectocele. PMID- 26487220 TI - Robotic single-site adrenalectomy. AB - INTRODUCTION: Technological advances have brought about robotic single-site (RSS) cholecystectomy and hysterectomy. The application of RSS to additional procedures requires careful assessment of the surgeon learning curve, the technological limitations, patient selection criteria and associated outcomes. METHODS: Patient demographics, BMI, surgical indications, adrenal size, OR times, length of stay, postoperative pain and complications were assessed. RESULTS: Thirty-three patients underwent RSS-A by a single surgeon with 53 % being male, mean age 54 +/ 16 years and mean BMI of 32.7. There were 18 left, 10 right, and 5 bilateral procedures for a total of 38 adrenal glands removed (mean tumor size 3.2 cm). There were 5 conversions to a laparoscopic approach, and two to open approach. The necessity for conversion was not associated with age, BMI, tumor size, surgical side or pathology (p > 0.05). The patients who underwent successful unilateral RSS-A had a profile of mean age 55, BMI 31, tumor size 3 cm, and a mean operative time of 118 +/- 25.8 min. Pain scores were <4 (10 point scale) in 67 % of patients. 74 % of patients were discharged on POD 1 and 96 % were discharged by POD 2. An assessment of the quartile learning curve for the unilateral RSS-A showed operative times decreased from a mean of 124 to 103 min after 21 cases (p = 0.05). CONCLUSION: Patients with functioning and non functioning tumors, along with those with obesity can safely be treated with RSS A. The surgeon learning curve was associated with shortened operative times and not increased complication rates. PMID- 26487221 TI - Comparison between submucosal tunneling endoscopic resection and video-assisted thoracoscopic surgery for large esophageal leiomyoma originating from the muscularis propria layer. AB - BACKGROUND: Submucosal tunneling endoscopic resection (STER) has been proved to be safe and effective for removal of esophageal leiomyoma originating from the muscularis propria (MP) layer. However, there are still technical challenges for tumors >=35 mm due to the limited space of the submucosal tunnel. The aim of the study was to estimate the safety and efficacy of STER for large esophageal leiomyoma originating from the MP layer as well as compare its efficacy with video-assisted thoracoscopic surgery (VATS), which is a standard procedure for treating esophageal leiomyoma. METHODS: We retrospectively collected the clinical data of the patients with esophageal leiomyoma of 35-55 mm who underwent STER or VATS at our hospital between January 2010 and December 2014. Epidemiological data (gender, age), tumor location, tumor size, procedure-related parameters, complications, length of stay and cost were compared between STER and VATS. RESULTS: A total of 31 patients were enrolled, and 18 patients underwent STER and the other 13 received VATS. There was no significant difference between the two groups in gender, age, tumor location, tumor size, complications and rate of en bloc resection (P > 0.05). However, patients in the STER groups had a shorter operation time, a less decrease in hemoglobin level, a shorter length of hospital stay and a decreased cost (P < 0.05). No recurrence was noted in the STER and VATS groups during a mean follow-up of 10.9 and 30.8 months, respectively. CONCLUSIONS: The treatment efficacy was comparable between the STER and VATS for esophageal leiomyoma of 35-55 mm. However, STER is superior to VATS in a shorter operation time, a less decrease in hemoglobin level, a shorter length of hospital stay and a decreased cost. PMID- 26487222 TI - Laparoscopic hepatectomy by curettage and aspiration: a report of 855 cases. AB - BACKGROUND: In 1998, the technique of laparoscopic hepatectomy by curettage and aspiration was developed and a special instrument, laparoscopic multifunctional operative dissector (LPMOD), was designed for this procedure. In the past 17 years, this procedure was developed gradually and had become the routine procedure for laparoscopic hepatectomy in local area. This paper is to report results of 17-year practice of this procedure. METHODS: Patients who underwent laparoscopic hepatectomy from August 1998 to March 2015 were reviewed. Hepatectomies were performed using the technique of laparoscopic hepatectomy by curettage and aspiration. By using the LPMOD, liver parenchyma was crashed and aspirated immediately and the intrahepatic ducts and small vessels were preserved and were safely dissected for ligation. Laparoscopic selective hepatic flow occlusion was performed routinely for hemi-hepatectomies to control intraoperative blood loss. RESULTS: A total of 855 cases underwent laparoscopic hepatectomy by curettage and aspiration. No perioperative death, 105 patients were converted to open operation, and 84 of them were converted before liver transection without any emergency. Postoperative bleeding occurred in three patients (0.4 %), and bile leakage occurred in seven patients (0.8 %). CONCLUSION: Laparoscopic hepatectomy by curettage and aspiration is a safe procedure for liver resection with acceptable morbidity and mortality. PMID- 26487223 TI - A multi-modal approach to training in laparoscopic colorectal surgery accelerates proficiency gain. AB - BACKGROUND: How to efficiently train and transfer skills in laparoscopic colorectal surgery is unclear. Errors are rarely avoidable during learning but may incur patient morbidity. Multi-modality training with a modular operative approach provides proficiency-based structured task-specific training in a sequential manner, fragmenting complex laparoscopic colorectal procedures by difficulty allowing more than one trainee to gain experience irrespective of prior experience. This study assessed multi-modality training and its effect on proficiency gain in laparoscopic colorectal fellows. METHODS: A prospective study of 750 consecutive laparoscopic colon and rectal resection training cases assessing proficiency gain using a modified direct observation of procedural skills (DOPS) (behaviors-assessment) and weighted global modular attainment score (GMAS) (maneuvers-assessment) was carried out. Two mentors delivered training in a standardized format from 2008. Consequential intra-operative errors (requiring a corrective maneuver to permit further progression of the operation) were recorded. Eight Laparoscopic Fellows were assessed in six-month periods over 4 years. Primary outcome was proficiency gain measured by cumulative sum (CUSUM) analysis with boot-strapping comparing weighted GMAS and modified DOPS assessment. Morbidity (Clavien-Dindo classification), and consequential errors were submitted to similar analysis to assess significant variations during the training period. RESULTS: Fellows were trained on over 100 laparoscopic colorectal resections in a six Fellowship month period. Proficiency gain was identifiable in the DOPS and GMAS with 32 (99 % CI 25-37) and 39 (99 % CI 32-44) cases, respectively. Two- versus single-mentor training improved proficiency gain 35 (99 % CI 30-43) versus 55 (99 % CI 50-60). Overall consequential error rate and major morbidity rate (CD III-IV) were stable over time at 25 and 8.7 %, respectively. CONCLUSIONS: Multi-modality training with modular operative training and technique standardization shortens the time to proficiency gain with low morbidity accepting an intra-operative consequential error rate of 25 %. PMID- 26487224 TI - Risk of infection after iatrogenic perforation of the gut wall? Evaluation of preventive strategies in a randomized controlled animal trial. AB - BACKGROUND: Interventional endoscopies entail a risk of infection secondary to perforation of the luminal wall. Thereby, bacteria may be introduced into the sterile environment of the peritoneal cavity (PC). Limited data are available regarding the efficacy of prophylactic anti-infective treatments. The aim of the study was to examine the efficacy/safety of anti-infective means in the prevention of infection by interventional endoscopies in a randomized controlled animal trial. METHODS: Forty pigs were randomized to: 1: control; 2: oral lavage; 3: gastric lavage; 4: oral/gastric lavage; 5: i.m. antibiotics. Lavage was performed with Octenisept prior to the operation. After gastric wall perforation, peritoneoscopy was performed. Before the procedure, after closure and prior to autopsy, intraabdominal lavage for bacterial culture was taken using mini laparoscopy. At autopsy, macroscopic appearance of the PC was scored. Lavage fluids were grown to identify/quantify bacterial load. Concentration of intraperitoneal bacteria at autopsy was defined as main outcome parameter. RESULTS: No major complications occurred in any of the procedures. Bacterial load of the PC at autopsy was significantly reduced with antibiotics compared to all other groups, whereas it did not differ between the lavage groups and control. Macroscopic scoring of the PC showed significant lower rate of intraabdominal abscesses in the antibiotic group compared to the lavage groups and control (p < 0.01). CONCLUSION: Only antibiotic prophylaxis is effective for the prevention of infection after iatrogenic perforation of the gastrointestinal wall. There was no difference between any form of lavage and the control group. Further studies in humans are required to prove these animal data. PMID- 26487225 TI - HybridKnife high-pressure glycerol jet injection for endoscopic submucosal dissection increases procedural ease and speed: a randomised study in pigs and a human case series. AB - BACKGROUND AND AIMS: Good use of the submucosal space is key during endoscopic submucosal dissection (ESD). High-pressure injection of a long-lasting viscous solution using the HybridKnife water-jet system has been demonstrated to be feasible. We compared jet injection of glycerol and normal saline during pig gastric ESD and assessed its feasibility and efficiency during human ESD. MATERIALS AND METHODS: A blinded randomised controlled study of ESD with the HybridKnife injecting either a glycerol mixture or normal saline and a prospective human case series were performed. Twenty gastric pig dissections (10/group) and 38 human ESDs along the gastrointestinal tract were performed. Dissection speed, specimen size, procedure duration, rates of en bloc and R0 resection, and rates of bleeding and perforation were prospectively recorded. An evaluation of operator comfort and perceived safety (dissection score) was performed using a visual analogue scale with zero being the worst score and ten the best. RESULTS: Dissection was significantly more rapid (1.38-fold) with glycerol injection than with normal saline injection (28.94 vs. 20.91 mm(2)/min; p = 0.037). The dissection score was significantly higher in the glycerol group than in the normal saline group (7.3 vs. 4.7; p = 0.0064). No differences were observed in the rates of en bloc resection, bleeding, or perforation. The 38 human cases along the gastrointestinal tract revealed good results (en bloc resection rate = 100 %, R0 resection rate = 90 %) without any complications. CONCLUSION: High-pressure jet injection of glycerol with the HybridKnife for ESD increased the speed and operator comfort of the procedure compared with the use of normal saline, and the procedure was safe and efficient for human ESD. The advantages of using a combination of the HybridKnife system and a viscous glycerol solution will help to spread the use of the ESD technique, particularly in non-Asian countries. PMID- 26487226 TI - What do residents need to be competent laparoscopic and endoscopic surgeons? AB - BACKGROUND: Despite numerous efforts to ensure that surgery residents are adequately trained in the areas of laparoscopy and flexible endoscopy, there remain significant concerns that graduates are not comfortable performing many of these procedures. METHODS: Online surveys were sent to surgery residents (98 items, PGY1-5 Categorical) and faculty (78 items, general surgery, and gastrointestinal specialties) at seven institutions. De-identified data were analyzed under an IRB-approved protocol. RESULTS: Ninety-five faculty and 121 residents responded, with response rates of 65 and 52 %, respectively. Seventy three percent of faculty indicated that competency of their graduating residents were dramatically or slightly worse than previous graduates. Only 29 % of graduating residents felt very comfortable performing advanced laparoscopic (AL) cases and 5 % performing therapeutic endoscopy (TE) cases immediately after graduation. Over half of interns expressed a need for fellowship to feel comfortable performing AL and TE procedures, and this need did not decrease as residents neared graduation. For these procedures, residents receive only "little to some" autonomy, as reported by both faculty and PGY5s. Residents reported that current curricula for laparoscopy and endoscopy consist primarily of clinical experience. Both residents and faculty, though, reported considerable value in other training modalities, including simulations, live animal laboratories, cadavers, and additional didactics. CONCLUSIONS: These data indicate that both residents and faculty perceive significant competency gaps for both laparoscopy and flexible endoscopy, with the most notable shortcomings for advanced and therapeutic cases, respectively. Improvement in resident training methods in these areas is warranted. PMID- 26487227 TI - Intraoperative measurement of esophagogastric junction cross-sectional area by impedance planimetry correlates with clinical outcomes of peroral endoscopic myotomy for achalasia: a multicenter study. AB - BACKGROUND: Peroral endoscopic myotomy (POEM) has been introduced as an endoscopic alternative to surgical myotomy. The endoluminal functional lumen imaging probe (endoFLIP) evaluates esophagogastric junction (EGJ) distensibility based on cross-sectional area and pressure in response to volume distension. The aim of this study was to evaluate whether there is a correlation between endoFLIP measurements during POEM and postoperative clinical outcomes in terms of symptom relief and development of post-procedure reflux. METHODS: We conducted a retrospective review of achalasia patients who underwent POEM and intraoperative endoFLIP at three tertiary centers. Patients were divided into two groups based on clinical response measured by Eckardt score (ES): good response (ES < 3) or poor response (ES >= 3). Post-procedure reflux was defined as the presence of esophagitis and/or abnormal pH study. EGJ diameter, cross-sectional area, and distensibility measured by endoFLIP were compared. RESULTS: Of the 63 treated patients, 50 had good and 13 had poor clinical response. The intraoperative final EGJ cross-sectional area was significantly higher in the good-response group versus poor-response group; median (interquartile range): 89.0 (78.5-106.7) versus 72.4 (48.8-80.0) mm(2) [p = 0.01]. The final EGJ cross-sectional area was also significantly higher in patients who had reflux esophagitis after POEM: 99.5 (91.2-103.7) versus 79.3 (57.1-94.2) mm(2) [p = 0.02]. CONCLUSION: Intraoperative EGJ cross-sectional area during POEM for achalasia correlated with clinical response and post-procedure reflux. Impedance planimetry is a potentially important tool to guide the extent and adequacy of myotomy during POEM. PMID- 26487228 TI - Comparison of symptomatic anastomotic leakage following laparoscopic and open low anterior resection for rectal cancer: a propensity score matching analysis of 1014 consecutive patients. AB - BACKGROUND: This observational study was conducted to compare the rate of symptomatic anastomotic leakage (AL), as defined by precise criteria, between laparoscopic and open surgery in patients with mid-to-low rectal cancer using a relatively novel statistical technique. METHODS: A total of 1014 consecutive low anterior resection (LAR) patients were registered, of whom 936 were included in this prospective, multicenter, and cohort study (UMIN-CTR, Number 000004017). Patients with rectal cancer within 10 cm from the anal verge underwent either open or laparoscopic LAR at one of the 40 institutions in Japan from June 2010 to February 2013. The primary endpoint of this study was to compare the rate of symptomatic AL between the two groups before and after propensity score matching (PSM). The secondary endpoint was to analyze the risk factors for symptomatic AL in open and laparoscopic surgery. RESULTS: After PSM, the incidence of symptomatic AL in open and laparoscopic surgery was 12.4 and 15.3 %, respectively (p = 0.48). AL requiring relaparotomy occurred after 3.8 % of open surgeries and 6.2 % of laparoscopic surgeries (p = 0.37). Multivariate analysis identified male gender as an independent risk factor for symptomatic AL following laparoscopic surgery (p = 0.001; odds ratio 5.2; 95 % CI 2.0-13.8), and male gender (p = 0.004; odds ratio 2.6; 95 % CI 1.3-5.6), tumor size (p = 0.002; odds ratio 1.2; 95 % CI 0.7-0.9), and number of stapler firing (p = 0.04; odds ratio 4.1; 95 % CI 1.0-15.0) following open surgery. CONCLUSION: The rate of symptomatic AL was comparable following laparoscopic and open LAR in this large, multicenter, cohort study after PSM. Male gender was associated with an increased risk of symptomatic AL after laparoscopic LAR. PMID- 26487229 TI - An experimental study in six fresh human cadavers using a novel approach to avoid abdominal wall incisions in total colectomy: totally transanal laparoendoscopic single-site pull-through colectomy with J-pouch creation. AB - BACKGROUND: The use of transanal laparoscopic access to completely avoid abdominal wall incisions represents the most current evolution in minimally invasive surgery. The combination of single-site surgery and natural orifice transluminal endoscopic surgery (NOTESTM) can be used for totally transanal laparoendoscopic pull-through colectomy with J-pouch creation (TLPC-J). The aim of the present study was to provide evidence for the feasibility of TLPC-J in adult human cadavers. METHODS: TLPC-J was performed in six fresh adult human cadavers. The procedure involved endorectal submucosal dissection from 1 cm above the dentate line to a point above the peritoneal reflection, where the rectal muscle was divided circumferentially. The edge of the mucosal cuff was closed distally in order to prevent fecal contamination and the endorectal tube was placed back into the abdomen. A Triport+TM or QuadPort+TM system was introduced transanally, and it served as a multiport device (MD). Resection of the entire colon, mobilization of the distal ileal segment, and extracorporeal suture of the ileal J-loop were performed via the transanal approach. The J-pouch was created using Endo GIATM. After removal of the MD, the J-pouch was sutured to the rectal wall. RESULTS: TLPC-J was performed in all cadavers, with a mean operation duration of 236 +/- 22 min. Conversion to either transabdominal laparoscopy or laparotomy was not required in any of the cadavers. No bowel perforation or damage to other organs was observed. The use of a curved endoscope greatly facilitated visualization during transanal laparoscopic dissection for partial and total colectomy, making the procedure feasible. All specimens were retrieved through the anus, eliminating the need for additional transabdominal incisions. CONCLUSIONS: TLPC-J was technically feasible in adult human cadavers, and abdominal wall incisions were not required. However, clinical studies are needed to determine its feasibility in living adults. PMID- 26487230 TI - A pilot study of confocal laser endomicroscopy for diagnosing gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma. AB - BACKGROUND: Patients with gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma require lifelong endoscopic follow-up. This study aimed to establish and evaluate confocal laser endomicroscopy (CLE) criteria for gastrointestinal MALT lymphoma. METHODS: This prospective trial was conducted after IRB approval at the Medical University of Vienna. Twenty-four consecutive patients (14 males and 10 females, median age 65 years) referred for staging or follow-up of (former) gastrointestinal MALT lymphoma underwent endosonography (EUS) and CLE including white light endoscopy (WLE) and conventional biopsy sampling of the upper gastrointestinal tract. CLE criteria of the disease were based on the first five patients with histologically proven MALT lymphoma. All CLE datasets were reviewed separately by two CLE experts. The diagnostic modalities were compared using conventional histology as the gold standard. RESULTS: Sixty-two percentages had a positive diagnosis of MALT lymphoma based on histology. The sensitivity was 80 % for EUS (0.51-0.95), 100 % for WLE (0.75-1) and 93 % for CLE (0.66-1); the specificity was 67 % for EUS (0.31-0.91), 23 % for WLE (0.04-0.60) and 100 % for CLE (0.63-1). The agreement with histology was moderate for EUS (kappa 0.47, p = 0.02), fair for WLE (kappa 0.26, p = 0.06) and almost perfect for CLE (kappa 0.91, p < 0.01). Expert evaluation identified all but one case of MALT lymphoma with excellent interobserver agreement (kappa 0.89, p < 0.01). In the case missed by CLE, MALT lymphoma involvement was restricted to deep tissue structures. CONCLUSIONS: Despite minor technical limitations, CLE is a promising alternative to conventional biopsy sampling in patients with gastrointestinal MALT lymphoma. CLINICALTRIALS. GOV NUMBER: NCT01583699. PMID- 26487231 TI - Different accuracy of endosonographic tumor staging after neoadjuvant chemotherapy and chemoradiotherapy in esophageal cancer. AB - BACKGROUND: Treatment response to neoadjuvant therapy is histologically associated with more or less intensive inflammation and fibrosis. In consequence, accuracy of endosonographic TN-tumor staging after neoadjuvant treatment is hampered. We analyzed whether the kind of treatment chosen [chemoradiotherapy (CRT) or chemotherapy (CT)] differently influences the accuracy of endoscopic ultrasound after neoadjuvant therapy in esophageal cancer. METHODS: We performed serial endoscopic ultrasound examinations in 18 patients after neoadjuvant CRT and 30 patients after neoadjuvant CT. TN-stage was classified according to the standard parameter. Histological examination of the surgical resection specimen served as gold standard. RESULTS: The most frequent error was overstaging, especially in patients with complete tumor response or minimal residual disease. Accuracy of T-staging was significantly worse after CRT (0.16) than after CT (0.43), obviously due to difficulty in distinguishing residual tumor from treatment-associated fibrosis and inflammation. Accuracy of N-staging was also hampered, but to a less extent (sensitivity/specificity 0.85/0.36 after CRT, and 0.5/0.42 after CT). CONCLUSIONS: Accuracy of endosonographic TN-tumor staging is significantly more hampered by neoadjuvant CRT than after CT. However, endoscopic ultrasound is insufficient for TN-staging irrespective of the kind of neoadjuvant therapy performed. PMID- 26487232 TI - Cholecystectomy after endoscopic papillary balloon dilation for bile duct stones reduced late biliary complications: a propensity score-based cohort analysis. AB - BACKGROUND: Cholecystectomy after endoscopic sphincterotomy for bile duct stones with concomitant gallstones is known to reduce late biliary complications. Endoscopic papillary balloon dilation for bile duct stones develops fewer late biliary complications than endoscopic sphincterotomy, but no randomized controlled trials have been conducted about the role of cholecystectomy after endoscopic papillary balloon dilation. Therefore, we conducted this propensity score-matched analysis to compare cholecystectomy and wait-and-see approach after endoscopic papillary balloon dilation. METHODS: Propensity score matching extracted 147 pairs of patients with cholecystectomy after endoscopic papillary balloon dilation and with gallbladder left in situ with stones (wait-and-see) from 725 patients who underwent endoscopic papillary balloon dilation for bile duct stones. Late biliary complications such as recurrent bile duct stones and cholecystitis were evaluated. Cumulative incidence of late biliary complications was calculated treating death without biliary complications as a competing risk, and its prognostic factor was evaluated. RESULTS: The rates of late biliary complications were 5.4 and 25.2 % in the cholecystectomy after endoscopic papillary balloon dilation and wait-and-see groups: Recurrent bile duct stones rates were 4.1 and 19.0 %, and cholecystitis rates were 0.7 and 6.1 %. The cumulative incidences of biliary complications in the cholecystectomy after endoscopic papillary balloon dilation and wait-and-see approach were 3.1 versus 13.0 % at 1 year and 5.7 versus 28.0 % at 5 year after endoscopic papillary balloon dilation (p = 0.008). Subdistribution hazard ratio of late biliary complications in the wait-and-see group was 5.1 (p = 0.020). CONCLUSION: Cholecystectomy after endoscopic papillary balloon dilation for choledocholithiasis was associated with fewer late biliary complications. Prophylactic cholecystectomy should be offered to all surgically fit patients after endoscopic papillary balloon dilation for bile duct stones with concomitant gallstones. PMID- 26487233 TI - Decision-making in the management of colonoscopic perforation: a multicentre retrospective study. AB - BACKGROUND: The incidence of colonoscopic perforation has increased following the widespread use of colonoscopy for the diagnosis and treatment of colorectal disease. The purpose of our study was to compare the clinical outcomes between surgical and non-surgical treatment of colonoscopic perforation. METHODS: We retrospectively reviewed the medical records of patients with colonoscopic perforation, which was treated between January 2005 and December 2014. Patients were divided into two groups depending on whether they received non-surgical (conservative management or endoscopic clipping) or surgical (primary closure, bowel resection and anastomosis, and/or faecal diversion) initial treatment for the perforation. Conversion was defined as the change from a non-surgical to surgical procedure after treatment failure. RESULTS: One hundred and nine patients were analysed. Surgical treatment was more common following diagnostic than therapeutic colonoscopic procedures (74.5 vs. 53.7 %, P = 0.023). Of 55 patients in the non-surgical group, 11 patients required conversion to surgery. The surgical group comprised 54 patients. The complication rate (P = 0.001), and the length of hospital stay (P < 0.001) were significantly greater in the patients requiring conversion than in the surgical group. Multivariate analysis showed that old age, American Society for Anesthesiologists score >= 3, and conversion were independent predictors of poor outcomes (P = 0.048, 0.032, and 0.001, respectively). Only perforation size was associated with conversion in multivariate analysis (P = 0.022). CONCLUSION: It is important to select an appropriate treatment in patients with colonoscopic perforation. To avoid non surgical treatment failure, surgery should be considered in patients with a large perforation. By decreasing the rate of conversion, we might reduce the complication and mortality rates associated with colonoscopic perforation. PMID- 26487234 TI - Laparoscopy, computerised tomography and fluorodeoxyglucose positron emission tomography in the management of gastric and gastro-oesophageal junction cancers. AB - BACKGROUND: The staging laparoscopy has been used in the management of gastrointestinal cancers. The aim of this study was to evaluate the role of staging laparoscopy, in comparison with computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in staging patients with gastro-oesophageal junction (GOJ) and gastric cancers. METHODS: The data were collected for patients between 1996 and 2013 undergoing investigation and treatment for GOJ and gastric cancers at a single institute. The pre operative data (staging data), intraoperative details, post-operative course and follow-up were analysed for individual cases. RESULTS: Staging laparoscopy altered management plan in 64 (17 %) of 387 patients with negative staging CT and FDG-PET scan. Twenty-seven (7 %) patients with GOJ cancer (types I, II and III) were identified with pathological intraperitoneal nodes, 15 (4 %) gastric cancer with metastatic intraperitoneal deposits and liver metastases and 3 % gastric cancers with positive ascitic fluid for cancer cells. Ten (3 %) of patients were downstaged and were offered curative resection. Patients with metastatic disease were referred for palliative chemotherapy. The overall sensitivity of staging laparoscopy in diagnosing intraabdominal pathology was 86 % in comparison with CT (81 %) and FDG-PET (78 %). CONCLUSIONS: The diagnostic laparoscopy is useful for detecting and confirming nodal involvement and distant metastatic disease not evident on the staging CT scan and FDG-PET. This could potentially alter treatment and prognosis in patients with upper gastrointestinal cancer. The diagnostic laparoscopy should be performed as part of investigation and treatment planning for patients suffering from GOJ and gastric cancers. This can help to avoid surgery in patients with advanced disease. PMID- 26487235 TI - Mesenteric root dissection with individualized ileo-colic vessel ligation versus mesenteric pedicle stapling. AB - BACKGROUND: Numerous factors have been associated with the number of lymph nodes retrieved during laparoscopic colectomy. This study compared the impact of vascular pedicle ligation method on the number of retrieved lymph nodes in patients undergoing laparoscopic right hemicolectomy for cancer. Mesenteric root dissection with individualized vessel ligation was compared to en bloc vascular root stapling. METHODS: Data were retrospectively collected from a database of patients' charts including operative and pathological reports. All patients that underwent laparoscopic colectomy in a single department were identified. Patients that underwent elective laparoscopic right hemicolectomy for cancer were further evaluated. The impact of the method used for ileo-colic vascular transection, age, gender, nodes status, T stage, BMI and the operating surgeon on the number of retrieved lymph nodes was studied. RESULTS: Among 239 laparoscopic colectomies, 75 patients underwent elective laparoscopic right colectomy for cancer. Ileo-colic vascular transection was routinely performed at the level of the inferior border of the pancreas. In total, 34 patients underwent ileo-colic vascular root dissection with individualized vessel ligation and 41 underwent vascular root stapling. No difference was found in the mean number of retrieved lymph nodes between pedicle dissection and vascular root stapling (18.7 +/- 5.9 vs. 19.6 +/- 7.9, P = 0.396), and in the rate of patients who had 12 nodes or more (97.1 vs. 92.7 %, P = 0.401). BMI above 30 was associated with decreased number of retrieved nodes (P = 0.001). CONCLUSIONS: No difference was found in the number of retrieved lymph nodes between ileo-colic vascular root dissection with individual vessel ligation and vascular root stapling in patients undergoing laparoscopic right hemicolectomy for cancer. High BMI was associated with decreased number of retrieved nodes in both groups. A standard approach regarding the level of mesenteric root transection, regardless of the ligation approach, leads to adequate lymph node harvesting by different surgeons. PMID- 26487236 TI - Erratum to: Robotic-assisted laparoscopic versus open lateral lymph node dissection for advanced lower rectal cancer. PMID- 26487237 TI - Long-term outcomes of cruroplasty reinforcement with composite versus biologic mesh for gastroesophageal reflux disease. AB - AIM: The aim of this study was to evaluate the issue of improvement of disadvantages of different type meshes. METHODS: A retrospective analysis was performed on 101 gastroesophageal reflux disease patients who underwent reinforcement of crura with or without prosthetic mesh. Three types of mesh, 4 ply biologic small intestine submucosa (SIS, Surgisis((r)), since November 2010), 6-ply SIS (BiodesignTM Surgisis((r)), since March 2011), and composite synthetic mesh (Crurasoft((r)), since May 2010), were used. All patients were assigned to simple suture group (n = 35), 4-ply SIS group (n = 13), 6-ply BiodesignTM group (n = 26) or Crurasoft((r)) group (n = 27). Postoperative follow-up was performed via clinical visit or phone call contact. Subjective assessment included dysphagia, patients' symptomatic outcome judgment according to Visick and patients' satisfaction. Objective evaluation included hiatal hernia recurrence according to upper endoscopy and barium contrast swallow. Follow-up was completed in 83 patients with a mean duration of 45 months (range 16-149 months). RESULTS: For the objective outcomes, although anatomic recurrence of hiatal hernia did not significantly differ between groups at 6 months postoperatively, long-term results showed a protective effect of mesh implantation on hernia recurrence (p = 0.047). For the subjective outcomes, the mesh group had a more significant improvement in Visick score (p = 0.020) compared to the simple suture group. Patient satisfaction was significantly higher in the mesh group (p = 0.014), and subgroup analysis showed a clear trend as follows: Crurasoft((r)) ~ Biodesign((r)) > SIS((r)). A higher frequency of postoperative dysphagia was presented in the Crurasoft group compared with other two groups at 6 months postoperatively, but the difference was not significant over time (p = 0.227). CONCLUSION: Mesh cruroplasty results in satisfactory symptom control with a low recurrence rate. 6-ply biologic mesh is promising with respect to the reduction in anatomic recurrences. Postoperative dysphagia does not occur commonly following mesh cruroplasty with PTFE/ePTFE mesh. PMID- 26487239 TI - Skill acquisition and stress adaptations following laparoscopic surgery training and detraining in novice surgeons. AB - BACKGROUND: Surgical training and practice is stressful, but adaptive changes in the stress circuitry (e.g. perceptual, physiological, hormonal, neural) could support skill development. This work examined skill acquisition and stress adaptations in novice surgeons during laparoscopic surgery (LS) training and detraining. METHODS: Twelve medical students were assessed for skill performance after 2 h (BASE), 5 h (MID) and 8 h (POST) of LS training in weeks 1-3, and then after 4 weeks of no training (RETEST). The stress outcomes included state anxiety, perceived stress and workload, heart rate (HR), heart rate variability (HRV), and salivary testosterone and cortisol concentrations. Functional near infrared spectroscopy was used to assess cortical oxygenation change, as a marker of prefrontal cortex (PFC) activity. RESULTS: Skill performance improved in every session from BASE (p < 0.01), with corresponding decreases in state anxiety, stress, workload, low- and high-frequency HRV in the MID, POST and/or RETEST sessions (p < 0.05). Left and right PFC were symmetrically activated within each testing session (p < 0.01). The stress and workload measures predicted skill performance and changes over time (p < 0.05), with state anxiety, mean HR and the HRV measures also showing some predictive potential (p < 0.10). CONCLUSIONS: A 3 week LS training programme promoted stress-related adaptations likely to directly, or indirectly, support the acquisition of new surgical skills, and many outcomes were retained after a 4-week period without further LS training. These results have implications for medical training and education (e.g. distributed training for skill development and maintenance, stress resource and management training) and highlighted possible areas for new research (e.g. longitudinal stress and skill profiling). PMID- 26487238 TI - Creation of a neopylorus after pyloric exclusion using a "double-endoscope" technique. AB - OBJECTIVE: Pyloric exclusion may be implemented in the setting of a high-grade duodenal or pancreatic injury. After exclusion, the pylorus should spontaneously open in 3-6 weeks. However, we present the case of a critically ill 17-year-old male with a gunshot wound to the abdomen that underwent stapled pyloric exclusion with gastrostomy and jejunostomy tube placement who did not achieve pyloric patency after 5 months, and describe an innovative "double-endoscope" technique to correct it. METHODS: A gastroscope was inserted through the mouth into the stomach, and an endoscope was inserted retrograde through the jejunostomy site to the duodenum. The closed pylorus was seen from both ends with transillumination. A needle knife was pushed through the membrane with clear visualization from the contralateral side. A balloon dilation catheter was then passed over a guidewire, and the neopylorus was sequentially dilated. A gastrojejunostomy tube was placed to ensure patency of the neopylorus. Postoperative imaging showed no evidence of leak or pneumoperitoneum. Serial endoscopic dilations were performed every 1-4 weeks to prevent restricturing. RESULTS: The patient recovered well. After the first follow-up endoscopic dilation, he was eating a regular diet and had no retained food products. After four endoscopic dilations, the patient remained symptom free and the pylorus was widely patent. His gastrostomy and jejunostomy tubes were removed. CONCLUSIONS: Here we presented a rare complication of pyloric exclusion and an innovative approach that used a "double-endoscope" technique and serial endoscopic dilations to establish and maintain a neopylorus, avoiding the morbidity of a major surgical procedure. PMID- 26487240 TI - Minimally invasive video-assisted submandibular sialadenectomy: surgical technique and results from two institutions. AB - BACKGROUND: Submandibular gland excision is traditionally performed using a transcervical approach. However, innovative surgical trials have recently been conducted to investigate techniques that can prevent or reduce visible scarring and nerve injury. The aim of the present study was to evaluate the feasibility of a new approach to submandibular gland excision that is based on the use of a minimally invasive video-assisted technique and an ultrasound scalpel in an endoscopic neck surgery program with a low annual flow of procedures. METHODS: We retrospectively studied 15 patients with submandibular gland disease who underwent minimally invasive video-assisted submandibular sialadenectomy performed by two surgeons at two institutions. Eight patients had proximally located salivary calculi, three had chronic sialadenitis, and four had benign neoplasms. All dissections were carried out by a single-port gasless approach, using the Miccoli technique, involving endoscope magnification and an ultrasonic scalpel. RESULTS: All 15 submandibular gland resections were performed successfully, with no conversions to conventional open resection. The operative time ranged from 45 to 125 min (median 84 min). A total of 67 % of patients were discharged the day after surgery, and the maximum length of stay was 3 days. One patient experienced postoperative bleeding, and one experienced postoperative infection. There was no neural injury. The incision scar healed well in all cases, and all patients reported excellent cosmetic results. CONCLUSIONS: Endoscopic submandibular gland resection using a minimally invasive video assisted technique, endoscopic magnification, and ultrasonic scalpel was feasible and resulted in excellent surgical outcomes. PMID- 26487241 TI - Pain intensity, temperament traits and social support as determinants of trauma symptoms in patients suffering from rheumatoid arthritis and low-back pain. AB - AIM: The main goal of our study was to investigate the relationship between age, duration of pain, pain intensity, temperament traits as postulated by the Regulative Theory of Temperament (RTT), social support dimensions and the level of trauma symptoms, as appear in post-traumatic stress disorder (PTSD) in a sample of 300 patients suffering from chronic pain in two groups comprised of 150 patients with a clinical diagnosis of rheumatoid arthritis (RA) and 150 patients with a clinical diagnosis of low-back pain (LBP). They were analyzed together as a one group of 300 patients with chronic pain. METHOD: Temperament was measured with the Formal Characteristics of Behaviour - Temperament Inventory (FCB-TI). Social support was tested with the Berlin Social Support Scales (BSSS). The Numerical Rating Scale (NRS-11) was used to measure pain intensity. The level of trauma symptoms was assessed with the Post-Traumatic Stress Disorder Factorial Version Inventory (PTSDF). RESULTS: The results of our study suggest that the intensity of pain, participants' age, Emotional Reactivity and Sensory Sensitivity as temperament traits, need for support, and actually received social support were related to the level of trauma symptoms. The sum of the squared semi partial correlations showed that all six variables (age, pain intensity, Emotional Reactivity, Sensory Sensitivity, need for support and actually received support), account for 20% of the variance of general trauma symptoms level. CONCLUSION: The importance of temperament traits, social support and trauma symptoms should be taken into an account in psychotherapy accompanying pharmacotherapy for pain. PMID- 26487242 TI - Enantioselective Synthesis of Spirocyclohexadienones by NHC-Catalyzed Formal [3+3] Annulation Reaction of Enals. AB - The enantioselective synthesis of pyrazolone-fused spirocyclohexadienones was demonstrated by the reaction of alpha,beta-unsaturated aldehydes with alpha arylidene pyrazolinones under oxidative N-heterocyclic carbene (NHC)catalysis. This atom-economic and formal [3+3] annulation reaction proceeds through a vinylogous Michael addition/spiroannulation/dehydrogenation cascade to afford spirocyclic compounds with an all-carbon quaternary stereocenter in moderate to good yields and excellent ee values. Key to the success of the reaction is the cooperative NHC-catalyzed generation of chiral alpha,beta-unsaturated acyl azoliums from enals, and base-mediated tandem generation of dienolate/enolate intermediates from pyrazolinones. PMID- 26487243 TI - The Relationship Between Soil Arthropods and the Overwinter Survival of Ixodes scapularis (Acari: Ixodidae) Under Manipulated Snow Cover. AB - We explored the relationship between the diversity and abundance of the soil arthropod predator community and the overwinter survival of engorged larval Ixodes scapularis Say under variable snow cover in a hardwood forest. We reduced the snow cover over 30 soil core field microcosms, simulating predicted changes in snow pack in the northeastern United States. An additional 29 microcosms were used as references with no snow pack manipulation. Each microcosm contained 15 engorged larval I. scapularis. We expected lower soil temperature without insulating snow cover to reduce tick survival. However, we observed that reduced snow cover had no effect, with 44.2 and 44.7% overwintering successfully in the reference and snow-removal plots, respectively. Increasing taxonomic family richness of arthropod predators and the total number of large (>1 mm) arthropod predators significantly reduced the overwinter survivorship of I. scapularis within the microcosms. Small (<1 mm) arthropod predator abundance had no effect. Our results suggest that forests with complex natural arthropod predator communities show reduced tick survival. PMID- 26487244 TI - Life Cycle of Amblyomma romitii (Acari: Ixodidae) Under Laboratory Conditions. AB - The life cycle of Amblyomma romitii Tonelli-Rondelli, 1939 is reported for the first time, using rabbits (Oryctolagus cuniculus) for larvae and capybara (Hydrochoerus hydrochaeris) for nymphs and adults, as experimental hosts. Developmental periods of free-living stages were observed in an incubator at 27 +/- 1 degrees C, 80 +/- 10% relative humidity (RH), and 24-h darkness. The life cycle of A. romitii in the laboratory could be completed in an average period of 216.4 d. The overall sex ratio (M:F) was 1:1.4. The results showed that rabbits are quite suitable as experimental hosts for the larval stages of A. romitii, while capybaras are suitable experimental hosts for nymphs and adults. PMID- 26487245 TI - Experimental Infection of Lutzomyia (Nyssomyia) whitmani (Diptera: Psychodidae: Phlebotominae) With Leishmania (Viannia) braziliensis and Leishmania (L.) amazonensis, Etiological Agents of American Tugumentary Leishmaniasis. AB - Leishmania (L.) amazonensis (Lainson & Shaw, 1972) and Leishmania (Viannia) braziliensis (Vianna, 1911) are the principal causative agents of American tegumentary leishmaniasis (ATL) in Brazil. L. amazonensis also causes diffuse cutaneous leishmaniasis (DCL) vectored principally by Lutzomyia flaviscutellata and secondarily by Lutzomyia whitmani (Antunes & Coutinho, 1939). The latter is the most common phlebotomine in the state of Maranhao, and it is the focal species for potential ATL transmission. For this reason, we tested the ability of L. whitmani to become infected with Lutzomyia parasites. Phlebotomines were derived from a colony maintained in the laboratorial conditions. The first generation, uninfected females were offered a bloodmeal with mice infected with the strains of both parasites. We found that L. whitmani can become infected with both parasite species, with infection rates of 65.2% (L. braziliensis) and 47.4% (L. amazonensis). We conclude that in Maranhao, L. whitmani is likely an important vector in the transmission of ATL and may function as a vector of DCL. This possibility should be further investigated. PMID- 26487246 TI - Dynamics of Necrophagous Insect and Tissue Bacteria for Postmortem Interval Estimation During the Warm Season in Romania. AB - The estimation of postmortem interval (PMI) is affected by several factors including the cause of death, the place where the body lay after death, and the weather conditions during decomposition. Given the climatic differences among biogeographic locations, the understanding of necrophagous insect species biology and ecology is required when estimating PMI. The current experimental model was developed in Romania during the warm season in an outdoor location. The aim of the study was to identify the necrophagous insect species diversity and dynamics, and to detect the bacterial species present during decomposition in order to determine if their presence or incidence timing could be useful to estimate PMI. The decomposition process of domestic swine carcasses was monitored throughout a 14-wk period (10 July-10 October 2013), along with a daily record of meteorological parameters. The chronological succession of necrophagous entomofauna comprised nine Diptera species, with the dominant presence of Chrysomya albiceps (Wiedemann 1819) (Calliphoridae), while only two Coleoptera species were identified, Dermestes undulatus (L. 1758) and Creophilus maxillosus Brahm 1970. The bacterial diversity and dynamics from the mouth and rectum tissues, and third-instar dipteran larvae were identified using denaturing gradient gel electrophoresis analysis and sequencing of bacterial 16S rRNA gene fragments. Throughout the decomposition process, two main bacterial chronological groups were differentiated, represented by Firmicutes and Gammaproteobacteria. Twenty-six taxa from the rectal cavity and 22 from the mouth cavity were identified, with the dominant phylum in both these cavities corresponding to Firmicutes. The present data strengthen the postmortem entomological and microbial information for the warm season in this temperate-continental area, as well as the role of microbes in carcass decomposition. PMID- 26487247 TI - Geographic Distribution and Ecology of Triatoma dimidiata (Hemiptera: Reduviidae) in Colombia. AB - Triatoma dimidiata Latreille is the second most important vector of Chagas' disease in Colombia and is found in urban and periurban areas. From January 2007 to June 2008, we performed field work in 8 departments, 18 municipalities, and 44 rural villages, covering most of its known distribution and all of its ecological zones in the country. The goal was to determine the geographical distribution, the ecology, and house infestation indices of T. dimidiata over its range and hence the Chagas' disease transmission risk. In Colombia, T. dimidiata occupies a wide variety of ecosystems, from transformed ecosystems in the Andean biome with shrub and xerofitic vegetation to very dense forests in the humid tropical forests in the Sierra Nevada of Santa Marta. According to genetic and ecological criteria, at least two T. dimidiata forms of this species are present: populations from the northwest of the country (Caribbean plains) are restricted to palm tree habitats, and domestic involvement is limited to sporadic visits because of attraction by light; and populations of the east region (Andean mountains) presenting a complex distributional pattern including sylvatic, peridomestic, and domiciliated ecotopes, and occupying a great variety of life zones. The latter population is of epidemiological importance due to the demonstrated migration and genetical flow of individuals among the different habitats. Control, therefore, must take into account its diversity of habitats. PMID- 26487249 TI - A Preliminary Investigation on Ticks (Acari: Ixodidae) Infesting Birds in Kizilirmak Delta, Turkey. AB - Ticks are mandatory blood-feeding ectoparasites of mammals, birds, reptiles, and even amphibians. Turkey has a rich bird fauna and is located on the main migration route for many birds. However, information on ticks infesting birds is very limited. In the present study, we aimed to determine ticks infesting birds in Kizilirmak Delta, Turkey. In 2014 autumn bird migration season, a total of 7,452 birds belonging to 79 species, 52 genera, 35 families, and 14 orders were examined for tick infestation. In total, 287 (234 larvae, 47 nymphs, 6?) ticks were collected from 54 passerine birds (prevalence = 0.72%) belonging to 12 species. Ticks were identified as Amblyomma sp., Dermacentor marginatus (Sulzer), Haemaphysalis concinna Koch, Haemaphysalis punctata Canestrini and Fanzago, Hyalomma sp., Ixodes frontalis (Panzer), and Ixodes ricinus (L). The most common tick species were I. frontalis (223 larvae, 23 nymphs, 6?) followed by I. ricinus (3 larvae, 12 nymphs) and H. concinna (4 larvae, 6 nymphs). Based on our results, it can be said that Erithacus rubecula (L.) is the main host of immature I. frontalis, whereas Turdus merula L. is the most important carrier of immature stages of some ticks in Kizilirmak Delta, Turkey. To the best of our knowledge, most of the tick-host associations found in this study have never been documented in the literature. PMID- 26487250 TI - Quantitative study of optical and mechanical bone status using multispectral photoacoustics. AB - Osteoporosis is a major public health problem worldwide. Here, we present a quantitative multispectral photoacoustic method for the evaluation of bone pathologies which has significant advantages over pure ultrasonic or pure optical methods as it provides both molecular information and bone mechanical status. This is enabled via a simultaneous measurement of the bone's optical properties as well as the speed of sound and ultrasonic attenuation in the bone. To test the method's quantitative predictions, a combined ultrasonic and photoacoustic system was developed. Excitation was performed optically via a portable triple laser diode system and acoustically via a single element transducer. Additional dual transducers were used for detecting the acoustic waves that were generated by the two modalities. Both temporal and spectral parameters were compared between different excitation wavelengths and measurement modalities. Short photoacoustic excitation wavelengths allowed sensing of the cortical layer while longer wavelengths produced results which were compatible with the quantitative ultrasound measurements. PMID- 26487248 TI - Hyaluronidase Activity in Saliva of European Culicoides (Diptera: Ceratopogonidae). AB - Biting midges of the genus Culicoides transmit pathogens of veterinary importance such as bluetongue virus (Reoviridae: Orbivirus). The saliva of Culicoides is known to contain bioactive molecules including peptides and proteins with vasodilatory and immunomodulative properties. In this study, we detected activity of enzyme hyaluronidase in six Culicoides species that commonly occur in Europe and that are putative vectors of arboviruses. Hyaluronidase was present in all species studied, although its molecular size, sensitivity to SDS, and substrate specificity differed between species. Further studies on the potential effect of hyaluronidase activity on the vector competence of Culicoides species for arboviruses would be beneficial. PMID- 26487251 TI - Editorial: Omental transposition for cerebral revascularization. AB - Studies over the past decade have shown that when the omentum is placed on the brain of a patient with cerebral ischemia and/or infarction, beneficial clinical effects have occurred in roughly half the patients. It is believed that these neurological improvements following surgery are due to angiogenic, neurotransmitter, and nerve growth substances that are derived from the omentum and affect the underlying brain. The presence of these biological neurochemicals in the omentum may open up future treatment avenues for a host of neurological conditions. Only with additional experience, experimentation, and controlled clinical trials will the eventual place of the omentum be established in the treatment of a variety of CNS disorders. PMID- 26487253 TI - Longitudinal outcome among patients with ischemic vascular dementia(1). AB - Longitudinal studies carried out in this laboratory for the past 12 years among patients with ischemic vascular dementia (IVD) are summarized. The criteria for the diagnosis of probable IVD and definite IVD are described and are consonant with the State of California Alzheimer's Disease Diagnostic and Treatment Centers recommended criteria. Demography of IVD patients and associated risk factors are described, and the types of cerebral infarcts causing IVD are listed. Control of risk factors for stroke stabilizes patients with IVD as judged by serial cognitive testing. Control of hypertension and cigarette smoking and a reduction in hyperlipidemia all benefit IVD patients. Best cognitive results are obtained if hypertension is controlled within the upper limits of normal with mean systolic blood pressure values maintained above and around 137 mm Hg. Serial measurements of cerebral perfusion indicate that cognition and cerebral perfusion fluctuate together. When demented and nondemented patients with stroke are compared, overall cerebral perfusion is reduced to a greater extent in the stroke patients with dementia, particularly within cortical gray matter and subcortical white matter. Leuko-araiosis is twice as great in demented stroke patients compared to stroke patients who are cognitively intact. In longitudinal studies, cerebral perfusion declined further among stroke patients with cognitive deterioration, but, when cerebral perfusion became stabilized, cognitive performance likewise stabilized or improved. PMID- 26487252 TI - Thalamic infarcts: Effects on cerebral blood flow, metabolism, and neuropsychological function. AB - In four patients with thalamic infarcts causing severe neuropsychological deficits, regional cerebral blood flow (rCBF) was measured by single-photon emission computed tomography using (99m)Tc-d,l,-hexamethylpropyleneamine oxime as tracer. In one of these patients, cerebral glucose metabolism was measured by positron emission tomography using (18)F-fluorodeoxyglucose as tracer. Three patients had left paramedian thalamic infarcts, in one case combined with an infarction of the right cerebellar hemisphere, and one had bilateral paramedian and left anterior thalamic infarcts. Neuropsychological assessment revealed profound impairment of memory, verbal fluency, and abstract reasoning, as well as perseveration and varying degrees of dyscalculia and constructional apraxia in all patients. There were distinct personality changes and deficient judgment and insight. All four patients had reduced cortical rCBF in the left frontoparietal regions. In three cases, flow was also reduced in the left temporal lobe; they all presented with a fluent aphasia, which only partly remitted over time. Prosody and mimics were impaired only in the patient with bilateral thalamic infarction. In one of the patients with unilateral thalamic infarct extending into the mesencephalon, glucose metabolism was reduced in the ipsilateral frontal, temporal, and occipital regions. Thalamic infarcts can alter the activity in widespread functional systems of the brain and thus lead to extensive neuropsychological deficits. PMID- 26487254 TI - Differences in erythrocyte aggregability between multi-infarct dementia and Alzheimer's disease. AB - We reported previously that erythrocyte aggregability (RBC-A) is enhanced in patients with cerebral infarction. The purpose of the present study was to examine whether or not differences in RBC-A exist between multi-infarct dementia (MID) and Alzheimer's disease. The subjects comprised 16 patients with MID (7 males and 9 females, 73 +/- 11 years old) who had Hachinski's ischemic scores of 7 or more and displayed multiple infarctions on brain computed tomography and 18 patients with Alzheimer's disease (8 males and 10 females, 70 +/- 8 years old) who were diagnosed using the criteria proposed by the NINCDS-ADRDA Work Group. The patients underwent tests for cognitive function employing Hasegawa's dementia scale. RBC-A was measured using the whole-blood RBC aggregometer developed by us with concomitant measurement of blood factors such as the hematocrit, albumin/globulin ratio (A/G ratio) and fibrinogen. The RBC-A value in MID (0.170 +/- 0.030/s) was significantly higher (p < 0.01) than that in Alzheimer's disease (0.135 +/- 0.022/s). The hematocrit and concentration of fibrinogen did not reveal any differences between MID and Alzheimer's disease. However, the A/G ratio in MID (1.59 +/- 0.43) was significantly lower (p < 0.01) than in Alzheimer's disease (2.01 +/- 0.35). The above results suggest a potential usefulness for erythrocyte aggregability in differentiating between the two types of dementia. PMID- 26487255 TI - Diagonal earlobe creases and ischemic stroke: Preliminary report. AB - Diagonal earlobe creases are associated with coronary arterial disease, cardiac morbidity and mortality, and all-cause mortality. We studied the influence of earlobe creases on the incidence of ischemic stroke as well as the relationship between earlobe creases and gender, coronary arterial disease, hypertension, diabetes mellirus, and hypercholesterolemia. Data were obtained prospectively from the medical records of 116 patients with ischemic stroke and 232 age- and gender-matched patients without ischemic stroke. All patients were seen in neurological consultation and were examined for the presence of earlobe creases. In the total group of 348 patients, earlobe creases were significantly related to advancing age. In those with ischemic stroke, earlobe creases were significantly related to coronary arterial disease, diabetes mellitus, and nonlacunar ischemic stroke. The cumulative incidences of coronary arterial disease, hypertension, diabetes mellitus, and hypercholesterolemia were also significantly higher in those patients with earlobe creases who also had ischemic stroke. When controlled for coronary arterial disease, earlobe creases, in those with ischemic stroke, continued to be significantly related to nonlacunar ischemic stroke. PMID- 26487256 TI - Nosocomial stroke. AB - Nosocomial stroke occurs during hospitalization for unrelated problems. Increased understanding of this relatively ignored entity may provide the key to improved stroke prophylaxis for the hospitalized patient at risk and provide clues to the precipitants of stroke in the general population. We compared nosocomial stroke to stroke occurring outside the hospital in a mixed prospective and retrospective analysis of 372 consecutive strokes occurring over 2 years. We excluded nosocomial stroke associated with cardiac bypass surgery, carotid endarterectomy, and cerebral angiography for cerebrovascular disease because of the known associations of these procedures with stroke. Of our 372 strokes, 47 were nosocomial. There were no significant age and sex differences between nosocomial stroke and stroke admissions. Nosocomial stroke patients were significantly more likely than stroke admission patients to be normotensive (p = 0.001), diabetic (p = 0.01), and have cardiac disease (p = 0.03). Nosocomial stroke patients were significantly less likely to have brain hemorrhages (p = 0.001), lacunar infarcts (p = 0.03), or infarcts of undetermined cause (p = 0.047). Half of the nosocomial stroke patients died versus 11% of stroke admission patients. Nosocomial stroke differs in stroke type, associated diseases, and prognosis from stroke occurring outside the hospital. PMID- 26487258 TI - Sneddon's and the primary antiphospholipid syndrome: Confusion clarified. PMID- 26487257 TI - Platelet antiaggregants in secondary prevention after stroke: Does dipyridamole add to the effect of aspirin? AB - Eleven randomized trials of platelet antiaggregant treatment, comprising 9,256 patients with a history of transient ischemic attacks or minor stroke, were identified. Trials without placebo controls were not included. Data were pooled based on two nonmutually exclusive groups: aspirin only and aspirin combined with dipyridamole. Each of these treatment groups was compared with a placebo group or with an aspirin group for the following nonmutually exclusive endpoints: (a) vascular events (stroke, myocardial infarction, vascular death) and (b) total strokes (including fatal and nonfatal stroke as well as cerebral hemorrhage). Aspirin was effective in preventing stroke or other vascular events after transient ischemic attacks. However, the risk reduction was small (about 15%), whereas the dosage used (900-1,500 mg vs. 75-300 mg) was not an influence. Placebo-controlled trials of aspirin in combination with dipyridamole indicated more effectiveness with a risk reduction of 30% for all vascular endpoints and 40% for the occurrence of stroke. There was no additional benefit of the combination in trials in the direct comparison with aspirin alone. Therefore, we contend that the benefit of aspirin with dipyridamole over aspirin alone has yet to be demonstrated in confirmative comparison studies. PMID- 26487259 TI - Peri-Infarct perfusion in human ischemia: Its relation to tissue metabolism, morphology, and clinical outcome. AB - Although experimental cerebral ischemia is well studied, little is actually known about the pathophysiology of human peri-infarct tissue. In a follow-up study concentrating on human peri-infarct tissue, we assessed the relationship among different perfusion conditions, metabolism, morphological damage, and clinical outcome. Cerebral blood flow was examined in 22 patients within 6-48 h after the ictus using (15)O-H2O positron emission tomography. The outcome of peri-infarct tissue was judged functionally, by using (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography for repeated measurements of glucose metabolism, and morphologically, by obtaining computed tomography or magnetic resonance images that were three-dimensionally aligned to the positron emission tomography scans. The individual clinical outcome was estimated using the Barthel index. In nine patients, both hyper- and hypoperfused peri-infarct tissue was seen. The clinical outcome of the patients with or without hyperperfused peri-infarct tissue was found not to be different. None of the hyperperfused peri-infarct regions underwent complete cystic degeneration, yet magnetic resonance imaging showed definite signal intensity changes. Glucose metabolic rates of hypoperfused peri infarct tissue, measured initially and at least 2 weeks after the ictus, were significantly lower (p < 0.01) than those of hyperperfused or normoperfused peri infarct tissue. Early spontaneous peri-infarct hyperperfusion occurs frequently. The metabolic and morphological data are suggestive of partial ischemic damage in these areas. It was only for hypoperfused peri-infarct tissue that a significantly poorer tissue outcome was demonstrated. The metabolic and morphological fate of hyper- and normoperfused peri-infarct tissue did not differ. PMID- 26487260 TI - Stroke: The first six hours-Editorial. PMID- 26487261 TI - Stroke:The first six hours: Emergency evaluation and treatment. PMID- 26487262 TI - Potential-Assisted DNA Immobilization as a Prerequisite for Fast and Controlled Formation of DNA Monolayers. AB - Highly reproducible and fast potential-assisted immobilization of single-stranded (ss)DNA on gold surfaces is achieved by applying a pulse-type potential modulation. The desired DNA coverage can be obtained in a highly reproducible way within minutes. Understanding the underlying processes occurring during potential assisted ssDNA immobilization is crucial. We propose a model that considers the role of ions surrounding the DNA strands, the distance dependence of the applied potentials within the electrolyte solution, and most importantly the shift of the potential of zero charge during the immobilization due to the surface modification with DNA. The control of the surface coverage of ssDNA as well as the achieved speed and high reproducibility are seen as prerequisites for improved DNA-based bioassays. PMID- 26487263 TI - Excitation, detection, and electrostatic manipulation of terahertz-frequency range plasmons in a two-dimensional electron system. AB - Terahertz frequency time-domain spectroscopy employing free-space radiation has frequently been used to probe the elementary excitations of low-dimensional systems. The diffraction limit, however, prevents its use for the in-plane study of individual laterally-defined nanostructures. Here, we demonstrate a planar terahertz frequency plasmonic circuit in which photoconductive material is monolithically integrated with a two-dimensional electron system. Plasmons with a broad spectral range (up to ~ 400 GHz) are excited by injecting picosecond duration pulses, generated and detected by a photoconductive semiconductor, into a high mobility two-dimensional electron system. Using voltage modulation of a Schottky gate overlying the two-dimensional electron system, we form a tuneable plasmonic cavity, and observe electrostatic manipulation of the plasmon resonances. Our technique offers a direct route to access the picosecond dynamics of confined electron transport in a broad range of lateral nanostructures. PMID- 26487264 TI - Fast and intense green emission of Tb(3+) in borosilicate glass modified by Cu(.). AB - We present photoluminescence properties of Tb(3+) doped borosilicate glasses modified by Cu(+). Around 5-time enhanced emission at 541 nm due to the superposed emission of Tb(3+) and Cu(+) is observed under the deep UV excitation. Excitation spectra demonstrate a greatly increased absorption of Tb(3+) ions in the deep UV region towards the Cu(+) excitation band, while the shortened Cu(+) emission lifetime of glasses in association with presence of Tb(3+) ions implies an energy transfer process from Cu(+) to Tb(3+) ions. Meanwhile, the Tb(3+) emission lifetime is significantly shortened from the conventional millisecond level (~4 ms) to the microsecond regime up to around 90 MUs. This most likely starts with the role of Cu(+) as a co-activator by initiating the d-f orbital hybridization process via an interaction with Tb(3+), thus relaxing the spin forbidden transition of Tb(3+) ions to the partially allowed one. Moreover, combination of emissions from Cu(+) and Tb(3+) ions generates a composite green emission with adjustable CIE (Commission Internationale de L'Eclairage) chromaticity coordinates achievable by co-doping Cu(+)/Tb(3+) in the different ratio and/or altering the excitation wavelength from deep UV to near UV region. PMID- 26487265 TI - A copper-based layered coordination polymer: synthesis, magnetic properties and electrochemical performance in supercapacitors. AB - A copper-based layered coordination polymer ([Cu(hmt)(tfbdc)(H2O)]; hmt = hexamethylenetetramine, tfbdc = 2,3,5,6-tetrafluoroterephthalate; Cu-LCP) has been synthesized, and it has been structurally and magnetically characterized. The Cu-LCP shows ferromagnetic interactions between the adjacent copper(II) ions. Density functional theory calculations on the special model of Cu-LCP support the occurrence of ferromagnetic interactions. As an electrode material for supercapacitors, Cu-LCP exhibits a high specific capacitance of 1274 F g(-1) at a current density of 1 A g(-1) in 1 M LiOH electrolyte, and the capacitance retention is about 88% after 2000 cycles. PMID- 26487267 TI - Emergency Care Capabilities in North East Haiti: A Cross-sectional Observational Study. AB - INTRODUCTION: The North East Department is a resource-limited region of Haiti. Health care is provided by hospitals and community clinics, with no formal Emergency Medical System and undefined emergency services. As a paucity of information exists on available emergency services in the North East Department of Haiti, the objective of this study was to assess systematically the existing emergency care resources in the region. METHODS: This cross-sectional observational study was carried out at all Ministry of Public Health and Population (MSPP)-affiliated hospitals in the North East Department and all clinics within the Fort Liberte district. A modified version of the World Health Organization (WHO) Tool for Situational Analysis to Assess Emergency and Essential Surgical Care and Generic Essential Emergency Equipment Lists were completed for each facility. RESULTS: Three MSPP hospitals and five clinics were assessed. Among hospitals, all had a designated emergency ward with 24 hour staffing by a medical doctor. All hospitals had electricity with backup generators and access to running water; however, none had potable water. All hospitals had x-ray and ultrasound capabilities. No computed tomography scanners existed in the region. Invasive airway equipment and associated medications were not present consistently in the hospitals' emergency care areas, but they were available in the operating rooms. Pulse oximetry was unavailable uniformly. One hospital had intermittently functioning defibrillation equipment, and two hospitals had epinephrine. Basic supplies for managing obstetrical and traumatic emergencies were available at all hospitals. Surgical services were accessible at two hospitals. No critical care services were available in the region. Clinics varied widely in terms of equipment availability. They uniformly had limited emergency medical equipment. The clinics also had inconsistent access to basic assessment tools (sphygmomanometers 20% and stethoscopes 60%). A protocol for transferring patients requiring a higher level of care was present in most (80%) clinics and one of the hospitals. However, no facility had a written protocol for transferring patients to other facilities. One hospital reported intermittent access to an ambulance for transfers. CONCLUSIONS: Deficits in the supply of emergency equipment and limited protocols for inter-facility transfers exist in North East Department of Haiti. These essential areas represent appropriate targets for interventions aimed at improving access to emergency care within the North East region of Haiti. PMID- 26487269 TI - Epizootic of vesicular disease in pigs caused by coxsackievirus B4 in the Soviet Union in 1975. AB - Swine vesicular disease virus (SVDV) emerged around 1960 from a human enterovirus ancestor, coxsackievirus B5 (CVB5), and caused a series of epizootics in Europe and Asia. We characterized a coxsackievirus B4 strain that caused an epizootic involving 24 488 pigs in the Soviet Union in 1975. Phylogenetic evidence suggested that the swine virus emerged from a human ancestor between 1945 and 1975, almost simultaneously with the transfer of CVB5. PMID- 26487270 TI - Polarization-dependent extraordinary optical transmission from upconversion nanoparticles. AB - Enhanced upconversion (UC) emission was experimentally demonstrated using gold double antenna nanoparticles coupled to nanoslits in gold films. The transmitted red emission from UC ytterbium and erbium co-doped sodium yttrium fluoride (NaYF4:Yb(3+)/Er(3+)) nanoparticles (UC NPs) at ~665 nm (excited with a 980 nm diode laser) was enhanced relative to the green emission at ~550 nm. The relatively enhanced UC NP emission could be tuned by the different polarization dependent extraordinary optical transmission modes coupled to the gold nanostructures. Finite-difference time-domain calculations suggest that the preferential enhanced UC emission is related to a combination of different surface plasmon mode excitation coupling to cavity Fabry-Perot interactions. A maximum UC enhancement of 6-fold was measured for nanoslit arrays in the absence of the double antennas. In the presence of the double nanoantennas inside the nanoslits, the UC enhancement was between 2- and 4-fold, depending on the experimental conditions. PMID- 26487268 TI - Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization. AB - Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies. PMID- 26487271 TI - Complete mitochondrial genome and the phylogenetic position of the Lesser Cuckoo, Cuculus poliocephalus (Aves: Cuculiformes). AB - The complete mitochondrial genome of the Lesser Cuckoo Cuculus poliocephalus was determined using next-generation sequencing. Phylogenetic analyses with 20 cuckoo species and six genes (12S, ATP6, CYTb, ND2, ND3, and ND6) strongly verified the identity of our sample as grouping with C. poliocephalus, which was sister to a clade of other Cuculus spp., including C. canorus, C. micropterus, and C. saturatus. The mitogenomic length of C. poliocephalus was 17 508 bp, including 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, one control region with 48 bp unit tandem repeats close to 3' end, and one short pseudo control region with 33 tandem repeats of CAACAAA. An extra nucleotide (T) was identified at position 174 of ND3. The mitogenome of C. poliocephalus will contribute to studies of mitogenomic evolution, the phylogenetic relationship of cuckoos, and the co-evolutionary pattern between brood parasitic birds and their hosts. PMID- 26487272 TI - Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo. PMID- 26487274 TI - Clarification of the definition of complete response in multiple myeloma. PMID- 26487273 TI - Halting pro-survival autophagy by TGFbeta inhibition in bone marrow fibroblasts overcomes bortezomib resistance in multiple myeloma patients. AB - Bortezomib (bort) has improved overall survival in patients with multiple myeloma (MM), but the majority of them develop drug resistance. In this study, we demonstrate that bone marrow (BM) fibroblasts (cancer-associated fibroblasts; CAFs) from bort-resistant patients are insensitive to bort and protect the RPMI8226 and patients' plasma cells against bort-induced apoptosis. Bort triggers CAFs to produce high levels of interleukin (IL)-6, IL-8, insulin-like growth factor (IGF)-1 and transforming growth factor (TGF) beta. Proteomic studies on CAFs demonstrate that bort resistance parallels activation of oxidative stress and pro-survival autophagy. Indeed, bort induces reactive oxygen species in bort resistant CAFs and activates autophagy by increasing light chain 3 protein (LC3) II and inhibiting p62 and phospho-mammalian target of rapamycin. The small interfering RNA knockdown of Atg7, and treatment with 3-methyladenine, restores bort sensitivity in bort-resistant CAFs and produces cytotoxicity in plasma cells co-cultured with CAFs. In the syngeneic 5T33 MM model, bort-treatment induces the expansion of LC3-II(+) CAFs. TGFbeta mediates bort-induced autophagy, and its blockade by LY2109761, a selective TbetaRI/II inhibitor, reduces the expression of p-Smad2/3 and LC3-II and induces apoptosis in bort-resistant CAFs. A combination of bort and LY2109761 synergistically induces apoptosis of RPMI8226 co-cultured with bort-resistant CAFs. These data define a key role for CAFs in bort resistance of plasma cells and provide the basis for a novel targeted therapeutic approach. PMID- 26487276 TI - Anion exchange in ionic liquid mixtures. AB - Advantage of ionic liquids as designer solvents can be maximized by mixing different ionic liquids (ILs) for a possibility of continuous tunability of material properties. The property of these mixed ILs would be determined by their microscopic conformation between cations and anions. The mixtures of two ILs having 1-butyl-3-methylimidaolium cations and different anions were investigated by IR and NMR spectroscopy, utilizing that the vibrational frequencies of the C-H stretching and bending modes of the most acidic proton in the imidazolium ring of the cation and the NMR chemical shift for the corresponding proton were clearly distinct between the ILs having different anions. The IR absorption spectra of the IL mixtures at different concentrations were well-matched to weighted sums of the two spectra of the pure ILs. In contrast, the two distinct peaks in the NMR spectra of the pure ILs coalesced into a single peak, which shifted continuously following the relative portion of two different ILs in the mixture. IR spectroscopy in the optical frequency range seems to take the instantaneous snapshot of the cation-anion interaction, while NMR spectroscopy in the radio frequency (~500 MHz) range samples over a much longer timescale, enough for the cation to interact with different anion species in the mixture. PMID- 26487275 TI - Impact of cytogenetic classification on outcomes following early high-dose therapy in multiple myeloma. AB - Early high-dose therapy (HDT), consisting of high-dose melphalan and autologous stem cell transplantation following doublet or triplet novel agent induction, is a preferred management strategy for transplant-eligible myeloma patients. We set out to examine the utility of the current fluorescence in situ hybridization (FISH)-based risk stratification in a homogenously treated population of transplant-eligible myeloma patients receiving novel induction regimens and early HDT with or without posttransplant maintenance therapy. FISH was available in 409 patients at the time of diagnosis for patients receiving HDT within 12 months of diagnosis. We present comprehensive outcomes for chromosome 14 translocations and 17p abnormalities that both support and refute current risk stratification models. In contrast to its current classification as a marker of 'standard risk' (SR), t(11;14) was associated with inferior overall survival (OS) when compared with the classical SR cohort. The use of novel agent maintenance therapy (bortezomib or lenalidomide) following early HDT ameliorates the negative prognostic value of high-risk (HR) cytogenetic markers. HR patients who received maintenance following early HDT had similar OS compared with the SR cohort at 5 years. PMID- 26487277 TI - Erratum to: A randomised dose-ranging study of tiotropium Respimat(r) in children with symptomatic asthma despite inhaled corticosteroids. PMID- 26487280 TI - Correction: Synthesis, characterisation, and catalytic evaluation of hierarchical faujasite zeolites: milestones, challenges, and future directions. AB - Correction for 'Synthesis, characterisation, and catalytic evaluation of hierarchical faujasite zeolites: milestones, challenges, and future directions' by D. Verboekend et al., Chem. Soc. Rev., 2015, DOI: . PMID- 26487278 TI - Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma. AB - Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC. PMID- 26487281 TI - Screening for iron deficiency and iron deficiency anaemia in pregnancy: a structured review and gap analysis against UK national screening criteria. AB - BACKGROUND: Iron deficiency anaemia is a common problem in pregnancy despite national recommendations and guidelines for treatment. The aim of this study was to appraise the evidence against the UK National Screening Committee (UKNSC) criteria as to whether a national screening programme could reduce the prevalence of iron deficiency anaemia and/or iron deficiency in pregnancy and improve maternal and fetal outcomes. METHODS: Search strategies were developed for the Cochrane library, Medline and Embase to identify evidence relevant to UK National Screening Committee (UKNSC) appraisal criteria which cover the natural history of iron deficiency and iron deficiency anaemia, the tests for screening, clinical management and evidence of cost effectiveness. RESULTS: Many studies evaluated haematological outcomes of anaemia, but few analysed clinical consequences. Haemoglobin and ferritin appeared the most suitable screening tests, although future options may follow recent advances in understanding iron homeostasis. The clinical consequences of iron deficiency without anaemia are unknown. Oral and intravenous iron are effective in improving haemoglobin and iron parameters. There have been no trials or economic evaluations of a national screening programme for iron deficiency anaemia in pregnancy. CONCLUSIONS: Iron deficiency in pregnancy remains an important problem although effective tests and treatment exist. A national screening programme could be of value for early detection and intervention. However, high quality studies are required to confirm whether this would reduce maternal and infant morbidity and be cost effective. PMID- 26487283 TI - Effect of acute exercise on circulating angiogenic cell and microparticle populations. AB - Subpopulations of peripheral blood mononuclear cells (PMBCs), known as circulating angiogenic cells (CACs), have been implicated in endothelial repair, angiogenesis and vascular homeostasis. Conversely, microparticles released from endothelial cells, platelets and leucocytes in response to injury or apoptosis are elevated in chronic diseases. We investigated the effect of acute exercise on CAC subpopulations, specifically CD34(+)/VEGFR2(+), CD3(+)/CD31(+), CD14(+)/CD31(+) and CD62E(+) PBMCs and CD62E(+), CD31(+)/CD42b(-) and CD34(+) MPs in men and women. Additionally, we examined angiogenesis-related gene expression in CD34(+), CD31(+) and CD62E(+) PBMCs at baseline and after exercise. Finally, we examined whether acute exercise modulates CD62E(+) PBMC paracrine actions on cultured endothelial cells. Blood samples for CAC and MP analyses were obtained before and after cycling exercise at 70% peak oxygen uptake that elicited an energy expenditure of 600 kcal. Exercise produced a decrease in CD14(+)/CD31(+) PBMCs, whereas CD62E expression on PBMCs increased with exercise. CD34(+)/VEGFR2(+) and CD3(+)/CD31(+) PBMC levels were not altered with exercise. Gene expression analysis revealed a more proangiogenic phenotype in CD62E(+) cells at baseline compared with CD31(+) and CD34(+) cells. Conditioned media from CD62E(+) PBMCs obtained after exercise exerted a proangiogenic influence on human umbilical vein endothelial cells, with increases in genes encoding receptors for growth factors (KDR, FGFR1 and EGFR) and inflammatory mediators (TLR4 and TNFR1). Finally, exercise increased CD62E(+) endothelial MPs in men and increased CD34(+) MPs in women. Our work highlights the potential role of CD62E(+) cells as a novel, exercise-responsive proangiogenic cell population and demonstrates sex specific exercise-induced changes in circulating MPs. PMID- 26487282 TI - Herpes Simplex Virus type-1 infection induces synaptic dysfunction in cultured cortical neurons via GSK-3 activation and intraneuronal amyloid-beta protein accumulation. AB - Increasing evidence suggests that recurrent Herpes Simplex Virus type 1 (HSV-1) infection spreading to the CNS is a risk factor for Alzheimer's Disease (AD) but the underlying mechanisms have not been fully elucidated yet. Here we demonstrate that in cultured mouse cortical neurons HSV-1 induced Ca(2+)-dependent activation of glycogen synthase kinase (GSK)-3. This event was critical for the HSV-1 dependent phosphorylation of amyloid precursor protein (APP) at Thr668 and the following intraneuronal accumulation of amyloid-beta protein (Abeta). HSV-1 infected neurons also exhibited: i) significantly reduced expression of the presynaptic proteins synapsin-1 and synaptophysin; ii) depressed synaptic transmission. These effects depended on GSK-3 activation and intraneuronal accumulation of Abeta. In fact, either the selective GSK-3 inhibitor, SB216763, or a specific antibody recognizing Abeta (4G8) significantly counteracted the effects induced by HSV-1 at the synaptic level. Moreover, in neurons derived from APP KO mice and infected with HSV-1 Abeta accumulation was not found and synaptic protein expression was only slightly reduced when compared to wild-type infected neurons. These data further support our contention that HSV-1 infections spreading to the CNS may contribute to AD phenotype. PMID- 26487285 TI - Stand-alone interspinous spacer versus decompressive laminectomy for treatment of lumbar spinal stenosis. AB - OBJECTIVE: To compare the two-year clinical outcomes of a prospective, randomized controlled trial of an FDA-approved interspinous spacer with the compilation of published findings from 19 studies of decompressive laminectomy for the treatment of lumbar spinal stenosis. METHODS: Back and leg pain, Oswestry disability index (ODI), and Zurich Claudication Questionnaire (ZCQ) values were compared between spacer- and laminectomy-treated patients preoperatively and at 12 and 24 months. RESULTS: Percentage improvements between baseline and 24 months uniformly favored patients treated with the spacer for back pain (65% vs. 52%), leg pain (70% vs. 62%), ODI (51% vs. 47%) and ZCQ symptom severity (37% vs. 29%) and physical function (36% vs. 32%). CONCLUSION: Both treatments provide effective and durable symptom relief of claudicant symptoms. This stand-alone interspinous spacer offers the patient a minimally invasive option with less surgical risk. PMID- 26487286 TI - Readiness and learning in health care education. PMID- 26487284 TI - Efficacy of cognitive rehabilitation on psychosocial functioning in Borderline Personality Disorder: a randomized controlled trial. AB - BACKGROUND: Follow-up studies revealed that subjects with borderline personality disorder (BPD) present high rates of clinical remission, although psychosocial functioning often remains impaired. The aim of this study is to evaluate the efficacy of a cognitive rehabilitation intervention versus a psychoeducational program on psychosocial functioning in subjects with BPD. METHODS: A multicenter, randomized, and positive-controlled clinical trial was conducted. Seventy outpatients with BPD were randomized to cognitive rehabilitation or psychoeducational group interventions. Participants were evaluated after completion of the intervention period (16 weeks) and after the follow-up period (6 months). Psychosocial functioning, clinical and neuropsychological outcomes were evaluated. RESULTS: No main effects of group or group x time were observed on functionality but a significant effect of time was found. Post-hoc analyses showed that only cognitive rehabilitation increased psychosocial functioning significantly at endpoint. Psychoeducation showed a significant enhancement of depressive symptoms. CONCLUSIONS: Cognitive rehabilitation and psychoeducational interventions appeared to show good efficacy in improving disabilities in daily life in subjects with BPD. These interventions are easily implemented in mental health settings and have the advantage of improving general functioning and clinical symptoms. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02033044. Registered 9 January 2014. PMID- 26487288 TI - Preclinical Alterations in the Serum of COL(IV)A3(-)/(-) Mice as Early Biomarkers of Alport Syndrome. AB - The efficiency of the inhibition of the angiotensin converting enzyme, the most widely used therapy for the Alport syndrome, depends on the onset of the therapy the earlier the better. Hence, early progressive biomarkers are urgently required to allow for preclinical diagnosis, an early start of possible therapy as well as the monitoring of this therapy. In the present study, an improved comprehensive and precise proteomic approach has been applied to the serum of juvenile Alport mice, nontreated and treated, and wild-type controls of various ages to search for biomarkers. With a total of 2542 stringently altered proteins, the serum composition clearly shows a dependency on age, that is, stage, and therapy. Initially, the serum constituents indicate an enhanced extracellular matrix remodeling, cell damage, and the production of particular acute phase proteins. A panel of 15 potential biomarker candidates has been identified. In later stages, renal filtration failure and systemic acute phase reaction determine the composition of the serum; an effect that is well-known for manifested human Alport syndrome. With a small number of mouse urine samples, for example, the proteomic results for gelsolin could be verified using ELISA. Once verified in man, these early biomarkers would allow for a sensitive and specific diagnosis of the Alport syndrome in children as well as facilitate the monitoring of a possible therapy. PMID- 26487287 TI - New global analysis of the microRNA transcriptome of primary tumors and lymph node metastases of papillary thyroid cancer. AB - BACKGROUND: Papillary Thyroid Cancer (PTC) is the most prevalent type of endocrine cancer. Its incidence has rapidly increased in recent decades but little is known regarding its complete microRNA transcriptome (miRNome). In addition, there is a need for molecular biomarkers allowing improved PTC diagnosis. METHODS: We performed small RNA deep-sequencing of 3 PTC, their matching normal tissues and lymph node metastases (LNM). We designed a new bioinformatics framework to handle each aspect of the miRNome: whole expression profiles, isomiRs distribution, non-templated additions distributions, RNA editing or mutation. Results were validated experimentally by qRT-PCR on normal samples, tumors and LNM from 14 independent patients and in silico using the dataset from The Cancer Genome Atlas (small RNA deepsequencing of 59 normal samples, 495 PTC, and 8 LNM). RESULTS: We performed small RNA deep-sequencing of 3 PTC, their matching normal tissues and lymph node metastases (LNM). We designed a new bioinformatics framework to handle each aspect of the miRNome: whole expression profiles, isomiRs distribution, non-templated additions distributions, RNA-editing or mutation. Results were validated experimentally by qRT-PCR on normal samples, tumors and LNM from 14 independent patients and in silico using the dataset from The Cancer Genome Atlas (small RNA deep-sequencing of 59 normal samples, 495 PTC, and 8 LNM). We confirmed already described up-regulations of microRNAs in PTC, such as miR-146b-5p or miR-222-3p, but we also identified down regulated microRNAs, such as miR-7-5p or miR-30c-2-3p. We showed that these down regulations are linked to the tumorigenesis process of thyrocytes. We selected the 14 most down-regulated microRNAs in PTC and we showed that they are potential biomarkers of PTC samples. Nevertheless, they can distinguish histological classical variants and follicular variants of PTC in the TCGA dataset. In addition, 12 of the 14 down-regulated microRNAs are significantly less expressed in aggressive PTC compared to non-aggressive PTC. We showed that the associated aggressive expression profile is mainly due to the presence of the BRAF V600E mutation. In general, primary tumors and LNM presented similar microRNA expression profiles but specific variations like the down-regulation of miR-7-2 3p and miR-30c-2-3p in LNM were observed. Investigations of the 5p-to-3p arm expression ratios, non-templated additions or isomiRs distributions revealed no major implication in PTC tumorigenesis process or LNM appearance. CONCLUSIONS: Our results showed that down-regulated microRNAs can be used as new potential common biomarkers of PTC and to distinguish main subtypes of PTC. MicroRNA expressions can be linked to the development of LNM of PTC. The bioinformatics framework that we have developed can be used as a starting point for the global analysis of any microRNA deep-sequencing data in an unbiased way. PMID- 26487289 TI - Mesorectal pathologic assessment in two grades predicts accurately recurrence, positive circumferential margin, and correlates with survival. AB - BACKGROUND AND OBJECTIVES: We aimed to determine the prognostic value of the mesorectum quality assessed in a two-grade system compared with a classic system. METHODS: Consecutive patients undergoing surgery for rectal cancer were included (n = 103). Mesorectum was assessed into three grades (classic system: complete, nearly complete, incomplete) and compared with a two-grade system (adequate, inadequate). RESULTS: Mesorectum was complete in 62 (60.25%) patients, nearly complete in 21, and incomplete in 20. Reassessment showed adequate mesorectum in 83 (80.5%) patients and inadequate in 20. A R0 resection was achieved in 90.4% of adequate mesorectum and in 65% of inadequate mesorectum (P = 0.006). Recurrence was present in 18% of adequate mesorectum patients as compared with 50% of inadequate mesorectum (P = 0.003). The classic system failed to accurately predict the 5-year survival rate between complete (78.9%) and nearly complete (86.2%) categories (P = 0.235); whereas a two grading system showed a 5-year survival rate of 80.8% for adequate versus 39.3% for inadequate (P = 0.034). CONCLUSION: High recurrence occurred in inadecuate mesorectum patients and was correlated with R1/R2 resections, positive margins, and decreased survival. We propose a simplified classification of mesorectum that correlates with survival and overall recurrence. PMID- 26487290 TI - Intra-hospital organ and tissue donation coordination project: cost-effectiveness and social benefits. AB - OBJECTIVE To evaluate the viability of a professional specialist in intra hospital committees of organ and tissue donation for transplantation.METHODS Epidemiological, retrospective and cross-sectional study (2003-2011 and 2008 2012), which was performed using organ donation for transplants data in the state of Sao Paulo, Southeastern Brazil. Nine hospitals were evaluated (hospitals 1 to 9). Logistic regression was used to evaluate the differences in the number of brain death referrals and actual donors (dependent variables) after the professional specialist started work (independent variable) at the intra-hospital committee of organ and tissue donation for transplantation. To evaluate the hospital invoicing, the hourly wage of the doctor and registered nurse, according to the legislation of the Consolidation of Labor Laws, were calculated, as were the investment return and the time elapsed to do so.RESULTS Following the nursing specialist commencement on the committee, brain death referrals and the number of actual donors increased at hospital 2 (4.17 and 1.52, respectively). At hospital 7, the number of actual donors also increased from 0.005 to 1.54. In addition, after the nurse started working, hospital revenues increased by 190.0% (ranging 40.0% to 1.955%). The monthly cost for the nurse working 20 hours was US$397.97 while the doctor would cost US$3,526.67. The return on investment was 275% over the short term (0.36 years).CONCLUSIONS This paper showed that including a professional specialist in intra-hospital committees for organ and tissue donation for transplantation proved to be cost-effective. Further economic research in the area could contribute to the efficient public policy implementation of this organ and tissue harvesting model. PMID- 26487291 TI - Burden of physical inactivity and hospitalization costs due to chronic diseases. AB - OBJECTIVE: To evaluate the physical inactivity-related inpatient costs of chronic non-communicable diseases. METHODS: This study used data from 2013, from Brazilian Unified Health System, regarding inpatient numbers and costs due to malignant colon and breast neoplasms, cerebrovascular diseases, ischemic heart diseases, hypertension, diabetes, and osteoporosis. In order to calculate the share physical inactivity represents in that, the physical inactivity-related risks, which apply to each disease, were considered, and physical inactivity prevalence during leisure activities was obtained from Pesquisa Nacional por Amostra de Domicilio(Brazil's National Household Sample Survey). The analysis was stratified by genders and residing country regions of subjects who were 40 years or older. The physical inactivity-related hospitalization cost regarding each cause was multiplied by the respective share it regarded to. RESULTS: In 2013, 974,641 patients were admitted due to seven different causes in Brazil, which represented a high cost. South region was found to have the highest patient admission rate in most studied causes. The highest prevalences for physical inactivity were observed in North and Northeast regions. The highest inactivity related share in men was found for osteoporosis in all regions (~ 35.0%), whereas diabetes was found to have a higher share regarding inactivity in women (33.0% to 37.0% variation in the regions). Ischemic heart diseases accounted for the highest total costs that could be linked to physical inactivity in all regions and for both genders, being followed by cerebrovascular diseases. Approximately 15.0% of inpatient costs from Brazilian Unified Health System were connected to physical inactivity. CONCLUSIONS: Physical inactivity significantly impacts the number of patient admissions due to the evaluated causes and through their resulting costs, with different genders and country regions representing different shares. PMID- 26487292 TI - Specialized care for people with AIDS in the state of Ceara, Brazil. AB - OBJECTIVE: To analyze if the distribution of specialized care services for HIV/AIDS is associated with AIDS rates. METHODS: Ecological study, for which the distribution of 10 specialized care services in the Ceara state, Northeastern Brazil, was obtained, and the mean rates of the disease were estimated per mesoregion. We evaluated 7,896 individuals who had been diagnosed with AIDS, were aged 13 years or older, lived in Ceara, and had been informed of their condition between 2001 and 2011. Maps were constructed to verify the relationship between the distribution of AIDS cases and institutionalized support networks in the 2001 2006 and 2007-2011 periods. BoxMap and LisaMap were used for data analysis. The Voronoi diagram was applied for the distribution of the studied services. RESULTS: Specialized care services concentrated in AIDS clusters in the metropolitan area. The Noroeste Cearense and west of the Sertoes Cearenseshad high AIDS rates, but a low number of specialized care services over time. Two of these services were implemented where clusters of the disease exist in the second period. The application of the Voronoi diagram showed that the specialized care services located outside the metropolitan area covered a large territory. We identified one polygon that had no services. CONCLUSIONS: The scenario of AIDS cases spread away from major urban areas demands the creation of social support services in areas other than the capital and the metropolitan area of the state; this can reduce access barriers to these institutions. It is necessary to create specialized care services for HIV/AIDS in the Noroeste Cearense and north of Jaguaribe. PMID- 26487293 TI - Prevalence of chronic low back pain: systematic review. AB - OBJECTIVE: To estimate worldwide prevalence of chronic low back pain according to age and sex. METHODS: We consulted Medline (PubMed), LILACS and EMBASE electronic databases. The search strategy used the following descriptors and combinations: back pain, prevalence, musculoskeletal diseases, chronic musculoskeletal pain, rheumatic, low back pain, musculoskeletal disorders and chronic low back pain. We selected cross-sectional population-based or cohort studies that assessed chronic low back pain as an outcome. We also assessed the quality of the selected studies as well as the chronic low back pain prevalence according to age and sex. RESULTS: The review included 28 studies. Based on our qualitative evaluation, around one third of the studies had low scores, mainly due to high non-response rates. Chronic low back pain prevalence was 4.2% in individuals aged between 24 and 39 years old and 19.6% in those aged between 20 and 59. Of nine studies with individuals aged 18 and above, six reported chronic low back pain between 3.9% and 10.2% and three, prevalence between 13.1% and 20.3%. In the Brazilian older population, chronic low back pain prevalence was 25.4%. CONCLUSIONS: Chronic low back pain prevalence increases linearly from the third decade of life on, until the 60 years of age, being more prevalent in women. Methodological approaches aiming to reduce high heterogeneity in case definitions of chronic low back pain are essential to consistency and comparative analysis between studies. A standard chronic low back pain definition should include the precise description of the anatomical area, pain duration and limitation level. PMID- 26487294 TI - Gender and other factors associated with the use of hearing protection devices at work. AB - OBJECTIVE: To analyze whether sociodemographic, occupational, and health-related data are associated with the use of hearing protection devices at work, according to gender. METHODS: A cross-sectional study was conducted in 2006, using a random sample of 2,429 workers, aged between 18 and 65 years old, from residential sub areas in Salvador, BA, Northeastern Brazil. Questionnaires were used to obtain sociodemographic, occupational, and health-related data. Workers who reported that they worked in places where they needed to shout in order to be heard were considered to be exposed to noise. Exposed workers were asked whether they used hearing protection devices, and if so, how frequently. Analyses were conducted according to gender, with estimates made about prevalence of the use of hearing protection devices, prevalence ratios, and their respective 95% confidence intervals. RESULTS: Twelve percent (12.3%) of study subjects reported that they were exposed to noise while working. Prevalence of the use of hearing protection devices was 59.3% for men and 21.4% for women. Men from higher socioeconomic levels (PR = 1.47; 95%CI 1.14;1.90) and who had previous audiometric tests (PR = 1.47; 95%CI 1.15;1.88) were more likely to use hearing protection devices. For women, greater perceived safety was associated with the use of protection devices (PR = 2.92; 95%CI 1.34;6.34). This perception was specifically related to the presence of supervisors committed to safety (PR = 2.09; 95%CI 1.04;4.21), the existence of clear rules to prevent workplace injuries (PR = 2.81; 95%CI 1.41;5.59), and whether they were informed about workplace safety (PR = 2.42; 95%CI 1.23;4.76). CONCLUSIONS: There is a gender bias regarding the use of hearing protection devices that is less favorable to women. The use of such devices among women is positively influenced by their perception of a safe workplace, suggesting that gender should be considered as a factor in hearing conservation programs. PMID- 26487295 TI - Necessity to review the Brazilian regulation about fluoride toothpastes. AB - The aim of this study was to evaluate the adequacy of the Brazilian legislation about fluoride toothpaste. A search was conducted in LILACS, Medline and SciELO databases about the fluoride concentration found in Brazilians toothpastes, using descriptors on health. Publications since 1981 have shown that some Brazilian toothpastes are not able to maintain, during their expiration time, a minimum of 1,000 ppm F of soluble fluoride in the formulation. However, the Brazilian regulation (ANVISA, Resolution 79, August 28, 2000) only sets the maximum total fluoride (0.15%; 1,500 ppm F) that a toothpaste may contain but not the minimum concentration of soluble fluoride that it should contain to have anticaries potential, which according to systematic reviews should be 1,000 ppm F. Therefore, the Brazilian regulation on fluoride toothpastes needs to be revised to assure the efficacy of those products for caries control. PMID- 26487296 TI - Correction to Pressure Selected Reactivity and Kinetics Deduced from Photoinduced Dissociation of Ethylene Glycol. PMID- 26487297 TI - Plectin isoform 1-dependent nuclear docking of desmin networks affects myonuclear architecture and expression of mechanotransducers. AB - Plectin is a highly versatile cytoskeletal protein that acts as a mechanical linker between intermediate filament (IF) networks and various cellular structures. The protein is crucial for myofiber integrity. Its deficiency leads to severe pathological changes in skeletal muscle fibers of patients suffering from epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). Skeletal muscle fibers express four major isoforms of plectin which are distinguished solely by alternative, relatively short, first exon-encoded N-terminal sequences. Each one of these isoforms is localized to a different subcellular compartment and plays a specific role in maintaining integrity and proper function(s) of myofibers. The unique role of individual isoforms is supported by distinct phenotypes of isoform-specific knockout mice and recently discovered mutations in first coding exons of plectin that lead to distinct, tissue-specific, pathological abnormalities in humans. In this study, we demonstrate that the lack of plectin isoform 1 (P1) in myofibers of mice leads to alterations of nuclear morphology, similar to those observed in various forms of MD. We show that P1 mediated targeting of desmin IFs to myonuclei is essential for maintenance of their typically spheroidal architecture as well as their proper positioning and movement along the myofiber. Furthermore, we show that P1 deficiency affects chromatin modifications and the expression of genes involved in various cellular functions, including signaling pathways mediating mechanotransduction. Mechanistically, P1 is shown to specifically interact with the myonuclear membrane-associated (BAR domain-containing) protein endophilin B. Our results open a new perspective on cytoskeleton-nuclear crosstalk via specific cytolinker proteins. PMID- 26487298 TI - Factors Associated with Prescription of Opioids and Co-prescription of Sedating Medications in Individuals with HIV. AB - Opioids are often prescribed for chronic pain, and opioid risks such as overdose and death are heightened when opioids are co-prescribed with other sedating medications. We investigated factors associated with chronic opioid prescription, alone and in combination with benzodiazepines and muscle relaxants, in a clinical cohort of individuals with HIV. We used multivariable logistic regression models to determine participant clinical and demographic characteristics that are associated with chronic prescription of opioids or chronic co-prescription of opioids with sedating medications. Among 1474 participants, chronic prescription of opioids occurred in 253 individuals (17.2 %), and chronic co-prescription occurred in 90 individuals (6.1 %). Age >50, public insurance as compared to private insurance, and symptoms of depression and anxiety were significantly associated with chronic opioid prescription and chronic co-prescription. Our findings raise concern that opioid prescription and co-prescription of sedating medications occurs disproportionately in patients for whom use is riskier. PMID- 26487299 TI - Safer Conception Methods and Counseling: Psychometric Evaluation of New Measures of Attitudes and Beliefs Among HIV Clients and Providers. AB - With data from 400 HIV clients with fertility intentions and 57 HIV providers in Uganda, we evaluated the psychometrics of new client and provider scales measuring constructs related to safer conception methods (SCM) and safer conception counselling (SCC). Several forms of validity (i.e., content, face, and construct validity) were examined using standard methods including exploratory and confirmatory factor analysis. Internal consistency was established using Cronbach's alpha correlation coefficient. The final scales consisted of measures of attitudes towards use of SCM and delivery of SCC, including measures of self efficacy and motivation to use SCM, and perceived community stigma towards childbearing. Most client and all provider measures had moderate to high internal consistency (alphas 0.60-0.94), most had convergent validity (associations with other SCM or SCC-related measures), and client measures had divergent validity (poor associations with depression). These findings establish preliminary psychometric properties of these scales and should facilitate future studies of SCM and SCC. PMID- 26487300 TI - Randomized Controlled Trial of an Internet Application to Reduce HIV Transmission Behavior Among HIV Infected Men Who have Sex with Men. AB - We conducted a prospective, randomized controlled trial of an internet-based safer-sex intervention to reduce HIV transmission risk behaviors. HIV-infected men who have sex with men (n = 179) were randomized to receive a monthly internet survey alone or a monthly survey plus tailored risk reduction messages over 12 months. The primary outcome was the cumulative sexually transmitted infection (STI) incidence over 12 months. Secondary outcomes included self-reported unprotected sex with an at risk partner and disclosure of HIV status to partners. In a modified intent to treat analysis, there was no difference in 12-month STI incidence between the intervention and control arms (30 vs. 25 %, respectively; p = 0.5). Unprotected sex decreased and disclosure increased over time in both study arms. These improvements suggest that addition of the risk-reduction messages provided little benefit beyond the self-monitoring of risky behavior via regular self-report risk behavior assessments (as was done in both study arms). PMID- 26487301 TI - LncRNA-ATB mediated E-cadherin repression promotes the progression of colon cancer and predicts poor prognosis. AB - BACKGROUND: Long non-coding RNA-activated by TGF-beta (lncRNA-ATB) promotes the invasion-metastasis cascade in hepatocellular carcinoma via downregulating E cadherin (E-cad) and inducing epithelial-to- mesenchymal transition (EMT) and is clinically significant in human colon cancer. However, its molecular mechanisms in colon cancer progression remain unclear. This study aimed to elucidate the role of lncRNA-ATB and its clinical value in colon cancer. METHODS: Expression levels of lncRNA-ATB in colon cancer tissues and colon cancer cell lines were evaluated using quantitative real-time polymerase chain reaction. The clinicopathological significance and prognostic value of lncRNA-ATB were investigated, and roles of lncRNA-ATB in regulating E-cad and other EMT-related markers expression and colon cancer progression were evaluated in vitro. Expression levels of lncRNA-ATB and E-cad in human plasma were evaluated. RESULTS: Long non-coding RNA-activated by TGF-beta was upregulated in colon cancer tissues compared with adjacent mucosa (P < 0.001). LncRNA-ATB levels were also higher in metastatic cancer tissues (P < 0.001). Among the three highly invasive colon cancer cell lines, lncRNA-ATB levels were relatively higher with concurrent low levels of E-cad compared with levels in the three low-invasive cell lines. LncRNA-ATB expression correlated with pN stage (P < 0.01) and American Joint Committee on Cancer stage (P < 0.01). Striking differences were observed in overall survival and disease-free survival in cases with both high lncRNA-ATB expression and low E-cad expression. Reduction of lncRNA-ATB increased expression of epithelial markers E-cad, ZO-1, and decreased expression of mesenchymal markers ZEB1 and N-cadherin (N-cad), and significantly influenced colon cancer cell progression. Plasma lncRNA-ATB was upregulated in colon cancer patients one month after surgery (P < 0.05). CONCLUSIONS: Long non-coding RNA activated by TGF-beta may act on colon tumorigenesis by suppressing E-cad expression and promoting EMT process, and lncRNA-ATB inhibition may provide a promising therapeutic option for suppressing colon cancer progression. PMID- 26487302 TI - Truly Fluorescent Excitation-Dependent Carbon Dots and Their Applications in Multicolor Cellular Imaging and Multidimensional Sensing. AB - Truly fluorescent excitation-dependent carbon dots are prepared, and the relationship between their chemical composition and fluorescent emission is discussed. Furthermore, potential applications of the as-prepared carbon dots to multicolor bio-labeling and multidimodal sensing are demonstrated. PMID- 26487303 TI - Effects of changing from sevoflurane to desflurane on the recovery profile after sevoflurane induction: a randomized controlled study. AB - PURPOSE: Desflurane has the lowest solubility of currently available volatile anesthetics and may allow for more rapid emergence and recovery compared with sevoflurane. Nevertheless, after volatile induction with sevoflurane, it has not been determined whether the use of desflurane provides faster emergence and recovery. The present study aimed to elucidate the effects of changing from sevoflurane to desflurane during the early part of anesthesia. METHODS: Fifty-two patients who were scheduled for vitreous surgery with general anesthesia were enrolled in this randomized controlled study. Anesthesia was induced with volatile induction consisting of 100% oxygen (6 L.min(-1)) and 5% sevoflurane. For anesthesia maintenance, patients were randomized to receive 1-2% sevoflurane or 3-6% desflurane. In the desflurane group, the anesthetic agent was changed from sevoflurane to desflurane within five minutes following endotracheal intubation. After surgery, we assessed the following endpoints: the times from discontinuing volatile anesthetics to eye opening, obeying the command to squeeze the investigator's hand, tracheal extubation, and orientation to the patients' full name, date, and place. RESULTS: Emergence and recovery were significantly faster in the desflurane group than in the sevoflurane group in times to mean (SD) eye opening [6.5 (2.9) vs 10.1(3.0) min, respectively; mean difference, 3.6 min; 95% confidence interval (CI), 1.9 to 5.3; P < 0.001], obeying commands [6.6 (2.7) vs 10.1 (3.1) min, respectively; mean difference, 3.5 min; 95% CI, 1.9 to 5.2; P < 0.001], and tracheal extubation [7.0 (2.5) vs 10.6 (3.0) min, respectively; mean difference, 3.6 min; 95% CI, 1.9 to 5.1; P < 0.001]. Similarly, the times from discontinuation of volatile anesthetics to orientation to the patients' full name, date, and place were significantly shorter in the desflurane group compared with the sevoflurane group. There were no significant differences between groups on a 100-mm visual analogue scale assessing postoperative nausea and vomiting, eye pain, and patient satisfaction regarding anesthesia. CONCLUSION: Changing the anesthetic agent from sevoflurane to desflurane after sevoflurane induction provides faster emergence and recovery compared with sevoflurane anesthesia. This study protocol was registered at http://www.umin.ac.jp/ctr/index.htm , (UMIN000009941). PMID- 26487304 TI - HPV Vaccine Triggers Regression of Precancers. AB - According to a phase IIb clinical trial, an investigational DNA vaccine that targets the human papillomavirus caused precancerous cervical lesions to regress or disappear. The vaccine stimulated production of CD8+ T cells that make perforin, a protein that helps kill infected cervical cells, and eliminated the virus in 81% of women whose lesions regressed. PMID- 26487305 TI - Current Trends and Future Projection of HIV/AIDS Epidemic in Taiwan: A Modeling Analysis. AB - BACKGROUND: In the past decade, HIV/AIDS epidemic in Taiwan experienced an outbreak of HIV-1 CRF07_BC among intravenous drug users (IDU) in 2004-2006 that led to the reported HIV/AIDS case number more than doubled in less than 3 years and subsequent changes in free antiretroviral therapy (ART) treatment program for persons living with HIV/AIDS (PLWHA). METHODS: We investigate HIV underreporting in Taiwan by utilizing a discrete-time compartmental mathematical model for disease transmission and HIV/AIDS surveillance data during 2001-2011. RESULTS: The estimated underreporting ratio in 2011 is 0.45:1, down from 1:1 ratio in 2000. We also provide future projections of the numbers of reported and unreported PLWHA in Taiwan, assuming that model parameters remain unchanged in the near future. CONCLUSION: N-step-ahead forecasting comparison with 2012-2014 observed data indicates lower than expected number of known PLWHA and new deaths, perhaps attributable to increased treatment, but higher number of newly reported HIV/AIDS cases, which requires further investigation. PMID- 26487306 TI - Attitudes of College Undergraduates Towards Coyotes (Canis latrans) in an Urban Landscape: Management and Public Outreach Implications. AB - Understanding and assessing the public's attitudes towards urban wildlife is an important step towards creating management plans, increasing knowledge and awareness, and fostering coexistence between people and wildlife. We conducted a survey of undergraduate college students in the Washington, D.C. metropolitan area-where coyotes are recent arrivals-to determine existing attitudes towards coyotes and coyote management methods. Amongst other findings, we found that the more a person feared coyotes, the less likely they were to support their presence (p < 0.001), and the less likely they were to believe that pet owners should be directly responsible for protecting their pets (p < 0.001). Respondents demonstrated major gaps in their understanding of basic coyote biology and ecology. Respondents broke wildlife management practices into two categories: those that involved an action on coyotes (both lethal or non-lethal; referred to as "Coyote"), and those that restricted human behavior (referred to as "Human"); the "Human" methods were preferred. We found important differences between key demographic groups in terms of attitudes and management preferences. Our study suggests that wildlife professionals have unique opportunities in urban areas to prevent and reduce conflict before it escalates, in part by targeting tailored outreach messages to various demographic and social groups. PMID- 26487307 TI - Possible Electromagnetic Effects on Abnormal Animal Behavior Before an Earthquake. AB - The former statistical properties summarized by Rikitake (1998) on unusual animal behavior before an earthquake (EQ) have first been presented by using two parameters (epicentral distance (D) of an anomaly and its precursor (or lead) time (T)). Three plots are utilized to characterize the unusual animal behavior; (i) EQ magnitude (M) versus D, (ii) log T versus M, and (iii) occurrence histogram of log T. These plots are compared with the corresponding plots for different seismo-electromagnetic effects (radio emissions in different frequency ranges, seismo-atmospheric and -ionospheric perturbations) extensively obtained during the last 15-20 years. From the results of comparisons in terms of three plots, it is likely that lower frequency (ULF (ultra-low-frequency, f <= 1 Hz) and ELF (extremely-low-frequency, f <= a few hundreds Hz)) electromagnetic emissions exhibit a very similar temporal evolution with that of abnormal animal behavior. It is also suggested that a quantity of field intensity multiplied by the persistent time (or duration) of noise would play the primary role in abnormal animal behavior before an EQ. PMID- 26487308 TI - Variation in Protein and Calorie Consumption Following Protein Malnutrition in Rattus norvegicus. AB - Catch-up growth rates, following protein malnutrition, vary with timing and duration of insult, despite unlimited access to calories. Understanding changing patterns of post-insult consumption, relative rehabilitation timing, can provide insight into the mechanisms driving those differences. We hypothesize that higher catch-up growth rates will be correlated with increased protein consumption, while calorie consumption could remain stable. As catch-up growth rates decrease with age/malnutrition duration, we predict a dose effect in protein consumption with rehabilitation timing. We measured total and protein consumption, body mass, and long bone length, following an increase of dietary protein at 40, 60 and 90 days, with two control groups (chronic reduced protein or standard protein) for 150+ days. Immediately following rehabilitation, rats' food consumption decreased significantly, implying that elevated protein intake is sufficient to fuel catch up growth rates that eventually result in body weights and long bone lengths greater or equal to final measures of chronically fed standard (CT) animals. The duration of protein restriction affected consumption: rats rehabilitated at younger ages had more drastic alterations in consumption of both calories and protein. While rehabilitated animals did compensate with greater protein consumption, variable responses in different ages and sex highlight the plasticity of growth and how nutrition affects body form. PMID- 26487309 TI - Modelling Niche Differentiation of Co-Existing, Elusive and Morphologically Similar Species: A Case Study of Four Macaque Species in Nakai-Nam Theun National Protected Area, Laos. AB - Species misidentification often occurs when dealing with co-existing and morphologically similar species such as macaques, making the study of their ecology challenging. To overcome this issue, we use reliable occurrence data from camera-trap images and transect survey data to model their respective ecological niche and potential distribution locally in Nakai-Nam Theun National Protected Area (NNT NPA), central-Eastern Laos. We investigate niche differentiation of morphologically similar species using four sympatric macaque species in NNT NPA, as our model species: rhesus Macaca mulatta (Taxonomic Serial Number, TSN 180099), Northern pig-tailed M. leonina (TSN not listed); Assamese M. assamensis (TSN 573018) and stump-tailed M. arctoides (TSN 573017). We examine the implications for their conservation. We obtained occurrence data of macaque species from systematic 2006-2011 camera-trapping surveys and 2011-2012 transect surveys and model their niche and potential distribution with MaxEnt software using 25 environmental and topographic variables. The respective suitable habitat predicted for each species reveals niche segregation between the four species with a gradual geographical distribution following an environmental gradient within the study area. Camera-trapping positioned at many locations can increase elusive-species records with a relatively reduced and more systematic sampling effort and provide reliable species occurrence data. These can be used for environmental niche modelling to study niche segregation of morphologically similar species in areas where their distribution remains uncertain. Examining unresolved species' niches and potential distributions can have crucial implications for future research and species' management and conservation even in the most remote regions and for the least-known species. PMID- 26487310 TI - Early Results of Three-Year Monitoring of Red Wood Ants' Behavioral Changes and Their Possible Correlation with Earthquake Events. AB - Short-term earthquake predictions with an advance warning of several hours or days are currently not possible due to both incomplete understanding of the complex tectonic processes and inadequate observations. Abnormal animal behaviors before earthquakes have been reported previously, but create problems in monitoring and reliability. The situation is different with red wood ants (RWA; Formica rufa-group (Hymenoptera: Formicidae)). They have stationary mounds on tectonically active, gas-bearing fault systems. These faults may be potential earthquake areas. For three years (2009-2012), two red wood ant mounds (Formica rufa-group), located at the seismically active Neuwied Basin (Eifel, Germany), have been monitored 24/7 by high-resolution cameras with both a color and an infrared sensor. Early results show that ants have a well-identifiable standard daily routine. Correlation with local seismic events suggests changes in the ants' behavior hours before the earthquake: the nocturnal rest phase and daily activity are suppressed, and standard daily routine does not resume until the next day. At present, an automated image evaluation routine is being applied to the more than 45,000 hours of video streams. Based on this automated approach, a statistical analysis of the ants' behavior will be carried out. In addition, other parameters (climate, geotectonic and biological), which may influence behavior, will be included in the analysis. PMID- 26487311 TI - Prevalence and Risk Factors Associated with Musculoskeletal Discomfort in Spay and Neuter Veterinarians. AB - A cross-sectional study to investigate musculoskeletal discomfort (MSD) surveyed 219 veterinarians who currently or previously perform spays and neuters at least 4 hours per week. Participants were asked about the presence and severity of hand and body MSD during the previous month, whether MSD interfered with work or daily activities, whether they attributed their MSD to their spay/neuter work, and whether MSD had ever necessitated absence from work. The period prevalence of MSD was 99.1%, with 76.7% experiencing hand or wrist pain and 98.2% experiencing body pain. Hand discomfort was most commonly reported in the right thumb and/or thumb base (49.8%) and the right wrist (37.9%). Body discomfort was most commonly reported in the lower back (76.7%), shoulders (72.6%), and neck (71.7%). Increasing career length, increasing weekly hours in surgery and decreasing job satisfaction were the work-related factors with the greatest relative contribution accounting for variation in hand pain severity and total pain. Although 94.4% of respondents felt that posture during surgery is important, only 30.6% had received any instruction in posture and positioning for surgery. Future interventions should aim to optimize surgical efficiency, surgeon work schedules, and working environment. Analysis and intervention studies are required to determine further causes of MSD in these veterinarians and develop interventions to prevent MSD. PMID- 26487312 TI - The "Super Chimpanzee": The Ecological Dimensions of Rehabilitation of Orphan Chimpanzees in Guinea, West Africa. AB - To date few studies, especially among non-human primates, have evaluated or monitored rehabilitation effectiveness and identified key species-specific behavioral indicators for release success. This four-months study aimed to identify behavioral indicators of rehabilitation success among ten infant and juvenile orphaned chimpanzees cared for in peer groups at the Centre for Conservation of Chimpanzees (CCC), Guinea, West Africa. Behavioral data focused on foraging skills and activity budget. During bush-outings, rehabilitants spent on average nearly a quarter of their activity budget foraging, resting or traveling, respectively. Neither age, sex, the level of abnormal behaviors demonstrated upon arrival nor human contact during bush-outings predicted individual dietary knowledge. However, individuals who spent more time arboreal demonstrated a greater dietary breadth than conspecifics who dwelled more terrestrially. Although our data failed to demonstrate a role of conspecific observation in dietary acquisition, we propose that the mingling of individuals from different geographical origins may act as a catalyst for acquiring new dietary knowledge, promoted by ecological opportunities offered during bush outings. This "Super Chimpanzee" theory opens up new questions about cultural transmission and socially-biased learning among our closest living relatives and provides a novel outlook on rehabilitation in chimpanzees. PMID- 26487313 TI - Methodological Considerations in Designing and Evaluating Animal-Assisted Interventions. AB - This paper presents a discussion of the literature on animal-assisted interventions and describes limitations surrounding current methodological quality. Benefits to human physical, psychological and social health cannot be empirically confirmed due to the methodological limitations of the existing body of research, and comparisons cannot validly be made across different studies. Without a solid research base animal-assisted interventions will not receive recognition and acceptance as a credible alternative health care treatment. The paper draws on the work of four systematic reviews conducted over April-May 2009, with no date restrictions, focusing exclusively on the use of canine-assisted interventions for older people residing in long-term care. The reviews revealed a lack of good quality studies. Although the literature base has grown in volume since its inception, it predominantly consists of anecdotal accounts and reports. Experimental studies undertaken are often flawed in aspects of design, conduct and reporting. There are few qualitative studies available leading to the inability to draw definitive conclusions. It is clear that due to the complexities associated with these interventions not all weaknesses can be eliminated. However, there are basic methodological weaknesses that can be addressed in future studies in the area. Checklists for quantitative and qualitative research designs to guide future research are offered to help address methodological rigour. PMID- 26487314 TI - An Investigation of a Cluster of Parapoxvirus Cases in Missouri, Feb-May 2006: Epidemiologic, Clinical and Molecular Aspects. AB - In the spring of 2006, four human cases of parapoxvirus infections in Missouri residents were reported to the Centers for Disease Control and Prevention (CDC), two of which were initially diagnosed as cutaneous anthrax. This investigation was conducted to determine the level of recognition of zoonotic parapoxvirus infections and prevention measures, the degree to which veterinarians may be consulted on human infections and what forces were behind this perceived increase in reported infections. Interviews were conducted and clinical and environmental sampling was performed. Swab and scab specimens were analyzed by real-time polymerase chain reaction (PCR), whereas serum specimens were evaluated for parapoxvirus antibodies. Three case patients were found to have fed ill juvenile animals without using gloves. Forty-six percent of veterinarians reported having been consulted regarding suspected human orf infections. Orf virus DNA was detected from five of 25 asymptomatic sheep. Analysis of extracellular envelope gene sequences indicated that sheep and goat isolates clustered in a species preferential fashion. Parapoxvirus infections are common in Missouri ruminants and their handlers. Infected persons often do not seek medical care; some may seek advice from veterinarians rather than physicians. The initial perception of increased incidence in Missouri may have arisen from a reporting artifact stemming from heightened concern about anthrax. Asymptomatic parapoxvirus infections in livestock may be common and further investigation warranted. PMID- 26487316 TI - Unusual Childhood Waking as a Possible Precursor of the 1995 Kobe Earthquake. AB - Nearly 1,100 young students living in Japan at a range of distances up to 500 km from the 1995 Kobe M7 earthquake were interviewed. A statistically significant abnormal rate of early wakening before the earthquake was found, having exponential decrease with distance and a half value approaching 100 km, but decreasing much slower than from a point source such as an epicentre; instead originating from an extended area of more than 100 km in diameter. Because an improbably high amount of variance is explained, this effect is unlikely to be simply psychological and must reflect another mechanism-perhaps Ultra-Low Frequency (ULF) electromagnetic waves creating anxiety-but probably not (222)Rn excess. Other work reviewed suggests these conclusions may be valid for animals in general, not just children, but would be very difficult to apply for practical earthquake prediction. PMID- 26487317 TI - Animal Experiments in Biomedical Research: A Historical Perspective. AB - The use of non-human animals in biomedical research has given important contributions to the medical progress achieved in our day, but it has also been a cause of heated public, scientific and philosophical discussion for hundreds of years. This review, with a mainly European outlook, addresses the history of animal use in biomedical research, some of its main protagonists and antagonists, and its effect on society from Antiquity to the present day, while providing a historical context with which to understand how we have arrived at the current paradigm regarding the ethical treatment of animals in research. PMID- 26487318 TI - Bio-Mimetics of Disaster Anticipation-Learning Experience and Key-Challenges. AB - Anomalies in animal behavior and meteorological phenomena before major earthquakes have been reported throughout history. Bio-mimetics or bionics aims at learning disaster anticipation from animals. Since modern science is reluctant to address this problem an effort has been made to track down the knowledge available to ancient natural philosophers. Starting with an archaeologically documented human sacrifice around 1700 B.C. during the Minoan civilization immediately before a large earthquake, which killed the participants, earthquake prediction knowledge throughout antiquity is evaluated. Major practical experience with this phenomenon has been gained from a Chinese earthquake prediction initiative nearly half a century ago. Some quakes, like that of Haicheng, were recognized in advance. However, the destructive Tangshan earthquake was not predicted, which was interpreted as an inherent failure of prediction based on animal phenomena. This is contradicted on the basis of reliable Chinese documentation provided by the responsible earthquake study commission. The Tangshan earthquake was preceded by more than 2,000 reported animal anomalies, some of which were of very dramatic nature. They are discussed here. Any physical phenomenon, which may cause animal unrest, must involve energy turnover before the main earthquake event. The final product, however, of any energy turnover is heat. Satellite based infrared measurements have indeed identified significant thermal anomalies before major earthquakes. One of these cases, occurring during the 2001 Bhuj earthquake in Gujarat, India, is analyzed together with parallel animal anomalies observed in the Gir national park. It is suggested that the time window is identical and that both phenomena have the same geophysical origin. It therefore remains to be demonstrated that energy can be released locally before major earthquake events. It is shown that by considering appropriate geophysical feedback processes, this is possible for large scale energy conversion phenomena within highly non-linear geophysical mechanisms. With satellite monitored infrared anomalies indicating possible epicenters and local animal and environmental observations immediately initiated, the learning experience towards an understanding of the phenomena involved could be accelerated. PMID- 26487315 TI - Ethnopharmacological Survey of Plants Used in the Traditional Treatment of Gastrointestinal Pain, Inflammation and Diarrhea in Africa: Future Perspectives for Integration into Modern Medicine. AB - There is a growing need to find the most appropriate and effective treatment options for a variety of painful syndromes, including conditions affecting the gastrointestinal tract, for treating both veterinary and human patients. The most successful regimen may come through integrated therapies including combining current and novel western drugs with acupuncture and botanical therapies or their derivatives. There is an extensive history and use of plants in African traditional medicine. In this review, we have highlighted botanical remedies used for treatment of pain, diarrheas and inflammation in traditional veterinary and human health care in Africa. These preparations are promising sources of new compounds comprised of flavonoids, bioflavanones, xanthones, terpenoids, sterols and glycosides as well as compound formulas and supplements for future use in multimodal treatment approaches to chronic pain, gastrointestinal disorders and inflammation. The advancement of plant therapies and their derivative compounds will require the identification and validation of compounds having specific anti nociceptive neuromodulatory and/or anti-inflammatory effects. In particular, there is need for the identification of the presence of compounds that affect purinergic, GABA, glutamate, TRP, opioid and cannabinoid receptors, serotonergic and chloride channel systems through bioactivity-guided, high-throughput screening and biotesting. This will create new frontiers for obtaining novel compounds and herbal supplements to relieve pain and gastrointestinal disorders, and suppress inflammation. PMID- 26487319 TI - Significant laryngeal destruction in a northern European cohort of Behcet's disease patients. AB - OBJECTIVES: Behcet's disease (BD) is a multisystem autoimmune disease of unknown origin typically affecting the triad of oral and genital mucosa and the eye. Limited data are available in the literature regarding the otolaryngology-related manifestations of BD, particularly in northern Europeans. This is a novel study detailing surprising and significant laryngeal structural changes in a northern European cohort of BD. METHODS: Patients meeting the International Study Group for Behcet's Disease (ISGBD) and the International Criteria for Behcet's Disease (ICBD) criteria for diagnosis were identified from an institutional database. Patients underwent examination with an otolaryngologist, including flexible laryngoscopy. Intra-oral, pharyngeal and laryngeal manifestations of BD were documented and characterised. Patients underwent hearing assessment with pure tone audiometry. RESULTS: Fifteen patients with BD were identified (4 male, 11 female; median age 36 years). 60% (n=9) showed evidence of disease on examination and flexible laryngoscopy. 33% (n=5) showed laryngeal changes related to BD. 13% (n=2) demonstrated bilateral sensorineural hearing loss. The 5 cases demonstrating laryngeal manifestations of disease are described in detail with photographic records. CONCLUSIONS: Limited data has been published regarding the laryngeal manifestations of BD, particularly in a northern European population. Our cohort of BD patients demonstrate significant laryngeal structural changes. It would appear that these clinically relevant changes may be more common than was previously thought. Raised awareness of the risk of laryngeal pathology in BD patients, often in the absence of overt clinical symptomatology, may result in earlier diagnosis and treatment. Rheumatologists and otolaryngologists should consider closer multi-disciplinary co-operation in the management and follow up of patients with BD. PMID- 26487320 TI - Burn depth assessments by photoacoustic imaging and laser Doppler imaging. AB - Diagnosis of burn depths is crucial to determine the treatment plan for severe burn patients. However, an objective method for burn depth assessment has yet to be established, although a commercial laser Doppler imaging (LDI) system is used limitedly. We previously proposed burn depth assessment based on photoacoustic imaging (PAI), in which thermoelastic waves originating from blood under the burned tissue are detected, and we showed the validity of the method by experiments using rat models with three different burn depths: superficial dermal burn, deep dermal burn and deep burn. On the basis of those results, we recently developed a real-time PAI system for clinical burn diagnosis. Before starting a clinical trial, however, there is a need to reveal more detailed diagnostic characteristics, such as linearity and error, of the PAI system as well as to compare its characteristics with those of an LDI system. In this study, we prepared rat models with burns induced at six different temperatures from 70 to 98 degrees C, which showed a linear dependence of injury depth on the temperature. Using these models, we examined correlations of signals obtained by PAI and LDI with histologically determined injury depths and burn induction temperatures at 48 hours postburn. We found that the burn depths indicated by PAI were highly correlative with histologically determined injury depths (depths of viable vessels) as well as with burn induction temperatures. Perfusion values measured by LDI were less correlative with these parameters, especially for burns induced at higher temperatures, being attributable to the limited detectable depth for light involving a Doppler shift in tissue. In addition, the measurement errors in PAI were smaller than those in LDI. On the basis of these results, we will be able to start clinical studies using the present PAI system. PMID- 26487321 TI - Using Bayesian Imputation to Assess Racial and Ethnic Disparities in Pediatric Performance Measures. AB - OBJECTIVE: To analyze health care disparities in pediatric quality of care measures and determine the impact of data imputation. DATA SOURCES: Five HEDIS measures are calculated based on 2012 administrative data for 145,652 children in two public insurance programs in Florida. METHODS: The Bayesian Improved Surname and Geocoding (BISG) imputation method is used to impute missing race and ethnicity data for 42 percent of the sample (61,954 children). Models are estimated with and without the imputed race and ethnicity data. PRINCIPAL FINDINGS: Dropping individuals with missing race and ethnicity data biases quality of care measures for minorities downward relative to nonminority children for several measures. CONCLUSIONS: These results provide further support for the importance of appropriately accounting for missing race and ethnicity data through imputation methods. PMID- 26487322 TI - Investigating hyperkalaemia in adults. PMID- 26487323 TI - From Oedipus to PACE, using the concepts of shame and guilt as golden thread. AB - OBJECTIVES: To demonstrate that antiquity's concepts of shame and guilt developed in their meaning over the centuries and can still have practical applicability in psychological therapies these days. METHODS: To review shame and guilt in philosophy, history, ethics and psychiatry contexts. Within limitations, a narrative is presented, starting with Oedipus in antiquity, visiting several important philosophical theories and ending in the present time with, for example, Dan Hughes' PACE model for therapy. RESULTS: The first part expands on selected ideas presented in Melvyn Bragg's 2007 BBC radio programme entitled 'Guilt'; the second part adds selected therapeutic models where concepts of shame and guilt play a role. CONCLUSIONS: Shame and guilt are archaic but quintessential concepts that already occupied thinkers in antiquity. Shame and guilt are concepts that preoccupied science and art over the millennia and continue as useful concepts to the present day. Moreover, shame and guilt, as concepts, continue to play a salient role in recent and contemporary psychiatry. PMID- 26487324 TI - #IHMayDay: tweeting for empowerment and social and emotional wellbeing. AB - OBJECTIVE: This paper examines the themes of #IHMayDay, a day-long Twitter discussion about Indigenous health led by Aboriginal and Torres Strait Islander peoples on 1 May 2014. METHOD: The Symplur analytics tool was used to identify the Twitter activity associated with #IHMayDay. This paper reviews the content of 423 tweets that were tweeted and retweeted by 346 individuals and 108 organisations. RESULTS: Issues related to social and emotional wellbeing were dominant, and the analysis highlights the empowering nature of the strengths based discourse. CONCLUSIONS: Twitter-based events such as #IHMayDay and initiatives such as the rotated, curated account @IndigenousX are powerful platforms for learning, exchange, advocacy and dialogue about the social and emotional wellbeing and mental health of Aboriginal and Torres Strait Islander peoples. PMID- 26487325 TI - Acute ischemic stroke and abnormal blood hemoglobin concentration. AB - OBJECTIVES: This study examines whether low or high blood hemoglobin concentration (HGB) is associated with stroke severity, worse clinical outcomes, and poorer prognosis after acute ischemic stroke (AIS). METHODS: This retrospective cohort study included data from the Ontario Stroke Registry on consecutive patients with AIS who were admitted between July 2003 and March 2008. We excluded patients taking anticonvulsants or iron supplement; patients with cancer, renal failure, history of gastro-intestinal or genitourinary bleeding, and pregnancy. Patients were divided into groups as follows: low HGB, normal HGB, and high HGB. Outcome measures included the frequency of greater degree of disability at discharge (modified Rankin score: 3-6), 7-day, 30-day and 90-day mortality, and length of stay in the acute stroke care hospital. RESULTS: Hemoglobin levels higher than the upper limit of normal are associated with a greater disability at discharge (OR = 1.49, 95% CI: 1.03-2.15, P = 0.0331), and higher 30-day mortality (HR = 1.98, 95% CI: 1.44-2.74, P < 0.0001) after adjustment for major potential confounders. The Kaplan-Meier curves indicate that abnormal HGB levels are associated with higher mortality after AIS (P < 0.0001). HGB levels below the lower limit of normal are associated with longer lengths of stay in the acute care hospital (OR = 1.11, 95% CI: 1.02-1.22, P = 0.017). Elevated HGB was associated with greater neurological deficit on admission (OR = 1.45, 95% CI: 1.06-1.95, P = 0.0195). CONCLUSIONS: Our results suggest that an elevated HGB on the initial admission is associated with more severe strokes, greater disability at discharge, and higher 30-day mortality after AIS. A low HGB on admission is associated with longer stay in the acute care hospital. PMID- 26487326 TI - Ciliary neurotrophic factor has intrinsic and extrinsic roles in regulating B cell differentiation and bone structure. AB - The gp130 receptor and its binding partners play a central role in cytokine signalling. Ciliary neurotrophic factor (CNTF) is one of the cytokines that signals through the gp130 receptor complex. CNTF has previously been shown to be a negative regulator of trabecular bone remodelling and important for motor neuron development. Since haematopoietic cell maintenance and differentiation is dependent on the bone marrow (BM) microenvironment, where cells of the osteoblastic lineage are important regulators, we hypothesised that CNTF may also have important roles in regulating haematopoiesis. Analysis of haematopoietic parameters in male and female Cntf(-/-) mice at 12 and 24 weeks of age revealed altered B lymphopoiesis. Strikingly, the B lymphocyte phenotype differed based on sex, age and also the BM microenvironment in which the B cells develop. When BM cells from wildtype mice were transplanted into Cntf(-/-) mice, there were minimal effects on B lymphopoiesis or bone parameters. However, when Cntf(-/-) BM cells were transplanted into a wildtype BM microenvironment, there were changes in both haematopoiesis and bone parameters. Our data reveal that haematopoietic cell-derived CNTF has roles in regulating BM B cell lymphopoiesis and both trabecular and cortical bone, the latter in a sex-dependent manner. PMID- 26487327 TI - Virtual Nursing Intervention Adjunctive to Conventional Care: The Experience of Persons Living With HIV. AB - BACKGROUND: Persons living with HIV (PLHIV) must adhere optimally to antiretroviral therapy (ART) on a daily basis and for their lifetime to maintain an undetectable viral load, allowing them to preserve their health. Taking advantage of the opportunity that information and communication technologies provide to broaden intervention modalities and intensify clinical follow-up, a virtual nursing intervention consisting of four interactive computer sessions was developed to empower PLHIV to manage their ART and symptoms optimally. Compared with other types of information and communication technologies-assisted interventions such as text messages, HIV Treatment, Virtual Nursing Assistance and Education (VIH-TAVIE) requires a certain degree of active engagement on the part of the user to develop and strengthen the self-management skills to optimize adherence. After the intervention's impact on ART adherence was measured quantitatively, a qualitative study was undertaken to describe how users experience the intervention. Understanding how PLHIV perceive being assisted asynchronously by a virtual nurse was of particular interest. OBJECTIVE: The objective of the study was to explore and describe how PLHIV experience VIH TAVIE, that is, receiving customized asynchronous accompaniment via a virtual nurse. METHODS: A qualitative study was conducted with 26 PLHIV (20 men, 6 women) who received all four VIH-TAVIE sessions. Participants had been diagnosed with HIV 14 years earlier on average and had been on ART for a mean period of 10 years. The sessions lasted 20-30 minutes each and were received two weeks apart. They are hosted by a virtual nurse who engages the user in a self-management skills-learning process for the purpose of treatment adherence. Semistructured interviews were conducted lasting 30-40 minutes to get participants to share their experience of the intervention through personal stories and what they thought and felt during their participation. Data were analyzed using Miles and Huberman's method, by performing these three steps: (1) data reduction (data coding, summaries); (2) data display (in tables and text form); and (3) recontextualization of results. RESULTS: Content analysis yielded five themes regarding how PLHIV experience VIH-TAVIE: (1) exposure to the virtual nursing intervention; (2) virtual nurse humanizes experience of the computer-delivered intervention; (3) learner's experience of the virtual nursing intervention; (4) perceived benefits following participation in the virtual nursing intervention; and (5) relevance of the virtual nursing intervention in relation to the medication management trajectory. CONCLUSIONS: Analyzing the participants' experience revealed they found the intervention's content and format appropriate. To them, the virtual nurse humanized the experience and helped them acquire new skills for achieving optimal ART adherence. Results seem to underscore the importance of offering the intervention to persons who have more problems with drug intake or who are just beginning ART. PMID- 26487328 TI - Roles of inter-SWCNT junctions in resistive humidity response. AB - As a promising chemiresistor for gas sensing, the single-walled carbon nanotube (SWCNT) network has not yet been fully utilized for humidity detection. In this work, it is found that as humidity increases from 10% to 85%, the resistance of as-grown SWCNT networks first decreases and then increases. This non-monotonic resistive response to humidity limits their sensing capabilities. The competition between SWCNT resistance and inter-tube junction resistance changes is then found to be responsible for the non-monotonic resistive humidity responses. Moreover, creating sp(3) scattering centers on the SWCNT sidewall by monovalent functionalization of four-bromobenzene diazonium tetrafluoroborate is shown to be capable of eliminating the influence from the inter-tube junctions, resulting in a continuous resistance drop as humidity increases from 10% to 85%. Our results revealed the competing resistive humidity sensing process in as-grown SWCNT networks, which could also be helpful in designing and optimizing as-grown SWCNT networks for humidity sensors and other gas sensors. PMID- 26487329 TI - Biological Substrate of the Rapid Volumetric Changes Observed in the Human Liver During the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy Approach. AB - BACKGROUND: The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) strategy induces rapid future liver remnant (FLR) hypertrophy. Hepatocyte cellular and molecular changes associated with liver hypertrophy during ALPPS remain ill-defined in humans. METHODS: Patients undergoing the ALPPS approach between June 2011 and October 2014 were extracted. Biopsies from the FLR were obtained during the first and second stages. Hematoxylin-eosin staining and immunohistochemical analysis for expression of the proliferating cell nuclear antigen (PCNA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were performed. The proliferative index was defined as: PCNA-TUNEL ratio. RESULTS: Eleven of 34 patients treated were studied during both stages. Median FLR hypertrophy was 104 % in 6 days, with a mean difference between preoperative and postoperative volume of 361 ml (P < 0.001). The mean hepatocyte number increased from 52.7 cells/mm(2) in the first stage to 89.6 cells/mm(2) in the second stage (P = 0.001). PCNA expression increased by 190 % between stages with a linear correlation (r = 0.58) with macroscopic hypertrophy. The proliferative index increased from -3.78 cells/mm(2) in first stage to 2.32 cells/mm(2) in the second stage (P = 0.034). CONCLUSIONS: The results of the present study indicate that the rapid FLR volumetric increase observed in ALPPS is accompanied by histological and molecular features of hepatocyte cell proliferation. PMID- 26487330 TI - Thirty-Day Readmission After Laparoscopic Sleeve Gastrectomy-a Predictable Event? AB - BACKGROUND: Thirty-day readmission post-bariatric surgery is used as a metric for surgical quality and patient care. We sought to examine factors driving 30-day readmissions after laparoscopic sleeve gastrectomy (LSG). METHODS: We reviewed 1257 LSG performed between March 2012 and June 2014. Readmitted and nonreadmitted patients were compared in their demographics, medical histories, and index hospitalizations. Multivariable regression was used to identify risk factors for readmission. RESULTS: Forty-five (3.6 %) patients required 30-day readmissions. Forty-seven percent were readmitted with malaise (emesis, dehydration, abdominal pain) and 42 % with technical complications (leak, bleed, mesenteric vein thrombosis). Factors independently associated with 30-day readmission include index admission length of stay (LOS) >=3 days (OR 2.54, CI = [1.19, 5.40]), intraoperative drain placement (OR 3.11, CI = [1.58, 6.13]), postoperative complications (OR 8.21, CI = [2.33, 28.97]), and pain at discharge (OR 8.49, CI = [2.37, 30.44]). Patients requiring 30-day readmissions were 72 times more likely to have additional readmissions by 6 months (OR 72.4, CI = [15.8, 330.5]). CONCLUSIONS: The 30-day readmission rate after LSG is 3.6 %, with near equal contributions from malaise and technical complications. LOS, postoperative complications, drain placement, and pain score can aid in identifying patients at increased risk for 30-day readmissions. Patients should be educated on postoperative hydration and pain management, so readmissions can be limited to technical complications requiring acute inpatient management. PMID- 26487331 TI - Extracorporeal Hypothermic Perfusion Device for Intestinal Graft Preservation to Decrease Ischemic Injury During Transportation. AB - INTRODUCTION: The small intestine is one of the most ischemia-sensitive organs used in transplantation. To better preserve the intestinal graft viability and decrease ischemia-reperfusion injury, a device for extracorporeal perfusion was developed. We present the results for the first series of perfused human intestine with an intestinal perfusion unit (IPU). METHODS: Five human intestines were procured for the protocol. (1) An experimental segment was perfused by the IPU delivering cold preservation solution to the vascular and luminal side continually at 4 oC for 8 h. (2) Control (jejunum and ileum) segments were preserved in static cold preservation. Tissue samples were obtained for histopathologic grading according to the Park/Chiu scoring system (0 = normal, 8 = transmural infarction). RESULTS: Jejunal experimental segments scored 2.2 with the Park/Chiu system compared to the control segments, which averaged 3.2. Overall scoring for ileum experimental and control segments was equal with 1.6. CONCLUSION: This data presents proof of concept that extracorporeal intestinal perfusion is feasible. The evidence shows that the IPU can preserve the viability of human intestine, and histopathologic evaluation of perfused intestine is favorable. Our early results can eventually lead to expanding the possibilities of intestinal preservation. PMID- 26487332 TI - Total Pancreatectomy with Celiac Axis Resection and Hepatic Artery Restoration Using Splenic Artery Autograft Interposition. AB - Although the indication of locally advanced pancreatic cancer with arterial involvement is controversial, the outcome of the patients with such disease treated by combined resection and reconstruction of the invaded artery has improved recently. For pancreatic body carcinoma invading the celiac axis, distal pancreatectomy with celiac axis resection has been safely performed. However, in case of pancreatic body carcinoma with involvement of the celiac axis, the common hepatic artery and the gastroduodenal artery, margin-negative resection requires total pancreatectomy with celiac axis resection and restoration of hepatic arterial flow. Here, we describe an interposition grafting technique using the splenic artery harvested from the resected specimen. This technique is effective and may widen the resectability of pancreatic cancer in selected patients. PMID- 26487333 TI - Surgeon Volume Correlates with Reduced Mortality and Improved Quality in the Surgical Management of Diverticulitis. AB - BACKGROUND: Volume has been shown to be an important determinant of quality and cost outcomes. METHODS: We performed a retrospective study of patients who underwent surgery for diverticulitis using the University HealthSystem Consortium database from 2008-2012. Outcomes evaluated included minimally invasive approach, stoma creation, intensive-care admission, post-operative complications, length of stay, and total direct hospital costs by surgeon volume. Surgeon volume was categorized into four categories by mean annual volumes: very-high (VHVS) (>31), high (HVS) (13-31), medium (MVS) (6-12), and low (LVS) (<=5). RESULTS: A total of 19,212 patients with a mean age of 59 years, 54 % female makeup, and 55 % rate of private insurance were included. Similar to the unadjusted analysis, multivariable analysis revealed decreasing odds of stoma creation, complications, ICU admission, reoperation, readmission, and inpatient mortality with increasing surgeon volume. Additionally, compared with LVS, a higher surgeon volume was associated with higher rates of the minimally invasive approach. Median length of stay and costs were also notably lower with increasing surgeon volume. CONCLUSION: Quality and the use of minimally invasive technique are tightly associated with surgeon volume. Further studies are necessary to validate the direct association of volume with outcomes in surgery for diverticulitis. PMID- 26487334 TI - Patients with Adenocarcinoma of the Small Intestine with 9 or More Regional Lymph Nodes Retrieved Have a Higher Rate of Positive Lymph Nodes and Improved Survival. AB - PURPOSE: To assess the influence of regional lymph node (RLN) retrieval on stage migration of adenocarcinoma of the small intestine and survival. PATIENTS AND METHODS: From the Surveillance, Epidemiology, and End Results database,1090 patients with nonmetastatic small bowel adenocarcinoma were identified in between 2004 and 2011. The impact of the number of RLNs removed on histopathological staging and oncological outcome was assessed utilizing Cox proportional hazard regression models with and without risk-adjustment, propensity score methods, and joinpoint regression analysis. RESULTS: The rate of node-positive cancer increased steadily with the number of retrieved RLNs up to 9 RLNs, which suggests that a minimum of 9 (95 % CI 5.5-10.5) retrieved RLNs are needed for the detection of node-positive disease (P < 0.001). From 657 of 1090 patients (60.3 %), 9 or more RLNs were retrieved. While in 2004 only in 46.0 % of all cases 9+ RLNs were retrieved, this rate increased to 69.3 % in 2011 (P < 0.001). The multivariable analysis demonstrated that the retrieval of 9+ RLNs was associated with better overall (hazard ratio of death [HR] = 0.67, 95 % CI 0.55-0.82, P < 0.001) and cancer-specific survival (HR = 0.77, 95 % CI 0.61-0.96, P = 0.022). This finding was confirmed by a propensity score-adjusted analysis, which indicated increased overall (HR = 0.67, 95 % CI 0.50-0.89, P < 0.001) and cancer specific survival (HR = 0.67, 95 % CI 0.49-0.92, P = 0.013) in patients with the retrieval of 9+ RLNs. CONCLUSION: To our knowledge, this is the first population based propensity score-adjusted investigation in small bowel adenocarcinoma. A sufficient number of RLNs should be retrieved to achieve an optimal oncological outcome PMID- 26487335 TI - Tolerating Uncertainty: Perceptions of the Future for Ageing Parent Carers and Their Adult Children with Intellectual Disabilities. AB - BACKGROUND: Improved life expectancy means that more adults with intellectual disabilities are now living with ageing parents. This study explored older families' perceptions of the future. METHODS: Semi-structured interviews were conducted with nine older parents and three adults with intellectual disabilities and analysed to produce an explanatory thematic framework. RESULTS: 'Tolerating uncertainty' was the major theme in participants' attempts to manage anxieties about the future, encompassing sub-themes of 'accepting the parenting role', 'facing challenges', 'being supported/isolated', 'positive meaning making', 're evaluating as time moves on' and 'managing future thinking'. Some participants expressed preferences for their future which were in contrast to their parents' views, and provide a unique perspective that has often been neglected in prior research. CONCLUSIONS: This research has found commonalities in how families tolerate the uncertainty of the future, but also unique differences that require tailored interventions and prospective action by services. PMID- 26487336 TI - Do ICP-MS based methods fulfill the EU monitoring requirements for the determination of elements in our environment? AB - Undoubtedly, the most important advance in the environmental regulatory monitoring of elements of the last decade is the widespread introduction of ICP mass spectrometry (ICP-MS) due to standards developed by the European Committee for Standardization. The versatility of ICP-MS units as a tool for the determination of major, minor and trace elements (Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Mo, Na, Ni, P, Pb, Sb, Se, Sn, Ti, V and Zn) in surface water, groundwater, river sediment, topsoil, subsoil, fine particulates and atmospheric deposition is illustrated in this paper. Ranges of background concentrations for major, minor and trace elements obtained from a regional case study (Flanders, Belgium) are summarized for all of these environmental compartments and discussed in the context of a harmonized implementation of European regulatory monitoring requirements. The results were derived from monitoring programs in support of EU environmental quality directives and were based on a selection of (non-polluted) background locations. Because of the availability of ICP-MS instruments nowadays, it can be argued that the main hindrance for meeting the European environmental monitoring requirements is no longer the technical feasibility of analysis at these concentration levels, but rather (i) potential contamination during sampling and analysis, (ii) too limited implementation of quality control programs, validating the routinely applied methods (including sampling and low level verification) and (iii) lack of harmonization in reporting of the chemical environmental status between the individual member states. PMID- 26487337 TI - Toxicopathological Effects of the Sunscreen UV Filter, Oxybenzone (Benzophenone 3), on Coral Planulae and Cultured Primary Cells and Its Environmental Contamination in Hawaii and the U.S. Virgin Islands. AB - Toxicity persistence to the nontarget amphipod Hyalella curvispina in runoff events following chlorpyrifos applications to soy experimental plots was compared in conventional and no-till management. Two application scenarios were compared: an early-season application with the soil almost bare and a late-season application after the foliage had attained complete soil cover. H. curvispina was exposed to chlorpyrifos using two different test systems: a short-term (48 h) runoff water exposure and a long-term (10 days) soil exposure. Both commonly used crop management practices for soybean production resulted in runoff toxicity following pesticide applications and represent a toxicity risk for adjacent inland waters. Toxicity persistence was longer after the earlier than the late season application, likely because of higher volatilization and photodecomposition losses from the soy canopy than from the soil. For the early season application, toxicity persisted longer in the no-till plots than in the conventional tillage plots. Suspended matter was higher in the conventional treatment. Chlorpyrifos sorption to suspended matter likely contributed to the shorter persistence. For the late-season application, toxicity persisted longer in the conventional treatment. The causes remain conjectural. The soil organic carbon content was higher in the no-till treatment. Sorption to organic matter might have contributed to the shorter chlorpyrifos toxicity persistence in no till management. Late applications are more frequent and prevail longer throughout the soy growing season. Overall, the no-till management practice seems preferably because shorter toxicity persistence in runoff represents a lower environmental risk for the adjacent inland waters. PMID- 26487338 TI - Acute Atrazine Exposure has Lasting Effects on Chemosensory Responses to Food Odors in Crayfish (Orconectes virilis). AB - The herbicide atrazine is known to impact negatively olfactory-mediated behaviors in aquatic animals. We have shown that atrazine exposure has deleterious effects on olfactory-mediated behavioral responses to food odors in crayfish; however, recovery of chemosensory abilities post-atrazine exposure has not been investigated. We examined whether crayfish (Orconectes virilis) recovered chemosensory abilities after a 96-h exposure to sublethal, environmentally relevant concentrations of 80 ppb (ug/L) atrazine. Following treatment, we analyzed the ability of the crayfish to locate a food source using a Y-maze with one arm containing fish-flavored gelatin and the other containing unflavored gelatin. We compared the time spent in the food arm of the Y-maze, near the food source, as well as moving and walking speed of control and atrazine-treated crayfish. We also compared the number of crayfish that handled the food source and the amount of food consumed. Following 24-, 48-, and 72-h recovery periods in fresh water, behavioral trials were repeated to determine if there was any observable recovery of chemosensory-mediated behaviors. Atrazine-treated crayfish spent less time in the food arm, at the odor source, and were less successful at finding the food odor source than control crayfish for all times tested. Additionally, atrazine-treated crayfish consumed less fish-flavored than control crayfish; however, treatment did not affect locomotion. Overall, we found that crayfish are not able to recover chemosensory abilities 72 h post-atrazine exposure. Because crayfish rely heavily on their chemosensory abilities to acquire food, the negative impacts of atrazine exposure could affect population size in areas where atrazine is heavily applied. PMID- 26487339 TI - Incidence and Characteristics of Late Catch-Up Phenomenon Between Sirolimus Eluting Stent and Everolimus-Eluting Stent: A Propensity Matched Study. AB - OBJECTIVES: We evaluated and compared the incidence and characteristics of late catch-up phenomenon (LCU) between everolimus-eluting stent (EES) and sirolimus eluting stent (SES) implantations. BACKGROUND: Late catch-up phenomenon after everolimus-eluting stent (EES) implantation has not yet been evaluated sufficiently. METHODS: Between April 2007 and May 2011, 1,234 patients with coronary artery disease were treated with SES and 502 patients with EES. Following propensity score matching, we evaluated 495 SES-treated patients and 495 ESS-treated patients. The incidences of LCU (i.e., late target lesion revascularization [TLR] [1-3 years]) were compared. RESULTS: The cumulative incidence of TLR at 3 years was 11.9% in the SES group and 6.1% in the EES group (P = 0.001). The incidence of late TLR was 7.5% in the SES group and 3.4% in the EES group (P = 0.004). Even though not statistically significant, intravascular ultrasound showed a higher tendency of stent fracture (SF) in late restenosis lesions in the SES group than in the EES group (37.0% vs 7.7%; P = 0.052). Moreover, the SF rate tended to increase in late restenosis compared with early restenosis (within 1 year) in the SES group compared with the EES group (SES: 37.0% vs 22.2%; P = 0.293, EES: 7.7% vs 10.0%; P = 0.846), although the increase was not significantly different. CONCLUSIONS: EES was superior to SES in terms of LCU. SF may be associated with LCU after SES implantation. PMID- 26487340 TI - Does the Presence of a Major Psychiatric Disorder Affect Tolerance and Outcomes in Men With Prostate Cancer Receiving Radiation Therapy? AB - Prior studies have suggested that men with prostate cancer and psychiatric disorders (+Psy) have worse outcomes compared with those without (-Psy), particularly due to delayed diagnosis or reduced access to definitive treatment. In the current study, the toxicity and outcomes of men who were primarily diagnosed through prostate-specific antigen screening and who underwent definitive treatment with external beam radiation was investigated. The charts of 469 men diagnosed with prostate cancer from 2003 to 2010 were reviewed. The presence of +Psy was based on a Diagnostic and Statistical Manual of Mental Disorders-Fourth edition diagnosis of posttraumatic stress disorder, depression, schizophrenia, bipolar disorder, and/or generalized anxiety disorder. Kaplan Meier analysis was used to analyze biochemical control, distant control, prostate cancer-specific survival, and overall survival. One hundred patients (21.3%) were identified as +Psy. At a median follow-up of 73 months, there were no differences regarding 6-year biochemical control (79.8% -Psy vs. 80.4% +Psy, p = .50) or 6 year distant metastatic-free survival (96.4% -Psy vs. 98.0% +Psy, p = .36). There were also no differences regarding the 6-year prostate cancer-specific survival (98.4% -Psy vs. 99.0% +Psy, p = .45) or 6-year overall survival (80.2% -Psy vs. 82.2% +Psy, p = .35). Short- and long-term genitourinary and gastrointestinal toxicities were similar between the groups. On multivariate analyses with propensity score adjustment, +Psy was not a significant predictor for toxicity, biochemical recurrence, or survival. The presence of +Psy was not associated with higher toxicity or worse clinical outcomes, suggesting that effective removal of screening and treatment barriers may reduce the survival disparities of these patients. PMID- 26487341 TI - Murnane, Coley, and Baeten respond to "every good randomization deserves observation". PMID- 26487342 TI - Invited commentary: every good randomization deserves observation. AB - Preexposure prophylaxis (PrEP) is a promising approach to prevention of human immunodeficiency virus (HIV) transmission, in which an HIV-negative individual takes a single daily dose of an antiretroviral drug so that, if exposed to HIV, an active antiretroviral drug is already present in his or her system. In this issue of the Journal, Murnane et al. (Am J Epidemiol. 2015;182(10):848-856) use data from the Partners PrEP Study (Kenya and Uganda, 2008-2011) to estimate the efficacy of PrEP under perfect adherence. We discuss Murnane et al.'s work and then examine the larger issues of generalizability or transportability of findings from a randomized trial to a new setting when adherence to an intervention determines its effectiveness. We discuss sufficient conditions for generalizability and use causal directed acyclic graphs to show how these assumptions might play out when trials are used to make inferences about the effect of PrEP in current and future real-world target populations. PMID- 26487343 TI - Estimating efficacy in a randomized trial with product nonadherence: application of multiple methods to a trial of preexposure prophylaxis for HIV prevention. AB - Antiretroviral preexposure prophylaxis (PrEP) for persons at high risk of human immunodeficiency virus infection is a promising new prevention strategy. Six randomized trials of oral PrEP were recently conducted and demonstrated efficacy estimates ranging from 75% to no effect, with nonadherence likely resulting in attenuated estimates of the protective effect of PrEP. In 1 of these trials, the Partners PrEP Study (Kenya and Uganda, 2008-2011), participants (4,747 serodiscordant heterosexual couples) were randomized to receipt of tenofovir (TDF), coformulated TDF/emtricitabine (FTC), or placebo. Intention-to-treat analyses found efficacy estimates of 67% for TDF and 75% for TDF/FTC. We applied multiple methods to data from that trial to estimate the efficacy of PrEP with high adherence, including principal stratification and inverse-probability-of censoring (IPC) weights. Results were further from the null when correcting for nonadherence: 1) among the strata with an estimated 100% probability of high adherence (TDF hazard ratio (HR) = 0.19, 95% confidence interval (CI): 0.07, 0.56; TDF/FTC HR = 0.12, 95% CI: 0.03, 0.52); 2) with IPC weights used to approximate a continuously adherent population (TDF HR = 0.18, 95% CI: 0.06, 0.53; TDF/FTC HR = 0.15, 95% CI: 0.04, 0.52); and 3) in per-protocol analysis (TDF HR = 0.18, 95% CI: 0.06, 0.53; TDF/FTC HR = 0.16, 95% CI: 0.05, 0.53). Our results suggest that the efficacy of PrEP with high adherence is over 80%. PMID- 26487344 TI - The Public Stigma of Problem Gambling: Its Nature and Relative Intensity Compared to Other Health Conditions. AB - Problem gambling attracts considerable public stigma, with deleterious effects on mental health and use of healthcare services amongst those affected. However, no research has examined the extent of stigma towards problem gambling within the general population. This study aimed to examine the stigma-related dimensions of problem gambling as perceived by the general public compared to other health conditions, and determine whether the publicly perceived dimensions of problem gambling predict its stigmatisation. A sample of 2000 Australian adults was surveyed, weighted to be representative of the state population by gender, age and location. Based on vignettes, the online survey measured perceived origin, peril, concealability, course and disruptiveness of problem gambling and four other health conditions, and desired social distance from each. Problem gambling was perceived as caused mainly by stressful life circumstances, and highly disruptive, recoverable and noticeable, but not particularly perilous. Respondents stigmatised problem gambling more than sub-clinical distress and recreational gambling, but less than alcohol use disorder and schizophrenia. Predictors of stronger stigma towards problem gambling were perceptions it is caused by bad character, is perilous, non-recoverable, disruptive and noticeable, but not due to stressful life circumstances, genetic/inherited problem, or chemical imbalance in the brain. This new foundational knowledge can advance understanding and reduction of problem gambling stigma through countering inaccurate perceptions that problem gambling is caused by bad character, that people with gambling problems are likely to be violent to other people, and that people cannot recover from problem gambling. PMID- 26487345 TI - Transcription factor and miRNA co-regulatory network reveals shared and specific regulators in the development of B cell and T cell. AB - The maturation process of lymphocyte was related to many blood diseases, such as lymphoma and lymphoid leukemia. Many TFs and miRNAs were separately studied in the development of B and T cells. In this study, we aim to discover the TF and miRNA co-regulation and identify key regulators in the B and T cells maturation. We obtained the candidate genes, miRNAs and TFs for each stage of their maturation, then constructed the TF-miRNA-gene feed-forward loops (FFLs) for each stage by our previous methods. Statistical test for FFLs indicated their enrichment and significance. TF-miRNA co-regulatory networks for each stage were constructed by combining their FFLs. Hub analysis revealed the key regulators in each stage, for example, MYC, STAT5A, PAX5 and miR-17 ~ 92 in the transition of pro-B cells into pre-B cells. We also identified a few common regulators and modules in two stages of B cell maturation (e.g. miR-146a/NFKB1/BCL11A) and two stages of T cell maturation (e.g. miR-20/CCND2/SORL1), as well as some shared regulators in the early stages of both B and T cell development. Our network will help to increase understanding of mature process of B and T cell, as well as the related blood diseases. PMID- 26487346 TI - Optimal definition of biological tumor volume using positron emission tomography in an animal model. AB - BACKGROUND: The goal of the study is to investigate (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET)'s ability to delineate the viable portion of a tumor in an animal model using cross-sectional histology as the validation standard. METHODS: Syngeneic mammary tumors were grown in female Lewis rats. Macroscopic histological images of the transverse tumor sections were paired with their corresponding FDG micro-PET slices of the same cranial-caudal location to form 51 pairs of co-registered images. A binary classification system based on four FDG-PET tumor contouring methods was applied to each pair of images: threshold based on (1) percentage of maximum tumor voxel counts (Cmax), (2) percentage of tumor peak voxel counts (Cpeak), (3) multiples of liver mean voxel counts (Cliver) derived from PERCIST, and (4) an edge-detection-based automated contouring system. The sensitivity, which represented the percentage of viable tumor areas correctly delineated by the gross tumor area (GTA) generated from a particular tumor contouring method, and the ratio (expressed in percentage) of the overestimated areas of a gross tumor area (GTAOE)/whole tumor areas on the macroscopic histology (WTAH), which represented how much a particular GTA extended into the normal structures surrounding the primary tumor target, were calculated. RESULTS: The receiver operating characteristic curves of all pairs of FDG-PET images have a mean area under the curve value of 0.934 (CI of 0.911-0.954), for representing how well each contouring method accurately delineated the viable tumor area. FDG-PET single value threshold tumor contouring based on 30 and 35 % of tumor Cmax or Cpeak and 6 * Cliver + 2 * SD achieved a sensitivity greater than 90 % with a GTAOE/WTAH ratio less than 10 %. Contouring based on 50 % of Cmax or Cpeak had a much lower sensitivity of 67.2-75.6 % with a GTAOE/WTAH ratio of 1.1-1.7 %. Automated edge detection was not reliable in this system. CONCLUSIONS: Single-value-threshold tumor contouring using (18)F-FDG-PET is able to accurately delineate the viable portion of a tumor. 30 and 35 % of Cmax, 30 and 35 % of Cpeak, and 6 * Cliver + 2 * SD are three appropriate threshold values to delineate viable tumor volume in our animal model. The commonly used threshold value of 50 % of Cmax or Cpeak failed to detect one third of the viable tumor volume in our model. PMID- 26487348 TI - Ferroelectric Single-Crystal Gated Graphene/Hexagonal-BN/Ferroelectric Field Effect Transistor. AB - The effect of a ferroelectric polarization field on the charge transport in a two dimensional (2D) material was examined using a graphene monolayer on a hexagonal boron nitride (hBN) field-effect transistor (FET) fabricated using a ferroelectric single-crystal substrate, (1-x)[Pb(Mg1/3Nb2/3)O3]-x[PbTiO3] (PMN PT). In this configuration, the intrinsic properties of graphene were preserved with the use of an hBN flake, and the influence of the polarization field from PMN-PT could be distinguished. During a wide-range gate-voltage (VG) sweep, a sharp inversion of the spontaneous polarization affected the graphene channel conductance asymmetrically as well as an antihysteretic behavior. Additionally, a transition from antihysteresis to normal ferroelectric hysteresis occurred, depending on the V(G) sweep range relative to the ferroelectric coercive field. We developed a model to interpret the complex coupling among antihysteresis, current saturation, and sudden conductance variation in relation with the ferroelectric switching and the polarization-assisted charge trapping, which can be generalized to explain the combination of 2D structured materials with ferroelectrics. PMID- 26487347 TI - Respiratory plasticity is insufficient to alleviate blood acid-base disturbances after acclimation to ocean acidification in the estuarine red drum, Sciaenops ocellatus. AB - The changes in ocean chemistry stemming from anthropogenic CO2 release--termed ocean acidification (OA)--are predicted to have wide-ranging effects on fish and ultimately threaten global populations. The ability of fish to adapt to environmental change is currently unknown, but phenotypic plasticity has been highlighted as a crucial factor in determining species resilience. Here we show that red drum, a long-lived estuarine-dependent fish species native to the Gulf of Mexico, exhibit respiratory plasticity that increases CO2 excretion capacity when acclimated to OA conditions. Specifically, fish exposed to 14 days of 1000 uatm CO2 had a 32% reduction in branchial diffusion distance and increased expression of two putative CO2 channel proteins--rhag and rhcg1. No changes were observed in the erythrocyte CO2 transport pathways. Surprisingly, no significant changes in blood chemistry were observed between acclimated and acutely challenged animals; however, a non-significant 30 % drop in the magnitude of plasma C(CO2) elevation was observed. Reduced diffusion distance also comes with the cost of increased diffusive water loss, which would require greater osmoregulatory investment by the animal. OA exposure induced increased gill Na(+), K(+) ATPase activity and intestinal nkcc2 expression, supporting both the presumed osmotic stress and increased osmoregulatory investment. However, no differences in standard metabolic rate, maximum metabolic rate or aerobic scope were detected between control and OA acclimated individuals. Similarly, no differences in critical swim speed were detected between groups, suggesting the energetic cost related to respiratory plasticity is negligible against background metabolism. The current study demonstrated that red drum exhibit respiratory plasticity with only mild physiological trade-offs; however, this plasticity is insufficient to fully offset the OA-induced acid-base disturbance and as such is unlikely to impact species resilience. PMID- 26487349 TI - A case of familial Mediterranean fever with triple MEFV gene mutations. PMID- 26487350 TI - Seawater as Alternative to Freshwater in Pretreatment of Date Palm Residues for Bioethanol Production in Coastal and/or Arid Areas. AB - The large water consumption (1.9-5.9 m(3) water per m(3) of biofuel) required by biomass processing plants has become an emerging concern, which is particularly critical in arid/semiarid regions. Seawater, as a widely available water source, could be an interesting option. This work was to study the technical feasibility of using seawater to replace freshwater in the pretreatment of date palm leaflets, a lignocellulosic biomass from arid regions, for bioethanol production. It was shown that leaflets pretreated with seawater exhibited lower cellulose crystallinity than those pretreated with freshwater. Pretreatment with seawater produced comparably digestible and fermentable solids to those obtained with freshwater. Moreover, no significant difference of inhibition to Saccharomyces cerevisiae was observed between liquids from pretreatment with seawater and freshwater. The results showed that seawater could be a promising alternative to freshwater for lignocellulose biorefineries in coastal and/or arid/semiarid areas. PMID- 26487353 TI - Association of thromboxane B2 production to hypoxemic periods during sleep in male stroke patients. AB - To evaluate the possible association between sleep apneas and platelet function, we recorded sleep-related hypoxemic periods and measured platelet thromboxane B2 release in 10 male patients with a previous brain infarction. Four of them revealed an increased morning release of thromboxane B2 compared with the night before, whereas six had an opposite situation. Those with an increased morning release revealed more hypoxemic episodes during the night than the others (median numbers were 58.5 and 2, respectively; p = 0.031), suggesting that sleep apneas may influence platelet function among male stroke victims. This finding might be involved in the suggested role of obstructive sleep apnea syndrome as a risk factor for ischemic stroke as well as the peaking of ischemic strokes in the early morning hours. PMID- 26487352 TI - Spatiotemporal models for predicting high pollen concentration level of Corylus, Alnus, and Betula. AB - Corylus, Alnus, and Betula trees are among the most important sources of allergic pollen in the temperate zone of the Northern Hemisphere and have a large impact on the quality of life and productivity of allergy sufferers. Therefore, it is important to predict high pollen concentrations, both in time and space. The aim of this study was to create and evaluate spatiotemporal models for predicting high Corylus, Alnus, and Betula pollen concentration levels, based on gridded meteorological data. Aerobiological monitoring was carried out in 11 cities in Poland and gathered, depending on the site, between 2 and 16 years of measurements. According to the first allergy symptoms during exposure, a high pollen count level was established for each taxon. An optimizing probability threshold technique was used for mitigation of the problem of imbalance in the pollen concentration levels. For each taxon, the model was built using a random forest method. The study revealed the possibility of moderately reliable prediction of Corylus and highly reliable prediction of Alnus and Betula high pollen concentration levels, using preprocessed gridded meteorological data. Cumulative growing degree days and potential evaporation proved to be two of the most important predictor variables in the models. The final models predicted not only for single locations but also for continuous areas. Furthermore, the proposed modeling framework could be used to predict high pollen concentrations of Corylus, Alnus, Betula, and other taxa, and in other countries. PMID- 26487354 TI - Contribution of remote cortical dysfunction to the pathogenesis of subcortical aphasia: A (99m)Tc-HMPAO SPECT study. AB - Remote cortical effects of deep-seated lesions were studied by (99m)Tc-hexamethyl propylenenamine oxime single-photon emission computed tomography at about 50 days after stroke in a population of 16 right-handed aphasic patients. A left-sided regional cortical hypoperfusion was present in all cases. Significant relations were observed between the severity of verbal expression disorders and the degree of regional cortical flow decrease, suggesting that, from a given level of remote dysfunction, the affected cortical areas no longer would be able to play their functional role in language elaboration. There was no difference between the degree of cortical hypoperfusion, whether the morphological lesion was of thromboembolic or hemorrhagic origin. PMID- 26487355 TI - Racial differences for lacunar infarcts documented by computed tomography: A comparison of black and white patients. AB - Lacunar stroke in 100 black and 30 white patients with lacunar syndrome and computed tomography (CT) positive for lacunar infarct were compared. Of blacks, 88% were hypertensive, 77% had target-organ damage, and 86% were hypertensive for longer than 8 years. Of whites, 60% were hypertensive, 61% had target-organ damage, and 72% were hypertensive for longer than 8 years. Prior clinical stroke occurred in 7% of blacks and 50% of whites. Transient ischemic attacks (TIAs) were found in 33% of blacks and 53% of whites. In blacks, CT showed single lacunes in 57% and multiple lacunes in 43%. In whites, CT showed single lacunes in 64% and multiple lacunes in 36%. Angiography was abnormal in 22% of blacks and 54% of whites. In blacks, lacunar stroke was associated with hypertension in 88%, and lacunar stroke was the initial cerebrovascular manifestation in 80%; CT showed "silent" lacune(s) in 41% of hypertensive blacks. In whites, lacunar stroke was associated with hypertension in 60%, and 6% had "silent" lacunes. Based on CT findings, only hypertensive patients had "silent" lacunes. PMID- 26487356 TI - Lacunar infarction due to carotid stenosis. AB - Previous reports have distinguished lacunar infarctions from larger strokes both on clinical grounds and on the basis of proposed pathophysiology. This report describes a patient with critical carotid stenosis resulting in a clinical syndrome and radiological findings typical of the lacunar syndrome of ataxic hemiparesis. This supports recent suggestions that patients with lacunar strokes should undergo the same evaluation as patients with larger strokes. PMID- 26487357 TI - Ticlopidine versus aspirin for stroke prevention: On-treatment results from the ticlopidine aspirin stroke study. AB - Ticlopidine is the newest antiplatelet agent that has been compared with aspirin for stroke prevention. Results from the intent-to-treat analysis of the Ticlopidine Aspirin Stroke Study, a randomized, triple-blind trial, showed ticlopidine to be more effective than aspirin for the prevention of threatened stroke. We present the on-treatment analysis from this study in 3,034 eligible patients receiving either ticlopidine (500 mg daily) or aspirin (1,300 mg daily). Follow-up was for 2-6 years. During year 1, the high-risk period for stroke in patients with threatened stroke, ticlopidine reduced the risk of stroke over aspirin by 48% (p = 0.0004: the event rates were 3.4 and 6.4, respectively). The overall risk for fatal and nonfatal stroke was 27% (95% confidence intervals were 6.6 and 42.3), less with ticlopidine than with aspirin. Ticlopidine significantly decreased the risk of fatal and nonfatal stroke in both sexes and has a different adverse effect profile than aspirin. More adverse effects, primarily diarrhea and rash, were reported with ticlopidine. PMID- 26487358 TI - Delay between emergency room arrival and stroke consultation. AB - We reviewed retrospectively the charts of all stroke patients admitted through our emergency room (ER) during the first halves of 1986 (Group A) and 1992 (Group B). Specifically, the time elapsed between ER arrival and the request for consultation by neurology or neurosurgery was subjected to comparison by analysis of variance. In Group A, the time elapsed from arrival to consultation request varied between 1 and 100 min (mean, 32.5). In Group B, the same period ranged from 2 to 285 min (mean, 84). The difference in mean elapsed time between the two groups was statistically significant (<0.0001). In Group A, patients with hemorrhagic events had significantly shorter delay between arrival and consultation (p = 0.026). This was not the case in Group B. Stroke type did not influence the time to consultation in Group A (p = 0.18) orGroupB (p = 0.60). The results show that neurologic and neurosurgical consultations of stroke patients in the ER are delayed more now than in the past. This finding may have a significant impact on acute stroke intervention trials and underscores the need for active collaboration between stroke specialists and emergency physicians. PMID- 26487359 TI - A differential effect of aspirin on prevention of stroke in atrial fibrillation. AB - Aspirin reduces the risk of stroke in patients with nonrheumatic atrial fibrillation, but its efficacy may not be uniform in patient subgroups. We sought patient characteristics predictive of aspirin efficacy. Exploratory multivariate analyses of a multicenter, double-blind, randomized clinical trial comparing aspirin (325 mg/ day) to placebo in 1,120 patients for prevention of thromboembolism were performed. Patients <=75 years of age assigned to aspirin had a 62% (95% confidence interval, 27-81%; p = 0.002) reduction in thromboembolism, significantly different from older patients given aspirin (p = 0.03). The rate of thromboembolism in patients <=75 years old treated with aspirin was 2.1% per year (95% confidence interval, 1.2-3.8). Patients with a history of hypertension were at high risk (9.0% per year) of thromboembolism during placebo treatment and had a 57% reduction (p = 0.005) when given aspirin; even so, the remaining absolute risk during aspirin therapy was 3.8% per year. These exploratory analyses suggest that aspirin is more effective in patients <=75 years old than in those >75 years old. Although aspirin is effective in patients with a history of hypertension, aspirin may not lower the absolute risk adequately, particularly in patients >75 years old. These secondary results require confirmation before influencing the antithrombotic prophylaxis of patients with atrial fibrillation in clinical practice. The adequacy of aspirin prophylaxis according to patient age is being assessed in the second phase of the study. PMID- 26487360 TI - Small deep cerebral infarcts: Is there synergism between hypertension and diabetes? AB - Diabetics have a stroke risk similar to that of nondiabetic hypertensives. The prevalence of hypertension is greater in diabetics than in nondiabetics, and hypertension is probably the principal cause of the increased stroke risk in diabetics. Diabetes itself, however, also contributes independently to the risk for stroke. It has recently been suggested that a synergistic interaction between diabetes and hypertension is a major contributor to the risk of stroke in diabetics. In order to look for synergistic interaction between diabetes and hypertension, we compared the frequency of small deep infarcts seen on computed tomography [small deep infarcts (SDIs)] between a group of diabetics and a group of nondiabetics individually matched for age, hypertension, and sex. There were no significant differences between diabetics and nondiabetics in the number or size of SDIs, the ventricular size, or the severity of paraventricular white matter lesions. This study is against the presence of a synergistic effect between diabetes and hypertension on small cerebral arteries and suggests that the majority of the risk for SDIs in diabetics is due to hypertension. PMID- 26487361 TI - Recognizing depression: Preliminary testing of the Whitney Observational Depression Index. AB - The preliminary results of an observational instrument for depression is presented. The Whitney Observational Depression Index (WODI) was developed to capitalize on the observational powers of both formal and informal caregivers who care for vulnerable populations (such as stroke victims), among whom self-report depression measures are unreliable or impossible to use. It is a 59-item checklist with a total score and subscale scores related to verbal-cognitive, affective, and vegetative signs noted on observation. The scale shows good construct, content, face, and criterion validity (convergent and divergent), inter-rater reliability, and within-subject reliability. The WODI shows significant correlations with accepted depression measures (Beck Depression Index, r = 0.19, p = <0.05; Zung Depression Scale, r = 0.23, p= <0.01). Further testing is suggested to allow factor analysis of the items and other statistical testing. There is optimism expressed for the use of this instrument in both research and clinical settings. PMID- 26487362 TI - Natural history of patients with chronic occlusion of the internal carotid artery. AB - Although 3% of the elderly population may have asymptomatic unilateral internal carotid artery occlusion (ICAO), between 10% and 20% of patients with initial stroke in the carotid territory have appropriate ipsilateral extracranial ICAO. In the latter instance, it is often difficult to establish whether ICAO is (a) an acute thrombotic process on an underlying atheromatous stenosis; (b) an acute embolic ICAO (from heart or aorta); or (c) an old ICAO that was previously asymptomatic. Intracranial studies show that the first stroke ipsilateral to ICAO is usually associated with occlusions distal to ICAO, which suggest artery-to artery embolism. On the other hand, the follow-up of stroke patients with ICAO shows that delayed cerebral infarction distal to the established ICAO often involves watershed areas and may correspond to hemodynamic disturbances. Because the international extracranial/intracranial arterial bypass study did not show any surgical benefit, current management is mainly directed to stabilization of associated causes of hemodynamic failure (hypotension, bradycardia, etc.). Attempts to find subgroups that may benefit from bypass surgery are still ongoing. However, the prognosis of these patients is negatively influenced by a particularly high risk of cardiac death. PMID- 26487363 TI - In vivo sub-femtoliter resolution photoacoustic microscopy with higher frame rates. AB - Microscopy based on non-fluorescent absorption dye staining is widely used in various fields of biomedicine for 400 years. Unlike its fluorescent counterpart, non-fluorescent absorption microscopy lacks proper methodologies to realize its in vivo applications with a sub-femtoliter 3D resolution. Regardless of the most advanced high-resolution photoacoustic microscopy, sub-femtoliter spatial resolution is still unattainable, and the imaging speed is relatively slow. In this paper, based on the two-photon photoacoustic mechanism, we demonstrated a in vivo label free laser-scanning photoacoustic imaging modality featuring high frame rates and sub-femtoliter 3D resolution simultaneously, which stands as a perfect solution to 3D high resolution non-fluorescent absorption microscopy. Furthermore, we first demonstrated in vivo label-free two-photon acoustic microscopy on the observation of non-fluorescent melanin distribution within mouse skin. PMID- 26487364 TI - Synergistic Effect of Sorafenib and Radiation on Human Oral Carcinoma in vivo. AB - Oral squamous cell carcinoma often causes bone invasion resulting in poor prognosis and affects the quality of life for patients. Herein, we combined radiation with sorafenib, to evaluate the combination effect on tumor progression and bone erosion in an in situ human OSCC-bearing mouse model. Treatment procedure were arranged as following groups: (a) normal (no tumor); (b) control (with tumor); (c) sorafenib (10 mg/kg/day); (d) radiation (single dose of 6 Gy); (e) pretreatment (sorafenib treatment for 3 days prior to radiation), and (f) concurrent treatment (sorafenib and radiation on the same day). The inhibition of tumor growth and expression level of p65 of NF-kappaB in tumor tissues were the most significant in the pretreatment group. EMSA and Western blot showed that DNA/NF-kappaB activity and the expressions of NF-kappaB-associated proteins were down-regulated. Notably, little to no damage in mandibles and zygomas of mice treated with combination of sorafenib and radiation was found by micro-CT imaging. In conclusion, sorafenib combined with radiation suppresses radiation induced NF-kappaB activity and its downstream proteins, which contribute to radioresistance and tumorigenesis. Additionally, bone destruction is also diminished, suggesting that combination treatment could be a potential strategy against human OSCC. PMID- 26487365 TI - Determination of Triazine Herbicides in Drinking Water by Dispersive Micro Solid Phase Extraction with Ultrahigh-Performance Liquid Chromatography-High-Resolution Mass Spectrometric Detection. AB - A novel dispersive micro solid phase extraction (DMSPE) method based on a polymer cation exchange material (PCX) was applied to the simultaneous determination of the 30 triazine herbicides in drinking water with ultrahigh-performance liquid chromatography-high-resolution mass spectrometric detection. Drinking water samples were acidified with formic acid, and then triazines were adsorbed by the PCX sorbent. Subsequently, the analytes were eluted with ammonium hydroxide/acetonitrile. The chromatographic separation was performed on an HSS T3 column using water (4 mM ammonium formate and 0.1% formic acid) and acetonitrile (0.1% formic acid) as the mobile phase. The method achieved LODs of 0.2-30.0 ng/L for the 30 triazines, with recoveries in the range of 70.5-112.1%, and the precision of the method was better than 12.7%. These results indicated that the proposed method had the advantages of convenience and high efficiency when applied to the analysis of the 30 triazines in drinking water. PMID- 26487366 TI - Developing Legacy: Health Planning in the Host City of Porto Alegre for the 2014 Football World Cup. AB - AIM: To describe the process adopted to identify, classify, and evaluate legacy of health care planning in the host city of Porto Alegre for the Football World Cup 2014. BACKGROUND: There is an emerging interest in the need to demonstrate a sustainable health legacy from mass gatherings investments. Leaving a public health legacy for future host cities and countries is now an important part of planning for these events. PROCESS: The Ministry of Sports initiated and coordinated the development of projects in the host cities to identify actions, projects, and constructions to be developed to prepare for the World Cup. In Porto Alegre, a common structure was developed by the coordinating team to instruct legacy identification, classification, and evaluation. This structure was based on international documentary analysis (including official reports, policy documents, and web-based resources) and direct communication with recognized experts in the field. FINDINGS AND INTERPRETATION: Sixteen total legacies were identified for health surveillance (5) and health services (11). They were classified according to the strategic area, organizations involved, dimension, typology, planned or unplanned, tangible or intangible, territorial coverage, and situation prior to the World Cup. Possible impacts were then assessed as positive, negative, and potentiating, and mitigating actions were indicated. CONCLUSIONS: The project allowed the identification, classification, and development of health legacy, including risk analysis, surveillance, mitigation measures, and provision of emergency medical care. Although the project intended the development of indicators to measure the identified legacies, evaluation was not possible at the time of publication due to time. PMID- 26487367 TI - Host and microbiota interactions are critical for development of murine Crohn's like ileitis. AB - Deregulation of host-microbiota interactions in the gut is a pivotal characteristic of Crohn's disease. It remains unclear, however, whether commensals and/or the dysbiotic microbiota associated with pathology in humans are causally involved in Crohn's pathogenesis. Here, we show that Crohn's-like ileitis in Tnf(DeltaARE/+) mice is microbiota-dependent. Germ-free Tnf(DeltaARE/+) mice are disease-free and the microbiota and its innate recognition through Myd88 are indispensable for tumor necrosis factor (TNF) overexpression and disease initiation in this model. The epithelium of diseased mice shows no major defects in mucus barrier and paracellular permeability. However, Tnf(DeltaARE/+) ileitis associates with the reduction of lysozyme expressing Paneth cells, mediated by adaptive immune effectors. Furthermore, we show that established but not early ileitis in Tnf(DeltaARE/+) mice involves defective expression of antimicrobials and dysbiosis, characterized by Firmicutes expansion, including epithelial-attaching segmented filamentous bacteria, and decreased abundance of Bacteroidetes. Microbiota modulation by antibiotic treatment at an early disease stage rescues ileitis. Our results suggest that the indigenous microbiota is sufficient to drive TNF overexpression and Crohn's ileitis in the genetically susceptible Tnf(DeltaARE/+) hosts, whereas dysbiosis in this model results from disease-associated alterations including loss of lysozyme-expressing Paneth cells. PMID- 26487369 TI - Nitrogen-fluorine co-doped titania inverse opals for enhanced solar light driven photocatalysis. AB - Three dimensionally ordered nitrogen-fluorine (N-F) co-doped TiO2 inverse opals (IOs) were fabricated by templating with polystyrene (PS) colloidal photonic crystals (CPCs) by infiltration. During preparation, the TiO2 precursor was treated with a mixture of nitric acid and trifluoroacetic acid to facilitate N-F co-doping into the TiO2 lattice. Enhanced solar light absorption was observed in the samples as a consequence of the red shift in the electronic band gap of TiO2 due to N-F co-doping. The photonic band gap (PBG) of these TiO2 IO films was tuned by varying the sphere size of the PS CPC templates. The as-prepared N-F co doped TiO2 IO films were used as photocatalysts for the degradation of Rhodamine B (RhB) dye under solar light irradiation. A significant enhancement in the photocatalytic activity was observed in N-F co-doped TiO2 IO films prepared using PS spheres of 215 nm as a template, with the red edge of the PBG closer to the electronic band gap (EBG) of TiO2. 100% of the dye molecules were degraded within 2 minutes under direct solar irradiation, which is one of the fastest reaction times ever reported for RhB degradation in the presence of TiO2 photocatalysts. The N-F co-doped TiO2 IO film prepared using PS of 460 nm with its PBG centered at 695 nm also showed good photocatalytic activity. It was found that the IO films displayed improved photocatalytic activity in comparison to ordinary nanocrystalline (nc)-TiO2 films. The enhancement could be attributed to the bandgap scattering effect and the slow photon effect, leading to a significant improvement in solar light harvesting. PMID- 26487368 TI - Atomic cobalt on nitrogen-doped graphene for hydrogen generation. AB - Reduction of water to hydrogen through electrocatalysis holds great promise for clean energy, but its large-scale application relies on the development of inexpensive and efficient catalysts to replace precious platinum catalysts. Here we report an electrocatalyst for hydrogen generation based on very small amounts of cobalt dispersed as individual atoms on nitrogen-doped graphene. This catalyst is robust and highly active in aqueous media with very low overpotentials (30 mV). A variety of analytical techniques and electrochemical measurements suggest that the catalytically active sites are associated with the metal centres coordinated to nitrogen. This unusual atomic constitution of supported metals is suggestive of a new approach to preparing extremely efficient single-atom catalysts. PMID- 26487370 TI - The mitochondrial genome of the Vespa mandarinia Smith (Hymenoptera: Vespidae: Vespinae) and a phylogenetic analysis of the Vespoidea. AB - We report the mitochondrial genome of the Vespa mandarinia Smith (GenBank accession no. KR059904) for the subfamily Vespinae (Hymenoptera: Vespidae). This is the first completely sequenced mitochodrial genome from the genus Vespa. All of the typical mitochondrial genes were sequenced with a length of 15 902 bp. In the V. mandarinia mitochondrial genome, four rearrangement events occurred compared with the pupative ancestral arrangement of insects, corresponding to the shuffling of trnQ and trnM, translocation of trnY to the region between A + T rich region and trnI-trnM-trnQ, shuffling of trnS1 and trnE in the tRNA cluster of trnA-trnR-trnN-trnS1-trnE-trnF, and translocation of trnL1 from a location between nad1 and rrnL to the upstream of nad1 gene. Phylogenetic analysis using the Bayesian method based on all codon positions of the 13 protein-coding genes supports the monophyly of Vespidae and Formicidae. Within the Formicidae, the Myrmicinae and Dolichoderinae form a sister group, while within the Vespidae, the Eumeninae sister to lineage of Vespinae + Polistinae. Our study showed that the mitochondrial genomes between Vespinae and Polistinae shared more arrangement patterns than that between Vespinae and Eumeninae. PMID- 26487371 TI - Dielectric function of two-phase colloid-polymer nanocomposite. AB - The plasmon resonance of metal nanoparticles determines their optical response in the visible spectral range. Many details such as the electronic properties of gold near the particle surface and the local environment of the particles influence the spectra. We show how the cheap but highly precise fabrication of composite nanolayers by spin-assisted layer-by-layer deposition of polyelectrolytes can be used to investigate the spectral response of gold nanospheres (GNS) and gold nanorods (GNR) in a self-consistent way, using the established Maxwell-Garnett effective medium (MGEM) theory beyond the limit of homogeneous media. We show that the dielectric function of gold nanoparticles differs from the bulk value and experimentally characterize the shape and the surrounding of the particles thoroughly by SEM, AFM and ellipsometry. Averaging the dielectric functions of the layered surrounding by an appropriate weighting with the electric field intensity yields excellent agreement for the spectra of several nanoparticles and nanorods with various cover-layer thicknesses. PMID- 26487373 TI - The potential distribution of Bactrocera dorsalis: considering phenology and irrigation patterns. AB - A species in the Bactrocera dorsalis (Hendel) complex was detected in Kenya during 2003 and classified as Bactrocera invadens Drew, Tsuruta & White. Having spread rapidly throughout Africa, it threatens agriculture due to crop damage and loss of market access. In a recent revision of the B. dorsalis complex, B. invadens was incorporated into the species B. dorsalis. The potential distribution of B. dorsalis has been previously modelled. However, previous models were based on presence data and did not incorporate information on the seasonal phenology of B. dorsalis, nor on the possible influence that irrigation may have on its distribution. Methyl eugenol-baited traps were used to collect B. dorsalis in Africa. Seasonal phenology data, measured as fly abundance throughout the year, was related to each location's climate to infer climatic growth response parameters. These functions were used along with African distribution records and development studies to fit the niche model for B. dorsalis, using independent global distribution records outside Africa for model validation. Areas at greatest risk of invasion by B. dorsalis are South and Central America, Mexico, southernmost USA, parts of the Mediterranean coast, parts of Southern and Eastern Australia and New Zealand's North Island. Under irrigation, most of Africa and Australia appear climatically suitable. PMID- 26487372 TI - IgY antibodies in human nutrition for disease prevention. AB - Oral administration of preformed specific antibodies is an attractive approach against infections of the digestive system in humans and animals in times of increasing antibiotic resistances. Previous studies showed a positive effect of egg yolk IgY antibodies on bacterial intoxications in animals and humans. Immunization of chickens with specific antigens offers the possibility to create various forms of antibodies. Research shows that orally applied IgY's isolated from egg yolks can passively cure or prevent diseases of the digestive system. The use of these alternative therapeutic drugs provides further advantages: (1) The production of IgY's is a non-invasive alternative to current methods; (2) The keeping of chickens is inexpensive; (3) The animals are easy to handle; (4) It avoids repetitive bleeding of laboratory animals; (5) It is also very cost effective regarding the high IgY concentration within the egg yolk. Novel targets of these antigen specific antibodies are Helicobacter pylori and also molecules involved in signaling pathways in gastric cancer. Furthermore, also dental caries causing bacteria like Streptococcus mutans or opportunistic Pseudomonas aeruginosa in cystic fibrosis patients are possible targets. Therefore, IgY's included in food for human consumption may be able to prevent or cure human diseases. PMID- 26487374 TI - GT3X+ accelerometer placement affects the reliability of step-counts measured during running and pedal-revolution counts measured during bicycling. AB - Accelerometers provide a measure of step-count. Reliability and validity of step count and pedal-revolution count measurements by the GT3X+ accelerometer, placed at different anatomical locations, is absent in the literature. The purpose of this study was to investigate the reliability and validity of step and pedal revolution counts produced by the GT3X+ placed at different anatomical locations during running and bicycling. Twenty-two healthy adults (14 men and 8 women) completed running and bicycling activity bouts (5 minutes each) while wearing 6 accelerometers: 2 each at the waist, thigh and shank. Accelerometer and video data were collected during activity. Excellent reliability and validity were found for measurements taken from accelerometers mounted at the waist and shank during running (Reliability: intraclass correlation (ICC) >= 0.99; standard error of measurement (SEM) <=1.0 steps; VALIDITY: Pearson >= 0.99) and at the thigh and shank during bicycling (Reliability: ICC >= 0.99; SEM <=1.0 revolutions; VALIDITY: Pearson >= 0.99). Excellent reliability was found between measurements taken at the waist and shank during running (ICC >= 0.98; SEM <=1.6 steps) and between measurements taken at the thigh and shank during bicycling (ICC >= 0.99; SEM <=1.0 revolutions). These data suggest that the GT3X+ can be used for measuring step-count during running and pedal-revolution count during bicycling. Only shank placement is recommended for both activities. PMID- 26487375 TI - Structural insights into the cooperative remodeling of membranes by amphiphysin/BIN1. AB - Amphiphysin2/BIN1 is a crescent-shaped N-BAR protein playing a key role in forming deeply invaginated tubes in muscle T-tubules. Amphiphysin2/BIN1 structurally stabilizes tubular formations in contrast to other N-BAR proteins involved in dynamic membrane scission processes; however, the molecular mechanism of the stabilizing effect is poorly understood. Using cryo-EM, we investigated the assembly of the amphiphysin/BIN1 on a membrane tube. We found that the N-BAR domains self-assemble on the membrane surface in a highly cooperative manner. Our biochemical assays and 3D reconstructions indicate that the N-terminal amphipathic helix H0 plays an important role in the initiation of the tube assembly and further in organizing BAR-mediated polymerization by locking adjacent N-BAR domains. Mutants that lack H0 or the tip portion, which is also involved in interactions of the neighboring BAR unit, lead to a disruption of the polymer organization, even though tubulation can still be observed. The regulatory region of amphiphysin/BIN1 including an SH3 domain does not have any apparent involvement in the polymer lattice. Our study indicates that the H0 helix and the BAR tip are necessary for efficient and organized self-assembly of amphiphysin/N-BAR. PMID- 26487376 TI - Controlled ovarian hyperstimulation with sequential letrozole co-treatment in normo/high responders. AB - OBJECTIVE: To investigate the effect of co-administration of letrozole in an ovarian stimulation protocol using recombinant FSH and GnRH antagonists for ICSI in normo/high responders. METHODS: Computerized data of 320 antagonist ICSI/ET cycles with or without letrozole were retrospectively analyzed. In 105 cases, letrozole (5 mg/day) was started at the second day of the cycle continued for 5 days. At the second day of letrozole, gonadotropins were added. The remaining 215 cases were stimulated with recombinant FSH only. In all cases on day 6, GnRH antagonist was started. Ovarian stimulation protocols with or without letrozole were compared for cycle outcome parameters. RESULTS: In cycles with letrozole, significantly lower gonadotropin consumption and lower peak estradiol levels were found. In cycles with letrozole, mean number of metaphase II and fertilized oocytes retrieved were significantly higher compared to cycles without letrozole. The pregnancy and clinical pregnancy rates were similar. CONCLUSION: Should the number of oocytes retrieved being higher in letrozole group might indicate that letrozole might contribute to successful ovarian stimulation with a lower dosage of gonadotropins. Despite the lower peak estradiol levels, pregnancy rates being similar to other group also support the idea that letrozole can contribute to normal potential of implantation. PMID- 26487377 TI - Severe cerebral white matter lesions in ischemic stroke patients are associated with less time spent at home and early institutionalization. AB - BACKGROUND: Cerebral white matter lesions are one imaging surrogate for cerebral small vessel disease. These white matter lesions are associated with increased morbidity and mortality in both the general population and ischemic stroke patients. AIMS: To investigate whether severe white matter lesions in a cohort of ischemic stroke patients are associated with fewer days spent at home and earlier permanent institutionalization. METHODS: We included 391 consecutive patients aged 55-85 years with ischemic stroke admitted to the Helsinki University Central Hospital (the Stroke Aging Memory cohort) with a 21-year follow-up. Hospitalization and nursing home admissions were reviewed from national registers.white matter lesions were rated using magnetic resonance imaging performed three-months poststroke, dichotomized as none-to-moderate and severe. Kaplan-Meier plots log-rank and binary logistic regression (odds ratio) and Cox multivariable proportional hazards model were used to study the association of white matter lesions with days spent at home and the time of permanent institutionalization. Hazards and odds ratio with their 95% confidence intervals are reported. RESULTS: Severe white matter lesions were associated with fewer days spent at home, and more frequent, and earlier permanent institutionalization (1487 vs. 2354 days; log-rank P < 0.001).After adjusting for significant covariates from univariable analyses, severe white matter lesions were associated with fewer days spent at home (odds ratio 1.62; confidence interval 1.16-2.25), permanent institutionalization within five-years (odds ratio 2.29; confidence interval 1.23-4.29), and increased hazards ratio of permanent institutionalization during 21 years of follow-up (1.64; confidence interval 1.119-2.26). CONCLUSIONS: After ischemic stroke, patients with severe white matter lesions spend fewer days at home and become permanently institutionalized earlier, especially within the first five-years. PMID- 26487378 TI - Evaluation of the impact of breast milk expression in early postpartum period on breastfeeding duration: a prospective cohort study. AB - BACKGROUND: Breast milk expression (breast pumping) has become prevalent as an important dimension of breastfeeding behavior. It is, however, not clear whether increasing breast milk expression contributes to extend the duration of breastfeeding. The objective of the present study was to evaluate the impact of breast milk expression in early postpartum period on breastfeeding duration amongst mothers of healthy term infants. METHODS: A prospective cohort study had been conducted from March to June 2010. Mothers who gave birth to healthy, full term and singleton babies were enrolled at discharge. These women were interviewed at 6 weeks postpartum about their breastfeeding behaviors. According to expressing patterns at 6 week postpartum, women were divided into three groups: direct breastfeeding (group 1), combining direct breastfeeding with expressing (group 2), exclusive expressing (group 3). The investigators followed up the women by telephone thereafter at a bimonthly basis and documented breastfeeding duration. Survival analysis was conducted to explore the association between expressing patterns at 6 weeks postpartum and breastfeeding duration. Associated factors of exclusive expressing at 6 weeks postpartum were characterized by logistic regression analysis. RESULTS: Four hundred one eligible women were enrolled at discharge. Among the 389 women who attended the face-to face interview at 6 weeks postpartum, 345 women continued breastfeeding. They were divided into 3 groups by their expressing patterns. According to survival analysis, women who exclusively expressed breast milk at 6 months postpartum (group 3) were 1.77 times as likely to stop breastfeeding as those who did not (group 1 and 2) (95% confidence interval: 1.25-2.48; P <0.001). There is, however, no significant difference of breastfeeding duration between group 1 and group 2. Subgroup analysis showed that exclusive expressing women who were exclusively breastfeeding at 6 weeks postpartum had the shortest breastfeeding duration. Mother's high education level, short maternity leave, breast milk expression in hospital and bottle-feeding in hospital were associated factors to exclusive expressing at 6 weeks postpartum. CONCLUSIONS: Exclusive expressing in the early postpartum period may not help women to achieve long-term breastfeeding duration, especially in women who were exclusively breastfeeding. PMID- 26487379 TI - A qualitative study exploring adolescents' experiences with a school-based mental health program. AB - BACKGROUND: Supporting positive mental health development in adolescents is a major public health concern worldwide. Although several school-based programs aimed at preventing depression have been launched, it is crucial to evaluate these programs and to obtain feedback from participating adolescents. This study aimed to explore adolescents' experiences with a -based cognitive-behavioral depression prevention program. METHODS: Eighty-nine adolescents aged 13-15 years were divided into 12 focus groups. The focus group interviews were analyzed using qualitative content analysis. RESULTS: Three categories and eight subcategories were found to be related to the experience of the school-based program. The first category, intrapersonal strategies, consisted of the subcategories of directed thinking, improved self-confidence, stress management, and positive activities. The second category, interpersonal awareness, consisted of the subcategories of trusting the group and considering others. The third category, structural constraints, consisted of the subcategories of negative framing and emphasis on performance. CONCLUSIONS: The school-based mental health program was perceived as beneficial and meaningful on both individual and group levels, but students expressed a desire for a more health-promoting approach. PMID- 26487380 TI - Transcriptional response to sulfide in the Echiuran Worm Urechis unicinctus by digital gene expression analysis. AB - BACKGROUND: Urechis unicinctus, an echiuran worm inhabiting the U-shaped burrows in the coastal mud flats, is an important commercial and ecological invertebrate in Northeast Asian countries, which has potential applications in the study of animal evolution, coastal sediment improvement and marine drug development. Furthermore, the worm can tolerate and utilize well-known toxicant-sulfide. However, knowledge is limited on the molecular mechanism of U. unicinctus responding to sulfide due to deficiency of its genetic information. METHODS: In this study, we performed Illumina sequencing to obtain the first Urechis unicinctus transcriptome data. Sequenced reads were assembled and then annotated using blast searches against Nr, Nt, Swiss-Prot, KEGG and COG. The clean tags from four digital gene expression (DGE) libraries were mapped to the U. unicinctus transcriptome. DGE analysis and functional annotation were then performed to reveal its response to sulfide. The expressions of 12 candidate genes were validated using quantitative real-time PCR. The results of qRT-PCR were regressed against the DGE analysis, with a correlation coefficient and p value reported for each of them. RESULTS: Here we first present a draft of U. unicinctus transcriptome using the Illumina HiSeq(TM) 2000 platform and 52,093 unique sequences were assembled with the average length of 738 bp and N50 of 1131 bp. About 51.6 % of the transcriptome were functionally annotated based on the databases of Nr, Nt, Swiss-Prot, KEGG and COG. Then based on the transcriptome, the digital gene expression analysis was conducted to examine the transcriptional response to sulfide during 6, 24 and 48 h exposure, and finally 1705, 1181 and 1494 tag-mapped genes were identified as differentially expressed genes in the 6 h, 24-h and 48-h libraries, then were further subjected to pathway analyses. CONCLUSIONS: In the DGE database of U. unicinctus, the alterations in certain known sulfide-related pathways indicate similar changes in response to sulfide. For more than 80 % of the identified pathway members, this is the first report on their association with sulfide stress, among which glycolysis pathway and PIDD involving pathways were unique and discussed in details, and were thought to play important roles in the sulfide tolerance of U. unicinctus. All the results are helpful to explain the mechanism of sulfide tolerance and detoxification. PMID- 26487381 TI - Background Paper for the update of meningococcal vaccination recommendations in Germany: use of the serogroup B vaccine in persons at increased risk for meningococcal disease. AB - In December 2013 Bexsero(r) became available in Germany for vaccination against serogroup B meningococci (MenB). In August 2015 the German Standing Committee on Vaccination (STIKO) endorsed a recommendation for use of this vaccine in persons at increased risk of invasive meningococcal disease (IMD). This background paper summarizes the evidence underlying the recommendation. Bexsero(r) is based on surface protein antigens expressed by about 80% of circulating serogroup B meningococci in Germany. The paper reviews available data on immunogenicity and safety of Bexsero(r) in healthy children and adolescents; data in persons with underlying illness and on the effectiveness in preventing clinical outcomes are thus far unavailable.STIKO recommends MenB vaccination for the following persons based on an individual risk assessment: (1) Persons with congenital or acquired immune deficiency or suppression. Among these, persons with terminal complement defects and properdin deficiency, including those under eculizumab therapy, are at highest risk with reported invasive meningococcal disease (IMD) incidences up 10,000-fold higher than in the general population. Persons with asplenia were estimated to have a ~ 20-30-fold increased risk of IMD, while the risk in individuals with other immune defects such as HIV infection or hypogammaglobulinaemia was estimated at no more than 5-10-fold higher than the background risk. (2) Laboratory staff with a risk of exposure to N. meningitidis aerosols, for whom an up to 271-fold increased risk for IMD has been reported. (3) Unvaccinated household (-like) contacts of a MenB IMD index case, who have a roughly 100-200-fold increased IMD risk in the year after the contact despite chemoprophylaxis. Because the risk is highest in the first 3 months and full protective immunity requires more than one dose (particularly in infants and toddlers), MenB vaccine should be administered as soon as possible following identification of the serogroup of the index case. PMID- 26487382 TI - [Hygiene requirements in donor processes and microbiological monitoring]. PMID- 26487383 TI - [Determining donor eligibility and donor suitability of hemochromatosis marker carriers ]. PMID- 26487384 TI - [Human immunodeficiency virus: position of Blood Working Group of the Federal Ministry of Health]. PMID- 26487385 TI - [Position on blood collection and use of convalescent plasma as a treatment option in the outbreak of severe infections]. PMID- 26487386 TI - [Indoor air guide values for dimethylbenzene: Communication from the Committee on Indoor air guide values]. AB - The German Committee on Indoor Guidelines is issuing indoor air guide values to protect public health. No sufficiently valid human studies are available for the health evaluation of xylenes in indoor air. In a validated subchronic inhalation animal study on m-xylene using male rats, neurotoxic effects were observed, which led to an decreased neuromuscular coordination as observed in a rotarod test. Conversion of experimental to continuous exposure leads to a LOAEC of 39 mg xylene/m(3) for the endpoint neurotoxicity. A health hazard guide value (RW II) of 0.8 mg xylene/m(3) is derived by applying an interspecies factor of 2.5, a factor of 10 for interindividual variability, and a factor of 2 to account for the higher respiratory rate of children compared to adults. A health precaution guide value of 0.1 mg xylene/m(3) is recommended. PMID- 26487387 TI - A new extension of the polarizable continuum model: Toward a quantum chemical description of chemical reactions at extreme high pressure. AB - A quantum chemical method for studying potential energy surfaces of reactive molecular systems at extreme high pressures is presented. The method is an extension of the standard Polarizable Continuum Model that is usually used for Quantum Chemical study of chemical reactions at a standard condition of pressure. The physical basis of the method and the corresponding computational protocol are described in necessary detail, and an application of the method to the dimerization of cyclopentadiene (up to 20 GPa) is reported. PMID- 26487390 TI - Solid-State NMR/Dynamic Nuclear Polarization of Polypeptides in Planar Supported Lipid Bilayers. AB - Dynamic nuclear polarization has been developed to overcome the limitations of the inherently low signal intensity of NMR spectroscopy. This technique promises to be particularly useful for solid-state NMR spectroscopy where the signals are broadened over a larger frequency range and most investigations rely on recording low gamma nuclei. To extend the range of possible investigations, a triple resonance flat-coil solid-state NMR probe is presented with microwave irradiation capacities allowing the investigation of static samples at temperatures of 100 K, including supported lipid bilayers. The probe performance allows for two dimensional separated local field experiments with high-power Lee-Goldberg decoupling and cross-polarization under simultaneous irradiation from a gyrotron microwave generator. Efficient cooling of the sample turned out to be essential for best enhancements and line shape and necessitated the development of a dedicated cooling chamber. Furthermore, a new membrane-anchored biradical is presented, and the geometry of supported membranes was optimized not only for good membrane alignment, handling, stability, and filling factor of the coil but also for heat and microwave dissipation. Enhancement factors of 17-fold were obtained, and a two-dimensional PISEMA spectrum of a transmembrane helical peptide was obtained in less than 2 h. PMID- 26487391 TI - Accuracy, reliability, and efficiency of intraoral scanners for full-arch impressions: a systematic review of the clinical evidence. AB - OBJECTIVES: The interest on intraoral scanners for digital impressions has been growing and new devices are continuously introduced on the market. It is timely to verify whether the several scanners proposed for full-arch digital impressions have been tested under clinical conditions for validity, repeatability, reproducibility, as well as for time efficiency, and patient acceptance. SEARCH METHODS: An electronic search of the literature was conducted through PubMed, Scopus, Cochrane Library, Web of Science, and Embase, entering the query terms 'digital impression', 'intraoral digital impression', 'intraoral scanning', 'intraoral scanner', 'intraoral digital scanner', combined by the Boolean operator 'OR'. No language or time limitation was applied. SELECTION CRITERIA: Only studies where digital full-arch impressions had been recorded intraorally were considered. RESULTS: In only eight studies full-arch scans had been performed intraorally. Only four studies reported data on validity, repeatability, reproducibility of digital measurements and their samples were limited to subjects in complete permanent dentition. Only two intraoral scanners, Lava COS and iTero, were tested. Scanning times were measured in six studies and varied largely. Patients' acceptance of intraoral scanning was evaluated in four studies, but it was not specifically assessed for children. CONCLUSIONS: The scientific evidence so far collected on intraoral scanning is neither exhaustive, nor up-to-date. Data from full-arch scans performed in children should be collected. For a meaningful assessment of time efficiency, agreement should be reached on the procedural steps to be included in the computation of scanning time. PMID- 26487392 TI - Post-training Beliefs, Intentions, and Use of Prolonged Exposure Therapy by Clinicians in the Veterans Health Administration. AB - To examine how changes in beliefs during the training process predict adoption of prolonged exposure therapy (PE) by veterans health administration clinicians who received intensive training in this evidence-based treatment. Participants completed a 4-day PE workshop and received expert consultation as they used PE with two or more training cases. Participants were surveyed prior to the workshop, after the workshop, after case consultation (n = 1.034), and 6 months after training (n = 810). Hierarchical regression was used to assess how pre training factors, and changes in beliefs during different stages of training incrementally predicted post-training intent to use PE and how many patients clinicians were treating with PE 6 months after training. Post-training intent to use PE was high (mean = 6.2, SD = 0.81 on a 1-7 scale), yet most participants treated only 1 or 2 patients at a time with PE. Pre-training factors predicted intent to use and actual use of PE. Changes in beliefs during the workshop had statistically significant yet modest effects on intent and use of PE. Changes in beliefs during case consultation had substantial effects on intent and actual use of PE. Pre-training factors and changes in beliefs during training (especially during case consultation) influence clinicians' adoption of PE. Use of PE was influenced not only by its perceived clinical advantages/disadvantages, but also by contextual factors (working in a PTSD specialty clinic, perceived control over one's schedule, and ability to promote PE to patients and colleagues). PMID- 26487393 TI - The Effect of a Change Agent on Use of Evidence-Based Mental Health Practices. AB - Children's service systems are faced with a critical need to disseminate evidence based mental health interventions. Despite the proliferation of comprehensive implementation models, little is known about the key active processes in effective implementation strategies. This proof of concept study focused on the effect of change agent interactions as conceptualized by Rogers' diffusion of innovation theory on providers' (N = 57) use of a behavioral intervention in a child welfare agency. An experimental design compared use for providers randomized to training as usual or training as usual supplemented by change agent interactions after the training. Results indicate that the enhanced condition increased use of the intervention, supporting the positive effect of change agent interactions on use of new practices. Change agent types of interaction may be a key active process in implementation strategies following training. PMID- 26487394 TI - Combined administration of propranolol + AG490 offers better effects on portal hypertensive rats with cirrhosis. AB - BACKGROUND AND AIMS: AG490, the specific inhibitor of JAK2/STAT3 signaling, has been shown to decrease portal pressure, splanchnic hyperdynamic circulation and liver fibrosis in cirrhotic rats. Nonselective betablockers such as propranolol are the only drugs recommended in the treatment of portal hypertension. The aim of this study was to explore the combinative effect of treatment with propranolol and AG490 on portal hypertension. METHODS: Rats induced by common bile duct ligation were treated with vehicle, AG490, propranolol, or AG490 + propranolol for 2 weeks. Hemodynamics parameters were assessed. Expressions of phospho-STAT3 protein and its down-regulated cytokines in splanchnic organs were detected by ELISA or western blot. Lipopolysaccharide binding protein (LBP) and IL-6 were assessed by ELISA or western blot. Characterization of liver and mesentery was performed by histological analyses. RESULTS: Highly expressed phospho-STAT3 protein in cirrhotic rats could successfully be inhibited by AG490 or AG490 + propranolol treatments but not by propranolol alone. Both AG490 and propranolol significantly reduced portal pressure and hyperdynamic splanchnic circulation, and combination of AG490 and propranolol achieved an additive effect than with either drug alone. AG490, alone or in combination with propranolol, inhibited liver fibrosis, splenomegaly and splanchnic angiogenesis. Increased markers of bacterial translocation (LBP and IL6) were greatly reduced by propranolol but not by AG490. CONCLUSIONS: The combination of propranolol and AG490 caused a greater improvement of portal hypertension and might therefore offer a potentially promising therapy in the portal hypertension treatment. PMID- 26487395 TI - The full metagenomics cycle. PMID- 26487397 TI - Magnetic Nanocomposite Cilia Tactile Sensor. AB - A multifunctional biomimetic nanocomposite tactile sensor is developed that can detect shear and vertical forces, feel texture, and measure flow with extremely low power consumption. The sensor's high performance is maintained within a wide operating range that can be easily adjusted. The concept works on rigid and flexible substrates and the sensors can be used in air or water without any modifications. PMID- 26487398 TI - Indian National Association for Study of the Liver. PMID- 26487399 TI - Coagulopathy in cirrhosis: A prospective study to correlate conventional tests of coagulation and bleeding following invasive procedures in cirrhotics. AB - BACKGROUND: Conventional tests of coagulation which only measure procoagulant factors do not correctly estimate the actual in vivo hemostatic balance in cirrhosis. This prospective multicenter study was conducted to evaluate safety of various invasive procedures in the presence of abnormal coagulation tests and to correlate conventional coagulation parameters with clinically significant bleeding in cirrhotics. METHODS: Three hundred and eighty patients (median age 54 years, 287 males) enrolled in the study were divided into two groups (A and B), according to the presence or absence of abnormal coagulation parameters (defined as INR >=1.5 and/or platelet count <=50,000/cum). RESULTS: One hundred and twenty eight patients (33.68%) were qualified in group A. Alcohol was the predominant etiology of cirrhosis (40% and 32% in groups A and B, respectively). The two groups were similar in baseline characteristics other than tests of coagulation and severity of liver disease. Low risk procedures (abdominal paracentesis most common) were carried out in 47% and 53% patients in two groups, respectively. None of the patients in either group had clinically significant bleeding. Similarly, high risk procedures (central vein cannulation, liver biopsy, etc.) were carried out in 14% and 10%, respectively, in two groups. Three patients in group A developed clinically significant bleeding, however, the difference was statistically nonsignificant (p=0.061). None of our patients received periprocedural correction of abnormal coagulation parameters with plasma/platelet concentrate. CONCLUSIONS: Deranged conventional coagulation parameters did not predict clinically significant bleeding in cirrhosis. Whenever indicated, any invasive procedure could be safely carried out in patients with cirrhosis without prior correction of coagulation abnormalities. PMID- 26487400 TI - Familial Mediterranean fever in Armenia in 2015: some interesting lessons. PMID- 26487401 TI - Leptin and Adiponectin Modulate the Self-renewal of Normal Human Breast Epithelial Stem Cells. AB - Multiple mechanisms are likely to account for the link between obesity and increased risk of postmenopausal breast cancer. Two adipokines, leptin and adiponectin, are of particular interest due to their opposing biologic functions and associations with breast cancer risk. In the current study, we investigated the effects of leptin and adiponectin on normal breast epithelial stem cells. Levels of leptin in human adipose explant-derived conditioned media positively correlated with the size of the normal breast stem cell pool. In contrast, an inverse relationship was found for adiponectin. Moreover, a strong linear relationship was observed between the leptin/adiponectin ratio in adipose conditioned media and breast stem cell self-renewal. Consistent with these findings, exogenous leptin stimulated whereas adiponectin suppressed breast stem cell self-renewal. In addition to local in-breast effects, circulating factors, including leptin and adiponectin, may contribute to the link between obesity and breast cancer. Increased levels of leptin and reduced amounts of adiponectin were found in serum from obese compared with age-matched lean postmenopausal women. Interestingly, serum from obese women increased stem cell self-renewal by 30% compared with only 7% for lean control serum. Taken together, these data suggest a plausible explanation for the obesity-driven increase in postmenopausal breast cancer risk. Leptin and adiponectin may function as both endocrine and paracrine/juxtacrine factors to modulate the size of the normal stem cell pool. Interventions that disrupt this axis and thereby normalize breast stem cell self renewal could reduce the risk of breast cancer. PMID- 26487403 TI - Conceptualising the Impact of Arousal and Affective State on Training Outcomes of Operant Conditioning. AB - Animal training relies heavily on an understanding of species-specific behaviour as it integrates with operant conditioning principles. Following on from recent studies showing that affective states and arousal levels may correlate with behavioural outcomes, we explore the contribution of both affective state and arousal in behavioural responses to operant conditioning. This paper provides a framework for assessing how affective state and arousal may influence the efficacy of operant training methods. It provides a series of three-dimensional conceptual graphs as exemplars to describing putative influences of both affective state and arousal on the likelihood of dogs and horses performing commonly desired behaviours. These graphs are referred to as response landscapes, and they highlight the flexibility available for improving training efficacy and the likely need for different approaches to suit animals in different affective states and at various levels of arousal. Knowledge gaps are discussed and suggestions made for bridging them. PMID- 26487404 TI - Assessing Ulcerative Pododermatitis of Breeding Rabbits. AB - Rabbits in conventional farms are housed in wire net cages with mesh floors to separate them from droppings. In time, lacerations appear on the legs of adult rabbits causing ulcerative pododermatitis or sore hocks, a severe health and welfare problem. Pain causes behavioral changes; productivity is reduced and the most seriously affected animals die or are culled. In this study we evaluated the attention producers have given to this problem and its prevention by installing footrests in cages. We made 2,331 visits to 664 commercial farms in Spain and Portugal between 2001 and 2012, and evaluated morbidity by examining 105,009 females and 10,722 males. The study highlights that the rate of farms with footrests increased from 27.8% in 2001 to 75.2% in 2012. Prevalence of sore hocks in does in 2001 was 11.4%, decreasing to 6.3% in 2012; prevention of ulcerative pododermatitis was associated (P < 0.001) with the presence of footrests. Overall, prevalence was 4.87 +/- 0.26 on farms with footrests and 13.71 +/- 0.32 without (P < 0.01). PMID- 26487405 TI - Use of Anecdotal Occurrence Data in Species Distribution Models: An Example Based on the White-Nosed Coati (Nasua narica) in the American Southwest. AB - Species distributions are usually inferred from occurrence records. However, these records are prone to errors in spatial precision and reliability. Although influence of spatial errors has been fairly well studied, there is little information on impacts of poor reliability. Reliability of an occurrence record can be influenced by characteristics of the species, conditions during the observation, and observer's knowledge. Some studies have advocated use of anecdotal data, while others have advocated more stringent evidentiary standards such as only accepting records verified by physical evidence, at least for rare or elusive species. Our goal was to evaluate the influence of occurrence records with different reliability on species distribution models (SDMs) of a unique mammal, the white-nosed coati (Nasua narica) in the American Southwest. We compared SDMs developed using maximum entropy analysis of combined bioclimatic and biophysical variables and based on seven subsets of occurrence records that varied in reliability and spatial precision. We found that the predicted distribution of the coati based on datasets that included anecdotal occurrence records were similar to those based on datasets that only included physical evidence. Coati distribution in the American Southwest was predicted to occur in southwestern New Mexico and southeastern Arizona and was defined primarily by evenness of climate and Madrean woodland and chaparral land-cover types. Coati distribution patterns in this region suggest a good model for understanding the biogeographic structure of range margins. We concluded that occurrence datasets that include anecdotal records can be used to infer species distributions, providing such data are used only for easily-identifiable species and based on robust modeling methods such as maximum entropy. Use of a reliability rating system is critical for using anecdotal data. PMID- 26487406 TI - On the Possible Detection of Lightning Storms by Elephants. AB - Theoretical calculations suggest that sounds produced by thunderstorms and detected by a system similar to the International Monitoring System (IMS) for the detection of nuclear explosions at distances >=100 km, are at sound pressure levels equal to or greater than 6 * 10(-3) Pa. Such sound pressure levels are well within the range of elephant hearing. Frequencies carrying these sounds might allow for interaural time delays such that adult elephants could not only hear but could also locate the source of these sounds. Determining whether it is possible for elephants to hear and locate thunderstorms contributes to the question of whether elephant movements are triggered or influenced by these abiotic sounds. PMID- 26487408 TI - The Release of a Captive-Raised Female African Elephant (Loxodonta africana) in the Okavango Delta, Botswana. AB - Wild female elephants live in close-knit matrilineal groups and housing captive elephants in artificial social groupings can cause significant welfare issues for individuals not accepted by other group members. We document the release of a captive-raised female elephant used in the safari industry because of welfare and management problems. She was fitted with a satellite collar, and spatial and behavioural data were collected over a 17-month period to quantify her interactions with the wild population. She was then monitored infrequently for a further five-and-a-half years. We observed few signs of aggression towards her from the wild elephants with which she socialized. She used an area of comparable size to wild female elephants, and this continued to increase as she explored new areas. Although she did not fully integrate into a wild herd, she had three calves of her own, and formed a social unit with another female and her calf that were later released from the same captive herd. We recommend that release to the wild be considered as a management option for other captive female elephants. PMID- 26487407 TI - Impact of Heat Stress on Poultry Production. AB - Understanding and controlling environmental conditions is crucial to successful poultry production and welfare. Heat stress is one of the most important environmental stressors challenging poultry production worldwide. The detrimental effects of heat stress on broilers and laying hens range from reduced growth and egg production to decreased poultry and egg quality and safety. Moreover, the negative impact of heat stress on poultry welfare has recently attracted increasing public awareness and concern. Much information has been published on the effects of heat stress on productivity and immune response in poultry. However, our knowledge of basic mechanisms associated to the reported effects, as well as related to poultry behavior and welfare under heat stress conditions is in fact scarce. Intervention strategies to deal with heat stress conditions have been the focus of many published studies. Nevertheless, effectiveness of most of the interventions has been variable or inconsistent. This review focuses on the scientific evidence available on the importance and impact of heat stress in poultry production, with emphasis on broilers and laying hens. PMID- 26487409 TI - Animal Welfare and Food Safety Aspects of Confining Broiler Chickens to Cages. AB - In most areas of the world, broiler chickens are raised in floor systems, but cage confinement is becoming more common. The welfare of broiler chickens in cages is affected by movement restriction, poor bone strength due to lack of exercise, and prevention of key behavioral patterns such as dustbathing and ground scratching. Cages for broiler chickens also have a long history of causing skin and leg conditions that could further compromise welfare, but a lack of controlled studies makes it difficult to draw conclusions about newer cage designs. Cage environments are usually stocked at a higher density than open floor systems, and the limited studies available suggest that caging may lead to increased levels of fear and stress in the birds. Further, birds reared on the floor appear less likely to harbor and shed Salmonella, as litter may serve as a seeding agent for competitive exclusion by other microorganisms. Cages for laying hens used in egg production have met with substantial opposition due to welfare concerns and caging broiler chickens will likely be subject to the same kinds of social disapproval. PMID- 26487410 TI - The Future of Pork Production in the World: Towards Sustainable, Welfare-Positive Systems. AB - Among land animals, more pork is eaten in the world than any other meat. The earth holds about one billion pigs who deliver over 100 mmt of pork to people for consumption. Systems of pork production changed from a forest-based to pasture based to dirt lots and finally into specially-designed buildings. The world pork industry is variable and complex not just in production methods but in economics and cultural value. A systematic analysis of pork industry sustainability was performed. Sustainable production methods are considered at three levels using three examples in this paper: production system, penning system and for a production practice. A sustainability matrix was provided for each example. In a comparison of indoor vs. outdoor systems, the food safety/zoonoses concerns make current outdoor systems unsustainable. The choice of keeping pregnant sows in group pens or individual crates is complex in that the outcome of a sustainability assessment leads to the conclusion that group penning is more sustainable in the EU and certain USA states, but the individual crate is currently more sustainable in other USA states, Asia and Latin America. A comparison of conventional physical castration with immunological castration shows that the less-common immunological castration method is more sustainable (for a number of reasons). This paper provides a method to assess the sustainability of production systems and practices that take into account the best available science, human perception and culture, animal welfare, the environment, food safety, worker health and safety, and economics (including the cost of production and solving world hunger). This tool can be used in countries and regions where the table values of a sustainability matrix change based on local conditions. The sustainability matrix can be used to assess current systems and predict improved systems of the future. PMID- 26487411 TI - Modelling Farm Animal Welfare. AB - The use of models in the life sciences has greatly expanded in scope and advanced in technique in recent decades. However, the range, type and complexity of models used in farm animal welfare is comparatively poor, despite the great scope for use of modeling in this field of research. In this paper, we review the different modeling approaches used in farm animal welfare science to date, discussing the types of questions they have been used to answer, the merits and problems associated with the method, and possible future applications of each technique. We find that the most frequently published types of model used in farm animal welfare are conceptual and assessment models; two types of model that are frequently (though not exclusively) based on expert opinion. Simulation, optimization, scenario, and systems modeling approaches are rarer in animal welfare, despite being commonly used in other related fields. Finally, common issues such as a lack of quantitative data to parameterize models, and model selection and validation are discussed throughout the review, with possible solutions and alternative approaches suggested. PMID- 26487413 TI - GeoBioScience: Red Wood Ants as Bioindicators for Active Tectonic Fault Systems in the West Eifel (Germany). AB - In a 1.140 km2 study area of the volcanic West Eifel, a comprehensive investigation established the correlation between red wood ant mound (RWA; Formica rufa-group) sites and active tectonic faults. The current stress field with a NW-SE-trending main stress direction opens pathways for geogenic gases and potential magmas following the same orientation. At the same time, Variscan and Mesozoic fault zones are reactivated. The results showed linear alignments and clusters of approx. 3,000 RWA mounds. While linear mound distribution correlate with strike-slip fault systems documented by quartz and ore veins and fault planes with slickensides, the clusters represent crosscut zones of dominant fault systems. Latter can be correlated with voids caused by crustal block rotation. Gas analyses from soil air, mineral springs and mofettes (CO2, Helium, Radon and H2S) reveal limiting concentrations for the spatial distribution of mounds and colonization. Striking is further the almost complete absence of RWA mounds in the core area of the Quaternary volcanic field. A possible cause can be found in occasionally occurring H2S in the fault systems, which is toxic at miniscule concentrations to the ants. Viewed overall, there is a strong relationship between RWA mounds and active tectonics in the West Eifel. PMID- 26487414 TI - The Prospect of Market-Driven Improvements in Animal Welfare: Lessons from the Case of Grass Milk in Denmark. AB - Citizens in many European countries urge that the welfare of farm animals should be improved. Policy-makers propose that this could, at least to some extent, be achieved through increased consumption of animal products produced under labeling schemes guaranteeing higher standards of animal welfare. Yet considerable uncertainties exist about the ability of the market to promote animal welfare. So far the consumption of most welfare-friendly products has been limited, and the impact of driving and limiting factors is poorly understood. Reviewing market studies, we identify the factors that have shaped the relatively successful market for grass milk in Denmark. We conclude that the positive drivers such as an appealing animal welfare attribute and animal welfare being bundled with other qualities are essentially the same as those operating in connection with less successful animal welfare-friendly products. It is therefore to be expected that other animal welfare-friendly food products marketed via "natural behaviors" in the farm animals will catch the interest of consumers. However, grass milk consumption has been supported by proper labeling, ready availability and low price premiums as well as multifaceted public support. This suggests that successful cases require the joint presence of a number of positive drivers as well as low consumption barriers. PMID- 26487412 TI - Exploration of the Hypothalamic-Pituitary-Adrenal Axis to Improve Animal Welfare by Means of Genetic Selection: Lessons from the South African Merino. AB - It is a difficult task to improve animal production by means of genetic selection, if the environment does not allow full expression of the animal's genetic potential. This concept may well be the future for animal welfare, because it highlights the need to incorporate traits related to production and robustness, simultaneously, to reach sustainable breeding goals. This review explores the identification of potential genetic markers for robustness within the hypothalamic-pituitary-adrenal axis (HPAA), since this axis plays a vital role in the stress response. If genetic selection for superior HPAA responses to stress is possible, then it ought to be possible to breed robust and easily managed genotypes that might be able to adapt to a wide range of environmental conditions whilst expressing a high production potential. This approach is explored in this review by means of lessons learnt from research on Merino sheep, which were divergently selected for their multiple rearing ability. These two selection lines have shown marked differences in reproduction, production and welfare, which makes this breeding programme ideal to investigate potential genetic markers of robustness. The HPAA function is explored in detail to elucidate where such genetic markers are likely to be found. PMID- 26487415 TI - Nature of Pre-Earthquake Phenomena and their Effects on Living Organisms. AB - Earthquakes occur when tectonic stresses build up deep in the Earth before catastrophic rupture. During the build-up of stress, processes that occur in the crustal rocks lead to the activation of highly mobile electronic charge carriers. These charge carriers are able to flow out of the stressed rock volume into surrounding rocks. Such outflow constitutes an electric current, which generates electromagnetic (EM) signals. If the outflow occurs in bursts, it will lead to short EM pulses. If the outflow is continuous, the currents may fluctuate, generating EM emissions over a wide frequency range. Only ultralow and extremely low frequency (ULF/ELF) waves travel through rock and can reach the Earth surface. The outflowing charge carriers are (i) positively charged and (ii) highly oxidizing. When they arrive at the Earth surface from below, they build up microscopic electric fields, strong enough to field-ionize air molecules. As a result, the air above the epicentral region of an impending major earthquake often becomes laden with positive airborne ions. Medical research has long shown that positive airborne ions cause changes in stress hormone levels in animals and humans. In addition to the ULF/ELF emissions, positive airborne ions can cause unusual reactions among animals. When the charge carriers flow into water, they oxidize water to hydrogen peroxide. This, plus oxidation of organic compounds, can cause behavioral changes among aquatic animals. PMID- 26487416 TI - A Longitudinal Study on Feeding Behaviour and Activity Patterns of Released Chimpanzees in Conkouati-Douli National Park, Republic of Congo. AB - Wild chimpanzee populations are still declining due to logging, disease transmission and hunting. The bushmeat trade frequently leads to an increase in the number of orphaned primates. HELP Congo was the first project to successfully release wild-born orphan chimpanzees into an existing chimpanzee habitat. A collection of post monitoring data over 16 years now offers the unique opportunity to investigate possible behavioural adaptations in these chimpanzees. We investigated the feeding and activity patterns in eight individuals via focal observation techniques from 1997-1999 and 2001-2005. Our results revealed a decline in the number of fruit and insect species in the diet of released chimpanzees over the years, whereas within the same period of time, the number of consumed seed species increased. Furthermore, we found a decline in time spent travelling, but an increase in time spent on social activities, such as grooming, as individuals matured. In conclusion, the observed changes in feeding and activity patterns seem to reflect important long-term behavioural and ecological adaptations in wild-born orphan released chimpanzees, demonstrating that the release of chimpanzees can be successful, even if it takes time for full adaptation. PMID- 26487417 TI - Contrasting Attitudes towards Animal Welfare Issues within the Food Chain. AB - Intensive systems have facilitated the production of animal-based products at relatively low prices. On one hand, these methods have been increasingly considered to be responsible for a dramatic reduction in animal welfare, as indicated by the high prevalence of stereotypies in sows, brittle bones in hens, lameness in broilers and short life span in dairy cattle. As a consequence, large segments of animal welfare-sensitive consumers have been identified. On the other hand, price conscious consumers, if accepting higher prices, are more likely to require explicit justification of returns in quality. Therefore, scientifically validated monitoring systems for assessing the welfare of farm animals have been developed in order to provide a certification system, allow the differentiation of animal-based products through constant and reliable signaling systems, and promote animal welfare friendly farming systems. PMID- 26487418 TI - Isotopic evidence of human mobility and diet in a prehistoric/protohistoric Fijian coastal environment (c. 750-150 BP). AB - OBJECTIVES: Bourewa, on the southwest coast of Viti Levu in Fiji, is a multi period site that contained burials dated to the later Vuda Phase (750-150 BP), a period of climatic fluctuations that potentially impacted the availability of food resources. We aim to investigate diet and movement at this site during a time of possible ecological pressure and political change. MATERIALS AND METHODS: We analyzed delta(13) C, delta(15) N, and (87) Sr/(86) Sr of these Vuda Phase individuals (n = 25) interred at the site. By analyzing dentin and bone, both childhood diet and the diet within the past few years of adults' lives were examined. RESULTS: The paleodietary results suggested that adult diets consisted largely of low trophic level marine organisms. Dentin and bone isotopic values differed significantly: childhood diet involved consumption of more higher trophic level terrestrial foods. Most individuals displayed (87) Sr/(86) Sr ratios expected of people living along a marine coastline. However, a few individuals displayed (87) Sr/(86) Sr ratios and paleodietary values (delta(13) Cdentin , delta(15) Ndentin ) suggestive of living further inland or consuming a more terrestrial-based childhood diet. DISCUSSION: The results are compared with past studies of sites from Fiji and nearby archipelagoes, placing our interpretations into a wider regional context. The Bourewa community appears to have consumed more low trophic level marine foods than any nearby site, possibly because terrestrial foods were more difficult to acquire. Interpreting the childhood diet is challenging due to the paucity of ethnohistoric literature on Fijian childhood; small meals outside of communal mealtimes or feeding children terrestrial animal protein as a means of cultural buffering are potential explanations. PMID- 26487419 TI - Recovery of strain-hardening rate in Ni-Si alloys. AB - In this study, the recovery of strain-hardening rate (RSHR) was discovered for the first time in polycrystalline materials (Ni-Si alloys) that have only dislocation activities during tensile test. Detailed microstructure characterizations show that the activation of dislocations in the secondary slip systems during tensile deformation is the major reason for this RSHR. By taking into account other metals that also exhibit RSHR during tension, a more general mechanism for the RSHR was proposed, i.e. the occurrence of a sharp decrease of dislocation mean free path (Lambda) during plastic deformation, caused by either planar defects or linear defects. PMID- 26487420 TI - Hypoxia Activated Prodrugs: Factors Influencing Design and Development. AB - Hypoxia in tumor cells is characterized by a lack of oxygen resulting from reduced blood supply to the surrounding tissue, and is a common characteristic of solid tumors as a consequence of rapid cell growth. Hypoxia in tumors is a predictor of both resistance to chemotherapy and of a metastatic/aggressive form of cancer, and as a result, development of cancer therapies which target hypoxia is of vital importance. One such targeting strategy is the development of hypoxia activated prodrugs (HAP) which can preferentially release chemotherapeutic agents within hypoxic tumor regions. This targeting strategy is accomplished by attaching a hypoxia activated trigger to a chemotherapeutic agent and under oxygen-poor conditions, the agent (effector) is released into the tumor, while remaining intact in normal tissue, and leaving non-hypoxic cells undamaged. Overall, this strategy can achieve an increased therapeutic benefit over conventional small molecule chemotherapeutic treatments by concentrating the drugs within hypoxic tumor environments, while simultaneously reducing the side effects and toxicity issues that surround the systemic distribution of traditional drugs on normoxic cells. In this review, we will describe the factors that should be considered when designing an effective HAP, such as the mechanism of prodrug action, the elements that influence the rational design of HAP (i.e. reduction potential), and the activating enzymes of HAP. As part of this description, we will utilize select examples from the literature to reinforce these factors, and make a case for the intelligent design of new HAPs, leading to the development of novel hypoxia targeting chemotherapeutic agents. PMID- 26487421 TI - The importance of neuronal growth factors in the ovary. AB - The neurotrophin family consists of nerve growth factor (NGF), neurotrophin 3 (NT3) and neurotrophin 4/5 (NT4/5), in addition to brain-derived neurotrophic factor (BDNF) and the neuronal growth factors, glial cell line-derived neurotrophic factor (GDNF) and vasointestinal peptide (VIP). Although there are a few literature reviews, mainly of animal studies, on the importance of neurotrophins in the ovary, we aimed to provide a complete review of neurotrophins as well as neuronal growth factors and their important roles in normal and pathological processes in the ovary. Follicular assembly is probably stimulated by complementary effects of NGF, NT4/5 and BDNF and their receptors. The neurotrophins, GDNF and VIP and their receptors have all been identified in preantral and antral follicles of mammalian species, including humans. Transgenic mice with mutations in the genes encoding for Ngf, Nt4/5 and Bdnf and their tropomyosin-related kinase beta receptor showed a reduction in preantral follicles and an abnormal ovarian morphology, whereas NGF, NT3, GDNF and VIP increased the in vitro activation of primordial follicles in rats and goats. Additionally, NGF, NT3 and GDNF promoted follicular cell proliferation; NGF, BDNF and VIP were shown to be involved in ovulation; VIP inhibited follicular apoptosis; NT4/5, BDNF and GDNF promoted oocyte maturation and NGF, NT3 and VIP stimulated steroidogenesis. NGF may also exert a stimulatory effect in ovarian cancer and polycystic ovarian syndrome (PCOS). Low levels of NGF and BDNF in follicular fluid may be associated with diminished ovarian reserve and high levels with endometriosis. More knowledge of the roles of neuronal growth factors in the ovary has important implications for the development of new therapeutic drugs (such as anti-NGF agents) for ovarian cancer and PCOS as well as various infertility problems, warranting further research. PMID- 26487422 TI - Breakdown of magnetism in sub-nanometric Ni clusters embedded in Ag. AB - Downsizing to the nanoscale has opened up a spectrum of new magnetic phenomena yet to be discovered. In this context, we investigate the magnetic properties of Ni clusters embedded in a metallic Ag matrix. Unlike in Ni free-standing clusters, where the magnetic moment increases towards the atomic value when decreasing the cluster size, we show, by tuning the Ni cluster size down to the sub-nanoscale, that there is a size limit below which the clusters become non magnetic when embedded in Ag. To this end, we have fabricated by DC-sputtering a system composed of sub-nanometer sized and non interacting Ni clusters embedded into a Ag matrix. A thorough experimental characterization by means of structural techniques (x-ray diffraction, x-ray absorption spectroscopy) and DC magnetization confirms that the cluster size is in the sub-nanometric range and shows that the magnetization of the system is dramatically reduced, reaching only 38% of the bulk value. The experimental system has been reproduced by density functional theory calculations on Ni m clusters (m = 1-6, 10 and 13) embedded in Ag. The combination of the experimental and theoretical analysis points out that there is a breakdown of magnetism occurring below a cluster size of six atoms. According to our results, the loss of magnetic moment is not due to Ag-Ni hybridization but to charge transfer between the Ni sp and d orbitals, and the reduced magnetization observed experimentally is explained on the basis of the presence of a narrow cluster size-distribution where magnetic and non-magnetic clusters coexist. PMID- 26487423 TI - "Yes" vote predicted for junior doctors' ballot on industrial action. PMID- 26487424 TI - Hyperinsulinemic hypoglycemia in a patient with an intragenic NSD1 mutation. PMID- 26487425 TI - How diaries written for critically ill influence the relatives: a systematic review of the literature. AB - BACKGROUND: Diaries written by nurses for the critically ill patient helps relatives cope and support the patient. When relatives participate in writing a diary for the critically ill, patients appreciate it. Furthermore, the diary may reduce post-traumatic stress disorder, anxiety and depression in patients and relatives. AIM: To explore how relatives perceive reading and writing in the diary and how it affects their well-being. SEARCH STRATEGIES: A systematic search was carried out in the databases PubMed, Embase, CiNAHL and PsycINFO and supplemented by a citation search in Scopus on four-selected articles. Finally, 10 articles were included in this review structured by the Matrix method. INCLUSION CRITERIA: (a) Original scientific work, (b) relatives participation and experience of the diary as subject and (c) diaries studied in an intensive care unit setting. FINDINGS: Relatives were given instructions on how to write in the diary. They expressed strong feelings in the diary in a very different way than health care staff. The relatives used the diary themselves to gain understanding and to cope. The diary has been shown to prevent post-traumatic stress symptoms. CONCLUSION: The relatives express their love for the patient, when they author the diary and this may be beneficial to the relatives as it helps them cope and support the patient. The organized account of the time in the intensive care unit in the diary may explain the diary's ability to reduce the occurrence of post traumatic stress disorder; however, further research is needed to confirm this. How relatives interact through writing and reading a diary, originally intended for the patient, is unclear. RELEVANCE TO CLINICAL PRACTICE: Providing relatives with a diary may help them cope. However, caution should be taken as possible adverse effects related to the interaction between relatives in the diary may not yet be known. PMID- 26487426 TI - Determining PM2.5 calibration curves for a low-cost particle monitor: common indoor residential aerosols. AB - Real-time particle monitors are essential for accurately estimating exposure to fine particles indoors. However, many such monitors tend to be prohibitively expensive for some applications, such as a tenant or homeowner curious about the quality of the air in their home. A lower cost version (the Dylos Air Quality Monitor) has recently been introduced, but it requires appropriate calibration to reflect the mass concentration units required for exposure assessment. We conducted a total of 64 experiments with a suite of instruments including a Dylos DC1100, another real-time laser photometer (TSI SidePakTM Model AM-510 Personal Aerosol Monitor), and a gravimetric sampling apparatus to estimate Dylos calibration factors for emissions from 17 different common indoor sources including cigarettes, incense, fried bacon, chicken, and hamburger. Comparison of minute-by-minute data from the Dylos with the gravimetrically calibrated SidePak yielded relationships that enable the conversion of the raw Dylos particle counts less than 2.5 MUm (in #/0.01 ft(3)) to estimated PM2.5 mass concentration (e.g. MUg m(-3)). The relationship between the exponentially-decaying Dylos particle counts and PM2.5 mass concentration can be described by a theoretically-derived power law with source-specific empirical parameters. A linear relationship (calibration factor) is applicable to fresh or quickly decaying emissions (i.e., before the aerosol has aged and differential decay rates introduce curvature into the relationship). The empirical parameters for the power-law relationships vary greatly both between and within source types, although linear factors appear to have lower uncertainty. The Dylos Air Quality Monitor is likely most useful for providing instantaneous feedback and context on mass particle levels in home and work situations for field-survey or personal awareness applications. PMID- 26487427 TI - Expression of human cell cycle regulators in the primary cell line of the African savannah elephant (loxodonta africana) increases proliferation until senescence, but does not induce immortalization. AB - The African savannah elephant (Loxodonta africana) is one of the critically endangered animals. Conservation of genetic and cellular resources is important for the promotion of wild life-related research. Although primary cultured cells are a useful model for the physiology and genomics of the wild-type animals, their distribution is restricted due to the limited number of cell divisions allowed in them. Here, we tried to immortalize a primary cell line of L. africana with by overexpressing human mutant form of cyclin-dependent kinase 4 (CDK4R24C), cyclin D, and telomerase (TERT). It has been shown before that the combination of human CDK4R24C, cyclin D, and TERT induces the efficient cellular immortalization of cells derived from humans, bovine, swine, and monkeys. Interestingly, although the combination of these three genes extended the cellular proliferation of the L. africana-derived cells, they did not induce cellular immortalization. This study suggest that control of cellular senescence in L. africana-derived cells would be different molecular mechanisms compared to those governing human, bovine, swine, and monkey cells. PMID- 26487428 TI - Sp1 upregulates the proximal promoter activity of the mouse collagen alpha1(XI) gene (Col11a1) in chondrocytes. AB - Type XI collagen is a cartilage-specific extracellular matrix, and is important for collagen fibril formation and skeletal morphogenesis. We have previously reported that NF-Y regulated the proximal promoter activity of the mouse collagen alpha1(XI) gene (Col11a1) in chondrocytes (Hida et. al. In Vitro Cell. Dev. Biol. Anim. 2014). However, the mechanism of the Col11a1 gene regulation in chondrocytes has not been fully elucidated. In this study, we further characterized the proximal promoter activity of the mouse Col11a1 gene in chondrocytes. Cell transfection experiments with deletion and mutation constructs indicated that the downstream region of the NF-Y binding site (-116 to +1) is also necessary to regulate the proximal promoter activity of the mouse Col11a1 gene. This minimal promoter region has no TATA box and GC-rich sequence; we therefore examined whether the GC-rich sequence (-96 to -67) is necessary for the transcription regulation of the Col11a1 gene. Luciferase assays using a series of mutation constructs exhibited that the GC-rich sequence is a critical element of Col11a1 promoter activity in chondrocytes. Moreover, in silico analysis of this region suggested that one of the most effective candidates was transcription factor Sp1. Consistent with the prediction, overexpression of Sp1 significantly increased the promoter activity. Furthermore, knockdown of Sp1 expression by siRNA transfection suppressed the proximal promoter activity and the expression of endogenous transcript of the mouse Col11a1 gene. Taken together, these results indicate that the transcription factor Sp1 upregulates the proximal promoter activity of the mouse Col11a1 gene in chondrocytes. PMID- 26487429 TI - Effects of rosiglitazone on proliferation and differentiation of duck preadipocytes. AB - Rosiglitazone (RSG), one member of the thiazolidinediones (TZDs), is a type of anti-diabetic drug in diabetic humans and animal models, whose function remains unknown in waterfowl. In this study, effects of RSG on duck preadipocyte differentiation were investigated. We detected cell viability using CCK method and measured the mRNA expression of key genes and protein contents involved in preadipocyte differentiation via qRT-PCR and ELISA kits, respectively. Lipid accumulation was determined via Oil Red O staining extraction, and lipolysis was measured by free fatty acid release in the culture medium. Results showed that high concentrations of RSG (50, 100 MUM) significantly decreased cell viability. RSG (0-10 MUM) enhanced preadipocyte differentiation in a dose-dependent manner and thus promoted lipid accumulation. With increasing RSG concentrations, cellular lipid content gradually decreased and preadipocyte differentiation was suppressed. mRNA expression of key genes involved in preadipocyte differentiation including FAS, ACC, SCD1, LPL, PLIN, SREBP1c, and ATGL were significantly upregulated by RSG, and the protein content of FAS, ACC, and ATGL were also increased in response to RSG. Meanwhile, RSG exposure increased free fatty acid release in the culture medium. Similar results were obtained in response to RSG plus oleate that was used to induce cell differentiation. These findings suggest that RSG does not promote duck preadipocyte viability, but it does induce duck preadipocyte differentiation, which might influence both lipogenesis and lipolysis pathways. PMID- 26487431 TI - Optimization of culture conditions for porcine embryonic germ cells. PMID- 26487430 TI - Vitamin C stimulates human gingival stem cell proliferation and expression of pluripotent markers. AB - Gingival stem cells (GSCs) are a novel source of mesenchymal stem cells (MSCs) that are easily accessed from the oral cavity. GSCs were considered valuable autograft MSCs with particular characteristics. However, the limitation in the number of available GSCs remains an obstacle. Therefore, this study aimed to stimulate GSC proliferation by ascorbic acid (AA) and determined the effects of AA on GSC pluripotent potential-related gene expression. GSCs were isolated from gum tissue by explant culture and continuously subcultured before analysis of stemness and effects of AA on pluripotent-related gene expression. GSCs cultured with various concentrations of AA showed increased proliferation in a dose dependent manner. AA-treated GSCs showed significantly higher expression of SSEA 3, Sox-2, Oct-3/4, Nanog, and TRA-1-60 compared with control cells. More importantly, GSCs also maintained their stemness with MSC phenotypes and failed to cause tumors in nude athymic mice. Our results show that AA is a suitable factor to stimulate GSC proliferation. PMID- 26487432 TI - Long-term culture and cryopreservation does not affect the stability and functionality of human embryonic stem cell-derived hepatocyte-like cells. AB - Human embryonic stem cells (hESCs) are predicted to be an unlimited source of hepatocytes which can pave the way for applications such as cell replacement therapies or as a model of human development or even to predict the hepatotoxicity of drug compounds. We have optimized a 23-d differentiation protocol to generate hepatocyte-like cells (HLCs) from hESCs, obtaining a relatively pure population which expresses the major hepatic markers and is functional and mature. The stability of the HLCs in terms of hepato-specific marker expression and functionality was found to be intact even after an extended period of in vitro culture and cryopreservation. The hESC-derived HLCs have shown the capability to display sensitivity and an alteration in the level of CYP enzyme upon drug induction. This illustrates the potential of such assays in predicting the hepatotoxicity of a drug compound leading to advancement of pharmacology. PMID- 26487433 TI - Early Outcomes With Direct Flow Medical Versus First-Generation Transcatheter Aortic Valve Devices: A Single-Center Propensity-Matched Analysis. AB - OBJECTIVES: To compare early outcomes between Direct Flow Medical (DFM) and 1(st) -generation transcatheter aortic valve replacement (TAVR) devices. BACKGROUND: The effectiveness of new-generation TAVR devices compared with earlier generations is unclear. METHODS AND RESULTS: Overall, 496 patients treated between November 2007 and March 2014 were included: 44 (8.7%) treated with DFM, 179 (36.9%) with Medtronic CoreValve (MCV) and 273 (54.4%) with Edwards Sapien / Sapien XT (SXT) valve. Because of differences in baseline characteristics, propensity-score matching among patients treated in the same time span (March 2012-March 2014) was performed. The primary objective was the VARC-2 device success composite endpoint. Propensity-score matching identified 41 patients in each group. A higher device success composite endpoint was observed in DFM (DFM 97.6% vs. MCV 65.9% vs. SXT 92.7%; P < 0.001). This was attributed to a significantly lower incidence of moderate-to-severe post-procedural aortic regurgitation (AR; 2.4% vs. 22% vs. 7.3%; P < 0.001), lower rate of valve embolization (0% vs. 7.3% vs. 0%; 0.041) and need for a 2nd valve implantation (0% vs. 7.3% vs. 0%; P = 0.041). CONCLUSIONS: DFM was associated with higher rates of device success and a lower incidence of post-procedural AR. New generation devices appear to address several of the limitations of earlier generation devices. PMID- 26487434 TI - Impact of surgical correction of pectus excavatum on cardiac function: insights on the right ventricle. A cardiovascular magnetic resonance study?. AB - OBJECTIVES: Pectus excavatum (PE) is often regarded as a cosmetic disease, while its effect on cardiac function is under debate. Data regarding cardiac function before and after surgical correction of PE are limited. We aimed to assess the impact of surgical correction of PE on cardiac function by cardiovascular magnetic resonance (CMR). METHODS: CMR at 1.5 T was performed in 38 patients (mean age 21 +/- 8.3; 31 men) before and after surgical correction to evaluate thoracic morphology, indices and its relation to three-dimensional left and right ventricular cardiac function. RESULTS: Surgery was successful in all patients as shown by the Haller Index ratio of maximum transverse diameter of the chest wall and minimum sternovertebral distance [pre: 9.64 (95% CI 8.18-11.11) vs post: 3.0 (2.84-3.16), P < 0.0001]. Right ventricular ejection fraction (RVEF) was reduced before surgery and improved significantly at the 1-year follow-up [pre: 45.7% (43.9-47.4%) vs 48.3% (46.9-49.5%), P = 0.0004]. Left ventricular ejection fraction was normal before surgery, but showed a further improvement after 1 year [pre: 61.0% (59.3-62.7%) vs 62.7% (61.3-64.2%), P = 0.0165]. Cardiac compression and the asymmetry index changed directly after surgery and were stable at the 1 year follow-up [3.93 (3.53-4.33) vs 2.08 (1.98-2.19) and 2.36 (2.12-2.59) vs 1.38 (1.33-1.44), respectively; P < 0.0001 for both]. None of the obtained thoracic indices were predictors of the improvement of cardiac function. A reduced preoperative RVEF was predictive of RVEF improvement. CONCLUSIONS: PE is associated with reduced RVEF, which improves after surgical correction. CMR has the capability of offering additional information prior to surgical correction. PMID- 26487435 TI - The significance of microvascular invasion after complete resection of early stage non-small-cell lung cancer. AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'in patients with non-small-cell lung cancer who have undergone complete resection, does the presence of microvascular invasion (MVI) significantly impact long-term survival or prognosis?' Altogether, more than 250 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. Outcome parameters that were used in the assessment include 5-year overall survival, event-free or recurrence-free survival (RFS) and incidence of metastatic relapse. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. The majority of the data collected were retrospective. Meta-analysis of data of over 16 000 patients showed that when considering RFS, MVI positivity was associated with a significantly reduced period of RFS; pooled hazard ratio estimates by univariate and multivariate analyses were 3.28 (95% CI 2.14-5.05; P < 0.0001) and 3.98 (95% CI 2.24-7.06; P < 0.0001), respectively. Eight of the studies showed a significantly worse 5-year survival in the presence of MVI, whereas a further study found a reduced median survival with MVI. One study showed no difference, but concurred with five other studies that MVI was associated with a significantly shorter event-free or RFS. Multivariate analyses have furthermore demonstrated that MVI positivity correlates with larger tumour size, an increased risk of distant metastases, visceral pleural involvement, lymphovascular invasion, higher tumour grade and nodal status. We conclude that the presence of microvascular invasion in resected early-stage non-small-cell lung cancer is a negative prognostic factor. PMID- 26487436 TI - Mitral valve endocarditis due to Abiotrophia defectiva in a 14th week pregnant woman. AB - Infective endocarditis during pregnancy carries a high mortality risk, both for the mother and for the foetus and requires a multidisciplinary team in the management of complicated cases. We report our experience with a 39-year old patient, affected by an acute active mitral endocarditis due to Abiotrophia defectiva at the 14th gestational week, strongly motivated to continue the pregnancy. Our patient successfully underwent mitral valve replacement with a normothermic high-flow cardiopulmonary bypass under continuous intraoperative foetal monitoring. Caesarean section occurred at the 38th gestational week. The delivery was uneventful and both the mother and child are doing well at the 16 month follow-up. PMID- 26487437 TI - Soil-Derived Microbial Consortia Enriched with Different Plant Biomass Reveal Distinct Players Acting in Lignocellulose Degradation. AB - Here, we investigated how different plant biomass, and-for one substrate-pH, drive the composition of degrader microbial consortia. We bred such consortia from forest soil, incubated along nine aerobic sequential - batch enrichments with wheat straw (WS1, pH 7.2; WS2, pH 9.0), switchgrass (SG, pH 7.2), and corn stover (CS, pH 7.2) as carbon sources. Lignocellulosic compounds (lignin, cellulose and xylan) were best degraded in treatment SG, followed by CS, WS1 and WS2. In terms of composition, the consortia became relatively stable after transfers 4 to 6, as evidenced by PCR-DGGE profiles obtained from each consortium DNA. The final consortia differed by ~40 % (bacteria) and ~60 % (fungi) across treatments. A 'core' community represented by 5/16 (bacteria) and 3/14 (fungi) bands was discerned, next to a variable part. The composition of the final microbial consortia was strongly driven by the substrate, as taxonomically diverse consortia appeared in the different substrate treatments, but not in the (WS) different pH one. Biodegradative strains affiliated to Sphingobacterium kitahiroshimense, Raoultella terrigena, Pseudomonas putida, Stenotrophomonas rhizophila (bacteria), Coniochaeta ligniaria and Acremonium sp. (fungi) were recovered in at least three treatments, whereas strains affiliated to Delftia tsuruhatensis, Paenibacillus xylanexedens, Sanguibacter inulus and Comamonas jiangduensis were treatment-specific. PMID- 26487438 TI - Testate Amoebae Like It Hot: Species Richness Decreases Along a Subalpine-Alpine Altitudinal Gradient in Both Natural Calluna vulgaris Litter and Transplanted Minuartia sedoides Cushions. AB - Most groups of higher organisms show a decrease in species richness toward high altitude, but the existence of such a pattern is debated for micro-eukaryotes. Existing data are scarce and mostly confounded with the diversity of habitats that also decreases with elevation. In order to disentangle these two factors, one approach is to consider only similar types of habitats occurring across an elevational gradient. We assessed the diversity and community structure of testate amoebae in two specific habitats: (1) natural Calluna vulgaris litter and (2) Minuartia sedoides cushions 7 years after their transplantation along a vertical transect from 1770 to 2430 m in the subalpine and alpine zones of the Swiss Alps. Analyses of co-variance and variance showed that testate amoeba species richness, equitability, and diversity declined with elevation and were significantly correlated to habitat type. In a redundancy analysis, the variation in the relative abundance of the testate amoeba taxa in Calluna vulgaris litter was equally explained by elevation and litter pH. This is the first study documenting a monotonic decrease of protist diversity in similar habitats across an elevational gradient. PMID- 26487439 TI - Propranolol for the treatment of anxiety disorders: Systematic review and meta analysis. AB - The effects of propranolol in the treatment of anxiety disorders have not been systematically evaluated previously. The aim was to conduct a systematic review and meta-analysis of randomised controlled trials, addressing the efficacy of oral propranolol versus placebo or other medication as a treatment for alleviating either state or trait anxiety in patients suffering from anxiety disorders. Eight studies met the inclusion criteria. These studies concerned panic disorder with or without agoraphobia (four studies, total n = 130), specific phobia (two studies, total n = 37), social phobia (one study, n = 16), and posttraumatic stress disorder (PTSD) (one study, n = 19). Three out of four panic disorder trials qualified for pooled analyses. These meta-analyses found no statistically significant differences between the efficacy of propranolol and benzodiazepines regarding the short-term treatment of panic disorder with or without agoraphobia. Also, no evidence was found for effects of propranolol on PTSD symptom severity through inhibition of memory reconsolidation. In conclusion, the quality of evidence for the efficacy of propranolol at present is insufficient to support the routine use of propranolol in the treatment of any of the anxiety disorders. PMID- 26487440 TI - Sex-specific association of rs4746172 of VCL gene with hypertension in two Han populations from Southern China. AB - Hypertension is the most common and lethal risk factor for cardiovascular disease (CVD). Numerous variants have been associated with hypertension, however, most of which failed to get replication due to ethnic differences. In this study, we analyzed associations of 10 newly reported single nucleotide polymorphisms (SNPs) in Europeans with hypertension in Chinese. A total of 1766 samples consisting of 880 subjects with hypertension and 886 controls were collected and the SNPs were genotyped using multiple assays based on the SNaPshot mini-sequencing approach. Our results revealed a significant genotypic association of rs4746172 of VCL with hypertension with a lower frequency of minor allele in male subjects (OR = 0.70, 95% CI: 0.54-0.92, p = 0.011) but not in females. To validate the result, we genotyped the SNPs in another Chinese population with 546 individuals, and got a consistent association for the rs4746172 (OR = 0.56, 95% CI: 0.38-0.82, p = 2.4 * 10(-3)) in males. The VCL-encoding protein was involved in cardiomyopathy that associated with hypertension, therefore our results suggest the rs4746172 of VCL may be a novel target for clinical interventions to reduce CVD risk by regulating blood pressure in male Chinese. PMID- 26487441 TI - The Perceived and Actual Physical Activity Behaviors of African American Women. AB - Lack of physical activity is a leading contributor to obesity in the US. The unusually high rates of obesity in African-American (AA) women corroborate with lack of recommended levels of exercise in this population. The purpose of this study was to describe exercise behaviors and intention to change using the stages of change (SOC) model in a sample of AA women. A population-based observational study was conducted with 292 AA women in Florida. Outcome variables were engaging in aerobic, strength-based, and stretching exercise. More than half (61.25 %) did not engage in strength-based exercise, more than a third (37.7 %) did not engage in aerobic exercise, and a little less than half (45.9 %) did not participate in stretching exercise. SOC was the main independent variable. Women in action and maintenance SOC were significantly more likely to engage in aerobic exercise (OR 16.1, 95 % CI 7.09-25.7), strength-based exercise (OR 15.4, 95 % CI 6.58-22.7), and stretching exercise (OR 3.80, 95 % CI 1.91-7.52). The SOC is reflective of actual exercise behavior in AA women. A large number of AA women do not engage in regular recommended levels of exercise. Understanding SOC can be essential to developing culturally appropriate and motivation matched interventions for improving AA women's exercise habits. PMID- 26487442 TI - Computational allosteric ligand binding site identification on Ras proteins. AB - A number of computational techniques have been proposed to expedite the process of allosteric ligand binding site identification in inherently flexible and hence challenging drug targets. Some of these techniques have been instrumental in the discovery of allosteric ligand binding sites on Ras proteins, a group of elusive anticancer drug targets. This review provides an overview of these techniques and their application to Ras proteins. A summary of molecular docking and binding site identification is provided first, followed by a more detailed discussion of two specific techniques for binding site identification in ensembles of Ras conformations generated by molecular simulations. PMID- 26487443 TI - The greedy nature of mutant RAS: a boon for drug discovery targeting cancer metabolism? AB - RAS oncogene mutations are frequently detected in human cancers. Among RAS mediated tumorigenesis, KRAS-driven cancers are the most frequently diagnosed and resistant to current therapies. Despite more than three decades of intensive efforts, there are still no specific therapies for mutant RAS proteins. While trying to block those well-established downstream pathways, such as the RAF-MAPK pathway and the PI3K-AKT pathway, attentions have been paid to potential effects of RAS on metabolic pathways and the feasibility for targeting these pathways. Recent studies have proved that RAS not only promotes aerobic glycolysis and glutamine metabolism reprograming to provide energy, but it also facilitates branched metabolism pathways, autophagy, and macropinocytosis. These alterations generate building blocks for tumor growth and strengthen antioxidant defense in tumor cells. All of these metabolic changes meet different demands of RAS-driven cancers, making them distinct from normal cells. Indeed, some achievements have been made to inhibit tumor growth through targeting specific metabolism rewiring in preclinical models. Although there is still a long way to elucidate the landscape of altered metabolism, we believe that specific metabolic enzymes or pathways could be therapeutically targeted for selective inhibition of RAS-driven cancers. PMID- 26487444 TI - Erratum to: Iron Deficiency Without Anemia Is Associated with Anger and Fatigue in Young Japanese Women. PMID- 26487445 TI - Were Plasma Trace Element Levels Changed in the Children with ADHD? PMID- 26487446 TI - Serum Magnesium Status in Patients Subjects with Depression in the City of Yazd in Iran 2013-2014. AB - Depression is the most common mental disorder and involves many factors. The regulatory effects of magnesium on N-methyl-D-aspartate (NMDA) channels make it a factor in the treatment of depression. The present study investigated the level of serum magnesium in subjects diagnosed with depression in the city of Yazd in Iran. This cross-sectional study was done from January 2013 to January 2014 on 650 patients with depression who agreed to participate in this study. Diagnosis was made using the Beck Depression Inventory test (BDI-II); those scoring higher than 11 were sent to the medical school laboratory for further testing of serum magnesium levels. The mean age of the patients was 34.16 +/- 9.12 years. Of the 650 subjects, 195 were male (30 %) and 455 were female (70 %). The total mean serum magnesium was 2.1 +/- 0.26 mg/dl. The prevalence of hypomagnesemia 13.7 %, hypermagnesemia 8.3 %, and sub-optimal magnesium levels was 26.5 %. Sub-optimal prevalence in women (28.1 %) was higher than in men (26.2 %). A significant relationship was observed between depression and serum magnesium level (p = 0.02). The results indicated that the prevalence of hypomagnesemia in subjects diagnosed with depression is high compared to non-depressed individuals. Moreover, there was a significant relationship between hypomagnesemia and intensity of depression that suggests a role for this element in the pathogenesis of the disorder. The high sub-optimal prevalence among women indicates that increased attention should be paid to this group. PMID- 26487447 TI - Generation of Dynamic Free-Form Temperature Gradients in a Disposable Microchip. AB - Temperature gradients (TGs) provide an effective approach to controlling solvated molecules and creating spatiotemporally varying thermal stimuli for biochemical research. Methods developed to date for generating TGs can only create a limited set of static temperature profiles. This article describes a method for establishing dynamic free-form TGs in polydimethylsiloxane (PDMS) as well as in gases and liquids in contact with the PDMS. The heating mechanism relies on the efficient acoustic absorption by the PDMS of high-frequency (5-200 MHz) surface acoustic waves (SAWs). MATLAB-aided actuation of a transducer enabled the generation and propagation of SAWs in a controlled fashion, which permitted spatiotemporal control over the temperature in the PDMS microstructures. This technique is exploited to perform one-shot high-resolution melting (HRM) analysis to detect single nucleotide polymorphisms (SNPs) in DNA. The experimental results displayed a 10-fold higher resolution and an enhanced signal-to-noise ratio compared to the results obtained using a conventional real-time PCR machine. PMID- 26487448 TI - Evidence for the widespread production of DSF family signal molecules by members of the genus Burkholderia by the aid of novel biosensors. AB - Many bacteria employ cis-2-unsaturated fatty acids, referred to as DSF (diffusible signal factor) family signals, to communicate with each other. Such systems have been shown to control biofilm formation, motility, production of hydrolytic enzymes and expression of virulence factors. We report the construction of novel biosensors on the basis of components of the Burkholderia DSF (BDSF) dependent circuitry of Burkholderia cenocepacia H111 and evaluated their utility for detecting the production of DSF family signal molecules. We show that a luxAB-based biosensor responds to nM levels of synthetic BDSF and is suitable to detect a wide range of cis-2 fatty acid molecules. Using this biosensor we show that the production of DSF family molecules is widespread among members of the B. cepacia complex and demonstrate for the first time that DSF based molecules are also produced by plant-associated Burkholderia species. PMID- 26487449 TI - Characterization and isolation of immature neurons of the adult mouse piriform cortex. AB - Physiological studies indicate that the piriform or primary olfactory cortex of adult mammals exhibits a high degree of synaptic plasticity. Interestingly, a subpopulation of cells in the layer II of the adult piriform cortex expresses neurodevelopmental markers, such as the polysialylated form of neural cell adhesion molecule (PSA-NCAM) or doublecortin (DCX). This study analyzes the nature, origin, and potential function of these poorly understood cells in mice. As previously described in rats, most of the PSA-NCAM expressing cells in layer II could be morphologically classified as tangled cells and only a small proportion of larger cells could be considered semilunar-pyramidal transitional neurons. Most were also immunoreactive for DCX, confirming their immature nature. In agreement with this, detection of PSA-NCAM combined with that of different cell lineage-specific antigens revealed that most PSA-NCAM positive cells did not co-express markers of glial cells or mature neurons. Their time of origin was evaluated by birthdating experiments with halogenated nucleosides performed at different developmental stages and in adulthood. We found that virtually all cells in this paleocortical region, including PSA-NCAM-positive cells, are born during fetal development. In addition, proliferation analyses in adult mice revealed that very few cells were cycling in layer II of the piriform cortex and that none of them was PSA-NCAM-positive. Moreover, we have established conditions to isolate and culture these immature neurons in the adult piriform cortex layer II. We find that although they can survive under certain conditions, they do not proliferate in vitro either. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 748-763, 2016. PMID- 26487450 TI - Enantioselective Oxidative Aerobic Dealkylation of N-Ethyl Benzylisoquinolines by Employing the Berberine Bridge Enzyme. AB - N-Dealkylation methods are well described for organic chemistry and the reaction is known in nature and drug metabolism; however, to our knowledge, enantioselective N-dealkylation has not been yet reported. In this study, exclusively the (S)-enantiomers of racemic N-ethyl tertiary amines (1-benzyl-N ethyl-1,2,3,4-tetrahydroisoquinolines) were dealkylated to give the corresponding secondary (S)-amines in an enantioselective fashion at the expense of molecular oxygen. The reaction is catalyzed by the berberine bridge enzyme, which is known for C?C bond formation. The dealkylation was demonstrated on a 100 mg scale and gave optically pure dealkylated products (ee>99 %). PMID- 26487455 TI - Coping and life satisfaction after stroke. AB - This study examined the coping strategies and life satisfaction of 73 elderly couples at 6-12 months after a cerebrovascular accident. Instruments included the Life Satisfaction Index A, the Ways of Coping Scale, and the Gulick Activity of Daily Living Scale. A series of mixed model analyses of variance were performed. A single significant main effect was obtained for the variable, Seeking Social Support. Stroke survivors were less likely to use Seeking Social Support coping strategies than were their spouses. Correlations indicated that survivors manifested more positive affect when (a) they did not use Accepting Responsibility coping strategies; (b) they did not use Escape-Avoidance coping strategies; (c) their spouse did not use Escape-Avoidance; and (d) their spouses used fewer Planful Problem Solving coping strategies. Survivors were more likely to express satisfaction with past actions to the extent that (a) the survivor's spouse did not use Confrontive Coping strategies and (b) the survivor's spouse did not indicate using Planful Problem Solving coping strategies. The spouse's affect was positive to the extent that he or she did not use Escape-Avoidance coping strategies. More positive affect in stroke survivors was noted when their functional skills allowed them to do more independent activities of daily living. These relationships remained constant regardless of the functional skill of the survivor. The study supports the idea that groups with a psychoeducational component would provide useful social support and coping alternatives. Continued rehabilitation efforts to improve daily living skills are recommended. PMID- 26487452 TI - Breast and cervical cancer screening in Great Britain: Dynamic interrelated processes. AB - No previous analysis has investigated the determinants of screening uptake for breast and cervical cancer screening for possible spillover effects from one type of screening examination to the other type of screening examination with a dynamic bivariate panel probit model. For our analysis, we used a dynamic random effects bivariate panel probit model with initial conditions (Wooldridge-type estimator) and dependent variables were the participation of breast and cervical cancer screening in the recent year. The balanced panel sample consisted of 844 women from the British Household Panel Survey (BHPS) from the time period 1992 to 2008. Our analysis showed the high relevance of past screening behaviour and the importance of state dependency for the same and the other type of cancer screening examinations even after controlling for covariates and unobserved heterogeneity. The uptake for breast and cervical cancer screening was higher when the same screening examination was done one or three years earlier. This result is in accordance with the medical screening programmes in Great Britain. With regard to breast and cervical cancer screening positive spillover effects existed between screening examinations in the third order lags. Women with a previous visit to a general practitioner and individuals in the recommended age groups had a higher uptake for breast and cervical cancer screening. Other socioeconomic and health related variables had non-uniform results in both screening examinations. Promoting the uptake of one female prevention activity could also enhance the uptake of the other prevention activity. PMID- 26487456 TI - Headache characteristics in aneurysmal subarachnoid hemorrhage. AB - To investigate the nature of the headache accompanying aneurysmal subarachnoid hemorrhage, a retrospective study was conducted. Fifty-four patients and 54 controls completed questionnaires regarding headache, medical history, and family history, in an attempt to derive further information regarding symptoms and factors that might be predictive of aneurysmal subarachnoid hemorrhage. Factors that appear to be of importance in evaluating headache caused by subarachnoid hemorrhage include ominously severe headache, a history of vigorous physical activity precipitating headache, syncope or transient lethargy accompanying headache, previous medical attention for headache, a family history of aneurysmal subarachnoid hemorrhage, or catastrophic central nervous system event at an early age. An algorithm for the management of serious headache is suggested. PMID- 26487451 TI - Effects of chronic sugar consumption on lipid accumulation and autophagy in the skeletal muscle. AB - PURPOSE: In recent years, the increasing consumption of soft drinks containing high-fructose corn syrup or sucrose has caused a rise in fructose intake, which has been related to the epidemic of metabolic diseases. As fructose and glucose intake varies in parallel, it is still unclear what the effects of the increased consumption of the two single sugars are. In the present study, the impact of chronic consumption of glucose or fructose on skeletal muscle of healthy mice was investigated. METHODS: C57BL/6J male mice received water (C), 15 % fructose (ChF) or 15 % glucose (ChG) to drink for up to 7 months. Lipid metabolism and markers of inflammation and autophagy were assessed in gastrocnemius muscle. RESULTS: Increased body weight and gastrocnemius muscle mass, as well as circulating glucose, insulin, and lipid plasma levels were observed in sugar-drinking mice. Although triglycerides increased in the gastrocnemius muscle of both ChF and ChG mice (+32 and +26 %, vs C, respectively), intramyocellular lipids accumulated to a significantly greater extent in ChF than in ChG animals (ChF +10 % vs ChG). Such perturbations were associated with increased muscle interleukin-6 levels (threefold of C) and with the activation of autophagy, as demonstrated by the overexpression of LC3B-II (ChF, threefold and ChG, twofold of C) and beclin-1 (ChF, sevenfold and ChG, tenfold of C). CONCLUSIONS: The present results suggest that intramyocellular lipids and the pro-inflammatory signaling could contribute to the onset of insulin resistance and lead to the induction of autophagy, which could be an adaptive response to lipotoxicity. PMID- 26487457 TI - Cerebrovascular complications of infective endocarditis. AB - We reviewed the cerebrovascular complications of 158 episodes of infective endocarditis occurring in 155 patients. Cerebrovascular complications occurred in 21 patients (14%). The incidences of cerebral embolism, intracerebral hemorrhage, and subarachnoid hemorrhage were 10%, 3%, and 1%, respectively. Death occurred in 33% of patients with cerebrovascular complications and 4% without. Patients whose condition was complicated by intracerebral hemorrhage had an even greater rate of mortality (80%). Sixty-two percent of cerebrovascular complications occurred within 2 days of antibiotic therapy; 29% occurred 2 weeks later. Two of three patients receiving open-heart surgery within 2 days of cerebrovascular complications died. Seventeen of 133 patients with native valve endocarditis and 4 of 22 patients with prosthetic valve endocarditis had cerebrovascular complications. Echocardiographic evidence of vegetation was seen in 120 patients, and cerebrovascular complications were noted in 16 patients. Twelve of 62 patients with mitral valve involvement detected by echocardiography and 4 of 40 patients with aortic valve involvement had cerebrovascular complications. According to the findings of surgery or pathology, 4 of 24 patients with mitral valve involvement and 4 of 36 patients with aortic valve involvement had cerebrovascular complications. We conclude that vegetation detected by echocardiography does not increase the risk of cerebrovascular complicatons; there is no difference in the incidence of cerebrovascular complications between the mitral and aortic valve groups, either by the involvement of vegetation detected by echocardiography or the surgical or pathologic findings; there is no difference in the incidence of cerebrovascular complications when comparing the native and prosthetic valve groups or the streptococcus viridans and Staphylococcus aureus groups; cerebrovascular complications, especially intracerebral hemorrhage, increase the risk of mortality in patients with infective endocarditis; although most cerebrovascular complications occurred within 2 days of antibiotic therapy, late onset of cerebrovascular complications are not uncommon; and it is better to avoid early open heart surgery in patients whose condition is complicated by intracerebral hemorrhage or hemorrhagic infarction. PMID- 26487458 TI - Delay time between onset of ischemic stroke and hospital arrival. AB - Some current experimental protocols for acute ischemic stroke require the initiation of treatment within hours of the onset of stroke symptoms. We prospectively evaluated 30 patients with acute ischemic stroke based on clinical and computed tomography findings. The time between the onset of stroke symptoms and arrival in the emergency room and subsequently on the stroke service was determined. Within 3, 6,12, and 24 h of the onset of stroke symptoms, 16 (53%), 19 (63%), 22 (73%), and 25 (83%) patients had arrived at the emergency room and 0 (0%), 4 (13%), 14 (47%), and 22 (73%) of them on the stroke service, respectively. From the onset of stroke symptoms, the mean arrival time to the emergency room was 24 h (range, 30 min to 144 h) and to the stroke service was 61 h (range, 4-150 h). The mean time between arrival in the emergency room and stroke service was 8.6 h (range, 0-47 h). Even though 53% and 63% of our patients arrived at the emergency room within 3 and 6 h of the onset of stroke symptoms, only 0% and 13% of them arrived on the stroke service within the same time period for the initiation of treatment, respectively. Thus, in order for more patients to qualify for current experimental protocols, they must arrive on the stroke service more quickly or treatment must be initiated in the emergency room. PMID- 26487459 TI - A prospective evaluation of the utility of clinical data in distinguishing acute large vessel from lacunar cerebral infarctions. AB - A stroke registry of 290 patients was developed to determine the value of various clinical data in discriminating acute large vessel from lacunar infarctions. Clinical or computed tomography (CT) localization was achieved in 98% of patients with infarcts. Among 216 localizable supratentorial infarcts, CT demonstrated the responsible lesion in 22 of 54 lacunes (42%) and 109 of 162 large vessel infarcts (67%). History provided the basis for localization, i.e., distinction between large vessel and lacunar events, in 74% with 88% sensitivity and 59% specificity; higher cortical function examination in 88% with 96% sensitivity and 74% specificity; neurologic examination in 79% with 72% sensitivity and 75% specificity; graphes-thesia in 57% with 63% sensitivity and 89% specificity; and EEG in 76% with 71% sensitivity and 100% specificity. PMID- 26487460 TI - Reversal of acute ischemic hypodense lesions on computed tomography. AB - Hypodense ischemic lesions on computed tomography (CT) are usually associated with cerebral infarction and permanent tissue injury. We describe three cases of acute ischemic lesions detected by CT that rapidly resolved following therapy. In two cases, the appearance of hypodense lesions was associated with the onset of vasospasm after subarachnoid hemorrhage, and resolution correlated with successful treatment. In the third case, multiple acute hypodense lesions in a patient with eclampsia improved following treatment with diuretic agents. PMID- 26487461 TI - Decision analysis and carotid endarterectomy. AB - A data base and a framework for clinical decision analysis are provided to enable the clinician to determine the value of carotid endarterectomy in patients with transient ischemic attacks. This approach permits optimal utilization of available data, maximizes the value of informed consent by clearly delineating areas of physician and patient expertise, and permits a quantitative assessment of the impact of uncertainty regarding underlying variables on decision outcome. The results of the analysis indicate that (a) the late nonstroke death rate has little effect on the value of endarterectomy, (b) the patient's relative valuation of stroke and immediate versus delayed death are among the most crucial variables underlying the value of endarterectomy, and (c) endarterectomy may be indicated in certain patients with transient ischemic attacks, but when its utility is measured in terms of value rendered to the patient, its relative cost may be greater than that of certain life-saving operations such as heart or liver transplant. PMID- 26487462 TI - Big-endothelin in acute ischemic stroke. AB - Plasma big-endothelin (BE) in 12 patients with acute severe ischemic stroke was studied. Six patients developed complete supratentorial infarctions, and six patients had severe infarctions of pons, cerebellum, and/or medulla. Significant elevations of BE during the first 2 weeks after the initial stroke and significant differences between the pathophysiological subgroups of stroke did not occur. Only patients with a poor outcome showed significant elevations of BE in contrast to patients with a better prognosis (p <= 0.05). Patients with supratentorial infarctions demonstrated a tendency of higher BE levels than patients with infratentori-al stroke (p <= 0.07). These results support the theory that endothelins represent the amount of damaged cerebral tissue rather than the endothelium leakage. Low endothelin concentrations may play a role in local vasodilation and reperfusion. PMID- 26487463 TI - Shoulder pain in stroke patients and its effects on rehabilitation. AB - The purpose of this study was to examine whether prompt diagnosis and management of shoulder pain is beneficial in decreasing pain and increasing range of motion and functional recovery. Among 116 stroke patients receiving outpatient rehabilitation, 48 had shoulder pain. Twenty-eight of the patients with shoulder pain received occupational therapy and physiatric management. Five of the 28 patients had specific diagnoses. Etiology of the pain in the remaining 23 patients (Group 1) was not known, and these patients were treated with nonsteroidal antiinflammatory drugs (NSAIDs). The remaining 20 (Group 2) received only occupational therapy and were used as the control group. Pain relief, range of motion (ROM) in flexion, and abduction and functional recovery were compared in the two groups. Results show that a significantly higher percentage of Group 1 was found to have pain relief; 91% versus 15% with p < 0.00001 for the difference. A significant number of patients improved ROM for flexion and abduction in Group 1 versus Group 2 (p < 0.006 and p < 0.055 for the difference for flexion and abduction, respectively). Functional recovery was highly significant for Group 1,100% compared to 55% for Group 2, with p < 0.0001 for the difference. These results emphasize the importance of management of shoulder pain with NSAIDs along with ROM exercises for successful rehabilitation of hemiplegic patients. PMID- 26487464 TI - Comparisons of polio-araiosis and leuko-araiosis in dementias of ischemic vascular and alzheimer types. AB - Computed tomography scanners were utilized to quantitate, by Hounsfield unit (HU) densities, normal and abnormal cerebral gray and white matter compartments and their perfusion values, among patients with probable dementia of ischemic vascular (IVD: n= 10,72.7 +/- 9.0 years) and Alzheimer's types (DAT: n = 10, 72.7 +/- 5.8 years). Results were compared with similar measures among age-matched normal volunteers (n = 10, 71.0 +/- 8.2 years). "Normal" HU values for gray and white matter were previously obtained among younger normal volunteers (n = 27, 49.7 +/- 8.9). After adjusting for cerebral atrophy, IVD patients showed reduced HU and cerebral blood flow (CBF) values in white matter, but gray matter HU values were only reduced in frontotemporal cortex. In DAT, mean HU and CBF values for cortical and subcortical gray matter were severely reduced compared with age matched normal and with IVD patients. Cognitive test performance correlated directly with volumes of hypodense cortex or "polio-araiosis" in DAT, but not in IVD, in which cognitive performance correlated directly with volumes of leuko araiosis. PMID- 26487465 TI - Kinetic surface roughening and wafer bow control in heteroepitaxial growth of 3C SiC on Si(111) substrates. AB - A thin, chemically inert 3C-SiC layer between GaN and Si helps not only to avoid the "melt-back" effect, but also to inhibit the crack generation in the grown GaN layers. The quality of GaN layer is heavily dependent on the unique properties of the available 3C-SiC/Si templates. In this paper, the parameters influencing the roughness, crystalline quality, and wafer bow are investigated and engineered to obtain high quality, low roughness 3C-SiC/Si templates suitable for subsequent GaN growth and device processing. Kinetic surface roughening and SiC growth mechanisms, which depend on both deposition temperature and off-cut angle, are reported for heteroepitaxial growth of 3C-SiC on Si substrates. The narrower terrace width on 4 degrees off-axis Si enhances the step-flow growth at 1200 degrees C, with the roughness of 3C-SiC remaining constant with increasing thickness, corresponding to a scaling exponent of zero. Crack-free 3C-SiC grown on 150-mm Si substrate with a wafer bow of less than 20 MUm was achieved. Both concave and convex wafer bow can be obtained by in situ tuning of the deposited SiC layer thicknesses. The 3C-SiC grown on off-axis Si, compared to that grown on on-axis Si, has lower surface roughness, better crystallinity, and smaller bow magnitude. PMID- 26487466 TI - Percutaneous nerve field stimulation (PENS) of the occipital region as a possible predictor for occipital nerve stimulation (ONS) responsiveness in refractory headache disorders? A feasibility study. AB - BACKGROUND: Occipital nerve stimulation (ONS) has been reported to diminish pain levels in intractable chronic headache syndromes of different origin. No reliable objective markers exist to predict ONS responsiveness. This study investigated the predictive value of occipital percutaneous nerve field stimulation (PENS) prior to ONS. METHODS: This trial included 12 patients (CCH, CM, PTH, CH) with chronic refractory headache syndromes eligible for ONS. Repetitive PENS (3 * /10 days) was performed and the headache severity/frequency monitored over four weeks before ONS implantation. Further assessment of PENS/ONS outcomes were stimulation related complications, perception/tolerance stimulation threshold, the Migraine Disability Scale (MIDAS) and the Beck Depression Inventory (BDI). RESULTS: All PENS responders benefited from ONS. Of the seven PENS-nonresponders with VAS 6.1(+/-1.1), six experienced significant pain relief from ONS after three months and one patient failed the PENS/ONS trial (VAS 3.7 (+/-1.6)); (95% CI 3.6 to 5.7, p < 0.001). The VAS baseline was 8.4 (+/-0.5) and decreased significantly (50% reduction in severity/frequency) in five patients after PENS, while seven failed to improve (VAS 4.9 (+/-1.1); (95% CI 2.5 to 4.5, p < 0.001). BDI baseline (from 22.6 (+/-4.2) to 10.6 (+/-5.9) (95% CI 7.4 to 16.6, p < 0.001)) and MIDAS baseline (from 143.9 (+/-14.5) to 72.8 (+/-28.7) (95% CI 1.17 to 2.3, p < 0.001)) significantly declined after ONS. No PENS/ONS-related complications occurred. CONCLUSIONS: Presurgical applied occipital PENS failed to identify ONS responders sufficiently according to our study protocol, thus requiring further specific investigations to determine its predictive usefulness. PMID- 26487467 TI - Hypoxia triggers high-altitude headache with migraine features: A prospective trial. AB - BACKGROUND: Given the high prevalence and clinical impact of high-altitude headache (HAH), a better understanding of risk factors and headache characteristics may give new insights into the understanding of hypoxia being a trigger for HAH or even migraine attacks. METHODS: In this prospective trial, we simulated high altitude (4500 m) by controlled normobaric hypoxia (FiO2 = 12.6%) to investigate acute mountain sickness (AMS) and headache characteristics. Clinical symptoms of AMS according to the Lake Louise Scoring system (LLS) were recorded before and after six and 12 hours in hypoxia. O2 saturation was measured using pulse oximetry at the respective time points. History of primary headache, especially episodic or chronic migraine, was a strict exclusion criterion. FINDINGS: In total 77 volunteers (43 (55.8%) males, 34 (44.2%) females) were enrolled in this study. Sixty-three (81.18%) and 40 (71.4%) participants developed headache at six or 12 hours, respectively, with height and SpO2 being significantly different between headache groups at six hours (p < 0.05). Binary logistic regression model revealed a significant association of SpO2 and headache development (p < 0.05, OR 1.123, 95% CI 1.001-1.259). In a subgroup of participants, with history of migraine being a strict exclusion criterion, hypoxia triggered migraine-like headache according to the International Classification of Headache Disorders (ICHD-3 beta) in n = 5 (8%) or n = 6 (15%), at six and 12 hours, respectively. INTERPRETATION: Normobaric hypoxia is a trigger for HAH and migraine-like headache attacks even in healthy volunteers without any history of migraine. Our study confirms the pivotal role of hypoxia in the development of AMS and beyond that suggests hypoxia may be involved in migraine pathophysiology. PMID- 26487468 TI - Nurses improve migraine management in primary care. AB - INTRODUCTION: Migraine is a common disorder with a high burden. Adequate treatment results in improvement of quality of life. Migraine patients are mainly treated by general practitioners (GPs), but there is still room for improvement. This study investigated whether primary care nurses could improve the treatment of migraine patients compared to usual care as provided by the GPs. PARTICIPANTS AND METHODS: We conducted a non-randomized controlled prospective trial in 235 patients diagnosed with migraine with or without aura according to ICHD-II criteria, aged between 18 and 65 years. Patients with migraine treated only by their GP were compared to management by a nurse supervised by a GP. RESULTS: In the intervention group, fewer migraine patients were referred to a neurologist (p < 0.001). The reduction in monthly migraine days compared to baseline was more apparent in the intervention group at six (p = 0.09) and nine months (p = 0.006). There was no significant change in dichotomized HIT score (p = 0.076). Change in satisfaction of patients did not differ significantly (p = 0.070). CONCLUSIONS: The care administered by a headache nurse in the primary care setting supervised by a GP resulted in fewer referrals to the neurologist and more migraine-free days per month, but no change in HIT score. There was no difference in satisfaction scores between both groups. PMID- 26487469 TI - Corrigendum. PMID- 26487471 TI - EuroSpine Task Force on Research: support for spine researchers. PMID- 26487472 TI - The surgical vascular anatomy of the minimally invasive lateral lumbar interbody approach: a cadaveric and radiographic analysis. AB - PURPOSE: The minimally invasive (MI) lateral lumbar interbody fusion (LLIF) approach has become increasingly popular for the treatment of degenerative lumbar spine disease. The neural anatomy of the lumbar plexus has been studied; however, the pertinent surgical vascular anatomy has not been examined in detail. The goal of this study is to examine the vascular structures that are relevant in relation to the MI-LLIF approach. METHODS: Anatomic dissection of the lumbar spines and associated vasculature was performed in three embalmed, adult cadavers. Right and left surgeon perspective views during LLIF were for a total of six approaches. During the dissection, all vascular elements were noted and photographed, and anatomical relationships to the vertebral bodies and disc spaces were analyzed. In addition, several axial and sagittal MRI images of the lumbar spine were analyzed to complement the cadaveric analysis. RESULTS: The aorta descends along the left anterior aspect of lumbar vertebra with an average distance of 2.1 cm (range 1.9-2.3 cm) to the center of each intervertebral disc. The vena cava descends along the right anterior aspect of lumbar vertebrates with average distance of 1.4 cm (range 1.3-1.6 cm) to the center of the intervertebral disc. Each vertebral body has two lumbar arteries (direct branches from the aorta); one exits to the left and one to the right side of the vertebral body. The lumbar arteries pass underneath the sympathetic trunk, run in the superior margin of the vertebral body and extend all the way across it, with average length of 3.8 cm (range 2.5-5 cm). The mean distance between the arteries and the inferior plate of the superior disc space is 4.2 mm (range 2-5 mm) and mean distance of 3.1 cm (range 2.8-3.8 cm) between two arteries in adjacent vertebrae. One of the cadavers had an expected normal anatomical variation where the left arteries at L3-L4 anastomosed dorsally of the vertebral bodies at the middle of the intervertebral disc. CONCLUSIONS: Understanding the vascular anatomy of the lateral and anterior lumbar spine is paramount for successfully and safely executing the LLIF procedure. It is imperative to identify anatomical variations in lumbar arteries and veins with careful assessment of the preoperative imaging. PMID- 26487473 TI - Lumbar spinal degenerative "microinstability": hype or hope? Proposal of a new classification to detect it and to assess surgical treatment. AB - PURPOSE: The stage of unstable dysfunction, also defined as "active discopathy" by Nguyen in 2015 and configuring the first phase of the degenerative cascade described by Kirkaldy-Willis, has specific pathoanatomical and clinical characteristics (low back pain) in the interested vertebral segment, without the presence of spondylolisthesis in flexion-extension radiography. This clinical condition has been defined as "microinstability" (MI). The term has currently not been recognized by the scientific community and is subject of debate for its diagnostic challenge. MI indicates a clinical condition in which the patient has a degeneration of the lumbar spine, causing low back pain, and radiological examinations do not show a spondylolisthesis. METHODS: We elaborated a clinical score test based on preoperative radiological examinations (static and dynamic X Rays, CT and MRI) to detect and assess MI. Then, we enrolled 74 patients, all the levels from L1 to S1 were analysed, for a total amount of 370 retrospectively analysed levels. We excluded patients with degenerative scoliosis, as it is related to an advanced stage of degeneration. The test has been developed with the aim of furnishing quantitative data on the basis of the aforementioned radiological examinations and of elaborating a diagnosis and a treatment for the degenerative pathology in dysfunctional phase, responsible for low back pain. RESULTS: We performed a statistical analysis on the results obtained from the test in terms of significativity and predictive value with a 1-year follow-up, calculating the p value and the chi (2) value. CONCLUSIONS: In patients with low back pain and negative dynamic X-Rays, an accurate analysis of the radiological exams (CT, MRI, X-Rays) allows to formulate a diagnosis of suspect MI with a good predictive value. This situation opens many clinical and medicolegal scenarios. The preliminary results seem to validate the test with a good predictive value, especially towards ASD, but they need further studies. On the basis of the results obtained, the test seems to allow a good classification of the dysfunctional phase of the degenerative cascade, identifying and classifying MI as a pathologic entity, defining its pathoanatomical and clinical relevance and elaborating a treatment algorithm. PMID- 26487474 TI - An auto-adaptive optimization approach for targeting nonpoint source pollution control practices. AB - To solve computationally intensive and technically complex control of nonpoint source pollution, the traditional genetic algorithm was modified into an auto adaptive pattern, and a new framework was proposed by integrating this new algorithm with a watershed model and an economic module. Although conceptually simple and comprehensive, the proposed algorithm would search automatically for those Pareto-optimality solutions without a complex calibration of optimization parameters. The model was applied in a case study in a typical watershed of the Three Gorges Reservoir area, China. The results indicated that the evolutionary process of optimization was improved due to the incorporation of auto-adaptive parameters. In addition, the proposed algorithm outperformed the state-of-the-art existing algorithms in terms of convergence ability and computational efficiency. At the same cost level, solutions with greater pollutant reductions could be identified. From a scientific viewpoint, the proposed algorithm could be extended to other watersheds to provide cost-effective configurations of BMPs. PMID- 26487475 TI - Metabolite Profiling of Soybean Seed Extracts from Near-Isogenic Low and Normal Phytate Lines Using Orthogonal Separation Strategies. AB - Untargeted metabolomic profiling using liquid chromatography-mass spectrometry (LC-MS) was applied to lipid-depleted methanolic extracts of soybean seeds utilizing orthogonal chromatographic separations (reversed-phase and hydrophilic interaction) in both positive and negative ionization modes. Four near-isogenic lines (NILs) differing in mutations for two genes encoding highly homologous multidrug resistant proteins (MRPs) were evaluated. The double mutant exhibited a low phytate phenotype, whereas the other three NILs, the two single mutants and the wild type, did not. Principal component analysis (PCA) of the four LC-MS data sets fully separated the low phytate line from the other three. While the levels of neutral oligosaccharides were the same for all lines, there were significant metabolite differences residing in the levels of malonyl isoflavones, soyasaponins, and arginine. Two methanol-soluble polypeptides were also found as differing in abundance levels, one of which was identified as the allergen Gly m 1. PMID- 26487476 TI - War Wounded and Victims of Traffic Accidents in a Surgical Hospital in Africa: An Observation on Injuries. AB - INTRODUCTION: Weapon injuries in armed conflict are likely to receive medical attention. Other types of injuries, like traffic accidents, continue to occur during armed conflict. PROBLEM: Injuries caused by weapons and by traffic accidents require treatment, but reports and figures to help in prioritizing care are scarce. METHODS: In a prospective observational study, all emergency patients admitted to the surgical ward in a public hospital of the Central African Republic were evaluated for the cause of their main injury. The proportion of patients injured by weapons and by traffic accidents was analyzed with respect to the level of violence. RESULTS: Seventy-eight patients were included in this study. Weapon injuries accounted for 50 (64%) admissions and traffic accidents for 28 (36%). These proportions varied significantly according to the weekly level of violence (chi(2)=46.8; P<.001). CONCLUSION: People injured in traffic accidents are an important, but overlooked, drain on surgical resources in low income countries with armed conflict. Their proportion in relation to weapon wounded fluctuates with the level of violence. Humanitarian medical organizations might prepare themselves not only for weapon injuries, but also for wounds caused by traffic accidents. PMID- 26487477 TI - Neurofibromin regulates HCN activity in Parvalbumin-positive interneurons. PMID- 26487478 TI - Corrigendum: strong coupling between chlorosomes of photosynthetic bacteria and a confined optical cavity mode. PMID- 26487480 TI - A reversible metal ion fueled DNA three-way junction molecular device for "turn on and -off" fluorescence detection of mercury ions (II) and biothiols respectively with high selectivity and sensitivity. AB - We constructed a reversible molecular device in the nanoscale based on a DNA three-way junction (3WJ) fueled by Hg(2+) binding and sequestration. It is highly responsive to external stimuli, which brings about optically detectable global structural changes. Such a DNA device can serve as a novel "turn-on and -off" fluorescent sensor for Hg(2+) and biothiol detection with high selectivity and sensitivity. PMID- 26487481 TI - Quantum chemical MP2 results on some hydrates of cytosine: binding sites, energies and the first hydration shell. AB - A detailed quantum chemical investigation was undertaken to obtain the structure and energetics of cytosine hydrates Cyt.nH2O, with n = 1 to 7. The MP2(fc)/aug-cc pVDZ level was used as the standard, with some DFT (B3LYP) and coupled cluster calculations, as well as calculations with the aug-cc-pVTZ basis set added for comparison. In a systematic search for microhydrated forms of cytosine, we have found that several structures have not yet been reported in the literature. The energies of different isomers, as well as binding energies are compared. When predicting the stability of a complex, we suggest using a scheme where the water molecules are extracted from a finite model of bulk water. Finally, based on energetic data, we suggest a rational definition of the first hydration shell; with this definition, it contains just six water molecules. PMID- 26487482 TI - Comparison of arginase isoform expression in patients with different subtypes of chronic rhinosinusitis. AB - OBJECTIVE: Although human paranasal sinuses are critical organs for nitric oxide production, little information is available regarding the role of arginase in alterations of arginine metabolism and nasal nitric oxide levels that may be informative for classifying chronic rhinosinusitis subtypes. METHODS: The expression and localisation of arginase and nitric oxide synthase isoforms in paranasal sinus mucosa were examined, and the fractional exhaled nitric oxide was measured in chronic rhinosinusitis without nasal polyps (n=18) and chronic rhinosinusitis with nasal polyps (n = 27) patients. RESULTS: Increased arginase-2 activities in chronic rhinosinusitis without nasal polyps patients were associated with significantly lower levels of nasal fractional exhaled nitric oxide. Chronic rhinosinusitis with nasal polyps patients showed significant NOS2 messenger RNA upregulation with concomitant higher levels of oral and nasal fractional exhaled nitric oxide. CONCLUSION: These results indicate that fractional exhaled nitric oxide is a valid marker for differentiating chronic rhinosinusitis phenotypes based on a delicate balance between arginase and nitric oxide synthase activities in nitric oxide production. PMID- 26487483 TI - The first complete mitochondrial genome of Serranidae sp. (Percoidea, Serranidae) and phylogenetic analysis based on Bayesian. AB - In the present study, the complete mitochondrial genome of Serranidae sp. was determined first. The entire mitochondrial genome of Serranidae sp. is 16 512 bp in length, containing 13 protein-coding genes and 2 ribosomal RNA genes (rRNA), 22 transfer RNA genes (tRNA) and 2 main non-coding regions (the control region and the origin of the light-strand replication). The gene arrangement, base composition and tRNA structures of Serranidae sp. are similar to most of the bony fishes. The central conserved sequence blocks (CSB-1, CSB-2, and CSB-3) and the core sequence (ACATATATGT) of terminal-associated sequences were recognized in the control region. Meanwhile, the conserved motif 5'-GCCGG-3' was identified in the origin of light-strand replication of Serranidae sp. Phylogenetic tree, which is constructed based on the complete mitochondrial genome sequences of Serranidae sp., shows that Serranidae sp. is clustered with the fishes of the family Pentacerotidae. We expect that the mitochondrial genome of Serranidae sp. would play a key role in phylogenetic analysis of Serranidae. PMID- 26487484 TI - Proteomic analysis of neurons microdissected from formalin-fixed, paraffin embedded Alzheimer's disease brain tissue. AB - The vast majority of human tissue specimens are formalin-fixed, paraffin embedded (FFPE) archival samples, making this type of tissue a potential gold mine for medical research. It is now accepted that proteomics can be done using FFPE tissue and can generate similar results as snap-frozen tissue. However, the current methodology requires a large amount of starting protein, limiting the questions that can be answered in these types of proteomics studies and making cell-type specific proteomics studies difficult. Cell-type specific proteomics has the potential to greatly enhance understanding of cell functioning in both normal and disease states. Therefore, here we describe a new method that allows localized proteomics on individual cell populations isolated from FFPE tissue sections using laser capture microdissection. To demonstrate this technique we microdissected neurons from archived tissue blocks of the temporal cortex from patients with Alzheimer's disease. Using this method we identified over 400 proteins in microdissected neurons; on average 78% that were neuronal and 50% that were associated with Alzheimer's disease. Therefore, this technique is able to provide accurate and meaningful data and has great potential for any future study that wishes to perform localized proteomics using very small amounts of archived FFPE tissue. PMID- 26487485 TI - Energy Metabolism in Mesenchymal Stem Cells During Osteogenic Differentiation. AB - There is emerging interest in stem cell energy metabolism and its effect on differentiation. Bioenergetic changes in differentiating bone marrow mesenchymal stem cells (MSCs) are poorly understood and were the focus of our study. Using bioenergetic profiling and transcriptomics, we have established that MSCs activate the mitochondrial process of oxidative phosphorylation (OxPhos) during osteogenic differentiation, but they maintain levels of glycolysis similar to undifferentiated cells. Consistent with their glycolytic phenotype, undifferentiated MSCs have high levels of hypoxia-inducible factor 1 (HIF-1). Osteogenically induced MSCs downregulate HIF-1 and this downregulation is required for activation of OxPhos. In summary, our work provides important insights on MSC bioenergetics and proposes a HIF-based mechanism of regulation of mitochondrial OxPhos in MSCs. PMID- 26487486 TI - Absence of luteal phase defect and spontaneous pregnancy in IVF patients despite GnRH-agonist trigger and "freeze all policy" without luteal phase support: a report of four cases. AB - Human chorionic gonadotropin (hCG) is commonly used for final oocyte maturation in "in vitro fertilization" (IVF)-treatment cycles, however, the main important risk is development of severe ovarian hyperstimulation syndrome (OHSS). OHSS can almost be avoided by using gonadotrophin-releasing-hormone agonist for final oocyte maturation in an antagonist protocol. However, primarily this approach lead to a very poor reproductive outcome, despite the use of a standard luteal phase support. The reason seems to be severe luteolysis. Obviously, luteolysis post-gonadotropin-releasing-hormone-agonist (post-GnRH-a) trigger is individual specific, and not all patients will develop a complete luteolysis, as expected previously. Luteolysis can been reverted by the administration of hCG. Unprotected intercourse around the time of ovulation induction and oocyte retrieval can lead to a spontaneous conception in IVF treatment and, endogenous hCG, produced by the trophoblast, will rescue the corpora lutea. Therefore, one should not rely on complete luteolysis after GnRH-a triggering and, especially patients for egg donation and pre-implantation-genetic diagnosis for single gene disorder, have to be counselled to avoid unprotected intercourse. PMID- 26487488 TI - Resignation not accepted: employment, education and training in early intervention, past, present and future. PMID- 26487487 TI - B vitamins related to homocysteine metabolism in adults celiac disease patients: a cross-sectional study. AB - BACKGROUND: The only treatment for celiac disease is the gluten-free diet. Few studies have assessed the nutritional adequacy of this diet, especially of B vitamins related to homocysteine metabolism. The aim of this study was to assess the nutritional status and serum concentrations of B vitamins involved in homocysteine metabolism, and to determine whether the dietary intake of these vitamins are meeting Dietary Reference Intakes in celiac patients. METHODS: A cross-sectional study enrolled a total of 20 celiac patients (36.3 +/- 13.7 years old; 65% women), following strict gluten-free diet (GFD) and 39 healthy controls matched by sex and age. The dietary intake was assessed by 3-day food records, and serum concentrations of homocysteine and vitamins B6, B12, and folate were determined after overnight fasting. Comparisons between the two groups were performed by Student's t test or Mann-Whitney U-test, for continuous variables. Pearson's chi-square test or Fisher's exact test was used for categorical variables. An alpha level of 5% were considered significant. RESULTS: Celiac patients had lower serum folate concentrations (7.7 +/- 3.5 ng/mL, P < 0.05) than controls. All celiac patients had folate intake below the Estimated Average Requirement (EAR) (130.8 +/- 53.6 MUg/d). However, only a small proportion of celiac patients had hyperhomocysteinemia. CONCLUSIONS: Celiac patients treated with GFD presented inadequacy of dietary folate intake and low-serum concentrations of folate, suggesting that more attention should be given to the quality of the nutrients offered by the GFD, as it constitutes a lifelong treatment. PMID- 26487489 TI - Energy-Cascaded Upconversion in an Organic Dye-Sensitized Core/Shell Fluoride Nanocrystal. AB - Lanthanide-doped upconversion nanoparticles hold promises for bioimaging, solar cells, and volumetric displays. However, their emission brightness and excitation wavelength range are limited by the weak and narrowband absorption of lanthanide ions. Here, we introduce a concept of multistep cascade energy transfer, from broadly infrared-harvesting organic dyes to sensitizer ions in the shell of an epitaxially designed core/shell inorganic nanostructure, with a sequential nonradiative energy transfer to upconverting ion pairs in the core. We show that this concept, when implemented in a core-shell architecture with suppressed surface-related luminescence quenching, yields multiphoton (three-, four-, and five-photon) upconversion quantum efficiency as high as 19% (upconversion energy conversion efficiency of 9.3%, upconversion quantum yield of 4.8%), which is about ~100 times higher than typically reported efficiency of upconversion at 800 nm in lanthanide-based nanostructures, along with a broad spectral range (over 150 nm) of infrared excitation and a large absorption cross-section of 1.47 * 10( 14) cm(2) per single nanoparticle. These features enable unprecedented three photon upconversion (visible by naked eye as blue light) of an incoherent infrared light excitation with a power density comparable to that of solar irradiation at the Earth surface, having implications for broad applications of these organic-inorganic core/shell nanostructures with energy-cascaded upconversion. PMID- 26487490 TI - Identification and regulation of host genes related to Rice stripe virus symptom production. AB - Viral infections cause plant chlorosis, stunting, necrosis or other symptoms. The down-regulation of chloroplast-related genes (ChRGs) is assumed to be responsible for chlorosis. We identified the differentially expressed genes (DEGs) in Rice stripe virus (RSV)-infected Nicotiana benthamiana, and examined the contribution of 75 down-regulated DEGs to RSV symptoms by silencing them one by one using Tobacco rattle virus (TRV)-induced gene silencing. Silencing of 11 of the 75 down regulated DEGs caused plant chlorosis, and nine of the 11 were ChRGs. Silencing of a down-regulated DEG encoding the eukaryotic translation initiation factor 4A (eIF4A) caused leaf-twisting and stunting that were visible on RSV-infected N. benthamiana. A region of RSV RNA4 was complementary to part of eIF4A mRNA and virus-derived small interfering (vsiRNAs) from that region were present in infected N. benthamiana. When expressed as artificial microRNAs, those vsiRNAs could target NbeIF4A mRNA for regulation. We provide experimental evidence supporting the association of ChRGs with chlorosis and show that eIF4A is involved in RSV symptom development. This is also the first report demonstrating that siRNA derived directly from a plant virus can target a host gene for regulation. PMID- 26487491 TI - Stomatin-like protein 2 is overexpressed in epithelial ovarian cancer and predicts poor patient survival. AB - BACKGROUND: Stomatin-like protein 2 (SLP-2, also known as STOML2) is a stomatin homologue of uncertain function. SLP-2 overexpression has been suggested to be associated with cancer progression, resulting in adverse clinical outcomes in patients. Our study aim to investigate SLP-2 expression in epithelial ovarian cancer cells and its correlation with patient survival. METHODS: SLP-2 mRNA and protein expression levels were analysed in five epithelial ovarian cancer cell lines and normal ovarian epithelial cells using real-time PCR and western blotting analysis. SLP-2 expression was investigated in eight matched-pair samples of epithelial ovarian cancer and adjacent noncancerous tissues from the same patients. Using immunohistochemistry, we examined the protein expression of paraffin-embedded specimens from 140 patients with epithelial ovarian cancer, 20 cases with borderline ovarian tumours, 20 cases with benign ovarian tumours, and 20 cases with normal ovarian tissues. Statistical analyses were applied to evaluate the clinicopathological significance of SLP-2 expression. RESULTS: SLP-2 mRNA and protein expression levels were significantly up-regulated in epithelial ovarian cancer cell lines and cancer tissues compared with normal ovarian epithelial cells and adjacent noncancerous ovarian tissues. Immunohistochemistry analysis revealed that the relative overexpression of SLP-2 was detected in 73.6 % (103/140) of the epithelial ovarian cancer specimens, 45.0 % (9/20) of the borderline ovarian specimens, 30.0 % (6/20) of the benign ovarian specimens and none of the normal ovarian specimens. SLP-2 protein expression in epithelial ovarian cancer was significantly correlated with the tumour stage (P < 0.001). Epithelial ovarian cancer patients with higher SLP-2 protein expression levels had shorter progress free survival and overall survival times compared to patients with lower SLP-2 protein expression levels. Multivariate analyses showed that SLP-2 expression levels were an independent prognostic factor for survival in epithelial ovarian cancer patients. CONCLUSIONS: SLP-2 mRNA and proteins were overexpressed in epithelial ovarian cancer tissues. SLP-2 protein overexpression was associated with advanced stage disease. Patients with higher SLP-2 protein expression had shorter progress free survival and poor overall survival times. Thus, SLP-2 protein expression was an independent prognostic factor for patients with epithelial ovarian cancer. PMID- 26487492 TI - Ethnic inequalities in acute myocardial infarction and stroke rates in Norway 1994-2009: a nationwide cohort study (CVDNOR). AB - BACKGROUND: Immigrants to Norway from South Asia and Former Yugoslavia have high levels of cardiovascular disease (CVD) risk factors. Yet, the incidence of CVD among immigrants in Norway has never been studied. Our aim was to study the burden of acute myocardial infarction (AMI) and stroke among ethnic groups in Norway. METHODS: We studied the whole Norwegian population (n = 2,637,057) aged 35-64 years during 1994-2009. The Cardiovascular Disease in Norway (CVDNOR) project provided information about all AMI and stroke hospital stays for this period, as well as deaths outside hospital through linkage to the Cause of Death Registry. The direct standardization method was used to estimate age standardized AMI and stroke event rates for immigrants and ethnic Norwegians. Rate ratios (RR) with ethnic Norwegians as reference were calculated using Poisson regression. RESULTS: The highest risk of AMI was seen in South Asians (men RR = 2.27; 95 % CI 2.08-2.49; women RR = 2.10; 95 % CI 1.76-2.51) while the lowest was seen in East Asians (RR = 0.38 in both men (95 % CI 0.25-0.58) and women (95 % CI 0.18-0.79)). Immigrants from Former Yugoslavia and Central Asia also had increased risk of AMI compared to ethnic Norwegians. South Asians had increased risk of stroke (men RR = 1.26; 95 % CI 1.10-1.44; women RR = 1.58; 95 % CI 1.32-1.90), as did men from Former Yugoslavia, Sub-Saharan Africa and women from Southeast Asia. CONCLUSIONS: Preventive measures should be aimed at reducing the excess numbers of CVD among immigrants from South Asia and Former Yugoslavia. PMID- 26487494 TI - [Granuloma annulare]. AB - Granuloma annulare is a benign, chronic inflammatory skin disease. Its pathogenesis is still unclear, but reports on infections as a trigger can be found. In addition, some authors reported an association with other systemic disease, e.g., cancer, trauma, and diabetes mellitus; however, these have not been verified. The clinical picture of granuloma annulare ranges from the localized form predominantly at the extremities to disseminated, subcutaneous, or perforating forms. Diagnosis is based on the typical clinical presentation which may be confirmed by a biopsy. Histologically, necrobiotic areas within granulomatous inflammation are typical. The prognosis of the disease is good with spontaneous resolution being frequently observed, especially in localized forms. Disseminated manifestations tend to persist longer, and recurrences are reported. When choosing between different therapeutic options, the benign disease character versus the individual degree of suffering and the potential therapy side effects must be considered. For local treatment, topical application of corticosteroids is most common. Disseminated forms can be treated systemically with corticosteroids for several weeks; alternatively, dapsone, hydroxychloroquine, retinoids, fumaric acid, cyclosporine, and anti-TNFalpha appear to be effective. PMID- 26487493 TI - Helicobacter pylori modulates host cell survival regulation through the serine threonine kinase, 3-phosphoinositide dependent kinase 1 (PDK-1). AB - BACKGROUND: Helicobacter pylori (H. pylori) infection affects cell survival signaling pathways including cell apoptosis and proliferation, which are considered risk factors for the development of gastric cancer when unregulated. In the present study, we investigated the effect of H. pylori infection on the phosphorylation state of 3-phosphoinositide-dependent kinase-1 (PDK-1), a master kinase that regulates phosphorylation of Akt (also known as protein kinase B, PKB) and cell survival. METHODS: The activity of PDK-1 was examined in human gastric epithelial cells incubated in the presence or absence of different H. pylori strains. In addition, the role of H. pylori type IV secretion system and the mechanism of H. pylori effect on PDK-1 activity was examined. RESULTS: In the presence of H. pylori, phosphorylation of the activation loop (serine 241) PDK-1 was rapidly lost suggesting that dephosphorylation of PDK-1 is a target for H. pylori to modulate cell survival. The extent of dephosphorylation was strain dependent with H. pylori 60190 being the most effective. H. pylori infection of gastric epithelial cells resulted in altered phosphorylation and degradation of Akt, suggesting that PDK-1 dephosphorylation affects cell survival pathways and thereby may contribute to disease pathogenesis. CONCLUSION: We propose that dephosphorylation of PDK-1 and the resulting changes to Akt phosphorylation is one of the mechanisms by which infection with H. pylori alter the balance between apoptosis and cell proliferation and identify a host molecular mechanism regulated by H. pylori that ultimately contributes to carcinogenesis. Our studies therefore provide insights into one of the mechanisms by which H. pylori infection contributes to gastric cancer by regulating the activity of a cell survival signaling pathway. PMID- 26487495 TI - [Andrologically relevant findings from the perspective of the dermatologist]. AB - In clinical practice dermatologists may be faced with andrological findings raising interdisciplinary problems. Consideration of them may not only improve the clinical course of the patient but also the dermatologist's interdisciplinary standing. This overview describes and explains the most important andrological findings, which may be apparent in a dermatologic whole-body examination. PMID- 26487497 TI - Carbon-Dot-Sensitized, Nitrogen-Doped TiO2 in Mesoporous Silica for Water Decontamination through Nonhydrophobic Enrichment-Degradation Mode. AB - Mesoporous silica synthesized from the cocondensation of tetraethoxysilane and silylated carbon dots containing an amide group has been adopted as the carrier for the in situ growth of TiO2 through an impregnation-hydrothermal crystallization process. Benefitting from initial complexation between the titania precursor and carbon dot, highly dispersed anatase TiO2 nanoparticles can be formed inside the mesoporous channel. The hybrid material possesses an ordered hexagonal mesostructure with p6mm symmetry, a high specific surface area (446.27 m(2) g(-1) ), large pore volume (0.57 cm(3) g(-1) ), uniform pore size (5.11 nm), and a wide absorption band between lambda=300 and 550 nm. TiO2 nanocrystals are anchored to the carbon dot through Ti?O?N and Ti?O?C bonds, as revealed by X ray photoelectron spectroscopy. Moreover, the nitrogen doping of TiO2 is also verified by the formation of the Ti?N bond. This composite shows excellent adsorption capabilities for 2,4-dichlorophenol and acid orange 7, with an electron-deficient aromatic ring, through electron donor-acceptor interactions between the carbon dot and organic compounds instead of the hydrophobic effect, as analyzed by the contact angle analysis. The composite can be photocatalytically recycled through visible-light irradiation after adsorption. The narrowed band gap, as a result of nitrogen doping, and the photosensitization effect of carbon dots are revealed to be coresponsible for the visible-light activity of TiO2 . The adsorption capacity does not suffer any clear losses after being recycled three times. PMID- 26487496 TI - Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERalpha-positive breast cancer. AB - Tamoxifen (Tam) resistance represents a significant clinical problem in estrogen receptor (ER) alpha-positive breast cancer. We previously showed that decreased expression of Rho guanine nucleotide dissociation inhibitor (Rho GDI) alpha, a negative regulator of the Rho GTPase pathway, is associated with Tam resistance. We now discover that androgen receptor (AR) is overexpressed in cells with decreased Rho GDIalpha and seek to determine AR's contribution to resistance. We engineered ERalpha-positive cell lines with stable knockdown (KD) of Rho GDIalpha (KD cells). Resistance mechanisms were examined using microarray profiling, protein-interaction studies, growth and reporter gene assays, and Western blot analysis combined with a specific AR antagonist and other signaling inhibitors. Tam-resistant tumors and cell lines with low Rho GDIalpha levels exhibited upregulated AR expression. Microarray of Rho GDIalpha KD cells indicated that activation of EGFR and ERalpha was associated with Tam treatment. When AR levels were elevated, interaction between AR and EGFR was detected. Constitutive and Tam induced phosphorylation of EGFR and ERK1/2 was blocked by the AR antagonist Enzalutamide, suggesting that AR-mediated EGFR activation was a mechanism of resistance in these cells. Constitutive ERalpha phosphorylation and transcriptional activity was inhibited by Enzalutamide and the EGFR inhibitor gefitinib, demonstrating that AR-mediated EGFR signaling activated ERalpha. Tam exhibited agonist activity in AR overexpressing cells, stimulating ERalpha transcriptional activity and proliferation, which was blocked by Enzalutamide and gefitinib. We describe a novel model of AR-mediated Tam resistance through activation of EGFR signaling leading to ER activation in ERalpha-positive cells with low expression of Rho GDIalpha. PMID- 26487498 TI - Evaluation of the Level of Knowledge of Oral Cancer Among High School Students. AB - The present study aims to determine the knowledge level of high school students regarding oral cancer. The present study included students from 20 high schools located in the city center of Kahramanmaras between 1 and 28 April 2015. The students were informed prior to the study and 2759 students who gave written consent were included in the study. The participants were administered a questionnaire that was prepared by the investigators. The questionnaire included 25 questions that were prepared using literature in order to establish the knowledge level of the students about oral cancer, and it was evaluated scoring one point to each question. There were 1711 (62.0 %) female students and 1048 (38.0 %) male students; the mean age was 16.01 +/- 1.09 years. The knowledge score of the male students was 7.48 +/- 5.15 and the knowledge score of the female students was 7.58 +/- 4.96. The knowledge score of the female and male participants was similar (p = 0.605). Of the students, 2107 (76.4 %) stated that they heard the expression of oral cancer before compared to 652 (23.6 %) students stating they did not. The study found that high school students had insufficient levels of knowledge about oral cancer. There was a general lack of knowledge about oral cancer and the risks among these students. PMID- 26487499 TI - Direct monitoring of bias-dependent variations in the exciton formation ratio of working organic light emitting diodes. AB - In typical operation of organic light emitting diodes (OLEDs), excitons are assumed to generate with a ratio of 1:3 for singlet and triplet excitons, respectively, based on a simple spin statistics model. This assumption has been used in designing efficient OLEDs. Despite the larger generation ratio of triplet excitons, physical properties of fluorescent OLEDs are usually evaluated only through the electroluminescence (EL) intensity from singlets and the behaviors of triplets during the LED operation are virtually black-boxed, because the triplets are mostly non-emissive. Here, we employ transient spectroscopy combined with LED operation for directly monitoring the non-emissive triplets of working OLEDs. The spectroscopic techniques are performed simultaneously with EL- and current measurements under various operation biases. The simultaneous measurements reveal that the relative formation ratio of singlet-to-triplet excitons dramatically changes with the magnitude of bias. The measurements also show that the generation efficiency of singlets scales with the bias, whereas that of triplets is nearly bias-independent. These features of the formation ratio and efficiency are compatibly explained by considering the yield of intersystem crossing and the energy separation of excitons from electron-hole pairs. The obtained findings via the spectroscopic measurements enable prediction of the formation pathways in OLEDs. PMID- 26487500 TI - Behcet's syndrome: a critical digest of the 2014-2015 literature. AB - Several studies were published last year which focused on the epidemiology, immunopathogenesis, genetics, clinical manifestations and management of Behcet's syndrome. Recent epidemiologic studies support the earlier contention that the frequency of BS increases from North to South in Europe, BS is rare in Sub Saharan Africa, it follows a more severe course among young men, especially if the disease onset is at a young age and that in European countries, the frequency is higher among immigrants from BS prevalent countries compared to locals living in the same environment. The relationship between HLA-B51 and Behcet's was re emphasised and a functional role affecting cellular cytotoxicity was proposed. Innate immunity was explored and TLR7 copy number variations and nucleic acid sensors of varying inflammasome pathways were studied. Vascular relapse risk is decreased when BS patients are treated with immunosuppressives with or without anti-coagulation rather than anti-coagulation alone. Although rare in the Far East, the clinical picture of the vascular involvement was quite similar to the previously published reports. Interestingly a female predominance among those with cerebral vein thrombosis was noted. Venous claudication is a frequent and severe symptom among BS patients with lower extremity DVT. Budd-Chiari syndrome associated with BS is usually associated with IVC thrombosis. Silent cases exist and have a better prognosis. The mortality rate among the patients symptomatic for liver disease remains high. Methotrexate seems to be effective in the treatment of chronic progressive neuro-Behcet's disease. Renal involvement is an uncommon disorder in BS. Suicidal thoughts are increased among BS patients with severe organ involvement. Work-related disability in BS is high and under appreciated. Apremilast, an inhibitor of phosphodiesterase-4, was effective in a phase 2, double blind, placebo-controlled study. Adalimumab seems to be effective in severe uveitis of BS even after failure of infliximab. New cytokine inhibitors targeting IL-1 and IL-6 appear to be effective especially for uveitis and CNS involvement refractory to anti TNF agents. PMID- 26487501 TI - Multiplane wave imaging increases signal-to-noise ratio in ultrafast ultrasound imaging. AB - Ultrafast imaging using plane or diverging waves has recently enabled new ultrasound imaging modes with improved sensitivity and very high frame rates. Some of these new imaging modalities include shear wave elastography, ultrafast Doppler, ultrafast contrast-enhanced imaging and functional ultrasound imaging. Even though ultrafast imaging already encounters clinical success, increasing even more its penetration depth and signal-to-noise ratio for dedicated applications would be valuable. Ultrafast imaging relies on the coherent compounding of backscattered echoes resulting from successive tilted plane waves emissions; this produces high-resolution ultrasound images with a trade-off between final frame rate, contrast and resolution. In this work, we introduce multiplane wave imaging, a new method that strongly improves ultrafast images signal-to-noise ratio by virtually increasing the emission signal amplitude without compromising the frame rate. This method relies on the successive transmissions of multiple plane waves with differently coded amplitudes and emission angles in a single transmit event. Data from each single plane wave of increased amplitude can then be obtained, by recombining the received data of successive events with the proper coefficients. The benefits of multiplane wave for B-mode, shear wave elastography and ultrafast Doppler imaging are experimentally demonstrated. Multiplane wave with 4 plane waves emissions yields a 5.8 +/- 0.5 dB increase in signal-to-noise ratio and approximately 10 mm in penetration in a calibrated ultrasound phantom (0.7 d MHz(-1) cm(-1)). In shear wave elastography, the same multiplane wave configuration yields a 2.07 +/- 0.05 fold reduction of the particle velocity standard deviation and a two-fold reduction of the shear wave velocity maps standard deviation. In functional ultrasound imaging, the mapping of cerebral blood volume results in a 3 to 6 dB increase of the contrast-to-noise ratio in deep structures of the rodent brain. PMID- 26487503 TI - End-of-life care provision: experiences of intensive care nurses in Iraq. AB - BACKGROUND: Nurses play a key role in providing care for the critically ill in the intensive care unit (ICU). The physical, psychological, emotional and spiritual intimate care given by Kurdish nurses allows them to develop a therapeutic relationship with terminally ill patients in the ICU. AIMS: This study sought to explore the meaning of caring for terminally ill patients from the perspective of Kurdish ICU nurses. DESIGN: Van Manen's (1990) hermeneutic phenomenological design was adopted. METHOD: The data were collected through in depth semi-structured interviews with a purposive sample of 10 nurses working in ICUs. Interviews were transcribed and finally analysed according to Van Manen's method. RESULTS: Four major themes including emotional labour, death as a positive dimension, optimistic rather than futile care and working within constraints emerged. CONCLUSIONS: Kurdish nurses in their caring encounters with terminally ill patients experienced a range of feelings from emotional strain to being optimistic while working within limited resources in the ICU. Further research is needed to explore the experiences of nurses with other cultures of caring for terminally ill patients in ICUs. RELEVANCE TO PRACTICE: End-of-life care in ICU is emotionally challenging, therefore, nurses in this setting require psychological and spiritual support to ensure optimal care provision. PMID- 26487502 TI - Histone Deacetylase (HDAC) Inhibitors - emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration. AB - Epigenetic regulation of neuronal signalling through histone acetylation dictates transcription programs that govern neuronal memory, plasticity and learning paradigms. Histone Acetyl Transferases (HATs) and Histone Deacetylases (HDACs) are antagonistic enzymes that regulate gene expression through acetylation and deacetylation of histone proteins around which DNA is wrapped inside a eukaryotic cell nucleus. The epigenetic control of HDACs and the cellular imbalance between HATs and HDACs dictate disease states and have been implicated in muscular dystrophy, loss of memory, neurodegeneration and autistic disorders. Altering gene expression profiles through inhibition of HDACs is now emerging as a powerful technique in therapy. This review presents evolving applications of HDAC inhibitors as potential drugs in neurological research and therapy. Mechanisms that govern their expression profiles in neuronal signalling, plasticity and learning will be covered. Promising and exciting possibilities of HDAC inhibitors in memory formation, fear conditioning, ischemic stroke and neural regeneration have been detailed. PMID- 26487504 TI - Helix aspersa gelatin as an emulsifier and emulsion stabilizer: functional properties and effects on pancreatic lipolysis. AB - Emulsions are widely used in food and pharmaceutical applications for the encapsulation, solubilization, entrapment, and controlled delivery of active ingredients. In order to fulfill the increasing demand for clean label excipients, natural polymers could be used to replace the potentially irritative synthetic surfactants used in emulsion formulation. In the present study, we have studied the properties of oil-in-water emulsions prepared with land snail gelatin (LSG) as the sole emulsifying agent, extracted and described for the first time. LSG was evaluated in terms of proximate composition, oil and water holding capacity, emulsifying and foaming properties, color and amino acid composition. Emulsions of trioctanoylglycerol (TC8) and olive oil were made at different gelatin/oil ratios and changes in droplet-size distribution were determined. The superior emulsifying properties of LSG, the susceptibility of gelatin protein emulsions increasing flocculation on storage, and the coalescence of gelatin emulsions following centrifugation were demonstrated. Furthermore, the effect of LSG on the activity of turkey pancreatic lipase (TPL) was evaluated through the pH-stat methodology with TC8 and olive oil emulsions. The LSG affected the TPL activity in a concentration-dependent way. Our results showed that LSG, comparably to gum arabic, increases the pancreatic lipase activity and improves its stability at the oil-water interface. PMID- 26487506 TI - Clinical commissioning group asks GPs to scrap procedures in bid to reduce L23m deficit. PMID- 26487505 TI - Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by Chiral O,N,O tridentate Phenol Ligands Derived From Camphor. AB - Chiral O,N,O-tridentate phenol ligands bearing a camphor backbone were found to be effective chiral catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes, resulting in high enantioselectivities (80-95% ee) at room temperature. PMID- 26487507 TI - MOCVD Growth of High-Quality and Density-Tunable GaAs Nanowires on ITO Catalyzed by Au Nanoparticles Deposited by Centrifugation. AB - High-quality and density-tunable GaAs nanowires (NWs) are directly grown on indium tin oxide (ITO) using Au nanoparticles (NPs) as catalysts by metal organic chemical vapor deposition (MOCVD). Au catalysts were deposited on ITO glass substrate using a centrifugal method. Compared with the droplet-only method, high area density Au NPs were uniformly distributed on ITO. Tunable area density was realized through variation of the centrifugation time, and the highest area densities were obtained as high as 490 and 120 NP/MUm(2) for 10- and 20-nm diameters of Au NPs, respectively. Based on the vapor-liquid-solid growth mechanism, the growth rates of GaAs NWs at 430 degrees C were 18.2 and 21.5 nm/s for the highest area density obtained of 10- and 20-nm Au NP-catalyzed NWs. The growth rate of the GaAs NWs was reduced with the increase of the NW density due to the competition of precursor materials. High crystal quality of the NWs was also obtained with no observable planar defects. 10-nm Au NP-induced NWs exhibit wurtzite structure whereas zinc-blende is observed for 20-nm NW samples. Controllable density and high crystal quality of the GaAs NWs on ITO demonstrate their potential application in hybrid a solar cell. PMID- 26487508 TI - Pathology test-ordering behaviour of Australian general practice trainees: a cross-sectional analysis. AB - OBJECTIVE: In the context of increasing over-testing and the implications for patient safety, to establish the prevalence and nature of pathology test-ordering of GP trainees, and to describe the associations of this test-ordering. DESIGN: A cross-sectional analysis of data from the Registrar Clinical Encounters in Training (ReCEnT) cohort study. SETTING: Five of Australia's 17 general practice regional training providers, encompassing urban-to-very remote practices. PARTICIPANTS: GP trainees. MAIN OUTCOME MEASURES: The number of pathology tests ordered per problem/diagnosis managed. RESULTS: A total of 856 individual trainees (response rate 95.2%) contributed data from 1832 trainee-terms, 108 759 encounters and 169 304 problems. Pathology test-ordering prevalence was 79.3 tests (95% CI: 78.8-79.8) per 100 encounters, 50.9 (95% CI: 50.6-51.3) per 100 problems, and at least 1 test was requested in 22.4% of consultations. Most commonly ordered was full blood count (6.1 per 100 problems). The commonest problem prompting test-ordering was 'check-up' (18.6%). Test-ordering was significantly associated, on multivariable analysis, with the trainee having worked at the practice previously; the patient being adult, male and new to both trainee and practice; the practice being urban; the problem/diagnosis being new; imaging being ordered; referral being made and follow-up being arranged. Trainees were significantly less likely to order tests for problems/diagnoses for which they had sought in-consultation information or advice. CONCLUSIONS: Compared with the established GPs, trainees order more pathology tests per consultation and per problem managed, and in a higher proportion of consultations. Our findings will inform educational policy to enhance quality and safety in general practice training. PMID- 26487509 TI - Observation of Exchange Anisotropy in Single-Phase Layer-Structured Oxides with Long Periods. AB - A remarkable exchange bias effect arising from the temperature-dependent interaction among the ferromagnetic-like cluster glasses and antiferromagnetic regions was observed in a newly developed single-phase multiferroic compound of Bi10Fe6Ti3O30 which has a nine-layer Aurivillius structure. Inhomogeneous distribution of magnetic Fe ions inside this long-period layered structure was experimentally identified via the atomic level imaging. The results confirmed the presence of the short-range magnetic ordering (the cluster glassy state) and the canted antiferromagnetism, and then the direct interaction among them was further confirmed. Finding of this new single-phase material accompanying this remarkable exchange bias effect would be beneficial to both basic physics understanding and the potential device development. PMID- 26487510 TI - Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins. AB - Aldose reductase (AKR1B1) is a critical drug target because of its involvement in diabetic complications, inflammation, and tumorigenesis. However, to date, development of clinically useful inhibitors has been largely unsuccessful. Cyclopentenone prostaglandins (cyPGs) are reactive lipid mediators that bind covalently to proteins and exert anti-inflammatory and antiproliferative effects in numerous settings. By pursuing targets for modification by cyPGs we have found that the cyPG PGA1 binds to and inactivates AKR1B1. A PGA1-AKR1B1 adduct was observed, both by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and by SDS-PAGE using biotinylated PGA1 (PGA1-B). Insight into the molecular interactions between AKR1B1 and PGA1 was advanced by molecular modeling. This anticipated the addition of PGA1 to active site Cys298 and the potential reversibility of the adduct, which was supported experimentally. Indeed, loss of biotin label from the AKR1B1-PGA1-B adduct was favored by glutathione, indicating a retro-Michael reaction, which unveils new implications of cyPG-protein interaction. PGA1 elicited only marginal inhibition of aldehyde reductase (AKR1A1), considered responsible for the severe adverse effects of many AKR1B1 inhibitors. Interestingly, other prostaglandins (PGs) inhibited the enzyme, including non-electrophilic PGE1 and PGE2, currently used in clinical practice. Moreover, both PGA1 and PGE1 reduced the formation of sorbitol in an ex vivo model of diabetic cataract to an extent comparable to that attained by the known AKR inhibitor epalrestat. Taken together, these results highlight the role of PGs as AKR1B1 inhibitors and the interest in PG-related molecules as leads for the development of novel pharmacological tools. PMID- 26487512 TI - Incremental diagnostic utility of gastric distension FDG PET/CT. AB - PURPOSE: To assess the diagnostic utility of gastric distension (GD) FDG PET/CT in both patients with known gastric malignancy and those not known to have gastric malignancy but with incidental focal FDG uptake in the stomach. METHODS: This retrospective analysis included 88 patients who underwent FDG PET/CT following GD with hyoscine N-butylbromide (Buscopan(r)) and water ingestion as part of routine clinical evaluation between 2004 and 2014. FDG PET/CT scans before and after GD were reported blinded to the patient clinical details in 49 patients undergoing pretreatment staging of gastric malignancy and 39 patients who underwent GD following incidental suspicious gastric uptake. The PET findings were validated by a composite clinical standard. RESULTS: In the 49 patients undergoing pretreatment staging of gastric malignancy, GD improved PET detection of the primary tumour (from 80 % to 90 %). PET evaluation of tumour extent was concordant with endoscopic/surgical reports in 31 % (interpreter 1) and 45 % (interpreter 2) using pre-GD images and 73 % and 76 % using GD images. Interobserver agreement also improved with GD (kappa = 0.29 to 0.69). Metabolic and morphological quantitative analysis demonstrated a major impact of GD in normal gastric wall but no significant effect in tumour, except a minor increase in SUV related to a delayed acquisition time. The tumour to normal stomach SUVmax ratio increased from 3.8 +/- 2.9 to 9.2 +/- 8.6 (mean +/- SD) with GD (p < 0.0001), facilitating detection and improved assessment of the primary tumour. In 25 (64 %) of the 39 patients with incidental suspicious gastric uptake, acquisition after GD correctly excluded a malignant process. In 10 (71 %) of the remaining 14 patients with persistent suspicious FDG uptake despite GD, malignancy was confirmed and in 3 (21 %) an active but benign pathology was diagnosed. CONCLUSION: GD is a simple way to improve local staging with FDG PET in patients with gastric malignancy. In the setting of incidental suspicious gastric uptake, GD is also an effective tool for ruling out malignancy and leads to the avoidance of unnecessary endoscopy. PMID- 26487513 TI - Avulsed Nasoenteric Bridle System Magnet as an Intranasal Foreign Body. AB - Nasoenteric tubes provide short-term nutrition support to patients unable to take an adequate oral diet. Bridling systems may be used to secure tubes to guard against displacement. We present the first case of an avulsed magnet from a bridling system to raise awareness of this potential complication. The primary methods of securing a nasogastric tube are reviewed, and comparative assessment of the 3 main systems is presented. Diagnosis and management of nasal foreign bodies relevant to this case are reviewed and prevention/safety considerations discussed. PMID- 26487514 TI - Well-Being and Wellness in the Twenty-First Century: A Theanthropocosmic Approach. AB - In this paper, clarification and definition of the concept well-being of human beings are reflected upon from a faith perspective. The author will define well being and wellness within the following conceptual definitions: firstly, well being and wellness will be defined in term of African-Christian approach (the interconnectedness of God-human-and-world approach). Secondly, the author will focus on differentiation of well-being and wellness in a human being. Thirdly, the focal point will be on the mixing of holistic, dualist and triadic approaches to define well-being. PMID- 26487511 TI - The Dual Estrogen Receptor alpha Inhibitory Effects of the Tissue-Selective Estrogen Complex for Endometrial and Breast Safety. AB - The conjugated estrogen /: bazedoxifene tissue-selective estrogen complex (TSEC) is designed to minimize the undesirable effects of estrogen in the uterus and breast tissues and to allow the beneficial effects of estrogen in other estrogen target tissues, such as the bone and brain. However, the molecular mechanism underlying endometrial and breast safety during TSEC use is not fully understood. Estrogen receptor alpha (ERalpha)-estrogen response element (ERE)-DNA pull-down assays using HeLa nuclear extracts followed by mass spectrometry-immunoblotting analyses revealed that, upon TSEC treatment, ERalpha interacted with transcriptional repressors rather than coactivators. Therefore, the TSEC-mediated recruitment of transcriptional repressors suppresses ERalpha-mediated transcription in the breast and uterus. In addition, TSEC treatment also degraded ERalpha protein in uterine tissue and breast cancer cells, but not in bone cells. Interestingly, ERalpha-ERE-DNA pull-down assays also revealed that, upon TSEC treatment, ERalpha interacted with the F-box protein 45 (FBXO45) E3 ubiquitin ligase. The loss-of- and gain-of-FBXO45 function analyses indicated that FBXO45 is involved in TSEC-mediated degradation of the ERalpha protein in endometrial and breast cells. In preclinical studies, these synergistic effects of TSEC on ERalpha inhibition also suppressed the estrogen-dependent progression of endometriosis. Therefore, the endometrial and breast safety effects of TSEC are associated with synergy between the selective recruitment of transcriptional repressors to ERalpha and FBXO45-mediated degradation of the ERalpha protein. PMID- 26487516 TI - Creating and Controlling Biointerfaces. PMID- 26487515 TI - Hydrophilins in the filamentous fungus Neosartorya fischeri (Aspergillus fischeri) have protective activity against several types of microbial water stress. AB - Hydrophilins are proteins that occur in all domains of life and protect cells and organisms against drought and other stresses. They include most of the late embryogenesis abundant (LEA) proteins and the heat shock protein (HSP) Hsp12. Here, the role of a predicted LEA-like protein (LeamA) and two Hsp12 proteins (Hsp12A and Hsp12B) of Neosartorya fischeri was studied. This filamentous fungus forms ascospores that belong to the most stress-resistant eukaryotic cells described to date. Heterologous expression of LeamA, Hsp12A and Hsp12B resulted in increased tolerance against salt and osmotic stress in Escherichia coli. These proteins were also shown to protect lactate dehydrogenase against dry heat and freeze-thaw cycles in vitro. Deletion of leamA caused diminished viability of sexual ascospores after drought and heat. This is the first report on functionality of Hsp12 and putative LeamA proteins derived from filamentous fungi, and their possible role in N. fischeri ascospore resistance against desiccation, high temperature and osmotic stress is discussed. PMID- 26487517 TI - The association between higher body mass index and poor school performance in high school students. AB - BACKGROUND/OBJECTIVE: This study aimed to examine the association between body mass index (BMI) and school performance in high school students by controlling for relevant mediators such as sleep quality, sleep duration and socioeconomic status. METHODS: Thirty-seven high school students (mean age: 18.16 +/- 0.44 years) attending the same school type, i.e. 'liceo scientifico' (science-based high school), were enrolled. Students' self-reported weight and height were used to calculate BMI. Participants wore an actigraph to objectively assess the quality and duration of sleep. School performance was assessed through the actual grade obtained at the final school-leaving exam, in which higher grades indicate higher performance. RESULTS: BMI, get-up time, mean motor activity, wake after sleep onset and number of awakenings were negatively correlated with the grade, while sleep efficiency was positively correlated. When performing a multiple regression analysis, BMI proved the only significant (negative) predictor of grade. CONCLUSIONS: When controlling for sleep quality, sleep duration and socioeconomic status, a higher BMI is associated with a poorer school performance in high school students. PMID- 26487519 TI - Editorial. PMID- 26487518 TI - Notch3 Ameliorates Cardiac Fibrosis After Myocardial Infarction by Inhibiting the TGF-beta1/Smad3 Pathway. AB - Notch3 and TGF-beta1 signaling play a key role in the pathogenesis and progression of chronic cardiovascular disease. However, whether Notch3 protects against myocardial infarction (MI) and the underlying mechanisms remains unknown. C57BL/6 mice were randomized to be treated with Notch3 siRNA (siNotch3) or lentivirus carrying Notch3 cDNA (Notch3) before coronary artery ligation. Four weeks after constructing MI model, cardiac function and fibrosis were compared between groups. The cardiac fibroblast cells (CFs) were isolated from newborn C57BL/6 mice (1-3 days old) and transfected with lentivirus carrying Notch3 cDNA. TGF-beta1 (5 ng/ml), a well-known pro-fibrotic factor, was administered 72 h after Notch3 cDNA administration in CFs. The related proteins of fibrosis such as a-smooth muscle actin (a-SMA), Type I collagen, metalloprotease (MMP)-9 and the tissue inhibitor of metalloproteinases (TIMP)-2 were examined by western blot analysis. Notch3 cDNA treatment attenuated cardiac damage and inhibited fibrosis in mice with MI. Meanwhile, Notch3 siRNA administration aggravated cardiac function damage and markedly enhanced cardiac fibrosis in mice with MI. Overexpression of Notch3 inhibited TGF-beta1-induced fibroblast-myofibroblast transition of mouse cardiac fibroblast cells, as evidenced by down-regulating a SMA and Type I collagen expression. Notch3 cDNA treatment also increased MMP-9 expression and decreased TIMP-2 expression in the TGF-beta1-stimulated cells. This study indicates that Notch3 is an important protective factor for cardiac fibrosis in a MI model, and the protective effect of Notch3 is attributable to its action on TGF-beta1/Smad3 signaling. PMID- 26487520 TI - The clinical spectrum of aneurysmal subarachnoid hemorrhage. AB - Delays in diagnosis are one of the major problems in the treatment of aneurysmal subarachnoid hemorrhage (SAH). To study reasons for delayed diagnosis, we reviewed the symptoms of 286 patients seen between 1978 and 1985. Delays in diagnosis occurred in 56 patients (19%). Less than half of our patients had the complete classic syndrome of the sudden onset of a violent headache, with or without alteration in consciousness, accompanied by nuchal rigidity. Many patients had atypical symptoms. Gradual evolution of symptoms, nonintense headaches, severe pain at other sites, disturbed consciousness, or mild meningeal signs often lead to misdiagnosis. Nine patients with preserved consciousness had minimal or no headache. Based on our experience, atypical symptoms are common with SAH and need to receive more emphasis. PMID- 26487521 TI - Prevention of recurrent stroke in patients with systemic lupus erythematosus or lupus anticoagulant. AB - Patients with systemic lupus erythematosus (SLE) or lupus anticoagulant (LA) may have antibodies, including anticardiolipin antibodies (aCL), which may be associated with stroke and a high risk of recurrent stroke. Optimum preventive treatment is uncertain. We report and analyze experience with 26 patients with SLE or LA, some of whom also had aCL, who were treated with heparin and/or warfarin, often after failure of aspirin and/or steroids to prevent cerebral ischemia. Representative summaries of cases are included. Potential mechanisms of the thrombotic tendency in these patients are reviewed. Complications of anticoagulant therapy can be serious; contraindications to this treatment are discussed. Patients with either SLE or LA who have a history of a cerebral ischemic event have a high risk of recurrent stroke, which may be ameliorated by administering anticoagulants if there are no contraindications. PMID- 26487522 TI - Noninvasive imaging of the cervical vertebral artery in the diagnosis of vertebrobasilar insufficiency. AB - The cervical vertebral arteries were visualized by real-time B-mode ultrasonography with duplex Doppler in 595 consecutive patients. Comparison with angiography in 40 patients showed a sensitivity of 84% and a specificity of 97% in identifying vertebral artery lesions. The incidence of vertebral artery lesions in patients with symptoms of ischemia referable to the vertebrobasilar distribution was 28% (24/84), significantly higher (p = 0.05) than the incidence of 13% (7/54) in patients with carotid artery insufficiency. Patients with completed strokes in the vertebrobasilar territory had an even higher incidence of vertebral lesions (44%,14/ 32) than patients with transient symptoms of vertebrobasilar insufficiency (19%, 10/52) (p < 0.001). The incidence of vertebral lesions in patients with nonlocalizing symptoms of syncope (8%, 5/67), presyncope (10%, 3/31), isolated vertigo (5%,4/77), unsteadiness (4%,2/55), lightheadedness (0/27), and transient global amnesia (0/18) were all significantly lower than the incidence in patients with focal vertebrobasilar symptoms (p < 0.01). Imaging of the cervical vertebral arteries by real-time B mode ultrasonography may be helpful in determining the etiology of symptoms in patients with a diagnosis of vertebrobasilar insufficiency. PMID- 26487523 TI - Toward an optimal "antiplatelet" dose of aspirin: Preliminary observations. AB - It remains unclear which dose of aspirin (ASA) confers the optimal antiplatelet effect. This study focuses on long-term responses to different ASA doses by selected normal subjects. Their baseline platelet aggregabilities exemplified both the average values and the extremes of hyper-and hypoaggregability. Only 41 mg ASA daily stopped all arachidonic acid aggregations and maximally spared endogenous nucleotides. When 2.8 and 9 MUM adenosine diphosphate were used as the aggregants, it became evident that higher ASA doses yielded still further grades of change both in aggregation and disaggregation. Disaggregations proved of special interest: distinctive for each subject, they clearly improved more on 325 mg ASA daily than on 41 mg or 81 mg. "Low-dose" ASA, at longer dose intervals of 48 or 72 h, may not be optimal to sustain an adequate antiplatelet effect. More individualized ASA doses, based on selected in vitro measurements of platelet function, might prove useful both in reducing the size and number of cerebral ischemic infarcts and in avoiding hemorrhagic complications in certain patients. PMID- 26487524 TI - Potentiation of rehabilitation: Medication effects on the recovery of function after brain injury and stroke. AB - In neurologic rehabilitation nothing is currently in clinical use that is effective in restoring lost neurologic function. This paper presents an overview of the various medicines that have been studied for their potential to facilitate recovery after brain injury. Early studies of acetylcholine and anticholinesterase drugs were reported favorably, but subsequent experience with them has not substantiated the initial enthusiasm. In the last two decades, data from work on rodents and cats suggest that certain drugs may facilitate or impede neurologic recovery after brain injury. Human studies on the effects of d amphetamine and related compounds are sparse, and, although provocative, several problems make the results controversial. Data from studies in the laboratory suggest that clinicians may be impeding clinical outcome in stroke patients with some frequently used poststroke medications. A table lists (with references) the drugs that may impede recovery or reinstate deficits and drugs that may accelerate recovery. PMID- 26487525 TI - Cardiorespiratory arrest in aneurysmal subarachnoid hemorrhage. AB - Aneurysmal subarachnoid hemorrhage (ASAH) can cause sudden death from cardiorespiratory arrest (CRA). Successful resuscitation (SR) allows diagnosis and treatment of survivors. We studied incidences of CRA and the influence of SR in ASAH prognosis. Hospital records of patients with ASAH diagnosed by computed tomography, lumbar puncture, surgery, or autopsy and treated from 1980 to 1988 were reviewed. Symptoms, aneurysm location, treatment, course, and outcome were tabulated. The literature was reviewed. Of 95 consecutive ASAH patients, 15 (16%, 2 males, 13 females) had CRA, seven primary cardiac, six primary respiratory, and two combined CRA. Four of 11(36.4%) had posterior circulation aneurysm (PCA);13 (86.6%) had intracerebral-ventricular clot (ICC). All were clinically Stage V, six improved and had angiography, two had surgery, and one (7%) survived hospitalization. Of other ASAH patients (37 males and 43 females), 4.4% of 68 had PCA, 37.5% had ICC, and 56% survived hospitalization. Of 287 patients hospitalized after out-of-hospital SR in the same period, 18% survived; 14 (4.9%) had ASAH and 1 (7%) survived hospitalization. CRA is not infrequent after onset of ASAH and occurs more commonly in women with PCA. Most likely, it is due to a very large initial hemorrhage disrupting diencephalic circulatory and respiratory centers. Prognosis of patients suffering CRA from ASAH is dismal and not influenced by SR. PMID- 26487526 TI - MU3-eta(2):eta(2):eta(2)-Coordination of Primary Silane on a Triruthenium Plane. AB - A MU3-eta(2):eta(2):eta(2)-silane complex, [(Cp*Ru)3(MU3-eta(2):eta(2):eta(2) H3SitBu)(MU-H)3] (2 a; Cp* = eta(5)-C5Me5), was synthesized from the reaction of [{Cp*Ru(MU-H)}3(MU3-H)2] (1) with tBuSiH3. Complex 2 a is the first example of a silane ligand adopting a MU3-eta(2):eta(2):eta(2) coordination mode. This unprecedented coordination mode was established by NMR and IR spectroscopy as well as X-ray diffraction analysis and supported by a density functional study. Variable-temperature NMR analysis implied that 2 a equilibrates with a tautomeric MU3-silyl complex (3 a). Although 3 a was not isolated, the corresponding MU3 silyl complex, [(Cp*Ru)3(MU3-eta(2):eta(2)-H2SiPh)(H)(MU-H)3] (3 b), was obtained from the reaction of 1 with PhSiH3. Treatment of 2 a with PhSiH3 resulted in a silane exchange reaction, leading to the formation of 3 b accompanied by the elimination of tBuSiH3. This result indicates that the MU3-silane complex can be regarded as an "arrested" intermediate for the oxidative addition/reductive elimination of a primary silane to a trinuclear site. PMID- 26487527 TI - Editorial: Extracranial-intracranial bypass study eight years later. PMID- 26487528 TI - Isolated dizziness in vertebrobasilar insufficiency: Clinical features, angiography, and follow-up. AB - Dizziness is the most common manifestation of vertebrobasilar insufficiency (VBI) and may occur as an isolated symptom in some patients. In order to determine if there is a characteristic pattern of vascular occlusion associated with this symptom, we reviewed the cerebral angiograms of seven patients (average age, 62 years) who presented with isolated episodes of dizziness. Six of seven had atherosclerotic occlusion of the vertebrobasilar junction between the takeoff of the posterior and anterior inferior cerebellar arteries. The other patient had basilar dolichoectasia without luminal narrowing. Our data suggest that isolated episodes of dizziness with VBI probably result from transient ischemia in territories supplied by the anterior inferior cerebellar artery. Anticoagulation stopped the attacks in six of seven patients who had recurrent symptoms despite aspirin therapy. Overall the prognosis was good. PMID- 26487529 TI - Silent cerebral infarction in stroke patients: Results from the klosterneuburg stroke data bank (Austria). AB - The incidence, topology, and risks of clinically silent cerebral ischemia were studied in a series of stroke patients entering the Klosterneuburg Stroke Data Bank, a prospective single-center stroke registry in Lower Austria that was established in 1988. Among 462 first-ever stroke patients, 340 (74%) showed only one lesion, which corresponded to the syndrome of their presenting stroke. However, 57 (12%) patients either showed an additional or a noncorresponding lesion, or both. Most silent strokes in our study were singular, deep, small infarctions (52%) by their location known to be asymptomatic, whereas eight additional cases with cortical involvement and one deep, large infarction could have been either unreported or largely asymptomatic. No significant difference was found for age, sex, or the hemispheric side of any lesion type (deep, small, or cortical), nor for the etiology of the presenting stroke. Silent cerebral infarctions were not associated with known additional or disproportional risk factors. The differing incidences and risks of silent stroke known from previous studies probably are not only due to the differing accuracy of neuroimaging techniques to detect small ischemic lesions but also to differences in awareness of unspecific and transient symptoms. Therefore, a continuum between clinically silent infarcts, unspecific symptoms, and short-lasting transient ischemia must be acknowledged. PMID- 26487530 TI - Stroke in patients with isolated IgM anticardiolipin antibody. AB - Eight of 90 patients with ischemic neurologic events were found to have persistent, isolated high-level IgM anticardiolipin antibodies. Strokes were multiple in four patients. Six patients were under 50 years of age at the time of the first stroke. PMID- 26487531 TI - Transcranial doppler and (15)O-H2O-positron emission tomography findings in patients with acute brain infarction and middle cerebral artery stenosis. AB - Transcranial Doppler (TCD) is a useful noninvasive tool for the assessment of the state of main intracranial arteries. Since present techniques for quantitative measurement of regional tissue perfusion (CBF) are invasive and expensive, the question was raised as to whether TCD could also be used to estimate CBF under normal and pathologic conditions. We compared TCD with CBF measurements using (15)O-H2O-positron emission tomography in 26 patients with either acute cerebral infarction or MCA mainstem stenosis and in 6 controls. No correlation was found between any blood velocity parameter and positron emission tomography blood flow values in middle cerebral artery territory neither in cerebrovascular patients nor in controls. We conclude that TCD cannot be used to quantitatively determine regional tissue perfusion. For optimal evaluation of brain blood supply, TCD should be coupled with a CBF imaging technique. PMID- 26487532 TI - Selective intra-arterial thrombolysis in acute stroke: Implications for emergency management. AB - Stroke, the most common life-threatening neurological disease, is a problem encountered frequently in the acute phase. Therapeutic options in this major cause of death and disability have previously been considered limited. Two cases of acute stroke are presented in which emergency treatment with selective intraarterial thrombolysis resulted in significant resolution of neurological deficits. The necessity for treating acute stroke as a medical emergency and management implications in the acute phase are discussed. PMID- 26487533 TI - Migraine and vertebrobasilar dissection: Case reports. AB - We report two patients with chronic migraine headaches who developed vertebrobasilar arterial dissections. In both cases, there was a change in both the character and location of the headaches, which prompted further evaluation with magnetic resonance imaging and angiography, which led to the diagnosis. Other possible risk factors for dissection in these patients included hypertension, exercise, and chiropractic manipulation. Both patients were treated with anticoagulation and recovered with little to no neurologic deficit. A review of the literature relating migraine and arterial dissection suggests that there may be an association. Although more extensive controlled studies are needed to demonstrate the significance of this association, we suggest that the diagnosis of cervicocranial arterial dissection be strongly considered in migraine patients who develop an abrupt change in the nature of their headaches. PMID- 26487534 TI - Glioblastoma multiforme presenting with recurrent neurological deficits: Transient ischemic attacks or tumor attacks. AB - Transient ischemic attacks result from the temporary focal interruption of blood flow to the brain. We present three patients with glioblastoma multiforme and recurrent speech arrests or right-sided numbness. The clinical diagnosis of "transient ischemic attack" was made in each patient. This diagnosis remained unchanged for months to 2 years after initial presentation and investigations. The correct diagnosis was made with a brain biopsy in two patients and as a result of additional investigations in the third patient. It is important to remember brain tumor in the differential diagnosis of patients presenting with recurrent brief neurological symptoms. PMID- 26487535 TI - Cerebrovascular espial. AB - Remarks are made on various stroke topics-potential hazards in the early diagnosis of occlusion of the carotid, basilar, and middle cerebral arteries, dissection, discontinuing angicoagulants, lowering blood pressure, and delaying endarterectomy. The commentary also includes bolus versus continuous drip heparin, long-term warfarin therapy, extensive craniectomy for brain edema, the percentage narrowing of the carotid versus the residual diameter, stroke during anesthesia, the duration of a TIA, TIAs in congophilic angiopathy and the interpretation of transient spells of vertigo. PMID- 26487536 TI - Vascular dementia: Problems with nomenclature, definition, and classification. AB - This article considers three aspects of vascular dementia that are a source of confusion and about which some consensus is needed: nomenclature, definition, and classification. PMID- 26487537 TI - Ischemic stroke in children: Relationship to unsuspected trauma. AB - Thirteen cases of ischemic stroke in children were seen and followed up between 1981 and 1990. Brain hemorrhage and strokes due to meningitis, leukemia, or other malignancy were excluded. In four, no cause was found. Three were related to trauma that preceded the stroke by up to 24 h. Two were due to cardiac emboli, which occurred during cardiac catheterization for dilation of stenotic valves, and two occurred spontaneously in association with mitral valve prolapse. One stroke was related to an inapparent neurocutaneous syndrome, and one was related to a hyperlipidemia. Follow-up showed no recurrence. School performance and developmental assessment was normal in 11 of 13 (one had a learning disability and the other had hyperactivity). Mild motor deficits persisted in five, were moderate in two, and were severe in one. The overall prognosis was best in children under 5 years. PMID- 26487538 TI - Analysis of 30-day stroke mortality in a community-based registry in Warsaw, Poland. AB - Between January 1, 1991, and December 31, 1992, in the upper Mokotow district of Warsaw, Poland (population 182,285), 462 first-ever-in-a-lifetime (FEL) strokes were registered, 12% (55/462) with parenchymatous intracerebral hemorrhages (PICH) and 88% (407/462) with ischemic strokes. Confirmation by either computed tomography or autopsy was made in 72.3% of cases. The overall 30-day case fatality rate (CFR) for FEL strokes was 40% (186/462), 60% for PICH (33/55), and 38% for ischemic stroke (153/407). Of the 186 patients who died within 30 days of their FEL stroke, 49% (91) underwent full autopsy examination. Fifty-two percent of these 91 patients were found to have died from direct neurological sequelae, 21% from cardiac causes, 17% from pneumonia, 5.6% from septicemia, 2.2% from pulmonary emboli, and 2.2% from metastatic cancer. Despite our high 30-day stroke CFR compared with Western Europe and North America, mechanisms of death were similar. PMID- 26487539 TI - MiR-129-3p promotes docetaxel resistance of breast cancer cells via CP110 inhibition. AB - Docetaxel is commonly used as an effective chemotherapeutic agent in breast cancer treatment, but the underlying mechanisms of drug resistance are not fully understood. The purpose of this study was to investigate the possible role of miR 129-3p in breast cancer cell resistance to docetaxel. MiR-129 and miR-129-3p inhibitor were transfected into breast cancer cells to investigate their effects on chemoresistance to docetaxel. The function of miR-129-3p was evaluated by apoptosis, cell proliferation, and cell cycle assays. We found that miR-129-3p was up-regulated in MDA-MB-231/Doc cells, concurrent with CP110 down-regulation, compared to the parental MDA-MB-231 cells. In vitro drug sensitivity assays demonstrated that miR-129-3p inhibition sensitized MDA-MB-231/Doc and MCF-7 cells to docetaxel, whereas miR-129 overexpression enhanced MDA-MB-231 and MCF-7 cell resistance to docetaxel. Ectopic miR-129 expression reduced CP110 expression and the luciferase activity of a CP110 3' untranslated region-based reporter construct in MDA-MB-231 cells, suggesting that CP110 is a direct miR-129-3p target. We demonstrated that restoration of CP110 expression in MDA-MB-231 and MCF-7 cells by miR-129 overexpression rendered the cells sensitive to docetaxel. In a nude xenograft model, miR-129 up-regulation significantly decreased MDA-MB 231 cells' response to docetaxel. Our findings suggest that miR-129-3p down regulation potentially sensitizes breast cancer cells to docetaxel treatment. PMID- 26487540 TI - BRAF alteration status and the histone H3F3A gene K27M mutation segregate spinal cord astrocytoma histology. PMID- 26487541 TI - Axitinib: a review in advanced renal cell carcinoma. AB - Axitinib (Inlyta((r))) is a potent, selective inhibitor of vascular endothelial growth factor receptor-1, -2 and -3. This article reviews the clinical efficacy and tolerability of axitinib in patients with previously-treated advanced renal cell carcinoma (RCC), as well as summarizing its pharmacological properties. Axitinib was effective in the second-line treatment of advanced RCC, according to the results of the pivotal, phase III AXIS trial. Median progression-free survival (PFS) was significantly prolonged with axitinib versus sorafenib (primary endpoint; independent review committee assessment); this PFS benefit was seen in patients who had received prior treatment with cytokines or sunitinib. The objective response rate was also significantly higher with axitinib than with sorafenib, with no significant between-group difference in median overall survival. Axitinib had a manageable tolerability profile in the AXIS trial, with the most commonly reported treatment-related adverse events including diarrhoea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome and hypothyroidism. In conclusion, axitinib is an important option in previously treated patients with advanced RCC. PMID- 26487542 TI - Luminescent Iridium(III) Complexes Supported by N-Heterocyclic Carbene-based C^C^C-Pincer Ligands and Aromatic Diimines. AB - Iridium(III) hydrido complexes containing N-heterocyclic carbene (NHC)-based pincer ligand 1,3-bis(1-butylimidazolin-2-ylidene)phenyl anion (C(1)^C^C(1)) or 1,3-bis(3-butylbenzimidazolin-2-ylidene)phenyl anion (C(2)^C^C(2)) and aromatic diimine (2,2'-bipyridine (bpy), 1,10-phenanthroline (phen), 4,4'-dimethyl-2,2' bipyridine (Me2bpy), or dipyrido-[3,2-f:2',3'-h]-quinoxaline (dpq)) in the form of [Ir(C^C^C)(N^N)(H)](+) have been prepared. Crystal structures for these complexes show that the Ir-CNHC distances are 2.043(5)-2.056(5) A. The hydride chemical shifts for complexes bearing C(1)^C^C(1) (-20.6 to -20.3 ppm) are more upfield than those with C(2)^C^C(2) (-19.5 and -19.2 ppm), revealing that C(1)^C^C(1) is a better electron donor than C(2)^C^C(2). Spectroscopic comparisons and time-dependent density functional theory (TD-DFT) calculations suggest that the lowest-energy electronic transition associated with these complexes (lambda = 340-530 nm (epsilon <= 10(3) dm(3) mol(-1) cm(-1))) originate from a dpi(Ir(III)) -> pi*(N^N) metal-to-ligand charge transfer transition, where the dpi(Ir(III)) level contain significant contribution from the C^C^C ligands. All these complexes are emissive in the yellow-spectral region (553-604 nm in CH3CN and CH2Cl2) upon photo-excitation with quantum yields of 10(-3)-10(-1). PMID- 26487543 TI - Efficient Biosynthesis of Lactosucrose from Sucrose and Lactose by the Purified Recombinant Levansucrase from Leuconostoc mesenteroides B-512 FMC. AB - Lactosucrose, a rare trisaccharide formed from sucrose and lactose by enzymatic transglycosylation, is a type of indigestible carbohydrate with a good prebiotic effect. In this study, lactosucrose biosynthesis was efficiently carried out by a purified levansucrase from Leuconostoc mesenteroides B-512. The target gene was cloned and expressed in Escherichia coli, and the recombinant enzyme was purified to homogeneity by nickel affinity and gel filtration chromatography. The effects of pH, temperature, substrate concentration, substrate ratio, and enzyme amount on lactosucrose biosynthesis were studied in detail, and the optimized conditions were determined to be pH 6.5, 50 degrees C, 27% (W/V) sucrose, 27% (W/V) lactose, and 5 U mL(-1) of the purified recombinant enzyme. Under the optimized reaction conditions, the maximal lactosucrose yield reached 224 g L(-1) after reaction for 1 h. Therefore, L. mesenteroides levansucrase could be considered a potential candidate for future industrial production of lactosucrose. PMID- 26487544 TI - Reducing discretionary food and beverage intake in early childhood: a systematic review within an ecological framework. AB - OBJECTIVE: To systematically review the literature and map published studies on 4 8-year-olds' intake of discretionary choices against an ecological framework (ANalysis Grid for Environments Linked to Obesity; ANGELO). DESIGN: Articles were identified through database searches (PubMed, PyscINFO(r), Web of Science) in February and March 2014 and hand-searching reference lists. Studies were assessed for methodological quality and mapped against the ANGELO framework by environment size (macro and micro setting) and type (physical, economic, policy and socio cultural influences). SETTING: Studies were conducted in the USA (n 18), Australia (n 6), the UK (n 3), the Netherlands (n 3), Belgium (n 1), Germany (n 1) and Turkey (n 1). SUBJECTS: Children aged 4-8 years, or parents/other caregivers. RESULTS: Thirty-three studies met the review criteria (observational n 23, interventions n 10). Home was the most frequently studied setting (67 % of exposures/strategies), with the majority of these studies targeting family policy type influences (e.g. child feeding practices, television regulation). Few studies were undertaken in government (5.5 %) or community (11 %) settings, or examined economic-type influences (0 %). Of the intervention studies only four were categorised as effective. CONCLUSIONS: The present review is novel in its focus on mapping observational and intervention studies across a range of settings. It highlights the urgent need for high-quality research to inform interventions that directly tackle the factors influencing children's excess intake of discretionary choices. Interventions that assist in optimising a range of environmental influences will enhance the impact of future public health interventions to improve child diet quality. PMID- 26487545 TI - Predictive factors for a distal adjacent disorder with L3 as the lowest instrumented vertebra in Lenke 5C patients. AB - OBJECTIVE: To investigate what type of Lenke 5C patient benefits most from a fusion to L3 as the LIV. METHODS: The subjects were 16 patients who underwent fusion surgery to L3 as the lowest instrumented vertebra (LIV), and who were then observed for a minimum of 2 years postoperatively. We considered an unsatisfactory radiologic outcome for the distal adjacent curve (DAD) to be an L3 or L4 tilt angle less than 10 degrees or L3/4 disc wedging less than 10 degrees . Patients were divided into 2 groups based on the radiologic outcome of the distal curve: the distal adjacent disorder+ (DAD+) and the distal adjacent disorder-(DAD-). We compared global balance, Cobb angles (thoracic and lumbar), L3 and L4 tilt angles and L3/4/5 disc angles between the 2 groups on preoperative, postoperative and final radiographs. RESULTS: Seven patients (43.8 %) met the criteria for the DAD+ group. On preoperative radiographs, there was a significant difference in the L3/4 disc angle: the DAD+ group opened to the preoperative convex side (-2.1 degrees +/- 3.0 degrees ) and the DAD- group opened to the preoperative concave side (4.7 degrees +/- 5.1 degrees ). The standing L3- and L4-CSVL and the L4-CSVL under traction were significantly different. CONCLUSIONS: In Lenke 5C patients who underwent fusion surgery to L3 as the LIV, preoperative LIV (L3), LIV + 1 (L4) translation and L3/4 disc angle on standing, plus LIV + 1 translation under traction were very important parameters correlating with postoperative global coronal balance. PMID- 26487546 TI - Prospects for Creation of Cardioprotective Drugs Based on Cannabinoid Receptor Agonists. AB - Cannabinoids can mimic the infarct-reducing effect of early ischemic preconditioning, delayed ischemic preconditioning, and ischemic postconditioning against myocardial ischemia/reperfusion. They do this primarily through both CB1 and CB2 receptors. Cannabinoids are also involved in remote preconditioning of the heart. The cannabinoid receptor ligands also exhibit an antiapoptotic effect during ischemia/reperfusion of the heart. The acute cardioprotective effect of cannabinoids is mediated by activation of protein kinase C, extracellular signal regulated kinase, and p38 kinase. The delayed cardioprotective effect of cannabinoid anandamide is mediated via stimulation of phosphatidylinositol-3 kinase-Akt signaling pathway and enhancement of heat shock protein 72 expression. The delayed cardioprotective effect of another cannabinoid, Delta9 tetrahydrocannabinol, is associated with augmentation of nitric oxide (NO) synthase expression, but data on the involvement of NO synthase in the acute cardioprotective effect of cannabinoids are contradictory. The adenosine triphosphate-sensitive K(+)channel is involved in the synthetic cannabinoid HU 210-induced cardiac resistance to ischemia/reperfusion injury. Cannabinoids inhibit Na(+)/Ca(2+)exchange via peripheral cannabinoid receptor (CB2) activation that may also be related to the antiapoptotic and cardioprotective effects of cannabinoids. The cannabinoid receptor agonists should be considered as prospective group of compounds for creation of drugs that are able to protect the heart against ischemia-reperfusion injury in the clinical setting. PMID- 26487547 TI - Corrigendum: the microbiome of New World vultures. PMID- 26487549 TI - Black-CuO: surface-enhanced Raman scattering and infrared properties. AB - Large surface area samples of nanotextured black CuO were prepared by chemical etching of Cu for use in surface-enhanced Raman scattering (SERS). The SERS intensity of a self-assembled monolayer (SAM) of thiophenol was proportional to the thickness of a nanoscale-conformal Au film deposited by magnetron sputtering over the black CuO. A very high SERS yield of ~10(4) counts per s per mW was observed for the thiophenol SAM on the thickest Au films studied here. Synchrotron X-ray photoelectron spectroscopy was used to confirm that the surface of the chemically etched Cu was covered by high purity CuO. IR spectral characterization of the black CuO showed a close to linear increase in reflectivity from 25 to 100% over the range of 4000-500 cm(-1) wavenumbers (or 2.5-20 MUm in wavelength). Sensing applications and thermal effects in SERS are discussed. PMID- 26487550 TI - Stabilization of Al(III) solutions by complexation with cacodylic acid: speciation and binding features. AB - Aluminium ions are believed to play a role in a number of neurological and skeletal disorders in the human body. The study of the biological processes and molecular mechanisms that underlie these pathological disorders is rendered a difficult task due to the wide variety of complex species that result from the hydrolysis of Al(3+) ions. In addition, this ion displays a pronounced tendency to precipitate as a hydroxide, so certain complexing agents should be envisaged to stabilize Al(III) solutions in near physiological conditions. In this work, we show that the common buffer cacodylic acid (dimethylarsinic acid, HCac) interacts with Al(III) to give stable complexes, even at pH 7. After preliminary analyses of the speciation of the metal ion and also of the ligand, a systematic study of the formation of different Al/Cac complexes at different pH values has been conducted. UV-Vis titrations, mass spectrometry NMR measurements and DTF calculations were performed to enlighten the details of the speciation and stoichiometry of Al/Cac complexes. The results altogether show that Al/Cac dimer complexes prevail, but monomer and trimer forms are also present. Interestingly, it was found that cacodylate promotes the formation of such relatively simple complexes, even under conditions where the polymeric form, Al13O4(OH)24(7+), should predominate. The results obtained can help to shed some light into the reactivity of aluminium ions in biological environments. PMID- 26487551 TI - Early verb constructions in French: adjacency on the left edge. AB - Children acquiring French elaborate their early verb constructions by adding adjacent morphemes incrementally at the left edge of core verbs. This hypothesis was tested with 2657 verb uses from four children between 1;3 and 2;7. Consistent with the Adjacency Hypothesis, children added clitic subjects first only to present tense forms (as in il saute 'he jumps'); modals to infinitives (as in faut sauter 'has to jump'); and auxiliaries to past participles (as in a saute 'has jumped'). Only after this did the children add subjects to the left of a modal or auxiliary, as in elle veut sauter 'she wants to jump', or elle a saute 'she has jumped'. The order in which these elements were added, and the development in the frequencies of the constructions, all support the predictions of the Adjacency Hypothesis for left edge development in early verb constructions. PMID- 26487552 TI - Cancers of the breast and prostate: a stem cell perspective. PMID- 26487553 TI - Disparate developmental patterns of immune responses to bacterial and viral infections in fish. AB - During early stages of development vertebrates rely on an immature immune system to fight pathogens, but in non mammalian species few studies have taken an in depth analysis of the transition from reliance on innate immune mechanisms to the appearance of adaptive immunity. Using rainbow trout as a model we characterized responses to two natural pathogens of this species, the Gram negative bacterium Aeromonas salmonicida and the virus VHSV, using microarray analysis at four early life history stages; eyed egg, post hatch, first feeding and three weeks post first feeding when adaptive immunity starts to be effective. All stages responded to both infections, but the complexity of the response increased with developmental stage. The response to virus showed a clear interferon response only from first feeding. In contrast, bacterial infection induced a marked response from early stages, with modulation of inflammatory, antimicrobial peptide and complement genes across all developmental stages. Whilst the viral and bacterial responses were distinct, there were modulated genes in common, mainly of general inflammatory molecules. This work provides a first platform to explore the development of fish immunity to infection, and to compare the age dependent changes (from embryo to adults) across vertebrates. PMID- 26487554 TI - Resistance integrons: class 1, 2 and 3 integrons. AB - As recently indiscriminate abuse of existing antibiotics in both clinical and veterinary treatment leads to proliferation of antibiotic resistance in microbes and poses a dilemma for the future treatment of such bacterial infection, antimicrobial resistance has been considered to be one of the currently leading concerns in global public health, and reported to widely spread and extended to a large variety of microorganisms. In China, as one of the currently worst areas for antibiotics abuse, the annual prescription of antibiotics, including both clinical and veterinary treatment, has approaching 140 gram per person and been roughly estimated to be 10 times higher than that in the United Kingdom, which is considered to be a potential area for the emergence of "Super Bugs". Based on the integrons surveillance in Guangzhou, China in the past decade, this review thus aimed at summarizing the role of integrons in the perspective of both clinical setting and environment, with the focus on the occurrence and prevalence of class 1, 2 and 3 integrons. PMID- 26487555 TI - Correlation between apparent diffusion coefficients and HER2 status in gastric cancers: pilot study. AB - BACKGROUND: To evaluate whether apparent diffusion coefficient (ADC) value of gastric cancer obtained from diffusion weighted imaging (DWI) correlates with the HER2 status. METHODS: Forty-five patients, who had been diagnosed with gastric cancer through biopsy, were enrolled in this IRB-approved study. Each patient underwent a DWI (b values: 0 and 1,000 sec/mm(2)) prior to surgery (curative gastrectomy or palliative resection). Postoperative microscopic findings, HER2 status by immunohistochemical analysis and fluorescence in situ hybridization (FISH) were obtained. HER2 status was compared among gastric cancers with various histopathological features using the chi square test. The ADC values of gastric cancers with positive and negative HER2 were compared using the student t test. RESULTS: A weak yet significant correlation was observed between the mean ADC values and HER2 status (r = 0.312, P = 0.037) and scores (r = 0.419, P = 0.004). The mean ADC value of HER2-positive gastric cancers was significantly higher than those of HER2-negative tumors (1.211 vs. 0.984 mm(2)/s, P = 0.020). The minimal ADC value of HER2-positive gastric cancers was significantly higher than those of HER2-negative tumors (1.105 vs. 0.905 * 10(-3) mm(2)/s, P = 0.036). CONCLUSIONS: In this pilot study, we have demonstrated that the ADC values of gastric cancer correlate with the HER2 status. Future research is warranted to see if DWI can predict HER2 status and help in tailoring therapy for gastric cancer. PMID- 26487556 TI - TGFbeta signalling pathway regulates angiogenesis by endothelial cells, in an adipose-derived stromal cell/endothelial cell co-culture 3D gel model. AB - OBJECTIVE: This study aimed to investigate the role of the TGFbeta signalling pathway in angiogenesis in a three-dimensional (3D) collagen gel model, with co culture between adipose-derived stromal cells (ASCs) and endothelial cells (ECs). MATERIALS AND METHODS: A 3D collagen gel, implanted with green fluorescent protein-labelled mouse ASCs and red fluorescent protein-labelled mouse ECs, was established in vitro. Phenomena of angiogenesis with or without type I TGFbeta receptor inhibitor (LY2157299) treatment, were observed 7 days post-implantation, using confocal laser scanning microscopy. To detect expression of angiogenesis related genes, semi-quantitative PCR and quantitative real-time PCR were conducted. Zymography was performed to explore secretion of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) after treatment with LY2157299 of 5, 10, 20 to 50 MUm concentrations, for 24 h. RESULTS: Angiogenesis was found to be attenuated in co-culture gels after ASC and EC treatment with LY2157299. Genes VEGF-A, VEGF-B, VE-ca, FGF-1, FGF-2, PDGF, HGF, BMP-4 were significantly reduced in the presence of LY2157299 in both mono cultured and co-cultured ECs. Furthermore, reduction in co-cultured ECs was prominent relative to mono-cultured ECs, while the same results did not occur to ASCs. We further confirmed that gelatinases secreted by ECs were reduced in a dose-dependent manner, after treatment with LY2157299. CONCLUSIONS: These results indicate that in ASC/EC co-culture, the TGFbeta signalling pathway regulated angiogenesis via EC activity. Co-cultured ECs were regulated more significantly than mono-cultured ECs suggesting that inhibition of TGFbetaRI may regulate paracrine secretion of ASCs to further modulate EC angiogenesis. PMID- 26487557 TI - The 'vicious cycle' of personalised asthma action plan implementation in primary care: a qualitative study of patients and health professionals' views. AB - BACKGROUND: Personal asthma action plans (PAAPs) have been guideline recommended for years, but consistently under-issued by health professionals and under utilised by patients. Previous studies have investigated sub-optimal PAAP implementation but more insight is needed into barriers to their use from the perspective of professionals, patients and primary care teams. METHODS: A maximum variation sample of professional and patient participants were recruited from five demographically diverse general practices and another group of primary care professionals in one Scottish region. Interviews were digitally recorded and data thematically analysed using NVivo. RESULTS: Twenty-nine semi-structured interviews were conducted (11 adults with asthma, seven general practitioners, ten practice nurses, one hospital respiratory nurse). Three over-arching themes emerged: 1) patients generally do not value PAAPs, 2) professionals do not fully value PAAPs and, 3) multiple barriers reduce the value of PAAPs in primary care. Six patients had a PAAP but these were outdated, not reflecting their needs and not used. Patients reported not wanting or needing PAAPs, yet identified circumstances when these could be useful. Fifteen professionals had selectively issued PAAPs with eight having reviewed one. Many professionals did not value PAAPs as they did not see patients using these and lacked awareness of times when patients could have benefited from one. Multi-level compounding barriers emerged. Individual barriers included poor patient awareness and professionals not reinforcing PAAP use. Organisational barriers included professionals having difficulty accessing PAAP templates and fragmented processes including patients not being asked to bring PAAPs to their asthma appointments. CONCLUSIONS: Primary care PAAP implementation is in a vicious cycle. Professionals infrequently review/update PAAPs with patients; patients with out-dated PAAPs do not value or use these; professionals observing patients' lack of interest in PAAPs do not discuss these. Patients observing this do not refer to their plans and perceive them to be of little value in asthma self-management. Twenty-five years after PAAPs were first recommended, primary care practices are still not ready to support their implementation. Breaking this vicious cycle to create a healthcare context more conducive to PAAP implementation requires a whole systems approach with multi-faceted interventions addressing patient, professional and organisational barriers. PMID- 26487558 TI - [Post-surgical palatal mucosal swelling without clinical signs and symptoms]. PMID- 26487559 TI - Inner Workings: Legos in the lab. PMID- 26487561 TI - Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments. AB - Evidence suggests that autophagy promotes the development of cellular senescence. Because cellular senescence contributes to renal aging and promotes the progression from AKI to CKD, we investigated the potential effect of tubular autophagy on senescence induction. Compared with kidneys from control mice, kidneys from mice with conditional deletion of autophagy-related 5 (Atg5) for selective ablation of autophagy in proximal tubular S3 segments (Atg5(Delta) (flox/) (Delta) (flox)) presented with significantly less tubular senescence, reduced interstitial fibrosis, and superior renal function 30 days after ischemia/reperfusion injury. To correlate this long-term outcome with differences in the early injury process, kidneys were analyzed 2 hours and 3 days after reperfusion. Notably, compared with kidneys of control mice, Atg5(Delta) (flox/) (Delta) (flox) kidneys showed more cell death in outer medullary S3 segments at 2 hours but less tubular damage and inflammation at day 3. These data suggest that the lack of autophagy prevents early survival mechanisms in severely damaged tubular cells. However, if such compromised cells persist, then they may lead to maladaptive repair and proinflammatory changes, thereby facilitating the development of a senescent phenotype and CKD. PMID- 26487562 TI - AKI after Transcatheter or Surgical Aortic Valve Replacement. AB - Transcatheter aortic valve replacement (TAVR) is an alternative to surgical aortic valve replacement (SAVR) for patients with symptomatic severe aortic stenosis who are at high risk of perioperative mortality. Previous studies showed increased risk of postoperative AKI with TAVR, but it is unclear whether differences in patient risk profiles confounded the results. To conduct a propensity-matched study, we identified all adult patients undergoing isolated aortic valve replacement for aortic stenosis at Mayo Clinic Hospital in Rochester, Minnesota from January 1, 2008 to June 30, 2014. Using propensity score matching on the basis of clinical characteristics and preoperative variables, we compared the postoperative incidence of AKI, defined by Kidney Disease Improving Global Outcomes guidelines, and major adverse kidney events in patients treated with TAVR with that in patients treated with SAVR. Major adverse kidney events were the composite of in-hospital mortality, use of RRT, and persistent elevated serum creatinine >=200% from baseline at hospital discharge. Of 1563 eligible patients, 195 matched pairs (390 patients) were created. In the matched cohort, baseline characteristics, including Society of Thoracic Surgeons risk score and eGFR, were comparable between the two groups. Furthermore, no significant differences existed between the TAVR and SAVR groups in postoperative AKI (24.1% versus 29.7%; P=0.21), major adverse kidney events (2.1% versus 1.5%; P=0.70), or mortality >6 months after surgery (6.0% versus 8.3%; P=0.51). Thus, TAVR did not affect postoperative AKI risk. Because it is less invasive than SAVR, TAVR may be preferred in high-risk individuals. PMID- 26487564 TI - TIM-1 acts a dual-attachment receptor for Ebolavirus by interacting directly with viral GP and the PS on the viral envelope. AB - Ebolavirus can cause hemorrhagic fever in humans with a mortality rate of 50% 90%. Currently, no approved vaccines and antiviral therapies are available. Human TIM1 is considered as an attachment factor for EBOV, enhancing viral infection through interaction with PS located on the viral envelope. However, reasons underlying the preferable usage of hTIM-1, but not other PS binding receptors by filovirus, remain unknown. We firstly demonstrated a direct interaction between hTIM-1 and EBOV GP in vitro and determined the crystal structures of the Ig V domains of hTIM-1 and hTIM-4. The binding region in hTIM-1 to EBOV GP was mapped by chimeras and mutation assays, which were designed based on structural analysis. Pseudovirion infection assays performed using hTIM-1 and its homologs as well as point mutants verified the location of the GP binding site and the importance of EBOV GP-hTIM-1 interaction in EBOV cellular entry. PMID- 26487565 TI - The creation of synthetic crystalline bovine insulin. PMID- 26487563 TI - The effects of exercise training in a weight loss lifestyle intervention on asthma control, quality of life and psychosocial symptoms in adult obese asthmatics: protocol of a randomized controlled trial. AB - BACKGROUND: Asthma and obesity are public health problems with increasing prevalence worldwide. Clinical and epidemiologic studies have demonstrated that obese asthmatics have worse clinical control and health related quality of life (HRQL) despite an optimized medical treatment. Bariatric surgery is successful to weight-loss and improves asthma control; however, the benefits of nonsurgical interventions remain unknown. METHODS/DESIGN: This is a randomized controlled trial with 2-arms parallel. Fifty-five moderate or severe asthmatics with grade II obesity (BMI >= 35 kg/m(2)) under optimized medication will be randomly assigned into either weight-loss program + sham (WL + S group) or weight-loss program + exercise (WL + E group). The weight loss program will be the same for both groups including nutrition and psychological therapies (every 15 days, total of 6 sessions, 60 min each). Exercise program will include aerobic and resistance muscle training while sham treatment will include a breathing and stretching program (both programs twice a week, 3 months, 60 min each session). The primary outcome variable will be asthma clinical control. Secondary outcomes include HRQL, levels of depression and anxiety, lung function, daily life physical activity, body composition, maximal aerobic capacity, strength muscle and sleep disorders. Potential mechanism (changes in lung mechanical and airway/systemic inflammation) will also be examined to explain the benefits in both groups. DISCUSSION: This study will bring a significant contribution to the literature evaluating the effects of exercise conditioning in a weight loss intervention in obese asthmatics as well as will evaluate possible involved mechanisms. TRIAL REGISTRATION: NCT02188940. PMID- 26487566 TI - A conserved co-chaperone is required for virulence in fungal plant pathogens. AB - The maize pathogenic fungus Ustilago maydis experiences endoplasmic reticulum (ER) stress during plant colonization and relies on the unfolded protein response (UPR) to cope with this stress. We identified the U. maydis co-chaperone, designated Dnj1, as part of this conserved cellular response to ER stress. ?dnj1 cells are sensitive to the ER stressor tunicamycin and display a severe virulence defect in maize infection assays. A dnj1 mutant allele unable to stimulate the ATPase activity of chaperones phenocopies the null allele. A Dnj1-mCherry fusion protein localizes in the ER and interacts with the luminal chaperone Bip1. The Fusarium oxysporum Dnj1 ortholog contributes to the virulence of this fungal pathogen in tomato plants. Unlike the human ortholog, F. oxysporum Dnj1 partially rescues the virulence defect of the Ustilago dnj1 mutant. By enabling the fungus to restore ER homeostasis and maintain a high secretory activity, Dnj1 contributes to the establishment of a compatible interaction with the host. Dnj1 orthologs are present in many filamentous fungi, but are absent in budding and fission yeasts. We postulate a conserved and essential role during virulence for this class of co-chaperones. PMID- 26487568 TI - Parental perceptions of barriers to mental health services for young people. AB - AIM: This study explores a range of barriers that parents encountered in accessing mental health services. The study also explored whether parents experienced similar barriers to accessing services in 2003 and 2013. METHODS: One hundred and thirty-four parents of young people attending an initial assessment at a Child and Adolescent Mental Health Service (CAMHS) or headspace centre completed a questionnaire assessing 10 general barriers to care. These data were compared to those collected from 129 participants at CAMHS in 2003. RESULTS: The ranking of barriers to mental health care for their children was similar for both survey years, with 'wait time being too long' and 'help being too expensive' the two highest ranked barriers. Cost factors were related to not knowing that the services did not charge fees and having to take time off work to attend appointments. Multiple referral steps and uncertain wait times were the main concerns regarding wait times. The overall strength with which barriers were endorsed remained relatively low; however, at least 40% of the sample agreed they had experienced four of the barriers in both years. CONCLUSIONS: Despite relatively low endorsement of barriers, there are substantial proportions of parents who experienced some barriers to services, and services should continue working to reduce them to facilitate timely access. There is a particular need for more service-related information to clarify that public sector mental health services do not charge fees. Methods such as rapid initial assessment and actively managing wait lists may go some way to reducing perceived wait time barriers. PMID- 26487567 TI - Children's Mental Health and Well-Being After Parental Intimate Partner Homicide: A Systematic Review. AB - When one parent kills the other, children are confronted with multiple losses, involving their attachment figures and their direct living environment. In these complex situations, potentially drastic decisions are made, for example, regarding new living arrangements and contact with the perpetrating parent. We aimed to synthesize the empirical literature on children's mental health and well being after parental intimate partner homicide. A systematic search identified 17 relevant peer-reviewed articles (13 independent samples). We recorded the theoretical background, methodology, and sample characteristics of the studies, and extracted all child outcomes as well as potential risk and protective factors. Children's outcomes varied widely and included psychological, social, physical, and academic consequences (e.g., post-traumatic stress, attachment difficulties, weight and appetite changes, and drops in school grades). Potential risk and protective factors for children's outcomes included 10 categories of pre , peri-, and post-homicide characteristics such as cultural background of the family, whether the child witnessed the homicide, and the level of conflict between the families of the victim and the perpetrator. We integrated the findings into a conceptual model of risk factors to direct clinical reflection and further research. PMID- 26487569 TI - Influence of the surface charge of PLGA nanoparticles on their in vitro genotoxicity, cytotoxicity, ROS production and endocytosis. AB - With the ongoing commercialization of nanotechnology products, human exposure to nanoparticles (NPs) is set to increase dramatically and an evaluation of their potential adverse effects is essential. Surface charge, among other physico chemicals parameters, is a key criterion that should be considered when using a definition for nanomaterials in a regulatory context. It has recently been recognized as an important factor in determining the toxicity of NPs; however, a complete understanding of the mechanisms involved is still lacking. In this context, the aim of the present study was to investigate the influence of the surface charge modification of NPs on in vitro toxicity assays. Poly(lactic-co glycolic acid) (PLGA) nanoparticles bearing different surface charges, positive(+), neutral(n) or negative(-), were synthesized. In vitro genotoxicity assays (micronucleus and comet assays) coupled with an assessment of cytotoxicity, were performed in different cell lines (L5178Y mouse lymphoma cells, TK6 human B-lymphoblastoid cells and 16HBE14o- human bronchial epithelial cells). Reactive oxygen species (ROS) production and endocytosis studies were also performed. Our results showed that PLGA(+) NPs were cytotoxic. They are endocytosed by the clathrin pathway and induced ROS in the three cell lines. They led to chromosomal aberrations without primary DNA damage in 16HBE14o- cells, suggesting that aneuploidy may be considered as an important biomarker when assessing the genotoxic potential of NPs. Moreover, 16HBE14o- cells seem to be more suitable for the in vitro screening of inhaled NPs than the regulatory L5178Y and TK6 cells. PMID- 26487570 TI - Enantioselective Trichloromethylation of MBH-Fluorides with Chloroform Based on Silicon-assisted C-F Activation and Carbanion Exchange Induced by a Ruppert Prakash Reagent. AB - Enantioselective trichloromethylation of Morita-Baylis-Hillman (MBH)-type allylic fluorides with chloroform (HCCl3 ) under organocatalysis was achieved with high to excellent enantioselectivities. Silicon-assisted C?F bond activation by a Ruppert-Prakash reagent and direct activation of HCCl3 by a carbanion exchange process with trifluoromethyl (CF3 ) carbanion generated in situ from the Ruppert Prakash reagent realized the direct asymmetric trichloromethylation at a stereogenic allylic positon, without any help from transition metal catalysis, and under very mild conditions. Pre-activation of HCCl3 was not required. This method was extended to the direct enantioselective introduction of other C-H compounds such as alkyne, arene, indene, and FBSM without any pre-activation under a metal-free system. PMID- 26487571 TI - Reliability of blood test results in samples obtained using a 2-mL discard volume from the proximal lumen of a triple-lumen central venous catheter in the critically ill patient. AB - BACKGROUND: Intensive care patients require a high frequency of blood testing, which results in a significant amount of blood loss. When blood is obtained from a central venous catheter (CVC), a large volume is usually discarded to obtain an unaltered sample for testing. AIM: To determine the reliability of complete blood test results in blood samples obtained from the proximal lumen of a triple-lumen CVC using a 2-mL discard volume DESIGN: Observational study with the prospective collection of data METHODS: The subjects enrolled were all patients with a subclavian triple-lumen CVC, older than 17 years and consecutively admitted to intensive care over a 2-year period. In each of the 54 participants, one blood sample was drawn from the proximal lumen of the catheter, discarding 1.61 mL of blood plus 0.39 mL of catheter deadspace (2 mL) and without interrupting infusion in the middle and distal lumens. A second sample was then obtained by direct venous puncture. The reliability of blood test results was determined by comparing sets of variables recorded for the two sampling methods through intraclass correlation coefficients in the Bland-Altman method. RESULTS: Inter method reliability for the variables examined was excellent, >0.75; range (0.868 0.998). Mean differences between the two sample types for the variables most often determined in critically ill patients were leukocytes: 0.200 * 103 /uL, 95% confidence interval (CI) (0.025 to 0.375); erythrocytes: 0.045 * 106 /uL, 95% CI (-0.003 to 0.094); sodium: 0.074 mEq/L, 95% CI (-0.369 to 0.517); potassium: 0.002mEq/L, 95% CI (-0.065 to 0.061) and glucose: 2.426 mg/dL, 95% CI (0.498 4.354). CONCLUSIONS: The sampling method proposed minimizes blood loss while offering reliable blood test results. RELEVANCE TO CLINICAL PRACTICE: The main benefit of the method proposed is reduced blood loss, improving the care of a critically ill patient. PMID- 26487572 TI - Secondary Binding Interactions in a Synthetic Receptor for Trimethyllysine. AB - We have systematically studied how secondary interactions with neighboring lysine (Lys) and arginine (Arg) residues influence the binding and selectivity of the synthetic receptor A2 N for trimethyllysine (Kme3 ). Multiple secondary binding sites on A2 N are formed by carboxylates rigidly positioned over aromatic rings, a motif that has been shown to stabilize salt bridges. We varied the spacing between KmeX (X=0, 3) and an ancillary Lys or Arg and measured binding by isothermal titration calorimetry (ITC). These studies revealed that both neighboring residues improve the binding of A2 N to KmeX by approximately 1 kcal mol(-1) , with little influence of the spacing. Nonetheless, the improvement in affinity caused by Arg is enthalpically driven, while for Lys it is entropically driven, suggesting different mechanisms by which the residues interact with the secondary binding site. PMID- 26487573 TI - Metagenomic investigation of the geologically unique Hellenic Volcanic Arc reveals a distinctive ecosystem with unexpected physiology. AB - Hydrothermal vents represent a deep, hot, aphotic biosphere where chemosynthetic primary producers, fuelled by chemicals from Earth's subsurface, form the basis of life. In this study, we examined microbial mats from two distinct volcanic sites within the Hellenic Volcanic Arc (HVA). The HVA is geologically and ecologically unique, with reported emissions of CO2 -saturated fluids at temperatures up to 220 degrees C and a notable absence of macrofauna. Metagenomic data reveals highly complex prokaryotic communities composed of chemolithoautotrophs, some methanotrophs, and to our surprise, heterotrophs capable of anaerobic degradation of aromatic hydrocarbons. Our data suggest that aromatic hydrocarbons may indeed be a significant source of carbon in these sites, and instigate additional research into the nature and origin of these compounds in the HVA. Novel physiology was assigned to several uncultured prokaryotic lineages; most notably, a SAR406 representative is attributed with a role in anaerobic hydrocarbon degradation. This dataset, the largest to date from submarine volcanic ecosystems, constitutes a significant resource of novel genes and pathways with potential biotechnological applications. PMID- 26487574 TI - Work-life balance/imbalance: the dominance of the middle class and the neglect of the working class. AB - The paper was stimulated by the relative absence of the working class from work life debates. The common conclusion from work-life studies is that work-life imbalance is largely a middle-class problem. It is argued here that this classed assertion is a direct outcome of a particular and narrow interpretation of work life imbalance in which time is seen to be the major cause of difficulty. Labour market time, and too much of it, dominates the conceptualization of work-life and its measurement too. This heavy focus on too much labour market time has rendered largely invisible from dominant work-life discourses the types of imbalance that are more likely to impact the working class. The paper's analysis of large UK data-sets demonstrates a reduction in hours worked by working-class men, more part-time employment in working-class occupations, and a substantial growth in levels of reported financial insecurity amongst the working classes after the 2008-9 recession. It shows too that economic-based work-life imbalance is associated with lower levels of life satisfaction than is temporal imbalance. The paper concludes that the dominant conceptualization of work-life disregards the major work-life challenge experienced by the working class: economic precarity. The work-life balance debate needs to more fully incorporate economic-based work life imbalance if it is to better represent class inequalities. PMID- 26487576 TI - It will take more than an opt-out system to increase organ donation: prioritise donors to receive organs. PMID- 26487575 TI - Views on electronic cigarette use in tobacco screening and cessation in an Alaska Native healthcare setting. AB - BACKGROUND: American Indian (AI) and Alaska Native (AN) communities confront some of the highest rates of tobacco use and its sequelae. METHODS: This formative research project sought to identify the perspectives of 41 stakeholders (community members receiving care within the healthcare system, primary care providers, and tribal healthcare system leaders) surrounding the use of pharmacogenetics toward tobacco cessation treatment in the setting of an AI/AN owned and operated health system in south central Alaska. RESULTS: Interviews were held with 20 adult AI/AN current and former tobacco users, 12 healthcare providers, and 9 tribal leaders. An emergent theme from data analysis was that current tobacco screening and cessation efforts lack information on electronic cigarette (e-cigarette) use. Perceptions of the use of e-cigarettes role in tobacco cessation varied. CONCLUSION: Preventive screening for tobacco use and clinical cessation counseling should address e-cigarette use. Healthcare provider tobacco cessation messaging should similarly address e-cigarettes. PMID- 26487577 TI - Bevacizumab/high-dose chemotherapy with autologous stem-cell transplant for poor risk relapsed or refractory germ-cell tumors. PMID- 26487579 TI - Immunity and HER2-positive disease: never stop questioning. PMID- 26487580 TI - Metabolic phenotyping of human blood plasma: a powerful tool to discriminate between cancer types? AB - BACKGROUND: Accumulating evidence has shown that cancer cell metabolism differs from that of normal cells. However, up to now it is not clear whether different cancer types are characterized by a specific metabolite profile. Therefore, this study aims to evaluate whether the plasma metabolic phenotype allows to discriminate between lung and breast cancer. PATIENTS AND METHODS: The proton nuclear magnetic resonance spectrum of plasma is divided into 110 integration regions, representing the metabolic phenotype. These integration regions reflect the relative metabolite concentrations and were used to train a classification model in discriminating between 80 female breast cancer patients and 54 female lung cancer patients, all with an adenocarcinoma. The validity of the model was examined by permutation testing and by classifying an independent validation cohort of 60 female breast cancer patients and 81 male lung cancer patients, all with an adenocarcinoma. RESULTS: The model allows to classify 99% of the breast cancer patients and 93% of the lung cancer patients correctly with an area under the curve (AUC) of 0.96 and can be validated in the independent cohort with a sensitivity of 89%, a specificity of 82% and an AUC of 0.94. Decreased levels of sphingomyelin and phosphatidylcholine (phospholipids with choline head group) and phospholipids with short, unsaturated fatty acid chains next to increased levels of phospholipids with long, saturated fatty acid chains seem to indicate that cell membranes of lung tumors are more rigid and less sensitive to lipid peroxidation. The other discriminating metabolites are pointing to a more pronounced response of the body to the Warburg effect for lung cancer. CONCLUSION: Metabolic phenotyping of plasma allows to discriminate between lung and breast cancer, indicating that the metabolite profile reflects more than a general cancer marker. CLINICAL TRIAL REGISTRATION NUMBER: NCT02362776. PMID- 26487578 TI - Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001 02). AB - BACKGROUND: Metastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients. PATIENTS AND METHODS: Elderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 * 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan [IRI: LV5FU2-irinotecan or simplified LV5FU2-irinotecan (FOLFIRI)]. The CLASSIC arm was defined as LV5FU2 or LV5FU2-irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR). RESULTS: From June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2-irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75-92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66 1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67-1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75-1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55 0.92). More patients presented grade 3-4 toxicities in IRI (52.2% versus 76.3%). CONCLUSION: In this elderly population, adding irinotecan to an infusional 5-FU based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2. CLINICALTRIALSGOV: NCT00303771. PMID- 26487581 TI - Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis. AB - BACKGROUND: Neuroendocrine neoplasms (NENs) are rare cancers mainly of lung and digestive tract. Little is known on risk factors. The aim of this work is to define the risk factors for NEN development by extensive review and meta-analysis of published data. METHODS: The search was conducted on Medline, Scopus, and Web of Science following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The Newcastle-Ottawa scale was used for study quality. Meta analyses were conducted by primary site. Odds ratio (OR), hazard ratio, risk ratio, standardized incidence ratio, and associated 95% confidence intervals (CIs) were abstracted. Data were combined and analyses carried out for risk factors considered by at least two studies. Random-effects model was adopted for study variation. RESULTS: Of 1535 extracted articles, 24 were enrolled. Meta analyses were possible for pancreas, small intestine, and rectum. Risk for NEN associated with: (i) family history of cancer at all investigated sites (lung, stomach, pancreas, small intestine, appendix, and colon; OR 2.12 [95% CI 1.40 3.22, I(2) = 0.0%, P = 0.681] at meta-analysis in pancreas); (ii) body mass index (BMI) or diabetes (stomach, pancreas, and small intestine; OR of 2.76 [95% CI 1.65-4.64, I(2) = 58.5%, P = 0.090] for diabetes at meta-analysis in pancreas); (iii) cigarette smoking (lung, stomach, pancreas, and small intestine; OR of 1.34 [95% CI 1.10-1.63, I(2) = 0.0%, P = 0.780] and of 1.59 [95% CI 1.07-2.37, I(2) = 32.9%, P = 0.225] for smokers versus never-smokers at meta-analysis for pancreas and small intestine); (iv) alcohol consumption (pancreas and rectum; OR of 2.44 [95% CI 1.07-5.59, I(2) = 65.8%, P = 0.054] and of 1.53 [95% CI 0.99-2.35, I(2) = 0.0%, P = 0.630] for heavy drinkers versus never-drinkers at meta-analysis for pancreas and rectum). CONCLUSIONS: Family history of cancer is the most relevant risk factor for NEN development at all investigated sites, followed by BMI and diabetes. Cigarette smoking and alcohol consumption are potential risk factors for selected anatomical sites. PMID- 26487582 TI - Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis. AB - BACKGROUND: The efficacy and safety of a combination of chemotherapeutic agent compared with single-agent chemotherapy in the second-line setting of advanced urothelial carcinoma (UC) are unclear. We aimed to study the survival impact of single-agent compared with doublet chemotherapy as second-line chemotherapy of advanced UC. PATIENTS AND METHODS: Literature was searched for studies including single-agent or doublet chemotherapy in the second-line setting after platinum based chemotherapy. Random-effects models were used to pool trial-level data according to treatment arm, including median progression-free survival (PFS), overall survival (OS), objective response rate (ORR) probability, and grade 3-4 toxicity. Univariable and multivariable analyses, including sensitivity analyses, were carried out, adjusting for the percent of patients with ECOG performance status >=1 and hepatic metastases. RESULTS: Forty-six arms of trials including 1910 patients were selected: 22 arms with single agent (n = 1202) and 24 arms with doublets (n = 708). The pooled ORR with single agents was 14.2% [95% confidence interval (CI) 11.1-17.9] versus 31.9% [95% CI 27.3-36.9] with doublet chemotherapy. Pooled median PFS was 2.69 and 4.05 months, respectively. The pooled median OS was 6.98 and 8.50 months, respectively. Multivariably, the odds ratio for ORR and the pooled median difference of PFS were statistically significant (P < 0.001 and P = 0.002) whereas the median difference in OS was not (P = 0.284). When including single-agent vinflunine or taxanes only, differences were significant only for ORR (P < 0.001) favoring doublet chemotherapy. No statistically significant differences in grade 3-4 toxicity were seen between the two groups. CONCLUSIONS: Despite significant improvements in ORR and PFS, doublet regimens did not extend OS compared with single agents for the second-line chemotherapy of UC. Prospective trials are necessary to elucidate the role of combination chemotherapy, with or without targeted agents, in the salvage setting. Currently, improvements in this field should be pursued considering single-agent chemotherapy as the foundation for new more active combinations. PMID- 26487583 TI - Early market access of cancer drugs in the EU. AB - Patient access to new cancer drugs in the EU involves centralised licensing decisions by regulators as well as reimbursement recommendations in the context of national healthcare systems. Differences in assessment criteria and evidence requirements may result in divergent decisions at central and national levels, ultimately compromising effective access to patients. Early access decisions are particularly challenging due to the limited clinical evidence available to conclude on the benefit-risk and relative (cost-) effectiveness of new high priced cancer drugs. We describe mechanisms to accelerate approval of promising anticancer drugs that fulfil an unmet medical need, review the experience from the European Medicines Agency, compare timelines and outcomes of reimbursement decisions in major EU markets, and discuss shortcomings of the current system, ongoing initiatives, and future steps to facilitate effective early access. PMID- 26487584 TI - A clinical case of invasive lobular breast carcinoma with ERBB2 and CDH1 mutations presenting a dramatic response to anti-HER2-directed therapy. PMID- 26487586 TI - Comprehensive serum cytokine analysis identifies IL-1RA and soluble IL-2Ralpha as predictors of event-free survival in T-cell lymphoma. AB - BACKGROUND: T-cell malignancies are heterogeneous in their clinical presentation and pathology, and have a poor prognosis. New biomarkers are needed to predict prognosis and to provide insights into signal pathways used by these cells. The goal of this study was to evaluate pretreatment serum cytokines in patients with newly diagnosed T-cell neoplasms and correlate with clinical outcome. PATIENTS AND METHODS: We evaluated 30 cytokines in pretreatment serum from 68 untreated patients and 14 normal controls. Significantly elevated cytokines were correlated with patterns of abnormalities, event-free survival (EFS) and overall survival (OS). RESULTS: Our data demonstrated significantly elevated levels (versus controls) of seven cytokines-epidermal growth factor (EGF), IL-6, IL-12, interferon gamma-induced protein (IP)-10, soluble interleukin (sIL)-2Ralpha, monokine induced by gamma interferon (MIG), and IL-1RA-in all T-cell neoplasms (P < 0.05). In the angioimmunoblastic subset, all seven cytokines except IP-10 and in the peripheral T-cell lymphoma (TCL)-not otherwise specified subset, only IP 10, sIL-2Ralpha, MIG, and IL-8 were statistically elevated compared with control. Of these, elevated cytokines all but EGF were predictive of an inferior EFS; IL 1RA, sIL-2Ralpha, and MIG predicted an inferior OS. In a multivariate analysis, sIL-2Ralpha [hazard ratio (HR) = 3.95; 95% confidence interval (CI) 1.61-8.38] and IL-1RA (HR = 3.28; 95% CI 1.47-7.29) levels remained independent predictors of inferior EFS. TCL cell lines secreted high levels of sIL-2Ralpha and expressed the IL-2Ralpha surface receptor. CONCLUSIONS: This report describes the cytokines relevant to prognosis in patients with untreated TCL and provides the rationale to include serum IL-1RA and sIL-2Ralpha as biomarkers in future trials. Inhibition of these cytokines may also be of therapeutic benefit. PMID- 26487587 TI - PD-L1 copy number gain in nonsmall-cell lung cancer defines a new subset of patients for anti PD-L1 therapy. PMID- 26487585 TI - Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study). AB - BACKGROUND: Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. PATIENTS AND METHODS: In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. RESULT: ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. CONCLUSIONS: Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. REGISTRATION NUMBER: JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center). PMID- 26487588 TI - Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study. AB - BACKGROUND: To determine whether time from surgery to initiation of chemotherapy impacts survival in advanced ovarian carcinoma. PATIENTS AND METHODS: This is a post-trial ad hoc analysis of Gynecologic Oncology Group protocol 218, a phase III randomized, double-blind, placebo-controlled trial designed to study the antiangiogenesis agent, bevacizumab, in primary and maintenance therapy for patients with newly diagnosed advanced ovarian carcinoma. Maximum attempt at debulking was an eligibility criterion. Stage III patients, not stage IV, were required to have gross macroscopic or palpable residual disease following surgery. The survival impact of time from surgery to initiation of chemotherapy was studied using Cox regression models and stratified by treatment arm, residual disease and other clinical and pathologic factors. RESULTS: One thousand seven hundred eighteen assessable patients were randomized (stage III (n = 1237); stage IV (n = 477), including those with complete resection (stage IV only, n = 81), low-volume residual (<=1 cm, n = 701), and suboptimal (>1 cm, n = 932). On multivariate analysis, time to chemotherapy initiation was predictive of overall survival (P < 0.001), with the complete resection group (i.e. stage IV) encountering an increased risk of death when time to initiation of chemotherapy exceeded 25 days (95% confidence interval 16.6-49.9 days). CONCLUSION: Survival for women with advanced ovarian cancer may be adversely affected when initiation of chemotherapy occurs >25 days following surgery. Our analysis applies to stage IV only as women with stage III who underwent complete resection were not eligible for this trial. These results, however, are consistent with Gompertzian first-order kinetics where patients with microscopic residual are most vulnerable. CLINICAL TRIALS IDENTIFIER: NCT00262847. PMID- 26487589 TI - A prospective study of total plasma cell-free DNA as a predictive biomarker for response to systemic therapy in patients with advanced non-small-cell lung cancers. AB - BACKGROUND: While previous studies have reported on the prognostic value of total plasma cell-free deoxyribonucleic acid (cfDNA) in lung cancers, few have prospectively evaluated its predictive value for systemic therapy response. PATIENTS AND METHODS: We conducted a prospective study to evaluate the association between changes in total cfDNA and radiologic response to systemic therapy in patients with stage IIIB/IV non-small-cell lung cancers (NSCLCs). Paired blood collections for cfDNA and computed tomography (CT) assessments by RECIST v1.0 were performed at baseline and 6-12 weeks after therapy initiation. Total cfDNA levels were measured in plasma using quantitative real-time polymerase chain reaction. Associations between changes in cfDNA and radiologic response, progression-free survival (PFS), and overall survival (OS) were measured using Kruskal-Wallis and Kaplan-Meier estimates. RESULTS: A total of 103 patients completed paired cfDNA and CT response assessments. Systemic therapy administered included cytotoxic chemotherapy in 57% (59/103), molecularly targeted therapy in 17% (17/103), and combination therapy in 26% (27/103). Median change in cfDNA from baseline to response assessment did not significantly differ by radiologic response categories of progression of disease, stable disease and partial response (P = 0.10). However, using radiologic response as continuous variable, there was a weak positive correlation between change in radiologic response and change in cfDNA (Spearman's correlation coefficient 0.21, P = 0.03). Baseline cfDNA levels were not associated with PFS [hazard ratio (HR) = 1.06, 95% confidence interval (CI) 0.93-1.20, P = 0.41] or OS (HR = 1.04, 95% CI 0.93-1.17, P = 0.51), neither were changes in cfDNA. CONCLUSIONS: In this large prospective study, changes in total cfDNA over time did not significantly predict radiologic response from systemic therapy in patients with advanced NSCLC. Pretreatment levels of total cfDNA were not prognostic of survival. Total cfDNA level is not a highly specific predictive biomarker and future investigations in cfDNA should focus on tumor-specific genomic alterations using expanded capabilities of next generation sequencing. PMID- 26487592 TI - Effects of overweight and obesity on motor and mental development in infants and toddlers. AB - BACKGROUND: A consequence of childhood obesity may be poor developmental outcomes. OBJECTIVES: This study aimed to examine the relationship between weight and developmental delays in young children. METHODS: We conducted a secondary analysis of the Early Childhood Longitudinal Study Birth Cohort data. Logistic regression models quantified the association between different weight statuses (normal weight <85th, overweight >=90th, obese >=95th percentile for weight) and delays in motor and mental development. RESULTS: Children classified as overweight in both waves had higher percentages of delays in wave 2 (motor [7.5 vs. 6.2-6.4%], mental [8.6 vs. 5.9-6.7%]), as well as wave 1 and/or wave 2 (motor [14.8 vs. 10.9-13.0%], mental [11.9 vs. 9.0-10.1%]), compared with other children. This association was also found in children who were obese at both time points in wave 2 (motor delay [8.9 vs. 4.9-7.3%], mental delay [10.3 vs. 6.0 7.2%]), as well as wave 1 and/or wave 2 (motor delay [14.5 vs. 10.9-12.9%], mental delay [14.1 vs. 9.4-10.1%]). In the adjusted models, children classified as always obese were more likely to have a mental delay in wave 2 (adjusted odds ratio [aOR] 1.89, 95% confidence interval [CI]: 1.21-2.95) as well as wave 1 and/or wave 2 (aOR 1.56, 95% CI: 1.08-2.26). These children were also more likely to have motor delay (aOR 1.47, 95% CI: 1.02-2.13) in wave 1 and/or wave 2. CONCLUSION: Overweight children are more likely than their normal-weight peers to have motor and mental developmental delays. Preventing obesity during infancy may facilitate reducing developmental delays in young children. PMID- 26487591 TI - Single incision laparoscopic surgery for multiple colorectal cancers. AB - INTRODUCTION: The aim of this study was to evaluate short-term outcomes of single incision surgery with two segmental colorectal resections and anastomoses for multiple synchronous colorectal cancers. METHODS: Ten patients with multiple colorectal cancers underwent two synchronous segmental colorectal resections and anastomoses. The methodology of the procedures, operative results, and postoperative outcomes were evaluated. RESULTS: The median operative time was 270 min (range, 146-427 min), and the median blood loss was 70 mL (range, 10-260 mL). No conversions to open surgery or intraoperative complications occurred. Four cases needed additional ports, and one case required a diverting stoma. CONCLUSION: SILS with two segmental colorectal resections and anastomoses was safely performed in all cases without severe postoperative complications. This procedure seems to be a feasible option for resecting multiple synchronous colorectal cancers. PMID- 26487594 TI - Etiology of stroke in Broca's aphasia. AB - We reviewed clinical and diagnostic data from 36 patients with Broca's aphasia due to stroke who were evaluated at the University of Iowa Hospitals and Clinics between 1982 and 1989. The group consisted of 20 women and 16 men, aged 28-80 (median, 63.5; mean, 57.5). The presumptive cause of cerebral infarction was embolism in 15 patients (42%), atherothrombosis in 9 (25%), undetermined in 9 (25%), and "other" in 3 (8%). The ratios of women to men were 8:7, 3:6, 7:2, and 2:1, respectively. A majority of emboli were of presumed cardiac origin: atrial fibrillation, 7; prosthetic cardiac valve, 3; and recent myocardial infarction, 2. Eight of nine patients with atherothrombotic infarction had complete occlusion of the left internal carotid artery by duplex scan and/or angiography. Our data demonstrate (a) Broca's aphasia is frequently caused by cerebral embolism, (b) carotid occlusion can result in selective infarction of anterior language areas; and (c) women outnumbered men in our Broca's aphasia group. The latter finding is in contrast to a similar study of 38 patients with Wernicke's aphasia due to cerebral infarction studied at our institution, in which men outnumbered women 25 to 13, with most of the difference in the embolic and undetermined groups. Gender differences in types of aphasia might be due to a predilection for middle cerebral artery emboli to result in infarction of anterior language areas in women and posterior language areas in men. PMID- 26487590 TI - Mapping anhedonia-specific dysfunction in a transdiagnostic approach: an ALE meta analysis. AB - Anhedonia is a prominent symptom in neuropsychiatric disorders, most markedly in major depressive disorder (MDD) and schizophrenia (SZ). Emerging evidence indicates an overlap in the neural substrates of anhedonia between MDD and SZ, which supported a transdiagnostic approach. Therefore, we used activation likelihood estimation (ALE) meta-analysis of functional magnetic resonance imaging studies in MDD and SZ to examine the neural bases of three subdomains of anhedonia: consummatory anhedonia, anticipatory anhedonia and emotional processing. ALE analysis focused specifically on MDD or SZ was used later to dissociate specific anhedonia-related neurobiological impairments from potential disease general impairments. ALE results revealed that consummatory anhedonia was associated with decreased activation in ventral basal ganglia areas, while anticipatory anhedonia was associated with more substrates in frontal-striatal networks except the ventral striatum, which included the dorsal anterior cingulate, middle frontal gyrus and medial frontal gyrus. MDD and SZ patients showed similar neurobiological impairments in anticipatory and consummatory anhedonia, but differences in the emotional experience task, which may also involve affective/mood general processing. These results support that anhedonia is characterized by alterations in reward processing and relies on frontal striatal brain circuitry. The transdiagnostic approach is a promising way to reveal the overall neurobiological framework that contributes to anhedonia and could help to improve targeted treatment strategies. PMID- 26487593 TI - Youth's Perceptions of Parental Support and Parental Knowledge as Moderators of the Association Between Youth-Probation Officer Relationship and Probation Non compliance. AB - As a community-based sanction, juvenile probation exemplifies the potential of both communities and families to make significant contributions in promoting positive changes among offending youth. Yet, surprisingly little research has explored the nature of these relationships and its association with offending. This study (1) examined the associations between youth-officer relationships, youth perceptions of parental support and knowledge, and probation non-compliance and (2) explored the role of parental support and knowledge as moderators of the association between youth-officer relationships and probation non-compliance among 110 youth supervised on probation (23 % females; 60 % African American). The findings showed that tough or punitive youth-officer relationships were associated with greater counts of technical violations, but fewer counts of delinquent offenses. Parental support was associated with fewer counts of delinquent offenses and parental knowledge was associated with fewer counts of both delinquent offenses and technical violations. These findings provide evidence to the important role of both parents and probation officers and underscore the potential benefits of parent-officer collaboration in facilitating successful interventions among offending youth. PMID- 26487595 TI - Risk of stroke in patients with congenital bicuspid valve. AB - The records of 75 patients with the diagnosis of bicuspid aortic valve (BAV) confirmed at the time of valve replacement were reviewed retrospectively to assess the frequency of cerebrovascular events. There were four transient ischemic attacks, one stroke, and one retinal embolus; four of these could be explained by factors other than embolism from the aortic valve (infective endocarditis, two; carotid plaque, one; prolapsed mitral valve, one). Cerebrovascular complications occurred close in time (median, 2 months prior) to valve replacement. We conclude that BAV is a rare cause of cardioembolic stroke, which occurs only with severe valvular dysfunction. The risk of cerebrovascular events with a functionally normal BAV is probably very low. PMID- 26487596 TI - Relationship among paretic knee extension strength, maximum weight-bearing, and gait speed in patients with stroke. AB - The purpose of this study was to determine the intercorrelations among maximum weight-bearing through the paretic lower extremity, paretic knee extension strength, and comfortable gait speed in hemiparetic patients following stroke. Twenty patients, who could ambulate at least 10.0 m with no more assistance than contact guarding of one person, participated. Isometric muscle strength (force) was measured with a hand-held dynamometer. Maximum weight-bearing measurements were normalized against (divided by) body weight. Gait speed was determined using a digital stopwatch as subjects walked 8.0 m. Significant correlations (r>0.611) were demonstrated among the three variables. The relationship between maximum weight-bearing and gait speed was the strongest and was best described by a curvilinear model (R = 0.830). The results suggest that both maximum weight bearing through the paretic lower extremity and paretic knee extension strength are valid predictors of gait speed among patients with stroke but that the former is superior to the latter for such a purpose. Given their simplicity and objectivity, these measures can be recommended for predicting and documenting improvement in patients with stroke undergoing rehabilitation. PMID- 26487597 TI - Treatment of adult moyamoya disease by encephalo-duro-arterio-synangiosis: Five case reports. AB - Encephalo-duro-arterio-synangiosis (EDAS) is considered the surgical treatment of choice for most pediatric cases of moyamoya disease, but the success of this treatment in adults is less clear. We have compared pre- and postoperative angiograms of four adults and one adolescent with symptomatic moyamoya disease who underwent bilateral EDAS at Hermann Hospital in Houston. The postoperative follow-up period ranged from 6 to 18 months. The correlation of postoperative collateral flow and clinical course was good: of the three patients with documented collateralization, two experienced excellent clinical outcomes, and one experienced a good outcome. One patient had minimal collateralization and experienced progression of her neurologic symptoms. One patient experienced a good outcome and refused a postoperative angiogram. PMID- 26487598 TI - Ataxia-hemiparesis and cardiac embolic disease. AB - Ataxia-hemiparesis is a clinical stroke syndrome with mild weakness and ataxia out of proportion to the weakness. Although most patients with ataxia-hemiparesis have small (lacunar) infarctions in the brainstem, internal capsule, or corona radiata, the syndrome has also been reported with infection, hemorrhage, and neoplasm in the same region. We now report a patient who presented with right ataxia-hemiparesis whose initial cranial computed tomography (CT) scan was normal and a second CT scan showed infarctions in the right cerebellum, left thalamus, and left frontal cortex. Initial echocardiogram showed segmental akinesis; a second study revealed a thrombus in the left ventricle. Ataxia-hemiparesis can sometimes be secondary to multiple infarcts resulting from cardiac emboli. In such cases, early recognition and anticoagulation could help prevent recurrences. PMID- 26487599 TI - Transesophageal echocardiography in the etiologic diagnosis of stroke. AB - One-sixth of all cerebral infarctions are the result of cardioembolic phenomena. The certainty with which the diagnosis of cardioembolic stroke is made, however, is frequently questioned. This has partly been the result of the low sensitivity of traditional cardiac diagnostic procedures, such as surface transthoracic echocardiography and Holter monitoring. Transesophageal echocardiography is a relatively new technique that has been shown to increase the yield for demonstrating cardiac abnormalities capable of producing brain embolism, particularly disease of the left atrium, left atrial appendage, and atrial septum. The sensitivity of this technique for documenting intracardiac thrombi, mitral valve prolapse, left atrial spontaneous contrast, particularly in comparison with transthoracic echocardiography is examined after reviewing the published series. PMID- 26487600 TI - Evaluation of coexistent carotid and coronary disease by combined angiography. AB - We studied 247 patients who underwent combined coronary and carotid angiography to determine (a) the frequency of angiographic carotid stenosis (> 50%) in patients with coronary artery disease (CAD) and (b) the technical quality and safety of the combined procedure. All patients were evaluated primarily for CAD. Combined carotid angiography was performed for asymptomatic carotid bruits (115 patients, 47%), transient ischemic attacks (TIA) or stroke (66 patients, 26.5%), or inapparent/other reasons (66 patients, 26.5%). The extracranial internal carotid arteries were well visualized in 219 patients (89%); poor visualization of the internal carotid arteries was due to overlap by the vertebral or external carotid arteries. The frequency of >50% internal carotid stenosis was 36% in patients with asymptomatic carotid bruits, 42% in patients with TIA or stroke, and 8% in patients without TIA, stroke, or carotid bruits. Complication rates during combined coronary and carotid angiography in the 247 study patients were not statistically different from complication rates during coronary angiography alone in 686 control patients. These data indicate that (a) patients with CAD who have asymptomatic carotid bruits or a history of TIA or stroke have a high frequency of carotid stenosis, and (b) combined coronary and carotid angiography is a safe and technically adequate procedure. PMID- 26487601 TI - Evidence for arterial embolization in dissecting aneurysm of the cervical vertebral artery. AB - Ultrasonographic imaging of the right cervical vertebral artery in a 57-year-old man with recurrent episodes of ischemia in the vertebrobasilar territory revealed a dissecting aneurysm with communication of the true and false lumen. This finding demonstrates that arterial dissection can form a nidus for distal embolization and supports the use of anticoagulation in this disorder. PMID- 26487602 TI - Carotid artery findings associated with infarcts in different carotid vascular territories. AB - Brain infarctions in different vascular territories may be caused by different principal mechanisms. To assess the importance of extracranial carotid artery stenosis as a cause of brain infarctions, we compared carotid findings with infarcts in different vascular territories within the carotid circulation in 141 patients. Infarct location was documented with computed tomography, magnetic resonance imaging, or ophthalmoscopy. All patients had a carotid artery study (arteriography in 83 and duplex ultrasound in the remaining 58). Carotid stenosis ipsilateral to infarct was found in 37/69 (54%) patients with superficial infarcts, 7/17 (41%) patients with lenticulostriate territory infarcts, 14/24 (58%) patients with retinal infarcts, but in only 4/31 (13%) patients with anterior choroidal artery territory infarcts (p = 0.001). Among patients with superficial infarcts, hypertension was less common (p = 0.05), and the side with greater carotid stenosis correlated with the side of infarction (p < 0.001). Extracranial carotid stenosis appears to be an important cause of infarctions in the carotid territory, especially in the superficial territories, but not in the anterior choroidal artery territory. PMID- 26487603 TI - Reversible basilar artery blood flow in subclavian steal syndrome. AB - Transcranial Doppler ultrasound examination of intracranial vertebral and basilar arteries was performed on a 61-year-old man who presented with symptoms of amaurosis fugax and subclavian steal syndrome. During arm exercise, flow in the basilar artery reversed direction from cephalad to caudal, coincident with symptoms of vertebrobasilar insufficiency. Following bilateral carotid endarterectomies, exercise-induced reverse flow velocities in the basilar artery were markedly increased, and the patient remained asymptomatic. These findings suggest that collateral flow from the anterior cerebral circulation may play an important role in the pathogenesis of brainstem ischemia in subclavian steal syndrome and that transcranial Doppler may identify a subgroup of patients who will benefit from procedures to augment cerebral blood flow. PMID- 26487604 TI - EPR Study of Backbiting in the Aqueous-Solution Polymerization of Acrylamide. AB - Via electron paramagnetic resonance (EPR) spectroscopy, the type of radicals occurring during acrylamide (AAm) homopolymerization in aqueous solution is investigated between -5 and +100 degrees C. The radicals are produced photochemically under stationary conditions. Midchain AAm radicals (MCRs) are clearly identified by EPR which demonstrates that secondary propagating AAm radicals (SPRs) undergo backbiting reactions. Above 50 degrees C, the fraction of MCRs even exceeds the one of SPRs. The extent of backbiting is however well below the one in butyl acrylate polymerization at identical temperature. PMID- 26487605 TI - Silent cerebrovascular lesions in patients with first-ever stroke. AB - Of 200 patients admitted for first-ever stroke and no prior history of transient ischemic attacks, 33 (16.5%) were found to have evidence of prior subclinical cerebral infarction on computed tomography (CT) or autopsy, so-called "silent strokes." Nineteen had one additional lesion, eight had two, and six had three or more. Most were small, 84% involved less than half a lobe, and the majority of these were <1 cm. Silent lesions were significantly more prevalent in patients with atherothrombotic stroke and less prevalent in hemorrhagic stroke. Age and sex distribution were similar in both groups. Risk factor levels and 30-day outcome parameters were similar with the exception of average 30-day Mini-Mental State Examination scores, which were significantly lower in patients with two or more silent lesions compared with patients without silent lesions. PMID- 26487606 TI - Parkinson's disease, ischemic stroke, dementia, and cranial computed tomography: Preliminary study. AB - We sought to determine whether clinical features, stroke profiles, and cranial computed tomography (CCT) findings differed in nondemented and demented Parkinson's disease (PD) patients. Data were collected from our previously published case-control review of 119 idiopathic PD patients discharged from our Veterans Affairs Medical Center Neurology Service from 1982 through 1990. Historical, physical, age, age at onset of PD, duration of PD, motor severity, frequency of ischemic stroke and stroke risk factors, modified Hachinski Ischemic Score (MHIS), and CCT findings were recorded. We previously estimated that the number ofpatients with PD and dementia was 31 of 119 (26%) from our case-control review of idiopathic PD patients. Eighty-two male PD patients, 31 demented and 51 nondemented, had CCT data available for review. Demented PD patients were older (p < 0.01), had fewer normal CT scans (p = 0.0004), and more cerebral atrophy and leuko-araiosis (p = 0.0003) than nondemented PD patients. Clinical atherosclerosis did not significantly distinguish the groups, but 9 of 31 (29%) demented PD patients had a modified HIS >= 5 and thus suggestive of, at least, multi-infarct dementia. Demented PD patients were older overall at PD onset, but did not appear to have significantly longer PD duration or more motor severity. Demented PD patients were also apt to have had a much more current CCT (p < 0.01) than nondemented patients. Although clinical atherosclerosis did not clearly separate groups, more than one-quarter of demented PD patients seem to have components of vascular dementia. PMID- 26487607 TI - Screening cerebrovascular patients for silent myocardial ischemia with stress testing and ambulatory left ventricular function monitor. AB - Patients with symptomatic cerebrovascular disease suffer a high mortality from myocardial ischemia, which may occur during rest or following the conclusion of exercise. In a pilot study, we screened 11 patients with transient cerebral ischemic attack or stroke for silent myocardial ischemia using bicycle ergometer stress testing with electrocardiographic (EKG) monitoring and ambulatory left ventricular function monitoring (VEST). Three of 11 patients had nondiagnostic exercise EKGs due to failure to achieve their target heart rates during exercise but had positive VEST tests during and after exercise. One patient was falsely positive. VEST may be useful in combination with stress EKG for the detection of silent myocardial ischemia in cerebrovascular patients, but further assessment of the sensitivity and specificity in this patient population needs to be accomplished. PMID- 26487608 TI - Composition of particles associated with embolic signals on transcranial doppler untrasonography. AB - The composition of particulate emboli associated with detectable signals on transcranial Doppler (TCD) ultrasonography has previously been studied in vitro. The purpose of this investigation was to study the composition of particles associated with similar signals in patients undergoing carotid endarterectomy. We studied carotid endarterectomy specimens from four consecutive patients with internal carotid artery origin, symptomatic, severe, stenosis, and preoperative TCD showing signals that were unidirectional from the baseline, occurred throughout the cardiac cycle, lasted 25-100 ms, had intensities exceeding that of surrounding blood by at least 12 dB, and were associated with a characteristic chirping sound. In all patients, signals with the preceding characteristics were detected in the sup-raclinoid internal carotid artery distal to the symptomatic, cervical stenosis. In Cases 1, 3, and 4, no signals were detected in the contralateral, asymptomatic supraclinoid internal carotid artery, and signals resolved after surgery. Examination of the endarterectomy specimens showed intraluminal thrombi composed of fibrin and platelets in all cases. Our findings suggest that TCD signals with the preceding characteristics may correspond to platelet and fibrin particles originating at stenotic lesions of the cervical internal carotid artery. PMID- 26487609 TI - Circannual and latitudinal variation in the incidence of subarachnoid hemorrhage. AB - Numerous epidemiological studies have shown a preponderance of cerebrovascular accidents occurring during the winter or colder months in both hemispheres. However, many of these studies used no or inappropriate statistical tests to demonstrate cyclic trends or relied on a small number of poorly documented cerebrovascular accident cases. Data were obtained for this study from the International Cooperative Aneurysm Study that evaluated 3,521 clinical records from 68 neurosurgical centers in 14 countries. We used the Edwards cyclic trends method to examine the monthly occurrence of subarachnoid hemorrhage between March 1981 and February 1983. Significant (p < 0.05) seasonal variation was noted with more subarachnoid hemorrhage cases occurring during the winter relative to the summer in the northern hemisphere, whereas the reverse of this was noted in the southern hemisphere. Significant (p < 0.025) seasonal periodicity was noted above the latitude of 43.2 degrees N, but not below it. This report, and others, suggest that subarachnoid hemorrhage may be a seasonal and geographic risk disease. An overview of the literature examining seasonality and cerebrovascular accidents is also presented. PMID- 26487610 TI - Nontraumatic hemorrhagic stroke in young adults in taiwan. AB - We reviewed the medical records and imaging studies on the in-hospital patients to investigate the clinical and etiological patterns in hemorrhagic stroke in young patients. We evaluated 210 patients (131 males and 79 females) aged 15-45 years who had traumatic hemorrhagic stroke between April 1, 1986, and November 30, 1992. Nontraumatic intracerebral hemorrhage was diagnosed in 170 patients (80.9%). The main causes of nontraumatic intracerebral hemorrhage were hypertension, ruptured arteriovenous malformation, and blood dyscrasia. A cause was not found in 42 patients (24.7%). Subarachnoid hemorrhage was found in 40 patients (19.1%). The main causes were ruptured aneurysms and arteriovenous malformations. The overall in-hospital survival of young patients with hemorrhagic stroke was 64.7%. Young adults with nontraumatic intracerebral and subarachnoid hemorrhage are a heterogeneous group. Hypertension accounts for about one-third of intracerebral hemorrhage and is an important preventable cause of hemorrhagic stroke in young adults in Taiwan. PMID- 26487611 TI - Ultra-rapid identification, triage, and enrollment of stroke patients into clinical trials. AB - Effective therapy for acute ischemic stroke will require very rapid evaluation of patients so that treatment can begin soon enough to salvage injured but viable brain. Limited data suggest that neurons in the ischemic penumbra survive for a few hours, at the most. It is critical to know whether our medical system can overcome the many practical obstacles to ultra-rapid recognition,, transport, and treatment of stroke patients. We analyzed our patient recruitment into clinical treatment trials over time, attempting to identify strategies that improved recruitment. Specifically, we studied whether the imposition of an ultra-short time limit for treatment initiation, 3 h from stroke onset, impaired recruitment Prior to adopting the strict time limit, we enrolled about 0.4 patients per month per participating hospital. After adopting the limit, we enrolled about 0.7 patients per month per hospital. Our data indicate that patient recruitment may be maintained and even increased despite a demanding time limit for treatment. The data also suggest that a very short time window of survivability of the ischemic penumbra should not discourage efforts to develop new methods of salvaging brain, for we have shown that the medical delivery system in one county can be modified to allow ultra-rapid patient recognition, evaluation, and treatment. PMID- 26487612 TI - Brain infarcts in the arterial border zones: Clinical-pathologic correlations. AB - Most brain infarcts are correctly attributed to the circulatory alterations caused by the occlusion of a vessel, usually arterial. In this article, the authors review selected publications dealing with the mechanisms and the clinical expressions of brain infarcts secondary to nonocclusive causes. Hemodynamic crises, usually of cardiac origin, are among the main causes of the so-called arterial border-zone infarcts of the brain. Depending on the etiology and the distribution of the brain lesions, at least three separate neurologic syndromes have been outlined. The most frequently observed syndrome is attributed to the involvement, by the ischemic event, of tissues located in the border zone between the territories of the anterior and middle cerebral arteries. These anterior, bilateral arterial-border-zone infarcts produce a syndrome of bilateral brachial paralysis, with maximal involvement of the proximal limbs musculature, i.e., the "man-in-a-barrel" syndrome. Other neurologic syndromes in patients with arterial border-zone infarcts are associated with ischemic injury of specific anatomic sites. PMID- 26487613 TI - Lacune-associated cerebral hypoperfusion correlates with cognitive testing. AB - The hypothesis was tested among 83 patients with multiple lacunar infarctions that cerebral hypoperfusion will correlate with cognitive impairments. Patients were subdivided according to Cognitive Capacity Screening Examination (CCSE) scores into a cognitively impaired group (Group D, n = 40; mean age, 68.2 years) with CCSE scores between 6 and 25 (mean, 19.9) and a cognitively intact group (Group I, n = 43; mean age, 66.0) with normal scores (mean, 29.4). Gray and white matter tissue densities were measured by plain computed tomography (CT), and their compartmental perfusions were estimated during stable xenon inhalation. Eighty infarcts in basal ganglia and white matter were detected in Group D and 62 in Group I. Cognitive impairments correlated with (a) multiplicity and bilaterality of lacunes; (b) hypertension, diabetes mellitus, and multiplicity of risk factors for stroke; (c) hypoperfusion of white and gray matter, but particularly of frontal white matter; (d) leuko-araiosis; (e) aging; and (f) lower education. The conclusion was that hypertension and diabetes mellitus are potent risk factors for cerebral small vessel disease or arteriolosclerosis ultimately resulting in lacunar infarcts, leuko-araiosis, white matter hypoperfusion, and impaired cognitive test performance. PMID- 26487614 TI - Takayasu's disease: Ultrasonic evaluation of extracranial and intracranial hemodynamics. AB - In Takayasu's disease, inflammatory vessel wall changes occur in the large extracranial arteries and may consequently influence cerebral hemodynamics. This study describes the extra- and intracranial hemodynamic states in three young patients, aged 32, 29, and 22 years, without permanent neurological deficit. Extracranial vessels were investigated primarily by duplex scanner and intracranial vessels by three-dimensional transcranial Doppler before and after intravenous administration of 1 g acetazolamide. The ultrasonic findings were confirmed by aortocervical angiography. Two patients were treated by corticosteroids. In spite of extracranial vessel narrowing, all three patients had normal MCA velocities in the resting condition. Impaired vasomotor reactivity was found in the middle cerebral artery corresponding to the high degree stenosis of the brachiocephalic trunk in one patient and in the anterior and posterior cerebral arteries unilaterally in two patients and bilaterally in one. Decrease in the pulsatility index after acetazolamide administration probably depends on the vasodilation and decrease in peripheral resistance. Extra- and intracranial Doppler ultrasound is valuable to follow the progress of arteritis and to adjust treatment. PMID- 26487616 TI - Complex Fractionated Atrial Electrograms in Catheter Ablation of Atrial Fibrillation: Dead and Buried? PMID- 26487615 TI - Sex difference in the association between habitual daytime napping and prevalence of diabetes: a population-based study. AB - Our objective was to evaluate the associations between habitual daytime napping and diabetes and whether it varies by sex, menopause, and sleep quality. We conducted a population-based cross-sectional study in 8621 eligible individuals aged 40 years or older. Information on daytime napping hours, night-time sleep duration, history of menstruation, and sleep quality was self-reported. Diabetes was diagnosed according to the 1999 World Health Organization diagnostic criteria. The prevalence of diabetes was 19.4 % in men and 15.6 % in women. Increased daytime napping hours were positively associated with parameters of glycometabolism in women, such as fasting plasma glucose, oral glucose tolerance test (OGTT) 2-h plasma glucose, and Hemoglobin A1c (HbA1c, all P for trend <0.05). In women, the prevalence of diabetes in no-habitual daytime napping group, 0-1-h daytime napping group, and more than 1-h daytime napping group were 14.5, 15.6, and 20.8 %, respectively (P for trend = 0.0004). A similar trend was detected in postmenopausal women (P for trend = 0.002). In multivariate logistic regression analysis, compared with no-habitual daytime napping postmenopausal women, those with daytime napping more than 1 h had higher prevalent diabetes (odds ratios 1.36, 95 % confidence interval, 1.04-1.77). In subgroup analysis of postmenopausal women, associations of daytime napping levels and prevalent diabetes were detected in older, overweight participants with good sleep quality who have not retired from work. In conclusion, our study suggests that habitual daytime napping is associated with prevalence of diabetes in postmenopausal women. PMID- 26487617 TI - Atrial Fibrillation and the Risk of Stroke: Does Timing Matter? PMID- 26487618 TI - Does Atrial Fibrillation Follow Function? Ion Channel Mutations and Lone Atrial Fibrillation. PMID- 26487619 TI - Left Cardiac Sympathetic Denervation: Should We Sweat the Side Effects? PMID- 26487620 TI - Remote Monitoring of Implantable Defibrillators: Reducing Hospitalizations and Saving Lives? PMID- 26487621 TI - Dynamic Clamp: Insights From State-of-the-Art Experimentation. PMID- 26487622 TI - Ablation of Ganglionated Plexi in the Long Term: Is Half a Loaf as Good as None? PMID- 26487623 TI - Sustained Multiple Railroad Tracks on Implantable Cardiac Defibrillator Interval Plots: Mechanisms and Management. PMID- 26487624 TI - Lockstep. PMID- 26487625 TI - Diagnosing Supraventricular Tachycardia: When Physical Examination Trumps the Electrocardiogram. PMID- 26487626 TI - Postmortem Histopathological Examination of a Leadless Pacemaker Shows Partial Encapsulation After 19 Months. PMID- 26487627 TI - Letter by Jalife et al Regarding Article, "Quantitative Analysis of Localized Sources Identified by Focal Impulse and Rotor Modulation Mapping in Atrial Fibrillation". PMID- 26487628 TI - Response to Letter by Jalife et al Regarding Article, "Quantitative Analysis of Localized Sources Identified by Focal Impulse and Rotor Mapping in Atrial Fibrillation". PMID- 26487629 TI - Letter From Yamada et al Regarding Article, "Differentiation of Papillary Muscle From Fascicular and Mitral Annular Ventricular Arrhythmias in Patients With and Without Structural Heart Disease". PMID- 26487630 TI - Response to Letter by Yamada et al Regarding "Differentiation of Papillary Muscle From Fascicular and Mitral Annular Ventricular Arrhythmias in Patients With and Without Structural Heart Disease". PMID- 26487631 TI - Signalling in ciliates: long- and short-range signals and molecular determinants for cellular dynamics. AB - In ciliates, unicellular representatives of the bikont branch of evolution, inter and intracellular signalling pathways have been analysed mainly in Paramecium tetraurelia, Paramecium multimicronucleatum and Tetrahymena thermophila and in part also in Euplotes raikovi. Electrophysiology of ciliary activity in Paramecium spp. is a most successful example. Established signalling mechanisms include plasmalemmal ion channels, recently established intracellular Ca2+ release channels, as well as signalling by cyclic nucleotides and Ca2+ . Ca2+ binding proteins (calmodulin, centrin) and Ca2+ -activated enzymes (kinases, phosphatases) are involved. Many organelles are endowed with specific molecules cooperating in signalling for intracellular transport and targeted delivery. Among them are recently specified soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), monomeric GTPases, H+ -ATPase/pump, actin, etc. Little specification is available for some key signal transducers including mechanosensitive Ca2+ -channels, exocyst complexes and Ca2+ -sensor proteins for vesicle-vesicle/membrane interactions. The existence of heterotrimeric G-proteins and of G-protein-coupled receptors is still under considerable debate. Serine/threonine kinases dominate by far over tyrosine kinases (some predicted by phosphoproteomic analyses). Besides short-range signalling, long-range signalling also exists, e.g. as firmly installed microtubular transport rails within epigenetically determined patterns, thus facilitating targeted vesicle delivery. By envisaging widely different phenomena of signalling and subcellular dynamics, it will be shown (i) that important pathways of signalling and cellular dynamics are established already in ciliates, (ii) that some mechanisms diverge from higher eukaryotes and (iii) that considerable uncertainties still exist about some essential aspects of signalling. PMID- 26487632 TI - Association between dementia and postoperative complications after hip fracture surgery in the elderly: analysis of 87,654 patients using a national administrative database. AB - INTRODUCTION: Mortality following hip fracture surgery is higher in patients with dementia than those without; however, few large-scale studies have investigated postoperative in-hospital complications in such patients. The aim of this study was to elucidate the complications that occur after hip fracture surgery in patients with and without dementia using a large national database. MATERIALS AND METHODS: We retrospectively identified patients aged >=70 years who underwent hemiarthroplasty, osteosynthesis for femoral neck fracture or osteosynthesis for intertrochanteric fracture, and compared the occurrence of postoperative complications between patients with and without dementia. Multivariate logistic regression analysis was performed to adjust for patient characteristics and hospital factors. RESULTS: A total of 87,654 patients were included in this study, including 9419 with dementia. Compared with the non-dementia group, the dementia group showed a higher incidence of overall postoperative complications [odds ratio (OR) 1.45; p < 0.001), surgical site infection (OR 1.58; p = 0.004), urinary tract infection (OR 1.87; p < 0.001) and respiratory complications (OR 1.49; p < 0.001). The rate of postoperative complications was higher for all types of hip fracture surgery. The occurrence of a postoperative complication was significantly higher in patients aged >=80 years (OR 1.37; p < 0.001) and those with dementia (OR 1.45; p < 0.001), any type of malignancy (OR 1.42; p < 0.001), a history of cardiovascular disease (OR 1.33; p < 0.001), a history of cerebrovascular disease (OR 1.15; p = 0.029), chronic renal failure (OR 1.36; p < 0.001), liver cirrhosis (OR 1.41; p < 0.001) or blood transfusion after surgery (OR 1.49; p < 0.001). CONCLUSIONS: Our results highlight the need to pay particular attention to surgical site infection, urinary tract infection and respiratory complications in patients with preoperative dementia after hip fracture surgery. These results provide additional useful evidence to inform the management of these patients. PMID- 26487634 TI - C7orf30 is necessary for biogenesis of the large subunit of the mitochondrial ribosome. PMID- 26487633 TI - Predictive and Reactive Locomotor Adaptability in Healthy Elderly: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Locomotor adaptability is based on the implementation of error feedback information from previous perturbations to predictively adapt to expected perturbations (feedforward) and to facilitate reactive responses in recurring unexpected perturbations ('savings'). The effect of aging on predictive and reactive adaptability is yet unclear. However, such understanding is fundamental for the design and application of effective interventions targeting fall prevention. METHODS: We systematically searched the Web of Science, MEDLINE, Embase and Science Direct databases as well as the reference lists of the eligible articles. A study was included if it addressed an investigation of the locomotor adaptability in response to repeated mechanical movement perturbations of healthy older adults (>=60 years). The weighted average effect size (WAES) of the general adaptability (adaptive motor responses to repeated perturbations) as well as predictive (after-effects) and reactive adaptation (feedback responses to a recurring unexpected perturbation) was calculated and tested for an overall effect. A subgroup analysis was performed regarding the factor age group [i.e., young (<=35 years) vs. older adults]. Furthermore, the methodological study quality was assessed. RESULTS: The review process yielded 18 studies [1009 participants, 613 older adults (70 +/- 4 years)], which used various kinds of locomotor tasks and perturbations. The WAES for the general locomotor adaptability was 1.21 [95% confidence interval (CI) 0.68-1.74, n = 11] for the older and 1.39 (95% CI 0.90-1.89, n = 10) for the young adults with a significant (p < 0.05) overall effect for both age groups and no significant subgroup differences. Similar results were found for the predictive (older: WAES 1.10, 95% CI 0.37-1.83, n = 8; young: WAES 1.54, 95% CI 0.11-2.97, n = 7) and reactive (older: WAES 1.09, 95% CI 0.22-1.96, n = 5; young: WAES 1.35, 95% CI 0.60-2.09, n = 5) adaptation featuring significant (p < 0.05) overall effects without subgroup differences. The average score of the methodological quality was 67 +/- 8 %. CONCLUSIONS: The present meta-analysis provides elaborate statistical evidence that locomotor adaptability in general and predictive and reactive adaptation in particular remain highly effective in the elderly, showing only minor, not statistically significant age-related deficits. Consequently, interventions which use adaptation and learning paradigms including the application of the mechanisms responsible for an effective predictive and reactive dynamic stability control may progressively improve older adults' recovery performance and, thus, reduce their risk of falling. PMID- 26487636 TI - Uncovering productive morphosyntax in French-learning toddlers: a multidimensional methodology perspective. AB - The present study applies a multidimensional methodological approach to the study of the acquisition of morphosyntax. It focuses on evaluating the degree of productivity of an infrequent subject-verb agreement pattern in the early acquisition of French and considers the explanatory role played by factors such as input frequency, semantic transparency of the agreement markers, and perceptual factors in accounting for comprehension of agreement in number (singular vs. plural) in an experimental setting. Results on a pointing task involving pseudo-verbs demonstrate significant comprehension of both singular and plural agreement in children aged 2;6. The experimental results are shown not to reflect input frequency, input marker reliability on its own, or lexically driven knowledge. We conclude that toddlers have knowledge of subject-verb agreement at age 2;6 which is abstract and productive despite its paucity in the input. PMID- 26487635 TI - Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti cancer agents. AB - G-quadruplex (G4) is a promising target for anti-cancer treatment. In this paper, we provide the first evidence supporting the presence of G4 in the mitochondrial DNA (mtDNA) of live cells. The molecular engineering of a fluorescent G4 ligand, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC), can change its major cellular localization from the nucleus to the mitochondria in cancer cells, while remaining primarily in the cytoplasm of normal cells. A number of BMVC derivatives with sufficient mitochondrial uptake can induce cancer cell death without damaging normal cells. Fluorescence studies of these anti-cancer agents in live cells and in isolated mitochondria from HeLa cells have demonstrated that their major target is mtDNA. In this study, we use fluorescence lifetime imaging microscopy to verify the existence of mtDNA G4s in live cells. Bioactivity studies indicate that interactions between these anti-cancer agents and mtDNA G4 can suppress mitochondrial gene expression. This work underlines the importance of fluorescence in the monitoring of drug-target interactions in cells and illustrates the emerging development of drugs in which mtDNA G4 is the primary target. PMID- 26487637 TI - Assessing Child Nutrient Intakes Using a Tablet-Based 24-Hour Recall Tool in Rural Zambia. AB - BACKGROUND: Detailed dietary intake data in low-income populations are needed for research and program evaluation. However, collection of such data by paper-based 24-hour recall imposes substantial demands for staff time and expertise, training, materials, and data entry. OBJECTIVE: To describe our development and use of a tablet-based 24-hour recall tool for conducting dietary intake surveys in remote settings. METHODS: We designed a 24-hour recall tool using Open Data Kit software on an Android tablet platform. The tool contains a list of local foods, questions on portion size, cooking method, ingredients, and food source and prompts to guide interviewers. We used this tool to interview caregivers on dietary intakes of children participating in an efficacy trial of provitamin A biofortified maize conducted in Mkushi, a rural district in central Zambia. Participants were children aged 4 to 8 years not yet enrolled in school (n = 938). Dietary intake data were converted to nutrient intakes using local food composition and recipe tables. RESULTS: We developed a tablet-based 24-hour recall tool and used it to collect dietary data among 928 children. The majority of foods consumed were maize, leafy vegetable, or small fish dishes. Median daily energy intake was 6416 kJ (1469 kcal). CONCLUSIONS: Food and nutrient intakes assessed using the tablet-based tool were consistent with those reported in prior research. The tool was easily used by interviewers without prior nutrition training or computing experience. Challenges remain to improve programming, but the tool is an innovation that enables efficient collection of 24-hour recall data in remote settings. PMID- 26487638 TI - CtxB1 outcompetes CtxB7 in Vibrio cholerae O1, Bangladesh. PMID- 26487639 TI - On-Line Restricted Access Molecularly Imprinted Solid-Phase Extraction of Selective Serotonin Reuptake Inhibitors Directly from Untreated Human Plasma Samples Followed by HPLC-UV Analysis. AB - In this article, we proposed a new restricted access molecularly imprinted polymer coated with bovine serum albumin (RAMIP-BSA) to be used in a multidimensional chromatographic system applied for the analysis of six selective serotonin reuptake inhibitors (SSRIs) directly from untreated human plasma samples. Fluoxetine, methacrylic acid and ethylene glycol dimethacrylate were used as the template, functional monomer and cross-linker, respectively. The imprinted polymer was covered with a bovine serum albumin (BSA) layer via the interconnections between the amine groups of the BSA using glutaraldehyde as a cross-linker. The obtained RAMIP-BSA was able to extract the SSRIs directly from the human plasma, while ~100% of the proteins were excluded from the sample. Selectivity coefficients were calculated for fluoxetine (template) in comparison with venlafaxine, duloxetine, citalopram, fluvoxamine, paroxetine and sertraline, and the values were >1 in all cases, attesting to the presence of binding sites in the imprinted polymer. The method presented analytical ranges from 20 to 500 ug/L and correlation coefficients >0.99 for all of the SSRIs (fluoxetine, venlafaxine, duloxetine, citalopram, fluvoxamine and sertraline). Precision and accuracy presented variation coefficients and relative errors <14.5% and within the range of -19.18 to 3.8%, respectively. In all cases, the apparent recoveries were >85%. The proposed method was able to analyze three samples per hour, and each column was used at least 50 times without any significant changes in its performance. PMID- 26487640 TI - Detection of Cannabinoids by ELISA and GC-MS Methods in a Hair Sample Previously Used to Detect Other Drugs of Abuse. AB - A forensic standard procedure is described that combines enzyme-linked immunoassay for screening and gas chromatography-mass spectrometry (GC-MS) for confirmation to detect drugs of abuse in a sample before used to detect opioids and cocaine. We used two equal aliquots of the same previously selected cannabinoid positive hair samples, one of which was subjected to acid hydrolysis. Afterward, both the aliquots were subjected to basic extraction and then to immunoassay screening. After derivatization, the GC-MS parameters were the same for both the aliquots for the determination of the cannabinoids (Delta(9) tetrahydrocannabinol, cannabidiol and cannabinol). The results show that there were no statistical differences between the nonpreviously treated and the pretreated hair samples for the quantification of the three cannabis products for immunochemical procedure. No differences between the two groups were shown as for GC-MS confirmation procedures. All substances showed a good linearity between 0.05 and 2 ng/mg. The limit of detection ranged from 0.02 to 0.03 ng/mg, and the limit of quantification was 0.05 ng/mg for all substances. To our knowledge, this is the first time that screening and confirmation procedures have been applied on the same sample of hair to detect more than one drug of abuse. PMID- 26487641 TI - An Investigation of Liquid Chromatography-Mass Spectral Attributes and Analytical Performance Characteristics of Tenofovir, Emtricitabine and Efavirenz in Human Plasma. AB - Liquid chromatography (LC) and mass spectral behavior and analytical performance characteristics of efavirenz (EFV), emtricitabine (EMT) and tenofovir (TFV), i.e., individual components of Atripla((r)), were probed. This was followed by estimation of their analytical performance characteristics employing LC and a parallel direct infusion sample introduction procedure. Performance characteristics using both types of sample introduction procedures were compared. Using liquid chromatography-mass spectrometry (LC-MS), linearities, i.e., correlation coefficients of the calibration curves of EFV, EMT and TFV, ranged between 0.9300 and 0.9990 in the full scan, selected ion monitoring and mass spectrometry/mass spectrometry (MS-MS) modes. The limits of detection (LODs) ranged between 0.5 and 11.6 ug/L. The lower limits of quantification (LLOQs) and the upper limits of quantification (ULOQs) were in the ranges of 0.9-23.2 and 1.6 38.7 ug/L, respectively. The LODs ranged between 0.8 and 114.7 ug/L. The LLOQs and the ULOQs were in the ranges of 1.6-29.4 and 2.7-49.0 ug/L, respectively. In the case of EMT, sodiated molecular ion at m/z 270 was used to adduce analytical performance characteristics from which lower detection limits were obtained compared with those in the literature where [M+H](+) at m/z 248 was used. PMID- 26487642 TI - The Potential of Various Living Tissues for Monitoring Clenbuterol Abuse in Food Producing Chinese Simmental Beef Cattle. AB - We aimed to evaluate whether living tissues such as urine, plasma and hair were suitable for monitoring clenbuterol (CL) abuse after its subchronic administration of a growth-promoting dose to the Chinese Simmental beef cattle. Eight male, white and red pied Chinese Simmental beef cattle were involved in the experiment, and the CL dose was 16 ug/kg BW/day. Liquid chromatography tandem mass spectrometry (LC-MS-MS) was used to determine CL residues in different tissues, and the addition of D9-clenbuterol internal standard was applied to increase determination accuracy. The recovery of plasma, urine, hair and in vivo tissues was 88.5-114.2, 83.9-114.3, 88.6-116.9 and 85.3-121.7%, respectively. The results showed that CL residue concentrations in the plasma, on Days 14 after withdrawal and later, were lower than the limit of detection (LOD) (0.06 ng/mL) and CL residue in urine was lower than LOD (0.16 ng/mL) 42 days after treatment. CL significantly accumulated in the white and red hair and maintained more than 7.19 +/- 2.19 pg/mg within the early withdrawal period of 70 days. A large number of CL were determined in all tested biological tissues, in which residues were higher than the maximum residue limits (MRLs) after dietary administration of CL for 21 days and pre-slaughter withdrawal period of ~6 h. A particular concern is the slow depletion of residues of CL in some tissues like gluteus and liver still exceeding theirs MRLs, respectively, on Days 14 or 28 days after withdrawal. Our study indicated that plasma and urine could be available for monitoring CL abuse only within a short period of time. However, hair (including light-pigmented) as a target matrix can be selected to perform the long-period monitor of CL. PMID- 26487643 TI - High expression of myocyte enhancer factor 2C (MEF2C) is associated with adverse risk features and poor outcome in pediatric acute myeloid leukemia: a report from the Children's Oncology Group. AB - BACKGROUND: Recent studies have identified myocyte enhancer factor 2C (MEF2C) as cooperating oncogene in acute myeloid leukemia (AML) and suggested a contribution to the aggressive nature of at least some subtypes of AML, raising the possibility that MEF2C could serve as marker of poor-risk AML and, therefore, have prognostic significance. METHODS: To test this hypothesis, we retrospectively quantified MEF2C expression in pretreatment bone marrow specimens in participants of the AAML0531 trial by reverse-transcriptase polymerase chain reaction and correlated expression levels with disease characteristics and clinical outcome. RESULTS: In all 751 available patient specimens, MEF2C messenger RNA (mRNA) was detectable and varied >3000-fold relative to beta glucuronidase. Patients with the highest relative MEF2C expression (4th quartile) less likely achieved a complete remission after one course of chemotherapy than the other patients (67 vs. 78 %, P = 0.005). They also had an inferior overall survival (P = 0.014; at 5 years 55 +/- 8 vs. 67 +/- 4 %), inferior event-free survival (P < 0.001; at 5 years 38 +/- 7 vs. 54 +/- 4 %), and higher relapse risk than patients within the lower 3 quartiles of MEF2C expression (P < 0.001; at 5 years 53 +/- 9 vs. 35 +/- 5 %). These differences were accounted for by lower prevalence of cytogenetically/molecularly defined low-risk disease (16 vs. 46 %, P < 0.001) and higher prevalence of standard-risk disease (68 vs. 42 %, P < 0.001) in patients with high MEF2C expression, suggesting that MEF2C cooperates with additional pathogenic abnormalities. CONCLUSIONS: High MEF2C expression identifies a subset of AML patients with adverse-risk disease features and poor outcome. With confirmation that high MEF2C mRNA expression leads to overexpression of MEF2C protein, these findings provide the rationale for therapeutic targeting of MEF2C transcriptional activation in AML. PMID- 26487644 TI - miR-320b suppresses cell proliferation by targeting c-Myc in human colorectal cancer cells. AB - BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNAs that potentially play a critical role in tumorigenesis. Mounting evidence indicates that one specific miRNA: miR-320b is down regulated in numerous human cancers, including colorectal cancer (CRC); making the hypothesis that miR-320b may play a key role in tumorigenesis plausible. However, its role in carcinogenesis remains poorly defined. The goal of this study is to better clarify the role of miR-320b in tumor growth of CRC. METHODS: Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was conducted to detect the expression of miR-320b in CRC tissues and 5 CRC cell lines. The effect of miR-320b on cell proliferation was analyzed in vitro and in vivo. Furthermore, a luciferase reporter assay was performed to measure the target effects of miR-320b. Lastly, the messenger RNA (mRNA) and protein levels of the gene c-MYC were measured in CRC cell lines and tissues by qRT-PCR, and confirmed via Western blot and Immunohistochemical (IHC) staining. RESULTS: The results presented here showed that miR-320b expression was down regulated in both CRC tissues and cells. Overexpression of miR-320b in CRC cells was statistically correlated with a decrease of cell growth in vitro and in vivo, while c-MYC was identified as a target gene of miR-320b in CRC. Furthermore, it was found that up-regulation of c-Myc can attenuate the effects induced by miR-320b. CONCLUSIONS: Our identification of c-MYC as a target gene of miR-320b provides new insights into the pathophysiology of CRC proliferation, and identifies miR-320b as a novel therapeutic target for the treatment of CRC. PMID- 26487645 TI - The potential risk of spinal cord injury from pedicle screw at the apex of adolescent idiopathic thoracic scoliosis: magnetic resonance imaging evaluation. AB - BACKGROUND: The pedicle screw placement in scoliosis correction at the apex underlies potential risk for neurological injury. This research is to investigate the relative position of spinal cord at the apex in idiopathic thoracic scoliosis and to explore the risk of spinal cord injury from pedicle screw at the apex. METHODS: Thirty-three adolescents with thoracic scoliosis were recruited in this study. The relative position of the spinal cord in the spinal canal was calculated by measuring the distance between the spinal cord and the medial wall of the pedicle on the convex and concave side through the axial plane of the apex in T2 weighted MR image. The distance from the spinal cord to the medial wall of pedicle between concave and convex side was compared respectively. The percentage of patients was calculated according to hypothesized different space (0 mm, less than 1 mm and less than 2 mm) between medial wall of pedicle and spinal cord at the apex. RESULTS: The average distance from the spinal cord to the medial wall of pedicle at the concave side was significantly less than that at the convex side (p = 0.000) of the apex in the major thoracic curves before operation. In the concave side of the apex, the percentage of patients was 39.4, 66.7, 84. 5 % in hypothesized space (0 mm, less than 1 mm and less than 2 mm) between medial wall of pedicle and spinal cord. However, in the convex side of apex, the percentage of cases was 0, 0, 3.0 % in the same hypothesized space respectively. CONCLUSIONS: The screw placement is at a higher risk of spinal cord injury on the concave side than that on the convex side of apex in thoracic curve in MRI images. The screw placement in the concave side of apex should be evaluated carefully with MRI before operation. PMID- 26487647 TI - Postoperative radiograph of the hip arthroplasty: what the radiologist should know. AB - This pictorial review aims to provide the radiologist with simple and systematic guidelines for the radiographic evaluation of a hip prosthesis. Currently, there is a plethora of commercially available arthroplasties, making postoperative analysis not always straightforward. Knowledge of the different types of hip arthroplasty and fixating techniques is a prerequisite for correct imaging interpretation. After identification of the type of arthroplasty, meticulous and systematic analysis of the following parameters on an anteroposterior standing pelvic radiograph should be undertaken: leg length, vertical and horizontal centre of rotation, lateral acetabular inclination, and femoral stem positioning. Additional orthogonal views may be useful to evaluate acetabular anteversion. Complications can be classified in three major groups: periprosthetic lucencies, sclerosis or bone proliferation, and component failure or fracture. Teaching Points * To give an overview of the different types of currently used hip arthroplasties. * To provide a simple framework for a systematic approach to postoperative radiographs. * To discuss radiographic findings of the most common complications. PMID- 26487646 TI - Recent time trends in incidence, outcome and premorbid treatment of atrial fibrillation-related stroke and other embolic vascular events: a population-based study. AB - BACKGROUND: Prevalence of atrial fibrillation (AF) is increasing, due partly to the ageing population. The Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) Trial, published in 2007, provided strong evidence of the effectiveness of warfarin at age>=80 years, but the impact on incidence of AF-related stroke and peripheral embolic vascular events is uncertain. METHODS: We studied age specific incidence and outcome of all AF-related incident strokes and systemic emboli from 2002 to 2012 in the Oxford Vascular Study. RESULTS: Of 3096 acute cerebral or peripheral vascular events, 748 (24.2%) were AF-related. Of the 597 disabling/fatal incident ischaemic strokes, 369 occurred at age >=80 years, of which 124 (33.6%) were in non-anticoagulated patients with known prior AF. There was no reduction in incident AF-related events after 2007 at all ages (n=231 vs 211; adjusted RR=1.11, 0.91 to 1.36, p=0.29) or at age >=80 (137 vs 135, RR=1.15, 0.94 to 1.40, p=0.17). Scope for improved prevention at older ages was considerable. Among 208 patients with incident AF-related events at age >=80 and known prior AF, only 19 (9.1%) were anticoagulated. Of the 189 patients not anticoagulated, 166 (87.8%) had no major disability prior to the event and 167 (88.4%) had a high embolism risk score, of whom 139 (83.2%) were also at low risk of complications. Yet, 125/167 (74.9%) were dead or institutionalised after the event. Potentially preventable embolic events outnumbered warfarin-related intracerebral haemorrhages by about 15-fold (280 vs 19), rising to 50-fold (189 vs 4) at age >=80 years. CONCLUSIONS: We found no reduction in incidence of AF related vascular events since publication of the BAFTA trial. A third of all disabling/fatal strokes occur in non-anticoagulated patients with known prior AF. PMID- 26487648 TI - Experiences of Domestic and School Violence Among Child and Adolescent Psychiatric Outpatients. AB - The experience of cumulative childhood adversities, such as exposure to domestic violence or abuse by caregivers, has been described as risk factor for poor mental health outcomes in adolescence and adulthood. We performed an investigation of experience of violence in all patients aged 6 to 20 years who had consulted the Department of Child and Adolescent Psychiatry, Medical University of Vienna, as outpatients during the period of one year. We were using the Childhood Trauma Interview (CTI) in order to obtain information on the kind of violence. Seventy-five percent of all patients had reported experiences of violence. These youth were significantly more often involved in acts of school violence, thus a significant correlation between experience of domestic violence and violence at school could be revealed. The results of our study emphasize the need for interventions preventing violence both in domestic and in school environments. PMID- 26487649 TI - Risk of cancer from occupational exposure to ionising radiation: retrospective cohort study of workers in France, the United Kingdom, and the United States (INWORKS). AB - STUDY QUESTION: Is protracted exposure to low doses of ionising radiation associated with an increased risk of solid cancer? METHODS: In this cohort study, 308,297 workers in the nuclear industry from France, the United Kingdom, and the United States with detailed monitoring data for external exposure to ionising radiation were linked to death registries. Excess relative rate per Gy of radiation dose for mortality from cancer was estimated. Follow-up encompassed 8.2 million person years. Of 66,632 known deaths by the end of follow-up, 17,957 were due to solid cancers. STUDY ANSWER AND LIMITATIONS: Results suggest a linear increase in the rate of cancer with increasing radiation exposure. The average cumulative colon dose estimated among exposed workers was 20.9 mGy (median 4.1 mGy). The estimated rate of mortality from all cancers excluding leukaemia increased with cumulative dose by 48% per Gy (90% confidence interval 20% to 79%), lagged by 10 years. Similar associations were seen for mortality from all solid cancers (47% (18% to 79%)), and within each country. The estimated association over the dose range of 0-100 mGy was similar in magnitude to that obtained over the entire dose range but less precise. Smoking and occupational asbestos exposure are potential confounders; however, exclusion of deaths from lung cancer and pleural cancer did not affect the estimated association. Despite substantial efforts to characterise the performance of the radiation dosimeters used, the possibility of measurement error remains. WHAT THIS STUDY ADDS: The study provides a direct estimate of the association between protracted low dose exposure to ionising radiation and solid cancer mortality. Although high dose rate exposures are thought to be more dangerous than low dose rate exposures, the risk per unit of radiation dose for cancer among radiation workers was similar to estimates derived from studies of Japanese atomic bomb survivors. Quantifying the cancer risks associated with protracted radiation exposures can help strengthen the foundation for radiation protection standards. FUNDING, COMPETING INTERESTS, DATA SHARING: Support from the US Centers for Disease Control and Prevention; Ministry of Health, Labour and Welfare of Japan; Institut de Radioprotection et de Surete Nucleaire; AREVA; Electricite de France; US National Institute for Occupational Safety and Health; US Department of Energy; and Public Health England. Data are maintained and kept at the International Agency for Research on Cancer. PMID- 26487650 TI - Are we operating too late? Mortality Analysis and Stochastic Simulation of Costs Associated with Bariatric Surgery: Reconsidering the BMI Threshold. AB - BACKGROUND: Present guidelines recommend bariatric surgery at BMI >= 40 kg/m2 or BMI >= 35 kg/m2 with obesity-related morbidity. METHODS: Evidence for cost and mortality/morbidity risk of bariatric surgery and obesity-related diseases was evaluated determining equivalency point of absolute incremental mortality risk by BMI and risks associated with bariatric surgery. A stochastic model was developed evaluating costs related to surgical procedure at a given BMI. RESULTS: Bariatric surgery produces significant lifetime cost savings associated with diabetes, gallstones, hypertension, high cholesterol, colon cancer, heart disease, and stroke in men at BMI 30 kg/m2 for laparoscopic gastric bypass. For women, laparoscopic gastric bypass saves cost at BMI 32 kg/m2 and laparoscopic gastric banding at BMI 37 kg/m2. In white men, relative to single-year mortality risks by BMI, surgical intervention becomes risk-beneficial at BMI 25 kg/m2 for laparoscopic gastric banding, BMI 27 kg/m2 for laparoscopic gastric bypass procedure and open gastric banding, and BMI 37 kg/m2 for open gastric bypass. Risk benefit for African-American men by procedure occurs at BMI <25 kg/m2, BMI 27 kg/m2, and BMI 42 kg/m2, respectively. In white women, surgical intervention is beneficial at BMI 25.5 kg/m2 (laparoscopic gastric banding), BMI 28.5 kg/m2 (laparoscopic gastric bypass procedure), and BMI 45 kg/m2 (open gastric banding). Risk benefit for black women by procedure occurs at BMI 27.5 kg/m2, BMI 33.5 kg/m2, and BMI 50+ kg/m2, respectively. CONCLUSION: Risk and cost benefit suggest surgical guidelines should be reconsidered. Threshold for bariatric surgery should be redefined to BMI 35 kg/m2 or BMI 30 kg/m2 with comorbidities. PMID- 26487652 TI - From BLISS to ILLUMINATE studies: "Blys repetita placent"? PMID- 26487653 TI - The Multi-Lock System for Rhinoplasty. AB - BACKGROUND: Among the greatest challenges in rhinoplasty are setting the nasal tip contour and projection, and avoiding excessive upward rotation of the nose. Many suture and graft fixation techniques have attempted to achieve this result but may still produce results lacking in refinement. This study aims to describe in detail a new approach to stabilize the nasal tip for a durable and more predictable result. METHODS: Twenty-eight surgeries were performed by the author, following a standardized technique which included: a modified distal onlay dorsal graft, a modified columella strut, and bilateral caudal septal sliver grafts. Follow-ups were conducted with all patients for at least 365 days. Twelve patients had follow-ups ranging from 456 to 619 days. RESULTS: At the nasal tip there was no loss of projection or rotation. One patient had a traumatic nasal fracture and left the study. Two patients had unilateral alar retraction not related to the technique described. One patient with thin nasal skin was submitted to a surgical revision to thin the caudal septal extension grafts and improve the nasal airflow. CONCLUSIONS: The Multi-Lock System for rhinoplasty is a good option to assure nasal length as well as projection and rotation of the tip. Also, it seemed to decrease the dead space of the supra-tip area which avoided pollybeak deformity. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26487651 TI - Change in Sexual Dysfunction Following Bariatric Surgery. AB - Obesity is associated with multiple comorbidities and psychosocial burdens, but often sexual dysfunction (SD) is overlooked. Bariatric surgery is the most effective treatment for morbid obesity, and its role in reversing SD is reviewed. A literature search of MEDLINE, PubMed Central, and Cochrane databases was conducted. Fifty-six articles were identified and 32 selected for inclusion. SD was measured via hormonal studies, questionnaires, and a combination of both (n = 14 males SD studies, n = 13 female SD studies, 5 = both sexes). There is an exponential rise in patients reporting post-surgical improvements in SD in both genders. The emerging use of quality of life indices to measure sexual function as part of a more global enjoyment of life may be a helpful adjunct to existing hormonal and sex-specific measures. PMID- 26487654 TI - Double Lateral Flap: A New Technique for Lower Eyelid Reconstruction Alternative to the Tenzel Procedure. AB - BACKGROUND: The final esthetic result is a common concern of patients with eyelid tumors, especially young patients and those with tumors affecting the medial edge of the lower eyelid. METHODS: The procedure herein described combines two lateral flaps: one tarsoconjunctival and the other from the periosteum. The first step is removal of the tumor lesion. Preseptal dissection is then performed through a subciliary incision on both the lateral and medial halves of the eyelid up to the orbital rim. Next, the lateral canthal tendon, lateral attachment of the orbital septum, capsulopalpebral fascia, and conjunctiva are cut. This allows the medial displacement of the tarsoconjunctival flap, which is sutured to the defect area. The second flap, a periosteal strip, is used to reconstruct the tarsus and lateral canthal tendon, providing firm support for the posterior lamella. The orbicularis muscle is anchored to the orbital rim, and the skin of the lower eyelid is directly sutured to the subciliary incision and periosteal strip. RESULTS: The author successfully carried out this procedure on nine patients. None of the patients developed ocular irritation or postoperative epiphora. CONCLUSIONS: The defects that can be repaired by this technique are equivalent in size to those repaired by the Tenzel procedure. Unlike the semicircular flap procedure, this technique allows eyelid reconstruction with no vertical scarring and a smaller lateral incision, and it ensures soft contact between the palpebral rim and surface of the eyeball. This procedure confers an attractive eyelid appearance that may be crucial for some patients. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26487655 TI - Aesthetic Surgery Reality Television Shows: Do they Influence Public Perception of the Scope of Plastic Surgery? AB - BACKGROUND: The purpose of this survey was to assess the influence of aesthetic surgery "reality television" shows viewing on the public's perception of the scope of plastic surgery practice. METHODS: Perceptions of the scope of plastic surgery (33 scenarios), aesthetic surgery "reality television" viewing patterns ("high," "moderate," or "low" familiarity, similarity, confidence, and influence viewers), sociodemographic data, and previous plastic surgery interaction were collected from 2148 members of the public. Response patterns were created and bivariate and multivariate analyses were applied to assess the possible determinants of overall public choice of plastic surgeons as experts in the plastic surgery-related scenarios. RESULTS: Both "plastic surgeons" and "plastic surgeons alone" were the main response patterns (all p < 0.05) in ten (83.3%) aesthetic interventions-related scenarios. "Plastic surgeons" and "plastic surgeons alone" were significantly (all p < 0.05) more identified as experts in ten (47.6%) and eight (38.1%) general/reconstructive-related scenarios, respectively. There were positive (health care professionals and prior plastic surgery interaction) and negative ("high-familiarity" viewers, "high-influence" viewers, "high-confidence" viewers, and "high-similarity" viewers) significant (all p < 0.05) determinants of response plastic surgeons in the bivariate and multivariate analyses. CONCLUSION: Aesthetic surgery "reality television" viewing negatively influences the public perception of the broad scope of plastic surgery. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26487656 TI - Inguinal Fold as a Closed-Suction Drain Exit Site in Abdominoplasty. PMID- 26487657 TI - Flap Failure and Wound Complications in Autologous Breast Reconstruction: A National Perspective. AB - PURPOSE: There are many options for breast reconstruction following a mastectomy, and data on outcomes are greatly needed for both the patient and the care provider. This study aims to identify the prevalence and predictors of adverse outcomes in autologous breast reconstruction in order to better inform patients and surgeons when choosing a surgical technique. METHODS: This study retrospectively reviewed the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) and identified each autologous breast reconstruction performed between 2005 and 2012. Of the 6855 autologous breast reconstructions, there were 2085 latissimus dorsi (LD) flap procedures, 2464 pedicled transverse rectus abdominis myocutaneous (TRAM) flap procedures, and 2306 free flap procedures that met the inclusion criteria. The prevalence of complications in each of the three procedures was calculated and compared using chi(2) analysis for binomial categorical variables. Univariate and multivariate logistic regression analyses identified independent risk factors for adverse outcomes in autologous reconstruction as a whole. RESULTS: The prevalence of general complications was 10.8% in LD flaps, 20.6% in TRAM flaps, and 26.1% in free flaps for autologous breast reconstruction (p < 0.001). The prevalence of wound complications was 4.3% in LD flaps, 8.1% in TRAM flaps, and 6.2% in free flaps for autologous breast reconstruction (p < 0.001). The prevalence of flap failure was 1.1 % in LD flaps, 2.7% in TRAM flaps, and 2.4% in free flaps for autologous breast reconstruction (p < 0.001). Multivariate regression analysis showed that obesity [odds ratio (OR) 1.495, p = 0.024], hypertension (OR 1.633, p = 0.008), recent surgery (OR 3.431, p < 0.001), and prolonged operative times (OR 1.944, p < 0.001) were independently associated with flap failure in autologous breast reconstruction procedures. When controlling for confounding variables, TRAM flaps were twice as likely (OR 2.279, p = 0.001) and free flaps were three times as likely (OR 3.172, p < 0.001) to experience flap failure when compared to LD flaps. CONCLUSIONS: Latissimus dorsi flaps are associated with the fewest short-term general complications and free flaps are associated with the most short-term general complications in autologous breast reconstruction. Free flaps are the most likely to experience flap failure, though there is no significant difference when compared to pedicled TRAM flaps. Free and TRAM flaps remain as the widely acceptable forms of breast reconstruction in the patient without many risk factors for flap failure or wound complications. The identified risk factors will aid in surgical planning and risk adjustment for both the patient and the care provider. Though many other factors will be taken into consideration with surgical planning of autologous breast reconstruction, the presence of these identified risk factors may encourage the use of a surgical technique associated with fewer adverse outcomes, like the LD flap. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26487658 TI - Blepharoplasty Combined with Fat Grafting: A Treatment of Complications Following Polyacrylamide Hydrogel Injections in Tear Troughs. AB - BACKGROUND: Polyacrylamide hydrogel (PAAG) can cause serious complications during facial augmentation. Previous studies have reported complications following PAAG injections to correct tear troughs. METHODS: We report a rare case of tear trough deformity following PAAG injections. We developed a comprehensive treatment plan including transcutaneous blepharoplasty and fat grafting to address the presenting complications. RESULTS: The patient showed flat lower lids and no more complications 1 year after surgery. CONCLUSIONS: Blepharoplasty combined with fat grafting is an effective approach to eliminate PAAG injection complications in tear troughs. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26487659 TI - Sexuality in Aesthetic Breast Surgery. AB - BACKGROUND: The breasts are important for a woman's psychological well-being, which may be negatively affected by distortions of breast size and shape. Improvements in self-esteem and sexuality are important psychological factors associated with motivation for cosmetic surgery. Mammaplasty is among the most sought-after and performed cosmetic procedures. The aim of this study was to evaluate the impact of aesthetic breast surgery on a woman's sexuality. METHODS: This study was conducted in a plastic surgery clinic of a hospital university in Brazil, between 2009 and 2012. Forty-six patients with hypomastia and 30 patients with breast hypertrophy, who expressed the desire for aesthetic breast surgery, were selected for the study. The patients were assessed preoperatively and 6 months postoperatively using the sexual quotient-Female version scale (QS-F). The QS-F is a validated Brazilian questionnaire to assess sexual function. It contains ten items covering five domains of female sexual function: desire and interest, foreplay, excitement and harmony, comfort, and orgasm and satisfaction. Higher QS-F scores indicate better sexual functioning. RESULTS: There was a significant increase in the mean total QS-F score after surgery in both groups (p < 0.001). No significant improvement in desire and comfort was reported by patients who underwent breast augmentation and in comfort by patients who underwent breast reduction. Improvement in sexuality after surgery was observed in both groups, which is consistent with the literature. CONCLUSION: Aesthetic breast surgery has a positive impact on the sexuality of patients. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26487660 TI - "Thinking a Lot" Among the Khwe of South Africa: A Key Idiom of Personal and Interpersonal Distress. AB - "Thinking too much", and variations such as "thinking a lot", are common idioms of distress across the world. The contextual meaning of this idiom of distress in particular localities remains largely unknown. This paper reports on a systematic study of the content and cause, consequences, and social response and coping related to the local terms |x'an n|a te and |eu-ca n|a te, both translated as "thinking a lot", and was part of a larger ethnographic study among the Khwe of South Africa. Semi-structured exploratory interviews with community members revealed that "thinking a lot" refers to a common experience of reflecting on personal and interpersonal problems. Consequences were described in emotional, psychological, social, behavioral, and physical effects. Coping strategies included social support, distraction, and religious practices. Our contextualized approach revealed meanings and experiences of "thinking a lot" that go beyond a psychological state or psychopathology. The common experience of "thinking a lot" is situated in socio-political, economic, and social context that reflect the marginalized and displaced position of the Khwe. We argue that "thinking a lot" and associated local meanings may vary across settings, may not necessarily indicate psychopathology, and should be understood in individual, interpersonal, community, and socio-political dimensions. PMID- 26487661 TI - The age-dependent plasticity highlights the conceptual interface between borderline personality disorder and PTSD. PMID- 26487662 TI - The human chemokine receptor CCRL2 suppresses chemotaxis and invasion by blocking CCL2-induced phosphorylation of p38 MAPK in human breast cancer cells. AB - The human chemokine receptor CCRL2 is a member of the atypical chemokine receptor family. CCRL2 is unable to couple with G-proteins and fails to induce classical chemokine signaling for the highly conserved DRYLAIV motif essential for signaling has been changed to QRYLVFL. We investigated whether CCRL2 is involved in the chemotaxis, invasion, and proliferation of human breast cancer cells. Firstly, expression of CCRL2 was determined in six breast cancer cell lines by real-time RT-PCR and Western blot. Then, we established stable cell lines overexpressing CCRL2 to explore the function of CCRL2 in chemotaxis and invasion by transwell assays, and the signaling downstream was further investigated. The effect of CCRL2 on proliferation was detected by colony formation assays and tumor xenograft study. We found that stable overexpression of CCRL2 in MDA-MB-231 and BT-549 cells attenuated the chemotaxis and invasion stimulated by its ligand CCL2. CCRL2 inhibits p38 MAPK (p38) phosphorylation and up-regulates the expression of E-cadherin. This effect was eliminated by the inhibitor of p38 MAPK. CCRL2 inhibited the growth of breast cancer cells in vitro and in vivo. Our results suggest that CCRL2 functions as a tumor suppressor in human breast cancer cells. PMID- 26487663 TI - The role of protein oxidation and DNA damage in elderly hypertension. AB - INTRODUCTION: This study aimed to evaluate the role of protein oxidation and DNA damage in the elderly hypertensive (HT) patients. MATERIALS AND METHODS: This study consisted of four groups: two elderly groups with 30 HT patients and 30 normotensive healthy volunteers, and two young groups with 30 HT patients and 30 normotensive healthy volunteers. Plasma total thiol (T-SH), advanced oxidation protein products (AOPPs), protein carbonyl (PCO), ischemia modified albumin (IMA), urine 8-hydroxy-2'-deoxyguanosine (8-OHdG), and prooxidant-antioxidant balance (PAB) levels were measured. RESULTS: In the elderly HT group AOPPs, PCO, 8-OHdG, and PAB were significantly higher than the elderly control group. In the young HT group T-SH levels were significantly lower and the other oxidative stress parameters were significantly higher than the young control group. In the elderly control group AOPPs, PCO, IMA, 8-OHdG and PAB were significantly higher than the young control group. T-SH was significantly lower in the elderly control than the young control group. In the elderly HT group, T-SH levels were significantly lower and AOPPs, PCO, IMA, 8-OHdG, and PAB levels were significantly higher than the young HT group. CONCLUSION: Protein and DNA cell damage occurs by oxidation of free radicals throughout life. Our study supports the view that these radicals may be responsible for the development of hypertension with aging process. Urine 8-OHdG levels can be used as a marker for oxidative DNA damage in the elderly hypertensive patients. Finally, our results suggest that oxidative stress may influence both the development and progression of hypertension and aging. PMID- 26487664 TI - Specific PCR, bacterial culture, serology and pharyngeal sampling to enhance the aetiological diagnosis of cellulitis. AB - It is often difficult to obtain a bacteriological diagnosis in patients with cellulitis. We examined the utility of molecular techniques and skin and throat cultures, as well as serology, in providing evidence of either Staphylococcus aureus or group A Streptococcus (GAS) presence inpatients with cellulitis. Samples were collected from patients with a clinical diagnosis of cellulitis who were recruited into a prospective placebo-controlled clinical trial (C4C study, EudraCT 2013-001218-14). Specific PCR, paired serology and culture for both organisms were carried out on a variety of samples where appropriate. Despite utilizing a range of diagnostic methods,a bacteriological diagnosis was only achieved in 43 % of patients with a clinical diagnosis of cellulitis. Seventeen per cent of patients tested positive for GAS by any method but only 4 % were positive by PCR, whilst S. aureus was detected in 34% of samples. Bacterial diagnosis in cases of cellulitis remains challenging. This is probably due to a very low bacterial burden with toxin production resulting in inflammation mediating skin damage. Further consideration for the need for long courses of antimicrobial therapy for cellulitis therefore appears merited. PMID- 26487665 TI - Interrelationship between electrocardiographic left ventricular hypertrophy, QT prolongation, and ischaemic stroke: the REasons for Geographic and Racial Differences in Stroke Study. AB - AIMS: To determine if the association between electrocardiographic left ventricular hypertrophy (ECG-LVH) and ischaemic stroke is partially explained by the concomitant presence of QT prolongation. METHODS AND RESULTS: A total of 24 948 (mean age = 65 +/- 9.4 years; 40% black; 55% women) participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included in this analysis. Electrocardiographic left ventricular hypertrophy was defined by the Sokolow-Lyon criteria. Heart rate-adjusted QT (QTa) was computed using a linear regression model. Adjudicated ischaemic stroke events were the outcome of interest. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between ECG-LVH and prolonged QTa, in isolation and combined, with ischaemic stroke. There were 2422 (9.7%) participants with ECG-LVH, 820 (3.3%) with prolonged QTa, and 161 (0.6%) with both. Over a median follow-up of 7.6 years, 714 (2.9%) ischaemic stroke events occurred. After adjustment for stroke risk factors and potential confounders, an increased risk of ischaemic stroke was observed among participants with ECG-LVH and prolonged QTa (HR = 1.85, 95% CI = 1.04-3.30), isolated ECG-LVH (HR = 1.40, 95% CI = 1.13-1.75), and isolated prolonged QTa (HR = 1.45, 95% CI = 1.04-2.03) compared with participants without either condition. When ECG-LVH and prolonged QTa were examined as separate variables, the risk of ischaemic stroke for each condition remained statistically significant. CONCLUSION: The combination of ECG LVH and prolonged QT is associated with a higher risk of ischaemic stroke compared with either condition in isolation, and the stroke risk for each condition does not depend on the presence of the other. PMID- 26487666 TI - Management of a previously unreported implantable cardioverter-defibrillator lead complication. PMID- 26487667 TI - Is a pacemaker implantation warranted in this patient? PMID- 26487668 TI - Patient-reported treatment satisfaction and budget impact with rivaroxaban vs. standard therapy in elective cardioversion of atrial fibrillation: a post hoc analysis of the X-VeRT trial. AB - AIMS: We compared patient-reported treatment satisfaction and the economic impact of anticoagulation therapy with rivaroxaban vs. vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation undergoing elective cardioversion procedures. METHODS AND RESULTS: The current study is a post hoc analysis of the prospective, multicentre X-VeRT (EXplore the efficacy and safety of once-daily oral riVaroxaban for the prevention of caRdiovascular events in subjects with non valvular aTrial fibrillation scheduled for cardioversion) trial. Patient-reported treatment satisfaction with anticoagulation therapy was assessed using the Treatment Satisfaction Questionnaire for Medication version II in seven countries (US, UK, Canada, Germany, France, Italy, and the Netherlands). An economic model was also developed to estimate the impact of postponed cardioversions for two countries (UK and Italy). This model estimated the total costs of cardioversion, taking into consideration the costs for drug therapy (including extended treatment duration due to cardioversion postponement), international normalized ratio monitoring of VKAs, the cardioversion procedure, and rescheduling the procedure. These costs were linked to the respective X-VeRT study data to estimate the total costs. Patients receiving rivaroxaban in the delayed cardioversion group had significantly higher scores for Convenience, Effectiveness, and Global satisfaction (81.74 vs. 65.78; 39.41 vs. 32.95; and 82.07 vs. 66.74, respectively; P < 0.0001). Based on the total patient population included in the treatment satisfaction substudy (n = 632) in the delayed cardioversion group in X-VeRT, the use of rivaroxaban was estimated to result in a saving of L421 and ?360 per patient in UK and Italian settings, respectively. CONCLUSION: The use of rivaroxaban in the setting of cardioversion resulted in greater patient satisfaction and cost savings, compared with that of VKA. PMID- 26487669 TI - Clinical outcomes in cardiac resynchronization therapy-defibrillator recipients 80 years of age and older. AB - AIMS: Very elderly patients have not been well-represented in the randomized trials that established the benefits of cardiac resynchronization therapy (CRT) in heart failure (HF) patients. We therefore compared clinical outcomes in CRT defibrillator (CRT-D) recipients >=80 and <80 years old. METHODS AND RESULTS: We compared mortality and time to first appropriate shock in 258 consecutive CRT-D patients >=80 years old with New York Heart Association II-IV HF, left ventricular ejection fraction <=35%, QRS duration >=120 ms, and no prior sustained ventricular tachyarrhythmias to 1058 patients <80 years old implanted with CRT-D during the same timeframe. Comorbidities and medical therapy differed significantly between the groups. During 52 +/- 36 months, 123 (48%) patients >=80 and 474 (45%) patients <80 died; mortality was significantly higher among patients >=80 [corrected hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.12-1.72; P = 0.003]. Among 258 patients >=80 with device follow-up, only 20 (8%) received an appropriate shock compared with 172 (17%) shocks in 1053 patients <80 years old. Time to first appropriate shock was significantly shorter in patients <80 (corrected HR 0.51, 95% CI 0.30-0.87, P = 0.013). Older patients experienced 14 inappropriate shocks, and while life-threatening device complications were rare, complications related to the high-power components of the CRT-D system were not infrequent (n = 11). CONCLUSION: Mortality among CRT-D recipients >=80 years old is higher than in younger patients but is not excessive. The risk of appropriate device shocks in older patients is relatively low and significantly less than in younger patients. These observations suggest that CRT-pacemakers should be given due consideration in elderly HF patients. PMID- 26487670 TI - Personalized and automated remote monitoring of atrial fibrillation. AB - AIMS: Remote monitoring of cardiac implantable electronic devices is a growing standard; yet, remote follow-up and management of alerts represents a time consuming task for physicians or trained staff. This study evaluates an automatic mechanism based on artificial intelligence tools to filter atrial fibrillation (AF) alerts based on their medical significance. METHODS AND RESULTS: We evaluated this method on alerts for AF episodes that occurred in 60 pacemaker recipients. AKENATON prototype workflow includes two steps: natural language processing algorithms abstract the patient health record to a digital version, then a knowledge-based algorithm based on an applied formal ontology allows to calculate the CHA2DS2-VASc score and evaluate the anticoagulation status of the patient. Each alert is then automatically classified by importance from low to critical, by mimicking medical reasoning. Final classification was compared with human expert analysis by two physicians. A total of 1783 alerts about AF episode >5 min in 60 patients were processed. A 1749 of 1783 alerts (98%) were adequately classified and there were no underestimation of alert importance in the remaining 34 misclassified alerts. CONCLUSION: This work demonstrates the ability of a pilot system to classify alerts and improves personalized remote monitoring of patients. In particular, our method allows integration of patient medical history with device alert notifications, which is useful both from medical and resource management perspectives. The system was able to automatically classify the importance of 1783 AF alerts in 60 patients, which resulted in an 84% reduction in notification workload, while preserving patient safety. PMID- 26487671 TI - Faecal transplants. PMID- 26487672 TI - Gut Lactobacillus protects against the progression of renal damage by modulating the gut environment in rats. AB - BACKGROUND: The role of gut microbiota in the progression of chronic kidney disease (CKD) has not been fully elucidated. METHODS: Renal failure was induced in 6-week-old spontaneously hypertensive rats by 5/6 nephrectomy (Nx). We analyzed the gut microbiota population to identify the relevant species potentially involved in inducing renal damage. Human colon Caco-2 cells were used to delineate the mechanism involved in the molecular changes in the gut of Nx rats. RESULTS: Nx rats showed an increase in Bacteroides (Bact) and a decrease in Lactobacillus (Lact) species compared with sham-operated rats. Lact, but not Bact, populations were significantly associated with urinary protein excretion. Treatment of Nx rats with 1 * 10(10) CFU/kg/day Lact ameliorated increased urinary protein excretion and higher serum levels of the uremic toxins, indoxyl sulfate and p-cresyl sulfate, and serum urea nitrogen levels. Lact also attenuated systemic inflammation in Nx rats, as evaluated by serum lipopolysaccharide, interleukin-6 and C-reactive protein levels. Histologically, renal sclerosis in Nx rats was restored by Lact treatment. A reduction in the expression of tight junction proteins and the Toll-like receptor 2 (TLR2), a putative Lact receptor, in the colons of Nx rats were mitigated by Lact. Treatment of Caco-2 cells with indole downregulated tight junction protein expression, which was abolished by exposure to Lact. The effects of Lact were reversed by treatment with OxPAPC, a TLR inhibitor. Similarly, the increase in the permeability of the Caco-2 cell monolayer was reversed by the administration of Lact. Lact upregulated TLR2 expression in Caco-2 cells. Lact also attenuated the increase in serum indoxyl sulfate and urea levels and urinary protein excretion in Nx rats even in the pseudogerm-free environment. CONCLUSIONS: Lact supplementation mitigated the systemic inflammation and proteinuria associated with renal failure, suggesting that in the gut microbiota, Lact plays a protective role against the progression of CKD. PMID- 26487673 TI - The application of multi-omics and systems biology to identify therapeutic targets in chronic kidney disease. AB - The quest for the ideal therapeutic target in chronic kidney disease (CKD) has been riddled with many obstacles stemming from the molecular complexity of the disease and its co-morbidities. Recent advances in omics technologies and the resulting amount of available data encompassing genomics, proteomics, peptidomics, transcriptomics and metabolomics has created an opportunity for integrating omics datasets to build a comprehensive and dynamic model of the molecular changes in CKD for the purpose of biomarker and drug discovery. This article reviews relevant concepts in omics data integration using systems biology, a mathematical modelling method that globally describes a biological system on the basis of its modules and the functional connections that govern their behaviour. The review describes key databases and bioinformatics tools, as well as the challenges and limitations of the current state of the art, along with practical application to CKD therapeutic target discovery. Moreover, it describes how systems biology and visualization tools can be used to generate clinically relevant molecular models with the capability to identify specific disease pathways, recognize key events in disease development and track disease progression. PMID- 26487674 TI - Prediabetes linked to excess glucagon in transgenic mice with pancreatic active AKT1. AB - Protein kinase B/AKT has three isoforms (AKT1-3) and is renowned for its central role in the regulation of cell growth and proliferation, due to its constitutive activation in various cancers. AKT2, which is highly expressed in insulin responsive tissues, has been identified as a primary regulator of glucose metabolism as Akt2 knockout mice (Akt2(-/-)) are glucose-intolerant and insulin resistant. However, the role of AKT1 in glucose metabolism is not as clearly defined. We previously showed that mice with myristoylated Akt1 (AKT1(Myr)) expressed through a bicistronic Pdx1-TetA and TetO-MyrAkt1 system were susceptible to islet cell carcinomas, and in this study we characterized an early onset, prediabetic phenotype. Beginning at weaning (3 weeks of age), the glucose intolerant AKT1(Myr) mice exhibited non-fasted hyperglycemia, which progressed to fasted hyperglycemia by 5 months of age. The glucose intolerance was attributed to a fasted hyperglucagonemia, and hepatic insulin resistance detectable by reduced phosphorylation of the insulin receptor following insulin injection into the inferior vena cava. In contrast, treatment with doxycycline diet to turn off the transgene caused attenuation of the non-fasted and fasted hyperglycemia, thus affirming AKT1 hyperactivation as the trigger. Collectively, this model highlights a novel glucagon-mediated mechanism by which AKT1 hyperactivation affects glucose homeostasis and provides an avenue to better delineate the molecular mechanisms responsible for diabetes mellitus and the potential association with pancreatic cancer. PMID- 26487676 TI - Community-level impacts of white-tailed deer on understorey plants in North American forests: a meta-analysis. AB - The impacts of introduced or overabundant large herbivores are a concern for the conservation of forest plant communities and the sustainability of ecosystem function. White-tailed deer (Odocoileus virginianus) are considered ecologically overabundant in much of North America. Previous work suggests that impacts of deer overabundance are broadly negative and are consequently degrading forests at multiple ecological and taxonomic levels. However, no quantitative synthesis currently exists to verify the generality or magnitude of these impacts. Here, we report the results of a meta-analysis quantifying the effects of deer exclusion on the diversity, cover and abundance of woody, herbaceous and whole community components of forest understories in North America. In addition, we explore the relationships of environmental and experimental factors on the direction and magnitude of plant community outcomes using meta-regression. Using 119 calculated effect sizes sourced from 25 peer-reviewed articles, we constructed 10 community specific data sets and found strongly positive diversity, cover and abundance responses of the woody community to deer exclusion, but no significant effects for the herbaceous or whole community components of forest understories. Local deer density and time since exclusion were significant moderators of both whole community and woody community richness. Local deer density also moderated the effects of deer exclusion on whole community cover. Plot area, in contrast, showed no relationship to any of the community response outcomes. We suggest that the use of inadequate diversity indices, non-native species replacement or legacy effects of chronic deer overabundance might explain why the herbaceous and whole community components of forest understories showed no diversity or cover responses to deer exclusion. We also suggest some strategies to increase opportunities for future quantitative syntheses of deer impacts on forests, including providing better access to existing and future data. Ultimately, we show that white-tailed deer have strongly negative impacts on forest understorey plant communities in North America, but these impacts are not ubiquitous for all components of the plant community. PMID- 26487675 TI - Hypothalamic leptin gene therapy reduces body weight without accelerating age related bone loss. AB - Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related cancellous bone loss. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature (9 months old) female rats and determined the impact of leptin-induced weight loss on bone mass, density, and microarchitecture, and serum biomarkers of bone turnover (CTx and osteocalcin). Rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either recombinant adeno-associated virus encoding the gene for rat leptin (rAAV-Leptin, n=7) or a control vector encoding green fluorescent protein (rAAV-GFP, n=10) and sacrificed 18 weeks later. A baseline control group (n=7) was sacrificed at vector administration. rAAV-Leptin-treated rats lost weight (-4+/-2%) while rAAV-GFP-treated rats gained weight (14+/-2%) during the study. At study termination, rAAV-Leptin-treated rats weighed 17% less than rAAV-GFP-treated rats and had lower abdominal white adipose tissue weight ( 80%), serum leptin (-77%), and serum IGF1 (-34%). Cancellous bone volume fraction in distal femur metaphysis and epiphysis, and in lumbar vertebra tended to be lower (P<0.1) in rAAV-GFP-treated rats (13.5 months old) compared to baseline control rats (9 months old). Significant differences in cancellous bone or biomarkers of bone turnover were not detected between rAAV-Leptin and rAAV-GFP rats. In summary, rAAV-Leptin-treated rats maintained a lower body weight compared to baseline and rAAV-GFP-treated rats with minimal effects on bone mass, density, microarchitecture, or biochemical markers of bone turnover. PMID- 26487677 TI - Origins and diversity of a cosmopolitan fern genus on an island archipelago. AB - Isolated oceanic islands are characterized by patterns of biological diversity different from that on nearby continental mainlands. Isolation can provide the opportunity for evolutionary divergence, but also set the stage for hybridization between related taxa arriving from different sources. Ferns disperse by haploid spores, which are produced in large numbers and can travel long distances in air currents, enabling these plants to become established on most oceanic islands. Here, we examine the origins and patterns of diversity of the cosmopolitan fern genus Pteridium (Dennstaedtiaceae; bracken) on the Galapagos Islands. We use nucleotide sequences from two plastid genes, and two nuclear gene markers, to examine phylogeography of Pteridium on the Galapagos Islands. We incorporate data from a previous study to provide a worldwide context. We also sampled new specimens from South and Central America. We used flow cytometry to estimate genome size of some accessions. We found that both plastid and nuclear haplotypes fall into two distinct clades, consistent with a two-diploid-species taxonomy of P. aquilinum and P. esculentum. As predicted, the allotetraploid P. caudatum possesses nuclear haplotypes from both diploid species. Samples from the Galapagos include P. esculentum subsp. arachnoideum, P. caudatum and possible hybrids between them. Multiple Pteridium taxa were also observed growing together at some sites. We find evidence for multiple origins of Pteridium on the Galapagos Islands and multiple origins of tetraploid P. caudatum throughout its range in Central and South America. We also posit that P. caudatum may include recent diploid hybrids, backcrosses to P. esculentum, as well as allotetraploid plants. The Galapagos Islands are positioned close to the equator where they can receive dispersing propagules from both hemispheres. This may partly explain the high levels of diversity found for this cosmopolitan fern on these islands. PMID- 26487678 TI - Implanted defibrillators and cancer: the power of registries. PMID- 26487679 TI - Cell-cycle progress in obligate predatory bacteria is dependent upon sequential sensing of prey recognition and prey quality cues. AB - Predators feed on prey to acquire the nutrients necessary to sustain their survival, growth, and replication. In Bdellovibrio bacteriovorus, an obligate predator of Gram-negative bacteria, cell growth and replication are tied to a shift from a motile, free-living phase of search and attack to a sessile, intracellular phase of growth and replication during which a single prey cell is consumed. Engagement and sustenance of growth are achieved through the sensing of two unidentified prey-derived cues. We developed a novel ex vivo cultivation system for B. bacteriovorus composed of prey ghost cells that are recognized and invaded by the predator. By manipulating their content, we demonstrated that an early cue is located in the prey envelope and a late cue is found within the prey soluble fraction. These spatially and temporally separated cues elicit discrete and combinatory regulatory effects on gene transcription. Together, they delimit a poorly characterized transitory phase between the attack phase and the growth phase, during which the bdelloplast (the invaded prey cell) is constructed. This transitory phase constitutes a checkpoint in which the late cue presumably acts as a determinant of the prey's nutritional value before the predator commits. These regulatory adaptations to a unique bacterial lifestyle have not been reported previously. PMID- 26487680 TI - SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis. AB - Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation. PMID- 26487681 TI - From residue coevolution to protein conformational ensembles and functional dynamics. AB - The analysis of evolutionary amino acid correlations has recently attracted a surge of renewed interest, also due to their successful use in de novo protein native structure prediction. However, many aspects of protein function, such as substrate binding and product release in enzymatic activity, can be fully understood only in terms of an equilibrium ensemble of alternative structures, rather than a single static structure. In this paper we combine coevolutionary data and molecular dynamics simulations to study protein conformational heterogeneity. To that end, we adapt the Boltzmann-learning algorithm to the analysis of homologous protein sequences and develop a coarse-grained protein model specifically tailored to convert the resulting contact predictions to a protein structural ensemble. By means of exhaustive sampling simulations, we analyze the set of conformations that are consistent with the observed residue correlations for a set of representative protein domains, showing that (i) the most representative structure is consistent with the experimental fold and (ii) the various regions of the sequence display different stability, related to multiple biologically relevant conformations and to the cooperativity of the coevolving pairs. Moreover, we show that the proposed protocol is able to reproduce the essential features of a protein folding mechanism as well as to account for regions involved in conformational transitions through the correct sampling of the involved conformers. PMID- 26487682 TI - Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality. AB - Leiomodin 2 (Lmod2) is an actin-binding protein that has been implicated in the regulation of striated muscle thin filament assembly; its physiological function has yet to be studied. We found that knockout of Lmod2 in mice results in abnormally short thin filaments in the heart. We also discovered that Lmod2 functions to elongate thin filaments by promoting actin assembly and dynamics at thin filament pointed ends. Lmod2-KO mice die as juveniles with hearts displaying contractile dysfunction and ventricular chamber enlargement consistent with dilated cardiomyopathy. Lmod2-null cardiomyocytes produce less contractile force than wild type when plated on micropillar arrays. Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood. Thus, to our knowledge, Lmod2 is the first identified mammalian protein that functions to elongate actin filaments in the heart; it is essential for cardiac thin filaments to reach a mature length and is required for efficient contractile force and proper heart function during development. PMID- 26487683 TI - Agonist antibody that induces human malignant cells to kill one another. AB - An attractive, but as yet generally unrealized, approach to cancer therapy concerns discovering agents that change the state of differentiation of the cancer cells. Recently, we discovered a phenomenon that we call "receptor pleiotropism" in which agonist antibodies against known receptors induce cell fates that are very different from those induced by the natural agonist to the same receptor. Here, we show that one can take advantage of this phenomenon to convert acute myeloblastic leukemic cells into natural killer cells. Upon induction with the antibody, these leukemic cells enter into a differentiation cascade in which as many as 80% of the starting leukemic cells can be differentiated. The antibody-induced killer cells make large amounts of perforin, IFN-gamma, and granzyme B and attack and kill other members of the leukemic cell population. Importantly, induction of killer cells is confined to transformed cells, in that normal bone marrow cells are not induced to form killer cells. Thus, it seems possible to use agonist antibodies to change the differentiation state of cancer cells into those that attack and kill other members of the malignant clone from which they originate. PMID- 26487684 TI - Clique topology reveals intrinsic geometric structure in neural correlations. AB - Detecting meaningful structure in neural activity and connectivity data is challenging in the presence of hidden nonlinearities, where traditional eigenvalue-based methods may be misleading. We introduce a novel approach to matrix analysis, called clique topology, that extracts features of the data invariant under nonlinear monotone transformations. These features can be used to detect both random and geometric structure, and depend only on the relative ordering of matrix entries. We then analyzed the activity of pyramidal neurons in rat hippocampus, recorded while the animal was exploring a 2D environment, and confirmed that our method is able to detect geometric organization using only the intrinsic pattern of neural correlations. Remarkably, we found similar results during nonspatial behaviors such as wheel running and rapid eye movement (REM) sleep. This suggests that the geometric structure of correlations is shaped by the underlying hippocampal circuits and is not merely a consequence of position coding. We propose that clique topology is a powerful new tool for matrix analysis in biological settings, where the relationship of observed quantities to more meaningful variables is often nonlinear and unknown. PMID- 26487686 TI - Towards critical digital health studies: Reflections on two decades of research in health and the way forward. AB - In this article, I provide some reflections on critical digital health research in the context of Health's 20th anniversary. I begin by outlining the various iterations of digital technologies that have occurred since the early 1990s--from Web 1.0 to Web 2.0 to Web 3.0. I then review the research that has been published on the topic of digital health in this journal over the past two decades and make some suggestions for the types of directions and theoretical perspectives that further sociocultural and political research could tackle. My concluding comments identify four main areas for further research: (1) devices and software, (2) data materialisations, (3) data practices and (4) data mobilities. PMID- 26487685 TI - Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance. AB - Inheritance of the callipyge phenotype in sheep is an example of polar overdominance inheritance, an unusual mode of inheritance. To investigate the underlying molecular mechanism, we profiled the expression of the genes located in the Delta-like 1 homolog (Dlk1)-type III iodothyronine deiodinase (Dio3) imprinting region in mice. We found that the transcripts of the microRNA (miR) 379/miR-544 cluster were highly expressed in neonatal muscle and paralleled the expression of the Dlk1. We then determined the in vivo role of the miR-379/miR 544 cluster by establishing a mouse line in which the cluster was ablated. The maternal heterozygotes of young mutant mice displayed a hypertrophic tibialis anterior muscle, extensor digitorum longus muscle, gastrocnemius muscle, and gluteus maximus muscle and elevated expression of the DLK1 protein. Reduced expression of DLK1 was mediated by miR-329, a member of this cluster. Our results suggest that maternal expression of the imprinted miR-379/miR-544 cluster regulates paternal expression of the Dlk1 gene in mice. We therefore propose a miR-based molecular working model for polar overdominance inheritance. PMID- 26487687 TI - The consent process: Enabling or disabling patients' active participation? AB - Standards expected by doctors' regulatory bodies in respect of the process of consent to treatment have arguably sought to restructure the nature of the doctor patient relationship from one of the paternalism to that of shared decision making. Yet, few studies have explored empirically, from patients' perspectives, the extent to which the process of consent to treatment enables or disables patients' participation in medical decision-making. Our article examines patients' attitudes towards the consent process, exploring how and why these attitudes influence patients' active participation in decision-making and considering possible consequent medico-legal issues. Data were collected longitudinally using semi-structured interviews and field observations involving 35 patients and 19 of their caregivers, in an English hospital between February and November 2014. These indicate that generally patients defer to the doctor in respect of treatment decision-making. Although most patients and their caregivers wanted detailed information and discussion, they did not necessarily expect that this would be provided. Furthermore, patients perceived that signing the consent form was an obligatory routine principally to protect doctors from legal action should something go wrong. Our study suggests that patients' predominantly paternalistic perceptions of the consent process can not only undermine attempts by doctors to involve them in decision-making but, as patients are now considered in law as informed actors, their perceptions of the consent form as not being in their interests could be a self-fulfilling prophecy if signing is undertaken without due consideration to the content. PMID- 26487688 TI - A personal reflection on health: 20 years on. AB - This article looks back to the origins of health: from the perspective of its Founding Editor. Reviewing the journal's original statement of aims, the terms 'refraction' and 'moment' are selected to provide a brief discussion of health and illness as defining the journal's continuing focus. PMID- 26487689 TI - Magnesium Modifies the Impact of Calcitriol Treatment on Vascular Calcification in Experimental Chronic Kidney Disease. AB - Chronic kidney disease (CKD) patients are commonly treated with vitamin D analogs, such as calcitriol. Recent epidemiologic evidence revealed a significant interaction between vitamin D and magnesium, since an inverse relationship between vitamin D levels and mortality mainly occurs in patients with a high magnesium intake. The aim of the study was to assess the mechanisms involved by determining whether magnesium alone or combined with calcitriol treatments differentially impacts vascular calcification (VC) in male Sprague-Dawley rats with adenine-induced CKD. Treatment with moderate doses of calcitriol (80 MUg/kg) suppressed parathyroid hormone to near or slightly below control levels. Given alone, this dose of calcitriol increased the prevalence of VC; however, when magnesium was given in combination, the severity of calcification was attenuated in the abdominal aorta (51% reduction), iliac (44%), and carotid arteries (46%) compared with CKD controls. The decreases in vascular calcium content were associated with a 20-50% increase in vascular magnesium. Calcitriol treatment alone significantly decreased TRPM7 protein (? to ~11%), whereas the combination treatment increased both mRNA (1.7*) and protein (6.8*) expression compared with calcitriol alone. In summary, calcitriol increased VC in certain conditions, but magnesium prevented the reduction in TRPM7 and reduced the severity of VC, thereby increasing the bioavailable magnesium in the vascular microenvironment. These findings suggest that modifying the adverse effect profile of calcitriol with magnesium may be a plausible approach to benefiting the increasing number of CKD patients being prescribed calcitriol. PMID- 26487691 TI - Intensive chemoimmunotherapy and bilateral globe irradiation as initial therapy for primary intraocular lymphoma. AB - BACKGROUND: Primary intraocular lymphoma is a rare variant of primary CNS lymphoma for which the optimum treatment strategy remains unknown. METHODS: We performed a retrospective single-center study including patients who underwent uniform management from October 2007 in which patients were offered sequential rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by binocular radiotherapy and consolidative high-dose cytarabine. RESULTS: Eleven patients with median age 66 years (range, 48-72) were included. All patients received binocular radiotherapy to a median dose of 36 Gy (range, 30.6-39.6) in 20 fractions. Grade 3+ anemia, thrombocytopenia, and neutropenia occurred in 1 (9%), 2 (18%), and 3 (27%) patients, respectively; raised creatinine and peripheral sensory neuropathy occurred in 4 (36%) and 3 (27%) patients, respectively. Grade 3+ ocular toxicities included cataract formation and keratitis in 6 (54%) and 3 (27%) patients, respectively. Ten patients (91%) achieved complete response and 1 (9%) partial response. After median follow-up of 4.2 years (range, 1.8-7.6), the median progression-free survival was 3.8 years and the estimated 4-year overall survival was 75.8% (95% CI: 30.5%-93.7%). The initial site of disease progression was the CNS in 4 of 7 patients (57%) and within the eye in 3 of 7 (43%). Five patients achieved responses to salvage therapies. CONCLUSIONS: Combined modality treatment with R-MPV, binocular radiation, and high-dose cytarabine is effective with moderate toxicity. Both local and CNS relapses occur; however, the achievement of second and subsequent remissions is possible. PMID- 26487690 TI - Apparent diffusion coefficient histogram metrics correlate with survival in diffuse intrinsic pontine glioma: a report from the Pediatric Brain Tumor Consortium. AB - BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is associated with poor survival regardless of therapy. We used volumetric apparent diffusion coefficient (ADC) histogram metrics to determine associations with progression-free survival (PFS) and overall survival (OS) at baseline and after radiation therapy (RT). METHODS: Baseline and post-RT quantitative ADC histograms were generated from fluid-attenuated inversion recovery (FLAIR) images and enhancement regions of interest. Metrics assessed included number of peaks (ie, unimodal or bimodal), mean and median ADC, standard deviation, mode, skewness, and kurtosis. RESULTS: Based on FLAIR images, the majority of tumors had unimodal peaks with significantly shorter average survival. Pre-RT FLAIR mean, mode, and median values were significantly associated with decreased risk of progression; higher pre-RT ADC values had longer PFS on average. Pre-RT FLAIR skewness and standard deviation were significantly associated with increased risk of progression; higher pre-RT FLAIR skewness and standard deviation had shorter PFS. Nonenhancing tumors at baseline showed higher ADC FLAIR mean values, lower kurtosis, and higher PFS. For enhancing tumors at baseline, bimodal enhancement histograms had much worse PFS and OS than unimodal cases and significantly lower mean peak values. Enhancement in tumors only after RT led to significantly shorter PFS and OS than in patients with baseline or no baseline enhancement. CONCLUSIONS: ADC histogram metrics in DIPG demonstrate significant correlations between diffusion metrics and survival, with lower diffusion values (increased cellularity), increased skewness, and enhancement associated with shorter survival, requiring future investigations in large DIPG clinical trials. PMID- 26487692 TI - Enhanced atheroprotection and lesion remodelling by targeting the foam cell and increasing plasma cholesterol acceptors. AB - AIMS: Atherosclerosis development can be ameliorated by promoting reverse cholesterol transport (RCT) from arteries. The process involves cholesterol efflux from foam cells to extracellular acceptors such as apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL) that mediate transport to the liver. Perilipin-2 (PLIN2) is a lipid droplet (LD)-associated protein that in macrophages facilitates cholesterol storage and prevents efflux. We hypothesized that atheroprotection would be enhanced by concurrently targeting PLIN2 to increase the efflux capacity of foam cells and increasing plasma apoA-I and HDL. METHODS AND RESULTS: PLIN2-knockout and wild-type mice lacking apolipoprotein E (PLIN2(-/-)/apoE(-/-) and PLIN2(+/+)/apoE(-/-)) were treated with a helper dependent adenoviral vector encoding human apoA-I (HDAd-AI) or with control empty vector. Treatment with HDAd-AI increased hepatic apoA-I production, plasma apoA-I and HDL-cholesterol (HDL-C), and apoA-I deposition in lesions to a similar extent in PLIN2(-/-)/apoE(-/-) and PLIN2(+/+)/apoE(-/-) mice. However, atherosclerosis development at the aortic sinus was considerably lower in HDAd-AI-treated PLIN2( /-)/apoE(-/-) mice. A more stable lesion phenotype, with increased collagen content, was primarily associated to treatment with HDAd-AI, but was enhanced under PLIN2 deficiency. PLIN2 deficiency and apoA-I cumulatively reduced LDs and cholesterol ester content in cultured macrophages. Neutral lipid in atheroma was significantly reduced in HDAd-AI-treated PLIN2(-/-)/apoE(-/-) mice, and RCT from macrophages to feces was enhanced in PLIN2(-/-) macrophages. CONCLUSION: These studies demonstrate a mutually beneficial relationship between PLIN2 deficiency and elevated apoA-I/HDL-C in preventing atherosclerosis development. The data support that targeting foam cell components to mobilize cholesterol may be a promising strategy to enhance the atheroprotection of plasma cholesterol acceptors. PMID- 26487693 TI - Translational failure of anti-inflammatory compounds for myocardial infarction: a meta-analysis of large animal models. AB - AIMS: Numerous anti-inflammatory drugs have been tested in large animal studies of myocardial infarction (MI). Despite positive results, translation of anti inflammatory strategies into clinical practice has proved to be difficult. Critical disparities between preclinical and clinical study design that influence efficacy may partly be responsible for this translational failure. The aim of the present systematic review was to better understand which factors underlie the failure of transition towards the clinic. METHODS AND RESULTS: Meta-analysis and regression of large animal studies were performed to identify sources that influenced effect size of anti-inflammatory compounds in large animal models of MI. We included 183 studies, containing 3331 large animals. Infarct size (IS) as a ratio of the area at risk (12.7%; 95% confidence interval, CI 11.1-14.4%, P < 0.001) and IS as a ratio of the left ventricle (3.9%; 95% CI 3.1-4.7%, P < 0.001) were reduced in treatment compared with control groups. Effect size was higher when outcome was assessed early after MI (P = 0.013) and where studies included only male animals (P < 0.001). Mortality in treated animals was higher in studies that blinded the investigator during the experiment (P = 0.041) and depended on the type of drug used (P < 0.001). CONCLUSIONS: As expected, treatment with anti inflammatory drugs leads to smaller infarct size in large animal MI models. Timing of outcome assessment, sex, and study quality are significantly associated with outcome and may explain part of the translational failure in clinical settings. Effect size depends on the type of drug used, enabling identification of compounds for future clinical testing. PMID- 26487694 TI - PDIA6 regulates insulin secretion by selectively inhibiting the RIDD activity of IRE1. AB - Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling. In this study, shRNA silencing of PDIA6 expression in insulin-producing mouse cells reduced insulin production (5-fold) and, consequently, glucose-stimulated insulin secretion (3-4 fold). This inhibition of insulin release was independent of the PDIA6-PERK interaction or PERK activity. Acute inhibition of PERK did not change the short term response of beta cells to glucose. Rather, PDIA6 affected insulin secretion by modulating one of the activities of IRE1. At 11 mM glucose and lower, the regulated IRE1-dependent decay (RIDD) of the mRNA activity of IRE1 was activated, but not its X-box binding protein (XBP)-1 splicing activity. In the absence of PDIA6, RIDD activity toward insulin transcripts was enhanced up to 4-fold, as shown by molecular assays in cultured cells and the use of a fluorescent reporter in intact islets. Such physiologic activation of IRE1 by glucose contrasted with IRE1 activation by chemical stress, when both IRE1 activities were induced. Thus, whereas the stimulus determines the quality of IRE1 signaling, PDIA6 attenuates multiple enzymatic activities of IRE1, maintaining its signaling within a physiologically tolerable range. PMID- 26487696 TI - Co-occurrence of Myeloproliferative Neoplasms and Solid Tumors Is Attributed to a Synergism Between Cytoreductive Therapy and the Common TERT Polymorphism rs2736100. AB - BACKGROUND: The germline telomerase reverse transcriptase (TERT) rs2736100_C variant was identified as a susceptibility factor for a variety of solid tumors and recently for myeloproliferative neoplasms (MPN). METHODS: LightCycler melting curve analysis was applied to detect risk alleles of TERT rs2736100_C and Janus kinase 2 (JAK2) rs12343867_C tagging 46/1 haplotype in 584 BCR-ABL1-negative MPN, 308 acute, and 86 chronic myeloid leukemia (AML and CML) patients and 400 healthy individuals. RESULTS: TERT rs2736100_C showed an increased allele frequency in BCR-ABL1-negative MPN patients compared with controls (62.7%+/-2.8% vs. 48.8%+/ 3.5%, P < 0.0001) regardless of molecular background or disease type, but not in CML or AML. Combined TERT and JAK2 hetero- or homozygosity conferred even higher risk for classic MPN. Common complications (thrombosis, myelofibrosis, or leukemia) were not associated with the TERT variant; however, adverse survival was noted in TERT variant carrier polycythemia vera patients. MPN patients with the TERT CC genotype had a higher probability (44.4%) to die from solid tumors compared with TERT AC/AA individuals (5.3%; P = 0.004). TERT rs2736100_C carriers had increased risk of solid tumors independently from cytoreductive treatment [3.08 (1.03-9.26), P = 0.045]. CONCLUSIONS: TERT rs2736100_C polymorphism predisposes to the development of BCR-ABL1-negative MPN with the co-occurrence of solid tumors, especially with the usage of cytoreductive treatment. IMPACT: The high frequency of TERT variant in the classic MPN population highlights the importance of the avoidance of long-term cytoreductive treatment in MPN patients. PMID- 26487697 TI - Structural and functional insight into the different oxidation states of SAV1875 from Staphylococcus aureus. AB - The DJ-1/ThiJ/PfpI superfamily is a group of proteins found in diverse organisms. This superfamily includes versatile proteins, such as proteases, chaperones, heat shock proteins and human Parkinson's disease protein. Most members of the DJ 1/ThiJ/PfpI superfamily are oligomers and are classified into subfamilies depending on discriminating quaternary structures (DJ-1, YhbO and Hsp types). SAV1875, a conserved protein from Staphylococcus aureus, is a member of the YhbO type subfamily. However, its structure and function remain unknown. Thus, to understand the function and activity mechanism of this protein, the crystal structure of SAV1875 from S. aureus was determined. The overall fold of SAV1875 is similar to that observed for the DJ-1/ThiJ/PfpI superfamily. The cysteine residue located in the dimeric interface (Cys(105)) forms a catalytic triad with His(106) and Asp(77), and it is spontaneously oxidized to Cys(105)-SO2H in the crystal structure. To study the oxidative propensity of Cys(105) and the corresponding functional differences with changes in cysteine oxidation state, the crystal structures of SAV1875 variants E17N, E17D and C105D, and over oxidized SAV1875 were determined. We identified SAV1875 as a novel member of the YhbO-type subfamily exhibiting chaperone function. However, if SAV1875 is over oxidized further with H2O2, its chaperone activity is eliminated. On the basis of our study, we suggest that SAV1875 functions as a chaperone and the redox state of Cys(105) may play an important role. PMID- 26487695 TI - Skeletal muscle-specific eukaryotic translation initiation factor 2alpha phosphorylation controls amino acid metabolism and fibroblast growth factor 21 mediated non-cell-autonomous energy metabolism. AB - The eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle-specific derivative of the eIF2alpha protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2alpha phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non-cell-autonomous metabolic regulation by induced expression of a potent myokine. PMID- 26487698 TI - Metastasis-associated S100A4 is a specific amine donor and an activity independent binding partner of transglutaminase-2. AB - Transglutaminase-2 (TG2) is best known as a Ca(2+)-dependent cross-linking enzyme; however, some of its extracellular matrix-related functions are independent of its catalytic activity and include matrix remodelling, adhesion and migration. S100A4 belongs to the Ca(2+)-binding EF-hand S100 protein family and acts both intra- and extra-cellularly through binding to various partners. It regulates cell migration and its overexpression is strongly associated with metastasis and poor survival in various cancers. It has recently been suggested that TG2 mediates S100A4-dependent tumour cell migration. In the present study we provide evidence that S100A4 is an interacting partner and also a specific amine donor of TG2. TG2 incorporates a glutamine donor peptide to Lys(100) in the C terminal random coil region of S100A4. Importantly, the enzyme activity is not necessary for the interaction: S100A4 also binds to TG2 in the presence of a specific inhibitor that keeps the enzyme in an open conformation, or to an enzymatically inactive mutant. We also found that S100A4 considerably enhances TG2-mediated adhesion of A431 epithelial carcinoma cells to the extracellular matrix. This role is independent of enzyme activity and requires the open conformation of TG2. We propose that S100A4 stabilizes the open conformation of TG2, which binds to its cell-surface receptor in this state and increases cell adhesion. PMID- 26487699 TI - Zinc-induced oligomerization of zinc alpha2 glycoprotein reveals multiple fatty acid-binding sites. AB - Zinc alpha2 glycoprotein (ZAG) is an adipokine with a class I MHC protein fold and is associated with obesity and diabetes. Although its intrinsic ligand remains unknown, ZAG binds the dansylated C11 fatty acid 11 (dansylamino)undecanoic acid (DAUDA) in the groove between the alpha1 and alpha2 domains. The surface of ZAG has approximately 15 weak zinc-binding sites deemed responsible for precipitation from human plasma. In the present study the functional significance of these metal sites was investigated. Analytical ultracentrifugation (AUC) and CD showed that zinc, but not other divalent metals, causes ZAG to oligomerize in solution. Thus ZAG dimers and trimers were observed in the presence of 1 and 2 mM zinc. Molecular modelling of X-ray scattering curves and sedimentation coefficients indicated a progressive stacking of ZAG monomers, suggesting that the ZAG groove may be occluded in these. Using fluorescence-detected sedimentation velocity, these ZAG-zinc oligomers were again observed in the presence of the fluorescent boron dipyrromethene fatty acid C16 BODIPY (4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-hexadecanoic acid). Fluorescence spectroscopy confirmed that ZAG binds C16-BODIPY. ZAG binding to C16-BODIPY, but not to DAUDA, was reduced by increased zinc concentrations. We conclude that the lipid-binding groove in ZAG contains at least two distinct fatty acid-binding sites for DAUDA and C16-BODIPY, similar to the multiple lipid binding seen in the structurally related immune protein CD1c. In addition, because high concentrations of zinc occur in the pancreas, the perturbation of these multiple lipid-binding sites by zinc may be significant in Type 2 diabetes where dysregulation of ZAG and zinc homoeostasis occurs. PMID- 26487700 TI - Increasing medical students' engagement in public health: case studies illustrating the potential role of online learning. AB - BACKGROUND: The value of e-learning in medical education is widely recognized but there is little evidence of its value in teaching medical students about public health. Such evidence is needed because medical students' engagement with public health has been low. We present three recent case studies from UK medical schools to illustrate diverse ways in which online approaches can increase medical students' engagement with learning public health. METHODS: A comparative case study approach was used applying quantitative and qualitative data to examine engagement in terms of uptake/use amongst eligible students, acceptability and perceived effectiveness using an analytic framework based on Seven Principles of Effective Teaching. RESULTS: Across the three case studies, most (67-85%) eligible students accessed online materials, and rated them more favourably than live lectures. Students particularly valued opportunities to use e-learning flexibly in terms of time and place. Online technologies offered new ways to consolidate learning of key public health concepts. Although students found contributing to online discussions challenging, it provided opportunities for students to explore concepts in depth and enabled students that were uncomfortable speaking in face-to-face discussions to participate. CONCLUSIONS: E learning can be applied in diverse ways that increase medical student engagement with public health teaching. PMID- 26487701 TI - Integration, influence and change in public health: findings from a survey of Directors of Public Health in England. AB - BACKGROUND: Following the Health and Social Care Act in England, public health teams were formally transferred from the NHS to local authorities in April 2013. METHODS: Online survey of Directors of Public Health (DsPH) in local authorities in England (n = 152) to investigate their experience within local government 1 year on. Tests of association were used to explore relationships between the perceived integration and influence of public health, and changes in how the public health budget was being spent. RESULTS: The organization of and managerial arrangements for public health within councils varied. Most DsPH felt that good relationships had been established within the council, and the move had made them more able to influence priorities for health improvement, even though most felt their influence was limited. Changes in commissioning using the public health budget were already widespread and included the de-commissioning of services. CONCLUSIONS: There was a widespread feeling amongst DsPH that they had greater influence since the reforms, and that this went across the local authority and beyond. Public health's influence was most apparent when the transfer of staff to local government had gone well, when collaborative working relationships had developed, and when local partnership groups were seen as being effective. PMID- 26487702 TI - Maternal obesity in Africa: a systematic review and meta-analysis. AB - BACKGROUND: Maternal obesity is emerging as a public health problem, recently highlighted together with maternal under-nutrition as a 'double burden', especially in African countries undergoing social and economic transition. This systematic review was conducted to investigate the current evidence on maternal obesity in Africa. METHODS: MEDLINE, EMBASE, Scopus, CINAHL and PsycINFO were searched (up to August 2014) and identified 29 studies. Prevalence, associations with socio-demographic factors, labour, child and maternal consequences of maternal obesity were assessed. Pooled risk ratios comparing obese and non-obese groups were calculated. RESULTS: Prevalence of maternal obesity across Africa ranged from 6.5 to 50.7%, with older and multiparous mothers more likely to be obese. Obese mothers had increased risks of adverse labour, child and maternal outcomes. However, non-obese mothers were more likely to have low-birthweight babies. The differences in measurement and timing of assessment of maternal obesity were found across studies. No studies were identified either on the knowledge or attitudes of pregnant women towards maternal obesity; or on interventions for obese pregnant women. CONCLUSIONS: These results show that Africa's levels of maternal obesity are already having significant adverse effects. Culturally adaptable/sensitive interventions should be developed while monitoring to avoid undesired side effects. PMID- 26487703 TI - Prevalence and Risk Factors of Self-Reported Smell and Taste Alterations: Results from the 2011-2012 US National Health and Nutrition Examination Survey (NHANES). AB - Chemosensory problems challenge health through diminished ability to detect warning odors, consume a healthy diet, and maintain quality of life. We examined the prevalence and associated risk factors of self-reported chemosensory alterations in 3603 community-dwelling adults (aged 40+ years), from the nationally representative, US National Health and Nutrition Examination Survey (NHANES) 2011-2012. In this new NHANES component, technicians surveyed adults in the home about perceived smell and taste problems, distortions, and diminished abilities since age 25 (termed "alterations"), and chemosensory-related health risks and behaviors. The prevalence of self-reported smell alteration was 23%, including phantosmia at 6%; taste was 19%, including dysgeusia at 5%. Prevalence rates increased progressively with age, highest in those aged 80+ years (smell, 32%; taste, 27%). In multivariable logistic regression, controlling for sociodemographics, health behaviors, and chemosensory-related conditions, the strongest independent risk factor for smell alteration was sinonasal symptoms (odds ratio [OR] = 2.06; 95% confidence interval [CI]: 1.63-2.61), followed by heavy drinking, loss of consciousness from head injury, family income <=110% poverty threshold, and xerostomia. For taste, the strongest risk factor was xerostomia (OR = 2.65; 95% CI: 1.97-3.56), followed by nose/facial injury, lower educational attainment, and fair/poor health. Self-reported chemosensory alterations are prevalent in US adults, supporting increased attention to decreasing their modifiable risks, managing safety/health consequences, and expanding chemosensory screening/testing and treatments. PMID- 26487704 TI - Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons. AB - Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (>= 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength. PMID- 26487705 TI - Intrauterine growth restriction perturbs nucleosome depletion at a growth hormone responsive element in the mouse IGF-1 gene. AB - Intrauterine growth restriction (IUGR) is a common human pregnancy complication. IUGR offspring carry significant postnatal risk for early-onset metabolic syndrome, which is associated with persistent reduction in IGF-1 protein expression. We have previously shown that preadolescent IUGR male mice have decreased hepatic IGF-1 mRNA and circulating IGF-1 protein at postnatal day 21, the age when growth hormone (GH) normally upregulates hepatic IGF-1 expression. Here we studied nucleosome occupancy and CpG methylation at a putative growth hormone-responsive element in intron 2 (in2GHRE) of the hepatic IGF-1 gene in normal, sham-operated, and IUGR mice. Nucleosome occupancy and CpG methylation were determined in embryonic stem cells (ESCs) and in liver at postnatal days 14, 21, and 42. For CpG methylation, additional time points out to 2 yr were analyzed. We confirmed the putative mouse in2GHRE was GH-responsive, and in normal mice, a single nucleosome was displaced from the hepatic in2GHRE by postnatal day 21, which exposed two STAT5b DNA binding sites. Nucleosome displacement correlated with developmentally programmed CpG demethylation. Finally, IUGR significantly altered the nucleosome-depleted region (NDR) at the in2GHRE of IGF-1 on postnatal day 21, with either complete absence of the NDR or with a shifted NDR exposing only one of two STAT5b DNA binding sites. An NDR shift was also seen in offspring of sham-operated mothers. We conclude that prenatal insult such as IUGR or anesthesia/surgery could perturb the proper formation of a well-positioned NDR at the mouse hepatic IGF-1 in2GHRE necessary for transitioning to an open chromatin state. PMID- 26487706 TI - Integrating primary and secondary care for children and young people: sharing practice. AB - OBJECTIVE: To share innovative practice with enough detail to be useful for paediatricians involved in planning services. DESIGN: A review of practice, adopting a realist approach. SETTING: We collected detailed information about five initiatives which were presented at two meetings in July and October 2014 and telephone interviews between July and November 2014 with key informants, updating information again in February 2015. RESULTS: The five case studies involved three clinical commissioning groups (CCGs): Islington CCG and Southwark and Lambeth CCG in London and Taunton CCG in the Southwest. All five initiatives involved acute paediatric units. We heard about four distinct types of services designed to bring paediatric expertise into primary care and/or improve joint working between paediatricians and primary care professionals: telephone multidisciplinary team, hospital at home, general practitioner (GP) outreach clinics, and advice and guidance. We defined four common ways that initiatives might work: promoting shared responsibility; upskilling GPs; establishing relationships between paediatricians and primary healthcare professionals; and by taking specialist care to the patient. CONCLUSIONS: We derived common aims and mechanisms and generated programme (mid-level) theory for each integrated care initiative about how they might work. These descriptions of what is being done can inform debate about which interventions should be prioritised for wider implementation. There is an urgent need for evaluation of these interventions and more indepth research into how mechanisms and their effectiveness could be assessed. PMID- 26487707 TI - Mode of interaction of the Galphao subunit of heterotrimeric G proteins with the GoLoco1 motif of Drosophila Pins is determined by guanine nucleotides. AB - Drosophila GoLoco motif-containing protein Pins is unusual in its highly efficient interaction with both GDP- and the GTP-loaded forms of the alpha subunit of the heterotrimeric Go protein. We analysed the interactions of Galphao in its two nucleotide forms with GoLoco1-the first of the three GoLoco domains of Pins-and the possible structures of the resulting complexes, through combination of conventional fluorescence and FRET measurements as well as through molecular modelling. Our data suggest that the orientation of the GoLoco1 motif on Galphao significantly differs between the two nucleotide states of the latter. In other words, a rotation of the GoLoco1 peptide in respect with Galphao must accompany the nucleotide exchange in Galphao. The sterical hindrance requiring such a rotation probably contributes to the guanine nucleotide exchange inhibitor activity of GoLoco1 and Pins as a whole. Our data have important implications for the mechanisms of Pins regulation in the process of asymmetric cell divisions. PMID- 26487708 TI - Epsilon glutathione transferases possess a unique class-conserved subunit interface motif that directly interacts with glutathione in the active site. AB - Epsilon class glutathione transferases (GSTs) have been shown to contribute significantly to insecticide resistance. We report a new Epsilon class protein crystal structure from Drosophila melanogaster for the glutathione transferase DmGSTE6. The structure reveals a novel Epsilon clasp motif that is conserved across hundreds of millions of years of evolution of the insect Diptera order. This histidine-serine motif lies in the subunit interface and appears to contribute to quaternary stability as well as directly connecting the two glutathiones in the active sites of this dimeric enzyme. PMID- 26487709 TI - Medical and DNBI admissions to the UK Role 3 field hospital in Iraq during Op TELIC. PMID- 26487710 TI - Operation GRITROCK: the Defence Medical Services' story and emerging lessons from supporting the UK response to the Ebola crisis. AB - This paper is a record of the UK Defence Medical Services (DMS) contribution to the UK response to the Ebola crisis in West Africa from the start of planning in July 2014 to the closure of the Ministry of Defence Ebola Virus Disease Treatment Unit at the end of June 2015. The context and wider UK government decisions are summarised. This paper describes the decisions and processes that resulted in the deployment of a DMS delivered Ebola Treatment Unit in conjunction with the Department for International Development and Save the Children. It covers arrangements for medical care for disease and non-battle injury, the Air Transportable Isolator and Force Health Protection policy, and finally, considers the medical lessons from this deployment. The core message is that the UK DMS are the only part of the UK health sector that is trained, equipped, manned and available to rapidly deploy and operate a complete medical unit as part of an international response to a health crisis. PMID- 26487711 TI - Reconstitution of the receptor-binding motif of the SARS coronavirus. AB - The severe acute respiratory syndrome (SARS) coronavirus (CoV) identified in 2003 has infected ~8000 people worldwide, killing nearly 10% of them. The infection of target cells by the SARS CoV is mediated through the interaction of the viral Spike (S) protein (1255 amino acids) and its cellular receptor, angiotensin converting enzyme 2 (ACE2). The SARS CoV receptor-binding domain (amino acids N318-T509 of S protein) harbors an extended excursion along its periphery that contacts ACE2 and is designated the receptor-binding motif (RBM, amino acids S432 T486). In addition, the RBM is a major antigenic determinant, able to elicit production of neutralizing antibodies. Hence, the role of the RBM is a bi functional bioactive surface that can be demonstrated by antibodies such as the neutralizing human anti-SARS monoclonal antibody (mAb) 80R which targets the RBM and competes with the ACE2 receptor for binding. Here, we employ phage-display peptide-libraries to reconstitute a functional RBM. This is achieved by generating a vast collection of candidate RBM peptides that present a diversity of conformations. Screening such 'Conformer Libraries' with corresponding ligands has produced short RBM constructs (ca. 40 amino acids) that can bind both the ACE2 receptor and the neutralizing mAb 80R. PMID- 26487712 TI - A solenoid design for assessing determinants of parallel beta-sheet registration. AB - A novel protein construct is presented that combines a homotrimeric, triple stranded beta-helix as a guest to a homotrimeric foldon unit from bacteriophage T4 fibritin. The beta-helical solenoid selected is short (46 residues) and is part of a subdomain of the T4 cell-puncturing device. The resultant design is trimeric and displays greatly enhanced stability over each sub-component alone. The intended goal is a design that will enable evaluation of sequence determinants that promote in-register versus out-of-register parallel beta-sheet homotrimerization. Towards that end, the importance of a set of three buried salt bridges was evaluated by converting them to residues otherwise consistently found throughout the natural solenoid at the same positions. The critical role of the charged residues in the salt-bridges was evident in that their elimination resulted in amyloid-like aggregation. PMID- 26487713 TI - Stereotactic body radiotherapy for chronic obstructive pulmonary disease patients undergoing or eligible for long-term domiciliary oxygen therapy. AB - A major cause of death in patients undergoing long-term domiciliary oxygen therapy (LTOT) is lung cancer progression. In our institution, we actively perform stereotactic body radiotherapy (SBRT) on patients with early-stage non small-cell lung cancer undergoing LTOT. In this study, we retrospectively analyzed the treatment efficacy and safety of SBRT for patients with T1-3N0M0 non small-cell lung cancer who had been prescribed LTOT for treatment of chronic obstructive pulmonary disease (COPD). A total of 24 patients were studied. Their median age was 74 years (range, 63-87 years). The median duration from the start of LTOT to SBRT was 23 months (range, 0-85 months). Four of the 24 patients underwent lobectomy due to lung cancer. The median follow-up duration was 29 months (range, 5-79 months). One patient had a local recurrence. The median survival time was 30 months. The 3-year overall survival was 49%. In 6 of the 24 patients (25%), COPD presented with interstitial pneumonia. The 3-year overall survival for patients with COPD without interstitial pneumonia was significantly better than that for patients with both COPD and interstitial pneumonia (67% and 0%, respectively; P < 0.0001). Grade 5 radiation pneumonitis occurred in one patient (4%) with COPD with interstitial pneumonia. SBRT was tolerated by patients with early-stage non-small-cell lung cancer undergoing LTOT. SBRT should be considered for patients undergoing LTOT. However, clinicians should consider the risk of severe radiation pneumonitis in patients with interstitial pneumonia. PMID- 26487714 TI - C1q Deficiency Promotes Pulmonary Vascular Inflammation and Enhances the Susceptibility of the Lung Endothelium to Injury. AB - The collectin proteins are innate immune molecules found in high concentrations on the epithelial and endothelial surfaces of the lung. While these proteins are known to have important anti-inflammatory actions in the airways of the lung little is known of their functional importance in the pulmonary circulation. We recently demonstrated that the circulating collectin protein adiponectin has potent anti-inflammatory effects on the lung endothelium, leading us to reason that other structurally related proteins might have similar effects. To test this hypothesis, we investigated the anti-inflammatory actions of C1q in lung endothelial homeostasis and the pulmonary vascular response to LPS or HCl injury. We show that lung endothelium from C1q-deficient (C1q(-/-)) mice expresses higher baseline levels of the vascular adhesion markers ICAM-1, VCAM-1, and E-selectin when compared with wild-type mice. Further, we demonstrate that these changes are associated with enhanced susceptibility of the lung to injury as evident by increased expression of adhesion markers, enhanced production of pro-inflammatory cytokines, and augmented neutrophil recruitment. Additionally, we found that C1q( /-) mice also exhibited enhanced endothelial barrier dysfunction after injury as manifested by decreased expression of junctional adherens proteins and enhanced vascular leakage. Mechanistically, C1q appears to mediate its effects by inhibiting phosphorylation of p38 mitogen-activated protein kinase (MAPK) and blocking nuclear translocation of the P65 subunit of nuclear factor (NF)-kappaB. In summary, our findings indicate a previously unrecognized role for C1q in pulmonary vascular homeostasis and provide added support for the hypothesis that circulating collectin proteins have protective effects on the lung endothelium. PMID- 26487715 TI - Normal Fertility Requires the Expression of Carbonic Anhydrases II and IV in Sperm. AB - HCO3 (-) is a key factor in the regulation of sperm motility. High concentrations of HCO3 (-) in the female genital tract induce an increase in sperm beat frequency, which speeds progress of the sperm through the female reproductive tract. Carbonic anhydrases (CA), which catalyze the reversible hydration of CO2 to HCO3 (-), represent potential candidates in the regulation of the HCO3 (-) homeostasis in sperm and the composition of the male and female genital tract fluids. We show that two CA isoforms, CAII and CAIV, are distributed along the epididymal epithelium and appear with the onset of puberty. Expression analyses reveal an up-regulation of CAII and CAIV in the different epididymal sections of the knockout lines. In sperm, we find that CAII is located in the principal piece, whereas CAIV is present in the plasma membrane of the entire sperm tail. CAII and CAIV single knockout animals display an imbalanced HCO3 (-) homeostasis, resulting in substantially reduced sperm motility, swimming speed, and HCO3 (-) enhanced beat frequency. The CA activity remaining in the sperm of CAII- and CAIV null mutants is 35% and 68% of that found in WT mice. Sperm of the double knockout mutant mice show responses to stimulus by HCO3 (-) or CO2 that were delayed in onset and reduced in magnitude. In comparison with sperm from CAII and CAIV double knockout animals, pharmacological loss of CAIV in sperm from CAII knockout animals, show an even lower response to HCO3 (-). These results suggest that CAII and CAIV are required for optimal fertilization. PMID- 26487716 TI - Defining the Apoptotic Trigger: THE INTERACTION OF CYTOCHROME c AND CARDIOLIPIN. AB - The interaction between cytochrome c and the anionic lipid cardiolipin has been proposed as a primary event in the apoptotic signaling cascade. Numerous studies that have examined the interaction of cytochrome c with cardiolipin embedded in a variety of model phospholipid membranes have suggested that partial unfolding of the protein is a precursor to the apoptotic response. However, these studies lacked site resolution and used model systems with negligible or a positive membrane curvature, which is distinct from the large negative curvature of the invaginations of the inner mitochondrial membrane where cytochrome c resides. We have used reverse micelle encapsulation to mimic the potential effects of confinement on the interaction of cytochrome c with cardiolipin. Encapsulation of oxidized horse cytochrome c in 1-decanoyl-rac-glycerol/lauryldimethylamine-N oxide/hexanol reverse micelles prepared in pentane yields NMR spectra essentially identical to the protein in free aqueous solution. The structure of encapsulated ferricytochrome c was determined to high precision (bb ~ 0.23 A) using NMR-based methods and is closely similar to the cryogenic crystal structure (bb ~ 1.2 A). Incorporation of cardiolipin into the reverse micelle surfactant shell causes localized chemical shift perturbations of the encapsulated protein, providing the first view of the cardiolipin/cytochrome c interaction interface at atomic resolution. Three distinct sites of interaction are detected: the so-called A- and L-sites, plus a previously undocumented interaction centered on residues Phe-36, Gly-37, Thr-58, Trp-59, and Lys-60. Importantly, in distinct contrast to earlier studies of this interaction, the protein is not significantly disturbed by the binding of cardiolipin in the context of the reverse micelle. PMID- 26487717 TI - N-helix and Cysteines Inter-regulate Human Mitochondrial VDAC-2 Function and Biochemistry. AB - Human voltage-dependent anion channel-2 (hVDAC-2) functions primarily as the crucial anti-apoptotic protein in the outer mitochondrial membrane, and additionally as a gated bidirectional metabolite transporter. The N-terminal helix (NTH), involved in voltage sensing, bears an additional 11-residue extension (NTE) only in hVDAC-2. In this study, we assign a unique role for the NTE as influencing the chaperone-independent refolding kinetics and overall thermodynamic stability of hVDAC-2. Our electrophysiology data shows that the N helix is crucial for channel activity, whereas NTE sensitizes this isoform to voltage gating. Additionally, hVDAC-2 possesses the highest cysteine content, possibly for regulating reactive oxygen species content. We identify interdependent contributions of the N-helix and cysteines to channel function, and the measured stability in micellar environments with differing physicochemical properties. The evolutionary demand for the NTE in the presence of cysteines clearly emerges from our biochemical and functional studies, providing insight into factors that functionally demarcate hVDAC-2 from the other VDACs. PMID- 26487718 TI - Humanized Affinity-matured Monoclonal Antibody 8H9 Has Potent Antitumor Activity and Binds to FG Loop of Tumor Antigen B7-H3. AB - B7-H3 (CD276) is both an inhibitory ligand for natural killer cells and T cells and a tumor antigen that is widely expressed among human solid tumors. Anti-B7-H3 mouse monoclonal antibody 8H9 has been successfully used for radioimmunotherapy for patients with B7-H3(+) tumors. We present the humanization, affinity maturation, and epitope mapping of 8H9 based on structure determination, modeling, and yeast display methods. The crystal structure of ch8H9 Fab fragment was solved to 2.5-A resolution and used as a template for humanization. By displaying the humanized 8H9 single chain Fv (scFv) on the surface of yeast, the affinity was matured by sequential random mutagenesis and fluorescence-activated cell sorting. Six mutations (three in the complementarity-determining region and three in the framework regions) were identified and incorporated into an affinity matured humanized 8H9 construct (hu8H9-6m) and an affinity-matured chimeric 8H9 construct (ch8H9-6m). The hu8H9-6m scFv had a 160-fold improvement in affinity (0.9 nm KD) compared with parental hu8H9 scFv (144 nm KD). The IgG formats of ch8H9-6m and hu8H9-6m (nanomolar to subnanomolar KD) had 2-9-fold enhancements in affinity compared with their parental forms, potent in vitro antibody-dependent cell-mediated cytotoxicity (0.1-0.3 MUg/ml EC50), and high tumor uptake in mouse xenografts. Based on in silico docking studies and experimental validation, the molecular epitope of 8H9 was determined to be dependent on the FG loop of B7-H3, a region critical to its function in immunologic blockade and unique among anti B7-H3 antibodies published to date. PMID- 26487719 TI - Twist1 Is Essential for Tooth Morphogenesis and Odontoblast Differentiation. AB - Twist1 is a basic helix-loop-helix-containing transcription factor that is expressed in the dental mesenchyme during the early stages of tooth development. To better delineate its roles in tooth development, we generated Twist1 conditional knockout embryos (Twist2(Cre) (/+);Twist1(fl/fl)) by breeding Twist1 floxed mice (Twist1(fl/fl)) with Twist2-Cre recombinase knockin mice (Twist2(Cre) (/+)). The Twist2(Cre) (/+);Twist1(fl/fl) embryos formed smaller tooth germs and abnormal cusps during early tooth morphogenesis. Molecular and histological analyses showed that the developing molars of the Twist2(Cre) (/+);Twist1(fl/fl) embryos had reduced cell proliferation and expression of fibroblast growth factors 3, 4, 9, and 10 and FGF receptors 1 and 2 in the dental epithelium and mesenchyme. In addition, 3-week-old renal capsular transplants of embryonic day 18.5 Twist2(Cre) (/+);Twist1(fl/fl) molars showed malformed crowns and cusps with defective crown dentin and enamel. Immunohistochemical analyses revealed that the implanted mutant molars had defects in odontoblast differentiation and delayed ameloblast differentiation. Furthermore, in vitro ChIP assays demonstrated that Twist1 was able to bind to a specific region of the Fgf10 promoter. In conclusion, our findings suggest that Twist1 plays crucial roles in regulating tooth development and that it may exert its functions through the FGF signaling pathway. PMID- 26487720 TI - Steric Crowding of the Turn Region Alters the Tertiary Fold of Amyloid-beta18-35 and Makes It Soluble. AB - Abeta self-assembles into parallel cross-beta fibrillar aggregates, which is associated with Alzheimer's disease pathology. A central hairpin turn around residues 23-29 is a defining characteristic of Abeta in its aggregated state. Major biophysical properties of Abeta, including this turn, remain unaltered in the central fragment Abeta18-35. Here, we synthesize a single deletion mutant, DeltaG25, with the aim of sterically hindering the hairpin turn in Abeta18-35. We find that the solubility of the peptide goes up by more than 20-fold. Although some oligomeric structures do form, solution state NMR spectroscopy shows that they have mostly random coil conformations. Fibrils ultimately form at a much higher concentration but have widths approximately twice that of Abeta18-35, suggesting an opening of the hairpin bend. Surprisingly, two-dimensional solid state NMR shows that the contact between Phe(19) and Leu(34) residues, observed in full-length Abeta and Abeta18-35, is still intact in these fibrils. This is possible if the monomers in the fibril are arranged in an antiparallel beta-sheet conformation. Indeed, IR measurements, supported by tyrosine cross-linking experiments, provide a characteristic signature of the antiparallel beta-sheet. We conclude that the self-assembly of Abeta is critically dependent on the hairpin turn and on the contact between the Phe(19) and Leu(34) regions, making them potentially sensitive targets for Alzheimer's therapeutics. Our results show the importance of specific conformations in an aggregation process thought to be primarily driven by nonspecific hydrophobic interactions. PMID- 26487721 TI - The Cysteine-rich Domain of the DHHC3 Palmitoyltransferase Is Palmitoylated and Contains Tightly Bound Zinc. AB - DHHC palmitoyltransferases catalyze the addition of the fatty acid palmitate to proteins on the cytoplasmic leaflet of cell membranes. There are 23 members of the highly diverse mammalian DHHC protein family, all of which contain a conserved catalytic domain called the cysteine-rich domain (CRD). DHHC proteins transfer palmitate via a two-step catalytic mechanism in which the enzyme first modifies itself with palmitate in a process termed autoacylation. The enzyme then transfers palmitate from itself onto substrate proteins. The number and location of palmitoylated cysteines in the autoacylated intermediate is unknown. In this study, we present evidence using mass spectrometry that DHHC3 is palmitoylated at the cysteine in the DHHC motif. Mutation of highly conserved CRD cysteines outside the DHHC motif resulted in activity deficits and a structural perturbation revealed by limited proteolysis. Treatment of DHHC3 with chelating agents in vitro replicated both the specific structural perturbations and activity deficits observed in conserved cysteine mutants, suggesting metal ion binding in the CRD. Using the fluorescent indicator mag-fura-2, the metal released from DHHC3 was identified as zinc. The stoichiometry of zinc binding was measured as 2 mol of zinc/mol of DHHC3 protein. Taken together, our data demonstrate that coordination of zinc ions by cysteine residues within the CRD is required for the structural integrity of DHHC proteins. PMID- 26487722 TI - A Nucleolar PUF RNA-binding Protein with Specificity for a Unique RNA Sequence. AB - PUF proteins are a conserved group of sequence specific RNA-binding proteins that bind to RNA in a modular fashion. The RNA-binding domain of PUF proteins typically consists of eight clustered Puf repeats. Plant genomes code for large families of PUF proteins that show significant variability in their predicted Puf repeat number, organization, and amino acid sequence. Here we sought to determine whether the observed variability in the RNA-binding domains of four plant PUFs results in a preference for nonclassical PUF RNA target sequences. We report the identification of a novel RNA binding sequence for a nucleolar Arabidopsis PUF protein that contains an atypical RNA-binding domain. The Arabidopsis PUM23 (APUM23) binding sequence was 10 nucleotides in length, contained a centrally located UUGA core element, and had a preferred cytosine at nucleotide position 8. These RNA sequence characteristics differ from those of other PUF proteins, because all natural PUFs studied to date bind to RNAs that contain a conserved UGU sequence at their 5' end and lack specificity for cytosine. Gel mobility shift assays validated the identity of the APUM23 binding sequence and supported the location of 3 of the 10 predicted Puf repeats in APUM23, including the cytosine-binding repeat. The preferred 10-nucleotide sequence bound by APUM23 is present within the 18S rRNA sequence, supporting the known role of APUM23 in 18S rRNA maturation. This work also reveals that APUM23, an ortholog of yeast Nop9, could provide an advanced structural backbone for Puf repeat engineering and target-specific regulation of cellular RNAs. PMID- 26487723 TI - Human Telomerase Reverse Transcriptase (hTERT) Transcription Requires Sp1/Sp3 Binding to the Promoter and a Permissive Chromatin Environment. AB - The transcription of human telomerase gene hTERT is regulated by transcription factors (TFs), including Sp1 family proteins, and its chromatin environment. To understand its regulation in a relevant chromatin context, we employed bacterial artificial chromosome reporters containing 160 kb of human genomic sequence containing the hTERT gene. Upon chromosomal integration, the bacterial artificial chromosomes recapitulated endogenous hTERT expression, contrary to transient reporters. Sp1/Sp3 expression did not correlate with hTERT promoter activity, and these TFs bound to the hTERT promoters in both telomerase-positive and telomerase negative cells. Mutation of the proximal GC-box resulted in a dramatic decrease of hTERT promoter activity, and mutations of all five GC-boxes eliminated its transcriptional activity. Neither mutations of GC-boxes nor knockdown of endogenous Sp1 impacted promoter binding by other TFs, including E-box-binding proteins, and histone acetylation and trimethylation of histone H3K9 at the hTERT promoter in telomerase-positive and -negative cells. The result indicated that promoter binding by Sp1/Sp3 was essential, but not a limiting step, for hTERT transcription. hTERT transcription required a permissive chromatin environment. Importantly, our data also revealed different functions of GC-boxes and E-boxes in hTERT regulation; although GC-boxes were essential for promoter activity, factors bound to the E-boxes functioned to de-repress hTERT promoter. PMID- 26487725 TI - Finding the Therapeutic Sweet Spot: Using Naturally Occurring Human Variants to Inform Drug Design. PMID- 26487724 TI - Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45alphaa Stress Sensor Gene. AB - Histone lysine methylation is important in early zebrafish development; however, the role of histone arginine methylation in this process remains unclear. H3R2me2a, generated by protein arginine methyltransferase 6 (Prmt6), is a repressive mark. To explore the role of Prmt6 and H3R2me2a during zebrafish embryogenesis, we identified the maternal characteristic of prmt6 and designed two prmt6-specific morpholino-oligos (MOs) to study its importance in early development, application of which led to early epiboly defects and significantly reduced the level of H3R2me2a marks. prmt6 mRNA could rescue the epiboly defects and the H3R2me2a reduction in the prmt6 morphants. Functionally, microarray data demonstrated that growth arrest and DNA damage-inducible, alpha, a (gadd45alphaa) was a significantly up-regulated gene in MO-treated embryos, the activity of which was linked to the activation of the p38/JNK pathway and apoptosis. Importantly, gadd45alphaa MO and p38/JNK inhibitors could partially rescue the defect of prmt6 morphants, the downstream targets of Prmt6, and the apoptosis ratios of the prmt6 morphants. Moreover, the results of ChIP quantitative real time PCR and luciferase reporter assay indicated that gadd45alphaa is a repressive target of Prmt6. Taken together, these results suggest that maternal Prmt6 is essential to early zebrafish development by directly repressing gadd45alphaa. PMID- 26487727 TI - Back to the future: Patient experience and the link to quality, safety, and financial performance. AB - Improving patient experience has emerged as an important healthcare policy priority across Canada. Tools and systems for monitoring patient experience metrics are becoming increasingly refined and standardized, and the trend toward greater accountability for improvements that are sustainable and affordable is well underway. For many healthcare professionals, this represents a renewed focus on core patient needs and priorities, following decades during which structural and technological changes have dominated healthcare agendas. Improving patient experience in our contemporary healthcare environment presents major challenges and opportunities-for Canadian health leaders. The experience of Studer Group partner organizations in Canada is relevant and instructive in this context. These organizations have adopted a model known as Evidence-Based Leadership (EBL) that enables and supports the alignment of all activities and behaviours toward specific organizational goals, including measurable patient experience improvements. This article reviews case studies of organizations that have adopted EBL. These organizations are demonstrating rapid progress in patient experience indicators while simultaneously making gains in critical areas such as clinical outcomes, safety, physician and staff engagement, and financial performance. Emerging evidence concerning the factors and processes that underlie these improvements is also discussed. PMID- 26487726 TI - Aryl Hydrocarbon Receptor Repressor Methylation: A Link Between Smoking and Atherosclerosis. PMID- 26487728 TI - Three perspectives on partnering to close the care gap. AB - Given their frontline relationship with patients, community pharmacists fill a vital role in our healthcare system. This article offers three perspectives on how a team-based approach, which integrates the community pharmacist, can enhance patient care and reduce system costs. It is the success of these partnership models which have helped drive system-level change. It offers reflections by Dr. Ross T. Tsuyuki, among Canada's leading researchers on the subject, and presents some findings over his 20-year partnership with Merck in Canada. Dr. Tsuyuki's peer-reviewed studies have been largely centred in Alberta, one province in which the scope of practice for pharmacists has been expanded. PMID- 26487729 TI - Just leg pain? Think again: What health leaders must know about peripheral arterial disease. AB - Approximately 800,000 Canadians have Peripheral Arterial Disease (PAD). Peripheral arterial disease is also a leading cause of limb amputation. Yet public and clinical awareness of PAD is very limited. This article discusses the "Just Leg Pain? Think Again" awareness campaign the Canadian Association of Wound Care has launched in response. This article also summarizes PAD risk factors, screening, linkage with diabetes, treatment and care interventions, PAD care innovations, and the need for policy leadership on this issue. PMID- 26487730 TI - Retour vers le futur: l'experience des patients et le lien avec la qualite, la securite et le rendement financier. AB - Au Canada, l'amelioration de l'experience des patients est devenue une priorite des politiques de sante. Le perfectionnement et la normalisation des outils et systemes pour surveiller les mesures de l'experience des patients augmentent, tandis que la tendance vers une plus grande reddition de compte sur des ameliorations durables et abordables se confirme. Pour de nombreux professionnels de la sante, ce phenomene fait foi d'un interet renouvele pour les besoins et priorites fondamentaux des patients, apres des decennies ou les changements structurels et technologiques ont domine les programmes de sante. Pour les leaders en sante canadiens, l'amelioration de l'experience des patients comporte actuellement de grands defis et de belles possibilites. A cet egard, l'experience des organisations partenaires du groupe Studer au Canada est a la fois pertinente et instructive. Ces organisations ont adopte un modele, du nom de Evidence-Based Leadership (EBL, ou leadership fonde sur des donnees probantes), qui favorise et soutient l'harmonisation de l'ensemble des activites et des comportements, conformement a des objectifs organisationnels precis, y compris des ameliorations mesurables de l'experience des patients. Le present article expose des etudes de cas d'organisations qui ont adopte l'EBL. Ces organisations ont realise des progres rapides en matiere d'indicateurs de l'experience des patients, ainsi que dans des secteurs essentiels comme les resultats cliniques, la securite et le rendement financier. Les donnees emergentes sur les facteurs et processus qui sous-tendent ces ameliorations sont egalement abordees. PMID- 26487731 TI - Message du redacteur en chef. PMID- 26487732 TI - L'emergence de la therapeutique de precision: de nouveaux defis et de nouvelles possibilites pour les leaders en sante du Canada. AB - A l'ere de la medecine personnalisee et de la medecine de precision, l'approche envers les soins est en rapide mutation. Les cliniciens exigent de plus en plus d'information genetique et moleculaire et les patients s'attendent a la fournir pour la prevention, le depistage, le diagnostic, le pronostic, la promotion de la sante et le traitement d'un nombre croissant de maladies. Les leaders en sante canadiens doivent comprendre les changements necessaires lies a ces technologies perturbantes et ouvrir la voie. Le present article s'attarde sur la therapeutique de precision, mais contient egalement de l'information generale sur les concepts et la terminologie lies a la medecine personnalisee et a la medecine de precision. Il explore egalement le leadership en sante canadien et les problemes lies au systeme qui peuvent nuire a leur mise en oeuvre. L'article vise a inspirer, informer et mobiliser les leaders en sante canadiens a amorcer un dialogue sur les transformations necessaires pour preparer le systeme de sante a profiter des bienfaits de la therapeutique de precision. PMID- 26487733 TI - Si vous pensez que c'est juste un mal de jambe... detrompez-vous: ce que les leaders en sante doivent savoir sur la maladie arterielle peripherique. AB - Environ 800 000 Canadiens ont une maladie arterielle peripherique (MAP), une cause majeure d'amputation. Pourtant, le public et les cliniciens connaissent tres peu cette maladie. Le present article traite de la campagne de sensibilisation Si vous pensez que c'est juste un mal de jambe... detrompez-vous que l'Association canadienne du soin des plaies a lancee pour contrer cette tendance. Il porte egalement sur les facteurs de risque et le depistage de la MAP, son lien avec le diabete, son traitement et ses soins, ses innovations en matiere de soins de la MAP et la necessite de faire preuve de leadership sur le plan des politiques. PMID- 26487734 TI - The emergence of precision therapeutics: New challenges and opportunities for Canada's health leaders. AB - In the era of personalized and precision medicine, the approach to healthcare is quickly changing. Genetic and other molecular information are being increasingly demanded by clinicians and expected by patients for prevention, screening, diagnosis, prognosis, health promotion, and treatment of an increasing number of conditions. As a result of these developments, Canadian health leaders must understand and be prepared to lead the necessary changes associated with these disruptive technologies. This article focuses on precision therapeutics but also provides background on the concepts and terminology related to personalized and precision medicine and explores Canadian health leadership and system issues that may pose barriers to their implementation. The article is intended to inspire, educate, and mobilize Canadian health leaders to initiate dialogue around the transformative changes necessary to ready the healthcare system to realize the benefits of precision therapeutics. PMID- 26487735 TI - IgG4-related double duct sign mimicking pancreatic head cancer. PMID- 26487736 TI - RNA structure framework: automated transcriptome-wide reconstruction of RNA secondary structures from high-throughput structure probing data. AB - SUMMARY: The rapidly increasing number of discovered non-coding RNAs makes the understanding of their structure a key feature toward a deeper comprehension of gene expression regulation. Various enzymatic- and chemically- based approaches have been recently developed to allow whole-genome studies of RNA secondary structures. Several methods have been recently presented that allow high throughput RNA structure probing (CIRS-seq, Structure-seq, SHAPE-seq, PARS, etc.) and unbiased structural inference of residues within RNAs in their native conformation. We here present an analysis toolkit, named RNA Structure Framework (RSF), which allows fast and fully-automated analysis of high-throughput structure probing data, from data pre-processing to whole-transcriptome RNA structure inference. AVAILABILITY AND IMPLEMENTATION: RSF is written in Perl and is freely available under the GPLv3 license from http://rsf.hugef-research.org. CONTACT: salvatore.oliviero@hugef-torino.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26487737 TI - 'Drinking with respect': Drinking constructions of men who live in a Cape Winelands farm community in South Africa. AB - This article aims to provide a community-specific understanding of a subgroup of South African men who exhibit particularly high rates of hazardous alcohol consumption. Adopting a social constructionist framework, we interviewed 13 Cape Winelands men who lived on farms to explore their drinking constructions. We present three themes that shed light on problematic drinking in this group: (1) the notion of weekend binge-drinking as 'respectable' drinking, (2) drinking as shared activity that fulfils various psycho-social needs and (3) a sense of powerlessness to affect their own or their children's alcohol consumption. These findings are viewed against a specific socio-historical backdrop. PMID- 26487738 TI - Older Adults in Clinical Research and Drug Development: Closing the Geriatric Gap. PMID- 26487739 TI - Modest Associations Between Electronic Health Record Use and Acute Myocardial Infarction Quality of Care and Outcomes: Results From the National Cardiovascular Data Registry. AB - BACKGROUND: In 2009, national legislation promoted wide-spread adoption of electronic health records (EHRs) across US hospitals; however, the association of EHR use with quality of care and outcomes after acute myocardial infarction (AMI) remains unclear. METHODS AND RESULTS: Data on EHR use were collected from the American Hospital Association Annual Surveys (2007-2010) and data on AMI care and outcomes from the National Cardiovascular Data Registry Acute Coronary Treatment and Interventions Outcomes Network Registry-Get With The Guidelines. Comparisons were made between patients treated at hospitals with fully implemented EHR (n=43 527), partially implemented EHR (n=72 029), and no EHR (n=9270). Overall EHR use increased from 82.1% (183/223) hospitals in 2007 to 99.3% (275/277) hospitals in 2010. Patients treated at hospitals with fully implemented EHRs had fewer heparin overdosing errors (45.7% versus 72.8%; P<0.01) and a higher likelihood of guideline-recommended care (adjusted odds ratio, 1.40 [confidence interval, 1.07 1.84]) compared with patients treated at hospitals with no EHR. In non-ST-segment elevation AMI, fully implemented EHR use was associated with lower risk of major bleeding (adjusted odds ratio, 0.78 [confidence interval, 0.67-0.91]) and mortality (adjusted odds ratio, 0.82 [confidence interval, 0.69-0.97]) compared with no EHR. In ST-segment-elevation MI, outcomes did not significantly differ by EHR status. CONCLUSIONS: EHR use has risen to high levels among hospitals in the National Cardiovascular Data Registry. EHR use was associated with less frequent heparin overdosing and modestly greater adherence to acute MI guideline recommended therapies. In non-ST-segment-elevation MI, slightly lower adjusted risk of major bleeding and mortality were seen in hospitals implemented with full EHRs; however, in ST-segment-elevation MI, differences in outcomes were not seen. PMID- 26487740 TI - Bitter Melon (Momordica charantia) Extract Inhibits Tumorigenicity and Overcomes Cisplatin-Resistance in Ovarian Cancer Cells Through Targeting AMPK Signaling Cascade. AB - Objective Acquired chemoresistance is a major obstacle in the clinical management of ovarian cancer. Therefore, searching for alternative therapeutic modalities is urgently needed. Bitter melon (Momordica charantia) is a traditional dietary fruit, but its extract also shows potential medicinal values in human diabetes and cancers. Here, we sought to investigate the extract of bitter melon (BME) in antitumorigenic and cisplatin-induced cytotoxicity in ovarian cancer cells. METHODS: Three varieties of bitter melon were used to prepare the BME. Ovarian cancer cell lines, human immortalized epithelial ovarian cells (HOSEs), and nude mice were used to evaluate the cell cytotoxicity, cisplatin resistance, and tumor inhibitory effect of BME. The molecular mechanism of BME was examined by Western blotting. RESULTS: Cotreatment with BME and cisplatin markedly attenuated tumor growth in vitro and in vivo in a mouse xenograft model, whereas there was no observable toxicity in HOSEs or in nude mice in vivo Interestingly, the antitumorigenic effects of BME varied with different varieties of bitter melon, suggesting that the amount of antitumorigenic substances may vary. Studies of the molecular mechanism demonstrated that BME activates AMP-activated protein kinase (AMPK) in an AMP-independent but CaMKK (Ca(2+)/calmodulin-dependent protein kinase)-dependent manner, exerting anticancer effects through activation of AMPK and suppression of the mTOR/p70S6K and/or the AKT/ERK/FOXM1 (Forkhead Box M1) signaling cascade. CONCLUSION: BME functions as a natural AMPK activator in the inhibition of ovarian cancer cell growth and might be useful as a supplement to improve the efficacy of cisplatin-based chemotherapy in ovarian cancer. PMID- 26487742 TI - Semiautomated Identification of European Corn Borer (Lepidoptera: Crambidae). AB - The European corn borer Ostrinia nubilalis (Hubner, 1796) is a serious and widely studied pest of corn. The most common method of its control is by means of insecticides. However, biological control is becoming more and more popular. The hymenopteran parasitoid Trichogramma sp. is the most promising and effective one among the biological agents and is now widely used in North America and Europe. Its application should occur at the time when the European corn borer is at the beginning of the eggs laying period. However, the discrimination between the European corn borer and some other species occurring in agricultural landscapes at the same time can be difficult, especially for farmers which are neither familiar with the morphological nor molecular methods of identification. The scope of this study is to test the ability of the automatic computer equipment to determine the European corn borer and to separate it from the most common Lepidoptera pests found in corn plantations. The experiment showed that the 97.0% of the 247 specimens belonging to four common pestlepidopterans were correctly classified by the use of a personal computer, desktop scanner, and the special software. The obtained results showed that this technique based on wing measurements can be an effective tool for monitoring of the European corn borer. In the future, this method can be used by farmers to identify this pest and apply control measures at optimal time. PMID- 26487743 TI - Toxicity of Six Insecticides on Codling Moth (Lepidoptera: Tortricidae) and Effect on Expression of Detoxification Genes. AB - The codling moth, Cydia pomonella (L.), is a key worldwide fruit pest that has evolved high levels of resistance to almost all classes of conventional insecticides. Neonicotinoids, a new reduced-risk biorational insecticide class, have remained an effective control approach. In this study, the toxicity and sublethal effect of conventional and reduced-risk biorational insecticides on transcripts abundance of three detoxification genes in codling moth were determined. Bioassays on a codling moth laboratory strain suggested that acetamiprid had the highest oral toxicity against the third-instar larvae compared with the other five pesticides. Results also indicated that acetamiprid exhibits long-term efficacy against codling moth even at 120 h post feeding. Real time quantitative polymerase chain reaction showed that the detoxification genes CYP9A61, CpGST1, and CpCE-1 were differentially induced or suppressed by deltamethrin, cypermethrin, methomyl, carbaryl, and imidacloprid, depending on the type of insecticides; in contrast, no significant difference in CYP9A61, CpGST1, and CpCE-1 expressions were observed after acetamiprid exposure, when compared with the control. These results suggest that the reduced-risk biorational insecticide acetamiprid is an effective insecticide with no induction of detoxification genes and can be integrated into the management of codling moth. PMID- 26487741 TI - Identifying Novel Gene Variants in Coronary Artery Disease and Shared Genes With Several Cardiovascular Risk Factors. AB - RATIONALE: Coronary artery disease (CAD) is a critical determinant of morbidity and mortality. Previous studies have identified several cardiovascular disease risk factors, which may partly arise from a shared genetic basis with CAD, and thus be useful for discovery of CAD genes. OBJECTIVE: We aimed to improve discovery of CAD genes and inform the pathogenic relationship between CAD and several cardiovascular disease risk factors using a shared polygenic signal informed statistical framework. METHODS AND RESULTS: Using genome-wide association studies summary statistics and shared polygenic pleiotropy-informed conditional and conjunctional false discovery rate methodology, we systematically investigated genetic overlap between CAD and 8 traits related to cardiovascular disease risk factors: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. We found significant enrichment of single-nucleotide polymorphisms associated with CAD as a function of their association with low-density lipoprotein, high density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. Applying the conditional false discovery rate method to the enriched phenotypes, we identified 67 novel loci associated with CAD (overall conditional false discovery rate <0.01). Furthermore, we identified 53 loci with significant effects in both CAD and at least 1 of low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, systolic blood pressure, and type 1 diabetes mellitus. CONCLUSIONS: The observed polygenic overlap between CAD and cardiometabolic risk factors indicates a pathogenic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to CAD. PMID- 26487744 TI - High Spatial Genetic Structure and Genetic Diversity in Chinese Populations of Sitobion miscanthi (Hemiptera: Aphididae). AB - The wheat aphid, Sitobion miscanthi Takahashi, a serious wheat pest, was previously considered to be highly migratory and anholocyclic in China. We recorded 69 alleles and 346 multilocus genotypes among 708 aphid individuals from 12 populations in China using 5 microsatellite loci. This genotypic diversity indicates that at least some holocyclic lineages exist. Bayesian clustering analysis revealed that there are two differentiated genetic groups of S. misanthi, one northern and one southern, in China. Principal coordinates analysis of population genetic distance, pairwise F(ST)'s, and network analysis of individual minimum spanning distance also supported the division. Low levels of migration were detected between the northern and southern sampling sites, but the high genetic differentiation does not support the hypothesis S. miscanthi overwinters in the south and migrates to the north in the spring annually. PMID- 26487745 TI - Molecular Markers Detect Cryptic Predation on Coffee Berry Borer (Coleoptera: Curculionidae) by Silvanid and Laemophloeid Flat Bark Beetles (Coleoptera: Silvanidae, Laemophloeidae) in Coffee Beans. AB - The coffee berry borer, Hypothenemus hampei (Ferrari) (Coleoptera: Curculionidae), is a serious pest of coffee worldwide. It was first detected in Hawai'i in 2010. Two predatory beetles, Cathartus quadricollis (Coleoptera: Silvanidae) and Leptophloeus sp. (Coleoptera: Laemophloeidae), have been observed in H. hampei-infested coffee. Under laboratory conditions, colony-reared C. quadricollis and Leptophloeus sp. prey upon all life stages of H. hampei. However, the H. hampei life cycle occurs almost exclusively within a coffee bean obscured from direct observation. Thus, it is unknown if C. quadricollis and Leptophloeus sp. consume H. hampei as prey in the wild. To demonstrate predation of H. hampei by C. quadricollis and Leptophloeus sp., a molecular assay was developed utilizing species-specific primers targeting short regions of the mitochondrial COI gene to determine species presence. Using these primers, wild C. quadricollis and Leptophloeus sp. were collected and screened for the presence of H. hampei DNA using PCR. Analysis of collections from five coffee farms revealed predation of C. quadricollis and Leptophloeus sp. on H. hampei. Further laboratory testing showed that H. hampei DNA could be detected in predators for as long as 48 h after feeding, indicating the farm-caught predators had preyed on H. hampei within 2 d of sampling. This study demonstrates the utility of molecular markers for the study of the ecology of predators and prey with cryptic behavior, and suggests C. quadricollis and Leptophloeus sp. might be useful biocontrol agents against H. hampei. PMID- 26487746 TI - Comparison of the Feasibility and Safety of Nasotracheal Suctioning With Curved Edge Catheter Versus Conventional Suction Catheter in Critically Ill Subjects: A Prospective Randomized Crossover Trial. AB - BACKGROUND: Nasotracheal suctioning (NTS) is accomplished by inserting a suction catheter into the trachea through the nasopharynx. It is a useful procedure in critically ill patients whose ability to cough and mobilize secretions is impaired. Iotat was assumed that using a suction catheter with an angular tip would facilitate entry into the trachea. The primary outcome was the success rate and the ease of insertion by using a curved edge catheter (Tiemann type) compared with a conventional suction catheter. The secondary outcome was the monitoring of subject's vital signs during the intervention. METHODS: Non-intubated subjects hospitalized in 2 adult ICUs underwent 2 consecutive NTSs each, using either a 14 French curved edge catheter or a 14 French conventional suction catheter, randomly. RESULTS: Twenty subjects with a mean age of 75.5 y were enrolled for a time period of 5 months. The tracheal access success rate was 19/52 (successful/unsuccessful attempts) using a curved edge catheter (36.5%, 95% CI 23.6-51.0%) compared with 12/130 (9.2%, 95% CI 4.8-15.5%) using a conventional suction catheter. The insertion was 5.6 times more likely to be achieved by using a curved edge catheter (odds ratio 5.66, 95% CI 2.49-12.84, P < .001). The number of attempts required to succeed in the insertion was significantly lower when using a curved edge catheter than when using a conventional suction catheter (for nasopharynx, median [range] of 1 [1] versus 2.5 [8], P = .001; for trachea, median [range] of 2 [9] versus 9 [9], P = .002). The time required for successful insertion into the nasopharynx and trachea was significantly shorter when using a curved edge catheter than when using a conventional suction catheter (for nasopharynx, median [range] of 3 [11] s versus 5.3 [18] s, P = .038; for trachea, median [range] of 6 [27] s versus 20 [25] s, P = .002). The traumatic rate (percentage of catheters with blood present on the tip) was exactly the same for both catheters (30%). CONCLUSIONS: It is more likely that tracheal access will be achieved using a curved edge catheter. A shorter process time and fewer attempts are required for successful NTS using a curved edge catheter, and it seems to be an equally safe procedure. (ClinicalTrials.gov registration NCT02261428.). PMID- 26487747 TI - Evidence for Autonomic Function and Its Influencing Factors in Subjects With COPD: A Systematic Review. AB - Cardiovascular autonomic neuropathy is one of the factors implicated in the high morbidity and mortality rate in patients with COPD. Thus, several studies and nonsystematic reviews have increasingly reported autonomic function impairment in these subjects. For a better understanding, this systematic review was performed to evaluate not only the evidence for autonomic function impairment, but also factors influencing it. The results of the studies reviewed showed a strong level of evidence to support the impairment of heart rate variability in the time domain. A similar evidence level was also found to support impairment in baroreceptor sensitivity and muscle sympathetic nerve activity. Furthermore, this review identified physical activity level, muscle function, and circadian rhythm as the major influencing factors (strong evidence) of autonomic function in subjects with COPD. However, no definite conclusion could be reached for factors such as dyspnea, anxiety, body composition, pulmonary function, age, breathing frequency, ventilatory effort, quality of life, and disease severity due to limited, conflicting, or lack of existing evidence. The results of this review highlight relevant clinical messages for clinicians and other health-care providers regarding the role autonomic function can play as an important physiological marker for prognostication and stratification. Hence, autonomic function outcomes should be identified and considered during management of patients with COPD. Moreover, this review can serve as basis for future research aimed at assessing the interventions for autonomic function abnormalities in these patients. PMID- 26487748 TI - Using the Lower Limit of Normal Instead of the Conventional Cutoff Values to Define Predictors of Pulmonary Function Impairment in Subjects With Chronic Heart Failure. AB - BACKGROUND: Using the newer lower limit of normal criterion instead of the conventional cutoff values to define pulmonary function abnormalities may result in different predictors of pulmonary function impairment in patients with heart failure. Therefore, we assessed predictors of pulmonary function impairment in subjects with chronic heart failure according to the lower limit of normal in comparison with conventional cutoff values. METHODS: In this prospective cross sectional study, 164 chronic heart failure subjects (age 68 +/- 10 y, 78% men, 88% New York Heart Association class I-II) with left ventricular ejection fraction <40% underwent pulmonary function tests. Predictors of pulmonary function impairment were assessed using the lower limit of normal and conventional cutoff values (ie, 80% predicted value and the fixed ratio of FEV1/FVC <0.7). RESULTS: The lower limit of normal criterion identified an extra independent predictor of diffusion impairment compared with the 80% predicted value; in addition to body mass index, pack-years, and alveolar volume, female sex also turned out to be an independent predictor. A smoking history of >=10 pack-years was a significant predictor of diffusion impairment and airway obstruction using the lower limit of normal criterion but not using the conventional cutoff values. However, lowering the cutoff points of conventional criteria to match the more stringent lower limit of normal and thus avoid overdiagnosis of diffusion impairment and airway obstruction in the elderly produced similar results as the lower limit of normal. CONCLUSIONS: The lower limit of normal identifies more predictors of diffusion impairment and airway obstruction compared with conventional cutoff values in subjects with chronic heart failure with left ventricular systolic dysfunction. However, lowering the conventional cutoff points yielded similar results as the lower limit of normal. (ClinicalTrials.gov registration NCT01429376.). PMID- 26487749 TI - Optimizing Mask Ventilation: Literature Review and Development of a Conceptual Framework. AB - Mask ventilation is lifesaving, especially in cases of difficult intubation. Many publications have offered distinct techniques for optimizing mask ventilation. This article reviews currently available difficult mask ventilation literature and theory. We divide difficult mask ventilation into 3 broad categories based on etiology: inadequate mask seal, increased airway resistance, and decreased respiratory compliance. Published strategies for overcoming difficulty are presented and organized by etiology. PMID- 26487750 TI - ITERATIVE SCATTER CORRECTION FOR GRID-LESS BEDSIDE CHEST RADIOGRAPHY: PERFORMANCE FOR A CHEST PHANTOM. AB - The aim of this work was to experimentally compare the contrast improvement factors (CIFs) of a newly developed software-based scatter correction to the CIFs achieved by an antiscatter grid. To this end, three aluminium discs were placed in the lung, the retrocardial and the abdominal areas of a thorax phantom, and digital radiographs of the phantom were acquired both with and without a stationary grid. The contrast generated by the discs was measured in both images, and the CIFs achieved by grid usage were determined for each disc. Additionally, the non-grid images were processed with a scatter correction software. The contrasts generated by the discs were determined in the scatter-corrected images, and the corresponding CIFs were calculated. The CIFs obtained with the grid and with the software were in good agreement. In conclusion, the experiment demonstrates quantitatively that software-based scatter correction allows restoring the image contrast of a non-grid image in a manner comparable with an antiscatter grid. PMID- 26487751 TI - Interdisciplinary Strategies for Treating Oral Aversions in Children. AB - Oral aversion is a frequent diagnosis in the pediatric population. For a minority of children, feeding challenges rise to the level of requiring clinical evaluation and intervention. Determining the best evaluation and treatment plan can be challenging, but there is a consensus that treatment for children with a severe oral aversion involves an interdisciplinary approach. Within the team model, multiple strategies have demonstrated effectiveness, including sensorimotor skill building, behavioral modification, hunger provocation, and sensory integration therapy. This tutorial reviews the diagnostic and treatment process for a child with oral aversion, including identification of an underlying etiology, the medical and behavioral evaluation, and formulation of a treatment plan. PMID- 26487752 TI - JPEN Journal Club 16. Trial Registries. PMID- 26487753 TI - Corrigendum. AB - Choban P, Dickerson R, Malone A, et al. A.S.P.E.N. clinical guidelines: nutrition support of hospitalized adult patients with obesity. JPEN J Parenter Enteral Nutr. 2013;37:714-744. (Original DOI: 10.1177/0148607113499374). PMID- 26487754 TI - Highly diverse MLVA-ompA genotypes of rectal Chlamydia trachomatis among men who have sex with men in Brighton, UK and evidence for an HIV-related sexual network. AB - OBJECTIVES: In this prospective study, we aimed to determine the distribution of genotypes by multilocus variable number tandem repeat (VNTR) analysis plus analysis of the ompA gene (MLVA-ompA) of rectal Chlamydia trachomatis among men who have sex with men (MSM) attending Brighton Genitourinary Medicine (GUM) Clinic and to examine any correlations with clinical variables, including HIV status, and to isolate rectal C. trachomatis cultures maximising the possibility of obtaining complete genotyping data. METHODS: Samples were assigned genotypes by PCR and sequencing of the markers of the MLVA-ompA genotyping system. Rectal C. trachomatis was isolated in cell culture using McCoy cells. Data regarding demographics, HIV status, rectal symptoms and history of sexually transmitted infections, including C. trachomatis, were collected. RESULTS: 1809 MSM attending the clinic between October 2011 and January 2013 took part in the study, 112 (6.2%) of whom had rectal samples that tested positive for C. trachomatis. 85/112 (75.9%) C. trachomatis-positive rectal samples were assigned 66 different genotypes. Two distinct genotype subclusters were identified: subcluster 1 consisted of more HIV-negative men than subcluster 2 (p=0.025), and the MLVA-ompA genotypes in these subclusters reflected this. Isolates were successfully cultured from 37 of the 112 specimens, from which 27 otherwise unobtainable (from direct PCR) MLVA-ompA genotypes were gained. CONCLUSIONS: The most prevalent genotypes were G, E and D representing some overlap with the heterosexual distribution in UK. Subcluster 1 consisted of more 'heterosexual genotypes' and significantly more HIV-negative men than subcluster 2, associated with 'MSM genotypes'. There was a higher diversity of C. trachomatis strains among MSM in Brighton than observed in other cities. PMID- 26487755 TI - 9p21.3 Coronary Artery Disease Risk Variants Disrupt TEAD Transcription Factor Dependent Transforming Growth Factor beta Regulation of p16 Expression in Human Aortic Smooth Muscle Cells. AB - BACKGROUND: The mechanism whereby the 9p21.3 locus confers risk for coronary artery disease remains incompletely understood. Risk alleles are associated with reduced expression of the cell cycle suppressor genes CDKN2A (p16 and p14) and CDKN2B (p15) and increased vascular smooth muscle cell proliferation. We asked whether risk alleles disrupt transcription factor binding to account for this effect. METHODS AND RESULTS: A bioinformatic screen was used to predict which of 59 single nucleotide polymorphisms at the 9p21.3 locus disrupt (or create) transcription factor binding sites. Electrophoretic mobility shift and luciferase reporter assays examined the binding and functionality of the predicted regulatory sequences. Primary human aortic smooth muscle cells (HAoSMCs) were genotyped for 9p21.3, and HAoSMCs homozygous for the risk allele showed reduced p15 and p16 levels and increased proliferation. rs10811656 and rs4977757 disrupted functional TEF-1 TEC1 AbaA domain (TEAD) transcription factor binding sites. TEAD3 and TEAD4 overexpression induced p16 in HAoSMCs homozygous for the nonrisk allele, but not for the risk allele. Transforming growth factor beta, known to activate p16 and also to interact with TEAD factors, failed to induce p16 or to inhibit proliferation of HAoSMCs homozygous for the risk allele. Knockdown of TEAD3 blocked transforming growth factor beta-induced p16 mRNA and protein expression, and dual knockdown of TEAD3 and TEAD4 markedly reduced p16 expression in heterozygous HAoSMCs. CONCLUSIONS: Here, we identify a novel mechanism whereby sequences at the 9p21.3 risk locus disrupt TEAD factor binding and TEAD3-dependent transforming growth factor beta induction of p16 in HAoSMCs. This mechanism accounts, in part, for the 9p21.3 coronary artery disease risk. PMID- 26487757 TI - Cardiac Diseases Following Childhood Cancer Treatment: Cohort Study. AB - BACKGROUND: Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD. METHODS AND RESULTS: The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade >=3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5-12.7) and 7.4% (95% CI, 6.2-8.9) when only the CDs of grade >=3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD<0.1Gy, the risk was multiplied by 18.4 (95% CI, 7.1-48.0) in patients who had received anthracycline and no radiotherapy or a HRD <0.1Gy, by 60.4 (95% CI, 22.4 163.0) in those who had received no anthracycline and an HRD>=30Gy, and 61.5 (95% CI, 19.6-192.8) in those who had received both anthracycline and an HRD>=30Gy. CONCLUSIONS: Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it. PMID- 26487758 TI - Effect Size Does Matter: The Long Road to Mechanistic Insight From Genome-Wide Association. PMID- 26487756 TI - Estrogen Metabolite 16alpha-Hydroxyestrone Exacerbates Bone Morphogenetic Protein Receptor Type II-Associated Pulmonary Arterial Hypertension Through MicroRNA-29 Mediated Modulation of Cellular Metabolism. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a proliferative disease of the pulmonary vasculature that preferentially affects women. Estrogens such as the metabolite 16alpha-hydroxyestrone (16alphaOHE) may contribute to PAH pathogenesis, and alterations in cellular energy metabolism associate with PAH. We hypothesized that 16alphaOHE promotes heritable PAH (HPAH) via microRNA-29 (miR-29) family upregulation and that antagonism of miR-29 would attenuate pulmonary hypertension in transgenic mouse models of Bmpr2 mutation. METHODS AND RESULTS: MicroRNA array profiling of human lung tissue found elevation of microRNAs associated with energy metabolism, including the miR-29 family, among HPAH patients. miR-29 expression was 2-fold higher in Bmpr2 mutant mice lungs at baseline compared with controls and 4 to 8-fold higher in Bmpr2 mice exposed to 16alphaOHE 1.25 MUg/h for 4 weeks. Blot analyses of Bmpr2 mouse lung protein showed significant reductions in peroxisome proliferator-activated receptor-gamma and CD36 in those mice exposed to 16alphaOHE and protein derived from HPAH lungs compared with controls. Bmpr2 mice treated with anti-miR-29 (20-mg/kg injections for 6 weeks) had improvements in hemodynamic profile, histology, and markers of dysregulated energy metabolism compared with controls. Pulmonary artery smooth muscle cells derived from Bmpr2 murine lungs demonstrated mitochondrial abnormalities, which improved with anti-miR-29 transfection in vitro; endothelial like cells derived from HPAH patient induced pluripotent stem cell lines were similar and improved with anti-miR-29 treatment. CONCLUSIONS: 16alphaOHE promotes the development of HPAH via upregulation of miR-29, which alters molecular and functional indexes of energy metabolism. Antagonism of miR-29 improves in vivo and in vitro features of HPAH and reveals a possible novel therapeutic target. PMID- 26487759 TI - Perceptions of Child Body Size and Health Care Seeking for Undernourished Children in Southern Malawi. AB - Child undernutrition affects millions of children globally, but little is known about the ability of adults to detect different types of child undernutrition in low-income countries. We used focused ethnographic methods to understand how Malawian parents and grandparents describe the characteristics they use to identify good and poor child growth, their actual or preferred patterns of health seeking for undernourished children, and the perceived importance of child undernutrition symptoms in relation to other childhood illnesses. Malawians value adiposity rather than stature in assessing child growth. Symptoms of malnutrition, including wasting and edema, were considered the least severe childhood illness symptoms. Parents delayed health care seeking when a child was ill. When they sought care, it was for symptoms such as diarrhea or fever, and they did not recognize malnutrition as the underlying cause. These findings can be used to tailor strategies for preventing and treating growth faltering in Malawian children. PMID- 26487760 TI - Lenvatinib in Advanced, Radioactive Iodine-Refractory, Differentiated Thyroid Carcinoma. AB - Management options are limited for patients with radioactive iodine refractory, locally advanced, or metastatic differentiated thyroid carcinoma. Prior to 2015, sorafenib, a multitargeted tyrosine kinase inhibitor, was the only approved treatment and was associated with a median progression-free survival (PFS) of 11 months and overall response rate (ORR) of 12% in a phase III trial. Lenvatinib, a multikinase inhibitor with high potency against VEGFR and FGFR demonstrated encouraging results in phase II trials. Recently, the pivotal SELECT trial provided the basis for the FDA approval of lenvatinib as a second targeted therapy for these patients. Median PFS of 18.3 months in the lenvatinib group was significantly improved from 3.6 months in the placebo group, with an HR of 0.21 (95% confidence interval, 0.4-0.31; P < 0.0001). ORR was also significantly increased in the lenvatinib arm (64.7%) compared with placebo (1.5%). In this article, we will review the molecular mechanisms of lenvatinib, the data from preclinical studies to the recent phase III clinical trial, and the biomarkers being studied to further guide patient selection and predict treatment response. PMID- 26487761 TI - "Big Data" in Laboratory Medicine. PMID- 26487762 TI - Family residency and psychosomatic problems among adolescents in Sweden: The impact of child-parent relations. AB - AIMS: Profound changes in family structure took place in many countries, during the second part of the previous century. The purpose of this paper is to analyse the association between the type of family residency and psychosomatic problems in younger and older adolescents, particularly focusing on alternate residency, and to examine the impact of child-parent relations. METHODS: We used data collected in 2009 by Statistics Sweden among 172,298 Swedish students in Grade 6 and Grade 9 (approximate ages 12 and 15 years old); comprising 80% and 86%, respectively, of the entire population of students in those grades. We collected the data with a questionnaire, completed anonymously in school: We used the Psychosomatic Problems (PSP) scale as the outcome measure. RESULTS: The type of family residency showed a weaker association with psychosomatic problems than the child-parent relationships did. Living in non-intact families increased the probability of adolescent psychosomatic problems by 0-0.05, compared to intact families. In Grade 9, there were no differences in psychosomatic problems between the students in alternate residency and those living with their two parents; and in Grade 6, these differences were relatively small. In comparison, a worse relationship with parents increased the probability of psychosomatic problems by 0.11-0.17, depending on the school grade and type of family residency. CONCLUSIONS: The structure of the family, as well as the child-parent relationships needs to be taken into account, to properly estimate the magnitude of the family situation as a determinant of adolescent psychosomatic problems. Our results justify universal intervention at the policy level. PMID- 26487763 TI - Measuring tobacco dependence in the general population: Evaluation of the Cigarette Dependence Scale (CDS-12) and its adaptation to smokeless tobacco use (STDS-12) in two Swedish surveys. AB - AIMS: The 12-item Cigarette Dependence Scale (CDS-12) is an instrument suitable to assess tobacco dependence in non-clinical populations. The aim of this study was twofold: a) to evaluate the scale's performance in a smoking population including non-daily smokers; b) to explore the scale's adaptation to the assessment of dependence on smokeless tobacco. METHODS: In a cross-sectional study we investigated performance and construct validity of the CDS-12 and of its adaptation to smokeless tobacco (STDS-12) in two Swedish population samples. The first sample consisted of young adults (1246 ever daily smokers and 1086 ever daily snus (the Swedish type of moist oral snuff) users between 19 and 28 years of age). The second sample included 1229 current smokers and 855 current users of snus between 16 and 84 years of age. Score distribution, internal consistency, factor structure, and associations with other indicators of tobacco dependence were analysed. RESULTS: Both scales had a small amount of missing answers (below 2% in most items) and had acceptable internal consistency. Factor analyses suggested a one-factor model. CDS-12 score and proportions classified as dependent were significantly higher among daily smokers compared to non-daily smokers, positively correlated with the number of cigarettes, and negatively with quit attempts as well as their duration. The same pattern was seen for STDS-12, apart from correlation with quit attempts. CONCLUSIONS: Both the CDS-12 and its adaptation to smokeless tobacco, tested for the first time in this study, appear to perform well in population-based samples including young and non-daily tobacco users. PMID- 26487766 TI - Retraction for Anderson et al., Recombinant Bacillus subtilis That Grows on Untreated Plant Biomass. PMID- 26487764 TI - Dietary intake in Swedish medical students during 2007-2012. AB - BACKGROUND: The dietary intake in Swedish medical students has been reported for the periods 1987-1993 and 1994-2006. OBJECTIVE: To analyse dietary intake in medical students between 2007 and 2012, in relation to Nordic Nutrition Recommendations, to previous surveys and to a contemporary Swedish population. DESIGN: Nutrient intake was calculated from 3-day food records conducted by 698 medical students. The differences between surveys were evaluated using a t-test and the changes over time by linear regression. RESULTS: The energy intake in valid female and male reporters was 8.7 and 11.9 MJ respectively. The intake of protein, fat and alcohol, as proportions of energy (E%) and dietary fibre, was within recommendations. The intake of most micronutrients was above recommendations, except for vitamin D, and in women, iron and folate. In women, E% fat increased between 2007 and 2012, while E% carbohydrate decreased. Compared to the 1994-2006 period, medical students in the present survey consumed less carbohydrates and more fat, more folate and more vitamin E. The students were more compliant with the dietary recommendations than the same age group of the Swedish population. CONCLUSIONS: Energy intake in medical students, and dietary intake with some exceptions, remained stable during 1987-2012, and close to the Nordic Nutrition Recommendations for most nutrients. Between 2007 and 2012, fat intake increased and carbohydrate intake decreased significantly in women and also tended to do so in men. Similar trends were seen in the Swedish population, possibly indicating the impact of diet trends such as the Low-Carb/High-Fat diet. PMID- 26487768 TI - Long-Term Renal Function after Abdominal Aortic Aneurysm Repair. PMID- 26487769 TI - A Systematic Review and Meta-Analysis of Outcomes of Pregnancy in CKD and CKD Outcomes in Pregnancy. AB - BACKGROUND AND OBJECTIVES: We undertook a systematic review and meta-analysis of published cohort studies and case-control studies to estimate (1) the risk of pregnancy complications among patients with CKD versus those without CKD and (2) the risk of CKD progression among pregnant patients versus nonpregnant controls with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We searched electronic databases for studies published between 1946 and 2014, and we reviewed articles using validity criteria. Random-effects analytical methods were used. RESULTS: Twenty-three studies (14 with data for adverse pregnancy outcomes and 9 for renal outcomes) with 506,340 pregnancies were included. Pregnancy with CKD had greater odds of preeclampsia (odds ratio [OR], 10.36; 95% confidence interval [95% CI], 6.28 to 17.09), premature delivery (OR, 5.72; 95% CI, 3.26 to 10.03), small for gestational age/low birth weight (OR, 4.85; 95% CI, 3.03 to 7.76), cesarean section (OR, 2.67; 95% CI, 2.01 to 3.54), and failure of pregnancy (OR, 1.80; 95% CI, 1.03 to 3.13). Subgroup analysis showed that odds of preeclampsia (P<0.01) and premature delivery (P<0.01) were higher in women with nondiabetic nephropathy compared with diabetic nephropathy, and the odds of preeclampsia (P=0.01) and premature delivery (P<0.01) were higher in women with macroproteinuria compared with microproteinuria. The median for follow-up time for renal events was 5 years (interquartile range, 5-14.7 years). There were no significant differences in the occurrence of renal events between CKD pregnant women and those without pregnancy (OR, 0.96; 95% CI, 0.69 to 1.35). Subgroup analysis showed that publication year, sample size, follow-up years, type of primary disease, CKD classification, level of serum creatinine at baseline, proteinuria, and level of systolic BP did not modify the renal outcomes. CONCLUSIONS: The risks of adverse maternal and fetal outcomes in pregnancy are higher for women with CKD versus pregnant women without CKD. However, pregnancy was not a risk factor for progression of renal disease in women with CKD before pregnancy. PMID- 26487771 TI - HIV testing in Europe: how can primary care contribute? PMID- 26487770 TI - Long-Term Renal Function after Endovascular Aneurysm Repair. AB - BACKGROUND AND OBJECTIVES: Endovascular repair (EVAR) is a common treatment for abdominal aortic aneurysm (AAA). However, its long-term effects on renal function remain unclear. We aimed to assess long-term renal dysfunction after EVAR using a contemporary estimate of GFR and to compare long-term renal outcomes in patients after EVAR with open aneurysm repair (OAR) and in patients without an AAA. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: We performed a nested case matched analysis of 726 patients (using a prospectively maintained database for repairs that took place between January 2000 and May 2010 in a tertiary center): 121 patients undergoing OAR (with data at baseline and 5 years postrepair) were case matched (age, sex, smoking, diabetes, baseline eGFR) to patients undergoing suprarenal and infrarenal fixation EVAR (242 in each group) and to 121 patients undergoing carotid endarterectomy (CEA) without AAA. Changes in eGFR were compared (1 and 5 years). RESULTS: The OAR patients lost an average of 7.4 ml/min per 1.73 m2 at 5 years (95% confidence interval [95% CI], 4.8 to 10.6), compared with 8.2 ml/min per 1.73 m2 (95% CI, 6.5 to 10.8; P<0.001) for infrarenal fixation EVAR, 16.9 ml/min per 1.73 m2 (95% CI, 13.0 to 21.9, P<0.001) for suprarenal-fixation EVAR, and 5.4 ml/min per 1.73 m2 (95% CI, 1.7 to 7.5; P<0.001) for CEA. The decrease in eGFR was steeper during the first postoperative year, with each group losing -2.2 ml/min per 1.73 m2 (infrarenal-fixation EVAR), 10.7 ml/min per 1.73 m2 (suprarenal-fixation EVAR), and -4.6 ml/min per 1.73 m2 (OAR), compared with -1.9 ml/min per 1.73 m2 for CEA. CONCLUSIONS: Elective EVAR is associated with a significant decline in eGFR after 5 years, which is steeper in the first postoperative year and more pronounced compared with a similar population with atherosclerotic disease. PMID- 26487772 TI - The STI Foundation: STIF International. PMID- 26487773 TI - Lymphogranuloma venereum in North-West Italy, 2009-2014. PMID- 26487774 TI - How and why do we do testicular ultrasounds? A national clinical development group survey of genitourinary medicine clinics. PMID- 26487775 TI - Chlamydia testing in male further education college students. PMID- 26487776 TI - An interview with Mike Levine. AB - Mike Levine, director of the Lewis-Sigler Institute for Integrative Genomics at Princeton University, is a developmental biologist who has dedicated his career to understanding how gene expression is regulated during development. Some of his most significant research, such as the co-discovery of the homeobox genes and his work on even skipped stripe 2, was performed in Drosophila, but he has since branched out to Ciona intestinalis, which he is using as a model to understand how vertebrate features have evolved. We had a lively chat with Mike at this year's Society for Developmental Biology (SDB) meeting, where he was awarded the Edwin Grant Conklin Medal. PMID- 26487778 TI - Lin-28 promotes symmetric stem cell division and drives adaptive growth in the adult Drosophila intestine. AB - Stem cells switch between asymmetric and symmetric division to expand in number as tissues grow during development and in response to environmental changes. The stem cell intrinsic proteins controlling this switch are largely unknown, but one candidate is the Lin-28 pluripotency factor. A conserved RNA-binding protein that is downregulated in most animals as they develop from embryos to adults, Lin-28 persists in populations of adult stem cells. Its function in these cells has not been previously characterized. Here, we report that Lin-28 is highly enriched in adult intestinal stem cells in the Drosophila intestine. lin-28 null mutants are homozygous viable but display defects in this population of cells, which fail to undergo a characteristic food-triggered expansion in number and have reduced rates of symmetric division as well as reduced insulin signaling. Immunoprecipitation of Lin-28-bound mRNAs identified Insulin-like Receptor (InR), forced expression of which completely rescues lin-28-associated defects in intestinal stem cell number and division pattern. Furthermore, this stem cell activity of lin-28 is independent of one well-known lin-28 target, the microRNA let-7, which has limited expression in the intestinal epithelium. These results identify Lin-28 as a stem cell intrinsic factor that boosts insulin signaling in intestinal progenitor cells and promotes their symmetric division in response to nutrients, defining a mechanism through which Lin-28 controls the adult stem cell division patterns that underlie tissue homeostasis and regeneration. PMID- 26487779 TI - Trithorax regulates systemic signaling during Drosophila imaginal disc regeneration. AB - Although tissue regeneration has been studied in a variety of organisms, from Hydra to humans, many of the genes that regulate the ability of each animal to regenerate remain unknown. The larval imaginal discs of the genetically tractable model organism Drosophila melanogaster have complex patterning, well characterized development and a high regenerative capacity, and are thus an excellent model system for studying mechanisms that regulate regeneration. To identify genes that are important for wound healing and tissue repair, we have carried out a genetic screen for mutations that impair regeneration in the wing imaginal disc. Through this screen we identified the chromatin-modification gene trithorax as a key regeneration gene. Here we show that animals heterozygous for trithorax are unable to maintain activation of a developmental checkpoint that allows regeneration to occur. This defect is likely to be caused by abnormally high expression of puckered, a negative regulator of Jun N-terminal kinase (JNK) signaling, at the wound site. Insufficient JNK signaling leads to insufficient expression of an insulin-like peptide, dILP8, which is required for the developmental checkpoint. Thus, trithorax regulates regeneration signaling and capacity. PMID- 26487777 TI - Heparan sulfate proteoglycans: a sugar code for vertebrate development? AB - Heparan sulfate proteoglycans (HSPGs) have long been implicated in a wide range of cell-cell signaling and cell-matrix interactions, both in vitro and in vivo in invertebrate models. Although many of the genes that encode HSPG core proteins and the biosynthetic enzymes that generate and modify HSPG sugar chains have not yet been analyzed by genetics in vertebrates, recent studies have shown that HSPGs do indeed mediate a wide range of functions in early vertebrate development, for example during left-right patterning and in cardiovascular and neural development. Here, we provide a comprehensive overview of the various roles of HSPGs in these systems and explore the concept of an instructive heparan sulfate sugar code for modulating vertebrate development. PMID- 26487780 TI - Epigenetic regulation of Atoh1 guides hair cell development in the mammalian cochlea. AB - In the developing cochlea, sensory hair cell differentiation depends on the regulated expression of the bHLH transcription factor Atoh1. In mammals, if hair cells die they do not regenerate, leading to permanent deafness. By contrast, in non-mammalian vertebrates robust regeneration occurs through upregulation of Atoh1 in the surviving supporting cells that surround hair cells, leading to functional recovery. Investigation of crucial transcriptional events in the developing organ of Corti, including those involving Atoh1, has been hampered by limited accessibility to purified populations of the small number of cells present in the inner ear. We used uChIP and qPCR assays of FACS-purified cells to track changes in the epigenetic status of the Atoh1 locus during sensory epithelia development in the mouse. Dynamic changes in the histone modifications H3K4me3/H3K27me3, H3K9ac and H3K9me3 reveal a progression from poised, to active, to repressive marks, correlating with the onset of Atoh1 expression and its subsequent silencing during the perinatal (P1 to P6) period. Inhibition of acetylation blocked the increase in Atoh1 mRNA in nascent hair cells, as well as ongoing hair cell differentiation during embryonic organ of Corti development ex vivo. These results reveal an epigenetic mechanism of Atoh1 regulation underlying hair cell differentiation and subsequent maturation. Interestingly, the H3K4me3/H3K27me3 bivalent chromatin structure observed in progenitors persists at the Atoh1 locus in perinatal supporting cells, suggesting an explanation for the latent capacity of these cells to transdifferentiate into hair cells, and highlighting their potential as therapeutic targets in hair cell regeneration. PMID- 26487781 TI - 4D atlas of the mouse embryo for precise morphological staging. AB - After more than a century of research, the mouse remains the gold-standard model system, for it recapitulates human development and disease and is quickly and highly tractable to genetic manipulations. Fundamental to the power and success of using a mouse model is the ability to stage embryonic mouse development accurately. Past staging systems were limited by the technologies of the day, such that only surface features, visible with a light microscope, could be recognized and used to define stages. With the advent of high-throughput 3D imaging tools that capture embryo morphology in microscopic detail, we now present the first 4D atlas staging system for mouse embryonic development using optical projection tomography and image registration methods. By tracking 3D trajectories of every anatomical point in the mouse embryo from E11.5 to E14.0, we established the first 4D atlas compiled from ex vivo 3D mouse embryo reference images. The resulting 4D atlas comprises 51 interpolated 3D images in this gestational range, resulting in a temporal resolution of 72 min. From this 4D atlas, any mouse embryo image can be subsequently compared and staged at the global, voxel and/or structural level. Assigning an embryonic stage to each point in anatomy allows for unprecedented quantitative analysis of developmental asynchrony among different anatomical structures in the same mouse embryo. This comprehensive developmental data set offers developmental biologists a new, powerful staging system that can identify and compare differences in developmental timing in wild-type embryos and shows promise for localizing deviations in mutant development. PMID- 26487782 TI - A transport and retention mechanism for the sustained distal localization of Spn F-IKKepsilon during Drosophila bristle elongation. AB - There was an error published in Development 142, 2338-2351. Otani et al. reported the genetic interactions between ikkepsilon and spn-F, using the allele ikkepsilon66. This allele was referred to in the Materials and Methods on p. 2349, Fig. 3 on p. 2343 and Table S1. However, they subsequently found that the allele used in the experiments was ikkepsilon1 (also known as ikkepsilon36). This was as a result of misannotation in their laboratory stock list. Both alleles are strong loss-of-function alleles with a missense mutation in the kinase domain and show similar phenotypes (Oshima et al., 2006; Shapiro and Anderson, 2006). Therefore, this error does not affect the conclusions of the paper. The authors apologise to readers for this mistake. PMID- 26487783 TI - Defining the three cell lineages of the human blastocyst by single-cell RNA-seq. AB - There were errors published in Development 142, 3151-3165.In the issue published online on 22 September 2015, Fig. 3 was mislabelled: panels A, B, C and D should have been B, C, D and A, respectively. In the legend, the text prior to '(A) Cytoscape enrichment map...' should not have been included. The correct version of the figure and legend now appear online and in print.We apologise to the authors and readers for this mistake. PMID- 26487784 TI - The advancement of human pluripotent stem cell-derived therapies into the clinic. AB - There was an error published in Development 142, 3077-3084.On p. 3081, it was incorrectly stated that Dr Lorenz Studer's group is supported by the New York Stem Cell Foundation. The correct funding credit is the New York State Stem Cell Science program.The authors apologise to readers for this mistake. PMID- 26487785 TI - Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression. AB - Genetic variants in SLC16A11 were recently reported to be associated with type 2 diabetes in Mexican and other Latin American populations. The diabetes risk haplotype had a frequency of 50% in Native Americans from Mexico but was rare in Europeans and Africans. In the current study, we analyzed SLC16A11 in 12,811 North American Indians and found that the diabetes risk haplotype, tagged by the rs75493593 A allele, was nominally associated with type 2 diabetes (P = 0.001, odds ratio 1.11). However, there was a strong interaction with BMI (P = 5.1 * 10( 7)) such that the diabetes association was stronger in leaner individuals. rs75493593 was also strongly associated with BMI in individuals with type 2 diabetes (P = 3.4 * 10(-15)) but not in individuals without diabetes (P = 0.77). Longitudinal analyses suggest that this is due, in part, to an association of the A allele with greater weight loss following diabetes onset (P = 0.02). Analyses of global gene expression data from adipose tissue, skeletal muscle, and whole blood provide evidence that rs75493593 is associated with expression of the nearby RNASEK gene, suggesting that RNASEK expression may mediate the effect of genotype on diabetes. PMID- 26487787 TI - Rapid retraction of microvolume aqueous plugs traveling in a wettable capillary. AB - We report a transport behavior-specifically, rapid retraction movement-of small (~MUL) deionized water plugs traveling in series within a small wettable tubular geometry. In this study, two water plugs separated by a certain distance in a dry cylindrical glass capillary were moved by positive pressure airflow applied at the tube inlet. As the plugs travel, a thin aqueous film is generated between the plugs as a result of the leading plug's aqueous deposition onto the inner surface of the tube. The leading plug continuously loses volume by film deposition onto the surface and eventually ruptures. Then, the lagging plug quickly travels the distance initially separating the two plugs (plug retraction). Our studies show that the rapid retraction of the lagging plug is caused by surface tension in addition to the positive pressure applied. Furthermore, the plug retraction speed is strongly affected by tube radius and the distance between the plugs. PMID- 26487788 TI - A high-order boundary integral method for surface diffusions on elastically stressed axisymmetric rods. AB - Many applications in materials involve surface diffusion of elastically stressed solids. Study of singularity formation and long-time behavior of such solid surfaces requires accurate simulations in both space and time. Here we present a high-order boundary integral method for an elastically stressed solid with axi symmetry due to surface diffusions. In this method, the boundary integrals for isotropic elasticity in axi-symmetric geometry are approximated through modified alternating quadratures along with an extrapolation technique, leading to an arbitrarily high-order quadrature; in addition, a high-order (temporal) integration factor method, based on explicit representation of the mean curvature, is used to reduce the stability constraint on time-step. To apply this method to a periodic (in axial direction) and axi-symmetric elastically stressed cylinder, we also present a fast and accurate summation method for the periodic Green's functions of isotropic elasticity. Using the high-order boundary integral method, we demonstrate that in absence of elasticity the cylinder surface pinches in finite time at the axis of the symmetry and the universal cone angle of the pinching is found to be consistent with the previous studies based on a self similar assumption. In the presence of elastic stress, we show that a finite time, geometrical singularity occurs well before the cylindrical solid collapses onto the axis of symmetry, and the angle of the corner singularity on the cylinder surface is also estimated. PMID- 26487786 TI - Measurements of CD34+/CD45-dim Stem Cells Predict Healing of Diabetic Neuropathic Wounds. AB - Management of neuropathic foot ulcers in patients with diabetes (DFUs) has changed little over the past decade, and there is currently no objective method to gauge probability of successful healing. We hypothesized that studies of stem/progenitor cells (SPCs) in the early weeks of standard wound management could predict who will heal within 16 weeks. Blood and debrided wound margins were collected for 8 weeks from 100 patients undergoing weekly evaluations and treatment. SPC number and intracellular content of hypoxia-inducible factors (HIFs) were evaluated by flow cytometry and immunohistochemistry. More SPCs entered the bloodstream in the first 2 weeks of care in patients who healed (n = 37) than in those who did not (n = 63). Logistic regression demonstrated that the number of blood-borne SPCs and the cellular content of HIFs at study entry and the first-week follow-up visit predicted healing. Strong correlations were found among week-to-week assessments of blood-borne SPC HIF factors. We conclude that assays of SPCs during the first weeks of care in patients with DFUs can provide insight into how well wounds will respond and may aid with decisions on the use of adjunctive measures. PMID- 26487789 TI - Patient Activation: A Primary Care Tool to Tackle Overweight and Obesity. PMID- 26487790 TI - Managing Diabetes in Pregnancy Using Cell Phone/Internet Technology. AB - In Brief For pregnant women with diabetes, using cell phone/Internet technology to track and report self-monitoring of blood glucose results improves compliance and satisfaction compared to using the more traditional methods of log books, telephone calls, and voicemail messages. PMID- 26487791 TI - Therapeutic Options for the Management of Postprandial Glucose in Patients With Type 2 Diabetes on Basal Insulin. AB - In Brief For patients with type 2 diabetes who require add-on therapy to metformin plus basal insulin, GLP-1 receptor agonists may be a favorable option because they effectively manage postprandial glucose, reduce body weight, and have an overall favorable safety profile compared to other agents. Given the wide range of treatment combinations available for type 2 diabetes management, health professionals must partner with patients to determine the best choices based on patients' individual lifestyle, resources, and treatment goals. PMID- 26487793 TI - Redesigning the Traditional Community Health Screening Model to Provide Blood Glucose Screening and Interdisciplinary Health Education. PMID- 26487794 TI - Metformin-Associated Lactic Acidosis in a Patient With Normal Renal Function. PMID- 26487792 TI - Self-Reported Gastrointestinal Symptoms in Type 2 Diabetes Improve With an Intensive Lifestyle Intervention: Results From the Action for Health in Diabetes (Look AHEAD) Clinical Trial. AB - In Brief This article reports on an investigation of whether an intensive lifestyle intervention (ILI) would reduce gastrointestinal symptoms over 4 years of follow-up for participants in the Action for Health in Diabetes (Look AHEAD) trial compared to a diabetes support and education (DSE) group. Look AHEAD is a randomized, multicenter trial comparing overweight and obese adults with type 2 diabetes treated with ILI versus DSE. ILI, and weight loss in general, had beneficial effects on gastrointestinal (GI) symptoms, with some variability in the strength of the effect depending on the specific symptom and time course. Potential modifiers were analyzed, yet ILI retained an association with improvement in GI symptoms. PMID- 26487795 TI - A Continuous Subcutaneous Insulin Infusion Needle Break. PMID- 26487796 TI - Legumes: Health Benefits and Culinary Approaches to Increase Intake. PMID- 26487797 TI - A Call to Action: Eliminating Diabetes Disparities in Native Communities. PMID- 26487798 TI - C5a and toll-like receptor 4 crosstalk in retinal pigment epithelial cells. AB - PURPOSE: To investigate the effect of the complement activation product C5a on toll-like receptor (TLR) 4-induced responses in RPE cells. METHODS: Confluent cultures of human RPE cells (ARPE-19) were stimulated with C5a, lipopolysaccharide (LPS), or a combination of the two. The expression of TLR4 was determined by real-time PCR and flow cytometry. Cytokine profiles were determined by real-time PCR and enzyme-linked immunosorbent assay (ELISA). The phosphorylation of p38, ERK 1/2, and JNK was measured by flow cytometry. RESULTS: C5a stimulation enhanced the expression of TLR4 in a dose- and time-dependent manner. C5a was able to stimulate the production of TLR4-induced IL-6 and IL-8 by ARPE-19 cells. Blocking experiments showed that the effect of C5a on cytokine production was mediated via C5aR. ERK1/2, but not JNK or p38, were involved in the production of IL-6 and IL-8. CONCLUSIONS: The results indicate that C5a can induce the TLR4 expression and enhance the production of TLR4-induced IL-6 and IL 8 by ARPE-19. The effect of C5a on cytokine production was mediated by C5aR and the phosphorylation of ERK1/2. PMID- 26487799 TI - Clinical results of Trabectome surgery for open-angle glaucoma. AB - BACKGROUND: The purpose of this study was to determine outcomes when using Trabectome surgery and to evaluate factors associated with its effects in primary open-angle glaucoma (POAG) and exfoliation glaucoma (EXG). METHODS: This was a prospective, non-randomized, observational, comparative cohort study in which Trabectome surgery was used alone in patients with POAG or EXG. Trabectome surgery was considered to have failed when at least one of the following three criteria was fulfilled: intraocular pressure (IOP) >=21 mmHg and a <20% reduction below the baseline IOP on two consecutive follow-up visits 3 months or more after surgery; need for additional glaucoma surgery; and an increase in number of medications compared with baseline. RESULTS: The subjects were 32 males (34 eyes) and 46 females (48 eyes). POAG was observed in 43 eyes and EXG in 39 eyes. IOP after Trabectome surgery decreased significantly from 22.3+/-6.8 mmHg at baseline to 14.0+/-3.9 mmHg (23.0% reduction) at month 24 in all cases (P<0.0000). The success rate at 2 years was 51.2% for all cases (POAG, 50.9%; EXG, 49.2%). There was no significant difference in success rate between POAG and EXG (P=0.91). Preoperative IOP (P=0.033) and number of medications (P=0.041) were significant factors for surgical success/failure in multivariate logistic regression. No serious complications were observed. CONCLUSION: Trabectome surgery achieved favorable IOP control and was equally effective in patients with POAG and those with EXG. Its effects were influenced by preoperative IOP and number of preoperative medications. PMID- 26487800 TI - Association between a relative afferent pupillary defect using pupillography and inner retinal atrophy in optic nerve disease. AB - PURPOSE: The aim of this study was to compare the asymmetrical light reflex of the control subjects and patients with optic nerve disease and to evaluate the relationships among the relative afferent pupillary defect (RAPD), visual acuity (VA), central critical fusion frequency (CFF), ganglion cell complex thickness (GCCT), and circumpapillary retinal nerve fiber layer thickness (cpRNFLT) using spectral-domain optical coherence tomography. MATERIALS AND METHODS: Using a pupillography device, the RAPD scores from 15 patients with unilateral optic nerve disease and 35 control subjects were compared. The diagnostic accuracy of the RAPD amplitude and latency scores was compared using the area under the receiver operating characteristic curve. Thereafter, we assessed the relationships among the RAPD scores, VA, central CFF, GCCT, and cpRNFLT. RESULTS: The average RAPD amplitude score in patients with optic nerve disease was significantly higher than that of the control subjects (P<0.001). The average RAPD latency score in patients with optic nerve disease was significantly higher than that of the control subjects (P=0.001). The area under the receiver operating characteristic curve for the RAPD amplitude score was significantly higher than that for the latency score (P=0.010). The correlation coefficients for the RAPD amplitude and latency scores were 0.847 (P<0.001) and 0.874 (P<0.001) for VA, -0.868 (P<0.001) and -0.896 (P<0.001) for central CFF, -0.593 (P=0.020) and -0.540 (P=0.038) for GCCT, and -0.267 (P=0.337) and -0.228 (P=0.413) for cpRNFLT, respectively. CONCLUSION: Our results suggest that pupillography is useful for detecting optic nerve disease. PMID- 26487801 TI - Novel dehydroepiandrosterone troche supplementation improves the serum androgen profile of women undergoing in vitro fertilization. AB - Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in the circulation and has potent multifunctional activity. Epidemiological evidence suggests that levels of serum DHEA decrease with advancing age, and this has been associated with onset or progression of various age-related ailments, including cognitive decline and dementia, cardiovascular disease, and obesity. Consequently, these findings have sparked intense research interest in DHEA supplementation as an "antiaging" therapy. Currently, DHEA is being used by 25% of in vitro fertilization (IVF) clinicians as an adjuvant in assisted reproductive programs, yet the therapeutic benefit of DHEA is unclear. Here, we examined the use of novel DHEA-containing oral troches in patients undertaking IVF and investigated the impact of these troches on their serum androgen profile. This retrospective study determined the androgen profile of 31 IVF patients before (baseline) and after DHEA supplementation (with DHEA). Baseline serum measurements of testosterone (total and free), DHEA sulfate (DHEAS), sex hormone binding globulin (SHBG), and androstenedione were made before and after supplementation. Each patient received DHEA troches containing 25 mg of micronized DHEA, and troches were administered sublingually twice daily for a period of no greater than 4 months. Adjuvant treatment with DHEA boosted the serum concentration of a number of androgen-related analytes, including total and free testosterone, androstenedione, and DHEAS, while serum SHBG remained unchanged. Supplementation also significantly increased the free-androgen index in IVF patients. Interestingly, the increase in serum analyte concentration following DHEA supplementation was found to be dependent on body mass index (BMI), but not individual age. Patients with the lowest BMI (<20.0 kg/m(2)) tended to have lower testosterone and DHEAS, but higher SHBG and androstenedione levels in comparison with other BMI groups postsupplementation. However, patients in the highest BMI group (>30.0 kg/m(2)) tended to have lower androgen responses following DHEA supplementation, but these were not statistically different from the corresponding baseline level. This method of DHEA administration results in a similar enhancement of testosterone, DHEAS, and androstenedione levels in comparison with other methods of administration. Furthermore, we showed that BMI significantly influences DHEA uptake and metabolism, and that BMI should be carefully considered during dosage calculation to ensure a significant and robust androgen-profile boost. PMID- 26487802 TI - Arsenic sulfide inhibits cell migration and invasion of gastric cancer in vitro and in vivo. AB - BACKGROUND: We previously showed that arsenic sulfide (As4S4) induced cell cycle arrest and apoptosis in several human solid tumor cell lines, including those of gastric cancer. In this study, we investigated the effect of As4S4 on the migration and invasion of gastric cancer cells both in vitro and in vivo. METHODS: The human gastric cancer cell lines AGS and MGC803 were selected as in vitro models. Wound-healing migration assay and Transwell invasion assay were carried out to determine the effects of As4S4 on cell migration and invasion. The expressions of E-cadherin, beta-catenin, Sp1, KLF4, and VEGF were measured by Western blotting analysis. The activities of matrix metalloproteinase (MMP)-2 and MMP-9 in MGC803 cells were demonstrated by zymography assay. A mouse xenograft model was established by inoculation with MGC803 cells, then intraperitoneal injected with As4S4 for 3 weeks and monitored for body weight and tumor changes. Finally, the inhibition rate of tumor growth was calculated, and the expression of proteins and genes associated with tumor invasion and metastasis in tumor tissues were measured by immunohistochemistry, Western blotting, and real-time polymerase chain reaction assay. RESULTS: As4S4 significantly inhibited the migration and invasion of gastric cancer cell lines. The expression of E-cadherin and KLF4 was upregulated, while the expressions of beta-catenin, VEGF, and Sp1 were downregulated following treatment with As4S4. Moreover, the protease activities of MMP-2 and MMP-9 were suppressed by As4S4 in MGC803 cells. Meanwhile, As4S4 effectively suppressed the abilities of tumor growth and invasion in the xenograft tumor model. We found that As4S4 upregulated the expression of E-cadherin and downregulated the expression of beta-catenin, Sp1, VEGF, and CD34 in mouse tumor tissues, consistent with the results in vitro. CONCLUSION: As4S4 inhibited the migration and invasion of gastric cancer cells by blocking tumor cell adhesion, decreasing the ability of tumor cells to destroy the basement membrane, and therefore suppressing their angiogenesis. PMID- 26487803 TI - Antimicrobial activity of bone cements embedded with organic nanoparticles. AB - Infections after orthopedic surgery are a very unwelcome outcome; despite the widespread use of antibiotics, their incidence can be as high as 10%. This risk is likely to increase as antibiotics are gradually losing efficacy as a result of bacterial resistance; therefore, novel antimicrobial approaches are required. Parabens are a class of compounds whose antimicrobial activity is employed in many cosmetic and pharmaceutical products. We developed propylparaben nanoparticles that are hydrophilic, thus expanding the applicability of parabens to aqueous systems. In this paper we assess the possibility of employing paraben nanoparticles as antimicrobial compound in bone cements. The nanoparticles were embedded in various types of bone cement (poly(methyl methacrylate) [PMMA], hydroxyapatite, and brushite) and the antimicrobial activity was determined against common causes of postorthopedic surgery infections such as: Staphylococcus aureus, methicillin-resistant S. aureus, Staphylococcus epidermidis, and Acinetobacter baumannii. Nanoparticles at concentrations as low as 1% w/w in brushite bone cement were capable of preventing pathogens growth, 5% w/w was needed for hydroxyapatite bone cement, while 7% w/w was required for PMMA bone cement. No detrimental effect was determined by the addition of paraben nanoparticles on bone cement compression strength and cytocompatibility. Our results demonstrate that paraben nanoparticles can be encapsulated in bone cement, providing concentration-dependent antimicrobial activity; furthermore, lower concentrations are needed in calcium phosphate (brushite and hydroxyapatite) than in acrylic (PMMA) bone cements. These nanoparticles are effective against a wide spectrum of bacteria, including those already resistant to the antibiotics routinely employed in orthopedic applications, such as gentamicin. PMID- 26487804 TI - Addition of a renin-angiotensin-aldosterone system inhibitor to a calcium channel blocker ameliorates arterial stiffness. AB - BACKGROUND: The aim of controlling hypertension is to protect against arteriosclerosis. Calcium channel blockers (CCBs) and renin-angiotensin aldosterone system (RAAS) inhibitors have been reported to have antihypertensive effects, but their effect on the progression of arteriosclerosis is not fully understood. The cardio-ankle vascular index (CAVI) was developed to estimate arterial stiffness, which reflects arteriosclerosis. In this study, we investigated the longer term effects of CCBs and RAAS inhibitors on the progression of arteriosclerosis by monitoring the CAVI. METHODS: Our subjects were 115 consecutive, non-smoking hypertensive patients on oral treatment with a CCB and/or RAAS inhibitor for at least 3 years in whom the CAVI was measured on two occasions approximately 1 year apart during the period from January 2009 to December 2011. Changes in CAVI were evaluated in patients administered a CCB alone (group C), an RAAS inhibitor (group R) alone, or both drugs together (group B). Changes in laboratory findings, blood pressure, and ankle-brachial index were similarly evaluated. RESULTS: No significant change in laboratory findings, blood pressure, or ankle-brachial index was noted in any of the groups. The CAVI decreased slightly in group R (first recording 8.80+/-1.03, second recording 8.57+/-0.97, P=0.517) and increased significantly in group C (first 8.45+/-0.92, second 8.95+/-1.04, P=0.038), but showed no significant change in group B (first 9.01+/-1.26, second 9.05+/-1.35, P=0.851). CONCLUSION: Long-term administration of a CCB alone increased the CAVI, but this effect was offset by the concomitant use of a RAAS inhibitor, indicating that a RAAS inhibitor might protect against arteriosclerosis. PMID- 26487805 TI - Anxiety and DSM-5. AB - The DSM-5 process, and the publication of DSM-5 in 2013, have had a considerable impact on the classification of anxiety disorders. Major changes included the reorganization of the chapter structure, individual groupings of disorders within each chapter from a life span viewpoint, and the use of specifiers. The DSM-5 chapter on anxiety disorders does not include obsessive-compulsive disorder or post-traumatic stress disorder. The chapter itself now reflects a developmental approach. The text of each disorder has been enhanced with short sections on development and course, risk and prognostic factors, etc. It is expected that the reformulation of anxiety disorders in DSM-5 will lead to greater precision in a variety of ways, as illustrated in the papers in this issue of Dialogues in Clinical Neuroscience. In summary, these changes in the way we classify anxiety disorders reflect our best view on the clinical empirical data and should prove useful in the assessment of specific anxiety disorders. PMID- 26487806 TI - The overlap between anxiety, depression, and obsessive-compulsive disorder. AB - The anxiety disorders include generalized anxiety disorder, specific phobia, social phobia, agoraphobia, and panic disorder. In addition to the specific symptoms of these disorders, there may be a common experience of anxiety and even dysphoria across the conditions, and of course recourse to the same drug or choice of drugs for treatment. This overlap probably occurs because of universal dimensions of distress or negative affectivity, a shared genetic predisposition, and a common neurobiology Evidence of shared genes is still based mainly on twin studies, but the shared neurobiology can be investigated directly by the investigation of emotional or cognitive bias either behaviorally or using functional brain imaging. This intermediate phenotype can then provide a substrate for understanding and developing medicines and psychological treatments. PMID- 26487807 TI - A systematic review of the neural bases of psychotherapy for anxiety and related disorders. AB - Brain imaging studies over two decades have delineated the neural circuitry of anxiety and related disorders, particularly regions involved in fear processing and in obsessive-compulsive symptoms. The neural circuitry of fear processing involves the amygdala, anterior cingulate, and insular cortex, while cortico striatal-thalamic circuitry plays a key role in obsessive-compulsive disorder. More recently, neuroimaging studies have examined how psychotherapy for anxiety and related disorders impacts on these neural circuits. Here we conduct a systematic review of the findings of such work, which yielded 19 functional magnetic resonance imaging studies examining the neural bases of cognitive behavioral therapy (CBT) in 509 patients with anxiety and related disorders. We conclude that, although each of these related disorders is mediated by somewhat different neural circuitry, CBT may act in a similar way to increase prefrontal control of subcortical structures. These findings are consistent with an emphasis in cognitive-affective neuroscience on the potential therapeutic value of enhancing emotional regulation in various psychiatric conditions. PMID- 26487808 TI - Separation anxiety: at the neurobiological crossroads of adaptation and illness. AB - Physiological and adaptive separation anxiety (SA) is intimately connected with the evolutionary emergence of new brain structures specific of paleomammalians, the growth of neomammalian--and later hominid--brain and skull size, and the appearance of bipedalism. All these evolutionary milestones have contributed to expanding the behavioral repertoire and plasticity of prehuman and human beings, at the cost of more prolonged dependency of the infant and of the child on parental care. Separation anxiety disorder (SAD) can be seen as an exaggerated/inappropriate manifestation of SA that constitutes a gateway to poorer mental and physical health. By blending epidemiological, genetic epidemiological, endophenotypic, and animal laboratory approaches, it is possible to delineate some of the mechanisms that link childhood-adolescence SA and SAD to health problems later in life. Causal mechanisms include gene-environment interplays and likely differential regulation of genes and functional net-works that simultaneously affect multiple behavioral and physical phenotypes after exposure to early-life adversity, including parental separation/loss. PMID- 26487809 TI - Neuroendocrine models of social anxiety disorder. AB - Social anxiety disorder (SAD) is a highly prevalent and disabling disorder with key behavioral traits of social fearfulness, social avoidance, and submissiveness. Here we argue that hormonal systems play a key role in mediating social anxiety, and so may be important in SAD. Hormonal alterations, often established early in development through the interaction between biological and psychological factors (eg, genetic predisposition x early trauma), predispose to socially fearful, avoidant, and submissive behavior. However, whereas gene variants and histories of trauma persist, hormonal systems can be remodeled over the course of life. Hormones play a key role during the periods of all sensitive developmental windows (ie, prenatal, neonatal, puberty, aging), and are capable of opening up new developmental windows in adulthood. Indeed, the developmental plasticity of our social brain, and thus of social behavior in adulthood, critically depends on steroid hormones such as testosterone and peptide hormones such as oxytocin. These steroid and peptide hormones in interaction with social experiences may have potential for reprogramming the socially anxious brain. Certainly, single administrations of oxytocin and testosterone in humans reduce socially fearful, avoidant, and submissive behavior. Such work may ultimately lead to new approaches to the treatment of SAD. PMID- 26487810 TI - Animal models for screening anxiolytic-like drugs: a perspective. AB - Contemporary biological psychiatry uses experimental animal models to increase our understanding of affective disorder pathogenesis. Modern anxiolytic drug discovery mainly targets specific pathways and molecular determinants within a single phenotypic domain. However, greater understanding of the mechanisms of action is possible through animal models. Primarily developed with rats, animal models in anxiety have been adapted with mixed success for mice, easy-to-use mammals with better genetic possibilities than rats. In this review, we focus on the three most common animal models of anxiety in mice used in the screening of anxiolytics. Both conditioned and unconditioned models are described, in order to represent all types of animal models of anxiety. Behavioral studies require careful attention to variable parameters linked to environment, handling, or paradigms; this is also discussed. Finally, we focus on the consequences of re exposure to the apparatus. Test-retest procedures can provide new answers, but should be intensively studied in order to revalidate the entire paradigm as an animal model of anxiety. PMID- 26487812 TI - A history of anxiety: from Hippocrates to DSM. AB - This article describes the history of the nosology of anxiety disorders. Greek and Latin physicians and philosophers distinguished anxiety from other types of negative affect, and identified it as a medical disorder. Ancient Epicurean and Stoic philosophers suggested techniques to reach an anxiety-free state of mind that are reminiscent of modern cognitive psychology. Between classical antiquity and the late 19(th) century there was a long interval during which anxiety was not classified as a separate illness. However, typical cases of anxiety disorders kept being reported, even if under different names. In the 17(th) century, Robert Burton described anxiety in The Anatomy of Melancholy. Panic attacks and generalized anxiety disorder may be recognized in the "panophobias" in the nosology published by Boissier de Sauvages in the 18(th) century. Also, anxiety symptoms were an important component of new disease constructs, culminating in neurasthenia in the 19(th) century. Emil Kraepelin devoted much attention to the possible presence of severe anxiety in manic-depressive illness, thereby anticipating the "anxious distress" specifier of bipolar disorders in DSM-5. A pitfall to consider is that the meaning of common medical terms, such as melancholia, evolves according to places and epochs. PMID- 26487811 TI - Biological predictors of pharmacological therapy in anxiety disorders. AB - At least one third of patients with anxiety disorders do not adequately respond to available pharmacological treatment. The reason that some patients with anxiety disorders respond well, but others not, to the same classes of medication is not yet fully understood. It is suggested that several biological factors may influence treatment mechanisms in anxiety and therefore could be identified as possible biomarkers predicting treatment response. In this review, we look at current evidence exploring different types of treatment predictors, including neuroimaging, genetic factors, and blood-related measures, which could open up novel perspectives in clinical management of patients with anxiety disorders. PMID- 26487813 TI - Epidemiology of anxiety disorders in the 21st century. AB - Anxiety disorders, including panic disorder with or without agoraphobia, generalized anxiety disorder, social anxiety disorder, specific phobias, and separation anxiety disorder, are the most prevalent mental disorders and are associated with immense health care costs and a high burden of disease. According to large population-based surveys, up to 33.7% of the population are affected by an anxiety disorder during their lifetime. Substantial underrecognition and undertreatment of these disorders have been demonstrated. There is no evidence that the prevalence rates of anxiety disorders have changed in the past years. In cross-cultural comparisons, prevalence rates are highly variable. It is more likely that this heterogeneity is due to differences in methodology than to cultural influences. Anxiety disorders follow a chronic course; however, there is a natural decrease in prevalence rates with older age. Anxiety disorders are highly comorbid with other anxiety disorders and other mental disorders. PMID- 26487814 TI - Cognitive-behavioral therapy for anxiety disorders: an update on the empirical evidence. AB - A large amount of research has accumulated on the efficacy and effectiveness of cognitive-behavioral therapy (CBT) for anxiety disorders including posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and specific phobia. The purpose of the current article is to provide an overview of two of the most commonly used CBT methods used to treat anxiety disorders (exposure and cognitive therapy) and to summarize and discuss the current empirical research regarding the usefulness of these techniques for each anxiety disorder. Additionally, we discuss the difficulties that arise when comparing active CBT treatments, and we suggest directions for future research. Overall, CBT appears to be both efficacious and effective in the treatment of anxiety disorders, but dismantling studies are needed to determine which specific treatment components lead to beneficial outcomes and which patients are most likely to benefit from these treatment components. PMID- 26487815 TI - Cognitive behavioral group therapy for anxiety: recent developments. AB - Anxiety disorders occur frequently, and can have a negative impact on the quality of people's lives. They often begin at an early age and can have some serious consequences. This article is an overview of the recent studies concerning group cognitive-behavioral interventions for anxiety disorders. In the last few years, anxiety disorder prevention for children and adolescents has become an important focus of research work. Group prevention programs are based on standard cognitive behavioral therapy (CBT) strategies and are aimed at preventing anxiety disorders as early as possible. Numerous cognitive behavioral group therapies for children as well as adults have been well studied. There are many CBT protocols that have been developed for treating specific anxiety disorders. Now, specialized CBT programs are available for individuals who suffer from different anxiety disorders, enabling them to be treated together in groups. PMID- 26487816 TI - Taxonomic review and phylogenetic analysis of fifteen North American Entomobrya (Collembola, Entomobryidae), including four new species. AB - The chaetotaxy of 15 species of eastern North American Entomobrya is redescribed in order to determine potential characters for the diagnosis of cryptic lineages and evaluate the diagnostic and phylogenetic utility of chaetotaxy. As a result, four new species (Entomobrya citrensis Katz & Soto-Adames, sp. n., Entomobrya jubata Katz & Soto-Adames, sp. n., Entomobrya neotenica Katz & Soto-Adames, sp. n. and Entomobrya unifasciata Katz & Soto-Adames, sp. n.) are described, and new diagnoses are provided for Entomobrya assuta Folsom, Entomobrya atrocincta Schott, Entomobrya decemfasciata (Packard), Entomobrya ligata Folsom, Entomobrya multifasciata (Tullberg), and Entomobrya quadrilineata (Bueker). Furthermore, previously undocumented levels of intraspecific variation in macrosetal pattern are reported, tempering the exclusive use of chaetotaxy for species delimitation. Phylogenetic relationships, estimated using both morphological and molecular data, indicate that Entomobrya is likely paraphyletic. The phylogenies also suggest that unreliable character homology, likely fostered by Entomobrya's profusion of macrosetae, may limit the phylogenetic utility of chaetotaxy in groups characterized by an abundance of dorsal macrosetae. PMID- 26487817 TI - Two new phragmotic ant species from Africa: morphology and next-generation sequencing solve a caste association problem in the genus Carebara Westwood. AB - Phragmotic or "door head" ants have evolved independently in several ant genera across the world, but in Africa only one case has been documented until now. Carebara elmenteitae (Patrizi) is known from only a single phragmotic major worker collected from sifted leaf-litter near Lake Elmenteita in Kenya, but here the worker castes of two species collected from Kakamega Forest, a small rainforest in Western Kenya, are studied. Phragmotic major workers were previously identified as Carebara elmenteitae and non-phragmotic major and minor workers were assigned to Carebara thoracica (Weber). Using evidence of both morphological and next-generation sequencing analysis, it is shown that phragmotic and non-phragmotic workers of the two different species are actually the same and that neither name - Carebara elmenteitae or Carebara thoracica - correctly applies to them. Instead, this and another closey related species from Ivory Coast are both morphologically different from Carebara elmenteitae, and thus they are described as the new species Carebara phragmotica sp. n. and Carebara lilith sp. n. PMID- 26487818 TI - A new species of Themus (Themus) Motschulsky from Yunnan, China and a redescription of T. (T.) testaceicollis Wittmer, 1983 (Coleoptera, Cantharidae). AB - A new species is described, Themus (Themus) dimorphus sp. n. from Yunnan, China. Themus (Themus) testaceicollis Wittmer, 1983 is redescribed and compared with the new species. The two species are illustrated with habitus and genitalia of both sexes and abdominal sternites VIII of female. PMID- 26487819 TI - New species without dead bodies: a case for photo-based descriptions, illustrated by a striking new species of Marleyimyia Hesse (Diptera, Bombyliidae) from South Africa. AB - A new bombyliid species Marleyimyia xylocopae Marshall & Evenhuis, sp. n., an apparent mimic of the carpenter bee Xylocopa flavicollis (De Geer), is described from South Africa on the basis of photographs only. The pros and cons of species descriptions in the absence of preserved type specimens are discussed. PMID- 26487820 TI - Two new species of the genus Anisomysis (Anisomysis) (Crustacea, Mysida, Mysidae) from coral reef waters in Thailand. AB - Two new species of Anisomysis Hansen, 1910 (Mysida, Mysidae), Anisomysis (Anisomysis) spinaintus sp. n. and Anisomysis (Anisomysis) phuketensis sp. n., from coral-reef waters in Thailand are described. Anisomysis (Anisomysis) spinaintus, collected in the Chaolao Beach, Chanthaburi Province, is distinguished from the closely allied species Anisomysis (Anisomysis) incisa Tattersall, 1936, and Anisomysis (Anisomysis) hawaiiensis Murano, 1995, by the presence of 6-9 spines on the apical cleft of telson, which are absent in the latter two allied species. The new species can also be distinguished from Anisomysis (Anisomysis) aikawai Ii, 1964, by the presence of a deep telson cleft and a large number of spines on the lateral margin of telson. Anisomysis (Anisomysis) phuketensis sp. n., collected in Ko Lon, Phuket, is distinguished from the allied species Anisomysis (Anisomysis) robustispina Panampunnayil, 1984, by having a short telson and a pair of long spines on the apical part of the telson. Keys to the subgenera and species of Anisomysis, including the two new species, are presented. PMID- 26487821 TI - A new species of Hemichela Stock, 1954 from the South China Sea (Arthropoda, Pycnogonida, Ammotheidae). AB - A new species of pycnogonid collected by the Chinese research vessel, R/V HY IV, during deep sea cruises to the South China Sea in 2013, is described. The new species, Hemichela nanhaiensis, obtained from more than 1300 m depth, is distinguished from the other two species in the genus by the characters of the chela dactylus with 12 denticulations on the inner margin and by the presence of taller tubercles on the lateral processes. PMID- 26487822 TI - Taxonomic studies on the ant genus Ponera Latreille, 1804 (Hymenoptera, Formicidae), with the description of a new species from India. AB - Four species of the ant genus Ponera Latreille, 1804, are recorded from India. The present study reports one new species Ponera sikkimensis sp. n., a divergent population of Ponera indica Bharti & Wachkoo, 2012 and one new record, Ponera paedericera Zhou, 2001 from India. An identification key and distributions for the four known Indian species of Ponera based on the worker caste are provided. PMID- 26487823 TI - Diagnostic survey of Malagasy Nesomyrmex species-groups and revision of hafahafa group species via morphology based cluster delimitation protocol. AB - Madagascar and its surrounding islands are among the world's greatest biodiversity hotspots, harboring predominantly endemic and threatened communities meriting special attention from biodiversity scientists. Building on the considerable efforts in recent years to inventory the Malagasy ant fauna, the myrmicine genus Nesomyrmex is reviewed and (1) subdivided into four major groups based on salient morphological features corroborated by numeric morphology: angulatus-, hafahafa-, madecassus- and sikorai-groups, and (2) the hafahafa species-group endemic to Madagascar is revised. Diversity within hafahafa species group was assessed via hypothesis-free nest-centroid-clustering combined with gap statistic to assess the number of clusters and to determine the most probable boundaries between them. This combination of methods provides a highly automatized, objective species delineation protocol based on continuous morphometric data. Delimitations of clusters recognized by these exploratory analyses were tested via confirmatory Linear Discriminant Analysis. These results suggest the existence of four morphologically distinct species, Nesomyrmex capricornis sp. n., Nesomyrmex hafahafa sp. n., Nesomyrmex medusus sp. n. and Nesomyrmex spinosus sp. n.; all are described and an identification key for their worker castes using morphometric data is provided. Two members of the newly outlined hafahafa species-group, Nesomyrmex hafahafa sp. n., Nesomyrmex medusus sp. n., are distributed along the southeastern coast Madagascar and occupy rather large ranges, but two other species, Nesomyrmex capricornis sp. n. and Nesomyrmex spinosus sp. n., are only known to occur in small and isolated forest, highlighting the importance of small forest patches for conserving arthropod diversity. PMID- 26487824 TI - How small is the smallest? New record and remeasuring of Scydosella musawasensis Hall, 1999 (Coleoptera, Ptiliidae), the smallest known free-living insect. AB - The smallest known beetle Scydosella musawasensis Hall is recorded for the second time. Precise measurements of its body size are given, and it is shown that the smallest examined representative of this species has a length of 325 um. PMID- 26487825 TI - Description of Trichophoromyia ruifreitasi, a new phlebotomine species (Diptera, Psychodidae) from Acre State, Brazilian Amazon. AB - Trichophoromyia ruifreitasi sp. n. is described as a new species of sand fly from the genus Trichophoromyia Barretto. This description is supported with illustrations and photographs that detail the morphological characteristics of male specimens collected in the municipality of Assis Brasil, Acre State, Brazilian Amazon. This species is similar to Trichophoromyia auraensis (Mangabeira), but the two species can be easily differentiated by the distribution of setae on their parameres, and by the presence of a dorsal lobe in the parameres of the new species. PMID- 26487826 TI - Revised generic placement of Brachypelma embrithes (Chamberlin & Ivie, 1936) and Brachypelma angustum Valerio, 1980, with definition of the taxonomic features for identification of female Sericopelma Ausserer, 1875 (Araneae, Theraphosidae). AB - The tarantula genus Sericopelma was originally defined based on male specimens, most notably lacking tibial spurs on leg I. Early female specimens were unrecognised as Sericopelma, and typically placed in Eurypelma - a dumping ground for problem specimens. The first females were only later recognised, but authors failed to adequately define female Sericopelma. Here, the holotypes of the southern-most alleged Brachypelma species, Brachypelma embrithes (Chamberlin & Ivie, 1936) and Brachypelma angustum Valerio, 1980 were examined, and finding both to possess defining characteristics of Sericopelma were transferred. The taxonomic attributes to define Sericopelma relative to Brachypelma and select other Neotropical genera are discussed, especially for females. As important diagnostic characters for Sericopelma, the single (unilobar) spermathecae swollen at the apex forming a P-shaped cross-section, metatarsus IV with trace scopula, femur IV with a dense retrolateral pad of plumose hair, plus other attributes. Some past confusion in these characters are clarified and Sericopelma relative to Brachypelma and Megaphobema mesomelas are discussed. Finally recommendations are given about these taxonomic changes for CITES regulations. PMID- 26487827 TI - Description of a new species of Julolaelaps (Acari, Mesostigmata, Laelapidae) from Iran. AB - Julolaelaps hallidayi sp. n., was collected from soil of river verge in Brujen, Chaharmahal va Bakhtiari province, Iran. Description and illustrations of this new species based on adult females are presented. Some entries are added to the key of Moraza and Kazemi (2012) to include the new species. PMID- 26487828 TI - Two new species of Xestoblatta Hebard, 1916 from Brazil, a redescription of Xestoblatta roppai Rocha e Silva Albuquerque & Fraga, 1975 and a key for the species of the buscki group (Blattodea, Ectobiidae, Blattellinae). AB - Two new species of Xestoblatta from northern Brazil are described, Xestoblatta buhrnheimi sp. n. and Xestoblatta rondonensis sp. n., included in the buscki group Gurney (1939), and new characters are added to the description of Xestoblatta mamorensis Lopes & Oliveira, 2006. Xestoblatta roppai Rocha e Albuquerque-Silva & Fraga, 1975, from midwestern Brazil is redescribed, including its genital characters which were not previously described. Additionally, a key for the species of this group is provided, and photographs are given of the species in the habitus, of tergal modifications, and of the genitalia. PMID- 26487829 TI - Three new species of Fonsecaiulus (Hemiptera, Cicadellidae, Cicadellini) from Brazil and key to species of the genus. AB - Three new sharpshooter species of the genus Fonsecaiulus Young, 1977 are described and illustrated from specimens collected in the Brazilian Atlantic Forest, Fonsecaiulus rectangularis and Fonsecaiulus guttiformis, and in the Brazilian Cerrado, Fonsecaiulus filiformis. The descriptions are based on features from the external morphology, color pattern, and male and female genital structures. Comparisons of the three new taxa with the remaining six Fonsecaiulus species are provided. An identification key to males of all known species of the genus is given. PMID- 26487830 TI - Curcumin and Apigenin - novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease. AB - Alzheimer's disease is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Current treatments for Alzheimer's disease primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease modifying drug is available for Alzheimer's disease patients. This review will provide an overview of the proven antioxidant, anti-inflammatory, anti amyloidogenic, neuroprotective, and cognition-enhancing effects of curcumin and apigenin and discuss the potential of these compounds for Alzheimer's disease prevention and treatment. We suggest that these compounds might delay the onset of Alzheimer's disease or slow down its progression, and they should enter clinical trials as soon as possible. PMID- 26487831 TI - Neuroimmunomodulatory effects of transcranial laser therapy combined with intravenous tPA administration for acute cerebral ischemic injury. AB - At present, the only FDA approved treatment for ischemic strokes is intravenous administration of tissue plasminogen activator within 4.5 hours of stroke onset. Owing to this brief window only a small percentage of patients receive tissue plasminogen activator. Transcranial laser therapy has been shown to be effective in animal models of acute ischemic stroke, resulting in significant improvement in neurological score and function. NEST-1 and NEST-2 clinical trials in human patients have demonstrated the safety and positive trends in efficacy of transcranial laser therapy for the treatment of ischemic stroke when initiated close to the time of stroke onset. Combining intravenous tissue plasminogen activator treatment with transcranial laser therapy may provide better functional outcomes. Statins given within 4 weeks of stroke onset improve stroke outcomes at 90 days compared to patients not given statins, and giving statins following transcranial laser therapy may provide an effective treatment for patients not able to be given tissue plasminogen activator due to time constraints. PMID- 26487832 TI - Nanotechnology and bio-functionalisation for peripheral nerve regeneration. AB - There is a high clinical demand for new smart biomaterials, which stimulate neuronal cell proliferation, migration and increase cell-material interaction to facilitate nerve regeneration across these critical-sized defects. This article briefly reviews several up-to-date published studies using Arginine-Glycine Aspartic acid peptide sequence, nanocomposite based on polyhedral oligomeric silsesquioxane nanoparticle and nanofibrous scaffolds as promising strategies to enhance peripheral nerve regeneration by influencing cellular behaviour such as attachment, spreading and proliferation. The aim is to establish the potent manipulations, which are simple and easy to employ in the clinical conditions for nerve regeneration and repair. PMID- 26487833 TI - A case to be made: theoretical and empirical arguments for the need to consider fatigue in post-stroke motor rehabilitation. PMID- 26487835 TI - The neuroprotective effects of human growth hormone as a potential treatment for amyotrophic lateral sclerosis. PMID- 26487834 TI - Distribution pattern of axonal cytoskeleton proteins in the human optic nerve head. PMID- 26487836 TI - The vascular stem cell niche: roadmap for transplanted neural progenitor cells during environmental enrichment? PMID- 26487837 TI - Localized regulation of the axon shaft during the emergence of collateral branches. PMID- 26487838 TI - Ubiquitin homeostasis: from neural stem cell differentiation to neuronal development. PMID- 26487839 TI - The neuroprotective potential of endoplasmic reticulum chaperones. PMID- 26487840 TI - Fractalkine: multiple strategies to counteract glutamate receptors activation leading to neuroprotection. PMID- 26487841 TI - A useful electroencephalography (EEG) marker of brain plasticity: delta waves. PMID- 26487842 TI - Combining motor learning and brain stimulation to enhance post-stroke neurorehabilitation. PMID- 26487843 TI - The neuroprotective effects of (S)-3,5-dihydroxyphenylglycine preconditioning in middle cerebral artery occluded rats: a perspective as a contrivance for stroke. PMID- 26487844 TI - Nogo-A and its functions beyond axonal inhibition: the controversial role of Nogo A in Parkinson's disease. PMID- 26487845 TI - A new mechanism for protection of dopaminergic neurons mediated by astrocytes. PMID- 26487846 TI - Identifying specific RGC types may shed light on their idiosyncratic responses to neuroprotection. PMID- 26487847 TI - A new tool for monitoring brain function: eye tracking goes beyond assessing attention to measuring central nervous system physiology. PMID- 26487848 TI - Central plasticity resulting from chronic low back pain in degenerative disorders of the spine. PMID- 26487849 TI - Aminoacyl tRNA synthetases and their relationships with peripheral nerve degeneration and regeneration. PMID- 26487850 TI - Neuroprotective effects of atorvastatin against cerebral ischemia/reperfusion injury through the inhibition of endoplasmic reticulum stress. AB - Cerebral ischemia triggers secondary ischemia/reperfusion injury and endoplasmic reticulum stress initiates cell apoptosis. However, the regulatory mechanism of the signaling pathway remains unclear. We hypothesize that the regulatory mechanisms are mediated by the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2alpha in the endoplasmic reticulum stress signaling pathway. To verify this hypothesis, we occluded the middle cerebral artery in rats to establish focal cerebral ischemia/reperfusion model. Results showed that the expression levels of protein kinase-like endoplasmic reticulum kinase and caspase-3, as well as the phosphorylation of eukaryotic initiation factor 2alpha, were increased after ischemia/reperfusion. Administration of atorvastatin decreased the expression of protein kinase-like endoplasmic reticulum kinase, caspase-3 and phosphorylated eukaryotic initiation factor 2alpha, reduced the infarct volume and improved ultrastructure in the rat brain. After salubrinal, the specific inhibitor of phosphorylated eukaryotic initiation factor 2alpha was given into the rats intragastrically, the expression levels of caspase-3 and phosphorylated eukaryotic initiation factor 2alpha in the were decreased, a reduction of the infarct volume and less ultrastructural damage were observed than the untreated, ischemic brain. However, salubrinal had no impact on the expression of protein kinase-like endoplasmic reticulum kinase. Experimental findings indicate that atorvastatin inhibits endoplasmic reticulum stress and exerts neuroprotective effects. The underlying mechanisms of attenuating ischemia/reperfusion injury are associated with the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2alpha/caspase-3 pathway. PMID- 26487851 TI - Exercise preconditioning exhibits neuroprotective effects on hippocampal CA1 neuronal damage after cerebral ischemia. AB - Recent evidence has suggested the neuroprotective effects of physical exercise on cerebral ischemic injury. However, the role of physical exercise in cerebral ischemia-induced hippocampal damage remains controversial. The aim of the present study was to evaluate the effects of pre-ischemia treadmill training on hippocampal CA1 neuronal damage after cerebral ischemia. Male adult rats were randomly divided into control, ischemia and exercise + ischemia groups. In the exercise + ischemia group, rats were subjected to running on a treadmill in a designated time schedule (5 days per week for 4 weeks). Then rats underwent cerebral ischemia induction through occlusion of common carotids followed by reperfusion. At 4 days after cerebral ischemia, rat learning and memory abilities were evaluated using passive avoidance memory test and rat hippocampal neuronal damage was detected using Nissl and TUNEL staining. Pre-ischemic exercise significantly reduced the number of TUNEL-positive cells and necrotic cell death in the hippocampal CA1 region as compared to the ischemia group. Moreover, pre ischemic exercise significantly prevented ischemia-induced memory dysfunction. Pre-ischemic exercise mighct prevent memory deficits after cerebral ischemia through rescuing hippocampal CA1 neurons from ischemia-induced degeneration. PMID- 26487852 TI - Activation of immediate-early response gene c-Fos protein in the rat paralimbic cortices after myocardial infarction. AB - c-Fos is a good biological marker for detecting the pathogenesis of central nervous system disorders. Few studies are reported on the change in myocardial infarction-induced c-Fos expression in the paralimbic regions. Thus, in this study, we investigated the changes in c-Fos expression in the rat cingulate and piriform cortices after myocardial infarction. Neuronal degeneration in cingulate and piriform cortices after myocardial infarction was detected using cresyl violet staining, NeuN immunohistochemistry and Fluoro-Jade B histofluorescence staining. c-Fos-immunoreactive cells were observed in cingulate and piriform cortices at 3 days after myocardial infarction and peaked at 7 and 14 days after myocardial infarction. But they were hardly observed at 56 days after myocardial infarction. The chronological change of c-Fos expression determined by western blot analysis was basically the same as that of c-Fos immunoreactivity. These results indicate that myocardial infarction can cause the chronological change of immediate-early response gene c-Fos protein expression, which might be associated with the neural activity induced by myocardial infarction. PMID- 26487853 TI - Activation of the Notch signaling pathway promotes neurovascular repair after traumatic brain injury. AB - The Notch signaling pathway plays a key role in angiogenesis and endothelial cell formation, but it remains unclear whether it is involved in vascular repair by endothelial progenitor cells after traumatic brain injury. Therefore, in the present study, we controlled the Notch signaling pathway using overexpression and knockdown constructs. Activation of the Notch signaling pathway by Notch1 or Jagged1 overexpression enhanced the migration, invasiveness and angiogenic ability of endothelial progenitor cells. Suppression of the Notch signaling pathway with Notch1 or Jagged1 siRNAs reduced the migratory capacity, invasiveness and angiogenic ability of endothelial progenitor cells. Activation of the Notch signaling pathway in vivo in a rat model of mild traumatic brain injury promoted neurovascular repair. These findings suggest that the activation of the Notch signaling pathway promotes blood vessel formation and tissue repair after brain trauma. PMID- 26487854 TI - Bone marrow mesenchymal stem cells transplantation promotes the release of endogenous erythropoietin after ischemic stroke. AB - This study investigated whether bone marrow mesenchymal stem cell (BMSC) transplantation protected ischemic cerebral injury by stimulating endogenous erythropoietin. The model of ischemic stroke was established in rats through transient middle cerebral artery occlusion. Twenty-four hours later, 1 * 10(6) human BMSCs (hBMSCs) were injected into the tail vein. Fourteen days later, we found that hBMSCs promoted the release of endogenous erythropoietin in the ischemic region of rats. Simultaneously, 3 MUg/d soluble erythropoietin receptor (sEPOR) was injected into the lateral ventricle, and on the next 13 consecutive days. sEPOR blocked the release of endogenous erythropoietin. The neurogenesis in the subventricular zone was less in the hBMSCs + sEPOR group than in the hBMSCs + heat-denatured sEPOR group. The adhesive-removal test result and the modified Neurological Severity Scores (mNSS) were lower in the hBMSCs + sEPOR group than in the heat-denatured sEPOR group. The adhesive-removal test result and mNSS were similar between the hBMSCs + heat-denatured sEPOR group and the hBMSCs + sEPOR group. These findings confirm that BMSCs contribute to neurogenesis and improve neurological function by promoting the release of endogenous erythropoietin following ischemic stroke. PMID- 26487855 TI - The key target of neuroprotection after the onset of ischemic stroke: secretory pathway Ca(2+)-ATPase 1. AB - The regulatory mechanisms of cytoplasmic Ca(2+) after myocardial infarction induced Ca(2+) overload involve secretory pathway Ca(2+)-ATPase 1 and the Golgi apparatus and are well understood. However, the effect of Golgi apparatus on Ca(2+) overload after cerebral ischemia and reperfusion remains unclear. Four vessel occlusion rats were used as animal models of cerebral ischemia. The expression of secretory pathway Ca(2+)-ATPase 1 in the cortex and hippocampus was detected by immunoblotting, and Ca(2+) concentrations in the cytoplasm and Golgi vesicles were determined. Results showed an overload of cytoplasmic Ca(2+) during ischemia and reperfusion that reached a peak after reperfusion. Levels of Golgi Ca(2+) showed an opposite effect. The expression of Golgi-specific secretory pathway Ca(2+)-ATPase 1 in the cortex and hippocampus decreased before ischemia and reperfusion, and increased after reperfusion for 6 hours. This variation was similar to the alteration of calcium in separated Golgi vesicles. These results indicate that the Golgi apparatus participates in the formation and alleviation of calcium overload, and that secretory pathway Ca(2+)-ATPase 1 tightly responds to ischemia and reperfusion in nerve cells. Thus, we concluded that secretory pathway Ca(2+)-ATPase 1 plays an essential role in cytosolic calcium regulation and its expression can be used as a marker of Golgi stress, responding to cerebral ischemia and reperfusion. The secretory pathway Ca(2+)-ATPase 1 can be an important neuroprotective target of ischemic stroke. PMID- 26487856 TI - Dantrolene enhances the protective effect of hypothermia on cerebral cortex neurons. AB - Therapeutic hypothermia is the most promising non-pharmacological neuroprotective strategy against ischemic injury. However, shivering is the most common adverse reaction. Many studies have shown that dantrolene is neuroprotective in in vitro and in vivo ischemic injury models. In addition to its neuroprotective effect, dantrolene neutralizes the adverse reaction of hypothermia. Dantrolene may be an effective adjunctive therapy to enhance the neuroprotection of hypothermia in treating ischemic stroke. Cortical neurons isolated from rat fetuses were exposed to 90 minutes of oxygen-glucose deprivation followed by reoxygenation. Neurons were treated with 40 MUM dantrolene, hypothermia (at 33 degrees C), or the combination of both for 12 hours. Results revealed that the combination of dantrolene and hypothermia increased neuronal survival and the mitochondrial membrane potential, and reduced intracellular active oxygen cytoplasmic histone associated DNA fragmentation, and apoptosis. Furthermore, improvements in cell morphology were observed. The combined treatment enhanced these responses compared with either treatment alone. These findings indicate that dantrolene may be used as an effective adjunctive therapy to enhance the neuroprotective effects of hypothermia in ischemic stroke. PMID- 26487857 TI - The E3 ubiquitin ligase seven in absentia homolog 1 may be a potential new therapeutic target for Parkinson's disease. AB - In this study, we investigated the effect of an antibody against E3 ubiquitin ligase seven in absentia homolog 1 (SIAH-1) in PC12 cells. 1-Methyl-4 phenylpyridinium (MPP(+)) treatment increased alpha-synuclein, E1 and SIAH-1 protein levels in PC12 cells, and it reduced cell viability; however, there was no significant change in light chain 3 expression. Treatment with an SIAH-1 antibody decreased mRNA expression levels of alpha-synuclein, light chain 3 and SIAH-1, but increased E1 mRNA expression. It also increased cell viability. Combined treatment with MPP(+) and rapamycin reduced SIAH-1 and alpha-synuclein levels. Treatment with SIAH-1 antibody alone diminished alpha-synuclein immunoreactivity in PC12 cells, and reduced the colocalization of alpha-synuclein and light chain 3. These findings suggest that the SIAH-1 antibody reduces the monoubiquitination and aggregation of alpha-synuclein, promoting its degradation by the ubiquitin-proteasome pathway. Consequently, SIAH-1 may be a potential new therapeutic target for Parkinson's disease. PMID- 26487858 TI - Protective effects of components of the Chinese herb grassleaf sweetflag rhizome on PC12 cells incubated with amyloid-beta42. AB - The major ingredients of grassleaf sweetflag rhizome are beta-asarone and eugenol, which can cross the blood-brain barrier and protect neurons. This study aimed to observe the neuroprotective effects and mechanisms of beta-asarone and eugenol, components of the Chinese herb grassleaf sweetflag rhizome, on PC12 cells. First, PC12 cells were cultured with different concentrations (between 1 * 10(-10) M and 1 * 10(-5) M) of beta-asarone and eugenol. Survival rates of PC12 cells were not significantly affected. Second, PC12 cells incubated with amyloid beta42, which reduced cell survival, were cultured under the same conditions (1 * 10(-6) M beta-asarone and eugenol). The survival rates of PC12 cells significantly increased, while expression levels of the mRNAs for the pro apoptotic protein Bax decreased, and those for the anti-apoptotic protein Bcl mRNA increased. In addition, the combination of beta-asarone with eugenol achieved better results than either component alone. Our experimental findings indicate that both beta-asarone and eugenol protect PC12 cells through inhibiting apoptosis, and that the combination of the two is better than either alone. PMID- 26487859 TI - Electroacupuncture pretreatment exhibits anti-depressive effects by regulating hippocampal proteomics in rats with chronic restraint stress. AB - The clinical effect of electroacupuncture on depression is widely recognized. However, the signal transduction pathways and target proteins involved remain unclear. In the present study, rat models of chronic restraint stress were used to explore the mechanism by which electroacupuncture alleviates depression. Rats were randomly divided into control, model, and electroacupuncture groups. Chronic restraint stress was induced in the model and electroacupuncture groups by restraining rats for 28 days. In the electroacupuncture group, electroacupuncture pretreatment at Baihui (GV20) and Yintang (GV29) acupoints was performed daily (1 mA, 2 Hz, discontinuous wave, 20 minutes) prior to restraint for 28 days. Open field tests and body weight measurements were carried out to evaluate the depressive symptoms at specific time points. On day 28, the crossing number, rearing number, and body weights of the model group were significantly lower than those in the control group. Behavior test results indicated that rat models of depressive-like symptoms were successfully established by chronic restraint stress combined with solitary raising. On day 28, an isobaric tag for a relative and absolute quantitation-based quantitative proteomic approach was performed to identify differentially expressed proteins in hippocampal samples obtained from the model and electroacupuncture groups. The potential function of these differential proteins was predicted through the use of the Cluster of Orthologous Groups of proteins (COG) database. Twenty-seven differential proteins (uncharacteristic proteins expected) were selected from the model and electroacupuncture groups. In addition to unknown protein functions, COG are mainly concentrated in general prediction function, mechanism of signal transduction, amino acid transport and metabolism groups. This suggests that electroacupuncture improved depressive-like symptoms by regulating differential proteins, and most of these related proteins exist in nerve cells. PMID- 26487860 TI - Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation. AB - Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-labeled bone marrow mesenchymal stem cells and fluorogold-labeled nerve fibers were increased and hindlimb motor function of spinal cord-injured rats was markedly improved. These improvements were more prominent in rats subjected to bone marrow mesenchymal cell transplantation combined with propofol administration than in rats receiving monotherapy. These results indicate that propofol can enhance the therapeutic effects of bone marrow mesenchymal stem cell transplantation on spinal cord injury in rats. PMID- 26487861 TI - Differentiation of Wharton's jelly mesenchymal stem cells into neurons in alginate scaffold. AB - Alginate scaffold has been considered as an appropriate biomaterial for promoting the differentiation of embryonic stem cells toward neuronal cell lineage. We hypothesized that alginate scaffold is suitable for culturing Wharton's jelly mesenchymal stem cells (WJMSCs) and can promote the differentiation of WJMSCs into neuron-like cells. In this study, we cultured WJMSCs in a three-dimensional scaffold fabricated by 0.25% alginate and 50 mM CaCl2 in the presence of neurogenic medium containing 10 MUM retinoic acid and 20 ng/mL basic fibroblast growth factor. These cells were also cultured in conventional two-dimensional culture condition in the presence of neurogenic medium as controls. After 10 days, immunofluorescence staining was performed for detecting beta-tubulin (marker for WJMSCs-differentiated neuron) and CD271 (motor neuron marker). beta Tubulin and CD271 expression levels were significantly greater in the WJMSCs cultured in the three-dimensional alginate scaffold than in the conventional two dimensional culture condition. These findings suggest that three-dimensional alginate scaffold cell culture system can induce neuronal differentiation of WJMSCs effectively. PMID- 26487862 TI - Panax notoginseng saponins improve recovery after spinal cord transection by upregulating neurotrophic factors. AB - Saponins extracted from Panax notoginseng are neuroprotective, but the mechanisms underlying this effect remain unclear. In the present study, we established a rat model of thoracic (T10) spinal cord transection, and injected Panax notoginseng saponins (100 mg/kg) or saline 30 minutes after injury. Locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) scale from 1 to 30 days after injury, and immunohistochemistry was carried out in the ventral horn of the spinal cord at 1 and 7 days to determine expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Our results show that at 7-30 days post injury, the BBB score was higher in rats treated with Panax notoginseng saponins than in those that received saline. Furthermore, at 7 days, more NGF- and BDNF-immunoreactive neurons were observed in the ventral horn of the spinal cord of rats that had received Panax notoginseng saponins than in those that received saline. These results indicate that Panax notoginseng saponins caused an upregulation of NGF and BDNF in rats with spinal cord transection, and improved hindlimb motor function. PMID- 26487863 TI - Buyang Huanwu decoction up-regulates Notch1 gene expression in injured spinal cord. AB - Expression of genes in the Notch signaling pathway is altered in the injured spinal cord, which indicates that Notch participates in repair after spinal cord injury. Buyang Huanwu decoction, a traditional Chinese herbal preparation, can promote the growth of nerve cells and nerve fibers; however, it is unclear whether Buyang Huanwu decoction affects the Notch signaling pathway in injured spinal cord. In this study, a rat model was established by injuring the T10 spinal cord. At 2 days after injury, rats were intragastrically administered 2 mL of 0.8 g/mL Buyang Huanwu decoction daily until sacrifice. Real-time reverse transcription polymerase chain reaction analysis demonstrated that at 7, 14 and 28 days after injury, the expression of Notch1 was increased in the Buyang Huanwu decoction group compared with controls. These findings confirm that Buyang Huanwu decoction can promote the expression of Notch1 in rats with incomplete spinal cord injury, and may indicate a mechanism to promote the repair of spinal cord injury. PMID- 26487864 TI - Blockade of transient receptor potential cation channel subfamily V member 1 promotes regeneration after sciatic nerve injury. AB - The transient receptor potential cation channel subfamily V member 1 (TRPV1) provides the sensation of pain (nociception). However, it remains unknown whether TRPV1 is activated after peripheral nerve injury, or whether activation of TRPV1 affects neural regeneration. In the present study, we established rat models of unilateral sciatic nerve crush injury, with or without pretreatment with AMG517 (300 mg/kg), a TRPV1 antagonist, injected subcutaneously into the ipsilateral paw 60 minutes before injury. At 1 and 2 weeks after injury, we performed immunofluorescence staining of the sciatic nerve at the center of injury, at 0.3 cm proximal and distal to the injury site, and in the dorsal root ganglia. Our results showed that Wallerian degeneration occurred distal to the injury site, and neurite outgrowth and Schwann cell regeneration occurred proximal to the injury. The number of regenerating myelinated and unmyelinated nerve clusters was greater in the AMG517-pretreated rats than in the vehicle-treated group, most notably 2 weeks after injury. TRPV1 expression in the injured sciatic nerve and ipsilateral dorsal root ganglia was markedly greater than on the contralateral side. Pretreatment with AMG517 blocked this effect. These data indicate that TRPV1 is activated or overexpressed after sciatic nerve crush injury, and that blockade of TRPV1 may accelerate regeneration of the injured sciatic nerve. PMID- 26487865 TI - Microencapsulation improves inhibitory effects of transplanted olfactory ensheathing cells on pain after sciatic nerve injury. AB - Olfactory bulb tissue transplantation inhibits P2X2/3 receptor-mediated neuropathic pain. However, the olfactory bulb has a complex cellular composition, and the mechanism underlying the action of purified transplanted olfactory ensheathing cells (OECs) remains unclear. In the present study, we microencapsulated OECs in alginic acid, and transplanted free and microencapsulated OECs into the region surrounding the injured sciatic nerve in rat models of chronic constriction injury. We assessed mechanical nociception in the rat models 7 and 14 days after surgery by measuring paw withdrawal threshold, and examined P2X2/3 receptor expression in L4-5 dorsal root ganglia using immunohistochemistry. Rats that received free and microencapsulated OEC transplants showed greater withdrawal thresholds than untreated model rats, and weaker P2X2/3 receptor immunoreactivity in dorsal root ganglia. At 14 days, paw withdrawal threshold was much higher in the microencapsulated OEC-treated animals. Our results confirm that microencapsulated OEC transplantation suppresses P2X2/3 receptor expression in L4-5 dorsal root ganglia in rat models of neuropathic pain and reduces allodynia, and also suggest that transplantation of microencapsulated OECs is more effective than transplantation of free OECs for the treatment of neuropathic pain. PMID- 26487867 TI - Neuroprotective effects of monosialotetrahexosylganglioside. PMID- 26487866 TI - Axon regeneration impediment: the role of paired immunoglobulin-like receptor B. AB - Regenerative capacity is weak after central nervous system injury because of the absence of an enhancing microenvironment and presence of an inhibitory microenvironment for neuronal and axonal repair. In addition to the Nogo receptor (NgR), the paired immunoglobulin-like receptor B (PirB) is a recently discovered coreceptor of Nogo, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein. Concurrent blocking of NgR and PirB almost completely eliminates the inhibitory effect of myelin-associated inhibitory molecules on axonal regeneration. PirB participates in a key pathological process of the nervous system, specifically axonal regeneration inhibition. PirB is an inhibitory receptor similar to NgR, but their effects are not identical. This study summarizes the structure, distribution, relationship with common nervous system diseases, and known mechanisms of PirB, and concludes that PirB is also distributed in cells of the immune and hematopoietic systems. Further investigations are needed to determine if immunomodulation and blood cell migration involve inhibition of axonal regeneration. PMID- 26487868 TI - "World heart day 2014", Significance of cardiovascular diseases in east of Iran. PMID- 26487869 TI - Red cell distribution width predicts deaths in patients with acute pancreatitis. AB - BACKGROUND: To investigate the association between the red cell distribution width (RDW) and mortality in patients with acute pancreatitis (AP), and to assess the ability of RDW to predict mortality in AP patients. MATERIALS AND METHODS: This retrospective cohort study included 120 patients (50 males and 70 females) with AP who were admitted to the First Affiliated Hospital of Zhongshan Medical University from January 2011 to October 2013. Demographic data and laboratory measures including RDW were obtained from medical records of each patient. A receiver operating characteristic (ROC) curve analysis was used to assess RDW values to predict the death of AP patients. RESULTS: The serum concentration levels of total Ca(2+) (P = 0.007) and albumin (P < 0.001), and the white blood cell counts (P = 0.005) were significantly lower, and the mortality rate (P < 0.001) and body mass index (P < 0.001) were significantly higher (P = <0.001, <0.001) in patients with RDW values of >13.4% than in patients with RDW values of <=13.4%. RDW values were negatively correlated with the serum concentration levels of albumin (r = -0.212, P = 0.012) and total Ca(2+) (r = -0.206, P = 0.033), and were positively correlated with the patient's age (r = 0.201, P = 0.035). ROC analysis showed that the AUC for the RDW value was 0.894 (P < 0.001, 95% confidence interval = 0.823-0.966), and the optimal cut-off value to predict death was 14.35 (sensitivity = 88.2%, specificity = 91.8%). CONCLUSION: Red cell distribution width is a potentially new and sensitive predictor of mortality in patients with AP. PMID- 26487870 TI - The rate of antibiotic utilization in Iranian under 5-year-old children with acute respiratory tract illness: A nationwide community-based study. AB - BACKGROUND: To investigate the prevalence of antibiotic usage in children aged <5 years with acute respiratory tract illness (ARTI) in Iran. MATERIALS AND METHODS: Data were collected from a national health survey conducted in 2010 (Iran's Multiple Indicator Demographic and Health Survey). Participants of this cross sectional study were selected by multistage stratified cluster-random sampling from 31 provinces of Iran. Parents of children with <5 years of age responded to questions about the occurrence of any cough during the previous 2 weeks, referral to private/governmental/other health care systems, and utilization of any oral/injection form of antibiotics. Data were analyzed using SPSS software18. The chi-square test was used to determine antibiotic consumption in various gender and residency groups and also a place of residence with the referral health care system. RESULTS: Of the 9345 children under 5 years who participated in the study, 1506 cases (16.2%) had ARTI during 2 weeks prior to the interview, in whom 1143 (75.9%) were referred to urban or rural health care centers (43.4 vs. 30.4%; P < 0.001). Antibiotics were utilized by 715 (62.6%) of affected children. Injection formulations were used for 150 (13.1%) patients. The frequency of receiving antibiotics was higher in urban than in rural inhabitants (66.0% vs. 57.7% P < 0.05). CONCLUSION: The prevalence of total and injection antibiotics usage in children <5 years with ARTI is alarmingly high in Iran. Therefore, interventions to reduce antibiotic use are urgently needed. PMID- 26487871 TI - Spatial analysis of myocardial infarction in Iran: National report from the Iranian myocardial infarction registry. AB - BACKGROUND: Myocardial infarction (MI) is a leading cause of mortality and morbidity in Iran. No spatial analysis of MI has been conducted to date. The present study was conducted to determine the pattern of MI incidence and to identify the associated factors in Iran by province. MATERIALS AND METHODS: This study has two parts. One part is prospective and hospital-based, and the other part is an ecological study. In this study, the data of 20,750 new MI cases registered in Iranian Myocardial Infarction Registry in 2012 were used. For spatial analysis in global and local, spatial autocorrelation, Moran's I, Getis Ord, and logistic regression models were used. Data were analyzed by Stata software and ArcGIS 9.3. RESULTS: Based on autocorrelation coefficient, a specific pattern was observed in the distribution of MI incidence in different provinces (Moran's I: 0.75, P < 0.001). Spatial pattern of incidence was approximately the same in men and women. MI incidence was clustering in six provinces (North Khorasan, Yazd, Kerman, Semnan, Golestan, and Mazandaran). Out of the associated factors with clustered MI in six provinces, temperature, humidity, hypertension, smoking, and body mass index (BMI) could be mentioned. Hypertension, smoking, and BMI contributed to clustering with, respectively, 2.36, 1.31, and 1.31 odds ratio. CONCLUSION: Addressing the place-based pattern of incidence and clarifying their epidemiologic dimension, including spatial analysis, has not yet been implemented in Iran. Report on MI incidence rate by place and formal borders is useful and is used in the planning and prioritization in different levels of health system. PMID- 26487873 TI - Results of distraction callus osteogenesis in hand and foot in Iran: A 15-year experience. AB - BACKGROUND: Distraction osteogenesis (DS) is currently an important technique for lengthening shortened bones of the hand and foot. Authors report their experience in applying DS for various conditions of the hand and foot using a distractor that the senior author has designed. MATERIALS AND METHODS: Records of patients who underwent DS for hand and foot conditions in a private clinic were retrieved between January 2001 and January 2015. Data concerning distraction, outcome, and complications were recorded. RESULTS: There were 17 patients, 7 males, and 10 females with a total 24 distractions. The mean length gained was 21.2 mm (1.69) and the mean total treatment time was 198.58 (15.88) days. Overall, complications occurred in 9 (37.5%) distractions. Major complications occurred in 2 (8.33%) of distractions. Minor complications occurred in 7 (29.2%) distractions. CONCLUSION: DS is an effective modality for lengthening bones of the hand and feet for both traumatic and congenital conditions. Joint stiffness/contracture is an important complication following DS of the metatarsals. PMID- 26487872 TI - Weight disorders and anthropometric indices according to socioeconomic status of living place in Iranian children and adolescents: The CASPIAN-IV study. AB - BACKGROUND: Excess weight in children and adolescents is a multi-factorial phenomenon and associated with earlier risk of obesity-related diseases. This study aims to assess the prevalence of weight disorders and the mean values of anthropometric indices according to regional, socioeconomic, and urban-rural variations among Iranian children and adolescents. MATERIALS AND METHODS: This nationwide study was performed in 2011-2012 among a representative multi-stage cluster sample of 14,880 Iranian students aged 6-8 years. The World Health Organization (WHO) reference curves were used to define weight disorders. Abdominal obesity was defined as the waist-to-height ratio (WHtR) of more than 0.5. Iran was classified into four regions according to the socioeconomic status (SES). RESULTS: The mean (95% confidence interval) of body mass index (BMI), waist circumference (WC), and hip circumference (HC) was 18.8 (18.7, 18.9) kg/m(2), 67.0 (66.7, 67.3) cm, and 80.8 (80.3, 81.2) cm, respectively. The prevalence of underweight was 12.2%. A total of 9.7%, 11.9%, and 19.1% of students overweight, obese, and abdominally obese, respectively. The highest mean of BMI, WC, wrist circumference, HC, and WHtR were related to the second high SES (North-northeast) area (19.2 [18.8, 19.5], 68.3 [67.3, 69.4], 14.8 [14.7, 15.0], 82.6 [81.1, 84.0], and 0.464 [0.460, 0.468]). In contrast, the lowest SES (Southeast) region had the lowest mean of these anthropometric indices (17.6 [17.1, 18.2], 63.2 [61.7, 64.8], 14.5 [14.2, 14.8], 76.9 [74.9, 79.0], and 0.439 [0.434, 0.444]). CONCLUSION: We found considerable differences in the prevalence of anthropometric measures throughout the country by SES of the region. Health policy making and implementing health strategies should consider SES of regions. PMID- 26487874 TI - Significance of pulmonary nodules in multi-detector computed tomography scan of noncancerous patients. AB - BACKGROUND: Computed tomography (CT) scan is one the most useful devices in chest imaging. CT scan can be used in mediastinal abnormality, lungs, and pleural evaluations. According to the high prevalence and different causes of pulmonary nodules, we designed this study to evaluate the prevalence and the types of pulmonary nodules in noncancerous patients who underwent chest multi-detector CT (MDCT) scan. MATERIALS AND METHODS: This was a cross-sectional study which was in our hospital to evaluate the prevalence of pulmonary nodules in noncancerous patients who underwent MDCT. A checklist was used for data collection containing number, location, size, and shape of pulmonary nodules if present in CT scan, and we also included patient's age and history of smoking. We analyzed the data with Statistical Program for Social Sciences software (version 18). RESULTS: In this study, 115 patients (40%) had a pulmonary nodule. The mean number of a total nodule in each patient was 0.8 +/- 0.07. Mean number of intra-parenchymal, sub pleural, and perivascular nodules were 0.34 +/- 0.04, 0.31 +/- 0.04, and 0.14 +/- 0.02, respectively. The mean number of calcified nodules was 0.13 +/- 0.02. There was no significant correlation between age and nodule characteristics (P > 0.05). CONCLUSION: The prevalence of pulmonary nodules was quite frequent in MDCT scan of noncancerous cases. So, it should not be overvalued in noncancerous cases. PMID- 26487875 TI - Metabolic syndrome and its components associated with chronic kidney disease. AB - BACKGROUND: There is limited information on the relationship between metabolic syndrome (MetS) and chronic kidney disease (CKD) in the Iranian population, a group that has a high prevalence of CKD and obesity. The aim of present study was to determine the relationship between MetS and CKD in West of Iran. MATERIALS AND METHODS: A total of 800 subjects aged more than 35 years admitted from 2011 to 2013 were enrolled in the study. MetS was defined based on the Adult Treatment Panel III criteria, and CKD was defined from the Kidney Disease Outcomes Quality Initiative practice guidelines. Waist circumference and body mass index were calculated, as well, blood samples were taken and lipid profile, plasma glucose levels, and serum creatinine were measured. Data were analyzed with SPSS version 17 (SPSS Inc., Chicago, IL, USA). RESULTS: CKD was seen in 14.8% patients with MetS and 8.3% individuals without MetS. MetS was associated with an increased odds ratio (OR) for a glomerular filtration rate <60 ml/min/1.73 m(2) (OR: 1.91; 95% confidence interval [CI]: 1.22-2.99; P = 0.004). Individuals with 2, 3, 4, and 5 components of the MetS had an increased OR for CKD: 2.19 (95% CI: 0.95 3.62), 2.65 (95% CI: 1.03-4.71), 2.86 (95% CI: 1.08-5.53), and 5.03 (95% CI: 1.80 8.57), respectively, compared with individuals with none of the components. CONCLUSION: We found a high prevalence of CKD in patients with MetS compared with the subject without MetS. Our observations raised major clinical and public health concerns in Iran, where both the MetS and kidney diseases are becoming common. PMID- 26487876 TI - The relationship between five-factor model and diagnostic and statistical manual of mental disorder-fifth edition personality traits on patients with antisocial personality disorder. AB - BACKGROUND: Despite the fact that new criteria of antisocial personality disorder (ASPD) in diagnostic and statistical manual of mental disorders-fifth edition (DSM-5) were resulted from five-factor model (FFM), there is a small amount of studies that investigate the relations between proposed personality traits and FFM. Also, cross-cultural study in this field continuously would be needed. The aim of the present study was to evaluate the relation between the FFM and DSM-5 ASPD pathological traits. MATERIALS AND METHODS: This study was a cross-sectional study design. The participants consisted of 122 individuals with ASPD that selected from prisoners (73.0%), outpatients (18.0%), and inpatients (9.0%). They were recruited from Tehran Prisoners, and Clinical Psychology and Psychiatry Clinics of Razi and Taleghani Hospitals, Tehran, Iran, since 2013-2014. The Sample was selected based on judgmental sampling. The structured clinical interview for DSM-IV axis II disorders-Personality Questionnaire, NEO-Personality Inventory-Revised, and DSM-5 personality trait rating form were used to diagnosis and assessment of personality disorder. Pearson correlation has been used for data analysis. All statistical analyses were performed using the SPSS 16 software. RESULTS: The results indicate that neuroticism (N) has positive significant relationship with hostility (r = 0.33, P < 0.01), manipulativeness (r = 0.25, P < 0.01), deceitfulness (r =.23, P < 0.01), impulsivity (r = 0.20, P < 0.05), and negative relation with risk taking (r = -0.23, P < 0.01). Also, there was significant relationship between extraversion (E) with manipulativeness (r = 0.28, P < 0.01) and deceitfulness (r = 0.32, P < 0.01). Agreeableness and conscientiousness have negative significant relation with DSM-5 traits. In addition, results showed that there is positive significant relationship between FFM and DSM-5 personality traits with DSM-fourth edition-text revision (DSM-IV TR) ASPD symptoms (P < 0.01). CONCLUSION: Except manipulativeness, deceitfulness, and callousness, there is positively significant relationship between DSM-5 ASPD traits and DSM-IV-TR ASPD symptoms. The present study helps to understand the adequacy of dimensional approach to evaluation of ASPD pathology, specifically on Iranian sample. PMID- 26487877 TI - Effect of Vitamin D supplementation on symptoms and C-reactive protein in migraine patients. AB - BACKGROUND: Migarine is the most common headache around the world including Iran. In recent years, Vitamin D deficiency has been shown to a global health problem. A few studies have been determined inverse association between serum levels of Vitamin D with a headache. So, in this study, we investigated the effect of Vitamin D supplementation on symptoms and C-reactive protein (CRP) among patients with migraine. MATERIALS AND METHODS: This study was randomized, double-blind, and controlled-placebo clinical trial. Sixty-five migraine patients aged 10-61 years were included for analysis. Vitamin D was administrated for 10 weeks with 50,000 IU dosage of Vitamin D per week. Multivariate analysis of covariate and univariate analysis of covariate were done to determine the effects of Vitamin D supplementation on symptoms, including severity, duration, frequency of headache, and the headache diary result (HDR). RESULTS: Mean headache frequency and HDR had significant difference among two groups (5.9 +/- 7.0 vs. 7.0 +/- 6.0, P = 0.06 and 85.0 +/- 134.2 vs. 132.1 +/- 147.1, P = 0.04). But, a mean difference of headache frequency was marginally significant (P = 0.06). These values were lower among the intervention group compared to placebo group. The association was not observed between CRP with migraine disease. CONCLUSION: In this study, we shown Vitamin D supplementation may be useful in decreasing frequency of headache attacks and HDR among patients with migraine. PMID- 26487878 TI - Comparison of the effectiveness and safety of formoterol versus salmeterol in the treatment of patients with asthma: A systematic review and meta-analysis. AB - BACKGROUND: Formoterol and salmeterol are two long-acting beta2-agonists given by inhalation, with bronchodilating effects lasting for at least 12 h after a single administration. Formoterol has a faster onset of action compared with salmeterol. The aim of this study was to perform a systematic review and meta-analysis on the data published from previous review in order to calculate pooled estimates of effectiveness and safety assessment of formoterol and salmeterol in treatment of patients with asthma. MATERIALS AND METHODS: In this study, we conducted an electronic search for medical citation databases including Cochrane, PubMed, Scopus, PsycInfo, and IranMedex. Besides manual search of the databases that record randomized clinical trials, conference proceedings, and journals related to asthma were included. Studies were evaluated by two independent people based on inclusion and exclusion criteria, and the common outcomes of studies were entered into the RevMan 5.0.1 software, after evaluation of studies and extraction of data from them; and in cases where there were homogeneous studies, meta-analysis was performed, and for heterogeneous studies, the results were reported qualitatively. RESULTS: Of the 1539 studies initially found, 13 were included in the study. According to the meta-analysis conducted, no significant difference was found between the inhalation of formoterol 12 MUg and salmeterol 50 MUg in the two outcomes of mean forced expiratory volume 1 s (FEV1), 12 h after inhalation of medication and Borg score (A frequently used scale for quantifying breathlessness) after inhalation of medication. In addition, salmeterol was more effective than formoterol in the two outcomes of percent decrease in FEV1 after inhalation of methacholine and the number of days without an attack. Since the two outcomes of FEV1 30-60 min after inhalation of medication and morning peak expiratory flow after inhalation of medication were heterogeneous, they had no meta-analysis capabilities, and its results were reported qualitatively. CONCLUSION: The data from included studies shows that, more efficacy has been achieved with Salmeterol, especially in some outcomes such as the percent decrease in FEV1 after inhalation of Methacholine, and the number of days without an attack; and therefore, the administration of Salmeterol seems to be beneficial for patients, compared with Formoterol. PMID- 26487881 TI - Cognitive-analytical therapy for a patient with functional neurological symptom disorder-conversion disorder (psychogenic myopia): A case study. AB - Functional neurological symptom disorder commonly presents with symptoms and defects of sensory and motor functions. Therefore, it is often mistaken for a medical condition. It is well known that functional neurological symptom disorder more often caused by psychological factors. There are three main approaches namely analytical, cognitive and biological to manage conversion disorder. Any of such approaches can be applied through short-term treatment programs. In this case, study a 12-year-old boy with the diagnosed functional neurological symptom disorder (psychogenic myopia) was put under a cognitive-analytical treatment. The outcome of this treatment modality was proved successful. PMID- 26487879 TI - Antioxidant plants and diabetes mellitus. AB - The incidence of diabetes mellitus (DM) is increasing rapidly and it is expected to increase by 2030. Other than currently available therapeutic options, there are a lot of herbal medicines, which have been recommended for its treatment. Herbal medicines have long been used for the treatment of DM because of the advantage usually having no or less side-effects. Most of these plants have antioxidant activities and hence, prevent or treat hard curable diseases, other than having the property of combating the toxicity of toxic or other drugs. In this review other than presenting new findings of DM, the plants, which are used and have been evaluated scientifically for the treatment of DM are introduced. PMID- 26487880 TI - Prevalence of dyslipidemia in Iranian children and adolescents: A systematic review. AB - BACKGROUND: Dyslipidemia is considered as an important modifiable risk factor for cardiovascular disease (CVD). The link between childhood dyslipidemia and occurrence of atherosclerosis and its sequels in adulthood are well-documented. This study aimed to systematically review the prevalence of dyslipidemia among Iranian children and adolescents. MATERIALS AND METHODS: An electronic search was conducted on studies published from January 1990 to January 2014. The main international electronic data sources were PubMed and the NLM Gateway (for MEDLINE), Institute of Scientific Information (ISI), and SCOPUS. For Persian databases, we used domestic databases with systematic search capability including IranMedex, Irandoc, and Scientific Information Database (SID). We included all available population-based studies and national surveys conducted in the pediatric age group (aged <21 years). RESULTS: In this review, 1772 articles were identified (PubMed: 1464; Scopus: 11; ISI: 58; SID: 90; IranMedex: 149; Irandoc: 57). During three refine steps and after removing of duplicates, 182 articles related to the study domain were selected. After quality assessment, 46 studies were selected for text appraisal, of which 26 qualified articles were evaluated at the final step. The prevalence range of hypercholesterolemia, hypertriglyceridemia, elevated low-density lipoprotein cholesterol, and low high density lipoprotein cholesterol (HDL-C) were 3-48%, 3-50%, 5-20% and 5-88%, respectively. Low HDL-C and hypertriglyceridemia were the most prevalent lipid disorders in this group of population. CONCLUSION: Dyslipidemia is a common health problem among Iranian children and adolescents. Few data were available in preschool children. This finding provides useful information for health policy makers to implement action-oriented interventions for prevention and early control of this important CVD risk factor. PMID- 26487882 TI - Gastric involvement of sarcoidosis in a patient with multiple lung nodules. AB - Sarcoidosis is a granulomatous disorder mostly could involve intrathoracic structures. The gastric involvement is rare and the symptoms may be non-specific. We herein report a case of a 56-year-old female patient who was admitted due to chest tightness and discomfort. Computed tomography (CT) of the thorax revealed bilaterally nodular lesions in the lower lobes of the lung and pleural effusion on the left side. Positron emission tomography/CT showed lung nodules and gastric involvement with mesenteric lymphadenomegalies with pathological uptake of 18F fluoro-2-deoxy-d-glucose. Pathological examination of the lung biopsy taken by thoracotomy demonstrated non-caseating granulomas. The gastric biopsies taken by endoscopy also showed non-caseating granulomas consistent with a diagnosis of sarcoidosis. PMID- 26487883 TI - Legacy of Ebola outbreak: Potential risk of measles outbreak in Guinea, Sierra Leone and Liberia. PMID- 26487884 TI - Trend of disability prevalence in Iran: An evidence to improve disability data. PMID- 26487885 TI - Cognitive dysfunction in multiple sclerosis: Usually forgotten in the clinical assessment of MS patients. PMID- 26487886 TI - Nanosizing of drugs: Effect on dissolution rate. AB - The solubility, bioavailability and dissolution rate of drugs are important parameters for achieving in vivo efficiency. The bioavailability of orally administered drugs depends on their ability to be absorbed via gastrointestinal tract. For drugs belonging to Class II of pharmaceutical classification, the absorption process is limited by drug dissolution rate in gastrointestinal media. Therefore, enhancement of the dissolution rate of these drugs will present improved bioavailability. So far several techniques such as physical and chemical modifications, changing in crystal habits, solid dispersion, complexation, solubilization and liquisolid method have been used to enhance the dissolution rate of poorly water soluble drugs. It seems that improvement of the solubility properties ofpoorly water soluble drugscan translate to an increase in their bioavailability. Nowadays nanotechnology offers various approaches in the area of dissolution enhancement of low aqueous soluble drugs. Nanosizing of drugs in the form of nanoparticles, nanocrystals or nanosuspensions not requiring expensive facilities and equipment or complicated processes may be applied as simple methods to increase the dissolution rate of poorly water soluble drugs. In this article, we attempted to review the effects of nanosizing on improving the dissolution rate of poorly aqueous soluble drugs. According to the reviewed literature, by reduction of drug particle size into nanometer size the total effective surface area is increased and thereby dissolution rate would be enhanced. Additionally, reduction of particle size leads to reduction of the diffusion layer thickness surrounding the drug particles resulting in the increment of the concentration gradient. Each of these process leads to improved bioavailability. PMID- 26487887 TI - Comparison of antispasmodic effects of Dracocephalum kotschyi essential oil, limonene and alpha-terpineol. AB - Dracocephalum kotschyi is an essential oil containing plant found in Iran. In Iranian traditional medicine, D. kotschyi has been used as antispasmodic and analgesic but so far there is no pharmacological report about its antispasmodic activity. Therefore, the objective of this research was to study antispasmodic activity of the essential oil of D. kotschyi and two of its constituents namely limonene and alpha-terpineol. The essential oil was obtained from aerial parts of D. kotschyi using hydrodistillation method. The main components found in the essential oil were alpha-pinene (10%), neral (11%), geraniol (10%), alpha-citral (12%), limonene (9%) and alpha-terpineol (1.1%). For antispasmodic studies, a portion of rat ileum was suspended under 1 g tension in Tyrode's solution at 37 degrees C and gassed with O2. Effect of the D. kotschyi essential oil, limonene and alpha-terpineol were studied on ileum contractions induced by KCl (80 mM), acetylcholine (ACh, 500 nM) and electrical field stimulation (EFS). The essential oil, in a concentration dependent manner inhibited the response to KCl (IC50=51 +/- 8.7 nl/ml), ACh (IC50=19 +/- 2.7 nl/ml) and EFS (IC50=15 +/- 0.5 nl/ml). Limonene and alpha-terpineol showed same pattern of inhibitory effect on ileum contraction. Their inhibitory effects were also concentration dependent. However, limonene was more potent than the essential oil while the alpha-terpineol was less potent than either limonene or the essential oil. From this experiment it was concluded that D. kotschyi essential oil has inhibitory effect on ileum contractions. Limonene contribute a major role in inhibitory effect of the essential oil while alpha-terpineol has weak antispasmodic activity. PMID- 26487888 TI - Antiangiogenic and antiproliferative effects of black pomegranate peel extract on melanoma cell line. AB - In the present study possible effects of black pomegranate peel extract (PPE) on the B16F10 melanoma cells proliferation and Human Umbilical Vein Endothelial Cells (HUVECs) angiogenesis were investigated. PPE was added into the cell lines (B16F10 and HUVECs) media with different concentrations (10-450 MUg/ml). After 48 h, the cell survival was measured by 3-(Dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Angiogenesis was investigated by matrigel assay (PPE (200, 300, 400 MUg/ml)); HUVECs, vascular endothelial growth factor (VEGF) mRNA expression was detected by quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) assay. VEGF concentration in culture medium of HUVECs was determined by enzyme-linked immunosorbent assay (ELISA). PPE had positive anti proliferative effect on melanoma cells in a dose-dependent manner, but not on HUVECs. The matrigel assay results indicated that PPE significantly inhibited length, size and junction of the tube like structures (P<0.05). VEGF mRNA expression and concentration levels in culture medium of PPE treated HUVECs reduced significantly in a concentration-dependent manner (P<0.05). Simultaneous inhibition of melanoma cell proliferation and angiogenesis proposed that, PPE can be a good candidate against melanoma development. Based on the results, PPE could effectively suppress angiogenesis potentially through a VEGF dependent mechanism. Further studies are needed to confirm these results. PMID- 26487889 TI - Hydroalcoholic extract of Allium eriophyllum leaves attenuates cardiac impairment in rats with simultaneous type 2 diabetes and renal hypertension. AB - Some species of Allium family have been shown to offer cardioprotection in animal studies. This study aimed at examining possible role of oxidative stress in the cardioprotective effects of hydroalcoholic extract of Allium eriophyllum in rats with simultaneous type 2 diabetes and renal hypertension. Six groups of male Spargue-Dawley rats (8-10 rats each) including a sham-control, a diabetic group, a renal hypertensive group, three groups of animals with simultaneous diabetes and hypertension receiving vehicle, or the extract at 30 or 100 mg/kg/day were used. Four weeks after receiving vehicle or extract, blood pressure, fasting blood glucose, and serum superoxide dismutase and glutathione reductase levels were measured, and isolated heart studies were performed. Systolic blood pressure, fasting blood glucose, coronary effluent creatine kinase-MB, infarct size and coronary resistance of diabetic hypertensive group receiving vehicle were significantly higher than those of the sham-control group and treatment with the extract prevented the increase of these variables. Moreover, rate of rise and decrease of left ventricular pressure, left ventricular developed pressure, rate pressure product and serum levels of superoxide dismutase and glutathione reductase of diabetic hypertensive group receiving vehicle were significantly lower than those the sham-control group, and treatment with the extract prevented the decrease of these variables. The findings indicate that hydroalcoholic extract of A. eriophyllum leaves, possibly by an antioxidant mechanism, protected against simultaneous diabetes and hypertension-induced cardiac dysfunction. PMID- 26487890 TI - Effect of human Wharton's jelly mesenchymal stem cell secretome on proliferation, apoptosis and drug resistance of lung cancer cells. AB - Multipotent mesenchymal stem cells (MSCs) are recently found to alter the tumor condition. However their exact role in tumor development is not yet fully unraveled. MSCs were established to perform many of their actions through paracrine effect. Thus investigation of MSC secretome interaction with tumor cells may provide important information for scientists who are attempting to apply stem cells in the treatment of the disease. In this study we investigated the effect of human Wharton's jelly derived MSC (WJ-MSCs) secretome on proliferation, apoptotic potential of A549 lung cancer cells, and their response to the chemotherapeutic agent doxorubicin. WJ-MSCs were isolated from human umbilical cord and then characterized according to the International Society for Cellular Therapy criteria and WJ-MSC secretome was collected. BrdU cell proliferation assay and Annexin V-PI staining were used for the evaluation of cytotoxic and proapoptotic effects of WJ-MSC secretome on A549 cells. WJ-MSC secretome neither induced proliferation of lung cancer cells nor affected the apoptotic potential of the tumor cells. We also studied the combinatorial effect of WJ-MSC secretome and the anticancer drug doxorubicinwhich showed no induction of drug resistance when A549 cells was treated with combination of WJ-MSC secretome and doxorubicin. Although MSCs did not show antitumor properties, our in vitro results showed that MSC secretome was not tumorigenic and also did not make lung cancer cells resistant to doxorubicin. Thus MSC secretome could be considered safe for other medical purposes such as cardiovascular, neurodegenerative, and autoimmune diseases which may exist or occur in cancer patients. PMID- 26487891 TI - Mitigation of statins-induced cytotoxicity and mitochondrial dysfunction by L carnitine in freshly-isolated rat hepatocytes. AB - Statins are widely used as anti hyperlipidemic agents. Hepatotoxicity is one of their adverse effects appearing in some patients. No protective agents have yet been developed to treat statins-induced hepatotoxicity. Different investigations have suggested L-carnitine as a hepatoprotective agent against drugs-induced toxicity. This study was designed to evaluate the effect of L-carnitine on the cytotoxic effects of statins on the freshly-isolated rat hepatocytes. Hepatocytes were isolated from male Sprague-Dawley rats by collagenase enzyme perfusion via portal vein. Cells were treated with the different concentrations of statins (simvastatin, lovastatin and atorvastatin), alone or in combination with L carnitine. Cell death, reactive oxygen species (ROS) formation, lipid peroxidation, and mitochondrial depolarization were assessed as toxicity markers. Furthermore, the effects of statins on cellular reduced and oxidized glutathione reservoirs were evaluated. In accordance with previous studies, an elevation in ROS formation, cellular oxidized glutathione and lipid peroxidation were observed after statins administration. Moreover, a decrease in cellular reduced glutathione level and cellular mitochondrial membrane potential collapse occurred. L-carnitine co-administration decreased the intensity of aforementioned toxicity markers produced by statins treatment. This study suggests the protective role of L-carnitine against statins-induced cellular damage probably through its anti oxidative and reactive radical scavenging properties as well as its effects on sub cellular components such as mitochondria. The mechanism of L carnitine protection may be related to its capacity to facilitate fatty acid entry into mitochondria; possibly adenosine tri-phosphate or the reducing equivalents are increased, and the toxic effects of statins toward mitochondria are encountered. PMID- 26487892 TI - Protection of lactoperoxidase activity with sugars during lyophilization and evaluation of its antibacterial properties. AB - The purpose of the present study was to compare the stabilizing effect of four disaccharides alone or in combination on the lactoperoxidase (LP) derived from bovine milk during lyophilization. Sucrose, lactose, maltose, and trehalose at different concentrations (5-500 mM) were used to compare their protective effects on LP activity. The activity of lyophilized and native LP enzyme was evaluated using the procedure of Schindler with slight modifications. The antibacterial activity of the lyophilized enzyme against Pseudomonas aeroginosa, Escherichia coli, and Staphylococcus aureus was also investigated using the antimicrobial effectiveness test. Trehalose at concentration of 500 mM was the most effective cryoprotectant in protecting the enzyme activity. It preserved LP activity for 40 days, while the native enzyme lost its activity after 6 days. Combinations of disaccharides resulted in an increment in the stability of the enzyme, compared to the native enzyme. Combination of 200 mM trehalose and 200 mM sucrose were found most effective cryoprotectant in freeze-drying of LP. The lyophilized LP decreased the growth rate of Ps.aeroginosa, E.coli, and S.aureus between up to 30.8% in 10(6) cfu/ml and 53.3% in 10(5) cfu/ml. Antimicrobial efficacy of LP was more pronounced when 10(5) cfu/ml was used as compared to 10(6) cfu/ml. PMID- 26487893 TI - Encapsulation in PLGA-PEG enhances 9- nitro-camptothecin cytotoxicity to human ovarian carcinoma cell line through apoptosis pathway. AB - Ovarian cancer is the fifth leading cause of the cancer-related death among women. 9-nitrocamptothecin (9-NC) is a water-insoluble derivative of camptothecin used for the treatment of patients with advanced ovarian cancer. Previous studies showed that the encapsulation of 9-NC in poly (lactic-co-glycolic acid, PLGA) nanoparticles increased the cytotoxic effect of the drug on different cancer cell lines. In the present study, the cytotoxic effects of 9-NC, 9-NC-loaded PLGA and PLGA-polyethylene glycol (PLGA-PEG) nanoparticles with varying degree of PEG (5, 10, and 15%) were evaluated on human ovarian carcinoma cell line. Furthermore, the mode of cell death induced by 9-NC and the optimized 9-NC-loaded PLGA-PEG nanoparticles on A2780 cell line were investigated. 9-NC incorporating nanoparticles were prepared by nanopercipitation method and their physicochemical characteristics were evaluated using standard methods. The results showed that activation of caspase-3 and -9 significantly increased by free 9-NC and PLGA-PEG loaded nanoparticles in A2780 cells. In contrast to the free drug which increased the activation of caspase-8, 9-NC-loaded PLGA-PEG nanoparticles did not alter the activation of caspase-8. Collectively, it appears that apoptosis induced by 9-NC incorporated in PLGA-PEG 5% occurred through the activation of caspase-9 rather than activation of caspase-8 which is the mediator of extrinsic pathway. Moreover, our results confirmed that 9-NC in nanoparticles at the level of gene expression potentiated down-regulation of Bcl-2, up regulation of Bax, and Smac/DIABLO leading to a decrease in mitochondrial membrane potential. Taken together, our results showed that 9-NC incorporated in PLGA-PEG 5% nanoparticles is able to induce apoptosis in A2780 human ovarian carcinoma cells and has the potential for the treatment of ovarian carcinoma. PMID- 26487894 TI - Cytotoxic evaluation of volatile oil from Descurainia sophia seeds on MCF-7 and HeLa cell lines. AB - Descurainia sophia is a plant widely distributed and used as folk medicine throughout the world. Different extracts of aerial parts and seeds of this plant have been shown to inhibit the growth of different cancer cell lines in vitro. In this study, cytotoxic activity of D. sophia seed volatile oil was evaluated. D. sophia seed powder was mixed with distilled water and left at 25 degrees C for 17 h (E1), 23 h (E2) and 28 h (E3) to autolyse. Then, the volatile fractions of E1, E2, and E3 were collected after steam distillation for 3 h. Cytotoxic effects of the volatile oils alone or in combination with doxorubicin (mixture of E1 or E2 at 50 MUg/ml or E1 at 100 MUg/ml with doxorubicin at 0.1, 1, 10 MUM) against MCF-7 cell line were determined using MTT assay. Cytotoxic effect of E1 volatile oil was also determined on HeLa cell line. The results indicated that 1-buten-4 isothiocyanate was the major isothiocyanate found in the volatile oils. The results of cytotoxic evaluations showed that volatile constituents were more toxic on MCF-7 cells with IC50< 100 MUg/ml than HeLa cells with IC50> 100 MUg/ml. No significant differences were observed between cytotoxic activities of E1, E2 and E3 on MCF-7 cell line. Concomitant use of E1 and E2 (50 MUg/ml) with doxurubicin (1 MUM) significantly reduced the viability of MCF-7 cells compared to the negative control, doxorubicin alone, or each volatile fraction. The same result was obtained on HeLa cells, when E1 (100 MUg/ml) was concurrently used with doxorubicin (1 MUM). PMID- 26487895 TI - The effects of increasing PGE2 on translocation of labeled albumin into rat brain. AB - Under pathophysiological conditions, infiltration of leukocyte plays a key role in the progression of the neuroinflammatory reaction in the CNS. Prostaglandin E2 (PGE2) is known to accumulate at lesion sites of the post-ischemic brain. Although post-ischemic treatments with cyclooxygenase-2 inhibitors reduce blood brain barrier (BBB) leukocyte infiltration, the direct effect of PGE2 on BBB has not been fully implemented. Therefore, the direct effect of increasing PGE2 infusion on translocation of labeled albumin into the brain was assessed. Under anesthesia rats were drilled stereo-taxicaly a burr hole in the right forebrain and PGE2 was infused into the forebrain and the hole was occluded. The animals were then injected with fluorescent labeled albumin (FA), via internal right jugular vein and decapitated at different infusion time points. The forebrain was removed and each forebrain hemisphere was homogenized and fluorescence intensities were measured in the supernatant. The fluorescence intensities measured in the right and left forebrain hemispheres of the control group (0.0 MUg PGE2) were almost identical. Four hours after infusion of PGE2 at doses higher than 250 MUg, fluorescence intensity increased in the right forebrain supernatant, even if it was not statistically significant. The fluorescence intensity was detectable in the brain supernatant 4 h after infusion of PGE2 in doses higher than 250 MUg PGE2. The highest fluorescence intensity was 16 h after infusion of 500 MUg PGE2, which returned to near control values after 48 h. Increased fluorescence intensity in the brain following PGE2 infusion is concluded to be associated with disruption of the BBB. PMID- 26487896 TI - Quick chip assay using locked nucleic acid modified epithelial cell adhesion molecule and nucleolin aptamers for the capture of circulating tumor cells. AB - The role of circulating tumor cells (CTCs) in disease diagnosis, prognosis, monitoring of the therapeutic efficacy, and clinical decision making is immense and has attracted tremendous focus in the last decade. We designed and fabricated simple, flat channel microfluidic devices polydimethylsiloxane (PDMS based) functionalized with locked nucleic acid (LNA) modified aptamers (targeting epithelial cell adhesion molecule (EpCAM) and nucleolin expression) for quick and efficient capture of CTCs and cancer cells. With optimized flow rates (10 MUl/min), it was revealed that the aptamer modified devices offered reusability for up to six times while retaining optimal capture efficiency (>90%) and specificity. High capture sensitivity (92%) and specificity (100%) was observed in whole blood samples spiked with Caco-2 cells (10-100 cells/ml). Analysis of blood samples obtained from 25 head and neck cancer patients on the EpCAM LNA aptamer functionalized chip revealed that an average count of 5 +/- 3 CTCs/ml of blood were captured from 22/25 samples (88%). EpCAM intracellular domain (EpICD) immunohistochemistry on 9 oral squamous cell carcinomas showed the EpICD positivity in the tumor cells, confirming the EpCAM expression in CTCs from head and neck cancers. These microfluidic devices also maintained viability for in vitro culture and characterization. Use of LNA modified aptamers provided added benefits in terms of cost effectiveness due to increased reusability and sustainability of the devices. Our results present a robust, quick, and efficient CTC capture platform with the use of simple PDMS based devices that are easy to fabricate at low cost and have an immense potential in cancer diagnosis, prognosis, and therapeutic planning. PMID- 26487897 TI - Flip channel: A microfluidic device for uniform-sized embryoid body formation and differentiation. AB - This paper reports a two-layered polydimethylsiloxane microfluidic device-Flip channel, capable of forming uniform-sized embryoid bodies (EBs) and performing stem cell differentiation within the same device after flipping the microfluidic channel. The size of EBs can be well controlled by designing the device geometries, and EBs with multiple sizes can be formed within a single device to study EB size-dependent stem cell differentiation. During operation of the device, cells are positioned in the designed positions. As a result, observation and monitoring specific population of cells can be achieved for further analysis. In addition, after flipping the microfluidic channel, stem cell differentiation from the EBs can be performed on an unconfined flat surface that is desired for various differentiation processes. In the experiments, murine embryonic stem cells (ES-D3) are cultured and formed EBs inside the developed device. The size of EBs is well controlled inside the device, and the neural differentiation is performed on the formed EBs after flipping the channel. The EB size-dependent stem cell differentiation is studied using the device to demonstrate its functions. The device provides a useful tool to study stem cell differentiation without complicated device fabrication and tedious cell handling under better controlled microenvironments. PMID- 26487898 TI - Interplay between motility and cell-substratum adhesion in amoeboid cells. AB - The effective migration of amoeboid cells requires a fine regulation of cell substratum adhesion. These entwined processes have been shown to be regulated by a host of biophysical and biochemical cues. Here, we reveal the pivotal role played by calcium-based mechanosensation in the active regulation of adhesion resulting in a high migratory adaptability. Using mechanotactically driven Dictyostelium discoideum amoebae, we uncover the existence of optimal mechanosensitive conditions-corresponding to specific levels of extracellular calcium-for persistent directional migration over physicochemically different substrates. When these optimal mechanosensitive conditions are met, noticeable enhancement in cell migration directionality and speed is achieved, yet with significant differences among the different substrates. In the same narrow range of calcium concentrations that yields optimal cellular mechanosensory activity, we uncovered an absolute minimum in cell-substratum adhesion activity, for all considered substrates, with differences in adhesion strength among them amplified. The blocking of the mechanosensitive ion channels with gadolinium i.e., the inhibition of the primary mechanosensory apparatus-hampers the active reduction in substrate adhesion, thereby leading to the same undifferentiated and drastically reduced directed migratory response. The adaptive behavioral responses of Dictyostelium cells sensitive to substrates with varying physicochemical properties suggest the possibility of novel surface analyses based on the mechanobiological ability of mechanosensitive and guidable cells to probe substrates at the nanometer-to-micrometer level. PMID- 26487899 TI - Osmotically driven drug delivery through remote-controlled magnetic nanocomposite membranes. AB - Implantable drug delivery systems can provide long-term reliability, controllability, and biocompatibility, and have been used in many applications, including cancer pain and non-malignant pain treatment. However, many of the available systems are limited to zero-order, inconsistent, or single burst event drug release. To address these limitations, we demonstrate prototypes of a remotely operated drug delivery device that offers controllability of drug release profiles, using osmotic pumping as a pressure source and magnetically triggered membranes as switchable on-demand valves. The membranes are made of either ethyl cellulose, or the proposed stronger cellulose acetate polymer, mixed with thermosensitive poly(N-isopropylacrylamide) hydrogel and superparamagnetic iron oxide particles. The prototype devices' drug diffusion rates are on the order of 0.5-2 MUg/h for higher release rate designs, and 12-40 ng/h for lower release rates, with maximum release ratios of 4.2 and 3.2, respectively. The devices exhibit increased drug delivery rates with higher osmotic pumping rates or with magnetically increased membrane porosity. Furthermore, by vapor deposition of a cyanoacrylate layer, a drastic reduction of the drug delivery rate from micrograms down to tens of nanograms per hour is achieved. By utilizing magnetic membranes as the valve-control mechanism, triggered remotely by means of induction heating, the demonstrated drug delivery devices benefit from having the power source external to the system, eliminating the need for a battery. These designs multiply the potential approaches towards increasing the on-demand controllability and customizability of drug delivery profiles in the expanding field of implantable drug delivery systems, with the future possibility of remotely controlling the pressure source. PMID- 26487901 TI - On-chip DNA preconcentration in different media conductivities by electrodeless dielectrophoresis. AB - Electrodeless dielectrophoresis is the best choice to achieve preconcentration of nanoparticles and biomolecules due to its simple, robust, and easy implementation. We designed a simple chip with microchannels and nano-slits in between and then studied the trapping of DNA in high conductive medium and low conductive medium, corresponding to positive and negative dielectrophoresis (DEP), respectively. It is very important to investigate the trapping in media with different conductivities since one always has to deal with the sample solutions with different conductivities. The trapping process was analyzed by the fluorescent intensity changes. The results showed that DNA could be trapped at the nano-slit in both high and low conductive media in a lower electric field strength (10 V/cm) compared to the existing methods. This is a significant improvement to suppress the Joule heating effect in DEP related experiments. Our work may give insight to researchers for DNA trapping by a simple and low cost device in the Lab-on-a-Chip system. PMID- 26487900 TI - Microfluidic size separation of cells and particles using a swinging bucket centrifuge. AB - Biomolecular separation is crucial for downstream analysis. Separation technique mainly relies on centrifugal sedimentation. However, minuscule sample volume separation and extraction is difficult with conventional centrifuge. Furthermore, conventional centrifuge requires density gradient centrifugation which is laborious and time-consuming. To overcome this challenge, we present a novel size selective bioparticles separation microfluidic chip on a swinging bucket minifuge. Size separation is achieved using passive pressure driven centrifugal fluid flows coupled with centrifugal force acting on the particles within the microfluidic chip. By adopting centrifugal microfluidics on a swinging bucket rotor, we achieved over 95% efficiency in separating mixed 20 MUm and 2 MUm colloidal dispersions from its liquid medium. Furthermore, by manipulating the hydrodynamic resistance, we performed size separation of mixed microbeads, achieving size efficiency of up to 90%. To further validate our device utility, we loaded spiked whole blood with MCF-7 cells into our microfluidic device and subjected it to centrifugal force for a mere duration of 10 s, thereby achieving a separation efficiency of over 75%. Overall, our centrifugal microfluidic device enables extremely rapid and label-free enrichment of different sized cells and particles with high efficiency. PMID- 26487902 TI - Modeling of chemotactic steering of bacteria-based microrobot using a population scale approach. AB - The bacteria-based microrobot (Bacteriobot) is one of the most effective vehicles for drug delivery systems. The bacteriobot consists of a microbead containing therapeutic drugs and bacteria as a sensor and an actuator that can target and guide the bacteriobot to its destination. Many researchers are developing bacteria-based microrobots and establishing the model. In spite of these efforts, a motility model for bacteriobots steered by chemotaxis remains elusive. Because bacterial movement is random and should be described using a stochastic model, bacterial response to the chemo-attractant is difficult to anticipate. In this research, we used a population-scale approach to overcome the main obstacle to the stochastic motion of single bacterium. Also known as Keller-Segel's equation in chemotaxis research, the population-scale approach is not new. It is a well designed model derived from transport theory and adaptable to any chemotaxis experiment. In addition, we have considered the self-propelled Brownian motion of the bacteriobot in order to represent its stochastic properties. From this perspective, we have proposed a new numerical modelling method combining chemotaxis and Brownian motion to create a bacteriobot model steered by chemotaxis. To obtain modeling parameters, we executed motility analyses of microbeads and bacteriobots without chemotactic steering as well as chemotactic steering analysis of the bacteriobots. The resulting proposed model shows sound agreement with experimental data with a confidence level <0.01. PMID- 26487903 TI - An integrated microfluidic chip for immunocapture, preconcentration and separation of beta-amyloid peptides. AB - We present an integrated microfluidic chip for detection of beta-amyloid (Abeta) peptides. Abeta peptides are major biomarkers for the diagnosis of Alzheimer's disease (AD) in its early stages. This microfluidic device consists of three main parts: (1) An immunocapture microcolumn based on self-assembled magnetic beads coated with antibodies specific to Abeta peptides, (2) a nano-porous membrane made of photopolymerized hydrogel for preconcentration, and (3) a microchip electrophoresis (MCE) channel with fluorescent detection. Sub-milliliter sample volume is either mixed off-chip with antibody coated magnetic beads and injected into the device or is injected into an already self-assembled column of magnetic beads in the microchannel. The captured peptides on the beads are then electrokinetically eluted and re-concentrated onto the nano-membrane in a few nano-liters. By integrating the nano-membrane, total assay time was reduced and also off-chip re-concentration or buffer exchange steps were not needed. Finally, the concentrated peptides in the chip are separated by electrophoresis in a polymer-based matrix. The device was applied to the capture and MCE analysis of differently truncated peptides Abeta (1-37, 1-39, 1-40, and 1-42) and was able to detect as low as 25 ng of synthetic Abeta peptides spiked in undiluted cerebrospinal fluid (CSF). The device was also tested with CSF samples from healthy donors. CSF samples were fluorescently labelled and pre-mixed with the magnetic beads and injected into the device. The results indicated that Abeta1 40, an important biomarker for distinguishing patients with frontotemporal lobe dementia from controls and AD patients, was detectable. Although the sensitivity of this device is not yet enough to detect all Abeta subtypes in CSF, this is the first report on an integrated or semi-integrated device for capturing and analyzing of differently truncated Abeta peptides. The method is less demanding and faster than the conventional Western blotting method currently used for research. PMID- 26487904 TI - Automatic sequential fluid handling with multilayer microfluidic sample isolated pumping. AB - To sequentially handle fluids is of great significance in quantitative biology, analytical chemistry, and bioassays. However, the technological options are limited when building such microfluidic sequential processing systems, and one of the encountered challenges is the need for reliable, efficient, and mass production available microfluidic pumping methods. Herein, we present a bubble free and pumping-control unified liquid handling method that is compatible with large-scale manufacture, termed multilayer microfluidic sample isolated pumping (mMUSIP). The core part of the mMUSIP is the selective permeable membrane that isolates the fluidic layer from the pneumatic layer. The air diffusion from the fluidic channel network into the degassing pneumatic channel network leads to fluidic channel pressure variation, which further results in consistent bubble free liquid pumping into the channels and the dead-end chambers. We characterize the mMUSIP by comparing the fluidic actuation processes with different parameters and a flow rate range of 0.013 MUl/s to 0.097 MUl/s is observed in the experiments. As the proof of concept, we demonstrate an automatic sequential fluid handling system aiming at digital assays and immunoassays, which further proves the unified pumping-control and suggests that the mMUSIP is suitable for functional microfluidic assays with minimal operations. We believe that the mMUSIP technology and demonstrated automatic sequential fluid handling system would enrich the microfluidic toolbox and benefit further inventions. PMID- 26487905 TI - Flow distribution in parallel microfluidic networks and its effect on concentration gradient. AB - The architecture of microfluidic networks can significantly impact the flow distribution within its different branches and thereby influence tracer transport within the network. In this paper, we study the flow rate distribution within a network of parallel microfluidic channels with a single input and single output, using a combination of theoretical modeling and microfluidic experiments. Within the ladder network, the flow rate distribution follows a U-shaped profile, with the highest flow rate occurring in the initial and final branches. The contrast with the central branches is controlled by a single dimensionless parameter, namely, the ratio of hydrodynamic resistance between the distribution channel and the side branches. This contrast in flow rates decreases when the resistance of the side branches increases relative to the resistance of the distribution channel. When the inlet flow is composed of two parallel streams, one of which transporting a diffusing species, a concentration variation is produced within the side branches of the network. The shape of this concentration gradient is fully determined by two dimensionless parameters: the ratio of resistances, which determines the flow rate distribution, and the Peclet number, which characterizes the relative speed of diffusion and advection. Depending on the values of these two control parameters, different distribution profiles can be obtained ranging from a flat profile to a step distribution of solute, with well-distributed gradients between these two limits. Our experimental results are in agreement with our numerical model predictions, based on a simplified 2D advection diffusion problem. Finally, two possible applications of this work are presented: the first one combines the present design with self-digitization principle to encapsulate the controlled concentration in nanoliter chambers, while the second one extends the present design to create a continuous concentration gradient within an open flow chamber. PMID- 26487908 TI - 5-Aryl-1-imino-1-oxo-[1,2,4]thiadiazines. PMID- 26487906 TI - Correlation between cell migration and reactive oxygen species under electric field stimulation. AB - Cell migration is an essential process involved in the development and maintenance of multicellular organisms. Electric fields (EFs) are one of the many physical and chemical factors known to affect cell migration, a phenomenon termed electrotaxis or galvanotaxis. In this paper, a microfluidics chip was developed to study the migration of cells under different electrical and chemical stimuli. This chip is capable of providing four different strengths of EFs in combination with two different chemicals via one simple set of agar salt bridges and Ag/AgCl electrodes. NIH 3T3 fibroblasts were seeded inside this chip to study their migration and reactive oxygen species (ROS) production in response to different EF strengths and the presence of beta-lapachone. We found that both the EF and beta-lapachone level increased the cell migration rate and the production of ROS in an EF-strength-dependent manner. A strong linear correlation between the cell migration rate and the amount of intracellular ROS suggests that ROS are an intermediate product by which EF and beta-lapachone enhance cell migration. Moreover, an anti-oxidant, alpha-tocopherol, was found to quench the production of ROS, resulting in a decrease in the migration rate. PMID- 26487907 TI - Higher cord blood 25-hydroxyvitamin D concentrations reduce the risk of early childhood eczema: in children with a family history of allergic disease. AB - BACKGROUND: In recent years the role of vitamin D status in early life on the development of allergic disease has generated much interest. The aim of this study was to determine whether cord blood vitamin D concentrations were associated with risk of early childhood allergic disease. METHODS: Measurements of cord blood 25-hydroxyvitamin D [25(OH)D] concentrations were available in 270 mother-child pairs who were participating in the allergy follow-up (n = 706) of the Docosahexaenoic Acid to Optimise Mother Infant Outcome randomised controlled trial. All of the children had a hereditary risk of allergic disease. The diagnosis of allergic disease was made during medical assessments at 1 and 3 years of age. RESULTS: The mean (standard deviation) standardised cord blood 25(OH)D concentration was 57.0 (24.1) nmol/L. The cumulative incidence of eczema to 3 years of age, n = 101/250 (40 %) was associated with standardised cord blood 25(OH)D concentration, with a 10 nmol/L rise in 25(OH)D concentration reducing the risk of eczema by 8 % (relative risk 0.92, 95 % confidence interval 0.86 0.97; P = 0.005). This association was stronger at 1 year of age, when a 10 nmol/L rise in standardised cord blood 25(OH)D concentration reduced the risk of eczema by 12 % (relative risk 0.88, 95 % confidence interval 0.81-0.96; P = 0.002). No associations between cord blood 25(OH)D concentrations and development of allergic sensitisation, allergic rhinitis or asthma in early childhood were found. CONCLUSION: In children with a family history of allergic disease, a higher cord blood 25(OH)D concentration appears to be associated with reduced risk of eczema in early childhood. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606). PMID- 26487909 TI - Nitrofuranyl Methyl Piperazines as New Anti-TB Agents: Identification, Validation, Medicinal Chemistry, and PK Studies. AB - Whole-cell screening of 20,000 drug-like small molecules led to the identification of nitrofuranyl methylpiperazines as potent anti-TB agents. In the present study, validation followed by medicinal chemistry has been used to explore the structure-activity relationship. Ten compounds demonstrated potent MIC in the range of 0.17-0.0072 MUM against H37Rv Mycobacterium tuberculosis (MTB) and were further investigated against nonreplicating and resistant (Rif(R) and MDR) strains of MTB. These compounds were also tested for cytotoxicity. Among the 10 tested compounds, five showed submicromolar to nanomolar potency against nonreplicating and resistant (Rif(R) and MDR) strains of MTB along with a good safety index. Based on their overall in vitro profiles, the solubility and pharmacokinetic properties of five potent compounds were studied, and two analogues, 14f and 16g, were found to have comparatively better solubility than others tested and acceptable pharmacokinetic properties. This study presents the rediscovery of a nitrofuranyl class of compounds with improved aqueous solubility and acceptable oral PK properties, opening a new direction for further development. PMID- 26487910 TI - Thioxo-dihydroquinazolin-one Compounds as Novel Inhibitors of Myeloperoxidase. AB - Myeloperoxidase (MPO) is a key antimicrobial enzyme, playing a normal role in host defense, but also contributing to inflammatory conditions including neuroinflammatory diseases such as Parkinson's and Alzheimer's. We synthesized and characterized more than 50 quinazolin-4(1H)-one derivatives and showed that this class of compounds inhibits MPO with IC50 values as low as 100 nM. Representative compounds showed partially reversible inhibition that was competitive with respect to Amplex Red substrate and did not result in the accumulation of MPO Compound II. Members of this group show promise for therapeutic development for the treatment of diseases in which inflammation plays a pathogenic role. PMID- 26487911 TI - Influence of Sugar Amine Regiochemistry on Digitoxigenin Neoglycoside Anticancer Activity. AB - The synthesis of a set of digitoxigenin neogluco/xylosides and corresponding study of their anticancer SAR revealed sugar amine regiochemistry has a dramatic effect upon activity. Specifically, this study noted sugar 3-amino followed by 4 amino-substitution to be most advantageous where the solvent accessibility of the appended amine within neoglycoside-Na(+),K(+)-ATPase docked models correlated with increased anticancer potency. This study presents a preliminary model for potential further warhead optimization in the context of antibody-directed steroidal glycosides and extends the demonstrated compatibility of aminosugars in the context of neoglycosylation. PMID- 26487912 TI - Synthesis and Biological Evaluation of Polar Functionalities Containing Nitrodihydroimidazooxazoles as Anti-TB Agents. AB - Novel polar functionalities containing 6-nitro-2,3-dihydroimidazooxazole (NHIO) analogues were synthesized to produce a compound with enhanced solubility. Polar functionalities including sulfonyl, uridyl, and thiouridyl-bearing NHIO analogues were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H37Rv. The aqueous solubility of compounds with MIC values <=0.5 MUg/mL were tested, and six compounds showed enhanced aqueous solubility. The best six compounds were further tested against resistant (Rif(R) and MDR) and dormant strains of MTB and tested for cytotoxicity in HepG2 cell line. Based on its overall in vitro characteristics and solubility profile, compound 6d was further shown to possess high microsomal stability, solubility under all tested biological conditions (PBS, SGF and SIF), and favorable oral in vivo pharmacokinetics and in vivo efficacy. PMID- 26487913 TI - Design, Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors. AB - 6-Endo-dig-cyclization is an efficient method for the synthesis of 1,2 dihydroisoquinolines. We have synthesized few 1,2-dihydroisoquinolines having different functionality at the C-1, C-3, C-7, and N-2 positions for evaluation against HIV-1 integrase (HIV1-IN) inhibitory activity. A direct nitro-Mannich condensation of o-alkynylaldimines and dual activation of o-alkynyl aldehydes by inexpensive cobalt chloride yielded desired compounds. Out of 24 compounds, 4m and 6c came out as potent integrase inhibitors in in vitro strand transfer (ST) assay, with IC50 value of 0.7 and 0.8 MUM, respectively. Molecular docking of these compounds in integrase revealed strong interaction between metal and ligands, which stabilizes the enzyme-inhibitor complex. The ten most active compounds were subjected to antiviral assay. Out of those, 6c reduced the level of p24 viral antigen by 91%, which is comparable to RAL in antiviral assay. Interestingly, these compounds showed similar ST inhibitory activity in G140S mutant, suggesting they can act against resistant strains. PMID- 26487914 TI - Inhibition of Invasion in Pancreatic Cancer Cells by Conjugate of EPA with beta(3,3)-Pip-OH via PI3K/Akt/NF-kB Pathway. AB - The present work describes the anti-invasive effect of conjugate BC06, a novel conjugate of EPA, (2E,4E)-4-(benzo[d][1,3]dioxol-5-ylmethylene) hex-2-enoic acid with beta,beta-disubstituted-beta-amino acid, beta(3,3)-Pip-OH (2-(4 aminopiperidin-4-yl)acetic acid), in human pancreatic carcinoma. The conjugate BC06 inhibited invasion and migration of PANC-1 cells in wound healing, matrigel invasion, and gelatin degradation assays. Apart from suppressing PI3K/Akt/NF-kB signaling, which is involved in the up-regulation of matrix metalloproteinases, our study also demonstrated that dose-dependent treatment of BC06 results in the upregulation of TIMP-1 and E-cadherin expression. Further, BC06 was found to be inhibiting the metastatic ability of PANC-1 cells by reducing MMP-2 and MMP-9 expression. These findings suggest that EPA conjugate with beta(3,3)-Pip-OH, BC06, may be used as an anti-invasive agent against human pancreatic carcinoma. PMID- 26487915 TI - Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance. AB - Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine. PMID- 26487916 TI - Discovery of Indazole Derivatives as a Novel Class of Bacterial Gyrase B Inhibitors. AB - Antibacterials with a novel mechanism of action offer a great opportunity to combat widespread antimicrobial resistance. Bacterial DNA Gyrase is a clinically validated target. Through physiochemical property optimization of a pyrazolopyridone hit, a novel class of GyrB inhibitors were discovered. Guided by structure-based drug design, indazole derivatives with excellent enzymatic and antibacterial activity as well as great animal efficacy were discovered. PMID- 26487917 TI - Synthesis and Evaluation of Novel Erlotinib-NSAID Conjugates as More Comprehensive Anticancer Agents. AB - A series of novel anticancer agents were designed and synthesized based on coupling of different nonsteroidal anti-inflammatory drugs (NSAIDs) with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers where both EGFR overexpression and inflammation play a direct role in disease progression. PMID- 26487918 TI - Lamivudine Resistance and Precore Variants in Iranian Patients With Chronic Hepatitis B: Correlation With Virological and Clinical Features. AB - BACKGROUND: Long-term lamivudine therapy, despite its initial effectiveness against hepatitis B virus (HBV), is associated with the emergence of drug resistance mutations in polymerase protein. OBJECTIVES: The aim of the present study was to determine the prevalence of precore and lamivudine drug resistance mutations in lamivudine treated patients with chronic B hepatitis. PATIENTS AND METHODS: Sequential sera were obtained from 88 chronic HBV carriers who received lamivudine for more than 24 months. Polymerase and precore regions were directly sequenced for these groups: I (before treatment), II, and III (12 and 24 months after treatment, respectively). RESULTS: All patients (100%) were contained genotype D, subtype ayw2. One (1.1%), 12 (13.6%), and 22 (25%) members of groups I, II, and III had the replacement of either isoleucine or valine instead of methionine in tyrosine-methionine-aspartate-aspartate (YMDD) motif, respectively. The frequency of mutations from 0 time point to 12 and 24 months showed that there was an increasing trend between sequential samples (P < 0.001). In group I, 31 (35.2%); II, 36 (41.0%) and III, 41 (46.6%) members had the precore stop codon mutations. The frequency of mutations from 0 time point to 12 and 24 months showed that there was an ascending trend between sequential samples. Indeed, frequency of precore stop codon was significantly increased with the passage of time (P < 0.001). CONCLUSIONS: Presence of drug resistance mutations among the patients was significant. Precore mutations were common amongst Iranian HBV chronic carriers under lamivudine therapy and these mutations were accompanied by clinical relapse. PMID- 26487919 TI - Phenotypic and Genotypic Characterization of Enteroaggregative Escherichia coli Strains Isolated From Diarrheic Children in Iran. AB - BACKGROUND: Several studies performed in developed and developing countries have identified enteroaggregative Escherichia coli (EAEC) as the emerging cause of pediatric diarrhea. OBJECTIVES: This study investigated the phenotypic and genetic characteristics of EAEC strains isolated from children with diarrhea between 2007 - 2008 in Tehran, Iran. MATERIALS AND METHODS: EAEC strains were examined for virulence plasmid genes (aap, aggR, and aatA), biofilm formation, and drug resistance. In addition, pulsed-field gel electrophoresis (PFGE) profiles of these strains were determined. RESULTS: Significant percentage of local EAEC strains carried the virulence plasmid genes and formed biofilms. In addition, these strains showed high resistance to ampicillin (100%), tetracycline (65.7%), streptomycin (58.7%), chloramphenicol (52.6%), and trimethoprim/sulfamethoxazole (51.7%) and had different PFGE patterns. CONCLUSIONS: These results indicated that EAEC strains isolated from Iranian children with diarrhea were heterogeneous and showed high resistance rates against commonly used antibiotics, which was similar to that reported in studies performed in other countries. PMID- 26487920 TI - Effect of Propranolol Alone and in Combination with Pyrimethamine on Acute Murine Toxoplasmosis. AB - BACKGROUND: Toxoplasmosis is a public health problem worldwide. This complication principally affects immunodeficient patients and pregnant women. Toxoplasma gondii is an opportunistic parasite, causing severe illness among and death of high-risk individuals and treatment is becoming increasingly difficult owing to side effects and low efficacies of drugs. OBJECTIVES: In this study, we investigated the anti-Toxoplasma gondii efficacy of propranolol in vivo. MATERIALS AND METHODS: This study was performed in two separate pre-treatment and post-treatment groups. In each group, 18 female Balb/c mice in six subgroups (n = 3) were used to assess the anti-Toxoplasma effect of propranolol at 2 and 3 mg/kg/day, pyrimethamine at 50 mg/kg/day, propranolol at 2 and 3 mg/kg/day plus pyrimethamine, and phosphate-buffered saline (PBS; as negative control). Treatment was performed 4, 24, and 48 hours before and after an intraperitoneal challenge of 1 * 10(3) tachyzoites of the virulent RH strain of T. gondii, in pre treatment and post-treatment groups. Mice peritoneal exudates were collected on the seventh day after the challenge and parasite numbers were recorded as percent of growth inhibition and survival rate. RESULTS: In the pre-treatment group, results showed that propranolol at 2 and 3 mg/kg combined with pyrimethamine was more effective in inhibiting growth of tachyzoites (86% and 98%, respectively) when compared with propranolol at 2 and 3 mg/kg (37% and 39%, respectively) and pyrimethamine (41%) alone. In the post-treatment group, all combined treatments significantly reduced parasite load. The growth inhibition of tachyzoites in mice receiving propranolol (2 and 3 mg/kg) was 75% and 51%, with the mean tachyzoites count being 1526 +/- 171.4 and 2948 +/- 1452.8, respectively, compared with pyrimethamine treatment outcome, which represents 99.9% growth inhibition. CONCLUSIONS: Our results demonstrated the promising prophylactic and therapeutic effects of propranolol against T. gondii infection. Propranolol also increases the efficacy of pyrimethamine in combination therapies. PMID- 26487921 TI - Distributions and Types of Multidrug-Resistant Acinetobacter baumannii in Different Departments of a General Hospital. AB - BACKGROUND: Acinetobacter baumannii is the most prevalent strain in hospitals and different clinical departments. OBJECTIVES: The current study aimed to investigate the genetic characteristics and resistance mechanisms of A. baumannii isolated from clinical samples in Shaoxing people's hospital affiliated to Zhejiang University, Shaoxing, China. PATIENTS AND METHODS: Acinetobacter baumannii strains were isolated from blood, phlegm and skin of the patients hospitalized in different departments as respiratory medicine, plastic surgery and intensive care unit (ICU). Multilocus sequence typing (MLST) was used to characterize the isolates. Kirby-Bauer test was used to evaluate antibiotic resistance of the bacteria. The expression of resistance inducing genes was detected by reverse transcription polymerase chain reaction (RT-PCR). The results were analyzed and compared. RESULTS: Two bacterial types, ST208, and ST218, were identified in all 140 samples. The ST208 mainly came from ICU and department of respiratory medicine, while ST218 from department of plastic surgery; 70.21% of ST208 and 84.78% of ST218 were carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-susceptible Acinetobacter baumannii (CSAB), respectively. Multidrug-resistance genes in CRAB isolated from the hospital mainly included, oxa-23, oxa-5, intl 1 and qaceDelta1-sul 1. Besides, the highest and lowest antibiotic resistance was observed in the strains isolated from blood samples and wounds, respectively. CONCLUSIONS: The distribution of AB varies in different clinical departments and samples. In the hospital under study, the main types of AB were ST208 and ST218. The genes which affect the ability of antibiotic resistance were oxa-23, oxa-51, intl 1 and qaceDelta1-sul 1. PMID- 26487922 TI - Expression and Purification of the Uropathogenic Escherichia coli PapG Protein and its Surface Absorption on Lactobacillus reuteri: Implications for Surface Display System Vaccines. AB - BACKGROUND: Uropathogenic Escherichia coli (UPEC) is one of the most common bacteria that can cause urinary tract infections (UTIs). Unfortunately, no human vaccine against UTIs has been developed. Therefore, it is necessary to develop an efficient and safe vaccine that is able to induce mucosal and systemic immune responses. The use of lactic acid bacteria as a delivery system is a promising method to induce the immune system. OBJECTIVES: The aim of this study was to establish Lactobacillus reuteri harboring the E. coli PapG antigen on its surface. MATERIALS AND METHODS: In this study, the gene encoding PapG was fused to the AcmA gene (which encodes an anchor protein in Lactobacillus) and cloned into the pEX A vector. The PapG.AcmA fusion gene was digested with BamHI and NdeI and sub-cloned into the pET21a expression vector at the digestion sites. Subsequently, the recombinant plasmids (pET21a-PapG.AcmA and pET21a-PapG) were transformed into the E. coli Origami strain using the calcium chloride method and the fusion protein was expressed under 1 mM IPTG induction. The expression of the fusion protein was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting. Purification of the PapG and PapG.AcmA proteins was carried out using a Ni-NTA column, and surface adsorption was estimated on Lactobacillus. Finally, surface localization of the fusion protein was verified by an enzyme-linked immunosorbent assay (ELISA). RESULTS: The PapG.AcmA fusion was successfully sub-cloned in the pET21a expression vector. The expression of PapG and PapG.AcmA proteins in the E. coli Origami strain was indicated as protein bands in SDS-PAGE and confirmed by western blotting. In addition, the fusion protein was displayed on the surface of L. reuteri. CONCLUSIONS: In conclusion, we developed a method to express the PapG.AcmA protein on the surface of Lactobacillus. This is the first report on the successful application of lactic acid bacteria displaying the PapG.AcmA fusion protein. It will be interesting to determine the immune responses against the PapG protein in near future using this surface display strategy. PMID- 26487923 TI - Analysis of Healing Effect of Alginate Sulfate Hydrogel Dressing Containing Antimicrobial Peptide on Wound Infection Caused by Methicillin-Resistant Staphylococcus aureus. AB - BACKGROUND: Wound infections caused by methicillin-resistant Staphylococcus aureus are a health problem worldwide; therefore, it is necessary to develop new antimicrobial compounds. Considering broad-spectrum antimicrobial activity and low probability of drug resistance to peptides, applications these peptides are being studied extensively. OBJECTIVES: In this study, to control drug release over time, an alginate sulfate-based hydrogel impregnated with the CM11 peptide as the antimicrobial agent was developed, and its healing effects were tested on skin infections caused by methicillin-resistant S. aureus strains in a mouse model. MATERIALS AND METHODS: Minimum inhibitory and minimum bactericidal concentrations of the CM11 peptide and alginate hydrogel in combination with the peptide were determined. Forty mice were divided into 4 groups: 1 group as a negative control (without treatment; however, 5 mice received hydrogel dressing without peptide), 1 group as a positive control (2% mupirocin treatment), and 2 groups as test groups. To establish skin infection, 200 MUL of bacterial suspension with 3 * 10(8) CFU/mL concentration was subcutaneously injected in the scapular region of the mice. On the basis of the in vitro minimal bactericidal concentration of the alginate hydrogel containing peptide for 15 clinical isolates, hydrogel containing 128 mg/L of peptide was used for wound dressing over an 8-day period. RESULTS: The highest and lowest numbers of wounds were observed on day 2 in the negative and positive control groups, respectively. During the 8-day period, the positive control and hydrogel containing peptide treatment groups showed similar levels of wound healing. CONCLUSIONS: This study showed that compared to standard drug treatment, treatment with hydrogel containing peptide had substantial antibacterial effects on S. aureus wound infections in mice. PMID- 26487924 TI - Controlled Study of Correlation of Biomechanical Profile of Hemiparetic Patients with Distance Travelled in Six Minutes. AB - The six-minute walking test (6MWT) is used to assess exercise tolerance that is associated with motor function of the lower limbs in hemiparetic patients. It is suggested that, for post-stroke subjects, performance in the 6MWT may be limited by biomechanical and cardiovascular factors. Our aim is to determine the correlation between the six-minute walk distance (6MWD) and the biomechanical profile of hemiparetic patients. During this cross-sectional controlled study, 10 hemiparetic patients with heart failure underwent 6MWT (ATS protocol). Tonus (Ashworth Scale) and goniometry of the lower limbs were measured. The average of 6MWD in two tests was 279+/-8 m. There was a negative correlation between the degree of spasticity for both the sural triceps (r=-0.57, P<0.05), quadriceps (r= 0.58, P<0.05) and the limitation in ankle dorsiflexion and the 6MWD (r=-0.76, P<0.05). Also, there was correlation between hip extension and ankle dorsiflexion limitations with 6MWD (r=0.66, P<0.05), (r=0.77, P<0.05). The negative correlation between the highest spasticity in paretic limb and the 6MWD and the correlation between the lower movement range of paretic hip and ankle suggest association with these factors and gait velocity in 6MWT. Loss percentage represents the percentage calculation between distance traveled and the distance predicted achieved by patients. In this study, the negative correlation between the percentage of loss of 6MWD and the limitation in the ankle dorsiflexion movement suggests that for a minor motion arch of the ankle, there is a higher percentage of walking distance loss foretold. PMID- 26487925 TI - Yet Another Atypical Presentation of Anti-GQ1b Antibody Syndrome. AB - Variants of Guillain-Barre syndrome such as Bickerstaff encephalitis and Miller Fisher syndrome have been reported. We report a 15-year-old boy who presented, after a prodromal illness, with 3-day progressive limb weakness, diplopia, and acute urinary retention. Clinically, he had horizontal gaze-evoked and upbeat nystagmus, bilateral extensor plantars in addition to quadriparesis and areflexia. Magnetic resonance imaging of the brain and spine was unremarkable and cerebral spinal fluid analysis showed lymphocytic pleocytosis. Nerve conduction study revealed symmetrical axonal neuropathy. Anti-GQ1b antibody was positive. A combination of IV methylprednisone followed by IVIg was instituted which led to remarkable clinical recovery. This case underpins the importance of recognizing atypical presentations of acute autonomic dysfunction and central nervous system features such as nystagmus, which may be associated with anti-GQ1b antibody syndrome. Features mimicking myelitis and brainstem encephalitis may pose diagnostic and therapeutic dilemma among the treating physicians. PMID- 26487926 TI - Effect of Heparin on Recanalization in Acute Stroke Patients with Intra-Arterial Thrombi. AB - Anticoagulant use, such as heparin, is usually contraindicated in acute stroke patients. We present a study of patients, who were treated with intravenous heparin after a stroke that were also found to have an intraluminal thrombus. Prior studies imply that recanalization is achieved with heparin; however heparin should only prevent thrombus propagation. Therefore it is unclear whether and how IV heparin can achieve recanalization of intraluminal thrombi in acute stroke patients. A retrospective review of all acute stroke patients from a single stroke center who received a therapeutic IV heparin infusion from 5/2006 to 9/2011 were included in the study. We compared patients who had complete/partial recanalization and/or improved flow versus those that did not, with both these groups on a standard intravenous heparin infusion protocol. Demographic data was compared between the groups. Average partial thromboplastin time (PTT) during heparin infusion, time between computed tomography angiographies (CTAs), time from stroke onset to receiving IV heparin, and vessel occluded were also compared between groups. Forty-one patients (19 female, 22 male) were included in the study with a total of 55 vessels (either carotid, middle cerebral artery, anterior cerebral artery, posterior cerebral artery/posterior circulation) having intraluminal thrombi; 31 patients had 41 vessels with either partial or complete recanalization of effected vessels, while 10 patients had 14 vessels that did not have at least one vessel recanalize while on heparin. Using t-test we noted that the average PTT between the vessels that had partial/complete recanalization group (61.74) and nonrecanalization group (66.30) was not statistical significantly different (P=0.37).The average time in days on heparin between vascular imaging studies (CTA/conventional angiogram) in the group of vessels with partial/complete recanalization (7.12 days) and the ones with no change (6.11 days) was not significantly different between the two groups (P=0.59). Patient's vessels receiving heparin for <24 hours versus those >24 hours did not significantly differ either (P=0.17). This study compares patient characteristics associated with recanalization of intraluminal thrombi in acute stroke patients on heparin. Recanalization of intraluminal thrombi are not associated with average PTT or duration on heparin. PMID- 26487927 TI - Amyotrophic Lateral Sclerosis: New Perpectives and Update. AB - Amyotrophic lateral sclerosis (ALS), Charcot's disease or Lou Gehrig's disease, is a term used to cover the spetrum of syndromes caracterized by progressive degeneration of motor neurons, a paralytic disorder caused by motor neuron degeneration. Currently, there are approximately 25,000 patients with ALS in the USA, with an average age of onset of 55 years. The incidence and prevalence of ALS are 1-2 and 4-6 per 100,000 each year, respectively, with a lifetime ALS risk of 1/600 to 1/1000. It causes progressive and cumulative physical disabilities, and leads to eventual death due to respiratory muscle failure. ALS is diverse in its presentation, course, and progression. We do not yet fully understand the causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. In this chapter, we will discuss the diagnosis, treatment, and how to cope with impaired function and end of life based on of our experience, guidelines, and clinical trials. Nowadays ALS seems to be a more complex disease than it did two decades - or even one decade - ago, but new insights have been plentiful. Clinical trials should be seen more as experiments on pathogenic mechanisms. A medication or combination of medications that targets more than one pathogenic pathway may slow disease progression in an additive or synergistic fashion. PMID- 26487928 TI - Botulinum Neurotoxin Type A in Neurology: Update. AB - This paper reviews the current and most neurological (central nervous system, CNS) uses of the botulinum neurotoxin type A. The effect of these toxins at neuromuscular junction lends themselves to neurological diseases of muscle overactivity, particularly abnormalities of muscle control. There are seven serotypes of the toxin, each with a specific activity at the molecular level. Currently, serotypes A (in two preparations) and B are available for clinical purpose, and they have proved to be safe and effective for the treatment of dystonia, spasticity, headache, and other CNS disorders in which muscle hyperactivity gives rise to symptoms. Although initially thought to inhibit acetylcholine release only at the neuromuscular junction, botulinum toxins are now recognized to inhibit acetylcholine release at autonomic cholinergic nerve terminals, as well as peripheral release of neuro-transmitters involved in pain regulation. Its effects are transient and nondestructive, and largely limited to the area in which it is administered. These effects are also graded according to the dose, allowing individualized treatment of patients and disorders. It may also prove to be useful in the control of autonomic dysfunction and sialorrhea. In over 20 years of use in humans, botulinum toxin has accumulated a considerable safety record, and in many cases represents relief for thousands of patients unaided by other therapy. PMID- 26487929 TI - Relapsing Remitting Multiple Sclerosis in an Iranian Patient with Neurofibromatosis Type I. AB - Neurofibromatosis type 1 (NF-1) is a common hereditary neuro-cutaneous disease, with known gene mutations, that mainly involves the skin and nervous system. Multiple sclerosis (MS) is an acquired inflammatory disease in which the myelin of nerve cells in the brain and spinal cord is damaged. These two disease do not share any apparent pathological similarities. We herein present a 32-year-old woman with definite NF-1, who has recently been diagnosed with MS, which to the best of our knowledge is a rare co-occurrence. Though there are often neurologic sign and symptoms in patients with NF-1, they should not always be considered as the natural history of the disease, and other overlapped pathologies should be kept in mind, in order to not miss or postpone the efficient treatment. PMID- 26487930 TI - Inflammatory Pseudotumors After Stem Cell Transplantation. AB - Inflammatory pseudotumors (IPT) are rare tumors that occur in various organs and tissues. The clinical picture varies from the more frequent benign lesions to rare malignant tumors with distant metastases. IPTs associated with hematopoietic stem cell transplantation (HSCT) is rarely reported. In this article, we review the reports of IPT after HSCT. We also review the possible factors involved in the pathogenesis. IPT may be rare but they are a potentially serious complication of HSCT. A knowledge of these entities and insistence on a definitive biopsy of mass lesions in the post-HSCT period can avoid unnecessary treatment such as radical surgery, chemotherapy or radiotherapy. PMID- 26487931 TI - A Rare Case of Myelodysplastic Syndrome with Refractory Thrombocytopenia. AB - Myelodysplastic syndromes (MDS) represent a variety of clonal abnormalities, possibly preleukemic and display numerous phenotypic manifestations. Specific mutations carry high morbidity and mortality rates due to cell line dysplasia. MDS commonly presents with symptoms related to anemia, and approximately two thirds will develop thrombocytopenia, a rare, but potentially lethal complication that increases complexity in treatment and morbidity, and may be due to unique genetic mutations leading to refractory thrombocytopenia, ultimately leading to an overall reduction in survival. Careful identification and monitoring of this patient subdivision can significantly reduce morbidity and mortality, and potential identification of specific gene mutations and advances in treatment options will hopefully provide guidance on detecting at-risk patients in the future. We present a case of a man with MDS-U (karyotype 46, XY, del (20) (q11.2q13.3) (20) with no detected JAK2 V617F mutation), who in despite of appropriate evidenced based treatment, continued to exhibit refractory thrombocytopenia. PMID- 26487932 TI - B-Cell-Rich T-Cell Lymphoma Associated with Epstein-Barr Virus-Reactivation and T Cell Suppression Following Antithymocyte Globulin Therapy in a Patient with Severe Aplastic Anemia. AB - B-cell lymphoproliferative disorder (B-LPD) is generally characterized by the proliferation of Epstein-Barr virus (EBV)-infected B lymphocytes. We here report the development of EBV-negative B-LPD associated with EBV-reactivation following antithymocyte globulin (ATG) therapy in a patient with aplastic anemia. The molecular autopsy study showed the sparse EBV-infected clonal T cells could be critically involved in the pathogenesis of EBV-negative oligoclonal B-LPD through cytokine amplification and escape from T-cell surveillances attributable to ATG based immunosuppressive therapy, leading to an extremely rare B-cell-rich T-cell lymphoma. This report helps in elucidating the complex pathophysiology of intractable B-LPD refractory to rituximab. PMID- 26487933 TI - Long Standing Eculizumab Treatment without Anticoagulant Therapy in High-Risk Thrombogenic Paroxysmal Nocturnal Hemoglobinuria. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-orphan disease affecting all hematopoietic cell types. The abnormality of red blood cells in this disease predisposes to intravascular complement-mediated hemolysis. Eculizumab is an orphan drug used to treat this rare disease. Thrombosis is the key cause of death in PNH patients in about 40% to 67% of cases. We report the case of a woman presenting with PNH complicated with serious Budd-Chiari syndrome thrombosis and with a stent inserted in the portal vein. She refused to take any anticoagulant treatment since she commenced eculizumab 4 years before. No thrombotic events happened since that time. This case could add an extra benefit for eculizumab, which could be used as an anti-thromboembolic prophylactic agent in PNH, especially in patients with thrombocytopenia, where the use of anticoagulant agents is extremely hazardous. More randomized studies might establish the use of eculizumab without anticoagulants to avoid serious bleeding that could happen in thrombocytopenic PNH patients. PMID- 26487934 TI - Acute Non-Atherosclerotic ST-Segment Elevation Myocardial Infarction in an Adolescent with Concurrent Hemoglobin H-Constant Spring Disease and Polycythemia Vera. AB - Thrombosis is a major complication of polycythemia vera (PV) and also a well known complication of thalassemia. We reported a case of non-atherosclerotic ST segment elevation myocardial infarction (STEMI) in a 17-year-old man with concurrent post-splenectomized hemoglobin H-Constant Spring disease and JAK2 V617F mutation-positive PV. The patient initially presented with extreme thrombocytosis (platelet counts greater than 1,000,000/uL) and three months later developed an acute STEMI. Coronary artery angiography revealed an acute clot in the right coronary artery without atherosclerotic plaque. He was treated with plateletpheresis, hydroxyurea and antiplatelet agents. The platelet count decreased and his symptoms improved. This case represents the importance of early diagnosis, awareness of the increased risk for thrombotic complications, and early treatment of PV in patients who have underlying thalassemia with marked thrombocytosis. PMID- 26487935 TI - Acute Liver Failure in a Pediatric Patient with Congenital Dysery-Thropoietic Anemia Type I Treated with Deferasirox. AB - Congenital dyserythropoietic anemias (CDA) represent a heterogeneous group of disorders characterized by morphological abnormalities of erythroid precursor cells and various degrees of hemolysis. Iron overload is a result of continuous hemolysis and recurrent transfusions. It is treated with iron chelators, including deferasirox. We present here a case of acute liver failure in a 12 years old girl with CDA type I treated with deferasirox and discuss the approach to treatment. PMID- 26487936 TI - Idiopathic Hemophagocytic Lymphohistiocytosis During Pregnancy Treated with Steroids. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe clinical syndrome characterized by a dysregulated hyperinflammatory immune response. The diagnosis of HLH during pregnancy is especially challenging due to the rarity of this condition. The highly variable clinical presentation, laboratory findings, and associated diagnoses accompanying this syndrome further complicate the problem. A pronounced hyperferritinemia in the setting of systemic signs and symptoms along with a negative infectious and rheumatological workup should raise suspicions for HLH. While treatment ideally consists of immunosuppressive chemotherapy and hematopoietic stem cell transplant, the potential toxicity to both the pregnant woman and the fetus poses a challenging decision. We report the first case of idiopathic HLH presenting as fever of unknown origin in a pregnant woman successfully treated with steroids. PMID- 26487937 TI - Surgery for gallbladder cancer in the US: a need for greater lymph node clearance. AB - BACKGROUND: Gallbladder cancer (GBC) is a rare malignancy with a dismal prognosis. Often identified incidentally after laparoscopic cholecystectomy for presumably benign biliary disease, reoperation with partial hepatic resection and periportal lymph node dissection (LND) is frequently performed. The impact of lymph node (LN) clearance for GBC remains unclear. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients diagnosed with GBC between 1988 and 2009. Survival was calculated using Kaplan-Meier method and compared using log-rank test. Multivariate analysis was performed to identify predictors of survival. RESULTS: A total of 11,815 patients diagnosed with GBC were identified. Cancer-directed surgery was performed in 8,436 (71.3%) patients. Optimal LN clearance (defined as >=4 LNs) is associated with young age, advanced T-stage, no radiation therapy, and radical surgery (all <0.001). Greater LND improves survival for all stages (P<0.001). After adjusting for confounding factors, multivariable analysis of patients with node-negative disease demonstrated that early stage, greater LND, and radical surgery were strong independent predictors of survival. CONCLUSIONS: Extensive lymphadenectomy correlates with longer survival even in node negative patients. Extensive LND should be performed in patients with GBC as many patients in the USA are undertreated. PMID- 26487938 TI - Increased risk of colorectal polyps in patients with non-alcoholic fatty liver disease undergoing liver transplant evaluation. AB - BACKGROUND: Screening colonoscopy is a standard part of the liver transplant (LT) evaluation process. We aimed to evaluate the yield of screening colonoscopy and determine whether non-alcoholic fatty liver disease (NAFLD) was associated with an increased risk of colorectal neoplasia. METHODS: We retrospectively assessed all patients who completed LT evaluation at our center between 1/2008-12/2012. Patients <50 years old and those without records of screening colonoscopy, or with greater than average colon cancer risk were excluded. RESULTS: A total of 1,102 patients were evaluated, 591 met inclusion criteria and were analyzed. The mean age was 60 years, 67% were male, 12% had NAFLD and 88% had other forms of chronic liver disease. Overall, 42% of patients had a polyp found on colonoscopy: 23% with adenomas, 14% with hyperplastic polyps and with 1% inflammatory polyps. In the final multivariable model controlling for age, NAFLD [odds ratio (OR) 2.41, P=0.001] and a history of significant alcohol use (OR 1.69, P=0.004) were predictive of finding a polyp on colonoscopy. In addition, NAFLD (OR 1.95, P=0.02), significant alcohol use (OR 1.70, P=0.01) and CTP class C (OR 0.57, P=0.02) were associated with adenoma, controlling for age. CONCLUSIONS: Screening colonoscopy in patients awaiting LT yields a high rate of polyp (43%) and adenoma (22%) detection, perhaps preventing the accelerated progression to carcinoma that can occur in immunosuppressed post-LT patients. Patients with NAFLD may be at a ~2 fold higher risk of adenomas and should be carefully evaluated prior to LT. PMID- 26487940 TI - Evaluation and comparison of postoperative levels of serum bilirubin, serum transaminases and alkaline phosphatase in laparoscopic cholecystectomy versus open cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) requires the creation of a pneumoperitoneum via insufflations of carbon dioxide; resulting in increased partial pressure of carbon dioxide (CO2) and intraperitoneal pressure which leads to the changes in pulmonary function and hemodynamic measurements. Hypercarbia leads to visceral organ ischemia including liver and venous stasis/thromboembolism or both due to impaired flow. The present study has been undertaken to see the changes in liver function tests (LFTs) after laparoscopic/open cholecystectomy (OC), the incidences of such change, their relation to age, sex, duration of surgery and to know the clinical significances of such disturbances. AIMS AND OBJECTIVES: To compare and correlate the serum level of bilirubin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) in patients who underwent LC to those who underwent OC. MATERIALS AND METHODS: The present study was conducted in the Department of Surgery at MMIMSR, MM University, Mullana, Ambala. A total number of 200 patients diagnosed as cholelithiasis were included in the study from May 2012 to May 2014. These cases were randomly divided into two groups (A and B) consisting of 100 cases each. LC was performed in group A patients and OC was done in group B patients. Three blood samples were taken: (I) pre-operatively; (II) after 24 hours of surgery; and (III) after 72 hours of surgery for comparison of the enzyme level alterations. RESULTS: In LC patients, there were rise in the levels of serum bilirubin, AST and ALT after 24 hrs of surgery from the preoperative value and then again fall was noted (near to normal value) after 72 hrs of surgery except in that of ALP. ALP levels showed slight fall after 24 hrs of surgery and then slight rise after 72 hrs which was within the normal limit. Whereas in OC patients, there were slight variations in the liver enzymes (which were within the normal range). CONCLUSIONS: Transient elevation of serum bilirubin, AST and ALT occurs after LC or after OC. The alteration in the liver enzymes can be attributed to CO2 pneumoperitoneum, surgical manipulations, diathermy, patient position, and arterial injury may also other factors. These changes return to normal in 3-4 days after procedure and they have no clinical consequences in patients with normal hepatic function but they may still cause worry to the surgeon regarding the integrity of biliary tree. PMID- 26487939 TI - Radioembolization with Yttrium-90 microspheres for patients with unresectable hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is aggressive primary malignancy of the liver that most commonly presents late in the disease course. As a result, the majority of patients are not candidates for curative therapies. Locoregional therapies including Yttrium-90 (Y-90) radioembolization play an important role in management of the vast majority of patients with HCC. METHODS: Patients with unnresectable HCC (n=17) treated with Y-90 radioembolization from 2005 to 2014 were evaluated retrospectively. Data was abstracted from medical records including patient charts, laboratory data, and imaging. Toxicities were recorded using Common Terminology Criteria 3.0. Response was recorded according to modified RECIST (mRECIST) criteria. RESULTS: Seventeen patients received 33 treatments with Y-90 radioembolization. A majority (65%) received TheraSphere with a minority (35%) receiving SIR-Spheres. The median treatment activity delivered was 1.725 gBq (range, 1.4-2.5 gBq). The median treatment dose delivered was 100 Gy (range, 90-120 Gy). The median lung shunt fraction was 2.02% (range, 1.5-4.1%). The most common clinical toxicity among all patients was nausea and vomiting (59%), primarily grade 1 and 2. Other post-treatment findings included abdominal pain (29%), fatigue (53%), and weight loss (18%). One patient developed a grade 5 gastric ulcer after the treatment. A clinical benefit, defined as patients achieving complete response (CR), partial response (PR) or stable disease (SD), was seen in 48% of patients. PR was seen in 24% of cases; progressive disease (PD) was noted in 35%. Patients survived for a median of 8.4 months (range, 1.3 to 21.1 months) after the first radioembolization treatment. Median survival after Y-90 treatment was 8.4 months among patients treated TheraSphere as compared with 7.8 months in patients treated with SIR-Spheres. The mean overall survival from the time of diagnosis was 11.7 months (range, 3.4 to 43.2 months). CONCLUSIONS: For patients with unresectable HCC, Y-90 radioembolization is a safe and well-tolerated procedure. Our experience suggests that a significant percentage of patients achieve clinical benefit including many with PR. Survival after treatment from this single-center, transplant center is in line with prior reports. Prospective, randomized data is required to compare radioembolization with other therapies including chemoembolization and systemic therapy with sorafenib. PMID- 26487941 TI - Palliative oxaliplatin-based chemotherapy after exposure to oxaliplatin in the adjuvant setting for colon cancer. AB - BACKGROUND: Little is known regarding the efficacy of oxaliplatin-based chemotherapy for metastatic colon cancer patients who have already received adjuvant oxaliplatin-based chemotherapy. METHODS: We retrospectively reviewed 22 consecutive patients who developed recurrence after adjuvant oxaliplatin-based chemotherapy for stage III colon cancer and received another course of oxaliplatin-based chemotherapy for their metastatic disease. The main endpoint was progression-free survival (PFS). RESULTS: A total of 635 patients received oxaliplatin-based chemotherapy for stage III colon cancer at the British Columbia Cancer Agency from 2006 to 2011. A total of 176 patients recurred, 22 (12.5%) of whom were re-exposed to oxaliplatin in the metastatic scenario. Oxaliplatin in combination with fluoropyrimidine was given as first, second and third line in in 3 (13.6%), 14 (63.6%), and 5 (22.7%) patients respectively. Median time from the last cycle of adjuvant oxaliplatin-based chemotherapy to the first cycle of palliative oxaliplatin-based chemotherapy was 44.3 months. Median PFS and overall survival (OS) were 3.3 (95% CI, 1.4-5.1) and 10.0 months (95% CI, 5.3-14.6), respectively. There was no difference in PFS for patients re-exposed to oxaliplatin less than 36 months compared to longer (3.6 versus 3.1 months, P=0.793, HR =0.88). CONCLUSIONS: In this population-based study, only a small proportion of pts who recurred after oxaliplatin-based adjuvant therapy received oxaliplatin in the metastatic setting. Re-exposure of oxaliplatin in combination with fluoropyrimidine is associated with only modest PFS benefit. Larger studies evaluating the role of oxaliplatin re-exposure are needed. PMID- 26487942 TI - Establishing the link between hepatitis B virus infection and colorectal adenoma. AB - BACKGROUND: Chronic hepatitis B (CHB) infection has been associated with malignancy, most notably hepatocellular carcinoma. Previous research has shown that hepatitis C is associated with increased colorectal adenomas and neoplasia. Currently, there are no studies on the association of CHB and colorectal adenomas. We aimed to identify a possible link between CHB and colorectal adenoma. METHODS: A retrospective chart review was performed on 588 consecutive patients undergoing screening or diagnostic colonoscopy that were previously screened or diagnosed with hepatitis B. Comparisons between categorical variables were analyzed with Chi Square test and t-test for continuous variables. Unconditional logistic regression was used to generate age-, gender-and race adjusted odds ratios and their 95% confidence intervals (CI) comparing medication users with non-users. Statistical analyses were performed with SAS 9.3 software. RESULTS: A total of 487 patients were analyzed in the control group vs. 71 in the hepatitis B group. The adenoma detection rate was 23.9% in hepatitis B vs. 15.9% in the non-hepatitis B group for all cause colonoscopy; however this did not reach statistical significance. There was a significantly higher number of adenomas present in the distal colon compared to control (OR =2.16; 95% CI, 1.06 4.43; P=0.04). There were no significant findings between hepatitis B infection with size, multiplicity or presence of proximal adenomas. There was a significant difference noted in regards to smoking history, BMI and age between two groups. CONCLUSIONS: Although the adenoma detection rate was higher in hepatitis B population vs. the non-hepatitis B group this did not reach statistical significance. However, we did find an association between CHB infection and the presence of distal colorectal adenomas. Larger prospective studies are needed to strengthen our findings along with future studies examining hepatitis B virus (HBV) and mechanisms inducing colorectal carcinogenesis. PMID- 26487943 TI - Outcomes of resected pancreatic cancer in patients age >=70. AB - OBJECTIVE: To determine outcomes of patients >=70 years with resected pancreatic cancer. METHODS: A study was conducted to identify pancreatic cancer patients >=70 years who underwent surgery for pancreatic carcinoma from 2000 to 2012. Patients were excluded if they had neoadjuvant therapy. The primary endpoint was overall survival (OS). RESULTS: We identified 112 patients with a median follow up of surviving patients of 36 months. The median patient age was 77 years. The median and 5 year OS was 20.5 months and 19%, respectively. Univariate analysis (UVA) showed a significant correlation for increased mortality with N1 (P=0.03) as well as post-op CA19-9 >90 (P<0.001), with a trend towards decreased mortality with adjuvant chemoradiation (P=0.08). Multivariate analysis (MVA) showed a statistically significant increased mortality associated with N1 (P=0.008), post op CA19-9 >90 (P=0.002), while adjuvant chemoradiation (P=0.04) was associated with decreased mortality. CONCLUSIONS: These data show that in patients >=70, nodal status, post-op CA19-9, and adjuvant chemoradiation, were associated with OS. The data suggests that outcomes of patients >=70 years who undergo upfront surgical resection are not inferior to younger patients. PMID- 26487944 TI - Delayed diagnosis of pancreatic cancer reported as more common in a population of North African young adults. AB - BACKGROUND: Pancreatic cancer is one of the most challenging tumor entities worldwide, characterized as a highly aggressive disease with dismal overall prognosis and an incidence rate equaling mortality rate. OBJECTIVE: In order to have an update about pancreatic cancer incidence and evolution in North Africa, we conducted an epidemiological analytical retrospective study at the level of three Algerian regions: Sidi-bel-Abbes, Oran and Tlemcen along the last eight years [2006-2013]. METHODS: We performed a retrospective hospital-based study in which we analyzed the records of 160 pancreatic cancer patients registered, evaluated and treated in a Northern African region; at the level of hospital centers of the three western Algerian regions from 2006 to 2013. RESULTS: Along the period of study, 160 patients were diagnosed with pancreatic cancer; with a mean age of 66.2 years, and a sex ratio of 1.65; other parameters such as a medical history smoking and alcoholism history, tumor site; histological type as well as the stage of diagnosis were also enrolled in the study. Our statistical analyses reported a very significant correlation between patients who belonged to the age group of 21-40 years and the advanced stage of diagnosis (basing on TNM classification) with P=0.02. CONCLUSIONS: Pancreatic cancer is increasingly diagnosed in young adults at an advanced stage in North African regions. PMID- 26487945 TI - Role of gemcitabine as second-line therapy after progression on FOLFIRINOX in advanced pancreatic cancer: a retrospective analysis. AB - BACKGROUND: Cancer of the exocrine pancreas is a highly lethal malignancy. Surgical resection is the only potentially curative treatment. Unfortunately, because of the late presentation, the majority have either locally advanced cancer at initial diagnosis. Systemic chemotherapy provides benefit to patients with advanced pancreatic cancer, improving disease-related symptoms and survival when compared to best supportive care alone. Based on fase III study, FOLFIRINOX regimen became the standard first-line treatment. But, the optimal management strategy for patients who fail initial FOLFIRINOX is undefined. Despite the lack of clinical trials that report the real benefit of gemcitabine in patients with advanced exocrine pancreatic cancer as second line treatment. We aim at reporting our experience with this regimen. METHODS: Patients with advanced exocrine pancreatic cancer who received gemcitabine (1.000 mg/m(2) on days 1, 8 and 15 every 4 weeks) until disease progression, as second-line therapy at our institution were retrospectively evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. RESULTS: A total of 20 patients were reviewed. Median age was 57 years (range, 43-74 years), and 55% were older than 60 years. Most patients were male (80%), had metastatic disease (60%), and ECOG performance status of 0 or 1 (65%). PFS and OS were 2.0 (95% CI, 1.2-2.8) and 5.7 months (95% CI, 3.9-7.4), respectively. There were no deaths due to the treatment. CONCLUSIONS: In this study, gemcitabine was a reasonable second-line treatment option for patients with advanced pancreatic adenocarcinoma and good ECOG performance status. Phase III trials are urgently needed comparing gemcitabine versus best supportive of care (BSC) can evaluate the real benefit of this chemotherapy after progression on FOLFIRINOX. PMID- 26487946 TI - Increased risk of death due to heart disease after radiotherapy for esophageal cancer. AB - OBJECTIVE: To evaluate the risk of heart disease related death (HDRD) following radiation therapy (RT) for esophageal cancer (EC). METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, two cohorts of patients with EC were created: (I) patients who received RT with their initial therapy; and (II) those who did not. Heart disease specific survival (HDSS) was analyzed using Kaplan-Meier methods. Cox proportional-hazards regression methods were used for univariate and multivariate analyses. RESULTS: We identified 40,778 patients with EC. A total of 26,377 patients received RT and 14,401 did not. HDSS analysis revealed increased risk of HDRD in those receiving RT (P<0.05), with an absolute risk of HDRD of 2.8%, 5.3% and 9.4% at 5-, 10- and 20-year, respectively. Log rank test of HDSS revealed the risk of HDRD became significant at 8 months (P<0.05). The following were associated with HDRD: RT, age, race, stage at presentation, time period of diagnosis, and known comorbid condition keeping one from esophagectomy. On multivariate analysis, RT remained predictive of HDRD [hazard ratio (HR) 1.46, P<0.05]. When considering only candidates for definitive therapy, RT remained predictive of HDRD on univariate (HR 1.53, P<0.0001) and multivariate (HR 1.62, P<0.0001) analyses. CONCLUSIONS: The use of RT leads to increased risk of HDRD that is detectable as early as eight months from diagnosis. More research is needed to define optimal dose volume parameters to prevent cardiac death. Consideration should be given to this risk in relation to prognosis and the expected benefits of RT. PMID- 26487947 TI - Comparison of anal cancer outcomes in public and private hospital patients treated at a single radiation oncology center. AB - OBJECTIVE: To compare clinical and treatment characteristics and outcomes in locally advanced anal cancer, a potentially curable disease, in patients referred from a public or private hospital. METHODS: We retrospectively reviewed 112 anal cancer patients from a public and a private hospital who received definitive chemoradiotherapy at the same cancer center between 2004 and 2013. Tumor stage, radiotherapy delay, radiotherapy duration, and unplanned treatment breaks >=10 days were compared using t-test and chi(2) test. Overall survival (OS), disease free survival (DFS), and colostomy free survival (CFS) were examined using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard models for OS and DFS were developed. RESULTS: The follow-up was 14.9 months (range, 0.7-94.8 months). Public hospital patients presented with significantly higher clinical T stage (P<0.05) and clinical stage group (P<0.05), had significantly longer radiotherapy delays (P<0.05) and radiotherapy duration (P<0.05), and had more frequent radiation therapy (RT) breaks >=10 days (P<0.05). Three-year OS showed a marked trend in favor of private hospital patients for 3 year OS (72.8% vs. 48.9%; P=0.171), 3-year DFS (66.3% vs. 42.7%, P=0.352), and 3 year CFS (86.4% vs. 68.9%, P=0.299). Referral hospital was not predictive of OS or DFS on multivariate analysis. CONCLUSIONS: Public hospital patients presented at later stage and experienced more delays in initiating and completing radiotherapy, which may contribute to the trend in poorer DFS and OS. These findings emphasize the need for identifying clinical and treatment factors that contribute to decreased survival in low socioeconomic status (SES) populations. PMID- 26487948 TI - Neoadjuvant therapy for gastric cancer: current evidence and future directions. AB - Although surgical resection remains the only potentially curative treatment for gastric cancer (GC), poor long-term outcomes with resection alone compel a multimodality approach to this disease. Multimodality strategies vary widely; while adjuvant approaches are typically favored in Asia and the United States (USA), a growing body of evidence supports neoadjuvant and/or perioperative strategies in locally advanced tumors. Neoadjuvant approaches are particularly attractive given the morbidity associated with surgical management of GC and the substantial risk of omission of adjuvant therapy. The specific advantages of chemoradiotherapy (CRT) compared to chemotherapy have not been well defined, particularly in the preoperative setting and trials aimed at determining the optimal elements and sequencing of therapy are underway. Future studies will also define the role of targeted and biologic therapies. PMID- 26487949 TI - Systematic review on quality of life outcomes after gastrectomy for gastric carcinoma. AB - BACKGROUND: Despite advances in chemotherapy and radiotherapy, gastrectomy is the only curative intervention for gastric carcinoma. This study reviews post operative health-related quality of life (HRQOL) after gastrectomy. METHODS: A literature search was conducted on PubMed for all studies published after January 2000 matching strict eligibility criteria. Bibliographies of included studies were also reviewed. Quality appraisal and data tabulation were performed using pre-determined forms. Results were synthesised by narrative review according to PRISMA guidelines with full tabulation of results of all included studies. RESULTS: A total of 21 studies (3,575 patients) were included. Post-operative HRQOL improvements were demonstrated across most or all domains in different HRQOL instruments. Patients experienced declines in HRQOL 1 month after surgery, but reached at least pre-operative levels with recovery by 1 year. The greatest improvements were demonstrated in the emotional health domain with favourable functional benefits. Partial gastrectomy appears to be superior to total gastrectomy in physical, emotional and functional health domains. However, patients remain susceptible to gastrointestinal symptoms following surgery, which negatively impact upon HRQOL. Post-operative complications did not appear to affect HRQOL. Most studies were prospective, but data is heterogeneous. CONCLUSIONS: Gastrectomy results in significant HRQOL benefits across a broad range of health domains. This is critical outcome of surgery and an important consideration in pre-operative decision making. PMID- 26487950 TI - Immunotherapy for advanced gastric and esophageal cancer: preclinical rationale and ongoing clinical investigations. AB - Gastric and esophageal cancers represent a major global cancer burden and novel approaches are needed. Despite recent improvements in outcomes with trastuzumab and ramucirumab the prognosis for advanced disease remains poor, with a median overall survival of 1 year. Comprehensive genomic characterization has defined molecular subgroups and potentially actionable genomic alterations, but the majority of patients do not yet benefit from molecularly directed therapies. Breakthroughs in immune checkpoint blockade have provided new therapeutic avenues in melanoma, and continue to expand into other tumor types, with ongoing investigations in gastrointestinal (GI) malignancies. The frequency of programmed death ligand 1 (PD-L1) overexpression, a putative response biomarker, approaches forty percent in gastric cancers. Translational studies and molecular classification suggest gastric and esophageal cancers are candidate malignancies for immune checkpoint inhibition trials and early clinical data is promising. Here we review the mechanisms, preclinical, and early clinical data supporting the role for immune checkpoint blockade in gastric and esophageal cancer. PMID- 26487951 TI - Trans-arterial embolisation therapies for unresectable intrahepatic cholangiocarcinoma: a systematic review. AB - BACKGROUND: Unresectable intrahepatic cholangiocarcinoma (ICC) portends a poor prognosis despite standard systemic treatments which confer minimal survival benefits and significant adverse effects. This study aimed to assess clinical outcomes, complications and prognostic factors of TAE therapies using chemotherapeutic agents or radiation. METHODS: A literature search and article acquisition was conducted on PubMed (MEDLINE), OVID (MEDLINE) and EBSCOhost (EMBASE). Original articles published after January 2000 on trans-arterial therapies for unresectable ICC were selected using strict eligibility criteria. Radiological response, overall survival, progression-free survival, safety profile, and prognostic factors for overall survival were assessed. Quality appraisal and data tabulation were performed using pre-determined forms. Results were synthesized by narrative review and quantitative analysis. RESULTS: Twenty articles were included (n=929 patients). Thirty three percent of patients presented with extrahepatic metastases. After treatment, the average rate of complete and partial radiological response was 10% and 22.2%, respectively. Overall median survival time was 12.4 months with a median 30-day mortality and 1 year survival rate of 0.6% and 53%, respectively. Acute treatment toxicity (within 30 days) was reported in 34.9% of patients, of which 64.3% were mild to moderate in severity. The most common clinical toxicities were abdominal pain, nausea and vomiting, and fatigue. Multiplicity, localization and vascularity of the tumor may predict worse overall survival. CONCLUSIONS: Trans-arterial therapies are safe and effective treatment options which should be considered routinely for unresectable ICC. Consistent and standardized methodology and data collection is required to facilitate a meta-analysis. Randomized controlled trials will be valuable in the future. PMID- 26487952 TI - "This is not me": patient, family, cultural and clinician considerations in cases of severe cancer-related debility. PMID- 26487953 TI - Fatal hepatitis B reactivation in a patient with islet cell tumor on octreotide and sirolimus. AB - Reactivation of hepatitis B viral infection (HBVr) is a known risk in cancer patients with a history of chronic hepatitis B infection receiving cytotoxic or immunosuppressive therapies. Patients with hematologic malignancies or those who have received stem cell transplantation seem to be most at risk but reactivation has been reported with various malignancies. Reactivation can present as asymptomatic liver function test abnormalities (LFTs), with symptoms of abdominal pain, encephalopathy, or as fulminant hepatitis and liver failure. Here we report the first case of a patient with islet cell tumor on octreotide and sirolimus who developed hepatitis B reactivation with fulminant liver failure and death. PMID- 26487954 TI - Liver resection for metastatic colorectal leiomyosarcoma: a single center experience. AB - BACKGROUND: Leiomyosarcoma arising in the colorectum is a rare malignancy of the smooth muscles accounting for less than 1% of gastrointestinal tumors. Surgery remains the most accepted modality for the treatment of this entity however management of liver metastases remains controversial. METHODS & RESULTS: From 1998 to 2009, five patients diagnosed with primary leiomyosarcoma of colorectal origin with metastatic liver disease, underwent liver resections at the American University of Beirut Medical Center. The median overall survival was 47 months (range, 7-135 months). CONCLUSIONS: Leiomyosarcoma of colorectal origin with liver metastasis is a very rare entity. Long-term survival can be achieved after surgical resection and should be considered for all patients. PMID- 26487955 TI - Duodenal and gallbladder metastasis of regressive melanoma: a case report and review of the literature. AB - BACKGROUND: Malignant melanoma involving the gastrointestinal (GI) tract may be primary or metastatic. Small bowel is the commonest site of GI metastases from cutaneous malignant melanoma, metastatic lesion in the gallbladder is extremely rare. CASE PRESENTATION: This case report describes the presentation of metastatic melanoma in duodenum and gallbladder. A 45-year-old man has presented melena with intermittent abdominal pain. On physical examination we found a small lesion between the fourth and fifth toes, associated with inguinal lymph node. An Abdominal ultrasound revealed diffuse duodenal thickening. Upper endoscopy was performed and discovered an ulcerative lesion in the second part of the duodenum. The biopsy with immunohistochemical stains was in favor of a duodenal location of melanoma. Computed tomography (CT) revealed many circumferential thickening of ileal loops associated with a nodular lesion in the anterior wall of the gallbladder. The patient was treated by palliative chemotherapy. DISCUSSION: Malignant melanoma of the GI tract may be primary or secondary. The small bowel is the most affected, but it's rare in the gallbladder. The clinical presentation can mimic the other intestinal tumors, and the diagnosis is based on imaging; CT scan and GI endoscopy have a key role on the diagnosis, and the treatment depends on the location and the number of lesions. CONCLUSIONS: Metastases of melanoma in the GI tract are uncommon, the diagnosis must be suspected in any patient with a history of melanoma with digestive signs. PMID- 26487956 TI - Cetuximab in combination with cisplatin and 5-Fluorouracil induces dramatic response in metastatic refractory squamous cell carcinoma of the anal canal. AB - Metastatic squamous cell carcinoma (SCC) of the anal canal is rare with limited data regarding treatment. Epidermal growth factor receptor (EGFR) expression has been observed in SCC of the anal canal and Kristen rat sarcoma vial oncogene (KRAS) mutations are rare. EGFR monoclonal antibodies, cetuximab and panitumumab, represent a potential option in this patient population. We report a metastatic SCC of the anal canal patient treated with cetuximab in combination with cisplatin plus 5-Fluorouracil (5-FU) that had a dramatic response. PMID- 26487957 TI - Tracheo-oesophageal fistula after palliative treatment of oesophageal cancer. AB - We present a case of an 86-year-old male who presented with severe pneumonia in the context of having undergone radiotherapy and then an oesophageal stent insertion for palliation of oesophageal cancer. He was diagnosed with a tracheo oesophageal fistula (TOF) which was successfully managed by deploying a second stent within the first stent. PMID- 26487958 TI - Advances in cancer nanomedicine. PMID- 26487959 TI - Ultrasensitive detection of DNA and protein markers in cancer cells. AB - Cancer cells differ from normal cells in various parameters, and these differences are caused by genomic mutations and consequential altered gene expression. The genetic and functional heterogeneity of tumor cells is a major challenge in cancer research, detection, and effective treatment. As such, the use of diagnostic methods is important to reveal this heterogeneity at the single cell level. Droplet microfluidic devices are effective tools that provide exceptional sensitivity for analyzing single cells and molecules. In this review, we highlight two novel methods that employ droplet microfluidics for ultra sensitive detection of nucleic acids and protein markers in cancer cells. We also discuss the future practical applications of these methods. PMID- 26487961 TI - Human induced pluripotent stem cells labeled with fluorescent magnetic nanoparticles for targeted imaging and hyperthermia therapy for gastric cancer. AB - OBJECTIVE: Human induced pluripotent stem (iPS) cells exhibit great potential for generating functional human cells for medical therapies. In this paper, we report for use of human iPS cells labeled with fluorescent magnetic nanoparticles (FMNPs) for targeted imaging and synergistic therapy of gastric cancer cells in vivo. METHODS: Human iPS cells were prepared and cultured for 72 h. The culture medium was collected, and then was co-incubated with MGC803 cells. Cell viability was analyzed by the MTT method. FMNP-labeled human iPS cells were prepared and injected into gastric cancer-bearing nude mice. The mouse model was observed using a small-animal imaging system. The nude mice were irradiated under an external alternating magnetic field and evaluated using an infrared thermal mapping instrument. Tumor sizes were measured weekly. RESULTS: iPS cells and the collected culture medium inhibited the growth of MGC803 cells. FMNP-labeled human iPS cells targeted and imaged gastric cancer cells in vivo, as well as inhibited cancer growth in vivo through the external magnetic field. CONCLUSION: FMNP labeled human iPS cells exhibit considerable potential in applications such as targeted dual-mode imaging and synergistic therapy for early gastric cancer. PMID- 26487960 TI - Texosome-based drug delivery system for cancer therapy: from past to present. AB - Rising worldwide cancer incidence and resistance to current anti-cancer drugs necessitate the need for new pharmaceutical compounds and drug delivery system. Malfunction of the immune system, particularly in the tumor microenvironment, causes tumor growth and enhances tumor progression. Thus, cancer immunotherapy can be an appropriate approach to provoke the systemic immune system to combat tumor expansion. Texosomes, which are endogenous nanovesicles released by all tumor cells, contribute to cell-cell communication and modify the phenotypic features of recipient cells due to the texosomes' ability to transport biological components. For this reason, texosome-based delivery system can be a valuable strategy for therapeutic purposes. To improve the pharmaceutical behavior of this system and to facilitate its use in medical applications, biotechnology approaches and mimetic techniques have been utilized. In this review, we present the development history of texosome-based delivery systems and discuss the advantages and disadvantages of each system. PMID- 26487962 TI - Polymeric nanocomposites loaded with fluoridated hydroxyapatite Ln(3+) (Ln = Eu or Tb)/iron oxide for magnetic targeted cellular imaging. AB - OBJECTIVE: To fabricate polymeric nanocomposites with excellent photoluminescence, magnetic properties, and stability in aqueous solutions, in order to improve specificity and sensitivity of cellular imaging under a magnetic field. METHODS: Fluoridated Ln(3+)-doped HAP (Ln(3+)-HAP) NPs and iron oxides (IOs) can be encapsulated with biocompatible polymers via a modified solvent exaction/evaporation technique to prepare polymeric nanocomposites with fluoridated Ln(3+)-HAP/iron oxide. The nanocomposites were characterized for surface morphology, fluorescence spectra, magnetic properties and in vitro cytotoxicity. Magnetic targeted cellular imaging of such nanocomposites was also evaluated with confocal laser scanning microscope using A549 cells with or without magnetic field. RESULTS: The fabricated nanocomposites showed good stability and excellent luminescent properties, as well as low in vitro cytotoxicity, indicating that the nanocomposites are suitable for biological applications. Nanocomposites under magnetic field achieved much higher cellular uptake via an energy-dependent pathway than those without magnetic field. CONCLUSION: The nanocomposites fabricated in this study will be a promising tool for magnetic targeted cellular imaging with improved specificity and enhanced selection. PMID- 26487963 TI - Single-cell analyses of circulating tumor cells. AB - Circulating tumor cells (CTCs) are a population of tumor cells mediating metastasis, which results in most of the cancer related deaths. The number of CTCs in the peripheral blood of patients is rare, and many platforms have been launched for detection and enrichment of CTCs. Enumeration of CTCs has already been used as a prognosis marker predicting the survival rate of cancer patients. Yet CTCs should be more potential. Studies on CTCs at single cell level may help revealing the underlying mechanism of tumorigenesis and metastasis. Though far from developed, this area of study holds much promise in providing new clinical application and deep understanding towards metastasis and cancer development. PMID- 26487964 TI - Reality of evidence-based practice in palliative care. AB - There has been a paradigm shift in medicine away from tradition, anecdote and theoretical reasoning from the basic sciences towards evidence-based medicine (EBM). In palliative care however, statistically significant benefits may be marginal and may not be related to clinical meaningfulness. The typical treatment vs. placebo comparison necessitated by 'gold standard' randomised controlled trials (RCTs) is not necessarily applicable. The complex multimorbidity of end of life care involves considerations of the patient's physical, psychological, social and spiritual needs. In addition, the field of palliative care covers a heterogeneous group of chronic and incurable diseases no longer limited to cancer. Adequate sample sizes can be difficult to achieve, reducing the power of studies and high attrition rates can result in inadequate follow up periods. This review uses examples of the management of cancer-related fatigue and death rattle (noisy breathing) to demonstrate the current state of EBM in palliative care. The future of EBM in palliative care needs to be as diverse as the patients who ultimately derive benefit. Non-RCT methodologies of equivalent quality, validity and size conducted by collaborative research networks using a 'mixed methods approach' are likely to pose the correct clinical questions and derive evidence based yet clinically relevant outcomes. PMID- 26487965 TI - Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors. AB - Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing. PMID- 26487966 TI - Advances in immunotherapy for treatment of lung cancer. AB - Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 (PD-1) and its ligand (PD-L1), on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab, another anti PD-1 antibody, has received FDA breakthrough therapy designation for treatment of non small cell lung cancer (NSCLC), supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months. PMID- 26487968 TI - Female breast cancer in Vietnam: a comparison across Asian specific regions. AB - Breast cancer is one of the most commonly diagnosed malignancies and the leading cause of cancer death of women over the world. A large number of females with breast cancer in Vietnam and other Southeast Asian (SEA) countries present at an early age with more aggressive tumors compared with women in Australia. Despite experiencing a low incidence rate, the increasing incidence rate among SEA countries exceeds that of the Westernized world. Changes in reproductive factors, environmental exposures, and lifestyle are the possible causes of this trend. However, limited evidence shows that these factors are associated with breast cancer in the Vietnamese population. Breast cancer incidence rates within Vietnam are not uniform and appear to be dependent on geographic location. Findings from this review have important implications for breast cancer control and treatment in Vietnam. A good understanding of the morphology of the breast and the type and nature of breast cancers presenting in Vietnam is required to facilitate the introduction of an effective national breast screening program. PMID- 26487967 TI - Development of targeted therapies in treatment of glioblastoma. AB - Glioblastoma (GBM) is a type of tumor that is highly lethal despite maximal therapy. Standard therapeutic approaches provide modest improvement in progression-free and overall survival, necessitating the investigation of novel therapies. Oncologic therapy has recently experienced a rapid evolution toward "targeted therapy", with drugs directed against specific targets which play essential roles in the proliferation, survival, and invasiveness of GBM cells, including numerous molecules involved in signal transduction pathways. Inhibitors of these molecules have already entered or are undergoing clinical trials. However, significant challenges in their development remain because several preclinical and clinical studies present conflicting results. In this article, we will provide an up-to-date review of the current targeted therapies in GBM. PMID- 26487969 TI - Quantitative proteomic analysis for high-throughput screening of differential glycoproteins in hepatocellular carcinoma serum. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Novel serum biomarkers are required to increase the sensitivity and specificity of serum screening for early HCC diagnosis. This study employed a quantitative proteomic strategy to analyze the differential expression of serum glycoproteins between HCC and normal control serum samples. METHODS: Lectin affinity chromatography (LAC) was used to enrich glycoproteins from the serum samples. Quantitative mass spectrometric analysis combined with stable isotope dimethyl labeling and 2D liquid chromatography (LC) separations were performed to examine the differential levels of the detected proteins between HCC and control serum samples. Western blot was used to analyze the differential expression levels of the three serum proteins. RESULTS: A total of 2,280 protein groups were identified in the serum samples from HCC patients by using the 2D LC-MS/MS method. Up to 36 proteins were up-regulated in the HCC serum, whereas 19 proteins were down-regulated. Three differential glycoproteins, namely, fibrinogen gamma chain (FGG), FOS-like antigen 2 (FOSL2), and alpha-1,6-mannosylglycoprotein 6 beta-N-acetylglucosaminyltransferase B (MGAT5B) were validated by Western blot. All these three proteins were up-regulated in the HCC serum samples. CONCLUSION: A quantitative glycoproteomic method was established and proven useful to determine potential novel biomarkers for HCC. PMID- 26487970 TI - Acute coronary syndrome: a rare case of multiple endocrine neoplasia syndromes with pheochromocytoma and medullary thyroid carcinoma. AB - Pheochromocytoma is a tumor arising from neuroectodermal chromaffin tissues in the adrenal gland or extra-adrenal paraganglia (paragangliomas). The prevalence of the tumor is 0.1%-0.6% in the hypertensive population, of which 10%-20% are malignant. Pheochromocytoma produces, stores, and secretes catecholamines, as well as leads to hypertensive crisis, arrhythmia, angina, and acute myocardial infarction without coronary artery diseases. We report a case of acute coronary syndrome (ACS) with a final diagnosis of multiple endocrine neoplasia with pheochromocytoma and medullary thyroid carcinoma (MTC). PMID- 26487971 TI - Erratum to Assays for predicting and monitoring responses to lung cancer immunotherapy. AB - [This corrects the article on p. 87 in vol. 12, PMID: 26175924.]. PMID- 26487972 TI - Surgical decompression coupled with diagnostic dynamic intraoperative angiography for bow hunter's syndrome. AB - BACKGROUND: Bow hunter's syndrome, also known as rotational vertebrobasilar insufficiency, arises from mechanical compression of the vertebral artery during the neck rotation. Surgical options have been the mainstay treatment of choice. Postoperative imaging is typically used to assess adequate decompression. On the other hand, intraoperative assessment of decompression has been rarely reported. CASE DESCRIPTION: A 52-year-old male began to see "black spots," and experienced presyncope whenever he rotated his head toward the right. The patient ultimately underwent a dynamic diagnostic cerebral angiogram, which revealed a dominant right vertebral artery and complete proximal occlusion of the right vertebral artery with the head rotated toward the right. Subsequently, the patient underwent an anterior transcervical approach to the right C6/C7 transverse process. The bone removal occurred along with the anterior wall of the C6 foramen transversarium, followed by the upper portion of the anterior C6 body medially, and the transverse process of C6 laterally. An oblique osseofibrous band was noted to extend across the vertebral artery; it was dissected and severed. An intraoperative cerebral angiogram confirmed no existing compression of the vertebral artery with the head rotated toward the right. The patient recovered from surgery without issues; he denied recurrence of preoperative symptoms at follow-up. CONCLUSIONS: The authors report the third instance where intraoperative dynamic angiography was employed with good outcomes. Although intraoperative cerebral angiography is an invasive procedure, which prompts additional risks, the authors believe the modality affords better, real-time visualization of the vertebral artery, allowing for assessment of the adequacy of the decompression. This advantage may reduce the probability for a second procedure, which has its own set of risks, and may counteract the risks involved with intraoperative dynamic angiography. PMID- 26487973 TI - A multidisciplinary approach to the treatment of severe cerebral vasospasm following bacterial meningitis: A case report and literature review. AB - BACKGROUND: Although cerebrovascular complications of bacterial meningitis are common, postmeningitic cerebral vasospasm significant enough to result in ischemic injury has been reported in only limited fashion. CASE DESCRIPTION: We describe a case of severe cerebral vasospasm following streptococcal meningitis managed successfully with emergency suboccipital decompression, extracranial intracranial bypass, intra-arterial vasodilator infusion, and maximal medical therapy. To our knowledge, this may be the first case in which surgical cerebral revascularization has been utilized to limit ischemic injury in the setting of postmeningitic cerebral vasospasm. CONCLUSIONS: Patients presenting with abrupt neurological decline following recent treatment for bacterial meningitis may be suffering from a reversible vasoconstriction of the cerebral arteries, and prompt aggressive treatment can result in a favorable outcome even in patients who present in very poor neurological condition. PMID- 26487974 TI - Intraparenchymal brain lesion biopsy guided by a rigid endoscope and navigation system. AB - BACKGROUND: The authors report a continuous case series of navigation-guided rigid endoscopic biopsy via the transcortical route for intraparenchymal brain lesions to assess the feasibility and efficacy of the method. METHODS: Thirty four patients with intraparenchymal brain lesions found on neurovisualization underwent navigation-guided rigid endoscopic biopsy. Most of the preoperative diagnoses were glioma WHO Grade II-IV (16 cases) or malignant lymphoma (15 cases). Intraoperative photodynamic diagnosis and intraoperative pathological diagnosis were used in 28 and 29 cases, respectively. In 2 cases with small and deep lesions, intraoperative magnetic resonance imaging was used for confirming the accuracy of the biopsy point. RESULTS: The sampling accuracy determined by postoperative imaging and the definitive diagnosis ratio were 94% (32 out of 34 cases) and 97% (33 out of 34 cases), respectively. There was no postoperative mortality. In 2 patients, mild postoperative permanent morbidity (5.9%), presumably related to this technique, was observed in the early cases in the current group (34 case series). CONCLUSION: The method was estimated as safe and feasible for diagnostic tissue sampling of intraparenchymal brain lesions. PMID- 26487975 TI - The effects of sodium-2-mercaptoethanesulfonate application on the neural and neurovascular tissues: An experimental animal study. AB - BACKGROUND: Sodium-2-mercaptoethanesulfonate (MESNA) is a protective agent that is also used as "a chemical dissector" in various surgical fields. The aim of this study is to evaluate the toxic effects of MESNA on neural and neurovascular structures based on a morphological analysis and examine its safety in neurotological applications. METHODS: Three groups of guinea pigs were used as subjects. MESNA solution (50 and 100%) and saline solution were applied to the subarachnoid space over the brain tissue via a middle fossa approach of study and control groups, respectively. Effects of MESNA were assessed by means of light microscope. McNemar Chi-square test was used to evaluate the histopathological findings. Statistical significance of P < 0.05 was taken as criterion. RESULTS: No morphological changes were observed on vascular and neural structures in the study groups in both concentrations, compared to the control group. CONCLUSIONS: On a morphological basis, a single application of MESNA does not cause any morphological changes that indicate a toxicity in neural and neurovascular structures. PMID- 26487976 TI - Second Annual Meeting of the International Society of Pediatric Wound Care. AB - The overarching goals of the International Society of Pediatric Wound Care (ISPeW) are to (1) set global standards for the assessment and treatment of pediatric wounds of varying etiologies; (2) provide a forum for international interprofessional collaboration among healthcare professionals, researchers, educators, and industry leaders dedicated to the care of pediatric wounds; (3) promote and support clinical research focused on the prevention, assessment, and treatment of pediatric wounds; (4) collaborate with wound care organizations worldwide on pediatric wound care issues; and (5) provide evidence-based pediatric wound care education to healthcare professionals, parents, and lay caregivers. This edition of Advances in Wound Care includes some of the work that was presented at the 2014 ISPeW meeting in Rome. The first article by Dr. Romanelli, is an in-depth description of the progression of skin physiology throughout its maturational stages and clinical implication. A cutting edge article by Dr. Timothy King then follows, with regard to scar prevention in postnatal tissues. This is followed by a comprehensive look at debridement techniques in pediatric trauma by Dr. Ankush Gosain. Next, is a cautionary article by Dr. Luca Spazzapan that examines the prevalence of diabetic foot ulcers in children and the potential for an epidemic. The last article in this series is from the keynote speaker, Dr. Amit Geffen, who eloquently examines the use of biomaterials to offload and prevent pediatric pressure ulcers. PMID- 26487977 TI - Skin Physiology of the Neonate and Infant: Clinical Implications. AB - Significance: The skin is a complex and dynamic organ that performs several vital functions. The maturation process of the skin starts at birth with the adaption of the skin to the comparatively dry environment compared to the in utero milieu. This adaptive flexibility results in the unique properties of infant skin. To deliver appropriate care to infant skin, it is necessary to understand that it is evolving with unique characteristics. Recent Advances: The role of biophysical noninvasive techniques in the assessment of skin development underlines the importance of an objective evaluation of skin physiology parameters. Skin hydration, transepidermal water loss, and pH values are measurable with specific instruments that give us an accurate and reproducible assessment during infant skin maturation. The recording of these values, following standard measurement procedures, allows us to evaluate the integrity of the skin barrier and to monitor the functionality of the maturing skin over time. Critical Issues: During the barrier development, impaired skin function makes the skin vulnerable to chemical damage, microbial infections, and skin diseases, possibly compromising the general health of the infant. Preterm newborns, during the first weeks of life, have an even less developed skin barrier and, therefore, are even more at risk. Thus, it is extremely important to evaluate the risk of infection, skin breakdown, topical agent absorption, and the risk of thermoregulation failure. Future Directions: Detailed and objective evaluations of infant skin maturation are necessary to improve infant skin care. The results of these evaluations should be formed into general protocols that will allow doctors and caregivers to give more personalized care to full-term newborns, preterm newborns, and infants. PMID- 26487978 TI - Debridement Techniques in Pediatric Trauma and Burn-Related Wounds. AB - Significance: Traumatic injuries are the leading cause of morbidity and mortality in children. The purpose of this review is to provide an overview of the initial assessment and management of traumatic and burn wounds in children. Special attention is given to wound cleansing, debridement techniques, and considerations for pain management and psychosocial support for children and families. Recent Advances: Basic and translational research over the last 5-7 years has advanced our knowledge related to the optimal care of acute pediatric traumatic and burn wounds. Data concerning methods, volume, solution and timing for irrigation of acute traumatic wounds, timing and methods of wound debridement, including hydrosurgery and plasma knife coblation, and wound dressings are presented. Additionally, data concerning the long-term psychosocial outcomes following acute injury are presented. Critical Issues: The care of pediatric trauma and burn related wounds requires prompt assessment, pain control, cleansing, debridement, application of appropriate dressings, and close follow-up. Ideally, a knowledgeable multidisciplinary team cares for these patients. A limitation in the care of these patients is the relative paucity of data specific to the care of acute traumatic wounds in the pediatric population. Future Directions: Research is ongoing in the arenas of new debridement techniques and instruments, and in wound dressing technology. Dedicated research on these topics in the pediatric population will serve to strengthen and advance the care of pediatric patients with acute traumatic and burn wounds. PMID- 26487979 TI - Emerging Therapies for Scar Prevention. AB - Significance: There are ~12 million traumatic lacerations treated in the United States emergency rooms each year, 250 million surgical incisions created worldwide every year, and 11 million burns severe enough to warrant medical treatment worldwide. In the United States, over $20 billion dollars per year are spent on the treatment and management of scars. Recent Advances: Investigations into the management of scar therapies over the last decade have advanced our understanding related to the care of cutaneous scars. Scar treatment methods are presented including topical, intralesional, and mechanical therapies in addition to cryotherapy, radiotherapy, and laser therapy. Critical Issues: Current treatment options for scars have significant limitations. This review presents the current and emerging therapies available for scar management and the scientific evidence for scar management is discussed. Future Directions: Based upon our new understanding of scar formation, innovative scar therapies are being developed. Additional research on the basic science of scar formation will lead to additional advances and novel therapies for the treatment of cutaneous scars. PMID- 26487980 TI - Adjustability and Adaptability Are Critical Characteristics of Pediatric Support Surfaces. AB - Significance: Pressure ulcers (PUs) in newborns and children are remarkably different from those in adults, both in their possible causal factors and in the etiology and biomechanical pathways for tissue damage. Recent Advances: Pediatric muscle and fat tissue structures are overall softer than those of adults, making newborns and young children more susceptible to deformation-inflicted injuries at their weight-bearing soft tissues. Critical Issues: The unique medical environment of neonatal and pediatric intensive care units, which is overloaded with medical devices, wiring, tubing, electrodes, and so on, is, in fact, an extrinsic risk factor for device-related PUs, since accidently misplaced tubes, wires, or electrodes can become trapped between the skin and the mattress, causing large sustained soft tissue deformations around them. Future Directions: Mattresses that are being used in neonatal and pediatric intensive care units must be able to respond to frequent movements and changing positions and also be able to effectively adapt and conform around such misplaced tubing or wires, which might contact the body and deform soft tissues. We used computer simulations of a tube caught under a preterm neonate's arm in a supine position to illustrate what adaptability of the support surface means in such cases. Our present simulations indicate that an air-cell-based technology provides considerably better protection against PUs in such cases, as the air-cells are able to locally buckle and conform around objects that are stiffer than the pediatric tissues (e.g., wires, tubes, electrodes), which minimizes exposure to tissue deformations. PMID- 26487981 TI - Improvement of Distribution and Osteogenic Differentiation of Human Mesenchymal Stem Cells by Hyaluronic Acid and beta-Tricalcium Phosphate-Coated Polymeric Scaffold In Vitro. AB - Bone tissue engineering requires a well-designed scaffold that can be biodegradable, biocompatible, and support the stem cells to osteogenic differentiation. Porous polycaprolactone (PCL) scaffold prepared by fused deposition modeling is an attractive biomaterial that has been used in clinic. However, PCL scaffolds lack biological function and osteoinductivity. In this study, we functionalized the PCL scaffolds by embedding them with a matrix of hyaluronic acid/beta-tricalcium phosphate (HA/TCP). Human mesenchymal stem cells (MSCs) were cultured on scaffolds with and without coating to investigate proliferation and osteogenic differentiation. The DNA amount was significantly higher in the HA/TCP-coated scaffold on day 21. At the gene expression level, HA/TCP coating significantly increased the expression of ALP and COLI on day 4. These data correlated with the ALP activity peaking on day 7 in the HA/TCP-coated scaffold. Scanning electron microscope and histological analysis revealed that the cell matrix and calcium deposition were distributed more uniformly in the coated scaffolds compared to scaffolds without coating. In conclusion, the HA/TCP coating improved cellular proliferation, osteogenic differentiation, and uniform distribution of the cellular matrix in vitro. The HA/TCP-PCL scaffold holds great promise to accommodate human bone marrow-derived MSCs for bone reconstruction purposes, which warrants future in vivo studies. PMID- 26487983 TI - Understanding Democracy and Development Traps Using a Data-Driven Approach. AB - Methods from machine learning and data science are becoming increasingly important in the social sciences, providing powerful new ways of identifying statistical relationships in large data sets. However, these relationships do not necessarily offer an understanding of the processes underlying the data. To address this problem, we have developed a method for fitting nonlinear dynamical systems models to data related to social change. Here, we use this method to investigate how countries become trapped at low levels of socioeconomic development. We identify two types of traps. The first is a democracy trap, where countries with low levels of economic growth and/or citizen education fail to develop democracy. The second trap is in terms of cultural values, where countries with low levels of democracy and/or life expectancy fail to develop emancipative values. We show that many key developing countries, including India and Egypt, lie near the border of these development traps, and we investigate the time taken for these nations to transition toward higher democracy and socioeconomic well-being. PMID- 26487982 TI - Porous, Ventricular Extracellular Matrix-Derived Foams as a Platform for Cardiac Cell Culture. AB - To more closely mimic the native cellular microenvironment, 3D scaffolds derived from the extracellular matrix (ECM) are being developed as alternatives to conventional 2D culture systems. In the present study, we established methods to fabricate nonchemically cross-linked 3D porous foams derived entirely from decellularized porcine left ventricle (DLV) for use as an in vitro cardiac cell culture platform. Furthermore, we explored the effects of physically preprocessing the DLV through mechanical mincing versus cryomilling, as well as varying the ECM concentration on the structure, composition, and physical properties of the foams. Our results indicate that the less highly processed minced foams had a more cohesive and complex network of ECM components, enhanced mechanical properties, and improved stability under simulated culturing conditions. To validate the DLV foams, a proof-of-concept study was conducted to explore the early cardiomyogenic differentiation of pericardial fat adipose derived stem/stromal cells (pfASCs) on the minced DLV foams relative to purified collagen I gel controls. Differentiation was induced using a modified cardiomyogenic medium (MCM) or through stimulation with 5-azacytidine (5-aza), and cardiomyocyte marker expression was characterized by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction. Our results indicate that early markers of cardiomyogenic differentiation were significantly enhanced on the DLV foams cultured in MCM, suggesting a synergistic effect of the cardiac ECM-derived scaffolds and the culture medium on the induction of pfASC differentiation. Furthermore, in analyzing the response in the noninduced control groups, the foams were observed to provide a mildly inductive microenvironment for pfASC cardiomyogenesis, supporting the rationale for using tissue-specific ECM as a substrate for cardiac cell culture applications. PMID- 26487984 TI - Utilization and Monetization of Healthcare Data in Developing Countries. AB - In developing countries with fledgling healthcare systems, the efficient deployment of scarce resources is paramount. Comprehensive community health data and machine learning techniques can optimize the allocation of resources to areas, epidemics, or populations most in need of medical aid or services. However, reliable data collection in low-resource settings is challenging due to a wide range of contextual, business-related, communication, and technological factors. Community health workers (CHWs) are trusted community members who deliver basic health education and services to their friends and neighbors. While an increasing number of programs leverage CHWs for last mile data collection, a fundamental challenge to such programs is the lack of tangible incentives for the CHWs. This article describes potential applications of health data in developing countries and reviews the challenges to reliable data collection. Four practical CHW-centric business models that provide incentive and accountability structures to facilitate data collection are presented. Creating and strengthening the data collection infrastructure is a prerequisite for big data scientists, machine learning experts, and public health administrators to ultimately elevate and transform healthcare systems in resource-poor settings. PMID- 26487985 TI - Does Medical School Training Relate to Practice? Evidence from Big Data. AB - On April 2nd, 2014, the Department of Health and Human Services (HHS) announced a historic policy in its effort to increase the transparency in the American healthcare system. The Center for Medicare and Medicaid Service (CMS) would publicly release a dataset containing information about the types of Medicare services, requested charges, and payments issued by providers across the country. In its release, HHS stated that the data would shed light on "Medicare fraud, waste, and abuse." While this is most certainly true, we believe that it can provide so much more. Beyond the purely financial aspects of procedure charges and payments, the procedures themselves may provide us with additional information, not only about the Medicare population, but also about the physicians themselves. The procedures a physician performs are for the most part not novel, but rather recommended, observed, and studied. However, whether a physician decides on advocating a procedure is somewhat discretionary. Some patients require a clear course of action, while others may benefit from a variety of options. This article poses the following question: How does a physician's past experience in medical school shape his or her practicing decisions? This article aims to open the analysis into how data, such as the CMS Medicare release, can help further our understanding of knowledge transfer and how experiences during education can shape a physician's decision's over the course of his or her career. This work begins with an evaluation into similarities between medical school charges, procedures, and payments. It then details how schools' procedure choices may link them in other, more interesting ways. Finally, the article includes a geographic analysis of how medical school procedure payments and charges are distributed nationally, highlighting potential deviations. PMID- 26487986 TI - Does Television Viewership Predict Presidential Election Outcomes? AB - The days of surprise about actual election outcomes in the big data world are likely to be fewer in the years ahead, at least to those who may have access to such data. In this paper we highlight the potential for forecasting the Unites States presidential election outcomes at the state and county levels based solely on the data about viewership of television programs. A key consideration for relevance is that given the infrequent nature of elections, such models are useful only if they can be trained using recent data on viewership. However, the target variable (election outcome) is usually not known until the election is over. Related to this, we show here that such models may be trained with the television viewership data in the "safe" states (the ones where the outcome can be assumed even in the days preceding elections) to potentially forecast the outcomes in the swing states. In addition to their potential to forecast, these models could also help campaigns target programs for advertisements. Nearly two billion dollars were spent on television advertising in the 2012 presidential race, suggesting potential for big data-driven optimization of campaign spending. PMID- 26487987 TI - Using Big Data to Understand the Human Condition: The Kavli HUMAN Project. AB - Until now, most large-scale studies of humans have either focused on very specific domains of inquiry or have relied on between-subjects approaches. While these previous studies have been invaluable for revealing important biological factors in cardiac health or social factors in retirement choices, no single repository contains anything like a complete record of the health, education, genetics, environmental, and lifestyle profiles of a large group of individuals at the within-subject level. This seems critical today because emerging evidence about the dynamic interplay between biology, behavior, and the environment point to a pressing need for just the kind of large-scale, long-term synoptic dataset that does not yet exist at the within-subject level. At the same time that the need for such a dataset is becoming clear, there is also growing evidence that just such a synoptic dataset may now be obtainable-at least at moderate scale using contemporary big data approaches. To this end, we introduce the Kavli HUMAN Project (KHP), an effort to aggregate data from 2,500 New York City households in all five boroughs (roughly 10,000 individuals) whose biology and behavior will be measured using an unprecedented array of modalities over 20 years. It will also richly measure environmental conditions and events that KHP members experience using a geographic information system database of unparalleled scale, currently under construction in New York. In this manner, KHP will offer both synoptic and granular views of how human health and behavior coevolve over the life cycle and why they evolve differently for different people. In turn, we argue that this will allow for new discovery-based scientific approaches, rooted in big data analytics, to improving the health and quality of human life, particularly in urban contexts. PMID- 26487988 TI - Opportunities for New Insights on the Life-Course Risks and Outcomes of Cognitive Decline in the Kavli HUMAN Project. AB - The Kavli HUMAN Project (KHP) will provide groundbreaking insights into how biological, medical, and social factors interact and impact the risks for cognitive decline from birth through older age. It will richly measure the effect of cognitive decline on the ability to perform key activities of daily living. In addition, due to its family focus, the KHP will measure the impact on family members, including the amount of time that family members spend providing care to older adults with dementia. It will also clarify the division of caregiving duties among family members and the effects on caregivers' work, family life, and balance thereof. At the same time, for care that the family cannot provide, it will clarify the extent to which cognitive decline impacts healthcare utilization and end-of-life decision making. PMID- 26487989 TI - Diets and Health: How Food Decisions Are Shaped by Biology, Economics, Geography, and Social Interactions. AB - Health is shaped by both personal choices and features of the food environment. Food-choice decisions depend on complex interactions between biology and behavior, and are further modulated by the built environment and community structure. That lower-income families have lower-quality diets is well established. Yet, diet quality also varies across small geographic neighborhoods and can be influenced by transportation, retail, and ease of access to healthy foods, as well as by attitudes, beliefs, and social interactions. The learnings from the Seattle Obesity Study (SOS II) can be usefully applied to the much larger, more complex, and far more socially and ethnically diverse urban environment of New York City. The Kavli HUMAN Project (KHP) is ideally positioned to advance the understanding of health disparities by exploring the multiple underpinnings of food decision making. By combining geo-localized food shopping and consumption data with health behaviors, diet quality measures, and biomarkers, also coded by geographic location, the KHP will create the first-of its-kind bio-behavioral, economic, and cultural atlas of diet quality and health for New York City. PMID- 26487990 TI - How Genetic and Other Biological Factors Interact with Smoking Decisions. AB - Despite clear links between genes and smoking, effective public policy requires far richer measurement of the feedback between biological, behavioral, and environmental factors. The Kavli HUMAN Project (KHP) plans to exploit the plummeting costs of data gathering and to make creative use of new technologies to construct a longitudinal panel data set that would compare favorably to existing longitudinal surveys, both in terms of the richness of the behavioral measures and the cost-effectiveness of the data collection. By developing a more comprehensive approach to characterizing behavior than traditional methods, KHP will allow researchers to paint a much richer picture of an individual's life cycle trajectory of smoking, alcohol, and drug use, and interactions with other choices and environmental factors. The longitudinal nature of KHP will be particularly valuable in light of the increasing evidence for how smoking behavior affects physiology and health. The KHP could have a transformative impact on the understanding of the biology of addictive behaviors such as smoking, and of a rich range of prevention and amelioration policies. PMID- 26487991 TI - Real-Time Assessment of Wellness and Disease in Daily Life. AB - The next frontier in medicine involves better quantifying human traits, known as "phenotypes." Biological markers have been directly associated with disease risks, but poor measurement of behaviors such as diet and exercise limits our understanding of preventive measures. By joining together an uncommonly wide range of disciplines and expertise, the Kavli HUMAN Project will advance measurement of behavioral phenotypes, as well as environmental factors that impact behavior. By following the same individuals over time, KHP will liberate new understanding of dynamic links between behavioral phenotypes, disease, and the broader environment. As KHP advances understanding of the bio-behavioral complex, it will seed new approaches to the diagnosis, prevention, and treatment of human disease. PMID- 26487992 TI - Infant Trauma Management in the Emergency Department: An Emergency Medicine Simulation Exercise. AB - In a trauma situation, it is essential that emergency room physicians are able to think clearly, make decisions quickly and manage patients in a way consistent with their injuries. In order for emergency medicine residents to adequately develop the skills to deal with trauma situations, it is imperative that they have the opportunity to experience such scenarios in a controlled environment with aptly timed feedback. In the case of infant trauma, sensitivities have to be taken that are specific to pediatric medicine. The following describes a simulation session in which trainees were tasked with managing an infantile patient who had experienced a major trauma as a result of a single vehicle accident. The described simulation session utilized human patient simulators and was tailored to junior (year 1 and 2) emergency medicine residents. PMID- 26487993 TI - An Algorithm to Predict Success of Indirect Decompression Using the Extreme Lateral Lumbar Interbody Fusion Procedure. AB - PURPOSE: The purpose of this study is to define an algorithm that will predict the success of indirect decompression without the need for direct decompression in patients undergoing lateral lumbar interbody fusions. METHODS AND MATERIALS: A prospective cohort study was undertaken for patients undergoing indirect decompression with lateral lumbar interbody fusion. Patients had to meet the following criteria prior to indirect fusion: lack of facet fusion on CT, absence of free disc fragment or compressive facet joint cyst on MRI, absence of frank osteoporosis, lack of congenital and/or severe spinal stenosis on MRI, and significant reduction (greater than 50%) in leg and back pain at rest. We then assessed which patients at follow-up required a second stage open decompression procedure because of continued back and/or leg pain. RESULTS: Our series included 28 patients who underwent indirect decompression with extreme lateral lumbar interbody fusion. Of the 28 patients, one patient required a second stage open decompression at follow-up. The most common level operated on was the L4-L5 level. Twelve patients underwent more than a single level fusion. Average preoperative lumbar lordosis was 29 degrees and average postoperative lordosis was 45 degrees. The average patient age was 66.3 years and average follow-up was 1.21 years. CONCLUSIONS: Our algorithm can be used as an aid to assess which patients may benefit from indirect decompression alone, compared to indirect decompression combined with posterior decompression procedures. PMID- 26487994 TI - Organized Pneumonia Secondary to Increasing Doses of Temozolomide. AB - Surgery, radiotherapy (RT), and chemotherapy have a role in the control of tumor growth, progression, and recurrence in high-grade gliomas. Temozolomide has been incorporated as the main chemotherapy agent for managing these tumors. Here, we present a case of a patient who developed a severe organizing pneumonia after increasing doses of temozolomide for a high-grade glioma. PMID- 26487995 TI - Diagnostic Yield of FDG-PET/CT, MRI, and CSF Cytology in Non-Biopsiable Neurolymphomatosis as a Heralding Sign of Recurrent Non-Hodgkin's Lymphoma. AB - Neurolymphomatosis (NL) is a rare condition associated with lymphomas in which various structures of the nervous system are infiltrated by malignant lymphocytes. Rarely, it may be the presenting feature of recurrence of lymphoma otherwise deemed to be in remission. It is crucial, as is the case with all types of nodal or visceral involvement of lymphoma, to identify the disease early and initiate treatment with chemotherapy and/or radiation therapy. Positron emission tomography-computed tomography (PET-CT) has been shown to be a sensitive modality for staging, restaging, biopsy guidance, therapy response assessment, and surveillance for recurrence of lymphoma. Magnetic resonance imaging (MRI) is another useful imaging modality, which, along with PET/CT, compliment cerebrospinal spinal fluid (CSF) cytology and electromyography (EMG) in the diagnosis of NL. Performing nerve biopsies to confirm neurolymphomatosis can be challenging and with associated morbidity. The case presented herein illustrates the practical usefulness of these tests in detecting NL as a heralding feature of lymphoma recurrence, especially in the absence of histopathologic correlation. PMID- 26487996 TI - Safety and Patient Acceptability of Stellate Ganglion Blockade as a Treatment Adjunct for Combat-Related Post-Traumatic Stress Disorder: A Quality Assurance Initiative. AB - OBJECTIVE: To perform a quality assurance and performance improvement project through review of our single center data on the safety and patient acceptability of the stellate ganglion blockade (SGB) procedure for the relief of symptoms related to chronic post-traumatic stress disorder. BACKGROUND: Our interventional pain management service has been offering trials of SGB therapy to assist with the management of the sympathetically mediated anxiety and hyperarousal symptoms of severe and treatment-refractory combat-related PTSD. There have been multiple case series in the literature describing the potential impact of this procedure for PTSD symptom management as well as the safety of image-guided procedures. We wished to ensure that we were performing this procedure safely and that patients were tolerating and accepting of this adjunctive treatment option. METHODS: We conducted a review of our quality assurance and performance improvement data over the past 18 months during which we performed 250 stellate ganglion blocks for the management of PTSD symptoms to detect any potential complications or unanticipated side effects. We also analyzed responses from an anonymous patient de-identified survey collected regarding the comfort and satisfaction associated with the procedure. RESULTS: We did not identify any immediate post-procedural complications or delayed complications from any of the 250 procedures performed from November 2013 to April 2015. Of the 110 surveys that were returned and tabulated, 100% of the patients surveyed were overall satisfied with our process and with the procedure, 100% said they would recommend the procedure to a friend, and 95% stated that they would be willing to undergo as many repeat procedures as necessary based on little discomfort and tolerable side effects. CONCLUSION: Our quality assurance assessment suggests that in our center the SGB procedure for PTSD is a safe, well tolerated, and acceptable treatment adjunct in the management of severe symptoms associated with chronic treatment-refractory PTSD. Patient satisfaction responses are strongly suggestive of high therapeutic value, and further studies are indicated to determine the effectiveness, duration of action, and optimal treatment regimen. PMID- 26487997 TI - Meningiomas of the Anterior Clinoid Process: Is It Wise to Drill Out the Optic Canal? AB - INTRODUCTION: Meningiomas of the anterior clinoid process are uncommon tumors, acknowledged by most experienced surgeons to be among the most challenging meningiomas to completely remove. In this article, we summarize our institutional experience removing these uncommon and challenging skull base meningiomas. METHODS: We analyzed the clinical outcomes of patients undergoing surgical removal of anterior at our institution over an 18-year period. We characterized the radiographic appearance of these tumors and related tumor features to symptoms and ability to obtain a gross total resection. We also analyzed visual outcomes in these patients, focusing on visual outcomes with and without optic canal unroofing. RESULTS: We identified 29 patients with anterior clinoid meningiomas who underwent surgical resection at our institution between 1991 and 2007. The median length of follow-up was 7.5 years (range: 2.0 to 18.6 years). Similar to others, we found gross total resection was seldom safely achievable in these patients. Despite this, only 1/20 of patients undergoing subtotal resection without immediate postoperative radiosurgery experienced tumor progression. The optic canal was unroofed in 18/29 patients in this series, while in 11/29 patients it was not. Notably, all five patients experiencing visual improvement underwent optic canal unroofing, while three of four patients experiencing visual worsening did not. CONCLUSIONS: These data provide some evidence suggesting that unroofing the optic canal in anterior clinoid meningiomas might improve visual outcomes in these patients. PMID- 26487998 TI - Patterns of Relapse in Squamous Cell Carcinoma of the Tonsil - Unilateral vs. Bilateral Radiation in the HPV-Era. AB - OBJECTIVES: In the pre-human papillomavirus (HPV) era, unilateral radiation therapy (URT) for tonsil cancer was associated with low contralateral failure rates and had less toxicity than bilateral radiation therapy (BRT). This study explores the validity of URT in HPV-positive tonsil cancers. METHODS: Tonsil squamous cell carcinomas (SCC) treated (typically with 70 Gy radiation and Cisplatin-based chemotherapy) between 2001 and 2007 were reviewed. Retrospective p16 immunohistochemistry staining was undertaken. Baseline, treatment, and response data were collected. RESULTS: Of 182 patients, 78% were p16-positive, were younger (predominantly male), mostly former or non-smokers, and had a more advanced nodal stage. With a median follow-up of 68 months, contralateral recurrence (CLR) rates were low (3.5% p16-positive versus 2.5% p16-negative, p=0.63). Overall survival (OS) was 74% for p16-positive versus 54% for p16 negative subjects (p=0.01), but all other outcomes were similar. Analysis amongst only p16-positive subjects revealed URT was delivered to 37%, with CLR rates of 7.5% versus 1.1% for those treated with BRT, p=0.05. Of the four p16-positive subjects treated with URT who developed contralateral recurrences, three were managed with neck dissection (two disease-free and one died of lung metastases) and one received palliative radiation to the neck and distant metastatic site. All disease control and survival outcomes were similar between those treated with URT versus BRT. CONCLUSION: While CLRs remain rare overall, there appears to be a slightly increased rate among HPV-positive subjects treated with URT. However, overall outcomes do not appear to be impacted, suggesting that URT remains a reasonable approach in HPV-positive subjects. PMID- 26487999 TI - The Origin and History of the N-Localizer for Stereotactic Neurosurgery. AB - Nearly four decades after the invention of the N-localizer, its origin and history remain misunderstood. Some are unaware that a third-year medical student invented this technology. The following conspectus accurately chronicles the origin and early history of the N-localizer and corrects some misconceptions related to both. PMID- 26488000 TI - SBRT Treatment of Multiple Recurrent Auricular Squamous Cell Carcinomas Following Surgical and Conventional Radiation Treatment Failure. AB - The treatment of recurrent skin cancers of the head and neck following curative doses of radiotherapy and/or surgery is usually palliative radiation therapy (RT) but with mediocre control rates leading to symptomatic local recurrences. We present a 93-year-old male treated with 50 Gy in five fractions for a subauricular cutaneous squamous cell carcinoma who initially underwent partial auriculectomy and accelerated concomitant boost radiotherapy (60 Gy in 21 fractions over 23 days), and then two additional surgeries ending with completion auriculectomy. Re-irradiation with SBRT was well tolerated despite prior high dose therapy. PMID- 26488001 TI - Embolization of Ruptured Aneurysm Arising From Basilar Artery Fenestration Using Hydrocoils. AB - Aneurysms arising from the basilar artery fenestration are considered among the rare cerebrovascular diseases. Here, we report on a 44-year-old gentleman who presented with the sudden onset of severe headache complicated by several episodes of vomiting and an altered level of consciousness. A subarachnoid hemorrhage in the interpeduncle and ambient cisterns was detected by computed tomography of the head. During left vertebral arteriography, a basilar fenestration with a ruptured aneurysm just above the proximal end of vertebrobasilar junction was identified. The aneurysm was successfully occluded by means of endovascular treatment using Hydrosoft coils. In the 15-month follow up angiography, 100% occlusion without recurrence and recanalization was observed. Bilateral anterior inferior cerebellar arteries and both channels of the basilar artery fenestration were entirely filled in follow-up angiograms. PMID- 26488002 TI - Focused issue on "Melanoma". PMID- 26488003 TI - Recent advances in the treatment of melanoma with BRAF and MEK inhibitors. AB - Selective inhibition of the mitogen activated protein kinase (MAPK) pathway with either BRAF or MEK inhibition has emerged as the key component for the treatment of BRAF-mutant metastatic melanoma. New evidence from several phase III trials suggests that the combination of BRAF and MEK inhibitors improves tumor response rate and progression-free survival (PFS). Some of the serious adverse events, in particular, the incidence of cutaneous squamous cell carcinoma seen with the monotherapy treatment with a BRAF inhibitor are attenuated with combination therapy, whereas milder side effects such as pyrexia can be more common with combination therapy. Although dose reductions and dose interruptions are slightly more common with combination therapy, overall data supports the notion that combination therapy is safe and improves the outcomes for metastatic melanoma patients compared to single agent BRAF inhibitors. PMID- 26488004 TI - Predictive factors for immunotherapy in melanoma. AB - Immunotherapy has emerged as an exciting strategy for cancer treatment. Therapeutic blockade of immune checkpoint regulators favors the ability of T cell responses to increase anti-tumor immunity. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) are two T cell-inhibitory receptors with independent mechanisms of action. Immune checkpoint inhibitors targeting either CTLA-4, PD-1 or its ligand PD-L1 are currently yielding promising results in terms of efficacy in several clinical studies with melanoma patients and are being developed and tested as immunotherapy agents for multiple cancer types. To date, no reliable predictors of activity and efficacy of immunotherapy have yet been identified or validated. Even so, determining which patients derive clinical benefit from immune checkpoint agents remains an important clinical question and efforts to identify predictive markers of response are ongoing. This article reviews the current potential predictive factors for CTLA-4 and PD-1/PD-L1 immune checkpoints inhibitors in melanoma. PMID- 26488005 TI - Epigenetic mechanisms involved in melanoma pathogenesis and chemoresistance. AB - The discovery of highly recurrent mutations in melanoma, such as BRAF(V600E), completely changed the clinical management including therapy of melanoma patients. In the era of Personalized Medicine targeted melanoma therapies showed high response rates, currently evidenced by BRAF inhibitors or immune-stimulating therapies. In addition to genetic biomarkers, epigenetic knowledge in melanoma has undergone a major step forward in recent years. In particular, epigenetics is unveiling new perspectives to fight this disease, providing an encouraging number of DNA methylation based biomarkers that will likely improve patient stratification for prognosis and treatment. In this regard, putative targetable biomarkers or those with predictive value for the outcome of currently applied therapies are promising tools for future precision oncology strategies. In addition, the progress made in genetic and epigenetic profiling technologies and their reconfiguration to real-time clinical screening approaches makes personalized medicine in melanoma an achievable objective in upcoming years. PMID- 26488007 TI - Electric vs. harmonic scalpel in treatment of primary focal hyperhidrosis with thoracoscopic sympathectomy. AB - BACKGROUND: Hyperhidrosis is defined as excessive sweating beyond the physiologic needs of a person. Palmar hyperhidrosis in the adolescent period may have an impact on school work and may cause psychological problems. Thoracoscopic sympathectomy is now used routinely to treat patients with disabling primary hyperhidrosis or facial blushing. PATIENTS AND METHODS: From January 2008 to December of 2009 bilateral thoracoscopic sympathectomy Th2-Th4 was performed to 79 patients aged from 17 to 55, who suffered from palmar, axillar or craniofacial hyperhidrosis. For the first 39 patients (group A) thoracoscopic sympathectomy was performed using electric scalpel and for the next 40 patients (group B) thoracoscopic sympathectomy was performed using harmonic scalpel. RESULTS: Based on our results we did not find any significant differences between electric or harmonic scalpel usages for thoracoscopic sympathectomy. Moreover, there was no significant difference between complications and the severity of pain, with slightly higher intensity of pain with harmonic scalpel usage. Both electric and harmonic scalpel provided adequate treatment for primary hyperhidrosis, with the fact that non-disposable electric scalpel costs were less than that of the disposable harmonic scalpel. CONCLUSIONS: Sympathectomy should be preferred for palmar hyperhidrosis treatment, as it is much technically shorter, simpler to implement, and also easier to learn. Thoracoscopic sympathectomy is safe and effective for the treatment of primary palmar hyperhidrosis in the adolescent period without any major side effects. PMID- 26488006 TI - Update in genetic susceptibility in melanoma. AB - Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual. PMID- 26488008 TI - Surgical anatomy of the internal thoracic arteries and their branching pattern: a cadaveric study. AB - BACKGROUND: The purpose of this study is to review the anatomic characteristics of internal thoracic artery (ITA) and its branches, in order to pursue the extension of its utilization and avoid intraoperative and postoperative complications. METHODS: The study was carried out on anterior chest walls obtained during routine autopsies of 50 specimens (30 male, 20 female). Macroscopic and microscopic dissection was performed and the following were studied: origin, length and termination of ITA, size and distance from the sternum, and types of branches. RESULTS: From the origin to the termination point, the length of the left internal thoracic artery (LITA) varied from 159 to 220 mm; with a mean of 182.60 mm. The length of the right internal thoracic artery (RITA) varied from 150 to 231 mm; with a mean of 185 mm. Four types of branches were distinguished. The RITA mean diameter was 2.31 mm, measured at the 2(nd) intercostal space, while the distance from the sternum was 12.77 mm, measured at the 3(rd) intercostal space. The LITA mean diameter was 1.98 mm with the distance from the sternum measured at 12.01 mm. CONCLUSIONS: ITA has become the primary conduit for cardiac bypass surgery; many studies have generated fundamental anatomical knowledge for its clinical utilization, which is always useful in order to avoid intraoperative and postoperative complications. PMID- 26488009 TI - Clinical guidelines on intraoperative neuromonitoring during thyroid and parathyroid surgery. PMID- 26488010 TI - Intraarticular hyaluronate injection for knee osteoarthritis-reconsider the rationale. PMID- 26488011 TI - Rapid infectious diseases diagnostics using Smartphones. AB - The "Smartphone" is an almost universal possession in high-income populations, and is rapidly becoming so in lower-income regions, particularly among urban populations, and serves social networking and a quest for information and knowledge. The field of infectious disease diagnostics is at a potential watershed moment, with the essential building blocks for the development of diagnostic assays being ever more available and affordable, which is leading to creative innovative approaches to developing much-needed accurate and simple point-of-care (POC) diagnostic tools for high disease burden, low-income settings. We review the importance and implications of a paper published in Science Translational Medicine on the development of a smartphone-powered and controlled multiplex immunological assay that tests for HIV and syphilis simultaneously. This is reviewed in the context of other prototype smartphone enabled/assisted diagnostic devices, and how such developments might shape the future of the POC diagnostics field. PMID- 26488012 TI - Editorial on "Comprehensive geriatric care for patients with hip fractures: a prospective, randomized, controlled trial" published in The Lancet on April 25(th), 2015. AB - A third of elderly adults fall every year, many leading to hip fractures with a 24% mortality rate just within the first year. As a growing number of the US population approaches old age, these hip fractures are expected to cost the US over 25 billion annually. In the near future, physicians will need to not only improve the treatment for a larger patient population but also reduce the medical costs associated. The authors in this paper sought to determine whether specialized geriatric care positively impacted patient outcome compared to standard orthopaedic care for hip fractures. The study found that geriatric care significantly increased patient mobility within 4 months after hip fracture and will likely reduce overall medical costs. Similar studies have shown promising results as well. Moving forward, geriatric fracture programs need more prospective randomized trials to determine the effectiveness of these programs to increase patient quality while also reducing overall medical costs. This study in correlation with others further demonstrates the importance and need of specialized geriatric programs in the US. PMID- 26488013 TI - Why arthroscopic partial meniscectomy? AB - "Arthroscopic Partial Meniscectomy versus Sham Surgery for a Degenerative Meniscal Tear" published in the New England Journal of Medicine on December 26, 2013 draws the conclusion that arthroscopic partial medial meniscectomy provides no significant benefit over sham surgery in patients with a degenerative meniscal tear and no knee osteoarthritis. This result argues against the current practice of performing arthroscopic partial meniscectomy (APM) in patients with a degenerative meniscal tear. Since the number of APM performed has been increasing, the information provided by this study should lead to a change in clinical care of patients with a degenerative meniscus tear. PMID- 26488014 TI - A bone to pick with Fc gamma receptors. PMID- 26488015 TI - The promise of lung master protocol for squamous cell carcinoma: one trial to rule them all, one trial to find them...? AB - The recently initiated lung master protocol (Lung-MAP) trial provides hope that the successes of targeted molecular therapy in lung adenocarcinoma can be extended to squamous cell carcinoma (SCC). It also is a template for rapid translation of clinical research through regulatory approval to clinical practice. This is vital in cancers with multiple possible oncogenic genomic aberrations, for which clinical trials would be too costly and impractical to conduct for individual targets making up less than 10% of cases. PMID- 26488016 TI - Hybrid Ivor Lewis esophagectomy with robotic assisted gastric mobilization and thoracoscopic esophageal dissection and anastomosis. PMID- 26488017 TI - Mutations in SOD1 and FUS caused juvenile-onset sporadic amyotrophic lateral sclerosis with aggressive progression. AB - Juvenile onset amyotrophic lateral sclerosis (ALS) is a very rare form of motor neuron disease, with the first symptoms of motor neuron degeneration manifested before 25 years of age. Juvenile ALS is more frequently familial in nature than the adult-onset forms. Mutations in the alsin (ALS2), senataxin (SETX), and Spatacsin (SPG11) have been associated with familial ALS with juvenile onset and slowly progression. Here we reported two apparently sporadic ALS with juvenile onset and aggressive progression caused by mutations in the SOD1 and FUS gene. We also reviewed juvenile-onset ALS in publications. Our findings, together with other researches, confirms that both SOD1 and FUS mutations can lead to juvenile onset malignant form of ALS and should be screened in ALS patients with an earlier age of onset, aggressive progression, even if there is no apparent family history. PMID- 26488018 TI - Lifestyle changes might prevent Alzheimer's disease. PMID- 26488019 TI - The world's first radical resection for lung cancer using glasses-free 3D thoracoscope was completed in Guangzhou. PMID- 26488020 TI - Proliferative verrucous leukoplakia may initially mimic lichenoid reactions. AB - Proliferative verrucous leukoplakia is an intriguing disease, which occurs particularly in women aged greater than 60 years, is not associated with tobacco and alcohol, and has a high risk of recurrence and malignant transformation. Although it is well known that the typical presentation is characterized by multifocal and verrucous white lesions, there is no description that its initial clinical presentation may simulate a lichenoid reaction. PMID- 26488021 TI - Port site infection in laparoscopic surgery: A review of its management. AB - Laparoscopic surgery (LS), also termed minimal access surgery, has brought a paradigm shift in the approach to modern surgical care. Early postoperative recovery, less pain, improved aesthesis and early return to work have led to its popularity both amongst surgeons and patients. Its application has progressed from cholecystectomies and appendectomies to various other fields including gastrointestinal surgery, urology, gynecology and oncosurgery. However, LS has its own package of complications. Port site infection (PSI), although infrequent, is one of the bothersome complications which undermine the benefits of minimal invasive surgery. Not only does it add to the morbidity of the patient but also spoils the reputation of the surgeon. Despite the advances in the field of antimicrobial agents, sterilization techniques, surgical techniques, operating room ventilation, PSIs still prevail. The emergence of rapid growing atypical mycobacteria with multidrug resistance, which are the causative organism in most of the cases, has further compounded the problem. PSIs are preventable if appropriate measures are taken preoperatively, intraoperatively and postoperatively. PSIs can often be treated non-surgically, with early identification and appropriate management. Macrolides, quinolones and aminoglycosides antibiotics do show promising activity against the atypical mycobacteria. This review article highlights the clinical burden, presentations and management of PSIs in LS as shared by various authors in the literature. We have given emphasis to atypical mycobacteria, which are emerging as a common etiological agent for PSIs in LS. Although the existing literature lacks consensus regarding PSI management, the complication can be best avoided by strictly abiding by the commandments of sterilization techniques of the laparoscopic instruments with appropriate sterilizing agent. PMID- 26488022 TI - Arrhythmogenic epilepsy and pacing need: A matter of controversy. AB - There is increasing awareness among the cardiology community regarding ictal bradyarrhythmias as a cause of loss of consciousness. A high degree of suspicion is necessary when diagnosing ictal bradyarrhythmias, and delay in diagnosing this condition may lead to morbidity associated with falls and trauma. Ictal bradyarrhythmias have also been suggested to be associated with sudden unexplained death in epilepsy, although evidence related to this association is limited. There is no guideline-directed therapy for symptomatic ictal bradyarrhythmias due to a lack of randomized, controlled trials. Cardiac pacemaker therapy is commonly used for these patients; however, currently, there is no universal agreement on the pacing indications for these patients. In this review, we focus on the pathophysiology and clinical presentation of ictal bradyarrhythmias and then discuss the pacing need based on the available literature data. PMID- 26488023 TI - Disease that should be remembered: Sacrococcygeal pilonidal sinus disease and short history. AB - Pilonidal sinus disease has led to heated debates since it was first described in the medical literature. Although a consensus has been built on its etiology and pathogenesis, the same course has not progressed for treatment modality. This review is a short article about the process of pilonidal sinus disease from past to present. Some important points were mentioned between the years 1833, which is accepted as the milestone for the awareness of the disease, in which it was first reported until the year of 1880, in which it was given its name. Although its name has been the same for about two centuries, some other names such as "Jeep Disease" have also been used depending on the population affected by the disease. At present, it is indisputable that the disease is acquired. Large series were presented about the treatment in the last two decades. Some surgical methods were even named after the ones who first described them and they have many supporters. However, since the treatment modalities have some advantages and disadvantages and they do not have marked superiority over others, debates still continue. We hope that pilonidal sinus disease will not lose its significance and be underrated in parallel with the developments in technology and specialization in medicine. PMID- 26488024 TI - Improved bowel preparation increases polyp detection and unmasks significant polyp miss rate. AB - AIM: To retrospectively compare previous-day vs split-dose preparation in terms of bowel cleanliness and polyp detection in patients referred for polypectomy. METHODS: Fifty patients underwent two colonoscopies: one diagnostic in a private clinic and a second for polypectomy in a University Hospital. The latter procedures were performed within 12 wk of the index ones. Examinations were accomplished by two experienced endoscopists, different in each facility. Twenty seven patients underwent screening/surveillance colonoscopy, while the rest were symptomatic. Previous day bowel preparation was utilized initially and split-dose for polypectomy. Colon cleansing was evaluated using the Aronchick scale. We measured the number of detected polyps, and the polyp miss rates per-polyp. RESULTS: Excellent/good preparation was reported in 38 cases with previous-day preparation (76%) vs 46 with split-dose (92%), respectively (P = 0.03). One hundred and twenty-six polyps were detected initially and 169 subsequently (P < 0.0001); 88 vs 126 polyps were diminutive (P < 0.0001), 25 vs 29 small (P = 0.048) and 13 vs 14 equal or larger than 10 mm. The miss rates for total, diminutive, small and large polyps were 25.4%, 30.1%, 13.7% and 6.6%, respectively. Multivariate analysis revealed that split-dose preparation was significantly associated (OR, P) with increased number of polyps detected overall (0.869, P < 0.001), in the right (0.418, P = 0.008) and in the left colon (0.452, P = 0.02). CONCLUSION: Split-dose preparation improved colon cleansing, enhanced polyp detection and unmasked significant polyp miss rates. PMID- 26488025 TI - New tapered metallic stent for unresectable malignant hilar bile duct obstruction. AB - AIM: To examine the usefulness of a new tapered metallic stent (MS) in patients with unresectable malignant hilar bile duct obstruction. METHODS: This new tapered MS was placed in 11 patients with Bismuth II or severer unresectable malignant hilar bile duct obstruction, as a prospective study. The subjects were six patients with bile duct carcinoma, three with gallbladder cancer, and two with metastatic bile duct obstruction. Stenosis morphology was Bismuth II: 7, IIIa: 3, and IV: 1. UMIN Clinical Trial Registry (UMIN000004758). RESULTS: MS placement was 100% (11/11) successful. There were no procedural accidents. The mean patency period was 208.401 d, the median survival period was 142.000 d, and the mean survival period was 193.273 d. Occlusion rate was 36.4% (4/11); the causes of occlusion were ingrowth and overgrowth in 2 patients each, 18.2%, respectively. Patients with occlusion underwent endoscopic treatment one more time and all were treatable. CONCLUSION: The tapered MS proved useful in patients with unresectable malignant hilar bile duct obstruction because it provided a long patency period, enabled re-treatment by re-intervention, and no procedural accidents occurred. PMID- 26488026 TI - Littoral cell angioma: A case report. AB - Primary splenic lesions are rare entities among which littoral cell angioma (LCA) is a recently described, uncommon vascular lesion that is unique to the spleen. It has heretofore been described primarily in pathologic series and has been found mostly to behave as a benign entity. A few reports of malignant variants have been reported. We present a case report of a solitary LCA discovered after splenectomy for an incidentally discovered splenic lesion, along with a literature review. PMID- 26488027 TI - Acute hepatitis after amiodarone infusion. AB - Acute hepatitis is a very rare, but potentially fatal, adverse effect of intravenous amiodarone. We present a case of an 88-year-old man with history of ischemic dilated cardiomyopathy and severely depressed left ventricular function that was admitted to our coronary care unit with diagnosis of decompensated heart failure and non-sustained ventricular tachycardia. A few hours after the beginning of intravenous amiodarone he developed an acute hepatitis. There was a completely recovery within the next days after amiodarone withdrawn and other causes of acute hepatitis have been ruled out. This case highlights the need for close monitoring of hepatic function during amiodarone infusion in order to identify any potential hepatotoxicity and prevent a fatal outcome. Oral amiodarone is, apparently, a safe option in these patients. PMID- 26488028 TI - Novel variant syndrome associated with congenital hepatic fibrosis. AB - Congenital hepatic fibrosis is part of many different malformation syndromes, of which oculo-encephalo-hepato-renal syndrome is the most common. These syndromes largely overlap, and so accurate classification of individual patients may be difficult. We present herein three syndromic siblings who were products of a consanguineous marriage. We investigated in detail at least six organ systems in these patients, namely the liver, brain, eye, kidneys, skeleton, and gonads. The common features observed in these three cases were congenital hepatic fibrosis, retinitis pigmentosa, truncal obesity, rotatory nystagmus, mental retardation, advanced myopia, and high-arched palate. The clinical dysmorphology in these patients was distinct and lacked the major features of the known syndromes associated with congenital hepatic fibrosis. Although some features of these presented cases are similar to those found in Bardet-Biedl syndrome (BBS), the absence of some major criteria of BBS (polydactyly, renal abnormality, and hypogonadism) suggests that this may be a new syndrome. All three patients remain under follow-up in the departments of Gastroenterology, Ophthalmology, and Neurology at Hacettepe University. PMID- 26488029 TI - Acute dapsone poisoning in a 3-year-old child: Case report with review of literature. AB - Dapsone (DDS-diamino diphenyl sulphone) is a sulfone antibiotic being used for a variety of clinical conditions. Poisoning in children by DDS is rarely reported. Poisoning in acute cases will be frequently unrecognized due to relative lack of severe signs and symptoms. Methemoglobinemia is the major life-threatening situation associated with poisoning of DDS. Hence, any delay for medical attention can lead to increased rate of mortality. In this case, we describe acute DDS poisoning in a 3-year-old child and the successful management using intravenous methylene blue. PMID- 26488030 TI - Mediastinal small cell carcinoma with liver and bone marrow metastasis, mimicking lymphoma. AB - Primary mediastinal neuroendocrine tumors are a rare malignancy that accounts for < 10% of all mediastinal tumors. The case presented here involves a 52-year-old man who had been suffering for 3 mo from chronic cough, anorexia and substantial weight loss, as well as 2 wk of jaundice prior to his admission. A computed tomography scan showed a 4.3 cm * 6.6 cm mediastinal mass with multiple liver nodules scattered along both hepatic lobes. Endoscopic ultrasound showed a large heterogeneous hypoechoic mass at the mediastinum with multiple target-like nodules in the liver. Fine-needle aspiration specimens revealed numerous, small, round cells with hyperchromatic nuclei, scarce cytoplasm, and frequent mitotic features. Immunohistochemical study revealed positive results for AE1/AE3, CD56 and chromogranin A, with negative findings for synaptophysin, CK20, vimentin, CK8/18 and CD45. The patient was subsequently diagnosed with a poorly differentiated neuroendocrine carcinoma, small cell type. A bone marrow biopsy also revealed extensive involvement by the carcinoma. PMID- 26488031 TI - Repeated pancreatitis-induced splenic vein thrombosis leads to intractable gastric variceal bleeding: A case report and review. AB - Gastric varices (GV) are one of the most common complications for patients with portal hypertension. Currently, histoacryl injection is recommended as the initial treatment for bleeding of GV, and this injection has been confirmed to be highly effective for most patients in many studies. However, this treatment might be ineffective for some types of GV, such as splenic vein thrombosis-related localized portal hypertension (also called left-sided, sinistral, or regional portal hypertension). Herein, we report a case of repeated pancreatitis-induced complete splenic vein thrombosis that led to intractable gastric variceal bleeding, which was treated by splenectomy. We present detailed radiological and pathological data and blood rheology analysis (the splenic artery - after a short gastric vein or stomach vein - gastric coronary vein - portal vein). The pathophysiology can be explained by the abnormal direction of blood flow in this patient. To our knowledge, this is the first reported case for which detailed pathology and blood rheology data are available. PMID- 26488032 TI - Empagliflozin: a new treatment option for patients with type 2 diabetes mellitus. AB - Empagliflozin is an oral sodium-glucose cotransporter 2 (SGLT2) inhibitor that reduces hyperglycemia in type 2 diabetes mellitus (T2DM) by decreasing renal glucose reabsorption and promoting urinary glucose excretion. In clinical trials, empagliflozin demonstrated significant improvements in glycemic control, as monotherapy and in combination regimens. In addition, empagliflozin was associated with weight loss and moderate reductions in blood pressure. In the EMPA-REG OUTCOME study, empagliflozin significantly reduced the risk of the composite primary endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. Across the trials in general, empagliflozin was well tolerated, with no increased risk of hypoglycemia except when used with an insulin secretagogue or insulin. An increased risk of genital infections and urinary tract infections has been reported, although the association is less clear for urinary tract infections. Overall, empagliflozin appears to be a promising treatment for T2DM. PMID- 26488033 TI - Filgrastim for the treatment of hematopoietic acute radiation syndrome. AB - The U.S. Food and Drug Administration (FDA) recently approved Neupogen((r)) (filgrastim) for the treatment of patients with radiation-induced myelosuppression following a radiological/nuclear incident. It is the first medical countermeasure currently approved by the FDA for this indication under the criteria of the FDA "animal rule". This article summarizes the consequences of high-dose radiation exposure, a description of the hematopoietic acute radiation syndrome (H-ARS), the use of hematopoietic growth factors in radiation accident victims and current available treatments for H-ARS with an emphasis on the use of Neupogen in this scenario. PMID- 26488034 TI - Talimogene laherparepvec (T-VEC) as cancer immunotherapy. AB - Talimogene laherparepvec (T-VEC) is the first-in-class oncolytic virus immunotherapy for the treatment of cancer and was generated from an attenuated, recombinant herpes simplex virus. T-VEC has demonstrated therapeutic activity in melanoma patients and is being tested in a number of other cancers alone and in combination with standard cancer therapeutics and other immunotherapy agents. This review will discuss the current landscape of melanoma, the construction and application of T-VEC for melanoma along with other indications for T-VEC, as well as highlight some of the novel challenges with oncolytic virus immunotherapy as it enters into clinical practice. PMID- 26488035 TI - A report from the World Conference on Lung Cancer (September 6-9, 2015 - Denver, Colorado, USA). AB - The mile-high city of Denver was the site of this year's World Conference on Lung Cancer, which reached its 16th event. The conference scheduled 3 days of intensive scientific research presentations and discussions arranged in oral, mini-oral and poster sessions, plus an array of additional educational sessions. Being the largest international gathering of lung cancer and thoracic malignancy clinicians and researchers, important new research on prevention, screening and treatment of lung cancer and other malignancies of the thorax, with special emphasis on thymoma and mesothelioma, was presented during the conference. PMID- 26488036 TI - Cancer Vaccines - SMi's Fourth Annual Conference (September 16-17, 2015 - London, UK). AB - Recent years have seen the academic, medical and pharmaceutical communities gain a new understanding of the central role of the immune system in fighting cancer. With the approval of the first cancer vaccine by the U.S. Food and Drug Administration (FDA) and the success of immuno-oncology, new avenues are opening for the successful development of therapeutic cancer vaccines. Opportunity for combination therapies exploiting immune checkpoint inhibitors is being realized and delivery mechanisms and adjuvants are likewise being optimized. The incorporation of monoclonal antibodies alongside genetically engineered viral vectors is also being pursued. This year's conference focused on the development of personalized therapies and their commercial viability, with in-depth discussions of novel T-cell therapies, oncolytic viruses, gene therapies and adoptive T-cell transfer. The meeting brought together key academic and medical experts with leading industry figures to debate future directions and the next generations of tools in cancer immunotherapy. PMID- 26488037 TI - The management of unresolved gastrointestinal symptoms in Australian general practice. AB - BEACH data collected in 2012-14 were used to investigate the management of unresolved gastrointestinal (GI) symptoms in Australian general practice. This included the characteristics of patients who had unresolved GI symptoms managed, and a comparison with the management of new GI symptoms. Nearly half of the GI symptoms managed in 2012-14 were unresolved (had been managed previously). The findings suggest that general practitioners order pathology and imaging tests more often during first presentations of GI symptoms, and often refer patients when GI symptoms are unresolved. PMID- 26488038 TI - Managing medically unexplained illness in general practice. AB - BACKGROUND: Patients with medically unexplained symptoms commonly present to general practice and experience significant disability. Many have a history of trauma, which complicates the therapeutic relationship between doctor and patient. Because diagnosis is an expected outcome of a medical interaction, doctors and patients can feel frustrated and lost without one. OBJECTIVE: This article provides practical management strategies that general practitioners (GPs) can use when patients present with medically unexplained symptoms. DISCUSSION: Three types of common presentations are discussed. Enigmatic illnesses occur when the doctor and patient believe that a bio-medical disease is likely, but a diagnosis is not forthcoming. Contested illnesses occur when a patient is committed to a diagnosis the doctor does not accept. Chaotic illnesses occur when symptoms are over-determined; there are many possible diagnoses, but none fully explain the complex web of distress the patient experiences. Common strategies for managing medically unexplained symptoms are discussed, and specific approaches to each presentation are outlined. PMID- 26488039 TI - Rare diseases are a 'common' problem for clinicians. AB - BACKGROUND: Approximately 8% of the Australian population live with any one of about 10,000 known rare diseases. This is similar to the proportion of people living with diabetes or asthma. OBJECTIVE: The aim of this article is to review the impact of rare diseases on families and health services, and the role of the general practitioner (GP) and policy response in Australia. DISCUSSION: Research from the Australian Paediatric Surveillance Unit indicates that people living with rare diseases face significant challenges, including diagnostic delays, lack of available treatment and difficulty in finding the right health service. Families feel isolated, under-supported, and often face economic hardship. All GPs see people with rare diseases and have a crucial role in making appropriate referrals, coordinating care, supporting families, and linking them with psychosocial and other supports. GPs require access to current, relevant resources to assist them to help patients with rare diseases. A coordinated national approach to rare diseases is also needed in Australia. PMID- 26488040 TI - A powerful team: the family physician advocating for patients with a rare disease. AB - BACKGROUND: Rare diseases are characteristically difficult to diagnose and for the majority, there are no effective treatments or evidence-based management guidelines. Although it is unrealistic to expect family physicians to recognise the wide clinical spectrum of rare diseases, their longitudinal and holistic approach to medicine place them in a unique position to consider the possibility of a rare disease. OBJECTIVE: This article outlines the challenges faced by the rare disease community, and the role of the primary care physician to advocate for answers as their patients transition through the healthcare system. DISCUSSION: The road to the diagnosis of a rare disease can test the doctor patient relationship. Patients often struggle for answers and family physicians are stymied by a lack of information. At the same time, the availability of cyber based health information and online rare-disease patient groups has led to the emergence of the 'expert' patient, who seeks a collaborative and empowering relationship with their physician. Following diagnosis, the family physician plays a crucial part in providing continuity of care, advocating access to expert healthcare, coordinating complex management and becoming a source of psychological support. PMID- 26488041 TI - Cancer of unknown primary site. AB - BACKGROUND: Cancer of unknown primary (CUP) is the diagnosis given to patients with metastatic cancer with no known site of origin. OBJECTIVE: This review summarises the current knowledge regarding the epidemiology, diagnosis, treatment and care of CUP. DISCUSSION: The incidence and mortality rates of CUP are declining in Australia. CUP was the twelfth most common cancer and fifth most common cause of cancer death in 2011. Smoking is the only identified risk factor. Incidence patterns implicate reduced access to healthcare and many registered cases have only a clinical diagnosis. Favourable prognosis subtypes with specific clinical and histopathological criteria must be recognised and treated on the basis of the presumed primary site. Emerging data reveal high rates of emergency department admission, hospitalisations and psychological distress, and low rates of specialist consultations for patients with CUP. General practitioners (GPs) have a key role in earlier identification, integrated care and preventing patients with CUP from falling through the cracks. PMID- 26488042 TI - Supporting patients with a rare disease. PMID- 26488043 TI - Is there a role for prazosin in the treatment of post-traumatic stress disorder? AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is a common disorder with significant morbidity and associated comorbidities, including mood disorders and substance abuse, and is frequently misdiagnosed or under-diagnosed. Management of PTSD requires combined psychotherapy and pharmacotherapy, but some symptoms, particularly nightmares and sleep disturbance, are often resistant to treatment. OBJECTIVE: The aim of this article is to inform primary healthcare professionals of the prevalence and significance of PTSD, and to review the evidence that prazosin is a useful option for managing PTSD-associated nightmares and sleep disturbance. DISCUSSION: PTSD should be considered in patients with treatment resistant mood disorders. A trauma history should be taken for these patients and in recognised groups of patients who have a high incidence of PTSD. The treatment of PTSD is challenging, frequently requiring specialist input from psychiatrists. Prazosin has been proven to be safe and effective in the management of nightmares and sleep disturbances associated with PTSD and is indicated where these distressing symptoms are present. PMID- 26488044 TI - Your questions about complementary medicines answered: St John's wort. PMID- 26488045 TI - An update on epistaxis. AB - BACKGROUND: Epistaxis is one of the most common ear, nose and throat (ENT) emergencies to present to general practitioners (GPs). The management of epistaxis has evolved significantly in recent years, including the use of nasal cautery and packs. Successful treatment requires knowledge of nasal anatomy, and potential risks and complications of treatment. OBJECTIVE: Epistaxis is often a simple and readily treatable condition. However, given the potential consequences of a significant bleed, GPs should have an understanding of the causes, potential risks and emergency management. DISCUSSION: Epistaxis can be classified into anterior or posterior bleeds, the former being the most common. Anterior bleeds can often be treated with cauterisation with silver nitrate sticks, provided there is good preparation, correct equipment and assistance close at hand. If there is a lack in any of these aspects, prompt use of nasal packing and referral to an emergency department or a specialist ENT service is recommended. PMID- 26488046 TI - Disseminated brown macules in an infant. AB - Urticaria pigmentosa is the most common form of mastocytosis. Mastocytosis usually presents at birth or early childhood, and may involve only the skin or, less commonly, other internal organs. Diagnosis is clinical, but a skin biopsy may be useful. Prognosis is usually good, and treatment focuses on the avoidance of certain triggers and administration of topical and systemic medications. Appropriate counselling of parents regarding the benign nature of this disease is important as most cases resolve by adolescence. PMID- 26488047 TI - Early detection and non-invasive diagnosis of basal cell carcinoma using a dermatoscope. PMID- 26488048 TI - Advances in radiotherapy technology for prostate cancer: What every GP should know. AB - BACKGROUND: One in five Australian men are diagnosed with prostate cancer. External beam radiation therapy (EBRT) is an effective treatment for men suitable for definitive therapy. OBJECTIVE: This article outlines the processes involved in EBRT for prostate cancer, with particular emphasis on recent technological advances that have had a positive impact on patient outcomes. The patient's experience is explained and comparisons are made with surgery. DISCUSSION: Patients diagnosed with localised prostate cancer may have multiple treatment options. General practitioners have an important role in helping patients navigate their way through the information needed to make this decision. Radiotherapy technologies, including image guidance, intensity-modulated radiation therapy and stereotactic (ablative) radiation therapy are discussed in this article. PMID- 26488049 TI - Low levels of vitamin B12 can persist in the early resettlement of refugees: symptoms, screening and monitoring. AB - BACKGROUND: Many refugees have vitamin B12 (B12) deficiency. It has been assumed that deficiency would be predictable from macrocytosis or symptoms, and borderline levels would improve after a period of resettlement in countries rich with animal-source foods. We explored B12 levels and symptoms soon after the refugees' arrival and 4-8 months after settlement in Australia. METHODS: Newly arrived refugees aged >18 years (n = 136) were tested for vitamin B12 and haematological indices. They also completed a language-validated questionnaire, which they repeated 4-8 months after arrival. B12 levels were reassessed in patients with levels <=240 pmol at baseline. RESULTS: We found that 21 participants (15%) had low levels of B12 ?(<=150 pmol/L) and 65 (48%) had borderline B12 levels ?(151-240 pmol/L). There was no relationship between B12 level and mean corpuscular volume, ferritin or symptoms. Borderline B12 levels persisted in 64% of participants at follow-up and deficiency developed in 11%. CONCLUSION: B12 levels cannot be predicted from macrocytosis or symptoms, and may not 'self-correct' after resettlement. Health assessments for newly arrived refugees should include B12 measurement and those with borderline levels should be followed up. PMID- 26488050 TI - Patients' and providers' satisfaction with shared medical appointments. AB - BACKGROUND: Shared medical appointments (SMAs) are comprehensive medical visits conducted with groups of patients. We have previously discussed the potential and assessed likely support for SMAs in Australia. In this paper, we report on patient and provider satisfaction, and some subjective outcomes. OBJECTIVE: To measure patients' and providers' attitude and satisfaction with SMAs after attending at least two, and consider the most appropriate form of SMA suited to Australian conditions. METHODS: A total of 24 SMAs were conducted in eight medical centres in New South Wales, South Australia and Queensland. Satisfaction and subjective outcomes from these sessions were tested in a mixed method analysis after more than 200 attendances. RESULTS: Satisfaction with SMAs was high among patients and providers. Almost all of the patients involved said they would continue using SMAs, if these were available. All providers wished to continue being involved as an alternative form of clinical management. DISCUSSION: The results of this pilot study, and our previously reported studies, suggest that SMAs could be a valuable process tool in chronic disease management in Australia. PMID- 26488052 TI - General practice ethics: Issues in family relationships. PMID- 26488053 TI - Long-term stability of phase-separated half-Heusler compounds. AB - Half-Heusler (HH) compounds have shown high figure of merit up to 1.5. Here, we address the long-term stability of n- and p-type HH materials. For this purpose, we investigated HH materials based on the Ti0.3Zr0.35Hf0.35NiSn-system after 500 cycles (1700 h) from 373 to 873 K. Both compounds exhibit a maximum Seebeck coefficient of |alpha|~ 210 MUV K(-1) and a phase separation into two HH phases. The dendritic microstructure is temperature resistant and upon cycling the changes in the microstructure are so marginal that the low thermal conductivity values (kappa < 4 W m(-1) K(-1)) could be maintained. Our results emphasize that phase-separated HH compounds are suitable low cost materials and can lead to enhanced thermoelectric efficiencies beyond the set benchmark for industrial applications. PMID- 26488054 TI - Port site metastases following laparoscopic liver resection for hepatocellular carcinoma. AB - A laparoscopic approach is being used increasingly in specialist centres for the resection of hepatocellular carcinomas and compares favourably with the traditional open approach, in terms of perioperative morbidity and mortality as well as long-term survival. We present a case of port site recurrence in a patient who underwent a laparoscopic left lateral segmentectomy for a hepatocellular carcinoma diagnosed during investigation of symptomatic gallstones. Nearly three years following surgery, surveillance computed tomography demonstrated a suspicious lesion at the site of one of the laparoscopic ports. Further resection was carried out and the lesion was confirmed histologically to be an isolated recurrence of the primary hepatocellular carcinoma, involving peritoneum and adominal wall. This case demonstrates that it is possible to encounter port site metastasis following laparoscopic resection of primary liver tumours although the incidence is very rare. PMID- 26488055 TI - Diagnostic role of (18)F-FDG-PET or PET/CT in salivary gland tumors: A systematic review. AB - Salivary gland tumors are rare neoplasms that have not been extensively studied with (18)F-FDG-PET- or PET/CT up to now. This review aims to evaluate the diagnostic performance of PET in this particular setting, analyzing the available literature. A comprehensive literature search in the PubMed/MEDLINE, Embase and Scopus databases was performed including articles up to November 2014, resulting in the selection of 22 articles. The studies selected suggest that: (1) PET is not useful in discriminating benign from malignant SGTs because of the overlap of uptake in both conditions; (2) PET not only is complementary to conventional imaging techniques for the staging and restaging but in some cases could also be superior to them; (3) PET may often have a highly positive impact on clinical decision making. Despite many limitations affecting the analysis, PET seems to be useful in SGTs. However, more extensive studies and cost-effectiveness analyses are desirable to determine its correct position in the diagnostic flow chart. PMID- 26488056 TI - In memoriam, Giovanni Castrucci (1928-2015). PMID- 26488057 TI - Professor Fereydoun Ala. PMID- 26488059 TI - It's the time of year when journals get their annual impact factors. Introduction. PMID- 26488058 TI - Are Service Deliveries Studies a Priority of Mental Health Research in Iran? PMID- 26488060 TI - Drug abuse scientists should use social media to engage the public because their primary translational product is information. PMID- 26488061 TI - Reply to Letter to the Editor. PMID- 26488062 TI - Support for safe staffing levels in aged care. PMID- 26488063 TI - Dementia investment welcome but more needs to be done. PMID- 26488064 TI - NSW launches TV ads against privatisation. PMID- 26488065 TI - NSW Opposition commits to nurse-led walk-in centres. PMID- 26488066 TI - Perinatal depression and anxiety. PMID- 26488067 TI - What to Think About in 2015. AB - Every organization and facility has issues that they need to address. There is no such thing as a perfect organization or a perfect process. It is easy to get overwhelmed and think the challenges are too big to tackle, but don't give up! While some issues may require immediate changes due to compliance concerns, most can be made one small step at a time. The phrase "success is a journey, not a destination" is very applicable here and for any area within our responsibility where change needs to occur. Change is our only constant so we might as well embrace it and look forward to the future with excitement on the new opportunities ahead. PMID- 26488068 TI - ICD-10: Refresher on 7th Characters. PMID- 26488069 TI - Seed Crystal Homogeneity Controls Lateral and Vertical Heteroepitaxy of Monolayer MoS2 and WS2. AB - Heteroepitaxy between transition-metal dichalcogenide (TMDC) monolayers can fabricate atomically thin semiconductor heterojunctions without interfacial contamination, which are essential for next-generation electronics and optoelectronics. Here we report a controllable two-step chemical vapor deposition (CVD) process for lateral and vertical heteroepitaxy between monolayer WS2 and MoS2 on a c-cut sapphire substrate. Lateral and vertical heteroepitaxy can be selectively achieved by carefully controlling the growth of MoS2 monolayers that are used as two-dimensional (2D) seed crystals. Using hydrogen as a carrier gas, we synthesize ultraclean MoS2 monolayers, which enable lateral heteroepitaxial growth of monolayer WS2 from the MoS2 edges to create atomically coherent and sharp in-plane WS2/MoS2 heterojunctions. When no hydrogen is used, we obtain MoS2 monolayers decorated with small particles along the edges, inducing vertical heteroepitaxial growth of monolayer WS2 on top of the MoS2 to form vertical WS2/MoS2 heterojunctions. Our lateral and vertical atomic layer heteroepitaxy steered by seed defect engineering opens up a new route toward atomically controlled fabrication of 2D heterojunction architectures. PMID- 26488070 TI - Condom effectiveness in reducing heterosexual HIV transmission: a systematic review and meta-analysis of studies on HIV serodiscordant couples. AB - OBJECTIVE: This systematic review and meta-analysis aimed to reassess the effectiveness of condoms in reducing heterosexual transmission of HIV. METHODS: Medline, Scopus, and the ISI Web of Science databases were searched up to June 2014. Eligible studies were synthesized using random-effects models. RESULTS: Twenty-five studies with 10,676 HIV serodiscordant heterosexual couples were analyzed. The risk of HIV transmission was considerably lower among couples that were always using condoms compared to never-users (RR: 0.29, 95% CI: 0.20-0.43) or inconsistent users (RR: 0.23, 0.13-0.40). The protective effect was slightly higher when the male rather than the female partner was infected (RR: 0.31, 0.20 0.48; vs. RR: 0.44, 0.24-0.80), and very high in Asian settings (RR: 0.06, 0.01 0.46). CONCLUSIONS: Though imperfect, condoms reduce HIV transmission by more than 70% when used consistently by HIV serodiscordant heterosexual couples. Social, cultural and biological differences need to be studied further to inform projection modelers and policy makers. PMID- 26488071 TI - Anode Biofilms of Geoalkalibacter ferrihydriticus Exhibit Electrochemical Signatures of Multiple Electron Transport Pathways. AB - Thriving under alkaliphilic conditions, Geoalkalibacter ferrihydriticus (Glk. ferrihydriticus) provides new applications in treating alkaline waste streams as well as a possible new model organism for microbial electrochemistry. We investigated the electrochemical response of biofilms of the alkaliphilic anode respiring bacterium (ARB) Glk. ferrihydriticus voltammetry (CV), electrochemical impedance spectroscopy (EIS), and chronoamperometry. We observed there to be at least four dominant electron transfer pathways, with their contribution to the overall current produced dependent on the set anode potential. These pathways appear to be manifested at midpoint potentials of approximately -0.14 V, -0.2 V, 0.24 V, and -0.27 V vs standard hydrogen electrode. The individual contributions of the pathways change upon equilibration from a set anode potential to another anode potential. Additionally, the contribution of each pathway to the overall current produced is reversible when the anode potential is changed back to the original set potential. The pathways involved in anode respiration in Glk. ferrihydriticus biofilms follow a similar, but more complicated, pattern as compared to those in the model ARB, Geobacter sulfurreducens. This greater diversity of electron transport pathways in Glk. ferrihydriticus could be related to its wider metabolic capability (e.g., higher pH and larger set of possible substrates, among others). PMID- 26488072 TI - Efficient PEDOT:PSS-Free Polymer Solar Cells with an Easily Accessible Polyacrylonitrile Polymer Material as a Novel Solution-Processable Anode Interfacial Layer. AB - We demonstrate that an easily accessible polyacrylonitrile (PAN) polymer can efficiently function as a novel solution-processable anode interfacial layer (AIL) to boost the device performances of polymer:fullerene-based solar cells (PSCs). The PAN thin film was simply prepared with spin-coating of a cost efficient PAN solution dissolved in dimethylformamide on indium tin oxide (ITO), and the thin polymeric interlayer on PSC parameters and stability were systemically investigated. As a result, the cell efficiency of the PSC with PAN was remarkably enhanced compared to the device using bare ITO. Furthermore, with PAN, we finally achieved an excellent power conversion efficiency (PCE) of 6.7% and a very high PSC stability in PTB7:PC71BM systems, which constitute a highly comparable PCE and superior device lifetime relative to those of conventional PSCs with poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS). These results demonstrate that the inexpensive solution-processed PAN polymer can be an attractive PEDOT: PSS alternative and is more powerful for achieving better cell performances and lower cost PSC production. PMID- 26488073 TI - Increased circulating urocortin-3 levels is associated with polycystic ovary syndrome. AB - This study was aimed to compare serum urocortin-3 (UCN3) levels in women with polycystic ovary syndrome (PCOS) and healthy women, and establish what role UCN3 levels play in PCOS. Fifty-two patients with PCOS and 55 healthy women were included in the study, matched for age and body mass index. Fasting blood glucose (FBG), insulin, hs-CRP, UCN3 and free-testosterone levels of the all participants were measured. HOMA-IR was used to calculate the insulin resistance. Circulating UCN3 levels were significantly increased in women with PCOS than in control subjects (54.49 +/- 5.77 versus 51.28 +/- 5.86 pmol/l, p = 0.005). Serum insulin, hs-CRP and HOMA-IR levels were higher in women with PCOS than in control group. UCN3 levels positively correlated with hs-CRP in PCOS group (r = 0.391, p = 0.004). Receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curves were 0.732 (95% CI 0.634-0.830, p < 0.001) for UCN3 levels. The optimal cut-off value of UCN3 for detecting PCOS was >=51.46 pmol/l, at which the sensitivity was 75% and specificity was 68%. Our results suggest that there is a potential link between PCOS and UCN3 levels. The results of this study support the presence of increased UCN3 levels for the association of inflammation with PCOS. PMID- 26488075 TI - Anti-PRRSV effect and mechanism of tetrahydroaltersolanol C in vitro. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an important arterivirus that causes substantial economic losses to the swine industry. Current control strategies against PRRSV are still inadequate and there is an urgent need for new antiviral therapies. Tetrahydroaltersolanol C (TD-C) is a new anthraquinone derivative isolated from the marine-derived fungi. In the present study, we first demonstrated its anti-PRRSV activity in vitro through assessing the inhibition of TD-C on cytopathic effect, viral ORF7 gene and N protein expressions, progeny virions production by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, relative-quantitative RT-PCR, Western blotting, and indirect immunofluorescence assay. Our experimental results showed that TD-C could significantly inhibit PRRSV replication in a dose-dependent manner. The 50% effective concentration, 50% cytotoxic concentration and the selectivity index were 12.11, 395.31 MUM, and 32.64, respectively. Furthermore, the possible anti-PRRSV mechanism was explored by virucidal assay, virus adsorption inhibition assay, and the time-of-addition assay. The results showed that TD-C might inhibit the internalization and replication of PRRSV, but did not directly inactivate the virus or block its adsorption to cell surface. In conclusion, our findings indicated that TD-C possessed a significant anti-PRRSV activity, and provided a strong basis for further exploration of this compound as an antiviral agent against PRRSV. PMID- 26488076 TI - Histoplasmosis in HIV-Infected Persons, Yaounde, Cameroon. PMID- 26488077 TI - Skin Bond Electron Relaxation Dynamics of Germanium Manipulated by Interactions with H2 , O2 , H2 O, H2 O2 , HF, and Au. AB - Although germanium performs amazingly well at sites surrounding hetero coordinated impurities and under-coordinated defects or skins with unusual properties, having important impact on electronic and optical devices, understanding the behavior of the local bonds and electrons at such sites remains a great challenge. Here we show that a combination of density functional theory calculations, zone-resolved X-ray photoelectron spectroscopy, and bond order length strength correlation mechanism has enabled us to clarify the physical origin of the Ge 3d core-level shift for the under-coordinated (111) and (100) skin with and without hetero-coordinated H2 , O2 , H2 O, H2 O2 , HF impurities. The Ge 3d level shifts from 27.579 (for an isolated atom) by 1.381 to 28.960 eV upon bulk formation. Atomic under-coordination shifts the binding energy further to 29.823 eV for the (001) and to 29.713 eV for the (111) monolayer skin. Addition of O2 , HF, H2 O, H2 O2 and Au impurities results in quantum entrapment by different amounts, but H adsorption leads to polarization. PMID- 26488074 TI - Modulatory Role of Surface Coating of Superparamagnetic Iron Oxide Nanoworms in Complement Opsonization and Leukocyte Uptake. AB - Notwithstanding rapid advances of nanotechnology in diagnostic imaging and drug delivery, the engineered nanocarriers still exhibit substantial lack of hemocompatibility. Thus, when injected systemically, nanoparticles are avidly recognized by blood leukocytes and platelets, but the mechanisms of immune recognition are not well understood and strategies to mitigate these phenomena remain underexplored. Using superparamagnetic dextran iron oxide (SPIO) nanoworms (NWs) we demonstrate an efficient and predominantly complement-dependent uptake by mouse lymphocytes, neutrophils and monocytes from normal and tumor bearing mice in vitro. Following intravenous injection into wild type mice, blood leukocytes as well as platelets became magnetically labeled, while the labeling was decreased by 95% in complement C3-deficient mice. Using blood cells from healthy and cancer patient donors, we demonstrated that neutrophils, monocytes, lymphocytes and eosinophils took up SPIO NWs, and the uptake was prevented by EDTA (a general complement inhibitor) and by antiproperdin antibody (an inhibitor of the alternative pathway of the complement system). Cross-linking and hydrogelation of SPIO NWs surface by epichlorohydrin decreased C3 opsonization in mouse serum, and consequently reduced the uptake by mouse leukocytes by more than 70% in vivo. Remarkably, the cross-linked particles did not show a decrease in C3 opsonization in human serum, but showed a significant decrease (over 60%) of the uptake by human leukocytes. The residual uptake of cross-linked nanoparticles was completely blocked by EDTA. These findings demonstrate species differences in complement-mediated nanoparticle recognition and uptake by leukocytes, and further show that human hemocompatibility could be improved by inhibitors of complement alternative pathway and by nanoparticle surface coating. These results provide important insights into the mechanisms of hemocompatibility of nanomedicines. PMID- 26488078 TI - Circulation of human metapneumovirus among children with influenza-like illness in Wuhan, China. AB - Human metapneumovirus (HMPV) is a worldwide distributed pathogen of the respiratory tract. The objectives of this study were to identify HMPV infections among children with influenza-like illness (ILI) in Wuhan and to assess circulation patterns and molecular diversity of HMPV in this area. From July 2008 to December 2013, a total of 3,883 throat swab samples were collected from ILI outpatients under 16 years old. HMPV RNA was detected in 171 samples (4.40%). All the four subtypes of HMPV were identified, among which A2 was the most common subtype (61/145, 42.1%), followed by B1, B2, and A1. During the study period, HMPV circulation presented a biennial alternation between high and low incidence in Wuhan and the seasonal peak also shift between winter and spring in two continuous seasons. Subtype A2, B1, and B2 co-circulated during the study period, with genotype A prevailing in epidemic season 2008-2009 and 2012-2013, and genotype B prevailing during other periods. This large-scale analysis of HMPV prevalence in ILI outpatient children improves the understanding of local HMPV circulation patterns and provides molecular epidemic evidence for comparative analysis of HMPV infection. PMID- 26488079 TI - Clinical Diagnosis of Opioid-Induced Hyperalgesia. PMID- 26488080 TI - Pain Management With Bilateral Continuous Thoracic Paravertebral Block in a Patient With Fontan-Associated Hepatocellular Carcinoma Undergoing Hepatectomy. AB - OBJECTIVE: We report a case of perioperative management of a single-ventricle patient with Fontan-associated liver disease undergoing hepatectomy. CASE REPORT: A 12-year-old boy with Fontan circulation was scheduled for partial hepatectomy to remove a liver mass in segment 6. He received stent implantation to relieve conduit stenosis 6 months before the operation. The operation was performed under general anesthesia and with a bilateral thoracic paravertebral block (PVB). A continuous paravertebral infusion of levobupivacaine was administered via right and left catheters postoperatively. He was hemodynamically stable throughout the perioperative period, extubated soon after surgery, and had an uncomplicated postoperative course. CONCLUSIONS: An analgesic regimen including thoracic PVB resulted in a rapid recovery without opioid-related side effects and early reinitiation of anticoagulation therapy. Our case illustrates the effective application of thoracic PVB in congenital heart disease patients for non-cardiac related surgery. PMID- 26488081 TI - Redefining PECS Blocks for Postmastectomy Analgesia. PMID- 26488082 TI - A Novel Freehand (Underhand), Out-of-Plane Ultrasound Technique to Optimize Visualization of Needle Tip During Subacromial Bursa Injection. PMID- 26488083 TI - Transversus Abdominis Plane Block and Treatment of Viscerosomatic Abdominal Pain. PMID- 26488084 TI - The Subsartorial Plexus Block: A Variation on the Adductor Canal Block. PMID- 26488085 TI - The Retroclavicular Brachial Plexus Block: Additional Advantages. PMID- 26488086 TI - Spherical nanoparticle supported lipid bilayers for the structural study of membrane geometry-sensitive molecules. AB - Many essential cellular processes including endocytosis and vesicle trafficking require alteration of membrane geometry. These changes are usually mediated by proteins that can sense and/or induce membrane curvature. Using spherical nanoparticle supported lipid bilayers (SSLBs), we characterize how SpoVM, a bacterial development factor, interacts with differently curved membranes by magic angle spinning solid-state NMR. Our results demonstrate that SSLBs are an effective system for structural and topological studies of membrane geometry sensitive molecules. PMID- 26488087 TI - Molecular hydrogen inhibits lipopolysaccharide-triggered NLRP3 inflammasome activation in macrophages by targeting the mitochondrial reactive oxygen species. AB - The NLRP3 inflammasome, an intracellular multi-protein complex controlling the maturation of cytokine interleukin-1beta, plays an important role in lipopolysaccharide (LPS)-induced inflammatory cascades. Recently, the production of mitochondrial reactive oxygen species (mtROS) in macrophages stimulated with LPS has been suggested to act as a trigger during the process of NLRP3 inflammasome activation that can be blocked by some mitochondria-targeted antioxidants. Known as a ROS scavenger, molecular hydrogen (H2) has been shown to possess therapeutic benefit on LPS-induced inflammatory damage in many animal experiments. Due to the unique molecular structure, H2 can easily target the mitochondria, suggesting that H2 is a potential antagonist of mtROS-dependent NLRP3 inflammasome activation. Here we have showed that, in mouse macrophages, H2 exhibited substantial inhibitory activity against LPS-initiated NLRP3 inflammasome activation by scavenging mtROS. Moreover, the elimination of mtROS by H2 resultantly inhibited mtROS-mediated NLRP3 deubiquitination, a non transcriptional priming signal of NLRP3 in response to the stimulation of LPS. Additionally, the removal of mtROS by H2 reduced the generation of oxidized mitochondrial DNA and consequently decreased its binding to NLRP3, thereby inhibiting the NLRP3 inflammasome activation. Our findings have, for the first time, revealed the novel mechanism underlying the inhibitory effect of molecular hydrogen on LPS-caused NLRP3 inflammasome activation, highlighting the promising application of this new antioxidant in the treatment of LPS-associated inflammatory pathological damage. PMID- 26488088 TI - [Is antibiotic prophylaxis really necessary?]. PMID- 26488089 TI - [Is antibiotic prophylaxis really necessary?]. PMID- 26488090 TI - [WHO-5-campaign is successful]. PMID- 26488091 TI - [High-risk medical devices: Variable evidence after approval]. PMID- 26488092 TI - [Hypersensitivity: Special care with allopurinol in certain risk groups]. PMID- 26488093 TI - [Thoracic pain: Hospitalisation always required?]. PMID- 26488094 TI - [23-year old woman with painful redness on both shanks]. PMID- 26488095 TI - [Stroke and dementia - An epidemic of our century?]. PMID- 26488096 TI - [Management of acute ischemic stroke]. AB - Targets of acute ischemic stroke management include verification of clinical diagnosis, start of basic care and decision-making about specific treatments.Effectiveness of most therapeutic options is time dependent. Time delays within the rescue chain are associated with worse outcome. Trained and multidisciplinary teams on Stroke Unit form the backbone of acute management. Moreover, technical infrastructure influences therapeutic options. Cerebral imaging is pivotal.The following five therapies are evidence-based: treatment on a stroke unit, thrombolysis within 4.5hrs after symptom onset, mechanical recanalization in patients with occlusion of proximal, intracranial arteries, early administration of Aspirin, and hemicraniectomy in patients with so-called malignant infarction.This article describes the necessary diagnostic steps and specific as well as non-specific therapeutic options that compose acute management within the first 72 hours. PMID- 26488097 TI - [Blood pressure treatment in the acute stage of stroke]. AB - The results of previous studies on blood pressure in acute stroke therapy allow a few generally valid therapeutic recommendations. Efforts should be made to achieve a constant blood pressure level without major fluctuations. An antihypertensive therapy in the acute stage of stroke should be initiated only at highly elevated values. High blood pressure levels can be tolerated in patients with ischemic stroke unless thrombolytic comes into consideration. Should this be desired, the blood pressure must be quickly lowered to a target range of at least < 180 mmHg. In the case of intracerebral hemorrhage a blood pressure reduction appears to be beneficial. The ESO recommends a reduction to < 140 mmHg systolic within one hour, according to recommendations of the ESH and the EUSI but not more than 20 %. PMID- 26488098 TI - [Primary and secondary prevention of stroke]. AB - The basis for primary and secondary prevention of stroke (and also TIA) are both a healthy lifestyle with a healthy diet, non smoking, weight reduction and regular exercise, and consistent treatment of arterial hypertension with a target of < 140 /90 mmHg. The choice of the antihypertensive is depending on concomitant diseases, more important than the class of antihypertensive is treatment to target. Reduction of cholesterol with statins in primary prevention is dependant on total cardiovascular risk, in secondary prevention statins are integral part of modern treatment in non cardioembolic stroke. Atrial fibrillation is one of the major causes of stroke and should be treated with anticoagulation depending on the CHA2DS2-VASc score. Platelet inhibition is mandatory lifelong in all non cardioembolic strokes, in primary prevention only for patients with high total cardiovascular risk. Treatment of asymptomatic carotid artery stenosis should be determined on an individual basis. Symptomatic carotid artery stenosis should be treated immediately after the index stroke. PMID- 26488099 TI - [Dementia and hypertension]. AB - Dementia and associated diseases will have increasing impact on economical and social system in most countries. As long as no causal therapy for dementia exists, primary prevention, diagnosis and control of risk factors for dementia are crucial. Uncontrolled hypertension is one of the most important risk factors for vascular dementia. An early antihypertensive treatment may reduce cognitive impairment or at least prolong the time to onset of dementia. PMID- 26488100 TI - [Emergency ultrasound in patients with abdominal pain - where should we "look"]. AB - Diagnostic ultrasound is without doubt the imaging technique of choice in patients with acute abdominal pain. Point-of-care ultrasound examinations can help to reduce the number of possible differential diagnoses by exclusion or - as a best case scenario - show us directly the correct diagnosis. Hence patients can benefit from a very early appropriate therapeutic approach. This article illustrates where and how we should "look". After focusing on basic technical settings, typical pathological sonomorphologic changes in patients with some of the most important illnesses are characterized (e. g. acute appendicitis, acute cholecystitis, acute diverticulitis, acute pancreatitis and urinary tract occlusion). Ultrasound beginners are the target group of this survey. PMID- 26488102 TI - [13-year old girl with fever 6 months after returning from sub-Saharan Africa]. AB - HISTORY AND ADMISSION FINDINGS: A 13-year-old girl presented with regular fevers, 6 months after a prolonged trip through Africa. The patient reported relapsing fevers at 48 hour intervals. Each febrile episode was followed by pronounced fatigue and a subsequent recovery back to her usual state of health. She reported having taken weekly mefloquine during and after the trip to Africa. INVESTIGATIONS: Labortory evaluation revealed a hemoltytic anemia (hemoglobin: 10.8 g / dl, normal range: 12.3-16.0; haptoglobin: < 13 mg / dl, normal range 38 205). An abdominal ultrasound showed a marked splenomegaly (diameter: > 13.1 cm). DIAGNOSIS, TREATMENT AND COURSE: A peripheral blood film showed Plasmodium parasites with marked stippling. PCR and sequenicing of the ribosomal RNA gene identified Plasmodium ovale. The patient responded well to oral chloroquine therapy and laboratory parameters normalized within 8 days. After determination of a normal glucose-6-phosphate dehydrogenase activity a 2-week-long therapy with primaquine was initiated (0,3 mg / kg per kg bodyweight of primaquine base daily for 14 days) to eliminate the hyponozoite stage of the parasite. CONCLUSIONS: Currently used prophylacic agents against Malaria (mefloquine, atovaquone / proguanil hydrochloride, doxyxycline) do not prevent chronic liver stage infection (hypnozoite stage) with Plasmodium ovale or Plasmodium vivax. After chemoprophylaxis tertian malaria due Plasmodium vivax or Plasmodium ovale can occur. Therefore, tertian malaria should always be considered in febrile individuals who returned from a trip to the tropics even if chemoprophylaxis was taken. PMID- 26488101 TI - [Partynight outcome]. AB - HISTORY AND CLINICAL FINDINGS: An 18 year old girl was admitted with progressive painful dysphagia and a severe hemorrhagic endoscopically impassable esophagitis. She reported to have consumed an unknown liquid from a small flask on a party three weeks ago. Later on, this liquid was identified as a party- and sex-drug known as "Poppers", designed to be consumed by sniffing. On admission she had difficulties in swallowing liquids and even saliva. She had lost 8 kg of weight during the last 3 weeks. Clinical examination revealed tachycardia, a moderate tenderness in the epigastrium and sparse bowel sounds. Investigation and treatment: On endoscopy, there was a severe corrosion injury of the esophagus with a consecutive stenosis at 40 cm ab ore. The stenosis could not be passed even with a 4.9 mm instrument. After initial placement of a feeding tube the stenosis was dilated with Savary-Bougies. In the following years, the patient suffered from recurrent stenosis due to excessive scar formation. Repeated treatment with longitudinal incisions by needle knife and steroid injections improved symptoms to a tolerable degree. 5 years after ingestion, the patient still carries a long segment esophageal scarring with mild to moderate stenosis. CONCLUSION: The party drug Poppers is an organic nitrogen compound that has increasingly come into use over the past years. It may cause severe and life threatening esophageal chemical burn injury. Symptoms of painful dysphagia after intake of an "unknown" liquid party drug should raise the suspicion of an accidental oral ingestion of Poppers. PMID- 26488103 TI - [Hyperuricemia and gout]. AB - In most cases (98-99 %) primary hyperuricemia is caused by impaired renal excretion of uric acid. Overproduction of uric acid is rare. Secondary hyperuricemia has to be differentiated from primary forms. Clinical manifestations of hyperuricemia are acute inflammatory arthritis, tenosynovitis, bursitis, chronic arthropathy and accumulation of urate crystals in the form of tophaceous deposits. In addition renal complications can occur. Pathophysiology and diagnosis of gout were described. Treatment of gout has two goals: Treatment of the acute gout attack, to terminate pain and disability and treatment of hyperuricemia by lifestyle modification and with urate lowering drugs. A serum uric acid value below 6 mg/dl (360 umol/L) should be achieved. PMID- 26488104 TI - [Exploiting placebo and nocebo effects in patients with chronic pain]. AB - In recent years, the knowledge behind placebo analgesia has strongly increased. The underlying mechanisms are depictable in a comprehensive way. They can be used to enhance placebo responses in all active pain treatments. Expectations of the patient are pivotal and can be influenced specifically by learning processes and instructions, both in the positive direction (placebo response), as well as in the negative direction (nocebo response). In conversations, these principles can be considered to optimize the expectation with respect to treatment outcome and to reduce negative cognitions. PMID- 26488105 TI - [Why medicine? Analyzing students' motives for studying medicine]. AB - BACKGROUND: Despite increasing numbers of physicians, shortage of doctors is a predominant problem in the German health care system. AIM: AIM of the present study is a detailed and gendered analysis of current motives to study medicine in order to deduce implications for securing medical care in the future. METHODS: Study motives of medical students from Duisburg-Essen and Muenster were assessed using an online questionnaire. 13 given motives had to be rated on a 5 point Likert-scale according to their relevance for the decision to study medicine. Descriptive analysis regarding age, gender, location and study period was performed and a dichotomization of data (agreement vs. disagreement) was undertaken for logistic regression analysis. RESULTS: 1545 medical students took part in the survey (64.5% female). "Many-faceted workspaces", "varied tasks", "helping patients", "scientific interest" and "good career prospects" - backward sorted - were the most frequent study motives indicated by medical students. The aspect "helping patients" was more important to female than to male students, the latter rated career-associated motives e. g. income, reputation etc. as more relevant. Only for about 8% of the respondents - independently of gender - compatibility of job and family was a motive to study medicine. CONCLUSION: Perspectively, results of this study could help to shape medicine in a way that will appeal to the growing up generation of doctors: a sophisticated, demanding and fulfilling occupation compatible with family with options to carve out a career for those who want to - regardless of gender. Furthermore, coaching programs paralleling either medical studies or work as clinician should be considered to improve the matching of gender-specific study motives and careers. PMID- 26488106 TI - [People with Intellectual and Multiple Disabilities in the Acute-In-Patient Care Selected Results of a Qualitative Exploratory Study]. AB - BACKGROUND: National and international publications indicate a higher importance of people with disabilities in health and nursing care. From the international literature it can be seen that for this target group the hospital care is to be regarded as deficient in many ways. AIM OF THE STUDY: This project intends to study on a qualitative exploratory basis experiences of employees of outpatient and residential care facilities for people with mental and multiple disabilities and family members of the target group concerning their experiences in health and nursing care. METHODS: 21 guided interviews with employees of outpatient and in patient residential facilities for people with mental and multiple disabilities and family members of the target group were conducted. RESULTS: 21 interviews could be evaluated according to Grounded Theory with the software program MAXQDA. The results show above all that in the perception and from the experience of the interviewees mainly a "lack" exists in the care of the target group, e. g., in time, staff, resources, qualification, cooperation and so forth. Employees of outpatient and inpatient residential facilities for people with mental and multiple disabilities and family members must contribute to a high degree to the care in hospitals, so that nursing and health measures are performed. CONCLUSION: The results point to an inadequate care of people with disabilities in hospitals. It is necessary to reflect critically on the medical and nursing care and to develop adequate measures, concepts, interventions and policies. PMID- 26488107 TI - Laparoscopic Pyeloplasty for Ureteropelvic Junction Obstruction Following Open Pyeloplasty in Children. AB - OBJECTIVE: Few studies have evaluated the role of laparoscopic dismembered pyeloplasty in the setting of recurrent ureteropelvic junction (UPJ) obstruction following open dismembered pyeloplasty in the pediatric population. We present our experience at a single institution. PATIENTS AND METHODS: A retrospective analysis was performed of patients treated with laparoscopic pyeloplasty for secondary UPJ obstruction from March 2003 to August 2011 at a single institution. These patients were age and temporally matched with a control group of patients undergoing primary laparoscopic pyeloplasty. RESULTS: In total, 5 patients were identified as having undergone laparoscopic pyeloplasty for secondary UPJ obstruction following open dismembered pyeloplasty. Operative time was longer in the secondary repair group compared with the control group (190 versus 141 minutes; P = .24), although this was complicated by 1 patient in the secondary repair group undergoing multiple procedures. Morphine equivalent use and length of stay were similar (4.1 versus 6.6 mg [P = .21] and 1.4 versus 1.2 days [P = .67] in control patients versus secondary repair patients, respectively). All of the 5 (100%) patients undergoing secondary repair had successful outcomes with improved hydronephrosis on ultrasound, and 4 of 4 (100%) had improved or normal T1/2 times on postoperative mercaptoacetyltriglycine (MAG3) renal scan. One family in each group declined the renal scan for personal reasons. No complications were noted with a mean follow-up time of 13 months in both groups. CONCLUSIONS: Laparoscopic repair of secondary UPJ obstruction is a well-tolerated and effective option. When this technique is compared with primary laparoscopic pyeloplasty, results appear equivalent even after failed open repair, with comparable postoperative narcotic requirement and length of stay. Further studies are needed to better define the role of secondary laparoscopic pyeloplasty in the pediatric population, especially with regard to cost compared with other open and minimally invasive techniques. PMID- 26488108 TI - Transition-Metal-Free Synthesis of Carbonyl-Containing Oxindoles from N Arylacrylamides and alpha-Diketones via TBHP- or Oxone-Mediated Oxidative Cleavage of C(sp(2))-C(sp(2)) Bonds. AB - Carbonyl-containing oxindoles can be prepared from N-arylacrylamides and alpha diketones by TBHP- or oxone (KHSO5)-mediated C(sp(2))-C(sp(2)) bond cleavage and new C(sp(2))-C(sp(3)) bond formation. This methodology is characterized by its simple and transition-metal-free conditions and good functional group compatibility utilizing inexpensive and readily available reagents, thus providing a practical and efficient approach to an important class of 3-(2 oxoethyl)indolin-2-ones which are highly valued synthetic intermediates of biologically active molecules. In this transformation, alkylcarbonyl-containing oxindoles were obtained in majority when N-arylacrylamides reacted with asymmetric aliphatic/aromatic alpha-diketones. On the basis of the preliminary experiments, a plausible mechanism of this transformation is disclosed. PMID- 26488110 TI - Functional Impairment and Changes in Depression Subtypes for Women in STAR*D: A Latent Transition Analysis. AB - OBJECTIVE: To characterize the association between functional impairment and major depression subtypes at baseline and to characterize changes in subtypes by functional impairment level in women receiving citalopram in level 1 of the Sequenced Treatment Alternatives to Relieve Depression trial. METHOD: Women who completed baseline and week 12 study visits were included. Items from the self reported Quick Inventory of Depressive Symptomatology were used to define the latent depression subtypes. The Work and Social Adjustment Scale was used to classify baseline functional impairment. A latent transition analysis model provided estimates of the prevalence of subtype membership and transition probabilities by functional impairment level. RESULTS: Of the 755 women included, 69% had major functional impairment at baseline. Regardless of functional impairment level, the subtypes were differentiated by depression severity, appetite changes, psychomotor disturbances, and insomnia. Sixty-seven percent of women with normal/significant functional impairment and 60% of women with major impairment were likely to transition to a symptom resolution subtype at week 12. Women with baseline major impairment who were in the severe with psychomotor agitation subtype at the beginning of the study were least likely to transition to the symptom resolution subtype (4% chance). CONCLUSIONS: Functional impairment level was related to both the baseline depression subtype and the likelihood of moving to a different subtype. These results underscore the need to incorporate not only depression symptoms but also functioning in the assessment and treatment of depression. PMID- 26488111 TI - Early weight gain in family-based treatment predicts greater weight gain and remission at the end of treatment and remission at 12-month follow-up in adolescent anorexia nervosa. AB - OBJECTIVE: To Identify whether early weight gain in family-based treatment (FBT) predicted greater weight and remission at end of FBT and 12-month follow-up. METHOD: Eighty-two adolescents, with anorexia nervosa, participated in a randomized control trial comparing brief hospitalization for medical stabilization and hospitalization for weight restoration to 90% expected body weight (EBW) (1:1), followed by 20 sessions of FBT. Sixty-nine completed trial protocol. Receiver operating characteristic analyses were conducted investigating whether early weight-gain in FBT predicted outcomes at end of FBT and 12-month follow-up. Participants were analyzed according to their original randomization and as a combined set. Binary logistic regression was used to control for randomization arm effect in combined set analysis. RESULTS: Weight gain greater than 1.8 kg at FBT Session 4 predicted greater %EBW (99.18 SD = 6.93 vs. 92.79 SD = 7.74, p < .05) and remission at end of FBT (46% vs. 11%, p < .05) and at 12 month follow-up (64% vs. 36%, p = .05). Binary logistic regression confirmed weight gain greater than 1.8 kg predicted remission (p < .05) while treatment arm randomization did not add significantly to the model. DISCUSSION: Early weight gain has potential to distinguish likely responders in FBT from those who may need more intensive intervention to achieve remission offering the potential to improve outcomes. PMID- 26488112 TI - The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1. AB - The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukaemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA) is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose- and time dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression. However, normal B and T cells were less sensitive than CLL cells (P=0.006 and P<0.001, respectively). SSA altered the splicing of anti apoptotic MCL-1(L) to MCL-1(s) in CLL cells coincident with induction of apoptosis. Overexpression studies in Ramos cells suggested that Mcl-1 was important for SSA-induced killing since its expression inversely correlated with apoptosis (P=0.001). IL4 and CD40L, present in patient lymph nodes, are known to protect tumour cells from apoptosis and significantly inhibited SSA, ABT-263 and ABT-199 induced killing following administration to CLL cells (P=0.008). However, by combining SSA with the Bcl-2/Bcl-x(L) antagonists ABT-263 or ABT-199, we were able to overcome this pro-survival effect. We conclude that SSA combined with Bcl 2/Bcl-x(L) antagonists may have therapeutic utility for CLL. PMID- 26488114 TI - Organic radicals for the enhancement of oxygen reduction reaction in Li-O2 batteries. AB - We examine for the first time the ability of inert carbon free-radicals as soluble redox mediators to catalyze and enhance the oxygen reduction reaction in a (TEGDME)-based electrolyte. We demonstrate that the tris(2,4,6 trichlorophenyl)methyl (TTM) radical is capable of chemically favoring the oxygen reduction reaction improving significantly the Li-O2 battery performance. PMID- 26488113 TI - Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia. AB - We conducted a comprehensive analysis of 28 recurrently mutated genes in acute myeloid leukemia (AML) in 271 patients with de novo AML. Co-mutations were frequently detected in the intermediate cytogenetic risk group, at an average of 2.76 co-mutations per patient. When assessing the prognostic impact of these co mutations in the intermediate cytogenetic risk group, overall survival (OS) was found to be significantly shorter (P=0.0006) and cumulative incidence of relapse (CIR) significantly higher (P=0.0052) in patients with complex molecular genetic abnormalities (CMGAs) involving three or more mutations. This trend was marked even among patients aged ?65 years who were also FLT3-ITD (FMS-like tyrosine kinase 3 internal tandem duplications)-negative (OS: P=0.0010; CIR: P=0.1800). Moreover, the multivariate analysis revealed that CMGA positivity was an independent prognostic factor associated with OS (P=0.0007). In stratification based on FLT3-ITD and CEBPA status and 'simplified analysis of co-mutations' using seven genes that featured frequently in CMGAs, CMGA positivity retained its prognostic value in transplantation-aged patients of the intermediate cytogenetic risk group (OS: P=0.0002. CIR: P<0.0001). In conclusion, CMGAs in AML were found to be strong independent adverse prognostic factors and simplified co-mutation analysis to have clinical usefulness and applicability. PMID- 26488116 TI - Contact Tracing Activities during the Ebola Virus Disease Epidemic in Kindia and Faranah, Guinea, 2014. AB - The largest recorded Ebola virus disease epidemic began in March 2014; as of July 2015, it continued in 3 principally affected countries: Guinea, Liberia, and Sierra Leone. Control efforts include contact tracing to expedite identification of the virus in suspect case-patients. We examined contact tracing activities during September 20-December 31, 2014, in 2 prefectures of Guinea using national and local data about case-patients and their contacts. Results show less than one third of case-patients (28.3% and 31.1%) were registered as contacts before case identification; approximately two thirds (61.1% and 67.7%) had no registered contacts. Time to isolation of suspected case-patients was not immediate (median 5 and 3 days for Kindia and Faranah, respectively), and secondary attack rates varied by relationships of persons who had contact with the source case-patient and the type of case-patient to which a contact was exposed. More complete contact tracing efforts are needed to augment control of this epidemic. PMID- 26488115 TI - Hypoxic Gene Expression of Donor Bronchi Linked to Airway Complications after Lung Transplantation. AB - RATIONALE: Central airway stenosis (CAS) after lung transplantation has been attributed in part to chronic airway ischemia; however, little is known about the time course or significance of large airway hypoxia early after transplantation. OBJECTIVES: To evaluate large airway oxygenation and hypoxic gene expression during the first month after lung transplantation and their relation to airway complications. METHODS: Subjects who underwent lung transplantation underwent endobronchial tissue oximetry of native and donor bronchi at 0, 3, and 30 days after transplantation (n = 11) and/or endobronchial biopsies (n = 14) at 30 days for real-time polymerase chain reaction of hypoxia-inducible genes. Patients were monitored for 6 months for the development of transplant-related complications. MEASUREMENTS AND MAIN RESULTS: Compared with native endobronchial tissues, donor tissue oxygen saturations (Sto2) were reduced in the upper lobes (74.1 +/- 1.8% vs. 68.8 +/- 1.7%; P < 0.05) and lower lobes (75.6 +/- 1.6% vs. 71.5 +/- 1.8%; P = 0.065) at 30 days post-transplantation. Donor upper lobe and subcarina Sto2 levels were also lower than the main carina (difference of -3.9 +/- 1.5 and -4.8 +/- 2.1, respectively; P < 0.05) at 30 days. Up-regulation of hypoxia-inducible genes VEGFA, FLT1, VEGFC, HMOX1, and TIE2 was significant in donor airways relative to native airways (all P < 0.05). VEGFA, KDR, and HMOX1 were associated with prolonged respiratory failure, prolonged hospitalization, extensive airway necrosis, and CAS (P < 0.05). CONCLUSIONS: These findings implicate donor bronchial hypoxia as a driving factor for post-transplantation airway complications. Strategies to improve airway oxygenation, such as bronchial artery re-anastomosis and hyperbaric oxygen therapy merit clinical investigation. PMID- 26488118 TI - Growth and Tolerance of Preterm Infants Fed a New Extensively Hydrolyzed Liquid Human Milk Fortifier. AB - OBJECTIVES: This study was a comparison of growth and tolerance in premature infants fed either standard powdered human milk fortifier (HMF) or a newly formulated concentrated liquid that contained extensively hydrolyzed protein. METHODS: This was an unblinded randomized controlled multicenter noninferiority study on preterm infants receiving human milk (HM) supplemented with 2 randomly assigned HMFs, either concentrated liquid HMF containing extensively hydrolyzed protein (LE-HMF) or a powdered intact protein HMF (PI-HMF) as the control. The study population consisted of preterm infants <=33 weeks who were enterally fed HM. Infants were studied from the first day of HM fortification until day 29 or hospital discharge, whichever came first. RESULTS: A total of 147 preterm infants were enrolled. Noninferiority was observed in weight gain reported in the intent to-treat (ITT) analysis was 18.2 and 17.5 g . kg(-1) . day(-1) for the LE-HMF and PI-HMF groups, respectively. In an a priori defined subgroup of strict protocol followers (n = 75), the infants fed LE-HMF achieved greater weight over time than those fed PI-HMF (P = 0.036). The LE-HMF group achieved greater linear growth over time compared to the PI-HMF (P = 0.029). The protein intake from fortified HM was significantly higher in the LE-HMF group compared with the PI-HMF group (3.9 vs 3.3 g . kg(-1) . day(-1), P < 0.0001). Both fortifiers were well tolerated with no significant differences in overall morbidity. CONCLUSIONS: Both fortifiers showed excellent weight gain (grams per kilograms per day), tolerance, and low incidence of morbidity outcomes with the infants who were strict protocol followers fed LE-HMF having improved growth during the study. These data point to the safety and suitability of this new concentrated liquid HMF (LE-HMF) in preterm infants. Growth with this fortifier closely matches the recent recommendations for a weight gain of >18 g . kg(-1) . day(-1). PMID- 26488119 TI - Age of Onset of Functional Constipation. AB - In a review of 538 children with functional constipation, we analyzed ages of presentation and onset, symptom duration, and behavioral/developmental problems. We divided the subjects into quartiles (Q1-Q4) based on age of onset. Median onset age was 2.3 years. The oldest group had the shortest symptom duration before referral at 1.8 +/- 1.8 years (compared with Q3 to Q1, P = 0.039, P = 0.001, P < 0.001, respectively). Of the Q4 subjects, 22% had a behavioral/developmental problem (P < 0.001 compared with Q1-Q3). We conclude that most children develop functional constipation as infants and toddlers, but those with later onset are more likely to have behavioral/developmental issues and see a specialist sooner. PMID- 26488117 TI - Cellular and chromatin dynamics of antibody-secreting plasma cells. AB - Plasma cells are terminally differentiated B cells responsible for maintaining protective serum antibody titers. Despite their clinical importance, our understanding of the linear genomic features and chromatin structure of plasma cells is incomplete. The plasma cell differentiation program can be triggered by different signals and in multiple, diverse peripheral B cell subsets. This heterogeneity raises questions about the gene regulatory circuits required for plasma cell specification. Recently, new regulators of plasma cell differentiation have been identified and the enhancer landscapes of naive B cells have been described. Other studies have revealed that the bone marrow niche harbors heterogeneous plasma cell subsets. Still undefined are the minimal requirements to become a plasma cell and what molecular features make peripheral B cell subsets competent to become antibody-secreting plasma cells. New technologies promise to reveal underlying chromatin configurations that promote efficient antibody secretion. For further resources related to this article, please visit the WIREs website. PMID- 26488121 TI - Hepatoblastoma in Children With Congenital Portosystemic Shunts. AB - Two children developed hepatoblastoma concurrent with congenital portosystemic shunts (PSSs) (Abernethy malformations). Both underwent operative ligation of their PSSs. One received concurrent tumor resection, whereas the other was deemed initially unresectable and underwent biopsy followed by neoadjuvant chemotherapy. Although benign hepatic masses, such as focal nodular hyperplasia and nodular regenerative hyperplasia, are common in patients with Abernethy malformations, malignant tumors have also been documented and should always be considered in the differential diagnosis of a patient with a congenital PSS and a hepatic mass. PMID- 26488122 TI - Early Enteral Nutrition in Children With Acute Pancreatitis. AB - Nutrition is an integral part of acute pancreatitis (AP) management and is not adequately studied in pediatrics. The goal from the present study was to evaluate the effect of nutrition and fat content on the length of stay and pain severity in patients with AP. This is a retrospective review of our nutrition database between May 1, 2014 and December 1, 2014. Pain levels were similar between patients who were allowed to feed and patients kept nill per os. Higher fat intake grams per kilogram per day was associated with significantly lower pain scores. Early feeds are feasible in pediatric patients with AP. Pain was not increased in the group that had more fat in their diet. PMID- 26488123 TI - Early Clinical Diagnosis of PC1/3 Deficiency in a Patient With a Novel Homozygous PCSK1 Splice-Site Mutation. AB - Autosomal recessive proprotein convertase 1/3 (PC1/3) deficiency, caused by mutations in the PCSK1 gene, is characterized by severe congenital malabsorptive diarrhea, early-onset obesity, and certain endocrine abnormalities. We suspected PC1/3 deficiency in a 4-month-old girl based on the presence of congenital diarrhea and polyuria. Sequencing the whole coding region and splice sites detected a novel homozygous PCSK1 splice-site mutation, c.544-2A>G, in the patient. The mutation resulted in the skipping of exon 5, the generation of a premature termination codon, and nonsense-mediated PCSK1 messenger ribonucleic acid decay, which was demonstrated in complementary DNA derived from fibroblasts. PMID- 26488125 TI - Resolution of Hepatic Artery Thrombosis in 2 Pediatric Liver Transplant Patients. AB - Hepatic artery thrombosis (HAT) is a serious complication after liver transplantation. This is the first report of spontaneous resolution of HAT in pediatric liver transplant patients on low molecular weight heparin therapy. A total of 2 patients, a 26-month-old boy who presented with acute liver failure and required emergent liver transplantation and a 15-year-old boy with ulcerative colitis and autoimmune hepatitis-primary sclerosing cholangitis overlap underwent liver transplantation for progressive cirrhosis; both developed HAT during the postoperative period. They were both treated with low molecular weight heparin. Follow-up imaging for both patients showed resolution of HAT without evidence of collateral flow. PMID- 26488124 TI - Iron and Vitamin D Deficiency in Healthy Young Children in Western Europe Despite Current Nutritional Recommendations. AB - BACKGROUND AND AIM: Iron deficiency (ID) and vitamin D deficiency (VDD) are the 2 most common micronutrient deficiencies in young children worldwide and may lead to impaired neurodevelopment and rickets, respectively. Risk factors for ID and VDD differ between populations. The objective of this study was to determine the prevalence of and risk factors for ID and VDD in 12- to 36-month-old children in Western Europe. METHODS: This study took place in Germany, the Netherlands, and the United Kingdom from 2012 to 2014. A venous blood sample was taken to establish iron and vitamin D status. ID was defined as serum ferritin <12 MUg/L in the absence of infection (high sensitivity C-reactive protein <10 mg/L). VDD was defined as serum 25-hydroxyvitamin D <50 nmol/L (20 ng/mL). Furthermore, parents were asked to fill out a questionnaire regarding their child's demographic- and socioeconomic characteristics, food intake, sun exposure, and medical history. RESULTS: In 325 children (white race 95%, boys 56%, mean age 20.7 months) the overall prevalence of ID and VDD was 11.8% and 22.8%, respectively. The use of primarily cow's milk as major type of milk was associated with ID (odds ratio [OR] 3.20, 95% confidence interval [CI] 1.12-8.53) and VDD (OR 7.17, 95% CI 3.10-16.57). The use of vitamin D supplements (OR 0.20, 95% CI 0.07-0.56) was associated with a lower prevalence of VDD. CONCLUSION: Despite current nutritional recommendations, ID and VDD are common in healthy young white children. Health programs focusing on adequate iron and vitamin D intake at an early age should be implemented to prevent deficiencies. PMID- 26488126 TI - In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate. AB - Four-factor prothrombin complex concentrate (PCC) 50 iu/kg is able to swiftly restore haemostatic parameters in healthy subjects on rivaroxaban. We hypothesized that lower dosages of PCC may be sufficient to restore normal haemostasis. In this double-blind, crossover, placebo-controlled study, we compared the effects of PCC 37.5 iu/kg, PCC 25 iu/kg, and placebo on thrombin generation (endogenous thrombin potential, ETP) and prothrombin time in six healthy subjects receiving twice-daily rivaroxaban 15 mg for 2.5 days. Fifteen min after infusion of PCC 37.5 iu/kg, ETP increased from 47 +/- 16% to 64 +/- 22% (P = 0.03; pre-rivaroxaban ETP: 92 +/- 14%) and remained higher than after placebo over 24 h (P = 0.001). PCC 25 iu/kg did not modify ETP within 15 min (53 +/- 11% to 59 +/- 12%; P = 0.14) and was not different from placebo over 24 h (P = 0.31). ETP reached pre-rivaroxaban levels within 6 h after PCC 37.5 iu/kg infusion and within 12-24 h after PCC 25 iu/kg infusion. Both dosages restored rivaroxaban-induced prothrombin time prolongation after 15 min (P < 0.001). Placebo did not have an effect on coagulation parameters. 37.5 iu/kg of PCC leads to partial restoration of thrombin generation, whereas 25 iu/kg does not. PCC 37.5 iu/kg may be insufficient for immediate full reversal of peak therapeutic rivaroxaban levels. PMID- 26488127 TI - Element-specific characterization of transient electronic structure of solvated Fe(II) complexes with time-resolved soft X-ray absorption spectroscopy. AB - Polypyridyl transition-metal complexes are an intriguing class of compounds due to the relatively facile chemical designs and variations in ligand-field strengths that allow for spin-state changes and hence electronic configurations in response to external perturbations such as pressure and light. Light-activated spin-conversion complexes have possible applications in a variety of molecular based devices, and ultrafast excited-state evolution in these complexes is of fundamental interest for understanding of the origins of spin-state conversion in metal complexes. Knowledge of the interplay of structure and valence charge distributions is important to understand which degrees of freedom drive spin conversion and which respond in a favorable (or unfavorable) manner. To track the response of the constituent components, various types of time-resolved X-ray probe methods have been utilized for a broad range of chemical and biological systems relevant to catalysis, solar energy conversions, and functional molecular devices. In particular, transient soft X-ray spectroscopy of solvated molecules can offer complementary information on the detailed electronic structures and valence charge distributions of photoinduced intermediate species: First-row transition-metal L-edges consist of 2p-3d transitions, which directly probe the unoccupied valence density of states and feature lifetime broadening in the range of 100 meV, making them sensitive spectral probes of metal-ligand interactions. In this Account, we present some of our recent progress in employing picosecond and femtosecond soft X-ray pulses from synchrotron sources to investigate element specific valence charge distributions and spin-state evolutions in Fe(II) polypyridyl complexes via core-level transitions. Our results on transient L-edge spectroscopy of Fe(II) complexes clearly show that the reduction in sigma donation is compensated by significant attenuation of pi-backbonding upon spin crossover. This underscores the important information contained in transient metal L-edge spectroscopy on changes in the 3d orbitals including oxidation states, orbital symmetries, and covalency, which largely define the chemistry of these complexes. In addition, ligand K-edge spectroscopy reveals the "ligand view" of the valence charge density by probing 1s-2p core-level transitions at the K-edge of light elements such as nitrogen, carbon, and oxygen. In the case of Fe(II) spin-conversion complexes, additional details of the metal-ligand interactions can be obtained by this type of X-ray spectroscopy. With new initiatives in and construction of X-ray free-electron laser sources, we expect time-resolved soft X-ray spectroscopy to pave a new way to study electronic and molecular dynamics of functional materials, thereby answering many interesting scientific questions in inorganic chemistry and material science. PMID- 26488128 TI - Serogroup W Meningitis Outbreak at the Subdistrict Level, Burkina Faso, 2012. AB - In 2012, Neisseria meningitidis serogroup W caused a widespread meningitis epidemic in Burkina Faso. We describe the dynamic of the epidemic at the subdistrict level. Disease detection at this scale allows for a timelier response, which is critical in the new epidemiologic landscape created in Africa by the N. meningitidis A conjugate vaccine. PMID- 26488129 TI - Pyogenic Intraperitoneal Pantoea agglomerans Abscesses. PMID- 26488130 TI - Drug-induced osteoporosis: from Fuller Albright to aromatase inhibitors. AB - Many commonly prescribed medications, such as selective serotonin reuptake inhibitors, proton pump inhibitors, thiazolidinediones, aromatase inhibitors, and androgen deprivation therapy, have been associated with adverse skeletal effects. The levels of evidence in support of a causal relationship between drug use and the development of bone loss and fractures are variable. For some drugs, a causal relationship is suspected (but not proven) based on observational studies, while in others causality is firmly established with randomized, controlled clinical trials. The mechanism of action for skeletal damage is poorly understood for some drugs and well known for others. Guidelines for managing bone health in patients taking some medications with potential skeletal toxicity have been developed using the best available evidence and expert opinion. This is a review of selected medications that have been associated with bone loss and fractures, with recommendations for clinical care. PMID- 26488131 TI - Attachment style and oxytocin receptor gene variation interact in influencing social anxiety. AB - OBJECTIVES: Social anxiety has been suggested to be promoted by an insecure attachment style. Oxytocin is discussed as a mediator of trust and social bonding as well as a modulator of social anxiety. Applying a gene-environment (G * E) interaction approach, in the present pilot study the main and interactive effects of attachment styles and oxytocin receptor (OXTR) gene variation were probed in a combined risk factor model of social anxiety in healthy probands. METHODS: Participants (N = 388; 219 females, 169 males; age 24.7 +/- 4.7 years) were assessed for anxiety in social situations (Social Phobia and Anxiety Inventory) depending on attachment style (Adult Attachment Scale, AAS) and OXTR rs53576 A/G genotype. RESULTS: A less secure attachment style was significantly associated with higher social anxiety. This association was partly modulated by OXTR genotype, with a stronger negative influence of a less secure attachment style on social anxiety in A allele carriers as compared to GG homozygotes. CONCLUSIONS: The present pilot data point to a strong association of less secure attachment and social anxiety as well as to a gene-environment interaction effect of OXTR rs53576 genotype and attachment style on social anxiety possibly constituting a targetable combined risk marker of social anxiety disorder. PMID- 26488132 TI - Solubility of C60 and PCBM in Organic Solvents. AB - The ability to correlate fullerene solubility with experimentally or computationally accessible parameters can significantly facilitate nanotechnology nowadays for a wide range of applications, while providing crucial insight into optimum design of future fullerene species. To date, there has been no single relationship that satisfactorily describes the existing data clearly manifesting the effects of solvent species, system temperature, and isomer. Using atomistic molecular dynamics simulations on two standard fullerene species, C60 and PCBM ([6,6]-phenyl-C61-butyric acid methyl ester), in a representative series of organic solvent media (i.e., chloroform, toluene, chlorobenzene, 1,3 dichlorobenzene, and 1,2-dichlorobenzene), we show that a single time constant characterizing the dynamic stability of a tiny (angstrom-sized) solvation shell encompassing the fullerene particle can be utilized to effectively capture the known trends of fullerene solubility as reported in the literature. The underlying physics differs substantially between the two fullerene species, however. Although C60 was previously shown to be dictated by a diffusion-limited aggregation mechanism, the side-chain-substituted PCBM is demonstrated herein to proceed with an analogous reaction-limited aggregation with the "reaction rate" set by the fullerene rotational diffusivity in the medium. The present results suggest that dynamic quantities-in contrast to the more often employed, static ones-may provide an excellent means to characterize the complex (entropic and enthalpic) interplay between fullerene species and the solvent medium, shed light on the factors determining the solvent quality of a nanoparticle solution, and, in particular, offer a practical pathway to foreseeing optimum fullerene design and fullerene-solvent interactions. PMID- 26488133 TI - Advanced Inorganic Nanoarchitectures from Oriented Self-Assembly. AB - Complex and well-defined nanostructures are promising for emerging properties with broad applications. Self-assembly processes driven by diverse interactions generate varied nanostructures by using versatile nanocrystals as building blocks, while oriented attachment growth allows individual nanocrystals to be integrated and fused into highly anisotropic structures. By a combination of self assembly technique and oriented attachment growth, many advanced nanostructures can be made. Such approaches can be viewed as an architecture of the nanoscale counterparts in the microworld, named as nanoarchitectures. PMID- 26488134 TI - Determination of Estrogens in Milk Samples by Magnetic-Solid-Phase Extraction Technique Coupled With High-Performance Liquid Chromatography. AB - A magnetic-solid-phase extraction method coupled with high-performance liquid chromatography and diode array detection has been developed for simultaneous determination of 3 estrogens in milk samples. In this work, Fe3O4 NPs were synthesized by a simple chemical co-precipitation reaction, and the surface of Fe3O4 was modified with cetyltrimethyl ammonium bromide (CTAB; designed as Fe3O4@CTAB). The synthesized Fe3O4@CTAB NPs were characterized by Fourier transformed infrared spectroscopy, scanning electron microscopy, and transmission electron microscope. Fe3O4@CTAB NPs have high binding affinity toward estrone (E1), 17beta-estradiol (17beta-E2), and diethylstilbestrol (DES). Fe3O4@CTAB NPs can be easily separated from sample solutions using an external magnet due to the high super-paramagnetic property. The separation, preconcentration procedure is fast and will be completed in 2 min. Estrogens linear dynamic ranges were achieved in the range of 10 to 1000 ng/mL with regression coefficients (R(2)) higher than 0.9992. The limits of detection were between 0.26 and 0.61 ng/mL. Parameters influencing the recoveries were investigated and optimized. The proposed method was used for the determination of E1, 17beta-E2, and DES in milk samples, and recoveries were ranged from 91.3% to 105.0%, with the relative standard deviations in the range of 2.7% to 4.0%. PMID- 26488135 TI - Synthesis of the kyotorphin precursor benzoyl-L-tyrosine-L-argininamide with immobilized alpha-chymotrypsin in sequential batch with enzyme reactivation. AB - alpha-Chymotrypsin was immobilized in activated agarose support and the stability of the biocatalyst was assessed in three polar organic solvents, namely, ethanol, diglyme, and acetonitrile. Ethanol was the solvent in which the stability of the enzyme was higher and was then selected to perform the synthesis of the kyotorphin derivative benzoyl-tyrosine argininamide, evaluating enzyme reactivation after synthesis. Substrates for reaction were benzoyl tyrosine ethyl ester and argininamide, the reaction being performed under kinetic control. High conversion yield (85%) was obtained and the immobilized enzyme was successfully used in sequential batch reactor operation with enzyme reactivation after three batches. PMID- 26488136 TI - The Human Endometrium-Specific Proteome Defined by Transcriptomics and Antibody Based Profiling. AB - The human uterus includes the complex endometrial mucosa, the endometrium that undergoes dynamic, hormone-dependent alterations throughout the life of fertile females. Here we have combined a genome-wide transcriptomics analysis with immunohistochemistry-based protein profiling to analyze gene expression patterns in the normal endometrium. Human endometrial tissues from five women were used for deep sequencing (RNA-Seq). The mRNA and protein expression data from the endometrium were compared to 31 (RNA) and 44 (protein) other normal tissue types, to identify genes with elevated expression in the endometrium and to localize the expression of corresponding proteins at a cellular resolution. Based on the expression levels of transcripts, we could classify all putative human protein coding genes into categories defined by expression patterns and found altogether 101 genes that showed an elevated pattern of expression in the endometrium, with only four genes showing more than five-fold higher expression levels in the endometrium compared to other tissues. In conclusion, our analysis based on transcriptomics and antibody-based protein profiling reports here comprehensive lists of genes with elevated expression levels in the endometrium, providing important starting points for a better molecular understanding of human reproductive biology and disease. PMID- 26488137 TI - Global Nursing Issues and Development: Analysis of World Health Organization Documents. AB - PURPOSE: To analyze World Health Organization (WHO) documents to identify global nursing issues and development. DESIGN: Qualitative content analysis. METHODS: Documents published by the six WHO regions between 2007 and 2012 and with key words related to nurse/midwife or nursing/midwifery were included. Themes, categories, and subcategories were derived. The final coding reached 80% agreement among three independent coders, and the final coding for the discrepant coding was reached by consensus. FINDINGS: Thirty-two documents from the regions of Europe (n = 19), the Americas (n = 6), the Western Pacific (n = 4), Africa (n = 1), the Eastern Mediterranean (n = 1), and Southeast Asia (n = 1) were examined. A total of 385 units of analysis dispersed in 31 subcategories under four themes were derived. The four themes derived (number of unit of analysis, %) were Management & Leadership (206, 53.5), Practice (75, 19.5), Education (70, 18.2), and Research (34, 8.8). CONCLUSIONS: The key nursing issues of concern at the global level are workforce, the impacts of nursing in health care, professional status, and education of nurses. International alliances can help advance nursing, but the visibility of nursing in the WHO needs to be strengthened. CLINICAL RELEVANCE: Organizational leadership is important in order to optimize the use of nursing competence in practice and inform policy makers regarding the value of nursing to promote people's health. PMID- 26488138 TI - Polymer based graphene/titanium dioxide nanocomposite (GTNC): an emerging and efficient thermoelectric material. AB - An ecofriendly procedure for the synthesis of graphene-titanium dioxide nanocomposites (GTNC) has been developed by dispersing nano-titanium dioxide (TiO2) and graphene nanosheets (GNSs) in ethanol via ultrasonication followed by microwave irradiation. Such nanohybrids were characterized by X-Ray Diffraction (XRD), High Resolution Transmission Electron Microscopy (HRTEM), Fourier Transform Infrared Spectroscopy (FTIR) and Raman spectroscopy. We have also demonstrated the synthesis of highly conductive composites like poly(3,4 ethylenedioxythiophene)polystyrene sulphonate ( PEDOT: PSS)-GTNC, polyvinyl acetate (PVAc)-GTNC, PEDOT:PSS-graphene, and PVAc-graphene by ultrasonication followed by hot compaction towards their thermoelectric application. The filler (graphene, GTNC) concentration and polymer matrix were judiciously varied and optimized for the sake of high electrical conductivity and Seebeck coefficient which leads to a higher power factor (PF). The PVAc based composite with a composition of PVAc (20%) and GTNC (80%) was found to be the most promising material with an electrical conductivity of 2.6 * 10(4) S m(-1) and a Seebeck coefficient of -42 MUV K(-1) at room temperature (RT). As a result, the PF reaches 47 MUW m(-1) K(-2) at RT which is approximately 37 times, 5 times and 3 times higher than that for the PVAc-graphene based composite, the PEDOT: PSS-GTNC based composite and the PEDOT: PSS-graphene based composite respectively. The origin of the thermoelectric performance of the GTNC composite seems to be from the synergistic effect of graphene nanosheets and TiO2 nanoparticles. The composite shows a large power factor value without using any conducting polymer. PMID- 26488139 TI - Evaluation of the performance of the OneTouch Select Plus blood glucose test system against ISO 15197:2013. AB - OBJECTIVES: Assess laboratory and in-clinic performance of the OneTouch Select((r)) Plus test system against ISO 15197:2013 standard for measurement of blood glucose. METHODS: System performance assessed in laboratory against key patient, environmental and pharmacologic factors. User performance was assessed in clinic by system-naive lay-users. Healthcare professionals assessed system accuracy on diabetes subjects in clinic. RESULTS: The system demonstrated high levels of performance, meeting ISO 15197:2013 requirements in laboratory testing (precision, linearity, hematocrit, temperature, humidity and altitude). System performance was tested against 28 interferents, with an adverse interfering effect only being recorded for pralidoxime iodide. Clinic user performance results fulfilled ISO 15197:2013 accuracy criteria. Subjects agreed that the color range indicator clearly showed if they were low, in-range or high and helped them better understand glucose results. CONCLUSION: The system evaluated is accurate and meets all ISO 15197:2013 requirements as per the tests described. The color range indicator helped subjects understand glucose results and supports patients in following healthcare professional recommendations on glucose targets. PMID- 26488140 TI - Repeated appearance and disappearance of localized surface plasmon resonance in 1.2 nm gold clusters induced by adsorption and desorption of hydrogen atoms. AB - Addition of an aqueous solution of NaBH4 to a dispersion of small (~1.2 nm) gold clusters stabilized by poly(N-vinyl-2-pyrrolidone) (Au:PVP) induced a localized surface plasmon resonance (LSPR) absorption for a certain period of time while maintaining the cluster size. The duration of the LSPR band could be lengthened by increasing the NaBH4 concentration and shortened by increasing the concentration of dissolved O2, and the LSPR band could be made to appear and reappear repeatedly. The appearance of the LSPR band is explained by the electron donation to the Au core from the adsorbed H atoms that originate from NaBH4, whereas its disappearance is ascribed to the removal of H atoms by their reaction with O2. These results suggest that the transition between the metallic and non metallic electronic structures of the Au clusters can be reversibly induced by the adsorption and desorption of H atoms, which are electronically equivalent to Au. PMID- 26488141 TI - A randomized practical behavioural trial of curriculum-based advocacy training for individuals with traumatic brain injury and their families. AB - PRIMARY OBJECTIVE: To test whether a curriculum-based advocacy training programme improves advocacy behaviour when compared to a matched group engaged in self directed advocacy activities. RESEARCH DESIGN: Community-based randomized practical behavioural trial. METHODS AND PROCEDURES: Adults with moderate-severe TBI 1 or more years post-injury and their family members were recruited in Minnesota (4 years), Iowa and Wisconsin (each 3 years) and randomized into a curriculum-based or self-directed advocacy training group. Both groups met on the same day, at separate locations in the same city, once per month for 4 consecutive months. MAIN OUTCOMES AND RESULTS: Pre-post written and video testimony were rated using the Advocacy Behaviour Rating Scale (ABRS). Mean ABRS scores increased after intervention in both groups (curriculum n = 129, self directed n = 128), but there was no significant difference in this increase between groups. When groups were combined, a significant pre-post improvement in mean ABRS scores was observed. CONCLUSIONS: Curriculum-based advocacy training was not superior to a self-directed approach in improving ABRS scores. A significant improvement in expression of an advocacy message was observed when intervention groups were combined. These findings suggest that bringing together like-minded motivated individuals is more important than programme structure or content in changing advocacy behaviour. PMID- 26488143 TI - Frostbite Arthritis. PMID- 26488144 TI - Feasibility of Using Mobile Health to Promote Self-Management in Spina Bifida. AB - OBJECTIVE: To determine feasibility of using the interactive Mobile Health and Rehabilitation (iMHere) system in spina bifida and its effects on psychosocial and medical outcomes. DESIGN: In a randomized controlled trial, 13 intervention participants using the iMHere system and receiving usual care and 10 control participants receiving usual care were followed for 1 year. RESULTS: Feasibility of use of the system was demonstrated by participants using a customized smartphone system for reminders to conduct various self-care tasks, upload photos of wounds, manage medications, complete mood surveys, and for secure messaging. High usage of the system was associated with positive changes in the subscales of the Adolescent Self-Management and Independence Scale II. CONCLUSION: Use of the iMHere system in spina bifida is feasible and was associated with short-term self reported improvements in self-management skill. This system holds promise for use in many diverse chronic care models to support and increase self-management skills. PMID- 26488145 TI - Effect on Pain and Symptoms of Aspiration Before Hyaluronan Injection for Knee Osteoarthritis: A Prospective, Randomized, Single-blind Study. AB - OBJECTIVE: The main objective of this study was to observe whether synovial fluid aspiration of the knee joint compared to no aspiration, before and after 5 weekly injections of intra-articular hyaluronan, provides an improvement in knee pain and physical function. DESIGN: Patients were randomized to an arthrocentesis group (n = 92) or a nonarthrocentesis group (n = 88). In the arthrocentesis group, knee joints were maximally aspirated before each hyaluronan administration. In the nonarthrocentesis group, synovial fluid was not removed. Hyaluronan was injected into the knee joints once a week for 5 weeks. Patients were followed up for 25 weeks. Outcome measures included patient pain (using the 100-mm visual analog scale [VAS] during a 50-foot walking test), Western Ontario McMaster University Osteoarthritis Index (WOMAC) function scores, and overall effectiveness evaluated by patients and investigators on a scale of 1 to 6. RESULTS: The arthrocentesis group showed significantly greater improvement from baseline to week 25 in VAS pain (P < 0.001) and WOMAC function scores (P < 0.001) than the nonarthrocentesis group. However, the differences of patient and investigator assessment of effectiveness did not achieve significance. CONCLUSIONS: Synovial fluid drainage before injection of intra-articular hyaluronan significantly improved VAS pain and WOMAC function scores in patients with knee osteoarthritis, however, the differences of patient and investigator assessment did not achieve significance. PMID- 26488147 TI - The Authors' Response to the Letter to the Editor on "Ultrasound Guided Injection of the Carpal Tunnel: Do You Mind the Retinaculum?". PMID- 26488146 TI - Factors Associated with Mobility Outcomes in a National Spina Bifida Patient Registry. AB - OBJECTIVE: To provide descriptive data on ambulatory ability and muscle strength in a large cohort of individuals with spina bifida enrolled in a National Spina Bifida Patient Registry and to investigate factors associated with ambulatory status. DESIGN: Cross-sectional analysis of data from a multisite patient registry. RESULTS: Descriptive analysis of mobility variables for 2604 individuals with spina bifida aged 5 and older are presented from 19 sites in the United States. Analysis of a subset of National Spina Bifida Patient Registry data from 380 individuals from 3 sites accompanied by data from a specialized spina bifida electronic medical record revealed that those with no history of a shunt, lower motor level, and no history of hip or knee contracture release surgery were more likely to be ambulatory at the community level than at the household or wheelchair level. CONCLUSION: This study is the first to examine factors associated with ambulatory status in a large sample of individuals with myelomeningocele and nonmyelomeningocele subtypes of spina bifida. Results of this study delineate the breadth of strength and functional abilities within the different age groups and subtypes of spina bifida. The results may inform physicians of the characteristics of those with varying ambulatory abilities. PMID- 26488148 TI - Transbronchial Cryobiopsies in the Evaluation of Lung Allografts: Do the Benefits Outweigh the Risks? AB - CONTEXT: Transbronchial cryobiopsy technique yields larger biopsies with enhanced quality. The benefits and safety of cryobiopsies have not been thoroughly studied in lung allografts. OBJECTIVE: To compare size, quality, reproducibility of interpretation of rejection and complications of cryobiopsies with those of conventional biopsies from lung allografts. DESIGN: All cryobiopsies (March 2014 January 2015) of lung allografts performed at Mayo Clinic, Rochester, and medical records were reviewed. For comparison, conventional biopsies from the same patient or, if unavailable, from a random patient, were selected. Two pathologists blinded to outcome reviewed all biopsies. Specimen volume, number of alveoli, small airways, and pulmonary vessels were counted and statistically compared. RESULTS: Fifty-four biopsies (27 cryobiopsies) from 18 patients (11 men) were reviewed. A median of 3 (range, 2-5) and 10 (range, 6-12) specimens were obtained with cryobiopsies and conventional biopsies, respectively. Cryobiopsies were larger and contained more alveoli (P < .001, both) and small airways (P = .04). Conventional biopsies showed more fresh alveolar hemorrhage (procedural) and crush artifact/atelectasis (P < .001, both). Cryobiopsies contained more pulmonary veins and venules (P < .001). There was no significant difference between the types of biopsies with respect to the reviewers' agreement on grades of rejection. Complications were more frequent in the cryobiopsy group, though the difference was not statistically significant. CONCLUSIONS: Cryobiopsies of lung allografts are larger and have less artifact. However, complications occur and should be considered. Three cryobiopsy specimens appear sufficient for histopathologic evaluation of lung allografts. PMID- 26488149 TI - Corrigendum. PMID- 26488150 TI - Cement Selection for Cement-Retained Implant-Supported Prostheses: A Literature Review. AB - Cement-retained implant-supported prostheses are widely used for restoring missing teeth; however, they show some complications in comparison to screw retained restorations, such as difficulty in retrieving the restoration and biocompatibility of cement. Therefore, the practitioner should consider several important aspects when using this type of restoration. In this regard, one major concern is appropriate cement selection, with considerations including cement biologic compatibility, methods for limiting the excess cement, ease of removing the excess cement, radiographic view of the cement, and also the possibility of future retrieval of the prosthesis. The aim of this review article was to address most aspects related to this type of prosthesis in terms of cementation. PMID- 26488151 TI - Access and Quality of Care in Direct-to-Consumer Telemedicine. AB - BACKGROUND: Direct-to-consumer (DTC) telemedicine serves millions of patients; however, there is limited research on the care provided. This study compared the quality of care at Teladoc ( www.teladoc.com ), a large DTC telemedicine company, with that at physician offices and compared access to care for Teladoc users and nonusers. MATERIALS AND METHODS: Claims from all enrollees 18-64 years of age in the California Public Employees' Retirement System health maintenance organization between April 2012 and October 2013 were analyzed. We compared the performance of Teladoc and physician offices on applicable Healthcare Effectiveness Data and Information Set measures. Using geographic information system analyses, we compared Teladoc users and nonusers with respect to rural location and available primary care physicians. RESULTS: Of enrollees offered Teladoc (n = 233,915), 3,043 adults had a total of 4,657 Teladoc visits. For the pharyngitis performance measure (ordering strep test), Teladoc performed worse than physician offices (3% versus 50%, p < 0.01). For the back pain measure (not ordering imaging), Teladoc and physician offices had similar performance (88% versus 79%, p = 0.20). For the bronchitis measure (not ordering antibiotics), Teladoc performed worse than physician offices (16.7 versus 27.9%, p < 0.01). In adjusted models, Teladoc users were not more likely to be located within a healthcare professional shortage area (odds ratio = 1.12, p = 0.10) or rural location (odds ratio = 1.0, p = 0.10). CONCLUSIONS: Teladoc providers were less likely to order diagnostic testing and had poorer performance on appropriate antibiotic prescribing for bronchitis. Teladoc users were not preferentially located in underserved communities. Short-term needs include ongoing monitoring of quality and additional marketing and education to increase telemedicine use among underserved patients. PMID- 26488152 TI - Ammine-Stabilized Transition-Metal Borohydrides of Iron, Cobalt, and Chromium: Synthesis and Characterization. AB - Iron and cobalt borohydrides stabilized by ammonia (NH3), [Fe(NH3)6](BH4)2 and [Co(NH3)6](BH4)2, were synthesized along with a solid solution, [Co(NH3)6](BH4)(2 x)Cl(x) (x ~ 1), and a bimetallic compound, [Fe(NH3)6](Li2(BH4)4). The compounds were prepared by new low-temperature, solvent-based synthesis methods, using dimethyl sulfide or liquid NH3, which allow for the removal of inert metal halides. The crystal structures were determined from synchrotron radiation powder X-ray diffraction (SR-PXD) data. [M(NH3)6](BH4)2 (M = Fe, Co) and [Co(NH3)6](BH4)(2-x)Cl(x) crystallize in the cubic crystal system, where the transition metals are octahedrally coordinated by NH3. Polymeric chains of lithium coordinated by four bridging BH4(-) anions are found in [Fe(NH3)6](Li2(BH4)4). The new compounds have high hydrogen densities of ~14 wt % H2 and ~140 g H2/L and release a mixture of hydrogen and NH3 gas at low temperatures, T < 80 degrees C. The decomposition mechanisms of the prepared compounds along with the composites [Fe(NH3)6](BH4)2.nNH3BH3 (n = 2, 4, 6) were studied by thermal analysis and in situ SR-PXD. PMID- 26488153 TI - Structural and Chemical Dynamics of Pyridinic-Nitrogen Defects in Graphene. AB - High density and controllable nitrogen doping in graphene is a critical issue to realize high performance graphene-based devices. In this paper, we demonstrate an efficient method to selectively produce graphitic-N and pyridinic-N defects in graphene by using the mixture plasma of ozone and nitrogen. The atomic structure, electronic structure, and dynamic behavior of these nitrogen defects are systematically studied at the atomic level by using a scanning transmission electron microscopy. The pyridinic-N exhibits higher chemical activity and tends to trap a series of transition metal atoms (Mg, Al, Ca, Ti, Cr, Mn, and Fe) as individual atoms. PMID- 26488154 TI - Interactions among osteoblastic cells, Staphylococcus aureus, and chitosan immobilized titanium implants in a postoperative coculture system: An in vitro study. AB - Biomaterial-related infections (BRIs) have become a major challenge in the field of orthopedic implants. In this study, we delved into the problem of BRI and attempted to reduce the possibility of BRI incidence via surface modification of titanium (Ti) with chitosan (SA-CS-Ti). To comprehensively evaluate the anti infection potential of SA-CS-Ti, we first constructed a postoperative infection (POI) model with varying concentrations of bacteria (102 CFU/sample and 104 CFU/sample) and a constant number of SaOS-2 cells (105 /sample). Then, we biologically characterized the interactions between the SaOS-2 cells, bacteria, and different Ti implants using the POI model. The results from the osteoblastic cell and bacterial attachment tests demonstrated that the SA-CS-Ti surfaces exhibit superior osteogenic behavior relative to other Ti surfaces studied while showing significant anti-infective activities in the POI model with a low infection ratio (bacteria: cell ratio of 0.001:1) 30 min after infection. Additionally, the SA-CS-Ti surfaces showed significantly reduced (p < 0.05) bacteria proliferation compared to the control Ti surfaces (UN-Ti), demonstrating their antifouling property. The significantly increased (p < 0.05) sensitivity of Staphylococcus. aureus adhered to the SA-CS-Ti surfaces against cefazolin (1 mg/L treatment) and gentamicin (10 mg/L and 100 mg/L treatment) in the coculture system augmented potential of SA-CS-Ti to be used as orthopedic implants. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 586-594, 2016. PMID- 26488155 TI - A Comparative Study Between an Oil-in-Water Emulsion and Nonlipid Eye Drops Used for Rewetting Contact Lenses. AB - OBJECTIVES: The purpose of this study was to determine the clinical impact of using SYSTANE BALANCE Lubricant Eye Drops (Alcon, Fort Worth, TX), an oil-in water emulsion, as a rewetting eye drop in symptomatic contact lens wearers. METHODS: Subjects who had previously experienced contact lens discomfort (CLD), with a mean lens wearing history of 18.6+/-12.8 years, were randomly assigned to use a Test (SYSTANE BALANCE Lubricant Eye Drops; n=76) or control (habitual nonlipid contact lens rewetting eye drop; n=30) drop over their contact lenses within 5 min of lens insertion and then subsequently at 2 hr intervals up to a maximum of 4 drops per eye daily for a 1-month period. Assessments of subjective comfort, comfortable wearing time, lid wiper epitheliopathy (LWE), and corneal staining were conducted at baseline and after 1 month, after 6 hr of lens wear. RESULTS: Comfort, wearing time, LWE, and corneal staining all showed statistically significant improvements in the test group using SYSTANE BALANCE Lubricant Eye Drops at the 1-month visit compared with baseline data (all P<0.01) and compared with the control group at the 1-month visit (P<0.01, P=0.01, P<0.01, and P=0.03, respectively). CONCLUSIONS: The use of SYSTANE BALANCE Lubricant Eye Drops as a rewetting drop in a group of wearers who experienced symptoms of CLD improved subjective comfort scores, increased comfortable wearing time, and reduced signs of LWE and corneal staining, when compared with the use of non lipid-containing contact lens rewetting eye drops. PMID- 26488156 TI - Adsorptive Separation of Olefin/Paraffin Mixtures with ZIF-4. AB - The microporous zeolitic imidazolate framework ZIF-4 has been synthesized, and its ethylene/ethane and propylene/propane separation potentials have been evaluated by single-component adsorption isotherms and breakthrough experiments of the respective binary mixtures. In all experiments, a higher selectivity for the paraffin is observed that is manifested by a steeper equilibrium isotherm as well as a later breakthrough in the fixed-bed adsorber experiments. Microporous adsorbents with paraffin selectivity are rare but highly interesting for cyclic adsorption processes such as pressure-swing adsorption (PSA). PMID- 26488157 TI - Extensive Penetration of Evaporated Electrode Metals into Fullerene Films: Intercalated Metal Nanostructures and Influence on Device Architecture. AB - Although it is known that evaporated metals can penetrate into films of various organic molecules that are a few nanometers thick, there has been little work aimed at exploring the interaction of the common electrode metals used in devices with fullerene derivatives, such as organic photovoltaics (OPVs) or perovskite solar cells that use fullerenes as electron transport layers. In this paper, we show that when commonly used electrode metals (e.g., Au, Ag, Al, Ca, etc.) are evaporated onto films of fullerene derivatives (such as [6,6]-phenyl-C61-butyric acid methyl ester (PCBM)), the metal penetrates many tens of nanometers into the fullerene layer. This penetration decreases the effective electrical thickness of fullerene-based sandwich structure devices, as measured by the device's geometric capacitance, and thus significantly alters the device physics. For the case of Au/PCBM, the metal penetrates a remarkable 70 nm into the fullerene, and we see penetration of similar magnitude in a wide variety of fullerene derivative/evaporated metal combinations. Moreover, using transmission electron microscopy to observed cross-sections of the films, we show that when gold is evaporated onto poly(3-hexylthiophene) (P3HT)/PCBM sequentially processed OPV quasi-bilayers, Au nanoparticles with diameters of ~3-20 nm are formed and are dispersed entirely throughout the fullerene-rich overlayer. The plasmonic absorption and scattering from these nanoparticles are readily evident in the optical transmission spectrum, demonstrating that the interpenetrated metal significantly alters the optical properties of fullerene-rich active layers. This opens a number of possibilities in terms of contact engineering and light management so that metal penetration in devices that use fullerene derivatives could be used to advantage, making it critical that researchers are aware of the electronic and optical consequences of exposing fullerene-derivative films to evaporated electrode metals. PMID- 26488158 TI - Downregulation of Integrins in Cancer Cells and Anti-Platelet Properties Are Involved in Holothurian Glycosaminoglycan-Mediated Disruption of the Interaction of Cancer Cells and Platelets in Hematogenous Metastasis. AB - Activated platelets have been recognized as an accessory character in the cascade of tumor hematogenous metastasis, and intervention of tumor cell attachment to the activated platelets or microemboli formation might be a leading strategy to prevent tumor cells surviving in the blood vessels and sequential metastasis. Recently, we have demonstrated that holothurian glycosaminoglycan (hGAG), a sulfated polysaccharide with potent anticoagulant activity extracted from the sea cucumber Holothuria leucospilota Brandt, was highly efficacious against tumor metastasis. In this study, we identified the potential effects of hGAG on the disruption of interactions of cancer cells and platelets and the underlying mechanisms, which were supported by the following evidence: hGAG (1) inhibited thrombin-induced platelet activation and aggregation, (2) reduced adhesion between platelet and breast cancer cells, and abrogated platelets/cancer cells adhering to fibrinogen, (3) attenuated platelet-cancer cell complex formation (the number and size of aggregates) and (4) suppressed both mRNA and protein levels of beta1 and beta3 integrins, matrix metalloproteinase (MMP)-2 and MMP-9, while increasing the expression of the MMP inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 in MDA-MB-231 cells. These results suggested that both the antiplatelet properties and mitigation of the levels of cellular adhesion molecules contributed to the anticancer effects of hGAG, and might thus be exploited for clinical adjuvant therapy to attenuate tumor hematogenous metastasis. PMID- 26488160 TI - Conscious Sedation Using Midazolam and Sequential Flumazenil in Cirrhotic Patients for Prophylactic Endoscopic Variceal Ligation. AB - BACKGROUND/AIMS: This study investigated the safety of endoscopic variceal ligation (EVL) under conscious sedation with midazolam and sequential flumazenil after procedure in these patients. METHODS: A total of 279 patients who underwent secondary prophylactic EVL at our institution between April 2012 and June 2014, were enrolled. Conscious sedation was achieved using intravenous midazolam, and flumazenil was routinely used as an antidote immediately after EVL. Patients with sleep (n = 165) and non-sleep (n = 55) endoscopy were matched using propensity score analysis (3:1). Frequencies of overt hepatic encephalopathy (HEP) and patient' satisfactions with EVL were compared between the 2 groups. RESULTS: Of the 279 patients, 155 (55.6%) were of Child-Turcotte-Pugh (CTP) class, B or C, and 224 (80.3%) patients underwent sleep endoscopy. After propensity score analysis, overt HEP was observed in 1 (0.4%) of the 165 patients in the sedated group, but not found in any in the non-sedated group. Patient' satisfaction with EVL was better in the sedated group (p < 0.001). Twenty-nine (65.9%) of the 44 patients with CTP class C underwent sleep endoscopy, and only one (3.4%) experienced overt HEP. CONCLUSIONS: Prophylactic EVL under conscious sedation using midazolam and flumazenil is probably safe in cirrhotic patients without experience of HEP, even in those of CTP class C. PMID- 26488161 TI - Home Bodies and Wanderers: Sympatric Lineages of the Deep-Sea Black Coral Leiopathes glaberrima. AB - Colonial corals occur in a wide range of marine benthic habitats from the shallows to the deep ocean, often defining the structure of their local community. The black coral Leiopathes glaberrima is a long-lived foundation species occurring on carbonate outcrops in the Northern Gulf of Mexico (GoM). Multiple color morphs of L. glaberrima grow sympatrically in the region. Morphological, mitochondrial and nuclear ribosomal markers supported the hypothesis that color morphs constituted a single biological species and that colonies, regardless of color, were somewhat genetically differentiated east and west of the Mississippi Canyon. Ten microsatellite loci were used to determine finer-scale population genetic structure and reproductive characteristics. Gene flow was disrupted between and within two nearby (distance = 36.4 km) hardground sites and two sympatric microsatellite lineages, which might constitute cryptic species, were recovered. Lineage one was outbred and found in all sampled locations (N = 5) across 765.6 km in the Northern Gulf of Mexico. Lineage two was inbred, reproducing predominantly by fragmentation, and restricted to sites around Viosca Knoll. In these sites the lineages and the color phenotypes occurred in different microhabitats, and models of maximum entropy suggested that depth and slope influence the distribution of the color phenotypes within the Vioska Knolls. We conclude that L. glaberrima is phenotypically plastic with a mixed reproductive strategy in the Northern GoM. Such strategy might enable this long-lived species to balance local recruitment with occasional long-distance dispersal to colonize new sites in an environment where habitat is limited. PMID- 26488159 TI - Potential for Drug-Drug Interactions between Antiretrovirals and HCV Direct Acting Antivirals in a Large Cohort of HIV/HCV Coinfected Patients. AB - OBJECTIVES: Development of direct acting antivirals (DAA) offers new benefits for patients with chronic hepatitis C. The combination of these drugs with antiretroviral treatment (cART) is a real challenge in HIV/HCV coinfected patients. The aim of this study was to describe potential drug-drug interactions between DAAs and antiretroviral drugs in a cohort of HIV/HCV coinfected patients. METHODS: Cross-sectional study of all HIV/HCV coinfected patients attending at least one visit in 2012 in the multicenter French Dat'AIDS cohort. A simulation of drug-drug interactions between antiretroviral treatment and DAAs available in 2015 was performed. RESULTS: Of 16,634 HIV-infected patients, 2,511 had detectable anti-HCV antibodies, of whom 1,196 had a detectable HCV-RNA and were not receiving HCV treatment at the time of analysis. 97.1% of these patients were receiving cART and 81.2% had a plasma HIV RNA <50 copies/mL. cART included combinations of nucleoside reverse transcriptase inhibitors with a boosted protease inhibitor in 43.6%, a non-nucleoside reverse transcriptase inhibitor in 17.3%, an integrase inhibitor in 15.4% and various combinations or antiretroviral drugs in 23.7% of patients. A previous treatment against HCV had been administered in 64.4% of patients. Contraindicated associations/potential interactions were expected between cART and respectively sofosbuvir (0.2%/0%), sofosbuvir/ledipasvir (0.2%/67.6%), daclatasvir (0%/49.4%), ombitasvir/boosted paritaprevir (with or without dasabuvir) (34.4%/52.2%) and simeprevir (78.8%/0%). CONCLUSIONS: Significant potential drug-drug interactions are expected between cART and the currently available DAAs in the majority of HIV/HCV coinfected patients. Sofosbuvir/ledipasvir and sofosbuvir/daclatasvir with or without ribavirin appeared the most suitable combinations in our population. A close collaboration between hepatologists and HIV/AIDS specialists appears necessary for the management of HCV treatment concomitantly to cART. PMID- 26488163 TI - Sawfishes and Other Elasmobranch Assemblages from the Mio-Pliocene of the South Caribbean (Urumaco Sequence, Northwestern Venezuela). AB - The Urumaco stratigraphic sequence, western Venezuela, preserves a variety of paleoenvironments that include terrestrial, riverine, lacustrine and marine facies. A wide range of fossil vertebrates associated with these facies supports the hypothesis of an estuary in that geographic area connected with a hydrographic system that flowed from western Amazonia up to the Proto-Caribbean Sea during the Miocene. Here the elasmobranch assemblages of the middle Miocene to middle Pliocene section of the Urumaco sequence (Socorro, Urumaco and Codore formations) are described. Based on new findings, we document at least 21 taxa of the Lamniformes, Carcharhiniformes, Myliobatiformes and Rajiformes, and describe a new carcharhiniform species (?Carcharhinus caquetius sp. nov.). Moreover, the Urumaco Formation has a high number of well-preserved fossil Pristis rostra, for which we provide a detailed taxonomic revision, and referral in the context of the global Miocene record of Pristis as well as extant species. Using the habitat preference of the living representatives, we hypothesize that the fossil chondrichthyan assemblages from the Urumaco sequence are evidence for marine shallow waters and estuarine habitats. PMID- 26488162 TI - The Effect of Ginger (Zingiber officinale) on Platelet Aggregation: A Systematic Literature Review. AB - BACKGROUND: The potential effect of ginger on platelet aggregation is a widely cited concern both within the published literature and to clinicians; however, there has been no systematic appraisal of the evidence to date. METHODS: Using the PRISMA guidelines, we systematically reviewed the results of clinical and observational trials regarding the effect of ginger on platelet aggregation in adults compared to either placebo or baseline data. Studies included in this review stipulated the independent variable was a ginger preparation or isolated ginger compound, and used measures of platelet aggregation as the primary outcome. RESULTS: Ten studies were included, comprising eight clinical trials and two observational studies. Of the eight clinical trials, four reported that ginger reduced platelet aggregation, while the remaining four reported no effect. The two observational studies also reported mixed findings. DISCUSSION: Many of the studies appraised for this review had moderate risks of bias. Methodology varied considerably between studies, notably the timeframe studied, dose of ginger used, and the characteristics of subjects recruited (e.g. healthy vs. patients with chronic diseases). CONCLUSION: The evidence that ginger affects platelet aggregation and coagulation is equivocal and further study is needed to definitively address this question. PMID- 26488164 TI - Biogeographical Interpretation of Elevational Patterns of Genus Diversity of Seed Plants in Nepal. AB - This study tests if the biogeographical affinities of genera are relevant for explaining elevational plant diversity patterns in Nepal. We used simultaneous autoregressive (SAR) models to investigate the explanatory power of several predictors in explaining the diversity-elevation relationships shown in genera with different biogeographical affinities. Delta akaike information criterion (DeltaAIC) was used for multi-model inferences and selections. Our results showed that both the total and tropical genus diversity peaked below the mid-point of the elevational gradient, whereas that of temperate genera had a nearly symmetrical, unimodal relationship with elevation. The proportion of temperate genera increased markedly with elevation, while that of tropical genera declined. Compared to tropical genera, temperate genera had wider elevational ranges and were observed at higher elevations. Water-related variables, rather than mid domain effects (MDE), were the most significant predictors of elevational patterns of tropical genus diversity. The temperate genus diversity was influenced by energy availability, but only in quadratic terms of the models. Though climatic factors and mid-domain effects jointly explained most of the variation in the diversity of temperate genera with elevation, the former played stronger roles. Total genus diversity was most strongly influenced by climate and the floristic overlap of tropical and temperate floras, while the influences of mid-domain effects were relatively weak. The influences of water-related and energy-related variables may vary with biogeographical affinities. The elevational patterns may be most closely related to climatic factors, while MDE may somewhat modify the patterns. Caution is needed when investigating the causal factors underlying diversity patterns for large taxonomic groups composed of taxa of different biogeographical affinities. Right-skewed diversity-elevation patterns may be produced by the differential response of taxa with varying biogeographical affinities to climatic factors and MDE. PMID- 26488165 TI - Influence of Development and Dietary Phospholipid Content and Composition on Intestinal Transcriptome of Atlantic Salmon (Salmo salar). AB - The inclusion of intact phospholipids in the diet is essential during larval development and can improve culture performance of many fish species. The effects of supplementation of dietary phospholipid from marine (krill) or plant (soy lecithin) sources were investigated in Atlantic salmon, Salmo salar. First feeding fry were fed diets containing either krill oil or soybean lecithin supplying phospholipid at 2.6%, 3.2%, 3.6% and 4.2% of diet. Fish were sampled at ~ 2.5 g (~1,990 degrees day post fertilization, dpf) and ~10 g (2,850 degrees dpf). By comparison of the intestinal transcriptome in specifically chosen contrasts, it was determined that by 2,850 degrees dpf fish possessed a profile that resembled that of mature and differentiated intestinal cell types with a number of changes specific to glycerophospholipid metabolism. It was previously shown that intact phospholipids and particularly phosphatidylcholine are essential during larval development and that this requirement is associated with the inability of enterocytes in young fry to endogenously synthesize sufficient phospholipid for the efficient export of dietary lipid. In the immature phase (~1,990 degrees dpf), the dietary phospholipid content as well as its class composition impacted on several biochemical and morphological parameters including growth, but these differences were not associated with differences in intestinal transcriptomes. The results of this study have made an important contribution to our understanding of the mechanisms associated with lipid transport and phospholipid biosynthesis in early life stages of fish. PMID- 26488167 TI - Correction: Selecting One of Several Mating Types through Gene Segment Joining and Deletion in Tetrahymena thermophila. PMID- 26488166 TI - Proactive and Reactive Response Inhibition across the Lifespan. AB - One expression of executive control involves proactive preparation for future events, and this contrasts with stimulus driven reactive control exerted in response to events. Here we describe findings from a response inhibition task, delivered using a smartphone-based platform, that allowed us to index proactive and reactive inhibitory self-control in a large community sample (n = 12,496). Change in stop-signal reaction time (SSRT) when participants are provided with advance information about an upcoming trial, compared to when they are not, provides a measure of proactive control while SSRT in the absence of advance information provides a measure of reactive control. Both forms of control rely on overlapping frontostriatal pathways known to deteriorate in healthy aging, an age related decline that occurs at an accelerated rate in men compared to women. Here we ask whether these patterns of age-related decline are reflected in similar changes in proactive and reactive inhibitory control across the lifespan. As predicted, we observed a decline in reactive control with natural aging, with a greater rate of decline in men compared to women (~10 ms versus ~8 ms per decade of adult life). Surprisingly, the benefit of preparation, i.e. proactive control, did not change over the lifespan and women showed superior proactive control at all ages compared to men. Our results suggest that reactive and proactive inhibitory control partially rely on distinct neural substrates that are differentially sensitive to age-related change. PMID- 26488168 TI - Does School-Based Health Promotion Affect Physical Activity on Weekends? And, Does It Reach Those Students Most in Need of Health Promotion? AB - OBJECTIVE: To determine whether a school-based health promotion program affects children's weekend physical activity and whether this effect varies according to socioeconomic-status. METHODS: This was a quasi-experimental trial of school based programs on physical activity levels implemented in disadvantaged neighborhoods in Alberta, Canada. In 2009 and 2011, 7 full days of pedometer data were collected from cross-sectional samples of grade 5 students (age 10-11 years) from 10 intervention schools in low-socioeconomic neighbourhoods and 20 comparison schools in middle-socioeconomic neighbourhoods. Multilevel models assessed differences in step-counts between intervention and comparison groups over-time by weight (objectively measured) and socioeconomic status subgroups. RESULTS: In 2009, children from intervention schools were less active on weekends relative to comparison schools (9212 vs. 11186 steps/day p<0.01). Two years later, daily step-counts on weekend days among children in low socioeconomic intervention schools increased such that they approximated those of children from middle socioeconomic comparison schools (12148 vs. 12121 steps/day p = 0.96). The relative difference in steps between intervention and comparison schools on weekends reduced from -21.4% to 0.2% following the intervention. The normalization of weekend step counts was similar for normal weight (-21.4% to +2.0%) and overweight (-19.1 to +3.9%) children, and was balanced across socioeconomic subgroups. CONCLUSIONS: These data suggest that school-based health promotion is effective for reducing inequities in physical activity levels outside school hours. Investments in school-based health promotion lead to behavior modification beyond the school environment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01914185. PMID- 26488170 TI - Inequality as a Powerful Predictor of Infant and Maternal Mortality around the World. AB - BACKGROUND: Maternal and infant mortality are highly devastating, yet, in many cases, preventable events for a community. The human development of a country is a strong predictor of maternal and infant mortality, reflecting the importance of socioeconomic factors in determinants of health. Previous research has shown that the Human Development Index (HDI) predicts infant mortality rate (IMR) and the maternal mortality ratio (MMR). Inequality has also been shown to be associated with worse health in certain populations. The main purpose of the present study was to determine the correlation and predictive power of the Inequality Adjusted Human Development Index (IHDI) as a measure of inequality with the Infant Mortality Rate (IMR), Maternal Mortality Rate (MMR), Early Neonatal Mortality Rate (ENMR), Late Neonatal Mortality Rate (LNMR), and the Post Neonatal Mortality Rate (PNMR). METHODS AND FINDINGS: Data for the present study were downloaded from two sources: infant and maternal mortality data were downloaded from the Global Burden of Disease 2013 Cause of Death Database and the Human Development Index (HDI) and Inequality-Adjusted Human Development Index (IHDI) data were downloaded from the United Nations Development Program (UNDP). Pearson correlation coefficients were estimated, following logarithmic transformations to the data, to examine the relationship between HDI and IHDI with MMR, IMR, ENMR, LNMR, and PNMR. Steiger's Z test for the equality of two dependent correlations was utilized in order to determine whether the HDI or IHDI was more strongly associated with the outcome variables. Lastly, we constructed OLS regression models in order to determine the predictive power of the HDI and IHDI in terms of the MMR, IMR, ENMR, LNMR, and PNMR. Maternal and infant mortality were both strongly and negatively correlated with both HDI and IHDI; however, Steiger's Z test for the equality of two dependent correlations revealed that IHDI was more strongly correlated than HDI with MMR (Z = 4.897, p < 0.001), IMR (Z = 2.524, p = 0.012), ENMR (Z = 2.936, p = 0.003), LNMR (Z = 2.272, p = 0.023), and PNMR (Z = 2.277, p = 0.023). Furthermore, side-by-side OLS regression models revealed that, when IHDI was used as the predictor variable instead of HDI, the R2 value was 0.053 higher for MMR, 0.025 higher for IMR, 0.038 higher for ENMR, 0.029 higher for LNMR, and 0.026 higher for PNMR. CONCLUSIONS: Even when both the HDI and the IHDI correlate with the infant and maternal mortality rates, the IHDI is a better predictor for these two health indicators. Therefore, these results add more evidence that inequality is playing an important role in determining the health status of various populations in the world and more efforts should be put into programs to fight inequality. PMID- 26488169 TI - An Emerging Approach for Parallel Quantification of Intracellular Protozoan Parasites and Host Cell Characterization Using TissueFAXS Cytometry. AB - Characterization of host-pathogen interactions is a fundamental approach in microbiological and immunological oriented disciplines. It is commonly accepted that host cells start to change their phenotype after engulfing pathogens. Techniques such as real time PCR or ELISA were used to characterize the genes encoding proteins that are associated either with pathogen elimination or immune escape mechanisms. Most of such studies were performed in vitro using primary host cells or cell lines. Consequently, the data generated with such approaches reflect the global RNA expression or protein amount recovered from all cells in culture. This is justified when all host cells harbor an equal amount of pathogens under experimental conditions. However, the uptake of pathogens by phagocytic cells is not synchronized. Consequently, there are host cells incorporating different amounts of pathogens that might result in distinct pathogen-induced protein biosynthesis. Therefore, we established a technique able to detect and quantify the number of pathogens in the corresponding host cells using immunofluorescence-based high throughput analysis. Paired with multicolor staining of molecules of interest it is now possible to analyze the infection profile of host cell populations and the corresponding phenotype of the host cells as a result of parasite load. PMID- 26488172 TI - sPLA2-IIA Augments Oxidized LDL-Induced MCP-1 Expression in Vitro Through Activation of Akt. AB - BACKGROUND/AIMS: Group IIA secretory phospholipase A2 (sPLA2-IIA) has an important role in atherosclerosis. In this study, we explored whether sPLA2-IIA overexpression could promote atherosclerosis in normal environment alone or with other inflammatory factors. METHODS: Human aortic smooth muscle cells (HASMCs) were transduced with Lv-GFP-sPLA2-IIA, a plasmid containing sPLA2-IIA coupled with green fluorescent protein (GFP). Cells were incubated in the presence or absence of oxidized low-density lipoprotein (LDL), sPLA2 inhibitor LY315920 or PI3K/Akt inhibitor LY294002. The mRNA expression and protein secretion of monocyte chemoattractant protein-1 (MCP-1) were assessed by quantitative real time polymerase chain reaction (QRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Phosphorylation of Akt was examined by western blotting. RESULTS: Lv-GFP-sPLA2-IIA-transduced HASMCs remained fluorescent during 72 h of the study period with infection ratio of around 80%. The mRNA expression and protein secretion of MCP-1 was not altered in groups of HASMCs, Lv-GFP transduced and Lv-GFP-sPLA2-IIA-transduced HASMCs (p>0.05), but was significantly increased in the presence of oxidized LDL especially in Lv-GFP-sPLA2-IIA transduction group (p<0.01). However, with the addition of LY315920, this enhancement was notably decreased (p<0.05). This enhancement was also markedly abolished by co-incubation with LY294002, paralleled with suppressed Akt phosphorylation. CONCLUSIONS: Overexpression of sPLA2-IIA does not alter MCP-1 level at baseline, but could enhance the atherogenic effect of oxidized LDL in HASMCs, at least partly due to activation of Akt. These findings may provide a strategy for treatment of inflammatory cardiovascular diseases. PMID- 26488171 TI - Postsynaptic VAMP/Synaptobrevin Facilitates Differential Vesicle Trafficking of GluA1 and GluA2 AMPA Receptor Subunits. AB - Vertebrate organisms adapt to a continuously changing environment by regulating the strength of synaptic connections between brain cells. Excitatory synapses are believed to increase their strength by vesicular insertion of transmitter glutamate receptors into the postsynaptic plasma membrane. These vesicles, however, have never been demonstrated or characterized. For the first time, we show the presence of small vesicles in postsynaptic spines, often closely adjacent to the plasma membrane and PSD (postsynaptic density). We demonstrate that they harbor vesicle-associated membrane protein 2 (VAMP2/synaptobrevin-2) and glutamate receptor subunit 1 (GluA1). Disrupting VAMP2 by tetanus toxin treatment reduces the concentration of GluA1 in the postsynaptic plasma membrane. GluA1/VAMP2-containing vesicles, but not GluA2/VAMP2-vesicles, are concentrated in postsynaptic spines relative to dendrites. Our results indicate that small postsynaptic vesicles containing GluA1 are inserted directly into the spine plasma membrane through a VAMP2-dependent mechanism. PMID- 26488173 TI - General Rules for the Clinical and Pathological Study of Primary Liver Cancer, Nationwide Follow-Up Survey and Clinical Practice Guidelines: The Outstanding Achievements of the Liver Cancer Study Group of Japan. AB - This review outlines the significance of establishing general rules, a nationwide follow-up survey, and clinical practice guidelines for liver cancer in Japan. The general rules are an essential part of hepatocellular carcinoma (HCC) treatment, enabling a 'common language' to be used in daily clinical practice and for the nationwide follow-up survey. The Japanese General Rules for the Clinical and Pathological Study of Primary Liver Cancer, which provide detailed descriptions of HCC, are excellent and are unique to Japan. Items in the General Rules for the Clinical and Pathological Study of Primary Liver Cancer are used substantially in another important project, the Nationwide Follow-Up Survey of Primary Liver Cancer, which has been rigorously undertaken with great effort by the Liver Cancer Study Group of Japan biannually since 1969. Both evidence-based and consensus-based treatment algorithms for HCC are used to complement each other in clinical practice in Japan. PMID- 26488175 TI - Simultaneous Increases in Proliferation and Apoptosis of Vascular Smooth Muscle Cells Accelerate Diabetic Mouse Venous Atherosclerosis. AB - AIMS: This study was designed to demonstrate simultaneous increases in proliferation and apoptosis of vascular smooth muscle cells (VSMCs) leading to accelerated vein graft remodeling and to explore the underlying mechanisms. METHODS: Vein grafts were performed in non-diabetic and diabetic mice. The cultured quiescent VSMCs were subjected to mechanical stretch stress (SS) and/or advanced glycosylation end products (AGEs). Harvested vein grafts and treated VSMCs were used to detect cell proliferation, apoptosis, mitogen-activated protein kinases (MAPKs) activation and SM-alpha-actin expression. RESULTS: Significantly thicker vessel walls and greater increases in proliferation and apoptosis were observed in diabetic vein grafts than those in non-diabetic. Both SS and AGEs were found to induce different activation of three members of MAPKs and simultaneous increases in proliferation and apoptosis of VSMCs, and combined treatment with both had a synergistic effect. VSMCs with strong SM-alpha-actin expression represented more activated JNKs or p38MAPK, and cell apoptosis, while the cells with weak SM-alpha-actin expression demonstrated preferential activation of ERKs and cell proliferation. In contrast, inhibition of MAPKs signals triggered significant decreases in VSMC proliferation, and apoptosis. Treatment of the cells with RNA interference of receptor of AGEs (RAGE) also resulted in significant decreases in both proliferation and apoptosis. CONCLUSIONS: Increased pressure-induced SS triggers simultaneous increases in proliferation and apoptosis of VSMCs in the vein grafts leading to vein arterializations, which can be synergistically accelerated by high glucose induced AGEs resulting in vein graft atherosclerosis. Either SS or AGEs and their combination induce simultaneous increases in proliferation and apoptosis of VSMCs via different activation of three members of MAPKs resulting from different VSMC subtypes classified by SM-alpha-actin expression levels. PMID- 26488176 TI - Relationship between Polycystic Ovarian Syndrome and Subsequent Gestational Diabetes Mellitus: A Nationwide Population-Based Study. AB - OBJECTIVE: This nationwide population-based study aims to explore the relationship between polycystic ovarian syndrome (PCOS) and subsequent gestational diabetes mellitus (GDM). METHODS: Data from 1998-2012 Taiwan National Health Insurance Research Database were used for this study. ICD9-CM codes 256.4X and 648.X were used separately for the diagnoses of PCOS and GDM, which were further confirmed by records of blood tests or ultrasonography to ensure the accuracy of the diagnoses. Women diagnosed at < 15 or > 45 years of age, and those diagnosed with overt diabetes mellitus or GDM prior to PCOS were excluded. During pregnancy, each woman with a previous diagnosis of PCOS was age-matched to 10 women without PCOS. Odds ratios (ORs) for risk of GDM were calculated by logistic regression analysis with adjustment for economic status and co morbidities. RESULTS: Among 7,629 eligible women with a valid PCOS diagnosis, 3,109 (42.87%) had subsequent pregnancies. GDM occurred frequently among women with a history of PCOS as compared to those without PCOS (20.46% vs. 10.54%, p<0.0001). Logistic regression analysis revealed that PCOS was associated with GDM (adjusted OR = 2.15; 95% CI:1.96-2.37). Among 3,109 affected patients, 1,160 (37.31%) had used medications for PCOS and 261 (8.39%) were treated with an oral hypoglycemic agent (OHA). There was no significant difference in development of GDM between the medication and no medication sub-groups (p>0.05). If not used after conception, OHAs did not reduce the risk of GDM (adjusted OR = 1.20; 95% CI:0.88-1.62). CONCLUSIONS: A history of PCOS is a significant and independent risk factor for development of GDM. Medication for PCOS or pre-pregnancy use of OHAs does not reduce the risk of GDM. When at-risk women become pregnant, they require closer surveillance for maternal and fetal well-being, and should follow a strict diet and adhere to weight gain control to avoid obstetric complications due to GDM. PMID- 26488177 TI - Soft Discoidal Polymeric Nanoconstructs Resist Macrophage Uptake and Enhance Vascular Targeting in Tumors. AB - Most nanoparticles for biomedical applications originate from the self-assembling of individual constituents through molecular interactions and possess limited geometry control and stability. Here, 1000 * 400 nm discoidal polymeric nanoconstructs (DPNs) are demonstrated by mixing hydrophobic and hydrophilic polymers with lipid chains and curing the resulting paste directly within silicon templates. By changing the paste composition, soft- and rigid-DPNs (s- and r DPNs) are synthesized exhibiting the same geometry, a moderately negative surface electrostatic charge (-14 mV), and different mechanical stiffness (~1.3 and 15 kPa, respectively). Upon injection in mice bearing nonorthotopic brain or skin cancers, s-DPNs exhibit ~24 h circulation half-life and accumulate up to ~20% of the injected dose per gram tumor, detecting malignant masses as small as ~0.1% the animal weight via PET imaging. This unprecedented behavior is ascribed to the unique combination of geometry, surface properties, and mechanical stiffness which minimizes s-DPN sequestration by the mononuclear phagocyte system. Our results could boost the interest in using less conventional delivery systems for cancer theranosis. PMID- 26488178 TI - Should the Dose of Antiplatelet Drugs Be Adjusted for Body Weight? The Example of Vorapaxar. AB - BACKGROUND: In contrast to the vast majority of pharmaceuticals on the market, antiplatelet agents are widely prescribed in a uniform, 'one size fits all' manner, without conventional dose adjustments. However, strong evidence yielded from clinical trials repeatedly suggests that patients with a low body weight (LBW), the elderly and those with renal or hepatic impairment may benefit from reduced doses, while younger, heavier patients, males and diabetics may benefit from a dose escalation. Vorapaxar, a thrombin protease-activated receptor-1 inhibitor, has been tested in the TRA2P and TRACER clinical trials, but its efficacy and safety in patients with a LBW is unclear. OBJECTIVE: To determine the impact of LBW on primary end point rates (PER) and bleeding risk after vorapaxar, as yielded from the TRA2P and TRACER secondary FDA review. RESULTS: The LBW (<60 kg) groups in TRA2P (n = 1,852; 7%) and TRACER (n = 1,046; 8%) were small. However, the PER repeatedly suggested inferiority of vorapaxar over placebo in both the successful TRA2P study (10.6 vs. 8.4%; p = 0.012) and the failed TRACER study (19.3 vs. 18.2%; p = not significant). In TRA2P, the PER monotonically escalated with increasing weight for placebo, while those in the vorapaxar arm formed a flat U- or J-shaped distribution across the weight quintiles. In TRACER, the PER by weight quintile appear much higher, but also more random than in TRA2P. The bleeding rates in TRA2P were higher for the 2 lowest-weight quintiles with both placebo and vorapaxar. In TRACER, bleeding rates were more than doubled when compared to TRA2P, and they varied little by weight quintile, with a slight decrease for the heaviest patients in the placebo population and being the highest in the 2 lowest-weight quintiles after vorapaxar. CONCLUSION: The FDA analyses revealed no definite proof that LBW is associated with reduced efficacy of vorapaxar. While these data are striking, they can be explained by better outcomes in LBW placebo patients already sufficiently treated with dual-antiplatelet therapy. In contrast to efficacy, both TRA2P and TRACER definitely suggest that bleeding rates after vorapaxar are higher in patients with LBW. Dose adjustment for antiplatelet agents may soon become a reality. PMID- 26488180 TI - Linearly Polymerized Benzene Arrays As Intermediates, Tracing Pathways to Carbon Nanothreads. AB - How might fully saturated benzene polymers of composition [(CH)6]n form under high pressure? In the first approach to answering this question, we examine the stepwise increase in saturation of a one-dimensional stack of benzene molecules by enumerating the partially saturated polymer intermediates, subject to constraints of unit cell size and energy. Defining the number of four-coordinate carbon atoms per benzene formula unit as the degree of saturation, a set of isomers for degree-two and degree-four polymers can be generated by either thinking of the propagation of partially saturated building blocks or by considering a sequence of cycloadditions. There is also one 4 + 2 reaction sequence that jumps directly from a benzene stack to a degree-four polymer. The set of degree-two polymers provides several useful signposts toward achieving full saturation: chiral versus achiral building blocks, certain forms of conformational freedom, and also dead ends to further saturation. These insights allow us to generate a larger set of degree-four polymers and enumerate the many pathways that lead from benzene stacks to completely saturated carbon nanothreads. PMID- 26488181 TI - Divergent Gemycircularvirus in HIV-Positive Blood, France. PMID- 26488182 TI - 2,6-Pyridodicarboxamide-Bridged Triptycene Molecular Transmission Devices: Converting Rotation to Rocking Vibration. AB - A series of N(2),N(6)-bis(triptycene-9-yl)pyridine-2,6-dicarboxamides 1-4 were designed and synthesized. Due to rotational constraint of the 2,6-diamidopyridine bridge, the triptycene components in the systems are held together. X-ray structures of 1-4 show that the molecules adopt a gear-like geometry in the solid states. DFT (B3LYP/6-31G(d)) calculations predict the gear-like C2 conformation as global minimum structures for 1 and 2 and suggest that, through a slippage transition process, rotation of one triptycene component would give rise to a rocking vibration of the counter component due to the barrier for rotation of the triptycene components. VT NMR studies on 1-4 show that the pair of triptycene components undergo ceaseless slippage at room temperature but nearly freeze at temperatures as low as 183 K. Decreasing the temperature freezes the slippage between triptycene components as well, thus producing the appearance of phase isomers of 3 and 4. The dynamic features of the studied molecules indicate that this kind of molecule is able to function as a kind of molecular transmission device for transforming the mode of motion from rotation to rocking vibration. PMID- 26488179 TI - The Features of Genetic Prion Diseases Based on Chinese Surveillance Program. AB - OBJECTIVE: To identify the features of Chinese genetic prion diseases. METHODS: Suspected Creutzfeldt-Jakob disease (CJD) cases that were reported under CJD surveillance were diagnosed and subtyped using the diagnostic criteria issued by the WHO. The general information concerning the patient, their clinical, MRI and EEG data, and the results of CSF 14-3-3 and PRNP sequencing were carefully collected from the database of the national CJD surveillance program and analyzed using the SPSS 11.5 statistical software program. RESULTS: Since 2006, 69 patients were diagnosed with genetic prion diseases and as having 15 different mutations. The median age of the 69 patients at disease onset was 53.5 years, varying from 19 to 80 years. The majority of patients displaying clinical symptoms were in the 50-59 years of age. FFI, T188K gCJD and E200K were the three most common subtypes. The disease appeared in the family histories of 43.48% of the patients. The clinical manifestations varied considerably among the various diseases. Patients who carried mutations in the N-terminus displayed a younger age of onset, were CSF 14-3-3 negative, had a family history of the condition, and experienced a longer duration of the condition. The clinical courses of T188K were significantly shorter than those of FFI and E200K gCJD, while the symptoms in the FFI group appeared at a younger age and for a longer duration. Moreover, the time intervals between the initial neurologist visit to the final diagnosis were similar among patients with FFI, T188K gCJD, E200K gCJD and other diseases. CONCLUSION: The features of Chinese genetic prion diseases are different from those seen in Europe and other Asian countries. PMID- 26488183 TI - Taming Healthcare Costs: Promise and Pitfalls for Women's Health. AB - When it comes to healthcare, women are often the primary decision makers for their families. Therefore, focusing on women and their health needs can have a profound effect on health reform efforts to control costs and improve quality for all segments of the population. The promise and pitfalls of cost containment reform in Massachusetts can serve as an informative case study for policymakers at the local, state, and federal levels as they attempt to reduce costs while maintaining quality of care. Massachusetts cost containment law, Chapter 224, seeks to control the healthcare cost growth through innovative approaches to increase efficiency and transparency including the adoption of new delivery system models, investments in wellness and prevention programs, and implementation of standard quality and evaluation measures. In this paper, we outline four approaches to delivering on the promise of cost containment reform to maximize women's access to comprehensive, quality healthcare while avoiding the pitfalls of cost containment's adverse impact on women's health. PMID- 26488184 TI - New cytotoxic clerodane diterpenes from the leaves of Premna tomentosa. AB - Bio-activity directed investigation of hexane extract from the leaves of Premna tomentosa led to the isolation of three new clerodane diterpenes (1-3) along with four known compounds (4-7). The structures of new compounds were established using IR, MS, 1D, and 2D NMR techniques. The in vitro cytotoxicity of the crude hexane extract and the isolated compounds were evaluated against seven human cancer cell lines and results indicated that compounds 2 and 4 depicted significant cytotoxicity against hepatocellular carcinoma cell line. PMID- 26488185 TI - Correction to Evidence of sigma- and pi-Dimerization in a Series of Phenalenyls. PMID- 26488186 TI - The cost-effectiveness of ustekinumab for moderate-to-severe psoriasis. AB - Given its chronicity and impact on quality of life, psoriasis is a costly disease. As new and better treatments are developed, the cost of treating psoriasis has risen. In this drug profile, the authors discuss ustekinumab, its pharmacokinetics, safety profile, and direct and indirect costs to determine its cost-efficacy. The authors searched PubMed with specific search phrases for clinical trials investigating this issue over 5 years. Eleven articles analyzed cost-effectiveness of ustekinumab, and the references of these articles were included. Studies limited to 12 weeks reported that ustekinumab may not be cost effective as it has high cost per injection and is costly when loading doses are required. Studies that went beyond 12 weeks documented that, with ustekinumab's infrequent dosing, it is cost-effective during the maintenance period. PMID- 26488187 TI - Innate Lymphoid Cells Are the Predominant Source of IL-17A during the Early Pathogenesis of Acute Respiratory Distress Syndrome. AB - RATIONALE: IL-17A is purported to help drive early pathogenesis in acute respiratory distress syndrome (ARDS) by enhancing neutrophil recruitment. Although IL-17A is the archetypal cytokine of T-helper 17 cells, it is produced by a number of lymphocytes, the source during ARDS being unknown. OBJECTIVES: To identify the cellular source and the role of IL-17A in the early phase of lung injury. METHODS: Lung injury was induced in wild-type (C57BL/6) and IL-17 knockout (KO) mice with aerosolized LPS (100 MUg) or Pseudomonas aeruginosa infection. Detailed phenotyping of the cells expressing RORgammat, the transcriptional regulator of IL-17 production, in the mouse lung at 24 hours was performed by flow cytometry. MEASUREMENTS AND MAIN RESULTS: A 100-fold reduction in neutrophil infiltration was observed in the lungs of the IL-17A KO compared with wild-type mice. The majority of RORgammat(+) cells in the mouse lung were the recently identified group 3 innate lymphoid cells (ILC3s). Detailed characterization revealed these pulmonary ILC3s (pILC3s) to be discrete from those described in the gut. The critical role of these cells was verified by inducing injury in recombinase-activating gene 2 KO mice, which lack T cells but retain innate lymphoid cells. No amelioration of pathology was observed in the recombinase-activating gene 2 KO mice. CONCLUSIONS: IL-17 is rapidly produced during lung injury and significantly contributes to early immunopathogenesis. This is orchestrated largely by a distinct population of pILC3s. Modulation of the activity of pILC3s may potentiate early control of the inflammatory dysregulation seen in ARDS, opening up new therapeutic targets. PMID- 26488188 TI - Geotechnical behaviour of low-permeability soils in surfactant-enhanced electrokinetic remediation. AB - Electrokinetic processes provide the basis of a range of very interesting techniques for the remediation of polluted soils. These techniques consist of the application of a current field in the soil that develops different transport mechanisms capable of mobilizing several types of pollutants. However, the use of these techniques could generate nondesirable effects related to the geomechanical behavior of the soil, reducing the effectiveness of the processes. In the case of the remediation of polluted soils with plasticity index higher than 35, an excessive shrinkage can be observed in remediation test. For this reason, the continued evaporation that takes place in the sample top can lead to the development of cracks, distorting the electrokinetic transport regime, and consequently, the development of the operation. On the other hand, when analyzing silty soils, in the surroundings of injection surfactant wells, high seepages can be generated that give rise to the development of piping processes. In this article methods are described to allow a reduction, or to even eliminate, both problems. PMID- 26488189 TI - [New Dutch guideline on spinal metastasis: extended to include spinal localisations of haematological malignancies]. AB - In 2015, the Dutch Neuro-Oncology Working Group produced the multidisciplinary evidence-based guideline 'Spinal metastasis'. The guideline applies to patients with spinal metastases of solid tumours and patients with spinal localisations of haematological malignancies. This article gives a short overview of some key recommendations in the areas of diagnostics, treatment and follow-up. PMID- 26488190 TI - [Alarm symptoms of spinal metastases in patients with cancer]. AB - Recently, the evidence-based guideline 'Spinal metastasis' produced by the Dutch National Working Group on Neuro-Oncology appeared. This guideline applies to patients with spinal metastases and spinal localizations of haematological malignancies, with or without epidural extension. Timely diagnosis and treatment of spinal metastases is essential in order to reduce pain and neurological deficit in particular. An important aim of this guideline is to reduce both patient and doctor delay by providing information to high-risk patients and their general practitioners and to give clear advice on the organization of care. In this case report we describe two patients with spinal metastases in order to illustrate the difficulties in providing a timely diagnosis and optimal treatment for symptomatic spinal metastases. Furthermore, we provide advice to all health care professionals involved to secure the highest possible quality of life for patients with spinal metastases. PMID- 26488192 TI - [Axillary lymph node dissection versus axillary radiotherapy in patients with a positive sentinel node: the AMAROS trial]. AB - OBJECTIVE: To investigate whether axillary radiotherapy (ART) in patients with primary breast cancer and a tumour-positive sentinel node results in a similar axillary tumour recurrence rate compared with axillary lymph node dissection (ALND), and whether ART results in lower morbidity. DESIGN: Randomised, multicentre non-inferiority trial. METHOD: Patients with breast cancer <= 5 cm without clinical signs of lymph node metastases but with a tumour-positive sentinel node were randomised between ALND or ART. The primary endpoint was the 5 year axillary recurrence rate. Secondary endpoints were disease-free survival, overall survival, morbidity (lymphoedema and shoulder function) and quality of life. (www.clinicaltrials.gov, study number NCT00014612.) RESULTS: Between 2001 and 2010, 1425 patients with a tumour-positive sentinel node were included, 744 of whom had been randomised to ALND and 681 to ART. After a median follow-up period of 6.1 years, the 5-year axillary recurrence rate was 0.43% after ALND and 1.19% after ART; the difference was not statistically significant. The primary analysis was underpowered due to the low number of axillary recurrences. At 5 years the disease-free survival rate was 86.9% after ALND and 82.7% after ART. Overall survival was 93.3% and 92.5% respectively. Lymphoedema was noted significantly more often after ALND than after ART at 1 year, 3 years and 5 years. There were no significant differences in shoulder function or quality of life. CONCLUSION: Both ART and ALND produce very low axillary recurrence rates in patients with breast cancer <= 5 cm and a tumour-positive sentinel node. ART results in significantly less lymphoedema than ALND. PMID- 26488191 TI - [No need to spare the arm after axillary dissection: the prohibition on interventions such as venepuncture is obsolete]. AB - Annually, around 11,500 patients are treated surgically for breast cancer. In the past, 5-25% of these underwent an axillary dissection. This procedure can entail complications such as lymphoedema. Known risk factors are obesity and infections or wounds in the arm concerned. There is a traditional assumption that interventions on this arm, such as venepuncture, infusion or measurement of blood pressure, may induce lymphoedema. This assumption has been queried in recent years. Based on our analysis of the current literature, we believe that the above mentioned interventions after non-complicated axillary dissection do not increase the risk of lymphoedema or other complications. We recommend changing the policy that prohibits interventions such as venepuncture after axillary dissection. PMID- 26488193 TI - [Oocyte vitrification: for whom?]. AB - OBJECTIVE: To study the indications of oocyte vitrification in women who undergo this intervention. DESIGN: Cross-sectional study. METHOD: We collected the indications of oocyte vitrification in women who underwent, or started ovarian stimulation for, this intervention between May 2006 and December 31st 2013. Indications were subcategorized into six groups: no sperm available during IVF or ICSI treatment, planned gonadotoxic therapy, ovarian surgery, risk on premature ovarian insufficiency , previous gonadotoxic therapy, and anticipated gamete exhaustion. RESULTS: During the study period 298 women vitrified oocytes or started with ovarian stimulation for oocyte vitrification. The majority of the women (33%) vitrified oocytes because of anticipated gamete exhaustion. Planned gonadotoxic treatment was for 81 women (27%) the reason for oocyte vitrification. CONCLUSION: With oocyte vitrification women are able to extend the time at which they can conceive. The future will tell whether the benefits of oocyte vitrification outweigh the risks and costs. PMID- 26488194 TI - [Axillary treatment in breast cancer: surgery, radiotherapy, or none of these?]. AB - The AMAROS trial showed that substituting axillary lymph node dissection by radiotherapy of the axillary and periclavicular nodes (ART) in patients with sentinel node (SN) metastases results in less lymphoedema, without a significant difference in the 5-year axillary recurrence rate (ARR). Three surgical studies showed no increase in ARR after omitting axillary treatment in cases of limited SN metastases, provided that adjuvant systemic therapy and tangential breast radiotherapy were applied. On the other hand, several recent radiotherapy trials, including a meta-analysis by the Early Breast Cancer Trialists' Collaborative Group, showed that regional radiotherapy improves disease-free survival where there are positive axillary nodes. In view of the low ARR and good overall survival with contemporary breast cancer treatments, limiting axillary treatment and its associated morbidity is a logical development. However, it is too early to omit axillary treatment in all SN-positive patients. ART is a safe next step in reducing axillary treatment. PMID- 26488195 TI - Association of Higher MERS-CoV Virus Load with Severe Disease and Death, Saudi Arabia, 2014. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) causes a spectrum of illness. We evaluated whether cycle threshold (Ct) values (which are inversely related to virus load) were associated with clinical severity in patients from Saudi Arabia whose nasopharyngeal specimens tested positive for this virus by real-time reverse transcription PCR. Among 102 patients, median Ct of 31.0 for the upstream of the E gene target for 41 (40%) patients who died was significantly lower than the median of 33.0 for 61 survivors (p=0.0087). In multivariable regression analyses, risk factors for death were age>60 years), underlying illness, and decreasing Ct for each 1-point decrease in Ct). Results were similar for a composite severe outcome (death and/or intensive care unit admission). More data are needed to determine whether modulation of virus load by therapeutic agents affects clinical outcomes. PMID- 26488196 TI - Economic impact of using fesoterodine for the treatment of overactive bladder with urge urinary incontinence in a vulnerable elderly population in the United States. AB - OBJECTIVES: To assess the costs of treating overactive bladder (OAB) with fesoterodine compared to no OAB pharmacotherapy among vulnerable elderly from the US payer perspective. METHODS: A decision analytic cost model was developed to estimate the 52-week costs of a cohort of vulnerable elderly with OAB initiating treatment with fesoterodine or no OAB pharmacotherapy. Vulnerable elderly OAB patients were defined as those aged >=65 years with self-reported urge urinary incontinence (UUI) symptoms for >=3 months, 2-15 UUI episodes/day, and at risk of deteriorating health by a score of >=3 on the Vulnerable Elders Survey (VES)-13. Patients were evaluated for fesoterodine treatment response (defined as no UUI episodes) and persistence at weeks 12, 26, and 52. The model included a hypothetical health plan with 100,000 elderly members. A total of 7096 vulnerable elderly subjects were identified as the model target population based on the percentage of vulnerable elderly and annual prevalence of OAB among vulnerable elderly. OAB-related costs included fesoterodine drug acquisition costs, healthcare resource use (inpatient hospitalization, outpatient visits, and physician office visits), and OAB-related co-morbidities (falls/fractures, urinary tract infections, depression, and nursing home admissions). All costs were inflated to 2013 US$ using the medical care component of the consumer price index (CPI). RESULTS: When 7096 vulnerable elderly OAB patients were treated with fesoterodine, US healthcare payers could save $11,463,981 per year, or $1616 per patient vs no OAB pharmacotherapy. Univariate one-way sensitivity analyses supported the robustness of the findings and showed results were most sensitive to changes in fesoterodine efficacy followed by annual costs of inpatient hospitalization. CONCLUSIONS: From a US payer perspective, treating vulnerable elderly OAB patients with fesoterodine was cost-saving compared to no OAB pharmacotherapy. PMID- 26488197 TI - [NiFeSe]-hydrogenase chemistry. AB - The development of technology for the inexpensive generation of the renewable energy vector H2 through water splitting is of immediate economic, ecological, and humanitarian interest. Recent interest in hydrogenases has been fueled by their exceptionally high catalytic rates for H2 production at a marginal overpotential, which is presently only matched by the nonscalable noble metal platinum. The mechanistic understanding of hydrogenase function guides the design of synthetic catalysts, and selection of a suitable hydrogenase enables direct applications in electro- and photocatalysis. [FeFe]-hydrogenases display excellent H2 evolution activity, but they are irreversibly damaged upon exposure to O2, which currently prevents their use in full water splitting systems. O2 tolerant [NiFe]-hydrogenases are known, but they are typically strongly biased toward H2 oxidation, while H2 production by [NiFe]-hydrogenases is often product (H2) inhibited. [NiFeSe]-hydrogenases are a subclass of [NiFe]-hydrogenases with a selenocysteine residue coordinated to the active site nickel center in place of a cysteine. They exhibit a combination of unique properties that are highly advantageous for applications in water splitting compared with other hydrogenases. They display a high H2 evolution rate with marginal inhibition by H2 and tolerance to O2. [NiFeSe]-hydrogenases are therefore one of the most active molecular H2 evolution catalysts applicable in water splitting. Herein, we summarize our recent progress in exploring the unique chemistry of [NiFeSe] hydrogenases through biomimetic model chemistry and the chemistry with [NiFeSe] hydrogenases in semiartificial photosynthetic systems. We gain perspective from the structural, spectroscopic, and electrochemical properties of the [NiFeSe] hydrogenases and compare them with the chemistry of synthetic models of this hydrogenase active site. Our synthetic models give insight into the effects on the electronic properties and reactivity of the active site upon the introduction of selenium. We have utilized the exceptional properties of the [NiFeSe] hydrogenase from Desulfomicrobium baculatum in a number of photocatalytic H2 production schemes, which are benchmark systems in terms of single site activity, tolerance toward O2, and in vitro water splitting with biological molecules. Each system comprises a light-harvesting component, which allows for light-driven electron transfer to the hydrogenase in order for it to catalyze H2 production. A system with [NiFeSe]-hydrogenase on a dye-sensitized TiO2 nanoparticle gives an enzyme-semiconductor hybrid for visible light-driven generation of H2 with an enzyme-based turnover frequency of 50 s(-1). A stable and inexpensive polymeric carbon nitride as a photosensitizer in combination with the [NiFeSe]-hydrogenase shows good activity for more than 2 days. Light-driven H2 evolution with the enzyme and an organic dye under high O2 levels demonstrates the excellent robustness and feasibility of water splitting with a hydrogenase-based scheme. This has led, most recently, to the development of a light-driven full water splitting system with a [NiFeSe]-hydrogenase wired to the water oxidation enzyme photosystem II in a photoelectrochemical cell. In contrast to the other systems, this photoelectrochemical system does not rely on a sacrificial electron donor and allowed us to establish the long sought after light-driven water splitting with an isolated hydrogenase. PMID- 26488198 TI - Molecular organization of the 5S rDNA gene type II in elasmobranchs. AB - The 5S rDNA gene is a non-coding RNA that can be found in 2 copies (type I and type II) in bony and cartilaginous fish. Previous studies have pointed out that type II gene is a paralog derived from type I. We analyzed the molecular organization of 5S rDNA type II in elasmobranchs. Although the structure of the 5S rDNA is supposed to be highly conserved, our results show that the secondary structure in this group possesses some variability and is different than the consensus secondary structure. One of these differences in Selachii is an internal loop at nucleotides 7 and 112. These mutations observed in the transcribed region suggest an independent origin of the gene among Batoids and Selachii. All promoters were highly conserved with the exception of BoxA, possibly due to its affinity to polymerase III. This latter enzyme recognizes a dT4 sequence as stop signal, however in Rajiformes this signal was doubled in length to dT8. This could be an adaptation toward a higher efficiency in the termination process. Our results suggest that there is no TATA box in elasmobranchs in the NTS region. We also provide some evidence suggesting that the complexity of the microsatellites present in the NTS region play an important role in the 5S rRNA gene since it is significantly correlated with the length of the NTS. PMID- 26488199 TI - Economic Costs of Measles Outbreak in the Netherlands, 2013-2014. AB - In 2013 and 2014, the Netherlands experienced a measles outbreak in orthodox Protestant communities with low measles-mumps-rubella vaccination coverage. Assessing total outbreak costs is needed for public health outbreak preparedness and control. Total costs of this outbreak were an estimated $4.7 million. PMID- 26488200 TI - Elucidating the molecular interaction of sinigrin, a potent anticancer glucosinolate from cruciferous vegetables with bovine serum albumin: effect of methylglyoxal modification. AB - The present study employed the spectroscopic techniques, i.e. fluorescence, and circular dichroism (CD) and the molecular docking approach to investigate the mechanism of interaction of a potent anticancer glucosinolate, sinigrin (SIN), with bovine serum albumin (BSA). SIN binding to BSA resulted in the quenching of intrinsic fluorescence, and the analysis of results revealed the presence of static quenching mechanism. Based on the results, it was evident that the interaction of SIN with BSA was mainly stabilized by hydrogen bonding. Results from CD analysis revealed that the binding of SIN does not induce significant conformational changes in BSA. Molecular docking studies showed that four hydrogen bonds stabilize the binding of SIN in the site I of BSA with a binding energy of -6.2 kcal mol(-1). These findings will not only provide insights about the mechanism of interaction of sinigrin but also showed the effect of methylglyoxal-mediated glycation on ligand binding with BSA. PMID- 26488201 TI - High Expression of Cathepsin E is Associated with the Severity of Airflow Limitation in Patients with COPD. AB - BACKGROUND: It was reported that Cathepsin E (Cat E) plays a critical role in antigen processing and in the development of pulmonary emphysema. The aim of this study was to investigate the role of Cat E and airflow limitation in the pathogenesis of COPD. METHODS: Sixty-five patients with COPD, 20 smoking control subjects without COPD and 15 non-smoking healthy control subjects were enrolled. Cat E and EIC (Elastase inhibitory capacity) expressions were measured by ELISA in sputum and serum samples and compared according to different subgroups. RESULTS: Cat E concentrations were significantly higher in patients with COPD than smoking control and non-smoking control subjects (P < 0.01). The levels of CatE were inversely correlated with FEV1% predicted in COPD patients (r = -0.95, P < 0.01). The levels of EIC were inversely positively correlated with FEV1% predicted in COPD patients (r = 0.926, P < 0.01). Levels of Cat E were also inversely correlated with the levels of EIC (r = -0.922, P < 0.01). CONCLUSIONS: Cat E contributes to the severity of airflow limitation during progression of COPD. PMID- 26488202 TI - Polymorphism of Two-Dimensional Cyanine Dye J-Aggregates and Its Genesis: Fluorescence Microscopy and Atomic Force Microscopy Study. AB - Polymorphic J-aggregates of monomethine cyanine dye 3,3'-di(gamma-sulfopropyl) 5,5'-dichlorotiamonomethinecyanine (TC) have been studied by fluorescence optical microscopy (FOM) and by atomic force microscopy (AFM). The in situ FOM observations in a solution drop distinguish two J-aggregate morphology classes: flexible strips and rigid rods. The AFM imaging of dried samples reveals a strong J-aggregate structural rearrangement under adsorption on a mica surface with the strips self-folding and the rods squashing into rectangular bilayers and much deeper destruction. In the present work, the following structural conclusions have been drawn on the basis of careful consideration of strip crystal habits and various structural features of squashed/destructed rods: (1) the tubular morphology of TC rods is directly proved by FOM measurements in the solution bulk; (2) the staircase model of molecular arrangement in strips is proposed explaining the characteristic ~44 degrees skew angle in strip vertices; (3) a model of tube formation by a close-packed helical winding of flexible monolayer strips is proposed and justified which explains the observed J-aggregate polymorphism and strip-to-rod polymorphic transformations in a wide spatiotemporal scale; (4) at a nanoscale, an unexpectedly complex quasi-one dimensional organization in J-aggregate two-dimensional monolayers is observed by high-resolution AFM imaging of constituent nanostrips separated by a characteristic distance in the range of 6-10 nm. The obtained results indicate that the underlying monolayer structure is the same for all J-aggregate polymorphs. PMID- 26488203 TI - High Permittivity (1 - x)Ba(Zr(0.2)Ti(0.8))O3 - x(Ba(0.7)Ca(0.3))TiO3 (x = 0.45) Epitaxial Thin Films with Nanoscale Phase Fluctuations. AB - Epitaxial (1 - x)Ba(Ti0.8Zr0.2)TiO3 - x(Ba0.7Ca0.3)TiO3, x = 0.45 (BCZT 45), thin films have been deposited on (001) SrTiO3 (STO) and (001/100) SrLaAlO4 (SLAO) substrates by pulsed laser deposition. X-ray diffraction and high-resolution transmission electron microscopy (HRTEM) confirmed the epitaxial growth of the films. A high structural quality has been evidenced for the BCZT/STO films. Geometric phase analysis (GPA) associated with the HRTEM enabled us to obtain microstrain analysis and the in-plane and out-of-plane lattice parameter variation on different areas. Tetragonality ratio fluctuations at nanoscale level which are relevant for the existence of nanodomains have been evidenced on the BCZT/STO films. The in-plane dielectric constant has been measured on interdigital electrodes deposited by lift-off technique on the top of the films. High values of dielectric permittivity (>3000) combined with low dielectric loss (<0.01) are obtained for BCZT 45 film deposited on STO substrate, showing nearly constant values between 1 kHz and 10 MHz. The high dielectric permittivity of BCZT thin films was attributed to their high structural quality and to the loss of rotation stability of the polarization associated with the presence of nanodomains. This results into a divergence of fluctuations of polarization direction and a peak of dielectric susceptibility. The enhanced switching of such nanodomain configuration was probed by piezoforce microscopy, by writing and reading domains during topography scanning. PMID- 26488204 TI - Mycophenolate Mofetil Therapy in Children With Idiopathic Nephrotic Syndrome: Does Therapeutic Drug Monitoring Make a Difference? AB - BACKGROUND: Idiopathic nephrotic syndrome (INS) necessitates administration of corticosteroids or corticoid-sparing agents in 60% of the cases for prolonged periods resulting in serious adverse effects. METHODS: To avoid these complications, we investigated the efficacy and safety of mycophenolate mofetil (MMF) in our retrospective single-center study with 15 patients presenting with complicated courses of INS and aspired to estimate a cutoff level for mycophenolic acid-area under the curve (MPA-AUC) values, which can predict relapses with high sensitivity. RESULTS: Seven of 15 patients stayed in remission while receiving MMF. Average frequency of relapses was 1.39 (0.28-2.5) per year. In case of relapses, patients had lower predose and estimated AUC0-12 levels of MPA (P = 0.02 and 0.001, respectively). Based on the results of receiver operating characteristic analysis, we consider an estimated MPA-AUC0-12 lower than 44.6 mg.h.L(-1) as a risk factor for future relapses (91% sensitivity, 57% specificity, P = 0.06) because the prevalence of relapse is significantly lower (0.07 versus 0.5, P = 0.02), if the estimated MPA-AUC0-12 is >44.6 mg.h.L(-1). During MMF administration, we did not detect any adverse event requiring discontinuation of treatment. CONCLUSIONS: In conclusion, we demonstrate MMF as an alternative treatment for children with complicated INS to maintain remission without serious side effects. Furthermore, we propose a higher therapeutic target range of MPA-AUC0-12 (>45 mg.h.L(-1)) than used in transplanted children underlining the crucial role of therapeutic drug monitoring. PMID- 26488205 TI - Development and Validation of a Simple and Rapid UPLC-MS Assay for Valproic Acid and Its Comparison With Immunoassay and HPLC Methods. AB - BACKGROUND: Valproic acid (VPA), a widely used antiepileptic drug, has a narrow therapeutic range of 50-100 mcg/mL and shows large individual variability. It is very important to monitor the trough concentration of VPA using a reliable method. Therefore, the aim of this study was to develop and validate a rapid ultraperformance liquid chromatographic-mass spectrometry (UPLC-MS) method for quantification of VPA in human serum and to compare with fluorescence polarization immunoassay (FPIA), chemiluminescence microparticle immunoassay (CMIA), and high-performance liquid chromatography (HPLC) methods. METHODS: The method included extraction of VPA in serum by deproteinization with acetonitrile. The analysis was performed using an EC-C18 column (2.7 MUm, 4.6 * 50 mm) under isocratic conditions with a mobile phase of acetonitrile/water (containing 0.1% formic acid) (45/55, vol/vol) at a flow rate of 0.6 mL/min. The detection was performed on a triple-quadrupole tandem mass spectrometer using an electrospary probe in the negative ionization mode. The method was validated by studies of selectivity, linearity, lower limit of quantification, accuracy, precision, recovery, matrix effect, and stability. Furthermore, all the 4 methods including FPIA, CMIA, and HPLC were subsequently used to assay the VPA concentration in 498 clinical serum samples collected from patients who received VPA. These methods were compared by Deming regression and Bland-Altman analysis. RESULTS: The retention time of VPA was 2.09 minutes. The calibration curve was linear over the concentration range of 1-200 mcg/mL, with a lower limit of quantification of 1 mcg/mL. The interday and intraday precision (RSD %) was less than 4.6% and 4.5%, respectively, and the accuracy (RE %) was below 7.9%. The recoveries and matrix effect of VPA at concentrations of 2, 50, and 160 mcg/mL met the requirement for the analysis of biological samples. No obvious degradation of VPA was observed under various storage conditions including room temperature for 12 hour, 3 freeze thaw cycles, and -20 degrees C for 3 months. Regression analysis showed that the correlation coefficients for the UPLC-MS versus FPIA, CMIA, and HPLC were 0.989, 0.988, and 0.987, respectively. The results of agreement tests between UPLC-MS and other methods showed that the mean difference of UPLC-MS and FPIA was -1.4 mcg/mL and 95% confidence interval of -7.7 to 4.9 mcg/mL, and the values for UPLC MS and CMIA were -0.8 mcg/mL and -7.5 to 5.8 mcg/mL, for UPLC-MS and HPLC were 1.1 mcg/mL and -5.7 to 7.9 mcg/mL. CONCLUSION: The rapid UPLC-MS method we developed showed a good analytical performance required for therapeutic drug monitoring, leading to potential improvements in patient care and laboratory management. Compared with the FPIA, CMIA, and HPLC methods, the UPLC-MS method correlated well and displayed comparable VPA concentrations. PMID- 26488206 TI - Pulsed Direct Current Electrospray: Enabling Systematic Analysis of Small Volume Sample by Boosting Sample Economy. AB - We had developed pulsed direct current electrospray ionization mass spectrometry (pulsed-dc-ESI-MS) for systematically profiling and determining components in small volume sample. Pulsed-dc-ESI utilized constant high voltage to induce the generation of single polarity pulsed electrospray remotely. This method had significantly boosted the sample economy, so as to obtain several minutes MS signal duration from merely picoliter volume sample. The elongated MS signal duration enable us to collect abundant MS(2) information on interested components in a small volume sample for systematical analysis. This method had been successfully applied for single cell metabolomics analysis. We had obtained 2-D profile of metabolites (including exact mass and MS(2) data) from single plant and mammalian cell, concerning 1034 components and 656 components for Allium cepa and HeLa cells, respectively. Further identification had found 162 compounds and 28 different modification groups of 141 saccharides in a single Allium cepa cell, indicating pulsed-dc-ESI a powerful tool for small volume sample systematical analysis. PMID- 26488207 TI - TAVR: Imaging Spectrum of Complications. AB - Transcatheter aortic valve replacement has recently become a suitable alternative for senile aortic stenosis in patients not suitable for surgery. With growing operative experience, appropriate patient selection, advances in imaging evaluation, and technical refinements, the outcomes have improved. Despite its less invasive nature, a unique set of complications and events are encountered during the transcatheter aortic valve replacement procedure and in the postoperative period. Knowledge of these complications, their prompt detection, and quick adequate treatment are critical in reducing the mortality and morbidity. PMID- 26488208 TI - A Rare Case of Primary Pulmonary Glomus Tumor. PMID- 26488209 TI - A Case of Apparent Lung Adenocarcinoma Size Reduction During Steroid Therapy. AB - Spontaneous regression of lung cancer is a rare phenomenon. We described a case of lung adenocarcinoma size reduction during steroid therapy. In this case, histopathologic findings showed a lung adenocarcinoma surrounded by obstructive pneumonia and inflammatory cell infiltration. Steroid use might have diminished the inflammatory response around the lung cancer, resulting in the apparent shrinkage of the lung cancer. This phenomenon is a potential pitfall in lung cancer diagnosis. PMID- 26488210 TI - Thoracic Metastases From Primary Hepatobiliary and Pancreatic Malignancies: Predictable Patterns of Metastatic Spread. AB - This article reviews common and uncommon patterns of thoracic metastatic disease in primary hepatobiliary and pancreatic malignancies that are often overlooked or improperly diagnosed because of atypical location or imaging appearance. An understanding of the pathophysiology and routes of tumor spread aids in tailoring a search pattern allowing for more accurate evaluation of disease activity. PMID- 26488211 TI - Surface-Confined Supramolecular Self-Assembly of Molecular Nanocranes for Chemically Lifting and Positioning C60 above a Conducting Substrate. AB - 2D supramolecular self-assembly is a good way to form well-defined nanostructures on various substrates. One of the current challenges is to extend this approach to 3D functional building blocks. Here, we address this issue by providing a strategy for the controlled lifting and positioning of functional units above a graphitic substrate. This is the first time that multistory cyclophane-based 3D tectons incorporating C60 units have been designed and synthesized. Molecular modelling provides a description of the 3D geometries and evidences the flexible character of the building blocks. Despite this later feature, the supramolecular self-assembly of Janus tectons on HOPG yields well-ordered adlayers incorporating C60 arrays at well-defined mean distances from the surface. As our approach is not limited to C60 , the results reported here open-up possibilities for applications where the topological and electronic interactions between the substrate and the functional unit are of prime importance. PMID- 26488213 TI - Halogen-Adjusted Chemoselective Synthesis of Fluorene Derivatives with Position Controlled Substituents. AB - Fluorenes have been synthesized through an efficient novel Pd-catalyzed tandem cross-coupling reaction; these substrates are fascinating building blocks found in organic photoelectric materials. The position of the substituent on fluorenes could be conveniently tuned by changing the halogen in the ortho-halobenzyl bromide substrates when coupled with various arylboronic acids. This newly developed synthetic approach could achieve the potential diversity in fluorene based molecular architectures. PMID- 26488212 TI - Clinicopathological and genetic differences between low-grade and high-grade colorectal mucinous adenocarcinomas. AB - BACKGROUND: Although colorectal mucinous adenocarcinomas (MCs) are conventionally regarded as exhibiting high-grade differentiation, they can be divided by differentiation into 2 groups according to the glandular appearance: low-grade mucinous adenocarcinoma (low-MC) and high-grade mucinous adenocarcinoma (high MC). METHODS: Patients with colorectal cancer (CRC) who underwent surgical resection between 2000 and 2012 were enrolled in this study. Among the cases with MC, the clinicopathological and genetic differences between low-MC and high-MC were investigated with next-generation sequencing. RESULTS: A total of 1373 patients with CRC were analyzed. Forty patients (2.9%) had MC, and 13 patients had high-MC. Patients with MC had significantly shorter disease-free survival (DFS) and overall survival (OS) periods than those with nonmucinous carcinoma. When low-MC patients and high-MC patients were compared, those with high-MC had significantly shorter DFS and OS periods than those with low-MC. Multivariate analyses revealed that high-MC was significantly associated with both shorter DFS and shorter OS, but low-MC was not. A genome analysis revealed that low-MC had a considerably larger number of mutations than high-MC, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and adenomatous polyposis coli mutations were particularly frequently found in low-MC. In contrast, SMAD family member 4 (SMAD4) mutations were frequently found in high-MC. CONCLUSIONS: High-MC is an independent prognostic factor in CRC (but low-MC is not), and it is genetically different from other CRCs, including low-MC. Both the clinicopathological differences and the genetic differences suggest that low-MC and high-MC should be distinguished in clinical settings. PMID- 26488214 TI - Influence of delta virus infection on the virologic status in Egyptian patients with chronic hepatitis B virus genotype D. AB - Hepatitis delta virus (HDV) usually have an unfavorable clinical outcome in chronic hepatitis B virus (HBV) patients. In Egypt, data about epidemiology, the spectrum of disease, and impact of HDV on HBV infection are rare. To assess the prevalence, clinical and virological characteristics of HDV infection among Egyptian patients with chronic HBV. Adult patients with Hepatitis B surface antigen (HBsAg)-positive were evaluated for the presence of HDV using anti HDV IgG and HDV RNA by RT-PCR. Routine laboratory investigations, genotypes and subtypes for both HBV and HDV, abdominal sonography, and transient elastography (TE) were done. Liver biopsy was performed only in whenever indicated. One hundred and twenty-one treatment-naive chronic HBV patients were included. Wild HBV genotype-D2 was found in 98.2% and 81.9% were HBeAg negative. Prevalence of HDV was 8.3% by anti-HDV IgG and 9.9% by RT-PCR. Wild HDV genotype-IIb was reported in 83.3%. HDV infection was more common in males, 90.9% of delta patients were HBeAg negative. Compared to the mono-infected HBV, concomitant HBV/HDV infection was not associated with more derangment in ALT nor advanced stage of fibrosis. 66.7% of HDV patients had significantly lower HBV-DNA level compared to the non-delta patients (P < 0.001). HDV is not uncommon in Egypt. HBV genotype-D was associated with HDV genotype-IIb. Delta infection was associated with negative HBeAg status, reduction of HBV replication, but neither influenced the clinical course nor increased significant liver damage risk. PMID- 26488215 TI - Orthogonal Control of Stability and Tunable Dry Adhesion by Tailoring the Shape of Tapered Nanopillar Arrays. AB - Tapered nanopillar structures of different cross-sectional geometries including cone-, pencil-like, and stepwise are prepared from anodized aluminum oxide templates. The shape effect on the adhesion strength is investigated in experiments and simulation. Cone-shaped nanopillars are highly bendable under load and can recover after unloading, thus, warranting high adhesion strength, 34 N cm(-2) . The pencil-like and stepwise nano-pillars are, however, easily fractured and are not recoverable under the same conditions. PMID- 26488216 TI - Glucarpidase for the Treatment of Methotrexate-Induced Renal Dysfunction and Delayed Methotrexate Excretion. PMID- 26488217 TI - Pityriasis versicolor atrophicans: Is it true atrophy or pseudoatrophy? PMID- 26488218 TI - Thrombolytic-Enhanced Extracorporeal Cardiopulmonary Resuscitation After Prolonged Cardiac Arrest. AB - OBJECTIVE: To investigate the effects of the combination of extracorporeal cardiopulmonary resuscitation and thrombolytic therapy on the recovery of vital organ function after prolonged cardiac arrest. DESIGN: Laboratory investigation. SETTING: University laboratory. SUBJECTS: Pigs. INTERVENTIONS: Animals underwent 30-minute untreated ventricular fibrillation cardiac arrest followed by extracorporeal cardiopulmonary resuscitation for 6 hours. Animals were allocated into two experimental groups: t-extracorporeal cardiopulmonary resuscitation (t ECPR) group, which received streptokinase 1 million units, and control extracorporeal cardiopulmonary resuscitation (c-ECPR), which did not receive streptokinase. In both groups, the resuscitation protocol included the following physiologic targets: mean arterial pressure greater than 70 mm Hg, cerebral perfusion pressure greater than 50 mm Hg, PaO2 150 +/- 50 torr (20 +/- 7 kPa), PaCO2 40 +/- 5 torr (5 +/- 1 kPa), and core temperature 33 degrees C +/- 1 degrees C. Defibrillation was attempted after 30 minutes of extracorporeal cardiopulmonary resuscitation. MEASUREMENTS AND MAIN RESULTS: A cardiac resuscitability score was assessed on the basis of success of defibrillation, return of spontaneous heart beat, weanability from extracorporeal cardiopulmonary resuscitation, and left ventricular systolic function after weaning. The addition of thrombolytic to extracorporeal cardiopulmonary resuscitation significantly improved cardiac resuscitability (3.7 +/- 1.6 in t-ECPR vs 1.0 +/- 1.5 in c ECPR). Arterial lactate clearance was higher in t-ECPR than in c-ECPR (40% +/- 15% vs 18% +/- 21%). At the end of the experiment, the intracranial pressure was significantly higher in c-ECPR than in t-ECPR. Recovery of brain electrical activity, as assessed by quantitative analysis of electroencephalogram signal, and ischemic neuronal injury on histopathologic examination did not differ between groups. Animals in t-ECPR group did not have increased bleeding complications, including intracerebral hemorrhages. CONCLUSIONS: In a porcine model of prolonged cardiac arrest, t-ECPR improved cardiac resuscitability and reduced brain edema, without increasing bleeding complications. However, early electroencephalogram recovery and ischemic neuronal injury were not improved. PMID- 26488220 TI - Hyperbaric Oxygen Therapy Alleviates Carbon Monoxide Poisoning-Induced Delayed Memory Impairment by Preserving Brain-Derived Neurotrophic Factor-Dependent Hippocampal Neurogenesis. AB - OBJECTIVE: To test the hypothesis that hyperbaric oxygen therapy ameliorates delayed cognitive impairment after acute carbon monoxide poisoning by promoting neurogenesis through upregulating the brain-derived neurotrophic factor in the hippocampus. DESIGN: Laboratory animal experiments. SETTING: University/Medical center research laboratory. SUBJECTS: Adult, male Sprague-Dawley rats. INTERVENTIONS: Rats were divided into five groups: (1) non-carbon monoxide treated control, (2) acute carbon monoxide poisoning, (3) acute carbon monoxide poisoning followed by 7-day hyperbaric oxygen treatment, (4) carbon monoxide + hyperbaric oxygen with additional intracerebroventricular infusion of Fc fragment of tyrosine kinase receptor B protein (TrkB-Fc) chimera, and (5) acute carbon monoxide poisoning followed by intracerebroventricular infusion of brain-derived neurotrophic factor. Acute carbon monoxide poisoning was achieved by exposing the rats to carbon monoxide at 2,500 ppm for 40 minutes, followed by 3,000 ppm for 20 minutes. Hyperbaric oxygen therapy (at 2.5 atmospheres absolute with 100% oxygen for 60 min) was conducted during the first 7 days after carbon monoxide poisoning. Recombinant human TrkB-Fc chimera or brain-derived neurotrophic factor was infused into the lateral ventricle via the implanted osmotic minipump. For labeling of mitotic cells in the hippocampus, bromodeoxyuridine was injected into the peritoneal cavity. Distribution of bromodeoxyuridine and two additional adult neurogenesis markers, Ki-67 and doublecortin, in the hippocampus was evaluated by immunohistochemistry or immunofluorescence staining. Tissue level of brain derived neurotrophic factor was assessed by enzyme-linked immunosorbent assay. Cognitive behavior was evaluated by the use of eight-arm radial maze. MEASUREMENTS AND MAIN RESULTS: Acute carbon monoxide poisoning significantly suppressed adult hippocampal neurogenesis evident by the reduction in number of bromodeoxyuridine-positive, Ki-67+, and doublecortin+ cells in the subgranular zone of the dentate gyrus. This suppression of adult neurogenesis by the carbon monoxide poisoning was appreciably alleviated by early treatment of hyperbaric oxygen. The hyperbaric oxygen treatment also promoted a sustained increase in hippocampal brain-derived neurotrophic factor level. Blockade of hippocampal brain-derived neurotrophic factor signaling with intracerebroventricular infusion of recombinant human TrkB-Fc chimera significantly blunted the protection by the hyperbaric oxygen on hippocampal neurogenesis; whereas intracerebroventricular infusion of brain-derived neurotrophic factor mimicked the action of hyperbaric oxygen and preserved hippocampal neurogenesis after acute carbon monoxide poisoning. Furthermore, acute carbon monoxide poisoning resulted in a delayed impairment of cognitive function. The hyperbaric oxygen treatment notably restored the cognitive impairment in a brain-derived neurotrophic factor dependent manner. CONCLUSIONS: The early hyperbaric oxygen treatment may alleviate delayed memory impairment after acute carbon monoxide poisoning by preserving adult neurogenesis via an increase in hippocampal brain-derived neurotrophic factor content. PMID- 26488219 TI - Safety and Efficacy of Combined Extracorporeal CO2 Removal and Renal Replacement Therapy in Patients With Acute Respiratory Distress Syndrome and Acute Kidney Injury: The Pulmonary and Renal Support in Acute Respiratory Distress Syndrome Study. AB - OBJECTIVE: To assess the safety and efficacy of combining extracorporeal CO2 removal with continuous renal replacement therapy in patients presenting with acute respiratory distress syndrome and acute kidney injury. DESIGN: Prospective human observational study. SETTINGS: Patients received volume-controlled mechanical ventilation according to the acute respiratory distress syndrome net protocol. Continuous venovenous hemofiltration therapy was titrated to maintain maximum blood flow and an effluent flow of 45 mL/kg/h with 33% predilution. PATIENTS: Eleven patients presenting with both acute respiratory distress syndrome and acute kidney injury required renal replacement therapy. INTERVENTIONS: A membrane oxygenator (0.65 m) was inserted within the hemofiltration circuit, either upstream (n = 7) or downstream (n = 5) of the hemofilter. Baseline corresponded to tidal volume 6 mL/kg of predicted body weight without extracorporeal CO2 removal. The primary endpoint was 20% reduction in PaCO2 at 20 minutes after extracorporeal CO2 removal initiation. Tidal volume was subsequently reduced to 4 mL/kg for the remaining 72 hours. MEASUREMENTS AND MAIN RESULTS: Twelve combined therapies were conducted in the 11 patients. Age was 70 +/- 9 years, Simplified Acute Physiology Score II was 69 +/- 13, Sequential Organ Failure Assessment score was 14 +/- 4, lung injury score was 3 +/- 0.5, and PaO2/FIO2 was 135 +/- 41. Adding extracorporeal CO2 removal at tidal volume 6 mL/kg decreased PaCO2 by 21% (95% CI, 17-25%), from 47 +/- 11 to 37 +/- 8 Torr (p < 0.001). Lowering tidal volume to 4 mL/kg reduced minute ventilation from 7.8 +/- 1.5 to 5.2 +/- 1.1 L/min and plateau pressure from 25 +/- 4 to 21 +/ 3 cm H2O and raised PaCO2 from 37 +/- 8 to 48 +/- 10 Torr (all p < 0.001). On an average of both positions, the oxygenator's blood flow was 410 +/- 30 mL/min and the CO2 removal rate was 83 +/- 20 mL/min. The oxygenator blood flow (p <0.001) and the CO2 removal rate (p = 0.083) were higher when the membrane oxygenator was placed upstream of the hemofilter. There was no safety concern. CONCLUSIONS: Combining extracorporeal CO2 removal and continuous venovenous hemofiltration in patients with acute respiratory distress syndrome and acute kidney injury is safe and allows efficient blood purification together with enhanced lung protective ventilation. PMID- 26488222 TI - Erratum to: A review of canola meal as an alternative feed ingredient for ducks. AB - [This corrects the article DOI: 10.1186/s40781-015-0062-4.]. PMID- 26488223 TI - The use of alvimopan for postoperative ileus in small and large bowel resections. AB - Transient ileus is a normal physiologic process after surgery. When prolonged, it is an important contributor to postoperative complications, increased length of stay and increased healthcare costs. Efforts have been made to prevent and manage postoperative ileus; alvimopan is an oral, peripheral MU-opioid receptor antagonist, and the only currently US FDA-approved medication to accelerate the return of gastrointestinal function postoperatively. PMID- 26488221 TI - Gene Expression of Proresolving Lipid Mediator Pathways Is Associated With Clinical Outcomes in Trauma Patients. AB - OBJECTIVES: Specialized proresolving lipid mediators have emerged as powerful modulators of inflammation and activators of resolution. Animal models show significant benefits of specialized proresolving lipid mediators on survival and wound healing after major burn trauma. To date, no studies have investigated specialized proresolving lipid mediators and their relation to other lipid mediator pathways in humans after trauma. Here we determine if patients with poor outcomes after trauma have dysregulated lipid mediator pathways. DESIGN: We studied blood leukocyte expression of 18 genes critical to the synthesis, signaling, and metabolism of specialized proresolving lipid mediators and proinflammatory lipid mediators, and we correlated these expression patterns with clinical outcomes in trauma patients from the Inflammation and the Host Response to Injury study. SETTING: Seven U.S. medical trauma centers. SUBJECTS: Ninety-six patients enrolled in the Inflammation and Host Response to Injury study, after blunt trauma and unambiguously classified as having uncomplicated or complicated recoveries. Twenty-eight healthy volunteers were enrolled as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Within each patient, the 18 genes of interest were used to calculate scores for distinct families of lipid mediators, including resolvins, lipoxins, prostaglandins, and leukotrienes, as well as leukotriene to resolvin score ratios. Scores were built using a simple weighting scheme, taking into consideration both dependent and independent activities of enzymes and receptors responsible for lipid mediator biosynthesis and function. Individually, ALOX12, PTGS2, PTGES, PTGDS, ALOX5AP, LTA4H, FPR2, PTGER2, LTB4R, HPGD, PTGR1, and CYP4F3 were expressed differentially over 28 days posttrauma between patients with uncomplicated and complicated recoveries (p < 0.05). When all genes were combined into scores, patients with uncomplicated recoveries had differential and higher resolvin scores (p < 0.001) and lower leukotriene scores (p < 0.001). A final combined ratio was calculated for each patient, and posttrauma leukotriene score to resolvin score ratios were significantly lower in patients with uncomplicated clinical courses (p < 0.001). CONCLUSIONS: proresolving lipid mediator lipidomics and/or protein expression, and identifying associated therapeutic targets, may influence the clinical management of trauma patients. PMID- 26488224 TI - Opportunities and dangers for neurosurgery in the current NHS. AB - The NHS is entering a third decade of administrative turbulence and cost pressures and many view the new NHS structure and systems as complex and confusing. Health and social care budgets are being merged in some geographical areas and large efficiency savings are needed by 2020. There are risks that lie ahead for neurosurgery and our patients if the specialty becomes further fragmented and opportunities for positive change are missed. One of the new care models proposed in the NHS five year plan is specialist care provided across multiple hospital sites by a single overarching specialist trust, mirroring ophthalmology where the Moorfields trust provides specialist eye services in over 20 locations in London and the South East. This model lends itself to adoption by neurosurgery and has the potential to increase standards, efficiency, training and research. PMID- 26488226 TI - Nanoscale electric polarizability of ultrathin biolayers on insulating substrates by electrostatic force microscopy. AB - We measured and quantified the local electric polarization properties of ultrathin (~5 nm) biolayers on mm-thick mica substrates. We achieved it by scanning a sharp conductive tip (<10 nm radius) of an electrostatic force microscope over the biolayers and quantifying sub-picoNewton electric polarization forces with a sharp-tip model implemented using finite-element numerical calculations. We obtained relative dielectric constants epsilonr = 3.3, 2.4 and 1.9 for bacteriorhodopsin, dioleoylphosphatidylcholine (DOPC) and cholesterol layers, chosen as representative of the main cell membrane components, with an error below 10% and a spatial resolution down to ~50 nm. The ability of using insulating substrates common in biophysics research, such as mica or glass, instead of metallic substrates, offers both a general platform to determine the dielectric properties of biolayers and a wider compatibility with other characterization techniques, such as optical microscopy. This opens up new possibilities for biolayer research at the nanoscale, including nanoscale label free composition mapping. PMID- 26488225 TI - Depression and frailty: concurrent risks for adverse health outcomes. AB - OBJECTIVES: This study used latent growth curve modeling (LGCM) to estimate the independent and joint associations between frailty and depression trajectories and likelihood of nursing home admission and falls resulting in injury. METHODS: Data come from five waves (2004-2012) of the Health and Retirement Study. Community-dwelling individuals aged 51 and older (N = 13,495) were analyzed using LGCM. Frailty was measured using a frailty index consisting of 30 deficits. Depressive symptoms were measured using the eight-item Centers for Epidemiologic Studies - Depression scale. Adverse health outcomes included nursing home admissions and falls resulting in injury. RESULTS: Prevalence of frailty increased over the study period (24.1%-32.1%), while the prevalence of depression was relatively constant over time (approximately 13%). Parallel process LGCM showed that more rapid increases of frailty and depressive symptoms were associated with higher odds of both nursing home admission and serious falls over time (Frailty: ORNursinghome = 1.33, 95% CI: 1.09-1.66; ORFall = 1.52, 95% CI: 1.12-2.08; Depression: ORNursinghome = 3.63, 95% CI: 1.29-9.97; ORFall = 1.16, 95% CI: 1.01-1.34). Associations between frailty and adverse outcomes were attenuated, and in some cases were no longer statistically significant, after accounting for concurrent depression. CONCLUSION: Frailty trajectories may be important indicators of risk for nursing home admissions and falls, independent of baseline frailty status; however, concurrent depression trajectories are associated with adverse outcomes to a similar degree as frailty. Focus should be given to distilling elements of the frailty index which confer most risk for poor health outcomes. PMID- 26488227 TI - Photoinduced water splitting via benzoquinone and semiquinone sensitisation. AB - The splitting of water into H and OH radicals by sensitisation of a redox-active chromophore with sunlight may eventually become a viable way of producing unlimited, clean and sustainable energy. In this work, we explore the possibility of photo-oxidation of water via sensitisation of benzoquinone with ultraviolet (UV) light in the hydrogen-bonded complex of benzoquinone with a single water molecule. Using state-of-the-art quantum chemical calculations, the mechanisms of electron/proton transfer reactions between photoexcited benzoquinone and water are characterised. In the benzoquinone-H2O complex, photoexcitation of the chromophore leads to the population of locally excited pipi* and npi* singlet states, which are coupled to hitherto unknown charge-transfer states. In the latter, an electron is transferred from the oxygen atom of the water molecule to the lowest pi* orbital of benzoquinone. These charge-separated states drive the transfer of a proton from the water molecule to the carbonyl acceptor site, yielding the semiquinone-OH biradical. Upon absorption of a second UV photon, the semiquinone radical may undergo O-H bond fission, which generates an H radical and restores the benzoquinone photocatalyst. Our computational results shed light on long-standing questions regarding the nature of the photoreactive electronic states in the aqueous photochemistry of benzoquinone. PMID- 26488228 TI - Approaches to prepare perfluoroalkyl and pentafluorophenyl copper couples for cross-coupling reactions with organohalogen compounds. AB - The reactions of iodoperfluoroalkanes CnF2n+1I (n = 2, 3, 4) and n-BuLi at low temperatures give NMR spectroscopic evidence for LiCnF2n+1 which were converted into LiCu(CnF2n+1)2 derivatives upon treatment with 0.5 mol copper(i) bromide, CuBr. An alternative route to obtain perfluoroorgano copper couples, Cu(Rf)2Ag (Rf = n-C3F7, n-C4F9, C6F5) was achieved from the reactions of the corresponding perfluoroorgano silver(i) reagents, AgRf, and elemental copper through redox transmetallations. The composition of the resulting reactive intermediates was investigated by means of (19)F NMR spectroscopy and ESI mass spectrometry. Perfluoro-n-propyl and perfluoro-n-butyl copper-silver reagents prepared by the oxidative transmetallation route exhibited good properties in C-C bond formation reactions with acid chlorides even under moderate conditions. Substitution of bromine directly bound to aromatics for perfluoroalkyl groups was achieved at elevated temperatures, while success in halide substitution reactions using lithium copper couples remained poor. PMID- 26488229 TI - Palm oil and cardiovascular disease: a randomized trial of the effects of hybrid palm oil supplementation on human plasma lipid patterns. AB - This study examines, for the first time, the effect of hybrid Elaeis oleifera * E. guineensis palm oil supplementation on human plasma lipids related to CVD risk factors. One hundred sixty eligible participants were randomized and assigned to one of the two treatments: 25 mL hybrid palm oil (HPO group) or 25 mL extra virgin olive oil (EVOO group) daily for 3 months. Fasting venous samples were obtained at baseline and after 1, 2 and 3 months for measurement of plasma lipids (TC, LDL-C, HDL-C and TAGs). Changes in body mass index and waist circumference were also assessed. Although there was an overall reduction in TC (7.4%, p < 0.001) and in LDL-C (15.6%, p < 0.001), no significant differences were found between the treatment groups in a repeated measures analysis of variance for TC (p = 0.0525), LDL-C (p = 0.2356), HDL-C (p = 0.8293) or TAGs (p = 0.3749). Furthermore, HPO consumption had similar effects on plasma lipids to EVOO, thus providing additional support for the concept that hybrid Elaeis oleifera * E. guineensis palm oil can be seen as a "tropical equivalent of olive oil". PMID- 26488230 TI - Evaluation of Mandibular Movement Functions Using Instrumental Ultrasound System. AB - PURPOSE: The article deals with routinely performed instrumental temporomandibular joint (TMJ) examinations and interpretation of findings obtained from the Arcus Digma ultrasound device in individuals with or without clinical symptoms of temporomandibular disorders (TMD). The aim of this study was to analyze mandibular movement functions and the relationship between incisors and condylar movement parameters during jaw opening, which may be helpful for clinical evaluation in these patients. MATERIALS AND METHODS: The study group consisted of 84 young students with no dental problems and other serious acute or chronic diseases in the medical history; the students were examined both clinically and with the Arcus Digma ultrasound device. RESULTS: Helkimo Di = I was the most common score in 49 participants, and Helkimo Di = II in a significantly (p < 0.01, Di = I vs. Di = II) smaller number of participants. Medical history revealed symptoms of unilateral mastication in 15 participants and a statistically significant increased (p < 0.02, participants with symptoms of unilateral mastication vs. asymptomatic) condylar range of motion parameter during retrusion. Also a significant decrease (p < 0.03, participants with symptoms of unilateral mastication vs. asymptomatic) of the incisal and condylar ranges of motion during mouth opening was found. Limitation of mouth opening, defined as a decrease of inter-incisal distance, appeared in 19 participants (22.6%) and in 25 participants (29.8%) measured instrumentally with the Arcus Digma device. A comparison of instrumental result examinations of the right and left TMJs showed positive correlations of the range of mandible opening movement with the Posselt opening movement (r = 0.75) and opening/closing movements with the Posselt closing movements (r = 0.70). A correlation was demonstrated (r = 0.81) between the condylar range of motion studied on the left and on the right TMJ during mandible opening movement. Correlations were also found between opening-closing movements and the condylar range of motion of the left TMJ, and between the opening-closing movement and the condylar range of motion of the right TMJ during the opening movement. CONCLUSIONS: According to the results of this study with instrumental Arcus Digma ultrasound device measurements of mandibular movements, data were provided on irregularities in TMJ function not detected in participants with or without clinical symptoms of TMD. PMID- 26488231 TI - Pediatric Chest Tubes And Pigtails: An Evidence-Based Approach To The Management Of Pleural Space Diseases. AB - Pediatric thoracostomy procedures are used in the emergency department to treat diseases of the pleural space. As children have unique thoracic anatomy and physiology, they may present with management challenges that the emergency clinician must consider. This issue reviews the use of chest tubes and pigtail catheters in pediatric patients, techniques and indications for placement, and possible complications. Diagnostic and treatment options for diseases of the pleural space, such as spontaneous pneumothorax, traumatic injury, and parapneumonic effusions/empyema, are examined. Additionally, this issue discusses the use of imaging modalities to aid in the diagnosis of pleural space diseases and the emerging practice of ambulatory management in certain cases. PMID- 26488232 TI - Synthesis and characterisation of a mesocyclic tripodal triamine ligand. AB - Meso- and macrocyclic polydentate amine ligands have been widely explored in oxidation catalysis and for the stabilization of unstable metal-superoxide, peroxide, and -oxo intermediates. Herein we report on the design and synthesis of a novel mesocyclic, tripodal, triamine ligand that we believe will be an excellent addition to this field. We explored a number of synthetic procedures towards the mesocyclic asymmetric tetraalkylated ligand 1. We expect that 1 will bind metals in a facially capping manner, yielding complexes that display pseudo tetrahedral geometry, potentially providing access to unprecedented late transition metal-oxo complexes (metal = Co, Ni, Cu). We describe the preparation of a library of mesocyclic polyamine synthons (8, 16, 17, 18, 19) that are precursors in the synthesis of 1. These synthons will be used to tailor the electronic properties of metal complexes of 1 and derivatives thereof. The X-ray crystal structures of 19 and mono- and di-protonated forms of 1b show that the triamine crystalises in a boat-chair conformation which is undesirable for metal coordination. However, solution (1)H NMR studies show that in solution both 19 and the tetraalkylated derivative 1b are remarkably flexible. 1b reacted with [CuI(NCCH3)4](OTf) yielding a 1:1 copper(I) complex [CuI(NCCH3)(1b)](+). PMID- 26488233 TI - Shear-Induced Reactive Gelation. AB - In this work, we describe a method for the production of porous polymer materials in the form of particles characterized by narrow pore size distribution using the principle of shear-induced reactive gelation. Poly(styrene-co-divinylbenzene) primary particles with diameter ranging from 80 to 200 nm are used as building blocks, which are assembled into fractal-like clusters when exposed to high shear rates generated in a microchannel. It was found that independent of the primary particle size, it is possible to modulate the internal structure of formed fractal-like aggregates having fractal dimension ranging from 2.4 to 2.7 by varying the residence time in the microchannel. Thermally induced postpolymerization was used to increase the mechanical resilience of such formed clusters. Primary particle interpenetration was observed by SEM and confirmed by light scattering resulting in an increase of fractal dimension. Nitrogen sorption measurements and mercury porosimetry confirmed formation of a porous material with surface area ranging from 20 to 40 m(2)/g characterized by porosity of 70% and narrow pore size distribution with an average diameter around 700 nm without the presence of any micropores. The strong perfusive character of the synthesized material was confirmed by the existence of a plateau of the height equivalent to a theoretical plate measured at high reduced velocities using a chromatographic column packed with the synthesized microclusters. PMID- 26488234 TI - Differences in the calcification of preosteoblast cultured on sputter-deposited titanium, zirconium, and gold. AB - In this study, osteogenic differentiation and calcification of preosteoblast (MC3T3-E1) cultured on sputter-deposited titanium (Ti), zirconium (Zr), and gold (Au) on cover glasses were evaluated to understand the differences in bone formation ability among these three metals; these metals show the same high corrosion resistance, but Ti and Zr are covered by surface passive oxide film while Au is not covered by the oxide film. Ti and Zr promoted cellular proliferation without osteogenic differentiation. Cells cultured on Ti and Zr expressed higher levels of Runx2, Col1alpha1, and Akp2 at an earlier stage, which indicated faster promotion of osteogenic differentiation, as compared to those cultured on Au. Moreover, after 21 days of culture, the Bglap1 and Ifitm5 expression peaks in cells cultured on Ti and Zr were higher than those in cells cultured on Au, which indicated faster promotion of calcification. Cells cultured on Ti showed an advantage in osteogenic differentiation at an early stage, while cells on Zr showed better calcification promotion with a long-term culture. The amount of extracellular calcified deposits was in good agreement with the gene expression results. On the other hand, the intracellular calcium content of cells on Au specimens was higher than that of cells on Ti and Zr specimens. The results indicate that preosteoblasts on Ti and Zr showed faster osteogenic differentiation and calcification than those on Au, whereas Au improved the intracellular calcium content. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 639-651, 2016. PMID- 26488236 TI - How Bonding in Manganous Phosphates Affects their Mn(II)-(31)P Hyperfine Interactions. AB - Manganous phosphates have been postulated to play an important role in cells as antioxidants. In situ Mn(II) electron-nuclear double resonance (ENDOR) spectroscopy has been used to measure their speciation in cells. The analyses of such ENDOR spectra and the quantification of cellular Mn(II) phosphates has been based on comparisons to in vitro model complexes and heuristic modeling. In order to put such analyses on a more physical and theoretical footing, the Mn(II)-(31)P hyperfine interactions of various Mn(II) phosphate complexes have been measured by 95 GHz ENDOR spectroscopy. The dipolar components of these interactions remained relatively constant as a function of pH, esterification, and phosphate chain length, while the isotropic contributions were significantly affected. Counterintuitively, although the manganese-phosphate bonds are weakened by protonation and esterification, they lead to larger isotropic values, indicating higher unpaired-electron spin densities at the phosphorus nuclei. By comparison, extending the phosphate chain with additional phosphate groups lowers the spin density. Density functional theory calculations of model complexes quantitatively reproduced the measured hyperfine couplings and provided detailed insights into how bonding in Mn(II) phosphate complexes modulates the electron-spin polarization and consequently their isotropic hyperfine couplings. These results show that various classes of phosphates can be identified by their ENDOR spectra and provide a theoretical framework for understanding the in situ (31)P ENDOR spectra of cellular Mn(II) complexes. PMID- 26488235 TI - Warming accelerates termination of a phytoplankton spring bloom by fungal parasites. AB - Climate change is expected to favour infectious diseases across ecosystems worldwide. In freshwater and marine environments, parasites play a crucial role in controlling plankton population dynamics. Infection of phytoplankton populations will cause a transfer of carbon and nutrients into parasites, which may change the type of food available for higher trophic levels. Some phytoplankton species are inedible to zooplankton, and the termination of their population by parasites may liberate otherwise unavailable carbon and nutrients. Phytoplankton spring blooms often consist of large diatoms inedible for zooplankton, but the zoospores of their fungal parasites may serve as a food source for this higher trophic level. Here, we investigated the impact of warming on the fungal infection of a natural phytoplankton spring bloom and followed the response of a zooplankton community. Experiments were performed in ca. 1000 L indoor mesocosms exposed to a controlled seasonal temperature cycle and a warm (+4 degrees C) treatment in the period from March to June 2014. The spring bloom was dominated by the diatom Synedra. At the peak of infection over 40% of the Synedra population was infected by a fungal parasite (i.e. a chytrid) in both treatments. Warming did not affect the onset of the Synedra bloom, but accelerated its termination. Peak population density of Synedra tended to be lower in the warm treatments. Furthermore, Synedra carbon: phosphorus stoichiometry increased during the bloom, particularly in the control treatments. This indicates enhanced phosphorus limitation in the control treatments, which may have constrained chytrid development. Timing of the rotifer Keratella advanced in the warm treatments and closely followed chytrid infections. The chytrids' zoospores may thus have served as an alternative food source to Keratella. Our study thus emphasizes the importance of incorporating not only nutrient limitation and grazing, but also parasitism in understanding the response of plankton communities towards global warming. PMID- 26488237 TI - Seedless Growth of Palladium Nanocrystals with Tunable Structures: From Tetrahedra to Nanosheets. AB - Despite the great success that has been accomplished on the controlled synthesis of Pd nanocrystals with various sizes and morphologies, an efficient approach to systematic production of well-defined Pd nanocrystals without seed-mediated approaches remains a significant challenge. In this work, we have developed an efficient synthetic method to directly produce Pd nanocrystals with a highly controllable feature. Three distinct Pd nanocrystals, namely, Pd nanosheets, Pd concave tetrahedra, and Pd tetrahedra, have been selectively prepared by simply introducing a small amount of ascorbic acid (AA) and/or water without the other synthesis conditions changed. We found that the combined use of AA and water is of importance for the successful production of the unique Pd nanosheets. Detailed catalytic investigations showed that all the obtained Pd nanocrystals exhibit higher activity in the formic acid electrooxidation and styrene hydrogenation with respect to the Pd black, and their activities are highly shape-dependent with Pd nanosheets demonstrating a higher activity than both the Pd concave tetrahedra and Pd tetrahedra, which is likely due to the simple yet important feature of ultrathin thickness of Pd nanosheets. The present work highlights the importance of structures in tuning the related properties of metallic nanocrystals. PMID- 26488238 TI - Interactions of Bacterial Lipopolysaccharides with Gold Nanorod Surfaces Investigated by Refractometric Sensing. AB - The interface between nanoparticles and bacterial surfaces is of great interest for applications in nanomedicine and food safety. Here, we demonstrate that interactions between gold nanorods and bacterial surface molecules are governed by the nanoparticle surface coating. Polymer-coated gold nanorod substrates are exposed to lipopolysaccharides extracted from Pseudomonas aeruginosa, Salmonella enterica and Escherichia coli, and attachment is monitored using localized surface plasmon resonance refractometric sensing. The number of lipopolysaccharide molecules attached per nanorod is calculated from the shift in the plasmon maximum, which results from the change in refractive index after analyte binding. Colloidal gold nanorods in water are also incubated with lipopolysaccharides to demonstrate the effect of lipopolysaccharide concentration on plasmon shift, zeta-potential, and association constant. Both gold nanorod surface charge and surface chemistry affect gold nanorod-lipopolysaccharide interactions. In general, anionic lipopolysaccharides was found to attach more effectively to cationic gold nanorods than to neutral or anionic gold nanorods. Some variation in lipopolysaccharide attachment is also observed between the three strains studied, demonstrating the potential complexity of bacteria nanoparticle interactions. PMID- 26488239 TI - What roles do middle managers play in implementation of innovative practices? AB - BACKGROUND: Middle managers play key roles in hospitals as the bridge between senior leaders and frontline staff. Yet relatively little research has focused on their role in implementing new practices. PURPOSE: The aim of this study was to expand the understanding of middle managers' influence in organizations by looking at their activities through the lens of two complementary conceptual frameworks. METHODOLOGY/APPROACH: We analyzed qualitative data from 17 Veterans Affairs Medical Centers with high and low potential to change organizational practices. We analyzed 98 interviews with staff ranging from senior leaders to frontline staff to identify themes within an a priori framework reflecting middle manager activities. FINDINGS: Analyses yielded 14 emergent themes that allowed us to classify specific expressions of middle manager commitment to implementation of innovative practices (e.g., facilitate improvement innovation, garner staff buy-in). In comparing middle manager behaviors in high and low change potential sites, we found that most emergent themes were present in both groups. However, the activities and interactions described differed between the groups. PRACTICE IMPLICATIONS: Middle managers can use the promising strategies identified by our analyses to guide and improve their effectiveness in implementing new practices. These strategies can also inform senior leaders striving to guide middle managers in those efforts. PMID- 26488240 TI - Science masterclass. PMID- 26488241 TI - Cell imaging: Beyond the limits. PMID- 26488242 TI - Q&A: Memory man. PMID- 26488243 TI - Q&A: End-game winner. PMID- 26488244 TI - Q&A: Microbe cheerleader. PMID- 26488246 TI - Q&A: Boson beginnings. PMID- 26488245 TI - Q&A: Chance encounters. PMID- 26488247 TI - When a Care Map is Not a True Predictor of Clinical Outcomes. PMID- 26488250 TI - The 2014 Doris Schwartz Gerontological Nursing Research Award: Heather M. Young, PhD, RN, FAAN-Living Her Legacy of Caring for Older Adults. PMID- 26488251 TI - Medication Management and e-Care Planning: What are the Opportunities for the Future? AB - Effective communication and coordination of care is a priority strategy to improve health care quality in the United States. To address this strategy, care coordinators are being integrated into clinical practice settings and tasked with developing patient-centered care plans. One component of the care plan is the development of a medication list. This care plan medication list facilitates many medication management functions performed by pharmacists, such as identifying and resolving medication-related problems. Health information technology enables access to data to assist developing the medication list for the care plan and also provides routes to communicate the care plan with other health care providers, patients, and caregivers. The current article reviews the current landscape for promoting effective medication-related communication and care plan information. PMID- 26488252 TI - Older Adults Engaging in Online Dating: What Gerontological Nurses Should Know. AB - Many older adults maintain interest in intimate partner relationships and actively seek dates. Online dating websites are gaining popularity as being a convenient way to link with potential dates, particularly for women and individuals who live in independent dwellings or rural areas. Several online dating websites market exclusively to individuals 50 and older. Although connecting with others via the Internet can decrease social isolation, there are potential risks involved in online dating. Health care providers do not always assess dating and sexual health in the older adult population. Nurses are in a position to assess the dating relationships of older patients and can ask targeted questions to determine if patients are in a potentially risky relationship. A non-judgmental attitude and compassionate approach is essential. Knowledge of safe practices, alerting red flags, and available resources are essential tools for gerontological nurses to possess. PMID- 26488254 TI - Institutionalizing Clinical Reasoning: A Grounded Theory of the Clinical Reasoning Processes RNs Use to Recognize Delirium. AB - Delirium is a common disorder among hospitalized older adults often leading to prolonged hospitalization, increased health care costs, and sometimes death. The goal of the current study was to construct a grounded theory that explains the clinical reasoning processes that RNs use to recognize delirium in older adults in acute care settings. Seventeen participants in three hospitals were interviewed. The core category that emerged from the data was institutionalizing clinical reasoning. Findings from the current study can be a starting point for RNs to bring self-awareness to variables that influence their reasoning processes. PMID- 26488255 TI - Using a Robotic Cat in Dementia Care: A Pilot Study. AB - The current study aimed to explore (a) reactions of individuals with dementia to an interactive robotic cat and their relatives' and professional caregivers' experiences, and (b) to measure usability in developing the care/treatment of individuals with dementia using interactive robotic pets. An intervention design in a pilot study using mixed methods was conducted in two stages: a quantitative single-case study (n = 4) and a qualitative interview study (n = 14). Results indicated less agitated behavior and better quality of life for individuals with dementia. Interviews showed positive effects by providing increased interaction, communication, stimulation, relaxation, peace, and comfort to individuals with dementia. The tested interactive robotic cat was also considered easy to use. There is an increased need for alternative/complementary forms of care to meet an increasing number of individuals with dementia. For some individuals with dementia, an interactive robot, such as a robotic cat, can increase well-being and quality of life. PMID- 26488257 TI - Electrochemical Single-Molecule Transistors with Optimized Gate Coupling. AB - Electrochemical gating at the single molecule level of viologen molecular bridges in ionic liquids is examined. Contrary to previous data recorded in aqueous electrolytes, a clear and sharp peak in the single molecule conductance versus electrochemical potential data is obtained in ionic liquids. These data are rationalized in terms of a two-step electrochemical model for charge transport across the redox bridge. In this model the gate coupling in the ionic liquid is found to be fully effective with a modeled gate coupling parameter, xi, of unity. This compares to a much lower gate coupling parameter of 0.2 for the equivalent aqueous gating system. This study shows that ionic liquids are far more effective media for gating the conductance of single molecules than either solid-state three-terminal platforms created using nanolithography, or aqueous media. PMID- 26488256 TI - Lateralization of cervical spinal cord activity during an isometric upper extremity motor task with functional magnetic resonance imaging. AB - The purpose of this study was to use an isometric upper extremity motor task to detect activity induced blood oxygen level dependent signal changes in the cervical spinal cord with functional magnetic resonance imaging. Eleven healthy volunteers performed six 5minute runs of an alternating left- and right-sided isometric wrist flexion task, during which images of the cervical spinal cord were acquired with a reduced field-of-view T2*-weighted gradient-echo echo-planar imaging sequence. Spatial normalization to a standard spinal cord template was performed, and group average activation maps were generated in a mixed-effects analysis. The task activity significantly exceeded that of the control analyses. The activity was lateralized to the hemicord ipsilateral to the task and reliable across the runs at the group and subject level. Finally, a multi-voxel pattern analysis was able to successfully decode the left and right tasks at the C6 and C7 vertebral levels. PMID- 26488259 TI - Cooling Particle-Coated Bubbles: Destabilization beyond Dissolution Arrest. AB - Emulsions and foams that remain stable under varying environmental conditions are central in the food, personal care, and other formulated products industries. Foams stabilized by solid particles can provide longer-term stability than surfactant-stabilized foams. This stability is partly ascribed to the observation that solid particles can arrest bubble dissolution, which is driven by the Laplace pressure across the curved gas-liquid interface. We studied experimentally the effect of changes in temperature on the lifetime of particle coated air microbubbles in water. We found that a decrease in temperature destabilizes particle-coated microbubbles beyond dissolution arrest. A quasi steady model describing the effect of the change in temperature on mass transfer suggests that the dominant mechanism of destabilization is the increased solubility of the gas in the liquid, leading to a condition of undersaturation. Experiments at constant temperature confirmed that undersaturation alone can drive destabilization of particle-coated bubbles, even for vanishing Laplace pressure. We also found that dissolution of a particle-coated bubble can lead either to buckling of the coating or to gradual expulsion of particles, depending on the particle-to-bubble size ratio, with potential implications for controlled release. PMID- 26488258 TI - Co-infection with Drug-Susceptible and Reactivated Latent Multidrug-Resistant Mycobacterium tuberculosis. PMID- 26488260 TI - [Asylum Law and Mental Health: An Interdisciplinary Analysis of the Coaction of Medical and Legal Aspects]. AB - OBJECTIVE: Interdisciplinary analysis of the consequences of laws and legal practice for mental health conditions of asylum seekers and psychiatric care. METHODS: Based on the case study of a Kurdish woman with complex trauma-related psychiatric disorder, who had been in psychiatric hospital care for 25 months, the legal and medical facts are exposed, followed by a discussion referring to theoretical approaches from medical anthropology. RESULTS: Immigration laws and legal practice can have harmful consequences, which can be interpreted as "structural violence". CONCLUSION: In case of traumatized refugees, the coaction of legal and medical aspects has to be acknowledged seriously by the medical, legal and political parts involved. PMID- 26488261 TI - [ADHD: Burden of Disease According to Subtypes in Adult Patients]. AB - OBJECTIVES: In consideration of ADHD subtype we assessed burden of disease of adult ADHD patients and neuroticism. METHODS: 511 adult ADHD patients were enrolled in the study. We measured ADHD symptoms categorically and dimensionally by the "Homburger ADHS-Skalen fur Erwachsene (HASE)". All participants rated their ADHD associated level of suffering. To assess personality traits, the psychometric instrument NEO-PI-R was used. RESULTS: In patients with higher levels of neuroticism, there was no significant difference in the level of suffering between the ADHD subtypes. In the group of ADHD patients which scored low on the neuroticism scale, ADHD combined patients are significant more affected compared to the predominantly hyperactive-impulsive or the predominantly inattentive type. CONCLUSIONS: These results underline the hypothesis that the burden of disease is not only related to the level of ADHD symptoms and subtype but also moderated by neuroticism. PMID- 26488262 TI - [Establishment of an Animal Based Therapy at a University Hospital for Psychiatry: Results of a Preliminary Study and Future Prospects]. AB - Objective: Dogs have been integrated in human society over centuries. This process has selected unique social and communicative skills. Dogs are thus able to represent social substitutes for human counterparts in cases of social withdrawal. Furthermore, dogs act as "social catalysts" in promoting interhuman encounters. Thus, the integration of dogs in psychotherapeutic concepts addressing social and interpersonal deficits may be of special interest. Methods: The present investigation reports the results of a pilot study to establish animal-assisted therapy (dogs) at a psychiatric department. The animal-assisted intervention straddled the following areas: (1) contact making, communication and orientation to needs, (2) recreation and play, (3) outward orientation, (4) release and farewell. The sample comprised 22 subjects. Results: The results demonstrated in particular that the animal-assisted intervention significantly promoted unspecific aspects of positive affectivity and wellbeing. Evaluation of the overall acceptance of the dog on the psychiatric ward revealed very positive feedback. Conclusions: We conclude that animal-assisted therapies represent a significant enchrichment of the therapeutic context, that may be used to enhance the patients' openness and adherence to conventional therapies. PMID- 26488263 TI - [Evaluation of a Public Campaign on Mental Disorders - Results from "psychenet"]. AB - Objective: From 2011 to 2014, an information and awareness campaign was conducted in the framework of psychenet - Hamburg network for mental health. Evaluation is focused on two aspects: First, the reach of the campaign is examined. Second, effects of the campaign's key messages on public attitudes concerning mental disorders are analyzed. Methods: Analyses are based on two representative telephone surveys, conducted in Hamburg (intervention region) and Munich (control region) in 2011 prior (N = 2014) and 2014 post-campaign (N = 2006). Respondents were asked about their awareness of the psychenet campaign and to state their agreement or disagreement regarding attitudes and beliefs about mental disorders. Results: 7.3 % (74 of 1005) of the respondents from Hamburg were aware of psychenet. Compared to the other respondents, this subgroup displayed a stronger accordance with the campaign's key messages. However, regarding the total population over the course of time, differences in attitudes towards mental disorders were minor. Conclusion: Information and awareness campaigns seem to have minor effects on public attitudes towards mental disorders. Effects of specific campaign messages need to be examined more systematically. PMID- 26488264 TI - [Studies to Evaluate Outpatient Mental Health Services: Are Patients' Priorities Considered?] AB - Objective: To evaluate whether outcome measures in studies to evaluate outpatient mental health services reflect patients' priorities. Methods: Two systematic literature reviews were conducted to identify, 1) patients' priorities and 2) outcome measures that are used for evaluating outpatient mental health care. 3) The findings from the literature review for patients' priorities were contrasted with the findings from the literature review for outcome measures. Results: 19 patients' priorities and 48 outcome measures were identified. Only eight priorities were directly assessed by an outcome measure in evaluations of outpatient mental health care. Conclusion: The majority of studies that evaluate outpatient mental health care do not consider patients' priorities as an outcome. PMID- 26488265 TI - [Family Burden in the Case of Intellectual Disability and a Comorbid Mental Disorder]. AB - Objective: Within the MEMENTA-study informal caregivers of grown-up persons with an intellectual disability (ID) with and without a comorbid mental disorder were interviewed. Main outcomes were family burden, quality of life, psychiatric symptomatology and problem behavior. Methods: The sample consisted of 123 informal caregivers. Results: Problem behavior was associated with a higher family burden than psychiatric symptomatology. Conclusion: Rather than mental disorders, problem behavior seemed to be more relevant for the experience of family burden. PMID- 26488266 TI - [Subscription Rates of Psychiatric Patients to an Integrated Care Program in the Context of a Psychiatric Model Project]. AB - Objective: In the past years different model projects have been developed in Germany to counteract the known deficits of the German psychiatric care system. Among these, an "integrated care" model project has been set up which offers a more flexible way of managing psychiatric care, especially for patients with a severe mental illness. It however implies an active subscription to the program. In this study we analyzed factors influencing patients' subscription rates. Methods: Subscription rates during the first 18 months of the program were analyzed with regard to the patients' main diagnoses and gender. Results: We found an overall subscription rate of 59.3 %. Diagnosis explained 24.1 % of the overall variance of the inpatients' subscription rate. This effect was significantly smaller in outpatients. No effect of gender could be observed. The highest subscription rate was found by patients with an affective disorder. Only 34.6 % of the patients with an F2 diagnosis subscribed. Conclusion: The target groups of the program could not be sufficiently reached in this model. The need of a new legal basis for psychiatric care models, namely a subscription-free program, is thereby reinforced. PMID- 26488267 TI - [From the Auschwitz Syndrome to a Psyche Model--Life and Work of the Polish Psychiatrist Antoni Kepinski (1918-1972)]. AB - OBJECTIVE: Life and work of the Polish psychiatrist Antoni Kepinski (1918 - 1972) are barely known today, although his writings about the Auschwitz syndrome have had an impact all over the world. We present his biography and work. METHODS: Compilation and evaluation of literature about Kepinski's work and historical critical analysis of his key texts. RESULTS: Kepinski's work about the Auschwitz syndrome formed the basis for his understanding of the psyche and his theory on information metabolism. Kepinski posited that the mind processes outside stimuli based on its own set of values and that it determines the subject's actions. In doing so, it affects its environment. If these interactions are disrupted, pathological disorders might result. The therapist should consequently empower the patient to get in touch with his own value-system. CONCLUSION: Kepinskis work serves as a foundation for research on disease patterns that are known today as post-traumatic stress disorder (PTSD). His theory on information metabolism is essential for the current treatment of patients. It is therefore important to further explore his work and adjust it to the requirements of medical practice. PMID- 26488268 TI - Making ADHD Evident: Data, Practices, and Diagnostic Protocols in Portugal. AB - Drawing on medical anthropology and science and technology studies, I present a case study of the diagnosis of attention deficit hyperactivity disorder (ADHD) in Portugal. In a country where ADHD is a relatively recent medical category, still undergoing validation, the diagnosis is not primarily bound to an evidence-making role, and its epidemiology remains largely unknown. Notwithstanding, the diagnosis has been carried out by child psychiatrists and developmental clinicians who describe it as the most prevalent disorder that affects school aged children and adolescents. In this article, I examine the global data, local diagnostic protocols, and clinical practices that are adapted and selectively mobilized in the making of the diagnosis, in a context in which making ADHD evident is at stake. The findings show that what counts as ADHD and what it means in each setting varies, and that the diagnosis may be understood as a situated process. PMID- 26488270 TI - Prostate Cancer Immunotherapy with Sipuleucel-T: Current Standards and Future Directions. AB - The management of advanced prostate cancer, specifically metastatic castrate resistant prostate cancer (mCRPC), remains a therapeutic challenge. Sipuleucel-T (Provenge; APC8015) was approved by the FDA in 2010 for the treatment of asymptomatic or minimally symptomatic mCRPC patients, and it remains the only FDA approved immunotherapy for prostate cancer of any indication to date. Given the continued need to improve therapeutics in patients with advanced prostate cancer, as well as recent enthusiasm for cancer immunotherapy, there is a wide range of ongoing trials evaluating combinations of sipuleucel-T with other therapeutics. Additional trials are aiming to expand the application of sipuleucel-T to prostate cancer patients beyond the mCRPC setting. Ongoing challenges include understanding the full mechanism of action of sipuleucel-T, optimizing the sequence of sipuleucel-T in relation to other therapies for mCRPC in clinical practice, and the identification of surrogate markers to predict survival benefit in clinical trials. PMID- 26488269 TI - Human Papillomavirus Vaccine Uptake After a Tailored, Online Educational Intervention for Female University Students: A Randomized Controlled Trial. AB - BACKGROUND: Educational interventions may be a strategy to increase human papillomavirus (HPV) vaccination among female university students, but studies to date have shown mixed results. This study evaluated the effect of MeFirst, an individually tailored, online educational intervention, on HPV vaccine-related knowledge, vaccination intention, and uptake among previously unvaccinated female university students. METHODS: All female students aged 18-26 years who reported being unvaccinated against HPV at a midwestern university were invited via email to enroll. Participants completed an online survey that assessed baseline HPV vaccine-related knowledge, attitudes and vaccination intention. Participants (n = 661) were then randomized to receive either an educational website automatically tailored to their baseline survey responses (MeFirst intervention) or a standard CDC information factsheet on HPV vaccine (control). Vaccine uptake and repeat knowledge and attitude measures were assessed with online surveys 3 months following the intervention and analyzed using logistic regression models. RESULTS: HPV vaccine uptake was similar in both the MeFirst and control groups at 3 months following the intervention (p = 0.98). Three months after the intervention, the proportion of participants with high knowledge regarding HPV vaccination increased from baseline (32% to 50%; p < 0.0001) but the proportion with favorable intention was unchanged. CONCLUSIONS: We found that an individually tailored, online educational tool had similar effects as a nontailored factsheet on HPV-related knowledge, intention to HPV undergo vaccination, and HPV vaccine uptake among previously unvaccinated female university students. PMID- 26488271 TI - Cystic Fibrosis Transmembrane Conductance Regulator in Sarcoplasmic Reticulum of Airway Smooth Muscle. Implications for Airway Contractility. AB - RATIONALE: An asthma-like airway phenotype has been described in people with cystic fibrosis (CF). Whether these findings are directly caused by loss of CF transmembrane conductance regulator (CFTR) function or secondary to chronic airway infection and/or inflammation has been difficult to determine. OBJECTIVES: Airway contractility is primarily determined by airway smooth muscle. We tested the hypothesis that CFTR is expressed in airway smooth muscle and directly affects airway smooth muscle contractility. METHODS: Newborn pigs, both wild type and with CF (before the onset of airway infection and inflammation), were used in this study. High-resolution immunofluorescence was used to identify the subcellular localization of CFTR in airway smooth muscle. Airway smooth muscle function was determined with tissue myography, intracellular calcium measurements, and regulatory myosin light chain phosphorylation status. Precision cut lung slices were used to investigate the therapeutic potential of CFTR modulation on airway reactivity. MEASUREMENTS AND MAIN RESULTS: We found that CFTR localizes to the sarcoplasmic reticulum compartment of airway smooth muscle and regulates airway smooth muscle tone. Loss of CFTR function led to delayed calcium reuptake following cholinergic stimulation and increased myosin light chain phosphorylation. CFTR potentiation with ivacaftor decreased airway reactivity in precision-cut lung slices following cholinergic stimulation. CONCLUSIONS: Loss of CFTR alters porcine airway smooth muscle function and may contribute to the airflow obstruction phenotype observed in human CF. Airway smooth muscle CFTR may represent a therapeutic target in CF and other diseases of airway narrowing. PMID- 26488272 TI - My Lifelong Passion for Biochemistry and Anaerobic Microorganisms. AB - Early parental influence led me first to medical school, but after developing a passion for biochemistry and sensing the need for a deeper foundation, I changed to chemistry. During breaks between semesters, I worked in various biochemistry labs to acquire a feeling for the different areas of investigation. The scientific puzzle that fascinated me most was the metabolism of the anaerobic bacterium Clostridium kluyveri, which I took on in 1965 in Karl Decker's lab in Freiburg, Germany. I quickly realized that little was known about the biochemistry of strict anaerobes such as clostridia, methanogens, acetogens, and sulfate-reducing bacteria and that these were ideal model organisms to study fundamental questions of energy conservation, CO2 fixation, and the evolution of metabolic pathways. My passion for anaerobes was born then and is unabated even after 50 years of study. PMID- 26488275 TI - Molecular Pathogenesis of Ehrlichia chaffeensis Infection. AB - Ehrlichia chaffeensis is an obligatory intracellular and cholesterol-dependent bacterium that has evolved special proteins and functions to proliferate inside leukocytes and cause disease. E. chaffeensis has a multigene family of major outer membrane proteins with porin activity and induces infectious entry using its entry-triggering protein to bind the human cell surface protein DNase X. During intracellular replication, three functional pairs of two-component systems are sequentially expressed to regulate metabolism, aggregation, and the development of stress-resistance traits for transmission. A type IV secretion effector of E. chaffeensis blocks mitochondrion-mediated host cell apoptosis. Several type I secretion proteins are secreted at the Ehrlichia-host interface. E. chaffeensis strains induce strikingly variable inflammation in mice. The central role of MyD88, but not Toll-like receptors, suggests that Ehrlichia species have unique inflammatory molecules. A recent report about transient targeted mutagenesis and random transposon mutagenesis suggests that stable targeted knockouts may become feasible in Ehrlichia. PMID- 26488274 TI - Bacterial Proteasomes. AB - Interest in bacterial proteasomes was sparked by the discovery that proteasomal degradation is required for the pathogenesis of Mycobacterium tuberculosis, one of the world's deadliest pathogens. Although bacterial proteasomes are structurally similar to their eukaryotic and archaeal homologs, there are key differences in their mechanisms of assembly, activation, and substrate targeting for degradation. In this article, we compare and contrast bacterial proteasomes with their archaeal and eukaryotic counterparts, and we discuss recent advances in our understanding of how bacterial proteasomes function to influence microbial physiology. PMID- 26488276 TI - The Unique Molecular Choreography of Giant Pore Formation by the Cholesterol Dependent Cytolysins of Gram-Positive Bacteria. AB - The mechanism by which the cholesterol-dependent cytolysins (CDCs) assemble their giant beta-barrel pore in cholesterol-rich membranes has been the subject of intense study in the past two decades. A combination of structural, biophysical, and biochemical analyses has revealed deep insights into the series of complex and highly choreographed secondary and tertiary structural transitions that the CDCs undergo to assemble their beta-barrel pore in eukaryotic membranes. Our knowledge of the molecular details of these dramatic structural changes in CDCs has transformed our understanding of how giant pore complexes are assembled and has been critical to our understanding of the mechanisms of other important classes of pore-forming toxins and proteins across the kingdoms of life. Finally, there are tantalizing hints that the CDC pore-forming mechanism is more sophisticated than previously imagined and that some CDCs are employed in pore independent processes. PMID- 26488277 TI - Ion Regulation in the Malaria Parasite. AB - Some hours after invading the erythrocytes of its human host, the malaria parasite Plasmodium falciparum induces an increase in the permeability of the erythrocyte membrane to monovalent ions. The resulting net influx of Na(+) and net efflux of K(+), down their respective concentration gradients, converts the erythrocyte cytosol from an initially high-K(+), low-Na(+) solution to a high Na(+), low-K(+) solution. The intraerythrocytic parasite itself exerts tight control over its internal Na(+), K(+), Cl(-), and Ca(2+) concentrations and its intracellular pH through the combined actions of a range of membrane transport proteins. The molecular mechanisms underpinning ion regulation in the parasite are receiving increasing attention, not least because PfATP4, a P-type ATPase postulated to be involved in Na(+) regulation, has emerged as a potential antimalarial drug target, susceptible to inhibition by a wide range of chemically unrelated compounds. PMID- 26488273 TI - Candida albicans Biofilms and Human Disease. AB - In humans, microbial cells (including bacteria, archaea, and fungi) greatly outnumber host cells. Candida albicans is the most prevalent fungal species of the human microbiota; this species asymptomatically colonizes many areas of the body, particularly the gastrointestinal and genitourinary tracts of healthy individuals. Alterations in host immunity, stress, resident microbiota, and other factors can lead to C. albicans overgrowth, causing a wide range of infections, from superficial mucosal to hematogenously disseminated candidiasis. To date, most studies of C. albicans have been carried out in suspension cultures; however, the medical impact of C. albicans (like that of many other microorganisms) depends on its ability to thrive as a biofilm, a closely packed community of cells. Biofilms are notorious for forming on implanted medical devices, including catheters, pacemakers, dentures, and prosthetic joints, which provide a surface and sanctuary for biofilm growth. C. albicans biofilms are intrinsically resistant to conventional antifungal therapeutics, the host immune system, and other environmental perturbations, making biofilm-based infections a significant clinical challenge. Here, we review our current knowledge of biofilms formed by C. albicans and closely related fungal species. PMID- 26488278 TI - Physics of Intracellular Organization in Bacteria. AB - With the realization that bacteria achieve exquisite levels of spatiotemporal organization has come the challenge of discovering the underlying mechanisms. In this review, we describe three classes of such mechanisms, each of which has physical origins: the use of landmarks, the creation of higher-order structures that enable geometric sensing, and the emergence of length scales from systems of chemical reactions coupled to diffusion. We then examine the diversity of geometric cues that exist even in cells with relatively simple geometries, and end by discussing both new technologies that could drive further discovery and the implications of our current knowledge for the behavior, fitness, and evolution of bacteria. The organizational strategies described here are employed in a wide variety of systems and in species across all kingdoms of life; in many ways they provide a general blueprint for organizing the building blocks of life. PMID- 26488279 TI - Assembly of the Mycobacterial Cell Wall. AB - Mycobacterium tuberculosis remains one of the most successful bacterial pathogens, claiming over 1.3 million lives worldwide in 2013. The emergence of multidrug-resistant and extensively drug-resistant isolates has prompted the need for new drugs and drug targets. M. tuberculosis possesses an unusual cell wall dominated by lipids and carbohydrates that provides a permeability barrier against hydrophilic drugs and is crucial for its survival and virulence. This large macromolecular structure, termed the mycolyl-arabinogalactan-peptidoglycan complex, and the phosphatidyl-myo-inositol-based lipoglycans are key features of the mycobacterial cell wall. Assembly of these cell wall components is an attractive target for the development of chemotherapeutics against tuberculosis. Herein, we focus on recent biochemical and molecular insights into these complex molecules of M. tuberculosis cell wall. PMID- 26488280 TI - Mechanisms of Bacterial Colonization of the Respiratory Tract. AB - Respiratory tract infections are an important cause of morbidity and mortality worldwide. Chief among these are infections involving the lower airways. The opportunistic bacterial pathogens responsible for most cases of pneumonia can cause a range of local and invasive infections. However, bacterial colonization (or carriage) in the upper airway is the prerequisite of all these infections. Successful colonizers must attach to the epithelial lining, grow on the nutrient limited mucosal surface, evade the host immune response, and transmit to a susceptible host. Here, we review the molecular mechanisms underlying these conserved stages of carriage. We also examine how the demands of colonization influence progression to disease. A range of bacteria can colonize the upper airway; nevertheless, we focus on strategies shared by many respiratory tract opportunistic pathogens. Understanding colonization opens a window to the evolutionary pressures these pathogens face within their animal hosts and that have selected for attributes that contribute to virulence and pathogenesis. PMID- 26488283 TI - How Is Fe-S Cluster Formation Regulated? AB - Iron-sulfur (Fe-S) clusters are fundamental to numerous biological processes in most organisms, but these protein cofactors can be prone to damage by various oxidants (e.g., O2, reactive oxygen species, and reactive nitrogen species) and toxic levels of certain metals (e.g., cobalt and copper). Furthermore, their synthesis can also be directly influenced by the level of available iron in the environment. Consequently, the cellular need for Fe-S cluster biogenesis varies with fluctuating growth conditions. To accommodate changes in Fe-S demand, microorganisms employ diverse regulatory strategies to tailor Fe-S cluster biogenesis according to their surroundings. Here, we review the mechanisms that regulate Fe-S cluster formation in bacteria, primarily focusing on control of the Isc and Suf Fe-S cluster biogenesis systems in the model bacterium Escherichia coli. PMID- 26488284 TI - Fenofibrate Reverses Palmitate Induced Impairment in Glucose Uptake in Skeletal Muscle Cells by Preventing Cytosolic Ceramide Accumulation. AB - BACKGROUNDS/AIMS: The lipid induced insulin resistance is a major pathophysiologic mechanism underlying glucose intolerance of varying severity. PPARalpha-agonists are proven as effective hypolipidemic agents. The aim of this study was to see if impaired glucose uptake in palmitate treated myotubes is reversed by fenofibrate. METHODS: Palmitate-treated myotubes were used as a model for insulin resistance, impaired glucose uptake, fatty acid oxidation and ceramide synthesis. mRNA levels of CPT1 and CPT2 were determined by PCR array and Q-PCR. RESULTS: The incubation of myotubes with 750 uM palmitate not only reduced glucose uptake but also impaired fatty acid oxidation and cytosolic ceramide accumulation. Palmitate upregulated CPT1b expression in L6 myotubes, while CPT2 expression level remained unchanged. The altered stoichiometric ratio between the two CPT isoforms led to reduced fatty acid oxidation (FAO), ceramide accumulation and impaired glucose uptake, whereas administration of 200 uM fenofibrate significantly reversed the above abnormalities by increasing CPT2 mRNA levels and restoring CPT1b to CPT2 ratio. CONCLUSION: Palmitate-induced alteration in the stoichiometric ratio of mitochondrial CPT isoforms leads to incomplete FAO and enhanced cytosolic ceramide accumulation that lead to insulin resistance. Fenofibrate ameliorated insulin resistance by restoring the altered stoichiometry by upregulating CPT2 and preventing, cytoplasmic ceramide accumulation. PMID- 26488282 TI - Septins and Generation of Asymmetries in Fungal Cells. AB - Polarized growth is critical for the development and maintenance of diverse organisms and tissues but particularly so in fungi, where nutrient uptake, communication, and reproduction all rely on cell asymmetries. To achieve polarized growth, fungi spatially organize both their cytosol and cortical membranes. Septins, a family of GTP-binding proteins, are key regulators of spatial compartmentalization in fungi and other eukaryotes. Septins form higher order structures on fungal plasma membranes and are thought to contribute to the generation of cell asymmetries by acting as molecular scaffolds and forming diffusional barriers. Here we discuss the links between septins and polarized growth and consider molecular models for how septins contribute to cellular asymmetry in fungi. PMID- 26488281 TI - Interactions Between the Gastrointestinal Microbiome and Clostridium difficile. AB - Antibiotics have significant and long-lasting effects on the intestinal microbiota and consequently reduce colonization resistance against pathogens, including Clostridium difficile. By altering the community structure of the gut microbiome, antibiotics alter the intestinal metabolome, which includes both host and microbe-derived metabolites. The mechanisms by which antibiotics reduce colonization resistance against C. difficile are unknown yet important for development of preventative and therapeutic approaches against this pathogen. This review focuses on how antibiotics alter the structure of the gut microbiota and how this alters microbial metabolism in the intestine. Interactions between gut microbial products and C. difficile spore germination, growth, and toxin production are discussed. New bacterial therapies to restore changes in bacteria driven intestinal metabolism following antibiotics will have important applications for treatment and prevention of C. difficile infection. PMID- 26488285 TI - Effects of Propofol on the Dynamic Properties of Sensory Information Processing in the Mouse Cerebellar Cortical Molecular Layer in vivo. AB - Propofol is a global central nervous system depressant that affects information processing in the central nervous system. However, the effects of propofol on sensory information processing in the cerebellar cortical molecular layer are unknown. In this study, we examined the effects of propofol on the dynamics of sensory stimulation-evoked responses in the cerebellar molecular layer in urethane-anesthetized mice, using electrophysiological and pharmacological methods. Our results showed that cerebellar surface perfusion of propofol (10 1,000 MUmol/l) significantly decreased amplitude and area under the curve (AUC) of the sensory stimulation-evoked inhibitory component (P1) but increased the rise time and decay time of P1. In contrast, administration of propofol significantly enhanced the sensory stimulation-evoked excitatory component (N1), which exhibited increases in amplitude and AUC, as well as increases in rise time and decay time. By blocking the GABAA receptor activity, propofol failed to increase the amplitude and the AUC of the excitatory postsynaptic component (N2) of PCs. Our present results suggest that propofol modulates the dynamic properties of the sensory information processing in the cerebellar molecular layer through the modulation of GABAA receptors activity in the adult mouse. PMID- 26488286 TI - Profiling Surgical Staplers: Does Staple Direction Affect the Strength of the Anastomosis. AB - BACKGROUND: Few studies have been conducted regarding the optimal staple direction in gastrointestinal anastomosis. The purpose of this study was to evaluate the burst pressure of the anastomosis depending on the firing direction of the stapler. METHODS: Pig esophagus and small bowel were used for all experiments. The small intestine represented a thin intestinal tract and the esophagus represented a thick intestinal tract. A side-to-side anastomosis was performed using a linear stapler, and the burst pressure was measured. A leak test on the anastomosis was then performed and burst pressures measured. RESULTS: Burst pressures after anastomosis using a GIATM 100-3.8 were 47.4 +/- 10.4 mm Hg. With the same GIA, the burst pressure was significantly greater when the staples were driven from the small intestine into the esophagus (83.3 +/- 17.3 mm Hg). Using the GIATM 100-4.8, it was found that the burst pressure was significantly greater when the staplers were driven into the small intestine versus the esophagus (51.6 +/- 7.1 vs. 68.6 +/- 16.1 mm Hg). There was no significant difference between the different GIAs when fired in the same direction. CONCLUSION: Burst pressures were significantly greater when the staplers were driven from the small intestine into the esophagus. The direction of the staple line influences the strength of the anastomosis. PMID- 26488287 TI - Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage. Many molecular targeted agents are being developed for the treatment of advanced HCC; however, the only promising drug to have been developed is sorafenib, which acts as a multi-kinase inhibitor. Unfortunately, a subgroup of HCC is resistant to sorafenib, and the majority of these HCC patients show disease progression even after an initial satisfactory response. To date, a number of studies have examined the underlying mechanisms involved in the response to sorafenib, and trials have been performed to overcome the acquisition of drug resistance. The anti-tumor activity of sorafenib is largely attributed to the blockade of the signals from growth factors, such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor, and the downstream RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade. The activation of an escape pathway from RAF/MEK/ERK possibly results in chemoresistance. In addition, there are several features of HCCs indicating sorafenib resistance, such as epithelial-mesenchymal transition and positive stem cell markers. Here, we review the recent reports and focus on the mechanism and prediction of chemoresistance to sorafenib in HCC. PMID- 26488288 TI - Comparison of Medial and Lateral Meniscus Root Tears. AB - The meniscus root plays an essential role in maintaining the circumferential hoop tension and preventing meniscal displacement. Studies on meniscus root tears have investigated the relationship of osteoarthritis and an anterior cruciate ligament tear. However, few studies have directly compared the medial and lateral root tears. To assess the prevalence of meniscal extrusion and its relationship with clinical features in medial and lateral meniscus root tears, we performed a retrospective review of the magnetic resonance imaging (MRI) results of 42 knee patients who had meniscus posterior horn root tears and who had undergone arthroscopic operations. The presence of meniscal extrusion was evaluated and the exact extent was measured from the tibial margin. The results were correlated with arthroscopic findings. Clinical features including patients' ages, joint abnormalities, and previous trauma histories were evaluated. Twenty-two patients had medial meniscus root tears (MMRTs) and twenty patients had lateral meniscus root tears (LMRTs). Meniscal extrusion was present in 18 MMRT patients and one LMRT patient. The mean extent of extrusion was 4.2mm (range, 0.6 to 7.8) in the MMRT group and 0.9mm (range, -1.9 to 3.4) in the LMRT group. Five patients with MMRT had a history of trauma, while 19 patients with LMRT had a history of trauma. Three patients with MMRT had anterior cruciate ligament (ACL) tears, while 19 patients with LMRT had ACL tears. The mean age of the patients was 52 years (range: 29-71 years) and 30 years (range: 14-62 years) in the MMRT and LMRT group, respectively. There was a significant correlation between a MMRT and meniscal extrusion (p<0.0001), and between an ACL tear and LMRT (p<0.0001). A history of trauma was significantly common in LMRT (p<0.0001). LMRT patients were significantly younger than MMRT patients (p<0.0001). Kellgren-Lawrence (K-L) grade differed significantly between MMRT and LMRT group (p<0.0001). Meniscal extrusion is common in patients with MMRTs. However, it is rare in patients with LMRTs, which are more commonly associated with a history of trauma and ACL tears. PMID- 26488289 TI - Functional Activation during the Rapid Visual Information Processing Task in a Middle Aged Cohort: An fMRI Study. AB - The Rapid Visual Information Processing (RVIP) task, a serial discrimination task where task performance believed to reflect sustained attention capabilities, is widely used in behavioural research and increasingly in neuroimaging studies. To date, functional neuroimaging research into the RVIP has been undertaken using block analyses, reflecting the sustained processing involved in the task, but not necessarily the transient processes associated with individual trial performance. Furthermore, this research has been limited to young cohorts. This study assessed the behavioural and functional magnetic resonance imaging (fMRI) outcomes of the RVIP task using both block and event-related analyses in a healthy middle aged cohort (mean age = 53.56 years, n = 16). The results show that the version of the RVIP used here is sensitive to changes in attentional demand processes with participants achieving a 43% accuracy hit rate in the experimental task compared with 96% accuracy in the control task. As shown by previous research, the block analysis revealed an increase in activation in a network of frontal, parietal, occipital and cerebellar regions. The event related analysis showed a similar network of activation, seemingly omitting regions involved in the processing of the task (as shown in the block analysis), such as occipital areas and the thalamus, providing an indication of a network of regions involved in correct trial performance. Frontal (superior and inferior frontal gryi), parietal (precuenus, inferior parietal lobe) and cerebellar regions were shown to be active in both the block and event-related analyses, suggesting their importance in sustained attention/vigilance. These networks and the differences between them are discussed in detail, as well as implications for future research in middle aged cohorts. PMID- 26488290 TI - Dynamic Behavior of Reciprocating Plunger Pump Discharge Valve Based on Fluid Structure Interaction and Experimental Analysis. AB - The influence of spring stiffness and valve quality on the motion behaviors of reciprocating plunger pump discharge valves was investigated by fluid structure interaction (FSI) simulation and experimental analysis. The mathematical model of the discharge valve motion of a 2000-fracturing pump was developed and the discrete differential equations were solved according to FSI and results obtained by ANDINA software. Results indicate that spring stiffness influences the maximum lift, the opening resistance and shut-off lag angle, as well as the fluid velocity of the clearance, the impact stress and the volume efficiency of the pump valve in relation to the valve quality. An optimal spring stiffness parameter of 14.6 N/mm was obtained, and the volumetric efficiency of the pumping valve increased by 40/00 in comparison to results obtained with the original spring stiffness of 10.09N/mm. The experimental results indicated that the mathematical model and FSI method could provide an effective approach for the subsequent improvement of valve reliability, volumetric efficiency and lifespan. PMID- 26488292 TI - Chronic Liver Diseases and Liver Cancer: An Update in 2015. PMID- 26488291 TI - Paleopathological Study of Dwarfism-Related Skeletal Dysplasia in a Late Joseon Dynasty (South Korean) Population. AB - Skeletal dysplasias related to genetic etiologies have rarely been reported for past populations. This report presents the skeletal characteristics of an individual with dwarfism-related skeletal dysplasia from South Korea. To assess abnormal deformities, morphological features, metric data, and computed tomography scans are analyzed. Differential diagnoses include achondroplasia or hypochondroplasia, chondrodysplasia, multiple epiphyseal dysplasia, thalassemia related hemolytic anemia, and lysosomal storage disease. The diffused deformities in the upper-limb bones and several coarsened features of the craniofacial bones indicate the most likely diagnosis to have been a certain type of lysosomal storage disease. The skeletal remains of EP-III-4-No.107 from the Eunpyeong site, although incomplete and fragmented, provide important clues to the paleopathological diagnosis of skeletal dysplasias. PMID- 26488293 TI - A Simple Method for Discovering Druggable, Specific Glycosaminoglycan-Protein Systems. Elucidation of Key Principles from Heparin/Heparan Sulfate-Binding Proteins. AB - Glycosaminoglycans (GAGs) affect human physiology and pathology by modulating more than 500 proteins. GAG-protein interactions are generally assumed to be ionic and nonspecific, but specific interactions do exist. Here, we present a simple method to identify the GAG-binding site (GBS) on proteins that in turn helps predict high specific GAG-protein systems. Contrary to contemporary thinking, we found that the electrostatic potential at basic arginine and lysine residues neither identifies the GBS consistently, nor its specificity. GBSs are better identified by considering the potential at neutral hydrogen bond donors such as asparagine or glutamine sidechains. Our studies also reveal that an unusual constellation of ionic and non-ionic residues in the binding site leads to specificity. Nature engineers the local environment of Asn45 of antithrombin, Gln255 of 3-O-sulfotransferase 3, Gln163 and Asn167 of 3-O-sulfotransferase 1 and Asn27 of basic fibroblast growth factor in the respective GBSs to induce specificity. Such residues are distinct from other uncharged residues on the same protein structure in possessing a significantly higher electrostatic potential, resultant from the local topology. In contrast, uncharged residues on nonspecific GBSs such as thrombin and serum albumin possess a diffuse spread of electrostatic potential. Our findings also contradict the paradigm that GAG-binding sites are simply a collection of contiguous Arg/Lys residues. Our work demonstrates the basis for discovering specifically interacting and druggable GAG-protein systems based on the structure of protein alone, without requiring access to any structure-function relationship data. PMID- 26488294 TI - Design and Characterization of Bioengineered Cancer-Like Stem Cells. AB - Cancer stem cells (CSCs) are a small subset of cancer cells responsible for maintenance and progression of several types of cancer. Isolation, propagation, and the differentiation of CSCs in the proper stem niches expose the intrinsic difficulties for further studies. Here we show that induced cancer like stem cells (iCLSCs) can be generated by in vitro oncogenic manipulation of mouse embryonic stem cells (mESCs) with well-defined oncogenic elements; SV40 LTg and HrasV12 by using a mouse stem virus long terminal repeat (MSCV-LTR)-based retroviral system. The reprogrammed mESCs using both oncogenes were characterized through their oncogenic gene expression, the enhancement of proliferation, and unhampered maintenance of stem properties in vitro and in vivo. In addition, these transformed cells resulted in the formation of malignant, immature ovarian teratomas in vivo. To successfully further expand these properties to other organs and species, more research needs to be done to fully understand the role of a tumor- favorable microenvironment. Our current study has provided a novel approach to generate induced cancer like stem cells through in vitro oncogenic reprogramming and successfully initiated organ-specific malignant tumor formation in an orthotopic small animal cancer model. PMID- 26488295 TI - Correction: Multivariate Meta-Analysis of Genetic Association Studies: A Simulation Study. PMID- 26488296 TI - Abscisic Acid Stimulates Glucagon-Like Peptide-1 Secretion from L-Cells and Its Oral Administration Increases Plasma Glucagon-Like Peptide-1 Levels in Rats. AB - In recent years, Abscisic Acid (ABA) has been demonstrated to be involved in the regulation of glucose homeostasis in mammals as an endogenous hormone, by stimulating both insulin release and peripheral glucose uptake. In addition, ABA is released by glucose- or GLP-1-stimulated beta-pancreatic cells. Here we investigated whether ABA can stimulate GLP-1 release. The human enteroendocrine L cell line hNCI-H716 was used to explore whether ABA stimulates in vitro GLP-1 secretion and/or transcription. ABA induced GLP-1 release in hNCI-H716 cells, through a cAMP/PKA-dependent mechanism. ABA also enhanced GLP-1 transcription. In addition, oral administration of ABA significantly increased plasma GLP-1 and insulin levels in rats. In conclusion, ABA can stimulate GLP-1 release: this result and the previous observation that GLP-1 stimulates ABA release from beta cells, suggest a positive feed-back mechanism between ABA and GLP-1, regulating glucose homeostasis. Type 2 diabetes treatments targeting the GLP-1 axis by either inhibiting its rapid clearance by dipeptidyl-peptidase IV or using GLP-1 mimetics are currently used. Moreover, the development of treatments aimed at stimulating GLP-1 release from L cells has been considered as an alternative approach. Accordingly, our finding that ABA increases GLP-1 release in vitro and in vivo may suggest ABA and/or ABA analogs as potential anti-diabetic treatments. PMID- 26488297 TI - Molecular Genetic and Crystal Structural Analysis of 1-(4-Hydroxyphenyl)-Ethanol Dehydrogenase from 'Aromatoleum aromaticum' EbN1. AB - The dehydrogenation of 1-(4-hydroxyphenyl)-ethanol to 4-hydroxyacetophenone represents the second reaction step during anaerobic degradation of p-ethylphenol in the denitrifying bacterium 'Aromatoleum aromaticum' EbN1. Previous proteogenomic studies identified two different proteins (ChnA and EbA309) as possible candidates for catalyzing this reaction [Wohlbrand et al: J Bacteriol 2008;190:5699-5709]. Physiological-molecular characterization of newly generated unmarked in-frame deletion and complementation mutants allowed defining ChnA (renamed here as Hped) as the enzyme responsible for 1-(4-hydroxyphenyl)-ethanol oxidation. Hped [1-(4-hydroxyphenyl)-ethanol dehydrogenase] belongs to the 'classical' family within the short-chain alcohol dehydrogenase/reductase (SDR) superfamily. Hped was overproduced in Escherichia coli, purified and crystallized. The X-ray structures of the apo- and NAD(+)-soaked form were resolved at 1.5 and 1.1 A, respectively, and revealed Hped as a typical homotetrameric SDR. Modeling of the substrate 4-hydroxyacetophenone (reductive direction of Hped) into the active site revealed the structural determinants of the strict (R)-specificity of Hped (Phe(187)), contrasting the (S)-specificity of previously reported 1-phenylethanol dehydrogenase (Ped; Tyr(93)) from strain EbN1 [Hoffken et al: Biochemistry 2006;45:82-93]. PMID- 26488298 TI - Korean Version of a Model to Estimate Survival in Ambulatory Patients with Hepatocellular Carcinoma (K-MESIAH). AB - BACKGROUND AND AIM: A model to estimate survival in ambulatory hepatocellular carcinoma patients (MESIAH) is useful for estimating patient prognosis but needs improvement for Korean patients, most of whom have a hepatitis B virus. We aimed to modify the MESIAH for better prognostication through enhancing calibration for Korean patient population (K-MESIAH). METHODS: Utilizing a cohort of 1,969 hepatocellular carcinoma (HCC) patients from the National Cancer Center of Korea between 2004 and 2009, a survival prediction model was developed using the Cox proportional hazards model. The model's performance was evaluated using C statistical and chi2-statistical analyses. External validation was performed using an independent cohort of 328 patients from the Seoul National University Bundang Hospital. RESULTS: To develop the K-MESIAH, etiology was added to the original risk factors (age, Model for Endstage Liver Disease, albumin, size of the largest nodule, number of tumor nodules, vascular invasion, metastasis, and alpha fetoprotein) in the MESIAH. From the internal validation study, the C statistics and chi2-statistics for one-, three-, and five-years of survival were 0.83 (95% Confidence Interval: 0.82-0.85), 49.07; 0.81 (95% Confidence Interval: 0.79-0.82), 28.95; and 0.80 (95% Confidence Interval: 0.79-0.81), 20.93, respectively. The K-MESIAH also showed a high prediction ability for the external validation cohort. CONCLUSIONS: A survival prediction model for Korean HCC patients was developed and validated to have a high level of performance. This K MESIAH may be more useful in clinical practice and personalized care in a hepatitis B virus endemic area. PMID- 26488299 TI - Spatially Extensive Standardized Surveys Reveal Widespread, Multi-Decadal Increase in East Antarctic Adelie Penguin Populations. AB - Seabirds are considered to be useful and practical indicators of the state of marine ecosystems because they integrate across changes in the lower trophic levels and the physical environment. Signals from this key group of species can indicate broad scale impacts or response to environmental change. Recent studies of penguin populations, the most commonly abundant Antarctic seabirds in the west Antarctic Peninsula and western Ross Sea, have demonstrated that physical changes in Antarctic marine environments have profound effects on biota at high trophic levels. Large populations of the circumpolar-breeding Adelie penguin occur in East Antarctica, but direct, standardized population data across much of this vast coastline have been more limited than in other Antarctic regions. We combine extensive new population survey data, new population estimation methods, and re interpreted historical survey data to assess decadal-scale change in East Antarctic Adelie penguin breeding populations. We show that, in contrast to the west Antarctic Peninsula and western Ross Sea where breeding populations have decreased or shown variable trends over the last 30 years, East Antarctic regional populations have almost doubled in abundance since the 1980's and have been increasing since the earliest counts in the 1960's. The population changes are associated with five-year lagged changes in the physical environment, suggesting that the changing environment impacts primarily on the pre-breeding age classes. East Antarctic marine ecosystems have been subject to a number of changes over the last 50 years which may have influenced Adelie penguin population growth, including decadal-scale climate variation, an inferred mid 20th century sea-ice contraction, and early-to-mid 20th century exploitation of fish and whale populations. PMID- 26488300 TI - CD8+ T Cells Mediate Female-Dominant IL-4 Production and Airway Inflammation in Allergic Asthma. AB - The prevalence and severity of bronchial asthma are higher in females than in males after puberty. Although antigen-specific CD8+ T cells play an important role in the development of asthma through their suppressive effect on cytokine production, the contribution of CD8+ T cells to sex differences in asthmatic responses remains unclear. In the present study, we investigated the sex-specific effect of CD8+ T cells in the suppression of asthma using an ovalbumin mouse model of asthma. The number of inflammatory cells in bronchoalveolar lavage (BAL) fluid, lung type 2 T-helper cytokine levels, and interleukin-4 (IL-4) production by bronchial lymph node cells were significantly higher in female wild-type (WT) mice compared with male mice, whereas no such sex differences were observed between male and female cd8alpha-disrupted mice. The adaptive transfer of male, but not female, CD8+ T cells reduced the number of inflammatory cells in the recovered BAL fluid of male recipient mice, while no such sex difference in the suppressive activity of CD8+ T cells was observed in female recipient mice. Male CD8+ T cells produced higher levels of IFN-gamma than female CD8+ T cells did, and this trend was associated with reduced IL-4 production by male, but not female, CD4+ T cells. Interestingly, IFN-gamma receptor expression on CD4+ T cells was significantly lower in female mice than in male mice. These results suggest that female-dominant asthmatic responses are orchestrated by the reduced production of IFN-gamma by CD8+ T cells and the lower expression of IFN-gamma receptor on CD4+ T cells in females compared with males. PMID- 26488301 TI - PCR-Free Enrichment of Mitochondrial DNA from Human Blood and Cell Lines for High Quality Next-Generation DNA Sequencing. AB - Recent advances in sequencing technology allow for accurate detection of mitochondrial sequence variants, even those in low abundance at heteroplasmic sites. Considerable sequencing cost savings can be achieved by enriching samples for mitochondrial (relative to nuclear) DNA. Reduction in nuclear DNA (nDNA) content can also help to avoid false positive variants resulting from nuclear mitochondrial sequences (numts). We isolate intact mitochondrial organelles from both human cell lines and blood components using two separate methods: a magnetic bead binding protocol and differential centrifugation. DNA is extracted and further enriched for mitochondrial DNA (mtDNA) by an enzyme digest. Only 1 ng of the purified DNA is necessary for library preparation and next generation sequence (NGS) analysis. Enrichment methods are assessed and compared using mtDNA (versus nDNA) content as a metric, measured by using real-time quantitative PCR and NGS read analysis. Among the various strategies examined, the optimal is differential centrifugation isolation followed by exonuclease digest. This strategy yields >35% mtDNA reads in blood and cell lines, which corresponds to hundreds-fold enrichment over baseline. The strategy also avoids false variant calls that, as we show, can be induced by the long-range PCR approaches that are the current standard in enrichment procedures. This optimization procedure allows mtDNA enrichment for efficient and accurate massively parallel sequencing, enabling NGS from samples with small amounts of starting material. This will decrease costs by increasing the number of samples that may be multiplexed, ultimately facilitating efforts to better understand mitochondria-related diseases. PMID- 26488302 TI - Functional Analyses of Bitter Taste Receptors in Domestic Cats (Felis catus). AB - Cats are obligate carnivores and under most circumstances eat only animal products. Owing to the pseudogenization of one of two subunits of the sweet receptor gene, they are indifferent to sweeteners, presumably having no need to detect plant-based sugars in their diet. Following this reasoning and a recent report of a positive correlation between the proportion of dietary plants and the number of Tas2r (bitter receptor) genes in vertebrate species, we tested the hypothesis that if bitter perception exists primarily to protect animals from poisonous plant compounds, the genome of the domestic cat (Felis catus) should have lost functional bitter receptors and they should also have reduced bitter receptor function. To test functionality of cat bitter receptors, we expressed cat Tas2R receptors in cell-based assays. We found that they have at least 7 functional receptors with distinct receptive ranges, showing many similarities, along with some differences, with human bitter receptors. To provide a comparative perspective, we compared the cat repertoire of intact receptors with those of a restricted number of members of the order Carnivora, with a range of dietary habits as reported in the literature. The numbers of functional bitter receptors in the terrestrial Carnivora we examined, including omnivorous and herbivorous species, were roughly comparable to that of cats thereby providing no strong support for the hypothesis that a strict meat diet influences bitter receptor number or function. Maintenance of bitter receptor function in terrestrial obligate carnivores may be due to the presence of bitter compounds in vertebrate and invertebrate prey, to the necessary role these receptors play in non-oral perception, or to other unknown factors. We also found that the two aquatic Carnivora species examined had fewer intact bitter receptors. Further comparative studies of factors driving numbers and functions of bitter taste receptors will aid in understanding the forces shaping their repertoire. PMID- 26488304 TI - Crawling and Gliding: A Computational Model for Shape-Driven Cell Migration. AB - Cell migration is a complex process involving many intracellular and extracellular factors, with different cell types adopting sometimes strikingly different morphologies. Modeling realistically behaving cells in tissues is computationally challenging because it implies dealing with multiple levels of complexity. We extend the Cellular Potts Model with an actin-inspired feedback mechanism that allows small stochastic cell rufflings to expand to cell protrusions. This simple phenomenological model produces realistically crawling and deforming amoeboid cells, and gliding half-moon shaped keratocyte-like cells. Both cell types can migrate randomly or follow directional cues. They can squeeze in between other cells in densely populated environments or migrate collectively. The model is computationally light, which allows the study of large, dense and heterogeneous tissues containing cells with realistic shapes and migratory properties. PMID- 26488303 TI - The Low Noise Limit in Gene Expression. AB - Protein noise measurements are increasingly used to elucidate biophysical parameters. Unfortunately noise analyses are often at odds with directly measured parameters. Here we show that these inconsistencies arise from two problematic analytical choices: (i) the assumption that protein translation rate is invariant for different proteins of different abundances, which has inadvertently led to (ii) the assumption that a large constitutive extrinsic noise sets the low noise limit in gene expression. While growing evidence suggests that transcriptional bursting may set the low noise limit, variability in translational bursting has been largely ignored. We show that genome-wide systematic variation in translational efficiency can-and in the case of E. coli does-control the low noise limit in gene expression. Therefore constitutive extrinsic noise is small and only plays a role in the absence of a systematic variation in translational efficiency. These results show the existence of two distinct expression noise patterns: (1) a global noise floor uniformly imposed on all genes by expression bursting; and (2) high noise distributed to only a select group of genes. PMID- 26488305 TI - The complete mitochondrial genome sequence of the dwarf blue sheep, Pseudois schaeferi haltenorth in China. AB - The dwarf blue sheep (Pseudois schaeferi haltenorth) belongs the subfamily Caprinae, which is distributed in Sichuan, Tibet, Yunnan, and Qinghai in China. In this study, the complete mitochondrial genome of Pseudois schaeferi haltenorth was sequenced. The mitogenome was 16 741 bp in length, consisting of 13 protein coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes, and a non-coding control region (D-loop region). As in other mammals, most mitochondrial genes are encoded on the heavy strand, except for ND6 and eight tRNA genes which are encoded on the light strand. The overall base composition of the Pseudois schaeferi haltenorth is 33.54% A, 26.37% T, 26.91% C, and 13.18% G, A + T (59.91%) was higher than G + C (40.09%). The phylogenetic relationships was analyzed using the complete mitogenome sequence, results show that P. schaeferi haltenorth should be a different species differ from the Genus pseudois hodgson. These information provide useful data for further study on the protection of genetic resources and the taxonomy of Caprinae. PMID- 26488306 TI - Exosome-mediated microRNA transfer plays a role in radiation-induced bystander effect. AB - Bystander effects can be induced through cellular communication between irradiated cells and non-irradiated cells. The signals that mediate this cellular communication, such as cytokines, reactive oxygen species, nitric oxide and even microRNAs, can be transferred between cells via gap junctions or extracellular medium. We have previously reported that miR-21, a well described DDR (DNA damage response) microRNA, is involved in radiation-induced bystander effects through a medium-mediated way. However, the mechanisms of the microRNA transfer have not been elucidated in details. In the present study, it was found that exosomes isolated from irradiated conditioned medium could induce bystander effects. Furthermore, we demonstrated plenty of evidences that miR-21, which is up regulated as a result of mimic transfection or irradiation, can be transferred from donor or irradiated cells into extracellular medium and subsequently get access to the recipient or bystander cells through exosomes to induce bystander effects. Inhibiting the miR-21 expression in advance can offset the bystander effects to some extent. From all of these results, it can be concluded that the exosome-mediated microRNA transfer plays an important role in the radiation induced bystander effects. These findings provide new insights into the functions of microRNAs and the cellular communication between the directly irradiated cells and the non-irradiated cells. PMID- 26488307 TI - No Geographic Correlation between Lyme Disease and Death Due to 4 Neurodegenerative Disorders, United States, 2001-2010. AB - Associations between Lyme disease and certain neurodegenerative diseases have been proposed, but supportive evidence for an association is lacking. Similar geographic distributions would be expected if 2 conditions were etiologically linked. Thus, we compared the distribution of Lyme disease cases in the United States with the distributions of deaths due to Alzheimer disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Parkinson disease; no geographic correlations were identified. Lyme disease incidence per US state was not correlated with rates of death due to ALS, MS, or Parkinson disease; however, an inverse correlation was detected between Lyme disease and Alzheimer disease. The absence of a positive correlation between the geographic distribution of Lyme disease and the distribution of deaths due to Alzheimer disease, ALS, MS, and Parkinson disease provides further evidence that Lyme disease is not associated with the development of these neurodegenerative conditions. PMID- 26488308 TI - Photochemistry within a water-soluble organic capsule. AB - Photochemistry along with life as we know it originated on earth billions of years ago. Supramolecular Photochemistry had its beginning when plants that sustain life began transforming water into oxygen by carrying out light initiated reactions within highly organized assemblies. Prompted by the efforts of J. Priestly (photosynthesis), F. Sestini, S. Cannizaro, and C. Liebermann (solid state photochemistry of santonin, quinones, and cinnamic acid), orderly scientific investigations of the link between light absorption by matter and molecules and the chemical and physical consequences began in the mid-1700s. By 1970 when Molecular Photochemistry had matured, it was clear that controlling photochemical reactions by conventional methods of varying reaction parameters like temperature and pressure would be futile due to the photoreactions' very low activation energies and enthalpies. During the last 50 years, the excited state behavior of molecules has been successfully manipulated with the use of confining media and weak interactions between the medium and the reactant molecule. In this context, with our knowledge from experimentation with micelles, cyclodextrins (CD), cucurbitruils (CB), calixarenes (CA), Pd nanocage, crystals, and zeolites as media, we began about a decade ago to explore the use of a new water-soluble synthetic organic cavitand, octa acid (OA) as a reaction container. The uniqueness of OA as an organic cavitand lies in that two OA molecules form a closed hydrophobic capsule to encapsulate water-insoluble guest molecule(s). The ability to include a large number of guest molecules in OA has provided an opportunity to examine the excited state chemistry of organic molecules in a hydrophobic, confined environment. OA distinguishes itself from the well-known cavitands CD and CB by its active reaction cavity absorbing UV-radiation between 200 and 300 nm and serving as energy, electron, and hydrogen donor. The freedom of guest molecules in OA, between that in crystals and isotropic solution can be transformed into photoproducts selectivity. The results of our photochemical investigations elaborated in this Account demonstrate that OA with a medium sized cavity exerts better control on excited state processes than the more common and familiar organic hosts such as CD, CB, CA, and micelles. By examining the photochemistry of a number of molecules (olefins, carbonyls, aromatics and singlet oxygen) that undergo varied reactions (cleavage, cycloaddition, cis-trans isomerization, oxidation and cyclization) within OA capsule, we have demonstrated that the free space within the container, the capsule influenced conformation and preorientation of guest molecules, supramolecular steric control, and capsular dynamics contribute to the altered excited state behavior. In this Account, we have shown that photochemistry based on concepts of physical organic and supramolecular chemistry continues to be a discipline with unlimited potential. The future of supramolecular photochemistry lies in synthetic, materials, medicinal, and biological chemistries. Success in these areas depends on synthesizing well-designed water-soluble hosts that can emulate complex biological assemblies, organizing and examining the behavior of supramolecular assemblies on solid surfaces, rendering the photoreactions catalytic, and delivering encapsulated drugs in a targeted fashion. PMID- 26488309 TI - The Association of Reproductive Hormone Levels and All-Cause, Cancer, and Cardiovascular Disease Mortality in Men. AB - CONTEXT: Testosterone (T) levels have been associated with mortality, but controversy exists. OBJECTIVE: Our objective was to investigate associations between serum levels of total T, SHBG, free T, estradiol, LH and FSH, and subsequent mortality with up to 30 years of follow-up. DESIGN: This was a prospective cohort study consisting of men participating in four independent population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with complete registry follow-up. SETTING AND PARTICIPANTS: A total of 5350 randomly selected men from the general population aged 30, 40, 50, 60, or 70 years at baseline participated. MAIN OUTCOMES AND MEASURES: All-cause mortality, cardiovascular disease (CVD) mortality, and cancer mortality were the main outcomes. RESULTS: A total of 1533 men died during the follow-up period; 428 from CVD and 480 from cancer. Cox proportional hazard models revealed that men in highest LH quartile had an increased all-cause mortality compared to lowest quartile (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.14-1.53). Likewise, increased quartiles of LH/T and estradiol increased the risk of all-cause mortality (HR, 1.23; 95% CI, 1.06-1.43; HR, 1.23; 95% CI 1.06-1.43). No association to T levels was found. Higher LH levels were associated with increased cancer mortality (HR, 1.42; 95% CI, 1.10-1.84) independently of smoking status. Lower CVD mortality was seen for men with T in the highest quartile compared to lowest (HR, 0.72; 95% CI, 0.53-0.98). Furthermore, negative trends were seen for SHBG and free T in relation to CVD mortality, however insignificant. CONCLUSION: The observed positive association of LH and LH/T, but not T, with all-cause mortality suggests that a compensated impaired Leydig cell function may be a risk factor for death by all causes in men. Our findings underpin the clinical importance of including LH measurement in the diagnostic work-up of male patients seeking help for possible androgen insufficiency. PMID- 26488310 TI - COPD Patients Have Short Lung Magnetic Resonance T1 Relaxation Time. AB - Magnetic resonance imaging (MRI) may provide attractive biomarkers for assessment of pulmonary disease in clinical trials as it is free from ionizing radiation, minimally invasive and allows regional information. The aim of this study was to characterize lung MRI T1 relaxation time as a biomarker of chronic obstructive pulmonary disease (COPD); and specifically its relationship to smoking history, computed tomography (CT), and pulmonary function test (PFT) measurements in comparison to healthy age-matched controls. Lung T1 and inter-quartile range (IQR) of T1 maps from 24 COPD subjects and 12 healthy age-matched non-smokers were retrospectively analyzed from an institutional review board approved study. The subjects underwent PFTs and two separate MR imaging sessions at 1.5 tesla to test T1 repeatability. CT scans were performed on the COPD subjects. T1 repeatability (intraclass correlation coefficient) was 0.72 for repeated scans acquired on two visits. The lung T1 was significantly shorter (p < 0.0001) and T1 IQR was significantly larger (p = 0.0002) for the COPD subjects compared to healthy controls. Lung T1 significantly (p = 0.001) correlated with lung density assessed with CT. Strong significant correlations (p < 0.0001) between lung T1 and all PFT measurements were observed. Cigarette exposure did not correlate with lung T1 in COPD subjects. In conclusion, lung MRI T1 mapping shows potential as a repeatable, radiation free, non-invasive imaging technique in the evaluation of COPD. PMID- 26488311 TI - Glycosylation of Human Plasma Clusterin Yields a Novel Candidate Biomarker of Alzheimer's Disease. AB - Specific glycosylated peptides of clusterin are found associated with hippocampal atrophy. The glycosylation of clusterin from human plasma was comprehensively analyzed and characterized using mass spectrometry (MS)-based glycoproteomics analysis. All six known N-glycosylation sites are covered, three in the alpha subunit (alpha64N, alpha81N and alpha123N) and three in the beta subunit (beta64N, beta127N, and beta147N). More detailed structural characterization of clusterin glycopeptides was also performed, demonstrating the presence of glycosylated peptides and their corresponding glycans. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we have determined the differences in the glycoforms associated at each of the different glycosylation sites in plasma clusterin obtained from subjects of low hippocampal atrophy (n = 13) and high hippocampal atrophy (n = 14). In our pilot study, the beta64N site shows the most significant regulations between clinical groups. Eight beta64N glycoforms are significantly reduced in patients with high atrophy compared with those with low atrophy, which demonstrates the utility of clusterin isoforms as diagnostic and prognostic Alzheimer's disease (AD) markers. These results provide a novel and robust workflow suitable for rapid verification of specific clusterin glycoforms with utility as AD biomarkers. PMID- 26488312 TI - Chikungunya Virus as Cause of Febrile Illness Outbreak, Chiapas, Mexico, 2014. AB - Since chikungunya virus (CHIKV) was introduced into the Americas in 2013, its geographic distribution has rapidly expanded. Of 119 serum samples collected in 2014 from febrile patients in southern Mexico, 79% were positive for CHIKV or IgM against CHIKV. Sequencing results confirmed CHIKV strains closely related to Caribbean isolates. PMID- 26488313 TI - Refined models of New Delhi metallo-beta-lactamase-1 with inhibitors: an QM/MM modeling study. AB - New Delhi metallo-beta-lactamase 1 (NDM-1) has been identified as a potential target for the treatment of multi-drug resistance bacterial infections. We used molecular docking, normal MD, SIE, QM/MM MD simulations, QM/MM GBSA binding free energy, and QM/MM GBSA alanine-scanning mutagenesis techniques to investigate interactions of the NDM-1 with 11 inhibitors (Tigecycline, BAL30072, D-captopril, Penicillin G, Ampicillin, Carbenicillin, Cephalexin, Cefaclor, Nitrocefin, Meropenem, and Imipenem). From our normal MD and QM/MM simulations, the correlation coefficients between the predicted binding free energies and experimental values are .88 and .93, respectively. Then simulations, which combined QM/MM/GBSA and alanine-scanning mutagenesis techniques, were performed and our results show that two residues (Lys211 and His250) have the strongest impact on the binding affinities of the 11 NDM-1/inhibitors. Therefore, our approach theoretically suggests that the two residues (Lys211 and His250) are responsible for the selectivity of NDM-1 associated inhibitors. PMID- 26488314 TI - "Blind" interviewing: Is ignorance bliss? AB - Current investigative interviewing guidelines [e.g., Technical Working Group: Eyewitness evidence. (1999). Eyewitness evidence: A guide for law enforcement. U.S. Department of Justice, Office of Justice Programs, National Institute of Justice. Retrieved from https://www.ncjrs.gov/pdffiles1/nij/178240.pdf ] suggest that interviewers review available case information prior to conducting a witness interview. The present study investigated the effect of interviewers' pre interview awareness of crime details on eyewitnesses' memory and interviewer behaviour shortly after a mock crime or a week later. Results indicate that blind interviewers with no knowledge about the crime elicited more correct information than those who were correctly informed about the crime. Differences in interviewer behaviour emerged only in the very first question of the interview: Blind interviewers were more likely to begin the interview with a non-suggestive question than the informed interviewers. Blind interviewers also recalled more details than the informed interviewers when asked to generate a report after the witness interview documenting the witness' account. PMID- 26488315 TI - Sensitive Trimodal Magnetic Resonance Imaging-Surface-Enhanced Resonance Raman Scattering-Fluorescence Detection of Cancer Cells with Stable Magneto-Plasmonic Nanoprobes. AB - Novel magneto-plasmonic nanoprobes were designed for multimodal diagnosis of cancer by combination of magnetic resonance imaging (MRI), surface-enhanced resonance Raman scattering (SERRS), and fluorescence emission in the very near infrared (VNIR). A controlled electrostatic assembly of silver nanoparticles (AgNPs), superparamagnetic iron oxide nanoparticles (SPIONs), VNIR dye Nile Blue (NB), and biopolymer chitosan (Chi) was used to formulate the AgIONs-Chi nanoprobes. The formulation protocol did not involve organic solvents and was rapid and efficient as confirmed by magnetic sorting. The SERRS response of the nanoprobes was very intense and constant for days. It decreased linearly upon 1000-fold dilution and was still recognizable at 0.1 nM NB concentration. After 30 days of storage, the SERRS loss was less than 30% and the hydrodynamic size of the AgIONs-Chi in PBS remained below 200 nm. The gradual decrease of the ratio SERRS/fluorescence allowed one to monitor the release of the fluorescent molecule upon long-term nanoprobe dissociation. The AgIONs-Chi exhibited 2-fold higher MRI contrast than that of commercially available SPION suspensions. Finally, the nanoprobes were actively uptaken by HeLa cancer cells and ensured trimodal MRI SERRS-fluorescence detection of 10 MUL cell inclusions in cm-sized agarose gels used here as phantom models of microtumors. The above results show that the magneto-plasmonic AgIONs-Chi are promising substrates for SERRS analysis in solution and for multimodal imaging of cancer cells. PMID- 26488316 TI - Correction to Emergence Flux Declines Disproportionately to Larval Density along a Stream Metal Gradient. PMID- 26488317 TI - The "high-risk" deep venous thrombosis screening protocol for trauma patients: Is it practical? AB - BACKGROUND: Many centers advocate aggressive lower extremity deep venous thrombosis (DVT) screening using ultrasound (LUS) for patients meeting high-risk criteria. We hypothesized that a high-risk screening protocol is impractical and costly to implement. METHODS: The University of Virginia's trauma database was queried to identify 6,656 patients admitted between 2009 and 2013. Patient characteristics and outcomes were recorded. Multivariate analyses were performed on patients who underwent LUS to assess the association between patient characteristics and the development of DVT. A predictive model for DVT was applied to the entire population to determine performance and resources required for implementation. RESULTS: Overall, 2,350 (35.3%) of admitted patients underwent LUS. A total of 146 patients (6.2%) developed DVT. Patients who underwent LUS were significantly older (54.5 years vs. 50.4 years, p < 0.0001), had higher Injury Severity Scores (ISSs) (13.5 vs. 8.6, p < 0.0001), and had longer admissions to the intensive care unit (5.6 days vs. 0.9 days, p < 0.0001). Backward selection multivariable logistic regression identified intensive care unit length of stay, transfusion of blood products, spinal cord injury, and pelvic fracture to be associated with DVT (c statistic, 0.76). The model was applied to the entire population to evaluate probability of DVT (c statistic, 0.87). Predictive performance and costs were determined using a cost per LUS of $228. The most sensitive threshold for screening would detect 53% of DVTs, require screening of 26% of all trauma patients, and cost nearly $600,000 to implement during the study period. CONCLUSION: Although a predictive model identified high-risk criteria for the development of DVT at our institution, the model demonstrated poor sensitivity and positive predictive value. These results suggest that implementing a high-risk screening protocol in trauma patients would require a costly and burdensome commitment of resources and that high-risk DVT screening protocols may not be practical or cost-effective for trauma patients. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 26488318 TI - James Henry Duke, Jr., MD (1928-2015). PMID- 26488319 TI - Cadaveric comparison of the optimal site for needle decompression of tension pneumothorax by prehospital care providers. AB - BACKGROUND: Computed tomographic and cadaveric studies have demonstrated needle decompression of tension pneumothorax at the fifth intercostal space (ICS), anterior axillary line (AAL) has advantages over the second ICS midclavicular line (MCL). The purpose of this study was to compare the ability of prehospital care providers to accurately decompress the chest at these two locations. METHODS: Randomly selected US Navy hospital corpsmen (n = 25) underwent a standardized training session followed by timed needle decompression on unmarked fresh cadavers. A 14-gauge angiocatheter was inserted in the right and left second ICS MCL and fifth ICS AAL in a predetermined computer-generated order. Time from needle uncapping to insertion, accuracy, and ease of placement were examined. RESULTS: A total of 25 corpsmen inserted 100 needles into 25 cadavers. Mean (SD) age was 25.9 (3.7) years, 72.0% were male, with 4.2 (3.2) years of experience, and 52.0% had previously deployed. A total of 60.0% had attempted decompression previously, 93.3% in a model and 6.7% in a patient. Time to decompression did not differ between the second and fifth ICS (16.8 [10.1] seconds vs. 16.9 [12.3] seconds, p = 0.438). Accuracy however was superior at the fifth ICS, with a misplacement rate of only 22.0% versus 82.0% at the second ICS (p < 0.001). The aggregate distance from the target position was also significantly greater for the second ICS (3.1 [1.7] cm vs. 1.2 [1.5] cm, p < 0.001). Insertion at the fifth ICS was rated as being easier than the second by 76.0% of providers, the same by 12.0%, and more difficult by 12.0%. CONCLUSION: For prehospital care providers, the fifth ICS AAL can be localized and decompressed with a higher degree of accuracy than the traditional second ICS MCL. It is rated as easier to perform and can be done just as quickly. Based on these data, the fifth ICS AAL should be considered as an equivalent first-line position for needle decompression in patients with clinical evidence of a tension pneumothorax. PMID- 26488320 TI - Subcapsular hematoma in blunt splenic injury: A significant predictor of failure of nonoperative management. AB - BACKGROUND: In patients with blunt splenic injury (BSI), patient selection, angiography, and embolization have contributed to low nonoperative management (NOM) failure rates. Despite these advances, some patients will fail NOM. We noted that a significant proportion of NOM failures had subcapsular hematomas (SCHs) identified on imaging. We sought to determine if there is a correlation between SCH and higher risk of NOM failure after BSI. METHODS: Our institutional trauma registry was queried for all patients with BSI during a 2-year period. Charts were reviewed to determine grade, presence of SCH, and outcome of NOM. Under current institutional protocol, all stable patients with BSI Grades III to V and those with contrast blush on computed tomography are referred for angiography and embolization. Failure of NOM was declared if splenectomy was required for bleeding after an initial plan of nonoperation. RESULTS: From May 2012 to May 2014, 312 patients with BSI were identified. A total of 253 patients (81%) underwent NOM. Overall, 15 (5.9%) failed NOM. Of those undergoing NOM, 34 had SCH and 12 failed (35.3% vs. 1.5% without SCH, p = 0.0001). Failure rates in Grades 1 to 4 were 2.3%, 3.8%, 8.8%, and 19.2%, respectively. NOM failure rates in the subset with SCH for Grades I to IV were 20%, 25%, 30.8%, and 80%, respectively. These are significantly higher than patients without SCH in Grades II to IV (0%, p = 0.003; 2.3%, p = 0.008; and 4.8%, p = 0.016) and approach significance in Grade I (1.2%, p = 0.11). There were no SCHs and no failures of NOM in Grade V injuries. CONCLUSION: The NOM failure rate of BSI patients with SCH is significantly higher than those without SCH. Patients with BSI Grades I to III slated for NOM must be observed as the failure rate approaches 30%. Splenectomy should be considered in patients with Grade IV BSI with SCH, as NOM failure rate is 80%. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 26488321 TI - The elimination of anastomosis in open trauma vascular reconstruction: A novel technique using an animal model. AB - BACKGROUND: The standard approach to vascular trauma involves arterial exposure and reconstruction using either a vein or polytetrafluoroethylene graft. We have developed a novel technique to repairing arterial injuries by deploying commercially available vascular stents through an open approach, thus eliminating the need for suture anastomosis. The objective of this study was to evaluate the feasibility, stent deployment time (SDT), and stent patency of this technique in a ewe vascular injury model. METHODS: After proximal and distal control, a 2-cm superficial femoral arterial segment was resected in 8 Dorper ewes to simulate an arterial injury. Two stay sutures were placed in the 3- and 9-o'clock positions of the transected arterial ends to prevent further retraction. Ten milliliters of 10-IU/mL heparinized saline was flushed proximally and distally. An arteriotomy was then created 2.5 cm from the transected distal end through which we deployed Gore Viabahn stents with a 20% oversize and at least 1-cm overlap with the native vessel on either end. The arteriotomy was then closed with 3 (1) interrupted 6-0 Prolene sutures. The ewes were fed acetylsalicylic acid 325 mg daily. Duplex was performed at 2 months postoperatively to evaluate stent patency. SDT was defined as time from stay suture placement to arteriotomy closure. RESULTS: The 8 ewes weighed a mean (SD) of 34.4 (4.3) kg. The mean (SD) superficial femoral arterial was 4.3 (0.6) mm. Six 5 mm * 5 cm and two 6 mm * 5 cm Gore Viabahn stents were deployed. The mean (SD) SDT was 34 (19) minutes, with a trend toward less time with increasing experience (SDTmax, 60 minutes; SDTmin, 10 minutes). Duplex performed at 2 months postoperatively showed stent patency in five of eight stents. There was an association between increasing SDT and stent thrombosis. CONCLUSION: Open deployment of commercially available vascular stents to treat vascular injuries is a conceptually sound and technically feasible alternative to standard open repair. Larger studies are needed to refine this technique and minimize stent complications, which are likely technical in nature. PMID- 26488322 TI - A new kid on the block: Outcomes with Kcentra 1 year after approval. AB - BACKGROUND: As the population ages, more trauma patients are admitted with coagulopathy. Fresh frozen plasma is effective in reversing coagulopathy caused by warfarin; however, it is not appropriate for all patients. Prothrombin complex concentrates (PCCs) are an alternative for patients who require emergent reversal, minimal-volume administration and who have a supratherapeutic international normalized ratio (INR). A four-factor PCC initially approved in Europe is now available in the United States. We sought to review our experience with Kcentra (4F-PCC) in the first year following Food and Drug Administration approval. METHODS: All trauma patients admitted to an academic Level 1 trauma center between July 15, 2013, and July 15, 2014, who received 4F-PCC for reversal of warfarin-induced coagulopathy were reviewed. 4F-PCC was given as per protocol. Univariate analysis was performed to examine patient demographics, injury characteristics, coagulation studies, 4F-PCC dose, vitamin K use, transfusions, response to reversal, duration of reversal, complications, and mortality. RESULTS: Twenty-six patients met study criteria. Of these patients, 34.6% were reversed because of intracranial hemorrhage. The mean INR decreased from 5.7 +/- 6.1 (range, 1.6-30) to 1.5 +/- 0.4 (range, 1.2-2.6) after 4F-PCC administration. One patient (3.8%) received concurrent fresh frozen plasma. For patients with an initial INR greater than 5.0, the mean INR decreased from 12.0 +/- 8.2 to 1.6 +/- 0.5. Forty-eight hours following 4F-PCC administration, mean INR for all patients remained 1.4 +/- 0.4 (range, 1.0-2.6). Of the patients, 80.8% received vitamin K over this period. Fourteen patients had a pre-4F-PCC thromboelastogram; four were hypocoagulable. Two patients had repeat thromboelastograms after 4F-PCC was given, which demonstrated normal coagulation. Of the patients with intracranial hemorrhage, 66.7% showed radiographic progression of the initial insult on post 4F-PCC head computed tomography, while only 11.1% progressed clinically. In hospital mortality was 0%. There were no thromboembolic complications. CONCLUSION: 4F-PCC effectively reverses elevated INRs in trauma patients with warfarin-induced coagulopathy, with results lasting more than 48 hours after administration. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 26488323 TI - The found down patient: A Western Trauma Association multicenter study. AB - BACKGROUND: Unconscious patients who present after being "found down" represent a unique triage challenge. These patients are selected for either trauma or medical evaluation based on limited information and have been shown in a single-center study to have significant occult injuries and/or missed medical diagnoses. We sought to further characterize this population in a multicenter study and to identify predictors of mistriage. METHODS: The Western Trauma Association Multicenter Trials Committee conducted a retrospective study of patients categorized as found down by emergency department triage diagnosis at seven major trauma centers. Demographic, clinical, and outcome data were collected. Mistriage was defined as patients being admitted to a non-triage-activated service. Logistic regression was used to assess predictors of specified outcomes. RESULTS: Of 661 patients, 33% were triaged to trauma evaluations, and 67% were triaged to medical evaluations; 56% of all patients had traumatic injuries. Trauma-triaged patients had significantly higher rates of combined injury and a medical diagnosis and underwent more computed tomographic imaging; they had lower rates of intoxication and homelessness. Among the 432 admitted patients, 17% of them were initially mistriaged. Even among properly triaged patients, 23% required cross-consultation from the non-triage-activated service after admission. Age was an independent predictor of mistriage, with a doubling of the rate for groups older than 70 years. Combined medical diagnosis and injury was also predictive of mistriage. Mistriaged patients had a trend toward increased late-identified injuries, but mistriage was not associated with increased length of stay or mortality. CONCLUSION: Patients who are found down experience significant rates of mistriage and triage discordance requiring cross-consultation. Although the majority of found down patients are triaged to nontrauma evaluation, more than half have traumatic injuries. Characteristics associated with increased rates of mistriage, including advanced age, may be used to improve resource use and minimize missed injury in this vulnerable patient population. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 26488325 TI - End-of-life care in trauma. PMID- 26488324 TI - The "Death Diamond": Rapid thrombelastography identifies lethal hyperfibrinolysis. AB - BACKGROUND: Postinjury hyperfibrinolysis (HF), defined as LY30 of 3% or greater on rapid thrombelastography (rTEG), is associated with high mortality and large use of blood products. We observed that some cases of HF are reversible and are associated with patients who respond to hemostatic resuscitation; however, other cases of severe HF seem to be associated with these patients' inevitable demise. We therefore sought to define this unsurvivable subtype of HF as a recognizable rTEG tracing pattern. METHODS: We queried our trauma registry for patients who either died or spent at least 1 day in the intensive care unit, received at least 1 U of packed red blood cells, and had an admission rTEG. Within this group of 572 patients, we identified 42 pairs of nonsurvivors and survivors who matched on age, sex, injury mechanism, and New Injury Severity Score (NISS). We inspected the rTEG tracings to ascertain if any pattern was found exclusively within the nonsurviving group and applied these findings to the cohort of 572 patients to assess the predictive value for mortality. RESULTS: Within the matched group, 17% of the patients developed HF. Within the HF subgroup, a unique rTEG pattern was present in 14 HF patients who died and in none of the survivors. This pattern was a "diamond-shaped" tracing with a short time to maximum amplitude of 14 minutes or shorter and complete lysis before the LY30 point. When these criteria are applied to the 572 unmatched patients, this pattern had a 100% positive predictive value for mortality. CONCLUSION: Patients displaying the "death diamond" pattern on their admission rTEG are at higher risk for mortality. Given the volume of blood products and other resources that these patients consume, this thrombelastography pattern may represent an objective criterion to discontinue efforts at hemostatic resuscitation. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 26488326 TI - Mild traumatic brain injury increases risk for the development of posttraumatic stress disorder. AB - BACKGROUND: Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) occur in individuals who sustain physical injury and share a significant overlap in symptoms. PTSD rates in the civilian injury population range from 20% to 40%. The current study examined the presence of PTSD symptoms at multiple time points (3 months and 6 months after injury) among individuals with and without TBI after admission to a Level I trauma center. METHODS: This prospective cohort study included patients 18 years and older admitted to a Level I trauma center for 24 hours or greater. Demographic and injury-related data were gathered in addition to assessments of PTSD during initial hospitalization after injury, as well as 3 months and 6 months later. The Primary Care PTSD Screen and PTSD Checklist Civilian version were used to determine probable PTSD. International Classification of Diseases, 9th Rev. codes were used to determine mild TBI (MTBI). RESULTS: A total of 494 patients were enrolled at baseline, 311 (63%) completed 3-month follow-up, and 231 (47%) completed 6-month follow-up at the time of analysis. Preinjury PTSD was reported by 7% of the participants. At 3 months, patients with MTBI evidenced a probable PTSD rate of 18%, compared with a rate of 9% for patients with no MTBI (p = 0.04), although this relationship became a nonsignificant trend (p = 0.06) when demographics were included. At 6 months, patients with MTBI evidenced a probable PTSD rate of 26%, compared with a rate of 15% for patients with no MTBI (p = 0.04), and this relationship remained significant when demographics were included. Preinjury history of TBI did not predict PTSD, but incidence of TBI for the injury in which they were hospitalized did predict PTSD. CONCLUSION: TBI at time of injury demonstrated a nonsignificant trend toward higher rates of PTSD at 3 months and significantly predicted PTSD at 6 months after injury. This important finding may help clinicians identify patients at high risk for PTSD after injury and target these patients for screening, intervention, and referral for treatment. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 26488327 TI - Complexation of Lysozyme with Sodium Poly(styrenesulfonate) via the Two-State and Non-Two-State Unfoldings of Lysozyme. AB - To provide an in-depth understanding of the complexation mechanism of protein and polyelectrolyte, a heating-cooling-reheating protocol was employed to study the unfolding and refolding behaviors of a model protein, lysozyme, in the presence of a negatively charged polyelectrolyte, sodium poly(styrenesulfonate) (PSS). It was found that, with elevated PSS concentration, a new state (state I) was first formed via a "two-state" conversion process and this state could further convert to a completely unfolded state (state II) via a "non-two-state" conversion. This non-two-state conversion process occurs without the coexistence of states I and II but involves the formation of various intermediate unfolded protein structures. Different from the pure lysozyme that exhibited refolding upon cooling from its heat-denatured state, lysozyme in state I could undergo unfolding upon heating but no refolding upon cooling, while lysozyme in state II did not undergo unfolding or refolding upon thermal treatments. In addition, the effects of ionic strength and molecular weight of polyelectrolyte on the unfolding and refolding behaviors of lysozyme were also investigated. The present work provides a better understanding of the principles governing protein polyelectrolyte interactions and may have implications for the fabrication of biocolloids and biofilms. PMID- 26488328 TI - Onyx Embolization for Isolated Type Dural Arteriovenous Fistula Using a Dual Lumen Balloon Catheter. AB - BACKGROUND: Utilization of a dual-lumen balloon may improve Onyx penetration into isolated dural arteriovenous fistulas (i-DAVFs). OBJECTIVE: To compare the results of Onyx embolization using a dual-lumen balloon with those using a non balloon catheter for i-DAVFs. METHODS: Twenty-nine patients underwent Onyx embolization for i-DAVFs using a non-balloon (n = 14) or a dual-lumen balloon catheter (n = 15). Since its introduction, a dual-lumen balloon catheter has been preferred. We compared the dual-lumen balloon group with the non-balloon catheter group regarding angiographic outcome, treatment-related complications, total procedural time, Onyx injection time, and the number of feeders requiring embolization. RESULTS: The dual-lumen balloon group showed complete occlusion of i-DAVFs in 13 and near-complete in 2 patients, while the non-balloon group showed complete occlusion in 5, near-complete in 5, and incomplete in 4 patients (P < .05). Treatment-related complications occurred in 2 patients: 1 in the non balloon group and 1 in the dual-lumen balloon group. The mean total procedural time was 62 +/- 32 minutes in the dual-lumen balloon and 171 +/- 88 minutes in the non-balloon group (P < .05). The mean Onyx injection time was 10 +/- 6 minutes in the dual-lumen balloon and 49 +/- 32 minutes in the non-balloon group (P < .05). The median number of feeders requiring embolization was 1 (range, 1-3) in the dual-lumen balloon and 2 (range, 1-4) in the non-balloon group (P < .05). CONCLUSION: Utilization of a dual-lumen balloon catheter for Onyx embolization of i-DAVF seemed to significantly increase the immediate complete occlusion rate and decrease total procedural time, Onyx injection time, and number of feeders requiring embolization. PMID- 26488329 TI - Gamma Knife Stereotactic Radiosurgery for Brain Metastases Using Only 3 Pins. AB - BACKGROUND: Removal of a pin during Gamma Knife stereotactic radiosurgery (GK SRS) may be necessary to prevent collision and allow treatment. OBJECTIVE: To investigate outcomes after GK-SRS for treatment of brain metastases using a head frame immobilized to the skull with only 3 pins. METHODS: Between 2009 and 2014, we retrospectively reviewed the records of 1971 patients and identified 20 patients with multiple brain metastases treated with GK-SRS in which 1 anterior pin was removed immediately before treatment of a single posterior lesion. GK-SRS was also delivered to 116 other lesions in these 20 patients using the standard 4 pins during the same session, serving as an internal control for comparison. Endpoints included local control, dosimetric parameters, toxicity, and overall survival. RESULTS: The median number of lesions treated per session was 6 (range, 2-14). The lesions treated using 3 pins were located in the occipital lobe (n = 14) or the cerebellum (n = 6). Median follow-up was 12.3 months. There was 1 local failure involving a control lesion. Lesions treated using 3 pins had a lower prescription isodose line. GK-SRS of a lesion using 3 pins did not cause any clinical toxicities or increase in radiographic edema or hemorrhage. CONCLUSION: Treating posteriorly located brain metastases with GK-SRS using only 3 pins provided excellent local control and no difference in treatment toxicity, which may make it a safe and reasonable option for lesions that may otherwise be difficult to treat. PMID- 26488330 TI - A New Protocol for Anticoagulation With Tirofiban During Flow Diversion. AB - BACKGROUND: Flow diversion is increasingly used to treat intracranial aneurysms. In previous reports, patients were pretreated with aspirin and clopidogrel before the intervention for the prevention of thromboembolic complications. OBJECTIVE: To assess the safety and efficacy of a new protocol for anticoagulation using tirofiban during flow diversion. METHODS: All patients received a 0.10-MUg.kg.min maintenance infusion of tirofiban intraoperatively without a loading dose. All patients were loaded with aspirin (325 mg) and clopidogrel (600 mg) just before the procedure or intraoperatively. No patient was pretreated with aspirin or clopidogrel. Thromboembolic and hemorrhagic complications were recorded. RESULTS: A total of 46 patients were treated with this protocol. Six patients (13%) had sustained a subarachnoid hemorrhage and were treated with the Pipeline Embolization Device within 24 hours of aneurysm rupture. The mean number of devices was 1.2 +/- 0.66; adjunctive coiling was performed in 3 patients (6.5%). There were 2 complications (4.3%), 1 thromboembolic (2.2%) and 1 hemorrhagic (2.2%; monocular vision loss from occlusion of the central retinal artery in 1 patient and a parenchymal hemorrhage managed conservatively in another patient). No patient developed thrombocytopenia or retroperitoneal, gastrointestinal, or genitourinary bleeding. Of 46 patients, 44 (95.7%) had a modified Rankin Scale score of 0 to 2 at their follow-up visit. CONCLUSION: A protocol of anticoagulation with tirofiban during flow diversion has an excellent safety profile. This protocol provides a reasonable alternative to pretreatment with aspirin and clopidogrel and is useful in patients with ruptured aneurysms or when the use of a stent is unexpected. PMID- 26488331 TI - A Bemisia tabaci midgut protein interacts with begomoviruses and plays a role in virus transmission. AB - Begomoviruses are a major group of plant viruses, transmitted exclusively by Bemisia tabaci (Gennadius) in a persistent circulative non-propagative manner. The information regarding molecular and cellular basis underlying Begomovirus - whitefly interaction is very scarce. Evidences have suggested that the insect gut possesses some crucial protein receptors that allow specific entry of virus into the insect haemolymph. We have performed yeast two hybrid gut cDNA expression library screening against coat protein of Tomato leaf curl New Delhi virus (ToLCV) and Cotton leaf curl Rajasthan virus (CLCuV) as bait. Midgut protein (MGP) was the common protein found interacting with both ToLCV and CLCuV. MGP was localized in whole mount B. tabaci as well as in dissected guts through confocal microscopy. Pull down and dot blot assays confirmed in vitro interaction between ToLCV/CLCuV coat protein and MGP. Immunolocalization analysis also showed colocalization of ToLCV/CLCuV particles and MGP within insect's gut. Finally, anti-MGP antibody fed B. tabaci, exhibited 70% reduction in ToLCV transmission, suggesting a supportive role for MGP in virus transmission. PMID- 26488332 TI - Impact of continued mailed fecal tests in the patient-centered medical home: Year 3 of the Systems of Support to Increase Colon Cancer Screening and Follow-Up randomized trial. AB - BACKGROUND: The current study was conducted to determine the effect of continuing a centralized fecal occult blood test (FOBT) mailed program on screening adherence. METHODS: A patient-level randomized controlled trial was conducted in 21 patient-centered medical home primary care clinics between January 2010 and November 2012. A total of 2208 patients ranging in age from 52 to 75 years in a substudy of the Systems of Support to Increase Colon Cancer Screening and Follow Up (SOS) trial were randomized at year 3 to continued automated interventions (Continued group), which included mailed information regarding colorectal cancer (CRC) screening choices, and were mailed stool kit tests or to a group in which interventions were stopped (Stopped group). The main outcomes and measures were the completion of CRC screening in year 3 and by subgroup characteristics, respectively. RESULTS: Adherence to CRC screening in year 3 was found to be significantly higher in patients in the Continued group compared with those in the Stopped group (53.3% vs 37.3%; adjusted net difference, 15.6% [P<.001]). This difference was entirely due to greater completion of FOBT (adjusted net difference, 18.0% [P<.001]). Year 3 CRC screening rates were highest in patients in the Continued group completing FOBT in both years 1 and 2 (77.2%), followed by patients completing only 1 FOBT in 1 of the 2 years (44.6%), with low rates of CRC testing reported among patients not completing any FOBT within the first 2 years (18.1%). CONCLUSIONS: A centralized mailed FOBT CRC screening program continued to be more effective than patient-centered medical home usual-care interventions, but only for those patients who had previously completed FOBT testing. Research is needed regarding how to engage patients not completing CRC testing after being mailed at least 2 rounds of FOBT tests. Cancer 2016;122:312 321. (c) 2015 American Cancer Society. PMID- 26488333 TI - Inhibition of Peripheral Nerve Scarring by Calcium Antagonists, Also Known as Calcium Channel Blockers. AB - The aim of this research was to investigate the impact of calcium channel blockers (verapamil) on the formation of scars in the sciatic nerve anastomosis after peripheral nerve injury. One hundred twenty healthy, male Sprague-Dawley rats were selected and prepared with right sciatic nerve injury for this study. Samples were selected at the fourth and 12th weeks, respectively, after treatment and observations were made on the nerve anastomosis healing and diameter. Image analysis and statistical processing were carried out relating to the results of the study. The diameter of the anastomosis of the treatment group at weeks 4 and 12 was noticeably smaller than the control group (P < 0.05). In the treatment group at week 4, there were many vesicles observed in the fibroblasts' cytosol and in the control group, the fibroblasts exhibited high number of rough endoplasmic reticulum. The collagen content of the nerve scarring at week 12 in the treatment group was apparently less than the control group (P < 0.01). The calcium channel blocker (verapamil) reduced the axon resistance through the anastomosis during nerve regeneration. It can effectively inhibit the formation of scarring from nerve injury. It also provided an excellent microenvironment for the regeneration of nerve fibers. PMID- 26488334 TI - Fabricating Continuous Supercapacitor Fibers with High Performances by Integrating All Building Materials and Steps into One Process. AB - Supercapacitor fibers are rapidly produced in minutes by an integrated one-step fabrication process. This method is simple and efficient for large production. A variety of pseudocapacitive active materials including graphene oxide, metal oxide, and conducting polymers can be incorporated. The resulting all-solid-state supercapacitor fibers show remarkable energy-storage capabilities with both high power and energy densities. PMID- 26488335 TI - Acute generalized exanthematous pustulosis induced by celecoxib. PMID- 26488336 TI - Identification of target proteins of mangiferin in mice with acute lung injury using functionalized magnetic microspheres based on click chemistry. AB - Prevention of the occurrence and development of inflammation is a vital therapeutic strategy for treating acute lung injury (ALI). Increasing evidence has shown that a wealth of ingredients from natural foods and plants have potential anti-inflammatory activity. In the present study, mangiferin, a natural C-glucosyl xanthone that is primarily obtained from the peels and kernels of mango fruits and the bark of the Mangifera indica L. tree, alleviated the inflammatory responses in lipopolysaccharide (LPS)-induced ALI mice. Mangiferin modified magnetic microspheres (MMs) were developed on the basis of click chemistry to capture the target proteins of mangiferin. Mass spectrometry and molecular docking identified 70 kDa heat-shock protein 5 (Hspa5) and tyrosine 3 monooxygenase (Ywhae) as mangiferin-binding proteins. Furthermore, an enzyme linked immunosorbent assay (ELISA) indicated that mangiferin exerted its anti inflammatory effect by binding Hspa5 and Ywhae to suppress downstream mitogen activated protein kinase (MAPK) signaling pathways. Thoroughly revealing the mechanism and function of mangiferin will contribute to the development and utilization of agricultural resources from M. indica L. PMID- 26488338 TI - The potential role of the left atrial septal pouch in cryptogenic stroke. AB - The left atrial septal pouch (LASP) is an anatomic variant of the atrial septum that forms a blind-ending pouch, communicating exclusively with the left atrium (LA). Case reports have demonstrated thrombus within LASP and in the setting of cryptogenic stroke. Initial epidemiologic results are mixed, one study showing and others not showing an association between LASP and cryptogenic stroke. Additional investigation should take place to determine the clinical significance of LASP and what interventions are required to prevent ischemic stroke in at-risk individuals. PMID- 26488339 TI - An interesting case of intractable proctalgia cured with decompression spinal surgery. AB - We report a case of intractable proctalgia on a background of lower back and bilateral leg pain secondary to spinal canal stenosis and spondylolisthesis. A complete resolution was observed following spinal surgery. This case highlights consideration of a spinal aetiology when intractable proctalgia is associated with back and leg pain. PMID- 26488337 TI - Psychosocial Late Effects in Pediatric Cancer Survivors: A Report From the Children's Oncology Group. AB - BACKGROUND: This review was conducted to update the Children's Oncology Group (COG) Long-Term Follow-Up Guidelines (COG-LTFU Guidelines, version 4.0) regarding screening for psychosocial late effects of pediatric cancer. PROCEDURE: Articles published between August 2009 and January 2011 that addressed psychosocial late effects of long-term survivors of pediatric cancer (n = 35) were reviewed by a multidisciplinary team of COG late effect experts. RESULTS: The majority of studies in this time period indicate that survivors experience few psychosocial problems in long-term survivorship. A critical subset, however, is at increased risk for psychosocial late effects secondary to the treatment. Highlighted findings from this review include increased rates of suicidal ideation (SI), and health beliefs as robust predictors of SI, anxiety, and global distress. Survivors' health beliefs were associated with their perceptions of physical limitations, overall late effects, and cancer-related pain. While many survivorship studies continue to specify risk factors for anxiety and posttraumatic stress symptoms/posttraumatic stress disorder, others outcomes (e.g., developmental, interpersonal, and familial factors) appear to be emerging in importance. CONCLUSIONS: Although the majority of childhood cancer survivors do not experience psychosocial problems, a subset will. The recent research findings have been included in the new COG-LTFU Guidelines that will assist in the targeted assessment and the treatment of survivors' psychosocial health. PMID- 26488340 TI - Below-gap excitation of semiconducting single-wall carbon nanotubes. AB - We investigate the optoelectronic properties of the semiconducting (6,5) species of single-walled carbon nanotubes by measuring ultrafast transient transmission changes with 20 fs time resolution. We demonstrate that photons with energy below the lowest exciton resonance efficiently lead to linear excitation of electronic states. This finding challenges the established picture of a vanishing optical absorption below the fundamental excitonic resonance. Our result points towards below-gap electronic states as an intrinsic property of semiconducting nanotubes. PMID- 26488341 TI - Cobalt and copper pyridylmethylphosphonates with two- and three-dimensional structures and field-induced magnetic transitions. AB - Two novel metal pyridylmethylphosphonates, namely, [Co(4-pmp)] (1) and [Cu(4 pmp)(H2O)] (2), (4-pmpH2 = 4-pyridylmethylphosphonic acid), have been hydrothermally synthesized and characterized by X-ray diffraction, infrared spectroscopy, elemental analysis, and thermogravimetric analysis. In compound 1, each {PO3C} tetrahedron is corner-shared with three {CoNO3} tetrahedra and vice versa, thus forming a one-dimensional (1-D) inorganic chain along the a axis containing 8-membered rings of [(Co-O-P-O)2]. The inorganic chains are further connected by a 4-pmp(2-) ligand, generating a 2-D layered structure. Compound 2 displays a three-dimensional (3-D) framework structure, in which the inorganic layers are pillared by the pyridyl groups of the ligand, generating a 3-D pillared-layered structure. The magnetic properties of 1 and 2 have been studied. Compounds 1 and 2 behave as metamagnets at low temperature. The critical fields are about 70 kOe for 1 and 47 kOe for 2 at 1.8 K. PMID- 26488342 TI - Editorial. PMID- 26488343 TI - Classification of mood disorders. AB - This paper looks at some recent developments in the official diagnostic definitions (DSM-5) and in the research domain. The spectrum concept of mood disorders consists of the components of depression and mania, alone or in combination, on a continuum. Its international operational classification changes regularly, being based on symptoms, their duration and consequences. Causation is as yet unknown. DSM-5 excludes unipolar mania and mania with mild depression as separate diagnoses (they come under bipolar I and bipolar II disorders) and introduces a new hierarchy of manic symptoms, placing energy/activity above mood (elated, irritable). This is shown to be problematic on the basis of recent data. The validity of the duration criteria for mania (1 week), hypomania (4 days) and depression (2 weeks) is also seriously questioned. Shorter episodes are clinically very relevant. The definition of mania/hypomania is a persistent problem, contributing to frequent un- derdiagnosis of bipolar disorder in depressed patients. Other contributory factors include that patients often do not feel ill or seek treatment for the consequences of their high mood, and that hypomania can be hidden by substance use disorders (SUD). Hidden hypomanic syndromes are important because associated with treatment resistance, high comorbidity with anxiety/panic and SUD, psychotic and cognitive symptoms, dementia and higher mortality. Anxiety, too, is doubtless a mood disorder but there is still no concept which integrates anxiety with bipolar disorder and depression. PMID- 26488344 TI - Acute psychosis in the course of treatment of acute adrenal crisis with hydrocortisone in the patient with secondary adrenal insufficiency - a case study. AB - OBJECTIVES: Presentation of the risk of psychosis induced by the treatment of adrenal crisis with high doses of hydrocortisone. METHODS: A case analysis in the context of the literature. RESULTS: There are reported psychoses in the patients with adrenal hypofunction and hyperfunction. Psychoses following implementation of substitution with small doses of corticosteroids due to adrenal insufficiency were also observed. The hypereactivity of the glucocorticoid receptor is supposed mechanism. We have not found any description of psychosis connected with steroid administration in adrenal crisis. We present a case of 55 years old female, so far mentally healthy with untreated adrenocortical insufficiency secondary to radiotherapy of pituitary adenoma (prolactinoma) performed 3 years ago. She was admitted to the hospital because of acute adrenal crisis provoked by infection. In the fourth day of treatment with intravenous Hydrocortisone (up to 400mg/24 hours) there occurred acute psychosis with hallucinations, delusions and life threatening behaviours. The patient was admitted to the psychiatric inpatient unit. Following 3 days of treatment with haloperidol, and decreasing the steroid dosage - the psychosis disappeared, without recurrence, despite of discontinuation of haloperidol. CONCLUSIONS: The case focuses attention on the risk of psychosis connected with the treatment of the adrenal crisis with high doses of Hydrocortisone. Because of the risk of psychiatric complications, the patients treated with high doses of corticosteroids, require an evaluation of risk factors for mental disturbances, and safety precautions in cooperation of endocrinologist and psychiatrist. PMID- 26488345 TI - Clinical utility of chosen factors in predicting post-stroke depression: a one year follow-up. AB - OBJECTIVES: The aim of the study was to identify possible interrelation between the presence of post-stroke depression (PSD) and chosen clinical and demographic parameters. METHODS: Initially 116 patients (61.4 +/- 12.6 years, women N = 42) hospitalized in Neurology Department, Medical University of Gdansk (April 2003 - December 2005) due to first ischemic stroke, were included in the study. We analysed demographic data, the lesion's side and location according to neuroimaging and global neurological deficit estimated on the first day after the stroke and at discharge using NIHSS (National Institutes of Health Stroke Scale) and Barthel Index of Activity of Daily Living. Psychiatric evaluation was done:6 (42 +/- 3 days) and 12 weeks (84 +/- 7 days), as well as 6 (+/-14 days) and 12 months (+/-14 days) after stroke based on ICD-10 and functional assessment scale (Rankin Scale). RESULTS: Depression was diagnosed in 29 patients (27.6%). No correlation was found between PSD and sex or age. On the first day and at discharge patients without PSD were functioning slightly better but the difference was not statistically significant. We found association between the presence of PSD and the results of Rankin scale with the exception of degree of improvement during whole observation. In the group of patients with PSD left hemisphere strokes were slightly more common, but the difference did not reach statistical significance. The location of lesions in frontal lobes and basal ganglia was associated with presence of depression. CONCLUSIONS: We found the association between the presence of PSD and location of lesions (frontal lobes or basal ganglia), as well as with the degree of functional improvement during 12 months after stroke. PMID- 26488346 TI - Relationships between various temperament dimensions, levels of selected cytokines and Posttraumatic Stress Disorder (PTSD) in males, incurred as a result of mechanical injuries of lower extremities. AB - OBJECTIVES: This analysis addresses the relationships between various temperament dimensions, levels of selected cytokines and PTSD in males, incurred as a result of mechanical injuries of lower extremities. METHODS: PTSD was assessed with a PTSD Factorial Version Inventory. Temperamental traits were evaluated by means of Formal Characteristics of Behaviour - Temperament Inventory (FCB-TI). Cytokine levels were determined using ELISA kits. The study population was selected from among a larger population of 80 persons. 15 persons with signs of inflammation were excluded. PTSD group included 33 persons, 32 subjects were included in the control group. RESULTS: Positive statistical correlation with PTSD was observed for: perseverance and emotional reactivity. On the other hand, negative relationship was shown between PTSD and: briskness, endurance and activity. No statistically significant correlations were revealed between the levels of selected cytokines (sIL-2, IL-6, IL-10, TNF-alpha & IFN-gamma) and temperamental traits. Moreover, this study investigates the relationships between temperamental traits, PTSD and various personality dimensions. CONCLUSIONS: 1. Patients with temperamental traits such as high perseverance and emotional reactivity had a greater risk of PTSD. 2. Patients with temperamental traits such as high briskness, endurance and activity had lower risk of PTSD. 3. The level of cytokines (sIL-2, IL-6, IL-10, TNF-alpha, IFN-gamma) was not dependent on the temperamental traits. PMID- 26488347 TI - Parotid salivary parameters in bulimic patients - a controlled clinical trial. AB - OBJECTIVES: The aim of this study was to determine whether patients with purging type bulimia and/or non-bulimic patients, treated with serotonin reuptake inhibitor SI-5-HT (fluoxetine), have dental erosion and changes in selected buffer components of parotid saliva (bicarbonates, phosphates, urea), compared with the healthy population. METHODS: A controlled clinical trial was designed for three, age-matched, female groups of 94 patients: 1) bulimic patients treated with fluoxetine 40 mg/day (n = 25), 2) non-bulimic patients diagnosed with bipolar affective disorder, treated with fluoxetine 20mg/day (n = 25), and 3) healthy controls (n = 44). Parotid saliva was collected from the subjects by means of Lashley cup at rest and stimulated chemically with a 3% citric acid solution. In clinical examination the dental erosion was determined as non carious tooth substance loss using the Tooth Wear Index (TWI). The concentrations of inorganic phosphates, bicarbonate, urea and pH in saliva were measured. RESULTS: In the bulimic subjects higher TWI (24%) and lower levels of pH, bicarbonates and phosphates compared with controls were observed. There were no significant differences in urea concentration. CONCLUSIONS: Erosive-abrasive tooth surface loss seems to be a significant diagnostic tool of bulimia nervosa. The presence of pathological changes in teeth structure indicates the loss of protective properties of saliva, which is proved by pH value and concentration of buffer ions. It is advisable to monitor salivary parameters, such as salivary flow rate, pH and the concentration of buffer ions in long-term treatment with SI 5-HT drugs in case of patients with purging-type bulimia. There is also a need for regular dental check-ups of the oral cavity tissues. PMID- 26488348 TI - Gastrointestinal motility disorders in patients with anorexia nervosa - a review of the literature. AB - Anorexia nervosa is a disease carrying havoc on many levels of the body functioning. The presence of numerous somatic complications as a consequence of starvation is an important part of the clinical picture of this disease. Symptoms of the gastrointestinal tract are one of the most common complaints reported by patients, especially in the initial period of realimentation. Most common symptoms are associated with gastrointestinal motility disorders. The available data show that as many as half of patients suffering from anorexia nervosa manifest significant gastrointestinal motility disorders (incomplete relaxation of the upper and lower oesophageal sphincter, impaired compliance of the stomach, delayed gastric emptying, intestinal transit extension, decreased motility of the rectum and anus). These disorders along with gastrointestinal tract ailments may impede the restoration of proper diet, if not detected early and treated. There are relatively few studies on gastrointestinal motility disorders in patients suffering from anorexia nervosa, which do not clearly answer the question whether these disorders are genetic, or result from cachexia and whether they disappear along with the restoration of the normal body weight. No reference of research results to the clinical practice, and the lack of standard procedures for diagnosis and treatment of gastrointestinal disorders in patients with anorexia nervosa are significant problems for specialists in the field of psychiatry and gastroenterology. PMID- 26488349 TI - The perception of relations in the family of origin of patients with eating disorders and the perception of relations in families of origin of their parents. AB - OBJECTIVES: Analysis of the correlation between the assessment of current family relations in families of patients diagnosed with eating disorders and the assessment of the relations in the family of origin of their parents. METHODS: 54 female patients with restrictive anorexia nervosa, 22 female patients with binge purge anorexia, 36 female patients with bulimia. Two control groups were included: 36 female patients with depressive disorders and 85 schoolgirls from Krakow. The study also covered the girls' parents. Family of Origin Scale and FAM Family Assessment Measure (Polish version). RESULTS: In the families of schoolgirls from Krakow better evaluation of the experience of intimacy and autonomy in the family of origin of parents of the investigated girls was associated with their and their children more favourable perception of relations in the present nuclear family. What proved particularly significant were perception of transgenerational experiences of the fathers. Only a few statistically significant correlations were observed in all clinical groups. In the parents of the investigated patients a weak correlation was observed between the current marital relations perception and transgenerational experiences evaluation and a significant correlation between parents' transgenerational experience evaluation and the assessment of the relations with their daughters. CONCLUSIONS: No specific correlations were found between the perception of the transgenerational experience of parents and evaluation of current relations in the nuclear family of their children with eating disorders. The results in the group with eating disorders suggest that the relations between parents and daughters are more intense than marital relations. PMID- 26488350 TI - The association between self-image and defence mechanisms in a group of adolescent patients receiving psychiatric treatment. AB - OBJECTIVES: The aim of the study was to explore the relationship between various areas of self-image and defence mechanisms in adolescents. The study included a division into groups according to whether or not they were receiving psychiatric treatment. METHODS: Data were obtained from two groups: a clinical group (30 persons), consisting of adolescent patients of the Adolescent Inpatient Ward of the Child and Adolescent Psychiatry Clinic and a control group (40 persons), adolescents attending upper secondary school. The Defence Style Questionnaire DSQ 40 and the Offer Self Image Questionnaire were used in the study. RESULTS: Results showed no differences, in the maturity levels of the defence mechanisms, between the two groups. Subjects from the clinical group had a significantly lower self-image of themselves than subjects from the control group.. In both groups, the use of mature defence mechanisms was accompanied by a positive self image, while the use of less mature defence mechanisms was associated with a lower self-image. Comparison of the groups revealed different relationships between the aspects of self-image and used defence mechanisms, in particular the mechanism of projection. Number of significant correlations was greater in the clinical group. CONCLUSIONS: In the context of lower self-image, the study revealed the importance of such defence mechanisms as projection, acting out, somatization or schizoid fantasies. The obtained results seem to confirm a hypothesis that the assessment of the maturity of defence mechanisms in the period of adolescence is less clear and clinically useful. PMID- 26488351 TI - Personality disorders in adolescence. AB - Adult personality disorders are well recognized and described in the literature. The discussion about the possibility of the presence of personality disorders in adolescents started about 20 years ago. Some authors claim the before the age of 18 it is only possible to identify precursors of future personality disorders and such a standpoint is reflected in diagnostic criteria. This is based on the assumption that personality in adolescence is still not well established. Consequently, the criterion on the persistence of symptoms for the period of time cannot be met (the persistence of symptoms of personality disorders for the period of at least two years). Other approach postulates that problems presented in adolescence should not be exclusively limited to Axis I according to DSM. The proponents of this approach claim that current diagnostic tools are not adjusted to adolescents, thus it is very difficult to measure stability and persistence of symptoms in this age group. This paper presents literature review on personality disorders in adolescence. PMID- 26488352 TI - The prevalence of Non-suicidal Self-Injury (NSSI) among high school students in relation to age and sex. AB - OBJECTIVES: The undertaken research aimed at determining the frequency of deliberate self-injurious behaviour (D-SIB) among the students of secondary schools and also the analysis of the frequency of repeated Non-Suicidal Self Injury (NSSI) occurrences in accordance with DSM-5 criteria in reference to the age and sex in the studied population. METHODS: The data was collected via survey method according to the questionnaire prepared in compliance with the criteria DSM-5 and Self-Harm Inventory. The study included randomly selected students: 1193 boys and 1027 girls in Bialystok aged 12 and 19 (average age +/- SD:16.8 +/- 1.65). Statistical analysis of the data was carried out using the application Statistica 10.0 PL, StatSoft. RESULTS: These results indicate that D-SIB and NSSI affect both sexes. In the studied group 8.3 % of students engage in deliberate self-injurious behaviour. The percentage of NSSI was 4.8% (6.3% in the group of boys, 3.2 % among girls; p(Chi2)=0.01). Self-cutting was most common among 15 year-old pupils ((D-SIB:14.75%; NNSI:8.1%). The majority of respondents (82% of girls and 74% of boys) revealed that as a result of self-injury behaviour they experience relief. CONCLUSIONS: Conducting further research in the area of NSSI seems to be crucial due to chronicity and prevalence as well as the fact that numerous repeated self-injuries bringing relief or causing positive state of mind might indicate a mechanism similar to an addiction syndrome in adolescence. PMID- 26488353 TI - Transcranial magnetic stimulation in treatment of various psychiatric disorders - review of the most prominent studies and the latest news. AB - The aim of this paper was to present the current use of repetitive transcranial magnetic stimulation (rTMS) in psychiatric disorders with the mode of its application and results of most prominent studies. The most robust data concerns its use in major depressive disorder, while in other psychiatric disorders results are preliminary. TMS with the development of new techniques and new treatment protocols has a potential to become a very useful treatment tool in pharmacoresistant patients or patients intolerant of pharmacotherapy. PMID- 26488354 TI - The use of DBS stimulation in mental disorders - opportunities and risks. AB - Enlarging the knowledge on the biological background of mental disorder is the cause of the growth of interest in cooperation between psychiatrists and neurosurgeons. The experience gained over the last 20 years in research on the use of neuromodulation techniques in neurological disorders suggest that deep brain stimulation (DBS), in addition to improving the neurological condition can lead to positive changes in mood and drive. The use of functional brain research and neuroimaging allowed us to isolate key areas for the emergence of depressive symptoms and obsessive-compulsive disorder. The results of recent studies on the use of DBS in psychiatric disorders indicate, however, both the high efficiency of this method and possible complications and risks associated with it. The paper briefly presents the opportunities of using this method in drug-resistant patients, not responding to other, less invasive forms of treatment, as well as the potential risks and difficulties. However, further research in this area are still required to determine the actual effectiveness of the method, the optimal stereotactic targets, neurostimulation parameters, the risk of side effects and ways to avoid them. PMID- 26488355 TI - Fibromyalgia Syndrome - a multidisciplinary approach. AB - According to American College of Rheumatology fibromyalgia syndrome (FMS) is a common health problem characterized by widespread pain and tenderness. The pain and tenderness, although chronic, present a tendency to fluctuate both in intensity and location around the body. Patients with FMS experience fatigue and often have sleep disorders. It is estimated that FMS affects two to four percent of the general population. It is most common in women, though it can also occur in men. FMS most often first occur in the middle adulthood, but it can start as early as in the teen years or in the old age. The causes of FMS are unclear. Various infectious agents have recently been linked with the development of FMS. Some genes are potentially linked with an increased risk of developing FMS and some other health problems, which are common comorbidities to FMS. It is the genes that determine individual sensitivity and reaction to pain, quality of the antinociceptive system and complex biochemistry of pain sensation. Diagnosis and therapy may be complex and require cooperation of many specialists. Rheumatologists often make the diagnosis and differentiate FMS with other disorders from the rheumatoid group. FMS patients may also require help from the Psychiatric Clinic (Out-Patients Clinic) due to accompanying mental problems. As the pharmacological treatment options are limited and only complex therapy gives relatively good results, the treatment plan should include elements of physical therapy. PMID- 26488356 TI - Non-adaptive reaction to disease - coping, demographic variables and trauma symptoms in cancer patients. AB - OBJECTIVES: The aim of the presented study was to determine the relations of styles and strategies of coping with stress and demographic variables with the intensity of PTSD symptoms in persons diagnosed with cancer. The study tried to determine which style of coping with stress is the best predictor of posttraumatic symptoms in the group. METHODS: This study was conducted on the group of 150 patients (55 females and 95 males) that were treated for cancer. Polish version of the Mini-Mental Adjustment to Cancer Scale - mini-MAC - was used to study styles of coping with stress. PTSD Inventory (PTSD-C) allowing for the quantitative estimation of the symptoms was used measure the intensity of PTSD symptoms. Additionally, a demographic questionnaire containing the questions about the age, sex, education, and the time since the diagnosis was employed for the benefits of this study. RESULTS: The results of the study indicate non adaptive function of destructive style. In the situation of being subjected to a traumatic event this style is propitious to the development of the symptoms of posttraumatic stress disorder. The individual strategies of coping, sex and age are correlated with higher intensity of posttraumatic symptoms in sick persons. CONCLUSIONS: Destructive style, of coping with stress is less beneficial for the adaptation to a cancerous disease. It may significantly influence the development of pathological symptoms characteristic to PTSD. PMID- 26488357 TI - Quality of life of patients with irritable bowel syndrome before and after education. AB - OBJECTIVES: The aim of the present study was to analyse the impact of education of patients with irritable bowel syndrome (IBS) on their quality of life. METHODS: The study was carried out at the Gastroenterology Outpatient Clinic of the Independent Public Clinical Hospital No. 4 in Lublin and Gastroenterology Outpatient Clinic of the Cardinal Stefan Wyszynski Regional Specialist Hospital in Lublin in the years 2010-2011. The quality of life was analysed using the Quality of Life Questionnaire (QOL-Q R. Schalock, K. Keith). The group of 83 patients with the diagnosis of irritable bowel syndrome, who gave their consent for inclusion in the study, was provided with information about the essence of the disease, disease-related diet and lifestyle, course of the disease, medications, and check-ups. RESULTS: Our patients educated by the physician, nurse and those provided with written information had substantially higher scores in multi-dimensional aspects of the quality of life after education. Six months after education patients with IBS showed a significantly higher quality of life in all aspects, i.e. Satisfaction, Competence/productivity, Empowerment/independence and Social inclusion/community integration. The understanding of the essence of their disease contributed to a decrease in anxiety associated with the neoplastic disease and worrying symptoms, which significantly reduced the incidence of complaints. CONCLUSIONS: 1. Quality of life of patients with irritable bowel syndrome is substantially reduced in all the examined spheres. 2. Education of patients with IBS resulted in enhanced quality of life and reduced disease-related complaints. 3. Education of patients with IBS plays a significant role in the entire therapeutic process. PMID- 26488358 TI - Music therapy in neurological rehabilitation settings. AB - The neurologic music therapy is a new scope of music therapy. Its techniques deal with dysfunctions resulting from diseases of the human nervous system. Music can be used as an alternative modality to access functions unavailable through non musical stimulus. Processes in the brain activated by the influence of music can be generalized and transferred to non-musical functions. Therefore, in clinical practice, the translation of non-musical therapeutic exercises into analogous, isomorphic musical exercises is performed. They make use of the executive peculiarity of musical instruments and musical structures to prime, cue and coordinate movements. Among musical components, a repetitive rhythm plays a significant role. It regulates physiologic and behavioural functions through the mechanism of entrainment (synchronization of biological rhythms with musical rhythm based on acoustic resonance). It is especially relevant for patients with a deficient internal timing system in the brain. Additionally, regular rhythmic patterns facilitate memory encoding and decoding of non-musical information hence music is an efficient mnemonic tool. The music as a hierarchical, compound language of time, with its unique ability to access affective/motivational systems in the brain, provides time structures enhancing perception processes, mainly in the range of cognition, language and motor learning. It allows for emotional expression and improvement of the motivation for rehabilitation activities. The new technologies of rhythmic sensory stimulation (i.e. Binaural Beat Stimulation) or rhythmic music in combination with rhythmic light therapy appear. This multimodal forms of stimulation are used in the treatment of stroke, brain injury, dementia and other cognitive deficits. Clinical outcome studies provide evidence of the significant superiority of rehabilitation with music over the one without music. PMID- 26488360 TI - Conference report: Progress in Biomedicine & Neuromedicine. Workshop with Nobel Prize Winner Professor Erwin Neher), Krakow 21-23.06.2015. PMID- 26488359 TI - Reduction of suicidal ideation in patients undergoing psychotherapy in the day hospital for the treatment of neurotic and behavioral disorders and neurotic symptoms reported by them before the hospitalization. AB - OBJECTIVES: Analysis of associations between symptoms reported before the beginning of the hospitalization and reduction of suicidal ideation - or its lack - obtained until the end of the hospitalization in patients of the day hospital for the treatment of neurotic and behavioral disorders. METHODS: Symptoms Checklist KO"O" and Life Inventory completed by 461 women and 219 men treated with intensive integrative psychotherapy with predominance of psychodynamic approach in the day hospital due to neurotic, behavioral and personality disorders between 2005-2013. Percentages of patients reporting SI initially and at the end of the treatment were 29.1% and 10.2% respectively in women and 36.5% and 13.7% in men. The improvement in terms of initially reported SI was obtained by 84.3% of women and 77.5% of men. Among patients, those initially reporting SI were characterized by greater intensity of neurotic symptoms (p<0.001) and greater intensity of nearly all of 14 subtypes of neurotic symptoms(p<0.05). RESULTS: Among those reporting SI, subgroups of women with greater intensity of Obsessive-compulsive symptoms (p=0.003), Neurasthenia (p=0.005), Autonomic disorders (p=0.044) and women reporting episodes of uncontrollable hunger (p<0.01) had significantly lower chances of improvement in terms of SI than others. CONCLUSIONS: Patients initially reporting SI constituted approximately 1/3 in both genders and were characterized by greater intensity of neurotic disorders. Among those, women with particularly higher intensity of Obsessive compulsive symptoms, Neurasthenia and Autonomic disorders and women reporting episodes of uncontrollable hunger seemed to suffer from SI that were more resistant to the psychotherapy. As such, those subgroups of women require special attention and diligent selection of the therapeutic methods. PMID- 26488361 TI - Help us save the National Programme for the Protection of Mental Health (open letter). PMID- 26488362 TI - Comparison of the Clinical Effectiveness of PFNA, PFLCP, and DHS in Treatment of Unstable Intertrochanteric Femoral Fracture. AB - In this study, a randomized trial was conducted to compare the clinical effectiveness of proximal femoral locking compression plate (PFLCP), dynamic hip screw (DHS), and proximal femoral nail antirotation (PFNA) for unstable intertrochanteric femoral fracture treatment. Ninety patients diagnosed with unstable intertrochanteric femoral fracture were enrolled in this study at the department of orthopedics at Linyi Second People's Hospital between May 2010 and May 2012. Fractures were classified according to Tronzo-Evans classification, and the patients were randomly divided into 3 groups, PFLCP, DHS, and PFNA, with 30 patients in each group. The length of incision, operative time, intraoperative blood loss, postoperative drainage, postoperative weight-bearing ambulation time, and duration of fracture union were significantly lower in patients who underwent PFNA and PFLCP compared to patients treated with DHS. Furthermore, when the same clinical parameters were used for comparison, the PFNA group showed markedly lower values compared with the PFLCP group. The total incidence of postoperative complications was significantly different among the PFNA, PFLCP, and DHS groups, with the PFNA group exhibiting markedly lower complication rates compared with PFLCP and DHS groups. However, PFLCP and DHS groups did not show significant differences in the incidence of postoperative complications. Notably, the Harris hip score of PFNA group was markedly higher than the DHS group. In conclusion, our results provide convincing evidence that PFNA may be the most effective internal fixation treatment of unstable intertrochanteric femoral fracture. PMID- 26488363 TI - Evaluation of Surface Roughness of Ceramic and Resin Composite Material Used for Conservative Indirect Restorations, after Repolishing by Intraoral Means. AB - PURPOSE: To evaluate and compare the mean surface roughness (Ra) of one ceramic and one resin composite material used for indirect restorations, after grinding and repolishing by intraoral means. MATERIALS AND METHODS: The materials used were the lithium disilicate glass ceramic IPS e.max Press (EMP) and the indirect resin composite restoration system Gradia (GR). Twelve specimen disks were prepared from each material according to the manufacturer of each material. Five initial measurements of the Ra (Ra1 ) were made on each specimen as a referral basis, and the specimens were ground with a fine (red) diamond bur. The specimens were repolished using (a) Komet Dialite Polishing Kit for EMP and (b) Enhance Finishing and Polishing System and Prisma Gloss Polishing Paste for GR. Five final Ra (Ra2 ) measurements were performed on each specimen. All measurements were made using a laser profilometer. Scanning electron microscopy (SEM) was also used to visualize the initial surface morphology and the morphological changes on the specimens' surface after repolishing. RESULTS: A highly significant difference was found between Ra1EMP and Ra2EMP (p < 0.001), between Ra1GR and Ra2GR (p < 0.001), as well as between Ra2EMP and Ra2GR (p < 0.001), when compared in pairs. A highly significant difference (p < 0.001) was also found between DeltaRaEMP and DeltaRaGR , with DeltaRaGR being higher than DeltaRaEMP . The RaGR values were higher than the RaEMP values at all times. SEM revealed that both EMP and GR repolished surfaces presented with irregularities; however, in GR specimens major voids and craters were present. CONCLUSIONS: EMP was found to perform better when polished by intraoral means compared with GR. Both materials exhibited Ra2 above the critical threshold for increased plaque accumulation and periodontal inflammation. If enamel-to-enamel roughness found in occlusal contact areas is considered as baseline, both materials were clinically acceptable after repolishing. PMID- 26488365 TI - Synthesis of novel polysubstituted N-benzyl-1H-pyrroles via a cascade reaction of alkynyl Fischer carbenes with alpha-imino glycine methyl esters. AB - An efficient and simple synthesis of novel and densely substituted N-benzyl-1H pyrroles 6a-r is described by a 1,4-addition/isomerization/ring closure/demetalation cascade process of alkynyl Fischer carbene complexes 1a-f and 2a and alpha-imino glycine methyl esters 3a, b, d, g, h, and k promoted with LDA. PMID- 26488364 TI - Digital signaling decouples activation probability and population heterogeneity. AB - Digital signaling enhances robustness of cellular decisions in noisy environments, but it is unclear how digital systems transmit temporal information about a stimulus. To understand how temporal input information is encoded and decoded by the NF-kappaB system, we studied transcription factor dynamics and gene regulation under dose- and duration-modulated inflammatory inputs. Mathematical modeling predicted and microfluidic single-cell experiments confirmed that integral of the stimulus (or area, concentration * duration) controls the fraction of cells that activate NF-kappaB in the population. However, stimulus temporal profile determined NF-kappaB dynamics, cell-to-cell variability, and gene expression phenotype. A sustained, weak stimulation lead to heterogeneous activation and delayed timing that is transmitted to gene expression. In contrast, a transient, strong stimulus with the same area caused rapid and uniform dynamics. These results show that digital NF-kappaB signaling enables multidimensional control of cellular phenotype via input profile, allowing parallel and independent control of single-cell activation probability and population heterogeneity. PMID- 26488366 TI - Lack of Reproductive Toxicity in Adult Male Rats Exposed to Interferon-Alpha. AB - Interferon-alpha (IFN- alpha), a type I IFN, is a protein with antiviral, antiproliferative, and immunoregulatory activities, widely used in the treatment of several types of cancers as well as hepatitis B and C. Decrease of libido and erectile dysfunction are commonly reported by male patients during treatment of chronic hepatitis C with IFN- alpha . However, IFN therapy-associated underlying factors attributed to sexual dysfunction are still not well defined. Currently, there are few studies investigating the effects of IFN on male reproductive system functions. Given that, the aim of the present investigation was to examine effects of subchronic exposure to IFN- alpha (5 * 10(4) U/kg and 10 * 10(4) U/kg, 30 d) on serum hormones, sperm parameters, fertility, and testicular and epididymal hystopathology and morphometry in adult male Wistar rats. None of the evaluated parameters was markedly altered by IFN- alpha . Thus, our results suggest that exposure to IFN- alpha , in this experimental design, did not adversely affect sperm quality and fertile capacity of male rats. PMID- 26488367 TI - Surface Mobility and Ordered Rearrangement of Immobilized DNA Origami. AB - The immobilization of DNA nanostructures on a surface is a key step for the integration of DNA-based material in nanotechnology for electronic or sensorial applications. Thereby the arrangement and distribution at the substrate surface is of growing interest. Top-down approaches such as lithography have been reported, but show certain limitations regarding costs and/or throughput. Here we present a self-assembly effect observed when already immobilized and dried origami preparations were again rehydrated under certain conditions, resulting in a certain ordering of densely packed origami structures. We investigate the influence of different parameters in order to reveal the underlying mechanisms, and find that subsequent droplet formation and interfacial tension during the droplet drying play a role. Further adjustment of these parameters could develop the introduced effect to an additional tool for controlled integration of DNA nanostructures. PMID- 26488369 TI - Structural and Magnetic Properties of the Iridium Double Perovskites Ba(2 x)Sr(x)YIrO6. AB - The crystal structures of the series of ordered double perovskites Ba(2 x)Sr(x)YIrO6 (0 <= x <= 2) were refined using a combination of high-resolution synchrotron X-ray and high-intensity neutron diffraction data. The materials displayed a sequence of structures Fm3m(a(0)a(0)a(0)) (x = 0.6)--> I4/m(a(0)a(0)c(-)) (x = 1.0)--> I2/m(a(-)a(-)c(0)) (x = 1.4)--> P2(1)/n(a(-)a( )c(+)) associated with increased tilting of the corner-sharing octahedra induced by increasing amount of the smaller Sr cation present. A similar sequence of transitions was induced by heating selected samples. Magnetic susceptibility measurements between 2 and 300 K showed no evidence for long-range magnetic ordering, an observation that was supported by neutron diffraction measurements, and rather strong spin-orbit coupling results in a Jeff = 0 ground state. PMID- 26488368 TI - Development and characterization of a rapid polymerizing collagen for soft tissue augmentation. AB - A liquid collagen has been developed that fibrilizes upon injection. Rapid polymerizing collagen (RPC) is a type I porcine collagen that undergoes fibrillization upon interaction with ionic solutions, such as physiological solutions. The ability to inject liquid collagen would be beneficial for many soft tissue augmentation applications. In this study, RPC was synthesized and characterized as a possible dermal filler. Transmission electron microscopy, ion induced RPC fibrillogenesis tests, collagenase resistance assay, and injection force studies were performed to assess RPC's physicochemical properties. An in vivo study was performed which consisted of a 1-, 3-, and 6-month study where RPC was injected into the ears of miniature swine. The results demonstrated that the liquid RPC requires low injection force (<7 N); fibrillogenesis and banding of collagen occurs when RPC is injected into ionic solutions, and RPC has enhanced resistance to collagenase breakdown. The in vivo study demonstrated long-term biocompatibility with low irritation scores. In conclusion RPC possesses many of the desirable properties of a soft tissue augmentation material. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 758-767, 2016. PMID- 26488370 TI - Multicomponent Synthesis of Functionalized Tetrahydroacridinones: Insights into a Mechanistic Route. AB - A mechanistic study of three-component reactions of various aromatic amines with a number of aldehydes and 1,3-diones was achieved. The unprecedented reaction involved a nucleophilic attack of an aromatic amine on the in situ generated Michael adduct intermediate followed by six-electron ring cyclizations. It is contrary to the common belief that advocates involvement of coupling reactions between a Knoevenagel adduct and an aromatic amine to deliver substituted tetrahydroacridinones. PMID- 26488371 TI - Distance-Based Tear Lactoferrin Assay on Microfluidic Paper Device Using Interfacial Interactions on Surface-Modified Cellulose. AB - "Distance-based" detection motifs on microfluidic paper-based analytical devices (MUPADs) allow quantitative analysis without using signal readout instruments in a similar manner to classical analogue thermometers. To realize a cost-effective and calibration-free distance-based assay of lactoferrin in human tear fluid on a MUPAD not relying on antibodies or enzymes, we investigated the fluidic mobilities of the target protein and Tb(3+) cations used as the fluorescent detection reagent on surface-modified cellulosic filter papers. Chromatographic elution experiments in a tear-like sample matrix containing electrolytes and proteins revealed a collapse of attractive electrostatic interactions between lactoferrin or Tb(3+) and the cellulosic substrate, which was overcome by the modification of the paper surface with the sulfated polysaccharide iota carrageenan. The resulting MUPAD based on the fluorescence emission distance successfully analyzed 0-4 mg mL(-1) of lactoferrin in complex human tear matrix with a lower limit of detection of 0.1 mg mL(-1) by simple visual inspection. Assay results of 18 human tear samples including ocular disease patients and healthy volunteers showed good correlation to the reference ELISA method with a slope of 0.997 and a regression coefficient of 0.948. The distance-based quantitative signal and the good batch-to-batch fabrication reproducibility relying on printing methods enable quantitative analysis by simply reading out "concentration scale marks" printed on the MUPAD without performing any calibration and using any signal readout instrument. PMID- 26488372 TI - Accelerated Time-Resolved Contrast-Enhanced Magnetic Resonance Angiography of Dural Arteriovenous Fistulas Using Highly Constrained Reconstruction of Sparse Cerebrovascular Data Sets. AB - OBJECTIVE: Time-resolved contrast-enhanced magnetic resonance angiography (MRA) is commonly used to noninvasively characterize vascular malformations. However, the spatial and temporal resolution of current methods often compromises the clinical value of the examinations. Constrained reconstruction is a temporal spatial correlation strategy that exploits the relative sparsity of vessels in space to dramatically reduce the amount of data required to generate fast high resolution time-resolved contrast-enhanced MRA studies. In this report, we use a novel temporal spatial acceleration method termed HYPRFlow to diagnose and classify dural arteriovenous fistulas (DAVFs). Our hypothesis is that HYPRFlow images are of adequate diagnostic image quality to delineate the arterial and venous components of DAVFs and allow correct classification using the Cognard system. SUBJECTS AND METHODS: Eight patients with known DAVFs underwent HYPRFlow imaging with isotropic resolution of 0.68 mm and temporal resolution of 0.75 second and 3-dimensional time-of-flight (3DTOF) MRA. The 3DTOF images and HYPRFlow images were evaluated by 2 readers and scored for arterial anatomic image quality. Digital subtraction angiography (DSA) was available for comparison in 7 subjects, and for these patients, each DAVF was classified according to the Cognard system using HYPRFlow and DSA examinations. Digital subtraction angiography was considered the reference examination or criterion standard. RESULTS: HYPRFlow imaging classification was concordant with DSA in all but 1 case. There was no difference in the arterial image quality scores between HYPRFlow and 3DTOF MRA (95% confidence interval). Arterial-to-venous separation was rated excellent (n = 3), good (n = 4), or poor (n = 1), and arteriovenous shunting was easily appreciated. Undersampling artifacts were reduced by using a low pass filter and did not interfere with the diagnostic quality of the examinations. CONCLUSIONS: HYPRFlow is a novel acquisition and reconstruction technique that exploits the relative sparsity of intracranial vessels in space to increase temporal and spatial resolution and provides accurate delineation of DAVF vasculature. PMID- 26488373 TI - Parenchymal Blood Volume Assessed by C-Arm-Based Computed Tomography in Immediate Posttreatment Evaluation of Drug-Eluting Bead Transarterial Chemoembolization in Hepatocellular Carcinoma. AB - OBJECTIVES: The aim of this study was to assess clinical utility of the quantitative perfusion parameter called parenchymal blood volume (PBV), as derived from C-arm-based computed tomography (CT), for immediate posttreatment assessment of drug-eluting bead (DEB) transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Twenty-four patients with early- or intermediate-stage HCC received DEB-TACE. A total of 52 HCC lesions were treated and assessed by C-arm CT before and after intervention. C-arm CT consisted of nonenhanced and contrast-enhanced acquisitions; from these, PBV maps were reconstructed. Lesion diameter, maximum PBV, and unenhanced parenchyma density were assessed before and after treatment. Diameter of visible contrast media deposits as well as residual vascularization was assessed after delivery of DEB. All patients underwent follow-up using cross-sectional imaging. All assessed lesions were evaluated concerning modified Response Evaluation Criteria in Solid Tumors for HCC. RESULTS: All treated lesions showed significant decrease in PBV after DEB-TACE (mean difference, -15.61 mL/100 mL, P < 0.0001). Eleven lesions showed residual tumoral perfusion in PBV maps associated with an unfavorable outcome compared with completely treated lesions in terms of a lower tumor shrinkage over time (-0.02 +/- 0.49 vs -0.76 +/- 0.38; P < 0.0001). A contrast media deposit was seen in 78% of treated HCC lesions with a tendency toward better visibility in encapsulated lesions. Nonenhanced parenchyma density was significantly higher in all treated segments (149.69 +/- 58.6 vs 68.42 +/- 18.04, P < 0.0001). CONCLUSIONS: Parenchymal blood volume values as derived from C-arm CT acquisitions in combination with nonenhanced and contrast-enhanced C-arm CT images are useful in posttreatment assessment of DEB-TACE in HCC. Residual tumor perfusion in PBV maps have predictive potential for mid-term tumor response in HCC and could allow a more individualized treatment schedule for DEB-TACE in HCC patients. PMID- 26488374 TI - A Novel and Sensitive Approach for the Evaluation of Liver Ischemia-Reperfusion Injury After Liver Transplantation. AB - OBJECTIVES: The purpose of our study was to evaluate the potential of x-ray propagation-based phase-contrast imaging (PCI) computed tomography (CT) for the detection and characterization of early changes after ischemia-reperfusion (IR) in a standardized rat liver transplantation (LTx) model. MATERIALS AND METHODS: Syngeneic orthotopic liver transplantation was performed in male Lewis rats. Ischemia-reperfusion injury (IRI)-induced changes of liver parenchyma were investigated in a time-dependent manner (2, 16, 24, and 32 hours). X-ray phase contrast images of formalin-fixated liver specimens were acquired in CT mode by using a voxel size of 8 * 8 * 8 MUm. Necrapoptotic cell death was visualized with the TdT-mediated dUTP-biotin nick end labeling technique, and alterations of liver graft microhemodynamics, that is, acinar and sinusoidal perfusion failure, were evaluated by in vivo fluorescence microscopy. RESULTS: Acquired and reconstructed PCI-CT images showed an increase in necrotic liver parenchyma dependent on cold storage time, measuring 5.7% +/- 1.6% after 2 hours (comparable to 2.6% +/- 0.4% for sham livers), 11.5% +/- 2.1% (16 hours; P < 0.05 vs control), 23.0% +/- 0.5% (24 hours; P < 0.001 vs control), and 31.3% +/- 2.2% (32 hours; P < 0.001 vs control). There were a significant lower number of perfused acini in dependence on increasing cold storage time. The acinar perfusion index reached 0.970 +/- 0.006 after 2 hours of cold ischemia (comparable to 0.960 +/- 0.009 for sham livers) and declined continuously after 16, 24, and 32 hours cold ischemia (0.58 +/- 0.03, 0.49 +/- 0.02, 0.41 +/- 0.03, each P < 0.0001 vs controls). Comparable results were found for sinusoidal perfusion, reaching 1.8% +/- 0.4% of nonperfused sinusoids for 2 hours of cold ischemia and 8.2% +/- 0.8% after 16 hours, 18.8% +/- 1.4% after 24 hours, and 39.0% +/- 2.4% after 32 hours (each P < 0.0001 vs controls). Prolonged cold ischemia was associated with an increasing number of TdT-mediated dUTP-biotin nick end labeling-positive cells (hepatocytes and sinusoidal lining cells), reaching 0.4 +/- 0.1 (sham), 0.7 +/- 0.4 (2 hours), 6.4 +/- 1.1 (16 hours), 2.1 +/- 0.3 (24 hours), and 14.7 +/- 3.5 (32 hours; P = 0.002) for hepatocytes. CONCLUSIONS: X-ray PCI of histological liver specimens can detect IR-induced tissue necrosis and can provide detailed complementary 3-dimensional information to standard histopathologic findings. PMID- 26488375 TI - Left Atrial 4-Dimensional Flow Magnetic Resonance Imaging: Stasis and Velocity Mapping in Patients With Atrial Fibrillation. AB - OBJECTIVES: Left atrial (LA) 4-dimensional flow magnetic resonance imaging (MRI) was used to derive anatomic maps of LA stasis, peak velocity, and time-to-peak (TTP) velocity in patients with atrial fibrillation (AF) and to identify relationships between LA flow with LA volume and patient characteristics. MATERIALS AND METHODS: Four-dimensional flow MRI for the in vivo assessment of time-resolved 3-dimensional LA blood flow velocities was performed in 111 subjects: 42 patients with a history of AF and in sinus rhythm (AF-sinus), 39 patients with persistent AF (AF-afib), 10 young healthy volunteers (HVs), and 20 age-appropriate controls (CTRL). Data analysis included the 3-dimensional segmentation of the LA and the calculation of LA stasis, peak velocity, and TTP maps. Regional LA flow dynamics were quantified by calculating mean stasis, peak velocity, and TTP in the LA center region and the region adjacent to the LA wall. RESULTS: A sensitivity analysis identified thresholds for global LA stasis (<0.1 m/s) and peak velocity (top 5% LA velocities), which detected significant differences between AF patients and controls for global LA stasis (HV, 25% +/- 5%; CTRL, 29% +/- 10%; AF-sinus, 41% +/- 13%; AF-afib, 52% +/- 17%) and peak velocity (HV, 0.43 +/- 0.02 m/s; CTRL, 0.37 +/- 0.04 m/s; AF-sinus, 0.33 +/- 0.05 m/s; AF-afib, 0.30 +/- 0.05 m/s). Regional analysis revealed significantly increased stasis at both LA center and wall for AF patients compared with age appropriate controls (29%-84% difference, P < 0.006) and for AF-afib versus AF sinus patients (22%-30% difference, P < 0.004). In addition, stasis close to the LA wall was significantly elevated (P < 0.001) compared with the LA center for all subject groups. Multiple regressions revealed significant (RAdj = 0.45-0.50, P < 0.001) relationships between impaired global LA flow (reduced velocity and increased stasis) with age (|beta| = 0.27-0.50, P < 0.002) and LA volume (|beta| = 0.26-0.50, P < 0.003). CONCLUSIONS: Atrial 4-dimensional flow MRI detected changes in global and regional LA flow dynamics associated with AF, age, and LA volume. Longitudinal studies are needed to test the diagnostic value of LA flow metrics as potential risk factors for thromboembolic events. PMID- 26488376 TI - Hypotensive effect of alpha-lipoic acid after a single administration in rats. AB - OBJECTIVE: The effect of alpha-lipoic acid on blood pressure was investigated many times in chronic studies, but there are no studies on the effect of this compound after a single administration. Alpha-lipoic acid is a drug used in diabetic neuropathy, often in obese patients, to treat hypertension. Therefore, knowledge of the potential antihypertensive effect of alpha-lipoic acid even after a single dose and possibly too much pressure reduction is interesting and useful. METHODS: The mechanism of the hypotensive effect of alpha-lipoic acid was examined in normotensive rats in vivo after a single intraperitoneal administration, blood pressure in the left carotid artery of the rats was measured prior to the administration of the compounds (alpha- lipoic acid and/or glibenclamide) and 80 min thereafter. RESULTS: Alpha-lipoic acid at a dosage of 50 mg/kg b.w. i.p. significantly decreased the blood pressure from the 50th min after drug administration. This cardiovascular effect of this compound was reversed by glibenclamide, a selective KATP blocker. Glibenclamide alone at this dose did not significantly affect the blood pressure. Statistical significance was evaluated using two-way ANOVA. CONCLUSION: This suggests that alpha-lipoic acid affects ATP-dependent potassium channels. It is possible that this is an indirect effect of hydrogen sulfide because alpha-lipoic acid can increase its concentration. The results obtained in this study are very important because the patients taking alpha-lipoic acid may be treated for co-existing hypertension. Therefore, the possibility of blood pressure lowering by alpha-lipoic acid should be taken into account, although it does not lead to excessive orthostatic hypotension. PMID- 26488377 TI - Therapeutic effects of pentoxifylline on diabetic heart tissue via NOS. AB - OBJECTIVE: Diabetes mellitus causes a decrease in cardiac output, arterial blood pressure, and heart rate. In this study, we aimed to investigate, at the molecular level, the effect of nitric oxide synthase (NOS) on heart pathology in type 1 diabetes and look at the therapeutic effect of pentoxifylline on this pathology. METHODS: In this experimental study, 50 Wistar albino male rats were used. The rats were divided into 5 groups: group C, control; group D, only diabetes; group D+PI and D+PII, diabetes + pentoxifylline; group P, only pentoxifylline. Group D+PI rats received 50 mg/kg/day pentoxifylline over two months. However, group D+PII rats received saline in the first month and 50 mg/kg/day of pentoxifylline over the following month. At the end of two months, NOS expressions in heart tissue were assessed through immunohistochemistry analysis. The data were compared by one-way ANOVA. RESULTS: At the end of the experiments, there was increased cytoplasmic vacuolization, myofibrillar loss, cytoplasmic eosinophilia, and degeneration of cardiomyocytes; nNOS and iNOS expressions in group D decreased compared with that in group C. In group D+PI and group D+PII, nNOS and iNOS expressions improved compared with group D. CONCLUSION: As a result, we found that diabetes, a known chronic disease, causes serious damage in heart tissue. NOS plays a role in this damage, and pentoxifylline aided in improving nNOS and iNOS expression in this damage. PMID- 26488378 TI - Evaluation of left atrial volume and function in systemic sclerosis patients using speckle tracking and real-time three-dimensional echocardiography. AB - OBJECTIVE: The aim of the present study was to evaluate left atrial (LA) volume and functions using real-time three-dimensional echocardiography (RT3DE) and speckle tracking in systemic sclerosis (SSc) patients. METHODS: The study was designed as a cross-sectional observational study. We studied 41 consecutive SSc patients (38 females, mean age: 49.5+/-11.6 years) and 38 healthy controls (35 females, mean age: 48.5+/-10.8 years). Patients with evidence or history of cardiovascular disease and patients with risk factors as hypertension, diabetes and chronic renal failure were excluded from the study. All study subjects underwent standard echocardiography; LA speckle tracking and RT3DE was performed to assess LA volume and phasic functions. Differences between numeric variables were tested using the independent sample Student's t-test or Mann-Whitney U test, where appropriate. RESULTS: There were no significant differences between SSC patients and controls regarding left ventricular (LV) systolic functions and two dimensional (2-D) atrial diameters. Presence of LV diastolic dysfunction (LVDD) was evaluated and graded according to recommendations of the American Society of Echocardiography. Accordingly, LVDD was observed to be significantly more frequent in SSc patients; 16 SSc patients (39%) and 5 controls (12.8%) were observed to have LVDD (p=0.007). With regard to results obtained from RT3DE, LA maximum, minimum, and before atrial contraction volumes were significantly higher (40.5+/-14.6 vs. 32.6+/-8.9, 15.5+/-8.4 vs. 9.9+/-3.5 and 28.7+/-11.7 vs. 21.4+/ 7.0 mL respectively, p<0.05 for all), whereas LA active emptying fraction, LA total emptying fraction, LA expansion index, and passive emptying fraction values were significantly (47.1+/-12.0 vs. 52.9+/-10.1%, 62.8+/-10.5 vs. 69.5+/-6.7%, 187.5+/-76.0 vs. 246.6+/-96.0, 29.6+/-9.3 vs. 34.4+/-11.0% respectively, p<0.05 for all) in SSc patients than in controls. In addition, regarding results obtained from speckle tracking echocardiography, atrial peak-systolic longitudinal strain (epsilon), early negative strain rate (SR), late negative SR, and peak positive SR values were observed to be significantly lower in SSc patients. CONCLUSION: LA volumes were significantly increased, and LA reservoir, conduit, and contractile functions were significantly impaired in SSc patients compared with controls. LA volume and functional analyses with RT3DE and speckle tracking may facilitate the recognition of subtle LA dysfunction in SSc patients. PMID- 26488379 TI - Heart rate variability and heart rate turbulence in patients with polycystic ovary syndrome. AB - OBJECTIVE: Cardiac autonomic dysfunction may develop in patients with polycystic ovary syndrome (PCOS). Heart rate variability (HRV) and heart rate turbulence (HRT) are used in assessing cardiac autonomic functions. The goal of this study was to compare the cardiac autonomic functions in patients with PCOS and healthy controls. To our knowledge, this is the first study evaluating cardiac autonomic functions in patients with PCOS with respect to both HRV and HRT. METHODS: Twenty three patients with PCOS (mean age 22.8+/-3.9 years) and 25 healthy female volunteers who were matched for age and body mass index (BMI) (mean age 23.5+/ 6.2 years) were enrolled in this as case-control study. Twenty-four hour ambulatory electrocardiogram recordings of all participants were taken using Pathfinder software. The time domain parameters of HRV and HRT, including turbulence onset (TO) and turbulence slope, were calculated. Diagnosis of PCOS was made with physical and laboratory findings of hirsutism or biochemical hyperandrogenism and chronic anovulation. Diabetes mellitus, other hormon disorders or hormon therapy, pregnancy, atrial fibrilation, obesite, chronic diseases, disorders of the autonomic nervous system, a history of drug use affecting the autonomic nervous system were excluded. RESULTS: There were no significant differences in HRV and HRT parameters between the two groups. Cardiovascular risk factors, such as BMI, blood pressure, fasting blood glucose, and lipid parameters, were also similar. Triangular index measure of HRV was negatively correlated with high density lipoprotein cholesterol levels (r=-0.47, p<0.05), while age and BMI were significantly correlated with TO (r=0.31 and 0.47, respectively; p<0.05 for all). CONCLUSION: Cardiac autonomic functions were not found to be altered in patients with PCOS in comparison with healthy controls. These results may be explained with the absence of concomitant cardiovascular risk factors with the patients being in the early stage of the disease. PMID- 26488380 TI - Effects of balanced propofol sedation on QT, corrected QT, and P-wave dispersion on upper endoscopy. AB - OBJECTIVE: Combined sedation with propofol and benzodiazepines, known as balanced propofol sedation (BPS), was developed to increase patient comfort during endoscopy. However, the effects of BPS on P-wave dispersion (Pwd), QT interval, and corrected QT (QTc) interval after endoscopy have not been investigated. METHODS: The study population consisted of 40 patients with BPS and 42 without sedation who were scheduled to undergo upper endoscopy in this cross-sectional prospective study. Patients with hypertension, diabetes mellitus, renal failure, chronic obstructive pulmonary disease, coronary artery disease, or valvular heart disease and those on medications that interfere with cardiac conduction times were excluded. Electrocardiograms (ECGs) was recorded in all patients pre endoscopy and 10 min post-endoscopy. QT, QT dispersion (QTd), and Pwd were defined from 12-lead ECG. The QTc interval was calculated using Bazett's formula. All analyses were performed using SPSS 15.0. RESULTS: Post-endoscopy P max duration and Pwd were prolonged compared with baseline values (86+/-13 ms vs. 92+/-10 ms and 29+/-12 ms vs. 33+/-12 ms, respectively; p<0.05). Post-endoscopy QTc and QTd were decreased compared with baseline values, but these decreases were not statistically significant (431+/-25 ms vs. 416+/-30 ms and 62+/-28 ms vs. 43+/-22 ms, respectively; p>0.05). CONCLUSION: The present study showed that P-wave duration and Pwd values increased after endoscopy with a combination of midazolam and propofol sedation. Physicians should be made aware of the potential effects of BPS in terms on P-wave duration and Pwd values. PMID- 26488381 TI - Galectin-3 levels in patients with hypertrophic cardiomyopathy and its relationship with left ventricular mass index and function. AB - OBJECTIVE: Cardiac fibrosis is an important contributor to adverse left ventricular (LV) remodeling and arrhythmias in patients with hypertrophic cardiomyopathy (HCM). Galectin-3 (Gal-3) is a novel marker of cardiac fibrosis and inflammation. In this study, we investigated Gal-3 levels in patients with HCM and controls and assessed the relationship between Gal-3 level and echocardiographic indices using strain echocardiography in patients with HCM. METHODS: Forty patients with HCM in sinus rhythm and 35 healthy controls were prospectively enrolled in this case-control study. The HCM diagnosis was based on two-dimensional echocardiographic demonstration of a hypertrophied and non dilated left ventricle (LV) with a wall thickness >=15 mm in one or more LV myocardial segments in the absence of any cardiac or systemic disease capable of inducing LV hypertrophy. Patients with one of the followings were excluded: coronary artery disease, atrial fibrillation episodes on 24-h Holter electrocardiogram (ECG) monitoring, history of an invasive intervention to alleviate an LV outflow (LVOT) obstruction, inadequate image quality, renal disease, diabetes mellitus, hyperlipidemia, liver cirrhosis, and pulmonary fibrosis. Global LV longitudinal, circumferential strain and strain rates, peak torsion, and LV mass index (LVMI) of all subjects were assessed by echocardiography. Gal-3 levels were measured in all subjects. RESULTS: Left ventricular global longitudinal strain (-13.37+/-4.6% vs. -18.93+/-2.5%, p<0.001) and strain rate (0.66+/-0.22 s-1 vs. 1.08+/-0.14 s-1, respectively; p<0.001) values were lower in patients with HCM than in controls. Gal-3 levels were significantly higher in patients with HCM than in controls (16.9+/-6.64 ng/mL vs. 13.21+/-3.42 ng/mL, p=0.005). Gal-3 levels were associated with the thickness of the interventricular septum (r=0.444, p=0.004) and LVMI (r=0.365, p=0.021); however, they were not associated with LV global longitudinal strain (p=0.42) or strain rate (p=0.28). CONCLUSION: Gal-3 levels increased and were correlated with the degree of LV hypertrophy in patients with HCM. Gal-3 is not a good marker of decreased myocardial LV diastolic and systolic functions in these patients. PMID- 26488382 TI - Association between platelet to lymphocyte ratio and saphenous vein graft disease in patients with stable angina pectoris. AB - OBJECTIVE: In this study, we aimed to investigate the relation of platelet to lymphocyte ratio (PLR) in saphenous vein graft disease (SVGD) in patients with stable angina pectoris after coronary artery bypass graft surgery. METHODS: A total of 455 patients were included in the study. There were 210 patients with SVGD and 245 patients without SVGD. The effects of different variables on SVGD were computed in logistic regression analysis. RESULTS: The platelet count, lymphocyte count, PLR, high-density lipoprotein (HDL), Na, and ALT were significantly associated with SVGD. In multivariate regression analysis, HDL and PLR were found to be significantly associated with SVGD. CONCLUSION: To the best of our knowledge, this is the first study showing the significant association of PLR with SVGD. This study suggests that PLR can be used as a marker of SVGD because it is an easily available and inexpensive test. PMID- 26488384 TI - Phosphoric acid-catalyzed asymmetric classic Passerini reaction. AB - An efficient enantioselective classic three-component Passerini reaction with a broad substrate scope in the presence of a chiral phosphoric acid catalyst has been developed. This represents the general example for classic three-component Passerini reaction with good to excellent enantioselectivies involving aromatic aldehydes and the bulky pivalaldehyde under mild reaction conditions. The feature of this method is highlighted by using a chiral phosphoric acid to activate carboxylic acid, aldehyde, and isocyanide for the facile construction of widely useful complex compounds. PMID- 26488383 TI - Determination of reference values for tricuspid annular plane systolic excursion in healthy Turkish children. AB - OBJECTIVE: Tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic measurement used for evaluating right ventricular systolic function. While established reference values of TAPSE exist for the adult population, only a limited number of studies have attempted to evaluate reference values for the pediatric population. The aim of the present study was to determine the reference values for TAPSE in healthy children in Turkey. METHODS: A total of 765 healthy children aged between 0 and 18 years, all of whom were referred to our clinic with cardiac murmurs, were evaluated prospectively. Patients with no cardiac pathologies or other disorders were excluded from the study. The measurement of TAPSE was obtained using a 2D-guided M-mode technique with echocardiography, and the relationship between age and surface area with TAPSE was investigated. The statistical analysis was carried out using the SPSS 20.0 software package (SPSS Inc., Chicago, IL, USA, 2012). RESULTS: The mean TAPSE value was found to be 19.56+/-5.54 mm, and no significant difference was identified between male and female children. TAPSE values showed a positive correlation with increasing age and surface area. The mean TAPSE value was 9.09+/ 1.36 mm in newborns and 25.91+/-3.60 mm in the 13-18 years age group. A negative correlation was seen between TAPSE and heart rate. CONCLUSION: In the present study, the reference values for TAPSE in healthy Turkish children were presented in percentile tables and the corresponding z-scores were determined. These reference values may be useful in daily practice for the evaluation of right ventricular systolic function in children. PMID- 26488385 TI - Sensitivity to Polymyxin B in El Tor Vibrio cholerae O1 Strain, Kolkata, India. PMID- 26488386 TI - Solvent Effects on the Formation of Surface Nanodroplets by Solvent Exchange. AB - Solvent exchange is a simple process to form oil nanodroplets at solid-liquid interfaces with well-defined location and morphology. In this process, a good solvent of the oil is displaced by a poor solvent, leading to the nucleation and growth of oil droplets from a transient oversaturation at the mixing front. Our recent work has shown that the final volume of the droplets is related to the flow conditions. In this work, we investigate the effects of the type and the composition of solvents on the droplet formation under the same flow conditions. Water nanodroplets were produced by ethanol/cyclohexane (solution A) and cyclohexane (solution B) on a hydrophilic substrate. We found that the droplet size increases first and then decreases with an increase of the initial ethanol concentration in solution A. This is attributed to the phase separation of ethanol-cyclohexane-water; in particular, the composition of solution A on the phase boundary above the Ouzo region. The same reason also contributes to the lower efficiency in droplet formation for a longer alkane. The important implication from this work is that the maximal droplet volume is limited by the phase separation of the solvents used in the solvent exchange. PMID- 26488387 TI - Induction Therapy versus Initial Surgery in Advanced Thymic Tumors: Perioperative and Oncological Outcome. AB - Background Despite the intense debate concerning management of advanced thymic tumors, no specific oncological strategies have been yet recommended. We report our 13 years' experience to investigate this issue. Methods From 01/2001 to 12/2013, the clinical data of 28 patients treated for Masaoka stages III-IV thymic tumors were retrospectively reviewed. Eleven potentially nonresectable patients (Group A) underwent induction chemotherapy plus surgery, while immediate surgery was performed in 17 patients (Group B). The endpoint was to compare the two groups on (1) surgical resectability; (2) postoperative course; (3) disease free survival; and (4) overall survival. Results Both groups were comparable in terms of age, gender, clinical stage, clinical tumor size, histology, and adjuvant therapy. Length of surgery was statistically longer in Group A (p = 0.015). Combined surgery and R0 resection was similarly performed in both groups (p = 0.14 and p = 0.99, respectively). The 3-year overall survival was 71.4% for Group A and 93.3% for Group B (p = 0.84). On the other hand, 3-year disease-free survival was 40.5 and 53.7% for Group A and B, respectively (p = 0.67). At multivariate analysis, gender was the strongest predictor for recurrence (hazard ratio = 5.71 [1.22; 26.67], p = 0.03). Conclusion Our results suggest that induction therapy allows obtaining acceptable clinical responses as well as resectability, survival, and recurrence rates. In selected patients with "clinically resectable" stage III-IV cancers, surgery (as first step of a multimodality therapy) could be a feasible treatment option. PMID- 26488389 TI - Service Transformed: Illustrations of Women Veterans Past and Present. PMID- 26488388 TI - "It's Not All About My Baby's Sleep": A Qualitative Study of Factors Influencing Low-Income African American Mothers' Sleep Quality. AB - Low-income African American mothers are at particular risk for poor postpartum sleep. This study sought to understand facilitators and barriers that exist to getting a good night's sleep among these high-risk mothers. Semistructured interviews with 18 low-income African Americans (3-6 months postpartum) were conducted. Most mothers described their own sleep quality to be poor, despite the fact that their babies' sleep improved substantially from the newborn period. Mothers kept themselves awake due to their own internal worry and anxiety, along with external factors that were largely independent of babies' sleep, including work and school commitments and the home environment. For the few mothers with good sleep quality, time management and family support were strong facilitators. Findings lay the groundwork for sleep improvement interventions. PMID- 26488391 TI - Can we predict future allergies from our infant gut microbiota? PMID- 26488392 TI - Peer-Review Fraud--Hacking the Scientific Publication Process. PMID- 26488390 TI - Suppression of von Hippel-Lindau Protein in Fibroblasts Protects against Bleomycin-Induced Pulmonary Fibrosis. AB - We have reported that von Hippel-Lindau protein (pVHL) expression is elevated in human and mouse fibrotic lungs and that overexpression of pVHL stimulates fibroblast proliferation. We sought to determine whether loss of pVHL in fibroblasts prevents injury and fibrosis in mice that are treated with bleomycin. We generated heterozygous fibroblast-specific pVHL (Fsp-VHL) knockdown mice (Fsp VHL(+/-)) and homozygous Fsp-VHL knockout mice (Fsp-VHL(-/-)) by crossbreeding vhlh 2-lox mice (VHL(fl/fl)) with Fsp-Cre recombinase mice. Our data show that Fsp-VHL(-/-) mice, but not Fsp-VHL(+/-) mice, have elevated red blood cell counts, hematocrit, hemoglobin content, and expression of hypoxia-inducible factor (HIF) targets, indicating HIF activation. To examine the role of pVHL in bleomycin-induced lung injury and fibrosis in vivo, we administered PBS or bleomycin to age-, sex-, and strain-matched 8-week-old VHL(fl/fl), Fsp-VHL(+/-), and Fsp-VHL(-/-) mice. In Fsp-VHL(+/-) and Fsp-VHL(-/-) mice, bleomycin-induced collagen accumulation, fibroblast proliferation, differentiation, and matrix protein dysregulation were markedly attenuated. Suppression of pVHL also decreased bleomycin-induced Wnt signaling and prostaglandin E2 signaling but did not affect bleomycin-induced initial acute lung injury and lung inflammation. These results indicate that pVHL has a pivotal role in bleomycin-induced pulmonary fibrosis, possibly via an HIF-independent pathway. Paradoxically, pVHL does not affect bleomycin-induced lung injury and inflammation, indicating a separation of the mechanisms involved in injury/inflammation from those involved in pulmonary fibrosis. PMID- 26488393 TI - Establishment of a Novel Bladder Cancer Xenograft Model in Humanized Immunodeficient Mice. AB - BACKGROUND/AIMS: The aim of this study was to develop a novel model by transplanting human bladder cancer xenografts into humanized immunodeficient mice (SCID). METHODS: The animals first underwent sublethal irradiation and then were subjected to simultaneous transplantation of human lymphocytes (5 * 107 cells/mouse i.p.) and human bladder cancer cells (3 * 106 cells/mouse s.c.). RESULTS: The xenografts developed in all 12 mice that had received bladder cancer BIU-87 cells, and the tumor specimens were evaluated histologically. All 6 model mice expressed human CD3 mRNA and/or protein in the peripheral blood, spleens and xenografts. The mean proportion of human CD3+ cells was 19% with a level of human IgG 532.4 u/ml in the peripheral blood at Week 6 after transplant inoculation. The re-constructed human immune system in these mice was confirmed to be functional by individual in vitro testing of their proliferative, secretory and cytotoxic responses. CONCLUSION: The successful engraftment of the human bladder cancer xenografts and the establishment of the human immune system in our in vivo model described here may provide a useful tool for the development of novel therapeutic strategies targeting at bladder cancer. PMID- 26488394 TI - Cavernous Hemangiomas of the Pediatric Calvaria. AB - This series reports 2 pediatric cases of calvarial cavernous hemangioma (cavernoma, cavernous malformation) treated surgically at Children's Hospital Colorado between 2008 and 2010. Both cases presented as painless bony masses which enlarged over time. Both patients underwent surgical resection without complication and have remained recurrence free since surgery. Because so few cases have been reported among pediatric populations, little is known regarding the epidemiology and prognosis of calvarial cavernous hemangiomas in children. These cases represent interesting additions to the small body of literature on these rare tumors. PMID- 26488395 TI - Identification of Critical Amino Acids Conferring Lethality in VopK, a Type III Effector Protein of Vibrio cholerae: Lessons from Yeast Model System. AB - VopK, a type III effector protein, has been implicated in the pathogenesis of Vibrio cholerae strains belonging to diverse serogroups. Ectopic expression of this protein exhibits strong toxicity in yeast model system. In order to map critical residues in VopK, we scanned the primary sequence guided by available data on various toxins and effector proteins. Our in silico analysis of VopK indicated the presence of predicted MCF1-SHE (SHxxxE) serine peptidase domain at the C-terminus region of the protein. Substitution of each of the predicted catalytic triad residues namely Ser314, His353 and Glu357 with alanine resulted in recombinant VopK proteins varying in lethality as evaluated in yeast model system. We observed that replacement of glutamate357 to alanine causes complete loss in toxicity while substitutions of serine314 and histidine353 with alanine exhibited partial loss in toxicity without affecting the stability of variants. In addition, replacement of another conserved serine residue at position 354 (S354) within predicted S314H353E357 did not affect toxicity of VopK. In essence, combined in silico and site directed mutagenesis, we have identified critical amino acids contributing to the lethal activity of VopK in yeast model system. PMID- 26488396 TI - The Utility of Neutrophil-to-Lymphocyte Ratio as a Severity Predictor of Acute Appendicitis, Length of Hospital Stay and Postoperative Complication Rates. AB - BACKGROUND: Numerous screening tools have been reported to aid in diagnosing appendicitis, but have poor severity prediction and lack accurate estimation of postoperative complications or total length of hospital stay (LOS). AIM: This study aims at evaluating the utility of neutrophil-to-lymphocyte (NLR) ratio in predicting the severity of appendicitis, LOS and 30-day complication rates. METHODS: Patients who underwent appendicectomy over a 4-year period were evaluated. Demographics, blood results, severity of appendicitis, LOS and 30-day complications were recorded. Recommended cut-off values of NLR and C-reactive protein (CRP) for severity of appendicitis were determined using receiver operating characteristic analysis. The Mann-Whitney test was performed to assess the correlations between LOS and 30-day complications with NLR. RESULTS: A total of 663 patients were included in the study of which 57.3% (n = 380) were male with mean patient age of 23.6 years, and 461 appendix specimens (69.6%) had simple inflammation on histological evaluation. A NLR of >6.35 or CRP of >55.6 were statistically associated with severe acute appendicitis, with a median of one extra hospital day admission (p < 0.0001). Mean NLR was statistically higher in patients with postoperative co(13.69 for severe vs. 7.29 for simple appendicitis group, p = 0.016). CONCLUSION: We advocate that NLR is a useful adjunct in predicting severity of appendicitis. It aids in delineating severe inflammation requiring surgery without substantial delay. PMID- 26488397 TI - Periconceptional and Gestational Exposure to Antibiotics and Childhood Asthma. AB - BACKGROUND: Previous studies suggest that maternal antibiotics exposure during pregnancy may increase the risk of childhood asthma, but the results were inconsistent. Furthermore, most studies did not examine periconception period as an exposure window. We aim to assess the associations between maternal exposure to specific antibiotics before and during pregnancy and the risk of asthma in early childhood. METHODS: Data from the Collaborative Perinatal Project were used. Maternal exposure to antibiotics before and during pregnancy was recorded at each prenatal visit. A total of 39,907 singleton children were followed up to 7 years of age. Multilevel multiple logistic regression models were used to control for potential confounders and account for multiple pregnancies per woman. RESULTS: Maternal use of penicillin or chloramphenicol was associated with an increased risk of asthma in the offspring (adjusted odds ratio = 1.21, 95% confidence interval 1.08-1.36 for penicillin; 1.72 [1.14-2.59] for chloramphenicol). The risk was significantly increased if penicillin or chloramphenicol was used in the 1st trimester (1.09 [1.04-1.13] for penicillin and 1.23 [1.01-1.51] for chloramphenicol). CONCLUSION: Maternal exposure to certain antibiotics is associated with childhood asthma by 7 years of age. Early pregnancy may be a sensitive window. PMID- 26488399 TI - Challenges of Clinical Research on Hepatocellular Carcinoma. AB - Challenges of clinical practice and research on hepatocellular carcinoma (HCC) were reviewed. There are several differences in clinical practice between Japan and the Western countries such as tumor markers, understanding of pathological early HCC, imaging diagnosis, treatment strategy, staging system and subclassification of HCC. Further studies are warranted for the clinical practices of Japan to be adopted in the rest of the world. PMID- 26488398 TI - Brca1 Mutations Enhance Mouse Reproductive Functions by Increasing Responsiveness to Male-Derived Scent. AB - We compared the gene expression profiles of ovarian granulosa cells harboring either mutant or wild type Brca1 to follow up on our earlier observation that absence of a functional Brca1 in these important regulators of menstrual/estrous cycle progression leads to prolongation of the pre-ovulatory phase of the estrous cycle and to increased basal levels of circulating estradiol. Here we show that ovarian granulosa cells from mice carrying a conditional Brca1 gene knockout express substantially higher levels of olfactory receptor mRNA than granulosa cells from wild type littermates. This led us to hypothesize that reproductive functions in mutant female mice might be more sensitive to male-derived scent than in wild type female mice. Indeed, it is well established that isolation from males leads to complete cessation of mouse estrous cycle activity while exposure to olfactory receptor ligands present in male urine leads to resumption of such activity. We found that Brca1-/- female mice rendered anovulatory by unisexual isolation resumed ovulatory activity more rapidly than their wild type littermates when exposed to bedding from cages where males had been housed. The prime mediator of this increased responsiveness appears to be the ovary and not olfactory neurons. This conclusion is supported by the fact that wild type mice in which endogenous ovaries had been replaced by Brca1-deficient ovarian transplants responded to male-derived scent more robustly than mutant mice in which ovaries had been replaced by wild type ovarian transplants. Our findings not only have important implications for our understanding of the influence of olfactory signals on reproductive functions, but also provide insights into mechanisms whereby genetic risk factors for breast and extra uterine Mullerian carcinomas may influence menstrual activity in human, which is itself an independent risk factor for these cancers. PMID- 26488400 TI - Early Viral Response Predicts the Efficacy of Antiviral Triple Therapy with Simeprevir, Peg-Interferon and Ribavirin in Patients Infected with Hepatitis C Virus Genotype 1. AB - OBJECTIVES: Triple therapy using peg-interferon, ribavirin and simeprevir (PEG IFN/RBV/SMV) has reportedly resulted in high-sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC), especially in naive cases and relapsers to prior PEG-IFN/RBV therapy. Here, we retrospectively analyzed the antiviral response associated with a triple regimen, in the context of early reduction of viral load during treatment. METHODS: Forty-six CHC patients with HCV genotype 1b were treated with PEG-IFN/RBV/SMV triple therapy: 20 were naive cases, 12 were relapsers and 14 were non-responders to prior PEG-IFN/RBV therapy. We evaluated rapid virological response (RVR), complete early virological response (EVR), viral clearance at the end of the treatment (EOT) and at 12 weeks after the EOT (SVR12). In addition, we quantified the serum HCV-RNA on the 1st day and the 7th day after initiating treatment. RESULTS: Multivariate analysis revealed that response to prior treatment was identified as an independent factor for achieving SVR12 after triple therapy (p = 0.0005). The achievement of serum HCV-RNA <2 log(10) IU/ml on day 7, RVR, EVR and EOT were associated with SVR12 (p = 0.0050, p = 0.0002, p = 0.0009 and p = 0.0002, respectively). CONCLUSIONS: Rapid decline of HCV is a predictive factor for the achievement of SVR12, even in antiviral triple therapy with PEG-IFN/RBV/SMV. An extended treatment period should be applied for patients who show detectable serum HCV-RNA at week 4. PMID- 26488401 TI - Nicotinic Activity of Arecoline, the Psychoactive Element of "Betel Nuts", Suggests a Basis for Habitual Use and Anti-Inflammatory Activity. AB - Habitual chewing of "betel nut" preparations constitutes the fourth most common human self-administration of a psychoactive substance after alcohol, caffeine, and nicotine. The primary active ingredient in these preparations is arecoline, which comes from the areca nut, the key component of all such preparations. Arecoline is known to be a relatively non-selective muscarinic partial agonist, accounting for many of the overt peripheral and central nervous system effects, but not likely to account for the addictive properties of the drug. We report that arecoline has activity on select nicotinic acetylcholine receptor (nAChR) subtypes, including the two classes of nAChR most related to the addictive properties of nicotine: receptors containing alpha4 and beta2 subunits and those which also contain alpha6 and beta3 subunits. Arecoline is a partial agonist with about 6-10% efficacy for the alpha4* and alpha6* receptors expressed in Xenopus oocytes. Additionally, arecoline is a silent agonist of alpha7 nAChR; while it does not activate alpha7 receptors when applied alone, it produces substantial activation when co-applied with the positive allosteric modulator PNU-120696. Some alpha7 silent agonists are effective inhibitors of inflammation, which might account for anti-inflammatory effects of arecoline. Arecoline's activity on nAChR associated with addiction may account for the habitual use of areca nut preparations in spite of the well-documented risk to personal health associated with oral diseases and cancer. The common link between betel and tobacco suggests that partial agonist therapies with cytisine or the related compound varenicline may also be used to aid betel cessation attempts. PMID- 26488402 TI - A Conserved Secondary Structural Element in the Coding Region of the Influenza A Virus Nucleoprotein (NP) mRNA Is Important for the Regulation of Viral Proliferation. AB - Influenza A virus is a threat to humans due to seasonal epidemics and infrequent, but dangerous, pandemics that lead to widespread infection and death. Eight segments of RNA constitute the genome of this virus and they encode greater than eight proteins via alternative splicing of coding (+)RNAs generated from the genomic (-)RNA template strand. RNA is essential in its life cycle. A bioinformatics analysis of segment 5, which encodes nucleoprotein, revealed a conserved structural motif in the (+)RNA. The secondary structure proposed by energy minimization and comparative analysis agrees with structure predicted based on experimental data using a 121 nucleotide in vitro RNA construct comprising an influenza A virus consensus sequence and also an entire segment 5 (+)RNA (strain A/VietNam/1203/2004 (H5N1)). The conserved motif consists of three hairpins with one being especially thermodynamically stable. The biological importance of this conserved secondary structure is supported in experiments using antisense oligonucleotides in cell line, which found that disruption of this motif led to inhibition of viral fitness. These results suggest that this conserved motif in the segment 5 (+)RNA might be a candidate for oligonucleotide based antiviral therapy. PMID- 26488404 TI - Correction: Intratumor Heterogeneity of ALK-Rearrangements and Homogeneity of EGFR-Mutations in Mixed Lung Adenocarcinoma. PMID- 26488403 TI - On the Ultrastructure and Function of Rhogocytes from the Pond Snail Lymnaea stagnalis. AB - Rhogocytes, also termed "pore cells", occur as solitary or clustered cells in the connective tissue of gastropod molluscs. Rhogocytes possess an enveloping lamina of extracellular matrix and enigmatic extracellular lacunae bridged by cytoplasmic bars that form 20 nm diaphragmatic slits likely to act as a molecular sieve. Recent papers highlight the embryogenesis and ultrastructure of these cells, and their role in heavy metal detoxification. Rhogocytes are the site of hemocyanin or hemoglobin biosynthesis in gastropods. Based on electron microscopy, we recently proposed a possible pathway of hemoglobin exocytosis through the slit apparatus, and provided molecular evidence of a common phylogenetic origin of molluscan rhogocytes, insect nephrocytes and vertebrate podocytes. However, the previously proposed secretion mode of the respiratory proteins into the hemolymph is still rather hypothetical, and the possible role of rhogocytes in detoxification requires additional data. Although our previous study on rhogocytes of the red-blooded (hemoglobin-containing) freshwater snail Biomphalaria glabrata provided much new information, a disadvantage was that the hemoglobin molecules were not unequivocally defined in the electron microscope. This made it difficult to trace the exocytosis pathway of this protein. Therefore, we have now performed a similar study on the rhogocytes of the blue blooded (hemocyanin-containing) freshwater snail Lymnaea stagnalis. The intracellular hemocyanin could be identified in the electron microscope, either as individual molecules or as pseudo-crystalline arrays. Based on 3D-electron microscopy, and supplemented by in situ hybridization, immunocytochemistry and stress response experiments, we provide here additional details on the structure and hemocyanin biosynthesis of rhogocytes, and on their response in animals under cadmium and starvation stress. Moreover, we present an advanced model on the release of synthesized hemocyanin molecules through the slit apparatus into the hemolymph, and the uptake of much smaller particles such as cadmium ions from the hemolymph through the slit apparatus into the cytoplasm. PMID- 26488405 TI - New Insight into Old Bacillus Lipase: Solvent Stable Mesophilic Lipase Demonstrating Enzyme Activity towards Cold. AB - BACKGROUND: Bacillus lipases are grouped in subfamily 1.4, which are the smallest known lipases having a molecular mass of 19.6 kDa. Lipases active in a wide range of temperatures, specifically at low temperatures, have an advantage under low water conditions for industrial application. METHODS: The lipase gene was cloned and expressed in Escherichia coli. The protein was purified and biochemically characterized in detail. RESULTS: A lipase gene was cloned from a mesophilic Bacillus isolate. Sequence analysis revealed an open reading frame of 633 bp in length. The predicted molecular mass of protein was 22.6 kDa. The purified enzyme displayed optimal activity at 35 degrees C and pH 8.0. Interestingly, this mesophilic enzyme was also cold active showing retention of 75 and 55% relative enzyme activity at 20 and 10 degrees C, respectively. The purified lipase was stable in various organic solvents (50% v/v) and ionic liquids (5% v/v). The enzyme displayed maximum activity with paranitrophenyl laurate (C12). kcat/Km values for the purified lipase were calculated to be 5.8 +/- 0.6 * 10(-6). CONCLUSIONS: The lipase showed tolerance to various solvents as well as activity at low temperature. Therefore, this lipase might be of great potential to be employed in various industrial applications. PMID- 26488406 TI - Obesity and Pulmonary Function in African Americans. AB - BACKGROUND: Obesity prevalence in United States (US) adults exceeds 30% with highest prevalence being among blacks. Obesity is known to have significant effects on respiratory function and obese patients commonly report respiratory complaints requiring pulmonary function tests (PFTs). However, there is no large study showing the relationship between body mass index (BMI) and PFTs in healthy African Americans (AA). OBJECTIVE: To determine the effect of BMI on PFTs in AA patients who did not have evidence of underlying diseases of the respiratory system. METHODS: We reviewed PFTs of 339 individuals sent for lung function testing who had normal spirometry and lung diffusion capacity for carbon monoxide (DLCO) with wide range of BMI. RESULTS: Functional residual capacity (FRC) and expiratory reserve volume (ERV) decreased exponentially with increasing BMI, such that morbid obesity resulted in patients breathing near their residual volume (RV). However, the effects on the extremes of lung volumes, at total lung capacity (TLC) and residual volume (RV) were modest. There was a significant linear inverse relationship between BMI and DLCO, but the group means values remained within the normal ranges even for morbidly obese patients. CONCLUSIONS: We showed that BMI has significant effects on lung function in AA adults and the greatest effects were on FRC and ERV, which occurred at BMI values < 30 kg/m2. These physiological effects of weight gain should be considered when interpreting PFTs and their effects on respiratory symptoms even in the absence of disease and may also exaggerate existing lung diseases. PMID- 26488407 TI - Large-Scale Biomonitoring of Remote and Threatened Ecosystems via High-Throughput Sequencing. AB - Biodiversity metrics are critical for assessment and monitoring of ecosystems threatened by anthropogenic stressors. Existing sorting and identification methods are too expensive and labour-intensive to be scaled up to meet management needs. Alternately, a high-throughput DNA sequencing approach could be used to determine biodiversity metrics from bulk environmental samples collected as part of a large-scale biomonitoring program. Here we show that both morphological and DNA sequence-based analyses are suitable for recovery of individual taxonomic richness, estimation of proportional abundance, and calculation of biodiversity metrics using a set of 24 benthic samples collected in the Peace-Athabasca Delta region of Canada. The high-throughput sequencing approach was able to recover all metrics with a higher degree of taxonomic resolution than morphological analysis. The reduced cost and increased capacity of DNA sequence-based approaches will finally allow environmental monitoring programs to operate at the geographical and temporal scale required by industrial and regulatory end-users. PMID- 26488408 TI - Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2. AB - The most frequent disorder of glycosylation is due to mutations in the gene encoding phosphomannomutase2 (PMM2-CDG). For this disease, which is autosomal and recessive, there is no cure at present. Most patients are composite heterozygous and carry one allele encoding an inactive mutant, R141H, and one encoding a hypomorphic mutant. Phosphomannomutase2 is a dimer. We reproduced composite heterozygosity in vitro by mixing R141H either with the wild type protein or the most common hypomorphic mutant F119L and compared the quaternary structure, the activity and the stability of the heterodimeric enzymes. We demonstrated that the activity of R141H/F119L heterodimers in vitro, which reproduces the protein found in patients, has the same activity of wild type/R141H, which reproduces the protein found in healthy carriers. On the other hand the stability of R141H/F119L appears to be reduced both in vitro and in vivo. These findings suggest that a therapy designed to enhance protein stability such as those based on pharmacological chaperones or modulation of proteostasis could be beneficial for PMM2-CDG patients carrying R141H/F119L genotype as well as for other genotypes where protein stability rather than specific activity is affected by mutations. PMID- 26488409 TI - Complete mitochondrial genome of the speckled dace Rhinichthys osculus, a widely distributed cyprinid minnow of western North America. AB - The speckled dace Rhinichthys osculus (order Cypriniformes), also known as the carpita pinta, is a small cyprinid minnow native to western North America. Here, we report the sequencing of the full mitochondrial genome (mitogenome) of R. osculus from a male fish collected from the Amargosa River Canyon in eastern California, USA. The assembled mitogenome is 16 658 base pair (bp) nucleotides, and encodes 13 protein-coding genes, and includes both a 12S and a 16S rRNA, 22 tRNAs, and a 985 bp D-loop control region. Mitogenome synteny reflects that of other Ostariophysian fishes with the majority of genes and RNAs encoded on the heavy strand (H-strand) except nd6, tRNA-Gln, tRNA-Ala, tRNA-Asn, tRNA-Cys, tRNA Tyr, tRNA-Ser, tRNA-Glu, and tRNA-Pro. The availability of this R. osculus mitochondrial genome - the first complete mitogenome within the lineage of Rhinichthys riffle daces - provides a foundation for resolving evolutionary relationships among morphologically differentiated populations of R. osculus. PMID- 26488410 TI - Effects of Sublethal Doses of Imidacloprid on Young Adult Honeybee Behaviour. AB - Imidacloprid (IMI), a neonicotinoid used for its high selective toxicity to insects, is one of the most commonly used pesticides. However, its effect on beneficial insects such as the honeybee Apis mellifera L is still controversial. As young adult workers perform in-hive duties that are crucial for colony maintenance and survival, we aimed to assess the effect of sublethal IMI doses on honeybee behaviour during this period. Also, because this insecticide acts as a cholinergic-nicotinic agonist and these pathways take part in insect learning and memory processes; we used IMI to assess their role and the changes they suffer along early adulthood. We focused on appetitive behaviours based on the proboscis extension response. Laboratory reared adults of 2 to 10 days of age were exposed to sublethal IMI doses (0.25 or 0.50ng) administered orally or topically prior to behavioural assessment. Modification of gustatory responsiveness and impairment of learning and memory were found as a result of IMI exposure. These outcomes differed depending on age of evaluation, type of exposure and IMI dose, being the youngest bees more sensitive and the highest oral dose more toxic. Altogether, these results imply that IMI administered at levels found in agroecosystems can reduce sensitivity to reward and impair associative learning in young honeybees. Therefore, once a nectar inflow with IMI traces is distributed within the hive, it could impair in-door duties with negative consequences on colony performance. PMID- 26488411 TI - Genome-Wide Association Study of Peripheral Arterial Disease in a Japanese Population. AB - Characteristics of peripheral arterial disease (PAD) are the occlusion or stenosis of multiple vessel sites caused mainly by atherosclerosis and chronic lower limb ischemia. To identify PAD susceptible loci, we conducted a genome-wide association study (GWAS) with 785 cases and 3,383 controls in a Japanese population using 431,666 single nucleotide polymorphisms (SNP). After staged analyses including a total of 3,164 cases and 20,134 controls, we identified 3 novel PAD susceptibility loci at IPO5/RAP2A, EDNRA and HDAC9 with genome wide significance (combined P = 6.8 x 10-14, 5.3 x 10-9 and 8.8 x 10-8, respectively). Fine-mapping at the IPO5/RAP2A locus revealed that rs9584669 conferred risk of PAD. Luciferase assay showed that the risk allele at this locus reduced expression levels of IPO5. To our knowledge, these are the first genetic risk factors for PAD. PMID- 26488412 TI - Mutational robustness and resilience of a replicative cis-element of RNA virus: Promiscuity, limitations, relevance. AB - Since replication of RNA-viruses is generally a low-fidelity process, it would be advantageous, if specific interactions of their genomic cis-elements with dedicated ligands are relatively tolerant to mutations. The specificity/promiscuity trade-off of such interactions was addressed here by investigating structural requirements of the oriL (also known as the clover leaf like element), of poliovirus RNA, a replicative cis-element containing a conserved essential tetraloop functionally interacting with the viral protein 3CD. The sequence of this tetraloop and 2 adjacent base-pairs was randomized in the viral genome, and viable viruses were selected in susceptible cells. Strikingly, each position of this octanucleotide in 62 investigated viable viruses could be occupied by any nucleotide (with the exception of one position, which lacked U), though with certain sequence preferences, confirmed by engineering mutant viral genomes whose phenotypic properties were found to correlate with the strength of the cis-element/ligand interaction. The results were compatible with a hypothesis that functional recognition by 3CD requires that this tetraloop should stably or temporarily adopt a YNMG-like (Y=U/C, N=any nucleotide, M=A/C) fold. The fitness of "weak" viruses could be increased by compensatory mutations "improving" the tetraloops. Otherwise, the recognition of "bad" tetraloops might be facilitated by alterations in the 3CD protein. The virus appeared to tolerate mutations in its cis-element relaying on either robustness (spatial structure degeneracy) or resilience (a combination of dynamic RNA folding, low-fidelity replication modifying the cis-element or its ligand, and negative selection). These mechanisms (especially resilience involving metastable low-fit intermediates) can also contribute to the viral evolvability. PMID- 26488413 TI - Rewriting the Central European Early Bronze Age Chronology: Evidence from Large Scale Radiocarbon Dating. AB - The transition from the Neolithic to the Early Bronze Age in Central Europe has often been considered as a supra-regional uniform process, which led to the growing mastery of the new bronze technology. Since the 1920s, archaeologists have divided the Early Bronze Age into two chronological phases (Bronze A1 and A2), which were also seen as stages of technical progress. On the basis of the early radiocarbon dates from the cemetery of Singen, southern Germany, the beginning of the Early Bronze Age in Central Europe was originally dated around 2300/2200 BC and the transition to more complex casting techniques (i.e., Bronze A2) around 2000 BC. On the basis of 140 newly radiocarbon dated human remains from Final Neolithic, Early and Middle Bronze Age cemeteries south of Augsburg (Bavaria) and a re-dating of ten graves from the cemetery of Singen, we propose a significantly different dating range, which forces us to re-think the traditional relative and absolute chronologies as well as the narrative of technical development. We are now able to date the beginning of the Early Bronze Age to around 2150 BC and its end to around 1700 BC. Moreover, there is no transition between Bronze (Bz) A1 and Bronze (Bz) A2, but a complete overlap between the type objects of the two phases from 1900-1700 BC. We thus present a revised chronology of the assumed diagnostic type objects of the Early Bronze Age and recommend a radiocarbon-based view on the development of the material culture. Finally, we propose that the traditional phases Bz A1 and Bz A2 do not represent a chronological sequence, but regionally different social phenomena connected to the willingness of local actors to appropriate the new bronze technology. PMID- 26488414 TI - Genotypic Tannin Levels in Populus tremula Impact the Way Nitrogen Enrichment Affects Growth and Allocation Responses for Some Traits and Not for Others. AB - Plant intraspecific variability has been proposed as a key mechanism by which plants adapt to environmental change. In boreal forests where nitrogen availability is strongly limited, nitrogen addition happens indirectly through atmospheric N deposition and directly through industrial forest fertilization. These anthropogenic inputs of N have numerous environmental consequences, including shifts in plant species composition and reductions in plant species diversity. However, we know less about how genetic differences within plant populations determine how species respond to eutrophication in boreal forests. According to plant defense theories, nitrogen addition will cause plants to shift carbon allocation more towards growth and less to chemical defense, potentially enhancing vulnerability to antagonists. Aspens are keystone species in boreal forests that produce condensed tannins to serve as chemical defense. We conducted an experiment using ten Populus tremula genotypes from the Swedish Aspen Collection that express extreme levels of baseline investment into foliar condensed tannins. We investigated whether investment into growth and phenolic defense compounds in young plants varied in response to two nitrogen addition levels, corresponding to atmospheric N deposition and industrial forest fertilization. Nitrogen addition generally caused growth to increase, and tannin levels to decrease; however, individualistic responses among genotypes were found for height growth, biomass of specific tissues, root:shoot ratios, and tissue lignin and N concentrations. A genotype's baseline ability to produce and store condensed tannins also influenced plant responses to N, although this effect was relatively minor. High-tannin genotypes tended to grow less biomass under low nitrogen levels and more at the highest fertilization level. Thus, the ability in aspen to produce foliar tannins is likely associated with a steeper reaction norm of growth responses, which suggests a higher plasticity to nitrogen addition, and potentially an advantage when adapting to higher concentrations of soil nitrogen. PMID- 26488415 TI - Invasive Pneumococcal Disease 3 Years after Introduction of 10-Valent Pneumococcal Conjugate Vaccine, the Netherlands. AB - Three years after a 7-valent pneumococcal conjugate vaccine was replaced by a 10 valent pneumococcal conjugate vaccine in the Netherlands, we observed a decrease in incidence of invasive pneumococcal disease caused by Streptococcus pneumoniae serotypes 1, 5, and 7F. Our data do not support or exclude cross-protection against serotype 19A. PMID- 26488416 TI - Effect of White Kidney Beans (Phaseolus vulgaris L. var. Beldia) on Small Intestine Morphology and Function in Wistar Rats. AB - The chronic ingestion of raw or undercooked kidney beans (Phaseolus vulgaris L.) causes functional and morphological derangement in various tissues. The major objectives of this study were to investigate the gavage effects of a raw Beldia bean variety that is widely consumed in Tunisia, on the small intestine morphology and jejunal absorption of water, electrolytes, and glucose in Wistar rats. Twenty young male rats were randomly divided into two groups of 10 rats. The first group served as the control and was gavaged with 300 mg of a rodent pellet flour suspension (RPFS), whereas the second experimental group was challenged with 300 mg of a Beldia bean flour suspension (BBFS) for 10 days. Histological studies were performed using light and electron microcopy. The intestinal transport of water, sodium, potassium, and glucose was studied by perfusing the jejunal loops of the small bowels in vivo. The feeding experiments indicated that BBFS did not affect weight gain. Histomorphometric analyses showed that the villus heights, crypt depths, and crypt/villus ratios in the jejunum and ileum were greater in the BBFS-fed rats than controls. Electron microscopy studies demonstrated that the rats exposed to RPFS exhibited intact intestinal tracts; however, the BBFS-treated rats demonstrated intestinal alterations characterized by abnormal microvillus architectures, with short and dense or long and slender features, in addition to the sparse presence of vesicles near the brush border membrane. BBFS administration did not significantly affect glucose absorption. However, significant decreases were observed in water and electrolyte absorption compared with the uptake of the controls. In conclusion, raw Beldia beans distorted jejunum morphology and disturbed hydroelectrolytic flux. PMID- 26488418 TI - Lung Transplantation in Alpha-1-Antitrypsin Deficiency. AB - BACKGROUND: Lung transplantation is a therapeutic option for patients with end stage lung disease and a survival benefit has been described in patients with alpha-1-antitrypsin deficiency (A1ATD). The aims of the current study were to determine the survival and health benefits of lung transplantation in UK patients with A1ATD compared to carefully matched non-transplant patients. METHODS: Patients with the PiZZ (alpha-1-antitrypsin deficiency) genotype who had undergone lung transplantation between 1996 and 2011 were identified from the UK A1ATD registry. Lung physiology, health status and survival were compared pre- and post-transplant using carefully matched non-transplant patients. RESULTS: Thirty-two A1ATD patients who had undergone lung transplant were identified. Lung function decline pre-transplant was not different to the closely matched non transplanted cohort. The transplant group pre-transplant, although matched for FEV1, had lower gas transfer measurements, (mean KCO% predicted 41.0% SE +/- 3.86 vs 55.6% SE +/- 3.10 p < 0.001) and worse health status (SGRQ mean score 64.2 SE +/- 2.5 vs 55.3 SE +/- 2.0, p < 0.001). Post-transplant, physiology and health status improved significantly (p < 0.002). However, the post-operative mortality over 5 years was no better than for a second group of non-transplant patients further matched for gas transfer or a third group also matched for SGRQ. CONCLUSION: Patients who underwent lung transplant had lower gas transfer and quality-of-life pre-transplant compared to non-transplant patients matched for FEV1, age and sex, suggesting that these parameters provide extra information helpful in decision making. Lung transplantation for A1ATD patients significantly improves quality-of-life but not survival. PMID- 26488419 TI - Multiwalled Carbon Nanotube Oxygen Sensor: Enhanced Oxygen Sensitivity at Room Temperature and Mechanism of Sensing. AB - A pyrolysis assisted method was applied for the synthesis of defect controlled carbon nanotubes (CNTs) by varying different growth temperatures. The fabricated resistive devices containing a random network of CNTs were tested for oxygen sensing under standard room-temperature and pressure conditions. Nanotubes grown at moderate growth temperatures (870 degrees C), when exposed to different concentrations of oxygen, displayed a higher sensitivity (3.6%), with fast response and recovery times of about 60 and 180 s, respectively, compared to nanotubes grown at higher and lower temperatures. A room-temperature oxygen detection concentration as low as 0.3% is achieved. The fast response and recovery of CNTs are explained in terms of physisorption of oxygen molecules at (i) carboxyl functional sites and (ii) graphitic carbon sites (pristine CNT) rather than chemisorption at (iii) defected sites. Interestingly, the density functional theory simulated interaction energies (Eads) of oxygen molecules with defected CNTs (-3.381 eV) and pristine CNTs (-0.753 eV) are higher than that of the carboxyl functional sites (-0.551 eV) and are well correlated with the observed sensing response and recovery times of CNT sensors. Our results show that the carboxyl sites provide lower activation energy or shorter time for desorption of oxygen molecules to yield higher response and fast recovery of the CNT sensors. PMID- 26488417 TI - Path Similarity Analysis: A Method for Quantifying Macromolecular Pathways. AB - Diverse classes of proteins function through large-scale conformational changes and various sophisticated computational algorithms have been proposed to enhance sampling of these macromolecular transition paths. Because such paths are curves in a high-dimensional space, it has been difficult to quantitatively compare multiple paths, a necessary prerequisite to, for instance, assess the quality of different algorithms. We introduce a method named Path Similarity Analysis (PSA) that enables us to quantify the similarity between two arbitrary paths and extract the atomic-scale determinants responsible for their differences. PSA utilizes the full information available in 3N-dimensional configuration space trajectories by employing the Hausdorff or Frechet metrics (adopted from computational geometry) to quantify the degree of similarity between piecewise linear curves. It thus completely avoids relying on projections into low dimensional spaces, as used in traditional approaches. To elucidate the principles of PSA, we quantified the effect of path roughness induced by thermal fluctuations using a toy model system. Using, as an example, the closed-to-open transitions of the enzyme adenylate kinase (AdK) in its substrate-free form, we compared a range of protein transition path-generating algorithms. Molecular dynamics-based dynamic importance sampling (DIMS) MD and targeted MD (TMD) and the purely geometric FRODA (Framework Rigidity Optimized Dynamics Algorithm) were tested along with seven other methods publicly available on servers, including several based on the popular elastic network model (ENM). PSA with clustering revealed that paths produced by a given method are more similar to each other than to those from another method and, for instance, that the ENM-based methods produced relatively similar paths. PSA applied to ensembles of DIMS MD and FRODA trajectories of the conformational transition of diphtheria toxin, a particularly challenging example. For the AdK transition, the new concept of a Hausdorff-pair map enabled us to extract the molecular structural determinants responsible for differences in pathways, namely a set of conserved salt bridges whose charge charge interactions are fully modelled in DIMS MD but not in FRODA. PSA has the potential to enhance our understanding of transition path sampling methods, validate them, and to provide a new approach to analyzing conformational transitions. PMID- 26488420 TI - Encephalitis-Associated Human Metapneumovirus Pneumonia in Adult, Australia. AB - Human metapneumovirus pneumonia, most commonly found in children, was diagnosed in an adult with encephalitis. This case suggests that testing for human metapneumovirus RNA in nasopharyngeal aspirate and cerebrospinal fluid samples should be considered in adults with encephalitis who have a preceding respiratory infection. PMID- 26488421 TI - Structural modeling of HLA-B*1502/peptide/carbamazepine/T-cell receptor complex architecture: implication for the molecular mechanism of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. AB - Drug-induced adverse reactions are a significant problem in healthcare worldwide and are estimated to cost billions of dollars annually in the United States. A portion of such reactions is observed to strongly associate with certain human leukocyte antigen (HLA) alleles; one of the strongest associations is the HLA B*1502 protein with carbamazepine (CBZ)-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) - the odds ratio value can even be higher than one thousand. The particularly strong association in CBZ-induced SJS/TEN suggests that the HLA-B*1502 is not only a genetic marker but also a participant in the pathogenesis of the disease. In the current study, we attempt to computationally model the atomic-level structure of the complete HLA-B*1502/peptide/CBZ/T-cell receptor (TCR) complex architecture based on prior knowledge obtained from epidemiological investigations as well as in vitro and in vivo assays. The model tells a different story about the molecular mechanism of CBZ-induced SJS/TEN from that previously reported for abacavir (ABC)-induced hypersensitivity (HSR); the CBZ molecule is located at the interface between HLA-B*1502/peptide and TCR, directly contacts the P3-P6 residues of antigen peptide, and bound within a pocket region encompassed by two TCR CDR3 fingers. Molecular dynamics simulation and binding energy analysis further reveal that the CBZ shows considerably high affinity to TCR over HLA-B*1502/peptide, which can tightly interact with the former rather than the latter. From the model, two hypotheses are proposed that can well explain most previous observations and are expected to guide next wet lab experiments. This study could help to promote our understanding of the molecular mechanism and pathological implication underlying CBZ-induced SJS/TEN. PMID- 26488423 TI - Steam Pyrolysis of Polyimides: Effects of Steam on Raw Material Recovery. AB - Aromatic polyimides (PIs) have excellent thermal stability, which makes them difficult to recycle, and an effective way to recycle PIs has not yet been established. In this work, steam pyrolysis of the aromatic PI Kapton was performed to investigate the recovery of useful raw materials. Steam pyrolysis significantly enhanced the gasification of Kapton at 900 degrees C, resulting in 1963.1 mL g(-1) of a H2 and CO rich gas. Simultaneously, highly porous activated carbon with a high BET surface area was recovered. Steam pyrolysis increased the presence of polar functional groups on the carbon surface. Thus, it was concluded that steam pyrolysis shows great promise as a recycling technique for the recovery of useful synthetic gases and activated carbon from PIs without the need for catalysts and organic solvents. PMID- 26488424 TI - Cangrelor (Kengreal)--an IV antiplatelet drug for PCI. PMID- 26488422 TI - Delta-Opioid Receptor (deltaOR) Targeted Near-Infrared Fluorescent Agent for Imaging of Lung Cancer: Synthesis and Evaluation In Vitro and In Vivo. AB - In the United States, lung cancer is the leading cause of cancer death and ranks second in the number of new cases annually among all types of cancers. Better methods or tools for diagnosing and treating this disease are needed to improve patient outcomes. The delta-opioid receptor (deltaOR) is reported to be overexpressed in lung cancers and not expressed in normal lung. Thus, we decided to develop a lung cancer-specific imaging agent targeting this receptor. We have previously developed a deltaOR-targeted fluorescent imaging agent based on a synthetic peptide antagonist (Dmt-Tic) conjugated to a Cy5 fluorescent dye. In this work, we describe the synthesis of Dmt-Tic conjugated to a longer wavelength near-infrared fluorescent (NIRF) dye, Li-cor IR800CW. Binding affinity of Dmt-Tic IR800 for the deltaOR was studied using lanthanide time-resolved fluorescence (LTRF) competitive binding assays in cells engineered to overexpress the deltaOR. In addition, we identified lung cancer cell lines with high and low endogenous expression of the deltaOR. We confirmed protein expression in these cell lines using confocal fluorescence microscopy imaging and used this technique to estimate the cell-surface receptor number in the endogenously expressing lung cancer cell lines. The selectivity of Dmt-Tic-IR800 for imaging of the deltaOR in vivo was shown using both engineered cell lines and endogenously expressing lung cancer cells in subcutaneous xenograft models in mice. In conclusion, the deltaOR specific fluorescent probe developed in this study displays excellent potential for imaging of lung cancer. PMID- 26488425 TI - Drugs for hypothyroidism. PMID- 26488426 TI - In brief: a new albuterol inhaler (ProAir RespiClick) for asthma. PMID- 26488427 TI - The impact of sarcopenia on survival and complications in surgical oncology: A review of the current literature. PMID- 26488428 TI - 64Cu-DOTA as a surrogate positron analog of Gd-DOTA for cardiac fibrosis detection with PET: pharmacokinetic study in a rat model of chronic MI. AB - OBJECTIVES: The aim of this study was to investigate the pharmacokinetics of (64)Cu-DOTA (1,4,7,10-azacyclododecane-N,N',N'',N'''-tetraacetic acid), a positron surrogate analog of the late gadolinium (Gd)-enhancement cardiac magnetic resonance agent, Gd-DOTA, in a rat model of chronic myocardial infarction (MI) and its microdistribution in the cardiac fibrosis by autoradiography. METHODS: DOTA was labeled with (64)Cu-acetate. CD rats (n=5) with MI by left anterior descending coronary artery ligation and normal rats (n=6) were injected intravenously with (64)Cu-DOTA (18.5 MBq, 0.02 mmol DOTA/kg). Dynamic PET imaging was performed for 60 min after injection. (18)F Fluorodeoxyglucose ([(18)F]-FDG) PET imaging was performed to identify the viable myocardium. For the region of interest analysis, the (64)Cu-DOTA PET image was coregistered to the [(18)F]-FDG PET image. To validate the PET images, slices of heart samples from the base to the apex were analyzed using autoradiography and by histological staining with Masson's trichrome. RESULTS: (64)Cu-DOTA was rapidly taken up in the infarct area. The time-activity curves demonstrated that (64)Cu-DOTA concentrations in the blood, fibrotic tissue, and perfusion-rich organs peaked within a minute post injection; thereafter, it was rapidly washed out in parallel with blood clearance and excreted through the renal system. The blood clearance curve was biphasic, with a distribution half-life of less than 3 min and an elimination half-life of ~21.8 min. The elimination half-life of (64)Cu-DOTA from the focal fibrotic tissue (~22.4 min) and the remote myocardium (~20.1 min) was similar to the blood elimination half-life. Consequently, the uptake ratios of focal fibrosis-to-blood and remote myocardium-to-blood remained stable for the time period between 10 and 60 min. The corresponding ratios obtained from images acquired from 30 to 60 min were 1.09 and 0.59, respectively, indicating that the concentration of (64)Cu-DOTA in the focal fibrosis was 1.85 (1.09/0.59) times greater than that in the remote myocardium. Thus, this finding indicates that the extracellular volume fraction was 1.85 times greater in the focal fibrosis than in the remote myocardium. The accumulation of (64)Cu-DOTA in fibrotic tissue was further supported by autoradiography and histology images. The autoradiography images of (64)Cu-DOTA in the fibrotic tissues were qualitatively superimposed over the histology images of the fibrotic tissues. The histology images of the infarct areas were characterized by a heterogeneous distribution of thin bands of fibrotic collagen, myocytes, and expanded extracellular space. CONCLUSION: (64)Cu-DOTA is a useful surrogate positron analog of Gd-DOTA, enabling quantitative measurement of the uptake values in fibrotic tissues by dynamic PET imaging and calculation of the extracellular volume fractions of the fibrotic tissues. At a microscopic level, the distribution of (64)Cu-DOTA is nonuniform, corresponding to the heterogeneous distribution of expanded extracellular space in the setting of MI. PMID- 26488429 TI - Photoprotolytic Processes of Umbelliferone and Proposed Function in Resistance to Fungal Infection. AB - The photoprotolytic processes of 7-hydroxy-coumarin (Umb) were investigated by steady-state and time-resolved-fluorescence techniques. We found that the Umb compound is a photoacid with pK(a)* ~ 0.4 and a rate constant of the excited state proton transfer (ESPT) to water of 2 * 10(10) s(-1). Umb is also a photobase and accepts an excess proton in solution and also directly from weak acids like acetic acid. When Umb is adsorbed on cellulose it also functions as a photoacid and a photobase. Hydroxycoumarins are known to accumulate next to fungal-, bacterial-, and viral-infected regions in the leaves and stems of plants in general and also in trees. We propose that these compounds when irradiated by sunlight UV, combat the fungi or bacteria by excited-state proton-transfer reactions. These photoprotolytic reactions provide a universal resistance mechanism to infections in plants. PMID- 26488433 TI - Snail-like Particles from Compartmentalized Microfibers. AB - Electrohydrodynamic cojetting has been employed to synthesize compartmentalized microfibers from thermally responsive hydrogels. The synthesis of the hydrogels as well as their transformation into compartmentalized microcylinders is discussed. After programmable shape-shifting, snail-like particles are obtained that undergo functional and structural reconfiguration in response to a change in temperature. PMID- 26488431 TI - High speed sCMOS-based oblique plane microscopy applied to the study of calcium dynamics in cardiac myocytes. AB - Oblique plane microscopy (OPM) is a form of light sheet microscopy that uses a single high numerical aperture microscope objective for both fluorescence excitation and collection. In this paper, measurements of the relative collection efficiency of OPM are presented. An OPM system incorporating two sCMOS cameras is then introduced that enables single isolated cardiac myocytes to be studied continuously for 22 seconds in two dimensions at 667 frames per second with 960 * 200 pixels and for 30 seconds with 960 * 200 * 20 voxels at 25 volumes per second. In both cases OPM is able to record in two spectral channels, enabling intracellular calcium to be studied via the probe Fluo-4 AM simultaneously with the sarcolemma and transverse tubule network via the membrane dye Cellmask Orange. The OPM system was then applied to determine the spatial origin of spontaneous calcium waves for the first time and to measure the cell transverse tubule structure at their point of origin. Further results are presented to demonstrate that the OPM system can also be used to study calcium spark parameters depending on their relationship to the transverse tubule structure. PMID- 26488434 TI - A multivariate approach using attenuated total reflectance mid-infrared spectroscopy to measure the surface mannoproteins and beta-glucans of yeast cell walls during wine fermentations. AB - Yeast cells possess a cell wall comprising primarily glycoproteins, mannans, and glucan polymers. Several yeast phenotypes relevant for fermentation, wine processing, and wine quality are correlated with cell wall properties. To investigate the effect of wine fermentation on cell wall composition, a study was performed using mid-infrared (MIR) spectroscopy coupled with multivariate methods (i.e., PCA and OPLS-DA). A total of 40 yeast strains were evaluated, including Saccharomyces strains (laboratory and industrial) and non-Saccharomyces species. Cells were fermented in both synthetic MS300 and Chardonnay grape must to stationery phase, processed, and scanned in the MIR spectrum. PCA of the fingerprint spectral region showed distinct separation of Saccharomyces strains from non-Saccharomyces species; furthermore, industrial wine yeast strains separated from laboratory strains. PCA loading plots and the use of OPLS-DA to the data sets suggested that industrial strains were enriched with cell wall proteins (e.g., mannoproteins), whereas laboratory strains were composed mainly of mannan and glucan polymers. PMID- 26488435 TI - Quality of Life Assessment in Retinoblastoma: A Cross-Sectional Study of 122 Survivors from India. AB - BACKGROUND: With current modalities, cure rates of retinoblastoma are high and hence the number of survivors is increasing. However, data on quality of life (QOL) are minimal. PROCEDURE: We analyzed QOL in 122 retinoblastoma survivors using the PedsQL(TM) 4.0 generic core scale. The self-reported questionnaire was filled by children of more than 5 years of age who had completed treatment for more than 12 months. The questionnaire consists of 23 questions on physical, social, emotional, and school domains on a scale from 0 to 4. This was converted to a scale from 0 to 100, where higher values represented better QOL. The QOL was compared with 50 siblings. Factors predicting the QOL were assessed. RESULTS: The median age of retinoblastoma survivors was 98 months (range 60-247) and 68% were males. Overall QOL was significantly poorer in retinoblastoma survivors as compared with the controls. The emotional health domain of QOL was significantly affected. Difficulties in maintaining friendships and competing were reported in the social health domain. The school health domain showed significantly higher absenteeism. However, the physical health domain, including household work, exercise, and self-care, was similar in both the groups. Lower age at diagnosis (<= 18 months) predicted better QOL (P = 0.05), whereas age at assessment, sex, IRSS stage, and previous surgery and radiotherapy were not predictive of poor QOL. CONCLUSIONS: We found a significantly poorer QOL in retinoblastoma survivors with the psychosocial health domain being more affected than the physical domain. Age less than 18 months at diagnosis predicted better QOL. PMID- 26488436 TI - The excitonic photoluminescence mechanism and lasing action in band-gap-tunable CdS(1-x)Se(x) nanostructures. AB - Bandgap tunable semiconductor materials have wide application in integrated optoelectronic and communication devices. The CdS1-xSex ternary semiconductor materials covering green-red bands have been reported previously, but their basic band-gap and optical properties crucial to the performance of the CdS1-xSex-based optoelectronic devices have not been deeply understood. In this paper, we theoretically simulated and discussed the feasibility of bandgap-tunable CdS1 xSex nanomaterials for designing wavelength tunable microlasers. Then we fabricated the CdS1-xSex nanobelts with their band gap ranging from 2.4 to 1.74 eV by adjusting the composition ratio x in the vapor-phase-transport growth process. The temperature-dependent photoluminescence and exciton-related optical constants of the CdS1-xSex nanobelts were carefully demonstrated. Finally, the wavelength-tunable Fabry-Perot lasing in CdS1-xSex nanobelts was obtained, and the Fabry-Perot lasing mechanism was numerically simulated by the FDTD method. The systematic results on the mechanism of the tunable band gap, exciton properties and lasing of the CdS1-xSex nanostructure help us deeply understand the intrinsic optical properties of this material, and will build a strong foundation for future application of green-red wavelength-tunable CdS1-xSex microlasers. PMID- 26488437 TI - Emerging strategies to treat ruptured abdominal aortic aneurysms. AB - Population screening programmes and a falling population prevalence of smoking have led to a declining incidence of ruptured abdominal aortic aneurysms in men. However, ruptured abdominal aortic aneurysms remain a common vascular surgical emergency, with an increasing proportion of ruptures being in women. About one quarter of the ruptures have a juxta-renal aneurysm and are more challenging to repair using endovascular technologies. Endovascular technologies may not reduce the overall mortality, compared with open surgical repair, but appear to offer early benefits with respect to patient quality of life at acceptable cost. Challenges over the next 5 years include widening the access to repair, developing an accurate bedside risk scoring tool, as well as optimising strategies for pre-operative resuscitation, standardising peri-operative care and the management of post-operative complications. PMID- 26488438 TI - Straightforward synthesis of iron cyclopentadienone N-heterocyclic carbene complexes. AB - Novel iron complexes bearing both cyclopentadienone and N-heterocyclic carbene ancillary ligands were obtained by a straightforward synthesis from Fe2(CO)9. The preparation represents a rare example of silver transmetallation involving iron. The reaction is general and occurs in the presence of variously functionalized NHC and cyclopentadienones. PMID- 26488439 TI - Anxiety and Depression Symptoms Among Farmers: The HUNT Study, Norway. AB - Agriculture has undergone profound changes, and farmers face a wide variety of stressors. Our aim was to study the levels of anxiety and depression symptoms among Norwegian farmers compared with other occupational groups. Working participants in the HUNT3 Survey (The Nord-Trondelag Health Study, 2006-2008), aged 19-66.9 years, were included in this cross-sectional study. We compared farmers (women, n = 317; men, n = 1,100) with HUNT3 participants working in other occupational groups (women, n = 13,429; men, n = 10,026), classified according to socioeconomic status. We used the Hospital Anxiety and Depression Scale (HADS) to measure anxiety and depression symptoms. Both male and female farmers had higher levels of depression symptoms than the general working population, but the levels of anxiety symptoms did not differ. The differences in depression symptom levels between farmers and the general working population increased with age. In an age adjusted logistic regression analysis, the odds ratio (OR) for depression caseness (HADS-D >=8) when compared with the general working population was 1.49 (95% confidence interval [CI]: 1.22-1.83) in men and 1.29 (95% CI: 0.85-1.95) in women. Male farmers had a higher OR of depression caseness than any other occupational group (OR = 1.94, 95% CI: 1.52-2.49, using higher-grade professionals as reference). Female farmers had an OR similar to men (2.00, 95% CI: 1.26-3.17), but lower than other manual occupations. We found that farmers had high levels of depression symptoms and average levels of anxiety symptoms compared with other occupational groups. PMID- 26488440 TI - Co-operative motion of multiple benzoquinone disks at the air-water interface. AB - Self-motion of physical-chemical systems is a promising avenue for studying and developing mechanical functions with inanimate systems. In this paper, we investigate spontaneous motion of collections of solid macroscopic benzoquinone (BQ) disks at the air-water interface without intervention of chemical reactions. The BQ particles slowly dissolve and create heterogeneous interfacial tension fields on the water surface that drive the motion. Spontaneous, continuous locomotion was observed between multiple BQ particles, along with coupling, collisions, cycling and collective foraging for interfacial free energy. Analysis of the motion suggests co-operative behavior depends strongly on particle shape. PMID- 26488442 TI - Genetic differences in ChTLR15 gene polymorphism and expression involved in Salmonella enterica natural and artificial infection respectively, of Chinese native chicken breeds, with a focus on sexual dimorphism. AB - Chicken Toll-like receptor 15 (ChTLR15) has been shown to participate in immune activation in response to various pathogens and in the innate defence against infection. Two genetically distinct Chinese breeds of chicken (Qinyuan Partridge and Baier breeds) were used to study the correlation between ChTLR15 single nucleotide polymorphisms and the natural infection status of salmonella in hens, and also to examine genetic and sex-specific effects on ChTLR15 mRNA expression in heterophils and spleen during acute infection with Salmonella enterica serovar Enteritidis (SE) from 1 to 10 days after experimental infection. Three single nucleotide polymorphisms (G168A, C726T and A1166G) in a single exon of ChTLR15 were identified in the two breeds, but only C726T showed a significant association with salmonella infection. Compared with layer-type Baier chicks, meat-type Qingyuan chicks showed a higher tolerance for capture stress and (SE) infection, as measured, respectively, by the modified body weight of chicks in the control group and in the infection group. Meanwhile, ChTLR15 down-regulation in heterophils and up-regulation in spleen were involved in the response to pathogenic SE colonization during the acute infection period. These significant genetic effects in females led to greater differences in both innate and adaptive immune responses than those exhibited in males. These results suggest that genetics, time and gender play important roles in the modulation of ChTLR15 mRNA level elicited by the SE-mediated immune response differentially in the two genetically distinct breeds, with a focus on sexual dimorphism. PMID- 26488444 TI - Practical experiences with eribulin in patients with metastatic breast cancer. AB - There is currently no standard therapy for women with metastatic or locally recurrent breast cancer. The microtubule polymerization inhibitor eribulin, approved in March 2011, is the first monochemotherapy with a proven survival benefit and tolerable toxicity in this patient group. Using a retrospective analysis of 27 mostly heavily pretreated patients in two large German breast cancer centers, the efficacy and tolerability of eribulin in daily practice were compared with the results of the pivotal EMBRACE and 301 studies. Despite the patients being older and having more advanced disease, the retrospective analysis showed a comparable progression-free survival of 3.7 months. When eribulin was used in an early-line treatment, the progression-free survival observed was 7 weeks longer compared with use in a late-line therapy. The differences in tolerability were not significant. Overall, the results confirm that eribulin represents an effective and tolerable therapeutic option for metastatic breast cancer in daily practice. PMID- 26488441 TI - HIV Tat controls RNA Polymerase II and the epigenetic landscape to transcriptionally reprogram target immune cells. AB - HIV encodes Tat, a small protein that facilitates viral transcription by binding an RNA structure (trans-activating RNA [TAR]) formed on nascent viral pre messenger RNAs. Besides this well-characterized mechanism, Tat appears to modulate cellular transcription, but the target genes and molecular mechanisms remain poorly understood. We report here that Tat uses unexpected regulatory mechanisms to reprogram target immune cells to promote viral replication and rewire pathways beneficial for the virus. Tat functions through master transcriptional regulators bound at promoters and enhancers, rather than through cellular 'TAR-like' motifs, to both activate and repress gene sets sharing common functional annotations. Despite the complexity of transcriptional regulatory mechanisms in the cell, Tat precisely controls RNA polymerase II recruitment and pause release to fine-tune the initiation and elongation steps in target genes. We propose that a virus with a limited coding capacity has optimized its genome by evolving a small but 'multitasking' protein to simultaneously control viral and cellular transcription. PMID- 26488445 TI - The Challenges of Living with Inflammatory Bowel Disease: Summary of a summit on patient and health care provider perspectives. PMID- 26488443 TI - Proapoptotic effect of control-released basic fibroblast growth factor on skin wound healing in a diabetic mouse model. AB - The ability of basic fibroblast growth factor (bFGF) to improve wound healing is attenuated by its short half-life in free form. This study aimed to enhance skin wound healing in a diabetes mouse model while concomitantly decreasing scar formation using control-released bFGF together with acidic gelatin hydrogel microspheres (AGHMs). Bilateral full-thickness wounds (10 mm in diameter) were made on the backs of db/db mice. Forty-five mice were divided into three groups, and the base of the wound under the panniculus carnosus and the wound periphery were injected with phosphate-buffered saline (300 MUL) containing (1) control released bFGF (50 MUg), (2) control-released bFGF (20 MUg), or (3) AGHMs alone. The size of the wound area was recorded on each postoperative day (POD). Mice were sacrificed on postoperative day 4, 7, 10, 14, and 28, and skin wound specimens were obtained to assess the endothelium/angiogenesis index via cluster of differentiation 31 immunohistochemistry, the proliferation index via Ki-67 immunohistochemistry, and the myofibroblast and fibroblast apoptosis indices by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and alpha smooth muscle actin or vimentin staining, respectively. Epithelialization rates and indices of proliferation and myofibroblast/fibroblast apoptosis were higher in the bFGF groups than in the AGHM group, mainly within 2 weeks of injury. No dose-effect relationship was found for control-released bFGF, although the actions of 50 MUg bFGF seemed to last longer than those of 20 MUg bFGF. Therefore, control-released bFGF may accelerate diabetic skin wound healing and induce myofibroblast/fibroblast apoptosis, thereby reducing scar formation. PMID- 26488446 TI - Binding of Folic Acid Induces Specific Self-Aggregation of Lactoferrin: Thermodynamic Characterization. AB - In the study presented here, we investigated the interaction at pH 5.5 between folic acid (FA) and lactoferrin (LF), a positively charged protein. We found a binding constant Ka of 10(5) M(-1) and a high stoichiometry of 10 mol of FA/mol of LF. The size and charge of the complexes formed evolved during titration experiments. Increasing the ionic strength to 50 mM completely abolished the isothermal titration calorimetry (ITC) signal, suggesting the predominance of electrostatic interactions in the exothermic binding obtained. We developed a theoretical model that explains the complex triphasic ITC profile. Our results revealed a two-step mechanism: FA/LF interaction followed by self-association of the complexes thus formed. We suggest that 10 FA molecules bind to LF to form saturated reactive complexes (FA10/LF) that further self-associate into aggregates with a finite size of around 15 nm. There is thus a critical saturation degree of the protein, above which the self-association can take place. We present here the first results that provide comprehensive details of the thermodynamics of FA/LF complexation-association. Given the high stoichiometry, allowing a load of 55 mg of FA/g of LF, we suggest that FA/LF aggregates would be an effective vehicle for FA in fortified drinks. PMID- 26488447 TI - Organocatalyzed Multicomponent Synthesis of Isoxazolidin-5-ones. AB - An unprecedented multicomponent organocatalyzed Knoevenagel-aza-Michael cyclocondensation reaction between Meldrum's acid, hydroxylamines, and aldehydes afforded a straightforward entry to a large array of racemic and syn diastereoenriched isoxazolidinones as synthetically useful scaffolds. This process revealed a markedly facile aza-Michael-cyclocondensation sequence as a key domino reaction between RCO2NHOH and transient alkylidene Meldrum's acid upon Bronsted base catalysis. PMID- 26488448 TI - Diagnostic utility of BNP, corin and furin as biomarkers for cardiovascular complications in type 2 diabetes mellitus patients. AB - CONTEXT: The number of patients with type 2 diabetes mellitus (T2DM) is progressively increasing, and diabetic cardiovascular complications have become a public health problem. Brain or B-type natriuretic peptide (BNP) is a cardiac hormone synthesized as a pre-pro-peptide. pro-BNP is produced by cleaving the signal peptide then two proprotein convertases, corin and furin cleave pro-BNP to form a biologically active hormone. Two corin single nucleotide polymorphisms (SNPs) have been reported to alter corin protein conformation and impair its biological activity. OBJECTIVE: We aimed to investigate the potential role of corin and furin in comparison to BNP as biomarkers for predicting cardiovascular complications in T2DM patients. The association of corin gene SNPs with corin levels was also examined. METHODS: Seventy-five subjects were recruited in this study, including 25 T2DM patients with complications, 25 T2DM patients without complications as well as 25 healthy subjects. Plasma BNP, corin and furin levels were measured using enzyme-linked immunosorbent assays. Two corin SNPs were genotyped using allele specific oligonucleotide-polymerase chain reaction. RESULTS: Both furin and BNP were found to be more sensitive than corin (80% versus 56%, p = 0.008), whereas furin showed higher specificity when compared to BNP (96% versus 84%, p = 0.041) and corin (96% versus 64%, p < 0.0001) in predicting cardiovascular complications in T2DM patients. Corin SNPs are not associated with corin levels, neither in the entire study cohort nor in the subgroup of T2DM patients with cardiovascular complications (p > 0.05). CONCLUSIONS: Furin may be useful, either alone or in combination with other biomarkers, for cardiovascular risk stratification assessment in T2DM patients. PMID- 26488449 TI - Capture and Release of Cancer Cells by Combining On-Chip Purification and Off Chip Enzymatic Treatment. AB - As "liquid biopsies", circulating tumor cells (CTCs) have been thought to hold significant insights for cancer diagnosis and treatment. Despite the advances of microfluidic techniques that improve the capture of CTCs to a certain extent, recovering the captured CTCs with enhanced purity at the same time remains a challenge. Here, by combining on-chip purification and off-chip enzymatic treatment, we demonstrate a two-stage strategy to enhance the purity of captured cancer cells from blood samples. The on-chip purification introduces a stirring flow to increase the capture sensitivity and decrease nonspecifically bounded cells. The off-chip enzymatic treatment enables the cancer cells to be released from the attached magnetic beads, further improving the purity and enabling next reculture. For the proof-of-concept study, spiked cancer cells are successfully obtained from unprocessed whole blood with high recovery rate (~68%) and purity (~61%), facilitating subsequent RNA expression analysis. PMID- 26488450 TI - A curcumin-based molecular probe for near-infrared fluorescence imaging of tau fibrils in Alzheimer's disease. AB - In recent years, there has been growing interest in the near-infrared (NIR) fluorescence imaging of tau fibrils for the early diagnosis of Alzheimer's disease (AD). In order to develop a curcumin-based NIR fluorescent probe for tau fibrils, structural modification of the curcumin scaffold was attempted by combining the following rationales: the curcumin derivative should preserve its binding affinity to tau fibrils, and, upon binding to tau fibrils, the probe should show favorable fluorescence properties. To meet these requirements, we designed a novel curcumin scaffold with various aromatic substituents. Among the series, the curcumin derivative with a (4-dimethylamino-2,6-dimethoxy)phenyl moiety showed a significant change in its fluorescence properties (22.9-fold increase in quantum yield; Kd, 0.77 MUM; lambdaem, 620 nm; Phi, 0.32) after binding to tau fibrils. In addition, fluorescence imaging of tau-green fluorescent protein-transfected SHSY-5Y cells with confirmed that detected tau fibrils in live cells. PMID- 26488451 TI - A Family of {Cr(III)2Ln(III)2} Butterfly Complexes: Effect of the Lanthanide Ion on the Single-Molecule Magnet Properties. AB - We report the synthesis of several heterometallic 3d-4f complexes which result from the replacement of the Dy(III) ions in the [Cr(III)2Dy(III)2(OMe)2(mdea)2(O2CPh)4(NO3)2] single-molecule magnet (SMM) by the trivalent Pr, Nd, Gd, Tb, Ho, and Er lanthanide ions. The parent {Cr2Dy(III)2} compound displayed an anisotropy barrier to magnetization reversal of 53 cm(-1), with magnetic hysteresis observed up to 3.5 K and with large coercive fields at low temperatures (2.7 T at 1.8 K). Magnetic studies for the new complexes revealed significantly different static and dynamic magnetic behavior in comparison to the parent {Cr(III)2Dy(III)2} complex. When Ln(III) = Pr, a complete loss of SMM behavior is found, but when Ln(III) = Nd or Er, frequency dependent tails in the out-of-phase susceptibility at low temperatures are observed, indicative of slow magnetic relaxation, but with very small anisotropy barriers and fast relaxation times. When Ln(III) = Tb and Ho, SMM behavior is clearly revealed with anisotropy barriers of 44 and 36 cm(-1), respectively. Magnetic hysteresis is also observed up to 2.5 and 1.8 K (0.003 T/s) for the Tb and Ho complexes, respectively. A large loss of the magnetization is, however, observed at zero-field, and as a result, the large coercivity which is present in the {Cr2Dy2} example is lost. The {Cr2Tb2} and {Cr2Ho2} complexes are rare examples of Tb- and Ho-based SMMs which reveal both slow relaxation in the absence of a static dc field (ac susceptibility) and open hysteresis loops above 1.8 K. PMID- 26488452 TI - Characterizing the degradation of alginate hydrogel for use in multilumen scaffolds for spinal cord repair. AB - Alginate was studied as a degradable nerve guidance scaffold material in vitro and in vivo. In vitro degradation rates were determined using rheology to measure the change in shear modulus vs time. The shear modulus decreased from 155 kPa to 5 kPa within 2 days; however, alginate samples maintained their superficial geometry for over 28 days. The degradation behavior was supported by materials characterization data showing alginate consisted of high internal surface area (400 m2 /g), which likely facilitated the release of cross-linking cations resulting in the rapid decrease in shear modulus. To assess the degradation rate in vivo, multilumen scaffolds were fabricated using a fiber templating technique. The scaffolds were implanted in a 2-mm-long T3 full transection rodent spinal cord lesion model for 14 days. Although there was some evidence of axon guidance, in general, alginate scaffolds degraded before axons could grow over the 2-mm long lesion. Enabling alginate-based scaffolds for nerve repair will likely require approaches to slow its degradation. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 611-619, 2016. PMID- 26488453 TI - Tenofovir Therapy for Hepatitis B May Be Commonly Prescribed Without HIV Testing. PMID- 26488454 TI - G2P[4]-RotaTeq Reassortant Rotavirus in Vaccinated Child, United States. PMID- 26488455 TI - Spiropyran-Decorated SiO2-Pt Janus Micromotor: Preparation and Light-Induced Dynamic Self-Assembly and Disassembly. AB - The controlled self-assembly of self-propelled Janus micromotors may give the micromotors some potential applications in many fields. In this work, we design a kind of SiO2-Pt Janus catalytic micromotor functionalized by spiropyran (SP) moieties on the surface of the SiO2 hemisphere. The spiropyran-modified SiO2-Pt Janus micromotor exhibits autonomous self-propulsion in the presence of hydrogen peroxide fuel in N,N-dimethylformamide (DMF)/H2O (1:1 in volume) mixture. We demonstrate that the self-propelled Janus micromotors can dynamically assemble into multiple motors because of the electrostatic attractions and pi-pi stacking between MC molecules induced by UV light irradiation (lambda = 365 nm) and also quickly disassemble into mono motors when the light is switched to green light (lambda = 520 nm) for the first time. Furthermore, the assembled Janus motors can move together automatically with different motion patterns propelled by the hydrogen peroxide fuels upon UV irradiation. The work provides a new approach not only to the development of the potential application of Janus motors but also to the fundamental science of reversible self-assembly and disassembly of Janus micromotors. PMID- 26488456 TI - A Highly Selective Ratiometric Two-Photon Fluorescent Probe for Human Cytochrome P450 1A. AB - Cytochrome P450 1A (CYP1A), one of the most important phase I drug-metabolizing enzymes in humans, plays a crucial role in the metabolic activation of procarcinogenic compounds to their ultimate carcinogens. Herein, we reported the development of a ratiometric two-photon fluorescent probe NCMN that allowed for selective and sensitive detection of CYP1A for the first time. The probe was designed on the basis of substrate preference of CYP1A and its high capacity for O-dealkylation, while 1,8-naphthalimide was selected as fluorophore because of its two-photon absorption properties. To achieve a highly selective probe for CYP1A, a series of 1,8-naphthalimide derivatives were synthesized and used to explore the potential structure-selectivity relationship, by using a panel of human CYP isoforms for selectivity screening. After screening and optimization, NCMN displayed the best combination of selectivity, sensitivity and ratiometric fluorescence response following CYP1A-catalyzed O-demetylation. Furthermore, the probe can be used to real-time monitor the enzyme activity of CYP1A in complex biological systems, and it has the potential for rapid screening of CYP1A modulators using tissue preparation as enzyme sources. NCMN has also been successfully used for two-photon imaging of intracellular CYP1A in living cells and tissues, and showed high ratiometric imaging resolution and deep-tissue imaging depth. In summary, a two-photon excited ratiometric fluorescent probe NCMN has been developed and well-characterized for sensitive and selective detection of CYP1A, which holds great promise for bioimaging of endogenous CYP1A in living cells and for further investigation on CYP1A associated biological functions in complex biological systems. PMID- 26488457 TI - Single-Center, Adult Chronic Intestinal Failure Cohort Analyzed According to the ESPEN-Endorsed Recommendations, Definitions, and Classifications. AB - BACKGROUND/AIMS: The objective of this study was to describe a clinically well defined, single-center, intestinal failure (IF) cohort based on a template of definitions and classifications endorsed by the European Society for Clinical Nutrition and Metabolism (ESPEN). METHODS: A cross-sectional, retrospective, adult IF cohort, receiving parenteral support (PS), was extracted from the Copenhagen IF database at the tertiary IF center, Copenhagen University Hospital, Rigshospitalet, Denmark. RESULTS: Rigshospitalet provided PS to 188 adult patients with IF on December 31, 2011. Six patients received only fluids and electrolytes, while 97% required parenteral energy (17 +/- 12 kcal/kg/d). Although 92% of the cohort had undergone intestinal resection, only 53% were classified as patients with short bowel syndrome (SBS) according to the pathophysiological classification. In the remaining cohort, patients were distributed as 5% with intestinal fistula, 12% with intestinal dysmotility, 5% with mechanical obstruction, and 14% with mucosal diseases. Twelve percent had a combination of pathophysiological causes. The patients with SBS (n = 100) were subdivided according to bowel anatomy into group 1 (jejuno/ileostomy, n = 82), group 2 (jejuno-colonic-anastomosis, n = 16), and group 3 (jejuno-ileo-colonic anastomosis, n = 2). When evaluating the cohort requirements for PS using the ESPEN chronic IF classification based on the need for fluid volume and energy, 53% of the patients with IF were distributed in the maximum categories. CONCLUSION: The orphan condition of IF with its large patient heterogeneity mandates establishment of uniform definitions and a harmonization of classifications. As illustrated, the ESPEN-endorsed definitions and classifications are well designed and may serve as a common uniform template to facilitate both intra- and intercenter comparisons between reference centers and thus outcome results. PMID- 26488458 TI - Cytochrome c Complexes with Cardiolipin Monolayer Formed under Different Surface Pressure. AB - The formation of the complex of cytochrome c (Cytc) with a phospholipid cardiolipin (CL) in mitochondria is a crucial event in apoptosis development. There are two viewpoints on the structure of the complex. (1) Cytc is bound on the surface of the lipid bilayer. (2) The complex is a hydrophobic nanoparticle Cytc-CL formed by Cytc molten globule, covered by CL monolayer.1 In the present work, we attempted to bridge the gap between these two structures. We investigated the interaction between Cytc and Langmuir monolayers of CL. The surface pressure increase during incorporation of Cytc into CL monolayer obeys the equation: pi = pi0 + Deltapiinfinity[1 - exp(-betat)], where beta is pseudo first-order rate constant of Cytc binding, directly proportional to the initial Cytc concentration c0. Parameters Deltapiinfinity and the rate beta measured in different conditions were virtually equal for natural bovine CL and peroxidation resistant tetraoleoyl CL in all experiments. Surface area-surface pressure isotherms of Cytc alone and in combination with a CL monolayer were similar in shape. Apparently, the protein exposes hydrophilic groups to the water phase and hydrophobic to the air or to the hydrocarbon chains of CL. The 30% ethanol dramatically accelerated the adsorption of Cytc on the water surface. The protein lipid surface films showed, in compression-expansion cycles, that hysteresis loops were observed always when Cytc present, reproducible in repeating cycles. Taken together, our data show that when incorporated in a lipid monolayer or after adsorption on the water-air interface, Cytc undergoes conformational transition. In that, one part of the globule sphere becomes predominantly hydrophobic and the other, hydrophilic and charged ("stratified" Cytc). We hypothesize that in CL-containing bilayer membranes, Cytc incorporation into the lipid monolayer would result in membrane folding with subsequent formation of either catalytically reactive "bubbles" inside the bilayer, formed by Cytc-CL, or the appearance of hydrophilic pores. The role of lipid peroxidation catalyzed by Cytc-CL in the appearance of pores and apoptosis is also discussed. PMID- 26488459 TI - Stiripentol for focal refractory epilepsy. AB - BACKGROUND: This is an updated version of the original Cochrane review published in 2014 (Issue 1). For nearly 30% of people with epilepsy, seizures are not controlled by current treatments. Stiripentol is a new antiepileptic drug (AED) that was developed in France and was approved by the European Medicines Agency (EMA) in 2007 for the treatment of Dravet syndrome as adjunctive therapy with valproate and clobazam, with promising effects. OBJECTIVES: To evaluate the efficacy and tolerability of stiripentol as add-on treatment for patients with focal refractory epilepsy who are taking AEDs. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (10 August 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; August 2015, Issue 8)and MEDLINE (Ovid) (1946 to 10 August 2015). We contacted Biocodex (the manufacturer of stiripentol) and epilepsy experts to identify published, unpublished and ongoing trials. SELECTION CRITERIA: Randomised controlled add-on trials of stiripentol in patients with focal refractory epilepsy. DATA COLLECTION AND ANALYSIS: Review authors independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life. MAIN RESULTS: On the basis of our selection criteria, we included no new studies in the present review. However, we did include one study from the earlier review (32 children with focal epilepsy). This study adopted a 'responder enriched' design and found no clear evidence of a reduction in seizure frequency (>= 50% seizure reduction) (risk ratio (RR) 1.51, 95% confidence interval (CI) 0.81 to 2.82) nor evidence of seizure freedom (RR 1.18, 95% CI 0.31 to 4.43) when add-on stiripentol was compared with placebo. Stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47). When specific adverse events were considered, confidence intervals were very wide and showed the possibility of substantial increases and small reductions in risks of neurological (RR 2.65, 95% CI 0.88 to 8.01) or gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36). Researchers noted no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group). The external validity of this study was limited because only responders to stiripentol (i.e. patients experiencing a >= 50% decrease in seizure frequency compared with baseline) were included in the randomised add-on placebo-controlled double-blind phase. Furthermore, carry-over and withdrawal effects probably influenced outcomes related to seizure frequency. Very limited information derived from the only included study shows that adverse effects considered as a whole seemed to occur significantly more often with add-on stiripentol than with add-on placebo. AUTHORS' CONCLUSIONS: Since the last version of this review was published, we have found no new studies. Hence, we have made no changes to the conclusions of this update as presented in the initial review. We can draw no conclusions to support the use of stiripentol as add-on treatment for focal refractory epilepsy. Additional large, randomised, well-conducted trials are needed. PMID- 26488460 TI - A Structural Equation Modeling Analysis of the Relationships between Depression, Anxiety, and Sexual Problems over Time. AB - Sexual dysfunctions are related to depressive and anxiety disorders, but the nature of these relationships remains unclear. This study examined the relationship among symptoms of these disorders over time by comparing (a) a model that included causal relationships, (b) a model that accounted for change over time with a shared underlying factor (or latent liability) among all the disorders, and (c) a model that conceptualized sexual dysfunctions as unrelated to depressive and anxiety disorders over time. Participants (n = 1,012) completed online self-report measures of sexual dysfunctions and depressive and anxiety disorders across six time points at either weekly or monthly intervals. Models 1 and 2 provided equal best fit for men and women based on data collected four weeks apart, but there were no evident causal relationships in Model 1. Subsequent analyses using data collected one week and six months apart found Model 2 provided robust fit for women, but these data were not examined for men due to inadequate sample sizes. The results are consistent with a shared latent liability of internalizing psychopathology driving the change in these disorders over time, which provides a clear direction for an empirically driven nosology and for future research into transdiagnostic treatments. PMID- 26488461 TI - Molecular Aluminum Additive for Burn Enhancement of Hydrocarbon Fuels. AB - Additives to hydrocarbon fuels are commonly explored to change the combustion dynamics, chemical distribution, and/or product integrity. Here we employ a novel aluminum-based molecular additive, Al(I) tetrameric cluster [AlBrNEt3]4 (Et = C2H5), to a hydrocarbon fuel and evaluate the resultant single-droplet combustion properties. This Al4 cluster offers a soluble alternative to nanoscale particulate additives that have recently been explored and may mitigate the observed problems of particle aggregation. Results show the [AlBrNEt3]4 additive to increase the burn rate constant of a toluene-diethyl ether fuel mixture by ~20% in a room temperature oxygen environment with only 39 mM of active aluminum additive (0.16 wt % limited by additive solubility). In comparison, a roughly similar addition of nano-aluminum particulate shows no discernible difference in burn properties of the hydrocarbon fuel. High speed video shows the [AlBrNEt3]4 to induce microexplosive gas release events during the last ~30% of the droplet combustion time. We attribute this to HBr gas release based on results of temperature-programmed reaction (TPR) experiments of the [AlBrNEt3]4 dosed with O2 and D2O. A possible mechanism of burn rate enhancement is presented that is consistent with microexplosion observations and TPR results. PMID- 26488463 TI - Precision, reproducibility, and accuracy of bone crest level measurements of CBCT cross sections using different resolutions. AB - OBJECTIVE: To evaluate the precision, reproducibility, and accuracy of alveolar crest level measurements on CBCT images obtained with different voxel sizes. MATERIALS AND METHODS: CBCT exams were made of 12 dried human mandibles with voxel dimensions of 0.2, 0.3, and 0.4 mm. Bone crest level was measured directly on the mandibles with a digital caliper and on CBCT images. Images were measured twice by two examiners. Intra- and interexaminer precision and reproducibility were assessed using paired and t-tests, respectively. Accuracy was evaluated using t-tests. RESULTS: Precision and reproducibility of bone crest level tomographic measurements was good for all voxel sizes evaluated. The images with 0.2-mm voxel size showed a decreased number of intraexaminer errors. A high accuracy for measurements of bone crest level was observed for all CBCT definitions, except for the mandibular incisors using the 0.4-mm voxel size. CONCLUSIONS: Precision and reproducibility of alveolar bone level measurements were good for various voxel sizes. CBCT images demonstrated good accuracy for 0.2 mm and 0.3-mm voxel sizes. The mandibular incisor region needs better resolution than that provided by 0.4-mm voxel size for bone crest level measurements. PMID- 26488462 TI - Baculovirus expression: old dog, new tricks. AB - Since its inception more than 30 years ago, the baculovirus expression vector system (BEVS) has been used prolifically to produce heterologous proteins for research and development. In the cell, a cornerstone of biological activity are multiprotein complexes, catalyzing essential functions. BEVS has been uniquely successful to unlock such complex assemblies for high-resolution structural and functional analysis. Synthetic biology approaches have been implemented to optimize multigene assembly methods, accelerating upstream processes. Specialized baculoviral genomes are being created with functions tailored to enhance production of particular target protein classes. Here we comment on current and emerging developments in the field and their potential to accelerate protein complex research. PMID- 26488464 TI - Electrical impedance tomography: functional lung imaging on its way to clinical practice? AB - Electrical impedance tomography (EIT) has the potential to become a bedside tool for monitoring and guiding ventilator therapy as well as tracking the development of chronic lung diseases. This review article summarizes recent publications (from 2011) dealing with the applications of pulmonary EIT. Original papers on EIT lung imaging in clinical settings are analyzed and divided into several categories according to the lung pathology of the study subjects. Studies on children and infants are presented separately from studies on adult patients. Information on the study objectives and main results, the number of studied patients, the performed ventilatory maneuvers or interventions and the analyzed EIT information is given. Limitations that hinder EIT to become a routinely used tool in a clinical setting are also discussed. PMID- 26488465 TI - Vaccine-Resistant Malaria. PMID- 26488467 TI - Endothelial Cell Autophagy in Atherosclerosis is Regulated by miR-30-Mediated Translational Control of ATG6. AB - BACKGROUND/AIMS: Endothelial cell injury and subsequent death play an essential role in the pathogenesis of atherosclerosis. Autophagy of endothelial cells has a protective role against development of atherosclerosis, whereas the molecular regulation of endothelial cell autophagy is unclear. MicroRNA-30 (miR-30) is a known autophagy suppressor in some biological processes, while it is unknown whether this regulatory axis may be similarly involved in the development of atherosclerosis. Here, we aimed to answer these questions in the current study. METHODS: We examined the levels of endothelial cell autophagy in ApoE (-/-) mice suppled with high-fat diet (HFD), a mouse model for atherosclerosis (simplified as HFD mice). We analyzed the levels of autophagy-associated protein 6 (ATG6, or Beclin-1) and the levels of miR-30 in the purified CD31+ endothelial cells from mouse aorta. Prediction of the binding between miR-30 and 3'-UTR of ATG6 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-30 were further analyzed in an in vitro model using oxidized low-density lipoprotein (ox-LDL)-treated human aortic endothelial cells (HAECs). RESULTS: HFD mice developed atherosclerosis in 12 weeks, while the control ApoE (-/-) mice that had received normal diet (simplified as NOR mice) did not. Compared to NOR mice, HFD mice had significantly lower levels of endothelial cell autophagy, resulting from decreases in ATG6 protein, but not mRNA. The decreases in ATG6 in endothelial cells were due to HFD-induced increases in miR-30, which suppressed the translation of ATG6 mRNA via 3'-UTR binding. These in vivo findings were reproduced in vitro on ox-LDL-treated HAECs. CONCLUSION: Upregulation of miR-30 by HFD may impair the protective effects of endothelial cell autophagy against development of atherosclerosis through suppressing protein translation of ATG6. PMID- 26488468 TI - Bilateral Optic Pathway Ganglioglioma: The Fifth Case in the Literature. AB - Gangliogliomas are mixed tumors which contain both glial and neuronal elements. The optic pathway is a very rare location for gangliogliomas, with less than 23 cases reported in the literature. Bilateral involvement of the entire optic pathway was reported in only 4 cases before. Because of similar radiological appearance of other pathological entities such as gliomas and craniopharyngiomas, histopathological diagnosis is essential. We report a ganglioglioma case that involved both optic pathways. A 12-year-old patient suffering from visual deterioration for 6 months was evaluated. After a visual field test and radiological examinations, a microsurgical biopsy procedure was performed. Pathological examination revealed dysplastic/neoplastic ganglion cells and neoplastic glial cells, and the diagnosis was a World Health Organization (WHO) grade 1 ganglioglioma. The patient is scheduled for adjuvant radiotherapy with the hope of prevention of progression. PMID- 26488469 TI - Detection of Alicyclobacillus spp. in Fruit Juice by Combination of Immunomagnetic Separation and a SYBR Green I Real-Time PCR Assay. AB - An approach based on immunomagnetic separation (IMS) and SYBR Green I real-time PCR (real-time PCR) with species-specific primers and melting curve analysis was proposed as a rapid and effective method for detecting Alicyclobacillus spp. in fruit juices. Specific primers targeting the 16S rDNA sequences of Alicyclobacillus spp. were designed and then confirmed by the amplification of DNA extracted from standard strains and isolates. Spiked samples containing known amounts of target bacteria were used to obtain standard curves; the correlation coefficient was greater than 0.986 and the real-time PCR amplification efficiencies were 98.9%- 101.8%. The detection limit of the testing system was 2.8*101 CFU/mL. The coefficient of variation for intra-assay and inter-assay variability were all within the acceptable limit of 5%. Besides, the performance of the IMS-real-time PCR assay was further investigated by detecting naturally contaminated kiwi fruit juice; the sensitivity, specificity and accuracy were 91.7%, 95.9% and 95.3%, respectively. The established IMS-real-time PCR procedure provides a new method for identification and quantitative detection of Alicyclobacillus spp. in fruit juice. PMID- 26488470 TI - Reversible Growth Hormone Excess in Two Girls with Neurofibromatosis Type 1 and Optic Pathway Glioma. AB - BACKGROUND: A total of 12 children with neurofibromatosis type 1 (NF-1) with optic pathway glioma (OPG) and growth hormone (GH) excess are reported to date, but no data exist on the long-term outcome. We describe 2 girls with NF-1 with OPG and GH excess treated with somatostatin analogue (SSa) who maintained a normal GH axis after stopping SSa therapy. METHODS: The diagnosis of GH excess was established from auxological data, persistently high levels of insulin-like growth factor 1 (IGF-1) and a lack of GH suppression during an oral glucose tolerance test. RESULTS: Both patients were started on SSa treatment. During treatment, growth deceleration and normal IGF-1 levels were documented. The first case stopped treatment following the development of SSa side effects. The second case interrupted SSa when, closed to her final height, a normal IGF-1 level was documented. While off treatment, both cases maintained normal IGF-1 levels and appropriate growth velocity for their age and development, with normal GH secretion on biochemical testing. Both cases received treatment for central precocious puberty. CONCLUSION: GH excess in NF-1 children with OPG can be reversed and only short-term SSa therapy may be required. The aetiology remains undetermined, but the course suggests a hypothalamic dysfunction. PMID- 26488471 TI - PFTK1 Promotes Gastric Cancer Progression by Regulating Proliferation, Migration and Invasion. AB - PFTK1, also known as PFTAIRE1, CDK14, is a novel member of Cdc2-related serine/threonine protein kinases. Recent studies show that PFTK1 is highly expressed in several malignant tumors such as hepatocellular carcinoma, esophageal cancer, breast cancer, and involved in regulation of cell cycle, tumors proliferation, migration, and invasion that further influence the prognosis of tumors. However, the expression and physiological significance of PFTK1 in gastric cancer remain unclear. In this study, we analyzed the expression and clinical significance of PFTK1 by Western blot in 8 paired fresh gastric cancer tissues, nontumorous gastric mucosal tissues and immunohistochemistry on 161 paraffinembedded slices. High PFTK1 expression was correlated with the tumor grade, lymph node invasion as well as Ki-67. Through Cell Counting Kit (CCK)-8 assay, flow cytometry, colony formation, wound healing and transwell assays, the vitro studies demonstrated that PFTK1 overexpression promoted proliferation, migration and invasion of gastric cancer cells, while PFTK1 knockdown led to the opposite results. Our findings for the first time supported that PFTK1 might play an important role in the regulation of gastric cancer proliferation, migration and would provide a novel promising therapeutic strategy against human gastric cancer. PMID- 26488472 TI - The Effect of Timing of Female Vibrational Reply on Male Signalling and Searching Behaviour in the Leafhopper Aphrodes makarovi. AB - Sexual communication in animals often involves duetting characterized by a coordinated reciprocal exchange of acoustic signals. We used playback experiments to study the role of timing of a female reply in the species-specific duet structure in the leafhopper Aphrodes makarovi (Hemiptera: Cicadellidae). In leafhoppers, mate recognition and location is mediated exclusively by species- and sex-specific substrate-borne vibrational signals and a female signal emitted in reply to male advertisement calls is essential for recognition and successful location of the female. In A. makarovi, males have to initiate each exchange of vibrational signals between partners, and in a duet the beginning of a female reply overlaps the end of the male advertisement call. Results of playback treatments in which female replies were delayed and did not overlap with the male call revealed that in order to trigger an appropriate behavioural response of the male, female reply has to appear in a period less than 400 ms after the end of the initiating male call. Results also suggest that males are not able to detect a female reply while calling, since female reply that did not continue after the end of male call triggered male behaviour similar to behaviour observed in the absence of female reply. Together, our results show that vibrational duets are tightly coordinated and that the species-specific duet structure plays an important role in mate recognition in location processes. PMID- 26488473 TI - Subclassification of BCLC B Stage Hepatocellular Carcinoma and Treatment Strategies: Proposal of Modified Bolondi's Subclassification (Kinki Criteria). AB - Intermediate stage hepatocellular carcinoma (HCC) is a very heterogeneous tumor in terms of tumor size (>3 cm ~ over 10 cm), tumor number (4 ~ over 20) and liver function (Child-Pugh score 5-9). However, transarterial chemoembolization is the only recommended treatment option according to the Barcelona Clinic Liver Cancer (BCLC) staging. Bolondi's subclassification of BCLC B stage is feasible; however, there are several weak points. Therefore, by modifying Bolondi's subclassification, we have proposed a more simplified subclassification, Kinki criteria. The Kinki criteria consist of 2 factors: liver function (Child-Pugh score 5-7 or 8, 9) and tumor status (Beyond Milan and within up-to-7 criteria; IN and OUT). The Kinki criteria classifies BCLC B stage from B1 (Child-Pugh score 5 7 and within up-to-7), B2 (Child-Pugh score 5-7 and beyond up-to-7) and B3 (Child Pugh score 8, 9 and any tumor status). These criteria are simple and easy to apply to clinical practice. Therefore, these criteria will stratify the heterogeneous population of BCLC B group patient well and give the treatment indication according to each substage. These criteria should be further validated both retrospectively and prospectively. PMID- 26488474 TI - Usefulness of Cytokeratin-18M65 in Diagnosing Non-Alcoholic Steatohepatitis in Japanese Population. AB - OBJECTIVE: The aim of this study was to evaluate cytokeratin-18M65 (CK-18M65) for distinguishing between simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) against healthy individuals (HIs) in Japanese population. METHODS: The serum from 24 HIs, 21 patients with SS and 20 patients with NASH were examined. Serum CK-18M65 was measured by enzyme-linked immunosorbent assay. RESULTS: Aspartate aminotransferase was significantly different between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001), as was alanine aminotransferase between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001). Serum CK-18M65 increased in a stepwise fashion in HIs and also in SS and NASH patients. Multivariate logistic regression analysis revealed that NASH could be diagnosed with the use of CK-18M65 alone (p = 0.0285, OR 1.0038, 95% CI 1.0004-1.0073). At the optimal cut-off level of 548 U/l, CK-18M65 had an AUC value of 0.7369, 60.00% sensitivity and 85.70% specificity. In patients with NASH, no significant difference was observed between low fibrosis (Stage 0-1, 794.30 +/- 454.41, n = 10) and high fibrosis (Stage 2-3, 809.70 +/- 641.43, n = 10; p = 0.5967) and between slight steatosis (<33%, 512.89 +/- 229.65, n = 9) and moderate steatosis (>=33%, 655.13 +/- 480.78, n = 32) in patients with non alcoholic fatty liver disease (NAFLD; p = 0.7647) with the use of CK-18M65. CONCLUSION: Serum CK-18M65 distinguished NASH from SS, but could not assess the severity of steatosis in NAFLD patients or the grade of fibrosis in NASH patients in Japanese population. PMID- 26488475 TI - West Nile Virus Surveillance in 2013 via Mosquito Screening in Northern Italy and the Influence of Weather on Virus Circulation. AB - West Nile virus (WNV) is a recently re-emerged health problem in Europe. In Italy, an increasing number of outbreaks of West Nile disease, with occurrences of human cases, have been reported since 2008. This is particularly true in northern Italy, where entomological surveillance systems have been implemented at a regional level. The aim of this study was to use, for the first time, all the entomological data collected in the five regions undergoing surveillance for WNV in northern Italy to characterize the viral circulation (at a spatial and temporal scale), identify potential mosquito vectors, and specify relationships between virus circulation and meteorological conditions. In 2013, 286 sites covering the entire Pianura Padana area were monitored. A total of 757,461 mosquitoes were sampled. Of these, 562,079 were tested by real-time PCR in 9,268 pools, of which 180 (1.9%) were positive for WNV. The largest part of the detected WNV sequences belonged to lineage II, demonstrating that, unlike those in the past, the 2013 outbreak was mainly sustained by this WNV lineage. This surveillance also detected the Usutu virus, a WNV-related flavivirus, in 241 (2.6%) pools. The WNV surveillance systems precisely identified the area affected by the virus and detected the viral circulation approximately two weeks before the occurrence of onset of human cases. Ninety percent of the sampled mosquitoes were Culex pipiens, and 178/180 WNV-positive pools were composed of only this species, suggesting this mosquito is the main WNV vector in northern Italy. A significantly higher abundance of the vector was recorded in the WNV circulation area, which was characterized by warmer and less rainy conditions and greater evapotranspiration compared to the rest of the Pianura Padana, suggesting that areas exposed to these conditions are more suitable for WNV circulation. This observation highlights warmer and less rainy conditions as factors able to enhance WNV circulation and cause virus spillover outside the sylvatic cycle. PMID- 26488476 TI - The Profile of Heparanase Expression Distinguishes Differentiated Thyroid Carcinoma from Benign Neoplasms. AB - INTRODUCTION: The search for a specific marker that could help to distinguish between differentiated thyroid carcinoma and benign lesions remains elusive in clinical practice. Heparanase (HPSE) is an endo-beta-glucoronidase implicated in the process of tumor invasion, and the heparanase-2 (HPSE2) modulates HPSE activity. The aim of this study was to evaluate the role of heparanases in the development and differential diagnosis of follicular pattern thyroid lesions. METHODS: HPSE and HPSE2 expression by qRT-PCR, immunohistochemistry evaluation, western blot analysis and HPSE enzymatic activity were evaluated. RESULTS: The expression of heparanases by qRT-PCR showed an increase of HPSE2 in thyroid carcinoma (P = 0.001). HPSE activity was found to be higher in the malignant neoplasms than in the benign tumors (P<0.0001). On Western blot analysis, HPSE2 isoforms were detected only in malignant tumors. The immunohistochemical assay allowed us to establish a distinct pattern for malignant and benign tumors. Carcinomas showed a typical combination of positive labeling for neoplastic cells and negative immunostaining in colloid, when compared to benign tumors (P<0.0001). The proposed diagnostic test presents sensitivity and negative predictive value of around 100%, showing itself to be an accurate test for distinguishing between malignant and benign lesions. CONCLUSIONS: This study shows, for the first time, a distinct profile of HPSE expression in thyroid carcinoma suggesting its role in carcinogenesis. PMID- 26488478 TI - Correction: Multi-Method Approach for Characterizing the Interaction between Fusarium verticillioides and Bacillus thuringiensis Subsp. Kurstaki. PMID- 26488477 TI - Sex and STEM Occupation Predict Autism-Spectrum Quotient (AQ) Scores in Half a Million People. AB - This study assesses Autism-Spectrum Quotient (AQ) scores in a 'big data' sample collected through the UK Channel 4 television website, following the broadcasting of a medical education program. We examine correlations between the AQ and age, sex, occupation, and UK geographic region in 450,394 individuals. We predicted that age and geography would not be correlated with AQ, whilst sex and occupation would have a correlation. Mean AQ for the total sample score was m = 19.83 (SD = 8.71), slightly higher than a previous systematic review of 6,900 individuals in a non-clinical sample (mean of means = 16.94) This likely reflects that this big data sample includes individuals with autism who in the systematic review score much higher (mean of means = 35.19). As predicted, sex and occupation differences were observed: on average, males (m = 21.55, SD = 8.82) scored higher than females (m = 18.95; SD = 8.52), and individuals working in a STEM career (m = 21.92, SD = 8.92) scored higher than individuals non-STEM careers (m = 18.92, SD = 8.48). Also as predicted, age and geographic region were not meaningfully correlated with AQ. These results support previous findings relating to sex and STEM careers in the largest set of individuals for which AQ scores have been reported and suggest the AQ is a useful self-report measure of autistic traits. PMID- 26488479 TI - Use of in vivo Expression Technology for the Identification of Putative Host Adaptation Factors of the Lyme Disease Spirochete. AB - The causative agent of Lyme disease, Borrelia burgdorferi, is an obligate parasite that requires either a tick vector or a mammalian host for survival. Identification of the bacterial genes that are specifically expressed during infection of the mammalian host could provide targets for novel therapeutics and vaccines. In vivo expression technology (IVET) is a reporter-based promoter trap system that utilizes selectable markers to identify promoters of bacterial host specific genes. Using previously characterized genes for in vivo and in vitro selection, this study utilized an IVET system that allows for selection of B. burgdorferi sequences that act as active promoters only during murine infection. This promoter trap system was able to successfully distinguish active promoter sequences both in vivo and in vitro from control sequences and a library of cloned B. burgdorferi genomic fragments. However, a bottleneck effect during the experimental mouse infection limited the utility for genome-wide promoter screening. Overall, IVET was demonstrated as a tool for the identification of in vivo-induced promoter elements of B. burgdorferi, and the observed infection bottleneck apparent using a polyclonal infection pool provides insight into the dynamics of experimental infection with B. burgdorferi. PMID- 26488480 TI - The MRI marker gene MagA attenuates the oxidative damage induced by iron overload in transgenic mice. AB - We aimed to create transgenic (Tg) mice engineered for magnetic resonance imaging (MRI). To ascertain if MagA expression contributes to oxidative stress and iron metabolism, we report the generation of Tg mice in which ubiquitous expression of MagA can be detected by MRI in vivo. Expression of MagA in diverse tissues of Tg mice was assessed, and iron accumulation and deposition of nanoparticles in tissues were analyzed. Levels of antioxidant enzymes, lipid peroxidation and cytokine production were determined, and iron metabolism-related proteins were also detected. MagA Tg showed no apparent pathologic symptoms and no histologic changes compared with wild-type (WT) mice. Overexpression of MagA resulted in specific alterations of the transverse relaxation rate (R2) of water. Transgene dependent changes in R2 were detectable by MRI in iron-overloaded mice. We also evaluated antioxidant abilities between WT and Tg groups or two iron-overloaded groups. Together with the data of cytokines and iron metabolism-related proteins, we inferred that MagA could regulate nanoparticle production and thus attenuate the oxidative damage induced by iron overload. The novel MagA Tg mouse, which expresses an MRI reporter in many tissues, would be a valuable model of MagA molecular imaging in which to study diseases related to iron metabolism. PMID- 26488481 TI - Mosquito-specific microRNA-1890 targets the juvenile hormone-regulated serine protease JHA15 in the female mosquito gut. AB - Females of the hematophagous mosquito species require a vertebrate blood meal to supply amino acids and other nutrients necessary for egg development, serving as the driving force for the spread of many vector-borne diseases in humans. Blood digestion utilizes both early and late phase serine proteases (SPs) that are differentially regulated at the transcriptional and post-transcriptional level. To uncover the regulatory complexity of SPs in the female mosquito midgut, we investigated involvement of miRNAs in regulating the juvenile hormone (JH) controlled chymotrypsin-like SP, JHA15. We identified regulatory regions complementary to the mosquito-specific miRNA, miR-1890, within the 3' UTR of JHA15 mRNA. The level of the JHA15 transcript is highest post eclosion and drastically declines post blood meal (PBM), exhibiting an opposite trend to miR 1890 that peaks at 24 h PBM. Depletion of miR-1890 results in defects in blood digestion, ovary development and egg deposition. JHA15 mRNA and protein levels are elevated in female mosquitoes with miR-1890 inhibition. JHA15 RNA interference in the miR-1890 depletion background alleviates miR-1890 depletion phenotypes. The miR-1890 gene is activated by the 20-hydroxyecdysone pathway that involves the ecdysone receptor and the early genes, E74B and Broad Z2. Our study suggests that miR-1890 controls JHA15 mRNA stability in a stage- and tissue- specific manner. PMID- 26488482 TI - A Fungal-Prokaryotic Consortium at the Basalt-Zeolite Interface in Subseafloor Igneous Crust. AB - We have after half a century of coordinated scientific drilling gained insight into Earth's largest microbial habitat, the subseafloor igneous crust, but still lack substantial understanding regarding its abundance, diversity and ecology. Here we describe a fossilized microbial consortium of prokaryotes and fungi at the basalt-zeolite interface of fractured subseafloor basalts from a depth of 240 m below seafloor (mbsf). The microbial consortium and its relationship with the surrounding physical environment are revealed by synchrotron-based X-ray tomographic microscopy (SRXTM), environmental scanning electron microscopy (ESEM), and Raman spectroscopy. The base of the consortium is represented by microstromatolites-remains of bacterial communities that oxidized reduced iron directly from the basalt. The microstromatolites and the surrounding basalt were overlaid by fungal cells and hyphae. The consortium was overgrown by hydrothermally formed zeolites but remained alive and active during this event. After its formation, fungal hyphae bored in the zeolite, producing millimetre long tunnels through the mineral substrate. The dissolution could either serve to extract metals like Ca, Na and K essential for fungal growth and metabolism, or be a response to environmental stress owing to the mineral overgrowth. Our results show how microbial life may be maintained in a nutrient-poor and extreme environment by close ecological interplay and reveal an effective strategy for nutrient extraction from minerals. The prokaryotic portion of the consortium served as a carbon source for the eukaryotic portion. Such an approach may be a prerequisite for prokaryotic-eukaryotic colonisation of, and persistence in, subseafloor igneous crust. PMID- 26488483 TI - Characterization of Sugarcane Mosaic Virus Scmv1 and Scmv2 Resistance Regions by Regional Association Analysis in Maize. AB - Sugarcane Mosaic Virus (SCMV) causes one of the most severe virus diseases in maize worldwide, resulting in reduced grain and forage yield in susceptible cultivars. In this study, two association panels consisting of 94 inbred lines each, from China and the U.S., were characterized for resistance to two isolates: SCMV-Seehausen and SCMV-BJ. The population structure of both association panels was analyzed using 3072 single nucleotide polymorphism (SNP) markers. The Chinese and the U.S. panel were both subdivided into two sub-populations, the latter comprised of Stiff Stalk Synthetic (SS) lines and Non Stiff Stalk Synthetic (NSS). The relative kinships were calculated using informative 2947 SNPs with minor allele frequency >= 5% and missing data <= 20% for the Chinese panel and 2841 SNPs with the same characteristics were used for the U.S. panel. The Scmv1 region was genotyped using 7 single sequence repeat (SSR) and sequence-tagged site (STS) markers, and 12 SSR markers were used for the Scmv2 region in the U.S. panel, while 5 of them were used for the Chinese panel. For all traits, a MLM (Mix Linear Model) controlling both population structure and relative kinship (Q + K) was used for association analysis. Three markers Trx-1, STS-11, and STS-12 located in the Scmv1 region were strongly associated (P = 0.001) with SCMV resistance, and explained more than 16.0%, 10.6%, and 19.7% of phenotypic variation, respectively. 207FG003 located in the Scmv2 region was significantly associated (P = 0.001) with SCMV resistance, and explained around 18.5% of phenotypic variation. PMID- 26488484 TI - Footwear Decreases Gait Asymmetry during Running. AB - Previous research on elderly people has suggested that footwear may improve neuromuscular control of motion. If footwear does in fact improve neuromuscular control, then such an influence might already be present in young, healthy adults. A feature that is often used to assess neuromuscular control of motion is the level of gait asymmetry. The objectives of the study were (a) to develop a comprehensive asymmetry index (CAI) that is capable of detecting gait asymmetry changes caused by external boundary conditions such as footwear, and (b) to use the CAI to investigate whether footwear influences gait asymmetry during running in a healthy, young cohort. Kinematic and kinetic data were collected for both legs of 15 subjects performing five barefoot and five shod over-ground running trials. Thirty continuous gait variables including ground reaction forces and variables of the hip, knee, and ankle joints were computed for each leg. For each individual, the differences between the variables for the right and left leg were calculated. Using this data, a principal component analysis was conducted to obtain the CAI. This study had two main outcomes. First, a sensitivity analysis suggested that the CAI had an improved sensitivity for detecting changes in gait asymmetry caused by external boundary conditions. The CAI may, therefore, have important clinical applications such as monitoring the progress of neuromuscular diseases (e.g. stroke or cerebral palsy). Second, the mean CAI for shod running (131.2 +/- 48.5; mean +/- standard deviation) was significantly lower (p = 0.041) than the CAI for barefoot running (155.7 +/- 39.5). This finding suggests that in healthy, young adults gait asymmetry is reduced when running in shoes compared to running barefoot, which may be a result of improved neuromuscular control caused by changes in the afferent sensory feedback. PMID- 26488485 TI - Fosfomycin Resistance in Escherichia coli, Pennsylvania, USA. AB - Fosfomycin resistance in Escherichia coli is rare in the United States. An extended-spectrum beta-lactamase-producing E. coli clinical strain identified in Pennsylvania, USA, showed high-level fosfomycin resistance caused by the fosA3 gene. The IncFII plasmid carrying this gene had a structure similar to those found in China, where fosfomycin resistance is commonly described. PMID- 26488488 TI - Correction. Elevated Plasma Ceramides in Depression. PMID- 26488486 TI - Antipsychotic Use in a Diverse Population With Dementia: A Retrospective Review of the National Alzheimer's Coordinating Center Database. AB - A cross-sectional analysis examined medication records in the National Alzheimer's Coordinating Center Database for community-dwelling patients with dementia who visited an Alzheimer's Disease Center between 2008 and 2014. Hispanic participants had a 1.62-fold greater use of antipsychotic medications, which was largely accounted for by a higher prevalence of neuropsychiatric symptoms and more severe dementia compared with non-Hispanic whites. These results are consistent with reports of later transition to nursing home care among Hispanic participants. Further studies are needed to clarify ethnic differences in how families and physicians address dementia progression and neuropsychiatric symptoms in community-dwelling patients with dementia. PMID- 26488489 TI - Neurobiology of Implicit and Explicit Bias: Implications for Clinicians. PMID- 26488490 TI - The Influence of Malnutrition and Micronutrient Status on Anemic Risk in Children under 3 Years Old in Poor Areas in China. AB - BACKGROUND: Malnutrition and anemia affect large numbers of young children living in poor areas of China. Multi-micronutrient deficiencies may be related to the prevalence of anemia in different populations, and identifying the risk factors that render children susceptible to anemia is the first step in combating anemia effectively. METHODS: In this cross-sectional study, a total of 1370 children under 3 years old were selected based on probability proportional to size sampling principles from poor counties of China. Basic characteristics data were collected by questionnaire; then anthropometrics and hemoglobin were measured in the field and anemia prevalence evaluated. Venous blood was drawn from children aged 12-35 months (N = 553) to evaluate micronutrient status. Logistic regression was used to identify the risk factors for children's anemia. RESULTS: Among children aged 0-35 months, the prevalence of stunting, low body weight and wasting was 17.5%, 8.6% and 5.1%, respectively, and 25.6% of the children were affected by anemia, with more anemic infants and younger children than older children (P <0.01). There were 26.5%, 12.8%, 14.1% and 20.0% of the children aged 12-35 months affected by iron deficiency, vitamin D deficiency, folic acid deficiency and vitamin B12 deficiency, respectively. For children aged 0-11 months who were breastfed, the mothers' anemic status was the only factor associated with the child's anemia (OR = 2.6; 95% CI: 1.2-5.4, P < 0.05). For children aged 12-35 months, multivariate logistic regression indicated that anemia was significantly associated with iron and vitamin B12 deficiency (OR = 5.3; 95% CI: 1.9-14.5, P < 0.01) and monotonous diet (OR = 2.3; 95% CI: 1.1-4.7, P < 0.05) after adjusting for age and gender. CONCLUSION: The prevalence of anemia was higher in children under 2 years old and requires urgent intervention. An effective intervention strategy should include iron and vitamin B12 supplements, improving dietary diversity and controlling breastfeeding mothers' anemia. PMID- 26488491 TI - Pegfilgrastim for the prevention of chemotherapy-induced febrile neutropenia in patients with solid tumors. AB - INTRODUCTION: Neutropenia and febrile neutropenia are the most common and most severe bone marrow toxicities of chemotherapy. Recombinant granulocyte-colony stimulating factors (G-CSFs), both daily (filgrastim and biosimilars, and lenograstim) and long-acting (pegfilgrastim and lipegfilgrastim) formulations, are currently available to counteract the negative consequences of these side effects. AREAS COVERED: The purpose of this article is to review the physiopathology of chemotherapy-induced febrile neutropenia and its consequences, and the current evidence regarding the pharmacological properties, clinical efficacy and cost-effectiveness of pegfilgrastim as a strategy to prevent chemotherapy-induced febrile neutropenia in patients with solid tumors. EXPERT OPINION: Chemotherapy-induced febrile neutropenia and its complications are still a major health-care concern, and the inappropriate employment of G-CSFs in clinical practice can partially explain its burden. Pegfilgrastim has pharmacological advantages over daily G-CSFs that makes it easily administrable, thus reducing the chance of incorrect delivery. The once-per-cycle administration might explain the findings derived from observational studies suggesting a possible superior efficacy of pegfilgrastim over daily G-CSFs. For patients at higher risk of failure with daily G-CSF prophylaxis (e.g. risk of non-compliance, difficulties on performing regular hemograms, high risk of developing febrile neutropenia), pegfilgrastim might be the most appropriate option. PMID- 26488492 TI - A Novel Electrochemiluminescence Immunosensor for the Analysis of HIV-1 p24 Antigen Based on P-RGO@Au@Ru-SiO2 Composite. AB - Ru(bpy)3(2+)-doped silica (Ru-SiO2) nanoparticles and gold-nanoparticle-decorated graphene (P-RGO@Au) were combined to form a P-RGO@Au@Ru-SiO2 composite. The composite was used to develop a novel sandwich-type electrochemiluminescence immunosensor for the analysis of HIV-1 p24 antigen. The composite worked as carrier to immobilize target antibody and to build a sandwich-type electrochemiluminescence immunosensor through an interaction between antigen and antibody. Importantly, high ECL signal could be obtained due to the large amounts of Ru(bpy)3(2+) molecules per Ru-SiO2 nanoparticle. The P-RGO@Au composite with good conductivity and high surface area not only accelerated the electron transfer rate but also improved the loading of both ECL molecules and capture antibody, which could further increase the ECL response and result in high sensitivity. Taking advantage of both Ru-SiO2 nanoparticles and the P-RGO@Au composite, the proposed immunosensor exhibited a linear range from 1.0 * 10(-9) to 1.0 * 10(-5) mg mL(-1) with a detection limit of 1.0 * 10(-9) mg mL(-1) for HIV-1 p24 antigen. The proposed ECL immunosensor was used to analyze HIV-1 p24 antigen in human serum, and satisfactory recoveries were obtained, indicating that the proposed method is promising for practical applications in the clinical diagnosis of HIV infection. PMID- 26488493 TI - Increased Wounding of Southern Right Whale (Eubalaena australis) Calves by Kelp Gulls (Larus dominicanus) at Peninsula Valdes, Argentina. AB - At least 626 southern right whale (Eubalaena australis) calves died at the Peninsula Valdes calving ground, Argentina, between 2003 and 2014. Intense gull harassment may have contributed to these deaths. In the 1970s, Kelp Gulls (Larus dominicanus) began feeding on skin and blubber pecked from the backs of living right whales at Valdes. The frequency of gull attacks has increased dramatically over the last three decades and mother-calf pairs are the primary targets. Pairs attacked by gulls spend less time nursing, resting and playing than pairs not under attack. In successive attacks, gulls open new lesions on the whales' backs or enlarge preexisting ones. Increased wounding could potentially lead to dehydration, impaired thermoregulation, and energy loss to wound healing. The presence, number and total area of gull-inflicted lesions were assessed using aerial survey photographs of living mother-calf pairs in 1974-2011 (n = 2680) and stranding photographs of dead calves (n = 192) in 2003-2011. The percentage of living mothers and calves with gull lesions increased from an average of 2% in the 1970s to 99% in the 2000s. In the 1980s and 1990s, mothers and calves had roughly equal numbers of lesions (one to five), but by the 2000s, calves had more lesions (nine or more) covering a greater area of their backs compared to their mothers. Living mother-calf pairs and dead calves in Golfo Nuevo had more lesions than those in Golfo San Jose in the 2000s. The number and area of lesions increased with calf age during the calving season. Intensified Kelp Gull harassment at Peninsula Valdes could be compromising calf health and thereby contributing to the high average rate of calf mortality observed in recent years, but it cannot explain the large year-to-year variance in calf deaths since 2000. PMID- 26488494 TI - Workplace Safety Concerns among Co-workers of Responder Returning from Ebola Affected Country. AB - We surveyed public health co-workers regarding attitudes toward a physician who returned to New Hampshire after volunteering in the West African Ebola outbreak. An unexpectedly large (18.0%) proportion of staff expressed discomfort with the Ebola responder returning to work. Employers should take proactive steps to address employee fears and concerns. PMID- 26488495 TI - Self-nanoemulsifying powders for improved oral delivery of poorly water-soluble drugs. PMID- 26488497 TI - Dietary Patterns and Socioeconomic Status in the Very Old: The Newcastle 85+ Study. AB - BACKGROUND: Dietary patterns (DP) are associated with health outcomes in younger adults but there is a lack of evidence in the very old (aged 85+) on DP and their association with sociodemographic factors, lifestyle, health and functioning measures. Higher socioeconomic status (SES) has been linked with healthier DP but it is not known whether these associations are sustained in the very old. OBJECTIVE: We aimed to (a) characterise DP in the very old and (b) assess the relationships between three SES indicators (education, occupational class and area-deprivation index [IMD]) and DP. METHODS: Complete dietary data at baseline (2006/07) for 793 participants in the Newcastle 85+ Study were established through 24-hr multiple pass recall. We used Two-Step clustering and 30 food groups to derive DP, and multinomial logistic regression models to assess the association with SES. RESULTS: We identified three distinct DP (characterised as 'High Red Meat', 'Low Meat', and 'High Butter') that varied with key sociodemographic, health and functioning measures. 'Low Meat' participants were more advantaged (i.e. higher education and occupational class, and lived in more affluent areas in owned homes), were least disabled, cognitively impaired, and depressed, and were more physically active than those in the other DP. After adjusting for other lifestyle factors, cognitive status and BMI, lower educational attainment remained a significant predictor of 'High Red Meat' and 'High Butter' membership compared with 'Low Meat' ('High Red Meat': OR [95% CI] for 0-9 and 10-11 years of education vs. >=12 years: 5.28 [2.85-9.79], p<0.001 and 3.27 [1.65-6.51], p = 0.001, respectively; 'High Butter': 3.32 [1.89-5.82], p<0.001 and 2.83 [1.52-5.28], p = 0.001). CONCLUSIONS: In this cohort of very old adults, we detected a favourable DP ('Low Meat'), which was associated with better health and functioning and higher SES. PMID- 26488499 TI - On-Line Analysis and Kinetic Behavior of Arsenic Release during Coal Combustion and Pyrolysis. AB - The kinetic behavior of arsenic (As) release during coal combustion and pyrolysis in a fluidized bed was investigated by applying an on-line analysis system of trace elements in flue gas. This system, based on inductively coupled plasma optical emission spectroscopy (ICP-OES), was developed to measure trace elements concentrations in flue gas quantitatively and continuously. Obvious variations of arsenic concentration in flue gas were observed during coal combustion and pyrolysis, indicating strong influences of atmosphere and temperature on arsenic release behavior. Kinetic laws governing the arsenic release during coal combustion and pyrolysis were determined based on the results of instantaneous arsenic concentration in flue gas. A second-order kinetic law was determined for arsenic release during coal combustion, and the arsenic release during coal pyrolysis followed a fourth-order kinetic law. The results showed that the arsenic release rate during coal pyrolysis was faster than that during coal combustion. Thermodynamic calculations were carried out to identify the forms of arsenic in vapor and solid phases during coal combustion and pyrolysis, respectively. Ca3(AsO4)2 and Ca(AsO2)2 are the possible species resulting from As Ca interaction during coal combustion. Ca(AsO2)2 is the most probable species during coal pyrolysis. PMID- 26488498 TI - Motor Skill Learning Is Associated with Phase-Dependent Modifications in the Striatal cAMP/PKA/DARPP-32 Signaling Pathway in Rodents. AB - Abundant evidence points to a key role of dopamine in motor skill learning, although the underlying cellular and molecular mechanisms are still poorly understood. Here, we used a skilled-reaching paradigm to first examine changes in the expression of the plasticity-related gene Arc to map activity in cortico striatal circuitry during different phases of motor skill learning in young animals. In the early phase, Arc mRNA was significantly induced in the medial prefrontal cortex (mPFC), cingulate cortex, primary motor cortex, and striatum. In the late phase, expression of Arc did not change in most regions, except in the mPFC and dorsal striatum. In the second series of experiments, we studied the learning-induced changes in the phosphorylation state of dopamine and cAMP regulated phosphoprotein, 32k Da (DARPP-32). Western blot analysis of the phosphorylation state of DARPP-32 and its downstream target cAMP response element binding protein (CREB) in the striatum revealed that the early, but not late, phase of motor skill learning was associated with increased levels of phospho Thr34-DARPP-32 and phospho-Ser133-CREB. Finally, we used the DARPP-32 knock-in mice with a point mutation in the Thr34 regulatory site (i.e., protein kinase A site) to test the significance of this pathway in motor skill learning. In accordance with our hypothesis, inhibition of DARPP-32 activity at the Thr34 regulatory site strongly attenuated the motor learning rate and skilled reaching performance of mice. These findings suggest that the cAMP/PKA/DARPP-32 signaling pathway is critically involved in the acquisition of novel motor skills, and also demonstrate a dynamic shift in the contribution of cortico-striatal circuitry during different phases of motor skill learning. PMID- 26488500 TI - Common Polymorphisms in the NFKBIA Gene and Cancer Susceptibility: A Meta Analysis. AB - BACKGROUND: NFKBIA encodes the inhibitors of nuclear factor-kappaB (NF-kappaB), which regulate the translation of the genes involved in the inflammatory and immune reactions. Polymorphisms (rs2233406, rs3138053, and rs696) of NFKBIA have been implicated in susceptibility to many cancer types. MATERIAL AND METHODS: To evaluate the association between polymorphisms of NFKBIA and cancer susceptibility, a meta-analysis including a total of 7182 cancer cases and 10 057 controls from 28 case-control studies was performed. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Combined data demonstrated that rs3138053 polymorphism of NFKBIA was associated with cancer susceptibility in an allelic model (C vs. T: OR=10.754, 95%CI=4.175-27.697, Pheterogeneity=0.000), while the polymorphism of rs696 appeared to play a protective role in tumorigenesis (CC+CT vs. TT: OR=0.879, 95%CI=0.787-0.982, Pheterogeneity=0.107). When stratification analysis was performed by cancer type, an increased association of rs3138053 was recognized in hepatocarcinoma (C vs. T: OR=42.180, 95%CI=27.970-63.612, Pheterogeneity=0.007), while a decreased association of rs696 was identified in Hodgkin lymphoma (C vs. T: OR=0.792, 95%CI=0.656-0.956, Pheterogeneity=0.116; CC vs. TT: OR=0.658, 95%CI=0.448-0.965, Pheterogeneity=0.076; CC vs. CT+TT: OR=0.734, 95%CI=0.562 0.958, Pheterogeneity=0.347). By ethnicity, rs696 appears to be a protective candidate among Caucasians (CT vs. TT: OR=0.809, 95%CI=0.676-0.969, Pheterogeneity=0.459). CONCLUSIONS: Our data demonstrated that the rs3138053 polymorphism of NFKBIA gene is a candidate for susceptibility to overall cancers, while rs696 plays a protective role. PMID- 26488496 TI - Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer. AB - Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood-brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future. PMID- 26488502 TI - Promotion of Nursing Student Civility in Nursing Education: A Concept Analysis. AB - PURPOSE: Substantive research into the development of civility within nursing education is long overdue. Behaviors learned by nursing students while in the school of nursing transfer to the work environment and culture of nursing. This paper reveals a concept analysis of civility within nursing education using Rodgers' evolutionary concept analysis method. CONCLUSION: Civility is defined to provide clarity for the current terminology of civility within nursing education. Nurse educators must set socially acceptable behavioral expectations in the learning environment, establishing positive interpersonal relationships with students, maintaining moral and academic integrity, and role model civil behaviors. Suggestions are included to help nurse educators outline acceptable behaviors in the learning environment and promote the development of civility. PRACTICE IMPLICATIONS: The development of civil behaviors in nursing students will carry into professional practice after graduation. Civility is necessary to establish meaningful interpersonal relationships, supportive communication, and optimum learning environments to ensure quality patient care with optimum outcomes. Woodworth. PMID- 26488503 TI - Mifepristone With Buccal Misoprostol for Medical Abortion: A Systematic Review. PMID- 26488501 TI - Quantitative Differences in Nuclear beta-catenin and TCF Pattern Embryonic Cells in C. elegans. AB - The Wnt signaling pathway plays a conserved role during animal development in transcriptional regulation of distinct targets in different developmental contexts but it remains unclear whether quantitative differences in the nuclear localization of effector proteins TCF and beta-catenin contribute to context specific regulation. We investigated this question in Caenorhabditis elegans embryos by quantifying nuclear localization of fluorescently tagged SYS-1/beta catenin and POP-1/TCF and expression of Wnt ligands at cellular resolution by time-lapse microscopy and automated lineage tracing. We identified reproducible, quantitative differences that generate a subset of Wnt-signaled cells with a significantly higher nuclear concentration of the TCF/beta-catenin activating complex. Specifically, beta-catenin and TCF are preferentially enriched in nuclei of daughter cells whose parents also had high nuclear levels of that protein, a pattern that could influence developmental gene expression. Consistent with this, we found that expression of synthetic reporters of POP-1-dependent activation is biased towards cells that had high nuclear SYS-1 in consecutive divisions. We identified new genes whose embryonic expression patterns depend on pop-1. Most of these require POP-1 for either transcriptional activation or repression, and targets requiring POP-1 for activation are more likely to be expressed in the cells with high nuclear SYS-1 in consecutive divisions than those requiring POP-1 for repression. Taken together, these results indicate that SYS-1 and POP-1 levels are influenced by the parent cell's SYS-1/POP-1 levels and this may provide an additional mechanism by which POP-1 regulates distinct targets in different developmental contexts. PMID- 26488504 TI - In Reply. PMID- 26488505 TI - Feminism and the Moral Imperative for Contraception. PMID- 26488506 TI - In Reply. PMID- 26488507 TI - Care of the Pregnant Patient With Inflammatory Bowel Disease. PMID- 26488508 TI - In Reply. PMID- 26488509 TI - Trends and Predictors of Cerclage Use in the United States From 2005 to 2012. PMID- 26488510 TI - In Reply. PMID- 26488514 TI - College Publications. PMID- 26488515 TI - ACOG Practice Bulletin No. 154 Summary: Operative Vaginal Delivery. PMID- 26488516 TI - ACOG Practice Bulletin No. 155 Summary: Urinary Incontinence in Women. PMID- 26488517 TI - ACOG Obstetric Care Consensus No. 3 Summary: Periviable Birth. AB - Approximately 0.5% of all births occur before the third trimester of pregnancy, and these very early deliveries result in the majority of neonatal deaths and more than 40% of infant deaths. A recent executive summary of proceedings from a joint workshop defined periviable birth as delivery occurring from 20 0/7 weeks to 25 6/7 weeks of gestation. When delivery is anticipated near the limit of viability, families and health care teams are faced with complex and ethically challenging decisions. Multiple factors have been found to be associated with short-term and long-term outcomes of periviable births in addition to gestational age at birth. These include, but are not limited to, nonmodifiable factors (eg, fetal sex, weight, plurality), potentially modifiable antepartum and intrapartum factors (eg, location of delivery, intent to intervene by cesarean delivery or induction for delivery, administration of antenatal corticosteroids and magnesium sulfate), and postnatal management (eg, starting or withholding and continuing or withdrawing intensive care after birth). Antepartum and intrapartum management options vary depending upon the specific circumstances but may include short-term tocolytic therapy for preterm labor to allow time for administration of antenatal steroids, antibiotics to prolong latency after preterm premature rupture of membranes or for intrapartum group B streptococci prophylaxis, and delivery, including cesarean delivery, for concern regarding fetal well-being or fetal malpresentation. Whenever possible, periviable births for which maternal or neonatal intervention is planned should occur in centers that offer expertise in maternal and neonatal care and the needed infrastructure, including intensive care units, to support such services. This document describes newborn outcomes after periviable birth, provides current evidence and recommendations regarding interventions in this setting, and provides an outline for family counseling with the goal of incorporating informed patient preferences. Its intent is to provide support and guidance regarding decisions, including declining and accepting interventions and therapies, based on individual circumstances and patient values. PMID- 26488518 TI - ACOG Committee Opinion No. 645 Summary: Dual Therapy for Gonococcal Infections. AB - Gonorrhea is the second most commonly reported bacterial sexually transmitted disease in the United States, with an estimated 820,000 new Neisseria gonorrhoeae infections occurring each year. Antimicrobial resistance limits treatment success, heightens the risk of complications, and may facilitate the transmission of sexually transmitted infections. Neisseria gonorrhoeae has developed resistance to the sulfonamides, the tetracyclines, and penicillin. Dual therapy with ceftriaxone and azithromycin remains the only recommended first-line regimen for the treatment of gonorrhea in the United States. Dual therapy with ceftriaxone and azithromycin should be administered together on the same day, preferably simultaneously, and under direct observation. Pregnant women who are infected with N gonorrhoeae should be treated with the recommended dual therapy. A test-of-cure is not needed for individuals diagnosed with uncomplicated urogenital or rectal gonorrhea who are treated with the recommended or alternative regimens. Repeat N gonorrhoeae infection is prevalent among patients who have been diagnosed with and treated for gonorrhea in the preceding several months. Most of these infections result from reinfection; therefore, clinicians should advise patients with gonorrhea to be retested 3 months after treatment. Pregnant women with antenatal gonococcal infection should be retested in the third trimester unless recently treated. PMID- 26488519 TI - ACOG Committee Opinion No. 646 Summary: Ethical Considerations for Including Women as Research Participants. AB - Inclusion of women in research studies is necessary for valid inferences about health and disease in women. The generalization of results from trials conducted in men may yield erroneous conclusions that fail to account for the biologic differences between men and women. Although significant changes in research design and practice have led to an increase in the proportion of women included in research trials, knowledge gaps remain because of a continued lack of inclusion of women, especially those who are pregnant, in premarketing research trials. This document provides a historical overview of issues surrounding women as participants in research trials, followed by an ethical framework and discussion of the issues of informed consent, contraception requirements, intimate partner consent, and the appropriate inclusion of pregnant women in research studies. PMID- 26488520 TI - ACOG Committee Opinion No. 647 Summary: Limitations of Perineal Lacerations as an Obstetric Quality Measure. AB - Perineal lacerations are a common occurrence with vaginal delivery. Although perineal lacerations are tracked easily from coding data, there are a variety of problems with using rates of such tears as a quality measure. The rate of severe perineal lacerations should not be used as a measure of obstetric quality for the following three reasons: 1) third-degree and fourth-degree perineal lacerations may not be defined uniformly; 2) severe perineal lacerations are associated strongly with nonmodifiable risk factors; and 3) diminishing the use of operative vaginal delivery, in an effort to decrease severe perineal lacerations, likely would result in an increased rate of cesarean delivery. Measuring the rate of episiotomy with unassisted vaginal deliveries is an alternative candidate for quality measurement, but it requires validation before widespread implementation. PMID- 26488521 TI - ACOG Committee Opinion No. 646: Ethical Considerations for Including Women as Research Participants. AB - Inclusion of women in research studies is necessary for valid inferences about health and disease in women. The generalization of results from trials conducted in men may yield erroneous conclusions that fail to account for the biologic differences between men and women. Although significant changes in research design and practice have led to an increase in the proportion of women included in research trials, knowledge gaps remain because of a continued lack of inclusion of women, especially those who are pregnant, in premarketing research trials. This document provides a historical overview of issues surrounding women as participants in research trials, followed by an ethical framework and discussion of the issues of informed consent, contraception requirements, intimate partner consent, and the appropriate inclusion of pregnant women in research studies. PMID- 26488522 TI - ACOG Committee Opinion No. 647: Limitations of Perineal Lacerations as an Obstetric Quality Measure. AB - Perineal lacerations are a common occurrence with vaginal delivery. Although perineal lacerations are tracked easily from coding data, there are a variety of problems with using rates of such tears as a quality measure. The rate of severe perineal lacerations should not be used as a measure of obstetric quality for the following three reasons: 1) third-degree and fourth-degree perineal lacerations may not be defined uniformly; 2) severe perineal lacerations are associated strongly with nonmodifiable risk factors; and 3) diminishing the use of operative vaginal delivery, in an effort to decrease severe perineal lacerations, likely would result in an increased rate of cesarean delivery. Measuring the rate of episiotomy with unassisted vaginal deliveries is an alternative candidate for quality measurement, but it requires validation before widespread implementation. PMID- 26488523 TI - ACOG Practice Bulletin No. 154: Operative Vaginal Delivery. PMID- 26488524 TI - ACOG Practice Bulletin No. 155: Urinary Incontinence in Women. PMID- 26488525 TI - ACOG Obstetric Care Consensus No. 3: Periviable Birth. AB - Approximately 0.5% of all births occur before the third trimester of pregnancy, and these very early deliveries result in the majority of neonatal deaths and more than 40% of infant deaths. A recent executive summary of proceedings from a joint workshop defined periviable birth as delivery occurring from 20 0/7 weeks to 25 6/7 weeks of gestation. When delivery is anticipated near the limit of viability, families and health care teams are faced with complex and ethically challenging decisions. Multiple factors have been found to be associated with short-term and long-term outcomes of periviable births in addition to gestational age at birth. These include, but are not limited to, nonmodifiable factors (eg, fetal sex, weight, plurality), potentially modifiable antepartum and intrapartum factors (eg, location of delivery, intent to intervene by cesarean delivery or induction for delivery, administration of antenatal corticosteroids and magnesium sulfate), and postnatal management (eg, starting or withholding and continuing or withdrawing intensive care after birth). Antepartum and intrapartum management options vary depending upon the specific circumstances but may include short-term tocolytic therapy for preterm labor to allow time for administration of antenatal steroids, antibiotics to prolong latency after preterm premature rupture of membranes or for intrapartum group B streptococci prophylaxis, and delivery, including cesarean delivery, for concern regarding fetal well-being or fetal malpresentation. Whenever possible, periviable births for which maternal or neonatal intervention is planned should occur in centers that offer expertise in maternal and neonatal care and the needed infrastructure, including intensive care units, to support such services. This document describes newborn outcomes after periviable birth, provides current evidence and recommendations regarding interventions in this setting, and provides an outline for family counseling with the goal of incorporating informed patient preferences. Its intent is to provide support and guidance regarding decisions, including declining and accepting interventions and therapies, based on individual circumstances and patient values. PMID- 26488526 TI - ACOG Committee Opinion No. 645: Dual Therapy for Gonococcal Infections. AB - Gonorrhea is the second most commonly reported bacterial sexually transmitted disease in the United States, with an estimated 820,000 new Neisseria gonorrhoeae infections occurring each year. Antimicrobial resistance limits treatment success, heightens the risk of complications, and may facilitate the transmission of sexually transmitted infections. Neisseria gonorrhoeae has developed resistance to the sulfonamides, the tetracyclines, and penicillin. Dual therapy with ceftriaxone and azithromycin remains the only recommended first-line regimen for the treatment of gonorrhea in the United States. Dual therapy with ceftriaxone and azithromycin should be administered together on the same day, preferably simultaneously, and under direct observation. Pregnant women who are infected with N gonorrhoeae should be treated with the recommended dual therapy. A test-of-cure is not needed for individuals diagnosed with uncomplicated urogenital or rectal gonorrhea who are treated with the recommended or alternative regimens. Repeat N gonorrhoeae infection is prevalent among patients who have been diagnosed with and treated for gonorrhea in the preceding several months. Most of these infections result from reinfection; therefore, clinicians should advise patients with gonorrhea to be retested 3 months after treatment. Pregnant women with antenatal gonococcal infection should be retested in the third trimester unless recently treated. PMID- 26488527 TI - The cardiovascular status of isoflurane-anaesthetized horses with and without dexmedetomidine constant rate infusion evaluated at equivalent depths of anaesthesia. AB - OBJECTIVE: To compare cardiac index and oxygen extraction at equivalent depths of anaesthesia between isoflurane-anaesthetized horses and horses anesthetized with isoflurane and dexmedetomidine CRI. STUDY DESIGN: Sequential, blinded, randomized, balanced, crossover study. ANIMALS: Eight horses weighing a mean +/- standard deviation of 478 +/- 58 kg. METHODS: Horses were premedicated with 0.03 mg kg(-1) acepromazine intramuscularly (IM) and 8 MUg kg(-1) dexmedetomidine intravenously (IV). Anaesthesia was induced with 2.5 mg kg(-1) ketamine and 0.1 mg kg(-1) midazolam IV and maintained with isoflurane in oxygen and air. Horses were mechanically ventilated. Fractional concentration of end-tidal isoflurane (Fe'Iso) was stabilized at 1.7% with a CRI of 0.9% NaCl (IsoNaCl), or at 1.1% with 1.75 MUg kg(-1) hour(-1) dexmedetomidine (IsoDex). Mean arterial blood pressure was maintained above 60 mmHg by dobutamine infusion. Following nociceptive electrical stimulation, Fe'Iso was stabilized at a 0.1% lower concentration and nociceptive stimulation was repeated. This procedure was continued until the horse moved. Fe'Iso values prior to the concentration at which movement occurred were considered to indicate equivalent depths of anaesthesia between treatments. Cardiac index and oxygen extraction were compared at equivalent depths of anaesthesia using a paired Student's t-test. RESULTS: Cardiac index differed between IsoNaCl at 61 +/- 12 mL kg(-1) minute(-1) and IsoDex at 48 +/- 10 mL kg(-1) minute(-1) (p = 0.047). In addition, oxygen extraction differed between IsoNaCl at 3.4 +/- 0.8 mL kg(-1) minute(-1) and IsoDex at 4.5 +/- 0.5 mL kg(-1) minute(-1) (p = 0.0042). Two horses receiving IsoNaCl were administered dobutamine at equivalent depths of anaesthesia (7.0 and 28.8 MUg kg(-1) hour(-1) , respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Cardiovascular function in horses receiving isoflurane and 1.75 MUg kg(-1) minute(-1) dexmedetomidine is more compromised than in horses receiving a higher concentration of isoflurane and 0.9% NaCl CRI. PMID- 26488528 TI - Practice patterns and organizational commitment of inpatient nurse practitioners. AB - PURPOSE: Nurse practitioners (NPs) deliver a wide array of healthcare services in a variety of settings. The purpose of this study was to examine the practice patterns and organizational commitment of inpatient NPs. METHODS: A quantitative design was used with a convenience sample (n = 183) of NPs who attended the American Association of Nurse Practitioners (AANP) national conference. The NPs were asked to complete a demographic questionnaire, the Practice Patterns of Acute Nurse Practitioners tool and the Organizational Commitment Questionnaire. CONCLUSIONS: Over 85% of inpatient practice time consists of direct and indirect patient care activities. The remaining nonclinical activities of education, research, and administration were less evident in the NP's workweek. This indicates that the major role of inpatient NPs continues to be management of acutely ill patients. Moderate commitment was noted in the Organizational Commitment Questionnaire. IMPLICATIONS FOR PRACTICE: Supportive hospital/nursing leadership should acknowledge the value of the clinical and nonclinical roles of inpatient NPs as they can contribute to the operational effectiveness of their organization. By fostering the organizational commitment behaviors of identification, loyalty, and involvement, management can reap the benefits of these professionally dedicated providers. PMID- 26488529 TI - The Expendables: Natural selection driving reduced gene function (Comment on DOI 10.1002/bies.201500083). PMID- 26488531 TI - Alemtuzumab, Fludarabine, Low-Dose TBI, and Double Umbilical Cord Transplant for Primary Graft Failure in a Patient with Recurrent HLH. AB - Graft failure occurs at relatively low frequency, but commonly in hemophagocytic lymphohistiocytosis (HLH), especially with umbilical cord blood transplant (UCBT). No standard approaches to management of graft failure exist. We present a challenging case of relapsed HLH following first UCBT with primary graft failure following second UCBT. We report a novel reduced intensity conditioning regimen of alemtuzumab, 4 Gy total body irradiation and fludarabine for salvage of primary graft failure followed by double UCBT. The reported patient successfully engrafted with 100% donor chimerism following salvage UCBT with no occurrence of acute or chronic graft-versus-host disease. PMID- 26488532 TI - Chronic nasal dysfunction in children: Allergic rhinitis? Infectious? What to do if neither? AB - PURPOSE OF REVIEW: To review challenges in the diagnosis, work-up, and management of healthy children who present to the otolaryngologist with nasal dysfunction. Common symptoms include chronic nasal congestion, with or without rhinorrhea, with or without previous empirically treated 'allergic rhinitis' and/or 'sinus' infection. Symptoms are often unresolved despite chronic use of intranasal steroid, antihistamine, and/or leukotriene receptor antagonists. RECENT FINDINGS: There are no published studies addressing nasal symptoms in children who test negative for allergies yet report persistent nasal obstruction, congestion, and/or rhinorrhea. Recent publications continue to address efficacy of medical and/or surgical treatment for allergic rhinitis or acute/chronic rhinosinusitis. Best practice for children who 'fail' medical therapy but have impaired quality of life because of nasal dysfunction remains unknown. SUMMARY: Chronic nasal symptoms are common in childhood despite daily treatment using intranasal steroid, antihistamines, and/or leukotriene receptor antagonist therapies. Diet and dietary habit history should be included during evaluation and differential diagnosis as excessive dairy and sugar may contribute to chronic symptoms. Children who fail medical therapy for persistent nasal symptoms, allergic or not, should be referred and considered for outfracture of inferior turbinates and inferior turbinoplasty. Turbinate reduction procedures have demonstrated significant improvement in all domains of SinoNasal Quality of Life as measured by 'SN-5' survey. PMID- 26488533 TI - Pediatric otolaryngology, molecular diagnosis of hereditary hearing loss: next generation sequencing approach. AB - PURPOSE OF REVIEW: Sensorineural hearing loss (SNHL) is the most common sensory birth defect. The purpose of this article is to review the advances in next generation sequencing (NGS) and molecular diagnosis of hereditary hearing loss. RECENT FINDINGS: Early diagnosis and detection of SNHL is critical for the development of appropriate speech and language, as neuroplasticity peaks in the first few years of life. There has been increased accuracy of NGS genetic testing, which has helped created a paradigm shift in the diagnosis of hearing loss. The diagnostic yield of genetic testing now approaches that of radiographic imaging; however, there remains a difference in cost and time delay. With the introduction of comprehensive genetic panels, 23-129 genes can be sequenced from the same blood sample. SUMMARY: Diagnostic genetic testing of SNHL in the past has been confined to a few genes through Sanger sequencing. The advent of NGS allows for development of comprehensive genetic panels, which test for up to 129 genes while improving the accuracy and efficiency of testing. This type of testing may become more common as the costs decrease and more genes are discovered. PMID- 26488534 TI - Perspectives in the reconstruction of paediatric facial paralysis. AB - PURPOSE OF REVIEW: In this review article, aimed at those likely to encounter but relatively unfamiliar with paediatric facial paralysis, we summarize reconstructive options in its surgical management. RECENT FINDINGS: The article looks at static and dynamic reconstructions available to address the problems encountered in the different anatomical regions of paralyzed face. SUMMARY: Although multiple surgical options are available for each anatomical region, decision-making should be taken in a multidisciplinary environment, and take into account the individual requirements of the family and patients. PMID- 26488535 TI - Adult obstructive sleep apnoea and the larynx. AB - PURPOSE OF REVIEW: The review examines current evidence and thinking regarding the relationship between the larynx and obstructive sleep apnoea (OSA) in adults. RECENT FINDINGS: Drug-induced sleep endoscopy has an emerging role in the identification of laryngeal obstruction associated with sleep apnoea and may be adjunctive to awake dynamic assessment in specific cases. Nocturnal stridor and OSA is a common and treatable finding in patients with multiple system atrophy. Acromegaly can cause OSA by obstruction at the laryngeal level via supraglottic soft tissue hypertrophy or decreased vocal fold mobility. Emerging evidence suggests a relationship between OSA, laryngopharyngeal reflux, and laryngeal sensory dysfunction including chronic cough. The mechanisms remain unclear and warrant further investigation. SUMMARY: The larynx plays an important role in assessment and treatment of adult sleep apnoea. Laryngeal afferent sensory pathways play a critical role in reflexes controlling airway patency during sleep. Airway obstruction at the laryngeal level should be considered and assessed especially in OSA patients nonresponsive to standard therapies. Isolated laryngeal airway obstruction is rare but identification of specific conditions is important as they are amenable to appropriate treatments. OSA can also affect normal laryngeal function. People with OSA exhibit higher levels of laryngeal inflammation, laryngopharyngeal reflux, and chronic cough. Treatment with continuous positive airway pressure has a potential role in improving laryngeal symptomatology in these cases. PMID- 26488536 TI - Stabilization of ultrafine metal nanocatalysts on thin carbon sheets. AB - A novel strategy was proposed to anchor ultrafine metal nanoparticles (NPs) on thin carbon sheets for highly stable and efficient heterogeneous catalysts. In this facile approach, a dense monolayer of ultrafine AuNPs was sandwiched between a silica core and a resin shell, followed by carbonization of the shell at a high temperature and then selective removal of the silica core. The shrinkage of the shells during carbonization facilitates partial embedment of the AuNPs on the carbon shell surface and provides superior stability against particle sintering during high temperature/mechanical post-treatments and catalytic reactions. It was also found that diffusion of reactants to the surface of AuNPs could be maximized by reducing the thickness of the hollow shells or simply by cracking the shells into thin carbon sheets, both significantly benefiting the catalytic efficiency. The advantages of this ultra-stable architecture together with the densely dispersed catalytic sites were demonstrated by their high stability and superior catalytic activity in reducing hydrophilic 4-nitrophenol and hydrophobic nitrobenzene. PMID- 26488537 TI - Technique profile: mesenteric reconstructions for occlusive disease. AB - Visceral ischemic syndromes are rare but catastrophic disorders. In acute presentations, treatment modalities include thrombolytic therapy, open surgical revascularization and percutaneous endovascular therapy. Endovascular therapy has become the most commonly utilized treatment option for chronic mesenteric ischemia and should be considered the first line of therapy for patients with anatomically suitable lesions or excessive open surgical risk. Open surgical revascularization has been associated with outstanding long-term outcomes. The various surgical and endovascular techniques and their associated outcomes for the treatment of mesenteric ischemic syndromes are reviewed in detail. PMID- 26488538 TI - Synthesis and properties of mono- and dimetal Fischer multicarbene complexes derived from thiophene and thieno[2,3-b]thiophene. AB - Access to multicarbene complexes of a fused thienothiophene substrate was obtained by the use of the tetrabrominated thieno[2,3-b]thiophene precursor in a lithium-bromide exchange reaction, followed by nucleophilic attack on metal hexacarbonyls (M = Cr, W). Subsequent alkylation afforded unique triscarbene complexes [M(CO)4{{C(OEt)}2C6H1S2C(OEt)}M(CO)5] (M = Cr 12, W 13) featuring three non-equivalent carbene ligands on a single thiophene linker, as well as the bischelated tetracarbene complexes [M(CO)4{{C(OEt)}2C6S2{C(OEt)}2}M(CO)4] (M = Cr 14, W 15). The triscarbene complexes 12 and 13 are the first examples of multi alkoxycarbene complexes featuring three non-equivalent carbene ligands. The reaction also afforded the chelated mononuclear biscarbene complexes [M(CO)4{C(OEt)}2C6H2S2] (M = Cr 10, W 11) in low yields. Similarly, employing tetrabromothiophene as precursor yielded the mononuclear chelate biscarbene complexes [M(CO)4{C(OEt)}2C4H2S] (M = Cr 6, W 7) and the dinuclear tetracarbene complexes [M(CO)4{{C(OEt)}2C4S{C(OEt)}2}M(CO)4] (M = Cr 8, W 9). Modification of the classic Fischer carbene synthetic methodology to a process of stepwise additions of lithiating agent and metal carbonyls to thieno[2,3-b]thiophene, facilitates the formation of the mixed metal biscarbene complex [W(CO)5C(OEt){C6H2S2}C(OEt)Cr(CO)5] 5, as analogue of the homonuclear biscarbene complexes [M(CO)5C(OEt){C6H2S2}C(OEt)M(CO)5], (M = Cr 3, W 4). The monocarbene complexes [M(CO)5{C(OEt)C6H3S2}], (M = Cr 1, W 2) were also obtained in high yields, and the molecular structures of the tungsten complexes, with the exception of 9 and 11, were confirmed by single crystal X-ray diffraction studies. PMID- 26488540 TI - Practical Solutions for Pesticide Safety: A Farm and Research Team Participatory Model. AB - Development of the Practical Solutions for Pesticide Safety guide used participatory research strategies to identify and evaluate solutions that reduce pesticide exposures for workers and their families and to disseminate these solutions. Project principles were (1) workplace chemicals belong in the workplace, and (2) pesticide handlers and farm managers are experts, with direct knowledge of production practices. The project's participatory methods were grounded in self-determination theory. Practical solutions were identified and evaluated based on five criteria: practicality, adaptability, health and safety, novelty, and regulatory compliance. Research activities that had more personal contact provided better outcomes. The Expert Working Group, composed of farm managers and pesticide handlers, was key to the identification of solutions, as were farm site visits. Audience participation, hands-on testing, and orchard field trials were particularly effective in the evaluation of potential solutions. Small work groups in a Regional Advisory Committee provided the best direction and guidance for a "user-friendly" translational document that provided evidence-based practical solutions. The "farmer to farmer" format of the guide was endorsed by both the Expert Working Group and the Regional Advisory Committee. Managers and pesticide handlers wanted to share their solutions in order to "help others stay safe," and they appreciated attribution in the guide. The guide is now being used in educational programs across the region. The fundamental concept that farmers and farmworkers are innovators and experts in agricultural production was affirmed by this study. The success of this process demonstrates the value of participatory industrial hygiene in agriculture. PMID- 26488541 TI - Anharmonicities and coherent vibrational dynamics of phosphate ions in bulk H2O. AB - Phosphates feature prominently in the energetics of metabolism and are important solvation sites of DNA and phospholipids. Here we investigate the ion H2PO4(-) in aqueous solution combining 2D IR spectroscopy of phosphate stretching vibrations in the range from 900-1300 cm(-1) with ab initio calculations and hybrid quantum classical molecular dynamics based simulations of the non-linear signal. While the line shapes of diagonal peaks reveal ultrafast frequency fluctuations on a sub-100 fs timescale caused by the fluctuating hydration shell, an analysis of the diagonal and cross-peak frequency positions allows for extracting inter-mode couplings and anharmonicities of 5-10 cm(-1). The excitation with spectrally broad pulses generates a coherent superposition of symmetric and asymmetric PO2( ) stretching modes resulting in the observation of a quantum beat in aqueous solution. We follow its time evolution through the time-dependent amplitude and the shape of the cross peaks. The results provide a complete characterization of the H2PO4(-) vibrational Hamiltonian including fluctuations induced by the native water environment. PMID- 26488542 TI - The soot of all evil. AB - Nanoparticles of carbon black in cigarette smoke trigger inflammation in the lung. PMID- 26488543 TI - TGF-beta improves myocardial function and prevents apoptosis induced by anoxia reoxygenation, through the reduction of endoplasmic reticulum stress. AB - BACKGROUND: Transforming growth factor-beta (TGF-beta) is known for its role in ventricular remodeling, inflammatory response, cell survival, and apoptosis. However, its role in improving myocardial function in rat hearts subjected to ischemia-reperfusion (I/R) and protecting against apoptosis induced in cardiomyocytes by anoxia-reoxygenation (A/R) has not been elucidated. This study investigated the protective effects and molecular mechanisms of TGF-beta on myocardial function and cardiomyocyte apoptosis. METHODS AND RESULTS: We used TUNEL staining, we tested cell viability, and we measured mitochondrial membrane potential and levels of mitochondrial ROS after 6 h of simulated anoxia together with various durations of simulated reoxygenation in H9c2 cells. We further observed the contractile function in rat hearts after they were subjected to 30 min global ischemia and 180 min reperfusion. Pretreatment with TGF-beta markedly inhibited apoptosis in H9c2 cells, as evidenced by increased cell viability and decreased numbers of TUNEL-positive cells, maintained mitochondrial membrane potential, and diminished mitochondrial production of reactive oxygen species (ROS). These changes were associated with the inhibition of endoplasmic reticulum (ER) stress-dependent markers of apoptosis (GRP78, CHOP, caspase-12, and JNK), and the modulation of the expression of Bcl2/Bax. Furthermore, TGF-beta improved I/R-induced myocardial contractile dysfunction. All of these protective effects were concentration-dependent. CONCLUSION: Our results show that TGF-beta prevents A/R-induced apoptosis of cardiomyocytes and improves myocardial function in rat hearts injured by I/R. PMID- 26488544 TI - IN MEMORIAM: REMEMBERING ALIES MUSKIN. PMID- 26488547 TI - Conjugation of Hyaluronic Acid onto Surfaces via the Interfacial Polymerization of Dopamine to Prevent Protein Adsorption. AB - A versatile, convenient, and cost-effective method that can be used for grafting antifouling materials onto different surfaces is highly desirable in many applications. Here, we report the one-step fabrication of antifouling surfaces via the polymerization of dopamine and the simultaneous deposition of anionic hyaluronic acid (HA) on Au substrates. The water contact angle of the Au surfaces decreased from 84.9 degrees to 24.8 degrees after the attachment of a highly uniform polydopamine (PDA)/HA hybrid film. The results of surface plasmon resonance analysis showed that the Au-PDA/HA surfaces adsorbed proteins from solutions of bovine serum albumin, lysozyme, beta-lactoglobulin, fibrinogen, and soybean milk in ultralow or low amounts (4.8-31.7 ng/cm(2)). The hydrophilicity and good antifouling performance of the PDA/HA surfaces is attributable to the HA chains that probably attached onto their upper surface via hydrogen bonding between PDA and HA. At the same time, the electrostatic repulsion between PDA and HA probably prevents the aggregation of PDA, resulting in the formation of a highly uniform PDA/HA hybrid film with the HA chains (with a stretched structure) on the upper surface. We also developed a simple method for removing this PDA/HA film and recycling the Au substrates by using an aqueous solution of NaOH as the hydrolyzing agent. The Au surface remained undamaged, and a PDA/HA film could be redeposited on the surface, with the surface exhibiting good antifouling performance even after 10 such cycles. Finally, it was found that this grafting method is applicable to other substrates, including epoxy resins, polystyrene, glass, and steel, owing to the strong adhesion of PDA with these substrates. PMID- 26488548 TI - Sulfonamide and Tertiary Amine as Nucleophiles in Pd(II)-Catalyzed Diamination of Alkynes: Synthesis of Tetracyclic Indolobenzothiazine S,S-Dioxides. AB - Pd(II)-catalyzed oxidative double cyclization of the 1,2-diarylethynes bearing an N-methyl-N-(2-methoxycarbonyl)ethylamino and an aminosulfonyl group afforded indolobenzothiazine S,S-dioxides in good to excellent yields. The 2 (methoxycarbonyl)ethyl group attached to the indolyl nitrogen is readily removed under basic conditions (DBU, DMF, 120 degrees C) to provide the corresponding tetracycles with a free indolyl nitrogen in excellent yields. PMID- 26488549 TI - Heat shock protein 72 (Hsp72) specific induction and temporal stability in urine samples as a reliable biomarker of acute kidney injury (AKI). AB - We demonstrated that urinary heat shock protein of 72 KDa (Hsp72) is a sensitive biomarker for the early detection of acute kidney injury (AKI). However, whether Hsp72 induction during an AKI episode is kidney-specific is unknown, as well as, the degree of Hsp72 stability in urine samples. In rats that underwent bilateral renal ischemia and reperfusion (I/R), Hsp72 levels were evaluated in several tissues and in collected urines under different storage and temperature conditions, as well as in variable numbers of freeze-thaw cycles. The effect of room temperature and five freeze-thaw cycles on urinary Hsp72 levels was also evaluated in urine samples from AKI patients. We found that Hsp72 increased exclusively in the renal cortex of I/R group, emphasizing its performance as an AKI biomarker. Urinary-Hsp72 remained constant at room temperature (48 h), during 9 months of storage and was not affected by five freeze/thaw cycles. PMID- 26488550 TI - Does lipophilicity affect the effectiveness of a transmembrane anion transporter? Insight from squaramido-functionalized bis(choloyl) conjugates. AB - Six squaramido-functionalized bis(choloyl) conjugates were synthesized and fully characterized on the basis of NMR ((1)H and (13)C) and ESI MS (LR and HR) data. Their transmembrane anionophoric activity was investigated in detail by means of chloride ion selective electrode technique and pyranine assay. The data indicate that this set of compounds is capable of promoting the transmembrane transport of anions presumably via proton/anion symport and anion exchange processes, and that lipophilicity in terms of clog P from 3.90 to 8.32 affects the apparent ion transport rate in a concentration-dependent fashion. Detailed kinetic analysis on the data obtained from both the chloride efflux and pH discharge experiments reveals that there may exist an optimum clog P range for the intrinsic ion transport rate. However, lipophilicity exhibits little effect on the effectiveness of this set of compounds in terms of either k2/Kdiss or EC50 values. PMID- 26488551 TI - Molecular Tectonics: Design of Enantiopure Luminescent Heterometallic Ir(III) Cd(II) Coordination Network. AB - With the aim of combining luminescence and chirality in heterometallic Ir(III) Cd(II) coordination networks, synthetic strategies for the formation of new Ir(III)-based chiral metallatectons ([Ir(dFppy)2(1)][PF6]), both as a racemic mixture of Delta and Lambda enantiomers (rac-[Ir(dFppy)2(1)][PF6]) and as enantiopure complexes (Delta-[Ir(dFppy)2(1)][PF6] and Lambda [Ir(dFppy)2(1)][PF6]), were developed. The final compounds were characterized both in solution and in the crystalline phase. Notably, their crystal structures were determined by single crystal X-ray diffraction, and their photophysical properties in solution and in the solid state were investigated. Combination of the cationic linear metallatecton with Cd(2+) iodide salt ([CdI3](-)), behaving as an anionic two-connecting node, leads to the formation of 1D chiral and neutral heterometallic Ir(III)-Cd(II) luminescent coordination networks both as a racemic mixture and as enantiomerically pure infinite architectures. The latter have been structurally studied in the solid state by X-ray diffraction both on single crystals and on microcrystalline powders. The infinite coordination networks display phosphorescence in the solid state at ca. 600 nm upon excitation at 400 nm. PMID- 26488552 TI - Inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model. AB - BACKGROUND: Increased bilirubin production due to hemolysis can lead to neonatal hyperbilirubinemia. Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, by metalloporphyrins (Mps) may be an ideal preventive strategy for neonatal hemolytic disease. Zinc protoporphyrin (ZnPP) is a naturally occurring Mp, potent, not phototoxic, with minimal HO-1 upregulation, but is not orally absorbed. Recently, we designed a lipid-based ZnPP formulation (ZnPP-Lipid), which is orally absorbed by newborn mice. Here, we evaluated the efficacy of ZnPP-Lipid in heme-loaded newborn mice, a model analogous to hemolytic infants. METHODS: After 24 h of heme administration (30 umol/kg s.c.), 4-d-old mice were given 30 umol ZnPP-Lipid/kg via intragastric injections. After 3 h, liver and brain HO activity were measured. HO-1 upregulation was assessed by determinations of HO-1 protein, promoter activity, and mRNA by Western blot, in vivo bioluminescence imaging, and RT-PCR, respectively. RESULTS: After heme loading, liver HO activity significantly increased ~1.6-fold, which was inhibited in a dose-dependent manner by ZnPP-Lipid. A dose of 30 umol/kg returned activity to control levels. Brain HO activity was not inhibited. No significant increases in liver and brain HO-1 protein, promoter activity, and mRNA were observed. CONCLUSION: ZnPP-Lipid is effective and thus has potential for treating neonatal hyperbilirubinemia due to hemolysis. PMID- 26488553 TI - Dummy/pacifier use in preterm infants increases blood pressure and improves heart rate control. AB - BACKGROUND: Preterm infants are at increased risk of sudden infant death syndrome (SIDS). Use of a dummy/pacifier is thought to be protective against SIDS; accordingly, we assessed the effects of dummy/pacifier use on blood pressure, cerebral oxygenation, and heart rate control over the first 6 mo of life after term corrected age (CA) when SIDS risk is greatest. METHODS: Thirty-five preterm infants were studied longitudinally at 2-4 wk, 2-3 mo, and 5-6 mo CA. Cardiac control was assessed from spectral indices of heart rate variability (HRV) in the low frequency (LF) and the high frequency (HF) range, and the ratio of HF/LF indicating sympathovagal balance was calculated. RESULTS: Overall, at 2-3 mo, mean arterial pressure was significantly higher in the supine position in dummy/pacifier users in both quiet sleep (70 +/- 2 vs. 60 +/- 2 mm Hg; P < 0.05) and active sleep (74 +/- 3 vs. 69 +/- 2 mm Hg; P < 0.05). Dummy/pacifier users had higher LF HRV and LF/HF ratio and lower HF HRV. CONCLUSION: Dummy/pacifier use increased blood pressure during sleep, at the age of greatest SIDS risk. Overall, LF HRV was elevated and HF HRV reduced in dummy/pacifier users, suggesting that dummy use alters cardiac control in preterm infants. PMID- 26488554 TI - Seasonal variations in growth and body composition of 8-11-y-old Danish children. AB - BACKGROUND: Earlier studies on seasonality in growth reported the largest height gains during spring and largest body weight gains during autumn. We examined seasonality in height, body weight, BMI, fat mass index (FMI), and fat-free mass index (FFMI) among contemporary Danish 8-11-y olds. METHODS: A total of 760 children from the OPUS School Meal Study provided >2,200 measurements on height, body weight, and composition between September and June. Average velocities were calculated using change-score analyses based on 3-mo intervals. As a complementary analysis, point velocities derived from estimated growth curves were fitted using semiparametric regression that included covariate adjustment and allowed flexible modeling of the time trend. RESULTS: Average velocities showed the following trends: height was higher than the average (6.10 cm/y) in January-April. Body weight was below the average (4.02 kg/y) in August-January and above in January-May; BMI (average: 0.49 kg/ m(2)/y) and FFMI (average: 0.17 kg/m(2)/y) showed similar trends. In contrast, FMI was above the average (0.38 kg/m(2)/y) in November-March. Similar trends were seen for point velocities. CONCLUSION: Our findings suggest seasonality in growth and body composition of Danish children. We recovered the well-known height velocity peak during spring time, but unlike earlier studies, we found coincident peaks in body weight, BMI, and FFMI velocities. PMID- 26488556 TI - Multidrug-Resistant Tuberculosis in Child Successfully Treated with 9-Month Drug Regimen. PMID- 26488555 TI - Insomnia Symptoms Are Associated With Abnormal Endothelial Function. AB - BACKGROUND: Insomnia is a prevalent sleep disorder, and it has been increasingly associated with cardiovascular morbidity and mortality. The reasons for this relationship are not completely understood but may involve endothelial dysfunction. In this study, we hypothesized that insomnia symptoms would be associated with reduced endothelial function. METHODS: Working adults (n = 496, 67.5% female, 78.6% white, mean age 48.7 [SD, 10.8] years, body mass index 28.2 [SD, 6.7] kg/m, diabetes 5.8%, hypertension 20.0%, hyperlipidemia 17.9%, heart disease 2.6%) enrolled in the Emory-Georgia Tech Predictive Health Institute study completed baseline demographic, clinical, depression (Beck Depression Inventory II), anxiety (General Anxiety Disorder 7), sleep (Pittsburg Sleep Quality Index), and noninvasive endothelial function (brachial artery flow mediated dilation [FMD]) measures. Insomnia symptoms were defined as subjective sleep latency of 30 minutes or longer, nighttime or early morning awakenings, and/or sleep medication use occurring 3 times or more per week in the past month. RESULTS: Insomnia symptoms were reported by 39.5% of participants. Multivariable regression models showed that insomnia symptoms, age, baseline artery diameter, and dyslipidemia were inversely related to FMD. After adjusting for age, baseline artery diameter, and dyslipidemia, participants reporting insomnia symptoms had lower FMD than did participants reporting better sleep (adjusted FMD mean, 6.13% [SD, 0.28%] vs 6.83% [SD, 0.26%], P = .035). CONCLUSION: In this study, insomnia symptoms were associated with reduced FMD. Research examining the therapeutic benefits of treating insomnia on endothelial function and future cardiovascular risk is warranted. PMID- 26488557 TI - Novel Active Surface Prepared by Embedded Functionalized Clays in an Acrylate Coating. AB - The research on a self-decontaminating surface has received significant attention because of the growth of pathogenic microorganisms on surfaces. In this study, a novel and simple technique for producing an active surface with antimicrobial functionality is demonstrated. A tethering platform was developed by grafting the biocide ampicillin (Amp) to a nanoclay and dispersing the nanoclay in a UV curable acrylate coating applied on polypropylene films as the substrate. A coupling agent, [3-(glycidyloxy)propyl]trimethoxysilane, was used as a linker between the nanoclay and Amp. The Amp-functionalized clay was further modified with an organic surfactant to improve the compatibility with the coating. Several characterization assays, such as Fourier infrared transform analysis, thermogravimetric analysis, and X-ray diffraction, were conducted to confirm the presence of Amp in the nanoclay. Transmission electron microscopy images revealed that the clay particles were well dispersed in the coating and had a partial exfoliated morphology. The active coating surface was effective in inhibiting the growth of Gram-positive Listeria monocytogenes and Gram-negative Salmonella Typhimurium via contact. These findings suggest the potential for the development of active surfaces with the implementation of nanotechnology to achieve diverse functionalities. PMID- 26488558 TI - Dynamic signaling cascades: reversible covalent reaction-coupled molecular switches. AB - The research of systems chemistry exploring complex mixtures of interacting synthetic molecules has been burgeoning recently. Herein we demonstrate for the first time the coupling of molecular switches with a dynamic covalent reaction (DCR) and the modulation of created chemical cascades with a variety of inputs, thus closely mimicking a biological signaling system. A novel Michael type DCR of 10-methylacridinium perchlorate and monothiols exhibiting excellent regioselectivity and tunable affinity was discovered. A delicate balance between the unique reactivity of the reactant and the stability of the adduct leads to the generation of a strong acid in a thermodynamically controlled system. The dynamic cascade was next created via coupling of the DCR and a protonation induced configurational switch (E/Z isomerization) through a proton relay. Detailed examination of the interdependence of the equilibrium enabled us to rationally optimize the cascade and also shed light on the possible intermediate of the switching process. Furthermore, relative independence of the coupled reactions was verified by the identification of stimuli that are able to facilitate one reaction but suppress the other. To further enhance systematic complexity, a second DCR of electrophilic aldehydes and thiols was employed for the reversible inhibition of the binary system, thus achieving the interplay of multiple equilibria. Finally, a fluorescence switch was turned on through coupling with the DCR, showcasing the versatility of our strategy. The results described herein should pave the way for the exploitation of multifunctional dynamic covalent cascades. PMID- 26488559 TI - WITHDRAWN: Prophylactic steroids for pediatric open heart surgery. PMID- 26488560 TI - Natural Rubber-Filler Interactions: What Are the Parameters? AB - Reinforcement of a polymer matrix through the incorporation of nanoparticles (fillers) is a common industrial practice that greatly enhances the mechanical properties of the composite material. The origin of such mechanical reinforcement has been linked to the interaction between the polymer and filler as well as the homogeneous dispersion of the filler within the polymer matrix. In natural rubber (NR) technology, knowledge of the conditions necessary to achieve more efficient NR-filler interactions is improving continuously. This study explores the important physicochemical parameters required to achieve NR-filler interactions under dilute aqueous conditions by varying both the properties of the filler (size, composition, surface activity, concentration) and the aqueous solution (ionic strength, ion valency). By combining fluorescence and electron microscopy methods, we show that NR and silica interact only in the presence of ions and that heteroaggregation is favored more than homoaggregation of silica-silica or NR-NR. The interaction kinetics increases with the ion valence, whereas the morphology of the heteroaggregates depends on the size of silica and the volume percent ratio (dry silica/dry NR). We observe dendritic structures using silica with a diameter (d) of 100 nm at a ~20-50 vol % ratio, whereas we obtain raspberry-like structures using silica with d = 30 nm particles. We observe that in liquid the interaction is controlled by the hydrophilic bioshell, in contrast to dried conditions, where hydrophobic polymer dominates the interaction of NR with the fillers. A good correlation between the nanoscopic aggregation behavior and the macroscopic aggregation dynamics of the particles was observed. These results provide insight into improving the reinforcement of a polymer matrix using NR-filler films. PMID- 26488561 TI - Gender Differences in the Development of Sexual Excitation and Inhibition Through the Life Course: Preliminary Findings from a Representative Study in Flanders. AB - The dual control model proposes that there are individual differences in the propensity for sexual excitation and sexual inhibition. Research to date has considered the effect of age on these traits as a simple linear effect, and studies examining gender differences in age effects are lacking. There are, however, indications that the associations of age with excitation and inhibition are nonlinear and that there might be gender differences in these associations. The aim of this study was to examine how these traits develop through an individual's life and whether there are gender differences in this development. In this study we applied polynomial regression analyses to examine the interaction effects of age and gender on sexual excitation and inhibition. We used data from a representative cross-sectional survey on sexual health in Flanders (N = 1,825; mean age = 43.77; SD = 17.98). Most of the associations of excitation and inhibition with age were nonlinear, and there were substantial gender differences in these associations. This indicates that the interplay between age, gender, and excitation and inhibition should be taken into account in research on (dys)functional sexuality. PMID- 26488562 TI - Growth of Ammonium Bisulfate Clusters by Adsorption of Oxygenated Organic Molecules. AB - Quantum chemical calculations were employed to model the interactions of the [(NH4(+))4(HSO4(-))4] ammonium bisulfate cluster with one or more molecular products of monoterpene oxidation. A strong interaction was found between the bisulfate ion of this cluster and a carboxylic acid, aldehyde, or ketone functionality of the organic molecule. Free energies of adsorption for carboxylic acids were in the -70 to -73 kJ/mol range, while those for aldehydes and ketones were in the -46 to -50 kJ/mol range. These values suggest that a small ambient [(NH4(+))4(SO4(-))4]cluster is able to adsorb an oxygenated organic molecule. While adsorption of the first molecule is highly favorable, adsorption of subsequent molecules is less so, suggesting that sustained uptake of organic molecules does not occur, and thus is not a pathway for continuing growth of the cluster. This result is consistent with ambient measurements showing that particles below ~1 nm grow slowly, while those above 1 nm grow at an increasing rate presumably due to a lower surface energy barrier enabling the uptake of organic molecules. This work provides insight into the molecular level interactions which affect sustained cluster growth by uptake of organic molecules. PMID- 26488563 TI - Polymyxin B versus colistin: an update. AB - Polymyxin B and colistin (polymyxin E) are polypeptide antibiotics that were developed in the 1940s, but fell into disfavor due to their high toxicity rates. These two antibiotics were previously regarded to be largely equivalent, due to similarities in their chemical structure and spectrum of activity. In recent years, several pertinent differences, especially in terms of potency and disposition, have been revealed between polymyxin B and colistin. These differences are mainly attributed to the fact that polymyxin B is administered parenterally in its active form, while colistin is administered parenterally as an inactive pro-drug, colistimethate. In this review, we summarize the similarities and differences between polymyxin B and colistin. We also discuss the potential clinical implications of these findings, and provide our perspectives on how polymyxins should be employed to preserve their utility in this era of multi-drug resistance. PMID- 26488564 TI - T-type channels: release a brake, engage a gear. PMID- 26488566 TI - The Urban Medicine Program: Developing Physician-Leaders to Serve Underserved Urban Communities. AB - PURPOSE: Medical school graduates are poorly prepared to address health care inequities found in urban, underserved communities. The University of Illinois College of Medicine developed the Urban Medicine Program (UMed) to prepare students for the roles of advocate, researcher, policy maker, and culturally competent practitioner through a four-year curriculum integrating principles of public health with direct interventions in local, underserved communities. This study assessed the program's effectiveness and evaluated early outcomes. METHOD: The authors analyzed data for UMed students (graduating classes 2009-2013) from pre- and postseminar assessments and longitudinal community project progress reports. They also compared UMed and non-UMed outcomes from the same classes, using graduation data and data from two surveys: Medical Students' Attitudes Toward the Underserved (MSATU) and the Intercultural/Professional Assessment. RESULTS: UMed students were more likely than non-UMed students to endorse MSATU constructs ("Universal medical care is a right" [P = .01], "Access to basic medical care is a right" [P = .03], "Access is influenced by social determinants" [P = .03]); to be selected for the Gold Humanism Honor Society (P < .0001); to complete joint degrees (P < .0001); and to enter primary care residencies (P = .002). CONCLUSIONS: Early outcomes reveal that a longitudinal, experiential curriculum can provide students with competencies that may prepare them for leadership roles in advocacy, research, and policy making. Contact with diverse communities inculcates-in medical students with predispositions toward helping underserved populations-the self-efficacy and skills to positively influence underserved, urban communities. PMID- 26488567 TI - The New Academic Environment and Faculty Misconduct. AB - Faculty members are expected to abide by codes of conduct that are delineated in institutional policies and to behave ethically when engaging in scientific pursuits. As federal funds for research decrease, faculty members face increasing pressure to sustain their research activities, and many have developed new collaborations and pursued new entrepreneurial opportunities. As research collaborations increase, however, there may be competition to get credit as the first person to develop ideas, make new discoveries, and/or publish new findings. This increasingly competitive academic environment may contribute to intentional or unintentional faculty misconduct. The authors, who work in the Dean's Office at a large U.S. medical school (University of California, San Francisco), investigate one to two cases of alleged misconduct each month. These investigations, which are stressful and unpleasant, may culminate in serious disciplinary action for the faculty member. Further, these allegations sometimes result in lengthy and acrimonious civil litigation. This Perspective provides three examples of academic misconduct: violations of institutional conflict-of interest policies, disputes about intellectual property, and authorship conflicts.The authors also describe prevention and mitigation strategies that their medical school employs, which may be helpful to other institutions. Prevention strategies include training campus leaders, using attestations to reduce violations of institutional policies, encouraging open discussion and written agreements about individuals' roles and responsibilities, and defining expectations regarding authorship and intellectual property at the outset. Mitigation strategies include using mediation by third parties who do not have a vested academic, personal, or financial interest in the outcome. PMID- 26488565 TI - Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine. AB - BACKGROUND: The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS: We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS: In the per-protocol group of 4577 RTS,S/AS01 vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS: These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.). PMID- 26488568 TI - Educating for the 21st-Century Health Care System: An Interdependent Framework of Basic, Clinical, and Systems Sciences. AB - In the face of a fragmented and poorly performing health care delivery system, medical education in the United States is poised for disruption. Despite broad based recommendations to better align physician training with societal needs, adaptive change has been slow. Traditionally, medical education has focused on the basic and clinical sciences, largely removed from the newer systems sciences such as population health, policy, financing, health care delivery, and teamwork. In this article, authors examine the current state of medical education with respect to systems sciences and propose a new framework for educating physicians in adapting to and practicing in systems-based environments. Specifically, the authors propose an educational shift from a two-pillar framework to a three pillar framework where basic, clinical, and systems sciences are interdependent. In this new three-pillar framework, students not only learn the interconnectivity in the basic, clinical, and systems sciences but also uncover relevance and meaning in their education through authentic, value-added, and patient-centered roles as navigators within the health care system. Authors describe the Systems Navigation Curriculum, currently implemented for all students at the Penn State College of Medicine, as an example of this three-pillar educational model. Simple adjustments, such as including occasional systems topics in medical curriculum, will not foster graduates prepared to practice in the 21st-century health care system. Adequate preparation requires an explicit focus on the systems sciences as a vital and equal component of physician education. PMID- 26488569 TI - Use of a Night Float System to Comply With Resident Duty Hours Restrictions: Perceptions of Workplace Changes and Their Effects on Professionalism. AB - PURPOSE: Although some evidence suggests that resident duty hours reforms can lead to shift-worker mentality and loss of patient ownership, other evidence links long hours and fatigue to poor work performance and loss of empathy, suggesting the restrictions could positively affect professionalism. The authors explored perceived impacts of a 16-hour duty restriction, achieved using a night float (NF) system, on the workplace and professionalism. METHOD: In 2013, the authors conducted semistructured interviews with 18 residents, 9 staff physicians, and 3 residency program directors in the McGill University core internal medicine residency program regarding their perceptions of the program's 12-hour shift-based NF system. Interviews were transcribed and coded for common themes. The authors used a descriptive qualitative methodology. RESULTS: Participants viewed implementation of the NF system as leading to decreased physical and mental exhaustion, more consistent interaction with patients, and more stable team structure within shifts compared with the previous 24-hour call system. These workplace changes were felt to improve teamwork and patient ownership within shifts, quality of work performed, and empathy. Across shifts, however, more frequent sign-overs, stricter application of shift time boundaries, and loose integration between daytime and NF teams were perceived as leading to emergence of shift-worker mentality around sign-over. Perceptions of optimal patient ownership changed from the traditional single-physician-24/7 model to team-based shared ownership. CONCLUSIONS: Duty hours restrictions, as exemplified by an NF system, have both positive and negative impacts on professionalism. Interventions and training toward effective team-based care are needed to curb emergence of shift-worker mentality. PMID- 26488570 TI - Reporting Achievement of Medical Student Milestones to Residency Program Directors: An Educational Handover. AB - PROBLEM: Competency-based education, including assessment of specialty-specific milestones, has become the dominant medical education paradigm; however, how to determine baseline competency of entering interns is unclear-as is to whom this responsibility falls. Medical schools should take responsibility for providing residency programs with accurate, competency-based assessments of their graduates. APPROACH: A University of Michigan ad hoc committee developed (spring 2013) a post-Match, milestone-based medical student performance evaluation for seven students matched into emergency medicine (EM) residencies. The committee determined EM milestone levels for each student based on assessments from the EM clerkship, end-of-third-year multistation standardized patient exam, EM boot camp elective, and other medical school data. OUTCOMES: In this feasibility study, the committee assessed nearly all 23 EM milestones for all seven graduates, shared these performance evaluations with the program director (PD) where each student matched, and subsequently surveyed the PDs regarding this pilot. Of the five responding PDs, none reported using the traditional medical student performance evaluation to customize training, four (80%) indicated that the proposed assessment provided novel information, and 100% answered that the assessment would be useful for all incoming trainees. NEXT STEPS: An EM milestone-based, post-Match assessment that uses existing assessment data is feasible and may be effective for communicating competency-based information about medical school graduates to receiving residency programs. Next steps include further aligning assessments with competencies, determining the benefit of such an assessment for other specialties, and articulating the national need for an effective educational handover tool between undergraduate and graduate medical education institutions. PMID- 26488571 TI - Identifying and Promoting Best Practices in Residency Application and Selection in a Complex Academic Health Network. AB - Medical education institutions have a social mandate to produce a diverse physician workforce that meets the public's needs. Recent reports have framed the admission process outcome of undergraduate and postgraduate medical education (UGME and PGME) programs as a key determinant of the collective contributions graduating cohorts will make to society, creating a sense of urgency around the issue of who gets accepted. The need for evidence-informed residency application and selection processes is growing because of the increasing size and diversity of the applicant pool and the need for equity, fairness, social accountability, and health human resource planning. The selection literature, however, is dominated by a UGME focus and emphasizes determination of desirable qualities of future physicians and selection instrument reliability and validity. Gaps remain regarding PGME selection, particularly the creation of specialty-specific selection criteria, suitable outcome measures, and reliable selection systems.In this Perspective, the authors describe the University of Toronto's centralized approach to defining system-level best practices for residency application and selection. Over the 2012-2013 academic year, the Best Practices in Application and Selection working group reviewed relevant literature and reports, consulted content experts, surveyed local practices, and conducted iterative stakeholder consultations on draft recommendations. Strong agreement arose around the resulting 13 principles and 24 best practices, which had either empirical support or face validity. These recommendations, which are shared in this article, have been adopted by the university's PGME advisory committee and will inform a national initiative to improve trainees' transition from UGME to PGME in Canada. PMID- 26488572 TI - The Effect of Differential Weighting of Academics, Experiences, and Competencies Measured by Multiple Mini Interview (MMI) on Race and Ethnicity of Cohorts Accepted to One Medical School. AB - PURPOSE: To examine whether academic scores, experience scores, and Multiple Mini Interview (MMI) core personal competencies scores vary across applicants' self reported ethnicities, and whether changes in weighting of scores would alter the proportion of ethnicities underrepresented in medicine (URIM) in the entering class composition. METHOD: This study analyzed retrospective data from 1,339 applicants to the Rutgers Robert Wood Johnson Medical School interviewed for entering classes 2011-2013. Data analyzed included two academic scores-grade point average (GPA) and Medical College Admission Test (MCAT) service/clinical/research (SCR) scores, and MMI scores. Independent-samples t tests evaluated whether URIM ethnicities differed from non-URIM across GPA, MCAT, SCR, and MMI scores. A series of "what-if" analyses were conducted to determine whether alternative weighting methods would have changed final admissions decisions and entering class composition. RESULTS: URIM applicants had significantly lower GPAs (P < .001), MCATs (P < .001), and SCR scores (P < .001). However, this pattern was not found with MMI score (non-URIM 10.4 [1.6], URIM 10.4 [1.3], P = .55). Alternative weighting analyses show that including academic/experiential scores impacts the percentage of URIM acceptances. URIM acceptance rate declined from 57% (100% MMI) to 43% (10% GPA/10% MCAT/10% SCR/70% MMI), 39% (30% GPA/70% MMI), to as low as 22% (50% MCAT/50% MMI). CONCLUSIONS: Sole reliance on the MMI for final admissions decisions, after threshold academic/experiential preparation are met, promotes diversity with the accepted applicant pool; weighting of "the numbers" or what is written about the application may decrease the acceptance of URIM applicants. PMID- 26488573 TI - Design and evaluation of a UV LED Photocatalytic Reactor Using Anodized TiO2 Nanotubes. AB - A bench-scale flow-through photocatalytic reactor using light emitting diodes (LED) as light source and a TiO2 nanotube array (TN) as immobilized catalyst has been designed, fabricated and tested on commonly studied contaminants. The photoreactor is comprised of 144, 365-nm UV-LED lamps mounted along the inner periphery of an annular cylinder. An ordered array of TN, as catalyst, was immobilized by electrochemical anodization of a titanium cylinder and placed in the center of the reactor. Synthesized TN was characterized by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). Laboratory investigations were conducted on the photoreactor to treat 4-chlorophenol (4-CP), atrazine and methylene blue. The performance of the photoreactor at different flow rates and at varying distances of photocatalyst from the light source was monitored. The photocatalytic reaction rates increased with bubbling oxygen into the reservoir. Significant improvement was observed when H2O2 was added and degradation to detection limits was observed. PMID- 26488574 TI - Dachengqi Decoction Attenuates Inflammatory Response via Inhibiting HMGB1 Mediated NF-kappaB and P38 MAPK Signaling Pathways in Severe Acute Pancreatitis. AB - BACKGROUND/AIMS: Severe acute pancreatitis (SAP) is a sudden inflammation of the pancreas. The traditional Chinese medicine formula Dachengqi decoction (DCQD) is proven to be beneficial in the comprehensive treatment for pancreatitis patients in clinical practice. However, the molecular mechanism of DCQD on SAP remains unclear. High mobility group box 1(HMGB1) that functions as a damage-associated molecular pattern molecule (DAMP) has attracted much interest. METHODS: In this study, we used lipopolysaccharide (LPS) and cerulein to induce severe acute pancreatitis in C57BL/6 mice with subsequent administration with low, medium and high dose (2.3 g/kg, 7 g/kg and 21 g/kg, respectively) of DCQD. RESULTS: DCQD treatment improved the pathological score and decreased serum amylase and lipase in a dose-dependent manner. In addition, it suppressed the immune cell-induced secretion of HMGB1 and its translocation from the nucleus to the cytoplasm, thus repressing the expression of IL-6 and TNF-alpha. Further, pretreatment with DCQD decreased responses of TLRs, and suppressed the activation of NF-kappaB and p38 MAPK pathway. CONCLUSION: Decreasing the secretion of HMGB1 could reduce pro inflammatory cytokines, which may help cutting down the risks of development from localized pathological changes to a systemic inflammatory response syndrome and even lead to multiple organ failure. PMID- 26488575 TI - Inhibition of Matriptase Activity Results in Decreased Intestinal Epithelial Monolayer Integrity In Vitro. AB - Barrier dysfunction in inflammatory bowel diseases implies enhanced paracellular flux and lowered transepithelial electrical resistance (TER) causing effective invasion of enteropathogens or altered intestinal absorption of toxins and drug compounds. To elucidate the role of matriptase-driven cell surface proteolysis in the maintenance of intestinal barrier function, the 3-amidinophenylalanine derived matriptase inhibitor, MI-432 was used on porcine IPEC-J2 cell monolayer. Studies with two fluorescent probes revealed that short (2 h) treatment with MI 432 caused an altered distribution of oxidative species between intracellular and extracellular spaces in IPEC-J2 cells. This perturbation was partially compensated when administration of inhibitor continued for up to 48 h. Significant decrease in TER between apical and basolateral compartments of MI-432 treated IPEC-J2 cell monolayers proved that matriptase is one of the key effectors in the maintenance of barrier integrity. Changes in staining pattern of matriptase and in localization of the junctional protein occludin were observed suggesting that inhibition of matriptase by MI-432 can also exert an effect on paracellular gate opening via modulation of tight junctional protein assembly. This study confirms that non-tumorigenic IPEC-J2 cells can be used as an appropriate small intestinal model for the in vitro characterization of matriptase-related effects on intestinal epithelium. These findings demonstrate indirectly that matriptase plays a pivotal role in the development of barrier integrity; thus matriptase dysfunction can facilitate the occurence of leaky gut syndrome observed in intestinal inflammatory diseases. PMID- 26488579 TI - 25th Anniversary State-of-the-Art Expert Discussion With Todd A. Ponsky, MD, FACS, on the Advances of Surgical Practice in Pediatric Hernia Repair. PMID- 26488577 TI - Presence of Zea luxurians (Durieu and Ascherson) Bird in Southern Brazil: Implications for the Conservation of Wild Relatives of Maize. AB - Records of the occurrence of wild relatives of maize in South American lowlands are unprecedented, especially in sympatric coexistence with landraces. This fact is relevant, because regions of occurrence of wild relatives of cultivated plants should be a priority for conservation, even if they do not correspond to the center of origin of the species. The aim of this study was to identify and characterize the wild relatives of maize in the Far West of Santa Catarina, southern Brazil. Therefore, phenotypic characterization was performed for five populations, based on 22 morphological traits deemed as fundamental for classifying the species of the genus Zea, and validated through the characterization of chromosomal knobs of two populations. The occurrence and distribution of teosinte populations were described through semi-structured interviews applied to a sample of 305 farmers. A total of 136 teosinte populations were identified; 75% of them occur spontaneously, 17% are cultivated populations, and 8% occur both ways, for the same farm. Populations that were characterized morphologically had trapezoidal fruits mostly, upright tassel branch (4-18), non-prominent main branch and glabrous glumes, with two protruding outer ribs and 8 inner ribs, on average. Cytogenetic analysis identified 10 pairs of homologous chromosomes (2n = 20) with 26 knobs, located in the terminal region of all chromosomes. The similarity of these results with the information reported in the literature indicates that the five populations of wild relatives of maize in this region of Santa Catarina belong to the botanical species Zea luxurians. PMID- 26488576 TI - Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study. AB - Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk. PMID- 26488580 TI - Characteristics of Hypovascular versus Hypervascular Well-Differentiated Hepatocellular Carcinoma Smaller Than 2 cm - Focus on Tumor Size, Markers and Imaging Detectability. AB - OBJECTIVES: The characteristics of hypovascular and hypervascular well differentiated hepatocellular carcinomas (HCCs) were compared in terms of tumor size, tumor markers and detectability by imaging modalities. METHODS: Well differentiated HCC nodules that are smaller than 2 cm (n = 27) were evaluated in 27 patients using histopathology and divided into 2 groups: hypovascular (n = 10) and hypervascular (n = 17). The diagnostic sensitivity of imaging modalities was then evaluated for efficiency in disclosing tumor size and tumor markers in the 2 types. RESULTS: No difference was observed in tumor size and tumor markers between the 2 types; however, the sensitivity of contrast-enhanced CT, contrast enhanced ultrasonography and arterioportal angiography was significantly different between the 2 types, whereas that by Gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging (Gd-EOB DTPA MRI) demonstrated no difference. CONCLUSION: Hypovascular HCC could be diagnosed by Gd-EOB-DTPA MRI in the hepatobiliary phase. PMID- 26488582 TI - Performance Assessment of Internal Quality Control (IQC) Products in Blood Transfusion Compatibility Testing in China. AB - Internal quality control (IQC) is a critical component of laboratory quality management, and IQC products can determine the reliability of testing results. In China, given the fact that most blood transfusion compatibility laboratories do not employ IQC products or do so minimally, there is a lack of uniform and standardized IQC methods. To explore the reliability of IQC products and methods, we studied 697 results from IQC samples in our laboratory from 2012 to 2014. The results showed that the sensitivity and specificity of the IQCs in anti-B testing were 100% and 99.7%, respectively. The sensitivity and specificity of the IQCs in forward blood typing, anti-A testing, irregular antibody screening, and cross matching were all 100%. The reliability analysis indicated that 97% of anti-B testing results were at a 99% confidence level, and 99.9% of forward blood typing, anti-A testing, irregular antibody screening, and cross-matching results were at a 99% confidence level. Therefore, our IQC products and methods are highly sensitive, specific, and reliable. Our study paves the way for the establishment of a uniform and standardized IQC method for pre-transfusion compatibility testing in China and other parts of the world. PMID- 26488581 TI - Transgenic Rice Expressing Ictb and FBP/Sbpase Derived from Cyanobacteria Exhibits Enhanced Photosynthesis and Mesophyll Conductance to CO2. AB - To find a way to promote the rate of carbon flux and further improve the photosynthetic rate in rice, two CO2-transporting and fixing relevant genes, Ictb and FBP/Sbpase, which were derived from cyanobacteria with the 35SCaMV promotor in the respective constructs, were transformed into rice. Three homologous transgenic groups with Ictb, FBP/Sbpase and the two genes combined were constructed in parallel, and the functional effects of these two genes were investigated by physiological, biochemical and leaf anatomy analyses. The results indicated that the mesophyll conductance and net photosynthetic rate were higher at approximately 10.5-36.8% and 13.5-34.6%, respectively, in the three groups but without any changes in leaf anatomy structure compared with wild type. Other physiological and biochemical parameters increased with the same trend in the three groups, which showed that the effect of FBP/SBPase on improving photosynthetic capacity was better than that of ICTB and that there was an additive effect in ICTB+FBP/SBPase. ICTB localized in the cytoplasm, whereas FBP/SBPase was successfully transported to the chloroplast. The two genes might show a synergistic interaction to promote carbon flow and the assimilation rate as a whole. The multigene transformation engineering and its potential utility for improving the photosynthetic capacity and yield in rice were discussed. PMID- 26488584 TI - Correction: Exome Sequencing in 53 Sporadic Cases of Schizophrenia Identifies 18 Putative Candidate Genes. PMID- 26488583 TI - Bulliform Phytolith Research in Wild and Domesticated Rice Paddy Soil in South China. AB - Bulliform phytoliths play an important role in researching rice origins as they can be used to distinguish between wild and domesticated rice. Rice bulliform phytoliths are characterized by numerous small shallow fish-scale decorations on the lateral side. Previous studies have shown that domesticated rice has a larger number of these decorations than wild rice and that the number of decorations >=9 is a useful feature for identifying domesticated rice. However, this standard was established based on limited samples of modern rice plants. In this study, we analyzed soil samples from both wild and domesticated rice paddies. Results showed that, in wild rice soil samples, the proportion of bulliform phytoliths with >=9 decorations was 17.46% +/- 8.29%, while in domesticated rice soil samples, the corresponding proportion was 63.70% +/- 9.22%. This suggests that the proportion of phytoliths with >=9 decorations can be adopted as a criterion for discriminating between wild and domesticated rice in prehistoric soil. This indicator will be of significance in improving the application of fish-scale decorations to research into rice origins and the rice domestication process. PMID- 26488585 TI - Epidemiology of Primary Multidrug-Resistant Tuberculosis, Vladimir Region, Russia. AB - We studied the epidemiology of drug-resistant tuberculosis (TB) in Vladimir Region, Russia, in 2012. Most cases of multidrug-resistant TB (MDR TB) were caused by transmission of drug-resistant strains, and >33% were in patients referred for testing after mass radiographic screening. Early diagnosis of drug resistance is essential for preventing transmission of MDR TB. PMID- 26488586 TI - Attentional Selection Can Be Predicted by Reinforcement Learning of Task-relevant Stimulus Features Weighted by Value-independent Stickiness. AB - Attention includes processes that evaluate stimuli relevance, select the most relevant stimulus against less relevant stimuli, and bias choice behavior toward the selected information. It is not clear how these processes interact. Here, we captured these processes in a reinforcement learning framework applied to a feature-based attention task that required macaques to learn and update the value of stimulus features while ignoring nonrelevant sensory features, locations, and action plans. We found that value-based reinforcement learning mechanisms could account for feature-based attentional selection and choice behavior but required a value-independent stickiness selection process to explain selection errors while at asymptotic behavior. By comparing different reinforcement learning schemes, we found that trial-by-trial selections were best predicted by a model that only represents expected values for the task-relevant feature dimension, with nonrelevant stimulus features and action plans having only a marginal influence on covert selections. These findings show that attentional control subprocesses can be described by (1) the reinforcement learning of feature values within a restricted feature space that excludes irrelevant feature dimensions, (2) a stochastic selection process on feature-specific value representations, and (3) value-independent stickiness toward previous feature selections akin to perseveration in the motor domain. We speculate that these three mechanisms are implemented by distinct but interacting brain circuits and that the proposed formal account of feature-based stimulus selection will be important to understand how attentional subprocesses are implemented in primate brain networks. PMID- 26488587 TI - Pupil Diameter Tracks the Exploration-Exploitation Trade-off during Analogical Reasoning and Explains Individual Differences in Fluid Intelligence. AB - The ability to adaptively shift between exploration and exploitation control states is critical for optimizing behavioral performance. Converging evidence from primate electrophysiology and computational neural modeling has suggested that this ability may be mediated by the broad norepinephrine projections emanating from the locus coeruleus (LC) [Aston-Jones, G., & Cohen, J. D. An integrative theory of locus coeruleus-norepinephrine function: Adaptive gain and optimal performance. Annual Review of Neuroscience, 28, 403-450, 2005]. There is also evidence that pupil diameter covaries systematically with LC activity. Although imperfect and indirect, this link makes pupillometry a useful tool for studying the locus coeruleus norepinephrine system in humans and in high-level tasks. Here, we present a novel paradigm that examines how the pupillary response during exploration and exploitation covaries with individual differences in fluid intelligence during analogical reasoning on Raven's Advanced Progressive Matrices. Pupillometry was used as a noninvasive proxy for LC activity, and concurrent think-aloud verbal protocols were used to identify exploratory and exploitative solution periods. This novel combination of pupillometry and verbal protocols from 40 participants revealed a decrease in pupil diameter during exploitation and an increase during exploration. The temporal dynamics of the pupillary response was characterized by a steep increase during the transition to exploratory periods, sustained dilation for many seconds afterward, and followed by gradual return to baseline. Moreover, the individual differences in the relative magnitude of pupillary dilation accounted for 16% of the variance in Advanced Progressive Matrices scores. Assuming that pupil diameter is a valid index of LC activity, these results establish promising preliminary connections between the literature on locus coeruleus norepinephrine-mediated cognitive control and the literature on analogical reasoning and fluid intelligence. PMID- 26488588 TI - The Speed of Serial Attention Shifts in Visual Search: Evidence from the N2pc Component. AB - Finding target objects among distractors in visual search display is often assumed to be based on sequential movements of attention between different objects. However, the speed of such serial attention shifts is still under dispute. We employed a search task that encouraged the successive allocation of attention to two target objects in the same search display and measured N2pc components to determine how fast attention moved between these objects. Each display contained one digit in a known color (fixed-color target) and another digit whose color changed unpredictably across trials (variable-color target) together with two gray distractor digits. Participants' task was to find the fixed-color digit and compare its numerical value with that of the variable-color digit. N2pc components to fixed-color targets preceded N2pc components to variable-color digits, demonstrating that these two targets were indeed selected in a fixed serial order. The N2pc to variable-color digits emerged approximately 60 msec after the N2pc to fixed-color digits, which shows that attention can be reallocated very rapidly between different target objects in the visual field. When search display durations were increased, thereby relaxing the temporal demands on serial selection, the two N2pc components to fixed-color and variable color targets were elicited within 90 msec of each other. Results demonstrate that sequential shifts of attention between different target locations can operate very rapidly at speeds that are in line with the assumptions of serial selection models of visual search. PMID- 26488589 TI - Information Processing in the Mental Workspace Is Fundamentally Distributed. AB - The brain is a complex, interconnected information processing network. In humans, this network supports a mental workspace that enables high-level abilities such as scientific and artistic creativity. Do the component processes underlying these abilities occur in discrete anatomical modules, or are they distributed widely throughout the brain? How does the flow of information within this network support specific cognitive functions? Current approaches have limited ability to answer such questions. Here, we report novel multivariate methods to analyze information flow within the mental workspace during visual imagery manipulation. We find that mental imagery entails distributed information flow and shared representations throughout the cortex. These findings challenge existing, anatomically modular models of the neural basis of higher-order mental functions, suggesting that such processes may occur at least in part at a fundamentally distributed level of organization. The novel methods we report may be useful in studying other similarly complex, high-level informational processes. PMID- 26488590 TI - A Neural Correlate of Strategic Exploration at the Onset of Adolescence. AB - The onset of adolescence is associated with an increase in the behavioral tendency to explore and seek novel experiences. However, this exploration has rarely been quantified, and its neural correlates during this period remain unclear. Previously, activity within specific regions of the rostrolateral PFC (rlPFC) in adults has been shown to correlate with the tendency for exploration. Here we investigate a recently developed task to assess individual differences in strategic exploration, defined as the degree to which the relative uncertainty of rewards directs responding toward less well-evaluated choices, in 62 girls aged 11-13 years from whom resting state fMRI data were obtained in a separate session. Behaviorally, this task divided our participants into groups of explorers (n = 41) and nonexplorers (n = 21). When seed ROIs within the rlPFC were used to interrogate resting state fMRI data, we identified a lateralized connection between the rlPFC and posterior putamen/insula whose strength differentiated explorers from nonexplorers. On the basis of Granger causality analyses, the preponderant direction of influence may proceed from posterior to anterior. Together, these data provide initial evidence concerning the neural basis of exploratory tendencies at the onset of adolescence. PMID- 26488591 TI - Reduction of Dual-task Costs by Noninvasive Modulation of Prefrontal Activity in Healthy Elders. AB - Dual tasking (e.g., walking or standing while performing a cognitive task) disrupts performance in one or both tasks, and such dual-task costs increase with aging into senescence. Dual tasking activates a network of brain regions including pFC. We therefore hypothesized that facilitation of prefrontal cortical activity via transcranial direct current stimulation (tDCS) would reduce dual task costs in older adults. Thirty-seven healthy older adults completed two visits during which dual tasking was assessed before and after 20 min of real or sham tDCS targeting the left pFC. Trials of single-task standing, walking, and verbalized serial subtractions were completed, along with dual-task trials of standing or walking while performing serial subtractions. Dual-task costs were calculated as the percent change in markers of gait and postural control and serial subtraction performance, from single to dual tasking. Significant dual task costs to standing, walking, and serial subtraction performance were observed before tDCS (p < .01). These dual-task costs were less after real tDCS as compared with sham tDCS as well as compared with either pre-tDCS condition (p < .03). Further analyses indicated that tDCS did not alter single task performance but instead improved performance solely within dual-task conditions (p < .02). These results demonstrate that dual tasking can be improved by modulating prefrontal activity, thus indicating that dual-task decrements are modifiable and may not necessarily reflect an obligatory consequence of aging. Moreover, tDCS may ultimately serve as a novel approach to preserving dual-task capacity into senescence. PMID- 26488592 TI - Xanthelasma Is Associated with an Increased Amount of Epicardial Adipose Tissue. AB - OBJECTIVE: In the present study, we aimed to compare the amount of epicardial adipose tissue in subjects with and without xanthelasma. SUBJECTS AND METHODS: Fifty-two subjects with xanthelasma and 52 age- and gender-matched control subjects were enrolled in this study. Epicardial adipose tissue was assessed by measuring epicardial fat thickness (EFT) with echocardiography. Participants were dichotomized according to median EFT, which was 4 mm. The group with EFT >4 mm was defined as the supramedian group. Body mass index (BMI) was calculated by weight (kilograms) divided by height (meters) squared. Conditional logistic regression analysis was performed to find independent factors associated with supramedian EFT (>4 mm). RESULTS: Subjects with xanthelasma had higher BMI (31.2 +/- 5.6 vs. 28.6 +/- 5.7, p = 0.01) and higher levels of total cholesterol (216 +/- 54 vs. 181 +/- 42 mg/dl, p < 0.001), LDL cholesterol (142 +/- 45 vs. 115 +/- 36 mg/dl, p = 0.003) and triglycerides (median, 154 vs. 101 mg/dl, p = 0.01) than control subjects. EFT was significantly higher in subjects with xanthelasma than in controls (5.04 +/- 2.02 vs. 3.81 +/- 2.03 mm, p = 0.002). In the conditional logistic regression analysis, the presence of xanthelasma (OR, 3.55; 95% CI, 1.43 8.78, p = 0.006) and lower HDL cholesterol level (OR, 0.96; 95% CI, 0.92-0.99, p = 0.023) were independently associated with supramedian EFT. CONCLUSION: The amount of epicardial adipose tissue found in subjects with xanthelasma was higher than in subjects without xanthelasma. In addition, the presence of xanthelasma was independently associated with supramedian EFT. PMID- 26488593 TI - The safety and tolerability of beta blockers in heart failure with reduced ejection fraction: is the current underutilization of this evidence-based therapy justified? AB - INTRODUCTION: Beta blockers are one of the cornerstones for treatment of Heart Failure with Reduced Ejection fraction (HFRef), yet their use is often limited by adverse effects, either perceived or real. We performed a review of available data using PubMed.gov utilizing beta blocker, heart failure, reduced ejection fraction and safety as key words. AREAS COVERED: Several well designed, large scale randomized clinical trials including CIBS-II (bisoprolol), MERIT-HF (metoprolol succinate), and Copernicus (carvedilol) among others, have been conducted in patients with HFRef and demonstrated an improvement in cardiac mortality and morbidity. Despite the preponderance of data supporting the use of beta blockers for patients HFRef, these medications remain underutilized and/or are often prescribed at lower than recommended dosages. Some of the reluctance to embrace beta blockade may be attributed to concern on the part of both the patient and prescriber about the non-cardiac adverse effects of this class of drugs. We have reviewed several recent reviews and meta-analyses of trials of beta blocker in heart failure which have conclusively demonstrated their tolerability in the populations studied. EXPERT OPINION: In the final section of this paper we provide our opinions regarding initiating and optimizing beta blocker therapy for patients with HFRef. PMID- 26488595 TI - High Surface Area Antimony-Doped Tin Oxide Electrodes Templated by Graft Copolymerization. Applications in Electrochemical and Photoelectrochemical Catalysis. AB - Mesoporous ATO nanocrystalline electrodes of micrometer thicknesses have been prepared from ATO nanocrystals and the grafted copolymer templating agents poly vinyl chloride-g-poly(oxyethylene methacrylate). As-obtained electrodes have high interfacial surface areas, large pore volumes, and rapid intraoxide electron transfer. The resulting high surface area materials are useful substrates for electrochemically catalyzed water oxidation. With thin added shells of TiO2 deposited by atomic layer deposition (ALD) and a surface-bound Ru(II) polypyridyl chromophore, they become photoanodes for hydrogen generation in the presence of a reductive scavenger. PMID- 26488594 TI - The Different Substrate Characteristics of Arrhythmogenic Triggers in Idiopathic Right Ventricular Outflow Tract Tachycardia and Arrhythmogenic Right Ventricular Dysplasia: New Insight from Noncontact Mapping. AB - BACKGROUND: The aim of this study was to investigate the different substrate characteristics of repetitive premature ventricular complexed (PVC) trigger sites by the non-contact mapping (NCM). METHODS: Thirty-five consecutive patients, including 14 with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) and 21 with idiopathic right ventricular outflow tract tachycardia (RVOT VT), were enrolled for electrophysiological study and catheter ablation guided by the NCM. Substrate and electrogram (Eg) characteristics of the earliest activation (EA) and breakout (BO) sites of PVCs were investigated, and these were confirmed by successful PVC elimination. RESULTS: Overall 35 dominant focal PVCs were identified. PVCs arose from the focal origins with preferential conduction, breakout, and spread to the whole right ventricle. The conduction time and distance from EA to BO site were both longer in the ARVC than the RVOT group. The conduction velocity was similar between the 2 groups. The negative deflection of local unipolar Eg at the EA site (EA slope3,5,10ms values) was steeper in the RVOT, compared to ARVC patients. The PVCs of ARVC occurred in the diseased substrate in the ARVC patients. More radiofrequency applications were required to eliminate the triggers in ARVC patients. CONCLUSIONS/INTERPRETATION: The substrate characteristics of PVC trigger may help to differentiate between idiopathic RVOT VT and ARVC. The slowing and slurred QS unipolar electrograms and longer distance from EA to BO in RVOT endocardium suggest that the triggers of ARVC may originate from mid- or sub-epicardial myocardium. More extensive ablation to the trigger site was required in order to create deeper lesions for a successful outcome. PMID- 26488596 TI - Resveratrol Prevents High Fluence Red Light-Emitting Diode Reactive Oxygen Species-Mediated Photoinhibition of Human Skin Fibroblast Migration. AB - BACKGROUND: Skin fibrosis is a significant medical problem that leads to a functional, aesthetic, and psychosocial impact on quality-of-life. Light-emitting diode-generated 633-nm red light (LED-RL) is part of the visible light spectrum that is not known to cause DNA damage and is considered a safe, non-invasive, inexpensive, and portable potential alternative to ultraviolet phototherapy that may change the treatment paradigm of fibrotic skin disease. OBJECTIVE: The goal of our study was to investigate the how reactive oxygen species (ROS) free radicals generated by high fluence LED-RL inhibit the migration of skin fibroblasts, the main cell type involved in skin fibrosis. Fibroblast migration speed is increased in skin fibrosis, and we studied cellular migration speed of cultured human skin fibroblasts as a surrogate measure of high fluence LED-RL effect on fibroblast function. To ascertain the inhibitory role of LED-RL generated ROS on migration speed, we hypothesized that resveratrol, a potent antioxidant, could prevent the photoinhibitory effects of high fluence LED-RL on fibroblast migration speed. METHODS: High fluence LED-RL generated ROS were measured by flow cytometry analysis using dihydrorhodamine (DHR). For purposes of comparison, we assessed the effects of ROS generated by hydrogen peroxide (H2O2) on fibroblast migration speed and the ability of resveratrol, a well known antioxidant, to prevent LED-RL and H2O2 generated ROS-associated changes in fibroblast migration speed. To determine whether resveratrol could prevent the high fluence LED-RL ROS-mediated photoinhibition of human skin fibroblast migration, treated cells were incubated with resveratrol at concentrations of 0.0001% and 0.001% for 24 hours, irradiated with high fluences LED-RL of 480, 640, and 800 J/cm2. RESULTS: High fluence LED-RL increases intracellular fibroblast ROS and decreases fibroblast migration speed. LED-RL at 480, 640 and 800 J/cm2 increased ROS levels to 132.8%, 151.0%, and 158.4% relative to matched controls, respectively. These LED-RL associated increases in ROS were prevented by pretreating cells with 0.0001% or 0.001% resveratrol. Next, we quantified the effect of hydrogen peroxide (H2O2)-associated ROS on fibroblast migration speed, and found that while H2O2-associated ROS significantly decreased relative fibroblast migration speed, pretreatment with 0.0001% or 0.001% resveratrol significantly prevented the decreases in migration speed. Furthermore, we found that LED-RL at 480, 640 and 800 J/cm2 decreased fibroblast migration speed to 83.0%, 74.4%, and 68.6% relative to matched controls, respectively. We hypothesized that these decreases in fibroblast migration speed were due to associated increases in ROS generation. Pretreatment with 0.0001% and 0.001% resveratrol prevented the LED-RL associated decreases in migration speed. CONCLUSION: High fluence LED-RL increases ROS and is associated with decreased fibroblast migration speed. We provide mechanistic support that the decreased migration speed associated with high fluence LED-RL is mediated by ROS, by demonstrating that resveratrol prevents high fluence LED-RL associated migration speed change. These data lend support to an increasing scientific body of evidence that high fluence LED-RL has anti-fibrotic properties. We hypothesize that our findings may result in a greater understanding of the fundamental mechanisms underlying visible light interaction with skin and we anticipate clinicians and other researchers may utilize these pathways for patient benefit. PMID- 26488597 TI - Pneumococcal Infection among Children before Introduction of 13-Valent Pneumococcal Conjugate Vaccine, Cambodia. AB - Vaccination of children with pneumococcal conjugate vaccine (PCV13) was initiated in Cambodia in 2015. To determine baseline data, we collected samples from children in 2013 and 2014. PCV13 serotypes accounted for 62.7% of colonizing organisms in outpatients and 88.4% of invasive pneumococci overall; multidrug resistance was common. Thus, effectiveness of vaccination should be high. PMID- 26488598 TI - Similar but Different: Dynamic Social Network Analysis Highlights Fundamental Differences between the Fission-Fusion Societies of Two Equid Species, the Onager and Grevy's Zebra. AB - Understanding why animal societies take on the form that they do has benefited from insights gained by applying social network analysis to patterns of individual associations. Such analyses typically aggregate data over long time periods even though most selective forces that shape sociality have strong temporal elements. By explicitly incorporating the temporal signal in social interaction data we re-examine the network dynamics of the social systems of the evolutionarily closely-related Grevy's zebras and wild asses that show broadly similar social organizations. By identifying dynamic communities, previously hidden differences emerge: Grevy's zebras show more modularity than wild asses and in wild asses most communities consist of solitary individuals; and in Grevy's zebras, lactating females show a greater propensity to switch communities than non-lactating females and males. Both patterns were missed by static network analyses and in general, adding a temporal dimension provides insights into differences associated with the size and persistence of communities as well as the frequency and synchrony of their formation. Dynamic network analysis provides insights into the functional significance of these social differences and highlights the way dynamic community analysis can be applied to other species. PMID- 26488599 TI - Biscationic Tartaric Acid-Based Amphiphiles: Charge Location Impacts Antimicrobial Activity. AB - Cationic amphiphiles have received increasing attention as antimicrobials given their unique ability to disrupt bacteria cell membranes. While extensive research has demonstrated that amphiphiles' hydrophobic-to-charge ratio significantly modulates antibacterial activity, less work has focused on elucidating the specific impact of charge location on amphiphile bioactivity. In this study, two series of cationic amphiphiles, termed bola-like and gemini-like, were synthesized with analogous hydrophobic-to-charge ratios yet differing charge location, and their resulting antibacterial activity was assessed. Bola-like amphiphiles exhibited preferential activity against two Gram-positive bacteria, with activity increasing with increasing hydrophobicity, whereas gemini-like amphiphiles were active against both Gram-positive and Gram-negative bacteria, with activity decreasing with increasing hydrophobicity. After identifying lead compounds from each amphiphile series (bola- and gemini-like), biophysical experiments indicated that both amphiphiles were membrane-active; notably, the lead gemini-like amphiphile exhibited a strong dependence on electrostatic interactions for membrane interaction. In contrast, the lead bola-like amphiphile exhibited a reliance on both hydrophobic and electrostatic contributions. These results demonstrate that charge location significantly impacts cationic amphiphiles' antibacterial and membrane activity. PMID- 26488600 TI - Genetic Analysis of East Asian Grape Cultivars Suggests Hybridization with Wild Vitis. AB - Koshu is a grape cultivar native to Japan and is one of the country's most important cultivars for wine making. Koshu and other oriental grape cultivars are widely believed to belong to the European domesticated grape species Vitis vinifera. To verify the domesticated origin of Koshu and four other cultivars widely grown in China and Japan, we genotyped 48 ancestry informative single nucleotide polymorphisms (SNPs) and estimated wild and domesticated ancestry proportions. Our principal components analysis (PCA) based ancestry estimation revealed that Koshu is 70% V. vinifera, and that the remaining 30% of its ancestry is most likely derived from wild East Asian Vitis species. Partial sequencing of chloroplast DNA suggests that Koshu's maternal line is derived from the Chinese wild species V. davidii or a closely related species. Our results suggest that many traditional East Asian grape cultivars such as Koshu were generated from hybridization events with wild grape species. PMID- 26488601 TI - Sexual behavioral pattern, consequences and adopted solutions among senior secondary schools students in a military barracks in Nigeria. AB - PURPOSE: To determine the sexual behavioral pattern, consequences, and adopted solutions among senior secondary schools students in Ojo military barracks, Lagos. MATERIALS AND METHODS: This was a cross-sectional study of 400 senior secondary schools students in Ojo military barracks, Lagos, selected using a multistage sampling technique. Data was collected using pre-tested, self administered semi-structured questionnaires. Data was analysed using statistical package for social sciences version 17. Tests of statistical significance were carried out using chi2-test, and a p-value of <0.05 was considered significant. RESULTS: The majority of them 391 (97.8%), were in the age group (10-19 years) while the mean age was 15+/-2.4 for males and 15+/-2.2 for females, respectively. One hundred and fifty four (38.5%) of the respondents have had penetrative sexual intercourse and were influenced mainly by peer pressure (p=0.0000). Their age at first sexual intercourse ranged between 10-19 years. Ten (6.5%) of the respondents (all males) had their sexual debut with a commercial sex worker. More girls 41 (56.2%) than boys 12 (14.8%), were forced into sexual intercourse (p=0.0000). Over half of the sexually active respondents had at least two sexual partners for either sex. CONCLUSION: Findings from this study have shown that young people living in the barracks indulged in sexual activity at very early ages and engaged in risky sexual behavior. We therefore recommend an improved multi-sectoral approach in reproductive health and sexually transmitted infections including HIV/AIDS education. PMID- 26488602 TI - Barriers in communication and available resources to facilitate conversation about infertility with girls diagnosed with Turner syndrome. AB - BACKGROUND: Delayed discussion about infertility with individuals affected by Turner syndrome (TS) has been found to result in psychological and social harm. The aim of this study was to identify barriers experienced when discussing infertility and determine resource types that may facilitate this conversation. METHODS: An electronic survey, given to caregivers of girls with TS diagnosed at <5 years. RESULTS AND CONCLUSIONS: Fifty percent of parents surveyed had spoken to their daughter about their possible infertility. Parents who had not yet discussed infertility with their daughter had younger daughters and reported more barriers in having the conversation. Although most individuals did not use resources to facilitate the conversation, they did express interest in additional resources. PMID- 26488603 TI - Obesity-associated sympathetic overactivity in children and adolescents: the role of catecholamine resistance in lipid metabolism. AB - BACKGROUND: Obesity in children and adolescents is characterized by chronic sympathetic overdrive and reduced epinephrine-stimulated lipolysis. This resistance to catecholamines occurs during the dynamic phase of fat accumulation. This review will focus on the relationship between sympathetic-adrenal activity and lipid metabolism, thereby highlighting the role of catecholamine resistance in the development of childhood obesity. RESULTS AND CONCLUSIONS: Catecholamine resistance causes lipid accumulation in adipose tissue by reducing lipolysis, increasing lipogenesis and impeding free fatty acid (FFA) transportation. Exercise improves catecholamine resistance, as evidenced by attenuated systemic sympathetic activity, reduced circulating catecholamine levels and enhanced beta adrenergic receptor signaling. Insulin resistance is mostly a casual result rather than a cause of childhood obesity. Therefore, catecholamine resistance in childhood obesity may promote insulin signaling in adipose tissue, thereby increasing lipogenesis. This review outlines a series of evidence for the role of catecholamine resistance as an upstream mechanism leading to childhood obesity. PMID- 26488604 TI - Changes in facial appearance from neonate to adult in 3-M syndrome patient with novel CUL7 gene mutations. AB - 3-M syndrome (OMIM #273750, #612921, and #614205) is a rare autosomal recessive growth disorder that is characterized by pre- and postnatal growth retardation, normal intelligence, and characteristic faces. This syndrome also has characteristic radiological features, such as slender long bones and tall vertebral bodies. Three genes, cullin 7 (CUL7), coiled-coil domain containing 8, and obscurin-like 1 are genetic candidates of 3-M syndrome. Patients with 3-M syndrome have a characteristic facial appearance, including a triangular face, frontal bossing, an anteverted nose, dolichocephaly, and a long philtrum. However, information on adult 3-M syndrome patients, including facial appearance, is scarce. We report an adult female with 3-M syndrome that was caused by novel compound heterozygous mutations (c.4023-1 G>A in splice acceptor site of exon 22 and c.4359_4363dupGGCTG in exon 23) in the CUL7 gene. We also report the growth chart and changes in facial appearance of this patient from the neonate to adult. PMID- 26488605 TI - Neurotransmitter receptor complexes: methods for bioanalysis, their potentials and limitations. AB - Neurotransmitter receptors are key elements for brain function, but work so far has been focusing on the individual receptor subunits. It is, however, the receptor complexes that execute work rather than the subunits; of course, the multitude of possible combinations of the many receptors forming homomeric or heteromeric complexes is hampering studies. Moreover, not only receptors are observed in the complexes but also their corresponding protein kinases, phosphatases, and anchoring proteins, to name a few. Studying receptor complexes is still an analytical challenge. Thus far, no methods exist to unequivocally characterize or even quantify these assemblies. Major problems and limitations for the analysis exist, such as solubility, as the use of detergents is critical and may dissociate the receptor complexes as well as their separation in the native state. Gel-based techniques are able to separate and semiquantitatively quantify receptor complexes by subsequent immunochemical methods but do not allow the characterization of complex components. Immunoprecipitation methods are highly dependent on antibody availability and specificity, and the result of coimmunoprecipitation does not verify the direct physical interaction of proteins in the immunoprecipitate. Antibody shift assays are suitable to identify individual known proteins within a complex as are immunogold electron microscopic techniques and energy transfer technologies. Most techniques are simply showing the proximity of proteins rather than their physical interaction. Although fluorescence correlation spectroscopy is a promising technique, the use for quantification or comparing biological samples is limited. A lot of work remains to be done to provide tools for the characterization and quantification of receptor complexes in the brain. PMID- 26488606 TI - Biochemical effects of lead exposure on oxidative stress and antioxidant status of battery manufacturing workers of Western Maharashtra, India. AB - BACKGROUND: Lead induces oxidative stress and alters the antioxidant status of population exposed to high lead levels, i.e. battery manufacturing workers. The aim of this study was to know the current scenario of blood lead (PbB) levels and their effect on the oxidative stress parameter, i.e. serum lipid peroxide (LP), and antioxidant parameters, such as red blood cell (RBC)-superoxide dismutase (SOD), RBC-catalase (CAT), plasma ceruloplasmin (CP), and serum nitrite, of battery manufacturing workers. METHODS: Forty-three battery manufacturing workers from Western Maharashtra, India, with ages between 19 and 42 years, were selected as study group and compared with 38 age-matched, healthy male subjects (control group). From both group subjects, 10 mL of blood sample was drawn by puncturing the antecubital vein, and PbB, serum LP, RBC-SOD, RBC-CAT, plasma CP, and serum nitrite were estimated using standard methods. RESULTS: The PbB levels of the battery manufacturing workers were significantly higher (p<0.001, 1050%) as compared with the control subjects. The serum LP levels were significantly increased (p<0.001, 96.86%); all antioxidant status parameters such as RBC-SOD (p<0.001, -26.32%), RBC-CAT (p<0.001, -51.57%), and plasma CP (p<0.001, -35.13%) were significantly decreased; and serum nitrite levels (p<0.001, 154%) were significantly increased in the battery manufacturing workers as compared with the control subjects. CONCLUSIONS: Despite modern techniques used to reduce lead exposure in battery manufacturing workers, PbB levels remain high, inducing oxidative stress and altering the antioxidant status of battery manufacturing workers. PMID- 26488607 TI - In Vitro Generation of Functional Liver Organoid-Like Structures Using Adult Human Cells. AB - In this study we used differentiated adult human upcyte(r) cells for the in vitro generation of liver organoids. Upcyte(r) cells are genetically engineered cell strains derived from primary human cells by lenti-viral transduction of genes or gene combinations inducing transient proliferation capacity (upcyte(r) process). Proliferating upcyte(r) cells undergo a finite number of cell divisions, i.e., 20 to 40 population doublings, but upon withdrawal of proliferation stimulating factors, they regain most of the cell specific characteristics of primary cells. When a defined mixture of differentiated human upcyte(r) cells (hepatocytes, liver sinusoidal endothelial cells (LSECs) and mesenchymal stem cells (MSCs)) was cultured in vitro on a thick layer of MatrigelTM, they self-organized to form liver organoid-like structures within 24 hours. When further cultured for 10 days in a bioreactor, these liver organoids show typical functional characteristics of liver parenchyma including activity of cytochromes P450, CYP3A4, CYP2B6 and CYP2C9 as well as mRNA expression of several marker genes and other enzymes. In summary, we hereby describe that 3D functional hepatic structures composed of primary human cell strains can be generated in vitro. They can be cultured for a prolonged period of time and are potentially useful ex vivo models to study liver functions. PMID- 26488608 TI - Degradation of Amino Acids and Structure in Model Proteins and Bacteriophage MS2 by Chlorine, Bromine, and Ozone. AB - Proteins are important targets of chemical disinfectants. To improve the understanding of disinfectant-protein reactions, this study characterized the disinfectant:protein molar ratios at which 50% degradation of oxidizable amino acids (i.e., Met, Tyr, Trp, His, Lys) and structure were observed during HOCl, HOBr, and O3 treatment of three well-characterized model proteins and bacteriophage MS2. A critical question is the extent to which the targeting of amino acids is driven by their disinfectant rate constants rather than their geometrical arrangement. Across the model proteins and bacteriophage MS2 (coat protein), differing widely in structure, methionine was preferentially targeted, forming predominantly methionine sulfoxide. This targeting concurs with its high disinfectant rate constants and supports its hypothesized role as a sacrificial antioxidant. Despite higher HOCl and HOBr rate constants with histidine and lysine than for tyrosine, tyrosine generally was degraded in preference to histidine, and to a lesser extent, lysine. These results concur with the prevalence of geometrical motifs featuring histidines or lysines near tyrosines, facilitating histidine and lysine regeneration upon Cl[+1] transfer from their chloramines to tyrosines. Lysine nitrile formation occurred at or above oxidant doses where 3,5-dihalotyrosine products began to degrade. For O3, which lacks a similar oxidant transfer pathway, histidine, tyrosine, and lysine degradation followed their relative O3 rate constants. Except for its low reactivity with lysine, the O3 doses required to degrade amino acids were as low as or lower than for HOCl or HOBr, indicating its oxidative efficiency. Loss of structure did not correlate with loss of particular amino acids, suggesting the need to characterize the oxidation of specific geometric motifs to understand structural degradation. PMID- 26488609 TI - Regulation of PKR by RNA: formation of active and inactive dimers. AB - PKR is a member of the eIF2alpha family of protein kinases that inhibit translational initiation in response to stress stimuli and functions as a key mediator of the interferon-induced antiviral response. PKR contains a dsRNA binding domain that binds to duplex regions present in viral RNAs, resulting in kinase activation and autophosphorylation. An emerging theme in the regulation of protein kinases is the allosteric linkage of dimerization and activation. The PKR kinase domain forms a back-to-back parallel dimer that is implicated in activation. We have developed a sensitive homo-Forster resonance energy transfer assay for kinase domain dimerization to directly probe the relationship among RNA binding, activation, and dimerization. In the case of perfect duplex RNAs, dimerization is correlated with activation and dsRNAs containing 30 bp or more efficiently induce kinase domain dimerization and activation. However, more complex duplex RNAs containing a 10-15 bp 2'-O-methyl RNA barrier produce kinase dimers but do not activate. Similarly, inactivating mutations within the PKR dimer interface that disrupt key electrostatic and hydrogen binding interactions fail to abolish dimerization. Our data support a model in which activating RNAs induce formation of a back-to-back parallel PKR kinase dimer whereas nonactivating RNAs either fail to induce dimerization or produce an alternative, inactive dimer configuration, providing an additional mechanism for distinguishing between host and pathogen RNA. PMID- 26488610 TI - Diagnostic Value of MR Imaging in the Diagnosis of Adnexal Torsion. AB - PURPOSE: To retrospectively evaluate the diagnostic performance of magnetic resonance (MR) imaging for the diagnosis of adnexal torsion in a series of patients with an equivocal adnexal mass at ultrasonography (US) in the context of acute or subacute pelvic pain. MATERIALS AND METHODS: The institutional ethics committee approved the study and waived informed consent. All patients with acute or subacute pelvic pain who were undergoing MR examination for the exploration of an equivocal adnexal mass (January 2007 to December 2012) with surgical exploration or clinical and radiologic follow-up of at least 3 months were retrospectively included (n = 58). The prospective interpretations were recorded. Additionally, three radiologists who were blinded to the clinical, US, and surgical data retrospectively and independently reviewed MR images. Features associated with adnexal torsion were identified by using univariate and recursive partitioning multivariate analysis. RESULTS: Twenty-two patients (38%) had a diagnosis of adnexal torsion. The accuracy of MR imaging at the time of prospective interpretation was 80.6% (25 of 31 patients) and 85.1% (23 of 27 patients) in acute and subacute torsion, respectively. The accuracy of image interpretation by each retrospective reader was 83.9% (26 of 31 patients), 90.3% (28 of 31 patients), and 83.9% (26 of 31 patients) in the context of acute pelvic pain and 92.6% (25 of 27 patients), 88.9% (24 of 27 patients), and 81.5% (22 of 27 patients) in the context of subacute pelvic pain for readers 1, 2, and 3, respectively. At multivariate analysis, the whirlpool sign (odds ratio = 6.5 [95% confidence interval: 1.36, 31.0], P = .01) and a thickened tube (>10 mm) (odds ratio = 8.2 [95% confidence interval: 1.2, 56.8], P = .03) were associated with adnexal torsion, with substantial interreader agreement (kappa = 0.71-0.84 and 0.82-0.86, respectively). The presence of adnexal hemorrhagic content was associated with nonviable ovaries in seven of 10 patients (70%) and with viable ovaries in 12 of 45 patients (27%) (P = .009). CONCLUSION: MR imaging is an accurate technique for the diagnosis of adnexal torsion in patients who have an adnexal mass with acute or subacute pelvic pain. PMID- 26488611 TI - To See or Not to See: Do Front of Pack Nutrition Labels Affect Attention to Overall Nutrition Information? AB - BACKGROUND: Front of pack (FOP) nutrition labels are concise labels located on the front of food packages that provide truncated nutrition information. These labels are rapidly gaining prominence worldwide, presumably because they attract attention and their simplified formats enable rapid comparisons of nutritional value. METHODS: Eye tracking was conducted as US consumers interacted with actual packages with and without FOP labels to (1) assess if the presence of an FOP label increases attention to nutrition information when viewers are not specifically tasked with nutrition-related goals; and (2) study the effect of FOP presence on consumer use of more comprehensive, traditional nutrition information presented in the Nutritional Facts Panel (NFP), a mandatory label for most packaged foods in the US. RESULTS: Our results indicate that colored FOP labels enhanced the probability that any nutrition information was attended, and resulted in faster detection and longer viewing of nutrition information. However, for cereal packages, these benefits were at the expense of attention to the more comprehensive NFP. Our results are consistent with a potential short cut effect of FOP labels, such that if an FOP was present, participants spent less time attending the more comprehensive NFP. For crackers, FOP labels increased time spent attending to nutrition information, but we found no evidence that their presence reduced the time spent on the nutrition information in the NFP. CONCLUSIONS: The finding that FOP labels increased attention to overall nutrition information by people who did not have an explicit nutritional goal suggests that these labels may have an advantage in conveying nutrition information to a wide segment of the population. However, for some food types this benefit may come with a short-cut effect; that is, decreased attention to more comprehensive nutrition information. These results have implications for policy and warrant further research into the mechanisms by which FOP labels impact use of nutrition information by consumers for different foods. PMID- 26488614 TI - Vieussens ring: an important coronary collateral circulation from the conus artery to the left anterior descending artery. PMID- 26488613 TI - Robuvit(r) and endurance in triathlon: improvements in training performance, recovery and oxidative stress. AB - AIM: The aim of this registry study was to evaluate the effects of supplementation with Robuvit(r) (Quercus robur wood extract, or "QR") on performance and endurance in triathlon by evaluating amateur athletes in a period of 2 weeks of training. Supplementation with QR may improve training efficiency (by decreasing post-triathlon, muscular pain, cramps and by improving recovery time). Robuvit(r) should decrease post-training plasma free radicals (PFR). METHODS: Sixty-one subjects (age range 30-40) were included in the study. Subjects followed a free diet. An isotonic saline drink was suggested to all subjects. RESULTS: After 2 weeks there were 27 subjects using the supplement and 27 without supplementation. The groups were comparable. All subjects improved in training considering the 3 events (swim, biking, run). The improvement was greater with Robuvit(r) (P<0.05) for the swim and biking (P<0.05); the running time decreased by 12.32% in subjects using Robuvit(r) (3.6% in controls; P<0.05). The improvement the total triathlon time was -10.56% with Robuvit(r) in comparison to -3.41% in controls. SAFETY: no side effects or tolerance problems were reported; all QR capsules were used as indicated. CONCLUSION: In conclusion, the -10.56% shorter total trioathlon time was considered as very good improvement, considering that for this type of athletes being almost at the top of their form it is difficult to improve even further without severe training. Training was considered better (on an analogue scale) in the QR group (P<0.05). Postrun muscular pain, cramps, localized pain, straining and the recovery time, were all considered better with QR (P<0.05). Plasma free radical (PFR) values 1 hour after the final run were, on average,16.98% higher in controls (P<0.05), indicating a higher level of oxidative stress. Higher levels of PFR are associated with a slower recovery. All routine blood tests were normal at inclusion and after the final triathlon. After the final test run triathlon athletes using QR had a lower increase of UBR and LDH (indicator of hemolysis). These two tests were significantly increased in controls (P<0.05) but not in the Robuvit(r) group. Robuvit(r) supplementation improved training, results and decreased hemolysis. PMID- 26488612 TI - A Tendon Cell Specific RNAi Screen Reveals Novel Candidates Essential for Muscle Tendon Interaction. AB - Tendons are fibrous connective tissue which connect muscles to the skeletal elements thus acting as passive transmitters of force during locomotion and provide appropriate body posture. Tendon-derived cues, albeit poorly understood, are necessary for proper muscle guidance and attachment during development. In the present study, we used dorsal longitudinal muscles of Drosophila and their tendon attachment sites to unravel the molecular nature of interactions between muscles and tendons. We performed a genetic screen using RNAi-mediated knockdown in tendon cells to find out molecular players involved in the formation and maintenance of myotendinous junction and found 21 candidates out of 2507 RNAi lines screened. Of these, 19 were novel molecules in context of myotendinous system. Integrin-betaPS and Talin, picked as candidates in this screen, are known to play important role in the cell-cell interaction and myotendinous junction formation validating our screen. We have found candidates with enzymatic function, transcription activity, cell adhesion, protein folding and intracellular transport function. Tango1, an ER exit protein involved in collagen secretion was identified as a candidate molecule involved in the formation of myotendinous junction. Tango1 knockdown was found to affect development of muscle attachment sites and formation of myotendinous junction. Tango1 was also found to be involved in secretion of Viking (Collagen type IV) and BM-40 from hemocytes and fat cells. PMID- 26488615 TI - Modulation of ERP components by task instructions in a cued go/no-go task. AB - The present study investigated how components of ERPs are modulated when participants optimize speed versus accuracy in a cued go/no-go task. Using a crossover design, 35 participants received instructions to complete the task prioritizing response speed in half of the task, and accurate responding in the other half of the task. Analysis was performed on the contingent negative variation (CNV), P3go, and P3no-go and the corresponding independent components (IC), as identified by group independent component analysis. After speed instructions, the IC CNV(late), P3go(anterior), P3no-go(early), and P3no-go(late) all had larger amplitudes than after accuracy instructions. Furthermore, both the IC P3go(posterior) and IC P3go(anterior) had shorter latencies after speed than after accuracy instructions. The results demonstrate that components derived from the CNV and P3 components are facilitated when participants optimize response speed. These findings indicate that these ERP components reflect executive processes enabling adjustment of behavior to changing demands. PMID- 26488617 TI - Accuracy and precision of oscillometric blood pressure in standing conscious horses. AB - BACKGROUND: Arterial blood pressure (BP) is a relevant clinical parameter that can be measured in standing conscious horses to assess tissue perfusion or pain. However, there are no validated oscillometric noninvasive blood pressure (NIBP) devices for use in horses. ANIMALS: Seven healthy horses from a teaching and research herd. HYPOTHESIS/OBJECTIVE: To evaluate the accuracy and precision of systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) in conscious horses obtained with an oscillometric NIBP device when compared to invasively measured arterial BP. METHODS: An arterial catheter was placed in the facial or transverse facial artery and connected to a pressure transducer. A cuff for NIBP was placed around the tail base. The BP was recorded during normotension, dobutamine-induced hypertension, and subnormal BP induced by acepromazine administration. Agreement analysis with replicate measures was utilized to calculate bias (accuracy) and standard deviation (SD) of bias (precision). RESULTS: A total of 252 pairs of invasive arterial BP and NIBP measurements were analyzed. Compared to the direct BP measures, the NIBP MAP had an accuracy of -4 mm Hg and precision of 10 mm Hg. SAP had an accuracy of -8 mm Hg and a precision of 17 mm Hg and DAP had an accuracy of -7 mm Hg and a precision of 14 mm Hg. CONCLUSIONS AND CLINICAL RELEVANCE: MAP from the evaluated NIBP monitor is accurate and precise in the adult horse across a range of BP, with higher variability during subnormal BP. MAP but not SAP or DAP can be used for clinical decision making in the conscious horse. PMID- 26488616 TI - CYP3A4 intronic SNP rs35599367 (CYP3A4*22) alters RNA splicing. AB - Cytochrome P450 3A4 (CYP3A4) metabolizes 30-50% of clinically used drugs. Large interperson variability in CYP3A4 activity affects response to CYP3A4 substrate drugs. We had demonstrated that an intronic single nucleotide polymorphism rs35599367 (CYP3A4*22, located in intron 6) reduces mRNA/protein expression; however, the underlying mechanism remained unknown. Here we show that CYP3A4*22 is associated with a two-fold or greater increase in formation of a nonfunctional CYP3A4 alternative splice variant with partial intron 6 retention in human liver (P=0.006), but not in small intestines. Consistent with this observation, in vitro transfection experiments with a CYP3A4 minigene (spanning from intron 5 to intron 7) demonstrated that plasmids carrying the rs35599367 minor T allele caused significantly greater intron 6 retention than the C allele in liver derived HepG2 cells, but not in intestine-derived LS-174T cells. These results indicate that tissue-specific increased formation of nonfunctional alternative splice variant causes reduced CYP3A4 mRNA/protein expression in CYP3A4*22 carriers. PMID- 26488618 TI - Characterization of operating parameters for XMuLV inactivation by low pH treatment. AB - To ensure the viral safety of protein therapeutics made in mammalian cells, purification processes include dedicated viral clearance steps to remove or inactivate adventitious and endogenous viruses. One such dedicated step is low pH treatment, a robust and effective method commonly used in monoclonal antibody production to inactivate enveloped viruses. To characterize the operating space for low pH viral inactivation, we performed a statistically designed experiment evaluating the effect of pH, temperature, hold duration, acid type, and buffer concentration on inactivation of the retrovirus model, XMuLV. An additional single factor experiment was performed to study the effect of protein concentration. These data were used to generate predictive models of inactivation at each time point studied, which can be used to identify conditions for robust and effective XMuLV inactivation. At pH 3.6, XMuLV inactivation was rapid, robust, and relatively unaffected by the other factors studied, providing support for this as a generic viral inactivation condition for products that can tolerate this low pH. At pH 3.7 and 3.8, other factors besides pH affected XMuLV inactivation. By understanding the impact of each factor on inactivation, the factors can be manipulated within the operating space to ensure effective inactivation while achieving desired product quality goals. PMID- 26488619 TI - The metabolomic study on atherosclerosis mice and its application in a traditional Chinese medicine Sishen granule. AB - Although an atherosclerosis (AS) model using low-density lipoprotein receptor deletion mice has been widely applied, its pathological pathway in metabolite level is still not clear. To further reveal the metabolite profile and identify the potential biomarkers in AS development, a serum metabolomic approach was developed based on reversed-phase liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS). The established metabolomic platform was also used for elucidating the therapeutic mechanism of a traditional Chinese medicine named Sishen granule (SSKL). Twenty-one potential biomarkers in AS mouse serum were identified. Through functional analysis of these biomarkers, inflammation, proliferation, dysfunction of energy metabolism and amino acid metabolism were considered the most relevant pathological changes in AS. DNA damage products were found for the first time in the metabolomic study of AS. The network established by 20 biomarkers revealed that pyruvate metabolism, citrate cycle, fatty acid metabolism and urea metabolism were seriously disturbed. This metabolomic study not only supplied a systematic view of the progression of AS but also provided a theoretical basis for the treatment of AS. This metabolomic study also demonstrated that SSKL had therapeutic effectiveness for AS through partly reversing the inflammation reaction and amino acid metabolism dysfunction. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26488620 TI - Cholera Transmission in Ouest Department of Haiti: Dynamic Modeling and the Future of the Epidemic. AB - In the current study, a comprehensive, data driven, mathematical model for cholera transmission in Haiti is presented. Along with the inclusion of short cycle human-to-human transmission and long cycle human-to-environment and environment-to-human transmission, this novel dynamic model incorporates both the reported cholera incidence and remote sensing data from the Ouest Department of Haiti between 2010 to 2014. The model has separate compartments for infectious individuals that include different levels of infectivity to reflect the distribution of symptomatic and asymptomatic cases in the population. The environmental compartment, which serves as a source of exposure to toxigenic V. cholerae, is also modeled separately based on the biology of causative bacterium, the shedding of V. cholerae O1 by humans into the environment, as well as the effects of precipitation and water temperature on the concentration and survival of V. cholerae in aquatic reservoirs. Although the number of reported cholera cases has declined compared to the initial outbreak in 2010, the increase in the number of susceptible population members and the presence of toxigenic V. cholerae in the environment estimated by the model indicate that without further improvements to drinking water and sanitation infrastructures, intermittent cholera outbreaks are likely to continue in Haiti. PMID- 26488621 TI - Efficient modification of the myostatin gene in porcine somatic cells and generation of knockout piglets. AB - Myostatin (MSTN) is a negative regulator of myogenesis, and disruption of its function causes increased muscle mass in various species. Here, we report the generation of MSTN-knockout (KO) pigs using genome editing technology combined with somatic-cell nuclear transfer (SCNT). Transcription activator-like effector nuclease (TALEN) with non-repeat-variable di-residue variations, called Platinum TALEN, was highly efficient in modifying genes in porcine somatic cells, which were then used for SCNT to create MSTN KO piglets. These piglets exhibited a double-muscled phenotype, possessing a higher body weight and longissimus muscle mass measuring 170% that of wild-type piglets, with double the number of muscle fibers. These results demonstrate that loss of MSTN increases muscle mass in pigs, which may help increase pork production for consumption in the future. PMID- 26488622 TI - Reply to: Glucarpidase for the Treatment of Methotrexate-Induced Renal Dysfunction and Delayed Methotrexate Excretion. PMID- 26488623 TI - Evaluation of Tear Osmolarity Changes After Photorefractive Keratectomy. AB - PURPOSE: To assess tear film stability, ocular surface disease index (OSDI) score, Schirmer test value, tear film breakup time (TBUT), and tear osmolarity after photorefractive keratectomy (PRK). METHODS: We enrolled 50 eyes from 25 patients who were PRK candidates (15 men, 10 women). The mean age was 31.9 +/- 4.5 years. Dry eye severity was evaluated using OSDI questionnaire, TBUT, Schirmer test, and tear osmolarity preoperatively and in each postoperative follow-up visit during the 4-month follow-up period. RESULTS: Tear osmolarity changed from 302 +/- 5.9 mOsm/L preoperatively to 308.8 +/- 5.8 mOsm/L (P < 0.0001) and 304.1 +/- 9.4 mOsm/L (P = 0.40) after 2 and 4 months, respectively. Schirmer test did not change significantly 4 months after PRK (P = 0.410). TBUT decreased significantly after 2 months and did not return to its preoperative value after 4 months. Subjective complaints measured by OSDI score, improved after 4 months compared with the preoperative level. CONCLUSIONS: Although dry eye tests (Schirmer, TBUT, and tear osmolarity) are abnormal 2 months after PRK, they returned to preoperative values after 4 months. We can conclude that post PRK dry eye is a transient complication which will last less than 4 months with regular use of topical lubricants. PMID- 26488624 TI - Fungal Infections After Boston Type 1 Keratoprosthesis Implantation: Literature Review and In Vitro Antifungal Activity of Hypochlorous Acid. AB - PURPOSE: To review the current literature describing cases of fungal keratitis and endophthalmitis after Boston keratoprosthesis (KPro) implantation and to characterize the antifungal activity of 0.01% hypochlorous acid against medically relevant fungi. METHODS: A literature review of fungal keratitis or endophthalmitis in KPro patients from January 2001 to April 2015, and an in vitro time kill assay characterizing the fungicidal activity of 0.01% hypochlorous acid against fungi causing ocular infections. RESULTS: Fifteen publications, predominantly retrospective case series, were identified. Infection rates after KPro implantation ranged from 0.009 to 0.02 fungal infections per patient-year of follow-up. The largest single-surgeon series reported an incidence of 2.4% for fungal endophthalmitis during a 10-year period. Causative organisms included both yeasts and molds. Outcomes were favorable if infections were caught early and treated appropriately; less favorable outcomes were reported in developing countries where fungal species are endemic and resources are limited. 0.01% hypochlorous acid is rapidly fungicidal, reducing the number of viable yeast cells or mold conidia by at least 99.99% within 60 seconds. The antifungal activity extended to all molds (Acremonium kiliense, Aspergillus flavus, Aspergillus fumigatus, Fusarium solani, and Mucor indicus) and yeast species (Candida albicans and Candida parapsilosis) tested. CONCLUSIONS: Fungal infections remain a lifelong concern in patients after KPro implantation. There is a growing need for a standard antifungal prophylaxis regimen, especially in the developing world. The rapid broad-spectrum in vitro fungicidal activity of 0.01% hypochlorous acid against all fungi tested makes it an attractive candidate as an antifungal prophylaxis in KPro patients. PMID- 26488625 TI - Aspheric Ablation Depth as the Target Depth for Enhanced Wavefront-Guided Myopic Retreatments After Laser-Assisted In Situ Keratomileusis. AB - PURPOSE: To propose a new adjustment method and present the clinical result of wavefront-guided myopic laser-assisted in situ keratomileusis (LASIK) retreatment with an aspheric program-targeted central ablation depth to avoid refractive overcorrection. METHODS: Thirty-two eyes (of 20 consecutive patients) that underwent wavefront-guided LASIK myopic retreatment between January 2009 and February 2012 after primary wavefront-guided LASIK for myopia were included. Wavefront-guided retreatments were performed using the Bausch and Lomb Technolas 217z100 excimer laser system. Wavefront-guided retreatments were adjusted by setting the ablation depth corresponding to the ablation depth determined by the aspheric program. The refractive outcome, visual outcome, and outcome of high order aberrations (HOAs) were analyzed. Linear mixed models were also used to evaluate the predicting factors for retreatment offset. RESULTS: Mean age was 29.5 +/- 3.1 years. Spherical equivalent (SE) before retreatment was -1.0 +/- 0.44 diopters (D) (range, -2.25 to -0.5). Twelve months postoperatively, SE was 0.03 +/- 0.12 D, and 31 of 32 eyes had an uncorrected visual acuity 20/20 or better. All eyes were within +/-0.5 D. None of the eyes had lost >2 lines of Snellen visual acuity. Safety and efficacy indices were 1.03 and 1.00, respectively. Total HOA, coma, and trefoil were reduced significantly (P = 0.028, P = 0.036, P = 0.034, respectively). Predictive factors for the amount of offset required are significantly related to preoperative SE (P = 0.006) and spherical aberration (P = 0.03, adjusted by SE). CONCLUSIONS: Setting the target ablation depth using the aspheric program provided high refractive predictability with a satisfactory visual outcome, significant reduction of HOAs, and no overcorrections. PMID- 26488626 TI - Autofluorescence Signatures of Seven Pathogens: Preliminary in Vitro Investigations of a Potential Diagnostic for Acanthamoeba Keratitis. AB - PURPOSE: Acanthamoeba keratitis can cause devastating damage to the human cornea and is often difficult to diagnose by routine clinical methods. In this preliminary study, we investigated whether Acanthamoeba may be distinguished from other common corneal pathogens through its autofluorescence response. Although only a small number of pathogens were studied, the identification of a unique Acanthamoeba signature would indicate that autofluorescence spectroscopy as a diagnostic method merits further investigation. METHODS: Samples of 7 common pathogens (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Elizabethkingia miricola, Achromobacter ruhlandii, Candida albicans, and Acanthamoeba castellanii) in solution were excited with ultraviolet light at a number of successive, narrow wavebands between 260 and 400 nm, and their fluorescence response recorded. Principal Component Analysis was used to allow better visualization of the differences in response to UV light for different species. RESULTS: Acanthamoeba was found to possess a characteristic autofluorescence response and was easily distinguished from E. coli, S. aureus, P. aeruginosa, E. miricola, A. ruhlandii, and C. albicans over a wide range of excitation wavelengths. We also found a clear discrimination between E. coli, C. albicans, and P. aeruginosa at an excitation wavelength of 274 nm, whereas E. miricola, S. aureus, and A. ruhlandii could be separated using an excitation wavelength of 308 nm. CONCLUSIONS: Our results, although preliminary, indicate that autofluorescence spectroscopy shows promise as a diagnostic technique for keratitis. We intend to expand the set of pathogens studied before assessing the feasibility of the technique in vivo by introducing cultures onto pig corneas. PMID- 26488627 TI - Iris Fixation of Unstable Anterior Chamber Intraocular Lenses. AB - PURPOSE: To present a surgical approach for the treatment of unstable anterior chamber intraocular lenses (ACIOLs). METHODS: We present a series of 8 patients who underwent iris fixation of an unstable open-looped ACIOL associated with progressive corneal damage. The loops of the intraocular lens were firmly fixated to the iris using 9-0 or 10-0 polypropylene sutures. In 2 cases, iris fixation was associated with penetrating keratoplasty. The other cases were performed using a relatively closed-system technique. RESULTS: All procedures were uneventful, with no intraoperative or postoperative complications. Suture fixation effectively prevented anterior-posterior or propelling movement. The ACIOLs in all cases were stable and well centered at the end of follow-up. CONCLUSIONS: Fixation of an existing unstable angle-supported ACIOL to the iris is an effective and simple alternative to intraocular lens exchange and posterior chamber fixation. PMID- 26488628 TI - Retroillumination Photography Analysis Enhances Clinical Definition of Severe Fuchs Corneal Dystrophy. AB - PURPOSE: Retroillumination photography analysis (RPA) provides an objective assessment of the number and distribution of guttae in Fuchs corneal dystrophy. Here, we assess its correlation with clinical grading using slit-lamp biomicroscopy across varying levels of severity. METHODS: Retroillumination photographs were conducted for 95 affected corneas with slit-lamp flash photography after pupillary dilation. Individual guttae were counted manually and the position of individual points recorded. Clinical grading using the Krachmer scale was documented for each eye during examination, and regression analyses were performed to identify the strength of association with number of guttae. We assessed range at each stage of clinical grading and used the Mann-Whitney U test to assess whether clinical grading levels demonstrated successively higher numbers of guttae. RESULTS: Krachmer score ranged from 1 to 5, with mean of 2.6. Mean numbers of guttae at each level of severity were 289 (1+), 999 (2+), 2669 (3+), 5474 (4+), and 7133 (5+). Each stage demonstrated significantly higher numbers of guttae than its preceding level except from 4+ to 5+ (P = 0.30), consistent with the definition of 4+ as the highest level defined by the presence of guttae. Higher levels of clinical grading were associated with larger ranges of guttae (P < 0.01). A linear regression model resulted in a strong fit between RPA and Krachmer score (r = 0.81). CONCLUSIONS: In this largest study of RPA data and comparison with subjective clinical grading of Fuchs dystrophy severity, RPA correlates strongly and demonstrates enhanced definition of severity at advanced stages of disease. PMID- 26488629 TI - Incidence of Stevens-Johnson Syndrome and Chemical Burns to the Eye. AB - PURPOSE: This population-based observational study was designed to estimate the incidence and distribution of SJS-spectrum (Stevens-Johnson syndrome, toxic epidermal necrolysis, and toxic epidermal Necrolysis/Stevens-Johnson syndrome overlap) and chemical burns (alkali or acid burn of the cornea/conjunctiva) in the United States and extrapolate these numbers to the world. METHODS: All patients evaluated in 961 hospital-based US emergency departments between July 1, 2010, and June 30, 2012 were identified retrospectively using the Nationwide Emergency Department Sample (NEDS) from the Agency for Healthcare Research and Quality. SJS-spectrum and chemical burn cases were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes. RESULTS: A mean of 3834 new SJS-spectrum cases per year were identified in the United States, resulting in an incidence rate of 12.35 new cases per million per year. Similarly, a mean of 15,865 new chemical burn cases per year were identified, resulting in an incidence rate of 51.10 new cases per million per year. CONCLUSIONS: If the incidence of SJS-spectrum is approximately uniform the world-over, extrapolation from the US figure would amount to approximately 86,500 new cases per year in the world. Extrapolation of ocular chemical burns to the world is difficult because the incidence and severity are anticipated to be higher in the developing world than in the United States. Still, using a US incidence rate, a minimum of 357,710 burn accidents would be expected to occur worldwide every year; there are presently too few data available to calculate the degree of severity and bilaterality. PMID- 26488630 TI - Assessment of the Tear Meniscus Using Optical Coherence Tomography in Patients With Type 2 Diabetes Mellitus. AB - PURPOSE: To analyze tear meniscus dimensions with Fourier domain-optical coherence tomography (FD-OCT) in patients with type 2 diabetes mellitus. METHODS: Patients with type 2 diabetes without diabetic retinopathy (DR) (n = 54), with nonproliferative DR (n = 45), with proliferative DR (PDR) (n = 25), and controls (n = 45) were enrolled. Hemoglobin A1c and Early Treatment Diabetic Retinopathy Study (ETDRS) stages of DR were evaluated. Schirmer test (ST), tear breakup time test, and fluorescein corneal staining were carried out. Tear meniscus height (TMH), tear meniscus depth (TMD), and tear meniscus area (TMA) were obtained by FD-OCT. RESULTS: TMH, TMD, and TMA in the diabetes and control groups were 233 +/ 79 MUm, 148 +/- 53 MUm, and 0.026 +/- 0.015 mm, and 261 +/- 67 MUm, 167 +/- 49 MUm, and 0.032 +/- 0.017 mm, respectively. All parameters were lower in diabetes (all P < 0.01). And the values in PDR were 185 +/- 90 MUm, 117 +/- 50 MUm, and 0.017 +/- 0.010 mm which were lower than those in control and nonproliferative DR (227 +/- 71 MUm, 144 +/- 50 MUm, and 0.023 +/- 0.010 mm) (all P < 0.01). TMH, TMD, and TMA correlated with ST (P < 0.01, P = 0.02, and P < 0.01, respectively) and the corneal staining score (all P < 0.01). Patients with longer diabetes duration and a history of panretinal photocoagulation showed significantly decreased TMH, TMD, and TMA (P < 0.01). CONCLUSIONS: OCT, along with tear breakup time and ST, is an effective way to assess tear function in type 2 diabetes. Patients with PDR and a history of panretinal photocoagulation showed lower tear meniscus parameters. The decrease in tear meniscus parameters was correlated with diabetes duration. PMID- 26488631 TI - A Simple and Reliable Technique to Orient Donor Corneal Tissue Using the Radial Width of the Surgical Limbus. AB - PURPOSE: To develop a method based on identification of the widest region of the surgical limbus that can yield quick and accurate orientation of excised human donor corneas. METHODS: Corneoscleral tissue from donors 49 to 75 years old was marked at the temporal sclera at the time of recovery. Digital images obtained from 20 corneas stored in viewing chambers, retroilluminated and viewed from the endothelial side, were used to quantify the per-degree radial width of the surgical limbus, defined as the distance from the scleral spur to clear cornea. To evaluate differences in radial width among regions, measurements were compared with the intracorneal mean limbal width, and a per-degree z-score was calculated by averaging among corneas. Using images of corneas with the temporal mark masked and the sidedness known, 6 observers were subjected to a blinded trial of 10 corneas to determine the central point of the widest limbal region of each cornea. RESULTS: Compared with the intracorneal mean, the mean radial width of the surgical limbus was greatest in the superior quadrant, and the difference compared with the inferior, nasal, and temporal quadrants was significant (P < 0.0001). The superior region was identified with 100% accuracy in blinded trials. The average absolute difference between the predicted and actual central point of the superior limbus was 9.75 +/- 0.30 degrees. CONCLUSIONS: The radial width of the surgical limbus is greatest in the superior region of the cornea and can be used as a diagnostic feature to orient donor corneal tissue. PMID- 26488632 TI - Systemic Comorbidities of Dry Eye Syndrome: The Korean National Health and Nutrition Examination Survey V, 2010 to 2012. AB - PURPOSE: To identify systemic comorbidities in patients with dry eye syndrome in South Korea. METHODS: From 2010 to 2012, 17,364 participants aged 20 or older were randomly included in the nationwide Korean National Health and Nutrition Examination Survey V. The prevalence of dry eye syndrome and demographics of these patients were investigated. We performed conditional logistic regression analyses based on age, sex, residential area, education level, occupation type, and household income level to obtain the odds ratio for each systemic comorbidity among subjects with and without dry eye syndrome. RESULTS: The prevalence of dry eye syndrome in this study was 10.4%. Age [adjusted odds ratio (AOR): 1.02], female gender (AOR: 3.01), and indoor occupation (AOR: 1.30) were associated with a higher prevalence of dry eye syndrome and found to be less prevalent in those residing in rural areas (AOR: 0.73) and with lower education levels (AOR: 0.66 0.99). With regard to systemic comorbidities, dyslipidemia (AOR: 1.63), degenerative arthritis (AOR: 1.56), rheumatoid arthritis (AOR: 1.44), thyroid disease (AOR: 1.79), and renal failure (AOR: 2.56) were associated with a significantly higher prevalence of dry eye syndrome. CONCLUSIONS: We found that patients with dry eye syndrome have a higher prevalence of several systemic comorbidities. A more comprehensive therapeutic approach considering the effect of systemic medication may be necessary in these patients. PMID- 26488633 TI - Packaged triboelectric nanogenerator with high endurability for severe environments. AB - Many factors in the environment (such as dust, moisture and rain) severely influence the output performance of a triboelectric nanogenerator (TNG), which greatly limits its application. In this work, we designed and fabricated a kind of packaged TNG (PTNG) that can work normally in dust and humidity for harvesting noise energy. Under a sound wave of 110 dB and 200 Hz, the PTNG can generate a maximum output voltage of 72 V and a maximum output current of 0.66 mA. In the structure of the PTNG, the frictional layers are fully isolated from the ambient environment, which makes it work steadily in dusty and humid conditions without any damping of the output performance. Moreover, it can be used as a stable power source to directly light up 24 red commercial light emitting diodes (LEDs) driven by sound even in a severely rainy environment. This PTNG has great potential to be applied in real environments, which is critically important to the application of TNGs. PMID- 26488634 TI - Potential role of immunoglobulin replacement therapy on MRI measures in multiple sclerosis: a systematic review. AB - Multiple sclerosis is a chronic immune-mediated disease of the nervous system. In the early disease course, axonal loss and neurodegeneration occurs that could possibly lead to irreversible neurological impairments. Preventing brain atrophy may have important clinical implications affecting treatment decisions in the future. In recent years, research efforts have directed towards finding agents to modify the disease and reduce brain volume loss. Intravenous immunoglobulin (IVIg) may have some potential roles in this regard. PMID- 26488635 TI - Interplay between singlet and triplet excited states in a conformationally locked donor-acceptor dyad. AB - The synthesis and photophysical characterization of a palladium(II) porphyrin - anthracene dyad bridged via short and conformationally rigid bicyclo[2.2.2]octadiene spacer were achieved. A spectroscopic investigation of the prepared molecule in solution has been undertaken to study electronic energy transfer in excited singlet and triplet states between the anthracene and porphyrin units. By using steady-state and time-resolved photoluminescence spectroscopy it was shown that excitation of the singlet excited state of the anthracene leads to energy transfer to the lower-lying singlet state of porphyrin. Alternatively, excitation of the porphyrin followed by intersystem crossing to the triplet state leads to very fast energy transfer to the triplet state of anthracene. The rate of this energy transfer has been determined by transient absorption spectroscopy. Comparative studies of the dynamics of triplet excited states of the dyad and reference palladium octaethylporphyrin (PdOEP) have been performed. PMID- 26488636 TI - Selective Activation of Shoulder, Trunk, and Arm Muscles: A Comparative Analysis of Different Push-Up Variants. AB - CONTEXT: The push-up is a widely used exercise for upper limb strengthening that can be performed with many variants. A comprehensive analysis of muscle activation during the ascendant phase (AP) and descendant phase (DP) in different variants could be useful for trainers and rehabilitators. OBJECTIVE: To obtain information on the effect of different push-up variants on the electromyography (EMG) of a large sample of upper limb muscles and to investigate the role of the trunk and abdomen muscles during the AP and DP. DESIGN: Cross-sectional study. SETTING: University laboratory. PATIENTS OR OTHER PARTICIPANTS: Eight healthy, young volunteers without a history of upper extremity or spine injury. INTERVENTION(S): Participants performed a set of 10 repetitions for each push-up variant: standard, wide, narrow, forward (FP), and backward (BP). Surface EMG of 12 selected muscles and kinematics data were synchronously recorded to describe the AP and DP. MAIN OUTCOME MEASURE(S): Mean EMG activity of the following muscles was analyzed: serratus anterior, deltoideus anterior, erector spinae, latissimus dorsi, rectus abdominis, triceps brachii caput longus, triceps brachii caput lateralis, obliquus externus abdominis, pectoralis major sternal head, pectoralis major clavicular head, trapezius transversalis, and biceps brachii. RESULTS: The triceps brachii and pectoralis major exhibited greater activation during the narrow-base variant. The highest activation of abdomen and back muscles was recorded for the FP and BP variants. The DP demonstrated the least electrical activity across all muscles, with less marked differences for the abdominal and erector spinae muscles because of their role as stabilizers. CONCLUSIONS: Based on these findings, we suggest the narrow-base variant to emphasize triceps and pectoralis activity and the BP variant for total upper body strength conditioning. The FP and BP variants should be implemented carefully in participants with low back pain because of the greater activation of abdominal and back muscles. PMID- 26488637 TI - Metal Ni-loaded g-C3N4 for enhanced photocatalytic H2 evolution activity: the change in surface band bending. AB - A series of Ni@g-C3N4 composites were synthesized by a simple solvent thermal method using melamine and acetylacetone nickel as precursors. The results of X ray diffraction, transmission electron microscopy and high resolution transmission electron microscopy indicate that Ni was successfully loaded on g C3N4. And the Ni loaded greatly enhances the photocatalytic H2 evolution activity of g-C3N4 compared to the pure g-C3N4. In order to study the role of Ni, the surface photovoltage, the surface photocurrent and photoluminescence measurements were used to investigate the photogenerated charge properties of g-C3N4. What is more, Mott-Schottky plots and work function measurements confirmed the surface band bending change of g-C3N4 contacting with Ni. Those results demonstrate that Ni coating deepens surface band bending of g-C3N4, resulting in higher separation efficiency of photogenerated charge carriers, which is contributed to the enhanced photocatalytic H2 evolution activity. PMID- 26488639 TI - Atomistic Glimpse of the Orderly Chaos of One Protein. PMID- 26488640 TI - Dipole-Potential-Mediated Effects on Ion Pump Kinetics. AB - The kinetics of conformational changes of P-type ATPases necessary for the occlusion or deocclusion of transported ions are known to be sensitive to the composition of the surrounding membrane, e.g., phospholipid content, mole percentage of cholesterol, and the presence of lipid-bound anions. Research has shown that many membrane components modify the dipole potential of the lipid head group region. Based on the observation that occlusion/deocclusion reactions of ion pumps perturb the membrane surrounding the protein, a mechanism is suggested whereby dipole potential modifiers induce preferential stabilization or destabilization of occluded or nonoccluded states of the protein, leading to changes in the forward and backward rate constants for the transition. The mechanism relies on the assumption that conformational changes of the protein are associated with changes in its hydrophobic thickness that requires a change in local lipid packing density to allow hydrophobic matching with the membrane. The changes in lipid packing density cause changes in local lipid dipole potential that are responsible for the dependence of conformational kinetics on dipole potential modifiers. The proposed mechanism has the potential to explain effects of lipid composition on the kinetics of any membrane protein undergoing significant changes in its membrane cross-sectional area during its activity. PMID- 26488641 TI - 3D Data Mapping and Real-Time Experiment Control and Visualization in Brain Slices. AB - Here, we propose two basic concepts that can streamline electrophysiology and imaging experiments in brain slices and enhance data collection and analysis. The first idea is to interface the experiment with a software environment that provides a 3D scene viewer in which the experimental rig, the brain slice, and the recorded data are represented to scale. Within the 3D scene viewer, the user can visualize a live image of the sample and 3D renderings of the recording electrodes with real-time position feedback. Furthermore, the user can control the instruments and visualize their status in real time. The second idea is to integrate multiple types of experimental data into a spatial and temporal map of the brain slice. These data may include low-magnification maps of the entire brain slice, for spatial context, or any other type of high-resolution structural and functional image, together with time-resolved electrical and optical signals. The entire data collection can be visualized within the 3D scene viewer. These concepts can be applied to any other type of experiment in which high-resolution data are recorded within a larger sample at different spatial and temporal coordinates. PMID- 26488642 TI - MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories. AB - As molecular dynamics (MD) simulations continue to evolve into powerful computational tools for studying complex biomolecular systems, the necessity of flexible and easy-to-use software tools for the analysis of these simulations is growing. We have developed MDTraj, a modern, lightweight, and fast software package for analyzing MD simulations. MDTraj reads and writes trajectory data in a wide variety of commonly used formats. It provides a large number of trajectory analysis capabilities including minimal root-mean-square-deviation calculations, secondary structure assignment, and the extraction of common order parameters. The package has a strong focus on interoperability with the wider scientific Python ecosystem, bridging the gap between MD data and the rapidly growing collection of industry-standard statistical analysis and visualization tools in Python. MDTraj is a powerful and user-friendly software package that simplifies the analysis of MD data and connects these datasets with the modern interactive data science software ecosystem in Python. PMID- 26488643 TI - Traction Forces of Endothelial Cells under Slow Shear Flow. AB - Endothelial cells are constantly exposed to fluid shear stresses that regulate vascular morphogenesis, homeostasis, and disease. The mechanical responses of endothelial cells to relatively high shear flow such as that characteristic of arterial circulation has been extensively studied. Much less is known about the responses of endothelial cells to slow shear flow such as that characteristic of venous circulation, early angiogenesis, atherosclerosis, intracranial aneurysm, or interstitial flow. Here we used a novel, to our knowledge, microfluidic technique to measure traction forces exerted by confluent vascular endothelial cell monolayers under slow shear flow. We found that cells respond to flow with rapid and pronounced increases in traction forces and cell-cell stresses. These responses are reversible in time and do not involve reorientation of the cell body. Traction maps reveal that local cell responses to slow shear flow are highly heterogeneous in magnitude and sign. Our findings unveil a low-flow regime in which endothelial cell mechanics is acutely responsive to shear stress. PMID- 26488644 TI - Mapping the Processivity Determinants of the Kinesin-3 Motor Domain. AB - Kinesin superfamily members play important roles in many diverse cellular processes, including cell motility, cell division, intracellular transport, and regulation of the microtubule cytoskeleton. How the properties of the family defining motor domain of distinct kinesins are tailored to their different cellular roles remains largely unknown. Here, we employed molecular-dynamics simulations coupled with energetic calculations to infer the family-specific interactions of kinesin-1 and kinesin-3 motor domains with microtubules in different nucleotide states. We then used experimental mutagenesis and single molecule motility assays to further assess the predicted residue-wise determinants of distinct kinesin-microtubule binding properties. Collectively, our results identify residues in the L8, L11, and alpha6 regions that contribute to family-specific microtubule interactions and whose mutation affects motor microtubule complex stability and processive motility (the ability of an individual motor to take multiple steps along its microtubule filament). In particular, substitutions of prominent kinesin-3 residues with those found in kinesin-1, namely, R167S/H171D, K266D, and R346M, were found to decrease kinesin 3 processivity 10-fold and thus approach kinesin-1 levels. PMID- 26488645 TI - Active Biochemical Regulation of Cell Volume and a Simple Model of Cell Tension Response. AB - Active contractile forces exerted by eukaryotic cells play significant roles during embryonic development, tissue formation, and cell motility. At the molecular level, small GTPases in signaling pathways can regulate active cell contraction. Here, starting with mechanical force balance at the cell cortex, and the recent discovery that tension-sensitive membrane channels can catalyze the conversion of the inactive form of Rho to the active form, we show mathematically that this active regulation of cellular contractility together with osmotic regulation can robustly control the cell size and membrane tension against external mechanical or osmotic shocks. We find that the magnitude of active contraction depends on the rate of mechanical pulling, but the cell tension can recover. The model also predicts that the cell exerts stronger contractile forces against a stiffer external environment, and therefore exhibits features of mechanosensation. These results suggest that a simple system for maintaining homeostatic values of cell volume and membrane tension could explain cell tension response and mechanosensation in different environments. PMID- 26488646 TI - Discrimination of Kinetic Models by a Combination of Microirradiation and Fluorescence Photobleaching. AB - Fluorescence recovery after photobleaching (FRAP) is an excellent tool to measure the chemical rate constants of fluorescently labeled proteins in living cells. Usually FRAP experiments are conducted with the protein concentrations being in a steady state, i.e., when the association and dissociation of the proteins are equilibrated. This is a strong limitation because situations in which rate constants change with time are of great scientific interest. In this study, we present an approach in which FRAP is used shortly after DNA damage introducing laser microirradiation, which results in the recruitment of the DNA clamp protein proliferating cell nuclear antigen (PCNA) to DNA lesions. We establish different kinetic models that are compatible with the observed PCNA recruitment data if FRAP is not used. By using FRAP at different time points during protein accumulation, we can not only exclude two out of three models, but we can also determine the rate constants with increased reliability. This study thus demonstrates the feasibility of using FRAP during protein recruitment and its application in the discrimination of possible kinetic models. PMID- 26488647 TI - Characterizing Cellular Biophysical Responses to Stress by Relating Density, Deformability, and Size. AB - Cellular physical properties are important indicators of specific cell states. Although changes in individual biophysical parameters, such as cell size, density, and deformability, during cellular processes have been investigated in great detail, relatively little is known about how they are related. Here, we use a suspended microchannel resonator (SMR) to measure single-cell density, volume, and passage time through a narrow constriction of populations of cells subjected to a variety of environmental stresses. Osmotic stress significantly affects density and volume, as previously shown. In contrast to density and volume, the effect of an osmotic challenge on passage time is relatively small. Deformability, as determined by comparing passage times for cells with similar volume, exhibits a strong dependence on osmolarity, indicating that passage time alone does not always provide a meaningful proxy for deformability. Finally, we find that protein synthesis inhibition, cell-cycle arrest, protein kinase inhibition, and cytoskeletal disruption result in unexpected relationships among deformability, density, and volume. Taken together, our results suggest that by measuring multiple biophysical parameters, one can detect unique characteristics that more specifically reflect cellular behaviors. PMID- 26488648 TI - Cytoskeletal Network Morphology Regulates Intracellular Transport Dynamics. AB - Intracellular transport is essential for maintaining proper cellular function in most eukaryotic cells, with perturbations in active transport resulting in several types of disease. Efficient delivery of critical cargos to specific locations is accomplished through a combination of passive diffusion and active transport by molecular motors that ballistically move along a network of cytoskeletal filaments. Although motor-based transport is known to be necessary to overcome cytoplasmic crowding and the limited range of diffusion within reasonable timescales, the topological features of the cytoskeletal network that regulate transport efficiency and robustness have not been established. Using a continuum diffusion model, we observed that the time required for cellular transport was minimized when the network was localized near the nucleus. In simulations that explicitly incorporated network spatial architectures, total filament mass was the primary driver of network transit times. However, filament traps that redirect cargo back to the nucleus caused large variations in network transport. Filament polarity was more important than filament orientation in reducing average transit times, and transport properties were optimized in networks with intermediate motor on and off rates. Our results provide important insights into the functional constraints on intracellular transport under which cells have evolved cytoskeletal structures, and have potential applications for enhancing reactions in biomimetic systems through rational transport network design. PMID- 26488649 TI - Increased Energy Demand during Adrenergic Receptor Stimulation Contributes to Ca(2+) Wave Generation. AB - While beta-adrenergic receptor (beta-AR) stimulation ensures adequate cardiac output during stress, it can also trigger life-threatening cardiac arrhythmias. We have previously shown that proarrhythmic Ca(2+) waves during beta-AR stimulation temporally coincide with augmentation of reactive oxygen species (ROS) production. In this study, we tested the hypothesis that increased energy demand during beta-AR stimulation plays an important role in mitochondrial ROS production and Ca(2+)-wave generation in rabbit ventricular myocytes. We found that beta-AR stimulation with isoproterenol (0.1 MUM) decreased the mitochondrial redox potential and the ratio of reduced to oxidated glutathione. As a result, beta-AR stimulation increased mitochondrial ROS production. These metabolic changes induced by isoproterenol were associated with increased sarcoplasmic reticulum (SR) Ca(2+) leak and frequent diastolic Ca(2+) waves. Inhibition of cell contraction with the myosin ATPase inhibitor blebbistatin attenuated oxidative stress as well as spontaneous SR Ca(2+) release events during beta-AR stimulation. Furthermore, we found that oxidative stress induced by beta-AR stimulation caused the formation of disulfide bonds between two ryanodine receptor (RyR) subunits, referred to as intersubunit cross-linking. Preventing RyR cross-linking with N-ethylmaleimide decreased the propensity of Ca(2+) waves induced by beta-AR stimulation. These data suggest that increased energy demand during sustained beta-AR stimulation weakens mitochondrial antioxidant defense, causing ROS release into the cytosol. By inducing RyR intersubunit cross-linking, ROS can increase SR Ca(2+) leak to the critical level that can trigger proarrhythmic Ca(2+) waves. PMID- 26488650 TI - Measuring the Refractive Index of Bovine Corneal Stromal Cells Using Quantitative Phase Imaging. AB - The cornea is the primary refractive lens in the eye and transmits >90% of incident visible light. It has been suggested that the development of postoperative corneal haze could be due to an increase in light scattering from activated corneal stromal cells. Quiescent keratocytes are thought to produce crystallins that match the refractive index of their cytoplasm to the surrounding extracellular material, reducing the amount of light scattering. To test this, we measured the refractive index (RI) of bovine corneal stromal cells, using quantitative phase imaging of live cells in vitro, together with confocal microscopy. The RI of quiescent keratocytes (RI = 1.381 +/- 0.004) matched the surrounding matrix, thus supporting the hypothesis that keratocyte cytoplasm does not scatter light in the normal cornea. We also observed that the RI drops after keratocyte activation (RI = 1.365 +/- 0.003), leading to a mismatch with the surrounding intercellular matrix. Theoretical scattering models showed that this mismatch would reduce light transmission in the cornea. We conclude that corneal transparency depends on the matching of refractive indices between quiescent keratocytes and the surrounding tissue, and that after surgery or wounding, the resulting RI mismatch between the activated cells and their surrounds significantly contributes to light scattering. PMID- 26488651 TI - Temperature Effect on Ionic Current and ssDNA Transport through Nanopores. AB - We have investigated the role of electrostatic interactions in the transport of nucleic acids and ions through nanopores. The passage of DNA through nanopores has so far been conjectured to involve a free-energy barrier for entry, followed by a downhill translocation where the driving voltage accelerates the polymer. We have tested the validity of this conjecture by using two toxins, alpha-hemolysin and aerolysin, which differ in their shape, size, and charge. The characteristic timescales in each toxin as a function of temperature show that the entry barrier is ~15 kBT and the translocation barrier is ~35 kBT, although the electrical force in the latter step is much stronger. Resolution of this fact, using a theoretical model, reveals that the attraction between DNA and the charges inside the barrel of the pore is the most dominant factor in determining the translocation speed and not merely the driving electrochemical potential gradient. PMID- 26488652 TI - alpha-Tocopherol Is Well Designed to Protect Polyunsaturated Phospholipids: MD Simulations. AB - The presumptive function for alpha-tocopherol (alphatoc) in membranes is to protect polyunsaturated lipids against oxidation. Although the chemistry of the process is well established, the role played by molecular structure that we address here with atomistic molecular-dynamics simulations remains controversial. The simulations were run in the constant particle NPT ensemble on hydrated lipid bilayers composed of SDPC (1-stearoyl-2-docosahexaenoylphosphatidylcholine, 18:0 22:6PC) and SOPC (1-stearoyl-2-oleoylphosphatidylcholine, 18:0-18:1PC) in the presence of 20 mol % alphatoc at 37 degrees C. SDPC with SA (stearic acid) for the sn-1 chain and DHA (docosahexaenoic acid) for the sn-2 chain is representative of polyunsaturated phospholipids, while SOPC with OA (oleic acid) substituted for the sn-2 chain serves as a monounsaturated control. Solid-state (2)H nuclear magnetic resonance and neutron diffraction experiments provide validation. The simulations demonstrate that high disorder enhances the probability that DHA chains at the sn-2 position in SDPC rise up to the bilayer surface, whereby they encounter the chromanol group on alphatoc molecules. This behavior is reflected in the van der Waals energy of interaction between alphatoc and acyl chains, and illustrated by density maps of distribution for acyl chains around alphatoc molecules that were constructed. An ability to more easily penetrate deep into the bilayer is another attribute conferred upon the chromanol group in alphatoc by the high disorder possessed by DHA. By examining the trajectory of single molecules, we found that alphatoc flip-flops across the SDPC bilayer on a submicrosecond timescale that is an order-of-magnitude greater than in SOPC. Our results reveal mechanisms by which the sacrificial hydroxyl group on the chromanol group can trap lipid peroxyl radicals within the interior and near the surface of a polyunsaturated membrane. At the same time, water-soluble reducing agents that regenerate alphatoc can access the chromanol group when it locates at the surface. PMID- 26488653 TI - Effect of the N-Terminal Helix and Nucleotide Loading on the Membrane and Effector Binding of Arl2/3. AB - The small GTP-binding proteins Arl2 and Arl3, which are close homologs, share a number of interacting partners and act as displacement factors for prenylated and myristoylated cargo. Nevertheless, both proteins have distinct biological functions. Whereas Arl3 is considered a ciliary protein, Arl2 has been reported to be involved in tubulin folding, mitochondrial function, and Ras signaling. How these different roles are attained by the two homolog proteins is not fully understood. Recently, we showed that the N-terminal amphipathic helix of Arl3, but not that of Arl2, regulates the release of myristoylated ciliary proteins from the GDI-like solubilizing factor UNC119a/b. In the biophysical study presented here, both proteins are shown to exhibit a preferential localization and clustering in liquid-disordered domains of phase-separated membranes. However, the membrane interaction behavior differs significantly between both proteins with regard to their nucleotide loading. Whereas Arl3 and other Arf proteins with an N-terminal amphipathic helix require GTP loading for the interaction with membranes, Arl2 binds to membranes in a nucleotide-independent manner. In contrast to Arl2, the N-terminal helix of Arl3 increases the binding affinity to UNC119a. Furthermore, UNC119a impedes membrane binding of Arl3, but not of Arl2. Taken together, these results suggest an interplay among the nucleotide status of Arl3, the location of the N-terminal helix, membrane fluidity and binding, and the release of lipid modified cargos from carriers such as UNC119a. Since a specific Arl3-GEF is postulated to reside inside cilia, the N terminal helix of Arl3*GTP would be available for allosteric regulation of UNC119a cargo release only inside cilia. PMID- 26488654 TI - The Effect of Membrane Lipid Composition on the Formation of Lipid Ultrananodomains. AB - Some lipid mixtures form membranes containing submicroscopic (nanodomain) ordered lipid domains (rafts). Some of these nanodomains are so small (radius <5 nm) that they cannot be readily detected with Forster resonance energy transfer (FRET) labeled lipid pairs with large Ro. We define such domains as ultrananodomains. We studied the effect of lipid structure/composition on the formation of ultrananodomains in lipid vesicles using a dual-FRET-pair approach in which only one FRET pair had Ro values that were sufficiently small to detect the ultrananodomains. Using this approach, we measured the temperature dependence of domain and ultrananodomain formation for vesicles composed of various mixtures containing a high-Tm lipid (brain sphingomyelin (SM)) or dipalmitoyl phosphatidylcholine (DPPC)), low-Tm lipid (dioleoylphosphatidylcholine (DOPC) or 1-palmitoyl 2-oleoyl phosphatidylcholine (POPC)), and a lower (28 mol %) or higher (38 mol %) cholesterol concentration. For every lipid combination tested, the thermal stabilities of the ordered domains were similar, in agreement with our prior studies. However, the range of temperatures over which ultrananodomains formed was highly lipid-type dependent. Overall, vesicles that were closest to mammalian plasma membrane in lipid composition (i.e., with brain SM, POPC, and/or higher cholesterol) formed ultrananodomains in preference to larger domains over the widest temperature range. Relative to DPPC, the favorable effect of SM on ultrananodomain formation versus larger domains was especially large. In addition, the favorable effect of a high cholesterol concentration, and of POPC versus DOPC, on the formation of ultrananodomains versus larger domains was greater in vesicles containing SM than in those containing DPPC. We speculate that it is likely that natural mammalian lipids are tuned to maximize the tendency to form ultrananodomains relative to larger domains. The observation that domain size is more sensitive than domain formation to membrane composition has implications for how membrane domain properties may be regulated in vivo. PMID- 26488655 TI - Influence of Hydroxylation, Chain Length, and Chain Unsaturation on Bilayer Properties of Ceramides. AB - Mammalian ceramides constitute a family of at least a few hundred closely related molecules distinguished by small structural differences, giving rise to individual molecular species that are expressed in distinct cellular compartments, or tissue types, in which they are believed to execute distinct functions. We have examined how specific structural details influence the bilayer properties of a selection of biologically relevant ceramides in mixed bilayers together with sphingomyelin, phosphatidylcholine, and cholesterol. The ceramide structure varied with regard to interfacial hydroxylation, the identity of the headgroup, the length of the N-acyl chain, and the position of cis-double bonds in the acyl chains. The interactions of the ceramides with sphingomyelin, their lateral segregation into ceramide-rich domains in phosphatidylcholine bilayers, and the effect of cholesterol on such domains were studied with DSC and various fluorescence-based approaches. The largest differences arose from the presence and relative position of cis-double bonds, causing destabilization of the ceramide's interactions and lateral packing relative to common saturated and hydroxylated species. Less variation was observed as a consequence of interfacial hydroxylation and the N-acyl chain length, although an additional hydroxyl in the sphingoid long-chain base slightly destabilized the ceramide's interactions and packing relative to a nonhydroxyceramide, whereas an additional hydroxyl in the N acyl chain had the opposite effect. In conclusion, small structural details conferred variance in the bilayer behavior of ceramides, some causing more dramatic changes in the bilayer properties, whereas others imposed only fine adjustments in the interactions of ceramides with other membrane lipids, reflecting possible functional implications in distinct cell or tissue types. PMID- 26488656 TI - Can Specific Protein-Lipid Interactions Stabilize an Active State of the Beta 2 Adrenergic Receptor? AB - G-protein-coupled receptors are eukaryotic membrane proteins with broad biological and pharmacological relevance. Like all membrane-embedded proteins, their location and orientation are influenced by lipids, which can also impact protein function via specific interactions. Extensive simulations totaling 0.25 ms reveal a process in which phospholipids from the membrane's cytosolic leaflet enter the empty G-protein binding site of an activated beta2 adrenergic receptor and form salt-bridge interactions that inhibit ionic lock formation and prolong active-state residency. Simulations of the receptor embedded in an anionic membrane show increased lipid binding, providing a molecular mechanism for the experimental observation that anionic lipids can enhance receptor activity. Conservation of the arginine component of the ionic lock among Rhodopsin-like G protein-coupled receptors suggests that intracellular lipid ingression between receptor helices H6 and H7 may be a general mechanism for active-state stabilization. PMID- 26488657 TI - Thermodynamic Interrogation of the Assembly of a Viral Genome Packaging Motor Complex. AB - Viral terminase enzymes serve as genome packaging motors in many complex double stranded DNA viruses. The functional motors are multiprotein complexes that translocate viral DNA into a capsid shell, powered by a packaging ATPase, and are among the most powerful molecular motors in nature. Given their essential role in virus development, the structure and function of these biological motors is of considerable interest. Bacteriophage lambda-terminase, which serves as a prototypical genome packaging motor, is composed of one large catalytic subunit tightly associated with two DNA recognition subunits. This protomer assembles into a functional higher-order complex that excises a unit length genome from a concatemeric DNA precursor (genome maturation) and concomitantly translocates the duplex into a preformed procapsid shell (genome packaging). While the enzymology of lambda-terminase has been well described, the nature of the catalytically competent nucleoprotein intermediates, and the mechanism describing their assembly and activation, is less clear. Here we utilize analytical ultracentrifugation to determine the thermodynamic parameters describing motor assembly and define a minimal thermodynamic linkage model that describes the effects of salt on protomer assembly into a tetrameric complex. Negative stain electron microscopy images reveal a symmetric ring-like complex with a compact stem and four extended arms that exhibit a range of conformational states. Finally, kinetic studies demonstrate that assembly of the ring tetramer is directly linked to activation of the packaging ATPase activity of the motor, thus providing a direct link between structure and function. The implications of these results with respect to the assembly and activation of the functional packaging motor during a productive viral infection are discussed. PMID- 26488658 TI - Nucleosome Core Particle Disassembly and Assembly Kinetics Studied Using Single Molecule Fluorescence. AB - The stability of the nucleosome core particle (NCP) is believed to play a major role in regulation of gene expression. To understand the mechanisms that influence NCP stability, we studied stability and dissociation and association kinetics under different histone protein (NCP) and NaCl concentrations using single-pair Forster resonance energy transfer and alternating laser excitation techniques. The method enables distinction between folded, unfolded, and intermediate NCP states and enables measurements at picomolar to nanomolar NCP concentrations where dissociation and association reactions can be directly observed. We reproduced the previously observed nonmonotonic dependence of NCP stability on NaCl concentration, and we suggest that this rather unexpected behavior is a result of interplay between repulsive and attractive forces within positively charged histones and between the histones and the negatively charged DNA. Higher NaCl concentrations decrease the attractive force between the histone proteins and the DNA but also stabilize H2A/H2B histone dimers, and possibly (H3/H4)2 tetramers. An intermediate state in which one DNA arm is unwrapped, previously observed at high NaCl concentrations, is also explained by this salt induced stabilization. The strong dependence of NCP stability on ion and histone concentrations, and possibly on other charged macromolecules, may play a role in chromosomal morphology. PMID- 26488659 TI - Secondary Structure Analysis of a Functional Construct of Caveolin-1 Reveals a Long C-Terminal Helix. AB - Caveolin-1 is an integral membrane protein that is the primary component of cell membrane invaginations called caveolae. While caveolin-1 is known to participate in a myriad of vital cellular processes, structural data on caveolin-1 of any kind is severely limited. In order to rectify this dearth, secondary structure analysis of a functional construct of caveolin-1, containing the intact C terminal domain, was performed using NMR spectroscopy in lyso myristoylphosphatidylglycerol micelles. Complete backbone assignments of caveolin 1 (residues 62-178) were made, and it was determined that residues 62-79 were dynamic; residues 89-107, 111-128, and 132-175 were helical; and residues 80-88, 108-110, and 129-131 represent unstructured breaks between the helices. PMID- 26488660 TI - A Thermodynamic Model for Genome Packaging in Hepatitis B Virus. AB - Understanding the fundamentals of genome packaging in viral capsids is important for finding effective antiviral strategies and for utilizing benign viral particles for gene therapy. While the structure of encapsidated genomic materials has been routinely characterized with experimental techniques such as cryo electron microscopy and x-ray diffraction, much less is known about the molecular driving forces underlying genome assembly in an intracellular environment and its in vivo interactions with the capsid proteins. Here we study the thermodynamic basis of the pregenomic RNA encapsidation in human Hepatitis B virus in vivo using a coarse-grained molecular model that captures the essential components of nonspecific intermolecular interactions. The thermodynamic model is used to examine how the electrostatic interaction between the packaged RNA and the highly charged C-terminal domains (CTD) of capsid proteins regulate the nucleocapsid formation. The theoretical model predicts optimal RNA content in Hepatitis B virus nucleocapsids with different CTD lengths in good agreement with mutagenesis measurements, confirming the predominant role of electrostatic interactions and molecular excluded-volume effects in genome packaging. We find that the amount of encapsidated RNA is not linearly correlated with the net charge of CTD tails as suggested by earlier theoretical studies. Our thermodynamic analysis of the nucleocapsid structure and stability indicates that ~10% of the CTD residues are free from complexation with RNA, resulting in partially exposed CTD tails. The thermodynamic model also predicts the free energy of complex formation between macromolecules, which corroborates experimental results for the impact of CTD truncation on the nucleocapsid stability. PMID- 26488661 TI - Structural Basis for the Inhibition of Gas Hydrates by alpha-Helical Antifreeze Proteins. AB - Kinetic hydrate inhibitors (KHIs) are used commercially to inhibit gas hydrate formation and growth in pipelines. However, improvement of these polymers has been constrained by the lack of verified molecular models. Since antifreeze proteins (AFPs) act as KHIs, we have used their solved x-ray crystallographic structures in molecular modeling to explore gas hydrate inhibition. The internal clathrate water network of the fish AFP Maxi, which extends to the protein's outer surface, is remarkably similar to the {100} planes of structure type II (sII) gas hydrate. The crystal structure of this water web has facilitated the construction of in silico models for Maxi and type I AFP binding to sII hydrates. Here, we have substantiated our models with experimental evidence of Maxi binding to the tetrahydrofuran sII model hydrate. Both in silico and experimental evidence support the absorbance-inhibition mechanism proposed for KHI binding to gas hydrates. Based on the Maxi crystal structure we suggest that the inhibitor adsorbs to the gas hydrate lattice through the same anchored clathrate water mechanism used to bind ice. These results will facilitate the rational design of a next generation of effective green KHIs for the petroleum industry to ensure safe and efficient hydrocarbon flow. PMID- 26488662 TI - Disorder-to-Order Transition of an Active-Site Loop Mediates the Allosteric Activation of Sortase A. AB - Intrinsically disordered proteins and intrinsically disordered regions are implicated in many biological functions and associated with many diseases, but their conformational characterizations are challenging. The disordered beta6/beta7 loop of Staphylococcus aureus sortase A is involved in the binding of both sorting signals and calcium. Calcium binding allosterically activates the enzyme, but the detailed mechanism has been unclear. Here we adapted the replica exchange with solute tempering method to sample the conformations of the beta6/beta7 loop, in apo form and in three liganded forms (bound with a sorting signal or calcium or both). The extensive molecular dynamics simulations yield atomic details of the disordered-to-order transition of the loop and suggest a mechanism for allosteric activation: calcium binding results in partial closure and ordering of the loop, thereby leading to preorganization of the binding pocket for the sorting signal. The approach has general applicability to the study of intrinsically disordered regions. PMID- 26488663 TI - Local Crystalline Structure in an Amorphous Protein Dense Phase. AB - Proteins exhibit a variety of dense phases ranging from gels, aggregates, and precipitates to crystalline phases and dense liquids. Although the structure of the crystalline phase is known in atomistic detail, little attention has been paid to noncrystalline protein dense phases, and in many cases the structures of these phases are assumed to be fully amorphous. In this work, we used small-angle neutron scattering, electron microscopy, and electron tomography to measure the structure of ovalbumin precipitate particles salted out with ammonium sulfate. We found that the ovalbumin phase-separates into core-shell particles with a core radius of ~2 MUm and shell thickness of ~0.5 MUm. Within this shell region, nanostructures comprised of crystallites of ovalbumin self-assemble into a well defined bicontinuous network with branches ~12 nm thick. These results demonstrate that the protein gel is comprised in part of nanocrystalline protein. PMID- 26488664 TI - Critical Timing without a Timer for Embryonic Development. AB - Timing of embryonic development is precisely controlled, but the mechanisms underlying biological timers are still unclear. Here, a validated model for timing under control of Sonic Hedgehog is revisited and generalized to an arbitrary number of genes. The developmental dynamics where a temporal sequence of gene expression recapitulates a steady-state spatial pattern can be realized through a simple network close to criticality, controlled by the duration of exposure to a morphogen. Criticality simultaneously accounts for many observed biological properties, such as timing, multistability, and canalization of genetic expression. This process can be parsimoniously generalized in many dimensions with a minimum number of genes, all repressing each other with asymmetrical strengths, which also explains sequential activation of different fates. Separation of timescales allows for a simple analytical interpretation. Finally, it is shown that even in the presence of noise, coupling between cells preserves criticality and robust patterning. The model offers a simple theoretical framework for the study of emergent developmental timers. PMID- 26488665 TI - Theory of Triplet Excitation Transfer in the Donor-Oxygen-Acceptor System: Application to Cytochrome b6f. AB - Theoretical consideration is presented of the triplet excitation dynamics in donor-acceptor systems in conditions where the transfer is mediated by an oxygen molecule. It is demonstrated that oxygen may be involved in both real and virtual intramolecular triplet-singlet conversions in the course of the process under consideration. Expressions describing a superexchange donor-acceptor coupling owing to a participation of the bridging twofold degenerate oxygen's virtual singlet state are derived and the transfer kinetics including the sequential (hopping) and coherent (distant) routes are analyzed. Applicability of this theoretical description to the pigment-protein complex cytochrome b6f, by considering the triplet excitation transfer from the chlorophyll a molecule to distant beta-carotene, is discussed. PMID- 26488667 TI - Ambulatory Continuous Peripheral Nerve Blocks and the Perioperative Surgical Home. PMID- 26488666 TI - DNA-Binding Kinetics Determines the Mechanism of Noise-Induced Switching in Gene Networks. AB - Gene regulatory networks are multistable dynamical systems in which attractor states represent cell phenotypes. Spontaneous, noise-induced transitions between these states are thought to underlie critical cellular processes, including cell developmental fate decisions, phenotypic plasticity in fluctuating environments, and carcinogenesis. As such, there is increasing interest in the development of theoretical and computational approaches that can shed light on the dynamics of these stochastic state transitions in multistable gene networks. We applied a numerical rare-event sampling algorithm to study transition paths of spontaneous noise-induced switching for a ubiquitous gene regulatory network motif, the bistable toggle switch, in which two mutually repressive genes compete for dominant expression. We find that the method can efficiently uncover detailed switching mechanisms that involve fluctuations both in occupancies of DNA regulatory sites and copy numbers of protein products. In addition, we show that the rate parameters governing binding and unbinding of regulatory proteins to DNA strongly influence the switching mechanism. In a regime of slow DNA binding/unbinding kinetics, spontaneous switching occurs relatively frequently and is driven primarily by fluctuations in DNA-site occupancies. In contrast, in a regime of fast DNA-binding/unbinding kinetics, switching occurs rarely and is driven by fluctuations in levels of expressed protein. Our results demonstrate how spontaneous cell phenotype transitions involve collective behavior of both regulatory proteins and DNA. Computational approaches capable of simulating dynamics over many system variables are thus well suited to exploring dynamic mechanisms in gene networks. PMID- 26488668 TI - Effects of female sex hormones on expression of the Ang-(1-7)/Mas-R/nNOS pathways in rat brain. AB - Female sex hormones are considered to reduce the risk of ischemic stroke. As a part of the renin-angiotensin system, angiotensin-(1-7) [Ang-(1-7)] has recently been reported to play a role in protecting neuronal tissues from ischemic stroke. Thus, we examined the effects of female sex hormones on the levels of Ang-(1-7) and its downstream pathways in the brain. Female rats were ovariectomized and 17beta-estradiol (17beta-EST), progesterone (PGR), or a combination of 17beta-EST plus PGR were administered. Our data demonstrated that lack of female sex hormones significantly decreased the levels of Ang-(1-7) in the cerebral cortex and hippocampal CA1 area. Also, we observed a linear relationship between cortex levels of Ang-(1-7) and plasma brain natriuretic peptide levels (as an indicator for risk of ischemic stroke). We further showed that lack of female sex hormones decreased the expression of Ang-(1-7), Mas-receptor (Mas-R), and neuronal nitric oxide synthase (nNOS). Overall, our findings show for the first time that Ang-(1 7) and Mas-R/nNOS in the cortex are influenced by circulating 17beta-EST and (or) PGR, whereas Ang-(1-7) and its pathways in the hippocampal CA1 area are primarily altered by 17beta-EST. This suggests that female sex hormones play a role in regulating the expression of Ang-(1-7) and its pathways during ischemic brain injuries. PMID- 26488670 TI - Evidence for Conformational Mechanism on the Binding of TgMIC4 with beta Galactose-Containing Carbohydrate Ligand. AB - A deeper understanding of the role of sialic/desialylated groups during TgMIC4 glycoproteins interactions has importance to better clarify the odd process of host cell invasion by members of the apicomplexan phylum. Within this context, we evaluated the interaction established by recombinant TgMIC4 (the whole molecule) with sialylated (bovine fetuin) and desialylated (asialofetuin) glycoproteins by using functionalized quartz crystal microbalance with dissipation monitoring (QCM D). A suitable receptive surface containing recombinant TgMIC4 for monitoring beta-galactose-containing carbohydrate ligand (limit of quantification ~ 40 MUM) was designed and used as biomolecular recognition platform to study the binding and conformational mechanisms of TgMIC4 during the interaction with glycoprotein containing (fetuin), or not, terminal sialic group (asialofetuin). It was inferred that the binding/interaction monitoring depends on the presence/absence of sialic groups in target protein and is possible to be differentiated through a slower binding kinetic step using QCM-D approach (which we are inferring to be thus associated with beta-galactose ligand). This slower binding/interaction step is likely supposed (from mechanical energetic analysis obtained in QCM-D measurements) to be involved with Toxoplasma gondii (the causative agent of toxoplasmosis) parasitic invasion accompanied by ligand (galactose) induced binding conformational change (i.e., cell internalization process can be additionally dependent on structural conformational changes, controlled by the absence of sialic groups and to the specific binding with galactose), in addition to TgMIC4-glycoprotein solely recognition binding process. PMID- 26488671 TI - Benzoic Acid Catalyzed Annulations of alpha-Amino Acids and Aromatic Aldehydes Containing an ortho-Michael Acceptor: Access to 2,5-Dihydro-1H-benzo[c]azepines and 10,11-Dihydro-5H-benzo[e]pyrrolo[1,2-a]azepines. AB - A novel one-pot efficient synthesis of 2,5-dihydro-1H-benzo[c]azepines and 10,11 dihydro-5H-benzo[e]pyrrolo[1,2-a]azepines from alpha-amino acids and aromatic aldehydes containing an ortho-Michael acceptor is reported via decarboxylative annulations without metal catalysts in yields of 52-91%. Under microwave irradiation, this protocol provides rapid access to polycyclic ring systems (only 5 min in most cases). PMID- 26488672 TI - The role of medical and psychosocial factors for unfavourable coronary risk factor control. AB - OBJECTIVES: This project aims to identify socio-demographic, medical and psychosocial factors (study factors) associated with coronary risk control and prognosis, and to test their impact in a representative sample of coronary heart disease (CHD) patients. DESIGN: The first phase includes a cross-sectional study designed to explore the association between the study factors and coronary risk factor control in CHD patients. Data from hospital records, a questionnaire, clinical examination and blood samples were collected. The independent effects of study factors on subsequent coronary events will be explored prospectively by controlling for baseline coronary risk factors. In the second phase, we will test the effect of tailored interventions to modify the study factors associated with unfavourable risk profile in phase I. RESULTS: In all 1366 patients (21% women), aged 18-80 years with a coronary event on average 17 (2-38) months prior to study participation were identified (83% participation rate). Of the 239 patients who refused participation, 229 patients consented to analysis of hospital record data (non- participants). CONCLUSIONS: If the study variables contribute to CHD risk factors and prognosis, the present project may be important for the development of prevention programs by tailoring these to the patients perceived needs and behaviour profiles. PMID- 26488673 TI - Differences in ability to perform activities of daily living among women with fibromyalgia: A cross-sectional study. AB - OBJECTIVE: To investigate whether the Assessment of Motor and Process Skills (AMPS), the physical function subscales of the Fibromyalgia Impact Questionnaire (FIQ PF) and the 36-item Short Form (SF-36 PF) can identify subgroups of women with fibromyalgia with clinically relevant differences in ability to perform activities of daily living. DESIGN: Cross-sectional study. SUBJECTS: A total of 257 women with fibromyalgia. METHODS: Participants were evaluated with the AMPS (measuring activities of daily living motor and activities of daily living process ability), FIQ and SF-36. AMPS independence cut-offs were used to divide the participants into 4 subgroups. Clinically relevant differences between subgroups were investigated based on the AMPS, FIQ PF and SF-36 PF. RESULT: Participants in the 4 AMPS-derived subgroups demon-strated clinically relevant differences in observed activities of daily living motor and process ability. Neither the FIQ PF nor the SF-36 PF could differentiate between subgroups with clinically relevant differences in AMPS activities of daily living process ability. CONCLUSION: Activities of daily living process skills reflect underlying organizational and adaptive capacities of the individual and are relevant targets for interventions aiming at improving activities of daily living ability. Since self-report instruments do not capture differences in activities of daily living process ability, clinicians should include observations-based assessment of activities of daily living ability in order to individualize interventions offered. PMID- 26488674 TI - K2Pb3(CO3)3F2 and KCdCO3F: Novel Fluoride Carbonates with Layered and 3D Framework Structures. AB - Two new mixed metal fluoride carbonates, KCdCO3F and K2Pb3(CO3)3F2, have been synthesized by solvothermal and solid-state techniques. KCdCO3F crystallizes in the acentric nonpolar space group P6m2, and its structure features a three dimensional anionic framework in which the CdCO3 layers are further interconnected by bridging F(-) anions with the negative charge balanced by K(+) cations. K2Pb3(CO3)3F2 crystallizes in the centrosymmetric space group P63/mmc, and its structure exhibits a layered anionic skeleton featuring corner-shared PbO6F and PbO6F2 polyhedra. UV-vis diffuse reflectance spectroscopy studies show that the short-wavelength absorption edges of KCdCO3F and K2Pb3(CO3)3F2 are 227 and 287 nm, respectively. The second harmonic generation (SHG) measurement reveals that KCdCO3F is a phase-matchable material for generation of doubled frequency light at both 532 and 266 nm, with a large SHG response of approximately 5.2 times that of KH2PO4 (KDP) at 532 nm and a moderate SHG response of approximately 0.75 times that of beta-BaB2O4 (BBO) at 266 nm. Therefore, it is a promising UV material for fourth harmonic generation on a 1064 nm Q-switched Nd:YAG laser. PMID- 26488676 TI - Treatment of Antipsychotic-Related Akathisia Revisited: The Role of Serotonin 2A Receptor Antagonists. AB - Akathisia remains a prevalent, clinically significant, and therapeutically challenging adverse event associated with antipsychotic treatment. Compelling evidence supports therapeutic efficacy and clinical utility of agents with marked serotonin 2A receptor antagonism, primarily low-dose mirtazapine, as an effective and well-tolerated antiakathisia treatment. PMID- 26488675 TI - Fast Versus Slow Strategy of Switching Patients With Schizophrenia to Aripiprazole From Other Antipsychotics. AB - This study aimed to compare strategies differing in the speed of switching schizophrenic patients to aripiprazole from other antipsychotic agents, with dual administration for 2 weeks and then tapering off the current antipsychotic in fast (within 1 week) versus slow (within 4 weeks) strategies. This 8-week, open label, randomized, parallel study assigned patients with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizoaffective disorder to either the fast-switching (n = 38) or slow-switching (n = 41) group. Efficacy assessments at 5 time points included Positive and Negative Syndrome Scale and Clinical Global Impression scale. Safety assessments included extrapyramidal symptoms, metabolic profile, serum prolactin level, QTc interval, and adverse events. Drug concentrations and cytochrome P450 CYP2D6 and CYP3A4 genotypes were also measured. The fast- and slow-switching groups were comparable in demographical and clinical features at baseline and dropout rate. In the intention-to-treat analysis using mixed-effects models, there were significant within-group decreases over time in the Positive and Negative Syndrome Scale total scores (P = 0.03) and its subscores except for positive subscores, whereas no between-group differences were found. A reduction in body weight (P = 0.01) and lower levels of total cholesterol (P = 0.03), triglycerides (P = 0.03), and prolactin (P = 0.01) were noted in both groups but no increase in extrapyramidal symptoms or prolongation of QTc. The blood concentrations of aripiprazole in all patients were in a therapeutic range at day 56, with CYP2D6*10 polymorphisms being associated with aripiprazole concentrations. In conclusion, there is no significant difference between the fast- and slow-switching strategy in terms of improvements in clinical symptoms and metabolic profile in this 8-week study. PMID- 26488677 TI - Comparison of Site-Based Versus Central Ratings in a Study of Generalized Anxiety Disorder. AB - Lack of standardization across sites and raters, poor interrater reliability, and possible scoring bias affecting the primary outcome measure contribute to a high failure rate in anxiety trials. Remote centralized raters who are blinded to protocol inclusion and exclusion criteria as well as visit number may standardize assessments across raters and eliminate scoring bias, decreasing placebo response and thereby increasing signal detection. The purpose of the primary study was to test the safety and efficacy of an anxiolytic in a double-blind, placebo controlled (no active comparator), multicenter trial. However, there was an additional prospective objective to explore site ratings compared with remote centralized ratings in the cohort of subjects on placebo. Site raters assessed subjects 6 times over an 8-week period. The primary outcome measure was the week 8 site-rated Hamilton Anxiety Scale (HAM-A). Remote centralized raters by telephone independently rated these subjects on the HAM-A at baseline and week 6. Of the 122 subjects selected by site raters and therefore randomized, remote centralized raters would have admitted 59 (48%) and excluded 63 (52%), based on their HAM-A ratings. The mean change from baseline in HAM-A total score in the placebo group admitted to the study by site raters was 9.3, significantly higher than the 5.9 point mean change on placebo as measured by the remote centralized raters.The data are consistent with the potential for qualification bias at baseline when rated by sites. The results make a strong case for using strategies to ensure that baseline scoring is truly independent of the pressure to enroll. PMID- 26488678 TI - The Ascendancy of Second-Generation Antipsychotics as Frontline Antimanic Agents. AB - INTRODUCTION: Knowledge of the factors affecting the adoption of new medications can enhance mental health care and guide quality improvement and policy development. Food and Drug Administration indications for treating bipolar disorder with several second-generation antipsychotics (SGAs) in the 2000s represent an opportunity to identify factors that impact the spread of a then innovative treatment through a new population. METHODS: Analysis of Department of Veterans Affairs administrative data identified the population of 170,811 veterans diagnosed with bipolar disorder from 2003 to 2010. We analyzed time trends and predictors of antimanic choice (SGA vs other) among the 40,512 outpatients with bipolar disorder who initiated their first VA outpatient antimanic prescription, using multinomial logistic regression in month-by-month analyses. We conducted classwise analyses and investigated prespecified predictors among specific agents. RESULTS: In classwise analyses, SGAs supplanted lithium, valproate, and carbamazepine/oxcarbazepine as the most commonly initiated antimanics by 2007. Psychosis, but not other indices of severity, predicted SGA initiation. Demographic analyses did not identify substantial disparities in initiation of SGAs. Drug-specific analyses revealed some consideration of medical comorbidities in choosing among specific antimanic agents, although effect sizes were small. Most patients initiating an antimanic had received an antidepressant in the previous year. DISCUSSION: Second generation antipsychotics quickly became the frontline antimanic treatment for bipolar disorder, although antidepressants most commonly predated antimanic prescriptions. Second-generation antipsychotics were used for a broad range of patients rather than being restricted to a severely ill subpopulation. The modest association of antimanic choice with relevant medical comorbidities suggests that continued attention to quality prescribing practices is warranted. PMID- 26488679 TI - Self-assembly of Natural and Unnatural Nucleobases at Surfaces and Interfaces. AB - The self-assembly of small organic molecules interacting via non-covalent forces is a viable approach towards the construction of highly ordered nanostructured materials. Among various molecular components, natural and unnatural nucleobases can undergo non-covalent self-association to form supramolecular architectures with ad hoc structural motifs. Such structures, when decorated with appropriate electrically/optically active units, can be used as scaffolds to locate such units in pre-determined positions in 2D on a surface, thereby paving the way towards a wide range of applications, e.g., in optoelectronics. This review discusses some of the basic concepts of the supramolecular engineering of natural and unnatural nucleobases and derivatives thereof as well as self-assembly processes on conductive solid substrates, as investigated by scanning tunnelling microscopy in ultra-high vacuum and at the solid/liquid interface. By unravelling the structure and dynamics of these self-assembled architectures with a sub nanometer resolution, a greater control over the formation of increasingly sophisticated functional systems is achieved. The ability to understand and predict how nucleobases interact, both among themselves as well as with other molecules, is extremely important, since it provides access to ever more complex DNA- and RNA-based nanostructures and nanomaterials as key components in nanomechanical devices. PMID- 26488680 TI - Corrigendum: Fertilization competence of the egg-coating envelope is regulated by direct interaction of dicalcin and gp41, the Xenopus laevis ZP3. PMID- 26488681 TI - Human Infection with Sporolactobacillus laevolacticus, Marseille, France. PMID- 26488682 TI - Highly Robust Silver Nanowire Network for Transparent Electrode. AB - Solution-processed silver nanowire networks are one of the promising candidates to replace a traditional indium tin oxide as next-generation transparent and flexible electrodes due to their ease of processing, moderate flexibility, high transparency, and low sheet resistance. To date, however, high stability of the nanowire networks remains a major challenge because the long-term usages of these electrodes are limited by their poor thermal and chemical stabilities. Existing methods for addressing this challenge mainly focus on protecting the nanowire network with additional layers that require vacuum processes, which can lead to an increment in manufacturing cost. Here, we report a straightforward strategy of a sol-gel processing as a fast and robust way to improve the stabilities of silver nanowires. Compared with reported nanoparticles embedded in nanowire networks, better thermal and chemical stabilities are achieved via sol-gel coating of TiO2 over the silver nanowire networks. The conformal surface coverage suppressed surface diffusion of silver atoms and prevented chemical corrosion from the environment. These results highlight the important role of the functional layer in providing better thermal and chemical stabilities along with improved electrical properties and mechanical robustness. The silver nanowire/TiO2 composite electrodes were applied as the source and drain electrodes for In2O3 thin-film transistors (TFTs) and the devices exhibited improved electrical performance annealed at 300 degrees C without the degradation of the electrodes. These key findings not only demonstrated a general and effective method to improve the thermal and chemical stabilities of metal nanowire networks but also provided a basic guideline toward rational design of highly efficient and robust composite electrodes. PMID- 26488683 TI - Ni/Cu-Catalyzed Defluoroborylation of Fluoroarenes for Diverse C-F Bond Functionalizations. AB - Ni/Cu-catalyzed transformation of fluoroarenes to arylboronic acid pinacol esters via C-F bond cleavage has been achieved. Further versatile derivatization of an arylboronic ester has allowed for the facile two-step conversion of a fluoroarene to diverse functionalized arenes, demonstrating the synthetic utility of the method. PMID- 26488684 TI - Integration of Switchable DNA-Based Hydrogels with Surfaces by the Hybridization Chain Reaction. AB - A novel method to assemble acrylamide/acrydite DNA copolymer hydrogels on surfaces, specifically gold-coated surfaces, is introduced. The method involves the synthesis of two different copolymer chains consisting of hairpin A, HA, modified acrylamide copolymer and hairpin B, HB, acrylamide copolymer. In the presence of a nucleic acid promoter monolayer associated with the surface, the hybridization chain reaction between the two hairpin-modified polymer chains is initiated, giving rise to the cross-opening of hairpins HA and HB and the formation of a cross-linked hydrogel on the surface. By the cofunctionalization of the HA- and HB-modified polymer chains with G-rich DNA tethers that include the G-quadruplex subunits, hydrogels of switchable stiffness are generated. In the presence of K(+)-ions, the hydrogel associated with the surface is cooperatively cross-linked by duplex units of HA and HB, and K(+)-ion-stabilized G-quadruplex units, giving rise to a stiff hydrogel. The 18-crown-6-ether stimulated elimination of the K(+)-ions dissociates the bridging G-quadruplex units, resulting in a hydrogel of reduced stiffness. The duplex/G-quadruplex cooperatively stabilized hydrogel associated with the surface reveals switchable electrocatalytic properties. The incorporation of hemin into the G-quadruplex units electrocatalyzes the reduction of H2O2. The 18-crown-6-ether stimulated dissociation of the hemin/G-quadruplex bridging units leads to a catalytically inactive hydrogel. PMID- 26488685 TI - Hydrodynamics of Particles at an Oil-Water Interface. AB - This study is a theoretical and experimental investigation of the hydrodynamics of the mutual approach of two floating spherical particles moving along an oil water interface. An analytical expression is obtained for the (inertialess) Stokes drag for an isolated particle translating on a flat interface as a function of the immersion depth into the water phase for the case in which the viscosity of the oil is much larger than that of the water. An approximation for the viscous drag due to the mutual approach of identical spheres is formulated as the product of the isolated drag multiplied by the resistance of approaching spheres in an infinite medium. Experiments are undertaken on the capillary attraction of large, millimeter-sized Teflon spheres floating at the interface between a very viscous oil and water. With the use of image visualization and particle tracking, the separation distance as a function of time [[Formula: see text](t)] is measured along with the immersion depth and predicted by setting the capillary attraction force equal to the viscous drag resistance. The excellent agreement validates the approximating formula. PMID- 26488686 TI - Cognitive behavioural therapy (brief versus standard duration) for schizophrenia. AB - BACKGROUND: Cognitive behavioural therapy for people with schizophrenia is a psychotherapeutic approach that establishes links between thoughts, emotions and behaviours and challenges dysfunctional thoughts. There is some evidence to suggest that cognitive behavioural therapy for people with psychosis (CBTp) might be an effective treatment for people with schizophrenia. There are however, limitations in its provision due to available resource and training issues. One way to tackle this issue might be to offer a brief version of CBTp. OBJECTIVES: To review the effects of brief CBTp (6 to 10 regular sessions given in less than 4 months and using a manual) for people with schizophrenia compared with standard CBTp (12 to 20 regular sessions given in 4 to 6 months and using a manual). SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (August 21, 2013 and August 26, 2015) which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO and registries of Clinical Trials. There are no language, date, document type, or publication status limitations for inclusion of records in the register. We inspected all references of the selected articles for further relevant trials. We also contacted experts in the field regarding brief CBTp studies. SELECTION CRITERIA: Randomised controlled trials involving adults with schizophrenia or related disorders, comparing brief cognitive behavioural therapy for people with psychosis versus standard CBTp. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and assessed studies for inclusion using pre-specified inclusion criteria. MAIN RESULTS: We found only seven studies which used a brief version of CBTp, but no study compared brief CBTp with CBTp of standard duration. No studies could be included. AUTHORS' CONCLUSIONS: Currently there is no literature available to compare brief with standard CBTp for people with schizophrenia. We cannot, therefore, conclude whether brief CBTp is as effective, less effective or even more effective than standard courses of the same therapy. This lack of evidence for brief CBTp has serious implications for research and practice. Well planned, conducted and reported randomised trials are indicated. PMID- 26488687 TI - Gender, Race, and Risk: Intersectional Risk Management in the Sale of Sex Online. AB - Sex worker experience of risk (e.g., physical violence or rape) is shaped by race, gender, and context. For web-based sex workers, experience of risk is comparatively minimal; what is unclear is how web-based sex workers manage risk and if online advertising plays a role in risk management. Building on intersectionality theory and research exploring risk management in sex work, we content-analyzed 600 escort advertisements from Backpage.com ( http://www.backpage.com ) to explore risk management in web-based sex work. To guide our research we asked: Do advertisements contain risk management messages? Does the use of risk management messaging differ by sex worker race or gender? Which groups have the highest overall use of risk management messages? Through a multivariate analysis of covariance (MANCOVA) we found that advertisements contained risk management messages and that uses of these phrases varied by race and gender. Blacks, women, and transgender women drove the use of risk management messages. Black and White transgender women had the highest overall use of these phrases. We conclude that risk management is an intersectional practice and that the use of risk management messages is a venue-specific manifestation of broader risk management priorities found in all venues where sex is sold. PMID- 26488688 TI - Voriconazole-associated phototoxic dermatoses and skin cancer. AB - Voriconazole's antifungal spectrum, oral bioavailability, and proven efficacy in treatment of invasive mycoses have led to its widespread off-label use for antifungal prophylaxis. There is an increasing recognition that long-term voriconazole use is associated with accelerated sun-induced skin changes that include acute phototoxicity reactions, photoaging, actinic keratosis and esp. among immunocompromised patients, skin cancers. The mechanisms underlying these dermatologic adverse events are not clearly understood. Population-risks of long term voriconazole use need to be prospectively investigated. This review aims to provide an in-depth assessment of published literature and highlight salient findings from retrospective studies and case series. A broad practical guideline for assessment and management of these patients is provided. PMID- 26488689 TI - Structures of multidrug and toxic compound extrusion transporters and their mechanistic implications. AB - Multidrug resistance poses grand challenges to the effective treatment of infectious diseases and cancers. Integral membrane proteins from the multidrug and toxic compound extrusion (MATE) family contribute to multidrug resistance by exporting a wide variety of therapeutic drugs across cell membranes. MATE proteins are conserved from bacteria to humans and can be categorized into the NorM, DinF and eukaryotic subfamilies. MATE transporters hold great appeal as potential therapeutic targets for curbing multidrug resistance, yet their transport mechanism remains elusive. During the past 5 years, X-ray structures of 4 NorM and DinF transporters have been reported and guided biochemical studies to reveal how MATE transporters extrude different drugs. Such advances, although substantial, have yet to be discussed collectively. Herein I review these structures and the unprecedented mechanistic insights that have been garnered from those structure-inspired studies, as well as lay out the outstanding questions that present exciting opportunities for future work. PMID- 26488690 TI - Transitional Chaos or Enduring Harm? The EHR and the Disruption of Medicine. PMID- 26488691 TI - A Randomized, Controlled Trial of Total Knee Replacement. AB - BACKGROUND: More than 670,000 total knee replacements are performed annually in the United States; however, high-quality evidence to support the effectiveness of the procedure, as compared with nonsurgical interventions, is lacking. METHODS: In this randomized, controlled trial, we enrolled 100 patients with moderate-to severe knee osteoarthritis who were eligible for unilateral total knee replacement. Patients were randomly assigned to undergo total knee replacement followed by 12 weeks of nonsurgical treatment (total-knee-replacement group) or to receive only the 12 weeks of nonsurgical treatment (nonsurgical-treatment group), which was delivered by physiotherapists and dietitians and consisted of exercise, education, dietary advice, use of insoles, and pain medication. The primary outcome was the change from baseline to 12 months in the mean score on four Knee Injury and Osteoarthritis Outcome Score subscales, covering pain, symptoms, activities of daily living, and quality of life (KOOS4); scores range from 0 (worst) to 100 (best). RESULTS: A total of 95 patients completed the 12 month follow-up assessment. In the nonsurgical-treatment group, 13 patients (26%) underwent total knee replacement before the 12-month follow-up; in the total-knee replacement group, 1 patient (2%) received only nonsurgical treatment. In the intention-to-treat analysis, the total-knee-replacement group had greater improvement in the KOOS4 score than did the nonsurgical-treatment group (32.5 vs. 16.0; adjusted mean difference, 15.8 [95% confidence interval, 10.0 to 21.5]). The total-knee-replacement group had a higher number of serious adverse events than did the nonsurgical-treatment group (24 vs. 6, P=0.005). CONCLUSIONS: In patients with knee osteoarthritis who were eligible for unilateral total knee replacement, treatment with total knee replacement followed by nonsurgical treatment resulted in greater pain relief and functional improvement after 12 months than did nonsurgical treatment alone. However, total knee replacement was associated with a higher number of serious adverse events than was nonsurgical treatment, and most patients who were assigned to receive nonsurgical treatment alone did not undergo total knee replacement before the 12-month follow-up. (Funded by the Obel Family Foundation and others; MEDIC ClinicalTrials.gov number, NCT01410409.). PMID- 26488692 TI - Changing Trends in P. falciparum Burden, Immunity, and Disease in Pregnancy. AB - BACKGROUND: Prevention of reinfection and resurgence is an integral component of the goal to eradicate malaria. However, the adverse effects of malaria resurgences are not known. METHODS: We assessed the prevalence of Plasmodium falciparum infection among 1819 Mozambican women who delivered infants between 2003 and 2012. We used microscopic and histologic examination and a quantitative polymerase-chain-reaction (qPCR) assay, as well as flow-cytometric analysis of IgG antibody responses against two parasite lines. RESULTS: Positive qPCR tests for P. falciparum decreased from 33% in 2003 to 2% in 2010 and increased to 6% in 2012, with antimalarial IgG antibody responses mirroring these trends. Parasite densities in peripheral blood on qPCR assay were higher in 2010-2012 (geometric mean [+/-SD], 409+/-1569 genomes per microliter) than in 2003-2005 (44+/-169 genomes per microliter, P=0.02), as were parasite densities in placental blood on histologic assessment (50+/-39% of infected erythrocytes vs. 4+/-6%, P<0.001). The malaria-associated reduction in maternal hemoglobin levels was larger in 2010 2012 (10.1+/-1.8 g per deciliter in infected women vs. 10.9+/-1.7 g per deciliter in uninfected women; mean difference, -0.82 g per deciliter; 95% confidence interval [CI], -1.39 to -0.25) than in 2003-2005 (10.5+/-1.1 g per deciliter vs. 10.6+/-1.5 g per deciliter; difference, -0.12 g per deciliter; 95% CI, -0.67 to 0.43), as was the reduction in birth weight (2863+/-440 g in women with past or chronic infections vs. 3070+/-482 g in uninfected women in 2010-2012; mean difference, -164.5 g; 95% CI, -289.7 to -39.4; and 2994+/-487 g vs. 3117+/-455 g in 2003-2005; difference, -44.8 g; 95% CI, -139.1 to 49.5). CONCLUSIONS: Antimalarial antibodies were reduced and the adverse consequences of P. falciparum infections were increased in pregnant women after 5 years of a decline in the prevalence of malaria. (Funded by Malaria Eradication Scientific Alliance and others.). PMID- 26488693 TI - A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. AB - BACKGROUND: Nonmelanoma skin cancers, such as basal-cell carcinoma and squamous cell carcinoma, are common cancers that are caused principally by ultraviolet (UV) radiation. Nicotinamide (vitamin B3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses. METHODS: In this phase 3, double-blind, randomized, controlled trial, we randomly assigned, in a 1:1 ratio, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years to receive 500 mg of nicotinamide twice daily or placebo for 12 months. Participants were evaluated by dermatologists at 3-month intervals for 18 months. The primary end point was the number of new nonmelanoma skin cancers (i.e., basal cell carcinomas plus squamous-cell carcinomas) during the 12-month intervention period. Secondary end points included the number of new squamous-cell carcinomas and basal-cell carcinomas and the number of actinic keratoses during the 12-month intervention period, the number of nonmelanoma skin cancers in the 6-month postintervention period, and the safety of nicotinamide. RESULTS: At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% confidence interval [CI], 4 to 38) in the nicotinamide group than in the placebo group (P=0.02). Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, -6 to 39] lower rate with nicotinamide, P=0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P=0.05). The number of actinic keratoses was 11% lower in the nicotinamide group than in the placebo group at 3 months (P=0.01), 14% lower at 6 months (P<0.001), 20% lower at 9 months (P<0.001), and 13% lower at 12 months (P=0.001). No noteworthy between-group differences were found with respect to the number or types of adverse events during the 12-month intervention period, and there was no evidence of benefit after nicotinamide was discontinued. CONCLUSIONS: Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients. (Funded by the National Health and Medical Research Council; ONTRAC Australian New Zealand Clinical Trials Registry number, ACTRN12612000625875.). PMID- 26488695 TI - Drug-Induced Megaloblastic Anemia. PMID- 26488696 TI - IMAGES IN CLINICAL MEDICINE. Bullous Pemphigoid. PMID- 26488694 TI - Eosinophilic Esophagitis. PMID- 26488697 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 33-2015. A 57-Year-Old Woman with Hair Loss and Deepening Voice. PMID- 26488698 TI - Parachutes and Preferences--A Trial of Knee Replacement. PMID- 26488699 TI - Declining Malaria Transmission and Pregnancy Outcomes in Southern Mozambique. PMID- 26488700 TI - Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. PMID- 26488701 TI - Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. PMID- 26488702 TI - Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. PMID- 26488703 TI - Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. PMID- 26488704 TI - Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. PMID- 26488705 TI - Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. PMID- 26488706 TI - Ischemic Optic Neuropathies. PMID- 26488707 TI - Ischemic Optic Neuropathies. PMID- 26488708 TI - Ischemic Optic Neuropathies. PMID- 26488709 TI - Ischemic Optic Neuropathies. PMID- 26488710 TI - The 21st Century Cures Act. PMID- 26488711 TI - The 21st Century Cures Act. PMID- 26488712 TI - The 21st Century Cures Act. PMID- 26488713 TI - The 21st Century Cures Act. PMID- 26488714 TI - Intravenous Immune Globulin for Statin-Triggered Autoimmune Myopathy. PMID- 26488715 TI - IMAGES IN CLINICAL MEDICINE. Megaduodenum in Systemic Sclerosis. PMID- 26488716 TI - Dermatofibrosarcoma Protuberans in a Patient With Cowden Syndrome: Revisiting the PTEN and PDGF Pathways. AB - PTEN hamartoma tumor syndrome, of which Cowden syndrome (CS) is the most recognized variant, is characterized by multiple benign and malignant tumors of ectodermal, mesodermal, and endodermal origins, secondary to germline mutation in the phosphatase and tensin homolog (PTEN) gene. Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive malignant fibroblastic/myofibroblastic tumor of the skin, characterized by the t(17:22)(q22:q13) translocation resulting in fusion of the COL1A1 and PDGFB genes. An association between CS and DFSP has not been reported in the literature to date. The authors have encountered a male patient with CS and a history of DFSP that developed adjacent to a sclerotic fibroma on the parietal scalp, both excised at age 7. He presented at age 21 with an enlarging pink nodule at the same site on the parietal scalp. Excision revealed a dermal and subcutaneous storiform spindle cell proliferation with fat entrapment and positive staining for CD34, consistent with DFSP. Fluorescence in situ hybridization confirmed PDGFB gene rearrangement. PTEN expression in the patient's recurrent DFSP was nearly absent when compared with that of sporadic DFSP. To our knowledge, this is the first report of DFSP in a patient with CS. Although the association is likely to be coincidental, the authors revisited the PTEN and the PDGF pathways to speculate any possible interplay of the 2 conditions on a molecular level. PMID- 26488717 TI - Umbilical Granuloma in a 2-Month-Old Patient: Histopathology of a Common Clinical Entity. AB - Umbilical granulomas are the most common anomaly of the umbilicus in neonates and infants. These lesions are characterized by an overgrowth of granulation tissue that persists at the base of the umbilical cord after its separation. Histologically, they consist of granulation tissue, which is composed of fibroblasts, inflammatory cells, and vascular endothelial cells set in an edematous stroma. Although umbilical granulomas are commonly seen clinically, there are no reports of their histopathology in the literature. The authors present the histology of this clinical finding in a 2-month-old infant, as it is important for the pathologist to be aware of this benign entity and distinguish it from other umbilical anomalies that may be of greater clinical significance. PMID- 26488718 TI - Multiple Clustered Dermatofibromas Associated With Pulmonary Arterial Hypertension. AB - BACKGROUND: Dermatofibromas (DFs) are common, benign, fibrohistiocytic tumors of the skin. Clinically, if they present in a rapid succession, they are termed multiple eruptive DFs. When they arise in a localized distribution, they are termed multiple clustered dermatofibromas (MCDFs). These DF variants are rare, and the subtype of multiple eruptive DFs has been associated with autoimmune diseases, hypertriglyceridemia, pregnancy, HIV, and primary pulmonary hypertension. Conversely, there is a paucity of published clinical associations with MCDF. METHODS: A 23-year-old white woman with pulmonary arterial hypertension presented with a 7-year history of multiple, asymptomatic, firm, brown, and violaceous papules clustered on the right hip. RESULTS: Histopathologic examination of the biopsies demonstrated acanthotic epidermis, proliferation of cytologically bland fibrohistiocytic spindle cells in a fascicular pattern in the dermis, and collagen trapping on the periphery. Immunohistochemistry was focally positive for factor XIIIa and negative for CD34, thus supporting the clinical diagnosis of MCDF. CONCLUSIONS: A case of MCDF associated with pulmonary arterial hypertension is presented. To date, there have been greater than 25 reported cases of MCDF, but only one other publication has described an associated systemic comorbidity. PMID- 26488719 TI - An Unusual Growth on the Nipple: Question. PMID- 26488720 TI - An Unusual Growth on the Nipple: Answer. PMID- 26488721 TI - Removal and Re-use of Tar-contaminated Sediment by Freeze-dredging at a Coking Plant Lulea, Sweden. AB - Submerged tar-contaminated sediment are generally very loose, which makes remediation challenging. We tested if a modified version of freeze-dredging could be used to remove and dewater such sediment in a canal down-stream a coking plant. PVC hoses carrying a heat medium were placed horizontally in the submerged sediment. Five days of freezing allowed straightforward removal of most of the sediment. Flat freeze cells were placed side by side in the canal to remove the rest. The freeze-thaw process increased the dry substance content from approximately 50 to 80%. Outdoors storage under rainy conditions did not re-wet the dried sediment. The material was successfully used as feed-stock in the coking plant, with the double cost-benefit of avoided transportation to deposit and reduced use of coal. The study demonstrates that freeze-dredging can facilitate removal, storage and beneficial re-use of submerged tar-contaminated sediment. PMID- 26488724 TI - Thoracoscopic CDH Repair--A Survey on Opinion and Experience Among IPEG Members. AB - BACKGROUND: Thoracoscopic repair of congenital diaphragmatic hernia (CDH) has become a popular approach. As there is an ongoing discussion on whether the benefits of the thoracoscopic repair outweigh the potential side effects, we aimed to investigate the opinion and experience of the members of the International Pediatric Endosurgery Group (IPEG) on this topic. MATERIALS AND METHODS: An online survey was conducted between October and December 2013 on behalf of the IPEG Research Committee. All 536 IPEG members were contacted by e mail and asked to complete an anonymous questionnaire that included 28 items on the management of CDH. RESULTS: One hundred sixty-one pediatric surgeons completed the questionnaire. Contraindications to thoracoscopic repair included the following: patient on extracorporeal membrane oxygenation (ECMO) (78%); preoperative need for ECMO (42%); right-sided hernia (15%); liver in chest (32%); weight <2.5 kg (35%); and persistent right-to-left shunting (41%). Fifty-two percent of participants said that during thoracoscopic CDH repair they would tolerate any pH. In contrast, 48% indicated that they would only tolerate pH/partial pressure of CO2 (pCO2) levels down/up to 7.2/80 mm Hg (range: pH, 6.9 7.3; pCO2, 55-100 mm Hg). If a patch was needed, 39% of participants said they would continue thoracoscopically, 31% would convert, and 31% stated that the decision would depend on the size of the defect. Fifty-seven percent of participants reported recurrences after thoracoscopic repair, which occurred within 6 months in 43% of the cases, after 6 months in 37%, and both before and after in 20% of the cases. Overall, 50% of surgeons stated that CDH can be repaired equally by thoracoscopy and open approaches, and 50% disagreed with this statement. CONCLUSIONS: Thoracoscopic CDH repair is currently being performed by 89% of all participating IPEG members. ECMO, either active or previously, and persistent right-to-left shunting are the main deterrents to thoracoscopic repair. The fact that only 50% of surgeons stated that CDH can be repaired equally by thoracoscopy and open surgery suggests that future studies should focus on identifying the appropriate patient population. PMID- 26488725 TI - The Inhibition by Oxaliplatin, a Platinum-Based Anti-Neoplastic Agent, of the Activity of Intermediate-Conductance Ca2+-Activated K+ Channels in Human Glioma Cells. AB - Oxaliplatin (OXAL) is a third-generation organoplatinum which is effective against advanced cancer cells including glioma cells. How this agent and other related compounds interacts with ion channels in glioma cells is poorly understood. OXAL (100 uM) suppressed the amplitude of whole-cell K+ currents (I(K)); and, either DCEBIO or ionomycin significantly reversed OXAL-mediated inhibition of I(K) in human 13-06-MG glioma cells. In OXAL-treated cells, TRAM-34 did not suppress I(K) amplitude in these cells. The intermediate-conductance Ca(2+)-activated K+ (IK(Ca)) channels subject to activation by DCEBIO and to inhibition by TRAM-34 or clotrimazole were functionally expressed in these cells. Unlike cisplatin, OXAL decreased the probability of IK(Ca)-channel openings in a concentration-dependent manner with an IC50 value of 67 uM. No significant change in single-channel conductance of IK(Ca) channels in the presence of OXAL was demonstrated. Neither large-conductance Ca(2+)-activated K+ channels nor inwardly rectifying K+ currents in these cells were affected in the presence of OXAL. OXAL also suppressed the proliferation and migration of 13-06-MG cells in a concentration- and time-dependent manner. OXAL reduced IK(Ca)-channel activity in LoVo colorectal cancer cells. Taken together, the inhibition by OXAL of IK(Ca) channels would conceivably be an important mechanism through which it acts on the functional activities of glioma cells occurring in vivo. PMID- 26488726 TI - The Relationship of Serum 25-Hydroxyvitamin D and Insulin Resistance among Nondiabetic Canadians: A Longitudinal Analysis of Participants of a Preventive Health Program. AB - Observational and intervention studies have revealed inconsistent findings with respect to the relationship between vitamin D and insulin resistance. No intervention studies have been conducted in community samples whereas this may be particularly relevant to the primary prevention of type 2 diabetes (T2D) and cardiovascular disease (CVD). In the present study we examined whether temporal improvements in vitamin D status, measured as serum 25-hydroxyvitamin D [25(OH)D], reduce the risk of insulin resistance among individuals without T2D. We accessed and analyzed data from 5730 nondiabetic participants with repeated measures of serum 25(OH)D who enrolled in a preventive health program. We used the homeostatic model assessment for insulin resistance (HOMA-IR) and applied logistic regression to quantify the independent contribution of baseline serum 25(OH)D and temporal increases in 25(OH)D on HOMA-IR. The median time between baseline and follow up was 1.1 year. On average serum 25(OH)D concentrations increased from 89 nanomoles per liter (nmol/L) at baseline to 122 nmol/L at follow up. Univariate analyses showed that relative to participants with baseline serum 25(OH)D less than 50 nmol/L, participants with baseline concentrations of "50-<75", "75-<100", "100-<125", and >=125 nmol/L were 0.76 (95% confidence intervals: 0.61-0.95), 0.54 (0.43-0.69), 0.48 (0.36-0.64) and 0.36 (0.27-0.49) times as likely to have insulin resistance at follow up, respectively. More importantly, relative to participants without temporal increases in 25(OH)D, those with increases in serum 25(OH)D of "<25", "25-<50", "50-<75", ">=75" nmol/L were 0.92 (0.72-1.17), 0.86 (0.65-1.13), 0.66 (0.47-0.93), and 0.74 (0.55-0.99) times as likely to have insulin resistance at follow up, respectively. In the subgroup of participants without insulin resistance at baseline, this was 0.96 (0.72-1.27), 0.78 (0.56-1.10), 0.66 (0.44-0.99), and 0.67 (0.48-0.94), respectively. These observations suggest that improvements in vitamin D status reduce the risk for insulin resistance and herewith may contribute to the primary prevention of T2D and CVD. PMID- 26488728 TI - Desperate Prawns: Drivers of Behavioural Innovation Vary across Social Contexts in Rock Pool Crustaceans. AB - Innovative behaviour may allow animals to cope with changes in their environment. Innovative propensities are known to vary widely both between and within species, and a growing body of research has begun to examine the factors that drive individuals to innovate. Evidence suggests that individuals are commonly driven to innovate by necessity; for instance by hunger or because they are physically unable to outcompete others for access to resources. However, it is not known whether the factors that drive individuals to innovate are stable across contexts. We examined contextual variation in the drivers of innovation in rock pool prawns (Palaemon spp), invertebrates that face widely fluctuating environments and may, through the actions of tides and waves, find themselves isolated or in groups. Using two novel foraging tasks, we examined the effects of body size and hunger in prawns tested in solitary and group contexts. When tested alone, small prawns were significantly more likely to succeed in a spatial task, and faster to reach the food in a manipulation task, while hunger state had no effect. In contrast, size had no effect when prawns were tested in groups, but food-deprived individuals were disproportionately likely to innovate in both tasks. We suggest that contextual variation in the drivers of innovation is likely to be common in animals living in variable environments, and may best be understood by considering variation in the perception of relative risks and rewards under different conditions. PMID- 26488727 TI - Acinetobacter baumannii Repeatedly Evolves a Hypermutator Phenotype in Response to Tigecycline That Effectively Surveys Evolutionary Trajectories to Resistance. AB - The evolution of hypermutators in response to antibiotic treatment in both clinical and laboratory settings provides a unique context for the study of adaptive evolution. With increased mutation rates, the number of hitchhiker mutations within an evolving hypermutator population is remarkably high and presents substantial challenges in determining which mutations are adaptive. Intriguingly however, hypermutators also provide an opportunity to explore deeply the accessible evolutionary trajectories that lead to increased organism fitness, in this case the evolution of antibiotic resistance to the clinically relevant antibiotic tigecycline by the hospital pathogen Acinetobacter baumannii. Using a continuous culture system, AB210M, a clinically derived strain of A. baumannii, was evolved to tigecycline resistance. Analysis of the adapted populations showed that nearly all the successful lineages became hypermutators via movement of a mobile element to inactivate mutS. In addition, metagenomic analysis of population samples revealed another 896 mutations that occurred at a frequency greater than 5% in the population, while 38 phenotypically distinct individual colonies harbored a total of 1712 mutations. These mutations were scattered throughout the genome and affected ~40% of the coding sequences. The most highly mutated gene was adeS, a known tigecycline-resistance gene; however, adeS was not solely responsible for the high level of TGC resistance. Sixteen other genes stood out as potentially relevant to increased resistance. The five most prominent candidate genes (adeS, rpsJ, rrf, msbA, and gna) consistently re emerged in subsequent replicate population studies suggesting they are likely to play a role in adaptation to tigecycline. Interestingly, the repeated evolution of a hypermutator phenotype in response to antibiotic stress illustrates not only a highly adaptive strategy to resistance, but also a remarkably efficient survey of successful evolutionary trajectories. PMID- 26488730 TI - Real-Life Clinical Practice with Sorafenib in Advanced Hepatocellular Carcinoma: A Single-Center Experience Second Analysis. AB - OBJECTIVES: Sorafenib has become a standard therapy for advanced hepatocellular carcinoma following the demonstration of significant increase in progression-free survival as well as overall survival (OS) in the 2-phase III trials. We examined efficacy and adverse events (AEs) in patients treated with sorafenib over a 6 year period since approval in Japan. METHODS: Two hundred and forty-one patients treated with sorafenib at the Kinki University Hospital were retrospectively analyzed clinically for the factors related to survival periods, tumor response evaluated by the Response Evaluation Criteria In Cancer of the Liver (RECICL) and AEs. RESULTS: OS was 14.3 months. According to the RECICL, the objective response and disease control rates were 18.6% (43 of 241) and 61.1% (137 of 241), respectively. AEs were seen in 77.3% (187 of 241), with Grade 3 or higher in 23.6% (57 of 241). The most frequent AE was hand-foot skin reaction in 109 patients (45.0%), and 28 patients (11.8%) showed Grade 3 or higher. Significant factors contributing to the OS were treatment duration (p = 0.0204), up-to-7 criteria (p = 0.0400), increase of Child-Pugh score (p = 0.0008) and tumor response determined by the RECICL (p = 0.0007). CONCLUSION: Based on the analysis, using many cases at a single center, we concluded that continuation of treatment with sorafenib for >=90 days without decrease of liver function was critical if tumor response was determined as stable disease or higher. PMID- 26488732 TI - Use of Whole-Genome Sequencing to Link Burkholderia pseudomallei from Air Sampling to Mediastinal Melioidosis, Australia. AB - The frequency with which melioidosis results from inhalation rather than percutaneous inoculation or ingestion is unknown. We recovered Burkholderia pseudomallei from air samples at the residence of a patient with presumptive inhalational melioidosis and used whole-genome sequencing to link the environmental bacteria to B. pseudomallei recovered from the patient. PMID- 26488731 TI - Root Transcriptome Analysis of Wild Peanut Reveals Candidate Genes for Nematode Resistance. AB - Wild peanut relatives (Arachis spp.) are genetically diverse and were adapted to a range of environments during the evolution course, constituting an important source of allele diversity for resistance to biotic and abiotic stresses. The wild diploid A. stenosperma harbors high levels of resistance to a variety of pathogens, including the root-knot nematode (RKN) Meloidogyne arenaria, through the onset of the Hypersensitive Response (HR). In order to identify genes and regulators triggering this defense response, a comprehensive root transcriptome analysis during the first stages of this incompatible interaction was conducted using Illumina Hi-Seq. Overall, eight cDNA libraries were produced generating 28.2 GB, which were de novo assembled into 44,132 contigs and 37,882 loci. Differentially expressed genes (DEGs) were identified and clustered according to their expression profile, with the majority being downregulated at 6 DAI, which coincides with the onset of the HR. Amongst these DEGs, 27 were selected for further qRT-PCR validation allowing the identification of nematode-responsive candidate genes that are putatively related to the resistance response. Those candidates are engaged in the salycilic (NBS-LRR, lipocalins, resveratrol synthase) and jasmonic (patatin, allene oxidase cyclase) acids pathways, and also related to hormonal balance (auxin responsive protein, GH3) and cellular plasticity and signaling (tetraspanin, integrin, expansin), with some of them showing contrasting expression behavior between Arachis RKN-resistant and susceptible genotypes. As these candidate genes activate different defensive signaling systems, the genetic (HR) and the induced resistance (IR), their pyramidding in one genotype via molecular breeding or transgenic strategy might contribute to a more durable resistance, thus improving the long-term control of RKN in peanut. PMID- 26488733 TI - Interact with learning. PMID- 26488734 TI - Surgical site infection in elderly patients with hip fractures, silver-coated versus regular dressings: a randomised prospective trial. AB - OBJECTIVE: Surgical site infection (SSI) after hip fracture surgery is a well known complication with serious consequences for both the patient and the medical system. Silver ion treatment is considered an effective antibacterial agent, however, the use of silver dressing (SD) in the primary prevention of SSIs is controversial. The aims of this study were to compare SD with regular dressing (RD) in the prevention of SSI in elderly patients undergoing surgery for hip fractures, and to compare costs. METHOD: A matched group of 55 patients with hip fractures undergoing surgery with dynamic hip screw, cephalomedullary nail or hemiarthroplasty were randomised to either SD or RD groups. The dressings were applied in the operating theatre, and the patients were followed for one week for clinical signs of infection (discharge, erythema and fever). The RDs were replaced daily. The SDs were not removed for 5-7 days and kept moist. Skin swabs were taken from the wound surface on postoperative day 5-7 for bacterial skin colonisation. RESULTS: The SD (n=31) and RD (n=24) groups were similar in age, sex and comorbidities. Infection signs were seen in two (2/31, 6.4%) of the SD patients compared with 2 (2/24, 8.3%) RD patients (p=1.0). Skin colonisation by bacteria at postoperative day 5-7 was tested in 27 patients: it was higher in the SD group (positive skin swab, 12/19, 63.2%) compared to the RD group (4/8, 50%, p=0.67). The use of SD added ~US$5 (UK ~L3.19) per patient. CONCLUSION: The use of SD was associated with higher costs than RD, but not superior in preventing SSIs in elderly patients undergoing hemiarthroplasty or fixation of hip fractures. SD was also not effective in reducing bacterial skin colonisation following hip fracture and surgery. PMID- 26488735 TI - Keratin gel in the management of Epidermolysis bullosa. AB - OBJECTIVE: Epidermolysis bullosa (EB) describes a number of genetically inherited conditions which cause skin fragility and minor trauma leading to skin damage, skin loss and wounding. Owing to the fragility of the skin and requirement for frequent dressing changes, at present, the optimal dressing(s) is not clear. Our objective was to assess the use of a keratin gel in the management of wounds in patients with different forms of EB. METHOD: We treated patients with different types of EB and a range of wounds with a novel keratin gel. In a convenience sample of consecutive patients, we introduced the keratin gel into their treatment regimen maintaining other aspects of their care. RESULTS: Patients reported faster healing and more resilient healed skin. Of the ten patients treated in this pilot study, six found the gel effective; two found it ineffective; and in two patients, it caused itching leading to discontinuation of the treatment. CONCLUSION: The results of this case study series suggest that keratin gel can be useful in the management of EB and are consistent with previous published experiences. PMID- 26488736 TI - Hand amputations: epidemiology, management and resurfacing options for soft tissue coverage. AB - OBJECTIVE: Agricultural hand injuries occur mainly among young adults, many affecting the dominant hand, thereby impeding patients' ability to work or cope with social obligations. This study was carried out with the aim of collecting data on the epidemiology and management of agricultural hand injuries in Indian subjects. METHOD: The study was conducted in the Department of Plastic and Reconstructive Surgery, JN Medical College, AMU, Aligarh, India, from October 2009 to December 2013. Patients with agricultural hand injuries were included. Data collected included socio-demographic details, mode and type of injury, type of reconstruction, complications, length of hospital stay and assessment of post reconstruction status. These data were tabulated and analysed. RESULTS: The typical patient was young (mean 33.2 years), of lower socio-economic status and with a total disregard for safety regulations. There is clustering of cases during the wheat harvest season (April-June). Wheat thresher injuries were the most common cause of partial hand amputation (51%), especially during this season. This was followed by fodder cutting (kutti/chara) machine injury, especially in females and children (36%). A simple classification for these injuries has been described and Grade II injury was the commonest. Reverse radial forearm flap was the most suitable regional flap for coverage, whereas thoraco umbilical flap was the most commonly used distant flap. Patients who had the single-stage procedure had a significantly shorter stay. CONCLUSION: Agricultural hand injuries are not totally avoidable and their incidence can be reduced by proper education, but the low economic and literacy status of the patients is a big hurdle. The forearm offers many flaps for reconstruction of hand, which can be used in defects on dorsal or palmar aspect of hand and results in early discharge from the hospital and early rehabilitation. In patients with associated injury to the forearm, abdominal flaps can be used for cover. PMID- 26488738 TI - A national survey by the SDMA: use of evidence in nursing practice. AB - OBJECTIVE: Recently, two surveys were conducted by the Surgical Dressing Manufacturers Association (SDMA) to investigate the evidence required to support wound care products. These showed very clearly that industry provides significant amounts of evidence in a way that appears to meet the expectations of relevant health professionals and their practice for treating patients with wounds. The responses of health professionals refuted the opinion that evidence may be lacking for wound care products. Hopefully, the results of these surveys also add weight to the argument that the Cochrane Review approach is not always the most appropriate for wound care-where the comorbidities of patients are variable and often plural. PMID- 26488737 TI - Comparative trial of Aloe vera/olive oil combination cream versus phenytoin cream in the treatment of chronic wounds. AB - OBJECTIVE: Aloe vera is a medicinal plant that has been traditionally used to accelerate wound healing. Olive oil is also a natural product that may contribute to wound healing owing to its antimicrobial and anti-inflammatory effects. The present study aimed to evaluate the effect of an Aloe vera-olive oil (AVO) combination cream on the healing process of chronic wounds. METHOD: In this randomised, double-blind, comparator-controlled, parallel-group trial, patients with chronic wounds were treated with either AVO cream or phenytoin cream as the standard treatment for a period of 30 days. Wound healing was evaluated using Bates-Jensen assessment tool and the severity of pain was assessed using a visual analogue scale (VAS). RESULTS: After initial assessment, 60 patients with chronic wounds (41 with pressure ulcer, 13 with diabetic wounds and 6 with venous ulcers), were recruited and randomised into 2 groups of 30. After 30 days of treatment, significant improvements in the wound size, depth, and edges; necrotic tissue type and amount; exudate type and amount; colour of wound surroundings; and peripheral tissue oedema score were observed in the AVO cream group (p<0.001). The total score of wound healing showed significant improvement with both AVO (p<0.001) and phenytoin (p<0.01) creams, although AVO was more efficacious (p<0.001). Likewise, although both treatments reduced the initial VAS score, the efficacy of AVO was significantly greater (p<0.001). CONCLUSION: AVO cream significantly accelerates biological healing of chronic wounds and helps to reduce pain severity with a higher efficacy compared with phenytoin cream. PMID- 26488740 TI - Erratum. PMID- 26488739 TI - Treatment of pressure ulcers in patients with declining renal function using arginine, glutamine and beta-hydroxy-beta-methylbutyrate. AB - The aim of this study is to examine the efficacy on healing pressure ulcers (PU) of using a supplement combination containing arginine, glutamine and beta-hydroxy beta-methylbutyrate, which was given to two elderly patients with renal dysfunction. The PU was surgically opened, decompressed and treated by drugs. A half quantity of the defined dose of the supplement combination, with an enteral nutrition product, was administered to the patients twice a day. This combination improved the PUs, with no effect on renal function. This novel finding may provide a nutritional rationale of arginine, glutamine and beta-hydroxy-beta methylbutyrate for PUs associated with renal dysfunction. PMID- 26488741 TI - Corrigendum. PMID- 26488743 TI - Correction: Overcoming Stagnation in the Levels and Distribution of Child Mortality: The Case of the Philippines. PMID- 26488742 TI - Neuromuscular Activation of the Vastus Intermedius Muscle during Isometric Hip Flexion. AB - Although activity of the rectus femoris (RF) differs from that of the other synergists in quadriceps femoris muscle group during physical activities in humans, it has been suggested that the activation pattern of the vastus intermedius (VI) is similar to that of the RF. The purpose of present study was to examine activation of the VI during isometric hip flexion. Ten healthy men performed isometric hip flexion contractions at 25%, 50%, 75%, and 100% of maximal voluntary contraction at hip joint angles of 90 degrees , 110 degrees and 130 degrees . Surface electromyography (EMG) was used to record activity of the four quadriceps femoris muscles and EMG signals were root mean square processed and normalized to EMG amplitude during an isometric knee extension with maximal voluntary contraction. The normalized EMG was significantly higher for the VI than for the vastus medialis during hip flexion at 100% of maximal voluntary contraction at hip joint angles of 110 degrees and 130 degrees (P < 0.05). The onset of VI activation was 230-240 ms later than the onset of RF activation during hip flexion at each hip joint angle, which was significantly later than during knee extension at 100% of maximal voluntary contraction (P < 0.05). These results suggest that the VI is activated later than the RF during hip flexion. Activity of the VI during hip flexion might contribute to stabilize the knee joint as an antagonist and might help to smooth knee joint motion, such as in the transition from hip flexion to knee extension during walking, running and pedaling. PMID- 26488745 TI - Middle East Respiratory Syndrome in 3 Persons, South Korea, 2015. AB - In May 2015, Middle East respiratory syndrome coronavirus infection was laboratory confirmed in South Korea. Patients were a man who had visited the Middle East, his wife, and a man who shared a hospital room with the index patient. Rapid laboratory confirmation will facilitate subsequent prevention and control for imported cases. PMID- 26488744 TI - Soluble CD40 Ligand in Sera of Subjects Exposed to Leishmania infantum Infection Reduces the Parasite Load in Macrophages. AB - BACKGROUND: While CD40L is typically a membrane glycoprotein expressed on activated T cells and platelets that binds and activates CD40 on the surface on antigen presenting cells, a soluble derivative (sCD40L) that appears to retain its biological activity after cleavage from cell membrane also exists. We recently reported that sCD40L is associated with clinical resolution of visceral leishmaniasis and protection against the disease. In the present study we investigated if this sCD40L is functional and exerts anti-parasitic effect in L. infantum-infected macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Macrophages from normal human donors were infected with L. infantum promastigotes and incubated with either sera from subjects exposed to L. infantum infection, monoclonal antibodies against human CD40L, or an isotype control antibody. We then evaluated infection by counting the number of infected cells and the number of parasites in each cell. We also measured a variety of immune modulatory cytokines in these macrophage culture supernatants by Luminex assay. The addition of sCD40L, either recombinant or from infected individuals' serum, decreased both the number of infected macrophages and number of intracellular parasites. Moreover, this treatment increased the production of IL-12, IL-23, IL-27, IL-15, and IL1beta such that negative correlations between the levels of these cytokines with both the infection ratio and number of intracellular parasites were observed. CONCLUSIONS/SIGNIFICANCE: sCD40L from sera of subjects exposed to L. infantum is functional and improves both the control of parasite and production of inflamatory cytokines of infected macrophages. Although the mechanisms involved in parasite killing are still unclear and require further exploration, these findings indicate a protective role of sCD40L in visceral leishmaniasis. PMID- 26488746 TI - Spectrum-Dependent Spiro-OMeTAD Oxidization Mechanism in Perovskite Solar Cells. AB - We propose a spectrum-dependent mechanism for the oxidation of 2,2',7,7' tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (Spiro-OMeTAD) with bis(trifluoromethane)sulfonimide lithium salt (LiTFSI), which is commonly used in perovskite solar cells as the hole transport layer. The perovskite layer plays different roles in the Spiro-OMeTAD oxidization for various spectral ranges. The effect of oxidized Spiro-OMeTAD on the solar cell performance was observed and characterized. With the initial long-wavelength illumination (>450 nm), the charge recombination at the TiO2/Spiro-OMeTAD interface was increased due to the higher amount of the oxidized Spiro-OMeTAD. On the other hand, the increased conductivity of the Spiro-OMeTAD layer and enhanced charge transfer at the Au/Spiro-OMeTAD interface facilitated the solar cell performance. PMID- 26488747 TI - Neuroimaging Evaluation for First Attack of Unprovoked Nonfebrile Seizure in Pediatrics: When to Order? AB - OBJECTIVE: To assess the value of neuroimaging studies in evaluating pediatric patients presenting with a first attack of nonfebrile seizure. METHOD: We reviewed the medical records of pediatric patients aged 28 days to 12 years who were admitted between 1 January and 31 December 2013 with a first attack of unprovoked, afebrile seizure. These patients had undergone neuroimaging studies. The exclusion criterion was patients with known predisposing conditions for seizure. The computed tomography (CT) scan and magnetic resonance imaging (MRI) results were either normal or abnormal, and the abnormal ones were further classified into clinically insignificant or significant. Descriptive analysis was performed to summarize the data. RESULT: Fifty children were identified with a mean age of 5.2 +/- 3.8 years. Of the 50 subjects, 29 (58.0%) were males and 21 (42.0%) were females. Sixteen patients (32.0%) had abnormal neuroimaging studies (CT scan, MRI or both); however, only 1 was considered to have a clinically significant abnormality, later diagnosed as Moyamoya disease. CONCLUSION: In this study, the neuroimaging studies were found not to be useful in evaluating pediatric patients presenting with a first attack of unprovoked, nonfebrile seizures. PMID- 26488748 TI - The Mediating Role of Early Maladaptive Schemas in the Relation between Co Rumination and Depression in Young Adults. AB - Research on co-rumination has investigated its relationship with internalizing symptoms, but few studies have addressed underlying maladaptive cognitive affective processes that may play an important role in the maintenance of this relation. This study examines if Young's schema domains mediate the relation between co-rumination and depression in a community sample of non-clinical young adults. Participants completed the Co-Rumination Questionnaire, Young Schema Questionnaire-L3, and Teate Depression Inventory. Correlations and path analysis were calculated for the full sample and separately by gender. The schema domains of Overvigilance/Inhibition and Other-Directedness fully mediated the relation between co-rumination and depression. When analyses were performed separately for males and females, mediation persisted only for females. Findings suggest that among young women, co-rumination with a friend may be associated with depressive symptoms because of its activation of specific maladaptive cognitive schemas. Better understanding of the content and processes underpinning co-rumination may have important implications for the prevention and treatment of depression. PMID- 26488749 TI - Angiotensin Receptor Blockers Decrease the Risk of Major Adverse Cardiovascular Events in Patients with End-Stage Renal Disease on Maintenance Dialysis: A Nationwide Matched-Cohort Study. AB - BACKGROUND: Major adverse cardiovascular events (MACE) cause the leading cause of morbidity and mortality in patients with end-stage renal disease (ESRD) on maintenance Hemodialysis (HD) or peritoneal dialysis (PD). Many randomized controlled trials (RCTs) have proved that angiotensin receptor blockers (ARBs) can reduce the risk of MACE in the people with normal or impaired kidney function without dialysis. This study seeks to clarify whether ARBs therapy could also attenuate this risk in patients with ESRD on maintenance dialysis. MATERIALS AND METHODS: The National Health Research Institute provided a database of one million random subjects for the study. A random sample was taken of 1800 patients >=18 years y/o with ESRD on dialysis without a history of MACE and use of ARBs within 6-months prior to enrollment. Cox proportional hazard regression analysis was used to identify the risk factors and compute the hazard ratios accompanying 95% confidence intervals. RESULTS: In these 1800 patients, 1061 had never used ARBs, while 224 had used them for 1-90 days, and 515 had used them for more than 90 days. We found that ARBs significantly decrease the incidences of acute myocardial infarctions (AMI), coronary artery diseases (CAD) requiring coronary stent or percutaneous transluminal coronary angioplasty (PTCA), peripheral artery disease (PAD) requiring percutaneous transluminal angioplasty (PTA), and acute stroke. Cumulative prescription days of ARBs beyond 365-760 days or more were found to be negatively correlated with incidence of MACEs. For patients with dual comorbidity (i.e., mellitus and hyperlipidemia), 91-365 cumulative prescription days might also attenuate the risk. CONCLUSIONS: For patients on maintenance dialysis, the use of ARBs could significantly attenuate the risk of major cardiovascular events: AMI, acute stroke, and PAD requiring PTA. PMID- 26488750 TI - Projected Future Vegetation Changes for the Northwest United States and Southwest Canada at a Fine Spatial Resolution Using a Dynamic Global Vegetation Model. AB - Future climate change may significantly alter the distributions of many plant taxa. The effects of climate change may be particularly large in mountainous regions where climate can vary significantly with elevation. Understanding potential future vegetation changes in these regions requires methods that can resolve vegetation responses to climate change at fine spatial resolutions. We used LPJ, a dynamic global vegetation model, to assess potential future vegetation changes for a large topographically complex area of the northwest United States and southwest Canada (38.0-58.0 degrees N latitude by 136.6-103.0 degrees W longitude). LPJ is a process-based vegetation model that mechanistically simulates the effect of changing climate and atmospheric CO2 concentrations on vegetation. It was developed and has been mostly applied at spatial resolutions of 10-minutes or coarser. In this study, we used LPJ at a 30 second (~1-km) spatial resolution to simulate potential vegetation changes for 2070-2099. LPJ was run using downscaled future climate simulations from five coupled atmosphere-ocean general circulation models (CCSM3, CGCM3.1(T47), GISS ER, MIROC3.2(medres), UKMO-HadCM3) produced using the A2 greenhouse gases emissions scenario. Under projected future climate and atmospheric CO2 concentrations, the simulated vegetation changes result in the contraction of alpine, shrub-steppe, and xeric shrub vegetation across the study area and the expansion of woodland and forest vegetation. Large areas of maritime cool forest and cold forest are simulated to persist under projected future conditions. The fine spatial-scale vegetation simulations resolve patterns of vegetation change that are not visible at coarser resolutions and these fine-scale patterns are particularly important for understanding potential future vegetation changes in topographically complex areas. PMID- 26488751 TI - Assessment of the Economic Impact of Belimumab for the Treatment of Systemic Lupus Erythematosus in the Italian Setting: A Cost-Effectiveness Analysis. AB - OBJECTIVE: The purpose of this analysis is to evaluate the cost-effectiveness of belimumab, a new biological treatment specifically developed for the treatment of Systemic Lupus Erythematosus (SLE), in the Italian setting. SLE is a chronic non organ specific autoimmune disease characterized by a disregulation of the immune system that involves many organs and systems. METHODS: A cost-effectiveness micro simulation model with a lifetime horizon originally developed for the UK was adapted to the Italian setting. The analysis compared Standard of Care (SoC) alone vs belimumab plus SoC from a National Healthcare Service (NHS) and societal perspective. Health-economic consequences of treatments and organ damage progression were calculated. When available, Italian data were used, otherwise UK costs were converted using Purchasing Power Parities (PPPs). Utility values were based on the EQ-5DTM assessments in the belimumab clinical trials (BLISS 52 and 76). Results were discounted with 3% for costs and effects. A maximum belimumab treatment duration of 6 years was assumed and wastage costs were considered. RESULTS: Cost per life year gained (Incremental Cost-Effectiveness Ratio, ICER) and cost per Quality Adjusted Life Year (QALY) (Incremental Cost-Utility Ratio, ICUR) were ?22,990 and ?32,859, respectively. These values reduced to ?20,119 and ?28,754, respectively, when indirect costs were included. CONCLUSIONS: It may be concluded that in the Italian setting and according to the guidelines of the Italian Association of Health Economics (IAHE), belimumab was shown to be cost effective, in terms of both ICER and ICUR, (?25-40,000/QALY). PMID- 26488752 TI - Environmental Effects of Nanoceria on Seed Production of Common Bean (Phaseolus vulgaris): A Proteomic Analysis. AB - The rapidly growing literature on the response of edible plants to nanoceria has provided evidence of its uptake and bioaccumulation, which delineates a possible route of entry into the food chain. However, little is known about how the residing organic matter in soil may affect the bioavailability and resulting impacts of nanoceria on plants. Here, we examined the effect of nanoceria exposure (62.5-500 mg/kg) on kidney bean (Phaseolus vulgaris) productivity and seed quality as a function of soil organic matter content. Cerium accumulation in the seeds produced from plants in organic matter enriched soil showed a dose dependent increase, unlike in low organic matter soil treatments. Seeds obtained upon nanoceria exposure in soils with higher organic matter were more susceptible to changes in nutrient quality. A quantitative proteomic analysis of the seeds produced upon nanoceria exposure provided evidence for upregulation of stress related proteins at 62.5 and 125 mg/kg nanoceria treatments. Although the plants did not exhibit overt toxicity, the major seed proteins primarily associated with nutrient storage (phaseolin) and carbohydrate metabolism (lectins) were significantly down-regulated in a dose dependent manner upon nanoceria exposure. This study thus suggests that nanoceria exposures may negatively affect the nutritional quality of kidney beans at the cellular and molecular level. More confirmatory studies with nanoceria along different species using alternative and orthogonal "omic" tools are currently under active investigation, which will enable the identification of biomarkers of exposure and susceptibility. PMID- 26488753 TI - Reproduction in Risky Environments: The Role of Invasive Egg Predators in Ladybird Laying Strategies. AB - Reproductive environments are variable and the resources available for reproduction are finite. If reliable cues about the environment exist, mothers can alter offspring phenotype in a way that increases both offspring and maternal fitness ('anticipatory maternal effects'-AMEs). Strategic use of AMEs is likely to be important in chemically defended species, where the risk of offspring predation may be modulated by maternal investment in offspring toxin level, albeit at some cost to mothers. Whether mothers adjust offspring toxin levels in response to variation in predation risk is, however, unknown, but is likely to be important when assessing the response of chemically defended species to the recent and pervasive changes in the global predator landscape, driven by the spread of invasive species. Using the chemically defended two-spot ladybird, Adalia bipunctata, we investigated reproductive investment, including egg toxin level, under conditions that varied in the degree of simulated offspring predation risk from larval harlequin ladybirds, Harmonia axyridis. H. axyridis is a highly voracious alien invasive species in the UK and a significant intraguild predator of A. bipunctata. Females laid fewer, larger egg clusters, under conditions of simulated predation risk (P+) than when predator cues were absent (P-), but there was no difference in toxin level between the two treatments. Among P- females, when mean cluster size increased there were concomitant increases in both the mass and toxin concentration of eggs, however when P+ females increased cluster size there was no corresponding increase in egg toxin level. We conclude that, in the face of offspring predation risk, females either withheld toxins or were physiologically constrained, leading to a trade-off between cluster size and egg toxin level. Our results provide the first demonstration that the risk of offspring predation by a novel invasive predator can influence maternal investment in toxins within their offspring. PMID- 26488754 TI - Adsorption of Selected Antibiotics to Resins in Extracorporeal Blood Purification. AB - BACKGROUND/AIMS: Extracorporeal blood purification systems (EBS) use specific adsorbents for the elimination of toxins and cytokines. The aim of this study was to test different adsorbents for their ability to reduce antibiotics in parallel to extracorporeal blood purification therapy. METHODS: The in vitro adsorption experiments were carried out in human plasma with a newly established hydrophobic resin (Amberchrom CG161c) and adsorbents commercially available and approved in the clinics. The concentration of antibiotic was chosen equivalent to the recommended therapeutic dosage applied intravenously and was measured in plasma using ELISA test kits and high-performance liquid chromatography methods. RESULTS: The adsorbent that reduced all tested antibiotics in plasma close to the detection limit was the dia MARS AC250, which is an activated charcoal involved in the Molecular Adsorbents Recirculation System. CONCLUSION: For better antibiotic monitoring in sepsis treatment, further investigations have to be performed to determine the clearance rate of antibiotics by different EBS devices. PMID- 26488755 TI - Secondary Structure Alterations of Histones H2A and H2B in X-Irradiated Human Cancer Cells: Altered Histones Persist in Cells for at Least 24 Hours. AB - We measured and compared the circular dichroism (CD) spectra and secondary structures of histone proteins H2A, H2B and their variants extracted from X irradiated and unirradiated human HeLa cells. Compared to unirradiated cells, a relative increase in alpha-helix structure and decrease in other secondary structures was observed in X-irradiated cells. These structural alterations persisted for at least 24 h, which is substantially longer than the 2 h generally known to be required for DNA double-strand break repair. PMID- 26488756 TI - Triptolide Mitigates Radiation-Induced Pulmonary Fibrosis. AB - Triptolide (TPL) may mitigate radiation-induced late pulmonary side effects through its inhibition of global pro-inflammatory cytokines. In this study, we evaluated the effect of TPL in C57BL/6 mice, the animals were exposed to radiation with vehicle (15 Gy), radiation with TPL (0.25 mg/kg i.v., twice weekly for 1, 2 and 3 months), radiation and celecoxib (CLX) (30 mg/kg) and sham irradiation. Cultured supernatant of irradiated RAW 264.7 and MLE-15 cells and lung lysate in different groups were enzyme-linked immunosorbent assays at 33 h. Respiratory rate, pulmonary compliance and pulmonary density were measured at 5 months in all groups. The groups exposed to radiation with vehicle and radiation with TPL exhibited significant differences in respiratory rate and pulmonary compliance (480 +/- 75/min vs. 378 +/- 76/min; 0.6 +/- 0.1 ml/cm H2O/p kg vs. 0.9 +/- 0.2 ml/cm H2O/p kg). Seventeen cytokines were significantly reduced in the lung lysate of the radiation exposure with TPL group at 5 months compared to that of the radiation with vehicle group, including profibrotic cytokines implicated in pulmonary fibrosis, such as IL-1beta, TGF- beta1 and IL-13. The radiation exposure with TPL mice exhibited a 41% reduction of pulmonary density and a 25% reduction of hydroxyproline in the lung, compared to that of radiation with vehicle mice. The trichrome-stained area of fibrotic foci and pathological scaling in sections of the mice treated with radiation and TPL mice were significantly less than those of the radiation with vehicle-treated group. In addition, the radiation with TPL-treated mice exhibited a trend of improved survival rate compared to that of the radiation with vehicle-treated mice at 5 months (83% vs. 53%). Three radiation-induced profibrotic cytokines in the radiation with vehicle-treated group were significantly reduced by TPL treatment, and this partly contributed to the trend of improved survival rate and pulmonary density and function and the decreased severity of pulmonary fibrosis at 5 months. Our findings indicate that TPL could be a potential new agent to mitigate radiation-induced pulmonary fibrosis. PMID- 26488757 TI - A Simple Model to Quantify Radiolytic Production following Electron Emission from Heavy-Atom Nanoparticles Irradiated in Liquid Suspensions. AB - We present a simple model for a component of the radiolytic production of any chemical species due to electron emission from irradiated nanoparticles (NPs) in a liquid environment, provided the expression for the G value for product formation is known and is reasonably well characterized by a linear dependence on beam energy. This model takes nanoparticle size, composition, density and a number of other readily available parameters (such as X-ray and electron attenuation data) as inputs and therefore allows for the ready determination of this contribution. Several approximations are used, thus this model provides an upper limit to the yield of chemical species due to electron emission, rather than a distinct value, and this upper limit is compared with experimental results. After the general model is developed we provide details of its application to the generation of HO* through irradiation of gold nanoparticles (AuNPs), a potentially important process in nanoparticle-based enhancement of radiotherapy. This model has been constructed with the intention of making it accessible to other researchers who wish to estimate chemical yields through this process, and is shown to be applicable to NPs of single elements and mixtures. The model can be applied without the need to develop additional skills (such as using a Monte Carlo toolkit), providing a fast and straightforward method of estimating chemical yields. A simple framework for determining the HO* yield for different NP sizes at constant NP concentration and initial photon energy is also presented. PMID- 26488759 TI - Alterations in electrodermal activity and cardiac parasympathetic tone during hypnosis. AB - Exploring autonomic nervous system (ANS) changes during hypnosis is critical for understanding the nature and extent of the hypnotic phenomenon and for identifying the mechanisms underlying the effects of hypnosis in different medical conditions. To assess ANS changes during hypnosis, electrodermal activity and pulse rate variability (PRV) were measured in 121 young adults. Participants either received hypnotic induction (hypnosis condition) or listened to music (control condition), and both groups were exposed to test suggestions. Blocks of silence and experimental sound stimuli were presented at baseline, after induction, and after de-induction. Skin conductance level (SCL) and high frequency (HF) power of PRV measured at each phase were compared between groups. Hypnosis decreased SCL compared to the control condition; however, there were no group differences in HF power. Furthermore, hypnotic suggestibility did not moderate ANS changes in the hypnosis group. These findings indicate that hypnosis reduces tonic sympathetic nervous system activity, which might explain why hypnosis is effective in the treatment of disorders with strong sympathetic nervous system involvement, such as rheumatoid arthritis, hot flashes, hypertension, and chronic pain. Further studies with different control conditions are required to examine the specificity of the sympathetic effects of hypnosis. PMID- 26488760 TI - Innovative technology for colostomy irrigation: assessing the impact on patients. AB - AIM: The main purpose of the trial was to evaluate the opinions expressed by a sample of subjects with permanent colostomy, as a result of the use of a new device designed for the execution of transtomal intestinal irrigation; their feedback was analyzed in relation to the concept of Quality of Life. METHODS: The device was tested on a sample of 14 colostomized patients (10 men and 4 women, aged between 42 and 77 years) who were used to perform intestinal irrigation procedures independently and routinely, with standard technique. After testing the new device, the patients included in the study were asked to fill out a questionnaire built ad hoc for their situation. RESULTS: The analysis of the data collected led to the following conclusions: 93% of the patients described the new irrigation method as simpler than the standard procedure; the majority of the patients assessed bowel emptying as good; 64% of patients reported excellent comfort experienced during the procedure; the presence of a regulator to adjust the instillation speed of water into the intestinal lumen was considered useful to control the flow of the incoming fluid CONCLUSION: The use of the device guaranteed: psychological tranquility, minimum manual intervention, full achievement of the expected results and decrease in the issues normally encountered with the standard irrigation method. The practical features of the new device ensure easy and straightforward carrying out of the procedure; this ease of use affects the stomized patient's everyday life by reducing the time of procedure completion, thus positively influencing the perception of the patients' Quality of Life. PMID- 26488758 TI - FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target. AB - Although a standardized approach to radiotherapy has been used to treat breast cancer, regardless of subtype (e.g., luminal, basal), recent clinical data suggest that radiation response may vary significantly among subtypes. We hypothesized that this clinical variability may be due, in part, to differences in cellular radiation response. In this study, we utilized RNA samples for microarray analysis from two sources: 1. Paired pre- and postirradiation breast tumor tissue from 32 early-stage breast cancer patients treated in our unique preoperative radiation Phase I trial; and 2. Sixteen biologically diverse breast tumor cell lines exposed to 0 and 5 Gy irradiation. The transcriptome response to radiation exposure was derived by comparing gene expression in samples before and after irradiation. Genes with the highest coefficient of variation were selected for further evaluation and validated at the RNA and protein level. Gene editing and agonistic antibody treatment were performed to assess the impact of gene modulation on radiation response. Gene expression in our cohort of luminal breast cancer patients was distinctly different before and after irradiation. Further, two distinct patterns of gene expression were observed in our biologically diverse group of breast cancer cell lines pre- versus postirradiation. Cell lines that showed significant change after irradiation were largely luminal subtype, while gene expression in the basal and HER2+ cell lines was minimally impacted. The 100 genes with the most significant response to radiation in patients were identified and analyzed for differential patterns of expression in the radiation responsive versus nonresponsive cell lines. Fourteen genes were identified as significant, including FAS, a member of the tumor necrosis factor receptor family known to play a critical role in programed cell death. Modulation of FAS in breast cancer cell lines altered radiation response phenotype and enhanced radiation sensitivity in radioresistant basal cell lines. Our findings suggest that cell-type-specific, radiation-induced FAS contributes to subtype-specific breast cancer radiation response and that activation of FAS pathways may be exploited for biologically tailored radiotherapy. PMID- 26488761 TI - Obstructive jaundice secondary to endoclip migration into common bile duct after laparoscopic cholecystectomy. AB - Obstructive jaundice is a rare condition due to foreign body in common bile. In this article we report a 69 year-old man who was diagnosed obstructive jaundice secondary to the endoscopic clip migration. The patient had been performed laparoscopic cholecystectomy 5 years ago and had recovered without any complications. He presented with abdominal pain and jaundice. The magnetic resonance cholangiopancreatography (MRCP) revealed filling defect in choledoch consistent with a bile duct stone. The endoscopic retrograde cholangiopancreatography (ERCP) exhibited an endoclip migration into the common bile duct which caused bile duct stone. Endoclips can migrate into bile duct and cause obstructive jaundice. ERCP is the first option for its treatment. PMID- 26488762 TI - Evaluation of the clinical performance of a new foam with silver sulfadiazine 1. PMID- 26488763 TI - Combined robotically-assisted laparoscopic left hepatectomy and total hysterectomy of enlarged uterus. PMID- 26488764 TI - Our preliminary experiences in topical administration of insulin in addition to vacuum assisted closure for wound healing in diabetic patients. PMID- 26488765 TI - How can the risk of medicolegal claims in Italy be reduced? PMID- 26488766 TI - The Development of Functional Overreaching Is Associated with a Faster Heart Rate Recovery in Endurance Athletes. AB - PURPOSE: The aim of the study was to investigate whether heart rate recovery (HRR) may represent an effective marker of functional overreaching (f-OR) in endurance athletes. METHODS AND RESULTS: Thirty-one experienced male triathletes were tested (10 control and 21 overload subjects) before (Pre), and immediately after an overload training period (Mid) and after a 2-week taper (Post). Physiological responses were assessed during an incremental cycling protocol to exhaustion, including heart rate, catecholamine release and blood lactate concentration. Ten participants from the overload group developed signs of f-OR at Mid (i.e. -2.1 +/- 0.8% change in performance associated with concomitant high perceived fatigue). Additionally, only the f-OR group demonstrated a 99% chance of increase in HRR during the overload period (+8 +/- 5 bpm, large effect size). Concomitantly, this group also revealed a >80% chance of decreasing blood lactate (-11 +/- 14%, large), plasma norepinephrine (-12 +/- 37%, small) and plasma epinephrine peak concentrations (-51 +/- 22%, moderate). These blood measures returned to baseline levels at Post. HRR change was negatively correlated to changes in performance, peak HR and peak blood metabolites concentrations. CONCLUSION: These findings suggest that i) a faster HRR is not systematically associated with improved physical performance, ii) changes in HRR should be interpreted in the context of the specific training phase, the athletes perceived level of fatigue and the performance response; and, iii) the faster HRR associated with f-OR may be induced by a decreased central command and by a lower chemoreflex activity. PMID- 26488767 TI - Prostate cancer incidence in 43 populations worldwide: An analysis of time trends overall and by age group. AB - Prostate cancer is a significant public health burden and a major cause of morbidity and mortality among men worldwide. Analyzing geographic patterns and temporal trends may help identify high-risk populations, suggest the degree of PSA testing, and provide clues to etiology. We used incidence data available from the International Agency for Research on Cancer (IARC) and certain cancer registries for 43 populations across five continents during a median period of 24 years. Trends in overall prostate cancer rates showed five distinct patterns ranging from generally monotonic increases to peaking of rates followed by declines, which coincide somewhat with changes in the prevalence of PSA testing. Trends in age-specific rates generally mirrored those in the overall rates, with several notable exceptions. For populations where overall rates increased rapidly and then peaked, exemplified in North America and Oceania, the highest incidence tended to be most pronounced and occurred during earlier calendar years among older men compared with younger ones. For populations with almost continual increases in overall rates, exemplified in Eastern Europe and Asia, peaks were evident among men aged >= 75 years in many instances. Rates for ages 45-54 years did not clearly stabilize or decline in the majority of studied populations. Global geographic variation remained substantial for both overall and age specific incidence rates regardless of levels of PSA testing, with the lowest rates consistently in Asia. Explanations for the persistent geographic differences and the continuing increases of especially early-onset prostate cancer remain unclear. PMID- 26488768 TI - Methyltransferase-like 17 physically and functionally interacts with estrogen receptors. AB - Estrogen exerts its physiological and pathological functions through two estrogen receptors (ERs), ERalpha and ERbeta, which act as transcription factors. Coregulators, including coactivators and corepressors, have been shown to be crucial for regulation of ER transcriptional activity. Although many coregulators have been identified to regulate activities of ERs, novel coregulators are still needed to be investigated. Here, we show that human methyltransferase-like 17 (METTL17), whose function is unknown, physically interacts with ERalpha and ERbeta, and functionally acts as a coactivator for ERs. METTL17 interacts with ER in vitro and in yeast and mammalian cells. Activation function-1 (AF1) and AF2 domains of ERs are responsible for the interaction between METTL17 and ERs. Knockdown of METTL17 reduces transcriptional activities of ERalpha and ERbeta in breast cancer cells, whereas METTL17 overexpression increases ERalpha and ERbeta transcriptional activities. Inhibition of METTL17 expression decreases mRNA and protein levels of ER target genes, including PR, cathepsin D, and pS2. Moreover, METTL17 knockdown reduces breast cancer cell growth. These results indicate that METTL17 is a novel coactivator of ERs and may play a role in breast tumorigenesis. PMID- 26488769 TI - Scale-down of continuous protein producing Saccharomyces cerevisiae cultivations using a two-compartment system. AB - In the biotechnological industry, economic decisions in investment are typically based on laboratory-scale experiments. Scale-down as a tool is therefore of high industrial importance to transfer the processes into larger production scale without loss in performance. In this study, large-scale prolonged continuous cultivations with a heterologous protein producing Saccharomyces cerevisiae strain have been scaled-down to a two-compartment scale-down reactor system. The effects of glucose, pH, and oxygen concentration gradients have been investigated by comparison with corresponding 300 mL standard continuous cultivations. It was found that substrate gradients within a limited range result in increased productivity of the heterologous protein under regulation of glycolytic TPI promoter and delay the decrease of protein and trehalose production during continuous cultivation. Based on these results, it is argued that introduction of variations in substrate concentration can be beneficial for industrial continuous cultivations. PMID- 26488771 TI - Does the Presence of Risk Factors for Fetal Growth Restriction Increase the Probability of Antenatal Detection? A French National Study. AB - BACKGROUND: Screening for fetal growth restriction (FGR) is a major component of prenatal care. We investigated whether the presence of maternal and pregnancy risk factors for FGR improves the antenatal suspicion of FGR for infants born small-for-gestational age (SGA) as well as their impact on screening specificity. METHODS: Data are from a representative sample of births from the 2010 French National Perinatal Survey (n = 14 100). Detection of FGR was determined by a suspicion of FGR noted in medical charts. Analyses were performed for singleton infants with birthweight under the 10th percentile (SGA), under the 3rd percentile (severely SGA), and above the 10th percentile (false positives) of French references. We studied risk factors for FGR (medical and obstetric conditions, advanced maternal age, nulliparity, body mass index and smoking) using multivariable Poisson regression to derive adjusted risk ratios (aRR). RESULTS: Of SGA infants, 21.7% were suspected of FGR. The presence of obstetric and medical risk factors for FGR was associated with higher suspicion among SGA infants [RR 2.1, 95% confidence interval (CI) 1.7, 2.7]. However, despite the presence of these factors, 60% and 40% of SGA and severely SGA infants, respectively, were not suspected of FGR. Two per cent of normal birthweight infants were suspected of FGR, increasing to 5% when obstetric and medical risk factors were present. Smoking and older maternal age were unrelated to suspicion while females were more likely to be suspected of FGR. CONCLUSION: Our results suggest that better risk assessment could improve antenatal identification of FGR. Sex-specific fetal growth references should be used to avoid systematic bias linked to sex. PMID- 26488770 TI - Musculoskeletal Symptoms and Risk of Burnout in Child Care Workers - A Cross Sectional Study. AB - OBJECTIVES: German child care workers' job satisfaction is influenced by the consequences of unfavourable underlying conditions. Child care workers tend to suffer from psychosocial stress, as they feel that their work is undervalued. The objective of the present study is to investigate how the psychosocial factors of the effort-reward imbalance (ERI) model influence musculoskeletal symptoms (MS) and the risk of burnout. To our knowledge this is the first study investigating the association between the factors of the ERI model and MS in child care workers. METHODS AND FINDINGS: Data from 199 child care workers were examined in a cross-sectional study. Psychosocial factors were recorded with the ERI questionnaire. MS was recorded with the Nordic Questionnaire and risk of burnout with the Personal Burnout scale of the Copenhagen Burnout Inventory. Multivariate analysis was performed using linear and logistic regression models. The response rate was 57%. In most of the sample (65%), an effort-reward imbalance was observed. 56% of the child care workers were at risk of burnout and 58% reported MS. Factors associated with risk of burnout were subjective noise exposure (OR: 4.4, 95%CI: 1.55-12.29) and overcommitment (OR: 3.4; 95%CI: 1.46-7.75). There were statistically significant associations between MS and overcommitment (low back pain-OR: 2.2, 95%CI: 1.04-4.51), low control (overall MS OR: 3.8; 95%CI: 1.68-3.37) and risk of burnout (overall MS OR: 2.3, 95%CI: 1.01-5.28). For ERI no statistically significant associations were found with reference to risk of burnout or MS. CONCLUSION: Overcommitment in child care workers is related to MS and risk of burnout. There is also evidence that low control is associated with MS and subjective noise exposure with risk of burnout. Effort-reward imbalance is not related to either outcome. This occupational health risk assessment identifies changeable working factors in different types of facilities. PMID- 26488773 TI - How Can We Improve Outcomes Assessment? PMID- 26488772 TI - Systemic Lead Toxicity. AB - A 4-year-old girl with slow mentation had increasing knee tenderness and limping gait. PMID- 26488774 TI - Femoral Bone Plug in Total Knee Replacement. AB - The intramedullary alignment guides used in total knee replacement disrupt the intramedullary vessels, resulting in greater postoperative blood loss. The use of an autologous bone plug to seal the intramedullary femoral canal has been shown to be effective in reducing postoperative bleeding. The authors present a simple technique to create a bone plug from the anterior chamfer femoral cut to perfectly seal the intramedullary canal of the femur. PMID- 26488775 TI - Outcomes of a Newer-Generation Cementless Total Knee Arthroplasty Design. AB - Newer-generation cementless total knee arthroplasties (TKAs) aim to improve durability, function, and longevity. In a large series of cementless TKAs at a mean 4-year follow-up, the authors evaluated (1) survivorship, (2) range of motion, (3) patient-reported outcomes, and (4) complications. Mean age was 66 years (range, 34-88 years) and mean body mass index was 32.5 kg/m(2) (range, 20 54 kg/m(2)). Aseptic and septic implant survivorships were 99.6% and 99.5%, respectively. Mean extension, flexion, and Knee Society scores improved significantly. There were 3 septic failures. Aseptic failures included 3 aseptic loosenings, 1 polyethylene revision, and 1 revision to a cemented patella. This study showed excellent clinical and patient-reported outcomes of cementless TKA. PMID- 26488776 TI - Optimizing Stability in Femoral Neck Fracture Fixation. AB - Optimizing stability of femoral neck fracture fixation is important in obtaining a successful outcome. The mechanical problems and strategies for achieving optimal stability differ depending on patients' age and degree of osteoporosis. Femoral neck fractures in younger adults usually result from high-energy trauma and have a vertical fracture pattern. Strategies for optimizing fixation stability in this group include placing additional screws at right angles to the fracture plane and medial buttress plate augmentation. In elderly patients, screw position relative to the intact cortical femoral neck bone is of critical importance. Additional strategies for optimizing fixation stability in this group include the concept of length stable fixation, use of adjunctive calcium phosphate cement, and use of novel fixed angle fixation implants. PMID- 26488777 TI - Protocol-Based Arthroplasty: Less Is More. AB - EDUCATIONAL OBJECTIVES: As a result of reading this article, physicians should be able to: 1. State an argument for, and background information on, patient centered arthroplasty protocols. 2. Describe specific recommendations for designing a simplified arthroplasty care pathway that is reproducible in other institutions. 3. Discuss cost-effectiveness research on the latest value delivering protocols. 4. Recognize areas of continued research and opportunities for future improvement in protocol development. Total joint arthroplasty is a successful orthopedic procedure that is performed in high volume in the United States and internationally. As economic pressures continue to mount in the US health care system, it will become increasingly important to minimize cost and improve quality and value. At the authors' institution, a protocol-based arthroplasty model is used, in many ways based on simplification of the patient care pathway. The largely evidence-based protocol has its foundation in eliminating unnecessary dogmatic practices, enhancing the patient experience, and achieving cost-effectiveness. The authors believe that a model like this can be applied to joint arthroplasty practices across the country in the future to maximize the value delivered to patients. PMID- 26488778 TI - Bilateral Portal Percutaneous Endoscopic Debridement and Lavage for Lumbar Pyogenic Spondylitis. AB - Common management approaches for spinal infections include conservative administration of antibiotics and aggressive surgical debridement. Minimally invasive endoscopic treatment has been reported and is gaining widespread attention because of its simplicity and effectiveness. This study retrospectively evaluated the clinical outcomes of bilateral portal percutaneous endoscopic debridement and lavage with dilute povidone-iodine solution in the treatment of patients with lumbar pyogenic spondylitis. From January 2007 to December 2011, a total of 22 patients diagnosed with single-level lumbar pyogenic spondylitis underwent bilateral portal percutaneous endoscopic debridement and lavage with dilute povidone-iodine solution at the authors' institution. Clinical outcomes were assessed by careful physical examination, visual analog scale pain score, modified MacNab criteria functional score, regular serologic testing, and imaging studies to determine whether percutaneous endoscopic debridement and lavage treatment was successful or if surgical intervention was required. Causative bacteria were identified in 19 (86.4%) of 22 biopsy specimens. Eighteen patients had satisfactory relief of back pain and uneventful recovery after this treatment. The success rate was 81.8% (18 of 22). Both visual analog scale and modified MacNab criteria scores improved significantly in successfully treated patients. No major surgical complications were noted, except for 3 patients who had residual or subsequent paresthesia in the affected lumbar segment. Percutaneous endoscopic debridement and lavage is a minimally invasive procedure that can yield a higher bacterial diagnosis, relieve back pain, and help to eradicate lumbar pyogenic spondylitis. It is an effective alternative treatment for patients with spinal infection before extensive open surgery. PMID- 26488779 TI - Variability in Fluoroscopic Image Acquisition During Operative Fixation of Ankle Fractures. AB - The goal of this study was to determine whether injury, level of surgeon training, and patient factors are associated with increased use of fluoroscopy during open reduction and internal fixation of ankle fractures. These relationships are not well defined. The study was a retrospective chart review of patients treated at an academic institution with primary open reduction and internal fixation of an ankle. Patient demographics, including sex, age, and body mass index, were collected, as was surgeon year of training (residency and fellowship). Image acquisition data included total number of images, total imaging time, and cumulative dose. Ankle fractures were classified according to the Weber and Lauge-Hansen classifications and the number of fixation points. Bivariate analysis and multiple regression models were used to predict increasing fluoroscopic image acquisition. Alpha was set at 0.05. Of 158 patients identified, 58 were excluded. After bivariate analysis, fracture complexity and year of training showed a significant correlation with increasing image acquisition. After multiple regression analysis, fracture complexity and year of training remained clinically significant and were independent predictors of increased image acquisition. Increasing fracture complexity resulted in 20 additional images, 16 additional seconds, and an increase in radiation of 0.7 mGy. Increasing year of training resulted in an additional 6 images and an increase of 0.35 mGy in cumulative dose. The findings suggest that protocols to educate trainee surgeons in minimizing the use of fluoroscopy would be beneficial at all levels of training and should target multiple fracture patterns. PMID- 26488780 TI - National Trends in Operative Treatment of Pediatric Fractures in the Ambulatory Setting. AB - This study evaluated the expanding role of freestanding ambulatory surgery centers in pediatric fracture care based on the only national ambulatory surgery database within the United States. Released by the Centers for Disease Control and Prevention in 1996 and again in 2006, these reports were used to estimate the volume of outpatient pediatric operative fracture care in the United States over a decade, based on International Classification of Diseases, Ninth Revision, Clinical Modification, procedure codes. Particular attention focused on the prevalence of open vs closed vs percutaneous fixation. The estimated number of pediatric patients who presented to outpatient facilities and required operative fracture care between 1996 and 2006 increased by 88%, from 74,577 +/- 4663 to 140,152 +/- 9138. During this time, the use of outpatient surgical services for pediatric fractures increased threefold, from 10% +/- 1% in 1996 to 32% +/- 2% in 2006. An even greater preference for freestanding ambulatory surgery centers was observed during this same time by a factor of 7, from 3% +/- 1% to 21% +/- 4%. Additionally, a trend toward higher volumes of open and percutaneous fixation in freestanding ambulatory surgery centers and not in hospital-associated outpatient centers was observed. This study showed the expanding role of freestanding ambulatory surgery centers in the surgical treatment of pediatric fractures based on data from the only national ambulatory surgery database in the United States. The proportion of open and percutaneous treatment vs closed reduction of fractures in these facilities also greatly increased. Further study is needed to evaluate clinical outcomes and determine which fractures are most appropriately treated in the ambulatory vs hospital setting. PMID- 26488781 TI - Orthostetrics: Management of Orthopedic Conditions in the Pregnant Patient. AB - Managing orthopedic conditions in pregnant patients leads to challenges that must be carefully considered so that the safety of both the mother and the fetus is maintained. Both perioperative and intraoperative considerations must be made based on physiologic changes during pregnancy, risks of radiation, and recommendations for monitoring. Operative timing, imaging, and medication selection are also factors that may vary based on trimester and clinical scenario. Pregnancy introduces unique parameters that can result in undesirable outcomes for both mother and fetus if not handled appropriately. Ultimately, pregnant patients offer a distinct challenge to the orthopedic surgeon in that the well-being of 2 patients must be considered in all aspects of care. In addition, not only does pregnancy affect the management of orthopedic conditions but the pregnant state also causes physiologic changes that may actually induce various pathologies. These pregnancy-related orthopedic conditions can interfere with an otherwise healthy pregnancy and should be recognized as possible complications. Although the management of orthopedic conditions in pregnancy is often conservative, pregnancy does not necessarily preclude safely treating pathologies operatively. When surgery is considered, regional anesthesia provides less overall drug exposure to the fetus and less variability in fetal heart rate. Intraoperative fluoroscopy can be used when appropriate, with 360 degrees fetal shielding if possible. Lateral decubitus positioning is ideal to prevent hypotension associated with compression of the inferior vena cava. PMID- 26488783 TI - Glomus Tumors: A Review of Preoperative Magnetic Resonance Imaging to Detect Satellite Lesions. AB - Glomus tumors are malformations of the neuromyoarterial system that commonly develop in the digits and cause exquisite tenderness, especially with cold temperatures. Treatment typically involves surgical excision, although there is a tendency to avoid aggressive resections, which may lead to aesthetically displeasing nail plate deformities. In a minority of patients, symptoms may persist and the tumor may recur. The etiology of the persistent of symptoms is debatable. One theory for the persistence of symptoms is an incomplete initial excision of the glomus tumor. Another theory suggests that clinically unapparent satellite lesions exist at the time of diagnosis that are not excised, and they later mature into symptomatic recurrent tumors. Although not clinically visible, if present, these satellite lesions should be seen on preoperative magnetic resonance imaging. The authors reviewed all cases of pathology-confirmed glomus tumors in the past 7 years at a single institution in which preoperative magnetic resonance imaging using a high-powered 3.0 Tesla (General Electric, Buckinghamshire, United Kingdom) magnet was performed. Six cases met inclusion criteria and only 1 case developed a recurrent glomus tumor. None of the cases were found to have satellite lesions associated with the primary glomus tumor on magnetic resonance imaging. Preventing recurrence seems to be dependent on the completeness of the initial excision. Preoperative magnetic resonance imaging is a valuable tool used to delineate the extent of the tumor for surgical planning. PMID- 26488782 TI - Obesity Increases Early Complications After High-Energy Pelvic and Acetabular Fractures. AB - Elevated body mass index has been identified as a potential risk factor for complications in operatively treated pelvic trauma. Although obesity is an independent risk factor for morbidity and mortality following high-energy blunt force trauma, there is little information on the immediate complications following isolated pelvic and acetabular fractures in obese patients with trauma. The authors hypothesized that obesity (body mass index >=30 kg/m(2)) is a risk factor for complications in both operative and nonoperative pelvic and acetabular fractures. The authors conducted a 5-year retrospective data collection of all patients with isolated pelvic and acetabular fractures presenting to a Level I trauma center, excluding pediatric (age <18 years) patients, those with ballistic injuries, and those with concomitant long bone fractures or an Abbreviated Injury Scale score of greater than 2 in any other body region. Complications during the immediate hospitalization period were identified by the institution's Trauma Registry of the American College of Surgeons database, including wound infection, dehiscence, deep venous thrombosis, pulmonary embolus, pneumonia, and development of decubitus ulcers. Mean body mass index was 27.4 +/- 6.8 kg/m(2), with 68 (27.0%) obese patients. Mean body mass index of patients with complications was significantly higher (31.9 +/- 9.5 vs 27.0 +/- 6.5 kg/m(2); P=.001). Logistic regression showed that obesity was a significant risk factor for complications (odds ratio, 2.87; 95% confidence interval, 1.02-8.04), after adjusting for age (odds ratio, 1.03; 95% confidence interval, 1.01-1.06) and Injury Severity Score (odds ratio, 1.20; 95% confidence interval, 1.10-1.32). Obesity is associated with increasing complications following operative fixation of pelvic and acetabular fractures. However, it is important to recognize that even nonoperative management of pelvic and acetabular fractures in obese patients can have early complications. This study showed a significant obesity-related risk of complications after trauma in both operative and nonoperative pelvic injuries. PMID- 26488784 TI - Radiostereometric and Radiographic Analysis of Glenoid Component Motion After Total Shoulder Arthroplasty. AB - Aseptic glenoid component loosening is a common cause of total shoulder arthroplasty (TSA) failure, but early detection is difficult because pain often appears late and radiolucent lines are of uncertain significance. This study sought to answer the following questions: (1) What types of glenoid component motion may be observed during the first 3 years following implantation?; (2) Is the appearance of radiolucent lines around the glenoid component a reliable indicator of component motion?; and (3) Are clinical outcomes correlated with early glenoid component motion within the first 3 years after TSA? Eleven patients (mean age, 60.6 years) underwent TSA using a cemented, all-polyethylene glenoid component with tantalum bead implantation. Clinical outcomes (American Shoulder and Elbow Surgeons [ASES] score, visual analog scale [VAS] pain score, and range of motion) were compared pre- and postoperatively, and radiolucencies were graded according to the criteria of Lazarus et al. Patients were evaluated using radiostereometric analysis at 6 months and 1, 2, and 3 years postoperatively to measure component micromotion in translation and rotation. At a mean follow-up of 50.2 months, mean ASES score had improved from 30.3 to 81.3 (P<.001), mean VAS pain score had improved from 8 to 1 (P<.001), active forward flexion had improved from 109 degrees to 155 degrees (P=.001), active external rotation had improved from 28 degrees to 54 degrees (P=.003), and internal rotation had improved from the level of the sacrum to L3 (P=.002). Radiolucencies were detected around none of the components at 1 year, 6 components at 2 years, and 5 components at 3 years, and these radiolucencies were mostly found around components that experienced high levels of rotational motion. PMID- 26488785 TI - Prevalence of Vitamin D Deficiency and Its Association With Metabolic Disease in Korean Orthopedic Patients. AB - Vitamin D is considered essential for bone and muscle health, and some studies have demonstrated the positive effects of vitamin D on metabolic diseases and cancer. Nevertheless, a high prevalence of vitamin D deficiency has been reported in various populations, regardless of country or race. However, no studies regarding the prevalence of vitamin D deficiency in Korean orthopedic patients currently exist. This cross-sectional study included 272 male and 937 female patients aged 50 years and older who were consecutively admitted to the authors' orthopedic department. Vitamin D (25-hydroxy vitamin D), bone turnover markers (osteocalcin, c-telopeptide), and bone mineral density were measured. The prevalence of vitamin D deficiency and its association with other factors were evaluated. Mean patient age was 67.2 +/- 8.9 years, and mean level of vitamin D was 16.1 +/- 9.1 ng/mL. Overall, 91.2% of patients had deficient (<20 ng/mL; 70.6%) or insufficient (20-30 ng/mL; 20.6%) levels of vitamin D. Vitamin D level did not vary by age group or sex. The level of vitamin D was significantly associated with osteocalcin, c-telopeptide, calcium, alkaline phosphatase, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and glucose (P<.01). Vitamin D level in Korean orthopedic patients of this region was extremely low, regardless of sex and age. Although vitamin D was not directly associated with bone mineral density, there were significant associations between vitamin D and other factors related to bone health and metabolic diseases. PMID- 26488786 TI - Anatomic and Reverse Total Shoulder Arthroplasty in Patients Older Than 80 Years. AB - Anatomic total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (RSA) are routinely performed in patients older than 80 years. Often unaware of the differences between the 2 procedures, patients may expect similar outcomes from these procedures. This article reports the outcomes of primary TSA and RSA in patients older than 80 years, with attention directed toward differences in outcomes between the procedures. The authors evaluated a consecutive series of patients who were at least 80 years old and were treated with primary shoulder arthroplasty and had a minimum follow-up of 2 years. Of these patients, 18 underwent primary TSA for osteoarthritis and 33 underwent primary RSA for rotator cuff tear arthropathy. Pain scores, function scores, and range of motion were evaluated preoperatively and at final follow-up. Perioperative and postoperative complications, transfusion rates, length of stay, and subjective satisfaction with the outcome were reported. In these patients, TSA and RSA were similarly effective in improving pain scores, functional scores, and range of motion measurements. Patients who had TSA reported significantly greater satisfaction with surgery and had superior American Shoulder and Elbow Society total and function scores, forward elevation, and external rotation, but similar net improvement from preoperative levels. Although no significant differences were shown in complications, length of stay, or requirement for transfusion, patients treated with RSA had higher rates of transfusion and postoperative complications. Both procedures were similarly effective treatments for patients older than 80 years and showed similar improvements in pain, function, and motion. Patients undergoing RSA were less likely to have good to excellent results, with higher complication and transfusion rates. PMID- 26488787 TI - Frozen Autograft-Prosthesis Composite Reconstruction in Malignant Bone Tumors. AB - Several methods are available using an endoprosthesis or biological reconstruction for malignant bone tumors. Methods that use allograft-prosthesis composites have shown promising results. In 1999, the authors developed a method of reconstruction that uses a tumor-bearing autograft treated with liquid nitrogen. This technique was modified to produce a pedicle frozen autograft to maintain anatomical continuity on one side. In this study, the results of bone reconstructions using frozen autograft-prosthesis composites were retrospectively evaluated. The demographic data, histological records, surgical procedures, functional scores, and complications of 22 patients who had bone sarcoma or metastasis and at least 2 years of follow-up were reviewed. There were 19 patients with primary bone sarcoma and 3 with bone metastasis. Average age was 36 years (range, 9-73 years), and mean follow-up was 63 months (range, 24-176 months). Reconstructions were performed on 10 proximal femurs, 5 distal femurs, 4 proximal tibias, 1 proximal humerus, 1 proximal radius, and 1 hemipelvis. There were 12 pedicle-freezing and 10 free-freezing procedures. Union rate was 90% (9/10), and average union time was 9.5 months. Average Musculoskeletal Tumor Society score was 89.3%. Complications included 1 fracture, 2 infections, 3 soft tissue recurrences, and 1 posterior interosseous nerve palsy. The authors concluded that the frozen autograft-prosthesis composite demonstrated excellent Musculoskeletal Tumor Society scores, a low complication rate, and a good union rate and was superior when used with the pedicle-freezing technique. PMID- 26488788 TI - Prediction of Clinically Significant Leg-Length Discrepancy in Congenital Disorders. AB - Leg-length discrepancy greater than 2 to 2.5 cm can potentially have an adverse effect on our walking and standing mechanisms and requires proper correction involving surgical treatment. However, for minor leg-length discrepancy in childhood, decision making for the indications for and timing of epiphysiodesis is difficult because of unpredictable final discrepancy. The purpose of this study was to analyze longitudinal changes of minor leg-length discrepancy in congenital disorders and to determine earlier predictive values for the clinically significant discrepancy. Twenty-one patients with congenital disorders who had minor leg-length discrepancy less than 2 cm at the first presentation were retrospectively evaluated. The patients were divided into 2 groups according to leg-length discrepancy at latest follow-up: the significant group (n=11) had 25 mm or more of leg-length discrepancy and the minor group (n=10) had less than 25 mm of leg-length discrepancy. The authors evaluated longitudinal changes of leg-length discrepancy within the first 10 years by mixed-effects regression model. All patients showed monotonically increasing leg-length discrepancy with age, except for 2 (neurofibromatosis type 1 and macrodactyly of the foot) who demonstrated fluctuating leg-length discrepancy. Mean annual rate of leg-length discrepancy change in the significant group was 2.1 mm across the first decade of life and was significantly larger than that in the minor group (difference in slope, 1.3 mm; P<.0001). In minor leg-length discrepancy associated with congenital disorders, the incidence of clinically significant leg-length discrepancy can be predictable by the annual rate of leg-length discrepancy change in the first decade of life. PMID- 26488789 TI - Gender Effect on the Outcome of Partial Medial Meniscectomy. AB - Complex posterior horn tears of the medial meniscus are common. Previous reports performed statistical stratifications to address the influence of gender on outcome following arthroscopic partial medial meniscectomy with variable conclusions. The aim of this study was to compare the clinical results of arthroscopic partial meniscectomy of the knee between men and women with complex medial meniscal tear type while controlling for other variables that may affect outcome. This study compared groups of 86 men and 49 women who were followed prospectively using the Lysholm Knee Scoring Scale, the visual analogue scale, and patient's satisfaction. Mean age at operation was 51 years and mean follow-up was 26 months. Mean Lysholm score improved from 69 preoperatively to 82.1 postoperatively (P<.001) in the male group and from 64.2 preoperatively to 73.5 postoperatively (P=.04) in the female group. At last follow-up, 68 (79%) men and 35 (71%) women stated that they were satisfied with the operation. In both groups, the severity of chondral lesions was found to be negatively correlated to the preoperative score. Women had more severe chondral lesions at arthroscopy than men. This comparative study showed no significant difference between men and women in terms of clinical improvement following arthroscopic partial meniscectomies of complex tear types in stable knees with intact lateral meniscus. Women had lower functionality pre- and postoperatively, which correlated with more severe chondral degeneration at surgery compared with men. PMID- 26488790 TI - Relationship Between the Superior Gluteal Vessels and Nerve at the Greater Sciatic Notch. AB - Bleeding from the superior gluteal (SG) blood vessels at the greater sciatic notch is frequently encountered during acetabular fracture surgery. The purpose of this study is to define the positional anatomy of the superior gluteal vessels and nerve (SGVAN) at the greater sciatic notch. Twenty-three hemipelvi were dissected in whole human cadavers. The greater sciatic notch and SGVAN were visualized via a posterior surgical approach, identified deep in the greater sciatic notch, and traced superficially. Branches of the SGVAN and their anatomical relationship to each other were recorded. In the notch, SG arteries comprised a single vessel in 18 (78%) of 23 specimens, with all of these dividing at varying distances (1-3.5 cm) along the lateral ilium after dividing into superior and inferior branches. The SG artery branches were contiguous with periosteum of the bony notch in all specimens. More than 1 SG nerve branch was seen in the greater sciatic notch of all specimens, including an inferior branch that exited caudal or caudal-superficial to the SG vessels. The caudal-most SG nerve branch was directly adjacent to the bony notch's periosteum in 15 (65%) of 23 specimens. The SGVAN are at risk in patients undergoing acetabular fracture surgery. Individuals performing surgery along the acetabulum's posterior column would expect to encounter a major SG nerve branch (deep inferior) before encountering the SG vessels in all cases. Iatrogenic injuries to the SGVAN might be prevented by avoiding use of cautery in this area if hemorrhage is encountered. PMID- 26488791 TI - Cementless Acetabular Reconstruction for Arthropathy in Old Acetabular Fractures. AB - This study was conducted to identify the factors influencing mechanical failure of cementless acetabular reconstruction for arthropathy after operative treatment of acetabular fractures. Fifty-six patients (56 hips) undergoing cementless total hip arthroplasty were enrolled and followed for a mean of 120 months (range, 60 180 months). The 10-year survival rate, with mechanical failure (radiographic loosening or revision due to aseptic loosening) as the endpoint, was analyzed with respect to sex, age, body mass index (BMI), acetabular bone deficiency, sclerotic changes to the acetabulum, and use of the Trabecular Metal (TM) cup (Zimmer, Inc, Warsaw, Indiana). Mean 10-year survival rates of the acetabular component were as follows: 80% (range, 65%-96%) in males and 100% in females (P=.032); 77% (range, 60%-95%) in patients younger than 50 years and 91% (range, 82%-100%) in older patients (P=.027); 88% (range, 78%-98%) in patients with a BMI less than 30 kg/m(2) and 81% (range, 74%-89%) in patients with a BMI of 30 kg/m(2) or higher (P=.068); 54% (range, 32%-76%) in patients manifesting large acetabular deficiency and 90% (range, 78%-100%) in the remaining patients (P<.001); 78% (range, 65%-91%) in patients with the presence of sclerotic acetabulum and 92% (range, 86%-100%) in patients with the absence of sclerotic acetabulum (P=.022); and 82% (range, 73%-100%) in patients who received a conventional shell and 100% in patients who received the TM cup (P=.039). Male sex, age younger than 50 years, large acetabular deficiency, and sclerotic changes of the acetabulum were significant factors contributing to the mechanical failure of cementless acetabular reconstruction performed for old acetabular fractures treated with open reduction and internal fixation. Use of the TM cup seemed able to prolong the endurance of the acetabular component in the subsequent reconstruction. PMID- 26488792 TI - Snapping Knee Syndrome of the Medial Hamstrings. AB - Snapping of the medial hamstrings is a rare condition, with few cases reported throughout the literature. The snapping sensation reportedly occurs when a hamstring tendon passes over the medial tibial condyle, a muscle belly, or another tendon. The semitendinosus tendon is frequently involved, but concomitant involvement of the semitendinosus and gracilis tendons has also been described. Although the exact etiology remains unclear, authors have theorized that the condition results from a congenital malformation or degradation of the accessory tendinous expansions of the semitendinosus. Whereas most cases resolve with conservative treatments, select cases require surgical intervention. Both the distal surgical release and tendon harvest have proved viable surgical procedures, achieving symptom alleviation with minimal patient morbidity. In this article, a case of medial snapping hamstring tendons involving both the semitendinosus and gracilis tendons is reviewed. A 17-year-old African American girl presented with extreme pain and snapping on the posteromedial aspect of her knee was appreciated. Radiographs were ordered and showed no acute fracture, no acute dislocation, normal medial joint space, normal lateral joint space, and normal patellofemoral space. Conservative and surgical options were reviewed, and the patient elected to undergo harvest of the tendons. Four weeks postoperatively, the patient reported complete resolution of symptoms. To date, there has been no recurrence of symptoms. The authors hope to increase awareness of this condition and add to the existing body of literature. PMID- 26488793 TI - Use of Massive Allografts to Manage Hydatid Bone Disease of the Femur. AB - Hydatid disease is caused by the parasitic tapeworm Echinococcus granulosus. Osseous involvement accounts for 0.5% to 4% of cases in humans. Patients usually are from endemic zones and are initially asymptomatic, presenting with pain and edema at a later stage of disease. However, large lesions may present initially as pathologic fractures. Standard radiographs usually show expansive osteolytic lesions associated with initial cortical thinning, with compromise of the metaphysis or epiphysis, and may involve the diaphysis. The finding of periosteal reaction, osteocondensation, calcification, and clear delimitation of the lesions excludes the diagnosis of osseous hydatidosis. However, there are no specific radiographic signs in the affected bone. There is no generally accepted treatment algorithm for osseous hydatid disease. The usual treatment is surgical resection of the affected bone, followed by antihelmintic therapy. Some patients can be treated with intralesional procedures, such as curettage and allograft or polymethyl methacrylate cement. However, in some advanced cases, such as those with pathologic fractures or recurrences, wide resection may be needed. Several reconstructive alternatives have been reported, such as megaprosthesis, massive allograft, or alloprosthesis composite. The authors retrospectively reviewed 2 cases of femoral hydatidosis treated with wide resection and reconstruction with massive bone allograft. One patient had 5 years of follow-up, and the other had 9 years. No signs of relapse or complications were recorded, and functional outcomes evaluated with the Musculoskeletal Tumor Society scale showed excellent results. These 2 cases support the use of a massive bone allograft as a valid alternative to reconstruction after extensive bone resection for hydatidic disease. PMID- 26488794 TI - Cardiac Perforation and Multiple Emboli After Percutaneous Vertebroplasty. AB - Percutaneous vertebroplasty is a minimally invasive technique for treating vertebral compression fractures and tumors. Although percutaneous vertebroplasty is considered a relatively safe and technically simple procedure, it is also associated with life-threatening complications as a result of cement leakage, including cardiac perforation and pulmonary embolism. A 63-year-old woman underwent percutaneous vertebroplasty for an L3 vertebral fracture and had cement leaks into the inferior vena cava, pulmonary arteries, and right heart chambers, with a free wall perforation. Surgical removal of the cement emboli was recommended as a result of apparent penetration of the ventricle and the fragile nature of polymethyl methacrylate. A cardiopulmonary bypass was immediately performed via a right atriotomy. A foreign body 10 cm in length was removed from the right atrium and ventricle. Arteriotomies were then performed, and 4 cement filaments were retrieved from the pulmonary arteries. The inferior vena cava was also surgically opened, allowing extraction of a cement fragment that was 12 cm long. The postoperative course was uneventful, and the patient fully recovered. This is the first report of the migration of a cement fragment larger than 10 cm that had migrated and embedded in the heart chamber. This report showed that imaging analysis is valuable when cement leakage is detected during percutaneous vertebroplasty and can be used to avoid serious complications and improve patient outcomes. PMID- 26488795 TI - FE analysis of the effects of simplifications in experimental testing on micromotions of uncemented femoral knee implants. AB - Experimental testing of orthopaedic implants requires simplifications concerning load application and activities being analyzed. This computational study investigated how these simplifications affect micromotions at the bone-implant interface of an uncemented femoral knee implant. As a basis, validated in vivo loads of the stance phase of gait and a deep knee bend were adopted. Eventually, three configurations were considered: (i) simulation of the complete loading cycle; (ii) inclusion of only tibiofemoral loads (ignoring patellofemoral loads); and (iii) applying only a single peak tibiofemoral force. For all loading conditions the largest micromotions found at the proximal anterior flange. Without the patellofemoral force, peak micromotions increased 6% and 22% for gait and deep knee bend, respectively. By applying a single peak tibiofemoral force micromotions were overestimated. However, the peak micromotions corresponded to the maximum tibiofemoral force, and strong micromotion correlations were found between a complete loading cycle and a single peak load (R(2) = 0.73 and R(2) = 0.89 for gait and deep knee bend, respectively). Deep knee bend resulted in larger micromotions than gait. Our study suggests that a simplified peak force can be used to assess the stability of cementless femoral components. For more robust testing, implants should be subjected to different loading modes. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:812-819, 2016. PMID- 26488796 TI - Feasible, Efficient and Necessary, without Exception - Working with Sex Workers Interrupts HIV/STI Transmission and Brings Treatment to Many in Need. AB - BACKGROUND AND OVERVIEW: High rates of partner change in sex work-whether in professional, 'transactional' or other context-disproportionately drive transmission of HIV and other sexually transmitted infections. Several countries in Asia have demonstrated that reducing transmission in sex work can reverse established epidemics among sex workers, their clients and the general population. Experience and emerging research from Africa reaffirms unprotected sex work to be a key driver of sexual transmission in different contexts and regardless of stage or classification of HIV epidemic. This validation of the epidemiology behind sexual transmission carries an urgent imperative to realign prevention resources and scale up effective targeted interventions in sex work settings, and, given declining HIV resources, to do so efficiently. Eighteen articles in this issue highlight the importance and feasibility of such interventions under four themes: 1) epidemiology, data needs and modelling of sex work in generalised epidemics; 2) implementation science addressing practical aspects of intervention scale-up; 3) community mobilisation and 4) the treatment cascade for sex workers living with HIV. CONCLUSION: Decades of empirical evidence, extended by analyses in this collection, argue that protecting sex work is, without exception, feasible and necessary for controlling HIV/STI epidemics. In addition, the disproportionate burden of HIV borne by sex workers calls for facilitated access to ART, care and support. The imperative for Africa is rapid scale-up of targeted prevention and treatment, facilitated by policies and action to improve conditions where sex work takes place. The opportunity is a wealth of accumulated experience working with sex workers in diverse settings, which can be tapped to make up for lost time. Elsewhere, even in countries with strong interventions and services for sex workers, an emerging challenge is to find ways to sustain them in the face of declining global resources. PMID- 26488797 TI - Synthesis, Anticancer Activity, and Genome Profiling of Thiazolo Arene Ruthenium Complexes. AB - Sixteen hydrazinyl-thiazolo arene ruthenium complexes of the general formula [(eta(6)-p-cymene)Ru(N,N'-hydrazinyl-thiazolo)Cl]Cl were synthesized. All complexes were tested in vitro for their antiproliferative activity on three tumor cell lines (HeLa, A2780, and A2780cisR) and on a noncancerous cell line (HFL-1). A superior cytotoxic activity of the ruthenium complexes as compared to cisplatin and oxaliplatin, on both cisplatin-sensitive and cisplatin resistant ovarian cancer cells, was observed. In addition, the biological activity of two selected derivatives was evaluated using microarray gene expression assay and ingenuity pathway analysis. p53 signaling was identified as an important pathway modulated by both arene ruthenium compounds. New activated molecules such as FAS, ZMAT3, PRMT2, BBC3/PUMA, and PDCD4, whose overexpressions are correlated with overcoming resistance to cisplatin therapy, were also identified as potential targets. Moreover, the arene ruthenium complexes can be used in association with cisplatin to prevent cisplatin resistance development and synergistically to induce cell death in ovarian cancer cells. PMID- 26488798 TI - Reply to: Glucarpidase for the Treatment of Methotrexate-Induced Renal Dysfunction and Delayed Methotrexate Excretion. PMID- 26488799 TI - Topical amitriptyline and ketamine for the treatment of neuropathic pain. AB - A neuropathy is a disturbance of function or pathological change in nerves. In some cases, peripheral neuropathic pain may occur due to a lesion or disease of the peripheral somatosensory nervous system. Efficacy of different agents for peripheral neuropathic pain conditions is less than optimal. The administration of topical analgesics might be an option, due to the potential of reduced adverse effects and increased patient compliance. There is major interest in compounding topical analgesics for peripheral neuropathic pain, but several challenges remain for this approach. Topical analgesics have the potential to be a valuable additional approach for the management of peripheral neuropathic pain. Topical amitriptyline-ketamine combination (AK) is a promising agent for peripheral neuropathic pain conditions. Some studies have shown its efficacy in neuropathic pain conditions. However, this data was not uniformely obtained and its role remains still controversial. Efficacy may depend on many factors, including the choice of the vehicle, the concentration, the pain site, and specific diseases. More studies are necessary to support the use of AK in clinical practice. PMID- 26488800 TI - All-optical investigation of tunable picosecond magnetization dynamics in ferromagnetic nanostripes with a width down to 50 nm. AB - Ferromagnetic nanostripes are important elements for a number of interesting technologies including magnetic racetrack memory, spin logic and magnonics. Understanding and controlling magnetization dynamics in such nanostripes are hence important problems in nanoscience and technology. Here we present an all optical excitation and detection of ultrafast magnetization dynamics, including spin waves, in 5 MUm long Ni80Fe20 nanostripes with varying stripe widths from 200 nm down to 50 nm. We observed a strong width dependent variation in the frequency, anisotropy and the spatial nature of spin waves in these systems. The effect of inter-stripe interaction is also studied and the 50 nm wide stripe is found to be nearly magnetostatically isolated, allowing us to detect the dynamics of a 50 nm wide individual stripe using an all-optical measurement technique. The tunability in magnetization dynamics with stripe widths is important for their applications in various spin based technologies. PMID- 26488801 TI - Hydroxytyrosol and tyrosol sulfate metabolites protect against the oxidized cholesterol pro-oxidant effect in Caco-2 human enterocyte-like cells. AB - The aim of this study was to investigate the ability of the sulfate metabolites of hydroxytyrosol (HT) and tyrosol (TYR) to act as antioxidants counteracting the pro-oxidant effect of oxidized cholesterol in intestinal cells. For this purpose, we synthesized sulfate metabolites of HT and TYR using a chemical methodology and examined their antioxidant activity in Caco-2 monolayers in comparison with the parent compounds. Exposure to oxidized cholesterol led to ROS production, oxidative damage, as indicated by the MDA increase, a decrease of reduced glutathione concentration and an enhancement of glutathione peroxidase activity. All the tested compounds were able to counteract the oxidizing action of oxidized cholesterol; HT and TYR sulfate metabolites showed an efficiency in protecting intestinal cells comparable to that of the parent compounds, strengthening the assumption that the potential beneficial effect of the parent compounds is retained, although extensive metabolisation occurs, the resulting metabolites being able to exert a biological action themselves. PMID- 26488802 TI - Incidence of Mastitis in the Neonatal Period in a Traditional Breastfeeding Society: Results of a Cohort Study. AB - BACKGROUND: Mastitis is a painful problem experienced by breastfeeding women, especially in the first few weeks postpartum. There have been limited studies of the incidence of mastitis from traditionally breastfeeding societies in South Asia. This study investigated the incidence, determinants, and management of mastitis in the first month postpartum, as well as its association with breastfeeding outcomes at 4 and 6 months postpartum, in western Nepal. SUBJECTS AND METHODS: Subjects were a subsample of 338 mothers participating in a larger prospective cohort study conducted in 2014 in western Nepal. Mothers were interviewed during the first month postpartum and again at 4 and 6 months to obtain information on breastfeeding practices. The association of mastitis and determinant variables was investigated using multivariable logistic regression, and the association with breastfeeding duration was examined using Kaplan-Meier estimation. RESULTS: The incidence of mastitis was 8.0% (95% confidence interval, 5.1%, 10.8%) in the first month postpartum. Prelacteal feeding (adjusted odds ratio = 2.76; 95% confidence interval, 1.03, 7.40) and cesarean section (adjusted odds ratio = 3.52; 95% confidence interval, 1.09, 11.42) were associated with a higher likelihood of mastitis. Kaplan-Meier estimation showed no significant difference in the duration of exclusive breastfeeding among the mothers who experienced an episode of mastitis and those who did not. CONCLUSIONS: Roughly one in 10 (8.0%) women experienced mastitis in the first month postpartum, and there appeared to be little effect of mastitis on breastfeeding outcomes. Traditional breastfeeding practices should be encouraged, and the management of mastitis should be included as a part of lactation promotion. PMID- 26488803 TI - Attenuated total reflection Fourier-transform infrared (ATR-FTIR) imaging of tissues and live cells. AB - FTIR spectroscopic imaging is a label-free, non-destructive and chemically specific technique that can be utilised to study a wide range of biomedical applications such as imaging of biopsy tissues, fixed cells and live cells, including cancer cells. In particular, the use of FTIR imaging in attenuated total reflection (ATR) mode has attracted much attention because of the small, but well controlled, depth of penetration and corresponding path length of infrared light into the sample. This has enabled the study of samples containing large amounts of water, as well as achieving an increased spatial resolution provided by the high refractive index of the micro-ATR element. This review is focused on discussing the recent developments in FTIR spectroscopic imaging, particularly in ATR sampling mode, and its applications in the biomedical science field as well as discussing the future opportunities possible as the imaging technology continues to advance. PMID- 26488804 TI - Improvement of saccadic functions after dosing with methadone in opioid addicted individuals. AB - In the current experiment, we used the saccadometric test to study the effect of a single therapeutic dose of methadone on the integrity of cortico-subcortical brain functioning. In this prospective study, we used the Saccadometer System (Advanced Clinical Instrumentation, Cambridge, UK). The saccadometric test was performed before and 1.5 hours after methadone dosing. We analyzed the following saccadic parameters: latency, duration, amplitude, average and peak velocity, and processing performance (promptness) as well as a number of different types of saccades (like correct/incorrect, under/overshoot, and left-sided/right-sided). The sample consists of 40 subjects with an average 18 years of opioid addiction. The mean age is 35.3 +/- 7 (80% males and 20% females). The mean period of heroin dependence is 15.3 +/- 6.3 years. The mean daily dose of methadone in substitution therapy is 90 +/- 26.5 mg. After administration of a single therapeutic dose of methadone, there were statistically significant differences in the values of saccade duration and latency when compared to the values before the drug administration. Average duration of saccade was significantly longer [51.40 +/- 8.75 ms versus 48.93 +/- 6.91 ms, z = 2.53, p = .01] and average latency was significantly longer [198.85 +/- 52.57 ms versus 183.05 +/- 30.95 ms, z = 2.09 p < .03]. This is the first study to test the therapeutic effect of daily methadone dosing on the integrity of the cortico-subcortical brain functions as measured by the saccadometry. More research is needed to explore the effect of illicit opioid use on the integrity of brain structures and functions, and the protective effect of opioid agonist therapy on reversing the damaging effects of illicit opioid use. PMID- 26488805 TI - Intraday glucose fluctuation is common in preterm infants receiving intermittent tube feeding. AB - BACKGROUND: We previously reported on three preterm infants with blood glucose abnormalities after reaching full enteral feeding. Recently, it has been shown that clinically stable preterm infants may have large fluctuations in blood glucose after the establishment of enteral nutrition. We hypothesized that intraday glucose fluctuation is a common finding in preterm infants, but improves at term post-conceptual age. This report describes a case series. METHODS: From June 2010 to July 2012, 13 preterm infants (29.5 +/- 2.1 post-conceptual weeks, 1144 +/- 319 g) were enrolled in this study. Continuous glucose monitoring (CGM) was conducted on average at 33.5 +/- 1.4 post-conceptual weeks, when they received gastric tube feeding every 3 h in the absence of i.v. glucose supply. RESULTS: Eight infants (62%) had large intraday glucose fluctuation with repeated hyperglycemic (>150 mg/dL) and hypoglycemic (<50 mg/dL) events. In five infants, follow-up CGM at 36-38 weeks post-conceptual age showed more stable glycemic changes without any abnormal glucose levels. CONCLUSIONS: On CGM, in some preterm infants intermittent tube feeding resulted in large intraday glucose fluctuation at 31-35 post-conceptual weeks, but the pattern disappeared before discharge (36 38 post-conceptual weeks). PMID- 26488806 TI - Adjusted Hospital Sentinel Lymph Node Positivity Rates in Melanoma: A Novel Potential Measure of Quality. AB - OBJECTIVE: Our objectives were to examine whether hospital characteristics are associated with lower- and higher-than-expected sentinel lymph node biopsy (SLNB) positivity rates and whether hospitals with lower- or higher-than-expected SLNB positivity rates have worse patient outcomes. BACKGROUND: Surgeon and pathologist SLNB technical errors may lead to incorrect melanoma staging. A hospital's SLNB positivity rate may reflect its SLNB proficiency for melanoma, but this has never been investigated. METHODS: Stage IA-III melanoma patients undergoing SLNB were identified from the National Cancer Data Base (2004-2010). Hospital-level SLNB positivity rates were adjusted for patient- and tumor factors. Hospitals were divided into terciles of adjusted SLNB positivity rates. Hospital characteristics (using multinomial logistic regression) and survival (using Cox modeling) were examined across terciles. RESULTS: Of 33,639 SLNB patients (from 646 hospitals), 2916 (8.7%) had at least 1 positive lymph node. Hospitals with lower- (low tercile) and higher-than-expected (high tercile) SLNB positivity rates were more likely to be low-volume hospitals (low tercile: relative risk ratio (RRR) = 2.57, P = 0.002; high tercile: RRR = 2.3, P = 0.004) compared to hospitals with expected rates (middle tercile). Stage I patients treated at lower-than-expected SLNB positivity rate hospitals had worse 5-year survival than those treated at expected SLNB positivity rate hospitals (90.0% vs 91.9%, P = 0.014; hazard ratio = 1.28, 95% CI: 1.05-1.57); survival differences were not observed by SLNB positivity rates for stage II/III. CONCLUSIONS: Adjusted hospital SLNB positivity rates varied widely. Surgery at hospitals with lower-than-expected SLNB positivity rates was associated with decreased survival. Hospital SLNB positivity rates may be a novel measure to confidentially report to hospitals for internal quality assessment. PMID- 26488807 TI - Activation of Protein Kinase A in Mature Osteoblasts Promotes a Major Bone Anabolic Response. AB - Protein kinase A (PKA) regulates osteoblast cell function in vitro and is activated by important bone mass modulating agents. We determined whether PKA activation in osteoblasts is sufficient to mediate a bone anabolic response. Thus, a mouse model conditionally expressing a constitutively active PKA (CA-PKA) in osteoblasts (CA-PKA-OB mouse) was developed by crossing a 2.3-kb alpha1 (I) collagen promoter-Cre mouse with a floxed-CA-PKA mouse. Primary osteoblasts from the CA-PKA-OB mice exhibited higher basal PKA activity than those from control mice. Microcomputed tomographic analysis revealed that CA-PKA-OB female mice had an 8.6-fold increase in femoral but only 1.16-fold increase in lumbar 5 vertebral bone volume/total volume. Femur cortical thickness and volume were also higher in the CA-PKA-OB mice. In contrast, alterations in many femoral microcomputed tomographic parameters in male CA-PKA-OB mice were modest. Interestingly, the 3 dimensional structure model index was substantially lower both in femur and lumbar 5 of male and female CA-PKA-OB mice, reflecting an increase in the plate to rod-like structure ratio. In agreement, femurs from female CA-PKA-OB mice had greater load to failure and were stiffer compared with those of control mice. Furthermore, the CA-PKA-OB mice had higher levels of serum bone turnover markers and increased osteoblast and osteoclast numbers per total tissue area compared with control animals. In summary, constitutive activation of PKA in osteoblasts is sufficient to increase bone mass and favorably modify bone architecture and improve mechanical properties. PKA activation in mature osteoblasts is, therefore, an important target for designing anabolic drugs for treating diseases with bone loss. PMID- 26488808 TI - Vitamin D Regulates Fatty Acid Composition in Subcutaneous Adipose Tissue Through Elovl3. AB - Fatty acids (FAs) are a major energy source in the body. White adipose tissue (WAT) is a primary site where FAs are stored as triacylglycerols. Brown adipose tissue also stores and recruits FAs as a carbon source for uncoupled beta oxidation during thermogenesis. The deletion of the vitamin D nuclear hormone receptor (VDR) gene in mice (VDRKO) results in a lean WAT phenotype with increased levels of expression of the brown adipose tissue marker Ucp1 in the WAT. However, the impact of vitamin D/VDR on FA composition in WAT has not been explored in detail. To address this question, we examined the FA composition of sc and visceral white adipose depots of VDRKO mice. We found that the levels of a subset of saturated and monounsaturated FAs of C18-C24 are specifically increased in the sc adipose depot in VDRKO mice. We revealed that a specific elongase enzyme (Elovl3), which has an important role in brown fat biology, is directly regulated by VDR and likely contributes to the altered FA composition in VDRKO mice. We also demonstrate that Elovl3 is regulated by vitamin D in vivo and tissue specifically in the sc WAT depot. We discovered that regulation of Elovl3 expression is mediated by ligand-dependent VDR occupancy of a negative-response element in the promoter proximal region of the Elovl3 gene. These data suggest that vitamin D/VDR tissue specifically modulates FA composition in sc WAT through direct regulation of Elovl3 expression. PMID- 26488809 TI - Gut-Busters: IL-17 Ain't Afraid of No IL-23. AB - Interleukin-23 (IL-23) is considered a critical regulator of IL-17 in lymphocytes. Whereas antibodies targeting IL-23 ameliorate colitis, IL-17 neutralization exacerbates disease. In this issue, Cua and colleagues and Maxwell and colleagues show that IL-17 maintains intestinal barrier integrity, helping explain this dichotomy (Lee et al., 2015; Maxwell et al., 2015). PMID- 26488810 TI - Loss of CD47 Makes Dendritic Cells See Red. AB - Whereas dendritic cells (DCs) can be activated in many ways to trigger immunity, hardly anything is known about the mechanisms that counterbalance DC activation. Cyster and colleagues now demonstrate that the "self" molecule CD47 on erythrocytes critically restricts splenic DC activation. PMID- 26488811 TI - Keeping Off the Weight with DCs. AB - Long studied as modulators of insulin sensitivity, adipose tissue immune cells have recently been implicated in regulating fat mass and weight gain. In this issue of Immunity, Reisner and colleagues (2015) report that ablation of perforin expressing dendritic cells induces T cell expansion, worsening autoimmunity and surprisingly increasing adiposity. PMID- 26488812 TI - Licensed to Ill: IL-9 Generation in Immature Mast Cells Permits Food-Elicited Anaphylaxis. AB - Food-specific IgE is central to the pathobiology of food allergy, but not sufficient to induce disease. Chen et al. (2015) demonstrate that food-elicited reactions require an immature mast cell that generates IL-9 to induce its own maturation. PMID- 26488813 TI - Short, but Smart: SCFAs Train T Cells in the Gut to Fight Autoimmunity in the Brain. AB - In this issue of Immunity, Haghikia and colleagues (2015) demonstrate that dietary fatty acids, by modulating gut microbes and their metabolism, regulate mucosal immune cells to impact systemic immunity. Using this mechanism, dietary and bacteria-derived medium-chain and long-chain fatty acids exacerbate, whereas short-chain fatty acids ameliorate, autoimmunity in the brain. PMID- 26488814 TI - Tumor Microenvironment and Immunotherapy: The Whole Picture Is Better Than a Glimpse. AB - Predicting cancer patients' response to therapy is essential for curing disease and improving quality of life. Garraway and colleagues demonstrate that the frequency and number of neoantigens, non-synonymous mutations, and adaptive immune genes, but not the assessment of individual recurrent neoantigens or mutations, predicts patient responses to immunotherapy. PMID- 26488818 TI - Tuning and Switching Enantioselectivity of Asymmetric Carboligation in an Enzyme through Mutational Analysis of a Single Hot Spot. AB - Enantioselective bond making and breaking is a hallmark of enzyme action, yet switching the enantioselectivity of the reaction is a difficult undertaking, and typically requires extensive screening of mutant libraries and multiple mutations. Here, we demonstrate that mutational diversification of a single catalytic hot spot in the enzyme pyruvate decarboxylase gives access to both enantiomers of acyloins acetoin and phenylacetylcarbinol, important pharmaceutical precursors, in the case of acetoin even starting from the unselective wild-type protein. Protein crystallography was used to rationalize these findings and to propose a mechanistic model of how enantioselectivity is controlled. In a broader context, our studies highlight the efficiency of mechanism-inspired and structure-guided rational protein design for enhancing and switching enantioselectivity of enzymatic reactions, by systematically exploring the biocatalytic potential of a single hot spot. PMID- 26488817 TI - Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine. AB - Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis. PMID- 26488816 TI - Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation. AB - CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that similar to Card9-deficient mice, Trim62-deficient mice had increased susceptibility to fungal infection. In this study, we utilized a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation. PMID- 26488819 TI - Deconvoluting the Effect of the Hydrophobic and Hydrophilic Domains of an Amphiphilic Integral Membrane Protein in Lipid Bicontinuous Cubic Mesophases. AB - Lipidic bicontinuous cubic mesophases with encapsulated amphiphilic proteins are widely used in a range of biological and biomedical applications, including in meso crystallization, as drug delivery vehicles for therapeutic proteins, and as biosensors and biofuel cells. However, the effect of amphiphilic protein encapsulation on the cubic phase nanostructure is not well-understood. In this study, we illustrate the effect of incorporating the bacterial amphiphilic membrane protein Ag43, and its individual hydrophobic beta(43) and hydrophilic alpha(43) domains, in bicontinuous cubic mesophases. For the monoolein, monoalmitolein, and phytantriol cubic phases with and without 8% w/w cholesterol, the effect of the full length amphiphilic protein Ag43 on the cubic phase nanostructure was more significant than the sum of the individual hydrophobic beta(43) and hydrophilic alpha(43) domains. Several factors were found to potentially influence the impact of the hydrophobic beta(43) domain on the cubic phase internal nanostructure. These include the size of the hydrophobic beta(43) domain relative to the thickness of the lipid bilayer, as well as its charge and diameter. The size of the hydrophilic alpha(43) domain relative to the water channel radius of the cubic mesophase was also found to be important. The secondary structure of the Ag43 proteins was affected by the hydrophobic thickness and physicochemical properties of the lipid bilayer and the water channel diameter of the cubic phase. Such structural changes may be small but could potentially affect membrane protein function. PMID- 26488815 TI - Natural Killer Cell Memory. AB - Natural killer (NK) cells have historically been considered short-lived cytolytic cells that can rapidly respond against pathogens and tumors in an antigen independent manner and then undergo cell death. Recently, however, NK cells have been shown to possess traits of adaptive immunity and can acquire immunological memory in a manner similar to that of T and B cells. In this review, we discuss evidence of NK cell memory and the mechanisms involved in the generation and survival of these innate lymphocytes. PMID- 26488820 TI - Real-world treatment patterns, comorbidities, and disease-related complications in patients with multiple myeloma in the United States. AB - OBJECTIVES: To describe multiple myeloma (MM) treatment patterns and comorbidities over time in the US. RESEARCH DESIGN AND METHODS: Study patients were newly diagnosed with MM (ICD-9-CM 203.0x) between 1 July 2006 and 31 March 2014 and had >=6 months of data prior to the initial MM diagnosis in MarketScan Research Databases. Patients were followed until inpatient death or the end of data. First-line, second-line, and third-line treatment regimens were identified following diagnosis and were described over time based upon the start date of the first line of therapy (2006-2007, 2008-2014, 2013-2014). Comorbid conditions and disease-related complications were examined during the 6 months prior to the line of therapy start dates. RESULTS: A total of 24,507 MM patients were examined (mean age: 65.2 years, 54.1% male, mean follow-up: 23 months, 16.2% transplant). Across all lines of therapy, the proportion of patients on thalidomide-based regimens decreased over time. In the first line, bortezomib-based regimens became more common from 2006-2007 to 2008-2014 (2006-2007: 17.0%, 2008-2014: 44.3%, 2013 2014: 49.4%). In the second line, lenalidomide- and bortezomib-based regimens were the most common (2013-2014: lenalidomide: 28.9%, bortezomib: 26.2%). The combination regimen of lenalidomide + bortezomib became more common in the first and second lines. In the third line, carfilzomib- and/or pomalidomide-based regimens were 37.0% in 2013-2014. Skeletal-related events, hypertension, anemia, and chronic kidney disease were the most prevalent comorbidities and disease related complications. During the 6 months prior to each line of therapy, the prevalence of the majority of the comorbidities and complications increased as patients progressed to higher lines of therapy. CONCLUSIONS: MM treatment patterns have been dynamic over time. Comorbid conditions and myeloma-related complications increase as patients progress and may worsen MM patients' prognoses over time. Combination regimens such as lenalidomide + bortezomib are more widely used as first- and second-line therapy. Newly approved agents (carfilzomib, pomalidomide) are the prevailing treatments in the third line and are under further investigation for earlier lines of therapy. PMID- 26488821 TI - Correction to "Bridging the Gap: Electron Relay and Plasmonic Sensitization of Metal Nanocrystals for Metal Clusters". PMID- 26488822 TI - All-cause and circulatory disease-related hospitalization, by generation status: Evidence from linked data. AB - BACKGROUND: Immigrants tend to have better health than the Canadian-born. However, the "healthy immigrant" effect diminishes over time and varies by source country. This study examines whether lower hospitalization rates persist from the first (G1) to the second generation (G2) of immigrants, compared with other Canadians (G3+). All-cause and circulatory disease-related hospitalization rates were examined by generation, with special attention to people of Chinese and South Asian descent. DATA AND METHODS: Data from the 2006 Census-hospitalization linkage database (which excludes Quebec) were analysed using logistic regression. Age-standardized all-cause (excluding pregnancy) and circulatory disease-related hospitalization rates were derived for the urban population aged 30 or older for the 2006/2007 to 2008/2009 fiscal years. RESULTS: Over the generations, immigrants' all-cause and circulatory disease-related hospitalization rates converged with those of the Canadian population overall. Compared with G3+, the age-adjusted odds of all-cause hospitalization among men were 0.49 (CI = 0.48 0.51) for recent G1 immigrants, 0.78 (CI = 0.77-0.79) for long-term G1 immigrants, and 0.95 (CI = 0.94-0.97) for G2. Adjustments for socioeconomic status reduced the difference, especially between G2 and G3+. For South Asians, rates converged for circulatory disease, notably among men. Hospitalization rates for people of Chinese descent rose across generations, but remained significantly below rates for G3+. INTERPRETATION: The lower circulatory disease-related hospitalization risk experienced by G1 is maintained in G2 among people of Chinese descent, but not among South Asians. PMID- 26488823 TI - Linking 2006 Census and hospital data in Canada. AB - BACKGROUND: Record linkage is commonly used in health research to fill data gaps. This study summarizes the linkage of the 2006 Census of Population (excluding Quebec) to hospital data from the Discharge Abstract Database (DAD). DATA AND METHODS: Hierarchical deterministic exact matching was employed to link 2006 Census and DAD (2006/2007, 2007/2008 and 2008/2009) data, based on linkage keys derived from three variables common to both files-date of birth, postal code and sex. The full census file (short-form; 23.4 million) was used for record linkage; the 20% file (long-form; 4.65 million) representing the study cohort was used for validation. Linked files were compared across jurisdictions, years and other selected covariates in terms of eligibility for linkage, keys linked, and linkage and coverage rates. RESULTS: Overall, 80% of linkage keys identified in the DAD were linked to the 2006 Census. The percentage of long-form census respondents linked to at least one hospital record ranged between 5% and 8% across jurisdictions; linkage rates were higher among known high users of hospital services: older age groups, lower-income individuals, and Aboriginal people. In general, the linked census file represents the majority of hospital events that occurred during the study period. Coverage rates (weighted/unweighted) varied by geography and age group, with lower weighted rates for the territories and some younger age groups. INTERPRETATION: With hierarchical deterministic exact matching, census data can be linked to multiple years of DAD data. Incorporation of updated postal codes from tax files reduced linkage rate attrition over time. Lower coverage rates for the territories and younger age groups suggest that these populations may be underrepresented in the linked files. PMID- 26488824 TI - Oral contraceptive use among women aged 15 to 49: Results from the Canadian Health Measures Survey. AB - BACKGROUND: Oral contraceptives (OCs) have been available in Canada for over 50 years and are the most commonly used method of reversible contraception. OCs have evolved over time, with decreasing estrogen doses, new progestins, and different dosing regimens. Detailed data about OCs use among Canadian women are lacking. DATA AND METHODS: Data from Statistics Canada's 2007/2009 and 2009/2011 Canadian Health Measures Survey (CHMS) were used to estimate OC use, by selected sociodemographic characteristics, cardiovascular risk factors, and estrogen dose and progestin type. Logistic regression was used to model relationships between OC use and sociodemographic factors. RESULTS: An estimated 1.3 million (16%) women aged 15 to 49 reported taking OCs in the previous month. OC use decreased with age (30% among 15- to 19-year-olds; 3% among 40- to 49-year-olds). OC users were significantly more likely than non-users to be nulliparous, sexually active and Canadian-born. At ages 35 to 49, users were less likely than non-users to have one or more cardiovascular risk factors. Almost all (99%) OC users took combined formulations containing ethinyl estradiol (EE) and progestin. Two-thirds of OCs users took formulations containing 30 or more mcg of EE. Women aged 15 to 24 were more likely than those aged 35 to 49 to use lower-dose formulations (less than 30 mcg of EE). INTERPRETATION: A substantial percentage of reproductive-aged Canadian women, particularly younger women, used OCs. OC use varied by sociodemographic and some cardiovascular risk factors. The majority took formulations containing 30 or more mcg of EE. PMID- 26488825 TI - Could a Coagulation Nurse Liaison Improve Compliance With Venous Thromboembolism Prophylaxis in Medical Patients? AB - Medical patients worldwide are undertreated with venous thromboembolism prophylaxis. Our hypothesis was that the rate of prophylactic anticoagulation therapy for high-risk patients would improve with the use of a coagulation nurse liaison. Six months after appointing a nurse for this role, prophylaxis rates significantly improved, and patients were more likely to receive appropriate thromboprophylaxis. A coagulation nurse liaison substantially improves thromboprophylaxis in a medical ward. PMID- 26488826 TI - Programmable Downregulation of Enzyme Activity Using a Fever and NIR-Responsive Molecularly Imprinted Nanocomposite. AB - A fever and NIR-responsive molecularly imprinted nanocomposite is designed for programmable downregulation of enzyme activity. The target enzyme can be captured specifically and its activity can be downregulated only when body temperature increases abnormally. Upon NIR irradiation, the temperature of the destination region can increase accordingly inducing a further decrease in the enzyme activity. PMID- 26488827 TI - Clear as Glass. AB - Beginning with the first issue of 2016, the Oncology Nursing Forum (ONF) will join many other journals in publishing the contribution of each of the listed authors to the article. Why has this taken us so long? In part, this is an editorial decision, and I have always thought that nurses are honest and would not include anyone on a manuscript who had not contributed in a meaningful way to the writing of the manuscript. That belief has not changed. PMID- 26488828 TI - Glycosylated Hemoglobin A1c and Lack of Association With Symptom Severity in Patients Undergoing Chemotherapy for Solid Tumors. AB - PURPOSE/OBJECTIVES: To assess the effects of high blood sugar at the levels of diabetic or prediabetic states during cancer treatment because patients undergoing chemotherapy (CTX) experience multiple symptoms that vary among individuals and may be affected by glucose levels. DESIGN: Descriptive, cross sectional. SETTING: Two comprehensive cancer centers, one Veterans Affairs hospital, and four community-based oncology programs. SAMPLE: 244 outpatients with breast, gastrointestinal, gynecologic, and lung cancers. METHODS: Patients completed demographic and symptom questionnaires. Glycosylated hemoglobin A1c (HbA1c) was evaluated to determine diabetic state. Descriptive statistics and one way analyses of variance were used in the analyses. MAIN RESEARCH VARIABLES: HbA1c, symptom severity scores, patient and clinical characteristics (e.g., age, gender, comorbidities, sociodemographic information, body mass index [BMI], lifestyle factors). FINDINGS: HbA1c results showed 9% of the sample in the diabetic and 26% in the prediabetic state. Patients in the diabetic state reported a higher number of comorbid conditions and were more likely to be African American. Patients in the prediabetic state were older aged. Patients in the diabetic and prediabetic states had a higher BMI compared to nondiabetic patients. No differences in symptom severity or quality-of-life (QOL) scores were found among the three diabetic states. CONCLUSIONS: This study is the first to evaluate for associations between diabetic states and symptom severity and QOL scores in patients receiving CTX. This study confirmed that older age, as well as having higher BMI and having multiple comorbidities, were associated with increased mean glycemic levels. IMPLICATIONS FOR NURSING: Clinicians should assess and identify patients with diabetes or prediabetes undergoing treatment for cancer. Patients who are older aged, those with a high BMI, and those with multiple comorbid conditions may be at increased risk for higher glycemic states. PMID- 26488829 TI - A Phenomenologic Study of Family Caregivers of Patients With Head and Neck Cancers. AB - PURPOSE/OBJECTIVES: To describe and understand the lived experience of family caregivers of patients with head and neck cancers (HNCs). RESEARCH APPROACH: Phenomenology using van Manen's human science approach?. SETTING: Two hospital systems providing regional cancer care in upstate New York. ?. PARTICIPANTS: Nine family caregivers of patients with HNCs who had completed treatment?. METHODOLOGIC APPROACH: Qualitative analysis of semi-structured, conversational interviews about the lived experience of family caregivers. FINDINGS: Five major themes emerged related to the lived experiences of this sample of caregivers. CONCLUSIONS: Family caregivers of patients with HNCs play a fundamental role in the post-treatment phase of care, including meeting specific physical and psychosocial needs. Further investigation should explore the relationship between information needs and the experience of vigilance and fear. INTERPRETATION: Nurses must include caregivers in physical and psychosocial plans of care. Balancing and meeting information needs of caregivers to avoid undue emotional stress and recognizing their support needs are valuable components of care. PMID- 26488830 TI - The Teachable Moment After Cancer Diagnosis: Perceptions From Oncology Nurses. AB - PURPOSE/OBJECTIVES: To determine oncology nurses' perspectives of the receptiveness of survivors to receiving health behavior guidance, with secondary purposes to (a) explore other elements of oncology nurses' perceptions of the teachable moment and (b) examine differences in outcomes between American and Canadian nurses?. DESIGN: Cross-sectional survey.? SETTING: In- and outpatient oncology nursing departments in the United States and Canada. SAMPLE: 310 members of the Canadian Association of Nurses in Oncology (CANO/ACIO) and the Oncology Nursing Society (ONS) who currently care for patients?. METHODS: Oncology nurses recruited through emails distributed through the CANO/ACIO and ONS Listservs completed online investigator-developed surveys. MAIN RESEARCH VARIABLES: Measures related to oncology nurses' perceptions of survivors' receptiveness to health behavior change counseling and the teachable moment (i.e., general receptiveness, perceived benefits, guidance and referral seeking, long- and short term effectiveness, best time, and best resources). FINDINGS: Oncology nurses reported that survivors were receptive to receiving guidance on health behaviors, particularly during teachable moments after diagnosis and during treatment. They also perceived that a fairly low percentage of survivors asked for guidance about health behavior change; relatively few made improvements to their health behaviors.? CONCLUSIONS: Survivors are reported to be interested in receiving guidance concerning health behavior change during key teachable moments. Oncology nurses may need to initiate conversations with survivors, offer education regarding the benefits of positive health behavior change, and provide ongoing support throughout the cancer trajectory. IMPLICATIONS FOR NURSING: Oncology nurses may use findings from the current study to guide their health behavior change counseling with survivors?. PMID- 26488831 TI - Physical Activity and Self-Rated Health Status Among Older Adult Cancer Survivors: Does Intensity of Activity Play a Role? AB - PURPOSE/OBJECTIVES: To examine the association between routine physical activity and self-rated health status in older adults with cancer.. DESIGN: Cross sectional. SETTING: Community-dwelling older adult survivors who completed a screening tool and subsequent detailed interview from the 2004 wave of the National Long-Term Care Survey, a nationally representative study of Medicare beneficiaries aged 65 years or older.? SAMPLE: 251 older adult cancer survivors who regularly engaged in routine physical activity. METHODS: Participants were asked about chronic health conditions, depression, activities of daily living, participation in physical activities, self-rated health status, and sociodemographic characteristics. A weighted ordered probit model was used to estimate variables that predict self-reported health status. MAIN RESEARCH VARIABLES: Self-rated health status and participation in physical activity.? FINDINGS: Age and higher education level were found to be significant correlates of health status (p < 0.05) in the first model. Although education was not significant in subsequent models, age, functional disability, and depression all were identified as significant correlates of health status (p < 0.01). In the final model, in which moderate and vigorous activity participation were entered, older adult survivors who engaged in vigorous physical activity showed higher levels of health status than those who engaged in light physical activity (p < 0.05), but number of chronic health conditions was not significantly associated with health status. CONCLUSIONS: The association between vigorous activity and health status points to the primacy of physical activity within a post-cancer treatment health regimen.?. IMPLICATIONS FOR NURSING: Health programs and policies need to address physical activity to improve the overall well-being of older adult cancer survivors. PMID- 26488832 TI - Interventions for Nurse-Related Barriers in Cancer Pain Management. AB - PURPOSE/OBJECTIVES: To describe the findings and critique the studies of interventions for nursing staff to improve pain management in adults with cancer. DATA SOURCES: Publications were identified through database searches. Studies that describe interventions to overcome nurse-related barriers in cancer pain management practices were included in this review. DATA SYNTHESIS: Nine studies were found that met the inclusion criteria. All studies were experimental and conducted from 1993-2013. CONCLUSIONS: Increase in knowledge, change of attitudes and behaviors, and good relationships with specialists were found to be influential in overcoming existing nursing barriers to pain management in cancer survivors. Educational interventions are more effective in increasing knowledge than in improving attitudes. Specialists were acknowledged as important resources and role models for nurses, particularly when trust was established between the two. IMPLICATIONS FOR NURSING: A number of interventions have been developed to address healthcare provider barriers. However, scarce literature exists on whether interventions that aim to overcome nurse-related barriers have been successful. This literature review provides critical insights on the effectiveness of interventions aimed to overcome barriers to effective pain management by nurses for adults with cancer?. PMID- 26488833 TI - Feasibility of a Text Messaging Intervention to Promote Self-Management for Patients Prescribed Oral Anticancer Agents. AB - PURPOSE/OBJECTIVES: To determine proof of concept of a mobile health (mHealth) intervention delivering text messages (texts) to self-manage among patients prescribed oral anticancer agents (OAs) and to examine preliminary efficacy on symptoms and medication adherence. DESIGN: A longitudinal randomized, controlled trial. SETTING: Two community cancer centers in the midwestern United States and a national specialty pharmacy. SAMPLE: 80 adults with cancer who were newly prescribed OAs?. METHODS: Adherence and symptoms were assessed weekly for 10 weeks in both groups. The intervention group received daily texts for adherence and weekly for symptoms for 21-28 days, and satisfaction with the intervention was assessed?. MAIN RESEARCH VARIABLES: Medication adherence and symptom severity. FINDINGS: Mean age was 58.5 years (SD = 10.7 years), 48 participants were female, and 48 were Caucasian. Fewer symptoms were found in the intervention group with a moderate effect size. Adherence was higher in the text group using medical record and prescription data (n = 26) with greater relative dose intensity of moderate to large effect size. Regarding acceptability, 57% (83 of 145) of eligible participants consented, 39 of 40 participants completed the entire intervention, 30 participants read texts all of the time, and 34 participants were satisfied with the intervention.? CONCLUSIONS: Proof of concept and preliminary efficacy of an mHealth intervention using texts to promote self management for patients prescribed OAs was demonstrated. Patients had high satisfaction with the texts, and adherence and symptoms improved after the intervention. IMPLICATIONS FOR NURSING: Texts show promise for patients with cancer who must manage their OAs. Additional research is needed prior to use in practice. PMID- 26488834 TI - Secondary Exposure of Family Members to Cyclophosphamide After Chemotherapy of Outpatients With Cancer: A Pilot Study. AB - PURPOSE/OBJECTIVES: To measure the total amount of cyclophosphamide (CPA) excreted in the urine of patients with cancer and their cohabitating family members seven days after CPA administration. DESIGN: Biological monitoring.?. SETTING: Home setting with outpatients receiving chemo-therapy. SAMPLE: 8 patients administered CPA, 10 cohabitating family members, and 10 control participants. METHODS: During the first seven days after CPA administration, urine samples were collected from the participants. The samples were analyzed for the unchanged form of CPA using gas chromatography in tandem with mass spectroscopy. MAIN RESEARCH VARIABLES: CPA levels?. FINDINGS: CPA was detected in 112 of 276 patient urine samples. The last sample containing detectable CPA levels was collected after more than 48 hours in 63% of the patients, with a maximum length of five days post-treatment. In addition, 243 urine samples were collected from family members, and CPA was detected in the samples of five family members (17-252 ng per member). CPA was not detected in any control participants. CONCLUSIONS: These findings indicate that family members in close contact with patients receiving CPA are at high risk for drug exposure as many as seven days post-treatment?. IMPLICATIONS FOR NURSING: Nurses should educate patients and their family members about preventing exposure to antineoplastic drugs in the home setting.? PMID- 26488836 TI - Case Study Research Methodology in Nursing Research. AB - Through data collection methods using a holistic approach that focuses on variables in a natural setting, qualitative research methods seek to understand participants' perceptions and interpretations. Common qualitative research methods include ethnography, phenomenology, grounded theory, and historic research. Another type of methodology that has a similar qualitative approach is case study research, which seeks to understand a phenomenon or case from multiple perspectives within a given real-world context. PMID- 26488835 TI - Involvement in Decision Making and Satisfaction With Treatment Among Partners of Patients With Newly Diagnosed Localized Prostate Cancer. AB - PURPOSE/OBJECTIVES: To examine partner involvement in treatment decision making for localized prostate cancer, congruence between partner involvement and patient preference, reasons for partner noninvolvement, and partner satisfaction with patient treatment?. DESIGN: Cross-sectional exploratory study.? SETTING: 100 counties in North Carolina. SAMPLE: 281 partners of men with newly diagnosed localized prostate cancer. METHODS: Participants completed a phone survey. Logistic regression analyses were used. MAIN RESEARCH VARIABLES: Partners' involvement in treatment decision making, partner satisfaction with treatment, activities of partner involvement, and reasons for noninvolvement. FINDINGS: Of the 228 partners (81%) related to decision making, 205 (73%) were very satisfied with the treatment the patients received, and partner involvement was congruent with patient preference in 242 partners (86%). Partners reported several reasons for noninvolvement. CONCLUSIONS: Most partners engaged in multiple activities during treatment decision making for localized prostate cancer and were satisfied with the patient's treatment. Partner involvement was mostly congruent with patient preference. IMPLICATIONS FOR NURSING: Partners' active involvement in treatment decision making for localized prostate cancer (e.g., being involved in patients' conversations with doctors) should be encouraged and facilitated for those who prefer this type of decision making. ?. PMID- 26488837 TI - Practice Innovations, Change Management, and Resilience in Oncology Care Settings. AB - Our commitment to advancing nursing practice and quality care for our patients must be at the forefront of our minds. Nursing's role in designing and implementing new innovations is integral to the advancement of healthcare delivery across the country. PMID- 26488838 TI - Virchow's Node and Carcinoma of Unknown Primary. AB - Virchow's node is the enlargement of the left supraclavicular lymph node and is considered by clinicians to be a strong indicator of metastatic abdominal malignancy. Virchow's node is located medially and is a deep-seeded node, making it difficult to assess in a healthy individual. PMID- 26488839 TI - Next-Generation Gene Sequencing: Looking Beyond Hereditary Breast and Ovarian Cancer. AB - Oncology nurses have long been aware of the significance of recognizing patients' hereditary risk of cancer. Obtaining an accurate family history is an integral part of patient assessment and has helped to guide referrals for genetic counseling and testing for hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome. PMID- 26488840 TI - Keep Caregivers Safe: Reduce Secondary Exposure to Chemotherapy. AB - Chemotherapy exposure during drug administration and provision of care is a known risk for oncology nurses and other healthcare workers. Guidelines to minimize exposure to hazardous drugs, such as chemotherapy, have long been in place to decrease potential health risks. PMID- 26488841 TI - Psychological and Physical Interventions for ?the Management of Cancer-Related Pain in Pediatric and Young Adult Patients: An Integrative Review. AB - PURPOSE/OBJECTIVES: To identify and appraise current evidence related to the effectiveness of psychological and physical (nonpharmacologic) pain management modalities for children and young adults with cancer?. DATA SOURCES: Electronic searches in MEDLINE, EMBASE, CINAHL, PsycINFO, and Web of Science (from database inception to June 2013) for clinical trials. DATA SYNTHESIS: A total of 32 unique studies were identified. Substantial heterogeneity existed across identified studies, precluding meta-analysis. Therefore, a narrative review of included studies is presented. Studies featured psychological and/or physical pain interventions for children and young adults (N = 1,171) aged 1-21 years with a variety of cancer diagnoses. Interventions included aromatherapy, art therapy, distraction, hypnosis, physical activity, physical positioning, touch therapy, and multimodal cognitive-behavior therapy. Twenty-two studies (69%) reported success in preventing or reducing pain intensity. The level of evidence and methodologic quality of studies were generally low?. CONCLUSIONS: Current nonpharmacologic pain interventions for pediatric and young adult patients with cancer are diverse. Several modalities significantly decreased pain intensity, suggesting that these strategies may be effective methods of pain treatment, particularly in the case of painful medical procedures. Future well-designed, multicenter, randomized, controlled trials are needed to further discern treatment effects on pain and other health outcomes in this population and to compare the relative effectiveness of different modalities. IMPLICATIONS FOR NURSING: Nurses play a key role in pain assessment and management in pediatric and young adult patients with cancer. The studies included in this review constitute the beginnings of an evidence base that supports the need to implement psychological and physical interventions to improve pain outcomes in pediatric and young adult patients with cancer. PMID- 26488843 TI - Integrative Review: Effects of Music on Cancer Pain in Adults. AB - PROBLEM IDENTIFICATION: To evaluate the literature for music's effect on adult cancer pain.?. LITERATURE SEARCH: An electronic literature search from 1986-2014 was conducted to evaluate the effects of quantitative music among adults with cancer pain in settings including homes, hospitals, and palliative care units. Databases used were PubMed (MEDLINE) and Scopus.? DATA EVALUATION: The study designs, methods, measures, outcomes, and limitations were evaluated independently by the primary author and verified by the second author. The primary outcome measure of interest was the effect of music in cancer pain. SYNTHESIS: Of 82 studies, 5 of them--totaling 248 participants--met eligibility criteria. Review of findings suggests a paucity of innovative approaches for using music to mitigate cancer pain among adults. Psychological outcomes, anxiety, depression, and mood were understudied. Advanced pain, multiple cancer types, and lack of racial diversity characterize the samples.? CONCLUSIONS: Modern treatments for cancer have improved survival rates; however, patients often experience tumor- and treatment-related pain. Pharmacologic and nonpharmacologic methods may minimize cancer pain. The use of music as an adjunct to pain medication requires additional studies, particularly on mechanisms of its effect on pain among diverse, large samples with multiple cancer pain types. A limitation of this review is the small number of available studies to date. IMPLICATIONS FOR PRACTICE: The evidence for music therapy in the management of pain is limited. Integrative methods using music may represent an important intervention that nurses may be able to suggest as an inexpensive, nontoxic, and readily available intervention for potentially minimizing cancer pain. PMID- 26488844 TI - Nipple-Areola Tattoos: Making the Right Referral. AB - PURPOSE/OBJECTIVES: To examine oncology care providers' knowledge of tattooing options for patients who have elected to have breast reconstruction as part of their breast cancer treatment. ?. DESIGN: Cross-sectional survey. SETTING: A large metropolitan cancer center in New York and various locations across the United States?. SAMPLE: 68 oncology care providers who work with women with breast cancer, distributed into two groups. METHODS: Descriptive statistics were used to summarize online survey responses for the two groups, with inferential comparisons made with logistic regression models?. MAIN RESEARCH VARIABLES: Healthcare profession, discussion of reconstructive tattoo options with patients, knowledge of providers of reconstructive tattoos outside of traditional healthcare settings, and recommendations made to patients?. FINDINGS: RNs were significantly less likely to recommend a professional tattoo artist to a patient than non-RNs, despite a similar proportion of both groups believing that a tattoo artist would provide the patient with a better tattoo than healthcare providers (HCPs). CONCLUSIONS: Additional research is needed to identify education deficits in HCPs regarding tattoo reconstruction options. HCPs are recommending potentially substandard options for nipple-areola tattooing, even though many believe that tattoo artists, who are outside of the traditional healthcare setting, could provide better outcomes for patients. IMPLICATIONS FOR NURSING: Nurses and other HCPs require additional education about nipple-areola tattoo options for patients following breast cancer surgery?. PMID- 26488842 TI - Working Toward Normalcy Post-Treatment: A Qualitative Study of Older Adult Breast and Prostate Cancer Survivors. AB - PURPOSE/OBJECTIVES: To develop a better understanding of how older adult survivors of early-stage breast and prostate cancer managed the work of recovery.?. RESEARCH APPROACH: Multiple case study design embedded in a larger randomized, controlled trial of a nurse-led patient navigation intervention. ?. SETTING: Community-based research conducted via in-home visits and by phone with participants residing in non-metropolitan areas of a mid-Atlantic state.? PARTICIPANTS: Rural-dwelling adults aged 60 years or older with early-stage breast or prostate cancer and the people who support them (11 dyads).? METHODOLOGIC APPROACH: An approach to grounded theory analysis was used to evaluate the fit between existing theoretical knowledge and case findings and to generate new knowledge about the cancer recovery process.? FINDINGS: Working toward normalcy was a core process of cancer recovery prompted by participants' internal experiences and external interactions with their environments. This ongoing, iterative, and active process involved multiple concurrent strategies that were not necessarily medically oriented or cancer specific. Working toward normalcy resulted in movement along a continuum of self-appraisal anchored between participants experiencing life as completely disrupted by cancer to a life back to normal. A greater sense of normalcy was associated with higher engagement in valued activities and increased physical and psychological well being.? CONCLUSIONS: In addition to the core process of working toward normalcy, multiple theories from nursing, sociology, psychology, and gerontology helped to explain case findings. This knowledge could serve as a foundation on which to design survivorship care that supports the goals of cancer survivors working toward normalcy post-treatment. INTERPRETATION: Post-treatment wellness goals can include a desire to reestablish or maintain a sense of normalcy. Nursing actions that promote survivors' efforts to be perceived as capable, stay engaged in valued activities and roles, maintain a sense of control over their lives and bodies, and make plans for the future may help meet this goal. Existing theories about identity, dignity, inner strength, and the work of illness can inform nursing interventions. ? PMID- 26488845 TI - Uncommon Candida Species Fungemia among Cancer Patients, Houston, Texas, USA. AB - Many uncommon Candida species that cause bloodstream infections (BSIs) are not well-characterized. We investigated the epidemiology, antifungal use, susceptibility patterns, and factors associated with all-cause death among cancer patients in whom uncommon Candida spp. BSIs were diagnosed at a cancer treatment center during January 1998-September 2013. Of 1,395 Candida bloodstream isolates, 79 from 68 patients were uncommon Candida spp. The incidence density of uncommon Candida spp. BSIs and their proportion to all candidemia episodes substantively increased during the study period, and the rise was associated with increasing use of echinocandin antifungal drugs. Thirty-seven patients had breakthrough infections during therapy or prophylaxis with various systemic antifungal drugs for >7 consecutive days; 21 were receiving an echinocandin. C. kefyr (82%), and C. lusitaniae (21%) isolates frequently showed caspofungin MICs above the epidemiologic cutoff values. These findings support the need for institutional surveillance for uncommon Candida spp. among cancer patients. PMID- 26488846 TI - [Cu(o-phthalate)(phenanthroline)] Exhibits Unique Superoxide-Mediated NCI-60 Chemotherapeutic Action through Genomic DNA Damage and Mitochondrial Dysfunction. AB - The in cellulo catalytic production of reactive oxygen species (ROS) by copper(II) and iron(II) complexes is now recognized as a major mechanistic model in the design of effective cytotoxins of human cancer. The developmental complex, [Cu(o-phthalate)(1,10-phenanthroline)] (Cu-Ph), was recently reported as an intracellular ROS-active cytotoxic agent that induces double strand breaks in the genome of human cancer cells. In this work, we report the broad-spectrum action of Cu-Ph within the National Cancer Institute's (NCI) Developmental Therapeutics Program (DTP), 60 human cancer cell line screen. The activity profile is compared to established clinical agents-via the COMPARE algorithm-and reveals a novel mode of action to existing metal-based therapeutics. In this study, we identify the mechanistic activity of Cu-Ph through a series of molecular biological studies that are compared directly to the clinical DNA intercalator and topoisomerase II poison doxorubicin. The presence of ROS-specific scavengers was employed for in vitro and intracellular evaluation of prevailing radical species responsible for DNA oxidation with superoxide identified as playing a critical role in this mechanism. The ROS targeting properties of Cu-Ph on mitochondrial membrane potential were investigated, which showed that it had comparable activity to the uncoupling ionophore, carbonyl cyanide m-chlorophenyl hydrazine. The induction and origins of apoptotic activation were probed through detection of Annexin V and the activation of initiator (8,9) and executioner caspases (3/7) and were structurally visualized using confocal microscopy. Results here confirm a unique radical-induced mechanistic profile with intracellular hallmarks of damage to both genomic DNA and mitochondria. PMID- 26488848 TI - Anionic chemistry of noble gases: formation of Mg-NG (NG = Xe, Kr, Ar) compounds under pressure. AB - While often considered to be chemically inert, the reactivity of noble gas elements at elevated pressures is an important aspect of fundamental chemistry. The discovery of Xe oxidation transformed the doctrinal boundary of chemistry by showing that a complete electron shell is not inert to reaction. However, the reductive propensity, i.e., gaining electrons and forming anions, has not been proposed or examined for noble gas elements. In this work, we demonstrate, using first-principles electronic structure calculations coupled to an efficient structure prediction method, that Xe, Kr, and Ar can form thermodynamically stable compounds with Mg at high pressure (>=125, >=250, and >=250 GPa, respectively). The resulting compounds are metallic and the noble gas atoms are negatively charged, suggesting that chemical species with a completely filled shell can gain electrons, filling their outermost shell(s). Moreover, this work indicates that Mg2NG (NG = Xe, Kr, Ar) are high-pressure electrides with some of the electrons localized at interstitial sites enclosed by the surrounding atoms. Previous predictions showed that such electrides only form in Mg and its compounds at very high pressures (>500 GPa). These calculations also demonstrate strong chemical interactions between the Xe 5d orbitals and the quantized interstitial quasiatom (ISQ) orbitals, including the strong chemical bonding and electron transfer, revealing the chemical nature of the ISQ. PMID- 26488847 TI - Lead Telluride Quantum Dot Solar Cells Displaying External Quantum Efficiencies Exceeding 120%. AB - Multiple exciton generation (MEG) in semiconducting quantum dots is a process that produces multiple charge-carrier pairs from a single excitation. MEG is a possible route to bypass the Shockley-Queisser limit in single-junction solar cells but it remains challenging to harvest charge-carrier pairs generated by MEG in working photovoltaic devices. Initial yields of additional carrier pairs may be reduced due to ultrafast intraband relaxation processes that compete with MEG at early times. Quantum dots of materials that display reduced carrier cooling rates (e.g., PbTe) are therefore promising candidates to increase the impact of MEG in photovoltaic devices. Here we demonstrate PbTe quantum dot-based solar cells, which produce extractable charge carrier pairs with an external quantum efficiency above 120%, and we estimate an internal quantum efficiency exceeding 150%. Resolving the charge carrier kinetics on the ultrafast time scale with pump probe transient absorption and pump-push-photocurrent measurements, we identify a delayed cooling effect above the threshold energy for MEG. PMID- 26488849 TI - Hierarchical Micro/Nano Structures by Combined Self-Organized Dewetting and Photopatterning of Photoresist Thin Films. AB - Photoresists are the materials of choice for micro/nanopatterning and device fabrication but are rarely used as a self-assembly material. We report for the first time a novel interplay of self-assembly and photolithography for fabrication of hierarchical and ordered micro/nano structures. We create self organized structures by the intensified dewetting of unstable thin (~10 nm to 1 MUm) photoresist films by annealing them in an optimal solvent and nonsolvent liquid mixture that allows spontaneous dewetting to form micro/nano smooth dome like structures. The density, size (~100 nm to millimeters), and curvature/contact angle of the dome/droplet structures are controlled by the film thickness, composition of the dewetting liquid, and time of annealing. Ordered dewetted structures are obtained simply by creating spatial variation of viscosity by ultraviolet exposure or by photopatterning before dewetting. Further, the structures thus fabricated are readily photopatterned again on the finer length scales after dewetting. We illustrate the approach by fabricating several three-dimensional structures of varying complexity with secondary and tertiary features. PMID- 26488850 TI - Yoga versus standard care for schizophrenia. AB - BACKGROUND: Yoga is an ancient spiritual practice that originated in India and is currently accepted in the Western world as a form of relaxation and exercise. It has been of interest for people with schizophrenia to determine its efficacy as an adjunct to standard-care treatment. OBJECTIVES: To examine the effects of yoga versus standard care for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (November 2012 and January 29, 2015), which is based on regular searches of MEDLINE, PubMed, EMBASE, CINAHL, BIOSIS, AMED, PsycINFO, and registries of clinical trials. We searched the references of all included studies. There were no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: All randomised controlled trials (RCTs) including people with schizophrenia comparing yoga to standard-care control. DATA COLLECTION AND ANALYSIS: The review team independently selected studies, quality rated these, and extracted data. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed mixed-effect and fixed-effect models for analyses. We examined data for heterogeneity (I(2) technique), assessed risk of bias for included studies, and created 'Summary of findings' tables using GRADE (Grading of Recommendations Assessment, Development and Evaluation). MAIN RESULTS: We included eight studies in the review. All outcomes were short term (less than six months). There were clear differences in a number of outcomes in favour of the yoga group, although these were based on one study each, with the exception of leaving the study early. These included mental state (improvement in Positive and Negative Syndrome Scale, 1 RCT, n = 83, RR 0.70 CI 0.55 to 0.88, medium-quality evidence), social functioning (improvement in Social Occupational Functioning Scale, 1 RCT, n = 83, RR 0.88 CI 0.77 to 1, medium-quality evidence), quality of life (average change 36-Item Short Form Survey (SF-36) quality-of-life subscale, 1 RCT, n = 60, MD 15.50, 95% CI 4.27 to 26.73, low-quality evidence), and leaving the study early (8 RCTs, n = 457, RR 0.91 CI 0.6 to 1.37, medium-quality evidence). For the outcome of physical health, there was not a clear difference between groups (average change SF-36 physical-health subscale, 1 RCT, n = 60, MD 6.60, 95% CI 2.44 to 15.64, low-quality evidence). Only one study reported adverse effects, finding no incidence of adverse events in either treatment group. This review was subject to a considerable number of missing outcomes, which included global state, change in cognition, costs of care, effect on standard care, service intervention, disability, and activities of daily living. AUTHORS' CONCLUSIONS: Even though we found some positive evidence in favour of yoga over standard-care control, this should be interpreted cautiously in view of outcomes largely based each on one study with limited sample sizes and short-term follow-up. Overall, many outcomes were not reported and evidence presented in this review is of low to moderate quality - -too weak to indicate that yoga is superior to standard care control for the management of schizophrenia. PMID- 26488851 TI - Correction to: Hum Gene Ther 2015;26(8):525-537 DOI: 10.1089/hum.2015.064. PMID- 26488853 TI - Flux theory for Poisson distributed pores with Gaussian permeability. AB - The mean of the solute flux through membrane pores depends on the random distribution and permeability of the pores. Mathematical models including such randomness factors make it possible to obtain statistical parameters for pore characterization. Here, assuming that pores follow a Poisson distribution in the lipid phase and that their permeabilities follow a Gaussian distribution, a mathematical model for solute dynamics is obtained by applying a general result from a previous work regarding any number of different kinds of randomly distributed pores. The new proposed theory is studied using experimental parameters obtained elsewhere, and a method for finding the mean single pore flux rate from liposome flux assays is suggested. This method is useful for pores without requiring studies by patch-clamp in single cells or single-channel recordings. However, it does not apply in the case of ion-selective channels, in which a more complex flux law combining the concentration and electrical gradient is required. PMID- 26488854 TI - Efficacy of Current Practices for Pain Assessment in Premature Ventilated Infants in the NICU Exposed to a High Number of Pain-Associated Procedures. AB - OBJECTIVE: To study infant factors, characteristics of pain scores, and analgesic practices associated with patient-days in the NICU with a high frequency of pain associated procedures (defined as >10 pain-associated procedures in the day). METHODS: This is a secondary analysis of data from a cross-sectional study that used medical record audits of premature, ventilated infants. The primary two institution study yielded data for 196 patient-days. Data included 804 pain scores and 836 pain-associated procedures. RESULTS: A high frequency of pain associated procedures occurred in 8% of days at Site A and in 25% of days at Site B. Prevalence of days with high frequency of pain-associated procedures differed by institution, and was higher at the institution where infants were more mature at birth and had fewer surgical procedures. High frequency of pain-associated procedures was related to endotracheal intubation at both institutions. There were no elevated pain scores and no documented analgesic administrations on days with over 20 pain-associated procedures. CONCLUSIONS: High exposure to pain associated procedures during a 24-hour period for a premature, ventilated infant is rarely associated with elevated pain scores or analgesic administration. Prevalence of days with high-procedural exposure at an institution appears to be closely related to use of invasive ventilation and to individual institutional practices. Examination and discussion of the daily frequency of pain-associated procedures for premature, ventilated infants (especially for those receiving invasive ventilation) may be helpful in developing approaches for attenuating the cumulative pain experience for these babies. Resources that are expended on regular pain reassessment documentation processes in the NICU may need to be reconsidered in light of the very low yield for clinical alterations in care in this setting. PMID- 26488855 TI - Father Involvement and Psychological Well-Being of Pregnant Women. AB - PURPOSE: This study examined the relationships among father of the baby involvement during pregnancy, depressive symptoms, and psychological well-being in African American women. STUDY DESIGN AND METHODS: Using a prospective study design, a sample of 95 pregnant African American women receiving prenatal care at a medical center in Chicago completed the self-report instruments about father of the baby involvement, depressive symptoms, and psychological well-being twice during pregnancy, once at between 15 and 25 weeks and once between 25 and 37 weeks. RESULTS: Eighty percent of women reported that the father of the baby was involved during their pregnancy. Twenty-eight percent of women had clinically relevant depressive symptoms (CES-D scores >=16) at the first data collection and 25% of women had clinically relevant depressive symptoms at the second data collection. Compared with women who reported no father involvement during pregnancy, women who reported father involvement during pregnancy had lower levels of depressive symptoms and higher levels of psychological well-being. CLINICAL IMPLICATIONS: Fathers' involvement is important during pregnancy; nurses should encourage fathers to participate at prenatal visits and ask questions, and educate fathers on pregnancy process and procedures during prenatal care. PMID- 26488852 TI - Targets to treat metabolic syndrome in polycystic ovary syndrome. AB - INTRODUCTION: Metabolic syndrome is comprised of a combination of the following states: increased insulin resistance, dyslipidemia, cardiovascular disease, and increased abdominal obesity. Women with polycystic ovary syndrome (PCOS) have an increased risk of developing metabolic syndrome over the course of their lives. Metabolic syndrome increases risk of major cardiovascular events, morbidity, quality of life, and overall health care costs. Though metabolic syndrome in women with PCOS is an area of great concern, there is no effective individual medical therapeutic to adequately treat this issue. AREAS COVERED: This article will review key aspects of metabolic syndrome in PCOS. We will discuss classic and novel therapeutics to address metabolic syndrome in women with PCOS. We will conclude with the importance of developing strategic interventions to increase the compliance to lifestyle and dietary modification, in addition to appreciation of the emerging pharmaceutical therapeutics available. EXPERT OPINION: Innovation in lifestyle modification, including diet, exercise, with and without dedicated stress reduction techniques is the future in treatment of metabolic syndrome in PCOS. Application of novel interventions, such as group medical care, may improve future adherence to lifestyle modification recommendations, in addition to or in combination with pharmaceutical therapeutics. PMID- 26488856 TI - Developmental Screening and Follow-up by Nurses. AB - OBJECTIVE: The Ages and Stages Questionnaire (ASQ) and Modified Checklist for Autism in Toddlers (M-CHAT) are commonly used screening tools for developmental delay and autism, respectively. This study aimed to evaluate the effectiveness of implementing 18-month developmental and autism screening by mail, with a standardized follow-up process for abnormal screen results. METHODS: Within a prospective cohort study design, parents of 892 children received by mail the 18 month ASQ and M-CHAT questionnaires between December 2008 and September 2009. A registered nurse scored the questionnaires and, if needed, administered follow-up screening or set up a referral to Early Intervention or subspecialty pediatrics. Medical record reviews determined clinical outcomes of children who required intervention after initial screening through September 2010. Additionally, demographic factors were evaluated for association with responding to the questionnaires. RESULTS: The ASQ and M-CHAT questionnaires were returned by 529 (59.3%) of the parents. Parents of White children (390/575 [67.8%]) and those with private insurance (457/660 [69.2%]) were significantly more likely to return screening questionnaires than parents of non-White (64/171 [37.4%]; P < .001) and government-insured children (58/169 [34.3%]; P < .001), respectively. Of the 529 children with returned surveys, 109 (20.6%) did not pass at least 1 of the initial screens and 12 (2.3%) were referred after not passing the follow-up screening process. CONCLUSIONS: Developmental and autism screening by mail is not a sufficient method to comprehensively screen a general pediatric population. A nurse-completed, standardized follow-up process after an initial failed developmental screen may increase the yield of appropriate Early Intervention or subspecialty referrals. PMID- 26488857 TI - Magnesium Sulfate for Neuroprotection. PMID- 26488858 TI - Gluten-Free Diets. PMID- 26488859 TI - mHealth and Collecting Research Data From Patients With Mobile Tablet Apps. PMID- 26488860 TI - WASH: Highlighting Global Water, Sanitation, and Hygiene Initiatives. PMID- 26488862 TI - Nurse Staffing and Care During the Immediate Postpartum Recovery Period. PMID- 26488864 TI - The imbalance of sex-hormones related to depressive symptoms in obese men. AB - Obese men may present hypogonadothrofic hypogonadism, mainly related to higher insulinemia and aromatase activity. Our objectives were to evaluate the relationship of sex-hormones profiles and frequency of depressive symptoms in 43 obese men, in a cross-sectional study. They had 19-60 years, and body mass index 30-50 kg/m(2). LH, total and free testosterone (TT and FT), estradiol (E2), sex hormone binding globulin, estradiol/total testosterone ratio (E2/T) were analyzed. Depressive symptoms were evaluated by "beck depression inventory" (BDI), and significant depression was considered if BDI >= 16.Thirty-four (80%) presented low TT levels, but only 4 (14%) had low free testosterone and hypogonadism symptoms; 12 of 43 (28%) presented increased E2. Forty five (56%) presented depressive symptoms, but 16 (28% of the 45) had significant depression. BDI correlated positively with E2 (r = 0.407; p = 0.001) and E2/T (r = 0.473; p = 0.001), but not TT or FT. Patients with significant depressive showed higher levels of estradiol (136 +/- 48 versus 103 +/- 48 pg/ml, p = 0.02) and E2/T (16.0 +/- 9.9 versus 9.8 +/- 4.6; p = 0.002) (mean +/- SD).In conclusion, obese men may present relatively excess of estradiol and deficiency in testosterone, leading to an imbalance between these two hormones. The greater this imbalance, the more depressive symptoms had our patients. PMID- 26488865 TI - Application of Video-Assisted Thyroidectomy for Cervicomediastinal Goiter. AB - BACKGROUND: In the past several decades we have seen that most cervicomediastinal goiters (CMGs) can be removed through a cervical lower collar incision, but in some circumstances a median sternotomy or a thoracotomy is mandatory. In the last few years, video-assisted thyroidectomy (VAT) has been developed, and the indications are that its usage is becoming more widespread. This study aimed to evaluate the technical feasibility and safety of VAT for CMG. PATIENTS AND METHODS: Over a 5-year period (2009-2014), 602 patients underwent conventional thyroidectomy (CT), and 356 cases underwent VAT in the Department of General Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. Among all those patients, 33 (3.4%) were diagnosed with CMGs and operated on. These patients were divided into two groups: the CT group included 18 patients, and the VAT group included 15 patients. The incision length, operative time, blood loss, hospitalization time, and postoperative complications were recorded and analyzed. RESULTS: All 15 procedures in the VAT group were performed successfully with the help of endoscopy, whereas for 2 of the 18 patients (11.1%) in the CT group, a partial median sternotomy had to be done due to poor exposure and abnormal hemorrhage. Significant differences in the incisional length, operative time, and intraoperative blood loss occurred between the CT and VAT groups. The patients who underwent VAT had a better cosmetic result without going through an additional incision. There was no difference in the resected goiter weight between the two groups. The patients who underwent VAT recovered more rapidly and had a shorter hospitalization time than those in the CT group (P = .000). No significant difference was found in postoperative complications between the two different approaches. During a mean follow-up through 28 months (range, 3 66 months), no recurrence occurred. CONCLUSIONS: VAT is a safe and feasible approach for patients with CMG. The procedure has relatively satisfactory cosmetic effect and faster postoperative recovery. PMID- 26488866 TI - Adsorption of Oxyanions from Industrial Wastewater using Perlite-Supported Magnetite. AB - Most studies on oxyanion adsorption focus on their removal from synthetic solutions. It is often claimed that the considered adsorbents can be used to treat real (industrial) wastewaters, but this is seldom tested. Perlite-supported magnetite was characterized first by determining its specific surface area, magnetite content and by examining the coating. Tests on a synthetic solution showed that at the ideal pH values (pH 3 to 5), the order of adsorption is Mo(VI) > As(V) > Sb(V) > Cr(VI) > Se(VI). Most oxyanions can be removed for more than 75% with an adsorbent dosage of 1 g/l. Furthermore, perlite-supported magnetite has a higher removal efficiency for oxyanions than commercially available adsorbents and comparable adsorbents described in literature. Perlite-supported magnetite is suitable for treating real wastewaters: it can remove several oxyanions simultaneously from the considered industrial wastewater, but the adsorption order changes due to the presence of interfering anions. PMID- 26488867 TI - Correlates of Family Satisfaction with Hospice Care: General Inpatient Hospice Care versus Routine Home Hospice Care. AB - BACKGROUND: The quality of communication and support provided to families is associated with greater satisfaction with hospice care. Prior work has not explored whether the predictors of family satisfaction are different in different hospice care settings. OBJECTIVE: The study objective was to explore whether correlates of family satisfaction are different in general inpatient hospice care versus routine home hospice care. METHODS: Survey data from bereaved family members of approximately 1600 patients from a nonprofit, midsized hospice in western Pennsylvania were used. Data was obtained from Family Evaluation of Hospice Care (FEHC) survey responses from 2008-2013 and separated into two groups, general inpatient hospice care and routine home hospice care. The analysis was completed using a binomial logistic regression model. RESULTS: Three variables were associated with greater overall satisfaction in both care settings: being kept informed about the patient's condition (adjusted odds ratio [AOR]: 9.64, CI: 6.56-14.36); being provided with clear/consistent information (AOR: 2.34, CI: 1.47-3.72); and the perception that patients were provided with adequate treatment for anxiety (AOR: 2.64, CI: 1.19-5.81). Two variables, sufficient discussion with hospice team members concerning family members' religious or spiritual beliefs (AOR: 1.64, CI: 1.17-2.30) and being provided with the correct amount of emotional support after the patient's death (AOR: 2.01, CI: 1.10-3.66), were correlated with greater satisfaction in routine home hospice care only. CONCLUSIONS: Good communication is strongly associated with greater family satisfaction across hospice care settings. Hospices must ensure that they provide patients and families with consistent information and support. PMID- 26488868 TI - Rotavirus P[8] Infections in Persons with Secretor and Nonsecretor Phenotypes, Tunisia. AB - To determine whether rotavirus infections are linked to secretor status, we studied samples from children in Tunisia with gastroenteritis. We phenotyped saliva for human blood group antigens and tested feces for rotavirus. Rotavirus was detected in 32/114 patients. Secretor genotyping showed that P[8] rotavirus infected secretors and nonsecretors, and infection correlated with presence of Lewis antigen. PMID- 26488869 TI - Mortality Risk Factors for Middle East Respiratory Syndrome Outbreak, South Korea, 2015. AB - As of July 15, 2015, the South Korean Ministry of Health and Welfare had reported 186 case-patients with Middle East respiratory syndrome in South Korea. For 159 case-patients with known outcomes and complete case histories, we found that older age and preexisting concurrent health conditions were risk factors for death. PMID- 26488870 TI - Improving Dielectric Properties of PVDF Composites by Employing Surface Modified Strong Polarized BaTiO3 Particles Derived by Molten Salt Method. AB - BaTiO3/polyvinylidene fluoride (BT/PVDF) is the extensive reported composite material for application in modern electric devices. However, there still exists some obstacles prohibiting the further improvement of dielectric performance, such as poor interfacial compatibility and low dielectric constant. Therefore, in depth study of the size dependent polarization and surface modification of BT particle is of technological importance in developing high performance BT/PVDF composites. Here, a facile molten-salt synthetic method has been applied to prepare different grain sized BT particles through tailoring the calcination temperature. The size dependent spontaneous polarizationof BT particle was thoroughly investigated by theoretical calculation based on powder X-ray diffraction Rietveld refinement data. The results revealed that 600 nm sized BT particles possess the strong polarization, ascribing to the ferroelectric size effect. Furthermore, the surface of optimal BT particles has been modified by water-soluble polyvinylprrolidone (PVP) agent, and the coated particles exhibited fine core-shell structure and homogeneous dispersion in the PVDF matrix. The dielectric constant of the resulted composites increased significantly, especially, the prepared composite with 40 vol % BT loading exhibited the largest dielectric constant (65, 25 degrees C, 1 kHz) compared with the literature values of BT/PVDF at the same concentration of filler. Moreover, the energy storage density of the composites with tailored structure was largely enhanced at the low electric field, showing promising application as dielectric material in energy storage device. Our work suggested that introduction of strong polarized ferroelectric particles with optimal size and construction of core-shell structured coated fillers by PVP in the PVDF matrix are efficacious in improving dielectric performance of composites. The demonstrated approach can also be applied to the design and preparation of other polymers-based nanocomposites filled with ferroelectric particles to achieve desirable dielectric properties. PMID- 26488872 TI - The Pathological Buying Screener: Development and Psychometric Properties of a New Screening Instrument for the Assessment of Pathological Buying Symptoms. AB - The study was designed to develop a new screening instrument for pathological buying (PB), and to examine its psychometric properties in a large-scale sample. By using a facet theoretical approach and based on literature as well as on clinical experience, a 20-item Pathological Buying Screener (PBS) was developed and administered to a representative German sample (n = 2,539). Valid data were available from 2,403 participants who were subjects for three subsequent empirical studies. The first study explored the factor structure using exploratory factor analyses in a subsample of 498 participants. Based on factor loadings, a 13-item version with the two factors loss of control / consequences and excessive buying behavior was revealed. This two-factor model was confirmed in study 2 by confirmatory factor analysis performed on another subsample (n = 1,905). Study 3 investigated age and gender effects and convergent validity of the PBS using the Compulsive Buying Scale (CBS) in the full sample (N = 2,403). The total PBS score was adequately correlated with the CBS score. Hierarchical regression analyses with the CBS score as the dependent variable and the two PBS factors as the predictors indicated an own incremental validity of the two factors in participants <= 65 years. The reliability of the total score as well as of the two subscales was good to excellent. Overall, the PBS represents a useful measure for PB. Future studies are needed to replicate the two-factor structure in clinical samples and to define a valid cutoff for PB. PMID- 26488871 TI - Incidence of Hospitalized Pneumococcal Pneumonia among Adults in Guatemala, 2008 2012. AB - BACKGROUND: Streptococcus pneumoniae is a leading cause of pneumonia worldwide. However, the burden of pneumococcal pneumonia among adults in low- and middle income countries is not well described. METHODS: Data from 2008-2012 was analyzed from two surveillance sites in Guatemala to describe the incidence of pneumococcal pneumonia in adults. A case of hospitalized pneumococcal pneumonia was defined as a positive pneumococcal urinary antigen test or blood culture in persons aged >= 18 years hospitalized with an acute respiratory infection (ARI). RESULTS: Among 1595 adults admitted with ARI, 1363 (82%) had either urine testing (n = 1286) or blood culture (n = 338) performed. Of these, 188 (14%) had pneumococcal pneumonia, including 173 detected by urine only, 8 by blood culture only, and 7 by both methods. Incidence rates increased with age, with the lowest rate among 18-24 year-olds (2.75/100,000) and the highest among >=65 year-olds (31.3/100,000). The adjusted incidence of hospitalized pneumococcal pneumonia was 18.6/100,000 overall, with in-hospital mortality of 5%. CONCLUSIONS: An important burden of hospitalized pneumococcal pneumonia in adults was described, particularly for the elderly. However, even adjusted rates likely underestimate the true burden of pneumococcal pneumonia in the community. These data provide a baseline against which to measure the indirect effects of the 2013 introduction of the pneumococcal conjugate vaccine in children in Guatemala. PMID- 26488874 TI - Diversity and Systematics of Schizomavella Species (Bryozoa: Bitectiporidae) from the Bathyal NE Atlantic. AB - Eight NE Atlantic and Mediterranean species, which were originally assigned to the genus Schizoporella (Family Schizoporellidae) when introduced, are redescribed and stabilized by typification. Seven of these species are transferred to the bitectiporid genus Schizomavella: S. fischeri, S. glebula, S. neptuni, S. obsoleta, S. richardi, S. triaviculata, and S. triaviculata var. paucimandibulata, which is here raised to species rank. The eighth species, Schizoporella fayalensis, is transferred to the lanceoporid genus Stephanotheca. Schizomavella obsoleta and S. glebula are considered junior subjective synonyms of S. fischeri and S. richardi, respectively. Two new species are described: Schizomavella rectangularis n. sp. from the Strait of Gibraltar, and Schizomavella phterocopa n. sp. from the Great Meteor Bank. A new subgenus, Calvetomavella n. subgen. is established as a result of a phylogenetic analysis based on morphological characters; it includes S. neptuni, S. triaviculata, S. paucimandibulata and S. phterocopa n. sp., together with Schizomavella discoidea and Schizomavella noronhai. The rest of the species remain in the nominotypical subgenus Schizomavella. PMID- 26488875 TI - Cholangiocarcinoma in Cirrhosis: Value of Hepatocyte Specific Magnetic Resonance Imaging. AB - BACKGROUND: The diagnosis of intrahepatic cholangiocellular carcinoma (ICC) remains elusive at imaging, which is a critical issue in cirrhotic patients in whom a diagnosis of hepatocellular carcinoma (HCC) can be established only by imaging. AIM: The aim of the study was to evaluate the potential of MRI in the diagnosis of ICC in cirrhosis using 'hepatocyte-specific' Gadolinium (Gd)-based contrast agents. METHODS: Sixteen histologically proven and retrospectively identified ICCs on cirrhosis were investigated with hepatocyte-specific magnetic resonance contrast agents (6 in Bologna with Gd-EOB-DTPA and 10 in Milan with Gd BOPTA). The control group consisted of 41 consecutively and prospectively collected nodules (31 HCCs) imaged with Gd-EOB-DTPA. RESULTS: Fifteen ICC nodules (94%) displayed hypointensity in the hepatobiliary phase, suggesting malignancy. Thirteen cholangiocarcinomas (81%) showed hyperenhancement in the venous phase. Only 2 cholangiocarcinoma nodules showed hypoenhancement in the venous phase, corresponding to washout, in both cases preceded by rim enhancement in arterial phase. All the hepatocarcinomas showed hypointensity in hepatobiliary phase, but was always preceded by hypointensity in the venous phase; arterial rim enhancement was never observed in any hepatocarcinoma or regenerative nodule. CONCLUSIONS: MRI with hepatocyte-specific Gd-based contrast agents showed a pattern of malignancy in almost all the ICCs, concurrently avoiding misdiagnosis with hepatocarcinoma. These findings suggest a greater diagnostic capacity for this technique compared with the results of MRI with conventional contrast agents reported in the literature in this setting. PMID- 26488877 TI - Long-Term Dietary Fructose Causes Gender-Different Metabolic and Vascular Dysfunction in Rats: Modulatory Effects of Resveratrol. AB - BACKGROUND/AIMS: There is limited knowledge on the gender differences in the effects of dietary fructose. In the current study, we investigated whether long term fructose intake impacts metabolic parameters and vascular reactivity differently between male and female rats. Moreover, we tested whether resveratrol has a gender-specific effectiveness on the alterations. METHODS: Male and female rats were divided into four groups as control; resveratrol; fructose and resveratrol plus fructose. Fructose was given to the rats as 10% solution in drinking water for 24 weeks. All rats were fed with the standard diet with or without resveratrol. RESULTS: High-fructose diet increased plasma insulin, triglyceride and VLDL levels as well as omental weights in both genders. Long term dietary fructose causes marked increase in body weight of males, but not females. Dietary fructose impaired endothelial relaxation to acetylcholine and intensified contraction to phenylephrine in the aortas of male and female rats, but differently it also reduced insulin-induced vasodilation in aortas of female rats. These changes were associated with decreased expression levels of endothelial nitric oxide synthase (eNOS) mRNA and protein, but increased in inducible NOS (iNOS), in aortas of male and female rats. Dietary fructose suppressed expression levels of sirtuin 1 (SIRT1) and insulin receptor substrate 2 (IRS-2) mRNA in aortas from female rats. Resveratrol supplementation efficiently restored fructose-induced metabolic and vascular dysfunction in both genders probably by regulating eNOS and iNOS production. Moreover, the augmentations in SIRT1 and IRS-2 mRNA in females and IRS-1 mRNA in males may possibly contribute to the beneficial effects of resveratrol as well. CONCLUSION: Long-term fructose intake may differently affect metabolic and vascular function between male and female rats, which are modified by resveratrol. PMID- 26488878 TI - Corrigendum. PMID- 26488876 TI - Three-Dimensional Microfluidic Tri-Culture Model of the Bone Marrow Microenvironment for Study of Acute Lymphoblastic Leukemia. AB - Acute lymphoblastic leukemia (ALL) initiates and progresses in the bone marrow, and as such, the marrow microenvironment is a critical regulatory component in development of this cancer. However, ALL studies were conducted mainly on flat plastic substrates, which do not recapitulate the characteristics of marrow microenvironments. To study ALL in a model of in vivo relevance, we have engineered a 3-D microfluidic cell culture platform. Biologically relevant populations of primary human bone marrow stromal cells, osteoblasts and human leukemic cells representative of an aggressive phenotype were encapsulated in 3-D collagen matrix as the minimal constituents and cultured in a microfluidic platform. The matrix stiffness and fluidic shear stress were controlled in a physiological range. The 3-D microfluidic as well as 3-D static models demonstrated coordinated cell-cell interactions between these cell types compared to the compaction of the 2-D static model. Tumor cell viability in response to an antimetabolite chemotherapeutic agent, cytarabine in tumor cells alone and tri culture models for 2-D static, 3-D static and 3-D microfluidic models were compared. The present study showed decreased chemotherapeutic drug sensitivity of leukemic cells in 3-D tri-culture models from the 2-D models. The results indicate that the bone marrow microenvironment plays a protective role in tumor cell survival during drug treatment. The engineered 3-D microfluidic tri-culture model enables systematic investigation of effects of cell-cell and cell-matrix interactions on cancer progression and therapeutic intervention in a controllable manner, thus improving our limited comprehension of the role of microenvironmental signals in cancer biology. PMID- 26488880 TI - Correction: Indirect Energy Flows in Niche Model Food Webs: Effects of Size and Connectance. PMID- 26488879 TI - In Vitro Production of Echioidinin, 7-O-Methywogonin from Callus Cultures of Andrographis lineata and Their Cytotoxicity on Cancer Cells. AB - Andrographis lineata is an herbal medicinal plant used in traditional medicine as a substitute for Andrographis paniculata. Here, using mature leaf explants of A. lineata we demonstrate for the first time the callus induction established on MS medium containing 1.0 mg l-1 IAA. Dried callus was subjected to solvent extraction with acetone. Further the acetone residue was separated by silica gel column chromatography, crystallized and characterized on the basis of nuclear magnetic resonance (proton and c13) and liquid chromatographic mass spectroscopy. This analysis revealed the occurrence of two known flavones namely, 7-O methylwogonin (MW) and Echioidinin (ED). Furthermore, these compounds were tested for their cytotoxicity against leukemic cell line, CEM. We identify that ED and MW induced cytotoxicity in a time- and concentration-dependent manner. Further increase in the LDH release upon treatment with ED and MW further confirmed our cytotoxicity results against leukemic cell line. Strikingly, MW was more potent than ED when compared by trypan blue and MTT assays. Our results recapitulate the utility of callus cultures for the production of plant specific bioactive secondary metabolites instead of using wild plants. Together, our in vitro studies provide new insights of A. lineata callus cultures serving as a source for cancer chemotherapeutic agents. PMID- 26488881 TI - Allergens Induce the Release of Lactoferrin by Neutrophils from Asthmatic Patients. AB - BACKGROUND: Despite the evidence that Lactoferrin (Lf) is involved in allergic asthma processes, it is unknown whether neutrophils can be one of the main cellular sources of this key inflammatory mediator directly in response of an IgE mediated stimulus. The present study was undertaken to analyze this question. METHODS: Neutrophils from healthy subjects (n = 34) and neutrophils from allergic asthmatic patients (n = 102) were challenged in vitro with specific allergens to which the patients were sensitized, PAF, or agonist mAbs against IgE-receptors, and the levels of Lf were measured in the culture supernatant. The levels of serum IgE together with the severity of symptoms were also analyzed. RESULTS: Lf was released into the culture supernatant of neutrophils from allergic asthmatic patients in response to allergens and PAF. This response was highly allergen specific, and did not happen in neutrophils from healthy donors. Allergen effect was mimicked by Abs against FcepsilonRI and galectin-3 but not by FcepsilonRII. The levels of released Lf correlated well with the levels of serum specific IgE and severity of asthma symptoms. These observations represent a novel view of neutrophils as an important source of Lf in allergic asthma. Importantly, the levels of released Lf by neutrophils could therefore be used to evaluate disease severity in allergic asthmatic patients. PMID- 26488883 TI - Dermatan Sulfate-Free Mice Display Embryological Defects and Are Neonatal Lethal Despite Normal Lymphoid and Non-Lymphoid Organogenesis. AB - The epimerization of glucuronic acid into iduronic acid adds structural variability to chondroitin/dermatan sulfate polysaccharides. Iduronic acid containing domains play essential roles in processes such as coagulation, chemokine and morphogen modulation, collagen maturation, and neurite sprouting. Therefore, we generated and characterized, for the first time, mice deficient in dermatan sulfate epimerase 1 and 2, two enzymes uniquely involved in dermatan sulfate biosynthesis. The resulting mice, termed DKO mice, were completely devoid of iduronic acid, and the resulting chondroitin sulfate chains were structurally different from the wild type chains, from which a different protein binding specificity can be expected. As a consequence, a vast majority of the DKO mice died perinatally, with greatly variable phenotypes at birth or late embryological stages such as umbilical hernia, exencephaly and a kinked tail. However, a minority of embryos were histologically unaffected, with apparently normal lung and bone/cartilage features. Interestingly, the binding of the chemokine CXCL13, an important modulator of lymphoid organogenesis, to mouse DKO embryonic fibroblasts was impaired. Nevertheless, the development of the secondary lymphoid organs, including the lymph nodes and spleen, was normal. Altogether, our results indicate an important role of dermatan sulfate in embryological development and perinatal survival. PMID- 26488882 TI - Involvement of Membrane Blebbing in Immunological Disorders and Cancer. AB - Cellular blebbing is a unique form of dynamic protrusion emanating from the plasma membrane which can be either apoptotic or nonapoptotic in nature. Blebs have been observed in a wide variety of cell types and in response to multiple mechanical and chemical stimuli. They have been linked to various physiological and pathological processes including tumor motility and invasion, as well as to various immunological disorders. They can form and retract extremely rapidly in seconds or minutes, or slowly over hours or days. This review focuses on recent evidence regarding the role of blebbing in cell locomotion with particular emphasis on its role in tumor metastasis, indicating the role of specific causative molecules. The phenomenon of blebbing has been observed in endocrine resistant breast cancer cells in response to brief exposure to extracellular alkaline pH, which leads to enhanced invasive capacity. Genetic or pharmacological targeting of cellular blebs could serve as a potential therapeutic option to control tumor metastasis. PMID- 26488884 TI - Redox Interactions of Tc(VII), U(VI), and Np(V) with Microbially Reduced Biotite and Chlorite. AB - Technetium, uranium, and neptunium are contaminants that cause concern at nuclear facilities due to their long half-life, environmental mobility, and radiotoxicity. Here we investigate the impact of microbial reduction of Fe(III) in biotite and chlorite and the role that this has in enhancing mineral reactivity toward soluble TcO4(-), UO2(2+), and NpO2(+). When reacted with unaltered biotite and chlorite, significant sorption of U(VI) occurred in low carbonate (0.2 mM) buffer, while U(VI), Tc(VII), and Np(V) showed low reactivity in high carbonate (30 mM) buffer. On reaction with the microbially reduced minerals, all radionuclides were removed from solution with U(VI) reactivity influenced by carbonate. Analysis by X-ray absorption spectroscopy (XAS) confirmed reductive precipitation to poorly soluble U(IV) in low carbonate conditions and both Tc(VII) and Np(V) in high carbonate buffer were also fully reduced to poorly soluble Tc(IV) and Np(IV) phases. U(VI) reduction was inhibited under high carbonate conditions. Furthermore, EXAFS analysis suggested that in the reaction products, Tc(IV) was associated with Fe, Np(IV) formed nanoparticulate NpO2, and U(IV) formed nanoparticulate UO2 in chlorite and was associated with silica in biotite. Overall, microbial reduction of the Fe(III) associated with biotite and chlorite primed the minerals for reductive scavenging of radionuclides: this has clear implications for the fate of radionuclides in the environment. PMID- 26488885 TI - Characterization of Bacterial Communities Associated with the Tyrian Purple Producing Gland in a Marine Gastropod. AB - Dicathais orbita is a marine mollusc recognised for the production of anticancer compounds that are precursors to Tyrian purple. This study aimed to assess the diversity and identity of bacteria associated with the Tyrian purple producing hypobranchial gland, in comparison with foot tissue, using a high-throughput sequencing approach. Taxonomic and phylogenetic analysis of variable region V1-V3 of 16S rRNA bacterial gene amplicons in QIIME and MEGAN were carried out. This analysis revealed a highly diverse bacterial assemblage associated with the hypobranchial gland and foot tissues of D. orbita. The dominant bacterial phylum in the 16S rRNA bacterial profiling data set was Proteobacteria followed by Bacteroidetes, Tenericutes and Spirochaetes. In comparison to the foot, the hypobranchial gland had significantly lower bacterial diversity and a different community composition, based on taxonomic assignment at the genus level. A higher abundance of indole producing Vibrio spp. and the presence of bacteria with brominating capabilities in the hypobranchial gland suggest bacteria have a potential role in biosynthesis of Tyrian purple in D. orbita. PMID- 26488888 TI - Keynote Lectures. PMID- 26488886 TI - Description of a New Galapagos Giant Tortoise Species (Chelonoidis; Testudines: Testudinidae) from Cerro Fatal on Santa Cruz Island. AB - The taxonomy of giant Galapagos tortoises (Chelonoidis spp.) is currently based primarily on morphological characters and island of origin. Over the last decade, compelling genetic evidence has accumulated for multiple independent evolutionary lineages, spurring the need for taxonomic revision. On the island of Santa Cruz there is currently a single named species, C. porteri. Recent genetic and morphological studies have shown that, within this taxon, there are two evolutionarily and spatially distinct lineages on the western and eastern sectors of the island, known as the Reserva and Cerro Fatal populations, respectively. Analyses of DNA from natural populations and museum specimens, including the type specimen for C. porteri, confirm the genetic distinctiveness of these two lineages and support elevation of the Cerro Fatal tortoises to the rank of species. In this paper, we identify DNA characters that define this new species, and infer evolutionary relationships relative to other species of Galapagos tortoises. PMID- 26488887 TI - Construction of Nanowire Heterojunctions: Photonic Function-Oriented Nanoarchitectonics. AB - Nanophotonics has received broad research interest because it may provide an alternative opportunity to overcome the fundamental limitations of electronic circuits. So far, diverse photonic functions, such as light generation, modulation, and detection, have been realized based on various nano-materials. The exact structural features of these material systems, including geometric characteristics, surface morphology, and material composition, play a key role in determining the photonic functions. Therefore, rational designs and constructions of materials on both morphological and componential levels, namely nanoarchitectonics, are indispensable for any photonic device with specific functionalities. Recently, a series of nanowire heterojunctions (NWHJs), which are usually made from two or more kinds of material compositions, were constructed for novel photonic applications based on various interactions between different materials at the junctions, for instance, energy transfer, exciton plasmon coupling, or photon-plasmon coupling. A summary of these works is necessary to get a more comprehensive understanding of the relationship between photonic functions and architectonics of NWHJs, which will be instructive for designing novel photonic devices towards integrated circuits. Here, photonic function oriented nanoarchitectonics based on recent breakthroughs in nanophotonic devices are discussed, with emphasis on the design mechanisms, fabrication strategies, and excellent performances. PMID- 26488890 TI - Poster Presentations. PMID- 26488891 TI - Gene transfer of two entry inhibitors protects CD4+ T cell from HIV-1 infection in humanized mice. AB - Targeting viral entry is the most likely gene therapy strategy to succeed in protecting the immune system from pathogenic HIV-1 infection. Here, we evaluated the efficacy of a gene transfer lentiviral vector expressing a combination of viral entry inhibitors, the C46 peptide (an inhibitor of viral fusion) and the P2 CCL5 intrakine (a modulator of CCR5 expression), to prevent CD4+ T-cell infection in vivo. For this, we used two different models of HIV-1-infected mice, one in which ex vivo genetically modified human T cells were grafted into immunodeficient NOD.SCID.gammac-/-mice before infection and one in which genetically modified T cells were derived from CD34+ hematopoietic progenitors grafted few days after birth. Expression of the transgenes conferred a major selective advantage to genetically modified CD4+ T cells, the frequency of which could increase from 10 to 90% in the blood following HIV-1 infection. Moreover, these cells resisted HIV-1-induced depletion, contrary to non-modified cells that were depleted in the same mice. Finally, we report lower normalized viral loads in mice having received genetically modified progenitors. Altogether, our study documents that targeting viral entry in vivo is a promising avenue for the future of HIV-1 gene therapy in humans. PMID- 26488892 TI - HBV carriage in children born from HIV-seropositive mothers in Senegal: The need of birth-dose HBV vaccination. AB - Hepatitis B is a major public health problem in Senegal, a country with high prevalence and a transmission occurring mainly during infancy. Only, one 6-8 weeks vaccination campaign was initiated in 2005 and it was part of the expanded program of immunization. The aim of this study was to determine the prevalence of HBsAg in children born from HIV-seropositive mothers by using dried blood specimens. Specimens were collected between July 2007 and November 2012 from children aged 2-48 weeks in Dakar and decentralized sites working on HIV mother to-child transmission prevention. HBsAg detection was performed using Architect HBsAg Qualitative II kit (Abbott Diagnostics, Ireland) and for all reactive samples confirmation was done using Architect HBsAg Qualitative II Confirmatory kit (Abbott Diagnostics, Ireland). Nine hundred thirty samples were collected throughout the country with 66% out of Dakar, the capital city. The median age was 20 weeks and 88% of children were less than 1 year of age with a sex ratio of 1.27 in favor of boys. HBsAg was detected in 28 cases giving a global prevalence of 3%. According to age, HBsAg prevalences were 5.1% for children less than 6 weeks, 4.1% and 4.6%, respectively, for those aged 12-18 weeks and 18-24 weeks of age. The HIV prevalence was 2.6% with no HIV/HBV co-infection. This study showed a high rate of HBV infection in children under 24 months, highlighting the need to promote birth-dose HBV vaccination as recommended by WHO. PMID- 26488893 TI - Effects of Grammaticality and Morphological Complexity on the P600 Event-Related Potential Component. AB - We investigated interactions between morphological complexity and grammaticality on electrophysiological markers of grammatical processing during reading. Our goal was to determine whether morphological complexity and stimulus grammaticality have independent or additive effects on the P600 event-related potential component. Participants read sentences that were either well-formed or grammatically ill-formed, in which the critical word was either morphologically simple or complex. Results revealed no effects of complexity for well-formed stimuli, but the P600 amplitude was significantly larger for morphologically complex ungrammatical stimuli than for morphologically simple ungrammatical stimuli. These findings suggest that some previous work may have inadequately characterized factors related to reanalysis during morphosyntactic processing. Our results show that morphological complexity by itself does not elicit P600 effects. However, in ungrammatical circumstances, overt morphology provides a more robust and reliable cue to morphosyntactic relationships than null affixation. PMID- 26488894 TI - Network Properties of the Ensemble of RNA Structures. AB - We describe the first dynamic programming algorithm that computes the expected degree for the network, or graph G = (V, E) of all secondary structures of a given RNA sequence a = a1, ..., an. Here, the nodes V correspond to all secondary structures of a, while an edge exists between nodes s, t if the secondary structure t can be obtained from s by adding, removing or shifting a base pair. Since secondary structure kinetics programs implement the Gillespie algorithm, which simulates a random walk on the network of secondary structures, the expected network degree may provide a better understanding of kinetics of RNA folding when allowing defect diffusion, helix zippering, and related conformation transformations. We determine the correlation between expected network degree, contact order, conformational entropy, and expected number of native contacts for a benchmarking dataset of RNAs. Source code is available at http://bioinformatics.bc.edu/clotelab/RNAexpNumNbors. PMID- 26488895 TI - Effects of Early Hypertension Control after Ischaemic Stroke on the Outcome: A Meta-Analysis. AB - BACKGROUND: Accumulating evidence suggests that high blood pressure (BP) increases the risk of cerebral oedema and haemorrhagic transformation of the ischaemic stroke (IS), and that low BP in acute ischaemic stroke (AIS) is associated with a poor prognosis. The best possible management of hypertension after AIS is still uncertain. MATERIALS AND METHODS: English databases were searched to identify relevant randomized controlled trials assessing the effects of early BP lowering (started within the first 48 h) after IS on outcome from January 1990 to August 2015. We set strict inclusion criteria and used the Review Manager 5.2 software from Cochrane Collaboration to calculate the combined risk ratio (RR). RESULT: Eight studies met our criteria. Early BP lowering after AIS did not significantly affect the risk of early and long-term death (RR 1.22; 95% CI 0.69-2.16 and RR 1.03; 95% CI 0.62-1.71), early and long-term dependency (RR 1.02; 95% CI 0.94-1.10 and RR 1.07; 95% CI 0.84-1.36), early and long-term death or dependency (RR 1.04; 95% CI 0.94-1.19 and RR 1.00; 95% CI 0.95-1.05), long term stroke recurrence (RR 0.74; 95% CI 0.49-1.11), long-term myocardial infarction (RR 0.99; 95% CI 0.27-3.61), and long-term vascular events (RR 0.97; 95% CI 0.72-1.31). CONCLUSION: Our results revealed neither support nor opposition to early BP lowering (started within 48 h) after AIS; individualized BP management based on the patients' condition may be a good choice. PMID- 26488896 TI - Proton pump inhibitors and risk of periampullary cancers--A nested case-control study. AB - Considerable attention has been focused on long-term use of proton pump inhibitor (PPI) medications in relation to increased risk of cancer via stimulation of DNA damaged cells. The aim of this study is to examine the dose-dependent effect of PPI on periampullary cancers in a national population-based cohort. A nested case control analysis was constructed based on Taiwan's National Health Insurance Research Database and the Taiwan Cancer Registry between the years 2000 and 2010. Cases involving patients diagnosed with periampullary cancers were selected and controls were matched to cases according to age, sex and observational period. A "PPI user" was defined as any patient receiving more than 28 cumulative defined daily doses as measured by prescription drug claims. Conditional logistic regression analysis was conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs) according to the level of PPI exposure. A total of 7,681 cases and 76,762 matched controls were included with a mean follow-up period of 6.6 years (SD: 2.0). The odds of PPI exposure in patients with periampullary cancers were higher than that of control patients with an adjusted OR of 1.35 (95% CIs: 1.16-1.57). Our results also showed that PPI exposure was slightly linked to periampullary cancers in dose-dependent manner. A similar association was observed in patients who solely took PPI but no eradication therapy for Helicobacter pylori infection. Long-term PPI use was associated with an increased risk of periampullary cancers in the current population-based study. Physicians must weigh potential risks of long-term maintenance against therapeutic benefit. PMID- 26488897 TI - Valproic acid sensitizes human glioma cells to gefitinib-induced autophagy. AB - Autophagy and apoptosis represent important cellular processes involved in cancer cell killing mechanisms. Epidermal growth factor receptor inhibitor gefitinib and valproic acid have been implicated in the treatment of malignancies including glioma involving autophagic and apoptotic mechanisms. Therefore, it is interesting to investigate whether a combination of gefitinib and valproic acid shows better cancer cell killing effect on human glioma cells. We found that a nontoxic concentration of valproic acid sensitized U87 and T98G glioma cells to gefitinib cytotoxicity by inhibiting cell growth and long-term clonogenic survival. The augmented consequences were accompanied by the formation of autophagic vacuoles, conversion of microtubule-associated protein-1 light chain 3 II (LC3-II), and degradation of p62. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 but not broad-spectrum caspase inhibitor attenuated gefitinib/valproic acid-induced growth inhibition. Gefitinib/valproic acid-induced autophagy was accompanied by the activation of liver kinase-B1 (LKB1)/AMP-activated protein kinase (AMPK)/ULK1. Silencing of AMPK and ULK1 suppressed gefitinib/valproic acid-induced autophagy and growth inhibition. Mechanistic studies showed that gefitinib/valproic acid increased intracellular reactive oxygen species generation and N-acetyl cysteine attenuated gefitinib/valproic acid-caused autophagy and growth inhibition. In addition to demonstrating the autophagic mechanisms of gefitinib/valproic acid, the results of this study further suggest that intracellular oxidative stress and the LKB1/AMPK signaling might be a potential target for the development of therapeutic strategy against glioma. PMID- 26488898 TI - Optimization of naringenin and p-coumaric acid hydroxylation using the native E. coli hydroxylase complex, HpaBC. AB - Flavonoids are a growing class of bioactive natural products with distinct and interesting bioactivity both in vitro and in vivo. The extraction of flavonoids from plant sources is limited by their low natural abundance and commonly results in a mixture of products that are difficult to separate. However, due to recent advances, the microbial production of plant natural products has developed as a promising alternative for flavonoid production. Through optimization of media, induction temperature, induction point, and substrate delay time, we demonstrate the highest conversion of naringenin to eriodictyol (62.7 +/- 2.7 mg/L) to date, using the native E. coli hydroxylase complex, HpaBC. We also show the first evidence of in vivo HpaBC activity towards the monohydroxylated flavan-3-ol afzelechin with catechin product titers of 34.7 +/- 1.5 mg/L. This work confirms the wide applicability of HpaBC towards realizing efficient de novo production of various orthohydroxylated flavonoids and flavonoid derived products in E. coli. PMID- 26488899 TI - Gender in Science and Engineering Faculties: Demographic Inertia Revisited. AB - The under-representation of women on faculties of science and engineering is ascribed in part to demographic inertia, which is the lag between retirement of current faculty and future hires. The assumption of demographic inertia implies that, given enough time, gender parity will be achieved. We examine that assumption via a semi-Markov model to predict the future faculty, with simulations that predict the convergence demographic state. Our model shows that existing practices that produce gender gaps in recruitment, retention, and career progression preclude eventual gender parity. Further, we examine sensitivity of the convergence state to current gender gaps to show that all sources of disparity across the entire faculty career must be erased to produce parity: we cannot blame demographic inertia. PMID- 26488900 TI - Laser and electron-beam powder-bed additive manufacturing of metallic implants: A review on processes, materials and designs. AB - Additive manufacturing (AM), also commonly known as 3D printing, allows the direct fabrication of functional parts with complex shapes from digital models. In this review, the current progress of two AM processes suitable for metallic orthopaedic implant applications, namely selective laser melting (SLM) and electron beam melting (EBM) are presented. Several critical design factors such as the need for data acquisition for patient-specific design, design dependent porosity for osteo-inductive implants, surface topology of the implants and design for reduction of stress-shielding in implants are discussed. Additive manufactured biomaterials such as 316L stainless steel, titanium-6aluminium 4vanadium (Ti6Al4V) and cobalt-chromium (CoCr) are highlighted. Limitations and future potential of such technologies are also explored. PMID- 26488901 TI - Population Trend and Elasticities of Vital Rates for Steller Sea Lions (Eumetopias jubatus) in the Eastern Gulf of Alaska: A New Life-History Table Analysis. AB - Steller sea lion (Eumetopias jubatus) numbers are beginning to recover across most of the western distinct population segment following catastrophic declines that began in the 1970s and ended around the turn of the century. This study makes use of contemporary vital rate estimates from a trend-site rookery in the eastern Gulf of Alaska (a sub-region of the western population) in a matrix population model to estimate the trend and strength of the recovery across this region between 2003 and 2013. The modeled population trend was projected into the future based on observed variation in vital rates and a prospective elasticity analysis was conducted to determine future trends and which vital rates pose the greatest threats to recovery. The modeled population grew at a mean rate of 3.5% per yr between 2003 and 2013 and was correlated with census count data from the local rookery and throughout the eastern Gulf of Alaska. If recent vital rate estimates continue with little change, the eastern Gulf of Alaska population could be fully recovered to pre-decline levels within 23 years. With density dependent growth, the population would need another 45 years to fully recover. Elasticity analysis showed that, as expected, population growth rate (lambda) was most sensitive to changes in adult survival, less sensitive to changes in juvenile survival, and least sensitive to changes in fecundity. A population decline could be expected with only a 6% decrease in adult survival, whereas a 32% decrease in fecundity would be necessary to bring about a population decline. These results have important implications for population management and suggest current research priorities should be shifted to a greater emphasis on survival rates and causes of mortality. PMID- 26488903 TI - Anaplastic Ependymoma in a Child With Sickle Cell Anemia: A Case Report Highlighting Treatment Challenges for Young Children With Central Nervous System Tumors and Underlying Vasculopathy. AB - A 3-year-old boy with sickle cell anemia (SCA) presented with progressive daily emesis and was found to have an anaplastic ependymoma. Radiation therapy and chemotherapy are usually employed after subtotal resections of anaplastic ependymomas, although the benefits from chemotherapy are unclear. To mitigate the risks of adjuvant treatment in this patient at risk for SCA-associated vasculopathy, renal impairment, and other end-organ damage, proton beam irradiation without chemotherapy was chosen. Scheduled packed red blood cell transfusions were instituted to maintain sickle hemoglobin levels less than 30%. This case highlights treatment complexities for malignant brain tumors in patients predisposed to treatment-related adverse effects. PMID- 26488904 TI - Arresting HIV: Fostering Partnerships between Sex Workers and Police to Reduce HIV Risk and Promote Professionalization within Policing Institutions: A Realist Review. AB - In many countries around the world sex work is criminalised and its regulatory control is therefore often in the hands of the police. In addition to the impact of this criminalised legal environment, much literature describes the negative impact that certain police practices can have on the ability of sex workers and the programs that work with sex workers to access essential HIV prevention, treatment, care and support services. This situation has resulted in persistent concentrated HIV epidemics among sex workers in many countries of the world. The need for multi-sector partnerships between police and HIV programs is increasingly recognised in various UN declarations and resolutions yet descriptions of the process or key ingredients required to actually establish and sustain these necessary partnerships between police and sex workers [or the programs that provide essential services to sex workers] are sparse. The paper seeks to establish key considerations and critical processes that are required to foster partnerships that if further investigated and scaled up, could result in an enhanced enabling environment for the provision of essential HIV services for sex workers around the globe. This paper is based on a realist review that investigated isolated examples of partnership formation between law enforcement and HIV programs working with sex workers. This methodology research is designed to work with complex social interventions and is based on the emerging 'realist' approach to evaluation. A realist review methodology was chosen given the paucity of relevant literature in this vein and the authors' familiarity with the grey literature and relationships with experts who work in this sphere. The review found that political and police leadership, civil society strengthening and police reform in relation to HIV, are critical factors and key ingredients in changing the enabling environment in which sex work takes place to ensure that HIV prevention, individual and public health as well as HIV prevention and the promotion of human rights are the number one priority. Further research into this relationship is needed to provide evidence for effective HIV programming with police. PMID- 26488905 TI - Atomoxetine monotherapy compared with combination therapy for the treatment of ADHD: a retrospective chart review study. AB - OBJECTIVE: To analyze Clinical Global Impression-Severity (CGI-S) in ADHD patients treated with atomoxetine (ATX) monotherapy versus ATX combination therapy with another ADHD-indicated medication. METHODS: This was a 2-site retrospective observational chart review study of child and adult ADHD patients, not necessarily treatment naive, but treated >=50 days post baseline with an endpoint assessment. To adjust for measured confounders, monotherapy (n = 77) versus combination (n = 108) cohort comparisons were performed using propensity score stratification and adjusted ANCOVA. RESULTS: There were no significant baseline cohort differences after propensity stratification. CGI-S scores after a mean 264 days of treatment were not statistically significantly different between cohorts, with no cohort differences observed in any assessed symptom subcategory. The cohorts were similar in discontinuation due to any reason, adverse event, and lack of efficacy. CONCLUSION: ATX combination therapy showed no evidence of additional benefit over ATX monotherapy in the treatment of ADHD in a community based setting. PMID- 26488902 TI - Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators. AB - Ribonucleotide reductase (RR) catalyzes the rate-limiting step of dNTP synthesis and is an established cancer target. Drugs targeting RR are mainly nucleoside in nature. In this study, we sought to identify non-nucleoside small-molecule inhibitors of RR. Using virtual screening, binding affinity, inhibition, and cell toxicity, we have discovered a class of small molecules that alter the equilibrium of inactive hexamers of RR, leading to its inhibition. Several unique chemical categories, including a phthalimide derivative, show micromolar IC50s and KDs while demonstrating cytotoxicity. A crystal structure of an active phthalimide binding at the targeted interface supports the noncompetitive mode of inhibition determined by kinetic studies. Furthermore, the phthalimide shifts the equilibrium from dimer to hexamer. Together, these data identify several novel non-nucleoside inhibitors of human RR which act by stabilizing the inactive form of the enzyme. PMID- 26488906 TI - Controlled ligand distortion and its consequences for structure, symmetry, conformation and spin-state preferences of iron(II) complexes. AB - The ligand-field strength in metal complexes of polydentate ligands depends critically on how the ligand backbone places the donor atoms in three-dimensional space. Distortions from regular coordination geometries are often observed. In this work, we study the isolated effect of ligand-sphere distortion by means of two structurally related pentadentate ligands of identical donor set, in the solid state (X-ray diffraction, (57)Fe-Mossbauer spectroscopy), in solution (NMR spectroscopy, UV/Vis spectroscopy, conductometry), and with quantum-chemical methods. Crystal structures of hexacoordinate iron(II) and nickel(II) complexes derived from the cyclic ligand L(1) (6-methyl-6-(pyridin-2-yl)-1,4-bis(pyridin-2 ylmethyl)-1,4-diazepane) and its open-chain congener L(2) (N(1),N(3),2-trimethyl 2-(pyridine-2-yl)-N(1),N(3)-bis(pyridine-2-ylmethyl) propane-1,3-diamine) reveal distinctly different donor set distortions reflecting the differences in ligand topology. Distortion from regular octahedral geometry is minor for complexes of ligand L(2), but becomes significant in the complexes of the cyclic ligand L(1), where trans elongation of Fe-N bonds cannot be compensated by the rigid ligand backbone. This provokes trigonal twisting of the ligand field. This distortion causes the metal ion in complexes of L(1) to experience a significantly weaker ligand field than in the complexes of L(2), which are more regular. The reduced ligand-field strength in complexes of L(1) translates into a marked preference for the electronic high-spin state, the emergence of conformational isomers, and massively enhanced lability with respect to ligand exchange and oxidation of the central ion. Accordingly, oxoiron(IV) species derived from L(1) and L(2) differ in their spectroscopic properties and their chemical reactivity. PMID- 26488907 TI - A portable microcolumn based on silver nanoparticle functionalized glass fibers and its SERS application. AB - We presented a facile method for the preparation of a portable detection column integrated with silver nanoparticle (Ag NP) functionalized glass fibers for surface-enhanced Raman scattering (SERS). Ag NPs were immobilized onto the surface of fibers through a two-step self-assembly process, and the cycling of the assembly process was repeated to optimize the SERS activity. The optimized fibers coated with homogeneous and dense Ag NPs were combined with a glass column, displaying good reproducibility. This combination could construct more "hot spots" and the spatial intra-channel structure for high mass transfer, and provide more sufficient interactions between the probing laser and metallic nanoparticles. The capability of the prepared column to have high sensitivity to dyes was demonstrated by the measurements of rhodamine 6G, alizarin red and methyl orange, with low concentrations of 28 pM, 64 pM and 0.36 nM, respectively. The SERS-active column fabricated by a facile, low-cost and high-yield approach is expected to be an effective and practical means for on-site application when rapid separation and detection of analytes in the liquid sample is needed. PMID- 26488908 TI - PEGylated Cu3BiS3 hollow nanospheres as a new photothermal agent for 980 nm-laser driven photothermochemotherapy and a contrast agent for X-ray computed tomography imaging. AB - Developing multifunctional near-infrared (NIR) light-driven photothermal agents is in high demand for efficient cancer therapy. Herein, PEGylated Cu3BiS3 hollow nanospheres (HNSs) with an average diameter of 80 nm were synthesized through a facile ethylene glycol-mediated solvothermal route. The obtained PEGylated Cu3BiS3 HNSs exhibited strong NIR optical absorption with a large molar extinction coefficient of 4.1 * 10(9) cm(-1) M(-1) at 980 nm. Under the irradiation of a 980 nm laser with a safe power density of 0.72 W cm(-2), Cu3BiS3 HNSs produced significant photothermal heating with a photothermal transduction efficiency of 27.5%. The Cu3BiS3 HNSs also showed a good antitumoral drug doxorubicin (DOX) loading capacity and pH- and NIR-responsive DOX release behaviors. At a low dosage of 10 MUg mL(-1), HeLa cells could be efficiently killed through a synergistic effect of chemo- and photothermo-therapy respectively based on the DOX release and the photothermal effect of Cu3BiS3 HNSs. In addition, Cu3BiS3 HNSs displayed a good X-ray computed tomography (CT) imaging capability. Furthermore, Cu3BiS3 HNSs could be used for efficient in vivo photothermochemotherapy and X-ray CT imaging of mice bearing melanoma skin cancer. This multifunctional theranostic nanomaterial shows potential promise for cancer therapy. PMID- 26488909 TI - Motivation to quit or reduce gambling: Associations between Self-Determination Theory and the Transtheoretical Model of Change. AB - Motivation for change and recovery from addiction has been commonly assessed using the Transtheoretical Model's stages of change. Analogous to readiness for change, this measure of motivation may not recognize other elements of motivation relevant to successful change. The aim of this study was to examine the relationship between stages of change and reasons for change according to the Self-Determination Theory among problem gamblers motivated to quit. Motivations for change were examined for 200 adult problem gamblers with intent to quit in the next 6 months (contemplation stage) or 30 days (preparation stage). Analyses revealed that higher autonomous motivation for quitting gambling predicted greater likelihood of being in the preparation stage, whereas those with higher external motivation for change were less likely to be farther along the stage of change continuum. The findings suggest that autonomous motivations relate to readiness for quitting gambling, and may predict successful resolution from problem gambling. PMID- 26488910 TI - Antimicrobial Resistance and Molecular Typing of Salmonella Stanley Isolated from Humans, Foods, and Environment. AB - Salmonella enterica serovar Stanley is an important serovar that has been increasingly identified in human salmonellosis. The present study aimed to investigate the antimicrobial resistance and molecular typing of 88 Salmonella Stanley strains isolated from humans (diarrhea patients, n = 64; and healthy carrier, n = 1), foods (aquatic products, n = 16; vegetable, n = 1; and pork, n = 1), and environment (waste water, n = 2; and river water, n = 3) in Shanghai, China from 2006 to 2012. Nearly half of the strains were resistant to sulfafurazole (43/88, 48.9%), and many were resistant to streptomycin (35/88, 39.8%), tetracycline (22/88, 25%), and nalidixic acid (19/88, 21.6%). Approximately a quarter of the strains (24/88, 27.3%) were resistant to more than three antimicrobials, and five had ACSSuT resistance type. Six clusters (A-F) were identified by pulsed-field gel electrophoresis (PFGE) with 80% similarity. Interestingly, strains in the same cluster identified by PFGE possessed similar antibiotic resistance patterns. PFGE typing also indicated that aquatic products might serve as a transmission reservoir for Salmonella Stanley infections in humans. PMID- 26488911 TI - Suppression of Sertoli cell tumour development during the first wave of spermatogenesis in inhibin alpha-deficient mice. AB - A dynamic partnership between follicle-stimulating hormone (FSH) and activin is required for normal Sertoli cell development and fertility. Disruptions to this partnership trigger Sertoli cells to deviate from their normal developmental pathway, as observed in inhibin alpha-knockout (Inha-KO) mice, which feature Sertoli cell tumours in adulthood. Here, we identified the developmental windows by which adult Sertoli cell tumourigenesis is most FSH sensitive. FSH was suppressed for 7 days in Inha-KO mice and wild-type littermates during the 1st, 2nd or 4th week after birth and culled in the 5th week to assess the effect on adult Sertoli cell development. Tumour growth was profoundly reduced in adult Inha-KO mice in response to FSH suppression during Weeks 1 and 2, but not Week 4. Proliferative Sertoli cells were markedly reduced in adult Inha-KO mice following FSH suppression during Weeks 1, 2 or 4, resulting in levels similar to those in wild-type mice, with greatest effect observed at the 2 week time point. Apoptotic Sertoli cells increased in adult Inha-KO mice after FSH suppression during Week 4. In conclusion, acute FSH suppression during the 1st or 2nd week after birth in Inha-KO mice profoundly suppresses Sertoli cell tumour progression, probably by inhibiting proliferation in the adult, with early postnatal Sertoli cells being most sensitive to FSH action. PMID- 26488912 TI - Nanocathodoluminescence Reveals Mitigation of the Stark Shift in InGaN Quantum Wells by Si Doping. AB - Nanocathodoluminescence reveals the spectral properties of individual InGaN quantum wells in high efficiency light emitting diodes. We observe a variation in the emission wavelength of each quantum well, in correlation with the Si dopant concentration in the quantum barriers. This is reproduced by band profile simulations, which reveal the reduction of the Stark shift in the quantum wells by Si doping. We demonstrate nanocathodoluminescence is a powerful technique to optimize doping in optoelectronic devices. PMID- 26488913 TI - Examining the Impact of Public Service Announcements on Help Seeking and Stigma: Results of a Randomized Controlled Trial. AB - Health communication campaigns often seek to diminish stigma and promote care seeking, with public service announcements (PSAs) frequently prominent in these campaigns. One example is the Australian-based beyondblue campaign. As an alternative approach, campaigns may seek to reduce stigma by promoting stories of recovery. Participants completed measures of stigmatizing and empowering attitudes at pre-, post-, and 72-hour follow-up after being randomized to a PSA recovery-oriented video, treatable disease-oriented video (beyondblue), or control. When exposed to the recovery-oriented PSA, participants showed significant reduction in stigmatizing attitudes from pre- to posttest than beyondblue or the control group with the emergence of nonsignificant trends identified at follow-up. Findings suggest a recovery-oriented video leads to better change on measures of stigma and affirming attitudes than beyondblue. Despite the aforementioned findings, results failed to show either the recovery or beyondblue videos had a significant impact on intent to seek treatment. PMID- 26488914 TI - Sleep Paralysis Among Egyptian College Students: Association With Anxiety Symptoms (PTSD, Trait Anxiety, Pathological Worry). AB - Among Egyptian college students in Cairo (n = 100), this study examined the relationship between sleep paralysis (SP) and anxiety symptoms, viz., posttraumatic stress disorder (PTSD), trait anxiety, and pathological worry. SP rates were high; 43% of participants reported at least one lifetime episode of SP, and 24% of those who reported at least one lifetime episode had experienced four or more episodes during the previous year. Fourteen percent of men had experienced SP as compared to 86% of women. As hypothesized, relative to non-SP experiencers, participants who had SP reported higher symptoms of PTSD, trait anxiety, and pathological worry. Also, as hypothesized, the experiencing of hypnogogic/hypnopompic hallucinations during SP, even after controlling for negative affect, was highly correlated with symptoms of PTSD and trait anxiety. The study also investigated possible mechanisms by examining the relationship of hallucinations to anxiety variables. PMID- 26488915 TI - Does Sense of Control Predict Depression Among Individuals After Psychiatric Hospital Discharge? AB - Sense of control is known to be related to depression. Yet, few studies have examined the role of sense of control as related to depression for discharged psychiatric patients. In this study the longitudinal relationship between sense of control and depressive mood was examined using the MacArthur Violence Risk Assessment Study, a 6-wave, 1-year study of 948 ethnically diverse postdischarge psychiatric patients. Sense of control was decomposed into 2 components (i.e., a time-invariant as well as a time-varying component) and so as to examine which component of sense of control would more accurately explain this relationship. Results demonstrated that time-varying sense of control significantly predicted changes in depressive mood during the transition to community environment. Time invariant sense of control, however, was not significantly related to changes in depressive mood. Findings of this study hold important implications for intervention practice with people before or after psychiatric discharge, including the need for incorporation of therapeutic and psychoeducational efforts that bolster sense of control. PMID- 26488917 TI - Exploring Attachment Patterns in Patients With Comorbid Borderline Personality and Substance Use Disorders. AB - Studies exploring attachment patterns in samples of patients with borderline personality disorder (BPD) report a combination of preoccupied and fearful avoidant patterns. This has been interpreted as reflecting the approach-avoidance dilemma of BPD. Comorbid substance use disorders (SUD) have not been considered in these studies, despite the high proportions of SUD among BPD patients and despite the more avoidant attachment in SUD samples. This cross-sectional, naturalistic study explores attachment patterns in a sample of comorbid (BPD and SUD) patients, comparing them to two samples of patients with either SUD or BPD only. Within-group comparisons replicated findings of both preoccupied and fearful-avoidant attachment in BPD and comorbid groups. But between-group comparisons showed that comorbid patients were significantly less preoccupied (p = 0.018) and more dismissing-avoidant (p = 0.030). Although both groups were similar in several psychiatric measures, attachment patterns of the comorbid group were more similar to substance abusers than to borderline patients. PMID- 26488916 TI - A Qualitative Study of Mental Health Problems Among Orphaned Children and Adolescents in Tanzania. AB - Low- and middle-income countries have a high number of orphans, many of whom have unmet mental health needs. Effective mental health interventions are needed; however, it is necessary to understand how mental health symptoms and needs are perceived locally to tailor interventions and refine measurement of intervention effects. We used an existing rapid ethnographic assessment approach to identify mental health problems from the perspective of orphans and guardians to inform a subsequent randomized controlled trial of a Western-developed, evidence-based psychosocial intervention, Trauma-focused Cognitive Behavioral Therapy. Local Kiswahili-speaking interviewers conducted 73 free list interviews and 34 key informant interviews. Results identified both common cross-cultural experiences and symptoms as well as uniquely described symptoms (e.g., lacking peace, being discriminated against) not typically targeted by the intervention or included on standardized measures of intervention effects. We discuss implications for adapting mental health interventions in low- and middle-income countries and assessing effectiveness. PMID- 26488918 TI - Extrasensory Perception Experiences and Childhood Trauma: A Rorschach Investigation. AB - This study investigated whether people who report recurrent extrasensory perception (ESP) experiences (telepathy, clairvoyance, and precognition) have suffered more traumatic experiences and traumatic intrusions. Thirty-one nonclinical participants reporting recurrent ESP experiences were compared with a nonclinical sample of 31 individuals who did not report recurrent ESP phenomena. Past traumatic experiences were assessed via a self-report measure of trauma history (Childhood Trauma Questionnaire); traumatic intrusions were assessed via a performance-based personality measure (Rorschach Traumatic Content Index). Participants also completed the Anomalous Experience Inventory, the Minnesota Multiphasic Personality Inventory-2, the Dissociative Experience Scale, and the Revised Paranormal Belief Scale. The ESP group reported higher levels of emotional abuse, sexual abuse, emotional neglect, physical neglect, and traumatic intrusions. The association between ESP experiences and trauma was partly mediated by the effects of dissociation and emotional distress. Implications for health professionals are discussed. Results also showed the reliability of the twofold method of assessment of trauma. PMID- 26488919 TI - Protein-Specific Imaging of O-GlcNAcylation in Single Cells. AB - Thousands of intracellular proteins are post-translationally modified with O GlcNAc, and O-GlcNAcylation impacts the function of modified proteins and mediates diverse biological processes. However, the ubiquity of this important glycosylation makes it highly challenging to probe the O-GlcNAcylation state of a specific protein at the cellular level. Herein, we report the development of a FLIM-FRET-based strategy, which exploits the spatial proximity of the O-GlcNAc moiety and the attaching protein, for protein-specific imaging of O-GlcNAcylation in single cells. We demonstrated this strategy by imaging the O-GlcNAcylation state of tau and beta-catenin inside the cells. Furthermore, the changes in tau O GlcNAcylation were monitored when the overall cellular O-GlcNAc was pharmacologically altered by using the OGT and OGA inhibitors. We envision that the FLIM-FRET strategy will be broadly applicable to probe the O-GlcNAcylation state of various proteins in the cells. PMID- 26488920 TI - The Supersized Class III Lanthipeptide Stackepeptin Displays Motif Multiplication in the Core Peptide. AB - Lanthipeptides are ribosomally synthesized and post-translationally modified peptides bearing the characteristic amino acids lanthionine and/or labionin. Here, we report on the discovery and characterization of the stackepeptins, produced by the Actinomycete Stackebrandtia nassauensis DSM-44728(T). The stackepeptins are the first supersized class III lanthipeptides to be discovered. Unlike other class III lanthipeptides, they consist of three lanthionine/labionin moieties instead of two. In this study, both in vivo and in vitro maturation of the peptides have been investigated. Studies involving the wild type strain showed culture medium-dependent production of three stackepeptins consisting of one common N-terminal labionin ring and varying dehydration and cyclization patterns in the C-terminal rings. On the other hand, in vitro assessment of the heterologously expressed modifying enzyme StaKC, yielded one major product with an N-terminal lanthionine and C-terminal labionins. The discrepancy between in vivo and in vitro processing was discovered to be sequence-dependent and also implies that in vivo processing is facilitated by additional factors in the cell. Furthermore, a Ser -> Ala scan revealed the importance of C-terminal ring formation for full in vitro maturation of the stackepeptins. StaKC showed promiscuity toward the phosphorylating cosubstrate with a significant preference for purine nucleotides. Finally, in contrast to other known class III lanthipeptides, in vitro experiments showed that the leader peptide might not be required for partial dehydration by the modifying enzyme. PMID- 26488922 TI - [Molecular Concepts of Immunomodulation for the Treatment of Metastatic Renal Cell Carcinomas: Where are We Now?]. AB - The introduction of molecular targeted agents has started to transform the treatment of metastatic renal cell carcinoma (mRCC), leading to a significant improvement of the prognosis of patients affected by that disease. However, treatment of metastatic disease still remains challenging as almost all patients will experience tumour progression and long-term survivors are very rare. This clearly warrants a continued search for improved treatment options. In recent years, the development of new substances and treatment approaches involving the targeted activation and modulation of the immune system have moved immunotherapy back into the focus of interest. A major development is the use of checkpoint inhibitors, which enable a targeted (re)activation of T cells. The following article describes the current methods used to improve standard treatment with the established targeted substances and discusses them along with the new immunooncological approaches of checkpoint modulation in the context of the treatment of mRCC patients. PMID- 26488921 TI - Protonation and Trapping of a Small pH-Sensitive Near-Infrared Fluorescent Molecule in the Acidic Tumor Environment Delineate Diverse Tumors in Vivo. AB - Enhanced glycolysis and poor perfusion in most solid malignant tumors create an acidic extracellular environment, which enhances tumor growth, invasion, and metastasis. Complex molecular systems have been explored for imaging and treating these tumors. Here, we report the development of a small molecule, LS662, that emits near-infrared (NIR) fluorescence upon protonation by the extracellular acidic pH environment of diverse solid tumors. Protonation of LS662 induces selective internalization into tumor cells and retention in the tumor microenvironment. Noninvasive NIR imaging demonstrates selective retention of the pH sensor in diverse tumors, and two-photon microscopy of ex vivo tumors reveals significant retention of LS662 in tumor cells and the acid tumor microenvironment. Passive and active internalization processes combine to enhance NIR fluorescence in tumors over time. The low background fluorescence allows tumors to be detected with high sensitivity, as well as dead or dying cells to be delineated from healthy cells. In addition to demonstrating the feasibility of using small molecule pH sensors to image multiple aggressive solid tumor types via a protonation-induced internalization and retention pathway, the study reveals the potential of using LS662 to monitor treatment response and tumor targeted drug delivery. PMID- 26488923 TI - Red Blood Cell Membrane as a Biomimetic Nanocoating for Prolonged Circulation Time and Reduced Accelerated Blood Clearance. AB - For decades, poly(ethylene glycol) (PEG) has been widely incorporated into nanoparticles for evading immune clearance and improving the systematic circulation time. However, recent studies have reported a phenomenon known as "accelerated blood clearance (ABC)" where a second dose of PEGylated nanomaterials is rapidly cleared when given several days after the first dose. Herein, we demonstrate that natural red blood cell (RBC) membrane is a superior alternative to PEG. Biomimetic RBC membrane-coated Fe(3)O(4) nanoparticles (Fe(3)O(4) @RBC NPs) rely on CD47, which is a "don't eat me" marker on the RBC surface, to escape immune clearance through interactions with the signal regulatory protein-alpha (SIRP-alpha) receptor. Fe(3)O(4) @RBC NPs exhibit extended circulation time and show little change between the first and second doses, with no ABC suffered. In addition, the administration of Fe(3)O(4) @RBC NPs does not elicit immune responses on neither the cellular level (myeloid derived suppressor cells (MDSCs)) nor the humoral level (immunoglobulin M and G (IgM and IgG)). Finally, the in vivo toxicity of these cell membrane-camouflaged nanoparticles is systematically investigated by blood biochemistry, hematology testing, and histology analysis. These findings are significant advancements toward solving the long-existing clinical challenges of developing biomaterials that are able to resist both immune response and rapid clearance. PMID- 26488924 TI - A Facile Surface Passivation of Hematite Photoanodes with TiO2 Overlayers for Efficient Solar Water Splitting. AB - The surface modification of semiconductor photoelectrodes with passivation overlayers has recently attracted great attention as an effective strategy to improve the charge-separation and charge-transfer processes across semiconductor liquid interfaces. It is usually carried out by employing the sophisticated atomic layer deposition technique, which relies on reactive and expensive metalorganic compounds and vacuum processing, both of which are significant obstacles toward large-scale applications. In this paper, a facile water-based solution method has been developed for the modification of nanostructured hematite photoanode with TiO2 overlayers using a water-soluble titanium complex (i.e., titanium bis(ammonium lactate) dihydroxide, TALH). The thus-fabricated nanostructured hematite photoanodes have been characterized by X-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy. Photoelectrochemical measurements indicated that a nanostructured hematite photoanodes modified with a TiO2 overlayer exhibited a photocurrent response ca. 4.5 times higher (i.e., 1.2 mA cm(-2) vs RHE) than that obtained on the bare hematite photoanode (i.e., 0.27 mA cm(-2) vs RHE) measured under standard illumination conditions. Moreover, a cathodic shift of ca. 190 mV in the water oxidation onset potential was achieved. These results are discussed and explored on the basis of steady-state polarization, transient photocurrent response, open circuit potential, intensity-modulated photocurrent spectroscopy, and impedance spectroscopy measurements. It is concluded that the TiO2 overlayer passivates the surface states and suppresses the surface electron-hole recombination, thus increasing the generated photovoltage and the band bending. The present method for the hematite electrode modification with a TiO2 overlayer is effective and simple and might find broad applications in the development of stable and high performance photoelectrodes. PMID- 26488925 TI - Electric Destabilization of Supramolecular Lipid Vesicles Subjected to Fast Electric Pulses. AB - Biological membranes are weakly permeable to hydrophilic molecules and ions and electric pulses can induce their transient permeabilization, but this process is not well characterized. We directly assay the electropermeabilization process, on the minimum model of lipid vesicles, by using a highly sensitive fluorescence method based on manganese ion transport. The approach gives access, at the single lipid self-assembly level, to the transmembrane potential needed to detect divalent ion permeabilization on supramolecular giant unilamellar lipid vesicles. The critical values are strongly dependent on the lipid composition and are observed to vary from 10 to 150 mV. These values appear to be much lower than those previously reported in the literature for cells and vesicles. The detection method appears to be a decisive parameter as it is controlled by the transport of the reporter dye. We also provide evidence that the electropermeabilization process is a transient transition of the lipid self-organization due to the loss of assembly cohesion induced by bioelectrochemical perturbations of the zwitterionic interface with the solution. PMID- 26488926 TI - [Evidences 2015]. PMID- 26488927 TI - [The assessment of the effectiveness of long vs standard-length catheters in reducing complications: a randomized controlled trial]. AB - INTRODUCTION: From 30 to 80% of hospitalized patients is inserted a peripheral venous catheter (PVC). The PVC may be associated to several infective and non infective complications. AIMS: To assess whether a long-length vs standard-length PCV reduces the incidence of CRCs; to assess the patients' preferences and costs. METHODS: Randomized clinical trial on 211 patients (339 cannulas) admitted to an emergency medical and surgical wards. Patients were included if >18 years and prescribed a PVC. After the randomization the PVC were inspected daily, until removal. RESULTS: 186 complications occurred with the standard CVPs vs 16 with the midline, per 1000 catheter days; 47 phlebitis were observed in patients with standard PVCs vs none in those with midline; also infiltrations (66 vs 2 per 1000 catheter days), asymptomatic thromboses (34 vs 7 per 1000 catheter days), occlusions and accidental removals were greatly reduced. The higher cost of midline is counterbalanced by the complications prevented. In addition midline patients referred less limitations (96% vs 50.7%) and an higher satisfaction (91.9% vs 53.7%). CONCLUSIONS: The midline catheters radically reduce PVC associated complications, are preferred by patients and the higher costs should be weighted against the complications avoided. PMID- 26488928 TI - [The impact of closed system and 7 days intravascular administration set replacement on catheter related infections in a general intensive care unit: a before-after study]. AB - INTRODUCTION: The incidence of catheter related Bloodstream infections (BSI) is high in intensive care units (ICU). AIM: To evaluate the BSI rate in a population of patients admitted to a General ICU before and after the implementation of the 2011 CDC guidelines. METHODS: Retrospective observational study on patients admitted from January 2009 to December 2013. The infusion and monitoring lines were changed every 96 hours for the first 30 months, and every 7 days for the next 30. In all patients a closed infusion line with needle-free connectors pressure was used (Microclave). The following catheters were considered in the study: central venous catheter (CVC), arterial cannula (ART) and Swan Ganz catheter (SG). RESULTS: During the period with change every 96 hours 15 BSI were observed over 13395 catheters/days (C/D), 1.12 per 1000 C/D, while when lines where changed every 7 days 11 BSI were observed over 13120 C/D, 0.83 per 1000 C/D. A statistically significant reduction of BSI was observed in SG catheters (4.17 vs. no BSI p = 0.02), while the CVCS (1.12 vs 1.45 - p = 0.37) and ART (0.35 vs 0.36 - p = 0.61) infection rates remained unchanged. CONCLUSIONS: The replacement of infusion lines every 7 days in our sample did not increase the BSI, helping to reduce the costs. PMID- 26488929 TI - [Post-dural puncture headache: risk factors, associated variables and interventions]. AB - AIM: To identify nurses' doubts and questions (about lumbar puncture, related nursing interventions and post-dural puncture headache - PDPH) and to find answers in the available literature. METHODS: 26 nurses were asked to identify open questions and a literature review was conducted searching on Medline, Cochrane database of Systematic Reviews and Cinahl. RESULTS: Atraumatic needles, small gauge, cranial bevel oriented insertion and stylet reinsertion are variables that reduce the risk of PDPH. Bed rest has no efficacy in reducing this complication. On the contrary, it may increase the risk of PDPH. There are not enough evidences about the efficacy of additional fluid intake after the procedure. It's not clear if the risk of PDPH could be affected by the position during lumbar puncture and the volume of cerebrospinal fluid withdrawn. CONCLUSIONS: This literature review clarifies some aspects of lumbar puncture and PDPH: the use of traumatic or atraumatic needles, the bevel orientation and stylet reinsertion, bed rest. More research is needed to study the efficacy of other interventions, still uncertain (patient position during the procedure, volume of cerebrospinal fluid withdrawn, hydration and analgesic drugs' efficacy). PMID- 26488930 TI - [The emotional labor of nursing: critical incidents and coping strategies]. AB - INTRODUCTION: Despite the suggestion to adopt a balanced approach between detachment and involvement, the nurse-patient relationship is always embedded with emotional conflicts. AIMS: To collect data on how nurses manage the emotional support to patients. METHOD: The study adopted the theoretical perspective of the emotional work. Fifty-three nurses completed a questionnaire investigating everyday "emotional accidents." The data were analyzed considering the strategies employed to address and resolve them. RESULTS: All nurses exert an emotional work to try to outcome the dissonance between subjective emotions and emotional rules required by the professional role. There are three strategies: normalizing, regressive, transformative. Most of the emotional efforts are aimed at showing emotions in accordance with the role, even if they are dissonant with respect to the subjective feelings (surface acting). CONCLUSIONS: Nurses are expected to practice an "emotional neutrality", but their profession continually exposes them to a heavy emotional work that may be at the basis of emotional exhaustion and burnout. Strategies should be adopted to prevent stress and health damages. PMID- 26488931 TI - [Elderly, drugs, nursing homes: when settings matter more than problems]. PMID- 26488932 TI - [The new drugs of 2014: what is worthwile saving]. PMID- 26488934 TI - The association between hot flushes and smoking in midlife women: a meta analysis. AB - BACKGROUND: Several epidemiological studies have investigated the association between hot flushes and smoking, but the results are inconsistent. This meta analysis was performed to estimate an overall effect of former smoking and current smoking on the risk of hot flushes in midlife women. METHODS: We searched PubMed, Web of Science, and Scopus for observational studies addressing the association between hot flushes and smoking until March 2015. Data were independently extracted and analyzed using odds ratio with 95% confidence intervals (CI) based on the random-effects model. RESULTS: We identified 621 references and included eight studies with 27 054 participants. The odds ratio of an association between hot flushes and former smoking was estimated as 1.31 (95% CI 1.22-1.41) and that of current smoking was estimated as 1.97 (95% CI 1.81 2.14). No evidence of heterogeneity and publication bias was observed. CONCLUSION: The findings from this meta-analysis indicated that former and current smoking are associated with an increased risk of hot flushes. However, more evidence based on large, prospective cohort studies is required to provide stronger evidence whether former and current smoking may be associated with an increased risk of hot flushes. PMID- 26488935 TI - Evaluation of the correlation between body mass index and endometriosis among Iranian fertile women. AB - AIMS: The investigations have revealed an inverse correlation between body mass index (BMI) and endometriosis. Endometriosis is a common gynecological disease among women of reproductive age, which is defined as the implantation of endometrial glands and stroma outside the uterus. In this respect, we aimed to study the correlation between endometriosis and BMI in Iranian fertile women. METHODS: In a case-control design, 46 fertile women with endometriosis and 53 matched controls were recruited. All of the patients had a laparoscopy or laparotomy surgery and histologically confirmed endometriosis. The control group was selected from healthy volunteers who referred to gynecologist for tubal ligation or surgery of benign gynecological diseases. The participants were interviewed based on a structured questionnaire which covered inquiries regarding demographics, reproductive and menstrual history. RESULTS: Statistical analysis was performed by categorizing the BMI to four main groups: >30, 25-29.9, 18.5 24.9 and <18.5. The results showed a significant inverse correlation between BMI and endometriosis (p = 0.039). BMI over 30 was observed in 26% of healthy controls versus 13% of endometriosis patients. On the other hand, BMI under 18.5 were detected in 3 individuals, all of them belonged to the endometriosis group. DISCUSSION: Recent investigations have emphasized the role of BMI in endometriosis. The results of this study suggest that lower BMI is associated with an increased risk of endometriosis. As a parameter easily obtained, BMI may be useful for risk assessment of endometriosis. PMID- 26488936 TI - Clinical presentation and treatment responses in IgM-related AL amyloidosis. AB - Amyloid light-chain (AL) amyloidosis is a multi-organ disease due to deposition of misfolded monoclonal immunoglobulin light chains. IgM AL amyloidosis is a rare variant, about 6% of AL amyloidosis cases, and more data are needed for treatment guidance. In IgM AL amyloidosis, the clonal cell of origin may be a plasma or lymphoplasmacytic cell, and treatments targeting each are employed. We describe presenting clinical and laboratory features of 95 patients with IgM AL amyloidosis treated at Boston University Amyloidosis Center from 1996 to 2012. The median diagnosis age was 66 years (range: 38-89) with 56% males. Organ involvement rates were: kidney (51%); heart (40%); lymph nodes (25%) and gastrointestinal tract (17%). Treatment responses were analyzed for 46 patients seen after 2003. Five treatment regimens were assigned by bone marrow pathology and patient-specific factors. Overall hematologic response rates and very good partial or complete hematologic response rates, respectively, were: high-dose melphalan/stem cell transplant (HDM/SCT) 100%;80%, Bortezomib 82%;27%, Rituximab 80%;27%, immunomodulatory agents (IMids) 75%;0%, and standard dose alkylating agents (Melphalan or cyclophosphamide) 63%;19%. Overall, 5-year survival rates were significantly higher in patients with a hematological response: 79.2 +/- 8.5% versus 41 +/- 14.9% in non-responders, which is more favorable than typically expected in AL amyloidosis. PMID- 26488937 TI - RmtC and RmtF 16S rRNA Methyltransferase in NDM-1-Producing Pseudomonas aeruginosa. AB - We investigated 16S rRNA methyltransferases in 38 blaNDM-1-positive Pseudomonas aeruginosa isolates and found RmtC in 3 isolates, 1 of which also harbored RmtF. The isolates were clonally unrelated; rmtC and rmtF genes were located on a chromosome with the blaNDM-1 gene. Strategies are needed to limit the spread of such isolates. PMID- 26488940 TI - Pediatric Thoracoscopy and Bronchial Blockers: The Continued Search for the Ideal One-Lung Ventilation. AB - INTRODUCTION: Thoracoscopic surgical procedures in small infants and children require a growing demand for lung isolation in pediatric anesthesia practice. MATERIALS AND METHODS: Between January 2006 and September 2014, 16 children underwent thoracoscopic procedures that needed one-lung ventilation using a bronchial blocker. RESULTS: The thoracoscopic procedure was performed at a mean age of 99 months (range, 6-186 months) and a mean weight of 33 kg (range, 7-68 kg) without any conversion to open surgery in any case. We were able to achieve one-lung ventilation in all patients. The quality of lung deflation was excellent in all patients except in 1 due to malposition of the bronchial blocker, whereas dislodgement of this device occurred in 2 cases. CONCLUSIONS: The use of a bronchial blocker provided a highly effective means of one-lung ventilation for children undergoing the thoracoscopic approach. PMID- 26488939 TI - Expression of histone methyltransferases as novel biomarkers for renal cell tumor diagnosis and prognostication. AB - Renal cell tumors (RCTs) are the most lethal of the common urological cancers. The widespread use of imaging entailed an increased detection of small renal masses, emphasizing the need for accurate distinction between benign and malignant RCTs, which is critical for adequate therapeutic management. Histone methylation has been implicated in renal tumorigenesis, but its potential clinical value as RCT biomarker remains mostly unexplored. Hence, the main goal of this study was to identify differentially expressed histone methyltransferases (HMTs) and histone demethylases (HDMs) that might prove useful for RCT diagnosis and prognostication, emphasizing the discrimination between oncocytoma (a benign tumor) and renal cell carcinoma (RCC), especially the chromophobe subtype (chRCC). We found that the expression levels of 3 genes--SMYD2, SETD3, and NO66- was significantly altered in a set of RCTs, which was further validated in a large independent cohort. Higher expression levels were found in RCTs compared to normal renal tissues (RNTs) and in chRCCs comparatively to oncocytomas. SMYD2 and SETD3 mRNA levels correlated with protein expression assessed by immunohistochemistry. SMYD2 transcript levels discriminated RCTs from RNT, with 82.1% sensitivity and 100% specificity [area under curve (AUC) = 0.959], and distinguished chRCCs from oncocytomas, with 71.0% sensitivity and 73.3% specificity (AUC = 0.784). Low expression levels of SMYD2, SETD3, and NO66 were significantly associated with shorter disease-specific and disease-free survival, especially in patients with non-organ confined tumors. We conclude that expression of selected HMTs and HDMs might constitute novel biomarkers to assist in RCT diagnosis and assessment of tumor aggressiveness. PMID- 26488941 TI - Late-onset hypogonadism: the advantages of treatment with human chorionic gonadotropin rather than testosterone. AB - The traditional pharmacological treatment of patients with late onset hypogonadism (LOH) is represented by different formulations of testosterone (T) or alternatively by the extractive human chorionic gonadotropin (HCG). The hormone replacement treatment (HRT) is associated with the potential increase of hematocrit, serum concentrations of prostate-specific antigen (PSA) and prostate volume. Moreover, the gynecomastia represent a condition frequently associated with HRT. Recent evidences showed the role of leydig cells in the 25 hydroxylation of vitamin D and the elevated frequency of hypovitaminosis D among LOH patients. Finally, another important aspect of LOH is represented by the frequency of secondary infertility due to age or to traditional HRT. This study evaluated 40 LOH patients treated for 6 months with extractive HCG (n = 10 patients) and three different formulations of T: transdermal (n = 10 patients), undecaonate (n = 10 patients) and enantate (n = 10 patients). Hormonal, anthropometric, metabolic and sperm parameters were evaluated and compared. Moreover, the main safety parameters and the results of the main questionnaires were evaluated. After treatment, HCG group showed serum concentrations of 25-OH vitamin D significantly higher (p < 0.05) and serum concentrations of oestrogens significantly lower (p < 0.05) compared with other groups. Moreover, they showed a mean value of hematocrit, PSA and prostate volume significantly lower (p < 0.05) compared with other groups. Finally, all the groups treated with T showed a significant reduction (p < 0.05) of sperm density and of percentage of spermatozoa with progressive motility compared with HCG group. PMID- 26488942 TI - Abnormal Methylation Status of the GNAS Exon 1A Region in Pseudohypohyperparathyroidism Combined With Turner Syndrome. AB - Pseudohypohyperparathyroidism (PHHP) is a rare type of pseudohypoparathyroidism (PHP), which seems to have a normal skeletal response to parathyroid hormone but shows renal resistance. Almost all patients with PHHP have PHP Ib, a subtype of PHP that is usually caused by GNAS methylation defects, often in exon 1A. Some features of Albright hereditary osteodystrophy can occasionally be found in patients with PHHP, but these features are also common in Turner syndrome. The authors report on an extremely rare case of a patient with PHHP and Turner syndrome, a 47-year-old woman who sought medical attention for hypocalcemia and elevated parathyroid hormone. She had no family history of hypocalcemia and no STX16 gene deletions. She had a mosaic karyotype of 46, X, del(X)(p11.4)/45, XO. Pyrosequencing was performed to determine the GNAS exon 1A methylation. The degree of methylation found in exon 1A of the patient was lower than her unaffected relatives. PMID- 26488938 TI - Interventions to improve water quality for preventing diarrhoea. AB - BACKGROUND: Diarrhoea is a major cause of death and disease, especially among young children in low-income countries. In these settings, many infectious agents associated with diarrhoea are spread through water contaminated with faeces.In remote and low-income settings, source-based water quality improvement includes providing protected groundwater (springs, wells, and bore holes), or harvested rainwater as an alternative to surface sources (rivers and lakes). Point-of-use water quality improvement interventions include boiling, chlorination, flocculation, filtration, or solar disinfection, mainly conducted at home. OBJECTIVES: To assess the effectiveness of interventions to improve water quality for preventing diarrhoea. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register (11 November 2014), CENTRAL (the Cochrane Library, 7 November 2014), MEDLINE (1966 to 10 November 2014), EMBASE (1974 to 10 November 2014), and LILACS (1982 to 7 November 2014). We also handsearched relevant conference proceedings, contacted researchers and organizations working in the field, and checked references from identified studies through 11 November 2014. SELECTION CRITERIA: Randomized controlled trials (RCTs), quasi-RCTs, and controlled before-and-after studies (CBA) comparing interventions aimed at improving the microbiological quality of drinking water with no intervention in children and adults. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We used meta-analyses to estimate pooled measures of effect, where appropriate, and investigated potential sources of heterogeneity using subgroup analyses. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: Forty-five cluster-RCTs, two quasi-RCTs, and eight CBA studies, including over 84,000 participants, met the inclusion criteria. Most included studies were conducted in low- or middle-income countries (LMICs) (50 studies) with unimproved water sources (30 studies) and unimproved or unclear sanitation (34 studies). The primary outcome in most studies was self-reported diarrhoea, which is at high risk of bias due to the lack of blinding in over 80% of the included studies. Source-based water quality improvementsThere is currently insufficient evidence to know if source-based improvements such as protected wells, communal tap stands, or chlorination/filtration of community sources consistently reduce diarrhoea (one cluster-RCT, five CBA studies, very low quality evidence). We found no studies evaluating reliable piped-in water supplies delivered to households. Point-of-use water quality interventionsOn average, distributing water disinfection products for use at the household level may reduce diarrhoea by around one quarter (Home chlorination products: RR 0.77, 95% CI 0.65 to 0.91; 14 trials, 30,746 participants, low quality evidence; flocculation and disinfection sachets: RR 0.69, 95% CI 0.58 to 0.82, four trials, 11,788 participants, moderate quality evidence). However, there was substantial heterogeneity in the size of the effect estimates between individual studies.Point-of-use filtration systems probably reduce diarrhoea by around a half (RR 0.48, 95% CI 0.38 to 0.59, 18 trials, 15,582 participants, moderate quality evidence). Important reductions in diarrhoea episodes were shown with ceramic filters, biosand systems and LifeStraw(r) filters; (Ceramic: RR 0.39, 95% CI 0.28 to 0.53; eight trials, 5763 participants, moderate quality evidence; Biosand: RR 0.47, 95% CI 0.39 to 0.57; four trials, 5504 participants, moderate quality evidence; LifeStraw(r): RR 0.69, 95% CI 0.51 to 0.93; three trials, 3259 participants, low quality evidence). Plumbed in filters have only been evaluated in high-income settings (RR 0.81, 95% CI 0.71 to 0.94, three trials, 1056 participants, fixed effects model).In low income settings, solar water disinfection (SODIS) by distribution of plastic bottles with instructions to leave filled bottles in direct sunlight for at least six hours before drinking probably reduces diarrhoea by around a third (RR 0.62, 95% CI 0.42 to 0.94; four trials, 3460 participants, moderate quality evidence).In subgroup analyses, larger effects were seen in trials with higher adherence, and trials that provided a safe storage container. In most cases, the reduction in diarrhoea shown in the studies was evident in settings with improved and unimproved water sources and sanitation. AUTHORS' CONCLUSIONS: Interventions that address the microbial contamination of water at the point-of-use may be important interim measures to improve drinking water quality until homes can be reached with safe, reliable, piped-in water connections. The average estimates of effect for each individual point-of-use intervention generally show important effects. Comparisons between these estimates do not provide evidence of superiority of one intervention over another, as such comparisons are confounded by the study setting, design, and population.Further studies assessing the effects of household connections and chlorination at the point of delivery will help improve our knowledge base. As evidence suggests effectiveness improves with adherence, studies assessing programmatic approaches to optimising coverage and long-term utilization of these interventions among vulnerable populations could also help strategies to improve health outcomes. PMID- 26488944 TI - Meningoencephalitis Following Ipilimumab Administration in Metastatic Melanoma. PMID- 26488943 TI - Farnesoid X Receptor Expression Reduced in Obese Rat Model With Insulin Resistance. AB - BACKGROUND: Farnesoid X receptor (FXR) plays important roles in regulation of lipid, glucose and energy metabolism. The aim of the study was to observe expression level of FXR in obese rat models with insulin (INS) resistance. METHODS: A total of 100 Wistar male rats were randomly assigned to either standard diet (n = 20) or high-fat diet (HFD, n = 80) for 6 weeks. Oral glucose tolerance tests were administrated, and the extent of INS resistance was assessed at the end of the 6th weeks. In addition, the expression of FXR in the liver was tested by techniques of reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: Obese rats in HFD group showed elevated body weight, area under blood glucose curve, fasting INS, total cholesterol, low density lipoproteins and serum bile acid levels compared with rats in standard diet group (P < 0.05). The level of INS remained high at all time points after the INS injection in oral glucose tolerance tests. As for FXR expression levels, a nearly 50% reduction was calculated in the liver of HFD rats compared with rats fed normal diet. CONCLUSIONS: FXR is decreased in obese animal models associated with INS resistance. Regulation of bile acids and FXR in the stage of obesity may prevent more metabolism disorders. PMID- 26488945 TI - Frequency and Etiology of Ventilator-Associated Events in the Medical Intensive Care Unit. AB - BACKGROUND: The Centers for Disease Control and Prevention (CDC) has developed new criteria based on a significant deterioration in oxygenation to identify ventilator-associated events (conditions). The aim of this study was to determine how frequently this happened and what caused these conditions. METHODS: Electronic medical records and x-rays from 281 ventilator episodes in the medical intensive care unit were reviewed to determine the characteristics of patients requiring ventilation and the number of patients meeting the criteria for ventilator-associated conditions (VACs). RESULTS: This cohort included 257 patients (55.4% men) who required 281 episodes of mechanical ventilation. The mean Acute Physiology and Chronic Healthy Evaluation II score was 13.5 +/- 5.9. The initial mean PaO2/FiO2 was 210 +/- 110. The median number of ventilator days was 4 (interquartile range: 3-9). The overall mortality was 32.3%. Nineteen patients (11.7% of eligible episodes) met the CDC criteria for a VAC; 6 met FiO2 criteria (31.6%) and 13 met positive end expiratory pressure criteria (68.4%). Twelve patients (63.2%) had an increased white blood cell count (>12k/MUL) during the event. Eleven patients had an increase in temperature (>38 degrees C) during this period. The etiology of these conditions included pneumonia (n = 4), atelectasis (n = 4), congestive heart failure (n = 5), acute respiratory distress syndrome (n = 2), and miscellaneous reasons (n = 4). CONCLUSIONS: VACs occurred in 11.7% of patients in our medical intensive care unit. The etiology of these events was diverse and did not usually reflect complications. These new CDC criteria for institutional reporting of complications during mechanical ventilation do not necessarily identify complications or provide a good method for comparing outcomes in hospitals. PMID- 26488946 TI - Cutaneous Colon Metastases Mimicking Elefantiasis Verrucosa Nostra. PMID- 26488948 TI - Are NHS race equality policies up to standard? PMID- 26488947 TI - The Effect of Community-Based Specialist Palliative Care Teams on Place of Care. AB - BACKGROUND: Prior research on community-based specialist palliative care teams used outcome measures of place of death and/or dichotomous outcome measures of acute care use in the last two weeks of life. However, existing research seldom measured the diverse places of care used and their timing prior to death. OBJECTIVE: The study objective was to examine the place of care in the last 30 days of life. METHODS: In this retrospective cohort study, patients who received care from a specialist palliative care team (exposed) were matched by propensity score to patients who received usual care in the community (unexposed) in Ontario, Canada. Measured was the percentage of patients in each place of care in the last month of life as a proportion of the total cohort. RESULTS: After matching, 3109 patients were identified in each group, where 79% had cancer and 77% received end-of-life home care. At 30 days compared to 7 days before death, the exposed group's proportions rose from 33% to 41% receiving home care and 14% to 15% in hospital, whereas the unexposed group's proportions rose from 28% to 32% receiving home care and 16% to 22% in hospital. Linear trend analysis (proportion over time) showed that the exposed group used significantly more home care services and fewer hospital days (p < 0.001) than the unexposed group. On the last day of life (place of death), the exposed group had 18% die in an in patient hospital bed compared to 29% in usual care. CONCLUSION: Examining place of care in the last month can effectively illustrate the service use trajectory over time. PMID- 26488949 TI - Advice to be 'flexible' on staffing ratios could backfire, says RCN. PMID- 26488950 TI - Kline slams managers' race record. PMID- 26488951 TI - Capping agency staff rates 'will not resolve huge financial deficits'. PMID- 26488952 TI - Nursing put on shortage occupancy list for visas. PMID- 26488953 TI - Pauline Cafferkey's condition improves after Ebola relapse. PMID- 26488954 TI - Nurses awarded royal honours. PMID- 26488955 TI - CQC report on standards of care finds safety is the biggest concern. PMID- 26488956 TI - Hospitals should do more to reduce incidence of falls, says RCP report. PMID- 26488957 TI - Positive portraits for older people's unit. PMID- 26488958 TI - Nurse peer joins the House of Lords. PMID- 26488960 TI - RCN rejects a return to second level nursing roles. PMID- 26488961 TI - Running the rule over revalidation: how does the system measure up? PMID- 26488967 TI - Cardiovascular disease. PMID- 26488968 TI - 'I want nurses to flourish in all areas'. PMID- 26488969 TI - At what age are you too old to treat? PMID- 26488970 TI - Specialty that boosts survival. PMID- 26488981 TI - NICE BNF. PMID- 26488983 TI - Celebration of black history is as relevant now as ever. PMID- 26488984 TI - Every general practice should appoint a carers' champion. PMID- 26488985 TI - Safe staffing is much too important to be treated like a children's game. PMID- 26488986 TI - Time for reflection is a strength of the revalidation process. PMID- 26488987 TI - Poor choice of words to describe mental health therapy. PMID- 26488989 TI - The first nurses to revalidate won't have years to prepare. PMID- 26488990 TI - BME contribution would remain 'invisible' without this month. PMID- 26488992 TI - How to administer intramuscular injections. PMID- 26488993 TI - Thrombolysis for patients with acute ischaemic stroke. AB - Stroke is the leading cause of physical disability, and thrombolysis is a promising treatment for acute ischaemic stroke. Alteplase has significant benefits for patients if it is administered within four and a half hours of stroke onset. This article uses a case study approach to explore a patient's journey through admission, triage, eligibility and administration of alteplase therapy. It emphasises the post-monitoring role of the nurse. PMID- 26488994 TI - Prevention and management of comorbid diabetes and depression. AB - As the population ages, an increasing number of people are developing long-term conditions. This is a challenge for healthcare systems in terms of funding and support, and comorbidities add to the economic burden. This article considers the comorbid conditions diabetes and depression, which healthcare professionals increasingly encounter in clinical practice. It explores the reasons why diabetes and depression are associated, the influencing factors, and the bidirectional causes of diabetes and depression. In addition, the effects that a diagnosis of depression might have on a person having difficulty managing their diabetes are examined, and potential treatment strategies identified. PMID- 26488995 TI - Communication. PMID- 26488996 TI - Managing venous leg ulcers and oedema using compression hosiery. AB - Increasing demand for services and rising costs in the NHS have resulted in reduced consultation times and resources for clinicians when treating patients with compression therapy. This article emphasises the importance of considering alternative treatment approaches, while encouraging patient choice, independence and self-care. One alternative treatment is the use of compression hosiery kits for the management of venous leg ulceration and oedema. PMID- 26488997 TI - Efficiency and cost effectiveness of negative pressure wound therapy. AB - Negative pressure wound therapy can be used to treat wounds of varying aetiology. This article presents findings of a literature review investigating the efficiency and cost effectiveness of this form of therapy. Since negative pressure wound therapy is becoming more common, it is important to understand the evidence base for its use to ensure optimum care outcomes for patients and cost effectiveness. PMID- 26488998 TI - Making the trial run. PMID- 26489000 TI - Let's sit down and talk about it. PMID- 26489001 TI - Five steps to work happiness. PMID- 26489002 TI - A lack of understanding? PMID- 26489003 TI - Genetic and/or non-genetic causes for inter-individual and inter-cellular variability in transporter protein expression: implications for understanding drug efficacy and toxicity. AB - INTRODUCTION: Drug transporters are differentially expressed in many polarized tissues. The varied distribution and expression of transporters determines the net transcellular transport and influences the disposition of many clinically used drugs. ATP-binding cassette (ABC) and Solute Carrier (SLC) transporters interact dynamically to mediate the passage of drugs across cells. The variable expression of drug transporters could be attributed to genetic and non-genetic factors, which accounts for the differences in drug response among individuals, in terms of both efficacy and adverse effects. AREAS COVERED: The authors provide the background of ABC and SLC transporters, and highlight the fact that their expression is cell-specific and the study of a transporter in isolation is not an adequate measure of its function. The technologies and approaches to characterize the function of transporters, as well as the genetic and non-genetic factors underlying their variable expression in specific cells and among individuals were reviewed. EXPERT OPINION: Many studies have utilized tissue homogenization techniques to isolate mRNA for quantifying transporter expression levels. We highlight that transporter expression is cell-specific and mRNA expression does not always reflect its total functionality. In addition, transporter expression in immortalized cell lines may not mirror its expression in the target tissue site. PMID- 26489004 TI - Mycobacterium sherrisii Pulmonary Disease, Burkina Faso. PMID- 26489005 TI - Simple Chemical Solution Deposition of Co3O4 Thin Film Electrocatalyst for Oxygen Evolution Reaction. AB - Oxygen evolution reaction (OER) is the key reaction in electrochemical processes, such as water splitting, metal-air batteries, and solar fuel production. Herein, we developed a facile chemical solution deposition method to prepare a highly active Co3O4 thin film electrode for OER, showing a low overpotential of 377 mV at 10 mA/cm(2) with good stability. An optimal loading of ethyl cellulose additive in a precursor solution was found to be essential for the morphology control and thus its electrocatalytic activity. Our results also show that the distribution of Co3O4 nanoparticle catalysts on the substrate is crucial in enhancing the inherent OER catalytic performance. PMID- 26489006 TI - Key Amino Acids in the Bacterial (6-4) Photolyase PhrB from Agrobacterium fabrum. AB - Photolyases can repair pyrimidine dimers on the DNA that are formed during UV irradiation. PhrB from Agrobacterium fabrum represents a new group of prokaryotic (6-4) photolyases which contain an iron-sulfur cluster and a DMRL chromophore. We performed site-directed mutagenesis in order to assess the role of particular amino acid residues in photorepair and photoreduction, during which the FAD chromophore converts from the oxidized to the enzymatically active, reduced form. Our study showed that Trp342 and Trp390 serve as electron transmitters. In the H366A mutant repair activity was lost, which points to a significant role of His366 in the protonation of the lesion, as discussed for the homolog in eukaryotic (6-4) photolyases. Mutants on cysteines that coordinate the Fe-S cluster of PhrB were either insoluble or not expressed. The same result was found for proteins with a truncated C-terminus, in which one of the Fe-S binding cysteines was mutated and for expression in minimal medium with limited Fe concentrations. We therefore assume that the Fe-S cluster is required for protein stability. We further mutated conserved tyrosines that are located between the DNA lesion and the Fe-S cluster. Mutagenesis results showed that Tyr424 was essential for lesion binding and repair, and Tyr430 was required for efficient repair. The results point to an important function of highly conserved tyrosines in prokaryotic (6-4) photolyases. PMID- 26489007 TI - Renoprotective Mechanism of Remote Ischemic Preconditioning Based on Transcriptomic Analysis in a Porcine Renal Ischemia Reperfusion Injury Model. AB - Ischemic preconditioning (IPC) is a well-known phenomenon in which tissues are exposed to a brief period of ischemia prior to a longer ischemic event. This technique produces tissue tolerance to ischemia reperfusion injury (IRI). Currently, IPC's mechanism of action is poorly understood. Using a porcine single kidney model, we performed remote IPC with renal IRI and evaluated the IPC mechanism of action. Following left nephrectomy, 15 female Yorkshire pigs were divided into three groups: no IPC and 90 minutes of warm ischemia (control), remote IPC immediately followed by 90 minutes of warm ischemia (rIPCe), and remote IPC with 90 minutes of warm ischemia performed 24 hours later (rIPCl). Differential gene expression analysis was performed using a porcine-specific microarray. The microarray analysis of porcine renal tissues identified 1,053 differentially expressed probes in preconditioned pigs. Among these, 179 genes had altered expression in both the rIPCe and rIPCl groups. The genes were largely related to oxidation reduction, apoptosis, and inflammatory response. In the rIPCl group, an additional 848 genes had altered expression levels. These genes were primarily related to immune response and inflammation, including those coding for cytokines and cytokine receptors and those that play roles in the complement system and coagulation cascade. In the complement system, the membrane attack complex was determined to be sublytic, because it colocalized with phosphorylated extracellular signal-regulated kinase. Furthermore, alpha 2 macroglobulin, tissue plasminogen activator, uterine plasmin trypsin inhibitor, and arginase-1 mRNA levels were elevated in the rIPCl group. These findings indicate that remote IPC produces renoprotective effects through multiple mechanisms, and these effects develop over a long timeframe rather than immediately following IPC. PMID- 26489008 TI - The Role of Scent Marking in Mate Selection by Female Pumas (Puma concolor). AB - Mate selection influences individual fitness, is often based on complex cues and behaviours, and can be difficult to study in solitary species including carnivores. We used motion-triggered cameras at 29 community scrapes (i.e. scent marking locations used by multiple individuals) and home range data from 39 GPS collared pumas (Puma concolor) to assess the relevance of communication behaviours for mate selection by female pumas in California. Female pumas visited community scrapes irregularly and visitation bouts appeared to be correlated with oestrus. Female pumas on average selected from 1.7 collared males, and selection was based on multiple cues that varied among the different time periods measured (i.e. the female's visitation bout and in 90 days previous to the consorting event). Female mate selection over the course of a visitation bout was based on frequency of the male visitation, mass, and age. In the 90 days previous to consorting, the number of scrapes a male created was the most important contributor to selection, which was likely related to his residency status. We also found that at least 14% of females mated with multiple males, thus possibly confusing paternity. Our findings provide a mechanistic understanding of how female pumas use scent and auditory communication at community scrapes to select dominant resident males to mate with. PMID- 26489010 TI - Hepatic DNA Methylation Is Affected by Hepatocellular Carcinoma Risk in Patients with and without Hepatitis Virus. AB - OBJECTIVES: Several studies revealed that the proportion of hepatocellular carcinoma (HCC) without hepatitis virus infection (NBNC-HCC) is increasing. On the other hand, epigenetic alterations are reportedly responsible for HCC development. Here, we identified HCC risk factors that are associated with DNA methylation in the background liver tissue of NBNC-HCC patients. METHODS: We performed methylation analysis in 37 pairs of virus-positive and 22 pairs of NBNC HCC and non-cancerous livers using a HumanMethylation450 BeadChip array. After the selection of differentially methylated CpGs (DM-CpGs) in cancerous and non cancerous livers, we analyzed DNA methylation of DM-CpGs within the adjacent non cancerous liver tissue that is affected by specific HCC risk factors. RESULTS: A total of 38,331 CpGs were selected as DM-CpGs using the following criteria: difference of beta-value between HCC and non-cancerous liver >=0.15 and false discovery rate (FDR) q < 1.0E-12. We subsequently selected the DM-CpGs that had methylation differences with the background liver tissue (that has FDR q < 0.35). Among the virus-positive patients, the type of hepatitis virus was mostly associated with differences in methylation within the background liver tissues. However, we found that background methylation patterns were most significantly associated with aging in NBNC patients. Interestingly, age-related methylation differences in DM-CpGs were also observed in NBNC-HCC tissues. CONCLUSIONS: Hepatitis viruses affect the methylation profiles within background liver tissues. However, difference in background methylation was mostly associated with age in NCBC-HCC patients; some age-related methylation events could contribute to emergence of NBNC-HCC in elderly individuals. PMID- 26489011 TI - Estimating Potential Increased Bladder Cancer Risk Due to Increased Bromide Concentrations in Sources of Disinfected Drinking Waters. AB - Public water systems are increasingly facing higher bromide levels in their source waters from anthropogenic contamination through coal-fired power plants, conventional oil and gas extraction, textile mills, and hydraulic fracturing. Climate change is likely to exacerbate this in coming years. We estimate bladder cancer risk from potential increased bromide levels in source waters of disinfecting public drinking water systems in the United States. Bladder cancer is the health end point used by the United States Environmental Protection Agency (EPA) in its benefits analysis for regulating disinfection byproducts in drinking water. We use estimated increases in the mass of the four regulated trihalomethanes (THM4) concentrations (due to increased bromide incorporation) as the surrogate disinfection byproduct (DBP) occurrence metric for informing potential bladder cancer risk. We estimate potential increased excess lifetime bladder cancer risk as a function of increased source water bromide levels. Results based on data from 201 drinking water treatment plants indicate that a bromide increase of 50 MUg/L could result in a potential increase of between 10( 3) and 10(-4) excess lifetime bladder cancer risk in populations served by roughly 90% of these plants. PMID- 26489012 TI - Use of an Innovative Personality-Mindset Profiling Tool to Guide Culture-Change Strategies among Different Healthcare Worker Groups. AB - INTRODUCTION: Important culture-change initiatives (e.g. improving hand hygiene compliance) are frequently associated with variable uptake among different healthcare worker (HCW) categories. Inherent personality differences between these groups may explain change uptake and help improve future intervention design. MATERIALS AND METHODS: We used an innovative personality-profiling tool (ColourGrid(r)) to assess personality differences among standard HCW categories at five large Australian hospitals using two data sources (HCW participant surveys [PS] and generic institution-wide human resource [HR] data) to: a) compare the relative accuracy of these two sources; b) identify differences between HCW groups and c) use the observed profiles to guide design strategies to improve uptake of three clinically-important initiatives (improved hand hygiene, antimicrobial stewardship and isolation procedure adherence). RESULTS: Results from 34,243 HCWs (HR data) and 1045 survey participants (PS data) suggest that HCWs were different from the general population, displaying more individualism, lower power distance, less uncertainty avoidance and greater cynicism about advertising messages. HR and PS data were highly concordant in identifying differences between the three key HCW categories (doctors, nursing/allied-health, support services) and predicting appropriate implementation strategies. Among doctors, the data suggest that key messaging should differ between full-time vs part-time (visiting) senior medical officers (SMO, VMO) and junior hospital medical officers (HMO), with SMO messaging focused on evidence-based compliance, VMO initiatives emphasising structured mandatory controls and prestige loss for non-adherence, and for HMOs focusing on leadership opportunity and future career risk for non-adherence. DISCUSSION: Compared to current standardised approaches, targeted interventions based on personality differences between HCW categories should result in improved infection control-related culture-change uptake. Personality profiling based on HR data may represent a useful means of developing a national culture-change "blueprint" for HCW education. PMID- 26489013 TI - Atherosclerosis-Associated Endothelial Cell Apoptosis by MiR-429-Mediated Down Regulation of Bcl-2. AB - BACKGROUND/AIMS: Endothelial cell injury and subsequent apoptosis play a key role in the development and pathogenesis of atherosclerosis, which is hallmarked by dysregulated lipid homeostasis, aberrant immunity and inflammation, and plaque instability-associated coronary occlusion. Nevertheless, our understanding of the mechanisms underlying endothelial cell apoptosis is still limited. MicroRNA-429 (miR-29) is a known cancer suppressor that promotes cancer cell apoptosis. However, it is unknown whether miR-429 may be involved in the development of atherosclerosis through similar mechanisms. We addressed these questions in the current study. METHODS: We examined the levels of endothelial cell apoptosis in ApoE (-/-) mice suppled with high-fat diet (HFD), a mouse model for atherosclerosis (simplified as HFD mice). We analyzed the levels of anti apoptotic protein Bcl-2 and the levels of miR-429 in the purified CD31+ endothelial cells from mouse aorta. Prediction of the binding between miR-429 and 3'-UTR of Bcl-2 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-429 were further analyzed in an in vitro model using oxidized low-density lipoprotein (ox-LDL)-treated human aortic endothelial cells (HAECs). RESULTS: HFD mice developed atherosclerosis in 12 weeks, while the control ApoE (-/-) mice that had received normal diet (simplified as NOR mice) did not. HFD mice had significantly lower percentage of endothelial cells and significantly higher percentage of mesenchymal cells in the aorta than NOR mice. Significantly higher levels of endothelial cell apoptosis were detected in HFD mice, resulting from decreases in Bcl-2 protein, but not mRNA. The decreases in Bcl-2 in endothelial cells were due to increased levels of miR-429, which suppressed the translation of Bcl-2 mRNA via 3'-UTR binding. These in vivo findings were reproduced in vitro on ox-LDL-treated HAECs. CONCLUSION: Atherosclerosis-associated endothelial cell apoptosis may result from down regulation of Bcl-2, through increased miR-429 that binds and suppresses translation of Bcl-2 mRNA. PMID- 26489014 TI - Home Non-Invasive Ventilation Fails to Improve Quality of Life in the Elderly: Results from a Multicenter Cohort Study. AB - BACKGROUND: Home non-invasive ventilation (NIV) is a widely used treatment for chronic hypoventilation but little is known on its impact in the elderly. In a multicenter prospective cohort study, we studied tolerance and efficacy of domiciliary NIV in patients aged 75 or more compared to younger ones. METHODS AND RESULTS: 264 patients with at least a six-month follow-up were analyzed. Among them, 82 were elderly. In the elderly and the younger, we found an improvement of arterial blood gas, the Epworth sleepiness scale and the Pittsburgh sleep quality index at 6 months. Mean daily use of NIV at 6 months was 7 hours and the rate of non-adherent patients was similar in both group. Health-related quality of life (HRQL) assessed by SF-36 questionnaires did not change significantly after NIV initiation in the elderly whereas HRQL improved in the less than 75. On univariate analysis, we found that diabetes was a predictive factor for non adherence in the elderly (Odds ratio: 3.95% confidence interval: 1.06-8.52). CONCLUSION: NIV was efficient in the elderly while evaluation at 6 months showed a good adherence but failed to improve HRQL. PMID- 26489016 TI - A Solvothermal Route Decorated on Different Substrates: Controllable Separation of an Oil/Water Mixture to a Stabilized Nanoscale Emulsion. AB - A facile solvothermal route is developed to fabricate polydivinylbenzene (PDVB) and decorate the polymer onto porous substrates. "Controllable" separation can be realized by selecting substrates with different pore sizes. The PDVB-modified mesh shows superhydrophobicity/superoleophilicity, and can be used for oil/seawater mixture separation, while the PDVB-modified membrane exhibits high hydrophobicity/superoleophilicity, and is able to separate surfactant stabilized nanoscale water-in-oil emulsions. PMID- 26489015 TI - Depletion of M. tuberculosis GlmU from Infected Murine Lungs Effects the Clearance of the Pathogen. AB - M. tuberculosis N-acetyl-glucosamine-1-phosphate uridyltransferase (GlmUMtb) is a bi-functional enzyme engaged in the synthesis of two metabolic intermediates N acetylglucosamine-1-phosphate (GlcNAc-1-P) and UDP-GlcNAc, catalyzed by the C- and N-terminal domains respectively. UDP-GlcNAc is a key metabolite essential for the synthesis of peptidoglycan, disaccharide linker, arabinogalactan and mycothiols. While glmUMtb was predicted to be an essential gene, till date the role of GlmUMtb in modulating the in vitro growth of Mtb or its role in survival of pathogen ex vivo / in vivo have not been deciphered. Here we present the results of a comprehensive study dissecting the role of GlmUMtb in arbitrating the survival of the pathogen both in vitro and in vivo. We find that absence of GlmUMtb leads to extensive perturbation of bacterial morphology and substantial reduction in cell wall thickness under normoxic as well as hypoxic conditions. Complementation studies show that the acetyl- and uridyl- transferase activities of GlmUMtb are independently essential for bacterial survival in vitro, and GlmUMtb is also found to be essential for mycobacterial survival in THP-1 cells as well as in guinea pigs. Depletion of GlmUMtb from infected murine lungs, four weeks post infection, led to significant reduction in the bacillary load. The administration of Oxa33, a novel oxazolidine derivative that specifically inhibits GlmUMtb, to infected mice resulted in significant decrease in the bacillary load. Thus our study establishes GlmUMtb as a strong candidate for intervention measures against established tuberculosis infections. PMID- 26489018 TI - Retinal Pigment Epithelium Tears: Risk Factors, Mechanism and Therapeutic Monitoring. AB - Tears of the retinal pigment epithelium (RPE) are most commonly associated with vascularised RPE detachment due to age-related macular degeneration (AMD), and they usually involve a deleterious loss in visual acuity. Recent studies suggest an increase in RPE tear incidences since the introduction of anti-vascular endothelial growth factor (anti-VEGF) therapies as well as a temporal association between the tear event and the intravitreal injection. As the number of AMD patients and the number of administered anti-VEGF injections increase, both the challenge of RPE tear prevention and the treatment after RPE tear formation have become more important. At the same time, the evolution of retinal imaging has significantly contributed to a better understanding of RPE tear development in recent years. This review summarises the current knowledge on RPE tear development, predictive factors, and treatment strategies before and after RPE tear formation. PMID- 26489017 TI - NF-Protocadherin Regulates Retinal Ganglion Cell Axon Behaviour in the Developing Visual System. AB - Cell adhesion molecules play a central role in mediating axonal tract development within the nascent nervous system. NF-protocadherin (NFPC), a member of the non clustered protocadherin family, has been shown to regulate retinal ganglion cell (RGC) axon and dendrite initiation, as well as influencing axonal navigation within the mid-optic tract. However, whether NFPC mediates RGC axonal behaviour at other positions within the optic pathway remains unclear. Here we report that NFPC plays an important role in RGC axonogenesis, but not in intraretinal guidance. Moreover, axons with reduced NFPC levels exhibit insensitivity to Netrin-1, an attractive guidance cue expressed at the optic nerve head. Netrin-1 induces rapid turnover of NFPC localized to RGC growth cones, suggesting that the regulation of NFPC protein levels may underlie Netrin-1-mediated entry of RGC axons into the optic nerve head. At the tectum, we further reveal a function for NFPC in controlling RGC axonal entry into the final target area. Collectively, our results expand our understanding of the role of NFPC in RGC guidance and illustrate that this adhesion molecule contributes to axon behaviour at multiple points in the optic pathway. PMID- 26489019 TI - 2014 outbreak of enterovirus D68 in North America. AB - Enterovirus D68 (EV-D68) is an emerging picornavirus which causes severe respiratory disease, predominantly in children. In 2014, the largest and most widespread outbreak of EV-D68 described to date was reported in North America. Hospitals throughout the United States and Canada reported surges in patient volumes and resource utilization from August to October, 2014. In the US a total of 1,153 infections were confirmed in 49 states, although this is an underestimate of the likely millions of cases that occurred but were not tested. EV-D68 was detected in 14 patients who died; the role of the virus in these deaths is unknown. A possible association between EV-D68 and cases of acute flaccid paralysis with spinal cord gray matter lesions, known as acute flaccid myelitis, was observed during the outbreak and is under investigation. The 2014 outbreak of EV-D68 in North America demonstrates the public health importance of this emerging pathogen. PMID- 26489020 TI - Molecular Phylogeny Supports Repeated Adaptation to Burrowing within Small-Eared Shrews Genus of Cryptotis (Eulipotyphla, Soricidae). AB - Small-eared shrews of the New World genus Cryptotis (Eulipotyphla, Soricidae) comprise at least 42 species that traditionally have been partitioned among four or more species groups based on morphological characters. The Cryptotis mexicana species group is of particular interest, because its member species inhibit a subtly graded series of forelimb adaptations that appear to correspond to locomotory behaviors that range from more ambulatory to more fossorial. Unfortunately, the evolutionary relationships both among species in the C. mexicana group and among the species groups remain unclear. To better understand the phylogeny of this group of shrews, we sequenced two mitochondrial and two nuclear genes. To help interpret the pattern and direction of morphological changes, we also generated a matrix of morphological characters focused on the evolutionarily plastic humerus. We found significant discordant between the resulting molecular and morphological trees, suggesting considerable convergence in the evolution of the humerus. Our results indicate that adaptations for increased burrowing ability evolved repeatedly within the genus Cryptotis. PMID- 26489021 TI - MCA-NMF: Multimodal Concept Acquisition with Non-Negative Matrix Factorization. AB - In this paper we introduce MCA-NMF, a computational model of the acquisition of multimodal concepts by an agent grounded in its environment. More precisely our model finds patterns in multimodal sensor input that characterize associations across modalities (speech utterances, images and motion). We propose this computational model as an answer to the question of how some class of concepts can be learnt. In addition, the model provides a way of defining such a class of plausibly learnable concepts. We detail why the multimodal nature of perception is essential to reduce the ambiguity of learnt concepts as well as to communicate about them through speech. We then present a set of experiments that demonstrate the learning of such concepts from real non-symbolic data consisting of speech sounds, images, and motions. Finally we consider structure in perceptual signals and demonstrate that a detailed knowledge of this structure, named compositional understanding can emerge from, instead of being a prerequisite of, global understanding. An open-source implementation of the MCA-NMF learner as well as scripts and associated experimental data to reproduce the experiments are publicly available. PMID- 26489022 TI - High Intensity Interval- vs Moderate Intensity- Training for Improving Cardiometabolic Health in Overweight or Obese Males: A Randomized Controlled Trial. AB - PURPOSE: To compare the effects of six weeks of high intensity interval training (HIIT) vs continuous moderate intensity training (MIT) for improving body composition, insulin sensitivity (SI), blood pressure, blood lipids, and cardiovascular fitness in a cohort of sedentary overweight or obese young men. We hypothesized that HIIT would result in similar improvements in body composition, cardiovascular fitness, blood lipids, and SI as compared to the MIT group, despite requiring only one hour of activity per week compared to five hours per week for the MIT group. METHODS: 28 sedentary overweight or obese men (age, 20 +/ 1.5 years, body mass index 29.5 +/- 3.3 kg/m2) participated in a six week exercise treatment. Participants were randomly assigned to HIIT or MIT and evaluated at baseline and post-training. DXA was used to assess body composition, graded treadmill exercise test to measure cardiovascular fitness, oral glucose tolerance to measure SI, nuclear magnetic resonance spectroscopy to assess lipoprotein particles, and automatic auscultation to measure blood pressure. RESULTS: A greater improvement in VO2peak was observed in MIT compared to HIIT (11.1% vs 2.83%, P = 0.0185) in the complete-case analysis. No differences were seen in the intention to treat analysis, and no other group differences were observed. Both exercise conditions were associated with temporal improvements in % body fat, total cholesterol, medium VLDL, medium HDL, triglycerides, SI, and VO2peak (P < 0.05). CONCLUSION: Participation in HIIT or MIT exercise training displayed: 1) improved SI, 2) reduced blood lipids, 3) decreased % body fat, and 4) improved cardiovascular fitness. While both exercise groups led to similar improvements for most cardiometabolic risk factors assessed, MIT led to a greater improvement in overall cardiovascular fitness. Overall, these observations suggest that a relatively short duration of either HIIT or MIT training may improve cardiometabolic risk factors in previously sedentary overweight or obese young men, with no clear advantage between these two specific regimes (Clinical Trial Registry number NCT01935323). TRIAL REGISTRATION: ClinicalTrials.gov NCT01935323. PMID- 26489023 TI - Prognostic Value of the Six-Second Spirometry in Patients with Chronic Obstructive Pulmonary Disease: A Cohort Study. AB - BACKGROUND: The six-second spirometry has been proposed as an alternative to diagnose airflow limitation, although its prognostic value in patients with chronic obstructive pulmonary disease (COPD) remains unknown. The purpose of this study was to determine the prognostic value of the postbronchodilator forced expiratory volume in 1 second (FEV1)/forced expiratory volume in 6 seconds (FEV6) ratio and FEV6 in COPD patients. METHODS AND FINDINGS: The study population consisted of 2,614 consecutive stable patients with COPD. The patients were monitored for an average period of 4.3 years regarding mortality, hospitalizations by COPD exacerbations, diagnosis of lung cancer, and annual lung function decline. The overall rate of death was 10.7 (95%CI: 8.7-12.7) per 1000 person-years. In addition to male gender, age and comorbidity, FEV6 (hazard ratio [HR]: 0.981, 95%CI: 0.968-0.003) and FEV1/FEV6 quartiles (lowest quartile (<74% pred.): HR 3.558, 95%CI: 1.752-7.224; and second quartile (74-84% pred.): HR 2.599, 95%CI: 1.215-5.561; versus best quartile (>0.89% pred.)) were independently associated with mortality, whereas FEV1 was not retained in the model. 809 patients (30.9%) had at least one hospital admission due to COPD exacerbation. In addition to sex, age, smoking and comorbidity, FEV1 and FEV1/FEV6 quartiles were independent risk factors of hospitalization. FEV6 was the only spirometric parameter independently related with lung function annual decline, while the FEV6 and FEV1/FEV6 quartiles were independent risk factors for lung cancer. CONCLUSIONS: In a general COPD outpatient population, airflow obstruction assessed by the FEV1/FEV6 is an independent risk factor for both death and hospitalization. PMID- 26489024 TI - Testing the Prey-Trap Hypothesis at Two Wildlife Conservancies in Kenya. AB - Protecting an endangered and highly poached species can conflict with providing an open and ecologically connected landscape for coexisting species. In Kenya, about half of the black rhino (Diceros bicornis) live in electrically fenced private conservancies. Purpose-built fence-gaps permit some landscape connectivity for elephant while restricting rhino from escaping. We monitored the usage patterns at these gaps by motion-triggered cameras and found high traffic volumes and predictable patterns of prey movement. The prey-trap hypothesis (PTH) proposes that predators exploit this predictable prey movement. We tested the PTH at two semi-porous reserves using two different methods: a spatial analysis and a temporal analysis. Using spatial analysis, we mapped the location of predation events with GPS and looked for concentration of kill sites near the gaps as well as conducting clustering and hot spot analysis to determine areas of statistically significant predation clustering. Using temporal analysis, we examined the time lapse between the passage of prey and predator and searched for evidence of active prey seeking and/or predator avoidance. We found no support for the PTH and conclude that the design of the fence-gaps is well suited to promoting connectivity in these types of conservancies. PMID- 26489026 TI - National outcomes of kidney transplantation from deceased diabetic donors. AB - Use of deceased diabetic donor kidneys has increased over recent decades. However, scarce patient and allograft survival data are available taking into account recipient diabetes status. Here we performed a retrospective cohort study using data from the United Network of Organ Sharing in patients transplanted from 1994 to 2014. Multivariable Cox regression assessed recipient outcomes of 9074 diabetic vs. 152,555 non-diabetic donor kidneys. Recipients of diabetic donor kidneys had elevated rates of all-cause allograft failure (hazard ratio 1.21, 95% confidence interval 1.16-1.26) and death (1.19, 1.13-1.24) compared to recipients of kidneys from non-diabetic donors. Younger recipients of diabetic donor kidneys had worse allograft survival than older recipients of non-diabetic donor kidneys. There was significant interaction between donor and recipient diabetes status. To minimize the effect of unmeasured confounders, we used paired analyses of recipients of mate-kidneys from the same donor, with one diabetic recipient and the other non-diabetic. Among discordant recipient pairs of diabetic donor kidneys, diabetic recipients had significantly higher risk of allograft failure (1.27, 1.05-1.53) and death (1.53, 1.22-1.93) than non-diabetic recipients. After stratifying by Kidney Donor Profile Index risk category, diabetic recipients of diabetic donor kidneys continued to have worse allograft survival compared to all other patients. Thus, risks are associated with the use of diabetic donor kidneys. Understanding these risks will enable clinicians to better educate potential recipients.Kidney International advance online publication, 21 October 2015; doi:10.1038/ki.2015.325. PMID- 26489025 TI - Raloxifene improves skeletal properties in an animal model of cystic chronic kidney disease. AB - Patients with chronic kidney disease (CKD) have an increased risk of fracture. Raloxifene is a mild antiresorptive agent that reduces fracture risk in the general population. Here we assessed the impact of raloxifene on the skeletal properties of animals with progressive CKD. Male Cy/+ rats that develop autosomal dominant cystic kidney disease were treated with either vehicle or raloxifene for five weeks. They were assessed for changes in mineral metabolism and skeletal parameters (microCT, histology, whole-bone mechanics, and material properties). Their normal littermates served as controls. Animals with CKD had significantly higher parathyroid hormone levels compared with normal controls, as well as inferior structural and mechanical skeletal properties. Raloxifene treatment resulted in lower bone remodeling rates and higher cancellous bone volume in the rats with CKD. Although it had little effect on cortical bone geometry, it resulted in higher energy to fracture and modulus of toughness values than vehicle-treated rats with CKD, achieving levels equivalent to normal controls. Animals treated with raloxifene had superior tissue-level mechanical properties as assessed by nanoindentation, and higher collagen D-periodic spacing as assessed by atomic force microscopy. Thus, raloxifene can positively impact whole bone mechanical properties in CKD through its impact on skeletal material properties. PMID- 26489027 TI - Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT. AB - The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 5-15% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed. PMID- 26489028 TI - Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis. AB - No previous study has compared mycophenolate mofetil (MMF) with low-dose cyclophosphamide (CYC) in the treatment of lupus nephritis (LN). To do so, we recruited patients with LN (class III, IV, or V) and randomized them to receive either low-dose CYC or oral MMF. Those with crescentic LN, a serum creatinine over 265 MUmol/l, and neurological or pulmonary lupus were excluded. MMF was prescribed at daily doses of 1.5-3 g for 24 weeks, while CYC was administered as six fortnightly infusions of 500 mg each. All patients received three methylprednisolone injections, followed by oral corticosteroids. Maintenance therapy with azathioprine and low-dose corticosteroid was started at end of induction therapy. The primary end point was treatment response at 24 weeks, while secondary end points were complete remission, Systemic Lupus Erythematosus Disease Activity Index and adverse events. Of the 173 patients recruited, 100 were equally randomized to receive either CYC or MMF. Baseline characteristics were similar, except for higher 24 h proteinuria in the CYC group. At 24 weeks, 37 patients in each group achieved the primary end point. The complete remission rate was 50% in CYC and 54% in MMF group. Gastrointestinal symptoms were significantly more frequent in patients receiving MMF (52 vs. 4%). However, other adverse events were similar. Thus, low-dose intravenous CYC is comparable in safety and efficacy to oral MMF in the induction treatment of less severe LN. PMID- 26489029 TI - Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity. AB - Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes. PMID- 26489031 TI - Non-Random Distribution of 5S rDNA Sites and Its Association with 45S rDNA in Plant Chromosomes. AB - 5S and 45S rDNA sites are the best mapped chromosome regions in eukaryotic chromosomes. In this work, a database was built gathering information about the position and number of 5S rDNA sites in 784 plant species, aiming to identify patterns of distribution along the chromosomes and its correlation with the position of 45S rDNA sites. Data revealed that in most karyotypes (54.5%, including polyploids) two 5S rDNA sites (a single pair) are present, with 58.7% of all sites occurring in the short arm, mainly in the proximal region. In karyotypes of angiosperms with only 1 pair of sites (single sites) they are mostly found in the proximal region (52.0%), whereas in karyotypes with multiple sites the location varies according to the average chromosome size. Karyotypes with multiple sites and small chromosomes (<3 um) often display proximal sites, while medium-sized (between 3 and 6 um) and large chromosomes (>6 um) more commonly show terminal or interstitial sites. In species with holokinetic chromosomes, the modal value of sites per karyotype was also 2, but they were found mainly in a terminal position. Adjacent 5S and 45S rDNA sites were often found in the short arm, reflecting the preferential distribution of both sites in this arm. The high frequency of genera with at least 1 species with adjacent 5S and 45S sites reveals that this association appeared several times during angiosperm evolution, but it has been maintained only rarely as the dominant array in plant genera. PMID- 26489032 TI - The Occurrence of Beer Spoilage Lactic Acid Bacteria in Craft Beer Production. AB - Beer is one of the world's most ancient and widely consumed fermented alcoholic beverages produced with water, malted cereal grains (generally barley and wheat), hops, and yeast. Beer is considered an unfavorable substrate of growth for many microorganisms, however, there are a limited number of bacteria and yeasts, which are capable of growth and may spoil beer especially if it is not pasteurized or sterile-filtered as craft beer. The aim of this research study was to track beer spoilage lactic acid bacteria (LAB) inside a brewery and during the craft beer production process. To that end, indoor air and work surface samples, collected in the brewery under study, together with commercial active dry yeasts, exhausted yeasts, yeast pellet (obtained after mature beer centrifugation), and spoiled beers were analyzed through culture-dependent methods and PCR-DGGE in order to identify the contaminant LAB species and the source of contamination. Lactobacillus brevis was detected in a spoiled beer and in a commercial active dry yeast. Other LAB species and bacteria ascribed to Staphylococcus sp., Enterobaceriaceae, and Acetobacter sp. were found in the brewery. In conclusion, the PCR-DGGE technique coupled with the culture-dependent method was found to be a useful tool for identifying the beer spoilage bacteria and the source of contamination. The analyses carried out on raw materials, by-products, final products, and the brewery were useful for implementing a sanitization plan to be adopted in the production plant. PMID- 26489033 TI - From corneal shape to ocular wavefront in eyes with aspheric IOLs: the feasibility of IOL customisation. AB - PURPOSE: To determine if it is possible to predict the ocular wavefront aberrations of eyes with an aspheric IOL from the corneal shape and other readily available eye characteristics. A reliable prediction is a prerequisite for future IOL customisation. METHODS: Sixty pseudophakic eyes with aspheric IOLs of 60 patients were included. The corneal shape and the ocular wavefront aberrations were measured postoperatively with a Scheimpflug camera and an aberrometer, respectively. The elevation data of the anterior corneal surface were fitted by Zernike polynomials. Linear regression models for the Zernike coefficients describing the ocular wavefront aberrations up till the fourth order were determined, with as independent variables the Zernike coefficients describing the corneal shape, the eye (right/left), IOL power, and axial length. RESULTS: Linear regression equations with an explained variance (adjusted R-square) above 0.50 were found for five Zernike aberration terms: defocus (z(2,0); adjusted R-square 0.90), the astigmatism terms (0.81 for oblique astigmatism [z(2,-2)] and 0.88 for regular astigmatism [z(2,2)]), vertical coma (z(3,-1); 0.52), and spherical aberration (z(4,0); 0.71). CONCLUSION: The defocus, astigmatism, vertical coma, and spherical aberration terms of the ocular wavefront are strongly associated with the corneal shape in pseudophakic eyes and may thus be predicted from the corneal shape and other eye characteristics. PMID- 26489035 TI - Predation Risk within Fishing Gear and Implications for South Australian Rock Lobster Fisheries. AB - Depredation of southern rock lobster (Jasus edwardsii) within fishing gear by the Maori octopus (Pinnoctopus cordiformis) has economic and ecological impacts on valuable fisheries in South Australia. In addition, depredation rates can be highly variable resulting in uncertainties for the fishery. We examined how in pot lobster predation was influenced by factors such as lobster size and sex, season, fishing zone, and catch rate. Using mixed modelling techniques, we found that in-pot predation risk increased with lobster size and was higher for male lobsters. In addition, the effect of catch rate of lobsters on predation risk by octopus differed among fishing zones. There was both a seasonal and a spatial component to octopus predation, with an increased risk within discrete fishing grounds in South Australia at certain times of the year. Information about predation within lobster gear can assist fishery management decision-making, potentially leading to significant reduction in economic losses to the fishery. PMID- 26489034 TI - 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial Infarction: An update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. PMID- 26489036 TI - Screening and assessment of performance and molecule quality attributes of industrial cell lines across different fed-batch systems. AB - The major challenge in the selection process of recombinant cell lines for the production of biologics is the choice, early in development, of a clonal cell line presenting a high productivity and optimal cell growth. Most importantly, the selected candidate needs to generate a product quality profile which is adequate with respect to safety and efficacy and which is preserved across cell culture scales. We developed a high-throughput screening and selection strategy of recombinant cell lines, based on their productivity in shaking 96-deepwell plates operated in fed-batch mode, which enables the identification of cell lines maintaining their high productivity at larger scales. Twelve recombinant cell lines expressing the same antibody with different productivities were selected out of 470 clonal cell lines in 96-deepwell plate fed-batch culture. They were tested under the same conditions in 50 mL vented shake tubes, microscale and lab scale bioreactors in order to confirm the maintenance of their performance at larger scales. The use of a feeding protocol and culture conditions which are essentially the same across the different scales was essential to maintain productivity and product quality profiles across scales. Compared to currently used approaches, this strategy has the advantage of speeding up the selection process and increases the number of screened clones for getting high-producing recombinant cell lines at manufacturing scale with the desired performance and quality. PMID- 26489037 TI - Influence of CYP2D6 and beta2-adrenergic receptor gene polymorphisms on the hemodynamic response to propranolol in Chinese Han patients with cirrhosis. AB - BACKGROUND AND AIM: Propranolol is widely used to prevent gastroesophageal variceal bleeding; however, some patients could not benefit from propranolol. This study is to evaluate the relationship between CYP2D6 and beta2-adrenergic receptor (beta2-AR) gene polymorphisms and the hemodynamic response to propranolol in Chinese Han patients. METHODS: The clinical data of patients with gastroesophageal varices undergoing hepatic venous pressure gradient (HVPG) measurement before and 7 days after oral propranolol administration in our department were collected. Four single nucleotide polymorphisms of CYP2D6 and beta2-AR genes were detected. The relationship was identified by logistic regression model. RESULTS: Thirty patients were involved in the analysis. Sixty milligram propranolol twice each day was well tolerated by all the patients. The initial and secondary average of HVPG was 17.4 +/- 5.8 mmHg vs. 13.2 +/- 4.8 mmHg, respectively (t = 5.726, P < 0.001). Twenty patients responded to propranolol. The mean reduction value of HVPG was 6.6 +/- 3.6 mmHg (range from 3 to 19). Genotype analysis showed: 20 homozygotes for C/C188 and 10 for heterozygous C/T188, 8 homozygotes for G/G4268 and 22 heterozygotes for G/C4268, 14 homozygotes for Gly16 and 10 heterozygotes, and 6 homozygotes for Arg16, 27 homozygotes for Gln27 and 3 heterozygotes. The multivariate logistic regression analysis indicated that CYP2D6 (188C>T) genotype was an independent predicting factor for HVPG response to propranolol (P = 0.033). CONCLUSIONS: CYP2D6 (188C>T) gene polymorphisms influence the hemodynamic response to propranolol in this population of Chinese Han patients with gastroesophageal varices. However, HVPG response cannot be completely predicted from CYP2D6 and beta2-AR gene polymorphisms. PMID- 26489039 TI - Bond Strength of Artificial Teeth Attached to a Microwave-Polymerized Denture Base Resin after Immersion in Disinfectant Solutions. AB - PURPOSE: To evaluate the bond strength between two types of acrylic resin teeth and a microwave denture base resin after immersion in disinfectant solutions for 180 days. MATERIALS AND METHODS: Eighty specimens made of acrylic resin teeth (Biotone and Biotone IPN) attached to a microwave polymerized denture base resin (Nature-Cryl MC) were divided into eight groups (n = 10) according to the treatment (distilled water-control, 2% chlorhexidine digluconate, 1% sodium hypochlorite and sodium perborate solution-Corega Tabs). The shear strength tests (MPa) were carried out using a universal testing machine with a 0.5 mm/min speed. Data analysis was performed using ANOVA and multiple comparison Student-Newman Keuls post hoc test (alpha = 0.05). RESULTS: Biotone IPN showed similar results among the groups (distilled water, 8.25 +/- 1.81 MPa; chlorhexidine, 7.81 +/- 3.34 MPa; hypochlorite, 7.75 +/- 3.72 MPa; and Corega Tabs, 7.58 +/- 2.27 MPa, whereas Biotone showed significantly lower shear bond strength values for the groups immersed in Corega Tabs (5.25 +/- 3.27 MPa) and chlorhexidine (6.08 +/- 2.35 MPa). CONCLUSIONS: Soaking the dentures in 1% sodium hypochlorite could be recommended as a disinfectant solution for dentures fabricated with conventional acrylic resin denture teeth and microwave denture base resin. For dentures fabricated with IPN teeth and microwave denture base resin, all the soaking solutions evaluated in this study could be suggested to denture wearers. PMID- 26489038 TI - 1,3-Oxazin-6-one Derivatives and Bohemamine-Type Pyrrolizidine Alkaloids from a Marine-Derived Streptomyces spinoverrucosus. AB - Two new 1,3-oxazin-6-one derivatives (1 and 2) and six new bohemamine-type pyrrolizidine alkaloids (3-8) were isolated from the marine-derived Streptomyces spinoverrucosus strain SNB-048. Their structures including the absolute configurations were fully elucidated on the basis of spectroscopic analysis, ECD spectra, quantum chemical calculations, and chemical methods. Compounds 1 and 2 possess a gamma-lactam moiety and a 1,3-oxazin-6-one system. PMID- 26489040 TI - New guanidine-containing nanocomposites impeding the growth of Staphylococcus epidermidis 33 and the biofilm formation. AB - New water-soluble nanocomposites (AgNCs) based on Ag and copolymers of 2,2 diallyl-1,1,3,3-tetraethylguanidiniumchloride with N-vinylpyrrolidone [poly(AGC VP)] and vinylacetate [poly(AGC-VA)] have been developed. Antibacterial action of new silver nanocomposites on S. epidermidis 33 (planctonic cells and biofilms) is reported in this study. AgNCs strongly inhibited biofilms formation of S. epidermidis 33. The viability of S. epidermidis 33 cells in biofilms was considerably reduced by new AgNCs. It has been shown that S. epidermidis 33 inactivation in biofilms occurs at AgNC concentrations > 5 times higher as compared to those inhibiting completely the planktonic cells. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 630-638, 2016. PMID- 26489041 TI - C-N Coupling of Amides with Alcohols Catalyzed by N-Heterocyclic Carbene Phosphine Iridium Complexes. AB - N-Heterocyclic carbene-phosphine iridium complexes (NHC-Ir) were developed/found to be a highly reactive catalyst for N-monoalkylation of amides with alcohols via hydrogen transfer. The reaction produced the desired product in high isolated yields using a wide range of substrates with low catalyst loading and short reaction times. PMID- 26489030 TI - Genetic Predictors of Depressive Symptoms in the Look AHEAD Trial. AB - OBJECTIVES: Numerous studies have found elevated depressive symptoms among individuals with Type 2 diabetes, yet the mechanisms remain unclear. We examined whether genetic loci previously associated with depressive symptoms predict depressive symptoms among overweight/obese individuals with Type 2 diabetes or change in depressive symptoms during behavioral weight loss. METHODS: The Illumina CARe iSelect (IBC) chip and Cardiometabochip were characterized in 2118 overweight or obese participants with Type 2 diabetes from Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive life-style intervention and diabetes support and education on cardiovascular morbidity and mortality. Primary analyses focused on baseline Beck Depression Inventory (BDI) scores and depressive symptom change at 1 year. RESULTS: Of eight single nucleotide polymorphisms (SNPs) in six loci, three a priori SNPs in two loci (chromosome 5: rs60271; LBR: rs2230419, rs1011319) were associated with baseline BDI scores, but in the opposite direction of prior research. In joint analysis of 90,003 IBC and Cardiometabochip SNPs, rs1543654 in the region of KCNE1 predicted change in BDI scores at Year 1 in diabetes support and education (beta = -1.05, standard error [SE] = 0.21, p = 6.9 * 10(-7)) at the level of chip wide significance, while also showing a nominal association with baseline BDI (beta = 0.35, SE = 0.16, p = .026). Adjustment for antidepressant medication and/or limiting analyses to non-Hispanic white individuals did not meaningfully alter results. CONCLUSIONS: Previously reported genetic associations with depressive symptoms did not replicate in this cohort of overweight/obese individuals with Type 2 diabetes. We identified KCNE1 as a potential novel locus associated with depressive symptoms. PMID- 26489043 TI - It's About Time: A Survival Approach to Gestational Weight Gain and Preterm Delivery. AB - There is substantial interest in understanding the impact of gestational weight gain on preterm delivery (delivery <37 weeks). The major difficulty in analyzing the association between gestational weight gain and preterm delivery lies in their mutual dependence on gestational age, as weight naturally increases with increasing pregnancy duration. In this study, we untangle this inherent association by reframing preterm delivery as time to delivery and assessing the relationship through a survival framework, which is particularly amenable to dealing with time-dependent covariates, such as gestational weight gain. We derive the appropriate analytical model for assessing the relationship between weight gain and time to delivery when weight measurements at multiple time points are available. Since epidemiologic data may be limited to weight gain measurements taken at only a few time points or at delivery only, we conduct simulation studies to illustrate how several strategically timed measurements can yield unbiased risk estimates. Analysis of the study of successive small-for gestational-age births demonstrates that a naive analysis that does not account for the confounding effect of time on gestational weight gain suggests a strong association between higher weight gain and later delivery (hazard ratio: 0.89, 95% confidence interval = 0.84, 0.93). Properly accounting for the confounding effect of time using a survival model, however, mitigates this bias (hazard ratio: 0.98, 95% confidence interval = 0.97, 1.00). These results emphasize the importance of considering the effect of gestational age on time-varying covariates during pregnancy, and the proposed methods offer a convenient mechanism to appropriately analyze such data.See Video Abstract at http://links.lww.com/EDE/B13. PMID- 26489042 TI - Advanced technologies for the molecular diagnosis of fragile X syndrome. AB - Fragile X syndrome (FXS), a trinucleotide repeat disorder, is the most common heritable form of cognitive impairment. Since the discovery of the FMR1 gene in 1991, great strides have been made in the field of molecular diagnosis for FXS. Cytogenetic analysis, which was the method of diagnosis in the early 1990, was replaced by Southern blot and PCR analysis albeit with some limitations. In the past few years many PCR-based methodologies, able to amplify large full mutation expanded alleles, with or without methylation, have been proposed. Reviewed here are the advantages, disadvantages and limitations of the most recent developments in the field of FXS diagnosis. PMID- 26489044 TI - Polyphenolic extract from Hibiscus sabdariffa reduces body fat by inhibiting hepatic lipogenesis and preadipocyte adipogenesis. AB - Diets high in fat lead to excess lipid accumulation in adipose tissue, which is a crucial factor in the development of obesity, hepatitis, and hyperlipidemia. In this study, we investigated the anti-obesity effect of Hibiscus sabdariffa extract (HSE) in vivo. Hamsters fed a high-fat diet (HFD) develop symptoms of obesity, which were determined based on body weight changes and changes in plasma and serum triglycerides, free fatty acid concentrations, total cholesterol levels, LDL-C levels, HDL-C levels, and adipocyte tissue weight. HFD-fed hamsters were used to investigate the effects of HSE on symptoms of obesity such as adipogenesis and fatty liver, loss of blood glucose regulation, and serum ion imbalance. Interestingly, HSE treatment effectively reduced the effects of the HFD in hamsters in a dose-dependent manner. Further, after inducing maturation of preadipocytes, Hibiscus sabdariffa polyphenolic extract (HPE) was shown to suppress the adipogenesis of adipocytes. However, HPE does not affect the viability of preadipocytes. Therefore, both HSE and HPE are effective and viable treatment strategies for preventing the development and treating the symptoms of obesity. PMID- 26489045 TI - Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment naive adults infected with HIV-1 through 48 weeks of treatment. AB - This 96-week, randomized, open-label study was designed to assess the efficacy and safety of two single-tablet regimens in treatment naive HIV-1-infected adults: rilpivirine (RPV) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and efavirenz (EFV) + FTC/TDF. Assessments included patient-reported Medication Adherence Self-Report Inventory, SF-12v2 Quality of Life assessment, HIV Treatment Satisfaction Questionnaire, and HIV Symptom Index Questionnaire through Week 48. Additional evaluations included study drug discontinuations due to treatment-emergent adverse events (TEAEs). A total of 786 participants (n=394 RPV/FTC/TDF, n=392 EFV/FTC/TDF) were included. Fewer RPV/FTC/TDF-treated than EFV/FTC/TDF-treated participants discontinued study drug due to TEAEs (2.5% vs. 8.7%), with 41% (14/34) TEAE-related discontinuations in the EFV/FTC/TDF group occurring within the first four weeks of treatment. Treatment adherence and satisfaction remained high through Week 48 and quality of life improved from baseline in both groups. There were no significant between-group differences in virologic success (HIV-1 RNA <50 copies/mL) regardless of adherence (<95% or >=95%). Significant between-group differences favouring RPV/FTC/TDF were observed for the HIV SIQ symptoms of difficulty falling or staying asleep (p = .022) and diarrhea or loose bowel movements (p = .002). In conclusion, 48-week treatment with RPV/FTC/TDF or EFV/FTC/TDF was associated with high adherence, high treatment satisfaction, and improved quality of life. TEAE-related discontinuations and patient-reported symptoms indicate that RPV/FTC/TDF may be somewhat better tolerated than EFV/FTC/TDF. PMID- 26489046 TI - The Role of Extrinsic Rewards and Cue-Intention Association in Prospective Memory in Young Children. AB - The current study examined, for the first time, the effect of cue-intention association, as well as the effects of promised extrinsic rewards, on prospective memory in young children, aged 5-years-old (n = 39) and 7-years-old (n = 40). Children were asked to name pictures for a toy mole, whilst also having to remember to respond differently to certain target pictures (prospective memory task). The level to which the target picture was associated with the intention was manipulated across two conditions (low- or high-association) for all participants, whilst half of the participants were promised a reward for good prospective memory performance. Results showed a main effect of age, with the 7 year-olds outperforming the 5-year-olds. Furthermore, there was a main effect of reward, with those promised a reward performing better than those who were not. No effect was found for cue-association, with the participants of both age groups performing equally well in both association conditions. No significant interactions were found between any of the variables. The potentially important role of reward in young children's everyday prospective memory tasks, and possible reasons for the lack of a reflexive-associative effect, are discussed. PMID- 26489047 TI - Simultaneous electrochemical detection of catechol and hydroquinone based on gold nanoparticles@carbon nanocages modified electrode. AB - In the present study, carbon nanocages (CNCs) decorated with gold nanoparticles (AuNPs) with diameters of 2-5 nm were synthesized by simply mixing their solutions. The sizes of the AuNPs are small enough to diffuse into the inside of the CNCs by electrostatic incorporation and their morphologies were characterized by transmission electron microscopy, X-ray diffraction, energy dispersive spectrometry, Raman spectrometry and ultraviolet visible absorption spectra. The AuNPs@CNCs modified electrode was prepared for simultaneous highly sensitive determination of catechol (CC) and hydroquinone (HQ). This modified electrode demonstrated fantastic eletrochemical catalytic activities towards CC and HQ by cyclic voltammetry and differential pulse voltammetry. The calibration curves showed a linear response between the peak currents and the concentrations of CC and HQ. A wide dynamic detection range of 1.0-250.0 MUM and 0.1-200.0 MUM with a low detection limits (S/N = 3) of 0.0986 MUM and 0.0254 MUM can be obtained for CC and HQ respectively. The present method was successfully employed for determination of CC and HQ in a practical sample. PMID- 26489049 TI - Subtyping of Salmonella Food Isolates Suggests the Geographic Clustering of Serotype Telaviv. AB - Salmonella is commonly found in a variety of food products and is a major cause of bacterial foodborne illness throughout the world. In this study, we investigated the prevalence and diversity of Salmonella in eight different food types: sheep ground meat, cow ground meat, chicken meat, cow offal, traditional Sanliurfa cheese, unripened feta cheese, pistachios, and isot (a spice blend of dried red peppers specific to Sanliurfa), traditionally and commonly consumed in Turkey. Among 192 food samples, Salmonella was detected in 59 samples, with the highest prevalence in raw poultry parts (58%) and offal (58%) samples, while Salmonella was not detected in pistachios and dried red pepper. Resultant Salmonella isolates were characterized by serotyping, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). Ten different serotypes represented 10 MLST sequence types (STs) with 1 novel ST and 17 PFGE types. Antimicrobial resistance profiling revealed that 30.5% of the isolates were resistant to two or more antimicrobials. Salmonella enterica subsp. enterica serotype Telaviv, which is rare throughout the world, was the second most common serotype isolated from food samples in this study, suggesting that this serotype might be one of the subtypes that is endemic to Turkey. PMID- 26489048 TI - Antibody Derived Peptides for Detection of Ebola Virus Glycoprotein. AB - BACKGROUND: Current Ebola virus (EBOV) detection methods are costly and impractical for epidemic scenarios. Different immune-based assays have been reported for the detection and quantification of Ebola virus (EBOV) proteins. In particular, several monoclonal antibodies (mAbs) have been described that bind the capsid glycoprotein (GP) of EBOV GP. However, the currently available platforms for the design and production of full-length mAbs are cumbersome and costly. The use of antibody fragments, rather than full-length antibodies, might represent a cost-effective alternative for the development of diagnostic and possibly even therapeutic alternatives for EBOV. METHODS/PRINCIPAL FINDINGS: We report the design and expression of three recombinant anti-GP mAb fragments in Escherichia coli cultures. These fragments contained the heavy and light variable portions of the three well-studied anti-GP full-length mAbs 13C6, 13F6, and KZ52, and are consequently named scFv-13C6, scFv-13F6, and Fab-KZ52, respectively. All three fragments exhibited specific anti-GP binding activity in ELISA experiments comparable to that of full-length anti-GP antibodies (i.e., the same order of magnitude) and they are easily and economically produced in bacterial cultures. CONCLUSION/SIGNIFICANCE: Antibody fragments might represent a useful, effective, and low cost alternative to full-length antibodies in Ebola related capture and diagnostics applications. PMID- 26489050 TI - Preconditioning with peristaltic external pneumatic compression does not acutely improve repeated Wingate performance nor does it alter blood lactate concentrations during passive recovery compared with sham. AB - Application of dynamic external pneumatic compression (EPC) during recovery from athletic activities has demonstrated favorable effects on flexibility, soreness, swelling, and blood lactate (BLa) concentrations. However, the effects of "preconditioning" with a peristaltic pulse EPC device on subsequent performance and BLa concentrations have not been characterized. Herein, we demonstrate that pretreatment for 30 min with EPC has no effect on subsequent supramaximal exercise performance or BLa concentrations during passive recovery. PMID- 26489051 TI - Supplementation with a proprietary blend of ancient peat and apple extract may improve body composition without affecting hematology in resistance-trained men. AB - Adenosine-5'-triphosphate (ATP) is primarily known as a cellular source of energy. Increased ATP levels may have the potential to enhance body composition. A novel, proprietary blend of ancient peat and apple extracts has been reported to increase ATP levels, potentially by enhancing mitochondrial ATP production. Therefore, the purpose of this investigation was to determine the supplement's effects on body composition when consumed during 12 weeks of resistance training. Twenty-five healthy, resistance-trained, male subjects (age, 27.7 +/- 4.8 years; height, 176.0 +/- 6.5 cm; body mass, 83.2 +/- 12.1 kg) completed this study. Subjects supplemented once daily with either 1 serving (150 mg) of a proprietary blend of ancient peat and apple extracts (TRT) or placebo (PLA). Supervised resistance training consisted of 8 weeks of daily undulating periodized training followed by a 2-week overreach and a 2-week taper phase. Body composition was assessed using dual-energy X-ray absorptiometry and ultrasound at weeks 0, 4, 8, 10, and 12. Vital signs and blood markers were assessed at weeks 0, 8, and 12. Significant group * time (p < 0.05) interactions were present for ultrasound determined cross-sectional area, which increased in TRT (+0.91 cm(2)) versus PLA (-0.08 cm(2)), as well as muscle thickness (TRT: +0.46; PLA: +0.04 cm). A significant group * time (p < 0.05) interaction existed for creatinine (TRT: +0.06; PLA: +0.15 mg/dL), triglycerides (TRT: +24.1; PLA: -20.2 mg/dL), and very low-density lipoprotein (TRT: +4.9; PLA: -3.9 mg/dL), which remained within clinical ranges. Supplementation with a proprietary blend of ancient peat and apple extracts may enhance resistance training-induced skeletal muscle hypertrophy without affecting fat mass or blood chemistry in healthy males. PMID- 26489052 TI - Assessment of the MyWellness Key accelerometer in people with type 2 diabetes. AB - Accelerometers are designed to measure physical activity (PA) objectively. The MyWellness Key (MWK) accelerometer has been validated primarily in younger, normal-weight populations. The aims of this study were to examine the accuracy of the MWK against directly measured lab-based exercise and free-living PA in people with type 2 diabetes, many of whom are older and overweight or obese. Thirty-five participants with type 2 diabetes completed the protocol, which included a laboratory-based session and a free-living phase. In the laboratory visit, participants completed a structured treadmill protocol wearing MWKs on each hip (all subjects) and bra cup (women only). The speed where each MWK switched from recording light- to moderate-intensity activity was determined for each MWK worn. In the free-living phase, participants wore the MWK for all waking hours for 2 weeks, and recorded exercise in PA diaries immediately after each exercise session. The mean cut-points between low ("Free") and moderate ("Play") intensity for the right and left waist-worn MWKs were 4.1 +/- 0.5 km/h and 5.0 +/- 0.9 km/h for the bra-mounted MWK; ideal cut-point would be 4.0 km/h. In the free-living phase, the Spearman correlation between PA according to PA diary and the waist worn MWK was 0.81 (95% confidence interval (CI): 0.76, 0.85; P < 0.001), but only 0.66 (95% CI: 0.53, 0.77; P < 0.001) when on the bra. In conclusion, the waist worn MWK measured PA volume accurately, and was acceptably accurate at discriminating between low- and moderate-intensity PA in people with type 2 diabetes. The MWK underestimated PA volume and intensity when worn on a bra. PMID- 26489053 TI - Null current hysteresis for acetylacetonate electron extraction layer in perovskite solar cells. AB - Solution processed zirconium acetylacetonate (Zr(acac)) is successfully employed as an electron extraction layer, replacing conventional titanium oxide, in planar CH3NH3PbI3 perovskite solar cells. The as-prepared Zr(acac) film possesses high transparency, high conductivity, a smooth morphology, high wettability, compatibility with PbI2 DMF solution, and an energy level matching that of CH3NH3PbI3 perovskite material. An average power conversion efficiency of about 11.93%, along with a high fill factor of 74.36%, an open circuit voltage of 1.03 V, and a short-circuit current density of 15.58 mA cm(-2) is achieved. The overall performance of the devices is slight better than that of cells using ruthenium acetylacetonate (Ru(acac)). The differences between solar cells with different electron extraction layers in charge recombination, charge transport and transfer and lifetime are further explored and it is demonstrate that Zr(acac) is a more effective and promising electron extraction layer. This work provides a simple, and cost effective route for the preparation of an effective hole extraction layer. PMID- 26489054 TI - A Randomized Controlled Trial Comparison of NeuroSENSE and Bispectral Brain Monitors During Propofol-Based Versus Sevoflurane-Based General Anesthesia. AB - BACKGROUND: NeuroSENSE is a depth of anesthesia monitor that uses automated electroencephalogram quantification. The Wavelet-based Anesthetic Value for Central Nervous System (WAVCNS) index calculated by this monitor is based on wavelet analysis of a normalized electroencephalogram signal in the gamma frequency band. The aim of this study was to determine the extent of disagreement between the Bispectral Index (BIS) and the WAVCNS index during propofol-based and sevoflurane-based maintenance of general anesthesia in a routine surgical population. METHODS: Patients undergoing elective surgery were enrolled in the study and randomly assigned to receive either propofol or sevoflurane for the maintenance of anesthesia and remifentanil in both groups. Anesthesiologists were blinded to monitors in both groups. Discordance between the 2 monitors was assessed by the count of discrepancy in recommendation (DR) (type 1 defined as one parameter <40 and the other >60, or type 2 defined as BIS and WAVCNS values on different sides of a threshold [40 or 60]) and also by the proportion of agreement (P0) between WAVCNS and BIS, obtained every 5 seconds, in 3 categories of index (<40, 40-60, and >60). RESULTS: The analyzed data set consisted of 22 patients (36,872 data pairs) in the propofol group and 24 patients (32,826 data pairs) in the sevoflurane group. The type 1 DR rarely occurred in both the groups (<1%); however, the median (interquartile range) type 2 DR was significantly more frequent in the propofol group (20.6% [7.0-36.9] vs 4.5% [2.3-12.4]; P = 0.0005). The median difference in P0 was 11.53% (95% confidence interval, 0.57-21.32). Major disagreement between WAVCNS index and BIS was related to the weight of burst suppression pattern for the index calculation. CONCLUSIONS: Disagreement between BIS and NeuroSENSE during the maintenance of general anesthesia was worse in the propofol group than that in the sevoflurane groups. The disagreement increases during deep anesthesia or in the occurrence of burst suppression. PMID- 26489057 TI - Corrigendum: The Bright Future of Unconventional sigma/pi-Hole Interactions. PMID- 26489056 TI - No Difference in Adverse Events Between Surgically Treated Reduced and Unreduced Distal Radius Fractures. AB - OBJECTIVES: To determine if closed reduction is worthwhile for the subset of patients who choose operative treatment before attempted reduction of their distal radius fracture. We hypothesize that there are no differences in (1) adverse events and (2) subsequent surgeries between patients treated with manipulative reduction compared with those that were splinted without reduction. DESIGN: Retrospective cohort study. SETTING: Three affiliated urban hospitals in a single city in the United States. PATIENTS/PARTICIPANTS: One thousand five hundred eleven consecutive adult patients who underwent open reduction and internal fixation of their distal radius fracture between January 1, 2007, and December 31, 2012, of whom 102 (7%) were not reduced before surgery. INTERVENTION: Manipulative reduction compared with splinting without reduction. MAIN OUTCOME MEASUREMENTS: Adverse events were defined as any infections, hematomas treated operatively, disproportionate finger stiffness, (transient) neuropathology after surgery, delayed carpal tunnel release, malunion, reoperation for loss of alignment, hardware removal, and tendon ruptures within 1 year after surgery. Outcome measures were grouped to determine the overall adverse event rate and subsequent surgery rate. RESULTS: We found no difference in specific adverse events between unreduced and reduced fractures. After adjusting for possible confounding variables by logistic regression, we found no difference in overall rates of adverse events (adjusted odds ratio unreduced fractures 1.2, 95% confidence interval 0.67-2.0) and subsequent surgeries (adjusted odds ratio unreduced fractures 0.65, 95% confidence interval 0.23-1.8). CONCLUSIONS: Leaving the fracture unreduced before surgery was not associated with increased adverse events or subsequent surgeries. For patients who make an informed decision to undergo operative treatment for their closed neurovascular intact displaced distal radius fracture, manipulative reduction may not be helpful. PMID- 26489058 TI - Spotlights on our sister journals: ChemPhysChem 15/2015. PMID- 26489055 TI - Multicenter Randomized Clinical Trial of Nonoperative Versus Operative Treatment of Acute Acromio-Clavicular Joint Dislocation. AB - OBJECTIVE: To perform a randomized clinical trial of operative versus nonoperative treatment of acute acromio-clavicular (AC) joint dislocations using modern surgical fixation and both patient-based and surgeon-based outcome measures to determine which treatment method was superior. DESIGN: Prospective, randomized. SETTING: Multicenter. PATIENTS/PARTICIPANTS: Eight-three patients with acute (<28 days from the time of injury) complete (grade III, IV, and V) dislocations of the AC joint. INTERVENTION: Patients were randomized to operative repair with hook plate fixation versus nonoperative treatment (operative repair, 40; nonoperative treatment, 43). MAIN OUTCOME MEASUREMENTS: Disabilities of the Arm, Shoulder and Hand (DASH) score at 1 year after injury. Assessment also included a complete clinical assessment, evaluation of the constant score, and a radiographic evaluation at 6 weeks, and at 3, 6, 12, and 24 months. RESULTS: There were no demographic differences between the 2 groups, and the mechanisms of injury were similar between the 2 groups. The DASH scores (a disability score, lower score is better) were significantly better in the nonoperative group at 6 weeks (operative, 45; nonoperative, 31; P = 0.014) and 3 months (operative, 29; nonoperative, 16; P = 0.005). There were no significant differences between the groups at 6 months (operative, 14; nonoperative, 12; P = 0.442), 1 year (operative, 9; nonoperative, 9; P = 0.997), or 2 years (operative, 5; nonoperative, 6; P = 0.439) after injury. Constant scores were similar (better scores in the nonoperative group at 6 weeks, 3 months, and 6 months; P = 0.0001; and no difference thereafter). Although radiographic results were better in the operative group, the reoperation rate was significantly lower in the nonoperative group (P < 0.05). CONCLUSIONS: Although hook plate fixation resulted in superior radiographic alignment, it was not clinically superior to nonoperative treatment of acute complete dislocations of the AC joint. The nonoperative group had better early scores, although both groups improved from a significant level of initial disability to a good or excellent result (mean DASH score, 5-6; mean constant score, 91-95) at 2 years. At present, there is no clear evidence that operative treatment with the currently available hook plate improves short-term outcome for complete AC joint dislocations. PMID- 26489059 TI - Theoretical Insights into the Tuning of Metal Binding Sites of Paddlewheels in rht-Metal-Organic Frameworks. AB - Theoretical investigations of CO2 sorption are performed in four members of the highly tunable rht-metal-organic framework (MOF) platform. rht-MOFs contain two Cu(2+) ions that comprise the metal paddlewheels and both are in chemically distinct environments. Indeed, one type of Cu(2+) ion faces toward the center of the linker whereas the other type faces away from the center of the linker. Electronic structure calculations on the series of rht-MOFs demonstrate that one of the Cu(2+) ions has a consistently higher charge magnitude relative to the other. As a consequence, the Cu(2+) ion with the higher partial positive charge acts as the favored sorbate binding site at initial loading as revealed by grand canonical Monte Carlo (GCMC) simulations that include many-body polarization. It was found that the charge distribution about the copper paddlewheels is dependent on the type of functional groups present on the linker. This study demonstrates how the binding site about the metal paddlewheels in the rht-MOF platform can be controlled by changing the functionality on the organic ligand. PMID- 26489060 TI - Synthesis, X-Ray Structure, Magnetic Properties, and a Study of Intra/Intermolecular Radical-Radical Interactions of a Triradical TEMPO Compound. AB - A novel triradical compound with a P=S core and three branches functionalized with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) radicals is synthesized and characterized by IR, (1) H NMR, (31) P NMR, and EPR spectroscopy and MALDI-TOF mass spectrometry, and its chemical structure is confirmed by X-ray diffraction analysis. The triradical shows neither spin exchange interactions between its radical units nor detectable dipolar interactions. This is consistent with the separation between the radical units found in its X-ray diffraction structure, and discounts the existence of intramolecular interactions. This conclusion is confirmed by an EPR concentration study. The concentration at which intermolecular interactions start to appear is determined (5*10(-3) m) and this concentration should be taken into account as a higher concentration limit when studies on intramolecular radical-radical interactions in polyradicals with similar structure are required. SQUID magnetometry analysis of the compound shows antiferromagnetic interactions between the spin carriers of different molecules; that is, antiferromagnetic intermolecular interactions. PMID- 26489061 TI - Highly Oxidized Platinum Nanoparticles Prepared through Radio-Frequency Sputtering: Thermal Stability and Reaction Probability towards CO. AB - Platinum-oxide nanoparticles were prepared through the radio-frequency (RF) discharge sputtering of a Pt electrode in an oxygen atmosphere. The structure, particles size, electronic properties, and surface composition of the RF sputtered particles were studied by using transmission electron microscopy and X ray photoelectron spectroscopy. The application of the RF discharge method resulted in the formation of highly oxidized Pt(4+) species that were stable under ultrahigh vacuum conditions up to 100 degrees C, indicating the capability of Pt(4+) -O species to play an important role in the oxidation catalysis under real conditions. The thermal stability and reaction probability of Pt(4+) oxide species were analyzed and compared with those of Pt(2+) species. The reaction probability of PtO2 nanoparticles at 90 degrees C was found to be about ten times higher than that of PtO-like structures. PMID- 26489062 TI - Defining Physiological Predictors of Peripartum Maternal Bacteremia. AB - OBJECTIVE: This study aims to examine physiological and laboratory parameters associated with peripartum maternal bacteremia. STUDY DESIGN: This case-control study matched 115 cases (women with fever and bacteremia during the peripartum period) to 285 controls (defined as the next two febrile women with negative blood cultures at the same institution) from two academic medical centers from 2009 to 2013. Conditional logistic regression models were used to evaluate the association of physiological and laboratory parameters with maternal bacteremia at the time of initial and maximum fever. RESULTS: At the time of initial fever, temperature > 103 degrees F (adjusted odds ratio [aOR]: 5.58, 95% confidence interval [CI]: 2.05-15.19) and respiratory rate (RR) > 20 respirations per minute (aOR: 5.27, 95% CI: 2.32-11.96) were associated with bacteremia. At the time of maximum fever, temperature (> 102 degrees F, aOR: 3.37, 95% CI: 1.61-7.06; > 103 degrees F, aOR: 7.96, 95% CI: 3.56-17.82), heart rate > 110 beats per minute (aOR: 2.20, 95% CI: 1.21-3.99), and RR > 20 (aOR: 3.65, 95% CI: 1.65-8.08) were associated with bacteremia. Bandemia > 10% (aOR: 2.44, 95% CI: 1.07-5.54) was associated with bacteremia. CONCLUSION: Physiological and laboratory parameters associated with maternal bacteremia differed from those reported with sepsis in the adult critical care population. Further studies of objective markers are needed to improve detection and treatment of peripartum bacteremia. PMID- 26489063 TI - Extreme Obesity and Postcesarean Wound Complications in the Maternal-Fetal Medicine Unit Cesarean Registry. AB - OBJECTIVE: The objective of this study was to estimate the association between obesity and wound complications after cesarean delivery. METHODS: A secondary cohort analysis of the Maternal-Fetal Medicine Unit Cesarean Registry. We stratified the exposure, maternal body mass index (BMI) at delivery, as not obese (BMI < 30), obese (BMI 30-45), and extremely obese (BMI > 45). Our primary outcome was wound complication composite of wound infection, endometritis, wound opening, seroma/hematoma, and hospital readmission. Our secondary outcomes included infection composite (wound infection and endometritis) and each individual outcome included in the primary composite. We performed unadjusted and multivariable logistic regression analyses. RESULTS: We included 38,229 women who underwent cesarean; 39% were not obese, 55% were obese, and 6% were extremely obese. In our cohort, 40% of women underwent repeat cesarean and 57% underwent cesarean after labor. Extremely obese women had increased risk for any wound complication (14%, adjusted odds ratio [AOR], 1.65; 95% confidence interval [CI], 1.44-1.89), endometritis (8.3%, AOR, 1.26; 95% CI, 1.07-1.49), wound infection (2.0%, AOR, 3.77; 95% CI, 2.60-5.46), wound opening (0.8%, AOR, 5.47; 95% CI, 2.79-10.71), and wound infection-related hospital readmission (3.6%, AOR, 2.97; 95% CI, 2.26-3.91) compared with nonobese women. Obese women had increased risk for any wound complication (9.6%, AOR, 1.14; 95% CI, 1.06-1.23) and postcesarean infection (7.7%, AOR, 1.12; 95% CI, 1.03-1.22) but not other outcomes. CONCLUSION: In a large multicenter cohort study, we found that extreme obesity was associated with substantial increase in maternal postcesarean complications, and the association between obesity and postcesarean complications appears dose related. These findings validate associations found in single-center studies. PMID- 26489064 TI - Persistent Urogenital Sinus: Diagnostic Imaging for Clinical Management. What Does the Radiologist Need to Know? AB - BACKGROUND: Persistent urogenital sinus (PUGS) is a congenital pathological condition characterized by an abnormal communication between the urethra and vagina. It may be a part of a complex syndrome and can be more often associated with congenital malformations affecting the genitourinary tract system (33%) such as intersex, rectovaginal communication, bladder agenesis, absence of vagina, and hydrocolpos. The correct radiological assessment of PUGS is especially useful for clinicians since the exact anatomical evaluation of this abnormality is a crucial factor for surgical planning. The imaging study modalities, which are essentially based on ultrasonography, voiding cystourethrography, and magnetic resonance imaging, could be misinterpreted if not correctly performed. AIM: The aim of this article is to highlight this rare pathological condition and to help general radiologists in achieving the correct technical approach for the diagnosis. Special attention will be paid in discussing the role of different imaging modalities and their contribution to the diagnosis and clinical management of patients. PMID- 26489065 TI - A reversed-phase compatible thin-layer chromatography autography for the detection of acetylcholinesterase inhibitors. AB - A dual readout autographic assay to detect acetylcholinesterase inhibitors present in complex matrices adsorbed on reversed-phase or normal-phase thin-layer chromatography plates is described. Enzyme gel entrapment with an amphiphilic copolymer was used for assay development. The effects of substrate and enzyme concentrations, pH, incubation time, and incubation temperature on the sensitivity and the detection limit of the assay were evaluated. Experimental design and response surface methodology were used to optimize conditions with a minimum number of experiments. The assay allowed the detection of 0.01% w/w of physostigmine in both a spiked Sonchus oleraceus L. extract chromatographed on normal phase and a spiked Pimenta racemosa (Mill.) J.W. Moore leaf essential oil chromatographed on reversed phase. Finally, the reversed-phase thin-layer chromatography assay was applied to reveal the presence of an inhibitor in the Cymbopogon citratus (DC.) Stapf essential oil. The developed assay is able to detect acetylcholinesterase inhibitors present in complex matrixes that were chromatographed in normal phase or reversed-phase thin-layer chromatography. The detection limit for physostigmine on both normal and reversed phase was of 1*10( 4) MUg. The results can be read by a change in color and/or a change in fluorescence. PMID- 26489068 TI - [Legalization of cannabis: between political irresponsibility and loss of responsibility of psychiatrists]. AB - In Italy a political parliamentary majority, recognized by all the press as "cross party", is going to approve the law that will legalize the use of cannabis. As diversified in different Countries, it is a phenomenon which affects substantially homogeneous many European nations, as well as several states of the USA and other Countries of the world. The authors, after listing the main harmful effects of cannabis, especially in young people, on cognitive functions and on the onset of several psychotic disorders, express the need for reflection by the mental health experts on a problem of extreme relevance and urgency care. PMID- 26489069 TI - [Closing forensic psychiatric hospitals in Italy: a new deal for mental health care?]. AB - The date of March 31, 2015, following the Law 81/2014, has marked a historical transition with the final closure of the six forensic psychiatric hospitals in Italy. This law identifies a new pathway of care that involves small-scale high therapeutic profile facilities (Residenze per la Esecuzione della Misura di Sicurezza, REMS) instead of the old forensic psychiatric hospitals. The Law promotes a new recovery-oriented rehabilitation approach for the persons with mental disorders who committed a criminal offence, but lack criminal responsibility and deemed as socially dangerous. After a brief description of what happens abroad, this article highlights the positive aspects of the law that, as a whole, has to be considered innovative and unavoidable. The main debated problems are also reviewed, including the lack of changes to the Criminal Code; the improper equation between insanity and mental illness and social dangerousness; the evaluation of "socially dangerousness", based solely on "subjective qualities" of the person, assessed out of his/her context, without paying attention to family and social conditions suitable for discharge; the expensive implementation of the REMS, mainly based on security policies and less on care and rehabilitation, the delay in their construction, and the search for residential alternatives structures; the uncertain boundaries of professional responsibility. Finally, several actions are suggested that can support the implementation of the law: information programs addressed to the general population; training activities for mental health professionals; systematic monitoring and evaluation of the outcomes of the care provided to the forensic psychiatric population; implementation of Agreement Protocols and a better cooperation with the judiciary. Scientific societies dealing with psychosocial rehabilitation need to be involved in such issues relating to the identification of the best care and rehabilitation pathways, which should be implemented following closure of forensic psychiatric hospitals. PMID- 26489070 TI - Drug interactions with vortioxetine, a new multimodal antidepressant. AB - This article summarized the available knowledge on clinically relevant drug interactions of vortioxetine, a new antidepressant with a "multimodal" serotonergic mechanism of action, recently approved for the treatment of major depressive disorder. Although information is still limited and mainly based on studies performed in healthy volunteers, vortioxetine appears to have a favorable drug interaction profile. Concerning the potential for pharmacokinetic drug interactions, vortioxetine has little to no effect on various cytochrome P450 (CYP) isoforms and therefore is not expected to markedly affect plasma concentrations of other medications metabolized by these enzymes. This is a major advantage when compared to other antidepressants which are known to inhibit the activity of one or more CYP isoforms. On the other hand, dosage adjustments may be required when vortioxetine is coadministered with strong CYP2D6 inhibitors or broad-spectrum CYP inducers. Vortioxetine carries a relatively low risk for pharmacodynamic drug interactions, at least as compared to first-generation antidepressants. Like other antidepressants enhancing serotonergic activity, vortioxetine is associated with a potential risk of serotonin syndrome when used in combination with other serotonergic agents. Based on all available clinical data, vortioxetine has no increased risk of serotonin syndrome when used without other serotoninergic agents and at therapeutic doses. PMID- 26489071 TI - [Gambling Disorder: epidemiology, diagnosis, interpretative models and intervention]. AB - Gambling disorder is a frequently underdiagnosed and disabling disorder with a prevalence greatly increased in recent decades. For various reasons, only a small part of pathological gamblers seek a support making difficult an early identification and delaying the administration of appropriate treatment. In DSM 5, the disorder has been reclassified from an "Impulse-Control Disorder not elsewhere classified" to one of the "Substance-Related and Addictive Disorders" with the intention of improve the diagnosis, to better targeting the treatment and to stimulating further research efforts directed to the disorder. This article reviews assessment techniques, psychosocial and neurobiological factors in the development of pathological gambling and treatment strategies. PMID- 26489072 TI - [A survey on the use of patent expired drugs in psychiatric disorders: the psychiatrists' and neurologists' opinion and competence]. AB - The use of generic drugs is an increasing phenomenon in Italy, as well as in most other Countries. In front of this, the level of information of medical doctors about their characteristics is still frequently uncompletely defined and insufficiently documented. The Survey "InfoMind" explored by an on line questionnaire the level of knowledge and the principal modes of use of generic drugs in a wide group of Italian Psychiatrists and Neurologists. The attention was focused on the use of generic drugs both in general and in the field of antidepressant treatments. In the group of participants (246) who fulfilled the questionnaire, a valid degree of attention to the critical issues related to the use of generic drugs and a variable level of information with respect to the explored areas were found. Main topics of discordant opinions were those of the pharmacokinetic differences among generic and original drugs, the related potential influence on clinical response, the regulatory rules on production and quality control of generic drugs respect to original. The main issues emerged as critical also respect the use of antidepressant drugs. Also the opinions regarding the legal implications of the choice of prescribed drugs appear variable and of the greatest interest. PMID- 26489073 TI - Sexual dysfunctions in people with first-episode psychosis assessed according to a gender perspective. AB - AIM: Patients with chronic mental disorders often can suffer from sexual dysfunction. Nevertheless, the sexual functioning of new patients with first episode psychosis has been little explored. The aim of this study was to investigate gender differences in sexual functioning in people with first-episode psychosis. METHODS: A group of 40 males and 37 females with first-episode psychosis took part in the research. We administered a psychiatric protocol composed of the PANSS, UKU and SCID-DSM-IV diagnosis. RESULTS: We found that the 42.5% of the male group had sexual dysfunctions while the percentage of the female group was 37.8%. The correlation between sexual dysfunctions and psychopathology did not reveal any association in males. However, in females, general psychopathology and positive symptoms are linked to the alteration of vaginal lubrication: (r=0.547; p=0.003) and (r=0.485; p=0.011), although orgasm alteration was also associated with general psychopathology (r=0.500; p=0.013). Moreover, we found a relation between the alteration of vaginal lubrication with depression(r=0.627; p<0.0001) and disorder of volition (r=0.600; p<0.001). DISCUSSION AND CONCLUSIONS: These data suggest that the association between sexual dysfunctions and psychopathology regarded only women. Therefore, during the taking charge of patients it is fundamental to consider the gender-specific relationship between psychopathology and sexual problems. PMID- 26489074 TI - Alexithymia and self-reflectiveness in bronchial asthma. AB - The aim of the study was to investigate the role of alexithymia in bronchial asthma (BA) patients with low respiratory functioning hypothesizing that it could be used to differentiate a group of patients with clinically significant anxiety and depressive symptoms. We also aimed to investigate whether alexithymia was associated with reduced cognitive insight. Patients (n=153) were administered the State- Trait Anxiety Inventory-State subscale, the Beck Depression Inventory, the Toronto Alexithymia Scale, and the Beck Cognitive Insight Scale (BCIS). Alexithymia could help differentiate a group of patients with low respiratory functioning. Twenty-two percent of patients included in this subsample had airway obstruction, and 51% reported severe alexithymia. Patients with severe airway obstruction and high alexithymia (compared to other patients) also reported higher self-reflectiveness, and more depressive symptoms. Clinicians have to be aware of the presence of a subgroup of asthma patients with low respiratory functioning who report severe alexithymia. These patients often report moderate to severe depression and frequent doubts about one's own beliefs. PMID- 26489075 TI - [Me pinxit, me fecit]. PMID- 26489076 TI - FRAX and fracture prediction without bone mineral density. AB - The major application of FRAX in osteoporosis is to direct pharmacological interventions to those at high risk of fracture. Whereas the efficacy of osteoporosis treatment, with the possible exception of alendronate, is largely independent of baseline bone mineral density (BMD), it remains a widely held perception that osteoporosis therapies are only effective in the presence of low BMD. Thus, the use of FRAX in the absence of BMD to identify individuals requiring therapy remains the subject of some debate and is the focus of this review. The clinical risk factors used in FRAX have high evidence-based validity to identify a risk responsive to intervention. The selection of high-risk individuals with FRAX, without knowledge of BMD, preferentially selects for low BMD and thus identifies a risk that is responsive to pharmacological intervention. The prediction of fractures with the use of clinical risk factors alone in FRAX is comparable to the use of BMD alone to predict fractures and is suitable, therefore, in the many countries where facilities for BMD testing are sparse. In countries where access to BMD is greater, FRAX can be used without BMD in the majority of cases and BMD tests reserved for those close to a probability based intervention threshold. Thus concerns surrounding the use of FRAX in clinical practice without information on BMD are largely misplaced. PMID- 26489077 TI - Antiallergic effects of anti-interleukin-33 are associated with suppression of immunoglobulin light chain and inducible nitric oxide synthase. AB - OBJECTIVE: We aimed to find novel genes that are significantly induced in allergic mice and that are significantly downregulated with anti-interleukin (IL) 33 treatment. METHODS: Thirty-six mice were allocated into each of group A (intraperitoneal [i.p.]) sensitized and intranasally challenged to saline solution), group B (sensitized and challenged to ovalbumin), group C (sensitized and challenged with ovalbumin, and null treatment with i.p. saline solution), and group D (sensitized and challenged with ovalbumin, and treatment with anti-IL-33 i.p. injection). We counted the number of nose-scratching in 10 minutes, serum ovalbumin-specific immunoglobulin E (IgE), and titers of cytokines (IL-1, IL-4, IL-5, IL-10, IL-13) in bronchoalveolar lavage fluid. By using one whole lung from each mouse, we performed microarray analysis and real-time polymerase chain reaction. RESULTS: group D showed a significantly reduced nose-scratching events and lower serum ovalbumin-specific IgE compared with groups B and C. All the cytokines in the bronchoalveolar lavage fluid were significantly decreased after anti-IL-33 treatment. Microarray analysis revealed that group B (immunoglobulin free light chain [IgFLC], 89.1 times; nitric oxide synthase [NOS] 2, 11.5 times) and group C (IgFLC, 141.6 times; NOS2, 11.7 times) had significantly increased expression of IgFLC and NOS2 genes compared with group A. After anti-IL-33 treatment, group D showed significantly decreased expression of both IgFLC (49.3 times) and NOS2 (6.5 times). In real-time polymerase chain reaction, groups B and C had significantly increased expression of these genes (IgFLC, 10.4 times and 29 times, respectively; NOS2, 3.8 times and 4.5 times, respectively). After treatment, group D showed significantly decreased expression of IgFLC (5.0 times) and NOS2 (2.5 times). CONCLUSION: The antiallergic effect of anti-IL-33 can be explained by suppression of IgFLC and NOS2 in a murine model of allergic rhinitis. PMID- 26489078 TI - Orientation Dependent MR Signal Decay Differentiates between People with MS, Their Asymptomatic Siblings and Unrelated Healthy Controls. AB - R2* relaxometry of the brain is a quantitative magnetic resonance technique which is influenced by iron and myelin content across different brain regions. Multiple sclerosis (MS) is a common inflammatory, demyelinating disease affecting both white and grey matter regions of the CNS. Using R2*, increased iron deposition has been described in deep gray matter of MS patients. Iron accumulation might promote oxidative stress in the brain, which can lead to cell death and neurodegeneration. However, recent histological work indicates that iron may be reduced within the normal appearing white matter (WM) in MS. In the present study we analyzed the R2* signal across the white matter in 39 patients with MS, 31 asymptomatic age matched siblings of patients and 30 age-matched controls. The measurement of R2* in white matter is affected by the signal's dependency on white matter fibre orientation with respect to the main magnetic field which can be accounted using diffusion tensor imaging. We observed a clear separation of the three study groups in R2*. The values in the MS group were significantly lower compared to the siblings and controls, while the siblings group presented with significantly higher R2* values than both unrelated healthy controls and patients. Furthermore, we found significantly decreased normal-appearing white matter R2* values in patients with more severe disease course. Angle resolved analysis of R2* improves the sensitivity for detecting subtle differences in WM R2* compared to standard histogram based analyses. Our findings suggest that the decreased R2* values in MS are due to diffuse tissue damage and decreased myelin in the normal appearing and diffusely abnormal WM. The increased R2* in unaffected siblings may identify a predisposition to increased iron and the potential for oxidative stress as a risk factor for developing MS. PMID- 26489079 TI - The Relationship between Post-Traumatic Symptoms, Parenting Style, and Resilience among Adolescents in Liaoning, China: A Cross-Sectional Study. AB - BACKGROUND: In China, a growing number of adolescents have experienced traumatic events that have resulted in PTSD (post-traumatic stress disorder). Post traumatic symptoms are common psychological problems in adolescents who have experienced traumatic events. However, existing studies tend to focus on the factors influencing PTSD, such as the response styles and social support, and studies on the relationships between parenting style, resilience and post traumatic symptoms are still rare. OBJECTIVES: To analyze the relationships between parenting style, resilience and post-traumatic symptoms among adolescents in China. METHODS: A cross-sectional survey was conducted from June to December 2013 in the Liaoning Province, China. N = 5765 adolescents (aged 12 to 18 years old) were ultimately chosen to participate. The Chinese version of the Essen Trauma Inventory for Kids and Juveniles (ETI-KJ), a modified version of the Parental Authority Questionnaire, and the Chinese Resilience Scale were used to estimate the post-traumatic symptoms, parenting style, and resilience, respectively. Pearson's correlations, multiple linear regression analyses and structural equation modeling (SEM) were applied to analyze the data. RESULTS: Of the adolescents, 39.76% (N = 2292) had been exposed to traumatic events during their lives. The prevalence of probable PTSD at the time of the interview (one month-prevalence) was 12.65%. Parenting style and resilience were significantly associated with post-traumatic symptoms. According to the SEM, parenting style had a significant direct effect on resilience (0.70, P<0.01) and post-traumatic symptoms (-0.15, P<0.05), and resilience had a significant direct effect on the post-traumatic symptoms (-0.43, P<0.01). Furthermore, parenting style had a significant indirect effect (-0.43*0.70 = -0.30. P<0.01) on the post-traumatic symptoms through resilience. The SEM significantly explained 49% of the variance in resilience and 30% of the variance in post-traumatic symptoms. CONCLUSIONS: Parenting style and resilience have significant effects on adolescents' post traumatic symptoms. Schools and social-related departments could share knowledge on the impact of parenting style with parents enabling them to improve their own parenting style and their children's resilience and ability to respond effectively to traumatic events. PMID- 26489080 TI - Adolescent Heavy Drinking Does Not Affect Maturation of Basic Executive Functioning: Longitudinal Findings from the TRAILS Study. AB - BACKGROUND AND AIMS: Excessive alcohol use is assumed to affect maturation of cognitive functioning in adolescence. However, most existing studies that have tested this hypothesis are seriously flawed due to the use of selective groups and/or cross-sectional designs, which limits the ability to draw firm conclusions. This longitudinal study investigated whether patterns of alcohol use predicted differences in maturation of executive functioning in adolescence. Additionally, gender was tested as a possible moderator. METHODS: We used data from the Tracking Adolescents' Individual Lives Survey (TRAILS), which comprises a cohort of 2,230 Dutch adolescents. Maturation of executive functioning was measured by assessing the standardized improvement on each of four basic executive functions (i.e., inhibition, working memory, and shift- and sustained attention) between ages 11 and 19. Participants were assigned to one of six (heavy) drinking groups (i.e., non-drinkers, light drinkers, infrequent heavy drinkers, increased heavy drinkers, decreased heavy drinkers, and chronic heavy drinkers). We conducted linear regression analyses, and adjusted for relevant confounders. RESULTS: The six drinking groups did not reveal significant differences in maturation between drinking groups. E.g., maturation executive functioning of chronic heavy drinkers in comparison to non-drinkers; inhibition: B = -0.14, 95% CI [-0.41 to 0.14], working memory: B = -0.03, 95% CI [-0.26 to 0.21], shift attention: B = 0.13, 95% CI [-0.17 to 0.41], sustained attention: B = 0.12, 95% CI [-0.60 to 0.36]. Furthermore, gender was not found to be a significant moderator. CONCLUSIONS: Four years of weekly heavy drinking (i.e., chronic heavy drinkers) did not result in measurable impairments in four basic executive functions. Thus, regular heavy drinking in adolescence does not seem to affect these basic behavioural measures of executive functioning. PMID- 26489081 TI - The COMTp.Val158Met Polymorphism and Cognitive Performance in Adult Development, Healthy Aging and Mild Cognitive Impairment. AB - BACKGROUND: The impact of genetic polymorphisms on cognition is assumed to increase with age as losses of brain resources have to be compensated for. We investigate the relation of catechol-O-methyltransferase (COMT)p.Val158Met polymorphism and cognitive capacity in the course of adult development, healthy aging and the development of mild cognitive impairment (MCI) in two birth cohorts of subjects born between 1930 and 1932 or between 1950 and 1952. METHODS: Thorough neuropsychological assessment was conducted in a total of 587 participants across three examination waves between 1993 and 2008. The COMT genotype was determined as a restriction fragment length polymorphism after PCR amplification and digestion with NlaIII. RESULTS: Significant effects of the COMTp.Val158Met polymorphism were identified for attention and cognitive flexibility in the younger but not the older cohort. CONCLUSION: These results confirm the importance of the COMTp.Val158Met genotype on tasks assessing attention and cognitive flexibility in midlife but not in healthy aging and the development of MCI. Our findings suggest that the influence of COMT changes as a function of age, decreasing from midlife to aging. PMID- 26489082 TI - Cone-Beam CT Angiography for Hepatocellular Carcinoma: Current Status. AB - Cone-beam CT (CBCT) is generated during a rotational sweep of the C-arm around the patient, and can be a valuable imaging technique, providing in situ cross sectional imaging. It is easy to evaluate the morphologic characteristics of hepatic arteries from multiple views with the use of various reconstruction techniques, such as maximum intensity projection (MIP) and volume rendering. CBCT angiography is capable of providing more information than the standard 2 dimensional angiography in visualizing hepatocellular carcinomas (HCCs) and targeting tumors though precise microcatheter placement in close proximity to HCCs. It can also be useful in evaluating treatment success at the time of the procedure. It is anticipated that CBCT could reduce radiation exposure, the overall procedure time and contrast material use because it allows immediate feedback for an efficient angiographic procedure. Therefore, CBCT angiography is an exciting technology with the potential to significantly impact the practice of interventional radiology. The purpose of this article is to provide a review of the principles, clinical applications and technique of CBCT angiography for HCC treatment. PMID- 26489083 TI - Criteria Used in Clinical Practice to Guide Immunosuppressive Treatment in Patients with Primary Sclerosing Cholangitis. AB - BACKGROUND & AIMS: Current guidelines recommend immunosuppressive treatment (IT) in patients with primary sclerosing cholangitis (PSC) and elevated aminotransferase levels more than five times the upper limit of normal and elevated serum IgG-levels above twice the upper limit of normal. Since there is no evidence to support this recommendation, we aimed to assess the criteria that guided clinicians in clinical practice to initiate IT in patients with previously diagnosed PSC. METHODS: This is a retrospective analysis of 196 PSC patients from seven German hepatology centers, of whom 36 patients had received IT solely for their liver disease during the course of PSC. Analyses were carried out using methods for competing risks. RESULTS: A simplified autoimmune hepatitis (AIH) score >5 (HR of 36, p<0.0001) and a modified histological activity index (mHAI) greater than 3/18 points (HR 3.6, p = 0.0274) were associated with the initiation of IT during the course of PSC. Of note, PSC patients who subsequently received IT differed already at the time of PSC diagnosis from those patients, who did not receive IT during follow-up: they presented with increased levels of IgG (p = 0.004) and more frequently had clinical signs of cirrhosis (p = 0.0002). CONCLUSIONS: This is the first study which investigates the parameters associated with IT in patients with PSC in clinical practice. A simplified AIH score >5 and a mHAI score >3, suggesting concomitant features of AIH, influenced the decision to introduce IT during the course of PSC. In German clinical practice, the cutoffs used to guide IT may be lower than recommended by current guidelines. PMID- 26489084 TI - National Analysis of Short-Term Outcomes and Volume-Outcome Relationships for Transcatheter Aortic Valve Replacement in the Era of Commercialization. AB - OBJECTIVES: We queried the 2012 National Inpatient Sample in order to (1) further describe the short-term outcomes for transcatheter aortic valve replacement (TAVR) and (2) characterize possible volume-outcome relationships and other prognostic factors for this procedure. METHODS: Demographics and inhospital outcomes were tabulated for all patients, as were hospital characteristics and procedural-volume data for all centers at which patients underwent TAVR. Logistic regression analyses were performed to identify independent risk factors for mortality or morbidity. RESULTS: 7,635 patients aged >= 18 years received TAVR during the study period; 84.5% (n = 6,450) underwent transfemoral TAVR and the rest were treated transapically. The median age was 83 years (IQR 77-88 years) and cardiovascular comorbidities were widespread. Overall inhospital mortality was 5.0% (n = 380), and 1.4% (n = 105) of the patients experienced a stroke. All cause procedure-related morbidity was 24.7% (n = 1,885). Annual hospital TAVR volume did not predict inhospital mortality or morbidity (OR 1.00, 95% CI 0.99 1.00, p = 0.111 and OR 1.00, 95% CI 0.99-1.00, p = 0.947, respectively). CONCLUSIONS: Our analysis helps to confirm the short-term safety profile of TAVR and further demonstrates that inhospital outcomes have remained acceptable as this procedure has become commercialized. PMID- 26489085 TI - Enhancing Butanol Production under the Stress Environments of Co-Culturing Clostridium acetobutylicum/Saccharomyces cerevisiae Integrated with Exogenous Butyrate Addition. AB - In this study, an efficient acetone-butanol-ethanol (ABE) fermentation strategy integrating Clostridium acetobutylicum/Saccharomyces cerevisiae co-culturing system with exogenous butyrate addition, was proposed and experimentally conducted. In solventogenic phase, by adding 0.2 g-DCW/L-broth viable S. cerevisiae cells and 4.0 g/L-broth concentrated butyrate solution into C. acetobutylicum culture broth, final butanol concentration and butanol/acetone ratio in a 7 L anaerobic fermentor reached the highest levels of 15.74 g/L and 2.83 respectively, with the increments of 35% and 43% as compared with those of control. Theoretical and experimental analysis revealed that, the proposed strategy could, 1) extensively induce secretion of amino acids particularly lysine, which are favorable for both C. acetobutylicum survival and butanol synthesis under high butanol concentration environment; 2) enhance the utilization ability of C. acetobutylicum on glucose and over-produce intracellular NADH for butanol synthesis in C. acetobutylicum metabolism simultaneously; 3) direct most of extra consumed glucose into butanol synthesis route. The synergetic actions of effective amino acids assimilation, high rates of substrate consumption and NADH regeneration yielded highest butanol concentration and butanol ratio in C. acetobutylicum under this stress environment. The proposed method supplies an alternative way to improve ABE fermentation performance by traditional fermentation technology. PMID- 26489087 TI - 15th ESASO Retina Academy. October 22-24, 2015, Barcelona, Spain: Abstracts. PMID- 26489086 TI - Mechanical Loading Synergistically Increases Trabecular Bone Volume and Improves Mechanical Properties in the Mouse when BMP Signaling Is Specifically Ablated in Osteoblasts. AB - Bone homeostasis is affected by several factors, particularly mechanical loading and growth factor signaling pathways. There is overwhelming evidence to validate the importance of these signaling pathways, however, whether these signals work synergistically or independently to contribute to proper bone maintenance is poorly understood. Weight-bearing exercise increases mechanical load on the skeletal system and can improves bone quality. We previously reported that conditional knockout (cKO) of Bmpr1a, which encodes one of the type 1 receptors for Bone Morphogenetic Proteins (BMPs), in an osteoblast-specific manner increased trabecular bone mass by suppressing osteoclastogenesis. The cKO bones also showed increased cortical porosity, which is expected to impair bone mechanical properties. Here, we evaluated the impact of weight-bearing exercise on the cKO bone phenotype to understand interactions between mechanical loading and BMP signaling through BMPR1A. Male mice with disruption of Bmpr1a induced at 9 weeks of age, exercised 5 days per week on a motor-driven treadmill from 11 to 16 weeks of age. Trabecular bone volume in cKO tibia was further increased by exercise, whereas exercise did not affect the trabecular bone in the control genotype group. This finding was supported by decreased levels of osteoclasts in the cKO tibiae. The cortical porosity in the cKO bones showed a marginally significant decrease with exercise and approached normal levels. Exercise increased ductility and toughness in the cKO bones. Taken together, reduction in BMPR1A signaling may sensitize osteoblasts for mechanical loading to improve bone mechanical properties. PMID- 26489088 TI - Evaluation in a Dog Model of Three Antimicrobial Glassy Coatings: Prevention of Bone Loss around Implants and Microbial Assessments. AB - OBJECTIVES: The aim of the present study is to evaluate, in a ligature-induced peri-implantitis model, the efficacy of three antimicrobial glassy coatings in the prevention of biofilm formation, intrasulcular bacterial growth and the resulting peri-implant bone loss. METHODS: Mandibular premolars were bilaterally extracted from five beagle dogs. Four dental implants were inserted on each hemiarch. Eight weeks after, one control zirconia abutment and three with different bactericidal coatings (G1n-Ag, ZnO35, G3) were connected. After a plaque control period, bacterial accumulation was allowed and biofilm formation on abutments was observed by Scanning Electron Microscopy (SEM). Peri-implantitis was induced by cotton ligatures. Microbial samples and peri-implant crestal bone levels of all implant sites were obtained before, during and after the breakdown period. RESULTS: During experimental induce peri-implantitis: colony forming units counts from intrasulcular microbial samples at implants with G1n-Ag coated abutment remained close to the basal inoculum; G3 and ZnO35 coatings showed similar low counts; and anaerobic bacterias counts at control abutments exhibited a logarithmic increase by more than 2. Bone loss during passive breakdown period was no statistically significant. Additional bone loss occurred during ligature induce breakdown: 0.71 (SD 0.48) at G3 coating, 0.57 (SD 0.36) at ZnO35 coating, 0.74 (SD 0.47) at G1n-Ag coating, and 1.29 (SD 0.45) at control abutments; and statistically significant differences (p<0.001) were found. The lowest bone loss at the end of the experiment was exhibited by implants dressing G3 coated abutments (mean 2.1; SD 0.42). SIGNIFICANCE: Antimicrobial glassy coatings could be a useful tool to ward off, diminish or delay peri-implantitis progression. PMID- 26489089 TI - Where Failure Is Not an Option -Personalized Medicine in Astronauts. AB - Drug safety and efficacy are highly variable among patients. Most patients will experience the desired drug effect, but some may suffer from adverse drug reactions or gain no benefit. Pharmacogenetic testing serves as a pre-treatment diagnostic option in situations where failure or adverse events should be avoided at all costs. One such situation is human space flight. On the international space station (ISS), a list of drugs is available to cover typical emergency settings, as well as the long-term treatment of common conditions for the use in self-medicating common ailments developing over a definite period. Here, we scrutinized the list of the 78 drugs permanently available at the ISS (year 2014) to determine the extent to which their metabolism may be affected by genetic polymorphisms, potentially requiring genotype-specific dosing or choice of an alternative drug. The purpose of this analysis was to estimate the potential benefit of pharmacogenetic diagnostics in astronauts to prevent therapy failure or side effects. PMID- 26489090 TI - Cardioembolism and Involvement of the Insular Cortex in Patients with Ischemic Stroke. AB - BACKGROUND: To evaluate whether topographical characteristics of insular involvement in ischemic stroke are associated with cardioembolism. METHODS AND FINDINGS: A consecutive series of patients hospitalized for ischemic stroke within 7 days of symptom onset were identified. Based on diffusion-weighted imaging, we included those who had ischemic lesions in the middle cerebral artery (MCA) territory. Each patient was assigned to one of two groups based on the presence or absence of insular involvement. The primary outcome was the frequency of cardioembolism, which was compared based on insular involvement. Of 1,311 patients with ischemic stroke in the MCA territory, 112 had insular involvement (8.5%). The frequency of cardioembolism in patients with insular involvement (52.7%) was significantly higher than that in patients without insular involvement (30.4%, P < 0.001). Although insular involvement was associated with a severe baseline National Institutes of Health Stroke Scale score (13 vs. 4), it did not independently affect the 3-month functional outcome. CONCLUSIONS: In cases of stroke in the MCA territory, involvement of the insular cortex may be associated with a risk of cardioembolism. PMID- 26489092 TI - The Customer Isn't Always Right-Conservation and Animal Welfare Implications of the Increasing Demand for Wildlife Tourism. AB - Tourism accounts for 9% of global GDP and comprises 1.1 billion tourist arrivals per annum. Visits to wildlife tourist attractions (WTAs) may account for 20-40% of global tourism, but no studies have audited the diversity of WTAs and their impacts on the conservation status and welfare of subject animals. We scored these impacts for 24 types of WTA, visited by 3.6-6 million tourists per year, and compared our scores to tourists' feedback on TripAdvisor. Six WTA types (impacting 1,500-13,000 individual animals) had net positive conservation/welfare impacts, but 14 (120,000-340,000 individuals) had negative conservation impacts and 18 (230,000-550,000 individuals) had negative welfare impacts. Despite these figures only 7.8% of all tourist feedback on these WTAs was negative due to conservation/welfare concerns. We demonstrate that WTAs have substantial negative effects that are unrecognised by the majority of tourists, suggesting an urgent need for tourist education and regulation of WTAs worldwide. PMID- 26489091 TI - Disrupted Ipsilateral Network Connectivity in Temporal Lobe Epilepsy. AB - OBJECTIVE: The current practice under which patients with refractory epilepsy are surgically treated is based mainly on the identification of specific cortical areas, mainly the epileptogenic zone, which is believed to be responsible for generation of seizures. A better understanding of the whole epileptic network and its components and properties is required before more effective and less invasive therapies can be developed. The aim of the present study was to partially characterize the evolution of the functional network during the preictal-ictal transition in partial seizures in patients with temporal lobe epilepsy (TLE). METHODS: Scalp and foramen ovale (FOE) recordings from twenty-two TLE patients were analyzed under the complex network perspective. The density of links, average path length, average clustering coefficient, and modularity were calculated during the preictal and the ictal stages. Both linear-Pearson correlation-and non-linear-phase synchronization-measures were used as proxies of functional connectivity between the electrode locations areas. The transition from one stage to the other was evaluated in the whole network and in the mesial sub-networks. The results were compared with a voltage-dependent measure, namely, the spectral entropy. RESULTS: Changes in the global functional network during the transition from the preictal to the ictal stage show, in the linear case, that in sixteen cases (72.7%) the density of the links increased during the seizure, with a decrease in the average path length in fifteen cases (68.1%). There was also a preictal and ictal imbalance in functional connectivity during both stages (77.2% to 86.3%). The SE dropped during the seizure in 95.4% of the cases, but did not show any tendency towards lateralization. When using the nonlinear measure of functional connectivity, the phase synchronization, similar results were obtained. CONCLUSIONS: In TLE patients, the transition to the ictal stage is accompanied by increasing global synchronization and a more ordered spectral content of the signals, indicated by lower spectral entropy. The interictal connectivity imbalance (lower ipsilateral connectivity) is sustained during the seizure, irrespective of any appreciable imbalance in the spectral entropy of the mesial recordings. PMID- 26489093 TI - Changes in T-Tubules and Sarcoplasmic Reticulum in Ventricular Myocytes in Early Cardiac Hypertrophy in a Pressure Overload Rat Model. AB - BACKGROUND/AIMS: Pressure-overload (PO) causes cardiac hypertrophy (CH), and eventually leads to heart failure (HF). HF ventricular myocytes present transverse-tubules (TT) loss or disarrangement and decreased sarcoplasmic reticulum (SR) density, and both contribute to altered Ca2+ signaling and heart dysfunction. It has been shown that TT remodeling precedes HF, however, it is unknown whether SR structural and functional remodeling also starts early in CH. METHODS: Using confocal microscopy, we assessed TT (with Di-8-ANNEPS) and SR (with SR-trapped Mag-Fluo-4) densities, as well as SR fluorophore diffusion (fluorescence recovery after photobleach; FRAP), cytosolic Ca2+ signaling and ex vivo cardiac performance in a PO rat hypertrophy model induced by abdominal aortic constriction (at 6 weeks). RESULTS: Rats developed CH, while cardiac performance, basal and upon beta-adrenergic stimulation, remained unaltered. TT density decreased by ~14%, without spatial disarrangement, while SR density decreased by ~7%. More important, FRAP was ~30% slower, but with similar maximum recovery, suggesting decreased SR interconnectivity. Systolic and diastolic Ca2+ signaling and SR Ca2+ content were unaltered. CONCLUSION: SR remodeling is an early CH event, similar to TT remodeling, appearing during compensated hypertrophy. Nevertheless, myocytes can withstand those moderate structural changes in SR and TT, preserving normal Ca2+ signaling and contractility. PMID- 26489094 TI - Is It Necessary Managing Carnivores to Reverse the Decline of Endangered Prey Species? Insights from a Removal Experiment of Mesocarnivores to Benefit Demographic Parameters of the Pyrenean Capercaillie. AB - Mesopredator control has long been used to alleviate the effect of elevated predation pressure on vulnerable, threatened or valuable species. However, the convenience of using mesopredator controls is technically questionable and scientifically-sound research is therefore required to evaluate the impact of predation on prey case by case. In this study we evaluated the effect of the alteration of terrestrial mesopredator dynamics on the demographic parameters of a relict capercaillie Tetrao urogallus aquitanicus population currently in decline for which the impact of predation has not previously been assessed. We used a six-year mesocarnivore removal experiment (2008-2013) together with seven years of previous demographic information on capercaillies (1999-2007) within a before-after control-impact (BACI) design to evaluate the effect of mesocarnivore removal on capercaillie demographic parameters and on spatial behaviour of the most frequent predatory mesocarnivores of the capercaillie (Martes spp. and red fox Vulpes vulpes). Using a dynamic site-occupancy approach, the reduction of mesocarnivore population levels as a result of removal was clear for marten species, mainly during key months for capercaillie reproduction, but not for the red fox. Our results show that the breeding success of capercaillies was enhanced in areas where carnivores were removed and was inversely related to the occupation level of the studied mesocarnivores, although being only significant for Martes spp. Moreover, capercaillie predation rates were lower and adult survival seemingly higher in treatment during the removal phase. Cost-effective, long-term management interventions to ensure the recovery of this threatened capercaillie population are discussed in the light of the results. At our study area, the decision for implementing predation management should be included within a broader long-term conservation perspective. In this regard, a more feasible and sustainable management intervention in ecological and economic terms may be to balance the impact of mesocarnivores on capercaillies through the recovery of apex predators. PMID- 26489097 TI - Behavioral Addictions. PMID- 26489095 TI - EAST Organizes Drosophila Insulator Proteins in the Interchromosomal Nuclear Compartment and Modulates CP190 Binding to Chromatin. AB - Recent data suggest that insulators organize chromatin architecture in the nucleus. The best studied Drosophila insulator proteins, dCTCF (a homolog of the vertebrate insulator protein CTCF) and Su(Hw), are DNA-binding zinc finger proteins. Different isoforms of the BTB-containing protein Mod(mdg4) interact with Su(Hw) and dCTCF. The CP190 protein is a cofactor for the dCTCF and Su(Hw) insulators. CP190 is required for the functional activity of insulator proteins and is involved in the aggregation of the insulator proteins into specific structures named nuclear speckles. Here, we have shown that the nuclear distribution of CP190 is dependent on the level of EAST protein, an essential component of the interchromatin compartment. EAST interacts with CP190 and Mod(mdg4)-67.2 proteins in vitro and in vivo. Over-expression of EAST in S2 cells leads to an extrusion of the CP190 from the insulator bodies containing Su(Hw), Mod(mdg4)-67.2, and dCTCF. In consistent with the role of the insulator bodies in assembly of protein complexes, EAST over-expression led to a striking decrease of the CP190 binding with the dCTCF and Su(Hw) dependent insulators and promoters. These results suggest that EAST is involved in the regulation of CP190 nuclear localization. PMID- 26489096 TI - Experiences of Community-Living Older Adults Receiving Integrated Care Based on the Chronic Care Model: A Qualitative Study. AB - BACKGROUND: Integrated care models aim to solve the problem of fragmented and poorly coordinated care in current healthcare systems. These models aim to be patient-centered by providing continuous and coordinated care and by considering the needs and preferences of patients. The objective of this study was to evaluate the opinions and experiences of community-living older adults with regard to integrated care and support, along with the extent to which it meets their health and social needs. METHODS: Semi-structured interviews were conducted with 23 older adults receiving integrated care and support through "Embrace," an integrated care model for community-living older adults that is based on the Chronic Care Model and a population health management model. Embrace is currently fully operational in the northern region of the Netherlands. Data analysis was based on the grounded theory approach. RESULTS: Responses of participants concerned two focus areas: 1) Experiences with aging, with the themes "Struggling with health," "Increasing dependency," "Decreasing social interaction," "Loss of control," and "Fears;" and 2) Experiences with Embrace, with the themes "Relationship with the case manager," "Interactions," and "Feeling in control, safe, and secure". The prospect of becoming dependent and losing control was a key concept in the lives of the older adults interviewed. Embrace reinforced the participants' ability to stay in control, even if they were dependent on others. Furthermore, participants felt safe and secure, in contrast to the fears of increasing dependency within the standard care system. CONCLUSION: The results indicate that integrated care and support provided through Embrace met the health and social needs of older adults, who were coping with the consequences of aging. PMID- 26489100 TI - Can a Bug in the Gut Act Like a Drug in the Brain? AB - Microorganisms inhabiting the gut exist in a symbiotic relationship with our bodies, performing many essential metabolic tasks for human physiology. The gut brain axis is a bidirectional communication system integrating neural, hormonal, and immunological signaling between the gut and brain. There is strong experimental evidence from animal studies that the intestinal microbiome has an important role in the control of brain development, function, and behavior. A small number of clinical studies, mainly in healthy individuals, using probiotic formulations as an experimental probe suggest that gut bugs may indeed act like a drug and affect the brain, but much more work is needed. PMID- 26489101 TI - Risky Behaviors and Social Networking Sites: How Is YouTube Influencing Our Youth? AB - Choking, cutting, and setting oneself on fire are just a few of the risky behaviors that the YouTube video sharing website has allowed youth around the world to view, emulate, and comment on. Some researchers contend that the viewing of videos may normalize these behaviors for youth. Disturbing current trends are explored to illustrate the darker side of YouTube. Psychiatric-mental health nurses (PMHNs) are in key positions to help parents and youth better understand the benefits and risks of social networking sites, including YouTube, and to encourage healthy and safe use of the Internet. Nursing implications are offered for PMHNs, educators, health care providers, and parents who have contact with this population. PMID- 26489102 TI - Psychiatric-Mental Health Nurses' Exposure to Clients With Problematic Internet Experiences: A Mixed-Methods Pilot Study. AB - The current study explored the type and number of problematic Internet experiences (PIE) encountered by psychiatric-mental health nurses (PMHN) in clinical practice and analyzed PMHNs' clinical cases of clients with PIE. A mixed methods quantitative survey with a qualitative component measured the types and number of PIE cases via a descriptive survey and derived themes using narrative inquiry methodology from written case descriptions. A sample of 16 PMHNs provided quantitative data and nine participants summarized clinical cases. PMHNs reported 92 adult and 33 child cases of PIE. Six themes were derived from the narrative data: (a) searching for pornography; (b) developing online romantic relationships; (c) online gaming is ruining my life; (d) spending excessive time on the Internet; (e) coming to terms with online sexual behaviors and addiction; and (f) cyberbullying. Implications for PMHN practice include the need for further assessment and intervention as PIE increase in the future. PMID- 26489103 TI - The Impact of Disordered Gambling Among Older Adults. AB - The current study is a secondary analysis that describes the mental, social, and economic health impacts of disordered gambling in older adults recovering from pathological gambling. The study sought to answer the following research questions: (a) What are the problem behaviors in the mental, social, and economic health dimensions?; and (b) What is the association between mental, social, and economic health impact dimensions and the South Oaks Gambling Screen score? The study population comprised a convenience sample of 40 older adults recovering from pathological gambling in the Midwestern United States. Participants were originally recruited from Gamblers Anonymous((r)) meetings and gambling treatment centers. Significant findings for the current study population were: gambling causing depression, being fired from a job due to gambling, and still paying off gambling debt. Nurses should evaluate effects of disordered gambling, assess for disordered gambling, and include a financial assessment in routine care of this patient population. PMID- 26489104 TI - Addiction to Work: A Critical Review of the Workaholism Construct and Recommendations for Assessment. AB - Workaholism was first conceptualized in the early 1970s as a behavioral addiction, featuring compulsive use and interpersonal conflict. The current article briefly examines the empirical and theoretical literature over the past four decades. In relation to conceptualization and measurement, how the concept of workaholism has worsened from using dimensions based on anecdotal evidence, ad hoc measures with weak theoretical foundation, and poor factorial validity of multidimensional conceptualizations is highlighted. Benefits of building on the addiction literature to conceptualize workaholism are presented (including the only instrument that has used core addiction criteria: the Bergen Work Addiction Scale). Problems estimating accurate prevalence estimates of work addiction are also presented. Individual and sociocultural risk factors, and the negative consequences of workaholism from the addiction perspective (e.g., depression, burnout, poor health, life dissatisfaction, family/relationship problems) are discussed. The current article summarizes how current research can be used to evaluate workaholism by psychiatric-mental health nurses in clinical practice, including primary care and mental health settings. PMID- 26489105 TI - Behind Bars: Experiences Conducting Behavioral Addictions Research in a County Jail. AB - Individuals who are incarcerated experience disparities in mental health, warranting study by nurse researchers. However, nurse researchers' unfamiliarity with the jail environment may pose a barrier to conducting research with this vulnerable population. The current article presents an account of the planning and implementation needed to study perceived health and gambling behavior in county jail inmates. The challenges and rewards of research that aim to better understand the mental health issues affecting this population are also identified. Developing relationships with jail personnel and understanding the incarcerated population and their surroundings are key to conducting research in this environment. PMID- 26489107 TI - SAFETY AND EFFECTIVENESS OF AZITHROMYCIN IN THE TREATMENT OF LOWER RESPIRATORY INFECTIONS: AN INTERNATIONAL, MULTICENTER, NON-COMPARATIVE STUDY. AB - The aim of this study was to describe clinical effectiveness of azithromycin in the management of lower respiratory tract infections in daily clinical practice, to examine duration of symptoms after therapy initiation, and to record any possible adverse effects of azithromycin treatment. A total of 153 patients were included in the analysis of the effectiveness of azithromycin: 94 patients with community acquired pneumonia (CAP) and 59 with acute exacerbation of chronic bronchitis (AECB). Clinical effectiveness was assessed as improvement, cure or failure after three-day treatment with azithromycin. The assessment was based on a calculation of clinical score for each diagnosis before treatment and on days 4, 10 and 28 after treatment initiation. Clinical effectiveness of azithromycin was 93.6% in CAP group and 94.9% in AECB group. Azithromycin led to relief of symptoms within three days in 88.6% of CAP patients and 77.2% of AECB patients. Overall, 15 adverse events were reported in 14 (9.1%) patients. The most common adverse events were abdominal pain, diarrhea and vomiting, each reported in four (2.6%) patients. Accordingly, azithromycin was found to have high clinical effectiveness and a small number of adverse events in the treatment of lower respiratory tract infections. ISRCTN38391551. PMID- 26489108 TI - [Committee for guideline of febrile seizure]. PMID- 26489109 TI - Lessons learned from the endovascular management of blunt thoracic aortic injuries: A single-centre experience. AB - BACKGROUND: Blunt thoracic aortic injuries (BTAIs) remain a leading cause of death after blunt trauma. In severe injuries, thoracic endovascular aortic repair (TEVAR) has provided a less invasive alternative to conventional open repair. OBJECTIVE: To report the TEVAR-related complications and uncertainties in patients who presented with traumatic pseudoaneurysms (grade III BTAI). METHODS: From April 2004 to February 2012, 55 patients (42 male, mean age 34.7 years) with severe BTAI were treated with stent grafts. Computed tomography (CT) was used to diagnose the injuries, and follow-up scans were planned at 6 and 12 months. We report the complications and the technical uncertainties related to the procedure. RESULTS: Successful sealing of the injury sites was achieved in all patients, either with a thoracic stent graft (53/55) or infrarenal aortic aneurysm extender cuffs (2/55). During hospitalisation, 13 patients died after TEVAR (mean 14 days). Procedure-related complications included left common carotid artery coverage (1/55), ischaemic left leg (1/55) and graft collapse (1/55). The procedurerelated uncertainties included excessive graft oversizing (15/55), poor graft apposition to the inner curve of the aorta (19/55) and left subclavian artery coverage (24/55). CONCLUSION: Stent grafts appear safe and effective in treating pseudoaneurysms caused by BTAI. However, they are likely to be associated with long-term complications and monitoring strategies of >30 years may be necessary. PMID- 26489110 TI - Selective angioembolisation for splenic salvage following blunt abdominal trauma. AB - Isolated high-grade splenic injury following blunt abdominal trauma is an uncommon finding. The selected use of catheter-directed angiography and angioembolisation for splenic salvage has been successful in haemodynamically stable patients. PMID- 26489111 TI - Robert Maurice Andre Giraud. PMID- 26489112 TI - Resident remediation: start from scratch--the author's reply. PMID- 26489113 TI - Reference intervals data mining: getting the right paper--the author's reply. PMID- 26489114 TI - [New approach to corneal nerve fibers morphometry in diabetes mellitus on the basis of confocal biomicroscopy]. AB - AIM: to develop a new approach to morphometric analysis of corneal nerve fibers (CNF) and to evaluate their age-related changes in type 1 and type 2 diabetes mellitus patients. MATERIAL AND METHODS: The study enrolled 150 participants (300 eyes) aged from 13 to 83 years, of them 37 type 1 diabetes patients (74 eyes), 51 type 2 diabetes patients (102 eyes), and 62 healthy volunteers (124 eyes). All participants were examined with HRT III Rostock Corneal Module (Heidelberg Engineering GmbH). Digital images thus obtained were analyzed with specially developed original software that automatically computes coefficients of CNF orientation symmetry and anisotropy. RESULTS: A strong inverse correlation has been found between the coefficient of CNF orientation anisotropy and glycated hemoglobin levels (r = -0.83, p < 0.001 and r = -0.79, p < 0.005 in patients with type 1 and type 2 diabetes respectively) as well as the duration of the disease (r = -0,7, p < 0.005 and r = -0.72, p < 0.001, type 1 and type 2 diabetes respectively). On the contrary, the coefficient of CNF orientation symmetry has been shown to be directly correlated with both glycated hemoglobin levels (r = 0.64, p < 0.005 and r = 0.78, p < 0.05, type 1 and type 2 diabetes respectively) and the duration of the disease (r = 0.62, p < 0.05 and r = 0.73, p < 0.05, type 1 and type 2 diabetes respectively). Interocular asymmetry in both coefficients was found in diabetic patients but not in the controls. On the basis of the proposed coefficients, age-related changes in corneal nerve fibers orientation have been determined. Normally, the degree of CNF tortuosity increases with age. The rate of this increase is the highest before the age of 35-40. As shown, type 1 diabetes is associated with low coefficients of CNF orientation anisotropy and high coefficients of CNF orientation symmetry as compared to type 2 diabetes in the same age group. CONCLUSION: As suggested by the results, the two proposed coefficients that describe the state of corneal nerve fibers can possibly be used for diagnosis and monitoring of diabetic peripheral neuropathy (DPN). However, to produce enough evidence, further studies should be conducted. PMID- 26489115 TI - [Tomography findings in optic nerve head and retina in differential diagnosis between normal-tension glaucoma and ischemic optic neuropathies]. AB - AIM: to determine tomography findings in optic nerve head (ONH) and retinal nerve fiber layer (RFNL) that may be valuable for differential diagnosis between normal tension glaucoma (NTG) and ischemic optic neuropathy (ION) outcome. MATERIAL AND METHODS: Group 1 consisted of 17 patients (32 eyes) with NTG, group 2--17 patients (24 eyes) with ION outcome. The control group included 22 patients (22 eyes) with no sighs of optic neuropathy. Optic nerve head and retina assessment included scanning laser ophthalmoscopy (HRT 111) and optical coherence tomography (Stratus OCT 3000). Statistical analyses were performed using Statistica 10 software suite. RESULTS: Statistically significant changes in HRT parameters, namely, the mean RNFL thickness, retinal height variation along the contour line, and RB discriminant function, were observed in both study groups as compared to the controls. NTG patients also showed lower rim indices, larger cups, smaller values of the FSM discriminant function, and lower GPS (glaucoma probability score) than both ION patients and the controls. OCT findings included a statistically significant decrease in RNFL thickness in both study groups as compared to the controls. As for the difference between the groups, it was unreliable. Quadrant comparisons of RNFL thicknesses revealed that lower quadrant RNFL thinning was more significant in NTG patients, while temporal quadrant RNFL thinning--in ION patients. CONCLUSION: Both conditions are associated with a similar degree of RNFL thinning, as confirmed by OCT, however, HRT changes are much more pronounced in NTG than in ION patients. PMID- 26489116 TI - [Distortion of vitreous structure in eyes with lens dislocation]. AB - AIM: to study the range of structural changes in the vitreous and to determine spatial position of the lens in case of its dislocation. MATERIAL AND METHODS: A total of 47 patients (94 eyes) with so-called senile cataract aged from 59 to 83 years were examined. The state of the vitreous was evaluated by means of digital ultrasound examination. RESULTS: Combined structural changes in the basis and cortex of the vitreous in eyes with lens and/or its elements dislocation have been analyzed. The possibility of lens evaluation in terms of its integrity and topography as well as spatial position of its elements has been shown. The relationship between the vitreous and lens changes has also been established. CONCLUSION: Digital ultrasound examination is capable of producing a 3D image of the eye, thus, allowing to assess spatial defects of the vitreous and to determine the position of the lens in case of its dislocation. PMID- 26489117 TI - [Contribution of hemodynamic disturbances in magistral vessels to optic neuropathy progression and ocular tension changes in endocrine ophthalmopathy]. AB - AIM: to investigate the contribution of various hemodynamic disturbances in magistral vessels to optic neuropathy (ON) progression and ocular tension changes in endocrine ophthalmopathy (EOP). MATERIAL AND METHODS: A total of 39 patients (78 eyes) with subclinical EOP (clinical activity score, CAS <= 2) associated with Graves' disease (n = 32, 64 eyes) or autoimmune thyroiditis (n = 7, 14 eyes) were examined. Orbit echography was performed in all patients. Blood flow was assessed with a Voluson 730 PRO ultrasound diagnostic system ("Kretz", Austria) in triplex mode (B-scan, color Doppler flow mapping in combination with pulse wave Doppler). Thus obtained hemodynamic parameters in ophthalmic artery, central retinal artery (CRA), central retinal vein (CRV), short posterior ciliary arteries (SPCA), and long posterior ciliary arteries (LPCA) were analyzed. To reveal the role of hemodynamic disturbances in the above mentioned vessels in ON progression and eye pressure maintenance, the patients were divided into 7 groups. Only those eyes, whose peripheral indices were increased by more than 25% of normal values and diastolic blood flow decreased by not less than 25%, were selected for further study. Intraocular pressure changes were evaluated by group mean (Mmean = M +/- m mmHg), optic neuropathy progression--by the difference in group mean depth (dB) and number of scotomas between the first and the last visit (6 months of observation). RESULTS: In almost all types of perfusion disturbances, the resultant chronic ocular ischemia causes a decrease in IOP. The only exception, as shown, is simultaneous involvement of CRA, SPCA, and LPCA. The level of blood flow disturbance determines the severity of qualitative and quantitative changes in eyes with EOP-associated ON. The rate of ON progression directly correlates with baseline IOP values on day zero. CONCLUSION: Long lasting chronic impairment of blood supply of the eyeball leads to reduction in ocular tension and progression of optic neuropathy. Combined perfusion disturbances in CRA and LPCA as well as in CRA, LPCA, and SPCA can be considered a high-risk factor, while SPCA and/or LPCA involvement--a moderate-risk factor. PMID- 26489118 TI - [Fluorescein angiography and optical coherence tomography findings in central fundus of myopic patients]. AB - Myopia prevalence grows alike in many countries, including Russia, regardless of geographical and population conditions. AIM: to assess fundus changes in myopic patients at different ocular axial lengths by means of modern diagnostic tools. MATERIAL AND METHODS: The study enrolled 97 patients (194 eyes) aged 45 +/- 20.17 years with myopia of different degrees. Besides a standard ophthalmic examination, all patients underwent fundus fluorescein angiography and optical coherence tomography. RESULTS: The occurrence of retinal pigment epithelium (RPE) atrophy (diffuse or focal) has been shown to increase with increasing ocular axial length. Only 27 eyes (28.1%) appeared intact. As myopia progression implies axial growth of the eye, it is associated with a more severe decrease in choroid, RPE, and photoreceptor layer thicknesses: the longer the anterior-posterior axis, the thinner the above mentioned fundus structures. Age-related changes in the fundus are also likely to be more pronounced in longer axes. Myopic traction maculopathy, which in our case appeared the main cause of increased retinal thickness, was diagnosed in 105 eyes, "outer" macular retinoschisis--in 40 eyes. CONCLUSION: Thus, modern diagnostic tools, such as fluorescein angiography and optical coherence tomography, enable objective assessment of the central fundus. PMID- 26489119 TI - [Clinical and immunological comparisons of therapeutic regimens for corneal infiltrates secondary to adenoviral keratoconjunctivitis]. AB - The problem with post-adenoviral corneal infiltrates is that they cause a significant and persistent decrease in visual function, while corticosteroids in monotherapy bring only temporary improvement. AIM: to perform a comparative evaluation of topical corticosteroids and 0.05% cyclosporine A efficacy in the treatment of post-adenoviral corneal infiltrates on the basis of clinical presentation and local cytokine status. MATERIAL AND METHODS: The study involved two groups of patients after adenoviral keratoconjunctivitis: group 1 (25 patients, 45 eyes) were prescribed a diminishing regimen of corticosteroid eye drops for 12 weeks and corneal protectors; group 2 (24 patients, 42 eyes) received the same treatment as described above plus topical 0.05% cyclosporine A for 6 months. The follow-up period was from 6 to 12 months. Visual acuity measurements, biomicroscopy, and pneumatic tonometry were performed at months 1, 3, and 6. Local cytokine status was assessed by studying cytokine gene expression in cell culture from conjunctival scrapings and cytokines levels in the supernatant. The tests were done before the beginning of the treatment in both groups, at month 1 in group 1, at month 4 in group 2 (i.e. in a month after the cessation of dexamethasone) and also in a group of healthy volunteers (30 persons, 30 eyes). RESULTS: Long-term combined anti-inflammatory therapy with corticosteroids and 0.05% cyclosporine A in patients with post-adenoviral corneal infiltrates has yielded positive clinical results, including a persistent increase in visual acuity and complete resolution of corneal opacities (92.8%). In addition, we revealed a correlation between local cytokine status changes and clinical results. CONCLUSION: The proposed therapeutic regimen enabled complete suppression of residual interferon-alpha antiviral activity, an increase in interleukin-4 that regulates local humoral immunity, and a decrease (down to a complete suppression) in anti-inflammatory interleukin-2, which is responsible for activation of cell-mediated immunity, thus, resulting in resolution of the immune-mediated inflammation in the cornea. PMID- 26489120 TI - [Role of infection in the pathogenesis of age-related macular degeneration]. AB - AIM: to study the role of infectious agents in the development and progression of AMD by means of serodiagnostic assay for a complex of ophthalmotropic and opportunistic infections. MATERIAL AND METHODS: The study enrolled 61 patients (23 men, 38 women) aged 43-68 years and diagnosed in accordance with AREDS classification of AMD. Serodiagnostic tests were performed for 11 infections with the purpose of identifying antigen-specific antibodies in the serum. RESULTS: Activation markers of one or several infections were detected in most of the patients with AMD. CONCLUSION: Herpes viruses (HSV1 and CMV) along with some opportunistic pathogens are important factors in the pathogenesis of AMD, thereby, specific treatment should be performed in these patients. PMID- 26489121 TI - [Central retinal changes after ranibizumab injection for wet age-related macular degeneration]. AB - AIM: to assess the dynamics of macular morphofunctional parameters in wet age related macular degeneration after three injections of ranibizumab. MATERIAL AND METHODS: A total of 76 patients with classic choroidal neovascular membrane were examined. The latter could be seen on optical coherence tomography scans before the treatment as an optically heterogeneous formation beneath the neurosensory epithelium. The point of fixation was located 2-10 degrees from the fovea according to microperimetry testing. Wedge-like reduction of light sensitivity down to 0-2 dB corresponded to the area of neovascularization. RESULTS: Macular sensitivity improved from 7.24 +/- 2.73 dB to 13.88 +/- 1.94 dB (p < 0.05) after a course of three ranibizumab injections, the most significant changes taking place after the third one. The point of fixation moved somewhat back to the fovea after each injection. Morphological parameters of neovascular membranes gradually decreased: after the first injection the height went down to 20.29 +/- 17.84 um and the width--down to 1200 +/- 300 um on average, after the second one the height was 14.39 +/- 9.83 um, width--1000 +/- 175 um, after the third one the height and the width were 13.31 +/- 8.13 um and 900 +/- 100 um correspondingly (p < 0.05). CONCLUSION: Antivascular therapy reduces the pathological effect of neovascular membrane throughout the whole treatment period. The dynamics of studied parameters are characterized by an apparent response to the first injection, which indicates the advisability of further treatment. PMID- 26489122 TI - [Comparative analysis of the results of balloon dacryoplasty for stenoses at different levels of the vertical portion of lacrimal pathways]. AB - AIM: to compare the effectiveness of balloon dacryoplasty (DCP) for stenoses at different levels of the vertical portion of lacrimal pathways and to establish the necessity of consequent intubation. MATERIAL AND METHODS: A total of 120 clinical cases in 85 patients (66 females and 19 males with the mean age of 53.61 +/- 11.82 years) have been analyzed. Patients with cervical stenosis of the lacrimal sac constituted two groups: group 1 (19 patients, 30 balloon DCP surgeries) and group 2 (22 patients, 30 balloon DCP surgeries with Ritleng intubation). Two other groups consisted of patients with nasolacrimal orifice stenosis: group 3 (21 patients, 30 balloon DCP surgeries) and group 4 (23 patients, 30 balloon DCP surgeries with Ritleng intubation). Besides routine examinations, the assessment included collection of Munk's scores for epiphora, evaluation of health-related quality of life, lacrimal meniscometry, lacrimal scintigraphy, contrast enhanced multi-slice spiral computed tomography of lacrimal pathways, and single-photon emission computed tomography. The follow-up period was 6 months. RESULTS: In group 1 a complete recovery was achieved in 18 (60.00%) cases, improvement--in 9 (30.00%) cases, while a relapse occurred in 3 (3.00%) cases; in group 2, there were 18 (60.00%) recoveries, 10 (33.33%) improvements, and 2 (6.67%) relapses; in group 3--12 (40.00%) recoveries, 5 (16.66%) improvements, and 13 (43.34%) relapses; in group 4--19 (63.33%) recoveries, 8 (26.67%) improvements, and 3 (10.00%) relapses. CONCLUSION: Balloon dacryoplasty is effective in restoring patency of occluded lacrimal pathways. Success rate is higher in cervical stenoses of the lacrimal sac than in nasolacrimal orifice stenoses. Ritleng intubation after balloon DCP favors better outcomes in patients with nasolacrimal orifice stenosis. PMID- 26489123 TI - [Chemical microanalysis of mineral deposits on explanted hydrophilic acrylic intraocular lenses]. AB - AIM: to perform chemical microanalysis of mineral deposits on the surface of explanted hydrophilic acrylic intraocular lenses (IOL). MATERIAL AND METHODS: Two soft IOLs made of hydrophilic acryl (one, however, hydrophobic surface coated) and explanted 3 and 6 years after implantation were examined by scanning electron microscopy (EVO LS10, "Karl Zeiss", Germany). Chemical composition of the lens surface was studied using an energy-dispersive spectrometer (EDS X-Max50, Oxford, Great Britain). RESULTS: Chemical microanalysis allowed identification of the deposits, which turned out to be non-stoichiometric hydroxylapatite (also, hydroxyapatite (HA)) crystals with zinc impurity (up to 1.4%weight). CONCLUSION: The two samples represent two stages of a single process. The early stage is associated with newly formed HA crystals that are unable to cause any significant changes to the lens surface. However, as spherocrystals grow, they exert a crystallization effort that moves their growth centers apart with subsequent lens rupture and deformation. Crystal morphology undergoes dynamic changes: while primary (newly formed) crystals are sheaf-like, mature are spheres. A growing HA is non-stoichiometric. Zinc abundance accounts for appearance of its separate mineral phase. Hydrophilic properties of acrylic polymer determine its high affinity for HA crystals. Hydrophobic coating (sample no.1) does not completely prevent lens opacification due to mineral deposits on its surface. PMID- 26489124 TI - [Experimental study on ocular hypotensive efficacy of parenteral metoprolol]. AB - AIM: to evaluate ocular hypotensive efficacy of parenteral metoprolol in an experiment. MATERIAL AND METHODS: A total of 3 series of experiments on 24 rabbits were performed. The first series involved a single subconjunctival injection of 0.3 mg of metoprolol in the right eye, while the left served as a control. During the second series the rabbits received 0.5 mg of metoprolol intramuscularly. The third series also implied a subconjunctival injection of 0.3 mg of metoprolol in the right eye, however, supplemented with timolol 0.5% instilled in the left. In all rabbits tonometry was performed before the injection and then in 30 min, 1, 2, 3, 6, 8, and 24 hours. Biomicroscopy and ophthalmoscopy were also performed before and 1, 3, and 7 days after the injection. CONCLUSIONS: The maximum reduction (down to 30% from the baseline) of intraocular pressure (IOP) was registered in intramuscular metoprolol rabbits. Subconjunctival metoprolol was associated with a faster and more pronounced decrease in IOP as compared to timolol instillations. In case of local or systemic parenteral administration the hypotensive effect of metoprolol lasts for more than a day. PMID- 26489125 TI - Results of CAM therapy in amblyopic patients. AB - AIM: to evaluate changes in visual acuity and compliance after CAM therapy in patients that initially failed to respond to occlusion or were non-compliant. MATERIAL AND METHODS: Twenty nine patients aged 4-10 years that failed to improve under occlusion therapy were included in this prospective study. Patients were divided into two groups according to the age (16 patients of 4-7 years of age and 13 patients of 8-10 years of age) and two other groups according to the type of amblyopia (15 anisometropic and 14 strabismic cases). CAM stimulation was prescribed to all patients for six days. Occlusion therapy was then recommenced. Best corrected visual acuity was measured before the CAM course, immediately after, at 3- and 6-month follow-ups, and on the last visit. RESULTS: Visual acuities in all study groups increased significantly immediately after the CAM therapy with further improvement during the follow-up period. CONCLUSION: CAM therapy for amblyopia is helpful in improving visual acuity as well as patients' compliance to subsequent occlusion therapy. PMID- 26489126 TI - [Corneal collagen cross-linking for keratoconus]. AB - Over the last decade, corneal collagen cross-linking (CXL) has become a conventional treatment method for progressive keratoconus. Laboratory studies have shown that CXL increases the diameter of collagen fibers and also the number of intra- and interfibrillar cross-links, thus, increasing biomechanical strength of the irradiated cornea. As confirmed by a series of clinical and randomized controlled trials, CXL is able to slow down and, perhaps, to stop the progression of keratoconus. In most post-CXL patients visual acuity improves, while keratometric readings, spherical equivalent, and higher order aberrations reduce. Although published results prove CXL effective in the treatment of progressive keratoconus, its late consequences are yet unknown. This article reviews the stages of CXL development and results of published experimental and clinical studies. Prospects for CXL modifications that do not require epithelial debridement are discussed. PMID- 26489127 TI - [Justification of the use of particular biopolymers as matrix materials for artificial corneas]. AB - This article reviews distinctive features, advantages, and drawbacks of different biopolymers used to construct the 3D matrices of artificial corneas. Modern requirements for matrices are provided. PMID- 26489128 TI - [Triggering factors and pathogenesis of radiation cataract]. AB - Cataract is one of the most common eye diseases in the world. Many factors, including genetic, metabolic, nutritional, and environmental, are involved in its formation. It is necessary to know main causal agents and cellular mechanism of cataractogenesis. The tissue of the lens is considered radiosensitive, thus, lens opacities are possible late effects of exposure to ionizing radiation. The use of medical radiation for both diagnostic and therapeutic purposes grows worldwide. At the same time, there continues to be much confusion regarding the actual threshold dose of radiation exposure for cataract formation. Eye safety and the risk of cataract development are not entirely clear. However, with an ever widening range of interventional procedures, one should take attempts to reduce the risk for radiation cataract. PMID- 26489129 TI - [In memory of professor Oleg Vasil'evich Grusha]. PMID- 26489130 TI - [Professor V.V. Shmeleva--an army doctor, scientist, and teacher]. AB - This article is dedicated to the life and work (research, medical, educational) of V.V. Shmeleva, professor and Great Patriotic War participant. She was the head of ophthalmology department at the City Clinical Hospital No 67 and promoted the implementation of cataract cryoextraction into clinical practice. As a professor at the Order of Lenin Central Institute of Advanced Medical Training she was engaged in postgraduate training of ophthalmologists. V.V. Shmeleva is the author of Cataract monograph and many scientific articles. She was also the senior secretary of the Vestnik oftal'mologii journal for more than 25 years. PMID- 26489131 TI - ASNA: The Voice for Alabama Nurses. PMID- 26489132 TI - ASNA Helps Young Professionals Advance Their Career. PMID- 26489133 TI - Ethics and Professional Conduct. PMID- 26489134 TI - Report Sexual Harassment and Put a Stop to it! PMID- 26489135 TI - To Eat or Not to Eat? Nurses Offer Healthy Advice to Colleagues and Their Patients. PMID- 26489136 TI - Improving Adolescent Health through STD, HIV an Unintended Pregnancy Awareness. PMID- 26489137 TI - Bed Bugs: They Still are Among Us!! PMID- 26489138 TI - The effect of SNPs on expression levels in Nimblegen RNA expression microarrays. AB - In this paper the effect of SNPs on expression levels in Nimblegen RNA expression microarrays is investigated. A vast number of replicates of probe pairs representing both alleles of SNPs on 14 loci allows accurate estimation of the difference in signal intensities both within and between probe pairs. The majority of probe-pairs with sufficiently high expression have significant differences in expression levels within the pair and the difference shows concordance with the genotype of the samples. With two or more replicates of each probe, the allele-to-allele variance dominates the error in estimating the difference within the probe-pair, ten replicates are needed for adequate power in calling a true difference within a single probe-pair. Using the expression level of the probe within the probe-pair that has the higher value gives more accurate estimates. When using probes at loci containing known SNP's one should use probes containing both alleles of the SNP. PMID- 26489139 TI - Modelling and structural characteristics analysis of gene networks for prostate cancer. AB - Analysing structure of gene networks is an important way to understand regulatory mechanisms of organism at the molecular level. In this work, gene mutual information networks are constructed based on gene expression profiles in prostate tissues with and without cancer. In order to contrast structural difference of normal and diseased networks, curves of four structural parameters are given with the change of thresholds. Then threshold discrimination intervals and discrimination weights are defined. A method of finding structural key genes with significant degree-difference is proposed. The finding of key genes will help the biomedical scientists to further research the pathogenesis of prostate cancer. Finally randomisation test is performed to prove that these structural parameters can distinguish normal and prostate cancer in their structures compared with these results in real data. PMID- 26489140 TI - Discovering essential proteins based on PPI network and protein complex. AB - Most computational methods for identifying essential proteins focus on the topological centrality of protein-protein interaction (PPI) networks. However, these methods have limitations, such as the difficulty for identifying essential proteins with low centrality values and the poor performance for incomplete PPI network. In this paper, protein complex is proven to be an important factor for determining protein essentiality and a new centrality measure, complex centrality, is proposed. The weighted average of complex centrality and subgraph centrality, called harmonic centrality (HC), is proposed to predict essential proteins. It combines PPI network topology and protein complex information and has better performance than methods based on PPI network. The improvement is higher when the PPI network is incomplete. Furthermore, a weighted PPI network is generated by integrating cellular localisation and biological process to a PPI network. The performance of HC measure is improved 5% in this weighted PPI network. PMID- 26489141 TI - CORE: core-based synthetic minority over-sampling and borderline majority under sampling technique. AB - Class imbalance learning has recently drawn considerable attention among researchers. In this area, a rare class is the class of primary interest from the aim of classification. Unfortunately, traditional machine learning algorithms fail to detect this class because a huge majority class overwhelms a tiny minority class. In this paper, we propose a new technique called CORE to handle the class imbalance problem. The objective of CORE is to strengthen the core of a minority class and weaken the risk of misclassified minority instances nearby the borderline of a majority class. These core and borderline regions are defined by the applicability of a safe level. As a result, a minority class is more crowed and dominant. The experiment shows that CORE can significantly improve the predictive performance of a minority class when its dataset is imbalance. PMID- 26489142 TI - Signal transduction in the activation of spermatozoa compared to other signalling pathways: a biological networks study. AB - In this paper we represented Spermatozoa Activation (SA) the process that leads male gametes to reach their fertilising ability of sea urchin, Caenorhabditis elegans and human as biological networks, i.e. as networks of nodes (molecules) linked by edges (their interactions). Then, we compared them with networks representing ten pathways of relevant physio-pathological importance and with a computer-generated network. We have found that the number of nodes and edges composing each network is not related with the amount of published papers on each specific topic and that all the topological parameters examined are similar in all the networks, thus conferring them a scale free topology and small world behaviour. In conclusion, SA topology, independently from the reproductive biology of considered organism, as others signalling networks is characterised by robustness against random failure, controllability and efficiency in signal transmission. PMID- 26489143 TI - Condensing position-specific scoring matrixs by the Kidera factors for ligand binding site prediction. AB - Position-specific scoring matrix (PSSM) has been widely used for identifying protein functional sites. However, it is 20-dimentional and contains many redundant features. The Kidera factors were reported to contain information relating almost all physical properties of amino acids, but it requires appropriate weighting coefficients to express their properties. We developed a novel method, named as KSPSSMpred, which integrated PSSM and the Kidera Factors into a 10-dimensional matrix (KSPSSM) for ligand-binding site prediction. Flavin adenine dinucleotide (FAD) was chosen as a representative ligand for this study. When compared with five other feature-based methods on a benchmark dataset, KSPSSMpred performed the best. This study demonstrates that, KSPSSM is an effective feature extraction method which can enrich PSSM with information relating 188 physical properties of residues, and reduce 50% feature dimensions without losing information included in the PSSM. PMID- 26489144 TI - Metabolites production improvement by identifying minimal genomes and essential genes using flux balance analysis. AB - With the advancement in metabolic engineering technologies, reconstruction of the genome of host organisms to achieve desired phenotypes can be made. However, due to the complexity and size of the genome scale metabolic network, significant components tend to be invisible. We proposed an approach to improve metabolite production that consists of two steps. First, we find the essential genes and identify the minimal genome by a single gene deletion process using Flux Balance Analysis (FBA) and second by identifying the significant pathway for the metabolite production using gene expression data. A genome scale model of Saccharomyces cerevisiae for production of vanillin and acetate is used to test this approach. The result has shown the reliability of this approach to find essential genes, reduce genome size and identify production pathway that can further optimise the production yield. The identified genes and pathways can be extendable to other applications especially in strain optimisation. PMID- 26489145 TI - To screen the effective software for analysing gene interactions from Kashin-Beck disease genome profiling pathway and network, according to the tool of GeneMANIA. AB - In order to screen the more effective software for the pathway and network analysis of Kashin-Beck disease, gene microarrays, TranscriptomeBrowser, MetaCore and GeneMANIA were used for analysis. Three significant chondrocytic pathways and one network were screened by TranscriptomeBrowser; one significant pathway and one network were identified by MetaCore. BAX, APAF1, CASP6, BCL2, VEGF, SOCS3, BAK, TGFBI, TNFAIP6, TNFRSF11B and THBS1 were significant genes associated with the biological function of chondrocyte or cartilage involved in the TranscriptomeBrowser or MetaCore results. The interactions between the significant genes and their adjacent genes were searched and classified in GeneMANIA. In pathway analysis results, TranscriptomeBrowser is superior to get the interaction of pathway and co-expression compared with MetaCore; MetaCore is superior to get the interaction of physical interaction compared with TranscriptomeBrowser. In network analysis results, TranscriptomeBrowser contains more interaction message of co-localisation, MetaCore contains, more interaction message of co-expression. PMID- 26489146 TI - [EXAMINATION OF TUBERCULOSIS OUTBREAK INDEX CASES IN OSAKA CITY]. AB - OBJECTIVE: To analyze tuberculosis outbreak index cases in order to improve preventative measures. METHODS: Outbreaks reported in Osaka City between 2008 and 2014 were investigated. The index cases were examined according to category group, sex, age, chest radiograph findings, sputum smear examination, patient delay, doctor delay, total delay in case finding, and adherence to regular health examinations. As controls, 467 patients in Osaka City with newly registered sputum smear-positive pulmonary tuberculosis in 2011 were included. RESULTS: Thirteen outbreaks occurred. The group categories included enterprises (9 outbreaks), preparatory schools (2), a junior high school (1), and other (1). The group of index cases consisted of 12 men (92.3%) and one woman (7.7%), with a mean age of 39.1 years; 11 (84.6%) were 30 to 50 years of age. Their ages ranged from 15 to 54 years. Of the control group of patients with sputum smear-positive pulmonary tuberculosis, 69.2% were 60 years or older, with a mean age of 65.4 years. These results suggest that the index case group was significantly younger (p < 0.001). There were ten cases (76.9%) of patient delay (initial visit 2 months or more after onset), and 8 (61.5%) of total delay (diagnosed 3 months or more after onset). These rates were significantly higher than those in the control group (p < 0.001). There were regular health examinations in four cases; among those, one did not see a doctor and another did not receive further examination. Chest radiographs revealed cavities in 12 cases (92.3%). All sputum smears were positive, with grades of 1 + in one case (7.7%), 2 + in two cases (15.4%), and 3 + in 10 cases (76.9%). These cases had a significantly higher rate of smear positivity than those in the control group (p < 0.001). DISCUSSION: The index cases were predominantly male, in their prime, and had higher infectivity rates. These findings suggest the importance of preventing delays in case findings and receiving regular and adequate health examinations. PMID- 26489147 TI - [CLINICO-MICROBIOLOGICAL CHARACTERISTICS OF MYCOBACTERIUM KANSASII PULMONARY DISEASE AT A SPECIALIZED MYCOBACTERIOSIS HOSPITAL IN TOKYO, JAPAN]. AB - BACKGROUND: Mycobacterium kansasii is the second most common nontuberculous mycobacterial pulmonary disease pathogen in Japan. Fibrocavitary disease is characteristic of M. kansasii pulmonary disease in male patients. OBJECTIVE: To clarify the clinico-microbiological characteristics of M. kansasii pulmonary disease in recent years in a Tokyo hospital specializing in mycobacteriosis. METHODS: A retrospective chart review was performed on 77 M. kansasii culture positive cases from January 2003 to December 2010. Sequence analysis of the hsp65 gene using PCR-restriction enzyme pattern analysis (hsp65-PRA) was used to identify bacterial genotypes. RESULTS: Seventy-four cases fulfilled the diagnostic criteria for inclusion. Female patients comprised 22% of cases (16 cases, 63.2 +/- 24.6 years of age) and were older than male patients (58 cases, 55.5 +/- 17.5 years of age). Although the peak distribution among men was patients in their 50s, female patients showed a bimodal distribution with increased occurrence in older women. Radiological examination showed that approximately 90% of male and younger female patients had fibrocavitary disease. However, elderly female patients tended to have nodular bronchiectatic disease. Genotype analysis revealed that all bacterial strains from both genders were subtype I. CONCLUSIONS: Compared to previous reports, the number of female patients with M. kansasii pulmonary disease had increased, with an unusual age distribution. These different age-related radiological findings might be due to host factors. PMID- 26489148 TI - [A HEALTHY ADULT WITH DISSEMINATED NONTUBERCULOUS MYCOBACTERIAL INFECTION WITH MULTIPLE BONE LESIONS]. AB - A 54-year-old man was admitted to our hospital because of fever, dyspnea, and low back pain. Chest computed tomography showed a 30-mm mass in the left lung and bilateral pleural fluids, multiple bone lesions, enlarged lymph nodes, and skin abscesses. Mycobacterium avium was isolated from his sputum, a pleural fluid sample, the right cervical lymph node, and a precordial skin abscess. We thus diagnosed his illness as disseminated nontuberculous mycobacterial infection (DNTM) and treated him with multiple chemotherapeutic agents. However, the disease progressed, and he ultimately died. He was not in an obvious immunocompromised state. DNTM with multiple bone lesions in a healthy adult is very rare and we therefore report this case. PMID- 26489149 TI - [A TUBERCULOUS PSEUDO-ANEURYSM OF THE ABDOMINAL AORTA COMPLICATED BY MILIARY TUBERCULOSIS]. AB - A 66-year-old man was transferred to our hospital on November 2010 owing to a diagnosis of miliary tuberculosis. Treatment was initially started with INH, RFP, PZA, and EB. However, PZA and EB were discontinued because of their adverse effects. Subsequently, chest radiographic and laboratory findings gradually improved. However, the patient experienced lumbago, which exacerbated towards the end of March 2011. An abdominal CT scan showed an abdominal mass at the L3-L5 level between the abdominal aorta and lumbar vertebra. On the basis of the findings of abdominal ultrasonography, MRI, and PET-CT, infectious abdominal aortic aneurysm was highly suspected. Therefore, vascular graft replacement surgery was performed at the beginning of May 2011. The result of histopathological analysis showed the presence of acid-fast bacteria in the aneurysm and the lymph nodes around it, revealing that the aneurysm was due to systemic miliary tuberculosis. After the surgery, the patient was administered LVFX in addition to INH and RFP for 18 months and showed no recurrence. PMID- 26489150 TI - [ACUTE MYELOID LEUKEMIA COMPLICATED BY DISSEMINATED TUBERCULOSIS AT DIAGNOSIS]. AB - A 58-year-old man was admitted to our hospital because of fever and night sweating. Laboratory examinations showed pancytopenia on admission. Examination of bone marrow smear specimens revealed many myeloblasts, thus the diagnosis of acute myeloid leukemia (AML) was made. In contrast, many central necrotic epithelioid granulomas were found in clot specimens prepared from the same bone marrow sample. Computed tomography showed small lymphadenopathies and hepatosplenomegaly. Mycobacterium tuberculosis was isolated only from the urine culture. These findings of the bone marrow and the urine culture led to the diagnosis of disseminated tuberculosis. Therefore, these results mentioned above led to the diagnosis of AML complicated with disseminated tuberculosis. After disseminated tuberculosis treatment with anti-tuberculosis drugs, induction chemotherapy for AML helped the patient to achieve complete remission (CR). During treatment and CR, he showed a paradoxical reaction with lymph node enlargement without worsening of disseminated tuberculosis. This is a rare case of AML complicated by disseminated tuberculosis. PMID- 26489151 TI - [A SURGICAL CASE OF MYCOBACTERIUM KANSASII LUNG DISEASE MIMICKING PRIMARY LUNG CANCER]. AB - We report a rare surgical case of a solitary pulmonary nodule due to Mycobacterium kansasii. A 59-year-old man was admitted to our hospital for examination of an abnormal shadow in the left upper lobe incidentally found on a chest radiogram. Computed tomography of the chest showed that the nodule was located in the left segment 1+2 and was irregularly shaped with a diameter of 35 mm. Thoracic fluorine-18 fluoro-deoxy-glucose positron emission tomography showed a high metabolic pulmonary lesion, with a maximum standardized uptake value of 5.1, consistent with findings for lung cancer. A bronchoscopy was performed to establish the diagnosis of lung cancer; however, it failed to show malignant cells. Because we could not confirm the diagnosis by bronchoscopic examination, video-assisted thoracoscopic surgery was performed. The intraoperative rapid diagnosis of the nodule was epithelioid cell granuloma. Smear test of the resected specimen was positive for acid-fast bacilli, and a culture was also positive for mycobacteria, which were identified as Mycobacterium kansasii. Antibiotic treatment for M. kansasii infection was administered for a year after the surgical resection. Few cases of Mycobacterium kansasii infection present with solitary pulmonary nodules. PMID- 26489152 TI - [EVALUATION STANDARD OF EXTERNAL QUALITY ASSESSMENT PROGRAMME FOR DRUG SUSCEPTIBILITY TESTING OF MYCOBACTERIUM TUBERCULOSIS IN JAPANESE LABORATORIES: PROFICIENCY TESTING IN 2004-2010]. AB - OBJECTIVE: To analyze the results of the external quality assessments (EQA) for anti-tuberculosis drug susceptibility testing (DST) and to set-up its rational passing criterion. METHOD: Each participating laboratory in EQA performed DST, and the sensitivity, specificity, agreement (efficiency) and kappa coefficient were calculated from the results. We analysed the data of seven EQA results for DST from 2004 to 2010. RESULTS: A total of 20, 20, 10, 5, 10, 10, and 10 strains of M. tuberculosis with known susceptibility were sent to each participating laboratory in 2004, 2005, 2006, 2007, 2008, 2009, and 2010, respectively. The total of participating laboratories was 564. Each laboratory was asked to perform DST with its routine methods and reported 25,100 test results in these seven years. The laboratories showed relatively high specificity than sensitivity, and an improving sensitivity through the years. Sixteen laboratories participated the EQA continuously, and the sensitivity and specificity to isoniazid (INH), rifampicin (RFP), streptomycin (SM) and ethambutol (EB) were 0.999 (95% CI 0.992 1.000) and 0.998 (95% CI 0.991-1.000), 0.985 (95% CI 0.973-0.992) and 0.997 (95% CI 0.989-0.999), 0.932 (95% CI 0.912-0.948) and 0.977 (95% CI 0.962-0.986), and 0.965 (95% CI 0.947-0.977) and 0.978 (95% CI 0.966-0.986), respectively. DISCUSSION: The analyses revealed that the accuracy of DST for INH and RFP was highly maintained throughout the years. However, SM showed a high unevenness of performance quality and required situational considerations for evaluation. In conclusion, the EQA for DST would require a minimum number of 10 strains for each assessment, and INH and RFP should show over 95% of sensitivity and specificity with over 90% of efficiency to SM and EB as passing remark. PMID- 26489153 TI - [STUDY OF DIRECT TB-LAMP USING NON-CENTRIFUGAL SPUTUMS ABOUT EFFICIENCY FOR RAPID DIAGNOSIS OF TUBERCULOSIS]. AB - OBJECTIVE: To evaluate the efficiency of the direct tuberculosis-loop-mediated isothermal amplification (TB-LAMP) assay by using non-centrifuged sputum samples. STUDY PERIOD AND METHODS: The study was conducted between June 2013 and February 2014. We collected 111 sputum samples from patients who had been radiographically diagnosed with tuberculosis and had not received any treatments for longer than 5 days. In the direct TB-LAMP assay, a loop-mediated isothermal amplification kit and 60-MUL sputum samples were used. A direct smear microscopy test was used as the smear test. Then, the same sputum samples were processed with a CCE pretreatment reagent, and 100 MUL of the solution samples were cultured by using the mycobacterial growth indicator tube (MGIT) culture method. RESULTS: Forty-six of the 111 samples were positive in the smear microscopy tests. All the smear positive samples were positive in both the MGIT and direct TB-LAMP assay (100%). The mean positive detection time with the direct TB-LAMP assay was 13 minutes 55 seconds. Of 56 smear-negative and MGIT positive samples, 44 (78.6%) were judged to be positive using the direct TB-LAMP assay, with a mean positive detection time of 15 minutes 59 seconds. DISCUSSION: The direct TB-LAMP assay using non centrifuged sputum samples was demonstrated to have a high detection rate and thus may be considered useful for rapid and effective tuberculosis diagnosis. PMID- 26489154 TI - [A CASE OF NON-TUBERCULOUS MYCOBACTERIOSIS WITH PLEURAL EFFUSION AND THICKENING IN A PATIENT WITH AN OCCUPATIONAL HISTORY OF ASBESTOS EXPOSURE]. AB - We report a case of a 75-year-old man with pleural effusion and an occupational history of asbestos exposure. Fluorodeoxyglucose positron emission tomography computed tomography (FDG-PET/CT) examination revealed FDG up-takes along his pleura, leading to an initial suspicion of pleural mesothelioma. Pathological findings of a diagnostic video-associated pleural biopsy showed epithelioid cell granuloma. Repeated sputum cultures were positive for Mycobacterium intracellulare. The patient was diagnosed with pleuritis caused by non tuberculous mycobacteria (NTM). NTM should be considered a potential cause of pleuritis. PMID- 26489155 TI - [TUBERCULOSIS ANNUAL REPORT 2013--(2) Tuberculosis in Pediatric and Elderly Patients]. AB - In 2013, 66 patients with pediatric tuberculosis (TB; age range: 0-14 years) were newly notified in Japan, corresponding to a notification rate of 0.40 per 100,000 population. Since 2006, the annual number of notified patients with pediatric TB has been less than 100. Among the 66 patients with pediatric TB who were notified in 2013, 27 (40.9%) were aged 0-4 years, 14 (21.2%) were aged 5-9 years, and 25 (37.9%) were aged 10-14 years. The largest proportion of pediatric TB patients was aged 0-4 years. In 2013, two cases of TB meningitis and no cases of miliary TB were reported in children. Case detection occurred at rates similar to previous years, with 20 patients (30.3%) identified at medical institutions and 33 (50%) via household contact investigations. Since 2000, the number of all elderly patients (aged 65 years or older) with TB had decreased rapidly and remained stable until recently. However, the number of such patients has declined gradually since 2012. The proportion of TB patients aged 65 years or older has consistently increased to as high as 64.5% in 2013; notably, the proportion of TB patients aged 80 years or older has also increased to 36.1%. Since 1999, the TB notification rates in Japan have been consistently higher among patients aged 85 years or older than among those aged 65-84 years. The rate of notification for TB patients aged 65 years or older decreased by 0.6% from 2012 (13,307 patients) to 2013 (13,227 patients). The proportion of bacteriologically positive TB patients among the general population of pulmonary TB (PTB) patients was higher among those aged 65 years or older than among those aged 15-64 years. Among all symptomatic patients, the proportion of PTB patients with only non-respiratory symptoms increased with age to 30.3% among those aged 85 years or older. The proportion of TB patients with a patient delay of two months or longer was lower among patients aged 65 years or older than among those aged 15-64 years (14.2% vs. 25.6%), whereas the proportion of TB patients with a doctor delay of one month or longer was slightly higher among patients aged 65 years or older than among those aged 15-64 years (23.0% vs. 20.3%). Among TB patients aged 65 years or older who were newly notified in 2012, 32.2% died within one year after the initiation of TB treatment; of these patients, 19.2% died within three months. Among patients aged 65 years or older, the proportion of deaths within three months after the initiation of TB treatment increased substantially with age from 7.8% of those aged 65-69 years to 37.7% of those aged 90 years or older. PMID- 26489156 TI - [A CLINICAL EXPERIENCE OF RIFAMPICIN SUPPOSITORY FOR THE TREATMENT OF PULMONARY TUBERCULOSIS]. AB - PURPOSE: The usefulness of a rifampicin (RFP) suppository for treatment of pulmonary tuberculosis was examined in patients who had difficulty with oral consumption of medication. SUBJECTS AND METHODS: Among inpatients receiving first time treatment for pulmonary tuberculosis susceptible to both isoniazid (INH) and RFP, and who underwent standard 3- or 4-drug treatments including INH and RFP, we compared the number of days required for obtaining two and three consecutive negative sputum smears and cultures, respectively, in patients who received hospital-made suppositories or standard oral RFP administration. RESULTS: There was no significant difference between groups in the number of days required for negative cultures and smears; although the times were equivalent, there were more number of elderly patients and those in generally poor condition in the RFP suppository group than the oral intake group. CONCLUSION: RFP suppositories may be one method for administration of standard tuberculosis treatment in patients with difficulty in oral consumption of medication. PMID- 26489157 TI - [A CASE OF PULMONARY MYCOBACTERIUM ABSCESSUS INFECTION SUCCESSFULLY TREATED WITH SHORT-TERM CAM, AMK, AND IPM/cs FOLLOWED BY LONG-TERM ORAL CAM AND LVFX]. AB - A 78-year-old woman who had been treated for two years with ITCZ for chronic pulmonary aspergillosis associated with prior pulmonary tuberculosis was admitted to our hospital because of general fatigue and hemosputum along with deterioration of her chest radiographic findings. Mycobacterium abscessus had been isolated once from her sputum one year before admission. We performed fiberoptic bronchoscopy (FOB) in order to help establish a final diagnosis. Sputum aspirated from her bronchus on FOB stained positive for acid-fast bacilli and was negative for Tbc and MAC using PCR. From these results, we diagnosed the patient with pulmonary M. abscessus infection. Chemotherapy with AMK, IPM/cs, and CAM was initiated. Because her symptoms rapidly improved, we switched the chemotherapy to long-term oral CAM and LVFX, and she has been in a good condition at 12 months after the initiation of the therapy. Recently, subtypes of M. abscessus complex, such as M. massiliense, have been recognized, which are more sensitive to chemotherapy. Considering the good response to therapy, there is a possibility that is the patient in the current case had a M. massiliense infection. PMID- 26489158 TI - [TUBERCULOSIS ANNUAL REPORT 2013--(3) Case Finding and Condition of Tuberculosis on Diagnosis]. AB - In 2013, tuberculosis (TB) case findings from the nationwide TB surveillance data in Japan were reviewed with regard to the mode of detection, symptom at diagnosis, diagnostic delay, proportion of far-advanced cavitary lesions, co existence of human immunodeficiency virus (HIV) infection and diabetes mellitus (DM), and drug susceptibility testing (DST). Among the 20,495 new TB cases in 2013, 83.1% were diagnosed when the patients sought medical attention for TB symptoms or attended medical facilities because of other chief complaints. Among the 15,972 patients with pulmonary TB, 26.4% had only respiratory symptoms, 30.5% had respiratory and non-respiratory symptoms, 17.8% had only non-respiratory symptoms, and 24.5% were asymptomatic. The proportion of patient and doctor delays among the 11,933 symptomatic pulmonary TB cases was analyzed. A large proportion--around 30%--of patients aged 45-54 years with symptomatic pulmonary TB exhibited a patient delay of >= 2 months. The proportion of patients with a total delay (i.e., the sum of patient and doctor delays) of >= 3 months exhibited a similar tendency to that of those with a patient delay. The proportion of patients aged >= 65 years with a doctor delay of >= 1 month surpassed that of age matched patients with a patient delay. Among symptomatic smear-positive TB, a patient delay of >= 2 months exhibited a bimodal distribution, and its peak was > 35%. The proportion of patient delay in those aged 30-39 years decreased compared to that of recent years. Meanwhile, the proportion of patients--approximately 15% -with a doctor delay of >= 1 month was relatively stable across all the age groups. The proportion of patients with pulmonary TB who had far-advanced cavities in the lungs increased from 1.5% in 1975 to approximately 2% and then remained stable from 1985 to 2013. Among the 50 new TB cases with HIV in 2013, 5 occurred in women and 10 in foreigners. From 2007 to 2013, there were 416 patients with newly diagnosed TB and HIV infections, 359 (86.3%) and 57 (13.7%) of whom were men and women, respectively, including 86 (20.7%) foreigners. The proportions of newly diagnosed TB cases with DM in 2013 were 14.5% (2,964/20,495), of which 16.6% (2,072/12,504) occurred in men and 11.2% (892/7,991) in women. The DST results were obtained through the surveillance system for 7,701 (73.2%) of 10,523 culture-positive pulmonary TB cases in 2013. In previously untreated patients, the proportions of patients with multi-drug resistant TB, any isoniazid resistance, and any rifampicin resistance were 0.4%, 4.5%, and 0.6%, respectively; meanwhile, in previously treated patients, the proportions were 3.7%, 8.0%, and 5.1%, respectively. In previously untreated patients, the proportions of multi-drug resistant TB and any isoniazid resistance decreased comparing with 2012. PMID- 26489159 TI - [DISSEMINATED NONTUBERCULOUS MYCOBACTERIOSIS THAT IS POSITIVE FOR NEUTRALIZING ANTI-INTERFERON-GAMMA AUTOANTIBODIES: A NEW DISEASE CONCEPT BASED ON HOST FACTORS]. AB - Disseminated nontuberculous mycobacteriosis (NTM infection) is a disease that causes multiple organ lesions and occurs against an immunodeficiency background. Several host factors for this disease have been identified. Recently, neutralizing anti-interferon-gamma autoantibodies (IFN-gamma Ab) have been detected in some cases of disseminated NTM infection that had no previously known immunodeficiency, garnering attention as a new form of acquired immunodeficiency. We previously reported on methods for detecting IFN-gamma Ab in clinical specimens as part of the diagnostic process that are being used to evaluate suspected cases at various institutions. Overseas reports of positive results were achieved by administration of the anti-CD20 antibody rituximab in addition to antibacterial chemotherapy in cases of intractable disseminated NTM infection that tested positive for IFN-gamma Ab. This highlights the importance of diagnosis as well. Clinicians should consider the existence of this pathology. Although many host factors for NTM infection have yet to be identified, IFN-gamma Ab positivity should be investigated further as a new disease concept, not only for its pathological dimensions but also from the standpoint of treatment strategies. In the future, more cases need to be examined and analyzed to obtain further epidemiological and pathological findings. PMID- 26489160 TI - Continuing Professional Development. PMID- 26489161 TI - 2015 Sanford Scholars Day Abstracts. PMID- 26489162 TI - Heart Failure. AB - Heart failure is a major public health concern. It is the most common reason for hospitalization. It commonly affects older population and given the increasing life expectancy coupled with improved management of chronic medical conditions, the number of patients with heart failure is expected to increase. Heart failure has been recently categorized into heart failure with reduced and preserved ejection fraction. Despite differences in the two types, mortality remains high and similar in both conditions. Over the past few decades, numerous medical and device based therapies have been developed for the management of heart failure. These therapies have improved outcomes for the patients both in terms of morbidity and mortality. The objective of this review is to provide an overview of management of heart failure, specifically heart failure with reduced ejection fraction. It is of paramount importance for all health care providers to be aware of therapies for management of heart failure. We will also briefly discuss the role of mechanical circulatory support as an emerging new therapy for patients with advanced heart failure. PMID- 26489163 TI - Medication Therapy Management--An Opportunity to Collaborate. PMID- 26489164 TI - Extenuating Circumstances: Tobacco Cessation. PMID- 26489165 TI - Patient Education: The Leap of Parenting. PMID- 26489166 TI - DAKOTACARE Update: Shared Decision Making in the Internet Age. PMID- 26489168 TI - Orphans knocking on the door. PMID- 26489167 TI - Has the 340B Program Lost Its Way? PMID- 26489169 TI - Biosimilars Charge the Market But Still Face Many Hurdles. PMID- 26489170 TI - Still too many hysterectomies performed. PMID- 26489171 TI - PBMs: New Power And Influence. PMID- 26489172 TI - PBMs Just Say No to Some Drugs--But Not to Others. PMID- 26489173 TI - Come in and Talk With Us, Pharma. PMID- 26489174 TI - A Canary in the Coal Mine for Co-Ops? PMID- 26489175 TI - Lung Cancer Screening Comes of Age. PMID- 26489176 TI - Surgical Stick-to-itiveness. PMID- 26489178 TI - Value-based reimbursement coming on strong while the fall of FFS medicine accelerates. PMID- 26489177 TI - A Discrete Choice Experiment to Elicit Patient Willingness to Pay for Attributes of Treatment-Induced Symptom Relief in Comorbid. Insomnia. AB - PURPOSE: Insomnia is a burdensome, commonly comorbid condition. How patients value various aspects of the safety and efficacy of available drugs has not been studied. The aim of the present study was to quantify patient-rated utility by studying willingness to pay (WTP) for attributes of symptom relief via a discrete choice experiment (DCE). METHODOLOGY: Adult primary care patients (West Virginia University Hospital) with comorbid insomnia were enrolled. The attributes and levels examined were sleep onset latency (SOL; 10, 20,30 minutes), awakenings (1, 2, 3), wake time after sleep onset (WASO; 15,45, 60 minutes), total sleep time (TST; 6, 7, 8 hours), hangover (none, mild, moderate), FDA-approved duration of use (short term, not restricted to short term, no restrictions), and out-of pocket cost per month ($20, $35, $50). Willingness to pay (WTP) data were analyzed using a random effects binary logistic regression model. RESULTS: A total of 82 patients completed the DCE (74 analyzed). SOL, WASO, TST, and cost were all found to predict treatment choice. Higher values of SOL, WASO, and cost resulted in decreased preference for a particular treatment, while higher TST predicted increased preference. Modeling revealed an estimated marginal WTP of $66.69 for an example product that improved SOL by 10 minutes, reduced WASO by 15 minutes, and improved TST by 1 hour. CONCLUSION: Patient WTP for symptomatic relief in insomnia can help clinicians fine-tune interventions based on patient preferences, provide evidence for drug formulary and reimbursement decisions, and potentially guide the development of novel drugs. PMID- 26489179 TI - WOMEN AND SCIENCE. PMID- 26489180 TI - WOMEN, SCIENCE AND SUFFRAGE IN WORLD WAR I. AB - World War I is often said to have benefited British women by giving them the vote and by enabling them to take on traditionally male roles, including ones in science, engineering and medicine. In reality, conventional hierarchies were rapidly re-established after the Armistice. Concentrating mainly on a small group of well-qualified scientific and medical women, marginalized at the time and also in the secondary literature, I review the attitudes they experienced and the work they undertook during and immediately after the war. The effects of century-old prejudices are still felt today. PMID- 26489181 TI - WHITE COATS AND NO TROUSERS: NARRATING THE EXPERIENCES OF WOMEN TECHNICIANS IN MEDICAL LABORATORIES, 1930-90. AB - Laboratory technicians are a vital part of any working lab. Not only is their knowledge and expertise important for the success of research, but they also often maintain the lab's intellectual and social life. Despite the importance of their work, they are rarely acknowledged in publications, and leave only a few traces within the historical recordthe voices of women laboratory technicians are even harder to uncover. This paper attempts to correct this imbalance by presenting the narratives of women who worked as laboratory technicians at places such as the National Institute for Medical Research (NIMR), the Wellcome Research Laboratories, and established hospital and university labs in Cambridge, Oxford and London. The data were collected though narrative interviews. Specifically, the paper looks at the roles of these women within the lab, their experiences of the social and gender dynamics of the lab, and the development of expertise in regard to the work they carried out and the extent to which they received credit for their contributions to science. PMID- 26489182 TI - WOMEN PEERS IN THE SCIENTIFIC REALM: SARAH BOWDICH (LEE)'S EXPERT COLLABORATIONS WITH GEORGES CUVIER, 1825-33. AB - The accepted rule for women contributing to nineteenth-century science before 1851 was that they could play only secondary roles in its production and authorship--as translators, illustrators, popularizers--and these by virtue of kinship or marriage to eminent scientists in the field or the laboratory. Sarah Bowdich (Lee) (1791-1856) presents an important amendment to this rule. As an explorer of West Africa on an equal scientific footing with her husband, and then a writer of science independently after his early death, she had other key roles as Georges Cuvier's cross-Channel scientific collaborator and as his first biographer. This article investigates and reframes Sarah's many individual achievements in science and its writing, to examine the larger questions of her case. How were her publications and 'uneasy career' in science possible? Can research on women in science today find inspiration in her example? PMID- 26489183 TI - MARGARET FOUNTAINE: A LEPIDOPTERIST REMEMBERED. AB - Margaret Fountaine (1862-1940) was a lepidopterist during a period of transition and professionalization in natural history. Over her lifespan she collected more than 22000 butterflies, published extensively and wrote a diary of more than a million words. Wealthy and independent, Fountaine toured Europe in her early twenties and then, over the next 50 years, travelled the globe collecting butterflies. Fountaine straddles many of the boundaries that historians have constructed to aid understanding of natural history in this period, specifically those defining gender roles, the nature of scientific knowledge and the divide between amateur and professional. Fountaine reminds us that these categories are never a clear or perfect division and that the reality of natural history research and exchange was much more complex than these boundaries often allow for. Fountaine herself is under-researched and this article contains a useful account of her entomological career. PMID- 26489184 TI - CAROLINE HERSCHEL: AGENCY AND SELF-PRESENTATION. AB - Caroline Herschel was rare among her female contemporaries in gaining public recognition for her work in science, yet her role in this process and her role in designing her training have never previously been studied. We know that access to education and participation in science was different for men and women in the eighteenth century. However, drawing on feminist, pedagogical and biographical approaches to history, I argue that although access depended on a variety of factors, a more consistent gender divide came in lessons on how to learn, and in what was regarded as appropriate behaviour. Caroline's skill--so often misunderstood--was to be aware of the differences and to use them to her own advantage. PMID- 26489186 TI - Taboo? PMID- 26489185 TI - THE HIGH-ALTITUDE RESEARCH OF MABEL PUREFOY FITZGERALD, 1911-13. AB - Home schooled without a science education, Mabel Purefoy FitzGerald (1872-1973) attended physiology lectures at Oxford in 1897, even though the school was closed to women. She found work as a researcher, published early noted papers and earned the active respect and support of senior scientists of her day. Her laboratory work with the physiologist J. S. Haldane saw her invited to the join the Pikes Peak Expedition in 1911. While the male team members measured the physiological effects of long-term residency at 14101 feet, as the sole woman FitzGerald took measurements of haemoglobin and alveolar air from herself and from mining staff and families at altitudes from 6000 to 12500 feet, travelling to remote mining communities in the Colorado Rockies. A subsequent expedition collected data at lower altitudes. Recorded in two papers, the results presented pioneering evidence of the role of oxygen in breathing. PMID- 26489187 TI - God Bless You, Ray. PMID- 26489188 TI - It Can't Be Done... PMID- 26489190 TI - The Train is Leaving the Station... PMID- 26489191 TI - The Community Dental Health Coordinator: beyond the pilot study. PMID- 26489192 TI - Address to the House of Delegates IDA President Elect Dr. Chad Leighty. June 13, 2015. PMID- 26489193 TI - Stop and Embrace Your Instincts. PMID- 26489194 TI - Mucogingival Surgery--A Review of Clinical Procedures and Case Reports. PMID- 26489195 TI - "IDon't Run to Add Days to My Life I Run to Add Life to My Days". PMID- 26489196 TI - In Medio Stat Virtis. . PMID- 26489197 TI - President's Message. PMID- 26489198 TI - The Legacy Continues: FLORIDA NURSES FOUNDATION ... SHAPING THE FUTURE OF NURSING. PMID- 26489199 TI - I'm a Nurse ... I Didn't Sign Up for This! De-escalating the Aggressive and Violent Patient. PMID- 26489200 TI - Public Health Nursing: A Rich History. PMID- 26489201 TI - Implementing Training for Nursing Students on Bullying Awareness and Intervention Strategies. PMID- 26489202 TI - Becoming a Courageous Follower. PMID- 26489203 TI - Strengthening Nursing Engagement in Research and Evidence-Based Practice with a Successful MSN Student Research Practicum. PMID- 26489204 TI - The Evolution of a Nurse: A Systemic Journey. PMID- 26489205 TI - Seeing With the Ears. PMID- 26489206 TI - Depth-of-Focus Affects 3D Perception in Stereoscopic Displays. AB - Stereoscopic systems present binocular images on planar surface at a fixed distance. They induce cues to flatness, indicating that images are presented on a unique surface and specifying the relative depth of that surface. The center of interest of this study is on a second problem, arising when a 3D object distance differs from the display distance. As binocular disparity must be scaled using an estimate of viewing distance, object depth can thus be affected through disparity scaling. Two previous experiments revealed that stereoscopic displays can affect depth perception due to conflicting accommodation and vergence cues at near distances. In this study, depth perception is evaluated for farther accommodation and vergence distances using a commercially available 3D TV. In Experiment I, we evaluated depth perception of 3D stimuli at different vergence distances for a large pool of participants. We observed a strong effect of vergence distance that was bigger for younger than for older participants, suggesting that the effect of accommodation was reduced in participants with emerging presbyopia. In Experiment 2, we extended 3D estimations by varying both the accommodation and vergence distances. We also tested the hypothesis that setting accommodation open loop by constricting pupil size could decrease the contribution of focus cues to perceived distance. We found that the depth constancy was affected by accommodation and vergence distances and that the accommodation distance effect was reduced with a larger depth-of-focus. We discuss these results with regard to the effectiveness of focus cues as a distance signal. Overall, these results highlight the importance of appropriate focus cues in stereoscopic displays at intermediate viewing distances. PMID- 26489207 TI - Bilateral Advantages in Subitizing With Visual Masking. AB - Performance on a range of visual-processing tasks has been shown to improve when information is split bilaterally across the left and right visual hemifields rather than being restricted to a single visual hemifield. However, a recent study by Delvenne et al. found no such bilateral advantage for subitizing, which is our ability to rapidly and accurately enumerate small quantities of objects. This finding is particularly surprising, as it contradicts the prediction of FINgers of INSTantiation theory that subitizing should benefit from bilateral presentation. Our study investigated the issue by determining if there are any circumstances where a bilateral advantage for subitization occurs. Contrary to Delvenne et al., we found that subitizing could show bilateral advantages, but only when the display was backward-masked. We discuss these findings in relation to how the rate of encoding and the time available for this encoding may affect bilateral advantages in subitizing. A general model is proposed under which bilateral advantages could be explained. PMID- 26489208 TI - No Relationship Between Binocular Rivalry Rate and Eye-Movement Profiles in Healthy Individuals: A Bayes Factor Analysis. AB - Binocular rivalry (BR) is an intriguing phenomenon in which conflicting images are presented, one to each eye, resulting in perceptual alternations between each image. The rate of BR has been proposed as a potential endophenotype for bipolar disorder because (a) it is well established that this highly heritable psychiatric condition is associated with slower BR rate than in controls, and (b) an individual's BR rate is approximately 50% genetically determined. However, eye movements (EMs) could potentially account for the slow BR trait given EM anomalies are observed in psychiatric populations, and there has been report of an association between saccadic rate and BR rate in healthy individuals. Here, we sought to assess the relationship between BR rate and EMs in healthy individuals (N = 40, mean age = 34.4) using separate BR and EM tasks, with the latter measuring saccades during anticipatory, antisaccade, prosaccade, self-paced, free viewing, and smooth-pursuit tasks. No correlation was found between BR rate and any EM measure for any BR task (p > .01) with substantial evidence favoring this lack of association (BF(01) > 3). This finding is in contrast to previous data and has important implications for using BR rate as an endophenotype. If replicated in clinical psychiatric populations, EM interpretations of the slow BR trait can be excluded. PMID- 26489209 TI - An Illumination Representation Approach to the Chevreul Effect. AB - Within cognitive science of brightness and color perception, the argument has repeatedly been brought forward that it is necessary to consider mental representations for illuminations as well as mental representations for surfaces as integral elements of the functional architecture of the perceptual system. Here, we show that such an approach of dual semantic categories for perceptual representations can fruitfully be applied to the Chevreul effect, a brightness phenomenon of enhanced contrast at borders that played a prototypical role for a very different type of approaches. In these approaches, mechanisms processing retinal intensities are postulated that result in just one brightness dimension without explicitly referring to semantic categories of the perceptual system (surface vs. illumination representation). We argue that the Chevreul effect arises as a result of an interpretation by the visual system that the Chevreul stimulus is covered by a gradual illumination. Our first experiment shows that the Chevreul effect diminishes substantially when this interpretation is prevented by separating the elements of the Chevreul stimulus in depth. In the second experiment, we show that the strength of the Chevreul effect is strongly affected by embedding the Chevreul stimulus into three-dimensional scenes that either support or conflict with the interpretation of an illumination gradient across the stimulus. PMID- 26489210 TI - What Is Suspicious When Trying to be Inconspicuous? Criminal Intentions Inferred From Nonverbal Behavioral Cues. AB - The present study investigates whether nonverbal behavioral cues to hidden criminal intentions during the build-up phase of a criminal act can be measured. To this end, we created recordings of actors once in a search situation and once committing a mock crime (theft or bomb placing) in a public crowded area. For ecological validation, we used authentic CCTV footage of real crimes in Experiment I. In this experiment, the two behavioral clusters pattern of movement in space and nonverbal communication behavior were analyzed. The results showed a deviance in pattern of movement in space for offenders' compared with the nonoffenders' condition as well as a bystanders' baseline. There was no significant difference between nonverbal communication behavior in the offenders' and nonoffenders' conditions. Experiment 2 was conducted to examine the two behavior clusters use of object- and self-adaptors while controlling for interpersonal differences. The results showed an increased use of object- and decreased use of self-adaptors during the build-up phase of a mock crime compared with a control condition (search). Thus, nonverbal behavior of offenders seems to differ from nonverbal behavior of nonoffenders. However, this holds only under the conditions of a valid baseline and of judging not only a single, typical behavioral cue but a whole cluster of nonverbal behaviors, such as pattern of movement in space or use of object-adaptors in general. PMID- 26489211 TI - Are You Suggesting That's My Hand? The Relation Between Hypnotic Suggestibility and the Rubber Hand Illusion. AB - Hypnotic suggestibility (HS) is the ability to respond automatically to suggestions and to experience alterations in perception and behavior. Hypnotically suggestible participants are also better able to focus and sustain their attention on an experimental stimulus. The present study explores the relation between HS and susceptibility to the rubber hand illusion (RHI). Based on previous research with visual illusions, it was predicted that higher HS would lead to a stronger RHI. Two behavioral output measures of the RHI, an implicit (proprioceptive drift) and an explicit (RHI questionnaire) measure, were correlated against HS scores. Hypnotic suggestibility correlated positively with the implicit RHI measure contributing to 30% of the variation. However, there was no relation between HS and the explicit RHI questionnaire measure, or with compliance control items. High hypnotic suggestibility may facilitate, via attentional mechanisms, the multisensory integration of visuoproprioceptive inputs that leads to greater perceptual mislocalization of a participant's hand. These results may provide insight into the multisensory brain mechanisms involved in our sense of embodiment. PMID- 26489212 TI - Visual art and visual perception. PMID- 26489213 TI - Developmental improvement and age-related decline in unfamiliar face matching. AB - Age-related changes have been documented widely in studies of face recognition and eyewitness identification. However, it is not clear whether these changes arise from general developmental differences in memory or occur specifically during the perceptual processing of faces. We report two experiments to track such perceptual changes using a 1-in- 10 (experiment 1) and 1-in-1 (experiment 2) matching task for unfamiliar faces. Both experiments showed improvements in face matching during childhood and adult-like accuracy levels by adolescence. In addition, face-matching performance declined in adults of the age of 65 years. These findings indicate that developmental improvements and aging-related differences in face processing arise from changes in the perceptual encoding of faces. A clear face inversion effect was also present in all age groups. This indicates that those age-related changes in face matching reflect a quantitative effect, whereby typical face processes are engaged but do not operate at the best possible level. These data suggest that part of the problem of eyewitness identification in children and elderly persons might reflect impairments in the perceptual processing of unfamiliar faces. PMID- 26489214 TI - What's that smell? An ecological approach to understanding preferences for familiar odors. AB - How do odor preferences arise? Following Palmer and Schloss's (2010, PNAS, 107, 8877-8882) ecological valence theory of color preferences, we propose that preference for an odor is determined by preferences for all objects and/or entities associated with that odor. The present results showed that preferences for familiar odors were strongly predicted by average preferences for all things associated with the odors (eg people liked the apple odor which was associated with mostly positive things, such as apples, soap, and candy, but disliked the fish odor, which was associated with mostly negative things, such as dead fish, trash, and vomit). The odor WAVEs (weighted affective valence estimates) performed significantly better than one based on preference for only the namesake object (eg predicting preference for the apple odor based on preference for apples). These results suggest that preferences for familiar odors are based on a summary statistic, coding the valence of previous odor-related experiences. We discuss how this account of odor preferences is consistent with the idea that odor preferences exist to guide organisms to approach beneficial objects and situations and avoid harmful ones. PMID- 26489215 TI - Postural responses to various frequencies of vibration of the triceps surae and forefoot sole during quiet standing. AB - The purpose of this study was to determine the role of somatosensory input to the sensory reference system in quiet standing. We applied vibration (0.5 mm amplitude, 1-60 Hz) to the triceps surae and the forefoot sole to stimulate the muscle spindles and the mechanoreceptors, respectively, and evaluated postural responses. Thirteen young healthy adults who showed backward-lean and forward lean responses to vibration at high and low frequencies, respectively, participated in the full experiment. The lowest vibration frequencies inducing backward-lean responses (B-LF) were 15-55 Hz for the triceps surae and 16-60 Hz for the forefoot sole. The highest frequencies inducing forward-lean responses (F HF) were 3-18 Hz for the triceps surae and 1-20 Hz for the forefoot sole. When vibration was simultaneously applied to the triceps surae and forefoot sole at F HF, no response was induced in 70% of trials. A forward-lean response was induced in the remaining 30% of trials. Simultaneous vibration of the triceps surae and forefoot sole at B-LF induced backward-lean responses in all trials. All postural responses occurred 0.5-4.3 s after vibration onset. Postural responses to high frequency vibration conceivably occur as a compensatory movement to the illusionary perception that standing position is deviating forward from quiet standing, which must be a reference position. Postural responses to low-frequency vibration possibly occur to equalize the positional information that is received from the triceps surae and the forefoot sole. Both postural responses are likely to involve the sensory reference system, which is located in the supraspinal nervous system. PMID- 26489216 TI - Attentional biases and recognition accuracy: What happens when multiple own- and other-race faces are encountered simultaneously? AB - Adults recognize own-race faces more accurately than other-race faces. We investigated three characteristics of laboratory investigations hypothesized to minimize the magnitude of the own-race recognition advantage (ORA): lack of competition for attention and instructions that emphasize individuating faces during the study phase, and a lack of uncertainty during the test phase. Across two experiments, participants studied faces individually, in arrays comprising multiple faces and household objects, or in naturalistic scenes (presented on an eye-tracker); they were instructed to remember everything, memorize faces, or form impressions ofpeople. They then completed one of two recognition tasks--an old/new recognition task or a lineup recognition task. Task instructions influenced time spent looking at faces but not the allocation of attention to own versus other-race faces. The magnitude of the ORA was independent of both task instructions and test protocol, with some modulation by how faces were presented in the study phase. We discuss these results in light of current theories of the ORA. PMID- 26489217 TI - From sensation to perception: Using multivariate classification of visual illusions to identify neural correlates of conscious awareness in space and time. AB - An important goal of cognitive neuroscience is understanding the neural underpinnings of conscious awareness. Although the low-level processing of sensory input is well understood in most modalities, it remains a challenge to understand how the brain translates such input into conscious awareness. Here, I argue that the application of multivariate pattern classification techniques to neuroimaging data acquired while observers experience perceptual illusions provides a unique way to dissociate sensory mechanisms from mechanisms underlying conscious awareness. Using this approach, it is possible to directly compare patterns of neural activity that correspond to the contents of awareness, independent from changes in sensory input, and to track these neural representations over time at high temporal resolution. I highlight five recent studies using this approach, and provide practical considerations and limitations for future implementations. PMID- 26489218 TI - Facial cosmetics have little effect on attractiveness judgments compared with identity. AB - The vast majority of women in modern societies use facial cosmetics, which modify facial cues to attractiveness. However, the size of this increase remains unclear -how much more attractive are individuals after an application of cosmetics? Here, we utilised a 'new statistics' approach, calculating the effect size of cosmetics on attractiveness using a within-subjects design, and compared this with the effect size due to identity--that is, the inherent differences in attractiveness between people. Women were photographed with and without cosmetics, and these images were rated for attractiveness by a second group of participants. The proportion of variance in attractiveness explained by identity was much greater than the variance within models due to cosmetics. This result was unchanged after statistically controlling for the perceived amount of cosmetics that each model used. Although cosmetics increase attractiveness, the effect is small, and the benefits of cosmetics may be inflated in everyday thinking. PMID- 26489219 TI - Seeing red on the road. AB - Human and animal research has found that red perception is associated with specific behavioral reactions, generally characterized by intense responses. Here, we explored whether red cars are perceived as more dangerous than other colored cars. One hundred Spanish drivers examined several road scenarios which involved hazardous cars with different colors: red, green, yellow, black, gray, and white. Driver's behavior (response time and probability of braking) and the perceived level of risk for each scenario were analyzed. Although car color affected participants' response times, contrary to expectations, red cars did not elicit faster responses or higher perceived levels of risk. PMID- 26489220 TI - Change magnitude does not guide attention in an object change detection task. AB - Investigations of change detection consistently reveal an effect of change magnitude: changes involving more object parts are detected more easily than those involving fewer parts. Whether large changes improve detection by providing stronger preattentive signals to the change location is subject to debate. We report a cued object change detection experiment that tested this hypothesis while controlling for stimulus familiarity, semantic knowledge, and change type (addition versus deletion). We found strong magnitude effects regardless of whether trials were validly or invalidly cued. The size of the cueing effects, which were exhibited for all the change magnitudes examined, did not decrease with the number of parts changing. These findings provide little support for a preattentive guidance hypothesis and instead support the thesis that change detection requires attention. PMID- 26489221 TI - How perception affects racial categorization: On the influence of initial visual exposure on labelling people as diverse individuals or racial subjects. AB - In research on racial categorization we tend to focus on socialization, on environmental influences, and on social factors. One important factor, though, is perception itself In our experiment we let people label persons on dimensions which they could freely use. The participants were initially exposed to a full series either of black faces or of white faces. We observed a clear effect of initial exposure on explicit verbal categorizations. When initially exposed to white faces, participants used racial labels for the subsequent black faces only. In contrast, racial labels were used for black as well as white faces after initial exposure to black faces, which indicates a shift to in-group categorization after having initially inspected black faces. In conclusion, this effect documents highly adaptive categorizations caused by visual context alone, suggesting that racial thoughts are based on relatively volatile category representations. PMID- 26489222 TI - What's up with witch rings? AB - 'Witch rings' are well-known novelty rings that show a size-change illusion when rotated. We have replicated the illusion of expansion of the reflections in the rings in a variety of contexts with animations, though not as yet so successfully imitated the sense that the whole ring expands and contracts. PMID- 26489223 TI - Life After ICD-10. PMID- 26489224 TI - Answering the TOUGH ICD10 Questions. PMID- 26489225 TI - REMEDIATING ICD-10 KNOWLEDGE LOSS. . PMID- 26489226 TI - Ten skills that make a great leader. PMID- 26489227 TI - Privacy HOLES in the 'Hidden Healthcare System'. PMID- 26489228 TI - The Evolving Role of the Privacy and Security Officer. PMID- 26489229 TI - Rules of the Road Differ for Inpatient and Outpatient ICD-10 Coding. PMID- 26489230 TI - Achieving Health Information Systems Interoperability. PMID- 26489231 TI - Evaluating the Information Governance Principles for Healthcare: Compliance and Availability. PMID- 26489232 TI - Electronic Documentation Templates Support ICD-10-CM/PCS Implementation (Updated). PMID- 26489233 TI - How Deep Do You Dig into ICD-10-PCS Coding? PMID- 26489234 TI - Injection and Infusion Coding Offers High Stakes. PMID- 26489235 TI - A Final Message. PMID- 26489236 TI - Ashley Coerver, DDS, Moore, OK. PMID- 26489237 TI - ODA Past President Perspective: Scott Waugh, DDS, ODA President 2002-2003. PMID- 26489238 TI - Treating Diastemous Spaces without Orthodontics. PMID- 26489239 TI - OHCA Dental Audit Findings Summary. PMID- 26489240 TI - Bench Warmers Go play outside--your muscles will thank you. PMID- 26489241 TI - The Blame Game. How to go head-to-head with diabetes stigma--and come out a winner. PMID- 26489243 TI - Playing against type. THE CHALLENGES OF DIAGNOSING TYPE 1 DABETES IN ADULTS. PMID- 26489244 TI - Jeremy Hunt fails to rule out cuts to health visitors. PMID- 26489242 TI - The Motivating Factor. What impels you to use your blood glucose meter? PMID- 26489245 TI - Baby P child death 'likely' to happen again, say health visitors. PMID- 26489246 TI - Revalidation issues highlighted in case studies. PMID- 26489247 TI - Revalidation: The professional development discussion. AB - The professional development discussion (PDD) will be an essential component of revalidation with the Nursing and Midwifery Council. The Unite/CPHVA professional officers who participated in the pilot found the PDD to be the most beneficial part of the revalidation process. This article explores the experience of a PDD from both the revalidatee and the fellow registrant perspective. It goes on to make recommendations for ensuring an effective PDD. PMID- 26489248 TI - Smoking in pregnancy: The dangers of carbon monoxide exposure. PMID- 26489249 TI - Vitamin D-Day. PMID- 26489250 TI - The management of eczema in children. AB - Eczema is very common in children and impacts significantly on the quality of life of children and their families and carers. Poor adherence remains the main cause of treatment failure. Rigorous and consistent use of treatments is key to relieving symptoms, but many parents experience significant barriers to application. Community practitioners are ideally placed to educate parents in the use of emollients, and where necessary topical corticosteroids, identify and discuss problems and help parents to develop strategies to overcome difficulties. Food allergy is associated with eczema, particularly in infants and the risk increases with severity. Community practitioners need to be confident in its recognition and management. PMID- 26489251 TI - Postnatal Depression: Don't reinvent the wheel. AB - Poor mental health accounts for 23% of all ill health in the UK, with the cost of treating it expected to double in the next 20 years. In addition, postnatal depression (PND) in both mothers and fathers can have a detrimental long-term impact on a child's cognitive, social and behavioural development. This paper discusses the development process of an innovative evidence-based resource which involved professional expertise and parent involvement. This unique resource helps to recognise PND in both mothers and fathers and will support health visitors in making a real impact in improving outcomes for children and families. PMID- 26489252 TI - A Home-Start peer support scheme for women with low mood following childbirth. AB - Perinatal mental health problems vary in impact and severity, and can have long lasting effects on maternal health and child psychological health and development. The evidence to support the effectiveness of postnatal peer and volunteer support schemes to improve the long-term health of women is mixed, with some studies highlighting positive effects in terms of reducing symptoms of depression. Using data from a peer support scheme designed to support women with low mood following childbirth, this paper provides insight into the initial support needs of women, alongside the challenges of using volunteer and peer support services. This paper provides health visitors and others working in community settings with an understanding of how volunteer befriending services may, or may not work in community settings. The data suggests that Home-Start does have a positive impact on the lives of some women, however more work is required in order to understand which aspects of the Home-Start intervention women find effective and why. PMID- 26489253 TI - Short-term benefits from the Incredible Years Parents and Babies Programme in Powys. AB - The Incredible Years parent and babies programme has been delivered widely across Wales, mainly in high disadvantage Flying Start areas, following training for group leaders funded by the Welsh Government. The programme targets parents and their babies during the first year of their life and contains all of the key components of effective parenting programmes, discussion, observation of effective parenting skills and practice. The Children and Young People's partnership in Powys, a rural county in East Wales, incorporated the programmes into their early intervention/prevention strategy. This paper reports on the results from twelve groups with pre- and post-course measures from 79 (64%) group participants. Results showed significant benefits for parents in terms of improved mental health and parenting confidence post-course. These results provide short-term evidence of effectiveness and confirm the decision by Powys to deliver this evidence informed programme. PMID- 26489254 TI - Last word with ... Jackie Smith. PMID- 26489255 TI - Minnesota Supreme Court Holds that Medical Staff Bylaws are an Enforceable Contract. PMID- 26489256 TI - Health Information Exchange Improves Referral Management Workflow. PMID- 26489257 TI - Practicing in Michigan. PMID- 26489258 TI - Why Michigan Is an Ideal Place to Practice Medicine. PMID- 26489259 TI - Four Ways to Transfer Your Assets After You Die. PMID- 26489260 TI - Michigan's Vaccination Waiver Rules Are Strengthened. PMID- 26489261 TI - Michigan State Medical Alliance Promoting and Continuing Legislative Action. PMID- 26489262 TI - Nightmares to Dreams, Dreams to Reality. PMID- 26489263 TI - 2014 HIPAA Enforcement Actions Show You Must Take Documentation Requirements Seriously. PMID- 26489264 TI - Diagnostic Error Identified as the Most Common Allegation in Malpractice Lawsuits. PMID- 26489265 TI - Lock and Key. PMID- 26489266 TI - What is Physician Leadership? PMID- 26489267 TI - Take Financial Leadership in 2015. PMID- 26489268 TI - Protecting Persons Aged 65 Years and Older Against Pneumococcal Disease. PMID- 26489269 TI - On Being a Leader. PMID- 26489270 TI - Prior authorization: Undermining our health care system. PMID- 26489271 TI - We are listening. PMID- 26489272 TI - Here's to your success. PMID- 26489273 TI - The ACA exchange in Georgia: Confusion, frustration & questions. PMID- 26489274 TI - An update on the ICD-10 transition. PMID- 26489275 TI - An update on the Physicians' Institute for Excellence in Medicine. PMID- 26489276 TI - Georgia's primary care physician supply and its ties to chronic diseases. PMID- 26489278 TI - The need to educate medical students about health care policy. PMID- 26489277 TI - Tuition loan repayment program available for rural physicians. PMID- 26489279 TI - Should physicians exclude vaccine-refusing families from their practices? PMID- 26489280 TI - Expert witnesses in medical malpractice cases. PMID- 26489281 TI - Being a defendant. PMID- 26489282 TI - Where we practice: Gainesville. PMID- 26489283 TI - Retiring physicians: Maintenance and destruction of medical records. PMID- 26489285 TI - Repealing the SGR & alternative payment models: What H.R. 2 means for physicians. PMID- 26489284 TI - Patient dies after doctor's office visit. PMID- 26489286 TI - Life lessons: continued. PMID- 26489287 TI - President's Perspective. PMID- 26489288 TI - Oral and maxillofacial pathology. Case of the month. Multiple myeloma. PMID- 26489289 TI - SPIT TOBACCO: A Changing Landscape. PMID- 26489290 TI - The Surgical Management of Head and Neck Cancer by Oral and Maxillofacial Surgeons in Texas. PMID- 26489291 TI - Zirconia with Aluminum Oxide Sandblasting Treatment Followed by MDP-containing Primer has Greater Bond Strength than Zirconia with No Surface Treatment (UT CAT # 2812). PMID- 26489292 TI - Knowledge Assessment of the Dental Community in Texas on the Role of Human Papilloma Virus in Oropharyngeal Cancer. AB - OBJECTIVES: The epidemiology of oral cancer is changing. From 1988 to 2004, there has been a dramatic increase in Human Papilloma virus (HPV) positive oropharyngeal squamous cell carcinoma (OPC) in the U.S. At the same time there have been decreasing rates of OPC associated with the traditional risk factors of smoking and alcohol consumption. The epidemiology of oral cancer is changing. As the epidemiology changes, it is important that the dental community recognize these factors. The goal of this study was to assess the baseline level of knowledge about HPV and OPC within the Texas dental community. METHODS: Practicing dentists and dental hygienists from Texas dental professional networks and dental students from the three Texas schools of dentistry were recruited to participate in the study. Participants were requested to access and complete a 7 item online survey. To ensure anonymity, a third party practice facilitator or department administrator disseminated the survey link to participants. RESULTS: Of the 457 surveys completed, 100% of respondents reported conducting oral soft tissue examinations at least annually. However, only 73% included the oropharynx in their exam. Less than 50% of dental professionals selected the correct location of the greatest increase in oral cancer incidence during the last 10 years. Less than 30% of each of the groups answered correctly in indicating the age group with the most rapidly increasing incidence of oral cancer. Approximately 40% of all groups indicated that a biopsy from the posterior oropharynx should be tested for HPV. CONCLUSION: Survey results across Texas dentists, dental hygienists, and Texas dental students demonstrated a lack of knowledge of the changing profile of oral cancer regarding HPV-associated OPC. This aim of this initial phase was to determine the baseline level of knowledge surrounding the risks associated with oropharyngeal cancer in the survey population. Our goal is to utilize these findings to develop educational interventions that will be disseminated throughout the dental community in Texas to improve diagnosis of these devastating cancers. PMID- 26489293 TI - Updates Regarding Diagnostic Adjuncts for Oral Squamous Cell Carcinoma. AB - The 5-year survival rate for oral cancer (66%) is still one of the lowest among major human cancers, and delayed diagnosis until an advanced stage is thought to be the main factor contributing to this low survival rate. The detection and diagnosis of oral cancer is currently based on clinical visual examination and histopathological evaluation of a biopsy specimen. In response to the need for early detection of oral cancer, several diagnostic adjuncts have been developed and sold commercially over the years, including vital tissue staining, brush cytology, light-based visualization adjuncts, and the most recently developed test for salivary biomarkers for oral cancer. The purpose of this article is to review the current knowledge and research regarding these diagnostic adjuncts developed for early detection of oral cancer. Clinicians are best served by an awareness of the advantages and disadvantages of each adjunct, and to always consider and correlate with the clinical findings when interpreting the test results from these adjuncts. PMID- 26489294 TI - An Article to Share with your Team: CARE ENOUGH TO PROVIDE AN EXCEPTIONAL PATIENT EXPERIENCE. PMID- 26489295 TI - [Potential Source Contribution Analysis of the Particulate Matters in Shanghai During the Heavy Haze Episode in Eastern and Middle China in December, 2013]. AB - A heavy haze pollution episode occurred in early December, 2013 in middle and eastern China, which lasted for a long period, and covered a large area. During this episode, the hourly maximum concentrations of PM10 and PM2.5 in Shanghai exceeded 700 ug.m-3 and 600 ug.m-3, respectively. To obtain the major air mass transportation path, trajectories reaching urban Shanghai area were analyzed using HYSPLIT model and cluster analysis. Potential Source Contribution Function (PSCF) and Concentration-Weighted Trajectory (CWT) methods were applied to study the potential source regions and the individual contributions to PM10 in Shanghai in December, 2013. The results showed that the northwest and the north paths were the major air mass transport paths in December, among which 79. 6% of the total trajectories came from mainland, while 20. 4% reached Shanghai through the ocean. These were the main transportation paths causing high PM10 mass concentration in December in Shanghai. The potential regions affecting the heavy haze episode in early December in Shanghai were distributed in the Yangtze River Delta including Jiangsu, Zhejiang and Anhui. Besides, air mass from Shandong, Hebei and Henan also had certain impact. The results showed that regional and even super-regional pollution joint control was of significant importance to reduce the frequent heavy air pollution episodes. PMID- 26489296 TI - [Composition and Regional Characteristics of Atmosphere Aerosol and Its Water Soluble Ions over the Yangtze River Delta Region in a Winter Haze Period]. AB - To investigate the pollution characteristics of water soluble ions in fine atmospheric particles in Yangtze River Delta during the haze period from 18th to 24th Jan 2013, a joint sampling campaign using Andersen sampler was conducted at five cities (including Nanjing, Suzhou, Hangzhou, Lin'an and Ningbo). The analysis of size distribution of these ionic species coupled with the local meteorological conditions may shed some insightful light on the haze formation mechanism in this region. The result has shown: firstly, during the observation period, when Yangtze River Delta located at high pressure or in the front of high pressure, and has a large pressure gradient, the lower atmosphere has a significant airflow divergence in favor of pollutant dispersion; while located in weak low pressure and weak high pressure, the equalizing pressure field is not favorable for pollutant dispersion, especially accompanied with lower atmosphere convergence airflow. Secondly, during the hazy period, the concentration of fine particles and total water-soluble inorganic ions (TWSS) has increased dramatically; the increasing proportions of TWSS in fine particles are: Hangzhou 0. 9%, Lin'an 4. 2%, Nanjing 8. 1%. The particle size of secondary ions of SO(4)2 , NO3-, NH4+ complies fine mode(particle size <2. 1 um), whose peaks migrates from 0. 43-0. 65 um to 0. 65-1. 1 um during the observation period, the peak of particle size of Ca2+ , Mg2+ appears at 4.7-5. 8 um, while the ions of Na+, Cl-, K+ show a bimodal distribution. Moreover, secondary inorganic ions play a significant role in the formation of haze pollution, where the concentrations of secondary inorganic ions of NH4+, SO2- and NO3 have higher increasing rates; their relative proportions of increasing from each monitoring points are: Hangzhou 3%, Lin'an 55% and Nanjing 64.9%. Finally, SO(4)2- has the highest mass contribution to SNA, up to 45% ; also, the NO-/SO- ratios in each monitoring points are always higher than a fair 0. 5, which could indicate the significant contribution of mobile source towards this particle pollution. PMID- 26489297 TI - [Chemical Species of PM2.5 in the Urban Area of Beijing]. AB - From August 2012 to July 2013, 220 groups of PM2.5 samples were continuously collected at four locations in the urban area of Beijing (Shijingshan, Chegongzhuang, Dongsi, and Tongzhou), and the primary chemical species of PM2.5 were analysed by the chemical mass balance method. It was found that the mass of PM2.5 obtained from chemical mass balance method agreed well with the value from gravimetric measurement, with a good correlation of 0. 95 in spring, autumn, and winter. However, the correlation seasonally changed in summer, with a relatively lower correlation coefficient of 0. 77. The concentrations of OM, EC, SO(4)2-, NO3-, NH4+, Cl-, crustal matter, and trace species were 31. 4, 3. 8, 19. 9, 21. 6, 14. 4, 4. 0, 15. 4, and 2. 9 ug.m-3, which accounted for 25. 1%, 3. 0% , 15. 9%, 17. 2%, 11. 5%, 3. 2%, 12. 3%, and 2. 3% of PM2, , respectively. Besides crustal matter, concentrations of the primary chemical species in PM2.5 from the west to the east gradually increased. The most serious PM pollution occurred between 11 and 14 February 2013, during which concentrations of OM, SO2-, NO3-, NH4+ were 1. 9, 5. 0, 3.2 and 4. 2 times as high as the annual average. SO(4)2- was recognized as the most important species for the pollution in the process. OM was the largest component of urban PM2.5 during both heating and non-heating periods. Comparing to non-heating period, the concentrations of OM, NH4+, NO3-, and SO(4)2- all increased during the heating period, except for the component of crust and EC. The biggest difference between the two periods was the component of Cl- (4. 4 fold), which can be attributed to the burning of coal. For unknown components, the main component was moisture, which accounted for about 6.0% in urban PM2.5. The highest moisture appeared in summer (6. 5%), followed by spring and winter, and the least appeared in fall (3. 7% ). PMID- 26489298 TI - [Numerical Study on the Characteristics of Regional Transport of PM2.5 in Shandong Province During Spring in 2014]. AB - In this paper, spatial and temporal distribution, transportation and deposition of PM2.5 in Shandong Province in Spring, 2014 were all analyzed by applying PSAT of CAMx model and we also developed a transport matrix of PM2.5 between different cities in Shandong. The results showed that rho(PM2.5) presented obvious spatial distribution characteristics; rho(PM2.5) was higher in the western part compared to that in peninsula and rho(PM2.5) was mainly concentrated below 2 000 m in vertical direction. Simulated horizontal transport flux of PM2.5 was up to 110 ug.(m2.s)-1 and the total deposition amount of PM2.5 was 23. 05 x 10(4) t in Shandong during Spring, 2014. Analysis of regional contribution found that the pollutants mainly came from local districts and the average external transport contribution to the whole Shandong province was about 21. 08% +/- 3. 83% while it was 40. 45% +/- 5. 96% between different cities; the contribution rates of Jinjinji distrcit, background and boundary conditions gradually increased by 7. 56% and 6. 18% respectively as the altitude increased. PMID- 26489299 TI - [Characteristics of Water-Soluble Inorganic Ions in PM2.5 Emitted from Coal-Fired Power Plants]. AB - To characterize the primary PM2.5 emission from coal-fired power plants in China, and to quantitatively evaluate the effects of flue gas denitrification and desulfurization on PM2.5 emission, a pulverized coal fired (PC) power plant and a circulating fluidized bed (CFB) plant were selected for measuring the mass concentration and water-soluble ion composition of PM2.5 in flue gas. The results showed that the mass concentration of PM2.5 generated from the CFB was much higher than that from the PC, while the mass concentrations of PM2.5 emitted from these two plants were very similar, because the CFB was equipped with an electrostatic-bag precipitator (EBP) with higher PM2.5 removal efficiency than the common electrostatic precipitator (ESP). Although the total concentration of water-soluble ions in PM2.5 generated from the PC was lower than that from the CFB, the total concentration of water-soluble ions in PM2.5 emitted from the PC was much higher than that from the CFB, which implied that PM2.5 emission from the PC was greatly affected by the flue gas treatment installations. For example, the flue gas denitrification system produced H2SO4 mist, part of which reacted with the excessive NH3 in the flue gas to form NH4HSO4 in PM2.5 and to increase the acidity of PM2.5. In addition, the escaping of desulfurization solution during the flue gas desulfurization process could also introduce NH4+ and SO2- into PM2.5. Therefore, although the main water-soluble ions in PM2.5 generated from both of the plants were Ca2+ and SO(4)2-, the major cation was changed to NH4+ when emitted from PC. PMID- 26489300 TI - [Direct Observation on the Temporal and Spatial Patterns of the CO2 Concentration in the Atmospheric of Nanjing Urban Canyon in Summer]. AB - Direct observation of urban atmospheric CO2 concentration is vital for the research in the contribution of anthropogenic activity to the atmospheric abundance since cities are important CO2 sources. The observations of the atmospheric CO2 concentration at multiple sites/heights can help us learn more about the temporal and spatial patterns and influencing mechanisms. In this study, the CO2 concentration was observed at 5 sites (east, west, south, north and middle) in the main city area of Nanjing from July 18 to 25, 2014, and the vertical profile of atmospheric CO2 concentration was measured in the middle site at 3 heights (30 m, 65 m and 110 m). The results indicated that: (1) An obvious vertical CO2 gradient was found, with higher CO2 concentration [molar fraction of 427. 3 x 10(-6) (+/-18. 2 x 10(-6))] in the lower layer due to the strong influences of anthropogenic emissions, and lower CO2 concentration in the upper layers [411. 8 x 10(-6) (+/-15. 0 x 10(-6)) and 410. 9 x 10(-6) (+/-14. 6 x 10( 6)) at 65 and 110 m respectively] for the well-mixed condition. The CO2 concentration was higher and the vertical gradient was larger when the atmosphere was stable. (2) The spatial distribution pattern of CO2 concentration was dominated by wind and atmospheric stability. During the observation, the CO2 concentration in the southwest was higher than that in the northeast region with the CO2 concentration difference of 7. 8 x 10(-6), because the northwest wind was prevalent. And the CO2 concentration difference reduced with increasing wind speed since stronger wind diluted CO2 more efficiently. The more stable the atmosphere was, the higher the CO2 concentration was. (3) An obvious diurnal variation of CO2 concentration was shown in the 5 sites. A peak value occurred during the morning rush hours, the valley value occurred around 17:00 (Local time) and another high value occurred around 19:00 because of evening rush hour sometimes. PMID- 26489301 TI - [Emission Factors of Vehicle Exhaust in Beijing]. AB - Based on the investigation of basic data such as vehicle type composition, driving conditions, ambient temperature and oil quality, etc., emission factors of vehicle exhaust pollutants including carbon monoxide (CO), nitrogen oxides (NOx), hydrocarbons (HC) and particulate matter(PM) were calculated using COPERT IV model. Emission factors of typical gasoline passenger cars and diesel trucks were measured using on-board measurement system on actual road. The measured and modeled emission factors were compared and the results showed that: the measured emission factors of CO, NOx and HC were 0. 96, 0. 64 and 4. 89 times of the modeled data for passenger cars conforming to the national IV emission standard. For the light, medium and heavy diesel trucks conforming to the national III emission standard, the measured data of CO emission factors were 1.61, 1. 07 and 1.76 times of the modeled data, respectively, the measured data of NOx emission factors were 1. 04, 1. 21 and 1. 18 times of the modeled data, and the measured data of HC emission factors were 3. 75, 1. 84 and 1. 47 times of the modeled data, while the model data of PM emission factors were 1. 31, 3. 42 and 6. 42 times of the measured data, respectively. PMID- 26489302 TI - [Adsorption Capacity of the Air Particulate Matter in Urban Landscape Plants in Different Polluted Regions of Beijing]. AB - Urban landscape plants, as one of the important factors of the urban ecosystem, play an important role in stagnating airborne particulates and purifying urban atmospheric environment. In this article, six kinds of common garden plants were studied, and aerosol generator (QRJZFSQ-I) was used to measure the ability of their leaves to stagnate atmospheric particulates (TSP and PM2.5) in different polluted regions. Meanwhile, environmental scanning electron microscope was used to observe changes in the leaf structure of the tested tree species. The results showed: (1)Among the tested tree species, the ability of coniferous species to stagnate atmospheric particulates was higher than that of broad-leaved species per unit leaf area. Pinus tabuliformis stagnated the highest volume of (3. 89+/- 0. 026) ug . m-2, followed by Pinus bungeana of (2. 82 +/- 0. 392) ug . cm-2, and Populus tomentosa stagnated the minimum of (2. 00 +/- 0. 118) ug . cm-2; (2) Through observing the leaf microstructure morphology, coniferous species were found to have tightly packed stomas, stoma density and surface roughness higher than those of broad-leaved species, and they could also secrete oil; (3) In different polluted regions, the leaves of the same tree species showed significant difference in stagnating TSP. Per unit leaf area, the tree species leaves situated around the 5th Ring Road had higher ability to absorb TSP than the tree species leaves at Botanical Garden, while their abilities to absorb PM2.5 showed no significant difference; (4) In different polluted regions, significantly adaptive changes were found in leaf structure. Comparing to the region with light pollution, the outer epidermal cells of the plant leaves in region with heavy pollution shrank, and the roughness of the leaf skin textures as well as the stomatal frequency and villous length increased. In spite of the significant changes in plant leaves exposed to the heavy pollution, these plants could still maintain normal and healthy growth. PMID- 26489303 TI - [Major Air Pollutant Emissions of Coal-Fired Power Plant in Yangtze River Delta]. AB - The emission factor method was used to estimate major air pollutant emissions of coal-fired power plant in the Yangtze River Delta (YRD) region of the year 2012. Results showed that emissions of SO2, NOx, dust, PM10, PM2.5 were respectively 473 238, 1 566 195, 587 713, 348 773 and 179 820 t. For SO2 and NOx, 300 MW and above class units made contributions of 85% and 82% in emission; while in the respect of dust, PM10 and PM2.5 contribution rates of 100 MW and below class units were respectively 81%, 53% and 40%. Considering the regional distribution, Jiangsu discharged the most, followed by Zhejiang, Shanghai. According to discharge data of several local power plants, we also calculated and made a comparative analysis of emission factors in different unit levels in Shanghai, which indicated a lower emission level. Assuming an equal level was reached in whole YRD, SO2 emission would cut down 55. 8% - 65. 3%; for NOx and dust emissions were 50. 5% - 64. 1% and 3. 4% - 11. 3%, respectively. If technologies and pollution control of lower class units were improved, the emission cuts would improve. However, according to the pollution realities of YRD, we suggested to make a multiple-cuts plan, which could effectively improve the reaional atmospheric environment. PMID- 26489304 TI - [Estimation of N2O Emission from Anhui Croplands by Using a Regional Nitrogen Cycling Model IAP-N]. AB - N2O emissions from seven categories of Anhui croplands in 2011 were estimated by using a regional nitrogen cycling model IAP-N. The required statistical data were from each city's statistical yearbook in Anhui Province. The emission factors were from the published field data. The results showed that total N2O emissions from Anhui croplands in 2011 were 35. 1 thousand ton, in which direct and indirect N2O emissions were, respectively, 27. 6 thousand ton and 6. 6 thousand ton, and N2O emission from residues/straws burning in the field was 800 ton. Huaibei Plain (Region I) and Jianghuai Hilly (Region II) were the main contribution regions in Anhui, accounting for 41% and 35% of its regional total N2O emissions, respectively. The most important source for direct N2O emission is the year round upland fields with 74% contribution of the province total direct N2O emission. The second important source in Region II and Region III is upland cropping season of the rotation fields with rice and upland-crops, accounting for 19% and 14% , respectively. While in Region IV, the second direct N2O emission sources are tea gardens and orchards, accounting for 22%. About two-thirds of the indirect N2O were from atmospheric nitrogen deposition. The results can provide a scientific basis for policy makers to make agricultural soils GHG mitigation measures in Anhui Province, such as reasonable use of fertilizers. PMID- 26489305 TI - [Evaluation on the Impacts of Different Background Determination Methods on CO2 Sources and Sinks Estimation and Seasonal Variations]. AB - To accurately determine background conditions or extract sources and sinks information from the observed atmospheric carbon dioxide (CO2) concentration is crucial for quantitative estimation of regional and global carbon budget and future trends of atmospheric CO2. In this study, the synchronized observed surface winds and carbon monoxide (CO) concentration have been examined to test their effectiveness as filter factors to determine CO2 background conditions at Waliguan site. The results show that the surface winds and CO concentrations can be used as filter factor in winter, but they are not very effective in summer. Three statistical methods, robust estimation of background signal (REBS), Fourier transform algorithm (FTA) and a new developed moving average filtering (MAF), are applied to atmospheric CO2 background selection. The result suggested that our new developed MAF method, which can well estimate the elevated and sequestered CO2 concentrations due to using changing and adjusting filter criteria at every two-week fitting window, is thus better than the other two statistical methods. A good consistency is indicated by the three methods for estimating the elevated CO2 caused by local or regional emissions, but it showed large discrepancies when determining the sequestered CO2. The result suggested that the three methods can reasonable extract those anthropogenic influenced episodes, but only MAF method would well identify those episodes due to terrestrial CO2 fluxes. Mean seasonal amplitude of atmospheric CO2 at Waliguan during 1995-2008 is 10. 3 x 10(-6) estimated by MAF method, which is in good agreement with previous studies. Whereas, the seasonal amplitudes derived by REBS method are much lower, only with a value of ~9. 1 x 10(-6) during 1995-2008, which will result in an underestimation of regional or global CO2 fluxes. PMID- 26489306 TI - [Measured and Predicted Aquatic Life Criteria and Risk Assessment of Chromium (VI) in Liaohe River]. AB - In this study, toxicity data of aquatic species in Liaohe River for heavy metal chromium (VI) was collected and selected. The aquatic life criteria for chromium (VI) in Liaohe River was derived based on these toxicity data. Moreover, water samples of 25 sites in Liaohe River were collected, and the concentrations of chromium (VI) in these samples were analyzed. Finally, ecological risk assessment of chromium (VI) in Liaohe River was performed. Moreover, interspecies correlation estimation method (ICE) established by US EPA was used to predict the acute toxicity of species in Liaohe River, and aquatic life criteria based on predicted toxicity data was derived. The results showed that: the measured CMC (criteria maximum concentration), measured CCC (criteria continuous concentration) and the predicted CMC were 17. 73, 12. 15 and 13. 97 ug . L -1, respectively. Therefore, the ICE method could be used to predict the aquatic life criteria, because the predicted criteria value was very similar to the measured criteria value. Analysis of chromium (V) showed that the chromium (VI) concentrations of the 25 sites in Liaohe River were all below Class I or Class II water quality standards (GB 3838-2002), and the water quality was in good condition. However, for the potential risk of chromium (VI) exposure to the aquatic life of Liaohe River, the result of ecological risk assessment showed that chromium (V) concentrations in 7 sites exceeded the CCC in July, and chromium (VI) concentrations in 6 sites exceeded the CCC in December. Therefore, unacceptable effect on aquatic species caused by chromium (VI) exposure might have occurred in some sites of Liaohe River. PMID- 26489307 TI - [Pollution and Potential Ecology Risk Evaluation of Heavy Metals in River Water, Top Sediments on Bed and Soils Along Banks of Bortala River, Northwest China]. AB - This paper focuses on the sources, pollution status and potential ecology risks of heavy metals (Cr, Cu, Hg, As, Cd, Pb, and Zn) in the surface water, top sediment of river bed and soil along banks of Bortala River, which locates in the oasis region of Xinjiang, northwest China. Results showed that: (1) As a whole, contents of 7 tested heavy metals of Bortala River were low, while the maximum values of Hg, Cd, Pb, and Cr in the river water were significantly higher than those of Secondary Category of the Surface Water Quality Standards of People's Republic of China (GB 3838-2002) and Drinking Water Guideline from WHO. Analysis showed that the heavy metals contents of top sediment on river bed and soils along river banks were significantly higher than those of the river water. (Correlation analysis and enrichment factor (EF) calculation showed that in the river water, top sediment on river bed and soils along river banks, Hg, Cd, Pb, and Cr mainly originated from industrial emissions, urban and rural anthropogenic activities, transportation and agricultural production activities; While Cu, Zn, and As mainly originated from natural geological background and soil parent materials. (3) Pollution assessment showed that in three matrices, the single factor pollution index(Pi) and the integrated pollution index (Pz) of 7 heavy metals were all lower than 1, and they all belonged to safe and clean levels. (4) Potential ecology risk evaluation showed that as a whole the single factor potential ecological risk (Eir) and the integrated potential ecology risks (RI) of 7 heavy metals were relatively low, and would not cause threats to the health of water and soil environment of river basin, while the potential ecology risks of Cd, Hg, Pb, and Cr were significantly higher than those of other heavy metals. PMID- 26489308 TI - [Influencing Factors for Hydrochemistry and delta13CDIC of Karst Springs]. AB - To gain more knowledge on the change of karst spring and its influencing factors, the hydrochemistry and delta13CDIC of Baishuwan spring, Lanhuagou spring and Hougou spring were monitored in rainy season (from June 2014 to October 2014) and contrasted with the results obtained in dry season. The results showed that more carbonate rock was dissolved and less CO2 was consumed in rainy season. And for Lanhuagou spring and Hougou spring, the CO2 consumption was less than the production. Compared to other months in rainy season, the least carbonate rock dissolution and the most CO2 consumption were observed in July 2014. Influenced by hydrodynamic condition, carbonate rock dissolved by HNO3 and H2SO4 increased while that dissolved by H2CO3 decreased during the rainy season. The delta13CDIC increased due to the HNO3 and H2SO4 dissolution of carbonate rock and the dehydration of HCO3-. Therefore, delta13CDIC correlated negatively to HCO3- concentration and positively to NO3- + SO(4)2- concentration. It was indicated that the hydrochemistry and delta13CDIC of karst springs were affected by the HNO3, H2SO4 and hydrodynamic condition. PMID- 26489309 TI - [Hydrochemical Characteristics and the Dissolved Inorganic Carbon Flux in Liuzhou Section of Liujiang Basin]. AB - An important aspect of the current global change research is using river chemical composition to reveal the chemical weathering process and its effect of carbon sink. In this study, water samples were collected and analyzed 2 ~3 times per month from January to December in 2013. The hydrochemistry belonged to HCO3-Ca type. Ca+ and HCO3- were the main cation and anion, which reflected that the hydrochemical characteristics of river were mainly affected by the dissolution of carbonate rock. The concentration of main ions varied with the seasons, which reflected that the crest value occurred in winter, followed by those in autumn and spring, and the lowest value was observed in summer. Due to the interaction of effect of dilution and effect of C2, the seasonal variation of Ca2+ and HCO3- showed that the highest value was in autumn and the lowest value was in summer. The seasonal variation law of other ions should be attributed to the effect of dilution or agricultural activities or combined action of them. Both carbonic acid and sulfuric acid took part in the chemical weathering of carbonate rocks as evidenced by stoichiometric analysis. Besides, the delta34S of sulfate ion of the river waters (delta34S: from 7. 65 per thousand to 8. 55 per thousand) showed that SO2- was originated mainly from oxidation of sulfide minerals in ore deposits and acid rain. Chemical mass balance method was applied to estimate the proportion of HCO- coming from carbonate weathering by sulfuric acid. The result was 28. 26% . On this basis, the total carbon flux of carbon ( by CO2 calculation) in Liuzhou section calculated month by month was about 8. 95 x 10(5) t . a-1. What's more, the carbon flux showed a positive correlation with flow, which implied that the discharge of catchment was the main influencing factor of carbon flux rather than the HCO3- concentration. PMID- 26489310 TI - [Characteristics of Total Nitrogen and Total Phosphorus Pollution and Eutrophication Assessment of Secondary River in Urban Chongqing]. AB - To understand the secondary river quality in Chongqing urban area, six typical secondary rivers were chosen to investigate the pollution characteristics of total nitrogen and total phosphorus and to evaluate the water eutrophication level according to the monitoring data of water physicochemical characteristics and chlorophyll content from April 2013 to March 2014. The study results showed that: the six rivers mentioned above have been seriously polluted by TN and TP, with the monthly mean values of TN and TP far exceeding the universally accepted threshold values of water eutrophication. Water eutrophicaton appraisal result indicated that all rivers in each season were in a state of eutrophication, and the eutrophication level could be arranged in the order of Panxi River > Qingshui River > Tiaodeng River > Huaxi River > Funiu River > Chaoyang River. The seasonal changes in TN and TP of secondary rivers were significant, with high concentrations of TN and TP in spring and winter, and lower concentrations in summer and autumn. TN and TP of the rivers showed a trend of increasing from the upstream to the downstream in each season. Pollutant concentration accumulated gradually along rivers and the maximum accumulation rate reached 1. 25 mg . (L . km) -1. Therefore, further study on urban secondary river pollution characteristics is of great significance to urban water pollution control. PMID- 26489311 TI - [Static Migration and Release of Dibutyl-Phthalate in the Fluctuating Zone of Three Gorges Reservoir]. AB - Phthalic acid esters (PAEs) have received increasing attention in recent years due to their widespread use and hazards to human health and fertility in the environment. In order to understand the migration and release processes of organic pollutants in huge fluctuating zone soil, Dibutyl-phthalate(DBP) was chosen as a typical substance, and its migration and release characteristics in the fluctuating zone of the Three Gorges Reservoir to overlying water and the impacts of DBP concentration in the soil, ionic strength and the concentration of organic mater in overlying water on the process were studied using static flooding method. The results showed that DBP migrated from the soil to the overlying water in the early days after flooding, and the release process of DBP was divided into two phases: one was quick release with a relatively short releasing time and a rapid releasing rate; the other was slow release with a relatively long releasing time and a slow releasing rate. The migration and release processes were well fitted by two-compartment first-order kinetics. After different concentrations DBP were added into soil, the rate of quick release increased with the increasing DBP concentrations in soil while the percent of quick release decreased with the increasing DBP concentrations. The results of rate of slow release and the percent of slow release were on the contrary. The water conditions of overlying water could impact the migration and releasing process of DBP when the soil in fluctuating zone was flooded. The amount of DBP released into the overlying water would increase when the ionic strength in the water increased. At the same time, when the ionic strength increased, in spite of the decreasing quick release rate, the percent of quick release increased. The higher concentration of organic matter in overlying water, the more the amount of DBP released into the overlying water. At the same time, all of the rates of quick release, slow release and the percent of quick release would increase with the increasing concentrations of organic matter, while there was almost no influence on the percent of slow release of DBP. PMID- 26489312 TI - [Effect of Drought and Subsequent Re-wetting Cycles on Transferable Nitrogen and Its Form Distribution in the Sediment of Water Level Fluctuating Zone in the Tributary of Three Gorge Reservoir Areas]. AB - Nitrogen is the most comment source of eutrophication in freshwater systems. In current study, we investigated the various forms of transferable nitrogen in sediments, which potentially contributed to the nitrogen output into waters. Sediments samples were collected in the water level fluctuating zone of Pengxi River crossing three hydrological sections, e. g. upstream, midstream and downstream and two water level altitudes, 160 m and 170 m, with multiple depths for each site, 0-20, 20-40, 40-60, 60-80, 80-100 cm. To characterize the response of transformation of nitrogen in sediment of the water level fluctuating zone towards cycles of drought and re-wetting processes, we analyzed the content and distribution of transferable nitrogen (TF-N) and its forms. The result showed that the changing of the amount of total nitrogen followed the pattern of upstream > midstream > downstream, the mean value was in the range of 313.02-3 255.53 mg. kg-1, while the content of total transferable nitrogen was on an average of 639.40 mg . kg-1 and coincided with the pattern of total nitrogen. In addition, TF-N followed the pattern of OSF-N > IMOF-N > OSF-N > IEF-N. It indicated that both OSF-N and IMOF-N dominated the form of TF-N in sediments by proportions of 50. 9% and 33. 3%, respectively. Since the transformation rate of OSF-N into dissolved phase was relatively slow, its contribution as a source of nitrogen to eutrophication was limited. We, thus, concluded that IMOF-N was the most important fraction which could be potentially affected by water fluctuation and contributed as dissolved nitrogen into water phase. This study indicated that the manner of manipulating water resource in the Three Gorges Reservoir area has raised the potential risk of transforming IMOF-N from sediment into water phase. PMID- 26489313 TI - [Distribution of Chlorophyll-a and Eutrophication State in Tianchi Lake of Tianshan Mountains in Summer]. AB - From June to August in 2014, the distributions of chlorophyll-a (Chl-a) and correlations with environmental factors were investigated, the eutrophication status and causes were discussed in Tianchi Lake of Tianshan Mountains. The results showed that the Chl-a concentrations ranged from 2. 11 to 4. 06 ug. L -1 with a mean value of (2. 8 +/- 0. 69) ug . L-1 in summer, the vertical distribution of Chl-a in different monitoring zones had a similar characteristic that the Chl-a concentration in epilimnionis (2-12 m) was higher than those at the surface (0-2 m) and hypolimnion (below 12 m). The Chl-a concentration had significant negative correlations with depth and conductivity, significant positive correlations with water temperature, pH value, the concentration of dissolved oxygen, the cell density of algae and TP, and less correlation with TN. The mean concentrations of TN and TP in Tianchi Lake in summer were 0.27 mg . L-1 and 0.035 mg. L-1 respectively, both of which exceeded the international standards of general eutrophic lakes. The modified Carlson trophic state index was used to assess the eutrophication status of Tianchi Lake, which is currently at a moderate eutrophication level. The reasons might be the increased nutrients attributed to soil erosion, and algae blooms due to the changes in the composition of hydrobios. Therefore, it is important to use ecological restoration and management to protect the water quality and surrounding vegetation, which may mitigate the risk of eutrophication in Tianchi Lake. PMID- 26489314 TI - [Vertical Distribution Characteristics and Analysis in Sediments of Xidahai Lake]. AB - The organic matter (OM), total nitrogen (TN), total phosphorus (TP), the morphological changes of phosphorus and the particle size in columnar sediment core of Xidahai Lake were analyzed, to discuss the vertical distribution characteristics and influencing factors. The results showed that the contents of OM, TN and TP were 0. 633% -2. 756%, 0. 150% -0. 429% and 648. 00 - 1 480.67 mg . kg-1 respectively. The contents of Ca-P, IP and OM changed less, the contents of Fe/Al-P, OP, TP and TN fluctuated from 1843 to 1970; The contents of Ca-P, IP and TP tended to decrease, the contents of Fe/Al-P, OP and OM first decreased and then increased to different degree, TN fluctuated largely from 1970 to 1996; The nutrient elements contents showed relatively large fluctuation from 1996 to 2009, the average contents of Fe/Al-P, OP and OM were the highest in the three stages. The sediment core nutrients pollution sources were mainly from industrial wastewater, sewage and the loss of fertilizers of Xidahai Lake. The ratio of C/N in the sediments showed that organic matter was mainly from aquatic organisms. The sediment particle size composition was dominated by clay and fine silt. The correlation studies showed that Ca-P, IP and TP were significantly positively correlated, showing that the contribution of Ca-P to IP and TP growth was large. PMID- 26489315 TI - [Phytoplankton Community Structure and Water Quality Assessment in Jialing River After the Impoundment of Caojie Reservoir]. AB - The variation of phytoplankton community and the water quality in Jialing River after the impoundment of Caojie Reservoir was studied in this paper. There were 145 species of phytoplankton under the membership of 8 divisions and 74 genera. Bacillariophyta was the first dominant division, with a total of 57 species of 23 genera, accounted for 39. 3% of total phytoplankton species, followed by Chlorophyta, with 53 species of 28 genera and accounted for 36. 6%. Only 35 species of 23 genera belonged to Euglenphyta, Cryptophyta, Pyrrophyta, Chrysophyta, and Cyanophyta. The average phytoplankton abundance was 1. 82 x 10(5)cell . L-1, and the top three taxon of most abundant were Bacillariophyta, Cryptophyta and Pyrrophyta, accounted for 39. 2%, 29. 9%, and 24. 5% of total abundance, respectively. The cell abundance in spring was significantly higher than those in other seasons. The dominant species included Aulacoseria granulata, Melosira varians, Peridiniopsis niei, Komma caudata, Cryptomonas erosa etc., indicated by the dominant index. Excluded by cluster analysis, the influence on phytoplankton had initially emerged after the impoundment of Caojie Reservoir. The reservoir area could be divided into different ecological regions longitudinally after Caojie Reservoir impoundment, which had an important impact on the phytoplankton. Meanwhile, the phytoplankton and flow velocity between upstream and downstream of the dam significantly varied. Shannon-Wiener species diversity index, Margalef species richness index and Pielous evenness index ranged 2. 06 - 3. 55, 0. 76 - 1. 90 and 0. 50 - 0. 78, respectively. The evaluation results of phytoplankton community structure showed that the eutrophic state was at medium eutrophication level, while diversity analysis results indicated light to moderate pollution. PMID- 26489316 TI - [Analysis of Prokaryotic Community Structure in River Waters of the Ningbo Sanjiang Mouth]. AB - The prokaryotic community structure in river waters of the Ningbo Sanjiang Mouth was analyzed for the first time using 16S rRNA gene based-Illumina Miseq high throughput sequencing. A total of 215 504 high-quality sequences were obtained, and the results of alpha-diversity analysis revealed that Yongjiang River Watershed (YRW) harbored high diversity and richness of prokaryotic communities. Taxonomic assignment analysis indicated that beta-Proteobacterium, Actinobacteria and Bacteroidetes dominated in the river water of YRW, and accounted for 78. 88% of the total prokaryotic communities. Hydrological condition may play an important role in influencing the composition and structure of YRW prokaryotic community. In addition, several kinds of sewer- and fecal-pollution indicator bacterial groups were observed in this area with the highest abundance of pollution indicator bacteria occurring in the water sample of Yuyao River, implying that the Yuyao River might have a high potential risk of sewer- and fecal-pollution. Moreover, a total of 76 species and 18 subspecies of potential pathogenic bacteria, which accounted for 2. 19% and 0. 40% of total sequences respectively, were identified using BLASTN analysis with a local pathogenic bacteria database. Overall, this study provided an important basic data for shedding light on the structure and ecological function of YRW prokaryotic community. PMID- 26489317 TI - [Effects of Perfluoroalkyl Substances on the Microbial Community Structure in Surface Sediments of Typical River, China]. AB - In order to reveal the relationship between Perfluoroalkyl substances (PFASs) contamination and the bacterial community composition, surface sediment samples were collected along the Xiaoqing River in Shandong Province in April and July 2014 (XQ1-XQ10), where many PFASs manufacturers were located. PFASs were quantified by HPLC/MS-MS, related environmental factors affecting the microbial community structure were measured, and the microbial community structure in surface sediments was measured by the second-generation sequencing technology Illumina MiSeq. The results not only revealed the degree of PFASs pollution in the sediments of Xiaoqing River, but also illustrated the relationship between PFASs pollution and the microbial community structure. Among the twelve kinds of PFASs detected in this study, PFOA was the predominant compound, and the highest PFOA concentrations were detected in the sample of XQ5 (April: 456. 2 ng. g-1; July: 748.7 ng . g-1) located at the downstream of Xiaoqing River with many fluoropolymer producing facilities. PFOA contamination was the main factor affecting the microbial community structure in April, accordingly community richness and evenness were significantly negatively correlated with PFOA levels. The abundance of Thiobacillus increased with the increasing PFOA concentration in the sediment PFOA. This suggested that Thiobacillus was sensitive to PFOA pollution and might be the potential indicator to reveal the degree of PFOA pollution in sediment. When the concentrations of PFOA were below 100 ng . g-1, no significant effects on the microbial community structure were observed. PMID- 26489318 TI - [Coupling Effects of Decomposed Potamogeton crispus and Growing Ceratophyllum demersum on Water Quality and Plant Growth]. AB - In order to study the coupling effects of decomposed Potamogeton crispus (P. crispus) and growing Ceratophyllum demersum (C. demersum) on water quality and the effects of different decomposed biomass on plant growth, the simulating experiments for seasonal changes of submerged macrophytes were conducted. The results indicated that the nutrient concentrations in water remained at a relatively low level with different decomposed biomass and they remained stable after 29 days of the experiment. The concentrations of total dissolved nitrogen (DTN), total nitrogen (TN), total phosphorous (TP), total dissolved phosphorous (DTP), organic carbon (TOC) and chlorophyll-a (Chl-a) were lower than 0. 514, 0. 559, 0. 080, 0. 014, 13. 94 and 26. 546 mg . L-1, respectively. The obvious improving effects on water quality were observed under coupling condition of decomposition and growth, especially when the treatment of decomposed P. crispus was 20 g, and the removal efficiency of TN, DTN, TP, DTP, TOC and Chl-a reached 89. 67% , 52. 51%, 94. 99%, 55. 59% and 98. 55%, respectively. Compared with the physiology of C. demersum in the early stage, the contents of total chlorophyll, soluble protein and malondialdehyde all increased under different decomposed biomass conditions, which suggested that the nutrient released from decomposed P. crispus promoted the growth of C. demersum. The coupling effects between P. crispus decomposition and C. demersum growth showed better improving effect on water quality and growth of C. demersum with treatment of 20 g decomposed P. crispus. PMID- 26489319 TI - [Bioretention Media Screening for the Removal of Phosphorus in Urban Stormwater]. AB - Urban runoff is an increasingly important source of excess phosphorus (P) to local receiving waters. Bioretention, a promising technology for urban stormwater pollution treatment, was investigated to determine whether the mixture of purple soil and sand could adsorb sufficient P at low concentrations in urban stormwater. The TP concentrations of urban runoff from variously impervious areas in Chongqing City ranged from 0. 04 to 7. 00 mg . L-1 (mean +/- S. D. = 0. 75 mg . L-1 +/- 1. 08 mg . L-1); the TDP concentrations ranged from 0. 02-0. 46 mg . L 1 ( mean +/- S. D. = 0. 15 mg . L-1 +/- 0. 10 mg . L-1). The media adsorption benchmark was determined for a bioretention facility sized at 10% of the 100% impervious catchment area and having 10 years of capacity according to annual rainfall pattern and the runoff TDP range. The media benchmark for adsorption was calculated as 7. 5 mg . kg-1 at soluble P concentration of 0. 30 mg . L-1 which provided the necessary stormwater treatment. The oxalate-extractable aluminum and iron content influenced the P sorption capacity for neutral and acid purple soils. A strong positive linear relationship was observed between the oxalate ratio [OR = (Alox + Feox)/Pox] and media P sorption capacity. The media mixture of 20% purple soil and 80% sand showed excellent P removal, meeting the developed benchmark for adsorptive behavior. The media mixture in a large-scale (60 cm) column consistently produced soluble reactive phosphorus effluent event with mean concentrations <0. 05 mg . L-1. The media mixture of purple soil and sand can be used as a bioretention media to treat low-concentration phosphorus in urban runoff under various hydrologic and pollutant concentration conditions. PMID- 26489320 TI - [Treatment of Urban Runoff Pollutants by a Multilayer Biofiltration System]. AB - In order to control the non-point source pollution from road runoff in Wuxi City effectively, a multilayer biofiltration system was designed to remove a variety of pollutants according to the characteristics of road runoff in Wuxi, and the experimental research was carried out to study the effect on rainwater pollution purification. The results show that the system has a good performance on removing suspended solids (SS), organic pollutant (COD), nitrogen and phosphorus: all types of multilayer biofiltration systems have a high removal rate for SS, which can reach 90%. The system with activated carbon (GAC) has higher removal rates for COD and phosphorus. The system with zeolite (ZFM) has a relatively better removal efficiency for nitrogen. The addition of wood chips in the system can significantly improve the system efficiency for nitrogen removal. Between the two configurations of layered and distributed wood chips, configurations of distributed wood chips reach higher COD, phosphorus and nitrogen pollutants removal efficiencies since they can reduce the release of wood chips dissolution. PMID- 26489321 TI - [Effect of Three Typical Disinfection Byproducts on Bacterial Antibiotic Resistance]. AB - The effect of typical disinfection byproducts (DBPs) on bacterial antibiotic resistance was investigated in this study. chlorodibromomethane (CDBM), iodoacetic acid (IAA) and chloral hydrate (CH) were selected, which belong to trihalomethanes (THMs), haloacetic acids (HAAs) and aldehydes, respectively. After exposure to the selected DBPs, the resistance change of the tested strains to antibiotics was determined. As a result, all of the three DBPs induced Pseudomonas aeruginosa PAO1 to gain increased resistance to the five antibiotics tested, and the DBPs ranked as IAA > CH > CDBM according to their enhancement effects. Multidrug resistance could also be enhanced by treatment with IAA. The same result was observed in Escherichia coli K12, suggesting that the effect of DBPs on antibiotic resistance was a common phenomenon. The mechanism was probably that DBPs stimulated oxidative stress, which induced mutagenesis. And the antibiotic resistance mutation frequency could be increased along with mutagenesis. This study revealed that the acquisition of bacterial antibiotic resistance might be related to DBPs in drinking water systems. Besides the genotoxicological risks, the epidemiological risks of DBPs should not be overlooked. PMID- 26489322 TI - [Laboratory Investigation of DNAPL Migration Behavior and Distribution at Varying Flow Velocities Based on Light Transmission Method]. AB - The migration and distribution of dense non-aqueous phase liquid (DNAFL) in subsurtace are attectea ny many factors. We selected PCE as the substitute contaminant, and performed several well-controlled two-dimensional sandbox experiments to investigate the effect of flow velocity on DNAPL infiltration and redistribution. Light transmission method (LTM) was used to monitor the transport process of DNAPL in the sandbox and quantitatively measure DNAPL saturation. The spatial moments based on measured DNAPL saturation were used to describe the average spatial behavior of DNAPL plume at various times. Experimental results showed a strong correlation between results obtained by LTM and the known amounts of DNAPL added into the sandbox (R2 >0.98). The LTM accurately reflected the infiltration and redistribution processes. The results of DNAPL saturation and first moment (mass center) showed that the increased velocity promoted not only lateral but also vertical migration, leading to an inclined percolation path. Also vertical migration reacted more sensitive to flow velocity. The second moment (spread variance) showed that the increased velocity promoted lateral and vertical spread, increasing the pollution scope. The histogram of DNAPL saturation showed a unimodal distribution at low flow velocity, but showed a bimodal distribution at lager flow velocity, and the distance between two peaks became higher with the increasing flow velocity. PMID- 26489323 TI - [Comparative Study of Benzotriazole Electrochemical Oxidation at Boron-doped Diamond and PbO2 Anodes]. AB - Electrochemical systems were built to investigate the degradation of benzotriazole (BTA) on boron-doped diamond (BUU) and PbO2 anodes and give an insight into the mineralization ability of two electrodes in terms of the amount and activity of hydroxyl radicals. Results of bulk electrolysis showed that both BDD and PbO2 displayed perfect BTA degradation performance after 12 hours' electrolysis, with the removal percentages of 99. 48% and 98. 36%, respectively, while the mineralization ability of BDD was much stronger than that of PbO2, with the efficiency of 87. 69% for BDD and 35. 96% for PbO2. Less hydroxyl radical and hydrogen production in BDD system suggested the less amount of active sites on BDD surface, thus further verified that the generated hydroxyl radical amount was not the primary factor determining the mineralization ability of anodes. However, BDD displayed larger binding energy of adsorbed oxygen and thinner adsorption layer than those of PbO2, indicating that the BDD electrode surface was of greater catalytic activity, thus the generated hydroxyl radicals were more free, which was the key to its better mineralization ability. PMID- 26489324 TI - [Sorption of o-Phthalate onto Calcite in Open-System]. AB - The batch sorption methods were deployed to study the sorpti of p-phthalate on calcite in open-system. Results show that: (1) The o-phthalate sorption reached the equilibrium within 3 hours. Both pseudo first-order and pseudo second-order models described the kinetic characteristics well; (2) The o-phthalate sorption rate decreased with pH (7. 7-9.7). This phenomenon was due to the competition effect of HCO3- and CO(3)2-, and the electrostatic effect on the surface; (3) The o-phthalate sorption rate also decreased with the increase in ionic strength. This was due to the rise in concentration of HCO3- and CO(3)2- induced by salt effect; (4) Compared with m-phthalate and p-phthalate, o-phthalate sorption rate was much higher due to the proximity of its two carboxyl groups which easily formed a chelate ring of surface complex. By studying the factors that influence o-phthalate sorption onto calcite, the sorption mechanism can be well understood. This mechanism can be applied in the removal of o-phthalate from the environment. PMID- 26489325 TI - [Adsorption Behaviors of Lead on Multi-Walled Carbon Nanotube-Hydroxyapatite Composites]. AB - Multi-walled carbon nanotube-hydroxyapatite composites (MWCNT-HAP) were employed as the sorbent to study the sorption characteristic of Pb (II) using batch experiments. Effects of dosage of adsorbent, pH, ionic strength, contact time, initial concentration of lead and temperature were investigated. The results indicated that the removal of lead to MWCNT-HAP composites was strongly dependent on dosage of adsorbent, pH, temperature, and independent of ionic strength. The maximum adsorption capacity of lead was about 716. 13 mg.g-1 at 20 degrees C, with a solid/liquid ratio of 0.08 g.L-1, pH0 = 5.5 and an initial concentration of 100 mg.L-1. The adsorption of Pb(II) on MWCNT-HAP composites was a fast process and could reach the equilibrium within 60 minutes. Ninety percent of the maximum adsorption capacity could be reached in 30 minutes. The kinetic data were fitted to pseudo-second-order kinetic model reasonably well. The kinetic sorption of Pb(II) on MWCNT-HAP was well described by pseudo-second-order kinetic model. The negative free energy calculated from the temperature dependent sorption isotherms suggested that the sorption of Pb(II) on MWCNT-HAP composites was a spontaneous process, and high temperature favored the adsorption process. The higher correlation coefficient values (R2 = 0. 999 8 - 1. 000 0) of Langmuir isotherm model at different temperatures suggested that Langmuir model could be used to simulate the sorption of Pb(II) on MWCNT-HAP. The adsorption mechanism mainly involves surface complexation between the lead ions and the surface oxygen containing functional groups of the MWCNT-HAP, dissolution of HAP and precipitation of pyromorphite [Pb10 (PO4)6 (OH) 2], ion exchange reaction between Pb2+ and Ca2+ of hydroxyapatite. PMID- 26489326 TI - [Synthesis and Study on Adsorption Property of Congo Red Molecularly Imprinted Polymer Nanospheres]. AB - Molecularly imprinted polymer nanospheres (MIP) were prepared with Congo red as the template, methacrylic acid (MAA) as a functional monomer, ethylene glycol dimethacrylate (EGDMA) as the cross linker, azodiisobutyronitrile (AIBN) as an initiator, and acetonitrile as the porogen by precipitation polymerization. The morphology of MIP was characterized by SEM and TEM which showed that the diameter of MIP was nanometer grade (90 nm) and the shape was homogeneous. The specific surface area and pore volumes of MIP and NIP were examined through Brunauer-Emett Teller method of nitrogen adsorption experiments. Then, the adsorption and selective recognition ability of MIPs were evaluated using the equilibrium rebinding experiments. The results indicated that the prepared MIP showed a good selectivity recognition ability to its template. It concluded that MIP could be employed as an effective material for removing Congo red from waste water. PMID- 26489327 TI - [Simultaneous Removal of Cd (II) and Phenol by Titanium Dioxide-Titanate Nanotubes Composite Nanomaterial Synthesized Through Alkaline-Acid Hydrothermal Method]. AB - A composite nanomaterial, TiO2/TNTs, was synthesized by TiO2 (P25) through alkaline and acid hydrothermal reaction, which possessed both titanate nanotubes (TNTs) and TiO2 phase. It was found that the adsorption kinetics of Cd(II) onto TiO2/TNTs was very quick, and the adsorption could reach the equilibrium within 30 min. In addition, the maximum adsorption capacity of Cd(II) was as large as 120. 34 mg.g-1 calculated from Langmuir isotherm model. The adsorption mechanism of Cd(II) was ion-exchange between Cd2+ and Na+/H+ located in the interlayers of TNTs. However, the adsorption capacity of phenol on TiO2/TNTs was so small that the photocatalysis for phenol degradation was needed. In the adsorption photocatalysis system, the removal efficiencies of Cd(II) and phenol could reach up to 99. 6% and 99.7%, respectively. Especially, removal of Cd(II) was attributed to adsorption by TNTs of the composite nanomaterial, while removal of phenol was resulted from photocatalytic reaction by the TiO2 phase. Moreover, the co-existing Cd(II) enhanced the photocatalytic degradation of phenol due to the enhancement on photocatalytic activity of TiO2/TNTs after Cd(II) was adsorbed. Co existing Na+ did not show obvious effect on the co-removal of Cd(II) and phenol by TiO2/TNTs, but adsorption of Cd(II) was inhibited in the presence of Ca2+ as it could compete for the adsorption sites and enhance the aggregation of the material. Furthermore, TiO2/TNTs could be efficiently reused after desorption via HNO3 and regeneration via NaOH, and the removal efficiencies of Cd(II) and phenol were still as high as 91. 7% and 98. 1% even after three cycles. This study proposed a method to synthesize a material which had both adsorptive and photocatalytic performance, and it was of great importance for application of nanomaterials in the simultaneous removal of heavy metals and organic pollutants. PMID- 26489328 TI - [Immobilization of Estrogen-degrading Bacteria to Remove the 17beta-estradiol and Diethylstilbestrol from Polluted Water and Cow Dung]. AB - Estradiol (E2) and diethylstilbestrol (DES) can be enriched in sewage and cow dung, posing serious threats to human and ecological health. Strain Rhodococcus sp. JX-2 and strain Serratia sp. S, which could degrade 17beta-estradiol and diethylstilbestrol, respectively, were immobilized by alginate and then added into sewage and cow dung to remove E2 and DES. The immobilization was determined by orthogonal experiment, and the removal of E2 and DES from sewage and cow dung was compared between treatments of immobilized bacteria, free bacteria and control without bacteria. The influencing factors including inoculation amount, pH value, moisture content, turning time on the removal of E2 and DES were investigated. The optimal conditions of JX-2 and S immobilization were as follows: Strain JX-2: strain S (V/V) 1: 1, alginate concentration 5%, calcium chloride concentration 4%, bacteria-cement ratio 1 : 2. The immobilized strains removed 99. 42% and 84. 59% of the 2 mg.L-1 E2 and DES under laboratory conditions, respectively. The optimal conditions for E2 and DES removal from water by the immobilized strains were as follows: 300 g.L-1 inoculation volume of immobilized strains and pH 5. 0-6. 0. Immobilized bacteria could completely remove DES and remove 95. 85% of E2 from water. The optimal conditions for E2 and DES removal from cow dung by the immobilized strains were: inoculation volume 600 g.kg-1, moisture content 70% and pile turning time 12 h. The immobilized bacteria could completely remove E2 and remove 97. 41% of DES from cow dung. PMID- 26489329 TI - [Optoelectronic PCB Wastewater Treatment by Partial Nitrification-ANAMMOX Integrative Reactor]. AB - The feasibility and operating characteristics of treatment of printed circuit board (PCB) wastewater by using autotrophic nitrogen removal process in partial nitrification and ANAMMOX integrative reactor were investigated. The reactor had startup successfully and achieved the stable nitrogen removal efficiency. The results showed that, after 80d operation, the nitrogen removal rate increased and was up to 1. 29 kg . (m3 . d)-1, the effluent NH4+-N and NO2- -N were decreased and stabilized at 4. 0 mg . L -1, 9. 8 mg . L-1 respectively, when the influent concentration of NH4+-N maintained at 220 mg . L -1. At the same time, the concentration of total nitrogen was less than 50 mg . L-1 in effluent, which meet the quality emissions requirements. The NO2- -N production rate was up to 2. 05 kg . (m3 . d)-1 by nitrite bacteria in aerobic zone, and the highest nitrogen removal rate was 2. 91 kg . (m3 . d) -1 by ANAMMOX. bacteria in anaerobic zone, which illuminated functional bacteria were steadily grown in the corresponding region. The inorganic ammmonia in PCB wastewater could be removed by autotrophic nitrogen removal process in nitrification and ANAMMOX integrative reactor. PMID- 26489330 TI - [Treatment of Petrochemical Treatment Plant Secondary Effluent by Fenton Oxidation]. AB - Fenton oxidation was applied to treat the petrochemical treatment plant secondary effluent by the continuous flow configuration. The effect of Fenton agent dosage on the COD and phosphorus removal and the variation of the dissolved organic matter characteristics during the treatment process were investigated. The results showed the average COD and PO(4)3- -P concentrations were 64.8 mg.L-1 and 0. 79 mg.L-1, respectively. When the dosage of H2O (30%), FeSO4.7H2O and PAM were 0. 4 mL.L-1, 0. 8 mg.L-1 and 0. 9 mg.L-1 and the residence time was 30 min, the average removal rate of COD and PO(4)3- -P were 24. 3% and 95. 5% respectively. The effluent COD was lower than 50 mg.L-1. The percentage of dissolved organic matters with molecular weight less than 1 x 10(3) was 80. 4% in the raw wastewater, however, the percentage increased to 95. 6% when treated by Fenton oxidation. Three-dimensional fluorescence analysis showed that the Fenton oxidation can effectively remove protein and phenols. GC-MS results showed that there were about 117 kinds of organic matters detected in the secondary effluent, while the number reduced to 27 after oxidation by Fenton. The organics containing unsaturated bond had a better removal than those of other types of organics. Fenton oxidation can be used in the advanced treatment of petrochemical secondary effluent. PMID- 26489331 TI - [Comprehensive Toxicity Evaluation and Toxicity Identification Used in Tannery and Textile Wastewaters]. AB - To better evaluate the toxicity of tannery and textile effluents from various emission stages, the research attempted battery of toxicological bioassays and toxicological indices. The bioassays employed Microtox test, zebra fish embryo larval test and algae (Chlorella vulgaris) test. Meanwhile, toxicological indices including Toxicity Unit (TU), Average Toxicity (AvTx), Toxic Print (TxPr), Most Sensitive Test (MST) and Potential Ecotoxic Effects Probe (PEEP) were applied. The results illustrated that PEEP was the most comprehensive index to take account of the emissions and toxic potential of effluents. PEEP values showed that the reduction rates of toxicity in tannery and textile effluents were 36. 8% and 23. 2%, respectively. Finally, based on the Microtox toxicity test, toxicants in textile effluent were identified through the toxicity identification evaluation (TIE) studies. The results indicated that the main toxicant of textile effluent was non-polar organic pollutants, followed by filterable compounds, heavy metals, oxidizing substances and volatile components. PMID- 26489332 TI - [Carbon/nitrogen Removal and Bacterial Community Structure Change in an A/O Activated Sludge System Under Different Dissolved Oxygen Conditions]. AB - Carbon and nitrogen removal performance and microbial community structure under different dissolved oxygen (DO) conditions (3, 2, 1 and 0. 5 mg . L -1) in an anoxic/oxic (A/O) system were investigated. The results showed that the A/O activated sludge system still had an excellent performance in removing carbon and nutrient under low DO condition (0. 5 mg . L-1). The removal rates of chemical oxygen demand (COD), ammonia (NH4+ -N) and total nitrogen (TN) were 89. 7%, 98. 3% and 88. 0% respectively. The PCR-DGGE analysis showed that the bacterial community structure changed greatly under different DO conditions. However, there was still a high bacterial diversity even at low DO level, which ensured the functional stability of the A/O system. On the basis of the results of the phylogenetic tree, bacterial communities were observed to be very abundant, and Proteobacteria was identified as the dominant bacteria. PMID- 26489333 TI - [ORP in the Main Anoxic Stage as the Control Parameter for Nitrogen and Phosphorus Removal in the Single Sludge System with a Continuous Flow]. AB - To optimize the performance of nitrogen and phosphorus removal, based on test results and mass balance, the feasibility of control for nitrogen and phosphorus removal in the single sludge system with a continuous flow using ORP in the main anoxic stage (ORPm) was investigated, meanwhile, the objective laws of conversion for nitrogen and phosphorus under different ORPm were expounded. During the experiments, nitration liquid internal circulation flow rate was controlled as the variable. The OPRm was controlled by PLC automatically, and the other operation parameters remained unchanged. The experiments tested six different ORPs in main anoxic stage affecting nitrogen and phosphorus removal, i.e., -143, 123, -105, -95, -72, and -57 mV. The ammonia concentration changed a little in effluent under the condition of different ORP.s, however, the TN and TP concentrations changed obviously. When the ORPm was controlled as -95 mV, the active sludge reached the maximal nitrogen and phosphorus removal with the continuous flow. According to mass balance calculation, when ORPm increased from 143 mV to -57 mV, (1) In the main anoxic stage, nitrate nitrogen reaction rates were 214. 40, 235. 16, 241. 16, 244. 02, 240. 90 and 233. 65 mg.h-1, respectively; the amount of total nitrogen conversions were 244. 92, 255. 85, 328. 04, 347. 45, 336. 42 and 320. 60 mg.h-1, respectively; both reaction rates reached the peak at the ORPm of -95 mV; (2)Phosphorus release rates in anaerobic stage were -214. 12, -228. 64, -259. 26, -264.54, -256.92 and -252.84 mg.h-1, respectively; total phosphorus absorption rates were 252. 15, 275.85, 332. 25, 338. 10, 336. 15 and 324. 30 mg.h-1, respectively, and phosphorus absorption rates were 30. 27, 62. 14, 124. 58, 154. 41, 150. 41 and 138. 30 mg.h-1, respectively, in the main anoxic stage; phosphorus absorption rates reached the peak when ORPm was -95 mV. The experiments revealed that ORPm could be used as the control parameter of nitrogen and phosphorus removal in single sludge system with a continuous flow. PMID- 26489334 TI - [Cultivation of Aerobic Granular Sludge with Real Low Concentration Domestic Wastewater and Its Denitrification Performances Under the Continuous Flow]. AB - The COD, ammonia and total nitrogen removal efficiency, as well as the physical properties of aerobic granular sludge (AGS) and its denitrification kinetics were studied in the continuous flow reactor. The experimental results showed that the AGS was successfully cultivated in the continuous flow system within 40 days. The nitrogen and carbon removal efficiencies were gradually improved with the improvement of sludge granulation. In the running stage of 41 - 60 days, the COD, ammonia and TN removal efficiency could reach 85. 54% , 95. 5% and 65. 56%, respectively. And the nitrate and nitrite nitrogen accumulation was not high in the reaction process. Mature AGS had more void structure and a large number of extracellular polymeric substances. It had significant advantages compared with the seed sludge in the aspects of moisture content, wet density, sedimentation rate, mechanical strength, and SVI values. The simultaneous nitrification and denitrification efficiency was 81. 69% , the nitrification rate and denitrification rate were 5.78 mg . (L.h) -1 and 4. 90 mg . (L.h) -1, respectively. PMID- 26489335 TI - [Heavy Metal Contamination in Farmland Soils at an E-waste Disassembling Site in Qingyuan, Guangdong, South China]. AB - Crude e-waste dismantling activities have caused a series of environmental pollution problems, and the pollutants released from the dismantling activities would finally pose high risks to human health by means of the accumulation through food chains. To explore the contamination status of heavy metals to the surrounding farmland soils in Longtang and Shijiao Town, Qingyuan, Guangdong, China, 22 farmland soil samples were collected and analyzed for the contents, spatial distributions and chemical forms of 6 heavy metals (Pb, Cu, Cd, Zn, Cr and Ni). The results showed that the 6 heavy metals exhibited obvious accumulations when compared to the corresponding background values in Guangdong Province. According to farmland environmental quality evaluation standard for edible agricultural products HJ 332-2006, the pollution severity of heavy metals was evaluated by monomial pollution index and Nemerow synthetic pollution index methods, the results indicated that 72. 7% of the soil samples contained one or more kinds of heavy metals with higher concentrations than the corresponding standard values, Cd, Cu, Pb and Zn were the main metals in the polluted soils, and for the proportion of contaminated soil samples in all the 22 samples, Cd was the highest, followed by Cu, and finally Pb and Zn. Nemerow synthetic pollution index further revealed that 68. 2% of soil samples were contaminated, and among them 53. 3% of samples were heavily contaminated. Most of the heavy metals were well correlated with each other at the 0. 05 or 0. 01 level, which indicated that primitive e-waste recycling activities were an important source of the heavy metal contamination in Longtang and Shijiao Town. The contents of Cd, Pb, Cu and Zn in surface soils were higher than those of other soil layers, and the contents of these 4 metals in deep soils (20- 100 cm) did not show significant decreases with the increasing depths. The contents of Cr and Ni maintained constant, and exhibited no statistical differences with the sampling depths. Sequential leaching tests showed that the active fractions of Pb, Cu and Cd ranged from 36. 9% to 90. 6%, 39. 6% to 93. 9% and 43. 7% to 99. 6%, with mean values of 61. 3% 65. 3% and 80. 7%, respectively. The active fractions of these three metals in most samples accounted for more than half of their own total contents, which would cause a high ecological risk. PMID- 26489336 TI - [Residues and Spatial Distribution Characteristics of Organochlorine Pesticides DDTs in Soil of Linyi City, Shandong Province]. AB - Surface soil samples were collected every 36 km2 from Linyi City to study the residues, composition and origin, influencing factors, spatial distribution and environment quality characteristics of soil DDTs. Measurements were taken for DDTs, OrgC, N, etc. for all samples. The results indicated that the detectable rate of DDTs was 71. 75%, and the mean content of DDTs was 0. 035 ug.g-1. p,p' DDT and p,p'-DDE were the predominant contaminant compounds, with mean concentrations of 0.033 ug.g-1 and 0.010 ug.g-1, and accounted for 60. 99% and 34. 62% of the detectable samples, respectively. The degradation rate of DDTs suggested that 58% surface soils were recently inputted, these newly inputted locations were especially distributed in the middle to south of the study area, meanwhile, p,p'-DDD/p,p'-DDE revealed that the degradation of DDTs was mainly under oxidizing condition, and o,p'-DDT/p,p'-DDT illustrated that 71. 37% DDTs in soils of the study area were concerned with technical DDTs sources. Besides, the correlation, analysis showed that the external factors affecting the distribution of DDTs included OrgC, N, C and pH etc. and the higher the p, p'-DDT proportion of DDTs, the greater the effect. The distribution of DDTs had an obvious point source characteristic, and significant concentration centers were located nearby the cities and counties, typically, the DDTs concentrations of middle to southern area were much higher. However, DDTs environmental quality assessment suggested that the pollution level was relatively low, and the soil was mainly classified into grade I or II, which accounted for 78. 95% and 21. 05% of the whole study area, respectively. PMID- 26489337 TI - [Assessment of Soil Fluorine Pollution in Jinhua Fluorite Ore Areas]. AB - The contents of. soil total fluorine (TF) and water-soluble fluorine (WF) were measured in fluorite ore areas located in Jinhua City. The single factor index, geoaccumulation index and health risk assessment were used to evaluate fluorine pollution in soil in four fluorite ore areas and one non-ore area, respectively. The results showed that the TF contents in soils were 28. 36-56 052. 39 mg.kg-1 with an arithmetic mean value of 8 325.90 mg.kg-1, a geometric mean of 1 555. 94 mg.kg-1, and a median of 812. 98 mg.kg-1. The variation coefficient of TF was 172. 07% . The soil WF contents ranged from 0. 83 to 74. 63 mg.kg-1 with an arithmetic mean value of 16. 94 mg.kg-1, a geometric mean of 10. 59 mg.kg-1, and a median of 10. 17 mg.kg-1. The variation coefficient of WF was 100. 10%. The soil TF and WF contents were far higher than the national average level of the local fluorine epidemic occurrence area. The fluoride pollution in soil was significantly affected by human factors. Soil fluorine pollution in Yangjia, Lengshuikeng and Huajie fluorite ore areas was the most serious, followed by Daren fluorite ore area, and in non-ore area there was almost no fluorine pollution. Oral ingestion of soils was the main exposure route. Sensitivity analysis of model parameters showed that children's weight exerted the largest influence over hazard quotient. Furthermore, a significant positive correlation was found among the three kinds of evaluation methods. PMID- 26489338 TI - [Response of Straw and Straw Biochar Returning to Soil Carbon Budget and Its Mechanism]. AB - Direct straw returning and straw carbonization returning are the main measures of straw returning. Because of the differences in structure and nature as well as returning process between straw and straw biochar, the soil respiration and soil carbon budget after returning must have significant differences. In this study, outdoor pot experiment was carried out to study the response of soil respiration and carbon budget to straw and straw biochar returning and its possible mechanism. The results showed that soil respiration of straw biochar returning [mean value 21. 69 umol.(m2.s)-1] was significantly lower than that of direct straw returning [mean value 65.32 umol.(m2.s)-1], and its soil organic carbon content ( mean value 20. 40 g . kg-1) and plant biomass (mean value 138. 56 g) were higher than those of direct straw returning (mean values 17. 76 g . kg-1 and 76. 76 g). Considering the carbon loss after the biochar preparation process, its soil carbon budget was also significantly higher than that of direct straw returning, so it was a low carbon mode of straw returning. Direct straw returning significantly promoted soil dehydrogenase activity, soil beta-glycosidase activity and soil microorganism quantity, leading to higher soil respiration, but straw biochar did play an obvious role in promoting the microbial activity index. Easily oxidizable carbon (EOC) and biodegradability of straw biochar were lower than those of straw, which showed that straw biochar had higher stability, and was more difficult to degrade for soil microorganisms so its soil microbial activity was generally lower, and could be retained in the soil for a long time. PMID- 26489339 TI - [Changes of Soil Organic Carbon and Its Influencing Factors of Apple Orchards and Black Locusts in the Small Watershed of Loess Plateau, China]. AB - Orchard and black locust are two typical plants for comprehensive control in the small watershed of land uses in Loess area. The analysis of soil carbon sequestration function changes of growing two plants is important to gain a deep understanding of soil carbon cycle process and its influencing factors of terrestrial ecosystems under the condition of small watershed comprehensive control. The experiment was conducted in the Changwu State Key Agro-Ecological Station, Shanxi, China. SOC, TN, fine root biomass and litter amount were determined at different age apple orchards and black locusts on the slope land of Wangdonggou watershed to study the variation characteristics of soil organic carbon and its influencing factors under two measurements. The results showed that: (1) SOC and TN contents in apple orchards significantly decreased with the increased age, whereas those in black locust showed an increased tendency with the age increased. Compared with the adjacent cropland,the SOC and TN contents in year 3, year 8, year 12 and year 18 apple orchards were decreased 3. 26%, 10. 54%, 18. 08%, 22. 55% and - 8. 08%, - 0. 48%, 4. 97%, 16. 91%, respectively. However,SOC and TN contents increased 5. 31%, 32. 36%, 44. 13% and 2. 49%, 15. 75%, 24. 22%, in year 12, year 18 and year 25 black locusts, respectively. (2) The fine root biomass in year 3, year 8, year 12, and year 18 apple orchards were about 25. 97% 66. 23%, 85. 71% and 96. 10% of the adjacent cropland, respectively; and the litter amounts were all 0 g . m-2. However, compared with adjacent cropland, The fine root biomass in year 12, year 18 and year 25 black locusts were increased 23. 53%, 79. 41%, 157. 35%, respectively; and the litter input rates were 194, 298 , 433 g . (m2 . a) -1, respectively. (3) The difference of organic matter input was the major factor which drove the variability of soil carbon sequestration function of apple orchard and black locust ecosystems. PMID- 26489340 TI - [Impacts of Land Use Changes on Soil Light Fraction and Particulate Organic Carbon and Nitrogen in Jinyun Mountain]. AB - Four land types including the subtropical evergreen broad-leaved forest, sloping farmland, orchard and abandoned land were selected to collect soil samples from 0 to 60 cm depth at the same altitude of sunny slope in the Jinyun Mountain in this study. Soil light fraction organic carbon and nitrogen ( LFOC and LFON), and particulate organic carbon and nitrogen (POC and PON) were determined and the distribution ratios and C/N ratios were calculated. The results showed that the contents of LFOC and LFON decreased significantly by 71. 42% and 38. 46% after the forest was changed into sloping farmland (P <0. 05) but the change was not significant when it was changed into orchard (P >0. 05), while the contents of LFOC and LFON increased significantly by 3. 77 and 1. 38 times after the sloping farmland was changed into abandoned land (P <0. 05). The contents of POC and PON did not vary markedly after the forest was converted into orchard or sloping farmland, while the POC and PON contents increased markedly by 4. 12 and 1. 25 times after the sloping farmland was abandoned. Those above results indicated that abandoned land was easy for active organic carbon and nitrogen accumulation; on the contrary, sloping farmland was easy to lose soil labile carbon and nitrogen. The LFOC and LFON distribution ratios were significantly reduced by 31. 20% and 30. 08%, respectively after the forest was changed into the sloping farmland, and increased by 18. 74% and 20. 33% respectively after the forest was changed into the orchard. Nevertheless, the distribution ratios of LFOC and LFON were changed little by converting the forest into the sloping farmland and orchard. The distribution ratios of LFOC, LFON, POC and PON all increased significantly after the farmland was abandoned (P <0. 05). Those results showed that the activity of soil organic carbon and nitrogen was enhanced after forest reclamation, while reduced after the sloping farmland was abandoned. The ratios of carbon to nitrogen in soil organic matter, light fraction organic matter and particulate organic matter were in the order of abandoned land (12. 93) > forest (8. 53) > orchard (7. 52) > sloping farmland (4. 40), abandoned land (16. 32) > forest (14. 29) > orchard (11. 32) > sloping farmland (7. 60), abandoned land (23. 41) > sloping farmland (13. 85 ) > forest (10. 30) > orchard (9. 64), which indicated that the degree of organic nitrogen mineralization was higher after forest cultivation and lower after the sloping farmland was abandoned. PMID- 26489341 TI - [Soil Enzyme Activities and Their Relationships to Environmental Factors in a Typical Oasis in the Upper Reaches of the Tarim River]. AB - The intensity and direction of soil biochemical process can be reflected by soil enzyme. The relationship between enzyme activity of soil and environmental factors is deeply studied in this paper, which can contribute to explore the soil ecological process and to provide scientific evidence for scientific regulation of soil system. Soil samples from new cropland, ten-years cropland, thirty-years cropland, orchard, plantation, natural forest, grassland, saline land and desert in the upper reaches of the Tarim River were collected. The relationships between soil enzyme activities and environmental factors were analyzed by traditional statistics and redundancy analysis ( RDA) . The results showed that soil enzyme activities in this area were low, with the average of enzyme properties as follows: catalase, urease, invertase and alkaline phosphatase, with activity of 4. 27 mL . g -1, 0. 34 mg . g -1, 2. 08 mL . g -1 and 0. 08 mg . g -1, respectively. According to the RDA results, the total nitrogen, organic matter, available potassium, soil moisture and total salt were significantly correlated with enzyme activity while a relatively significant correlationship between bulk density and enzyme activity was found. There was no significant correlationship between available potassium/pH and enzyme activity. The importance of environmental factors to soil enzyme activities could be arranged as total nitrogen > organic matter > available potassium > soil moisture > total salt > bulk density > available potassium > pH. PMID- 26489342 TI - [Effects of Different Residue Part Inputs of Corn Straws on CO2 Efflux and Microbial Biomass in Clay Loam and Sandy Loam Black Soils]. AB - The decomposed rate of crop residues is a major determinant for carbon balance and nutrient cycling in agroecosystem. In this study, a constant temperature incubation study was conducted to evaluate CO2 emission and microbial biomass based on four different parts of corn straw (roots, lower stem, upper stem and leaves) and two soils with different textures (sandy loam and clay loam) from the black soil region. The relationships between soil CO2 emission, microbial biomass and the ratio of carbon (C) to nitrogen (N) and lignin of corn residues were analyzed by the linear regression. Results showed that the production of CO2 was increased with the addition of different parts of corn straw to soil, with the value of priming effect (PE) ranged from 215. 53 umol . g-1 to 335. 17 umol . g 1. Except for corn leaves, the cumulative CO2 production and PE of clay loam soil were significantly higher than those in sandy loam soil. The correlation of PE with lignin/N was obviously more significant than that with lignin concentration, nitrogen concentration and C/N of corn residue. The addition of corn straw to soil increased the contents of MBC and MBN and decreased MBC/MBN, which suggested that more nitrogen rather than carbon was conserved in microbial community. The augmenter of microbial biomass in sandy loam soil was greater than that in clay loam soil, but the total dissolved nitrogen was lower. Our results indicated that the differences in CO2 emission with the addition of residues to soils were primarily ascribe to the different lignin/N ratio in different corn parts; and the corn residues added into the sandy loam soil could enhance carbon sequestration, microbial biomass and nitrogen holding ability relative to clay loam soil. PMID- 26489343 TI - [Isolation, Identification of a p-tert-Butylcatechol-Degradaing Strains and Optimization for Its Degradation by Response Surface Methodology]. AB - A bacterial strain YHl that used p-tert-Butylcatechol (TBC) as the sole carbon and energy source was isolated from the activated sludge of the wastewater treatment plant of a chemical factory. The strain was identified as Pseudomonas corrugate by morphological characteristics, physiological and biochemical properties, BIOLOG and the 16S rDNA sequence analysis. The degration rate of TBC was above 82% with an initial concentration of 500 mg.L-1 at 24-36 degrees C and an initial pH of 7. 0-10. 0. Through single-factor experiments of its degradation characteristics of strain YH1, the results showed that its optimal additional carbon and nitrogen sources were sucrose and tryptone, the optimal temperature was 30 degrees C, the optimal initial pH was 7. 0, and the optimal inoculation volume was 2%. In order to improve the TBC degradation rate, the concentrations of sucrose and tryptone and initial pH were identified as the main factors by Placket-Burman Assay. Then these factors reached their optimal region by Steepest Ascent. Finally, the optimal levels of those main factors were further optimized using Box-Behnken design and response surface analysis. The optimal conditions were as follows: sucrose concentration 3% (rho), tryptone concentration 1. 44% (rho), TBC concentration 400 mg.L-1, initial pH value 8. 12, inoculation amount 2. 97% (phi), temperature 30 degrees C, training time 96 h. Under the optimal conditions mentioned above, the TBC degradation rate reached 98. 21%. Enzymology analysis and localization experiments showed that the TBC-degrading enzymes were intracellular proteins and the synthesis of catechol 1,2-dioxygenase (C12O) could be induced by TBC. Through design of specific PCR primers for the degrading enzymes, the gene encoding the catechol 1,2-dioxygenase was amplified from YHL. It was found that genes encoding TBC-degrading enzyme were located on plasmids by the plasmid detection and elimination experiments. In addition, YH1 was tolerant to high concentration of NaCl and many kinds of heavy metal ions, and resistant to multiple antibiotics. This paper provided some information for the effective treatment of complex industrial wastewater. PMID- 26489345 TI - [Coupled Cytotoxicity of C60 Nano-Crystal Particle with Cu2+ to the Mouse Peritoneal Macrophage RAW 264.7]. AB - This work evaluated the cytotoxicity effect of nC60 nano-crystal particle associated with Cu2+ by using mouse peritoneal microphage RAW264. 7 as the test cell line. The results showed that when exposed to nC60 of 6. 6 mg . L-1 and 9. 9 mg . L-1 for 24h, the cell viability decreased 45% and 70% , respectively, and had obvious time-response and dose-response. It was found that Cu2, could reduce the toxicity of nC60 on RAW 264. 7. The cell viability reduced to 25% when exposed to 6. 6 mg . L-1 nC60 with 2 mg . L-1 Cu2+, and reduced to 15% when exposed to 9. 9 mg . L-1 nC60 with 5 mg . L-1 Cu2+. The nC60 could adsorb Cu2+ and the adsorption isotherm was fitted to the Langmuir adsorptiqn isotherm. The adsprption of Cu2+ on the surface of nC60 may decrease the cytotoxicity nC60 on RAW 264.7. PMID- 26489344 TI - [Isolation, Identification and Characteristic Analysis of an Oil-producing Chlorella sp. Tolerant to High-strength Anaerobic Digestion Effluent]. AB - A Chlorella strain tolerant to high-strength anaerobic digestion effluent was isolated from the anaerobic digestion effluent with a long-term exposure to air. The strain was identified as a Chlorella by morphological and molecular biological methods, and named Chlorella sp. BWY-1, The anaerobic digestion effluent used in this study was from a biogas plant with the raw materials of swine wastewater after solid-liquid separation. The Chlorella regularis (FACHB 729) was used as the control strain. The comparative study showed that Chlorella sp, BWY-Ihad relatively higher growth rate, biomass accumulation capacity and pollutants removal rate in BG11. and different concentrations of anaerobic digestion effluent. Chlorella sp. BWY-1 had the highest growth rate and biomass productivity (324.40 mg.L-1) in BG11, but its lipid productivity and lipid content increased with the increase of anaerobic digestion effluent concentration, In undiluted anaerobic digestion effluent, the lipid productivity and lipid content of Chlorella sp. BWY-1 were up to 44. 43% and 108. 70 mg.L-1, respectively. Those results showed that the isolated algal strain bad some potential applications in livestock wastewater treatment and bioenergy production, it could be combined with a solid-liquid separation, anaerobic fermentation and other techniques for processing livestock wastewater and producing biodiesel. PMID- 26489346 TI - [Simultaneous Analysis of 18 Glucocorticoids in Surface Water]. AB - A method of ultra-performance liquid chomatography tandam mass spectrometry(UPLC MS/MS) combined with solid-phase extraction (SPE) has been developed for simultaneous analysis of 18 glucocorticoids in surface water. The analytes were first enriched and purified through a HLB cartridge, and eluted with acetonitrile/ethyl acetate (1:1, V/V), then detected by UPLC-MS/MS. The detection used gradient elution process with methanol and 0. 1% formic acid/water (V/V) as the mobile phase to achieve baseline separations of these 18 analytes. The linear range was 1. 0-1 000 ug.L-1. The method detection limits (MDLs) were 0. 10-1. 0 ng.L-1 except for cortisone acetate and cortisol acetate(10 ng.L-1) with overall mean recoveries of 65% - 108% in surface water. Application of this method for 5 surface waters from Beijing area showed that 8 glucocorticoids were detected with the concentration range of 0. 20-476 ng.L-1. Triamcinolone, triamcinolone acetonide, cortisol acetate and clobetasol propionate were detected for the first time in surface water samples, suggesting that this method is efficient for real sample analysis. PMID- 26489347 TI - Progress and Persistence in Action. PMID- 26489348 TI - Women, Poverty, and Trauma: An Empowerment Practice Approach. AB - This article describes an empowerment approach for working with diverse women who experience poverty, trauma, and multiple structural oppressions. The approach is the result of 20 years of experience developing, implementing, and evaluating this practice in a metropolitan community, and is grounded in women's empowerment theory and relational-cultural theory. The interventions combine social work's clinical interventions with community organizing strategies to promote personal and collective empowerment, supporting the "personal is political" tenet of feminist practice. The interventions, including nonclinical interviews, story circles, and leadership and advocacy education and training, can guide practitioners in providing services and programs that create a space for women to make changes in their personal lives and in their community. Program outcomes report successful changes for women in improving symptoms, increasing self efficacy, and engaging in community advocacy. Women who participated also reported an increased sense of power, balancing commonality and difference among women, and a sense of hope for their future. PMID- 26489349 TI - Sex Trafficking: Policies, Programs, and Services. AB - Sex trafficking (ST), a contemporary form of female slavery, is a human rights issue of critical concern to social work. The global response to ST has been substantial, and 166 countries have adopted anti-ST legislation. Despite considerable efforts to combat ST, the magnitude is increasing. To date, the majority of anti-ST efforts have focused on criminalization policies that target traffickers or purchasers of sexual services, who are predominantly male; prevention programming and services for predominantly female victims have received less support. Therapeutic services to assist pornography addicts and purchasers of sexual services are also necessary. In this article, authors examine current anti-ST policies, programs, and services, both domestically and globally, and present an innovative paradigm that addresses social inequities and emphasizes prevention programming. They conclude with a discussion of the paradigm's implications for social work policies, practices, and services. PMID- 26489350 TI - Reproductive Health in the United States: A Review of the Recent Social Work Literature. AB - Reproductive health is an important area affecting a woman's overall health and well-being. The examination of reproductive health and barriers to care is pertinent to the social work profession and should be a focus of social work practice, education, research, and advocacy. The authors conducted a literature search of articles published in the social work literature from 2010 to 2014. The findings reveal important published articles that increase our knowledge of the reproductive health of women in the United States. Most published articles focused on pregnancy and birth outcomes. Articles also addressed sexually transmitted infections; abortion; intimate partner violence; prostitution; access to care; cancer screening; views toward contraception; hysterectomies; breastfeeding; menopause; and the intersection of reproductive rights, religion, and social justice. This review also identified unexamined areas that require further social work attention and consideration. PMID- 26489351 TI - The State of Intimate Partner Violence Intervention: Progress and Continuing Challenges. AB - Over the past 40 years, intimate partner violence (IPV) has evolved from an emerging social problem to a socially unacceptable crime. The Violence Against Women Act of 1994 encourages state policies that focus on criminal justice intervention, including mandatory arrest and prosecution. Services offered to victim-survivors of IPV are often tied to criminal justice intervention, or otherwise encourage separation. These interventions have been seen as effectively using the authority of the state to enhance women's power relative to that of abusive men. However, these interventions do not serve the needs of women who, for cultural or personal reasons, want to remain in their relationship, or marginalized women who fear the power of the state due to institutionalized violence, heterosexism, and racism. The one-size-fits-all approach that encourages prosecution and batterer intervention programs for offenders and shelter and advocacy for victim-survivors fails to adhere to the social work value of client self-determination and the practice principle of meeting clients where they are. It is imperative that social workers in all areas of practice are aware of IPV policies, services, and laws. Social workers' challenge moving forward is to develop innovative and evidence-based interventions that serve all victim-survivors of IPV PMID- 26489352 TI - Why Women Join the Military: Enlistment Decisions and Postdeployment Experiences of Service Members and Veterans. AB - Over the past three decades women's enlistment has continued to increase. In an effort to help social workers better meet the needs of female veterans, this study sought to learn women's enlistment motivations and postdeployment experiences. This qualitative study was nested within the Women Veterans Cohort Study. Using a semistructured interview guide, authors interviewed 18 enlisted female service members and veterans. The themes that emerged, based on grounded theory, included not only opportunity and calling, but also outcomes. Unexpectedly, enlistment resulted in a professional military career, with over half of the participants making the military their life's work. Further study on the motivation, retention, and the reintegration needs of women postmilitary is necessary, particularly with military recruitment targets of 20 percent women by the year 2020 and the increased awareness of the military as a potentially hostile work environment for women. PMID- 26489353 TI - Muslim Women in America and Hijab: A Study of Empowerment, Feminist Identity, and Body Image. AB - This article presents an exploratory, qualitative study of 12 Muslim women living in the Triangle area of North Carolina, who were interviewed regarding their voluntary practice of hijab (Muslim tradition of veiling), exercise of choice in hijab, their relationship to feminist belief and identity, female empowerment, and body image. Through examining the influence of political movements in concert with market capitalism, this article examines how the hijab and those who voluntarily practice this Muslim tradition challenge or contradict mainstream images of what is marketed in the West as feminist. Moreover, this article seeks to examine how, if at all, the hijab empowers those women who practice it, whether it offers an avenue of female empowerment and liberation not traditionally included in prevailing feminist thought, and how this may contribute to third-wave feminist theory. This article informs social work practitioners of the strength of Muslim women, the exercise of choice in hijab, and contributions to feminist thought as participants respond to assumptions of oppression, patriarchal control, and prejudice in a post-9/11 society. PMID- 26489354 TI - Family Planning for Low-Income African American Families: Contributions of Social Work Pioneer Ophelia Settle Egypt. AB - Historically, African Americans made huge contributions to the field of social welfare and the social work profession, yet little has been written about them in the professional literature. This article explores the contributions of pioneering social worker Ophelia Settle Egypt. A thorough assessment of her pioneering role would reveal her unique work as an educator, researcher, and grassroots social worker, but the focus here is on her innovative commitment to the Planned Parenthood movement. Egypt's work around population control in her Southeast Washington, DC, neighborhood with low-income African American families in the early 1950s became a labor of love in her community that can help inform current practice approaches in urban environments with African American populations. PMID- 26489355 TI - Conquering the Black Girl Blues. AB - An examination of the literature on epidemiology, etiology, and use of services for this population reveals an insufficient application of culturally congruent approaches to intervening with black women. An exploration of the social work practice literature and other relevant fields indicate that black feminist perspectives offer the opportunity to gain a clearer understanding of the intersection and influence of oppression among black women struggling with psychiatric issues and provide a useful framework for mental health practice with this population. This article discusses the evolving black feminist thought and summarizes the scholarship on black women's mental health services needs and utilization issues. The article includes a discussion of black feminisms as an emerging mental health perspective, arguing that black feminist perspectives in therapy provide an ideal framework for services that are responsive to the values and health needs of black women. The article concludes with a case vignette that illustrates some of its points. PMID- 26489356 TI - Graduate Social Work Faculty's Support for Educational Content on Women and on Sexism. AB - Social work faculty play an important role in preparing students to address sexism and engage in culturally competent practice with women. This study examines the nature of U.S. and Anglo-Canadian graduate social work faculty's support for content on women and on sexism. Although support appears high for both content areas, results suggest that faculty endorsement for content on women is significantly greater than that for sexism. Further, bivariate and multivariate analyses indicate that the nature of support differs for each content area. Implications for social work education are discussed. PMID- 26489357 TI - Social Innovation from the Inside: Considering the "Intrapreneurship" Path. PMID- 26489358 TI - Finding Joy in Social Work (Private Practice, Too!). PMID- 26489359 TI - MR diffusion-weighted imaging-based subcutaneous tumour volumetry in a xenografted nude mouse model using 3D Slicer: an accurate and repeatable method. AB - Accurate and repeatable measurement of the gross tumour volume(GTV) of subcutaneous xenografts is crucial in the evaluation of anti-tumour therapy. Formula and image-based manual segmentation methods are commonly used for GTV measurement but are hindered by low accuracy and reproducibility. 3D Slicer is open-source software that provides semiautomatic segmentation for GTV measurements. In our study, subcutaneous GTVs from nude mouse xenografts were measured by semiautomatic segmentation with 3D Slicer based on morphological magnetic resonance imaging(mMRI) or diffusion-weighted imaging(DWI)(b = 0,20,800 s/mm(2)) . These GTVs were then compared with those obtained via the formula and image-based manual segmentation methods with ITK software using the true tumour volume as the standard reference. The effects of tumour size and shape on GTVs measurements were also investigated. Our results showed that, when compared with the true tumour volume, segmentation for DWI(P = 0.060-0.671) resulted in better accuracy than that mMRI(P < 0.001) and the formula method(P < 0.001). Furthermore, semiautomatic segmentation for DWI(intraclass correlation coefficient, ICC = 0.9999) resulted in higher reliability than manual segmentation(ICC = 0.9996-0.9998). Tumour size and shape had no effects on GTV measurement across all methods. Therefore, DWI-based semiautomatic segmentation, which is accurate and reproducible and also provides biological information, is the optimal GTV measurement method in the assessment of anti-tumour treatments. PMID- 26489360 TI - Broadening the scope of social neuroscience. PMID- 26489362 TI - Anisotropic photocurrent response at black phosphorus-MoS2 p-n heterojunctions. AB - We investigate the photocurrent generation mechanisms at a vertical p-n heterojunction between black phosphorus (BP) and molybdenum disulfide (MoS2) flakes through polarization-, wavelength-, and gate-dependent scanning photocurrent measurements. When incident photon energy is above the direct band gap of MoS2, the photocurrent response demonstrates a competitive effect between MoS2 and BP in the junction region. In contrast, if the incident photon energy is below the band gap of MoS2 but above the band gap of BP, the photocurrent response at the p-n junction exhibits the same polarization dependence as that at the BP-metal junction, which is nearly parallel to the MoS2 channel. This result indicates that the photocurrent signals at the MoS2-BP junction primarily result from the direct band gap transition in BP. These fundamental studies shed light on the knowledge of photocurrent generation mechanisms in vertical 2D semiconductor heterojunctions, offering a new way of engineering future two dimensional materials based optoelectronic devices. PMID- 26489361 TI - Physiological, pharmacokinetic and liver metabolism comparisons between 3-, 6-, 12- and 18-month-old male Sprague Dawley rats under ketamine-xylazine anesthesia. AB - The main objective of this study was to compare the physiological changes (withdrawal and corneal reflexes, respiratory and cardiac frequency, blood oxygen saturation, and rectal temperature) following intraperitoneal administration of ketamine (80 mg/kg) and xylazine (10 mg/kg) to 3-, 6-, 12- and 18-month-old male Sprague Dawley rats (n=6/age group). Plasma pharmacokinetics, liver metabolism, and blood biochemistry were examined for a limited number of animals to better explain anesthetic drug effects. Selected organs were collected for histopathology. The results for the withdrawal and corneal reflexes suggest a shorter duration and decreased depth of anesthesia with aging. Significant cardiac and respiratory depression, as well as decreased blood oxygen saturation, occurred in all age groups however, cardiac frequency was the most affected parameter with aging, since the 6-, 12-, and 18-month-old animals did not recuperate to normal values during recovery from anesthesia. Pharmacokinetic parameters (T1/2 and AUC) increased and drug clearance decreased with aging, which strongly suggests that drug exposure is associated with the physiological results. The findings for liver S9 fractions of 18-month-old rats compared with the other age groups suggest that following a normal ketamine anesthetic dose (80 mg/kg), drug metabolism is impaired, leading to a significant increase of drug exposure. In conclusion, age and related factors have a substantial effect on ketamine and xylazine availability, which is reflected by significant changes in pharmacokinetics and liver metabolism of these drugs, and this translates into shorter and less effective anesthesia with increasing age. PMID- 26489364 TI - Non-invasive Measurement of Thermal Diffusivity Using High-Intensity Focused Ultrasound and Through-Transmission Ultrasonic Imaging. AB - Thermal diffusivity at the site ablated by high-intensity focused ultrasound (HIFU) plays an important role in the final therapeutic outcome, as it influences the temperature's spatial and temporal distribution. Moreover, as tissue thermal diffusivity is different in tumors as compared with normal tissue, it could also potentially be used as a new source of imaging contrast. The aim of this study was to examine the feasibility of combining through-transmission ultrasonic imaging and HIFU to estimate thermal diffusivity non-invasively. The concept was initially evaluated using a computer simulation. Then it was experimentally tested on phantoms made of agar and ex vivo porcine fat. A computerized imaging system combined with a HIFU system was used to heat the phantoms to temperatures below 42 degrees C to avoid irreversible damage. Through-transmission scanning provided the time-of-flight values in a region of interest during its cooling process. The time-of-flight values were consequently converted into mean values of speed of sound. Using the speed-of-sound profiles along with the developed model, we estimated the changes in temperature profiles over time. These changes in temperature profiles were then used to calculate the corresponding thermal diffusivity of the studied specimen. Thermal diffusivity for porcine fat was found to be lower by one order of magnitude than that obtained for agar (0.313*10(-7)m(2)/s vs. 4.83*10(-7)m(2)/s, respectively, p < 0.041). The fact that there is a substantial difference between agar and fat implies that non invasive all-ultrasound thermal diffusivity mapping is feasible. The suggested method may particularly be suitable for breast scanning. PMID- 26489363 TI - Advance care planning as a shared endeavor: completion of ACP documents in a multidisciplinary cancer program. AB - OBJECTIVE: We examined the roles of oncology providers in advance care planning (ACP) delivery in the context of a multidisciplinary cancer program. METHODS: Semi-structured interviews were conducted with 200 women with recurrent and/or metastatic breast or gynecologic cancer. Participants were asked to name providers they deemed important in their cancer care and whether they had discussed and/or completed ACP documentation. Evidence of ACP documentation was obtained from chart reviews. RESULTS: Fifty percent of participants self-reported completing an advance directive (AD) and 48.5% had named a healthcare power of attorney (HPA), 38.5% had completed both, and 39.0% had completed neither document. Among women who self-reported completion of the documents, only 24.0% and 14.4% of women respectively had documentation of an AD and HPA in their chart. Completion of an AD was associated with number (adjusted odds ratio [AOR] = 1.49) and percentage (AOR = 6.58) of providers with whom the participant had a conversation about end-of-life decisions. Participants who named a social worker or nurse practitioner were more likely to report having completed an AD. Participants who named at least one provider in common (e.g., named the same oncologist) were more likely to have comparable behaviors related to naming a HPA (AOR = 1.13, p = 0.011) and completion of an AD (AOR = 1.06, p = 0.114). CONCLUSIONS: Despite the important role of physicians in facilitating ACP discussions, involvement of other staff was associated with a greater likelihood of completion of ACP documentation. Patients may benefit from opportunities to discuss ACP with multiple members of their cancer care team. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26489365 TI - Transcutaneous Ultrasound: Elastographic Lymph Node Evaluation. Current Clinical Applications and Literature Review. AB - Distinguishing malignant versus benign lymphadenopathies is a major diagnostic dilemma in clinical medicine. Metastatic deposits in normal-sized lymph nodes (LNs) can be smaller than a millimeter, thus presenting a diagnostic challenge. In most clinical settings, however, enlarged LNs detected on imaging need to be classified as malignant or benign. Ultrasound seems to be a very reliable method for LN characterization because of the high resolution, especially in the subcutaneous areas. However, B-mode and Doppler-ultrasound criteria for characterization of a lymphadenopathy as benign or malignant are lacking specificity. Newer methods such as elastography seem to be valuable for identifying metastatic deposits within LNs and may help discriminate malignant and benign LNs. This review summarizes the different elastographic methods available and provides an overview of the relevant publications. According to the literature, elastography can be used for identifying metastatic deposits, to guide fine needle aspiration and to non-invasively choose the most suspicious LN of a group of enlarged LNs for targeted biopsy. PMID- 26489366 TI - Nickel embedded in N-doped porous carbon for the hydrogenation of nitrobenzene to p-aminophenol in sulphuric acid. AB - An acid-resistant catalyst composed of nickel embedded in N-doped porous carbon is developed for the catalytic hydrogenation of nitrobenzene (NB) to p aminophenol (PAP). The catalyst, due to a special electron donation from nickel to the N-doped porous carbon, shows an excellent catalytic performance and stability in sulphuric acid solution. PMID- 26489367 TI - Circadian PER2::LUC rhythms in the olfactory bulb of freely moving mice depend on the suprachiasmatic nucleus but not on behaviour rhythms. AB - The temporal order of physiology and behaviour in mammals is regulated by the coordination of the master circadian clock in the suprachiasmatic nucleus (SCN) and peripheral clocks in various tissues outside the SCN. Because the circadian oscillator(s) in the olfactory bulb (OB) is regarded as SCN independent, we examined the relationship between the SCN master clock and the circadian clock in the OB. We also examined the role of vasoactive intestinal peptide receptor 2 in the circadian organization of the OB. We continuously monitored the circadian rhythms of a clock gene product PER2 in the SCN and OB of freely moving mice by means of a bioluminescence reporter and an optical fibre implanted in the brain. Robust circadian rhythms were detected in the OB and SCN for up to 19 days. Bilateral SCN lesions abolished the circadian behaviour rhythms and disorganized the PER2 rhythms in the OB. The PER2 rhythms in the OB showed more than one oscillatory component of a similar circadian period, suggesting internal desynchronization of constituent oscillators. By contrast, significant circadian PER2 rhythms were detected in the vasoactive intestinal peptide receptor 2 deficient mice, despite the substantial deterioration or abolition of circadian behavioural rhythms. These findings indicate that the circadian clock in the OB of freely moving mice depends on the SCN master clock but not on the circadian behavioural rhythms. The circadian PER2::LUC rhythm in the cultured OB was as robust as that in the cultured SCN but reset by slice preparation, suggesting that culturing of the slice reinforces the circadian rhythm. PMID- 26489368 TI - Synergetic effect enhanced photoelectrocatalysis. AB - We report synergetic effect enhanced photoelectrocatalysis, in which Fe(3+) and Br(-) are used as the acceptors of photogenerated charges on TiO2 nanoparticles. The kinetic rate of interfacial charge transfer is promoted from (4.0 +/- 0.5) * 10(-4) cm s(-1) (TiO2/(O2, Br(-))) to (1.5 +/- 0.5) * 10(-3) cm s(-1) (TiO2/(Fe(3+), Br(-))). The synergetic effect provides a valuable approach to the design of photoelectrocatalytic systems. PMID- 26489369 TI - Linking vertebral number to performance of aquatic escape responses in the axolotl (Ambystoma mexicanum). AB - Environmental conditions during early development in ectothermic vertebrates can lead to variation in vertebral number among individuals of the same species. It is often seen that individuals of a species raised at cooler temperatures have more vertebrae than individuals raised at warmer temperatures, although the functional consequences of this variation in vertebral number on swimming performance are relatively unclear. To investigate this relationship, we tested how vertebral number in axolotls (Ambystoma mexicanum) affected performance of aquatic escape responses (C-starts). Axolotls were reared at four temperatures (12-24 degrees C) encompassing their natural thermal range and then transitioned to a mean temperature (18 degrees C) three months before C-starts were recorded. Our results showed variation in vertebral number, but that variation was not significantly affected by developmental temperature. C-start performance among axolotls was significantly correlated with caudal vertebral number, and individuals with more caudal vertebrae were able to achieve greater curvature more quickly during their responses than individuals with fewer vertebrae. However, our results show that these individuals did not achieve greater displacements or velocities, and that developmental temperature did not have any effect on C-start performance. We highlight that the most important aspects of escape swim performance (i.e., how far individuals get from a threat and how quickly they move the most important parts of the body away from that threat) are consistent across individuals regardless of developmental temperature and morphological variation. PMID- 26489370 TI - Synthesis of a new beta-amino acid with a 3-deoxy-L-ara furnaoside side chain: the influence of the side chain on the conformation of alpha/beta-peptides. AB - The important role of side chains in the stabilization of helical folds in peptidic foldamers containing C-linked carbo-beta-amino acids (beta-Caa), an interesting class of beta-amino acids, with carbohydrate side chains has been extensively elaborated. As a pragmatic approach to alleviate the interference of substituents in the side chains on the folding propensities of the peptides, they are often modified or removed. The present study reports the synthesis of a new beta-Caa with a 3-deoxy-L-ara furanoside side chain, [(R)-beta-Caa(da)], from D glucose, and its use in the synthesis of alpha/beta-peptides in 1 : 1 alternation with D-Ala. The synthesis of peptides using (R)-beta-Caa(da), was facile unlike those from (R)-beta-Caa(a) having the L-ara furanoside side chain. The detailed NMR, molecular dynamics (MD) and CD studies on the new alpha/beta-peptides showed the presence of robust left-handed 11/9-mixed helices. The study demonstrates that the new (R)-beta-Caa(da), behaves differently compared to the other two related monomers, (R)-beta-Caa(x) with the D-xylo furanoside side chain and (R) beta-Caa(a). PMID- 26489371 TI - Evaluation of an Immunochromatographic Test to the Diagnosis of Canine Brucellosis Caused by Brucella canis. AB - This study evaluated the performance of an immunochromatographic test (ICT) for the diagnosis of canine brucellosis caused by Brucella canis, comparing its results with that of the rapid slide agglutination test with and without the use of 2-mercaptoethanol and the agar gel immunodiffusion test (AGID). The microbiological culture, PCR and clinical examination were used as reference. According to the results obtained in clinical examination, blood culture, culture of semen and vaginal swab and PCR in blood, semen and vaginal swab, a total of 102 dogs were divided into three groups: B. canis-infected dogs (Group 1), B. canis-non-infected dogs (Group 2) and dogs with suspected brucellosis (Group 3). The diagnostic sensitivity of RSAT, 2ME-RSAT, AGID and ICT in Group 1 was, respectively, 75%, 37.5%, 27.8% and 89.58%. The diagnostic specificity of RSAT, 2ME-RSAT, AGID and ICT in Group 2 was, respectively, 91%, 100%, 100%, and 100%. In dogs with suspected brucellosis, 9.67% were RSAT positive, none was positive by 2ME-RSAT, 3.22% were AGID positive and 6.45% were ICT positive. The main drawback concerning canine brucellosis diagnosis is the lack of a highly sensitive serological assay to be used as a screening test to the rapid identification of infected animals. The ICT showed a high diagnostic specificity and a diagnostic sensitivity value greater than that observed in the RSAT, 2ME RSAT and AGID. However, 10.41% of infected dogs had negative results by ICT. These dogs were positive by microbiological culture and/or PCR, indicating active infection and consequently a higher potential of spreading Brucella. Although rapid and simple to perform, the ICT lacked sensitivity to be used as a screening test. PMID- 26489372 TI - Improving Australian care home medicine supply services: Evaluation of a quality improvement intervention. AB - AIM: The study aims to determine the impact of a quality improvement intervention on how accurately and suitably medicines are supplied to residents of residential aged-care facilities (RACFs). METHODS: Between September 2012 and January 2013, pharmacy-supplied dose administration aids (DAAs) were audited at 45 Victorian RACFs (Australia). RACFs had previously received an intervention (education session/toolkit) and were involved in an earlier DAA audit. Recently supplied DAAs containing regular medicines were compared to prescriber-prepared medicine charts to identify, and classify risks of, inaccurate or unsuitable packing incidents. RESULTS: Of 2389 DAAs audited for 983 residents, 770 incidents in 502 DAAs were identified. The overall DAA incident rate increased significantly from 11.5% pre-intervention to 21.0% post-intervention (P < 0.001). The proportion of DAAs affected by incidents classified as 'insignificant' or 'minor' risk increased post-intervention (P < 0.001). CONCLUSIONS: Further wide-scale evaluation of RACF medicine supply services is needed. Interventions that are effective in reducing DAA incidents should be explored. PMID- 26489373 TI - Therapeutic Apheresis: Why? PMID- 26489376 TI - Observation of a two-dimensional liquid of Frohlich polarons at the bare SrTiO3 surface. AB - The polaron is a quasi-particle formed by a conduction electron (or hole) together with its self-induced polarization in a polar semiconductor or an ionic crystal. Among various polarizable examples of complex oxides, strontium titanate (SrTiO3) is one of the most studied. Here we examine the carrier type and the interplay of inner degrees of freedom (for example, charge, lattice, orbital) in SrTiO3. We report the experimental observation of Frohlich polarons, or large polarons, at the bare SrTiO3 surface prepared by vacuum annealing. Systematic analyses of angle-resolved photoemission spectroscopy and X-ray absorption spectra show that these Frohlich polarons are two-dimensional and only exist with inversion symmetry breaking by two-dimensional oxygen vacancies. Our discovery provides a rare solvable field theoretical model, and suggests the relevance of large (bi)polarons for superconductivity in perovskite oxides, as well as in high temperature superconductors. PMID- 26489377 TI - White matter microstructural damage and depressive symptoms in patients with mild cognitive impairment and cerebral small vessel disease: the VMCI-Tuscany Study. AB - BACKGROUND AND PURPOSE: Disruption of cortical-subcortical circuits related to small vessel disease (SVD) may predispose to depression in the elderly. We aimed to determine the independent association between white matter (WM) microstructural damage, evaluated with diffusion tensor imaging (DTI), and depressive symptoms in a cohort of elderly subjects with mild cognitive impairment (MCI) and SVD. METHODS: The vascular mild cognitive impairment (VMCI) Tuscany Study is an observational multicentric longitudinal study that enrolled patients with MCI and moderate to severe degrees of WM hyperintensities on MRI. Lacunar infarcts, cortical atrophy, medial temporal lobe atrophy, microbleeds, and DTI-derived indices (mean diffusivity, MD and fractional anisotropy, FA) were evaluated on baseline MRI. Geriatric Depression Scale (GDS) (score 0-15) was used to assess depressive symptoms. An extensive neuropsychological battery, Instrumental Activities of Daily Living scale, and the Short Physical Performance Battery were used for cognitive, functional, and motor assessments, respectively. RESULTS: Seventy-six patients (mean age: 75.1 +/- 6.8 years) were included. Univariate analyses showed a significant association between GDS score and both DTI-derived indices (MD: r = 0.307, p = 0.007; FA: r = -0.245; p = 0.033). The association remained significant after adjustment for age, WM hyperintensities severity, global cognitive, functional and motor performances, and antidepressant therapy (MD: r = 0.361, p = 0.002; FA: r = -0.277; p = 0.021). CONCLUSIONS: These results outline the presence of an association between WM microstructural damage and depressive symptoms in MCI patients with SVD. This relationship does not seem to be mediated by disability, cognitive, and motor impairment, thus supporting the vascular depression hypothesis. PMID- 26489378 TI - 'Now I use words like asymmetry and unstable': nurses' experiences in using a standardized assessment for motor performance within routine child health care. AB - RATIONALE, AIMS AND OBJECTIVES: There is an increasing recognition that early intervention is important for children with motor disorders. The use of standardized assessment methods within the Swedish Child Health Services (CHS) may improve early identification of these children and thereby their development and quality of care. Given the key role of nurses within the CHS, we explored their experiences of using a structured assessment of motor performance (SOMP-I) in a clinical setting, and investigated possible barriers and facilitators for implementation of the method within the CHS. METHODS: The study was conducted in 2013 in Uppsala County, Sweden. Ten child health nurses participated in two focus group interviews, which were analysed using systematic text condensation. RESULTS: The analysis yielded three themes: (1) increased knowledge and professional pride - nurses described their desire to provide high-quality care for which SOMP-I was a useful tool; (2) improved parent-provider relationship - nurses felt that using SOMP-I involved both the parents and their infant to a greater extent than routine care; and (3) conditions for further implementation - nurses described that the time and effort needed to master new skills must be considered and practical barriers, such as lack of examination space, resource constraints and difficulties in documenting the assessment must be addressed before implementing the SOMP-I method in routine care. CONCLUSION: Child health nurses felt that the SOMP-I method fitted well with their professional role and increased the quality of care provided. However, significant barriers to implementing SOMP-I into routine child health care were described. PMID- 26489380 TI - Re: Adductor Canal Blockade Following Total Knee Arthroplasty-Continuous or Single-Shot Technique? PMID- 26489379 TI - Laser in infrapopliteal and popliteal stenosis 2 study (LIPS2): Long-term outcomes of laser-assisted balloon angioplasty versus balloon angioplasty for below knee peripheral arterial disease. AB - BACKGROUND: Laser-assisted balloon angioplasty (LABA) has been shown to be more effective in achieving angiographic success for treatment for below knee peripheral artery disease (PAD) compared with balloon angioplasty alone(BA). However, long-term outcomes of LABA compared with BA for popliteal and infrapopliteal PAD are unknown. METHODS: We evaluated data on 726 patients undergoing LABA (n = 395) and BA (n = 331) for popliteal and infrapopliteal PAD retrospectively at a single center (2007-2012). Outcomes included long-term ipsilateral major limb amputation, revascularization and mortality (median follow up = 36 months). RESULTS: Baseline features were similar in two groups with the exception of more TASC-D lesions (92.4 vs. 66.5%; P < 0.0001) and chronic total occlusions (86.4 vs. 49.5%; P < 0.0001) in LABA group. Angiographic success was higher in LABA compared with BA (97.7 vs. 89.2%; P < 0.0001). Ipsilateral major limb amputation (4.1 vs. 5.1%, P = 0.48) and repeat revascularization (25.1 vs. 23.3%, P = 0.47) were similar in LABA and BA patients despite unfavorable baseline angiographic characteristics in the former. Compared with BA, death was more frequently in LABA group (35.2 and 26.3%, P = 0.01), a reflection of higher comorbid conditions in this group (adjusted HR 1.05, 95% CI 0.79-1.39). CONCLUSION: Despite worse baseline angiographic characteristics compared with BA, LABA was associated with higher angiographic success and similar ipsilateral major amputation, repeat revascularization, and long-term mortality. Future randomized clinical trial should evaluate the efficacy of LABA compared with BA (particularly drug-eluting) in improving limb salvage and reducing repeat revascularization in these high-risk PAD patients. PMID- 26489381 TI - Abductor Biomechanics Clinically Impact the Total Hip Arthroplasty Dislocation Rate: A Prospective Long-Term Study. AB - BACKGROUND: Factors related to the patient, implant, and surgery have been associated to the rate of dislocation for total hip arthroplasty (THA). We ask if the position of the cup and the reconstruction of the abductor mechanism actually lower the THA dislocation rate. METHODS: We evaluated 1318 patients (1414 hips) undergoing cementless THA between 1992 and 2012. All THAs had a 28- or a 32-mm femoral head size. Hip reconstruction was radiologically assessed evaluating cup position and the hip rotation center according to Ranawat. The reconstruction of the abductor mechanism was measured using 2 variables: the lever arm distance and the height of the greater trochanter. RESULTS: There were 38 dislocations (2.7%). After controlling the relevant confounding variables, such as demographic and implant data, multivariate regression analysis showed that the most important factors associated with dislocation were a greater distance to the anatomic hip rotation center and hips outside 2 safe windows for cup position (acetabular inclination and version angles) and abductor mechanism (lever arm distance and height of the greater trochanter). CONCLUSION: A proper reconstruction of the hip is essential to decrease the risk of dislocation after primary THA. The weakness of the abductor muscles of the hip may be one of the most important causes for dislocation. PMID- 26489383 TI - Comparison of methods to quantify histone H2AX phosphorylation and its usefulness for prediction of radiosensitivity. AB - PURPOSE: The number of radio-induced double-strand breaks is correlated with the number of histone gamma-H2AX (gamma-H2AX) foci. For this reason, foci quantification is a useful tool to measure radiation-induced DNA damage and the number of foci has been suggested as a predictive biomarker of radiosensitivity. The aim of the present study was to evaluate the reproducibility of different microscopic methodologies and flow cytometry analysis to score gamma-H2AX induction, and its suitability to distinguish a radiosensitive (RS) cell line from a radioresistant (RR) one. MATERIALS AND METHODS: gamma-H2AX analyses were performed by semi-automated and automated microscopic methods and by flow cytometry before and after irradiation in two human lymphoblastoid cell lines and in lymphocytes from three healthy donors. RESULTS: Reproducible results were obtained by all the methodologies tested, although not all showed the same sensitivity. The RS cell line always showed higher foci counts and higher levels of immunofluorescence intensity after irradiation than the RR cell line. CONCLUSIONS: Our results suggest that microscopic methodologies with z-stage capacity give the most accurate results after 1 Gy irradiation. However, for high doses of ionizing radiation, flow cytometry gives reliable results. Further studies will be necessary to determine the usefulness of gamma-H2AX analysis to predict adverse side reactions in radiotherapy patients. PMID- 26489382 TI - Defective mitochondrial fission augments NLRP3 inflammasome activation. AB - Despite the fact that deregulated NLRP3 inflammasome activation contributes to the pathogenesis of chronic inflammatory or metabolic disorders, the underlying mechanism by which NLRP3 inflammasome signaling is initiated or potentiated remains poorly understood. Much attention is being paid to mitochondria as a regulator of NLRP3 inflammasome activation, but little is known about the role of mitochondrial dynamics for the inflammasome pathway. Here, we present evidence that aberrant mitochondrial elongation caused by the knockdown of dynamin-related protein 1 (Drp1) lead to a marked increase in NLRP3-dependent caspase-1 activation and interleukin-1-beta secretion in mouse bone marrow-derived macrophages. Conversely, carbonyl cyanide m-chlorophenyl hydrazone, a chemical inducer of mitochondrial fission, clearly attenuated NLRP3 inflammasome assembly and activation. Augmented activation of NLRP3 inflammasome by mitochondrial elongation is not resulted from the increased mitochondrial damages of Drp1 knockdown cells. Notably, enhanced extracellular signal-regulated kinase (ERK) signaling in Drp1-knockdown macrophages is implicated in the potentiation of NLRP3 inflammasome activation, possibly via mediating mitochondrial localization of NLRP3 to facilitate the assembly of NLRP3 inflammasome. Taken together, our results provide a molecular insight into the importance of mitochondrial dynamics in potentiating NLRP3 inflammasome activation, leading to aberrant inflammation. PMID- 26489384 TI - Bio-based Wrinkled Surfaces Harnessed from Biological Design Principles of Wood and Peroxidase Activity. AB - A new and simple approach for surface wrinkling inspired by polymer assemblies in wood fibers is introduced. A hard skin is synthesized on a linear polysaccharide support that resembles the structural units of the cell wall. This skin, a wood mimetic layer, is produced through immersion in a solution containing phenolic precursor and subsequent surface reaction by horseradish peroxidase. A patterned surface with micron-scale wrinkles is formed upon drying and as a result of inhomogeneous shrinkage. We demonstrate that the design of the wrinkled surfaces can be controlled by the molecular structure of the phenolic precursor, temperature, and drying stress. It is noteworthy that this is a totally bio-based system involving green materials and processes. PMID- 26489385 TI - Amorphous Vanadium Oxide/Carbon Composite Positive Electrode for Rechargeable Aluminum Battery. AB - Amorphous vanadium oxide/carbon composite (V2O5/C) was first applied to the positive electrode active material for rechargeable aluminum batteries. Electrochemical properties of V2O5/C were investigated by cyclic voltammetry and charge-discharge tests. Reversible reduction/oxidation peaks were observed for the V2O5/C electrode and the rechargeable aluminum cell showed the maximum discharge capacity over 200 mAh g(-1) in the first discharging. The XPS analyses after discharging and the following charging exhibited that the redox of vanadium ion in the V2O5/C active material occurred during discharging and charging, and the average valence of V changed between 4.14 and 4.85. PMID- 26489386 TI - Optically Active Nanostructured ZnO Films. AB - Inorganic nanomaterials endowed with hierarchical chirality could open new horizons in physical theory and applications because of their fascinating properties. Here, we report chiral ZnO films coated on quartz substrates with a hierarchical nanostructure ranging from atomic to micrometer scale. Three levels of hierarchical chirality exist in the ZnO films: helical ZnO crystalline structures that form primary helically coiled nanoplates, secondary helical stacking of these nanoplates, and tertiary nanoscale circinate aggregates formed by several stacked nanoplates. These films exhibited optical activity (OA) at 380 nm and in the range of 200-800 nm and created circularly polarized luminescence centered at 510 nm and Raman OA at 50-1400 cm(-1) , which was attributed to electronic transitions, scattering, photoluminescent emission, and Raman scattering in a dissymmetric electric field. The unprecedented strong OA could be attributed to multiple light scattering and absorption-enhanced light harvesting in the hierarchical structures. PMID- 26489387 TI - Prognostic implications of epilepsy in glioblastomas. AB - OBJECTIVES: The role of seizures and antiepileptic treatments associated with glioblastoma is a current topic of discussion. The objective of this study is to characterize and establish implications of epilepsy associated with glioblastoma. PATIENTS AND METHODS: We retrospectively analyzed the medical history, focused on epileptic features of 134 histologically diagnosed glioblastoma over a period of 4 years. RESULTS: The sample group had an average age of 56 years and 66% were male. Complete tumor resection was performed in 66% and 64.2% received further radio-oncologic treatment. The average survival rate was 12.4 months and 11.5% survived to 5 years. Epileptic seizures were the presentation symptom in 27% of cases and 51% suffered seizures during the disease, 26% become drug-resistant. Focal evolving to a bilateral convulsive seizures were the most frequent type. Epileptic seizures at presentation independently predicted longer survival (p<0.001). Furthermore, a history of epilepsy or seizures during disease improved survival. Late onset seizures, recurrences or status epilepticus during the course of the disease indicated tumor progression or the final stages of life. Prophylactic antiepileptic drugs did not prevent seizures. Similarly, there was no difference in survival between patients who did not use antiepileptic drugs and those using valproate or levetiracetam. Patients under 60 years, full oncologic treatment and secondary glioblastomas were factors that improved survival (p<0.001). CONCLUSION: Previous history of epilepsy or the onset of seizures as a presentation symptom in glioblastomas predict longer survival. Half of patients have seizures during the course of the disease. Antiepileptic drugs alone do not increase survival in glioblastoma patients. PMID- 26489388 TI - Attenuating pain flare: a new role for an old therapy? PMID- 26489389 TI - Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a double-blind, randomised placebo-controlled, phase 3 trial. AB - BACKGROUND: Pain flare occurs after palliative radiotherapy, and dexamethasone has shown potential for prevention of such flare. We aimed to compare the efficacy of dexamethasone with that of placebo in terms of reduction of incidence of pain flare. METHODS: In this double-blind, randomised, placebo-controlled phase 3 trial, patients from 23 Canadian centres were randomly allocated (1:1) with a web-based system and minimisation algorithm to receive either two 4 mg dexamethasone tablets or two placebo tablets taken orally at least 1 h before the start of radiation treatment (a single 8 Gy dose to bone metastases; day 0) and then every day for 4 days after radiotherapy (days 1-4). Patients were eligible if they had a non-haematological malignancy and bone metastasis (or metastases) corresponding to the clinically painful area or areas. Patients reported their worst pain scores and opioid analgesic intake before treatment and daily for 10 days after radiation treatment. They completed the European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C15-PAL, the bone metastases module (EORTC QLQ-BM22), and the Dexamethasone Symptom Questionnaire at baseline, and at days 10 and 42 after radiation treatment. Pain flare was defined as at least a two-point increase on a scale of 0-10 in the worst pain score with no decrease in analgesic intake, or a 25% or greater increase in analgesic intake with no decrease in the worst pain score from days 0-10, followed by a return to baseline levels or below. Primary analysis of incidence of pain flare was by intention-to-treat (patients with missing primary data were classified as having pain flare). This study is registered with ClinicalTrials.gov, number NCT01248585, and is completed. FINDINGS: Between May 30, 2011, and Dec 11, 2014, 298 patients were enrolled. 39 (26%) of 148 patients randomly allocated to the dexamethasone group and 53 (35%) of 150 patients in the placebo group had a pain flare (difference 8.9%, lower 95% confidence bound 0.0, one-sided p=0.05). Two grade 3 and one grade 4 biochemical hyperglycaemic events occurred in the dexamethasone group (without known clinical effects) compared with none in the placebo group. The most common adverse events were bone pain (61 [41%] of 147 vs 68 [48%] of 143), fatigue (58 [39%] of 147 vs 49 [34%] of 143), constipation (47 [32%] of 147 vs 37 [26%] of 143), and nausea (34 [23%] of 147 vs 34 [24%] of 143), most of which were mild grade 1 or 2. INTERPRETATION: Dexamethasone reduces radiation-induced pain flare in the treatment of painful bone metastases. FUNDING: The NCIC CTG's programmatic grant from the Canadian Cancer Society Research Institute. PMID- 26489390 TI - Intervention decision-making processes and information preferences of parents of children with autism spectrum disorders. AB - BACKGROUND: When a child is diagnosed with autism, parents are faced with the task of choosing from many different intervention options. To find information about the options available, parents turn to a number of different sources. This study explores parents' (n = 23) intervention decision-making processes and information preferences following the diagnosis of ASD for their child. METHODS: Qualitative thematic analysis of verbatim transcripts from interviews and focus groups involving parents of children with an autism diagnosis was undertaken. RESULTS: Analysis of the results revealed that there are concurrent emotional and pragmatic intervention 'journeys' undertaken by parents post diagnosis, which encompass the primary themes of: (1) information sources used, (2) parents' information preferences and (3) factors influencing intervention decision making. Parents described a journey from the point of diagnosis that involved seeking information on ASD interventions from multiple sources, with the Internet being the primary source. They were overwhelmed by the sheer volume of information available, and their preferences for information varied according to their stage in the journey post diagnosis. Parents had a 'trial and error' approach to choosing ASD interventions, with confidence increasing as they became more familiar with their child's condition, and had opportunities to explore numerous information sources about their child's diagnosis. While confidence increased over time, consideration of the effectiveness or evidence supporting interventions remained largely absent throughout the journey. CONCLUSION: This study highlights the need for parents of children with ASD to be supported to make informed intervention decisions, particularly with consideration for research evidence. PMID- 26489391 TI - Cu-Ag core-shell nanoparticles with enhanced oxidation stability for printed electronics. AB - In this work, we synthesized uniform Cu-Ag core-shell nanoparticles using a facile two-step process that consists of thermal decomposition and galvanic displacement methods. The core-shell structure of these nanoparticles was confirmed through characterization using transmission electron microscopy, energy dispersive spectroscopy, and x-ray diffraction. Furthermore, we investigated the oxidation stability of the Cu-Ag core-shell nanoparticles in detail. Both qualitative and quantitative x-ray photoelectron spectroscopy analyses confirm that the Cu-Ag core-shell nanoparticles have considerably higher oxidation stability than Cu nanoparticles. Finally, we formulated a conductive ink using the synthesized nanoparticles and coated it onto glass substrates. Following the sintering process, we compared the resistivity of the Cu-Ag core-shell nanoparticles with that of the Cu nanoparticles. The results of this study clearly show that the Cu-Ag core-shell nanoparticles can potentially be used as an alternative to Ag nanoparticles because of their superior oxidation stability and electrical properties. PMID- 26489392 TI - A telephone questionnaire in order to assess functional outcome after post traumatic limb salvage surgery: Development and preliminary validation. AB - BACKGROUND: Post-traumatic limb salvage surgery is challenging and evaluation of the results remains arduous. No questionnaire specifically assessing functional outcome after post-traumatic limb salvage surgery of the lower extremity exists. Due to regionalization of specialized care, the patients' travel time to the hospital increases. To overcome a higher patients' travel burden, patients' follow up by telephone is an option. We aimed to develop a telephone questionnaire in order to assess functional outcome after post-traumatic limb salvage surgery of the lower extremity. METHODS: From a review of scores of functional assessment of the lower limb surgery, we have developed a telephone questionnaire. A prospective study was performed to validate this telephone questionnaire. Twenty patients were included. The participants were called to complete the telephone questionnaire twice with an interval of a week. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was completed during the second telephone call. The internal consistency was analyzed by the Cronbach's alpha (alpha). With the outcome scores of both completions, the test-retest reliability was analyzed by the interclass correlation coefficient (ICC) 2,k with a 95% confidence interval (95% CI). The outcome scores of the second telephone questionnaire and the WOMAC questionnaire were used for the construct validity analysis by the Spearman's rank correlation coefficient (r(s)) with a 95% CI. RESULTS: The internal consistency analysis revealed a alpha=0.62 which improved to alpha=0.92 after removing one question from the telephone questionnaire. The final version of the telephone questionnaire comprises 32 questions, divided in 3 subscales: function, daily life and psychology. The total score varies between 0 and 86 points. The test-retest reliability was ICC 2,k=0.93 (95% CI: 0.82-0.97) and the construct validity was r(s)=0.92 (95% CI: 0.81-0.97). CONCLUSIONS: We present a specific telephone questionnaire in order to assess functional outcomes after posttraumatic limb salvage surgery of the lower extremity. Further research on a large number of patients will be necessary to validate this newly developed questionnaire. PMID- 26489393 TI - Return to work outcomes for workers with mental health conditions: A retrospective cohort study. AB - OBJECTIVES: The aims of this study were to describe predictors of sustained return to work (RTW) among a cohort of workers with compensated work-related mental health conditions (MHCs); and to examine predictors of subsequent absences due to the same condition. METHODS: This study was a retrospective analysis of compensation claims data in Victoria, Australia. We selected workers with an accepted wage replacement claim due to a work-related MHC from 1 January 2002 to 31 December 2009, with two years of follow-up data. RESULTS: We identified 8358 workers meeting our inclusion criteria. The median age of workers was 44 years (Interquartile range (IQR): 36-51) and 56% were female. In a multivariable Cox regression analysis, older age, being from a small organisation, working in some specific industry segments, consulting a psychiatrist or psychologist, using medications, and having a previous claim were all associated with a delayed RTW. Workers experiencing work pressure, assault/workplace violence or other mental stress factors, working in the public administration and safety industry and having a medical incapacity certification between 3-4 days and 5-7 days had a higher rate of multiple RTW attempts. CONCLUSION: This study identified a number of risk factors associated with a delayed RTW and multiple attempts at RTW. Predictors may help identify high-risk groups and facilitate the RTW process of workers with MHCs. PMID- 26489394 TI - Exchange nailing for femoral diaphyseal fracture non-unions: Risk factors for failure. AB - The aim of this study was to identify risk factors for failure of exchange nailing for femoral diaphyseal fracture non-unions. The study cohort comprised 40 patients with femoral diaphyseal non-unions treated by exchange nailing, of which six were open injuries. The median time to exchange nailing from primary fixation was 8.4 months. The main outcome measures were union, number of secondary fixation procedures required to achieve union and time to union. Multiple causes for non-union were found in 16 (40%) cases, with infection present in 12 (30.0%) patients. Further surgical procedures were required in nine (22.5%) cases, one of whom (2.5%) required the use of another fixation modality to achieve union. Union was ultimately achieved with exchange nailing in 34/37 (91.9%) patients. The median time to union after the exchange nailing was 9.4 months. Cigarette smoking and infection were risk factors for failure of exchange nailing. Multivariate analysis found infection to be the strongest predictor of exchange failure (p<0.05). Exchange nailing is an effective treatment for aseptic femoral diaphyseal fracture non-union. However, 50% of patients undergoing exchange nailing in the presence of infection required at least one further procedure. It is important to counsel patients of this so that they can plan for it and do not consider that the first exchange operation has failed. PMID- 26489397 TI - Assessment of Fatty Acid Profile and Seed Mineral Nutrients of Two Soybean (Glycine max L.) Cultivars Under Elevated Ultraviolet-B: Role of ROS, Pigments and Antioxidants. AB - Current scenarios under global climate change envisage a considerable increase in ultraviolet B (UV-B) radiation in near future which may affect the productivity and yield quality of major agricultural crops. Present investigation was conducted to examine various defense strategies adopted against elevated UV-B (ambient + 7.2 kJ m-(2) day-(1) ) and their impact on seed nutrients, content and quality of oil including fatty acid profile of two soybean cultivars (JS-335 and PS-1042). Elevated UV-B (eUV-B) exposure leads toward higher unsaturation of fatty acids and changes in other oil quality parameters (acid, iodine and saponification value) indicated that eUV-B favored the synthesis of long-chain fatty acids with fewer carboxylic acid groups, making the oil rancid, with undesirable flavor and low nutritional value. The effect was more severe in JS 335 as compared to PS-1042. Negative effects were also seen on nutrients of soybean seeds. Adverse effects resulted due to insufficient quenching of ROS (superoxide radical and hydrogen peroxide) by the defense system and thus unable to overcome the imposed oxidative stress. Credit of better performance by PS-1042 against eUV-B may be given to the adoption of efficient defense strategies like higher wax deposition, increase in lignin and flavonoids (quercetin and kaempferol) contents. PMID- 26489395 TI - Zebrafish Models for Human Acute Organophosphorus Poisoning. AB - Terrorist use of organophosphorus-based nerve agents and toxic industrial chemicals against civilian populations constitutes a real threat, as demonstrated by the terrorist attacks in Japan in the 1990 s or, even more recently, in the Syrian civil war. Thus, development of more effective countermeasures against acute organophosphorus poisoning is urgently needed. Here, we have generated and validated zebrafish models for mild, moderate and severe acute organophosphorus poisoning by exposing zebrafish larvae to different concentrations of the prototypic organophosphorus compound chlorpyrifos-oxon. Our results show that zebrafish models mimic most of the pathophysiological mechanisms behind this toxidrome in humans, including acetylcholinesterase inhibition, N-methyl-D aspartate receptor activation, and calcium dysregulation as well as inflammatory and immune responses. The suitability of the zebrafish larvae to in vivo high throughput screenings of small molecule libraries makes these models a valuable tool for identifying new drugs for multifunctional drug therapy against acute organophosphorus poisoning. PMID- 26489398 TI - TORC2: a novel target for treating age-associated memory impairment. AB - Memory decline is one of the greatest health threats of the twenty-first century. Because of the widespread increase in life expectancy, 20 percent of the global population will be over 60 in 2050 and the problems caused by age-related memory loss will be dramatically aggravated. However, the molecular mechanisms underlying this inevitable process are not well understood. Here we show that the activity of the recently discovered mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) declines with age in the brain of both fruit flies and rodents and that the loss of mTORC2-mediated actin polymerization contributes to age associated memory loss. Intriguingly, treatment with a small molecule that activates mTORC2 (A-443654) reverses long-term memory (LTM) deficits in both aged mice and flies. In addition, we found that pharmacologically boosting either mTORC2 or actin polymerization enhances LTM. In contrast to the current approaches to enhance memory that have primarily targeted the regulation of gene expression (epigenetic, transcriptional, and translational), our data points to a novel, evolutionarily conserved mechanism for restoring memory that is dependent on structural plasticity. These insights into the molecular basis of age-related memory loss may hold promise for new treatments for cognitive disorders. PMID- 26489399 TI - Cyclic and constant hyperoxia cause inflammation, apoptosis and cell death in human umbilical vein endothelial cells. AB - BACKGROUND: Perioperative high-dose oxygen (O2 ) exposure can cause hyperoxia. While the effect of constant hyperoxia on the vascular endothelium has been investigated to some extent, the impact of cyclic hyperoxia largely remains unknown. We hypothesized that cyclic hyperoxia would induce more injury than constant hyperoxia to human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were exposed to cyclic hyperoxia (5-95% O2 ) or constant hyperoxia (95% O2 ), normoxia (21% O2 ), and hypoxia (5% O2 ). Cell growth, viability (Annexin V/propidium iodide and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide, MTT) lactate dehydrogenase (LDH), release, cytokine (interleukin, IL and macrophage migration inhibitory factor, MIF) release, total antioxidant capacity (TAC), and superoxide dismutase activity (SOD) of cell lysate were assessed at baseline and 8, 24, and 72 h. A signal transduction pathway finder array for gene expression analysis was performed after 8 h. RESULTS: Constant and cyclic hyperoxia-induced gradually detrimental effects on HUVECs. After 72 h, constant or cyclic hyperoxia exposure induced change in cytotoxic (LDH +12%, P = 0.026; apoptosis +121/61%, P < 0.01; alive cells -15%, P < 0.01; MTT -16/15%, P < 0.01), inflammatory (IL-6 +142/190%, P < 0.01; IL-8 +72/43%, P < 0.01; MIF +147/93%, P < 0.01), or redox-sensitive (SOD +278%, TAC-25% P < 0.01) markers. Gene expression analysis revealed that constant and cyclic hyperoxia exposure differently activates oxidative stress, nuclear factor kappa B, Notch, and peroxisome proliferator-activated receptor pathways. CONCLUSIONS: Extreme hyperoxia exposure induces inflammation, apoptosis and cell death in HUVECs. Although our findings cannot be transferred to clinical settings, results suggest that hyperoxia exposure may cause vascular injury that could play a role in determining perioperative outcome. PMID- 26489400 TI - Multistate product traceforward investigation to link imported romaine lettuce to a US cyclosporiasis outbreak - Nebraska, Texas, and Florida, June-August 2013. AB - During June-August 2013, 25 US states reported 631 cyclosporiasis cases including Nebraska and Iowa where a regional investigation implicated common-source imported salad mix served in two chain restaurants. At least two common-origin growing fields were likely sources of contaminated romaine lettuce. Using producer- and distributor-provided data, we conducted a grower-specific traceforward investigation to reveal exposures of ill US residents elsewhere who reported symptom onset during 11 June-1 July 2013, the time period established in the Nebraska and Iowa investigation. Romaine lettuce shipped on 2-6 June from one of these Mexico-origin growing fields likely caused cyclosporiasis in 78 persons reporting illness onsets from 11 June to 1 July in Nebraska, Texas, and Florida. Nationwide, 97% (314/324) of persons confirmed with cyclosporiasis with symptom onset from 11 June to 1 July 2013 resided in 11 central and eastern US states receiving approximately two-thirds of romaine lettuce from this field. This grower's production practices should be investigated to determine potential sources of contamination and to develop recommendations to prevent future illnesses. PMID- 26489401 TI - Development and persistence of DAA resistance associated mutations in patients failing HCV treatment. AB - BACKGROUND: Direct-acting antiviral agents (DAAs) combined with pegylated interferon (PegIFN) and ribavirin (RBV) are still a standard treatment in patients with genotype 1HCV infection. However, virologic response could be impaired by baseline or early selection of resistant HCV strains. OBJECTIVES: The aim of this study was to determine the onset and persistence of resistance associated mutations (RAMs) in the NS3 and NS5B genes of DAA-naive patients failing treatment. STUDY DESIGN: Direct sequencing of HCV NS3 was performed in 49 DAA-naive patients with HCV genotype 1 infection. RESULTS: Eight out of 23 patients (34.7%) failed PegIFN/RBV/telaprevir during the 12-weeks of therapy. Treatment failure was associated with the development of RAMs at amino-acids 36,54,80 and 155 of the HCV protease in 6/8 patients (75%). Among patients treated with PegIFN/RBV/boceprevir treatment, 4/18 (22.2%) failed therapy. Of these, 2 (50%) carried virus strains which developed a RAM at amino-acids 54 and 155. Among HCV strains with RAMs, 7 belonged to genotype 1a and 1 to 1b. Finally, in 6/10 (60%) patients, drug-resistant variants could still be detected for up to 3-7 months after stopping therapy. CONCLUSIONS: A higher rate (p=0.49) of treatment failure was observed in patients receiving telaprevir- compared to the boceprevir-based combination. In addition, compared with genotype 1b, genotype 1a was associated with higher rates (p=0.01) of treatment failure due to virus resistant strains. Resistance testing at baseline and during DAA treatment should be taken into consideration when treating patients with new HCV combination therapies. PMID- 26489402 TI - Atypical exanthems associated with HHV-6 reactivation after hematopoietic cell transplantation. PMID- 26489403 TI - A quality by design approach to scale-up of high-shear wet granulation process. AB - High-shear wet granulation is a complex process that in turn makes scale-up a challenging task. Scale-up of high-shear wet granulation process has been studied extensively in the past with various different methodologies being proposed in the literature. This review article discusses existing scale-up principles and categorizes the various approaches into two main scale-up strategies - parameter based and attribute-based. With the advent of quality by design (QbD) principle in drug product development process, an increased emphasis toward the latter approach may be needed to ensure product robustness. In practice, a combination of both scale-up strategies is often utilized. In a QbD paradigm, there is also a need for an increased fundamental and mechanistic understanding of the process. This can be achieved either by increased experimentation that comes at higher costs, or by using modeling techniques, that are also discussed as part of this review. PMID- 26489404 TI - Meanings of feeling well among women with Parkinson's disease. AB - We conducted a qualitative inquiry to describe the meanings of feeling well as experienced by women with Parkinson's disease. Nine women were interviewed and we analysed the interviews using a reflective lifeworld approach based on phenomenological epistemology. We present the analysis as five constituents: the body as unnoticed; being able to move on; feeling joy by being connected; finding peace and harmony; and being the director of one's own life. Our findings can be used to understand and promote well-being among women with Parkinson's disease. In care meetings, knowledge about the lived and experienced health processes supports the women's striving to not let illness dominate their experience of daily life. PMID- 26489405 TI - Determinants of stunting and severe stunting among under-fives in Tanzania: evidence from the 2010 cross-sectional household survey. AB - BACKGROUND: Stunting is one of the main public health problems in Tanzania. It is caused mainly by malnutrition among children aged less than 5 years. Identifying the determinants of stunting and severe stunting among such children would help public health planners to reshape and redesign new interventions to reduce this health hazard. This study aimed to identify factors associated with stunting and severe stunting among children aged less than five years in Tanzania. METHODS: The sample is made up of 7324 children aged 0-59 months, from the Tanzania Demographic and Health Surveys 2010. Analysis in this study was restricted to children who lived with the respondent (women aged 15-49 years). Stunting and severe stunting were examined against a set of individual-, household- and community-level factors using simple and multiple logistic regression analyses. RESULTS: The prevalence of stunting and severe stunting were 35.5% [95% Confidence interval (CI): 33.3-37.7] and 14.4% (95 % CI: 12.9-16.1) for children aged 0-23 months and 41.6% (95 % CI: 39.8-43.3) and 16.1% (95 % CI: 14.8-17.5) for children aged 0-59 months, respectively. Multivariable analyses showed that the most consistent significant risk factors for stunted and severely-stunted children aged 0-23 and 0-59 months were: mothers with no schooling, male children, babies perceived to be of small or average size at birth by their mothers and unsafe sources of drinking water [adjusted odds ratio (AOR) for stunted children aged 0-23 months = 1.37; 95% CI: (1.07, 1.75)]; [AOR for severely stunted children aged 0-23 months = 1.50; 95% CI: (1.05, 2.14)], [AOR for stunted children aged 0-59 months = 1.42; 95% CI: (1.13, 1.79)] and [AOR for severely stunted children aged 0-59 months = 1.26; 95% CI: (1.09, 1.46)]. CONCLUSIONS: Community-based interventions are needed to reduce the occurrence of stunting and severe stunting in Tanzania. These interventions should target mothers with low levels of education, male children, small- or average-size babies and households with unsafe drinking water. PMID- 26489406 TI - Chronic Subdural Hematoma Associated with Spontaneous Intracranial Hypotension: Therapeutic Strategies and Outcomes of 55 Cases. AB - Spontaneous intracranial hypotension (SIH) has increasingly been recognized, and it is well known that SIH is sometimes complicated by chronic subdural hematoma (SDH). In this study, 55 cases of SIH with SDH were retrospectively analyzed, focusing on therapeutic strategies and outcomes. Of 169 SIH cases (75 males, 84 females), 55 (36 males, 19 females) were complicated by SDH. SIH was diagnosed based on clinical symptoms, neuroimaging, and/or low cerebrospinal fluid pressure. Presence of orthostatic headache and diffuse meningeal enhancement on magnetic resonance imaging were regarded as the most important criteria. Among 55 SIH with SDH cases, 13 improved with conservative treatment, 25 initially received an epidural blood patch (EBP), and 17 initially underwent irrigation of the hematomas. Of the 25 initially treated with EBP, 7 (28.0%) needed SDH surgery and 18 (72.0%) recovered fully without surgery. Of 17 SDH cases initially treated with surgery, 6 (35.7%) required no EBP therapy and the other 11 (64.3%) needed EBP and/or additional SDH operations. In the latter group, 2 cases had transient severe complications during and after the procedures. One of these 2 cases developed a hoarse voice complication. Despite this single, non-severe complication, all enrolled in this study achieved good outcomes. The present study suggests that patients initially receiving SDH surgery may need additional treatments and may occasionally have complications. If conservative treatment is insufficient, EBP should be performed prior to hematoma irrigation. PMID- 26489407 TI - The Associated Venous Anomalies Variant and Adjacent Brain Function on Iron Sensitive Image Indicate Surgical Risk of Cavernous Malformation. AB - The cavernous malformations (CMs) associated with venous anomalies (VAs) are now being described with increasing frequency. Assessment of the associated VAs is overlooked in surgical management of the CM. The clinical profiles of CMs with VAs were reviewed to investigate the value of T2* gradient echo (GRE)/susceptibility weighted imaging (SWI) in surgical risk evaluation. Twenty six patients with symptomatic CMs associated with VAs between 2008 and 2013 were identified. Demographic, clinical, and radiological data were reviewed and functional outcomes were assessed using the modified Rankin Scale (mRS). The T2* GRE/SWI could allow more accurate evaluation of the boundary and drainage vicinity of VAs than contrast-enhanced images (6 vs. 2 patients with VAs on the eloquent region). Patients with VAs adjacent to eloquent brain showed poorer outcomes than those who had VAs in non-eloquent areas (P = 0.005), while the CMs adjacent to eloquent brain did not correlated with poor outcomes (P = 0.15). Type I and III variants of VAs were also significantly associated with poor outcomes, compared with type II variant (P = 0.002). Careful evaluation of VAs variant type and the association between VAs and eloquent brain is helpful for the management of CMs associated with VAs. We recommend T2* GRE/SWI in patients with CMs to assess the associated VAs. The evaluation of VA drainage vicinity on T2* GRE/SWI would be more useful for designing treatment strategies and risk stratification. PMID- 26489408 TI - Modelling control of Schistosoma haematobium infection: predictions of the long term impact of mass drug administration in Africa. AB - BACKGROUND: Effective control of schistosomiasis remains a challenging problem for endemic areas of the world. Given knowledge of the biology of transmission and past experience with mass drug administration (MDA) programs, it is important to critically evaluate the likelihood that MDA programs will achieve substantial reductions in Schistosoma prevalence. In implementing the World Health Organization Roadmap for Neglected Tropical Diseases it would useful for policymaking to model projections of the status of Schistosoma control in MDA treated areas in the next 5-10 years. METHODS: Calibrated mathematical models were used to project the effects of different frequency and coverage of MDA for schistosomiasis haematobia control in present-day endemic communities, taking into account uncertainties of parasite biology and input data. The modeling approach in this analysis was the Stratified Worm Burden model developed in our earlier works, calibrated using data from longitudinal S. haematobium control trials in Kenya. RESULTS: Model-based simulations of MDA control in typical low risk and higher-risk communities indicated that infection prevalence can be substantially reduced within 10 years only when there is a high degree of community participation (>70 %) with at least annual MDA. Significant risk for re emergence of infection remains if MDA is suspended. CONCLUSIONS: In a stable (stationary) ecosystem, Schistosoma reproduction and transmission are sufficiently robust that the process of human infection continues, even under pressure from aggressive MDA. MDA alone is unlikely to interrupt transmission, and once mass treatment is suspended, the prevalence of human infection is likely to rebound to pre-control levels over a period of 25-30 years. MDA success in achieving very low levels of infection prevalence is highly dependent on treatment coverage and frequency within the local human population, and requires that both adults and children be included in drug delivery coverage. Ultimately, supplemental snail control and significant improvements in sanitation will be required to achieve full control of schistosomiasis by elimination of ongoing Schistosoma transmission. PMID- 26489409 TI - PALB2 mutations in breast cancer patients from a multi-ethnic region in northwest China. AB - BACKGROUND: Germline mutations in PALB2 gene make a small contribution to heritable breast cancer susceptibility. A recent report has revealed that women with mutations in the PALB2 gene were more than nine times as likely to develop breast cancer compared to those without. The aim of this study is to understand the status of PALB2 mutations among Chinese high-risk breast cancer patients in a multi-ethnic region in China. METHODS: 152 patients with hereditary predisposition to breast cancer from the Xinjing region of China were enrolled in the study, and 100 control samples from healthy women were collected in the same locality. We sequenced the coding sequences and flanking intronic regions of PALB2 gene from DNA samples obtained from all subjects by direct sequencing. RESULTS: A total of 4 deleterious PALB2 mutations were identified in 152 breast cancer patients with a prevalence of about 2.6 % (4/152). The PALB2 mutation prevalence was 3.2 % (3/95) in cases with family history of breast cancer. In addition to the four deleterious mutations, we identified nine missense variants in 12 patients, using the prediction Softwares SIFT and PolyPhen, four of which might be disease associated (in 5 patients). Two of the 4 patients with deleterious mutations and 2 of the 5 patients presenting putative deleterious missense mutations had triple-negative breast cancer. No PALB2 mutation carriers were identified in 100 healthy controls. CONCLUSION: PALB2 mutations account for a small, but not negligible, proportion of patients with hereditary predisposition to breast cancer in the Xinjing region of China. PMID- 26489410 TI - Comprehensive Characterization of AMP-Activated Protein Kinase Catalytic Domain by Top-Down Mass Spectrometry. AB - AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that is essential in regulating energy metabolism in all eukaryotic cells. It is a heterotrimeric protein complex composed of a catalytic subunit (alpha) and two regulatory subunits (beta and gamma). C-terminal truncation of AMPKalpha at residue 312 yielded a protein that is active upon phosphorylation of Thr172 in the absence of beta and gamma subunits, which is refered to as the AMPK catalytic domain and commonly used to substitute for the AMPK heterotrimeric complex in in vitro kinase assays. However, a comprehensive characterization of the AMPK catalytic domain is lacking. Herein, we expressed a His-tagged human AMPK catalytic domin (denoted as AMPKDelta) in E. coli, comprehensively characterized AMPKDelta in its basal state and after in vitro phosphorylation using top-down mass spectrometry (MS), and assessed how phosphorylation of AMPKDelta affects its activity. Unexpectedly, we found that bacterially-expressed AMPKDelta was basally phosphorylated and localized the phosphorylation site to the His-tag. We found that AMPKDelta had noticeable basal activity and was capable of phosphorylating itself and its substrates without activating phosphorylation at Thr172. Moreover, our data suggested that Thr172 is the only site phosphorylated by its upstream kinase, liver kinase B1, and that this phosphorylation dramatically increases the kinase activity of AMPKDelta. Importantly, we demonstrated that top-down MS in conjunction with in vitro phosphorylation assay is a powerful approach for monitoring phosphorylation reaction and determining sequential order of phosphorylation events in kinase-substrate systems. PMID- 26489411 TI - High-Resolution Ambient MS Imaging of Negative Ions in Positive Ion Mode: Using Dicationic Reagents with the Single-Probe. AB - We have used the Single-probe, a miniaturized sampling device utilizing in-situ surface microextraction for ambient mass spectrometry (MS) analysis, for the high resolution MS imaging (MSI) of negatively charged species in the positive ionization mode. Two dicationic compounds, 1,5-pentanediyl-bis(1 butylpyrrolidinium) difluoride [C5(bpyr)2F2] and 1,3-propanediyl bis(tripropylphosphonium) difluoride [C3(triprp)2F2], were added into the sampling solvent to form 1+ charged adducts with the negatively charged species extracted from tissues. We were able to detect 526 and 322 negatively charged species this way using [C5(bpyr)2F2] and [C3(triprp)2F2], respectively, including oleic acid, arachidonic acid, and several species of phosphatidic acid, phosphoethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and others. In conjunction with the identification of the non-adduct cations, we have tentatively identified a total number of 1200 and 828 metabolites from mouse brain sections using [C5(bpyr)2F2] and [C3(triprp)2F2], respectively, through high mass accuracy measurements (mass error <5 ppm); MS/MS analyses were also performed to verify the identity of selected species. In addition to the high mass accuracy measurement, we were able to generate high spatial resolution (~17 MUm) MS images of mouse brain sections. Our study demonstrated that utilization of dicationic compounds in the surface microextraction with the Single-probe device can perform high mass and spatial resolution ambient MSI measurements of broader types of compounds in tissues. Other reagents can be potentially used with the Single-probe device for a variety of reactive MSI studies to enable the analysis of species that are previously intractable. PMID- 26489412 TI - [The epigenome. Target for innovative therapies in head and neck carcinoma]. AB - BACKGROUND: The pathogenesis of head and neck squamous carcinoma (HNSCC) is a complex and multistage process, which is characterized by the accumulation of genetic and epigenetic aberrations. Most of our knowledge concerning the regulation of gene expression by the epigenome is based on changes in DNA methylation and post-translational histone modifications that affect the phenotypic plasticity of cells under physiological and pathological conditions. STATE OF THE ART: Numerous experimental studies have unraveled the impact of epigenetic alterations during initiation and malignant progression of HNSCC and substantiate their contribution in the context of tumor stem cells and treatment resistance. Due to their stability epigenetic modifications serve as promising diagnostic and prognostic biomarkers, and the reversible nature makes key regulators attractive targets for innovative treatment options. PMID- 26489413 TI - Clinical efficiency of Piezo-ICSI using micropipettes with a wall thickness of 0.625 MUm. AB - PURPOSE: The purposes of the present study are to assess the clinical efficiency of Piezo-intracytoplasmic sperm injection (ICSI) and to improve the Piezo-ICSI method for human oocytes. METHODS: We examined three ICSI methods to determine their clinical efficiency by comparing the survival, fertilization, good-quality day-3 embryo, pregnancy, and live birth rates. The three ICSI methods tested were conventional ICSI (CI) (using beveled spiked micropipettes with a wall thickness of 1 MUm), conventional Piezo-ICSI (CPI) (using flat-tipped micropipettes with a wall thickness of 0.925 MUm), and improved Piezo-ICSI (IPI) (using flat-tipped micropipettes with a wall thickness of 0.625 MUm). We collectively investigated 2020 mature oocytes retrieved from 437 patients between October 2010 and January 2014. RESULTS: The survival rates after CI, CPI, and IPI were 90, 95, and 99 %, respectively. The fertilization rates after CI, CPI, and IPI were 68, 75, and 89 %, respectively. The good-quality day-3 embryo rates after CI, CPI, and IPI were 37, 43, and 55 %, respectively. The pregnancy rates after the transfer of good quality day-3 embryo of CI, CPI, and IPI were 19, 21, and 31 %, respectively. The live birth rates of CI, CPI, and IPI were 15, 16, and 25 %, respectively. Significantly higher survival, fertilization, good-quality day-3 embryo, pregnancy, and live birth rates were obtained using IPI. CONCLUSIONS: When comparing the IPI to the CI and CPI, the results revealed that the Piezo-ICSI using flat-tipped micropipettes with a wall thickness of 0.625 MUm significantly improves survival, fertilization, good-quality day-3 embryo, pregnancy, and live birth rates. PMID- 26489414 TI - Elective single-embryo transfer improves cumulative pregnancy outcome in young patients but not in women of advanced reproductive age. AB - PURPOSE: The purpose of the present study is to assess the significance of elective single-embryo transfer (eSET) in older women. METHODS: The outcomes of assisted reproductive technology between 2001 and 2013 at single institution were retrospectively evaluated. Cumulative live birth rates (CLBRs) in one oocyte retrieval cycle were compared between those who underwent eSET and multiple embryo transfer (MET) in fresh cycles. RESULTS: The outcomes of 429 eSET cycles and 965 MET cycles were compared. CLBRs in eSET were higher than those of MET in women under 37 and were comparable in women aged 37 and over. The analysis of the outcomes separately in three age subgroups showed a significantly higher CLBR in young eSET (aged under 37) than that in young MET and similar CLBR between older (aged 37-40 and over 40) eSET and MET. Multiple birth rates were lower in eSET in all age groups. Multivariate logistic regression analyses showed that, in women aged under 37, number of frozen embryos, presence of good-quality embryos, and eSET were significantly related to cumulative live birth. In women aged between 37 and 40, age and number of frozen embryos were significantly related, while eSET was not. CONCLUSIONS: eSET in women under 37 resulted in increased CLBR compared with MET. In women aged between 37 and 40, CLBR in eSET group was similar with that in MET group. In both age groups, eSET reduced multiple birth rates. The significance of eSET in older women is limited presently, and further research on the strategy to improve cumulative outcomes is necessary. PMID- 26489416 TI - Impact of temperature-humidity index on egg-laying characteristics and related stress and immunity parameters of Japanese quails. AB - The aim of this study was to investigate the effect of temperature-humidity index (THI) level on productive parameters, welfare, and immunity in Japanese quails. One hundred and eighty (180) birds of Japanese quail, 14 weeks old, were used. Birds were divided randomly into three equal groups, control (at low THI, less than 70), H1 (at moderate THI, 70-75), and H2 (at high THI, 76-80). Birds in the control group had higher body weight (281.2 g, p = 0.001), egg mass (745 g, p = 0.001), fertility (85.4 %, p = 0.039), hatchability (80.4 %, p = 0.001), and immune response titer to Newcastle disease virus (p = 0.031), compared with H2 group. Furthermore, the thermoneutral group had higher internal egg quality score [albumen height (5.14 mm, p = 0.001), yolk height (10.88 mm, p = 0.015), yolk index (42.32 %, p = 0.039), and Haugh unit (92.67, p = 0.001)]. Nevertheless, there were no significant differences in fertility percentage, immune response, and corticosterone concentration between control and H1 group. Birds in the H2 group had the lowest total leucocytic count and lymphocyte percentage (p = 0.001 and 0.020, respectively) but the highest H/L ratio (0.83, p = 0.001). Corticosterone concentration was lower in control and H1 groups (5.49 and 6.41 ng/mL, respectively, p = 0.024) than that in H2 group. Japanese quail exposed to heat stress revealed drop in production and immunological parameters, as well as a detrimental effects on welfare. Thus, practical approaches might be used to reduce the detrimental effects of greater THI level. PMID- 26489417 TI - Dynamically downscaling predictions for deciduous tree leaf emergence in California under current and future climate. AB - Models that predict the timing of deciduous tree leaf emergence are typically very sensitive to temperature. However, many temperature data products, including those from climate models, have been developed at a very coarse spatial resolution. Such coarse-resolution temperature products can lead to highly biased predictions of leaf emergence. This study investigates how dynamical downscaling of climate models impacts simulations of deciduous tree leaf emergence in California. Models for leaf emergence are forced with temperatures simulated by a general circulation model (GCM) at ~200-km resolution for 1981-2000 and 2031-2050 conditions. GCM simulations are then dynamically downscaled to 32- and 8-km resolution, and leaf emergence is again simulated. For 1981-2000, the regional average leaf emergence date is 30.8 days earlier in 32-km simulations than in ~200-km simulations. Differences between the 32 and 8 km simulations are small and mostly local. The impact of downscaling from 200 to 8 km is ~15 % smaller in 2031-2050 than in 1981-2000, indicating that the impacts of downscaling are unlikely to be stationary. PMID- 26489415 TI - Opioid substitution and antagonist therapy trials exclude the common addiction patient: a systematic review and analysis of eligibility criteria. AB - BACKGROUND: Eligibility criteria that result in the exclusion of a substantial number of patients from randomized trials jeopardize the generalizability of treatment effect to much of the clinical population. This is important when evaluating opioid substitution and antagonist therapies (OSATs), especially given the challenges associated with treating the opioid-dependent population. We aimed to identify OSAT trials' eligibility criteria, quantify the percentage of the clinical population excluded by these criteria, and determine how OSAT guidelines incorporate evidence from these trials. METHODS: We performed a systematic review to identify the eligibility criteria used across trials. We searched Medline, EMBASE, PsycINFO, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry (CTR), World Health Organization International CTR Platform Search Portal, and the National Institutes of Health CTR databases from inception to January 1, 2014. To quantify the effect of trials' eligibility criteria on generalizability, we applied these criteria to data from an observational study of opioid-dependent patients (n = 394). We then accessed the Canadian, American, British, and World Health Organization (WHO) OSAT guidelines to evaluate how evidence is used in the recommendations. RESULTS: Among the 60 trials identified the majority (>=50 % of trials) exclude patients with psychiatric (60 %) and physical comorbidity (51.7 %). Additionally, we found 19 trials exclude patients with current alcohol/substance-use problems (31.7 %), and 29 (48.3 %) exclude patients taking psychotropic medications. These criteria were restrictive and in some cases rendered 70 % of the observational sample ineligible. North American OSAT guidelines made strong recommendations supported by evidence with poor generalizability. National Institute of Health and Care Excellence (NICE) and WHO guidelines for opioid misuse provide a critical assessment of the literature used to inform their recommendations. CONCLUSIONS: Trials assessing OSATs often exclude patients with concurrent disorders. If the excluded patients respond differently to treatment, results from these trials are likely to overestimate the true effectiveness of OSATs. North American guidelines should consider these limitations when drafting clinical recommendations. PMID- 26489418 TI - Evaluating the role of a trypsin inhibitor from soap nut (Sapindus trifoliatus L. Var. Emarginatus) seeds against larval gut proteases, its purification and characterization. AB - BACKGROUND: The defensive capacities of plant protease Inhibitors (PI) rely on inhibition of proteases in insect guts or those secreted by microorganisms; and also prevent uncontrolled proteolysis and offer protection against proteolytic enzymes of pathogens. METHODS: An array of chromatographic techniques were employed for purification, homogeneity was assessed by electrophoresis. Specificity, Ki value, nature of inhibition, complex formation was carried out by standard protocols. Action of SNTI on insect gut proteases was computationally evaluated by modeling the proteins by threading and docking studies by piper using Schrodinger tools. RESULTS: We have isolated and purified Soap Nut Trypsin Inhibitor (SNTI) by acetone fractionation, ammonium sulphate precipitation, ion exchange and gel permeation chromatography. The purified inhibitor was homogeneous by both gel filtration and polyacrylamide gel electrophoresis (PAGE). SNTI exhibited a molecular weight of 29 kDa on SDS-PAGE, gel filtration and was negative to Periodic Acid Schiff's stain. SNTI inhibited trypsin and pronase of serine class. SNTI demonstrated non-competitive inhibition with a Ki value of 0.75 +/- 0.05*10-10 M. The monoheaded inhibitor formed a stable complex in 1:1 molar ratio. Action of SNTI was computationally evaluated on larval gut proteases from Helicoverpa armigera and Spodoptera frugiperda. SNTI and larval gut proteases were modeled and docked using Schrodinger software. Docking studies revealed strong hydrogen bond interactions between Lys10 and Pro71, Lys299 and Met80 and Van Der Waals interactions between Leu11 and Cys76amino acid residues of SNTI and protease from H. Armigera. Strong hydrogen bonds were observed between SNTI and protease of S. frugiperda at positions Thr79 and Arg80, Asp90 and Gly73, Asp2 and Gly160 respectively. CONCLUSION: We conclude that SNTI potentially inhibits larval gut proteases of insects and the kinetics exhibited by the protease inhibitor further substantiates its efficacy against serine proteases. PMID- 26489419 TI - SIS and SIR Epidemic Models Under Virtual Dispersal. AB - We develop a multi-group epidemic framework via virtual dispersal where the risk of infection is a function of the residence time and local environmental risk. This novel approach eliminates the need to define and measure contact rates that are used in the traditional multi-group epidemic models with heterogeneous mixing. We apply this approach to a general n-patch SIS model whose basic reproduction number [Formula: see text] is computed as a function of a patch residence-time matrix [Formula: see text]. Our analysis implies that the resulting n-patch SIS model has robust dynamics when patches are strongly connected: There is a unique globally stable endemic equilibrium when [Formula: see text], while the disease-free equilibrium is globally stable when [Formula: see text]. Our further analysis indicates that the dispersal behavior described by the residence-time matrix [Formula: see text] has profound effects on the disease dynamics at the single patch level with consequences that proper dispersal behavior along with the local environmental risk can either promote or eliminate the endemic in particular patches. Our work highlights the impact of residence-time matrix if the patches are not strongly connected. Our framework can be generalized in other endemic and disease outbreak models. As an illustration, we apply our framework to a two-patch SIR single-outbreak epidemic model where the process of disease invasion is connected to the final epidemic size relationship. We also explore the impact of disease-prevalence-driven decision using a phenomenological modeling approach in order to contrast the role of constant versus state-dependent [Formula: see text] on disease dynamics. PMID- 26489420 TI - Immobilization of inorganic pyrophosphatase on nanodiamond particles retaining its high enzymatic activity. AB - Nanodiamond (ND) particles are popular platforms for the immobilization of molecular species. In the present research, enzyme Escherichia coli inorganic pyrophosphatase (PPase) was immobilized on detonation ND through covalent or noncovalent bonding and its enzymatic activity was characterized. Factors affecting adsorption of PPase such as ND size and surface chemistry were studied. The obtained material is a submicron size association of ND particles and protein molecules in approximately equal amounts. Both covalently and noncovalently immobilized PPase retains a significant enzymatic activity (up to 95% of its soluble form) as well as thermostability. The obtained hybrid material has a very high enzyme loading capacity (~1 mg mg(-1)) and may be considered as a promising delivery system of biologically active proteinaceous substances, particularly in the treatment of diseases such as calcium pyrophosphate crystal deposition disease and related pathologies. They can also be used as recoverable heterogeneous catalysts in the traditional uses of PPase. PMID- 26489421 TI - Perceptions of the preparedness of medical graduates for internship responsibilities in district hospitals in Kenya: a qualitative study. AB - BACKGROUND: Aga Khan University is developing its undergraduate medical education curriculum for East Africa. In Kenya, a 1 year internship is mandatory for medical graduates' registration as practitioners. The majority of approved internship training sites are at district hospitals. The purposes of this study were to determine: (1) whether recent Kenyan medical graduates are prepared for their roles as interns in district hospitals upon graduation from medical school; (2) what working and training conditions and social support interns are likely to face in district hospital; and (3) what aspects of the undergraduate curriculum need to be addressed to overcome perceived deficiencies in interns' competencies. METHODS: Focus group discussions and semi-structured interviews were conducted with current interns and clinical supervisors in seven district hospitals in Kenya. Perceptions of both interns and supervisors regarding interns' responsibilities and skills, working conditions at district hospitals, and improvements required in medical education were obtained. RESULTS: Findings included agreement across informants on deficiencies in interns' practical skills and experience of managing clinical challenges. Supervisors were generally critical regarding interns' competencies, whereas interns were more specific about their weaknesses. Supervisor expectations were higher in relation to surgical procedures than those of interns. There was agreement on the limited learning, clinical facilities and social support available at district hospitals including, according to interns, inadequate supervision. Supervisors felt they provided adequate supervision and that interns lacked the ability to initiate communication with them. Both groups indicated transition challenges from medical school to medical practice attributable to inadequate practical experience. They indicated the need for more direct patient care responsibilities and clinical experience at a district hospital during undergraduate training. CONCLUSION: Perception of medical graduates' unpreparedness seemed to stem from a failure to implement the apprenticeship model of learning in medical school and lack of prior exposure to district hospitals. These findings will inform curriculum development to meet stakeholder requirements, improve the quality of graduates, and increase satisfaction with transition to practice. PMID- 26489422 TI - Evaluation of the role of HLA-DR antigens in Japanese type 1 autoimmune hepatitis. AB - BACKGROUND: The role of HLA-DR antigens in the clinicopathological features of autoimmune hepatitis (AIH) is not clearly understood. We examined the implications of HLA-DR antigens in Japanese AIH, including the effect of HLA-DR4 on the age and pattern of AIH onset, clinicopathological features, and treatment efficacy. METHODS: A total of 132 AIH patients consecutively diagnosed and treated in 2000-2014 at 2 major hepatology centers of eastern Tokyo district were the subjects of this study. The frequency of HLA-DR phenotypes was compared with that in the healthy Japanese population. AIH patients were divided into HLA-DR4 positive or HLA-DR4-negative groups and further sub-classified into elderly and young-to-middle-aged groups, and differences in clinical and histological features were examined. Clinical features associated with the response to immunosuppressive therapy were also determined. RESULTS: The frequency of the HLA DR4 phenotype was significantly higher in AIH than in control subjects (59.7 % vs. 41.8 %, P < 0.001), and the relative risk was 2.14 (95 % CI; 1.51-3.04). HLA DR4-positive AIH patients were younger than HLA-DR4-negative patients (P = 0.034). Serum IgG and IgM levels were higher (P < 0.001 and P = 0.007, respectively) in HLA-DR4-positive patients. These differences were more prominent in elderly AIH patients. However, there was no difference in IgG and IgM levels between HLA-DR4-positive and HLA-DR4-negative patients of the young-to-middle aged group. There were no differences in the histological features. In patients with refractory to immunosuppressive therapy, higher total bilirubin, longer prothrombin time, lower serum albumin, and lower platelet count were found. Imaging revealed splenomegaly to be more frequent in refractory patients than in non-refractory patients (60.0 % vs. 30.8 %, P = 0.038). HLA-DR phenotype distribution was similar regardless of response to immunosuppressive therapy. CONCLUSIONS: HLA-DR4 was the only DR antigen significantly associated with Japanese AIH. The clinical features of HLA-DR4-positive AIH differed between elderly patients and young-to-middle-aged patients. Treatment response depended on the severity of liver dysfunction but not on HLA-DR antigens. PMID- 26489423 TI - The effect of EGB on proliferation of gastric carcinoma SGC7901 cells. AB - OBJECTIVE: To investigate the effect of Ginkgo biloba extract (EGB) on the proliferation and cell cycles of gastric carcinoma SGC7901 cells, and make a preliminary exploration on possible molecular mechanisms associated with its inhibitory effect. METHODS: Human gastric carcinoma SGC7901 cells were cultured in vitro, and treated with various concentrations (100, 200, 300, 400 mg/L) of EGB for different incubation periods (24, 48 and 72 h). CCK-8 assay was used to detect cell proliferation and flow cytometry was performed to analyze the effect of EGB on cell cycles. In addition, mRNA and protein level of two cell cycle regulators cyclin D1 and c-myc in SGC7901 cells treated with EGB were determined using PCR and Western blot. And subcutaneous xenograft model of gastric carcinoma in nude mice was established to evaluate the anti-cancer effect of EGB in vivo. RESULTS: The proliferation of gastric carcinoma SGC7901 cells was inhibited by EGB in dose- and time-dependent manner. Flow cytometry showed cell cycle arrest in EGB-treated cells, with increased percentage of cells in G1 phase and decreased percentage in S stage. In addition, the mRNA and protein level of cyclin D1 and c-myc genes were significantly down-regulated in cells with EGB treatment with the concentration increasing. CONCLUSION: EGB conferred an inhibitory effect on the proliferation of gastric carcinoma SGC7901 cells both in vitro and in vivo. The inhibitory effect was dose dependent and possibly depended on inhibiting cell cycle through G1 arrest induction by suppressing cyclin D1 and c-myc expression. PMID- 26489424 TI - Landscape of early clinical trials for childhood and adolescence cancer in Spain. AB - PURPOSE: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. METHODS: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. RESULTS: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. CONCLUSIONS: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer. PMID- 26489425 TI - CCR6 overexpression predicted advanced biological behaviors and poor prognosis in patients with gastric cancer. AB - BACKGROUND: CCR6 expression is deregulated in some human malignancies and may be involved in the tumor progression. The aim of the present study was to determine the CCR6 expression in gastric cancer (GC) and to clarify its clinical significance. METHODS: We used western blotting to examine CCR6 protein expression in GC tissues and matched adjacent non-tumor tissues. Immunohistochemistry was performed on a large cohort of 372 postoperative GC samples. Chi-square test, Kaplan-Meier analysis and Cox regression model were used to analyze the data. RESULTS: Upregulated CCR6 protein expression was observed in the GC tissues by western blotting compared with the adjacent non cancerous gastric tissues. High CCR6 expression was detected in 56.5 % (210/372) samples and significantly associated with the extracapsular extension of the tumor, tumor relapse and poor overall survival in GC (P < 0.001). Further analysis demonstrated that the CCR6 expression level stratified the patient outcome in stage II, stage III, T3/4, N positive and poorly differentiated/undifferentiated tumor subgroups. The Cox regression analysis showed that high expression of CCR6 was an independent prognostic factor for GC patients. CONCLUSIONS: CCR6 expression may be a novel biomarker for predicting clinical outcomes for GC patients. PMID- 26489427 TI - BMJ editor writes to Hunt over misuse of weekend mortality data. PMID- 26489426 TI - Recommendations in the management of epithelial appendiceal neoplasms and peritoneal dissemination from mucinous tumours (pseudomyxoma peritonei). AB - The epithelial appendiceal neoplasms are uncommon and are usually detected as an unexpected surgical finding. The general surgeon should be aware of the diversity of its clinical manifestations and biological behaviors along with the significance of the surgical treatment on the progression of the illness and the prognosis of the patients. The operative findings and, especially, tumor histology, determine the type of surgery. Intestinal histologic subtype behaves and should be treated similarly to the right colon neoplasms; while mucinous tumors, often discordant between histology and its aggressiveness, can be treated with a simple appendectomy or require complex oncological surgeries. Mucinous tumors are often associated with the presence of mucin or tumor implants in the abdominal cavity, being the clinical syndrome known as pseudomyxoma peritonei (PMP). PMP tends to present an indolent but deadly evolution and requires a multimodal approach as a single treatment with curative potential: complete cytoreductive surgery plus hyperthermic Intra-peritoneal chemotherapy (CCRS + HIPEC) now considered the standard of care in this pathology. The general surgeon should be aware of the governing principles of the treatment of appendiceal neoplasms with or without peritoneal dissemination, know the therapeutic frontiers in every situation (avoiding unnecessary or counterproductive surgeries) and sending early these patients to specialised centres in the radical management of malignant diseases of the peritoneum in the conditions and with the necessary information to facilitate a possible radical treatment. PMID- 26489429 TI - Conflicts in serving both non-profit and for-profit medical centres. PMID- 26489428 TI - Host lung immunity is severely compromised during tropical pulmonary eosinophilia: role of lung eosinophils and macrophages. AB - Eosinophils play a central role in the pathogenesis of tropical pulmonary eosinophilia, a rare, but fatal, manifestation of filariasis. However, no exhaustive study has been done to identify the genes and proteins of eosinophils involved in the pathogenesis of tropical pulmonary eosinophilia. In the present study, we established a mouse model of tropical pulmonary eosinophilia that mimicked filarial manifestations of human tropical pulmonary eosinophilia pathogenesis and used flow cytometry-assisted cell sorting and real-time RT-PCR to study the gene expression profile of flow-sorted, lung eosinophils and lung macrophages during tropical pulmonary eosinophilia pathogenesis. Our results show that tropical pulmonary eosinophilia mice exhibited increased levels of IL-4, IL 5, CCL5, and CCL11 in the bronchoalveolar lavage fluid and lung parenchyma along with elevated titers of IgE and IgG subtypes in the serum. Alveolar macrophages from tropical pulmonary eosinophilia mice displayed decreased phagocytosis, attenuated nitric oxide production, and reduced T-cell proliferation capacity, and FACS-sorted lung eosinophils from tropical pulmonary eosinophilia mice upregulated transcript levels of ficolin A and anti-apoptotic gene Bcl2,but proapoptotic genes Bim and Bax were downregulated. Similarly, flow-sorted lung macrophages upregulated transcript levels of TLR-2, TLR-6, arginase-1, Ym-1, and FIZZ-1 but downregulated nitric oxide synthase-2 levels, signifying their alternative activation. Taken together, we show that the pathogenesis of tropical pulmonary eosinophilia is marked by functional impairment of alveolar macrophages, alternative activation of lung macrophages, and upregulation of anti apoptotic genes by eosinophils. These events combine together to cause severe lung inflammation and compromised lung immunity. Therapeutic interventions that can boost host immune response in the lungs might thus provide relief to patients with tropical pulmonary eosinophilia. PMID- 26489430 TI - Optimizing and validating the technical infrastructure of a novel tele-cystoscopy system. AB - INTRODUCTION: Bladder cancer is the most costly malignancy to manage per capita due to the technical nature and intensity of follow-up. There are few urologists in rural areas, often necessitating that patients travel hours to receive follow up care multiple times per year. We plan to train registered nurses and allied health professionals to perform cystoscopies which are monitored and interpreted in real-time by board-certified urologists. The key is to ensure optimal picture resolution to guarantee this technology is not inferior to traditional cystoscopy. Our objective was to develop the technical infrastructure needed for a tele-cystoscopy system through assessment of the transmitted video quality using expert reviewers and crowd-sourcing. METHODS: All combinations of the tele cystoscopy system were systematically tested using a single Thiel cadaver. The videos were reviewed by expert urologists and general reviewers using a crowd sourcing website. The video quality responses were assessed to determine concordance between each set of reviewers, and to determine the optimal equipment that should be selected for the tele-cystoscopy system. RESULTS: Of eight equipment combinations, only two were of high enough quality to be appropriate for medical use. We found there to be strong concordance of responses between the expert and crowd-sourced responses. The trade-offs between cost and tele cystoscopy system component quality were compared with efficiency frontiers to elucidate the optimal system. DISCUSSION: We created and tested the feasibility of a tele-cystoscopy system that was deemed suitable for medical diagnosis by a group of experts. We further validated tele-cystoscopy video quality using both experts and recently validated crowd-sourcing. PMID- 26489433 TI - Mapping Unhealthy Behavior Among Economically Active Men Using GIS in Suburban and Rural Areas of Sri Lanka. AB - The burden of noncommunicable diseases (NCDs) and certain behavioral risk factors related to NCDs (unhealthy behaviors) are becoming more common. This survey aims to map out such common unhealthy behaviors among all men 35 to 50 years old in a Medical Officer of Health area in the Western Province of Sri Lanka using a geographical information system (GIS) and an interviewer administered questionnaire by visiting all households in the study area. Data were analyzed with ARC GIS and SPSS software. Geographical areas where men with unhealthy behaviors cluster together (clusters) were identified and visually and statistically related to locations of schools, places of religious worship, and factories in the area. It was revealed that clusters of unhealthy behaviors are mostly seen in areas with less population density. Smoking and alcohol are clustering in estate areas occupied by Tamils. This way GIS mapping could be used to identify and reduce the burden of NCDs by visualizing clusters and how certain locations affect their spread. PMID- 26489431 TI - Increased male fertility using fertility-related biomarkers. AB - Conventional semen analyses are used to evaluate male factor fertility/infertility in humans and other animals. However, their clinical value remains controversial. Therefore, new tools that more accurately assess male fertility based on sperm function and fertilization mechanism are of interest worldwide. While protein markers in spermatozoa that might help differentiate fertile and infertile sperm have been identified, studies are in their infancy, and the markers require validation in field trials. In the present study, to discover more sensitive biomarkers in spermatozoa for predicting male fertility, we assessed protein expression in capacitated spermatozoa. The results demonstrated that cytochrome b-c1 complex subunit 2 (UQCRC2) was abundantly expressed in high-litter size spermatozoa (>3-fold). On the other hand, equatorin, beta-tubulin, cytochrome b-c1 complex subunit 1 (UQCRC1), speriolin, Ras-related protein Rab-2A (RAB2A), spermadhesin AQN-3, and seminal plasma sperm motility inhibitor were abundantly expressed in low-litter size spermatozoa (>3 fold). Moreover, RAB2A and UQCRC1 expression negatively correlated with litter size, while UQCRC2 expression positively correlated with litter size. Finally, the putative biomarkers predicted litter size in field trials. Our study suggests that biomarkers present in spermatozoa after capacitation can help differentiate superior male fertility from below-average fertility with high sensitivity. PMID- 26489434 TI - Differentiation of Isodon japonica and Adulterants Based on Identification and Quantitation 14 Diterpenoids Using LC-MS-MS Library Search Approach and Hierarchical Cluster Analysis. AB - The aim of this study was to investigate the chemical differences between genunine Isodon japonica and its adulterants. A linear ion trap liquid chromatography with tandem mass spectrometry analytical method has been developed for the identification and quantification of 14 major diterpenoids in I. japonica. Data acquisition was multiple reaction monitoring transitions mode followed by an information-dependent acquisition using the enhanced product ion (EPI) scan in a single run. The target compounds were further identified and confirmed using an EPI spectral library. Overall validation of the assay was carried out including linearity, accuracy, precision, limits of detection and quantification. The results demonstrated that the method was selective, sensitive and reliable. The determination results of 21 batches of I. japonica and adulterants were then analyzed and differentiated by hierarchical clustering analysis. PMID- 26489435 TI - Structural Analysis and Quantitative Determination of Clevidipine Butyrate Impurities Using an Advanced RP-HPLC Method. AB - Eleven potential impurities, including process-related compounds and degradation products, have been analyzed by comprehensive studies on the manufacturing process of clevidipine butyrate. Possible formation mechanisms could also be devised. MS and NMR techniques have been used for the structural characterization of three previously unreported impurities (Imp-3, Imp-5 and Imp-11). To separate and quantify the potential impurities in a simultaneous fashion, an efficient and advanced RP-HPLC method has been developed. In doing so, four major degradation products (Imp-2, Imp-4, Imp-8 and Imp-10) can be observed under varying stress conditions. This analytical method has been validated according to ICH guidelines with respect to specificity, accuracy, linearity, robustness and stability. The method described has been demonstrated to be applicable in routine quality control processes and stability evaluation studies of clevidipine butyrate. PMID- 26489436 TI - Dynamic control of light emission faster than the lifetime limit using VO2 phase change. AB - Modulation is a cornerstone of optical communication, and as such, governs the overall speed of data transmission. Currently, the two main strategies for modulating light are direct modulation of the excited emitter population (for example, using semiconductor lasers) and external optical modulation (for example, using Mach-Zehnder interferometers or ring resonators). However, recent advances in nanophotonics offer an alternative approach to control spontaneous emission through modifications to the local density of optical states. Here, by leveraging the phase-change of a vanadium dioxide nanolayer, we demonstrate broadband all-optical direct modulation of 1.5 MUm emission from trivalent erbium ions more than three orders of magnitude faster than their excited state lifetime. This proof-of-concept demonstration shows how integration with phase change materials can transform widespread phosphorescent materials into high speed optical sources that can be integrated in monolithic nanoscale devices for both free-space and on-chip communication. PMID- 26489437 TI - Personality and morphological traits affect pigeon survival from raptor attacks. AB - Personality traits have recently been shown to impact fitness in different animal species, potentially making them similarly relevant drivers as morphological and life history traits along the evolutionary pathways of organisms. Predation is a major force of natural selection through its deterministic effects on individual survival, but how predation pressure has helped to shape personality trait selection, especially in free-ranging animals, remains poorly understood. We used high-precision GPS tracking to follow whole flocks of homing pigeons (Columba livia) with known personalities and morphology during homing flights where they were severely predated by raptors. This allowed us to determine how the personality and morphology traits of pigeons may affect their risk of being predated by raptors. Our survival model showed that individual pigeons, which were more tolerant to human approach, slower to escape from a confined environment, more resistant to human handling, with larger tarsi, and with lighter plumage, were more likely to be predated by raptors. We provide rare empirical evidence that the personality of prey influences their risk of being predated under free-ranging circumstances. PMID- 26489438 TI - Developmental clock compromises human twin model created by embryo splitting. AB - STUDY QUESTION: Is the quality of the human embryos generated by twinning in vitro comparable to the quality of the embryos created by fertilization? SUMMARY ANSWER: Our data suggest that the human twin embryos created in vitro are unsuitable not only for clinical use but also for research purposes. WHAT IS KNOWN ALREADY: Pregnancy from in vitro generated monozygotic twins by embryo splitting or twinning leads to live birth of healthy animals. Similar strategies, however, have been less successful in primates. Recent reports suggest that the splitting of human embryos might result in viable, morphologically adequate blastocysts, although the qualitative analyses of the embryos created in such a way have been very limited. STUDY DESIGN, SIZE, DURATION: This study was a comparative analysis of embryos generated by twinning in vitro and the embryos created by in vitro fertilization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analysed morphokinetics and developmental competence of 176 twin embryos created by splitting of 88 human embryos from either early (2-5 blastomeres, n = 43) or late (6-10 blastomeres, n = 45) cleavage stages. We compared the data with morphometrics of embryos created by in vitro fertilization and resulting in pregnancy and live birth upon single blastocyst transfer (n = 42). MAIN RESULTS AND THE ROLE OF CHANCE: The morphokinetic data suggested that the human preimplantation development is subjected to a strict temporal control. Due to a 'developmental clock', the size of twin embryos was proportionate to the number of cells used for their creation. Furthermore, the first fate decision was somewhat delayed; the inner cell mass (ICM) became distinguishable later in the twin than in the normal blastocysts obtained through fertilization. If an ICM was present at all, it was small and of poor quality. The majority of the cells in the twin embryos expressed ICM and trophectoderm markers simultaneously. LIMITATIONS, REASONS FOR CAUTION: We created monozygotic twins by blastomere separation from cleavage stage embryos. Embryo twinning by blastocyst bisection may circumvent limitations set by the developmental clock. WIDER IMPLICATIONS OF THE FINDINGS: Taken together, our data suggest that the human twin embryos created in vitro are unsuitable not only for clinical use but also for research purposes. PMID- 26489439 TI - The necessity to define the sub-optimal responders. PMID- 26489440 TI - Reply: Is it necessary to recognize the sub-optimal responder. PMID- 26489441 TI - High-level production of violacein by the newly isolated Duganella violaceinigra str. NI28 and its impact on Staphylococcus aureus. AB - A violacein-producing bacterial strain was isolated and identified as a relative of Duganella violaceinigra YIM 31327 based upon phylogenetic analyses using the 16S rRNA, gyrB and vioA gene sequences and a fatty acid methyl ester (FAME) analysis. This new strain was designated D. violaceinigra str. NI28. Although these two strains appear related based upon these analyses, the new isolate was phenotypically different from the type strain as it grew 25% faster on nutrient media and produced 45-fold more violacein. When compared with several other violacein producing strains, including Janthinobacterium lividum, D. violaceinigra str. NI28 was the best violacein producer. For instance, the crude violacein yield with D. violaceinigra str. NI28 was 6.0 mg/OD at 24 hours, a value that was more than two-fold higher than all the other strains. Finally, the antibacterial activity of D. violaceinigra str. NI28 crude violacein was assayed using several multidrug resistant Staphylococcus aureus. Addition of 30 MUM crude violacein led to a 96% loss in the initial S. aureus population while the minimum inhibitory concentration was 1.8 MUM. Consequently, this novel isolate represents a phenotypic variant of D. violaceinigra capable of producing much greater quantities of crude violacein, an antibiotic effective against multidrug resistant S. aureus. PMID- 26489442 TI - A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. PMID- 26489443 TI - Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer. AB - BACKGROUND: A trial-level surrogate end point for a randomized clinical trial may allow assessment of the relative benefits of the treatment to be performed at an earlier time point and potentially with a smaller sample size. However, determining whether an end point is a reliable trial-level surrogate based on results of previous trials is not straightforward. The question of trial-level surrogacy is easily confused with the question of individual-level surrogacy, and this confusion can lead to controversy. A recent example concerns the evaluation of pathologic complete response (pCR) as a surrogate for event-free survival (EFS) and overall survival (OS) in early-stage breast cancer. MATERIALS AND METHODS: The differences between individual-level surrogacy (i.e. for patients receiving a specific treatment, the surrogate end point predicts the definitive end point) and trial-level surrogacy (the results of the trial for the surrogate end point predict the results of the trial for the definitive end point) are discussed. Trial-level data used in two previous meta-analyses evaluating pCR as a trial-level surrogate for EFS and OS were re-analyzed using methods that appropriately account for the variability in pCR rates as well as the variability in the hazard ratios for EFS and OS. RESULTS: There is no evidence that pCR is a trial-level surrogate for EFS or OS, nor is there evidence that pCR could be used reliably to screen out nonpromising agents from further drug development. CONCLUSIONS: At present, neoadjuvant RCTs should continue to follow patients to observe EFS and OS to assess clinical benefit, and they should be designed with sufficient sample size to reliably assess EFS. However, one cannot rule out the possibility that future meta-analyses involving more trials and in which the patient population or class of treatments is restricted could suggest the validity of pCR as a trial-level surrogate for EFS or OS in some focused settings. PMID- 26489444 TI - Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK: insights from the RECCORD registry. AB - BACKGROUND: The aim of the RECCORD registry was to gather real-world UK data on the use of targeted therapies in renal cell carcinoma (RCC) and assess clinical outcomes. Here, demographic and outcome data are presented with the treatment patterns and demographic profile of patients on the registry. PATIENTS AND METHODS: Patients were retrospectively identified at seven UK hospitals with large cancer centres in England (5), Scotland (1) and Wales (1). Anonymised data were collected through an online registry covering demographics, treatments and outcomes. Five hundred and fourteen UK adult patients with metastatic RCC were included in the study for analysis. Patients were included if they were treated for metastatic RCC at one of the seven centres, and started systemic anti-cancer treatment from March 2009 to November 2012 inclusive. In addition to demographic factors, the principal outcome measures were overall survival (OS), time to disease progression and toxicity. RESULTS: The majority of first-line treatment was with sunitinib; first-line use of pazopanib increased as the study progressed. 15.8% of patients received second-line treatment, half of whom were prescribed everolimus. Median OS (from initiation of first-line treatment) was 23.9 months (95% confidence interval [CI] 18.6-29.1 months), similar to that reported for clinical trials of targeted RCC therapies [Ljungberg B, Campbell SC, Choi HY et al. The epidemiology of renal cell carcinoma. Eur Urol 2011; 60: 615 621; Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol 2013; 20: 944-955; Motzer RJ, Hutson TE, Tomczak P et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584 3590]. OS was significantly longer for those who received second-line treatment after disease progression (33.0 months; 95% CI 30.8-35.2 months) than those who did not (20.9 months; 95% CI 16.4-25.3 months; P = 0.008). CONCLUSIONS: RECCORD is a large 'real-world' database assessing metastatic RCC treatment patterns and outcomes. Treatment patterns changed over time as targeted therapies were approved and became widely available; survival data in RECCORD are consistent with those reported for systemic treatments in clinical trials. Kaplan-Meier analysis of results demonstrated that receiving second-line therapy was a major prognostic factor for longer OS. PMID- 26489445 TI - Comprehensive analyses using next-generation sequencing and immunohistochemistry enable precise treatment in advanced gastric cancer. AB - BACKGROUND: In advanced gastric cancer (AGC), most clinical trials are designed on the basis of protein expression or gene amplification of specific genes. Recently, next-generation sequencing (NGS) allowed us to comprehensively profile the tumor gene status. This study aimed to elucidate the profiling between gene alterations and protein expression in AGC to aid in future clinical trials on AGC. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded tumor samples from 121 stage III/IV gastric cancer patients were examined for protein expression of tyrosine kinase receptors (RTKs; ERBB2, EGFR, c-MET, and FGFR2) using immunohistochemistry (IHC). Furthermore, 409 cancer-related genes were sequenced to detect mutations and copy number variations using NGS. RESULTS: Most ERBB2 overexpression (IHC 3+) cases (80.0%) had ERBB2 amplification and did not have other RTK amplification or oncogene mutations. However, one-fourth of MET overexpression cases (25.0%) had ERBB2 alterations. EGFR and FGFR2 overexpression cases had ERBB2 alterations or other gene alterations such as KRAS or PIK3CA. On the other hand, most of the four RTK amplification cases (88.2%) were mutually exclusive with each amplification. However, RTK amplification did not simply correlate with protein overexpression, whereas cases with RTK high-level amplification had protein overexpression and rarely showed other co-existing gene alterations. CONCLUSION: AGC involves a complicated arrangement of protein expression and gene alterations. Comprehensive analyses of NGS and IHC will be necessary to design the optimal therapy for treating the appropriate population of patients in future clinical trials. PMID- 26489446 TI - How much evidence isn't in evidence-based guidelines? PMID- 26489447 TI - Spectrometry of the Earth using Neutrino Oscillations. AB - The unknown constituents of the interior of our home planet have provoked the human imagination and driven scientific exploration. We herein demonstrate that large neutrino detectors could be used in the near future to significantly improve our understanding of the Earth's inner chemical composition. Neutrinos, which are naturally produced in the atmosphere, traverse the Earth and undergo oscillations that depend on the Earth's electron density. The Earth's chemical composition can be determined by combining observations from large neutrino detectors with seismic measurements of the Earth's matter density. We present a method that will allow us to perform a measurement that can distinguish between composition models of the outer core. We show that the next-generation large volume neutrino detectors can provide sufficient sensitivity to reject extreme cases of outer core composition. In the future, dedicated instruments could be capable of distinguishing between specific Earth composition models and thereby reshape our understanding of the inner Earth in previously unimagined ways. PMID- 26489448 TI - Nanographene charge trapping memory with a large memory window. AB - Nanographene is a promising alternative to metal nanoparticles or semiconductor nanocrystals for charge trapping memory. In general, a high density of nanographene is required in order to achieve high charge trapping capacity. Here, we demonstrate a strategy of fabrication for a high density of nanographene for charge trapping memory with a large memory window. The fabrication includes two steps: (1) direct growth of continuous nanographene film; and (2) isolation of the as-grown film into high-density nanographene by plasma etching. Compared with directly grown isolated nanographene islands, abundant defects and edges are formed in nanographene under argon or oxygen plasma etching, i.e. more isolated nanographene islands are obtained, which provides more charge trapping sites. As fabricated nanographene charge trapping memory shows outstanding memory properties with a memory window as wide as ~9 V at a relative low sweep voltage of +/-8 V, program/erase speed of ~1 ms and robust endurance of >1000 cycles. The high-density nanographene charge trapping memory provides an outstanding alternative for downscaling technology beyond the current flash memory. PMID- 26489449 TI - Insertion and confinement of air bubbles inside a liquid marble. AB - Nanoparticles at the air/liquid interface can serve as solid separating barriers to form stable foams or liquid marbles depending on the wettability of the nanoparticles. This paper presents an effect that enables the insertion and confinement of air bubbles inside a liquid marble, based on encapsulating an air bubble surrounded by surfactant molecules or hydrophilic particles. We have demonstrated that more than one bubble can be inserted and trapped inside one liquid marble so that liquid marbles can be divided into several separate compartments. The findings presented here may stimulate fundamental studies of this novel bubble-marble phenomenon, as well as developments of various practical applications. PMID- 26489450 TI - Highly efficient and durable TiN nanofiber electrocatalyst supports. AB - To date, carbon-based materials including various carbon nanostructured materials have been extensively used as an electrocatalyst support for proton exchange membrane fuel cell (PEMFC) applications due to their practical nature. However, carbon dissolution or corrosion caused by high electrode potential in the presence of O2 and/or water has been identified as one of the main failure modes for the device operation. Here, we report the first TiN nanofiber (TNF)-based nonwoven structured materials to be constructed via electrospinning and subsequent two-step thermal treatment processes as a support for the PEMFC catalyst. Pt catalyst nanoparticles (NPs) deposited on the TNFs (Pt/TNFs) were electrochemically characterized with respect to oxygen reduction reaction (ORR) activity and durability in an acidic medium. From the electrochemical tests, the TNF-supported Pt catalyst was better and more stable in terms of its catalytic performance compared to a commercially available carbon-supported Pt catalyst. For example, the initial oxygen reduction performance was comparable for both cases, while the Pt/TNF showed much higher durability from an accelerated degradation test (ADT) configuration. It is understood that the improved catalytic roles of TNFs on the supported Pt NPs for ORR are due to the high electrical conductivity arising from the extended connectivity, high inertness to the electrochemical environment and strong catalyst-support interactions. PMID- 26489451 TI - A near infrared luminescent metal-organic framework for temperature sensing in the physiological range. AB - A near infrared pumped luminescent metal-organic framework thermometer Nd(0.577)Yb(0.423)BDC-F4, with near infrared fluorescence and excellent sensitivity in the physiological temperature range (293-313 K), has been first realized, and might be potentially applied for biomedical systems. PMID- 26489452 TI - Layer like porous materials with hierarchical structure. AB - Many chemical compositions produce layered solids consisting of extended sheets with thickness not greater than a few nanometers. The layers are weakly bonded together in a crystal and can be modified into various nanoarchitectures including porous hierarchical structures. Several classes of 2-dimensional (2D) materials have been extensively studied and developed because of their potential usefulness as catalysts and sorbents. They are discussed in this review with focus on clays, layered transition metal oxides, silicates, layered double hydroxides, metal(iv) phosphates and phosphonates, especially zirconium, and zeolites. Pillaring and delamination are the primary methods for structural modification and pore tailoring. The reported approaches are described and compared for the different classes of materials. The methods of characterization include identification by X-ray diffraction and microscopy, pore size analysis and activity assessment by IR spectroscopy and catalytic testing. The discovery of layered zeolites was a fundamental breakthrough that created unprecedented opportunities because of (i) inherent strong acid sites that make them very active catalytically, (ii) porosity through the layers and (iii) bridging of 2D and 3D structures. Approximately 16 different types of layered zeolite structures and modifications have been identified as distinct forms. It is also expected that many among the over 200 recognized zeolite frameworks can produce layered precursors. Additional advances enabled by 2D zeolites include synthesis of layered materials by design, hierarchical structures obtained by direct synthesis and top-down preparation of layered materials from 3D frameworks. PMID- 26489453 TI - Dynamic cross-flow filtration: enhanced continuous small-scale solid-liquid separation. AB - In a previous study, a small-scale dynamic filtration device (SFD) was analyzed and the basic mechanisms governing the filtration process were characterized. The present work aims at improving the device's performance in terms of actual production. Various operation modes were tested in order to increase permeate flow and concentration factors (CF), while maintaining a fully continuous production mode. Both, a vacuum-enhanced and a pulsating operation mode, proved to be superior to the currently implemented open-operation mode. For example, for lactose, an increase of the CF could be achieved from 1.7 in open mode to 7.6 in pulsating operation mode. The investigated operation strategy enables process control systems to rapidly react to fluctuating feeds that may occur due to changes in upstream manufacturing steps. As a result, not only filtration performance in terms of permeate rate but also process flexibility can be significantly increased. Overall, vacuum-enhanced operation was shown to be most promising for integration into an industrial environment. The option to elevate achievable concentration factors, ease of flow monitoring as well as the ability to react to changes in the feed conditions allow for effective and efficient continuous small-scale filtration. PMID- 26489454 TI - Simultaneous Intravascular Ultrasound Usage Overcomes Misinterpretation When Evaluating Lipid-Rich Plaques With Optical Frequency Domain Imaging--Ex Vivo Study. AB - BACKGROUND: The aim of this study was to investigate the accuracy of optical frequency domain imaging (OFDI) in lipid-rich plaque detection and determine the causes of "misinterpretation," and evaluate whether these limitations can be overcome with intravascular ultrasound (IVUS) using ex-vivo human coronaries. METHODS AND RESULTS: The OFDI images and corresponding 218 histological segments were evaluated. Segments with a poor signal and diffuse borders on OFDI, classified as lipid-rich plaques, were compared with the histological segments and IVUS images. Using histological images as the gold standard, the sensitivity, specificity, positive predictive value, and negative predictive value of OFDI for the detection of lipid-rich plaques were 93%, 93%, 85%, and 97%, respectively. The causes of false-positive diagnosis of lipid-rich plaque (11 segments) were superficial macrophage infiltration causing signal attenuation (8/11 segments, 73%) and tangential signal dropout of light (3/11 segments, 27%), whereas the cause of false-negative diagnosis was thickening of the fibrous cap (5 segments, 100%). Simultaneous IVUS helped to correct the misinterpretation of OFDI results and improved the diagnostic accuracy; the sensitivity, specificity, positive predictive value, and negative predictive value of OFDI with adjunct use of IVUS were 96%, 99%, 99%, and 98%, respectively. CONCLUSIONS: OFDI occasionally over- or underestimates the existence of lipid-rich plaques, which may be overcome with adjunctive usage of IVUS. PMID- 26489455 TI - Prognostic Significance of Peripheral Microvascular Endothelial Dysfunction in Heart Failure With Reduced Left Ventricular Ejection Fraction. AB - BACKGROUND: Endothelial dysfunction plays a crucial role in heart failure (HF), but the association between peripheral microvascular endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and prognosis remains unknown in HF with reduced left ventricular (LV) ejection fraction (HFREF). We prospectively investigated the association between peripheral microvascular endothelial function and HF-related near-future cardiovascular outcomes in HFREF patients. METHODS AND RESULTS: The 362 HFREF patients (LVEF <50%) were followed for HF-related events (composite of cardiovascular death and HF hospitalization) up to 3 years. A natural logarithmic scaled RH-PAT index (Ln-RHI) was obtained for each patient. A total of 82 HF related events were recorded. The lower-RHI group (Ln-RHI <=0.49, median) experienced a higher rate of HF-related events compared with the higher-RHI group by Kaplan-Meier analysis (30.9% vs. 14.4%, log-rank test: P<0.001). Multivariable Cox hazard analysis identified Ln-RHI as an independent predictor for HF-related events (per 0.1, hazard ratio: 0.84, 95% confidence interval: 0.75-0.95, P=0.005). Adding Ln-RHI to the Meta-analysis Global Group in Chronic HF risk score (MAGGICs) and Seattle Heart Failure Model (SHFM), powerful prognostic predictors of HF, significantly improved the net reclassification index (MAGGICs: 20.11%, P=0.02, SHFM: 24.88%, P<0.001), and increased the C-statistics for prediction of HF-related events (MAGGICs+Ln-RHI: from 0.612 to 0.670, SHFM+Ln RHI: from 0.662 to 0.695). CONCLUSIONS: Peripheral microvascular endothelial dysfunction assessed by RH-PAT was associated with future HF-related events in HFREF. PMID- 26489456 TI - Calpains and Coronary Vascular Disease. AB - Despite many advances in percutaneous and surgical interventions in the treatment of coronary artery disease (CAD), up to one-third of patients are still either not candidates or receive suboptimal revascularization. Calpains are a class of calcium-activated non-lysosomal cysteine proteases that serve as a proteolytic unit for cellular homeostasis. Uncontrolled activation of calpain has been found to be involved in the pathogenesis of myocardial reperfusion injury, cardiac hypertrophy, myocardial stunning and cardiac ischemia. Inhibition of calpains has been shown to significantly attenuate myocardial stunning and reduced infarct size after ischemia-reperfusion. Calpain inhibition therefore serves as a potential medical therapy for patients suffering from a number of diseases, including CAD. PMID- 26489458 TI - Striatal Cholinergic Interneurons Control Motor Behavior and Basal Ganglia Function in Experimental Parkinsonism. AB - Despite evidence showing that anticholinergic drugs are of clinical relevance in Parkinson's disease (PD), the causal role of striatal cholinergic interneurons (CINs) in PD pathophysiology remains elusive. Here, we show that optogenetic inhibition of CINs alleviates motor deficits in PD mouse models, providing direct demonstration for their implication in parkinsonian motor dysfunctions. As neural correlates, CIN inhibition in parkinsonian mice differentially impacts the excitability of striatal D1 and D2 medium spiny neurons, normalizes pathological bursting activity in the main basal ganglia output structure, and increases the functional weight of the direct striatonigral pathway in cortical information processing. By contrast, CIN inhibition in non-lesioned mice does not affect locomotor activity, equally modulates medium spiny neuron excitability, and does not modify spontaneous or cortically driven activity in the basal ganglia output, suggesting that the role of these interneurons in motor function is highly dependent on dopamine tone. PMID- 26489457 TI - Prolyl Isomerase Pin1 Regulates Axon Guidance by Stabilizing CRMP2A Selectively in Distal Axons. AB - Axon guidance relies on precise translation of extracellular signal gradients into local changes in cytoskeletal dynamics, but the molecular mechanisms regulating dose-dependent responses of growth cones are still poorly understood. Here, we show that during embryonic development in growing axons, a low level of Semaphorin3A stimulation is buffered by the prolyl isomerase Pin1. We demonstrate that Pin1 stabilizes CDK5-phosphorylated CRMP2A, the major isoform of CRMP2 in distal axons. Consequently, Pin1 knockdown or knockout reduces CRMP2A levels specifically in distal axons and inhibits axon growth, which can be fully rescued by Pin1 or CRMP2A expression. Moreover, Pin1 knockdown or knockout increases sensitivity to Sema3A-induced growth cone collapse in vitro and in vivo, leading to developmental abnormalities in axon guidance. These results identify an important isoform-specific function and regulation of CRMP2A in controlling axon growth and uncover Pin1-catalyzed prolyl isomerization as a regulatory mechanism in axon guidance. PMID- 26489459 TI - New Functional Signatures for Understanding Melanoma Biology from Tumor Cell Lineage-Specific Analysis. AB - Molecular signatures specific to particular tumor types are required to design treatments for resistant tumors. However, it remains unclear whether tumors and corresponding cell lines used for drug development share such signatures. We developed similarity core analysis (SCA), a universal and unsupervised computational framework for extracting core molecular features common to tumors and cell lines. We applied SCA to mRNA/miRNA expression data from various sources, comparing melanoma cell lines and metastases. The signature obtained was associated with phenotypic characteristics in vitro, and the core genes CAPN3 and TRIM63 were implicated in melanoma cell migration/invasion. About 90% of the melanoma signature genes belong to an intrinsic network of transcription factors governing neural development (TFAP2A, DLX2, ALX1, MITF, PAX3, SOX10, LEF1, and GAS7) and miRNAs (211-5p, 221-3p, and 10a-5p). The SCA signature effectively discriminated between two subpopulations of melanoma patients differing in overall survival, and classified MEKi/BRAFi-resistant and -sensitive melanoma cell lines. PMID- 26489460 TI - Preventing Allograft Rejection by Targeting Immune Metabolism. AB - Upon antigen recognition and co-stimulation, T lymphocytes upregulate the metabolic machinery necessary to proliferate and sustain effector function. This metabolic reprogramming in T cells regulates T cell activation and differentiation but is not just a consequence of antigen recognition. Although such metabolic reprogramming promotes the differentiation and function of T effector cells, the differentiation of regulatory T cells employs different metabolic reprogramming. Therefore, we hypothesized that inhibition of glycolysis and glutamine metabolism might prevent graft rejection by inhibiting effector generation and function and promoting regulatory T cell generation. We devised an anti-rejection regimen involving the glycolytic inhibitor 2-deoxyglucose (2-DG), the anti-type II diabetes drug metformin, and the inhibitor of glutamine metabolism 6-diazo-5-oxo-L-norleucine (DON). Using this triple-drug regimen, we were able to prevent or delay graft rejection in fully mismatched skin and heart allograft transplantation models. PMID- 26489461 TI - Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy. AB - Impaired autophagy has been implicated in many neurodegenerative diseases, such as Parkinson's disease (PD), and might be responsible for deposition of aggregated proteins in neurons. However, little is known about how neuronal autophagy and clearance of aggregated proteins are regulated. Here, we show a role for Toll-like receptor 2 (TLR2), a pathogen-recognizing receptor in innate immunity, in regulation of neuronal autophagy and clearance of alpha-synuclein, a protein aggregated in synucleinopathies, including in PD. Activation of TLR2 resulted in the accumulation of alpha-synuclein aggregates in neurons as a result of inhibition of autophagic activity through regulation of the AKT/mTOR pathway. In contrast, inactivation of TLR2 resulted in autophagy activation and increased clearance of neuronal alpha-synuclein, and hence reduced neurodegeneration, in transgenic mice and in in vitro models. These results uncover roles of TLR2 in regulating neuronal autophagy and suggest that the TLR2 pathway may be targeted for autophagy activation strategies in treating neurodegenerative disorders. PMID- 26489462 TI - T-type Calcium Channel Regulation of Neural Tube Closure and EphrinA/EPHA Expression. AB - A major class of human birth defects arise from aberrations during neural tube closure (NTC). We report on a NTC signaling pathway requiring T-type calcium channels (TTCCs) that is conserved between primitive chordates (Ciona) and Xenopus. With loss of TTCCs, there is a failure to seal the anterior neural folds. Accompanying loss of TTCCs is an upregulation of EphrinA effectors. Ephrin signaling is known to be important in NTC, and ephrins can affect both cell adhesion and repulsion. In Ciona, ephrinA-d expression is downregulated at the end of neurulation, whereas, with loss of TTCC, ephrinA-d remains elevated. Accordingly, overexpression of ephrinA-d phenocopied TTCC loss of function, while overexpression of a dominant-negative Ephrin receptor was able to rescue NTC in a Ciona TTCC mutant. We hypothesize that signaling through TTCCs is necessary for proper anterior NTC through downregulation of ephrins, and possibly elimination of a repulsive signal. PMID- 26489463 TI - Whisking-Related Changes in Neuronal Firing and Membrane Potential Dynamics in the Somatosensory Thalamus of Awake Mice. AB - The thalamus transmits sensory information to the neocortex and receives neocortical, subcortical, and neuromodulatory inputs. Despite its obvious importance, surprisingly little is known about thalamic function in awake animals. Here, using intracellular and extracellular recordings in awake head restrained mice, we investigate membrane potential dynamics and action potential firing in the two major thalamic nuclei related to whisker sensation, the ventral posterior medial nucleus (VPM) and the posterior medial group (Pom), which receive distinct inputs from brainstem and neocortex. We find heterogeneous state dependent dynamics in both nuclei, with an overall increase in action potential firing during active states. Whisking increased putative lemniscal and corticothalamic excitatory inputs onto VPM and Pom neurons, respectively. A subpopulation of VPM cells fired spikes phase-locked to the whisking cycle during free whisking, and these cells may therefore signal whisker position. Our results suggest differential processing of whisking comparing thalamic nuclei at both sub and supra-threshold levels. PMID- 26489464 TI - Impaired LRP6-TCF7L2 Activity Enhances Smooth Muscle Cell Plasticity and Causes Coronary Artery Disease. AB - Mutations in Wnt-signaling coreceptor LRP6 have been linked to coronary artery disease (CAD) by unknown mechanisms. Here, we show that reduced LRP6 activity in LRP6(R611C) mice promotes loss of vascular smooth muscle cell (VSMC) differentiation, leading to aortic medial hyperplasia. Carotid injury augmented these effects and led to partial to total vascular obstruction. LRP6(R611C) mice on high-fat diet displayed dramatic obstructive CAD and exhibited an accelerated atherosclerotic burden on LDLR knockout background. Mechanistically, impaired LRP6 activity leads to enhanced non-canonical Wnt signaling, culminating in diminished TCF7L2 and increased Sp1-dependent activation of PDGF signaling. Wnt3a administration to LRP6(R611C) mice improved LRP6 activity, led to TCF7L2 dependent VSMC differentiation, and rescued post-carotid-injury neointima formation. These findings demonstrate the critical role of intact Wnt signaling in the vessel wall, establish a causal link between impaired LRP6/TCF7L2 activities and arterial disease, and identify Wnt signaling as a therapeutic target against CAD. PMID- 26489465 TI - Post-transcriptional Regulation of Nkx2-5 by RHAU in Heart Development. AB - RNA G-quadruplexes (G4s) play important roles in RNA biology. However, the function and regulation of mRNA G-quadruplexes in embryonic development remain elusive. Previously, we identified RHAU (DHX36, G4R1) as an RNA helicase that resolves mRNA G-quadruplexes. Here, we find that cardiac deletion of Rhau leads to heart defects and embryonic lethality in mice. Gene expression profiling identified Nkx2-5 mRNA as a target of RHAU that associates with its 5' and 3' UTRs and modulates its stability and translation. The 5' UTR of Nkx2-5 mRNA contains a G-quadruplex that requires RHAU for protein translation, while the 3' UTR of Nkx2-5 mRNA possesses an AU-rich element (ARE) that facilitates RHAU mediated mRNA decay. Thus, we uncovered the mechanisms underlying Nkx2-5 post transcriptional regulation during heart development. Meanwhile, this study demonstrates the function of mRNA 5' UTR G-quadruplex-mediated protein translation in organogenesis. PMID- 26489466 TI - Influx-Operated Ca(2+) Entry via PKD2-L1 and PKD1-L3 Channels Facilitates Sensory Responses to Polymodal Transient Stimuli. AB - The polycystic TRP subfamily member PKD2-L1, in complex with PKD1-L3, is involved in physiological responses to diverse stimuli. A major challenge to understanding whether and how PKD2-L1/PKD1-L3 acts as a bona fide molecular transducer is that recombinant channels usually respond with small or undetectable currents. Here, we discover a type of Ca(2+) influx-operated Ca(2+) entry (ICE) that generates pronounced Ca(2+) spikes. Triggered by rapid onset/offset of Ca(2+), voltage, or acid stimuli, Ca(2+)-dependent activation amplifies a small Ca(2+) influx via the channel. Ca(2+) concurrently drives a self-limiting negative feedback (Ca(2+) dependent inactivation) that is regulated by the Ca(2+)-binding EF hands of PKD2 L1. Our results suggest a biphasic ICE with opposite Ca(2+) feedback regulation that facilitates sensory responses to multimodal transient stimuli. We suggest that such a mechanism may also occur for other sensory modalities and other Ca(2+) channels. PMID- 26489467 TI - Structural and Functional Characterization of CRM1-Nup214 Interactions Reveals Multiple FG-Binding Sites Involved in Nuclear Export. AB - CRM1 is the major nuclear export receptor. During translocation through the nuclear pore, transport complexes transiently interact with phenylalanine-glycine (FG) repeats of multiple nucleoporins. On the cytoplasmic side of the nuclear pore, CRM1 tightly interacts with the nucleoporin Nup214. Here, we present the crystal structure of a 117-amino-acid FG-repeat-containing fragment of Nup214, in complex with CRM1, Snurportin 1, and RanGTP at 2.85 A resolution. The structure reveals eight binding sites for Nup214 FG motifs on CRM1, with intervening stretches that are loosely attached to the transport receptor. Nup214 binds to N- and C-terminal regions of CRM1, thereby clamping CRM1 in a closed conformation and stabilizing the export complex. The role of conserved hydrophobic pockets for the recognition of FG motifs was analyzed in biochemical and cell-based assays. Comparative studies with RanBP3 and Nup62 shed light on specificities of CRM1 nucleoporin binding, which serves as a paradigm for transport receptor nucleoporin interactions. PMID- 26489468 TI - Poly(ADP-Ribose) Mediates the BRCA2-Dependent Early DNA Damage Response. AB - Breast cancer susceptibility gene 2 (BRCA2) plays a key role in DNA damage repair for maintaining genomic stability. Previous studies have shown that BRCA2 contains three tandem oligonucleotide/oligosaccharide binding folds (OB-folds) that are involved in DNA binding during DNA double-strand break repair. However, the molecular mechanism of BRCA2 in DNA damage repair remains elusive. Unexpectedly, we found that the OB-folds of BRCA2 recognize poly(ADP-ribose) (PAR) and mediate the fast recruitment of BRCA2 to DNA lesions, which is suppressed by PARP inhibitor treatment. Cancer-associated mutations in the OB folds of BRCA2 disrupt the interaction with PAR and abolish the fast relocation of BRCA2 to DNA lesions. The quickly recruited BRCA2 is important for the early recruitment of exonuclease 1(EXO1) and is involved in DNA end resection, the first step of homologous recombination (HR). Thus, these findings uncover a molecular mechanism by which BRCA2 participates in DNA damage repair. PMID- 26489469 TI - Structure of a Human 4E-T/DDX6/CNOT1 Complex Reveals the Different Interplay of DDX6-Binding Proteins with the CCR4-NOT Complex. AB - The DEAD-box protein DDX6 is a central component of translational repression mechanisms in maternal mRNA storage in oocytes and microRNA-mediated silencing in somatic cells. DDX6 interacts with the CCR4-NOT complex and functions in concert with several post-transcriptional regulators, including Edc3, Pat1, and 4E-T. We show that the conserved CUP-homology domain (CHD) of human 4E-T interacts directly with DDX6 in both the presence and absence of the central MIF4G domain of CNOT1. The 2.1-A resolution structure of the corresponding ternary complex reveals how 4E-T CHD wraps around the RecA2 domain of DDX6 and contacts CNOT1. Although 4E-T CHD lacks recognizable sequence similarity with Edc3 or Pat1, it shares the same DDX6-binding surface. In contrast to 4E-T, however, the Edc3 and Pat1 FDF motifs dissociate from DDX6 upon CNOT1 MIF4G binding in vitro. The results underscore the presence of a complex network of simultaneous and/or mutually exclusive interactions in DDX6-mediated repression. PMID- 26489470 TI - Discovery and Characterization of piRNAs in the Human Fetal Ovary. AB - Piwi-interacting RNAs (piRNAs), a class of 26- to 32-nt non-coding RNAs (ncRNAs), function in germline development, transposon silencing, and epigenetic regulation. We performed deep sequencing and annotation of untreated and periodate-treated small RNA cDNA libraries from human fetal and adult germline and reference somatic tissues. This revealed abundant piRNAs originating from 150 piRNA-encoding genes, including some exhibiting gender-specific expression, in fetal ovary and adult testis-developmental periods coinciding with mitotic cell divisions expanding fetal germ cells prior to meiotic divisions. The absence of reads mapping uniquely to annotated piRNA genes demonstrated their paucity in fetal testis and adult ovary and absence in somatic tissues. We curated human piRNA-expressing regions and defined their precise borders and observed piRNA guided cleavage of transcripts antisense to some piRNA-producing genes. This study provides insights into sex-specific mammalian piRNA expression and function and serves as a reference for human piRNA analysis and annotation. PMID- 26489471 TI - Partial Loss of Rpl11 in Adult Mice Recapitulates Diamond-Blackfan Anemia and Promotes Lymphomagenesis. AB - Diamond-Blackfan anemia (DBA) is characterized by anemia and cancer susceptibility and is caused by mutations in ribosomal genes, including RPL11. Here, we report that Rpl11-heterozygous mouse embryos are not viable and that Rpl11 homozygous deletion in adult mice results in death within a few weeks, accompanied by bone marrow aplasia and intestinal atrophy. Importantly, Rpl11 heterozygous deletion in adult mice results in anemia associated with decreased erythroid progenitors and defective erythroid maturation. These defects are also present in mice transplanted with inducible heterozygous Rpl11 bone marrow and, therefore, are intrinsic to the hematopoietic system. Additionally, heterozygous Rpl11 mice present increased susceptibility to radiation-induced lymphomagenesis. In this regard, total or partial deletion of Rpl11 compromises p53 activation upon ribosomal stress or DNA damage in fibroblasts. Moreover, fibroblasts and hematopoietic tissues from heterozygous Rpl11 mice present higher basal cMYC levels. We conclude that Rpl11-deficient mice recapitulate DBA disorder, including cancer predisposition. PMID- 26489472 TI - DNA Topology and Global Architecture of Point Centromeres. AB - DNA is wrapped in a left-handed fashion around histone octasomes containing the centromeric histone H3 variant CENP-A. However, DNA topology studies have suggested that DNA is wrapped in a right-handed manner around the CENP-A nucleosome that occupies the yeast point centromere. Here, we determine the DNA linking number difference (DeltaLk) stabilized by the yeast centromere and the contribution of the centromere determining elements (CDEI, CDEII, and CDEIII). We show that the intrinsic architecture of the yeast centromere stabilizes +0.6 units of DeltaLk. This topology depends on the integrity of CDEII and CDEIII, but it is independent of cbf1 binding to CDEI and of the variable length of CDEII. These findings suggest that the interaction of the CBF3 complex with CDEIII and a distal CDEII segment configures a right-handed DNA loop that excludes CDEI. This loop is then occupied by a CENP-A histone complex, which does not have to be inherently right-handed. PMID- 26489473 TI - Hoxa2 Selects Barrelette Neuron Identity and Connectivity in the Mouse Somatosensory Brainstem. AB - Mouse whiskers are somatotopically mapped in brainstem trigeminal nuclei as neuronal modules known as barrelettes. Whisker-related afferents form barrelettes in ventral principal sensory (vPrV) nucleus, whereas mandibular input targets dorsal PrV (dPrV). How barrelette neuron identity and circuitry is established is poorly understood. We found that ectopic Hoxa2 expression in dPrV neurons is sufficient to attract whisker-related afferents, induce asymmetrical dendrite arbors, and allow ectopic barrelette map formation. Moreover, the thalamic area forming whisker-related barreloids is prenatally targeted by both vPrV and dPrV axons followed by perinatal large-scale pruning of dPrV axons and refinement of vPrV barrelette input. Ectopic Hoxa2 expression allows topographically directed targeting and refinement of dPrV axons with vPrV axons into a single whisker related barreloid map. Thus, a single HOX transcription factor is sufficient to switch dPrV into a vPrV barrelette neuron program and coordinate input-output topographic connectivity of a dermatome-specific circuit module. PMID- 26489475 TI - Re: Massimiliano Spaliviero, Bing Ying Poon, Christoph A. Karlo, et al. An Arterial Based Complexity (ABC) Scoring System to Assess the Morbidity Profile of Partial Nephrectomy. Eur Urol 2016;69:72-9. PMID- 26489474 TI - Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function. AB - Maximizing baseline function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is essential for their effective application in models of cardiac toxicity and disease. Here, we aimed to identify factors that would promote an adequate level of function to permit robust single-cell contractility measurements in a human induced pluripotent stem cell (hiPSC) model of hypertrophic cardiomyopathy (HCM). A simple screen revealed the collaborative effects of thyroid hormone, IGF-1 and the glucocorticoid analog dexamethasone on the electrophysiology, bioenergetics, and contractile force generation of hPSC CMs. In this optimized condition, hiPSC-CMs with mutations in MYBPC3, a gene encoding myosin-binding protein C, which, when mutated, causes HCM, showed significantly lower contractile force generation than controls. This was recapitulated by direct knockdown of MYBPC3 in control hPSC-CMs, supporting a mechanism of haploinsufficiency. Modeling this disease in vitro using human cells is an important step toward identifying therapeutic interventions for HCM. PMID- 26489477 TI - Re: Raj Satkunasivam, Sheaumei Tsai, Sumeet Syan, et al. Robotic Unclamped "Minimal-margin" Partial Nephrectomy: Ongoing Refinement of the Anatomic Zero ischemia Concept. Eur Urol 2015;68:705-12. PMID- 26489476 TI - Systematic Identification of MicroRNAs That Impact on Proliferation of Prostate Cancer Cells and Display Changed Expression in Tumor Tissue. AB - BACKGROUND: Systematic approaches to functionally identify key players in microRNA (miRNA)-target networks regulating prostate cancer (PCa) proliferation are still missing. OBJECTIVE: To comprehensively map miRNA regulation of genes relevant for PCa proliferation through phenotypic screening and tumor expression data. DESIGN, SETTING, AND PARTICIPANTS: Gain-of-function screening with 1129 miRNA molecules was performed in five PCa cell lines, measuring proliferation, viability, and apoptosis. These results were integrated with changes in miRNA expression from two cohorts of human PCa (188 tumors in total). For resulting miRNAs, the predicted targets were collected and analyzed for patterns with gene set enrichment analysis, and for their association with biochemical recurrence free survival. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Rank product statistical analysis was used to evaluate miRNA effects in phenotypic screening and for expression differences in the prostate tumor cohorts. Expression data were analyzed using the significance analysis of microarrays (SAM) method and the patient material was subjected to Kaplan-Meier statistics. RESULTS AND LIMITATIONS: Functional screening identified 25 miRNAs increasing and 48 miRNAs decreasing cell viability. Data integration resulted in 14 miRNAs, with aberrant expression and effect on proliferation. These miRNAs are predicted to regulate >3700 genes, of which 28 were found up-regulated and 127 down-regulated in PCa compared with benign tissue. Seven genes, FLNC, MSRB3, PARVA, PCDH7, PRNP, RAB34, and SORBS1, showed an inverse association to their predicted miRNA, and were identified to significantly correlate with biochemical recurrence free survival in PCa patients. CONCLUSIONS: A systematic in vitro screening approach combined with in vivo expression and gene set enrichment analysis provide unbiased means for revealing novel miRNA-target links, possibly driving the oncogenic processes in PCa. PATIENT SUMMARY: This study identified novel regulatory molecules, which impact on PCa proliferation and are aberrantly expressed in clinical tumors. Thus, our study reveals regulatory nodes with potential for therapy. PMID- 26489478 TI - Foodborne outbreaks caused by Cyclospora: the message is more important than the messenger. PMID- 26489479 TI - Insecticidal and sterilizing effect of Olyset Duo(r), a permethrin and pyriproxyfen mixture net against pyrethroid-susceptible and -resistant strains of Anopheles gambiae s.s.: a release-recapture assay in experimental huts. AB - In the context of the widespread distribution of pyrethroid resistance among malaria vectors, we did a release-recapture trial in experimental huts to investigate the insecticidal and sterilizing effects of a novel long-lasting net (LN), Olyset(r) Duo, incorporating a mixture of permethrin (PER) and the insect growth regulator (IGR), pyri-proxyfen (PPF). An LN containing PPF alone and a classic Olyset(r) Net were tested in parallel as positive controls. The effect of progressive number of holes (6, 30, or 150) that may accrue in nets over time was simulated. We used two laboratory Anopheles gambiae s.s. strains: the susceptible Kisumu strain and the pyrethroid-resistant VK-Per strain having solely kdr as resistance mechanism. The effect of these nets on the reproductive success of blood-fed females that survived the different LNs conditions was recorded. Regardless of the mosquito strain, the LNs containing PPF alone with as many as 30 holes drastically reduced the number of eggs laid by females succeeding in feeding, i.e. fecundity by 98% and egg hatching rate (fertility) by 93% relative to untreated control net. Very few of the resistant females blood fed and survived under the Olyset(r) Duo with similar number of holes (up to 30) but of these few, the inhibition of reproductive success was 100%. There was no evidence that the Olyset(r) Duo LN with 150 holes impacted fecundity or fertility of the resistant colony. The efficacy of Olyset(r) Duo is encouraging and clearly illustrates that this new net might be a promising tool for malaria transmission control and resistance management. PMID- 26489481 TI - Selective CO2 reduction on a polycrystalline Ag electrode enhanced by anodization treatment. AB - Electrochemical reduction of CO2 to CO on polycrystalline silver (Ag) was greatly improved by a simple anodization treatment. A CO faradaic efficiency of 92.8% was achieved at an overpotential of 0.50 V in an aqueous electrolyte. This study suggests that the enhanced performance is due to a preferred (220) orientation and a thin silver oxide layer formed by anodization. PMID- 26489480 TI - Efficacy of Olyset(r) Duo, a permethrin and pyriproxyfen mixture net against wild pyrethroid-resistant Anopheles gambiae s.s. from Cote d'Ivoire: an experimental hut trial. AB - Pyrethroid resistance in malaria vectors has spread across sub-Saharan Africa. Alternative tools and molecules are urgently needed for effective vector control. One of the most promising strategies to prevent or delay the development of resistance is to use at least two molecules having unrelated modes of action in combination in the same bed net. We evaluated in experimental huts in Cote d'Ivoire, a new polyethylene long-lasting insecticidal net (LN) product, Olyset(r) Duo, incorporating permethrin (PER) and pyriproxyfen (PPF), an insect growth regulator (IGR). PPF alone or in combination with permethrin had a significant impact on fertility (7-12% reduction relative to control) and no effect on fecundity of wild multi-resistant An. gambiae s.s. These results triggered crucial research questions on the behaviour of targeted mosquitoes around the LN. To maximize the sterilizing effect of PPF in the combination, there would be a need for a trade-off between the necessary contact time of the insect with PPF and the surface content of the pyrethroid insecticide that is bioavailable and induces excito-repellency. PMID- 26489482 TI - Prevalence, risk factors, and outcomes associated with physical restraint use in mechanically ventilated adults. AB - PURPOSE: The purpose was to describe characteristics and outcomes of restrained and nonrestrained patients enrolled in a randomized trial of protocolized sedation compared with protocolized sedation plus daily sedation interruption and to identify patient and treatment factors associated with physical restraint. METHODS: This was a post hoc secondary analysis using Cox proportional hazards modeling adjusted for center- and time-varying covariates to evaluate predictors of restraint use. RESULTS: A total of 328 (76%) of 430 patients were restrained for a median of 4 days. Restrained patients received higher daily doses of benzodiazepines (105 vs 41 mg midazolam equivalent, P < .0001) and opioids (1524 vs 919 MUg fentanyl equivalents, P < .0001), more days of infusions (benzodiazepines 6 vs 4, P < .0001; opioids 7 vs 5, P = .02), and more daily benzodiazepine boluses (0.2 vs 0.1, P < .0001). More restrained patients received haloperidol (23% vs 12%, P = .02) and atypical antipsychotics (17% vs 4%, P = .003). More restrained patients experienced unintentional device removal (26% vs 3%, P < .001) and required reintubation (8% vs 1%, P = .01). In the multivariable analysis, alcohol use was associated with decreased risk of restraint (hazard ratio, 0.22; 95% confidence interval, 0.08-0.58). CONCLUSIONS: Physical restraint was common in mechanically ventilated adults managed with a sedation protocol. Restrained patients received more opioids and benzodiazepines. Except for alcohol use, patient characteristics and treatment factors did not predict restraint use. PMID- 26489483 TI - Endothelial cell-specific molecule-1/endocan: Diagnostic and prognostic value in patients suffering from severe sepsis and septic shock. AB - PURPOSE: This study aims to assess the diagnostic and prognostic value of endocan in patients with severe sepsis or septic shock on a medical intensive care unit (ICU). METHODS: 150 patients suspected for at least severe sepsis were enrolled on a medical ICU. On days 1, 3, and 8, plasma levels of endocan, procalcitonin (PCT), and interleukin (IL)-6 were measured. Follow-up on all-cause mortality was performed after 30 days and 6 months. RESULTS: Endocan correlated with Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), and Simplified Acute Physiology Score II (SAPS II) (P < .006). Endocan was higher in patients with at least severe sepsis compared with systemic inflammatory response syndrome (SIRS) or sepsis patients (P = .0006) on days 1, 3, and 8. With a minimum sensitivity of 70%, uniform cutoff levels were set for >= sepsis at 1.8 ng/mL, for >= severe sepsis at 2.6 ng/mL, for >= septic shock at 2.9 ng/mL. On day 1, endocan levels of the fourth quartile were significantly associated with 30-days and 6-months mortality compared to lower levels. After adjustment in Cox regressions, endocan still revealed prognostic value. CONCLUSIONS: Endocan showed diagnostic capacity to diagnose patients with severe sepsis and septic shock and revealed prognostic information for 30-days and 6 months all-cause mortality. PMID- 26489484 TI - Speckle filtering of medical ultrasonic images using wavelet and guided filter. AB - Speckle noise is an inherent yet ineffectual residual artifact in medical ultrasound images, which significantly degrades quality and restricts accuracy in automatic diagnostic techniques. Speckle reduction is therefore an important step prior to the analysis and processing of the ultrasound images. A new de-noising method based on an improved wavelet filter and guided filter is proposed in this paper. According to the characteristics of medical ultrasound images in the wavelet domain, an improved threshold function based on the universal wavelet threshold function is developed. The wavelet coefficients of speckle noise and noise-free signal are modeled as Rayleigh distribution and generalized Gaussian distribution respectively. The Bayesian maximum a posteriori estimation is applied to obtain a new wavelet shrinkage algorithm. The coefficients of the low frequency sub-band in the wavelet domain are filtered by guided filter. The filtered image is then obtained by using the inverse wavelet transformation. Experiments with the comparison of the other seven de-speckling filters are conducted. The results show that the proposed method not only has a strong de speckling ability, but also keeps the image details, such as the edge of a lesion. PMID- 26489485 TI - Neurobiological origin of psychogenic nonepileptic seizures: A review of imaging studies. AB - Psychogenic nonepileptic seizures (PNES) are relatively common occurrences in epilepsy centers. Pathophysiology of PNES is still poorly understood. In this paper, the evidence for a neurobiological origin of PNES will be reviewed. Recent evidence suggests altered functional and structural brain connectivity as an underlying pathophysiological mechanism in patients with PNES. Pursuing the concept of connectome in patients with PNES and comparing the findings with healthy individuals may result in a breakthrough in identifying the exact neurobiological origin of PNES. Finding the neurobiological bases and identification of biomarkers of PNES will potentially have important clinical implications in formulating better diagnostic and therapeutic approaches for affected patients. PMID- 26489486 TI - A systematic review and meta-analysis of the epidemiology and burden of venous thromboembolism among pregnant women. AB - BACKGROUND: Pregnancy-related venous thromboembolism (VTE) is one of the leading causes of maternal morbidity and mortality. OBJECTIVES: To review the epidemiology, and humanistic and economic burden of pregnancy-related VTE. SEARCH STRATEGY: Medline, the Cochrane Central Register of Controlled Trials, Econlit, Science Direct, JSTOR, Oxford Journals, and Cambridge Journals were searched for reports published between January 2000 and December 2012. Keywords related to VTE, pregnancy, and epidemiology and the humanistic and economic burdens were combined. SELECTION CRITERIA: Eligible studies evaluated the incidence, mortality, recurrence, complications, quality-of-life, and economic burden of VTE among pregnant women, and had been published in English. DATA COLLECTION AND ANALYSIS: Background information of the study, participants' characteristics, and study outcomes were collected. Meta-analyses of data were performed. MAIN RESULTS: Twenty studies were included, none of which investigated the economic burden. The pooled overall incidence of pregnancy-related VTE was 1.2 per 1000 deliveries. The pooled VTE case fatality rate was 0.68% and the recurrence rate was 4.27%. The pooled risk of major bleeding was 1.05%. Post-thrombotic syndrome seemed to have a negative effect on quality of life. CONCLUSIONS: Although the incidence of VTE was found to be relatively low during pregnancy and the postpartum period, the clinical burden is high. Further research is required to assess the economic burden of pregnancy-relate VTE. PMID- 26489487 TI - Exploring disparities in prenatal care between refugees and local South African women. AB - OBJECTIVE: To explore possible disparities in prenatal care between refugees and South African women attending public health facilities in an urban setting in South Africa. METHODS: A cross-sectional, mixed methods study was conducted at four public health clinics providing prenatal services in Durban between January 29, 2013, and June 15, 2013. Pretested client-satisfaction questionnaires were administered to 200 women attending immunization services at the clinics whose infants were aged 6 months or younger. An additional 16 refugees participated in in-depth interviews. Finally, a maternity chart audit was conducted to compare the quality of basic prenatal care. RESULTS: Among the women enrolled, 78 (39.0%) were refugees and 122 (61.0%) were South African citizens. Dissatisfaction was reported by 23 (19.3%) of 119 citizens and 32 (43.2%) of 74 refugees (P<0.001). However, the maternity chart audit of 68 participants (31 refugees, 37 citizens) did not reveal significant disparities in the quality of prenatal care. The most recurring categories arising in the in-depth interviews were linguistic barriers and the challenges faced when using informal interpreters. CONCLUSION: There were no significant disparities in prenatal care; however, refugees unable to communicate in the local languages reported that they were not provided with relevant health information and occasionally faced restricted access to prenatal services. PMID- 26489488 TI - Obstetric anal sphincter injury rates among primiparous women with different modes of vaginal delivery. AB - OBJECTIVE: To determine whether rates of obstetric anal sphincter injuries (OASIS) are continuing to increase and whether risk of OASIS according to mode of delivery is constant over time. METHODS: In a retrospective population-based study, data were obtained for vaginal singleton vertex deliveries at 37-41 weeks of pregnancy among primiparous women in New South Wales, Australia, between January 2001 and December 2011. Annual OASIS rates were determined among non instrumental, forceps, and vacuum deliveries with and without episiotomy. Multivariable logistic regression was used to determine adjusted odds ratios for each delivery mode category by year. Trends in adjusted odds ratios over time for each delivery category were compared. RESULTS: OASIS occurred in 955 (4.1%) of 23 081 deliveries in 2001 and 1487 (5.9%) of 25 081 deliveries in 2011. After adjustment for known risk factors, the only delivery categories to show statistically significant increases in OASIS over the study period were non instrumental deliveries without episiotomy (linear trend P<0.001) and forceps deliveries with episiotomy (linear trend P=0.004). CONCLUSION: Overall, OASIS rates have continued to increase. Known risk factors do not fully explain the increase in OASIS rates in non-instrumental deliveries without an episiotomy and in forceps deliveries with an episiotomy. PMID- 26489489 TI - A systematic review and meta-analysis of progestogen use for maintenance tocolysis after preterm labor in women with intact membranes. AB - BACKGROUND: The use of progestogens for maintenance tocolysis remains controversial, with randomized controlled trials having conflicting results on their efficacy. OBJECTIVES: To evaluate the use of progestational agents for maintenance tocolysis after preterm labor in a systematic review of randomized controlled trials. SEARCH STRATEGY: Electronic databases were searched for reports published before December 2014. Keywords included "tocolysis," "progesterone," "preterm labor," "17-alpha-hydroxyprogesterone," and "vaginal progesterone." SELECTION CRITERIA: Only randomized controlled trials involving progestational agents for maintenance tocolysis were included. DATA COLLECTION AND ANALYSIS: Outcomes were analyzed on an intent-to-treat basis and meta analysis was performed where appropriate. Relative risks and mean differences with 95% confidence intervals were calculated. MAIN RESULTS: Four studies (362 women) were included. There were no significant differences between progestational agents and placebo/no treatment in terms of delivery before 34weeks or before 37weeks of pregnancy, time from randomization to delivery, and respiratory distress syndrome. Progestogens were associated with an increase in the neonatal birth weight (mean difference 203.32g, 95% confidence interval 110.85-295.80; P=0.032). CONCLUSIONS: The current evidence does not support the routine use of progestational agents for maintenance tocolysis after an episode of preterm labor. PMID- 26489490 TI - Naviculocuneiform Coalition: Case Reports of Two Sibling Soccer Players. AB - Tarsal coalitions are an abnormal union between 2 tarsal bones. They occur most commonly between the calcaneus and talus or the calcaneus and navicular but can also arise from other joints in the foot. Isolated cases of coalitions between the medial cuneiform and navicular are extremely rare, and only a few cases have been reported. Treatment recommendations are, therefore, sparse, and no long-term follow-up data have been reported. We present the case of 2 sisters, each diagnosed with a symptomatic naviculocuneiform coalition. To our knowledge, this is the first reported case in 2 first-degree relatives. Both sisters were involved in sports and presented with pain during physical activities. After conservative treatment had failed, they were both treated successfully with surgical excision of the coalition and arthrodiastasis, followed by a progressive return to activities. At the last follow-up examination at 5 and 3 years postoperatively, they remained pain free and fully involved in college soccer, making excision of a naviculocuneiform coalition with arthrodiastasis a valid treatment in the young athletic population. PMID- 26489491 TI - Duration of dual antiplatelet therapy after coronary stenting. PMID- 26489492 TI - MicroRNAs in Parasitic Helminthiases: Current Status and Future Perspectives. AB - MicroRNAs (miRNAs) play a variety of roles in diverse biological processes at the post-transcriptional regulatory level. Although numerous miRNAs have been identified in parasitic helminths, we still know little about their biological functions. As molecular signatures that can be stably detectable in serum and plasma, worm-derived miRNAs have shown promise as markers for the early detection of particular helminth infections. In addition, host miRNAs are dysregulated during the development of pathology associated with helminthiases and show potential as therapeutic intervention targets. This review discusses the possible biological roles of helminth miRNAs, the prediction of their specific targets, their application in diagnosis and anti-pathology therapy interventions, and the potential functions of miRNAs in extracellular vesicle cargo, such as exosomes, in helminth-host interplay. PMID- 26489493 TI - Broad patterns in domestic vector-borne Trypanosoma cruzi transmission dynamics: synanthropic animals and vector control. AB - BACKGROUND: Chagas disease (caused by Trypanosoma cruzi) is the most important neglected tropical disease (NTD) in Latin America, infecting an estimated 5.7 million people in the 21 countries where it is endemic. It is one of the NTDs targeted for control and elimination by the 2020 London Declaration goals, with the first goal being to interrupt intra-domiciliary vector-borne T. cruzi transmission. A key question in domestic T. cruzi transmission is the role that synanthropic animals play in T. cruzi transmission to humans. Here, we ask, (1) do synanthropic animals need to be targeted in Chagas disease prevention policies?, and (2) how does the presence of animals affect the efficacy of vector control? METHODS: We developed a simple mathematical model to simulate domestic vector-borne T. cruzi transmission and to specifically examine the interaction between the presence of synanthropic animals and effects of vector control. We used the model to explore how the interactions between triatomine bugs, humans and animals impact the number and proportion of T. cruzi-infected bugs and humans. We then examined how T. cruzi dynamics change when control measures targeting vector abundance are introduced into the system. RESULTS: We found that the presence of synanthropic animals slows the speed of T. cruzi transmission to humans, and increases the sensitivity of T. cruzi transmission dynamics to vector control measures at comparable triatomine carrying capacities. However, T. cruzi transmission is amplified when triatomine carrying capacity increases with the abundance of syntathoropic hosts. CONCLUSIONS: Our results suggest that in domestic T. cruzi transmission scenarios where no vector control measures are in place, a reduction in synanthropic animals may slow T. cruzi transmission to humans, but it would not completely eliminate transmission. To reach the 2020 goal of interrupting intra-domiciliary T. cruzi transmission, it is critical to target vector populations. Additionally, where vector control measures are in place, synanthropic animals may be beneficial. PMID- 26489494 TI - A new formulation of cannabidiol in cream shows therapeutic effects in a mouse model of experimental autoimmune encephalomyelitis. AB - BACKGROUND: The present study was designed to investigate the efficacy of a new formulation of alone, purified cannabidiol (CBD) (>98 %), the main non psychotropic cannabinoid of Cannabis sativa, as a topical treatment in an experimental model of autoimmune encephalomyelitis (EAE), the most commonly used model for multiple sclerosis (MS). Particularly, we evaluated whether administration of a topical 1 % CBD-cream, given at the time of symptomatic disease onset, could affect the EAE progression and if this treatment could also recover paralysis of hind limbs, qualifying topical-CBD for the symptomatic treatment of MS. METHODS: In order to have a preparation of 1 % of CBD-cream, pure CBD have been solubilized in propylene glycoland basic dense cream O/A. EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG35-55) in C57BL/6 mice. After EAE onset, mice were allocated into several experimental groups (Naive, EAE, EAE-1 % CBD-cream, EAE-vehicle cream, CTRL-1 % CBD-cream, CTRL-vehicle cream). Mice were observed daily for signs of EAE and weight loss. At the sacrifice of the animals, which occurred at the 28(th) day from EAE-induction, spinal cord and spleen tissues were collected in order to perform histological evaluation, immunohistochemistry and western blotting analysis. RESULTS: Achieved results surprisingly show that daily treatment with topical 1 % CBD-cream may exert neuroprotective effects against EAE, diminishing clinical disease score (mean of 5.0 in EAE mice vs 1.5 in EAE + CBD-cream), by recovering of paralysis of hind limbs and by ameliorating histological score typical of disease (lymphocytic infiltration and demyelination) in spinal cord tissues. Also, 1 % CBD-cream is able to counteract the EAE-induced damage reducing release of CD4 and CD8alpha T cells (spleen tissue localization was quantified about 10,69 % and 35,96 % of positive staining respectively in EAE mice) and expression of the main pro-inflammatory cytokines as well as several other direct or indirect markers of inflammation (p-selectin, IL-10, GFAP, Foxp3, TGF-beta, IFN-gamma), oxidative injury (Nitrotyrosine, iNOS, PARP) and apoptosis (Cleaved caspase 3). CONCLUSION: All these data suggest an interesting new profile of CBD that could lead to its introduction in the clinical management of MS and its associated symptoms at least in association with current conventional therapy. PMID- 26489495 TI - Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum disorder. AB - BACKGROUND: Deletions and mutations involving the SHANK3 gene lead to a nonspecific clinical presentation with moderate to profound intellectual disability, severely delayed or absent speech, and autism spectrum disorders (ASD). Better knowledge of the clinical spectrum of SHANK3 haploinsufficiency is useful to facilitate clinical care monitoring and to guide molecular diagnosis, essential for genetic counselling. CASE PRESENTATION: Here, we report a detailed clinical description of a 10-year-old girl carrying a pathogenic interstitial 22q13.3 deletion encompassing only the first 17 exons of SHANK3. The clinical features displayed by the girl strongly suggested the diagnosis of dementia infantilis, described by Heller in 1908, also known as childhood disintegrative disorder. CONCLUSION: Our present case confirms several observations according to which regression may be part of the clinical phenotype of SHANK3 haploinsufficiency. Therefore, we think it is crucial to look for mutations in the gene SHANK3 in patients diagnosed for childhood disintegrative disorder or any developmental disorder with a regressive pattern involving social and communicative skills as well as cognitive and instinctual functions, with onset around 3 years. PMID- 26489496 TI - [Molecular Prognostic Markers and Their Clinical Relevance in Chronic Lymphocytic Leukemia]. AB - Chronic lymphocytic leukemia is the most common leukemia in Western countries affecting particularly elderly adults. Despite the constantly improving therapy options, chronic lymphocytic leukemia is still an incurable disease owing to considerable clinical and bio-logical heterogeneity. Pathogenesis of chronic lymphocytic leukemia is not fully understood; however, aberrant antigenic stimulation, apoptosis deregulation and microenvironmental interactions play a crucial role in disease development. The most important molecular prognostic markers with clinical relevance include mutation status of heavychain immunoglobulin genes (IGHV), presence of cytogenetic aberrations and TP53 and ATM gene mutations. Recent implementation of next generation sequencing technologies has enabled more accurate analysis of both wellestablished and novel potential prognostic markers. The most relevant candidates are mutations in SF3B1, NOTCH1 and BIRC3 genes, which are now intensively studied with respect to their clinical importance. The other examined molecular mechanisms of chronic lympho-cytic leukemia pathogenesis include deregulation of B cell receptor signalization and abnormal regulation of gene expression by microRNA. The precise characterization of molecular abnormalities improves the risk stratification of chronic lymphocytic leukemia patients, which could possibly benefit from new treatment approaches. PMID- 26489497 TI - [Significance of Minimal Residual Disease in Chronic Lymphocytic Leukemia]. AB - Newly introduced highly effective treatment options increase the importance of minimal residual disease measurement in chronic lymphocytic leukemia. Minimal residual disease is gaining interest mainly as a predictive marker; however, clinical significance of minimal residual dis-ease in chronic lymphocytic leukemia in many different situations remains unresolved. Factors with a possible impact on the clinical significance of minimal residual disease are as follows: technique for minimal residual disease quantification, treatment regimen, peripheral blood vs. bone marrow analysis or time -point for sampling. Highly sensitive methods now available to evaluate minimal residual disease can detect a single chronic lymphocytic leukemia cell in 10(-4)- 10(-5) leukocytes using either allele -specific oligonucleotide polymerase chain reaction or multicolor flow cytometry. Minimal residual disease quantification as a surrogate marker to assess treatment efficacy in routine hematological practice has to be further evaluated. PMID- 26489498 TI - [Monoclonal Antibodies in the Treatment of Chronic Lymphocytic Leukemia in 2015]. AB - Chemotherapy combinations with monoclonal antibodies are now the basis for treatment of chronic lymphocytic leukemia. Rituximab, the most widely used anti CD20 antibody in routine clinical practice, led not only to improvement of progression-free survival, but also to improvement of overall survival in previously untreated patients with good performance status in combination with fludarabine and cyclophosphamide. This regimen has become the standard treatment for patients in good physical condition. Rituximab and the newest anti-CD20 antibody obinutuzumab in combination with chlorambucil, as compared with chlorambucil alone, prolonged overall survival in previously untreated patients with significant comorbidities, and the combination of anti-CD20 antibody with chlorambucil has become the standard regimen in this group of patients. Alemtuzumab and ofatumumab improved treatment results in refractory chronic lymphocytic leukemia. Targeted therapy with combination chemotherapy and monoclonal antibody in patients with chronic lymphocytic leukemia represents a significant advance in the treatment of this disease. PMID- 26489499 TI - [Therapeutic Options for "Slow go" Patients with Chronic Lymphocytic Leukemia]. AB - Chronic lymphocytic leukemia is a disease of older patients, most of them suffering from significant comorbidities or functional limitations (so -called 'slow- go' patients). Unfortunately, clinical trials in chronic lymphocytic leukemia have until recently focused mainly on the subgroup of younger patients in good overall condition ('go- go' patients). Clinico- biological parameters, such as performance status, calculated creatinine clearance, the number and severity of comorbidities along with individual clinical assessment can help guide decisions relating to the objectives and ultimately the intensity of treatment. Two large randomized studies have recently demonstrated that the addition of monoclonal antibodies against CD20 (obinutuzumab, rituximab and ofatumumab) to chlorambucil in untreated 'slow- go' patients resulted in a significant increase in the number of complete remissions, progression-free survival and even overall survival (for obinutuzumab and rituximab) with an acceptable safety profile. Chemoimmunotherapy combining chlorambucil with anti CD20 antibody is thus the new standard 1st line therapy in this group of patients. Treatment of relapsed/ refractory chronic lymphocytic leukemia in 'slow go' patients is very difficult and specific data is sparse. In this indication, we have witnessed an extraordinary breakthrough by means of small oral inhibitors interfering with B -cell receptor downstream signaling pathways: ibrutinib, the Brutons tyrosine kinase inhibitor, and idelalisib, the inhibitor of phosphatidylinositol 3- kinase delta. Both drugs radically changed the approach to the treatment of relapsed/ refractory chronic lymphocytic leukemia; relatively mild toxicity also predetermines their use in elderly/ comorbid patients. Other treatment options for relapsed/ refractory chronic lymphocytic leukemia in this subgroup include alemtuzumab, ofatumumab, high-dose glucocorticoids + anti-CD20 antibodies, or bendamustine + rituximab regimen. This review summarizes current data regarding the treatment of elderly and comorbid patients with chronic lymphocytic leukemia. PMID- 26489500 TI - [Treatment of Chronic Lymphocytic Leukemia with TP53 Aberrations]. AB - Patients with chronic lymphocytic leukemia with deletion of the short arm of chromosome 17 (17p -) or mutation of the TP53 gene have significantly worse prognosis with a higher risk of progression to symptomatic disease, worse and shorter responses to chemo immunotherapy, and more frequent occurrence of Richters syndrome. TP53 deletion/ mutation is currently the only genetic abnormality that independently predicts response to treatment and also affects the choice of therapeutic approach in chronic lymphocytic leukemia. This work summarizes treatment options available for this poor prognosis variant of chronic lymphocytic leukemia. Traditional chemo immunotherapy (e. g. FCR) does not offer longterm disease control, and patients with TP53 deletion/ mutation were usually considered to undergo allogeneic bone marrow transplantation. New molecules from the group of BCR inhibitors or BCL2 antagonists achieve excellent efficacy in chronic lymphocytic leukemia with del17p even in relapsed/ refractory (R/ R) cases, with a higher percentage of responses and prolonged survival without progression. Clinical trials are ongoing to determine optimal therapeutic approach and to induce longterm remission of the disease. The new molecules change algorithms for treatment of patients with TP53 aberration, including indication for allogeneic transplantation. Especially younger patients should be consulted in centers of intensive hematological care to consider their inclusion into clinical trials testing new molecules or to indicate allogeneic transplantation at the optimal time. PMID- 26489501 TI - [Small Molecules in the Treatment of Chronic Lymphocytic Leukemia in 2015 and in the Near Future]. AB - Chronic lymphocytic leukemia is one of the most common lymphoid malignancies and is characterized by a highly heterogeneous clinical course. Combined regimens, such as fludarabine, cyclophosphamide, and rituximab have led to improvements in survival in younger patients with chronic lymphocytic leukemia and have become the standard of care in fit patients. However, the majority of chronic lymphocytic leukemia patients are elderly and not all patients are eligible for aggressive chemoimmunotherapy. In addition, patients with poor- risk cytogenetics have inferior responses to standard treatments with often shorter durations of response. Furthermore, the treatment outcomes of refractory disease are dismal. Nevertheless, there has been a dramatic change in therapeutic paradigms in the past year. Several new drugs have been approved for the treatment of chronic lymphocytic leukemia, including ibrutinib and idelalisib. These new molecules are orally active agents and both target the B -cell receptor associated kinases. Ibrutinib is a selective, irreversible inhibitor of Bruton tyrosine kinase, whereas idelalisib selectively targets phosphatidylinositol 3- kinase (PI3K) delta isoform. These agents have demonstrated remarkable activity in patients with relapsed/ refractory chronic lymphocytic leukemia, as well as patients with high-risk deletion of the 17p chromosome and/ or TP53 mutation. This review focuses on some of the novel small molecules that are currently approved or in advanced clinical development. PMID- 26489502 TI - [News in the Supportive Care of Chronic Lymphocytic Leukemia]. AB - Patients with chronic lymphocytic leukemia have disrupted cellular and humoral immunity with quantitative and qualitative impairment of the cells of the immune system. Immunity disbalance leads to increased incidence of infections and autoimmune cytopenias. Supportive care for chronic lymphocytic leukemia focuses on prevention and treatment of these complications and consists of antimicrobial prophylaxis, substitution of immunoglobulins, immunosuppressive therapy, growth factors and blood transfusions. PMID- 26489503 TI - [Malignant Lymphomas - Past, Present and Future]. AB - This review summarizes the key steps on the way to understanding lymphoma biology and management. The history of lymphomas started in 1832 when Thomas Hodgkin first presented lymphomas. Classification of lymphoproliferative tumors has changed almost every 10 years as a reflection of deeper knowledge of this disease. Systemic therapy has developed in several steps starting by monotherapy with different chemotherapeutic agents, followed by the era of combination chemotherapy and by the rituximab era, which significantly changed the treatment paradigm. Several years ago, we entered into the fourth era characterized by many different targeted treatments. Radiotherapy remains an important part of lymphoma management. Lymphoproliferative tumors incidence is growing but mortality has started to decline starting in the year 2000 as the reflection of targeted therapy based on biology and pathogenesis. PMID- 26489504 TI - [Diffuse Large B cell Lymphoma - Modern Dia-gnostics and Molecularly Targeted Treatment]. AB - BACKGROUND: Diffuse large B -cell lymphoma is a common label for a number of clinico pathological entities, which differ in molecular pathogenesis, clinical presentation and prognosis. Exact correlation between clinico pathological and molecular subtypes of diffuse large B -cell lymphoma was not optimally defined; however, key signal transduction pathways were identified; blockage of these pathways may be therapeutically significant. AIM: The purpose of this review is to show current approach to dia-gnostics of diffuse large B -cell lymphoma on molecular levels, to summarize current firstline treatment options for newly diagnosed diffuse large B -cell lymphoma patients and to introduce new treatment possibilities, which are currently under investigation in clinical trials. RESULTS: Current molecular dia-gnostics of diffuse large B -cell lymphoma is evolving in two main directions. One direction is classification according to gene expression or protein levels. According to these studies, patients may be divided into subgroups according to the cell of origin or according their stromal signature. Most frequently used is classification accord-ing cell of origin (COO), which divides diffuse large B-cell lymphomas into GCB subtype (germinal B cell like) or ABC subtype (activated B-cell like). Second direction is studying genetic information on DNA level, where genetic mutations, deletions, amplifications and losses of heterozygozity are identified, which may be specific for subgroups defined by gene expression analysis, but may go across them. Both these directions aim at identifying signaling pathways important for survival and proliferation of tumor cells and in these, to identify targets for pharmacological block-age. Currently, standard of first-line treatment for all patients is antracyclinebased regimen with rituximab, which improved prognosis in both cell of origin subtypes, even if patients in the ABC subgroup have still inferior outcome. There is a number of new drugs with promising effectivity, which are studied in different phases of clinical trials (lenalidomide, bortezomib, idelalisib, venetoclax), but their possible effectivity will be limited only for precisely defined molecular subtypes of diffuse large B -cell lymphoma. CONCLUSION: The advent of new targeted drugs for diffuse large B- cell lymphoma is still awaited. For their effective use, besides the proof of their effectivity in randomized studies, also the extension of use of molecular methods in routine diagnostics and ensuring their wide availability will be necessary. PMID- 26489505 TI - [Follicular Lymphoma]. AB - Follicular lymphomas represent the second most frequent lymphoma subtype. Translocation t(14;18)(q32;q21) is a characteristic biologic hallmark. It is not sufficient to drive follicular lymphomas development and subsequent molecular defect appears which lead to follicular lymphomas development and progression. The microenvironment plays an important role. The disease is usually diagnosed in an advanced clinical stage. The course is mostly indolent, but there is a subgroup characterized by rapid progression. The outcome has been improved with median of progression free survival between 6-7 years and overall survival between 10 and 15 years. The outcome improvement was caused by introduction of immunotherapy - rituximab, both in induction as well as in maintenance therapy. Despite this improvement, subsequent relapses occur, they can be managed by a variety of approaches based on many factors. The most adverse event is histological transformation. The present review briefly summarizes understanding of biology, clinical course and management. PMID- 26489506 TI - [Mantle Cell Lymphoma - Cutting edge Dia-gnostics and Treatment Approaches]. AB - BACKGROUND: Mantle cell lymphoma represents a specific subtype of B -cell non Hodgkin lymphoma characterized on the molecular level by translocation t(11;14)(q13;q32) leading to aberrant overexpression of cyclin D1 and deregulation of the cell cycle. Despite sporadic indolent forms of mantle cell lymphoma, majority of patients present with advanced aggressive disease that requires immediate treatment. Despite chemosensitive nature of mantle cell lymphoma, approximately 10% patients present with a refractory disease, and the vast majority of patients who initially respond to therapy, relapse sooner or later. The course of mantle cell lymphoma thus represents a chronically relapsing malignancy requiring further and further lines of therapies. Prognosis of relapsed or refractory (R/ R) mantle cell lymphoma is dismal. AIM: The goal of this article is to provide a cutting -edge review of currently used diagnostic and treatment approaches for mantle cell lymphoma. RESULTS: Several key modifications of the therapeutic algorithm of mantle cell lymphoma treatment implemented in the past 10 years resulted in significantly improved prognosis of patients. The milestones in the therapy of mantle cell lymphoma include incorporation of anti-CD20 monoclonal antibody rituximab into induction therapy, intensification of polychemotherapeutic regimen including implementation of high dose cytarabine, consolidation of response with high-dose therapy and autologous stem cell transplantation (HDT ASCT) in younger fit patients, and maintenance therapy with rituximab in the elderly patients. Besides such "optimization" of frontline therapy, introduction of novel antilymphoma agents into therapy of R/ R mantle cell lymphoma also contributed (and will contribute in the future) to improved prognosis of mantle cell lymphoma. Among these agents, there is a new cytostatic drug bendamustine, Bruton tyrosine- kinase inhibitor ibrutinib, immunomodulatory agent lenalidomide, mTOR inhibitor temsirolimus and proteasome inhibitor bortezomib. CONCLUSION: The overall survival of mantle cell lymphoma virtually doubled in the recent 10 years as a result of two key factors: 1. optimization of frontline therapy with "conventional" antilymphoma agents, and 2. brand new possibilities of therapy for R/ R mantle cell lymphoma thanks to the introduction of novel antilymphoma agents. Combinatorial approaches using most efficacious combinations of novel and "conventional" anti-mantle cell lymphoma agents will definitely lead to further improvements of survival parameters in mantle cell lymphoma patients in near future. PMID- 26489507 TI - [Hodgkin's Lymhoma - the Treatment Aproaches Development and Current Trends]. AB - Hodgkins lymphoma is a relatively rare malignant disease, mostly affecting younger adults. It represents one of the most curable disease among all lymphomas and other malignant diseases of adult age, with curability more than 80%. The progress of curability and long term survival demonstrates the development of oncologic approach during the last few decades, depicted in this article, particularly by introduction of combined modality treatment (chemotherapy and radiotherapy), progress in radiotherapy technique, implementation of high intensity regimens for advanced stages and use of novel drugs as well. Because of high curability rate and young age of most of the patients, late toxic effects are of significant relevance. The ongoing clinical research is focused on better prognostic stratification offering the patients more individualized treatment by risk and response disease evaluation, aiming to reduce toxicity while maintaining high curability and introduction of novel, less toxic drugs and their use in early phases of treatment. PMID- 26489508 TI - [Salvage Treatment and the Role of Transplantation in Lymphomas]. AB - Despite achieving promising treatment results in patients with lymphoma, there is still a significant proportion of patients who relapse or have refractory disease. Salvage therapy followed by high dose treatment with autologous stem- cell transplantation is the standard of care in many of them. The role allogeneic stem- cell transplantation, especially after reduced intensity conditioning, is under extensive investigation. This review article presents current knowledge and recommendation in the salvage treatment of relapsed/ refractory lymphomas. PMID- 26489509 TI - [Current Approaches in Cancer Immunotherapy]. AB - Methods of cancer immunotherapy have finally entered clinical medicine after years of preclinical research. Currently, there are several methods, which have proven to be very effective even in cases of incurable cancer. Antitumor monoclonal antibodies are among major therapeutic anti-cancer drugs and have been successfully used for many ears. Novel group of antibodies are immunomodulatory antibodies which can break tumor -specific immune tolerance and induce regression of tumors by nonspecific activation of immune system. Bispecific antibodies represent a novel class of anticancer agents which can induce expansion of T cells in vivo, blinatumomab is an example of such agents and is currently available for the treatment of acute B -cell leukemia. Cellular immunotherapy is also very effective, especially the use of Chimeric receptor modified T-cells for the therapy of B- cell lymphoproliferative diseases. Although it is a very complicated and expensive method, it is highly effective approach which can induce remission even in previously hopeless conditions. The goal of this article is to explain the basic principles of cancer immunotherapy and summarize the newest findings in this field. PMID- 26489510 TI - Comparative study on gene set and pathway topology-based enrichment methods. AB - BACKGROUND: Enrichment analysis is a popular approach to identify pathways or sets of genes which are significantly enriched in the context of differentially expressed genes. The traditional gene set enrichment approach considers a pathway as a simple gene list disregarding any knowledge of gene or protein interactions. In contrast, the new group of so called pathway topology-based methods integrates the topological structure of a pathway into the analysis. METHODS: We comparatively investigated gene set and pathway topology-based enrichment approaches, considering three gene set and four topological methods. These methods were compared in two extensive simulation studies and on a benchmark of 36 real datasets, providing the same pathway input data for all methods. RESULTS: In the benchmark data analysis both types of methods showed a comparable ability to detect enriched pathways. The first simulation study was conducted with KEGG pathways, which showed considerable gene overlaps between each other. In this study with original KEGG pathways, none of the topology-based methods outperformed the gene set approach. Therefore, a second simulation study was performed on non-overlapping pathways created by unique gene IDs. Here, methods accounting for pathway topology reached higher accuracy than the gene set methods, however their sensitivity was lower. CONCLUSIONS: We conducted one of the first comprehensive comparative works on evaluating gene set against pathway topology-based enrichment methods. The topological methods showed better performance in the simulation scenarios with non-overlapping pathways, however, they were not conclusively better in the other scenarios. This suggests that simple gene set approach might be sufficient to detect an enriched pathway under realistic circumstances. Nevertheless, more extensive studies and further benchmark data are needed to systematically evaluate these methods and to assess what gain and cost pathway topology information introduces into enrichment analysis. Both types of methods for enrichment analysis require further improvements in order to deal with the problem of pathway overlaps. PMID- 26489511 TI - Danhong injection in the treatment of chronic stable angina: study protocol for a randomized controlled trial. AB - BACKGROUND: Chronic stable angina is a leading cause of death worldwide. Danhong injection, a complementary alternative medicine for chronic stable angina, has been demonstrated to be effective in numerous studies and is widely prescribed to patients. However, the methodological quality of most prior studies was found to be, in general, low. Therefore, we designed this randomized controlled trial to evaluate the efficacy and safety of using Danhong injection to treat chronic stable angina. METHODS/DESIGN: This is a randomized multicentre, double-blind, placebo-controlled, adaptive clinical trial. A total of 870 patients meeting the eligibility criteria will be randomly assigned into either the Danhong injection or the placebo group in a 2:1 ratio. Participants will then undergo a 2-week treatment regimen and a 76-day follow-up period. Because this is an adaptive trial, two interim analyses are prospectively planned. These will be performed after one-third and two-thirds of the patients, respectively, have completed the trial. Based on the results of these interim analyses, a data monitoring committee will determine how to modify aspects of the study without undermining the validity and integrity of the trial. The primary outcome measure is the proportion of patients who show a clinically significant change, which is defined as at least a 20-point improvement in angina frequency score on the Seattle Angina Questionnaire, which will be administered on day 30. Other secondary efficacy and safety outcomes will also be assessed. DISCUSSION: This trial will provide high-quality evidence regarding the use of Danhong injection to treat chronic stable angina. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01681316 . PMID- 26489512 TI - The German AugUR study: study protocol of a prospective study to investigate chronic diseases in the elderly. AB - BACKGROUND: The majority of patients suffering from chronic health disabilities is beyond 70 years of age. Typical late-onset chronic diseases include those affecting the heart, the kidney, cancer, and conditions of the eye such as age related macular degeneration. These diseases disable patients for many years and largely compromise autonomy in daily life. Due to challenges in recruiting the elderly, the collection of population-based epidemiological data as a prerequisite to understand associated risk factors and mechanisms is commonly done in the general population within an age-range of 20 to 70 years. METHODS/DESIGN: We establish the German AugUR study (Age-related diseases: understanding genetic and non-genetic influences - a study at the University of Regensburg), a prospective study in the mobile elderly general population in and around Regensburg in eastern Bavaria. In the long term, we aim to recruit 3,000 persons of Caucasian ethnicity with at least 70 years of age via residents' registration offices and conduct 3-year follow-ups. The study protocol includes a standardized interview regarding social and life-style factors, medication history, quality-of-life, and existing diagnoses of common diseases. The participants undergo medical examinations for ophthalmological, cardiovascular or diabetes-related conditions, and general measurements of body shape and fitness. The program is particularly tailored for the elderly. Biobanking of whole blood, serum, plasma, and urine is conducted and standard laboratory measurements are performed in fresh samples. DISCUSSION: AugUR is specifically designed as a research platform to host studies of late onset diseases. Consequently, this platform will help (1) to unravel the genetic and non-genetic etiology of disease development and progression, (2) to serve as control group of elderly individuals for comparisons with various patient groups, (3) to derive prevalence and incidence data on chronic diseases, and (4) to provide clinical reference parameters for the elderly mobile general population. This data will foster our understanding of disease mechanisms, which may ultimately help to improve prevention, diagnosis, and therapy for frequent chronic diseases. Here we present the baseline study protocol of AugUR. PMID- 26489513 TI - SIRT1 protects against myocardial ischemia-reperfusion injury via activating eNOS in diabetic rats. AB - BACKGROUND: Diabetic patients are more sensitive to myocardial ischemic injury than non-diabetic patients. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase making the heart more resistant to ischemic injury. As SIRT1 expression is considered to be reduced in diabetic heart, we therefore hypothesized that up-regulation of SIRT1 in the diabetic heart may overcome its increased susceptibility to ischemic injury. METHODS: Male Sprague-Dawley rats were fed with high-fat diet and injected with streptozotocin once to induce diabetes. Diabetic rats received injections of adenoviral vectors encoding SIRT1 (Ad-SIRT1) at five myocardial sites. Four days after adenoviral injection, the rats were subjected to myocardial ischemia and reperfusion (MI/R). Outcome measures included left ventricular function, infarct size, cellular death and oxidative stress. RESULTS: Delivery of Ad-SIRT1 into the hearts of diabetic rats markedly increased SIRT1 expression. Up-regulation of SIRT1 in diabetic hearts improved cardiac function and reduced infarct size to the extent as in non-diabetic animals following MI/R, which was associated with reduced serum creatine kinase-MB, lactate dehydrogenase activities and cardiomyocyte apoptosis. Moreover, Ad-SIRT1 reduced the increase in the superoxide generation and malonaldialdehyde content and simultaneously increased the antioxidant capability. Furthermore, Ad-SIRT1 increased eNOS phosphorylation and reduced eNOS acetylation in diabetic hearts. NOS inhibitor L NAME inhibited SIRT1-enhanced eNOS phosphorylation, and blunted SIRT1-mediated anti-apoptotic and anti-oxidative effects and cardioprotection. CONCLUSIONS: Overexpression of SIRT1 reduces diabetes-exacerbated MI/R injury and oxidative stress via activating eNOS in diabetic rats. The findings suggest SIRT1 may be a promising novel therapeutic target for diabetic cardiac complications. PMID- 26489514 TI - Runx2 contributes to the regenerative potential of the mammary epithelium. AB - Although best known for its role in bone development and associated structures the transcription factor RUNX2 is expressed in a wide range of lineages, including those of the mammary gland. Previous studies have indicated that Runx2 can regulate aspects of mammary cell function and influence the properties of cancer cells. In this study we investigate the role of Runx2 in the mammary stem/progenitor population and its relationship with WNT signalling. Results show that RUNX2 protein is differentially expressed throughout embryonic and adult development of the murine mammary gland with high levels of expression in mammary stem-cell enriched cultures. Importantly, functional analysis reveals a role for Runx2 in mammary stem/progenitor cell function in in vitro and in vivo regenerative assays. Furthermore, RUNX2 appears to be associated with WNT signalling in the mammary epithelium and is specifically upregulated in mouse models of WNT-driven breast cancer. Overall our studies reveal a novel function for Runx2 in regulating mammary epithelial cell regenerative potential, possibly acting as a downstream target of WNT signalling. PMID- 26489515 TI - Rearrangement of MICU1 multimers for activation of MCU is solely controlled by cytosolic Ca(2.). AB - Mitochondrial Ca(2+) uptake is a vital process that controls distinct cell and organelle functions. Mitochondrial calcium uptake 1 (MICU1) was identified as key regulator of the mitochondrial Ca(2+) uniporter (MCU) that together with the essential MCU regulator (EMRE) forms the mitochondrial Ca(2+) channel. However, mechanisms by which MICU1 controls MCU/EMRE activity to tune mitochondrial Ca(2+) signals remain ambiguous. Here we established a live-cell FRET approach and demonstrate that elevations of cytosolic Ca(2+) rearranges MICU1 multimers with an EC50 of 4.4 MUM, resulting in activation of mitochondrial Ca(2+) uptake. MICU1 rearrangement essentially requires the EF-hand motifs and strictly correlates with the shape of cytosolic Ca(2+) rises. We further show that rearrangements of MICU1 multimers were independent of matrix Ca(2+) concentration, mitochondrial membrane potential, and expression levels of MCU and EMRE. Our experiments provide novel details about how MCU/EMRE is regulated by MICU1 and an original approach to investigate MCU/EMRE activation in intact cells. PMID- 26489516 TI - Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury. AB - Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury. PMID- 26489518 TI - The Ehrlich-Schwoebel barrier on an oxide surface: a combined Monte-Carlo and in situ scanning tunneling microscopy approach. AB - The controlled growth of epitaxial films of complex oxides requires an atomistic understanding of key parameters determining final film morphology, such as termination dependence on adatom diffusion, and height of the Ehrlich-Schwoebel (ES) barrier. Here, through an in situ scanning tunneling microscopy study of mixed-terminated La5/8Ca3/8MnO3 (LCMO) films, we image adatoms and observe pile up at island edges. Image analysis allows determination of the population of adatoms at the edge of islands and fractions on A-site and B-site terminations. A simple Monte-Carlo model, simulating the random walk of adatoms on a sinusoidal potential landscape using Boltzmann statistics is used to reproduce the experimental data, and provides an estimate of the ES barrier as ~0.18 +/- 0.04 eV at T = 1023 K, similar to those of metal adatoms on metallic surfaces. These studies highlight the utility of in situ imaging, in combination with basic Monte Carlo methods, in elucidating the factors which control the final film growth in complex oxides. PMID- 26489517 TI - Aquaporin-9-expressing neutrophils are required for the establishment of contact hypersensitivity. AB - Aquaporin-9 (AQP9), a water/glycerol channel protein, is expressed in several immune cells including neutrophils; however, its role in immune response remains unknown. Here we show the involvement of AQP9 in hapten-induced contact hypersensitivity (CHS), as a murine model of skin allergic contact dermatitis, using AQP9 knockout (AQP9(-/-)) mice. First, the CHS response to hapten dinitrofluorobenzene (DNFB) was impaired in AQP9(-/-) mice compared with wild type (WT) mice. Adoptive transfer of sensitized AQP9(-/-) draining lymph node (dLN) cells into WT recipients resulted in a reduced CHS response, indicating impaired sensitization in AQP9(-/-) mice. Second, administration of WT neutrophils into AQP9(-/-) mice during sensitization rescued the impaired CHS response. Neutrophil recruitment to dLNs upon hapten application was attenuated by AQP9 deficiency. Coincidentally, AQP9(-/-) neutrophils showed a reduced CC chemokine receptor 7 (CCR7) ligand-induced migration efficacy, which was attributed to the attenuated recruitment of neutrophils to dLNs. Furthermore, we found that neutrophil deficiency, observed in AQP9(-/-) or neutrophil-depleted mice, decreased IL-17A production by dLN cells, which might be responsible for T cell activation during a subsequent CHS response. Taken together, these findings suggest that AQP9 is required for the development of sensitization during cutaneous acquired immune responses via regulating neutrophil function. PMID- 26489519 TI - Cell populations can use aneuploidy to survive telomerase insufficiency. AB - Telomerase maintains ends of eukaryotic chromosomes, telomeres. Telomerase loss results in replicative senescence and a switch to recombination-dependent telomere maintenance. Telomerase insufficiency in humans leads to telomere syndromes associated with premature ageing and cancer predisposition. Here we use yeast to show that the survival of telomerase insufficiency differs from the survival of telomerase loss and occurs through aneuploidy. In yeast grown at elevated temperatures, telomerase activity becomes limiting: haploid cell populations senesce and generate aneuploid survivors--near diploids monosomic for chromosome VIII. This aneuploidy results in increased levels of the telomerase components TLC1, Est1 and Est3, and is accompanied by decreased abundance of ribosomal proteins. We propose that aneuploidy suppresses telomerase insufficiency through redistribution of cellular resources away from ribosome synthesis towards production of telomerase components and other non-ribosomal proteins. The aneuploidy-induced re-balance of the proteome via modulation of ribosome biogenesis may be a general adaptive response to overcome functional insufficiencies. PMID- 26489520 TI - Associations between endothelial nitric oxide synthase polymorphisms and risk of diabetic nephropathy: an updated meta-analysis. AB - BACKGROUND: Genetic polymorphism of endothelial nitric oxide synthase (eNOS) has been implicated in the risk of diabetic nephropathy (DN), but the published findings were inconsistent. We performed a comprehensive meta-analysis to derive a more precise estimation of the association between genetic polymorphisms of eNOS and the risk of DN. METHODS: Six online database were researched on the associations between polymorphisms of eNOS (T786C, G894T, 4b/4a) and DN risk. PRISMA statement and Hardy-Weinberg equilibrium assessment were used in this report. Odds ratio and 95% confidence interval were estimated based on the following genetic contrast/models: allelic model, dominant model, recessive model and co-dominant model. The publication bias and sensitivity analysis were also performed to guarantee the statistical power. RESULTS: A total of 49 case-control studies with 11,990/9754/5131 participants for DN/DM/HC group were eligible for meta-analysis (7/25/31 studies for T786C/G984T/4b/a). For the eNOS-T786C, C allele showed a weak association between C allele and DN risk in DN/T2DM group. For eNOS-G894T, there was an association between T allele and DN risk in the global, Asian and African population in DN/T2DM group. For the eNOS-4b/4a, 4a allele was found contributing significantly to increased DN risk in the global population. CONCLUSION: Our comprehensive meta-analysis suggests that three polymorphisms of eNOS may be the increased risk factors of DN development, especially in Asian population and T2DM group. PMID- 26489521 TI - Coenzyme Q10 and alpha-Tocopherol Prevent the Lipid Peroxidation of Cooled Equine Semen. AB - Biotechnology applied for equine semen increases the levels of reactive oxygen species and reduces the natural antioxidant defence, by both dilution and removal of seminal plasma. Therefore, the aims of this study were to evaluate the effect of adding coenzyme Q10 (CoQ10) and alpha-tocopherol (alpha-TOH) to the cooling extender, singly or in combination, on sperm parameters, and their effectiveness in preventing lipid peroxidation (LPO) of equine semen during cooling at 5 degrees C for 72 h. Ten adult stallions of proven fertility were used, using two ejaculates each, subjecting them to the treatments with the following concentrations: alpha-TOH: 2 mm; CoQ10: 40 MUg/ml; and CoQ10 + alpha-TOH: 40 MUg/ml + 2 mm for control (C) without the addition of antioxidants and for vehicle control (EtOH) with 100 MUl ethanol. The CoQ10 group had a higher percentage of total motility (69.1 +/- 16.2%) compared to control (62.1 +/- 16.2%) and EtOH (58.1 +/- 18.6%). CoQ10 + alpha-TOH and alpha-TOH groups were most effective in preventing LPO compared to controls (1765.9 +/- 695.9, 1890.8 +/- 749.5, 2506.2 +/- 769.4 ng malondialdehyde/10(8) sptz, respectively). In conclusion, CoQ10 and alpha-TOH were effective during the cooling process of equine semen at 5 degrees C for 72 h, providing increased levels of total motility, as well as lower LPO. PMID- 26489523 TI - Probing the Ca(2+)-assisted pi-pi interaction during Ca(2+)-dependent protein folding. AB - Protein folding is governed by a balance of non-covalent interactions, of which cation-pi and pi-pi play important roles. Theoretical calculations revealed a strong cooperativity between cation-pi involving alkali and alkaline earth metal ions and pi-pi interactions, but however, no experimental evidence was provided in this regard. Here, we characterized a Ca(2+)-binding self-processing module (SPM), which mediates a highly-specific Ca(2+)-dependent autocatalytic processing of iron-regulated protein FrpC secreted by the pathogenic Gram-negative bacterium Neisseria meningitidis. The SPM undergoes a Ca(2+)-induced transition from an intrinsically unstructured conformation to the compact protein fold that is ultimately stabilized by the pi-pi interaction between two unique tryptophan residues arranged in the T-shaped orientation. Moreover, the pair of tryptophans is located in a close vicinity of a calcium-binding site, suggesting the involvement of a Ca(2+)-assisted pi-pi interaction in the stabilization of the tertiary structure of the SPM. This makes the SPM an excellent model for the investigation of the Ca(2+)-assisted pi-pi interaction during Ca(2+)-induced protein folding. PMID- 26489522 TI - Demographic, medical, and psychosocial predictors of benefit finding among caregivers of childhood cancer survivors. AB - BACKGROUND: There is a growing body of literature examining benefit finding, or finding positive outcomes in the face of adversity, among both adults and children with chronic conditions, and to some degree among caregivers. This study examined demographic, medical, and psychosocial predictors of greater benefit finding specifically among caregivers of childhood cancer survivors. METHODS: Caregivers of children who had completed treatment for cancer (n = 83) completed measures assessing child and caregiver demographic information and caregiver coping (active, acceptance, emotion-focused, and avoidant), optimism, social support, caregiving burden, posttraumatic stress symptoms, illness impact (how much caregivers feel impacted by their child's illness in various domains), and benefit finding (positive outcomes). RESULT: Regression analyses indicated that positive spiritual coping, optimism, and illness impact uniquely predicted overall benefit finding for caregivers of childhood cancer survivors. CONCLUSION: Results point to adaptive tendencies that are associated with finding benefits when caring for a childhood cancer survivor and suggest potential avenues for intervention among this population. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26489524 TI - Hollow silica-copper-carbon anodes using copper metal-organic frameworks as skeletons. AB - Hollow silica-copper-carbon (H-SCC) nanocomposites are first synthesized using copper metal-organic frameworks as skeletons to form Cu-MOF@SiO(2) and then subjected to heat treatment. In the composites, the hollow structure and the void space from the collapse of the MOF skeleton can accommodate the huge volume change, buffer the mechanical stress caused by lithium ion insertion/extraction and maintain the structural integrity of the electrode and a long cycling stability. The ultrafine copper with a uniform size of around 5 nm and carbon with homogeneous distribution from the decomposition of the MOF skeleton can not only enhance the electrical conductivity of the composite and preserve the structural and interfacial stabilization, but also suppress the aggregation of silica nanoparticles and cushion the volume change. In consequence, the resulting material as an anode for lithium-ion batteries (LIBs) delivers a reversible capacity of 495 mA h g(-1) after 400 cycles at a current density of 500 mA g(-1). The synthetic method presented in this paper provides a facile and low-cost strategy for the large-scale production of hollow silica/copper/carbon nanocomposites as an anode in LIBs. PMID- 26489525 TI - Life Cycle Assessment of Titania Perovskite Solar Cell Technology for Sustainable Design and Manufacturing. AB - Perovskite solar cells have attracted enormous attention in recent years due to their low cost and superior technical performance. However, the use of toxic metals, such as lead, in the perovskite dye and toxic chemicals in perovskite solar cell manufacturing causes grave concerns for its environmental performance. To understand and facilitate the sustainable development of perovskite solar cell technology from its design to manufacturing, a comprehensive environmental impact assessment has been conducted on titanium dioxide nanotube based perovskite solar cells by using an attributional life cycle assessment approach, from cradle to gate, with manufacturing data from our laboratory-scale experiments and upstream data collected from professional databases and the literature. The results indicate that the perovskite dye is the primary source of environmental impact, associated with 64.77% total embodied energy and 31.38% embodied materials consumption, contributing to more than 50% of the life cycle impact in almost all impact categories, although lead used in the perovskite dye only contributes to about 1.14% of the human toxicity potential. A comparison of perovskite solar cells with commercial silicon and cadmium-tellurium solar cells reveals that perovskite solar cells could be a promising alternative technology for future large-scale industrial applications. PMID- 26489526 TI - Serum concentration and skin tissue expression of insulin-like growth factor 2 in canine generalized demodicosis. AB - BACKGROUND: There is increasing evidence that insulin-like growth factor-2 (IGF 2) levels are altered in skin injury; there are no data evaluating the serum concentration and skin tissue expression of IGF-2 in canine generalized demodicosis. HYPOTHESIS/OBJECTIVES: To assess serum concentrations of IGF-2 collected from dogs with generalized demodicosis compared to healthy dogs and to determine the location of IGF-2 in the skin of affected dogs. METHODS: Blood and skin samples were collected from 12 dogs of differing breeds and gender at 1-2 years of age that had a confirmed diagnosis of generalized demodicosis. Age matched control skin and blood samples were collected from 11 normal dogs of different breeds and gender. Serum IGF-2 concentrations were measured by enzyme linked immunosorbent assay. Skin tissue expression of IGF-2 was analysed by immunohistochemical methods. RESULTS: Serum concentration and skin tissue expression of IGF-2 were increased in dogs with generalized demodicosis compared with control dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: These findings indicate that keratinocytes, histiocytes and fibrocytes in the dermis are positive for IGF 2; they may be a source of the elevated serum IGF-2 levels in dogs with generalized demodicosis. PMID- 26489527 TI - Hepatic splenosis. PMID- 26489528 TI - Markers of subsyndromal depression in very old persons. AB - OBJECTIVE: To investigate factors associated with subsyndromal depression (SSD) in very old persons, and to develop a model for prediction of SSD among very old persons. METHODS: A cross-sectional, population-based study was undertaken on 85 year-old persons in Sweden. Data were collected from a postal questionnaire, assessments in the participants' homes and at reception visits. Depressiveness was screened with GDS-15 (Geriatric Depression Scale), and the results were classified into three outcome categories: non-depression (ND), SSD and syndromal depression. Data were analysed with binary logistic, ordinal logistic and linear regression. RESULTS: With univariate logistic regression 20 factors associated with SSD were identified in very old persons, and the four hypothesized domains- sociodemographic factors, declining physical functioning, neuropsychiatric factors and existential factors--significantly related to SSD. The multivariate logistic model included seven independent factors that increase the likelihood of SSD instead of ND (lower self-perceived health, life not meaningful, problems with self-care, use of tranquilizing medication, no contact with neighbours, history of affective disorder and history of stroke). The ordinal logistic and the linear regression models resulted in seven partly different factors for predicting SSD and depressiveness, in the very old. CONCLUSIONS: The identified markers may help clinicians with the detection, prevention and treatment of SSD in very old persons. The findings indicate the importance of a comprehensive functional approach to diagnosing and treating depressiveness in this population, and the findings might be interpreted as offering support for the coexistence of a dimensional and a categorical view on depressive disorders. PMID- 26489529 TI - Evaluation of a protocol-based intervention to promote timely switching from intravenous to oral paracetamol for post-operative pain management: an interrupted time series analysis. AB - RATIONALE, AIMS AND OBJECTIVES: Timely switching from intravenous to oral therapy ensures optimized treatment and efficient use of health care resources. Intravenous (IV) paracetamol is widely used for post-operative pain management but not always switched to the oral form in a timely manner, leading to unnecessary increase in expenditure. This study aims to evaluate the impact of a multifaceted intervention to promote timely switching from the IV to oral form in the post-operative setting. METHODS: An evidence-based prescribing protocol was designed and implemented by the clinical pharmacy team in a single district general hospital in Egypt. The protocol specified the criteria for appropriate prescribing of IV paracetamol. Doctors were provided with information and educational sessions prior to implementation. A prospective, quasi-experimental study was undertaken to evaluate its impact on IV paracetamol utilization and costs. Data on monthly utilization and costs were recorded for 12 months before and after implementation (January 2012 to December 2013). Data were analysed using interrupted time series analysis. RESULTS: Prior to implementation, in 2012, total spending on IV paracetamol was 674 154.00 Egyptian Pounds (L.E.) ($23,668.00). There was a non-significant (P > 0.05) downward trend in utilization (-32 ampoules per month) and costs [reduction of 632 L.E. ($222) per month]. Following implementation, immediate decrease in utilization and costs (P < 0.05) and a trend change over the follow-up period were observed. Average monthly reduction was 26% (95% CI: 24% to 28%, P < 0.001). CONCLUSION: A multifaceted, protocol-based intervention to ensure timely switching from IV-to oral paracetamol achieved significant reduction in utilization and cost of IV paracetamol in the first 5 months of its implementation. PMID- 26489530 TI - Microhydration Effects on the Ultrafast Photodynamics of Cytosine: Evidences for a Possible Hydration-Site Dependence. AB - Ultrafast excited-state deactivation dynamics of small cytosine (Cy) and 1 methylcytosine (1mCy) microhydrates, Cy?(H2O)1-3 and 1mCy?(H2O)1,2, produced in a supersonic expansion have been studied by mass-selected femtosecond pump-probe photoionization spectroscopy at about 267 nm excitation. The seeded supersonic expansion of Ar/H2O gas mixtures allowed an extensive structural relaxation of Cy and 1mCy microhydrates to low-energy isomers. With the aid of electronic structure calculations, we assigned the observed ultrafast dynamics to the dominant microhydrate isomers of the amino-keto tautomer of Cy and 1mCy. Excited state lifetimes of Cy?(H2O)1-3 measured here are 0.2-0.5 ps. Comparisons of the Cy?H2O and 1mCy?H2O transients suggest that monohydration at the amino Watson Crick site induces a substantially stronger effect than at the sugar-edge site in accelerating excited-state deactivation of Cy. PMID- 26489531 TI - Outcomes of One straight-line flow with and without pedal arch in patients with critical limb ischemia. AB - OBJECTIVES: This study aimed to compare the outcomes of revascularization strategies for patients with critical limb ischemia (CLI) whereby single vessel run off to the foot was established with or without flow into a patent pedal arch. METHODS: We retrospectively analyzed data from 312 consecutive patients with CLI who underwent endovascular therapy (EVT) between December 2009 and February 2011. Below-the-knee angiography identified one vessel run off in 137 patients (44%), and we aimed to compare the outcomes between those patients where revascularization resulted in one-straight-line flow into a patent pedal arch (76 limbs, Group A) versus those who attained one straight-line flow to the distal end of a tibial vessel without flow into a patent pedal arch (61 limbs, Group B). The study endpoints were amputation free survival rate, limb salvage rate and wound healing rate at 12 months after EVT. RESULTS: Amputation free survival rate differed significantly between groups (88.2% in group A vs. 65.6% in group B, P = 0.01). Limb salvage rate also differed between groups (98.4% vs.89.3%, P = 0.03). Wound healing rate showed a trend towards difference between the two groups (89.4% vs. 80.6% P = 0.11). CONCLUSIONS: Among patients with CLI where only one vessel runoff can be established to the foot, direct flow into a patent pedal arch is essential to improve their clinical outcomes. (c) 2015 Wiley Periodicals, Inc. PMID- 26489532 TI - Azobenzene C-Nucleosides for Photocontrolled Hybridization of DNA at Room Temperature. AB - Herein, we report the reversible light-regulated destabilization of DNA duplexes by using azobenzene C-nucleoside photoswitches. The incorporation of two different azobenzene residues into DNA and their photoswitching properties are described. These new residues demonstrate a photoinduced destabilization effect comparable to the widely applied D-threoninol-linked azobenzene switch, which is currently the benchmark. The photoswitches presented herein show excellent photoswitching efficiencies in DNA duplexes - even at room temperature - which are superior to commonly used azobenzene-based nucleic acid photoswitches. In addition, these photoswitching residues exhibit high thermal stability and excellent fatigue resistance, thus rendering them one of the most efficient candidates for the regulation of duplex stability with light. PMID- 26489533 TI - Chasing the Mirage: a grounded theory of the clinical reasoning processes that Registered Nurses use to recognize delirium. AB - AIM: The aim of this study was to construct a grounded theory that explains the clinical reasoning processes that registered nurses use to recognize delirium in older adults in acute care hospitals. BACKGROUND: Delirium is under-recognized in acute hospital settings, this may stem from underdeveloped clinical reasoning processes. Little is known about registered nurses' (RNs) clinical reasoning processes in complex situations such as delirium recognition. DESIGN: A grounded theory approach was used to analyse interview data about the clinical reasoning processes of RNs in acute hospital settings. METHOD: Seventeen RNs were recruited. Concurrent data collection and comparative analysis and theoretical sampling were conducted in 2013-2014. FINDINGS: The core category to emerge from the data was 'chasing the mirage', which describes RNs' clinical reasoning processes to recognize delirium during their interaction with older adults. CONCLUSION: Understanding the reasoning that contributes to delirium under recognition provides a strategy by which, this problem can be brought to the forefront of RNs' awareness and intervention. Delirium recognition will contribute to quality care for older adults. PMID- 26489534 TI - A fluorosurfactant and photoreducible Cu(II)-tren click catalyst: surfactant and catalytic properties at liquid/liquid interfaces. AB - The fluorous copper(ii) complex [Cu(II)(trenRf6)3-benzoylbenzoate]3 benzoylbenzoate 2, composed of a highly fluorophilic tris(2-aminoethyl)amine ligand and two 3-benzoylbenzoates as counterions and photosensitizers, was synthesized from the dinuclear complex [Cu(3-benzoylbenzoate)4(H2O)2] 1 which was characterized by X-ray analysis. Complex 2, which is highly soluble in perfluorocarbons, moderately soluble in organic solvents while insoluble in water, was found to be a very effective fluorosurfactant. At the air/water interface it formed a Langmuir film, which upon compression slowly collapsed at about 28 mN m(-1), which corresponds to a surface area of about 220 A(2) per molecule. Tensiometric measurements revealed that 2 is more rapidly adsorbed at the diisopropyl ether (DIPE)/water interface than the perfluorodecalin (PFD)/water one, leading to a decrease of the interfacial tensions of about 14 mN m(-1) and 40 mN m(-1), respectively. Photoreduction of 2 occurs effectively in H donating solvents such as THF and DIPE, or even in PFD ensuring that an electron donor, such as propargyl alcohol, is present in a separate aqueous phase. Complex 2, when combined with light (365 nm), catalyzes the click reaction between the azide 3 and alkyne 4 under homogeneous conditions (methanol), to afford the disaccharide 5. Under emulsified biphasic DIPE/water or PFD/water conditions, the reactions proceeded well. However, it was shown that a fast and significant amount of copper and 3-benzoylbenzoate counterion was transferred into the aqueous phase, and that most of the catalysis could be ascribed to a copper species solubilised in the aqueous phase, and not to the fluorous copper complex accumulated at the interface. PMID- 26489535 TI - Nanoscale UiO-MOF-based luminescent sensors for highly selective detection of cysteine and glutathione and their application in bioimaging. AB - We report a practical approach, the first of its kind, to construct nanoscale UiO type metal-organic framework (Mi-UiO-66 and Mi-UiO-67) fluorescent probes for the detection of Cys and GSH. They showed high sensitivity (10(-11) M) and selectivity for Cys and GSH, and their fluorescence imaging of Cys and GSH in living cells was well demonstrated. PMID- 26489536 TI - Mitigating measles outbreaks in West Africa post-Ebola. AB - The Ebola outbreak in 2014-2015 devastated the populations, economies and healthcare systems of Guinea, Liberia and Sierra Leone. With this devastation comes the impending threat of outbreaks of other infectious diseases like measles. Strategies for mitigating these risks must include both prevention, through vaccination, and case detection and management, focused on surveillance, diagnosis and appropriate clinical care and case management. With the high transmissibility of measles virus, small-scale reactive vaccinations will be essential to extinguish focal outbreaks, while national vaccination campaigns are needed to guarantee vaccination coverage targets are reached in the long term. Rapid and multifaceted strategies should carefully navigate challenges present in the wake of Ebola, while also taking advantage of current Ebola-related activities and international attention. Above all, resources and focus currently aimed at these countries must be utilized to build up the deficit in infrastructure and healthcare systems that contributed to the extent of the Ebola outbreak. PMID- 26489537 TI - Sexual transmission of Lyme disease: challenging the tickborne disease paradigm. AB - Lyme disease caused by the spirochete Borrelia burgdorferi has become a major worldwide epidemic. In this article, we explore the clinical, epidemiological and experimental evidence for sexual transmission of Lyme disease in animal models and humans. Although the likelihood of sexual transmission of the Lyme spirochete remains speculative, the possibility of Lyme disease transmission via intimate human contact merits further study. PMID- 26489538 TI - Personalized treatment of severe pneumonia in cancer patients. AB - Patients with cancer are at increased risk for sepsis as a consequence of immunosuppression. The hospital mortality remains elevated and it could be attributed to antibiotic failure because of the presence of multiresistant pathogens. Once the patient is critically ill, the use of the American Thoracic Society/Infectious Diseases Society of America classification does not seem very useful in the assessment of outcomes and the choice of antimicrobials. In critically ill patients, the characteristics of clinical response to antibiotics are usually inaccurate and occur late in the course of disease. So, the sequential evaluation of C-reactive protein-ratio is useful in the early identification of patients with antibiotic failure. To achieve safe and efficient antimicrobial therapy, we proposed an algorithm that may aid clinicians in their decision-making process. PMID- 26489539 TI - Prevention of viral infections in patients with multiple myeloma: the role of antiviral prophylaxis and immunization. AB - Viral infections are a major cause of morbidity and mortality in patients with myeloma. Over the last decade, treatment of myeloma has undergone a paradigm shift with the use of immunomodulatory drugs, proteasome inhibitors and autologous stem cell transplantation, resulting in changes to risk periods and risk factors for viral infection. Viral infections affecting this patient group fall broadly into reactivation of latent viral infections (e.g., varicella zoster and hepatitis B) and acquisition of acute viral respiratory infections. The periods following autologous stem cell transplantation and progressive disease are identified as increased risk for viral infections. This review focuses on evidence-based prevention strategies for key viral infections, particularly approaches to prophylaxis and immunization. Recommended prevention strategies are summarized using a risk-stratified approach. Further studies evaluating preventative measures for newly identified risk periods are required. PMID- 26489540 TI - [Mechanisms of Epstein-Barr Virus-Mediated Oncogenesis]. AB - Epstein-Barr virus(EBV), a ubiquitous human double-stranded DNA virus, is associated with a variety of malignancies including Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. Latent EBV infections have been discovered in cases of EBV -associated cancers, suggesting that EBV latent genes contribute to oncogenesis. Here, I describe mechanisms of oncogenesis associated with EBV, focusing on functions of EBV latent membrane protein(LMP)and EBV-encoded small RNA (EBER). LMP2A, which mimics B cell receptor signaling, and LMP1, which mimics CD40 signaling, collaboratively contribute to malignant lymphoma development. It has been reported that LMP2A-mediated intracellular signaling plays significant roles in epithelial carcinogenesis. However, it has also been demonstrated that EBER, which is expected to have a double-stranded RNA(dsRNA)structure, triggers signal transduction via host viral RNA sensors, RIG-I and TLR3, causing EBV-associated pathogenesis, including carcinogenesis. PMID- 26489541 TI - [Chemoradiation Therapy]. AB - Chemoradiation therapy (CRT) is a standard treatment for various cancers, including squamous cell carcinoma of the head and neck, non-small cell lung cancer, and rectal cancer. Regarding the sequence of radiation therapy and chemotherapy, concurrent CRT has yielded superior clinical results. However, CRT causes an increase in acute and late toxicities, despite improving local control and survival rates. The introduction of high-precision radiation therapy such as intensity modulated radiation therapy and newly developed chemotherapeutic drugs or molecularly targeted agents may further improve clinical outcomes while keeping treatment-related toxicities at an acceptable level. PMID- 26489542 TI - [New Combination Therapy to Improve the Functional Preservation Rate of the Larynx in Laryngeal, Oropharyngeal, and Hypopharyngeal Cancers]. AB - A new combination therapy has been developed to achieve high overall survival and functional laryngeal preservation rates in head and neck cancers, which require laryngectomy. In order to treat the primary site without resection, superselective intra-arterial infusions with DCF anterogradely and 60 mg/m2 of DOC and 60 mg/m2 of CDDP via the femoral artery on day 1 were administered, followed by continuous intravenous instillation of 750 mg/m2/day of 5-FU for 5 days from day 2. The 5- year survival rate was 70.4% in laryngeal cancer, 72.8% in oropharyngeal cancer, and 68.5% in hypopharyngeal cancer. The 5-year functional laryngeal preservation rate was 71.0% in laryngeal cancer, 63.4% in oropharyngeal cancer, and 65.2% in hypopharyngeal cancer. In addition to regional lymph node control, a thorough neck dissection was performed. Good overall survival and functional laryngeal preservation rates were achieved. PMID- 26489543 TI - [Current Status and Future Prospects of Chemoradiotherapy for Esophageal Cancer]. AB - Chemoradiotherapy is a very important factor and one of the 2 pillars of esophageal cancer treatment. Although esophagectomy is the standard treatment for clinical stage I(T1N0M0)esophageal cancer, chemoradiotherapy is reported to be effective. Currently, a phaseIII clinical trial is underway to compare patients who undergo esophagectomy and those who receive radical chemoradiotherapy. Esophagectomy after neoadjuvant chemotherapy is the standard treatment for clinical stageII/III(except for T4) esophageal cancer, whereas chemoradiotherapy is regarded as the standard treatment for patients who wish to preserve their esophagus, those who refuse surgery, and those with inoperable disease. Chemoradiotherapy, rather than surgical treatment, is usually selected for clinical stageIV (T4/M1LYM) esophageal cancer. While curability increases with chemoradiotherapy, late adverse events such as cardiopulmonary toxicity and safety problems with salvage treatment of cases with residual tumor or recurrent cancer have been observed. New irradiation techniques using radiation technology are being developed, such as intensity-modulated radiation therapy (IMRT). These innovations are expected to improve treatment results by avoiding irradiation of at-risk organs, without reducing the target radiation volume. New treatments, including salvage protocols, introduction of new radiotherapy equipment such as IMRT, and new drugs, are being developed, and further advances are anticipated. PMID- 26489544 TI - [Chemoradiotherapy for Locally Advanced Pancreatic Cancer]. AB - The use of FOLFIRINOX and gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer is currently approved in Japan. Although the efficacies of these regimens were investigated only in patients with metastatic pancreatic cancer, they are also expected to be effective for locally advanced pancreatic cancer. Meanwhile, chemoradiotherapy is recognized as a treatment option for locally advanced pancreatic cancer. S-1 or capecitabine-based chemoradiotherapy is being developed in Japan or in Western countries, respectively. Recently, the concept of induction chemotherapy followed by chemoradiotherapy has been accepted and applied in clinical trials. In the JCOG1106 trial, induction gemcitabine followed by S-1 and concurrent radiotherapy demonstrated promising results. This regimen has been recognized as a very promising one for chemoradiotherapy in Japan. However, the optimal therapy for locally advanced pancreatic cancer remains controversial, especially in terms of which between chemotherapy and chemoradiotherapy is superior. PMID- 26489545 TI - [Current Status and Perspective of Chemoradiotherapy for Uterine Cervical Cancer]. AB - Fifteen years has passed since the NCI announced the clinical importance of concurrent chemoradiotherapy (CCRT) in radiotherapy for patients with locoregionally advanced uterine cervical cancer. Numerous clinical trials have been performed to further improve the outcomes of CCRT. In addition to investigations of chemotherapeutic regimens and schedules, adaptation of novel radiotherapy methods such as image-guided brachytherapy (IGBT) and intensity modulated radiotherapy (IMRT) is encouraged in CCRT for cervical cancer. PMID- 26489546 TI - [Gemcitabine in Combination with Cisplatin in Patients with Unresectable Advanced or Recurrent Biliary Tract Cancer--A Multicenter Prospective Observational Study in Fukuoka]. AB - The standard chemotherapy for the treatment of unresectable advanced and recurrent biliary tract cancers is considered gemcitabine plus cisplatin (GC) on the basis of favorable results reported in the ABC-02 study from the UK and the BT22 study from Japan. However, the GC cohort of the BT22 study consisted of only 42 patients, and we considered it necessary to confirm the effectiveness and safety of GC chemotherapy in a multicenter prospective observational study in Fukuoka. Thirty-seven patients were enrolled in this study, including two patients with recurrent disease. The median patient age was 67.5 years (range, 43 84 years). Twelve patients had intrahepatic cholangiocarcinoma, 13 patients had extrahepatic cholangiocarcinoma, and 12 patients had gallbladder cancer. The median survival time (MST) was 14.9 months, the 1-year survival rate was 54.5%, and the median progression free survival (PFS) was 7.7 months. No chemotherapy related deaths occurred, and Grade 3/4 adverse events were mainly hematological events including leucopenia in 13 (35.1%) patients and neutropenia in 12 (32.4%). The MST, 1-year survival rate, median PFS, and rate of Grade 3/4 adverse events in our study were similar to those of the BT22 study. In conclusion, this multicenter prospective observational study confirms the effectiveness and safety of GC chemotherapy for the treatment of unresectable advanced and recurrent biliary tract cancers. PMID- 26489547 TI - [Determination of the Appropriate Timing of Aprepitant Administration for Nausea in Patients with Head and Neck Cancer Receiving Combination Chemotherapy with Docetaxel, Nedaplatin(Divided Doses for 5 Days), and 5-fluorouracil]. AB - The objective of this study was to determine the appropriate timing of aprepitant administration in patients with oral cancer by comparing the antiemetic effect of aprepitant administered on the first day (first-day group) and third day (third day group) of combination chemotherapy with docetaxel, nedaplatin (divided doses for 5 days), and 5-fluorouracil. 1. In both groups, very few cases of vomiting were observed. Therefore, we could not compare the incidence of vomiting. 2. The mean highest grade of nausea in the third-day group was significantly higher than that in the first-day group (2.33+/-0.71 vs 0.78+/-0.22, p=0.002; U-test). 3. In addition, the mean area under the curve of the chronological changes in the grade of nausea in the third-day group was significantly higher than that in the first day group (13.44+/-9.58 vs 3.11+/-3.59, p=0.019; U-test). 4. The incidence of nausea of grade 2 or higher in the first-day group was significantly lower than that in the third-day group (11.1% [1/9] vs 88.9% [8/9], p<0.001; c 2 test). These results indicate that initiation of aprepitant administration on the first day of combination chemotherapy with docetaxel, nedaplatin, and 5-fluorouracil successfully prevented the development of nausea in patients with oral cancer. PMID- 26489548 TI - [Introduction and PDCA-Management of a Liaison-Clinical Pathway with Cancer Patients after a Curative Operation]. AB - Our hospital was appointed as an Osaka designated cancer care hospital in April 2012. At that time, we introduced the same liaison-clinical pathway with cancer patients after a curative operation in all of Osaka. Based on the management of the plan-do-check-act cycle, we found problems in the clinical pathway. These problems included the following: the clinical pathway was not known, was complicated, was troubling for patients, and not well understood by doctors. To solve these problems, we planned and carried out the following five measures. The first was public information, followed by practice processes, informed consent, patient referral documents, and clinical pathway investigation reports. We were able to promote the use of the liaison-clinical pathway by constantly improving these measures. PMID- 26489549 TI - [Thrombophlebitis in an Elderly Japanese Woman Treated with Tamoxifen for Breast Cancer]. AB - In this study, we report the rare case of an elderly woman who developed thrombophlebitis after being treated with tamoxifen for breast cancer. She visited our department with a lump in her left breast. She underwent core needle biopsy, and she was diagnosed with breast cancer (invasive ductal carcinoma, ER- and PgR-positive, HER2-negative). We chose hormonal therapy because surgical treatment was deemed too invasive considering her general status. She was administered tamoxifen (20 mg/day) instead of an aromatase inhibitor in consideration of her osteoporosis. Six months after initiating tamoxifen therapy, she exhibited swelling in her left leg. Computed tomography and ultrasound revealed thrombophlebitis in her left femoral vein. She stopped taking tamoxifen and started warfarin potassium as thrombolytic therapy, after which thrombophlebitis was relieved. Advanced age may be a risk factor for thrombophlebitis associated with tamoxifen treatment; therefore, precautions should be taken accordingly. PMID- 26489550 TI - [A Case of Abdominal Para-Aortic Lymph Node Recurrence of Gastric Cancer Treated with Radiotherapy, Surviving More Than 5 Years]. AB - A 66-year-old man was diagnosed with advanced type 2 gastric cancer and underwent total gastrectomy. The pathological diagnosis was T3N2H0P0CY0M0, stage IIIB gastric cancer. Consequently, the patient received adjuvant S-1 therapy for 12 months. Thirty months after the operation, para-aortic lymph node recurrence was evident by computed tomography (CT). As a result, combination chemotherapy with paclitaxel, 5-fluorouracil, and cisplatin was initiated. However, after three courses of chemotherapy, abdominal CT showed progressive disease of the recurrent lymph node. Thereafter, radiotherapy at a total dose of 56 Gy was performed. After the radiotherapy treatment, abdominal CT demonstrated a remarkable reduction of the recurrent lymph node. The patient remains alive, with no signs of relapse, 70 months later. Therefore, this case suggests that radiotherapy may represent an effective treatment for localized remote lymph node recurrence of gastric cancer. PMID- 26489551 TI - [Long-Term Survival of a Patient with KRAS Mutated Colon Cancer Successfully Treated with Regorafenib]. AB - A 65-year-old woman underwent iliocecal resection for cecal cancer. During post operative follow-up, she was diagnosed with metastasis to the abdominal wall and a curative resection was performed. After 12 courses of adjuvant chemotherapy with a modified combination of folinic acid, 5-fluorouracil, and oxaliplatin (mFOLFOX6), recurrence was noted in the lung. A curative resection was successfully performed and she was subsequently treated with bevacizumab and a combination of folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI). One year after surgical resection, recurrence in the remnant lung was diagnosed. Because of the KRAS mutation, she could not be treated with anti-epidermal growth factor antibodies. The metastatic lung tumor continued to enlarge. Therefore, we selected regorafenib as third-line chemotherapy. After treatment with regorafenib, the size of the target lesion decreased significantly. PMID- 26489552 TI - [Improved Response to 5-FU Using Dose Adjustment and Elastomeric Pump Selection Based on Monitoring of the 5-FU Level--A Case Report]. AB - A 6 1-year-old man with unresectable multiple hepatic metastases after resection of sigmoid colon carcinoma was treated with irinotecan and infused 5-fluorouracil (5-FU) plus Leucovorin (FOLFIRI). Since the levels of tumor markers increased, the 5-FU dose was increased from 2,700 to 3,000 mg/m2 using a Jackson-type pump and an extended infusion time of 53 hours. The blood level of 5-FU was 507 ng/mL 16 hours after starting the infusion. The pump was then changed to a bottle-type pump with the same dose of 3,000 mg/m2. At 16 hours, the 5-FU level was 964.5 ng/mL. The areas under the concentration vs. time curve (AUC mg?h/L)were 21 and 44 mg?h/L for the Jackson- and bottle-type pumps, respectively. Owing to the development of Grade 3 stomatitis and hand-foot syndrome, 5-FU was reduced to 2,700 mg/m2 with a bottle-type pump. The AUC decreased to 27 mg?h/L, but the liver metastases were reduced and the adverse effects subsided to Grade 1. This case shows that individual dose adjustment of 5-FU to the appropriate AUC based on pharmacokinetic monitoring of the blood 5-FU level can improve the response, reduce adverse effects, and have a clinical benefit. PMID- 26489553 TI - [Cooperation between a Hospital without Dentists and Local Dental Associations in Oral Management of Cancer Patients]. AB - Severe oral mucositis induced by cancer chemotherapy can cause intolerable pain and increase the risk of systemic infections, necessitating dose reduction and discontinuation of antineoplastic agents. Moreover, this adverse effect may have an impact on patient nutrition and quality of life. An effective and prophylactic intervention should be useful for alleviating this complication. Because Nagoya Memorial Hospital has neither a dentistry nor an oral surgery department, we collaborated with dental associations near the hospital. First, we performed a questionnaire survey on the present status of the members of the local dental associations. The survey showed that 86% of the community dentists were interested in communicating with our hospital. In addition, they agreed to provide us with information on their specialty and status of amenities. In discussion with the community dentists, we decided on fax-based communication for collaboration to improve the quality of oral management in cancer patients. Three seminar series were conducted to share updated information on cancer treatment and enhance communication between the medical doctors and the dentists. Our hospital has registered 129 community dentists and enrolled 81 cancer patients in this medical and dental cooperation initiative. PMID- 26489554 TI - [Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Aromatase Inhibitor-Resistant Metastatic Breast Cancer]. AB - We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) during fulvestrant therapy for aromatase inhibitor (AI)-resistant metastatic breast cancer. IDO activity can be measured by the tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured with high performance liquid chromatography (HPLC). Patients with AI resistant metastatic breast cancer had a 28.6% response rate to fulvestrant therapy, and the clinical benefit rate was 76.2%. AI-resistant metastatic breast cancer patients with distant metastases had a lower serum Trp/Kyn level than patients who had local recurrences. During fulvestrant therapy, IDO activity significantly decreased in the fulvestrant responder group compared to that in the fulvestrant non-responder group. During fulvestrant therapy, the IDO activity correlated with the number of metastatic lesions. These results suggest that measuring the Trp/Kyn ratio is useful for evaluating immunological metastatic status during endocrine therapy. PMID- 26489555 TI - [Therapeutic Potential of Targeting Cancer-Associated Fibroblasts in Esophageal Cancer]. AB - Advances in molecular and cellular biochemistry, such as the development of targeted cancer therapy, have dramatically improved the prognosis of cancer patients. Emerging data have suggested that bevacizumab treatment may act by controlling the cancer microenvironment. Many reports have examined the interaction of cancer cells with the tumor microenvironment, and cancer associated fibroblasts (CAFs) are thought to play a central role in this process. We speculated that the cancer microenvironment and in particular, CAFs, strongly influence the development of esophageal cancer. We have analyzed the signaling pathways of molecular targets. However, inhibition of a single signaling pathway is insufficient to treat cancer effectively. Photoimmunotherapy is a molecular targeted specific cancer therapy using near-infrared radiation, which was introduced by Mitsunaga et al. in 2011. We are using its specific method of killing cells to target CAFs. We will report the results of its effect on cancer cells in the future. PMID- 26489556 TI - [Local Microwave Hyperthermia for Advanced or Recurrent Breast Cancer]. AB - The purpose of our study was to test the efficacy and toxicity of hyperthermia for treating breast cancer. Ten patients received treatment (AC, paclitaxel, S-1, and aromatase inhibitor) in combination with hyperthermia. The hyperthermia device was a microwave heating device with water loaded and water-cooled waveguides. The temperature was monitored subcutaneously in the skin under the aperture of the waveguide. Two patients had a partial response to treatment with only mild toxicity (grade 1 acute skin toxicity). Therefore, hyperthermia combined with chemotherapy for treating breast cancer seems to be effective and generally tolerable. A larger patient cohort is needed to confirm these results in the future. PMID- 26489557 TI - [Skeletal Mass Depletion Is a Negative Prognostic Factor in Gastrointestinal Cancer Patients in the Terminal Stage]. AB - BACKGROUND: Skeletal mass depletion has been reported to be a prognostic factor for cancer patients. However, special and expensive devices are required to measure skeletal mass, and this is a major reason why skeletal mass is not used extensively for prognostic marker in clinical settings. We developed a new method to measure skeletal mass for use as a prognostic marker using CT images without special and expensive devices. In this study, we evaluated the usefulness of skeletal mass as measured by this new method as a prognostic marker for gastrointestinal cancer patients. METHOD: Patients who died from gastrointestinal cancer between March 2010 and October 2013 were included. We measured the right sided maximum psoas muscle cross sectional area (MPCA) by using CT images before surgery and after the patients developed a terminal condition. The maximum psoas muscle cross sectional area ratio (MPCA-R) was defined as follows: MPCA-R=MPCA before surgery/MPCA after developing a terminal condition. We evaluated the correlation between MPCA-R and survival. RESULT: Fifty-nine patients were included. The median survival was 44 days, and MPCA-R was significantly correlated with survival (p=0.001). On receiver operating characteristic (ROC) analysis, the area under the curve (AUC) to predict 30-day and 90-day survival was 0.710 and 0.748, respectively. CONCLUSION: MPCA-R is a new and novel prognostic marker for gastrointestinal cancer patients in terminal condition. PMID- 26489558 TI - [Pretreatment and Posttreatment Evaluations of Circulating Tumor Cells(CTC)in Patients with Metastatic Breast Cancer]. AB - Recently, circulating tumor cells (CTCs) of cancer patients have been analyzed as a biomarker of disease progression and as a new prognostic tool.We conducted a pilot study to determine whether CTCs present before and after chemotherapy or peptide vaccination predicted outcome in patients with metastatic breast cancer (MBC). CTCs were isolated from the peripheral blood of MBC patients and evaluated using the CellSearch(r)System (Janssen Diagnostics). The expression of the HLA classI molecule in the CTCs was analyzed simultaneously by using a flow cytometric system. A CTC-positive test result was defined as five or more CTCs/7.5 mL blood. Nine patients (median [range] age, 64.2 years [44-80 years]) were included. Four (57.1%) of 7 MBC patients with Luminal A subtype tested positive for CTC.Of 6 MBC patients, 5 (83.3%) had a decreased mean number of CTCs, from 35.8/7.5 to 0.4/7.5 mL, after 3 courses of systemic chemotherapy. Furthermore, CTC-HLA class Iexpression level was decreased in 2 (66.7%) of 3 patients after cytotoxic chemotherapy but increased in 4 (80.0%) of 5 patients after 6 vaccinations with tumor-specific peptide vaccines. The number of CTCs and CTC-HLA class I expression level in the patients with MBC changed after the treatment with systemic chemotherapy or peptide-vaccine therapy. PMID- 26489559 TI - [Identification of Circulating Tumor Cell(CTC)in Breast Cancer Patients Using a Newly Established CTC Detecting System]. AB - We developed a new circulating tumor cell (CTC) chip in order to identify CTCs in the peripheral blood of cancer patients. In this study, we aimed to identify CTCs in the blood of breast cancer patients by using this CTC detecting system. In addition, we used this system to evaluate the response to anticancer agents. We were able to identify CTCs in 5 of 6 patients. In addition, the system showed that the number of CTCs had decreased after chemotherapy. Thus, the CTC detecting system was useful in the identification of CTCs in the breast cancer patients and in the early prediction of response to anticancer agents. PMID- 26489560 TI - [Immuno-Nutritional Factors Affecting the Incidence of Surgical Site Infection(SSI)after Rectal Cancer Surgery]. AB - BACKGROUND: We analyzed immune nutritional factors that affected the incidence of SSI in rectal cancer surgery. METHOD: A total of 103 patients who underwent rectal cancer resection were enrolled in this retrospective study. The risk factors (DM, BMI<18.5, >=25.0, PNI<=40, G/L>2, CONUT>=2, mGPS D) for SSI (Grade>=II) were analyzed. RESULT: The factors that significantly affected SSI (in 13 cases) was PNI<=40 on univariate analysis. In the analysis adjusted by age and sex, mGPS D and PNI<=40 were significant factors. In the stepwise selection method, PNI<=40 was selected as an independent factor. CONCLUSION: As a risk factor for SSI after rectal cancer surgery, PNI<=40 and mGPS were risk factors. PMID- 26489561 TI - [Clinical Experience of Nutritional Support in Patients Treated with Chemoradiotherapy for Locally Advanced Esophageal Cancer]. AB - BACKGROUND: We investigated the efficacy of nutritional support in patients treated with chemoradiotherapy (CRT) for locally advanced esophageal cancer (LAEC). METHODS: Eleven patients treated with CRT for locally advanced esophageal squamous cell carcinoma were included. Oral intake energy expenditure (OIE) and total energy expenditure (TEE) of all patients were calculated. Oral nutrition supplementations (ONSs) were utilized as nutritional therapy for the patients with malnutrition (OIE/TEE<0.6). Enteral nutrition (EN) was used in the patients with tumor obstruction. RESULT: Two patients (18.9%) received ONS and 2 other patients received EN. Seven patients were able to take enough energy in the meal. The mean energy charge was increased from 67.9%to 84.9%. Nine patients (81.8%) completed the treatment regimen. During the CRT period, the prognostic nutritional index (PNI) and C-reactive protein level (mg/dL) were not significantly different. The body mass index decreased to 0.39 kg/m2 (p=0.039) and the mean weight loss was 1.57%. The overall response rate was 81.8%. CONCLUSION: The nutritional support in the patients treated with CRT for LAEC is effective for maintaining nutritional status. Moreover, the response rate is satisfactory. PMID- 26489562 TI - [Examination of the Response Rate of Paclitaxel and Bevacizumab Therapy for Metastatic Advanced Breast Cancer According to the Lymphopenia Grade]. AB - Bevacizumab is a well-established anti-VEGF monoclonal antibody that inhibits angiogenesis. Herein, we examined the response rates according to the grade of lymphopenia in metastatic breast cancer patients treated with bevacizumab+paclitaxel therapy. The objective responses were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) Guideline v1.1. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Twenty study patients were divided into group A (grade 2-4 lymphopenia) and group B (grade 1 lymphopenia or no decreased lymphocyte count) and compared. The mean progression-free survival (PFS)was 77.7 days in group A (n=7) and 56.8 days in group B (n=13). There was no significant difference between both groups (p=0.67, logrank test). The response rate (RR) was 14.3% (CR=0, PR=1, SD=3, PD=3) in group A, while in group B, it was 23.0% (CR=0, PR=3, SD= 6, PD=4). Furthermore, the clinical benefit rate (CBR) bwas 57.1% in group A and 69.2% in group B. PMID- 26489563 TI - [Effect of Natural Killer Cell Infiltration on the Growth of Breast Cancer Patient-Derived Tumor Xenografts]. AB - Natural killer (NK) cells, a component of the innate immunity, play important roles in tumor suppression. In this study, three human breast cancer patient derived tumor xenografts (PDXs), established by the transplantation of surgical specimens, were passaged in immunodeficient NOD/SCID mice or NSG mice, that further lacks NK cell activity. The intensity of the relative growth suppression between NOD/SCID and NSG mice was clearly different depending on the PDX lines, and it was associated with the intensities of the CD49b-positive NK cell infiltration in the PDX tumor tissues. However, no obvious association was observed between the mRNA expression levels of the NK cell ligands in the PDX tumor cells and the intensity of NK cell infiltration into the PDX tumors. These results suggest that the suppressive effect of NK cells on the growth of breast cancer PDX is highly variable depending on the PDX lines. Further studies are needed to elucidate the molecular mechanism of NK cell infiltration in PDX tumors. PMID- 26489564 TI - [The Postoperative C-Reactive Protein Level Is an Early Predictor of Infectious Complications after Gastric Cancer Resection]. AB - AIM: The aim of this study was to investigate whether postoperative serum C reactive protein (CRP) levels can be used to predict the risk of postoperative infections in patients undergoing gastric cancer resection. METHODS: Data from 77 patients who had undergone open gastrectomy for gastric cancer between 2008 and 2014 were retrospectively collected. Clinical details including postoperative white blood cell(WBC)count, CRP levels, and platelet (Plt) counts were obtained. The occurrence of complications as defined by the Clavien-Dindo classification was the outcome, particularly anastomotic leakage or pancreatic fistula. The diagnostic accuracy was determined by measuring the area under the receiver operating characteristic( ROC)curve. RESULTS: The overall incidence of anastomotic leakage or pancreatic fistula was 9.1%. Using CRP on POD 3 had superior diagnostic accuracy for anastomotic leakage or pancreatic fistula (area under the curve [AUC]: 0.898, 95%CI: 0.809-0.987). A cut off of 20.1 mg/dL for the CRP level on POD 3 yielded a sensitivity of 85.7% and a negative predictive value of 98.3%for the detection of anastomotic leakage or pancreatic fistula. CONCLUSIONS: Elevated CRP levels on POD 3 may help physicians predict the occurrence of postoperative complications after gastric cancer resection, particularly anastomotic leakage and pancreatic fistula. PMID- 26489565 TI - [Indoleamine 2,3-Dioxygenase Activity during I131-Radioisotope Therapy for Metastatic Thyroid Cancer]. AB - We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) during I131-radioisotope therapy for metastatic thyroid cancer. The IDO activity can be measured by the tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured by using high performance liquid chromatography (HPLC). The serum Trp/Kyn levels of were lower in thyroid cancer patients with lung metastases than in patients without metastases. The IDO activity increased after the development of lung metastases from thyroid cancer. The IDO activity was correlated with the number of metastatic lesions during I131-radioisotope therapy. These results suggest that measurement of the Trp/Kyn ratio is useful in the evaluation of the immunological metastatic status during I131-radioisotope therapy. PMID- 26489566 TI - [Stereotactic Body Radiotherapy with CyberKnife(r)for Liver Metastases from Colorectal Cancer]. AB - For treatment of colorectal liver metastases, liver resection is recommended for resectable cases in the clinical guidelines for colorectal cancer. On the other hand, there are currently no data supporting the efficacy of radiation therapy as a topical treatment, and this treatment can therefore not presently be recommended. With CyberKnife(r), it is possible to perform stereotactic radiation therapy using a linear accelerator with high accuracy, even for lesions in the trunk area such as liver metastases. Between December 2009 and September 2014 in our hospital, we performed radiation treatment using CyberKnife(r) for 14 cases with 22 colorectal liver metastases. As a result, we obtained response and local control rates of 76.2%and 81.0%, respectively. Moreover, no advanced adverse events were observed. Thus, we consider that CyberKnife(r) treatment for colorectal liver metastases is effective as a topical treatment, with low invasiveness and high safety. PMID- 26489567 TI - [A Case of Mucinous Cystadenocarcinoma of the Retroperitoneum Supposed to Be Derived from Ectopic Ovarian Tissue]. AB - Most tumors arising in the retroperitoneum are non-epithelial, and epithelial tumors are very rare. We report a case of mucinous cystadenocarcinoma of the retroperitoneum supposed to be derived from ectopic ovarian tissue. A 56-year-old woman was admitted to the hospital because of abdominal distention, and an abdominal CT scan revealed a cystic tumor of the right lower retroperitoneum. We had been observing the patient for 10 years for this lesion, but at this point, the tumor showed an increase in size and nodules had appeared inside of the cyst. It was presumed to be malignant, and so the decision was made to perform resection. Upon laparotomy, a large cystic tumor was found in the right iliac fossa displacing the ascending colon and the cecum medially. The cyst had no connection with any surrounding structures. The tumor was a simple large cyst, measuring 9*7 cm, with a protruding papillary tumor inside. The inner space of the cyst was filled with mucinous fluid. Histologically, the tumor was diagnosed as a mucinous cystadenocarcinoma. The patient has currently been undergoing follow-up for 7 months with no evidence of recurrence. PMID- 26489568 TI - [Experience of the Pharmacotherapy against Appendix and Sigmoid Colon Signet Ring Cell Carcinoma with the Peritoneal Dissemination]. AB - We report 2 cases of signet ring cell carcinoma of the appendix and colon. Case 1: A 61-year-old man was admitted for lower abdominal pain. Colonoscopy revealed an elevated lesion in the orifice of the appendix. Signet ring cell carcinoma was diagnosed on biopsy. The surgical findings showed multiple peritoneal dissemination nodules, while the primary tumor was unresectable owing to extensive invasion into the retroperitoneum. The histopathological findings were signet ring cell carcinoma, T4b (retroperitoneum), NX, P3, Stage IV. Although the patient received 14 courses of treatment with S-1 as postoperative chemotherapy, he died of his illness at 32 postoperative months. Case 2: A 76-year-old man was admitted for abdominal pain. Perforation of the lower gastrointestinal tract was diagnosed on abdominal CT, and an emergency operation was performed. The surgical findings demonstrated a large number of peritoneal dissemination nodules, cecal invasion of a sigmoid tumor, and perforation of the ascending colon. The primary tumor was thought to be unresectable, and the perforated segment was resected. The histopathological findings were signet ring cell carcinoma, T4b (cecum), NX, P3, Stage IV. Although 11 courses of treatment using FOLFIRI+Bev were administered as postoperative chemotherapy, the patient died of his illness at 26 postoperative months. PMID- 26489569 TI - [A Case of Adenosquamous Carcinoma of the Ascending Colon]. AB - We report a case of adenosquamous carcinoma of the colon. A 70-year-old woman underwent a colonoscopic examination because of a positive fecal occult blood test. Colonoscopy demonstrated a type 2 tumor of the ascending colon, and a biopsy specimen showed poorly-moderately differentiated tubular adenocarcinoma. We performed a right hemicolectomy with D2 lymphadenectomy. The histopathology of the tumor demonstrated adenosquamous adenocarcinoma. Primary adenosquamous carcinoma of the colon is relatively rare and has a poor prognosis. Therefore, adenosquamous carcinoma of the colon may require strict follow-up. PMID- 26489570 TI - [A Case of Radical Resection of Rectal Cancer with Multiple Liver and Lung Metastases after Preoperative Chemotherapy]. AB - We report a case of radical resection of rectal cancer with multiple liver and lung metastases after preoperative chemotherapy. A 54-year-old woman presented with abdominal pain and loss of body weight due to rectal cancer with multiple liver and lung metastases. Therefore, the patient received 14 courses of bevacizumab+mFOLFOX6, and 7 courses of panitumumab+FOLFIRI. After the chemotherapy, the size of the distant metastases reduced by 62% on computed tomography, according to RECIST. Due to the reduction in size, a conversion surgery was attempted. First, an abdominal operation with laparoscopy was performed, and 2 months later an operation to resect the lung metastases via thoracoscopy was performed. Currently, 3 months after surgery, the patient is alive, without recurrence. PMID- 26489571 TI - [Difficulty in Preoperative Diagnosis of Residual Gastric Cancer after Distal Gastrectomy for Duodenal Ulcer]. AB - A 67-year-old man underwent distal gastrectomy via the Billroth II method (B-II) for a duodenal ulcer. He presented with appetite loss and nausea in May 2014. Gastrointestinal endoscopy revealed wall thickness around gastrojejunostomy and the gastric mucosal fold. Biopsy and re-biopsy revealed a group 2 tumor. Laparotomy for diagnosis was performed because of stenosis and tumor progression. Intraoperative frozen section examination revealed adenocarcinoma in the lymph nodes of the jejunum. Residual gastrectomy with reconstruction using the Roux-en Y method was performed for residual gastric cancer. Histopathological findings revealed pT4a, pN0, pM1 for the tumor in the lymph nodes of the jejunum, pStage IV. A distorted gastrojejunostomy site and the presence of anastomotic strictures are important for the rapid diagnosis of residual gastric cancer. PMID- 26489572 TI - [Two Cases of Small Bowel Obstruction Due to Postoperative Adhesions Treated with Laparoscopic Adhesiolysis]. AB - We occasionally require surgical treatment for postoperative adhesion ileus. One patient had adhesion ileus 14 times in 14 years after distal gastrectomy and Billroth-Ireconstruction for gastric cancer. He underwent laparoscopic adhesiolysis for a small bowel obstruction that adhered to the entire surface. Another patient experienced adhesion ileus 7 times in 1.5 years after distal gastrectomy and Billroth-Ireconstruction for gastric cancer. He underwent laparoscopic adhesiolysis for a small bowel obstruction adhering to the scar and the retroperitoneum. After laparoscopic treatment, he underwent an open operation for ischemic colitis but no small bowel obstruction was found. Laparoscopic adhesiolysis was found to be useful in both cases. PMID- 26489573 TI - [Study of the Response Rate and Neutrophil Lymphocyte Ratio in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy]. AB - The neutrophil lymphocyte ratio (NLR) is associated with the outcomes of some cancer patients such as those with digestive cancer. Herein, we examined the relationship between the response rate following neoadjuvant chemotherapy and NLR in breast cancer patients. We recruited 19 primary breast cancer patients who were administered neoadjuvant chemotherapy. We evaluated the effects of this treatment and classified the patients into responder (CR and PR) and non responder (SD and PD) groups. We measured the value of NLR before or at the start of nab-PTX treatment, and 7 days after nab-PTX (1-1) and nab-PTX (4-3) treatment. The average age was 58.6 years. The responder and non-responder groups comprised 14 and 5 cases, respectively. The average values of NLR before or at the start of the nab-PTX phase were 4.33 and 5.05 in the responder and non-responder groups, respectively. The average NLR values 7 days after nab-PTX (1-1) were 6.72 and 5.60 in the responder and non-responder groups, respectively. The NLR values 7 days after nab-PTX (4-3) were 2.40 and 2.65 for the responder and non-responder groups, respectively. There were no significant differences between the responder and non-responder groups for each treatment phase. PMID- 26489574 TI - [Preoperative Chemotherapy and Risk Factors for Colorectal Liver Metastases]. AB - Between February 2007 and December 2013, 65 liver resections for colorectal metastases were performed in our institution. Preoperative chemotherapy was conducted in 47 patients, of whom 42 were treated with modified FOLFOX6 (mFOLFOX6)-based preoperative chemotherapy. For cases of solitary tumors smaller than 2 cm that are located in the liver surface area, we selected upfront surgery. In the patients who underwent preoperative chemotherapy and upfront surgery, the 3-year OS was 73.9% (Grade A: 81.8%, Grade B: 77.8%, and Grade C: 0%) and the 5-year OS was 62.5%. The 3-year OS in the preoperative chemotherapy group was 63.3%. OS did not differ significantly between the patients who were grouped according to the time of metastasis onset or the extent of metastasis according to the Japanese classification. In the multivariate analysis, no statistical differences were found between the risk factors for recurrence. However, further follow up is needed. Moreover, we believe that the relationships of morphological response to chemotherapy, pathological response, and clinical prognosis should be assessed in the future. PMID- 26489575 TI - [Clinicopathological Features and Outcomes of Treatment for HER2 Positive Gastric Cancer]. AB - In March 2011, trastuzumab was approved for treating human epidermal growth factor receptor 2 (HER2) positive advanced gastric cancer (AGC) in Japan. Therefore, all patients with AGC should be evaluated for HER2 status. In this study, we analyzed the clinicopathological features and current status of treatment in HER2 positive gastric cancer. One hundred 6 gastric cancer patients were examined for HER2 expression in our hospital between March 2011 and August 2014. Sixteen patients (15.1%) were HER2 positive. There was no correlation between HER2 status and age, sex, and location of tumor; however, HER2 positivity was significantly more frequent in patients with intestinal type tumors and had a tendency towards being more frequent in patients with macroscopic types 0, 1 or 2. Trastuzumab was administered to 10 patients with HER2 positive AGC. The total number of doses of trastuzumab was 1 to 44 (median 7.5), and the therapeutic effect of trastuzumab combination chemotherapy was 1 patient with a complete response and 4 with a partial response. Adverse events due to trastuzumab were not observed. The incidence of HER2 over-expression was 15.1%, and trastuzumab combination chemotherapy was relatively safe and effective. PMID- 26489576 TI - [A Case of Locally Advanced Rectal Cancer Successfully Treated by Conversion Surgery after Multidisciplinary Treatment]. AB - A 70-year-old woman who complained of abdominal pain and a prolapsed tumor from the anus was diagnosed with an intestinal obstruction resulting from anal canal cancer. Computed tomography (CT) and magnetic resonance imaging revealed a huge tumor (11*5*12 cm) invading the vagina and levator ani muscle. Enlarged inguinal lymph nodes on both sides indicated metastasis. The clinical stage was T4b (vagina, levator ani muscle, and pudenda) N0H0M1a (LYM), stage IV (Japanese Classification of Colorectal Carcinoma: 8th edition). As curative resection was not possible, a transvers colostomy was performed to relieve the intestinal obstruction. This was followed by chemoradiotherapy (45 Gy/1.8 Gy*25; TS-1, 80 mg/body for 2 weeks and a 1-week interval, for 2 courses) and up to 10 courses of Bev+mFOLFOX6 continuously. After this regimen, there was a remarkable reduction in tumor size. Positron emission tomography-CT revealed no FDG uptake in the primary rectal site or inguinal lymph nodes, but a maximum standardized uptake value (SUVmax) of 6.3 was detected in the vagina. Six weeks after chemotherapy, the patient underwent a pelvic exenteration including resection of the vagina, bladder, and pudenda. The pathological stage was yp T4b (vagina) N0H0M0, stageII. Curative resection was performed, and the patient had a Grade 2 pathological response after chemoradiotherapy. PMID- 26489577 TI - [A Case of HER-2 Positive Advanced Gastric Cancer Responding to Capecitabine+Cisplatin+Trastuzumab Chemotherapy]. AB - A 67-year-old woman was referred to our hospital for type 1 gastric cancer. We diagnosed the patient with advanced gastric cancer (tub2>por, HER2-positive), and the clinical findings were T4aN1M1 (lung), Stage IV. The patient had cancer cachexia. As first-line chemotherapy, a regimen consisting of capecitabine (X) (1,600 mg/m2/day, days 1-14), cisplatin (P) (60 mg/m2/day, day 1), and trastuzumab (H) (8 mg/kg/day>6 mg/kg/day, day 1) was administered every 3 weeks and repeated 6 times. After receiving 6 courses, the patient's general condition and cancer cachexia symptoms improved. The size of the primary lesion significantly decreased, and lung metastasis was not visible on a PET scan. Simultaneously, a new 0-IIc tumor was detected in the cardia, and a biopsy revealed a malignant lymphoma. Total gastrectomy and D2 lymph node dissection without splenectomy were performed. The final diagnosis was T4aN0M0. After treatment, the tumor was histologically evaluated as Grade 1b, and the remnant cancer cells were found to be HER2-negative (loss of HER2). The patient has been alive for 5 months and is receiving adjuvant chemotherapy comprising capecitabine and trastuzumab. Following chemotherapy containing trastuzumab, the patient with cachexia who was diagnosed with unresectable HER2-positive advanced gastric cancer showed improvement in the cachexia symptoms and the disappearance of lung metastasis. PMID- 26489578 TI - [A Case of Extranodal Nasal Type, NK/T Cell Lymphoma in the Ileum with Perforated Peritonitis during Chemotherapy]. AB - A 65-year-old woman complaining of melena and a high fever was admitted to our hospital. Colonoscopy revealed a large tumor with a wide ulcer in the terminal ileum, and nasal type, extranodal NK/T cell lymphoma was suspected via biopsy. Owing to rapid progression of hepatocellular damage with hepatomegaly and splenomegaly, chemotherapy with CHOP was initiated immediately. Two days later, the patient developed panperitonitis, and emergency laparotomy was performed. The tumor in the terminal ileum widely adhered to the bladder, where a deep perforated ulcer was found, for which palliative ileocecal resection was performed. Enlargement of the residual tumor caused an abdominal abscess, intestinal obstruction, and hepatic failure, and the patient died 75 days after surgery. In summary, we initiated chemotherapy to control the deteriorating systemic condition of the patient. However, nasal type, extranodal NK/T cell lymphoma is a rapidly progressing lymphoma occasionally accompanied by perforation of the tumor. Surgery preceding chemotherapy should be considered an alternative treatment. PMID- 26489579 TI - [A Case of Gastrointestinal Stromal Tumor of the Stomach after Pancreatoduodenectomy]. AB - We report a case of gastrointestinal stromal tumor of the stomach 17 years after pancreatoduodenectomy(PD). The patient was an 83-year-old man who had undergone PD for chronic pancreatitis at 65 years of age. Gastric endoscopy revealed a 2.5 cm gastric submucosal tumor on the lesser curvature of the stomach, which was the gastrojejunostomy site. As the gross appearance of the tumor showed ulceration at the top of the tumor, the patient underwent total gastrectomy and Roux-en-Y reconstruction. Histopathological examination demonstrated that the tumor was a GIST of the stomach. Currently, 5 years after surgery, no recurrence has been observed. Therefore, postsurgical care for a malignant disease may require a strict follow-up for a long time. PMID- 26489580 TI - [A Case of Resected Gastric Cancer Invading the Esophagus with Esophageal Recurrence That Responded to Weekly Docetaxel/Cisplatin Chemotherapy]. AB - A 77-year-old man underwent total gastrectomy with D1+ lymph node dissection after being diagnosed with cT4aN2M0, cStage IIIB gastric cancer. Peritoneal dissemination was detected in the bursa omentalis. The pathological diagnosis after surgery was pT4aN3b (21/41) M1 (P1). He was treated with 6 courses of S-1 chemotherapy. Two years after surgery, upper gastrointestinal endoscopy revealed the presence of a tumor in the mid-thoracic esophagus. It was diagnosed to as metastatic esophageal cancer and treated with combination chemotherapy consisting of docetaxel (25 mg/m2, days 1, 8, 15) and cisplatin (25 mg/m2, days 1, 8, 15) in a 28-day cycle. A clinically complete response was observed after 5 courses of chemotherapy. Currently, the patient is alive with no signs of recurrence 12 months after the initial recurrence. PMID- 26489581 TI - [A Case of Esophageal Cancer in a Patient with CMV Reactivation after Neoadjuvant Chemoradiation Therapy]. AB - A 68-year-old woman was diagnosed with advanced esophageal cancer with lymph node metastasis, for which she received neoadjuvant chemoradiotherapy. During therapy, she had loss of appetite and weight; therefore, we inserted a nasal feeding tube for her nutrition, after which, she gained weight soon. After therapy, she had a high fever with lymphocytopenia and was diagnosed with cytomegalovirus infection because of significantly high CMV antigenemia. Ganciclovir was administered immediately, and she recovered soon. Two months later, we performed esophagectomy, and she recovered without complications. Immediate diagnosis of CMV infection, ganciclovir administration, and nutrition through a feeding tube were useful for the esophageal cancer patient in this report who had immunosuppression and malnutrition during chemoradiation. PMID- 26489582 TI - [Relationship between Polymorphisms and the Efficacy of Cetuximab]. AB - BACKGROUND AND OBJECTIVES: Cetuximab has shown efficacy in patients with metastatic colorectal cancer (mCRC). Recent studies have demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC), mediated via the fragment c gamma receptors(FcgR)in mCRC. Since the establishment of KRAS mutations as a major negative predictor of efficacy, additional biomarkers have been found to be useful for the improvement of selection of patients likely to be responsive to cetuximab. We investigated the relationship between polymorphisms and the outcome of mCRC patients treated with cetuximab. METHODS: In this study, 57 patients were evaluated. The relationships of FcgR polymorphisms with response rate (RR), progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: The FcgR polymorphisms were not significantly related to RR, PFS, and OS. Compared with the other haplotypes, the haplotype containing the 131H and 158V alleles was related to a lower RR (p=0.018). The diplotypes containing 131H and 158V alleles had significantly lower RR than the other diplotypes (p=0.038). CONCLUSION: Our data suggest that FcgR polymorphisms may be associated with the outcome of mCRC patients treated with cetuximab and FOLFIRI. However, these results are currently controversial, and detailed investigations are needed to confirm the relationship between FcgRs polymorphisms and cetuximab efficacy. PMID- 26489583 TI - [Treatment Strategy for Stage IV Rectal Cancer]. AB - Eighteen consecutive patients who underwent rectal resection following preoperative chemotherapy for cStage IV rectal cancer at our institute, between 2009 and 2014, were retrospectively assessed. Preoperative chemotherapy with mFOLFOX6, SOX, XELOX, and other anticancer agents was administered to 8, 5, 3, and 2 patients, respectively. Combined molecular targeted therapy was administered to 12 patients. The response evaluation showed that an antitumor effect was observed in 10 and 8 patients with local tumors who achieved a partial response (PR) and stable disease (SD), respectively, and in 9 and 9 patients with distant metastases who achieved a PR and SD, respectively. The operative procedures included high/low anterior resection (n=12), intersphincteric resection (n=2), and abdominoperineal resection/Hartmann's operation (n=4). An ileostomy was performed in 6 patients before chemotherapy. Postoperative complications occurred in 6 patients. Two patients with an ileostomy had anastomotic insufficiency, but recovered without reoperation. There was no significant difference in overall survival (p=0.382) when these patients were compared with 45 cStage IV rectal cancer patients who underwent surgery without preoperative chemotherapy. However, the rate of curability B was higher in patients who received preoperative chemotherapy (44.4%) compared to those who did not (26.7%). The results of this study are inconclusive and have not determined whether preoperative chemotherapy results in better long-term survival for cStage IV rectal cancer patients. However, preoperative chemotherapy might contribute to higher operative curability. PMID- 26489584 TI - [Short-Term Outcome of TAS-102 for Refractory Metastatic Colorectal Cancer]. AB - We retrospectively analyzed 7 patients with refractory colorectal cancer treated with TAS-102 as salvage therapy. Subjects were 3 men and 4 women. The median age at initiation of TAS-102 was 71 years (range, 41-82 years). The number of target organs was 1 in 5 patients, 2 in 1 patient, and 3 in 1 patient. The median treatment courses were 2 courses (range, 1-6 courses). The reason for discontinuation was hematological toxicity in 1 patient, patients' wish in 3 patients, disease progression in 2 patients, and worsening of general condition in 1 patient. The median survival time since the first administration of TAS-102 was 9 months. PMID- 26489585 TI - [Everolimus plus Exemestane in Postmenopausal Metastatic Breast Cancer Patients]. AB - The purpose of our study was to test the efficacy and toxicity of everolimus plus exemestane therapy for breast cancer. Between 2014 and 2015, 20 patients diagnosed with breast carcinoma were selected for this retrospective study. Patients received everolimus plus exemestane. As a result, 4 patients showed a partial response to treatment and the median PFS was 2.5 months (range, 1-9). The most common adverse events (AEs) associated with combination therapy were stomatitis, rash, dysgeusia, and non-infectious lung disease. The AEs reported were mostly grade 1 and 2, and manageable with appropriate intervention. Therefore, everolimus plus exemestane therapy for breast cancer seems to be effective and generally tolerable. PMID- 26489586 TI - [A Case of Concurrent Cancer of the Esophagus and Stomach with Severe Sepsis following Chemotherapy]. AB - A 66-year-old man was diagnosed with synchronous early esophageal cancer and advanced gastric cancer. He received CDDP-based combination chemotherapy (docetaxcel, CDDP, and TS-1). During chemotherapy for gastric cancer, he suddenly developed septic shock, requiring intensive treatment with antibiotics, intravenous immunoglobulin, circulatory and respiratory care, and hemoperfusion with a polymyxin B column. He also had disseminated intravascular coagulation (DIC), complicated by sepsis. Recombinant human soluble thrombomodulin (rTM) was administered to treat DIC. The intensive treatments described above allowed the patient to recover from septic shock and DIC several days later. Early and adequate treatment could be used to rescue a compromised cancer-bearing patient from septic shock following chemotherapy. PMID- 26489587 TI - [A Case of Von Hippel-Lindau Disease with Nonfunctioning Pancreatic Neuroendocrine Tumors Treated by Duodenum-Preserving Resection of the Head of the Pancreas and Spleen-Preserving Resection of the Tail of the Pancreas]. AB - A 26-year-old woman presented to our department with a diagnosis of multiple nonfunctioning pancreatic neuroendocrine tumors. She had a family history of pheochromocytoma and a medical history of bilateral adrenalectomy for pheochromocytoma at the age of 25 years. During follow-up treatment for adrenal insufficiency after the surgery, highly enhanced tumors in the pancreas were detected on contrast-enhanced CT. Other examinations found that the patient did not satisfy the clinical criteria for von Hippel-Lindau (VHL) disease. Considering her age and risk of developing multiple heterotopic and heterochronous tumors, we performed a duodenum-preserving resection of the head of the pancreas and spleen-preserving resection of the tail of the pancreas with informed consent. The histopathological findings revealed that all of the tumors were NET G1. She underwent genetic testing postoperatively and was diagnosed with VHL disease. This diagnosis meant that we were able to create an optimal treatment plan for the patient. If a tumor predisposition syndrome is suspected, VHL disease should be borne in mind and genetic testing after genetic counseling should be duly considered. PMID- 26489588 TI - [A Case of Pseudo-Meigs Syndrome Associated with Metachronous Ovarian Metastasis from Ascending Colon Cancer]. AB - We experienced a case of pseudo-Meigs syndrome associated with metachronous metastasis to the ovary from ascending colon cancer. A 65-year-old woman underwent curative surgery for ascending colon cancer at another hospital. A follow-up CT carried out 3 months after the surgery revealed a right ovarian tumor and a large amount of ascites. The patient was diagnosed with ovarian metastasis from ascending colon cancer with carcinomatous peritonitis. Palliative care was recommended, and she presented at our department for a second opinion. In spite of a large amount of ascites and pleural effusion, no disseminating tumor was detected on contrast-enhanced CT at our hospital, and we recommended that she undergo a diagnostic laparotomy. The laparotomy was negative for carcinomatous peritonitis and a right oophorectomy was performed. The histopathological findings indicated that the ovarian tumor was consistent with metastasis from ascending colon cancer. After the surgery, we initiated chemotherapy with mFOLFOX6+bevacizumab and the symptoms were well controlled. A follow-up CT carried out 11 months after the surgery revealed a left ovarian tumor and increased ascites, and the patient underwent a left oophorectomy. Then, chemotherapy with the same regimen was administered for 12 months, and she did not develop any signs of recurrence for 27 months after the surgery. Ovarian metastasis from colon cancer may occasionally cause pseudo-Meigs syndrome, and it is important to be aware of the usefulness of oophorectomy for the control of ascites and pleural effusion. PMID- 26489589 TI - Benign multicystic peritoneal mesothelioma presenting as a ghost abdominal mass. PMID- 26489590 TI - The short- and long-term effectiveness of transcatheter arterial embolization in patients with intractable hematuria. AB - PURPOSE: Selective transarterial embolization (TAE) of the internal iliac artery is a well-known alternative technique to control intractable bladder hemorrhage (IBH). We explored the short- and long-term effectiveness of, and clinical outcomes after, TAE in patients with IBH. MATERIALS AND METHODS: In this retrospective study, we reviewed the hospital records of 18 IBH patients non responsive to conservative medications who underwent TAE between January 2003 and May 2014. The early- and long-term effectiveness of TAE was investigated in the context of hematuria control, complications, mortality, requirement for blood transfusions, and hematocrit level. RESULTS: Sixteen of the 18 patients underwent endovascular treatment; the technical success rate was 88%. TAE allowed complete remission in 16 patients (100% clinical success). On follow-up, mean hematocrit (P=0.003) and hemoglobin (P=0.005) levels significantly improved. Thirteen of the 16 patients (81%) required no further emergency admission after TAE during a mean follow-up period of 18.1months (range, 3-105months). CONCLUSION: TAE is a feasible, effective, and safe technique in both the short- and long-term for the treatment of IBH. PMID- 26489591 TI - Enzyme-linked immunosorbent assays in seroprevalence studies of Q fever: the need for cut-off adaptation and the consequences for prevalence data. AB - Large outbreaks of Q fever have recently increased the awareness of this disease as a public health issue. Knowledge of the general impact of Q fever relies mainly on seroprevalence studies and it is fundamental that seroprevalence is assessed accurately. Therefore we evaluated the few enzyme-linked immunosorbent assays (ELISAs) commercially available for this purpose. An outbreak in 2005 in Jena, a city of 100,000 inhabitants, gave us the opportunity for the evaluation. However, we found disappointingly low sensitivities for two (42% and 51%) of three commercial ELISAs for detecting past infection. Nevertheless, all assays had good classification potential but cut-off adaptation is needed. Based on the unequal worldwide distribution of the differently performing tests in studies, Q fever seroprevalence is likely to be underestimated in studies from Europe whereas the data from North America and Australia are likely to be more reliable. PMID- 26489592 TI - Culicoides vector species on three South American camelid farms seropositive for bluetongue virus serotype 8 in Germany 2008/2009. AB - Palearctic species of Culicoides (Diptera, Ceratopogonidae), in particular of the Obsoletus and Pulicaris complexes, were identified as putative vectors of bluetongue virus serotype 8 (BTV-8) on ruminant farms during the epizootic in Germany from 2006 to 2009. BTV may cause severe morbidity and mortality in ruminants and sporadically in South American camelids (SAC). However, the fauna of Culicoides spp. on SAC farms has not been investigated. Therefore, the ceratopogonid fauna was monitored on three farms with BTV-seropositive SAC in Germany. Black-light traps were set up on pastures and in stables from summer 2008 to autumn 2009. Additionally, ceratopogonids were caught in emergence traps mounted on llama dung and dung-free pasture from spring to autumn 2009. After morphological identification, selected Culicoides samples were analysed for BTV RNA by real-time RT-PCR. The effects of the variables 'location', 'temperature' and 'humidity' on the number of Culicoides caught in black-light traps were modelled using multivariable Poisson regression. In total, 26 species of Culicoides and six other genera of biting midges were identified. The most abundant Culicoides spp. collected both outdoors and indoors with black-light traps belonged to the Obsoletus (77.4%) and Pulicaris (16.0%) complexes. The number of Culicoides peaked in summer, while no biting midges were caught during the winter months. Daily collections of Culicoides were mainly influenced by the location and depended on the interaction of temperature and humidity. In the emergence traps, species of the Obsoletus complex predominated the collections. In summary, the absence of BTV-RNA in any of the analysed Culicoides midges and in the BTV-seropositive SAC on the three farms together with the differences in the pathogenesis of BTV-8 in SAC compared to ruminants suggests a negligible role of SAC in the spread of the virus. Although SAC farms may provide similar suitable habitats for putative Culicoides vectors than ruminant farms, the results suggest that geographic and meteorological factors had a stronger influence on Culicoides abundance than the animal species. PMID- 26489593 TI - CIUSuite: A Quantitative Analysis Package for Collision Induced Unfolding Measurements of Gas-Phase Protein Ions. AB - Ion mobility-mass spectrometry (IM-MS) is a technology of growing importance for structural biology, providing complementary 3D structure information for biomolecules within samples that are difficult to analyze using conventional analytical tools through the near-simultaneous acquisition of ion collision cross sections (CCSs) and masses. Despite recent advances in IM-MS instrumentation, the resolution of closely related protein conformations remains challenging. Collision induced unfolding (CIU) has been demonstrated as a useful tool for resolving isocrossectional protein ions, as they often follow distinct unfolding pathways when subjected to collisional heating in the gas phase. CIU has been used for a variety of applications, from differentiating binding modes of activation state-selective kinase inhibitors to characterizing the domain structure of multidomain proteins. With the growing utilization of CIU as a tool for structural biology, significant challenges have emerged in data analysis and interpretation, specifically the normalization and comparison of CIU data sets. Here, we present CIUSuite, a suite of software modules designed for the rapid processing, analysis, comparison, and classification of CIU data. We demonstrate these tools as part of a series of workflows for applications in comparative structural biology, biotherapeutic analysis, and high throughput screening of kinase inhibitors. These examples illustrate both the potential for CIU in general protein analysis as well as a demonstration of best practices in the interpretation of CIU data. PMID- 26489594 TI - Robust measurement of vitamin A status in plasma and blood dried on paper. AB - Vitamin A deficiency is the leading cause of preventable blindness in children and increases the risk of disease and death from severe infections. In addition, fat soluble vitamin A and associated retinoids directly regulate the expression of genes involved in fatty acid metabolism. Conventional methods for measuring vitamin A involve venipuncture, centrifugation and refrigeration all of which make measuring vitamin A in nutritional surveys expensive. We aimed to develop a simple and robust system for measurement of retinol (biomarker for vitamin A) using dried blood spot (DBS) samples. Low recoveries and inconsistent results reported by others were found to be due to poor extraction efficiency rather than retinol instability. Maintaining acid conditions during extraction resulted in recoveries >95% with <6.5% of coefficient of variation. Using isocratic high performance liquid chromatography, separation was achieved in <3.5 min. Detector response was linear (R(2)=0.9939) within a range of 0.05-2 MUg/mL, with a limit of quantification of 0.05 MUg/mL. Retinol in DBS was shown to be stable (>95%) at room temperature for up to 10 weeks. DBS values for retinol were highly correlated with venous blood samples from 24 healthy subjects (r=0.9724) and were consistent with results from a commercial laboratory. This simple and reliable method for the determination of vitamin A status should prove particularly valuable for population studies and large clinical trials. PMID- 26489595 TI - pH-responsive ion transport in polyelectrolyte multilayers of poly(diallyldimethylammonium chloride) (PDADMAC) and poly(4-styrenesulfonic acid co-maleic acid) (PSS-MA) bearing strong- and weak anionic groups. AB - The layer-by-layer construction of interfacial architectures displaying stimuli responsive control of mass transport is attracting increasing interest in materials science. In this work, we describe the creation of interfacial architectures displaying pH-dependent ionic transport properties which until now have not been observed in polyelectrolyte multilayers. We describe a novel approach to create pH-controlled ion-rectifying systems employing polyelectrolyte multilayers assembled from a copolymer containing both weakly and strongly charged pendant groups, poly(4-styrenesulfonic acid-co-maleic acid) (PSS-MA), alternately deposited with poly(diallyldimethylammonium chloride) (PDADMAC). The conceptual framework is based on the very contrasting and differential interactions of PSS and MA units with PDADMAC. In our setting, sulfonate groups play a structural role by conferring stability to the multilayer due to the strong electrostatic interactions with the polycations, while the weakly interacting MA groups remain "silent" within the film and then act as on-demand pH-responsive units. When these multilayers are combined with a strong cationic capping layer that repels the passage of cationic probes, a pH-gateable rectified transport of anions is observed. Concomitantly, we also observed that these functional properties are significantly affected when multilayers are subjected to extensive pH cycling as a consequence of irreversible morphological changes taking place in the film. We envision that the synergy derived from combining weak and strong interactions within the same multilayer will play a key role in the construction of new interfacial architectures displaying tailorable ion transport properties. PMID- 26489596 TI - Risk factors associated with benzodiazepine use among people who inject drugs in an urban Canadian setting. AB - BACKGROUND: Though known to have abuse potential, benzodiazepine medications remain widely prescribed. Furthermore, issues related to benzodiazepine use by people who inject drugs (PWID) remain to be fully characterized. We therefore sought to examine the prevalence of and risk factors associated with benzodiazepine use in a street-involved urban population. METHODS: Between May 1996 and November 2013, data were derived from two open prospective cohort studies in Vancouver, Canada, restricted to PWID. Multivariable logistic regression with generalized estimating equations (GEE) was used to determine factors independently associated with benzodiazepine use. RESULTS: Over the study period, 2806 individuals were recruited, including 949 (34%) women. Of these, 1080 (38.5%) participants reported benzodiazepine use at least once during the study period. In the multivariable analysis, Caucasian ethnicity, >= daily heroin injection, >= daily cocaine injection, non-fatal overdose, incarceration, syringe sharing, and unsafe sex were all independently associated with benzodiazepine use. Conversely, older age, homelessness, and >= daily crack smoking were negatively associated with benzodiazepine use. CONCLUSIONS: Use of benzodiazepines was common in this urban setting and was associated with several markers of addiction severity and significant health and social vulnerabilities including syringe sharing and unsafe sex. These findings underscore the need to promote treatment for benzodiazepine use, safer benzodiazepine prescribing, including greater recognition of the limited indications for evidence-based use of this medication class. PMID- 26489597 TI - Connecting low-income smokers to tobacco treatment services. AB - The Affordable Care Act calls for using population-level incentive-based interventions, and cigarette smoking is one of the most significant health behaviors driving costs and adverse health in low-income populations. Telehealth offers an opportunity to facilitate delivery of evidence-based smoking cessation services as well as incentive-based interventions to low-income populations. However, research is needed on effective strategies for linking smokers to services, how to couple financial incentives with telehealth, and on how to scale this to population-level practice. The current paper evaluates primary implementation and follow-up results of two strategies for connecting low-income, predominantly female smokers to a telephone tobacco quitline (QL). The population based program consisted of participant-initiated phone contact and two recruitment strategies: (1) direct mail (DM) and (2) opportunistic telephone referrals with connection (ORC). Both strategies offered financial incentives for being connected to the QL, and all QL connections were made by trained patient navigators through a central call center. QL connections occurred for 97% of DM callers (N=870) and 33% of ORC callers (N=4550). Self-reported continuous smoking abstinence (i.e., 30 smoke-free days at seven-month follow-up) was 20% for the DM group and 16% for ORC. These differences between intervention groups remained in ordered logistic regressions adjusting for smoking history and demographic characteristics. Each recruitment strategy had distinct advantages; both successfully connected low-income smokers to cessation services and encouraged quit attempts and continuous smoking abstinence. Future research and population based programs can utilize financial incentives and both recruitment strategies, building on their relative strengths. PMID- 26489598 TI - Response to Mustafa 2015: The Safewards study lacks rigour despite its randomised design. PMID- 26489599 TI - Discovery of an ultra-short linear antibacterial tetrapeptide with anti-MRSA activity from a structure-activity relationship study. AB - The overuse and misuse of antibiotics has resulted in the emergence of drug resistant pathogenic bacteria, including meticillin-resistant Staphylococcus aureus (MRSA), the primary pathogen responsible for human skin and soft-tissue infections. Antibacterial peptides are known to kill bacteria by rapidly disrupting their membranes and are deemed plausible alternatives to conventional antibiotics. One advantage of their membrane-targeting mode of action is that bacteria are unlikely to develop resistance as changing their cell membrane structure and morphology would likely involve extensive genetic mutations. However, major concerns in using peptides as antibacterial drugs include their instability towards plasma proteases, toxicity towards human cells due to their membrane-targeting mode of action and high manufacturing cost. These concerns can be mitigated by developing peptides as topical agents, by the judicial selection of amino acids and developing very short peptides respectively. In this preliminary report, we reveal a linear, non-hemolytic tetrapeptide with rapid bactericidal activity against MRSA developed from a structure-activity relationship study based on the antimicrobial hexapeptide WRWRWR-NH2. Our finding opens promising avenues for the development of ultra-short antibacterials to treat multidrug-resistant MRSA skin and soft tissue infections. PMID- 26489600 TI - A Sensitivity Analysis and Opportunity Cost Evaluation of the Surgical Council on Resident Education Curriculum. AB - OBJECTIVE: The study purpose is to evaluate the Surgical Council on Resident Education (SCORE) Curriculum regarding American Board of Surgery Qualifying Examination (ABS QE) outcomes. The goal is to perform effect size analyses, sensitivity analyses, and sample size analyses with opportunity cost estimates required to favor the SCORE Curriculum subscription regarding ABS QE outcomes. METHODS: Published data were used to construct 2 * 2 matrices regarding ABS QE outcome (pass/fail) and SCORE subscription status (subscriber/nonsubscriber). Post hoc analyses of effect sizes and sample sizes, with opportunity cost estimates, were performed to evaluate ABS QE outcomes favoring SCORE subscription (2-tailed and 1-tailed tests) using an alpha = 0.05. RESULTS: The absolute risk increase of SCORE subscription on ABS QE outcome was 1.6% (number needed to treat = 63). Sensitivity analyses showed that a pass rate difference of 4.9% to 7.5% was required to favor SCORE subscription (all p < 0.05). Sample size analyses required an 8- to 18-fold increase to favor SCORE subscription to achieve statistical significance with an opportunity cost of $6.0 to $13.5 million ($30,000-$67,000/program), not adjusting for inflation. CONCLUSIONS: The number needed to treat and pass rate differences required to favor SCORE subscription are large. The opportunity costs of SCORE subscription are substantial. Residency programs with more limited resources should determine if the subscription costs are financially sound. PMID- 26489601 TI - Exploring the Content of Intraoperative Teaching. AB - INTRODUCTION: Much teaching to surgical residents takes place in the operating room (OR). The explicit content of what is taught in the OR, however, has not previously been described. This study investigated the content of what is taught in the OR, specifically during laparoscopic cholecystectomies (LCs), for which a cognitive task analysis (CTA), explicitly delineating individual steps, was available in the literature. METHODS: A checklist of necessary technical and decision-making steps to be executed during performance of LCs, anchored in the previously published CTA, was developed. A convenience sample of LCs was identified over a 12-month period from February 2011 to February 2012. Using the checklist, a trained observer recorded explicit teaching that occurred regarding these steps during each observed case. All observations were tallied and analyzed. RESULTS: In all, 51 LCs were observed; 14 surgery attendings and 33 residents participated in the observed cases. Of 1042 observable teaching points, only 560 (53.7%) were observed during the study period. As a proportion of all observable steps, technical steps were observed more frequently, 377 (67.3%), than decision-making steps, 183 (32.7%). Also when focusing on technical and decision-making steps alone, technical steps were taught more frequently (60.9% vs 43.3%). CONCLUSIONS: Only approximately half of all possible observable teaching steps were explicitly taught during LCs in this study. Technical steps were more frequently taught than decision-making steps. These findings may have important implications: a better understanding of the content of intraoperative teaching would allow educators to steer residents' preoperative preparation, modulate intraoperative instruction by members of the surgical faculty, and guide residents to the most appropriate teaching venues. PMID- 26489602 TI - Applying participatory approaches in the evaluation of surveillance systems: A pilot study on African swine fever surveillance in Corsica. AB - The implementation of regular and relevant evaluations of surveillance systems is critical in improving their effectiveness and their relevance whilst limiting their cost. The complex nature of these systems and the variable contexts in which they are implemented call for the development of flexible evaluation tools. Within this scope, participatory tools have been developed and implemented for the African swine fever (ASF) surveillance system in Corsica (France). The objectives of this pilot study were, firstly, to assess the applicability of participatory approaches within a developed environment involving various stakeholders and, secondly, to define and test methods developed to assess evaluation attributes. Two evaluation attributes were targeted: the acceptability of the surveillance system and its the non-monetary benefits. Individual semi structured interviews and focus groups were implemented with representatives from every level of the system. Diagramming and scoring tools were used to assess the different elements that compose the definition of acceptability. A contingent valuation method, associated with proportional piling, was used to assess the non monetary benefits, i.e., the value of sanitary information. Sixteen stakeholders were involved in the process, through 3 focus groups and 8 individual semi structured interviews. Stakeholders were selected according to their role in the system and to their availability. Results highlighted a moderate acceptability of the system for farmers and hunters and a high acceptability for other representatives (e.g., private veterinarians, local laboratories). Out of the 5 farmers involved in assessing the non-monetary benefits, 3 were interested in sanitary information on ASF. The data collected via participatory approaches enable relevant recommendations to be made, based on the Corsican context, to improve the current surveillance system. PMID- 26489603 TI - Nursing students' perspectives on clinical instructors' effective teaching strategies: A descriptive study. AB - An important factor contributing to the quality of clinical education is instructors' teaching performance. The aim of this study was to identify clinical instructors' most effective teaching strategies from nursing and midwifery students' perspectives. This was a descriptive cross-sectional study. All third- and fourth-year bachelor's nursing and midwifery students studying at the Nursing and Midwifery Faculty of Kurdistan University of Medical Sciences were recruited to the study by using the census method. The study instrument consisted of a demographic questionnaire and the self-report 30-item Clinical Instructors' Effective Teaching Strategies Inventory. The SPSS v.16.0 was used for data analysis. The most effective teaching strategies of clinical instructors from nursing and midwifery students' perspectives were respectively 'treating students, clients, and colleagues with respect' and 'being eager for guiding students and manage their problems'. Clinical instructors need to be eager for education and also be able to establish effective communication with students. Empowering clinical instructors in specialized and technical aspects of clinical education seems necessary. PMID- 26489604 TI - The lymph node pre-metastatic niche. AB - Lymph node metastases occur frequently during the progression of many types of cancer, and their presence often reflects poor prognosis. The drainage of tumor derived factors such as antigens, growth factors, cytokines, and exosomes through the lymphatic system to the regional lymph nodes plays an important role in the pre-metastatic conditioning of the microenvironment in lymph nodes, making them receptive and supportive metastatic niches for disseminating tumor cells. Modified immunological responses and remodeling of the vasculature are the most studied tumor-induced pre-metastatic changes in the lymph node microenvironment that promote metastasis, although other metastasis-relevant alterations are also starting to be studied. Here, I review our current understanding of the lymph node pre-metastatic niche, how tumors condition this niche, and the relevance of this conditioning for our understanding of the process of metastasis. PMID- 26489605 TI - The biology and clinical implications of prostate cancer dormancy and metastasis. AB - Disseminated tumor cells (DTCs) are detected early in the disease process in prostate cancer (PCa) patients and can persist after radical prostatectomy. DTCs can remain dormant in patients with no evidence of disease for a prolonged period of time only to recur 10 or more years later. Recent advances in single-cell genomics and transcriptomics have provided much needed insight into DTC biology and cancer dormancy in patients. With the development of new in vitro and preclinical models, researchers recapitulate the clinical events in patients and therefore allow further elucidation of the molecular mechanisms underlying cancer dormancy and escape. In this review, we explore novel ideas on the detection, heterogeneous transcriptomic profiles, molecular and cellular mechanisms of dormancy, and potential mechanisms underlying dormancy escape by DTCs. As such, there is hope that identifying and targeting novel dormancy-associated pathways in patients with residual disease will have significant clinical implications for the treatment of PCa patients in the future. PMID- 26489606 TI - The lung metastatic niche. AB - Cancer cells that succeed in forming lung metastases need to survive in a foreign microenvironment and to protect themselves against immune surveillance. Lung metastatic niches facilitate this process. They can develop as pre-metastatic niches by inflammatory events that are provoked by primary tumors before tumor cell arrival, and/or they can be post-formed by reciprocal signaling between metastasizing tumor cells and local non-tumor cells. Primary tumor-derived factors induce expression of chemokines in the lungs to which bone marrow-derived myeloid cells are recruited. These cells work in concert with lung-specific resident cells to establish pre-metastatic niches. The role of the endogenous TLR4-dependent innate immune system in pre-metastatic niche formation illustrates this point. During lung infection, endotoxin induces inflammation by increasing vascular permeability and leukocyte mobilization to the lungs through the endotoxin receptor TLR4 that is expressed in endothelial cells and leukocytes, respectively. This innate immune system can be hijacked by primary tumors to generate a pre-metastatic niche. Specifically, primary tumor-produced chemokine CCL2 works in an endocrine manner to induce pulmonary overexpression of endogenous TLR4 ligands such as S100A8 and SAA3 resulting in lung inflammation similar to that caused by endotoxin. An endotoxin analog Eritoran inhibits pre metastatic niche formation in this system. PMID- 26489607 TI - MicroRNA let-7g cooperates with interferon/ribavirin to repress hepatitis C virus replication. AB - MicroRNAs (miRNA) have been implicated in HCV infection. The present study analyzed the effects of let-7g on HCV infection in vitro, in clinical tissue and serum samples. Here, we show that the expression of let-7g in serum and liver tissue is significantly higher in patients with sustained virologic response (SVR). We show that interferon (IFN)/ribavirin (RBV) induces let-7g expression through p38/AP-1 signaling. Overexpression of let-7g reduced HCV gene or core protein level and inhibited the HCV viral load. The let-7g and IFN/RBV have additively inhibitory effect on HCV replication. These data implicate let-7g as a new therapeutic drug to additively cooperate with IFN/RBV to repress HCV replication. Key messages: let-7g expression is increased in serum and liver tissue of patients with SVR. Interferon/ribavirin induces let-7g expression through p38/AP-1 signaling. Overexpression of let-7g can repress HCV replication. Let-7g additively cooperates with interferon/ribavirin to repress HCV replication. Lin28B silencing can reverse let-7g expression and repress HCV replication. PMID- 26489608 TI - The brain metastatic niche. AB - Metastasizing cancer cells that arrest in brain microvessels have to face an organ microenvironment that is alien, and exclusive. In order to survive and thrive in this foreign soil, the malignant cells need to successfully master a sequence of steps that includes close interactions with pre-existing brain microvessels, and other nonmalignant cell types. Unfortunately, a relevant number of circulating cancer cells is capable of doing so: brain metastasis is a frequent and devastating complication of solid tumors, becoming ever more important in times where the systemic tumor disease is better controlled and life of cancer patients is prolonged. Thus, it is very important to understand which environmental cues are necessary for effective brain colonization. This review gives an overview of the niches we know, including those who govern cancer cell dormancy, survival, and proliferation in the brain. Colonization of pre-existing niches related to stemness and resistance is a hallmark of successful brain metastasis. A deeper understanding of those host factors can help to identify the most vulnerable steps of the metastatic cascade, which might be most amenable to therapeutic interventions. PMID- 26489609 TI - Cardiac troponin T in patients with cardiac implantable electronic devices undergoing magnetic resonance imaging. AB - PURPOSE: Magnetic resonance imaging (MRI) has been safely performed in many patients with cardiac implantable electronic devices (CIEDs) using institution specific protocols. A potential risk of MRI is myocardial heating and cardiac injury, which might be detectable with cardiac Troponin (cTn). We evaluated this in patients with CIEDs undergoing MRI. METHODS: Prospective data were collected from 2008 to the present in patients with CIEDs undergoing clinically indicated MRI performed under institutional protocol. Cardiac Troponin T (cTnT) levels were drawn both before and 24-36 h after the procedure. The collective data were retrospectively analyzed. RESULTS: MRI exams (n=512) were performed in 398 patients. Of these, there were 348 unique scans with cTnT recorded before and after MRI (median age 68, IQ 56-78; 62%men). cTnT did not significantly change for the group as a whole (0.00+/-0.056). There were 22 (6.3 %) exams with cTnT change >=0.002 ng/mL following MRI (range 0.01-0.09 ng/mL). There were no clinically significant events in these patients directly attributable to MR. There were no significant changes in pacing threshold or impedance in the group with elevated cardiac biomarkers. CONCLUSION: There are very few situations where myocardial injury as detected by cTnT in patients undergoing MRI with CIEDs could be detected. No adverse clinical events or functional changes of the device were noted, even in those with increases in cTnT. Our experience supports that MRI can be performed safely for appropriately selected patients under close clinical observation. Proactive monitoring with the present iteration of cardiac biomarkers appears to be of limited utility, but prospective monitoring with high sensitivity assays may be able to detect subclinical myocardial damage. PMID- 26489610 TI - Association between dissociated firing in isolated pulmonary veins and the initiation and maintenance of atrial fibrillation. AB - BACKGROUND: Whether dissociated firing (DiFi) in isolated pulmonary veins (PVs) implies arrhythmogenicity of the particular PVand, therefore, a better outcome of PV isolation (PVI) for paroxysmal atrial fibrillation (PAF) is debated. METHODS: Thirty-one patients undergoing their first PVI for PAF were studied. Isoproterenol was infused for induction, and the triggering PV was identified. During sustained PAF, sequential recordings were made with a decapolar circular mapping catheter from each PV. The dominant frequency (DF) was determined using fast Fourier transformation. Spontaneous DiFi was monitored for 30 min after PVI. RESULTS: PAF was triggered by the PVs in all patients. Fourteen (45 %) patients had DiFi after PVI in at least one PV. It was recorded most commonly from the left upper (84 %) and lower (67 %), less commonly from the right upper (31 %) PV. Out of the 23 PVs with DiFi, 13 (57 %) showed sporadic ectopic beats while 10 (44 %) had sustained ectopic rhythm or isolated tachycardia. There was no difference in size between PVs with or without DiFi (5.9+/-1.2 vs. 5.6+/-1.0 cm ostial perimeter, p=0.40). Triggering PVs more commonly showed any DiFi, compared to nontriggering PVs (68 vs. 27 %, p=0.003) and more commonly had sustained DiFi (53 vs. 0 %, p<0.001). During PAF PVs with any DiFi showed faster maximal DF compared to PVs without DiFi (7.1+/-1.3 vs. 5.9+/-1.1 Hz, p=0.001). Higher maximal DF was recorded in PVs with sustained versus sporadic DiFi versus PVs without DiFi (7.5 +/-0.9 vs. 6.8+/-1.6 vs. 5.9+/-1.1 Hz, respectively, p=0.002). Patients with DiFi after PVI had a longer mean time to recurrent PAF compared to those without DiFi (52 vs. 32 months, p=0.048). CONCLUSIONS: Dissociated firing in isolated PVs is associated with their role in the initiation and maintenance of PAF. PMID- 26489612 TI - Efficacy and safety of tacrolimus vs. cyclophosphamide for idiopathic membranous nephropathy: A meta-analysis of Chinese adults. AB - The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) in the treatment of idiopathic membranous nephropathy (IMN) were compared in Chinese adult patients using a meta- analysis of the available literatures. Randomized controlled clinical trials (RCTs) of the treatment of primary IMN with TAC or CTX combined with corticosteroids in the English databases PubMed, Embase and Cochrane, as well as Chinese databases, were searched. Qualified studies were subjected to quality assessment and meta-analysis. A total of 8 RCTs, including 359 Chinese patients, were included in the meta-analysis. The complete remission rate and overall remission rate in the TAC treatment group after 6 months of treatment were higher than those in the CTX treatment group. No significant difference in remission rate was found after 12 months of treatment. There was no significant difference in the adverse reaction between the two groups at the 6th or 12th months. TAC-based treatment was associated with a faster response than CTX at the 6th month, but there was no significant difference between the two groups at 12th month in Chinese adults. Further study is needed to evaluate the long-term efficacy and safety of this treatment regimen. PMID- 26489611 TI - Tie-1: A potential target for anti-angiogenesis therapy. AB - The tyrosine kinase system angiopoietin (Ang)/Tie interacts with vascular endothelial growth factor pathway and regulates vessel quiescence in adults as well as later steps of the angiogenic cascade related to vessel maturation. Since all Angs are able to bind to Tie-2 but none binds to Tie-1, the function of Tie-2 and its ligands have captured attention. However, emerging evidence indicates unique roles of the orphan receptor Tie-1 in angiogenesis under physiological and pathological conditions. It is required for maintaining vascular endothelial cell integrity and survival during murine embryo development and in adult and may be involved in modulating differentiation of hematopoietic cells in adult. Tie-1 exhibits poor tyrosine kinase activity and signals via forming heterodimers with Tie-2, inhibiting Tie-2 signaling mediated by Angs. This inhibition can be relieved by Tie-1 ectodomain cleavage mediated by tumor- and inflammatory-related factors, which causes destabilization of vessels and initiates vessel remodeling. Up-regulated Tie-1 expression has been found not only in some leukemia cells and tumor related endothelial cells but also in cytoplasm of carcinoma cells of a variety of human solid tumors, which is associated with tumor progression. In addition, it has pro-inflammatory functions in endothelial cells and is involved in some inflammatory diseases associated with angiogenesis. Recent research indicated that Tie-1 gene ablation exhibited significant effects on tumor blood- and lymph-angiogenesis and improved anti-Ang therapy, suggesting Tie-1 may be a potential target for tumor anti-angiogenesis treatment. PMID- 26489613 TI - Effect of BRCA2 mutation on familial breast cancer survival: A systematic review and meta-analysis. AB - Reports of BRCA2 genetic mutations on the prognosis of familial breast cancer (BC) patients have been contradictory. True difference in survival, if it exists, would have important implications for genetic counseling and in treatment of hereditary BC. The purpose of this study was to compare overall survival rate (OSR) among BRCA2 mutation carriers, non-carriers and sporadic BC patients. We searched the PUBMED and EMBASE databases and retrieved 4529 articles using keywords that included breast cancer, BRCA, prognosis and survival. Nine articles were selected for systematic review and among them 6 were included in our meta analysis. We used the fixed and random effect models to calculate the summary odds ratio (OR) and corresponding 95% confidence interval (CI). BRCA2 mutation carriers had significantly higher long-term OSR than non-carriers (OR=0.69 [95% CI=0.5-0.95]), while both short-term and long-term OSR of BRCA2 mutation carriers did not differ from those of patients with sporadic disease (OR=1.11 [95% CI=0.74 1.65]; 0.85 [95% CI=0.38-1.94], respectively). For BC-specific survival rate (BCSSR), BRCA2 mutation carriers had a similar BCSSR to the non-carriers (OR=0.61 [95% CI=0.28-1.34]). There was no significant difference in disease-free survival (DFS) between BRCA2 mutation carriers and patients with sporadic disease. Our results suggest that BRCA2 mutation increases long-term OSR in hereditary BC, which reminds us a new prospect of management of the disease. PMID- 26489614 TI - Prodynorphin gene promoter polymorphism and temporal lobe epilepsy: A meta analysis. AB - Previous studies have reported the association of prodynorphin (PDYN) promoter polymorphism with temporal lobe epilepsy (TLE) susceptibility, but the results remain inconclusive. To further precisely evaluate this association, we performed a meta-analysis. Published studies of TLE and PDYN polymorphism up to February 2015 were identified. Subgroup analysis by TLE subtype was performed. Moreover, sensitivity, heterogeneity, and publication bias were also analyzed. Seven case control studies were finally included in this meta-analysis with 875 TLE cases and 1426 controls. We did not find synthetic evidence of association between PDYN promoter polymorphism and TLE susceptibility (OR=1.184, 95% CI: 0.873-1.606, P=0.277). Similar results were also obtained in non-familial-risk TLE subgroup. However, in the familial-risk TLE subgroup analysis, a significant association was observed (OR=1.739, 95% CI: 1.154-2.619, P=0.008). In summary, this meta analysis suggests that PDYN gene promoter polymorphism might contribute to familial-risk TLE. PMID- 26489615 TI - CYP2C8-derived epoxyeicosatrienoic acids decrease oxidative stress-induced endothelial apoptosis in development of atherosclerosis: Role of Nrf2 activation. AB - The aim of the present study is to investigate how cytochrome P450 enzymes (CYP) 2C8-derived epoxyeicosatrienoic acids (EETs) regulate the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and protect against oxidative stress-induced endothelial injuries in the development and progression of atherosclerosis. In this study, cultured human umbilical vein endothelial cells (HUVECs) were transfected with CYP2C8 or pretreated with exogenous EETs (1 MUmol/L) before TNF-alpha (20 ng/mL) stimulation. Apoptosis and intracellular ROS production were determined by flow cytometry. The expression levels of ROS associated NAD(P)H subunits gp91 and p47, the anti-oxidative enzyme catalase (CAT), Nrf2, heme oxygenase-1 (HO-1) and endothelial nitric oxide synthase (eNOS) were detected by Western blotting. The results showed that CYP2C8-derived EETs decreased apoptosis of HUVECs treated with TNF-alpha. Pretreatment with 11, 12 EET also significantly blocked TNF-alpha-induced ROS production. In addition, 11, 12-EET decreased oxidative stress-induced apoptosis. Furthermore, the ability of 11, 12-EET to protect cells against TNF-alpha-induced apoptosis via oxidative stress was abrogated by transient transfection with Nrf2-specific small interfering RNA (siRNA). In conclusion, CYP2C8-derived EETs prevented TNF-alpha induced HUVECs apoptosis via inhibition of oxidative stress associated with the Nrf2 signaling. PMID- 26489616 TI - Prognostic significance of lymphovascular invasion in bladder cancer after surgical resection: A meta-analysis. AB - Bladder cancer remains a commonly diagnosed malignancy worldwide, bringing huge economic burden and high morbidity for patients. Assessment of prognostic significance of lymphovascular invasion (LVI) is a critical issue in the surgical management of bladder cancer after transurethral resection or radical cystectomy. A systematic search of PubMed, Embase and Cochrane Library was performed up to Oct 10, 2014 to identify eligible studies. Outcomes of interest were collected from studies comparing overall survival (OS), cancer specific survival (CSS) and recurrence free survival (RFS) in patients with the LVI. Results of studies were pooled, and combined hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for survival were used as the effect size estimation. Funnel plots were done to show the publication bias, while the forest plots and subgroup analyses were used to limit the heterogeneity. A total of 20 studies (10 663 patients) met the eligibility criteria and were included for this meta-analysis. Our pooled results showed that there were significant differences in OS (pooled HR, 1.71; 95%CI, 1.52-1.92; P<0.00001), CSS (pooled HR, 2.25; 95% CI, 1.80-2.81; P<0.00001) and RFS (pooled HR, 1.91; 95% CI, 1.57-2.32; P<0.00001) between the patients with LVI and the patients without LVI. There were significant heterogeneities observed in the studies concerning the relationship between LVI and CSS, RFS. There was no clear evidence of publication bias. When tumor stage was beyond T3, LVI lost its predictive value for CSS and RFS. For the patients who had negative lymph nodes, LVI was still an adverse predictor. Our pooled results demonstrate that LVI indicates poor prognosis of patients with bladder cancer after surgical procedures, and it can be of particular importance in clinical practice. However, these results need to be further confirmed by more adequately designed prospective studies. PMID- 26489617 TI - Biventricular repair versus uni-ventricular repair for pulmonary atresia with intact ventrical septum: A systematic review. AB - The management of pulmonary atresia with intact ventricular septum (PA/IVS) remains controversial. The goal of separating systematic and pulmonary circulation can be achieved by biventricular or uni-ventricular (Fontan or one and a half ventricle repair) strategies. Although outcomes have been improved, these surgical procedures are still associated with high mortality and morbidity. An optimal strategy for definitive repair has yet to be defined. We searched databases for genetically randomized controlled trials (RCTs) comparing biventricular with uni-ventricular repair for patient with PA/IVS. Data extraction and quality assessment were performed following the guidelines of the Cochrane Collaboration. Primary outcome measures were overall survival, and secondary criteria included exercise function, arrhythmia-free survival and treatment-related mortality. A total number of 669 primary citations were screened for relevant studies. Detailed analysis revealed that no RCTs were found to adequately address the research question and no systematic meta-analysis would have been carried out. Nevertheless, several retrospective analyses and case series addressed the question of finding right balance between biventricular and uni-ventricular repair for patient with PA/IVS. In this review, we will discuss the currently available data. PMID- 26489618 TI - Melanocortin-4 receptor expression in the cuneiform nucleus is involved in modulation of opioidergic signaling. AB - Substantial evidence has suggested that deep brain stimulation of the cuneiform nucleus has become a remarkable treatment option for intractable pain, but the possible mechanism is poorly understood. Using a melanocortin-4 receptor (MC4R) green fluorescent protein (GFP) reporter knockin mouse, we showed that a large number of MC4R-GFP-positive neurons were expressed in the cuneiform nucleus. Immunofluorescence revealed that approximately 40%-50% of MC4R-GFP-positive neurons expressed mu opioid receptors, indicating that they were opioidergic signaling. Our findings support the hypothesis that MC4R expression in the cuneiform nucleus is involved in the modulation of opioidergic signaling. PMID- 26489619 TI - The function and meaning of receptor activator of NF-kappaB ligand in arterial calcification. AB - Osteoclast-like cells are known to inhibit arterial calcification. Receptor activator of NF-kappaB ligand (RANKL) is likely to act as an inducer of osteoclast-like cell differentiation. However, several studies have shown that RANKL promotes arterial calcification rather than inhibiting arterial calcification. The present study was conducted in order to investigate and elucidate this paradox. Firstly, RANKL was added into the media, and the monocyte precursor cells were cultured. Morphological observation and Tartrate resistant acid phosphatase (TRAP) staining were used to assess whether RANKL could induce the monocyte precursor cells to differentiate into osteoclast-like cells. During arterial calcification, in vivo and in vitro expression of RANKL and its inhibitor, osteoprotegerin (OPG), was detected by real-time PCR. The extent of osteoclast-like cell differentiation was also assessed. It was found RANKL could induce osteoclast-like cell differentiation. There was no in vivo or in vitro expression of osteoclast-like cells in the early stage of calcification. At that time, the ratio of RANKL to OPG was very low. In the late stage of calcification, a small amount of osteoclast-like cell expression coincided with a relatively high ratio of RANKL to OPG. According to the results, the ratio of RANKL to OPG was very low during most of the arterial calcification period. This made it possible for OPG to completely inhibit RANKL-induced osteoclast-like cell differentiation. This likely explains why RANKL had the ability to induce osteoclast-like cell differentiation but acted as a promoter of calcification instead. PMID- 26489620 TI - Kinetin inhibits proliferation of hepatic stellate cells by interrupting cell cycle and induces apoptosis by down-regulating ratio of Bcl-2/Bax. AB - Liver fibrosis is an important health problem that can further progress into cirrhosis or liver cancer, and result in significant morbidity and mortality. Inhibiting proliferation and inducing apoptosis of hepatic stellate cells (HSCs) may be the key point to reverse liver fibrosis. At present, anti-fibrosis drugs are rare. Kinetin is a type of plant-derived cytokinin which has been reported to control differentiation and induce apoptosis of human cells. In this study, the HSCs were incubated with different concentrations of kinetin. The proliferation of rat HSCs was measured by MTT assay, cell cycle and apoptosis were analyzed by flow cytometry, and the apoptosis was examined by TUNEL method. The expression of Bcl-2 and Bax proteins was detected by immunocytochemistry staining. It was found that kinetin could markedly inhibit proliferation of HSCs. In a concentration range of 2 to 8 MUg/mL, the inhibitory effects of kinetin on proliferation of HSCs were increased with the increased concentration and the extension of time (P < 0.01). Flow cytometry indicated that kinetin could inhibit the DNA synthesis from G0/G1 to S phase in a dose-dependent manner (P < 0.01). The apoptosis rates of the HSCs treated with 8, 4 and 2 MUg/mL kinetin (25.62% +/- 2.21%, 15.31% +/- 1.9% and 6.18% +/- 1.23%, respectively) were increased significantly compared with the control group (3.81% +/- 0.93%) (P < 0.01). All the DNA frequency histogram in kinetin-treated groups showed obvious hypodiploid peak (sub-G1 peak), and with the increase of kinetin concentrations, the apoptosis rate of HSCs also showed a trend of increase. It was also found that kinetin could down regulate the expression of Bcl-2, and up-regulate the expression of Bax, leading to the decreased ratio of Bcl-2/Bax significantly. The kinetin-induced apoptosis of HSCs was positively correlated with the expression of Bax, and negatively with the expression of Bcl-2. It was concluded that kinetin can inhibit activation and proliferation of HSCs by interrupting the cell cycle at G1/S restriction point and inducing apoptosis of HSCs via reducing the ratio of Bcl-2/Bax. PMID- 26489621 TI - IL-17 Induces MPTP opening through ERK2 and P53 signaling pathway in human platelets. AB - The opening of mitochondrial permeability transition pore (MPTP) plays a critical role in platelet activation. However, the potential trigger of the MPTP opening in platelet activation remains unknown. Inflammation is the crucial trigger of platelet activation. In this study, we aimed to explore whether and how the important inflammatory cytokine IL-17 is associated with MPTP opening in platelets activation by using MPTP inhibitor cyclosporine-A (CsA). The mitochondrial membrane potential (DeltaPsim) was detected to reflect MPTP opening levels. And the platelet aggregation, activation, and the primary signaling pathway were also tested. The results showed that the MPTP opening levels were increased and Deltapsim reduced in platelets administrated with IL-17. Moreover, the levels of aggregation, CD62P, PAC-1, P53 and the phosphorylation of ERK2 were enhanced along with the MPTP opening in platelets pre-stimulated with IL-17. However, CsA attenuated these effects triggered by IL-17. It was suggested that IL-17 could induce MPTP opening through ERK2 and P53 signaling pathway in platelet activation and aggregation. PMID- 26489622 TI - Dexmedetomidine alleviates pulmonary edema by upregulating AQP1 and AQP5 expression in rats with acute lung injury induced by lipopolysaccharide. AB - This study aims to elucidate the mechanisms by which dexmedetomidine alleviates pulmonary edema in rats with acute lung injury induced by lipopolysaccharide (LPS). Male Wistar rats were randomly divided into five groups: normal saline control (NS) group, receiving intravenous 0.9% normal saline (5 mL/kg); LPS group, receiving intravenous LPS (10 mg/kg); small-dose dexmedetomidine (S) group, treated with a small dose of dexmedetomidine (0.5 MUg . kg(-1) . h(-1)); medium-dose dexmedetomidine (M) group, treated with a medium dose of dexmedetomidine (2.5 MUg . kg(-1) . h(-1)); high-dose dexmedetomidine (H) group, treated with a high dose of dexmedetomidine (5 MUg . kg(-1) . h(-1)). The rats were sacrificed 6 h after intravenous injection of LPS or NS, and the lungs were removed for evaluating histological characteristics and determining the lung wet/dry weight ratio (W/D). The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in the lung tissues were assessed by enzyme- linked immunosorbent assay (ELISA). The mRNA and protein expression levels of aquaporin-1 (AQP1) and aquaporin-5 (AQP5) were detected by RT-PCR, immunohistochemistry, and Western blotting. The lung tissues from the LPS groups were significantly damaged, which were less pronounced in the H group but not in the small-dose dexmedetomidine group or medium-dose dexmedetomidine group. The W/D and the concentrations of TNF-alpha and IL-1beta in the pulmonary tissues were increased in the LPS group as compared with those in NS group, which were reduced in the H group but not in S group or M group (P<0.01). The expression of AQP1 and AQP5 was lower in the LPS group than in the NS group, and significantly increased in the H group but not in the S group or M group (P<0.01). Our findings suggest that dexmedetomidine may alleviate pulmonary edema by increasing the expression of AQP-1 and AQP-5. PMID- 26489623 TI - Effects of dendritic cell-activated and cytokine-induced killer cell therapy on 22 children with acute myeloid leukemia after chemotherapy. AB - The efficiency of dendritic cell-activated and cytokine-induced killer cell (DC CIK) therapy on children with acute myeloid leukemia (AML) after chemotherapy was investigated. Mononuclear cells were collected from children achieving complete remission after chemotherapy, cultured in vitro and transfused back into the same patient. Interleukin-2 (IL-2) was injected subcutaneously every other day 10 times at the dose of 1 * 10(6) units. Peripheral blood lymphocyte subsets and minimal residual disease (MRD) were detected by flow cytometry. Function of bone marrow was monitored by methods of morphology, immunology, cytogenetics and molecular biology. The side effects were also observed during the treatment. The average follow-up period for all the 22 patients was 71 months and relapse occurred in two AML patients (9.1%). The percentage of CD3(+)/CD8(+) cells in peripheral blood of 15 patients at the 3rd month after DC-CIK treatment (36.73% +/- 12.51%) was dramatically higher than that before treatment (29.20% +/- 8.34%, P < 0.05). The MRD rate was >0.1% in 5 patients before the treatment, and became lower than 0.1% 3 months after the treatment. During the transfusion of DC-CIK, side effects including fever, chills and hives appeared in 7 out of 22 (31.82%) cases but disappeared quickly after symptomatic treatments. There were no changes in electrocardiography and liver-renal functions after the treatment. MRD in children with AML can be eliminated by DC-CIK therapy which is safe and has fewer side effects. PMID- 26489624 TI - Angiogenic factors are associated with development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. AB - Acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms of aGVHD are not well understood. We aim to investigate the roles of the three angiogenic factors: angiopoietin-1 (Ang-1), Ang-2 and vascular endothelial growth factor (VEGF) in the development of aGVHD. Twenty-one patients who underwent allo-HSCT were included in our study. The dynamic changes of Ang-1, Ang-2 and VEGF were monitored in patients before and after allo-HSCT. In vitro, endothelial cells (ECs) were treated with TNF-beta in the presence or absence of Ang-1, and then the Ang-2 level in the cell culture medium and the tubule formation by ECs were evaluated. After allo-HSCT, Ang-1, Ang-2 and VEGF all exhibited significant variation, suggesting these factors might be involved in the endothelial damage in transplantation. Patients with aGVHD had lower Ang-1 level at day 7 but higher Ang-2 level at day 21 than those without aGVHD, implying that Ang-1 may play a protective role in early phase yet Ang-2 is a promotion factor to aGVHD. In vitro, TNF-beta promoted the release of Ang-2 by ECs and impaired tubule formation of ECs, which were both weakened by Ang-1, suggesting that Ang-1 may play a protective role in aGVHD by influencing the secretion of Ang-2, consistent with our in vivo tests. It is concluded that monitoring changes of these factors following allo-HSCT might help to identify patients at a high risk for aGVHD. PMID- 26489625 TI - A novel schiff base zinc coordination compound inhibits proliferation and induces apoptosis of human osteosarcoma cells. AB - Various kinds of schiff base metal complexes have been proven to induce apoptosis of tumor cells. However, it remains largely unknown whether schiff base zinc complexes induce apoptosis in human cancer cells. Here, we synthesized a novel schiff base zinc coordination compound (SBZCC) and investigated its effects on the growth, proliferation and apoptosis of human osteosarcoma MG-63 cells. A novel SBZCC was synthesized by chemical processes and used to treat MG-63 cells. The cell viability was determined by CCK-8 assay. The cell cycle progression, mitochondrial membrane potential and apoptotic cells were analyzed by flow cytometry. The apoptosis-related proteins levels were determined by immunoblotting. Treatment of MG-63 cells with SBZCC resulted in inhibition of cell proliferation and cell cycle arrest at G1 phase. Moreover, SBZCC significantly reduced the mitochondrial membrane potential and induced apoptosis, accompanied with increased Bax/Bcl-2 and FlasL/Fas expression as well as caspase 3/8/9 cleavage. Our results demonstrated that the synthesized novel SBZCC could inhibit the proliferation and induce apoptosis of MG-63 cells via activating both the mitochondrial and cell death receptor apoptosis pathways, suggesting that SBZCC is a promising agent for the development as anticancer drugs. PMID- 26489626 TI - A novel thermosensitive in-situ gel of gabexate mesilate for treatment of traumatic pancreatitis: An experimental study. AB - Gabexate mesilate (GM) is a trypsin inhibitor, and mainly used for treatment of various acute pancreatitis, including traumatic pancreatitis (TP), edematous pancreatitis, and acute necrotizing pancreatitis. However, due to the characteristics of pharmacokinetics, the clinical application of GM still needs frequently intravenous administration to keep the blood drug concentration, which is difficult to manage. Specially, when the blood supply of pancreas is directly damaged, intravenous administration is difficult to exert the optimum therapy effect. To address it, a novel thermosensitive in-situ gel of gabexate mesilate (GMTI) was developed, and the optimum formulation of GMTI containing 20.6% (w/w) P-407 and 5.79% (w/w) P188 with different concentrations of GM was used as a gelling solvent. The effective drug concentration on trypsin inhibition was examined after treatment with different concentrations of GMTI in vitro, and GM served as a positive control. The security of GMTI was evaluated by hematoxylin eosin (HE) staining, and its curative effect on grade II pancreas injury was also evaluated by testing amylase (AMS), C-reactive protein (CRP) and trypsinogen activation peptide (TAP), and pathological analysis of the pancreas. The trypsin activity was slightly inhibited at 1.0 and 5.0 mg/mL in GM group and GMTI group, respectively (P<0.05 vs. P-407), and completely inhibited at 10.0 and 20.0 mg/mL (P<0.01 vs. P-407). After local injection of 10 mg/mL GMTI to rat leg muscular tissue, muscle fiber texture was normal, and there were no obvious red blood cells and infiltration of inflammatory cells. Furthermore, the expression of AMS, CRP and TAP was significantly increased in TP group as compared with control group (P<0.01), and significantly decreased in GM group as compared with TP group (P<0.01), and also slightly inhibited after 1.0 and 5.0 mg/mL GMTI treatment as compared with TP group (P<0.05), and significantly inhibited after 10.0 and 20.0 mg/mL GMTI treatment as compared with TP group (P<0.01). HE staining results demonstrated that pancreas cells were uniformly distributed in control group, and they were loosely arranged, partially dissolved, with deeply stained nuclei in TP group. Expectedly, after gradient GMTI treatment, pancreas cells were gradually restored to tight distribution, with slightly stained nuclei. This preliminary study indicated that GMTI could effectively inhibit pancreatic enzymes, and alleviate the severity of trauma-induced pancreatitis, and had a potential drug developing and clinic application value. PMID- 26489627 TI - Role of inhibition of osteogenesis function by Sema4D/Plexin-B1 signaling pathway in skeletal fluorosis in vitro. AB - Skeletal fluorosis is a chronically metabolic bone disease with extensive hyperostosis osteosclerosis caused by long time exposure to fluoride. Skeletal fluorosis brings about a series of abnormal changes of the extremity, such as joint pain, joint stiffness, bone deformity, etc. Differentiation and maturation of osteoblasts were regulated by osteoclasts via Sema4D/Plexin-B1 signaling pathway. Furthermore, the differentiation and maturation of osteoclasts are conducted by osteoblasts via RANKL/RANK/OPG pathway. Both of these processes form a feedback circuit which is a key link in skeletal fluorosis. In this study, an osteoblast-osteoclast co-culture model in vitro was developed to illustrate the mechanism of skeletal fluorosis. With the increase of fluoride concentration, the expression level of Sema4D was decreased and TGF-beta1 was increased continuously. OPG/RANKL mRNA level, however, increased gradually. On the basis of that, the inhibition of Sema4D/Plexin-B1/RhoA/ROCK signaling pathway caused by fluoride promoted the level of TGF-beta1 and activated the proliferation of osteoblasts. In addition, osteroprotegerin (OPG) secreted by osteoblasts was up regulated by fluoride. The competitive combination of OPG and RANKL was strengthened and the combination of RANKL and RANK was hindered. And then the differentiation and maturation of osteoclasts were inhibited, and bone absorption was weakened, leading to skeletal fluorosis. PMID- 26489628 TI - Synaptic vesicle protein2A decreases in amygdaloid-kindling pharmcoresistant epileptic rats. AB - Synaptic vesicle protein 2A (SV2A) involvement has been reported in the animal models of epilepsy and in human intractable epilepsy. The difference between pharmacosensitive epilepsy and pharmacoresistant epilepsy remains poorly understood. The present study aimed to observe the hippocampus SV2A protein expression in amygdale-kindling pharmacoresistant epileptic rats. The pharmacosensitive epileptic rats served as control. Amygdaloid-kindling model of epilepsy was established in 100 healthy adult male Sprague-Dawley rats. The kindled rat model of epilepsy was used to select pharmacoresistance by testing their seizure response to phenytoin and phenobarbital. The selected pharmacoresistant rats were assigned to a pharmacoresistant epileptic group (PRE group). Another 12 pharmacosensitive epileptic rats (PSE group) served as control. Immunohistochemistry, real-time PCR and Western blotting were used to determine SV2A expression in the hippocampus tissue samples from both the PRE and the PSE rats. Immunohistochemistry staining showed that SV2A was mainly accumulated in the cytoplasm of the neurons, as well as along their dendrites throughout all subfields of the hippocampus. Immunoreactive staining level of SV2A-positive cells was 0.483 +/- 0.304 in the PRE group and 0.866 +/- 0.090 in the PSE group (P < 0.05). Real-time PCR analysis demonstrated that 2( DeltaDeltaCt) value of SV2A mRNA was 0.30 +/- 0.43 in the PRE group and 0.76 +/- 0.18 in the PSE group (P < 0.05). Western blotting analysis obtained the similar findings (0.27 +/- 0.21 versus 1.12 +/- 0.21, P < 0.05). PRE rats displayed a significant decrease of SV2A in the brain. SV2A may be associated with the pathogenesis of intractable epilepsy of the amygdaloid-kindling rats. PMID- 26489629 TI - High levels of testosterone inhibit ovarian follicle development by repressing the FSH signaling pathway. AB - The effect of high concentrations of testosterone on ovarian follicle development was investigated. Primary follicles and granulosa cells were cultured in vitro in media supplemented with a testosterone concentration gradient. The combined effects of testosterone and follicle-stimulating hormone (FSH) on follicular growth and granulosa cell gonadotropin receptor mRNA expression were also investigated. Follicle growth in the presence of high testosterone concentrations was promoted at early stages (days 1-7), but inhibited at later stage (days 7-14) of in vitro culture. Interestingly, testosterone-induced follicle development arrest was rescued by treatment with high concentrations of FSH (400 mIU/mL). In addition, in cultured granulosa cells, high testosterone concentrations induced cell proliferation, and increased the mRNA expression level of FSH receptor (FSHR), and luteinized hormone/choriogonadotropin receptor. It was concluded that high concentrations of testosterone inhibited follicle development, most likely through regulation of the FSH signaling pathway, although independently from FSHR downregulation. These findings are an important step in further understanding the pathogenesis of polycystic ovary syndrome. PMID- 26489630 TI - Knockdown of Bmi1 inhibits bladder cancer cell growth both in vitro and in vivo by blocking cell cycle at G1 phase and inducing apoptosis. AB - Bmi1 is a member of the polycomb group family of proteins, and it drives the carcinogenesis of various cancers and governs the self-renewal of multiple types of stem cells. However, its role in the initiation and progression of bladder cancer is not clearly known. The present study aimed to investigate the function of Bmi1 in the development of bladder cancer. Bmi1 expression was detected in human bladder cancer tissues and their adjacent normal tissues (n=10) by immunohistochemistry, qRT-PCR and Western blotting, respectively. Bmi1 small interference RNA (siRNA) was synthesized and transfected into human bladder carcinoma cells (EJ) by lipofectamine 2000. The Bmil expression at mRNA and protein levels was measured in EJ cells transfected with Bmil siRNA (0, 80, 160 nmol/L) by qRT-PCR and Western blotting, respectively. Cell viability and Ki67 expression (a marker of cell proliferation) were determined in Bmi1 siRNA transfected cells by CCK-8 assay and qRT-PCR, respectively. Cell cycle of transfected cells was flow-cytometrically determined. Immunofluorescence and Western blotting were used to detect the expression levels of cell cycle associated proteins cyclin D1 and cyclin E in the cells. Pro-apoptotic proteins Bax and caspase 3 and anti-apoptotic protein Bcl-2 were detected by Western blotting as well. Additionally, xenograft tumor models were established by inoculation of EJ cells (infected with Bmil shRNA/pLKO.1 lentivirus or not) into nude mice. The tumor volumes were measured every other day for 14 days. The results showed that the Bmil expression was significantly increased in bladder tumor tissues when compared with that in normal tissues (P<0.05). Perturbation of Bmi1 expression by using siRNA could significantly inhibit the proliferation of EJ cells (P<0.05). Bmi1 siRNA-transfected EJ cells were accumulated in G1 phase and the expression levels of cyclin D1 and cyclin E were down-regulated. Bax and caspase-3 expression levels were significantly increased and Bcl-2 levels decreased after Bmi1 knockdown. Tumor volume was conspicuously reduced in mice injected with EJ cells with Bmi1 knockdown. Our findings indicate that Bmi1 is a potential driver oncogene of bladder cancer and it may become a potential treatment target for human bladder cancer. PMID- 26489631 TI - Total triterpenoids from Ganoderma Lucidum suppresses prostate cancer cell growth by inducing growth arrest and apoptosis. AB - In this study, one immortalized human normal prostatic epithelial cell line (BPH) and four human prostate cancer cell lines (LNCaP, 22Rv1, PC-3, and DU-145) were treated with Ganoderma Lucidum triterpenoids (GLT) at different doses and for different time periods. Cell viability, apoptosis, and cell cycle were analyzed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR and Western blotting. It was found that GLT dose dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. GLT-induced apoptosis was due to activation of Caspases-9 and -3 and turning on the downstream apoptotic events. GLT-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and E2F1 expression at the late time. These findings demonstrate that GLT suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which might suggest that GLT or Ganoderma Lucidum could be used as a potential therapeutic drug for prostate cancer. PMID- 26489632 TI - Surgical challenges for lateral ventricle meningiomas: A consecutive series of 21 patients. AB - Lateral ventricular meningiomas (LVMs) are especially rare, and they often remain "silent" until they become very large. Several surgical approaches exist, but the optimal surgical strategy for them remains a challenge. The incidence, clinical features, radiological manifestations, pathological findings, and especially the surgical strategy in 21 patients with LVMs were analyzed retrospectively. The mean age of patients was 42.7 years (range, 17 to 78 years). Raised intracranial pressure was the main presenting symptom. The definite diagnosis of LVMs in most cases was made by computed tomography (CT) or magnetic resonance imaging (MRI). Six patients were subjected to plain CT scans, 15 to contrast MR scans, and 4 to a magnetic resonance angiogram (MRA). Large tumors were seen in most cases with an average diameter of more than 4.3 cm. Of the 21 cases of LVMs in our series, LVMs were resected in 16 cases via a posterior parieto-occipital transcortical approach, 2 cases via a transcallosal approach, and 3 cases via a posterior middle temporal gyrus approach. In 8 out of 21 cases, the tumors were located in the left lateral ventricle. The gross total surgical excision was achieved in 18 (86%) patients, and all LVMs were pathologically confirmed to be benign. Nine patients were followed up (range: 11 months-4.6 years). Eight (88.9%) cases obtained good recovery and one (11.1%) obtained moderate disability. Four approaches are available for the surgical treatment of LVMs. The choice of surgical approaches depends on tumor location, laterality, size and extension, and the function of the brain must be taken into account. Intracapsular resection and piecemeal resection of LVMs can be safely and easily performed. Preoperative MRA scan is important to know the feeder of LVMs and peripheral blood supply. PMID- 26489633 TI - Modified titration intratympanic gentamicin injection for unilateral intractable Meniere's disease. AB - This study looked into the efficacy of a modified titration protocol of intratympanic gentamicin injection (ITG) in the patients with unilateral intractable Meniere's disease (MD). Modified titration protocol of ITG at a low dose (20 mg/mL) was administered to 10 patients with definite unilateral intractable MD. After initial first two fixed ITGs on weekly basis, the patients might or might not be given any more injections, depending on the appearance of unilateral vestibular loss (UVL). ITG was terminated if the patients satisfied the criteria of UVL. All patients were followed-up for at least two years. The effects of ITG on the vertigo attack, functional level scores and postural balance were evaluated. Of the 10 cases, 8 showed the sign of UVL after receiving initial two ITGs and were not given any more intratympanic injections, and the other 2 patients were administered three ITGs. A two-year follow-up revealed that complete and substantial vertigo control was achieved in 9 cases, and limited vertigo control in 1 patient. Hearing level was lowered in 2 patients. The posture stability and functional level scores were improved. Our study showed that the modified titration protocol of ITG at a low dose could effectively control vertigo in patients with unilateral intractable MD. PMID- 26489634 TI - Association of single nucleotide polymorphisms of ABCB1, OPRM1 and COMT with pain perception in cancer patients. AB - Pain perception is influenced by multiple factors. The single nucleotide polymorphisms (SNPs) of some genes were found associated with pain perception. This study aimed to examine the association of the genotypes of ABCB1 C3435T, OPRM1 A118G and COMT V108/158M (valine 108/158 methionine) with pain perception in cancer patients. We genotyped 146 cancer pain patients and 139 cancer patients without pain for ABCB1 C3435T (rs1045642), OPRM1 A118G (rs1799971) and COMT V108/158M (rs4680) by the fluorescent dye-terminator cycle sequencing method, and compared the genotype distribution between groups with different pain intensities by chi-square test and pain scores between groups with different genotypes by non parametric test. The results showed that in these cancer patients, the frequency of variant T allele of ABCB1 C3435T was 40.5%; that of G allele of OPRM1 A118G was 38.5% and that of A allele of COMT V108/158M was 23.3%. No significant difference in the genotype distribution of ABCB1 C3435T (rs1045642) and OPRM1 A118G (rs1799971) was observed between cancer pain group and control group (P=0.364 and 0.578); however, significant difference occurred in the genotype distribution of COMT V108/158M (rs4680) between the two groups (P=0.001). And the difference could not be explained by any other confounding factors. Moreover, we found that the genotypes of COMT V108/158M and ABCB1 C3435T were associated with the intensities of pain in cancer patients. In conclusion, our results indicate that the SNPs of COMT V108/158M and ABCB1 C3435T significantly influence the pain perception in Chinese cancer patients. PMID- 26489635 TI - Effect of topical propranolol gel on plasma renin, angiotensin II and vascular endothelial growth factor in superficial infantile hemangiomas. AB - The effect of topical propranolol gel on the levels of plasma renin, angiotensin II (ATII) and vascular endothelial growth factor (VEGF) in superficial infantile hemangiomas (IHs) was investigated. Thirty-three consecutive children with superficial IHs were observed pre-treatment, 1 and 3 months after application of topical propranolol gel for the levels of plasma renin, ATII and VEGF in Department of General Surgery of Dongfang Hospital from February 2013 to February 2014. The plasma results of IHs were compared with those of 30 healthy infants of the same age from out-patient department. The clinical efficiency of topical propranolol gel at 1st, and 3rd month after application was 45%, and 82% respectively. The levels of plasma renin, ATII and VEGF in patients pre-treatment were higher than those in healthy infants (565.86 +/- 49.66 vs. 18.19 +/- 3.56, 3.20 +/- 0.39 vs 0.30 +/- 0.03, and 362.16 +/- 27.29 vs. 85.63 +/- 8.14, P < 0.05). The concentrations of VEGF and renin at 1st and 3rd month after treatment were decreased obviously as compared with those pre-treatment (271.51 +/- 18.59 vs. 362.16 +/- 27.29, and 405.18 +/- 42.52 vs. 565.86 +/- 49.66 P < 0.05; 240.80 +/- 19.89 vs. 362.16 +/- 27.29, and 325.90 +/- 35.78 vs. 565.86 +/- 49.66, P < 0.05, respectively), but the levels of plasma ATII declined slightly (2.96 +/- 0.37 vs. 3.20 +/- 0.39, and 2.47 +/- 0.27 vs. 3.20 +/- 0.39, P > 0.05). It was indicated that the increased renin, ATII and VEGF might play a role in the onset or development of IHs. Propranolol gel may suppress the proliferation of IHs by reducing VEGF. PMID- 26489636 TI - Fracture and migration of implantable venous access port catheters: Cause analysis and management of 4 cases. AB - This study aimed to investigate the causes and managements of the fractures and migrations of the implantable venous access port catheter (IVAPC). The fracture or migration of IVAPC occurred in 4 patients who were treated between May 2012 and January 2014 in Union Hospital, Wuhan, China. The port catheter leakage was found in 2 cases during drug infusion. Catheters that dislodged to the superior vena cava and right atrium were confirmed by port angiogram. The two dislodged catheters were successfully retrieved by interventional procedures. Catheter fracture occurred in two cases during port removal. One catheter was eventually removed from the subclavian vein through right clavicle osteotomy and subclavian venotomy, and the other removed by external jugular venotomy. Flushing the port in high pressure and injury of the totally implantable venous access port (TIVP) during implantation are usually responsible for catheter displacement. Interventional retrieval procedure can be used if the catheter dislodges to the vena cava and right atrium. Catheter fracture may occur during removal if clipping syndrome occurs or the catheter is sutured very tight during implantation. PMID- 26489637 TI - Repetitive magnetic stimulation promotes neural stem cells proliferation by upregulating MiR-106b in vitro. AB - Neural stem cells (NSCs) proliferation can be influenced by repetitive transcranial magnetic stimulation (rTMS) in vivo via microRNA-106b-25 cluster, but the underlying mechanisms are poorly understood. This study investigated the involvement of microRNA-106b-25 cluster in the proliferation of NSCs after repetitive magnetic stimulation (rMS) in vitro. NSCs were stimulated by rMS (200/400/600/800/1000 pulses per day, with 10 Hz frequency and 50% maximum machine output) over a 3-day period. NSCs proliferation was detected by using ki 67 and EdU staining. Ki-67, p21, p57, cyclinD1, cyclinE, cyclinA, cdk2, cdk4 proteins and miR-106b, miR-93, miR-25 mRNAs were detected by Western blotting and qRT-PCR, respectively. The results showed that rMS could promote NSCs proliferation in a dose-dependent manner. The proportions of ki-67+ and Edu+ cells in 1000 pulses group were 20.65% and 4.00%, respectively, significantly higher than those in control group (9.25%, 2.05%). The expression levels of miR 106b and miR-93 were significantly upregulated in 600-1000 pulses groups compared with control group (P<0.05 or 0.01 for all). The expression levels of p21 protein were decreased significantly in 800/1000 pulses groups, and those of cyclinD1, cyclinA, cyclinE, cdk2 and cdk4 were obviously increased after rMS as compared with control group (P<0.05 or 0.01 for all). In conclusion, our findings suggested that rMS enhances the NSCs proliferation in vitro in a dose-dependent manner and miR-106b/p21/cdks/cyclins pathway was involved in the process. PMID- 26489639 TI - Acceptability of physical examination by male doctors in medical care: Taking breast palpation as an example. AB - In this study, we conducted an investigation among medical workers, patients and college students concerning their acceptability of breast palpation performed by male doctors (hereinafter referred to as "acceptability", or "the examination", respectively, if not otherwise indicated), to get the information about their acceptability and reasons for accepting or declining the examination among the three population. A questionnaire investigation was conducted in 500 patients with breast diseases, 700 students of medical colleges, and 280 medical workers working in hospitals. The subjects were asked to choose between two options: accept or do not accept (the examination). The subjects were asked to fill out the questionnaire forms on free and anonymous basis and the questionnaire forms were collected on spot, immediately after completion. The questionnaires collected were coded, sorted out and checked. Data of the eligible questionnaires were input into Epidata software and analyzed by SPSS. Upon the establishment of the database, the intra-group data were tested by utilizing chi(2) test. Among 1480 questionnaires, 1293 (90.41%) questionnaires were retrieved. Our results showed that 56.78% of patients reported that they could accept breast palpation by male doctors. About 59.66% of medical staff expressed their acceptance of the examination, but only 35.03% of students said the examination. On the basis of this study, we were led to conclude that the examination is not well accepted by different populations, and therefore, (1) medical professionals and administrators should pay attention to the gender-related ethics in their practice and the feeling of patients should be respected when medical examinations involve private or sensitive body parts; (2) to this end, related departments should be properly staffed with doctors of both sexes, and this is especially true of the departments involving the examination or treatment of private or sensitive body parts; (3) health education should, among other things, include helping female patients to overcome the fear and anxiety in such examinations. This is of great importance since some women may miss the opportunity to get timely diagnosis. PMID- 26489638 TI - Toxic potential of palytoxin. AB - This review briefly describes the origin, chemistry, molecular mechanism of action, pharmacology, toxicology, and ecotoxicology of palytoxin and its analogues. Palytoxin and its analogues are produced by marine dinoflagellates. Palytoxin is also produced by Zoanthids (i.e. Palythoa), and Cyanobacteria (Trichodesmium). Palytoxin is a very large, non-proteinaceous molecule with a complex chemical structure having both lipophilic and hydrophilic moieties. Palytoxin is one of the most potent marine toxins with an LD50 of 150 ng/kg body weight in mice exposed intravenously. Pharmacological and electrophysiological studies have demonstrated that palytoxin acts as a hemolysin and alters the function of excitable cells through multiple mechanisms of action. Palytoxin selectively binds to Na(+)/K(+)-ATPase with a Kd of 20 pM and transforms the pump into a channel permeable to monovalent cations with a single-channel conductance of 10 pS. This mechanism of action could have multiple effects on cells. Evaluation of palytoxin toxicity using various animal models revealed that palytoxin is an extremely potent neurotoxin following an intravenous, intraperitoneal, intramuscular, subcutaneous or intratracheal route of exposure. Palytoxin also causes non-lethal, yet serious toxic effects following dermal or ocular exposure. Most incidents of palytoxin poisoning have manifested after oral intake of contaminated seafood. Poisonings in humans have also been noted after inhalation, cutaneous/systemic exposures with direct contact of aerosolized seawater during Ostreopsis blooms and/or through maintaining aquaria containing Cnidarian zoanthids. Palytoxin has a strong potential for toxicity in humans and animals, and currently this toxin is of great concern worldwide. PMID- 26489640 TI - A Practical Approach to Juvenile Dermatomyositis and Juvenile Scleroderma. AB - Juvenile dermatomyositis and juvenile scleroderma are rare multisystem autoimmune disorders. Although they share some pathognomonic hallmarks with adult onset myositis or scleroderma, there are significant differences in presentation, characteristics and associated features when the diseases present in childhood. In view of this, and the rarity of the conditions, it is important for care to be led by teams with expertise in pediatric rheumatology conditions. Prognosis has improved significantly in the West; likely due to early diagnosis and aggressive treatment with immunosuppressive medications. However, this trend is not replicated in the developing world. Early recognition of these diseases is crucial to achieve rapid and sustained remission and prevent disease or medication associated complications. This article aims to provide a practical overview for recognition, diagnosis and treatment of these conditions. PMID- 26489641 TI - [Wolfgang Oehmichen : 11.11.1923 - 27.09.2014]. PMID- 26489642 TI - [Report of the working group on dermatopathology]. PMID- 26489643 TI - A new direction for grid cells. AB - Krupic, Bauza, Burton, Barry, & O'Keefe (Grid cell symmetry is shaped by environmental geometry. Nature, 518, 232-235, 2015) found that the grids of grid cells in the entorhinal cortex of rats become sparser at the sharp end of a trapezoidal space. This makes grids, and grid cells, unsuitable for measuring distance traveled (odometry) and suggests that grid cells may have more to do with sorting out directions. PMID- 26489645 TI - Hyperkalaemia on the surgical ward. PMID- 26489644 TI - ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction. AB - In addition to triacylglycerols, adipocytes contain a large reserve of unesterified cholesterol. During adipocyte lipolysis and cell death seen during severe obesity and weight loss, free fatty acids and cholesterol become available for uptake and processing by adipose tissue macrophages (ATMs). We hypothesize that ATMs become cholesterol enriched and participate in cholesterol clearance from adipose tissue. We previously showed that ABCG1 is robustly upregulated in ATMs taken from obese mice and further enhanced by caloric restriction. Here, we found that ATMs taken from obese and calorie-restricted mice derived from transplantation of WT or Abcg1-deficient bone marrow are cholesterol enriched. ABCG1 levels regulate the ratio of classically activated (M1) to alternatively activated (M2) ATMs and their cellular cholesterol content. Using WT and Abcg1(-/ ) cultured macrophages, we found that Abcg1 is most highly expressed by M2 macrophages and that ABCG1 deficiency is sufficient to retard macrophage chemotaxis. However, changes in myeloid expression of Abcg1 did not protect mice from obesity or impaired glucose homeostasis. Overall, ABCG1 modulates ATM cholesterol content in obesity and weight loss regimes leading to an alteration in M1 to M2 ratio that we suggest is due to the extent of macrophage egress from adipose tissue. PMID- 26489646 TI - Duty of candour should not be tied to an "apology". PMID- 26489647 TI - Transcriptomic characterization of fibrolamellar hepatocellular carcinoma. AB - Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a deletion of ~ 400 kb in chromosome 19, resulting in a fusion of the genes for the heat shock protein, DNAJ (Hsp40) homolog, subfamily B, member 1, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA. The resulting chimeric transcript produces a fusion protein that retains kinase activity. No other recurrent genomic alterations have been identified. Here we characterize the molecular pathogenesis of FLHCC with transcriptome sequencing (RNA sequencing). Differential expression (tumor vs. adjacent normal tissue) was detected for more than 3,500 genes (log2 fold change >= 1, false discovery rate <= 0.01), many of which were distinct from those found in hepatocellular carcinoma. Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples. These and other dysregulated genes may serve as potential targets for therapeutic intervention. PMID- 26489648 TI - Mitochondrial retrograde signaling regulates neuronal function. AB - Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer's and Parkinson's. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFalpha) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson's disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment. PMID- 26489650 TI - Mutation-biased adaptation in Andean house wrens. PMID- 26489651 TI - Of goals and habits. PMID- 26489649 TI - Xist imprinting is promoted by the hemizygous (unpaired) state in the male germ line. AB - The long noncoding X-inactivation-specific transcript (Xist gene) is responsible for mammalian X-chromosome dosage compensation between the sexes, the process by which one of the two X chromosomes is inactivated in the female soma. Xist is essential for both the random and imprinted forms of X-chromosome inactivation. In the imprinted form, Xist is paternally marked to be expressed in female embryos. To investigate the mechanism of Xist imprinting, we introduce Xist transgenes (Tg) into the male germ line. Although ectopic high-level Xist expression on autosomes can be compatible with viability, transgenic animals demonstrate reduced fitness, subfertility, defective meiotic pairing, and other germ-cell abnormalities. In the progeny, paternal-specific expression is recapitulated by the 200-kb Xist Tg. However, Xist imprinting occurs efficiently only when it is in an unpaired or unpartnered state during male meiosis. When transmitted from a hemizygous father (+/Tg), the Xist Tg demonstrates paternal specific expression in the early embryo. When transmitted by a homozygous father (Tg/Tg), the Tg fails to show imprinted expression. Thus, Xist imprinting is directed by sequences within a 200-kb X-linked region, and the hemizygous (unpaired) state of the Xist region promotes its imprinting in the male germ line. PMID- 26489652 TI - Probing exoplanet clouds with optical phase curves. AB - Kepler-7b is to date the only exoplanet for which clouds have been inferred from the optical phase curve--from visible-wavelength whole-disk brightness measurements as a function of orbital phase. Added to this, the fact that the phase curve appears dominated by reflected starlight makes this close-in giant planet a unique study case. Here we investigate the information on coverage and optical properties of the planet clouds contained in the measured phase curve. We generate cloud maps of Kepler-7b and use a multiple-scattering approach to create synthetic phase curves, thus connecting postulated clouds with measurements. We show that optical phase curves can help constrain the composition and size of the cloud particles. Indeed, model fitting for Kepler-7b requires poorly absorbing particles that scatter with low-to-moderate anisotropic efficiency, conclusions consistent with condensates of silicates, perovskite, and silica of submicron radii. We also show that we are limited in our ability to pin down the extent and location of the clouds. These considerations are relevant to the interpretation of optical phase curves with general circulation models. Finally, we estimate that the spherical albedo of Kepler-7b over the Kepler passband is in the range 0.4-0.5. PMID- 26489653 TI - Holocentromeres in Rhynchospora are associated with genome-wide centromere specific repeat arrays interspersed among euchromatin. AB - Holocentric chromosomes lack a primary constriction, in contrast to monocentrics. They form kinetochores distributed along almost the entire poleward surface of the chromatids, to which spindle fibers attach. No centromere-specific DNA sequence has been found for any holocentric organism studied so far. It was proposed that centromeric repeats, typical for many monocentric species, could not occur in holocentrics, most likely because of differences in the centromere organization. Here we show that the holokinetic centromeres of the Cyperaceae Rhynchospora pubera are highly enriched by a centromeric histone H3 variant interacting centromere-specific satellite family designated "Tyba" and by centromeric retrotransposons (i.e., CRRh) occurring as genome-wide interspersed arrays. Centromeric arrays vary in length from 3 to 16 kb and are intermingled with gene-coding sequences and transposable elements. We show that holocentromeres of metaphase chromosomes are composed of multiple centromeric units rather than possessing a diffuse organization, thus favoring the polycentric model. A cell-cycle-dependent shuffling of multiple centromeric units results in the formation of functional (poly)centromeres during mitosis. The genome-wide distribution of centromeric repeat arrays interspersing the euchromatin provides a previously unidentified type of centromeric chromatin organization among eukaryotes. Thus, different types of holocentromeres exist in different species, namely with and without centromeric repetitive sequences. PMID- 26489654 TI - An intrinsic mechanism of secreted protein aging and turnover. AB - The composition and functions of the secreted proteome are controlled by the life spans of different proteins. However, unlike intracellular protein fate, intrinsic factors determining secreted protein aging and turnover have not been identified and characterized. Almost all secreted proteins are posttranslationally modified with the covalent attachment of N-glycans. We have discovered an intrinsic mechanism of secreted protein aging and turnover linked to the stepwise elimination of saccharides attached to the termini of N-glycans. Endogenous glycosidases, including neuraminidase 1 (Neu1), neuraminidase 3 (Neu3), beta-galactosidase 1 (Glb1), and hexosaminidase B (HexB), possess hydrolytic activities that temporally remodel N-glycan structures, progressively exposing different saccharides with increased protein age. Subsequently, endocytic lectins with distinct binding specificities, including the Ashwell Morell receptor, integrin alphaM, and macrophage mannose receptor, are engaged in N-glycan ligand recognition and the turnover of secreted proteins. Glycosidase inhibition and lectin deficiencies increased protein life spans and abundance, and the basal rate of N-glycan remodeling varied among distinct proteins, accounting for differences in their life spans. This intrinsic multifactorial mechanism of secreted protein aging and turnover contributes to health and the outcomes of disease. PMID- 26489656 TI - Reply to Lessios and Marko et al.: Early and progressive migration across the Isthmus of Panama is robust to missing data and biases. PMID- 26489655 TI - The adherens junctions control susceptibility to Staphylococcus aureus alpha toxin. AB - Staphylococcus aureus is both a transient skin colonizer and a formidable human pathogen, ranking among the leading causes of skin and soft tissue infections as well as severe pneumonia. The secreted bacterial alpha-toxin is essential for S. aureus virulence in these epithelial diseases. To discover host cellular factors required for alpha-toxin cytotoxicity, we conducted a genetic screen using mutagenized haploid human cells. Our screen identified a cytoplasmic member of the adherens junctions, plekstrin-homology domain containing protein 7 (PLEKHA7), as the second most significantly enriched gene after the known alpha-toxin receptor, a disintegrin and metalloprotease 10 (ADAM10). Here we report a new, unexpected role for PLEKHA7 and several components of cellular adherens junctions in controlling susceptibility to S. aureus alpha-toxin. We find that despite being injured by alpha-toxin pore formation, PLEKHA7 knockout cells recover after intoxication. By infecting PLEKHA7(-/-) mice with methicillin-resistant S. aureus USA300 LAC strain, we demonstrate that this junctional protein controls disease severity in both skin infection and lethal S. aureus pneumonia. Our results suggest that adherens junctions actively control cellular responses to a potent pore-forming bacterial toxin and identify PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections. PMID- 26489657 TI - Do large molecular sequence divergences imply an early closure of the Isthmus of Panama? PMID- 26489658 TI - Appearance of an early closure of the Isthmus of Panama is the product of biased inclusion of data in the metaanalysis. PMID- 26489659 TI - Feasibility of controlling hookworm infection through preventive chemotherapy: a simulation study using the individual-based WORMSIM modelling framework. AB - BACKGROUND: Globally, hookworms infect 440 million people in developing countries. Especially children and women of childbearing age are at risk of developing anaemia as a result of infection. To control hookworm infection and disease (i.e. reduce the prevalence of medium and heavy infection to <1 %), the World Health Organization has set the target to provide annual or semi-annual preventive chemotherapy (PC) with albendazole (ALB) or mebendazole (MEB) to at least 75 % of all children and women of childbearing age in endemic areas by 2020. Here, we predict the feasibility of achieving <1 % prevalence of medium and heavy infection, based on simulations with an individual-based model. METHODS: We developed WORMSIM, a new generalized individual-based modelling framework for transmission and control of helminths, and quantified it for hookworm transmission based on published data. We simulated the impact of standard and more intense PC strategies on trends in hookworm infection, and explored the potential additional impact of interventions that improve access to water, sanitation, and hygiene (WASH). The individual-based framework allowed us to take account of inter-individual heterogeneities in exposure and contribution to transmission of infection, as well as in participation in successive PC rounds. RESULTS: We predict that in low and medium endemic areas, current PC strategies (including targeting of WCBA) will achieve control of hookworm infection (i.e. the parasitological target) within 2 years. In highly endemic areas, control can be achieved with semi-annual PC with ALB at 90 % coverage, combined with interventions that reduce host contributions to the environmental reservoir of infection by 50 %. More intense PC strategies (high frequency and coverage) can help speed up control of hookworm infection, and may be necessary in some extremely highly endemic settings, but are not a panacea against systematic non participation to PC. CONCLUSIONS: Control of hookworm infection by 2020 is feasible with current PC strategies (including targeting of WCBA). In highly endemic areas, PC should be combined with health education and/or WASH interventions. PMID- 26489660 TI - Metamorphic remodeling of morphology and the body cavity in Phoronopsis harmeri (Lophotrochozoa, Phoronida): the evolution of the phoronid body plan and life cycle. AB - BACKGROUND: Phoronids undergo a remarkable metamorphosis, in which some parts of the larval body are consumed by the juvenile and the body plan completely changes. According to the only previous hypothesis concerning the evolution of the phoronid body plan, a hypothetical ancestor of phoronids inhabited a U-shaped burrow in soft sediment, where it drew the anterior and posterior parts of the body together and eventually fused them. In the current study, we investigated the metamorphosis of Phoronopsis harmeri with light, electron, and laser confocal microscopy. RESULTS: During metamorphosis, the larval hood is engulfed by the juvenile; the epidermis of the postroral ciliated band is squeezed from the tentacular epidermis and then engulfed; the larval telotroch undergoes cell death and disappears; and the juvenile body forms from the metasomal sack of the larva. The dorsal side of the larva becomes very short, whereas the ventral side becomes very long. The terminal portion of the juvenile body is the ampulla, which can repeatedly increase and decrease in diameter. This flexibility of the ampulla enables the juvenile to dig into the sediment. The large blastocoel of the larval collar gives rise to the lophophoral blood vessels of the juvenile. The dorsal blood vessel of the larva becomes the definitive median blood vessel. The juvenile inherits the larval protocoel, mesocoel, and metacoel. Late in metamorphosis, however, the protocoel loses its epithelial structure: the desmosomes between cells and the basal lamina under the cells disappear. This loss may reflect a reduction of the protocoel, which is a characteristic of some recent phoronids. CONCLUSIONS: Based on our investigation of P. harmeri metamorphosis, we hypothesize that the phoronid ancestor was worm-like animal that possessed preoral, tentacular, and trunk coeloms. It lived on the soft sediment and collected food with its tentacles. When threatened, this worm-like ancestor buried itself in the soft sediment by means of the ventral protrusion into which the loop of the intestine and the blood vessels were drawn. We propose that this behavior gave rise to the body plan of all recent phoronids. The evolution of phoronid life cycle seems having more in common with"intercalation" than "terminal addition" theories. PMID- 26489661 TI - Comparing three forms of early intervention for youth with borderline personality disorder (the MOBY study): study protocol for a randomised controlled trial. AB - BACKGROUND: Borderline personality disorder is a severe mental disorder that usually has its onset in youth, but its diagnosis and treatment are often delayed. Psychosocial 'early intervention' is effective in improving symptoms and behaviours, but no trial has studied adaptive functioning as a primary outcome, even though this remains the major persistent impairment in this patient group. Also, the degree of complexity of treatment and requirements for implementation in mainstream health services are unclear. The primary aim of this trial is to evaluate the effectiveness of three forms of early intervention for borderline personality disorder in terms of adaptive functioning. Each treatment is defined by combining either a specialised or a general service delivery model with either an individual psychotherapy or a control psychotherapy condition. METHODS/DESIGN: The study is a parallel-group, single-blind, randomised controlled trial, which has randomised permuted blocking, stratified by depression score, sex and age. The treatments are: (1) the specialised Helping Young People Early service model plus up to 16 sessions of individual cognitive analytic therapy; (2) the Helping Young People Early service plus up to 16 sessions of a control psychotherapy condition known as 'befriending'; (3) a general youth mental health care model plus up to 16 sessions of befriending. Participants will comprise 135 help seeking youth aged 15-25 years with borderline personality disorder. After baseline assessment, staff blind to the study design and treatment group allocation will conduct assessments at 3, 6, 12 and 18 months. At the 12-month primary endpoint, the primary outcome is adaptive functioning (measures of social adjustment and interpersonal problems); secondary outcomes include measures of client satisfaction, borderline personality disorder features, depression and substance use. DISCUSSION: The results of this trial will help to clarify the comparative effectiveness of a specialised early intervention service model over and above general youth mental health care, along with the contribution of individual cognitive analytic therapy over and above specialised general clinical care in early intervention for borderline personality disorder. Consequently, the findings will also inform the level of training and competency required for effective delivery of early intervention services. TRIAL REGISTRATION: Registered with the Australian New Zealand Clinical Trial Registry ACTRN12610000100099 on 1 February 2010. PMID- 26489664 TI - Use of physical restraints in nursing homes: a multicentre cross-sectional study. AB - BACKGROUND: Although many countries have implemented strict legal rules, the prevalence of physical restraints in nursing homes seems to remain high. In Switzerland, data related to the frequency of physical restraints are scarce and little is known about associations with resident and nursing home characteristics. The aim of this study was to investigate the prevalence and types of physical restraints in nursing homes in two Swiss cantons and to explore whether resident-related and organisational factors are associated with the use of physical restraints. METHODS: We conducted a multicentre cross-sectional study. Twenty nursing homes with 1362 residents from two culturally different cantons were included. Data on physical restraints and residents' characteristics were extracted from residents' records (11/2013 to 2/2014). Organisational data were collected by questionnaires addressing nursing home directors or nursing managers. Sample size calculation and outcome analysis took cluster-adjustment into account. Descriptive statistics and multiple logistic regression analysis with nursing homes as random effect were used for investigation. RESULTS: The prevalence of residents with at least one physical restraint was 26.8 % (95 % confidence interval [CI] 19.8-33.8). Centre prevalence ranged from 2.6 to 61.2 %. Bilateral bedrails were most frequently used (20.3 %, 95 % CI 13.5-27.1). Length of residence, degrees of care dependency and mobility limitation were significantly positively associated with the use of physical restraint, but none of the organisational characteristics was significantly associated. CONCLUSION: Approximately a quarter of the nursing home residents included in our study experienced physical restraints. Since variation between nursing homes was pronounced, it seems to be worthwhile to explore nursing homes with particularly low and high use of physical restraints in future research, especially by using qualitative methods. There is a need for effective interventions aiming at restraint-free nursing care. Development of interventional approaches should consider specific residents' characteristics associated with restraint use. PMID- 26489665 TI - Mechanical testing of pericardium for manufacturing prosthetic heart valves. AB - Mammalian pericardia are currently used for the production of percutaneous prosthetic heart valves. The characteristics of biological tissues largely influence the durability of prosthetic devices used in the percutaneous approach and in traditional surgery, too. This paper reviews methodologies employed to assess and compare mechanical properties of pericardial patches from different mammalian species in order to identify the biomaterials adequate for manufacturing prosthetic heart valves. PMID- 26489663 TI - Study protocol for the randomised controlled trial: Ketamine augmentation of ECT to improve outcomes in depression (Ketamine-ECT study). AB - BACKGROUND: There is a robust empirical evidence base supporting the acute efficacy of electroconvulsive therapy (ECT) for severe and treatment resistant depression. However, a major limitation, probably contributing to its declining use, is that ECT is associated with impairment in cognition, notably in anterograde and retrograde memory and executive function. Preclinical and preliminary human data suggests that ketamine, used either as the sole anaesthetic agent or in addition to other anaesthetics, may reduce or prevent cognitive impairment following ECT. A putative hypothesis is that ketamine, through antagonising glutamate receptors, protects from excess excitatory neurotransmitter stimulation during ECT. The primary aim of the ketamine-ECT study is to investigate whether adjunctive ketamine can attenuate the cognitive impairment caused by ECT. Its secondary aim is to examine if ketamine increases the speed of clinical improvement with ECT. METHODS/DESIGN: The ketamine ECT study is a multi-site randomised, placebo-controlled, double blind trial. It was originally planned to recruit 160 moderately to severely depressed patients who had been clinically prescribed ECT. This recruitment target was subsequently revised to 100 patients due to recruitment difficulties. Patients will be randomly allocated on a 1:1 basis to receive either adjunctive ketamine or saline in addition to standard anaesthesia for ECT. The primary neuropsychological outcome measure is anterograde verbal memory (Hopkins Verbal Learning Test Revised delayed recall task) after 4 ECT treatments. Secondary cognitive outcomes include verbal fluency, autobiographical memory, visuospatial memory and digit span. Efficacy is assessed using observer and self-report efficacy measures of depressive symptomatology. The effects of ECT and ketamine on cortical activity during cognitive tasks will be studied in a sub-sample using functional near infrared spectroscopy (fNIRS). DISCUSSION: The ketamine-ECT study aims to establish whether or not adjunctive ketamine used together with standard anaesthesia for ECT will significantly reduce the adverse cognitive effects observed after ECT. Potential efficacy benefits of increased speed of symptom improvement and a reduction in the number of ECT treatments required will also be assessed, as will safety and tolerability of adjunctive ketamine. This study will provide important evidence as to whether adjunctive ketamine is routinely indicated for ECT given for depression in routine NHS clinical practice. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN14689382 (assigned 30/07/2012); EudraCT Number: 2011-005476-41. PMID- 26489666 TI - Aortic root morphology: a paradigm for successful reconstruction. AB - Aortic root (AoR) components provide synchronous and precise 3D deformation of the aortic root during the cardiac cycle in order to ensure closure and opening of the three leaflets over a lifetime. Any deviation from the natural 3D morphology, such as with AoR annulus dilatation, enlarged sinuses and/or dilatation of the sinotubular junction, as in the case of ascending aortic dilatation, may result in disruption of the natural AoR function. Surgical treatment of AoR pathology has two modalities: the replacement of the aortic valve by artificial prosthesis or by preservation of the three leaflets and reconstruction of the aortic root components. Currently, there are two basic aortic root reconstruction procedures: aortic root sparing and aortic valve reimplantation techniques. Regardless of the technique used, the restoration of adequate cusp coaptation, is from a technical point of view, the most important element to consider. To achieve this, there are two requirements that need to be met: (i) the valve coaptation should be superior to the level of the aortic root base by at least 8 mm and (ii) the coaptation height per se has to be >=5 mm. Successful restoration of the aortic root requires adequate technical skills, detailed knowledge of aortic root anatomy and topography, and also knowledge of the spatial pattern of AoR elements. Recently, there has been growing interest in aortic root reconstructive procedures as well their modifications. As such, the aim of this review is to analyse aortic root topography and 3D anatomy from a surgical point of view. The review also focuses on potential risk regions that one should be aware of before the surgical journey into the 'deep waters area' of the AoR begins. PMID- 26489667 TI - Effects of low glycaemic index/low glycaemic load vs. high glycaemic index/ high glycaemic load diets on overweight/obesity and associated risk factors in children and adolescents: a systematic review and meta-analysis. AB - The objective of the present systematic review and meta-analysis was to synthesize the available literature data investigating the effects of low glycaemic index/low glycamic load dietary regimens on anthropometric parameters, blood lipid profiles, and indicators of glucose metabolism in children and adolescents. Literature search was performed using the electronic databases MEDLINE, EMBASE, and the Cochrane Central Register of trials with restrictions to randomized controlled trials, but no limitations concerning language and publication date. Parameters taken into account were: body weight, body mass index, z-score of body mass index, fat mass, fat-free mass, height, waist cicrumference, hip circumference, waist-to-hip ratio, total cholesterol, LDL cholesterol, HDL-cholesterol, triglycerides, diastolic and systolic blood pressure, fasting serum glucose, fasting serum insulin, HOMA-index, glycosylated haemoglobin, and C-reactive protein. Meta-analyses were performed for each parameter to assess pooled effect in terms of weighted mean differences between the post-intervention (or differences in means) of the low glycaemic index diets and the respective high glycaemic index counterparts. Data analysis was performed using the Review Manager 5.3. software. Nine studies enrolling 1.065 children or adolescents met the inclusion criteria. Compared to diets providing a high gylcaemic index, low glycaemic index protocols resulted in significantly more pronounced decreases in serum triglycerides [mean differences -15.14 mg/dl, 95% CI (-26.26, -4.00)] and HOMA-index [mean difference -0.70, 95%-CI (-1.37, -0.04), fixed-effects model only]. Other parameters under investigation were not affected by either low or high glycaemic indices. The present systematic review and meta analysis provides evidence of a beneficial effect of a low glycaemic index/load diet in children and adolescents being either overweight or obese. Regarding the limitations of this analysis, further studies adopting a homogenous design are necessary to assure the present findings. Since low glycaemic index/load regimens were not associated with a deterioration of the outcome parameters, these diets should not be categorically excluded when looking for alternatives to change lifestyle habits in this age group. PMID- 26489669 TI - Room-temperature carbon monoxide oxidation by oxygen over Pt/Al2O3 mediated by reactive platinum carbonates. AB - Room-temperature carbon monoxide oxidation, important for maintaining clean air among other applications, is challenging even after a century of research into carbon monoxide oxidation. Here we report using time-resolved diffuse reflectance infrared spectroscopy, X-ray absorption fine structure spectroscopy and mass spectrometry a platinum carbonate-mediated mechanism for the room-temperature oxidation of carbon monoxide. By applying a periodic reduction-oxidation mode of operation we further show that this behaviour is reversible and can be formed into a catalytic cycle that requires molecular communication between metallic platinum nanoparticles and highly dispersed oxidic platinum centres. A new possibility for the attainment of low-temperature oxidation of carbon monoxide is therefore demonstrated. PMID- 26489668 TI - A functional module-based exploration between inflammation and cancer in esophagus. AB - Inflammation contributing to the underlying progression of diverse human cancers has been generally appreciated, however, explorations into the molecular links between inflammation and cancer in esophagus are still at its early stage. In our study, we presented a functional module-based approach, in combination with multiple data resource (gene expression, protein-protein interactions (PPI), transcriptional and post-transcriptional regulations) to decipher the underlying links. Via mapping differentially expressed disease genes, functional disease modules were identified. As indicated, those common genes and interactions tended to play important roles in linking inflammation and cancer. Based on crosstalk analysis, we demonstrated that, although most disease genes were not shared by both kinds of modules, they might act through participating in the same or similar functions to complete the molecular links. Additionally, we applied pivot analysis to extract significant regulators for per significant crosstalk module pair. As shown, pivot regulators might manipulate vital parts of the module subnetworks, and then work together to bridge inflammation and cancer in esophagus. Collectively, based on our functional module analysis, we demonstrated that shared genes or interactions, significant crosstalk modules, and those significant pivot regulators were served as different functional parts underlying the molecular links between inflammation and cancer in esophagus. PMID- 26489671 TI - Chronic Wound Biofilms: Pathogenesis and Potential Therapies. AB - Chronic wounds are a growing medical problem that cause high rates of morbidity and mortality, costing the healthcare industry in the United States millions of dollars annually. Chronic wound healing is hampered by the presence of bacterial infections that form biofilms, in which the bacteria are encased in exopolysaccharide (EPS) and are less metabolically active than their free-living counterparts. Bacterial biofilms make chronic wounds more refractory to treatment and slow tissue repair by stimulating chronic inflammation at the wound site. Bacterial species communicate through a mechanism known as quorum sensing (QS) to regulate and coordinate the gene expression that is important for virulence factor production, including biofilm formation. This review focuses on the relationships between chronic wounds, biofilms, and QS in the virulence of chronic-wound pathogens. PMID- 26489670 TI - New Insights into the RNA-Binding and E3 Ubiquitin Ligase Activities of Roquins. AB - Roquins are a family of highly conserved RNA-binding proteins that also contain a RING-type E3 ubiquitin ligase domain. They repress constitutive decay elements containing mRNAs and play a critical role in RNA homeostasis and immunological self-tolerance. Here we present the crystal structures of the RNA-binding region of Roquin paralog RC3H2 in both apo- and RNA-bound forms. The RNA-binding region has a bipartite architecture composed of ROQ and HEPN domains, and can bind to stem-loop and double-stranded RNAs simultaneously. The two domains undergo a large orientation change to accommodate RNA duplex binding. We profiled E2 ubiquitin-conjugating enzymes that pair with Roquins and found that RC3H1 and RC3H2 interact with two sets of overlapping but not identical E2 enzymes to drive the assembly of polyubiquitin chains of different linkages. Crystal structures, small-angle X-ray scattering, and E2 profiling revealed that while the two paralogs are highly homologous, RC3H2 and RC3H1 are different in their structures and functions. We also demonstrated that RNA duplex binding to RC3H2 cross-talks with its E3 ubiquitin ligase function using an in vitro auto-ubiquitination assay. PMID- 26489672 TI - Computational Approach to Annotating Variants of Unknown Significance in Clinical Next Generation Sequencing. AB - Next generation sequencing (NGS) has become a common technology in the clinical laboratory, particularly for the analysis of malignant neoplasms. However, most mutations identified by NGS are variants of unknown clinical significance (VOUS). Although the approach to define these variants differs by institution, software algorithms that predict variant effect on protein function may be used. However, these algorithms commonly generate conflicting results, potentially adding uncertainty to interpretation. In this review, we examine several computational tools used to predict whether a variant has clinical significance. In addition to describing the role of these tools in clinical diagnostics, we assess their efficacy in analyzing known pathogenic and benign variants in hematologic malignancies. PMID- 26489673 TI - Measurement of HbA1c in Gingival Crevicular Blood Using a High-Pressure Liquid Chromatography Procedure. AB - OBJECTIVE: To validate an ion exchange high-pressure liquid chromatography (HPLC) method for measuring glycated hemoglobin (HbA1c) in gingival crevicular blood (GCB) spotted on filter paper, for use in screening dental patients for diabetes. METHODS: We collected the GCB specimens for this study from the oral cavities of patients during dental visits, using rigorous strategies to obtain GCB that was as free of debris as possible. The analytical performance of the HPLC method was determined by measuring the precision, linearity, carryover, stability of HbA1c in GCB, and correlation of HbA1c results in GCB specimens with finger-stick blood (FSB) specimens spotted on filter paper. RESULTS: The coefficients of variation (CVs) for the inter- and intrarun precision of the method were less than 2.0%. Linearity ranged between 4.2% and 12.4%; carryover was less than 2.0%, and the stability of the specimen was 6 days at 4 degrees C and as many as 14 days at -70 degrees C. Linear regression analysis comparing the HbA1c results in GCB with FSB yielded a correlation coefficient of 0.993, a slope of 0.981, and an intercept of 0.13. The Bland-Altman plot showed no difference in the HbA1c results from the GCB and FSB specimens at normal, prediabetes, and diabetes HbA1c levels. CONCLUSION: We validated an HPLC method for measuring HbA1c in GCB; this method can be used to screen dental patients for diabetes. PMID- 26489674 TI - Expression of FOXP1 and Colorectal Cancer Prognosis. AB - BACKGROUND: Forkhead box gene P1 (FOXP1) has proven to be a valuable prognostic biomarker in lymphomas, but little is known about this gene in colorectal cancer (CRC). OBJECTIVES: To investigate the expression of FOXP1 in CRC and its potential associations with outcome in CRC. METHODS: We studied the expression pattern of FOXP1 retrospectively via immunohistochemistry in a series of 165 - CRC cases. Fluorescent in situ hybridization and RNA sequencing on FOXP1 knockdown cell lines were performed to investigate the mechanism of action and target genes of FOXP1. RESULTS: Complete loss of nuclear FOXP1 expression was observed in 11.5% of the subjects. A total of 70.9% of subjects showed a heterogeneous FOXP1 expression pattern, and 17.6% of them had high FOXP1 expression. Impaired expression of FOXP1 was significantly correlated with reduced survival rates by multivariate analysis (P = .004). We found no chromosomal aberrations involving FOXP1 in individuals with FOXP1 negativity via immunohistochemical testing. RNA sequencing revealed that genes involved in inflammation and cell proliferation were differentially expressed after FOXP1 knockdown. CONCLUSIONS: In our case series, loss of FOXP1 was associated with reduced survival rates in CRC tissue. Also, FOXP1 affects proliferation and inflammatory reaction in colorectal neoplasia. PMID- 26489675 TI - Nitrous Oxide Abuse and Vitamin B12 Action in a 20-Year-Old Woman: A Case Report. AB - Herein, we report a case of a 20-year-old (ethnicity not reported) woman with a history of nitrous oxide abuse and clinical symptoms consistent with spinal cord subacute combined degeneration with associated low serum concentrations of vitamin B12, elevated methylmalonic acid levels, and radiologic evidence of demyelination of the dorsal region of the spinal column. The health of the patient improved dramatically with B12 supplementation. In this case, we discuss the interaction of nitrous oxide with the enzymatic pathways involved in the biochemistry of vitamin B12. PMID- 26489676 TI - Elevated CA125 Levels in a 72-Year-Old Ethnic Indian Patient: A Diagnostic Pointer Toward Tuberculosis? AB - Serum CA 125 is widely used as a tumor marker for epithelial ovarian cancer. Our laboratory receives few requests for evaluation of this marker in men. In males an elevation of this marker may occur due to malignant and benign lesions of organs derived from the coelomic epithelium. However, in the absence of evidence of a neoplasm (via clinical examination and other diagnostic modalities), it is useful to consider a diagnosis of tuberculosis, particularly in regions where the disease is endemic. Herein, we describe one such case that we investigated at our medical center in Kolkata, India. PMID- 26489677 TI - B Lymphoblastic Leukemia With a Novel t(11;15) (q23;q15) and Unique Burkittoid Morphologic and Immunophenotypic Findings in a 9-Year-Old Boy. AB - B lymphoblastic leukemia is a B progenitor cell neoplasm with a range of immature immunophenotypes and several associated cytogenetic lesions. In contrast, Burkitt leukemia/lymphoma is a mature B lymphocyte neoplasm with a characteristic germinal center immunophenotype and MYC rearrangement. With modern immunophenotyping and cytogenetic methods, the distinction between these 2 entities is seldom ambiguous. Herein, we report a case of a 9-year-old white boy with circulating leukemic cells that demonstrate morphologic overlap between Burkitt leukemia and B lymphoblastic leukemia. Flow cytometry and immunohistochemical stains demonstrated expression of sets of markers with overlap between immature and mature immunophenotypes. While the leukemic cells tested positive for terminal deoxynucleotidyl transferase (TdT), they expressed CD20, BCL6 (in a subset), and lambda-restricted surface light chain. Molecular studies confirmed a true clonal light chain rearrangement, whereas fluorescent in situ hybridization (FISH) results were negative for MYC rearrangement. Metaphase cytogenetics identified a novel gene rearrangement, t(11;15)(q23;q15), that does not involve the MLL gene. This unique cytogenetic abnormality involves the loss of INO80, an adenosine triphosphatase (ATPase) with DNA binding ability. This cytogenetic abnormality may represent a unique feature of this overlap entity of B lymphoblastic lymphoma that expresses markers of maturity and demonstrates Burkitt-like morphology. PMID- 26489678 TI - Mucoepidermoid Carcinoma in a 33-Year-Old White Man. AB - PATIENT DEMOGRAPHICS: A 33-year-old white man. CHIEF COMPLAINT: Longstanding bump on the roof of the mouth. TREATMENT: The patient was referred to an oral maxillofacial surgeon for a pathology consultation. The patient had been experiencing pain on both sides of his jaw, but the oral mass was not painful (Image 1). MEDICAL HISTORY: The patient has no history of smoking, is slightly overweight with a body mass index of 26.5, and has no systemic or chronic medical conditions. EXAMINATION FINDINGS: On initial examination by the oral surgeon, the vital signs of the patient were normal. An indurated lesion was noted on the left hard palate of the patient. Suspecting a benign lesion or possible carcinoma/neoplasm, the oral surgeon scheduled and performed an excisional biopsy (Image 2). The mass was sent for pathological processing. POSTOPERATIVE CARE: This included a diet of soft foods, with daily rinsing using 0.12% chlorhexidine gluconate, with a follow-up appointment made for 2 weeks later. PRINCIPAL LABORATORY FINDINGS: Figure 1; Image 3; Image 4. PMID- 26489679 TI - Invasive Paget Disease of the Nipple of Luminal-B Subtype With Axillary Lymph Node Metastasis in a 60-Year-Old White Woman. AB - Herein, we report a rare case of invasive Paget disease of the nipple with axillary-lymph-node metastasis in a 60-year-old white woman. The patient had intermittent, bloody nipple discharge without skin changes of the nipple-areolar region. We considered the clinical diagnosis of intraductal papilloma. A subareolar core biopsy revealed invasive ductal carcinoma in deep dermal tissue without the overlying epidermis biopsied. The patient underwent total mastectomy and axillary sentinel lymph-node biopsy that demonstrated invasive Paget disease of the nipple with 3.5-mm depth of invasion, ductal carcinoma in-situ in the underlying breast parenchyma, and macrometastasis (5.0 mm) in the sentinel lymph node. Prognostic marker studies of the metastatic site revealed a profile similar to that in the invasive mammary Paget disease (estrogen receptor [ER]+/progesterone receptor [PR]+/human epidermal growth factor receptor 2 [HER2] /proliferation index [Ki-67] of 30%). The patient received adjuvant chemotherapy and experienced no disease recurrence at 20-months of follow-up. This case of luminal-B subtype invasive Paget disease as the source of regional metastasis is unique in the literature, to our knowledge. PMID- 26489680 TI - Schistosoma haematobium Infection That Mimics Bladder Cancer in a 66-Year-Old Ethnic Egyptian Man. AB - PATIENT: 66-year-old ethnic Egyptian man. CHIEF COMPLAINT: Hematuria. HISTORY OF PRESENT ILLNESS: The patient had a history of multiple episodes of gross hematuria for the past 5 years. Because the hematuria usually resolved on its own, he did not seek medical attention during that time. Bladder cancer was suspected. PAST MEDICAL HISTORY: The patient had a history of coronary artery disease, hypertension, nephrolithiasis, congestive heart failure, lifelong smoking, and ischemic cardiomyopathy. He has been taking the anticoagulants clopidogrel (Plavix) and warfarin (Coumadin). RESIDENCY HISTORY: The patient is originally from Egypt and has been living in the United States for the past 10 years. PRINCIPAL LABORATORY FINDINGS: A complete blood count showed a hemoglobin of 13.0 g per dL (reference range, 14.0 to 18.0 g per dL), hematocrit 40% (40% to 54%), red blood cell count (RBC) 4.65 * 10(9) per L (4.60 to 6.00), and platelet count 179 * 10(9) per L (150 to 450). The urinalysis results showed 3+ protein, 4+ blood, and urine RBC of greater than 100 per high power field (hpf). The urinalysis results did not indicate the presence of parasitic ova or adult parasites. Based on these results, the physician ordered cystoscopic testing, suspecting bladder cancer. Analysis of the bladder tissue showed inflammation (Image 1) and several ova that were consistent with developing Schistosoma (Image 2). Many of the ova were calcified and surrounded by severely inflamed tissue (Image 3). PMID- 26489681 TI - Prenatal Detection and Postnatal Follow-Up of Segmental Aneusomies of Chromosome 13 in 4 Consecutive Pregnancies in an Ethnic South Indian Family With a Maternally Inherited Balanced Translocation. AB - OBJECTIVE: To assess the postnatal clinical manifestation of an antenatally detected unbalanced rearrangement involving chromosome 13 in an ethnic South Indian couple. METHODS: We used conventional cytogenetics on fetal cells obtained from prenatal specimens and on peripheral blood lymphocytes from consanguineous family members to ascertain the chromosomal abnormalities. RESULTS: We report the reproductive outcomes of a maternally inherited chromosome translocation involving chromosome 9 and 13 and the informed decisions of the couple, after genetic counseling in India, regarding their 4 pregnancies. CONCLUSION: This case report highlights the current practice in India of offering prenatal diagnosis and preimplantation genetic diagnosis to individuals who are carriers of balanced translocations, to reduce the risk of conceiving chromosomally abnormal offspring. PMID- 26489682 TI - Quality Improvement in the Coagulation Laboratory: Reducing the Number of Insufficient Blood Draw Specimens for Coagulation Testing. AB - OBJECTIVES: To report the efforts of our laboratory to reduce quantity-not sufficient (QNS) specimens via several methods and to directly measure the effect of expired collection tubes on the amount of blood that can be drawn. METHODS: We tracked the number of QNS venous-blood specimens per month received by our coagulation laboratory from March 2008 to December 2012. Interventions involved communications that informed nurses and phlebotomists how to avoid drawing QNS specimens and floor sweeps, in which laboratory staff searched for and removed expired vacuum-based blood-collection tubes (VBCTs) from inpatient hospital floors. Also, we assessed 11 healthy donors to determine the amount of blood that could be drawn into expired VBCTs. RESULTS: During the study period, the rate of QNS specimens dropped from a mean of 0.7% to 0.3%. In expired VBCTs collected from healthy donors, we observed a statistically significant difference in the amount of blood drawn into nonexpired vs expired VBCTs (P <.001). Also, there was a negative relationship between the number of months that the VBCT had been expired and the amount of blood that could be drawn into the VBCTs (P <.001). For every month that VBCTs were expired, the amount of blood drawn decreased by approximately 1.8 mm (0.1 mL), using linear regression analysis. CONCLUSION: Our evidence strongly suggests that expired VBCTs consistently and progressively yield QNS specimens. Methods to reduce blood draws from expired VBCTs may include communications promoting proper blood draw technique, floor sweeps to remove expired VBCTs, and improved inventory management. PMID- 26489683 TI - Benchmarking to Identify Practice Variation in Test Ordering: A Potential Tool for Utilization Management. AB - BACKGROUND: Appropriate test utilization is usually evaluated by adherence to published guidelines. In many cases, medical guidelines are not available. Benchmarking has been proposed as a method to identify practice variations that may represent inappropriate testing. This study investigated the use of benchmarking to identify sites with inappropriate utilization of testing for a particular analyte. METHODS: We used a Web-based survey to compare 2 measures of vitamin D utilization: overall testing intensity (ratio of total vitamin D orders to blood-count orders) and relative testing intensity (ratio of 1,25(OH)2D to 25(OH)D test orders). RESULTS: A total of 81 facilities contributed data. The average overall testing intensity index was 0.165, or approximately 1 vitamin D test for every 6 blood-count tests. The average relative testing intensity index was 0.055, or one 1,25(OH)2D test for every 18 of the 25(OH)D tests. Both indexes varied considerably. CONCLUSIONS: Benchmarking can be used as a screening tool to identify outliers that may be associated with inappropriate test utilization. PMID- 26489684 TI - Osmotic Edema Rapidly Increases Neuronal Excitability Through Activation of NMDA Receptor-Dependent Slow Inward Currents in Juvenile and Adult Hippocampus. AB - Cellular edema (cell swelling) is a principal component of numerous brain disorders including ischemia, cortical spreading depression, hyponatremia, and epilepsy. Cellular edema increases seizure-like activity in vitro and in vivo, largely through nonsynaptic mechanisms attributable to reduction of the extracellular space. However, the types of excitability changes occurring in individual neurons during the acute phase of cell volume increase remain unclear. Using whole-cell patch clamp techniques, we report that one of the first effects of osmotic edema on excitability of CA1 pyramidal cells is the generation of slow inward currents (SICs), which initiate after approximately 1 min. Frequency of SICs increased as osmolarity decreased in a dose-dependent manner. Imaging of real-time volume changes in astrocytes revealed that neuronal SICs occurred while astrocytes were still in the process of swelling. SICs evoked by cell swelling were mainly nonsynaptic in origin and NMDA receptor-dependent. To better understand the relationship between SICs and changes in neuronal excitability, recordings were performed in increasingly physiological conditions. In the absence of any added pharmacological reagents or imposed voltage clamp, osmotic edema induced excitatory postsynaptic potentials and burst firing over the same timecourse as SICs. Like SICs, action potentials were blocked by NMDAR antagonists. Effects were more pronounced in adult (8-20 weeks old) compared with juvenile (P15-P21) mice. Together, our results indicate that cell swelling triggered by reduced osmolarity rapidly increases neuronal excitability through activation of NMDA receptors. Our findings have important implications for understanding nonsynaptic mechanisms of epilepsy in relation to cell swelling and reduction of the extracellular space. PMID- 26489685 TI - Expression of the Astrocyte Water Channel Aquaporin-4 in the Mouse Brain. AB - Aquaporin-4 (AQP4) is a bidirectional water channel that is found on astrocytes throughout the central nervous system. Expression is particularly high around areas in contact with cerebrospinal fluid, suggesting that AQP4 plays a role in fluid exchange between the cerebrospinal fluid compartments and the brain. Despite its significant role in the brain, the overall spatial and region specific distribution of AQP4 has yet to be fully characterized. In this study, we used Western blotting and immunohistochemical techniques to characterize AQP4 expression and localization throughout the mouse brain. We observed AQP4 expression throughout the forebrain, subcortical areas, and brainstem. AQP4 protein levels were highest in the cerebellum with lower expression in the cortex and hippocampus. We found that AQP4 immunoreactivity was profuse on glial cells bordering ventricles, blood vessels, and subarachnoid space. Throughout the brain, AQP4 was expressed on astrocytic end-feet surrounding blood vessels but was also heterogeneously expressed in brain tissue parenchyma and neuropil, often with striking laminar specificity. In the cerebellum, we showed that AQP4 colocalized with the proteoglycan brevican, which is synthesized by and expressed on cerebellar astrocytes. Despite the high abundance of AQP4 in the cerebellum, its functional significance has yet to be investigated. Given the known role of AQP4 in synaptic plasticity in the hippocampus, the widespread and region specific expression pattern of AQP4 suggests involvement not only in fluid balance and ion homeostasis but also local synaptic plasticity and function in distinct brain circuits. PMID- 26489687 TI - Managing suicidal ideation in a breast cancer cohort seeking reconstructive surgery. PMID- 26489686 TI - A Distinct Class of Antibodies May Be an Indicator of Gray Matter Autoimmunity in Early and Established Relapsing Remitting Multiple Sclerosis Patients. AB - *These authors contributed equally to the work in this manuscript.We have previously identified a distinct class of antibodies expressed by B cells in the cerebrospinal fluid (CSF) of early and established relapsing remitting multiple sclerosis (RRMS) patients that is not observed in healthy donors. These antibodies contain a unique pattern of mutations in six codons along VH4 antibody genes that we termed the antibody gene signature (AGS). In fact, patients who have such B cells in their CSF are identified as either having RRMS or developing RRMS in the future. As mutations in antibody genes increase antibody affinity for particular antigens, the goal for this study was to investigate whether AGS(+) antibodies bind to brain tissue antigens. Single B cells were isolated from the CSF of 10 patients with early or established RRMS. We chose 32 of these B cells that expressed antibodies enriched for the AGS for further study. We generated monoclonal full-length recombinant human antibodies (rhAbs) and used both immunological assays and immunohistochemistry to investigate the capacity of these AGS(+) rhAbs to bind brain tissue antigens. AGS(+) rhAbs did not recognize myelin tracts in the corpus callosum. Instead, AGS(+) rhAbs recognized neuronal nuclei and/or astrocytes, which are prevalent in the cortical gray matter. This pattern was unique to the AGS(+) antibodies from early and established RRMS patients, as AGS(+) antibodies from an early neuromyelitis optica patient did not display the same reactivity. Prevalence of CSF-derived B cells expressing AGS(+) antibodies that bind to these cell types may be an indicator of gray matter directed autoimmunity in early and established RRMS patients. PMID- 26489688 TI - Self-aggregated nanoparticles of linoleic acid-modified glycol chitosan conjugate as delivery vehicles for paclitaxel: preparation, characterization and evaluation. AB - A series of linoleic acid-modified glycol chitosan (LAGC) conjugates were synthesized and characterized by FTIR and (1)H NMR. The effect of the amount of linoleic acid (LA) on the physicochemical properties of LAGC conjugates was investigated. The mean diameters of three LAGC nanoparticles determined by dynamic light scattering ranged from 204 to 289 nm. The critical aggregation concentration values of LAGC conjugates in aqueous solution were 0.0148, 0.0348, and 0.0807 mg/ml, respectively. Paclitaxel (PTX) was physically loaded into the LAGC nanoparticles by a dialysis method. The drug loading content and encapsulation efficiency of PTX-loaded LAGC (PTX-LAGC) nanoparticles increased with an increasing ratio of the hydrophobic LA to hydrophilic glycol chitosan in the conjugates. PTX-LAGC nanoparticles were almost spherical in shape observed by transmission electron microscopy. In vitro release revealed that PTX release from the nanoparticles was reduced as the LA substitution degree of LAGC conjugates increased. Compared with the commercial formulation Taxol, PTX-LAGC-1 nanoparticles exhibited comparable cellular uptake and cytotoxicity against HepG2 cells in vitro. Importantly, PTX-LAGC-1 nanoparticles demonstrated the stronger antitumor efficacy against hepatic H22 tumor-bearing mice than Taxol (p < 0.05). Therefore, glycolipid-like LAGC nanoparticles had a potential as delivery vehicles for tumor therapy. PMID- 26489689 TI - Biplot evaluation of test environments and identification of mega-environment for sugarcane cultivars in China. AB - Test environments and classification of regional ecological zones into mega environments are the two key components in regional testing of sugarcane cultivars. This study aims to provide the theoretical basis for test environment evaluation and ecological zone division for sugarcane cultivars. In the present study, sugarcane yield data from a three-year nationwide field trial involving 21 cultivars and 14 pilot test locations were analysed using both analysis of variance (ANOVA) and heritability adjusted-genotype main effect plus genotype environment interaction (HA-GGE) biplot. The results showed that among the interactive factors, the GE interaction had the greatest impact, while the genotype and year interaction showed the lowest impact. Kaiyuan, Lincang and Baoshan of Yunnan, Zhangzhou and Fuzhou of Fujian, and Hechi, Liuzhou and Chongzuo of Guangxi, and Lingao of Hainan were ideal test environments with a demonstrated high efficiency in selecting new cultivars with a wide adaptability, whereas Baise of Guangxi was not. Based on HA-GGE biplot analysis, there are three ecological sugarcane production zones in China, the Southern China Inland Zone, the Southwestern Plateau Zone, and the Southern Coastal Zone. The HA-GGE biplot analysis here presents the ideal test environments and also identifies the mega-environment for sugarcane cultivars in China. PMID- 26489691 TI - Angiogenic effect of platelet-rich plasma combined with gelatin hydrogel granules injected into murine subcutis. AB - Platelet-rich plasma (PRP), which contains highly concentrated platelets, is produced by centrifuging whole blood. It is a safe and readily available source of a wide range of growth factors necessary for angiogenesis. Gelatin hydrogel granules have been designed and prepared for the controlled release of many growth factors. The angiogenic effect of human PRP was examined in vitro, and the effect of its subcutaneous injection with gelatin hydrogel granules into murine subcutis was evaluated. Human PRP was prepared using a double-spin method. The concentration of growth factors and the platelet count were examined in PRP and in vitro, and the angiogenic activity of human umbilical vein endothelial cells (HUVECs) in co-culture with human dermal fibroblast cells (NHDFs) in the presence and absence of PRP was evaluated. Then, in vivo, PRP, either free or with gelatin hydrogel granules, was injected subcutaneously into tiebacks on mice. Using a microscope and Kurabo angiogenesis image analyser software, the area containing newly formed capillaries was evaluated histologically and the microvascular network score was calculated. PRP was shown to contain high concentrations of PDGF, VEGF and TGFbeta and had an angiogenic effect on the co-culture system. PRP with gelatin hydrogel granules significantly enlarged the area containing newly formed capillaries and promoted the microvascular network in murine subcutaneous tissue. PRP encapsulated in gelatin hydrogel microspheres shows promise for enhancing angiogenic effects in murine subcutis and could represent a potential therapeutic combination for the treatment of ischaemic disorders. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26489690 TI - Chromium exposure and incidence of metabolic syndrome among American young adults over a 23-year follow-up: the CARDIA Trace Element Study. AB - Studies suggest that chromium deficiency is associated with elevated levels of fasting blood glucose, circulating insulin, cholesterol and triglycerides, and decreased proportion of lean body mass. However, data directly relating chromium levels to metabolic syndrome (MetS) risk are lacking. A total of 3,648 American adults from the Coronary Artery Risk Development in Young Adults (CARDIA) study, aged 20-32 years, were prospectively examined for the incidence of MetS and its five components from 1987-88 to 2010-11. Baseline toenail chromium levels were measured with instrumental neutron-activation analysis. Incident MetS was defined by the NCEP-ATP III criteria. During the 23-year follow-up, 878 incident MetS cases were identified. Baseline toenail chromium was inversely associated with incidence of MetS as well as its blood lipid components. The multivariable adjusted hazard ratio (HR) (95% confidence interval [CI]) of MetS comparing the highest to the lowest quartiles of toenail chromium levels was 0.80 (0.66-0.98; Plinear trend = 0.006). The adjusted HRs were 0.82 (0.68-0.98; Ptrend = 0.045) for having abnormal triglycerides levels and 0.75 (0.64-0.88; Ptrend = 0.030) for having abnormal HDL cholesterol levels. Toenail chromium levels were inversely and longitudinally associated with incidence of MetS in American young adults. This inverse association was mainly explained by its relation to blood lipids. PMID- 26489692 TI - Void-Assisted Ion-Paired Proton Transfer at Water-Ionic Liquid Interfaces. AB - At the water-trihexyl(tetradecyl)phosphonium tris(pentafluoroethyl)trifluorophosphate ([P14,6,6,6][FAP]) ionic liquid interface, the unusual electrochemical transfer behavior of protons (H(+)) and deuterium ions (D(+)) was identified. Alkali metal cations (such as Li(+), Na(+), K(+)) did not undergo this transfer. H(+)/D(+) transfers were assisted by the hydrophobic counter anion of the ionic liquid, [FAP](-), resulting in the formation of a mixed capacitive layer from the filling of the latent voids within the anisotropic ionic liquid structure. This phenomenon could impact areas such as proton-coupled electron transfers, fuel cells, and hydrogen storage where ionic liquids are used as aprotic solvents. PMID- 26489693 TI - Contact dermatitis in patients undergoing serial intravitreal injections. AB - BACKGROUND: Anti-vascular endothelial growth factor (VEGF) medication, injected intravitreally, is currently the standard of care in patients with different retinal pathologies. Since its introduction in 2006, an increasing number of patients have undergone this procedure in Ghent University Hospital. Strikingly, more patients were diagnosed with contact dermatitis caused by ophthalmic products used during intravitreal injection procedure. OBJECTIVES: To identify which of the substances used during intravitreal injection is most likely to cause contact dermatitis. PATIENTS/MATERIALS/METHODS: Sixteen patients who developed a burning and stinging sensation and swelling of the eyelids after intravitreal injection were tested. All patients were patch tested with the Belgian baseline series, as well as a cosmetic, a pharmaceutical and an ophthalmic series, including the different eye drops used during the intravitreal injection procedure. RESULTS: Fourteen of 16 patients reacted to at least one of the substances used during the injection procedure. Nine patients reacted to phenylephrine (56%), 5 to iso-Betadine((r)) ophthalmic solution (31%), and 3 patients to sodium metabisulfite (16%). CONCLUSIONS: The most common causal allergen was phenylephrine, being positive in 56% of patients. Patients most likely become sensitized because of the high frequency of usage of phenylephrine during repeated intravitreal injections and follow-up consultations. PMID- 26489694 TI - Theranostic etoposide phosphate/indium nanoparticles for cancer therapy and imaging. AB - Etoposide phosphate (EP), a water-soluble anticancer prodrug, is widely used for treatment of many cancers. After administration it is rapidly converted to etoposide, its parent compound, which exhibits anticancer activity. Difficulty in parenteral administration necessitates the development of a suitable nanoparticle delivery system for EP. Here we have used indium both as a carrier to deliver etoposide phosphate to tumor cells and as a SPECT imaging agent through incorporation of (111)In. Etoposide phosphate was successfully encapsulated together with indium in nanoparticles, and exhibited dose dependent cytotoxicity and induction of apoptosis in cultured H460 cancer cells via G2/M cell cycle arrest. In a mouse xenograft lung cancer model, etoposide phosphate/indium nanoparticles induce tumor cell apoptosis, leading to significant enhancement of tumor growth inhibition compared to the free drug. PMID- 26489695 TI - JAK-2 V617F mutation increases heparanase procoagulant activity. AB - Patients with polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are at increased risk of arterial and venous thrombosis. In patients with ET a positive correlation was observed between JAK-2 V617F mutation, that facilitates erythropoietin receptor signalling, and thrombotic events, although the mechanism involved is not clear. We previously demonstrated that heparanase protein forms a complex and enhances the activity of the blood coagulation initiator tissue factor (TF) which leads to increased factor Xa production and subsequent activation of the coagulation system. The present study was aimed to evaluate heparanase procoagulant activity in myeloproliferative neoplasms. Forty bone marrow biopsies of patients with ET, PV, PMF and chronic myelogenous leukaemia (CML) were immunostained to heparanase, TF and TF pathway inhibitor (TFPI). Erythropoietin receptor positive cell lines U87 human glioma and MCF-7 human breast carcinoma were studied. Heparanase and TFPI staining were more prominent in ET, PV and PMF compared to CML. The strongest staining was in JAK-2 positive ET biopsies. Heparanase level and procoagulant activity were higher in U87 cells transfected to over express JAK-2 V617F mutation compared to control and the effect was reversed using JAK-2 inhibitors (Ruxolitinib, VZ3) and hydroxyurea, although the latter drug did not inhibit JAK 2 phosphorylation. Erythropoietin increased while JAK-2 inhibitors decreased the heparanase level and procoagulant activity in U87 and MCF-7 parental cells. In conclusion, JAK-2 is involved in heparanase up-regulation via the erythropoietin receptor. The present findings may potentially point to a new mechanism of thrombosis in JAK-2 positive ET patients. PMID- 26489696 TI - Identifying the causes, prevention and management of crises in dementia. An online survey of stakeholders. AB - BACKGROUND: Crisis situations in dementia can lead to hospital admission or institutionalisation. Offering immediate interventions may help avoid admission, whilst stabilising measures can help prevent future crises. OBJECTIVE: Our objective was to identify the main causes of crisis and interventions to treat or prevent crisis in persons with dementia based on different stakeholder perspectives. METHODS: An online questionnaire was developed to identify the causes of crisis and appropriate interventions in a crisis. Participants included people with dementia, family carers and staff working in health and social care, including emergency and voluntary sectors, and academia. RESULTS: The results ranked the main causes of crisis, interventions that can prevent a crisis and interventions that can be useful in a crisis. Wandering, falls and infection were highly rated as risk factors for crises across all stakeholder groups. Consumers rated aggression as less important but severity of memory impairment as much more important than the other groups did. Education and support for family carers and home care staff were highly valued for preventing crises. Well-trained home care staff, communication equipment, emergency contacts and access to respite were highly valued for managing crises. CONCLUSIONS: We identified triggers and interventions that different stakeholders see as important for crisis in dementia. Recognition of these may be critical to planning effective and accepted support and care for people with dementia. PMID- 26489697 TI - Out-of-hospital paediatric emergencies: a prospective, population-based study. AB - BACKGROUND: We wanted to study the incidence, distribution and characteristics of paediatric out-of-hospital emergency care on a population level. This knowledge could ameliorate the design and education of emergency medical services and their personnel. METHODS: We studied all (n = 1863) emergency medical services responses and the patient records for paediatric patients (age 0-16 years) in Helsinki, Finland (population 603,968, paediatric population 92,742) during a 12 month period (2012). Patient characteristics, diagnoses, time intervals, medical treatments, procedures, vital measurements and outcome of out-of-hospital treatment were available for analysis. RESULTS: The incidence of emergency medical services -treated paediatric out-of-hospital emergencies was 3.8/1000 inhabitants and 20/1000 1-16-year-old inhabitants. This formed 4.5% of all emergency calls, while children have a threefold share of the population (15%). Falls, dyspnoea, seizures and poisonings account for half of all emergencies. Few patients suffered from a life-threatening condition or trauma. Cardiac arrest or need for advanced life support measures (e.g. intubation) was rare. After evaluation by the emergency medical services, only half of the patients (56%) needed ambulance transportation to hospital. Only 30 (3.7%) of the non transported patients made an unpremeditated visit to the emergency department after the original contact with the emergency medical services. All of them were well upon arrival to the emergency department. CONCLUSION: Paediatric out-of hospital emergencies are infrequent and have specific characteristics differing from the adult population. The design and training of emergency medical services and their personnel should focus on evaluation and management of the most frequent situations. PMID- 26489698 TI - Evaluation of community-based treatment for drug-resistant tuberculosis in Bangladesh. AB - OBJECTIVE: Drug-resistant tuberculosis (TB) threatens global TB control because it is difficult to diagnose and treat. Community-based programmatic management of drug-resistant TB (cPMDT) has made therapy easier for patients, but data on these models are scarce. Bangladesh initiated cPMDT in 2012, and in 2013, we sought to evaluate programme performance. METHODS: In this retrospective review, we abstracted demographic, clinical, microbiologic and treatment outcome data for all patients enrolled in the cPMDT programme over 6 months in three districts of Bangladesh. We interviewed a convenience sample of patients about their experience in the programme. RESULTS: Chart review was performed on 77 patients. Sputum smears and cultures were performed, on average, once every 1.35 and 1.36 months, respectively. Among 74 initially culture-positive patients, 70 (95%) converted their cultures and 69 (93%) patients converted the cultures before the sixth month. Fifty-two (68%) patients had evidence of screening for adverse events. We found written documentation of musculoskeletal complaints for 16 (21%) patients, gastrointestinal adverse events for 16 (21%), hearing loss for eight (10%) and psychiatric events for four (5%) patients; conversely, on interview of 60 patients, 55 (92%) reported musculoskeletal complaints, 54 (90%) reported nausea, 36 (60%) reported hearing loss, and 36 (60%) reported psychiatric disorders. CONCLUSIONS: The cPMDT programme in Bangladesh appears to be programmatically feasible and clinically effective; however, inadequate monitoring of adverse events raises some concern. As the programme is brought to scale nationwide, renewed efforts at monitoring adverse events should be prioritised. PMID- 26489699 TI - Circular motion analysis of time-varying bioimpedance. AB - This paper presents a step forward towards the analysis of a linear periodically time-varying (PTV) bioimpedance ZPTV(jw, t), which is an important subclass of a linear time-varying (LTV) bioimpedance. Similarly to the Fourier coefficients of a periodic signal, a PTV impedance can be decomposed into frequency dependent impedance phasors, [Formula: see text], that are rotating with an angular speed of wr = 2pir/TZ. The vector length of these impedance phasors corresponds to the amplitude of the rth-order harmonic impedance |Zr( jw)| and the initial phase is given by Phir(w, t0) = [Symbol: see text]Zr( jw) + 2pirt0/TZ, with t0?[0, T] being a time instant within the measurement time T. The impedance period TZ stands for the cycle length of the bio-system under investigation; for example, the elapsed time between two consecutive R-waves in the electrocardiogram or the breathing periodicity in case of the heart or lungs, respectively. First, it is demonstrated that the harmonic impedance phasor [Formula: see text], at a particular measured frequency k, can be represented by a rotating phasor, leading to the so-called circular motion analysis technique. Next, the two dimensional (2D) representation of the harmonic impedance phasors is then extended to a three dimensional (3D) coordinate system by taking into account the frequency dependence. Finally, we introduce a new visualizing tool to summarize the frequency response behavior of ZPTV( jw, t) into a single 3D plot using the local Frenet-Serret frame. This novel 3D impedance representation is then compared with the 3D Nyquist representation of a PTV impedance. The concepts are illustrated through real measurements conducted on a PTV RC-circuit. PMID- 26489700 TI - Torsion of an ectopic spleen: a possible late complication of paraoesophageal hernia repair. PMID- 26489701 TI - Aortic iatrogenic perforation during transseptal puncture and successful occlusion with Amplatzer ductal occluder in a case of mitral paravalvular leak closure. AB - Complications of transseptal puncture are significant and potentially life threatening. Aortic perforation is one of these complications and it needs to be repaired immediately. We report the case of a 48-year-old female with a history of rheumatic mitral valve disease. She underwent three previous mitral valve replacements. Her last echocardiogram reported an anterolateral leak in the mitral prosthesis. Catheterization was performed. During the procedure, when attempting to perform transseptal puncture, catheterization was complicated by a forcefully puncture of the aortic root by the Brockenbrough needle followed by an immediately advancement of an 8-Fr Mullins sheath. We decided to leave the 8-Fr sheath in the aortic root recognizing the danger of removing the sheath and finally we advanced a 6/4 mm Amplatzer ductal occluder (ADO I) through the Mullins sheath and under fluoroscopy and TEE guidance we achieved a successful deployment of the device and closure of the perforation. Subsequently, the paravalvular leak was closed with an Amplatzer Vascular Plug (AVP III 10/5 mm). There are only three cases of a similar technique for the same injury in which the authors describe successful closing of aortic perforation with percutaneous closure devices. Our case is the first described during a mitral paravalvular leak closure. It is also the first to describe a different technique of leaving the Mullins sheath in the aortic root and advancing the Amplatzer device through it to achieve successful closure of the aortic perforation. We preferred the percutaneous closure over open-heart repair. (c) 2015 Wiley Periodicals, Inc. PMID- 26489702 TI - What Do People Find Incompatible With Causal Determinism? AB - Four studies explored people's judgments about whether particular types of behavior are compatible with determinism. Participants read a passage describing a deterministic universe, in which everything that happens is fully caused by whatever happened before it. They then assessed the degree to which different behaviors were possible in such a universe. Other participants evaluated the extent to which each of these behaviors had various features (e.g., requiring reasoning). We assessed the extent to which these features predicted judgments about whether the behaviors were possible in a deterministic universe. Experiments 1 and 2 found that people's judgments about whether a behavior was compatible with determinism were not predicted by their judgments about whether that behavior relies on physical processes in the brain and body, is uniquely human, is unpredictable, or involves reasoning. Experiment 3, however, found that a distinction between what we call "active" and "passive" behaviors can explain people's judgments. Experiment 4 extended these findings, showing that we can measure this distinction in several ways and that it is robustly predicted by two different cues. Taken together, these results suggest that people carve up mentally guided behavior into two distinct types-understanding one type to be compatible with determinism, but another type to be fundamentally incompatible with determinism. PMID- 26489703 TI - Prevalence of comorbidities and evaluation of their screening in spondyloarthritis: results of the international cross-sectional ASAS-COMOSPA study. AB - BACKGROUND: Increased risk of some comorbidities has been reported in spondyloarthritis (SpA). Recommendations for detection/management of some of these comorbidities have been proposed, and it is known that a gap exists between these and their implementation in practice. OBJECTIVE: To evaluate (1) the prevalence of comorbidities and risk factors in different countries worldwide, (2) the gap between available recommendations and daily practice for management of these comorbidities and (3) the prevalence of previously unknown risk factors detected as a result of the present initiative. METHODS: Cross-sectional international study with 22 participating countries (from four continents), including 3984 patients with SpA according to the rheumatologist. STATISTICAL ANALYSIS: The prevalence of comorbidities (cardiovascular, infection, cancer, osteoporosis and gastrointestinal) and risk factors; percentage of patients optimally monitored for comorbidities according to available recommendations and percentage of patients for whom a risk factor was detected due to this study. RESULTS: The most frequent comorbidities were osteoporosis (13%) and gastroduodenal ulcer (11%). The most frequent risk factors were hypertension (34%), smoking (29%) and hypercholesterolaemia (27%). Substantial intercountry variability was observed for screening of comorbidities (eg, for LDL cholesterol measurement: from 8% (Taiwan) to 98% (Germany)). Systematic evaluation (eg, blood pressure (BP), cholesterol) during this study unveiled previously unknown risk factors (eg, elevated BP (14%)), emphasising the suboptimal monitoring of comorbidities. CONCLUSIONS: A high prevalence of comorbidities in SpA has been shown. Rigorous application of systematic evaluation of comorbidities may permit earlier detection, which may ultimately result in an improved outcome of patients with SpA. PMID- 26489705 TI - Competition Between Different Social Ranked Rams has Similar Effects on Testosterone and Sexual Behaviour Throughout the Year. AB - Dominant rams have preferential access to females, as they frequently interrupt sexual behaviour from subordinated. Testosterone concentrations are directly linked to sexual and aggressive behaviour and have important variations along the year. Therefore, it may be expected that the effects of dominance relationships on reproductive behaviour differ according to testosterone concentrations, and thus to the period of the year. The aim of this study was to compare the effects of dominance relationships on testosterone and sexual behaviour in different moments of the year in rams. Twelve rams were maintained in a single group. Social rank was determined in January (maximum reproductive development), May (regression of the reproductive status) and August (lowest reproductive activity), and the four rams with higher (HR) and the four with lower (LR) success index were used. Testosterone serum concentration was weekly measured four times during each experimental period. Sexual behaviour was evaluated in each period with an oestrous ewe, and with the oestrous ewe and another ram from the other social rank (each HR with each LR ram). Testosterone concentration was greater in HR than LR rams in January (p = 0.03), and all the behaviours were displayed more frequently in non-competitive than in competitive tests (p < 0.05). Rams modified their sexual strategy in competitive environments decreasing the display of sexual behaviour independently of their social status. This effect was observed consistently throughout the year: high-ranked rams have greater testosterone concentrations than LR rams only during the pre-rut, when they naturally compete to join the groups of ewes. PMID- 26489704 TI - Clinical and radiographic outcome of a treat-to-target strategy using methotrexate and intra-articular glucocorticoids with or without adalimumab induction: a 2-year investigator-initiated, double-blinded, randomised, controlled trial (OPERA). AB - OBJECTIVES: To study clinical and radiographic outcomes after withdrawing 1 year's adalimumab induction therapy for early rheumatoid arthritis (eRA) added to a methotrexate and intra-articular triamcinolone hexacetonide treat-to-target strategy (NCT00660647). METHODS: Disease-modifying antirheumatic drug (DMARD) naive patients with eRA started methotrexate (20 mg/week) and intra-articular triamcinolone (20 mg/ml) for 2 years. In addition, they were randomised to receive placebo adalimumab (DMARD group, n=91) or adalimumab (40 mg/every other week) (DMARD+adalimumab group, n=89) during the first year. Sulfasalazine and hydroxychloroquine were added if disease activity persisted after 3 months. During year 2, synthetic DMARDs continued. Adalimumab was (re)initiated if active disease reoccurred. Clinical response, remission, disability, quality of life and radiographic changes were assessed. RESULTS: One year after adalimumab withdrawal, treatment profiles and clinical responses did not differ between groups. In the DMARD/DMARD+adalimumab groups, the median 2-year methotrexate dose was 20/20 mg/week (p=0.45), triple DMARD therapy had been initiated in 33/27 patients (p=0.49), adalimumab was (re)initiated in 12/12 patients and cumulative triamcinolone dose was 160/120 mg (p=0.15). The treatment target (disease activity score, 4 variables, C-reactive protein (DAS28CRP) <=3.2 or DAS28>3.2 without swollen joints) was achieved at all visits in >=85% of patients in year 2; remission rates were DAS28CRP<2.6:69%/66%; Clinical Disease Activity Index <=2.8:55%/57%; Simplified Disease Activity Index <3.3:54%/49%; American College of Rheumatology/European League against Rheumatism (28 joints):44%/45% (p=0.66 1.00). Radiographic progression (Deltatotal Sharp score/year) was similar 1.31/0.53 (p=0.12). Erosive progression (Deltaerosion score (ES)/year) was year 1:0.57/0.06 (p=0.02); year 2:0.38/0.05 (p=0.005). Proportion of patients without erosive progression (DeltaES<=0) was year 1: 59%/76% (p=0.03); year 2:64%/79% (p=0.04). CONCLUSIONS: An aggressive triamcinolone and synthetic DMARD treat-to target strategy in eRA provided excellent 2-year clinical and radiographic disease control independent of adalimumab induction therapy. ES progression was slightly less during and following adalimumab induction therapy. TRIAL REGISTRATION NUMBER: NCT00660647. PMID- 26489706 TI - Expedient Mechanosynthesis of N,N-Dialkyl Imidazoliums and Silver(I)-Carbene Complexes in a Ball-Mill. AB - The absence of solvent, associated with intensive mechanical agitation, allowed the first mechanosynthesis of high-value silver(I)-carbene complexes and the corresponding N,N-dialkylimidazolium precursors. This procedure gave outstanding results in terms of yield and reaction time, when compared to solution-based conditions previously described in literature, and was generalized to unprecedented compounds. Silver(I)-carbene complexes could either be obtained from N,N-dialkylimidazolium salts or directly from imidazole and alkyl halides in a one-pot two-step procedure without isolating the imidazolium intermediate. Additionally, an efficient one-pot three-step sequence, including imidazole alkylation, silver metalation, and transmetalation is reported. PMID- 26489707 TI - Synthesis, characterization and antibacterial behavior of water-soluble carbosilane dendrons containing ferrocene at the focal point. AB - A series of novel water-soluble ammonium-terminated carbosilane dendrons containing a ferrocene unit at the focal point were synthesized, in order to combine the unique redox activity of ferrocene and the precisely designed structure of the dendrons with the aim to evaluate them as a new class of potential organometallic-based antibacterial compounds. The synthetic route is based on the initial amination of ferrocenecarboxaldehyde with carbosilane dendrons that contain allyl groups on the surface followed by reduction of the in situ prepared imine product, and the subsequent functionalization of the periphery with terminal amine groups by hydrosilylation reactions. Systems quaternized with HCl are soluble and stable in water or other protic solvents. The obtained compounds were spectrally and electrochemically (cyclic voltammetry) characterized, and diffusion-ordered spectroscopy experiments were conducted to determine the size of the dendritic wedges in solution. The antibacterial activity of these compounds was evaluated using Gram-positive bacteria (Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli), which shows that the first and second generations of cationic dendrons are broad spectrum antibacterial agents, i.e. selective and effective in both bacterial strains. PMID- 26489708 TI - The regioselective iodination of quinolines, quinolones, pyridones, pyridines and uracil. AB - A radical based direct C-H iodination protocol for quinolines, quinolones, pyridones, pyridines, and uracil has been developed. The iodination occurs in a C3 selective manner for quinolines and quinolones. Pyridones and pyridines undergo C3 and C5 iodination, while dimethyl uracil undergoes C5 iodination. Scope of the method was demonstrated through the rapid synthesis of both electron rich as well as electron poor heteroaromatic iodides. The protocol was found to be scalable and general, while a mechanism has been proposed. PMID- 26489709 TI - Association of endoscopic ultrasonographic parameters and gastrointestinal stromal tumors (GISTs): can endoscopic ultrasonography be used to screen gastric GISTs for potential malignancy? AB - BACKGROUND: Previous research shows that only 10-30% of gastrointestinal stromal tumors (GISTs) are malignant. Nonetheless, some reports suggest that all of them have some degree of potential for malignancy. Endoscopic ultrasonography (EUS) is a useful technique for differentiation of subepithelial lesions in the gastrointestinal tract. We explored EUS characteristics that might predict the malignancy potential of GISTs. METHODS: In this retrospective review of the medical records from 1999 through 2007, patients who had gastric stromal tumors diagnosed prior to surgery using EUS were enrolled. The EUS images, procedure records and tissue histopathology were reviewed. All patients were positive for C kit. RESULTS: Of the 110 patients enrolled, 57 were males, and 53 were females. Most (67%) of the GISTs were located in the gastric body. The lesion size ranged from 6.3 to 150 mm (mean +/- SD: 39.73 +/- 22.49 mm). The high-risk GIST group had 19 (17.3%) patients, the intermediate-risk group had 12 (10.9%) patients and the low/very low-risk group had 79 (71.8%) patients. Thirty patients had cystic lesions (27.3%), while six patients had calcification in the lesion (5.5%). Additionally, 27 patients (24.5%) had surface ulceration visible on endoscopy. GISTs at high risk for malignancy were highly associated with lesion size (p < 0.0001), cystic change (p = 0.015) and surface ulceration (p = 0.036) but not with calcification (p = 0.667). We also found that mitosis was associated with lesion size (p < 0.0001) rather than other parameters. Age was not predictive of malignancy potential (p = 0.316). However, tumor size is the only one independent risk factor for malignancy (p <= 0.0001). CONCLUSIONS: The preliminary results show that large gastric GISTs with cystic change and surface ulceration may associate with a risk of malignancy, warranting more aggressive management. Nevertheless, the tumor size is more important than other factors. PMID- 26489710 TI - Gendered Processes in Hospice Palliative Home Care for Seniors With Cancer and Their Family Caregivers. AB - There has been limited investigation into the processes that shape gender (in)equities in hospice palliative home care. As part of a larger critical ethnographic study, we examined how and why gender relations occur in this context. Using a critical feminist lens, we conducted in-depth interviews with clients living with terminal cancer, their family caregivers and primary nurses; observations of agency home visits; and review of institutional documents. A gender-based analysis revealed that gender enactments of Regulating Gender Relations were legitimized through ideological processes of Normalizing Gender Relations and Equalizing Gender Relations (Re)produced through institutional discourses of individualism and egalitarianism, these gendered processes both advantaged and disadvantaged men and women in hospice palliative home care. Findings suggest that to promote equity, health care providers and policy makers must attend to gender as a prevalent social determinant of health and health care. Implications for policy, practice, education, and research are discussed. PMID- 26489711 TI - Reframing Narratives of Aboriginal Health Inequity: Exploring Cree Elder Resilience and Well-Being in Contexts of Historical Trauma. AB - A large body of literature explores historical trauma or intergenerational trauma among Aboriginal communities around the globe. This literature connects contemporary forms of social suffering and health inequity to broader historical processes of colonization and the residential school systems in Canada. There are tendencies within this literature, however, to focus on individual pathology and victimization while minimizing notions of resilience or well-being. Through a social constructionist lens, this research examined how interpersonal responses to historical traumas can be intertwined with moments of and strategies for resilience. Detailed narrative interviews occurred with four Aboriginal Cree elders living in central Saskatchewan, Canada, who all experienced historical trauma to some extent. From this analysis, we argue that health research among Aboriginal populations must be sensitive to the complex individual and social realities that necessarily involve both processes of historical and contemporary traumas as well as resilience, strength, and well-being. PMID- 26489712 TI - "It's in the Cards": The Contribution of Illustrated Metaphor Cards to Exploring Values Within Narratives. AB - In this article, we present the use of illustrated metaphorical cards as a technique to enrich the qualitative narrative interview. We examine the advantages of incorporating a projective tool to assist in constructing and understanding personal narratives of people living with severe mental illness. We interviewed 25 participants-staff and members of a clubhouse in Israel (an international community model of rehabilitation in mental health)-and sought to understand their stories focused on personal and organizational values. The findings revealed that, in most cases, the cards contributed to data collection by enhancing the interviewees' ability for expression and by facilitating richer, more comprehensive stories and descriptions. This in turn enhanced the researcher's ability to understand the messages and stories presented. The research conclusions discuss the cards' potential contribution to improving data collection and analysis. The cards became an additional channel for expressing participants' experiences, emotions, and unique voice. PMID- 26489713 TI - Laparoscopic-Assisted Live Donor Nephrectomy: A Comparison of Conventional and Transvaginal Routes for Kidney Extraction. AB - BACKGROUND: Laparoscopic approach has become the standard procedure for living donor nephrectomy in many transplant centers. Because the conventional approach results in cosmetic problems and pain during laparoscopic live donor nephrectomy, transvaginal extraction of an intact kidney has been recently introduced as a minimally invasive technique. Here, we aimed to investigate whether transvaginal extraction of an intact kidney during laparoscopic live donor nephrectomy is associated with decreased postoperative pain, nausea and vomiting, and morphine consumption. MATERIAL AND METHODS: This prospective data analysis included a total of 27 female donors who underwent laparoscopic removal of a single kidney for living donor nephrectomy through conventional or transvaginal route. Data collected included age, body mass index, ASA scores, histocompatibility, additional medical disorders, peri- and postoperative complications, postoperative pain scores with visual analogue pain scores (VAS), length of postoperative stay, morphine consumption, degree of nausea and vomiting, level of sedation, and pruritus. RESULTS: No significant differences between the transvaginal and conventional groups were observed in VAS scores and morphine consumption at postoperative 1, 3, 6, 12, and 24 hours. Although not reaching statistical significance, according to analysis of morphine consumption, there was a trend toward decreasing analgesic requirements in the transvaginal group at postoperative 12 and 24 hours. There were no significant differences between the groups in terms of degree of nausea or vomiting, or length of postoperative hospital stay. CONCLUSIONS: We suggest that with a more desirable cosmetic result, transvaginal natural orifice transluminal endoscopic surgery-assisted living donor nephrectomy (TVNALDN) is a suitable new minimally invasive laparoscopic technique associated with reduced postoperative pain and analgesic requirements in select women. PMID- 26489714 TI - Testing for clarithromycin hypersensitivity: A diagnostic challenge in childhood. PMID- 26489715 TI - Knowledge, practice, and views on precautionary allergen labeling for the management of patients with IgE-mediated food allergy--a survey of Australasian and UK health care professionals. PMID- 26489716 TI - Deferasirox desensitization. PMID- 26489717 TI - Predominance of Clostridium difficile ribotypes 012, 027 and 046 in a university hospital in Chile, 2012. AB - In a 1-year survey at a university hospital we found that 20.6% (81/392) of patients with antibiotic associated diarrohea where positive for C. difficile. The most common PCR ribotypes were 012 (14.8%), 027 (12.3%), 046 (12.3%) and 014/020 (9.9). The incidence rate was 2.6 cases of C. difficile infection for every 1000 outpatients. PMID- 26489718 TI - Invasive giant hogweeds in Poland: Risk of burns among forestry workers and plant distribution. AB - The Caucasian giant hogweeds (Heracleum sosnowskyi Manden. and Heracleum mantegazzianum Sommier et Lever) are aggressive invaders that are successfully spreading in different parts of the world. Exposure of human skin to these plants may lead to phototoxicity and even chemical burns manifested by cutaneous, full thickness, and long-lasting dermatitis, and in extreme cases, massive skin necrosis. Forestry workers are a group with potentially increased risk of exposure to these plants because of the outdoor nature of their work and their active involvement in managing invasive species. Therefore, in this study, we aimed at investigating their level of awareness with regard to the giant hogweeds in Poland. The morphology of the plants, health threats, treatment, and control methods were all considered. We also evaluated the distribution of these plants within forest districts in Poland. For this reason, we surveyed 1563 employees (forest rangers, manual workers, and administration staff) of the State Forests National Forest Holding in Poland "State Forests," working in 367 different forest districts. It was initially found that the forestry workers were generally aware of the giant hogweeds' morphology and phototoxicity. More than 20% of the surveyed individuals had been exposed to these plants at least once in their lives, but only less than half of them were aware of proceeding afterward. At the same time, <35% of those surveyed had any knowledge of the control and management of these giant hogweeds. As demonstrated by our study, stands of these species are widely distributed within the Polish forest districts (reported in over 50%). Therefore, there is an urgent need to implement an efficient, multistrategic, and long-term approach to both control their spread and protect human health. PMID- 26489719 TI - Surface-enhanced Raman scattering imaging of cancer cells and tissues via sialic acid-imprinted nanotags. AB - Molecularly imprinted nanoparticles were prepared as surface-enhanced Raman scattering tags for the selective imaging of cancer cells and tissues against normal cells and tissues relying on the use of sialic acid-templated imprinting to recognize cancer cells, which are over-expressed with sialic acid at the surface. PMID- 26489720 TI - Epidemiology and clinical outcomes. PMID- 26489721 TI - How Paul Hugenholtz helped shape the European Society of Cardiology as it is today. PMID- 26489722 TI - Three capsid amino acids notably influence coxsackie B3 virus stability. AB - Coxsackievirus B3 strain 28 (CVB3/28) is less stable at 37 degrees C than eight other CVB3 strains with which it has been compared, including four in this study. In a variant CVB3/28 population selected for increased stability at 37 degrees C, the capsid proteins of the stable variant differed from the parental CVB3/28 by two mutations in Vp1 and one mutation in Vp3, each of which resulted in altered protein sequences. Each of the amino acid changes was individually associated with a more stable virus. Competition between CVB3/28 and a more stable derivative of the strain showed that propagation of the less stable virus was favoured in receptor-rich HeLa cells. PMID- 26489723 TI - General Approach to the Immobilization of Glycoenzyme Chains Inside Calcium Alginate Beads for Bioassay. AB - A general method to obtain the efficient entrapment of mixtures of glycoenzymes in calcium alginate hydrogel is proposed in this paper. As a proof of principle, three glycoenzymes acting in series (trehalase, glucose oxidase, and horseradish peroxidase) have been coimmobilized in calcium alginate beads. The release of the enzymes from the hydrogel mesh (leakage) is avoided by exploiting the enzyme's aggregation induced by the concanavalin A. The aggregation process has been monitored by dynamic light scattering technique, while both enzyme encapsulation efficiency and leakage have been quantified spectrophotometrically. Obtained data show an encapsulation efficiency above 95% and a negligible leakage from the beads when enzyme aggregates are larger than 300 nm. Operational stability of "as prepared" beads has been largely improved by a coating of alternated shells of polycation poly(diallyldimethylammonium chloride) and of alginate. As a test for the effectiveness of the overall procedure, analytical bioassays exploiting the enzyme-containing beads have been developed for the optical determination of glucose and trehalose, and limit of detection values of 0.2 and of 40 MUM, respectively, have been obtained. PMID- 26489724 TI - Patent foramen ovale: Unanswered questions. AB - The foramen ovale is a remnant of the fetal circulation that remains patent in 20 25% of the adult population. Although long overlooked as a potential pathway that could produce pathologic conditions, the presence of a patent foramen ovale (PFO) has been associated with a higher than expected frequency in a variety of clinical syndromes including cryptogenic stroke, migraines, sleep apnea, platypnea-orthodeoxia, deep sea diving associated decompression illness, and high altitude pulmonary edema. A unifying hypothesis is that a chemical or particulate matter from the venous circulation crosses the PFO conduit between the right and left atria to produce a variety of clinical syndromes. Although observational studies suggest a therapeutic benefit of PFO closure compared to medical therapy alone in patients with cryptogenic stroke, 3 randomized controlled trials (RCTs) did not confirm the superiority of PFO closure for the secondary prevention of stroke. However, meta-analyses of these RCTs demonstrate a significant benefit of PFO closure over medical therapy alone. Similarly, observational studies provide support for PFO closure for symptomatic relief of migraines. But one controversial randomized study failed to replicate the results of the observational studies while another two demonstrated a partial benefit. The goal of this review is to discuss the clinical conditions associated with PFO and provide internists and primary care physicians with current data on PFO trials, and clinical insight to help guide their patients who are found to have a PFO on echocardiographic testing. PMID- 26489726 TI - Assessing the intersection of cardiovascular disease, venous thromboembolism, and polycystic ovary syndrome. AB - INTRODUCTION: No study has examined how the relationship between polycystic ovary syndrome (PCOS) and atherosclerotic cardiovascular diseases (aCVD), of ischemic stroke (ISCH), acute myocardial infarction (AMI), and peripheral vascular disease (PAD), differ in the presence of venous thromboembolism (VTE). MATERIALS AND METHODS: We performed a cross-sectional analysis using Truven Health Analytics MarketScan(r) Commercial databases from 2004-2011. The association between women aged 18-64 years with and without PCOS, and aCVD was assessed using VTE stratified multivariable logistic regression models. RESULTS: Overall, women with PCOS were more likely to have aCVD, (aOR, 1.27; 95% CI, 1.10-1.46) especially ISCH (aOR, 1.56; 95% CI, 1.30-1.88), than women without PCOS. When stratified by VTE status, women with PCOS and a VTE diagnosis had a decreased odds of having any aCVD (aOR 0.67; 95% CI, 0.46-0.98), and VTE diagnosis more often preceded the occurrence of ISCH and AMI among women with PCOS compared with women without PCOS. CONCLUSIONS: Overall, women with PCOS were more likely to have aCVD, with stroke being the most prevalent manifestation. Although VTE often occurred before any aCVD, it appeared to have an inverse association with the development of ISCH, AMI, and PAD among women with PCOS, suggesting that aggressively treating VTE or aCVD early may limit the chances of developing the other thrombogenic condition among women with PCOS. PMID- 26489725 TI - Pulsed EPR characterization of HIV-1 protease conformational sampling and inhibitor-induced population shifts. AB - The conformational landscape of HIV-1 protease (PR) can be experimentally characterized by pulsed-EPR double electron-electron resonance (DEER). For this characterization, nitroxide spin labels are attached to an engineered cysteine residue in the flap region of HIV-1 PR. DEER distance measurements from spin labels contained within each flap of the homodimer provide a detailed description of the conformational sampling of apo-enzyme as well as induced conformational shifts as a function of inhibitor binding. The distance distribution profiles are further interpreted in terms of a conformational ensemble scheme that consists of four unique states termed "curled/tucked", "closed", "semi-open" and "wide-open" conformations. Reported here are the DEER results for a drug-resistant variant clinical isolate sequence, V6, in the presence of FDA approved protease inhibitors (PIs) as well as a non-hydrolyzable substrate mimic, CaP2. Results are interpreted in the context of the current understanding of the relationship between conformational sampling, drug resistance, and kinetic efficiency of HIV 1PR as derived from previous DEER and kinetic data for a series of HIV-1PR constructs that contain drug-pressure selected mutations or natural polymorphisms. Specifically, these collective results support the notion that inhibitor-induced closure of the flaps correlates with inhibitor efficiency and drug resistance. This body of work also suggests DEER as a tool for studying conformational sampling in flexible enzymes as it relates to function. PMID- 26489727 TI - Cancer cells BXPC3 and MCF7 differentially reverse the inhibition of thrombin generation by apixaban, fondaparinux and enoxaparin. AB - INTRODUCTION: Cancer cells may alter the efficiency of the antithrombotic agents. To explore this possibility, the present study compared the capacity of the LMWH enoxaparin and the specific inhibitors of Xa (apixaban and fondaparinux) to inhibit thrombin generation triggered by pancreas adenocarcinoma cells (BXPC3) and human breast carcinoma cells (MCF7). MATERIALS AND METHODS: Samples of platelet poor (PPP) or platelet rich plasma (PRP) spiked with apixaban, fondaparinux or enoxaparin were added in micro wells carrying cancer cells and assessed for thrombin generation. In the control experiment thrombin generation was triggered with tissue factor reagent. RESULTS: The three antithrombotics inhibited thrombin generation in a concentration dependent manner. The BXPC3 and MCF7 cells reversed in a different intensity the effect of the studied agents. According to the histological type of the cancer the antithrombotic efficiency of apixaban was preserved or partially reversed. Fondaparinux, was more vulnerable to the presence of cancer cells as compared to apixaban. The effect of BXCP3 or MCF7 cells on the antithrombotic potency of enoxaparin was of similar magnitude as that on apixaban. CONCLUSIONS: The type of cancer cells is determinant for the antithrombotic efficiency of the specific factor Xa inhibitors. In contrast it does not significantly influence the potency of enoxaparin. The present study shows that the impact of the type of cancer cells on the antithrombotic activity of the specific Xa inhibitors should not be neglected. This has to be taken into consideration for the design of dose-finding studies of the direct orally active FXa inhibitors in patients with different histological types of cancer. PMID- 26489728 TI - Prevention of occlusive arterial thrombus formation by a single loading dose of prasugrel suppresses neointimal hyperplasia in mice. AB - The present study examined the effects of prasugrel in a mouse model of thrombosis-induced neointimal hyperplasia. Following carotid artery injury by application of ferric chloride solution, thrombus formation was assessed on Day 1 and neointimal thickening was assessed on Day 21. Single administrations of prasugrel at 0.3-3mg/kg (p.o.) resulted in a dose-related and sustained inhibition of ADP-induced platelet aggregation through 24h. Single and multiple (1 and 3 weeks) administration of prasugrel (3mg/kg loading and 1mg/kg/day maintenance doses) resulted in a marked inhibition of neointimal thickening in the injured artery. In the dose-response study, a single administration of prasugrel at 0.3-3mg/kg (p.o.) dose-relatedly inhibited thrombus formation and neointimal thickening on Days 1 and 21, respectively. The degree of neointimal hyperplasia in the injured artery correlated significantly with the thrombus indices, time to occlusion and patency rate. To explore possible mechanisms of inhibition of neointimal hyperplasia by prasugrel, mRNA expression levels of inflammatory and fibrosis markers were determined in injured arteries. Prasugrel treatment resulted in reduced MCP-1, ICAM-1 and TGF-beta mRNA levels on Day 2 (24h after the injury) and Day 8 (1 week after the injury) in the target arteries. In conclusion, we found that a single oral loading dose of prasugrel markedly prevented neointimal hyperplasia by inhibiting platelet activation and thrombus formation and was associated with inhibition of the expression of inflammatory and fibrosis markers, including MCP-1, ICAM-1 and TGF-beta, in the injured arteries. PMID- 26489730 TI - Influence of the presence of natural monosaccharides in the quantification of alpha-dicarbonyl compounds in high content sugar samples. A comparative study by ultra-high performance liquid chromatography-single quadrupole mass spectrometry using different derivatization reactions. AB - The goal of this work is to evaluate the formation of side alpha-dicarbonyl compounds in high content sugar samples. These compounds may be originated from fructose and glucose, during different derivatization reactions. The formation of D-glucosone, 3-deoxyglucosone, glyoxal, and methylglyoxal, using three derivatization agents (5,6-diamino-2,4-hydroxypyrimidine, 2,4,5-triamine-6 hydroxypyrimidine, and o-phenylenediamine), and ultra-high pressure liquid chromatography in combination with MS detection, has been assessed in the presence of different levels of monosaccharides. 2,4,5-triamine-6-hydroxy pyrimidine appears to be the most suitable for the analysis of alpha-dicarbonyl compounds, in this kind of food samples, and was selected as optimum reagent for the quantification of these compounds. The validation of the method was performed through the establishment of external standard calibration curves and analytical figures of merit, and it showed good linearity over a wide concentration range (r(2)>0.99), and limits of detection and quantification lower than 42MUgL(-1) and 142MUgL(-1), respectively. The validated method has been successfully applied to the determination of the target compounds in honey samples. The intraday and interday assay variability in the analysis of real samples was below 2.3 and 5.7%, respectively, for all analytes. PMID- 26489729 TI - Quantification of experimental venous thrombus resolution by longitudinal nanogold-enhanced micro-computed tomography. AB - INTRODUCTION: The assessment of thrombus size following treatments directed at preventing thrombosis or enhancing its resolution has generally relied on physical or histological methods. This cross-sectional design imposes the need for increased numbers of animals for experiments. Micro-computed tomography (microCT) has been used to detect the presence of venous thrombus in experimental models but has yet to be used in a quantitative manner. In this study, we investigate the use of contrast-enhanced microCT for the longitudinal assessment of experimental venous thrombus resolution. MATERIALS AND METHODS: Thrombi induced by stenosis of the inferior vena cava in mice were imaged by contrast enhanced microCT at 1, 7 and 14 days post-induction (n=18). Thrombus volumes were determined longitudinally by segmentation and 3D volume reconstruction of microCT scans and by standard end-point histological analysis at day 14. An additional group of thrombi were analysed solely by histology at 1, 7 and 14 days post induction (n=15). RESULTS: IVC resident thrombus was readily detectable by contrast-enhanced microCT. MicroCT-derived measurements of thrombus volume correlated well with time-matched histological analyses (ICC=0.75, P<0.01). Thrombus volumes measured by microCT were significantly greater than those derived from histological analysis (P<0.001). Intra- and inter-observer analyses were highly correlated (ICC=0.99 and 0.91 respectively, P<0.0001). Further histological analysis revealed noticeable levels of contrast agent extravasation into the thrombus that was associated with the presence of neovascular channels, macrophages and intracellular iron deposits. CONCLUSION: Contrast-enhanced microCT represents a reliable and reproducible method for the longitudinal assessment of venous thrombus resolution providing powerful paired data. PMID- 26489731 TI - Coronary artery calcium in hypertension: a review. AB - Coronary artery calcium (CAC) is a powerful independent predictor of future cardiovascular events. However, the clinical utility of calcium score testing specifically among patients with hypertension is not well defined. We performed a review of studies involving both high blood pressure (BP) and CAC to assess several aspects of the interrelationship. Among four specific topics evaluated, the main objective was to assess the independent association of CAC with cardiovascular risk among patients with hypertension. From 6822 identified publications, 21 studies met criteria for inclusion. All studies (n = 14) that reported the relationship between BP values and the presence or extent of coronary calcium found positive associations. The results from two studies linking coronary calcium with the risk for developing hypertension were mixed. Each of the five studies that evaluated the relationships between CAC score in regard to future cardiovascular events and/or all-cause mortality in patients with high BP reported independent positive associations. The inclusion of calcium score results into prediction models improved risk stratification when statistically evaluated. The findings of this review demonstrate that CAC testing is likely to be of clinical utility for tailoring the medical management of patients with high BP, particularly among individuals with mild or prehypertension. Future trials testing the clinical effectiveness of a calcium score-based treatment algorithm should be considered. PMID- 26489732 TI - Proximal Scallop in Thoracic Endovascular Aortic Aneurysm Repair to Overcome Neck Issues in the Arch. AB - OBJECTIVE: To evaluate initial experience with a custom made proximal scalloped stent graft for thoracic endovascular aortic repair (TEVAR) of aortic aneurysms involving the arch. METHODS: Between September 2012 and November 2014, patients presenting with a thoracic aortic aneurysm (TAA) with short or angulated neck were selected for treatment by custom made proximal scalloped Relay Plus stent grafts (ABS Bolton Medical, Barcelona, Spain). Prospectively acquired data relating to patient demographics, procedure details, clinical outcomes, and complications were analyzed retrospectively. RESULTS: Ten selected patients (50% male, mean age 77 +/- 8 years) were treated using a thoracic custom made Relay Plus stent graft, three of whom underwent additional cervical supra-aortic trunk revascularizations. TAA were fusiform in four cases, saccular in three, and three patients were treated for proximal type I endoleaks after previous standard TEVAR. The graft was landed in zone 2 in 3 cases, in zone 1 in 4 cases, and in zone 0 in 3 cases. The custom made scallop was designed to preserve flow in the left subclavian artery in three patients, in the left common carotid artery in four, and in the innominate artery in three. No proximal type I endoleak occurred and proximal sealing was achieved in all cases, with a technical success rate of 100%. All targeted vessels were patent. During a mean follow up of 12 +/- 5 months, no conversion to open surgical repair and no aortic rupture occurred. One patient died post-operatively from myocardial infarction and one patient suffered a stroke with complete recovery. One patient had a distal type I endoleak on the 6 month CT scan and is scheduled for distal extension. No paraplegia, retrograde dissection and no other aortic related complications were recorded. CONCLUSIONS: Proximal scalloped stent grafts appear to be an effective additional tool for TEVAR of TAA when dealing with short or angulated proximal necks. PMID- 26489734 TI - Maternal obesity legacy: exercise it away! PMID- 26489735 TI - Innate and adaptive immunity to human beta cell lines: implications for beta cell therapy. AB - AIMS/HYPOTHESIS: Genetically engineered human beta cell lines provide a novel source of human beta cells to study metabolism, pharmacology and beta cell replacement therapy. Since the immune system is essentially involved in beta cell destruction in type 1 diabetes and after beta cell transplantation, we investigated the interaction of human beta cell lineswith the immune system to resolve their potential for immune intervention protocol studies. METHODS: Human pancreatic beta cell lines (EndoC-betaH1 and ECi50) generated by targeted oncogenesis in fetal pancreas were assessed for viability after innate and adaptive immune challenges. Beta cell lines were pre-conditioned with T helper type 1 (Th1) cytokines or high glucose to mimic inflammatory and hyperglycaemia stressed conditions. Beta cells were then co-cultured with auto- and alloreactive cytotoxic T cells (CTL), natural killer (NK) cells, supernatant fraction from activated autoreactive Th1 cells, or alloantibodies in the presence of complement or effector cells. RESULTS: Low HLA expression protected human beta cell lines from adaptive immune destruction, but it was associated with direct killing by activated NK cells. Autoreactive Th1 cell inflammation, rather than glucose stress, induced increased beta cell apoptosis and upregulation of HLA, increasing beta cell vulnerability to killing by auto- and alloreactive CTL and alloreactive antibodies. CONCLUSIONS/INTERPRETATION: We demonstrate that genetically engineered human beta cell lines can be used in vitro to assess diverse immune responses that may be involved in the pathogenesis of type 1 diabetes in humans and beta cell transplantation, enabling preclinical evaluation of novel immune intervention strategies protecting beta cells from immune destruction. PMID- 26489733 TI - Engineering immunity: Modulating dendritic cell subsets and lymph node response to direct immune-polarization and vaccine efficacy. AB - While successful vaccines have been developed against many pathogens, there are still many diseases and pathogenic infections that are highly evasive to current vaccination strategies. Thus, more sophisticated approaches to control the type and quality of vaccine-induced immune response must be developed. Dendritic cells (DCs) are the sentinels of the body and play a critical role in immune response generation and direction by bridging innate and adaptive immunity. It is now well recognized that DCs can be separated into many subgroups, each of which has a unique function. Better understanding of how various DC subsets, in lymphoid organs and in the periphery, can be targeted through controlled delivery; and how these subsets modulate and control the resulting immune response could greatly enhance our ability to develop new, effective vaccines against complex diseases. In this review, we provide an overview of DC subset biology and discuss current immunotherapeutic strategies that utilize DC targeting to modulate and control immune responses. PMID- 26489736 TI - Electrophysiological validation of STN-SNr boundary depicted by susceptibility weighted MRI. AB - BACKGROUND: Direct targeting of subthalamic nucleus (STN) without secondary electrophysiological verification during deep brain stimulation (DBS) is replacing atlas-based indirect targeting techniques. Recent groups have reported increased contrast and better delineation of STN and substantia nigra (SNr) in susceptibility-weighted imaging protocols (SWI). We aim to validate the STN-SNr boundary seen in MRI- SWI by correlating with intraoperative microelectrode recordings (MER) as a part of developing a multi-contrast DBS MRI planning protocol. METHODS: Prospective service evaluation involving electrophysiological verification by correlation of MER trajectory and STN-SNr boundary seen in SWI in seven consecutive patients undergoing DBS surgery were analyzed. The angle of inclination of the STN-SNr boundary and DBS trajectory in the coronal plane were calculated. Considering 4-mm dispersion of a coronal 3 MER array, we predicted, measured, and correlated the depths at which each electrode engaged the boundary. RESULTS: All central microelectrodes identified the STN-SNr boundary within 1 mm of the predicted depth with 100 % accuracy. Ninety percent of the lateral MER identified the STN-SNr boundary as predicted from SWI and angle of the encounter of the MER front. CONCLUSIONS: The study demonstrates that STN morphology can be depicted using SWI MRI and coincides reliably with the electrophysiological MER boundary. Thus, this imaging modality can be used to refine STN direct targeting protocols in DBS surgery for PD. PMID- 26489737 TI - Extended endoscopic endonasal transclival clipping of posterior circulation aneurysms--an alternative to the transcranial approach. PMID- 26489738 TI - Professor Dr. John Anthony Jane, M.D., Ph.D., FRCS (C) The man of values and vision. PMID- 26489739 TI - Thoracic shock wave injury causes behavioral abnormalities in mice. AB - BACKGROUND: Mild traumatic brain injury (mTBI) is caused by complex mechanisms of systemic, local and cerebral responses to blast exposure. However, the molecular mechanisms of cognitive impairment after exposure to blast waves are not clearly known. We tested the hypothesis that thoracic injury induced functional and morphological impairment in the brain, leading to behavioral abnormalities. METHODS: Mice were exposed to laser-induced shock waves (LISWs) impacting the thorax and assessed for behavioral outcome at 7 and 28 days post injury. Hippocampus and lung were collected for histopathological analysis and gene expression profiling after injury. RESULTS: Thoracic injury transiently decreased the heart rate, blood pressure, peripheral oxyhemoglobin saturation and cerebral blood flow immediately after LISW exposure. Although LISWs exposure caused pulmonary contusions, hemorrhage was not apparent in the brain. At 7 and 28 days after, the injured mice exhibited impaired short-term memory and depression-like behavior compared with controls. Histological assessments showed an increase in neuronal cell death after shock wave exposure, especially in the CA3 region of the hippocampus. Moreover, shock wave exposure altered the expression of functionally relevant genes in the hippocampus at 1 h and 1 day post injury. CONCLUSIONS: Our findings indicate that the LISW-induced thoracic injury with no direct impact on the brain affected the hippocampal gene expression and led to morphological alterations, resulting in behavioral abnormalities. Therefore, body protection may be extremely important in the effective prevention against blast induced alterations in brain function. PMID- 26489740 TI - High-order nonlinear excitations in the Joyeux-Buyukdagli model of DNA. AB - By means of the semidiscrete multiple-scale method, we study the existence and properties of high-order envelope solitons and discrete breathers in a homogeneous DNA chain model that is based on pairing enthalpies and site dependent finite stacking. We obtain the analytical solutions for an envelope soliton, and find that at the Brillouin zone center, discrete breather solutions can appear below the bottom of the phonon band. The behavior of two solitons in collisions and the stability of discrete breathers are confirmed by numerical simulations of the exact equations of the system. PMID- 26489741 TI - GERD Is Associated with Higher Long-Term Reoperation Rates After Bariatric Surgery. AB - BACKGROUND: Although bariatric surgery is a safe and effective treatment for morbid obesity, long-term reoperation remains a significant source of morbidity and mortality for the patient. METHODS: We performed a retrospective analysis of all patients undergoing laparoscopic gastric bypass (LGBP) or laparoscopic sleeve gastrectomy (LSG) surgeries at our institution between 2009 and 2013. Main outcome of interest was reoperation rate up to current date. Final logistic regression model included age, gender, BMI at time of operation, race (Caucasian vs African American), surgery time, length of stay, history of diabetes, history of gastroesophageal reflux disease (GERD), type of surgery, and readmission. RESULTS: A total of 533 patients underwent either LGBP or LSG surgery between 2009 and 2013. Overall reoperation rate was 9.0% and mean follow-up was 43.9 months (median 45). When stratified by race, preoperative GERD in Caucasians was associated with a significant 2.2-fold increased risk of reoperation (OR 2.2, 95% CI 1.0-4.8, P = .043). GERD in African Americans had a small nonsignificant increased risk. Other significant predictors included length of stay and readmission (OR 2.1, P = 0.029; OR 5.0, P < 0.000). CONCLUSION: Preoperative GERD in Caucasian bariatric patients is associated with a higher risk of reoperation. Lengthy hospital stay and readmission within 30 days of laparoscopic bariatric surgery are independent predictors of higher reoperation rates. PMID- 26489742 TI - Venous Thromboembolism Prophylaxis in Liver Surgery. AB - BACKGROUND: At a recently concluded Americas Hepato-Pancreato-Biliary Association Annual Meeting, a Clinical Practice Guidelines Conference Series was convened with the topic focusing on Venous Thromboembolism (VTE) Prophylaxis in Liver Surgery. The symposium brought together hepatobiliary surgeons from three continents as well as medical experts in hematology and coagulation. METHODS: The content of the discussion included literature reviews, evaluation of multi institutional VTE outcome data, and examination of practice patterns at multiple high-volume centers. RESULTS: Literature review demonstrated that, within gastrointestinal surgery, liver resection patients are at particularly high-risk for VTE. Recent evidence clearly indicates a direct relationship between the magnitude of hepatectomy and postoperative VTE rates, however, the PT/INR does not accurately reflect the coagulation status of the post-hepatectomy patient. Evaluation of available data and practice patterns regarding the utilization and timing of anticoagulant VTE prophylaxis led to recommendations regarding preoperative and postoperative thromboprophylaxis for liver surgery patients. CONCLUSIONS: This conference was effective in consolidating our knowledge of coagulation abnormalities after liver resection. Based on the expert review of the available data and practice patterns, a number of recommendations were developed. PMID- 26489743 TI - Elevated Alkaline Phosphatase Prior to Transarterial Chemoembolization for Neuroendocrine Tumors Predicts Worse Outcomes. AB - INTRODUCTION: We hypothesized that an elevated preoperative alkaline phosphatase (AP) predicted worse outcomes for patients undergoing transarterial chemoembolization (TACE) for neuroendocrine tumor (NET) liver metastases. METHODS: We reviewed all patients who underwent TACE for metastatic NET between 2009 and 2013. Survival was evaluated using preprocedure variables. RESULTS: One hundred and nine patients underwent 210 TACE procedures. The average age was 57.7 years (range 20-78). Primary sites included pancreas (N = 20), other gastrointestinal (N = 52), lung (N = 9), and unknown (N = 28). The tumor was grade 1 in 68 (62 %), grade 2 in 21 (19 %), and grade 3 in 3 (3 %). Extrahepatic disease was present in 54 (50 %) and greater than 50 % hepatic tumor burden by imaging in 63 (58 %). Elevated bilirubin occurred in 8 (7 %), elevated AP in 22 (20 %), elevated ALT in 21 (19 %), and elevated AST in 41 (38 %). Univariate predictors included tumor grade (43 vs 27 vs 21 months, p = 0.015), hepatic tumor burden (59 vs 37 months, p = 0.009), and elevated AP (59 vs 23 months, p < 0.001). On multivariate analysis, only elevated AP (p = 0.001) predicted worse survival. CONCLUSIONS: Elevated AP prior to TACE for metastatic NET portends a worse survival outcome, even more so than tumor grade or extent of hepatic disease. PMID- 26489744 TI - Staple Line Reinforcement During Laparoscopic Sleeve Gastrectomy: Absorbable Monofilament, Barbed Suture, Fibrin Glue, or Nothing? Results of a Prospective Randomized Study. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is associated with serious complications, such as staple line (SL) leaks and bleeding. In order to prevent the occurrence of these complications, surgeons have advocated the need to strengthen the staple line. The aim of this randomized controlled study was to compare the efficacy of three different ways of strengthening of the SL in LSG in preventing surgical post-operative complications. METHODS: Between April 2012 and December 2014, 600 patients (pts) scheduled for LSG were prospectively randomized into groups without SL reinforcement (group A) or with SL reinforcement including fibrin glue coverage (group B), or oversewn SL with imbricating absorbable (MonocrylTM; group C) or barbed (V lock(r)) running suture (group D). Primary endpoints were post-operative leaks, bleeding, and stenosis, while secondary outcomes consisted of the time to perform the staple line reinforcement (SLR) and total operative time. RESULTS: Mean SLR operative time was lower for group B (3.4 +/- 1.3 min) compared with that for groups C (26.8 +/- 8.5 min) and D (21.1 +/- 8.4 min) (p < 0.0001). Mean total operative time was 100.7 +/- 16.4 min (group A), 104.4 +/- 22.1 min (group B), 126.2 +/- 18.9 min (group C), and 124.6 +/- 22.8 (group D) (p < 0.0001). Post-operative leaks, bleeding, and stenosis were recorded in 14 pts (2.3 %), 5 pts (0.8 %), and 7 pts (1.1 %), respectively, without statistical difference between the groups. CONCLUSION: Our study suggests that SLR during LSG, with an imbricating or non-imbricating running suture or with fibrin glue, is an unrewarding surgical act with the sole effect of prolonging the operative time. PMID- 26489745 TI - Managing Relationship Decay : Network, Gender, and Contextual Effects. AB - Relationships are central to human life strategies and have crucial fitness consequences. Yet, at the same time, they incur significant maintenance costs that are rarely considered in either social psychological or evolutionary studies. Although many social psychological studies have explored their dynamics, these studies have typically focused on a small number of emotionally intense ties, whereas social networks in fact consist of a large number of ties that serve a variety of different functions. In this study, we examined how entire active personal networks changed over 18 months across a major life transition. Family relationships and friendships differed strikingly in this respect. The decline in friendship quality was mitigated by increased effort invested in the relationship, but with a striking gender difference: relationship decline was prevented most by increased contact frequency (talking together) for females but by doing more activities together in the case of males. PMID- 26489746 TI - Selective Cooperation in the Supermarket : Field Experimental Evidence for Indirect Reciprocity. AB - Numerous laboratory experiments suggest that mechanisms of indirect reciprocity might account for human cooperation. However, conclusive field data supporting the predictions of indirect reciprocity in everyday life situations is still scarce. Here, we attempt to compensate for this lack by examining the determinants of cooperative behavior in a German supermarket. Our methods were as follows: Confederates of the experimenter lined up at the checkout, apparently to buy a single item. As an act of cooperation, the waiting person in front (the potential helper) could allow the confederate to go ahead. By this means, the potential helper could take a cost (additional waiting time) by providing the confederate with a benefit (saved waiting time). We recorded the potential helpers' behavior and the number of items they purchased as a quantitative measure proportional to the confederate's benefit. Moreover, in a field experimental design, we varied the confederates' image by manipulating the item they purchased (beer vs. water). As predicted, the more waiting time they could save, the more likely the confederates were to receive cooperation. This relationship was moderated by the confederates' image. Cost-to-benefit ratios were required to be more favorable for beer-purchasing individuals to receive cooperation. Our results demonstrate that everyday human cooperation can be studied unobtrusively in the field and that cooperation among strangers is selective in a way that is consistent with current models of indirect reciprocity. PMID- 26489747 TI - Inducing involuntary and voluntary mental time travel using a laboratory paradigm. AB - Although involuntary past and future mental time travel (MTT) has been examined outside the laboratory in diary studies, MTT has primarily been studied in the context of laboratory studies using voluntary construction tasks. In this study, we adapted and extended a paradigm previously used to elicit involuntary and voluntary memories (Schlagman & Kvavilashvili in Memory & Cognition, 36, 920-932, 2008). Our aim was - for the first time - to examine involuntary and voluntary future MTT under controlled laboratory conditions. The involuntary task involved a monotonous task that included potential cues for involuntary MTT. Temporal direction was manipulated between participants whereas retrieval mode was manipulated within participants. We replicated robust past-future differences, such as the future positivity bias. Additionally, we replicated key voluntary involuntary differences: Involuntary future representations had similar characteristics as involuntary memories in that they were elicited faster, were more specific, and garnered more emotional impact than their voluntary counterparts. We also found that the future and past involuntary MTT led to both positive and negative mood impact, and that the valence of the impact was associated with the emotional valence of the event. This study advances scientific understanding of involuntary future representations in healthy populations and validates a laboratory paradigm that can be flexibly and systematically utilized to explore different characteristics of voluntary and involuntary MTT, which has not been possible within naturalistic paradigms. PMID- 26489748 TI - Comparison of diagnostic performance for perinatal and paediatric post-mortem imaging: CT versus MRI. AB - OBJECTIVES: To compare the diagnostic yield of whole-body post-mortem computed tomography (PMCT) imaging to post-mortem magnetic resonance (PMMR) imaging in a prospective study of fetuses and children. METHODS: We compared PMCT and PMMR to conventional autopsy as the gold standard for the detection of (a) major pathological abnormalities related to the cause of death and (b) all diagnostic findings in five different body organ systems. RESULTS: Eighty two cases (53 fetuses and 29 children) underwent PMCT and PMMR prior to autopsy, at which 55 major abnormalities were identified. Significantly more PMCT than PMMR examinations were non-diagnostic (18/82 vs. 4/82; 21.9 % vs. 4.9 %, diff 17.1 % (95 % CI 6.7, 27.6; p < 0.05)). PMMR gave an accurate diagnosis in 24/55 (43.64 %; 95 % CI 31.37, 56.73 %) compared to 18/55 PMCT (32.73 %; 95 % CI 21.81, 45.90). PMCT was particularly poor in fetuses <24 weeks, with 28.6 % (8.1, 46.4 %) more non-diagnostic scans. Where both PMCT and PMMR were diagnostic, PMMR gave slightly higher diagnostic accuracy than PMCT (62.8 % vs. 59.4 %). CONCLUSION: Unenhanced PMCT has limited value in detection of major pathology primarily because of poor-quality, non-diagnostic fetal images. On this basis, PMMR should be the modality of choice for non-invasive PM imaging in fetuses and children. KEY POINTS: * Overall 17.1 % more PMCT examinations than PMMR were non-diagnostic * 28.6 % more PMCT were non-diagnostic than PMMR in fetuses <24 weeks * PMMR detected almost a third more pathological abnormalities than PMCT * PMMR gave slightly higher diagnostic accuracy when both were diagnostic. PMID- 26489749 TI - Association between breast cancer, breast density, and body adiposity evaluated by MRI. AB - OBJECTIVE: Despite the lack of reliable methods with which to measure breast density from 2D mammograms, numerous studies have demonstrated a positive association between breast cancer and breast density. The goal of this study was to study the association between breast cancer and body adiposity, as well as breast density quantitatively assessed from 3D MRI breast images. METHODS: Breast density was calculated from 3D T1-weighted MRI images. The thickness of the upper abdominal adipose layer was used as a surrogate marker for body adiposity. We evaluated the correlation between breast density, age, body adiposity, and breast cancer. RESULTS: Breast density was calculated for 410 patients with unilateral invasive breast cancer, 73 patients with ductal carcinoma in situ (DCIS), and 361 controls without breast cancer. Breast density was inversely related to age and the thickness of the upper abdominal adipose layer. Breast cancer was only positively associated with body adiposity and age. CONCLUSION: Age and body adiposity are predictive of breast density. Breast cancer was not associated with breast density; however, it was associated with the thickness of the upper abdominal adipose layer, a surrogate marker for body adiposity. Our results based on a limited number of patients warrant further investigations. KEY POINTS: * MRI breast density is negatively associated with body adiposity. * MRI breast density is negatively associated with age. * Breast cancer is positively associated with body adiposity. * Breast Cancer is not associated with MRI breast density. PMID- 26489750 TI - Secondhand smoke and incidence of dental caries in deciduous teeth among children in Japan: population based retrospective cohort study. AB - STUDY QUESTION: Does maternal smoking during pregnancy and exposure of infants to tobacco smoke at age 4 months increase the risk of caries in deciduous teeth? METHODS: Population based retrospective cohort study of 76 920 children born between 2004 and 2010 in Kobe City, Japan who received municipal health check-ups at birth, 4, 9, and 18 months, and 3 years and had information on household smoking status at age 4 months and records of dental examinations at age 18 months and 3 years. Smoking during pregnancy and exposure of infants to secondhand smoke at age 4 months was assessed by standardised parent reported questionnaires. The main outcome measure was the incidence of caries in deciduous teeth, defined as at least one decayed, missing, or filled tooth assessed by qualified dentists without radiographs. Cox regression was used to estimate hazard ratios of exposure to secondhand smoke compared with having no smoker in the family after propensity score adjustment for clinical and lifestyle characteristics. STUDY ANSWER AND LIMITATIONS: Prevalence of household smoking among the 76 920 children was 55.3% (n=42 525), and 6.8% (n=5268) had evidence of exposure to tobacco smoke. A total of 12 729 incidents of dental caries were observed and most were decayed teeth (3 year follow-up rate 91.9%). The risk of caries at age 3 years was 14.0% (no smoker in family), 20.0% (smoking in household but without evidence of exposure to tobacco smoke), and 27.6% (exposure to tobacco smoke). The propensity score adjusted hazard ratios of the two exposure groups compared with having no smoker in the family were 1.46 (95% confidence interval 1.40 to 1.52) and 2.14 (1.99 to 2.29), respectively. The propensity score adjusted hazard ratio between maternal smoking during pregnancy and having no smoker in the family was 1.10 (0.97 to 1.25). WHAT THIS STUDY ADDS: Exposure to tobacco smoke at 4 months of age was associated with an approximately twofold increased risk of caries, and the risk of caries was also increased among those exposed to household smoking, by 1.5-fold, whereas the effect of maternal smoking during pregnancy was not statistically significant. FUNDING, COMPETING INTERESTS, DATA SHARING: This study was supported by a grant in aid for scientific research 26860415. The authors have no competing interests or additional data to share. PMID- 26489751 TI - Data sharing is desirable, but benefits should not be exaggerated. PMID- 26489752 TI - Erratum to: Transoral laser microsurgery for the treatment of oropharyngeal cancer: the Dalhousie University experience. PMID- 26489753 TI - Modelling strategies to break transmission of lymphatic filariasis--aggregation, adherence and vector competence greatly alter elimination. AB - BACKGROUND: With ambitious targets to eliminate lymphatic filariasis over the coming years, there is a need to identify optimal strategies to achieve them in areas with different baseline prevalence and stages of control. Modelling can assist in identifying what data should be collected and what strategies are best for which scenarios. METHODS: We develop a new individual-based, stochastic mathematical model of the transmission of lymphatic filariasis. We validate the model by fitting to a first time point and predicting future timepoints from surveillance data in Kenya and Sri Lanka, which have different vectors and different stages of the control programme. We then simulate different treatment scenarios in low, medium and high transmission settings, comparing once yearly mass drug administration (MDA) with more frequent MDA and higher coverage. We investigate the potential impact that vector control, systematic non-compliance and different levels of aggregation have on the dynamics of transmission and control. RESULTS: In all settings, increasing coverage from 65 to 80 % has a similar impact on control to treating twice a year at 65 % coverage, for fewer drug treatments being distributed. Vector control has a large impact, even at moderate levels. The extent of aggregation of parasite loads amongst a small portion of the population, which has been estimated to be highly variable in different settings, can undermine the success of a programme, particularly if high risk sub-communities are not accessing interventions. CONCLUSION: Even moderate levels of vector control have a large impact both on the reduction in prevalence and the maintenance of gains made during MDA, even when parasite loads are highly aggregated, and use of vector control is at moderate levels. For the same prevalence, differences in aggregation and adherence can result in very different dynamics. The novel analysis of a small amount of surveillance data and resulting simulations highlight the need for more individual level data to be analysed to effectively tailor programmes in the drive for elimination. PMID- 26489754 TI - Mitochondrial genomes and comparative analyses of Culex camposi, Culex coronator, Culex usquatus and Culex usquatissimus (Diptera:Culicidae), members of the coronator group. AB - BACKGROUND: The Coronator Group currently encompasses six morphologically similar species (Culex camposi Dyar, Culex coronator Dyar and Knab, Culex covagarciai Forattini, Culex usquatus Dyar, Culex usquatissimus Dyar, and Culex ousqua Dyar). Culex coronator has been incriminated as a potential vector of West Nile Virus (WNV), Saint Louis Encephalitis Virus (SLEV), and Venezuelan Equine Encephalitis Virus (VEEV). The complete mitochondrial genome of Cx. coronator, Cx. usquatus, Cx.usquatissimus, and Cx. camposi was sequenced, annotated, and analyzed to provide genetic information about these species. RESULTS: The mitochondrial genomes of Cx. coronator, Cx. usquatus, Cx.usquatissimus, and Cx. camposi varied from 15,573 base pairs in Cx. usquatus to 15,576 in Cx. coronator. They contained 37 genes (13 protein-encoding genes, 2 rRNA genes, and 22 tRNA genes) and the AT rich control region. Comparative analyses of the 37 genes demonstrated the mitochondrial genomes to be composed of variable and conserved genes. Despite the small size, the ATP8, ATP6 plus NADH5 protein-encoding genes were polymorphic, whereas tRNAs and rRNAs were conserved. The control region contained some poly-T stretch. The Bayesian phylogenetic tree corroborated that both the Coronator Group and the Culex pipens complex are monophyletic taxa. CONCLUSIONS: The mitochondrial genomes of Cx. coronator, Cx. usquatus, Cx. usquatissimus and Cx. camposi share the same gene composition and arrangement features that match to those reported for most Culicidae species. They are composed of the same 37 genes and the AT-rich control region, which contains poly-T stretches that may be involved in the functional role of the mitochondrial genome. Taken together, results of the dN/dS ratios, the sliding window analyses and the Bayesian phylogenetic analyses suggest that ATP6, ATP8 and NADH5 are promising genes to be employed in phylogenetic studies involving species of the Coronator Group, and probably other species groups of the subgenus Culex. Bayesian topology corroborated the morphological hypothesis of the Coronator Group as monophyletic lineage within the subgenus Culex. PMID- 26489755 TI - T. gondii rhoptry protein ROP18 induces apoptosis of neural cells via endoplasmic reticulum stress pathway. AB - BACKGROUND: The neurotropic parasite T. gondii is widespread among mammalian hosts including humans. During the course of T. gondii infection, the central nervous system is the most commonly damaged of all invasive organs. The polymorphic rhoptry protein ROP18 has been identified as a key factor in the pathogenesis of T. gondii; however, the molecular mechanism by which this protein exerts neuropathogenesis remains elusive. METHODS: Immunofluorescence staining was performed to detect neuropathogenesis of the mouse brain tissues. The apoptosis of neural cells and the expressions of related proteins in the endoplasmic reticulum stress (ER Stress)-mediated apoptosis pathway were detected by flow cytometry and Western blotting. RESULTS: Immunofluorescence staining reveals induction of the propidium iodide (PI) - positive neural cells in mouse cerebral cortex and hippocampus infected with ROP18 over-expressing transgenic tachyzoites. Western blotting analyses reveal that ROP18 increases the expressions of cleaved caspase-12, CHOP and cleaved caspase-3 when compared to the control groups. After the pretreatment of Z-ATAD-FMK (a specific caspase-12 inhibitor), the apoptotic level of neural cells had an apparent decline, and correspondingly, the expressions of those related proteins were notably decreased. CONCLUSIONS: Our findings here highlight that the virulence factor ROP18 in T. gondii may contribute to neuronal apoptosis through the ER stress mediated apoptosis pathway, which may be a potential molecular mechanism responsible for neurological disorders of toxoplasmosis. PMID- 26489756 TI - Effectiveness of guided self-help in decreasing expressed emotion in family caregivers of people diagnosed with depression in Thailand: a randomised controlled trial. AB - BACKGROUND: High expressed emotion (EE) can extend the duration of illness and precipitate relapse; however, little evidence-based information is available to assist family caregivers of individuals with depression. In the present exploratory study, we examined the effectiveness of a cognitive behaviour therapy (CBT) based guided self-help (GSH) manual in decreasing EE in caregivers of people with depression, in Thailand. METHOD: A parallel group randomised controlled trial was conducted, following CONSORT guidelines, with 54 caregivers who were allocated equally to GSH or control group (standard outpatient department support). In addition, both groups were contacted weekly by telephone. EE was assessed, using the Family Questionnaire (FQ), at baseline, post-test (Week 8) and follow-up (Week 12). RESULTS: FQ scores at baseline indicated that both groups had similar, though moderately high level of EE. However, between baseline and post-test EE scores decreased markedly in the intervention group, but in contrast, they increased slightly in the control group. Between post-test and follow-up, little change took place in the EE scores of either group. Overall, the intervention group recipients of GSH showed a significant decrease in EE whereas the control group recipients of standard outpatient department support reported a slight increase in EE. CONCLUSION: These findings provide preliminary evidence that GSH is beneficial in reducing EE in caregivers, which is advantageous to family members with depression and caregivers. The approach may be used as an adjunct to the limited outpatient department support given to caregivers by mental health professionals and, perhaps, to caregivers who do not attend these departments. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366639. Registered 21 July 2014. PMID- 26489757 TI - Smoking as a predictor of frailty: a systematic review. AB - BACKGROUND: Evidence on longitudinal associations between smoking and frailty is scarce. The objective of this study was to systematically review the literature on smoking as a predictor of frailty changes among community-dwelling middle-aged and older population. METHODS: A systematic search was performed using three electronic databases: MEDLINE, Embase and Scopus for studies published from 2000 through May 2015. Reference lists of relevant articles, articles shown as related citations in PubMed and articles citing the included studies in Google Scholar were also reviewed. Studies were included if they were prospective observational studies investigating smoking status as a predictor and subsequent changes in frailty, defined by validated criteria among community-dwelling general population aged 50 or older. A standardised data collection tool was used to extract data. Methodological quality was examined using the Newcastle-Ottawa Scale for cohort studies. RESULTS: A total of 1020 studies were identified and systematically reviewed for their titles, abstracts and full-text to assess their eligibilities. Five studies met inclusion criteria and were included in this review. These studies were critically reviewed and assessed for validity of their findings. Despite different methodologies and frailty criteria used, four of the five studies consistently showed baseline smoking was significantly associated with developing frailty or worsening frailty status at follow-up. Although not significant, the other study showed the same trend in male smokers. It is of note that most of the estimate measures were either unadjusted or only adjusted for a limited number of important covariates. CONCLUSIONS: This systematic review provides the evidence of smoking as a predictor of worsening frailty status in community-dwelling population. Smoking cessation may potentially be beneficial for preventing or reversing frailty. PMID- 26489758 TI - A successful longitudinal graduate tracking system for monitoring Australian medical school graduate outcomes. AB - CONTEXT: Maintaining an adequate health workforce in rural and remote Australia is challenging. The Australian Government has addressed this challenge by encouraging the admission of rural background students and supporting the growth of regionally based academic health faculties and clinical schools. ISSUE: It is imperative to assess the relevance and effectiveness of regionally based academic health faculties and clinical schools so standards can be maintained and health workforce supply and distribution can be maximised to benefit local populations. APPROACH: The James Cook University (JCU) College of Medicine and Dentistry, the first regional Australian medical school, has developed a longitudinal tracking system for its medical graduates. Processes include administering an exit survey to each cohort immediately prior to graduation (which also collects each graduate's details and consent to be contacted for follow-up studies and practice/career choice data), a FacebookTM page to search for hard-to-trace graduates, and accessing the Australian Health Practitioner Regulation Authority (AHPRA) website. CONCLUSIONS: The comprehensive personal contact tracking system backed by the AHPRA website has resulted in a 98% complete longitudinal tracking database, and thus a comprehensive picture of the practice location of JCU medical graduates from 2006 to 2013, enabling exploration of the patterns of practice to be conducted with considerable confidence. It is intended that the tracking database will be maintained for many years to allow regular follow-up of graduates well into their established careers. However, as graduate numbers increase at the JCU medical school, personal contact will be made with the majority of graduates on a less frequent basis. PMID- 26489759 TI - A novel channel selection method for optimal classification in different motor imagery BCI paradigms. AB - BACKGROUND: For sensorimotor rhythms based brain-computer interface (BCI) systems, classification of different motor imageries (MIs) remains a crucial problem. An important aspect is how many scalp electrodes (channels) should be used in order to reach optimal performance classifying motor imaginations. While the previous researches on channel selection mainly focus on MI tasks paradigms without feedback, the present work aims to investigate the optimal channel selection in MI tasks paradigms with real-time feedback (two-class control and four-class control paradigms). METHODS: In the present study, three datasets respectively recorded from MI tasks experiment, two-class control and four-class control experiments were analyzed offline. Multiple frequency-spatial synthesized features were comprehensively extracted from every channel, and a new enhanced method IterRelCen was proposed to perform channel selection. IterRelCen was constructed based on Relief algorithm, but was enhanced from two aspects: change of target sample selection strategy and adoption of the idea of iterative computation, and thus performed more robust in feature selection. Finally, a multiclass support vector machine was applied as the classifier. The least number of channels that yield the best classification accuracy were considered as the optimal channels. One-way ANOVA was employed to test the significance of performance improvement among using optimal channels, all the channels and three typical MI channels (C3, C4, Cz). RESULTS: The results show that the proposed method outperformed other channel selection methods by achieving average classification accuracies of 85.2, 94.1, and 83.2 % for the three datasets, respectively. Moreover, the channel selection results reveal that the average numbers of optimal channels were significantly different among the three MI paradigms. CONCLUSIONS: It is demonstrated that IterRelCen has a strong ability for feature selection. In addition, the results have shown that the numbers of optimal channels in the three different motor imagery BCI paradigms are distinct. From a MI task paradigm, to a two-class control paradigm, and to a four-class control paradigm, the number of required channels for optimizing the classification accuracy increased. These findings may provide useful information to optimize EEG based BCI systems, and further improve the performance of noninvasive BCI. PMID- 26489760 TI - A syringe-sharing model for the spread of HIV: application to Omsk, Western Siberia. AB - A system of two differential equations is used to model the transmission dynamics of human immunodeficiency virus between 'persons who inject drugs' (PWIDs) and their syringes. Our vector-borne disease model hinges on a metaphorical urn from which PWIDs draw syringes at random which may or may not be infected and may or may not result in one of the two agents becoming infected. The model's parameters are estimated with data mostly from the city of Omsk in Western Siberia. A linear trend in PWID prevalence in Omsk could only be fitted by considering a time dependent version of the model captured through a secular decrease in the probability that PWIDs decide to share a syringe. A global sensitivity analysis is performed with 14 parameters considered random variables in order to assess their impact on average numbers infected over a 50-year projection. With obvious intervention implications the drug injection rate and the probability of syringe cleansing are the only parameters whose coefficients of correlations with numbers of infected PWIDs and infected syringes have an absolute value close to or larger than 0.40. PMID- 26489761 TI - Corrigendum: Rh D blood group conversion using transcription activator-like effector nucleases. PMID- 26489762 TI - Gene Expression Profiling Identifies Interferon Signalling Molecules and IGFBP3 in Human Degenerative Annulus Fibrosus. AB - Low back pain is a major cause of disability especially for people between 20 and 50 years of age. As a costly healthcare problem, it imposes a serious socio economic burden. Current surgical therapies fail to replace the normal disc in facilitating spinal movements and absorbing load. The focus of regenerative medicine is on identifying biomarkers and signalling pathways to improve our understanding about cascades of disc degeneration and allow for the design of specific therapies. We hypothesized that comparing microarray profiles from degenerative and non-degenerative discs will lead to the identification of dysregulated signalling and pathophysiological targets. Microarray data sets were generated from human annulus fibrosus cells and analysed using IPA ingenuity pathway analysis. Gene expression values were validated by qRT-PCR, and respective proteins were identified by immunohistochemistry. Microarray analysis revealed 238 differentially expressed genes in the degenerative annulus fibrosus. Seventeen of the dysregulated molecular markers showed log2-fold changes greater than +/-1.5. Various dysregulated cellular functions, including cell proliferation and inflammatory response, were identified. The most significant canonical pathway induced in degenerative annulus fibrosus was found to be the interferon pathway. This study indicates interferon-alpha signalling pathway activation with IFIT3 and IGFBP3 up-regulation, which may affect cellular function in human degenerative disc. PMID- 26489763 TI - Lysine-specific demethylase 1 mediates epidermal growth factor signaling to promote cell migration in ovarian cancer cells. AB - Epigenetic abnormalities play a vital role in the progression of ovarian cancer. Lysine-specific demethylase 1 (LSD1/KDM1A) acts as an epigenetic regulator and is overexpressed in ovarian tumors. However, the upstream regulator of LSD1 expression in this cancer remains elusive. Here, we show that epidermal growth factor (EGF) signaling upregulates LSD1 protein levels in SKOV3 and HO8910 ovarian cancer cells overexpressing both LSD1 and the EGF receptor. This effect is correlated with a decrease in the dimethylation of H3K4, a major substrate of LSD1, in an LSD1-dependent manner. We also show that inhibition of PI3K/AKT, but not MEK, abolishes the EGF-induced upregulation of LSD1 and cell migration, indicating that the PI3K/PDK1/AKT pathway mediates the EGF-induced expression of LSD1 and cell migration. Significantly, LSD1 knockdown or inhibition of LSD1 activity impairs both intrinsic and EGF-induced cell migration in SKOV3 and HO8910 cells. These results highlight a novel mechanism regulating LSD1 expression and identify LSD1 as a promising therapeutic target for treating metastatic ovarian cancer driven by EGF signaling. PMID- 26489764 TI - The role of the Src Homology-2 domain containing protein B (SHB) in beta cells. AB - This review will describe the SH2-domain signaling protein Src Homology-2 domain containing protein B (SHB) and its role in various physiological processes relating in particular to glucose homeostasis and beta cell function. SHB operates downstream of several tyrosine kinase receptors and assembles signaling complexes in response to receptor activation by interacting with other signaling proteins via its other domains (proline-rich, phosphotyrosine-binding and tyrosine-phosphorylation sites). The subsequent responses are context-dependent. Absence of Shb in mice has been found to exert effects on hematopoiesis, angiogenesis and glucose metabolism. Specifically, first-phase insulin secretion in response to glucose was impaired and this effect was related to altered characteristics of focal adhesion kinase activation modulating signaling through Akt, ERK, beta catenin and cAMP. It is believed that SHB plays a role in integrating adaptive responses to various stimuli by simultaneously modulating cellular responses in different cell-types, thus playing a role in maintaining physiological homeostasis. PMID- 26489765 TI - Wisp1 mediates Bmp3-stimulated mesenchymal stem cell proliferation. AB - Adipose tissue expansion, resulting from adipocyte hyperplasia and/or hypertrophy, is a hallmark of obesity. Adipocytes are derived from mesenchymal stem cells (MSCs) through adipogenesis, a process involving three key steps: proliferation, commitment and differentiation. Although studies have elaborated on the mechanisms regulating adipocyte commitment and differentiation, the factors that control MSC proliferation remain largely unknown. Previously, we demonstrated that bone morphogenetic protein 3 (Bmp3), the expression of which was upregulated in our rat model of hyperplasic visceral adiposity, potently stimulated MSC proliferation. In the present study, we investigate the molecular target of Bmp3. We conducted DNA microarray analysis on MSCs treated with and without Bmp3 and identified WNT1-inducible signaling pathway protein 1 (Wisp1) as a differentially expressed gene, whose expression was upregulated 3.7-fold by Bmp3. Wisp1 is a proliferative agent in various non-adipose cell types and is implicated in adipogenesis. Therefore, we tested the hypothesis that Wisp1 mediates Bmp3 stimulation of MSC proliferation. We showed that Bmp3 increased the expression of Wisp1 as early as 3 h following Bmp3 treatment in MSCs. Importantly, the upregulated Wisp1 expression preceded Bmp3-induced MSC proliferation, as determined by [(3)H]-thymidine incorporation. Furthermore, treatment of MSCs with recombinant Wisp1 led to a concentration-dependent increase in [(3)H]-thymidine incorporation with a maximal increase of 300%. In addition, siRNA-mediated knockdown of Wisp1 expression attenuated Bmp3-induced MSC proliferation. Taken together, our present findings reveal Wisp1 as a novel target of Bmp3 and suggest that the Bmp3/Wisp1 signaling pathway play a key role in MSC proliferation, and consequently adipogenesis. PMID- 26489766 TI - Pyrexia of unknown origin 90 years on: a paradigm of modern clinical medicine. AB - In 1925, Sir Thomas Horder, a leading physician of his day, gave a lecture, published in this journal, entitled 'Some cases of pyrexia without physical signs'. The paper highlighted what was already a familiar clinical presentation "which taxes our resources to the utmost". Fast-forward through 90 years of careful clinical description, technological innovation in diagnosis and treatment, emergent infections, novel diagnoses, demographic shifts, and radical changes in the health economy. Sir Thomas would find certain aspects familiar, and others revolutionary, in the differential diagnosis and management of the 21st century patient with pyrexia of unknown origin (PUO). Within high-income settings, the proportion of cases due to infection has declined, albeit unevenly. The era of untreated HIV, and the consequences of iatrogenic intervention and immunosuppression, led to Durack and Street's subclassification of the condition in the early 1990 s into classic, nosocomial, neutropenic and HIV-associated PUO. Shifts towards ambulatory care have driven a change in the definition of many diseases. An era of observant clinicians, who lent their names to eponymous syndromes, followed by meticulous serological, genetic and clinicopathological correlation, generated a battery of diagnoses that, along with malignancy, form a large proportion of diagnoses in more recent clinical care. In the current era, universal access to cross-sectional imaging and an infinite array of laboratory tests has undermined the attention paid to history and examination. In some areas of the clinical assessment, such as assessing the fever pattern, this shift is supported by research evidence. The issues that need to be addressed in the next 90 years of technological innovation, information sharing and health service transformation are likely to include: transcriptomic approaches to diagnosis; the place of positron emission tomography (PET) in the diagnostic pathway; the optimal management of high ferritin states; and the most cost-effective diagnostic environment, in the face of this era of specialisation and fragmentation of care. In the meantime, this review covers some important early 21st century lessons to be shared in avoiding diagnostic pitfalls and choosing empirical therapy. PMID- 26489767 TI - Clinical and diagnostic findings in patients with elevated cerebrospinal bilirubin. AB - INTRODUCTION: Cerebrospinal fluid (CSF) spectroscopy can identify subarachnoid haemorrhage (SAH) when CT is negative in patients presenting with acute severe headache. The primary objective of this study was to evaluate the clinical use and usefulness of CSF spectrophotometry. Secondary objectives were to identify other causes of elevated CSF bilirubin, to analyse headache descriptions and to compare clinical features in patients with an elevated CSF bilirubin among those with and without an intracranial vascular cause of SAH (avSAH). METHODS: Consecutive patients admitted to two hospitals in Enniskillen and Londonderry between 1 January 2004 and 30 September 2014 with CSF spectroscopy bilirubin results were identified from a clinical chemistry laboratory dataset. Patients with elevated CSF bilirubin were studied. Clinical demographics, delays to investigation and final diagnoses were recorded. Patients with avSAH were compared with patients without avSAH. RESULTS: Among 1813 patients with CSF spectrophotometry results, requests increased more than threefold during the study (p<0.001). Fifty-six patients had elevated CSF bilirubin. Ten (17.9%) had avSAH, of which 8 (14.3%) had aneurysmal SAH. Non-vascular causes of elevated CSF bilirubin included meningitis, spontaneous intracranial hypotension and carcinomatous meningitis. Headache descriptions varied. Time from headache onset to admission, CT scan and lumbar puncture did not differ significantly for patients with avSAH and non-avSAH. CSF red cell counts were higher among patients with avSAH than patients with non-avSAH (p=0.005). CONCLUSIONS: CSF bilirubin measurement has an important role in identifying avSAH in CT-negative patients presenting with a thunderclap headache. Better clinical selection of patients is required as CSF spectrophotometry, although sensitive, is not specific for SAH. PMID- 26489768 TI - Methoxy poly (ethylene glycol)-block-poly (glutamic acid)-graft-6-(2 nitroimidazole) hexyl amine nanoparticles for potential hypoxia-responsive delivery of doxorubicin. AB - Tumor microenvironment-responsive nano drug delivery vehicles are gaining mounting attention in the field of biomedical sciences. The hypoxic response of the tumorous cells due to very low partial pressure of oxygen (some time less than 2.5 mm of Hg) in the tumor tissues makes hypoxia-responsive drug delivery system as the more appealing in cancer chemotherapy. Based on these considerations, we synthesized hypoxia-responsive polymeric materials methoxy poly (ethylene glycol)-block-poly (glutamic acid)-graft-6-(2-nitroimidazole) hexyl amine (mPEG-b-PLG-g-NID) by conjugation of the hydrophobic nitro imidazole derivative (NID)[6-(2-nitroimidazole) hexyl amine] with the pendant carboxylic group of poly (ethylene glycol)-block-poly (L-glutamic acid)(mPEG-b-PLG). The structure and degree of substitution were confirmed by proton NMR, FTIR, and UV Vis spectroscopy. The degree of substitution was found to enhance with the increase in NID to polymer ratio. The hypoxia response of the material was evaluated by UV-Vis spectroscopy and zeta potential measurements. Doxorubicin was hydrophobically encapsulated in the micellar core of the hypoxia-responsive nanoparticles. The drug-loaded micelles showed faster release in hypoxic condition as compared to normoxic conditions. Moreover, the developed polymeric system was found non-toxic to MCF-7 cell line, thus suggesting its biocompatibility and suitability as drug delivery device. PMID- 26489769 TI - Principal nonlinear dynamical modes of climate variability. AB - We suggest a new nonlinear expansion of space-distributed observational time series. The expansion allows constructing principal nonlinear manifolds holding essential part of observed variability. It yields low-dimensional hidden time series interpreted as internal modes driving observed multivariate dynamics as well as their mapping to a geographic grid. Bayesian optimality is used for selecting relevant structure of nonlinear transformation, including both the number of principal modes and degree of nonlinearity. Furthermore, the optimal characteristic time scale of the reconstructed modes is also found. The technique is applied to monthly sea surface temperature (SST) time series having a duration of 33 years and covering the globe. Three dominant nonlinear modes were extracted from the time series: the first efficiently separates the annual cycle, the second is responsible for ENSO variability, and combinations of the second and the third modes explain substantial parts of Pacific and Atlantic dynamics. A relation of the obtained modes to decadal natural climate variability including current hiatus in global warming is exhibited and discussed. PMID- 26489770 TI - Psychometric properties of the Fear of Cancer Recurrence Inventory: an item response theory approach. AB - OBJECTIVE: Classical psychometric methods have been used to demonstrate the validity and reliability of the 42-item Fear of Cancer Recurrence Inventory (FCRI). Our aim was to expand on this evidence with information on the discriminative value of the individual items when administered to people with a personal history of melanoma, using an item response theory (IRT) approach. METHODS: We used a two-parameter IRT model to examine all items of the FCRI, primarily regarding whether people with a personal history of melanoma use the response scale as expected (as indicated by item characteristic curves), and whether the items can discriminate between those low and high on the constructs assessed by the instrument. RESULTS: The sample was comprised of 286 adults with a personal history of melanoma (58% male, mean age: 59.1 years). The established factor structure of the FCRI was generally confirmed. IRT highlighted several items with problematic item characteristic curves, including most items in the Reassurance and Coping Strategies domains. Several other items exhibited poor discrimination. CONCLUSIONS: Based on this IRT analysis, we outline suggestions for refinement of the FCRI and potential development of a short-form, that could reduce respondent burden. Generalisability of these findings beyond melanoma warrants further examination. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26489771 TI - Immobilization of gold nanoclusters inside porous electrospun fibers for selective detection of Cu(II): A strategic approach to shielding pristine performance. AB - Here, a distinct demonstration of highly sensitive and selective detection of copper (Cu(2+)) in a vastly porous cellulose acetate fibers (pCAF) has been carried out using dithiothreitol capped gold nanocluster (DTT.AuNC) as fluorescent probe. A careful optimization of all potential factors affecting the performance of the probe for effective detection of Cu(2+) were studied and the resultant sensor strip exhibiting unique features including high stability, retained parent fluorescence nature and reproducibility. The visual colorimetric detection of Cu(2+) in water, presenting the selective sensing performance towards Cu(2+) ions over Zn(2+), Cd(2+) and Hg(2+) under UV light in naked eye, contrast to other metal ions that didn't significantly produce such a change. The comparative sensing performance of DTT.AuNC@pCAF, keeping the nonporous CA fiber (DTT.AuNC@nCAF) as a support matrix has been demonstrated. The resulting weak response of DTT.AuNC@nCAF denotes the lack of ligand protection leading to the poor coordination ability with Cu(2+). The determined detection limit (50 ppb) is far lower than the maximum level of Cu(2+) in drinking water (1.3 ppm) set by U.S. Environmental Protection Agency (EPA). An interesting find from this study has been the specific oxidation nature between Cu(2+) and DTT.AuNC, offering solid evidence for selective sensors. PMID- 26489773 TI - Controlled Synthesis of N-Doped Carbon Nanospheres with Tailored Mesopores through Self-Assembly of Colloidal Silica. AB - Limited strategies have been established to prepare monodisperse mesoporous carbon nanospheres (MCNs) with tailored pore sizes. In this work, a method is reported to synthesize MCNs by combining polymerization of aniline with co assembly of colloidal silica nanoparticles. The controlled self-assembly behavior of colloidal silica enables the formation of uniform composite nanospheres and convenient modulation over mesopores. After carbonization and removal of sacrificial templates, the resultant MCNs possess tunable mesopores (7-42 nm) and spherical diameters (90-300 nm), as well as high surface area (785-1117 m(2) g( 1) ), large pore volume (1.46-2.01 cm(3) g(-1) ) and abundant nitrogen moieties (5.54-8.73 at %). When serving as metal-free electrocatalysts for the oxygen reduction reaction (ORR), MCNs with an optimum pore size of 22 nm, compared to those with 7 and 42 nm, exhibit the best ORR performance in alkaline medium. PMID- 26489772 TI - Diagnosis lost: Differences between children who had and who currently have an autism spectrum disorder diagnosis. AB - Autism spectrum disorder diagnoses sometimes change due to misdiagnosis, maturation, or treatment. This study uses a probability-based national survey-the Survey of Pathways to Diagnosis and Services-to compare currently diagnosed (n = 1420) and previously diagnosed (n = 187) children aged 6-17 years based on retrospective parental reports of early concerns about their children's development, responses to those concerns by doctors and other healthcare providers, the type of provider who made the first autism spectrum disorder diagnosis, and the autism spectrum disorder subtype diagnoses received (if any). Propensity score matching was used to control for differences between the groups on children's current level of functioning and other current characteristics that may have been related to diagnosis loss. Approximately 13% of the children ever diagnosed with autism spectrum disorder were estimated to have lost the diagnosis, and parents of 74% of them believed it was changed due to new information. Previously diagnosed children were less likely to have parents with early concerns about verbal skills, nonverbal communication, learning, and unusual gestures or movements. They were also less likely to have been referred to and diagnosed by a specialist. Previously diagnosed children were less likely to have ever received a diagnosis of Asperger's disorder or autistic disorder. PMID- 26489774 TI - Antisite defects in layered multiferroic CuCr(0.9)In(0.1)P2S6. AB - The CuCr1-xInxP2S6 system represents a large family of metal chalcogenophosphates that are unique and promising candidates for 2D materials with functionalities such as ferroelectricity. In this work, we carried out detailed microstructural and chemical characterization of these compounds using aberration-corrected STEM, in order to understand the origin of these different ordering phenomena. Quantitative STEM-HAADF imaging and analysis identified the stacking order of an 8-layer thin flake, which leads to the identification of anti-site In(3+)(Cu(+)) doping. We believe that these findings will pave the way towards understanding the ferroic coupling phenomena in van der Waals lamellar compounds, as well as their potential applications in 2-D electronics. PMID- 26489775 TI - Global assessment of the severity of epilepsy (GASE) Scale in children: Validity, reliability, responsiveness. AB - OBJECTIVE: The Global Assessment of Severity of Epilepsy (GASE) Scale is a single item, 7-point global rating scale designed for neurologist-report of overall severity of epilepsy in children. Building on previous preliminary evidence of its validity and reliability for research and clinical use, this study evaluated the GASE Scale's construct validity, reliability, and responsiveness to changes in severity of epilepsy. METHODS: Data used for the study arose from the Health Related Quality of Life in Children with Epilepsy Study (HERQULES), a 2-year multicenter prospective cohort study (n = 374) with observations taken at baseline, and 6, 12, and 24 months after diagnosis. Construct validity and reliability were quantified using Spearman's correlation and intraclass correlation coefficient (ICC). Responsiveness was assessed using both distribution-based and anchor-based indices. RESULTS: The GASE Scale was at least moderately correlated (r >= 0.30) with several key clinical aspects and most strongly correlated with frequency and intensity of seizures and interference of epilepsy or drugs with daily activities (r > 0.30). Total variation in GASE Scale scores explained by seven core clinical aspects of epilepsy increased over time (R(2) = 28% at baseline to R(2) = 70% at 24 months). The GASE Scale had modest test-retest reliability (ICC range: 0.52-0.64) and was responsive to changes in clinical criteria (standardized response mean range: 0.49-0.68; probability of change range: 0.69-0.75; Guyatt's responsiveness statistic range: 0.56-0.84). The GASE Scale showed potential to discriminate "stable" and "changed" patients according to select criteria and to a composite score (area under the receiver operating characteristic [ROC] curve range: 0.50-0.67). SIGNIFICANCE: Results offer additional evidence in support of the GASE Scale's validity, reliability, as well as responsiveness to changes in severity of epilepsy in children. We conclude that the GASE Scale is a potentially useful tool for assessing the severity of epilepsy in both clinical and research settings. PMID- 26489777 TI - Regarding "On the role of competent ligaments...". PMID- 26489776 TI - Cost-effectiveness of exercise as a therapy for behavioural and psychological symptoms of dementia within the EVIDEM-E randomised controlled trial. AB - OBJECTIVE: Although available evidence is modest, exercise could be beneficial in reducing behavioural and psychological symptoms of dementia. We aim to evaluate the cost-effectiveness of a dyadic exercise regimen for individuals with dementia and their main carer as therapy for behavioural and psychological symptoms of dementia. METHODS: Cost-effectiveness analysis within a two-arm, pragmatic, randomised, controlled, single-blind, parallel-group trial of a dyadic exercise regimen (individually tailored, for 20-30 min at least five times per week). The study randomised 131 community-dwelling individuals with dementia and clinically significant behavioural and psychological symptoms with a carer willing and able to participate in the exercise regimen; 52 dyads provided sufficient cost data for analyses. RESULTS: Mean intervention cost was L284 per dyad. For the subsample of 52 dyads, the intervention group had significantly higher mean cost from a societal perspective (mean difference L2728.60, p = 0.05), but costs were not significantly different from a health and social care perspective. The exercise intervention was more cost-effective than treatment as usual from both societal and health and social care perspectives for the measure of behavioural and psychological symptoms (Neuropsychiatric Inventory). It does not appear cost effective in terms of cost per quality-adjusted life year gain. CONCLUSIONS: The exercise intervention has the potential to be seen as cost-effective when considering behavioural and psychological symptoms but did not appear cost effective when considering quality-adjusted life year gains. PMID- 26489778 TI - Gait Analysis in Adults with Intellectual Disabilities Living in a Residential Facility. AB - BACKGROUND: Mobility limitations are of particular interest in people with intellectual disabilities. The aim of this study was to present feasibility and mean values of gait parameters in people with intellectual disability and it was hypothesized that several trials would be necessary to gain stable values for this cohort. MATERIAL AND METHODS: Thirty-two adults with intellectual disability living in a residential facility were asked to do four walks in both normal and fast speed conditions over an instrumented walkway. Mean values of gait parameters were calculated over two different trial combinations, with TC1&2 representing the mean value of trials 1 and 2, and TC1-4 representing the mean over all four trials. RESULTS: All participants (Mage = 59.6 years; SD = 16.71) successfully performed the protocol. Gait parameters remained constant over all trials. No significant differences were found between the trial combination TC1&2 and trial combination TC1-4. CONCLUSION: Gait analysis was found to be feasible in people with intellectual disability. Overall, the present authors recommend performing two trials and to calculate the means of gait parameters over these two trials to gain stable values. PMID- 26489779 TI - Validation of functional fetal autonomic brain age score fABAS in 5 min short recordings. AB - With the objective of evaluating the functional maturation age and developmental disturbances we have previously introduced the fetal autonomic brain age score (fABAS) using 30 min fetal magnetocardiographic recordings (fMCG, Jena). The score is based on heart rate pattern indices that are related to universal principles of developmental biology. The present work aims at the validation of the fABAS methodology on 5 min recordings from an independent database (fMCG, Bochum).We found high agreement of fABAS obtained from Jena normal fetuses (5 min subsets, n = 364) and Bochum recordings (n = 322, normal fetuses). fABAS of 48 recordings from fetuses with intra-uterine growth restriction (IUGR, Bochum) was reduced in most of the cases, a result consistent with IUGR fetuses from Jena previously reported. fABAS calculated from 5 min snapshots only partly covers the accuracy when compared to fABAS from 30 min recordings. More precise diagnosis requires longer recordings.fABAS obtained from fMCG recordings is a strong candidate for standardized assessment of functional maturation age and developmental disturbances. Even 5 min recordings seem to be valuable for screening for maturation problems. PMID- 26489781 TI - Using simulation for teaching femoral arterial access: A multicentric collaboration. AB - OBJECTIVE: To assess the impact of simulation training on complications associated with femoral arterial access obtained by first year cardiology fellows. BACKGROUND: Prior studies demonstrate a higher incidence of arterial access related complications among patients undergoing invasive cardiac procedures. METHODS: First year cardiology fellows at four teaching hospitals in Michigan tracked their femoral access experience and any associated complications between July 2011 and June 2013. Fellows starting their academic training in July 2012 were first trained on a specially developed simulator before starting their rotation in the catheterization laboratory. The primary outcome was access proficiency, defined as five successful femoral access attempts without any complication or need to seek help from a more experienced team member. RESULTS: A total of 1,278 femoral access attempts were made by 21 fellows in 2011-2012 compared with 869 femoral access attempts made by 21 fellows in 2012-2013. There was a lower rate of access related complications in patients undergoing access attempts by first year fellows in year 2 compared with year 1 (2.1% versus 4.5%, P = 0.003). The number of procedures to achieve procedural proficiency was significantly higher in year 1 compared with year 2 (median 20 versus 10, P = 0.007). CONCLUSIONS: Incorporation of simulation in the training of first year fellows was associated with an improvement in proficiency and a clinically meaningful reduction in vascular complications. PMID- 26489782 TI - Zinc promotes clot stability by accelerating clot formation and modifying fibrin structure. AB - Zinc released from activated platelets binds fibrin(ogen) and attenuates fibrinolysis. Although zinc also affects clot formation, the mechanism and consequences are poorly understood. To address these gaps, the effect of zinc on clot formation and structure was examined in the absence or presence of factor (F) XIII. Zinc accelerated a) plasma clotting by 1.4-fold, b) fibrinogen clotting by 3.5- and 2.3-fold in the absence or presence of FXIII, respectively, c) fragment X clotting by 1.3-fold, and d) polymerisation of fibrin monomers generated with thrombin or batroxobin by 2.5- and 1.8-fold, respectively. Whereas absorbance increased up to 3.3-fold when fibrinogen was clotted in the presence of zinc, absorbance of fragment X clots was unaffected by zinc, consistent with reports that zinc binds to the alphaC-domain of fibrin(ogen). Scanning electron microscopic analysis revealed a two-fold increase in fibre diameter in the presence of zinc and in permeability studies, zinc increased clot porosity by 30 fold with or without FXIII. Whereas FXIII increased clot stiffness from 128 +/- 19 Pa to 415 +/- 27 Pa in rheological analyses, zinc reduced clot stiffness by 10 and 8.5-fold in the absence and presence of FXIII, respectively. Clots formed in the presence of zinc were more stable and resisted rupture with or without FXIII. Therefore, zinc accelerates clotting and reduces fibrin clot stiffness in a FXIII independent manner, suggesting that zinc may work in concert with FXIII to modulate clot strength and stability. PMID- 26489783 TI - A SPoARC in the Dark: Spatialization in Verbal Immediate Memory. AB - In 2011, van Dijck and Fias described a positional SNARC (Spatial-Numerical Association of Response Codes) effect: the SPoARC (Spatial-Positional Association of Response Codes). To-be-remembered items (e.g., numbers, words) presented centrally on a screen seemed to acquire a left-to-right spatial dimension. If confirmed, this spatialization could be crucial for immediate memory theories. However, given the intricate links between visual and spatial dimensions, this effect could be due to the visual presentation (on a computer screen), which could have probed the left-to-right direction of reading/writing. To allow a generalization of this effect, we adapted van Dijck and Fias's (2011) task using an auditory version of Sternberg's paradigm. Lists of five consonants were auditorily presented at a rate of 3 s/item. A SPoARC effect was observed. The consequences are discussed first from an immediate memory perspective, putting forward the view that order could be coded through spatialization, and then in terms of similarities between SPoARC and SNARC. PMID- 26489784 TI - Highly Lewis Acidic Arylboronate Esters Capable of Colorimetric Turn-On Response. AB - A series of boronate-pi-acceptor compounds containing different types of pi bridges (1,4-phenylen or thien-2,5-diyl or furan-2,5-diyl) that link the switchable boronate ester group with the efficient TCF acceptor group (TCF=2 dicyanomethylen-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran) has been synthesized. A TCF chromophore of this type undergoes transition to a donor-pi-acceptor compound upon coordination of Lewis bases at the Lewis acidic boron center, which is accompanied by an enhanced intramolecular charge-transfer interaction. The Lewis acid character has been investigated by spectroscopic measurements (UV/Vis, NMR spectroscopies) as well as DFT and ab initio-based calculations. It is shown that the TCF acceptor group and thiophene or furan pi-bridges directly bound to the boron atom cooperatively increase the Lewis acidity. UV/Vis titration experiments confirm fluoride binding constants in the range of up to 10(8) M(-1) in CH2 Cl2 . In addition to the strong boron fluoride binding motif, Lewis interactions also occur with weaker Lewis bases, such as pyridine or aliphatic alcohols. The unique combination of chromophoric and Lewis acidic properties is responsible for the intense colorimetric turn-on response detectable after complex formation. PMID- 26489785 TI - Extending the Scope of the B(C6 F5 )3 -Catalyzed C=N Bond Reduction: Hydrogenation of Oxime Ethers and Hydrazones. AB - The B(C6 F5 )3 -catalyzed hydrogenation is applied to aldoxime triisopropylsilyl ethers and hydrazones bearing an easily removable phthaloyl protective group. The C?N reduction of aldehyde-derived substrates (oxime ethers and hydrazones) is enabled by using 1,4-dioxane as the solvent known to participate as the Lewis basic component in FLP-type heterolytic dihydrogen splitting. More basic ketone derived hydrazones act as Lewis bases themselves in the FLP-type dihydrogen activation and are therefore successfully hydrogenated in nondonating toluene. The difference in reactivity between aldehyde- and ketone-derived substrates is also reflected in the required catalyst loading and dihydrogen pressure. PMID- 26489786 TI - Ternary cooperative assembly--polymeric condensation of photoactive viologen, phosphonate-terminated dendrimers and crystalline anatase nanoparticles. AB - Photoactive viologen fragments were covalently embedded within the material framework during the self-assembly and sol-gel polymerisation of phosphonate terminated dendrimers and soluble titanium-oxo-species. The resulting porous anisotropic phosphonate-bridged-crystalline anatase materials serve as new hosts to disperse and stabilize small gold nanoparticles. PMID- 26489787 TI - The criteria for optimal down-regulation with gonadotropin-releasing hormone agonist: a retrospective cohort study. AB - OBJECTIVE: The objective of this study is to investigate whether the degree of down-regulation using GnRH-agonists is associated with pregnancy outcomes. STUDY DESIGN: This retrospective analysis was performed on 2708 cycles from 2514 patients undergoing down-regulation with the luteal phase long protocol. The serum oestradiol (E2D) and luteinising hormone (LHD) levels, the diameter of the largest follicle (DLFD) and the endometrial-thickness (ENTD) after down regulation were used to evaluate the degree of down-regulation. One-way analysis of variance with the Bonferroni adjustment, the chi-square test and multivariate logistic regression analyses were used for the statistical analysis. RESULTS: The cumulative clinical pregnancy rates (CCPR) and the cumulative live birth rates (CLBR) were higher in the cycles with E2D < 30 pg/ml (63.7%, OR = 1.405 (1.055 1.870) and 56.8%, OR = 1.372 (1.039-1.813)) and 30-55pg/ml (66.8%, OR = 1.439 (1.104-1.874) and 59.8%, OR = 1.397 (1.080-1.806)) than in those with E2D > 55 pg/ml (62.8% and 54.7%). There was a trend towards lower CCPRs and CLBRs in the cycles with DLFD > 10 mm or ENTD >= 6 mm; however, this difference was not significant. CONCLUSION: The degree of down-regulation is associated with ovarian response, pregnancy, and live birth. We propose the following criteria for optimal down-regulation: E2D 30-55 pg/ml, ENTD < 6 mm, and no apparent ovarian activity. PMID- 26489788 TI - Gut microbiota and the risk of childhood asthma. PMID- 26489789 TI - Regional investigation of a cyclosporiasis outbreak linked to imported romaine lettuce - Nebraska and Iowa, June-August 2013. AB - A regional, multistate investigation into a June-August 2013 cyclosporiasis outbreak was conducted in Nebraska, Iowa, and neighbouring states. Cases were confirmed on the basis of laboratory and clinical findings. Of 227 cases in Iowa (n = 140) and Nebraska (n = 87) residents, 162 (71%) reported dining at chain A/B restaurants - 96% reported house salad consumption. A case-control study identified chain A/B house salad as the most likely vehicle. Traceback was conducted to ascertain production lot codes of bagged salad mix (iceberg and romaine lettuce, red cabbage, and carrots) served as house salad in implicated restaurants. A single production lot code of salad mix supplied by both a common producer and distributor was linked to the majority of confirmed cases in persons reporting regional chain A/B exposure. The salad mix linked to illnesses contained imported romaine lettuce from two separate single-grower fields-of origin and ?1 additional field from another grower. PMID- 26489790 TI - A 45-Year-Old Undiagnosed Cirrhotic Patient with Hepatopulmonary Syndrome as First Presentation: A Case Report. AB - BACKGROUND: Hepatopulmonary syndrome (HPS) is a pulmonary complication characterized by a triad of chronic liver disease, arterial hypoxemia, and pulmonary vascular dilations. Agitated saline contrast echocardiography is a simple inexpensive criterion standard procedure for confirming the diagnosis of HPS. CASE REPORT: Here, we discuss a case of a 45-year-old male Indian patient with no medical history who presented to our hospital with exertional dyspnea, hypoxia, and classical signs of HPS. A diagnosis of cirrhosis was made on the basis of history, liver enzymes, and ultrasound, while HPS was diagnosed using transthoracic echocardiography with agitated saline. CONCLUSIONS: HPS, although a complication of cirrhosis, can be the initial presentation in undiagnosed cirrhotic patients. Thus, it is important to include HPS in differentials when dealing with cases of progressive dyspnea. Also, the possibility of a liver disease etiology should be explored in patients with unexplained hypoxemia. PMID- 26489791 TI - Peer Review: Lessons Learned in A Pediatric Radiology Department. AB - The purpose of this article is to illustrate types of diagnostic errors and feedback given to radiologists, using cases to support and clarify these categories. A comment-enhanced peer review system may be leveraged to generate a comprehensive feedback categorization scheme. These include errors of observation, errors of interpretation, inadequate patient data gathering, errors of communication, interobserver variability, informational feedback, and compliments. Much of this feedback is captured through comments associated with interpretative agreements. PMID- 26489792 TI - Diagnostic Inefficiency of Nonselective Spinal Angiography (Flush Aortography) in the Evaluation of the Normal and Pathological Spinal Vasculature. AB - Selective spinal angiography was introduced in the 1960s to palliate the poor sensitivity of nonselective techniques for the evaluation of the spinal cord vasculature. Recent advances made in the field of angiography seem to have prompted a renewed interest for nonselective spinal angiography, or flush aortograms. This pictorial essay, illustrated with 2 cases of presurgical evaluation of the spinal cord supply and 2 cases of spinal vascular malformation, suggests that nonselective techniques remain insufficient to properly document the normal or pathological spinal vasculature. While flush aortography can play a role as a complement to spinal angiography, for example, to locate vessels eluding selective catheterization, relying on nonselective studies to rule out the presence of a spinal vascular malformation or to identify the normal spinal cord supply before surgical interventions may lead to false-negative investigations with potentially devastating consequences. PMID- 26489793 TI - Nonurgent Use of the Emergency Department by Pediatric Patients: A Theory-Guided Approach for Primary and Acute Care Pediatric Nurse Practitioners. AB - Providing quality, cost-effective care to children and their families in the appropriate setting is the goal of nurse practitioners in primary and acute care. However, increased utilization of the emergency department (ED) for nonurgent care threatens cost-effective quality care, interrupts continuity of care, and contributes to ED overcrowding. To date, descriptive research has identified demographics of those using the ED for nonurgent care, the chief complaints of children seeking nonurgent care, the cost to the health care system of pediatric nonurgent care, and characteristics of associated primary care settings. Using Donabedian's Model of Quality of Healthcare and a Theory of Dependent Care by Taylor and colleagues, acute and primary care pediatric nurse practitioners can incorporate interventions that will channel care to the appropriate setting and educate caregivers regarding common childhood illnesses and the value of continuity of care. By using a theoretical framework as a guide, this article will help both acute and primary care pediatric nurse practitioners understand why parents seek nonurgent care for their children in the ED and actions they can take to ensure that care is provided in an optimal setting. PMID- 26489794 TI - Highly Sensitive FRET-FCS Detects Amyloid beta-Peptide Oligomers in Solution at Physiological Concentrations. AB - Oligomers formed by the amyloid beta-peptide (Abeta) are pathogens in Alzheimer's disease. Increased knowledge on the oligomerization process is crucial for understanding the disease and for finding treatments. Ideally, Abeta oligomerization should be studied in solution and at physiologically relevant concentrations, but most popular techniques of today are not capable of such analyses. We demonstrate here that the combination of Forster Resonance Energy Transfer and Fluorescence Correlation Spectroscopy (FRET-FCS) has a unique ability to detect small subpopulations of FRET-active molecules and oligomers. FRET-FCS could readily detect a FRET-active oligonucleotide present at levels as low as 0.5% compared to FRET-inactive dye molecules. In contrast, three established fluorescence fluctuation techniques (FCS, FCCS, and PCH) required fractions between 7 and 11%. When applied to the analysis of Abeta, FRET-FCS detected oligomers consisting of less than 10 Abeta molecules, which coexisted with the monomers at fractions as low as 2 +/- 2%. Thus, we demonstrate for the first time direct detection of small fractions of Abeta oligomers in solution at physiological concentrations. This ability of FRET-FCS could be an indispensable tool for studying biological oligomerization processes, in general, and for finding therapeutically useful oligomerization inhibitors. PMID- 26489795 TI - Appropriate conditions for applying NaOH-pretreated two-phase olive milling waste for codigestion with food waste to enhance biogas production. AB - The high methane gas production potential of two phase olive milling waste (2POMW) makes its application to biogas plants in business an economical process to increase the productivity of the plants. The objective of this study was to investigate the appropriate conditions for the codigestion of NaOH-pretreated 2POMW with food waste. NaOH pretreatment can increase the methane production by increasing the soluble chemical oxygen demand (sCOD), but it may cause inhibition because of higher levels of alkalinity, sodium ion, volatile fatty acids and long chain fatty acids (LCFAs). Therefore, the first experimental phase of this study aimed to investigate the effect of different mixing ratios of 2POMW to food waste. A continuous stirred tank reactor experiment with different mixing ratios of 3%, 4.3%, 5.7% and 8.3% (2POMW: food waste) was conducted. NaOH pretreatment in the range of 6-20% was used. A mixing ratio up to 4.3%, when 10% NaOH pretreatment was used, caused no inhibition and increased methane production by 445.9mL/g-VS(2POMW). For this mixing ratio an additional experimental phase was conducted with the 20% NaOH pretreatment as the 20% NaOH pretreatment had the highest sCOD. The methane gas production was increased by 503.6mL/g-VS(2POMW). However, pH adjustment was required for applying this concentration of the high alkalinity 20% NaOH-pretreated 2POMW. Therefore, we consider using 10% NaOH pretreatment in a mixing ratio of 4.3% to be more applicable. The increase in methane gas production was correlated to the oleic acid concentration inside the reactors. The high oleic acid concentration of 61.8mg/L for the 8.3% mixing ratio was responsible for the strong inhibition. This study showed that adjusting the appropriate mixing ratio of the NaOH-pretreated 2POMW could increase the electricity production of a reactor that regularly receives food waste. PMID- 26489796 TI - Changes in microbial dynamics during vermicomposting of fresh and composted sewage sludge. AB - Municipal sewage sludge is a waste with high organic load generated in large quantities that can be treated by biodegradation techniques to reduce its risk to the environment. This research studies vermicomposting and vermicomposting after composting of sewage sludge with the earthworm specie Eisenia andrei. In order to determine the effect that earthworms cause on the microbial dynamics depending on the treatment, the structure and activity of the microbial community was assessed using phospholipid fatty acid analysis and enzyme activities, during 112days of vermicomposting of fresh and composted sewage sludge, with and without earthworms. The presence of earthworms significantly reduced microbial biomass and all microbial groups (Gram+ bacteria, Gram- bacteria and fungi), as well as cellulase and alkaline phosphatase activities. Combined composting vermicomposting treatment showed a lesser development of earthworms, higher bacterial and fungal biomass than vermicomposting treatment and greater differences, compared with the control without earthworms, in cellulase, beta glucosidase, alkaline and acid phosphatase. Both treatments were suitable for the stabilization of municipal sewage sludge and the combined composting vermicomposting treatment can be a viable process for maturation of fresh compost. PMID- 26489797 TI - New insights into the photodissociation of methyl iodide at 193 nm: stereodynamics and product branching ratios. AB - The stereodynamics of methyl iodide photodissociation after excitation at 193 nm has been studied using a combination of slice imaging and resonance enhanced multiphoton ionization (REMPI) detection of the methyl and iodine products. A weak anisotropic ring appearing in the image corresponding to vibrationally excited CH3(nu1 = 1) confirms the production of ground state I((2)P3/2) atoms at this excitation wavelength as a signature of the predissociation channel reported previously [M. G. Gonzalez et al., J. Chem. Phys., 2011, 135, 021102] tentatively assigned to the coupling between the B-band (3)R1 Rydberg state and the A-band (1)Q1 repulsive state. Direct REMPI detection of ground state iodine atoms indicates that most of the I((2)P3/2) species are produced in correlation with highly internally excited methyl radicals, in excellent agreement with the recent results of Xu and Pratt [Xu et al., J. Chem. Phys., 2013, 139, 214310; Xu et al., J. Phys. Chem. A, 2015, 119, 7548]. From the comparison between the CH3(nu) second order Dixon's bipolar moments beta(2)(0)(20), beta(0)(0)(22), beta(2)(0)(02) and beta(2)(0)(22) measured in this work and those reported previously for the B-band origin and the A-band, a general picture of the CH3I photodissociation stereodynamics in terms of different effects, such as the breakdown of the unique recoil direction (URD) approximation, the non-adiabatic curve crossings and the depolarization induced by the parent molecule rotation, is drawn. PMID- 26489799 TI - Social Anxiety and Loneliness in Adults Who Solicit Minors Online. AB - This study examined the association of social anxiety, loneliness, and problematic Internet use (PIU) with the online solicitation of minors. Within a convenience sample of adult Internet users from Germany, Finland, and Sweden ( N = 2,828), we compared the responses of participants who had not interacted sexually with strangers online ( n = 2,049) with participants who sexually interacted with unknown adults online ( n = 642), and both groups with adults who sexually solicited unknown minors online ( n = 137). Online sexual interaction with adults was associated with higher levels of social anxiety, loneliness, and PIU compared with not sexually interacting with strangers online. Sexually soliciting minors online was associated with higher levels of social anxiety, loneliness, and PIU compared with sexually interacting with adults and not sexually interacting with strangers at all. Interestingly, compared with those with adult contacts, loneliness was specifically pronounced for participants who solicited children, whereas social anxiety and PIU were pronounced for participants soliciting adolescents. These findings suggest that social anxiety, loneliness, and PIU may be among the motivators for using the Internet to solicit individuals of different age groups for sexual purposes. These factors emerged as specifically relevant for adults who sexually solicited minors and who reported greater impairments compared with adults who sexually interacted with adults. These characteristics may thus be important to consider for assessment and treatment procedures for individuals soliciting minors online. PMID- 26489800 TI - Volunteers in Circles of Support and Accountability Job Demands, Job Resources, and Outcome. AB - In Circles of Support and Accountability (CoSA), volunteers support a medium- to high-risk sex offender in his process toward desistance by developing a long-term empathic relationship. More knowledge is needed about the impact of this work on volunteers themselves. In a sample of 40 Dutch CoSA volunteers-at the time constituting 37% of the national population of 108 then active CoSA volunteers-we measured outcome in terms of volunteer satisfaction, determination to continue, compassion satisfaction, burnout and secondary stress, vicarious growth, civic capacities, and professional skills. We explored theoretically derived predictors of positive and negative outcome, and conceptualized them within the Job Demands Resources model (JD-R). Volunteers reported mainly positive effects, especially high levels of volunteer satisfaction, compassion satisfaction, and determination to continue. Results indicated that job demands and most of the internal job resources were of minor importance. External job resources, especially social support and connectedness, were associated with positive outcome. Connectedness mediated the effect of social support on compassion satisfaction. PMID- 26489798 TI - Role of the single deaminase domain APOBEC3A in virus restriction, retrotransposition, DNA damage and cancer. AB - The apolipoprotein mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) proteins are a family of seven cytidine deaminases (A3A, A3B, A3C, A3D, A3F, A3G and A3H) that restrict certain viral infections. These innate defence factors are best known for their ability to restrict the replication of human immunodeficiency virus type 1 (HIV-1) lacking a functional Vif protein (HIV 1Deltavif) through the deamination of cytidine residues to uridines during reverse transcription, ultimately leading to lethal G -> A changes in the viral genome. The best studied of the A3 proteins has been APOBEC3G because of its potent activity against HIV-1Deltavif. However, one member of this family, A3A, has biological properties that make it unique among the A3 proteins. In this review, we will focus on the structural and phylogenetic features of the human and non-human primate A3A proteins, their role in the restriction of retroviruses and other viruses, and current findings on other biological properties affected by this protein. PMID- 26489801 TI - Large-scale data reporting of paediatric morbidity and mortality in developing countries: it can be done. AB - Although the WHO recommends all countries use International Classification of Diseases (ICD)-10 coding for reporting health data, accurate health facility data are rarely available in developing or low and middle income countries. Compliance with ICD-10 is extremely resource intensive, and the lack of real data seriously undermines evidence-based approaches to improving quality of care and to clinical and public health programme management. We developed a simple tool for the collection of accurate admission and outcome data and implemented it in 16 provincial hospitals in Papua New Guinea over 6 years. The programme was low cost and easy to use by ward clerks and nurses. Over 6 years, it gathered data on the causes of 96,998 admissions of children and 7128 deaths. National reports on child morbidity and mortality were produced each year summarising the incidence and mortality rates for 21 common conditions of children and newborns, and the lessons learned for policy and practice. These data informed the National Policy and Plan for Child Health, triggered the implementation of a process of clinical quality improvement and other interventions to reduce mortality in the neediest areas, focusing on diseases with the highest burdens. It is possible to collect large-scale data on paediatric morbidity and mortality, to be used locally by health workers who gather it, and nationally for improving policy and practice, even in very resource-limited settings where ICD-10 coding systems such as those that exist in some high-income countries are not feasible or affordable. PMID- 26489802 TI - Optimising adherence to childhood pneumonia treatment: the design and development of patient instructions and a job aid for amoxicillin dispersible tablets. AB - INTRODUCTION: Pneumonia is the leading cause of death from infection in children worldwide. Despite global treatment recommendations that call for children with pneumonia to receive amoxicillin dispersible tablets, only one-third of children with pneumonia receive any antibiotics and many do not complete the full course of treatment. Poor adherence to antibiotics may be driven in part by a lack of user-friendly treatment instructions. OBJECTIVE: In order to optimise childhood pneumonia treatment adherence at the community level, we developed a user friendly product presentation for caregivers and a job aid for healthcare providers (HCPs). This paper aims to document the development process and offers a model for future health communication tools. METHODS: We employed an iterative design process that included document review, key stakeholder interviews, engagement with a graphic designer and pre-testing design concepts among target users in India and Kenya. The consolidated criteria for reporting qualitative research were used in the description of results. RESULTS: Though resources for pneumonia treatment are available in some countries, their content is incomplete and inconsistent with global recommendations. Document review and stakeholder interviews provided the information necessary to convey to caregivers and recommendations for how to present this information. Target users in India and Kenya confirmed the need to support better treatment adherence, recommended specific modifications to design concepts and suggested the development of a companion job aid. There was a consensus among caregivers and HCPs that these tools would be helpful and improve adherence behaviours. CONCLUSIONS: The development of user-friendly instructions for medications for use in low-resource settings is a critically important but time-intensive and resource-intensive process that should involve engagement with target audiences. PMID- 26489803 TI - Trauma-related Pott's puffy tumour. PMID- 26489805 TI - Left Ventricular Hypertrophy in Asymptomatic Nonsevere Aortic Stenosis: Should We Worry? PMID- 26489804 TI - Relation of Left Ventricular Mass to Prognosis in Initially Asymptomatic Mild to Moderate Aortic Valve Stenosis. AB - BACKGROUND: The prognostic importance of left ventricular (LV) mass in nonsevere asymptomatic aortic stenosis has not been documented in a large prospective study. METHODS AND RESULTS: Cox regression analysis was used to assess the impact of echocardiographic LV mass on rate of major cardiovascular events in 1656 patients (mean age, 67 years; 39.6% women) with mild-to-moderate asymptomatic aortic stenosis participating in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study. Patients were followed during 4.3 years of randomized treatment with combined simvastatin 40 mg and ezetimibe 10 mg daily or placebo. At baseline, LV mass index was 45.9+14.9 g/m(2.7), and peak aortic jet velocity was 3.09+0.54 m/s. During follow-up, 558 major cardiovascular events occurred. In Cox regression analyses, 1 SD (15 g/m(2.7)) higher baseline LV mass index predicted increases in hazards of 12% for major cardiovascular events, 28% for ischemic cardiovascular events, 34% for cardiovascular mortality, and 23% for combined total mortality and hospitalization for heart failure (all P<0.01), independent of confounders. In time-varying models, taking the progressive increase in LV mass index during follow-up into account, 1 SD higher in-study LV mass index was consistently associated with 13% to 61% higher hazard for cardiovascular events (all P<0.01), independent of age, sex, body mass index, valvuloarterial impedance, LV ejection fraction and concentricity, and the presence of concomitant hypertension. CONCLUSIONS: Higher LV mass index is independently associated with increased cardiovascular morbidity and mortality during progression of aortic stenosis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677. PMID- 26489807 TI - Preventing new-onset diabetes in thiazide-treated patients. PMID- 26489806 TI - Cognitive rehabilitation in a child with Joubert Syndrome: Developmental trends and adaptive changes in a single case report. AB - We report the clinical and rehabilitative follow up of M, a female child carrying a compound heterozygous pathogenic mutations in the TCTN1 gene and affected by Joubert Syndrome (JS). JS is a congenital cerebellar ataxia characterized by "the molar tooth sign" on axial MRI, a pathognomonic neuroradiological malformation involving the cerebellum and brainstem. JS presents with high phenotypic/cognitive variability, and little is known about cognitive rehabilitation programs. We describe the therapeutic settings, intensive rehabilitation targets and outcome indexes in M's cognitive development. Using a single case evidence-based approach, we attempt to distinguish the effectiveness of the intervention from the overall developmental trend. We assume that an adequate amount of focused, goal directed treatment in a relative short period of time can be at least as effective as one provided in longer time, and much less interfering with the child's everyday life. We conclude by discussing specific issues in cognitive development and rehabilitation in JS and, more broadly, in cerebellar malformations. PMID- 26489808 TI - Type 2 diabetes in migrant south Asians: mechanisms, mitigation, and management. AB - South Asians, particularly when living in high-income countries, are at a substantially elevated risk of type 2 diabetes compared with white Europeans, and typically develop the disease 5-10 years earlier and at a lower BMI. Migrant south Asians seem to be more insulin resistant than white Europeans across the life course and potentially experience beta-cell exhaustion at a younger age. Differences in adiposity (high percentage of body fat and high proportion of deep subcutaneous and visceral fat) and skeletal muscle (low percentage of lean mass and low cardiorespiratory fitness) are likely to contribute these factors. No clear evidence is available suggesting genetic factors make a major contribution to the increased risk of diabetes in south Asians, but epigenetic factors might have a role. Irrespective of future mechanistic discoveries, south Asians need to be encouraged and helped-by various culturally appropriate methods--to maintain a high physical activity level and low bodyweight across the life course to prevent diabetes. In clinical terms, cardiovascular risks have attenuated over time in migrant south Asians with diabetes but retinopathy and renal complication risks remain high because of the high levels of glycaemia and rapid glycaemic deterioration noted in this population. We review these aspects and suggest areas for future research. PMID- 26489810 TI - Some advances in the field of physico-chemical characterization of pathological microcrystals. AB - Recent advances in the characterization of microcrystals in tissue samples based on physico-chemical techniques are reviewed. It is a new opportunity for the physician to access early a diagnosis of rare but severe pathologies and to start a specific therapy able to delay or to stop an irreversible alteration of the organ, for example to avoid dialysis and transplantation when kidney is mainly affected. To date, more than 400 biopsies of kidneys containing crystals were performed and characterized using such techniques. The data collected on crystals, tissue alteration, clinical and biological investigations are of prime importance to help a better understanding of biochemical process involved in crystal formation. Such techniques may be applied to microcrystalline pathologies affecting other organs than kidney, namely prostate, pancreas, thyroid, breast... Multicentric and international collaborations were developed, thus offering new opportunities in studying pathophysiology of deposited microcrystals and their consequences. In fact, crystals may be the consequence of various pathologies, but they are also involved in the dysfunction of the tissue where they accumulate. Two techniques are mainly applied to such diagnosis: scanning electron microscopy and Fourier transform infrared spectroscopy, including synchrotron radiation infrared microspectroscopy. PMID- 26489811 TI - Pitfalls in the biological diagnosis of common hemoglobin disorders. AB - In West-European countries, hemoglobin disorders are no more rare diseases. Programs for diagnosis of heterozygous carriers have been established to prevent cases with major sickle cell disease or thalassemias. These studies have been done essentially by high performance liquid chromatography on cation-exchange columns and electrophoresis (mostly capillary electrophoresis). They have been done through systematic population studies or premarital diagnosis. We describe in this work the frequent or rare pitfalls encountered, which led to false negative or positive diagnosis both in the field of sickle cell disease and thalassemias. In the absence of a well identified hemoglobin disorder in the proband's family, it is a rule that the use of a single test is insufficient to identify formally HbS. The presence of HbS could also be masked by another hemoglobin abnormality. The sole measurement of HbA2 level is insufficient to characterize a thalassemic trait: this level needs always to be interpreted considering RBC parameters and iron metabolic status. In difficult cases, the definitive answer may require a family study and/or a molecular genetic characterization. PMID- 26489812 TI - Thrombin time and anti-IIa dabigatran's activity: hypothesis of thrombin time's predictive value. AB - Dabigatran etexilate (Pradaxa(r)) is a new oral anticoagulant, competitive inhibitor, selective, fast, direct and reversible of thrombin. Dabigatran has an impact on a large panel of used coagulation tests. There is no relationship between thrombin time's lengthening and anti-IIa activity. This study defines thrombin time's predictive value, when its time is normal. The result of negative value is 97,6%. 255 patients were studied between January 2013 and July 2014. Thrombin time and anti-IIa activity were dosed for each patient. This study can be an assistant for therapeutic decision for laboratories without specialized test. PMID- 26489809 TI - Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial. AB - BACKGROUND: Potassium depletion by thiazide diuretics is associated with a rise in blood glucose. We assessed whether addition or substitution of a potassium sparing diuretic, amiloride, to treatment with a thiazide can prevent glucose intolerance and improve blood pressure control. METHODS: We did a parallel-group, randomised, double-blind trial in 11 secondary and two primary care sites in the UK. Eligible patients were aged 18-80 years; had clinic systolic blood pressure of 140 mm Hg or higher and home systolic blood pressure of 130 mmHg or higher on permitted background drugs of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta blockers, calcium-channel blockers, or direct renin inhibitors (previously untreated patients were also eligible in specific circumstances); and had at least one component of the metabolic syndrome in addition to hypertension. Patients with known diabetes were excluded. Patients were randomly assigned (1:1:1) to 24 weeks of daily oral treatment with starting doses of 10 mg amiloride, 25 mg hydrochlorothiazide, or 5 mg amiloride plus 12.5 mg hydrochlorothiazide; all doses were doubled after 12 weeks. Random assignment was done via a central computer system. Both participants and investigators were masked to assignment. Our hierarchical primary endpoints, assessed on a modified intention-to-treat basis at 12 and 24 weeks, were the differences from baseline in blood glucose measured 2 h after a 75 g oral glucose tolerance test (OGTT), compared first between the hydrochlorothiazide and amiloride groups, and then between the hydrochlorothiazide and combination groups. A key secondary endpoint was change in home systolic blood pressure at 12 and 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862, and the MHRA, Eudract number 2009-010068-41, and is now complete. FINDINGS: Between Nov 18, 2009, and Dec 15, 2014, 145 patients were randomly assigned to amiloride, 146 to hydrochlorothiazide, and 150 to the combination group. 132 participants in the amiloride group, 134 in the hydrochlorothiazide group, and 133 in the combination group were included in the modified intention-to-treat analysis. 2 h glucose concentrations after OGTT, averaged at 12 and 24 weeks, were significantly lower in the amiloride group than in the hydrochlorothiazide group (mean difference 0.55 mmol/L [95% CI -0.96 to -0.14]; p=0.0093) and in the combination group than in the hydrochlorothiazide group (-0.42 mmol/L [-0.84 to -0.004]; p=0.048). The mean reduction in home systolic blood pressure during 24 weeks did not differ significantly between the amiloride and hydrochlorothiazide groups, but the fall in blood pressure in the combination group was significantly greater than that in the hydrochlorothiazide group (p=0.0068). Hyperkalaemia was reported in seven (4.8%) patients in the amiloride group and three (2.3%) patients in the combination group; the highest recorded potassium concentration was 5.8 mmol/L in a patient in the amiloride group. 13 serious adverse events occurred but the frequency did not differ significantly between groups. INTERPRETATION: The combination of amiloride with hydrochlorothiazide, at doses equipotent on blood pressure, prevents glucose intolerance and improves control of blood pressure compared with montherapy with either drug. These findings, together with previous data about morbidity and mortality for the combination, support first-line use of amiloride plus hydrochlorothiazide in hypertensive patients who need treatment with a diuretic. FUNDING: British Heart Foundation and National Institute for Health Research. PMID- 26489813 TI - Fragmented red cells reference range (Sysmex XN((r)) automated blood cell counter). AB - Fragmented red cells (FRCs) is a new parameter automatedly determined by recent blood cell counters. Their count might be of interest because FRCs are supposed to reflect schistocytes counts measured on a stained peripheral blood smear observed under the microscope. But FRCs depend from the technical procedure used to detect them and thus reference ranges are device-dependent. The XN-9000((r)) is one of the last model from Sysmex series. We aimed to establish reference range for FRCs, from 2389 controls. The mean +/- SD was 0.32% +/- 0.81, the median 0.02% (95% confidence interval ot the mean: 0.29-0.35%). We observed that the percentage of red blood cells with less than 17 pg of hemoglobin content (Hypo-He) was correlated to FRC increase, Hypo-He increase resulting in spurious FRCs majoration. FRCs reference range should be useful for: 1) laboratory staff in order to select which blood smears to check optically; 2) Sysmex company to set-up more optimal rules proposed with the counter (automated making of blood smear). PMID- 26489814 TI - Association study between some renin-angiotensin system gene variants and essential hypertension in a sample of Algerian population: case control study. AB - Essential hypertension is an important risk factor for the development of cardiovascular disease. We aim in this study to analyse the relationship between AGT M235T gene variant and ACE I/D gene variant with essential hypertension in a sample of the Algerian population of the Oran city. A case-control study has been performed in 145 subjects including; 75 hypertensives and 70 controls from Algerian population of Oran city. Polymerase chain reaction (PCR) combined with restrictive fragment length polymorphism (RFLP) was used to detect the M235T variant of angiotensinogen (AGT) gene and a nested PCR to determine ACE I/D gene variant. The genotypic and allelic distribution of the M235Tvariant of the AGT gene did not differ in hypertensives and normotensives group (X(2) =7.81, P<0.05; X(2) =4.67, respectively) thus there was no association between the T allele and hypertension (OR=1.64; 95%CI [1.01-2.69]). The genotypic and allelic frequencies of the ACE I/D variant did differ significantly between hypertensives and controls (X(2)=13.98, P<0.05; X(2) =12.66, P<0.05, respectively) where a significant association between the D allele of the ACE I/D gene and essential hypertension has been observed (OR=0.46; 95%CI [0.27-0.75]). We reported a high prevalence of the D and T allele in hypertensives female. This study shows that the M235T variant of the AGT gene is not associated with essential hypertension while a significant association has been reported with the D allele in this sample of Algerian population of the Oran city. PMID- 26489815 TI - 6(th) International symposium " Critical care testing and blood gases ". PMID- 26489816 TI - A case of hypercalcemia Indications for 1,25-dihydroxyvitamin D prescription. AB - Circulating vitamin D is found in various forms: 25-hydroxyvitamin D or calcidiol, majority circulating form, is a "pro-hormon" which will be converted to 1,25-dihydroxyvitamin D or calcitriol, hormone corresponding to vitamin D active form. While determination of 25-hydroxyvitamin D serum levels reflects vitamin D status of patients, determination of 1,25-dihydroxyvitamin D serum level is only indicated in rare cases of suspected hypersensitivity vitamin D in children or of sarcoidosis in adults. There are too many confusion between these two vitamin forms, resulting in inappropriate prescription of 1,25 dihydroxyvitamin D. Here, we describe a case of hypersensitivity to vitamin D by mutation of CYP24A1. We propose to review the interest of 1,25-dihydroxyvitamin D assay in different pathologies, to describe the assay techniques and remind the good prescribing practices of this parameter. PMID- 26489817 TI - Type I hyperlipidaemia caused by lipoprotein lipase deficiency in a nurseling: the role of the clinical laboratory in processing biological samples and contributing to the diagnosis and therapeutic follow-up of patients. AB - We describe the case of a two-months-old nurseling admitted to the paediatric emergency unit for vomiting. Upon clinical examination, the paediatrician found the child pale with an alteration of the general condition, a tachycardia and severe hepatomegaly. Blood sampling revealed hyperlipasemia at 228 IU/L and lactescent plasma, prompting the biologist to complete the prescription by lipid profile analysis. Severe hypertriglyceridaemia peaking at 47 mmol/L was then identified. The hypothesis of acute pancreatitis due to familial chylomicronaemia was proposed. The diagnosis of type I hyperlipidaemia due to complete lipoprotein lipase deficiency was later confirmed by the molecular genetic identification of a homozygous mutation in the LPL gene encoding the enzyme. This disease is extremely rare, and occurrence of first clinical symptoms before one year of age is possible although exceptional. The treatment, including digestive rest and parenteral nutrition, allowed rapid improvement of the acute episode and long term dietary management prevented recurrent acute pancreatitis. In addition to the importance of clinical and laboratory cooperation, this case report provides an opportunity for discussing the analytical interferences and pre-analytical procedures involved in the exploration of biological parameters in hyperlipaemic plasma. PMID- 26489818 TI - Pyrimidine 5'-nucleotidase deficiency associated to a polymalformative syndrome. AB - A pyrimidine 5'-nucleotidase deficiency in an adult is reported. Interestingly, the P5'N-1 deficiency was associated to a polymalformative syndrome and was characterized by a chronic, pancytopenic evolution with concomitant dyserythropoiesis. PMID- 26489819 TI - Female hypofertility: collaboration between clinician and biologist. AB - Hypofertility is defined as the absence of conception after one year of trying. Women's exploration needs biologist attendance for the ovarian reserve evaluation and radiologist attendance for the exploration of the uterus, the fallopian tubes and the ovary. The management of women's treatment as ovarian stimulation combine hormonal levels and transvaginal ultrasonography during all the treatment. The collaboration between clinician and biologist is necessary for the diagnosis and during women's infertily treatment. PMID- 26489820 TI - Molecular dynamics insights into human aquaporin 2 water channel. AB - In this study, the first molecular dynamics simulation of the human aquaporin 2 is performed and for a better understanding of the aquaporin 2 permeability performance, the characteristics of water transport in this protein channel and key biophysical parameters of AQP2 tetramer including osmotic and diffusive permeability constants and the pore radius are investigated. For this purpose, recently recovered high resolution X-ray crystal structure of' the human aquaporin 2 is used to perform twenty nanosecond molecular dynamics simulation of fully hydrated tetramer of this protein embedded in a lipid bilayer. The resulting water permeability characteristics of this protein channel showed that the water permeability of the human AQP2 is in a mean range in comparison with other human aquaporins family. Finally, the results reported in this research demonstrate that molecular dynamics simulation of human AQP2 provided useful insights into the mechanisms of water permeation and urine concentration in the human kidney. PMID- 26489821 TI - Electrocardiographic detection of pulmonary hypertension in patients with systemic sclerosis using the ventricular gradient. AB - BACKGROUND: Pulmonary hypertension (PH) is a leading cause of death in systemic sclerosis (SSc) patients. The current study assessed the ability of the ECG derived ventricular gradient (VG-RVPO) to detect PH and predict all-cause mortality in PH patients with subtypes of SSc differing in the extent of multi organ involvement. METHODS: ECGs were obtained from 196 patients with limited and 77 patients with diffuse SSc included from our screening programme on cardiac complications. The association of the VG-RVPO with (1) the presence of PH, (2) conventional screening parameters and (3) survival in PH patients was assessed. RESULTS: In limited SSc patients an elevated VG-RVPO corresponded with the presence of PH (-5+/-12 mV.ms vs -22+/-16 mV.ms, P<0.01), correlated significantly with conventional screening parameters and had a better diagnostic performance than the presence of a right heart axis (AUC 0.81 vs 0.60; P=0.04). These differences were not observed in patients with diffuse SSc. An elevated VG RVPO was associated with decreased survival in all SSc patients with PH (3 year survival 30% vs 64%, P=0.02). CONCLUSION: An elevated VG-RVPO is associated with PH in limited SSc patients and with decreased survival in all SSc patients with PH. PMID- 26489822 TI - Trends in sepsis incidence and outcomes among people with or without type 2 diabetes mellitus in Spain (2008-2012). AB - AIMS: There is conflicting evidence on how type 2 diabetes mellitus (T2DM) influences in-hospital mortality (IHM) in sepsis. We aimed to compare trends in outcomes for sepsis in people with or without T2DM in Spain between 2008 and 2012. METHODS: We identified all cases with any sepsis diagnosis using national hospital discharge data. We evaluated annual incidence rates for sepsis stratified by T2DM status. We calculated IHM and analyzed trends over time. In a multivariate analysis including potential confounding factors, we tested T2DM as an independent factor for IHM. RESULTS: Overall, 217,280 cases of any-stage sepsis were diagnosed, of whom 50,611 (23.3%) had T2DM. The annual incidence of sepsis increased during the 5-year period (from 76.5 to 113.3cases/10(5) population). The incidence increase was higher for the population with T2DM (from 16.8 to 27.1 cases/10(5) population; 61.3% relative increment). People with T2DM were significantly older (75.8 +/- 11.2 years vs. 71.0 +/- 16.4 years) and suffered from more coexisting medical conditions. In the univariate analysis, mortality was higher for the population with T2DM only when septic shock was present (53.3% vs. 51.9%; P=0.002). IHM decreased over time both in participants with (from 45.7% to 38.1%) and without T2DM (from 46.1% to 39.5%). After accounting for all other potential confounders, T2DM was significantly associated with a lower IHM (odds ratio=0.88; 95% confidence interval, 0.86-0.90). CONCLUSIONS: In Spain, the annual increase in sepsis incidence was higher in people with T2DM, but the risk of dying with sepsis during admission was moderately lower in people with T2DM. PMID- 26489823 TI - Women with a history of gestational diabetes on long-term follow up have normal vascular function despite more dysglycemia, dyslipidemia and adiposity. AB - AIMS: Previous gestational diabetes (GDM) is a risk factor for type 2 diabetes and increased metabolic risk, but the link with vascular dysfunction is not clear. This study examined vascular function in women 4-10 years after a diagnosis of GDM who had a normal oral glucose tolerance test (OGTT) in the first postpartum year. METHODS: We studied 90 women with a history of GDM and 59 age matched controls, examining differences in insulin resistance as measured by the Homeostatic Model Assessment (HOMA-IR) and glucose responses during an OGTT, adiposity, lipid profile and C-reactive protein (CRP). Using pulse wave analysis, we also measured cardiac function, vascular compliance, and systemic vascular resistance. RESULTS: Women with a history of GDM had higher measures of adiposity (body mass index 28.9 +/- 6.5 vs. 26.6 +/- 6.9 kg/m(2), P=0.04, waist-hip ratio 0.85 +/- 0.06 vs. 0.79 +/- 0.07, P<0.001), dyslipidemia (LDL cholesterol 2.78 +/- 0.64 vs. 2.41 +/- 0.56 mmol/L, P<0.001, total cholesterol: HDL cholesterol 3.93 +/- 1.2 vs. 3.21 +/- 0.82 mmol/L, P<0.001) and abnormal glucose metabolism (50% vs. 12%, P<0.001). However, there was no difference in CRP, HOMA-IR, or measures of cardiovascular function including pulse rate, pulse pressure, mean arterial pressure, cardiac output, systemic vascular resistance, small and large artery elasticity index. After controlling for adiposity, blood pressure, lipids and CRP, glycemic status did not contribute to vascular function. CONCLUSION: Despite a higher incidence of adiposity, dyslipidemia, and impaired glycemia, women with a history of GDM who had a normal postpartum OGTT did not have impaired vascular function 4-10 years postpartum, when compared to healthy controls. PMID- 26489824 TI - Higher insulin infusion rate but not 24-h insulin consumption is associated with hypoglycemia in critically ill patients. AB - AIMS: To assess the association between insulin infusion rates, and 24-h insulin consumption on hypoglycemia in the intensive care unit (ICU). METHODS: This was a retrospective case-control study, conducted at an academic institution in the United States. Adult patients admitted to the ICU receiving intravenous insulin infusions for blood glucose control were included. Hypoglycemic (blood glucose <70 mg/dL) patients were matched 1:1 with non-hypoglycemic controls based on age, gender, and body mass index. Multivariable conditional logistic regression analyses were conducted to determine the effect of: (1) weight-adjusted insulin infusion rate (units/kg/h), (2) non-weight-adjusted insulin infusion rate (units/h), or (3) 24-h insulin consumption (units/day) on hypoglycemia. RESULTS: A total of 122 patients were included in the study (61 cases, 61 controls). Compared to those patients who received <0.05 units/kg/h, the odds of hypoglycemia was higher in those who received was >=0.1 units/kg/h (OR 4.57, 95% CI 1.45-14.41, p=0.010). Compared to those patients who received <4 units/h, the odds of hypoglycemia was higher in those who received was >=8 units/h (4.17, 95% CI 1.18-14.75, p=0.027). The risk of hypoglycemia did not increase with higher 24 h insulin consumption. CONCLUSIONS: Higher insulin infusion rates rather than 24 h insulin consumption may be associated with hypoglycemia in critically ill patients in the ICU. PMID- 26489825 TI - [Congenital hip dysplasia, screening and therapy]. AB - Congenital hip dysplasia and hip dislocation are relatively common pathological conditions of the musculoskeletal system in infants. An early and certain diagnosis can now be achieved by sonographic hip screening within the framework of screening examination programs. This early diagnostic procedure in infants is essential particularly for a conservative treatment strategy. Therefore, apart from possessing in-depth knowledge, training of the examiner in specialist courses is of central importance. This article presents an overview of the entity of congenital hip dysplasia and hip dislocation, the diagnostics and treatment with special emphasis on recent developments. PMID- 26489826 TI - Estimation of dietary flavonoid intake and major food sources of Korean adults. AB - Epidemiological studies have suggested that flavonoids exhibit preventive effects on degenerative diseases. However, lack of sufficient data on flavonoid intake has limited evaluating the proposed effects in populations. Therefore, we aimed to estimate the total and individual flavonoid intakes among Korean adults and determine the major dietary sources of these flavonoids. We constructed a flavonoid database of common Korean foods, based on the food list reported in the 24-h recall of the Korea National Health and Nutrition Examination Survey (KNHANES) 2007-2012, using data from the Korea Functional Food Composition Table, US Department of Agriculture flavonoid database, Phenol-Explorer database and other analytical studies. This database, which covers 49 % of food items and 76 % of food intake, was linked with the 24-h recall data of 33 581 subjects aged >=19 years in the KNHANES 2007-2012. The mean daily intake of total flavonoids in Korean adults was 318.0 mg/d, from proanthocyanidins (22.3%), flavonols (20.3%), isoflavones (18.1%), flavan-3-ols (16.2%), anthocyanidins (11.6%), flavanones (11.3%) and flavones (0.3%). The major contributing food groups to the flavonoid intake were fruits (54.4%), vegetables (20.5%), legumes and legume products (16.2%) and beverages and alcohols (3.1%), and the major contributing food items were apples (21.9%), mandarins (12.5%), tofu (11.5%), onions (9.6%) and grapes (9.0%). In the regression analysis, the consumption of legumes and legume products, vegetables and fruits predicted total flavonoid intake the most. The findings of this study could facilitate further investigation on the health benefits of flavonoids and provide the basic information for establishing recommended flavonoid intakes for Koreans. PMID- 26489827 TI - Nonclinical Safety and Toxicology. AB - Nonclinical safety pharmacology and toxicology testing of drug candidates assess the potential adverse effects caused by the drug in relation to its intended use in humans. Hazards related to a drug have to be identified and the potential risks at the intended exposure have to be evaluated in comparison to the potential benefit of the drug. Preclinical safety is thus an integral part of drug discovery and drug development. It still causes significant attrition during drug development.Therefore, there is a need for smart selection of drug candidates in drug discovery including screening of important safety endpoints. In the recent years,there was significant progress in computational and in vitro technology allowing in silico assessment as well as high-throughput screening of some endpoints at very early stages of discovery. Despite all this progress, in vivo evaluation of drug candidates is still an important part to safety testing. The chapter provides an overview on the most important areas of nonclinical safety screening during drug discovery of small molecules. PMID- 26489828 TI - New Compound Classes: Protein-Protein Interactions. AB - "Protein-protein interactions (PPIs) are one of the most promising new targets in drug discovery. With estimates between 300,000 and 650,000 in human physiology, targeted modulation of PPIs would tremendously extend the "druggable" genome. In fact, in every disease a wealth of potentially addressable PPIs can be found making pharmacological intervention based on PPI modulators in principle a generally applicable technology. An impressing number of success stories in small molecule PPI inhibition and natural-product PPI stabilization increasingly encourage academia and industry to invest in PPI modulation. In this chapter examples of both inhibition as well as stabilization of PPIs are reviewed including some of the technologies which has been used for their identification." PMID- 26489829 TI - Predictive In Vivo Models for Oncology. AB - Experimental oncology research and preclinical drug development both substantially require specific, clinically relevant in vitro and in vivo tumor models. The increasing knowledge about the heterogeneity of cancer requested a substantial restructuring of the test systems for the different stages of development. To be able to cope with the complexity of the disease, larger panels of patient-derived tumor models have to be implemented and extensively characterized. Together with individual genetically engineered tumor models and supported by core functions for expression profiling and data analysis, an integrated discovery process has been generated for predictive and personalized drug development.Improved "humanized" mouse models should help to overcome current limitations given by xenogeneic barrier between humans and mice. Establishment of a functional human immune system and a corresponding human microenvironment in laboratory animals will strongly support further research.Drug discovery, systems biology, and translational research are moving closer together to address all the new hallmarks of cancer, increase the success rate of drug development, and increase the predictive value of preclinical models. PMID- 26489830 TI - Genome-wide survey of two-component signal transduction systems in the plant growth-promoting bacterium Azospirillum. AB - BACKGROUND: Two-component systems (TCS) play critical roles in sensing and responding to environmental cues. Azospirillum is a plant growth-promoting rhizobacterium living in the rhizosphere of many important crops. Despite numerous studies about its plant beneficial properties, little is known about how the bacterium senses and responds to its rhizospheric environment. The availability of complete genome sequenced from four Azospirillum strains (A. brasilense Sp245 and CBG 497, A. lipoferum 4B and Azospirillum sp. B510) offers the opportunity to conduct a comprehensive comparative analysis of the TCS gene family. RESULTS: Azospirillum genomes harbour a very large number of genes encoding TCS, and are especially enriched in hybrid histidine kinases (HyHK) genes compared to other plant-associated bacteria of similar genome sizes. We gained further insight into HyHK structure and architecture, revealing an intriguing complexity of these systems. An unusual proportion of TCS genes were orphaned or in complex clusters, and a high proportion of predicted soluble HKs compared to other plant-associated bacteria are reported. Phylogenetic analyses of the transmitter and receiver domains of A. lipoferum 4B HyHK indicate that expansion of this family mainly arose through horizontal gene transfer but also through gene duplications all along the diversification of the Azospirillum genus. By performing a genome-wide comparison of TCS, we unraveled important 'genus-defining' and 'plant-specifying' TCS. CONCLUSIONS: This study shed light on Azospirillum TCS which may confer important regulatory flexibility. Collectively, these findings highlight that Azospirillum genomes have broad potential for adaptation to fluctuating environments. PMID- 26489831 TI - What is required in terms of mass drug administration to interrupt the transmission of schistosome parasites in regions of endemic infection? AB - BACKGROUND: Schistosomiasis is endemic in 54 countries, but has one of the lowest coverages by mass drug administration of all helminth diseases. However, with increasing drug availability through donation, the World Health Organisation has set a goal of increasing coverage to 75 % of at-risk children in endemic countries and elimination in some regions. In this paper, we assess the impact on schistosomiasis of the WHO goals in terms of control and elimination. METHODS: We use an age-structured deterministic model of schistosome transmission in a human community and the effect of mass drug administration. The model is fitted to baseline data from a longitudinal re-infection study in Kenya and validated against the subsequent re-infection data. We examine the impact on host worm burden of the current treatment trend, extrapolated to meet the WHO goals, and its sensitivity to uncertainty in important parameters. We assess the feasibility of achieving elimination. RESULTS: Model results show that the current treatment trend, extrapolated to the WHO goals, is able to greatly reduce host worm burdens. If coverage is continued at the same level beyond 2020, elimination is possible for low to moderate transmission settings, where transmission intensity is defined by the basic reproduction number, R0. Low levels of adult coverage have a significant impact on worm burden in all settings. Model validation against the re-infection survey demonstrates that the age-structured model is able to match post-treatment data well in terms of egg output, but that some details of re-infection among school children and young adults are not currently well represented. CONCLUSIONS: Our work suggests that the current WHO treatment goals should be successful in bringing about a major reduction in schistosome infection in treated communities. If continued over a 15 year period, they are likely to result in elimination, at least in areas with lower transmission. PMID- 26489832 TI - Development of quality indicators and data assessment strategies for the prevention of central venous catheter-related bloodstream infections (CRBSI). AB - BACKGROUND: The number of catheter related bloodstream infections (CRBSI) could be reduced and the outcome improved if specific standards in the quality of care were maintained. Therefore, the development of quality assurance (QA) procedures was commissioned to be included in the national mandatory QA programme in Germany. METHODS: Indicators representing quality deficiencies and potential for improvement of quality in relation to prevention and management of central venous catheters (CVC) were developed by (1) evidence-based literature searches and the compiling of an indicator register; (2) a multi-professional expert panel including patient representatives who selected indicators from this register by using a modified RAND/UCLA Appropriateness Method; (3) defining methods for data assessment, risk adjustment and feedback of indicator results to service providers; and (4) consulting all relevant medical societies and other stakeholders with regard to the QA procedures that had been developed. RESULTS: Thirty-two indicators for CRBSI prevention and management were eventually approved by the expert panel. These indicators represent quality of care at predefined points with regard to indication, insertion and care of CVCs, management of sepsis, general hygiene and training of health care personnel. Fourteen indicators represent processes, together with 7 representing structures and 11 outcomes. For assessing these indicators, data was obtained from four sources: claims data from health insurance funds, routine claims data from hospital electronic information systems, case specific longitudinal documentation from service providers and cross-sectional annual assessment of structures. CONCLUSIONS: It was possible to develop indicators for mandatory QA procedures on CRBSI that take into account the different perspectives of all stakeholders involved. Despite efforts to use routine data for documentation wherever possible, most indicators required extra documentation. PMID- 26489833 TI - Electrophysiologically-Active Maize Volatiles Attract Gravid Female European Corn Borer, Ostrinia nubilalis. AB - The European corn borer (ECB) is an important pest of maize in the northern hemisphere, but no reliable techniques exist for monitoring females during their reproductive period. In this study, we aimed to identify host-plant volatiles used by gravid Z-strain females in search for oviposition sites. Headspace of maize plants, to which gravid females orientated in a wind tunnel, was collected, and physiologically-active components were identified by using gas chromatography (GC) coupled with electroantennographic detection followed by GC-mass spectrometry. The antennae of female moths consistently responded to two maize volatiles, nonanal and decanal. Although these compounds are individually not characteristic for maize, a synthetic mix in a ratio found in maize headspace, 1:2.4 at 1 MUg MUl(-1) induced source contact and landing responses similar to maize plants in the wind tunnel. However, fewer females took flight in response to the mix, and those that took flight did so with an increased latency. To our knowledge, this is the first blend of host-plant volatiles that has been found to be physiologically active and to be able to induce attraction of gravid ECB females under laboratory conditions. Future tests will evaluate the attractiveness of the blend to the E-strain of ECB, the attractiveness of the blend in the field, and its potential in monitoring ECB populations. PMID- 26489834 TI - Characterizing noise structure in single-cell RNA-seq distinguishes genuine from technical stochastic allelic expression. AB - Single-cell RNA-sequencing (scRNA-seq) facilitates identification of new cell types and gene regulatory networks as well as dissection of the kinetics of gene expression and patterns of allele-specific expression. However, to facilitate such analyses, separating biological variability from the high level of technical noise that affects scRNA-seq protocols is vital. Here we describe and validate a generative statistical model that accurately quantifies technical noise with the help of external RNA spike-ins. Applying our approach to investigate stochastic allele-specific expression in individual cells, we demonstrate that a large fraction of stochastic allele-specific expression can be explained by technical noise, especially for lowly and moderately expressed genes: we predict that only 17.8% of stochastic allele-specific expression patterns are attributable to biological noise with the remainder due to technical noise. PMID- 26489835 TI - Postoperative inspiratory muscle training in addition to breathing exercises and early mobilization improves oxygenation in high-risk patients after lung cancer surgery: a randomized controlled trial. AB - OBJECTIVES: The aim was to investigate whether 2 weeks of inspiratory muscle training (IMT) could preserve respiratory muscle strength in high-risk patients referred for pulmonary resection on the suspicion of or confirmed lung cancer. Secondarily, we investigated the effect of the intervention on the incidence of postoperative pulmonary complications. METHODS: The study was a single-centre, parallel-group, randomized trial with assessor blinding and intention-to-treat analysis. The intervention group (IG, n = 34) underwent 2 weeks of postoperative IMT twice daily with 2 * 30 breaths on a target intensity of 30% of maximal inspiratory pressure, in addition to standard postoperative physiotherapy. Standard physiotherapy in the control group (CG, n = 34) consisted of breathing exercises, coughing techniques and early mobilization. We measured respiratory muscle strength (maximal inspiratory/expiratory pressure, MIP/MEP), functional performance (6-min walk test), spirometry and peripheral oxygen saturation (SpO2), assessed the day before surgery and again 3-5 days and 2 weeks postoperatively. Postoperative pulmonary complications were evaluated 2 weeks after surgery. RESULTS: The mean age was 70 +/- 8 years and 57.5% were males. Thoracotomy was performed in 48.5% (n = 33) of cases. No effect of the intervention was found regarding MIP, MEP, lung volumes or functional performance at any time point. The overall incidence of pneumonia was 13% (n = 9), with no significant difference between groups [IG 6% (n = 2), CG 21% (n = 7), P = 0.14]. An improved SpO2 was found in the IG on the third and fourth postoperative days (Day 3: IG 93.8 +/- 3.4 vs CG 91.9 +/- 4.1%, P = 0.058; Day 4: IG 93.5 +/- 3.5 vs CG 91 +/- 3.9%, P = 0.02). We found no association between surgical procedure (thoracotomy versus thoracoscopy) and respiratory muscle strength, which was recovered in both groups 2 weeks after surgery. CONCLUSIONS: Two weeks of additional postoperative IMT, compared with standard physiotherapy alone, did not preserve respiratory muscle strength but improved oxygenation in high-risk patients after lung cancer surgery. Respiratory muscle strength recovered in both groups 2 weeks after surgery. CLINICAL TRIALSGOV ID: NCT01793155. PMID- 26489836 TI - Two giant thoracic aortic aneurysms with thoracic vertebral erosion. PMID- 26489837 TI - Inflammatory response following stent grafting for acute aortic syndrome. PMID- 26489838 TI - Multiscale modelling of single-ventricle hearts for clinical decision support: a Leducq Transatlantic Network of Excellence. PMID- 26489839 TI - Retraction of biased journal articles. PMID- 26489840 TI - A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4 thiadiazine-5-ones inhibits intracellular growth and persistence of Chlamydia trachomatis. AB - Chlamydia trachomatis is one of the most common sexually transmitted pathogens in the world and often causes chronic inflammatory diseases that are insensitive to antibiotics. The type 3 secretion system (T3SS) of pathogenic bacteria is a promising target for therapeutic intervention aimed at bacterial virulence and can be an attractive alternative for the treatment of chronic infections. Recently, we have shown that a small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones produced through the chemical modification of the thiohydrazides of oxamic acids, designated CL-55, inhibited the intracellular growth of C. trachomatis in a T3SS-dependent manner. To assess the feasibility of CL-55 as a therapeutic agent, our aim was to determine which point(s) in the developmental cycle CL-55 affects. We found that CL-55 had no effect on the adhesion of elementary bodies (EBs) to host cells but significantly suppressed EB internalization. We further found that CL-55 inhibited the intracellular division of reticulate bodies (RBs). An ultrastructural analysis revealed loss of contact between the RBs and the inclusion membrane in the presence of CL-55. Finally, we found that our T3SS inhibitor prevented the persistence of Chlamydia in cell culture and its reversion to the infectious state. Our findings indicate that our T3SS inhibitor may be effective in the treatment of both productive and persistent infections. PMID- 26489841 TI - Corrigendum: Quantifying the Antiviral Effect of IFN on HIV-1 Replication in Cell Culture. PMID- 26489842 TI - Enabling or Cultivating? The Role of Prostate Cancer Patients' Received Partner Support and Self-Efficacy in the Maintenance of Pelvic Floor Exercise Following Tumor Surgery. AB - BACKGROUND: To manage incontinence following tumor surgery, prostate cancer patients are advised to perform pelvic floor exercise (PFE). Patients' self efficacy and support from partners were shown to facilitate PFE. Whereas support may enhance self-efficacy (enabling function), self-efficacy may also cultivate support (cultivation function). PURPOSE: Cross-lagged inter-relationships among self-efficacy, support, and PFE were investigated. METHOD: Post-surgery patient reported received support, self-efficacy, PFE, and partner-reported provided support were assessed from 175 couples at four times. Autoregressive models tested interrelations among variables, using either patients' or partners' reports of support. RESULTS: Models using patients' data revealed positive associations between self-efficacy and changes in received support, which predicted increased PFE. Using partners' accounts of support provided, these associations were partially cross-validated. Furthermore, partner-provided support was related with increases in patients' self-efficacy. CONCLUSION: Patients' self-efficacy may cultivate partners' support provision for patients' PFE, whereas evidence of an enabling function of support as a predictor of self efficacy was inconsistent. PMID- 26489843 TI - The Interdependence of Advanced Cancer Patients' and Their Family Caregivers' Mental Health, Physical Health, and Self-Efficacy over Time. AB - BACKGROUND: The challenges of advanced cancer have health implications for patients and their family caregivers from diagnosis through end of life. The nature of the patient/caregiver experience suggests that their mental and physical health maybe interdependent, but limited empirical evidence exists. PURPOSE: This study used social cognitive theory as a framework to investigate individual and interpersonal influences on patients' and their family caregivers' mental health, physical health, and self-efficacy as individuals to manage the challenges of advanced disease over time. METHODS: Patients and caregivers (484 patient-caregiver dyads) completed surveys at baseline, 3 and 6 months. Longitudinal dyadic analysis techniques were used to examine (i)the influence that patients and caregivers had on their own mental health, physical health, and self-efficacy (actor effects)and (ii) the influence that they had on each other's health outcomes (partner effects). We also examined the influence of self efficacy on mental and physical health over time. RESULTS: Consistent with our hypotheses, each person's mental health, physical health, and self-efficacy had significant effects on their own outcomes over time (actor effects). Patients and caregivers influenced one another's mental and physical health (partner effects), but not their self-efficacy. In addition, patients and caregivers with higher self-efficacy had better mental health, and their partners had better physical health. CONCLUSIONS: Patients' and caregivers' mental and physical health were interdependent. Each person's cancer-related self-efficacy influenced their own mental and physical health. However, a person's self-efficacy did not influence the other person's self-efficacy. PMID- 26489844 TI - Discrimination, Racial/Ethnic Identity, and Substance Use Among Latina/os: Are They Gendered? AB - BACKGROUND: Prior research suggests that stronger racial/ethnic identification offsets negative effects of discrimination on substance use. Yet research in this area and on whether gender modifies this association is limited for Latina/os. PURPOSE: The purpose of the present study is to examine whether different sources of discrimination (everyday and racial/ethnic) are associated with substance use (alcohol use disorder, smoking), if racial/ethnic identity buffers this association, and the potential moderating role of gender among these variables. METHODS: We present cross-sectional, US population-based data from the Latina/o adult sample (1427 females and 1127 males) of the National Latino and Asian American Study. Respondents completed self-reported measures of everyday and racial/ethnic discrimination, racial/ethnic identity, smoking status, and Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) lifetime alcohol use disorder. RESULTS: Weighted logistic regression analyses showed that before inclusion of three-way interactions and adjusting for covariates, everyday discrimination predicted increased risk for any DSM-IV lifetime alcohol use disorders. Moderation analyses revealed that the effect of everyday discrimination on the risk of being a current smoker was strongest for Latino men with high levels of racial/ethnic identity compared to those with low racial/ethnic identity. No differences were noted among Latino women. There were no main or interaction effects of racial/ethnic discrimination for any substance use outcome. CONCLUSIONS: Findings suggest differential associations for type of discrimination and outcome and that the role of racial/ethnic identity is gender specific for smoking, appearing particularly detrimental for Latino men reporting high levels of racial/ethnic identity. PMID- 26489846 TI - Spontaneous penetration of gold nanoparticles through the blood brain barrier (BBB). AB - BACKGROUND: The blood brain barrier (BBB) controls the brain microenvironment and limits penetration of the central nervous system (CNS) by chemicals, thus creating an obstacle to many medical imaging and treatment procedures. Research efforts to identify viable routes of BBB penetration have focused on structures such as micelles, polymeric nanoparticles and liposomes as drug carriers, however, many of them failed to provide unequivocal proof of BBB penetration. Here we proved that gold nanoparticles (AuNPs) penetrate the BBB in rats to reach brain regions. RESULTS: Injection of AuNPs to the abdominal cavity of rats resulted in levels of gold found in blood, urine, brain regions and body organs. After perfusion the concentration of gold in brain regions diminished dramatically indicating that most of the gold was in venous blood and not in the brain tissues. Injection of Na, K or Ca ion channel blockers reduced BBB penetration by half. A biological half-life of 12.9 +/- 4.9 h was found for the gold nanoparticles. Possible mechanisms for the transport of AuNPs through the BBB are discussed. CONCLUSIONS: BBB penetration by AuNPs is spontaneous without the application of an external field. A major amount of gold resides in blood vessels therefore perfusion required. Ion channel blockers can be used to control the transport of AuNPs. PMID- 26489847 TI - Filament Geometry Induced Bipolar, Complementary, and Unipolar Resistive Switching under the Same Set Current Compliance in Pt/SiOx/TiN. AB - The decidedly unusual co-occurrence of bipolar, complementary, and unipolar resistive switching (BRS, CRS, and URS, respectively) behavior under the same high set current compliance (set-CC) is discussed on the basis of filament geometry in a Pt/SiOx/TiN stack. Set-CC-dependent scaling behavior with relations Ireset ~ R0(-alpha) and Vreset ~ R0(-beta) differentiates BRS under low set-CC from other switching behaviors under high set-CC due to a low alpha and beta involving a narrow filamentary path. Because such co-occurrence is observed only in the case of a high alpha and beta involving a wide filamentary path, such a path can be classified into three different geometries according to switching behavior in detail. From the cyclic switching and a model simulation, we conclude that the reset of BRS originates from a narrower filamentary path near the top electrode than that of CRS due to the randomness of field-driven migration even under the same set-CC. Also, we conclude that URS originates from much narrower inversed conical filamentary path. Therefore, filament-geometry-dependent electric field and/or thermal effects can precisely describe the entire switching behaviors in this experiment. PMID- 26489845 TI - Prevalence of obesity in panama: some risk factors and associated diseases. AB - BACKGROUND: To estimate the prevalence of obesity in Panama and determine some risk factors and associated diseases in adults aged 18 years and older. METHODS: A cross-sectional descriptive study was conducted in the provinces of Panama and Colon where 60.4 % of all Panamanians 18 years or older reside, by administering a survey regarding the consumption of protective and predisposing foods and assessing the development of obesity by measuring the weight, height, and waist circumference of 3590 people. A single-stage, probabilistic, and randomized sampling strategy employing multivariate stratification was used. Individuals with a body mass index >= 30 kg/m(2) (men and women) were considered obese. Prevalence and descriptive analysis were conducted according to sex using Odds Ratio, with statistical significance set at a p value <= 0.05. RESULTS: The general prevalence of obesity was 27.1 % (30.9 % women and 18.3 % men). In women, obesity was associated with living in urban areas, being 40-59 years of age, being Afro-Panamanian, consuming beverages / foods rich in sugar, being physically inactive and having a family history of obesity. In men, obesity was associated with living in urban areas, consuming beverages/foods rich in sugar, and having a family history of obesity. Almost the totality of obese women (97.9 %), and 80.0 % of men with obesity had abdominal obesity according to the WHO classification. In both sexes, obesity was a risk factor associated to type 2 Diabetes Mellitus, hypertension, LDL values >= 100 mg/dL, and low HDL values (<50 mg/dL for women and < 40 mg/dL for men), Odds Ratio > 1.0; P < 0.05. CONCLUSIONS: Obesity represents a very serious threat to Panamanian public health. Our study confirms a direct association in Panama between excess weight, hypertension, type 2 Diabetes Mellitus, LDL values >= 100 mg/dL and low HDL values for women and men (<50 mg/dL and < 40 mg/dL, respectively). Intervention / treatment programs should be targeted, specially, to Afro-Panamanian women, whom are 40-59 years old, living in urban areas, and those having a family history of obesity. PMID- 26489848 TI - A new Mooney test. AB - Since its introduction in 1957, the Mooney test has continued to see active use in studies of visual perception, in studies using brain imaging, and in clinical research. Mooney's original version is of limited length, however, and was designed to be administered by time-consuming personal interview. We have developed a new, extended version of the Mooney test that is suitable for online testing and for use in a test-retest paradigm. The Mooney-Verhallen Test (MVT) comprises 144 trials, takes on average less than 10 min to complete, and has a Spearman-Brown-corrected test-retest reliability of rho = .89. We outline our methods for developing the stimuli and for selecting the final stimulus set, and we present the results from two rounds of testing on two independent samples of 374 participants and 505 participants, respectively. The test is freely available for scientific use. PMID- 26489849 TI - Sphericity estimation bias for repeated measures designs in simulation studies. AB - In this study, we explored the accuracy of sphericity estimation and analyzed how the sphericity of covariance matrices may be affected when the latter are derived from simulated data. We analyzed the consequences that normal and nonnormal data generated from an unstructured population covariance matrix-with low (epsilon = .57) and high (epsilon = .75) sphericity-can have on the sphericity of the matrix that is fitted to these data. To this end, data were generated for four types of distributions (normal, slightly skewed, moderately skewed, and severely skewed or log-normal), four sample sizes (very small, small, medium, and large), and four values of the within-subjects factor (K = 4, 6, 8, and 10). Normal data were generated using the Cholesky decomposition of the correlation matrix, whereas the Vale-Maurelli method was used to generate nonnormal data. The results indicate the extent to which sphericity is altered by recalculating the covariance matrix on the basis of simulated data. We concluded that bias is greater with spherical covariance matrices, nonnormal distributions, and small sample sizes, and that it increases in line with the value of K. An interaction was also observed between sample size and K: With very small samples, the observed bias was greater as the value of K increased. PMID- 26489850 TI - [Conjunctival melanoma: a systemic disease: Novel surgical and adjuvant therapies]. PMID- 26489851 TI - The role of the Black Church in the lives of young Black men who have sex with men. AB - In the USA, the Black Church is among the most important institutions in the Black community, offering numerous spiritual, social and health benefits. Yet, the presence of homonegativity in many Black Churches may mitigate those effects for gay Black youth. This research examines the role of the Church in the lives of gay and bisexual Black youth to understand how they reconcile any tension between their religious and sexual identities. Through interviews with pastors of Black churches (n = 21) and young Black men who have sex with men (n = 30), we explored homonegativity and young men's experiences within the Black Church. Findings reveal that despite the prevalence of homonegativity within Black churches, religious involvement remains important for young men and many remain involved in non-affirming churches. The importance of the Church for young men stems from their significant involvement as youth and the integration of religion, family and community. Young men may not be able to leave their religious homes as readily as other gay youth given the cultural relevance of the Church. As a result, young men made attempts to conceal their sexuality in church to avoid shame and gossip and find opportunities to balance their sexuality and religiosity. PMID- 26489852 TI - Difficulty accessing data from randomised trials of drugs for heart failure: a call for action. PMID- 26489853 TI - Metabolomics reveals metabolic changes in male reproductive cells exposed to thirdhand smoke. AB - Thirdhand smoke (THS) is a new term for the toxins in cigarette smoke that linger in the environment long after the cigarettes are extinguished. The effects of THS exposure on male reproduction have not yet been studied. In this study, metabolic changes in male germ cell lines (GC-2 and TM-4) were analyzed after THS treatment for 24 h. THS-loaded chromatography paper samples were generated in a laboratory chamber system and extracted in DMEM. At a paper: DMEM ratio of 50 MUg/ml, cell viability in both cell lines was normal, as measured by the MTT assay and markers of cytotoxicity, cell cycle, apoptosis and ROS production were normal as measured by quantitative immunofluorescence. Metabolomic analysis was performed on methanol extracts of GC-2 and TM-4 cells. Glutathione metabolism in GC-2 cells, and nucleic acid and ammonia metabolism in TM-4 cells, was changed significantly by THS treatment. RT-PCR analyses of mRNA for enzyme genes Gss and Ggt in GC-2 cells, and TK, SMS and Glna in TM-4 cells reinforced these findings, showing changes in the levels of enzymes involved in the relevant pathways. In conclusion, exposure to THS at very low concentrations caused distinct metabolic changes in two different types of male reproductive cell lines. PMID- 26489854 TI - Hydrothermal Synthesis of Silver Vanadium Oxide (Ag0.35V2O5) Nanobelts for Sensing Amines. AB - A simple hydrothermal method for the synthesis of Ag0.35V2O5 nanobelts with the assistance of sodium dodecyl sulfate (SDS) is reported in this study. The experimental variables that may affect the nanoparticle structures were investigated. And several advanced techniques, such as TEM, HRTEM, X-ray diffraction (XRD), were used to characterize the morphology and composition of the as-prepared nanobelts. The mechanism of the formation and growth of Ag0.35V2O5 nanobelts was also investigated and discussed. The results show that SDS, as a weak reducing agent, plays a crucial role in the formation of Ag0.35V2O5. According to N2 sorption isothermals, the as-prepared Ag0.35V2O5 nanobelts are found to exhibit relative high surface area. The gas sensing performance of the Ag0.35V2O5 nanobelts towards organic amine was tested. It is found that the nanobelts show superior sensitivity of amine(s) to V2O5 particles, lower detection limit (5 ppm), and higher selectivity of amine versus ammonia at an optimized working temperature of ~260 degrees C. Moreover, the density functional theory (DFT) simulation was conducted to better understand the sensing mechanism. These findings may be useful in designing promising materials to detect amine gases for medical or food industrial applications. PMID- 26489855 TI - Core-shell of FePt@SiO2-Au magnetic nanoparticles for rapid SERS detection. AB - In this study, multifunctional hybrid nanoparticles composed of iron platinum (FePt), silica (SiO2), and gold nanoparticles (AuNPs) had been developed for surface-enhanced Raman scattering (SERS) application. Core-shell structure of SiO2 and FePt nanoparticles (FePt@SiO2) was fabricated through sol-gel process and then immobilized gold nanoparticles onto the surface of FePt@SiO2, which displays huge Raman enhancement effect and magnetic separation capability. The resulting core-shell nanoparticles were subject to evaluation by transmission electron microscopy (TEM), Energy-dispersive X-ray spectroscopy (EDX), zeta potential measurement, and X-ray photoelectron spectroscopy (XPS). TEM observation revealed that the particle size of resultant nanoparticles displayed spherical structure with the size ~30 nm and further proved the successful immobilization of Au onto the surface of FePt@SiO2. Zeta potential measurement exhibited the successful reaction between FePt@SiO2 and AuNPs. The rapid SERS detection and identification of small biomolecules (adenine) and microorganisms (gram-positive bacteria, Staphylococcus aureus) was conducted through Raman spectroscopy. In summary, the novel core-shell magnetic nanoparticles could be anticipated to apply in the rapid magnetic separation under the external magnetic field due to the core of the FePt superparamagnetic nanoparticles and label-free SERS bio-sensing of biomolecules and bacteria. PMID- 26489856 TI - PLGA-PEG Nanoparticles Coated with Anti-CD45RO and Loaded with HDAC Plus Protease Inhibitors Activate Latent HIV and Inhibit Viral Spread. AB - Activating HIV-1 proviruses in latent reservoirs combined with inhibiting viral spread might be an effective anti-HIV therapeutic strategy. Active specific delivery of therapeutic drugs into cells harboring latent HIV, without the use of viral vectors, is a critical challenge to this objective. In this study, nanoparticles of poly(lactic-co-glycolic acid)-polyethylene glycol diblock copolymers conjugated with anti-CD45RO antibody and loaded with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and/or protease inhibitor nelfinavir (Nel) were tested for activity against latent virus in vitro. Nanoparticles loaded with SAHA, Nel, and SAHA + Nel were characterized in terms of size, surface morphology, zeta potential, entrapment efficiency, drug release, and toxicity to ACH-2 cells. We show that SAHA- and SAHA + Nel-loaded nanoparticles can target latently infected CD4(+) T-cells and stimulate virus production. Moreover, nanoparticles loaded with SAHA + NEL were capable of both activating latent virus and inhibiting viral spread. Taken together, these data demonstrate the potential of this novel reagent for targeting and eliminating latent HIV reservoirs. PMID- 26489857 TI - Self-reported sexually transmitted infections among female university students. AB - AIM: To investigate the occurrence of self-reported sexually transmitted infections (STIs) and associated factors among female university students requesting contraceptive counselling. MATERIAL AND METHODS: Cross-sectional study. Female university students (n = 353) completed a waiting-room questionnaire in connection with contraceptive counselling at a Student Health Centre in Uppsala, Sweden. RESULTS: Ninety-three (26.3%) female students had experienced an STI. The three most frequently reported STIs were chlamydia trachomatis, condyloma, and genital herpes. The experience of an STI was significantly associated with the total number of sexual partners (OR 1.060, 95% CI 1.030-1.091, P < 0.001), being heterosexual (OR 4.640, 95% CI 1.321-16.290, P = 0.017), having experienced an abortion (OR 2.744, 95% CI 1.112-6.771, P = 0.028), not being HPV-vaccinated (OR 2.696, 95% CI 1.473-4.935, P = 0.001), and having had intercourse on first night without using a condom (OR 2.375, 95% CI 1.182-4.771, P = 0.015). CONCLUSIONS: Contraceptive counselling should also include information about primary and secondary prevention of STI, such as the importance of correct use of a condom and STI testing, to prevent a further spread of STIs. PMID- 26489858 TI - Untangling the biological effects of cerium oxide nanoparticles: the role of surface valence states. AB - Cerium oxide nanoparticles (nanoceria; CNPs) have been found to have both pro oxidant and anti-oxidant effects on different cell systems or organisms. In order to untangle the mechanisms which underlie the biological activity of nanoceria, we have studied the effect of five different CNPs on a model relevant aquatic microorganism. Neither shape, concentration, synthesis method, surface charge (zeta-potential), nor nominal size had any influence in the observed biological activity. The main driver of toxicity was found to be the percentage of surface content of Ce(3+) sites: CNP1 (58%) and CNP5 (40%) were found to be toxic whereas CNP2 (28%), CNP3 (36%) and CNP4 (26%) were found to be non-toxic. The colloidal stability and redox chemistry of the most and least toxic CNPs, CNP1 and CNP2, respectively, were modified by incubation with iron and phosphate buffers. Blocking surface Ce(3+) sites of the most toxic CNP, CNP1, with phosphate treatment reverted toxicity and stimulated growth. Colloidal destabilization with Fe treatment only increased toxicity of CNP1. The results of this study are relevant in the understanding of the main drivers of biological activity of nanoceria and to define global descriptors of engineered nanoparticles (ENPs) bioactivity which may be useful in safer-by-design strategies of nanomaterials. PMID- 26489859 TI - Specific hopanoid classes differentially affect free-living and symbiotic states of Bradyrhizobium diazoefficiens. AB - A better understanding of how bacteria resist stresses encountered during the progression of plant-microbe symbioses will advance our ability to stimulate plant growth. Here, we show that the symbiotic system comprising the nitrogen fixing bacterium Bradyrhizobium diazoefficiens and the legume Aeschynomene afraspera requires hopanoid production for optimal fitness. While methylated (2Me) hopanoids contribute to growth under plant-cell-like microaerobic and acidic conditions in the free-living state, they are dispensable during symbiosis. In contrast, synthesis of extended (C35) hopanoids is required for growth microaerobically and under various stress conditions (high temperature, low pH, high osmolarity, bile salts, oxidative stress, and antimicrobial peptides) in the free-living state and also during symbiosis. These defects might be due to a less rigid membrane resulting from the absence of free or lipidA bound C35 hopanoids or the accumulation of the C30 hopanoid diploptene. Our results also show that C35 hopanoids are necessary for symbiosis only with the host Aeschynomene afraspera but not with soybean. This difference is likely related to the presence of cysteine-rich antimicrobial peptides in Aeschynomene nodules that induce drastic modification in bacterial morphology and physiology. The study of hopanoid mutants in plant symbionts thus provides an opportunity to gain insight into host-microbe interactions during later stages of symbiotic progression, as well as the microenvironmental conditions for which hopanoids provide a fitness advantage. IMPORTANCE: Because bradyrhizobia provide fixed nitrogen to plants, this work has potential agronomical implications. An understanding of how hopanoids facilitate bacterial survival in soils and plant hosts may aid the engineering of more robust agronomic strains, especially relevant in regions that are becoming warmer and saline due to climate change. Moreover, this work has geobiological relevance: hopanes, molecular fossils of hopanoids, are enriched in ancient sedimentary rocks at discrete intervals in Earth history. This is the first study to uncover roles for 2Me- and C35 hopanoids in the context of an ecological niche that captures many of the stressful environmental conditions thought to be important during (2Me)-hopane deposition. Though much remains to be done to determine whether the conditions present within the plant host are shared with niches of relevance to the rock record, our findings represent an important step toward identifying conserved mechanisms whereby hopanoids contribute to fitness. PMID- 26489860 TI - Evolutionary landscape of the Mycobacterium tuberculosis complex from the viewpoint of PhoPR: implications for virulence regulation and application to vaccine development. AB - Different members of the Mycobacterium genus have evolved to cause tuberculosis in diverse human populations and in a variety of animal species. Our cumulative knowledge of mycobacterial genomes indicates that mutations in the PhoPR two component virulence system were acquired not only during the natural evolution of mycobacterial species but also during in vitro subculture, which has given rise to the attenuated reference strain H37Ra or to different daughter strains of Mycobacterium bovis BCG. PhoPR is a well-known regulator of pathogenic phenotypes, including secretion of the virulence factor ESAT-6, biosynthesis of acyltrehalose-based lipids, and modulation of antigen export, in members of the Mycobacterium tuberculosis complex (MTBC). Evolutionarily conserved polymorphisms in PhoPR from Mycobacterium africanum, M. bovis, or M. tuberculosis H37Ra result in loss of functional phenotypes. Interestingly, some members of the MTBC have acquired compensatory mutations to counteract these polymorphisms and, probably, to maintain their pathogenic potential. Some of these compensatory mutations include the insertion of the IS6110 element upstream from phoPR in a particular M. bovis strain that is able to transmit between humans or polymorphisms in M. africanum and M. bovis that affect the regulatory region of the espACD operon, allowing PhoPR-independent ESAT-6 secretion. This review highlights the increasing knowledge of the significance of PhoPR in the evolution of the MTBC and its potential application in the construction of new attenuated vaccines based on phoPR inactivation. In this context, the live attenuated vaccine MTBVAC, based on a phoP fadD26 deletion mutant of M. tuberculosis, is the first vaccine of this kind to successfully enter into clinical development, representing a historic milestone in the field of human vaccinology. PMID- 26489861 TI - Convergence of alarmone and cell cycle signaling from trans-encoded sensory domains. AB - Despite the myriad of different sensory domains encoded in bacterial genomes, only a few are known to control the cell cycle. Here, suppressor genetics was used to unveil the regulatory interplay between the PAS (Per-Arnt-Sim) domain protein MopJ and the uncharacterized GAF (cyclic GMP-phosphodiesterase-adenylyl cyclase-FhlA) domain protein PtsP, which resembles an alternative component of the phosphoenolpyruvate (PEP) transferase system. Both of these systems indirectly target the Caulobacter crescentus cell cycle master regulator CtrA, but in different ways. While MopJ acts on CtrA via the cell cycle kinases DivJ and DivL, which control the removal of CtrA at the G1-S transition, our data show that PtsP signals through the conserved alarmone (p)ppGpp, which prevents CtrA cycling under nutritional stress and in stationary phase. We found that PtsP interacts genetically and physically with the (p)ppGpp synthase/hydrolase SpoT and that it modulates several promoters that are directly activated by the cell cycle transcriptional regulator GcrA. Thus, parallel systems integrate nutritional and systemic signals within the cell cycle transcriptional network, converging on the essential alphaproteobacterial regulator CtrA while also affecting global cell cycle transcription in other ways. IMPORTANCE: Many alphaproteobacteria divide asymmetrically, and their cell cycle progression is carefully regulated. How these bacteria control the cell cycle in response to nutrient limitation is not well understood. Here, we identify a multicomponent signaling pathway that acts on the cell cycle when nutrients become scarce in stationary phase. We show that efficient accumulation of the master cell cycle regulator CtrA in stationary-phase Caulobacter crescentus cells requires the previously identified stationary-phase/cell cycle regulator MopJ as well as the phosphoenolpyruvate protein phosphotransferase PtsP, which acts via the conserved (p)ppGpp synthase SpoT. We identify cell cycle-regulated promoters that are affected by this pathway, providing an explanation of how (p)ppGpp-signaling might couple starvation to control cell cycle progression in Caulobacter spp. and likely other Alphaproteobacteria. This pathway has the potential to integrate carbon fluctuation into cell cycle control, since in phosphotransferase systems it is the glycolytic product phosphenolpyruvate (PEP) rather than ATP that is used as the phosphor donor for phosphorylation. PMID- 26489862 TI - Nonreplicating influenza A virus vaccines confer broad protection against lethal challenge. AB - New vaccine technologies are being investigated for their ability to elicit broadly cross-protective immunity against a range of influenza viruses. We compared the efficacies of two intranasally delivered nonreplicating influenza virus vaccines (H1 and H5 S-FLU) that are based on the suppression of the hemagglutinin signal sequence, with the corresponding H1N1 and H5N1 cold-adapted (ca) live attenuated influenza virus vaccines in mice and ferrets. Administration of two doses of H1 or H5 S-FLU vaccines protected mice and ferrets from lethal challenge with homologous, heterologous, and heterosubtypic influenza viruses, and two doses of S-FLU and ca vaccines yielded comparable effects. Importantly, when ferrets immunized with one dose of H1 S-FLU or ca vaccine were challenged with the homologous H1N1 virus, the challenge virus failed to transmit to naive ferrets by the airborne route. S-FLU technology can be rapidly applied to any emerging influenza virus, and the promising preclinical data support further evaluation in humans. IMPORTANCE: Influenza viruses continue to represent a global public health threat, and cross-protective vaccines are needed to prevent seasonal and pandemic influenza. Currently licensed influenza vaccines are based on immunity to the hemagglutinin protein that is highly variable. However, T cell responses directed against highly conserved viral proteins contribute to clearance of the virus and confer broadly cross-reactive and protective immune responses against a range of influenza viruses. In this study, two nonreplicating pseudotyped influenza virus vaccines were compared with their corresponding live attenuated influenza virus vaccines, and both elicited robust protection against homologous and heterosubtypic challenge in mice and ferrets, making them promising candidates for further evaluation in humans. PMID- 26489863 TI - Herpesvirus entry mediator on radiation-resistant cell lineages promotes ocular herpes simplex virus 1 pathogenesis in an entry-independent manner. AB - Ocular herpes simplex virus 1 (HSV-1) infection leads to a potentially blinding immunoinflammatory syndrome, herpes stromal keratitis (HSK). Herpesvirus entry mediator (HVEM), a widely expressed tumor necrosis factor (TNF) receptor superfamily member with diverse roles in immune signaling, facilitates viral entry through interactions with viral glycoprotein D (gD) and is important for HSV-1 pathogenesis. We subjected mice to corneal infection with an HSV-1 mutant in which HVEM-mediated entry was specifically abolished and found that the HVEM entry mutant produced clinical disease comparable to that produced by the control virus. HVEM-mediated induction of corneal cytokines, which correlated with an HVEM-dependent increase in levels of corneal immune cell infiltrates, was also gD independent. Given the complexity of HVEM immune signaling, we used hematopoietic chimeric mice to determine which HVEM-expressing cells mediate HSV-1 pathogenesis in the eye. Regardless of whether the donor was a wild-type (WT) or HVEM knockout (KO) strain, HVEM KO recipients were protected from ocular HSV-1, suggesting that HVEM on radiation-resistant cell types, likely resident cells of the cornea, confers wild-type-like susceptibility to disease. Together, these data indicate that HVEM contributes to ocular pathogenesis independently of entry and point to an immunomodulatory role for this protein specifically on radiation-resistant cells. IMPORTANCE: Immune privilege is maintained in the eye in order to protect specialized ocular tissues, such as the translucent cornea, from vision-reducing damage. Ocular herpes simplex virus 1 (HSV-1) infection can disrupt this immune privilege, provoking a host response that ultimately brings about the majority of the damage seen with the immunoinflammatory syndrome herpes stromal keratitis (HSK). Our previous work has shown that HVEM, a host TNF receptor superfamily member that also serves as a viral entry receptor, is a critical component contributing to ocular HSV-1 pathogenesis, although its precise role in this process remains unclear. We hypothesized that HVEM promotes an inflammatory microenvironment in the eye through immunomodulatory actions, enhancing disease after ocular inoculation of HSV-1. Investigating the mechanisms responsible for orchestrating this aberrant immune response shed light on the initiation and maintenance of HSK, one of the leading causes of infectious blindness in the developed world. PMID- 26489864 TI - Binding of alphaherpesvirus glycoprotein H to surface alpha4beta1-integrins activates calcium-signaling pathways and induces phosphatidylserine exposure on the plasma membrane. AB - Intracellular signaling connected to integrin activation is known to induce cytoplasmic Ca(2+) release, which in turn mediates a number of downstream signals. The cellular entry pathways of two closely related alphaherpesviruses, equine herpesviruses 1 and 4 (EHV-1 and EHV-4), are differentially regulated with respect to the requirement of interaction of glycoprotein H (gH) with alpha4beta1 integrins. We show here that binding of EHV-1, but not EHV-4, to target cells resulted in a rapid and significant increase in cytosolic Ca(2+) levels. EHV-1 expressing EHV-4 gH (gH4) in lieu of authentic gH1 failed to induce Ca(2+) release, while EHV-4 with gH1 triggered significant Ca(2+) release. Blocking the interaction between gH1 and alpha4beta1-integrins, inhibiting phospholipase C (PLC) activation, or blocking binding of inositol 1,4,5-triphosphate (IP3) to its receptor on the endoplasmic reticulum (ER) abrogated Ca(2+) release. Interestingly, phosphatidylserine (PS) was exposed on the plasma membrane in response to cytosolic calcium increase after EHV-1 binding through a scramblase dependent mechanism. Inhibition of both Ca(2+) release from the ER and scramblase activation blocked PS scrambling and redirected virus entry to the endocytic pathway, indicating that PS may play a role in facilitating virus entry directly at the plasma membrane. IMPORTANCE: Herpesviruses are a large family of enveloped viruses that infect a wide range of hosts, causing a variety of diseases. These viruses have developed a number of strategies for successful entry into different cell types. We and others have shown that alphaherpesviruses, including EHV-1 and herpes simplex virus 1 (HSV-1), can route their entry pathway and do so by manipulation of cell signaling cascades to ensure viral genome delivery to nuclei. We show here that the interaction between EHV-1 gH and cellular alpha4beta1-integrins is necessary to induce emptying of ER calcium stores, which induces phosphatidylserine exposure on the plasma membrane through a scramblase dependent mechanism. This change in lipid asymmetry facilitates virus entry and might help fusion of the viral envelope at the plasma membrane. These findings will help to advance our understanding of herpesvirus entry mechanism and may facilitate the development of novel drugs that can be implemented for prevention of infection and disease. PMID- 26489865 TI - Knockout of Epstein-Barr virus BPLF1 retards B-cell transformation and lymphoma formation in humanized mice. AB - BPLF1 of Epstein-Barr virus (EBV) is classified as a late lytic cycle protein but is also found in the viral tegument, suggesting its potential involvement at both initial and late stages of viral infection. BPLF1 possesses both deubiquitinating and deneddylating activity located in its N-terminal domain and is involved in processes that affect viral infectivity, viral DNA replication, DNA repair, and immune evasion. A recently constructed EBV BPLF1-knockout (KO) virus was used in conjunction with a humanized mouse model that can be infected with EBV, enabling the first characterization of BPLF1 function in vivo. Results demonstrate that the BPLF1-knockout virus is approximately 90% less infectious than wild-type (WT) virus. Transformation of human B cells, a hallmark of EBV infection, was delayed and reduced with BPLF1-knockout virus. Humanized mice infected with EBV BPLF1 knockout virus showed less weight loss and survived longer than mice infected with equivalent infectious units of WT virus. Additionally, splenic tumors formed in 100% of mice infected with WT EBV but in only 25% of mice infected with BPLF1 KO virus. Morphological features of spleens containing tumors were similar to those in EBV-induced posttransplant lymphoproliferative disease (PTLD) and were almost identical to cases seen in human diffuse large B-cell lymphoma. The presence of EBV genomes was detected in all mice that developed tumors. The results implicate BPLF1 in human B-cell transformation and tumor formation in humanized mice. IMPORTANCE: Epstein-Barr virus infects approximately 90% of the world's population and is the causative agent of infectious mononucleosis. EBV also causes aggressive lymphomas in individuals with acquired and innate immune disorders and is strongly associated with diffuse large B-cell lymphomas, classical Hodgkin lymphoma, Burkitt lymphoma, and nasopharyngeal carcinoma (NPC). Typically, EBV initially infects epithelial cells in the oropharynx, followed by a lifelong persistent latent infection in B-cells, which may develop into lymphomas in immunocompromised individuals. This work is the first of its kind in evaluating the effects of EBV's BPLF1 in terms of pathogenesis and lymphomagenesis in humanized mice and implicates BPLF1 in B-cell transformation and tumor development. Currently, there is no efficacious treatment for EBV, and therapeutic targeting of BPLF1 may lead to a new path to treatment for immunocompromised individuals or transplant recipients infected with EBV. PMID- 26489867 TI - Dialog Across Boundaries: A Tribute to Dieter Falkenhagen. PMID- 26489866 TI - The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome. AB - Viruses make up a major component of the human microbiota but are poorly understood in the skin, our primary barrier to the external environment. Viral communities have the potential to modulate states of cutaneous health and disease. Bacteriophages are known to influence the structure and function of microbial communities through predation and genetic exchange. Human viruses are associated with skin cancers and a multitude of cutaneous manifestations. Despite these important roles, little is known regarding the human skin virome and its interactions with the host microbiome. Here we evaluated the human cutaneous double-stranded DNA virome by metagenomic sequencing of DNA from purified virus like particles (VLPs). In parallel, we employed metagenomic sequencing of the total skin microbiome to assess covariation and infer interactions with the virome. Samples were collected from 16 subjects at eight body sites over 1 month. In addition to the microenviroment, which is known to partition the bacterial and fungal microbiota, natural skin occlusion was strongly associated with skin virome community composition. Viral contigs were enriched for genes indicative of a temperate phage replication style and also maintained genes encoding potential antibiotic resistance and virulence factors. CRISPR spacers identified in the bacterial DNA sequences provided a record of phage predation and suggest a mechanism to explain spatial partitioning of skin phage communities. Finally, we modeled the structure of bacterial and phage communities together to reveal a complex microbial environment with a Corynebacterium hub. These results reveal the previously underappreciated diversity, encoded functions, and viral-microbial dynamic unique to the human skin virome. IMPORTANCE: To date, most cutaneous microbiome studies have focused on bacterial and fungal communities. Skin viral communities and their relationships with their hosts remain poorly understood despite their potential to modulate states of cutaneous health and disease. Previous studies employing whole-metagenome sequencing without purification for virus-like particles (VLPs) have provided some insight into the viral component of the skin microbiome but have not completely characterized these communities or analyzed interactions with the host microbiome. Here we present an optimized virus purification technique and corresponding analysis tools for gaining novel insights into the skin virome, including viral "dark matter," and its potential interactions with the host microbiome. The work presented here establishes a baseline of the healthy human skin virome and is a necessary foundation for future studies examining viral perturbations in skin health and disease. PMID- 26489868 TI - Current Techniques and Outcomes in Extracorporeal Life Support. PMID- 26489869 TI - Implantation of Total Artificial Heart in a Patient With Absent Superior Vena Cava. PMID- 26489871 TI - Ruthenium Oxidase Catalysis for Site-Selective C-H Alkenylations with Ambient O2 as the Sole Oxidant. AB - Ruthenium(II) oxidase catalysis by direct dioxygen-coupled turnover enabled step economical oxidative C-H alkenylation reactions at ambient pressure. Versatile ruthenium(II) biscarboxylate catalysts displayed ample substrate scope and proved applicable to weakly coordinating and removable directing groups. The twofold C-H functionalization strategy was characterized by exceedingly mild reaction conditions as well as excellent positional selectivity. PMID- 26489872 TI - Phosphine-free synthesis of Ag-In-Se alloy nanocrystals with visible emissions. AB - As promising heavy metal-free emitting materials, Ag-In-Se nanocrystals (NCs) are conventionally synthesized using organic phosphine agents and exhibit near infrared emissions. In this work, we demonstrate a rapid phosphine-free approach for synthesizing Ag-In-Se alloy NCs with the emissions tunable to the visible region on the basis of the phosphine-free dissolution of Se powder. At room temperature, Se powder is reduced by dodecanethiol and dissolved in oleylamine to produce a Se precursor. The resultant Se precursor is highly active, which permits rapid synthesis at a relatively low temperature, such as at 90 degrees C for 150 s. By optimizing the size, structure, and composition, the photoluminescence quantum yield of the as-synthesized Ag-In-Se NCs is enhanced to up to 10%. The growth of the Ag-In-Se NCs involves composition and phase transition, which strongly depend on the reaction temperature. The Ag2Se nuclei form first, and the Ag-In-Se NCs are produced by doping In(3+) into the preformed Ag2Se nuclei. Tetragonal phase Ag-In-Se is obtained below 170 degrees C, while the orthorhombic phase appears over 190 degrees C. The potential of Ag-In-Se NCs as red emitting phosphors for lighting-emitting diodes is further demonstrated. PMID- 26489875 TI - Changes in induction methods have not influenced cesarean section rates among women with induced labor. AB - INTRODUCTION: Induction of labor has become more common in most countries during the last decade. We have compared methods and routines of labor induction as practiced in Norway in 2003 and 2013, and surveyed practices with regard to induction of labor without a medical indication in 2013. MATERIAL AND METHODS: A telephone interview with all delivery units in Norway was conducted in 2003. Data on preferred induction methods, use of prostaglandin, dosages, dose intervals and routes of administration were collected. In 2013, the same questionnaire was used, with additional questions on induction of labor without a medical indication. Data on overall cesarean section and induction rates were obtained from the Medical Birth Registry of Norway. RESULTS: From 2003 to 2013 the induction rate increased by 62% and the cesarean section rate by 6%. The cesarean section rate in women with induced labor remained stable at 17.1 and 17.4%, respectively. In 2003, 31 of 43 hospitals used dinoprostone for cervical ripening and induction. In 2013, 34 of 39 hospitals used misoprostol. A cervical balloon was used in three of 43 hospitals in 2003 compared with 31 of 39 in 2013. All but one hospital induced labor without a strict medical indication in 2013. CONCLUSION: The preferred methods for induction of labor changed within a decade to the use of misoprostol and cervical balloon. Induction of labor without strict medical indications is widely practiced. The changed induction methods have not influenced the cesarean section rates in women with induced labors. PMID- 26489873 TI - Epitope specific T-cell responses against influenza A in a healthy population. AB - Pre-existing human CD4(+) and CD8(+) T-cell-mediated immunity may be a useful correlate of protection against severe influenza disease. Identification and evaluation of common epitopes recognized by T cells with broad cross-reactivity is therefore important to guide universal influenza vaccine development, and to monitor immunological preparedness against pandemics. We have retrieved an optimal combination of MHC class I and class II restricted epitopes from the Immune Epitope Database (www.iedb.org), by defining a fitness score function depending on prevalence, sequence conservancy and HLA super-type coverage. Optimized libraries of CD4(+) and CD8(+) T-cell epitopes were selected from influenza antigens commonly present in seasonal and pandemic influenza strains from 1934 to 2009. These epitope pools were used to characterize human T-cell responses in healthy donors using interferon-gamma ELISPOT assays. Upon stimulation, significant CD4(+) and CD8(+) T-cell responses were induced, primarily recognizing epitopes from the conserved viral core proteins. Furthermore, the CD4(+) and CD8(+) T cells were phenotypically characterized regarding functionality, cytotoxic potential and memory phenotype using flow cytometry. Optimized sets of T-cell peptide epitopes may be a useful tool to monitor the efficacy of clinical trials, the immune status of a population to predict immunological preparedness against pandemics, as well as being candidates for universal influenza vaccines. PMID- 26489874 TI - The Test Your Memory cognitive screening tool: sociodemographic and cardiometabolic risk correlates in a population-based study of older British men. AB - OBJECTIVE: This study aimed to examine the association of Test Your Memory (TYM) defined cognitive impairment groups with known sociodemographic and cardiometabolic correlates of cognitive impairment in a population-based study of older adults. METHODS: Participants were members of the British Regional Heart Study, a cohort across 24 British towns initiated in 1978-1980. Data stemmed from 1570 British men examined in 2010-2012, aged 71-92 years. Sociodemographic and cardiometabolic factors were compared between participants defined as having TYM scores in the normal cognitive ageing, mild cognitive impairment (MCI) and severe cognitive impairment (SCI) groups, defined as >=46 (45 if >=80 years of age), >=33 and <33, respectively. RESULTS: Among 1570 men, 636 (41%) were classified in the MCI and 133 (8%) in the SCI groups. Compared with participants in the normal cognitive ageing category, individuals with SCI were characterized primarily by lower socio-economic position (odds ratio (OR) = 6.15, 95% confidence interval (CI) 4.00-9.46), slower average walking speed (OR = 3.36, 95% CI 2.21-5.10), mobility problems (OR = 4.61, 95% CI 3.04-6.97), poorer self-reported overall health (OR = 2.63, 95% CI 1.79-3.87), obesity (OR = 2.59, 95% CI 1.72-3.91) and impaired lung function (OR = 2.25, 95% CI 1.47-3.45). A similar albeit slightly weaker pattern was observed for participants with MCI. CONCLUSION: Sociodemographic and lifestyle factors as well as adiposity measures, lung function and poor overall health are associated with cognitive impairments in late life. The correlates of cognitive abilities in the MCI and SCI groups, as defined by the TYM, resemble the risk profile for MCI and Alzheimer's disease outlined in current epidemiological models. PMID- 26489876 TI - Effect of socioeconomic status (SES) disparity on neural development in female African-American infants at age 1 month. AB - There is increasing interest in both the cumulative and long-term impact of early life adversity on brain structure and function, especially as the brain is both highly vulnerable and highly adaptive during childhood. Relationships between SES and neural development have been shown in children older than age 2 years. Less is known regarding the impact of SES on neural development in children before age 2. This paper examines the effect of SES, indexed by income-to-needs (ITN) and maternal education, on cortical gray, deep gray, and white matter volumes in term, healthy, appropriate for gestational age, African-American, female infants. At 5 weeks postnatal age, unsedated infants underwent MRI (3.0T Siemens Verio scanner, 32-channel head coil). Images were segmented based on a locally constructed template. Utilizing hierarchical linear regression, SES effects on MRI volumes were examined. In this cohort of healthy African-American female infants of varying SES, lower SES was associated with smaller cortical gray and deep gray matter volumes. These SES effects on neural outcome at such a young age build on similar studies of older children, suggesting that the biological embedding of adversity may occur very early in development. PMID- 26489877 TI - "FISHed" out the diagnosis: A case of DiGeorge syndrome. AB - Our patient presented with congenital heart disease (CHD: Tetralogy of Fallot), hypocalcemia, hypoparathyroidism, and facial dysmorphisms. Suspecting DiGeorge syndrome (DGS), a fluorescence in situ hybridization (FISH) analysis for 22q11.2 deletion was made. The child had a hemizygous deletion in the 22q11.2 region, diagnostic of DGS. Unfortunately, the patient succumbed to the heart disease. DGS is the most common microdeletion syndrome, and probably underrecognized due to the varied manifestations. This case stresses the importance of a detailed physical examination and a high index of suspicion for diagnosing this genetic condition. Timely diagnosis can help manage and monitor these patients better and also offer prenatal diagnosis in the next pregnancy. PMID- 26489879 TI - Stable folding intermediates prevent fast interconversion between the closed and open states of Mad2 through its denatured state. AB - Different states of metamorphic proteins can interconvert under physiological conditions to realize corresponding functions. The mechanism behind the conversion is critical for understanding how these proteins work. We report a combined thermodynamic and kinetic study on the folding/unfolding process of the open and closed conformers of mitotic arrest deficient protein 2 (Mad2), a metamorphic protein. It has been observed that open Mad2 (O-Mad2) can convert to closed Mad2 (C-Mad2). Our results show that O-Mad2 and C-Mad2 have similar thermodynamic stability, which explains the presence of metamorphosis. The folding/unfolding kinetics suggest that the conversion between O-Mad2 and C-Mad2 would be much faster than that reported previously if this conversion goes through the denatured state (U) directly, i.e. through an O-Mad2-denatured state (U)-C-Mad2 (O-U-C) pathway. This inconsistency implies that there exist stable intermediates in between the native and denatured states of Mad2, which would either slow down the O-U-C interconversion or prevent it going through the denatured state. PMID- 26489878 TI - Engineering a genetically encoded competitive inhibitor of the KEAP1-NRF2 interaction via structure-based design and phage display. AB - In its basal state, KEAP1 binds the transcription factor NRF2 (Kd = 5 nM) and promotes its degradation by ubiquitylation. Changes in the redox environment lead to modification of key cysteines within KEAP1, resulting in NRF2 protein accumulation and the transcription of genes important for restoring the cellular redox state. Using phage display and a computational loop grafting protocol, we engineered a monobody (R1) that is a potent competitive inhibitor of the KEAP1 NRF2 interaction. R1 bound to KEAP1 with a Kd of 300 pM and in human cells freed NRF2 from KEAP1 resulting in activation of the NRF2 promoter. Unlike cysteine reactive small molecules that lack protein specificity, R1 is a genetically encoded, reversible inhibitor designed specifically for KEAP1. R1 should prove useful for studying the role of the KEAP1-NRF2 interaction in several disease states. The structure-based phage display strategy employed here is a general approach for engineering high-affinity binders that compete with naturally occurring interactions. PMID- 26489880 TI - Association of moderate chronic kidney disease with insufficient improvement of fractional flow reserve after stent implantation. AB - OBJECTIVES: This study aims to investigate the association of moderate chronic kidney disease (CKD) with fractional flow reserve (FFR) after stent implantation. BACKGROUND: Patients with moderate CKD have a higher prevalence of severe and diffuse coronary artery disease, and have increased risk of cardiovascular events even after stent implantation. On the other hand, in some patients, FFR could not be sufficiently improved even after stent implantation. However, the association between these pathophysiological processes is unclear. METHODS AND RESULTS: A total of 102 patients with stable angina, in whom a stent was implanted for the left anterior descending coronary artery (LAD) lesion, were included. Patients with a severely decreased glomerular filtration rate (GFR; > CKD stage 4) were excluded. Patients were stratified into 3 groups: those with an estimated GFR (eGFR) >= 60 mL per min per 1.73 m(2) (stage 0-2), 45 to 59 mL per min per 1.73 m(2) (stage 3a), and 30 to 44 mL per min per 1.73 m(2) (stage 3b). FFR after stent implantation (post-stent FFR) was significantly lower in the stage 3b group than in both the stage 0-2 group and the stage 3a group (P < 0.01). Post-stent FFR had a significant positive correlation with eGFR (r = 0.223, P = 0.024). Multivariate analysis demonstrated that eGFR was an independent predictor of post stent FFR. CONCLUSIONS: Moderate CKD was independently associated with insufficient improvement of FFR after stent implantation. This can partly explain the poor prognosis of patients with CKD. (c) 2015 Wiley Periodicals, Inc. PMID- 26489881 TI - Pretreatment with rivaroxaban attenuates stroke severity in rats by a dual antithrombotic and anti-inflammatory mechanism. AB - Stroke outcome is more favourable in patients receiving oral anticoagulants compared with non-anticoagulated patients. The reasons for this "stroke attenuating" property of oral anticoagulants are largely unknown. This study examined whether prestroke anticoagulation with rivaroxaban, a novel direct factor Xa inhibitor, influences stroke severity, thrombin-mediated intracerebral thrombus formation and pro-inflammatory processes in a rat model of brain ischaemia/reperfusion injury. Male Wistar rats were anticoagulated with rivaroxaban and subjected to 90 minutes of transient middle cerebral artery occlusion. Infarct size, functional outcome and the occurrence of intracranial haemorrhage (ICH) were assessed until day 7. Thrombin generation was determined by measuring the amount of thrombin/antithrombin complex. Intracerebral thrombus formation was evaluated by histology and Western blot. CD68-immunoreactivity and the expression of cytokines and adhesion molecules were investigated to assess postischaemic inflammation. The integrity of the blood-brain barrier was analysed using fluorescein isothiocyanate-dextran. Rats pretreated with rivaroxaban developed significantly smaller strokes and less severe functional deficits compared with controls. Although rivaroxaban strongly reduced thrombin-mediated thrombus formation, this was not accompanied by an increased risk of ICH. In addition, rivaroxaban dampened the inflammatory response in the ischaemic brain by downregulating ICAM-1 expression and the activation of CD68+-immune cells. In contrast, rivaroxaban had no effect on the integrity of the blood-brain barrier after stroke. Here, we identified reduced thrombo-inflammation as a major determinant of the stroke-protective property of rivaroxaban in rats. Further studies are needed to assess the therapeutic potential of novel oral anticoagulants in the acute phase after a stroke. PMID- 26489882 TI - Strong TCR-mediated signals suppress integrated stress responses induced by KDELR1 deficiency in naive T cells. AB - KDEL receptor 1 (KDELR1) regulates integrated stress responses (ISR) to promote naive T-cell survival in vivo. In a mouse line having nonfunctional KDELR1, T-Red (naive T-cell reduced) mice, polyclonal naive T cells show excessive ISR and eventually undergo apoptosis. However, breeding T-Red mice with TCR-transgenic mice bearing relatively high TCR affinity rescued the T-Red phenotype, implying a link between ISR-induced apoptosis and TCR-mediated signaling. Here, we showed that strong TCR stimulation reduces ISR in naive T cells. In mice lacking functional KDELR1, surviving naive T cells expressed significantly higher levels of CD5, a surrogate marker of TCR self-reactivity. In addition, higher TCR affinity/avidity was confirmed using a tetramer dissociation assay on the surviving naive T cells, suggesting that among the naive T-cell repertoire, those that receive relatively stronger TCR-mediated signals via self-antigens survive enhanced ISR. Consistent with this observation, weak TCR stimulation with altered peptide ligands decreased the survival and proliferation of naive T cells, whereas stimulation with ligands having higher affinity had no such effect. These results suggest a novel role of TCR-mediated signals in the attenuation of ISR in vivo. PMID- 26489883 TI - TANK-binding kinase 1-dependent or -independent signaling elicits the cell-type specific innate immune responses induced by the adenovirus vector. AB - Adenovirus vectors (Adv) elicit innate immune responses via several pattern recognition receptors. Although it has been suggested that various Adv-induced mechanisms play important roles in the induction of innate immunity in vitro, the impacts of these mechanisms in vivo remain unclear. Viral nucleic acids elicit innate immune responses through the recognition of cytosolic nucleic acid sensors and transduce intracellular signals to TANK-binding kinase (TBK) 1. In this study, to determine the impacts of viral nucleic acids on innate immune responses in vivo, we administered transgene-expressing Adv to Tbk1-deficient mice. The systemic Adv administration failed to induce type I interferons (type I IFNs) in the spleen, but not the liver, of Tbk1-deficient mice, resulting in the increase of transgene-expressing cells in the spleen, but not the liver. Moreover, Adv failed to induce type I IFNs in the bone-marrow-derived dendritic cells, but not the mouse embryonic fibroblasts, from Tbk1-deficient mice in vitro. These results support the idea that Adv elicit innate immunity in immune cells and non-immune cells in a TBK1-dependent and TBK1-independent manner, respectively. PMID- 26489884 TI - Guanosine and its modified derivatives are endogenous ligands for TLR7. AB - Toll-like receptor (TLR) 7and 8 were considered to recognize single-strand RNA (ssRNA) from viruses. Although these receptors also respond to synthetic small chemical ligands, such as CL075 and R848, it remains to be determined whether these receptors sense natural small molecules or not. In the structure of human TLR8 (huTLR8) with ssRNA, there are two ligand-binding sites: one binds a uridine and the other binds an oligoribonucleotide (ORN). This finding demonstrates that huTLR8 recognizes degradation products of ssRNA, suggesting the presence of natural small ligands. We here show that TLR7 works as the sensor for guanosine (G)/2'-deoxyguanosine (dG) in the presence of ORN where ORN strengthens TLR7 interaction with G/dG. In addition, modified nucleosides such as 7 methylguanosine, 8-hydroxyguanosine (8-OHG) and 8-hydroxydeoxyguanosine (8-OHdG) activated TLR7 with ORNs. Importantly, 8-OHdG-a well-known oxidative DNA damage marker with unknown function-induced strong cytokine production comparable to G and dG both in mouse and human immune cells. Although 8-OHdG bound TLR7/ORN with lower affinity than dG did in isothermal titration calorimetry, administered 8 OHdG was metabolically more stable than dG in the serum, indicating that 8-OHdG acts on TLR7 as an endogenous ligand in vivo To address a role of G analogs in the disease state, we also examined macrophages from Unc93b1 (D34A/D34A) mice, which suffer from TLR7-dependent systemic inflammation, and found that Unc93b1 (D34A/D34A) macrophages showed significantly enhanced response to G alone or 8 OHdG with ORN. In conclusion, our results provide evidence that G, dG, 8-OHG and 8-OHdG are novel endogenous ligands for TLR7. PMID- 26489885 TI - Unexpected Efficiency of a Luminescent Samarium(III) Complex for Combined Visible and Near-Infrared Biphotonic Microscopy. AB - An original samarium(III) complex based on a triazacyclononane platform functionalized with a charge-transfer antenna chromophore exhibited optimized brightness and was successfully used as an emissive species for two-photon microscopy experiments in both the visible and near-infrared spectral ranges. PMID- 26489886 TI - Combined evaluation of risk factors predicting poor ovarian responders in Chinese patients undergoing in vitro fertilization. AB - This study aimed to explore the parameters associated with poor ovarian response (POR) to develop an early warning score model (EWSM) for detecting POR in Chinese women undergoing in vitro fertilization, in order to improve the outcomes. Between 2005 and 2011, we recruited 736 patients with POR after IVF and 736 individuals with normal ovarian response after IVF as controls. Clinical parameters were determined to evaluate the ovarian reserve. We then compared the clinical parameters between the POR and control groups, and performed a multivariate analysis to determine the independent factors associated with ovarian response. Receiver-operator characteristic (ROC) was used to analyze the predicted values of individual and combined risk factors. The predicted values were further tested in another cohort of 957 patients. Age, basal follicle stimulating hormone (bFSH), antral follicle count (AFC), and FSH/luteinizing hormone (LH) ratio were identified as independent factors associated with ovarian response. The EWSM was established using a combination of these parameters. The sensitivity and specificity of the EWSM were 74.6% and 93.6%, respectively. In conclusion, combination of individual risk factors could predict POR with high specificity. The EWSM may help in the evaluation of IVF treatment at an early stage. PMID- 26489888 TI - Structure and bonding of [(SIPr)AgX] (X = Cl, Br, I and OTf). AB - A series of iso-structural complexes [(SIPr)AgX] (X = Cl, Br, I, OTf; SIPr = 1,3 bis(2,6-diisopropylphenyl)imidazolidene) were synthesised, including the first example of a N-heterocyclic carbene silver(I) complex containing an O-bound triflate. Bond Energy Dissociation and Natural Orbitals for Chemical Valence bond analyses (BEDA & ETS-NOCV) revealing a significant NHC -> M sigma-back-donation, which influences the stability and sigma-donicity of these complexes. PMID- 26489887 TI - Highly Luminescent, Water-Soluble Lanthanide Fluorobenzoates: Syntheses, Structures and Photophysics, Part I: Lanthanide Pentafluorobenzoates. AB - Highly luminescent, photostable, and soluble lanthanide pentafluorobenzoates have been synthesized and thoroughly characterized, with a focus on Eu(III) and Tb(III) complexes as visible emitters and Nd(III) , Er(III) , and Yb(III) complexes as infrared emitters. Investigation of the crystal structures of the complexes in powder form and as single crystals by using X-ray diffraction revealed five different structural types, including monomeric, dimeric, and polymeric. The local structure in different solutions was studied by using X-ray absorption spectroscopy. The photoluminescence quantum yields (PLQYs) of terbium and europium complexes were 39 and 15 %, respectively; the latter value was increased almost twice by using the heterometallic complex [Tb0.5 Eu0.5 (pfb)3 (H2 O)] (Hpfb=pentafluorobenzoic acid). Due to the effectively utilized sensitization strategy (pfb)(-) ->Tb->Eu, a pure europium luminescence with a PLQY of 29 % was achieved. PMID- 26489889 TI - Pentanuclear [2.2] spirocyclic lanthanide(III) complexes: slow magnetic relaxation of the Dy(III) analogue. AB - The reaction of LnCl3.6H2O (Ln = Dy(3+), Tb(3+) and Ho(3+)) with the multisite coordinating ligand N'-(2-hydroxy-3-(hydroxymethyl)-5 methylbenzylidene)acetohydrazide (LH3) in the presence of pivalic acid (PivH) leads to the formation of three isostructural homometallic pentanuclear complexes, [Dy5(LH)4(eta(1)-Piv)(eta(2)-Piv)3(MU2 eta(2)eta(1)Piv)2(H2O)].Cl.9.5H2O.5MeOH (1), [Tb5(LH)4(eta(1)-Piv)(eta(2) Piv)3(MU2-eta(2)eta(1)Piv)2(H2O)].Cl.10.5H2O.2MeOH.2CHCl3 (2) and [Ho5(LH)4(eta(1)-Piv)(eta(2)-Piv)3(MU2-eta(2)eta(1)Piv)2(H2O)].Cl.14.5H2O.2CHCl3 (3). 1-3 are monocationic and are comprised of four doubly deprotonated [LH](2-) ligands along with six pivalate ions. These complexes possess a [2.2] spirocyclic topology formed by the fusion of two triangles of Ln(III) ions at a common vertex. The magneto chemical analysis reveals the presence of antiferromagnetic exchange interactions at low temperature, and the Dy(III) complex 1 gives an out of-phase signal with a small curvature in alternating current (ac) magnetic susceptibility measurement. Application of a 3000 G static field during ac measurement intensifies the signals, revealing a second slow relaxation process in the Dy(III) analogue. PMID- 26489890 TI - Nanogold supported on manganese oxide doped alumina microspheres as a highly active and selective catalyst for CO oxidation in a H2-rich stream. AB - Manganese oxide-doped Al2O3 microspheres were synthesized via a redox method, and were then deposited with Au nanoparticles using a deposition-precipitation method. The obtained catalyst is not only highly active and selective for the preferential oxidation of CO in a H2-rich stream, but also shows excellent stability in the co-presence of H2O and CO2 at 80 degrees C. PMID- 26489891 TI - Prepregnancy Obesity and Primary Cesareans among Otherwise Low-Risk Mothers in 38 U.S. States in 2012. AB - BACKGROUND: The United States has recently experienced increases in both its rate of obesity and its cesarean rate. Our objective was to use a new item measuring prepregnancy body mass index (BMI) on the U.S. Standard Certificate of Live Birth to examine at a population level the relationship between maternal obesity and primary cesarean delivery for women at otherwise low risk for cesarean delivery. METHODS: By 2012, 38 states with 86 percent of United States births had adopted the U.S. Standard Certificate. The sample was limited to the 2,233,144 women who had a singleton, vertex, term (37-41 weeks) birth in 2012 and no prior cesarean. We modeled the likelihood of a primary cesarean by BMI category, controlling for maternal socio-demographic and medical characteristics. RESULTS: Overall, 46.4 percent of otherwise low-risk mothers had a prepregnancy BMI in the overweight (25.1%) or obese (21.3%) categories, with the obese category distributed as follows: obese I (BMI 30.0-34.9, 12.4%); obese II (BMI 35.0-39.9, 5.5%); and obese III (BMI 40+, 3.5%). Obesity rates were highest among American Indian and Alaska Native (32.5%) and non-Hispanic black mothers (30.5%). After adjustment for demographic and medical risks, the adjusted risk ratios (95% confidence intervals) of cesarean for low-risk primiparas were: 1.61 (1.60-1.63) for obese I, 1.86 (1.83-1.88) for obese II, and 2.21 (2.18-2.25) for obese III mothers compared with mothers in the normal weight category. DISCUSSION: A relationship between prepregnancy obesity and primary cesarean delivery among relatively low risk mothers remained even after controlling for social and medical risk factors. PMID- 26489892 TI - Neural Stem Cells Rescue Cognitive and Motor Dysfunction in a Transgenic Model of Dementia with Lewy Bodies through a BDNF-Dependent Mechanism. AB - Accumulation of alpha-synuclein (alpha-syn) into insoluble aggregates occurs in several related disorders collectively referred to as synucleinopathies. To date, studies have used neural stem cells (NSCs) to examine questions about alpha-syn propagation, but have overlooked the therapeutic potential of NSC transplantation to modulate cognition in disorders such as dementia with Lewy bodies or Parkinson's disease dementia. Here, we show that striatal transplantation of NSCs into aged alpha-syn transgenic mice significantly improves performance in multiple cognitive and motor domains. This recovery is associated with NSC expression of brain-derived neurotrophic factor (BDNF), which restores depleted levels and modulates dopaminergic and glutamatergic systems. Most importantly, transplantation of BDNF-depleted NSCs fails to improve behavior, whereas AAV mediated BDNF delivery mimics the benefits of NSC transplantation, supporting a critical role for this neurotrophin in functional improvement. Thus, NSC transplantation could offer a promising approach to treat the understudied yet devastating cognitive components of many synucleinopathies. PMID- 26489893 TI - Long Noncoding RNA ADINR Regulates Adipogenesis by Transcriptionally Activating C/EBPalpha. AB - C/EBPalpha is a critical transcriptional regulator of adipogenesis. How C/EBPalpha transcription is itself regulated is poorly understood, however, and remains a key question that needs to be addressed for a complete understanding of adipogenic development. Here, we identify a lncRNA, ADINR (adipogenic differentiation induced noncoding RNA), transcribed from a position ~450 bp upstream of the C/EBPalpha gene, that orchestrates C/EBPalpha transcription in vivo. Depletion of ADINR leads to a severe adipogenic defect that is rescued by overexpression of C/EBPalpha. Moreover, we reveal that ADINR RNA specifically binds to PA1 and recruits MLL3/4 histone methyl-transferase complexes so as to increase H3K4me3 and decrease H3K27me3 histone modification in the C/EBPalpha locus during adipogenesis. These results show that ADINR plays important roles in regulating the differentiation of human mesenchymal stem cells into adipocytes by modulating C/EBPalpha in cis. PMID- 26489894 TI - Distinct Processes and Transcriptional Targets Underlie CDX2 Requirements in Intestinal Stem Cells and Differentiated Villus Cells. AB - Lgr5-expressing intestinal stem cells (ISCs) renew the adult gut epithelium by producing mature villus cells (VCs); the transcriptional basis for ISC functions remains unclear. RNA sequencing analysis identified transcripts modulated during differentiation of Lgr5(+) ISCs into VCs, with high expression of the intestine restricted transcription factor (TF) gene Cdx2 in both populations. Cdx2-deleted mouse ISCs showed impaired proliferation and long-term inability to produce mature lineages, revealing essential ISC functions. Chromatin immunoprecipitation sequencing analysis of CDX2 in Lgr5(+) ISCs, coupled with mRNA profiling of control and Cdx2(-/-) ISCs, identified features of CDX2 regulation distinct from VCs. Most CDX2 binding in ISCs occurs in anticipation of future gene expression, but whereas CDX2 primarily activates VC genes, direct ISC targets are activated and repressed. Diverse CDX2 requirements in stem and differentiated cells may reflect the versatility of TFs that specify a tissue in development and control the same tissue in adults. PMID- 26489895 TI - Progressive Chromatin Condensation and H3K9 Methylation Regulate the Differentiation of Embryonic and Hematopoietic Stem Cells. AB - Epigenetic regulation serves as the basis for stem cell differentiation into distinct cell types, but it is unclear how global epigenetic changes are regulated during this process. Here, we tested the hypothesis that global chromatin organization affects the lineage potential of stem cells and that manipulation of chromatin dynamics influences stem cell function. Using nuclease sensitivity assays, we found a progressive decrease in chromatin digestion among pluripotent embryonic stem cells (ESCs), multipotent hematopoietic stem cells (HSCs), and mature hematopoietic cells. Quantitative high-resolution microscopy revealed that ESCs contain significantly more euchromatin than HSCs, with a further reduction in mature cells. Increased cellular maturation also led to heterochromatin localization to the nuclear periphery. Functionally, prevention of heterochromatin formation by inhibition of the histone methyltransferase G9A resulted in delayed HSC differentiation. Our results demonstrate global chromatin rearrangements during stem cell differentiation and that heterochromatin formation by H3K9 methylation regulates HSC differentiation. PMID- 26489896 TI - ESC-Derived Basal Forebrain Cholinergic Neurons Ameliorate the Cognitive Symptoms Associated with Alzheimer's Disease in Mouse Models. AB - Degeneration of basal forebrain cholinergic neurons (BFCNs) is associated with cognitive impairments of Alzheimer's disease (AD), implying that BFCNs hold potentials in exploring stem cell-based replacement therapy for AD. However, studies on derivation of BFCNs from embryonic stem cells (ESCs) are limited, and the application of ESC-derived BFCNs remains to be determined. Here, we report on differentiation approaches for directing both mouse and human ESCs into mature BFCNs. These ESC-derived BFCNs exhibit features similar to those of their in vivo counterparts and acquire appropriate functional properties. After transplantation into the basal forebrain of AD model mice, ESC-derived BFCN progenitors predominantly differentiate into mature cholinergic neurons that functionally integrate into the endogenous basal forebrain cholinergic projection system. The AD mice grafted with mouse or human BFCNs exhibit improvements in learning and memory performances. Our findings suggest a promising perspective of ESC-derived BFCNs in the development of stem cell-based therapies for treatment of AD. PMID- 26489897 TI - Cryopreserved human umbilical cord patch for in-utero spina bifida repair. AB - OBJECTIVE: To identify a patch system to repair surgically created spina bifida in a sheep model for its efficacy in healing the skin defect, protecting the underlying spinal cord and reducing the Chiari II malformation. METHODS: Spina bifida was created surgically in 16 fetuses from eight timed-pregnant sheep at gestational age of 75 days. Two fetuses did not survive the procedure. Repeat hysterotomy was performed at 95 days' gestation to cover the defect with either biocellulose film with underwater adhesive (BCF-adhesive) (n = 7) or human umbilical cord with suture (HUC-suture) (n = 7). Three fetuses without formation of the defect served as reference controls. The skin healing was examined by direct visualization after a planned Cesarean section at term, followed by histological analysis using hematoxylin and eosin and Masson's trichrome stains. Mid-sagittal sections of the fetal cranium and upper cervical spine were analyzed by a pediatric neuroradiologist who was blinded to the type of patch received. RESULTS: Three fetuses that received the BCF-adhesive and six fetuses that received the HUC-suture survived to term for final analysis. As a result of dislodgment of the BCF-adhesive, all spina bifida defects repaired using BCF adhesive were not healed and showed exposed spinal cord with leakage of cerebrospinal fluid. In contrast, all spinal defects repaired by HUC-suture were healed with complete regrowth of epidermal, dermal and subdermal tissue components, with no exposed spinal cord. The maximal skin wound width was 21 +/- 3.6 mm in the BCF-adhesive group but 3 +/- 0.8 mm in the HUC-suture group (P < 0.001). The spinal cord area (P = 0.001) and the number of anterior horn cells (P = 0.03) was preserved to a greater degree in the HUC-suture group than in the BCF adhesive group, whilst psammoma bodies, signifying neuronal degeneration, were only observed in the BCF-adhesive group. Anatomic changes, indicative of Chiari II malformation, were seen in all three fetuses of the BCF-adhesive group but in none of the HUC-suture group (P < 0.01). CONCLUSION: Cryopreserved umbilical cord graft is a promising regenerative patch for intrauterine repair of spina bifida. PMID- 26489898 TI - Serological survey in the Finnish human population implies human-to-human transmission of Ljungan virus or antigenically related viruses. AB - Ljungan virus (LV) is a picornavirus related to human parechoviruses (HPeV). The virus has been found in bank voles (Myodes glareolus) and several other rodent species, and suggested to have zoonotic potential. Thus far, seroepidemiological data on LV infections in humans are scarce. In this study, we aimed to characterize the demographic and geographical distribution of LV-reactive antibodies in Finland, and to investigate its occurrence in patients suspected of having a rodent-borne disease, nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV). Using an immunofluorescence assay (LV strain 145SLG), we screened human sera (n = 1378) and found LV-reactive antibodies in 36% of samples. The probability of possessing LV-reactive antibodies peaked at age of 14 years, suggesting that most infections occur in childhood. The prevalence of LV reactive antibodies was significantly higher in the urbanized area surrounding Helsinki than in more rural Central Finland. These findings are uncharacteristic of a rodent-borne pathogen, and therefore we consider human-to-human transmission of one or several Ljungan-like viruses as a likely cause for most of the observed antibody responses. PMID- 26489899 TI - Epigallocatechin-3-Gallate Reduces Cytotoxic Effects Caused by Dental Monomers: A Hypothesis. AB - Resin monomers from dental composite materials leached due to incomplete polymerization or biodegradation may cause contact allergies and damage dental pulp. The cytotoxicity of dental resin monomers is due to a disturbance of intracellular redox equilibrium, characterized by an overproduction of reactive oxygen species (ROS) and depletion of reduced glutathione (GSH). Oxidative stress caused by dental resin monomers leads to the disturbance of vital cell functions and induction of cell apoptosis in affected cells. The nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway plays a key role in the cellular defense system against oxidative and electrophilic stress. Epigallocatechin-3-gallate (EGCG) can activate the Nrf2 pathway and induce expression of a multitude of antioxidants and phase II enzymes that can restore redox homeostasis. Therefore, here, we tested the hypothesis that EGCG-mediated protection against resin monomer cytotoxicity is mediated by activation of the Nrf2 pathway. This study will help to elucidate the mechanism of resin monomer cytotoxicity and provide information that will be helpful in improving the biocompatibility of dental resin materials. PMID- 26489900 TI - Correction of Residual Radial Translation of the Distal Fragment in Distal Radius Fracture Open Reduction. AB - Distal radius fractures are common injuries of the upper extremity requiring treatment. In recent years, volar locking plate (VLP) fixation has become favored for operative treatment with the main goals being anatomic reduction and rigid fixation allowing for an early range of motion rehabilitation protocol. VLP fixation is excellent at correcting sagittal plane alignment with restoration of volar tilt. However, plate designs do not have any intrinsic features to their designs to assist with correction of coronal plane translation. One possible sequela of distal radius fractures is residual instability of the distal radioulnar joint. This instability can lead to pain and disability after treatment of distal radius fractures requiring further interventions. It has been demonstrated that coronal plane malreduction with residual radial translation of the distal fragment may contribute to ongoing distal radioulnar joint instability after distal radius fractures. We describe a technique for intraoperative correction of residual radial translation. It may be used when radial translation is recognized during internal fixation with a VLP or when correction of radial translation is required as part of a corrective osteotomy for radial malunion. PMID- 26489901 TI - Visible light-triggered disruption of micelles of an amphiphilic block copolymer with BODIPY at the junction. AB - A visible light-cleavable polymer is synthesised to overcome the limitations of UV-sensitive polymers. Photocleavable BODIPY functionalized with an ATRP initiator and alkyne was used to obtain an amphiphilic block copolymer by conducting the click reaction and polymerization simultaneously. Micellar assembly of the polymer was disintegrated under visible light irradiation with controlled release of cargo. PMID- 26489902 TI - Ratiometric Fluorescent Detection of Phosphate in Aqueous Solution Based on Near Infrared Fluorescent Silver Nanoclusters/Metal-Organic Shell Composite. AB - Synthesis of near-infrared (NIR) fluorescent AgNCs with high quantum yield and stability is challenging but important for sensing and bioimaging application. Here, we report the fabrication of AgNCs/metal-organic shell composite via the deposition of metal-organic (zinc-nitrogen) coordination shell around AgNCs for ratiometric detection of phosphate. The composite exhibits NIR emission at 720 nm with 30 nm red-shift in comparison to bare AgNCs and a weak emission at 510 nm from the shell. The absolute quantum yield of NIR fluorescence of the composite is 15%, owing to FRET from the shell to the AgNCs core under the excitation at 430 nm. Besides, the composite is stable due to the protection of the shell. On the basis of the composite, a novel ratiometric fluorescence probe for the detection of phosphate in aqueous solution with good sensitivity and selectivity was developed. The limit of detection (3s) is 0.06 MUM, and the relative standard deviation for 10 replicate detections of 10 MUM phosphate was 0.6%. The recoveries of spiked phosphate in water, human urine, and serum samples ranged from 94.1% to 103.4%. PMID- 26489903 TI - Editorial overview: Membranes. PMID- 26489904 TI - Structure-barrier property relationship of biodegradable poly(butylene succinate) and poly[(butylene succinate)-co-(butylene adipate)] nanocomposites: influence of the rigid amorphous fraction. AB - Composites composed of polyesters, poly(butylene succinate) (PBS) or poly[(butylene succinate)-co-(butylene adipate)] (PBSA), and 5 wt% of montmorillonite (CNa) or organo-modified montmorillonite (C30B) were melt processed and transformed into films by either compression-molding or extrusion calendering. XRD, rheological measurements and TEM images clearly indicated that films containing CNa are microcomposites, while nanocomposites were observed for those containing C30B. Using Flash DSC, it was possible, for the first time, not only to measure the heat capacity step at the glass transition of these two materials in their amorphous state, but also to investigate whether the preparation technique influenced the Rigid Amorphous Fraction (RAF) in our PBS- and PBSA-based nanocomposites. In this work, we have successfully shown the correlation between the microstructure of the films and their barrier properties, and especially the role played by the RAF. Indeed, the lowest permeabilities to gases and to water were determined in the films containing the highest RAF in both PBS- and PBSA-based materials. PMID- 26489905 TI - p6gag domain confers cis HIV-1 Gag-Pol assembly and release capability. AB - During virus assembly, HIV-1 Gag-Pol is packaged into virions via interaction with Pr55gag. Studies suggest that Gag-Pol by itself is incapable of virus particle assembly or cell release, perhaps due to the lack of a budding domain in the form of p6gag, which is truncated within Gag-Pol because of a ribosomal frameshift during Gag translation. Additionally (or alternatively), large molecular size may not support Gag-Pol assembly into virus-like particles (VLPs) or release from cells. To test these hypotheses, we constructed Gag-Pol expression vectors retaining and lacking p6gag, and then reduced Gag-Pol molecular size by removing various lengths of the Pol sequence. Results indicate that Gag-Pol constructs retaining p6gag were capable of forming VLPs with a WT HIV-1 particle density. Gag-Pol molecular size reduction via partial removal of the Pol sequence mitigated the Gag-Pol assembly defect to a moderate degree. Our results suggest that the Gag-Pol assembly and budding defects are largely due to a lack of p6gag, but also in part due to size limitation. PMID- 26489906 TI - Unified variable selection in semi-parametric models. AB - We propose a Bayesian variable selection method in semi-parametric models with applications to genetic and epigenetic data (e.g., single nucleotide polymorphisms and DNA methylation, respectively). The data are individually standardized to reduce heterogeneity and facilitate simultaneous selection of categorical (single nucleotide polymorphisms) and continuous (DNA methylation) variables. The Gaussian reproducing kernel is applied to the transformed data to evaluate joint effect of the variables, which may include complex interactions between, e.g., single nucleotide polymorphisms and DNA methylation. Indicator variables are introduced to the model for the purpose of variable selection. The method is demonstrated and evaluated using simulations under different scenarios. We apply the method to identify informative DNA methylation sites and single nucleotide polymorphisms in a set of genes based on their joint effect on allergic sensitization. The selected single nucleotide polymorphisms and methylation sites have the potential to serve as early markers for allergy prediction, and consequently benefit medical and clinical research to prevent allergy before its manifestation. PMID- 26489907 TI - Monitoring of embryonic and fetal losses in different breeds of goats using real time B-mode ultrasonography. AB - Compared to cattle and sheep, few studies had been undertaken to evaluate the incidence of embryonic and fetal losses (EFL) in goats. The objectives of the present study were to characterize the timing of EFL and to identify the factors that are associated with EFL in goats such as breed, age, parity, method of estrous synchronization, and breeding. Moreover, this study aimed to ensure whether a relationship existed between serum progesterone (P4) and EFL. Goats (n = 151) of different breeds (70 Zaraiebi, 42 Damascus, and 39 Cross goats [Baladi * Damascus]) were evaluated by ultrasonography to monitor EFL during different stages of gestation (D20-23, D26-29, D33-36, D40-45, and D47-54 after breeding). Blood samples were collected at D7, D20, and at each ultrasonographic scanning to clarify changes of serum P4 levels concurrently with EFL. Results revealed that 45 of 109 goats (41.28%) were exposed to EFL. A higher EFL % was observed between D20 to 23 and D47 to 54 (19.61%) compared with D47 to 54 to birth (11.76%). Moreover, a higher EFL % was observed in Zaraiebi goats compared with others. Age and goat parity had no significant effect on the EFL % in all goats. A high EFL % were observed in goats synchronized by P4 sponge, as well as artificially inseminated goats compared with goats with spontaneous estrus, and bred by natural mating, respectively. Serum P4 at D7 or D20 after breeding showed nonsignificant difference between normal pregnant goats and goats that experienced EFL. Unlike goats that experienced partial EFL, goats that experienced total EFL between D20 to 23 and D26 to 29 showed an abrupt P4 reduction (85.06%; P < 0.01) suggesting the probability of endocrine disruption of the CL. However, goats that were exposed to total EFL between D26 and 29 to D33 to 36 showed a low P4 reduction (24.90%; P < 0.05), which might be considered as an effect rather than a cause of EFL. In conclusion, different factors such as breed, estrous synchronization, breeding, and stage of pregnancy may be involved in EFL in goats. Therefore, improvement of the goat management in the early stage of pregnancy is important to decrease EFL % in goats. Although the P4 did not show any significant difference between normal pregnancy goats and goats that experienced EFL, CL disruption should be taken into the consideration, at least, in goats exposed to total embryonic losses. PMID- 26489908 TI - Effect of leptin on in vitro development of ovine preantral ovarian follicles. AB - The influence of human or ovine leptin on in vitro culture of preantral follicles (PFs) isolated from sheep ovaries was investigated. Among the 12 different concentrations (0-1000 ng/mL) of human leptin tested, proportion of PFs exhibiting growth, mean increase in diameter, antrum formation, and maturation of the oocytes to MII stage were the best in 10 ng/mL. Culture of sheep ovarian PFs in TCM 199 supplemented with 10 ng/mL of human or ovine leptin FSH (2.5 MUg/mL), thyroxine (1 MUg/mL), insulinlike growth factor I (10 ng/mL), and GH (1 mIU/mL) resulted in significantly (P <= 0.05) greater average increase in diameter (11 and 9 vs. 6 MUm), better proportions of PFs exhibiting growth (66% and 58% vs. 48%), antrum formation (51% and 51% vs. 34%), and maturation of oocytes to MII stage (24% and 22% vs. 7%) than the control medium. It is concluded that (1) the optimum dose of leptin for the growth of sheep PFs in vitro was 10 ng/mL, (2) human or ovine leptin supported similar development in vitro of PFs in sheep, (3) inclusion of leptin along with FSH, thyroxine, insulinlike growth factor I, and GH resulted in only a marginal further improvements in in vitro development of sheep PFs'. PMID- 26489909 TI - Reversible estrous cycle suppression in prepubertal female rabbits treated with slow-release deslorelin implants. AB - The aim of this study was to examine the long-term effect of a 4.7-mg deslorelin GnRH analog implant on ovarian function in the prepubertal female rabbit. Seven female rabbits (group 1) were treated with the implant at the age of 60 days. The implant was inserted subcutaneously in the umbilical region. Two animals (group 2) were not treated and served as a control group. The vulva of all 9 animals was examined for the presence of typical cyclical changes, additionally the occurrence of mounting behavior was recorded. Ovarian function was checked by administration of a short-acting GnRH agonist to induce ovulation and pseudopregnancy (0.8 MUg of buserelin per animal intramuscularly). Ten days after each treatment with buserelin, blood was collected for progesterone measurement to confirm pseudopregnancy. After implant insertion, the first blood collection (Day 10) was done without preceding induction of ovulation to screen for implant induced ovulation and pseudopregnancy. The implant was in situ for 273 days, and during this time span, 12 attempts of induction of ovulation were carried out in intervals of 21 days, beginning at the age of 81 days. Afterward, it was removed under local anesthesia and 3 further inductions of ovulation by the same scheme were conducted. The insertion of the implant led to the establishment of a pseudopregnancy in 2 of 7 animals; the remaining 5 animals did not show elevated progesterone values. Attempts to induce ovulation by administration of the short acting GnRH analog while the slow-release GnRH analog implant was in place were not successful in treated animals, and progesterone concentrations were basal. The effect was reversible as ovulation could be induced in 2 subsequent cycles in all animals by the third induction of ovulation after implant removal. Induction of ovulation in control animals at the age of 110 and 131 days resulted in elevated progesterone levels after 10 days. No adverse side effects could be observed in implant-treated animals. The typical red coloration of the vulva could be seen in group 2 and after implant removal in group 1. The results suggest that in 5 of 7 rabbits, puberty was delayed by the treatment with the 4.7 mg deslorelin slow-release analog until the implant had been removed. In the other animals, the treatment induced an initial flare-up phenomenon. Afterward, the treatment could reversibly suppress ovarian function in all 7 treated animals. PMID- 26489910 TI - Association between antral follicle count and reproductive measures in New Zealand lactating dairy cows maintained in a pasture-based production system. AB - The antral follicle count (AFC) in cattle is consistent throughout the estrous cycle of individual cows, and cows with a lower AFC have lower fertility. We assessed the AFC at random stages of the estrous cycle, examined the correlation between AFC classifications, and determined the relationship between the most rapid and practical laboratory-based AFC classification (AFC of follicles of >= 2 mm in diameter) and fertility measures in New Zealand lactating dairy cows. Cows detected in estrus (n = 202) or not (n = 239) during the first 4 weeks of the breeding season were subjected to ultrasonography and classified as having a high, medium, or low AFC at the time of scanning (on-site classification). Images from ultrasound scanning were recorded onto video for accurate follicle counting in an imaging laboratory. A strong association (P < 0.05) between the AFC of follicles with a diameter of 2 mm or greater and fertility was observed. Cows with a high AFC had a shorter (P < 0.05) interval from calving to conception by artificial insemination (AI; 82.4 +/- 1.6 vs. 87.3 +/- 1.2 days) and greater pregnancy rates (PRs; i.e., PR to the first AI [68.1% vs. 45.3%], 6-week PR [81.9% vs. 67.3%], and overall PR [91.3% vs. 79.7%]) than cows with a low AFC. The AFC was positively associated (P < 0.0001) with age. Progesterone concentrations during diestrus were greater (P < 0.05) in high-AFC cows (7.6 +/- 0.3 ng/mL) than in low-AFC cows (6.5 +/- 0.3 ng/mL), whether these were pregnant (7.7 +/- 0.3 ng/mL) or not (6.3 +/- 0.2 ng/mL). A rapid on-site scoring system determined that cows classified as having a high AFC had a shorter (P < 0.05) interval from calving to the first AI (76.5 +/- 1.7 vs. 82.3 +/- 1.9 days) and were more likely to show estrus (P < 0.01; 56.8% vs. 36.4%) and have a CL at the beginning of the breeding season (P < 0.01; 93.4% vs. 79.6%) than cows with a low on-site AFC. Collectively, we have confirmed an association between AFC2 and fertility, and these results support the hypothesis that cows with a greater number of antral follicles are more fertile than cows with a lesser number of follicles. Although the on-site classification was related to resumption of estrous cycles after calving, associations with other fertility measurements could not be observed, highlighting a need for further refinement of the on-site classification system for rapid phenotyping of the AFC. PMID- 26489911 TI - Supporting the mental health of trafficked people. PMID- 26489912 TI - Characteristics of trafficked adults and children with severe mental illness: a historical cohort study. AB - BACKGROUND: Evidence regarding the mental health needs of trafficked people is limited; however, prevalence of depression and post-traumatic stress disorder is high among trafficked people who are in contact with shelter services. We aimed to investigate the sociodemographic and clinical characteristics of trafficked people with severe mental illness. METHODS: We did a historical cohort study of trafficked people in contact with secondary mental health services in South London, UK, between Jan 1, 2006, and July 31, 2012. We searched and retrieved comprehensive clinical electronic health records for over 200 000 patients from the Case Register Interactive Search database to identify trafficked patients. A matched cohort of non-trafficked adults was generated by simple computer generated random selection of potential controls for each case within the parameters of matching criteria. We extracted data on sociodemographic and clinical characteristics and abuse history, and used multiple imputation to deal with missing data. We fitted logistic regression models to compare trafficked and non-trafficked patients. FINDINGS: We identified 133 trafficked patients, including 37 children. 78 (81%) of 96 adults and 25 (68%) of 37 children were female. 19 (51%) of 37 children were trafficked for sexual exploitation. Among both adults and children, the most commonly recorded diagnoses were post traumatic stress disorder, severe stress, or adjustment disorder (27 adults [28%] and ten children [27%]) and affective disorders (33 adults [34%] and ten children [27%]). Records documented childhood physical or sexual abuse among trafficked adults (41 [43%]) and children (28 [76%]), and adulthood abuse among trafficked adults (58 [60%]). Trafficked adults were more likely to be compulsorily admitted as a psychiatric inpatient than non-trafficked adults (adjusted odds ratio 7.61, 95% CI 2.18-26.60; p=0.002) and had longer admissions (1.48, 1.01-2.15; p=0.045). No association was found between trafficking status and either adverse pathway into care (adjusted odds ratio 0.91, 95% CI 0.40-2.05; p=0.82) or substance misuse problems (0.55, 0.27-1.17; p=0.12). INTERPRETATION: Severe mental illness in trafficked people is associated with longer admissions and high levels of abuse before and after trafficking. Evidence is needed on the effectiveness of interventions to promote recovery for this vulnerable group. FUNDING: Department of Health Policy Research Programme. PMID- 26489913 TI - Role of self-assembly coated Er(3+): YAlO3/TiO2 in intimate coupling of visible light-responsive photocatalysis and biodegradation reactions. AB - Conventionally used ultraviolet light can result in dissolved organic carbon (DOC) increasing and biofilm damage in intimate coupling of photocatalysis and biodegradation (ICPB). Visible-light-responsive photocatalysis offers an alternative for achieving ICPB. In this study, composite-cubes were developed using self-assembly to coat a thin and even layer of visible-light-responsive photocatalyst (Er(3+): YAlO3/TiO2) on sponge-type carriers, followed by biofilm cultivation. The degradations of phenol (50 mg L(-1)) were compared for four protocols in circulating beds: adsorption (AD), visible-light-responsive photocatalysis (VPC), biodegradation (B), and intimately coupled visible-light responsive photocatalysis and biodegradation (VPCB). The phenol and DOC removal efficiencies using VPCB in 16 h were 99.8% and 65.2%, respectively, i.e., higher than those achieved using VPC (71.6% and 50.0%) or B (99.4% and 58.2%). The phenol removal of 96.3% could be obtained even after 3 additional cycles. The 6.17-min intermediate detected by HPLC, continuously accumulated for VPC, appeared at 1-6 h and then was completely removed for VPCB in 10 h. ICPB was further illustrated in that most of the biofilm was protected in the carrier interiors, with less protection on the carrier exterior in VPCB. A self regulation mechanism that helped photocatalyst exposure to visible-light irradiation was identified, promoting the combined photocatalysis and biodegradation. PMID- 26489914 TI - VOCs elimination and health risk reduction in e-waste dismantling workshop using integrated techniques of electrostatic precipitation with advanced oxidation technologies. AB - Volatile organic compounds (VOCs) emitted during the electronic waste dismantling process (EWDP) were treated at a pilot scale, using integrated electrostatic precipitation (EP)-advanced oxidation technologies (AOTs, subsequent photocatalysis (PC) and ozonation). Although no obvious alteration was seen in VOC concentration and composition, EP technology removed 47.2% of total suspended particles, greatly reducing the negative effect of particles on subsequent AOTs. After the AOT treatment, average removal efficiencies of 95.7%, 95.4%, 87.4%, and 97.5% were achieved for aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, as well as nitrogen- and oxygen-containing compounds, respectively, over 60-day treatment period. Furthermore, high elimination capacities were also seen using hybrid technique of PC with ozonation; this was due to the PC unit's high loading rates and excellent pre-treatment abilities, and the ozonation unit's high elimination capacity. In addition, the non-cancer and cancer risks, as well as the occupational exposure cancer risk, for workers exposed to emitted VOCs in workshop were reduced dramatically after the integrated technique treatment. Results demonstrated that the integrated technique led to highly efficient and stable VOC removal from EWDP emissions at a pilot scale. This study points to an efficient approach for atmospheric purification and improving human health in e-waste recycling regions. PMID- 26489915 TI - Role of ingestion route in the perfluoroalkyl substance bioaccumulation by Chironomus plumosus larvae in sediments amended with carbonaceous materials. AB - The role of ingestion route in the bioaccumulation of six types of perfluoroalkyl substances (PFASs) by Chironomus plumosus larvae in sediments amended with four types of carbonaceous materials (CMs) was studied. The results showed that the body burden of PFASs decreased in the presence of CMs at mass ratios of 0.2-2%, regardless of ingestion. PFASs accumulated by the larvae with ingestion exposure were higher than those without ingestion, and the role of ingestion route was altered in the presence of CMs. The contribution of ingestion route to PFAS bioaccumulation was 2.7-31.6% without CMs, and it increased to more than 61.4% in the presence of fullerene at mass ratios of 0.2-2%. The enhancement of the ingestion route contribution caused by CMs is due to the fact that the CMs can be ingested and CM-associated PFASs can be partly desorbed in larvae. The maximum desorption efficiency of perfluorooctanoic acid was 20.8% from fullerene by the larval digestive juice. This study suggests that CM-associated PFASs could be accumulated partly by organisms, and the ecological risk of PFASs might increase in some cases with the presence of CMs. This should be considered when applying CMs in PFAS and other hydrophobic organic compound pollution remediation. PMID- 26489916 TI - Leaching modelling of slurry-phase carbonated steel slag. AB - In the present work the influence of accelerated mineral carbonation on the leaching behaviour of basic oxygen furnace steel slag was investigated. The environmental behaviour of the material as evaluated through the release of major elements and toxic metals under varying pH conditions was the main focus of the study. Geochemical modelling of the eluates was used to derive a theoretical description of the underlying leaching phenomena for the carbonated material as compared to the original slag. Among the investigated elements, Ca and Si were most appreciably affected by carbonation. A very clear effect of carbonation on leaching was observed for silicate phases, and lower-Ca/Si-ratio minerals were found to control leaching in carbonated slag eluates as compared to the corresponding untreated slag sample as a result of Ca depletion from the residual slag particles. Clear evidence was also gained of solubility control for Ca, Mg and Mn by a number of carbonate minerals, indicating a significant involvement of the original slag constituents in the carbonation process. The release of toxic metals (Zn, V, Cr, Mo) was found to be variously affected by carbonation, owing to different mechanisms including pH changes, dissolution/precipitation of carbonates as well as sorption onto reactive mineral surfaces. The leaching test results were used to derive further considerations on the expected metal release levels on the basis of specific assumptions on the relevant pH domains for the untreated and carbonated slag. PMID- 26489917 TI - Biodegradation of 4-nitroaniline by plant-growth promoting Acinetobacter sp. AVLB2 and toxicological analysis of its biodegradation metabolites. AB - 4-nitroaniline (4-NA) is one of the major priority pollutants generated from industrial productions and pesticide transformation; however very limited biodegradation details have been reported. This work is the first to report 4-NA biodegradation kinetics and toxicity reduction using a newly isolated plant growth promoting bacterium, Acinetobacter sp. AVLB2. The 4-NA-dependent growth kinetics parameters: MUmax, Ks and Ki, were determined to be 0.039 h(-1), 6.623 mg L(-1) and 25.57 mg L(-1), respectively using Haldane inhibition model, while the maximum biodegradation rate (Vmax) of 4-NA was at 0.541 mg L(-1) h(-1) and 0.551 mg L(-1) h(-1), following Michaelis-Menten and Hanes-Woolf models, respectively. Biodegradation pathway of 4-NA by Acinetobacter sp. AVLB2 was proposed, and successfully led to the reduction of 4-NA toxicity according to the following toxicity assessments: microbial toxicity using Escherichia coli DH5alpha, phytotoxicity with Vigna radiata and Crotalaria juncea, and cytogenotoxicity with Allium cepa root-tip cells. In addition, Acinetobacter sp. AVLB2 possess important plant-growth promoting traits, both in the presence and absence of 4-NA. This study has provided a new insight into 4-NA biodegradation ability and concurrent plant-growth promoting activities of Acinetobacter sp. AVLB2, which may indicate its potential role for rhizoremediation, while sustaining crop production even under 4-NA stressed environment. PMID- 26489918 TI - An eHealth Application in Head and Neck Cancer Survivorship Care: Health Care Professionals' Perspectives. AB - BACKGROUND: Although many cancer survivors could benefit from supportive care, they often do not utilize such services. Previous studies have shown that patient reported outcomes (PROs) could be a solution to meet cancer survivors' needs, for example through an eHealth application that monitors quality of life and provides personalized advice and supportive care options. In order to develop an effective application that can successfully be implemented in current health care, it is important to include health care professionals in the development process. OBJECTIVE: The aim of this study was to investigate health care professionals' perspectives toward follow-up care and an eHealth application, OncoKompas, in follow-up cancer care that monitors quality of life via PROs, followed by automatically generated tailored feedback and personalized advice on supportive care. METHODS: Health care professionals involved in head and neck cancer care (N=11) were interviewed on current follow-up care and the anticipated value of the proposed eHealth application (Step 1). A prototype of the eHealth application, OncoKompas, was developed (Step 2). Cognitive walkthroughs were conducted among health care professionals (N=21) to investigate perceived usability (Step 3). Interviews were recorded, transcribed verbatim, and analyzed by 2 coders. RESULTS: Health care professionals indicated several barriers in current follow-up care including difficulties in detecting symptoms, patients' perceived need for supportive care, and a lack of time to encourage survivors to obtain supportive care. Health care professionals expected the eHealth application to be of added value. The cognitive walkthroughs demonstrated that health care professionals emphasized the importance of tailoring care. They considered the navigation structure of OncoKompas to be complex. Health care professionals differed in their opinion toward the best strategy to implement the application in clinical practice but indicated that it should be incorporated in the HNC cancer care pathway to ensure all survivors would benefit. CONCLUSIONS: Health care professionals experienced several barriers in directing patients to supportive care. They were positive toward the development and implementation of an eHealth application and expected it could support survivors in obtaining supportive care tailored to their needs. The cognitive walkthroughs revealed several points for optimizing the application prototype and developing an efficient implementation strategy. Including health care professionals in an early phase of a participatory design approach is valuable in developing an eHealth application and an implementation strategy meeting stakeholders' needs. PMID- 26489919 TI - Uncertainties of deformable image registration for dose accumulation of high-dose regions in bladder and rectum in locally advanced cervical cancer. AB - PURPOSE: To compare the dose accumulation for bladder and rectum by deformable image registration (DIR) and direct addition (DA) of dose volume histogram parameters in magnetic resonance image-guided adaptive brachytherapy (IGABT). Two DIR algorithms, contour- and intensity-based, also have been analyzed. METHODS AND MATERIALS: Patients (n = 21) treated with IGABT for carcinoma cervix under the IntErnational study on MRI-guided BRachytherapy in locally Advanced CErvical cancer protocol were analyzed. Each patient underwent two HDR-BT applications, 1 week apart with two fractions of 7 Gy each delivered per application. For each application, magnetic resonance imaging, volume delineation, reconstruction, treatment planning (BT1 and BT2), and dose evaluation were carried out. BT1 and BT2 images were registered using an intensity-based DIR, followed by deformable dose accumulation (DDA), which was then compared with DA. To compare the intensity-based DIR to other DIR approaches, nine patients were further evaluated using an in-house contour-based DIR algorithm for bladder dose accumulation. RESULTS: Mean (+/-standard deviation; range) percentage variation between DA and DDA was found to be 2.4% (+/-3.3;-1.8, 11.5) and 5.2% (+/-5.1;-1.7, 16.5) for the rectum and bladder, respectively. The differences between the DA and DDA were found to be statistically significant for both rectum (p = 0.008) and bladder (p = 0.0003). Intensity-based DIR algorithm resulted in a larger mean deviation between DDA and DA as compared with contour-based DIR, although statistically insignificant (p = 0.32). The difference between DDA and DA was 2.4 +/- 2.0% and 1.3 +/- 1.2%, for intensity- and contour-based DIR, respectively. CONCLUSIONS: DA of dose volume histogram parameters provides a good estimate to the dose to the organs at risk; DIR based on image intensities may lead to systematic underestimation of dose due to implausible DIR. PMID- 26489920 TI - Prostate-specific antigen bounce after curative brachytherapy for early-stage prostate cancer: A study of 274 African-Caribbean patients. AB - BACKGROUND: Prostate cancer incidence in the African-Caribbean population ranks among the highest worldwide. We aim to evaluate the prostate-specific antigen (PSA) kinetics after brachytherapy, which so far remains unknown in this population. METHODS AND MATERIALS: From 2005 to 2013, 371 patients received (125)I brachytherapy of 145 Gy for early-stage prostate cancer. Eligibility criteria were cTNM <=T2c, Gleason score <=7, and initial PSA <=15 ng/mL. Pretreatment androgen deprivation therapy was allowed. PSA bounce was defined as an increase of >=0.4 ng/mL, lasting >=6 months, followed by a decrease without any anticancer therapy. We examined PSA kinetics during followup. RESULTS: For the 274 patients with at least 24 months followup, median age was 62 years old (range, 45-76). Initial PSA was <10 ng/mL in 244 and 10-15 ng/mL in 30 patients; 40 received androgen deprivation therapy. With a median followup of 50 months (range, 24-125), PSA declined continuously in 168 (61%) patients, bounced in 87 (31%), and initially declined and then rose in 22 (8%) patients. Among these latter patients, 18 presented clinical recurrence. Mean bounce intensity was 2.0 ng/mL (median, 1.2; range, 0.4-12.4). Bounces occurred in average 12 months after brachytherapy. Patients with bounce were significantly younger: mean age 59 vs. 63 years old in patients without bounce, p <0.001. Bounce was also significantly associated with the immediate post-brachytherapy PSA, mean 4.0 among bounce cases vs. 2.9 among non-bounce cases, p < 0.001. Bounce was not associated with recurrence. CONCLUSIONS: PSA bounce in our African-Caribbean population seemed earlier and was more intense than described in other populations. Early increase of PSA should not be ascribed to treatment failure. PMID- 26489921 TI - Significant association of brachytherapy boost with reduced prostate cancer specific mortality in contemporary patients with localized, unfavorable-risk prostate cancer. AB - PURPOSE: A randomized trial recently found that adding brachytherapy (BT) boost to external beam radiation therapy (EBRT) improves biochemical recurrence-free survival but not prostate cancer-specific mortality (PCSM). We investigated the relationship between BT boost and PCSM in a modern cohort from a large population based database. METHODS AND MATERIALS: We conducted an analysis of patients in Surveillance, Epidemiology, and End Results diagnosed with intermediate- or high risk prostate cancer in 2004-2011, treated with EBRT only or EBRT + BT. The cumulative incidence of PCSM was evaluated in the presence of other-cause mortality as a competing risk. Propensity score matching and multivariable Fine and Gray proportional hazard models were used to evaluate the association of combined modality RT on PCSM. RESULTS: A total of 52,535 patients were identified, of which 19.6% were treated with EBRT + BT. One-third of cases were high-risk. On multivariable analysis, the adjusted hazard ratio (AHR) of PCSM for EBRT + BT vs. EBRT alone was 0.69 (95% confidence interval [CI], 0.55-0.87, p = 0.002), and the adjusted incidence of PCSM was 1.8% vs. 2.7% at 8 years, respectively. In subgroup analyses, the AHR for PCSM was also significantly reduced with EBRT + BT for high-risk disease (AHR 0.70; 95% CI, 0.52-0.94, p = 0.02; adjusted incidence of PCSM at 8 years, 5.4% vs. 7.6%), but not for intermediate-risk disease. CONCLUSIONS: BT boost was associated with a moderate reduction to PCSM in men with localized unfavorable-risk prostate cancer. Those most likely to benefit are younger patients with high-risk disease. PMID- 26489922 TI - Hypofractionated high-dose-rate plesiotherapy in nonmelanoma skin cancer treatment. AB - PURPOSE: Nonmelanoma skin cancer (NMSC) is the commonest cancer in humans. NMSC treatment currently includes surgery, radiation therapy, and topical approaches. The objective was to analyze and compare the outcomes, toxicity, and cosmesis of NMSC treated by two hypofractionated high-dose-rate (HDR) plesiotherapy techniques. METHODS AND MATERIALS: A retrospective institutional clinical study of 134 basal cell or squamous cell skin carcinomas treated at Radiation Oncology Department. Lesions were treated from November 2006 to December 2011 with a moderate hypofractionated HDR plesiotherapy using a fixed applicator or a customized mold. RESULTS: After a median follow-up of 33 months, overall disease free survival at 3 and 5 years was 95.12% and 93.36%, respectively. For Leipzig applicator, disease-free survival at 3 years was 94.9% and 94.9% at 5 years, for customized mold was 93.1% at 3 years and 88% at 5 years. Complete regression was achieved in 98% of lesions. Two lesions persisted after treatment; both had been treated by a Leipzig applicator. Six lesions suffered local recurrence (five Leipzig applicators and three molds, p = 0.404). Grade <2 acute toxicity noted in 57.3% of patients. Only 2.2% of lesions had Grade 4 acute toxicity. Borderline significant increase of toxicity was associated with customized molds (p = 0.067). Larger tumors were associated with higher acute skin toxicity. The cosmesis outcomes were excellent or good in 82% of patients, fair in 13%, and not available in 5%. CONCLUSIONS: Hypofractionated HDR plesiotherapy is an effective and well-tolerated treatment for NMSC with different toxicity levels depending on the plesiotherapy technique used. PMID- 26489923 TI - Treatment outcomes with permanent brachytherapy in high-risk prostate cancer patients stratified into prognostic categories. AB - PURPOSE: To determine whether a previously reported substratification system can be extrapolated to patients with high-risk prostate cancer treated with permanent interstitial brachytherapy. METHODS AND MATERIALS: Four hundred six National Comprehensive Cancer Network patients with high-risk prostate cancer treated with permanent prostate brachytherapy with or without supplemental external beam radiotherapy were stratified into good (prostate-specific antigen >20 or Gleason score >=8 or >=T3), intermediate (prostate-specific antigen >20 and >=T3), and poor (Gleason score >=8 with >=1 additional high-risk feature) prognostic cohorts. Because of only 1 patient with intermediate high-risk disease, the analysis was performed on patients in the good and poor cohorts. Biochemical failure (BF), prostate cancer-specific mortality (PCSM), distant metastasis, and overall mortality were assessed as function of prognostic group. Multiple parameters were evaluated for impact on outcome. RESULTS: With a median followup time of 7.9 years, 10- and 14-year rates of BF and PCSM for the entire cohort were 7.8% and 3.7%, respectively. The BF rate was significantly greater in the poor prognostic category (16.8% vs. 7.8%, p = 0.041). The poor prognostic category was the strongest predictor of BF in univariate and multivariate analyses. No statistically significant differences in PCSM, distant metastasis, or overall mortality were identified between the good and poor prognostic categories. CONCLUSIONS: Patients with high-risk prostate cancer treated with a brachytherapy approach have excellent long-term biochemical control and cancer specific survival. The poor prognostic high-risk category had a higher rate of BF compared with the good prognostic category without a higher rate of PCSM or distant metastasis. PMID- 26489924 TI - Health workforce governance: Processes, tools and actors towards a competent workforce for integrated health services delivery. AB - A competent health workforce is a vital resource for health services delivery, dictating the extent to which services are capable of responding to health needs. In the context of the changing health landscape, an integrated approach to service provision has taken precedence. For this, strengthening health workforce competencies is an imperative, and doing so in practice hinges on the oversight and steering function of governance. To aid health system stewards in their governing role, this review seeks to provide an overview of processes, tools and actors for strengthening health workforce competencies. It draws from a purposive and multidisciplinary review of literature, expert opinion and country initiatives across the WHO European Region's 53 Member States. Through our analysis, we observe distinct yet complementary roles can be differentiated between health services delivery and the health system. This understanding is a necessary prerequisite to gain deeper insight into the specificities for strengthening health workforce competencies in order for governance to rightly create the institutional environment called for to foster alignment. Differentiating between the contribution of health services and the health system in the strengthening of health workforce competencies is an important distinction for achieving and sustaining health improvement goals. PMID- 26489926 TI - General and abdominal adiposity in a representative sample of Portuguese adults: dependency of measures and socio-demographic factors' influence. AB - The aims of this study were: (i) to estimate the dependency between BMI and waist:height ratio (WHtR) as measures of general and abdominal adiposity, and (ii) to evaluate the influence of socio-demographic factors on both measures and on their dependency in risk classification. Data from a cross-sectional study conducted in 2009 among a representative sample of 3529 Portuguese adults were used. Height, weight and waist were measured and socio-demographic data (sex, age, education level, occupational status, marital status, region of residence) were obtained. Using logistic regression, crude and adjusted OR for high general (BMI>=25.0 kg/m2) and abdominal (WHtR>=0.5) adiposity, and for incompatible classification between them, were calculated. Above half (50.8%) of the respondents had high BMI and 42.1% had high WHtR, and the rates were higher in men than in women. There was an inverse association between education level and both adiposity measures. The lowest prevalence of high general and abdominal adiposity was observed in students and singles, whereas the highest was found in retired, widowed and respondents from Azores, Madeira and Alentejo. Nearly a quarter of respondents (24.0%) were incompatibly classified by BMI and WHtR, with higher prevalence in men than in women and in low- than in high-educated people. Future surveys should focus on developing at least sex-specific cut-offs for both measures. Implementation of effective strategies for preventing and reducing high adiposity levels in Portugal should be directed primarily to men, older, low educated individuals, as well as those living in the islands and poor regions of the country. PMID- 26489925 TI - Circulating Growth Differentiation Factor 11/8 Levels Decline With Age. AB - RATIONALE: Growth differentiation factor 11 (GDF11) and GDF8 are members of the transforming growth factor-beta superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al reported that GDF11/8 levels increase with age in mouse serum. OBJECTIVE: Here, we clarify the direction of change of circulating GDF11/8 levels with age and investigate the effects of GDF11 administration on the murine heart. METHODS AND RESULTS: We validated our previous finding that circulating levels of GDF11/8 decline with age in mice, rats, horses, and sheep. Furthermore, we showed by Western analysis that the apparent age-dependent increase in GDF11 levels, as reported by Egerman et al, is attributable to cross-reactivity of the anti-GDF11 antibody with immunoglobulin, which is known to increase with age. GDF11 administration in mice rapidly activated SMAD2 and SMAD3 signaling in myocardium in vivo and decreased cardiac mass in both young (2-month-old) and old (22-month-old) mice in a dose dependent manner after only 9 days. CONCLUSIONS: Our study confirms an age dependent decline in serum GDF11/8 levels in multiple mammalian species and that exogenous GDF11 rapidly activates SMAD signaling and reduces cardiomyocyte size. Unraveling the molecular basis for the age-dependent decline in GDF11/8 could yield insight into age-dependent cardiac pathologies. PMID- 26489927 TI - Migrant crisis in Europe: implications for intensive care specialists. PMID- 26489928 TI - Negative randomized clinical trials (RCTs): further insight from the biostatistician's point of view. PMID- 26489929 TI - Whole exome sequencing identifies a heterozygous missense variant in the PRDM5 gene in a family with Axenfeld-Rieger syndrome. AB - Axenfeld-Rieger syndrome (ARS) is a disorder affecting the anterior segment of the eye, often leading to secondary glaucoma and several systemic malformations. It is inherited in an autosomal dominant fashion that has been associated with genetic defects in PITX2 and FOXC1. Known genes CYP1b1, PITX2, and FOXC1 were excluded by Sanger sequencing. The purpose of current study is to identify the underlying genetic causes in ARS family by whole exome sequencing (WES). WES was performed for affected proband of family, and variants were prioritized based on in silico analyses. Segregation analysis of candidate variants was performed in family members. A novel heterozygous PRDM5 missense variant (c.877A>G; p.Lys293Glu) was found to segregate with the disease in an autosomal dominant fashion. The novel missense variant was absent from population-matched controls, the Exome Variant Server, and an in-house exome variant database. The Lys293Glu variant is predicted to be pathogenic and affects a lysine residue that is conserved in different species. Variants in the PRDM5 gene were previously identified in anterior segment defects, i.e., autosomal recessive brittle cornea syndrome and keratoconus. The results of this study suggest that genetic variants in PRDM5 can lead to various syndromic and nonsyndromic disorders affecting the anterior segment of the eye. PMID- 26489931 TI - Does the informal caregiver notice HIV associated mild cognitive impairment in people living with HIV? AB - HIV associated minor neurocognitive disorder (MND) may be difficult to identify as key signs and symptoms (S & S) may be due to other clinical conditions. Using a self-assessment booklet "HIV and associated MND" we recruited 123 people living with HIV (PLHIV) from three sites: two hospital HIV clinics and a sexual health clinic in Sydney, Australia. Patients may down play S & S. Caregivers may notice subtle changes. By including caregivers, we aimed to find whether the caregivers noticed S & S undetected by the PLHIV. This is a sub-study of a prospective observational multi-site study aimed to validate the usefulness of a patient self assessment tool (HIV-associated MND booklet). Using the booklet, participants and their caregivers subsequently identified S & S of MND. Sixty-four per cent (79) did not nominate a caregiver to be contacted. Participants from 2 sites 44 (36%) nominated caregivers to be contacted. Twenty-five caregivers identified more than four S & S of MND. S & S reported most by caregivers related to participants being more tired at the end of the day (76%). Participants agreed (77%). Participants also reported that they found it more difficult to remember things such as taking medications or attending medical appointments (67%). The most agreed on symptom was the requirement for increased concentration to get the same things done (Kappa P 0.599 <0.001 and McNemar 0.289). For each question at least one caregiver identified a symptom when the PLHIV did not. Caregivers were more likely than participants to report irritability and communication difficulties. It is important to include caregivers when investigating PLHIV for MND, as caregivers may validate the experience of the patient, and may also be uniquely placed to identify S & S not otherwise identified. PMID- 26489930 TI - Pangenome analysis of Bifidobacterium longum and site-directed mutagenesis through by-pass of restriction-modification systems. AB - BACKGROUND: Bifidobacterial genome analysis has provided insights as to how these gut commensals adapt to and persist in the human GIT, while also revealing genetic diversity among members of a given bifidobacterial (sub)species. Bifidobacteria are notoriously recalcitrant to genetic modification, which prevents exploration of their genomic functions, including those that convey (human) health benefits. METHODS: PacBio SMRT sequencing was used to determine the whole genome seqeunces of two B. longum subsp. longum strains. The B. longum pan-genome was computed using PGAP v1.2 and the core B. longum phylogenetic tree was constructed using a maximum-likelihood based approach in PhyML v3.0. M.blmNCII was cloned in E. coli and an internal fragment if arfBarfB was cloned into pORI19 for insertion mutagenesis. RESULTS: In this study we present the complete genome sequences of two Bifidobacterium longum subsp. longum strains. Comparative analysis with thirty one publicly available B. longum genomes allowed the definition of the B. longum core and dispensable genomes. This analysis also highlighted differences in particular metabolic abilities between members of the B. longum subspecies infantis, longum and suis. Furthermore, phylogenetic analysis of the B. longum core genome indicated the existence of a novel subspecies. Methylome data, coupled to the analysis of restriction-modification systems, allowed us to substantially increase the genetic accessibility of B. longum subsp. longum NCIMB 8809 to a level that was shown to permit site-directed mutagenesis. CONCLUSIONS: Comparative genomic analysis of thirty three B. longum representatives revealed a closed pan-genome for this bifidobacterial species. Phylogenetic analysis of the B. longum core genome also provides evidence for a novel fifth B. longum subspecies. Finally, we improved genetic accessibility for the strain B. longum subsp. longum NCIMB 8809, which allowed the generation of a mutant of this strain. PMID- 26489932 TI - Erratum: RTN1 mediates progression of kidney disease by inducing ER stress. PMID- 26489933 TI - Short-term forecasting of the prevalence of clinical trachoma: utility of including delayed recovery and tests for infection. AB - BACKGROUND: The World Health Organization aims to control blinding trachoma by 2020. Decisions on whether to start and stop mass treatments and when to declare that control has been achieved are currently based on clinical examination data generated in population-based surveys. Thresholds are based on the district-level prevalence of trachomatous inflammation-follicular (TF) in children aged 1-9 years. Forecasts of which districts may and may not meet TF control goals by the 2020 target date could affect resource allocation in the next few years. METHODS: We constructed a hidden Markov model fit to the prevalence of two clinical signs of trachoma and PCR data in 24 communities from the recent PRET-Niger trial. The prevalence of TF in children in each community at 36 months was forecast given data from earlier time points. Forecasts were scored by the likelihood of the observed results. We assessed whether use of TF with additional TI and PCR data rather than just the use of TF alone improves forecasts, and separately whether incorporating a delay in TF recovery is beneficial. RESULTS: Including TI and PCR data did not significantly improve forecasts of TF. Forecasts of TF prevalence at 36 months by the model with the delay in TF recovery were significantly better than forecasts by the model without the delay in TF recovery (p = 0.003). A zero inflated truncated normal observation model was better than a truncated normal observation model, and better than a sensitivity-specificity observation model. CONCLUSION: The results in this study suggest that future studies could consider using just TF data for forecasting, and should include a delay in TF recovery. TRIAL REGISTRATION: Clinicaltrials.gov NCT00792922. PMID- 26489934 TI - Archived DNA reveals fisheries and climate induced collapse of a major fishery. AB - Fishing and climate change impact the demography of marine fishes, but it is generally ignored that many species are made up of genetically distinct locally adapted populations that may show idiosyncratic responses to environmental and anthropogenic pressures. Here, we track 80 years of Atlantic cod (Gadus morhua) population dynamics in West Greenland using DNA from archived otoliths in combination with fish population and niche based modeling. We document how the interacting effects of climate change and high fishing pressure lead to dramatic spatiotemporal changes in the proportions and abundance of different genetic populations, and eventually drove the cod fishery to a collapse in the early 1970s. Our results highlight the relevance of fisheries management at the level of genetic populations under future scenarios of climate change. PMID- 26489935 TI - Monitoring the Competence of a New Keto-tetrahydrocarbazole Based Fluorosensor Under Homogeneous, Micro-Heterogeneous and Serum Albumin Environments. AB - We present here a detailed photophysical study of a recently synthesised fluorophore 8-methyl-8,9-dihydro-5H-[1,3]dioxolo[4,5-b]carbazol-6(7H)-one. This is a synthetic precursor of bio-active carbazole skeleton Clausenalene. Spectroscopic investigation of the fluorophore has been carried out in different protic and aprotic solvents, as well as in binary solvent mixtures, using absorption, steady-state and time-resolved fluorescence techniques. This fluorophore is particularly responsive to the hydrogen bonding nature as well as polarity of the solvent molecules. When considered in micelles and beta cyclodextrin, this behaves as a reporter of its immediate microenvironment. Steady state and time resolved fluorometric and circular dichroism techniques have been used to explore the binding interaction of the fluorophore with transport proteins, bovine serum albumin and human serum albumin. The probable binding sites of the fluorophore in the proteinous environments have been evaluated from fluorescence resonance energy transfer study. Laser flash photolysis experiments also have been performed to observe the triplet excited state interaction between the fluorophore and albumin proteins. PMID- 26489936 TI - A case of meningococcal meningitis with multiple cerebellar microbleeds detected by susceptibility-weighted imaging. AB - BACKGROUND: Bacterial meningitis is a fatal infectious disease of the central nervous system complicating intravascular involvements. Multiple microbleeds are rarely identified as complications because of the limited detection threshold of conventional imaging modalities. We report the first case of meningococcal meningitis with successful identification of multiple microbleeds in the cerebellum by susceptibility-weighted imaging. CASE PRESENTATION: A 19-year-old Japanese female was brought to our emergency department because of fever and coma. A spinal tap was performed and turbid yellow fluid was collected. A diagnosis of bacterial meningitis was established and the patient was admitted to an intensive care unit. Dexamethasone and Antibiotics were administered and Neisseria meningitides was cultured from the spinal fluid. On day 10, postcontrast magnetic resonance imaging identified enhanced subarachnoid space in the cerebellum. Susceptibility-weighted imaging showed spotty low-intensity signals in the cerebellar tissue, indicating microbleeds. The patient made a full recovery from coma and was discharged without neurological sequelae on day 24. CONCLUSION: Meningococcal meningitis can cause multiple microbleeds in the cerebellum. In this report, we successfully identified microbleeds by susceptibility-weighed imaging. Using this imaging modality, further investigations will clarify its clinical incidence and significance. PMID- 26489938 TI - Multiplex characterization of human pathogens including species and antibiotic resistance gene identification. AB - The efficient medical treatment of infections requires detailed information about the pathogens involved and potential antibiotic-resistance mechanisms. The dramatically increasing incidence of multidrug-resistant bacteria especially highlights the importance of sophisticated diagnostic tests enabling a fast patient-customized therapy. However, the current molecular detection methods are limited to either the detection of species or only a few antibiotic-resistance genes.In this work, we present a human pathogen characterization assay using a rRNA gene microarray identifying 75 species comprising bacteria and fungi. A statistical classifier was developed to facilitate the automated species identification. Additionally, the clinically most important beta-lactamases were identified simultaneously in a 100-plex reaction using padlock probes and the same microarray. The specificity and sensitivity of the combined assay was determined using clinical isolates. The detection limit was 10(5) c.f.u. ml(-1), recovering 89 % of the detectable beta-lactamase-encoding genes specifically. The total assay time was less than 7 hand the modular character of the antibiotic resistance detection allows the easy integration of further genetic targets. In summary, we present a fast, highly specific and sensitive multiplex pathogen characterization assay. PMID- 26489937 TI - Required duration of mass ivermectin treatment for onchocerciasis elimination in Africa: a comparative modelling analysis. AB - BACKGROUND: The World Health Organization (WHO) has set ambitious targets for the elimination of onchocerciasis by 2020-2025 through mass ivermectin treatment. Two different mathematical models have assessed the feasibility of reaching this goal for different settings and treatment scenarios, namely the individual-based microsimulation model ONCHOSIM and the population-based deterministic model EPIONCHO. In this study, we harmonize some crucial assumptions and compare model predictions on common outputs. METHODS: Using a range of initial endemicity levels and treatment scenarios, we compared the models with respect to the following outcomes: 1) model-predicted trends in microfilarial (mf) prevalence and mean mf intensity during 25 years of (annual or biannual) mass ivermectin treatment; 2) treatment duration needed to bring mf prevalence below a provisional operational threshold for treatment interruption (pOTTIS, i.e. 1.4 %), and 3) treatment duration needed to drive the parasite population to local elimination, even in the absence of further interventions. Local elimination was judged by stochastic fade-out in ONCHOSIM and by reaching transmission breakpoints in EPIONCHO. RESULTS: ONCHOSIM and EPIONCHO both predicted that in mesoendemic areas the pOTTIS can be reached with annual treatment, but that this strategy may be insufficient in very highly hyperendemic areas or would require prolonged continuation of treatment. For the lower endemicity levels explored, ONCHOSIM predicted that the time needed to reach the pOTTIS is longer than that needed to drive the parasite population to elimination, whereas for the higher endemicity levels the opposite was true. In EPIONCHO, the pOTTIS was reached consistently sooner than the breakpoint. CONCLUSIONS: The operational thresholds proposed by APOC may have to be adjusted to adequately reflect differences in pre control endemicities. Further comparative modelling work will be conducted to better understand the main causes of differences in model-predicted trends. This is a pre-requisite for guiding elimination programmes in Africa and refining operational criteria for stopping mass treatment. PMID- 26489939 TI - My space, my body, my sexual subjectivity: social media, sexual practice and parental control among teenage girls in urban Chiang Mai. AB - This ethnographic study conducted among young women aged 18-21 years in Chiang Mai, northern Thailand, explored the parental control mechanisms imposed by Thai middle-class families on the sexuality of their daughters. It addressed the ways in which young women tactically use the social media in order to negotiate the sexual controls they encountered in everyday life. Taking the teenage girls' point of view, this paper argues that, as active agents, young women achieve a certain level of sexual autonomy and construct their own sexual selves in modern northern Thai society, despite their parents' attempts to prevent this. The paper highlights the ways in which social media are used by Thai girls in order to achieve such a goal. Research findings should inform the development of future programmes on sexual health promotion, parental skills and sexual communication between Thai parents and their children. PMID- 26489940 TI - Consideration on the health risk reduction related to attainment of the new particulate matter standards in Poland: A top-down policy risk assessment approach. AB - Policies can influence health of a population in various ways. Numerous epidemiological studies supported by toxicological investigations demonstrate a positive association between ambient concentrations of airborne particulate matter and increased adverse cardio-respiratory events, including morbidity and mortality. The aim of this paper was to present the concept of the top-down health policy risk assessment approach model developed to estimate the expected health risk reduction associated with policy aiming at attaining the new particulate matter <= 10 MUm in diameter (PM10) standards in Poland. The top-down approach guides the analysis of causal chains from the policy to health outcomes. In this case study we tried to estimate the predicted health effects of the policy change over the past 20 years. Since Polish annual standard for PM10 changed from 50 MUg/m3 in 1990 to 40 MUg/m3 in 2010, we calculated the relative risk associated with decreasing PM10 in diameter to 10 MUg/m3 in the annual level of PM10 for 6 adverse health effects. The relative risk slightly decreased for almost all adverse health effects, which means that the relative decrease in the incidence of health effects from the baseline incidence should range from about 0.5-0.6% for heart disease admissions to > 1% for respiratory admissions. The obtained results indicate that implementation of the new ambient air standards could influence improvement of the health status of Polish population. A top-down policy health risk assessment model can be one of the main tools in this process, providing harmonized guidance how to seek evidence-based information, which could serve policy-makers. PMID- 26489941 TI - Factorization methods applied to characterize the sources of volatile organic compounds in Montreal, Quebec. AB - OBJECTIVES: The study objective was to assemble emission characteristics of the sources of the ambient volatile organic compounds (VOCs) and to elaborate methods of organizing them into the sources' chemical profiles. MATERIAL AND METHODS: The UNMIX--sensor modeling method from the U.S. Environment Protection Agency (EPA)- was used to process the VOC concentration data acquired over the years 2000-2009 for 175 VOC species in 4 air quality monitoring stations in Montreal, Quebec. RESULTS: The method enabled to assess VOC emissions from the typically distributed sources existing in urban environment and VOC occurrences characterizing the local, or point-like, sources. The distributed sources were inextricably associated with hydrocarbons from exhaust, heavier hydrocarbons from contaminated urban soil, fugitive evaporations of gasoline and liquefied petroleum gases (LPG), leakage from the industrial and commercial use of solvents, and the inert, ozone depleting gases permeating urban atmosphere. The sources' profiles were charted involving 60-120 VOC species per source. Spatial distribution of the sources was examined. CONCLUSIONS: The UNMIX application and the source profiling methods, by building robust chemical profiles of VOC sources, provided information that can be used to assign the measured VOC emissions to physical sources. This, in turn, provides means of assessing the impact of environmental policies, on one hand, and of industrial activities on the other hand on VOC air pollution. PMID- 26489942 TI - Work environment factors and work sustainability in Norwegian cooks. AB - OBJECTIVES: Cooks have increased morbidity and mortality. A high turnover has also been reported. We aimed to elucidate work environment and work sustainability in Norwegian cooks. MATERIAL AND METHODS: A questionnaire inquiring about working conditions and work participation was sent to 2082 cooks who had qualified from 1988 onwards. Of these, 894 responded. Time at work was analyzed with Kaplan-Meier plots and possible determinants for quitting work as a cook was analyzed with Cox regression. RESULTS: The median time at work was 16.6 years. There were differences in sustainability between types of kitchens for both sexes (p = 0.00). The median time in the profession was 9.2 years for the cooks in restaurants, while the cooks in institutions and canteens showed a substantially higher sustainability with 75.4% still at work after 10 years, and 57% still at work after 20 years in the profession. Of those still at work as a cook, 91.4% reported a good or very good contentment, and the 67.4% who expected to stay in the profession the next 5 years frequently answered that excitement of cooking, the social working environment, and the creative features of cooking were reasons to continue. Musculoskeletal complaints were the most common health related reason for leaving work as a cook, while working hours was the most common non-health-related reason. CONCLUSIONS: There are significant differences in work sustainability between the cooks in the different types of kitchens. The identified determinants for length of time in the occupation can be used for preventive purposes. PMID- 26489943 TI - Byssinosis and COPD rates among factory workers manufacturing hemp and jute. AB - OBJECTIVES: Prior studies have been performed on cotton textile plants throughout the world. This study was planned to identify the rate of byssinosis and chronic obstructive pulmonary disease (COPD) in hemp and jute workers and those who worked with both of them. MATERIAL AND METHODS: The study was realized in a factory which consecutively processed hemp and jute. The study enrollment included 266 people, 164 of whom were active workers and 102 were retired. A questionnaire, plain chest X-rays, physical examination and pulmonary function tests were performed. Dust levels were measured in various sections of the factory during 8 h work shifts. Endotoxin levels of various quality hemp fibers and dusts were measured. RESULTS: The rate of byssinosis (28.2%) was higher among the workers that who exposed to both jute and hemp dust. The frequency of chronic bronchitis in retired workers who previously smoked was higher (20%) as compared to currently smoking workers (17%). High dust levels were measured in some parts of the factory (mean (M) = 2.69 mg/m3). Working in dense dust areas, active smoking, being older than 40 years of age, being an ex-smoker, and working in the factory for a period exceeding 15 years were significantly associated with bronchitis and emphysema development. High endotoxin levels were determined for fine hemp dust (605 EU/mg), coarse hemp dust (336 EU/mg) and poor quality hemp fibers (114 EU/mg), whereas in fresh hemp stalks the level of endotoxin was determined to be lower (0.27 EU/mg). CONCLUSIONS: Because of high exposures to jute and hemp dusts that are associated with high byssinosis rates, personal protection and environmental hygiene is crucial to prevention of byssinosis. PMID- 26489944 TI - Prevalence of temporomandibular disorders among junior high school students who play wind instruments. AB - OBJECTIVES: This study investigated whether playing wind instruments has adverse effects on musculoskeletal functions among junior high school students who play in music clubs. MATERIAL AND METHODS: The study included 210 junior high school students (35 boys, 175 girls) belonging to 1 of 4 different school clubs that practiced playing wind instruments more than 6 days/week. The mean age of the participants was 14 years. The study was performed using a questionnaire survey and an electromyographic examination of jaw and cervical muscle activities during playing wind instruments. RESULTS: The prevalence of temporomandibular disorders (TMD) among the children playing woodwind (WW) or brass wind (BW) instruments was higher than in those playing non-wind (NW) instruments. Long duration of playing WW with a reed mouthpiece or BW with a small mouthpiece was suggested to affect the incidence of TMD, which was more marked in girls than in boys, irrespective of height or weight. Muscle activity in the masseter muscle during playing an instrument was significantly higher in the BW with a small mouthpiece group than in the NW group (p < 0.05). In cervical muscles, muscle activity of both the sternocleidomastoid and trapezius muscles was higher during playing BW than in the case of other instruments, and activity in the sternocleidomastoid muscle was significantly higher in the BW with a small mouthpiece group than in the case of other instrument groups (p < 0.05). CONCLUSIONS: Playing wind instruments may have adverse effects on musculoskeletal functions among junior high school students playing in music clubs as compared with playing NW instruments. The prevalence of TMD among the students playing wind instruments was higher than in those playing other instruments. Long duration of playing those instruments affects musculoskeletal function, and this effect is more marked in girls than in boys, irrespective of height or weight. PMID- 26489945 TI - Quality of life, work ability and other important indicators of women's occupational health. AB - OBJECTIVES: Work ability may be considered as an important aspect of well-being and health status. One of the most important factors in association with work ability is health-related quality of life (HRQoL). The aim of this study has been to determine the association between work ability, individual characteristics and HRQoL of female workers. MATERIAL AND METHODS: The design of this study has been cross-sectional. The work ability index (WAI) and Short-Form General Health Survey (SF-12) questionnaires were used to collect data. Three hundred and twenty female workers were selected from food supplier factories in Karaj. One-way analysis of variance, Pearson's correlation analysis, independent sample t-test and multiple linear regression methods were used to analyze data. RESULTS: Mean (M) and standard deviation (SD) of the WAI stood at 35.02 and 5.57, respectively. The categories of the WAI for women being as follows: 8.8% poor, 62% moderate, 25.4% good and 3.7% excellent. Mean+/-SD for the physical component summary (PCS) and mental component summary (MCS) of quality of life was 58.84+/-11.12 and 57.45+/-9.94, respectively. There was a positive significant association between the PCS and MCS with the WAI (p = 0.0001). Workers with higher education had a better work ability (p = 0.002) and shift-work workers had a worse work ability (p = 0.03). CONCLUSIONS: Work ability of majority of women was moderate. Considering mean age of studied women (27.6 years old), this work ability is not satisfactory. Physical and mental components of the HRQoL were the important factors associated with work ability. PMID- 26489946 TI - Relationships between occupational functioning and stress among radio journalists -Assessment by means of the Psychosocial Risk Scale. AB - OBJECTIVES: Job characteristics and the consequences of everyday stress among radio journalists who are not exposed to traumatic events have not been studied sufficiently before. We aimed at determining the most common job characteristics and their stressfulness; relationships between stress exposure, health and occupational functioning; differences between radio journalists and other journalists, and also the psychosocial risk for health and functioning in this group. MATERIAL AND METHODS: The studied group involved 208 journalists, 134 of whom worked in radio stations. The respondents filled in the Psychosocial Risks Scale (PRS) developed by the Department of Health and Work Psychology of the Nofer Institute of Occupational Medicine, Lodz, Poland. RESULTS: Requirement of mental effort and readiness to response quickly for most of the time as well as limited possibilities for promotion were the most frequent journalists' complaints. We confirmed that higher levels of stress resulted in worse functioning--the radio journalists who experienced lower stress assessed their health status and ability to work better, were more satisfied with particular aspects of their work, and were more involved in their work. They also presented a significantly lower turnover intention. Moreover, the radio journalists were more involved in their work than other journalists, but experienced lower satisfaction, took more sick leaves and had more days of absence. CONCLUSIONS: Well-known relationships between stress level, satisfaction and occupational functioning were confirmed. The most important conclusion refers to the fact that psychosocial risks and stress analysis should be based on the understanding of specificity of each occupation or even position. It is so, because the same job characteristic may pose a challenge for one person, while for another--it can result in extreme discomfort and anxiety--such an attitude broadens understanding of the phenomenon. We also confirmed that the PRS is a well-designed method, appropriate to investigate an individual perception of job environment and its stressfulness. Future research on causal relationships between the variables is recommended. PMID- 26489947 TI - Entry into vocational rehabilitation program following work-related hand injury: Potential candidates. AB - OBJECTIVES: This case-control study aimed to investigate the predictors of return to work (RTW) following work-related major forearm, wrist or hand injury at the preparation stage of return to work. MATERIAL AND METHODS: A total of 80 clients were recruited and divided into 2 groups depending on their readiness of RTW. The groups were compared with each other with regard to their demographics, compensation status, hand injury severity, health perception, and time off work (TOW) using correlation coefficient. Predictors of RTW were measured by logistic regression analysis. RESULTS: There were no significant differences in demographics and the severity of hand injury between 2 groups. Self-perceived physical functioning (p = 0.04), vitality (p = 0.01), mental health (p = 0.03) and TOW (p = 0.001) were significantly different between Action group and Preparation group. With binary logistic regression analysis, self-perceived vitality (odds ratio (OR) = 1.041) and TOW (OR = 0.996) were shown to be strongly predictive of RTW at the preparation stage of return to work. CONCLUSIONS: This study has shown that shorter TOW and better self-perceived vitality could predict early readiness for RTW after major work-related forearm, wrist or hand injury. PMID- 26489948 TI - Hemimellitene (1,2,3-trimethylbenzene) in the liver, lung, kidney, and blood, and dimethylbenzoic acid isomers in the liver, lung, kidney and urine of rats after single and repeated inhalation exposure to hemimellitene. AB - OBJECTIVES: The aim of the study has been to explore hemimellitene distribution in blood, liver, lung and kidney as well as toxicokinetics of its elimination from blood of rats after single and repeated inhalation exposure to this compound. Tissue distribution and excretion with urine of 2-dimethylbenzoic acids (2,3-DMBA and 2,6-DMBA) were also evaluated. MATERIAL AND METHODS: Male outbred IMP:WIST rats were used in the experiment. The animals were exposed to hemimellitene vapors at the nominal concentration of 25 ppm, 100 ppm, and 250 ppm in the dynamic inhalation chambers for 6 h for single exposure purpose and for 4 weeks (6 h/day for 5 day/week) for repeated exposure purposes. RESULTS: Significantly lower concentrations of hemimellitene were detected in the blood and tissues of animals after repeated inhalation exposure of animals to hemimellitene vapors, which points to reduced retention of the chemical in the lungs of the experimental rats. The trend of hemimellitene elimination from the blood depended solely on exposure intensity, irrespective of exposure time, both after single and repeated exposure. As regards the 2 determined hemimellitene metabolites, the major trend of the metabolic transformation involved formation of 2,3-DMBA. CONCLUSIONS: The significantly higher urinary 2,3-DMBA concentration after repeated exposure shows that hemimellitene induces enzymatic processes in the rat. PMID- 26489949 TI - Ischaemic heart disease among workers in occupations associated with heavy lifting. AB - OBJECTIVES: To investigate a hypothesized positive association between employment in occupations where heavy lifting is likely to occur, and the risk of ischaemic heart disease (IHD). MATERIAL AND METHODS: Male blue-collar workers from Denmark (N = 516,180) were monitored with respect to hospital treatment or death due to IHD, through national registers over the years 2001-2010. Poisson regression was used to estimate relative rates of IHD between "workers in occupations which, according to an expert opinion, are likely to involve heavy lifting" and "other blue-collar workers." Prevalent cases were excluded from the analysis. RESULTS: The rate ratio was estimated at 0.97 (95% confidence interval (CI): 0.94-1.00) for deaths or hospitalizations due to IHD and 1.07 (95% CI: 0.94-1.21) for deaths due to IHD. CONCLUSIONS: The results do not support the hypothesis that occupational heavy lifting is an important risk factor for IHD. PMID- 26489950 TI - Implementation of smoke-free homes in Poland. AB - OBJECTIVES: Exposure to environmental tobacco smoke (ETS) constitutes a threat to the health of many people. In order to diminish ETS exposure, countries (including Poland) implemented legal restrictions of smoking in public places and worksites. Currently more attention is also paid to reduce overall and residential ETS exposure by voluntary smoke-free home policy adoption. The aim of current analysis was to evaluate the prevalence and determinants of implementing smoking bans at place of residence among economically active males and females in Poland. MATERIAL AND METHODS: Data from cross-sectional, household study - Global Adult Tobacco Survey (GATS 2009-2010) were analyzed. The logistic regression model was applied for appropriate calculations. RESULTS: Out of 3696 studied subjects only 37.1% adopted total smoking ban within the home. Decreased likelihood of adopting total smoking bans was associated with current smoker status, low education attainment, lack of awareness on adverse health consequences of ETS, low level of support for tobacco control policies, and cohabitation with a smoker in both genders. Having smoke-free homes was also linked with age in women, place of residence and work smoking policy in indoor areas in men. CONCLUSIONS: Targeted activities to encourage adopting voluntary smoke-free rules among groups least likely to implement 100% smoking bans in the home and activities to decrease social acceptance of smoking in the presence of nonsmokers, children, pregnant woman are urgently needed. PMID- 26489951 TI - An ecological study on the association between characteristics of hospital units and the risk of occupational injuries and adverse events on the example of an Italian teaching hospital. AB - OBJECTIVES: We explored the association of workplace characteristics with occupational injuries and adverse events in an Italian teaching hospital. MATERIAL AND METHODS: This ecological study was conducted using data routinely collected in the University Hospital of Udine, Northeastern Italy. Poisson regression models were used to investigate, at the hospital unit level, the association between 5 outcomes, including: occupational injuries, patient falls, medication errors, other adverse events and near-misses, and various characteristics of the units. RESULTS: The proportion of female workers in a unit, the average number of sick-leave days and of overtime hours, the number of medical examinations requested by employees, and being a surgical unit were significantly associated with some of the outcomes. CONCLUSIONS: Despite ecological nature of the study, which does not allow for inferences to be drawn at the individual level, the results of our study provide useful clues to support strategies and interventions directed towards healthier work environments and better patient care in hospitals. PMID- 26489952 TI - Estimate of radon exposure in geothermal spas in Poland. AB - OBJECTIVES: Geothermal waters may contain soluble, radioactive radon gas. Spa facilities that use geothermal water may be a source of an increased radiation dose to people who stay there. It has been necessary to assess the exposure to radon among people: workers and visitors of spa centers that use geothermal waters. MATERIAL AND METHODS: In 2013, workers of the Nofer Institute of Occupational Medicine measured concentrations of radon over the geothermal water surfaces in 9 selected Polish spa centers which use geothermal water for recreational and medicinal purposes. The measurements were performed by active dosimetry using Lucas scintillation cells. RESULTS: According to our research, the doses received by the personnel in Polish geothermal spas are < 0.6 mSv/year. In 1 of the investigated spas, the estimated annual dose to the staff may exceed 3 mSv/year. CONCLUSIONS: In Polish geothermal spas, neither the workers nor the visitors are at risk of receiving doses that exceed the safe limits. PMID- 26489953 TI - A novel surfactant-, NaCl-, and protease-tolerant beta-mannanase from Bacillus sp. HJ14. AB - A glycoside hydrolase family 5 beta-mannanase-encoding gene was cloned from Bacillus sp. HJ14 isolated from saline soil in Heijing town. Coding sequence of mature protein (without the predicted signal peptide from M1 to A30) was successfully expressed in Escherichia coli BL21 (DE3). Purified recombinant mannanase (rMan5HJ14) exhibited optimal activity at pH 6.5 and 65 degrees C. The enzyme showed good salt tolerance, retaining more than 56 % beta-mannanase activity at 3.0-30.0 % (w/v) NaCl and more than 94 % of the initial activity after incubation with 3.0-30.0 % (w/v) NaCl at 37 degrees C for 60 min. Almost no mannanase activity was lost after incubation of rMan5HJ14 with trypsin, proteinase K, and Alcalase at 37 degrees C for 60 min. Surfactants and chelating agents, namely SDS, CTAB, Tween 80, Triton X-100, EDTA, and sodium tripolyphosphate, showed little or no effect (retaining >82.4 % activity) on enzymatic activity. Liquid detergents, namely Tupperware, Walch, Bluemoon, Tide, and OMO, also showed little or no effect (retaining >72.4 % activity) on enzymatic activity at 0.5-2.0 % (v/v). The enzyme further presents a high proportion (11.97 %) of acidic amino acid residues (D and E), which may affect the SDS and NaCl tolerance of the enzyme. Together, the mannanase may be an alternative for potential use in liquid detergent industry. PMID- 26489955 TI - Predictors of early breastfeeding initiation among mothers of children under 24 months of age in rural part of West Ethiopia. AB - BACKGROUND: The World Health Organization recommends initiation of breastfeeding within the first hour after childbirth. In developing countries alone, early initiation of breastfeeding could save as many as 1.45 million lives each year by reducing deaths mainly due to diarrheal disorders and lower respiratory tract infections in children. The current study aimed to determine the rate and the predictors of breastfeeding initiation in East Wollega Zones of West Ethiopia. METHODS: A community-based, cross-sectional study was conducted from April to May 2014 among 594 mothers who had children less than 24 months. Multi stage cluster sampling method was used to select the study population. Eligible mothers were invited to interview using pretested questionnaires to gather data regarding sociodemographics, health-related variables, breastfeeding initiation, and current breastfeeding practices. A multivariable logistic regression analysis was used to identify independent predictors of early initiation of breastfeeding after controlling for confounding variables. RESULTS: A sample of 593 mothers was included in the study. Breastfeeding was initiated by 83.1 % of mothers within the first hour of childbirth. Being a housewife (AOR (95 % CI) = 2.48 (1.54- 3.99)) and infant received colostrum (AOR (95 % CI) =2.22 (1.08-4.55)) were significant positive predictors for early breastfeeding initiation as revealed by logistic regression. The multivariable logistic regression analysis showed that the mothers who had no radio and/or TV in the household (AOR (95 % CI = 0.55 (0.35-0.88)), were not exposure to health information (AOR (95 % CI) = 0.44 (0.25 0.75)), and infants were provided with prelacteal feeds (AOR (95 % CI)=0.30 (0.14 0.65)) were less likely to initiate breastfeeding. CONCLUSIONS: The rate of timely initiation of breastfeeding was high. Breastfeeding promotion program is essential to encourage the practice of timely initiation of breastfeeding, and reduce the practice of providing prelacteal feeds within three days of life. Thus appropriate health information is vital to boost early initiation of breastfeeding. PMID- 26489956 TI - Assessing the health of the general population in England: how do the three- and five-level versions of EQ-5D compare? AB - BACKGROUND: The EQ-5D is a brief, generic measure of health status that can be easily incorporated into population health surveys. There are two versions of the EQ-5D for use in adult populations, one with 3 response levels in each of the instrument's 5 dimensions (EQ-5D-3L) and one with 5 levels in each dimension (EQ 5D-5L). We compared the two versions as measures of self-reported health status in representative samples of the English general population. METHODS: EQ-5D-5L data were available from 996 respondents selected at random from residential postcodes who took part in the EQ-5D-5L value set for England study. EQ-5D-3L data were available from 7294 participants included in the 2012 Health Survey for England. Responses on the 3L and 5L versions of EQ-5D were compared by examining score distributions on the two versions, both in terms of the profile (dimensions) and the EQ-VAS. To determine the extent of variations in score according to respondent characteristics, we analysed health status reporting on the descriptive profile, EQ-5D Index, and EQ-VAS of both versions of EQ-5D by age, sex, and educational background. We used X (2) to test for differences between respondent categories when analyzing EQ-5D profile data and the t test when analyzing EQ-5D Index and VAS scores. RESULTS: The 5L version of EQ-5D led to a considerably reduced ceiling effect and a larger proportion of respondents reporting severe health problems compared to the 3L. The 5L version also led to the use of a wider spread of health states; just 3 health states on the 3L covered 75 % of the sample, compared to 12 states on the 5L. Both versions showed poorer health status in older respondents, females, and those in a lower educational category and the EQ-5D-5L descriptive system, though not the Index or VAS, discriminated better between age groups than the 3L. There were no appreciable differences between the two versions in their ability to discriminate between groups defined by gender or educational level. CONCLUSIONS: The new, expanded 5L version of EQ-5D may be a more useful instrument for the measurement of health status in population health surveys than the original 3L version. PMID- 26489957 TI - Low public health risk of MERS-CoV in people returning from the Hajj. PMID- 26489958 TI - Fluorine doping: a feasible solution to enhancing the conductivity of high resistance wide bandgap Mg0.51Zn0.49O active components. AB - N-type doping of high-resistance wide bandgap semiconductors, wurtzite high-Mg content MgxZn1-xO for instance, has always been a fundamental application motivated research issue. Herein, we report a solution to enhancing the conductivity of high-resistance Mg0.51Zn0.49O active components, which has been reliably achieved by fluorine doping via radio-frequency plasma assisted molecular beam epitaxial growth. Fluorine dopants were demonstrated to be effective donors in Mg0.51Zn0.49O single crystal film having a solar-blind 4.43 eV bandgap, with an average concentration of 1.0 * 10(19) F/cm(3).The dramatically increased carrier concentration (2.85 * 10(17) cm(-3) vs ~10(14) cm( 3)) and decreased resistivity (129 Omega . cm vs ~10(6) Omega cm) indicate that the electrical properties of semi-insulating Mg0.51Zn0.49O film can be delicately regulated by F doping. Interestingly, two donor levels (17 meV and 74 meV) associated with F were revealed by temperature-dependent Hall measurements. A Schottky type metal-semiconductor-metal ultraviolet photodetector manifests a remarkably enhanced photocurrent, two orders of magnitude higher than that of the undoped counterpart. The responsivity is greatly enhanced from 0.34 mA/W to 52 mA/W under 10 V bias. The detectivity increases from 1.89 * 10(9) cm Hz(1/2)/W to 3.58 * 10(10) cm Hz(1/2)/W under 10 V bias at room temperature.These results exhibit F doping serves as a promising pathway for improving the performance of high-Mg-content MgxZn1-xO-based devices. PMID- 26489959 TI - Opting Out and Leaning In: The Life Course Employment Profiles of Early Baby Boom Women in the United States. AB - Most literature on female employment focuses on the intersection between women's labor supply and family events such as marriage, divorce, or childbearing. Even when using longitudinal data and methods, most studies estimate average net effects over time and assume homogeneity among women. Less is known about diversity in women's cumulative work patterns over the long run. Using group based trajectory analysis, I model the employment trajectories of early Baby Boom women in the United States from ages 20 to 54. I find that women in this cohort can be classified in four ideal-type groups: those who were consistently detached from the labor force (21 %), those who gradually increased their market attachment (27 %), those who worked intensely in young adulthood but dropped out of the workforce after midlife (13 %), and those who were steadily employed across midlife (40 %). I then explore a variety of traits associated with membership in each of these groups. I find that (1) the timing of family events (marriage, fertility) helps to distinguish between groups with weak or strong attachment to the labor force in early adulthood; (2) external constraints (workplace discrimination, husband's opposition to wife's work, ill health) explain membership in groups that experienced work trajectory reversals; and (3) individual preferences influence labor supply across women's life course. This analysis reveals a high degree of complexity in women's lifetime working patterns, highlighting the need to understand women's labor supply as a fluid process. PMID- 26489960 TI - Can video recording revolutionise medical quality? PMID- 26489961 TI - Preclinical metabolism and disposition of luseogliflozin, a novel antihyperglycemic agent. AB - 1. We investigated the metabolism and disposition of luseogliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in rats and dogs, as well as in vitro metabolism in rats, dogs and humans. In addition, we studied its localization in the rat kidney. 2. [14C]Luseogliflozin was rapidly and well absorbed (>86% of the dose) after oral administration to rats and dogs. The drug-derived radioactivity was mainly excreted via the feces in both species. 3. The predominant radioactivity component in the excreta was associated with the metabolites, with only a minor fraction of unchanged luseogliflozin. The major metabolites were two glucuronides (M8 and M16) in the rats, and the O-deethylated form (M2) and other oxidative metabolites (M3 and M17) in the dogs. 4. The in vitro metabolism in dog and human hepatocytes was significantly slower than that in the rat hepatocytes. The biotransformation in animal hepatocytes was similar to that observed in vivo. Incubation with human hepatocytes resulted in the formation of metabolites, including M2, M3, M8 and M17, via multiple metabolic pathways. 5. [14C]Luseogliflozin was well-distributed to its target organ, the kidney, and was found to be localized in the renal cortex, which shows SGLT2 expression. This characteristic distribution was inhibited by preinjection of phlorizin, an SGLT inhibitor, suggesting that the renal radioactivity was associated with SGLT2. PMID- 26489963 TI - [Toxic substances to reproduction: Styrene]. PMID- 26489954 TI - Complement activation, regulation, and molecular basis for complement-related diseases. AB - The complement system is an essential element of the innate immune response that becomes activated upon recognition of molecular patterns associated with microorganisms, abnormal host cells, and modified molecules in the extracellular environment. The resulting proteolytic cascade tags the complement activator for elimination and elicits a pro-inflammatory response leading to recruitment and activation of immune cells from both the innate and adaptive branches of the immune system. Through these activities, complement functions in the first line of defense against pathogens but also contributes significantly to the maintenance of homeostasis and prevention of autoimmunity. Activation of complement and the subsequent biological responses occur primarily in the extracellular environment. However, recent studies have demonstrated autocrine signaling by complement activation in intracellular vesicles, while the presence of a cytoplasmic receptor serves to detect complement-opsonized intracellular pathogens. Furthermore, breakthroughs in both functional and structural studies now make it possible to describe many of the intricate molecular mechanisms underlying complement activation and the subsequent downstream events, as well as its cross talk with, for example, signaling pathways, the coagulation system, and adaptive immunity. We present an integrated and updated view of complement based on structural and functional data and describe the new roles attributed to complement. Finally, we discuss how the structural and mechanistic understanding of the complement system rationalizes the genetic defects conferring uncontrolled activation or other undesirable effects of complement. PMID- 26489964 TI - Are invasive plants more competitive than native conspecifics? Patterns vary with competitors. AB - Invasive plants are sometimes considered to be more competitive than their native conspecifics, according to the prediction that the invader reallocates resources from defense to growth due to liberation of natural enemies ['Evolution of Increased Competitive Ability' (EICA) hypothesis]. However, the differences in competitive ability may depend on the identity of competitors. In order to test the effects of competitors, Ageratina adenophora plants from both native and invasive ranges competed directly, and competed with native residents from both invasive (China) and native (Mexico) ranges respectively. Invasive A. adenophora plants were more competitive than their conspecifics from native populations when competing with natives from China (interspecific competition), but not when competing with natives from Mexico. Invasive A. adenophora plants also showed higher competitive ability when grown in high-density monoculture communities of plants from the same population (intrapopulation competition). In contrast, invasive A. adenophora plants showed lower competitive ability when competing with plants from native populations (intraspecific competition). Our results indicated that in the invasive range A. adenophora has evolved to effectively cope with co-occurring natives and high density environments, contributing to invasion success. Here, we showed the significant effects of competitors, which should be considered carefully when testing the EICA hypothesis. PMID- 26489965 TI - The synergistic effect of folate and RGD dual ligand of nanographene oxide on tumor targeting and photothermal therapy in vivo. AB - Effective delivery of nanoparticles to the target site is necessary for successful biomedical applications. Inefficient targeting is a major concern for nanomedicines in cancer therapy. Conjugation of multiple targeting ligands to the nanoparticle surface might further enhance the targeting efficiency by a co operative effect of individual ligands. In this study, a dual ligand targeting nanographene oxide (nGO) was developed by non-covalent interaction with folate and cRGD functionalized pluronic, which allowed precise control of ligand number on the nGO surface and ensured stability under physiological conditions. The tumor targeting abilities of single and dual ligand decorated nGOs were evaluated in vitro by using KB cells, over-expressing folate and integrin alphavbeta3 receptors. In vitro cellular uptake analysis by flow cytometry and confocal laser scanning microscopy showed enhanced uptake of dual ligand modified nGO compared to any of the single ligand modified nGOs. The cellular uptake of dual targeted cRGD-FA-nGO was increased by 1.9 and 2.4 folds compared to single targeted cRGD nGO or FA-nGO, respectively. The in vivo biodistribution experiment in a mouse xenograft model also confirmed the synergistic targeting effect of cRGD and folate dual functionalized nGO. A significantly higher tumor accumulation of cRGD FA-nGO was observed compared to cRGD-nGO or FA-nGO. The higher tumor accumulation of dual targeted nGO resulted in complete ablation of tumor tissue through an enhanced photothermal effect by NIR laser irradiation. Therefore, co functionalization of a nanoparticle by cRGD and folate is a potentially useful way to enhance the tumor targeting efficacy. PMID- 26489967 TI - Expanding the Ligand Framework Diversity of Carbodicarbenes and Direct Detection of Boron Activation in the Methylation of Amines with CO2. AB - A simple and convergent synthetic strategy used to increase the diversity of the carbodicarbene ligand framework through incorporation of unsymmetrical pendant groups is reported. Structural analysis and spectroscopic studies of ligands and their Rh complexes are reported. Reactivity studies reveal carbodicarbenes as competent organocatalysts for amine methylation using CO2 as a synthon. A unique B?H-activated boron-carbodicarbene complex was isolated as a reaction intermediate, providing mechanistic insight into the CO2 functionalization process. PMID- 26489966 TI - Sensitivity of GC-EI/MS, GC-EI/MS/MS, LC-ESI/MS/MS, LC-Ag(+) CIS/MS/MS, and GC ESI/MS/MS for analysis of anabolic steroids in doping control. AB - This study compared the sensitivity of various separation and ionization methods, including gas chromatography with an electron ionization source (GC-EI), liquid chromatography with an electrospray ionization source (LC-ESI), and liquid chromatography with a silver ion coordination ion spray source (LC-Ag(+) CIS), coupled to a mass spectrometer (MS) for steroid analysis. Chromatographic conditions, mass spectrometric transitions, and ion source parameters were optimized. The majority of steroids in GC-EI/MS/MS and LC-Ag(+) CIS/MS/MS analysis showed higher sensitivities than those obtained with other analytical methods. The limits of detection (LODs) of 65 steroids by GC-EI/MS/MS, 68 steroids by LC-Ag(+) CIS/MS/MS, 56 steroids by GC-EI/MS, 54 steroids by LC ESI/MS/MS, and 27 steroids by GC-ESI/MS/MS were below cut-off value of 2.0 ng/mL. LODs of steroids that formed protonated ions in LC-ESI/MS/MS analysis were all lower than the cut-off value. Several steroids such as unconjugated C3-hydroxyl with C17-hydroxyl structure showed higher sensitivities in GC-EI/MS/MS analysis relative to those obtained using the LC-based methods. The steroids containing 4, 9, 11-triene structures showed relatively poor sensitivities in GC-EI/MS and GC ESI/MS/MS analysis. The results of this study provide information that may be useful for selecting suitable analytical methods for confirmatory analysis of steroids. PMID- 26489968 TI - MicroRNA expression profiling in bladder cancer: the challenge of next-generation sequencing in tissues and biofluids. AB - Bladder cancer (BC) is a heterogeneous disease characterized by a high recurrence rate that necessitates continuous cystoscopic surveillance. MicroRNAs (miRNAs) are detectable in tissues and biofluids such as plasma/serum and urine. They represent promising biomarkers with potential not only for detecting BC but also informing on prognosis and monitoring treatment response. In this review, the many aspects of the application of next-generation sequencing (NGS) to evaluate miRNA expression in BC is discussed, including technical issues as well as a comparison with results obtained by qRT-PCR. The available studies investigating miRNA profiling in BC by NGS are described, with particular attention to the potential applicability on biofluids. Altered miRNA levels have been observed in BC tissues by NGS, but these results so far only partially overlapped among studies and with previous data obtained by qRT-PCR. The discrepancies can be ascribed to the small groups of BC patients sequenced. The few available studies on biofluids are mainly focused on implementing RNA isolation and sequencing workflow. Using NGS to analyze miRNAs in biofluids can potentially provide results comparable to tissues with no invasive procedures for the patients. In particular, the analyses performed on exosomes/microvesicles appear to be more informative. Thanks to the improvement of both wet-lab procedures and pipelines/tools for data analyses, NGS studies on biofluids will be performed on a larger scale. MiRNAs detected in urine and serum/plasma will demonstrate their potentiality to describe the variegated scenario of BC and to become relevant clinical markers. PMID- 26489969 TI - Facial speech gestures: the relation between visual speech processing, phonological awareness, and developmental dyslexia in 10-year-olds. AB - Successful communication in everyday life crucially involves the processing of auditory and visual components of speech. Viewing our interlocutor and processing visual components of speech facilitates speech processing by triggering auditory processing. Auditory phoneme processing, analyzed by event-related brain potentials (ERP), has been shown to be associated with impairments in reading and spelling (i.e. developmental dyslexia), but visual aspects of phoneme processing have not been investigated in individuals with such deficits. The present study analyzed the passive visual Mismatch Response (vMMR) in school children with and without developmental dyslexia in response to video-recorded mouth movements pronouncing syllables silently. Our results reveal that both groups of children showed processing of visual speech stimuli, but with different scalp distribution. Children without developmental dyslexia showed a vMMR with typical posterior distribution. In contrast, children with developmental dyslexia showed a vMMR with anterior distribution, which was even more pronounced in children with severe phonological deficits and very low spelling abilities. As anterior scalp distributions are typically reported for auditory speech processing, the anterior vMMR of children with developmental dyslexia might suggest an attempt to anticipate potentially upcoming auditory speech information in order to support phonological processing, which has been shown to be deficient in children with developmental dyslexia. PMID- 26489970 TI - Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. AB - Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1), which is partly responsible for augmenting glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). In patients with T2D, pharmacological doses/concentrations of GLP-1 can compensate for the inability of diabetic beta cells to respond to the main incretin hormone glucose-dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin-based glucose-lowering medications. Two classes of incretin-based therapies are available: GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs promote GLP-1 receptor (GLP-1R) signalling by providing GLP 1R stimulation through 'incretin mimetics' circulating at pharmacological concentrations, whereas DPP-4 inhibitors prevent the degradation of endogenously released GLP-1. Both agents produce reductions in plasma glucose and, as a result of their glucose-dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non-glycaemic benefits such as weight loss, improvements in beta-cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin-based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients. PMID- 26489972 TI - Longitudinal Geographic Miss (LGM) in Robotic Assisted Versus Manual Percutaneous Coronary Interventions. AB - OBJECTIVES: To evaluate the impact of robotic-assisted percutaneous coronary intervention (RA-PCI) versus manual PCI (M-PCI) on the incidence of Longitudinal Geographic Miss (LGM). BACKGROUND: The safety and feasibility of RA-PCI has been established in preclinical animal trials and human clinical trials. Patients with LGM have been shown to have worse clinical outcomes including significantly increased incidences of MACE. METHODS: Patients with significant coronary artery disease underwent RA-PCI in the PRECISE study (n=164) and standard M-PCI in the STLLR trial (n = 1,509). Longitudinal geographic miss was defined as cases where the entire length of the injured or stenotic segment was not fully covered by the total length of the stent. The incidence of LGM was compared between RA-PCI and M PCI cohorts. RESULTS: The RA-PCI cohort had a significantly greater prevalence of previous MI, previous coronary revascularization, and unstable angina. The robotic cohort exhibited a lower incidence of LGM when compared to the M-PCI patients, 12.2% to 43.1%, respectively (P < 0.0001). To account for the differences in baseline characteristics between the two studies, a propensity score analysis was conducted. The propensity modeling showed similar rates of LGM in both a larger group of patients that met key PRECISE study inclusion/exclusion criteria adjusted for propensity score (9.3% vs 55.0%; P < 0.0001) and in a smaller, matched on propensity score, subset of patients (10.3% vs 64.1%; P < 0.0001). CONCLUSION: Robotic-assisted PCI had significantly lower incidence of LGM compared to standard M-PCI. Reducing LGM potentially improves long-term clinical outcomes through reduction in MACE. PMID- 26489971 TI - F8 intron 22 inversions and SNP rs73563631 in unrelated families with severe haemophilia A: clinical features and gene testing implications. PMID- 26489973 TI - Safety and Efficacy of Immediate Rotational Atherectomy in Nondilatable Calcified Coronary Lesions Complicated by Coronary Artery Dissection (RAISE). AB - OBJECTIVES: To examine the safety and efficacy of immediate rotational atherectomy (RA) in nondilatable calcified coronary lesions complicated by coronary dissection during percutaneous coronary intervention (PCI). BACKGROUND: In the presence of coronary dissection in nondilatable calcified coronary lesions, conservative management is suggested to permit the dissection to heal prior to treatment with RA. However, many patients have frequent angina attacks and some patients develop serious complications during this period. METHODS: One hundred and nighty-eight patients with severe coronary calcification underwent PCI, and were randomized into immediate (n = 105) or delayed RA group (n = 93) when coronary dissections occur. The primary endpoint of the present study was all-cause death including cardiac and non-cardiac death in 4 years follow-up. Non fatal myocardial infarction, stent thrombosis, cardiac tamponade, stroke, target lesion revascularization, New York Heart Association (NYHA) class IV heart failure were analyzed as secondary end points. RESULTS: At a follow-up of 4 years, event-free survival rates were not statistically different between the immediate and delayed RA group (81.9% vs 80.6%, P = 0.820). Rates of PCI- and RA related major adverse cardiac events (MACE) and severe RA-related complications were not statistically different between groups. Luminal loss was not significantly different between the immediate and delayed RA group as evaluated by Intravascular ultrasound (IVUS). Two cases in the delayed RA group experienced myocardial infarction during the 4-week waiting. CONCLUSION: This study indicates that immediate RA during PCI is safe and effective in patients with coronary artery dissection. PMID- 26489974 TI - Effect of Hospital Volume on Outcomes of Transcatheter Mitral Valve Repair: An Early US Experience. AB - BACKGROUND: Transcatheter mitral valve repair (TMVR) is a complex procedure for patients with mitral regurgitation who cannot get surgery. However, there is a lack of data on how hospital volumes affect these outcomes. METHODS: We performed a cross sectional study based on Healthcare Cost and Utilization Project's Nationwide Inpatient Sample database of 2012 and identified subjects using the ICD-9-CM procedure code of 35.97, which was introduced in October 2010 for percutaneous mitral valve repair if present in the primary or secondary procedure field. Hospital volumes were divided into tertiles. The primary outcome was a composite of in-hospital mortality and peri-procedural complications. Length of stay and hospitalization cost were also assessed. RESULTS: A total of 95 (weighted n = 475) TMVR procedures were identified. The mean age of the overall cohort was 70 years; 43.2% were female and 63.2% had a significant baseline burden of co-morbidities. The composite of in-hospital mortality and peri procedural complications decreased with increasing TMVR hospital volume: 48.7% in the first tertile, 17.4% in the second tertile, and 9.1% in the third tertile. Additionally, we saw a decrease in the length of stay and a trend in decrease in the hospitalization cost. CONCLUSION: In hospitals performing TMVR, higher hospital volumes are associated with a reduction in a composite of in-hospital mortality and post-procedural complications, in addition to the shorter length of stay. PMID- 26489975 TI - Altered neural activation during prepotent response inhibition in breast cancer survivors treated with chemotherapy: an fMRI study. AB - While impairments in executive functions have been reported in breast cancer survivors (BCS) who have undergone adjuvant chemotherapy, only a limited number of functional neuroimaging studies have associated alterations in cerebral activity with executive functions deficits in BCS. Using fMRI, the current study assessed the neural basis underlying a specific facet of executive function, namely prepotent response inhibition. 12 BCS who self-reported cognitive problems up to 3 years following cancer treatment and 12 female healthy comparisons (HC) performed the Stroop task. We compared their neural activation between the incongruent and neutral experimental conditions. Relative to the HC group, BCS showed lower blood-oxygen level dependent signal in several frontal regions, including the anterior cingulate cortex, a region critical for response inhibition. Our data indicates reduced neural activation in BCS during a prepotent response inhibition task, providing support for the prevailing notion of neural alterations observed in BCS treated with chemotherapy. PMID- 26489977 TI - Disrupted default mode network connectivity in male adolescents with conduct disorder. AB - Conduct disorder (CD) is a serious behavioral disorder of childhood and adolescence. The default mode network (DMN) is a brain network which supports self-referential cognitive processes and is typically deactivated during task performance. The aim of this study was to investigate DMN connectivity in male adolescents with pure CD compared to typically-developing controls. Eighteen male adolescents with CD and 18 sex-, age- and education-matched typically-developing (TD) participants were recruited. Current and lifetime psychiatric disorders were assessed using the Chinese version of the Schedule for Affective Disorder and Schizophrenia for School-Age Children-Present and Lifetime Version. Resting state functional magnetic resonance imaging (fMRI) data were obtained using a 3.0 T scanner. Independent components analysis (ICA) was used to investigate functional connectivity between the DMN and related brain regions. DMN activity was observed in medial prefrontal, posterior cingulate, and lateral parietal cortices, and extended to the brainstem. Adolescents with CD showed significantly reduced functional connectivity within the bilateral posterior cingulate cortex (PCC), bilateral precuneus and right superior temporal gyrus relative to TD controls. CD is associated with reduced functional connectivity within the DMN and between the DMN and other regions. These preliminary results suggest that deficits in DMN functional connectivity may serve as a biomarker of CD. PMID- 26489976 TI - ADHD and cannabis use in young adults examined using fMRI of a Go/NoGo task. AB - Children diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for substance abuse. Response inhibition is a hallmark of ADHD, yet the combined effects of ADHD and regular substance use on neural networks associated with response inhibition are unknown. Task-based functional Magnetic Resonance Imaging (fMRI) data from young adults with childhood ADHD with (n = 25) and without (n = 25) cannabis use >= monthly in the past year were compared with a local normative comparison group (LNCG) with (n = 11) and without (n = 12) cannabis use. Go/NoGo behavioral and fMRI data were evaluated for main and interaction effects of ADHD diagnosis and cannabis use. ADHD participants made significantly more commission errors on NoGo trials than controls. ADHD participants also had less frontoparietal and frontostriatal activity, independent of cannabis use. No main effects of cannabis use on response inhibition or functional brain activation were observed. An interaction of ADHD diagnosis and cannabis use was found in the right hippocampus and cerebellar vermis, with increased recruitment of these regions in cannabis-using controls during correct response inhibition. ADHD participants had impaired response inhibition combined with less fronto-parietal/striatal activity, regardless of cannabis use history. Cannabis use did not impact behavioral response inhibition. Cannabis use was associated with hippocampal and cerebellar activation, areas rich in cannabinoid receptors, in LNCG but not ADHD participants. This may reflect recruitment of compensatory circuitry in cannabis using controls but not ADHD participants. Future studies targeting hippocampal and cerebellar-dependent function in these groups may provide further insight into how this circuitry is altered by ADHD and cannabis use. PMID- 26489978 TI - Increased spatial granularity of left brain activation and unique age/gender signatures: a 4D frequency domain approach to cerebral lateralization at rest. AB - Cerebral lateralization is a well-studied topic. However, most of the research to date in functional magnetic resonance imaging (fMRI) has been carried out on hemodynamic fluctuations of voxels, networks, or regions of interest (ROIs). For example, cerebral differences can be revealed by comparing the temporal activation of an ROI in one hemisphere with the corresponding homotopic region in the other hemisphere. While this approach can reveal significant information about cerebral organization, it does not provide information about the full spatiotemporal organization of the hemispheres. The cerebral differences revealed in literature suggest that hemispheres have different spatiotemporal organization in the resting state. In this study, we evaluate cerebral lateralization in the 4D spatiotemporal frequency domain to compare the hemispheres in the context of general activation patterns at different spatial and temporal scales. We use a gender-balanced resting fMRI dataset comprising over 600 healthy subjects ranging in age from 12 to 71, that have previously been studied with a network specific voxel-wise and global analysis of lateralization (Agcaoglu, et al. NeuroImage, 2014). Our analysis elucidates significant differences in the spatiotemporal organization of brain activity between hemispheres, and generally more spatiotemporal fluctuation in the left hemisphere especially in the high spatial frequency bands, and more power in the right hemisphere in the low and middle spatial frequencies. Importantly, the identified effects are not visible in the context of a typical assessment of voxelwise, regional, or even global laterality, thus our study highlights the value of 4D spatiotemporal frequency domain analyses as a complementary and powerful tool for studying brain function. PMID- 26489979 TI - BAS-drive trait modulates dorsomedial striatum activity during reward response outcome associations. AB - According to the Reinforcement Sensitivity Theory, behavioral studies have found that individuals with stronger reward sensitivity easily detect cues of reward and establish faster associations between instrumental responses and reward. Neuroimaging studies have shown that processing anticipatory cues of reward is accompanied by stronger ventral striatum activity in individuals with stronger reward sensitivity. Even though establishing response-outcome contingencies has been consistently associated with dorsal striatum, individual differences in this process are poorly understood. Here, we aimed to study the relation between reward sensitivity and brain activity while processing response-reward contingencies. Forty-five participants completed the BIS/BAS questionnaire and performed a gambling task paradigm in which they received monetary rewards or punishments. Overall, our task replicated previous results that have related processing high reward outcomes with activation of striatum and medial frontal areas, whereas processing high punishment outcomes was associated with stronger activity in insula and middle cingulate. As expected, the individual differences in the activity of dorsomedial striatum correlated positively with BAS-Drive. Our results agree with previous studies that have related the dorsomedial striatum with instrumental performance, and suggest that the individual differences in this area may form part of the neural substrate responsible for modulating instrumental conditioning by reward sensitivity. PMID- 26489980 TI - Streamlining the learning process for TAVI: Insight from a comparative analysis of the OCEAN-TAVI and the massy registries. AB - BACKGROUNDS: To facilitate the learning process of transcatheter aortic valve implantation (TAVI) in Japan, unique supporting systems (e.g., on-site proctor and web-based screening systems) have been developed. Nevertheless, little is known about real-world clinical outcomes after TAVI in Japan compared with their European counterparts. METHODS: From the optimized catheter valvular intervention (OCEAN-TAVI, Japan) and the Institut Cardiovasculaire Paris Sud (Massy, France) registries, we evaluated a total of 134 and 178 patients, respectively, who underwent transfemoral TAVI during the same time period. RESULTS: Among the French cohort, about half of the patients (N = 81, 45.5%) were treated with the Edwards SAPIEN XT. Body surface area was significantly smaller in the Japanese cohort, although operative risks for both cohorts were almost the same. A greater percentage of patients in the Japanese cohort were implanted with 23 mm valves compared with the French cohort (73.1% vs. 23.0%, P < 0.001), reflecting the smaller annulus diameter (21.8 +/- 1.6 vs. 23.8 +/- 2.4 mm, P < 0.001). All-cause 30-day mortality (0% vs. 0.6%, P = 1.000) and 30-day combined safety endpoint based on the Valve Academic Research Consortium 2 (VARC2) criteria (9.7% vs. 11.2%, P = 0.713) were similar when limiting the analysis to patients treated with the Edwards SAPIEN XT. CONCLUSIONS: Despite the unfavorable aortic anatomy of the Japanese patients, their clinical outcomes after transfemoral TAVI were excellent with the same degree of safety as in an experienced European institute. This minimized learning process achieved the use of unique support systems. PMID- 26489981 TI - Boosting Proton Conductivity in Highly Robust 3D Inorganic Cationic Extended Frameworks through Ion Exchange with Dihydrogen Phosphate Anions. AB - The limited long-term hydrolytic stability of rapidly emerging 3D-extended framework materials (MOFs, COFs, MOPs, etc.) is still one of major barriers for their practical applications as new solid-state electrolytes in fuel cells. To obtain hydrolytically stable materials, two H2 PO4 (-) -exchanged 3D inorganic cationic extended frameworks (CEFs) were successfully prepared by a facile anion exchange method. Both anion-exchanged CEFs (YbO(OH)P and NDTBP) show significantly enhanced proton conductivity when compared with the original materials (YbO(OH)Cl and NDTB) with an increase of up to four orders-of magnitude, reaching 2.36*10(-3) and 1.96*10(-2) S cm(-1) at 98 % RH and 85 degrees C for YbO(OH)P and NDTBP, respectively. These values are comparable to the most efficient proton-conducting MOFs. In addition, these two anion-exchanged materials are stable in boiling water, which originates from the strong electrostatic interaction between the H2 PO4 (-) anion and the cationic host framework, showing a clear advance over all the acid-impregnated materials (H2 SO4 @MIL-101, H3 PO4 @MIL-101, and H3 PO4 @Tp-Azo) as practical solid-state fuel cell electrolytes. This work offers a new general and efficient approach to functionalize 3D-extended frameworks through an anion-exchange process and achieves water-stability with ultra-high proton conductivity above 10(-2) S cm( 1) . PMID- 26489982 TI - Design of Lead(II) Metal-Organic Frameworks Based on Covalent and Tetrel Bonding. AB - Three solid materials, [Pb(HL)(SCN)2 ]?CH3 OH (1), [Pb(HL)(SCN)2 ] (2), and [Pb(L)(SCN)]n (3), were obtained from Pb(SCN)2 and an unsymmetrical bis-pyridyl hydrazone ligand that can act both as a bridging and as a chelating ligand. In all three the lead center is hemidirectionally coordinated and is thus sterically optimal for participation in tetrel bonding. In the crystal structures of all three compounds, the lead atoms participate in short contacts with thiocyanate sulfur or nitrogen atoms. These contacts are shorter than the sums of the van der Waals radii (3.04-3.47 A for Pb???S and 3.54 A for Pb???N) and interconnect the covalently bonded units (monomers, dimers, and 2D polymers) into supramolecular assemblies (chains and 3D structures). DFT calculations showed these contacts to be tetrel bonds of considerable energy (6.5-10.5 kcal mol(-1) for Pb???S and 16.5 kcal mol(-1) for Pb???N). A survey of structures in the CSD showed that similar contacts often appear in crystals of Pb(II) complexes with regular geometries, which leads to the conclusion that tetrel bonding plays a significant role in the supramolecular chemistry of Pb(II) . PMID- 26489984 TI - 2-Phosphino-1,3-diphosphonium ions. AB - A series of 2-phosphino-1,3-diphosphonium trifluoromethanesulfonate salts has been prepared and comprehensively characterized. The compounds represent rare examples of salts containing triphosphorus dications and establish important structural and spectroscopic parameters and trends for catenated phosphorus chains. PMID- 26489983 TI - Iodine status of pregnant women in a metropolitan city which proved to be an iodine-sufficient area. Is mandatory salt iodisation enough for pregnant women? AB - The objective of this study was to assess the iodine status of pregnant women in a metropolitan city which was stated as iodine sufficient area after salt iodination program. This multicenter, cross-sectional study was carried out on 3543 pregnant women. Age, gestational weeks, smoking, consumption of iodized salt, dietary salt restriction, history of stillbirth, abortus and congenital malformations were questioned. Spot urine samples were analyzed for urine iodine concentration (UIC). The outcomes were: (a) median UIC in three trimesters of pregnancy and (b) frequency of ID among pregnant women. The median UIC was 73 ug/L. The median UIC was 77 ug/L (1-324), 73 ug/L (1-600) and 70 ug/L (1-1650) in three trimesters of pregnancy, respectively (p: 0.14). UIC <50 ug/L was observed in 36.6% (n: 1295) and UIC<150 ug/L was observed in 90.7% (n: 3214) of pregnant women. Only 1% (n: 34) of the pregnant women had UIC levels higher than 500 ug/L. This study showed that more than 90% of the pregnant women in this iodine sufficient city are facing some degree of iodine deficiency during their pregnancy. A salt iodization program might be satisfactory for the non-pregnant population, but it seems to be insufficient for the pregnant population. PMID- 26489985 TI - Facile fabrication of structure-tunable bead-shaped hybrid microfibers using a Rayleigh instability guiding strategy. AB - A method allowing the fabrication of quantum-dot or photonic crystal loaded bead shaped hybrid microfiber arrays in a Rayleigh instability driven drop-sliding manner is demonstrated. PMID- 26489986 TI - Risk factors for recurrent admissions with diabetic ketoacidosis: a case-control observational study. AB - AIM: To perform a detailed analysis of patients with recurrent diabetic ketoacidosis admissions in order to establish risk factors for readmission. METHODS: The medical records of all adults and young people (> 15 years) with Type 1 diabetes admitted to Auckland City Hospital over a 15-year period from 1997 to 2011 with a primary diagnosis of ketoacidosis were analysed. Patients readmitted with ketoacidosis within 5 years of their index admission were identified and compared with patients without ketoacidosis readmission who were matched for age, gender, ethnicity and duration of diabetes. RESULTS: A total of 268 patients accounted for a total of 412 admissions. In all, 58 patients had more than one admission for diabetic ketoacidosis during this period. Of these, 40 patients readmitted with diabetic ketoacidosis were compared with matched control subjects (n = 40) who had only one admission for diabetic ketoacidosis. The mean +/- sd age of the cohort was 31 +/- 12 years. The readmission group had more severe diabetic ketoacidosis and poorer glycaemic control. Alcohol abuse was commonly noted in both groups, with insulin dose omission being the main contributor to the development of ketoacidosis. Both groups had high rates of clinic non-attendance. There were no other differences noted between the groups. CONCLUSION: When patients with recurrent diabetic ketoacidosis were matched for age, duration of diabetes, gender and ethnicity with patients who had only one admission for diabetic ketoacidosis, few differences were noted. This makes designing intervention strategies to reduce readmission with diabetic ketoacidosis difficult. PMID- 26489987 TI - Is the American College of Surgeons National Surgical Quality Improvement Program surgical risk calculator applicable for breast cancer patients undergoing breast conserving surgery? AB - BACKGROUND: We aimed to analyze the applicability of the National Surgical Quality Improvement Program (NSQIP) calculator to patients undergoing breast conserving surgery. METHODS: A total of 287 consecutive patients treated with breast-conserving surgery from 2010 to 2012 were identified retrospectively. The risk calculator was applied to each patient to generate an individual risk profile. Risk calculations were then compared with actual outcomes. The performance of the risk calculator was evaluated using 2 metrics: the Brier score and c statistic. RESULTS: The NSQIP calculator performed adequately for all complications, with Brier scores less than .05. However, 37 patients (12.9%) returned to the operating room for oncologic indications. Twenty-nine patients (10.1%) had positive margins, whereas 8 patients (2.8%) returned due to an upgrade in diagnosis. CONCLUSIONS: When considering return to the operating room for oncologic management, the observed rate of 13.9% is significantly higher than the NSQIP prediction. This deviation must be addressed when using the NSQIP risk calculator model during preoperative risk discussion. PMID- 26489988 TI - Establishing benchmarks for the management of elevated liver enzymes and/or dilated biliary trees in an urban safety net hospital: analysis of 915 subjects. AB - BACKGROUND: The push for public reporting of outcomes necessitates relevant benchmarks for disease states across different settings. This study establishes benchmarks for choledocholithiasis management in a safety net hospital setting. METHODS: We reviewed all patients admitted to our acute care surgery service with biochemical evidence of choledocholithiasis who underwent same-admission cholecystectomy (CCY) between July 2012 and December 2013. RESULTS: During this 18-month period, 915 patients were admitted with biochemical evidence of choledocholithiasis. Descriptive statistics for the cohort are provided, which include a 51% rate of obesity and 95% rate of pathologic cholecystitis. Conversion rates of 4% and complication rates of 6% were found. The majority had a CCY without biliary imaging (n = 630, 68.9%). CONCLUSIONS: Relevant benchmarks are characterized, and results of a practice pattern of omitting pre- or intraoperative biliary tree imaging are described. These findings serve as a first benchmark of choledocholithiasis management for urban safety net hospitals. PMID- 26489989 TI - Impact of adding a second layer to a single unlocked closure of a Cesarean uterine incision: randomized controlled trial. AB - OBJECTIVE: To investigate short- and long-term effects on residual myometrial thickness (RMT) of adding a second layer to a single unlocked closure of a Cesarean uterine incision. METHODS: This was a randomized double-blind controlled trial. Healthy nulliparous women scheduled for first-time elective Cesarean delivery were operated on using a modified version of the Misgav Ladach surgical technique. The women were examined by transabdominal ultrasound before discharge from the maternity ward and by transvaginal saline contrast sonohysterography at a minimum of 5 months postpartum. RESULTS: Seventy-six nulliparae met the criteria and agreed to participate in the study. Thirty-five women were assigned to the single-layer technique and 38 to the double-layer unlocked closure technique. Groups were comparable regarding gestational age at delivery, duration of surgery and perioperative blood loss. There was no difference in RMT between the two groups, both at time of discharge (mean +/- SD, 20.2 +/- 8.0 mm vs 21.0 +/- 9.7 mm) and after 5 months postpartum (mean, 5.7 +/- 2.9 mm vs 5.7 +/- 2.2 mm). RMT was approximately half that of the normal myometrium at both examinations. CONCLUSION: The results of this study suggest that double-layer closure of a Cesarean uterine incision does not increase RMT compared with single layer closure when an unlocked technique is used. PMID- 26489990 TI - Minimally invasive oesophagectomy: the Ivor Lewis approach. AB - Oesophagectomy is a challenging operation involving multiple body cavities. The traditional open approach has several described techniques. The Ivor Lewis approach is one of the most commonly utilized approaches and includes a laparotomy and a thoracotomy. Traditionally, this has resulted in some morbidity. This article describes a stepwise approach to a minimally invasive Ivor Lewis oesophagectomy including laparoscopic mobilization of the stomach, formation of the gastric conduit, placement of a feeding jejunostomy tube, thoracoscopic oesophageal mobilization and resection and a stapled oesophago-gastric anastomosis. Common pitfalls and technical insights will be presented. PMID- 26489991 TI - The reliability and validity of the informant AD8 by comparison with a series of cognitive assessment tools in primary healthcare. AB - BACKGROUND: The validity and reliability of the informant AD8 in primary healthcare has not been established. Therefore, the present study examined the validity and reliability of the informant AD8 in government subsidized primary healthcare centers in Singapore. METHODS: Eligible patients (>=60 years old) were recruited from primary healthcare centers and their informants received the AD8. Patient-informant dyads who agreed for further cognitive assessments received the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and a locally validated formal neuropsychological battery at a research center in a tertiary hospital. RESULTS: 1,082 informants completed AD8 assessment at two primary healthcare centers. Of these, 309 patients-informant dyads were further assessed, of whom 243 (78.6%) were CDR = 0; 22 (7.1%) were CDR = 0.5; and 44 (14.2%) were CDR>=1. The mean administration time of the informant AD8 was 2.3 +/- 1.0 minutes. The informant AD8 demonstrated good internal consistency (Cronbach's alpha = 0.85); inter-rater reliability (Intraclass Correlation Coefficient (ICC) = 0.85); and test-retest reliability (weighted kappa = 0.80). Concurrent validity, as measured by the correlation between total AD8 scores and CDR global (R = 0.65, p < 0.001), CDR sum of boxes (R = 0.60, p < 0.001), MMSE (R = -0.39, p < 0.001), MoCA (R = -0.41, p < 0.001), as well as the formal neuropsychological battery (R = -0.46, p < 0.001), was good and consistent with previous studies. Construct validity, as measured by convergent validity (R >= 0.4) between individual items of AD8 with CDR and neuropsychological domains was acceptable. CONCLUSIONS: The informant AD8 demonstrated good concurrent and construct validity and is a reliable measure to detect cognitive dysfunction in primary healthcare. PMID- 26489992 TI - In Memoriam: Mark Jeffery Chaffin (1952-2015): Flying by the Data. PMID- 26489995 TI - Veterinary team interactions, part 2: the personal effect. AB - Modern veterinary practices consist of multiple professions/occupations, often spread over multiple branches. Within these teams are identifiable 'key people' who are central to information and resource flow. Key people are frequently the appointed leaders, such as practice managers, but also include emergent leaders. Veterinary surgeons are commonly involved in the flow of higher order interactions such as problem solving, while administrators are often involved in information interactions. These key people are repeatedly boundary spanners, sharing resources across physical boundaries such as branches. Their marginal status (belonging to multiple groups) also allows them to interact across professional boundaries. Lower order interactions including asking for information and advice are often interprofessional; however, higher order interactions tend to be intraprofessional. Analysis of interaction reciprocity between professions demonstrated the prevalence of a profession based hierarchy, with veterinary surgeons at the top. Being social outside of work with a colleague is also linked to work based interactions. The results of this paper demonstrate the need for practices to consider key people and support them appropriately. Further to this, they suggest that, to promote an effective team, interactions should be based on experience as much as professional status, and that social interactions should be encouraged. PMID- 26489996 TI - Liver copper concentrations in cull cattle in the UK: are cattle being copper loaded? AB - With the release of the Department for the Environment, Food and Rural Affairs/Advisory Committee on Animal Feed Guidance Note for Supplementing Copper to Bovines it was noted that the current copper status of the national herd was not known. Liver samples were recovered from 510 cull cattle at a single abattoir across a period of three days. The samples were wet-ashed and liver copper concentrations determined by inductively coupled plasma mass spectrometry analysis. Breed, age and previous location information were obtained from the British Cattle Movement Service. Dairy breeds had higher liver copper concentrations than beef breeds. Holstein-Friesian and 'other' dairy breeds had 38.3 per cent and 40 per cent of cattle above the Animal Health and Veterinary Laboratories Agency (AHVLA) reference range (8000 umol/kg dry matter), respectively, whereas only 16.9 per cent of animals in the combined beef breeds exceeded this value. It was found that underlying topsoil copper concentration was not related to liver copper content and that age of the animal also had little effect on liver concentration. In conclusion, over 50 per cent of the liver samples tested had greater-than-normal concentrations of copper with almost 40 per cent of the female dairy cattle having liver copper concentrations above the AHVLA reference range, indicating that a significant proportion of the UK herd is at risk of chronic copper toxicity. PMID- 26489997 TI - We need to talk about error: causes and types of error in veterinary practice. AB - Patient safety research in human medicine has identified the causes and common types of medical error and subsequently informed the development of interventions which mitigate harm, such as the WHO's safe surgery checklist. There is no such evidence available to the veterinary profession. This study therefore aims to identify the causes and types of errors in veterinary practice, and presents an evidence based system for their classification. Causes of error were identified from retrospective record review of 678 claims to the profession's leading indemnity insurer and nine focus groups (average N per group=8) with vets, nurses and support staff were performed using critical incident technique. Reason's (2000) Swiss cheese model of error was used to inform the interpretation of the data. Types of error were extracted from 2978 claims records reported between the years 2009 and 2013. The major classes of error causation were identified with mistakes involving surgery the most common type of error. The results were triangulated with findings from the medical literature and highlight the importance of cognitive limitations, deficiencies in non-technical skills and a systems approach to veterinary error. PMID- 26489998 TI - Suppression of experimental autoimmune myasthenia gravis by autologous T regulatory cells. AB - Adoptive transfer of regulatory T (Treg) cells have been employed effectively for suppression of several animal models for autoimmune diseases. In order to employ Treg cell therapy in patients, it is necessary to generate Treg cells from the patient's own cells (autologous) that would be able to suppress effectively the disease in vivo, upon their reintroduction to the patient. Towards this objective, we report in the present study on a protocol for a successful immune regulation of experimental autoimmune myasthenia gravis (EAMG) by ex vivo- generated autologous Treg cells. For this protocol bone marrow (BM) cells, are first cultured in the presence of GM-CSF, giving rise to a population of CD11c(+)MHCII(+)CD45RA(+)CD8(-) DCs (BMDCs). Splenic CD4(+) T cells are then co cultured with the differentiated BM cells and expand to 90% of Foxp3(+) Treg cells. In vitro assay exhibits a similar dose dependent manner in the suppression of T effector cells proliferation between Treg cells obtained from either healthy or sick donors. In addition, both Treg cells inhibit similarly the secretion of IFN-gamma from activated splenocytes. Administration of 1 * 10(6) ex-vivo generated Treg cells, I.V, to EAMG rats, modulates the disease following a single treatment, given 3 days or 3 weeks after disease induction. Similar disease inhibition was achieved when CD4 cells were taken from either healthy or sick donors. The disease suppression was accompanied by reduced levels of total AChR specific antibodies in the serum. Moreover, due to the polyclonality of the described Treg cell, we have examined whether this treatment approach could be also employed for the treatment of other autoimmune diseases involving Treg cells. Indeed, we demonstrated that the ex-vivo generated autologous Treg cells suppress Adjuvant Arthritis (AA) in rats. This study opens the way for the application of induced autologous Treg cell therapy for myasthenia gravis, as well as for other human autoimmune diseases involving Treg cells. PMID- 26489999 TI - Larval Temperature-Food Effects on Adult Mosquito Infection and Vertical Transmission of Dengue-1 Virus. AB - Temperature-food interactions in the larval environment can affect life history and population growth of container mosquitoes Aedes aegypti (L.) and Aedes albopictus Skuse, the primary vectors of chikungunya and dengue viruses. We used Ae. aegypti, Ae. albopictus, and dengue-1 virus (DENV-1) from Florida to investigate whether larval rearing temperature can alter the effects of larval food levels on Ae. aegypti and Ae. albopictus life history and DENV-1 infection and vertical transmission. Although we found no effect of larval treatments on survivorship to adulthood, DENV-1 titer, or DENV-1 vertical transmission, rates of vertical transmission up to 16-24% were observed in Ae. albopictus and Ae. aegypti, which may contribute to maintenance of this virus in nature. Larval treatments had no effect on number of progeny and DENV-1 infection in Ae. aegypti, but the interaction between temperature and food affected number of progeny and DENV-1 infection of the female Ae. albopictus parent. The cooler temperature (24 degrees C) yielded the most progeny and this effect was accentuated by high food relative to the other conditions. Low and high food led to the highest (~90%) and lowest (~65%) parental infection at the cooler temperature, respectively, whereas intermediate infection rates (~75-80%) were observed for all food conditions at the elevated temperature. These results suggest that temperature and food availability have minimal influence on rate of vertical transmission and a stronger influence on adults of Ae. albopictus than of Ae. aegypti, which could have consequences for dengue virus epidemiology. PMID- 26490000 TI - Selective Insecticide Applications Directed Against Triatoma infestans (Hemiptera: Reduviidae) Affected a Nontarget Secondary Vector of Chagas Disease, Triatoma garciabesi. AB - The control of nondomiciliated triatomine species adapted to peridomestic habitats represents a challenge because they are connected to sylvatic colonies, and pyrethroid insecticides have limited effects outdoors. The effects of residual insecticide spraying have rarely been assessed on secondary triatomines. Triatoma garciabesi (Carcavallo, Martinez, Cichero, Prosen & Ronderos, 1967) is a nontarget vector that inhabits the dry western Chaco region, and a member of the Triatoma sordida Stal 1859 complex. Little is known on the capacity of T. garciabesi to invade and establish viable domestic or peridomestic colonies, and on its response to residual insecticide sprays directed against Triatoma infestans Klug 1834. The presence and abundance of triatomines were assessed by timed manual collections annually or biannually (spring and fall) during 10 yr after a community-wide insecticide spraying campaign and selective insecticide sprays directed against T. infestans in a rural village of northwestern Argentina. T. garciabesi mainly occupied peridomestic habitats associated with chickens, and was unable to colonize human sleeping quarters. Trees with chickens occurred in nearly all houses and were infested in >25% of the occasions. The abundance of bugs at house-compound level was best explained by a generalized estimating equation model that included selective insecticide sprays during the previous semester (negative effects), chicken abundance (positive effects), seasonality, and their interactions. Our results suggest that insecticide applications targeting T. infestans affected the abundance of T. garciabesi, and reduced the likelihood of future infestation. PMID- 26490001 TI - Computational modeling of self-trapped electrons in rutile TiO2. AB - In conjunction with the constrained density functional theory, a valence-bond representation has been employed to model the migration of anionic polaron in bulk rutile TiO2. It was found that the charge delocalization of a self-trapped electron proceeded predominately along the c crystal axis of rutile, thus exhibiting pronounced directional heterogeneity of polaron migration. As a result, the extrapolated polaron activation energies are 0.026 eV and 0.195 eV along the [001] and [111] lattice vectors, respectively. According to the Holstein theory, the difference on the activation energy makes the polaron drift over 100 times faster along the c crystal axis than on the ab crystal plane at room temperature. The notable anisotropy of the anionic polaron was also reflected through the electron paramagnetic resonance (EPR) g-matrix, whose principal component along [001] is substantially smaller than that along [110] or [110]. Finally, the extent of polaron charge was probed by our calculated isotropic hyperfine coupling constants on two groups of crystallographically inequivalent (17)O atoms, which manifest distinct strengths of spin-orbit interaction with the unpaired electron. PMID- 26490003 TI - Online emergency department ratings, patient satisfaction and the age-old issue of communication. PMID- 26490002 TI - Establishing the validity of English GP Patient Survey items evaluating out-of hours care. AB - BACKGROUND: A 2014 national audit used the English General Practice Patient Survey (GPPS) to compare service users' experience of out-of-hours general practitioner (GP) services, yet there is no published evidence on the validity of these GPPS items. OBJECTIVES: Establish the construct and concurrent validity of GPPS items evaluating service users' experience of GP out-of-hours care. METHODS: Cross-sectional postal survey of service users (n=1396) of six English out-of hours providers. Participants reported on four GPPS items evaluating out-of-hours care (three items modified following cognitive interviews with service users), and 14 evaluative items from the Out-of-hours Patient Questionnaire (OPQ). Construct validity was assessed through correlations between any reliable (Cochran's alpha>0.7) scales, as suggested by a principal component analysis of the modified GPPS items, with the 'entry access' (four items) and 'consultation satisfaction' (10 items) OPQ subscales. Concurrent validity was determined by investigating whether each modified GPPS item was associated with thematically related items from the OPQ using linear regressions. RESULTS: The modified GPPS item-set formed a single scale (alpha=0.77), which summarised the two-component structure of the OPQ moderately well; explaining 39.7% of variation in the 'entry access' scores (r=0.63) and 44.0% of variation in the 'consultation satisfaction' scores (r=0.66), demonstrating acceptable construct validity. Concurrent validity was verified as each modified GPPS item was highly associated with a distinct set of related items from the OPQ. CONCLUSIONS: Minor modifications are required for the English GPPS items evaluating out-of-hours care to improve comprehension by service users. A modified question set was demonstrated to comprise a valid measure of service users' overall satisfaction with out-of-hours care received. This demonstrates the potential for the use of as few as four items in benchmarking providers and assisting services in identifying, implementing and assessing quality improvement initiatives. PMID- 26490004 TI - The use of patient experience survey data by out-of-hours primary care services: a qualitative interview study. AB - BACKGROUND: English National Quality Requirements mandate out-of-hours primary care services to routinely audit patient experience, but do not state how it should be done. OBJECTIVES: We explored how providers collect patient feedback data and use it to inform service provision. We also explored staff views on the utility of out-of-hours questions from the English General Practice Patient Survey (GPPS). METHODS: A qualitative study was conducted with 31 staff (comprising service managers, general practitioners and administrators) from 11 out-of-hours primary care providers in England, UK. Staff responsible for patient experience audits within their service were sampled and data collected via face to-face semistructured interviews. RESULTS: Although most providers regularly audited their patients' experiences by using patient surveys, many participants expressed a strong preference for additional qualitative feedback. Staff provided examples of small changes to service delivery resulting from patient feedback, but service-wide changes were not instigated. Perceptions that patients lacked sufficient understanding of the urgent care system in which out-of-hours primary care services operate were common and a barrier to using feedback to enable change. Participants recognised the value of using patient experience feedback to benchmark services, but perceived weaknesses in the out-of-hours items from the GPPS led them to question the validity of using these data for benchmarking in its current form. CONCLUSIONS: The lack of clarity around how out-of-hours providers should audit patient experience hinders the utility of the National Quality Requirements. Although surveys were common, patient feedback data had only a limited role in service change. Data derived from the GPPS may be used to benchmark service providers, but refinement of the out-of-hours items is needed. PMID- 26490005 TI - Diminished Progression of Periapical Lesions with Zoledronic Acid in Ovariectomized Rats. AB - INTRODUCTION: The aim of this study was to investigate the effects of systemically administered zoledronic acid (ZOL) on the progression of periapical lesions in estrogen-deficient rats. METHODS: Female Wistar rats were divided into the following groups: SHAM-veh, sham surgery treated with vehicle (physiological saline); OVX-veh, ovariectomy treated with vehicle; SHAM-ZOL, sham surgery treated with ZOL; and OVX-ZOL, ovariectomy treated with ZOL. Vehicle or ZOL was administered intravenously once a week for 4 weeks. The pulp of the mandibular first molar of all rats was exposed to the oral environment to induce a periapical lesion, and the lesions were analyzed after 7 and 30 days. The mandibles were examined by micro-computed tomographic imaging and histopathologic, histometric, and immunohistochemical analyses. RESULTS: Histopathologically, the OVX-veh group had more severe inflammation and bone loss and a larger number of cells that were positive for tartrate-resistant acid phosphatase compared with the SHAM-veh and OVX-ZOL groups; the SHAM-veh and OVX ZOL groups were similar to each other. The SHAM-ZOL group had the lowest magnitude of these conditions. Tomographically, the OVX-veh group had greater bone loss than the other groups at both time points. The SHAM-veh, SHAM-ZOL, and OVX-ZOL groups had similar bone loss at both time points. In the sagittal section on day 30, the SHAM-ZOL group had lower bone loss compared with the SHAM-veh and OVX-ZOL groups. CONCLUSIONS: The hypoestrogenic condition aggravates the progression of periapical lesions. ZOL therapy may help contain bone destruction of periapical lesions. PMID- 26490006 TI - Identification of the IFN-beta response in H3N2 canine influenza virus infection. AB - Canine influenza viruses (CIVs) circulate continuously in the dog population, providing opportunities for exposure to humans and other species. Although the dog genome has been sequenced, innate immunity in dogs is not well characterized, which limits the understanding of H3N2 canine influenza virus pathogenesis. Equally, how this virus evades the canine host innate immune response to successfully establish infection remains unclear. To analyse the IFN-beta response to CIV infection in Madin-Darby canine kidney cells, the canine IFN-beta promoter sequence and its positive regulatory domain motifs were first cloned and identified using a luciferase reporter system. Next, we found that infection with the CIV strain GD/12 blocked the IFN-beta response primarily by inhibiting the NF kappaB and IFN regulatory factor 3 (IRF3) signalling pathways. Expression of GD/12 non-structural protein 1 alone was sufficient to inhibit Sendai virus induced NF-kappaB and IRF3 activation by suppressing p65 and IRF3 phosphorylation, suggesting the important role of this protein in the CIV mediated inhibition of the IFN-beta response. These results suggest that inhibition of the IFN-beta signalling pathway may have played a role in CIV establishment and spread in dog populations. PMID- 26490007 TI - Variation in rates of breast cancer surgery: A national analysis based on French Hospital Episode Statistics. AB - AIMS: Minimum volume thresholds were introduced in France in 2008 to improve the quality of cancer care. We investigated whether/how the quality of treatment decisions in breast cancer surgery had evolved before and after this policy was implemented. METHODS: We used Hospital Episode Statistics for all women having undergone breast conserving surgery (BCS) or mastectomy in France in 2005 and 2012. Three surgical procedures considered as better treatment options were analyzed: BCS, immediate breast reconstruction (IBR) and sentinel lymph node biopsy (SLNB). We studied the mean rates and variation according to the hospital profile and volume. RESULTS: Between 2005 and 2012, the volume of breast cancer surgery increased by 11% whereas one third of the hospitals no longer performed this type of surgery. In 2012, the mean rate of BCS was 74% and similar in all hospitals whatever the volume. Conversely, IBR and SLNB rates were much higher in cancer centers (CC) and regional teaching hospitals (RTH) [IBR: 19% and 14% versus 8% on average; SLNB: 61% and 47% versus 39% on average]; the greater the hospital volume, the higher the IBR and SLNB rates (p < 0.0001). Overall, whatever the surgical procedure considered, inter-hospital variation in rates declined substantially in CC and RTH. CONCLUSIONS: We identified considerable variation in IBR and SLNB rates between French hospitals. Although more complex and less standardized than BCS, most clinical guidelines recommended these procedures. This apparent heterogeneity suggests unequal access to high-quality procedures for women with breast cancer. PMID- 26490008 TI - Pattern injuries from blows with the muzzle end of a handgun. AB - Pistols, revolvers and blank guns are not only used to discharge cartridges, but also for hits to the victim. In such cases, the blows preferably affect the head and/or the interposed hands protecting the body. The impact is mostly exerted either by the grip of a pistol or the butt of a revolver. In vigorous thrusts inflicted with the muzzle end of the weapon, the edge of the barrel may produce circular punch lesions with central skin flaps roughly corresponding to the bore. As in other kinds of pistol-whipping, the scalp wounds may be associated with fractures of the skull and even with brain contusions. Using the example of a homicide committed by pistol-whipping, the morphological features of blunt injuries from a handgun's muzzle are presented. The characteristic wound pattern found on the victim's head could be reproduced experimentally by forceful blows to the forehead of a slaughtered pig. In the case presented, the dominant hand of the perpetrator showed friction blisters due to prolonged striking with an unhandy tool in the form of a pistol. PMID- 26490009 TI - Undiscovered regions on the molecular landscape of flagellar assembly. AB - The bacterial flagellum is a motility structure and one of the most complicated motors in the biosphere. A flagellum consists of several dozens of building blocks in different stoichiometries and extends from the cytoplasm to the extracellular space. Flagellar biogenesis follows a strict spatio-temporal regime that is guided by a plethora of flagellar assembly factors and chaperones. The goal of this review is to summarize our current structural and mechanistic knowledge of this intricate process and to identify the undiscovered regions on the molecular landscape of flagellar assembly. PMID- 26490010 TI - Laparoscopic adjustable gastric banding in adolescents: Results at two years including psychosocial aspects. AB - BACKGROUND/PURPOSE: Obesity now affects 3%-4% of the pediatric population and contributes to the increase in cardiac mortality in adulthood. Bariatric surgery is the best treatment for weight loss and the obesity-associated comorbidities in adults. We report here our experience of laparoscopic adjustable gastric banding (LAGB) in adolescents. METHODS: The medical charts of the first 16 patients operated on in our center were reviewed. Data were compiled concerning weight loss, physical and biological comorbidities, health-related quality of life (QOL) and surgical complications before surgery and during 24months of follow-up. RESULTS: The maximal pre-operative median body mass index was 43.0kg.m(-2), decreasing to 33.0kg.m(-2) at 2years post-LAGB, which corresponded to a 49.2% excess body weight loss (p<0.001). Most comorbidities (glucose intolerance, hypertension and sleep apnea) resolved within the first year post-LAGB and QOL was improved on the PedsQLTM scales. No severe surgical complications were noted, with only three re-interventions for device failure (2) or band removal (1). CONCLUSION: LAGB is well tolerated in adolescents and shows a beneficial impact on weight loss and obesity-related comorbidities. Associated with global management, it may have a positive impact on patients' QOL and social and psychological status. PMID- 26490011 TI - The long-term neurodevelopmental and psychological outcomes of gastroschisis: A cohort study. AB - OBJECTIVES: Previous gastroschisis specific neurodevelopmental studies have focused on the first 3years of life. The aim of this study was to assess the intellectual, behavioral and neurological outcomes of older children and adolescents born with gastroschisis. STUDY DESIGN: Of 99 gastroschisis survivors born in Western Australia, 1992 to 2005, and who were at least 5years old, 42 agreed to take part in this study. The study assessed: intellectual ability, with age appropriate Wechsler intelligence scales; neurological status; hearing; vision; behavioral status with the Strengths and Difficulties Questionnaire (SDQ); and parenting style with the Parenting Relationship Questionnaire (PRQ). All results were compared to normative means. RESULTS: Median age at follow-up was 10years (range 5-17). No child had evidence of cerebral palsy or hearing loss; 1 child had amblyopia. Psychometric tests were completed in 39 children: mean full scale IQ was 98.2 (standard deviation [SD] 10.7); the working memory index was the only subscale to show a significant decrease from the normative mean (mean 95.5, SD 12.4, p=0.038). The mean SDQ behavioral scores were significantly lower for 3 of 5 domains and the Total Difficulties score. PRQ scores were significantly abnormal for 4 of 7 domains: Communication, Discipline, Satisfaction with School and Relational Frustration. CONCLUSIONS: Overall intellectual abilities were within a normal range. The decrease in working memory index and the behavioral and parenting relationship impairments could be an effect of perinatal factors, gastroschisis management and complications or the complexity of the socio-economic environment. PMID- 26490012 TI - Text Message and Internet Support for Coronary Heart Disease Self-Management: Results From the Text4Heart Randomized Controlled Trial. AB - BACKGROUND: Mobile technology has the potential to deliver behavior change interventions (mHealth) to reduce coronary heart disease (CHD) at modest cost. Previous studies have focused on single behaviors; however, cardiac rehabilitation (CR), a component of CHD self-management, needs to address multiple risk factors. OBJECTIVE: The aim was to investigate the effectiveness of a mHealth-delivered comprehensive CR program (Text4Heart) to improve adherence to recommended lifestyle behaviors (smoking cessation, physical activity, healthy diet, and nonharmful alcohol use) in addition to usual care (traditional CR). METHODS: A 2-arm, parallel, randomized controlled trial was conducted in New Zealand adults diagnosed with CHD. Participants were recruited in-hospital and were encouraged to attend center-based CR (usual care control). In addition, the intervention group received a personalized 24-week mHealth program, framed in social cognitive theory, sent by fully automated daily short message service (SMS) text messages and a supporting website. The primary outcome was adherence to healthy lifestyle behaviors measured using a self-reported composite health behavior score (>=3) at 3 and 6 months. Secondary outcomes included clinical outcomes, medication adherence score, self-efficacy, illness perceptions, and anxiety and/or depression at 6 months. Baseline and 6-month follow-up assessments (unblinded) were conducted in person. RESULTS: Eligible patients (N=123) recruited from 2 large metropolitan hospitals were randomized to the intervention (n=61) or the control (n=62) group. Participants were predominantly male (100/123, 81.3%), New Zealand European (73/123, 59.3%), with a mean age of 59.5 (SD 11.1) years. A significant treatment effect in favor of the intervention was observed for the primary outcome at 3 months (AOR 2.55, 95% CI 1.12-5.84; P=.03), but not at 6 months (AOR 1.93, 95% CI 0.83-4.53; P=.13). The intervention group reported significantly greater medication adherence score (mean difference: 0.58, 95% CI 0.19-0.97; P=.004). The majority of intervention participants reported reading all their text messages (52/61, 85%). The number of visits to the website per person ranged from zero to 100 (median 3) over the 6-month intervention period. CONCLUSIONS: A mHealth CR intervention plus usual care showed a positive effect on adherence to multiple lifestyle behavior changes at 3 months in New Zealand adults with CHD compared to usual care alone. The effect was not sustained to the end of the 6-month intervention. A larger study is needed to determine the size of the effect in the longer term and whether the change in behavior reduces adverse cardiovascular events. TRIAL REGISTRATION: ACTRN 12613000901707; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364758&isReview= rue (Archived by WebCite at http://www.webcitation.org/6c4qhcHKt). PMID- 26490013 TI - Searching for new strategies against polymicrobial biofilm infections: guanylated polymethacrylates kill mixed fungal/bacterial biofilms. AB - OBJECTIVES: Biofilm-related human infections have high mortality rates due to drug resistance. Cohabitation of diverse microbes in polymicrobial biofilms is common and these infections present additional challenges for treatment compared with monomicrobial biofilms. Here, we address this therapeutic gap by assessing the potential of a new class of antimicrobial agents, guanylated polymethacrylates, in the treatment of polymicrobial biofilms built by two prominent human pathogens, the fungus Candida albicans and the bacterium Staphylococcus aureus. METHODS: We used imaging and quantitative methods to test the antibiofilm efficacy of guanylated polymethacrylates, a new class of drugs that structurally mimic antimicrobial peptides. We further compared guanylated polymethacrylates with first-line antistaphylococcal and anti-Candida agents used as combinatorial therapy against polymicrobial biofilms. RESULTS: Guanylated polymethacrylates were highly effective as a sole agent, killing both C. albicans and S. aureus when applied to established polymicrobial biofilms. Furthermore, they outperformed multiple combinations of current antimicrobial drugs, with one of the tested compounds killing 99.98% of S. aureus and 82.2% of C. albicans at a concentration of 128 mg/L. The extracellular biofilm matrix provided protection, increasing the MIC of the polymethacrylates by 2-4-fold when added to planktonic assays. Using the C. albicans bgl2DeltaDelta mutant, we implicate matrix polysaccharide beta-1,3 glucan in the mechanism of protection. Data for two structurally distinct polymers suggest that this mechanism could be minimized through chemical optimization of the polymer structure. Finally, we demonstrate that a potential application for these polymers is in antimicrobial lock therapy. CONCLUSIONS: Guanylated polymethacrylates are a promising lead for the development of an effective monotherapy against C. albicans/S. aureus polymicrobial biofilms. PMID- 26490014 TI - Detection of MRSA ST3061-t843-mecC and ST398-t011-mecA in white stork nestlings exposed to human residues. AB - OBJECTIVES: The objective of this study was to analyse the prevalence of tracheal carriage of Staphylococcus aureus/MRSA in storks and to study the resistance and virulence genes in the obtained isolates. METHODS: Tracheal samples from 92 stork nestlings of two landfill-associated and two natural-habitat colonies were inoculated in specific media for S. aureus and MRSA recovery. Antimicrobial susceptibility was tested, and the presence of resistance, virulence and immune evasion cluster (IEC) genes was analysed by PCR. S. aureus isolates were characterized by spa and agr typing. Staphylococcal cassette chromosome (SCC) mec type was determined for mecC-positive isolates, and MLST was performed for 17 selected S. aureus isolates. RESULTS: S. aureus isolates were identified in 32/92 samples (34.8%), and 38 isolates were recovered. The prevalence of S. aureus was higher in nestlings from landfills (24/43, 55.8%) than in those from natural habitats (8/49, 16.3%). Three birds from landfill-associated colonies carried MRSA, two with mecA-positive strains [clonal complex (CC) 5-spa-t002 and CC398 spa-t011] and one with a mecC-positive strain [sequence type (ST) 3061-CC130-spa t843-agr-III-SCCmecXI). None of the MRSA isolates presented IEC genes. Thirty five MSSA isolates, which showed 18 different spa types (ascribed to CC5, CC7, CC22, CC30, CC45, CC59, CC133 and CC398), were obtained. The agr types detected were I (63%), II (29%) and III (8%). Resistance and virulence genes identified in MSSA were blaZ (n = 25), erm(T) (n = 9), erm(A) (n = 1), tet(M) (n = 2), fexA (n = 3), str (n = 2), tst (n = 2), eta (n = 1) and cna (n = 15). The IEC types B, C, D and G were found in MSSA isolates, and two new STs were identified (ST3060 and ST3061). CONCLUSIONS: White storks are frequently tracheal carriers of S. aureus, including ST398 isolates. MRSA isolates of lineages CC398-mecA and CC130-mecC were detected in storks from landfill-associated colonies exposed to human residues. PMID- 26490015 TI - Improving antibiotic prescribing quality by an intervention embedded in the primary care practice accreditation: the ARTI4 randomized trial. AB - OBJECTIVES: Antibiotic overprescribing is a significant problem. Multifaceted interventions improved antibiotic prescribing quality; their implementation and sustainability, however, have proved difficult. We analysed the effectiveness of an intervention embedded in the quality cycle of primary care practice accreditation on quantity and quality of antibiotic prescribing for respiratory tract and ear infections (RTIs). METHODS: This was a pragmatic, cluster randomized intervention trial in 88 Dutch primary care practices. The intervention (physician education and audit/feedback on antibiotic prescribing quantity and quality) was integrated in practice accreditation by defining an improvement plan with respect to antibiotic prescribing for RTIs. Numbers and types of dispensed antibiotics were analysed from 1 year prior to the intervention to 2 years after the intervention (pharmacy data). Overprescribing, underprescribing and non-first-choice prescribing for RTIs were analysed at baseline and 1 year later (self-registration). RESULTS: There were significant differences between intervention and control practices in the changes in dispensed antibiotics/1000 registered patients (first year: -7.6% versus -0.4%, P = 0.002; second year: -4.3% versus +2%, P = 0.015), which was more pronounced for macrolides and amoxicillin/clavulanate (first year: -12.7% versus +2.9%, P = 0.001; second year: -7.8% versus +6.7%, P = 0.005). Overprescribing for RTIs decreased from 44% of prescriptions to 28% (P < 0.001). Most general practitioners (GPs) envisaged practice accreditation as a tool for guideline implementation. CONCLUSIONS: GP education and an audited improvement plan around antibiotics for RTIs as part of primary care practice accreditation sustainably improved antibiotic prescribing. Tools should be sought to further integrate and facilitate education and audit/feedback in practice accreditation. PMID- 26490016 TI - Transmission of MRSA between humans and animals on duck and turkey farms. AB - OBJECTIVES: The objectives of this study were to estimate the prevalence of MRSA on duck and turkey farms, identify risk factors for human carriage and study transmission between animals and humans. METHODS: On 10 duck and 10 turkey farms, samples were taken from animals, poultry houses, home residences and humans and cultured using pre-enrichment and selective enrichment. MRSA isolates were typed by spa typing and multiple-locus variable number tandem repeat analysis (MLVA) typing. A subset of isolates from animals and humans was investigated using whole genome mapping. RESULTS: MRSA was found on one duck farm and three turkey farms. On duck farms, all humans were MRSA negative. On turkey farms, 5 of 11 farmers, 2 of 32 family members and 15 of 49 samples from the home residences were MRSA positive. Individuals with daily contact with turkeys were significantly more often MRSA positive than individuals without daily contact. All MRSA isolates belonged to livestock-associated MLVA complex 398, belonged to spa type t011, were negative for Panton-Valentine leucocidin, were mecC negative and were mecA positive. Whole-genome mapping proved a valuable tool to study the transmission of livestock-associated MRSA and showed that on two turkey farms the isolates from the animals and humans were indistinguishable or closely related, indicating transmission. CONCLUSIONS: MRSA carriage in individuals in daily contact with turkeys was significantly higher than that in individuals only living on the farms or than in the general Dutch population. Therefore, persons with a high degree of contact with turkeys have an increased risk of MRSA carriage, and we propose that they should be screened prior to hospitalization in order to decrease the risk of nosocomial transmission. PMID- 26490017 TI - 2015 ACC/AHA/SCAI Focused Update on Primary Percutaneous Coronary Intervention for Patients With ST-Elevation Myocardial Infarction: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention and the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. PMID- 26490018 TI - Effect of supplementation of fermented milk drink containing probiotic Lactobacillus casei Shirota on the concentrations of aflatoxin biomarkers among employees of Universiti Putra Malaysia: a randomised, double-blind, cross-over, placebo-controlled study. AB - Human exposure to aflatoxin is through the diet, and probiotics are able to bind aflatoxin and prevent its absorption in the small intestine. This study aimed to determine the effectiveness of a fermented milk drink containing Lactobacillus casei Shirota (LcS) (probiotic drink) to prevent aflatoxin absorption and reduce serum aflatoxin B1-lysine adduct (AFB1-lys) and urinary aflatoxin M1 concentrations. The present study was a randomised, double-blind, cross-over, placebo-controlled study with two 4-week intervention phases. In all, seventy-one subjects recruited from the screening stage were divided into two groups--the Yellow group and the Blue group. In the 1st phase, one group received probiotic drinks twice a day and the other group received placebo drinks. Blood and urine samples were collected at baseline, 2nd and 4th week of the intervention. After a 2-week wash-out period, the treatments were switched between the groups, and blood and urine samples were collected at the 6th, 8th and 10th week (2nd phase) of the intervention. No significant differences in aflatoxin biomarker concentrations were observed during the intervention. A within-group analysis was further carried out. Aflatoxin biomarker concentrations were not significantly different in the Yellow group. Nevertheless, ANOVA for repeated measurements indicated that AFB1-lys concentrations were significantly different (P=0.035) with the probiotic intervention in the Blue group. The 2nd week AFB1-lys concentrations (5.14 (SD 2.15) pg/mg albumin (ALB)) were significantly reduced (P=0.048) compared with the baseline (6.24 (SD 3.42) pg/mg ALB). Besides, the 4th week AFB1-lys concentrations were significantly lower (P<0.05) with probiotic supplementation than with the placebo. Based on these findings, a longer intervention study is warranted to investigate the effects of continuous LcS consumption to prevent dietary aflatoxin exposure. PMID- 26490020 TI - Systematic overview of cost-effectiveness thresholds in ten countries across four continents. AB - AIM: To provide an overview of thresholds for incremental cost-effectiveness ratios (ICERs) representing willingness-to-pay (WTP) across multiple countries and insights into exemptions pertaining to the ICER (e.g., cancer). To compare ICER thresholds to individual country's estimated ability-to-pay. MATERIALS & METHODS: We included AHRQ/USA, BIQG-GOEG/Austria, CADTH/Canada, DAHTA@DIMDI/Germany, DECIT-CGATS/Brazil, HAS/France, HITAP/Thailand, IQWiG/Germany, LBI-HTA/Austria, MSAC/Australia, NICE/England/Wales and SBU/Sweden. ICER thresholds were derived from systematic literature/website search/expert surveys. WTP was compared with ATP using Spearman's rank correlation. RESULTS: Two general and explicitly acknowledged thresholds (England/Wales, Thailand), implicit thresholds in six countries and different ICER thresholds/decision-making rules in oncology were identified. Correlation between WTP and ability-to-pay was moderate. DISCUSSION: Our overview supports country-specific discussions on WTP and on how to define value(s) within societies. PMID- 26490019 TI - ChEC-seq kinetics discriminates transcription factor binding sites by DNA sequence and shape in vivo. AB - Chromatin endogenous cleavage (ChEC) uses fusion of a protein of interest to micrococcal nuclease (MNase) to target calcium-dependent cleavage to specific genomic loci in vivo. Here we report the combination of ChEC with high-throughput sequencing (ChEC-seq) to map budding yeast transcription factor (TF) binding. Temporal analysis of ChEC-seq data reveals two classes of sites for TFs, one displaying rapid cleavage at sites with robust consensus motifs and the second showing slow cleavage at largely unique sites with low-scoring motifs. Sites with high-scoring motifs also display asymmetric cleavage, indicating that ChEC-seq provides information on the directionality of TF-DNA interactions. Strikingly, similar DNA shape patterns are observed regardless of motif strength, indicating that the kinetics of ChEC-seq discriminates DNA recognition through sequence and/or shape. We propose that time-resolved ChEC-seq detects both high-affinity interactions of TFs with consensus motifs and sites preferentially sampled by TFs during diffusion and sliding. PMID- 26490021 TI - Racah materials: role of atomic multiplets in intermediate valence systems. AB - We address the long-standing mystery of the nonmagnetic insulating state of the intermediate valence compound SmB6. Within a combination of the local density approximation (LDA) and an exact diagonalization (ED) of an effective discrete Anderson impurity model, the intermediate valence ground state with the f-shell occupation = 5.6 is found for the Sm atom in SmB6. This ground state is a singlet, and the first excited triplet state ~3 meV higher in the energy. SmB6 is a narrow band insulator already in LDA, with the direct band gap of ~10 meV. The electron correlations increase the band gap which now becomes indirect. Thus, the many-body effects are relevant to form the indirect band gap, crucial for the idea of "topological Kondo insulator" in SmB6. Also, an actinide analog PuB6 is considered, and the intermediate valence singlet ground state is found for the Pu atom. We propose that [Sm, Pu]B6 belong to a new class of the intermediate valence materials with the multi-orbital "Kondo-like" singlet ground-state. Crucial role of complex spin-orbital f( n)-f ( n+1) multiplet structure differently hybridized with ligand states in such Racah materials is discussed. PMID- 26490022 TI - Pilot Analysis of Asbestos-induced Diffuse Pleural Thickening with Respiratory Compromise. AB - We investigated the clinical features of asbestos-induced diffuse pleural thickening (DPT) with severe respiratory compromise. We conducted a retrospective study of consecutive subjects with asbestos-induced DPT. Medical data such as initial symptoms, radiological findings, respiratory function test results, and clinical course were collected and analyzed. There were 24 patients between 2003 and 2012. All were men, and the median age at the development of DPT was 74 years. The top occupational category associated with asbestos exposure was dockyard workers. The median duration of asbestos exposure was 35.0 years, and the median latency from first exposure to the onset of DPT was 49.0 years. There were no significant differences in respiratory function test results between the higher and lower Brinkman index groups or between unilateral and bilateral DPT. Thirteen patients had a history of benign asbestos pleural effusion (BAPE), and the median duration from pleural fluid accumulation to DPT with severe respiratory compromise was 28.4 months. DPT with severe respiratory compromise can develop after a long latency following occupational asbestos exposure and a history of BAPE. PMID- 26490023 TI - A Case-matched Comparative Study of Laparoscopic and Open Total Proctocolectomy for Ulcerative Colitis. AB - The aim of this single-institution, retrospective, observational case-control study was to evaluate the safety and feasibility of laparoscopic proctocolectomy (PC) for ulcerative colitis (UC), by comparing it with a case-control series of open PC. Twenty UC patients who underwent laparoscopic PC were retrospectively compared with the open PC group of 12 patients matched for age, sex, and urgency of the operation. In the laparoscopic PC group, the operative time was significantly longer, but the amount of blood loss was significantly smaller. The open PC patients underwent an intraoperative blood transfusion significantly more often, and the serum C-reactive protein level on the first postoperative day was significantly higher in the open PC group. In the laparoscopic PC group, the rate of severe postoperative morbidities, grades 3 and 4 on the Clavien-Dindo classification, was significantly lower, and the median length of hospital stay was significantly shorter. Laparoscopic PC for patients with UC showed superior perioperative outcomes to open PC, except for longer operative time. PMID- 26490024 TI - Characteristics and Costs of Ladder Fall Injuries: A Report from a Single Emergency Center in Okayama. AB - We sought to identify the incidence, injury patterns, and financial burden of ladder fall injuries to provide a reference for reinforcing guidelines on the prevention of such injuries. We enrolled the patients who were injured in a ladder-related fall and required intensive care between April 2012 and March 2014 at Okayama University Hospital, a tertiary care hospital in Okayama City:9 patients injured in 7 stepladder falls and 2 straight ladder falls. The median patient age was 69 years, and 8 were males. Six falls occurred in non occupational settings. Head injuries predominated, and the injury severity score ranged from 2 to 35 (mean=21+/-12). At the time of discharge from the intensive care unit, one patient had died and 5 patients had some neurological disabilities. The case fatality rate was 11%. The total cost of care during the review period was ?16,705,794, with a mean cost of ?1,856,199 per patient. Ladder fall injuries are associated with a high rate of neurological sequelae and pose a financial burden on the health insurance system. A prevention education campaign targeting at older-aged males in non-occupational settings may be a worthwhile health service investment in this community. PMID- 26490025 TI - Inhibitory Effects of Edaravone, a Free Radical Scavenger, on Cytokine-induced Hyperpermeability of Human Pulmonary Microvascular Endothelial Cells:A Comparison with Dexamethasone and Nitric Oxide Synthase Inhibitor. AB - Lung hyperpermeability affects the development of acute respiratory distress syndrome (ARDS), but therapeutic strategies for the control of microvascular permeability have not been established. We examined the effects of edaravone, dexamethasone, and N-monomethyl-L-arginine (L-NMMA) on permeability changes in human pulmonary microvascular endothelial cells (PMVEC) under a hypercytokinemic state. Human PMVEC were seeded in a Boyden chamber. After monolayer confluence was achieved, the culture media were replaced respectively by culture media containing edaravone, dexamethasone, and L-NMMA. After 24-h incubation, the monolayer was stimulated with tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). Fluorescein-labeled dextran was added. Then the trans-human PMVEC leak was measured. Expressions of vascular endothelial-cadherin (VE-cadherin) and zonula occludens-1 protein (ZO-1) were evaluated using real time quantitative polymerase chain reaction and immunofluorescence microscopy. The results showed that TNF-alpha+IL-1beta markedly increased pulmonary microvascular permeability. Pretreatment with edaravone, dexamethasone, or L-NMMA attenuated the hyperpermeability and inhibited the cytokine-induced reduction of VE-cadherin expression on immunofluorescence staining. Edaravone and dexamethasone increased the expression of ZO-1 at both the mRNA and protein levels. Edaravone and dexamethasone inhibited the permeability changes of human PMVEC, at least partly through an enhancement of VE-cadherin. Collectively, these results suggest a potential therapeutic approach for intervention in patients with ARDS. PMID- 26490026 TI - Neoadjuvant Chemotherapy with or without Concurrent Hormone Therapy in Estrogen Receptor-Positive Breast Cancer: NACED-Randomized Multicenter Phase II Trial. AB - Although in the neoadjuvant setting for estrogen receptor (ER)-positive breast cancers, chemotherapy or hormone therapy alone does not result in satisfactory tumor response, it is unknown whether concurrent chemo-endocrine therapy is superior to chemotherapy alone in clinical outcomes. We conducted a randomized phase II trial to test the responses of ER-positive patients to concurrent administration of chemo-endocrine therapy in the neoadjuvant setting. Women with stage II-III, ER-positive, invasive breast cancer (n=28) received paclitaxel followed by fluorouracil, epirubicin, cyclophosphamide (T-FEC) and were randomized to receive concurrent chemo-endocrine therapy consisting of goserelin administered subcutaneously for premenopausal women or an aromatase inhibitor for postmenopausal women. The primary endpoint was the pathological complete response (pCR) rate after neoadjuvant therapy. Twenty-eight patients were randomized. There were no significant differences in pCR rate between the concurrent group (12.5%;2/16) and the chemotherapy alone group (8.3%;1/12). Tumor size after therapy was significantly reduced in the concurrent therapy group (p=0.035), but not in the chemotherapy-alone group (p=0.622). Neoadjuvant chemotherapy with concurrent hormone therapy provided no significant improvement in pCR rate in ER positive breast cancers. These preliminary results should be followed up by further studies. PMID- 26490027 TI - Primary Duodenal Follicular Lymphoma Treated With Rituximab Monotherapy and Followed-up for 15 Years. AB - A 41-year-old woman was diagnosed with duodenal follicular lymphoma. She had no other lesions and was assigned to a "watch and wait" policy. Swelling of the inguinal lymph nodes appeared 45 months later, and rituximab monotherapy resulted in complete remission. However, follicular lymphoma recurred in the stomach, rectum and mesenteric and external iliac lymph nodes 81 months after the therapy. The patient received rituximab monotherapy again and has remained in complete remission in the fifteenth year after the initial diagnosis. This case suggests the usefulness of rituximab monotherapy in the long-term management of intestinal follicular lymphoma. PMID- 26490028 TI - Liver Sarcoidosis with Unique MRI Images Using Gadolinium Ethoxybenzyl Diethylenetriamine Pentaacetic Acid. AB - Sarcoidosis is a systemic disease characterized by the formation of non-caseating granulomas in multiple organs. In the diagnosis of sarcoidosis, imaging modalities such as ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) are useful;however, there are few reports of MRI imaging using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB) MRI. A 46-year-old Japanese female with suspected pulmonary sarcoidosis was admitted to our hospital because low-density mottles in the liver were observed incidentally by chest CT. The low-density mottles were not enhanced at the arterial phase or portal phase by abdominal CT and MRI, and decreased uptake was observed in the hepatobiliary phase of Gd-EOB MRI. No hematological disorder was observed except for a slight increase of biliary enzymes. The lesion was diagnosed as liver sarcoidosis by the liver biopsy. Since the patient refused steroid therapy, we prescribed ursodeoxycholic acid (UDCA). 600mg/day. The serum levels of biliary enzymes were normalized and the abdominal CT findings gradually improved after the initiation of UDCA medication. Gd-EOB MRI showed unique hypointense areas in the liver at the hepatobiliary phase, which might be useful in the diagnosis of liver sarcoidosis. PMID- 26490029 TI - Paecilomyces lilacinus-induced Scleritis Following Bleb-associated Endophthalmitis after Trabeculectomy. AB - Paecilomyces lilacinus (P. lilacinus) is a rare cause of fungal scleritis. We herein report a case of P. lilacinus-induced scleritis following bleb-associated endophthalmitis after trabeculectomy that was successfully treated with surgical excision of the affected sclera in combination with antifungal medication. An 85 year-old female underwent trabeculectomy of the left eye. A dellen formed in the corneal periphery due to limbal elevation of the filtering bleb and progressed to an infectious corneal ulcer, leading to blebitis. Eight days after the onset of blebitis, the patient was diagnosed with endophthalmitis, which resolved after vitrectomy. The growth of P. lilacinus was identified on swabs of the conjunctiva and the corneal specimen. Scleritis developed after the resolution of the endophthalmitis, and an early excision of the affected sclera, in addition to antifungal medication, resolved it completely. However, the scleritis recurred in a different region of the left eye. After 7 months of antifungal medication, the left eye showed no residual infection. When treating P. lilacinus-induced scleritis, surgical excision of the affected sclera has been shown to be an effective treatment strategy. Nevertheless, it is possible that the infection may recur in another part of the eyeball after the complete resolution of the primary lesion. PMID- 26490030 TI - Cytomegalovirus as an Insidious Pathogen Causing Duodenitis. AB - A 60-year-old woman with rheumatoid arthritis treated with methotrexate for a decade complained of slight epigastric discomfort. A positive cytomegalovirus (CMV) antigenemia test indicated the probability of CMV-related gastrointestinal infection, for which esophagogastroduodenoscopy was performed. Endoscopic findings showed a non-specific duodenal mucosal lesion;however, pathological investigation revealed evidence of CMV duodenitis. There is scarce information on the clinical and pathological features of CMV-related duodenitis, likely due to its low prevalence. CMV infection in the upper gastrointestinal tract should be considered as a differential diagnosis in high-risk individuals, particularly those with symptoms relating to the digestive system. Biopsy examinations are preferable for the definitive diagnosis of CMV gastrointestinal infection, even without specific endoscopic features. PMID- 26490031 TI - Erratum. Venous Thromboembolism after Total Hip Arthroplasty Diagnosed by Enhanced Computed Tomography:Comparison of Selective Thromboprophylaxis and No Thromboprophylaxis. AB - Total hip arthroplasty (THA) is the most effective treatment for advanced or end stage hip osteoarthritis. However, venous thromboembolism (VTE) remains one of its unresolved complications. We reviewed the records of 322 patients undergoing primary THA and investigated the efficacy of anticoagulant prophylaxis for VTE. Our study cohort consisted of 60 patients who received no anticoagulants, 100 patients who received a factor Xa inhibitor (fondaparinux), 100 patients who received low molecular weight heparin (enoxaparin), and 62 patients who selectively received no anticoagulant prophylaxis due to perioperative bleeding, weight, and/or hemoglobin concentration. Enhanced 64-slice multidetector row computed tomography was performed postoperatively for 7 days in all cases. The incidence of VTE in the four groups was 15%, 9.0%, 6.0%, and 6.4%, respectively. The incidence of VTE was significantly lower in the groups receiving anticoagulant prophylaxis and the group selectively receiving no anticoagulant prophylaxis than in the group receiving no anticoagulants. Complications of fondaparinux therapy included hepatic dysfunction in 4 cases (4.0%), minor bleeding in 2 cases (2.0%), persistent wound drainage in 3 cases (3.0%), and eruption in 1 case (1.0%). The complications of enoxaparin therapy were persistent wound drainage in 1 case (1.0%) and progression of anemia in 1 case (1.0%). The incidence of VTE was low in patients who selectively received no anticoagulant prophylaxis, so we conclude that anticoagulant prophylaxis should be used selectively in THA cases. PMID- 26490032 TI - Structure and agency in long-distance truck drivers' lived experiences of condom use for HIV prevention. AB - Condom promotion has emerged as a mainstay of targeted HIV prevention interventions in India, with its emphasis on individual behaviour change and personal responsibility. However, such approaches often do not account for marginalised populations' structural vulnerability to HIV, arising from social, economic and political factors in the lived environment. In this paper, I use a critical health communication framework to analyse how structure and agency interact in influencing condom use among long-distance truck drivers in India. Drawing on an abductive discourse analysis of condom-use discourses among truckers and peer educators in two Indian cities, findings reveal that while truckers understand the biomedical logic of condoms as barriers, they also express anxiety about condom breakage and experience structural barriers to condom use. The paper concludes by calling for greater attention to structural vulnerabilities in future HIV prevention efforts with truck drivers. PMID- 26490034 TI - Effects of self-administered methamphetamine on discrimination learning and reversal in nonhuman primates. AB - RATIONALE: Frequent exposure to methamphetamine has been reported to adversely influence cognitive behavior and, in particular, inhibitory control processes. OBJECTIVE: The present studies were conducted in squirrel monkeys to assess the effects of daily intravenous methamphetamine self-administration on touch screen based repeated acquisition and discrimination reversal tasks thought to reflect behavioral dimensions of, respectively, learning and response inhibition. METHODS: First, stable methamphetamine-maintained behavior was established in each subject (0.35-1.6 mg/kg/session), and subsequently, a second daily session of discrimination learning was conducted (20 h later). Subjects first learned to discriminate between two simultaneously presented stimuli (acquisition) and, subsequently, to re-learn the discrimination with the contingencies switched (reversal). The role of the interval between self-administration and touch screen sessions was evaluated, as well as the effects of abrupt methamphetamine discontinuation. RESULTS: Results indicate that daily methamphetamine self administration markedly disrupted the development of discrimination learning, initially requiring nearly twice the number of trials to master discriminations. The magnitude of adverse effects in individual subjects correlated to the level of daily methamphetamine intake. Importantly, however, behavioral disruption of discrimination learning was surmounted following remedial training. Once criterion levels of discrimination performance were achieved, subsequent development of reversal performance was largely unaffected except when the interval between self-administration and touch screen session was short and, thus, likely a result of methamphetamine's direct effects. Discontinuation of methamphetamine produced no disruption in acquisition or reversal. CONCLUSION: These results indicate that self-administered methamphetamine can markedly disrupt learning processes and highlight key differences in its effects on different aspects of discrimination learning. PMID- 26490033 TI - Genome-wide protein-protein interactions and protein function exploration in cyanobacteria. AB - Genome-wide network analysis is well implemented to study proteins of unknown function. Here, we effectively explored protein functions and the biological mechanism based on inferred high confident protein-protein interaction (PPI) network in cyanobacteria. We integrated data from seven different sources and predicted 1,997 PPIs, which were evaluated by experiments in molecular mechanism, text mining of literatures in proved direct/indirect evidences, and "interologs" in conservation. Combined the predicted PPIs with known PPIs, we obtained 4,715 no-redundant PPIs (involving 3,231 proteins covering over 90% of genome) to generate the PPI network. Based on the PPI network, terms in Gene ontology (GO) were assigned to function-unknown proteins. Functional modules were identified by dissecting the PPI network into sub-networks and analyzing pathway enrichment, with which we investigated novel function of underlying proteins in protein complexes and pathways. Examples of photosynthesis and DNA repair indicate that the network approach is a powerful tool in protein function analysis. Overall, this systems biology approach provides a new insight into posterior functional analysis of PPIs in cyanobacteria. PMID- 26490035 TI - Inhibition of monoacylglycerol lipase (MAGL) enhances cue-induced reinstatement of nicotine-seeking behavior in mice. AB - RATIONALE: Tobacco smoking is still a major population health issue. The endocannabinoid system has been shown to control drug-seeking behaviors. There are two main endocannabinoids: anandamide degraded by fatty acid amide hydrolase (FAAH) and 2-arachidonoylglycerol (2-AG) degraded by monoacylglycerol lipase (MAGL). OBJECTIVES: The role of MAGL has only been explored recently, and so far, no study have been performed to evaluate the effects of MAGL inhibitor on nicotine reinforcing properties and cue-induced reinstatement of nicotine seeking. METHODS: Here, we investigated the effects of the MAGL inhibitor JZL184 on nicotine self-administration under fixed and progressive-ratio schedules of reinforcement and on cue-induced reinstatement of nicotine seeking in mice. We also evaluated the effects of JZL184 on food self-administration for possible non specific effects. RESULTS: JZL184 (0, 8, and 16 mg/kg) did not affect food taking, nicotine taking, or motivation for nicotine. MAGL inhibition by JZL184 (16 mg/kg) increased reinstatement of previously extinguished nicotine seeking induced by presentation of nicotine-associated cues, but did not produce reinstatement on its own. CONCLUSIONS: This study implicates involvement of 2-AG in nicotine-seeking behaviors. PMID- 26490036 TI - Copy number variations in the genome of the Qatari population. AB - BACKGROUND: The populations of the Arabian Peninsula remain the least represented in public genetic databases, both in terms of single nucleotide variants and of larger genomic mutations. We present the first high-resolution copy number variation (CNV) map for a Gulf Arab population, using a hybrid approach that integrates array genotyping intensity data and next-generation sequencing reads to call CNVs in the Qatari population. METHODS: CNVs were detected in 97 unrelated Qatari individuals by running two calling algorithms on each of two primary datasets: high-resolution genotyping (Illumina Omni 2.5M) and high depth whole-genome sequencing (Illumina PE 100bp). The four call-sets were integrated to identify high confidence CNV regions, which were subsequently annotated for putative functional effect and compared to public databases of CNVs in other populations. The availability of genome sequence was leveraged to identify tagging SNPs in high LD with common deletions in this population, enabling their imputation from genotyping experiments in the future. RESULTS: Genotyping intensities and genome sequencing data from 97 Qataris were analyzed with four different algorithms and integrated to discover 16,660 high confidence CNV regions (CNVRs) in the total population, affecting ~28 Mb in the median Qatari genome. Up to 40% of all CNVs affected genes, including novel CNVs affecting Mendelian disease genes, segregating at different frequencies in the 3 major Qatari subpopulations, including those with Bedouin, Persian/South Asian, and African ancestry. Consistent with high consanguinity levels in the Bedouin subpopulation, we found an increased burden for homozygous deletions in this group. In comparison to known CNVs in the comprehensive Database of Genomic Variants, we found that 5% of all CNVRs in Qataris were completely novel, with an enrichment of CNVs affecting several known chromosomal disorder loci and genes known to regulate sugar metabolism and type 2 diabetes in the Qatari cohort. Finally, we leveraged the availability of genome sequence to find suitable tagging SNPs for common deletions in this population. CONCLUSION: We combine four independently generated datasets from 97 individuals to study CNVs for the first time at high-resolution in a Gulf Arab population. PMID- 26490037 TI - Evaluating long-term effectiveness of sleeping sickness control measures in Guinea. AB - BACKGROUND: Human African Trypanosomiasis threatens human health across Africa. The subspecies T.b. gambiense is responsible for the vast majority of reported HAT cases. Over the past decade, expanded control efforts accomplished a substantial reduction in HAT transmission, spurring the WHO to include Gambian HAT on its roadmap for 2020 elimination. To inform the implementation of this elimination goal, we evaluated the likelihood that current control interventions will achieve the 2020 target in Boffa prefecture in Guinea, which has one of the highest prevalences for HAT in the country, and where vector control measures have been implemented in combination with the traditional screen and treat strategy. METHODS: We developed a three-species mathematical model of HAT and used a Bayesian melding approach to calibrate the model to epidemiological and entomological data from Boffa. From the calibrated model, we generated the probabilistic predictions regarding the likelihood that the current HAT control programs could achieve elimination by 2020 in Boffa. RESULTS: Our model projections indicate that if annual vector control is implemented in combination with annual or biennial active case detection and treatment, the probability of eliminating HAT as public health problem in Boffa by 2020 is over 90%. Annual implementation of vector control alone has a significant impact but a decreased chance of reaching the objective (77%). However, if the ongoing control efforts are interrupted, HAT will continue to remain a public health problem. In the presence of a non-human animal transmission reservoir, intervention strategies must be maintained at high coverage, even after 2020 elimination, to prevent HAT reemerging as a public health problem. CONCLUSIONS: Complementing active screening and treatment with vector control has the potential to achieve the elimination target before 2020 in the Boffa focus. However, surveillance must continue after elimination to prevent reemergence. PMID- 26490038 TI - Proposed HPV vaccination syndrome is unsubstantiated. PMID- 26490039 TI - Knee effusion: ultrasound as a useful tool for the detection of calcium pyrophosphate crystals. AB - The objective of this study was to evaluate the sensitivity and specificity of ultrasound (US) and conventional radiography (CR) for the detection of calcium pyrophosphate (CPP) crystals in patients with knee effusion. Consecutive patients >=50 years old with knee effusion were included. All patients underwent arthrocentesis with aspiration of synovial fluid (SF) and subsequent analysis of CPP crystals using plain light and polarizing light microscopy. US and CR of the involved knee were performed immediately after arthrocentesis. CR results were read by an experienced rheumatologist, searching for chondrocalcinosis. US examinations were carried out by an experienced rheumatologist blinded to all clinical and imaging data. The following US abnormal findings were considered indicative of CPP crystals deposition (CPPD): (1) hyperechoic bands within the femoral hyaline cartilage layer, and (2) hyperechoic sparkling spots in meniscal fibrocartilage. A total of 75 knees were evaluated in the same number of patients. Analysis of SF revealed CPP crystals in 15 out of 75 (20 %) knees: all (10) patients with previous diagnosis of CPPD, 3 patients with previous diagnosis of primary knee osteoarthritis (OA) and 2 patients without previous definitive diagnosis of a rheumatic condition. Using SF analysis as reference method, sensitivity and specificity for US findings was 60 and 96.7 %, respectively, while CR showed a sensitivity of 40 % and a specificity of 83.3 %. US results showed high specificity with acceptable sensitivity to detect CPP crystals in patients with knee effusion. Compared with CR, US results had better specificity and sensitivity. US may be used in daily rheumatologic practice when CPPD is suspected. PMID- 26490041 TI - Retrieval of Disseminated Tumor Cells Colonizing the Bone in Murine Breast Cancer Metastasis Models. AB - In breast cancer, the most frequent site of metastasis is bone. Disseminated tumor cells (DTCs) can be detected in the bone marrow of patients by their expression of epithelial oroncogenic markers [1], and the presence and frequency of these DTCs are associated with poor prognosis. However, many of the details behind this process remain elusive, including the biological properties and fates of these apparently indolent cancer cells. To provide pre-clinical models of DTCs, we have developed a procedure that allows for controlled and enhanced delivery of tumor cells to the bone in animal experiments via injection into the iliac artery of the hind limb [2]. To our surprise, we found that most cancer cells became integrated into the solid bone matrix shortly after arriving in the bone, and only a minority can be flushed out with the bone marrow.Here we describe a method that helps to retrieve DTCs homing to the bone in which we achieve an improved recovery of those tumor cells closely associated with the bone microenvironment. In our view it is especially important to analyze these tumor cell subpopulations, as they may take full advantage of growth-, survival- and immune-protective signals provided by neighbor cells. We also show a pilot study on how this approach may be applied to the analysis of cancer dormancy. Our study suggests that the detection and retrieval of DTCs in clinical studies are incomplete because they are conducted exclusively with bone marrow aspirates. PMID- 26490040 TI - Vaccination with the variable tick protein of the relapsing fever spirochete Borrelia hermsii protects mice from infection by tick-bite. AB - BACKGROUND: Tick-borne relapsing fevers of humans are caused by spirochetes that must adapt to both warm-blooded vertebrates and cold-blooded ticks. In western North America, most human cases of relapsing fever are caused by Borrelia hermsii, which cycles in nature between its tick vector Ornithodoros hermsi and small mammals such as tree squirrels and chipmunks. These spirochetes alter their outer surface by switching off one of the bloodstream-associated variable major proteins (Vmps) they produce in mammals, and replacing it with the variable tick protein (Vtp) following their acquisition by ticks. Based on this reversion to Vtp in ticks, we produced experimental vaccines comprised on this protein and tested them in mice challenged by infected ticks. METHODS: The vtp gene from two isolates of B. hermsii that encoded antigenically distinct types of proteins were cloned, expressed, and the recombinant Vtp proteins were purified and used to vaccinate mice. Ornithodoros hermsi ticks that were infected with one of the two strains of B. hermsii from which the vtp gene originated were used to challenge mice that received one of the two Vtp vaccines or only adjuvant. Mice were then followed for infection and seroconversion. RESULTS: The Vtp vaccines produced protective immune responses in mice challenged with O. hermsi ticks infected with B. hermsii. However, polymorphism in Vtp resulted in mice being protected only from the spirochete strain that produced the same Vtp used in the vaccine; mice challenged with spirochetes producing the antigenically different Vtp than the vaccine succumbed to infection. CONCLUSIONS: We demonstrate that by having knowledge of the phenotypic changes made by B. hermsii as the spirochetes are acquired by ticks from infected mammals, an effective vaccine was developed that protected mice when challenged with infected ticks. However, the Vtp vaccines only protected mice from infection when challenged with that strain producing the identical Vtp. A vaccine containing multiple Vtp types may have promise as an oral vaccine for wild mammals if applied to geographic settings such as small islands where the mammal diversity is low and the Vtp types in the B. hermsii population are defined. PMID- 26490043 TI - Caenorhabditis elegans star formation and negative chemotaxis induced by infection with corynebacteria. AB - Caenorhabditis elegans is one of the major model systems in biology based on advantageous properties such as short life span, transparency, genetic tractability and ease of culture using an Escherichia coli diet. In its natural habitat, compost and rotting plant material, this nematode lives on bacteria. However, C. elegans is a predator of bacteria, but can also be infected by nematopathogenic coryneform bacteria such Microbacterium and Leucobacter species, which display intriguing and diverse modes of pathogenicity. Depending on the nematode pathogen, aggregates of worms, termed worm-stars, can be formed, or severe rectal swelling, so-called Dar formation, can be induced. Using the human and animal pathogens Corynebacterium diphtheriae and Corynebacterium ulcerans as well as the non-pathogenic species Corynebacterium glutamicum, we show that these coryneform bacteria can also induce star formation slowly in worms, as well as a severe tail-swelling phenotype. While C. glutamicum had a significant, but minor influence on survival of C. elegans, nematodes were killed after infection with C. diphtheriae and C. ulcerans. The two pathogenic species were avoided by the nematodes and induced aversive learning in C. elegans. PMID- 26490042 TI - HEart and BRain interfaces in Acute ischemic Stroke (HEBRAS)--rationale and design of a prospective oberservational cohort study. AB - BACKGROUND: An effective diagnostic work-up in hospitalized patients with acute ischemic stroke is vital to optimize secondary stroke prevention. The HEart and BRain interfaces in Acute ischemic Stroke (HEBRAS) study aims to assess whether an enhanced MRI set-up and a prolonged Holter-ECG monitoring yields a higher rate of pathologic findings as compared to diagnostic procedures recommended by guidelines (including stroke unit monitoring for at least 24 h, echocardiography and ultrasound of brain-supplying arteries). METHODS/DESIGN: Prospective observational single-center study in 475 patients with acute ischemic stroke and without known atrial fibrillation. Patients will receive routine diagnostic care in hospital as wells as brain MRI, cardiac MRI, MR angiography of the brain supplying arteries and Holter-monitoring for up to 10 days. Study patients will be followed up for cardiovascular outcomes at 3 and 12 months after enrollment. DISCUSSION: By comparing the results of routine diagnostic care to the study specific MRI/ECG approach, the primary outcome of HEBRAS is the proportion of stroke patients with pathologic diagnostic findings. Predefined secondary outcomes are the association of stroke localization, autonomic dysbalance and cardiac dysfunction as well as the effect of impaired heart-rate-variability on long-term clinical outcome. The investigator-initiated HEBRAS study will assess whether an enhanced MRI approach and a prolonged ECG monitoring yield a higher rate of pathological findings than current standard diagnostic care to determine stroke etiology. These findings might influence current diagnostic recommendations after acute ischemic stroke. Moreover, HEBRAS will determine the extent and clinical impact of stroke-induced cardiac damage. TRIAL REGISTRATION: Clinicaltrials.gov NCT02142413. PMID- 26490044 TI - Modulation of local field potentials by high-frequency stimulation of afferent axons in the hippocampal CA1 region. AB - Modulation of the rhythmic activity of local field potentials (LFP) in neuronal networks could be a mechanism of deep brain stimulation (DBS). However, exact changes of LFP during the periods of high-frequency stimulation (HFS) of DBS are unclear because of the interference of dense stimulation artifacts with high amplitudes. In the present study, we investigated LFP changes induced by HFS of afferent axons in the hippocampal CA1 region of urethane-anesthetized rats by using a proper algorithm of artifact removal. Afterward, the LFP changes in the frequency bands of [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] rhythms were studied by power spectrum analysis and coherence analysis for the recorded signals collected in the pyramidal layer and in the stratum radiatum of CA1 region before, during and after 1-min long 100 and 200[Formula: see text]Hz HFS. Results showed that the power of LFP rhythms in higher-frequency band ([Formula: see text] rhythm) increased in the pyramidal layer and the power of LFP rhythms in lower-frequency bands ([Formula: see text], [Formula: see text] and [Formula: see text] rhythms) decreased in the stratum radiatum during HFS. The synchronization of [Formula: see text] rhythm decreased and the synchronization of [Formula: see text] rhythm increased during HFS in the stratum radiatum. These results suggest that axonal HFS could modulate LFP rhythms in the downstream brain areas with a plausible underlying mechanism of partial axonal blockage induced by HFS. The study provides new evidence to support the mechanism of DBS modulating rhythmic activity of neuronal populations. PMID- 26490045 TI - Multiple-site mutations of phage Bp7 endolysin improves its activities against target bacteria. AB - The widespread use of antibiotics has caused serious drug resistance. Bacteria that were once easily treatable are now extremely difficult to treat. Endolysin can be used as an alternative to antibiotics for the treatment of drug-resistant bacteria. To analyze the antibacterial activity of the endolysin of phage Bp7 (Bp7e), a 489-bp DNA fragment of endolysin Bp7e was PCR-amplified from a phage Bp7 genome and cloned, and then a pET28a-Bp7e prokaryotic expression vector was constructed. Two amino acids were mutated (L99A, M102E) to construct pET28a Bp7Deltae, with pET28a-Bp7e as a template. Phylogenetic analysis suggested that BP7e belongs to a T4-like phage endolysin group. Bp7e and its mutant Bp7Deltae were expressed in Escherichia coli BL21(DE3) as soluble proteins. They were purified by affinity chromatography, and then their antibacterial activities were analyzed. The results demonstrated that the recombinant proteins Bp7e and Bp7Deltae showed obvious antibacterial activity against Micrococcus lysodeikticus but no activity against Staphylococcus aureus. In the presence of malic acid, Bp7e and Bp7Deltae exhibited an effect on most E. coli strains which could be lysed by phage Bp7, but no effect on Salmonella paratyphi or Pseudomonas aeruginosa. Moreover, Bp7Deltae with double-site mutations showed stronger antibacterial activity and a broader lysis range than Bp7e. PMID- 26490046 TI - Modification of additive effect between vitamins and ETS on childhood asthma risk according to GSTP1 polymorphism: a cross -sectional study. AB - BACKGROUND: Asthma is characterized by airway inflammation, and bronchial airways are particularly susceptible to oxidant-induced tissue damage. OBJECTIVE: To investigate the effect of dietary antioxidant intake and environmental tobacco smoke (ETS) on the risk of childhood asthma according to genotypes susceptible to airway diseases. METHODS: This cross-sectional study included 1124 elementary school children aged 7-12 years old. Asthma symptoms and smoking history were measured using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Intake of vitamin A (including retinol and beta-carotene), C, and E was measured by a semi-quantitative food frequency questionnaire (FFQ). GSTP1 polymorphisms were genotyped from peripheral blood samples. RESULTS: ETS was significantly associated with presence of asthma symptoms (adjusted odds ratio [aOR], 2.48; 95 % confidence interval [CI], 1.29-4.76) and diagnosis (aOR, 1.91; 95 % CI, 1.19-3.06). Dietary antioxidant intake was not associated with asthma symptoms, although ETS plus low vitamin A intake showed a significant positive association with asthma diagnosis (aOR, 2.23; 95 % CI, 1.10-4.54). Children with AA at nucleotide 1695 in GSTP1 who had been exposed to ETS and a low vitamin A intake have an increased risk of asthma diagnosis (aOR, 4.44; 95 % CI,1.58-12.52) compared with children who had not been exposed to the two risk factors. However, ETS exposure and low vitamin A intake did not significantly increase odds of asthma diagnosis in children with AG or GG genotypes. CONCLUSION: Low vitamin A intake and ETS exposure may increase oxidative stress and thereby risk for childhood asthma. These relationships may be modified by gene susceptibility alleles of GSTP1. PMID- 26490048 TI - Proprotein convertase subtilisin/kexin type 9 (PCSK9), soluble lectin-like oxidized LDL receptor 1 (sLOX-1) and ankle brachial index in patients with differentiated thyroid cancer. AB - The cardiovascular effects of short-term overt hypothyroidism are not well known. We investigated proprotein convertase subtilisin/kexin type 9 (PCSK9), soluble lectin-like oxidized LDL receptor 1 (sLOX-1) and the ankle brachial index (ABI) in thyroid cancer patients with short-term overt hypothyroidism due to thyroid hormone withdrawal (THW). Twenty-one patients requiring radioactive iodine (RAI) ablation or scanning and 36 healthy control subjects were enrolled. Patients were evaluated in the subclinical thyrotoxic phase when they were on suppressive levothyroxine therapy and in the overt hypothyroid phase due to THW for four weeks. PCSK9, sLOX-1, lipids and ABI were measured in the patient and control groups. Total cholesterol, LDL cholesterol, triglycerides and Apo B levels were increased in short overt hypothyroidism compared with the control group (p<0.001). PCSK9 levels increased before THW and after THW in the patients compared to control group (p<0.001, p=0.004, respectively). sLOX-1 levels were not different between patients with short term overt hypothyroidism and control group (p=0.27). ABI was found to be significantly decreased in patients with thyroid cancer before and after THW compared to control group (p=0.04, p=0.002 respectively). PCSK9 levels were correlated negatively with ABI (r=-0.38, p=0.004). In conclusion; our study demonstrated that patients with differentiated thyroid cancer both before and after THW which is a short term overt hypothyroid phase, had increased PCSK9 levels and decreased ABI. Short term overt hypothyroidism also leads to increased HDL, LDL, total cholesterol, Apo A and Apo B levels. PMID- 26490047 TI - Reproductive health and lifestyle factors associated with health-related quality of life among perinatally HIV-infected adolescents in Uganda. AB - BACKGROUND: With increased survival of perinatally HIV - infected adolescents due to antiretroviral therapy (ART), the focus of HIV care has shifted to health related quality of life (HRQoL) as a measure of disease progression, effects of ART co-morbidity and prognosis. We assessed factors associated with better HRQoL in perinatally HIV -infected adolescents in Uganda by determining the associations between sexual and reproductive health (SRH) or lifestyle experiences on HRQoL. METHODS: In a cross-sectional study, data on SRH, lifestyle experiences, socio demographic factors, communication with parents on sexuality and satisfaction of SRH services in ART clinics were collected from 614 HIV perinatally infected adolescents aged 10-19 using an interviewer-administered survey questionnaire. HRQoL data were collected using the Medical Outcomes Study HIV Health Survey instrument (MOS-HIV). Factors associated with better HRQoL were analysed using multiple logistic regression. RESULTS: The mean age was 16.2 +/- 2.1 years, 362 (58.8 %) were females and 210 (34.2 %) were sexually active. Adolescents on ART were twice likely to present with better physical health (AOR = 2.07, 95 % CI: 1.24-3.46) and four times more likely to present with better mental health (AOR = 3.9, 95 % CI: 2.22-6.92) than those who were not on ART. There were no statistically significant associations between SRH (ever had sex, ever been pregnant, condom use, contraceptive use) or life style factors and physical health or mental health. Those with secondary or tertiary education were more likely to present with a better mental health (AOR = 5.3, 95 % CI: 1.86 15.41) compared those who had attained primary or no education. Participants who desired to have a child in future more likely (AOR 1.7, 95 % CI: 1.05-3.00) to present with a better mental health. Lack of communication with guardians on sexuality (AOR = 0.6, 95 % CI: 0.40-0.89), or dissatisfaction with SRH services (AOR 0.34, 95 % CI: 0.18-0.62) were associated with poorer mental health. CONCLUSION: Among perinatally HIV-infected adolescents in Uganda, being on ART was associated with better physical and mental health while lack of communication with guardians on sexuality or dissatisfaction with SRH services was associated with poor mental health. Adolescents with pregnancy intentions were more likely to have a better mental health. PMID- 26490049 TI - Clinical and endocrinological characteristics of adrenal incidentaloma in Osaka region, Japan. AB - The aim of this study was to investigate the clinical and endocrinological characteristics of adrenal incidentalomas in Osaka region, Japan. The study was a multicenter retrospective analysis of 150 patients with adrenal incidentalomas who underwent radiographic and endocrine evaluations between 2005 and 2013. Most adrenal incidentalomas were discovered by computed tomography (77.0%) and the rest were identified by abdominal ultrasonography (14.6%), magnetic resonance imaging (4.2%), or positron emission tomography (4.2%). Adrenal incidentalomas were more frequently localized on the left side than on the right. The average diameter of tumors was 21 +/- 11 mm. On endocrinological evaluation, 14 patients were diagnosed with primary aldosteronism (9.3%), 10 with subclinical Cushing's syndrome (6.7%), 7 with pheochromocytoma (4.7%), 7 with Cushing's syndrome (4.7%), 2 with both subclinical Cushing's syndrome and primary aldosteronism (1.3%), and 110 with non-functioning tumors (73.3%). Patients with functioning tumors were significantly younger and had larger tumor diameters than those with non-functioning tumors. Except for hypertension, complications were comparable between patients with functioning and non-functioning tumors, including the presence of glucose intolerance, cardiovascular disease, and dyslipidemia. In conclusion, a higher prevalence of primary aldosteronism was observed compared with a previous report. Complications were comparable between patients with functioning and non-functioning tumors, including the frequencies of glucose intolerance, cardiovascular disease, and dyslipidemia. Long-term follow-up is required in patients with non-functioning tumors because the frequency of complications, such as glucose intolerance, cardiovascular disease, and dyslipidemia, was equal to that in patients with functioning tumors. PMID- 26490050 TI - Managing risk of hepatitis B after sharps injuries. PMID- 26490051 TI - Structural and functional analysis of cell adhesion and nuclear envelope nano topography in cell death. AB - The cell death mechanisms of necrosis and apoptosis generate biochemical and morphological changes in different manners. However, the changes that occur in cell adhesion and nuclear envelope (NE) topography, during necrosis and apoptosis, are not yet fully understood. Here, we show the different alterations in cell adhesion function, as well as the topographical changes occurring to the NE, during the necrotic and apoptotic cell death process, using the xCELLigence system and atomic force microscopy (AFM). Studies using xCELLigence technology and AFM have shown that necrotic cell death induced the expansion of the cell adhesion area, but did not affect the speed of cell adhesion. Necrotic nuclei showed a round shape and presence of nuclear pore complexes (NPCs). Moreover, we found that the process of necrosis in combination with apoptosis (termed nepoptosis here) resulted in the reduction of the cell adhesion area and cell adhesion speed through the activation of caspases. Our findings showed, for the first time, a successful characterization of NE topography and cell adhesion during necrosis and apoptosis, which may be of importance for the understanding of cell death and might aid the design of future drug delivery methods for anti cancer therapies. PMID- 26490052 TI - Sacral nerve stimulation for faecal incontinence - efficacy confirmed from a two centre prospectively maintained database. AB - INTRODUCTION: Sacral nerve stimulation (SNS) has been recognised as an effective treatment for faecal incontinence. Many unresolved questions could be answered when comparing large data-series from different centres providing prospective data. AIM: To present data, from an international two-centre SNS prospective database (SNSPD) on functional outcome and management of surgical complications in patients treated with SNS for faecal incontinence. METHOD: The SNSPD was designed in order to gather detailed pre- and perioperative information followed by a close follow-up in all patients undergoing SNS for bowel dysfunction. The SNSPD was open for inclusion of newly SNS implanted patients in May 2009, and closed on 31 December 2013. Two-centres Aarhus, Denmark, and Nantes, France, included and monitored all patients implanted due to bowel dysfunction according to database criteria. RESULTS: In total, 164 faecal incontinent patients with a median follow-up of 22 (range 1-50) months were implanted. The Wexner incontinence score improved from 15 (range, 3-20) at baseline to 9 (range, 0-20) at latest follow-up (P < 0.001) and VAS impact on daily life improved from 85.5 (range, 3-100) to 20 (range, 0-100) (P < 0.001). Additional surgical intervention was required in 19.5 % during follow-up. Repositioning of the pacemaker due to pain or migration was the most common complication in 12.1 %. Infections leading to explantation occurred in 3.0 %. PMID- 26490053 TI - CT imaging for prediction of complications and recurrence in acute uncomplicated diverticulitis. AB - PURPOSE: The first randomized clinical trial of antibiotics in uncomplicated diverticulitis (the AVOD study) showed no benefit of antibiotics. The aim of this study was to re-evaluate the computed tomography (CT) scans of the patients in the AVOD study to find out whether there were CT findings that were missed and to study whether CT signs in uncomplicated diverticulitis could predict complications or recurrence. METHODS: The CT scan images from patients included in the AVOD study were re-evaluated and graded by two independent reviewers for different signs of diverticulitis, including complications, such as extraluminal gas or the presence of an abscess. RESULTS: Of the 623 patients included in the study, 602 CT scans were obtained and re-evaluated. Forty-four (7 %) patients were found to have complications on the admitting CT scan that had been overlooked. Twenty-seven had extraluminal gas and 17 had an abscess. Four of these patients deteriorated and required surgery, but the remaining patients improved without complications. Of the 18 patients in the no-antibiotic group, in whom signs of complications on CT were overlooked, 15 recovered without antibiotics. No CT findings in patients with uncomplicated diverticulitis could predict complications or recurrence. CONCLUSION: No CT findings that could predict complications or recurrence were found. A weakness in the initial assessment of the CT scans to detect extraluminal gas and abscess was found but, despite this, the majority of patients recovered without antibiotics. This further supports the non-antibiotic strategy in uncomplicated diverticulitis. PMID- 26490054 TI - Is transanal total mesorectal excision a reproducible and oncologically adequate technique? A pilot study in a single center. AB - PURPOSE: An oncologically effective total mesorectal excision (TME) still represents a technical challenge, especially in the presence of a low rectal cancer and anatomical restraints such as obesity or narrow pelvis. Recently, few reports have shown that transanal TME was feasible and associated with good outcomes. Nevertheless, a widespread employment of the technique has yet to happen due to the doubts about the reproducibility of the results outside a tertiary specialized center. METHODS: Between February 2014 and June 2015, patients with low rectal cancer underwent a transanal TME with laparoscopic assistance. The end points included the oncologic adequacy of the mesorectal excision and the perioperative outcomes. RESULTS: Eleven patients (9 male, median age 70.5 years) with proven low rectal cancer were enrolled in the study. The median distance of the tumor from the anal verge was 5 cm (2-7). Four patients (36.4 %) received preoperative chemoradiation. The median operative time was 360 min (275-445). Postoperative morbidity (36.4 %) included one (9.1 %) anastomotic leak requiring a reoperation. The median length of hospital stay was 8 days (3 28). The median distance from the circumferential and distal resection margins were, respectively, 5 (1-20) and 10 (5-20) mm, and the mean number of harvested lymph nodes was 21.7 (11-50). All cases had a complete or nearly complete mesorectal plane of surgery. CONCLUSIONS: Although technically challenging, the initial results suggest that transanal TME could be a feasible, oncologically safe, and reproducible operation. However, more robust studies are required to assess the short- and long-term outcomes. PMID- 26490056 TI - Practising what we preach: using cognitive load theory for workshop design and evaluation. AB - Theory-based instructional design is a top priority in medical education. The goal of this Show and Tell article is to present our theory-driven approach to the design of instruction for clinical educators. We adopted cognitive load theory as a framework to design and evaluate a series of professional development workshops that were delivered at local, national and international academic conferences in 2014. We used two rating scales to measure participants' cognitive load. Participants also provided narrative comments as to how the workshops could be improved. Cognitive load ratings from 59 participants suggested that the workshop design optimized learning by managing complexity for different levels of learners (intrinsic load), stimulating cognitive processing for long-term memory storage (germane load), and minimizing irrelevant distracters (extraneous load). Narrative comments could also be classified as representing intrinsic, extraneous, or germane load, which provided specific directions for ongoing quality improvement. These results demonstrate that a cognitive load theory approach to workshop design and evaluation is feasible and useful in the context of medical education. PMID- 26490055 TI - A scoring model for predicting survival following primary tumour resection in stage IV colorectal cancer patients with unresectable metastasis. AB - BACKGROUND: Stage IV colorectal cancer patients with unresectable metastasis who undergo elective primary tumour resection experience heterogeneous post-operative survival. We aimed to develop a scoring model for predicting post-operative survival using pre-operative variables to identify patients who are least likely to experience extended survival following the procedure. METHODS: Survival data were collected from stage IV colorectal cancer patients who had undergone elective primary tumour resection between January 1999 and December 2007. Coefficients of significant covariates from the multivariate Cox regression model were used to compute individual survival scores to classify patients into three prognostic groups. A survival function was derived for each group via Kaplan Meier estimation. Internal validation was performed. RESULTS: Advanced age (hazard ratio, HR 1.43 (1.16-1.78)); poorly differentiated tumour (HR 2.72 (1.49 5.04)); metastasis to liver (HR 1.76 (1.33-2.33)), lung (HR 1.37 (1.10-1.71)) and bone (HR 2.08 ((1.16-3.71)); carcinomatosis (HR 1.68 (1.30-2.16)); hypoalbuminaemia (HR 1.30 (1.04-1.61) and elevated carcinoembryonic antigen levels (HR 1.89 (1.49-2.39)) significantly shorten post-operative survival. The scoring model separated patients into three prognostic groups with distinct median survival lengths of 4.8, 12.4 and 18.6 months (p < 0.0001). Internal validation revealed a concordance probability estimate of 0.65 and a time dependent area under receiver operating curve of 0.75 at 6 months. Temporal split sample validation implied good local generalizability to future patient populations (p < 0.0001). CONCLUSION: Predicting survival following elective primary tumour resection using pre-operative variables has been demonstrated with the scoring model developed. Model-based survival prognostication can support clinical decisions on elective primary tumour resection eligibility. PMID- 26490057 TI - Raman fingerprinting of single dielectric nanoparticles in plasmonic nanopores. AB - Plasmonic nano-apertures are commonly used for the detection of small particles such as nanoparticles and proteins by exploiting electrical and optical techniques. Plasmonic nanopores are metallic nano-apertures sitting on a thin membrane with a tiny hole. It has been shown that plasmonic nanopores with a given geometry identify internal molecules using Surface Enhanced Raman Spectroscopy (SERS). However, label-free identification of a single dielectric nanoparticle requires a highly localized field comparable to the size of the particle. Additionally, the particle's Brownian motion can jeopardize the amount of photons collected from a single particle. Here, we demonstrate that the combination of optical trapping and SERS can be used for the detection and identification of 20 nm polystyrene nanoparticles in plasmonic nanopores. This work is anticipated to contribute to the detection of small bioparticles, optical trapping and nanotribology studies. PMID- 26490058 TI - Spontaneous Mirror-Symmetry Breaking in Isotropic Liquid Phases of Photoisomerizable Achiral Molecules. AB - Spontaneous mirror-symmetry breaking is of fundamental importance in science as it contributes to the development of chiral superstructures and new materials and has a major impact on the discussion around the emergence of uniform chirality in biological systems. Herein we report chirality synchronization, leading to spontaneous chiral conglomerate formation in isotropic liquids of achiral and photoisomerizable azobenzene-based rod-like molecules. The position of fluorine substituents at the aromatic core is found to have a significant effect on the stability and the temperature range of these chiral liquids. Moreover, these liquid conglomerates occur in a new phase sequence adjacent to a 3D tetragonal mesophase. PMID- 26490060 TI - Native Amazonian children forego egalitarianism in merit-based tasks when they learn to count. AB - Cooperation often results in a final material resource that must be shared, but deciding how to distribute that resource is not straightforward. A distribution could count as fair if all members receive an equal reward (egalitarian distributions), or if each member's reward is proportional to their merit (merit based distributions). Here, we propose that the acquisition of numerical concepts influences how we reason about fairness. We explore this possibility in the Tsimane', a farming-foraging group who live in the Bolivian rainforest. The Tsimane' learn to count in the same way children from industrialized countries do, but at a delayed and more variable timeline, allowing us to de-confound number knowledge from age and years in school. We find that Tsimane' children who can count produce merit-based distributions, while children who cannot count produce both merit-based and egalitarian distributions. Our findings establish that the ability to count - a non-universal, language-dependent, cultural invention - can influence social cognition. PMID- 26490059 TI - Weight maintenance: challenges, tools and strategies for primary care physicians. AB - Obesity is recognized as a chronic disease and one of the major healthcare challenges facing us today. Weight loss can be achieved via lifestyle, pharmacological and surgical interventions, but weight maintenance remains a lifetime challenge for individuals with obesity. Guidelines for the management of obesity have highlighted the role of primary care providers (PCPs). This review examines the long-term outcomes of clinical trials to identify effective weight maintenance strategies that can be utilized by PCPs. Because of the broad nature of the topic, a structured PubMed search was conducted to identify relevant research articles, peer-reviewed reviews, guidelines and articles published by regulatory bodies. Trials have demonstrated the benefit of sustained weight loss in managing obesity and its comorbidities. Maintaining 5-10% weight loss for >=1 year is known to ameliorate many comorbidities. Weight maintenance with lifestyle modification - although challenging - is possible but requires long-term support to reinforce diet, physical activity and behavioural changes. The addition of pharmacotherapy to lifestyle interventions promotes greater and more sustained weight loss. Clinical evidence and recently approved pharmacotherapy has given PCPs improved strategies to support their patients with maintenance of weight loss. Further studies are needed to assess the translation of these strategies into clinical practice. PMID- 26490061 TI - Selective class I histone deacetylase inhibitors suppress persistent spontaneous nociception and thermal hypersensitivity in a rat model of bee venom-induced inflammatory pain. AB - To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 MUL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring. PMID- 26490062 TI - Brain-derived neurotrophic factor in the anterior cingulate cortex is involved in the formation of fear memory. AB - Brain-derived neurotrophic factor (BDNF), a small dimeric secretory protein, plays a vital role in activity-dependent synaptic plasticity, learning and memory. It has been shown that BDNF in the hippocampus and amygdala participates in the formation of fear memory. However, little is known about the functional role of BDNF in the anterior cingulate cortex (ACC). To address this question, we examined the mRNA and protein levels of BDNF in the ACC of rats at various time points after fear conditioning, using quantitative real-time PCR and enzyme linked immunosorbent assay (ELISA). The results showed that BDNF exhibited a temporally specific increase in both mRNA and protein levels after CS (tone) and US (foot shock) was paired. Such increase did not occur after the animals were exposed to CS or US alone. When BDNF antibody was locally infused into the ACC prior to CS-US pairing, both contextual and auditory fear memories were severely impaired. Taken together, these results suggest that BDNF in the ACC is required for the formation of fear memory. PMID- 26490063 TI - [Effects of blockade of 5-HT2A receptors in inflammatory site on complete Freund's adjuvant-induced chronic hyperalgesia and neuropeptide Y expression in the spinal dorsal horn in rats]. AB - 5-hydroxytryptamine (5-HT) released in inflammatory tissues plays a pivotal role in pain hypersensitivity. However, it is not clear whether 5-HT2A receptors in the inflamed tissues mediate this effect. The present study investigated the contribution of 5-HT2A receptors in the periphery to chronic inflammatory pain. Complete Freund's adjuvant (CFA) was injected subcutaneously in the hindpaw of rats. The selective 5-HT2A receptor antagonist ketanserin was given in the inflamed site. Paw withdrawal latency responding to heat or mechanical stimuli was measured. Expression of neuropeptide Y (NPY) in the spinal dorsal horn and dorsal root ganglia (DRG) was assayed using immunohistochemistry technique. The results showed that ketanserin administered in the inflamed site inhibited thermal hyperalgesia in a dose-dependent manner (20, 40 and 80 ug) induced by the intraplantar injection of CFA. Ketanserin given once per day at a dose of 80 ug abolished heat hyperalgesia and also attenuated mechanical allodynia on the third day. CFA injection increased the expression of NPY in superficial laminae of the spinal cord, but not in the DRG. The local treatment of ketanserin completely inhibited CFA-induced increase in NPY expression in superficial laminae of the spinal cord. These results indicated that activation of 5-HT2A receptors in the inflamed tissues was involved in the pathogenesis of inflammatory pain and the blockade of 5-HT2A receptors in the periphery could relieve pain hypersensitivity and normalize the cellular disorder in the spinal dorsal horn associated with pathological pain. The present study suggests that the peripheral 5-HT2A receptors can be a promising target for pharmaceutical therapy to treat chronic inflammatory pain without central nervous system side effects. PMID- 26490064 TI - [The influence of sex and menstrual cycle on conditioned acquisition and extinction: Event-related potential research]. AB - Previous studies have indicated phase-related differences in conditioned acquisition and extinction. In recent years, many researchers used event-related potential (ERP) technology to assess the extent of the acquisition and extinction. Therefore, this study was aimed to assess the sex- and menstrual cycle-dependent effects on the conditioned acquisition and extinction using ERP technology. Thirty-two females at two phases (menses phase, FM, and luteal phase, FL) of their menstrual cycle and 16 males participated in the experiment. The experiment consisted of two stages: acquisition stage and extinction stage. In the acquisition stage, in the predictable context, a condition stimulus (CS) was always followed by the presentation of a negative picture or a neutral picture; but in the unpredictable context, a CS was paired with a negative picture or a neutral picture 20% of the time. In the extinction stage, only CS was presented. The results showed that at acquisition stage, significant larger P2 amplitudes were recorded in female subjects in FL and FM in comparison with those of males. The female subjects in FL may acquire the strongest CS-US conditional connection. At extinction stage, the female subjects in FL showed larger P2 amplitudes than males, but there were no significant differences in P2 amplitudes between the males and females in FM. The results suggest that the females in FL allocate more attention resources to the acquisition of a conditioned response and delayed extinction. In conclusion, we suggest that female menstrual cycle may modulate conditioned acquisition and extinction processes, and our ERP data may provide an explanation for the premenstrual dysphoric disorder. PMID- 26490065 TI - [Effect of sodium nitrite on phosphorylation of cytoskeletal proteins and spatial learning and memory in rats]. AB - The present study was aimed to explore the effect of sodium nitrite on cytoskeletal protein phosphorylation and spatial learning and memory in rats. Rats were served with drinking water containing sodium nitrite (100 mg/kg) for 60 days, then, the ability of spatial learning and memory of the rats was measured by Morris water maze. Phosphorylation level of tau and neurofilament, and the expression of protein phosphatase 2A (PP2A) catalytic subunit in the hippocampus were detected by immunohistochemistry and Western blot. In comparison with the rats served with normal tap water, the rats served with sodium nitrite water showed significantly longer latency to find the hidden platform in Morris water maze (P < 0.05), elevated phosphorylation level of tau and neurofilament, and decreased expression of PP2A catalytic subunit (P < 0.05). These results indicated that administration of sodium nitrite could impair the spatial learning and memory of the rats, and the hyperphosphorylation of cytoskeletal proteins and the down-regulation of PP2A might be underlying mechanisms for the impairment. PMID- 26490067 TI - [Toxic effect of formaldehyde on mouse different brain regions]. AB - The aim of this study was to explore the mechanism of the nervous system lesions induced by formaldehyde (FA). Male Balb/c mice were exposed to gaseous formaldehyde for 7 days (8 h/d) with three different concentrations (0, 0.5 and 3.0 mg/m(3)). A group of animals injected with the nitric oxide synthase inhibitor L-NMMA (0.01 mL/g) was also set and exposed to 3.0 mg/m(3) FA. The concentrations of cAMP, cGMP, NO and the activity of NOS in cerebral cortex, hippocampus and brain stem were determined by corresponding assay kits. The results showed that, compared with the control (0 mg/m(3) FA) group, the cAMP contents in cerebral cortex and brain stem were significantly increased in 0.5 mg/m(3) FA group (P < 0.05), but decreased in 3.0 mg/m(3) FA group (P < 0.05); The concentration of cAMP in hippocampus was significantly decreased in 3.0 mg/m(3) FA group (P < 0.05). In comparison with the control group, L-NMMA group showed unchanged cAMP contents and NOS activities in different brain regions, but showed increased cGMP contents in hippocampus and NO contents in cerebral cortex (P < 0.05). In addition, compared with 3.0 mg/m(3) FA group, L-NMMA group showed increased contents of cAMP and reduced NOS activities in different brain regions, as well as significantly decreased cGMP contents in cerebral cortex and brain stem and NO content in brain stem. These results suggest that the toxicity of FA on mouse nervous system is related to NO/cGMP and cAMP signaling pathways. PMID- 26490066 TI - [Alteration of neural oscillations in hippocampal CA3 area in the fast avoidance response rat before and after electric shock avoidance training]. AB - The purpose of the present study is to explore the relationship of spatial learning ability and specific electrical activities of neural oscillations in the rat. The fast and general avoidance response groups were selected on the basis of the animals' responses to the electric shock in Y type maze, and their local field potentials (LFPs) of hippocampal CA3 area were recorded by wireless telemetry before and after shock avoidance training, respectively. The components of neural oscillations related to spatial identifying and learning ability were analyzed. The results showed that, compared with the general avoidance response group, the fast avoidance response group did not show any differences of LFPs in hippocampal CA3 area before electric shock avoidance trial, but showed significantly increased percentages of 0-10 Hz and 30-40 Hz rhythm in right hippocampal CA3 area after the shock avoidance training (P < 0.01 or P < 0.05). Fast Fourier transform showed that percentage increase of 0-10 Hz band occurred mainly in theta (3-7 Hz) frequency, and 30-40 Hz frequency change was equivalent to the gamma1 band. Furthermore, compared with those before training, only the percentages of beta, beta2 (20-30 Hz) and gamma1 rhythm increased (P < 0.01 or P < 0.05) in fast avoidance response rats after training, while the theta rhythm percentage remained unchanged. In contrast, theta rhythm percentage and the large amplitude (intensity: +2.5 - -2.5 db) theta waves in right CA3 area of general avoidance response rats were significantly reduced after training (P < 0.01). These results suggest that the increased percentages of beta2 and gamma1 rhythm and high-level (unchanged) percentage of theta rhythm in the right hippocampus CA3 area might be related to strong spatial cognition ability of fast avoidance response rats. PMID- 26490068 TI - [Effect of Kv1.3 and KCa3.1 potassium ion channels on the proliferation and migration of monocytes/macrophages]. AB - This study was aimed to investigate the effects of blockade of Ca(2+) activated channel KCa3.1 and voltage-gated potassium channel Kv1.3 of the monocytes/macrophages on inflammatory monocyte chemotaxis. Chemotaxis assay was used to test the inflammatory Ly-6C(hi) monocyte chemotaxis caused by the monocytes/macrophages. The proliferation of monocytes/macrophages was detected by cell counting kit-8 (CCK8). Enzyme-linked immunosorbent assay (ELISA) was applied to detect the C-C motif ligand 7 (CCL7) in cultured media. The results showed that the recruitment of Ly-6C(hi) monocyte induced by monocytes/macrophages was suppressed by the potent Kv1.3 blocker Stichodactyla helianthus neurotoxin (ShK) or the specific KCa3.1 inhibitor TRAM-34. Meanwhile, the proliferation of monocytes/macrophages was significantly inhibited by ShK. The response of Ly 6C(hi) monocyte pretreated with ShK or TRAM-34 to CCL2 was declined. These results suggest that KCa3.1 and Kv1.3 may play an important role in monocytes/macrophages' proliferation and migration. PMID- 26490070 TI - [The influence of interfered circadian rhythm on pregnancy and neonatal rats]. AB - The aim of this study was to observe the influence of interfered circadian rhythm on pregnancy of rats and growth of neonatal rats, and to explore the relationship between the interfered circadian rhythm and the changes of melatonin and progesterone. Continuous light was used to inhibit melatonin secretion and therefore the interfered circadian rhythm animal model was obtained. The influence of interfered circadian rhythm on delivery of pregnant rats was observed. Serum was collected from rats during different stages of pregnancy to measure the concentrations of melatonin and progesterone. In order to observe the embryo resorption rate, half of pregnant rats were randomly selected to undergo a laparotomy, and the remainder was used to observe delivery and assess the growth of neonatal rats after delivery. The results showed that the interfered circadian rhythm induced adverse effects on pregnancy outcomes, including an increase of embryo resorption rate and a decrease in the number of live births; inhibited the secretion of melatonin along with decreased serum progesterone level; prolonged the stage of labor, but not the duration of pregnancy; and disturbed the fetal intrauterine growth and the growth of neonatal rats. The results suggest that interfered circadian rhythm condition made by continuous light could make adverse effects on both pregnant rats and neonatal rats. The results of our study may provide a way to modulate pregnant women's circadian rhythm and a possibility of application of melatonin on pregnant women. PMID- 26490069 TI - [Metabotropic glutamate receptor 8 activation promotes the apoptosis of lung carcinoma A549 cells in vitro]. AB - This study aims to detect the expression of metabotropic glutamate receptors (mGluRs) in lung carcinoma A549 cells, and to investigate the effects of mGluR8 and mGluR4 activation on the growth of A549 cells in vitro. The mRNA expression levels of the 8 subtypes of mGluRs in A549 cells were determined by real-time PCR. Immunohistochemistry was used to analyze the protein expression of mGluR4 and mGluR8 in A549 cells and lung tissue sections obtained from lung adenocarcinoma patients. To observe the effects of mGluR8 and mGluR4 activation on the growth of A549 cells, the cultured cells were treated with (S)-3,4-DCPG (an agonist of mGluR8) and VU0155041 (an agonist of mGluR4), respectively, and then the cell viability was analyzed by CCK-8 kit, the percentage of DNA synthesis was detected by EdU incorporation, and the apoptosis of the cells was measured by hoechst 33258 staining and flow cytometry. The results showed that there were low expressions of mGluR1, mGluR5, mGluR6, mGluR7 mRNA, no expression of mGluR2 and mGluR3 mRNA, and high expressions of mGluR8 and mGluR4 mRNA in A549 cells. Accordingly, there were also mGluR4 and mGluR8 protein expressions in the A549 cells and the lung adenocarcinoma tissue sections. VU0155041 had no effect on the growth of A549 cells, but (S)-3,4-DCPG significantly decreased the cells' growth in a dose-dependent manner and increased the apoptosis of the cells. The results revealed a role of mGluR8 in the growth and apoptosis of A549 cells and suggested a potential target for clinical treatment of lung cancer. PMID- 26490071 TI - [Research progress of TRPV4 and cerebral ischemic reperfusion injury]. AB - Transient receptor potential vanilloid 4 (TRPV4) channel is a member of transient receptor potential superfamily. TRPV4 is selectively permeable to calcium. Activation of the TRPV4 channel induces an increase in intracellular calcium concentration and plays an important role under physiological and pathological conditions. Especially, there is evidence showing that TRPV4 is involved in cerebral ischemic reperfusion injury. The present paper reviewed some research progress about the role of TRPV4 in cerebral ischemic reperfusion injury. PMID- 26490073 TI - Successful percutaneous coronary intervention for complex bifurcated lesions with combination of "Reverse wire technique" and "Reverse bent wiring with the crusade catheter" novel wire manipulation technique. AB - We encountered a case of percutaneous coronary intervention for complex bifurcated lesions in the mid portion of the left anterior descending (LAD) artery. The diagonal artery branched from the LAD artery with a markedly angulated pattern and there was severe stenosis from just proximal to this diagonal artery. The "reverse wire technique facilitated with the Crusade catheter" enabled us to cross a guidewire through to the markedly angulated diagonal side branch (SB). Next, we adopted a mini-crushing stent strategy for this true bifurcated lesion. Thereafter, we adopted "reverse bent wiring with the Crusade catheter" for wire re-crossing to the incarcerated side branch, and successfully completed all procedures. This technique for successful wire re crossing is simple but can be very effective in specific situations in practical percutaneous coronary intervention (PCI). Many PCI operators may empirically adopt this kind of wire manipulation technique. However, this case is the first report in the world describing the application of a "reverse bent wiring with the Crusade catheter" for wire re-crossing through a double-folded stent strut to a SB at the optimal point of the bifurcation. In this case, we made the most of the Crusade catheter. This catheter is a very useful device for multifactorial use in practical PCI. It can help us to perform complex PCI procedures successfully. PMID- 26490074 TI - Biofunctionalization of Polyoxometalates with DNA Primers, Their Use in the Polymerase Chain Reaction (PCR) and Electrochemical Detection of PCR Products. AB - The bioconjugation of polyoxometalates (POMs), which are inorganic metal oxido clusters, to DNA strands to obtain functional labeled DNA primers and their potential use in electrochemical detection have been investigated. Activated monooxoacylated polyoxotungstates [SiW11 O39 {Sn(CH2 )2 CO}](8-) and [P2 W17 O61 {Sn(CH2 )2 CO}](6-) have been used to link to a 5'-NH2 terminated 21-mer DNA forward primer through amide coupling. The functionalized primer was characterized by using a battery of techniques, including electrophoresis, mass spectrometry, as well as IR and Raman spectroscopy. The functionality of the POM labeled primers was demonstrated through hybridization with a surface-immobilized probe. Finally, the labeled primers were successfully used in the polymerase chain reaction (PCR) and the PCR products were characterized by using electrophoresis. PMID- 26490075 TI - Obstetric and perinatal complications in an oocyte donation programme. Is it time to limit the number of embryos to transfer? AB - The aim of this study is to describe obstetric and perinatal complications in pregnancies from oocyte donation (OD) cycles, delivering in our centre and to determine the impact of maternal age. Retrospective observational study of a 225 singleton pregnancies, 113 multiple pregnancies and 447 live birth. Pearson's chi(2) test or Fisher's exact test were used for the statistical analysis. A higher incidence of obstetric complications was observed in multiple compared to singleton pregnancies with regard to preeclampsia (24.8% versus 8%), premature rupture of membranes (9.7% versus 1.8%), preterm delivery at <37 weeks (54.9% versus 10.2%) and caesarean section (81.4% versus 64%) (p < 0.05). If the age factor is added, the caesarean sections are higher in the single pregnancy group aged >=40 years than in the group of <40 years (73.5% versus 49.4%) (p < 0.05). A higher incidence is found in multiple versus singleton pregnancies for low birth weight (<2500 g) (61.1% versus 8.2%), admissions to the intensive care unit (15.2% versus 4.7%) and perinatal mortality (13.50/00 versus 00/00) (p < 0.05). It is necessary to consider preconception counselling prior to an OD cycle to inform patients about the incidence complications observed and recommend to transfer only a single embryo. PMID- 26490076 TI - pH-Dependent solution dynamics of a manganese(II) polyoxometalate, [Mn4(H2O)2(P2W15O56)2](16-), and [Mn(H2O)6](2+). AB - The aqueous reaction dynamics of the manganese(II)-functionalised Wells-Dawson polyoxometalate [Mn4(H2O)2(P2W15O56)2](16-) has been determined as a function of pH using variable temperature (17)O NMR, and compared with that of the well studied monomeric manganese(II) hexa-aqua ion, [Mn(H2O)6](2+). While the rate of aquo-ligand exchange on the hexa-aqua ion remains independent of pH in the range 3.2-6.0, the rate of water exchange of the polyoxometalate ion varies by a factor of fifteen, from 1.98 * 10(7) s(-1) at pH 3.2 to 1.3 * 10(6) s(-1) at pH 6.0. This decrease in the rate of exchange correlates with the deprotonation of the polyoxometalate framework. PMID- 26490077 TI - Direct electrochemical analysis in complex samples using ITO electrodes modified with permselective membranes consisting of vertically ordered silica mesochannels and micelles. AB - Herein we report a simple and cost-effective method for the direct electrochemical detection of redox-active small organic analytes in complex media, such as soil dispersions, human serum and milk, without sample pre treatment using an indium tin oxide (ITO) electrode modified with permselective membranes consisting of vertically ordered surfactant micelles and silica mesochannels (OSM@SM). The OSM@SM/ITO electrode displayed excellent anti interference and anti-fouling ability. PMID- 26490078 TI - Statin Intolerance: the Clinician's Perspective. AB - Muscle problems and other adverse symptoms associated with statin use are frequent reasons for non-adherence and discontinuation of statin therapy, which results in inadequate control of hyperlipidemia and increased cardiovascular risk. However, most patients who experience adverse symptoms during statin use are able to tolerate at least some degree of statin therapy. Given the profound cardiovascular benefits derived from statins, an adequate practical approach to statin intolerance is, therefore, of great clinical importance. Statin intolerance can be defined as the occurrence of myalgia or other adverse symptoms that are attributed to statin therapy and that lead to its discontinuation. In reality, these symptoms are actually unrelated to statin use in many patients, especially in those with atypical presentations following long periods of treatment. Thus, the first step in approaching patients with adverse symptoms during the course of statin therapy is identification of those patients for whom true statin intolerance is unlikely, since most of these patients would probably be capable of tolerating adequate statin therapy. In patients with statin intolerance, an altered dosing regimen of very low doses of statins should be attempted and, if tolerated, should gradually be increased to achieve the highest tolerable doses. In addition, other lipid-lowering drugs may be needed, either in combination with statins, or alone, if statins are not tolerated at all. Stringent control of other risk factors can aid in reducing cardiovascular risk if attaining lipid treatment goals proves difficult. PMID- 26490079 TI - MicroRNA Biomarkers for Coronary Artery Disease? AB - MicroRNA (miRNA, miR) measurements in patients with coronary heart disease are hampered by the confounding effects of medication commonly used in cardiovascular patients such as statins, antiplatelet drugs, and heparin administration. Statins reduce the circulating levels of liver-derived miR-122. Antiplatelet medication attenuates the release of platelet-derived miRNAs. Heparin inhibits the polymerase chain reactions, in particular the amplification of the exogenous Caenorhabditis elegans spike-in control, thereby resulting in an artefactual rise of endogenous miRNAs. As these limitations have not been previously recognised, a reevaluation of the current miRNA literature, in particular of case-control studies in patients with cardiovascular disease or coronary interventions, is required. PMID- 26490080 TI - Advances in the Detection and Monitoring of Atrial Fibrillation for Patients with Cryptogenic Ischemic Stroke. AB - Atrial fibrillation (AF) is a significant etiologic cause of acute ischemic stroke (AIS) that leads to disabling deficits as well as significant morbidity and mortality in this population. Approximately 25 % of AIS is considered to be cryptogenic with no etiology ascertained at the time of the index event. Recent advances from the EMBRACE and CRYSTAL-AF trial have improved detection and treatment of AF and subsequently lead to changes in guidelines. However, with improved detection rates, the duration and frequency cutoffs for treating AF are currently being investigated to ensure optimization of patient selection and subsequent treatment. PMID- 26490081 TI - Role of Ezetimibe in Lipid-Lowering and Cardiovascular Disease Prevention. AB - With the goal of decreasing low-density cholesterol (LDL-C) to mitigate risk of both primary and secondary cardiovascular outcomes, statins have been the cornerstone of therapy, significantly reducing the incidence of coronary atherosclerotic vascular disease. Previous studies suggest that adding other non statin LDL-lowering agents may further lower LDL-C without negative side effects. Recent guidelines support the hypothesis that driving the LDL-C level below previously recommended targets may have a beneficial effect. Ezetimibe, a cholesterol absorption blocker that inhibits the Niemann-Pick C1-Like 1 (NPC1L1) receptor, has been the focus of recent trials that support its use in cardiovascular risk reduction. For patients not at goal on statin therapy alone, ezetimibe has proven to be a safe, well-tolerated medication that may be used as an adjunct to statin therapy to further reduce LDL-C, resulting in a significant mortality benefit. PMID- 26490082 TI - Efficacy and acceptability of very low energy diets in overweight and obese people with Type 2 diabetes mellitus: a systematic review with meta-analyses. AB - AIMS: To explore the efficacy and acceptability of very low energy diets in overweight or obese adults with Type 2 diabetes. METHODS: Controlled trials and qualitative studies of individuals with Type 2 diabetes that compared very low energy diets with standard care, minimal interventions, other weight loss interventions, less intensive very low energy diet interventions and very low energy diets with additional components were eligible for inclusion. Meta analyses of changes in weight, blood glucose levels and attrition rates were performed. Acceptability of very low energy diets was assessed by attrition rates, number and severity of side effects, and by qualitative evaluations of the interventions. RESULTS: Four randomized, five non-randomized controlled trials and no qualitative studies (21 references, 9 studies, 346 participants) were identified. Meta-analyses showed that very low energy diets induced greater weight losses than minimal interventions, standard care or low energy diets at 3 and 6 months. No conclusive evidence for differences in outcomes between very low energy diets and Roux-en-Y gastric bypass surgery was found. Greater differences in energy prescription between intervention and comparator arms were associated with greater differences in weight loss and fasting blood glucose levels at 3 months. Attrition rates did not differ between the very low energy diets and the comparator arms at any measurement point. CONCLUSIONS: Very low energy diets are effective in substantial weight loss among people with Type 2 diabetes. Levels of adherence to very low energy diets in controlled studies appear to be high, although details about behaviour support provided are usually poorly described. PMID- 26490083 TI - Psychotropic drugs for the management of cancer-related fatigue: a systematic review and meta-analysis. AB - Cancer-related fatigue (CRF) is a common symptom affecting 60-90% of cancer survivors, and effective management for CRF is not yet available. Recently, an increasing number of trials examining the use of psychotropic drugs for the treatment of CRF have been performed, but these trials have yielded inconsistent results. Therefore, we conducted a meta-analysis aimed at assessing the effect and safety of psychotropic drugs for the management of CRF. Ten eligible trials of the psychotropic drugs methylphenidate and modafinil in a total of 1582 participants treated for CRF were subjected to statistical analyses. A meta analysis of seven of these studies indicated that methylphenidate was superior to placebo for the treatment of CRF. Another meta-analysis of three studies evaluating modafinil found that this drug was no better than placebo. Adverse events were similar between both methylphenidate and modafinil and the placebo groups. Our meta-analysis indicated that the treatment of CRF with methylphenidate appears to be effective, whereas modafinil provides no benefit. These results of this analysis warrant further trials to confirm the efficacy and safety of psychotropic drugs for the treatment of CRF. PMID- 26490084 TI - "I should be doing more for my parent:" Chinese adult children's worry about performance in providing care for their oldest-old parents. AB - BACKGROUND: In China, as is the case in most of the world, family is the largest source of support for frail older adults. Confucian filial piety expectations hold children-in particular sons-responsible for the care of aging parents in China. During the course of caregiving, in addition to positive feelings, the caregiver may feel overwhelmed, entrapped, and worried about their performance, which can have negative health consequences. The purpose of this exploratory study is to examine one dimension of caregiver burden "worry about performance" (WaP) and investigate whether variables inspired by Pearlin's Stress Process Model help to explain the variation of WaP, so that at-risk caregivers can be identified and supported. METHODS: Multiple regression was used to analyze CLHLS data from 895 Chinese adult children providing care for their oldest old parent in eight coastal provinces in China. WaP was measured by two items from the Zarit Burden Inventory. Independent variables representing concepts from Pearlin's Stress Process Model and control variables were included in the models. RESULTS: Compared to a model of control variables only, using independent variables inspired by Pearlin's Stress Process Model increased the ability to explain the variation in WaP by three fold to 14%. The following variables increased WaP: parent's IADL level, the amount of time spent caregiving, being a daughter, reporting an emotionally close relationship with the parent, sharing a residence with the parent. CONCLUSION: Despite not being able to fully operationalize Pearlin's Model with this dataset, analyzing variables that represent concepts from the model was useful in increasing the ability to explain the variation in WaP. Results suggest that caregiver support directed at daughters may be particularly beneficial. PMID- 26490085 TI - Estimation of pulse wave velocity in patients with peripheral artery disease: a word of caution. PMID- 26490086 TI - Time course of cardiac inflammation during nitric oxide synthase inhibition in SHR: impact of prior transient ACE inhibition. AB - We have previously demonstrated that angiotensin-converting enzyme (ACE) inhibition with enalapril produces persistent effects that protect against future nitric oxide synthase (NOS) inhibitor (L-arginine methyl ester, L-NAME)-induced cardiac dysfunction and outer wall collagen deposition in spontaneously hypertensive rats (SHR). In the present study, we dissect the cytokine/chemokine release profile during NOS inhibition, its correlation to pathological cardiac remodeling and the impact of transient ACE inhibition on these effects. Adult male SHR were treated with enalapril (E+L) or tap water (C+L) for 2 weeks followed by a 2-week washout period. Rats were then subjected to 0, 3, 7 or 10 days of L-NAME treatment. The temporal response to NOS inhibition was evaluated by measuring arterial pressure, cardiac remodeling and cytokine/chemokine levels. L-NAME equivalently increased blood pressure and myocardial and vascular injury in C+L and E+L rats. However, pulse pressure (PP) was only transiently altered in C+L rats. The levels of several inflammatory mediators were increased during L NAME treatment. However, interleukin-6 (IL-6) and IL-10 and monocyte chemoattractant protein-1 were uniquely increased in C+L hearts; whereas IL-4 and fractalkine were only elevated in E+L hearts. By days 7 and 10 of L-NAME treatment, there was a significant increase in the cardiac density of macrophages and proliferating cells, respectively only in C+L rats. Although myocardial injury was similar in both treatment groups, PP was not changed and there was a distinct cardiac chemokine/cytokine signature in rats previously treated with enalapril that may be related to the lack of proliferative response and macrophage infiltration in these hearts. PMID- 26490087 TI - Combination of serum angiopoietin-2 and uterine artery Doppler for prediction of preeclampsia. AB - The aim of this study was to determine the predictive value of the combination of serum angiopoietin-2 (Ang-2) levels and uterine artery Doppler for the detection of preeclampsia in women at 16-18 weeks of gestation and to identify other pregnancy complications that could be predicted with these combined tests. Maternal serum Ang-2 levels were measured, and uterine artery Doppler was performed in 400 pregnant women. The main outcome was preeclampsia. The predictive values of this combination were calculated. Twenty-five women (6.3%) developed preeclampsia. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of uterine artery Doppler combined with serum Ang-2 levels for the prediction of preeclampsia were 24.0%, 94.4%, 22.2% and 94.9%, respectively. For the prediction of early-onset preeclampsia, the sensitivity, specificity, PPV and NPV were 57.1%, 94.1%, 14.8% and 99.2%, respectively. Patients with abnormal uterine artery Doppler and abnormal serum Ang-2 levels (above 19.5 ng ml(-1)) were at higher risk for preterm delivery (relative risk=2.7, 95% confidence interval 1.2-5.8). Our findings revealed that the combination of uterine artery Doppler and serum Ang-2 levels at 16-18 weeks of gestation can be used to predict early-onset preeclampsia but not overall preeclampsia. Thus, this combination may be a useful early second trimester screening test for the prediction of early-onset preeclampsia. PMID- 26490088 TI - Seeking a blood pressure-independent measure of vascular properties. AB - Pulse wave velocity (PWV) and pulse pressure (PP) are blood pressure (BP) dependent surrogates for vascular stiffness. Considering that there are no clinically useful markers for arterial stiffness that are BP-independent, our objective was to identify novel indices of arterial stiffness and compare them with previously described markers. PWV and PP were measured in young and old male Fisher rats and in young and old male spontaneously hypertensive rats (SHR) over a wide range of BPs. The BP dependence of these and several other indices of vascular stiffness were evaluated. An index incorporating PWV and PP was also constructed. Both PWV and PP increase in a non-linear manner with rising BP for both strains of animals (Fisher and SHRs). Age markedly changes the relationship between PWV or PP and BP. The previously described Ambulatory Arterial Stiffness Index (AASI) was able to differentiate between young and old vasculature, whereas the Cardio-Ankle Vascular Index (CAVI) did not reliably differentiate between the two. The novel Arterial Stiffness Index (ASI) differentiated stiffer from more compliant vasculature. Considering the limitations of the currently available indices of arterial stiffness, we propose a novel index of intrinsic arterial stiffness, the ASI, which is robust over a range of BPs and allows one to distinguish between compliant and stiff vasculature in both Fisher rats and SHRs. Further studies are necessary to validate this index in other settings. PMID- 26490091 TI - A mechanism-based pharmacological evaluation of efficacy of Flacourtia indica in management of dyslipidemia and oxidative stress in hyperlipidemic rats. AB - BACKGROUND: Flacourtia indica (Burm. f.) Merr. is a medicinal plant indigenous to India and is broadly used worldwide for the treatment of a variety of health ailments. The present study was experimented on hyperlipidemic Charles Foster rats with the aim to explore the possible mechanism responsible for the antidyslipidemic activity of the hydromethanolic extract from F. indica leaves (FIL). METHODS: Hyperlipidemia was induced by a single intraperitoneal dose of Triton WR-1339 in Charles Foster rats. The plasma lipid levels were estimated in control and treated groups. The antioxidant potential of F. indica was assessed in both enzymatic and non-enzymatic systems. An acute toxicity study of high performance liquid chromatography (HPLC)-fingerprinted extract was carried out in Swiss albino mice. RESULTS: The F. indica extract at a dose of 150 mg/kg significantly lowers the plasma level of total cholesterol (17%), triglycerides (13%), and phospholipids (16%) by increasing post-heparin lipolytic activity (19%) and lecithin-cholesterol-acyltransferase activity (20%) in Triton-induced hyperlipidemic rats. In addition, the F. indica extract showed significant in vitro antioxidant and anti-adipogenic activity. HPLC analysis indicates the presence of flavanones and flavones in the extract, and the extract was found to be non-toxic up to a dose of 2000 mg/kg body weight in the acute oral toxicity study. CONCLUSIONS: These finding suggest that F. indica holds significant potential in preventing clinical deterioration induced by dyslipidemia along with oxidative stress. PMID- 26490090 TI - The risk factors for labor onset hypertension. AB - Our aim was to clarify the perinatal outcomes of and risk factors for hypertension that is first detected after labor onset (labor onset hypertension, LOH), which may be a risk factor for eclampsia and stroke during labor. A total of 1349 parturient women who did not exhibit preeclampsia or gestational hypertension prior to labor were examined. The patients were classified into four groups: the normotensive (n=1023) (whose systolic blood pressure (SBP) remained below 140 mm Hg throughout labor), mild LOH (n=241) (whose maximum SBP during labor ranged from 140 to 159 mm Hg), severe LOH (n=66) (whose maximum SBP during labor ranged from 160 to 179 mm Hg) and emergent LOH groups (n=19) (whose maximum SBP during labor was greater than 180 mm Hg). The perinatal outcomes and patient characteristics of the four groups were compared. Twenty-four percent of the pregnant women who remained normotensive throughout pregnancy developed hypertension during labor. One of the patients in the emergent LOH group developed eclampsia. The blood pressure at delivery and frequencies of hypotensor use, interventional delivery and low Apgar scores differed significantly among the four groups. The following risk factors for severe/emergent LOH were extracted: being over 35 years old, a body mass index at delivery of >30, an SBP at 36 weeks' gestation of 130-134 mm Hg, an SBP at admission of 130-139 mm Hg, proteinuria (a score of 2+ on the dipstick test) and severe edema. The risk factors for severe/emergent LOH were identified in this study. In high risk cases, repeatedly measuring maternal blood pressure during delivery might help detect critical hypertension early. PMID- 26490092 TI - Ultrasonographic findings of the various diseases presenting as calf pain. AB - There are various causes of calf pain. The differential diagnoses affecting the lower leg include cystic lesions, trauma-related lesions, infection or inflammation, vascular lesions, neoplasms, and miscellaneous entities. Ultrasound (US) provide detailed anatomical information of the calf structures, and it offers the ability to confirm, other calf abnormalities, particularly when deep vein thrombosis (DVT) is ruled out. The purpose of this article is to review the causes of a painful calf presenting as DVT and incidental findings found as part of the work-up of DVT, and to provide a broad overview of US findings and clinical features of these pathologies. PMID- 26490093 TI - The effectiveness of mobile-health behaviour change interventions for cardiovascular disease self-management: A systematic review. AB - BACKGROUND: Mobile wireless devices (mHealth) have been used to deliver cardiovascular disease self-management interventions to educate and support patients in making healthy lifestyle changes. This systematic review aimed to determine the effectiveness of mHealth interventions on behavioural lifestyle changes and medication adherence for cardiovascular disease self-management. METHODS: A comprehensive literature search was conducted from inception through to 3 March 2015 using MEDLINE, PubMed, PsycINFO, EMBASE and The Cochrane Library. Eligible studies used an experimental trial design to determine the effectiveness of an mHealth intervention to change lifestyle behaviours in any cardiovascular disease population. Data extracted included intervention and comparison group characteristics with a specific focus on the use of behaviour change techniques. RESULTS: Seven studies met our inclusion criteria and were included in the qualitative synthesis. All interventions were delivered in part by mobile phone text messaging. Three studies were effective at improving adherence to medication and two studies increased physical activity behaviour. No effects were observed on dietary behaviour or smoking cessation, measured in one study each. Simple text messaging interventions appeared to be most effective; however, no clear relationships were found between study findings and intervention dose, duration or behaviour change techniques targeted. CONCLUSIONS: Our review found mHealth has the potential to change lifestyle behaviour. Results are still limited to a small number of trials, inconsistent outcome measures and ineffective reporting of intervention characteristics. Large scale, longitudinal studies are now warranted to gain a clear understanding of the effects of mHealth on behaviour change in the cardiovascular disease population. PMID- 26490094 TI - Phenylsilane as a safe, versatile alternative to hydrogen for the synthesis of actinide hydrides. AB - The thorium and uranium dihydride dimer complexes [(C5Me5)2An(H)(MU-H)]2 (An = Th, U) have been easily prepared using phenylsilane, which is an efficient and safer alternative to hydrogen gas. The synthetic utility of this new hydriding method has been demonstrated by the preparation of a variety of organometallic complexes, including, for the first time, (C5Me5)2U(SMe)2, (C5Me5)2Th(C4Ph4), (C5Me5)2U(C4Ph4), (C5Me5)2ThS5, and (C5Me5)2U(bipy) using [(C5Me5)2An(H)(MU-H)]2 (An = Th, U) as multi-electron reductants. PMID- 26490095 TI - Synthesis and biological evaluation of 1,3-diaryl pyrazole derivatives as potential antibacterial and anti-inflammatory agents. AB - Three series of 1,3-diaryl pyrazole derivatives bearing aminoguanidine or furan-2 carbohydrazide moieties have been synthesized, characterized and evaluated for antibacterial and anti-inflammatory activities. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains with minimum inhibitory concentration values in the range of 1-64 MUg/mL. Compounds 6g, 6l and 7l presented the most potent inhibitory activity against Gram-positive bacteria (e.g. Staphylococcus aureus 4220), Gram-negative bacteria (e.g. Escherichia coli 1924) and the fungus, Candida albicans 7535, with minimum inhibitory concentration values of 1 or 2 MUg/mL. Compared with previous studies, these compounds exhibited a broad spectrum of inhibitory activity. Furthermore, compound 7l showed the greatest anti-inflammatory activity (93.59% inhibition, 30 min after intraperitoneal administration), which was more potent than the reference drugs ibuprofen and indomethacin. PMID- 26490096 TI - Single water solvation dynamics in the 4-aminobenzonitrile-water cluster cation revealed by picosecond time-resolved infrared spectroscopy. AB - The dynamics of a solvent is important for many chemical and biological processes. Here, the migration dynamics of a single water molecule is triggered by the photoionization of the 4-aminobenzonitrile-water (4ABN-W) cluster and monitored in real time by picosecond time-resolved IR (ps TRIR) spectroscopy. In the neutral cluster, water is hydrogen-bonded to the CN group. When this CN-bound cluster is selectively ionized with an excess energy of 1238 cm(-1), water migrates with a lifetime of tau = 17 ps from the CN to the NH2 group, forming a more stable 4ABN(+)-W(NH) isomer with a yield of unity. By decreasing the ionization excess energy, the yield of the CN -> NH2 reaction is reduced. The relatively slow migration in comparison to the ionization-induced solvent dynamics in the related acetanilide-water cluster cation (tau = 5 ps) is discussed in terms of the internal excess energy after photoionization and the shape of the potential energy surface. PMID- 26490097 TI - Quantifying the prevalence of frailty in English hospitals. AB - OBJECTIVES: Population ageing has been associated with an increase in comorbid chronic disease, functional dependence, disability and associated higher health care costs. Frailty Syndromes have been proposed as a way to define this group within older persons. We explore whether frailty syndromes are a reliable methodology to quantify clinically significant frailty within hospital settings, and measure trends and geospatial variation using English secondary care data set Hospital Episode Statistics (HES). SETTING: National English Secondary Care Administrative Data HES. PARTICIPANTS: All 50,540,141 patient spells for patients over 65 years admitted to acute provider hospitals in England (January 2005-March 2013) within HES. PRIMARY AND SECONDARY OUTCOME MEASURES: We explore the prevalence of Frailty Syndromes as coded by International Statistical Classification of Diseases, Injuries and Causes of Death (ICD-10) over time, and their geographic distribution across England. We examine national trends for admission spells, inpatient mortality and 30-day readmission. RESULTS: A rising trend of admission spells was noted from January 2005 to March 2013 (daily average admissions for month rising from over 2000 to over 4000). The overall prevalence of coded frailty is increasing (64,559 spells in January 2005 to 150,085 spells by Jan 2013). The majority of patients had a single frailty syndrome coded (10.2% vs total burden of 13.9%). Cognitive impairment and falls (including significant fracture) are the most common frailty syndromes coded within HES. Geographic variation in frailty burden was in keeping with known distribution of prevalence of the English elderly population and location of National Health Service (NHS) acute provider sites. Overtime, in-hospital mortality has decreased (>65 years) whereas readmission rates have increased (esp.>85 years). CONCLUSIONS: This study provides a novel methodology to reliably quantify clinically significant frailty. Applications include evaluation of health service improvement over time, risk stratification and optimisation of services. PMID- 26490098 TI - Developing and validating a risk prediction model for acute care based on frailty syndromes. AB - OBJECTIVES: Population ageing may result in increased comorbidity, functional dependence and poor quality of life. Mechanisms and pathophysiology underlying frailty have not been fully elucidated, thus absolute consensus on an operational definition for frailty is lacking. Frailty scores in the acute medical care setting have poor predictive power for clinically relevant outcomes. We explore the utility of frailty syndromes (as recommended by national guidelines) as a risk prediction model for the elderly in the acute care setting. SETTING: English Secondary Care emergency admissions to National Health Service (NHS) acute providers. PARTICIPANTS: There were N=2,099,252 patients over 65 years with emergency admission to NHS acute providers from 01/01/2012 to 31/12/2012 included in the analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcomes investigated include inpatient mortality, 30-day emergency readmission and institutionalisation. We used pseudorandom numbers to split patients into train (60%) and test (40%). Receiver operator characteristic (ROC) curves and ordering the patients by deciles of predicted risk was used to assess model performance. Using English Hospital Episode Statistics (HES) data, we built multivariable logistic regression models with independent variables based on frailty syndromes (10th revision International Statistical Classification of Diseases, Injuries and Causes of Death (ICD-10) coding), demographics and previous hospital utilisation. Patients included were those>65 years with emergency admission to acute provider in England (2012). RESULTS: Frailty syndrome models exhibited ROC scores of 0.624 0.659 for inpatient mortality, 0.63-0.654 for institutionalisation and 0.57-0.63 for 30-day emergency readmission. CONCLUSIONS: Frailty syndromes are a valid predictor of outcomes relevant to acute care. The models predictive power is in keeping with other scores in the literature, but is a simple, clinically relevant and potentially more acceptable measurement for use in the acute care setting. Predictive powers of the score are not sufficient for clinical use. PMID- 26490099 TI - Does smoking cessation result in improved mental health? A comparison of regression modelling and propensity score matching. AB - OBJECTIVES: Smokers report that smoking is therapeutic; a recent meta-analysis suggests the contrary. However, the association in that review may be explained by group-membership bias and confounding. Propensity score matching (PSM) aims to produce causal estimates from observational data. We examined the association between cessation and change in mental health before and after PSM. DESIGN: A secondary analysis of prospective data from 5 placebo-controlled randomised trials for smoking reduction. PARTICIPANTS: All participants were adult smokers and had smoked for at least 3 years. Participants were excluded if they were pregnant, breast feeding, under psychiatric care, deemed to be unfit by a general practitioner or part of a cessation programme. In total, 937 participants provided smoking data at both 6-month and 12-month follow-ups. Of these, 68 were confirmed as abstinent at both 6 and 12 months and 589 as continuous smokers at both follow-ups. PRIMARY OUTCOME: Change in mental health (36-item Short Form Survey (SF-36), scored 0-100) from baseline (while all participants were smokers) to 12-month follow-up (after cessation) was compared between quitters and continuing smokers with and without adjustment, and after PSM. RESULTS: Before matching, quitters' mental health scores improved compared with continuing smokers', the mean difference and 95% CI was 5.5 (1.6 to 9.4). After adjustment, the difference was 4.5 (0.6 to 8.5), and after PSM, the difference was 3.4 (-2.2 to 8.9). CONCLUSIONS: Improvements in mental health after smoking cessation may be partly but not completely explained by group membership bias and confounding. PMID- 26490101 TI - Effect of grain size on the monoclinic transformation, hardness, roughness, and modulus of aged partially stabilized zirconia. AB - OBJECTIVE: Low-temperature-degradation (LTD) has been reported to cause property changes in yttria-tetragonal zirconia polycrystals (Y-TZP). The current study measured monoclinic phase transformation of Y-TZP with different grain sizes and corresponding property changes due to artificial aging. NULL HYPOTHESIS: the grain size of aged Y-TZP will not influence its transformation, roughness, hardness or modulus of elasticity. METHODS: Four groups of Y-TZP were examined with differing grain sizes (n=5). The line intercept technique was used to determine grain sizes on SEM images (100,000*). Artificial aging was accomplished by autoclaving at 2 bar pressure for 5 h. X-ray diffraction (30 mA, 40 kV) was used to measure tetragonal to monoclinic transformation (t->m). Surface roughness analysis was performed using a non-contact surface-profilometer. Nano-hardness and modulus of elasticity were measured using nano-indentation. RESULTS: SEM analyses showed different grain sizes for each sample group (0.350 MUm, 0.372 MUm, 0.428 MUm, and 0.574 MUm). The fraction of t->m transformation increased as grain size increased; furthermore, aging of zirconia caused increased roughness. Modulus and hardness after aging displayed no significant correlation or interaction with grain size. SIGNIFICANCE: Smaller grains caused less transformation, and aging caused increased roughness, but grain size did not influence the amount of increased surface roughness. Future studies are needed to determine the effects of grain size on the wear and fracture properties of dental zirconia. PMID- 26490100 TI - Diagnostic accuracy of calculated serum osmolarity to predict dehydration in older people: adding value to pathology laboratory reports. AB - OBJECTIVES: To assess which osmolarity equation best predicts directly measured serum/plasma osmolality and whether its use could add value to routine blood test results through screening for dehydration in older people. DESIGN: Diagnostic accuracy study. PARTICIPANTS: Older people (>=65 years) in 5 cohorts: Dietary Strategies for Healthy Ageing in Europe (NU-AGE, living in the community), Dehydration Recognition In our Elders (DRIE, living in residential care), Fortes (admitted to acute medical care), Sjostrand (emergency room) or Pfortmueller cohorts (hospitalised with liver cirrhosis). REFERENCE STANDARD FOR HYDRATION STATUS: Directly measured serum/plasma osmolality: current dehydration (serum osmolality>300 mOsm/kg), impending/current dehydration (>=295 mOsm/kg). INDEX TESTS: 39 osmolarity equations calculated using serum indices from the same blood draw as directly measured osmolality. RESULTS: Across 5 cohorts 595 older people were included, of whom 19% were dehydrated (directly measured osmolality>300 mOsm/kg). Of 39 osmolarity equations, 5 showed reasonable agreement with directly measured osmolality and 3 had good predictive accuracy in subgroups with diabetes and poor renal function. Two equations were characterised by narrower limits of agreement, low levels of differential bias and good diagnostic accuracy in receiver operating characteristic plots (areas under the curve>0.8). The best equation was osmolarity=1.86*(Na++K+)+1.15*glucose+urea+14 (all measured in mmol/L). It appeared useful in people aged >=65 years with and without diabetes, poor renal function, dehydration, in men and women, with a range of ages, health, cognitive and functional status. CONCLUSIONS: Some commonly used osmolarity equations work poorly, and should not be used. Given costs and prevalence of dehydration in older people we suggest use of the best formula by pathology laboratories using a cutpoint of 295 mOsm/L (sensitivity 85%, specificity 59%), to report dehydration risk opportunistically when serum glucose, urea and electrolytes are measured for other reasons in older adults. TRIAL REGISTRATION NUMBERS: DRIE: Research Register for Social Care, 122273; NU-AGE: ClinicalTrials.gov NCT01754012. PMID- 26490102 TI - 'Mini reimplantation' for the management of primary obstructed megaureter. AB - INTRODUCTION: The management of primary obstructed megaureter (POM) ranges from temporary double-J stenting to conventional ureteric reimplantation with tapering. Of late, several authors have favored refluxing reimplantation. In the present study the outcomes of 'mini reimplantation', where no tapering or advancement of the ureter was performed, have been analyzed. METHODS: Records of all children (n = 28) who underwent reimplantation for POM from 2004 to 2014 were retrospectively analyzed. During the initial 5 years, a Cohen's reimplantation with excisional tapering was performed (Group 1, n = 15). Due to complications, the technique was modified in the second 5 years (Group 2, n = 13). In this group, after opening the bladder, the distal narrow segment and grossly dilated POM (around 3-5 cm) were excised (Figure). After closing the detrusor behind the ureter, the ureter was reimplanted again at the original position without tapering or advancement. Bladder mucosa was closed cranial to the new ureteric orifice, providing a ureter:tunnel ratio of 1:2 (mini reimplantation). All patients underwent repeat ultrasonogram and MAG3 renogram, with indirect at 6 months and 1 year after stent removal to exclude obstruction/vesicoureteral reflux (VUR). RESULTS: In Group 1, a significantly higher proportion (P = 0.04) of patients (5/15) had to undergo repeat procedures for complications, compared with none in Group 2. In Group 1, there were two redo reimplants for recurrent obstructions; two nephrectomies for non-functioning kidneys; and one ureterostomy for pyonephrosis. Postoperative Grade 2-3 VUR was encountered in 3/15 patients in Group 1, and 2/13 patients in Group 2. These patients could be managed with antibiotic prophylaxis and no intervention was required. DISCUSSION: Conventional management of POM involved initial cutaneous ureterostomy, followed by reimplantation with tapering of the ureter. Megaureter reimplantation with and without tapering has been reported to have no significant difference in outcomes between them. To avoid a potentially difficult operation in a small infant bladder, a refluxing reimplantation has been proposed; however, there is a high re-operation rate following this technique. The author feels that the reported technique is superior to the refluxing reimplantation, as there is no need for re operation. The limitations of this study were the small numbers and short follow up. However, the proposed 'mini reimplantation' with no tapering or advancement had good success rates in this small series. Further larger studies are required to support or negate the usefulness of this technique. PMID- 26490105 TI - Hepatitis B virus X protein induces epithelial-mesenchymal transition by repressing E-cadherin expression via upregulation of E12/E47. AB - Previous reports have demonstrated that hepatitis B virus (HBV) X protein (HBx) represses E-cadherin expression to induce epithelial-mesenchymal transition (EMT), an essential component of cancer progression to more aggressive phenotypes characterized by tumour invasion, migration and metastasis; however, the underlying mechanism for this phenomenon is still unclear. In this study, we found that ectopic expression of HBx in human hepatocytes using overexpression and 1.2-mer WT HBV replicon systems upregulated levels of the transcriptional repressors E12 and E47, resulting in inactivation of the E-cadherin promoter, containing three E-box motifs, and subsequent repression of its expression. E12/E47 knockdown using a specific small interfering RNA almost completely abolished the potential of HBx to repress E-cadherin expression. HBx inhibited the ubiquitin-dependent proteasomal degradation of E12/E47 without affecting their expression at the transcriptional level. Upregulation of E12/E47 by HBx ultimately led to EMT in human hepatocytes, as demonstrated by morphological changes, altered protein levels of EMT markers, including E-cadherin, plakoglobin, fibronectin, vimentin and N-cadherin, and increased capacity for cell detachment and migration. PMID- 26490103 TI - Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy. AB - BACKGROUND: Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant agalsidase-beta therapy. METHODS AND DESIGN: The goal was maintenance of urine protein to creatinine ratio (UPCR) <0.5 g/g or a 50% reduction in baseline UPCR for 24 patients at eight study sites. The change in estimated glomerular filtration rate (eGFR) was assessed over 21 months of treatment. RESULTS: 18 out of 24 patients achieved the UPCR goal with eGFR slopes that were significantly better than six patients who did not achieve the UPCR goal (-3.6 (-4.8 to -1.1) versus -7.0 (-9.0 to -5.6) mL/min/1.73 m(2)/year, respectively, p=0.018). Despite achieving the UPCR goal, 67% (12/18 patients) still progressed with an eGFR slope <-2 mL/min/1.73 m(2)/year. Regression analysis showed that increased age at initiation of agalsidase-beta therapy was significantly associated with worsened kidney outcome. Hypotension and hyperkalaemia occurred in seven and eight patients, respectively, which required modification of antiproteinuric therapy but was not associated with serious adverse events. CONCLUSIONS: This study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) and antiproteinuric therapy with ACE inhibitors and/or ARB in patients with severe Fabry nephropathy. Patients had preservation of kidney function if agalsidase-beta treatment was initiated at a younger age, and UPCR maintained at or below 0.5 g/g with antiproteinuric therapy. TRIAL REGISTRATION NUMBER: NCT00446862. PMID- 26490106 TI - Rate of discontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care databases. AB - OBJECTIVES: To assess the proportion of RA patients who discontinued biologics in world registries and health care databases and to identify causes and predictors of discontinuation. METHODS: Medline, Embase, Cochrane Library and Web of Science electronic databases and ACR and EULAR meeting abstracts were used. The selection of studies from world registries and health care databases including RA patients treated with biologics was independently performed. Data extracted from articles and abstracts were combined using a random effects model. Meta-analyses of percentages and hazard ratios were used to assess discontinuation. RESULTS: Ninety-eight studies with >200 000 patients from 11 242 articles and 119 abstracts met the inclusion criteria. Overall discontinuation rates of TNF inhibitors at 0.5, 1, 2, 3 and 4 years were 21, 27, 37, 44 and 52%, respectively. Discontinuation of etanercept was significantly lower at 3 and 4 years (35% and 41%, respectively) than infliximab and adalimumab (46% and 52%, respectively). Predictors of time to discontinuation were etanercept [hazard ratios (HRs) 0.58 and 0.77 versus infliximab and adalimumab, respectively), concomitant use of DMARDs (HR 0.77), disease duration (HR 1.01) and female sex (HR 1.18). Studies from registries conducted after 2005 and from countries with lower biologics access showed higher percentages of discontinuation. Relevant data on abatacept and tocilizumab were missing. CONCLUSION: In RA, treatment with etanercept has a lower percentage of discontinuation than infliximab and adalimumab. Concomitant use of DMARDs, disease duration before treatment with a biologic and female sex predict time to discontinuation. PMID- 26490107 TI - Erratum: Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity. PMID- 26490104 TI - MKS1 regulates ciliary INPP5E levels in Joubert syndrome. AB - BACKGROUND: Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation 'the molar tooth sign'. Mutations in >27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1 related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS. METHODS: We measured cilium number, length and protein content (ARL13B and INPP5E) by immunofluorescence in fibroblasts from individuals with MKS1-related JS and in a three-dimensional (3D) spheroid rescue assay to test the effects of disease-related MKS1 mutations. RESULTS: We report MKS1 mutations (eight of them previously unreported) in nine individuals with JS. A minority of the individuals with MKS1-related JS have MKS features. In contrast to the truncating mutations associated with MKS, all of the individuals with MKS1 related JS carry >= 1 non-truncating mutation. Fibroblasts from individuals with MKS1-related JS make normal or fewer cilia than control fibroblasts, their cilia are more variable in length than controls, and show decreased ciliary ARL13B and INPP5E. Additionally, MKS1 mutant alleles have similar effects in 3D spheroids. CONCLUSIONS: MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content, through an ARL13B-dependent mechanism. Mutations in INPP5E also cause JS, so our findings in patient fibroblasts support the notion that loss of INPP5E function, due to either mutation or mislocalisation, is a key mechanism underlying JS, downstream of MKS1 and ARL13B. PMID- 26490108 TI - Conscientiousness and fruit and vegetable consumption: exploring behavioural intention as a mediator. AB - Clear associations have emerged between conscientiousness and health behaviours, such that higher levels of conscientiousness are predictive of beneficial health behaviours. This study investigated the conscientiousness-fruit and vegetable consumption relationship and whether behavioural intention mediated this relationship. A large sample of adults (N = 2136) completed an online battery of questionnaires measuring conscientiousness, behavioural intentions to consume fruit and vegetables, together with self-reported behaviour. Correlation analysis revealed that conscientiousness and each of its facets were positively associated with behavioural intention and self-reported behaviour. Hierarchical multiple regression analyses revealed that after controlling for age, gender and education, total conscientiousness, and the facets of responsibility, industriousness, order and virtue predicted self-reported behaviour. Further analysis revealed that in line with the Theory of Planned Behaviour, behavioural intention fully mediated the conscientiousness-fruit and vegetable behaviour relationship. In conclusion, low levels of conscientiousness were found to be associated with lower fruit and vegetable intentions, with the latter also associated with fruit and vegetable consumption. PMID- 26490109 TI - Games and Telerehabilitation for Balance Impairments and Gaze Dysfunction: Protocol of a Randomized Controlled Trial. AB - BACKGROUND: Digital media and gaming have received considerable interest from researchers and clinicians as a model for learning a broad range of complex tasks and facilitating the transfer of skills to daily life. These emerging rehabilitation technologies have the potential to improve clinical outcomes and patient participation because they are engaging, motivating, and accessible. Our research goal is to develop preventative and therapeutic point-of-care eHealth applications that will lead to equivalent or better long-term health outcomes and health care costs than existing programs. We have produced a novel computer-aided tele-rehabilitation platform that combines computer game-based exercises with tele-monitoring. OBJECTIVE: Compare the therapeutic effectiveness of an in-home, game-based rehabilitation program (GRP) to standard care delivered in an outpatient physical therapy clinic on measures of balance, gaze control, dizziness, and health-related quality of life. METHODS: A randomized, controlled, single-blind pilot trial will be conducted. Fifty-six participants with a diagnosis of peripheral vestibular disorder will be randomly assigned to either usual physical therapy (comparator group) or to a game-based intervention (experimental group). Measures to be assessed will include gaze control, dynamic balance, and self-reported measures of dizziness. RESULTS: The project was funded and enrollment was started in August 2014. To date, 36 participants have been enrolled. There have been 6 drop-outs. It is expected that the study will be completed January 2016 and the first results are expected to be submitted for publication in Spring of 2016. CONCLUSIONS: A successful application of this rehabilitation program would help streamline rehabilitation services, leverage therapist time spent with clients, and permit regular practice times at the client's convenience. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02134444; https://clinicaltrials.gov/ct2/show/NCT02134444 (Archived by WebCite at http://www.webcitation.org/6cE18bqqY). PMID- 26490110 TI - Graft revascularization is essential for non-invasive monitoring of transplanted islets with radiolabeled exendin. AB - Islet transplantation is a novel promising strategy to cure type 1 diabetes. However, the long-term outcome is still poor, because both function and survival of the transplant decline over-time. Non-invasive imaging methods have the potential to enable monitoring of islet survival after transplantation and the effects of immunosuppressive drugs on transplantation outcome. (111)In-labeled exendin-3 is a promising tracer to visualize native and transplanted islets by SPECT (Single Photon Emission Computed Tomography). In the present study, we hypothesized that islet microvasculature plays an important role determining the uptake of exendin-3 in islets when monitoring transplant survival. We observed (111)In-exendin-3 accumulation in the transplant as early as three days after transplantation and an increase in the uptake up to three weeks post transplantation. Islet-revascularization correlated with the increase in (111)In exendin-3 uptake, whereas fully re-established islet vasculature coincided with a stabilized uptake of the radiotracer in the transplant. Here, we demonstrate the importance of islet vasculature for in vivo delivery of radiotracers to transplanted islets and we demonstrate that optimal and stable uptake of exendin four weeks after transplantation opens the possibility for long-term monitoring of islet survival by SPECT imaging. PMID- 26490111 TI - Selling safety: the use of celebrities in improving awareness of safety in commercial aviation. AB - The aim of this study was to investigate the influential power of a celebrity to convey key safety messages in commercial aviation using a pre-flight safety briefing video. In addition, the present research sought to examine the effectiveness of subtitles in aiding the recall of these important messages as well as how in-cabin aircraft noise affects recall of this information. A total of 101 participants were randomly divided into four groups (no noise without subtitles, no noise with subtitles, noise without subtitles and noise with subtitles) and following exposure to a pre-recorded pre-flight safety briefing video were tested for recall of key safety messages within that video. Participants who recognised and recalled the name of the celebrity in the safety briefing video recalled significantly more of the messages than participants who did not recognise the celebrity. Subtitles were also found to be effective, however, only in the presence of representative in-cabin aircraft noise. Practitioner Summary: Passenger attention to pre-flight safety briefings on commercial aircraft is poor. Utilising the celebrity status of a famous person may overcome this problem. Results suggest that celebrities do increase the recall of safety-related information. PMID- 26490112 TI - Dietary patterns in Swedish adults; results from a national dietary survey. AB - Dietary patterns derived by statistical procedures is a way to identify overall dietary habits in specific populations. The aim of this study was to identify and characterise dietary patterns in Swedish adults using data from the national dietary survey Riksmaten adults 2010-11 (952 women, 788 men). Principal component analyses were used and two patterns were identified in both sexes: a healthy pattern loading positively on vegetables, fruits, fish and seafood, and vegetable oils, and negatively on refined bread and fast food, and a Swedish traditional pattern loading positively on potatoes, meat and processed meat, full-fat milk products, sweet bakery products, sweet condiments and margarine. In addition, a light-meal pattern was identified in women with positive loadings on fibre-rich bread, cheese, rice, pasta and food grain dishes, substitute products for meat and dairy products, candies and tea. The healthy pattern was positively correlated to dietary fibre (r 0.51-0.58) and n-3 (r 0.25-0.31) (all P<0.0001), and had a higher nutrient density of folate, vitamin D and Se. The Swedish traditional and the light-meal pattern were positively correlated to added sugar (r 0.20-0.25) and the Swedish traditional also to SFA (r 0.13-0.21) (all P<0.0001); both patterns were in general negatively correlated to micronutrients. Dietary pattern scores were associated with, for example, age, physical activity, education and income. In conclusion, we identified three major dietary patterns among Swedish adults. The patterns can be further used for examining the association between whole diet and health outcomes. PMID- 26490113 TI - Intrafollicular expression and potential regulatory role of cocaine- and amphetamine-regulated transcript in the ovine ovary. AB - Follicular growth is regulated by a complex interaction of pituitary gonadotropins with local regulatory molecules. Previous studies demonstrated an important role for cocaine- and amphetamine-regulated transcript (CART) in regulation of granulosa cell estradiol production associated with dominant follicle selection in cattle. However, intraovarian expression and actions of CART in other species, including sheep, are not known. The objective of this study was to investigate the expression of CART in sheep follicles and determine the effects of CART on indices of ovine granulosa cell function linked to follicular development. Results demonstrated the expression of CART messenger RNA and prominent intraovarian localization of CART peptide in granulosa cells of sheep follicles. Granulosa cell CART messenger RNA was lower, but follicular fluid estradiol concentrations were higher in large (>5 mm) follicles vs smaller 3- to 5-mm follicles harvested from sheep ovaries of abattoir origin. CART treatment inhibited follicle stimulating hormone-induced estradiol production by cultured ovine granulosal cells and also blocked the follicle stimulating hormone induced increase in granulosa cell numbers. Results demonstrate expression of CART in sheep follicular tissues and suggest potential biological actions of CART, which are inhibitory to ovine follicular growth and development. PMID- 26490114 TI - Regulation and localization of vascular endothelial growth factor within the mammary glands during the transition from late gestation to lactation. AB - The vascular network within the developing mammary gland (MG) grows in concert with the epithelium to prepare for lactation, although the mechanisms coordinating this vascular development are unresolved. Vascular endothelial growth factor A (VEGF-A) mediates angiogenesis and vascular permeability in the MG during pregnancy and lactation, where its expression is upregulated by prolactin. Given our previous finding that late-gestational hyperprolactinemia induced by domperidone (DOM) increased subsequent milk yield from gilts, we sought to establish changes in vascular development during late gestation and lactation in the MGs of these pigs and determine whether DOM altered MG angiogenesis and the factors regulating it. Gilts received either no treatment (n = 6) or DOM (n = 6) during late gestation, then had their MG biopsied from late gestation through lactation to assess microvessel density, VEGF-A distribution and messenger RNA expression, and aquaporin (AQP) gene expression. Microvessel density in the MG was unchanged during gestation then increased between days 2 and 21 of lactation (P < 0.05). The local expression of messenger RNA for VEGF A120, VEGF-A147, VEGF-A164, VEGF-A164b, VEGF-A188, VEGF receptors-1 and -2, and AQP1 and AQP3 all generally increased during the transition from gestation to lactation (P < 0.05). Immunostaining localized VEGF-A to the apical cytoplasm of secretory epithelial cells, consistent with a far greater concentration of VEGF-A in colostrum and/or milk vs plasma (P < 0.0001). There was no effect of DOM on any of the variables analyzed. In summary, we found that vascular development in the MG increases during lactation in first-parity gilts and that VEGF-A is a part of the mammary secretome. Although late-gestational hyperprolactinemia increases milk yield, there was no evidence that it altered vascular development. PMID- 26490115 TI - PLCbeta3 mediates cortactin interaction with WAVE2 in MCP1-induced actin polymerization and cell migration. AB - Monocyte chemotactic protein 1 (MCP1) stimulates vascular smooth muscle cell (VSMC) migration in vascular wall remodeling. However, the mechanisms underlying MCP1-induced VSMC migration have not been understood. Here we identify the signaling pathway associated with MCP1-induced human aortic smooth muscle cell (HASMC) migration. MCP1, a G protein-coupled receptor agonist, activates phosphorylation of cortactin on S405 and S418 residues in a time-dependent manner, and inhibition of its phosphorylation attenuates MCP1-induced HASMC G actin polymerization, F-actin stress fiber formation, and migration. Cortactin phosphorylation on S405/S418 is found to be critical for its interaction with WAVE2, a member of the WASP family of cytoskeletal regulatory proteins required for cell migration. In addition, the MCP1-induced cortactin phosphorylation is dependent on PLCbeta3-mediated PKCdelta activation, and siRNA-mediated down regulation of either of these molecules prevents cortactin interaction with WAVE2, affecting G-actin polymerization, F-actin stress fiber formation, and HASMC migration. Upstream, MCP1 activates CCR2 and Galphaq/11 in a time-dependent manner, and down-regulation of their levels attenuates MCP1-induced PLCbeta3 and PKCdelta activation, cortactin phosphorylation, cortactin-WAVE2 interaction, G actin polymerization, F-actin stress fiber formation, and HASMC migration. Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. PMID- 26490116 TI - The alpha-arrestin ARRDC3 mediates ALIX ubiquitination and G protein-coupled receptor lysosomal sorting. AB - The sorting of G protein-coupled receptors (GPCRs) to lysosomes is critical for proper signaling and cellular responses. We previously showed that the adaptor protein ALIX regulates lysosomal degradation of protease-activated receptor-1 (PAR1), a GPCR for thrombin, independent of ubiquitin-binding ESCRTs and receptor ubiquitination. However, the mechanisms that regulate ALIX function during PAR1 lysosomal sorting are not known. Here we show that the mammalian alpha-arrestin arrestin domain-containing protein-3 (ARRDC3) regulates ALIX function in GPCR sorting via ubiquitination. ARRDC3 colocalizes with ALIX and is required for PAR1 sorting at late endosomes and degradation. Depletion of ARRDC3 by small interfering RNA disrupts ALIX interaction with activated PAR1 and the CHMP4B ESCRT-III subunit, suggesting that ARRDC3 regulates ALIX activity. We found that ARRDC3 is required for ALIX ubiquitination induced by activation of PAR1. A screen of nine mammalian NEDD4-family E3 ubiquitin ligases revealed a critical role for WWP2. WWP2 interacts with ARRDC3 and not ALIX. Depletion of WWP2 inhibited ALIX ubiquitination and blocked ALIX interaction with activated PAR1 and CHMP4B. These findings demonstrate a new role for the alpha-arrestin ARRDC3 and the E3 ubiquitin ligase WWP2 in regulation of ALIX ubiquitination and lysosomal sorting of GPCRs. PMID- 26490089 TI - Effects of calcium channel blocker-based combinations on intra-individual blood pressure variability: post hoc analysis of the COPE trial. AB - Visit-to-visit blood pressure (BP) variability is an important predictor of stroke. However, which antihypertensive drug combination is better at reducing visit-to-visit BP variability and therefore at reducing stroke incidence remains uncertain. We have previously reported that the dihydropyridine calcium channel blocker benidipine combined with a beta-blocker appeared to be less beneficial in reducing the risk of stroke than a combination of benidipine and thiazide. Here, we further compare the visit-to-visit BP variability among three benidipine-based regimens, namely angiotensin receptor blocker (ARB), beta-blocker and thiazide combinations. The present post hoc analysis included 2983 patients without cardiovascular events or death during the first 18 months after randomization. We compared the BP variability (defined as the s.d. and the coefficient of variation (CV)), maximum systolic BP (SBP) and diastolic BP (DBP) of the clinic mean on treatment BPs obtained at 6-month intervals, starting 6 months after the treatment initiation, among the 3 treatments (ARB, n=1026; beta-blocker, n=966; thiazide, n=991). During the first 6-36 months after randomization, both the s.d. and CV-BPs were lower in the benidipine-thiazide group than in the benidipine beta-blocker group (s.d.-SBP, P=0.019; s.d.-DBP, P=0.030; CV-SBP, P=0.012; CV DBP, P=0.022). The s.d. and CV in the ARB group did not reach statistical significance compared with the other two groups. The maximum BPs did not differ among the three treatments. These findings suggest that the benidipine-thiazide combination may reduce visit-to-visit BP variability more than the benidipine beta-blocker combination. PMID- 26490117 TI - CARTS biogenesis requires VAP-lipid transfer protein complexes functioning at the endoplasmic reticulum-Golgi interface. AB - Vesicle-associated membrane protein-associated protein (VAP) is an endoplasmic reticulum (ER)-resident integral membrane protein that controls a nonvesicular mode of ceramide and cholesterol transfer from the ER to the Golgi complex by interacting with ceramide transfer protein and oxysterol-binding protein (OSBP), respectively. We report that VAP and its interacting proteins are required for the processing and secretion of pancreatic adenocarcinoma up-regulated factor, whose transport from the trans-Golgi network (TGN) to the cell surface is mediated by transport carriers called "carriers of the trans-Golgi network to the cell surface" (CARTS). In VAP-depleted cells, diacylglycerol level at the TGN was decreased and CARTS formation was impaired. We found that VAP forms a complex with not only OSBP but also Sac1 phosphoinositide phosphatase at specialized ER subdomains that are closely apposed to the trans-Golgi/TGN, most likely reflecting membrane contact sites. Immobilization of ER-Golgi contacts dramatically reduced CARTS production, indicating that association-dissociation dynamics of the two membranes are important. On the basis of these findings, we propose that the ER-Golgi contacts play a pivotal role in lipid metabolism to control the biogenesis of transport carriers from the TGN. PMID- 26490118 TI - Autophagy protects against de novo formation of the [PSI+] prion in yeast. AB - Prions are self-propagating, infectious proteins that underlie several neurodegenerative diseases. The molecular basis underlying their sporadic formation is poorly understood. We show that autophagy protects against de novo formation of [PSI(+)], which is the prion form of the yeast Sup35 translation termination factor. Autophagy is a cellular degradation system, and preventing autophagy by mutating its core components elevates the frequency of spontaneous [PSI(+)] formation. Conversely, increasing autophagic flux by treating cells with the polyamine spermidine suppresses prion formation in mutants that normally show a high frequency of de novo prion formation. Autophagy also protects against the de novo formation of another prion, namely the Rnq1/[PIN(+)] prion, which is not related in sequence to the Sup35/[PSI(+)] prion. We show that growth under anaerobic conditions in the absence of molecular oxygen abrogates Sup35 protein damage and suppresses the high frequency of [PSI(+)] formation in an autophagy mutant. Autophagy therefore normally functions to remove oxidatively damaged Sup35, which accumulates in cells grown under aerobic conditions, but in the absence of autophagy, damaged/misfolded Sup35 undergoes structural transitions favoring its conversion to the propagatable [PSI(+)] form. PMID- 26490121 TI - NUT carcinoma of the thorax: Case report and review of the literature. AB - NUT (nuclear protein in testis) carcinomas are exceedingly rare neoplasms with specific molecular alterations and often follow a devastating course. Thus, a precise early diagnosis is of utmost importance. Known from the sinonasal region for years, the new 2015 WHO classification now also recognizes the existence of this entity in the thorax, specifically the lungs and the mediastinum. However, yet available data on this entity are sparse. Here, we report on a 31 years old female patient with an aggressively growing tumor localized in the median line that was initially sampled by endobronchial ultrasound-guided transbronchial biopsies. Pathological assessment of the biopsy specimens revealed a NUT carcinoma with typical morphological characteristics and an uncommon NUT translocation variant with a NSD3-NUT fusion. Diagnosis was further confirmed in the subsequent resection specimen. We describe specific clinical, histomorphological, and molecular characteristics of this tumor and provide a comprehensive review of the current literature on these rare neoplasms. PMID- 26490120 TI - Oligomerization and endocytosis of Hedgehog is necessary for its efficient exovesicular secretion. AB - Hedgehog (Hh) is a secreted morphogen involved in both short- and long-range signaling necessary for tissue patterning during development. It is unclear how this dually lipidated protein is transported over a long range in the aqueous milieu of interstitial spaces. We previously showed that the long-range signaling of Hh requires its oligomerization. Here we show that Hh is secreted in the form of exovesicles. These are derived by the endocytic delivery of cell surface Hh to multivesicular bodies (MVBs) via an endosomal sorting complex required for transport (ECSRT)-dependent process. Perturbations of ESCRT proteins have a selective effect on long-range Hh signaling in Drosophila wing imaginal discs. Of importance, oligomerization-defective Hh is inefficiently incorporated into exovesicles due to its poor endocytic delivery to MVBs. These results provide evidence that nanoscale organization of Hh regulates the secretion of Hh on ESCRT derived exovesicles, which in turn act as a vehicle for long-range signaling. PMID- 26490122 TI - Transcutaneous Bilirubinometry for Preterm Infants-Are There More Things to Consider? PMID- 26490119 TI - Caenorhabditis elegans polo-like kinase PLK-1 is required for merging parental genomes into a single nucleus. AB - Before the first zygotic division, the nuclear envelopes of the maternal and paternal pronuclei disassemble, allowing both sets of chromosomes to be incorporated into a single nucleus in daughter cells after mitosis. We found that in Caenorhabditis elegans, partial inactivation of the polo-like kinase PLK-1 causes the formation of two nuclei, containing either the maternal or paternal chromosomes, in each daughter cell. These two nuclei gave rise to paired nuclei in all subsequent cell divisions. The paired-nuclei phenotype was caused by a defect in forming a gap in the nuclear envelopes at the interface between the two pronuclei during the first mitotic division. This was accompanied by defects in chromosome congression and alignment of the maternal and paternal metaphase plates relative to each other. Perturbing chromosome congression by other means also resulted in failure to disassemble the nuclear envelope between the two pronuclei. Our data further show that PLK-1 is needed for nuclear envelope breakdown during early embryogenesis. We propose that during the first zygotic division, PLK-1-dependent chromosome congression and metaphase plate alignment are necessary for the disassembly of the nuclear envelope between the two pronuclei, ultimately allowing intermingling of the maternal and paternal chromosomes. PMID- 26490123 TI - Neurodevelopmental Profile, Growth, and Psychosocial Environment of Preterm Infants with Difficult Feeding Behavior at Age 2 Years. AB - OBJECTIVE: To examine the association of difficult feeding behaviors in very preterm infants at age 2 years with growth and neurodevelopmental outcomes and family factors and functioning. STUDY DESIGN: Eighty children born <=30 weeks gestation were studied from birth until age 2 years. Feeding difficulties were assessed using the Eating Subscale of the Infant-Toddler Social Emotional Assessment at age 2 years, along with growth measurement and developmental testing. Maternal mental health and family factors were assessed using standardized questionnaires. ANOVA and chi(2) analyses were performed to determine associations between feeding difficulties and growth, neurodevelopmental outcomes, and family characteristics. RESULTS: Twenty-one children (26%) were at risk for feeding difficulties, and an additional 18 (23%) had definite feeding difficulties at age 2 years. Those with feeding difficulties were more likely to be subject to a range of neurodevelopmental problems, including impaired cognition (P = .02), language (P = .04), motor (P = .01), and socioemotional (P < .007) skills. Compared with the parents of children with fewer feeding difficulties, parents of the children with feeding difficulties had higher parenting stress (P = .02) and reported more difficulty managing their child's behavior (P = .002) and more frequent parent-child interaction problems (P = .002). No associations were found between difficult feeding behaviors and growth, maternal mental health, or family factors. CONCLUSION: Difficult feeding behaviors in children born very preterm appear to be highly comorbid with other developmental and family challenges, including neurodevelopmental impairment and parent-child interaction difficulties. Focusing on improving feeding skills, in conjunction with supporting positive parent-child interactions, may be beneficial for improving outcomes. PMID- 26490124 TI - Biomarkers of Insulin for the Diagnosis of Hyperinsulinemic Hypoglycemia in Infants and Children. AB - OBJECTIVE: To evaluate thresholds of various biomarkers for defining excess insulin activity to recognize congenital hyperinsulinism. STUDY DESIGN: This was a retrospective chart review of diagnostic fasting tests in children with ketotic hypoglycemia (n = 30) and genetically/pathology confirmed congenital hyperinsulinism (n = 28). Sensitivity and specificity for congenital hyperinsulinism were determined for plasma insulin, beta-hydroxybutyrate, free fatty acids (FFA), C-peptide, insulin-like growth factor binding protein-1 (IGFBP 1), and the glycemic response to glucagon (through the glucagon stimulation test [GST]) at the time of hypoglycemia. RESULTS: Only 23 of the 28 subjects with congenital hyperinsulinism had detectable insulin (median, 6.7 MUIU/mL), and insulin was undetectable in all subjects with ketotic hypoglycemia. Compared with ketotic hypoglycemia, subjects with congenital hyperinsulinism had higher GST values (57 vs 13 mg/dL; DeltaGST >=30 mg/dL in 24 of 27 subjects with congenital hyperinsulinism vs 0 of 30 subjects with ketotic hypoglycemia) and C-peptide levels (1.55 vs 0.11 ng/mL), with lower levels of FFA (0.82 vs 2.51 mM) and IGFBP 1 (59.5 vs 634 ng/mL). At the time of hypoglycemia, the upper limits of beta hydroxybutyrate and FFA in subjects with congenital hyperinsulinism were higher than reported previously (beta-hydroxybutyrate <1.8 mM and FFA <1.7 mM), providing the best sensitivity for congenital hyperinsulinism vs ketotic hypoglycemia. A C-peptide level >=0.5 ng/mL was 89% sensitive and 100% specific, and an IGFBP-1 level <=110 ng/mL was 85% sensitive and 96.6% specific. CONCLUSION: Because low or undetectable insulin level during hypoglycemia does not exclude the diagnosis of hyperinsulinism, C-peptide and IGFBP-1 may inform the diagnosis of congenital hyperinsulinism. In this group of children with well defined congenital hyperinsulinism, thresholds for "suppressed" beta hydroxybutyrate and FFA are higher than previously reported levels. PMID- 26490125 TI - A Need for Better Studies to Identify Those Populations at Greatest Risk of a Pollutant-Related Health Effect. PMID- 26490126 TI - Impact of Continuous Capnography in Ventilated Neonates: A Randomized, Multicenter Study. AB - OBJECTIVE: To compare the time spent within a predefined safe range of CO2 (30-60 mmHg) during conventional ventilation between infants who were monitored with distal end-tidal CO2 (dETCO2, or capnography) and those who were not. STUDY DESIGN: For this randomized, controlled multicenter study, ventilated infants with a double-lumen endotracheal tube were randomized to 1 of 2 groups: the open (monitored) group, in which data from the capnograph were recorded, displayed to the medical team, and used for patient care, and the masked group, in which data from the capnograph were recorded. However, the measurements were masked and not available for patient care. dETCO2 was compared with PaCO2 measurements recorded for patient care. RESULTS: Fifty-five infants (25 open, 30 masked) participated in the study (median gestational age, 28.6 weeks; range, 23.5-39.0 weeks). The 2 groups were comparable. dETCO2 was in good correlation (r = 0.73; P < .001) and adequate agreement (mean +/- SD of the difference, 3.0 +/- 8.5 mmHg) with PaCO2. Compared with infants in the masked group, those in the monitored group had significantly (P = .03) less time with an unsafe dETCO2 level (high: 3.8% vs 8.8% or low: 3.8% vs 8.9%). The prevalence of intraventricular hemorrhage or periventricular leukomalacia rate was lower in the monitored group (P = .02) and was significantly (P < .05) associated with the independent factors dETCO2 monitoring and gestational age. CONCLUSION: Continuous dETCO2 monitoring improved control of CO2 levels within a safe range during conventional ventilation in a neonatal intensive care unit. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01572272. PMID- 26490127 TI - Treating Pain in Preterm Infants: Moving from Opioids to Acetaminophen. PMID- 26490128 TI - Helping Hospitalized Patients with Hypertension: The Case for Hydralazine. PMID- 26490129 TI - Obesity, Vascular Changes, and the Development of Atherosclerosis. PMID- 26490131 TI - Successful Embolization of a Huge Hepatic Artery Pseudoaneurysm after Blunt Abdominal Trauma. PMID- 26490130 TI - Low Serum Magnesium Levels and Its Association with High Blood Pressure in Children. AB - OBJECTIVE: To evaluate the association of hypomagnesemia with prehypertension (preHTN) and hypertension in children. STUDY DESIGN: A total of 3954 apparently healthy Mexican children were enrolled in a cross-sectional study. Exclusion criteria were type 2 diabetes; hepatic, renal, or endocrine disease; impaired fasting glucose; chronic diarrhea; and intake of vitamins or magnesium supplements in the previous 6 months. preHTN was defined by systolic and/or diastolic blood pressure >=90th to <95th percentile and hypertension by systolic and/or diastolic blood pressure >=95th percentile, according to age, sex, and height percentile. Hypomagnesemia was defined by serum magnesium concentration <1.8 mg/dL (<0.74 mmol/L). To control for potential sources of bias related to age, participants were allocated into 2 groups, aged 6-10 years and 11-15 years. RESULTS: The prevalence of preHTN and hypertension was 12.2% and 6.4%, respectively, in children aged 6-10 years and 13.9% and 10.6% in those aged 11-15 years. Hypomagnesemia was identified in 59 children with preHTN (27.3%) and 52 (45.6%) with hypertension in the 6-10 year age group, and in 115 children with preHTN (36.0%) and 109 (49.6%) with hypertension in the 11-15 year age group. Adjusted multiple logistic regression analysis showed that in children in both age groups, hypomagnesemia was associated with both preHTN (6-10 years: OR, 2.18, P < .0005; 11-15 years: OR, 1.38, P = .018) and hypertension (6-10 years: OR, 4.87, P < .0005; 11-15 years: OR, 1.83, P = .0002). CONCLUSION: Our results indicate that serum magnesium level <1.8 mg/dL is significantly associated with preHTN and hypertension in apparently healthy children. PMID- 26490133 TI - Bioinspired superhydrophobic surfaces, fabricated through simple and scalable roll-to-roll processing. AB - A simple, scalable, non-lithographic, technique for fabricating durable superhydrophobic (SH) surfaces, based on the fingering instabilities associated with non-Newtonian flow and shear tearing, has been developed. The high viscosity of the nanotube/elastomer paste has been exploited for the fabrication. The fabricated SH surfaces had the appearance of bristled shark skin and were robust with respect to mechanical forces. While flow instability is regarded as adverse to roll-coating processes for fabricating uniform films, we especially use the effect to create the SH surface. Along with their durability and self-cleaning capabilities, we have demonstrated drag reduction effects of the fabricated films through dynamic flow measurements. PMID- 26490134 TI - Vertebral Augmentation for Osteoporotic Compression Fractures. AB - Vertebral augmentation procedures such as vertebroplasty and kyphoplasty were developed to reduce pain and improve quality of life for patients with osteoporotic vertebral compression fractures. However, the use of vertebral augmentation has been debated and questioned since its inception. This article addresses some of these issues. PMID- 26490132 TI - Growth Asymmetry, Head Circumference, and Neurodevelopmental Outcomes in Infants with Single Ventricles. AB - OBJECTIVE: To assess the variability in asymmetric growth and its association with neurodevelopment in infants with single ventricle (SV). STUDY DESIGN: We analyzed weight-for-age z-score minus head circumference-for-age z-score (HCAZ), relative head growth (cm/kg), along with individual growth variables in subjects prospectively enrolled in the Infant Single Ventricle Trial. Associations between growth indices and scores on the Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) of the Bayley Scales of Infant Development-II (BSID-II) at 14 months were assessed. RESULTS: Of the 230 subjects enrolled in the Infant Single Ventricle trial, complete growth data and BSID-II scores were available in 168 (73%). Across the cohort, indices of asymmetric growth varied widely at enrollment and before superior cavopulmonary connection (SCPC) surgery. BSID-II scores were not associated with these asymmetry indices. In bivariate analyses, greater pre-SCPC HCAZ correlated with higher MDI (r = 0.21; P = .006) and PDI (r = 0.38; P < .001) and a greater HCAZ increase from enrollment to pre-SCPC with higher PDI (r = 0.15; P = .049). In multivariable modeling, pre-SCPC HCAZ was an independent predictor of PDI (P = .03), but not MDI. CONCLUSION: In infants with SV, growth asymmetry was not associated with neurodevelopment at 14 months, but pre-SCPC HCAZ was associated with PDI. Asymmetric growth, important in other high risk infants, is not a brain-sparing adaptation in infants with SV. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00113087. PMID- 26490135 TI - An integrated linkage map reveals candidate genes underlying adaptive variation in Chinook salmon (Oncorhynchus tshawytscha). AB - Salmonids are an important cultural and ecological resource exhibiting near worldwide distribution between their native and introduced range. Previous research has generated linkage maps and genomic resources for several species as well as genome assemblies for two species. We first leveraged improvements in mapping and genotyping methods to create a dense linkage map for Chinook salmon Oncorhynchus tshawytscha by assembling family data from different sources. We successfully mapped 14 620 SNP loci including 2336 paralogs in subtelomeric regions. This improved map was then used as a foundation to integrate genomic resources for gene annotation and population genomic analyses. We anchored a total of 286 scaffolds from the Atlantic salmon genome to the linkage map to provide a framework for the placement 11 728 Chinook salmon ESTs. Previously identified thermotolerance QTL were found to colocalize with several candidate genes including HSP70, a gene known to be involved in thermal response, as well as its inhibitor. Multiple regions of the genome with elevated divergence between populations were also identified, and annotation of ESTs in these regions identified candidate genes for fitness related traits such as stress response, growth and behaviour. Collectively, these results demonstrate the utility of combining genomic resources with linkage maps to enhance evolutionary inferences. PMID- 26490136 TI - Identification of novel and conserved microRNAs in Panax notoginseng roots by high-throughput sequencing. AB - BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNAs that are important regulators of gene expression, and play major roles in plant development and their response to the environment. Root extracts from Panax notoginseng contain triterpene saponins as their principal bioactive constituent, and demonstrate medicinal properties. To investigate the novel and conserved miRNAs in P. notoginseng, three small RNA libraries constructed from 1-, 2-, and 3-year-old roots in which root saponin levels vary underwent high-throughput sequencing. METHODS: P. notoginseng roots, purified from 1-, 2-, and 3-year-old roots, were extracted for RNA, respectively. Three small libraries were constructed and subjected to next generation sequencing. RESULTS: Sequencing of the three libraries generated 67,217,124 clean reads from P. notoginseng roots. A total of 316 conserved miRNAs (belonging to 67 miRNA families and one unclassified family) and 52 novel miRNAs were identified. MIR156 and MIR166 were the largest miRNA families, while miR156i and miR156g showed the highest abundance of miRNA species. Potential miRNA target genes were predicted and annotated using Cluster of Orthologous Groups, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes. Comparing these miRNAs between root samples revealed 33 that were differentially expressed between 2- and 1-year-old roots (8 increased, 25 decreased), 27 differentially expressed between 3- and 1-year-old roots (7 increased, 20 decreased), and 29 differentially expressed between 3- and 2-year old roots (8 increased, 21 decreased). Two significantly differentially expressed miRNAs and four miRNAs predicted to target genes involved in the terpenoid backbone biosynthesis pathway were selected and validated by quantitative reverse transcription PCR. Furthermore, the expression patterns of these six miRNAs were analyzed in P. notoginseng roots, stems, and leaves at different developmental stages. CONCLUSIONS: This study identified a large number of P. notoginseng miRNAs and their target genes, functional annotations, and gene expression patterns. It provides the first known miRNA profiles of the P. notoginseng root development cycle. PMID- 26490137 TI - Spatial heterogeneity in projected leprosy trends in India. AB - BACKGROUND: Leprosy is caused by infection with Mycobacterium leprae and is characterized by peripheral nerve damage and skin lesions. The disease is classified into paucibacillary (PB) and multibacillary (MB) leprosy. The 2012 London Declaration formulated the following targets for leprosy control: (1) global interruption of transmission or elimination by 2020, and (2) reduction of grade-2 disabilities in newly detected cases to below 1 per million population at a global level by 2020. Leprosy is treatable, but diagnosis, access to treatment and treatment adherence (all necessary to curtail transmission) represent major challenges. Globally, new case detection rates for leprosy have remained fairly stable in the past decade, with India responsible for more than half of cases reported annually. METHODS: We analyzed publicly available data from the Indian Ministry of Health and Family Welfare, and fit linear mixed-effects regression models to leprosy case detection trends reported at the district level. We assessed correlation of the new district-level case detection rate for leprosy with several state-level regressors: TB incidence, BCG coverage, fraction of cases exhibiting grade 2 disability at diagnosis, fraction of cases in children, and fraction multibacillary. RESULTS: Our analyses suggest an endemic disease in very slow decline, with substantial spatial heterogeneity at both district and state levels. Enhanced active case finding was associated with a higher case detection rate. CONCLUSIONS: Trend analysis of reported new detection rates from India does not support a thesis of rapid progress in leprosy control. PMID- 26490138 TI - Number of positive blood cultures, biofilm formation, and adhesin genes in differentiating true coagulase-negative staphylococci bacteremia from contamination. AB - The significance of the number of coagulase-negative staphylococci (CNS)-positive blood cultures remains obscure in regards to determining true bacteremia versus contamination. The goal of this study was to determine the predictors of real CNS bloodstream infection among intensive care unit (ICU) patients. ICU patients with at least one CNS-positive blood culture were identified from the microbiology database. Biofilm formation was tested by glass tube and microtiter plate assay. mecA gene, ica operon genes (icaA, icaB, icaD), and adhesin genes (aap, bap, atlE, fbe, fnbA) were detected by polymerase chain reaction (PCR). CNS were recovered from 120 septic episodes, 20 of which were true CNS bacteremias, whereas from the remaining 100 episodes, the isolated CNS were characterized as contaminants. The number of positive blood cultures was significantly associated with true CNS bacteremia. Nineteen true bacteremic Staphylococcus epidermidis strains were compared to 38 contaminants. Biofilm synthesis was documented in 37 isolates associated with the presence of the ica operon (p = 0.048). There were 39, 26, 38, 21, and 10 strains positive for the presence of atlE, bap, fbe, aap, and fnbA genes, respectively. Rifampicin resistance, absence of severe sepsis, number of S. epidermidis-positive blood cultures, and absence of the bap gene were independently associated with true S. epidermidis bacteremia as compared to contaminant strains. The number of positive blood cultures is associated with true CNS bacteremia. The presence of adhesin genes may play a role in differentiating true infection from contamination, whereas absence of the bap gene is associated with true S. epidermidis bacteremia. PMID- 26490139 TI - Low rates of endocarditis in healthcare-associated Staphylococcus aureus bacteremia suggest that echocardiography might not always be required. AB - Healthcare-associated Staphylococcus aureus bacteremia (HA-SAB) is an increasingly frequently observed complication of medical treatment. Current guidelines recommend evaluation with echocardiography and preferably transesophageal echocardiography for the exclusion of infectious endocarditis (IE). We performed a retrospective analysis of all patients with HA-SAB between 1 January 2007 and 31 July 2012. Patients were divided into those with a high degree of clinical suspicion of IE (prosthetic intracardiac device, hemodialysis or positive blood cultures for 4 days or more) or those with a low degree of clinical suspicion of IE (absence of high-risk features based on previous literature as strong indicators of endocarditis). Three hundred and fifty-eight patients with HA-SAB were evaluated to determine the prevalence of IE, including 298 (83 %) who had echocardiography. Fourteen patients (4 %) had a final diagnosis of IE after echocardiography. In the group with a high degree of clinical suspicion 11 out of 84 patients (13 %) had IE. In the group with a low degree of clinical suspicion group 3 out 274 patients (1.1 %) had IE. HA-SAB has a low rate of IE, especially in the absence of high-risk features such as prolonged bacteremia, intracardiac prosthetic devices, and hemodialysis. Echocardiographic imaging in this low-risk population of patients is rarely helpful and may generally be avoided, although careful clinical follow-up is warranted. Patients with HA-SAB who have mechanical valves, intracardiac devices, prolonged bacteremia or dialysis dependency have a high incidence of IE and should be evaluated thoroughly using echocardiography. PMID- 26490140 TI - Temporal changes in blood-brain barrier permeability and cerebral perfusion in lacunar/subcortical ischemic stroke. AB - BACKGROUND: Cerebral microvascular abnormality is frequently associated with lacunar and subcortical ischemic lesions. We performed acute and follow-up CT perfusion scans over the first 3 months after ischemic stroke to investigate disturbances of the blood-brain barrier (BBB) and cerebral perfusion in patients with lacunar/subcortical lesions compared to those with cortical lesions alone. METHODS: Thirty-one patients with lacunar/subcortical infarct (n = 14) or with cortical large vessel infarct (n = 17) were recruited and underwent a CT perfusion study at admission, 24 h, 7 days and 3 months after stroke using a two phase imaging protocol. Functional maps of BBB permeability surface area product (BBB-PS), cerebral blood flow (CBF) and blood volume (CBV) at follow-up were co registered with those at admission, and the measurements in non-infarcted ipsilateral basal ganglia and thalamus were compared within each group and between the two groups. RESULTS: For the lacunar/subcortical group, BBB-PS within non-infarcted ipsilateral basal ganglia and thalamus peaked at day 7 compared to all other time points, and was significantly higher than the cortical group at day 7 and month 3. The CBF and CBV in the same region were significantly lower at admission and transient hyperemia was seen at day 7 in the lacunar/subcortical group. CONCLUSION: Disturbed BBB-PS and compromised cerebral perfusion over the first 3 months post stroke were shown in the non-infarcted basal ganglia and thalamus of lacunar/subcortical stroke using CT perfusion. Future studies are required to elucidate the relationship of post-stroke BBB disturbances to chronic cognitive impairment. PMID- 26490141 TI - The complete mitochondrial genome of Anoplocephala perfoliata, the first representative for the family Anoplocephalidae. AB - BACKGROUND: Mitochondrial (mt) genome sequences are widely used to understand phylogenetic relationships among parasites. However, no complete mt genome sequence is available in the family Anoplocephalidae to date. This study sequenced and annotated the complete mt genome of Anoplocephala perfoliata (Anoplocephalidae), and investigated its phylogenetic relationships with other species from the families Hymenolepididae, Dipylidiidae and Taeniidae of the order Cyclophyllidea using the amino acid sequences of the 12 proteins in their mt genomes. METHODS: The complete mt genome of A. perfoliata was amplified by Long-range PCR, sequenced using primer walking and annotated by comparing with those of other cestodes. Its phylogenetic relationship with the species from the families Hymenolepididae, Dipylidiidae and Taeniidae was inferred using the 12 protein sequences based on Maximum likelihood and Bayesian methods. RESULTS: The complete circular mt genome sequence for A. perfoliata is 14,459 bp in size, and includes 12 protein-coding genes, 2 rRNA genes and 22 tRNA genes. The mt gene arrangement of A. perfoliata is identical to those of previously reported Hymenolepis diminuta (Hymenolepididae) and Dipylidium caninum (Dipylidiidae), but slightly different from those of other taeniids due to an order switch between tRNA(S2) and tRNA(L1). The phylogenetic analyses showed that the Dipylidiidae was more closely related to Anoplocephalidae and Hymenolepididae than to Taeniidae. The relationship among the four families obtained by Maximum likelihood and Bayesian inferences based on predicted amino acid sequences of protein-coding genes is consistent with that based on their mt gene arrangement similarities. CONCLUSIONS: This study determined the first mt genome for the family Anoplocephalidae, providing rich sources for selecting useful molecular markers for ecological and phylogenetic studies. Analyses on mt genome sequences of the four families of cestodes provide novel insights into their phylogenetic relationships. Of course, more taxon sampling is necessary for future phylogenetic studies of these cestodes using mt genome sequences. PMID- 26490142 TI - Integration of Wearable Solutions in AAL Environments with Mobility Support. AB - The overall demographic profile of current societies point to a significant growth of the elderly people. Associated with the increase of the average hope of life and consequent increase in chronic diseases, there is the need for protection and daily care. Increasing investments in technology, such as Ambient Assisted Living (AAL) solutions, promote the quality of live extending the time people can live in their desired environment. This paper proposes the design, deployment, and real testbed of an e-health wearable monitoring system based on the integration of several AAL tools and platforms for elderly's bio-signals monitoring. This solution includes electrocardiography (ECG), respiration rate, beats per minute, body temperature, and falls detention and notification. The paper also describes, in detail, the real pilot and analyzes some early results concerning the users quality of experience, and the found results are very promising. PMID- 26490143 TI - A Semantic Big Data Platform for Integrating Heterogeneous Wearable Data in Healthcare. AB - Advances supported by emerging wearable technologies in healthcare promise patients a provision of high quality of care. Wearable computing systems represent one of the most thrust areas used to transform traditional healthcare systems into active systems able to continuously monitor and control the patients' health in order to manage their care at an early stage. However, their proliferation creates challenges related to data management and integration. The diversity and variety of wearable data related to healthcare, their huge volume and their distribution make data processing and analytics more difficult. In this paper, we propose a generic semantic big data architecture based on the "Knowledge as a Service" approach to cope with heterogeneity and scalability challenges. Our main contribution focuses on enriching the NIST Big Data model with semantics in order to smartly understand the collected data, and generate more accurate and valuable information by correlating scattered medical data stemming from multiple wearable devices or/and from other distributed data sources. We have implemented and evaluated a Wearable KaaS platform to smartly manage heterogeneous data coming from wearable devices in order to assist the physicians in supervising the patient health evolution and keep the patient up-to date about his/her status. PMID- 26490144 TI - iMStrong: Deployment of a Biosensor System to Detect Cocaine Use. AB - Biosensor systems are increasingly promoted for use in behavioral interventions. Portable biosensors might offer advancement over self-report use and can provide improved opportunity for detection and intervention in patients undergoing drug treatment programs. Fifteen participants wore a biosensor wristband capable of detecting multiple physiologic markers of sympathetic nervous system (SNS) arousal for 30 days. Urine drug screening and drug use self-report were obtained twice per week. A parameter trajectory description method was applied to capture abrupt changes in magnitude of three measures of SNS activity: Electrodermal activity (EDA), skin temperature and motion. Drug use events detected by the biosensor were verified using a triad of parameters: the biosensor data, urine drug screens, and patient self-report of substance use. Twelve positive cocaine urine screens were identified. Thirteen self-reported episodes of cocaine use were recorded. Distinct episodes with biometric parameters consistent with cocaine use were identified on biosensor data. Eleven potential cocaine use episodes were identified by biosensors that were missed by both self-report and drug screening. Study participants found mobile biosensors to be acceptable, and compliance with the protocol was high. Episodes of cocaine use, as measured by supraphysiologic changes in biophysiometric parameters, were detected by analysis of biosensor data in instances when self-report or drug screening or both failed. Biosensors have substantial potential in detecting substance abuse, in understanding the context of use in real time, and in evaluating the efficacy of behavioral interventions for drug abuse. PMID- 26490145 TI - Mild Depression Detection of College Students: an EEG-Based Solution with Free Viewing Tasks. AB - Depression is a common mental disorder with growing prevalence; however current diagnoses of depression face the problem of patient denial, clinical experience and subjective biases from self-report. By using a combination of linear and nonlinear EEG features in our research, we aim to develop a more accurate and objective approach to depression detection that supports the process of diagnosis and assists the monitoring of risk factors. By classifying EEG features during free viewing task, an accuracy of 99.1%, which is the highest to our knowledge by far, was achieved using kNN classifier to discriminate depressed and non depressed subjects. Furthermore, through correlation analysis, comparisons of performance on each electrode were discussed on the availability of single channel EEG recording depression detection system. Combined with wearable EEG collecting devices, our method offers the possibility of cost effective wearable ubiquitous system for doctors to monitor their patients with depression, and for normal people to understand their mental states in time. PMID- 26490146 TI - Data Division Scheme Based on Homomorphic Encryption in WSNs for Health Care. AB - The use of wireless sensor networks for wearable computing in health care is growing quickly. Numerous applications are already in use, such as blood pressure monitors and heart rate monitors. As such, it is very important for system designers to consider how to protect patient privacy, especially in wireless sensor networks. After studying and analyzing the features of wireless sensor networks in medical systems, a data division scheme was proposed in this paper, provided the advantages of homomorphic encryption. In the proposed scheme, even if a forwarding node is compromised, the attacker will not be able to eavesdrop on the data, resulting in much stronger privacy than existing schemes. Experimental results shows that the scheme provides a good trade off in resources consumed and system security, and is efficient for encrypting or decrypting sensitive medical data. PMID- 26490147 TI - CCS_WHMS: A Congestion Control Scheme for Wearable Health Management System. AB - Wearable computing is becoming a more and more attracting field in the last years thanks to the miniaturisation of electronic devices. Wearable healthcare monitoring systems (WHMS) as an important client of wearable computing technology has gained a lot. Indeed, the wearable sensors and their surrounding healthcare applications bring a lot of benefits to patients, elderly people and medical staff, so facilitating their daily life quality. But from a research point of view, there is still work to accomplish in order to overcome the gap between hardware and software parts. In this paper, we target the problem of congestion control when all these healthcare sensed data have to reach the destination in a reliable manner that avoids repetitive transmission which wastes precious energy or leads to loss of important information in emergency cases, too. We propose a congestion control scheme CCS_WHMS that ensures efficient and fair data delivery while used in the body wearable system part or in the multi-hop inter bodies wearable ones to get the destination. As the congestion detection paradigm is very important in the control process, we do experimental tests to compare between state of the art congestion detection methods, using MICAz motes, in order to choose the appropriate one for our scheme. PMID- 26490148 TI - A Lightweight Encryption Scheme Combined with Trust Management for Privacy Preserving in Body Sensor Networks. AB - With the pervasiveness of smart phones and the advance of wireless body sensor network (BSN), mobile Healthcare (m-Healthcare), which extends the operation of Healthcare provider into a pervasive environment for better health monitoring, has attracted considerable interest recently. However, the flourish of m Healthcare still faces many challenges including information security and privacy preservation. In this paper, we propose a secure and privacy-preserving framework combining with multilevel trust management. In our scheme, smart phone resources including computing power and energy can be opportunistically gathered to process the computing-intensive PHI (personal health information) during m-Healthcare emergency with minimal privacy disclosure. In specific, to leverage the PHI privacy disclosure and the high reliability of PHI process and transmission in m Healthcare emergency, we introduce an efficient lightweight encryption for those users whose trust level is low, which is based on mix cipher algorithms and pair of plain text and cipher texts, and allow a medical user to decide who can participate in the opportunistic computing to assist in processing his overwhelming PHI data. Detailed security analysis and simulations show that the proposed framework can efficiently achieve user-centric privacy protection in m Healthcare system. PMID- 26490149 TI - The Effect of Electrode Designs Based on the Anatomical Heart Location for the Non-Contact Heart Activity Measurement. AB - This research is an extension of a previous research [1] on the different effects of sensor location that is relatively suitable for heart rate sensing. This research aimed to elucidate the causes of wide variations in heart rate measurements from the same sensor position among subjects, as observed in previous research [1], and to enhance designs of the inductive textile electrode to overcome these variations. To achieve this, this study comprised two parts: In part 1, X-ray examinations were performed to determine the cause of the wide variations noted in the findings from previous research [1], and we found that at the same sensor position, the heart activity signal differed with slight differences in the positions of the heart of each subject owing to individual differences in the anatomical heart location. In part 2, three types of dual-loop type textile electrodes were devised to overcome variations in heart location that were confirmed in part 1 of the study. The variations with three types of sensor designs were compared with that with a single-round type of electrode design, by using computer simulation and by performing a t-test on the data obtained from the experiments. We found that the oval-oval shaped, dual-loop-type textile electrode was more suitable than the single round type for determining morphological characteristics as well as for measuring appropriate heart activity signals. Based on these results, the oval-oval, dual-loop-type was a better inductive textile electrode that more effectively overcomes individual differences in heart location during heart activity sensing based on the magnetic induced conductivity principle. PMID- 26490150 TI - Design of QoS-Aware Multi-Level MAC-Layer for Wireless Body Area Network. AB - With the advances in wearable computing and various wireless technologies, there is an increasing trend to outsource body signals from wireless body area network (WBAN) to outside world including cyber space, healthcare big data clouds, etc. Since the environmental and physiological data collected by multimodal sensors have different importance, the provisioning of quality of service (QoS) for the sensory data in WBAN is a critical issue. This paper proposes multiple level based QoS design at WBAN media access control layer in terms of user level, data level and time level. In the proposed QoS provisioning scheme, different users have different priorities, various sensory data collected by different sensor nodes have different importance, while data priority for the same sensor node varies over time. The experimental results show that the proposed multi-level based QoS provisioning solution in WBAN yields better performance for meeting QoS requirements of personalized healthcare applications while achieving energy saving. PMID- 26490151 TI - A Fatigue Measuring Protocol for Wireless Body Area Sensor Networks. AB - As players and soldiers preform strenuous exercises and do difficult and tiring duties, they are usually the common victims of muscular fatigue. Keeping this in mind, we propose FAtigue MEasurement (FAME) protocol for soccer players and soldiers using in-vivo sensors for Wireless Body Area Sensor Networks (WBASNs). In FAME, we introduce a composite parameter for fatigue measurement by setting a threshold level for each sensor. Whenever, any sensed data exceeds its threshold level, the players or soldiers are declared to be in a state of fatigue. Moreover, we use a vibration pad for the relaxation of fatigued muscles, and then utilize the vibrational energy by means of vibration detection circuit to recharge the in-vivo sensors. The induction circuit achieves about 68 % link efficiency. Simulation results show better performance of the proposed FAME protocol, in the chosen scenarios, as compared to an existing Wireless Soccer Team Monitoring (WSTM) protocol in terms of the selected metrics. PMID- 26490152 TI - An Adaptive Sensor Data Segments Selection Method for Wearable Health Care Services. AB - As cloud computing and wearable devices technologies mature, relevant services have grown more and more popular in recent years. The healthcare field is one of the popular services for this technology that adopts wearable devices to sense signals of negative physiological events, and to notify users. The development and implementation of long-term healthcare monitoring that can prevent or quickly respond to the occurrence of disease and accidents present an interesting challenge for computing power and energy limits. This study proposed an adaptive sensor data segments selection method for wearable health care services, and considered the sensing frequency of the various signals from human body, as well as the data transmission among the devices. The healthcare service regulates the sensing frequency of devices by considering the overall cloud computing environment and the sensing variations of wearable health care services. The experimental results show that the proposed service can effectively transmit the sensing data and prolong the overall lifetime of health care services. PMID- 26490153 TI - Reactive oxygen species involved in apoptosis induction of human respiratory epithelial (A549) cells by Streptococcus agalactiae. AB - Streptococcus agalactiae (Group B Streptococcus; GBS) is an important pathogen and is associated with pneumonia, sepsis and meningitis in neonates and adults. GBS infections induce cytotoxicity of respiratory epithelial cells (A549) with generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential (psim). The apoptosis of A549 cells by GBS was dependent on the activation of caspase-3 and caspase-9 with increased pro-apoptotic Bim and Bax molecules and decreased Bcl-2 pro-survival protein. Treatment of infected A549 cells with ROS inhibitors (diphenyleniodonium chloride or apocynin) prevented intracellular ROS production and apoptosis. Consequently, oxidative stress is included among the cellular events leading to apoptosis during GBS human invasive infections. PMID- 26490154 TI - Gamma knife radiosurgery (GKRS) for pineal region tumors: a study of 147 cases. AB - BACKGROUND: The purpose of this study is to evaluate the effectiveness of gamma knife radiosurgery (GKRS) in the treatment of pineal region tumors (PRTs). METHODS: We retrospectively reviewed 147 cases of PRTs primarily treated with GKRS at our hospital between 1999 and 2009. Mean follow-up time was 67 months (range 60.5-100.1). The local tumor control rates (LTCRs) and overall survival rates were calculated to evaluate the results of the GKRS treatment. RESULTS: At 2 months after GKRS, tumor volume was significantly reduced in 91 cases (61.9%). At 6 months, average tumor volume was 4.2 cm(3) as compared to 8.47 cm(3) before GKRS. By 1 year after GKRS, the tumor completely disappeared in 57 patients. Fourteen patients underwent second treatment, and one patient had third treatment. The overall survival rates were 72.1% at 3 years and 66.7% at 5 years for all patients and 62.4% at 3 years and 54.5% at 5 years for germ cell tumors (GCTs). The LTCRs were 94.30% at 3 years and 90.80% at 5 years for all patients and 88.00% at 3 years and 77.27% at 5 years for GCTs. CONCLUSIONS: GKRS is an effective and safe modality that can be widely used to PRTs as the primary therapy. PMID- 26490155 TI - Correlates Between Force and Postural Tremor in Older Individuals with Essential Tremor. AB - Essential tremor (ET) is commonly associated with kinetic tremor. However, other forms of tremor, such as force and postural tremor, may occur in ET with less severity. This study objectively assessed force and postural tremor characteristics in ET with the purpose of identifying the relationships between these tremors. Ten individuals with ET (age 71 +/- 5 years) and ten healthy controls (age 70 +/- 5 years) participated in the study. Force tremor was quantified as fluctuations in index finger abduction force during isometric contractions at 10 % maximum voluntary contraction (MVC) and 60 % MVC. Postural tremor was quantified as index finger acceleration when the subjects held their entire arm unsupported, and when their arm was supported so that only the index finger could move. Time- and frequency-domain parameters were extracted from tremor data, and then correlations within, and between, tremor subtypes were examined. ET force tremor was dependent on contraction intensity whereas postural tremor was unaffected by the level of limb support. Significant correlations existed between frequency components of postural tremor and force tremor amplitude. Force tremor amplitude normalised to the level of contraction intensity correlated to the proportion of power for postural tremor. These correlations were observed for both contraction intensities and both levels of postural support. The proportion of power represents the output of central oscillators in ET patients and therefore correlated well to force tremor. Given that significant relationships existed between spectral features of postural tremor and the overall force tremor amplitude, it is clear that these tremor modalities are not completely independent in older adults with ET. PMID- 26490157 TI - Valley depolarization in monolayer WSe2. AB - We have systematically examined the circular polarization of monolayer WSe2 at different temperature, excitation energy and exciton density. The valley depolarization in WSe2 is experimentally confirmed to be governed by the intervalley electron-hole exchange interaction. More importantly, a non-monotonic dependence of valley circular polarization on the excitation power density has been observed, providing the experimental evidence for the non-monotonic dependence of exciton intervalley scattering rate on the excited exciton density. The physical origination of our experimental observations has been proposed to be in analogy to the D'yakonov-Perel' mechanism that is operative in conventional GaAs quantum well systems. Our experimental results are fundamentally important for well understanding the valley pseudospin relaxation in atomically thin transition metal dichalcogenides. PMID- 26490158 TI - Weathering of a carbon nanotube/epoxy nanocomposite under UV light and in water bath: impact on abraded particles. AB - Weathering processes can influence the surface properties of composites with incorporated nanoparticles. These changes may affect the release behavior of nanoparticles when an abrasion process is applied. Therefore, the influence of two different weathering processes, immersion in water and exposure to UV light, on the properties of abraded particles from a carbon nanotube (CNT)/epoxy nanocomposite was investigated. The investigation included the measurement of the weathering impact on the surface chemistry of the exposed samples, the particle size of abraded particles, the quantity of exposed CNTs in the respirable part of the abraded particles, and the toxicity of abraded particles, measured by in vitro toxicity tests using the THP-1 monocyte-derived macrophages. The results showed that weathering by immersion in water had no influence on the properties of abraded particles. The exposure to UV light caused a degradation of the epoxy on the surface, followed by delamination of an approx. 2.5 MUm thick layer. An increased quantity of exposed CNTs in abraded particles was not found; on the contrary, longer UV exposure times decreased the released fraction of CNTs from 0.6% to 0.4%. The toxicity tests revealed that abraded particles from the nanocomposites did not induce additional acute cytotoxic effects compared to particles from the neat epoxy. PMID- 26490156 TI - Outcomes and second-look arthroscopic evaluation after combined arthroscopic treatment of tibial plateau and tibial eminence avulsion fractures: a 5-year minimal follow-up. AB - BACKGROUND: Tibial eminence avulsion fracture often co-occurs with tibial plateau fracture, which leads to difficult concomitant management. The value of simultaneous arthroscopy-assisted treatment continues to be debated despite its theoretical advantages. We describe a simple arthroscopic suture fixation technique and hypothesize that simultaneous treatment is beneficial. METHODS: Patients with a tibial eminence avulsion fracture and a concurrent tibial plateau fracture who underwent simultaneous arthroscopically assisted treatment between 2005 and 2008 were enrolled in this retrospective study. Second-look arthroscopic evaluation and Rasmussen scores of clinical and radiographic parameters were used to assess simultaneous treatment. RESULTS: Forty-one patients (41 knees) met the inclusion criteria. All 41 fractures were successfully united. All patients had side-to-side differences of less than 3 mm and negative findings in Lachman and pivot-shift tests at their final follow-up. The mean postoperative Rasmussen clinical score was 27.3 (range: 19-30), and the mean radiologic score was 16.5 (range: 12-18). Clinical and radiographic outcomes in 98 % of the patients were good or excellent. There were no complications directly associated with arthroscopy in any patient. CONCLUSIONS: Simultaneous arthroscopic suture fixation of associated tibial eminence avulsion fracture did not interfere with the plates and screws used to stabilize the tibial plateau fracture. It gave the knee joint adequate stability, minimal surgical morbidity, and satisfactory radiographic and clinical outcomes in a minimum follow-up of 5 years and in the arthroscopic second-look assessments. PMID- 26490159 TI - Knoevenagel Adducts as Trimethylenemethane Dipole Surrogates. AB - Knoevenagel adducts derived from readily available acetoxyacetone and malonic acid derivatives served as trimethylenemethane surrogates for formal 1,3 difunctionalization through a sequence of selective gamma-deprotonation/alpha alkylation and palladium(0)-catalyzed allylic alkylation. Herein, we report the discovery and development of a three-component 1,3-difunctionalization of Knoevenagel adducts as well as a unique palladium(0)-catalyzed branch-selective allylic alkylation. PMID- 26490160 TI - Authors' reply to De Schryver and colleagues. PMID- 26490161 TI - Nanoscale petrographic and geochemical insights on the origin of the Palaeoproterozoic stromatolitic phosphorites from Aravalli Supergroup, India. AB - Stromatolites composed of apatite occur in post-Lomagundi-Jatuli successions (late Palaeoproterozoic) and suggest the emergence of novel types of biomineralization at that time. The microscopic and nanoscopic petrology of organic matter in stromatolitic phosphorites might provide insights into the suite of diagenetic processes that formed these types of stromatolites. Correlated geochemical micro-analyses of the organic matter could also yield molecular, elemental and isotopic compositions and thus insights into the role of specific micro-organisms among these communities. Here, we report on the occurrence of nanoscopic disseminated organic matter in the Palaeoproterozoic stromatolitic phosphorite from the Aravalli Supergroup of north-west India. Organic petrography by micro-Raman and Transmission Electron Microscopy demonstrates syngeneity of the organic matter. Total organic carbon contents of these stromatolitic phosphorite columns are between 0.05 and 3.0 wt% and have a large range of delta(13) Corg values with an average of -18.50/00 (1sigma = 4.50/00). delta(15) N values of decarbonated rock powders are between -1.2 and +2.70/00. These isotopic compositions point to the important role of biological N2 -fixation and CO2 -fixation by the pentose phosphate pathway consistent with a population of cyanobacteria. Microscopic spheroidal grains of apatite (MSGA) occur in association with calcite microspar in microbial mats from stromatolite columns and with chert in the core of diagenetic apatite rosettes. Organic matter extracted from the stromatolitic phosphorites contains a range of molecular functional group (e.g. carboxylic acid, alcohol, and aliphatic hydrocarbons) as well as nitrile and nitro groups as determined from C- and N-XANES spectra. The presence of organic nitrogen was independently confirmed by a CN(-) peak detected by ToF-SIMS. Nanoscale petrography and geochemistry allow for a refinement of the formation model for the accretion and phototrophic growth of stromatolites. The original microbial biomass is inferred to have been dominated by cyanobacteria, which might be an important contributor of organic matter in shallow-marine phosphorites. PMID- 26490162 TI - Tibial Plateau Leveling Osteotomy Plate Contouring and Proximal Load Screw Angulation Affect Osteotomy Compression. AB - OBJECTIVE: To evaluate the effect of contouring a tibial plateau leveling osteotomy (TPLO) plate, the associated angulation of the dynamic compression plate (DCP) hole relative to the long axis of the tibia, and angulation of the screw relative to the DCP hole on the osteotomy compression generated by load screws in a TPLO model. STUDY DESIGN: In vitro biomechanical study. STUDY POPULATION: Polyoxymethylene (POM) rod and synthetic cortical bone substitute model (n = 9). METHODS: The distal portion of a Slocum TPLO plate was attached to a horizontally positioned POM rod that was connected to a load cell. A segment of synthetic cortical bone substitute was attached to the end mount of the testing frame and adjusted to conform to the angle of the proximal portion of the TPLO plate. A 3.5 mm cortical bone screw was inserted in the proximal DCP hole and tightened to 1.5 Nm. The peak longitudinal load (N) was recorded. Screw insertion and data collection were repeated for proximal plate angles of 0-40 degrees at 5 degrees increments. RESULTS: A significant increase in the compression generated was observed as the plate angle was increased from 0 degrees to 10 degrees . The compression ceased to significantly increase until the plate was bent more than 20 degrees , after which a significant decrease in compression was noted. A marked reduction in the compression generated occurred at plate angles greater than 30 degrees . CONCLUSION: Angulation of the DCP hole and screw insertion angle can have deleterious effects on the magnitude of osteotomy compression. PMID- 26490163 TI - Burns During Pregnancy: Implications for Maternal-Perinatal Providers and Guidelines for Practice. AB - IMPORTANCE: When a major burn is suffered during pregnancy, the obstetric provider is challenged to respond on an evidence basis because personal experience usually is lacking. Currently, there is a paucity of publications to inform the obstetrician, guide practice, and impact early critical decision making. OBJECTIVE: The aims of this study were to summarize the available information on early management of burns during pregnancy and to identify components of best practices for optimal outcome. EVIDENCE ACQUISITION: The PubMed database was searched for relevant titles and abstracts involving pregnant patients suffering from second-/third-degree burns. Among these studies, the bibliographies were investigated for further relevant literature. A total of 114 studies were identified during the initial search, and only studies published in English and French were included for a total of 42. Variable data were available for 1141 patients, with complete data for 139 cases. Mediation and regression analysis were used for available data. Insufficient data were available to undertake a systematic review. RESULTS: Total body surface area of burns (TBSAB) was positively associated with maternal death, and the odds of maternal mortality increase by 1.08 per percentage increase of TBSAB (P < 0.001). Fetal survival depends on maternal survival (P <= 0.001). Maternal survival declines incrementally when TBSAB exceeds 55%, and inhalation injury further exacerbates maternal-perinatal risk. CONCLUSIONS: Emergent assessment of the pregnant burn victimincludes determination of gestational age, extent of TBSAB, presence of inhalation injury, and continuous fetal monitoring. If gestational age is 24 weeks or longer and TBSAB exceeds 55%, urgent cesarean delivery appears desirable for the mother and baby. RELEVANCE: A specific analysis of maternal-perinatal outcome based on TBSAB and gestational age is relevant to obstetric and emergency providers who provide care to pregnant burn patients. PMID- 26490165 TI - Minimally Invasive Gynecologic Surgery for Benign Conditions: Progress and Challenges. AB - OBJECTIVE: The objective of this review is to evaluate the progress made in laparoscopic and hysteroscopic gynecologic surgery and address challenges still faced by surgeons using minimally invasive techniques to improve the care of women with noncancerous gynecologic problems. METHODS: Relevant literature was reviewed and evidence-based arguments put forward in the article for the progress that has been made and the deficiencies that still exist. RESULTS: In the last 2 decades, enormous progress has been made in providing minimally invasive surgical options for women with gynecologic diseases. The progress has been especially striking in the performance of hysterectomy, the most common major surgery performed on nonpregnant women. The recent controversy over power morcellation has revealed a poor understanding of the literature concerning leiomyosarcoma leading to confusion and consequently denial of minimally invasive surgical options for many women. Hysteroscopic surgery has been evolving rapidly with the development of hysteroscopic morcellator, global endometrial ablation systems, and hysteroscopic tubal sterilization. CONCLUSIONS: Although huge advances have been made in minimally invasive gynecologic surgery, high-quality evidence from well-designed clinical trials is lacking for many of the new technologies. Accurate estimates regarding the risk of occult leiomyosarcoma are also lacking. Additional research is urgently needed to address these deficiencies. PMID- 26490164 TI - Infections and Brain Development. AB - Several different bodies of evidence support a link between infection and altered brain development. Maternal infections, such as influenza and human immunodeficiency virus, have been linked to the development of autism spectrum disorders, differences in cognitive test scores, and bipolar disorder; an association that has been shown in both epidemiologic and retrospective studies. Several viral, bacterial, and parasitic illnesses are associated with alterations in fetal brain structural anomalies including brain calcifications and hydrocephalus. The process of infection can activate inflammatory pathways causing the release of various proinflammatory biomarkers and histological changes consistent with an infectious intrauterine environment (chorioamnionitis) or umbilical cord (funisitis). Elevations in inflammatory cytokines are correlated with cerebral palsy, schizophrenias, and autism. Animal studies indicate that the balance of proinflammatory and anti-inflammatory cytokines is critical to the effect prenatal inflammation plays in neurodevelopment. Finally, chorioamnionitis is associated with cerebral palsy and other abnormal neurodevelopmental outcomes. In conclusion, a plethora of evidence supports, albeit with various degrees of certainty, the theory that maternal infection and inflammation that occur during critical periods of fetal development could theoretically alter brain structure and function in a time-sensitive manner. PMID- 26490166 TI - Difficult temperament and negative parenting in early childhood: a genetically informed cross-lagged analysis. AB - A genetically informed longitudinal cross-lagged model was applied to twin data to explore etiological links between difficult temperament and negative parenting in early childhood. The sample comprised 313 monozygotic (MZ) and dizygotic (DZ) twin pairs. Difficult temperament and negative parenting were assessed at ages 2 and 3 using parent ratings. Both constructs were interrelated within and across age (rs .34-.47) and showed substantial stability (rs .65-.68). Difficult temperament and negative parenting were influenced by genetic and environmental factors at ages 2 and 3. The genetic and nonshared environmental correlations (rs .21-.76) at both ages suggest overlap at the level of etiology between the phenotypes. Significant bidirectional associations between difficult temperament and negative parenting were found. The cross-lagged association from difficult temperament at age 2 to negative parenting at age 3 and from negative parenting at age 2 and difficult temperament at age 3 were due to genetic, shared environmental, and nonshared environmental factors. Substantial novel genetic and nonshared environmental influences emerged at age 3 and suggest change in the etiology of these constructs over time. PMID- 26490168 TI - FancJ (Brip1) loss-of-function allele results in spermatogonial cell depletion during embryogenesis and altered processing of crossover sites during meiotic prophase I in mice. AB - Fancj, the gene associated with Fanconi anemia (FA) Complementation Group J, encodes a DNA helicase involved in homologous recombination repair and the cellular response to replication stress. FANCJ functions in part through its interaction with key DNA repair proteins, including MutL homolog-1 (MLH1), Breast Cancer Associated gene-1 (BRCA1), and Bloom syndrome helicase (BLM). All three of these proteins are involved in a variety of events that ensure genome stability, including the events of DNA double strand break (DSB) repair during prophase I of meiosis. Meiotic DSBs are repaired through homologous recombination resulting in non-crossovers (NCO) or crossovers (CO). The frequency and placement of COs are stringently regulated to ensure that each chromosome receives at least one CO event, and that longer chromosomes receive at least one additional CO, thus facilitating the accurate segregation of homologous chromosomes at the first meiotic division. In the present study, we investigated the role of Fancj during prophase I using a gene trap mutant allele. Fancj (GT/GT) mutants are fertile, but their testes are very much smaller than wild-type littermates, predominantly as a result of impeded spermatogonial proliferation and mildly increased apoptosis during testis development in the fetus. This defect in spermatogonial proliferation is consistent with mutations in other FA genes. During prophase I, early events of synapsis and DSB induction/repair appear mostly normal in Fancj (GT/GT) males, and the FANCJ-interacting protein BRCA1 assembles normally on meiotic chromosome cores. However, MLH1 focus frequency is increased in Fancj (GT/GT) males, indicative of increased DSB repair via CO, and is concomitant with increased chiasmata at diakinesis. This increase in COs in the absence of FANCJ is associated with increased localization of BLM helicase protein, indicating that BLM may facilitate the increased rate of crossing over in Fancj (GT/GT) males. Taken together, these results demonstrate a critical role for FANCJ in spermatogenesis at two stages: firstly in the proliferative activity that gives rise to the full complement of testicular spermatogonia and secondly in the establishment of appropriate CO numbers during prophase I. PMID- 26490169 TI - Activity of telomerase and telomeric length in Apis mellifera. AB - Telomerase is an enzyme that adds repeats of DNA sequences to the ends of chromosomes, thereby preventing their shortening. Telomerase activity is associated with proliferative status of cells, organismal development, and aging. We report an analysis of telomerase activity and telomere length in the honeybee, Apis mellifera. Telomerase activity was found to be regulated in a development and caste-specific manner. During the development of somatic tissues of larval drones and workers, telomerase activity declined to 10 % of its level in embryos and remained low during pupal and adult stages but was upregulated in testes of late pupae, where it reached 70 % of the embryo level. Upregulation of telomerase activity was observed in the ovaries of late pupal queens, reaching 160 % of the level in embryos. Compared to workers and drones, queens displayed higher levels of telomerase activity. In the third larval instar of queens, telomerase activity reached the embryo level, and an enormous increase was observed in adult brains of queens, showing a 70-fold increase compared to a brain of an adult worker. Southern hybridization of terminal TTAGG fragments revealed a high variability of telomeric length between different individuals, although the same pattern of hybridization signals was observed in different tissues of each individual. PMID- 26490170 TI - Speeding up chromosome evolution in Phaseolus: multiple rearrangements associated with a one-step descending dysploidy. AB - The genus Phaseolus L. has been subject of extensive cytogenetic studies due to its global economic importance. It is considered karyotypically stable, with most of its ca. 75 species having 2n = 22 chromosomes, and only three species (Phaseolus leptostachyus, Phaseolus macvaughii, and Phaseolus micranthus), which form the Leptostachyus clade, having 2n = 20. To test whether a simple chromosomal fusion was the cause of this descending dysploidy, mitotic chromosomes of P. leptostachyus (2n = 20) were comparatively mapped by fluorescent in situ hybridization (FISH) using bacterial artificial chromosomes (BACs) and ribosomal DNA (rDNA) probes. Our results corroborated the conservation of the 5S and 45S rDNA sites on ancestral chromosomes 10 and 6, respectively. The reduction from x = 11 to x = 10 was the result of the insertion of chromosome 10 into the centromeric region of chromosome 11, supporting a nested chromosome fusion (NCF) as the main cause of this dysploidy. Additionally, the terminal region of the long arm of chromosome 6 was translocated to this larger chromosome. Surprisingly, the NCF was accompanied by several additional translocations and inversions previously unknown for the genus, suggesting that the dysploidy may have been associated to a burst of genome reorganization in this otherwise stable, diploid plant genus. PMID- 26490167 TI - Reorganization of the interchromosomal network during keratinocyte differentiation. AB - The well-established human epidermal keratinocyte (HEK) differentiation model was investigated to determine possible alterations in chromosome territory (CT) association during differentiation. The seven human chromosomes (1, 4, 11, 12, 16, 17, and 18) selected for this analysis are representative of the chromosome size and gene density range of the overall human genome as well as including a majority of genes involved in epidermal development and differentiation (CT1, 12, and 17). Induction with calcium chloride (Ca(2+)) resulted in morphological changes characteristic of keratinocyte differentiation. Combined multi fluorescence in situ hybridization (FISH) and computational image analysis on the undifferentiated (0 h) and differentiated (24 h after Ca(2+) treatment) HEK revealed that (a) increases in CT volumes correspond to overall nuclear volume increases, (b) radial positioning is gene density-dependent at 0 h but neither gene density- nor size-dependent at 24 h, (c) the average number of interchromosomal associations for each CT is gene density-dependent and similar at both time points, and (d) there are striking differences in the single and multiple pairwise interchromosomal association profiles. Probabilistic network models of the overall interchromosomal associations demonstrate major reorganization of the network during differentiation. Only ~40 % of the CT pairwise connections in the networks are common to both 0 and 24 h HEK. We propose that there is a probabilistic chromosome positional code which can be significantly altered during cell differentiation in coordination with reprogramming of gene expression. PMID- 26490171 TI - [Report from the management board]. PMID- 26490172 TI - [Report of the presidial committee]. PMID- 26490173 TI - Studies of Household Air Pollution and Subclinical Indicators of Cardiovascular Disease Fill Important Knowledge Gaps. PMID- 26490174 TI - Synthesis of Long, Palladium End-Capped Polyynes through the Use of Asymmetric 1 Iodopolyynes. AB - The synthesis of a unique series of long, asymmetric 1-iodopolyynes (1-Cn I and 2 Cn I) with the sp-hybridized carbon chain up to a decapentayne is reported. These compounds were then used as substrates in reactions with Pd(PPh3 )4 leading to another series of palladium end-capped polyynes, which were unstable in solution. Organometallic octatetraynes 1-C8 [Pd]I, 2-C8 [Pd]I, and decapentayne 1-C10 [Pd]I are palladium end-capped polyyne compounds with the longest carbon chains reported so far. All the complexes as well as their organic precursors were fully characterized by NMR, HRMS(ESI), IR, TGA-DTA, and UV/Vis techniques, and the X ray crystal structures of two silyl-protected precursors and one palladium complex are presented. The synthetic approach for palladium species is envisioned as a general route for the synthesis of labile organometallic polyynes. PMID- 26490176 TI - Vitamin D and benign gynaecological diseases: a critical analysis of the current evidence. AB - Vitamin D is a fat-soluble pro-hormone that plays an important role in bone homeostasis; beside this principal function, vitamin D promotes modulation of cell growth, neuromuscular and immune function, and reduction of inflammation. In addition, several in vitro and in vivo studies have demonstrated that vitamin D deficiency could increase the risk of cancer, autoimmune and cardiovascular diseases. Moreover, vitamin D plays also an important role in female reproduction, because vitamin D receptors are expressed in ovarian tissue, endometrium, fallopian epithelial cells as well as in decidua and placenta. We aimed to review the most updated evidence, which suggests a link between vitamin D metabolism and the development of some gynaecological diseases, such as endometriosis, uterine fibroids and polycystic ovary syndrome. PMID- 26490177 TI - Directed synthesis of {Cu2(II)Zn2(II)} and {Cu8(II)Zn8(II)} heterometallic complexes. AB - Two new heterometallic complexes [Cu2Zn2(H4L)2(CH3COO)2Cl2].2.5CH3OH.0.5H2O (1) and [Cu8Zn8(OH)8(H4L)8](Cl)2(ClO4)6.16H2O (2) have been synthesised following two different preparative routes, by using the polydentate ligand Bis-tris propane (H6L = 2,2'-(propane-1,3-diyldiimino)bis[2-(hydroxymethyl)propane-1,3-diol]). Herein, we describe the synthesis, structure, and magnetic properties of 1, a tetramer which forms in the absence of base and 2, a hexadecanuclear complex with a remarkable double-concentric ring structure that forms in the presence of base. Antiferromagnetic coupling between Cu(II) ions is observed in both compounds despite the long distances between paramagnetic metal centres, due to the involvement of diamagnetic Zn(II) ions in the magnetic exchange pathway. PMID- 26490178 TI - How many MSM in Europe could benefit from PrEP--a 9 billion Euro question? PMID- 26490180 TI - Plasmonic multi-shell nanomatryoshka particles as highly tunable SERS tags with built-in reporters. AB - Here we report on the synthesis and averaged SERS measurements of multi-shell nanomatryoshka SERS tags. By tuning the number of shells or by changing the Raman reporters in different gap layers, their Raman intensities and spectral bands were tunable. These tags show great potential for SERS-based biosensing and bioimaging. PMID- 26490181 TI - Mass-gathering Events: The Public Health Challenge of the Kumbh Mela 2013. AB - Mass-gathering (MG) events pose challenges to the most adept of public health practitioners in ensuring the health safety of the population. These MGs can be for sporting events, musical festivals, or more commonly, have religious undertones. The Kumbh Mela 2013 at Allahabad, India may have been the largest gathering of humanity in history with nearly 120 million pilgrims having thronged the venue. The scale of the event posed a challenge to the maintenance of public health security and safety. A snapshot of the experience of managing the hygiene and sanitation aspects of this mega event is presented herein, highlighting the importance of proactive public health planning and preparedness. There having been no outbreaks of disease is vindication of the steps undertaken in planning and preparedness, notwithstanding obvious limitations of unsanitary behaviors and traditional beliefs of those attending the festival. The evident flaw on post event analyses was the failure to cater adequately for environmental mopping-up operations after the festival. Besides, a system of real-time monitoring of disease and morbidity patterns, harnessing low cost technology alternatives, should be planned for at all such future events. PMID- 26490179 TI - Gout in the Spine: Imaging, Diagnosis, and Outcomes. AB - Gout is characterized by the deposition of monosodium urate crystals and by acute and chronic inflammation in response to crystals so deposited. Multiple case reports and series describe the deposition of monosodium urate in the spine as a rare manifestation of gout, but the actual prevalence of spinal involvement is unknown and likely to be higher than generally anticipated. Here we review the characteristics of 131 previously reported cases of spinal involvement in gout. We focus in particular on the use of imaging modalities and the extent to which they correlate with presenting symptoms and tissue diagnoses. The recent innovation of using dual-energy computerized tomography to identify urate crystal deposition holds promise for reducing the need for surgical intervention and for establishing a true prevalence rate for spinal gout. PMID- 26490182 TI - A novel homozygous mutation in HSF4 causing autosomal recessive congenital cataract. AB - Cataract is defined as opacity in the crystalline lens and congenital cataract occurs during the first year of life. Until now, mutations of more than 50 genes in congenital cataract have been reported with various modes of inheritance. Among them, HSF4 mutations have been reported in autosomal dominant, autosomal recessive and age-related forms of cataract. The inheritance patterns of these mutations depend on their mutational positions in HSF4: autosomal dominant or recessive mutations are respectively found either in a DNA-binding domain or in (or downstream of) hydrophobic repeats. Here we report a novel homozygous HSF4 mutation (c.521T>C, p.Leu174Pro) in two affected sibs of an Iranian consanguineous family using whole exome sequencing. The mutation is predicted as highly pathogenic by in silico analysis (SIFT, Polyphen2 and MutationTaster) and is not found in any of control databases. This mutation is located in a hydrophobic repeat of the HSF4 protein, which is consistent with the mode of inheritance as an autosomal recessive trait. PMID- 26490183 TI - Unravelling the mechanism of action of enzyme replacement therapy in Fabry disease. AB - Fabry disease (FD) is a rare X-linked recessive glycosphingolipid-storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Intravenous enzyme replacement therapy (ERT) has been used to supplement deficient enzyme activity in patients with FD. Despite its clinical effect and manifestations, clear criteria for the clinical effectiveness and cost effectiveness of ERT have not been well established. In this study, we investigated the pharmacodynamic actions and short-term effects of ERT in patients with FD through direct molecular profiling from blood samples of patients before and after ERT. Based on this comparison, we observed that immune/inflammation-related pathways and growth factor-related pathways such as innate/adaptive immune pathway, lymphocyte proliferation and leukocyte proliferation were actively regulated under ERT. We also found that TINAGL1, DAAM2, CDK5R1 and MYO5B known to be related with clinical symptoms of FD showed increased levels after ERT, leading to the amelioration of clinical manifestations. Especially the catabolic process-related genes, including USP15 and ERUN1, showed direct increasing after ERT in vivo in male patients. These results suggest that male patients with FD respond more actively to ERT than do female patients with FD. Pathway analysis revealed that oxidative phosphorylation pathway-related genes are downregulated under ERT. ERT has a role to protect the proteins from oxidative damage and such deactivation of oxidative phosphorylation is one of direct pharmacodynamic actions of ERT. These results extended our understanding of the pathophysiology of ERT. To our knowledge, this is the first study to observe the molecular basis for the mechanism of ERT in vivo through the comprehensive comparison of transcriptome study with next-generation sequencing data. PMID- 26490184 TI - MECP2 missense mutations outside the canonical MBD and TRD domains in males with intellectual disability. AB - Methyl-CpG-binding protein 2 (MeCP2) is a nuclear protein highly expressed in neurons that is involved in transcriptional modulation and chromatin remodeling. Mutations in MECP2 in females are associated with Rett syndrome, a neurological disorder characterized by a normal neonatal period, followed by the arrest of development and regression of acquired skills. Although it was initially thought that MECP2 pathogenic mutations in males were not compatible with life, starting from 1999 about 60 male patients have been identified and their phenotype varies from severe neonatal encephalopathy to mild intellectual disability. Targeted next-generation sequencing of a panel of intellectual disability related genes was performed on two unrelated male patients, and two missense variants in MECP2 were identified (p.Gly185Val and p.Arg167Trp). These variants lie outside the canonical methyl-CpG-binding domain and transcription repression domain domains, where the pathogenicity of missense variants is more difficult to establish. In both families, variants were found in all affected siblings and were inherited from the asymptomatic mother, showing skewed X-chromosome inactivation. We report here the first missense variant located in AT-hook domain 1 and we underline the importance of MECP2 substitutions outside the canonical MeCP2 domains in X-linked intellectual disability. PMID- 26490185 TI - Diagnostic exome sequencing for patients with a family history of consanguinity: over 38% of positive results are not autosomal recessive pattern. AB - Diagnostic exome sequencing (DES) is an effective tool for diagnosis in intractable cases where the underlying cause is thought be genetic. It is commonly assumed that patients with a family history of consanguinity will have increased detection rates for rare autosomal recessive Mendelian disorders through DES. Herein, we analyzed the diagnostic yield and relevant inheritance patterns within the DES cases with a reported consanguineous family history. Of the first 500 unselected cases referred for DES, 40 (8.0%) had a known consanguineous family history. Among the 40 cases, 13 (32.5%) received a definitive molecular diagnosis through DES and such positive rate is similar to that of families with no reported consanguinity (139/460, 30.2%, P=0.63). Although homozygous alterations likely related to consanguinity have been identified in eight positive cases, the other five (38.4%) causative mutations were unrelated to autosomal recessive inheritance. Our retrospective analysis demonstrated that individuals with known consanguinity were not more likely to have a positive DES result and a significant portion of the positive findings were not within an autosomal recessive gene. These results highlight that all applicable inheritance patterns should be considered for patients with a known family history of consanguinity. PMID- 26490186 TI - Genetic mutation analysis in Japanese patients with non-syndromic congenital heart disease. AB - Congenital heart disease (CHD) is the most common birth defect occurring in humans and some transcriptional factors have been identified as causative. However, additional mutation analysis of these genes is necessary to develop effective diagnostic and medical treatment methods. We conducted sequence analysis of the coding regions of NKX2.5, GATA4, TBX1, TBX5, TBX20, CFC1 and ZIC3 in 111 Japanese patients with non-syndromic CHD and 9 of their relatives. All patient samples were also analyzed by multiplex ligation-dependent probe amplification using probes involved in chromosome deletion related to CHD. Five novel variations of TBX5, GATA4 and TBX20 were detected in 6 of the patients, whereas none were found in 200 controls. The TBX5 variation p.Pro108Thr, located in the T-box domain, was identified in a patient with tricuspid atresia, an exon intron boundary variation of GATA4 (IVS4+5G>A) was detected in a Tetralogy of Fallot patient and an 8p23 microdeletion was detected in one patient with atrioventricular septal defect and psychomotor delay. A total of seven non synonymous polymorphisms were found in the patients and controls. Accumulation of novel variations of genes involving the cardiac development may be required for better understanding of CHD. PMID- 26490188 TI - Estimation of genetic parameters for reproductive traits in alpacas. AB - One of the main deficiencies affecting animal breeding programs in Peruvian alpacas is the low reproductive performance leading to low number of animals available to select from, decreasing strongly the selection intensity. Some reproductive traits could be improved by artificial selection, but very few information about genetic parameters exists for these traits in this specie. The aim of this study was to estimate genetic parameters for six reproductive traits in alpacas both in Suri (SU) and Huacaya (HU) ecotypes, as well as their genetic relationship with fiber and morphological traits. Dataset belonging to Pacomarca experimental farm collected between 2000 and 2014 was used. Number of records for age at first service (AFS), age at first calving (AFC), copulation time (CT), pregnancy diagnosis (PD), gestation length (GL), and calving interval (CI) were, respectively, 1704, 854, 19,770, 5874, 4290 and 934. Pedigree consisted of 7742 animals. Regarding reproductive traits, model of analysis included additive and residual random effects for all traits, and also permanent environmental effect for CT, PD, GL and CI traits, with color and year of recording as fixed effects for all the reproductive traits and also age at mating and sex of calf for GL trait. Estimated heritabilities, respectively for HU and SU were 0.19 and 0.09 for AFS, 0.45 and 0.59 for AFC, 0.04 and 0.05 for CT, 0.07 and 0.05 for PD, 0.12 and 0.20 for GL, and 0.14 and 0.09 for CI. Genetic correlations between them ranged from -0.96 to 0.70. No important genetic correlations were found between reproductive traits and fiber or morphological traits in HU. However, some moderate favorable genetic correlations were found between reproductive and either fiber and morphological traits in SU. According to estimated genetic correlations, some reproductive traits might be included as additional selection criteria in HU. PMID- 26490187 TI - Tumor-suppressive microRNAs (miR-26a/b, miR-29a/b/c and miR-218) concertedly suppressed metastasis-promoting LOXL2 in head and neck squamous cell carcinoma. AB - In spite of considerable advances in multimodality therapy, including surgery, radiotherapy and chemotherapy, the overall survival rate for patients with head and neck squamous cell carcinoma (HNSCC) is very poor (only 15-45%). Understanding the molecular mechanisms of metastatic pathways underlying HNSCC using currently available genomic approaches might improve therapies for and prevention of the disease. Our previous studies showed that three tumor suppressive microRNAs (miRNAs), miR-26a/b, miR-29a/b/c and miR-218, significantly inhibited cancer cell migration and invasion. Therefore, we hypothesized that these miRNAs-regulated target genes deeply contributed to cancer metastasis. These tumor-suppressive miRNAs directly regulate LOXL2 expression in HNSCC cells by using in silico analysis and luciferase reporter assays. Overexpressed LOXL2 was confirmed in HNSCC clinical specimens, and silencing of LOXL2 inhibited cancer cell migration and invasion in HNSCC cell lines. Our present data showed that tumor-suppressive miRNAs regulation of LOXL2 will provide new insights into the novel molecular mechanisms of HNSCC metastasis. PMID- 26490190 TI - Evaluation of Statistical Treatments of Left-Censored Environmental Data Using Coincident Uncensored Data Sets. II. Group Comparisons. AB - The main classes of statistical treatments that have been used to determine if two groups of censored environmental data arise from the same distribution are substitution methods, maximum likelihood (MLE) techniques, and nonparametric methods. These treatments along with using all instrument-generated data (IN), even those less than the detection limit, were evaluated by examining 550 data sets in which the true values of the censored data were known, and therefore "true" probabilities could be calculated and used as a yardstick for comparison. It was found that technique "quality" was strongly dependent on the degree of censoring present in the groups. For low degrees of censoring (<25% in each group), the Generalized Wilcoxon (GW) technique and substitution of ?2/2 times the detection limit gave overall the best results. For moderate degrees of censoring, MLE worked best, but only if the distribution could be estimated to be normal or log-normal prior to its application; otherwise, GW was a suitable alternative. For higher degrees of censoring (each group >40% censoring), no technique provided reliable estimates of the true probability. Group size did not appear to influence the quality of the result, and no technique appeared to become better or worse than other techniques relative to group size. Finally, IN appeared to do very well relative to the other techniques regardless of censoring or group size. PMID- 26490189 TI - Inducing ovulation in wood bison (Bison bison athabascae) during the anovulatory season. AB - As part of the development of a germplasm biobank to preserve the genetic diversity of threatened wood bison (Bison bison athabascae), a 2 * 2 factorial study was designed to determine the effects of ovulation induction agent and follicle maturity on the ovulatory response in wood bison during the anovulatory season. Bison (n=32) were assigned randomly to four groups (n=8/group) and treated with either pLH or hCG when a growing dominant follicle was either 8-9 mm or >=10 mm. The ovaries were examined daily by ultrasonography to determine the timing of ovulation, and 7 days post-treatment to assess CL development. The proportion of bison that ovulated was greater in bison treated with hCG than pLH ([15/16] 94% vs. [8/16] 50%; P<0.05), and when the dominant follicle was >=10 mm vs. 8-9 mm at the time of treatment (88% vs. 56%; P<0.05). The interval from treatment to ovulation was 37.0 +/- 1.3h and was not affected by induction agent or follicle size. However, synchrony of ovulation tended to be greater (P=0.10) in the >=10 mm group vs. the 8-9 mm group, and the ensuing corpus luteum was larger (15.3 +/- 0.43 mm vs. 13.4 +/- 0.36; P<0.05). In conclusion, both ovulation inducing agent and follicle size influenced the ovulatory response in bison during the anovulatory season. Treatment with hCG was more effective than pLH for inducing ovulation in wood bison, and the effect was greater when treatment was given when the growing dominant follicle was >=10 mm. PMID- 26490192 TI - Resistive switching memory devices based on electrical conductance tuning in poly(4-vinyl phenol)-oxadiazole composites. AB - Nonvolatile memory devices, based on electrical conductance tuning in thin films of poly(4-vinyl phenol) (PVP) and 2-(4-tert-butylphenyl)-5-(4-biphenylyl)-1,3,4 oxadiazole (PBD) composites, are fabricated. The current-voltage characteristics of the fabricated devices show different electrical conductance behaviors, such as the write-once read-many-times (WORM) memory effect, the rewritable flash memory effect and insulator behavior, which depend on the content of PBD in the PVP + PBD composites. The OFF and ON states of the WORM and rewritable flash memory devices are stable under a constant voltage stress or a continuous pulse voltage stress at a read voltage. The memory mechanism is deduced from the modeling of the nature of currents in both states in the devices. PMID- 26490191 TI - Effect of breakfast omission: Constrained to morning? PMID- 26490193 TI - Hollow Co@C prepared from a Co-ZIF@microporous organic network: magnetic adsorbents for aromatic pollutants in water. AB - This work shows the new engineering strategy of magnetic adsorbents by the combination of zeolitic imidazolate framework (ZIF) and microporous organic network (MON) chemistry. ZIF-67 nanoparticles containing Co(2+) ions were coated with MON. The thermolysis of ZIF-67@MON under argon resulted in hollow carbon materials bearing cobalt nanoparticles which showed promising performance as magnetic adsorbents for aromatic pollutants in water. PMID- 26490194 TI - Genetics and phenotypes in inflammatory bowel disease. PMID- 26490196 TI - The Institute of Medicine: ensuring integrity and independence in scientific advice on health. AB - National science and medical academies across the world serve a range of roles and functions. In particular, the benefits of an independent academy tasked with the provision of formal advice are compelling. For nearly half a century, the Institute of Medicine (IOM) has served the USA and the world by providing independent, authoritative advice on issues related to health and medicine. Its influence reaches deep into the health and policy worlds. This paper provides insight into the principles, processes, and governance that confer unique credibility to IOM advice. The IOM can serve as a useful model for other academies to consider for strengthening their work or when other countries contemplate the creation of a new academy. PMID- 26490197 TI - Low-temperature heat capacities of confined liquid benzene, implying the behavior of ordinary bulk liquids. AB - Isobaric heat capacities C p of benzene confined in silica MCM-41 mesopores with average diameters equal to and smaller than 2.9 nm were measured by precise adiabatic calorimetry. The confined benzene samples revealed no thermal anomaly due to crystallization/fusion and vitrified at low temperatures. The C p curves displayed a hump and a considerably quick decrease on the low-temperature side of the hump as the pore diameter increased. The enthalpy-relaxation effects observed on intermittent heating showed that the anomaly of the C p hump and quick decrease is not assigned to a glass transition. The bend in the temperature dependence of density reported previously was interpreted as corresponding to the quick decrease in C p . We concluded that the anomalous C p and density behaviors originated from the ordering/excitation in the configurational state, close to the ground state, of confined molecular aggregate and proposed a scenario that explains the general C p curves of ordinary bulk supercooled liquids in equilibrium at low temperatures below the glass-transition temperatures. PMID- 26490198 TI - Reproductive traits and number of matings in males and females of Cerambyx welensii (Coleoptera: Cerambycidae) an emergent pest of oaks. AB - The longhorn beetle Cerambyx welensii is an emerging pest involved in oak decline episodes, whose damage is increasingly reported in dehesa open woodlands. Knowledge of the reproductive biology of C. welensii is a crucial goal due to its new pest status. In this study, we assess the reproductive traits of both sexes in the laboratory (25 degrees C and 60% relative humidity ). In females, body length was 44.9 +/- 0.9 mm (mean +/- SE), fecundity 132 +/- 12 eggs, fertility 70 +/- 1 %, longevity 70 +/- 3 days, preoviposition period 2 +/- 0.2 days, oviposition period 44 +/- 3 days and postoviposition period 19 +/- 3 days. Fecundity was positively correlated with female size, longevity and oviposition period. Daily fecundity was 3.0 +/- 0.2 eggs/day and showed a fluctuating synovigenic pattern with a slight decreasing trend over time. Egg length was 4.24 +/- 0.01 mm and egg volume 8.14 +/- 0.04 mm3. Egg size was correlated with female size but the relative size of eggs was larger in smaller females. Incubation time was 13.9 +/- 0.1 days and hatching did not depend on egg size. Neonate size was positively correlated with egg length. Females were polyandrous (more than 20 lifetime matings) but multiple mating did not increase fecundity, fertility or longevity. In males, body length was 43.7 +/- 0.6 mm and longevity 52 +/- 3 days. Unlike with females, longevity was positively correlated with male size. Males were polygynous (up to 30 lifetime matings) but mating history did not affect male longevity. Rather to the contrary, long-lived males mated more times because they had more mating chances. Lastly, C. welensii reproductive traits were compared with those other Cerambycidae species and discussed from an adaptive perspective. Our data will be useful to improve management of C. welensii in order to prevent or mitigate its impact in dehesa woodlands and other oak forests. PMID- 26490199 TI - Effects of a plant product consisting of green tea and curcuma extract on milk production and the expression of hepatic genes involved in endoplasmic stress response and inflammation in dairy cows. AB - During the periparturient phase, cows are typically in an inflammation-like condition, and it has been proposed that inflammation associated with the induction of stress of the endoplasmic reticulum (ER) in the liver contributes to the development of fatty liver syndrome and ketosis. In the present study, the hypothesis that supplementation of dairy cows with a plant product consisting of green tea (95%) and curcuma extract (5%) rich in polyphenols attenuates inflammation and ER stress in the liver during early lactation was investigated. Twenty-seven cows were assigned to two groups, either a control group (n=14) or a treatment group (n=13). Both groups of cows received a total mixed ration, and the ration of the treatment group was supplemented with 0.175 g of the plant product per kg dry matter from week 3 prepartum to week 9 postpartum. Dry matter intake and energy balance during week 2 to week 9 postpartum were not different between the two groups. However, cows supplemented with the plant product had a greater amount of energy-corrected milk during week 2 to week 9 postpartum and lower concentrations of triacylglycerols and cholesterol in the liver in week 1 and week 3 postpartum than cows of the control group (p<0.05). Cows supplemented with the plant product showed a trend towards a reduced mRNA concentration of haptoglobin (p<0.10), while relative mRNA concentrations of eight genes of the unfolded protein response considered in the liver were not different between the two groups of cows. Relative hepatic mRNA concentration of fibroblast growth factor, a stress hormone induced by various stress conditions, was reduced at week 1 and week 3 postpartum in cows supplemented with the plant product (p<0.05). Overall, the data of this study suggest that--although there were only minor effects on the occurrence of ER stress and inflammation--a supplementation of polyphenols might be useful to improve milk yield and prevent fatty liver syndrome in dairy cows. PMID- 26490200 TI - Effects of the dietary ratio of ruminal degraded to undegraded protein and feed intake on intestinal flows of endogenous nitrogen and amino acids in goats. AB - This study was conducted to evaluate the effects of the dietary ratio of ruminal degraded protein (RDP) to ruminal undegraded protein (RUP) and the dry matter intake (DMI) on the intestinal flows of endogenous nitrogen (N) and amino acids (AA) in goats. The experiment was designed as a 4*4 Latin square using four ruminally, duodenally and ileally cannulated goats. The treatments were arranged in a 2*2 factorial design; two ratios of RDP to RUP (65:35 and 45:55, RDP1 and RDP2, respectively) and two levels at 95% and 75% of voluntary feed intake (DMI1 and DMI2, respectively) were fed to the goats. There were no significant differences in the N intake, duodenal flow of total N, undegraded feed N, microbial N, endogenous N or ileal flow of endogenous N, but the duodenal and ileal flow of endogenous N numerically decreased by approximately 22% and 9%, respectively, when the feed intake changed from DMI1 (0.63 kg/d) to DMI2 (0.50 kg/d). The dietary ratio of RDP to RUP had significant effects (p<0.05) on the ileal flows of endogenous leucine, phenylalanine and cysteine. The present results implied that the duodenal flows of endogenous N and AA decreased when the dietary RDP to RUP ratio and DMI decreased, and the flow of endogenous AA at the ileum also decreased when the DMI decreased but increased with decreasing RDP to RUP ratios. PMID- 26490201 TI - Influence of feeding a fish oil-containing diet to young, lean, adult dogs: effects on lipid metabolites, postprandial glycaemia and body weight. AB - The aim of this study was to determine the effect of feeding a fish oil (FO) containing diet on lipid and protein metabolism, postprandial glycaemia and body weight in young, lean, adult dogs. Eight female Beagles were randomly assigned to one of two isonitrogenous and isoenergetic diets, Control or FO, in a crossover design. At the beginning of the experiment and at 30 and 60 d, a baseline blood sample was collected and the dogs then were fed their daily ration. Nitrogen balance began at 07:00 h on day 63 of each experimental period and ended at 07:00 h on day 69. On day 66 of each period, a single dose (7.5 mg/kg) of (15)N-glycine was administered orally to each dog via gelatin capsule. Postprandial glycaemia did not differ between treatments or among sampling days within treatment. Cholesterol concentration was increased (p<0.05) on the Control treatment throughout the experiment when compared to values of day 0. Dogs fed the FO treatment had higher plasma triglyceride and ghrelin concentrations than those fed the Control treatment. Body weight and food intake did not differ between dietary treatments. Faecal excretion was increased (p<0.05) in the FO treatment. Dry matter digestibility was decreased (p<0.05) and fat digestibility tended (p<0.10) to decrease in the FO treatment. Overall, feeding a FO-containing diet showed a protective effect against the rise of plasma cholesterol and it increased plasma ghrelin concentration. However, FO supplementation did not appear to affect protein metabolism or postprandial glycaemia in adult lean dogs. PMID- 26490204 TI - A checklist for photovoltaic research. PMID- 26490203 TI - Sculpting the band gap: a computational approach. AB - Materials with optimized band gap are needed in many specialized applications. In this work, we demonstrate that Hellmann-Feynman forces associated with the gap states can be used to find atomic coordinates that yield desired electronic density of states. Using tight-binding models, we show that this approach may be used to arrive at electronically designed models of amorphous silicon and carbon. We provide a simple recipe to include a priori electronic information in the formation of computer models of materials, and prove that this information may have profound structural consequences. The models are validated with plane-wave density functional calculations. PMID- 26490210 TI - Material witness: Materials touch across the void. PMID- 26490195 TI - Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. AB - BACKGROUND: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. METHODS: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10.5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1.65 * 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9.23 * 10( 18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6.8 * 10(-4)). INTERPRETATION: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list). PMID- 26490211 TI - Biological filaments: Self-healing microtubules. PMID- 26490212 TI - Bioinspired composites: Making a tooth mimic. PMID- 26490213 TI - Protein polymers: Encoding phase transitions. PMID- 26490214 TI - Active matter: Fleeting defects line up. PMID- 26490215 TI - Dielectric nanostructures: Ultrafast responses. PMID- 26490216 TI - Programmable and adaptive mechanics with liquid crystal polymer networks and elastomers. AB - Liquid crystals are the basis of a pervasive technology of the modern era. Yet, as the display market becomes commoditized, researchers in industry, government and academia are increasingly examining liquid crystalline materials in a variety of polymeric forms and discovering their fascinating and useful properties. In this Review, we detail the historical development of liquid crystalline polymeric materials, with emphasis on the thermally and photogenerated macroscale mechanical responses--such as bending, twisting and buckling--and on local feature development (primarily related to topographical control). Within this framework, we elucidate the benefits of liquid crystallinity and contrast them with other stimuli-induced mechanical responses reported for other materials. We end with an outlook of existing challenges and near-term application opportunities. PMID- 26490217 TI - The Transformation of Diabetes Care Through the Use of Person-Centered Data. AB - The health care industry is undergoing a major transformation. Despite spending more on health care than any other country, the United States has not seen a commensurate improvement in the quality of care. Chronic disease management puts the greatest burden on the health care system with estimates suggesting that 3 of 4 health care dollars are spent on managing chronic disease. Moreover, the number of older patients with chronic conditions, like diabetes, is rising as expected, which only serves to worsen the physician shortage problem we are currently experiencing, and further increase health care costs. Unless new models of health care are established for these patients, they simply will not be served. Consistent with the message above, there are generally 3 universal health care needs, (1) improved outcomes, (2) expanded access, and (3) optimized cost and efficiency. It is likely the future state will involve value-based health care, with payment based on outcomes, not services rendered, and incentives tied more directly to the value delivered. Medical device providers will be held more accountable for positive outcomes, and to ensure success, they will need to create better solutions with their therapies. Instead of the touch point with patients being solely at the time of a procedure or sale of the device, it is likely companies will need to drive toward a more comprehensive partnership with patients, providers, and payers, extending the scope of services and interactions to provide a continuum of care. In general, companies will need to start to think of their most important customers as people living with a condition, as opposed to patients needing immediate medical devices. In this article, I discuss the challenges of health care today and present some of the opportunities to revamp health care delivery in diabetes by leveraging the pervasive use of mobile technologies and digital data. PMID- 26490218 TI - Network analysis of wildlife translocations in New Zealand. AB - AIMS: To identify network measures with relevance to disease spread in a network of movements derived from the Department of Conservation (DOC) translocation records from 1970 to mid-2014, and to identify conservation sites that should be prioritised for surveillance activities and improvements to data collection to make the best use of network analysis techniques in the future. METHODS: Data included the source and destination of translocated specimens, the species and the dates the translocations were expected to occur. The data were used to construct a directed, non-weighted network in which a translocation event represented a tie in the network. Network density, in-degree (movements entering a node of interest) and out-degree (movements leaving a node of interest) and reciprocity were calculated. RESULTS: The data analysed consisted of 692 unique translocations between 307 sites, with the majority (518; 73%) being for birds. The constructed network for bird, reptile and frog translocations comprised 260 nodes, with 34/260 (13%) having two-way movements and 47/260 (18%) non-reciprocal movements. The median degree score (sum of in- and out-degree) was two (min 0, max 36) with a mean of 3.5 in a right skewed distribution. Most sites acted as receivers or senders of consignments with only a few having both high in- and high out-degree, and thus had characteristics that made them sites of interest for surveillance activities. These included the National Wildlife Centre at Mount Bruce, Tiritiri Matangi Island and Te Kakahu (Chalky Island). CONCLUSIONS: The presence of linking sites that join larger clusters within the network creates the potential for rapid disease spread if a pathogen were to be introduced. The important sites that supply or receive specimens for translocations are already well recognised by those performing translocations in New Zealand, and this paper provides further information by quantifying their role within the network. PMID- 26490219 TI - Distributed parameter estimation in unreliable sensor networks via broadcast gossip algorithms. AB - In this paper, we present an asynchronous algorithm to estimate the unknown parameter under an unreliable network which allows new sensors to join and old sensors to leave, and can tolerate link failures. Each sensor has access to partially informative measurements when it is awakened. In addition, the proposed algorithm can avoid the interference among messages and effectively reduce the accumulated measurement and quantization errors. Based on the theory of stochastic approximation, we prove that our proposed algorithm almost surely converges to the unknown parameter. Finally, we present a numerical example to assess the performance and the communication cost of the algorithm. PMID- 26490220 TI - Melatonin prevents lung injury induced by hepatic ischemia-reperfusion through anti-inflammatory and anti-apoptosis effects. AB - Melatonin is a free radical scavenger and broad-spectrum antioxidant with immunomodulatory effects. The objective of the study is to investigate the effects of melatonin in hepatic ischemia/reperfusion (I/R) induced lung injury and explore its underlying mechanisms. Hepatic I/R injury was induced via portal vein and hepatic artery occlusion for 30min followed by 3-h reperfusion. Male Sprague-Dawley rats were divided into three groups: sham, I/R+ Vehicle and I/R+melatonin. Melatonin (10mg/kg) or vehicle was injected intravenously 15min before ischemia and 10min before reperfusion. The histology of the liver and lung, plasma aminotransferase and cytokine secretion, and apoptosis in the lung were evaluated. The phosphorylation of JNK, p38, and NF-kB and Nrf2 nuclear translocation in the lung was examined by Western blotting. We found that melatonin administration significantly attenuated hepatic I/R induced lung injury in rats. Melatonin inhibited the pro-inflammatory responses and enhanced antioxidative responses. Melatonin alleviated pathological changes of the lung and liver, and inhibited apoptosis of cells in the lung. Phosphorylation of JNK, p38 and NF-kB and Nrf2 nuclear translocation was increased significantly in the lung by hepatic I/R. Melatonin administration inhibited the activation of JNK, p38, and NF-kB, however, melatonin further enhanced Nrf2 activation. We conclude that melatonin exerts a protective effect in hepatic I/R induced lung injury by attenuating the pro-inflammatory responses, inhibiting cell apoptosis, which was mediated in part through JNK, p38 MAPK, NF-kB and Nrf2 signaling pathways. Melatonin may be a promising therapeutic strategy for hepatic I/R induced lung injury. PMID- 26490221 TI - GTS-21 attenuates lipopolysaccharide-induced inflammatory cytokine production in vitro by modulating the Akt and NF-kappaB signaling pathway through the alpha7 nicotinic acetylcholine receptor. AB - OBJECTIVE: GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist, has recently been established as a promising treatment for inflammation. However, the detailed molecular mechanism of GTS-21 in suppressing pro-inflammatory cytokine production is only partially explored. The study aimed to analyze cytokine expression suppressed by GTS-21 with lipopolysaccharide (LPS)-induced inflammation in vitro and to gain insights into the role of Akt/NF-kappaB signaling pathway in this process. MATERIALS AND METHODS: Cell Counting Kit-8 (CCK-8) assay was performed to detect drug cytotoxicity. RAW 264.7 cells were stimulated with LPS and treated with GTS-21. Interleukin (IL)-1beta, IL-6, or tumor necrosis factor (TNF)-alpha production was detected using enzyme-linked immunosorbent assay. Western blot was used to assess the expression patterns of signal transduction protein. Nuclear translocation of nuclear factor (NF)-kappaB was analyzed by confocal fluorescence microscopy. In addition, alpha7 nicotinic acetylcholine receptors (alpha7 nAChR) were detected on RAW264.7, and the alpha7 nAChR-specific antagonist was adopted to verify whether the effect of GTS-21 was mediated by alpha7 nAChR. RESULTS: The CCK-8 assay showed that GTS-21 did not significantly affect cell proliferation. The production of IL-1beta, IL-6, and TNF-alpha decreased after being treated with GTS-21 in LPS-stimulated RAW 264.7 cells. GTS-21 also suppressed LPS-induced phosphorylation of NF-kappaBp65, IKKalpha/beta, IkappaBalpha, and Akt, as well as NF-kappaB p65 nuclear translocation. Moreover, alpha7 nAChR was expressed on the surfaces of RAW264.7 cells, and the alpha7 nAChR-specific antagonist almost completely prohibited the inhibitory effect of GTS-21 on NF-kappaB activation. CONCLUSION: These findings indicate that GTS-21 suppresses LPS-induced inflammation by inhibiting the Akt/NF kappaB signal pathway through alpha7 nAChR. GTS-21 has a potential application in inflammatory disease therapy. PMID- 26490222 TI - Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide. AB - BACKGROUND: Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis. OBJECTIVE: We performed an international survey among physicians known to treat patients with AGAT deficiency, to assess clinical characteristics and long-term outcomes of this ultra-rare condition. RESULTS: 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness. Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels. 3 families had protein truncation/null mutations. The rest had missense and splice mutations. Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions. CONCLUSION: AGAT deficiency is a treatable intellectual disability. Early diagnosis may prevent IDD and myopathy. Patients with unexplained IDD with and without myopathy should be assessed for AGAT deficiency by determination of urine/plasma GAA and cerebral creatine levels (via brain MRS), and by GATM gene sequencing. PMID- 26490223 TI - Phase Diagram and High-Temperature Superconductivity of Compressed Selenium Hydrides. AB - Recent discovery of high-temperature superconductivity (Tc = 190 K) in sulfur hydrides at megabar pressures breaks the traditional belief on the Tc limit of 40 K for conventional superconductors, and opens up the doors in searching new high temperature superconductors in compounds made up of light elements. Selenium is a sister and isoelectronic element of sulfur, with a larger atomic core and a weaker electronegativity. Whether selenium hydrides share similar high temperature superconductivity remains elusive, but it is a subject of considerable interest. First-principles swarm structure predictions are performed in an effort to seek for energetically stable and metallic selenium hydrides at high pressures. We find the phase diagram of selenium hydrides is rather different from its sulfur analogy, which is indicated by the emergence of new phases and the change of relative stabilities. Three stable and metallic species with stoichiometries of HSe2, HSe and H3Se are identified above ~120 GPa and they all exhibit superconductive behaviors, of which the hydrogen-rich HSe and H3Se phases show high Tc in the range of 40-110 K. Our simulations established the high-temperature superconductive nature of selenium hydrides and provided useful route for experimental verification. PMID- 26490225 TI - Microparticle levels after arterial injury and NO therapy in diabetes. AB - BACKGROUND: Little is known about how arterial injury, nitric oxide (NO), or the diabetic milieu impact microparticle (MP) levels in the vasculature. We hypothesized that MP levels would increase following local arterial injury, and that NO would modify MP levels differently based on the metabolic environment. MATERIALS AND METHODS: Type 1 diabetes was induced in male Lean Zucker (LZ) rats with streptozotocin, and type 2 diabetes was induced in male Zucker diabetic fatty rats through diet. Lean Zucker rats served as nondiabetic controls. The rat carotid balloon injury was performed +/- NO (n > 4/group). Blood was obtained at intervals from baseline to 14 d after injury and analyzed for platelet MP (PMP), leukocyte MP (LMP), and endothelial MP (EMP) using fluorescence-activated cell sorting (FACS) analysis. RESULTS: At baseline, type 1 diabetic rats had the highest EMP levels (P < 0.05). After arterial injury, type 1 and type 2 diabetic rats had a transient increase in EMP levels (P < 0.05) before decreasing below baseline levels. Both LMP and PMP levels generally declined after injury in all three animal models but were the lowest in both type 1 and type 2 diabetic rats. NO therapy had little impact on MP levels in nondiabetic and type 1 diabetic rats after injury. Conversely, NO caused a dramatic increase in EMP, LMP, and PMP levels in type 2 diabetic animals at early time points after injury (P < 0.05). CONCLUSIONS: These data demonstrate that the diabetic milieu impacts MP levels at baseline, after arterial injury and with NO treatment. PMID- 26490226 TI - Lateral thoracic artery perforator-based flap: a new experimental model. AB - BACKGROUND: The aim of this study was to describe a new experimental perforator based flap in rats, supplied by lateral thoracic artery perforator. METHODS: Through out the study, two control and two experimental groups were created consisting of six rats in each group. In the first control group (group 1), mid axillary line and the fourth intercostal space intersection were used as the center of the flap. A 3 * 2 cm flap was designed and elevated above the cutaneous maximus muscle by transecting all connections with the muscle. In the second control group (group 2), the flap was extended caudally, and 3 * 6 cm flap was designed. Then, the flap was elevated in the same manner as it was described for group 1. In the first experimental group (group 3) 3 * 2 cm flap and in the second experimental group (group 4) 3 * 6 cm flap were designed like control groups. The flaps were islanded on a single musculocutan perforator arising from lateral thoracic artery. The surviving skin paddle areas were calculated on postoperative day 7. RESULTS: The flap viability was calculated 0% for control groups (groups 1 and 2), 100% for the first experimental group (group 3), between 33.3% and 37.7% for the second experimental group (group 4; mean +/- standard deviation, 34.76% +/- 1.92%). CONCLUSIONS: This new lateral thoracic artery perforator-based flap has a constant anatomy and reliable survival pattern. Also, easy harvesting and the possibility of designing two flaps per animal make this new flap an appealing model for pathophysiological or pharmacologic researches. PMID- 26490224 TI - Modeling of autosomal-dominant retinitis pigmentosa in Caenorhabditis elegans uncovers a nexus between global impaired functioning of certain splicing factors and cell type-specific apoptosis. AB - Retinitis pigmentosa (RP) is a rare genetic disease that causes gradual blindness through retinal degeneration. Intriguingly, seven of the 24 genes identified as responsible for the autosomal-dominant form (adRP) are ubiquitous spliceosome components whose impairment causes disease only in the retina. The fact that these proteins are essential in all organisms hampers genetic, genomic, and physiological studies, but we addressed these difficulties by using RNAi in Caenorhabditis elegans. Our study of worm phenotypes produced by RNAi of splicing related adRP (s-adRP) genes functionally distinguishes between components of U4 and U5 snRNP complexes, because knockdown of U5 proteins produces a stronger phenotype. RNA-seq analyses of worms where s-adRP genes were partially inactivated by RNAi, revealed mild intron retention in developing animals but not in adults, suggesting a positive correlation between intron retention and transcriptional activity. Interestingly, RNAi of s-adRP genes produces an increase in the expression of atl-1 (homolog of human ATR), which is normally activated in response to replicative stress and certain DNA-damaging agents. The up-regulation of atl-1 correlates with the ectopic expression of the pro apoptotic gene egl-1 and apoptosis in hypodermal cells, which produce the cuticle, but not in other cell types. Our model in C. elegans resembles s-adRP in two aspects: The phenotype caused by global knockdown of s-adRP genes is cell type-specific and associated with high transcriptional activity. Finally, along with a reduced production of mature transcripts, we propose a model in which the retina-specific cell death in s-adRP patients can be induced through genomic instability. PMID- 26490228 TI - Metabolic and functional changes in retinitis pigmentosa: comparing retinal vessel oximetry to full-field electroretinography, electrooculogram and multifocal electroretinography. AB - PURPOSE: To determine a relationship between the retinal vessel saturation alterations and the residual retinal function measured by means of full-field electroretinography (full-field ERG), electrooculogram (EOG) and multifocal electroretinography (mfERG) in patients with retinitis pigmentosa (RP). METHODS: Retinal vessel oximetry (RO), full-field ERG, EOG and mfERG were performed on 43 eyes of 22 patients suffering from RP and were compared to those of 26 eyes of 13 healthy controls. The oxygen saturation in the first and second branch retinal arterioles (A-SO2 ) and venules (V-SO2 ) was measured, and their difference (A-V SO2 ) was calculated. Full-field ERG amplitudes, EOG parameters and averaged mfERG response amplitudes (within central 3 degrees , between 3 degrees and 8 degrees , 8 degrees and 15 degrees , 15 degrees and 24 degrees ) were evaluated in relation to the RO measurements. RESULTS: V-SO2 correlated negatively with the full-field ERG and EOG values, with increasing functional damage the V-SO2 was higher. The RP group was well distinguished from the controls when the RO measurements were correlated to the averaged N1 (baseline to trough), but also to the N1P1 (trough-to-peak) mfERG response amplitudes. Receiver operating characteristic (ROC) curve of V-SO2 , compared to those of N1 and N1P1 mfERG response averages (15-24 degrees ), presented a high differential margin between RP and controls (p < 0.001), shown by an area under the ROC curve of 0.912 (95% CI: 0.840-0.984). CONCLUSION: Retinal vessel saturation showed a significant relation to full-field ERG, EOG and mfERG. Thus, retinal vessel oximetry could potentially complement electrophysiological tests in monitoring disease progression in patients with RP. PMID- 26490227 TI - Sublobar resection is equivalent to lobectomy for T1a non-small cell lung cancer in the elderly: a Surveillance, Epidemiology, and End Results database analysis. AB - BACKGROUND: Anatomic lobectomy with mediastinal lymph node dissection is considered the optimal management for early stage non-small cell lung cancer (NSCLC). Limited lung resection may be preferable in the elderly population, who are more likely to have poor pulmonary reserve and multiple comorbidities. Our primary objective was to compare the survival of patients aged >= 75 y who underwent sublobar resection or lobectomy for stage IA NSCLC. MATERIALS AND METHODS: We queried the Surveillance, Epidemiology, and End Results database for patients aged >= 75 y who were diagnosed with stage IA NSCLC from 1998-2007. Patients were divided into three groups based on the type of surgery performed (wedge resection, segmentectomy, and lobectomy). Kaplan-Meier analysis and Cox proportional hazard model were used for survival analysis. RESULTS: A total of 1640 patients were analyzed. Lobectomy was performed in 1051 patients, 119 underwent segmentectomy, and 470 patients had wedge resection. Overall and cancer specific survival were significantly lower in the wedge resection group as compared with those in lobectomy (P < 0.05). However, for T1a tumors, no significant difference was found in risk adjusted 5-y cancer-specific survival for patients who underwent wedge resection, segmentectomy (hazard ratio, 1.009; 95% confidence interval 0.624-1.631; P = 0.972), or lobectomy (hazard ratio, 0.98; 95% confidence interval, 0.691-1.388; P = 0.908). CONCLUSIONS: Sublobar resection is not inferior to lobectomy for T1a N0 M0 NSCLC in the elderly and should be considered a viable alternative in this high-risk population. PMID- 26490230 TI - Performance Invalidity Base Rates Among Healthy Undergraduate Research Participants. AB - Few studies have examined base rates of suboptimal effort among healthy, undergraduate students recruited for neuropsychological research. An and colleagues (2012, Conducting research with non-clinical healthy undergraduates: Does effort play a role in neuropsychological test performance? Archives of Clinical Neuropsychology, 27, 849-857) reported high rates of performance invalidity (30.8%-55.6%), calling into question the validity of findings generated from samples of college students. In contrast, subsequent studies have reported much lower base rates ranging from 2.6% to 12%. The present study replicated and extended previous work by examining the performance of 108 healthy undergraduates on the Dot Counting Test, Victoria Symptom Validity Test, Word Memory Test, and a brief battery of neuropsychological measures. During initial testing, 8.3% of the sample scored below cutoffs on at least one Performance Validity Test, while 3.7% were classified as invalid at Time 2 (M interval = 34.4 days). The present findings add to a growing number of studies that suggest performance invalidity base rates in samples of non-clinical, healthy college students are much lower than An and colleagues initial findings. Although suboptimal effort is much less problematic than suggested by An and colleagues, recent reports as high as 12% indicate including measures of effort may be of value when using college students as participants. Methodological issues and recommendations for future research are presented. PMID- 26490229 TI - Development of a simple genotyping method for the HLA-A*31:01-tagging SNP in Japanese. AB - AIM: To construct a simple, low-cost typing method for the surrogate marker of HLA-A*31:01, a risk factor for carbamazepine (CBZ) related Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). MATERIALS & METHODS: DNAs from Japanese SJS/TEN patients were used for genotyping and developing the assay. RESULTS: HLA-A*31:01 was confirmed to be significantly associated with definite/probable cases of CBZ-related SJS/TEN (p = 0.0040). Three single nucleotide polymorphisms, rs1150738, rs3869066 and rs259945, were in absolute linkage disequilibrium with HLA-A*31:01 in 210 Japanese SJS/TEN patients. Robust genotyping of rs3869066 in ZNRD1-AS1 was developed using polymerase chain reaction-restriction fragment length polymorphism assays. CONCLUSION: Single nucleotide polymorphism genotyping is less time consuming and cheaper than conventional HLA typing, and would be useful for identifying Japanese patients at risk of CBZ-related SJS/TEN. PMID- 26490231 TI - A Confirmatory Factor Analytic Study of the Wechsler Memory Scale-III in an Elderly Norwegian Sample. AB - This study compared the factor structure of the translated Wechsler Memory Scale III (WMS-III), which is the latest available version in Norway, with the original U.S. version. A sample of 122 healthy, elderly Norwegians (mean age: 74; standard deviation = 8.8) completed the WMS-III. The factor structure of the translated WMS-III was tested, using Confirmatory Factor Analysis, with comparison of model fit based on five a priori hypothesized models. Several model fit indices pointed to a three-factor model (working memory, visual memory, and auditory memory) providing the best fit to the data. Our study supports updated findings of the original WMS-III in nonclinical samples and suggests that the translated version is structurally equal to the original. The study supports the cross-cultural validity of the WMS-III. However, based on the present data, one might expect scores on the Family Pictures subtest to fall below scores on other WMS-III subtests in elderly Norwegians. PMID- 26490232 TI - [Manufacture and Utilization of a Low-level Radioactive 68Ge/68Ga Generator in a Radiochemistry Laboratory Course]. AB - The low-level radioactivity of a (68)Ge/(68)Ga generator is a suitable tool for measuring radioactive growth and decay after (68)Ga milking due to their desirable nuclear decay properties, such as the EC decay of (68)Ge with no gamma ray emission andthe beta(+) decay of (68)Ga with a weak gamma-ray emission. To experience andund erstandrad ioactive equilibrium during a university laboratory course, we surveyedandtestedthe production of a small amount of (68)Ge and set up educational programs to manufacture a (68)Ge/(68)Ga generator for measuring the growth andd ecay of (68)Ga. The irradiation of natGa with 25 MUA of a 30 MeV proton beam from a cyclotron for 4 h yields ca. 111 MBq of (68)Ge, which was sufficient to supply to several universities. For use as the adsorbent of the generator column, particles of hydrated tin (VI) oxide were prepared from precipitated tin hydroxide gel. Repeated elution of (68)Ga from the handmade (68)Ge/(68)Ga generator gave constant amounts of (68)Ga with acceptable breakthrough of (68)Ge. The feedback from the student's experience with the (68)Ge/(68)Ga generator was evaluatedby annual questionnaire surveys, which were given to all students taking the course every year from 2012 to 2014. It has been made clear that more than half of the students were interested in the (68)Ge/(68)Ga generator program, andthis interest increasedfrom 54.9%in 2012 to 78.6%in 2014. A low-level radioactive (68)Ge/(68)Ga generator is thus expectedto be a suitable experimental tool for demonstrating the phenomenon of radioactivity to students in an intriguing way. PMID- 26490233 TI - [Evaluation of Resolution Characteristics in Three-dimensional MR Imaging Using Single Plate Thin-Ramp Method]. AB - Recent remarkable progress of fast imaging techniques in 3D MRI has emphasized the importance of evaluation of its resolution characteristics. A trial point spread function (PSF) measurement was conducted using the ramp method, a conventional measurement method for the slice profile of 2D imaging, as an approach to evaluate the resolution characteristics of 3D imaging. However, problems peculiar to 3D imaging have arisen, such as artifacts and offsets in the slice selective direction. Therefore, we attempted PSF measurement using a phantom having a single-plate construction with only a simple ramp part (Single Plate Thin-Ramp Method) to respond to these shortcomings. By employing appropriate positioning and simple post processing, we obtained a PSF easily in both phase encoding and slice selective directions without the artifacts and offsets described above. Furthermore, it was possible to evaluate the change of resolution characteristics depending on the scan condition in three-dimensional MR image. PMID- 26490234 TI - [Usefulness of the Training of Trigger Point in Coronary CT Using Test Bolus Tracking Method]. AB - BACKGROUND: Test bolus tracking (TBT) method has been used in coronary CT examination, because it is possible to examine the optimum contrast timing. However, the scan timing highly depends on an operators' recognition of peak in test bolus, thus there is a possibility of variation in contrast effect. PURPOSE: The aim of this study is to improve the variation of contrast effect among the operators. METHODS: The training for the operators was conducted to acknowledge them the optimal trigger points. The mean CT value and standard deviation of the ascending aorta were calculated to compare before and after the training. RESULTS: The mean CT value of the ascending aorta after the training was 485.02+/ 73.06 HU, compared to 462.53+/-78.26 HU before the training. Standard deviation was significantly lower than before the training. CONCLUSION: The variation of contrast effect between the operators has been reduced by the training, and reproducibility of the examination has been improved. PMID- 26490235 TI - [The Efficacy of Interpretation Support of Radiogram is a Research Theme as JSRT]. PMID- 26490236 TI - [Diffusion-weighted MR Imaging: Basic Principles and Clinical Applications]. PMID- 26490237 TI - [10. Summarize of Feature Article about the Cerebral Disease]. PMID- 26490238 TI - [Participation/Dispatch Reports on International Conferences in 2015]. PMID- 26490239 TI - [Participation/Dispatch Report on the Korean Society of Radiological Science in 2015]. PMID- 26490240 TI - [Review of Workshop "Plactice: How to Learn and Teach Normal Chest Radiograph?"]. PMID- 26490241 TI - [IMDRF Tokyo Meeting (The Activities for Harmonization and Convergence of Medical Device Regulations)]. PMID- 26490242 TI - [Lay the Foundations for Ten Years from Now]. PMID- 26490243 TI - An International Survey to Understand Infection Control Practices for Spinal Cord Stimulation. AB - OBJECTIVES: Surgical site infections (SSIs) are associated with significant healthcare costs and morbidity. Limited research exists specific to the prevention of spinal cord stimulation (SCS) SSIs. The objectives of this international survey were to examine current infection control practices for SCS trials and implants and to compare reported responses with evidence-based recommendations. MATERIALS AND METHODS: A 33-question survey was developed based on an extensive literature review for infection control policies. The survey was hosted on the Internet. Dispersion of the survey occurred through professional associations and device manufacturers. Responses to 15 questions directly related to defined CDC, NICE, and SCIP evidence-based infection control practice recommendations were classified as either compliant or noncompliant. The survey was open for 20 days. Responses also were grouped and analyzed based on geographic location, practice location, and procedural volumes. RESULTS: Five hundred six physicians responded to the survey. Compliance rates for CDC, NICE, SCIP infection control practice recommendations were low with only four of the 15 questions having compliance rates >=80%. Areas associated with high levels of noncompliance included weight-based antibiotic dosing, hair removal strategies, double gloving, surgical dressing, skin antiseptic agent selection, and postoperative continuation of antibiotics. Geographic and practice type variations existed for particular infection control practices. Procedural volume influenced operative implant times with low physician procedural volumes associated with extended operative times. CONCLUSIONS: The survey provided significant insight into current practices and will assist in the development of specific SCS infection control policies. Based on the survey, further education is warranted on infection control strategies for physicians performing spinal cord stimulator trials and implants. PMID- 26490245 TI - Voltage-Gated R-Type Calcium Channel Inhibition via Human MU-, delta-, and kappa opioid Receptors Is Voltage-Independently Mediated by Gbetagamma Protein Subunits. AB - Elucidating the mechanisms that modulate calcium channels via opioid receptor activation is fundamental to our understanding of both pain perception and how opioids modulate pain. Neuronal voltage-gated N-type calcium channels (Cav2.2) are inhibited by activation of G protein-coupled opioid receptors (ORs). However, inhibition of R-type (Cav2.3) channels by MU- or kappa-ORs is poorly defined and has not been reported for delta-ORs. To investigate such interactions, we coexpressed human MU-, delta-, or kappa-ORs with human Cav2.3 or Cav2.2 in human embryonic kidney 293 cells and measured depolarization-activated Ba(2+) currents (IBa). Selective agonists of MU-, delta-, and kappa-ORs inhibited IBa through Cav2.3 channels by 35%. Cav2.2 channels were inhibited to a similar extent by kappa-ORs, but more potently (60%) via MU- and delta-ORs. Antagonists of delta- and kappa-ORs potentiated IBa amplitude mediated by Cav2.3 and Cav2.2 channels. Consistent with G protein betagamma (Gbetagamma) interaction, modulation of Cav2.2 was primarily voltage-dependent and transiently relieved by depolarizing prepulses. In contrast, Cav2.3 modulation was voltage-independent and unaffected by depolarizing prepulses. However, Cav2.3 inhibition was sensitive to pertussis toxin and to intracellular application of guanosine 5'-[beta-thio]diphosphate trilithium salt and guanosine 5'-[gamma-thio]triphosphate tetralithium salt. Coexpression of Gbetagamma-specific scavengers-namely, the carboxyl terminus of the G protein-coupled receptor kinase 2 or membrane-targeted myristoylated phosducin-attenuated or abolished Cav2.3 modulation. Our study reveals the diversity of OR-mediated signaling at Cav2 channels and identifies neuronal Cav2.3 channels as potential targets for opioid analgesics. Their novel modulation is dependent on pre-existing OR activity and mediated by membrane delimited Gbetagamma subunits in a voltage-independent manner. PMID- 26490244 TI - Plasmodium parasites mount an arrest response to dihydroartemisinin, as revealed by whole transcriptome shotgun sequencing (RNA-seq) and microarray study. AB - BACKGROUND: Control of malaria is threatened by emerging parasite resistance to artemisinin and derivative drug (ART) therapies. The molecular detail of how Plasmodium malaria parasites respond to ART and how this could contribute to resistance are not well understood. To address this question, we performed a transcriptomic study of dihydroartemisinin (DHA) response in P. falciparum K1 strain and in P. berghei ANKA strain using microarray and RNA-seq technology. RESULTS: Microarray data from DHA-treated P. falciparum trophozoite stage parasites revealed a response pattern that is overall less trophozoite-like and more like the other stages of asexual development. A meta-analysis of these data with previously published data from other ART treatments revealed a set of common differentially expressed genes. Notably, ribosomal protein genes are down regulated in response to ART. A similar pattern of trophozoite transcriptomic change was observed from RNA-seq data. RNA-seq data from DHA-treated P. falciparum rings reveal a more muted response, although there is considerable overlap of differentially expressed genes with DHA-treated trophozoites. No genes are differentially expressed in DHA-treated P. falciparum schizonts. The transcriptional response of P. berghei to DHA treatment in vivo in infected mice is similar to the P. falciparum in vitro culture ring and trophozoite responses, in which ribosomal protein genes are notably down-regulated. CONCLUSIONS: Ring and trophozoite stage Plasmodium respond to ART by arresting metabolic processes such as protein synthesis and glycolysis. This response can be protective in rings, as shown by the phenomenon of dormancy. In contrast, this response is not as protective in trophozoites owing to their commitment to a highly active and vulnerable metabolic state. The lower metabolic demands of schizonts could explain why they are less sensitive and unresponsive to ART. The ART response pattern is revealed clearly from RNA-seq data, suggesting that this technology is of great utility for studying drug response in Plasmodium. PMID- 26490246 TI - Inactivation of Human Cytochrome P450 3A4 and 3A5 by Dronedarone and N-Desbutyl Dronedarone. AB - Dronedarone is an antiarrhythmic agent approved in 2009 for the treatment of atrial fibrillation. An in-house preliminary study demonstrated that dronedarone inhibits cytochrome P450 (CYP) 3A4 and 3A5 in a time-dependent manner. This study aimed to investigate the inactivation of CYP450 by dronedarone. We demonstrated for the first time that both dronedarone and its main metabolite N-desbutyl dronedarone (NDBD) inactivate CYP3A4 and CYP3A5 in a time-, concentration-, and NADPH-dependent manner. For the inactivation of CYP3A4, the inactivator concentration at the half-maximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 0.87 uM and 0.039 minute( 1), respectively, for dronedarone, and 6.24 uM and 0.099 minute(-1), respectively, for NDBD. For CYP3A5 inactivation, the inactivator concentration at the half-maximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 2.19 uM and 0.0056 minute(-1) for dronedarone and 5.45 uM and 0.056 minute(-1) for NDBD. The partition ratios for the inactivation of CYP3A4 and CYP3A5 by dronedarone are 51.1 and 32.2, and the partition ratios for the inactivation of CYP3A4 and CYP3A5 by NDBD are 35.3 and 36.6. Testosterone protected both CYP3A4 and CYP3A5 from inactivation by dronedarone and NDBD. Although the presence of Soret peak confirmed the formation of a quasi-irreversible metabolite-intermediate complex between dronedarone/NDBD and CYP3A4/CYP3A5, partial recovery of enzyme activity by potassium ferricyanide illuminated an alternative irreversible mechanism-based inactivation (MBI). MBI of CYP3A4 and CYP3A5 was further supported by the discovery of glutathione adducts derived from the quinone oxime intermediates of dronedarone and NDBD. In conclusion, dronedarone and NDBD inactivate CYP3A4 and CYP3A5 via unique dual mechanisms of MBI and formation of the metabolite-intermediate complex. Our novel findings contribute new knowledge for future investigation of the underlying mechanisms associated with dronedarone-induced hepatotoxicity and clinical drug drug interactions. PMID- 26490248 TI - Quantitative evaluation of the strategy to eliminate human African trypanosomiasis in the Democratic Republic of Congo. AB - BACKGROUND: The virulent vector-borne disease, Gambian human African trypanosomiasis (HAT), is one of several diseases targeted for elimination by the World Health Organization. This article utilises human case data from a high endemicity region of the Democratic Republic of Congo in conjunction with a suite of novel mechanistic mathematical models to address the effectiveness of on-going active screening and treatment programmes and compute the likely time to elimination as a public health problem (i.e. <1 case per 10,000 per year). METHODS: The model variants address uncertainties surrounding transmission of HAT infection including heterogeneous risk of exposure to tsetse bites, non participation of certain groups during active screening campaigns and potential animal reservoirs of infection. RESULTS: Model fitting indicates that variation in human risk of tsetse bites and participation in active screening play a key role in transmission of this disease, whilst the existence of animal reservoirs remains unclear. Active screening campaigns in this region are calculated to have been effective, reducing the incidence of new human infections by 52-53 % over a 15-year period (1998-2012). However, projections of disease dynamics in this region indicate that the elimination goal may not be met until later this century (2059-2092) under the current intervention strategy. CONCLUSIONS: Improvements to active detection, such as screening those who have not previously participated and raising overall screening levels, as well as beginning widespread vector control in the area have the potential to ensure successful and timely elimination. PMID- 26490249 TI - Characterization of intermittency in zooplankton behaviour in turbulence. AB - We consider Lagrangian velocity differences of zooplankters swimming in still water and in turbulence. Using cumulants, we quantify the intermittency properties of their motion recorded using three-dimensional particle tracking velocimetry. Copepods swimming in still water display an intermittent behaviour characterized by a high probability of small velocity increments, and by stretched exponential tails. Low values arise from their steady cruising behaviour while heavy tails result from frequent relocation jumps. In turbulence, we show that at short time scales, the intermittency signature of active copepods clearly differs from that of the underlying flow, and reflects the frequent relocation jumps displayed by these small animals. Despite these differences, we show that copepods swimming in still and turbulent flow belong to the same intermittency class that can be modelled by a log-stable model with non analytical cumulant generating function. Intermittency in swimming behaviour and relocation jumps may enable copepods to display oriented, collective motion under strong hydrodynamic conditions and thus, may contribute to the formation of zooplankton patches in energetic environments. PMID- 26490250 TI - Physicochemical analysis of slip flow phenomena in liquids under nanoscale confinement. AB - Eyring theory employs the statistical mechanical theory of absolute reaction rates to analyse the transport mechanisms in fluids. A physicochemical methodology combining molecular dynamics (MD) and Eyring theory of reaction rates is proposed for investigating the liquid slip on a solid wall in the nanoscale domain. The method involves the determination of activation energy required for the flow process directly from the MD trajectory information and then calculate the important transport properties of the confined fluid from the activation energy. In order to demonstrate the universal applicability of the proposed methodology in nanofluidics, the slip flow behavior of argon, water and ionic liquid confined in various nanostructures has been investigated. The slip length is found to be size dependent in all the cases. The novelty of this method is that the variations in slip length are explained on the basis of molecular interactions and the subsequent changes in the activation energy. PMID- 26490251 TI - Insertion and self-diffusion of a monotopic protein, the Aquifex aeolicus sulfide quinone reductase, in supported lipid bilayers. AB - Monotopic proteins constitute a class of membrane proteins that bind tightly to cell membranes, but do not span them. We present a FRAPP (Fluorescence Recovery After Patterned Photobleaching) study of the dynamics of a bacterial monotopic protein, SQR (sulfide quinone oxidoreductase) from the thermophilic bacteria Aquifex aeolicus, inserted into two different types of lipid bilayers (EggPC: L alpha-phosphatidylcholine (Egg, Chicken) and DMPC: 1,2-dimyristoyl-sn-glycero-3 phosphocholine) supported on two different types of support (mica or glass). It sheds light on the behavior of a monotopic protein inside the bilayer. The insertion of SQR is more efficient when the bilayer is in the fluid phase than in the gel phase. We observed diffusion of the protein, with no immobile fraction, and deduced from the diffusion coefficient measurements that the resulting inserted object is the same whatever the incubation conditions, i.e. homogeneous in terms of oligomerization state. As expected, the diffusion coefficient of the SQR is smaller in the gel phase than in the fluid phase. In the supported lipid bilayer, the diffusion coefficient of the SQR is smaller than the diffusion coefficient of phospholipids in both gel and fluid phase. SQR shows a diffusion behavior different from the transmembrane protein alpha-hemolysin, and consistent with its monotopic character. Preliminary experiments in the presence of the substrate of SQR, DecylUbiquinone, an analogue of quinone, component of transmembrane electrons transport systems of eukaryotic and prokaryotic organisms, have been carried out. Finally, we studied the behavior of SQR, in terms of insertion and diffusion, in bilayers formed with lipids from Aquifex aeolicus. All the conclusions that we have found in the biomimetic systems applied to the biological system. PMID- 26490252 TI - Downregulation of programmed cell death 10 is associated with tumor cell proliferation, hyperangiogenesis and peritumoral edema in human glioblastoma. AB - BACKGROUND: Neovascularization and peritumoral edema are hallmarks of glioblastoma (GBM). Programmed cell death 10 (PDCD10) plays a pivotal role in regulating apoptosis, neoangiogenesis and vessel permeability and is implicated in certain tumor signaling pathways. However, little is known about PDCD10 in GBM. We aimed to investigate the expression pattern of PDCD10 and to identify the association of its expression with some molecular and clinical parameters in human GBM. METHODS: mRNA and protein expression of PDCD10 were examined respectively by real-time RT-PCR and Western blotting in GBM (n = 27), astrocytoma grade II (n = 13) and control (n = 11). The protein level of p-Akt and GFAP was detected by Western blot. Double-imunofluorecent staining was performed to reveal the cellular expression profile of PDCD10. Brain edema and microvascular density (MVD) were respectively analyzed based on pre-operative MRI and after laminin immnostaining. MGMT promoter methylation was detected by methylation specific PCR. RESULTS: mRNA and protein levels of PDCD10 were significantly downregulated in GBM, concomitantly accompanied by the activation of Akt. PDCD10 immunoreactivity was absent in proliferating tumor cells, endothelial cells and GFAP-positive cells, but exclusively present in the hypoxic pseudopalisading cells which underwent apoptosis. Moreover, loss of PDCD10 was associated with a higher MVD and a more severe peritumoral edema but not with MGMT promoter methylation in GBM. CONCLUSION: We report for the first time that PDCD10 expression is downregulated in GBM, which is associated with the activation of Akt signaling protein. PDCD10 is potentially implicated in tumor proliferation and apoptosis, hyperangiogenesis and peritumoral edema in GBM. PMID- 26490253 TI - The spliceosome, a potential Achilles heel of MYC-driven tumors. AB - Alterations in RNA splicing are frequent in human tumors. Two recent studies of lymphoma and breast cancer have identified components of the spliceosome - the core splicing machinery - that are essential for malignant transformation driven by the transcription factor MYC. These findings provide a direct link between MYC and RNA splicing deregulation, and raise the exciting possibility of targeting spliceosome components in MYC-driven tumors. PMID- 26490254 TI - Multisensory Stimulation to Improve Low- and Higher-Level Sensory Deficits after Stroke: A Systematic Review. AB - The aim of this systematic review was to integrate and assess evidence for the effectiveness of multisensory stimulation (i.e., stimulating at least two of the following sensory systems: visual, auditory, and somatosensory) as a possible rehabilitation method after stroke. Evidence was considered with a focus on low level, perceptual (visual, auditory and somatosensory deficits), as well as higher-level, cognitive, sensory deficits. We referred to the electronic databases Scopus and PubMed to search for articles that were published before May 2015. Studies were included which evaluated the effects of multisensory stimulation on patients with low- or higher-level sensory deficits caused by stroke. Twenty-one studies were included in this review and the quality of these studies was assessed (based on eight elements: randomization, inclusion of control patient group, blinding of participants, blinding of researchers, follow up, group size, reporting effect sizes, and reporting time post-stroke). Twenty of the twenty-one included studies demonstrate beneficial effects on low- and/or higher-level sensory deficits after stroke. Notwithstanding these beneficial effects, the quality of the studies is insufficient for valid conclusion that multisensory stimulation can be successfully applied as an effective intervention. A valuable and necessary next step would be to set up well-designed randomized controlled trials to examine the effectiveness of multisensory stimulation as an intervention for low- and/or higher-level sensory deficits after stroke. Finally, we consider the potential mechanisms of multisensory stimulation for rehabilitation to guide this future research. PMID- 26490255 TI - Neurologic Disorders in Immunocompetent Patients with Autochthonous Acute Hepatitis E. AB - Neurologic disorders, mainly Guillain-Barre syndrome and Parsonage-Turner syndrome (PTS), have been described in patients with hepatitis E virus (HEV) infection in industrialized and developing countries. We report a wider range of neurologic disorders in nonimmunocompromised patients with acute HEV infection. Data from 15 French immunocompetent patients with acute HEV infection and neurologic disorders were retrospectively recorded from January 2006 through June 2013. The disorders could be divided into 4 main entities: mononeuritis multiplex, PTS, meningoradiculitis, and acute demyelinating neuropathy. HEV infection was treated with ribavirin in 3 patients (for PTS or mononeuritis multiplex). One patient was treated with corticosteroids (for mononeuropathy multiplex), and 5 others received intravenous immunoglobulin (for PTS, meningoradiculitis, Guillain-Barre syndrome, or Miller Fisher syndrome). We conclude that pleiotropic neurologic disorders are seen in HEV-infected immunocompetent patients. Patients with acute neurologic manifestations and aminotransferase abnormalities should be screened for HEV infection. PMID- 26490256 TI - Perceived discrimination amongst young people in socio-economically disadvantaged communities: Parental support and community identity buffer (some) negative impacts of stigma. AB - There is increasing acceptance that children are not unaware of when they are targets of discrimination. However, discrimination as a consequence of socio economic disadvantage remains understudied. The aim of this study was to examine the impact of perceived discrimination on well-being, perceptions of safety and school integration amongst children growing up within socio-economically disadvantaged communities in Limerick, Ireland. Mediation analysis was used to explore these relationships and to examine the potential role of parental support and community identity in boys and girls in the 6th to 9th year of compulsory education (N = 199). Results indicate perceived discrimination contributed to negative outcomes in terms of school integration, perceptions of safety and levels of well-being. Age and gender differences were observed which disadvantaged boys and younger children. All negative outcomes were buffered by parental support. Community identity also protected young people in terms of feelings of school integration and risk but not in terms of psychological well being. Findings are discussed in terms of the different role of family and community supports for children negotiating negative social representations of their community. PMID- 26490258 TI - Cycloamidination of Aminoalkenes with Nitriles: Synthesis of Substituted 2 Imidazolines and Tetrahydropyrimidines. AB - The first catalytic cycloamidination of aminoalkenes with nitriles has been achieved by using rare-earth complexes. This reaction is equivalent to the desired intramolecular hydroamination of alkenylamidines, and allows a new direct access to substituted 2-imidazolines and tetrahydropyrimidines in high yields under operationally simple reaction conditions. Moreover, the methodology is also efficient for synthesis of symmetric and unsymmetric bridged diimidazolines. Compared with the traditional stepwise-mediated synthetic approaches, the present method avoids the use of additives and harsh reaction conditions, and thus leads to a completely different product distribution. Mechanistic data suggest that the reaction involves the initial NH activation by lanthanide complex followed by nitrile insertion into a Ln-N bond to form an amidinate lanthanide intermediate which undergoes the cyclization. PMID- 26490259 TI - Age-related changes in murine myometrial transcript profile are mediated by exposure to the female sex hormones. AB - In humans, the risk of operative first delivery increases linearly with maternal age. We previously hypothesized that prolonged, cyclical, prepregnancy exposure to estrogen and progesterone contributes to uterine aging. Here, we test this hypothesis. Myometrium was obtained from four groups of virgin mice: (i) 10- to 12-week- and 28- to 30-week-old mice; (ii) 10- to 12-week- and 38- to 40-week-old mice; (iii) 38-week-old mice that had an ovariectomy or sham operation early in life; (iv) 38-week-old mice that had been treated with progesterone or vehicle containing implants from 8 to 36 weeks. Transcript profiling was carried out using Affymetrix Gene ST 1.1 arrays, and data were normalized. We identified 60 differentially regulated transcripts associated with advancing age (group 1). We validated these changes in group 2 (P for overlap = 5.8 * 10(-46) ). Early ovariectomy prevented the age-related changes in myometrial transcript profile. Similarly, progesterone-mediated long-term ovarian suppression prevented the age related changes in myometrial transcript profile. Interferon regulatory factor 7 (Irf7) mRNA was regulated by age and hormonal exposure, and was identified as a predicted regulator of the other differentially expressed transcripts by both promoter sequence and canonical pathway activation analysis (P = 8.47 * 10(-5) and P < 10(-10) , respectively). Immunohistochemistry demonstrated IRF7 in both mouse and human myometrium. We conclude the following: (i) Myometrial aging in mice is associated with reproducible changes in transcript profile; (ii) these changes can be prevented by interventions which inhibit cyclical changes in the female sex hormones; and (iii) IRF7 may be an important regulator of myometrial function and aging. PMID- 26490260 TI - Auditory Sensory Substitution is Intuitive and Automatic with Texture Stimuli. AB - Millions of people are blind worldwide. Sensory substitution (SS) devices (e.g., vOICe) can assist the blind by encoding a video stream into a sound pattern, recruiting visual brain areas for auditory analysis via crossmodal interactions and plasticity. SS devices often require extensive training to attain limited functionality. In contrast to conventional attention-intensive SS training that starts with visual primitives (e.g., geometrical shapes), we argue that sensory substitution can be engaged efficiently by using stimuli (such as textures) associated with intrinsic crossmodal mappings. Crossmodal mappings link images with sounds and tactile patterns. We show that intuitive SS sounds can be matched to the correct images by naive sighted participants just as well as by intensively-trained participants. This result indicates that existing crossmodal interactions and amodal sensory cortical processing may be as important in the interpretation of patterns by SS as crossmodal plasticity (e.g., the strengthening of existing connections or the formation of new ones), especially at the earlier stages of SS usage. An SS training procedure based on crossmodal mappings could both considerably improve participant performance and shorten training times, thereby enabling SS devices to significantly expand blind capabilities. PMID- 26490257 TI - Splenium development and early spoken language in human infants. AB - The association between developmental trajectories of language-related white matter fiber pathways from 6 to 24 months of age and individual differences in language production at 24 months of age was investigated. The splenium of the corpus callosum, a fiber pathway projecting through the posterior hub of the default mode network to occipital visual areas, was examined as well as pathways implicated in language function in the mature brain, including the arcuate fasciculi, uncinate fasciculi, and inferior longitudinal fasciculi. The hypothesis that the development of neural circuitry supporting domain-general orienting skills would relate to later language performance was tested in a large sample of typically developing infants. The present study included 77 infants with diffusion weighted MRI scans at 6, 12 and 24 months and language assessment at 24 months. The rate of change in splenium development varied significantly as a function of language production, such that children with greater change in fractional anisotropy (FA) from 6 to 24 months produced more words at 24 months. Contrary to findings from older children and adults, significant associations between language production and FA in the arcuate, uncinate, or left inferior longitudinal fasciculi were not observed. The current study highlights the importance of tracing brain development trajectories from infancy to fully elucidate emerging brain-behavior associations while also emphasizing the role of the splenium as a key node in the structural network that supports the acquisition of spoken language. PMID- 26490261 TI - A physical entrapment method for the preparation of carbon nanotube reinforced macroporous adsorption resin with enhanced selective extraction performance. AB - In this paper, we demonstrate a novel carbon nanotube (CNT) reinforced macroporous adsorption resin (MAR) for the first time. The CNTs were dispersed in water via sonication, and then in situ physically entrapped in the pores of MAR by capillary forces and sonication. The resulting CNT reinforced MAR (CNT-MAR) was proved by transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM), and subsequently applied to extract a mixture of 8 types, 14 natural products. For comparison, the extraction efficiency of original MAR without CNTs was also evaluated. After extraction, the supernatants were detected via high-performance liquid chromatography (HPLC). The results indicated that the introduction of carbon nanotubes (CNTs) into the pores of MAR can significantly improve the adsorptive selectivity of MAR for natural products. The original MAR without CNTs has almost the same adsorption capacity for selectively extracting 3 types of natural products (phenols, alkaloids and anthraquinones). However, the CNT-MAR only could selectively extract anthraquinones and the adsorption capacity for three anthraquinone natural products is 1.46-1.83 times higher than that of unmodified MAR. In order to achieve the highest extraction efficiency of CNT-MAR for anthraquinone natural products, the main extraction parameters such as the extraction time and the pH value were also optimized. The CNT-MAR demonstrated an excellent ability to extract anthraquinone natural products with high selectivity and adsorption capacity. Due to its low cost, easy preparation and use, and operational characteristics, it shows great potential for selective extraction of natural products. PMID- 26490263 TI - SDH-NET: a South-North-South collaboration to build sustainable research capacities on social determinants of health in low- and middle-income countries. AB - BACKGROUND: It is desirable that health researchers have the ability to conduct research on health equity and contribute to the development of their national health system and policymaking processes. However, in low- and middle-income countries (LMICs), there is a limited capacity to conduct this type of research due to reasons mostly associated with the status of national (health) research systems. Building sustainable research capacity in LMICs through the triangulation of South-North-South (S-N-S) collaborative networks seems to be an effective way to maximize limited national resources to strengthen these capacities. This article describes how a collaborative project (SDH-Net), funded by the European Commission, has successfully designed a study protocol and a S-N S collaborative network to effectively support research capacity building in LMICs, specifically in the area of social determinants of health (SDH); this project seeks to elaborate on the vital role of global collaborative networks in strengthening this practice. METHODS: The implementation of SDH-Net comprised diverse activities developed in three phases. Phase 1: national level mapping exercises were conducted to assess the needs for SDH capacity building or strengthening in local research systems. Four strategic areas were defined, namely research implementation and system performance, social appropriation of knowledge, institutional and national research infrastructure, and research skills and training/networks. Phase 2: development of tools to address the identified capacity building needs, as well as knowledge management and network strengthening activities. Phase 3: identifying lessons learned in terms of research ethics, and how policies can support the capacity building process in SDH research. RESULTS: The implementation of the protocol has led the network to design innovative tools for strengthening SDH research capacities, under a successful S-N-S collaboration that included national mapping reports, a global open-access learning platform with tools and resources, ethical guidelines for research, policy recommendations, and academic contributions to the global SDH discourse. CONCLUSIONS: The effective triangulation of S-N-S partnerships can be of high value in building sustainable research capacity in LMICs. If designed appropriately, these multicultural, multi-institutional, and multidisciplinary collaborations can enable southern and northern academics to contextualize global research according to their national realities. PMID- 26490262 TI - Nuclear import mechanism of neurofibromin for localization on the spindle and function in chromosome congression. AB - Neurofibromatosis type-1 (NF-1) is caused by mutations in the tumor suppressor gene NF1; its protein product neurofibromin is a RasGTPase-activating protein, a property that has yet to explain aneuploidy, most often observed in astrocytes in NF-1. Here, we provide a mechanistic model for the regulated nuclear import of neurofibromin during the cell cycle and for a role in chromosome congression. Specifically, we demonstrate that neurofibromin, phosphorylated on Ser2808, a residue adjacent to a nuclear localization signal in the C-terminal domain (CTD), by Protein Kinase C-epsilon (PKC-epsilon), accumulates in a Ran-dependent manner and through binding to lamin in the nucleus at G2 in glioblastoma cells. Furthermore, we identify CTD as a tubulin-binding domain and show that a phosphomimetic substitution of its Ser2808 results in a predominantly nuclear localization. Confocal analysis shows that endogenous neurofibromin localizes on the centrosomes at interphase, as well as on the mitotic spindle, through direct associations with tubulins, in glioblastoma cells and primary astrocytes. More importantly, analysis of mitotic phenotypes after siRNA-mediated depletion shows that acute loss of this tumor suppressor protein leads to aberrant chromosome congression at the metaphase plate. Therefore, neurofibromin protein abundance and nuclear import are mechanistically linked to an error-free chromosome congression. Concerned with neurofibromin's, a tumor suppressor, mechanism of action, we demonstrate in astrocytic cells that its synthesis, phosphorylation by Protein Kinase C-epsilon on Ser2808 (a residue adjacent to a nuclear localization sequence), and nuclear import are cell cycle-dependent, being maximal at G2. During mitosis, neurofibromin is an integral part of the spindle, while its depletion leads to aberrant chromosome congression, possibly explaining the development of chromosomal instability in Neurofibromatosis type-1. Read the Editorial Highlight for this article on page 11. Cover Image for this issue: doi: 10.1111/jnc.13300. PMID- 26490265 TI - Ultrathin g-C3 N4 Nanosheets Coupled with AgIO3 as Highly Efficient Heterostructured Photocatalysts for Enhanced Visible-Light Photocatalytic Activity. AB - The photocatalytic activity of graphite-like carbon nitride (g-C3 N4 ) could be enhanced by heterojunction strategies through increasing the charge-separation efficiency. As a surface-based process, the heterogeneous photocatalytic process would become more efficient if a larger contact region existed in the heterojunction interface. In this work, ultrathin g-C3 N4 nanosheets (g-C3 N4 NS) with much larger specific surface areas are employed instead of bulk g-C3 N4 (g-C3 N4 -B) to prepare AgIO3 /g-C3 N4 -NS nanocomposite photocatalysts. By taking advantage of this feature, the as-prepared composites exhibit remarkable performances for photocatalytic wastewater treatment under visible-light irradiation. Notably, the optimum photocatalytic activity of AgIO3 /g-C3 N4 -NS composites is almost 80.59 and 55.09 times higher than that of pure g-C3 N4 -B towards the degradation of rhodamine B and methyl orange pollutants, respectively. Finally, the stability and possible photocatalytic mechanism of the AgIO3 /g-C3 N4 -NS system are also investigated. PMID- 26490266 TI - Prognostic impact of TID in regadenoson MPI: Some patients and certain events. PMID- 26490268 TI - Erratum to: Global standards for global health in a globalized economy! PMID- 26490267 TI - Prognostic value of transient ischemic dilation with regadenoson myocardial perfusion imaging. AB - BACKGROUND: Transient ischemic dilation (TID) of the left ventricle seen on myocardial perfusion imaging (MPI) is sometimes used as a marker of severe coronary artery disease. The prognostic value of TID obtained using regadenoson, a selective adenosine A2A receptor agonist, as a stress agent for MPI has not been studied. METHODS: TID ratio was measured using an automated software program on consecutive patients with normal and abnormal perfusion pattern on regadenoson MPI at a single institution. An abnormal TID was defined as greater than 1.33. The primary outcome was a composite of cardiac death, non-fatal myocardial infarction (MI), and late coronary revascularization (CR, >90 days after MPI). RESULTS: The study population consisted of 887 patients (62 +/- 12 years, 66% male, 48% diabetes, 46% prior CR, 75% with abnormal perfusion pattern, left ventricular ejection fraction-LVEF 55 +/- 6%). An abnormal TID was present in 51 (6%) patients. Baseline characteristics were not different based on the presence or absence of TID. Early CR (<=90 days) was performed in 11 (22%) patients with vs 92 (11%) patients without TID (P = .04). During a mean follow-up of 29 +/- 19 months, the primary outcome occurred in 271 (31%) patients (22% cardiac death, 6% MI, 9% late CR). TID was associated with increased risk of the primary outcome (log-rank P = .017), an association largely driven by late CR. In a Cox proportional model adjusted for multiple variables including perfusion defect size (PDS) and LVEF, the hazard ratio for TID was 1.92 (95% CI 1.20-3.08, P = .007). In the subset of patients with normal perfusion pattern, there was no association between TID and outcomes. CONCLUSIONS: TID on regadenoson MPI carries important prognostic information that is independent from PDS and LVEF, but this association is restricted to patients with abnormal perfusion on imaging. PMID- 26490270 TI - Clear guidance on calcium and vitamin D supplements is lacking. PMID- 26490269 TI - Evaluation and directed evolution for thermostability improvement of a GH 13 thermostable alpha-glucosidase from Thermus thermophilus TC11. AB - BACKGROUND: Thermal stable alpha-glucosidases with transglycosylation activity could be applied to the industrial production of oligosaccharides as well as conjugation of sugars to biologically useful materials. Therefore, alpha glucosidases isolated from thermophiles have gained attention over the past decade. In this study, the characterization of a highly thermostable alpha glucosidase and its thermostability improved mutant from newly isolated strain Thermus thermophilus TC11 were investigated. RESULTS: The recombinant alpha glucosidase (TtAG) from Thermus thermophilus TC11 was expressed in Escherichia coli BL21 (DE3) and purified. The purified enzyme had a molecular mass of 184 kDa and consisted of 59-kDa subunits; it showed hydrolytic activity for pNP-alpha-D glucopyranoside (pNPG), sucrose, trehalose, panose, and isomaltooligosaccharides and very low activity for maltose. The highest specific activity of 288.96 U/mg was observed for pNPG at 90 degrees C and pH 5.0; Pb(2+) provided a 20 % activity increase. TtAG was stable at 70 degrees C for more than 7 h and had a half-life of 195 min at 80 degrees C and 130 min at 90 degrees C. Transglycosylation activity was also observed with sucrose and trehalose as substrates. TtAG showed differences on substrate specificity, transglycosylation, multimerization, effects of metal ions and optimal pH from other reported Thermus alpha-glucosidases. One single-substitution TtAG mutant Q10Y with improved thermostability was also obtained from random mutagenesis library. The site saturation mutagenesis and structural modelling analysis indicated that Q10Y substitution stabilized TtAG structure via additional hydrogen bonding and hydrophobic interactions. CONCLUSION: Our findings indicate that TtAG is a highly thermostable and more acidic alpha-glucosidase distinct from other reported Thermus alpha-glucosidases. And this work also provides new insights into the catalytic and thermal tolerance mechanisms of alpha-glucosidases, which may guide molecular engineering of alpha-glucosidase and other thermostable enzymes for industrial application. PMID- 26490271 TI - Post-mortem investigation of young deceased individuals with ischemic heart disease-outcome of supplementary genetic testing for dyslipidemia. PMID- 26490272 TI - Erratum to: Author's Reply to Brocherie and Millet: 'Is the Wet-Bulb Globe Temperature (WGBT) Index Relevant for Exercise in the Heat?' PMID- 26490273 TI - Redox Regulation of Dihydrofolate Reductase: Friend or Troublemaker? PMID- 26490274 TI - Neovascularization Driven by MicroRNA Delivery to the Endothelium. PMID- 26490275 TI - Road Repairs: Does Exposure to Traffic Affect Mechanisms of Vascular Injury and Repair? PMID- 26490276 TI - Chemokines. PMID- 26490277 TI - Correction. AB - In the article by Boren et al, which appeared in the October 2015 issue of the journal (Arterioscler Thromb Vasc Biol. 2015;35:2218-2224. DOI: 10.1161/ATVBAHA.115.305614), a correction was needed. Jesper Lundbom has been added as the seventh author. The authors apologize for the omission. PMID- 26490278 TI - Correction. AB - In the article by Heuslein et al, which published online ahead of print on September 3, 2015 (DOI: 10.1161/ATVBAHA.115.305775), a correction was needed. Brett R. Blackman was added as the penultimate author of the article. The article has been corrected for publication in the November 2015 issue. PMID- 26490279 TI - Mechanisms of favorable effects of Rho kinase inhibition on myocardial remodeling and systolic function after experimental myocardial infarction in the rat. AB - OBJECTIVE: The objective of this study was to determine the molecular mechanisms by which cardiac Rho-associated coiled-coil containing protein kinase (ROCK) activation after myocardial infarction (MI) does intervene in cardiac systolic function decline and remodeling. METHODS: Simultaneous measurement of different cardiac ROCK target proteins levels, in vivo left ventricular (LV) systolic function, myocardial fibrosis and hypertrophy in rats with MI under ROCK inhibition with fasudil. RESULTS: Seven days after MI, the ventricular mass increased significantly by 5.6% in the MI group and was reduced with fasudil. LV systolic dysfunction improved significantly with fasudil whereas cardiac ROCK activation was reduced to sham levels. The ROCK inhibitor also reduced increased cardiac levels of both ROCK1 and ROCK2 isoforms, cardiomyocyte ROCK2 fluorescence levels and beta-myosin heavy chain (MHC) levels in addition to myocardial collagen volume fraction decline. Compared with sham rats, troponin phosphorylation levels after MI were similar and ROCK inhibition reduced them. MI significantly increased phosphorylation levels of extracellular-signal-regulated kinase (ERK) 42 and ERK 44 by twofold and 63%, respectively, whereas in the fasudil-treated MI group these levels were similar to those in the sham group. MI significantly increased phosphorylated levels of the transcription factor GATA-4 and the ROCK inhibitor normalized them. CONCLUSIONS: LV systolic dysfunction after MI was strongly associated with cardiac ROCK activation and subsequent phosphorylation of ROCK target proteins that promote ventricular remodeling such as beta-MHC and the ERK/GATA-4 pathway. ROCK inhibition with fasudil significantly improved systolic function, diminished myocardial fibrosis and normalized beta-MHC and ERK/GATA-4 phosphorylation levels. PMID- 26490281 TI - tert-Butyl Iodide Mediated Reductive Fischer Indolization of Conjugated Hydrazones. AB - A novel reductive Fischer indolization of readily available N-aryl conjugated hydrazones with tert-butyl iodide has been developed. In this reaction, tert butyl iodide is used as anhydrous HI source, and the generated HI acts as a Bronsted acid and a reducing agent. This operationally simple method allows access to various indole derivatives. Furthermore, the procedure can be applied to the synthesis of biologically active compounds. PMID- 26490280 TI - Breast Cancer Survivorship and Cardiovascular Disease: Emerging Approaches in Cardio-Oncology. AB - OPINION STATEMENT: Cardiovascular disease (CVD) and breast cancer cause substantial morbidity and mortality in women and are major public health concerns in the USA. While aggressive screening and targeted, advanced treatment for breast cancer have had a measurable impact on breast cancer survival, treatment is not without significant cardiotoxic effects. Anthracycline-based chemotherapy can lead to left ventricular dysfunction and failure, as well as a decline in exercise tolerance and cardio-pulmonary reserve despite preserved ejection fraction. Trastuzumab, a newer monoclonal antibody targeting the Her2 receptor used in the treatment of Her2+ cancer, is also linked to left ventricular dysfunction, although the long-term cardiac effects are presently unclear. Radiation treatment particularly for left-sided breast cancer has been associated with increased rates of ischemic heart disease. As women have increasing survival and cure rates from early breast cancer, long-term consequences on the heart that are secondary to therapy are a major concern. These need to be identified, treated, and avoided when possible. Further research and clear surveillance guidelines are needed to aid the practicing clinician in CVD prevention in breast cancer survivors. PMID- 26490282 TI - Radial palsy in the emergency department. PMID- 26490283 TI - Best evidence topic reports. BET 1: is long-term Rivaroxaban superior to Warfarin in pulmonary embolism? AB - A short cut review was carried out to establish whether Rivaroxaban is superior to warfarin in the management of pulmonary embolism. Three studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that Rivaroxaban is a promising alternative to warfarin in the management of pulmonary embolism. PMID- 26490285 TI - Best evidence topic reports. BET 2: does a normal CT scan within 6 h rule out subarachnoid haemorrhage? AB - A short cut review was carried out to establish whether a normal CT scan within 6 h of onset of a severe, sudden onset headache can be used to rule out a subarachnoid haemorrhage. Four studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that a CT scan performed on a third generation scanner with thin slices, reported by a radiologist experienced in reporting CT brain scans, within 6 h of onset of the headache can be used to rule out a subarachnoid haemorrhage. PMID- 26490286 TI - Impacts of terminal modification of [Ru(phen)2dppz](2+) on the luminescence properties: a theoretical study. AB - [Ru(phen)2dppz](2+) and other closely related ruthenium(II) complexes containing pi-extended ligands were found to be non or weakly emissive in water, while exhibiting significant luminescence intensity growth when bound to DNA, however, a satisfactory interpretation has not been provided on this "light switch" mechanism. In the present study, we investigated the vertical transitions and triplet excited states of [Ru(phen)2dppz](2+) (1), [Ru(phen)2dppzi](2+) (2) and [Ru(phen)2dppz-idzo](2+) (3) in the gas phase and aqueous solution, through time dependent-density functional theory (TDDFT). Based on the optimized (3)MLCT and (3)LLCT structures and energies, we found that the (3)MLCT state might be responsible for the emissions of the complexes. Interesting connections between the singlet vertical transitions and the luminescence properties were noticed. Through ZORA-TDDFT calculation with perturbative SOC, we evaluated the intersystem crossing between the lowest singlet excited state, and both (3)MLCT state and (3)LLCT state, which gave a reasonable explanation for the luminescence properties of these complexes. PMID- 26490287 TI - Prefrontal spatial working memory network predicts animal's decision making in a free choice saccade task. AB - While neurons in the lateral prefrontal cortex (PFC) encode spatial information during the performance of working memory tasks, they are also known to participate in subjective behavior such as spatial attention and action selection. In the present study, we analyzed the activity of primate PFC neurons during the performance of a free choice memory-guided saccade task in which the monkeys needed to choose a saccade direction by themselves. In trials when the receptive field location was subsequently chosen by the animal, PFC neurons with spatially selective visual response started to show greater activation before cue onset. This result suggests that the fluctuation of firing before cue presentation prematurely biased the representation of a certain spatial location and eventually encouraged the subsequent choice of that location. In addition, modulation of the activity by the animal's choice was observed only in neurons with high sustainability of activation and was also dependent on the spatial configuration of the visual cues. These findings were consistent with known characteristics of PFC neurons in information maintenance in spatial working memory function. These results suggest that precue fluctuation of spatial representation was shared and enhanced through the working memory network in the PFC and could finally influence the animal's free choice of saccade direction. The present study revealed that the PFC plays an important role in decision making in a free choice condition and that the dynamics of decision making are constrained by the network architecture embedded in this cortical area. PMID- 26490288 TI - Synchronization of motor unit firings: an epiphenomenon of firing rate characteristics not common inputs. AB - Synchronous motor unit firing instances have been attributed to anatomical inputs shared by motoneurons. Yet, there is a lack of empirical evidence confirming the notion that common inputs elicit synchronization under voluntary conditions. We tested this notion by measuring synchronization between motor unit action potential trains (MUAPTs) as their firing rates progressed within a contraction from a relatively low force level to a higher one. On average, the degree of synchronization decreased as the force increased. The common input notion provides no empirically supported explanation for the observed synchronization behavior. Therefore, we investigated a more probable explanation for synchronization. Our data set of 17,546 paired MUAPTs revealed that the degree of synchronization varies as a function of two characteristics of the motor unit firing rate: the similarity and the slope as a function of force. Both are measures of the excitation of the motoneurons. As the force generated by the muscle increases, the firing rate slope decreases, and the synchronization correspondingly decreases. Different muscles have motor units with different firing rate characteristics and display different amounts of synchronization. Although this association is not proof of causality, it consistently explains our observations and strongly suggests further investigation. So viewed, synchronization is likely an epiphenomenon, subject to countless unknown neural interactions. As such, synchronous firing instances may not be the product of a specific design and may not serve a specific physiological purpose. Our explanation for synchronization has the advantage of being supported by empirical evidence, whereas the common input does not. PMID- 26490289 TI - Parallel updating and weighting of multiple spatial maps for visual stability during whole body motion. AB - It is known that the brain uses multiple reference frames to code spatial information, including eye-centered and body-centered frames. When we move our body in space, these internal representations are no longer in register with external space, unless they are actively updated. Whether the brain updates multiple spatial representations in parallel, or whether it restricts its updating mechanisms to a single reference frame from which other representations are constructed, remains an open question. We developed an optimal integration model to simulate the updating of visual space across body motion in multiple or single reference frames. To test this model, we designed an experiment in which participants had to remember the location of a briefly presented target while being translated sideways. The behavioral responses were in agreement with a model that uses a combination of eye- and body-centered representations, weighted according to the reliability in which the target location is stored and updated in each reference frame. Our findings suggest that the brain simultaneously updates multiple spatial representations across body motion. Because both representations are kept in sync, they can be optimally combined to provide a more precise estimate of visual locations in space than based on single-frame updating mechanisms. PMID- 26490290 TI - Functional plasticity in the respiratory drive to thoracic motoneurons in the segment above a chronic lateral spinal cord lesion. AB - A previous neurophysiological investigation demonstrated an increase in functional projections of expiratory bulbospinal neurons (EBSNs) in the segment above a chronic lateral thoracic spinal cord lesion that severed their axons. We have now investigated how this plasticity might be manifested in thoracic motoneurons by measuring their respiratory drive and the connections to them from individual EBSNs. In anesthetized cats, simultaneous recordings were made intracellularly from motoneurons in the segment above a left-side chronic (16 wk) lesion of the spinal cord in the rostral part of T8, T9, or T10 and extracellularly from EBSNs in the right caudal medulla, antidromically excited from just above the lesion but not from below. Spike-triggered averaging was used to measure the connections between pairs of EBSNs and motoneurons. Connections were found to have a very similar distribution to normal and were, if anything (nonsignificantly), weaker than normal, being present for 42/158 pairs, vs. 55/154 pairs in controls. The expiratory drive in expiratory motoneurons appeared stronger than in controls but again not significantly so. Thus we conclude that new connections made by the EBSNs following these lesions were made to neurons other than alpha-motoneurons. However, a previously unidentified form of functional plasticity was seen in that there was a significant increase in the excitation of motoneurons during postinspiration, being manifest either in increased incidence of expiratory decrementing respiratory drive potentials or in an increased amplitude of the postinspiratory depolarizing phase in inspiratory motoneurons. We suggest that this component arose from spinal cord interneurons. PMID- 26490292 TI - Neural population encoding and decoding of sound source location across sound level in the rabbit inferior colliculus. AB - At lower levels of sensory processing, the representation of a stimulus feature in the response of a neural population can vary in complex ways across different stimulus intensities, potentially changing the amount of feature-relevant information in the response. How higher-level neural circuits could implement feature decoding computations that compensate for these intensity-dependent variations remains unclear. Here we focused on neurons in the inferior colliculus (IC) of unanesthetized rabbits, whose firing rates are sensitive to both the azimuthal position of a sound source and its sound level. We found that the azimuth tuning curves of an IC neuron at different sound levels tend to be linear transformations of each other. These transformations could either increase or decrease the mutual information between source azimuth and spike count with increasing level for individual neurons, yet population azimuthal information remained constant across the absolute sound levels tested (35, 50, and 65 dB SPL), as inferred from the performance of a maximum-likelihood neural population decoder. We harnessed evidence of level-dependent linear transformations to reduce the number of free parameters in the creation of an accurate cross-level population decoder of azimuth. Interestingly, this decoder predicts monotonic azimuth tuning curves, broadly sensitive to contralateral azimuths, in neurons at higher levels in the auditory pathway. PMID- 26490293 TI - Doctor's Knowledge and Practices of Traumatic Brain Injury Management in Chinese Prehospital Settings. AB - OBJECTIVES: The incidence and mortality of traumatic brain injury (TBI) has increased rapidly in the last decade in China. Appropriate ambulance service can reduce case-fatality rates of TBI significantly. This study aimed to explore the factors (age, gender, education level, clinical experience, professional title, organization, specialty before prehospital care, and training frequency) that could influence prehospital doctors' knowledge level and practices in TBI management in China, Hubei Province. METHODS: A cross-sectional questionnaire survey was conducted in two cities in Hubei Province. The self-administered questionnaire consisted of demographic information and questions about prehospital TBI management. Independent samples t-test and one-way ANOVA were used to analyze group differences in the average scores in terms of demographic character. General linear regression was used to explore associated factors in prehospital TBI management. RESULTS: A total of 56 questionnaires were handed out and 52 (93%) were returned. Participants received the lowest scores in TBI treatment (0.64; SD=0.08) and the highest scores in TBI assessment (0.80; SD=0.14). According to the regression model, the education level was associated positively with the score of TBI identification (P=.019); participants who worked in the emergency department (ED; P=.011) or formerly practiced internal medicine (P=.009) tended to get lower scores in TBI assessment; participants' scores in TBI treatment were associated positively with the training frequency (P=.011); and no statistically significant associated factor was found in the overall TBI management. CONCLUSION: This study described the current situation of prehospital TBI management. The prehospital doctors' knowledge level and practices in TBI management were quantified and the influential factors hidden underneath were explored. The results indicated that an appropriate continuing medical education (CME) program enables improvement of the quality of ambulance service in China. PMID- 26490291 TI - Triptans disrupt brain networks and promote stress-induced CSD-like responses in cortical and subcortical areas. AB - A number of drugs, including triptans, promote migraine chronification in susceptible individuals. In rats, a period of triptan administration over 7 days can produce "latent sensitization" (14 days after discontinuation of drug) demonstrated as enhanced sensitivity to presumed migraine triggers such as environmental stress and lowered threshold for electrically induced cortical spreading depression (CSD). Here we have used fMRI to evaluate the early changes in brain networks at day 7 of sumatriptan administration that may induce latent sensitization as well as the potential response to stress. After continuous infusion of sumatriptan, rats were scanned to measure changes in resting state networks and the response to bright light environmental stress. Rats receiving sumatriptan, but not saline infusion, showed significant differences in default mode, autonomic, basal ganglia, salience, and sensorimotor networks. Bright light stress produced CSD-like responses in sumatriptan-treated but not control rats. Our data show the first brain-related changes in a rat model of medication overuse headache and suggest that this approach could be used to evaluate the multiple brain networks involved that may promote this condition. PMID- 26490294 TI - Estimating cut points: A simple method for new wearables. AB - Wearable technology is readily available for continuous assessment due to a growing number of commercial devices with increased data capture capabilities. However, many commercial devices fail to support suitable parameters (cut points) derived from the literature to help quantify physical activity (PA) due to differences in manufacturing. A simple metric to estimate cut points for new wearables is needed to aid data analysis. OBJECTIVE: The purpose of this pilot study was to investigate a simple methodology to determine cut points based on ratios between sedentary behaviour (SB) and PA intensities for a new wrist worn device (PRO-DiaryTM) by comparing its output to a validated and well characterised 'gold standard' (ActiGraphTM). STUDY DESIGN: Twelve participants completed a semi-structured (four-phase) treadmill protocol encompassing SB and three PA intensity levels (light, moderate, vigorous). The outputs of the devices were compared accounting for relative intensity. RESULTS: Count ratios (6.31, 7.68, 4.63, 3.96) were calculated to successfully determine cut-points for the new wrist worn wearable technology during SB (0-426) as well as light (427-803), moderate (804-2085) and vigorous (>= 2086) activities, respectively. CONCLUSION: Our findings should be utilised as a primary reference for investigations seeking to use new (wrist worn) wearable technology similar to that used here (i.e., PRO DiaryTM) for the purposes of quantifying SB and PA intensities. The utility of count ratios may be useful in comparing devices or SB/PA values estimated across different studies. However, a more robust examination is required for different devices, attachment locations and on larger/diverse cohorts. PMID- 26490295 TI - A population-based longitudinal study of suicide risk in male schizophrenia patients: Proximity to hospital discharge and the moderating effect of premorbid IQ. AB - Suicide is a major cause of death in schizophrenia. Identifying factors which increase the risk of suicide among schizophrenia patients might help focus prevention efforts. This study examined risk of suicide in male schizophrenia patients using population-based data, examining the timing of suicide in relation to the last hospital discharge, and the effect of premorbid IQ on risk of suicide. Data on 930,000 male adolescents from the Israeli military draft board were linked with data from the Israeli Psychiatric Hospitalization Case Registry and vital statistics from the Israeli Ministry of Health. The relationship between premorbid IQ and risk for suicide was examined among 2881 males hospitalized with schizophrenia and compared to a control group of 566,726 males from the same cohort, who were not hospitalized for a psychiatric disorder, using survival analysis methods. Over a mean follow-up period of 9.9 years (SD=5.8, range: 0-22 years), 77/3806 males with schizophrenia died by suicide (a suicide rate of 204.4 per 100,000 person-years). Approximately 48% of the suicides occurred within a year of discharge from the last hospital admission for schizophrenia. Risk of suicide was higher in male schizophrenia patients with high premorbid IQ (HR=4.45, 95% CI=1.37-14.43) compared to those with normal premorbid IQ. These data indicate that male schizophrenia patients with high premorbid IQ are at particularly high risk of suicide, and the time of peak risk is during the first year after the last hospitalization discharge. PMID- 26490296 TI - Economic evaluation among Chinese patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus and treated with linezolid or vancomycin: a secondary, post-hoc analysis based on a Phase 4 clinical trial study. AB - OBJECTIVE: To assess cost-effectiveness of linezolid vs vancomycin in treating nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA NP) in China and the impact of renal failure on healthcare resource utilization (HCRU) and costs. METHODS: Cost-effectiveness analysis was conducted based on data from the ZEPHyR trial, with efficacy measured by treatment success and costs calculated from HCRU. Confidence intervals (CI) for cost, efficacy and incremental cost-effectiveness ratios (ICER) were calculated by non-parametric bootstrap. Chi-square test was used for renal failure rate and t-test for HCRU/cost comparisons. Impact of renal failure was assessed using regression model. RESULTS: Data from 448 patients (1:1 linezolid:vancomycin) were analyzed. More patients treated with linezolid achieved success (55% [95% CI = 48-62%]) than with vancomycin (45% [38-52%]). Treatment cost were Y79,551 (95% CI = Y72,421-Y86,680) for linezolid vs Y77,587 (Y70,656-Y84,519) for vancomycin in Beijing, Y90,995 (Y82,598-Y99,393) vs Y89,448 (Y81,295-Y97,601) in Guangzhou, Y82,383 (Y74,956-Y89,810) vs Y80,799 (Y73,545-Y88,054) in Nanjing and Y59,413 (Y54,366-Y64,460) vs Y57,804 (Y52,613-Y62,996) in Xi'an. Per successful treatment, the ICER of linezolid over vancomycin were Y19,719 (-Y143,553 to Y320,980) (Beijing), Y15,532 (-Y185,411 to Y349,693) (Guangzhou), Y15,904 ( Y161,935 to Y314,987) (Nanjing) and Y16,145 (-Y100,738 to Y234,412) (Xi'an). From simulations, the majority of linezolid cases had greater efficacy and higher costs and more than one third had greater efficacy and lower costs. More vancomycin patients developed renal failure (15% vs 4%, p < 0.001). Patients with renal failure had higher cost (Nanjng: Y100,449 (SD = Y65,080) vs Y74,944 (SD = Y49,632), p = 0.002). CONCLUSION: Linezolid was more cost-effective than vancomycin in treating MRSA-NP from a Chinese payer's perspective, and associated with less renal failure, HCRU and cost. PMID- 26490297 TI - Constitutive NF-kappaB activation in AML: Causes and treatment strategies. AB - For more than a decade, it has been known that NF-kappaB is constitutively activated in a majority of acute myeloid leukemia (AML) patients which contributes to the resistance to apoptosis. Inhibition of NF-kappaB has been shown to induce apoptosis in AML cells, but the clinical effectiveness of NF kappaB inhibitors has been inadequate. In recent years, possible causes underlying this continuous NF-kappaB activity have been elucidated. It has been shown that chromosomal translocations or mutations leading to development of leukemia drive the increase in NF-kappaB activity. Furthermore, autocrine/paracrine cytokine signaling and increased expression of NF-kappaB signaling components play an important role in the continuous NF-kappaB activation. Moreover, high proteasome activity, which positively regulates NF kappaB activity, is often observed in AML patients. In the present study, we described these underlying molecular mechanisms leading to constitutive NF-kappaB activity and discussed the novel treatment strategies based on the inhibition of NF-kappaB activation. PMID- 26490299 TI - Carotenemia and hepatomegaly in an atopic child on an exclusion diet for a food allergy. AB - Eczema is a frequent childhood manifestation and a few atopic children are allergic to certain foods or aeroallergens. Anxious parents of atopic children often have a fear of topical steroid-related side-effects, and some may try a range of elimination diets to avoid allergies. Elimination diets increase the risk of anaphylaxis on re-exposure to previously tolerated foods from the loss of oral tolerance. Unbalanced diets together with an inadvertent excessive consumption of fruits and vegetables may lead to carotenemia from the carotenoids in the plant foods. Carotenemia is benign but unusual diets and the consumption of preformed vitamin A in health supplements can lead to vitamin A toxicity. We discuss a child with eczema on an exclusion diet presenting with anaphylaxis to dairy food. He had carotenemia with hepatomegaly, which resolved on dietary management. PMID- 26490298 TI - Prevalence, awareness, treatment and control of high blood pressure among Chinese rural population in Haimen, Jiangsu. AB - Nowadays, high blood pressure (HBP) is one of the most common chronic diseases in China. This survey aims to assess HBP prevalence, and related disease awareness, treatment and control among rural population in Haimen, Jiangsu province, China. A total of 7538 rural residents, aged over 18 years, from four randomly selected villages in Haimen, were selected to participate in the blood pressure examination in September 2010, the male-to-female ratio of participants was 1:1.57. In all, 2034 patients were diagnosed with HBP. The total crude prevalence of HBP was 26.98%, the overall standardized prevalence of HBP was 24.38%. Both male and female prevalence rates demonstrate ascending trend with age. Awareness, treatment and control rates among all patients were 68.34%, 61.46% and 27.43% respectively, whereas the corresponding rates in young group (18-44 years) were lower (50.94%, 35.85%, 24.53%). Improving treatment coverage and efficacy should be the focus of HBP prevention in rural areas in China. PMID- 26490300 TI - Disordered Eating/Eating Disorder: Hidden Perils of the Nation's Fight against Fat. AB - The nation's fight against fat has not reduced obesity, but it has had other worrying effects. Mental health researchers have raised the possibility that the intense pressures to lose weight have heightened the risks of developing eating disorders, especially among the young. Medical anthropology can help connect the dots between the war on fat and disordered eating, identifying specific mechanisms, pathways, and contextual forces that may lie beyond the scope of biomedical and psychiatric research. This article develops a biocitizenship approach that focuses on the pathologization of heaviness, the necessity of having a thin, fit body to belonging to the category of worthy citizen, and the work of pervasive fat-talk in defining who can belong. Ethnographic narratives from California illuminate the dynamics in individual lives, while lending powerful support to the idea that the battle against fat is worsening disordered eating and eating disorders among vulnerable young people. PMID- 26490301 TI - Identification of aphid (Hemiptera: Aphididae) species of economic importance in Kenya using DNA barcodes and PCR-RFLP-based approach. AB - Aphids are among pests of economic importance throughout the world. Together with transmitting plant viruses, aphids are capable of inflicting severe crop production losses. They also excrete honeydew that favours the growth of sooty mold which reduces the quality of vegetables and fruits and hence their market values. Rapid and accurate identification of aphids to the species level is a critical component in effective pest management and plant quarantine systems. Even though morphological taxonomy has made a tremendous impact on species-level identifications, polymorphism, morphological plasticity and immature stages are among the many challenges to accurate identification. In addition, their small size, presence of cryptic species and damaged specimens dictate the need for a strategy that will ensure timely and accurate identification. In this study, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) based on mitochondrial cytochrome c oxidase subunit I gene and DNA barcoding were applied to identify different aphid species collected from different agro ecological zones of Kenya. Three restriction enzymes RsaI, AluI and Hinf1 produced patterns that allowed unambiguous identification of the species except Aphis craccivora and Aphis fabae. Analyses of the barcode region indicated intraspecific and interspecific sequence divergences of 0.08 and 6.63%, respectively. DNA barcoding identified all species, including the morphologically indistinguishable A. craccivora and A. fabae and separated two subspecies of A. fabae. Based on these results, both PCR-RFLPs and DNA barcoding could provide quick and accurate tools for identification of aphid species within Aphididae subsequently aiding in effective pest management programmes and enhance plant quarantine systems. PMID- 26490302 TI - Transition energies of benzoquinone anions are immune to symmetry breaking by a single water molecule. AB - p-Benzoquinone is the prototypical member of the quinone class of molecules with a basic functionality relevant for the primary reactions of photosynthesis. As electronically excited quinone anions are formed in near-resonant electron transfer, key issues are how the local environment affects excited-state energy levels and deexcitation times. The former we address here with action spectroscopy of mass-selected bare radical anions (pBQ(-)) and one-water pBQ( ).H2O complexes, isolated in vacuo. The complex represents a precursor for internal proton transfer to form the semiquinone free radical, the first chemical product in the light-driven electron transport chain. Both ions display bands in the visible and ultraviolet with, importantly, almost identical maxima. Despite localizing negative charge, thereby breaking the high orbital symmetries, water is surprisingly innocent. This finding implies that natural fluctuations in the quinone microenvironment cause only minor variations in excited-state energies and thus electron-transfer rates. Hence quinones are robust participants in electron transport. PMID- 26490303 TI - Interplay between electronic and structural properties in the Pb/Ag(1 0 0) interface. AB - We report an investigation of the structural and electronic properties of a Pb monolayer (ML) grown on Ag(1 0 0), by combining x-ray photoelectron diffraction (XPD) and angle resolved photoelectron spectroscopy (ARPES). The Pb atoms are found to arrange in a pseudo-hexagonal adlayer commensurate to the underlying square Ag substrate, resulting in a coincidence cell with c([Formula: see text]) periodicity. The electronic structure of the Pb ML in proximity of the Fermi level consists in three p-derived bands, which show different degrees of hybridization with the substrate for their different orbital characters. In particular, we report that the p xy states disperse without forming energy gap, in contrast to previous ARPES studies of the Pb ML on different metallic substrates. We attribute the absence of energy gap to the commensurability between substrate and adlayer, resulting in a higher two-dimensionality of the Pb ML. PMID- 26490304 TI - Short-term enriched environment exposure facilitates fear extinction in adult rats: The NPY-Y1 receptor modulation. AB - Neuropeptides have an important role in several psychiatric conditions. Among them, neuropeptide Y (NPY) seems to be essential to modulate some features of stress-related disorders. Post-traumatic stress disorder (PTSD), characterized by inappropriate fear generalization to safe situations may be modulated by NPY manipulation since this neuropeptide is involved in the promotion of coping with stress. Experimentally, coping strategies have been obtained after exposure in enriched environment (EE) rather than standard one. Thus, in the present study we aimed to assess whether short-term EE situation and NPY-Y1 receptor (Y1r) modulation may affect the extinction of contextual fear conditioning, an experimental approach to PTSD. Here we show that EE-rats have the contextual fear extinction facilitated, and this facilitation was reverted by central infusion of BIBO3304, a nonpeptide Y1r antagonist. In addition, protein analysis revealed an upregulation of hippocampal Y1r in conditioned EE-rats, but no changes were observed in EE-rats that were not conditioned. Our results demonstrated that protective properties of EE on fear extinction can be regulated, at least in part, by activation of NPY-signaling through Y1r within hippocampus, an area that plays a major role in contextual memories. Overall, the activation of Y1r is important to promote better and faster perception of self-location (context), and to reduce fear generalization in rats exposed to EE. PMID- 26490305 TI - Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer. AB - PURPOSE: Five germline genetic variants (rs116909374, rs965513, rs944289, rs966423, and rs2439302) have been associated in genome-wide association studies (GWAS) with increased risk of differentiated thyroid cancer (DTC), but their role in mortality of patients has not been established. Also, no preoperative marker of the clinical outcome of thyroid cancer had yet been identified. The aim of the study was to investigate the relationship between the variants and overall mortality in patients with DTC. EXPERIMENTAL DESIGN: Retrospective study of 1,836 patients (1,643 women, 193 men) with median age at diagnosis of 49 years and overall median follow-up time of 8.7 years after initial treatment at a single comprehensive cancer center between 1990 and 2013. RESULTS: Among 5 variants, rs966423 was associated with increased mortality, which was 6.4% (33 of 518) versus 3.7% (47 of 1,259) in TT carriers versus CC/CT carriers (P = 0.017). The HR of TT versus TC/CC carriers was 1.6 [95% confidence interval (CI), 1.02-2.49; P = 0.038] after adjustment for age at diagnosis and sex. Importantly, the association of rs966423 with mortality remained valid when clinicopathologic risk factors were included in the model (HR, 1.89; 95% CI, 1.14-3.13; P = 0.014). Higher rs966423-associated patient mortality of TT versus CC/CT carriers was also observed in interaction with angioinvasion (adjusted HR, 3.48; 95% CI, 1.67-7.22; P < 0.001), lymph node metastasis (adjusted HR, 3.47; 95% CI, 1.16-10.4; P = 0.018), extrathyroidal invasion (adjusted HR, 2.07; 95% CI, 1.15-3.73; P = 0.013). CONCLUSIONS: The presence of the rs966423-TT genotype was associated with a significant increase in overall mortality of patients with DTC. Contrary to BRAF mutation and other somatic changes, the status of germline rs966423 is known before the treatment and might be used in the management of mortality risk by means of modification of therapy. PMID- 26490306 TI - Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination. AB - PURPOSE: Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. EXPERIMENTAL DESIGN: The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGFbeta secretion from microglia and in the serum and TGFbeta signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model. RESULTS: CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFbeta; however, blocking TGFbeta signaling with a small molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased TGFbeta secretion from microglia. CONCLUSIONS: These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS, whereas antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in contemporary melanoma models as well as human trials. PMID- 26490307 TI - The Impact of T2/FLAIR Evaluation per RANO Criteria on Response Assessment of Recurrent Glioblastoma Patients Treated with Bevacizumab. AB - PURPOSE: The RANO criteria have not been assessed using outcome data from prospective trials. We examined the radiologic data of patients with recurrent glioblastoma from the randomized phase II trial (AVF3708g) to determine the effect of including T2/FLAIR evaluation as per RANO criteria on measurements of objective response rates (ORRs) and progression-free survival (PFS) compared with assessment based on contrast enhancement (Macdonald criteria). EXPERIMENTAL DESIGN: The ORRs and median PFS were determined using the RANO criteria and compared with those obtained using the Macdonald criteria. Landmark analyses were performed at 2, 4, and 6 months, and Cox proportional hazard models were used to determine the associations between OR and progression with subsequent survival. RESULTS: The ORRs were 0.331 [95% confidence interval (CI), 0.260-0.409] and 0.393 (95% CI, 0.317-0.472) by RANO and Macdonald criteria, respectively (P < 0.0001). The median PFS was 4.6 months (95% CI, 4.1-5.5) using RANO criteria, compared with 6.4 months (95% CI, 5.5-7.1) as determined by Macdonald criteria (P = 0.01). At 2-, 4-, and 6-month landmarks, both OR status and PFS determined by either RANO or Macdonald criteria were predictive of overall survival [OS; hazard ratios for 4-month landmark (OR HR = 1.93, P = 0.0012; PFS HR, 4.23, P < 0.0001)]. CONCLUSIONS: The inclusion of T2/FLAIR assessment resulted in statistically significant differences in median PFS and ORRs compared with assessment of solely enhancing tumor (Macdonald criteria), although OR and PFS determined by both RANO and Macdonald criteria correlated with OS. PMID- 26490308 TI - Prognostic Utility of Molecular Factors by Age at Diagnosis of Colorectal Cancer. AB - PURPOSE: We hypothesized that adverse prognostic associations of specific tumor molecular factors vary by patient age at colorectal cancer diagnosis. EXPERIMENTAL DESIGN: We examined the prognostic associations and interactions by age at colorectal cancer diagnosis (<60 vs. 60-74 vs. >=75 years old) of key molecular factors-CpG island methylator phenotype (CIMP), microsatellite instability (MSI), KRAS, BRAF, and PIK3CA mutations, and nuclear CTNNB1 expression status-on colorectal cancer-specific survival (CSS) and overall survival (OS), using 1,280 incident colorectal cancer cases (median age, 69 years; range, 38-91 years) within the Nurses' Health Study and Health Professionals Follow-up Study cohorts. RESULTS: MSI-high was associated with better survival, whereas BRAF mutation was associated with worse survival, but these associations did not appreciably differ by age group. Status of CIMP, KRAS mutation, or PIK3CA mutation was not associated with prognosis regardless of age. Nuclear CTNNB1 expression was associated with a trend toward worse prognosis among older adults [age >= 75 years; multivariate HR, 1.67; 95% confidence interval (CI), 0.89-3.13 (for CSS); multivariate HR, 1.44; 95% CI, 0.93-2.24 (for OS)] but not among younger patients, and there was a statistically significant interaction by age (Pinteraction = 0.03 for CSS; Pinteraction = 0.007 for OS). CONCLUSIONS: Tumor nuclear CTNNB1 expression may be associated with higher mortality among older patients with colorectal cancer but not among younger patients. Our findings need to be confirmed in independent datasets. Detailed exploration of tumor molecular signatures in older patients with colorectal cancer in large populations is warranted. PMID- 26490310 TI - A Phase I First-in-Human Study of Nesvacumab (REGN910), a Fully Human Anti Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid Tumors. AB - PURPOSE: Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab. EXPERIMENTAL DESIGN: Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors. RESULTS: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade <= 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) > 16 weeks, with tumor regression and >50% decrease in alpha-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration. CONCLUSIONS: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D. PMID- 26490309 TI - Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer. AB - PURPOSE: Clinical evidence suggests increased cancer stem cells (CSCs) in a tumor mass may contribute to the failure of conventional therapies because CSCs seem to be more resistant than differentiated tumor cells. Thus, unveiling the mechanism regulating CSCs and candidate target molecules will provide new strategy to cure the patients. EXPERIMENTAL DESIGN: The stem-like cell properties were determined by a prostasphere assay and dye exclusion assay. To find critical stem cell marker and reveal regulation mechanism, basic biochemical and molecular biologic methods, such as quantitative real-time PCR, Western blot, reporter gene assay, and chromatin immunoprecipitation assay, were used. In addition, to determine the effect of combination therapy targeting both CSCs and its progeny, in vitro MTT assay and in vivo xenograft model was used. RESULTS: We demonstrate immortalized normal human prostate epithelial cells, appeared nontumorigenic in vivo, become tumorigenic, and acquire stem cell phenotype after knocking down a tumor suppressor gene. Also, those stem-like cells increase chemoresistance to conventional anticancer reagent. Mechanistically, we unveil that Wnt signaling is a key pathway regulating well-known stem cell marker CD44 by directly interacting to the promoter. Thus, by targeting CSCs using Wnt inhibitors synergistically enhances the efficacy of conventional drugs. Furthermore, the in vivo mouse model bearing xenografts showed a robust inhibition of tumor growth after combination therapy. CONCLUSIONS: Overall, this study provides strong evidence of CSC in castration-resistant prostate cancer. This new combination therapy strategy targeting CSC could significantly enhance therapeutic efficacy of current chemotherapy regimen only targeting non-CSC cells. PMID- 26490311 TI - Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K-AKT-mTOR Pathway Inhibitors. AB - PURPOSE: mTOR is a validated target in cancer. It remains to be determined whether melanoma patients bearing mTOR mutation could be selected for treatment with PI3K-AKT-mTOR pathway inhibitors. EXPERIMENTAL DESIGN: A total of 412 melanoma samples were included. Gene aberrations in all exons of mTOR were detected by Sanger sequencing and confirmed by using Agilent's SureSelect Target Enrichment System. HEK293T cells stably expressing mTOR mutants were constructed by using transcription activator-like effector nucleases technique. Function of mTOR mutants and in vitro sensitivity of gain-of-function mTOR mutations to PI3K AKT-mTOR pathway inhibitors were analyzed. RESULTS: The overall incidence of somatic nonsynonymous mutations of mTOR was 10.4% (43/412). mTOR nonsynonymous mutations were relatively more frequent in acral (11.0%) and mucosal (14.3%) melanomas than in chronic sun-induced damage (CSD; 6.7%) and non-CSD (3.4%) melanomas. Of the 43 cases with mTOR mutations, 41 different mutations were detected, affecting 25 different exons. The median survival time for melanoma patients with mTOR nonsynonymous mutation was significantly shorter than that for patients without mTOR nonsynonymous mutation (P = 0.028). Transient expression of mTOR mutants in HEK293T cells strongly activated the mTOR-p70S6K pathway. In HEK293T cells with stable expression of H1968Y or P2213S mTOR mutants, LY294002 and AZD5363 showed higher potency than temsirolimus or BYL719 in inhibiting the PI3K-AKT-mTOR pathway and cell proliferation. CONCLUSIONS: mTOR nonsynonymous mutations are frequent in melanoma patients. mTOR nonsynonymous mutation may predict a worse prognosis of melanoma. Clinical trials with PI3K-AKT-mTOR pathway inhibitors may be beneficial for melanoma patients with specific mTOR mutations. PMID- 26490312 TI - Loss of Glycogen Debranching Enzyme AGL Drives Bladder Tumor Growth via Induction of Hyaluronic Acid Synthesis. AB - PURPOSE: We demonstrated that amylo-alpha-1-6-glucosidase-4-alpha glucanotransferase (AGL) is a tumor growth suppressor and prognostic marker in human bladder cancer. Here we determine how AGL loss enhances tumor growth, hoping to find therapeutically tractable targets/pathways that could be used in patients with low AGL-expressing tumors. EXPERIMENTAL DESIGN: We transcriptionally profiled bladder cell lines with different AGL expression. By focusing on transcripts overexpressed as a function of low AGL and associated with adverse clinicopathologic variables in human bladder tumors, we sought to increase the chances of discovering novel therapeutic opportunities. RESULTS: One such transcript was hyaluronic acid synthase 2 (HAS2), an enzyme responsible for hyaluronic acid (HA) synthesis. HAS2 expression was inversely proportional to that of AGL in bladder cancer cells and immortalized and normal urothelium. HAS2 driven HA synthesis was enhanced in bladder cancer cells with low AGL, and this drove anchorage-dependent and independent growth. siRNA-mediated depletion of HAS2 or inhibition of HA synthesis by 4-methylumbelliferone (4MU) abrogated in vitro and xenograft growth of bladder cancer cells with low AGL. AGL and HAS2 mRNA expression in human tumors was inversely correlated in patient datasets. Patients with high HAS2 and low AGL tumor mRNA expression had poor survival, lending clinical support to xenograft findings that HAS2 drives growth of tumors with low AGL. CONCLUSIONS: Our study establishes HAS2-mediated HA synthesis as a driver of growth of bladder cancer with low AGL and provides preclinical rationale for personalized targeting of HAS2/HA signaling in patients with low AGL-expressing tumors. PMID- 26490313 TI - Correlating Surrogate Endpoints with Overall Survival at the Individual Patient Level in BRAFV600E-Mutated Metastatic Melanoma Patients Treated with Vemurafenib. AB - PURPOSE: Surrogate endpoints are needed that correlate with overall survival (OS). We analyzed individual patient tumor data from a phase III trial of vemurafenib versus dacarbazine (BRIM3) to identify criteria for tumor measures that correlated with OS. Correlates were validated using a separate data set from a phase II trial of vemurafenib (BRIM2). EXPERIMENTAL DESIGN: Deidentified tumor measurements and OS data from BRIM3 and from BRIM2 were analyzed. Target tumor measurement data and nontarget tumor data were available from pretreatment, weeks 6,12, and every 9 weeks thereafter. In the BRIM3 data set, associations of OS with both early tumor response (first 12 weeks) and time to progression (TTP) were assessed. Different definitions of response and progression were explored. Findings were validated using the BRIM2 data set. RESULTS: Thresholds of early response were explored ranging from any degree of tumor shrinkage to 100% tumor shrinkage. Correlation was weak at all thresholds tested. TTP, however, was more strongly correlated with OS. The strongest correlation was seen when progression was defined as >=50% increase in the sum of tumor diameters or appearance of new tumors. This was confirmed by similar analyses in the BRIM2 cohort. CONCLUSIONS: TTP defined as >=50% increase in the sum of tumor diameters or appearance of new tumors was more strongly associated with OS than early tumor shrinkage in melanoma patients treated with RAF inhibitor. In future trials, consideration should be given to replacing response rate with TTP or PFS as preferable clinical endpoints in early-phase studies. PMID- 26490314 TI - In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma. AB - PURPOSE: Germline mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy. EXPERIMENTAL DESIGN: A pulsed proton magnetic resonance spectroscopy ((1)H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb(-/-) or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n = 5) or not (n = 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors. RESULTS: A succinate peak was observed at 2.44 ppm by (1)H-MRS in all Sdhb(-/-) derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, (1)H-MRS results led to the identification of an unsuspected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene. CONCLUSIONS: Detection of succinate by (1)H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This noninvasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. PMID- 26490315 TI - Fluorescent Image-Guided Surgery with an Anti-Prostate Stem Cell Antigen (PSCA) Diabody Enables Targeted Resection of Mouse Prostate Cancer Xenografts in Real Time. AB - PURPOSE: The inability to visualize cancer during prostatectomy contributes to positive margins, cancer recurrence, and surgical side effects. A molecularly targeted fluorescent probe offers the potential for real-time intraoperative imaging. The goal of this study was to develop a probe for image-guided prostate cancer surgery. EXPERIMENTAL DESIGN: An antibody fragment (cys-diabody, cDb) against prostate stem cell antigen (PSCA) was conjugated to a far-red fluorophore, Cy5. The integrity and binding of the probe to PSCA was confirmed by gel electrophoresis, size exclusion, and flow cytometry, respectively. Subcutaneous models of PSCA-expressing xenografts were used to assess the biodistribution and in vivo kinetics, whereas an invasive intramuscular model was utilized to explore the performance of Cy5-cDb-mediated fluorescence guidance in representative surgical scenarios. Finally, a prospective, randomized study comparing surgical resection with and without fluorescent guidance was performed to determine whether this probe could reduce the incidence of positive margins. RESULTS: Cy5-cDb demonstrated excellent purity, stability, and specific binding to PSCA. In vivo imaging showed maximal signal-to-background ratios at 6 hours. In mice carrying PSCA(+) and negative (-) dual xenografts, the mean fluorescence ratio of PSCA(+/-) tumors was 4.4:1. In surgical resection experiments, residual tumors <1 mm that were missed on white light surgery were identified and resected using fluorescence guidance, which reduced the incidence of positive surgical margins (0/8) compared with white light surgery alone (7/7). CONCLUSIONS: Fluorescently labeled cDb enables real-time in vivo imaging of prostate cancer xenografts in mice, and facilitates more complete tumor removal than conventional white light surgery alone. PMID- 26490317 TI - Genomic Landscape of CXCR4 Mutations in Waldenstrom Macroglobulinemia. AB - PURPOSE: Whole-genome sequencing has revealed MYD88 L265P and CXCR4 mutations (CXCR4(mut)) as the most prevalent somatic mutations in Waldenstrom macroglobulinemia. CXCR4 mutation has proved to be of critical importance in Waldenstrom macroglobulinemia, in part due to its role as a mechanism of resistance to several agents. We have therefore sought to unravel the different aspects of CXCR4 mutations in Waldenstrom macroglobulinemia. EXPERIMENTAL DESIGN: We have scanned the two coding exons of CXCR4 in Waldenstrom macroglobulinemia using deep next-generation sequencing and Sanger sequencing in 98 patients with Waldenstrom macroglobulinemia and correlated with SNP array landscape and mutational spectrum of eight candidate genes involved in TLR, RAS, and BCR pathway in an integrative study. RESULTS: We found all mutations to be heterozygous, somatic, and located in the C-terminal domain of CXCR4 in 25% of the Waldenstrom macroglobulinemia. CXCR4 mutations led to a truncated receptor protein associated with a higher expression of CXCR4. CXCR4 mutations pertain to the same clone as to MYD88 L265P mutations but were mutually exclusive to CD79A/CD79B mutations (BCR pathway). We identified a genomic signature in CXCR4(mut) Waldenstrom macroglobulinemia traducing a more complex genome. CXCR4 mutations were also associated with gain of chromosome 4, gain of Xq, and deletion 6q. CONCLUSIONS: Our study panned out new CXCR4 mutations in Waldenstrom macroglobulinemia and identified a specific signature associated to CXCR4(mut), characterized with complex genomic aberrations among MYD88L265P Waldenstrom macroglobulinemia. Our results suggest the existence of various genomic subgroups in Waldenstrom macroglobulinemia. PMID- 26490316 TI - Stress-Related Signaling Pathways in Lethal and Nonlethal Prostate Cancer. AB - PURPOSE: Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and nonlethal disease. EXPERIMENTAL DESIGN: We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n = 150; n = 82 with normal) and the Health Professionals Follow-Up Study (n = 254; n = 120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome and to biomarkers as secondary outcomes. RESULTS: Differential mRNA expression of genes within the adrenergic (P = 0.001), glucocorticoid (P < 0.0001), serotoninergic (P = 0.0019), and muscarinic (P = 0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (P = 0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and nonlethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion. CONCLUSIONS: Our study suggests that stress related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies. PMID- 26490318 TI - What We Write about When We Write About AAC: The Past 30 Years of Research and Future Directions. AB - For the past 30 years, the Augmentative and Alternative Communication (AAC) journal has both documented and instigated change in the field of AAC. We reviewed the papers published in the AAC journal from 1985-2014 in order to identify trends in research and publication activities. Intervention research made up the largest proportion of the four types of research (i.e., intervention, descriptive, experimental, and instrument and measurement development) reported in the journal. Intervention research has most commonly focused on the individual with complex communication needs, and most frequently on younger individuals (aged 17 and younger) with developmental disabilities. While much has been learned in the past 30 years, there continues to be a need for high quality research in a large number of areas. There is a special need for reports of interventions with older individuals with complex communication needs as a result of acquired disabilities, and for information on effective interventions for the communication partners of persons with complex communication needs. PMID- 26490319 TI - Direct association between diet and the stability of human atherosclerotic plaque. AB - Mediterranean diet has been suggested to explain why coronary heart disease mortality is lower in southern than northern Europe. Dietary habits can be revealed by isotope ratio mass spectrometry (IRMS) measurement of carbon (delta(13)C) and nitrogen (delta(15)N) in biological tissues. To study if diet is associated with human plaque stability, atherosclerotic plaques from carotid endarterectomy on 56 patients (21 Portuguese and 35 Swedish) were analysed by IRMS and histology. Plaque components affecting rupture risk were measured. Swedish plaques had more apoptosis, lipids and larger cores, as well as fewer proliferating cells and SMC than the Portuguese, conferring the Swedish a more rupture-prone phenotype. Portuguese plaques contained higher delta(13)C and delta(15)N than the Swedish, indicating that Portuguese plaques were more often derived from marine food. Plaque delta(13)C correlated with SMC and proliferating cells, and inversely with lipids, core size, apoptosis. Plaque delta(15)N correlated with SMC and inversely with lipids, core size and apoptosis. This is the first observational study showing that diet is reflected in plaque components associated with its vulnerability. The Portuguese plaques composition is consistent with an increased marine food intake and those plaques are more stable than those from Swedish patients. Marine-derived food is associated with plaque stability. PMID- 26490320 TI - Factors associated with tonic-clonic seizures in patients with drug-resistant mesial temporal epilepsy. AB - PURPOSE: Among different seizure types, tonic-clonic seizures are more significant because they are more often associated with morbidity. No prior study has been done to investigate risk factors associated with tonic-clonic seizures in patients with mesial temporal epilepsy. METHODS: In this retrospective study, all drug-resistant mesial temporal epilepsy patients in the database of patients who underwent epilepsy surgery at Jefferson comprehensive epilepsy center were recruited. These patients were prospectively registered in a database from 1986 till 2014. Patients' age, gender, epilepsy risk factors, age at seizure onset, and preoperative seizure type(s) were registered routinely. Potential risk factors associated with experiencing preoperative tonic-clonic seizures were investigated. RESULTS: Two hundred seventy-five patients (132 males and 143 females) were studied. Aura type was associated with experiencing perioperative tonic-clonic seizures. Patients with epigastric auras less frequently reported having tonic-clonic seizures compared with those who had other types of auras (odds ratio: 0.37 and 95% confidence interval: 0.19-0.70; p=0.001) and those who did not have any auras (odds ratio: 0.35 and 95% confidence interval: 0.16-0.77; p=0.008). CONCLUSION: Epigastric auras may indicate that a specific anatomic location is involved in epileptogenesis from which generalization is harder because of that location's poor connections with other brain regions. PMID- 26490321 TI - We-Measure: Toward a low-cost portable posturography for patients with multiple sclerosis using the commercial Wii balance board. AB - This study was aimed at investigating whether postural sway measures derived from a standard force platform were similar to those generated by a custom-written software ("We-Measure") acquiring and processing data from a commercial Nintendo balance board (BB). For this purpose, 90 patients with multiple sclerosis (MS) and 50 healthy controls (HC) were tested in a single-day session with a reference standard force platform and a BB-based system. Despite its acceptable between device agreement (tested by visual evaluation of Bland-Altman plot), the low-cost BB-based system tended to overestimate postural sway when compared to the reference standard force platform in both MS and HC groups (on average +30% and +54%, respectively). Between-device reliability was just adequate (MS: 66%, HC: 47%), while test-retest reliability was excellent (MS: 84%, HC: 88%). Concurrent validity evaluation showed similar performance between the reference standard force platform and the BB-based system in discriminating fallers and non-fallers among patients with MS. All these findings may encourage the use of this balance board-based new device in longitudinal study, rather than in cross-sectional design, thus providing a potential useful tool for multicenter settings. PMID- 26490322 TI - Detection of human mammaglobin A mRNA in peripheral blood of breast cancer patients before treatment and association with metastasis. AB - BACKGROUND: Mammaglobin A (MGA), mainly expressed in the breast epithelium, is overexpressed in breast cancer, and has been established as a tumor and promissory marker for the early detection of metastasis. AIM: The main aim of this study was to evaluate the association between the presence of the MGA transcript in the peripheral blood of Brazilian breast cancer patients and healthy women and the development of breast cancer and tumor progression. MATERIAL AND METHODS: The expression of the MGA transcript in peripheral blood of 102 breast cancer patients and 102 healthy women was assessed by RT-PCR. RESULTS: MGA mRNA was expressed in the peripheral blood of 39 breast cancer patients and in none of the women from the control group. The presence of MGA was significantly associated with presence of metastasis and age at onset after 60 years. The presence of MGA mRNA in peripheral blood displayed a sensitivity of 38.2%, specificity of 100.0%, positive predictive value (PPV) of 100.0%, and negative predictive value (NPV) of 61.8% as a breast cancer marker. CONCLUSION: This study provides additional evidence of the presence of MGA in the peripheral blood of breast cancer patients, and its applicability as an efficient biomarker for breast cancer (High specificity and PPV). To our knowledge, this is the first study to assess the expression of MGA mRNA in peripheral blood obtained from the Brazilian population. PMID- 26490323 TI - Clinical presentation of intraocular retinoblastoma; 5-year hospital-based registry in Egypt. AB - PURPOSE: To study the presenting signs of Retinoblastoma in Egypt at Egypt's main pediatric oncology referral center. METHODS: This is a prospective descriptive study (hospital-based registry) conducted at Children's Cancer Hospital Egypt between July 2007 and December 2012. RESULTS: Out of 262 patients diagnosed with retinoblastoma, 244 were suffering from intra-ocular disease at presentation. One hundred thirty-nine (57%) patients presented with unilateral disease, while 105 (43%) suffered bilateral disease. The mean age at presentation was 20.6 +/- 17 months, averaging 18.87 +/- 11.76 months for bilateral and 25.72 +/- 18.78 months for unilateral disease. The most common clinical presentation was leukocoria in 180 (73.8%) patients, strabismus in 32 (13.1%) patients and decreased visual acuity in 12 (4.9%) patients. Group D and E disease represented 62% of all affected eyes. Patients with advanced disease (Group C-E) had longer duration of symptoms. CONCLUSION: In Egypt, retinoblastoma patients present more frequently with advanced disease. There is an ever-increasing need to develop a national team dedicated to studying disease significance and formulating a national awareness program. PMID- 26490324 TI - The rules of the game in graduate entry nursing: A longitudinal case study. AB - BACKGROUND: Graduate Entry Nursing programmes are pre-registration nursing curricula designed for candidates who already have a health related degree. The programmes aim to attract highly motivated individuals who have a commitment to nursing and hold the cognitive abilities associated with studying in higher education including critical thinking styles and capability to study independently. These attributes are termed within the literature as "graduateness". They are viewed by some as advantages to nursing. In contrast, however, there remains widespread scepticism amongst the public and some professionals towards those who are academically educated entering nursing. OBJECTIVES: To explore how GEN students anticipate, experience, explain and respond to attitudes which imply resistance to those who are academically educated. DESIGN: Longitudinal case study informed by the conventions advocated by Yin (2014). SETTINGS: School of Health Sciences in a British University. PARTICIPANTS: Eight GEN students participated over the two year duration of their programme. Twelve clinical assessors with a minimum of four months' experience of supporting GEN students in practice. METHODS: Students took part in individual interviews at six monthly periods which were informed by the content of diaries maintained throughout their clinical placements. Clinical assessors took part in focus group discussions. Practice documentation was accessed to identify the progression of clinical competency along with written feedback received by students from clinical assessors. RESULTS: Results demonstrate the ways in which GEN students position themselves performatively in order to pre-empt or challenge negative stereotypes relating to their competence, compassion and commitment. CONCLUSIONS: Students employ a number of strategies to navigate the challenges of learning within an environment in which they are viewed with suspicion and distrust. PMID- 26490325 TI - Literature review: Use of commercial films as a teaching resource for health sciences students. AB - PURPOSE: Analyze some of the characteristics of the publications focused on commercial cinema as a learning tool for university students engaged in health sciences degrees. DESIGN AND METHODS: The review was based on the search of information in three electronic databases: MEDLINE, CINAHL and ERIC. FINDINGS: 54 papers were selected and analyzed. CONCLUSION: Cinema is a commonly used resource; however there is still a lack of studies demonstrating its usefulness and validity. This review is limited on its analysis by the fact that a large number of experiences are described as having a loose design. PMID- 26490326 TI - Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy. AB - Spinocerebellar ataxia type 1 is one of nine polyglutamine expansion diseases and is characterized by cerebellar ataxia and neuronal degeneration in the cerebellum and brainstem. Currently, there are no effective therapies for this disease. Previously, we have shown that RNA interference mediated silencing of ATXN1 mRNA provides therapeutic benefit in mouse models of the disease. Adeno-associated viral delivery of an engineered microRNA targeting ATXN1 to the cerebella of well established mouse models improved motor phenotypes, neuropathy, and transcriptional changes. Here, we test the translatability of this approach in adult rhesus cerebella. Nine adult male and three adult female rhesus macaque were unilaterally injected with our therapeutic vector, a recombinant adeno associated virus type 1 (rAAV1) expressing our RNAi trigger (miS1) and co expressing enhanced green fluorescent protein (rAAV1.miS1eGFP) into the deep cerebellar nuclei using magnetic resonance imaging guided techniques combined with a Stealth Navigation system (Medtronics Inc.). Transduction was evident in the deep cerebellar nuclei, cerebellar Purkinje cells, the brainstem and the ventral lateral thalamus. Reduction of endogenous ATXN1 messenger RNA levels were >=30% in the deep cerebellar nuclei, the cerebellar cortex, inferior olive, and thalamus relative to the uninjected hemisphere. There were no clinical complications, and quantitative and qualitative analyses suggest that this therapeutic intervention strategy and subsequent reduction of ATXN1 is well tolerated. Collectively the data illustrate the biodistribution and tolerability of rAAV1.miS1eGFP administration to the adult rhesus cerebellum and are supportive of clinical application for spinocerebellar ataxia type 1. PMID- 26490327 TI - The challenges for research on deep brain stimulation and memory. PMID- 26490329 TI - Enhanced habit formation in Gilles de la Tourette syndrome. AB - Tics are sometimes described as voluntary movements performed in an automatic or habitual way. Here, we addressed the question of balance between goal-directed and habitual behavioural control in Gilles de la Tourette syndrome and formally tested the hypothesis of enhanced habit formation in these patients. To this aim, we administered a three-stage instrumental learning paradigm to 17 unmedicated and 17 antipsychotic-medicated patients with Gilles de la Tourette syndrome and matched controls. In the first stage of the task, participants learned stimulus response-outcome associations. The subsequent outcome devaluation and 'slip-of action' tests allowed evaluation of the participants' capacity to flexibly adjust their behaviour to changes in action outcome value. In this task, unmedicated patients relied predominantly on habitual, outcome-insensitive behavioural control. Moreover, in these patients, the engagement in habitual responses correlated with more severe tics. Medicated patients performed at an intermediate level between unmedicated patients and controls. Using diffusion tensor imaging on a subset of patients, we also addressed whether the engagement in habitual responding was related to structural connectivity within cortico-striatal networks. We showed that engagement in habitual behaviour in patients with Gilles de la Tourette syndrome correlated with greater structural connectivity within the right motor cortico-striatal network. In unmedicated patients, stronger structural connectivity of the supplementary motor cortex with the sensorimotor putamen predicted more severe tics. Overall, our results indicate enhanced habit formation in unmedicated patients with Gilles de la Tourette syndrome. Aberrant reinforcement signals to the sensorimotor striatum may be fundamental for the formation of stimulus-response associations and may contribute to the habitual behaviour and tics of this syndrome. PMID- 26490328 TI - TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson's disease via CNTF. AB - Currently there is no neuroprotective or neurorestorative therapy for Parkinson's disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRalpha) on nigral dopamine neurons in both the MPP(+)-lesioned or adeno-associated virus alpha-synuclein rat models of Parkinson's disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson's disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRalpha on dopamine neurons) might have relevance to human Parkinson's disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson's disease. PMID- 26490330 TI - Differential relationships between apathy and depression with white matter microstructural changes and functional outcomes. AB - Small vessel disease is a stroke subtype characterized by pathology of the small perforating arteries, which supply the sub-cortical structures of the brain. Small vessel disease is associated with high rates of apathy and depression, thought to be caused by a disruption of white matter cortical-subcortical pathways important for emotion regulation. It provides an important biological model to investigate mechanisms underlying these key neuropsychiatric disorders. This study investigated whether apathy and depression can be distinguished in small vessel disease both in terms of their relative relationship with white matter microstructure, and secondly whether they can independently predict functional outcomes. Participants with small vessel disease (n = 118; mean age = 68.9 years; 65% male) defined as a clinical and magnetic resonance imaging confirmed lacunar stroke with radiological leukoaraiosis were recruited and completed cognitive testing, measures of apathy, depression, quality of life and diffusion tensor imaging. Healthy controls (n = 398; mean age = 64.3 years; 52% male) were also studied in order to interpret the degree of apathy and depression found within the small vessel disease group. Firstly, a multilevel structural equation modelling approach was used to identify: (i) the relationships between median fractional anisotropy and apathy, depression and cognitive impairment; and (ii) if apathy and depression make independent contributions to quality of life in patients with small vessel disease. Secondly, we applied a whole-brain voxel based analysis to investigate which regions of white matter were associated with apathy and depression, controlling for age, gender and cognitive functioning. Structural equation modelling results indicated both apathy (r = -0.23, P <= 0.001) and depression (r = -0.41, P <= 0.001) were independent predictors of quality of life. A reduced median fractional anisotropy was significantly associated with apathy (r = -0.38, P <= 0.001), but not depression (r = -0.16, P = 0.09). On voxel-based analysis, apathy was associated with widespread reduction in white matter integrity, with the strongest effects in limbic association tracts such as the anterior cingulum, fornix and uncinate fasciculus. In contrast, when controlling for apathy, we found no significant relationship between our white matter parameters and symptoms of depression. In conclusion, white matter microstructural changes in small vessel disease are associated with apathy but not directly with depressive symptoms. These results suggest that apathy, but not depression, in small vessel disease is related to damage to cortical-subcortical networks associated with emotion regulation, reward and goal directed behaviour. PMID- 26490331 TI - Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the BACHD rat. AB - Huntington's disease is a fatal human neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, which translates into a mutant huntingtin protein. A key event in the molecular pathogenesis of Huntington's disease is the proteolytic cleavage of mutant huntingtin, leading to the accumulation of toxic protein fragments. Mutant huntingtin cleavage has been linked to the overactivation of proteases due to mitochondrial dysfunction and calcium derangements. Here, we investigated the therapeutic potential of olesoxime, a mitochondria-targeting, neuroprotective compound, in the BACHD rat model of Huntington's disease. BACHD rats were treated with olesoxime via the food for 12 months. In vivo analysis covered motor impairments, cognitive deficits, mood disturbances and brain atrophy. Ex vivo analyses addressed olesoxime's effect on mutant huntingtin aggregation and cleavage, as well as brain mitochondria function. Olesoxime improved cognitive and psychiatric phenotypes, and ameliorated cortical thinning in the BACHD rat. The treatment reduced cerebral mutant huntingtin aggregates and nuclear accumulation. Further analysis revealed a cortex-specific overactivation of calpain in untreated BACHD rats. Treated BACHD rats instead showed significantly reduced levels of mutant huntingtin fragments due to the suppression of calpain-mediated cleavage. In addition, olesoxime reduced the amount of mutant huntingtin fragments associated with mitochondria, restored a respiration deficit, and enhanced the expression of fusion and outer-membrane transport proteins. In conclusion, we discovered the calpain proteolytic system, a key player in Huntington's disease and other neurodegenerative disorders, as a target of olesoxime. Our findings suggest that olesoxime exerts its beneficial effects by improving mitochondrial function, which results in reduced calpain activation. The observed alleviation of behavioural and neuropathological phenotypes encourages further investigations on the use of olesoxime as a therapeutic for Huntington's disease. PMID- 26490332 TI - Re-establishing ataxin-2 downregulates translation of mutant ataxin-3 and alleviates Machado-Joseph disease. AB - Machado-Joseph disease is a progressive neurodegenerative disorder associated with the polyQ-expanded ataxin-3 (encoded by ATXN3), for which no therapy is available. With the aim of clarifying the mechanism of neurodegeneration, we hypothesized that the abnormally long polyQ tract would interact aberrantly with ataxin-2 (encoded by ATXN2), another polyQ protein whose function has recently been linked to translational regulation. Using patient's samples and cellular and animal's models we found that in Machado-Joseph disease: (i) ataxin-2 levels are reduced; and (ii) its subcellular localization is changed towards the nucleus. Restoring ataxin-2 levels by lentiviral-mediated overexpression: (i) reduced mutant ataxin-3 levels; and (ii) rescued behaviour defects and neuropathology in a transgenic mouse model of Machado-Joseph disease. Conversely (i) mutating the ataxin-2 motif that enables binding to its natural interactor and translation activator poly(A)-binding protein; or (ii) overexpressing poly(A)-binding protein, had opposite effects, increasing mutant ataxin-3 translation and aggregation. This work suggests that in Machado-Joseph disease, mutant ataxin-3 drives an abnormal reduction of ataxin-2 levels, which overactivates poly(A) binding protein, increases translation of mutant ataxin-3 and other proteins and aggravates Machado-Joseph disease. Re-establishment of ataxin-2 levels reduces mutant ataxin-3 and alleviates Machado-Joseph disease pathogenesis opening a new avenue for therapeutic intervention in this and potentially other polyQ disorders. PMID- 26490333 TI - Preclinical properties and human in vivo assessment of 123I-ABC577 as a novel SPECT agent for imaging amyloid-beta. AB - Non-invasive imaging of amyloid-beta in the brain, a hallmark of Alzheimer's disease, may support earlier and more accurate diagnosis of the disease. In this study, we assessed the novel single photon emission computed tomography tracer (123)I-ABC577 as a potential imaging biomarker for amyloid-beta in the brain. The radio-iodinated imidazopyridine derivative (123)I-ABC577 was designed as a candidate for a novel amyloid-beta imaging agent. The binding affinity of (123)I ABC577 for amyloid-beta was evaluated by saturation binding assay and in vitro autoradiography using post-mortem Alzheimer's disease brain tissue. Biodistribution experiments using normal rats were performed to evaluate the biokinetics of (123)I-ABC577. Furthermore, to validate (123)I-ABC577 as a biomarker for Alzheimer's disease, we performed a clinical study to compare the brain uptake of (123)I-ABC577 in three patients with Alzheimer's disease and three healthy control subjects. (123)I-ABC577 binding was quantified by use of the standardized uptake value ratio, which was calculated for the cortex using the cerebellum as a reference region. Standardized uptake value ratio images were visually scored as positive or negative. As a result, (123)I-ABC577 showed high binding affinity for amyloid-beta and desirable pharmacokinetics in the preclinical studies. In the clinical study, (123)I-ABC577 was an effective marker for discriminating patients with Alzheimer's disease from healthy control subjects based on visual images or the ratio of cortical-to-cerebellar binding. In patients with Alzheimer's disease, (123)I-ABC577 demonstrated clear retention in cortical regions known to accumulate amyloid, such as the frontal cortex, temporal cortex, and posterior cingulate. In contrast, less, more diffuse, and non-specific uptake without localization to these key regions was observed in healthy controls. At 150 min after injection, the cortical standardized uptake value ratio increased by ~ 60% in patients with Alzheimer's disease relative to healthy control subjects. Both healthy control subjects and patients with Alzheimer's disease showed minimal (123)I-ABC577 retention in the white matter. These observations indicate that (123)I-ABC577 may be a useful single photon emission computed tomography imaging maker to identify amyloid-beta in the human brain. The availability of an amyloid-beta tracer for single photon emission computed tomography might increase the accessibility of diagnostic imaging for Alzheimer's disease. PMID- 26490336 TI - Sensitive probes of protein structure and dynamics in well-controlled environments: combining mass spectrometry with fluorescence spectroscopy. AB - Combining the selectivity of mass spectrometry (MS) with laser-induced fluorescence (LIF) presents a promising route to probe the intrinsic conformation, stability and dynamics of biological macromolecules. However, applications to proteins are in their infancy. Recent advances include the realization of Forster (fluorescence) resonance energy transfer (FRET) to provide nm-range distance constraints in de-solvated proteins, and measurement of dynamic fluorescence quenching rates to assess shorter-range interactions in peptides and Trp-cage. Temperature-dependent experiments employing FRET and dynamic quenching as conformational probes enable determination of enthalpy and entropy of conformational change in de-solvated biomolecules. These developments show the feasibility of using MS-LIF to dissect complex molecular interactions. For example, MS-LIF of protein-ligand complexes and partially hydrated proteins will better elucidate the energetics of specific binding interactions and the role of the solvent in protein structure and folding. PMID- 26490337 TI - Piperacillin/tazobactam continuous infusion at 12G/1.5G per day in CF patients results in target plasma-concentrations. PMID- 26490335 TI - Primary motor cortex of the parkinsonian monkey: altered encoding of active movement. AB - Abnormalities in the movement-related activation of the primary motor cortex (M1) are thought to be a major contributor to the motor signs of Parkinson's disease. The existing evidence, however, variably indicates that M1 is under-activated with movement, overactivated (due to a loss of functional specificity) or activated with abnormal timing. In addition, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those gaps in knowledge were addressed by studying the extracellular activity of antidromically identified lamina 5b pyramidal-tract type neurons (n = 153) and intratelencephalic-type corticostriatal neurons (n = 126) in the M1 of two monkeys as they performed a step-tracking arm movement task. We compared movement related discharge before and after the induction of parkinsonism by administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and quantified the spike rate encoding of specific kinematic parameters of movement using a generalized linear model. The fraction of M1 neurons with movement related activity declined following MPTP but only marginally. The strength of neuronal encoding of parameters of movement was reduced markedly (mean 29% reduction in the coefficients from the generalized linear model). This relative decoupling of M1 activity from kinematics was attributable to reductions in the coefficients that estimated the spike rate encoding of movement direction (-22%), speed (-40%), acceleration (-49%) and hand position (-33%). After controlling for MPTP-induced changes in motor performance, M1 activity related to movement itself was reduced markedly (mean 36% hypoactivation). This reduced activation was strong in pyramidal tract-type neurons (-50%) but essentially absent in corticostriatal neurons. The timing of M1 activation was also abnormal, with earlier onset times, prolonged response durations, and a 43% reduction in the prevalence of movement-related changes beginning in the 150-ms period that immediately preceded movement. Overall, the results are consistent with proposals that under-activation and abnormal timing of movement-related activity in M1 contribute to parkinsonian motor signs but are not consistent with the idea that a loss of functional specificity plays an important role. Given that pyramidal tract-type neurons form the primary efferent pathway that conveys motor commands to the spinal cord, the dysfunction of movement-related activity in pyramidal tract-type neurons is likely to be a central factor in the pathophysiology of parkinsonian motor signs. PMID- 26490334 TI - Common polygenic variation enhances risk prediction for Alzheimer's disease. AB - The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 * 10(-26)). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 * 10(-19)). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes. PMID- 26490338 TI - Neuroanatomical characteristics of deep and superficial needling using LI11 as an example. AB - OBJECTIVES: To compare the neuroanatomical characteristics of the deep and superficial tissues at acupuncture point LI11 using a neural tracing technique, in order to examine the neural basis of potential differences between deep and superficial needling techniques. METHODS: In order to mimic the situations of the deep and superficial needling, the retrograde neural tracer Alexa Fluor 488 conjugate of cholera toxin subunit B (AF488-CTB) was injected into the muscle or subcutaneous tissue, respectively, at acupuncture point LI11 in eight rats (n=4 each). Three days following injection, the distribution of motor and sensory neurons labelled with AF488-CTB was examined in the spinal cord and dorsal root ganglia (DRG) under a fluorescent microscope. RESULTS: For both types of injection, labelled motor and sensory neurons were distributed on the side ipsilateral to the injection in the spinal cord and DRG between spinal levels C5 and T1. The number of labelled motor neurons following intramuscular injection was significantly higher than subcutaneous injection. By contrast, the number of labelled sensory neurons following subcutaneous injection was significantly higher in number and extended over a greater number of spinal segments compared to intramuscular injection. CONCLUSIONS: These data indicate that the motor and sensory innervation of muscle and subcutaneous tissue beneath LI11 differ, and suggest that acupuncture signals induced by deep and superficial needling stimulation may be transmitted through different neural pathways. PMID- 26490342 TI - Diameter Dependence of Lattice Thermal Conductivity of Single-Walled Carbon Nanotubes: Study from Ab Initio. AB - The effects of temperature, tube length, defects, and surface functionalization on the thermal conductivity (kappa) of single-walled carbon nanotubes (SWCNTs) were well documented in literature. However, diameter dependence of thermal conductivity of SWCNTs received less attentions. So far, diverse trends of the diameter dependence have been discussed by different methods and all the previous results were based on empirical interatomic potentials. In this paper, we emphasize to clarify accurate kappa values of SWCNTs with different diameters and in-plane kappa of graphene. All the studies were under the framework of anharmonic lattice dynamics and Boltzmann transport equation (BTE) based on first principle calculations. We try to infer the right trend of diameter dependent thermal conductivity of SWCNTs. We infer that graphene is the limitation as SWCNT with an infinite diameter. We analyzed the thermal conductivity contributions from each phonon mode in SWCNTs to explain the trend. Meanwhile, we also identify the extremely low thermal conductivity of ultra-thin SWCNTs. PMID- 26490343 TI - The rehabilitative effects on written language of a combined language and parietal dual-tDCS treatment in a stroke case. AB - In this paper we report the effect of a combined transcranial direct current stimulation (tDCS) and speech language therapy on linguistic deficits following left brain damage in a stroke case. We show that simultaneous electrical excitatory stimulation to the left and inhibitory stimulation to the right parietal regions (dual-tDCS) affected writing and reading rehabilitation, enhancing speech therapy outcomes. The results of a comparison with healthy controls showed that application of dual-tDCS could improve, in particular, sub lexical transcoding and, specifically, the reading of non-words with increasing length and complexity. Positive repercussions on patient's quality of functional communication were also ascertained. Significant changes were also found in other language and cognitive tasks not directly treated (comprehension and constructive apraxia). PMID- 26490344 TI - Physical Activity Program Is Helpful for Improving Quality of Life in Patients with Systemic Lupus Erythematosus. AB - Given the crucial events in systemic lupus erythematosus (SLE) such as joint and muscle pain, fatigue, depression, obesity and osteoporosis, the very thought of exercising can be challenging. This prospective study included 60 patients diagnosed with SLE in stable condition. A randomly selected group of 30 women had aerobic training on a bicycle ergometer for a period of 15 minutes, 3 times per week for 6 weeks, while the second group of 30 women performed isotonic exercises (to stretch and lengthen muscles and improve the range of motion) for 30 minutes, 3 times per week during the same period. Fatigue Severity Scale (FSS), Short Form 36 (SF36) questionnaire on the quality of life and Beck depression inventory (BDI) were analyzed at baseline and after 6 weeks. At baseline FSS score was 53.8 +/- 5.7 and after the physical activity FSS score was 29.1 +/- 7.8 (FSS >= 36; fatigue is present). The largest number of patients (66.7%) was in a moderate depressed state at the baseline, while after physical activities 61.7% of patients, had a mild mood disturbance. There were significant differences (p < 0.001) in values of all areas of quality of life questionnaire SF36 before and after the implementation of physical activity. The type of physical activity had no influence in FSS and BDI values. Continuous physical activity, regardless of its type, significantly improved quality of life of SLE patients. We recommend regular physical activity as an integral part of modern therapeutic approach in this patient population. PMID- 26490345 TI - Beneficial effects of previous exercise training on renal changes in streptozotocin-induced diabetic female rats. AB - This study evaluated the effects of aerobic exercise performed both previously and after the induction of diabetes mellitus on changes of renal function and structure in streptozotocin-induced diabetic rats. Female wistar rats were divided into five groups: sedentary control (C + Se); trained control (C + Ex); sedentary diabetic (D + Se); trained diabetic (D + Ex) and previously trained diabetic (D + PEx). The previous exercise consisted of treadmill running for four weeks before the induction of diabetes mellitus. After induction of diabetes mellitus with streptozotocin, the D + PEx, D + Ex and C + Ex groups were submitted to eight weeks of aerobic exercise. At the end of the training protocol, we evaluate the serum glucose, insulin and 17beta-estradiol levels, renal function and structure, proteinuria, and fibronectin, collagen IV and transforming growth factor beta 1 (TGF-beta1) renal expressions. Induction of diabetes mellitus reduced the insulin and did not alter 17beta-estradiol levels, and exercise did not affect any of these parameters. Previous exercise training attenuated the loss of body weight, the blood glucose, the increase of glomerular filtration rate and prevented the proteinuria in the D + PEx group compared to D + Se group. Previous exercise also reduced glomerular hypertrophy, tubular and glomerular injury, as well as the expressions of fibronectin and collagen IV. These expressions were associated with reduced expression of TGF-beta1. In conclusion, our study shows that regular aerobic exercise especially performed previously to induction of diabetes mellitus improved metabolic control and has renoprotective action on the diabetic kidney. PMID- 26490346 TI - Sulforaphane attenuates the development of atherosclerosis and improves endothelial dysfunction in hypercholesterolemic rabbits. AB - The aim of the present work was to explore possible protective effects of sulforaphane (SFN) against atherosclerosis development and endothelial dysfunction in hypercholesterolemic rabbits. Rabbits were assigned to three groups of five: group I fed normal chow diet for four weeks, group II fed 1% high cholesterol diet (HCD) and group III fed HCD + SFN (0.25 mg/kg/day). Blood samples were collected for measurement of serum triglycerides (TGs), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), lactate dehydrogenase (LDH) and C-reactive protein (CRP). Aortic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and total nitrite/nitrate (NOx) were measured. Vascular reactivity and intima/media (I/M) ratio were analyzed. Nuclear factor-kappa B (NF-kappaB) activation in aortic endothelial cells was identified immunohistochemically. HCD induced significant increases in serum TGs, TC, LDL-C, LDH, and CRP, and aortic MDA and SOD. Moreover, HCD caused significant reductions in serum HDL-C, aortic GSH and NOx. SFN administration significantly decreased HCD-induced elevations in serum TC, LDL-C, CRP, and LDH. while significantly increased HDL-C and GSH levels and normalized aortic SOD and NOx. Additionally, SFN significantly improved rabbit aortic endothelium-dependent relaxation to acetylcholine. Moreover, SFN significantly reduced the elevation in I/M ratio. This effect was confirmed by aortic histopathologic examination. The expression of NF-kappaB in aortic tissue showed a marked reduction upon treatment with SFN. In conclusion, this study reveals that SFN has the ability to ameliorate HCD-induced atherosclerotic lesions progression and vascular dysfunction, possibly via its lipid-lowering and antioxidant effects and suppression of NF-kappaB-mediated inflammation. PMID- 26490347 TI - A novel approach identifies the first transcriptome networks in bats: a new genetic model for vocal communication. AB - BACKGROUND: Bats are able to employ an astonishingly complex vocal repertoire for navigating their environment and conveying social information. A handful of species also show evidence for vocal learning, an extremely rare ability shared only with humans and few other animals. However, despite their potential for the study of vocal communication, bats remain severely understudied at a molecular level. To address this fundamental gap we performed the first transcriptome profiling and genetic interrogation of molecular networks in the brain of a highly vocal bat species, Phyllostomus discolor. RESULTS: Gene network analysis typically needs large sample sizes for correct clustering, this can be prohibitive where samples are limited, such as in this study. To overcome this, we developed a novel bioinformatics methodology for identifying robust co expression gene networks using few samples (N=6). Using this approach, we identified tissue-specific functional gene networks from the bat PAG, a brain region fundamental for mammalian vocalisation. The most highly connected network identified represented a cluster of genes involved in glutamatergic synaptic transmission. Glutamatergic receptors play a significant role in vocalisation from the PAG, suggesting that this gene network may be mechanistically important for vocal-motor control in mammals. CONCLUSION: We have developed an innovative approach to cluster co-expressing gene networks and show that it is highly effective in detecting robust functional gene networks with limited sample sizes. Moreover, this work represents the first gene network analysis performed in a bat brain and establishes bats as a novel, tractable model system for understanding the genetics of vocal mammalian communication. PMID- 26490348 TI - Acoustic noise reduction in T 1- and proton-density-weighted turbo spin-echo imaging. AB - OBJECTIVE: To reduce acoustic noise levels in T 1-weighted and proton-density weighted turbo spin-echo (TSE) sequences, which typically reach acoustic noise levels up to 100 dB(A) in clinical practice. MATERIALS AND METHODS: Five acoustic noise reduction strategies were combined: (1) gradient ramps and shapes were changed from trapezoidal to triangular, (2) variable-encoding-time imaging was implemented to relax the phase-encoding gradient timing, (3) RF pulses were adapted to avoid the need for reversing the polarity of the slice-rewinding gradient, (4) readout bandwidth was increased to provide more time for gradient activity on other axes, (5) the number of slices per TR was reduced to limit the total gradient activity per unit time. We evaluated the influence of each measure on the acoustic noise level, and conducted in vivo measurements on a healthy volunteer. Sound recordings were taken for comparison. RESULTS: An overall acoustic noise reduction of up to 16.8 dB(A) was obtained by the proposed strategies (1-4) and the acquisition of half the number of slices per TR only. Image quality in terms of SNR and CNR was found to be preserved. CONCLUSIONS: The proposed measures in this study allowed a threefold reduction in the acoustic perception of T 1-weighted and proton-density-weighted TSE sequences compared to a standard TSE-acquisition. This could be achieved without visible degradation of image quality, showing the potential to improve patient comfort and scan acceptability. PMID- 26490349 TI - Association between shift work and the risk of death from biliary tract cancer in Japanese men. AB - BACKGROUND: There is increasing evidence suggesting that shift work involving night work may increase cancer risk. METHODS: We examined the association between working rotating shifts and the risk of death from biliary tract cancer among Japanese men who participated in the Japan Collaborative Cohort Study. Of the 46,395 men recruited, 22,224 men aged 40-65 at baseline (1988-1990) who reported working full-time or were self-employed were included in the present analysis. The study subjects were followed through December 31, 2009. Information regarding occupation and lifestyle factors was collected using a self-administered questionnaire. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95 % confidence interval (CI) for the risk of death from biliary tract cancer in relation to shift work. RESULTS: During a mean 17-year follow-up, we observed 94 biliary tract cancer deaths, including 23 deaths from gallbladder cancer and 71 deaths from extrahepatic bile duct cancer. Overall, shift work was associated with a statistically non-significant increase in the risk of biliary tract cancer, with an HR of 1.50 (95 % CI: 0.81-2.77), among rotating shift workers. When the analysis was limited to extrahepatic bile duct cancer, a significant association appeared, with a multivariable-adjusted HR of 1.93 (95 % CI: 1.00-3.72) for rotating shift workers. CONCLUSION: Our data indicate that shift work may be associated with increased risk of death from extrahepatic bile duct cancer in this cohort of Japanese men. The association with gallbladder cancer remains unclear because of the small number of deaths. PMID- 26490350 TI - Bayesian calibration of simulation models for supporting management of the elimination of the macroparasitic disease, Lymphatic Filariasis. AB - BACKGROUND: Mathematical models of parasite transmission can help integrate a large body of information into a consistent framework, which can then be used for gaining mechanistic insights and making predictions. However, uncertainty, spatial variability and complexity, can hamper the use of such models for decision making in parasite management programs. METHODS: We have adapted a Bayesian melding framework for calibrating simulation models to address the need for robust modelling tools that can effectively support management of lymphatic filariasis (LF) elimination in diverse endemic settings. We applied this methodology to LF infection and vector biting data from sites across the major LF endemic regions in order to quantify model parameters, and generate reliable predictions of infection dynamics along with credible intervals for modelled output variables. We used the locally calibrated models to estimate breakpoint values for various indicators of parasite transmission, and simulate timelines to parasite extinction as a function of local variations in infection dynamics and breakpoints, and effects of various currently applied and proposed LF intervention strategies. RESULTS: We demonstrate that as a result of parameter constraining by local data, breakpoint values for all the major indicators of LF transmission varied significantly between the sites investigated. Intervention simulations using the fitted models showed that as a result of heterogeneity in local transmission and extinction dynamics, timelines to parasite elimination in response to the current Mass Drug Administration (MDA) and various proposed MDA with vector control strategies also varied significantly between the study sites. Including vector control, however, markedly reduced the duration of interventions required to achieve elimination as well as decreased the risk of recrudescence following stopping of MDA. CONCLUSIONS: We have demonstrated how a Bayesian data model assimilation framework can enhance the use of transmission models for supporting reliable decision making in the management of LF elimination. Extending this framework for delivering predictions in settings either lacking or with only sparse data to inform the modelling process, however, will require development of procedures to estimate and use spatio-temporal variations in model parameters and inputs directly, and forms the next stage of the work reported here. PMID- 26490351 TI - Analyzing pathogenic (double-stranded (ds) DNA-specific) plasma cells via immunofluorescence microscopy. AB - INTRODUCTION: While protective plasma cells (PCs) are an important part of the individual's immune defense, autoreactive plasma cells such as dsDNA-specific plasma cells contribute to the pathogenesis of autoimmune diseases like systemic lupus erythematosus (SLE). However, the research on dsDNA-specific plasma cells was restricted to the ELISpot technique, with its limitations, as no other attempt for identification of dsDNA-reactive plasma cells had been successful. METHODS: With improved fluorochrome labeling of dsDNA, removal of DNA aggregates, and enhanced blocking of unspecific binding, we were able to specifically detect dsDNA-reactive plasma cells by immunofluorescence microscopy. RESULTS: Via this novel technique we were able to distinguish short-lived (SLPCs) and long-lived (LLPCs) autoreactive plasma cells, discriminate dsDNA-specific plasma cells according to their immunoglobulin class (IgG, IgM, and IgA) and investigate autoreactive (dsDNA) and vaccine-induced ovalbumin (Ova) plasma cells in parallel. CONCLUSIONS: The detection of autoreactive dsDNA-specific plasma cells via immunofluorescence microscopy allows specific studies on pathogenic and protective plasma cell subsets and their niches, detailed evaluation of therapeutic treatments and therefore offers new possibilities for basic and clinical research. PMID- 26490352 TI - Perioperative care of infants with pyloric stenosis. AB - Pyloric stenosis (PS) is one of the most common surgical conditions affecting neonates and young infants. The definitive treatment for PS is surgical pyloromyotomy, either open or laparoscopic. However, surgical intervention should never be considered urgent or emergent. More importantly, emergent medical intervention may be required to correct intravascular volume depletion and electrolyte disturbances. Given advancements in surgical and perioperative care, morbidity and mortality from PS should be limited. However, either may occur related to poor preoperative resuscitation, anesthetic management difficulties, or postoperative complications. The following manuscript reviews the current evidence-based medicine regarding the perioperative care of infants with PS with focus on the preoperative assessment and correction of metabolic abnormalities, intraoperative care including airway management (particularly debate related to rapid sequence intubation), maintenance anesthetic techniques, and techniques for postoperative pain management. Additionally, reports of applications of regional anesthesia for either postoperative pain control or as an alternative to general anesthesia are discussed. Management recommendations are provided whenever possible. PMID- 26490353 TI - Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies. AB - PURPOSE: The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. METHODS: In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood. RESULTS: Mean maximum plasma concentration (C max) and area under total plasma concentration-time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5-7 days for all doses. C max and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ~2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses. CONCLUSIONS: Fostamatinib pharmacokinetics following single- and multiple dose administration was approximately dose proportional at all doses <=150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics. PMID- 26490354 TI - Off-label and unlicensed drug treatments in Neonatal Intensive Care Units: an Italian multicentre study. AB - PURPOSE: The use of medicines among newborns admitted to intensive care units is characterized by a high prevalence of off-label/unlicensed use and a wide variability in the absence of international guidelines. A prospective cross sectional study was organized with the aim to analyse drug prescriptions among all 107 Italian level III neonatal intensive care units. METHODS: An online questionnaire was used to collect detailed information for each newborn, and a classification was made about the license status of all prescriptions. In addition, prescriptions were analysed taking into account a practical guide prepared by the Italian Society of Neonatology (ISN). RESULTS: The 1-day survey (May-July 2014) regarded 220 newborn infants admitted to 36/107 Italian neonatal intensive care units: 191 prematures and 29 born at term. In total, 720 prescriptions (corresponding to 79 different drugs) were analysed: 191 (26.5 %) followed the terms of the product license, 529 (73.5 %) were off-label or unlicensed: 193/220 newborns (87.7 %) received at least one off-label/unlicensed prescription. Antiinfectives were the most common medicine used, followed by respiratory drugs and antianaemics; in an off-label manner, the most common was cardiovascular and central nervous system (CNS) drugs, gastrointestinals and antiinfectives. The most common categories of off-label use were age (34.4 %) and dosing frequency (20.6 %). Compared to ISN practical guide, prescriptions adhered more frequently to indications (100 % for ampicillin/sulbactam, >80 % for ampicillin, fluconazole, fentanyl, ranitidine and vancomicin). CONCLUSIONS: Our results confirm the high prevalence of off-label/unlicensed drug use in the neonatal population and underline a better adherence to indications based on clinical practice, suggesting the need to update information contained in the data sheets of medicines. PMID- 26490355 TI - Prevalence and predictors of non-steroidal anti-inflammatory drug/analgesic therapeutic duplication in the South Korean ambulatory care setting. AB - PURPOSE: Therapeutic duplication (TD) in prescriptions is a common cause of inappropriate drug use. This study aimed to determine the prevalence of TD in the Korean ambulatory setting and to determine the patient and prescriber characteristics that were associated with TD of non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics. METHODS: Ambulatory care cases with NSAID/analgesic prescriptions were extracted from the National Health Insurance database for January-March 2011. The Korean TD classification (64 ingredients) was used to define cases of TD. Multivariate logistic regression was used to determine the predictors of TD. The independent variables in the regression model included patient characteristics (sex, age, insurance type, comorbidity, diagnosis, and number of prescribed drugs) and prescriber characteristics (type of medical institution and specialty). RESULTS: Among 21 million patients, we identified 59,636,222 ambulatory care visits with NSAID/analgesic prescriptions; 13.3 % of these cases involved TD. The most frequent duplications were diclofenac/aceclofenac (12.4 % of TDs), diclofenac/talniflumate (11.2 %), and diclofenac/loxoprofen sodium (10.7 %). Male sex, older age, and a Charlson comorbidity index of >=1 were associated with an increased likelihood of TD. Arthritis, injection administration (OR 3.676, 95 % CI 3.670-3.683), and the number of drugs per prescription were associated with an increased likelihood of TD. Orthopedic and pediatric specialties were associated with an increased likelihood of TD. CONCLUSIONS: This study is the first to determine the prevalence of NSAID TD and the factors that were associated with its occurrence in South Korea. These results may help prevent TD and improve appropriate medication use. PMID- 26490356 TI - Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations after tyrosine kinase inhibitors treatment: a meta-analysis. AB - PURPOSE: Exon 19 deletion and exon 21 L858R mutation were the most common epidermal growth factor receptor (EGFR) mutations. We examined the clinical impact of these two mutations in patients with non-small-cell lung cancer (NSCLC) after EGFR tyrosine kinase inhibitor (TKI) treatment. METHODS: The outcomes of interest were progression-free survival (PFS), overall survival (OS) and objective response rates (ORR), network meta-analysis and direct meta-analysis were conducted to calculate the efficacy of EGFR-TKIs between these two mutations. We also investigated the association between EGFR mutation types and clinical characteristics. RESULTS: A total of 4835 patients from 26 trials were assessed. EGFR-TKIs, compared with chemotherapy, significantly prolonged PFS and OS in both exon 19 deletion and exon 21 L858R mutation based on 8 trials. Network meta-analysis revealed that treatment with EGFR-TKIs had greater benefit in exon 19 deletion than in exon 21 L858R mutation. Furthermore, direct meta-analysis from 12 studies showed the similar result; patients with exon 19 deletion had a significantly longer PFS compared with exon 21 L858R mutation (HR, 0.69; 95 % CI, 0.57-0.82; P < 0.001). There were also greater benefit on OS (HR, 0.61; 95 % CI, 0.43-0.86; P = 0.005) and higher ORR (OR, 2.14; 95 % CI, 1.63-2.81; P < 0.001). Additionally, we found that a significant association between the type of mutation and age (P < 0.001) or smoking status (P = 0.022), but no other significant differences were detected in sex, histologic subtype and performance status between these two mutations. CONCLUSIONS: Patients with NSCLC and EGFR exon 19 deletion had a longer PFS, OS and higher response rates after EGFR-TKI therapy compared with exon 21 L858R mutation. PMID- 26490357 TI - A limited sampling strategy based on maximum a posteriori Bayesian estimation for a five-probe phenotyping cocktail. AB - PURPOSE: Cocktail approach using a combination of probes to phenotype several cytochromes P450 or transporters is of high interest in anticipating drug-drug interactions and personalized medicine. Its clinical use remains however limited by the intensive sampling scheme required to obtain phenotyping indexes (PI) which consists in calculating the area under the concentration-time curves. We proposed to use maximum a posteriori Bayesian estimation (MAPBE) that incorporates available information from the whole population to derive PI from a few individual observations. The performance of a limited sampling strategy (LSS) based on MAPBE was evaluated for a five-probe cocktail. METHODS: The studied cocktail included midazolam, tolbutamide, caffeine, dextromethorphan, omeprazole and their relevant metabolites. Prior information for MAPBE was obtained by nonlinear mixed-effect modelling of data from a pilot study. Sampling times were chosen based on optimal design theory using the Bayesian Fisher information matrix. Through a simulation study, we investigated the predicted PI in terms of bias and imprecision for varying number and timing of samples. RESULTS: Some three-point Bayesian designs gave mean prediction errors in [-5 %, 5 %], root mean square errors below 30 % for all probes, except dextromethorphan whose model should be consolidated further with additional data. This approach gave overall less outlier predicted values than single-point metrics and was more flexible to the timing of the latest sampling. CONCLUSIONS: MAPBE is accurate for predicting simultaneously several PI while being flexible in terms of integrating clinical constraints. Therefore, LSS based on MAPBE could help reduce the time of presence in hospital for individuals to be phenotyped. PMID- 26490358 TI - Corrigendum: Control of eight predominant Eimeria spp. involved in economic coccidiosis of broiler chicken by a chemically characterized essential oil. PMID- 26490359 TI - Quantification of normal cerebral oxygen extraction and oxygen metabolism by phase-based MRI susceptometry: evaluation of repeatability using two different imaging protocols. AB - INTRODUCTION: Global oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) were quantified in a test-retest study. Cerebral blood flow (CBF) data, required for CMRO2 estimation, were obtained using dynamic susceptibility contrast MRI (DSC-MRI). OEF and CMRO2 were quantified using two separate data sets, that is, conventional high-resolution (HR) gradient echo (GRE) phase maps as well as echo planar imaging (EPI) phase maps taken from the baseline (precontrast) part of the DSC-MRI time series. The EPI phase data were included to elucidate whether an extra HR-GRE scan is needed to obtain information about OEF and CMRO2 , or if this information can be extracted from the DSC-MRI experiment only. METHODS: Twenty healthy volunteers were scanned using 3 T MRI on two occasions. Oxygen saturation levels were obtained from phase data measured in the great cerebral vein of Galen, based on HR-GRE as well as EPI phase maps. In combination with DSC-MRI CBF, this allowed for calculation of OEF and CMRO2 . RESULTS: High-resolution-gradient echo- and EPI-based phase images resulted in similar OEF spread and repeatability, with coefficients of variation/intraclass correlation coefficients of 0.26/0.95 and 0.23/0.81, respectively. Absolute OEF values (HR-GRE: 0.40 +/- 0.11, EPI: 0.35 +/- 0.08) were consistent with literature data. CMRO2 showed similar repeatability, somewhat increased spread and reasonable absolute values (HR-GRE: 3.23 +/- 1.26 ml O2 /100 g min-1 , EPI: 2.79 +/- 0.89 ml O2 /100 g min-1 ). DISCUSSION: In general, the results obtained by HR-GRE and EPI showed comparable characteristics. The EPI methodology could potentially be improved using a slightly modified DSC-MRI protocol (e.g. with regard to spatial resolution and slice gap). PMID- 26490360 TI - Programmable gradational micropatterning of functional materials using maskless lithography controlling absorption. AB - The demand for patterning functional materials precisely on surfaces of stimuli responsive devices has increased in many research fields. In situ polymerization technology is one of the most convenient ways to place the functional materials on a desired location with micron-scale accuracy. To fabricate stimuli-responsive surfaces, controlling concentration of the functional material is much as important as micropatterning them. However, patterning and controlling concentration of the functional materials simultaneously requires an additional process, such as preparing multiple co-flow microfluidic structures and numbers of solutions with various concentrations. Despite applying these processes, fabricating heterogeneous patterns in large scale (millimeter scale) is still impossible. In this study, we propose an advanced in situ polymerization technique to pattern the surface in micron scale in a concentration-controlled manner. Because the concentration of the functional materials is manipulated by self-assembly on the surface, a complex pattern could be easily fabricated without any additional procedure. The complex pattern is pre-designed with absorption amount of the functional material, which is pre-determined by the duration of UV exposure. We show that the resolution reaches up to 2.5 MUm and demonstrate mm-scale objects, maintaining the same resolution. We also fabricated Multi-bit barcoded micro particles verify the flexibility of our system. PMID- 26490361 TI - Guanidinium-Induced Denaturation by Breaking of Salt Bridges. AB - Despite its wide use as a denaturant, the mechanism by which guanidinium (Gdm(+) ) induces protein unfolding remains largely unclear. Herein, we show evidence that Gdm(+) can induce denaturation by disrupting salt bridges that stabilize the folded conformation. We study the Gdm(+) -induced denaturation of a series of peptides containing Arg/Glu and Lys/Glu salt bridges that either stabilize or destabilize the folded conformation. The peptides containing stabilizing salt bridges are found to be denatured much more efficiently by Gdm(+) than the peptides containing destabilizing salt bridges. Complementary 2D-infrared measurements suggest a denaturation mechanism in which Gdm(+) binds to side-chain carboxylate groups involved in salt bridges. PMID- 26490363 TI - Rapid flame synthesis of internal Mo(6+) doped TiO2 nanocrystals in situ decorated with highly dispersed MoO3 clusters for lithium ion storage. AB - The rational design of nanoheterostructured materials has attracted much attention because of its importance for developing highly efficient LIBs. Herein, we have demonstrated that internal Mo(6+) doped TiO2 nanocrystals in situ decorated with highly dispersed MoO3 clusters have been realized by a facile and rapid flame spray pyrolysis route for electrochemical energy storage. In such intriguing nanostructures, internal Mo(6+) doping can improve the conductivity of electrode materials and facilitate rapid Li(+) intercalation and ion transport and the heteroassembly of highly dispersed ultrafine MoO3 clusters with excellent electrochemical activity endows the TiO2 with extra Li(+) ion storage ability as well as incorporates Mo(6+). Thus, the as-prepared nanohybrid electrodes exhibit a high specific capacity and superior rate capability due to the maximum synergetic effect of TiO2, Mo(6+) and ultrafine MoO3 clusters. Moreover, the aerosol flame process with a unique temperature gradient opens a new strategy to design novel hybrid materials by the simultaneous doping and heteroassembly engineering for next-generation LIBs. PMID- 26490362 TI - Drug Permeation Characterization of Inhaled Dry Powder Formulations in Air-Liquid Interfaced Cell Layer Using an Improved, Simple Apparatus for Dispersion. AB - PURPOSE: An improved, simple apparatus was developed to easily and uniformly disperse dry powders onto an air-liquid interfaced cultured cell layer. We investigated drug permeation in cell cultures with access to the air-liquid interface (ALI) following deposition of a dry powder using the apparatus. METHOD: The improved apparatus for dispersing the powders was assembled. Dry powders containing model drugs were prepared and dispersed onto the cell layer with ALI. After the dispersion, the permeation of each model drug was measured and compared with other samples (solutions with the same compositions). RESULTS: The improved apparatus could with ease uniformly disperse 40% of the loading dose onto the cell layer with ALI. Dry powders showed higher drug permeability compared to the samples. without cytotoxicity or an effect on tight junctions. The high drug permeability of dry powders was independent of the molecular weight of model drugs. The contribution of active transport was small, while an increase in passive drug transport via trans- and paracellular routes was observed. CONCLUSIONS: Inhaled dry powder formulations achieved higher drug permeability than their solution formulations in ALI. A high local concentration of drugs on the cell layer, caused by direct attachment of the inhaled dry powder, contributed to increased drug permeability via both trans- and paracellular routes. PMID- 26490364 TI - Estrogen receptor beta signaling alters cellular inflammasomes activity after global cerebral ischemia in reproductively senescence female rats. AB - Periodic treatments with estrogen receptor subtype-beta (ER-beta) agonist reduce post-ischemic hippocampal injury in ovariectomized rats. However, the underlying mechanism of how ER-beta agonists protect the brain remains unknown. Global cerebral ischemia activates the innate immune response, and a key component of the innate immune response is the inflammasome. This study tests the hypothesis that ER-beta regulates inflammasome activation in the hippocampus, thus reducing ischemic hippocampal damage in reproductively senescent female rats that received periodic ER-beta agonist treatments. First, we determined the effect of hippocampal ER-beta silencing on the expression of the inflammasome proteins caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), and interleukin (IL)-1beta. Silencing of ER-beta attenuated 17beta-estradiol mediated decrease in caspase 1, ASC, and IL-1beta. Next, we tested the hypothesis that periodic ER-beta agonist treatment reduces inflammasome activation and ischemic damage in reproductively senescent female rats. Periodic ER-beta agonist treatments significantly decreased inflammasome activation and increased post ischemic live neuronal counts by 32% (p < 0.05) as compared to the vehicle treated, reproductively senescent rats. Current findings demonstrated that ER beta activation regulates inflammasome activation and protects the brain from global ischemic damage in reproductively senescent female rats. Further investigation on the role of a periodic ER-beta agonist regimen to reduce the innate immune response in the brain could help reduce the incidence and the impact of global cerebral ischemia in post-menopausal women. We propose that estrogen receptor subtype-beta (ER-beta) activation regulates inflammasome activation and protects the brain from global ischemic damage in reproductively senescent female rats. PMID- 26490366 TI - Naphthalene Imide Conjugates: Formation of Supramolecular Assemblies, and the Encapsulation and Release of Dyes through DNA-Mediated Disassembly. AB - We report the synthesis of two new amphiphilic conjugates 1 and 2 based on naphthalene di- and monoimide chromophores and the investigation of their photophysical, self-assembly and DNA-binding properties. These conjugates showed aqueous good solubility and exhibited strong interactions with DNA and polynucleotides such as poly(dG?dC)-poly(dG?dC) and poly(dA?dT)-poly(dA?dT). The interaction of these conjugates with DNA was evaluated by photo- and biophysical techniques. These studies revealed that the conjugates interact with DNA through intercalation with association constants in the order of 5-8*10(4) M(-1) . Of these two conjugates, bolaamphiphile 1 exhibited a supramolecular assembly that formed vesicles with an approximate diameter of 220 nm in the aqueous medium at a critical aggregation concentration of 0.4 mM, which was confirmed by SEM and TEM. These vesicular structures showed a strong affinity for hydrophobic molecules such as Nile red through encapsulation. Uniquely, when exposed to DNA the vesicles disassembled, and therefore this transformation could be utilised for the encapsulation and release of hydrophobic molecules by employing DNA as a stimulus. PMID- 26490368 TI - Air pollution: 6.6 million premature deaths in 2050! PMID- 26490367 TI - Protocol for the development of a CONSORT-equity guideline to improve reporting of health equity in randomized trials. AB - BACKGROUND: Health equity concerns the absence of avoidable and unfair differences in health. Randomized controlled trials (RCTs) can provide evidence about the impact of an intervention on health equity for specific disadvantaged populations or in general populations; this is important for equity-focused decision-making. Previous work has identified a lack of adequate reporting guidelines for assessing health equity in RCTs. The objective of this study is to develop guidelines to improve the reporting of health equity considerations in RCTs, as an extension of the Consolidated Standards of Reporting Trials (CONSORT). METHODS/DESIGN: A six-phase study using integrated knowledge translation governed by a study executive and advisory board will assemble empirical evidence to inform the CONSORT-equity extension. To create the guideline, the following steps are proposed: (1) develop a conceptual framework for identifying "equity-relevant trials," (2) assess empirical evidence regarding reporting of equity-relevant trials, (3) consult with global methods and content experts on how to improve reporting of health equity in RCTs, (4) collect broad feedback and prioritize items needed to improve reporting of health equity in RCTs, (5) establish consensus on the CONSORT-equity extension: the guideline for equity-relevant trials, and (6) broadly disseminate and implement the CONSORT equity extension. DISCUSSION: This work will be relevant to a broad range of RCTs addressing questions of effectiveness for strategies to improve practice and policy in the areas of social determinants of health, clinical care, health systems, public health, and international development, where health and/or access to health care is a primary outcome. The outcomes include a reporting guideline (CONSORT-equity extension) for equity-relevant RCTs and a knowledge translation strategy to broadly encourage its uptake and use by journal editors, authors, and funding agencies. PMID- 26490369 TI - Reliability of Semi-Automated Segmentations in Glioblastoma. AB - PURPOSE: In glioblastoma, quantitative volumetric measurements of contrast enhancing or fluid-attenuated inversion recovery (FLAIR) hyperintense tumor compartments are needed for an objective assessment of therapy response. The aim of this study was to evaluate the reliability of a semi-automated, region-growing segmentation tool for determining tumor volume in patients with glioblastoma among different users of the software. METHODS: A total of 320 segmentations of tumor-associated FLAIR changes and contrast-enhancing tumor tissue were performed by different raters (neuroradiologists, medical students, and volunteers). All patients underwent high-resolution magnetic resonance imaging including a 3D FLAIR and a 3D-MPRage sequence. Segmentations were done using a semi-automated, region-growing segmentation tool. Intra- and inter-rater-reliability were addressed by intra-class-correlation (ICC). Root-mean-square error (RMSE) was used to determine the precision error. Dice score was calculated to measure the overlap between segmentations. RESULTS: Semi-automated segmentation showed a high ICC (> 0.985) for all groups indicating an excellent intra- and inter-rater reliability. Significant smaller precision errors and higher Dice scores were observed for FLAIR segmentations compared with segmentations of contrast enhancement. Single rater segmentations showed the lowest RMSE for FLAIR of 3.3 % (MPRage: 8.2 %). Both, single raters and neuroradiologists had the lowest precision error for longitudinal evaluation of FLAIR changes. CONCLUSIONS: Semi automated volumetry of glioblastoma was reliably performed by all groups of raters, even without neuroradiologic expertise. Interestingly, segmentations of tumor-associated FLAIR changes were more reliable than segmentations of contrast enhancement. In longitudinal evaluations, an experienced rater can detect progressive FLAIR changes of less than 15 % reliably in a quantitative way which could help to detect progressive disease earlier. PMID- 26490371 TI - Gold-Catalyzed Ring Expansion of Alkynyl Heterocycles through 1,2-Migration of an Endocyclic Carbon-Heteroatom Bond. AB - A mild and efficient gold-catalyzed oxidative ring-expansion of a series of alkynyl heterocycles using pyridine-N-oxide as the oxidant has been developed, which affords highly valuable six- or seven-membered heterocycles with wide functional group toleration. The reaction consists of a regioselective oxidation and a chemoselective migration of an endocyclic carbon-heteroatom bond (favored over C-H migration) with the order of migratory aptitude for carbon-heteroatom bonds being C-S>C-N>C-O. In the absence of an oxidant, polycyclic products are readily constructed through a ring-expansion/Nazarov cyclization reaction sequence. PMID- 26490370 TI - Limbic-Auditory Interactions of Tinnitus: An Evaluation Using Diffusion Tensor Imaging. AB - OBJECTIVE: Tinnitus is defined as an imaginary subjective perception in the absence of an external sound. Convergent evidence proposes that tinnitus perception includes auditory, attentional and emotional components. The aim of this study was to investigate the thalamic, auditory and limbic interactions associated with tinnitus-related distress by Diffusion Tensor Imaging (DTI). METHODS: A total of 36 tinnitus patients, 20 healthy controls underwent an audiological examination, as well as a magnetic resonance imaging protocol including structural and DTI sequences. All participants completed the Tinnitus Handicap Inventory (THI) and Visual Analog Scales (VAS) related with tinnitus. The fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained for the auditory cortex (AC), inferior colliculus (IC), lateral lemniscus (LL), medial geniculate body (MGB), thalamic reticular nucleus (TRN), amygdala (AMG), hippocampus (HIP), parahippocampus (PHIP) and prefrontal cortex (PFC). RESULTS: In tinnitus patients the FA values of IC, MGB, TRN, AMG, HIP decreased and the ADC values of IC, MGB, TRN, AMG, PHIP increased significantly. The contralateral IC-LL and bilateral MGB FA values correlated negatively with hearing loss. A negative relation was found between the AMG-HIP FA values and THI and VAS scores. Bilateral ADC values of PHIP and PFC significantly correlated with the attention deficiency-VAS scores. CONCLUSION: In conclusion, this is the first DTI study to investigate the grey matter structures related to tinnitus perception and the significant correlation of FA and ADC with clinical parameters suggests that DTI can provide helpful information for tinnitus. Magnifying the microstructures in DTI can help evaluate the three faces of tinnitus nature: hearing, emotion and attention. PMID- 26490372 TI - Physical properties and biocompatibility of an injectable calcium-silicate-based root canal sealer: in vitro and in vivo study. AB - BACKGROUND: The aim of this study was to investigate the physical properties and biological effects of an experimentally developed injectable premixed calcium silicate root canal sealer (Endoseal) in comparison with mineral trioxide aggregate (MTA) and a resin-based sealer (AHplus). METHODS: The pH, solubility, dimensional change, flow, and radiopacity of the materials were evaluated. Biocompatibility was evaluated on the basis of cell morphology and a viability test using MC3T3-E1 cells. For evaluate inflammatory reaction, the tested sealers were implanted into dorsal subcutaneous connective tissue of Sprague Dawley rats. After 7 days, the implants with the surrounding tissue were retrieved, and histological evaluation was performed. RESULTS: Endoseal showed high alkalinity similar to that of MTA. The solubility of the tested materials was similar. The dimensional change and flow of Endoseal was significantly higher than that of other materials (P < 0.05). The radiopacity of Endoseal was lower than that of AHplus (P < 0.05). The biocompatibility was similar to those of MTA. Inflammatory reaction of Endoseal was similar with that of MTA, but lower than that of AHplus (P < 0.05). CONCLUSIONS: The present study indicates that Endoseal has favorable physical properties and biocompatibility. Therefore, we suggest that Endoseal has the potential to be used as a predictable root canal sealer. PMID- 26490373 TI - Functional assessment of the fundus autofluorescence pattern in Best vitelliform macular dystrophy. AB - PURPOSE: To identify the fundus autofluorescence (FAF) patterns in Best vitelliform macular dystrophy (VMD). METHODS: Patients affected by VMD in vitelliform, pseudohypopyon, and vitelliruptive stages underwent a complete ophthalmological examination, including best-corrected visual acuity (BCVA), short-wavelength FAF (SW-FAF), near-infrared FAF (NIR-FAF) and microperimetry. MAIN OUTCOME MEASURES: the identification of the correlation between SW-FAF and NIR-FAF patterns of the foveal region with BCVA, and central retinal sensitivity in eyes affected by VMD. The secondary outcomes included the definition of the frequency of foveal patterns on SW-FAF and NIR-FAF. RESULTS: Thirty-seven of 64 (58 %), 8 of 64 (12.5 %) and 19 of 64 (29.5 %) eyes showed vitelliform, pseudohypopyon, and vitelliruptive stages respectively. Three main FAF patterns were identified on both techniques: hyper-autofluorescent pattern, hypo autofluorescent pattern, and patchy pattern. BCVA was significantly different in eyes with hypo-autofluorescent and patchy patterns with respect to eyes showing a hyper-autofluorescent pattern. Similar differences were registered in the FS according to SW-FAF classification. However, the FS differed in each subgroup in the NIR-FAF analysis. Subgroup analyses were performed on the patchy pattern, combining FAF and fundus abnormalities. Considering both FAF techniques, the BCVA differed between the vitelliform and pseudohypopyon stages, and between the vitelliform and vitelliruptive stages. In the NIR-FAF classification, there was a significant statistical difference in the FS between each subgroup; in the SW FAF, there was a significant difference between the vitelliform and pseudohypopyon stages and the vitelliform and vitelliruptive stages. CONCLUSIONS: Three main FAF patterns can be identified in VMD. The patchy pattern is the most frequent, accounting for 70 % of eyes on SW-FAF and 80 % of eyes on NIR-FAF. A tighter correlation links the classification of NIR-FAF patterns and FS. Longitudinal investigations are warranted to evaluate the course of FAF patterns and their role in disease monitoring. PMID- 26490374 TI - Investigating the ocular temperature rise during femtosecond laser lens fragmentation: an in vitro study. AB - PURPOSE: To investigate the trend of temperature variation during lens fragmentation simulated by a femtosecond laser on an in vitro eye model. METHODS: In our experimental study, a convex cylinder of gelatinous material, usually employed in femtosecond laser calibration, was used to simulate both an anterior segment and a crystalline lens during fragmentation performed with the Victus femtosecond laser (Technolas Perfect Vision GmbH, Germany; Bausch + Lomb Incorporated, USA). Two radiated energies (7000 nJ and 9000 nJ) and three cutting patterns (crosses, circles and cross + circle) were applied. Trends of temperature variation as a function of time were obtained using a T-type thermocouple. RESULTS: The maximum value of temperature rise during lens fragmentation ranged from 3.53 to 5.13 degrees C; the rise was directly proportional to the intensity of the radiated energy (7000 nJ or 9000 nJ) and the cutting pattern performed. This behavior was experimentally represented by an asymmetric function with a characteristic bell curve shape, whereas it was mathematically described by a transport diffusive model. CONCLUSIONS: Since the temperature rise at the fragmentation volume base resulted to be around 5 degrees C in our in vitro study, lens fragmentation performed using the Victus femtosecond laser might be considered safe form a thermal point of view. PMID- 26490375 TI - The BMJ, take heed: almost all studies have some degree of bias. PMID- 26490377 TI - Computational Identification, Target Prediction, and Validation of Conserved miRNAs in Insulin Plant (Costus pictus D. Don). AB - Insulin plant (Costus pictus D. Don) is an economically important medicinal plant for the content of its high value secondary metabolites, bioactive compounds, and remarkable flowering features. MicroRNAs are a class of short (~21 nucleotides), endogenous, noncoding RNA molecules that play a vital role in regulating gene expression. Here, we used a computer-based homology approach to identify conserved miRNAs in Transcribed Sequence Assemblies (TSA) of C. pictus. It led us to identify 42 miRNAs of 13 different families in C. pictus for the first time. Using quantitative polymerase chain reaction (qPCR) assays, we further confirmed the expression of 8 miRNAs (miR394, miR159b, miR166k, miR172, miR159f, miR166, miR144, and miR858) in young and mature leaf tissues. A total of 109 potential target genes of the identified miRNAs were subsequently predicted in rice (Oryza sativa L.) genome. The target genes encode transcription factors, enzymes, and various functional proteins involved in the regulation of several metabolic pathways. The findings in the present study lay the foundation for further research on miRNAs and miRNA-mediated gene regulation in this important medicinal plant. PMID- 26490376 TI - Facial asymmetry assessment in adults using three-dimensional surface imaging. AB - BACKGROUND: The use of three-dimensional (3D) surface imaging is becoming more popular and accepted in the fields of Medicine and Dentistry. The present study aims to develop a technique to automatically localise and quantify soft-tissue asymmetry in adults using 3D facial scans. This may be applied as a diagnostic tool to monitor growth and dynamic changes and to evaluate treatment outcomes. METHODS: 3D facial surface data were captured from 55 adults comprising 28 symmetrical faces and 27 asymmetrical faces using a 3dMDface system. A landmark independent method, which compared the original and the mirrored 3D facial data, was developed to quantify the asymmetry. A Weibull distribution-based probabilistic model was generated from the root-mean-square (RMS) error data for the symmetrical group to designate a level of asymmetry which represented a normal range. RESULTS: Statistically significant (p < 0.0001) differences in the RMS error values were found when comparing symmetrical with asymmetrical groups and a similarly significant difference was identified between the lower and the upper face of the asymmetrical group. CONCLUSIONS: The proposed 3D imaging-based method of identifying and quantifying facial soft-tissue asymmetry was fast and effective. The Weibull distribution-based comparison of a person's asymmetry with respect to a large sample of symmetrical faces may also be used to evaluate growth, soft-tissue compensations and surgical outcomes. PMID- 26490378 TI - Aspergillus niger Enhance Bioactive Compounds Biosynthesis As Well As Expression of Functional Genes in Adventitious Roots of Glycyrrhiza uralensis Fisch. AB - In the present study, the culture conditions for the accumulation of Glycyrrhiza uralensis adventitious root metabolites in balloon-type bubble bioreactors (BTBBs) have been optimized. The results of the culture showed that the best culture conditions were a cone angle of 90 degrees bioreactor and 0.4-0.6-0.4 vvm aeration volume. Aspergillus niger can be used as a fungal elicitor to enhance the production of defense compounds in plants. With the addition of a fungal elicitor (derived from Aspergillus niger), the maximum accumulation of total flavonoids (16.12 mg g(-1)) and glycyrrhetinic acid (0.18 mg g(-1)) occurred at a dose of 400 mg L(-1) of Aspergillus niger resulting in a 3.47-fold and 1.8-fold increase over control roots. However, the highest concentration of polysaccharide (106.06 mg g(-1)) was achieved with a mixture of elicitors (Aspergillus niger and salicylic acid) added to the medium, resulting in a 1.09 fold increase over Aspergillus niger treatment alone. Electrospray ionization tandem mass spectrometry (ESI-MS(n)) analysis was performed, showing that seven compounds were present after treatment with the elicitors, including uralsaponin B, licorice saponin B2, liquiritin, and (3R)-vestitol, only identified in the mixed elicitor treatment group. It has also been found that elicitors (Aspergillus niger and salicylic acid) significantly upregulated the expression of the cinnamate 4-hydroxylase (C4H), beta-amyrin synthase (beta-AS), squalene epoxidase (SE) and a cytochrome P450 monooxygenase (CYP72A154) genes, which are involved in the biosynthesis of bioactive compounds, and increased superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) activity. PMID- 26490379 TI - Low-Cost Synthesis of Smart Biocompatible Graphene Oxide Reduced Species by Means of GFP. AB - The aim of this work is focused on the engineering of biocompatible complex systems composed of an inorganic and bio part. Graphene oxide (GO) and/or graphite oxide (GtO) were taken into account as potential substrates to the linkage of the protein such as Anemonia sulcata recombinant green fluorescent protein (rAsGFP). The complex system is obtained through a reduction process between GO/GtO and rAsGFP archiving an environmentally friendly biosynthesis. Spectroscopic measurements support the formation of reduced species. In particular, photoluminescence shows a change in the activity of the protein when a bond is formed, highlighted by a loss of the maximum emission signal of rAsGFP and a redshift of the maximum absorption peak of the GO/GtO species. Moreover, the hemolysis assay reveals a lower value in the presence of less oxidized graphene species providing evidence for a biocompatible material. This singular aspect can be approached as a promising method for circulating pharmaceutical preparations via intravenous administration in the field of drug delivery. PMID- 26490380 TI - Physicochemical Biomolecular Insights into Buffalo Milk-Derived Nanovesicles. AB - Milk is a natural nutraceutical produced by mammals. The nanovesicles of milk play a role in horizontal gene transfer and confer health-benefits to milk consumers. These nanovesicles contain miRNA, mRNA, and proteins which mediate the intercellular communication. In this work, we isolated and characterized the buffalo milk-derived nanovesicles by dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), scanning electron microscopy (SEM), Western probing, and Fourier transform infrared (FTIR) spectroscopy. The DLS data suggested a bimodal size distribution with one mode near 50 nm and the other around 200 nm for the nanovesicles. The NTA and SEM data also supported the size of nanovesicles within a range of 50-200 nm. The FTIR measurements of nanovesicles identified some prominent absorption bands attributable to the proteins (1300-1700 cm(-1), amide A and amide B bands), lipids (2800-3100 cm(-1)), polysaccharides, and nucleic acids (900-1200 cm(-1)). The comparative expression profiles of immune miRNA signatures (miR-15b, miR-21, miR-27b, miR-125b, miR-155, and miR-500) in nanovesicles isolated from milk, serum, and urine revealed that these miRNAs are present abundantly (P < 0.05) in milk-derived nanovesicles. Milk miRNAs (miR-21 and 500) that were also found stable under different household storage conditions indicated that these could be biologically available to milk consumers. Overall, nanovesicles are a new class of bioactive compounds from buffalo milk with high proportion of stable immune miRNAs compared to urine and plasma of same animals. PMID- 26490381 TI - Updates on drug-target network; facilitating polypharmacology and data integration by growth of DrugBank database. AB - Network pharmacology elucidates the relationship between drugs and targets. As the identified targets for each drug increases, the corresponding drug-target network (DTN) evolves from solely reflection of the pharmaceutical industry trend to a portrait of polypharmacology. The aim of this study was to evaluate the potentials of DrugBank database in advancing systems pharmacology. We constructed and analyzed DTN from drugs and targets associations in the DrugBank 4.0 database. Our results showed that in bipartite DTN, increased ratio of identified targets for drugs augmented density and connectivity of drugs and targets and decreased modular structure. To clear up the details in the network structure, the DTNs were projected into two networks namely, drug similarity network (DSN) and target similarity network (TSN). In DSN, various classes of Food and Drug Administration-approved drugs with distinct therapeutic categories were linked together based on shared targets. Projected TSN also showed complexity because of promiscuity of the drugs. By including investigational drugs that are currently being tested in clinical trials, the networks manifested more connectivity and pictured the upcoming pharmacological space in the future years. Diverse biological processes and protein-protein interactions were manipulated by new drugs, which can extend possible target combinations. We conclude that network based organization of DrugBank 4.0 data not only reveals the potential for repurposing of existing drugs, also allows generating novel predictions about drugs off-targets, drug-drug interactions and their side effects. Our results also encourage further effort for high-throughput identification of targets to build networks that can be integrated into disease networks. PMID- 26490382 TI - Record high magnetic exchange and magnetization blockade in Ln2@C79N (Ln = Gd(III) and Dy(III)) molecules: a theoretical perspective. AB - Ab initio and DFT calculations reveal a very strong ferromagnetic exchange of the order of 200 cm(-1) in an endohedral radical hetero-metallo-fullerene molecule Gd2@C79N. Calculations performed on the anisotropic Dy2@C79N molecule reveal that very strong Dy-radical exchange not only quenches the QTM effects but also immensely enhances the barrier height for magnetization reversal. PMID- 26490383 TI - FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties. AB - The biology of fibroblast growth factor 21 (FGF21) has evolved through its first decade at a revolutionary pace with dramatic refinements in this relatively short span of time. This field is poised now with a deeper understanding of its specific physiological role, pathological ramifications for its inappropriate function, and a much-enriched context of the complex hormonal network in which it serves to regulate metabolism. As a derivative of these discoveries, the application of FGF21 as a medicinal agent has emerged with structurally optimized protein-based analogs being preclinically explored in multiple species, and, more recently, through clinical studies. These novel findings set a foundation for ongoing inquiries that structure future research into this intriguing protein. PMID- 26490385 TI - Influence of Alkoxy Groups on the Photoinduced Dynamics of Organic Molecules Exemplified on Alkyl Vinyl Ethers. AB - A series of different alkyl vinyl ethers is investigated to decipher the possible reaction channels upon photoexcitation to the pi3s-Rydberg and the pipi*-valence state at 200 nm using time-resolved photoelectron spectroscopy and on-the-fly time-dependent density functional theory dynamics simulations. The results indicate two possible relaxation pathways: (1) a radiationless decay through the pipi*-state back to the ground state via torsion of the C?C double bond, in accordance with the dynamics found in ethylene; and (2) a fast dissociation of the C-O bond between the alkyl and the vinoxy group in the pisigma*-state. The latter state can be accessed only after excitation to the pi3s-Rydberg state (quantum yield of ~50% according to the dynamics simulations). Additionally, the excited state barrier leading to formation of a vinyl radical was found to be too high to be crossed. These results indicate that the dynamics of ethers crucially depend on the excitation wavelength and that the pisigma*-state constitutes an important competitive reaction channel that leads to dissociation of the molecules. PMID- 26490386 TI - Wilderness First Aid Training as a Tool for Improving Basic Medical Knowledge in South Sudan. AB - INTRODUCTION: The challenges presented by traumatic injuries in low-resource communities are especially relevant in South Sudan. This study was conducted to assess whether a 3-day wilderness first aid (WFA) training course taught in South Sudan improved first aid knowledge. Stonehearth Open Learning Opportunities (SOLO) Schools designed the course to teach people with limited medical knowledge to use materials from their environment to provide life-saving care in the event of an emergency. METHODS: A pre-test/post-test study design was used to assess first aid knowledge of 46 community members in Kit, South Sudan, according to a protocol approved by the University of New England Institutional Review Board. The course and assessments were administered in English and translated in real time to Acholi and Arabic, the two primary languages spoken in the Kit region. Descriptive statistics, t-test, ANOVA, and correlation analyses were conducted. RESULTS: Results included a statistically significant improvement in first aid knowledge after the 3-day training course: t(38)=3.94; P<.001. Although men started with more health care knowledge: (t(37)=2.79; P=.008), men and women demonstrated equal levels of knowledge upon course completion: t(37)=1.56; P=.88. CONCLUSIONS: This research, which may be the first of its kind in South Sudan, provides evidence that a WFA training course in South Sudan is efficacious. These findings suggest that similar training opportunities could be used in other parts of the world to improve basic medical knowledge in communities with limited access to medical resources and varying levels of education and professional experiences. PMID- 26490384 TI - Establishing the Role of PPARbeta/delta in Carcinogenesis. AB - The role of the nuclear hormone receptor peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) in carcinogenesis is controversial because conflicting studies indicate that it both inhibits and promotes tumorigenesis. In this review, we focus on recent studies on PPARbeta/delta including the significance of increased or decreased PPARbeta/delta expression in cancers; a range of opposing mechanisms describing how PPARbeta/delta agonists, antagonists, and inverse agonists regulate tumorigenesis and/or whether there may be cell context-specific mechanisms; and whether activating or inhibiting PPARbeta/delta is feasible for cancer chemoprevention and/or therapy. Research questions that need to be addressed are highlighted to establish whether PPARbeta/delta can be effectively targeted for cancer chemoprevention. PMID- 26490387 TI - Adropin concentrations in term pregnancies with normal, restricted and increased fetal growth. AB - OBJECTIVE: To determine levels of adropin (implicated in insulin resistance and endothelial dysfunction) in intrauterine growth restricted (IUGR), large (LGA) and appropriate for gestational age (AGA) pregnancies. METHODS: Cord-blood (UC) adropin and insulin concentrations were measured in 30 IUGR, 30 LGA and 20 AGA full-term infants and their mothers (MS). RESULTS: No significant differences in adropin concentrations were observed between the three groups. In the IUGR group MS adropin was significantly decreased when neonates had higher birth weights [b = -0.003, 95% CI -0.006 to 0.0, p = 0.043]. In all groups, MS adropin levels were positively correlated with UC ones (r = 0.282, p = 0.011) and were significantly increased in female neonates [b = 0.977, 95% CI 0.122-1.832, p = 0.026]. In the LGA group, MS insulin was negatively correlated with UC adropin (r = -0.362 p = 0.049). CONCLUSIONS: Increased maternal adropin levels in severe IUGR cases might represent a regulatory feedback mechanism against endothelial placental dysfunction. The positive correlation between maternal and umbilical cord adropin levels implies its transplacental transfer. Increased maternal adropin levels in female neonates could be attributed to interaction of adropin with fetal estrogens through vascular endothelial growth factor (VEGF). The negative correlation between maternal insulin and fetal adropin levels in the LGA group is probably attributed to their respective insulin resistance. PMID- 26490388 TI - Increased observation services in Medicare beneficiaries with chest pain. AB - INTRODUCTION: We examined trends in the use of observation services and the relationship between index service type (observation services, emergency department [ED] visits, inpatient stays) and both clinical outcomes and Medicare payments. METHODS: We created a yearly cohort panel of Medicare beneficiaries with chest pain. We evaluate the relationships between index service type and 30 day clinical outcomes using a multinomial logit model and between index service type and Medicare payments using generalized linear models. RESULTS: In 2009, 24% of patients with chest pain received observation services; this rose to 29% in 2011. Conversely, 20% were treated as hospital inpatients in 2009; this fell to 16% in 2011. In the adjusted analysis, the risk of 30-day return to the hospital was 7% less (95% confidence interval, 5%-8%) for those receiving observation services as compared with inpatients. Average Medicare payments ranged from $3032 for beneficiaries initially treated in the ED to $3885 for those initially treated in observation to $6545 for those initially treated as inpatients. DISCUSSION: Patients treated in observation are less likely than those treated in the ED or as inpatients to have an adverse event within 30 days. Adjusted Medicare payments, including the index stay and the subsequent 30 days, were substantially less for those treated in observation as compared with those treated as inpatients, but more than for those treated and released from the ED. Higher rates of observation service use do not appear to be negatively affecting patient outcomes and may lower costs relative to inpatient treatment. PMID- 26490389 TI - Flow Cytometry II: Mass and Imaging Cytometry. PMID- 26490390 TI - Pharmacomechanical thrombolysis with a rotator thrombolysis device in iliofemoral deep venous thrombosis. AB - OBJECTIVE: Deep venous thrombosis (DVT) is a life-threatening and morbid pathology. This study aimed to investigate the efficacy of an early thrombolysis procedure using a rotator thrombolysis device. METHODS: Sixty-seven patients with acute proximal DVT were enrolled in the study. Patients' data were recorded retrospectively. Initially, an infrarenal retrievable vena cava filter was placed through the femoral vein. Then, a rotator thrombolysis device and a thrombolytic agent injection were applied to the occluded segments of the deep veins by puncturing the popliteal vein. RESULTS: The identified reasons were trauma (43.3%), pregnancy (20.9%), undiagnosed (11.9%), major surgical operation (10.5%), immobilization (7.5%), and malignancy (5.9%). Immediate total recanalization was conducted in all patients, and the leg diameters returned to normal ranges in the early postoperative period. Hospital mortality or severe complications were not detected. CONCLUSION: New thrombolytic devices seem to reduce in-hospital mortality risks and may potentially decrease post-thrombotic morbidity. PMID- 26490392 TI - Dietary vitamin, mineral and herbal supplement use: a cross-sectional survey of before and during pregnancy use in Sydney, Australia. AB - AIM: To describe the use of dietary vitamin, mineral and herbal supplements before and during pregnancy. MATERIALS AND METHODS: Pregnant women attending for antenatal care at two tertiary Sydney hospitals between January and March 2014 completed an anonymous survey. Information on general maternal and pregnancy characteristics and the use of dietary and herbal supplements, including type, duration and sources of information, was collected. Frequency and contingency tabulations were performed. RESULTS: A total of 612 women agreed to participate (91% response rate). Of 589 women included in the analysis, mean gestational age at the time of survey was 28.5 weeks (SD 8.3), 55% had no children, and 67% were tertiary-educated. Overall, 62.9% of women reported taking a multivitamin (MV) and/or folic acid (FA) supplement in the 3 months prepregnancy, and 97.5% took a MV and/or FA in the first trimester. At the time of the survey, 93.8% of women were taking at least one supplement (median 2, range 1-13). During pregnancy, 79.1% of women were taking MVs, including 59.2% taking MV only and 19.9% taking MV and FA. The five most common supplements outside of a MV were FA (31%), iron (30%), vitamin D (23%), calcium (13%) and fish oil (12%). Reported herbal supplement rates were low. CONCLUSION: Folic acid, MVs and other supplements use during and prepregnancy is relatively high, although prepregnancy FA supplementation rates could still be improved. Further research on the actual dosages and dietary intakes consumed is needed to examine whether pregnant women have adequate intake of nutrients, regardless of supplement use. PMID- 26490391 TI - A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H-Related 3 Gene in Atypical Hemolytic Uremic Syndrome. AB - The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (CFH) and five complement factor H-related (CFHR) genes. This area of the genome arose from several large genomic duplications, and these low copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel CFH/CFHR3 hybrid gene secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise. PMID- 26490393 TI - Effect of TV and radio family planning messages on the probability of modern contraception utilization in post-Soviet Central Asia. AB - : This study evaluates the effects of family planning message broadcast on radio and TV on the probability of modern contraception utilization in post-Soviet Central Asia. Viewing family planning messages on TV improves the chances of using modern contraception for a woman who actually saw the messages by about 11 and 8 per cent in Kyrgyzstan and Tajikistan, respectively. If every woman in Kyrgyzstan and Tajikistan had an opportunity to watch a family planning message on TV, then the likelihood of using modern contraception would have improved by 10 and 7 per cent in Kyrgyzstan and Tajikistan, respectively. By contrast, the effect of hearing family planning messages on radio is not significant in both countries. (c) 2015 The Authors. International Journal of Health Planning and Management published by John Wiley & Sons, Ltd. KEY MESSAGES: Viewing family planning messages on TV improves the chances of using modern contraception for a woman who actually saw the messages by about 11 and 8 per cent in Kyrgyzstan and Tajikistan, respectively. If every woman in Kyrgyzstan and Tajikistan had an opportunity to watch a family planning message on TV, then the probability of using modern contraception would have improved by 10 and 7 per cent in Kyrgyzstan and Tajikistan, respectively. Consequently, using TV family planning messages in both countries should be encouraged. In comparison, the effect of hearing family planning messages on radio is not significant in both countries. PMID- 26490394 TI - Comparing staging by positron emission tomography with contrast-enhanced computed tomography and by pathology in head and neck squamous cell carcinoma. AB - OBJECTIVE: This study aimed to evaluate the ability of positron emission tomography with contrast-enhanced computed tomography to correctly stage head and neck squamous cell carcinomas, in comparison with pathological staging. METHODS: Positron emission tomography computed tomography was used to determine the tumour node-metastasis classification and overall cancer stage in 85 head and neck squamous cell carcinoma patients who underwent pre-operative imaging using this modality and primary surgery between July 2010 and January 2013. Staging by positron emission tomography computed tomography was retrospectively compared with staging using pathological specimens. Agreement between imaging stage and pathological stage was examined by univariate and multivariate analysis both overall and for each primary tumour site. RESULTS: This imaging modality was 87.5 per cent sensitive and 44.8 per cent specific in identifying regional cervical metastases, and had false positive and false negative rates of 18.8 per cent and 8.2 per cent, respectively. The positive predictive and negative predictive values were 75.4 per cent and 65.0 per cent, respectively. Univariate and multivariate analyses revealed a significant agreement between positron emission tomography computed tomography and pathological node classification in older patients and for the oral cavity primary tumour site. There was significant agreement between both methods in the overall classification only for tumours classified as T3 or greater. CONCLUSION: Positron emission tomography computed tomography should be used with caution for the pre-operative staging of head and neck cancers because of its high false positive and false negative rates. PMID- 26490395 TI - Autotransplantation of premolars to the maxillary incisor region: a long-term follow-up of 12-22 years. AB - OBJECTIVE: To investigate the long-term outcome of treatment of missing maxillary incisor teeth by transplantation of premolars, with special reference to aesthetics and patient satisfaction. SUBJECTS AND METHODS: Twenty subjects who had undergone transplantation of premolars to the maxillary incisor area were recalled for follow-up varying between 12 and 22 years post-surgery. Twelve subjects presented for examination, including radiography and three subjects participated only by answering questions. Three reference groups-general practitioners, orthodontists, and lay people-evaluated the aesthetic results from photographs. Patient satisfaction was evaluated by interviews and OHIP-14. RESULTS: The mean age at transplantation was 12.3 years: 1 subject had been 20 years old and 11 were in the range of 9-14 years. Twelve to 22 years after autotransplantation, 5 subjects could not be reached: of the 15 who could be contacted, the survival rate was 15 out of 15. In the 12 subjects who presented for clinical examination, 11 out of the 12 transplants were assessed as successful. Nine transplants were restored with crowns and five had been recontoured with composite build-ups. In one patient, no restorative treatment had been undertaken. The subjects were satisfied with the aesthetic result. CONCLUSION: Autotransplantation of premolars is an appropriate method for treatment of missing maxillary anterior teeth. Subjects with a transplanted tooth to the maxillary anterior region perceive their oral health as good long term. PMID- 26490398 TI - Reconciling randomness and precision. PMID- 26490399 TI - Plant cell biology: CRISPR-Cas protection from plant viruses. PMID- 26490401 TI - Electronic structure of CoPt based systems: from bulk to nanoalloys. AB - An accurate description of the local electronic structure is necessary for guiding the design of materials with targeted properties in a controlled way. For complex materials like nanoalloys, self-consistent tight-binding calculations should be a good alternative to ab initio methods, for handling the most complex and large systems (hundreds to thousands of atoms), provided that these parameterized method is well founded from ab initio ones that they intend to replace. Ab initio calculations (density functional theory) enabled us to derive rules for charge distribution as a function of structural change and alloying effects in Co and Pt based systems, from bulk to nanoalloys. A general local neutrality rule per site, orbital and species was found. Based on it, self consistent tight-binding calculations could be implemented and applied to CoPt nanoalloys. A very good agreement is obtained between tight-binding and DFT calculations in terms of local electronic structure. PMID- 26490402 TI - Cyclic enaminones. Part I: stereocontrolled synthesis using diastereoselective and catalytic asymmetric methods. AB - Cyclic enaminones are versatile intermediates to construct a variety of azacyclic frameworks and have been widely used in alkaloid synthesis. Here, we summarize three approaches for stereoselective syntheses of cyclic enaminones and their functionalized derivatives. These include chiral substrates (chirons) as starting materials, syntheses employing non-catalytic (stoichiometric) reagents, and catalytic asymmetric methods. PMID- 26490403 TI - The Nick Norgan Award 2015. PMID- 26490400 TI - Transcriptional regulation of hepatic lipogenesis. AB - Fatty acid and fat synthesis in the liver is a highly regulated metabolic pathway that is important for very low-density lipoprotein (VLDL) production and thus energy distribution to other tissues. Having common features at their promoter regions, lipogenic genes are coordinately regulated at the transcriptional level. Transcription factors, such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles in this process. Recently, insights have been gained into the signalling pathways that regulate these transcription factors. After feeding, high blood glucose and insulin levels activate lipogenic genes through several pathways, including the DNA-dependent protein kinase (DNA-PK), atypical protein kinase C (aPKC) and AKT mTOR pathways. These pathways control the post-translational modifications of transcription factors and co-regulators, such as phosphorylation, acetylation or ubiquitylation, that affect their function, stability and/or localization. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance. PMID- 26490405 TI - Sediment-bound metals as indicators of anthropogenic change in estuarine environments. AB - Sedimentary metal indicators were used to assess the environmental 'health' of 38 estuaries on the central Australian east coast. Unlike many environmental indicators, the mean enrichment quotient (MEQ) provides the pristine condition and magnitude of anthropogenic change in estuarine condition, not confounded by natural spatial and temporal variation. MEQ is the mean normalised surficial concentration of Cu, Pb and Zn divided by their normalised background concentration. MEQs, identified from an extensive sedimentary database (n=2269), were used to derive a Metal Enrichment Index (MEI) comprising five impact categories. Population density and proportion of urbanised catchment were consistent with increased sedimentary metal concentrations, whereas estuarine sensitivity and metal enrichment were poorly correlated. No correlation was established between metal enrichment and estuary type or sedimentary facies. MEI can be used as a tool to meet the needs of policy-makers and estuarine managers by providing a tool by which human-induced change may be measured. PMID- 26490404 TI - Complex folding and misfolding effects of deer-specific amino acid substitutions in the beta2-alpha2 loop of murine prion protein. AB - The beta2-alpha2 loop of PrP(C) is a key modulator of disease-associated prion protein misfolding. Amino acids that differentiate mouse (Ser169, Asn173) and deer (Asn169, Thr173) PrP(C) appear to confer dramatically different structural properties in this region and it has been suggested that amino acid sequences associated with structural rigidity of the loop also confer susceptibility to prion disease. Using mouse recombinant PrP, we show that mutating residue 173 from Asn to Thr alters protein stability and misfolding only subtly, whilst changing Ser to Asn at codon 169 causes instability in the protein, promotes oligomer formation and dramatically potentiates fibril formation. The doubly mutated protein exhibits more complex folding and misfolding behaviour than either single mutant, suggestive of differential effects of the beta2-alpha2 loop sequence on both protein stability and on specific misfolding pathways. Molecular dynamics simulation of protein structure suggests a key role for the solvent accessibility of Tyr168 in promoting molecular interactions that may lead to prion protein misfolding. Thus, we conclude that 'rigidity' in the beta2-alpha2 loop region of the normal conformer of PrP has less effect on misfolding than other sequence-related effects in this region. PMID- 26490406 TI - Metal concentrations in the growth bands of Porites sp.: A baseline record on the history of marine pollution in the Gulf of Mannar, India. AB - The present study was carried out on the Porites coral growth bands (1979 to 2014) to measure the metal accumulation for assessing the environmental pollution status. The concentrations of studied metals are compared with similar global studies, which indicate that the metals are probably derived from natural sources. The identical peaks of Fe and Mn are perfectly matched with Cu, Cr and Ni concentrations. However, the metal profile trend is slightly depressed from a regular trend in Zn, Cd and Pb peaks. The metal accumulation affinity of the reef skeleton is ranked in the following order Cr>Cd>Pb>Fe>Mn>Cu>Ni>Zn. The distribution of metal constituents in coral growth bands is primarily controlled by Fe and Mn in the reef skeleton. Other reef associated metals such as Pb and Cd are derived from other sources like coastal developments and anthropogenic sources. PMID- 26490408 TI - Radioactivity in the Kuwait marine environment--Baseline measurements and review. AB - The Arabian Gulf region is moving towards a nuclear energy option with the first nuclear power plant now operational in Bushehr, Iran, and others soon to be constructed in Abu Dhabi and Saudi Arabia. Radiological safety is becoming a prime concern in the region. This study compiles available data and presents recent radionuclide data for the northern Gulf waters, considered as pre-nuclear which will be a valuable dataset for future monitoring work in this region. Radionuclide monitoring in the marine environment is a matter of prime concern for Kuwait, and an assessment of the potential impact of radionuclides requires the establishment and regular updating of baseline levels of artificial and natural radionuclides in various environmental compartments. Here we present baseline measurements for (210)Po, (210)Pb, (137)Cs, (90)Sr, and (3)H in Kuwait waters. The seawater concentration of (3)H, (210)Po, (210)Pb, (137)Cs, and (90)Sr vary between 130-146, 0.48-0.68, 0.75-0.89, 1.25-1.38 and 0.57-0.78 mBq L(-1), respectively. The (40)K concentration in seawater varies between 8.9-9.3 Bq L( 1). The concentration of (40)K, total (210)Pb, (137)Cs, (90)Sr, (226)Ra, (228)Ra, (238)U, (235)U, (234)U, (239+240)Pu and (238)Pu were determined in sediments and range, respectively, between 353-445, 23.6-44.3, 1.0-3.1, 4.8-5.29, 17.3-20.5, 15 16.4, 28.7-31.4, 1.26-1.30, 29.7-30.0, 0.045-0.21 and 0.028-0.03 Bq kg(-1) dry weight. Since, radionuclides are concentrated in marine biota, a large number of marine biota samples covering several trophic levels, from microalgae to sharks, were analyzed. The whole fish concentration of (40)K, (226)Ra, (224)Ra, (228)Ra, (137)Cs, (210)Po and (90)Sr range between 230-447, 0.7-7.3, <0.5-6.6, <0.5-15.80, <0.17, 0.88-4.26 and 1.86-5.34 Bq kg(-1) dry weight, respectively. (210)Po was found to be highly concentrated in several marine organisms with the highest (210)Po concentration found in Marica marmorata (193.5-215.6 Bq kg(-1) dry weight). (210)Po in most dissected fish samples shows increasing concentrations in the following order: edible tissue, gills, digestive system, liver and fecal matter. Fish fecal pellets had (210)Po concentrations several orders of magnitude higher than the seawater, fish muscle, and the fishes' ingested food. The high (210)Po concentration in fish fecal matter, suggest that the bulk of (210)Po content in fish was eventually excreted back into the environment as fecal pellets. In most fish high concentrations were noted in liver, with the highest (210)Po concentration recorded in shark liver (126.2-141.5 Bq kg(-1) wet). Moreover, (210)Po concentration in the soft tissue of molluscs (10.36-215.60 Bq kg(-1) dry weight) was far higher than that in fish muscle (0.05-7.49 Bq kg(-1) wet weight). A seasonal drop in (210)Po concentration in seawater was observed to vary with the abundance of phytoplankton and macroalgae due possibly to biological dilution. (137)Cs concentration in all the fish sampled was below the detection limit, and the concentration in seawater was also low; hence such low levels provide an opportunity to use this radionuclide as an indicator for any future radiocesium releases in this region. PMID- 26490409 TI - The roles of polyculture with Eucheuma gelatinae and Gafrarium tumidum in purification of eutrophic seawater and control of algae bloom. AB - To control algae bloom and eutrophication in the tropical semi-closed harbor of the Hongsha Bay in Sanya, China, polyculture systems with macroalgae Eucheuma gelatinae and bivalves Gafrarium tumidum were studied. First, nine polyculture combinations with E. gelatinae and G. tumidum were selected in a pool. Two combinations were then chosen by response surface analysis and used for further study to validate their effect on controlling the microalgae density and reducing the nutrition concentration in the pool. Subsequently, the two selected combinations were used to study the effect on the purification of eutrophic seawater and control of algae bloom in a sea mesocosm. The results indicated that polyculture with E. gelatinae and G. tumidum enhanced the purification of eutrophic seawater and control of algae bloom. These two polyculture combinations are considered suitable for the Hongsha Bay of Sanya in China. The two combinations present an excellent effect on controlling the microalgae density and reducing the nutrition concentration. PMID- 26490407 TI - Changes in the water quality conditions of Kuwait's marine waters: Long term impacts of nutrient enrichment. AB - This work analyses a 30 year water quality data set collated from chemical analyses of Kuwait's marine waters. Spatial patterns across six sites in Kuwait Bay and seven sites located in the Arabian Gulf are explored and discussed in terms of the changing influences associated with point and diffuse sources. Statistical modelling demonstrated significant increases for dissolved nutrients over the time period. Kuwait marine waters have been subject to inputs from urban development, untreated sewage discharges and decreasing river flow from the Shatt al-Arab River. Chlorophyll biomass showed a small but significant reduction; the high sewage content of the coastal waters from sewage discharges likely favouring the presence of smaller phytoplankton taxa. This detailed assessment of temporal data of the impacts of sewage inputs into Kuwait's coastal waters establishes an important baseline permitting future assessments to be made as sewage is upgraded, and the river continues to be extracted upstream. PMID- 26490410 TI - Trace element and stable isotope analysis of fourteen species of marine invertebrates from the Bay of Fundy, Canada. AB - The Bay of Fundy, Canada, is a macrotidal bay with a highly productive intertidal zone, hosting a large abundance and diversity of marine invertebrates. We analysed trace element concentrations and stable isotopic values of delta(15)N and delta(13)C in 14 species of benthic marine invertebrates from the Bay of Fundy's intertidal zone to investigate bioaccumulation or biodilution of trace elements in the lower level of this marine food web. Barnacles (Balanus balanus) consistently had significantly greater concentrations of trace elements compared to the other species studied, but otherwise we found low concentrations of non essential trace elements. In the range of trophic levels that we studied, we found limited evidence of bioaccumulation or biodilution of trace elements across species, likely due to the species examined occupying similar trophic levels in different food chains. PMID- 26490411 TI - Mercury and selenium in tissues and stomach contents of the migratory sailfish, Istiophorus platypterus, from the Eastern Pacific: Concentration, biomagnification, and dietary intake. AB - Mercury and selenium were assessed in the sailfish, Istiophorus platypterus, from the Eastern Pacific. Sixty-seven individuals were sampled, muscle, liver, kidney, gonads and the prey found in the stomach contents were isolated during fishing 2011-2013 tournaments. Hg exhibited the following pattern (MUg g(-1) wet weight): liver (0.57 +/- 0.07)>muscle (0.56 +/- 0.04)>kidney (0.44 +/- 0.08)>gonad (0.14 +/- 0.01). The maximum concentration of Se was found in kidneys (14.1 +/- 1.9 MUg g(-1)), and the minimum in muscles (0.67 +/- 0.03 MUg g(-1)). High Se:Hg ratios were found for muscle (4.1 +/- 0.3), kidney (132.4 +/- 12.1), liver (54.0 +/- 4.4) and gonads (88.2 +/- 7.9); Hg:Se molar ratios were several orders of magnitude lower (muscle<0.4 and liver, kidney and gonad<0.03). Sailfish feed mainly on fishes and cephalopods with low Hg levels (<0.13 MUg g(-1)), these results indicate biomagnification of Hg and Se. The muscle of I. platypterus should be consumed (according the provisional tolerable weekly intake) by people cautiously so as not to exceed the recommended intake of 215 g per week. PMID- 26490412 TI - Polluter identification with spaceborne radar imagery, AIS and forward drift modeling. AB - This study defines and assesses a new operational concept to identify the origin of pollution at sea, based on Synthetic Aperture Radar, Automatic Identification System, and a forward drift model. As opposed to traditional methodologies where the SAR detected pollution is backtracked in the past, our approach assumes that all the vessels pollute all along their way. Based on all the AIS data flows, the forward-tracked simulated pollutions are then compared to the detected pollution, and the potential polluter can be finally identified. Case studies are presented to showcase its usefulness in a variety of maritime situations with a focus on orphan pollutions in a dense traffic area. Out of the identification of the suspected polluters, the age and eventually the type of the pollution can be retrieved. PMID- 26490413 TI - Coral reefs in the Gulf are mostly dead now, but can we do anything about it? AB - This article discusses two key issues: firstly, the demise of reefs in the Gulf which is happening probably more rapidly than elsewhere; and secondly, the reasons why this remains such an intractable problem. Most reasons for this decline are scientifically well understood, though clearly not by the region's managers. Several factors may cause people to ignore the problem, even though habitat loss is vastly costly to the region. About 70% of the Gulf's reefs have essentially disappeared in a few decades, and although scientific indicators confirm that this is happening, it is commonly discounted as even being a possibility. Management of human interactions with the Gulf's marine systems remains very inadequate, to the detriment of the Gulf's marine systems and its people. It is clear that this not a scientific issue any longer but rather it is a political problem and failure. PMID- 26490414 TI - I'm sexy and I glow it: female ornamentation in a nocturnal capital breeder. AB - In many species, males rely on sexual ornaments to attract females. Females, by contrast, rarely produce ornaments. The glow-worm (Lampyris noctiluca) is an exception where wingless females glow to attract males that fly in search of females. However, little is known about the factors that promote the evolution of female ornaments in a sexual selection context. Here, we investigated if the female ornament of the glow-worm is a signal of fecundity used in male mate choice. In support of this, we found brightness to correlate with female fecundity, and males to prefer brighter dummy females. Thus, the glow emitted by females is a reliable sexual signal of female fecundity. It is likely that male preference for the fecundity-indicating ornament has evolved because of large variation among females in fecundity, and because nocturnal males cannot directly assess female size and fecundity. These results indicate that female ornamentation may evolve in capital breeders (i.e. those in which stored resources are invested in reproduction) when females vary significantly in fecundity and this variation cannot be assessed directly by males. PMID- 26490415 TI - Physiological ramifications for loggerhead turtles captured in pelagic longlines. AB - Bycatch of endangered loggerhead turtles in longline fisheries results in high rates of post-release mortality that may negatively impact populations. The factors contributing to post-release mortality have not been well studied, but traumatic injuries and physiological disturbances experienced as a result of capture are thought to play a role. The goal of our study was to gauge the physiological status of loggerhead turtles immediately upon removal from longline gear in order to refine our understanding of the impacts of capture and the potential for post-release mortality. We analysed blood samples collected from longline- and hand-captured loggerhead turtles, and discovered that capture in longline gear results in blood loss, induction of the systemic stress response, and a moderate increase in lactate. The method by which turtles are landed and released, particularly if released with the hook or line still attached, may exacerbate stress and lead to chronic injuries, sublethal effects or delayed mortality. Our study is the first, to the best of our knowledge, to document the physiological impacts of capture in longline gear, and our findings underscore the importance of best practices gear removal to promote post-release survival in longline-captured turtles. PMID- 26490416 TI - Nest architecture shapes the collective behaviour of harvester ants. AB - Structures influence how individuals interact and, therefore, shape the collective behaviours that emerge from these interactions. Here I show that the structure of a nest influences the collective behaviour of harvester ant colonies. Using network analysis, I quantify nest architecture and find that as chamber connectivity and redundancy of connections among chambers increase, so does a colony's speed of recruitment to food. Interestingly, the volume of the chambers did not influence speed of recruitment, suggesting that the spatial organization of a nest has a greater impact on collective behaviour than the number of workers it can hold. Thus, by changing spatial constraints on social interactions organisms can modify their behaviour and impact their fitness. PMID- 26490417 TI - The butterfly Papilio xuthus detects visual motion using chromatic contrast. AB - Many insects' motion vision is achromatic and thus dependent on brightness rather than on colour contrast. We investigate whether this is true of the butterfly Papilio xuthus, an animal noted for its complex retinal organization, by measuring head movements of restrained animals in response to moving two-colour patterns. Responses were never eliminated across a range of relative colour intensities, indicating that motion can be detected through chromatic contrast in the absence of luminance contrast. Furthermore, we identify an interaction between colour and contrast polarity in sensitivity to achromatic patterns, suggesting that ON and OFF contrasts are processed by two channels with different spectral sensitivities. We propose a model of the motion detection process in the retina/lamina based on these observations. PMID- 26490418 TI - Out of the frying pan into the air--emersion behaviour and evaporative heat loss in an amphibious mangrove fish (Kryptolebias marmoratus). AB - Amphibious fishes often emerse (leave water) when faced with unfavourable water conditions. How amphibious fishes cope with the risks of rising water temperatures may depend, in part, on the plasticity of behavioural mechanisms such as emersion thresholds. We hypothesized that the emersion threshold is reversibly plastic and thus dependent on recent acclimation history rather than on conditions during early development. Kryptolebias marmoratus were reared for 1 year at 25 or 30 degrees C and acclimated as adults (one week) to either 25 or 30 degrees C before exposure to an acute increase in water temperature. The emersion threshold temperature and acute thermal tolerance were significantly increased in adult fish acclimated to 30 degrees C, but rearing temperature had no significant effect. Using a thermal imaging camera, we also showed that emersed fish in a low humidity aerial environment (30 degrees C) lost significantly more heat (3.3 degrees C min(-1)) than those in a high humidity environment (1.6 degrees C min( 1)). In the field, mean relative humidity was 84%. These results provide evidence of behavioural avoidance of high temperatures and the first quantification of evaporative cooling in an amphibious fish. Furthermore, the avoidance response was reversibly plastic, flexibility that may be important for tropical amphibious fishes under increasing pressures from climatic change. PMID- 26490419 TI - Mitochondrial membrane potential: a trait involved in organelle inheritance? AB - Which mitochondria are inherited across generations? Are transmitted mitochondria functionally silenced to preserve the integrity of their genetic information, or rather are those mitochondria with the highest levels of function (as indicated by membrane potential Deltapsim) preferentially transmitted? Based on observations of the unusual system of doubly uniparental inheritance of mitochondria and of the common strictly maternal inheritance mode, I formulate a general hypothesis to explain which mitochondria reach the primordial germ cells (PGCs), and how this happens. Several studies indicate that mitochondrial movements are driven by microtubules and that mitochondria with high Deltapsim are preferentially transported. This can be applied also to the mitochondria that eventually populate embryonic PGCs, so I propose that Deltapsim may be a trait that allows for the preferential transmission of the most active (and healthy) mitochondria. The topics discussed here are fundamental in cell biology and genetics but remain controversial and a subject of heated debate; I propose an explanation for how a Deltapsim-dependent mechanism can cause the observed differences in mitochondrial transmission. PMID- 26490420 TI - Correction to 'Colour learning when foraging for nectar and pollen: bees learn two colours at once'. PMID- 26490421 TI - Letter to the nutritionDay study. PMID- 26490422 TI - Expedient screening for HIV-1 protease inhibitors using a simplified immunochromatographic assay. AB - A colloidal gold-based immunochromatographic (IC) strip test was developed and validated for the detection of HIV-1 protease (HIV-PR) activity and inhibitory effect of HIV-PR inhibitors (PIs). It is a unique 'two-step' process requiring the combination of proteolysis of HIV-PR and an immunochromatographic reaction. Monoclonal antibodies to the free C-terminus of HIV matrix protein (HIV-MA) conjugated to gold particles and a monoclonal antibody against intact and cleaved forms of the HIV-MA are immobilized on the 'Test'-line of the IC strip. Using lopinavir, a potent HIV protease inhibitor, the IC-strip was optimized to detect inhibitory activity against HIV-protease. At a lopinavir concentration of 1000ng/mL (its suggested minimum effective concentration), a HIV-PRH6 concentration of 6mg/mL and incubation period of 60min were the optimal conditions. A preliminary comparison between a validated high-performance liquid chromatography assay and the IC-strip to semi-quantify HIV protease inhibitor concentrations (lopinavir and atazanavir) demonstrated good agreement. This simplified method is suitable for the rapid screening of novel protease inhibitors for future therapeutic use. Moreover, the IC strip could also be optimized to semi-quantify PIs concentrations in plasma samples. PMID- 26490424 TI - Ultralow thermal sensitivity of phase and propagation delay in hollow core optical fibres. AB - Propagation time through an optical fibre changes with the environment, e.g., a change in temperature alters the fibre length and its refractive index. These changes have negligible impact in many key fibre applications, e.g., telecommunications, however, they can be detrimental in many others. Examples are fibre-based interferometry (e.g., for precise measurement and sensing) and fibre based transfer and distribution of accurate time and frequency. Here we show through two independent experiments that hollow-core photonic bandgap fibres have a significantly smaller sensitivity to temperature variations than traditional solid-core fibres. The 18 times improvement observed, over 3 times larger than previously reported, makes them the most environmentally insensitive fibre technology available and a promising candidate for many next-generation fibre systems applications that are sensitive to drifts in optical phase or absolute propagation delay. PMID- 26490423 TI - Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma. AB - Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I-mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K-AKT-mTORC1 dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYC-driven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of EMU-Myc lymphoma-bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. SIGNIFICANCE: Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to EMU-Myc lymphoma-bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. PMID- 26490425 TI - Enhanced scope for extension of patent term for pharmaceuticals under Australian law. PMID- 26490428 TI - The determinants of presenteeism: a comprehensive investigation of stress-related factors at work, health, and individual factors among the aging workforce. AB - OBJECTIVES: The aim of this study was to identify the determinants of presenteeism, taking health and individual factors into account. METHODS: A quantitative analysis applying structural equation modelling analysis was conducted on the basis of secondary data from the Health and Retirement Survey (2008 wave), which measured presenteeism and its determinants. RESULTS: Stress related factors at work (beta =-0.35, p<0.001), individual factors (alpha =-0.27, p<0.001), and health (beta =0.24, p<0.001) were significantly related to presenteeism. Individual factors were found to be directly correlated with stress related factors at work (beta =0.22, p<0.001). Significant indirect effects between stress-related factors at work and presenteeism (Sobel z=-6.61; p<0.001) and between individual factors and presenteeism (Sobel z=-4.42; p<0.001), which were mediated by health, were also found. Overall, the final model accounted for 37% (R(2)=0.37) of the variance in presenteeism. CONCLUSIONS: Our study indicates some important and practical guidelines for employers to avoid the burdens of stress-related presenteeism among their employees. These findings could help select target factors in the design and implementation of effective presenteeism interventions in the aging working population. PMID- 26490427 TI - Study of risk factors for atopic sensitization, asthma, and bronchial hyperresponsiveness in animal laboratory workers. AB - OBJECTIVES: The aim of this estudy was to investigate the influence of allergen exposure levels and other risk factors for allergic sensitization, asthma, and bronchial hyperresponsiveness (BHR) in workers exposed to laboratory animals. METHODS: This was a cross-sectional study performed at two universities, 123 workplaces with 737 subjects. Dust samples were collected from laboratories and animal facilities housing rats, mice, guinea pigs, rabbits, or hamsters and analyzed by enzyme-linked immunosorbent assay (ELISA) to measure allergen concentrations. We also sampled workplaces without animals. Asthma was defined by both symptoms and BHR to mannitol. The concentrations of allergens were tested for association with a skin prick test, respiratory symptoms, spirometry data, and BHR. This multivariate analysis was performed by using Poisson regression to estimate the relative risk (RR) for the exposed group. RESULTS: Our sample comprised students and workers, with 336 subjects in the nonexposed group and 401 subjects in the exposed group. Sixty-nine subjects (17%) had positive results in the skin prick test for animal allergens in the exposed group; in the nonexposed group, 10 subjects had positive results (3%) (p<0.001). Exposure to laboratory animals over 2.8 years was associated with atopic sensitization (RR=1.85; 95% confidence interval: 1.09-3.15; p=0.02). Allergen concentration was not associated with sensitization, asthma, or BHR. CONCLUSION: Exposure to laboratory animals was associated with atopic sensitization. However, we did not find a cutoff allergen concentration that increased the risk for sensitization. Duration of exposure seems to be more relevant to sensitization than concentration of allergens in dust. PMID- 26490429 TI - Bioaccumulation and enantioselectivity of type I and type II pyrethroid pesticides in earthworm. AB - In this study, the bioavailability and enantioselectivity differences between bifenthrin (BF, typeIpyrethroid) and lambad-cyhalothrin (LCT, type II pyrethroid) in earthworm (Eisenia fetida) were investigated. The bio-soil accumulation factors (BSAFs) of BF was about 4 times greater than that of LCT. LCT was degraded faster than BF in soil while eliminated lower in earthworm samples. Compound sorption plays an important role on bioavailability in earthworm, and the soil-adsorption coefficient (K(oc)) of BF and LCT were 22 442 and 42 578, respectively. Metabolic capacity of earthworm to LCT was further studied as no significant difference in the accumulation of LCT between the high and low dose experiment was found. 3-phenoxybenzoic acid (PBCOOH), a metabolite of LCT produced by earthworm was detected in soil. The concentration of PBCOOH at high dose exposure was about 4.7 times greater than that of in low dose level at the fifth day. The bioaccumulation of BF and LCT were both enantioselective in earthworm. The enantiomer factors of BF and LCT in earthworm were approximately 0.12 and 0.65, respectively. The more toxic enantiomers ((+)-BF and (-)-LCT) had a preferential degradation in earthworm and leaded to less toxicity on earthworm for racemate exposure. In combination with other studies, a liner relationship between Log BSAF(S) and Log K(ow) was observed, and the Log BSAF(S) decreased with the increase of Log K(ow). PMID- 26490430 TI - Granular encapsulation of light hydrophobic liquids (LHL) in LHL-salt water systems: Particle induced densification with quartz sand. AB - Addition of granular materials to floating crude oil slicks can be effective in capturing and densifying the floating hydrophobic phase, which settles by gravity. Interaction of light hydrophobic liquids (LHL) with quartz sand was investigated in LHL-salt water systems. The LHLs studied were decane, tetradecane, hexadecane, benzene, toluene, ethylbenzene, m-xylene, and 2 cholorotoluene. Experiments were conducted with fine quartz sand (passing sieve No. 40 with openings 0.425 mm). Each LHL was dyed with few crystals of Sudan IV dye for ease of visual observation. A volume of 0.5 mL of each LHL was added to 100 mL salt water (34 g/L). Addition of one gram of quartz sand to the floating hydrophobic liquid layer resulted in formation of sand-encapsulated globules, which settled due to increased density. All LHLs (except for a few globules of decane) formed globules covered with fine sand particles that were heavy enough to settle by gravity. The encapsulated globules were stable and retained their shape upon settling. Polarity of hydrophobic liquids as the main factor of aggregation with minerals was found to be insufficient to explain LHL aggregation with sand. Contact angle measurements were made by submerging a large quartz crystal with the LHL drop on its surface into salt water. A positive correlation was observed between the wetting angle of LHL and the LHL volume captured (r = 0.75). The dependence of the globule density on globule radius was analyzed in relation to the coverage (%) of globule surface (LHL-salt water interface) by fine quartz particles. PMID- 26490431 TI - Unique Challenges of Type 1 Diabetes in the Preschool Population. AB - BACKGROUND: Extremely young children aged <=6 years old represent a unique population among patients with type 1 diabetes in terms of glycemic variation, diabetes management and complications. OBJECTIVE: We describe distinct features of diabetes care and outcomes in preschool age children. METHODS: We searched PubMed, Google Scholar, and authors' bibliographies in order to extract articles specific to type 1 diabetes in preschool age children. FINDINGS: The preschool age group is beset by many challenges to diabetes care, including more frequent hypo- and hyperglycemia, hypoglycemia unawareness, decreased residual beta cell function, and greater long-term neurocognitive effects from severe hypoglycemia and chronic hyperglycemia. Randomized controlled trials show that equally good metabolic control can be obtained with multiple daily injections or an insulin pump. Several non-randomized trials, including an 8 year longitudinal study, show lower hemoglobin A1C and decreased hypoglycemia on insulin pumps. Sensor augmented pump therapy resulted in superior A1C as long as sensors were used regularly. In contrast to adults, continuous glucose monitoring has little to no impact on A1C, although parents appreciate the improved monitoring for hypoglycemia. Children with onset of diabetes prior to age 5 are at risk for younger onset of microalbuminuria, however do not develop earlier onset retinopathy than children diagnosed after 5 years. Both severe hypoglycemia and chronic hyperglycemia have negative impact on neurocognition. CONCLUSION: Special knowledge about this young population is helpful for practitioners and parents. PMID- 26490432 TI - Family History of Type 2 Diabetes: Does Having a Diabetic Parent Increase the Risk? AB - BACKGROUND: It is well established that there is an important genetic predisposition for type 2 diabetes mellitus (T2DM). OBJECTIVE: To summarise available epidemiological data regarding T2DM transmission in various populations. METHOD: Narrative review. RESULTS: The estimated risk for the diagnosis of T2DM increases approximately by 2-4 times, when father, mother or both have this condition. Conversely, many T2DM patients have family members with DM. Studies have suggested that the likelihood of T2DM in the next generation is higher in the event of a diabetic mother than father. Both genetic factors, such as mitochondrial DNA mutations, and environmental components, such as intra uterine environment, have been implicated in the higher maternal transmission of T2DM. Despite the above findings, some studies in populations with high frequency of T2DM have not corroborated the predominantly maternal transmission. Such works have shown either an excess paternal or an equal transmission of T2DM. CONCLUSION: It appears that potential biases in reporting family history data, especially between the various racial groups, have contributed to the controversy over the existence of excess maternal transmission of DM. PMID- 26490433 TI - The Listeria monocytogenes Core-Genome Sequence Typer (LmCGST): a bioinformatic pipeline for molecular characterization with next-generation sequence data. AB - BACKGROUND: Next-generation sequencing provides a powerful means of molecular characterization. However, methods such as single-nucleotide polymorphism detection or whole-chromosome sequence analysis are computationally expensive, prone to errors, and are still less accessible than traditional typing methods. Here, we present the Listeria monocytogenes core-genome sequence typing method for molecular characterization. This method uses a high-confidence core (HCC) genome, calculated to ensure accurate identification of orthologs. We also developed an evolutionarily relevant nomenclature based upon phylogenetic analysis of HCC genomes. Finally, we created a pipeline (LmCGST; https://sourceforge.net/projects/lmcgst/files/) that takes in raw next-generation sequencing reads, calculates a subject HCC profile, compares it to an expandable database, assigns a sequence type, and performs a phylogenetic analysis. RESULTS: We analyzed 29 high-quality, closed Listeria monocytogenes chromosome sequences and identified loci that are reliable targets for automated molecular characterization methods. We identified 1013 open-reading frames that comprise our high-confidence core (HCC) genome. We then populated a database with HCC profiles from 114 taxa. We sequenced 84 randomly selected isolates from the Listeriosis Reference Service for Canada's collection and analysed them with the LmCGST pipeline. In addition, we generated pulsed-field gel electrophoresis, ribotyping, and in silico multi-locus sequence typing (MLST) data for the 84 isolates and compared the results to those obtained using the CGST method. We found that all of the methods yielded results that are generally congruent. However, due to the increased numbers of categories, the CGST method provides much greater discriminatory power than the other methods tested here. CONCLUSIONS: We show that the CGST method provides increased discriminatory power relative to typing methods such as pulsed-field gel electrophoresis, ribotyping, and multi-locus sequence typing while it addresses several shortcomings of other methods of molecular characterization with next-generation sequence data. It uses discrete, well-defined groupings (types) of organisms that are phylogenetically relevant and easily interpreted. In addition, the CGST scheme can be expanded to include additional loci and HCC profiles in the future. In total, the CGST method provides an approach to the molecular characterization of Listeria monocytogenes with next-generation sequence data that is highly reproducible, easily standardized, portable, and accessible. PMID- 26490434 TI - A feasibility study to inform the design of a randomised controlled trial to identify the most clinically effective and cost-effective length of Anticoagulation with Low-molecular-weight heparin In the treatment of Cancer Associated Thrombosis (ALICAT). AB - BACKGROUND: Venous thromboembolism is common in cancer patients and requires anticoagulation with low-molecular-weight heparin (LMWH). Current data recommend LMWH for anticoagulation as far as 6 months, yet guidelines recommend LMWH beyond 6 months in patients who have ongoing or active cancer. This recommendation, based on expert consensus, has not been evaluated in a clinical study. OBJECTIVES: (1) To identify the most clinically and cost-effective length of anticoagulation with LMWH in the treatment of cancer-associated thrombosis (CAT); (2) to identify practicalities of conducting a full randomised controlled trial (RCT) with regard to recruitment, retention and outcome measurement; and (3) to explore the barriers for progressing to a full RCT. DESIGN: The Anticoagulation with Low-molecular-weight heparin In the treatment of Cancer-Associated Thrombosis (ALICAT) trial is a randomised, multicentre, feasibility mixed-methods study with three components: (1) a RCT comparing ongoing LMWH treatment for CAT with cessation of LMWH at 6 months' treatment (current licensed practice) in patients with locally advanced or metastatic cancer, consulted in three clinical settings (haematology outpatients, oncology outpatients and primary care); (2) a nested qualitative study, including focus groups with clinicians to investigate attitudes for recruiting to the study and identify the challenges of progressing to a full RCT, and semistructured interviews with patients and relatives to explore their attitudes towards participating in the study, and potential barriers and concerns to participation; and (3) a UK-wide survey exercise to develop a classification and enumeration system for the CAT models and pathways of care. SETTING: A haematology outpatients department, an oncology outpatients department and primary care. PARTICIPANTS: Patients with ongoing active or metastatic cancer who have received 6 months of LMWH for CAT. INTERVENTIONS: Ongoing LMWH treatment for CAT versus cessation of LMWH at 6 months' treatment in patients with locally advanced or metastatic cancer. MAIN OUTCOME MEASURES: (i) The number of eligible patients over 12 months; (ii) the number of recruited patients over 12 months (target recruitment rate of 30% of eligible patients); and (iii) the proportion of randomised participants with recurrent venous thromboembolisms (VTEs) during follow-up. RESULTS: Following several delays in setting up the RCT component of the study, 5 out of 32 eligible patients consented to be randomised to the RCT suggesting progression to a full RCT was not feasible. Reasons for non-consenting were primarily based on a fixed preference for continuing or discontinuing treatment after 6 months of anticoagulation, and a fear of randomisation to their non-preferred option. Views were largely influenced by patients' initial experience of CAT. Focus groups with clinicians revealed that they would be reticent to recruit to such a study as they had fixed views of best management despite the lack of evidence. Patient pathway modelling suggested that there is a broad heterogeneity of practice with respect to CAT management and co-ordination, with no consensus on which specialty should best manage such cases. CONCLUSIONS: The results of the RCT reflect recruitment from the oncology site only and provide no recruitment data from haematology centres. However, it is unlikely that these other sites would have access to more eligible patients. The management of cancer-associated thrombosis beyond 6 months will remain a clinical challenge. As it is unlikely that a prospective study will successfully recruit, other strategies to accrue relevant data are necessary. Currently the LONGHEVA (Long-term treatment for cancer patients with deep-venous thrombosis or pulmonary embolism) registry is in development to prospectively evaluate this important and common clinical scenario. STUDY REGISTRATION: This study is registered as clinical trials.gov number NCT01817257 and International Standard Randomised Controlled Trial Number (ISRCTN) 37913976. FUNDING DETAILS: Funding for the ALICAT trial was provided by the Health Technology Assessment programme (10/145/01) in response to a themed funding call. The study was designed in accordance with the initial funding brief and feedback from the review process. PMID- 26490435 TI - Evaluation of BRCA1-related molecular features and microRNAs as prognostic factors for triple negative breast cancers. AB - BACKGROUND: The BRCA1 gene plays a key role in triple negative breast cancers (TNBCs), in which its expression can be lost by multiple mechanisms: germinal mutation followed by deletion of the second allele; negative regulation by promoter methylation; or miRNA-mediated silencing. This study aimed to establish a correlation among the BRCA1-related molecular parameters, tumor characteristics and clinical follow-up of patients to find new prognostic factors. METHODS: BRCA1 protein and mRNA expression was quantified in situ in the TNBCs of 69 patients. BRCA1 promoter methylation status was checked, as well as cytokeratin 5/6 expression. Maintenance of expressed BRCA1 protein interaction with BARD1 was quantified, as a marker of BRCA1 functionality, and the tumor expression profiles of 27 microRNAs were determined. RESULTS: miR-548c-5p was emphasized as a new independent prognostic factor in TNBC. A combination of the tumoral expression of miR-548c and three other known prognostic parameters (tumor size, lymph node invasion and CK 5/6 expression status) allowed for relapse prediction by logistic regression with an area under the curve (AUC) = 0.96. BRCA1 mRNA and protein in situ expression, as well as the amount of BRCA1 ligated to BARD1 in the tumor, lacked any associations with patient outcomes, likely due to high intratumoral heterogeneity, and thus could not be used for clinical purposes. CONCLUSIONS: In situ BRCA1-related expression parameters could be used for clinical purposes at the time of diagnosis. In contrast, miR-548c-5p showed a promising potential as a prognostic factor in TNBC. PMID- 26490436 TI - Possible changes in the transmissibility of trachoma following MDA and transmission reduction: implications for the GET2020 goals. AB - BACKGROUND: The role of mass drug administration (MDA) and the implementation of transmission reduction measures are essential to successfully control and eliminate a wide range of NTDs, including the ocular disease trachoma. Immunity to trachoma infection acts by reducing the duration of an individual's infectious period and by reducing their infectivity with each successive infection. METHODS: In this study, we use a model of trachoma infection, which includes population immunity, to explore the impact of treatment and transmission reduction measures on trachoma prevalence. Specifically, we investigate the possibility of increasing transmissibility of trachoma arising as MDA and transmission reduction measures are scaled up in endemic settings. RESULTS: We demonstrate this increase in transmissibility by calculating the effective reproduction number during several simulated control programmes and show that it is related to a decrease in the level of immunity in the population. CONCLUSIONS: This effect should be studied in the field by measuring the rate of return of infection and disease in at least two separate age groups. If the decline of population immunity is operating, it should be accounted for when planning for the GET2020 goal of eliminating blinding trachoma by 2020. PMID- 26490438 TI - Dysregulated miRNA in progression of hepatocellular carcinoma: A systematic review. AB - Hepatocellular carcinoma (HCC) is the fifth most frequent cancer and the third cause of cancer-related mortality worldwide. The primary risk factor for HCC is liver cirrhosis secondary to persistent infection with hepatitis B virus or hepatitis C virus. Although a number of cellular phenomena and molecular events have been reported to facilitate tumor initiation, progression and metastasis, the exact etiology of HCC has not yet been fully uncovered. miRNA, a class of non coding RNA, negatively regulate post-transcriptional processes that participate in crucial biological processes, including development, differentiation, apoptosis and proliferation. In the liver, specific miRNA can be negative regulators of gene expression. Recent studies have uncovered the contribution of miRNA to cancer pathogenesis as they can function as oncogenes or tumor suppressor genes. In addition, other studies have demonstrated their potential value in the clinical management of patients with HCC as some miRNA may be used as prognostic or diagnostic markers. In this review, we summarize the current knowledge about the roles of miRNA in the carcinogenesis and progression of HCC. PMID- 26490437 TI - Associations of socioeconomic determinants with community clinic awareness and visitation among women: evidence from Bangladesh Demographic and Health Survey 2011. AB - BACKGROUND: Although Bangladesh has achieved tremendous success in health care over the last four decades, it still lagged behind in the areas of maternal and child malnutrition and primary health care (PHC). To increase access to PHC, the Bangladesh government established approximately 18,000 community clinics (CCs). The purpose of this study was to examine the associations of socioeconomic determinants of women aged 12-49 years with the CCs awareness and visitation. METHODS: We analyzed secondary data provided by Bangladesh Demographic and Health Survey-2011. A two-stage cluster sampling was used to collect the data. A total of 18,222 ever married women aged 12-49 years were identified from selected households and 17,842 were interviewed. The main outcome measures of our study were awareness and visitation of CCs. Bivariate logistic regression was used to calculate odds ratio (OR) and 95% confidence interval (CI) to examine the associations between the awareness and visiting CCs with socioeconomic determinants. RESULTS: Low prevalence of awareness about CC (18 %) was observed among studied women and only 17 % of them visited CCs. Significant associations (P < 0.05) with CCs awareness and visitation were observed among aged 20-29 years (adjusted OR = 1.18; 95% CI = 1.03-1.35 and adjusted OR = 1.49; 95% CI = 1.05 2.11), primary education (adjusted OR = 1.20; 95% CI = 1.08-1.34 and adjusted OR = 1.37; 95% CI = 1.05-1.78), and poorest family (adjusted OR = 1.21; 95% CI = 1.03-1.42 and adjusted OR = 2.36; 95% CI = 1.56-3.55, respectively), after controlling potential confounders. CONCLUSIONS: Awareness and visitation of CCs were found to be positively associated with lower economic conditions, young age, and primary education. Awareness and access to CCs might be increased through community activities that involve health care workers. The government should also lower barriers to PHC access through CCs by providing adequate logistics, such as human resources and equipment. PMID- 26490439 TI - Cortical representation of facial and tongue movements: a task functional magnetic resonance imaging study. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) mapping can present the activated cortical area during movement, while little is known about precise location in facial and tongue movements. OBJECTIVE: To investigate the representation of facial and tongue movements by task fMRI. METHODS: Twenty right handed healthy subjects were underwent block design task fMRI examination. Task movements included lip pursing, cheek bulging, grinning and vertical tongue excursion. Statistical parametric mapping (SPM8) was applied to analysis the data. RESULTS: One-sample t-test was used to calculate the common activation area between facial and tongue movements. Also, paired t-test was used to test for areas of over- or underactivation in tongue movement compared with each group of facial movements. CONCLUSIONS: The common areas within facial and tongue movements suggested the similar motor circuits of activation in both movements. Prior activation in tongue movement was situated laterally and inferiorly in sensorimotor area relative to facial movements. Prior activation of tongue movement was investigated in left superior parietal lobe relative to lip pursing. Also, prior activation in bilateral cuneus lobe in grinning compared with tongue movement was detected. PMID- 26490440 TI - Accuracy of genomic selection for age at puberty in a multi-breed population of tropically adapted beef cattle. AB - Genomic selection is becoming a standard tool in livestock breeding programs, particularly for traits that are hard to measure. Accuracy of genomic selection can be improved by increasing the quantity and quality of data and potentially by improving analytical methods. Adding genotypes and phenotypes from additional breeds or crosses often improves the accuracy of genomic predictions but requires specific methodology. A model was developed to incorporate breed composition estimated from genotypes into genomic selection models. This method was applied to age at puberty data in female beef cattle (as estimated from age at first observation of a corpus luteum) from a mix of Brahman and Tropical Composite beef cattle. In this dataset, the new model incorporating breed composition did not increase the accuracy of genomic selection. However, the breeding values exhibited slightly less bias (as assessed by deviation of regression of phenotype on genomic breeding values from the expected value of 1). Adding additional Brahman animals to the Tropical Composite analysis increased the accuracy of genomic predictions and did not affect the accuracy of the Brahman predictions. PMID- 26490441 TI - Engineering a pyridoxal 5'-phosphate supply for cadaverine production by using Escherichia coli whole-cell biocatalysis. AB - Although the routes of de novo pyridoxal 5'-phosphate (PLP) biosynthesis have been well described, studies of the engineering of an intracellular PLP supply are limited, and the effects of cellular PLP levels on PLP-dependent enzyme-based whole-cell biocatalyst activity have not been described. To investigate the effects of PLP cofactor availability on whole-cell biocatalysis, the ribose 5 phosphate (R5P)-dependent pathway genes pdxS and pdxT of Bacillus subtilis were introduced into the lysine decarboxylase (CadA)-overexpressing Escherichia coli strain BL-CadA. This strain was then used as a whole-cell biocatalyst for cadaverine production from L-lysine. Co-expression strategies were evaluated, and the culture medium was optimised to improve the biocatalyst performance. As a result, the intracellular PLP concentration reached 1144 nmol/gDCW, and a specific cadaverine productivity of 25 g/gDCW/h was achieved; these values were 2.4-fold and 2.9-fold higher than those of unmodified BL-CadA, respectively. Additionally, the resulting strain AST3 showed a cadaverine titre (p = 0.143, alpha = 0.05) similar to that of the BL-CadA strain with the addition of 0.1 mM PLP. These approaches for improving intracellular PLP levels to enhance whole cell lysine bioconversion activity show great promise for the engineering of a PLP cofactor to optimise whole-cell biocatalysis. PMID- 26490443 TI - Boredom in the Workplace: A New Look at an Old Problem. AB - OBJECTIVE: We review historical and more recent efforts in boredom research and related fields. A framework is presented that organizes the various facets of boredom, particularly in supervisory control settings, and research gaps and future potential areas for study are highlighted. BACKGROUND: Given the ubiquity of boredom across a wide spectrum of work environments--exacerbated by increasingly automated systems that remove humans from direct, physical system interaction and possibly increasing tedium in the workplace--there is a need not only to better understand the multiple facets of boredom in work environments but to develop targeted mitigation strategies. METHOD: To better understand the relationships between the various influences and outcomes of boredom, a systems based framework, called the Boredom Influence Diagram, is proposed that describes various elements of boredom and their interrelationships. RESULTS: Boredom is closely related to vigilance, attention management, and task performance. This review highlights the need to develop more naturalistic experiments that reflect the characteristics of a boring work environment. CONCLUSION: With the increase in automation, boredom in the workplace will likely become a more prevalent issue for motivation and retention. In addition, developing continuous measures of boredom based on physiological signals is critical. APPLICATION: Personnel selection and improvements in system and task design can potentially mitigate boredom. However, more work is needed to develop and evaluate other potential interventions. PMID- 26490442 TI - The Effects of Cell Phone and Text Message Conversations on Simulated Street Crossing. AB - OBJECTIVE: A fully immersive, high-fidelity street-crossing simulator was used to examine the effects of texting on pedestrian street-crossing performance. BACKGROUND: Research suggests that street-crossing performance is impaired when pedestrians engage in cell phone conversations. Less is known about the impact of texting on street-crossing performance. METHOD: Thirty-two young adults completed three distraction conditions in a simulated street-crossing task: no distraction, phone conversation, and texting. A hands-free headset and a mounted tablet were used to conduct the phone and texting conversations, respectively. Participants moved through the virtual environment via a manual treadmill, allowing them to select crossing gaps and change their gait. RESULTS: During the phone conversation and texting conditions, participants had fewer successful crossings and took longer to initiate crossing. Furthermore, in the texting condition, smaller percentage of time with head orientation toward the tablet, fewer number of head orientations toward the tablet, and greater percentage of total characters typed before initiating crossing predicted greater crossing success. CONCLUSION: Our results suggest that (a) texting is as unsafe as phone conversations for street-crossing performance and (b) when subjects completed most of the texting task before initiating crossing, they were more likely to make it safely across the street. APPLICATION: Sending and receiving text messages negatively impact a range of real-world behaviors. These results may inform personal and policy decisions. PMID- 26490444 TI - A CNT@MoSe2 hybrid catalyst for efficient and stable hydrogen evolution. AB - Exploration of high-efficiency Pt-free electrochemical catalysts for hydrogen evolution reaction (HER) is considered as a great challenge for the development of sustainable and carbon dioxide free energy conversion systems. In this work, a unique hierarchical nanostructure of few-layered MoSe2 nanosheets perpendicularly grown on carbon nanotubes (CNTs) is synthesized through a one-step solvothermal reaction. This rationally designed architecture based on a highly conductive CNT substrate possesses fully exposed active edges and open structures for fast ion/electron transfer, thus leading to remarkable HER activity with a low onset potential of -0.07 V vs. RHE (reversible hydrogen electrode), a small Tafel slope of 58 mV per decade and excellent long-cycle stability. Therefore, this noble metal-free and highly efficient catalyst enables prospective applications for industrial, renewable hydrogen production. PMID- 26490447 TI - Efficient Rhodium-Catalyzed Multicomponent Reaction for the Synthesis of Novel Propargylamines. AB - [{Rh(MU-Cl)(H)2 (IPr)}2 ] (IPr = 1,3-bis-(2,6-diisopropylphenyl)imidazole-2 ylidene) was found to be an efficient catalyst for the synthesis of novel propargylamines by a one-pot three-component reaction between primary arylamines, aliphatic aldehydes, and triisopropylsilylacetylene. This methodology offers an efficient synthetic pathway for the preparation of secondary propargylamines derived from aliphatic aldehydes. The reactivity of [{Rh(MU-Cl)(H)2 (IPr)}2 ] with amines and aldehydes was studied, leading to the identification of complexes [RhCl(CO)IPr(MesNH2 )] (MesNH2 = 2,4,6-trimethylaniline) and [RhCl(CO)2 IPr]. The latter shows a very low catalytic activity while the former brought about reaction rates similar to those obtained with [{Rh(MU-Cl)(H)2 (IPr)}2 ]. Besides, complex [RhCl(CO)IPr(MesNH2 )] reacts with an excess of amine and aldehyde to give [RhCl(CO)IPr{MesN?CHCH2 CH(CH3 )2 }], which was postulated as the active species. A mechanism that clarifies the scarcely studied catalytic cycle of A3 coupling reactions is proposed based on reactivity studies and DFT calculations. PMID- 26490445 TI - A pig-to-mouse coronary artery transplantation model for investigating the pathogenicity of anti-pig antibody. AB - BACKGROUND: Rejection of Gal-free (GTKO) donor pig cardiac xenografts is strongly associated with vascular non-Gal antibody binding, endothelial cell (EC) injury, and activation and microvascular thrombosis. We adopted a pig-to-SCID/beige small animal transplant model to compare the pathogenicity of baboon and human anti-pig antibody. METHODS: Wild-type (GT(+) ) or GTKO porcine coronary arteries (PCAs) were transplanted into the infrarenal aorta of SCID/beige mice. Three days after transplant, recipients were infused with anti-pig antibody (anti-SLA class I, an isotype control, naive or sensitized baboon serum, or naive human serum). PCAs were recovered 24 h after antibody infusion and examined using histology, immunohistochemistry, and in situ hybridization. RESULTS: Dose-dependent intragraft thrombosis occurred after infusion of anti-SLA I antibody (but not isotype control) in GT(+) and GTKO PCA recipients. Naive baboon serum induced thrombosis in GT(+) grafts. Thrombosis was significantly reduced by pre-treating naive baboon serum with Gal polymer and not observed when this serum was infused to GTKO PCA recipients. Naive human serum caused dose-dependent intragraft thrombosis of GTKO PCAs. In all cases, thrombosis involved graft-specific vascular antibody and complement deposition, macrophage adherence, EC delamination, and subendothelial thrombus formation. CONCLUSIONS: This study provides the first direct in vivo comparison of the pathogenicity of naive human and baboon serum. The results suggest that human preformed non-Gal antibody may have increased pathogenicity compared to baboon. This model, which showed a rejected graft histopathology similar to antibody-mediated rejection in cardiac xenotransplantation, may be useful to assess the pathogenicity of individual protein or carbohydrate specific non-Gal reactive antibodies. PMID- 26490448 TI - Evaluation of Minerals, Phytochemical Compounds and Antioxidant Activity of Mexican, Central American, and African Green Leafy Vegetables. AB - The green leafy vegetables Cnidoscolus aconitifolius and Crotalaria longirostrata are native to Mexico and Central America, while Solanum scabrum and Gynandropsis gynandra are native to Africa. They are consumed in both rural and urban areas in those places as a main food, food ingredient or traditional medicine. Currently, there is limited information about their nutritional and phytochemical composition. Therefore, mineral, vitamin C, phenolic and flavonoid concentration, and antioxidant activity were evaluated in multiple accessions of these leafy vegetables, and their mineral and vitamin C contribution per serving was calculated. The concentrations of Ca, K, Mg and P in these leafy vegetables were 0.82-2.32, 1.61-7.29, 0.61-1.48 and 0.27-1.44 mg/g fresh weight (FW), respectively. The flavonoid concentration in S. scabrum accessions was up to 1413 MUg catechin equivalents/g FW, while the highest antioxidant activities were obtained in C. longirostrata accessions (52-60 MUmol Trolox equivalents/g FW). According to guidelines established by the US Food and Drug Administration, a serving size (30 g FW) of C. longirostrata would be considered an excellent source of Mo (20 % or more of the daily value), and a serving of any of these green leafy vegetables would be an excellent source of vitamin C. Considering the importance of the minerals, phytochemicals and antioxidants in human health and their presence in these indigenous green leafy vegetables, efforts to promote their consumption should be implemented. PMID- 26490449 TI - Inhibitory Activities of Thai Medicinal Plants with Promising Activities Against Malaria and Cholangiocarcinoma on Human Cytochrome P450. AB - Malaria and cholangiocarcinoma remain important public health problems in tropical countries including Southeast Asian nations. Newly developed chemotherapeutic and plant-derived drugs are urgently required for the control of both diseases. The aim of the present study was to investigate the propensity to inhibit cytochrome P450-mediated hepatic metabolism (CYP1A2, CYP2C19, CYP2D6 and CYP3A4) of the crude ethanolic extract of eight Thai medicinal plants with promising activities against malaria and cholangiocarcinoma, using human liver microsomes in vitro. Piper chaba Linn. (PC) and Atractylodes lancea (thung.) DC. (AL) exhibited the most potent inhibitory activities on CYP1A2-mediated phenacetin O-deethylation with mean IC50 of 0.04 and 0.36 ug/mL, respectively. Plumbago indica Linn. (PI) and Dioscorea membranacea Pierre. (DM) potently inhibited CYP2C19-mediated omeprazole 5-hydroxylation (mean IC50 4.71 and 6.92 ug/mL, respectively). DM, Dracaena loureiri Gagnep. (DL) and PI showed the highest inhibitory activities on dextromethorphan O-demethylation (mean IC50 2.93 9.57 ug/mL). PC, DM, DL and PI exhibited the most potent inhibitory activities on CYP3A4-mediated nifedipine oxidation (mean IC50 1.54-6.43 ug/mL). Clinical relevance of the inhibitory potential of DM, PC and PI is of concern for the further development of these plants for the treatment of malaria and/or cholangiocarcinoma. PMID- 26490450 TI - Additional right-sided upper "Half-Mini-Thoracotomy" for aortocoronary bypass grafting during minimally invasive multivessel revascularization. AB - BACKGROUND: Although minimally invasive coronary artery bypass grafting (MICS CABG) has been shown to result in excellent clinical outcomes overall adoption rates still remain low. Traditional strategies for minimally invasive multivessel revascularization - usually performed through single-thoracotomy - have to deal with restricted grafting possibilities and possible increased susceptibility of arterial grafts to competitive flow, restraining their applicability to very specific indications or hybrid approaches and on top, are prone to conversion to full-sternotomy in case of left internal thoracic artery (LITA) insufficiency. METHODS: Here, we present a novel alternative to the traditional MICS-CABG approaches by adding a right-sided upper "half-mini-thoracotomy", which allows for aortocoronary bypass grafting in standard "off-pump" manner and adoption of similar revascularization principles as with conventional CABG during minimally invasive multivessel revascularization, though reducing restrictions inherent to current MICS-CABG strategies. RESULTS: So far, feasibility and safety of this new approach has been successfully shown in 7 consecutive patients requiring surgical revascularization with no procedure-specific complications and graft configuration as well as intraoperative flow assessment comparable to those of similar patients operated via standard full-sternotomy off-pump coronary artery bypass (OPCAB) surgery. CONCLUSIONS: Further evaluation warranted, this technique might have the potential to develop into an additional approach for minimally invasive multivessel revascularization, especially in cases where competitive flow to arterial grafts is feared, while also serving as a bailout-strategy for traditional approaches in case of LITA insufficiency. PMID- 26490452 TI - Long-term outcome of moderate hypofractionated stereotactic radiotherapy for meningiomas. AB - PURPOSE: The aim of this work was to evaluate long-term results of moderate hypofractionated stereotactic radiotherapy (hFSRT) for intracranial meningiomas. PATIENTS AND METHODS: In all, 77 consecutive patients with 80 lesions were included. Median age was 65 years (range 23-82 years), male/female ratio was 21/56, and the median Karnofsky performance status was 90 (range 60-100). In 31 lesions (39 %), diagnosis was based upon clinical and radiological data; 37 lesions were histologically proven as World Health Organization (WHO) grade I and 12 grade II meningiomas. Median treatment volume was 23 cc. Prescribed doses were 45 Gy in 15 fractions of 3 Gy (15 * 3 Gy) or 42 Gy in 14 fractions of 3 Gy (14 * 3 Gy). RESULTS: After a median follow-up of 56 months, 49 (61 %) lesions received 14 * 3 Gy and 31 (39 %) 15 * 3 Gy. Local control (LC) rate remained unchanged at 84 % at 5 and 10 years. Overall survival and disease-specific survival (DSS) were 76 and 93 % at 5 years, 72 and 89 % at 10 years, respectively. With univariate analysis, previous surgery and WHO grade II tumor were negative prognostic factors for LC and DSS. With multivariate analysis only tumor grade was an independent prognostic factor for LC. No clinically significant acute and/or late toxicities were observed. CONCLUSION: Moderate hFSRT was effective and safe with an excellent tolerance profile. It can be an alternative treatment option for patients with recurrent or inoperable large meningiomas. The low number of fractions administered with hFSRT led to reduce treatment-related discomfort for patients. Grade II tumor and previous surgery were negative prognosis factors. PMID- 26490453 TI - Copper-catalyzed silylation of p-quinone methides: new entry to dibenzylic silanes. AB - An efficient and general copper(I)-catalyzed silylation of p-quinone-methides is described. Non-symmetric dibenzylic silanes are obtained in high yields under mild reaction conditions. These compounds can be used as bench-stable benzylic carbanion precursors. PMID- 26490451 TI - Communicating Cardiovascular Disease Risk to People with Psoriasis: What Techniques do Practitioners Use? AB - BACKGROUND: Psoriasis can be associated with unhealthy lifestyle behaviours such as smoking, excess alcohol use and insufficient physical activity, consequently increasing cardiovascular disease (CVD) risk. Health care practitioners are expected to discuss lifestyle risk factors with patients with a view to reducing health-related risk for patients. However, little is known about the techniques used to communicate information about risk to patients with psoriasis. PURPOSE: We aimed to examine how primary care practitioners communicate risk information when conducting CVD risk assessments. METHOD: Consultations (n = 44) between primary care practitioners (general practitioners and practice nurses) and patients with psoriasis across 10 practices were audio-recorded and analysed using content analysis. A coding frame was used to record specific techniques used by practitioners to communicate risk information. RESULTS: Most frequently used communication methods were verbal descriptors of risk factors accompanied by numerical data (n = 28) rather than verbal descriptors alone (n = 16). Practitioners did not use numerical risk communication methods alone. Where CVD risk factors were discussed with patients (n = 156 occasions across all consultations), interpretations of this information was provided to patients on 131 (84 %) occasions. However, specific advice about behaviour/risk modification was only given on 60 (38.5 %) out of a possible 156 occasions. CONCLUSIONS: Specific advice about how to change lifestyle behaviour to modify CVD risk factors was not always given by the practitioner, particularly when discussing behavioural risk factors. Developing a best practice for communicating complex health risk information would ensure that people with psoriasis are empowered to make lifestyle modifications to reduce CVD risk. PMID- 26490454 TI - "You can't always get what you want": from doctrine to practicability of study designs for clinical investigation in endometriosis. AB - BACKGROUND: Patients, now generally well informed through dedicated websites and support organizations, are beginning to look askance at clinical experimentation. We conducted a survey investigation to verify whether women with endometriosis would still accept to participate in a randomized controlled trial (RCT) on treatment for pelvic pain. METHODS: A total of 500 patients consecutively self referring to an academic outpatient endometriosis clinic, were asked to compile two questionnaires focused on hypothetical comparisons between a new drug and a standard drug, and between medical and surgical treatment, for endometriosis associated pelvic pain. The main outcome measure was the percentage of patients willing to participate in a theoretical RCT. RESULTS: A total of 239 (48 %) women would decline participation in a comparative study on a new drug and a standard drug, as 204 (41 %) would prefer the former medication, and 35 (7 %) the latter. Fifty women (10 %) would participate in a RCT, but only 24 (5 %) would accept blinding. The most frequently chosen option was the patient preference trial (211; 42 %). No significant differences were observed in demographic and clinical characteristics between the 50 women who would accept and the 450 who would decline to be enrolled in a RCT. A total of 229 women (46 %) would decline participation in a comparative study on medical versus surgical treatment, as 186 (37 %) would prefer pharmacological therapy and 43 (9 %) a surgical procedure. Only 11 (2 %) women would participate in such a RCT. More than half of the women (260; 52 %) selected the patient preference trial. No significant variations in distributions of answers were observed between women who did or did not undergo a previous surgical procedure. CONCLUSION: Only a small minority of the women included in our study sample would accept randomization, and even less so blinding. Patient preference appears to play a central role when planning interventional trials on endometriosis-associated pelvic pain. Adequately designed observational analytic studies could be considered when recruitment in a RCT appears cumbersome. PMID- 26490455 TI - Swallowable fluorometric capsule for wireless triage of gastrointestinal bleeding. AB - Real-time detection of gastrointestinal bleeding remains a major challenge because there does not yet exist a minimally invasive technology that can both i) monitor for blood from an active hemorrhage and ii) uniquely distinguish it from blood left over from an inactive hemorrhage. Such a device would be an important tool for clinical triage. One promising solution, which we have proposed previously, is to inject a fluorescent dye into the blood stream and to use it as a distinctive marker of active bleeding by monitoring leakage into the gastrointestinal tract with a wireless fluorometer. This paper reports, for the first time to our knowledge, the development of a swallowable, wireless capsule with a built-in fluorometer capable of detecting fluorescein in blood, and intended for monitoring gastrointestinal bleeding in the stomach. The embedded, compact fluorometer uses pinholes to define a microliter sensing volume and to eliminate bulky optical components. The proof-of-concept capsule integrates optics, low-noise analog sensing electronics, a microcontroller, battery, and low power Zigbee radio, all into a cylindrical package measuring 11 mm * 27 mm and weighing 10 g. Bench-top experiments demonstrate wireless fluorometry with a limit-of-detection of 20 nM aqueous fluorescein. This device represents a major step towards a technology that would enable simple, rapid detection of active gastrointestinal bleeding, a capability that would save precious time and resources and, ultimately, reduce complications in patients. PMID- 26490456 TI - Hypoxia regulates the hematopoietic stem cell niche. AB - Bone marrow, the site of hematopoiesis throughout adulthood, is a physiologically hypoxic organ. Thus, various biological oxygen sensors and their signaling cascades play a pivotal role in hematopoietic systems in the bone marrow under both physiologic and pathologic conditions. Hypoxia-inducible factors (HIFs) are hypoxic stress sensor proteins that are stabilized under homeostatic or stress induced hypoxia. In the hypoxic bone marrow, HIFs play crucial roles in hematopoietic stem cells (HSCs) and in the cells of the HSC niche. The signals downstream of the HIFs maintain HSC quiescence, survival, and metabolic homeostasis through both cell-autonomous and non-cell-autonomous mechanisms. Leukemic stem cells (LSCs) hijack these delicate hypoxia-sensing mechanisms to sustain their self-renewal potential, promoting disease progression and drug resistance even under normoxic conditions. This review focuses on HIF-mediated oxygen-sensing mechanisms of adult HSCs and LSCs and their niche cells in the hypoxic bone marrow. PMID- 26490457 TI - Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney. AB - Glutamine, the most abundant amino acid in mammals, is critical for cell and organ functions. Its metabolism depends on the ability of cells to take up or release glutamine by transporters located in the plasma membrane. Several solute carrier (SLC) families transport glutamine, but the SLC38 family has been thought to be mostly responsible for glutamine transport. We demonstrate that despite the large number of glutamine transporters, the loss of Snat3/Slc38a3 glutamine transporter has a major impact on the function of organs expressing it. Snat3 mutant mice were generated by N-ethyl-N-nitrosurea (ENU) mutagenesis and showed stunted growth, altered amino acid levels, hypoglycemia, and died around 20 days after birth. Hepatic concentrations of glutamine, glutamate, leucine, phenylalanine, and tryptophan were highly reduced paralleled by downregulation of the mTOR pathway possibly linking reduced amino acid availability to impaired growth and glucose homeostasis. Snat3-deficient mice had altered urea levels paralleled by dysregulation of the urea cycle, gluconeogenesis, and glutamine synthesis. Mice were ataxic with higher glutamine but reduced glutamate and gamma aminobutyric acid (GABA) levels in brain consistent with a major role of Snat3 in the glutamine-glutamate cycle. Renal ammonium excretion was lower, and the expression of enzymes and amino acid transporters involved in ammoniagenesis were altered. Thus, SNAT3 is a glutamine transporter required for amino acid homeostasis and determines critical functions in various organs. Despite the large number of glutamine transporters, loss of Snat3 cannot be compensated, suggesting that this transporter is a major route of glutamine transport in the liver, brain, and kidney. PMID- 26490458 TI - Modulation of spontaneous intracellular Ca2+ fluctuations and spontaneous cholinergic transmission in rat chromaffin cells in situ by endogenous GABA acting on GABAA receptors. AB - Using fluorescence [Ca(2+)]i imaging in rat adrenal slices, we characterized the effects of agonists and antagonists of the GABAA receptor (GABAA-R) on resting intracellular Ca(2+) ([Ca(2+)]i) and spontaneous [Ca(2+)]i fluctuations (SCFs) in hundreds of individual chromaffin cells (CCs) recorded simultaneously in situ. Muscimol, a GABAA-R agonist (20 MUM; 25 s), induced an increase of resting [Ca(2+)]i in 43 +/- 3 % of CCs, a decrease in 26 +/- 2 %, and no response in 30 +/- 5 %. In Ca(2+)-free external medium, SCFs ceased completely and muscimol failed to elicit [Ca(2+)]i rises. All muscimol-induced [Ca(2+)]i changes were blocked by the GABAA-R antagonist bicuculline, suggesting that they result from changes in membrane potential depending on the cell's Cl(-) equilibrium potential. Unexpectedly, bicuculline increased the amplitude and frequency of SCFs in 54 % of CCs, revealing a tonic inhibition of SCFs by ambient GABA acting through GABAA-R. Mecamylamine (a specific nicotinic cholinergic blocker) decreased basal SCF activity in 18 % of CCs and inhibited bicuculline-induced SCF intensification, suggesting that spontaneous acetylcholine (ACh) release from nerve endings contributes to SCF generation in CCs in situ and that blockade of presynaptic GABAA-Rs intensifies SCFs in part through the disinhibition of spontaneous cholinergic transmission. Electrophysiological experiments confirmed that spontaneous excitatory postsynaptic currents recorded from CCs in situ were enhanced by bicuculline. To our knowledge, this is the first description of a regulatory effect of endogenous GABA on synaptic currents and SCFs of adrenal CCs. These findings denote a novel GABA-mediated presynaptic and postsynaptic regulatory mechanism of CC activity which may participate in the control of catecholamine secretion. PMID- 26490459 TI - Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms. AB - Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-alpha (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2 nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N acetyl-beta-D-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain. PMID- 26490461 TI - Measurement of relative Ca2+ permeability during sustained activation of TRPV1 receptors. AB - Some cation permeable ligand-gated ion channels, including the capsaicin sensitive TRPV1, have been reported to exhibit a time-dependent increase in permeability to large inorganic cations during sustained activation, a phenomenon termed "pore dilation." TRPV1 conducts substantial Ca(2+) entry, and it has been suggested that this channel undergoes a time-dependent change in Ca(2+) permeability relative to Na(+) (P Ca/P Na) that parallels pore dilation. However, our experiments employing whole cell patch clamp photometry and single channel recordings to directly measure relative Ca(2+) current in TRPV1 expressing HEK293 cells show that relative Ca(2+) influx remains constant for the duration of capsaicin-evoked channel activation. Further, we present evidence from patch clamp photometry experiments suggesting that sustained activation of Ca(2+) permeable ion channels in the voltage-clamp configuration leads to rapid saturation of the pipette Ca(2+) chelator, and that subsequent observed shifts in the current reversal potentials in the presence of extracellular Ca(2+) are likely due to intracellular accumulation of this ion and a movement of the Ca(2+) equilibrium potential (E Ca) towards zero. Finally, using an adapted reversal potential-based protocol in which cells are only exposed to Ca(2+) after sustained capsaicin exposure in the absence of added extracellular Ca(2+), we demonstrate that the calculated P Ca/P Na is unaffected by duration of TRPV1 activation. In conclusion, we find no evidence in support of a time-dependent change in P Ca/P Na for TRPV1. Our data further urges caution in estimating relative Ca(2+) permeability using reversal potentials, as there is a limited time window in which the cytosolic Ca(2+) chelator included in the patch pipette can prevent localised elevations in cytosolic free Ca(2+) and thus allow for an accurate estimate of this important channel permeability parameter. PMID- 26490460 TI - Moderate inhibition of mitochondrial function augments carotid body hypoxic sensitivity. AB - A functional role for the mitochondria in acute O2 sensing in the carotid body (CB) remains undetermined. Whilst total inhibition of mitochondrial activity causes intense CB stimulation, it is unclear whether this response can be moderated such that graded impairment of oxidative phosphorylation might be a mechanism that sets and modifies the O2 sensitivity of the whole organ. We assessed NADH autofluorescence and [Ca2+]i in freshly dissociated CB type I cells and sensory chemoafferent discharge frequency in an intact CB preparation, in the presence of varying concentrations of nitrite (NO2 -), a mitochondrial nitric oxide (NO) donor and a competitive inhibitor of mitochondrial complex IV. NO2 - increased CB type I cell NADH in a manner that was dose-dependent and rapidly reversible. Similar concentrations of NO2 - raised type I cell [Ca2+]i via L-type channels in a PO2-dependent manner and increased chemoafferent discharge frequency. Moderate inhibition of the CB mitochondria by NO2 - augmented chemoafferent discharge frequency during graded hypoxia, consistent with a heightened CB O2 sensitivity. Furthermore, NO2 - also exaggerated chemoafferent excitation during hypercapnia signifying an increase in CB CO2 sensitivity. These data show that NO2 - can moderate the hypoxia sensitivity of the CB and thus suggest that O2 sensitivity could be set and modified in this organ by interactions between NO and mitochondrial complex IV. PMID- 26490463 TI - Peptide Arrays on Planar Supports. AB - On a past volume of this monograph we have reviewed general aspects of the varied technologies available to generate peptide arrays. Hallmarks in the development of the technology and a main sketch of preparative steps and applications in binding assays were used to walk the reader through details of peptide arrays. In this occasion, we resume from that work and bring in some considerations on quantitative evaluation of measurements as well as on selected reports applying the technology. PMID- 26490464 TI - High-Throughput Microarray Incubations Using Multi-Well Chambers. AB - Peptide microarrays are ideal tools for a variety of applications ranging from epitope mapping to immune monitoring. Here we present a method for high throughput screening of biological samples using only standard microtiter plate equipment. Parallel incubation of a large number of samples with a small library of peptides is enabled by printing multiple identical mini-arrays on one microarray slide and further combining four slides to yield an incubation frame possessing the dimensions of a 96-well microtiter plate. Applying conventional lab equipment such as ELISA washers, hundreds of samples can be processed in 1 day yielding approx. 200 data points in triplicates per sample. PMID- 26490462 TI - An Overview of Neural Differentiation Potential of Human Adipose Derived Stem Cells. AB - There is wide interest in application of adult stem cells due to easy to obtain with a minimal patient discomfort, capable of producing cell numbers in large quantities and their immunocompatible properties without restriction by ethical concerns. Among these stem cells, multipotent mesenchymal stem cells (MSCs) from human adipose tissue are considered as an ideal source for various regenerative medicine. In spite of mesodermal origin of human adipose-derived stem cells (hADSCs), these cells have differentiation potential toward mesodermal and non mesodermal lineages. Up to now, several studies have shown that hADSCs can undergo transdifferentiation and produce cells outside of their lineage, especially into neural cells when they are transferred to a specific cell environment. The purpose of this literature review is to provide an overview of the existing state of knowledge of the differentiation potential of hADSCs, specifically their ability to give rise to neuronal cells. The following review discusses different protocols considered for differentiation of hADSCs to neural cells, the neural markers that are used in each procedure and possible mechanisms that are involved in this differentiation. PMID- 26490465 TI - Analysis of Protein Tyrosine Kinase Specificity Using Positional Scanning Peptide Microarrays. AB - Protein tyrosine kinases phosphorylate their substrates within the context of specific consensus sequences surrounding the site of modification. We describe a peptide microarray approach to rapidly determine tyrosine kinase phosphorylation site motifs. This method uses a peptide library that systematically substitutes each of the amino acid residues at multiple positions surrounding a central tyrosine residue. Peptide substrates are synthesized as biotin conjugates for immobilization on avidin-coated slides. Following incubation of the slide with protein kinase and radiolabeled ATP, the relative extent of phosphorylation of each of the peptides is quantified by phosphor imaging. This method allows small quantities of kinase to be analyzed rapidly in parallel, facilitating analysis of large numbers of kinases. PMID- 26490466 TI - Secondary Structure Determination of Peptides and Proteins After Immobilization. AB - The presentation of immobilized peptides and other small biomolecules attached to surfaces can be greatly affected by the attachment chemistry and linking moieties, resulting in altered activity and specificity. For this reason, it is critical to understand how the various aspects of surface immobilization underlying substrate properties, tether structure, and site of linkage-affect the secondary and quaternary structures of the immobilized species. Here, we present methods for attaching cysteine-containing peptides to quartz surfaces and determining the secondary structure of surface-immobilized peptides. We specifically show that, even when covalently immobilized, changes in peptide conformation can still occur, with measurement occurring in real time. PMID- 26490467 TI - Peptides and Anti-peptide Antibodies for Small and Medium Scale Peptide and Anti peptide Affinity Microarrays: Antigenic Peptide Selection, Immobilization, and Processing. AB - This chapter describes the principles of selection of antigenic peptides for the development of anti-peptide antibodies for use in microarray-based multiplex affinity assays and also with mass-spectrometry detection. The methods described here are mostly applicable to small to medium scale arrays. Although the same principles of peptide selection would be suitable for larger scale arrays (with 100+ features) the actual informatics software and printing methods may well be different. Because of the sheer number of proteins/peptides to be processed and analyzed dedicated software capable of processing all the proteins and an enterprise level array robotics may be necessary for larger scale efforts. This report aims to provide practical advice to those who develop or use arrays with up to ~100 different peptide or protein features. PMID- 26490468 TI - Low-Cost Peptide Microarrays for Mapping Continuous Antibody Epitopes. AB - With the increasing need for understanding antibody specificity in antibody and vaccine research, pepscan assays provide a rapid method for mapping and profiling antibody responses to continuous epitopes. We have developed a relatively low cost method to generate peptide microarray slides for studying antibody binding. Using a setup of an IntavisAG MultiPep RS peptide synthesizer, a Digilab MicroGrid II 600 microarray printer robot, and an InnoScan 1100 AL scanner, the method allows the interrogation of up to 1536 overlapping, alanine-scanning, and mutant peptides derived from the target antigens. Each peptide is tagged with a polyethylene glycol aminooxy terminus to improve peptide solubility, orientation, and conjugation efficiency to the slide surface. PMID- 26490469 TI - The Peptide Microarray-Based Resonance Light Scattering Assay for Sensitively Detecting Intracellular Kinase Activity. AB - The peptide microarray technology is a robust, reliable, and efficient technique for large-scale determination of enzyme activities, and high-throughput profiling of substrate/inhibitor specificities of enzymes. Here, the activities of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) in different cell lysates have been detected by a peptide microarray-based resonance light scattering (RLS) assay with gold nanoparticle (GNP) probes. Highly sensitive detection of PKA activity in 0.1 MUg total cell proteins of SHG-44 (human glioma cell) cell lysate (corresponding to 200 cells) is achieved by a selected peptide substrate. The experimental results also demonstrate that the RLS assay can be employed to evaluate the chemical regulation of intracellular kinase activity. PMID- 26490470 TI - Anomalous Reflection of Gold: A Novel Platform for Biochips. AB - The importance of protein detection system for protein functions analyses in recent post-genomic era is rising with the emergence of label-free protein detection methods. We are focusing on a simple and practical label-free optical detection method called anomalous reflection (AR) of gold. When a molecular layer forms on the gold surface, significant reduction in reflectivity can be observed at wavelengths of 400-500 nm. This allows the detection of molecular interactions by monitoring changes in reflectivity. In this chapter, we describe the AR method with three different application platforms: (1) gold, (2) gold containing alloy/composite (AuAg2O), and (3) metal-insulator-metal (MIM) thin layers. The AuAg2O composite and MIM are implemented as important concepts for signal enhancement process for the AR technique. Moreover, the observed molecular adsorption and activity is aided by a three-dimensional surface geometry, performed using poly(amidoamine) or PAMAM dendrimer modification. The described system is suitable to be used as a platform for high-throughput detection system in a chip format. PMID- 26490471 TI - High-Throughput Peptide Screening on a Bimodal Imprinting Chip Through MS-SPRi Integration. AB - Screening of high affinity and high specificity peptide probes towards various targets is important in the biomedical field while traditional peptide screening procedure is manual and tedious. Herein, a bimodal imprinting microarray system to embrace the whole peptide screening process is presented. Surface Plasmon Resonance imaging (SPRi) and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) are combined for both quantitative and qualitative identification of the peptide. The method provides a solution for high efficiency peptide screening. PMID- 26490472 TI - Analyzing Peptide Microarray Data with the R pepStat Package. AB - In this chapter we demonstrate the use of R Bioconductor packages pepStat and Pviz on a set of paired peptide microarrays generated from vaccine trial data. Data import, background correction, normalization, and summarization techniques are presented. We introduce a sliding mean method for amplifying signal and reducing noise in the data, and show the value of gathering paired samples from subjects. Useful visual summaries are presented, and we introduce a simple method for setting a decision rule for subject/peptide responses that can be used with a set of control peptides or placebo subjects. PMID- 26490473 TI - Chemoselective Strategies to Peptide and Protein Bioprobes Immobilization on Microarray Surfaces. AB - Ordered and reproducible bioprobe immobilization onto sensor surfaces is a critical step in the development of reliable analytical devices. A growing awareness of the impact of the immobilization scheme on the consistency of the generated data is driving the demand for chemoselective approaches to immobilize biofunctional ligands, such as peptides, in a predetermined and uniform fashion. Herein, the most intriguing strategies to selective and oriented peptide immobilization are described and discussed. The aim of the current work is to provide the reader a general picture on recent advances made in this field, highlighting the potential associated with each chemoselective strategy. Case studies are described to provide illustrative examples, and cross-references to more topic-focused and exhaustive reviews are proposed throughout the text. PMID- 26490474 TI - Manufacturing of Peptide Microarrays Based on Catalyst-Free Click Chemistry. AB - Immobilization of peptides to a solid surface is frequently an important first step before they can be probed with a variety of biological samples in a heterogeneous assay format for research and clinical diagnostic purposes. Peptides can be derivatized in many ways to subsequently covalently attach them to an activated solid surface such as epoxy-functionalized glass slides. Here, we describe a clean, efficient, and reproducible fabrication process based on catalyst-free click chemistry compatible with the construction of low- to high density peptide microarrays. PMID- 26490475 TI - Clickable Polymeric Coating for Oriented Peptide Immobilization. AB - A new methodology for the fabrication of an high-performance peptide microarray is reported, combining the higher sensitivity of a layered Si-SiO2 substrate with the oriented immobilization of peptides using a N,N-dimethylacrylamide-based polymeric coating that contains alkyne monomers as functional groups. This clickable polymer allows the oriented attachment of azido-modified peptides via a copper-mediated azide/alkyne cycloaddition. A similar coating that does not contain the alkyne functionality has been used as comparison, to demonstrate the importance of a proper orientation for facilitating the probe recognition and interaction with the target antibody. PMID- 26490476 TI - Oriented Peptide Immobilization on Microspheres. AB - Reproducible immobilization of peptides and proteins on microsphere surfaces is a critical factor for optimal sensitivity and selectivity in bead-based assays. However, peptides with unusually large numbers of lysine residues-whose amines are targeted in the most common microsphere immobilization chemistries-may be particularly challenging to use in bead-based arrays, as they may lose activity through multipoint attachments and incorrect presentation. For this reason, it is imperative to achieve site-directed attachment chemistry, such that a single site of attachment provides reproducibly oriented peptides on the microsphere surface. This can be achieved by inserting a unique targetable residue, such as a cysteine. Here, we present methods for attaching cysteine-containing peptides to standard carboxy-functionalized microsphere surfaces using thiol- rather than amine-directed chemistries. We show that the presence of a cationic detergent (CTAB) and a "passivating" agent such as beta-mercaptoethanol facilitates improved bead recovery after peptide immobilization and may enhance functionality of the attached peptides. PMID- 26490477 TI - A Cell Microarray Format: A Peptide Release System Using a Photo-Cleavable Linker for Cell Toxicity and Cell Uptake Analysis. AB - There has been increasing interest in the potential use of microarray technologies to perform systematic and high-throughput cell-based assays. We are currently focused on developing more practical array formats and detection methods that will enable researchers to conduct more detailed analyses in cell microarray studies. In this chapter, we describe the construction of a novel peptide-array format system for analyzing cellular toxicity and cellular uptake. In this system, a peptide is immobilized at the bottom of a conventional 96-well plate using a photo-cleavable linker. The peptide can then be released from the bottom by irradiating the desired wells with UV light, thus allowing the cytotoxicity or cellular uptake of the peptide to be monitored. This system will facilitate the realization of high-throughput cell arrays for cellomics analyses and cell-based phenotypic drug screens. PMID- 26490478 TI - Peptide Microarrays for Medical Applications in Autoimmunity, Infection, and Cancer. AB - The diversity of the antigen-specific humoral immune response reflects the interaction of the immune system with pathogens and autoantigens. Peptide microarray analysis opens up new perspectives for the use of antibodies as diagnostic biomarkers and provides unique access to a more differentiated serological diagnosis. This review focusses on latest applications of peptide microarrays for the serologic medical diagnosis of autoimmunity, infectious diseases, and cancer. PMID- 26490480 TI - IgE and IgG4 Epitope Mapping of Food Allergens with a Peptide Microarray Immunoassay. AB - Peptide microarrays are a powerful tool to identify linear epitopes of food allergens in a high-throughput manner. The main advantages of the microarray based immunoassay are the possibility to assay thousands of targets simultaneously, the requirement of a low volume of serum, the more robust statistical analysis, and the possibility to test simultaneously several immunoglobulin subclasses. Among them, the last one has a special interest in the field of food allergy, because the development of tolerance to food allergens has been associated with a decrease in IgE and an increase in IgG4 levels against linear epitopes. However, the main limitation to the clinical use of microarray is the automated analysis of the data. Recent studies mapping the linear epitopes of food allergens with peptide microarray immunoassays have identified peptide biomarkers that can be used for early diagnosis of food allergies and to predict their severity or the self-development of tolerance. Using this approach, we have worked on epitope mapping of the two most important food allergens in the Spanish population, cow's milk and chicken eggs. The final aim of these studies is to define subsets of peptides that could be used as biomarkers to improve the diagnosis and prognosis of food allergies. This chapter describes the protocol to produce microarrays using a library of overlapping peptides corresponding to the primary sequences of food allergens and data acquisition and analysis of IgE- and IgG4-binding epitopes. PMID- 26490479 TI - Synthetic Peptide-Based ELISA and ELISpot Assay for Identifying Autoantibody Epitopes. AB - Enzyme-linked immunosorbent assay (ELISA) is an invaluable diagnostic tool to detect serum autoantibody binding to target antigen. To map the autoantigenic epitope(s), overlapping synthetic peptides covering the total sequence of a protein antigen are used. A large set of peptides synthesized on the crown of pins can be tested by Multipin ELISA for fast screening. Next, to validate the results, the candidate epitope peptides are resynthesized by solid-phase synthesis, coupled to ELISA plate directly, or in a biotinylated form, bound to neutravidin-coated surface and the binding of autoantibodies from patients' sera is tested by indirect ELISA. Further, selected epitope peptides can be applied in enzyme-linked immunospot assay to distinguish individual, citrullinated peptide specific autoreactive B cells in a pre-stimulated culture of patients' lymphocytes. PMID- 26490481 TI - IgE Epitope Mapping Using Peptide Microarray Immunoassay. AB - IgE epitope mapping of food allergens contributes to a better understanding of the pathogenesis of food allergy and may become an additional tool for food allergy diagnosis/prognosis. Microarray platforms which allow for simultaneous screening of a large number of peptides corresponding to the sequences of food allergens are ideally suited for large-scale IgE epitope mapping. Here we describe the method of performing a reliable and sensitive peptide microarray immunoassay, which was developed in our lab and results in the identification of candidate IgE epitope biomarkers useful in determining allergic disease severity and prognosis, as well as in the prediction of treatment outcomes. A gastric digestion model that can be applied to prescreen peptides and reduce costs in the peptide microarray is also described in this chapter. PMID- 26490482 TI - Spot Synthesis: An Optimized Microarray to Detect IgE Epitopes. AB - Peptide microarrays have become increasingly more affordable in recent years with the SPOT technique being one of the most frequently used methods for synthesis and screening of peptides in arrays. Here, a protocol is presented for the identification of the amino acid sites involved in the conversion of human IgG to IgE response during the passive administration of therapeutic, anti-snake venom sera. Similarly, the minimal region of both the IgG and IgE binding epitopes, important for its interaction with ligand, were identified. As the ratio of concentrations for IgG to IgE in human serum is 1:10,000, also presented is a reproductive protocol of chemiluminescence-scanning for the detection of both immunoglobulins. PMID- 26490483 TI - Mapping of Epitopes Occurring in Bovine alpha(s1)-Casein Variants by Peptide Microarray Immunoassay. AB - Immunoglobulin E epitope mapping of milk proteins reveals important information about their immunologic properties. Genetic variants of alphaS1-casein, one of the major allergens in bovine milk, are until now not considered when discussing the allergenic potential. Here we describe the complete procedure to assess the allergenicity of alphaS1-casein variants B and C, which are frequent in most breeds, starting from milk with identification and purification of casein variants by isoelectric focusing (IEF) and anion-exchange chromatography, followed by in vitro gastrointestinal digestion of the casein variants, identification of the resulting peptides by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), in silico analysis of the variant-specific peptides as allergenic epitopes, and determination of their IgE-binding properties by microarray immunoassay with cow's milk allergic human sera. PMID- 26490484 TI - Authors' reply to Waldron and Doherty. PMID- 26490486 TI - Photocyclization Reactions of Diarylethenes via the Excited Triplet State. AB - Cyclization reactions of three diarylethene derivatives, 1,2-bis(2-methyl-3 benzothienyl)perfluorocyclopentene (BT), 1,2-bis(2-hexyl-3 benzothienyl)perfluorocyclopentene (BTHex), and 1,2-bis(2-isopropyl-3 benzothienyl)perfluorocyclopentene (BTiPr), via their excited triplet states were studied by means of steady-state and nanosecond transient absorption spectroscopy. The excited triplet states of BT, BTHex, and BTiPr were generated by energy transfer from the photoexcited triplet states of sensitizers such as xanthone, phenanthrene, and pyrene. The single-step quantum yields of the cyclization reactions from the excited triplet states of BT, BTHex, and BTiPr were determined to be 0.34, 0.53, and 0.65, respectively. The triplet energies of these three BTs were estimated to be 190-200 kJ mol(-1). PMID- 26490485 TI - Terminal delirium misdiagnosed as major psychiatric disorder: Palliative care in a psychiatric inpatient unit. AB - BACKGROUND: Delirium is a neuropsychiatric condition characterized by acute change in cognition and disturbance of consciousness. A similar state during the final days of life is termed "terminal delirium." METHOD: We present three cases with end-stage chronic medical problems without any significant psychiatric history who were admitted to an inpatient psychiatric unit or a locked dementia unit for management of "depression," "dementia," or "psychosis." CONCLUSIONS: Early diagnosis of terminal delirium helps prevent patients, family members, and staff from undergoing severe emotional distress and facilitates appropriate end of-life care. PMID- 26490487 TI - Long-term outcomes of patients with intermediate-risk acute myeloid leukemia treated with autologous hematopoietic cell transplant in first complete remission. AB - In 2014, autologous hematopoietic cell transplant (autoHCT) was removed from the National Comprehensive Cancer Network guidelines as a recommended treatment for patients with intermediate-risk AML in first complete remission (CR1). We reviewed the outcomes of all patients with intermediate-risk AML treated with autoHCT in CR1 at our institution. Of 334 patients who underwent autoHCT for AML between 1988 and 2013, 133 patients with intermediate-risk AML in CR1 were identified. Cytogenetics were diploid in 97 (73%). With a median follow-up of 4.1 years (range 0.1-17), median overall survival (OS) is 6.7 years; at 5 years post transplant, 59% of patients remain alive and 43% remain relapse-free. Forty-eight percent of relapsing patients proceeded to salvage alloHCT. Our findings demonstrate that nearly half of patients with intermediate-risk AML in CR1 achieve sustained remissions, and that salvage alloHCT is feasible in those who relapse. AutoHCT therefore remains a reasonable option for intermediate-risk patients with AML in CR1. PMID- 26490488 TI - Improving patient-centered communication: Results of a randomized controlled trial. AB - OBJECTIVE: Patient-centered communication is a key element for improving the quality of care in terms of therapeutic relationship, patient participation, and treatment process. Postgraduate trainings provide an essential way of promoting patient centeredness on the job where learning opportunities are often limited by time, patient volume, and economic pressure. In the present study, changes in patient centeredness during clinical routines of postgraduate physicians (internal medicine) after a three-day communication training were assessed. METHODS: A randomized controlled trial was conducted in a primary care clinic. The intervention consisted of a communication training that aimed to enhance patient centeredness in postgraduate physicians. The training was based on a need assessment and the principles of deliberate practice. Workplace-based assessment of physicians' communication behavior was obtained using the Roter Interaction Analysis System. RESULTS: Three months after the intervention, trained physicians showed significantly increased patient centeredness (F=5.36, p=.04; d=0.42). CONCLUSION: The communication training significantly improved patient centeredness during routine clinical practice. Thus, this training provides a structured and theory-based concept to foster patient centeredness. PRACTICE IMPLICATIONS: The results support the implementation of communication trainings as a part of faculty development and medical specialization training. PMID- 26490490 TI - Clinically amyopathic dermatomyositis: clinical features, response to medications and malignancy-associated risk factors in a specific tertiary-care-centre cohort. AB - BACKGROUND: Clinically amyopathic dermatomyositis (CADM) is a subset of dermatomyositis (DM) characterized by the typical DM cutaneous manifestations but without myositis. There is a relative paucity of characterized cases of CADM in the peer-reviewed medical literature. OBJECTIVES: To characterize the clinical features, response to medications and malignancy-associated risk factors of patients with CADM with available baseline data seen at a single tertiary-care centre. METHODS: A retrospective review was undertaken of 44 patients with CADM with available clinical and serological data prior to onset of treatment. RESULTS: Patients with CADM comprised 18% of all patients with DM with baseline data available at our institution. Although the majority of patients showed improvement with the first prescribed treatment, most required additional medications to control their CADM. Six of 44 patients had an associated malignancy. Photosensitivity and periungual erythema were found to be associated with absence of malignancy (P = 0.03 and P = 0.02, respectively). Patients with malignancy-associated CADM were found to be more likely to have a cutaneous response with the first prescribed treatment than patients without malignancy (P = 0.04). CONCLUSIONS: CADM represents a significant subset of the DM population. As with classic DM, the cutaneous manifestations of CADM often represent a therapeutic challenge. A subset of patients with CADM has underlying malignancies, and these may differ from those typically associated with classic DM. Differences in serological abnormalities, cutaneous manifestations and response to first treatment among patients with CADM with and without malignancy were found, and suggest distinct pathophysiologies among CADM subsets. Characterization of this cohort expands the knowledge about this unique DM subset. PMID- 26490489 TI - 18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease. AB - Identification of patient sub-groups with smoldering multiple myeloma (SMM) at high risk of progression to active disease (MM) is an important goal. 18F-FDG PET/CT (positron emission tomography (PET) integrated with computed tomography (PET/CT) using glucose labelled with the positron-emitting radionuclide (18)F) allows for assessing early skeletal involvement. Identification of osteolytic lesions by this technique has recently been incorporated into the updated International Myeloma Working Group criteria for MM diagnosis. However, no data are available regarding the impact of focal lesions (FLs) without underlying osteolysis on time to progression (TTP) to MM. We hence prospectively studied a cohort of 120 SMM patients with PET/CT. PET/CT was positive in 16% of patients (1 FL: 8, 2 FLs: 3, >3 FLs: 6, diffuse bone marrow involvement: 2). With a median follow-up of 2.2 years, 38% of patients progressed to MM, in a median time of 4 years, including 21% with skeletal involvement. The risk of progression of those with positive PET/CT was 3.00 (95% confidence interval 1.58-5.69, P=0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients. The probability of progression within 2 years was 58% for positive versus 33% for negative patients. In conclusion, PET/CT positivity significantly increased the risk of progression of SMM to MM. PET/CT could become a new tool to define high risk SMM. PMID- 26490491 TI - Inability to match energy intake with energy expenditure at sustained near maximal rates of energy expenditure in older men during a 14-d cycling expedition. AB - BACKGROUND: The upper rates of energy expenditure (EE) and the corresponding regulation of energy intake (EI), as described in younger trained subjects, are not well elucidated in older subjects. OBJECTIVES: The aim was to investigate EE in older men during prolonged cycling and determine whether it is sufficiently matched by EI to maintain energy balance. In addition, we investigated appetite ratings and concentrations of appetite-regulating hormones. DESIGN: Six men (mean +/- SE age: 61 +/- 3 y) completed 2706 km of cycling, from Copenhagen to Nordkapp, in 14 d. EE was measured by using doubly labeled water, and food and drink intake was recorded by the accompanying scientific staff. Energy balance was calculated as the discrepancy between EI and EE and from changes in body energy stores as derived from deuterium dilution. Fasting hormones were measured before and after cycling, and appetite ratings were recorded twice daily. RESULTS: EE (+/-SE) increased from 17 +/- 1 MJ/d before to 30 +/- 2 MJ/d during the cycling trip (P < 0.001), which is equivalent to 4.0 +/- 0.1 times the basal metabolic rate. Although body weight remained stable during the 14 d of cycling, body fat decreased (-2.2 +/- 0.7 kg; P = 0.02) and fat-free mass increased (2.5 +/- 0.6 kg; P = 0.01). EI was 25 +/- 1 MJ/d during cycling, resulting in a negative energy balance calculated by the EE - EI gap (-5.2 +/- 1.2 MJ/d). Calculated from changes in body energy stores, energy balance was also negative ( 4.8 +/- 2.0 MJ/d) during the first week. In the morning and evening, hunger ratings increased (both P = 0.02), whereas ratings of fullness decreased in the evening (P = 0.04). Fasting plasma concentrations of insulin increased by 120% +/ 15% (P = 0.02), glucagon-like peptide 1 (GLP-1) by 60% +/- 20% (P < 0.01), and Polypeptide YY(3-36) by 80% +/- 30% (P < 0.02) after cycling. CONCLUSIONS: Older male cyclists sustained near-maximal rates of EE during prolonged cycling but were unable to upregulate EI to maintain energy balance. Despite the presence of increased motivation to eat, a more profound counteracting physiologic stimulus inhibiting increases in EI was present. This trial was registered at clinicaltrials.gov as NCT02353624. PMID- 26490492 TI - Association of habitual dietary resveratrol exposure with the development of frailty in older age: the Invecchiare in Chianti study. AB - BACKGROUND: Resveratrol may play a protective role against the frailty syndrome (FS) because of its antioxidant and anti-inflammatory properties. OBJECTIVE: We prospectively evaluated the association between habitual dietary resveratrol exposure and the development of FS after 3-, 6-, and 9-y follow-up periods in a community-dwelling older population. DESIGN: We conducted a longitudinal analysis with the use of data from 769 participants aged >=65 y from the Invecchiare in Chianti (Aging in Chianti) study. Total dietary resveratrol (TDR) intake was estimated at baseline with the use of a validated food-frequency questionnaire, which was developed to assess participants' usual food intakes over the previous year, and an ad hoc resveratrol database. Total urinary resveratrol (TUR) was analyzed with the use of liquid chromatography-tandem mass spectrometry with a previous solid-phase extraction at baseline. The combination of both measures [total dietary resveratrol plus total urinary resveratrol (TDR+TUR)] was computed with the use of the Howe's method. FS was assessed at baseline and at 3-, 6-, and 9-y of follow-up and was defined as the presence of >=3 of the following 5 criteria: shrinking, exhaustion, sedentariness, slowness, and weakness. RESULTS: TDR+TUR concentrations were inversely associated with FS risk over 3-y of follow up (OR for comparison of extreme tertiles: 0.11; 95% CI: 0.03, 0.45; P-trend = 0.002) but not after 6- and 9-y of follow-up in multinomial logistic regression models adjusted for baseline frailty status and potential confounders. These results did not differ when analyses were further adjusted for inflammatory markers. CONCLUSION: Higher habitual dietary resveratrol exposure was associated with lower risk of older community dwellers developing FS during the first 3 y of follow-up but not after longer follow-up periods. PMID- 26490493 TI - Adherence to a Mediterranean diet, genetic susceptibility, and progression to advanced macular degeneration: a prospective cohort study. AB - BACKGROUND: Adherence to a Mediterranean-type diet is linked to a lower risk of mortality and chronic disease, but the association with the progression of age related macular degeneration (AMD) and genetic susceptibility is unknown. OBJECTIVE: We examined the association of adherence to the Mediterranean diet and genetic susceptibility with progression to advanced AMD. DESIGN: Among 2525 subjects in the AREDS (Age-Related Eye Disease Study), 1028 eyes progressed to advanced AMD over 13 y. Baseline data for demographic and behavioral covariates were collected by using questionnaires. Dietary data were collected from food frequency questionnaires. The alternate Mediterranean diet (aMeDi) score (range: 0-9) was constructed from individual intakes of vegetables, fruit, legumes, whole grains, nuts, fish, red and processed meats, alcohol, and the ratio of monounsaturated to saturated fats. Ten genetic loci in 7 genes [complement factor H (CFH), age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1 (ARMS2/HTRA1), complement component 2 (C2), complement factor B (CFB), complement component 3 (C3), collagen type VIII alpha 1 (COL8A1), and RAD51 paralog B (RAD51B)] were examined. Survival analysis was used to assess individual eyes for associations between incident AMD and aMeDi score, as well as interaction effects between aMeDi score and genetic variation on risk of AMD. RESULTS: A high aMeDi score (score of 6-9) was significantly associated with a reduced risk of progression to advanced AMD after adjustment for demographic, behavioral, ocular, and genetic covariates (HR: 0.74; 95% CI: 0.61, 0.91; P-trend = 0.007). The aMeDi score was significantly associated with a lower risk of incident advanced AMD among subjects carrying the CFH Y402H nonrisk (T) allele (P trend = 0.0004, P-interaction = 0.04). The aMeDi score was not associated with AMD among subjects who were homozygous for the risk (C) allele. CONCLUSION: Higher adherence to a Mediterranean diet was associated with reduced risk of progression to advanced AMD, which may be modified by genetic susceptibility. This trial was registered at clinicaltrials.gov as NCT00594672. PMID- 26490494 TI - Healthy eating and lower mortality risk in a large cohort of cardiac patients who received state-of-the-art drug treatment. AB - BACKGROUND: Little is known about dietary scores and mortality risk in cardiac patients who are well treated with drugs with attendant relatively low risk of cardiovascular diseases (CVDs). OBJECTIVE: We assessed whether healthy eating lowers the risk of CVD and all-cause mortality in cardiac patients. DESIGN: We included 4307 patients from the Alpha Omega Trial aged 60-80 y with a clinically diagnosed myocardial infarction and monitored mortality for 10 y. Diet was assessed at baseline (2002-2006) with a validated 203-item food-frequency questionnaire. We created 2 dietary scores on the basis of nonoverlapping sets of foods: the Dutch Healthy Nutrient and Food Score (DHNaFS) and the Dutch Undesirable Nutrient and Food Score (DUNaFS). The associations of both dietary scores with CVD and all-cause mortality were assessed by using multivariable adjusted Cox regression models. RESULTS: The median time after myocardial infarction at baseline was 3.7 y (IQR: 1.7-6.3 y). During a median of 6.5 y of follow-up (IQR: 5.3-7.6 y), 801 patients died; 342 of those died of CVD. One patient was lost to follow-up. A substantially higher average amount of DHNaFS foods (~1750 g/d) than DUNaFS foods (~650 g/d) was consumed. Almost all patients received drug treatment: 86% used statins, 90% used antihypertensive medication, and 98% used antithrombotic medication. Patients in the fifth quintile of the DHNaFS had a 30% (HR: 0.70; 95% CI: 0.55, 0.91) lower CVD risk and a 32% (HR: 0.68; 95% CI: 0.47, 0.99) lower all-cause mortality risk than did patients in the first quintile. The DUNaFS was unrelated to both CVD and all-cause mortality. CONCLUSION: Beyond state-of-the-art drug treatment, healthy eating was associated with a lower risk of CVD and all-cause mortality in cardiac patients. This trial was registered at clinicaltrials.gov as NCT00127452. PMID- 26490496 TI - Risk of decline and chance of improvement in olfaction among patients with post traumatic olfactory loss. AB - OBJECTIVE: To evaluate the chance of improvement and risk of decline in olfaction among patients with post-traumatic olfactory loss. METHODS: This study comprised 80 patients. Changes in olfaction were determined using a visual analogue scale and the 'Sniffin' Sticks' test. Logistic regression was used to identify predictors for olfactory changes. RESULTS: Olfactory changes were observed in 9 35 per cent of patients. The rates of improvement and decline according to visual analogue scale scores were 35 per cent and 10 per cent respectively, whereas those in the Sniffin' Sticks test were 9 per cent and 11 per cent respectively. There was a predictive link between non-anosmia and decline in Sniffin' Sticks test scores (odds ratio = 16.61, p = 0.003). A positive correlation was observed between the scores in the first and last examinations (rho = 0.532, p < 0.001). CONCLUSION: Patients should be informed that they may experience an improvement or decline in olfaction following post-traumatic olfactory dysfunction. This study provides evidence to support comprehensive counselling regarding prognosis as an integral part of management strategies. PMID- 26490497 TI - Majoranas with and without a 'character': hybridization, braiding and chiral Majorana number. AB - In this paper we demonstrate under what conditions a pseudo-spin degree of freedom or character can be ascribed to Majorana bound states (MBS). These exotic states can be created at the boundaries of non-interacting systems, corresponding to D, DIII and BDI in the usual classification scheme, and we focus on one dimension. We have found that such a character is directly related to the class of the topological superconductor and its description by a Z, rather than a Zs, invariant which corresponds to the BDI class. We have also found that the DIII case with mirror symmetry, which supports multiple MBS, is in fact equivalent to the BDI class with an additional time-reversal symmetry. In all cases where a character can be given to the Majorana states we show how to construct the appropriate local operator explicitly with various examples. We also examine the consequences of the Majorana character by considering possible hybridization of MBS brought into proximity and find that two MBS with the same character do not hybridize. Finally, we show that having this character or not has no consequence on the braiding properties of MBS. PMID- 26490495 TI - Excessive gestational weight gain is associated with long-term body fat and weight retention at 7 y postpartum in African American and Dominican mothers with underweight, normal, and overweight prepregnancy BMI. AB - BACKGROUND: Excessive gestational weight gain (GWG) is associated with postpartum weight retention (PPWR) and abdominal adiposity, but long-term effects are understudied in low-income and minority populations at high risk of obesity and associated sequelae. OBJECTIVE: We examined associations between GWG and long term PPWR and adiposity in a prospective cohort of African American and Dominican mothers in the Bronx and Northern Manhattan. DESIGN: Women (n = 302) were enrolled during pregnancy and were followed for 7 y postpartum. Linear regression was used to relate excessive GWG [greater than 2009 Institute of Medicine (IOM) guidelines] to outcomes [percentage body fat and long-term PPWR (change in weight from prepregnancy to 7 y postpartum)], adjusting for covariates and included an interaction term between prepregnancy body mass index (BMI; in kg/m(2)) and GWG. RESULTS: Mean +/- SD prepregnancy BMI and total GWG were 25.6 +/- 5.8 (42% of women had BMI >=25) and 16.6 +/- 7.8 kg (64% of women had total GWG greater than IOM guidelines), respectively. Associations between GWG and long-term PPWR and the percentage body fat varied by prepregnancy BMI (P-interaction <= 0.06); excessive GWG was associated with a higher percentage body fat and greater long term PPWR in mothers with lower prepregnancy BMI. To illustrate the interaction, a predicted covariate-adjusted model, which was used to derive estimates for the percentage body fat and PPWR associated with excessive GWG, was estimated for 2 prepregnancy BMI examples. For a woman with prepregnancy BMI of 22, excessive GWG was associated with 3.0% higher body fat (P < 0.001) and a 5.6-kg higher PPWR (P < 0.001); however, for a woman with a prepregnancy BMI of 30, excessive GWG was associated with 0.58% higher body fat (P = 0.55) and 2.06 kg PPWR (P = 0.24). CONCLUSIONS: Long-term adiposity and PPWR in low-income African American and Dominican mothers were predicted by interacting effects of prepregnancy BMI and excessive GWG. The provision of support for mothers to begin pregnancy at a healthy weight and to gain weight appropriately during pregnancy may have important lasting implications for weight-related health in this population. This study was registered at clinicaltrials.gov as NCT00043498. PMID- 26490499 TI - Cyclic enaminones. Part II: applications as versatile intermediates in alkaloid synthesis. AB - Among many other strategies, the enaminone approach is an important strategy to construct and diversify the azacyclic core in various alkaloids syntheses. In this brief review we discuss the application of cyclic enaminones as building blocks, as well as potential intermediates in the total synthesis of selected alkaloids. PMID- 26490498 TI - Sildenafil in Term and Premature Infants: A Systematic Review. AB - PURPOSE: Numerous medications are used off-label in term and premature infants, with limited safety or efficacy data. Although sildenafil is approved by the US Food and Drug Administration for the treatment of pulmonary hypertension in adults, it is not approved for use in children. However, sildenafil use in term and premature infants with pulmonary hypertension is increasing. The goal of this study was to review controlled trials evaluating the efficacy of sildenafil use in: (1) term infants with pulmonary hypertension; (2) premature infants at risk for developing bronchopulmonary dysplasia (BPD); and (3) premature infants with BPD-associated pulmonary hypertension. METHODS: MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts databases were searched for citations related to sildenafil use in term or near term infants with pulmonary hypertension or premature infants at risk for BPD or with BPD-associated pulmonary hypertension. Randomized and nonrandomized controlled trials were searched for that evaluated sildenafil use in term and premature infants compared with placebo or inhaled nitric oxide alone. Included studies were limited to English or Spanish language. Risk of bias was determined by using the Cochrane risk of bias tool. FINDINGS: Five trials (4 full-text articles and 1 abstract) of the 802 screened citations met the criteria for inclusion. All 5 trials were randomized controlled trials; the largest had 51 participants. Four of the trials (with a total of 137 subjects) evaluated the use of sildenafil versus placebo for term or near-term infants with persistent pulmonary hypertension of the newborn in low-resource settings in which inhaled nitric oxide was unavailable; there were no trials of sildenafil in areas in which inhaled nitric oxide is routinely available. The trials showed improvements in oxygenation index and a reduction in mortality in the sildenafil groups (5.9% vs 44%). One trial evaluated early sildenafil use (after day 7 of life) in premature infants for the prevention of BPD (n = 20). More premature infants in the sildenafil group died, were exposed to postnatal steroids, and had higher right-sided ventricular pressures later during hospitalization; these differences were not statistically significant. No trials evaluated sildenafil versus placebo in premature infants with BPD-associated pulmonary hypertension. IMPLICATIONS: There is currently little evidence to support the use of sildenafil in term or near-term infants with persistent pulmonary hypertension of the newborn in areas in which inhaled nitric oxide is available. More data are needed to determine the effectiveness and dosing of sildenafil in improving outcomes for term and premature infants. Sildenafil dosing and safety studies are needed, especially among premature infants, before efficacy trials are performed. PMID- 26490500 TI - Cor triatriatum sinistrum with pulmonary vein atresia. PMID- 26490501 TI - Trauma induced myocardial infarction. AB - Chest Trauma in athletes is a common health problem. However, myocardial infarction secondary to coronary dissection in the setting of blunt chest trauma is extremely rare. We report a case of acute inferior wall myocardial infarction following blunt chest trauma. A 32-year-old male with no relevant medical problems was transferred to our medical center for retrosternal chest pain after being elbowed in the chest during a soccer game. Few seconds later, he started experiencing sharp retrosternal chest pain that was severe to that point where he called the emergency medical service. Upon arrival to the trauma department patient was still complaining of chest pain. ECG demonstrated ST segment elevation in the inferior leads with reciprocal changes in the lateral leads all consistent with active ischemia. After rolling out aortic dissection, patient was loaded with ASA, ticagerlor, heparin and was emergently taken to the cardiac catheterization lab. Coronary angiography demonstrated 100% thrombotic occlusion in the distal right coronary artery with TIMI 0 flow distally. After thrombus aspiration, a focal dissection was noted on the angiogram that was successfully stented. Two days after admission patient was discharged home. Echocardiography prior to discharge showed inferior wall akinesis, normal right ventricular systolic function and normal overall ejection fraction. PMID- 26490502 TI - An update on atrial fibrillation in 2014: From pathophysiology to treatment. AB - Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia. The trigger for initiation of AF is generally an enhanced vulnerability of pulmonary vein cardiomyocyte sleeves to either focal or re-entrant activity. The maintenance of AF is based on a "driver" mechanism in a vulnerable substrate. Cardiac mapping technology is providing further insight into these extremely dynamic processes. AF can lead to electrophysiological and structural remodelling, thereby promoting the condition. The management includes prevention of stroke by oral anticoagulation or left atrial appendage (LAA) occlusion, upstream therapy of concomitant conditions, and symptomatic improvement using rate control and/or rhythm control. Nonpharmacological strategies include electrical cardioversion and catheter ablation. There are substantial geographical variations in the management of AF, though European data indicate that 80% of patients receive adequate anticoagulation and 79% adequate rate control. High rates of morbidity and mortality weigh against perceived difficulties in management. Clinical research and growing experience are helping refine clinical indications and provide better technical approaches. Active research in cardiac electrophysiology is producing new antiarrhythmic agents that are reaching the experimental clinical arena, inhibiting novel ion channels. Future research should give better understanding of the underlying aetiology of AF and identification of drug targets, to help the move toward patient-specific therapy. PMID- 26490503 TI - Web-based Gene Pathogenicity Analysis (WGPA): a web platform to interpret gene pathogenicity from personal genome data. AB - As the volume of patient-specific genome sequences increases the focus of biomedical research is switching from the detection of disease-mutations to their interpretation. To this end a number of techniques have been developed that use mutation data collected within a population to predict whether individual genes are likely to be disease-causing or not. As both sequence data and associated analysis tools proliferate, it becomes increasingly difficult for the community to make sense of these data and their implications. Moreover, no single analysis tool is likely to capture all relevant genomic features that contribute to the gene's pathogenicity. Here, we introduce Web-based Gene Pathogenicity Analysis (WGPA), a web-based tool to analyze genes impacted by mutations and rank them through the integration of existing prioritization tools, which assess different aspects of gene pathogenicity using population-level sequence data. Additionally, to explore the polygenic contribution of mutations to disease, WGPA implements gene set enrichment analysis to prioritize disease-causing genes and gene interaction networks, therefore providing a comprehensive annotation of personal genomes data in disease. AVAILABILITY AND IMPLEMENTATION: wgpa.systems genetics.net. PMID- 26490504 TI - An algorithm to detect and communicate the differences in computational models describing biological systems. AB - MOTIVATION: Repositories support the reuse of models and ensure transparency about results in publications linked to those models. With thousands of models available in repositories, such as the BioModels database or the Physiome Model Repository, a framework to track the differences between models and their versions is essential to compare and combine models. Difference detection not only allows users to study the history of models but also helps in the detection of errors and inconsistencies. Existing repositories lack algorithms to track a model's development over time. RESULTS: Focusing on SBML and CellML, we present an algorithm to accurately detect and describe differences between coexisting versions of a model with respect to (i) the models' encoding, (ii) the structure of biological networks and (iii) mathematical expressions. This algorithm is implemented in a comprehensive and open source library called BiVeS. BiVeS helps to identify and characterize changes in computational models and thereby contributes to the documentation of a model's history. Our work facilitates the reuse and extension of existing models and supports collaborative modelling. Finally, it contributes to better reproducibility of modelling results and to the challenge of model provenance. AVAILABILITY AND IMPLEMENTATION: The workflow described in this article is implemented in BiVeS. BiVeS is freely available as source code and binary from sems.uni-rostock.de. The web interface BudHat demonstrates the capabilities of BiVeS at budhat.sems.uni-rostock.de. PMID- 26490506 TI - Predicting Rape Victim Empathy Based on Rape Victimization and Acknowledgment Labeling. AB - Two studies examined rape victim empathy based on personal rape victimization and acknowledgment labeling. Female undergraduates (Study 1, n = 267; Study 2, n = 381) from a Northeast U.S. midsize public university completed the Rape-Victim Empathy Scale and Sexual Experiences Survey. As predicted, both studies found that acknowledged "rape" victims reported greater empathy than unacknowledged victims and nonvictims. Unexpectedly, these latter two groups did not differ. Study 1 also found that acknowledged "rape" victims reported greater empathy than victims who acknowledged being "sexually victimized." Findings suggest that being raped and acknowledging "rape" together may facilitate rape victim empathy. PMID- 26490505 TI - Protective Efficacy and Mechanism of Passive Immunization with Polyclonal Antibodies in a Sepsis Model of Staphylococcus aureus Infection. AB - Staphylococcus aureus (S. aureus) is an opportunistic bacterial pathogen responsible for a diverse spectrum of human diseases, resulting in considerable yearly mortality rates. Due to its rapid acquisition of antibiotic resistance, it becomes increasingly difficult to cure S. aureus infections with conventional antibiotics. Immunotherapy represents a promising alternative strategy to prevent and/or treat the infection. In the present study, passive immunization with polyclonal antibodies targeting three possible S. aureus antigens, Hla, SEB and MntC (termed "SAvac-pcAb") after challenge with lethal dose of S. aureus resulted in reduced bacterial loads, inflammatory cell infiltration and decreased pathology, and was able to provide nearly complete protection in a murine sepsis model. In vitro studies confirmed the direct interaction of SAvac-pcAb with S. aureus bacteria. Additional studies validated that SAvac-pcAb contained both opsonic and neutralizing antibodies that contributed to its protective efficacy. The former mediated opsonophagocytosis in a neutrophil-dependent manner, while the later inhibited the biological functions of Hla and SEB, two major virulence factors secreted by S. aureus. Critically, we demonstrated that SAvac-pcAb was cross-reactive with different clinical strains of S. aureus. These results confirmed the efficacy for treatment of S. aureus infection by passive immunization as an important therapeutic option. PMID- 26490507 TI - "It Gave Me My Life Back": An Evaluation of a Specialist Legal Domestic Abuse Service. AB - Community-based advocacy services are important in enabling victims to escape domestic abuse and rebuild their lives. This study evaluated a domestic abuse service. Two phases of research were conducted following case-file analysis (n = 86): surveys (n = 22) and interviews (n = 12) with victims, and interviews with key individuals (n = 12) based in related statutory and community organizations. The findings revealed the holistic model of legal, practical, mental health related, and advocacy components resulted in a range of benefits to victims and enhanced interagency partnership working. Core elements of a successful needs led, victim-centered service could be distilled. PMID- 26490508 TI - Substolides A-G, germacrane sesquiterpenoids from Salvia substolonifera. AB - Chemical investigation of the whole plants of Salvia substolonifera E.Peter yielded seven germacrane sesquiterpenoids, substolides A-G (1-7), an ethoxylated artifact (8), and two known analogues, 6beta-tigloyloxyglechomafuran (9) and castanin F (10). Four germacrane 8-acetylation derivatives (1a-4a) were obtained by chemical transformation. Their structures and relative or absolute configurations were elucidated by intensive spectroscopic methods, and single crystal X-ray diffraction analysis. Compounds 1a-4a, and 5-10 were evaluated for their in vitro anti-angiogenic effects. Compounds 7 and 9 significantly inhibited VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation in vitro, with IC50 values of 16.15 +/- 0.19, and 4.03 +/- 0.26 MUM, respectively. The structure activity relationship of these compounds is discussed. PMID- 26490510 TI - Violent injuries and regional correlates among women in China: results from 21 cities study in China. AB - BACKGROUND: Ecological models depict violent injuries against women being influenced by both individual and environmental characteristics. However, only few studies examined the association between regional variables and the likelihood of violent injuries. Our study is a preliminary assessment of the impact of regional variables on the likelihood that a woman has experienced violent injuries. METHODS: Participants were 16 866 urban residents, who were identified through a multi-stage sampling process conducted in 21 Chinese cities. Out of the sampled population, 8071 respondents were female. Subsequent analyses focused solely on the female sample. Multilevel logistic regression analyses were performed to examine regional variation in violent injuries. RESULTS: Prevalence of violent injuries against women is 10.7% (95% CI: 7.8%, 15.5%). After controlling for individual-level characteristics, higher regional male-female ratio (OR: 1.97, P < 0.05), population growth rate (OR: 4.12, P < 0.01) and unemployment rate (OR: 2.45, P < 0.01) were all associated with an elevated risk of violent injuries among Chinese women caused by physical attack. CONCLUSIONS: The results suggest violent injuries among Chinese women caused by physical attack have become an important social and public health problem. The findings point to the importance of developing effective health policies, laws and interventions that focuses on the unequal economic development between different regions. PMID- 26490511 TI - Relative deprivation in the Nordic countries-child mental health problems in relation to parental financial stress. AB - BACKGROUND: The Nordic welfare system has been acknowledged as favourable for children, successfully contributing to low child mortality and poverty rates. Nevertheless, mental health problems among children and adolescents are common and the economic situation of the family has been highlighted as an important determinant. In spite of similar social, political and cultural structures, the Nordic countries differ; Iceland was most affected by the global financial crisis in 2008. The aim of this study was to examine potential differences in parental financial stress and the associations to child mental health between the Nordic countries as well as age and gender differences. METHODS: The study sample consisted of 6330 children aged 4-16 years old included in the 2011 version of the Nordic Study of Children's Health, Wellbeing and Quality of life. The Strengths and Difficulties Questionnaire was used to measure mental health problems. RESULTS: In Iceland, 47.7% of the parents reported financial stress while <=20% did so in the other countries except for Finland (33.5%). However, in case of parental financial stress the OR of mental health problems comparing children to parents with and without financial stress was significantly lower among the Icelandic children (OR 1.60, 95% CI 1.15-2.24) than among the others: Denmark OR 3.07 (95% CI 2.15-4.39), Finland OR 2.28 (95% CI 1.60-3.25), Norway OR 2.77 (95% CI 1.86-4.12), Sweden OR 3.31(95% CI 2.26-4.86). No significant age or gender differences in the ORs were observed. CONCLUSIONS: Besides socioeconomic situation, relative deprivation should be considered an important determinant of child mental health. PMID- 26490509 TI - Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters. AB - The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liver-derived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD. PMID- 26490512 TI - Prototype of a primary calibration system for measurement of radon activity concentration. AB - To calibrate measurement devices for monitoring the activity concentration of (222)Rn in air, a prototype of a calibration facility is tested using a solid (226)Ra source and a high-purity germanium (HPGe) detector. An emanation box was mounted on the detector for online gamma measurements. Inside this box, a 32.8 kBq +/-3% (226)Ra standard source was placed. An AlphaGUARD control radon monitor was connected to the emanation box with a pumping air system in an open flow mode as a reference monitor. The emanation coefficient of the source was controlled online by comparing the gamma activity of (214)Bi (Egamma=609.3 keV), progeny of (226)Ra, to that of the calibration source. A standard (137)Cs source, installed within the emanation box, was used as a reference for gamma spectroscopy using the HPGe detector, with a total systematic error of 4% and a random error less than 2%. The ratio between gamma measurements and AlphaGUARD was 0.94+/-0.4; which is within the 9% uncertainties of AlphaGUARD calibration. PMID- 26490513 TI - Burden and direct costs of non infectious uveitis in Spain. AB - OBJECTIVES: There is no updated information on epidemiology and cost of management of non infectious uveitis (NIU) in Spain. This study assessed the frequency of various types of uveitis as well as associated costs of resources used in their management. MATERIAL AND METHOD: NIU epidemiological data and direct costs were collected from a literature search. This was complemented with consensus information from 2 expert panel meetings and data from questionnaires to ophthalmologists and rheumatologists, experts on these conditions. Healthcare resources costs were obtained from the Oblikue database, from a medical society and from approved drug prices in Spain. RESULTS: During 2011 the estimate number of NIU was 9,398 (45% male, 70% aged 16-65 years). Incidence per type of uveitis was: acute anterior uveitis (AAU) 55%; posterior uveitis (PU) and pan-uveitis (PanU) 15% each; adult chronic anterior uveitis, paediatric chronic anterior uveitis and intermediate uveitis 5% each. Among total costs (77,834,282.10?), initial drug therapy was the highest (43,602,359.29?), followed by surgical treatment of complications (8,367,420.43?). With respect to types of uveitis, PanU (26,692,948.29?), PU (22,283,330.50?) and AAU (14,336,755.38?) showed the highest associated costs. CONCLUSIONS: Non infectious uveitis is associated to high costs in Spain, both in its diagnosis and in its treatment. Early diagnosis and treatment should allow for substantial savings for the National Health System. PMID- 26490515 TI - We are more selfish than we think: The endowment effect and reward processing within the human medial-frontal cortex. AB - Perceived ownership has been shown to impact a variety of cognitive processes: attention, memory, and--more recently--reward processing. In the present experiment we examined whether or not perceived ownership would interact with the construct of value-the relative worth of an object. Participants completed a simple gambling game in which they gambled either for themselves or for another while electroencephalographic data were recorded. In a key manipulation, gambles for oneself or for another were for either small or large rewards. We tested the hypothesis that value affects the neural response to self-gamble outcomes, but not other-gamble outcomes. Our experimental data revealed that while participants learned the correct response option for both self and other gambles, the reward positivity evoked by wins was impacted by value only when gambling for oneself. Importantly, our findings provide additional evidence for a self-ownership bias in cognitive processing and further demonstrate the insensitivity of the medial frontal reward system to gambles for another. PMID- 26490516 TI - Combination of CD157 and FLAER to Detect Peripheral Blood Eosinophils by Multiparameter Flow Cytometry. AB - The identification of eosinophils by flow cytometry is difficult because most of the surface antigens expressed by eosinophils are shared with neutrophils. Some methods have been proposed, generally based on differential light scatter properties, enhanced autofluorescence, lack of CD16 or selective positivity of CD52. Such methods, however, show several limitations. In the present study we report a novel method based on the analysis of glycosylphosphatidylinositol (GPI) linked molecules. The combination of CD157 and FLAER was used, since FLAER recognizes all GPI-linked molecules, while CD157 is absent on the membrane of eosinophils and expressed by neutrophils. Peripheral blood samples from normal subjects and patients with variable percentages of eosinophils (n = 31), and without any evidence for circulating immature myeloid cells, were stained with the combination of FLAER-Alexa Fluor and CD157-PE. A FascCanto II cytometer was used. Granulocytes were gated after CD33 staining and eosinophils were identified as CD157(-)/FLAER(+) events. Neutrophils were identified as CD157(+)/FLAER(+) events. The percentages of eosinophils detected by this method showed a very significant correlation both with automated counting and with manual counting (r = 0.981 and 0.989, respectively). Sorting assays were carried out by a S3 Cell Sorter: cytospins obtained from CD157(-)/FLAER(+) events consisted of 100% eosinophils, while samples from CD157(+)/FLAER(+) events were represented only by neutrophils. In conclusion, this method shows high sensitivity and specificity in order to distinguish eosinophils from neutrophils by flow cytometry. However, since CD157 is gradually up-regulated throughout bone marrow myeloid maturation, our method cannot be applied to cases characterized by immature myeloid cells. PMID- 26490517 TI - Follicular Dendritic Cell Meshwork in Angioimmunoblastic T-Cell Lymphoma Is Characterized by Accumulation of CXCL13(+) Cells. AB - Angioimmunoblastic T-cell lymphoma (AITL) is considered to originate from follicular helper T (TFH) cells. Currently, neoplastic cells in AITL are considered to express CXCL13 as a tumor marker. However, the identification of CXCL13(+) cells remains unclear in terms of whether they are neoplastic cells (or TFH cells) or follicular dendritic cells (FDCs) in both AITL and normal germinal centers. Therefore, the exact identification of CXCL13(+) cells was performed using 33 cases of AITL and normal germinal centers. Single-labeling immunohistochemistry and double-labeling immunofluorescent microscopy first confirmed that CXCL13 was expressed mainly in FDCs in the normal germinal centers. In 28 of 33 AITL cases, CXCL13 was expressed mainly in FDCs as a meshwork pattern, which was associated with CXCL13(+) neoplastic cells. In the other five cases, CXCL13 was expressed mainly in neoplastic cells, which were densely distributed in and around the FDC meshwork. These findings indicate the abundance of CXCL13(+) cells in the FDC meshwork irrespective of the cell type. Triple-labeling immunofluorescent microscopy showed that the CXCL13(+) FDC meshwork in AITL harbored both neoplastic cells and B cells. CXCR5, the cognate receptor of CXCL13, was expressed in neoplastic cells in AITL. The present study suggests that neoplastic cells in AITL preserve a certain level of TFH-cell function since neoplastic cells and B cells are closely enmeshed in the CXCL13(+) cell-rich FDC meshwork in a similar way as in normal germinal centers. PMID- 26490514 TI - The influence of cancer tissue sampling on the identification of cancer characteristics. AB - Cancer tissue sampling affects the identification of cancer characteristics. We aimed to clarify the source of differentially expressed genes (DEGs) in macro dissected cancer tissue and develop a robust prognostic signature against the effects of tissue sampling. For estrogen receptor (ER)+ breast cancer patients, we identified DEGs in macro-dissected cancer tissues, malignant epithelial cells and stromal cells, defined as Macro-Dissected-DEGs, Epithelial-DEGs and Stromal DEGs, respectively. Comparing Epithelial-DEGs to Stromal-DEGs (false discovery rate (FDR) < 10%), 86% of the overlapping genes exhibited consistent dysregulation (defined as Consistent-DEGs), and the other 14% of genes were dysregulated inconsistently (defined as Inconsistent-DEGs). The consistency score of dysregulation directions between Macro-Dissected-DEGs and Consistent-DEGs was 91% (P-value < 2.2 * 10(-16), binomial test), whereas the score was only 52% between Macro-Dissected-DEGs and Inconsistent-DEGs (P-value = 0.9, binomial test). Among the gene ontology (GO) terms significantly enriched in Macro Dissected-DEGs (FDR < 10%), 18 immune-related terms were enriched in Inconsistent DEGs. DEGs associated with proliferation could reflect common changes of malignant epithelial and stromal cells; DEGs associated with immune functions are sensitive to the percentage of malignant epithelial cells in macro-dissected tissues. A prognostic signature which was insensitive to the cellular composition of macro-dissected tissues was developed and validated for ER+ breast patients. PMID- 26490518 TI - Persistent Hypoplastic Acute Promyelocytic Leukemia with a Novel Chromosomal Abnormality of 46, XY, t(15;17), t(9;11)(q13;p13). AB - A diagnosis of acute promyelocytic leukemia (APL) is usually made when normal hematopoietic cells are substituted by APL cells. We encountered a unique APL patient who presented with persistent hypoplastic features of APL. An 84-year-old man presented with leukopenia (2.2 * 10(9)/L) and anemia (Hb 12.5 g/dL). Five months later, the bone marrow (BM) was hypoplastic with a normal proportion of blasts and promyelocytes (5.2%), although the latter cells were hypergranular. The karyotype of BM cells was 46, XY, t(15;17)(q22;q12), t(9;11)(q13;p13). Two months later, the BM remained hypoplastic with 8.5% hypergranular promyelocytes, some of which contained faggot of Auer rods. RT-PCR examination yielded the PML RARalpha transcript, and its sequencing revealed the breakpoint of PML to be bcr2. The patient was treated with all-trans retinoic acid under a diagnosis of APL with improvement of the bicytopenia. FISH analysis of BM cells yielded a negative result regarding t(15;17), although RT-PCR was positive for PML-RARalpha mRNA. Six months later, APL recurred with the same karyotypic abnormalities and therapeutic resistance, and the patient died of pneumonia. A persistent hypoplastic state of APL may be a rare event, and the association of t(15;17) and t(9;11) is novel. PMID- 26490519 TI - Modifications in B-Lymphocyte Number and Phenotype in the Course of Pregnancy in a Woman with Persistent Polyclonal B-Cell Lymphocytosis: A Flow Cytometric Study. AB - Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare clinical condition, characterized by a persistent, generally moderate lymphocytosis, generally due to stimulation of central memory B-lymphocytes, and by a moderate increase of polyclonal IgM. In some patients, slight or moderate splenomegaly is observed. A variable percentage of circulating, bone marrow and splenic lymphocytes display an abnormal nucleus (generally bilobated) or are binucleated. The clinical course is benign in most cases and transformation into splenic B-cell lymphoma occurs in few cases. In the current paper we report the first case of pregnancy in PPBL. Our patient became pregnant 18 months after diagnosis. In the course of pregnancy, a marked down-regulation of lymphocytosis (from 6 * 10(9)/L to 2.1 * 10(9)/L) and a decrease in B-lymphocyte number was observed (from 3.6 * 10(9)/L to 1 * 10(9)/L), mainly due to a marked reduction in the percentage and absolute number of central memory B-cells. Such modifications were similar to those described in normal pregnant women. One year after the delivery of a healthy female baby, the number of total lymphocytes and B-lymphocytes showed an inverse behavior, with a new expansion of central memory B-cells. Our case shows that a normal pregnancy can occur in patients with PPBL and that pregnancy can induce marked modifications in B-lymphocyte kinetics and phenotype. PMID- 26490520 TI - Rituximab Monotherapy and Rituximab-Containing Chemotherapy Were Effective for Paraneoplastic Pemphigus Accompanying Follicular Lymphoma, but not for Subsequent Bronchiolitis Obliterans. AB - A 60-year-old male patient suffered from mild exertional dyspnea, wheezing, and systemic blisters. He was diagnosed with paraneoplastic pemphigus (PNP) with follicular lymphoma in the pancreas head and pelvic cavity. He was first treated with eight cycles of rituximab; his blisters and erosions gradually improved and highly elevated levels of auto-antibodies related to PNP gradually decreased to normal levels. However, obstructive and restrictive respiratory failure still progressed. Computed tomography of the inspiratory and expiratory phases revealed obstructive pulmonary disorder, leading to a diagnosis of bronchiolitis obliterans (BO). The patient underwent plasma exchange and was repeatedly treated with rituximab monotherapy and rituximab-containing chemotherapies, but died 7 months after the diagnosis of BO. Early introduction of rituximab-containing regimens may be necessary to prevent the development of BO accompanying PNP. However, when a diagnosis of PNP-related BO is made, lung transplantation may also be considered for patients in whom rituximab-containing regimens are effective for PNP. PMID- 26490521 TI - Successful Secondary Umbilical Cord Blood Transplantation for Graft Failure in Acute Myelogenous Leukemia, Treated with Modified One-Day Conditioning Regimen, and Graft-Versus-Host Disease Prophylaxis Consisting of Mycophenolate and Tacrolimus. AB - Although graft failure (GF) is a fatal and life-threatening complication of umbilical cord blood transplantation (CBT), the standard treatment has not been established. We describe the case of a 28-year-old man diagnosed with acute myelogenous leukemia with myelodysplasia-related changes harboring a normal karyotype. This patient underwent 2 courses of idarubicin and cytosine arabinose therapy, and 3 courses of high-dose cytosine arabinose therapy. Subsequently, he underwent high-dose chemotherapy (total body irradiation and cyclophosphamide) followed by first CBT. Primary GF occurred after post-immunological reaction and hemophagocytic lymphohistiocytosis, and was diagnosed on day 27 after the first CBT. Therefore, the patient underwent secondary CBT for GF treated with a modified one-day conditioning regimen consisting of fludarabine (30 mg/m(2), 3 days), cyclophosphamide (2 g/m(2)), and total body irradiation (2 Gy), and graft versus-host disease prophylaxis consisting of mycophenolate and tacrolimus. Consequently, the patient achieved neutrophil engraftment on day 17 after the second CBT. During the clinical course of the second CBT, the main complications were sepsis, BK virus-associated cystitis, and acute graft-versus-host disease (skin, grade 2, stage 3). After these treatments, the patient was disease-free for 39 months. Our case suggests that these treatments may be feasible, safe, and effective for the treatment of patients with GF. This case study may be helpful to physicians who directly care for GF patients, and may provide a future direction for a more efficient treatment modality. PMID- 26490522 TI - Marked Thrombocytosis in Chronic Eosinophilic Pneumonia and Analysis of Cytokine Mechanism. AB - A 47-year-old woman with marked thrombocytosis of 1,650 * 10(9)/L was diagnosed with chronic eosinophilic pneumonia (CEP) based on imaging of the lung and abundant eosinophils in bronchoalveolar lavage fluid. Known gene abnormalities that cause eosinophilia were not detected in bone marrow cells. Treatment with oral prednisolone at 20 mg/day relieved the CEP and resolved the laboratory abnormalities, including eosinophilia and thrombocytosis. Serum concentrations of interleukin (IL)-5 and IL-6 were elevated to 9.6 and 14.0 pg/mL, respectively. The megakaryocyte-potentiating activity of IL-6 and possibly, that of IL-1beta, which is known to be secreted by activated eosinophils, may have caused the marked thrombocytosis in this patient. PMID- 26490523 TI - Multicentric Castleman Disease with Monoclonal Incomplete IgH Restriction: A Rare Coexistence. AB - Castleman disease is a rare lymphoproliferative disorder that may have a unicentric or multicentric clinical presentation. Herein we present the case of a 49-year-old female with a 3-year history of progressively worsening lymphadenopathy associated with fevers, chills and night sweats. Laboratory studies showed anemia and mildly elevated sedimentation rate. A computed tomogram scan of the chest, abdomen and pelvis showed multiple enlarged bilateral axillary, supraclavicular, subpectoral, submental, retroperitoneal, and para aortic lymph nodes. A right axillary lymph node biopsy was performed and found to display histopathologic features compatible with the plasma cell type of Castleman disease. The patient was found to be human immunodeficiency virus (HIV) positive, with a viral load of 104,000/mL and a CD4 cell count of 84 cells/mm(3). Molecular studies on the lymph node specimen revealed an incomplete monoclonal DH JH rearrangement in the IgH gene. The patient was initially treated with antiretroviral therapy with a combination of elvitegravir, cobicistat, emtricitabine and tenofovir that improved her fatigue and malaise. As treatment for Castleman disease, she was administered a combination of rituximab and etoposide, which led to a reduction in lymphadenopathy. To the best of the authors' knowledge, this is the first reported case of multicentric Castleman disease with monoclonal incomplete IgH gene rearrangement in an HIV-positive patient. PMID- 26490524 TI - Gradually-Deteriorating Liver Function due to Iron Overload Over Four Years after Allogeneic Stem Cell Transplantation. AB - In allogeneic hematopoietic stem cell transplantation (allo-SCT) recipients with liver dysfunction, it is often difficult to determine the cause. Several cases of liver dysfunction may be interpreted as chronic graft versus host disease without a definitive diagnosis, resulting in continued immunosuppressive therapy for longer periods. Allo-SCT recipients commonly require frequent red blood cell transfusions during the course of treatment and transplantation, leading to significant iron overload, which could be one of causes of liver dysfunction. Here we report an allo-SCT recipient with chronic deteriorating liver dysfunction due to iron overload, despite maintaining transfusion independence for more than four years. Using magnetic resonance-based liver iron concentration (MR-LIC), iron overload-related liver dysfunction was diagnosed. It drastically improved with monthly phlebotomy and has not recurred following its termination. The observations from our case suggested that iron overload should be recognized as a cause of chronic liver dysfunction even in patients who remain transfusion independent for several years and that MR-LIC analysis is a useful and reliable method for detecting iron overload and monitoring the effect of iron-reduction therapy. PMID- 26490525 TI - Successful Treatment of Bing-Neel Syndrome Accompanying Waldenstrom's Macroglobulinemia with R-MPV: A Case Report. AB - Waldenstrom's macroglobulinemia (WM) is a neoplasm of lymphoplasmacytic cells that produces monoclonal IgM protein. Although hyperviscosity syndrome is a common feature of WM, central nervous system (CNS) involvement in WM is rare and is known as Bing-Neel syndrome. A 60-year-old woman was referred to our hospital with bed-bound polyneuropathy, edema, splenomegaly, IgM-lambda-type monoclonal protein and CD20-positive lymphocyte infiltration in the bone marrow. She was diagnosed with WM accompanying POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) and was treated with rituximab and thalidomide. She achieved partial remission of WM, and thalidomide was continued for POEMS syndrome. She visited our outpatient clinic 6 years later with sudden onset of vertigo and nausea. Magnetic resonance imaging (MRI) revealed a low-density area 4 cm in diameter in her right cerebrum and right mid-brain and she was referred to our hospital. Pathological analysis of brain biopsy samples revealed diffuse large B-cell lymphoma (DLBCL) in the CNS. Nucleic acid sequence analysis of the VDJ region using DNA obtained from the original WM tumor cells and brain tissue revealed that the DLBCL cells were derived from the original WM malignant lymphoma cells. She received five cycles of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy and 23.4 Gy of whole-brain irradiation followed by two cycles of high-dose cytarabine, which resolved her neurological symptoms in association with reduction of IgM levels to 367 mg/dL. MRI and computed tomography of the brain demonstrated complete remission of her CNS lymphoma. PMID- 26490526 TI - An overlooked environmental issue? A review of the inadvertent formation of PCB 11 and other PCB congeners and their occurrence in consumer products and in the environment. AB - Polychlorinated biphenyls (PCBs) are banned from production and use in most countries as they are persistent organic pollutants (POPs) of concern for environment and health. Recent research has pointed at a new environment issue resulting from the inadvertent formation of PCBs in certain processes, in particular the pigment production. PCB-11 is a major by-product in these processes, but PCB-28, PCB-52, PCB-77 as well as the nonachlorinated PCBs and PCB 209 have been found in pigments and consumer products as well. In addition to environmental emissions via point sources, in particular related to industrial and municipal wastewater, atmospheric transport seems to be important for the global distribution of PCB-11. Thus, PCB-11 has also been detected in the polar regions. Worldwide air concentrations appear relatively uniform, but maxima have been found in urban and industrialised areas. Data on the uptake and accumulation of PCB-11 in the food chain are still inconclusive: Although food web studies do not show biomagnification, PCB-11 has been detected in humans. The human exposure might originate from the direct contact to consumer products as well as from the omnipresence of PCB-11 in the environment. PMID- 26490527 TI - Landscape structure and management alter the outcome of a pesticide ERA: Evaluating impacts of endocrine disruption using the ALMaSS European Brown Hare model. AB - There is a gradual change towards explicitly considering landscapes in regulatory risk assessment. To realise the objective of developing representative scenarios for risk assessment it is necessary to know how detailed a landscape representation is needed to generate a realistic risk assessment, and indeed how to generate such landscapes. This paper evaluates the contribution of landscape and farming components to a model based risk assessment of a fictitious endocrine disruptor on hares. In addition, we present methods and code examples for generation of landscape structures and farming simulation from data collected primarily for EU agricultural subsidy support and GIS map data. Ten different Danish landscapes were generated and the ERA carried out for each landscape using two different assumed toxicities. The results showed negative impacts in all cases, but the extent and form in terms of impacts on abundance or occupancy differed greatly between landscapes. A meta-model was created, predicting impact from landscape and farming characteristics. Scenarios based on all combinations of farming and landscape for five landscapes representing extreme and middle impacts were created. The meta-models developed from the 10 real landscapes failed to predict impacts for these 25 scenarios. Landscape, farming, and the emergent density of hares all influenced the results of the risk assessment considerably. The study indicates that prediction of a reasonable worst case scenario is difficult from structural, farming or population metrics; rather the emergent properties generated from interactions between landscape, management and ecology are needed. Meta-modelling may also fail to predict impacts, even when restricting inputs to combinations of those used to create the model. Future ERA may therefore need to make use of multiple scenarios representing a wide range of conditions to avoid locally unacceptable risks. This approach could now be feasible Europe wide given the landscape generation methods presented. PMID- 26490528 TI - Low uptake affinity cultivars with biochar to tackle Cd-tainted rice--A field study over four rice seasons in Hunan, China. AB - Biochar is becoming an environmentally friendly material for remediation of heavy metal contaminated soils and improving food safety. A field trial over four rice seasons was conducted to investigate the use of biochar and low Cd accumulating cultivars on Cd uptake in a heavy metal contaminated soil. Wheat straw derived biochar was applied at 0, 20 and 40 t ha(-1). Two rice cultivars with differing Cd accumulation abilities were selected in each season. The results showed that both biochar and low Cd affinity cultivars significantly reduced rice grain Cd accumulation. Biochar had no significant effect the first season but thereafter consistently reduced rice grain Cd by a maximum of 61, 86 and 57% over the next three seasons. Zn accumulation in the rice grains was not decreased by biochar application, although available soil Zn was sharply reduced (35-91%). Indica conventional rice cultivars had much lower Cd, but higher Zn and lower Cd/Zn ratios in the grain than indica hybrid cultivars. Biochar was more effective for mitigating grain Cd accumulation in low Cd affinity cultivars than in high affinity cultivars. Soil pH was sustainably increased (up to nearly 1 unit) while available Cd significantly decreased by a maximum of 85% after biochar addition. The translocation of Cd from rice roots to shoots was reduced from 20 to 80% by biochar. Low uptake affinity cultivars combined with biochar reduced late rice grain Cd concentration and Cd/Zn ratios by 69-80% and 72-80%, respectively. It indicated that the management of combining biochar and low Cd affinity cultivars should be an efficient way to remediate Cd contaminated rice paddies and reduce health risk associated with consuming rice from these soils. PMID- 26490529 TI - Evident elevation of atmospheric monoterpenes due to degradation-induced species changes in a semi-arid grassland. AB - Biogenic volatile organic compounds (BVOCs) emitted from plants have substantial effects on atmospheric chemistry/physics and feedbacks on ecosystem function. The on-going climate change and anthropogenic disturbance have been confirmed to cause the evident degradation of grassland with shift of plant community, and hence BVOCs emissions were suspected to be altered due to the different BOVCs emission potentials of different species. In this study, we investigated BVOCs concentration above ground surface during growing season in a degraded semi-arid grassland (41 degrees 2' N-45 degrees 6' N, 113 degrees 5'-117 degrees 8') in Inner Mongolia. The observed monoterpenes' concentrations varied from 0.10 to 215.78 MUg m(-3) (34.88 +/- 9.73 MUg m(-3) in average) across 41 sites. Compared to non-degraded grassland, concentrations of monoterpenes were about 180 times higher at the sites dominated by subshrub--Artemisia frigida, a preponderant species under drought stress and over-grazing. The biomass of A. frigida explained 51.39% of the variation of monoterpenes' concentrations. alpha-pinene, beta-pinene and gamma-terpinene dominated in the 10 determined monoterpenes, accounting for 37.72 +/- 2.98%, 14.65 +/- 2.55% and 10.50 +/- 2.37% of the total monoterpenes concentration, respectively. Low isoprene concentrations (<= 3.25 MUg m(-3)) were found and sedge biomass contributed about 51.76% to their spatial variation. alpha-pinene and isoprene emissions at noon were as high as 515.53 +/- 88.34 MUg m(-2)h(-1) and 7606.19 +/- 1073.94 MUg m(-2) h(-1) in A. frigida- and sedge-dominated areas where their biomass were 236.90 g m(-2) and 72.37 g m(-2), respectively. Our results suggested that the expansion of A. frigida and sedge caused by over-grazing and climatic stresses may increase local ambient BVOCs concentration in grassland. PMID- 26490530 TI - Dynamics of metallic contaminants at a basin scale--Spatial and temporal reconstruction from four sediment cores (Loire fluvial system, France). AB - From the 19th century, the Loire basin (France) presents potentially pollutant activities such as mining and heavy industries. This paper shows spatio-temporal distribution of trace elements in sediments at a basin-scale, based on a comparison of archived temporal signals recorded in four sedimentary cores. Anthropogenic sources contributing to sediment contamination are also characterized, using geochemical signatures recorded in river bank sediments of the most industrialized tributaries. This study highlights upstream-downstream differences concerning recorded contamination phases in terms of spatial influence and temporality of archiving processes. Such differences were related to (i) various spatial influences of contamination sources and (ii) polluted sediments dispersion controlled by transport capacity of metal-carrier phases and hydrosedimentary dynamics. PMID- 26490531 TI - Groundwater chemical baseline values to assess the Recovery Plan in the Matanza Riachuelo River basin, Argentina. AB - The two most exploited aquifers in the Matanza-Riachuelo River basin are being monitored in the framework of the Integrated Environmental Sanitation Plan that implements the Basin Authority, Autoridad de Cuenca Matanza Riachuelo. In this context, this work identifies the groundwater chemical types and the natural processes behind them; determines spatial and temporal changes; establishes ranges of variation for chemical components, and proposes concentration values for the upper limit of the natural chemical background. A total of 1007 samples from three aquifer-layers (Upper Aquifer, top and bottom of Puelche Aquifer) have been studied. As concrete guidelines for practical determination of baseline values are not available in the region, the methodology used follows the proposals of European projects which assessed European water directives. The groundwater composition is very stable in terms of both chemical facies and mineralization degree, and the changes observed in the dry and wet periods analysed are subtle in general. Most of the groundwater is Na-HCO3 type, except a few samples that are Ca-HCO3, Na-ClSO4 and Na-Cl types. The Ca-HCO3 waters are the result of calcium carbonate dissolution, Na-HCO3 waters result from cation exchange and carbonate dissolution, while in the Na-ClSO4 and Na-Cl waters, mixing with connate and with encroached old marine water from the underlying and overlying sediments are the most relevant processes. The proposed values for the upper limit of the natural background consider the influence of geology and Holocene marine ingressions in the baseline of coastal groundwater. This study allowed to know the initial chemical conditions of the groundwater system of the Matanza-Riachuelo River basin and to establish the reference from which Basin Authority can start to evaluate trends and monitor the recovery plan. At the same time, it sets a precedent for future studies in the region. PMID- 26490532 TI - The potential impact of municipal solid waste incinerators ashes on the anthropogenic osmium budget. AB - Osmium release from Municipal Solid Waste Incinerators (MSWI), even if acknowledged to occur at least over the last fifteen years, remains overlooked in the majority of recent studies. We present the osmium concentration and (187)Os/(188)Os isotopic measurements of different kinds of bottom and fly ash samples from MSWI plants and reference materials of incinerator fly ash (BCR176 and BCR176R). The analysis of the unknown ash samples shows a relatively wide range of (187)Os/(188)Os ratios (0.24-0.70) and Os concentrations (from 0.026 ng/g to 1.65 ng/g). Osmium concentrations and isotopic signatures differ from those of other known Os sources, either natural or manmade, suggesting a mixture of both contributions in the MSWI feedstock material. Furthermore, the comparison between the BCR176 and the renewed BCR176R indicates a decrease in Os concentration of one order of magnitude over the years (from 1 to 0.1 ng/g) due to improved recycling efficiency of Os-bearing waste. The estimated annual amount of Os from a typical incinerator (using average Os values and MSWI mass balance) is 13.4 g/a. The osmium potentially released from MSWI smokestacks is predicted to be from 16 to 38 ng Os/m(2)/a, considering a medium size country having 50 MSWI facilities; therefore much higher than the naturally transported osmium from continental dust in the atmosphere (about 1 pg Os/m(2)/a). MSWI systems are considered one of the best options for municipal solid waste management in industrialised countries, but their contribution to the Os budget can be significant. PMID- 26490533 TI - Risk assessment of triazine herbicides in surface waters and bioaccumulation of Irgarol and M1 by submerged aquatic vegetation in Southeast Florida. AB - Irgarol is a common antifoulant present in coastal environments experiencing high boating activities. Irgarol, its degradation product M1, and the similarly structured herbicide Atrazine, are highly toxic to non-target marine organisms and thus pose a continual risk to the environment. Nearshore areas with intensive boating activity were assessed for environmental exposure to Irgarol, M1, and Atrazine. Irgarol levels up to 241 ng/L were measured in surface water collected at Key Largo Harbor. Irgarol's metabolite, M1, was detected at levels up to 50 ng/L. Atrazine levels reached 21 ng/L throughout Miami River, and were also detected in waters within Biscayne Bay Aquatic Preserve at 7 +/- 4 ng/L. The Irgarol 90th percentile exposure concentration (176 ng/L) in Southeast Florida- including Biscayne Bay--surface waters were found to exceed most toxicity benchmarks, suggesting Irgarol concentrations may be high enough to cause undesired effects on aquatic plants. Indigenous species of SAVs were also collected throughout Southeast Florida and assessed for their Irgarol and M1 bioaccumulation capabilities. All SAV species collected revealed Irgarol bioaccumulation capabilities and a 90th centile bioconcentration factor (BCF) of 9830. Several of those species were also capable of bioaccumulating M1, with a 90th centile BCF of 391. A 43-day in situ transplant between an impacted area and a pristine area within Biscayne Bay waters showed SAVs were able to uptake Irgarol from the environment with quick kinetics: tissue concentrations were 66 times greater than the water concentration within 6 weeks. Halodule and Syringodium had the highest capacity to bioaccumulate from marina surface waters, as indicated by the Irgarol BCF (Halodule=6809, Syringodium=6681) and M1 BCF (Halodule=277, Syringodium=558). Halodule and Syringodium are therefore the best candidate species to serve as bioindicators indicators of acute Irgarol contamination. PMID- 26490534 TI - Impact of bromide on halogen incorporation into organic moieties in chlorinated drinking water treatment and distribution systems. AB - The impact of elevated bromide concentrations (399 to 750 MUg/L) on the formation of halogenated disinfection by-products (DBPs), namely trihalomethanes, haloacetic acids, haloacetonitriles, and adsorbable organic halogen (AOX), in two drinking water systems was investigated. Bromine was the main halogen incorporated into all of the DBP classes and into organic carbon, even though chlorine was present in large excess to maintain a disinfectant residual. Due to the higher reactivity of bromine compared to chlorine, brominated DBPs were rapidly formed, followed by a slower increase in chlorinated DBPs. Higher bromine substitution and incorporation factors for individual DBP classes were observed for the chlorinated water from the groundwater source (lower concentration of dissolved organic carbon (DOC)), which contained a higher concentration of bromide, than for the surface water source (higher DOC). The molar distribution of adsorbable organic bromine to chlorine (AOBr/AOCl) for AOX in the groundwater distribution system was 1.5:1 and almost 1:1 for the surface water system. The measured (regulated) DBPs only accounted for 16 to 33% of the total organic halogen, demonstrating that AOX measurements are essential to provide a full understanding of the formation of halogenated DBPs in drinking waters. In addition, the study demonstrated that a significant proportion (up to 94%) of the bromide in source waters can be converted AOBr. An evaluation of AOBr and AOCl through a second groundwater treatment plant that uses conventional treatment processes for DOC removal produced 70% of AOX as AOBr, with 69% of the initial source water bromide converted to AOBr. Exposure to organobromine compounds is suspected to result in greater adverse health consequences than their chlorinated analogues. Therefore, this study highlights the need for improved methods to selectively reduce the bromide content in source waters. PMID- 26490535 TI - Investigation of cytokines, oxidative stress, metabolic, and inflammatory biomarkers after orange juice consumption by normal and overweight subjects. AB - BACKGROUND: Abdominal adiposity has been linked to metabolic abnormalities, including dyslipidemia, oxidative stress, and low-grade inflammation. OBJECTIVE: To test the hypothesis that consumption of 100% orange juice (OJ) would improve metabolic, oxidative, and inflammatory biomarkers and cytokine levels in normal and overweight subjects with increased waist circumference. DESIGN: Subjects were divided into two groups in accordance with their body mass index: normal and overweight. Both groups of individuals consumed 750 mL of OJ daily for 8 weeks. Body composition (weight, height, percentage of fat mass, and waist circumference); metabolic biomarkers (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], triglycerides, glucose, insulin, HOMA-IR, and glycated hemoglobin); oxidative biomarkers (malondialdehyde and DPPH(*)); inflammatory biomarkers (high-sensitivity C reactive protein [hsCRP]); cytokines (IL-4, IL-10, IL-12, TNF-alpha, and IFN gamma); and diet were evaluated before and after consumption of OJ for 8 weeks. RESULTS: The major findings of this study were: 1) no alteration in body composition in either group; 2) improvement of the lipid profile, evidenced by a reduction in total cholesterol and LDL-C; 3) a potential stimulation of the immune response due to increase in IL-12; 4) anti-inflammatory effect as a result of a marked reduction in hsCRP; and 5) antioxidant action by the enhancement of total antioxidant capacity and the reduction of lipid peroxidation, in both normal and overweight subjects. CONCLUSIONS: OJ consumption has a positive effect on important biomarkers of health status in normal and overweight subjects, thereby supporting evidence that OJ acts as functional food and could be consumed as part of a healthy diet to prevent metabolic and chronic diseases. PMID- 26490536 TI - Protecting liver sinusoidal endothelial cells suppresses apoptosis in acute liver damage. AB - AIM: Apoptosis is associated with various types of hepatic disorders. We have developed a novel cell-transfer drug delivery system (DDS) using a multifunctional envelope-type nano device that targets liver sinusoidal endothelial cells (LSECs). The purpose of this study was to determine the efficacy of the novel DDS containing siRNA at suppressing apoptosis in LSECs. METHODS: Bax siRNA was transfected into a sinusoidal endothelial cell line (M1) to suppress apoptosis induced by an anti-Fas antibody and staurosporine. C57BL/6J mice were divided into three groups: (i) a control group, only intravenous saline; (ii) a nonselective group, injections of siRNA sealed in the nonselective DDS; and (iii) an LSEC-transfer efficient group, injections of siRNA sealed in an LSEC-transfer efficient DDS. Hepatic cell apoptosis was induced by an anti-Fas antibody. RESULTS: Bax siRNA had an anti-apoptotic effect on M1 cells. Serum alanine aminotransferase was reduced in the LSEC-transfer efficient group, as were cleaved caspase-3 and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive hepatocytes. Silver impregnation staining indicated that the sinusoidal space was maintained in the LSEC-transfer efficient group but not in the other groups. Electron microscopy showed that the LSECs were slightly impaired, although the sinusoidal structure was maintained in the LSEC transfer efficient group. CONCLUSION: Hepatocyte apoptosis was reduced by the efficient suppression of LSEC apoptosis with a novel DDS. Protecting the sinusoidal structure by suppressing LSEC damage will be an effective treatment for acute liver failure. PMID- 26490537 TI - Ralstonia solanacearum fatty acid composition is determined by interaction of two 3-ketoacyl-acyl carrier protein reductases encoded on separate replicons. AB - BACKGROUND: FabG is the only known enzyme that catalyzes reduction of the 3 ketoacyl-ACP intermediates of bacterial fatty acid synthetic pathways. However, there are two Ralstonia solanacearum genes, RSc1052 (fabG1) and RSp0359 (fabG2), annotated as encoding putative 3-ketoacyl-ACP reductases. Both FabG homologues possess the conserved catalytic triad and the N-terminal cofactor binding sequence of the short chain dehydrogenase/reductase (SDR) family. Thus, it seems reasonable to hypothesize that RsfabG1 and RsfabG2 both encode functional 3 ketoacyl-ACP reductases and play important roles in R. solanacearum fatty acid synthesis and growth. METHODS: Complementation of Escherichia coli fabG temperature-sensitive mutant with R. solanacearum fabGs encoded plasmids was carried out to test the function of RsfabGs in fatty acid biosynthesis. RsFabGs proteins were purified by nickel chelate chromatography and fatty acid biosynthetic reaction was reconstituted to investigate the 3-ketoacyl-ACP reductase activity of RsFabGs in vitro. Disruption of both RsfabG genes was done via DNA homologous recombination to test the function of both RsfabG in vivo. And more we also carried out pathogenicity tests on tomato plants using RsfabG mutant strains. RESULTS: We report that expression of either of the two proteins (RsFabG1 and RsFabG2) restores growth of the E. coli fabG temperature-sensitive mutant CL104 under non-permissive conditions. In vitro assays demonstrate that both proteins restore fatty acid synthetic ability to extracts of the E. coli strain. The RsfabG1 gene carried on the R. solanacearum chromosome is essential for growth of the bacterium, as is the case for fabG in E. coli. In contrast, the null mutant strain with the megaplasmid-encoded RsfabG2 gene is viable but has a fatty acid composition that differs significantly from that of the wild type strain. Our study also shows that RsFabG2 plays a role in adaptation to high salt concentration and low pH, and in pathogenesis of disease in tomato plants. CONCLUSION: R. solanacearum encodes two 3-ketoacyl-ACP reductases that both have functions in fatty acid synthesis. We supply the first evidence that, like other enzymes in the bacterial fatty acid biosynthetic pathway, one bacterium may simultaneously possess two or more 3-oxoacyl-ACP reductase isozymes. PMID- 26490538 TI - Unusual chromatin state in Rhynchosciara americana (Diptera: Sciaridae). AB - Euchromatin and heterochromatin are usually defined by the degree of DNA compaction, gene content and combinations of histone and non-histone proteins. More recent studies on protein location have been able to specify a variety of chromatin types thus adding chromatin configurations other than the two basic reference states. Chromatin research exploiting non-model organisms has the potential to provide novel information related to epigenetic modifications and their impact on chromosome structure and function. Polytene chromosomes of Rhynchosciara americana display a particular region within the A9 sub-section characterised by lack of DNA compaction as well as an usual polytene banding pattern. DNA content in the sub-section seems to be low as deduced by DAPI staining. Antibodies to H3K4me, a conserved epigenetic transcription marker,labelled the A9 sub-section strongly. In contrast,transcriptional activity in the region, if any, seems to be low as inferred by detection of RNA polymerase II and RNA. Histone markers related to heterochromatin formation such as H3K9me and H3K27me are underrepresented in the A9 sub-section. However, a chromodomain containing sciarid protein was detected in the region, displaying levels of fluorescence very close to those observed in pericentric heterochromatin.A plasmid micro-library constructed with microdissected DNA from the A9 sub-section was screened for repetitive DNA. The proportion of inserts containing repeats was found to be similar to that contained in another micro-library made with DNA from a single chromosome end of this species. The data suggest an unusual "chromatin colour" indicating that high levels of histone markers related to transcription coexist with a significant presence of chromodomain-containing proteins and the virtual absence of histone modifications observed in heterochromatin formation. PMID- 26490539 TI - Evaluation of the prognostic impact of postoperative adjuvant radiotherapy on head and neck mucosal melanoma: a meta-analysis. AB - BACKGROUND: Head and neck mucosal melanoma (HNMM) is a rare type of malignant tumor that frequently exhibits postoperative recurrence and distant metastasis. Many clinicians administer postoperative adjuvant radiotherapy to improve patient prognosis and enhance quality of life; however, the effects of this treatment remain controversial. Therefore, in this study, a meta-analysis was performed to evaluate the practical value of postoperative adjuvant radiotherapy for head and neck mucosal melanoma. METHODS: Articles in the PubMed, MEDLINE, Cochrane Library, Web of Science and EMBASE databases were systematically retrieved. Analyses were conducted to compare the impact of treatments involving postoperative radiotherapy with treatments entailing surgery alone on patient overall survival time, local recurrence and distant metastasis. The hazard ratio (HR) was used to evaluate the time-to-event data employing RevMan version 5.2 and Stata/SE version 13.0 software according to the principles specified for systematic reviews of interventions in the Cochrane handbook. RESULTS: Twelve cohort studies involving 1593 patients satisfied the desired conditions. In comparing surgery alone with postoperative radiotherapy, there was no significant difference regarding a decrease in the death risk in HNMM patients (HR, 1.07; 95 % CI, 0.95-1.2; p = 0.903; low heterogeneity, I(2) = 0); this was also the case for sinonasal melanoma after subgroup meta-analysis (HR, 1.04; 95 % CI, 0.8-1.36; p = 0.983; low heterogeneity, I(2) = 0 %). A sensitivity analysis and subgroup meta-analysis showed that disease progression was the main source of the instability in the results. Surgery combined with postoperative radiotherapy reduced the risk of local recurrence (HR, 0.51; 95 % CI, 0.35-0.76; p = 0.155) but did not reduce the risk of distant metastasis (HR, 2.26; 95 % CI, 1.01-5.05; p = 0.006). CONCLUSIONS: This study demonstrated that for HNMM patients surgery is recommended if indicated, and surgery combined with postoperative radiotherapy is also recommended for dramatically improved local control of the tumor bed. For patients not suitable for surgical treatment, radiotherapy is still advised. To control distant metastasis and finally lower the risk of death, immunological therapy is another potential option whose therapeutic effect needs to be proved with more data from clinical trials. PMID- 26490540 TI - Seven-site versus three-site method of body composition using BodyMetrix ultrasound compared to dual-energy X-ray absorptiometry. AB - : Obesity is a steadily growing epidemic affecting all segments of the population including college-aged students. The weight gain that is evidenced amid the transitional stage of college years increases the risks associated with cardiovascular and metabolic diseases. The BodyMetrix(r) BX-2000 (ULTRA) using a seven-site method has been evaluated against dual-energy X-ray absorptiometry (DXA) for estimation of body composition, which has yielded conflicting results. To date, no studies have compared the three-site method Jackson and Pollock three site method to DXA. PURPOSE: The purpose of the study was twofold (i) to compare agreement between Jackson-Pollock seven site (JP7), Jackson-Pollock three site (JP3) and Pollock three site (P3) to predict body fat (%BF) using ULTRA and (ii) and to compare the three ULTRA methodologies against DXA. METHODS: Seventy-six healthy college-aged subjects (ages = 22.08 +/- 2.50 years) participated in this study. DXA and ULTRA body composition assessments were performed following manufacturer's instructions to estimate %BF. Paired sample t-tests were used to assess agreement between JP7, P3 and JP3. Additionally, a two-tailed sample t test was performed by sex. ULTRA and DXA results were also performed for agreement and bivariate correlation. RESULTS: No significant differences between JP7 and P3, P = 0.38, were observed. In males, no significant differences were observed between JP7 and P3, P = 0.18. Significant differences were observed in all other pairs, P<=0.001 and between ULTRA and DXA. CONCLUSIONS: The Pollock 3 site method estimates body fat percentage with comparable accuracy to JP7 using ULTRA. PMID- 26490541 TI - Determination of the lipophilicity of Salvia miltiorrhiza Radix et Rhizoma (danshen root) ingredients by microemulsion liquid chromatography: optimization using cluster analysis and a linear solvation energy relationship-based method. AB - We evaluated 26 microemulsion liquid chromatography (MELC) systems for their potential as high-throughput screening platforms capable of modeling the partitioning behaviors of drug compounds in an n-octanol-water system, and for predicting the lipophilicity of those compounds (i.e. logP values). The MELC systems were compared by cluster analysis and a linear solvation energy relationship (LSER)-based method, and the optimal system was identified by comparing their Euclidean distances with the LSER coefficients. The most effective MELC system had a mobile phase consisting of 6.0% (w/w) Brij35 (a detergent), 6.6% (w/w) butanol, 0.8% (w/w) cyclohexane, 86.6% (w/w) buffer solution and 8 mm cetyltrimethyl ammonium bromide. The reliability of the established platform was confirmed by the agreement between the experimental data and the predicted values. The logP values of the ingredients of danshen root (Salvia miltiorrhiza Radix et Rhizoma) were then predicted. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26490542 TI - Endometriosis in a kidney with focal xanthogranulomatous pyelonephritis and a perinephric abscess. AB - BACKGROUND: The presence of endometriosis in the kidney is extremely rare. We report a case of endometriosis in renal parenchyma incidentally found in a malfunctioning kidney removed because of xanthogranulomatous pyelonephritis. CASE PRESENTATION: A 53-year-old Chinese premenopausal woman presented with intermittent right flank pain for many years. Imaging studies revealed a contracted non-functioning right kidney and a perinephric abscess. The contracted kidney was considered to have resulted from chronic pyelonephritis. The abscess was drained. The patient subsequently underwent a right nephrectomy. Histology revealed endometriosis of renal parenchyma in addition to xanthogranulomatous pyelonephritis and a perinephric abscess. No evidence of endometriosis was identified at the pelvic site. The patient was symptom-free after operation. CONCLUSION: Endometriosis is a common benign condition in women of reproductive age that is characterized by the presence of endometrial glands and stroma outside the uterine cavity, which affects either genital or extragenital sites. Involvement of the urinary tract is rare. Among the urinary tract endometriosis, only a few cases involve the kidney. Renal endometriosis is difficult to diagnose; a final diagnosis relies on the pathohistologic findings. Treatment involves hormonal manipulation or a hysterectomy with bilateral salpingo oophorectomy. Whether a nephrectomy required depends on the level of renal function. Although extremely rare, renal endometriosis should be part of the differential diagnostic spectrum when a contracted, non-functioning kidney is present. Early diagnosis might have prevented an unnecessary nephrectomy in cases of uncomplicated renal endometriosis. PMID- 26490543 TI - Stepwise work hardening induced by individual grain boundary in Cu bicrystal micropillars. AB - Vast experiments have demonstrated that the external specimen size makes a large difference in the deformation behavior of crystalline materials. However, as one important kind of internal planar defects, the role of grain boundary (GB) in small scales needs to be clarified in light of the scarce and inconsistent experimental results at present. Through compression of Cu bicrystal and its counterpart monocrystal micropillars, it is found that, in contrast to the monocrystals, the bicrystals are characterized by work hardening with discrete strain bursts. Interestingly, the stress rise between two adjacent strain bursts of the bicrystals increases with the decrease of specimen size. The results suggest that GBs play a critical role in the work hardening of materials in small scales, which may provide important implications to further understand the general work hardening behaviors of materials in the future. PMID- 26490545 TI - A frogspawn-inspired hierarchical porous NaTi2(PO4)3-C array for high-rate and long-life aqueous rechargeable sodium batteries. AB - Hollow micro/nano-arrays have attracted tremendous attention in the field of energy conversion and storage, but such structures usually compromise the volumetric energy density of the electrode materials. Frogspawn consists of a spawn core and a transparent jelly shell organized in a hierarchical porous array, which exhibits superior mechanical strength and high-efficiency oxygen permeability. It can be used as a model for designing a new high-performance electrode material, which has advantages such as a high surface area, fast mass transport and superior durability. Herein, we report a frogspawn-like NaTi2(PO4)3/C array prepared by a facile preform impregnation strategy. The framework is formed by a hollow carbon sphere connected by the NaTi2(PO4)3/C skeleton, and its hollow is filled with the NaTi2(PO4)3 nanospheres. The whole hierarchical porous three-dimensional array copies the structure of a frogspawn. This unique structure not only enables easy electrolyte percolation and fast electron/ion transport, but also enhances the reversible capacity and cycling durability. When it is applied as an anode of the aqueous sodium ion battery, it exhibits favorable high rate capability and superior cycling stability, and retains 89% of the initial capacity after two thousand cycles at 20 C. Moreover, the full cell using the frogspawn-inspired NaTi2(PO4)3-C as the anode and Na0.44MnO2 as the cathode is capable of ultralong cycling up to one thousand cycles at alternate 10 and 60 C, which is among the best of state-of-the-art aqueous sodium ion systems. Therefore, the frogspawn-inspired architecture provides a new strategy to the tailored design of polyanion materials for high power applications. PMID- 26490544 TI - What impact will the achievement of the current World Health Organisation targets for anthelmintic treatment coverage in children have on the intensity of soil transmitted helminth infections? AB - BACKGROUND: It is the aim of the World Health Organisation to eliminate soil transmitted helminths (STH) as a health problem in children. To this end, the goal is to increase anthelmintic treatment coverage for soil transmitted helminths to reach 75 % in pre-school aged and school aged children by 2020 in endemic countries. In this paper, we use mathematical models to investigate the impact of achieving this goal on the burdens of Ascaris lumbricoides, Trichuris trichuria and hookworm. METHODS: We employ a deterministic fully age-structured model of STH transmission and mass drug administration to examine the changes in worm burden in response to the known and projected coverage trends in children up to 2020 and beyond. Parameters are estimated from worm expulsion data and age intensity profiles before treatment using maximum likelihood methods. Model validation is performed using reinfection studies for Ascaris and analyses are conducted to assess the sensitivity of the predicted outcomes to variation in parameter estimates including transmission intensity (R0), children's contributions to the pool of infective stages and drug coverage levels. RESULTS: The impact of the required increase in coverage trends are quite different across the three species. Ascaris burdens are reduced dramatically by 2020 with elimination predicted within studied the setting a further 10 years. For Trichuris and hookworm, however, impact is more limited, due to issues of drug efficacy (Trichuris) and distribution of worms in the population (hookworm). Sensitivity analysis indicates that results are largely robust. However, validation against Ascaris data indicates that assumptions concerning re infection among children may have to be revised. CONCLUSIONS: The 2020 coverage target is predicted to have a major impact on Ascaris levels by 2020. However, there is evidence from model validation that Ascaris in children is more resilient to treatment than currently assumed in the model. Broader coverage across all age classes is required to break transmission for hookworm and alternative dual drug treatment approaches are needed for Trichuris. PMID- 26490546 TI - First olfactory fiber as an anatomical landmark for frontal sinus surgery. AB - OBJECTIVES/HYPOTHESIS: Access to the frontal sinuses is technically challenging owing to their anterosuperior location, diverse anatomy, close proximity to critical structures and the need to work in a relatively narrow space with angled lens endoscopes and instruments. This study attempts to study the relationship of the first olfactory fiber with the frontal sinus posterior wall, assessing its fidelity as a surgical landmark during frontal sinus surgery. STUDY DESIGN: Anatomic study. METHODS: Fifteen cadaveric specimens were studied. Measurements were obtained bilaterally using the data from individual CT scans. Median A-P was defined as the anteroposterior (A-P) diameter measured just lateral to the intersinus septum, paramedian A-P was measured 5 mm lateral to the septum, and maximum A-P was defined as the maximum anteroposterior diameter on axial images. A surgical navigation device was used to calculate the distance between the first olfactory fiber and the posterior table of the frontal sinus. RESULTS: The mean distance between the first olfactory fiber and the posterior wall of the frontal sinus was (4.03 +/- 2.7) mm on the right side and (4.2 +/- 2.9) mm on the left. This distance strongly correlated with the maximum A-P diameter of the sinus. CONCLUSIONS: In a cadaveric model, the first olfactory fiber was found to be an average of 4.0 mm posterior to the frontal sinus. The significant variability of this distance should be considered when using the first olfactory fiber to establish the posterior boundary of a frontal sinusotomy. Drilling no further posterior than 7 mm rostral to the first olfactory fiber would be safe in 91% of patients. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1039-1045, 2016. PMID- 26490549 TI - Engineered yeast whole-cell biocatalyst for direct degradation of alginate from macroalgae and production of non-commercialized useful monosaccharide from alginate. AB - Alginate is a major component of brown macroalgae. In macroalgae, an endolytic alginate lyase first degrades alginate into oligosaccharides. These oligosaccharides are further broken down into monosaccharides by an exolytic alginate lyase. In this study, genes encoding various alginate lyases derived from alginate-assimilating marine bacterium Saccharophagus degradans were isolated, and their enzymes were displayed using the yeast cell surface display system. Alg7A-, Alg7D-, and Alg18J-displaying yeasts showed endolytic alginate lyase activity. On the other hand, Alg7K-displaying yeast showed exolytic alginate lyase activity. Alg7A, Alg7D, Alg7K, and Alg18J, when displayed on yeast cell surface, demonstrated both polyguluronate lyase and polymannuronate lyase activities. Additionally, polyguluronic acid could be much easily degraded by Alg7A, Alg7K, and Alg7D than polymannuronic acid. In contrast, polymannuronic acid could be much easily degraded by Alg18J than polyguluronic acid. We further constructed yeasts co-displaying endolytic and exolytic alginate lyases. Degradation efficiency by the co-displaying yeasts were significantly higher than single alginate lyase-displaying yeasts. Alg7A/Alg7K co-displaying yeast had maximum alginate degrading activity, with production of 1.98 g/L of reducing sugars in a 60-min reaction. This system developed, along with our findings, will contribute to the efficient utilization and production of useful and non commercialized monosaccharides from alginate by Saccharomyces cerevisiae. PMID- 26490547 TI - Clonidine inhibits anti-non-Gal IgM xenoantibody elicited in multiple pig-to primate models. AB - BACKGROUND: Survival of vascularized xenografts is dependent on pre-emptive inhibition of the xenoantibody response against galactosyltransferase knockout (GTKO) porcine organs. Our analysis in multiple GTKO pig-to-primate models of xenotransplantation has demonstrated that the anti-non-gal-alpha-1,3-gal (anti non-Gal) xenoantibody response displays limited structural diversity. This allowed our group to identify an experimental compound which selectively inhibited induced anti-non-Gal IgM xenoantibodies. However, because this compound had an unknown safety profile, we extended this line of research to include screening small molecules with known safety profiles allowing rapid advancement to large animal models. METHODS: The NIH clinical collections of small molecules were screened by ELISA for their ability to inhibit xenoantibody binding to GTKO pig endothelial cells. Serum collected from non-immunosuppressed rhesus monkeys at day 14 post-injection with GTKO pig endothelial cells was utilized as a source of elicited xenoantibody for initial screening. Virtual small molecule screening based on xenoantibody structure was used to assess the likelihood that the identified small molecules bound xenoantibody directly. As a proxy for selectivity, ELISAs against tetanus toxoid and the natural antigens laminin, thyroglobulin, and single-stranded DNA (ssDNA) were utilized to assess the ability of the identified reagents to inhibit additional antibody responses. The identified inhibitory small molecules were further tested for their ability to inhibit xenoantibody elicited in multiple settings, including rhesus monkeys pre treated with an anti-non-Gal selective anti-idiotypic antibody, non immunosuppressed rhesus monkeys immunized with wild-type fetal pig isletlike cell clusters, and non-immunosuppressed baboons transplanted with GTKO multiple transgenic pig kidneys. RESULTS: Four clinically relevant small molecules inhibited anti-non-Gal IgM binding to GTKO pig endothelial cells in vitro. Three of these drugs displayed a limited region of structural similarity suggesting they may inhibit xenoantibody by a similar mechanism. One of these, the anti hypertensive agent clonidine, displayed only minimal inhibition of antibodies elicited by vaccination against tetanus toxoid or pre-existing natural antibodies against laminin, thyroglobulin, or ssDNA. Furthermore, clonidine inhibited elicited anti-non-Gal IgM from all animals that demonstrated a xenoantibody response in each experimental setting. CONCLUSIONS: Clinically relevant small molecule drugs with known safety profiles can inhibit xenoantibody elicited against non-Gal antigens in diverse experimental xenotransplantation settings. These molecules are ready to be tested in large animal models. However, it will first be necessary to optimize the timing and dosing required to inhibit xenoantibodies in vivo. PMID- 26490550 TI - Asymmetrical response of anaerobic digestion microbiota to temperature changes. AB - In natural settings, anaerobic digestion can take place in a wide temperature range, but industrial digesters are usually operated under either mesophilic (~35 degrees C) or thermophilic (~55 degrees C) conditions. The ability of anaerobic digestion microbiota to switch from one operating temperature to the other remains poorly documented. We therefore studied the effect of sudden temperature changes (35 degrees C/55 degrees C) in lab-scale bioreactors degrading 13C labelled cellulose. An asymmetric behaviour was observed. In terms of methane production, after an adaptation period, mesophilic inoculum exhibited a functional resistance to temperature increase but no functional resilience when temperature was reset to 35 degrees C, while thermophilic inoculum methanogenic activity strongly decreased under mesophilic conditions but partially recovered when temperature was reset to 55 degrees C. Automated ribosomal intergenic spacer analysis community fingerprints evidenced a strong influence of temperature on microbial diversity, particularly pronounced and persistent for Archaea. Key phylotypes involved in 13C-cellulose degradation were identified with a coupled stable isotope probing (SIP)-16S rDNA pyrotag sequencing approach, suggesting that the hydrolytic and fermentative metabolic functions could be maintained thanks to functional redundancy between members of the class Clostridia, whereas methanogenic activity primarily relied on specialized groups affiliated either to genus Methanosarcina (mesophilic conditions), Methanothermobacter or Methanoculleus (thermophilic conditions) that were irreversibly modified by temperature increase. PMID- 26490552 TI - Triclosan removal in wetlands constructed with different aquatic plants. AB - Triclosan (TCS) is widely used in consumer products as an antimicrobial agent. Constructed wetlands have the potential for TCS removal, but knowledge about the relative importance of sediment, plants, and microbes is limited. TCS removal performance was investigated in well-operated constructed wetlands planted with three different types of aquatic plants: emergent Cattail (C-T), submerged Hornwort (H-T), and floating Lemnaminor (L-T). Results showed that the TCS removal efficiencies from water were all greater than 97 %. Maximal TCS adsorption to sediment in the C-T wetland (13.8 +/- 0.6 ng/g) was significantly lower than in the H-T wetland (21.0 +/- 0.3 ng/g) or the L-T wetland (21.4 +/- 0.6 ng/g). The maximal TCS concentrations in plants were 5.7 +/- 0.2 and 7.2 +/- 0.5 MUg/g for H-T and L-T, respectively, and it was below the minimal detection limit (MDL) in C-T. Deep 16S rRNA gene sequencing results revealed that C-T wetland had the highest community richness and diversity. Some bacteria, like beta-Proteobacteria, gamma-Proteobacteria, and Bacteroidetes were detected and might have significant correlations with TCS degradation. Overall, with regard to soils, plants, and microorganism, accumulation in sediment and plants in H-T and L-T was high, while in C-T biodegradation likely played an important role. PMID- 26490551 TI - Characterization of a poly(butylene adipate-co-terephthalate)- hydrolyzing lipase from Pelosinus fermentans. AB - Certain alpha/beta hydrolases have the ability to hydrolyze synthetic polyesters. While their partial hydrolysis has a potential for surface functionalization, complete hydrolysis allows recycling of valuable building blocks. Although knowledge about biodegradation of these materials is important regarding their fate in the environment, it is currently limited to aerobic organisms. A lipase from the anaerobic groundwater organism Pelosinus fermentans DSM 17108(PfL1) was cloned and expressed in Escherichia coli BL21-Gold (DE3) and purified from the cell extract. Biochemical characterization with small substrates showed thermoalkalophilic properties (Topt=50 degrees C, pHopt=7.5) and higher activity towards para-nitrophenyl octanoate (12.7 U mg(-1)) compared to longer and shorter chain lengths (C14 0.7 U mg(-1) and C2 4.3 U mg(-1), respectively). Crystallization and determination of the 3-D structure displayed the presence of a lid structure and a zinc ion surrounded by an extra domain. These properties classify the enzyme into the I.5 lipase family. PfL1 is able to hydrolyze poly(1,4-butylene adipate-co-terephthalate) (PBAT) polymeric substrates. The hydrolysis of PBAT showed the release of small building blocks as detected by liquid chromatography mass spectrometry (LC-MS). Protein dynamics seem to be involved with lid opening for the hydrolysis of PBAT by PfL1. PMID- 26490553 TI - Modulating the function of a beta-1,3-glucanosyltransferase to that of an endo beta-1,3-glucanase by structure-based protein engineering. AB - A glycoside hydrolase (GH) family 17 beta-1,3-glucanosyltransferase (RmBgt17A) from Rhizomucor miehei CAU432 (CGMCC No. 4967) shared very low sequence homology (~20 % identity) with that of other beta-1,3-glucanases,despite their similar structural folds. Structural comparison and sequence alignment between RmBgt17A and GH family 17 beta-1,3-glucanases suggested important roles for three residues (Tyr102, Trp157, and Glu158) located in the substrate-binding cleft of RmBgt17A in transglycosylation activity. A series of site-directed mutagenesis studies indicated that a single Glu-to-Ala mutation (E158A) modulates the function of RmBgt17A to that of a beta-1,3-glucanase. Mutant E158A exhibited high hydrolytic activity (39.95 U/mg) toward reduced laminarin, 348.5-fold higher than the wild type. Optimal pH and temperature of the purified RmBgt17A-E158A were 4.5 and 55 degrees C, respectively. TLC analysis suggested that RmBgt17A-E158A is an endo beta-1,3-glucanase. Our study provides novel insight into protein engineering of the substrate-binding cleft of glycoside hydrolases to modulate the function of transglycosylation and hydrolysis. PMID- 26490554 TI - C-H Bond Activation by Early Transition Metal Carbide Cluster Anion MoC3 (-). AB - Although early transition metal (ETM) carbides can activate C?H bonds in condensed-phase systems, the electronic-level mechanism is unclear. Atomic clusters are ideal model systems for understanding the mechanisms of bond activation. For the first time, C?H activation of a simple alkane (ethane) by an ETM carbide cluster anion (MoC3 (-) ) under thermal-collision conditions has been identified by using high-resolution mass spectrometry, photoelectron imaging spectroscopy, and high-level quantum chemical calculations. Dehydrogenation and ethene elimination were observed in the reaction of MoC3 (-) with C2 H6 . The C?H activation follows a mechanism of oxidative addition that is much more favorable in the carbon-stabilized low-spin ground electronic state than in the high-spin excited state. The reaction efficiency between the MoC3 (-) anion and C2 H6 is low (0.23+/-0.05) %. A comparison between the anionic and a highly efficient cationic reaction system (Pt(+) +C2 H6 ) was made. It turned out that the potential-energy surfaces for the entrance channels of the anionic and cationic reaction systems can be very different. PMID- 26490555 TI - Hyponatremia in the outpatient setting: clinical characteristics, risk factors, and outcome. AB - PURPOSE: Hyponatremia is a common disorder and hyponatremia in the outpatient setting is not extensively studied. Our aim was to investigate the characteristics of hyponatremia in ambulatory patients. METHODS: Seventy-six adult outpatients with hyponatremia were enrolled in this prospective study. Demographic features, presenting symptoms and signs, associating morbidities, medications, laboratory findings, mortalities, and length of hospital stay, were recorded. RESULTS: Mean age was 74.7 +/- 12.7 years, and 52 (68.4 %) were female whereas 24 (31.6 %) were male. Mean sodium concentration was 123.6 +/- 6.6 mEq/L. Leading cause was thiazide diuretic use (n = 37, 48.7 %) and approximately half of the patients (n = 40, 52.6 %) had a multifactorial etiology. Severe hyponatremia (sodium < 125 mEq/L) was identified in 37 (48.7 %). Thiazide diuretic use, vomiting, and apathy were independent predictors of severe hyponatremia. Eight (10.5 %) patients had a mortal course. A relatively younger age, male gender, presenting sign of lethargy, associating morbidities of malignancy, chronic liver disease, and hypoalbuminemia were risk factors for mortality. CONCLUSIONS: Hyponatremia is prevalent among elderly, especially in women and with thiazide diuretics. Apart from the trend toward sodium depletion observed in healthy elderly which occurs due to changes in the tubular handling of sodium, a multifactorial etiology including thiazides seems to predict the occurrence and the severity of hyponatremia. Hyponatremia may be a significant cause of mortality in seniors. A relatively younger age, male gender, association of cirrhosis, malignancy, and hypoalbuminemia predict mortality. In elderly outpatients, identification of the risk factors for hyponatremia and close monitoring are imperative to reduce the related mortality and morbidity. PMID- 26490556 TI - The potential repertoire of the innate immune system in the bladder: expression of pattern recognition receptors in the rat bladder and a rat urothelial cell line (MYP3 cells). AB - PURPOSE: The urothelium is a frontline sensor of the lower urinary tract, sampling the bladder lumen and stimulating an immune response to infectious and noxious agents. Pattern recognition receptors (PRRs) recognize such agents and coordinate the innate response, often by forming inflammasomes that activate caspase-1 and the release of interleukin-1. We have shown the presence of one PRR (NLRP3) in the urothelia and its central role in the inflammatory response to cyclophosphamide. The purpose of this study was to (1) assess the likely range of the PPR response by assessing the repertoire present in the rat bladder and (2) determine the utility of the MYP3 rat urothelia cell line for in vitro studies by assessing its PPR repertoire and functional responsiveness. METHODS: Immunohistochemistry was performed for seven PPRs (NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4 and AIM2) on bladder sections and MYP3 cells. For functionality, MYP3 cells were challenged with the quintessential NLRP3 activator ATP and assessed for caspase-1 activation. RESULTS: All PPRs examined were expressed in the bladder and localized to the urothelial layer with several also in the detrusor (none in the interstitia). MYP3 cells also expressed all PRRs with a variable intracellular location. ATP-stimulated caspase-1 activity in MYP3 cells in a dose-dependent manner was reduced by knockdown of NLRP3 expression. CONCLUSION: The results suggest that the bladder possesses the capacity to initiate an innate immune response to a wide array of uropathological agents and the MYP3 cells will provide an excellent investigational tool for this field. PMID- 26490557 TI - NRF2 and NF-kappaB mRNA expression in chronic kidney disease: a focus on nondialysis patients. AB - PURPOSE: To evaluate nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-kappaB (NF-kappaB) mRNA expression in nondialysis chronic kidney disease (CKD) patients, comparing with data from hemodialysis (HD) patients and healthy individuals. METHODS: Twenty nondialysis CKD patients (62.0 +/- 8.1 years old, 11 men, estimated glomerular filtration rate of 36.8 +/- 13.6 mL/min/1.73 m(2)), twenty HD patients (55.0 +/- 15.2 years old, 13 men, and dialysis vintage of 76.5 +/- 46.3 months) and eleven healthy individuals (50.9 +/- 8.0 years old, 6 men) were enrolled in the study. The peripheral blood mononuclear cells were isolated and processed for the evaluation of expression of NF-kappaB and Nrf2 by quantitative real-time polymerase chain reaction. RESULTS: Nrf2 mRNA expression was significantly higher in nondialysis (1.12 +/- 0.57) when compared to HD patients (0.58 +/- 0.35, p = 0,006) but similar to healthy individuals (1.13 +/- 0.64). Inversely, NF-kappaB mRNA expression was lower in nondialysis (1.21 +/- 0.71) when compared to HD patients (2.08 +/- 0.7, p < 0.0001) and similar to healthy individuals (1.04 +/- 0.22). Nrf2 mRNA was positively correlated with NF kappaB mRNA expression in nondialysis CKD patients (r = 0.52, p = 0.02) and healthy individuals (r = 0.77, p < 0.006). By contrast, Nrf2 mRNA was inversely correlated with NF-kappaB mRNA expression (r = -0.65, p = 0.003) in HD patients. CONCLUSION: Nondialysis CKD patients may conserve regular homeostatic balance between Nrf2 and NF-kappaB expressions, being comparable to healthy individuals. However, HD patients seem to have Nrf2 downregulation and NF-kappaB upregulation. Thus, the association among Nrf2 and NF-kappaB expressions and nutritional status, kidney disease progression or immune deregulation deserve further investigation. PMID- 26490558 TI - Toll-like receptors TLR4 (Asp299Gly and Thr399Ile) and TLR2 (Arg677Trp and Arg753Gln) gene polymorphisms in end-stage renal disease patients on peritoneal dialysis. AB - BACKGROUND: Toll-like receptors (TLRs), expressed on cells of the innate immune system, are the first line of host defense. Recognition of bacterial pathogens by the peritoneum is mediated in part by TLR. In this study, we investigated the role of TLR4 (Asp299Gly and Thr399Ile) and TLR2 (Arg677Trp and Arg753Gln) gene polymorphisms in end-stage renal disease (ESRD) patients on peritoneal dialysis (PD). METHOD: A total of 100 ESRD patients on PD and 150 healthy controls were enrolled in the study. The patients were divided into two groups: ESRD patients on PD with peritonitis (n = 38) and without peritonitis (n = 62). Genotyping of TLR4 (Asp299Gly and Thr399Ile) and TLR2 (Arg677Trp and Arg753Gln) genes were performed by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). RESULTS: Heterozygous variant of TLR4 (Thr399Ile) Thr/Ile genotype showed significant association with both groups of patients (patients with and without peritonitis) with no difference between the groups. Overall, TLR4 (Thr399Ile) Thr/Ile genotype demonstrated an association with ESRD on PD (OR 3.9). Further, TLR4 (Thr399Ile) polymorphism showed significant association with PD patients having two or more episodes of peritonitis compared to patients with no peritonitis. No such association of increased risk of ESRD was observed with TLR4 (Asp299Gly) Asp/Gly genotype and TLR2 polymorphisms. Haplotype frequencies, Gly/Ile and Asp/Ile, conferred 2.46- and 4.62-fold increased risk of ESRD, respectively. CONCLUSIONS: TLR4 Thr399Ile genotype was associated with ESRD patients on PD; however, the genotype frequency was similar in PD patients with and without peritonitis. PMID- 26490559 TI - Comparison of the efficacy and histopathological effects of three hemostatic agents in a partial nephrectomy rat model. AB - PURPOSE: The major complications of partial nephrectomy are bleeding and urine leakage. While various hemostatic agents are used to control bleeding, the histopathological characteristics of these hemostatic agents have not been investigated adequately. We aimed to investigate and compare the histopathological and hemostatic effects of local hemostatic agents in a partial nephrectomy rat model. METHODS: Thirty-two rats were divided into four equal groups, and partial nephrectomy was done to all rats. Conventional suture repair, Glubran2(r), FloSeal(r), and CeloxTM were applied to every single group. The period of warm ischemia and hemostasis during surgical process was timed. Rats were killed later 3 weeks, and their partial nephrectomy applied kidneys were evaluated histopathologically. RESULTS: The fastest hemostasis was provided with Glubran2(r) (32.87 s). FloSeal(r) was the second (40.85 s), and CeloxTM was the third (55.75 s). Glomerular necrosis and calcification were seen more in the suture group than other groups (p < 0.001). Fibrosis was found significantly less in CeloxTM group. Fibroblast activation was found significantly less comparing to other groups (p < 0.01). The erythrocyte aggregation was significantly greater in the Glubran2(r) and FloSeal(r) groups than suture group (p < 0.01 and p < 0.001). CONCLUSION: The negative effects of hemostatic agents to the renal histopathology were less than conventional suture repair. CeloxTM was the best biocompatible agent. In comparison with three agents, it was observed that Glubran2(r) provided hemostasis faster than other agents. PMID- 26490560 TI - One-dimensional coordination polymers of [Co3(dpa)4](2+) and [MF6](2-) (M = Re(IV), Zr(IV) and Sn(IV)). AB - One-dimensional coordination polymers of alternating metal-metal bonded trinuclear [Co3(dpa)4](2+) (dpa = the anion of 2,2'-dipyridylamine) building blocks and [ReF6](2-) (1), [ZrF6](2-) (2) or [SnF6](2-) (3) linkers have been self-assembled and crystallographically characterized. Magnetic measurements reveal a significant ferromagnetic coupling (J/k(B) = +9.9 K) between S = 1/2 {Co3(6+)} and S = 3/2 Re(IV) magnetic sites through a single, unsupported fluoride bridge in 1. PMID- 26490562 TI - Society of Gastrointestinal Endoscopy of India. PMID- 26490564 TI - Autoethnography and severe perineal trauma--an unexpected journey from disembodiment to embodiment. AB - BACKGROUND: There is a lack of research reporting on the physical and emotional experiences of women who sustain severe perineal trauma (third and fourth degree tears). When the researcher identifies with the group being researched, autoethnography can allow an insight into the experiences of the marginalised group through the telling of a personal story. The aim of this paper is to share the journey travelled by an autoethnographer who on examining the issue of severe perineal trauma came to understand the challenges and rewards she experienced through this reflective and analytic process. METHODS: A transformative emancipatory approach guided the design, data collection and analysis of findings from this study. For this paper, a multivocal narrative approach was taken in presenting the findings, which incorporated the words of both the autoethnographer and the twelve women who were interviewed as a component of the study, all of whom had sustained severe perineal trauma. RESULTS: As an autoethnographer, being a member of the group being researched, can be confronting as the necessary reflection upon one's personal journey may lead to feelings of vulnerability, sadness, and emotional pain. The transformation from disembodied to embodied self, resulted in a physical and emotional breakdown that occurred for this autoethnographer. CONCLUSION: Autoethnographers may experience unexpected emotional and physical challenges as they reflect upon their experiences and research the experiences of others. When incorporating a transformative emancipatory framework, the hardships are somewhat balanced by the rewards of witnessing 'self-transformation' as a result of the research. PMID- 26490563 TI - Assessing bicycle-related trauma using the biomarker S100B reveals a correlation with total injury severity. AB - PURPOSE: Worldwide, the use of bicycles, for both recreation and commuting, is increasing. S100B, a suggested protein biomarker for cerebral injury, has been shown to correlate to extracranial injury as well. Using serum levels of S100B, we aimed to investigate how S100B could be used when assessing injuries in patients suffering from bicycle trauma injury. As a secondary aim, we investigated how hospital length of stay and injury severity score (ISS) were correlated to S100B levels. METHODS: We performed a retrospective, database study including all patients admitted for bicycle trauma to a level 1 trauma center over a four-year period with admission samples of S100B (n = 127). Computerized tomography (CT) scans were reviewed and remaining data were collected from case records. Univariate- and multivariate regression analyses, linear regressions and comparative statistics (Mann-Whitney) were used where appropriate. RESULTS: Both intra- and extracranial injuries were correlated with S100B levels. Stockholm CT score presented the best correlation of an intracranial parameter with S100B levels (p < 0.0001), while the presences of extremity injury, thoracic injury, and non-cervical spinal injury were also significantly correlated (all p < 0.0001, respectively). A multivariate linear regression revealed that Stockholm CT score, non-cervical spinal injury, and abdominal injury all independently correlated with levels of S100B. Patients with a ISS > 15 had higher S100 levels than patients with ISS < 16 (p < 0.0001). Patients with extracranial, as well as intracranial- and extracranial injuries, had significantly higher levels of S100B than patients without injuries (p < 0.05 and p < 0.01, respectively). The admission serum levels of S100B (log, ug/L) were correlated with ISS (log) (r = 0.53) and length of stay (log, days) (r = 0.45). CONCLUSIONS: S100B levels were independently correlated with intracranial pathology, but also with the extent of extracranial injury. Length of stay and ISS were both correlated with the admission levels of S100B in bicycle trauma, suggesting S100B to be a good marker of aggregated injury severity. Further studies are warranted to confirm our findings. PMID- 26490561 TI - Immunosuppressive drugs and fertility. AB - Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on fertility, pregnancy outcomes and the unborn child. This review aims to summarize the main gonadal side effects of immunosuppressants, to detail the effects on fertility and pregnancy of each class of drug, and to provide recommendations on the management of patients who are seen prior to starting or who are already receiving immunosuppressive treatment, allowing them in due course to bear children. The recommendations for use are established with a rather low level of proof, which needs to be taken into account in the patient management. Methotrexate, mycophenolate, and le- and teri-flunomide, cyclophosphamide, mitoxanthrone are contraindicated if pregnancy is desired due to their teratogenic effects, as well as gonadotoxic effects in the case of cyclophosphamide. Anti-TNF-alpha and mTOR-inhibitors are to be used cautiously if pregnancy is desired, since experience using these drugs is still relatively scarce. Azathioprine, glucocorticoids, mesalazine, anticalcineurins such as cyclosporine and tacrolimus, beta-interferon, glatiramer-acetate and chloroquine can be used during pregnancy, bearing in mind however that side effects may still occur. Experience is limited concerning natalizumab, fingolimod, dimethyl-fumarate and induction treatments. Conclusion: At the time of prescription, patients must be informed of the possible consequences of immunosuppressants on fertility and of the need for contraception. Pregnancy must be planned and the treatment modified if necessary in a pre-conception time period adapted to the half-life of the drug, imperatively in relation with the prescriber of the immunosuppressive drugs. PMID- 26490565 TI - Data research on child abuse and neglect without informed consent? Balancing interests under Dutch law. AB - According to the Declaration of Helsinki, participation of human subjects in medical research is only acceptable if subjects have given their consent. But in child abuse and neglect, many studies use a design in which subjects do not actively participate. Data in these studies are gathered from sources such as medical records or Child Protective Services. As long as such data are used anonymously, this does not interfere with individual privacy rights. However, some research is only possible when carried out with personally identifiable data, which could potentially be misused. In this paper, we discuss in which situations and under which conditions personal data of children may be used for a study without obtaining consent. In doing so, we make use of two recent studies, performed in our hospital, in which we encountered this issue. Both studies involved collecting personal data. After careful consideration, we decided not to ask informed consent; instead, we arranged for specific safeguards to protect the subject's and their parents' privacy as well as possible. CONCLUSION: Altogether, we conclude that our approach fits within the Dutch legal framework and seems a reasonable solution in situations in which individual privacy rights are at odds with the public interest of child abuse and neglect research. We argue that, although, in principle, data research is only acceptable after informed consent is obtained, the law should allow that, under specific circumstances and safeguards, this requirement is put aside to make research in the field of child abuse and neglect possible. WHAT IS KNOWN: * In principle, data research is only acceptable after informed consent is obtained.* In practice, this is not always feasible. WHAT IS NEW: * Under specific circumstances and safeguards, the informed consent requirement can be put aside. PMID- 26490566 TI - Physical activity and cardiorespiratory fitness, but not sedentary behavior, are associated with carotid intima-media thickness in obese adolescents. AB - This study aimed to analyze the associations between sedentary behavior, physical activity (PA), and cardiorespiratory fitness (CRF), with carotid intima-media thickness (cIMT), a marker of atherosclerosis already present at an early stage among obese adolescents. The associations between anthropometric measures, sedentary time, PA, CRF, and cIMT of 54 Caucasian obese adolescents were analyzed using partial correlations (controlling for age and sex) and multiple linear regressions. Differences between participants with and without a healthy CRF were also analyzed using independent sample t test. Sedentary time did not correlate with any of the variables. Light physical activity correlated positively with mean cIMT (r(38) = 0.36, p = 0.024). Moderate physical activity (MPA) correlated positively with both mean (r(38) = 0.37, p = 0.018) and maximum (r(38) = 0.33, p = 0.039) cIMT. CRF was inversely associated with mean cIMT (r(40) = -0.36, p = 0.019), even when controlling for sedentary time (r(37) = -0.35, p = 0.030). The best predictors of cIMT were MPA and weight. No significant differences in cIMT were found between participants with healthy and unhealthy CRF. CONCLUSION: Although we need to be cautious due to the limitations of the study, the results suggest that despite the importance of decreasing sedentary time, increasing PA intensity may be more effective in improving endothelial structural health among obese adolescents. PMID- 26490568 TI - Differences in the neural correlates of affective responses in depressed and healthy women. AB - We aimed to characterize the extent to which there were differences in neural activation between female participants who were diagnosed with or without depression while viewing negative and neutral imagery. The study enrolled 105 medication-free, right-handed female participants between 17 and 63 years who met criteria for current Major Depressive Disorder (n=47) or no prior psychiatric diagnoses (n=58). All participants completed a clinical assessment and underwent a functional Magnetic Resonance Imaging (fMRI) scan while responding to an implicit affect task that required them to identify the location of ideographs embedded in one of four corners of each valenced image. When unpleasant (termed negative) stimuli were presented, depressed relative to healthy participants showed significantly decreased activation of the left amygdala and right Inferior Parietal Lobe (IPL). When activation was assessed during the negative versus neutral condition, depressed relative to healthy participants showed significantly increased activation in the Anterior Cingulate Cortex (ACC) and the left IPL. Notably, within-group analyses of healthy participants under the negative condition showed that depressive severity was positively correlated with activation in the left amygdala and left IPL. Our findings suggest that depression influences bottom-up and top-down processing of unpleasant information. PMID- 26490567 TI - Neuro-developmental outcome of a large cohort of growth discordant twins. AB - Our aims were to study the effect of birthweight growth discordance (>=20%) on neuro-developmental outcome of monochorionic and dichorionic twins and to compare the relative effects of foetal growth discordance and prematurity on cognitive outcome. We performed a cross-sectional multicentre prospective follow-up study from a cohort of 948 twin pregnancies. One hundred nineteen birthweight discordant twin pairs were examined (24 monochorionic pairs) and were matched for gestational age at delivery with 111 concordant control pairs. Participants were assessed with the Bayley Scales between 24 and 42 months of age. Analysis was by paired t test for intra-twin pair differences and by multiple linear regression. Compared to the larger twin of a discordant pair, the smaller twin performed significantly worse in cognition (mean composite cognitive score difference = 1.7, 95% confidence interval (CI) = 0.3-3.1, p = 0.01) and also in language and motor skills. Prematurity prior to 33 weeks' gestation, however, had a far greater impact on cognitive outcomes (mean cognitive composite score difference = -5.8, 95% CI = 1.2-10.5, p = 0.008). CONCLUSION: Birthweight growth discordance of >=20% confers an independent adverse effect on long-term neuro-development of the smaller twin. However, prior to 33 weeks' gestation, gestational age at birth adversely affects cognitive development to a greater extent than foetal growth discordance. PMID- 26490570 TI - The Dark Matter of the Bibliome. PMID- 26490569 TI - Gray and white matter volume abnormalities in generalized anxiety disorder by categorical and dimensional characterization. AB - Increasing efforts have been made to investigate the underlying pathophysiology of generalized anxiety disorder (GAD), but only limited consistent information is available on gray (GM) and white matter (WM) volume changes in affected adults. Additionally, few studies employed dimensional approaches to GAD pathology. This study compares structural brain imaging data from n=19 GAD subjects and n=24 healthy comparison (HC) subjects, all medication-free and matched on age, sex and education. Separate categorical and dimensional models were employed using voxel based morphometry for GM and WM. Significantly higher GM volumes were found in GAD subjects mainly in basal ganglia structures and less consistently in the superior temporal pole. For WM, GAD subjects showed significantly lower volumes in the dlPFC. Largely consistent findings in dimensional and categorical models point toward these structural alterations being reliable and of importance for GAD. While lower volume in the dlPFC could reflect impaired emotional processing and control over worry in GAD, basal ganglia alterations may be linked to disturbed gain and loss anticipation as implicated in previous functional GAD studies. As perturbations in anticipation processes are central to GAD, these areas may warrant greater attention in future studies. PMID- 26490571 TI - Calf management practices and associations with herd-level morbidity and mortality on beef cow-calf operations. AB - The objective of this study was to investigate calf management practices on beef cow-calf operations and determine associations with herd-level morbidity and mortality of pre-weaned calves. A 40-question survey about management practices, morbidity and mortality was administered to cow-calf producers by distributing paper surveys and by circulating an online link through various media. A total of 267 producers completed the survey. Data were analyzed with descriptive statistics and multivariable linear regression models. Average herd-level treatment risk for pre-weaning calf diarrhea (PCD) and bovine respiratory disease (BRD) were 4.9% and 3.0%, respectively. Average herd-level mortality within the first 24 h of life (stillbirth), from 1 to 7 days and 7 days to weaning were 2.3%, 1.1%, and 1.4%, respectively. Operations that never intervened at parturition had 4.7% higher PCD than those that occasionally did. On operations using small elastrator bands for castration, PCD was 1.9% higher than those using other methods. For every increase of 100 cows in herd size, BRD decreased by 1.1%. The association between BRD and PCD varied by when calving season began. Operations that used off-farm, frozen colostrum had a 1.1% increase in stillbirths. Operations that verified a calf had suckled had 0.7% lower mortality from 1 to 7 days of age. Those that intervened when colostrum was abnormal or that used small elastrator bands for castration had 1.9% and 1.4% higher mortality during the 1st week of life, respectively, compared with other operations. Mortality from 7 days to weaning was lower by 0.7% when calving season started in April compared with January or February and was higher by 1.0% for each additional week of calving season. Operations that intervened with colostrum consumption for assisted calvings had lower mortality from 7 days to weaning by 0.8% compared with those that did not. For every 1.0% increase in BRD, mortality from 7 days to weaning increased by 1.0%. Stillbirths and mortality from 7 days to weaning decreased non-linearly with herd size. Factors related to calving season, herd size, interventions at calving, colostrum management and castration impacted herd-level morbidity and mortality. However, effect size was generally small and causation cannot be determined with a cross-sectional study design. This study identifies several common health management practices associated with calfhood morbidity and mortality that should be further investigated to establish evidence-based management strategies to improve the health and survival of beef calves. PMID- 26490572 TI - Benign soft tissue lesions that may mimic malignancy. AB - Soft tissue lesions which mimic malignancy (pseudosarcomas), represent a significant diagnostic challenge for pathologists. Many features often associated with malignancy including rapid and infiltrative growth, increased cellularity and mitotic activity, and nuclear pleomorphism are present in benign and reactive conditions. This review highlights repair reactions including nodular fasciitis, proliferative fasciitis/myositis, intravascular papillary endothelial hyperplasia, and fat necrosis; lipoma and spindle cell/pleomorphic lipoma; fibroepithelial stromal (pseudosarcomatoid) polyp; phosphaturic mesenchymal tumor; and myxoma. While not inclusive of every pseudoneoplastic soft tissue lesion, this review emphasizes important diagnostic pitfalls and stresses the value of clinical, pathologic, and radiologic correlation. PMID- 26490573 TI - The complete sequence of mitochondrial genome of Wuzhishan pig (Sus Scrofa). AB - In the present study, we sequenced the complete mitochondrial genome of Wuzhishan pig, which was 16,741 bp in size and had a nucleotide composition in A and T (60.46%). The genome consisted of a major non-coding control region (D-loop region) and 37 genes, including 2 ribosomal RNA (rRNA) genes, 13 protein-coding genes (PCGs), and 22 transfer RNA (tRNA) genes. The genes in the mitochondrial genomes of Wuzhishan pig used three kinds of initiation codons (ATA, ATG, and GTG) and four kinds of termination codons (TAA, AGA, TAG, and an incomplete termination codons T-). The complete mitochondrial genome sequence of Wuzhishan pig provides an important data set for further study on genetic mechanism. PMID- 26490574 TI - Diagnostic value of matrix metalloproteinase 9 and tissue inhibitor of matrix metalloproteinases 1 in cholesteatoma. AB - OBJECTIVES: Matrix metalloproteinase 9 (MMP-9), able to degrade type IV collagen, plays a key role in inflammatory cell migration as well as in the destructive behaviour of cholesteatoma. The aim of our study was to compare the expression of MMP-9 and TIMP-1 in cholesteatoma tissue and in the concentrations in serum and plasma concentrations. MATERIAL AND METHODS: Twenty five adult patients suffering from cholesteatoma (a study group) were included in the study. A comparison group consisted of 25 adult patients admitted to hospital due to nasal septum deviation. MM-9 and TIMP-1 serum and plasma concentrations as well as proteins' expressions in cholesteatoma tissues (study group) and normal retroauricular skin specimens (control group) were evaluated. MMP-9 and TIMP-1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Cholesteatoma tissues and normal retroauricular skin specimens were evaluated immunohistochemically. RESULTS: In the study and a comparison groups, MMP-9 and TIMP-1 concentrations were similar with no significant difference within the groups. In cholesteatoma tissues, the expression of the investigated enzyme and its inhibitor was higher than in normal skin specimens, limited mostly to cholesteatoma perimatrix. CONCLUSION: Cholesteatoma may be limited to the middle ear or parts of the temporal bones. Our findings suggest better clinical usefulness of MMP-9 and TIMP 1 expression in cholesteatoma tissues than either serum or plasma levels of these proteins. It might suggest that the higher the expression of MMP-9 the stronger the inflammation -accompanied cholesteatoma. PMID- 26490576 TI - Biological theories of aging. PMID- 26490577 TI - Russian roulette. PMID- 26490578 TI - Abstract thoughts. PMID- 26490579 TI - Pick and mix. PMID- 26490580 TI - Indigenous peoples must benefit from science. PMID- 26490593 TI - US astronomers rally to end sexual harassment. PMID- 26490594 TI - Why biomedical superstars are signing on with Google. PMID- 26490595 TI - Neutrino study made key priority for US nuclear physics. PMID- 26490596 TI - Russian secret service to vet research papers. PMID- 26490597 TI - Success against blindness encourages gene therapy researchers. PMID- 26490598 TI - Cuba forges links with United States to save sharks. PMID- 26490600 TI - Hunting the Godzilla El Nino. PMID- 26490601 TI - The lab that knows where your time really goes. PMID- 26490602 TI - Atmospheric chemistry: China's choking cocktail. PMID- 26490603 TI - Ancient civilization: Cracking the Indus script. PMID- 26490606 TI - Q&A: The nanomaterials designer. PMID- 26490607 TI - Interdisciplinarity: Less vague please. PMID- 26490608 TI - Research funding: Deposited grants buy time in Brazil. PMID- 26490609 TI - Emissions: Dutch government appeals climate law. PMID- 26490610 TI - Interdisciplinarity: Resources abound. PMID- 26490611 TI - Climate policy: US environmentalists must turn out to vote. PMID- 26490612 TI - Fluid dynamics: Turbulence spreads like wildfire. PMID- 26490613 TI - Immunology: Chronic effects of acute infections. PMID- 26490614 TI - Climate science: Small glacier has big effect on sea-level rise. PMID- 26490616 TI - Microbiology: Conductive consortia. PMID- 26490617 TI - Exoplanets: A glimpse of Earth's fate. PMID- 26490618 TI - Ecology: Mangrove maintenance. PMID- 26490619 TI - Flows of X-ray gas reveal the disruption of a star by a massive black hole. AB - Tidal forces close to massive black holes can violently disrupt stars that make a close approach. These extreme events are discovered via bright X-ray and optical/ultraviolet flares in galactic centres. Prior studies based on modelling decaying flux trends have been able to estimate broad properties, such as the mass accretion rate. Here we report the detection of flows of hot, ionized gas in high-resolution X-ray spectra of a nearby tidal disruption event, ASASSN-14li in the galaxy PGC 043234. Variability within the absorption-dominated spectra indicates that the gas is relatively close to the black hole. Narrow linewidths indicate that the gas does not stretch over a large range of radii, giving a low volume filling factor. Modest outflow speeds of a few hundred kilometres per second are observed; these are below the escape speed from the radius set by variability. The gas flow is consistent with a rotating wind from the inner, super-Eddington region of a nascent accretion disk, or with a filament of disrupted stellar gas near to the apocentre of an elliptical orbit. Flows of this sort are predicted by fundamental analytical theory and more recent numerical simulations. PMID- 26490620 TI - A disintegrating minor planet transiting a white dwarf. AB - Most stars become white dwarfs after they have exhausted their nuclear fuel (the Sun will be one such). Between one-quarter and one-half of white dwarfs have elements heavier than helium in their atmospheres, even though these elements ought to sink rapidly into the stellar interiors (unless they are occasionally replenished). The abundance ratios of heavy elements in the atmospheres of white dwarfs are similar to the ratios in rocky bodies in the Solar System. This fact, together with the existence of warm, dusty debris disks surrounding about four per cent of white dwarfs, suggests that rocky debris from the planetary systems of white-dwarf progenitors occasionally pollutes the atmospheres of the stars. The total accreted mass of this debris is sometimes comparable to the mass of large asteroids in the Solar System. However, rocky, disintegrating bodies around a white dwarf have not yet been observed. Here we report observations of a white dwarf--WD 1145+017--being transited by at least one, and probably several, disintegrating planetesimals, with periods ranging from 4.5 hours to 4.9 hours. The strongest transit signals occur every 4.5 hours and exhibit varying depths (blocking up to 40 per cent of the star's brightness) and asymmetric profiles, indicative of a small object with a cometary tail of dusty effluent material. The star has a dusty debris disk, and the star's spectrum shows prominent lines from heavy elements such as magnesium, aluminium, silicon, calcium, iron, and nickel. This system provides further evidence that the pollution of white dwarfs by heavy elements might originate from disrupted rocky bodies such as asteroids and minor planets. PMID- 26490621 TI - The rise of fully turbulent flow. AB - Over a century of research into the origin of turbulence in wall-bounded shear flows has resulted in a puzzling picture in which turbulence appears in a variety of different states competing with laminar background flow. At moderate flow speeds, turbulence is confined to localized patches; it is only at higher speeds that the entire flow becomes turbulent. The origin of the different states encountered during this transition, the front dynamics of the turbulent regions and the transformation to full turbulence have yet to be explained. By combining experiments, theory and computer simulations, here we uncover a bifurcation scenario that explains the transformation to fully turbulent pipe flow and describe the front dynamics of the different states encountered in the process. Key to resolving this problem is the interpretation of the flow as a bistable system with nonlinear propagation (advection) of turbulent fronts. These findings bridge the gap between our understanding of the onset of turbulence and fully turbulent flows. PMID- 26490624 TI - Junior doctors: it's not about the money. PMID- 26490622 TI - Intercellular wiring enables electron transfer between methanotrophic archaea and bacteria. AB - The anaerobic oxidation of methane (AOM) with sulfate controls the emission of the greenhouse gas methane from the ocean floor. In marine sediments, AOM is performed by dual-species consortia of anaerobic methanotrophic archaea (ANME) and sulfate-reducing bacteria (SRB) inhabiting the methane-sulfate transition zone. The biochemical pathways and biological adaptations enabling this globally relevant process are not fully understood. Here we study the syntrophic interaction in thermophilic AOM (TAOM) between ANME-1 archaea and their consortium partner SRB HotSeep-1 (ref. 6) at 60 degrees C to test the hypothesis of a direct interspecies exchange of electrons. The activity of TAOM consortia was compared to the first ANME-free culture of an AOM partner bacterium that grows using hydrogen as the sole electron donor. The thermophilic ANME-1 do not produce sufficient hydrogen to sustain the observed growth of the HotSeep-1 partner. Enhancing the growth of the HotSeep-1 partner by hydrogen addition represses methane oxidation and the metabolic activity of ANME-1. Further supporting the hypothesis of direct electron transfer between the partners, we observe that under TAOM conditions, both ANME and the HotSeep-1 bacteria overexpress genes for extracellular cytochrome production and form cell-to-cell connections that resemble the nanowire structures responsible for interspecies electron transfer between syntrophic consortia of Geobacter. HotSeep-1 highly expresses genes for pili production only during consortial growth using methane, and the nanowire-like structures are absent in HotSeep-1 cells isolated with hydrogen. These observations suggest that direct electron transfer is a principal mechanism in TAOM, which may also explain the enigmatic functioning and specificity of other methanotrophic ANME-SRB consortia. PMID- 26490625 TI - A prospective study of psychological resilience and depression among left-behind children in China. AB - This prospective study examined the longitudinal effects of psychological resilience on depression in a Chinese sample of left-behind children. A total of 386 left-behind children completed both a baseline and a 1-year follow-up survey. The prevalence of depression at the baseline and 1-year follow-up was 12.7 and 8.5 per cent, respectively. Multivariate analysis revealed that older age and baseline depressive symptoms were positively associated with follow-up depression, while psychological resilience and quality of life were negatively related to follow-up depression. Our findings provided preliminary evidence that higher psychological resilience was a significantly protective factor of developing depression among left-behind children. PMID- 26490626 TI - Prevent the blue, be true to you: Authenticity buffers the negative impact of loneliness on alcohol-related problems, physical symptoms, and depressive and anxiety symptoms. AB - This study investigated authenticity as a moderator of the association between loneliness and depressive symptoms, anxiety, physical symptoms, and alcohol related problems. It was expected that loneliness and health outcomes would be negatively related and that relationship would be weaker among those higher in authenticity. Significant interactions emerged between authenticity and loneliness for each outcome such that authenticity mitigated the relationship between higher loneliness and negative health outcomes. Results suggest that authenticity may be an underutilized resource for lonely individuals and warrants future investigation. The potential implications are diverse and could be incorporated in college adjustment and health promotion programs. PMID- 26490627 TI - Post-traumatic stress disorder symptoms may explain poor mental health in patients with fibromyalgia. AB - Symptoms of post-traumatic stress disorder are common in fibromyalgia patients. This study compared post-traumatic stress disorder symptoms in fibromyalgia patients and healthy controls and determined whether patient-control differences in post-traumatic stress disorder symptoms mediated differences in mental health. In all, 30 patients and 30 healthy controls completed questionnaires assessing symptoms of post-traumatic stress disorder and mental health. Fibromyalgia patients had greater symptoms of post-traumatic stress disorder and mental health than controls. Patient-control differences in mental health symptoms were fully or partially mediated by differences in post-traumatic stress disorder symptoms. Healthcare providers should understand the role of trauma as management of trauma symptoms may be one strategy for improving mental health. PMID- 26490628 TI - The cost of attack in competing networks. AB - Real-world attacks can be interpreted as the result of competitive interactions between networks, ranging from predator-prey networks to networks of countries under economic sanctions. Although the purpose of an attack is to damage a target network, it also curtails the ability of the attacker, which must choose the duration and magnitude of an attack to avoid negative impacts on its own functioning. Nevertheless, despite the large number of studies on interconnected networks, the consequences of initiating an attack have never been studied. Here, we address this issue by introducing a model of network competition where a resilient network is willing to partially weaken its own resilience in order to more severely damage a less resilient competitor. The attacking network can take over the competitor's nodes after their long inactivity. However, owing to a feedback mechanism the takeovers weaken the resilience of the attacking network. We define a conservation law that relates the feedback mechanism to the resilience dynamics for two competing networks. Within this formalism, we determine the cost and optimal duration of an attack, allowing a network to evaluate the risk of initiating hostilities. PMID- 26490629 TI - Choreographed swimming of copepod nauplii. AB - Small metazoan paddlers, such as crustacean larvae (nauplii), are abundant, ecologically important and active swimmers, which depend on exploiting viscous forces for locomotion. The physics of micropaddling at low Reynolds number was investigated using a model of swimming based on slender-body theory for Stokes flow. Locomotion of nauplii of the copepod Bestiolina similis was quantified from high-speed video images to obtain precise measurements of appendage movements and the resulting displacement of the body. The kinematic and morphological data served as inputs to the model, which predicted the displacement in good agreement with observations. The results of interest did not depend sensitively on the parameters within the error of measurement. Model tests revealed that the commonly attributed mechanism of 'feathering' appendages during return strokes accounts for only part of the displacement. As important for effective paddling at low Reynolds number is the ability to generate a metachronal sequence of power strokes in combination with synchronous return strokes of appendages. The effect of feathering together with a synchronous return stroke is greater than the sum of each factor individually. The model serves as a foundation for future exploration of micropaddlers swimming at intermediate Reynolds number where both viscous and inertial forces are important. PMID- 26490631 TI - Elasticity and glocality: initiation of embryonic inversion in Volvox. AB - Elastic objects across a wide range of scales deform under local changes of their intrinsic properties, yet the shapes are glocal, set by a complicated balance between local properties and global geometric constraints. Here, we explore this interplay during the inversion process of the green alga Volvox, whose embryos must turn themselves inside out to complete their development. This process has recently been shown to be well described by the deformations of an elastic shell under local variations of its intrinsic curvatures and stretches, although the detailed mechanics of the process have remained unclear. Through a combination of asymptotic analysis and numerical studies of the bifurcation behaviour, we illustrate how appropriate local deformations can overcome global constraints to initiate inversion. PMID- 26490630 TI - Methods for biological data integration: perspectives and challenges. AB - Rapid technological advances have led to the production of different types of biological data and enabled construction of complex networks with various types of interactions between diverse biological entities. Standard network data analysis methods were shown to be limited in dealing with such heterogeneous networked data and consequently, new methods for integrative data analyses have been proposed. The integrative methods can collectively mine multiple types of biological data and produce more holistic, systems-level biological insights. We survey recent methods for collective mining (integration) of various types of networked biological data. We compare different state-of-the-art methods for data integration and highlight their advantages and disadvantages in addressing important biological problems. We identify the important computational challenges of these methods and provide a general guideline for which methods are suited for specific biological problems, or specific data types. Moreover, we propose that recent non-negative matrix factorization-based approaches may become the integration methodology of choice, as they are well suited and accurate in dealing with heterogeneous data and have many opportunities for further development. PMID- 26490632 TI - Peroxidase-catalysed interfacial adhesion of aquatic caddisworm silk. AB - Casemaker caddisfly (Hesperophylax occidentalis) larvae use adhesive silk fibres to construct protective shelters under water. The silk comprises a distinct peripheral coating on a viscoelastic fibre core. Caddisworm silk peroxinectin (csPxt), a haem-peroxidase, was shown to be glycosylated by lectin affinity chromatography and tandem mass spectrometry. Using high-resolution H2O2 and peroxidase-dependent silver ion reduction and nanoparticle deposition, imaged by electron microscopy, csPxt activity was shown to be localized in the peripheral layer of drawn silk fibres. CsPxt catalyses dityrosine cross-linking within the adhesive peripheral layer post-draw, initiated perhaps by H2O2 generated by a silk gland-specific superoxide dismutase 3 (csSOD3) from environmental reactive oxygen species present in natural water. CsSOD3 was also shown to be a glycoprotein and is likely localized in the peripheral layer. Using a synthetic fluorescent phenolic copolymer and confocal microscopy, it was shown that csPxt catalyses oxidative cross-linking to external polyphenolic compounds capable of diffusive interpenetration into the fuzzy peripheral coating, including humic acid, a natural surface-active polyphenol. The results provide evidence of enzyme mediated covalent cross-linking of a natural bioadhesive to polyphenol conditioned interfaces as a mechanism of permanent adhesion underwater. PMID- 26490633 TI - Local cost minimization in ant transport networks: from small-scale data to large scale trade-offs. AB - Transport networks distribute resources and information in many human and biological systems. Their construction requires optimization and balance of conflicting criteria such as robustness against disruptions, transport efficiency and building cost. The colonies of the polydomous Australian meat ant Iridomyrmex purpureus are a striking example of such a decentralized network, consisting of trails that connect spatially separated nests. Here we study the rules that underlie network construction in these ants. We find that a simple model of network growth, which we call the minimum linking model (MLM), is sufficient to explain the growth of real ant colonies. For larger networks, the MLM shows a qualitative similarity with a Euclidean minimum spanning tree, prioritizing cost and efficiency over robustness. We introduce a variant of our model to show that a balance between cost, efficiency and robustness can be also reproduced at larger scales than ant colonies. Remarkably, such a balance is influenced by a parameter reflecting the specific features of the modelled transport system. The extended MLM could thus be a suitable source of inspiration for the construction of cheap and efficient transport networks with non-zero robustness, suggesting possible applications in the design of human-made networks. PMID- 26490634 TI - Increased exposure to Plasmodium chabaudi antigens sustains cross-reactivity and avidity of antibodies binding Nippostrongylus brasiliensis: dissecting cross phylum cross-reactivity in a rodent model. AB - Mounting an antibody response capable of discriminating amongst and appropriately targeting different parasites is crucial in host defence. However, cross-reactive antibodies that recognize (bind to) multiple parasite species are well documented. We aimed to determine if a higher inoculating dose of one species, and thus exposure to larger amounts of antigen over a longer period of time, would fine-tune responses to that species and reduce cross-reactivity. Using the Plasmodium chabaudi chabaudi (Pcc)-Nippostrongylus brasiliensis (Nb) co-infection model in BALB/c mice, in which we previously documented cross-reactive antibodies, we manipulated the inoculating dose of Pcc across 4 orders of magnitude. We investigated antigen-specific and cross-reactive antibody responses against crude and defined recombinant antigens by enzyme linked immunosorbent assay, Western blot and antibody depletion assays. Contrary to our hypothesis that increasing exposure to Pcc would reduce cross-reactivity to Nb, we found evidence for increased avidity of a subpopulation of antibodies that recognized shared antigens. Western blot indicated proteins of apparent monomer molecular mass 28 and 98 kDa in both Nb and Pcc antigen preparations and also an Nb protein of similar size to recombinant Pcc antigen, merozoite surface protein-1(19). The implications of antibodies binding antigen from such phylogenetically distinct parasites are discussed. PMID- 26490635 TI - Influence of H7N9 virus infection and associated treatment on human gut microbiota. AB - Between March and June, 2013, forty H7N9 patients were hospitalized in our hospital. Next-generation sequencing technologies have been used to sequence the fecal DNA samples of the patient, the within sample diversity analysis, enterotyping, functional gene and metagenomic species analysis have been carried on both the patients and healthy controls. The influence of associated treatment in H7N9 infected patients is dramatic and was firstly revealed in species level due to deep sequencing technology. We found that most of the MetaGenomic Species (MGS) enriched in the control samples were Roseburia inulinivorans DSM 16841, butyrate producing bacterium SS3/4 and most of MGS enriched in the H7N9 patients were Clostridium sp. 7 2 43FAA and Enterococcus faecium. It was concluded that H7N9 viral infection and antibiotic administration have a significant effect on the microbiota community with decreased diversity and overgrowth of the bacteria such as Escherichia coli and Enterococcus faecium. Enterotype analysis showed that the communities were unstable. Treatment including antivirals, probiotics and antibiotics helps to improve the microbiota diversity and the abundance of beneficial bacteria in the gut. PMID- 26490636 TI - Cell-autonomous requirement for TCF1 and LEF1 in the development of Natural Killer T cells. AB - Natural killer T (NKT) cells develop from common CD4(+) CD8(+) thymocyte precursors. Transcriptional programs that regulate the development of NKT cells in the thymus development remain to be fully delineated. Here, we demonstrate a cell-intrinsic requirement for transcription factors TCF1 and LEF1 for the development of all subsets of NKT cells. Conditional deletion of TCF1 alone results in a substantial reduction in NKT cells. The remaining NKT cells are eliminated when TCF1 and LEF1 are both deleted. These data reveal an essential role for TCF1 and LEF1 in development of NKT cells. PMID- 26490638 TI - MtiBase: a database for decoding microRNA target sites located within CDS and 5'UTR regions from CLIP-Seq and expression profile datasets. AB - MicroRNAs (miRNAs) play an important role in the regulation of gene expression. Previous studies on miRNA functions mainly focused on their target sites in the 3' untranslated regions (UTRs) of mRNAs. However, increasing evidence has revealed that miRNAs can also induce mRNA degradation and mediate translational repression via complementary interactions with the coding sequence (CDS) and 5'UTR of mRNAs. In this study, we developed a novel database, MtiBase, to facilitate the comprehensive exploration of CDS- and 5'UTR-located miRNA target sites identified from cross-linking immunoprecipitation sequencing (CLIP-Seq) datasets and to uncover their regulatory effects on mRNA stability and translation from expression profile datasets. By integrating 61 Argonaute protein binding CLIP-Seq datasets and miRNA target sites predicted by five commonly used programs, we identified approximately 4 400 000 CDS-located and 470 000 5'UTR located miRNA target sites. Moreover, we evaluated the regulatory effects of miRNAs on mRNA stability and translation using the data from 222 gene expression profiles, and 28 ribosome-protected fragment sequencing, and six pulsed stable isotope labeling with amino acids in culture. Finally, the effects of SNPs on the functions of miRNA target sites were systematically evaluated. Our study provides a useful tool for functional studies of miRNAs in regulating physiology and pathology. Database URL: http://mtibase.sysu.edu.cn. PMID- 26490639 TI - A novel method for in-vivo evaluation of finger kinematics including definition of healthy motion patterns. AB - BACKGROUND: Despite recent progress in motion capture technology, such as stereophotogrammetry based on the tracking of markers set on the subject, it remains challenging to develop a complete protocol for in-vivo functional evaluation of the hand. The current practical problems regarding small anatomical segments, such as the fingers, are mainly due to the high concentration of markers in a relatively reduced volume. METHODS: This paper proposes a novel procedure for hand functional analysis by analysing finger behaviour along the main displacement plane simultaneously with combined motions. The objective was two-fold. For one thing, a novel data collection protocol was implemented, which includes specific setting of the motion capture system and the development of finger marker clusters. The second purpose of this study was to create a reference database of a healthy sample for further clinical investigation. Twenty healthy volunteers took part in the study. Analytical motions (flexion/extension and abduction/adduction) of all five fingers were recorded. FINDINGS: Results showed good correspondence with the literature. Specific kinematic behaviour of each analysed joint is reported. Statistically significant differences were found between the right and left sides of the subjects for the flexion/extension movement only, between the finger joints and between the fingers for all movements. No significant difference was found between genders. A validation protocol was performed, which proved the validity of the presented methodology. INTERPRETATION: The protocol appears suitable for further use in motion analysis and for musculoskeletal modelling of the hand. It will also be considered for clinical application. PMID- 26490640 TI - Identification of preferred landing leg in athletes previously injured and uninjured: A brief report. AB - BACKGROUND: The preferred or dominant limb is often subjectively defined by self report. The purpose was to objectively classify preferred landing leg during landing in athletes previously injured and uninjured. METHODS: Subjects with a history of anterior cruciate ligament reconstruction (n=101) and uninjured controls (n=57) participated. Three trials of a drop vertical jump were collected. Leg dominance was defined as the leg used to kick a ball while landing leg preference was calculated as the leg which landed first during landing trials. Limb symmetry index was also calculated during a single leg hop battery. The distribution of subjects that landed first on their uninvolved or dominant leg, respectively, was statistically compared. Limb symmetry from the single leg hop tests were compared within each subgroup. FINDINGS: The distribution of preferred landing leg to uninvolved limb for injured (71%) and dominant limb for controls (63%) was not statistically different between groups (P=0.29). Limb symmetry was decreased in injured subjects that preferred to land on their uninvolved limb compared to their involved limb during single leg (P<0.001), triple (P<0.001), cross-over (P<0.001), and timed hops (P=0.007). Differences in limb symmetry were not statistically different in controls (P>0.05). INTERPRETATION: The leg that first contacts the ground during landing may be a useful strategy to classify preferred landing leg. Among the injured subjects, 29% preferred to land on their involved leg, which may relate to improved confidence and readiness to return to sport, as improved limb symmetry was present during hop tests. PMID- 26490641 TI - Use of shear wave ultrasound elastography to quantify muscle properties in cerebral palsy. AB - BACKGROUND: Individuals with cerebral palsy tend to have altered muscle architecture and composition, but little is known about the muscle material properties, specifically stiffness. Shear wave ultrasound elastography allows shear wave speed, which is related to stiffness, to be measured in vivo in individual muscles. Our aim was to evaluate the material properties, specifically stiffness, as measured by shear wave speed of the medial gastrocnemius and tibialis anterior muscles in children with hemiplegic cerebral palsy across a range of ankle torques and positions, and fascicle strains. METHOD: Shear wave speed was measured bilaterally in the medial gastrocnemius and tibialis anterior over a range of ankle positions and torques using shear wave ultrasound elastography in eight individuals with hemiplegic cerebral palsy. B-mode ultrasound was used to measure muscle thickness and fascicle strain. RESULTS: Shear waves traveled faster in the medial gastrocnemius and tibialis anterior of the more-affected limb by 14% (P=0.024) and 20% (P=0.03), respectively, when the ankle was at 90 degrees . Shear wave speed in the medial gastrocnemius increased as the ankle moved from plantarflexion to dorsiflexion (less affected: r(2)=0.82, P<0.001; more-affected: r(2)=0.69, P<0.001) and as ankle torque increased (less affected: r(2)=0.56, P<0.001; more-affected: r(2)=0.45, P<0.001). In addition, shear wave speed was strongly correlated with fascicle strain (less affected: r(2)=0.63, P<0.001; more-affected: r(2)=0.53, P<0.001). INTERPRETATION: The higher shear wave speed in the more-affected limb of individuals with cerebral palsy indicates greater muscle stiffness, and demonstrates the clinical potential of shear wave elastography as a non-invasive tool for investigating mechanisms of altered muscle properties and informing diagnosis and treatment. PMID- 26490643 TI - Phonon-drag thermopower in 3D Dirac semimetals. AB - A theory of low-temperature phonon-drag thermopower S(g) in three-dimensional (3D) Dirac semimetals has been developed considering screened electron-phonon deformation potential coupling. Numerical investigations of S(g), in the boundary scattering regime for phonons, are made in 3D Dirac semimetal Cd3As2, as a function of temperature T and electron concentration n e. S(g) is found to increase rapidly for about T < 1 K and nearly levels off for higher T. It is also seen that S(g) increases (decreases) with decreasing n e at lower (higher) T (<2 K). A screening effect is found to be very significant, strongly affecting T and n e dependence for about <1 K and becoming negligible at higher temperature. In the Bloch-Gruneisen (BG) regime the power laws S(g) ~ T(8) (T(4)) and S(g) ~ n(e)(-5/3)(n(e)(-1/3) with (without) screening are obtained. These laws with respect to T and n e are, respectively, characteristics of 3D phonons and Dirac 3D electrons. Comparison with diffusion thermopower S(d) shows that S (g) dominates (and is much greater than) S(d) for about T > 0.2 K. Herring's law S(g) MU p ~ T (-1), relating phonon limited mobility MU p and S(g) in the BG regime, is shown to be valid in 3D Dirac semimetals. The results obtained here are compared with those in 3D semiconductors, low-dimensional semiconductor heterojunctions and graphene. We conclude that n e-dependent measurements, rather than T-dependent ones, provide a clearer signature of the 3D Dirac semimetal phase. PMID- 26490642 TI - Mesenchymal Stem Cells Reduce Murine Atherosclerosis Development. AB - Mesenchymal stem cells (MSCs) have regenerative properties, but recently they were also found to have immunomodulatory capacities. We therefore investigated whether MSCs could reduce atherosclerosis, which is determined by dyslipidaemia and chronic inflammation. We adoptively transferred MSCs into low-density lipoprotein-receptor knockout mice and put these on a Western-type diet to induce atherosclerosis. Initially after treatment, we found higher levels of circulating regulatory T cells. In the long-term, overall numbers of effector T cells were reduced by MSC treatment. Moreover, MSC-treated mice displayed a significant 33% reduction in circulating monocytes and a 77% reduction of serum CCL2 levels. Most strikingly, we found a previously unappreciated effect on lipid metabolism. Serum cholesterol was reduced by 33%, due to reduced very low-density lipoprotein levels, likely a result of reduced de novo hepatic lipogenesis as determined by a reduced expression of Stearoyl-CoA desaturase-1 and lipoprotein lipase. MSCs significantly affected lesion development, which was reduced by 33% in the aortic root. These lesions contained 56% less macrophages and showed a 61% reduction in T cell numbers. We show here for the first time that MSC treatment affects not only inflammatory responses but also significantly reduces dyslipidaemia in mice. This makes MSCs a potent candidate for atherosclerosis therapies. PMID- 26490644 TI - Racial Differences in Treatment Approaches and Mortality Following Arterial Trauma. AB - OBJECTIVES: We sought to evaluate the impact of race on treatment approaches and mortality following arterial trauma. METHODS: The National Trauma Data Bank (version 7.2, American College of Surgeons) was queried from 2002 to 2012 to identify patients aged 18 to 65 years with arterial trauma. The association between race (white, black, and Hispanic) and mortality following arterial injury was assessed, stratified by penetrating or blunt injury. Temporal trends in the use of open and endovascular procedures were evaluated across the racial groups. Multivariable regression models adjusting for patient demographics, injury severity, hospital characteristics, insurance status, and type of intervention performed were used to evaluate potential contributors to the association of race with mortality. RESULTS: The study cohort consisted of 58 626 patients (52% white, 31% black, and 17% Hispanic). A majority (57%) of patients had penetrating injuries, with black and Hispanic patients being more likely to sustain penetrating injuries (80% and 65%, respectively) compared to white patients (41%, P < .001). Overall, black patients had higher mortality for penetrating injuries (16.8% vs 13.0% vs 7.8%, P < .001) when compared to Hispanic and white patients, correspondingly. Over the study period, there was increasing use of endovascular and decreasing open surgical procedures for treatment of arterial trauma. This finding was similar across all groups studied. In multivariable analysis, black race was found to be associated with higher mortality compared to white for both penetrating (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.33-1.75, P < .001) and blunt (OR 1.27 95%CI 1.09-1.47, P = .002) arterial trauma. CONCLUSION: Even after adjusting for potential confounders, minority patients had increased odds of mortality following arterial trauma compared to their white counterparts. Further studies are needed to understand and to eliminate these observed disparities in outcome. PMID- 26490645 TI - Orbital Atherectomy Plaque Modification Assessment of the Femoropopliteal Artery Via Intravascular Ultrasound (TRUTH Study). AB - OBJECTIVE: The Tissue Removal Assessment with Ultrasound of the SFA and Popliteal (TRUTH) study assessed the performance of the orbital atherectomy system (OAS) to treat femoropopliteal arteries, including determining its effect on plaque removal. METHODS: Patients with symptomatic femoropopliteal peripheral arterial disease were treated with the OAS followed by adjunctive balloon angioplasty (BA). Intravascular ultrasound (IVUS) images were collected pre- and post-OAS and post-OAS BA. Patients were followed through 12 months post-procedure. RESULTS: Twenty-nine lesions were treated with OAS-BA in 25 patients. The mean maximum balloon inflation pressure was 5.2 +/- 1.2 atm. Virtual histology IVUS (VH-IVUS) analysis revealed at the maximum calcium ablation site that calcium reduction was responsible for 86% of the lumen area increase. The minimum lumen area increased from 4.0 mm(2) to 9.1 mm(2) (<.0001), and the percentage of area stenosis decreased from 76.9% to 43.0% (<.0001) after OAS-BA. At 12 months, the target lesion revascularization rate was 8.2%, and ankle-brachial index and Rutherford classification improved significantly from baseline through follow-up. CONCLUSION: The VH-IVUS analysis reveals that OAS modifies the calcified component of the plaque burden. It is hypothesized that calcium modification by OAS changes the lesion compliance, allowing for low pressure adjunctive BA. The clinical outcomes were favorable through 12-month follow-up. PMID- 26490646 TI - Inhibition of Casein Kinase 1 Alpha Prevents Acquired Drug Resistance to Erlotinib in EGFR-Mutant Non-Small Cell Lung Cancer. AB - Patients with lung tumors harboring activating mutations in the EGF receptor (EGFR) show good initial treatment responses to the EGFR tyrosine kinase inhibitors (TKI) erlotinib or gefitinib. However, acquired resistance invariably develops. Applying a focused shRNA screening approach to identify genes whose knockdown can prevent and/or overcome acquired resistance to erlotinib in several EGFR-mutant non-small cell lung cancer (NSCLC) cell lines, we identified casein kinase 1 alpha (CSNK1A1, CK1alpha). We found that CK1alpha suppression inhibits the NF-kappaB prosurvival signaling pathway. Furthermore, downregulation of NF kappaB signaling by approaches independent of CK1alpha knockdown can also attenuate acquired erlotinib resistance, supporting a role for activated NF kappaB signaling in conferring acquired drug resistance. Importantly, CK1alpha suppression prevented erlotinib resistance in an HCC827 xenograft model in vivo. Our findings suggest that patients with EGFR-mutant NSCLC might benefit from a combination of EGFR TKIs and CK1alpha inhibition to prevent acquired drug resistance and to prolong disease-free survival. PMID- 26490647 TI - Synergism between carvacrol or thymol increases the antimicrobial efficacy of soy sauce with no sensory impact. AB - Here, we examined the antimicrobial effects of soy sauce containing essential oils (EOs) against Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes at 22 degrees C and 4 degrees C. To screen a variety of combined effects, soy sauce was mixed with six different EOs (carvacrol, thymol, eugenol, trans-cinnamaldehyde, beta-resorcylic acid, and vanillin), each at a concentration of 1mM for 10 min. None of the oils showed bactericidal activity when used alone. Soy sauce combined with carvacrol and thymol induced the greatest antibacterial activity against all tested bacteria; therefore, these oils were further tested at 0.25, 0.5, and 1mM (0.0039%, 0.0078%, and 0.0157%) for 1, 5, and 10 min at 4 degrees C and 22 degrees C. In addition, sensory evaluation of soy sauce containing each EO at 0.25, 0.5, 1, and 2mM was performed using the nine point hedonic test. Carvacrol or thymol (1mM) eliminated all the test bacteria (initial population, 7.0-7.5logCFU/ml) in 1-5 min at 22 degrees C and within 10 min at 4 degrees C. L. monocytogenes was slightly more tolerant at 4 degrees C, which may be attributable to the ability of the cell membrane to adapt to low temperatures. The sensory scores for soy sauce containing EOs were not significantly different from that of soy sauce without EOs (P>0.05). The stability of EO efficacy in soy sauce was also verified. These results suggest that carvacrol and thymol act synergistically with other factors present in soy sauce to increase antimicrobial activity against major foodborne pathogens at both 4 degrees C and 22 degrees C. The synergism may be attributable to the combination of factors (mainly high salt concentration and low pH imparted by organic acids) present in soy sauce and the membrane attacking properties of carvacrol and thymol. This method will facilitate the production of microbiologically safe soy sauce, soy sauce-based marinades, and various marinated foods. PMID- 26490648 TI - Inactivation of bacterial pathogens in yoba mutandabota, a dairy product fermented with the probiotic Lactobacillus rhamnosus yoba. AB - Mutandabota is a dairy product consumed as a major source of proteins and micronutrients in Southern Africa. In this study the microbial safety of traditional and a variant of mutandabota fermented with the probiotic Lactobacillus rhamnosus yoba (yoba mutandabota) was investigated by challenging the products with five important food pathogens: Listeria monocytogenes, Salmonella spp., Campylobacter jejuni, Escherichia coli O157:H7 and Bacillus cereus. Pasteurized full-fat cow's milk was used for producing traditional and yoba mutandabota, and was inoculated with a cocktail of strains of the pathogens at an inoculum level of 5.5 log cfu/mL. Survival of the pathogens was monitored over a potential consumption time of 24h for traditional mutandabota, and over 24h of fermentation followed by 24h of potential consumption time for yoba mutandabota. In traditional mutandabota (pH3.4 +/- 0.1) no viable cells of B. cereus and C. jejuni were detected 3h after inoculation, while L. monocytogenes, E. coli O157:H7 and Salmonella spp. significantly declined (P<0.05), but could still be detected (<3.5 log inactivation) at the end of the potential consumption time. This indicated that consumption of traditional mutandabota exposes consumers to the risk of food-borne microbial infections. In yoba mutandabota, L. rhamnosus yoba grew from 5.5 +/- 0.1 log cfu/mL to 9.1 +/- 0.4 log cfu/mL in the presence of pathogens. The pH of yoba mutandabota dropped from 4.2 +/- 0.1 to 3.3 +/- 0.1 after 24h of fermentation, mainly due to organic acids produced during fermentation. Only Salmonella spp. was able to grow in yoba mutandabota during the first 9h of fermentation, but then decreased in viable plate count. None of the tested pathogens were detected (>3.5 log inactivation) after 3h into potential consumption time of yoba mutandabota. Inactivation of pathogens in mutandabota is of public health significance because food-borne pathogens endanger public health upon consumption of contaminated food, especially in Southern Africa where there are many vulnerable consumers of mutandabota such as children, elderly and immuno-compromised people with HIV/AIDS. The findings of this study demonstrate that mutandabota fermented with L. rhamnosus yoba has antimicrobial properties against the tested pathogens and it is safer compared to the traditional mutandabota. PMID- 26490649 TI - Development of prototypes of bioactive packaging materials based on immobilized bacteriophages for control of growth of bacterial pathogens in foods. AB - Due to lack of adequate control methods to prevent contamination in fresh produce and growing consumer demand for natural products, the use of bacteriophages has emerged as a promising approach to enhance safety of these foods. This study sought to control Listeria monocytogenes in cantaloupes and RTE meat and Escherichia coli O104:H4 in alfalfa seeds and sprouts under different storage conditions by using specific lytic bacteriophage cocktails applied either free or immobilized. Bacteriophage cocktails were introduced into prototypes of packaging materials using different techniques: i) immobilizing on positively charged modified cellulose membranes, ii) impregnating paper with bacteriophage suspension, and iii) encapsulating in alginate beads followed by application of beads onto the paper. Phage-treated and non-treated samples were stored for various times and at temperatures of 4 degrees C, 12 degrees C or 25 degrees C. In cantaloupe, when free phage cocktail was added, L. monocytogenes counts dropped below the detection limit of the plating technique (<1 log CFU/g) after 5 days of storage at both 4 degrees C and 12 degrees C. However, at 25 degrees C, counts below the detection limit were observed after 3 and 6h and a 2-log CFU/g reduction in cell numbers was seen after 24h. For the immobilized Listeria phage cocktail, around 1-log CFU/g reduction in the Listeria count was observed by the end of the storage period for all tested storage temperatures. For the alfalfa seeds and sprouts, regardless of the type of phage application technique (spraying of free phage suspension, bringing in contact with bacteriophage-based materials (paper coated with encapsulated bacteriophage or impregnated with bacteriophage suspension)), the count of E. coli O104:H4 was below the detection limit (<1 log CFU/g) after 1h in seeds and about a 1-log cycle reduction in E. coli count was observed on the germinated sprouts by day 5. In ready-to-eat (RTE) meat, LISTEXTM P100, a commercial phage product, was able to significantly reduce the growth of L. monocytogenes at both storage temperatures, 4 degrees C and 10 degrees C, for 25 days regardless of bacteriophage application format (immobilized or non-immobilized (free)). In conclusion, the developed phage-based materials demonstrated significant antimicrobial effect, when applied to the artificially contaminated foods, and can be used as prototypes for developing bioactive antimicrobial packaging materials capable of enhancing the safety of fresh produce and RTE meat. PMID- 26490650 TI - Microbial community dynamics in thermophilic undefined milk starter cultures. AB - Model undefined thermophilic starter cultures were produced from raw milk of nine pasta-filata cheesemaking plants using a selective procedure based on pasteurization and incubation at high temperature with the objective of studying the microbial community dynamics and the variability in performances under repeated (7-13) reproduction cycles with backslopping. The traditional culture dependent approach, based on random isolation and molecular characterization of isolates was coupled to the determination of pH and the evaluation of the ability to produce acid and fermentation metabolites. Moreover, a culture-independent approach based on amplicon-targeted next-generation sequencing was employed. The microbial diversity was evaluated by 16S rRNA gene sequencing (V1-V3 regions), while the microdiversity of Streptococcus thermophilus populations was explored by using novel approach based on sequencing of partial amplicons of the phosphoserine phosphatase gene (serB). In addition, the occurrence of bacteriophages was evaluated by qPCR and by multiplex PCR. Although it was relatively easy to select for a community dominated by thermophilic lactic acid bacteria (LAB) within a single reproduction cycle, final pH, LAB populations and acid production activity fluctuated over reproduction cycles. Both culture dependent and -independent methods showed that the cultures were dominated by either S. thermophilus or Lactobacillus delbrueckii subsp. lactis or by both species. Nevertheless, subdominant mesophilic species, including lactococci and spoilage organisms, persisted at low levels. A limited number of serB sequence types (ST) were present in S. thermophilus populations. L. delbrueckii and Lactococcus lactis bacteriophages were below the detection limit of the method used and high titres of cos type S. thermophilus bacteriophages were detected in only two cases. In one case a high titre of bacteriophages was concurrent with a S. thermophilus biotype shift in the culture. This study largely confirms previous data on the composition of undefined thermophilic starters used for the production of traditional cheeses in Italy but it is the first one to systematically address the dynamics of the cultures under a repeated reproduction regime with backslopping. PMID- 26490651 TI - Early detection of Zygosaccharomyces rouxii--spawned spoilage in apple juice by electronic nose combined with chemometrics. AB - Spoilage spawned by Zygosaccharomyces rouxii can cause sensory defect in apple juice, which could hardly be perceived in the early stage and therefore would lead to the serious economic loss. Thus, it is essential to detect the contamination in early stage to avoid costly waste of products or recalls. In this work the performance of an electronic nose (e-nose) coupled with chemometric analysis was evaluated for diagnosis of the contamination in apple juice, using test panel evaluation as reference. The feasibility of using e-nose responses to predict the spoilage level of apple juice was also evaluated. Coupled with linear discriminant analysis (LDA), detection of the contamination was achieved after 12h, corresponding to the cell concentration of less than 2.0 log 10 CFU/mL, the level at which the test panelists could not yet identify the contamination, indicating that the signals of e-nose could be utilized as early indicators for the onset of contamination. Loading analysis indicated that sensors 2, 6, 7 and 8 were the most important in the detection of Z. rouxii-contaminated apple juice. Moreover, Z. rouxii counts in unknown samples could be well predicted by the established models using partial least squares (PLS) algorithm with high correlation coefficient (R) of 0.98 (Z. rouxii strain ATCC 2623 and ATCC 8383) and 0.97 (Z. rouxii strain B-WHX-12-53). Based on these results, e-nose appears to be promising for rapid analysis of the odor in apple juice during processing or on the shelf to realize the early detection of potential contamination caused by Z. rouxii strains. PMID- 26490652 TI - Absence of M-Ras modulates social behavior in mice. AB - BACKGROUND: The molecular mechanisms that determine social behavior are poorly understood. Pheromones play a critical role in social recognition in most animals, including mice, but how these are converted into behavioral responses is largely unknown. Here, we report that the absence of the small GTPase M-Ras affects social behavior in mice. RESULTS: In their interactions with other males, Mras(-/-) males exhibited high levels of territorial aggression and social investigations, and increased fear-related behavior. They also showed increased mating behavior with females. Curiously, increased aggression and mating behaviors were only observed when Mras(-/-) males were paired with Mras(-/-) partners, but were significantly reduced when paired with wild-type (WT) mice. Since mice use pheromonal cues to identify other individuals, we explored the possibility that pheromone detection may be altered in Mras(-/-) mice. Unlike WT mice, Mras(-/-) did not show a preference for exploring unfamiliar urinary pheromones or unfamiliar isogenic mice. Although this could indicate that vomeronasal function and/or olfactory learning may be compromised in Mras(-/-) mice, these observations were not fully consistent with the differential behavioral responses to WT and Mras(-/-) interaction partners by Mras(-/-) males. In addition, induction of c-fos upon pheromone exposure or in response to mating was similar in WT and Mras (-/-) mice, as was the ex vivo expansion of neural progenitors with EGF. This indicated that acute pheromone detection and processing was likely intact. However, urinary metabolite profiles differed between Mras(-/-) and WT males. CONCLUSIONS: The changes in behaviors displayed by Mras(-/-) mice are likely due to a complex combination of factors that may include an inherent predisposition to increased aggression and sexual behavior, and the production of distinct pheromones that could override the preference for unfamiliar social odors. Olfactory and/or social learning processes may thus be compromised in Mras(-/-) mice. PMID- 26490653 TI - Neuromodulation accompanying focused ultrasound-induced blood-brain barrier opening. AB - Burst-mode focused ultrasound (FUS) induces microbubble cavitation in the vasculature and temporarily disrupts the blood-brain barrier (BBB) to enable therapeutic agent delivery. However, it remains unclear whether FUS-induced BBB opening is accompanied by neuromodulation. Here we characterized the functional effects of FUS-induced BBB opening by measuring changes in somatosensory evoked potentials (SSEPs) and blood-oxygen-level dependent (BOLD) responses. Rats underwent burst-mode FUS (mechanical index (MI) of 0.3, 0.55 or 0.8) to the forelimb region in the left primary somatosensory cortex to induce BBB opening. Longitudinal measurements were followed for up to 1 week to characterize the temporal dynamics of neuromodulation. We observed that 0.8-MI FUS profoundly suppressed SSEP amplitude and prolonged latency, and this effect lasted 7 days. 0.55-MI FUS resulted in minimal and short-term suppression of SSEP for less than 60 minutes and didn't affect latency. BOLD responses were also suppressed in an MI-dependent manner, mirroring the effect on SSEPs. Furthermore, repetitive delivery of 0.55-MI FUS every 3 days elicited no accumulative effects on SSEPs or tissue integrity. This is the first evidence that FUS-induced BBB opening is accompanied by reversible changes in neuron responses, and may provide valuable insight toward the development of FUS-induced BBB opening for clinical applications. PMID- 26490654 TI - Sustained response to vemurafenib in a low grade serous ovarian cancer with a BRAF V600E mutation. AB - Low-grade serous ovarian adenocarcinomas (LGSOC) make up approximately 10 % of serous ovarian carcinomas. While rarely aggressive, this slow-growing tumor is well known to respond poorly to chemotherapy. Specific treatments for this ovarian subtype are lacking, with the same global approaches used for high grade cases being applied for LGSOC patients. LGSOCs have been reported to have a specific genetic profile, with notable implication of the MAPK pathway. This has opened up opportunities for novel therapeutic strategies, with in particular the use of targeted therapies. We report here the case of a heavily pretreated unresectable BRAF p.V600E-mutated LGSOC, which we treated vemurafenib, a BRAF inhibitor specific for V600E mutations. We saw impressive efficacy, with a long term partial response along with CA125 reductions and symptom relief. Although this mutation is present in LGSOC at very a low incidence, we recommend routine testing for BRAF and other targetable mutations in this patient population, along with further evaluation in the increasingly popular basket trial approach. PMID- 26490655 TI - A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors. AB - PURPOSE: The oral PI3K inhibitor BKM120 has been reported as safe and well tolerated in early phase clinical trials of advanced cancer patients. We performed a phase I trial of BKM120 plus mFOLFOX6 (5-FU/LV + oxaliplatin), a common chemotherapeutic backbone in GI malignancies, to establish the maximum tolerated dose (MTD) and characterize the safety and tolerability of the combination. METHODS: Patients with advanced solid tumors received oral BKM120 daily combined with standard doses of mFOLFOX6 every 2 weeks of a 28 day cycle. The study utilized a standard 3 + 3 dose escalation schema. RESULTS: A total of 17 patients received treatment with BKM120, 13 of which were evaluate for dose limited toxicity (DLT). The most common tumor types were colorectal cancer, cholangiocarcinoma, pancreatic cancer and hepatocellular carcinoma. DLT included grade 3 hyperglycemia, grade 3 AST/ALT elevation, grade 4 neutropenia and grade 4 thrombocytopenia. A total of 76 % of patients experienced treatment related grade 3/4 adverse events (AEs), the most common of which were neutropenia, fatigue, leukopenia, hyperglycemia and thrombocytopenia. One patient demonstrated an unconfirmed partial response and three patients had stable disease. DISCUSSION: The MTD of BKM120 in combination with standard doses of mFOLFOX6 was 40 mg daily, which is well below the 100 mg daily dose proven effective and tolerable both as a single agent and in combination with other chemotherapeutics. In addition, the regimen of BKM120 with mFOLFOX6 in patients with refractory solid tumors resulted in increased toxicity than would be expected from either the PI3K inhibitor or the chemotherapy backbone alone. PMID- 26490656 TI - Fluorouracil, leucovorin and irinotecan associated with aflibercept can induce microscopic colitis in metastatic colorectal cancer patients. AB - Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF). This molecule binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, preventing them from activating their respective receptors. Aflibercept is used for the treatment of metastatic colorectal cancer (mCRC) in association with irinotecan. For reasons that remain to be elucidated, the addition of aflibercept to irinotecan based chemotherapy increases the incidence of grade 3-4 diarrhea. We performed systematic colonic biopsies in three patients with grade 3 diarrhea after introduction of fluorouracil, leucovorin, irinotecan and aflibercept treatment for mCRC. For each patient, the diarrhea necessitated treatment discontinuation. Colonoscopy showed normal colonic mucosa. However, histopathological examination of the biopsies performed in these three patients revealed typical features of microscopic colitis. All three patients were treated with budesonide and mesalazine, leading to rapid regression of clinical symptoms. Chemotherapy was reintroduced in all patients, with only mild, grade 1 diarrhea under mesalazine and budesonide treatment. These are the first observations of aflibercept-induced microscopic colitis, and support the use of specific treatment on top of anti diarrheal treatment in case of important digestive adverse events. PMID- 26490657 TI - Effects of mTOR inhibitors and cytoskeletal-directed agents alone and in combination against normal and neoplastic hematopoietic cells in vitro. AB - The mechanistic target of rapamycin (mTOR) controls cell growth and enlargement and has been found to be aberrant in a wide variety of malignancies. Although mTOR is already an attractive antineoplastic target, overexpression or aberrant expression of mTOR may also provide an opportunity to further increase the size differential between malignant and normal cells, providing an opportunity to amplify and exploit cell size differences between neoplastic cells and their normal counterparts using physiochemical treatment modalities. Therefore, this study sought to quantify the concentration response and time course effects of rapamycin on cell cycle entry, cell enlargement, and cell proliferation in U937 human monocytic leukemia and human hematopoietic stem cells (hHSCs). In addition, the effects of combination treatment with mTOR inhibitors (rapamycin, everolimus, and temsirolimus) and cytoskeletal-directed agents (cytochalasin B and vincristine) in leukemic cells (U937, THP1, K562, Molt-4, and L1210) were assessed for potential drug synergy. While both U937 cells and hHSCs exhibited a marked reduction in cell volume, U937 cells were able to proliferate in the presence of rapamycin ranging from 0.5 nM to 10 MUM (10,000 nM), whereas hHSCs were able to proliferate only at lower concentrations, and were completely inhibited from proliferation by 8 nM rapamycin. These effects were observed with as little as 0.5 nM rapamycin, demonstrating the profound affinity the compound has for FK-binding protein 12 (FKBP12), which subsequently forms the FKBP12/rapamycin complex to inhibit mTOR. Rapamycin continued to exert effects on cell size and proliferation even at 10 MUM, without producing marked cytotoxicity. Although cytochalasin B and vincristine were unable to substantially enlarge rapamycin-treated leukemia cells, it appears that rapamycin and its associated analogs everolimus and temsirolimus have notable synergistic potential with microfilament-disrupting cytochalasin B and microtubule-disrupting vincristine as assessed by comparative effects on cell growth, annexin V staining, IC30 isobolograms, and Chou-Talalay statistics. These observations indicate a potentially novel therapeutic rationale for hematological malignancies and for other cancers to elicit the preferential destruction of neoplastic cells that aberrantly express mTOR. PMID- 26490658 TI - The helminth T2 RNase omega1 promotes metabolic homeostasis in an IL-33- and group 2 innate lymphoid cell-dependent mechanism. AB - Induction of a type 2 cellular response in the white adipose tissue leads to weight loss and improves glucose homeostasis in obese animals. Injection of obese mice with recombinant helminth-derived Schistosoma mansoni egg-derived omega1 (omega1), a potent inducer of type 2 activation, improves metabolic status involving a mechanism reliant upon release of the type 2 initiator cytokine IL 33. IL-33 initiates the accumulation of group 2 innate lymphoid cells (ILC2s), eosinophils, and alternatively activated macrophages in the adipose tissue. IL-33 release from cells in the adipose tissue is mediated by the RNase activity of omega1; however, the ability of omega1 to improve metabolic status is reliant upon effective binding of omega1 to CD206. We demonstrate a novel mechanism for RNase-mediated release of IL-33 inducing ILC2-dependent improvements in the metabolic status of obese animals. PMID- 26490660 TI - Compounds Derived from Epigallocatechin-3-Gallate (EGCG) as a Novel Approach to the Prevention of Viral Infections. AB - Pathogenic viral infections pose major health risks to humans and livestock due to viral infection-associated illnesses such as chronic or acute inflammation in crucial organs and systems, malignant and benign lesions. These lead to large number of illnesses and deaths worldwide each year. Outbreaks of emerging lethal viruses, such as Ebola virus, severe acute respiratory syndrome (SARS) virus and Middle East respiratory syndrome (MERS) virus, could lead to epidemics or even pandemics if they are not effectively controlled. Current strategies to prevent viral entry into the human body are focused on cleansing the surface of the skin that covers hands and fingers. Surface protection and disinfection against microorganisms, including viruses, is performed by sanitization of the skin surface through hand washing with soap and water, surface disinfectants, and hand sanitizers, particularly alcohol-based hand sanitizers. However, concerns about the overall ineffectiveness, toxicity of certain ingredients of disinfectants, pollution of the environment, and the short duration of antimicrobial activity of alcohol have not been addressed, and the epidemiology of certain major viral infections are not correlated inversely with the current measures of viral prevention. In addition to a short duration on the skin surface, alcohol is ineffective against certain viruses such as norovirus, rabies virus, and polio virus. There is a need for a novel approach to protect humans and livestock from infections of pathogenic viruses that is broadly effective, long-lasting (persistent), non-toxic, and environment-friendly. A strong candidate is a group of unique compounds found in Camellia sinensis (tea plant): the green tea polyphenols, in particular epigallocatechin-3-gallate (EGCG) and its lipophilic derivatives. This review discussed the weaknesses of current hand sanitizers, gathered published results from many studies on the antiviral activities of EGCG and its lipophilic derivatives, and the potential use of these compounds as a novel strategy for disease prevention, especially against pathogenic viruses. PMID- 26490659 TI - Does anti-p53 antibody status predict for clinical outcomes in metastatic colorectal cancer patients treated with fluoropyrimidine, oxaliplatin, plus bevacizumab as first-line chemotherapy? AB - BACKGROUND: TP53 gene mutation is widely known as one of the determinants of impaired chemosensitivity. p53 is a tumor-suppressor protein in humans encoded by the TP53 gene. Some studies have shown that TP53 gene mutation and accumulation of the p53 protein are closely related with serum anti-p53 antibody positivity. This study aimed to evaluate the predictive significance of the serum p53 antibody status in metastatic colorectal cancer (mCRC) patients treated with fluoropyrimidine, oxaliplatin, plus bevacizumab as first-line chemotherapy. METHODS: Ninety patients treated with fluoropyrimidine, oxaliplatin plus bevacizumab as first-line chemotherapy were enrolled, including 70 whose KRAS genotype was revealed at the beginning of treatment. Before chemotherapy initiation, the serum p53 antibody level was quantified by enzyme-linked immunosorbent assay using MESACUP(r) anti-p53 test kits. The cutoff value for positivity was 1.3 U/mL, as calculated previously. The KRAS genotype of the tumor samples was analyzed using the Luminex(r) assay. RESULTS: Overall response rates of Response Evaluation Criteria in Solid Tumors criteria were 77.7 % (42/54) in anti-p53-negative patients and 69.4 % (25/36) in anti-p53-positive patients. The odds ratio was 1.07. Median overall survival was 36.1 months in the anti-p53 positive patients, and not available in the anti-p53-negative patients (hazard ratio, 0.81; 95 % confidence interval, 0.37-1.77; P = 0.61). The corresponding values for median progression-free survival were 13.3 months and 14.6 months (hazard ratio, 0.69; 95 % confidence interval, 0.41-1.17; P = 0.17), respectively. CONCLUSIONS: Serum anti-p53 antibody positivity did not predict chemoresistance in mCRC treated with fluoropyrimidine, oxaliplatin, plus bevacizumab as first-line chemotherapy. PMID- 26490661 TI - Analgesic and Anti-Inflammatory Properties of Arylnitroalkenes. AB - In a recent work, we described the design and synthesis of arylnitroalkenes, able to scavenge macrophagederived oxidants, in particular peroxynitrite and peroxynitrite derived radicals. Four compounds emerged as potential leads, 1,1 dimethylamino-4-(2-nitro-1Z-ethenyl)benzene (1), 1,1-dimethylamino-4-(2-nitro-1Z propenyl)benzene (2), 5- (2-nitro-1Z-ethenyl)benzo[d][1,3]dioxol (3), and 5-(2 nitro-1Z-ethenyl)benzo[d][1,3]dioxol (4). In the present work, the possibility of the preclinical validation of these molecules as anti-inflammatory and analgesic was explored in appropriate in vivo mouse models. Compounds 1, 2 and 4, administered orally as a single dose (30 umol kg-(1)) to the mice showed anti inflammatory and analgesic properties similar to classic nonsteroidal anti inflammatory agents. The pharmacological effects were consistent with the inhibitory effect observed on prostaglandin endoperoxide H synthase (PGHS). In fact, both PGHS-1 and PGHS-2 were inhibited by the compounds, with compound 2 being more specific as PGHS-2 inhibitor with a specificity index superior to 70%. Conversely to classical nonsteroidal anti-inflammatory drugs, compound 2 inhibited peroxidase half reaction of the enzyme (IC50 2.3 uM) while the cyclooxygenase activity of hrPGHS-2 remained unchanged. In vitro experiments were reinforced by docking and molecular dynamics simulations showing arylnitroalkene moiety located in the region of the peroxidase active site, competing with the peroxide intermediate. The absence of toxicity and mutagenicity of the compounds was also demonstrated. PMID- 26490662 TI - In vitro effects of infrared A radiation on the synthesis of MMP-1, catalase, superoxide dismutase and GADD45 alpha protein. AB - Harmful influences in the process of photoaging and skin damage are associated with infrared A (IRA) radiation, such as, disturbance of dermal extracellular matrix by up regulation of matrix metalloproteinase-1 (MMP1). Furthermore, DNA damage, induction of cytotoxicity and oxidative stress by decreasing natural antioxidant ability has been reported after acute exposure to IRA. The present study provides additional evidence that IRA radiation response in human skin fibroblasts produces deleterious effects to the cell, such as accelerating aging and weakening of their antioxidant defense mechanism. Human skin fibroblasts were exposed to a non-cytotoxic dose of IRA radiation and cultured for different periods for further collection of cell-free supernatants and lysates, and quantification of MMP-1, catalase, superoxide dismutase, and GADD45a. Our results corroborate previous published data and strongly indicate a negative impact of IRA radiation on the skin physiological by mechanisms involving reduced endogenous antioxidant enzymatic defense, increased MMP-1 and decreased repair process of DNA by reducing GADD45a protein, in cultured human fibroblasts. From a clinical perspective, IRA radiation acts by mechanisms distinct from those observed in ultraviolet radiation indicating the need for developing and making available cosmetics for skin care with properties beyond protection exerted by traditional sunscreens. PMID- 26490666 TI - Pilot study of oral metformin in cancer-bearing cats. AB - A prospective dose escalation pilot study was performed in cancer-bearing cats to assess toxicity and surrogate biomarkers of pharmacologic activity of oral metformin hydrochloride. Nine cats with measurable spontaneous cancer were treated with oral metformin for 14 days. Monitoring included complete blood count (CBC), serum biochemistry, lactate, pH, insulin-like growth factor-1, and vascular endothelial growth factor serially until study completion. At the maximum tolerated dose of 10 mg kg-1 q12 h side effects were primarily mild to moderate gastrointestinal upset (anorexia, vomiting, and/or weight loss). All cats developed a reduction in haematocrit. Six of nine cats developed new or progressive hyperlactatemia and one cat developed asymptomatic lactic acidosis. There were no clinical responders and two cats had modest measurable reduction in tumour size. In conclusion, we demonstrate potential pharmacologic activity of metformin at a clinically relevant dose and identify parameters for clinical monitoring and supportive care. Further investigation of metformin in cancer bearing cats is warranted. PMID- 26490663 TI - Free exopolysaccharide from Mycoplasma mycoides subsp. mycoides possesses anti inflammatory properties. AB - In this study we explored the immunomodulatory properties of highly purified free galactan, the soluble exopolysaccharide secreted by Mycoplasma mycoides subsp. mycoides (Mmm). Galactan was shown to bind to TLR2 but not TLR4 using HEK293 reporter cells and to induce the production of the anti-inflammatory cytokine IL 10 in bovine macrophages, whereas low IL-12p40 and no TNF-alpha, both pro inflammatory cytokines, were induced in these cells. In addition, pre-treatment of macrophages with galactan substantially reduced lipopolysaccharide (LPS) induced production of pro-inflammatory cytokines TNF- and IL-12p40 while increasing LPS-induced secretion of immunosuppressive IL-10. Also, galactan did not activate naive lymphocytes and induced only low production of the Th1 cytokine IFN-gamma in Mmm-experienced lymphocytes. Finally, galactan triggered weak recall proliferation of CD4+ T lymphocytes from contagious bovine pleuropneumonia-infected animals despite having a positive effect on the expression of co-stimulatory molecules on macrophages. All together, these results suggest that galactan possesses anti-inflammatory properties and potentially provides Mmm with a mechanism to evade host innate and adaptive cell mediated immune responses. PMID- 26490667 TI - Synthetic Covalent and Non-Covalent 2D Materials. AB - The creation of synthetic 2D materials represents an attractive challenge that is ultimately driven by their prospective uses in, for example, electronics, biomedicine, catalysis, sensing, and as membranes for separation and filtration. This Review illustrates some recent advances in this diverse field with a focus on covalent and non-covalent 2D polymers and frameworks, and self-assembled 2D materials derived from nanoparticles, homopolymers, and block copolymers. PMID- 26490668 TI - Quantification of the natural history of visceral leishmaniasis and consequences for control. AB - BACKGROUND: Visceral leishmaniasis has been targeted for elimination as a public health problem (less than 1 case per 10,000 people per year) in the Indian sub continent by 2017. However, there is still a high degree of uncertainty about the natural history of the disease, in particular about the duration of asymptomatic infection and the proportion of asymptomatically infected individuals that develop clinical visceral leishmaniasis. Quantifying these aspects of the disease is key for guiding efforts to eliminate visceral leishmaniasis and maintaining elimination once it is reached. METHODS: Data from a detailed epidemiological study in Bangladesh in 2002-2004 was analysed to estimate key epidemiological parameters. The role of diagnostics in determining the probability and rate of progression to clinical disease was estimated by fitting Cox proportional hazards models. A multi-state Markov model of the natural history of visceral leishmaniasis was fitted to the data to estimate the asymptomatic infection period and the proportion of asymptomatic individuals going on to develop clinical symptoms. RESULTS: At the time of the study, individuals were taking several months to be diagnosed with visceral leishmaniasis, leading to many opportunities for ongoing transmission. The probability of progression to clinical disease was strongly associated with initial seropositivity and even more strongly with seroconversion, with most clinical symptoms developing within a year. The estimated average durations of asymptomatic infection and symptomatic infection for our model of the natural history are 147 days (95 % CI 130-166) and 140 days (95 % CI 123-160), respectively, and are significantly longer than previously reported estimates. We estimate from the data that 14.7 % (95 % CI 12.6-20.0 %) of asymptomatic individuals develop clinical symptoms-a greater proportion than previously estimated. CONCLUSIONS: Extended periods of asymptomatic infection could be important for visceral leishmaniasis transmission, but this depends critically on the relative infectivity of asymptomatic and symptomatic individuals to sandflies. These estimates could be informed by similar analysis of other datasets. Our results highlight the importance of reducing times from onset of symptoms to diagnosis and treatment to reduce opportunities for transmission. PMID- 26490669 TI - Anteriorly located zonular fibres as a tool for fine regulation in accommodation. AB - PURPOSE: To describe an anteriorly located system of zonular fibres that could be involved in fine-tuning of accommodation. METHODS: Forty-six human and 28 rhesus monkey eyes were dissected and special preparations were processed for scanning electron microscopy and reflected-light microscopy. Additional series of frontal and sagittal histological and ultrathin sections were analysed in respect to the origin and insertion of anteriorly located zonules. The presence of sensory terminals at the site of the originating zonules within the connective tissue of the ciliary body was studied by immunohistochemistry. For in-vivo visualization ultrasound biomicroscopy (UBM) was performed on 12 human subjects. RESULTS: Fine zonular fibres originated from the valleys and lateral walls of the most anterior pars plicata that covers the anterior and inner circular ciliary muscle portion. These most anterior zonules (MAZ) showed attachments either to the anterior or posterior tines or they inserted directly onto the surface of the lens. At the site of origin, the course of the MAZ merged into the connective tissue fibres connecting the adjacent pigmented epithelium to the ciliary muscle. Numerous afferent terminals directly at the site of this MAZ-origin were connected to the intrinsic nervous network of the ciliary muscle. CONCLUSIONS: A newly described set of zonular fibres features the capabilities to register the tensions of the zonular fork and lens capsule. The close location and neural connection towards the circular ciliary muscle portion could provide the basis for stabilization and readjustment of focusing that serves fast and fine-tuned accommodation and disaccommodation. PMID- 26490670 TI - Evolution of the dense packings of spherotetrahedral particles: from ideal tetrahedra to spheres. AB - Particle shape plays a crucial role in determining packing characteristics. Real particles in nature usually have rounded corners. In this work, we systematically investigate the rounded corner effect on the dense packings of spherotetrahedral particles. The evolution of dense packing structure as the particle shape continuously deforms from a regular tetrahedron to a sphere is investigated, starting both from the regular tetrahedron and the sphere packings. The dimer crystal and the quasicrystal approximant are used as initial configurations, as well as the two densest sphere packing structures. We characterize the evolution of spherotetrahedron packings from the ideal tetrahedron (s = 0) to the sphere (s = 1) via a single roundness parameter s. The evolution can be partitioned into seven regions according to the shape variation of the packing unit cell. Interestingly, a peak of the packing density Phi is first observed at s ~ 0.16 in the Phi-s curves where the tetrahedra have small rounded corners. The maximum density of the deformed quasicrystal approximant family (Phi ~ 0.8763) is slightly larger than that of the deformed dimer crystal family (Phi ~ 0.8704), and both of them exceed the densest known packing of ideal tetrahedra (Phi ~ 0.8563). PMID- 26490671 TI - Engraftment and reversal of diabetes after intramuscular transplantation of neonatal porcine islet-like clusters. AB - BACKGROUND: Intraportal infusion is currently the method of choice for clinical islet cell transplantation but suffers from poor efficacy. As the liver may not represent an optimal transplantation site for Langerhans islets, we examined the potential of neonatal porcine islet-like clusters (NPICCs) to engraft in skeletal muscle as an alternative transplantation site. METHODS: Neonatal porcine islet like clusters were isolated from 2- to 5-day-old piglets and either transplanted under the kidney capsule (s.k.) or injected into the lower hindlimb muscle (i.m.) of streptozotocin-diabetic NOD-SCID IL2rgamma(-/-) (NSG) mice. Survival, vascularization, maturation, and functional activity were analyzed by intraperitoneal glucose tolerance testing and immunohistochemical analyses. RESULTS: Intramuscular transplantation of NPICCs resulted in development of normoglycemia and restored glucose homeostasis. Time to reversal of diabetes and glucose tolerance (AUC glucose and AUC insulin) did not significantly differ as compared to s.k. transplantation. Intramuscular grafts exhibited rapid neovascularization and graft composition with cytokeratin-positive ductal cells and beta cells at post-transplant weeks 2 and 8 and after establishment of normoglycemia was comparable in both groups. CONCLUSIONS: Intramuscular injection represents a minimally invasive but efficient alternative for transplantation of NPICCs and, thus, offers an attractive alternative site for xenotransplantation approaches. These findings may have important implications for improving the outcome and the monitoring of pig islet xenotransplantation. PMID- 26490672 TI - Synthesis of 3,3'-carbonyl-bis(chromones) and their activity as mammalian alkaline phosphatase inhibitors. AB - Hitherto unknown 3,3'-carbonyl-bis(chromones) 8, dimeric chromones bridged by a carbonyl group, were prepared by reaction of chromone-3-carboxylic acid chloride with 3-(dimethylamino)-1- (2-hydroxyphenyl)-2-propen-1-ones 9. The method is generally applicable for the synthesis of novel symmetrical or non-symmetrical products which were found to inhibit mammalian alkaline phosphatases. PMID- 26490673 TI - Evolution of enlarged body size of coal tits Parus ater in geographic isolation from two larger competitors, the crested tit Parus cristatus and the willow tit Parus montanus, on six Scandinavian islands. AB - Here, we report that on six widely separated Scandinavian islands, the coal tit Parus ater has evolved morphologically in the direction of two absent competitors, the crested tit P. cristatus and the willow tit P. montanus, to the effect that it is up to 10% larger in linear dimensions than conspecifics on the adjacent Swedish mainland, where all three species coexist. The large size is genetically determined, as ascertained by clutch exchange experiments between island and mainland nests. We conclude that the increased size of P. ater in places where it is geographically isolated from its larger congeners is the result of evolutionary adaptation, due ultimately to relaxed interspecific competition. On the islands, P. ater has evolved into a medium-sized generalist, with selection pressures likely governed by the following causal relationships. When competitors are lacking, P. ater takes over the foraging space of the absentees. The enlarged food base allows higher population densities, which intensifies intraspecific interference competition. This, in turn, selects for increased body size. When P. ater coexists with its larger congeners, it occupies peripheral foraging sites in trees, which requires excellent manoeuvrability and energy-expensive locomotion modes. Reduction of body size increases locomotor capacity for mechanical and aerodynamic reasons and lowers energy consumption, so small size is favoured in sympatry. But in geographic isolation, P. ater exploits the tree periphery less and the inner tree regions more, and it also adopts the easier locomotion modes of the absent species. Therefore, selection for manoeuvrability and a small body size is relaxed. The new selection regime shifts the balance between opposing selection forces towards a larger body size. We were able to test 11 alternative hypotheses and available evidence conclusively eliminates them all. As a result, here, evolution could be predicted regarding both direction and amount of change. PMID- 26490674 TI - Generation of primitive neural stem cells from human fibroblasts using a defined set of factors. AB - In mice, leukemia inhibitory factor (LIF)-dependent primitive neural stem cells (NSCs) have a higher neurogenic potential than bFGF-dependent definitive NSCs. Therefore, expandable primitive NSCs are required for research and for the development of therapeutic strategies for neurological diseases. There is a dearth of suitable techniques for the generation of human long-term expandable primitive NSCs. Here, we have described a method for the conversion of human fibroblasts to LIF-dependent primitive NSCs using a strategy based on techniques for the generation of induced pluripotent stem cells (iPSCs). These LIF-dependent induced NSCs (LD-iNSCs) can be expanded for >100 passages. Long-term cultured LD iNSCs demonstrated multipotent neural differentiation potential and could generate motor neurons and dopaminergic neurons, as well as astrocytes and oligodendrocytes, indicating a high level of plasticity. Furthermore, LD-iNSCs easily reverted to human iPSCs, indicating that LD-iNSCs are in an intermediate iPSC state. This method may facilitate the generation of patient-specific human neurons for studies and treatment of neurodegenerative diseases. PMID- 26490675 TI - Generation and analysis of knock-in mice carrying pseudohypoaldosteronism type II causing mutations in the cullin 3 gene. AB - Pseudohypoaldosteronism type II (PHAII) is a hereditary hypertensive disease caused by mutations in four different genes: with-no-lysine kinases (WNK) 1 and 4, Kelch-like family member 3 (KLHL3), and cullin 3 (Cul3). Cul3 and KLHL3 form an E3 ligase complex that ubiquitinates and reduces the expression level of WNK4. PHAII-causing mutations in WNK4 and KLHL3 impair WNK4 ubiquitination. However, the molecular pathogenesis of PHAII caused by Cul3 mutations is unclear. In cultured cells and human leukocytes, PHAII-causing Cul3 mutations result in the skipping of exon 9, producing mutant Cul3 protein lacking 57 amino acids. However, whether this phenomenon occurs in the kidneys and is responsible for the pathogenesis of PHAII in vivo is unknown. We generated knock-in mice carrying a mutation in the C-terminus of intron 8 of Cul3, c.1207-1G>A, which corresponds to a PHAII-causing mutation in the human Cul3 gene. Heterozygous Cul3(G(-1)A/+) knock-in mice did not exhibit PHAII phenotypes, and the skipping of exon 9 was not evident in their kidneys. However, the level of Cul3 mRNA expression in the kidneys of heterozygous knock-in mice was approximately half that of wild-type mice. Furthermore, homozygous knock-in mice were nonviable. It suggested that the mutant allele behaved like a knockout allele and did not produce Cul3 mRNA lacking exon 9. A reduction in Cul3 expression alone was not sufficient to develop PHAII in the knock-in mice. Our findings highlighted the pathogenic role of mutant Cul3 protein and provided insight to explain why PHAII-causing mutations in Cul3 cause kidney-predominant PHAII phenotypes. PMID- 26490676 TI - Epigenetic regulator Lid maintains germline stem cells through regulating JAK STAT signaling pathway activity. AB - Signaling pathways and epigenetic mechanisms have both been shown to play essential roles in regulating stem cell activity. While the role of either mechanism in this regulation is well established in multiple stem cell lineages, how the two mechanisms interact to regulate stem cell activity is not as well understood. Here we report that in the Drosophila testis, an H3K4me3-specific histone demethylase encoded by little imaginal discs (lid) maintains germline stem cell (GSC) mitotic index and prevents GSC premature differentiation. Lid is required in germ cells for proper expression of the Stat92E transcription factor, the downstream effector of the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway. Our findings support a germ cell autonomous role for the JAK-STAT pathway in maintaining GSCs and place Lid as an upstream regulator of this pathway. Our study provides new insights into the biological functions of a histone demethylase in vivo and sheds light on the interaction between epigenetic mechanisms and signaling pathways in regulating stem cell activities. PMID- 26490677 TI - Targeted computerised tomography scanning of the ankle syndesmosis with low dose radiation exposure. AB - OBJECTIVES: To devise a new protocol for targeted CTscanning of the distal tibiofibular syndesmosis with minimal radiation exposure to patients. We also aimed to correlate the reduction of the syndesmosis as seen on CT scans with the functional outcome of patients. MATERIALS AND METHODS: Prospective study. Forty adults undergoing surgical stabilisation of an acute distal tibiofibular syndesmosis injury were recruited. A targeted five-cut computerised tomography scan protocol was developed. The radiation exposure to the patient with this protocol was only 0.002 mSv. Scans were performed 12 weeks after surgery. The contralateral ankle of every patient was used as a control to determine the accuracy of the reduction of the syndesmosis for that individual patient. American Orthopaedic Foot and Ankle Society (AOFAS) scores were obtained at a minimum of 1 year after surgery. RESULTS: After considering the exclusions, 36 patients formed the study group. A wide variation was observed in the anatomy of the normal syndesmosis. If we considered a difference of more than 2 mm between the normal and injured syndesmosis relationship as significant, 15 (41.6 %) of our patients had a significant difference between the injured and normal sides. AOFAS scores were available for 13 of these patients and were good to excellent in 11(84.6 %). CONCLUSION: Our study describes a reliable new CT scanning technique for the distal tibiofibular syndesmosis using only five cuts and a low radiation-dose protocol. Clinical correlation of the findings on the scan with functional outcomes suggests that routine post-operative CT of the syndesmosis is probably not justified. PMID- 26490678 TI - Dynamic sonography of snapping hip due to gluteus maximus subluxation over greater trochanter. AB - We report on the dynamic sonographic findings of a 10-year-old avid female dancer who presented with symptoms of abrupt left hip motion and associated painful snapping sensation while performing lateral motions of the pelvis suggesting external snapping hip syndrome. Dynamic sonographic evaluation of both hips demonstrated that symptoms were due to gluteus maximus subluxation over the greater trochanter. This etiology of external snapping hip syndrome is rare with limited imaging descriptions in the literature. We present case history, physical examination, and dynamic ultrasound examination, including multiple still images and cine clips, comprehensively characterizing this uncommon source of external snapping hip syndrome. PMID- 26490679 TI - Imaging diagnosis in relapsing polychondritis and correlation with clinical and serological data. AB - OBJECTIVE: We hypothesize that imaging findings from CT and MRI correlate better with clinical markers for assessment of disease activity in patients with the rare relapsing polychondritis (RPC) than with serological inflammatory markers. MATERIALS AND METHODS: Retrospective database search at our institution identified 28 patients (13 females; age 49.0 years+/-15.0 SD) with RP between September 2004 and March 2014. Institutional review board approval was obtained for this retrospective data analysis. All patients had clinically proven RPC with at least two episodes of active disease. Of those, 18 patients were examined with CT- and MRI and presented all morphologic features of RPC like bronchial/laryngeal/auricular cartilage thickness, contrast enhancement, increased T2-signal intensity. Imaging data was subsequently correlated with corresponding clinical symptoms like fever, dyspnea, stridor, uveitis, pain, hearing impairment as well as with acute-phase-inflammatory parameters like C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). RESULTS: The clinical parameters were in good agreement with imaging findings and clinical symptoms such as tracheal wall thickening and dyspnea (r =0.65 p=0.05), joint synovitis on MRI and a higher McAdam score (r=0.84 p<0.001). No correlations were found between inflammatory laboratory markers, imaging findings and clinical features. CONCLUSION: Imaging diagnosis in RPC using CT and/or MRI delivers information about the degree of disease activity that correlates better with clinical features than unspecific inflammatory laboratory markers. Additionally, clinically unapparent cartilage involvement can be assessed adding value to the clinical diagnosis and therapy planning in this rare disease. PMID- 26490680 TI - Retrosigmoid versus translabyrinthine approach to acoustic neuroma resection: A comparative cost-effectiveness analysis. AB - OBJECTIVES/HYPOTHESIS: Approach-specific economic data of acoustic neuroma (AN) resection is lacking. The purpose of this study was to analyze and compare adjusted total hospital costs, hospital and intensive care unit (ICU) length of stay (LOS), and associated factors in AN patients undergoing resection by translabyrinthine (TL) approach versus retrosigmoid (RS) approach. STUDY DESIGN: Retrospective chart review. METHODS: A total of 113 patients with AN undergoing TL (N = 43) or RS (N = 70) surgical resection between 1999 and 2012 were analyzed. Data including age, health status, preoperative hearing, tumor size, postoperative complications, hospital, ICU LOS, and disposition after discharge were collected from medical records and compared between both groups. Cost data was obtained from the hospital finance department and adjusted based on the Consumer Price Index for 2013. RESULTS: There were no significant differences in demographic data, preoperative hearing, preoperative health status, or postoperative complication rate. Total hospital LOS and ICU LOS were significantly longer in the RS compared to the TL group (4.3 +/- 3.6 vs. 2.6 +/- 1.1 days; P < 0.001, and 1.5 +/- 1.1 vs. 1.0 +/- 0.5 days; P = 0.015, respectively). Tumors were larger in RS compared to the TL group (2.1 +/- 1.0 cm vs. 1.5 +/- 0.7 cm, respectively; P = 0.002). When patients were stratified by tumor size < or >= 2 cm, the total hospital LOS remained greater in the RS group in both subgroups (< and >= 2 cm, P < 0.001, and P = 0.031, respectively). However, there was no difference in the total ICU LOS between both subgroups. The adjusted mean total hospital cost was higher in the RS compared to the TL group ($25,069 +/- 14,968 vs. $16,799 +/- 5,724; P < 0.001). The adjusted mean total hospital cost was greater in the RS group with tumor < 2 cm (P < 0.001) but not significantly different in patients with tumors >= 2 cm. Univariate analysis showed that greater tumor size, poorer preoperative health status, the presence of major postoperative complications, and the RS approach were independently significantly associated with higher total hospital LOS (P = 0.001, P = 0.009, P = 0.001, and P < 0.001, respectively) and a higher adjusted total hospital cost (P < 0.001, P = 0.002, P = 0.014, and P < 0.001, respectively). CONCLUSION: Hospital LOS and total adjusted costs are significantly less for patients undergoing translabyrinthine acoustic neuroma resection compared to the retrosigmoid approach. Many factors appear to influence these differences. Economic considerations in addition to tumor characteristics and surgeon preference should be considered in future acoustic neuroma resections. LEVEL OF EVIDENCE: 2c. PMID- 26490681 TI - A case of chronic inflammatory demyelinating polyneuropathy with reversible alternating diaphragmatic paralysis: case study. AB - Respiratory failure requiring mechanical ventilation has been reported in patients with bilateral diaphragmatic paralysis due to CIDP. We report a case of CIDP that progressed to respiratory failure with normal chest radiography despite unilateral diaphragmatic paralysis. This manifestation would have been missed if ultrasound was not employed. PMID- 26490683 TI - Novel synthesis of silver nanoparticles using Bauhinia variegata: a recent eco friendly approach for mosquito control. AB - Mosquito vectors are responsible for transmitting diseases such as malaria, dengue, chikungunya, Japanese encephalitis, dengue, and lymphatic filariasis. The use of synthetic insecticides to control mosquito vectors has caused physiological resistance and adverse environmental effects, in addition to high operational cost. Biosynthesis of silver nanoparticles has been proposed as an alternative to traditional control tools. In the present study, green synthesis of silver nanoparticles (AgNPs) using aqueous leaf extract of Bauhinia variegata by reduction of Ag(+) ions from silver nitrate solution has been investigated. The bioreduced silver nanoparticles were characterized by UV-visible spectrophotometry, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray analysis (EDX), and X-ray diffraction analysis (XRD). Leaf extract and synthesized AgNPs were evaluated against the larvae of Anopheles subpictus, Aedes albopictus, and Culex tritaeniorhynchus. Compared to aqueous extract, synthesized AgNPs showed higher toxicity against An. subpictus, Ae. albopictus, and Cx. tritaeniorhynchus with LC50 and LC90 values of 41.96, 46.16, and 51.92 MUg/mL and 82.93, 89.42, and 97.12 MUg/mL, respectively. Overall, this study proves that B. variegata is a potential bioresource for stable, reproducible nanoparticle synthesis and may be proposed as an efficient mosquito control agent. PMID- 26490682 TI - Hyperphosphorylation of ribosomal protein S6 predicts unfavorable clinical survival in non-small cell lung cancer. AB - BACKGROUND: Ribosomal protein S6 (rpS6), a component of the 40S ribosomal subunit, is involved in multiple cellular bioactivities. However, its clinicopathological significance in non-small cell lung cancer (NSCLC) is poorly understood. METHODS: Expressions of total rpS6 (t-rpS6) and phosphorylated rpS6 (Ser235/236, p-rpS6) were detected immunohistochemically in 316 NSCLC tissues and 82 adjacent controls, followed by statistical evaluation of the relationship between proteins expressions and patients' survivals to identify their prognostic values. Cytological experiments with overexpressing or silencing rpS6 by lentivirus in human bronchial epithelial (HBE) and NSCLC cell lines were performed to explore potential mechanisms by which rpS6 affects the clinical development of NSCLC. Additionally, specific RNA interference for Akt1, Akt2, Akt3, Akt inhibitor and subsequent cellular bioactivity tests were employed as well to investigate the upstream regulation of rpS6. RESULTS: Positive rates of t rpS6 and p-rpS6 were both significantly increased in NSCLC tissues, compared with controls (82.91 vs 62.20 % for t-rpS6; 52.22 vs 21.95 % for p-rpS6; both P < 0.001). However, only hyperphosphorylation of rpS6, expressed as either elevated p-rpS6 alone or the ratio of p-rpS6 to t-rpS6 (p-rpS6/t-rpS6) no less than 0.67, was greatly associated with the unfavorable survival of NSCLC patients, especially for cases at stage I (all P < 0.001). The independent adverse prognostic value of hyperphosphorylated rpS6 was confirmed by multivariate Cox regression analysis (hazard ratios for elevated p-rpS6 alone and p-rpS6/t-rpS6 no less than 0.67 were 2.403, 4.311 respectively, both P < 0.001). Overexpression or knockdown of rpS6, along with parallel alterations of p-rpS6, led to increased or decreased cells proliferations respectively, which were dependent on redistributions of cell cycles (all P < 0.05). Cells migration and invasion also changed with rpS6 interference (all P < 0.05). Furthermore, upstream overexpression or knockdown of Akt2 or Akt2 phosphorylation inhibition, rather than Akt1 or Akt3, resulted in striking hyperphosphorylation or dephosphorylation of mTOR, p70S6K and rpS6 (all P < 0.05), without any change in total proteins expressions. Further tests showed markedly accompanied variation of cells proliferation, cell cycle distribution and invasion (all P < 0.05). CONCLUSION: Hyperphosphorylation of rpS6, probably regulated by the Akt2/mTOR/p70S6K signaling pathway, is closely relevant to the progression of NSCLC and it might be served as a promising therapeutic target for NSCLC treatment. PMID- 26490684 TI - Is molecular xenomonitoring of mosquitoes for Dirofilaria repens suitable for dirofilariosis surveillance in endemic regions? AB - Dirofilaria repens is a parasite of animals and humans, transferred by mosquitoes. The assessment of the presence of D. repens-infected vertebrate hosts in the investigated area can be performed by xenomonitoring-detection of the parasite in blood-feeding arthropods. Our study aimed to evaluate PCR xenomonitoring of mosquitoes as a tool for dirofilariosis surveillance in Poland. We were also interested whether inter-study comparisons at the international level would be possible. Mosquitoes were collected in a single locality in Mazowsze province in Poland, in which between 12 and 20% of dogs were infected with D. repens and autochthonous human dirofilariosis was confirmed. All captured female mosquitoes were divided into pools; alternatively, single mosquitoes were analyzed; DNA was isolated and subjected to PCR and real-time PCR for detection of D. repens. The estimations of infection rates of mosquitoes with D. repens, based on PCR results, varied from 0 to 1.57% even between assays for detection of distinct fragments of the same marker-cytochrome oxidase subunit one gene. Polymorphisms of the DNA sequence within binding sites of the primers used in D. repens xenomonitoring assays, applied in European studies, were identified. Non specific amplification of Setaria tundra (Nematoda: Onchocercidae) DNA occurred. Surveillance of dirofilariosis by PCR mosquito xenomonitoring is possible; however, the efficiency of the approach on territories where the prevalence of the disease among definitive hosts is lower than 12% remains unknown. Furthermore, mosquito infection rate estimations can be PCR assay dependent, which makes inter-study comparisons difficult. The results obtained in independent European xenomonitoring studies were contradictory. International collaboration would be required to establish a standardized set of assays for sensitive and specific xenomonitoring-based dirofilariosis surveillance. PMID- 26490685 TI - [General principles of sonography, part 2: System technology, basic techniques and artifacts]. AB - Since the introduction of portable ultrasound systems, sonography has become well established as an integral part of the anesthesiological and critical care equipment and of monitoring. The selection of various ultrasound transducers, sonographic techniques and imaging modes enables a broad variety of clinical applications. In depth background knowledge of the technical aspects is crucial for obtaining what a highly sophisticated ultrasound system has to offer, i.e., sonographic transparency of the complete body and valid information on the structure and dynamics of organs and the circulation. PMID- 26490686 TI - Inhibitory effect of curcumin on testosterone induced benign prostatic hyperplasia rat model. AB - BACKGROUND: Benign prostatic hyperplasia (BPH) is one of the common male diseases, which is provoked by dihydrotestosterone (DHT) and androgen signals. Several studies showed that curcumin has various effects of prevention and treatment to diseases. We investigated whether curcumin may repress the development of BPH in male Wistar rats. METHODS: Seven weeks male Wistar rats were and divided into 4 groups (normal group, BPH group, finasteride group, curcumin group; n = 8 for each group). In order to induce BPH in rats, rats were castrated and testosterone was injected subcutaneously everyday (s.c., 20 mg/kg). Rats in the curcumin group were treated 50 mg/kg, administered orally for 4 weeks. After 4 weeks, all rats were sacrificed and their prostate and serum were analyzed. RESULTS: Compared to the finasteride group as positive group, the curcumin group showed similarly protective effect on BPH in histopathologic morphology, prostate volume. Results of immunohistochemistry and western-blot showed decreased expressions of VEGF, TGF-beta1, and IGF1 were also decreased in the curcumin group. CONCLUSIONS: These results suggested that curcumin inhibited the development of BPH and might a useful herbal treatment or functional food for BPH. PMID- 26490688 TI - Potential of serum metabolites for diagnosing post-stroke cognitive impairment. AB - Cognitive impairment commonly accompanies clinical syndromes associated with stroke. The identification of laboratory markers of post-stroke cognitive impairment (PSCI) may help detect patients at increased risk of cognitive deterioration and determine the appropriate treatment regimes. A non-targeted metabolomics approach based on ultra-high performance liquid chromatography coupled with Q-TOF mass spectrometry was applied to study PSCI. The stroke patients were significantly distinguishable from the healthy subjects. Stroke patients could be well-stratified based on cognitive impairment. Several differential serum metabolites were further identified for post-stroke non cognitive impairment (PSNCI) and PSCI patients, suggesting metabolic dysfunction in inflammation, neurotoxicity, bioenergetic homeostasis, oxidative stress, and apoptosis. In total, three serum metabolites (glutamine, kynurenine, and LysoPC(18:2)) were identified as candidate diagnostic biomarkers for PSCI, and their combined use yielded good diagnostic capacity for PSCI by receiver operating characteristic curves. The present metabolomics study provided a novel strategy for stratifying stroke patients with cognitive impairment using serum based metabolite markers, which could be of great importance in understanding the pathological mechanisms and determining the appropriate treatment regimes of PSCI patients. PMID- 26490687 TI - Ghrelin receptor activity amplifies hippocampal N-methyl-d-aspartate receptor mediated postsynaptic currents and increases phosphorylation of the GluN1 subunit at Ser896 and Ser897. AB - Although ghrelin and its cognate receptor growth hormone secretagogue receptor (GHSR1a) are highly localized in the hypothalamic nuclei for the regulation of metabolic states and feeding, GHSR1a is also highly localized in the hippocampus, suggesting its involvement in extra-hypothalamic functions. Indeed, exogenous application of ghrelin has been reported to improve hippocampal learning and memory. However, the underlying mechanism of ghrelin regulation of hippocampal functions is poorly understood. Here, we report ghrelin-promoted phosphorylation of GluN1 and amplified N-methyl-d-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents in the CA1 pyramidal cells of the hippocampus in slice preparations. The ghrelin-induced responses were sensitive to a GHSR1a antagonist and inverse agonist, and were absent in GHSR1a homozygous knock-out mice. These results indicated that activation of GHSR1a was critical in the ghrelin-induced enhancement of the NMDAR function. Interestingly, heterozygous mouse hippocampi were also insensitive to ghrelin treatment, suggesting that a slight reduction in the availability of GHSR1a may be sufficient to negate the effect of ghrelin on GluN1 phosphorylation and NMDAR channel activities. In addition, NMDAR-mediated spike currents, which are of dendritic origin, were blocked by the GHSR1a antagonist, suggesting the presence of GHSR1a on the pyramidal cell dendrites in physical proximity to NMDAR. Together with our findings on the localization of GHSR1a in the CA1 region of the hippocampus, which was shown by fluorescent ghrelin binding, immunoreactivity, and enhanced green fluorescent protein reporter gene expression, we conclude that the activation of GHSR1a favours rapid modulation of the NMDAR-mediated glutamatergic synaptic transmission by phosphorylating GluN1 in the hippocampus. PMID- 26490689 TI - Not All Post-FNA Spindle Cell Proliferations in the Thyroid Are of Myofibroblastic Origin: Follicular Adenoma with Spindle Cell Metaplasia. PMID- 26490690 TI - Voluntary community service in medical school: a qualitative study on obstacles faced by student leaders and potential solutions. AB - PURPOSE: In medical school, students may participate in various community involvement projects (CIP), which serve disadvantaged communities. However, several obstacles may arise during these projects. The authors conducted a qualitative study with the primary aim of understanding the obstacles and corresponding potential solutions when medical students in Singapore participate in local CIP (LCIP) and overseas CIP (OCIP). DESIGN: The authors recruited medical students from Yong Loo Lin School of Medicine, National University of Singapore, who were also leaders of a specific community service project done in medical school. Twelve one-to-one interviews were held for the participants from 6 to 8 January 2013. Participants were led in a discussion based on an interview guide. The interviews were audio-recorded and transcribed into free-flow text. Subsequently, content and thematic analyses of the transcripts were performed independently by three researchers. RESULTS: The medical students faced many common obstacles during their community service projects. These obstacles include difficulties in recruiting and managing volunteers, attaining recognition or credibility for the project to acquire funding and resources, adjusting to a different culture or language, setting goals, and facing project-specific obstacles. Potential solutions were offered for some obstacles, such as building a strong executive committee for the project, grooming successive batches of leaders, and improving the project's public image, mentorship, reflections, and sustainability plans. CONCLUSIONS: Mentorship, reflections, and sustainability are potential solutions that have been proposed to tackle the obstacles faced during community service participation in medical school. However, there may still be difficulty in solving some of the problems even after these measures are put into practice. Future research may focus on evaluating the effectiveness of these suggested solutions. PMID- 26490691 TI - Vitamin D supplements may be needed when calcium supplements are not. PMID- 26490692 TI - Interaction of Spin-Labeled Lipid Membranes with Transition Metal Ions. AB - The large values of spin relaxation enhancement (RE) for PC spin-labels in the phospholipid membrane induced by paramagnetic metal salts dissolved in the aqueous phase can be explained by Heisenberg spin exchange due to conformational fluctuations of the nitroxide group as a result of membrane fluidity, flexibility of lipid chains, and, possibly, amphiphilic nature of the nitroxide label. Whether the magnetic interaction occurs predominantly via Heisenberg spin exchange (Ni) or by the dipole-dipole (Gd) mechanism, it is essential for the paramagnetic ion to get into close proximity to the nitroxide moiety for efficient RE. For different salts of Ni the RE in phosphatidylcholine membranes follows the anionic Hofmeister series and reflects anion adsorption followed by anion-driven attraction of paramagnetic cations on the choline groups. This adsorption is higher for chaotropic ions, e.g., perchlorate. (A chaotropic agent is a molecule in water solution that can disrupt the hydrogen bonding network between water molecules.) However, there is no anionic dependence of RE for model membranes made from negatively charged lipids devoid of choline groups. We used Ni-induced RE to study the thermodynamics and electrostatics of ion/membrane interactions. We also studied the effect of membrane composition and the phase state on the RE values. In membranes with cholesterol a significant difference is observed between PC labels with nitroxide tethers long enough vs not long enough to reach deep into the membrane hydrophobic core behind the area of fused cholesterol rings. This study indicates one must be cautious in interpreting data obtained by PC labels in fluid membranes in terms of probing membrane properties at different immersion depths when it can be affected by paramagnetic species at the membrane surface. PMID- 26490693 TI - Granulocytes in coronary thrombus evolution after myocardial infarction--time dependent changes in expression of matrix metalloproteinases. AB - BACKGROUND: Remodeling of extracellular matrix is a key process during wound healing, which is strictly regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors [tissue inhibitors of metalloproteinases (TIMPs)]. In this study, we evaluated intrathrombotic MMPs and TIMPs and their cellular origin during thrombus evolution after disruption of coronary atherosclerotic plaque. MATERIALS AND METHODS: Thrombectomy materials (N=120) obtained from patients with acute myocardial infarction were histologically classified in three groups based on thrombus age: fresh (<1day), lytic (1-5days), or organized (>5days) thrombi; materials showing a heterogeneous composition were classified according to oldest part. Presence and cellular origin of MMPs (MMP-1, MMP-2, MMP-8, MMP-9, and MMP 14) and TIMPs (TIMP-1, TIMP-2, and TIMP-3) was evaluated with immunostains (double) and with polymerase chain reaction. RESULTS AND CONCLUSION: MMPs and TIMPs were present in all the thrombectomy samples. A distinct temporal change in extent and cellular origin of MMPs and TIMPs during thrombus evolution was observed. In the early (fresh and lytic) stages of thrombus, high numbers of neutrophilic granulocytes occupy the thrombus mass and produce large amounts of MMPs and TIMPs. However, with progression of thrombus evolution (organizing stage) and diminishment of neutrophil granulocytes, there is disappearance of MMP 8 and MMP-9, steep decline of MMP-1 and TIMP-2, and progressive decrease of TIMP 3. In contrast, intrathrombotic MMP-2 and MMP-14 are present at a constant high level during the entire process of thrombus evolution. These temporal changes indicate a complex time-dependent function of MMPs, which are largely granulocyte derived, in the healing process of thrombus after plaque disruption. PMID- 26490694 TI - Circadian patterns on ambulatory blood pressure monitoring: Do they really matter in daily clinical practice? PMID- 26490695 TI - Eukaryotic translation initiation factor 4-gamma, 1 gene mutations are rare in Parkinson's disease among Taiwanese. AB - BACKGROUND/PURPOSE: Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Although idiopathic PD accounts for most of the cases, several genetic mutations have been found to cause PD. Mutations in the eukaryotic translation initiation factor 4-gamma, 1 (EIF4G1) gene have been identified since 2011, which were reported to be associated with PD among Caucasians in subsequent research. However, this observation was not consistent. The contribution to other ethnic groups remains limited, with < 1% of sporadic cases. We conducted a case-control study to analyze if EIF4G1 is a risk factor for PD patients in Taiwan. METHODS: There were 595 PD patients and 600 controls without neurological diseases enrolled in this study. Four reported mutations A502V (c.1505C>T), G686C (c.2056 G>T), R1197W (c.3589C>T), and R1205H (c.3614G>A) were analyzed. RESULTS: There were no mutations found in either PD patients or controls. CONCLUSION: This study indicates that the EIF4G1 mutation is rare in Taiwan, which is consistent with other reports from Asia. Ethnicity could have a great influence on EIF4G1 in PD. Further large scale studies are warranted to evaluate the association of PD and EIF4G1 gene. PMID- 26490696 TI - Do nurse sows and foster litters have impaired animal welfare? Results from a cross-sectional study in sow herds. AB - Increasing litter size has led to introduction of so-called nurse sows in several EU countries. A nurse sow is a sow receiving piglets after having weaned her own piglets and thereby experiencing an extended lactation. In order to analyse whether nurse sows have more welfare problems than non-nurse sows a cross sectional study was conducted in 57 sow herds in Denmark. Clinical observations were made on nurse and non-nurse sows and their litters. The clinical observations were dichotomized and the effect of being a nurse sow was analysed based on eight parameters: thin (body condition score<2.5), swollen bursae on legs, dew claw wounds, vulva lesions, poor hygiene, poor skin condition, shoulder lesions and cuts and wounds on the udder. Explanatory variables included in the eight models were: nurse sow (yes=1/no=0), age of piglets (weeks old, 1 to 7), parity (1 to 8+) and all first order interactions between these three variables. The effect of using nurse sows on piglet welfare was analysed with five models. The outcomes were: huddling, poor hygiene, lameness, snout cuts and carpal abrasions. The explanatory variables included in the five models were: nurse sow (yes=1/no=0), age of piglets (weeks old, 1 to 7), parity (1 to 8+) and all first order interactions between these three variables. Herd identity was included as a random factor in all models. The nurse sows had a significantly higher risk of swollen bursae on legs (P=0.038) and udder wounds (P=0.001). No differences in risk of being thin or having shoulder lesions were found. Foster litters had significantly higher risk of being dirty (P=0.026) and getting carpal abrasions (P=0.024) than non-foster litters. There was a tendency for higher lameness in foster litters than in non-foster litters (P=0.052). The results show that nurse sows and their piglets to some extent experience more welfare problems than non nurse sows with piglets at a similar age. PMID- 26490697 TI - Helicobacter pylori treatment: Still a work in progress. AB - Helicobacter pylori is a common worldwide bacterium, possessing adaptability that has created difficulty achieving eradication. While the standard treatment was thought to be triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin, growing rates of treatment failure and antibiotic resistance have stimulated research into novel regimens. Quadruple therapy with bismuth has been compared for both first- and second-line treatments, but eradication still has not reached expected goals. Innovative regimens including sequential and concomitant therapy, as well as the introduction of new antibiotics into previous treatment schedules, have shown promising improvements in eradication rates. We discuss and compare these unique regimens, reviewing the current literature to deduce those which are most likely to provide the highest success in curing H. pylori infection. PMID- 26490698 TI - Risk-scoring systems for predicting preterm birth with the aim of reducing associated adverse outcomes. AB - BACKGROUND: Identification of pregnancies that are higher risk than average is important to allow the possibility of interventions aimed at preventing adverse outcomes like preterm birth. Many scoring systems designed to classify the risk of a number of poor pregnancy outcomes (e.g. perinatal mortality, low birthweight, and preterm birth) have been developed, but they have usually been introduced without evaluation of their utility and validity. OBJECTIVES: To determine whether the use of a risk-screening tool designed to predict preterm birth (in combination with appropriate consequent interventions) reduces the incidence of preterm birth and very preterm birth, and associated adverse outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2015). SELECTION CRITERIA: All randomised or quasi-randomised (including cluster-randomised) or controlled clinical trials that compared the incidence of preterm birth between groups that used a risk scoring instrument to predict preterm birth with those who used an alternative instrument, or no instrument; or that compared the use of the same instrument at different gestations. The reports may have been published in peer reviewed or non peer reviewed publications, or not published, and written in any language. DATA COLLECTION AND ANALYSIS: All review authors planned to independently assess for inclusion all the potential studies we identified as a result of the search strategy. However, we did not identify any eligible studies. MAIN RESULTS: Searching revealed no trials of the use of risk-scoring systems for preventing preterm birth. AUTHORS' CONCLUSIONS: The role of risk-scoring systems in the prevention of preterm birth is unknown.There is a need for prospective studies that evaluate the use of a risk-screening tool designed to predict preterm birth (in combination with appropriate consequent interventions) to prevent preterm birth, including qualitative and/or quantitative evaluation of their impact on women's well-being. If these prove promising, they should be followed by an adequately powered, well-designed randomised controlled trial. PMID- 26490699 TI - Taxonomy and phylogeny in Lepiota sect. Stenosporae from China. AB - Lepiota sect. Stenosporae (J.E. Lange) Kuhner contains species with spurred or truncate basidiospores and pileus covering composed of adnate, ascending or erect long and slender elements. Seven species from southwestern, northeastern and southern China in this section have been identified, described and illustrated. Lepiota mandarina and L. subcastanea are described as new. Lepiota mandarina is characterized by densely orange red to brownish red squamules on pileus and stipe, subtriangular basidiospores with truncate bottom, narrowly clavate cheilocystidia and pileus covering a trichodermial palisade. Lepiota subcastanea has a pileus with yellow-brown to dark brown squamules, non-dextrinoid subtriangular basidiospores with a distinct sac-like spur, narrowly clavate or narrowly utriform cheilocystidia, and pileus covering a trichodermial palisade with short clavate elements. It is hypothesized that this section evolved from sect. Ovisporae subsect. Helveolinae. It also is speculated that subtriangular and spurred basidiospores have evolved from ellipsoidal basidiospores and that a trichodermial pileus covering composing long, erect elements and basal short, clavate elements might have evolved from a cutis or a trichoderm lacking such an under layer of short elements. PMID- 26490700 TI - New Boletaceae taxa from Guyana: Binderoboletus segoi gen. and sp. nov., Guyanaporus albipodus gen. and sp. nov., Singerocomus rubriflavus gen. and sp. nov., and a new combination for Xerocomus inundabilis. AB - Binderoboletus segoi gen. and sp. nov., Guyanaporus albipodus gen. and sp. nov. and Singerocomus rubriflavus gen. and sp. nov. (Boletaceae, Boletales, Basidiomycota) are described from the Pakaraima Mountains and adjacent lowlands of Guyana. Xerocomus inundabilis, originally described from the central Brazilian Amazon and based solely on the type collection, is redescribed from numerous collections from Guyana and transferred into Singerocomus. These boletes occur in Neotropical forests dominated by ectomycorrhizal trees in the genera Dicymbe (Fabaceae subfam. Caesalpinioideae), Aldina (Fabaceae subfam. Papilionoideae) and Pakaraimaea (Dipterocarpaceae). Three of the species were repeatedly found in a multiyear sporocarp survey in Dicymbe corymbosa-monodominant forest. Macromorphological, micromorphological, habitat and multilocus DNA sequence data are provided for each species. A molecular phylogenetic analysis based on a large taxon set across the Boletaceae justifies erection of the new genera. PMID- 26490701 TI - Five new species of Inocybe (Agaricales) from tropical India. AB - Five new species of Inocybe, I. iringolkavensis, I. keralensis, I. kuruvensis, I. muthangensis and I. wayanadensis, are described from Kerala state, India, based on morphological and molecular data. All are associated with trees belonging to Dipterocarpaceae. Inocybe iringolkavensis is characterized by nodulose to somewhat stellate basidiospores, 1-4-spored basidia, and caulocystidia restricted to the stipe apex. Inocybe keralensis has a yellowish brown pileus, lamellae with whitish, serrate edges, smooth, ellipsoidal basidiospores and a duplex pileipellis with the superficial hyphae devoid of encrustations and encrusted hyphae beneath. The diagnostic features of I. kuruvensis include a dark brown pileus, stipe with a whitish base and grayish brown, floccose-fibrillose surface, nodulose basidiospores with saddle-shaped projections and faintly encrusted paracystidia with refractive contents. Violet basidiomata with a rimose, hygrophanous pileus, densely pruinose stipe with a marginate-bulbous base, and nodulose basidiospores are the major features of I. muthangensis. Inocybe wayanadensis is characterized by small, whitish basidiomata, a viscid pileus with a rimulose surface, a densely pruinose and fibrillose stipe with a marginate bulbous base, nodulose basidiospores, thick-walled pleuro- cheilo- and caulocystidia and an ixotrichoderm-type pileipellis. The phylogenetic relationships of these new species are inferred from an analysis of nuc rDNA sequences of the internal transcribed spacers (ITS1-5.8S-ITS2) and the 28S gene. Except I. keralensis, which belongs to the Pseudosperma clade, all other species belong to the Inocybe clade. This study represents the second report of an Inocybe species (I. muthangensis) that combines violet basidiomata with nodulose basidiospores. PMID- 26490702 TI - Distinct phylogeographic structure recognized within Desmazierella acicola. AB - Desmazierella acicola (anamorph Verticicladium trifidum, Chorioactidaceae) represents a frequent colonizer of pine needles in litter. Considering the global diversity and distribution of pine species, we expected different phylogenetic lineages to exist in different geographical and climatic areas inhabited by these hosts. We compared DNA sequence data with phenotypic characteristics (morphology of the anamorph and growth at three different temperatures) of 43 strains isolated mostly from pine and also spruce needle litter sampled in various geographical areas. Analyses of ITS rDNA recovered eight geographically structured lineages. Fragments of genes for the translation elongation factor 1 alpha, and the second largest subunit of RNA polymerase II reproduced similar lineages, although not all of them were monophyletic. The similarity in ITS sequences among the clade with samples from Continental-Atlantic Europe and four other clades was lower than 95%. Several lineages exhibit also a tendency toward host specificity to a particular pine species. Growth tests at different temperatures indicated a different tolerance to specific climatic conditions in different geographic areas. However, the surveyed phenotypic characteristics also showed high variation within lineages, most evident in the morphology of the anamorph. Until a morphological study of the teleomorph is carried out, all of these lineages should be treated as distinct populations within a single species. PMID- 26490703 TI - New species of Polysphondylium from Madagascar. AB - Two series of samples collected for isolation of dictyostelid cellular slime molds (dictyostelids) in Madagascar yielded a relatively large number of isolates of Polysphondylium. Most of these turned out to be species new to science that show varying degrees of clustering from unclustered to coremiform as well as an ability to migrate. Migratory ability (phototaxis) is a common feature of species assigned to Group 2 of the Polysphondylia and is common in the new species from Madagascar. Another common feature, clustering, appears to be a strategy for keeping fruiting bodies erect for a longer time in a climate that is relatively dry, whereas migratory ability may function seasonally when there is more rainfall. Thirteen species are described herein. Each of these is characterized by a particular set of distinguishing features, and collectively they expand our concept of the genus Polysphondylium. PMID- 26490704 TI - Tuber melosporum smooth spores: an anomalous feature in the genus Tuber. AB - This paper adds new insights on ecology and micromorphology of Tuber melosporum, a rare species with smooth spores. Eight T. melosporum ascomata collected in a 50 y old Pinus halepensis and Quercus ilex plantation in Sardinia, Italy, represent the first recovery of this species outside Spain. In comparison to the T. melosporum holotype, Italian specimens revealed differences in the number of spores in asci and spore shape. We propose an emended description of Tuber to include species without spore ornamentation. PMID- 26490705 TI - Halophilic and thermotolerant Gymnoascus species from several special environments, China. AB - This study introduces three new Gymnoascus species (Gymnoascaceae, Onygenales), G. halophilus, G. stercorarius and G. thermotolerans, isolated from sediments in Chaka Salt Lake, compost and cornfield soil, respectively, in China, based on a polyphasic characterization including morphology, physiology and molecular phylogeny. Phylogenetic relationships were assessed based on the nuclear internal transcribed spacer (ITS = ITS1 + 5.8S + ITS2) region and a combined multilocus alignment of the ITS, 18S subunit rRNA gene and 28S subunit rRNA genes. Our study identified phylogenetic and phenotypic characters that differentiated the three new species from known species in the genus. Salinity and temperature tolerance tests revealed that G. halophilus was an obligate halophile while G. stercorarius and G. thermotolerans were halotolerant and thermotolerant. A key to accepted species of Gymnoascus is provided. PMID- 26490706 TI - N and S co-doped porous carbon spheres prepared using L-cysteine as a dual functional agent for high-performance lithium-sulfur batteries. AB - Nitrogen and sulfur co-doped porous carbon spheres (NS-PCSs) were prepared using L-cysteine to control the structure and functionalization during the hydrothermal reaction of glucose and the subsequent activation process. As the sulfur hosts in Li-S batteries, NS-PCSs combine strong physical confinement and surface chemical interaction to improve the affinity of polysulfides to the carbon matrix. PMID- 26490708 TI - Health information systems and disability in the Lao PDR: a qualitative study. AB - The Convention on the Rights of Persons with Disabilities provides an opportunity to strengthen disability-related health information. This study analysed the health information system in Lao PDR and sought evidence of interventions to improve disability-related health information. The study was based on a literature review and key informant interviews (N = 17) informed by the Health Metrics Network's Framework and Standards and the Performance of Routine Information System Management framework. The Lao health information system is in an embryonic stage with health data often incomplete, inaccurate and poorly used. Indicators related to disability or functioning are not included, and capacity to diagnose the health condition of disability is limited. No studies of health information interventions were found. As a State Party to the CRPD, the Lao PDR has a legal obligation to collect health-related information on people with disabilities. Given the nascent stage of development of the health information system in the Lao PDR and diagnostic capacity, indicators related to basic functioning and access to services should be integrated into household level surveys. As the health information system further develops, small, incremental changes in the type of disability information and rehabilitation and the way it is collected can be implemented. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26490710 TI - Effects of psychoeducation on helpful support for complicated grief: a preliminary randomized controlled single-blind study. AB - BACKGROUND: Complicated grief is a distinct psychological response of individuals facing the loss of a loved one and can lead to many types of adverse health outcomes. Although social support may be beneficial, few studies have examined the beneficial effects of helpful support on complicated grief following bereavement. METHOD: A randomized controlled trial was conducted. Bereaved participants and supporters were randomized to psychoeducation on complicated grief and helpful social support or psychoeducation on complicated grief. The primary outcome was the Inventory of Complicated Grief. RESULTS: The results showed that psychoeducation of supporters of bereaved individuals has significant beneficial effects. Particularly, symptoms of complicated grief were decreased in bereaved individuals with supporters that received psychoeducation. CONCLUSIONS: The results highlight the potential of psychoeducation to facilitate helpful social support and reduce complicated grief. PMID- 26490711 TI - Computational metallomics of the anticancer drug cisplatin. AB - Cisplatin, cis-diamminedichlorido-platinum(II), is an important therapeutic tool in the struggle against different tumors, yet it is plagued with the emergence of resistance mechanisms after repeated administrations. This hampers greatly its efficacy. Overcoming resistance problems requires first and foremost an integrated and systematic understanding of the structural determinants and molecular recognition processes involving the drug and its cellular targets. Here we review a strategy that we have followed for the last few years, based on the combination of modern tools from computational chemistry with experimental biophysical methods. Using hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) simulations, validated by spectroscopic experiments (including NMR, and CD), we have worked out for the first time at atomic level the structural determinants in solution of platinated cellular substrates. These include the copper homeostasis proteins Ctr1, Atox1, and ATP7A. All of these proteins have been suggested to influence the pre-target resistance mechanisms. Furthermore, coupling hybrid QM/MM simulations with classical Molecular Dynamics (MD) and free energy calculations, based on force field parameters refined by the so-called "Force Matching" procedure, we have characterized the structural modifications and the free energy landscape associated with the recognition between platinated DNA and the protein HMGB1, belonging to the chromosomal high-mobility group proteins HMGB that inhibit the repair of platinated DNA. This may alleviate issues relative to on-target resistance process. The elucidation of the mechanisms by which tumors are sensitive or refractory to cisplatin may lead to the discovery of prognostic biomarkers. The approach reviewed here could be straightforwardly extended to other metal-based drugs. PMID- 26490709 TI - Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy. AB - Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8 mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax 7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGFbeta1 and PGC-1alpha were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3:BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments. PMID- 26490712 TI - Aggregates of a cationic porphyrin as supramolecular probes for biopolymers. AB - The copper(II) derivative of the dicationic trans-bis(N-methylpyridinium-4 yl)diphenylporphyrin (t-CuPagg) forms large fractal aggregates in aqueous solution under moderate ionic strength conditions. A kinetic investigation of the aggregation process allows for a choice of experimental conditions to quickly obtain stable assemblies in solution. These positively charged aggregates are able to interact efficiently with negatively charged chiral species, (including bacterial spores) leading to induced circular dichroism signals in the Soret region of the porphyrin, now acting as a sensitive chiroptical probe. PMID- 26490713 TI - Gold(III) complexes with hydroxyquinoline, aminoquinoline and quinoline ligands: Synthesis, cytotoxicity, DNA and protein binding studies. AB - In this article, we report on the synthesis and the chemical and biological characterization of novel gold(III) complexes based on hydroxyl- or amino quinoline ligands that are evaluated as prospective anticancer agents. To gain further insight into their reactivity and possible mode of action, their interactions with model proteins and standard nucleic acid molecules were investigated. PMID- 26490720 TI - Nonruptured Tubal Pregnancy With In Situ Embryo and Implantation Site. PMID- 26490707 TI - The transcriptional landscape of age in human peripheral blood. AB - Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts. PMID- 26490721 TI - Lanthanum Deposition Is Frequently Observed in the Gastric Mucosa of Dialysis Patients With Lanthanum Carbonate Therapy: A Clinicopathologic Study of 13 Cases, Including 1 Case of Lanthanum Granuloma in the Colon and 2 Nongranulomatous Gastric Cases. PMID- 26490722 TI - The Maize Leaf: Another Perspective on Growth Regulation. AB - The Arabidopsis thaliana root tip has been a key experimental system to study organ growth regulation. It has clear advantages for genetic, transcriptomic, and cell biological studies that focus on the control of cell division and expansion along its longitudinal axis. However, the system shows some limitations for methods that currently require too much tissue to perform them at subzonal resolution, including quantification of proteins, enzyme activity, hormone, and metabolite levels and cell wall extensibility. By contrast, the larger size of the maize leaf does allow such analyses. Here we highlight exciting new possibilities to advance mechanistic understanding of plant growth regulation by using the maize leaf as a complimentary system to the Arabidopsis root tip. PMID- 26490723 TI - Biconnectivity of the cellular metabolism: A cross-species study and its implication for human diseases. AB - The maintenance of stability during perturbations is essential for living organisms, and cellular networks organize multiple pathways to enable elements to remain connected and communicate, even when some pathways are broken. Here, we evaluated the biconnectivity of the metabolic networks of 506 species in terms of the clustering coefficients and the largest biconnected components (LBCs), wherein a biconnected component (BC) indicates a set of nodes in which every pair is connected by more than one path. Via comparison with the rewired networks, we illustrated how biconnectivity in cellular metabolism is achieved on small and large scales. Defining the biconnectivity of individual metabolic compounds by counting the number of species in which the compound belonged to the LBC, we demonstrated that biconnectivity is significantly correlated with the evolutionary age and functional importance of a compound. The prevalence of diseases associated with each metabolic compound quantifies the compounds vulnerability, i.e., the likelihood that it will cause a metabolic disorder. Moreover, the vulnerability depends on both the biconnectivity and the lethality of the compound. This fact can be used in drug discovery and medical treatments. PMID- 26490724 TI - Regarding: Impact of portal vein resection on oncologic long-term outcome in patients with hilar cholangiocarcinoma. PMID- 26490726 TI - New constraints for low-momentum electronic excitations in condensed matter: fundamental consequences from classical and quantum dielectric theory. AB - We present new constraints for the transportation behaviour of low-momentum electronic excitations in condensed matter systems, and demonstrate that these have both a fundamental physical interpretation and a significant impact on the description of low-energy inelastic electron scattering. The dispersion behaviour and characteristic lifetime properties of plasmon and single-electron excitations are investigated using popular classical, semi-classical and quantum dielectric models. We find that, irrespective of constrained agreement to the well known high-momentum and high-energy Bethe ridge limit, standard descriptions of low momentum electron excitations are inconsistent and unphysical. These observations have direct impact on calculations of transport properties such as inelastic mean free paths, stopping powers and escape depths of charged particles in condensed matter systems. PMID- 26490725 TI - Risk factors for permanent stoma after rectal cancer surgery with temporary ileostomy. AB - BACKGROUND: Although creation of a temporary diverting ileostomy during resection for rectal cancer surgery is used widely to decrease the risk of anastomotic leakage, a frequent outcome is maintenance of this "temporary" ileostomy as a permanent stoma (PS). Our aim was to assess the incidence of PS and identify potential risk factors. METHODS: This observational study included patients who underwent rectal cancer surgery with temporary ileostomy with curative intent between January 2001 and December 2008. Patient demographics, perioperative outcomes, and complications were analyzed. Incidences of primary PS (present at the endpoint of the study without stoma reversal) and secondary PS (created after closure of the primary stoma) were investigated. Univariate and multivariate analyses were conducted to determine risk factors. RESULTS: Of 673 enrolled patients, 64 (9.5%) developed PS, including 23 cases of primary PS and 41 of secondary PS. The causes of primary PS were systemic metastases (n = 12), anastomosis stricture (n = 4), poor general condition (n = 3), patient refusal (n = 2), and other (n = 2). The causes of secondary PS were local recurrence (n = 12), uncontrolled pelvic abscess (n = 11), unsatisfactory anorectal function (n = 10), anastomosis stricture (n = 6), and other (n = 2). In multivariate analysis, anastomosis leakage (P < .001), involvement of the circumferential resection margin (P = .013), and stage III tumor (P = .001) were independent risk factors for PS. CONCLUSION: Patients with advanced cancer or anastomotic leakage are at high risk of PS after temporary ileostomy. Surgeons should be aware and patients should be informed of the possibility of PS formation. PMID- 26490727 TI - Virological failure to raltegravir in Spain: incidence, prevalence and clinical consequences. AB - OBJECTIVES: The objective of this study was to evaluate the incidence, prevalence and clinical consequences of virological failure (VF) to raltegravir-based regimens in Spain. METHODS: A multicentre, retrospective, observational study was performed in 10 tertiary hospitals (January 2006 to June 2013). The study included HIV-1-infected patients with loss of virological suppression (LVS; two consecutive HIV-1 RNA >=50 copies/mL) while receiving raltegravir. VF and low level viraemia (LLV) were defined as two consecutive HIV-1 RNA >=200 copies/mL and 50 to <200 copies/mL, respectively. Integrase strand-transfer inhibitor resistance was investigated at LVS. During the 48 weeks following LVS, recorded data included clinical characteristics, treatment discontinuations, AIDS associated events and deaths. Effectiveness of therapy following LVS was evaluated by ITT and PP. Multivariate regression was used to assess predictors of efficacy. RESULTS: Of the 15 009 HIV-infected patients in participating centres, 2782 (18.5%) had received raltegravir-based regimens. Of those, 192 (6.9%), 125 (4.5%) and 67 (2.4%) experienced LVS, VF and LLV, respectively. The incidence of VF was 1.8 (95% CI, 1.5-2.1) per 100 patients/year. The prevalence of VF was 4.5% (95% CI, 3.8%-5.3%). Integrase-associated mutations were found in 78.8% of patients with integrase genotyping results available. High-level resistance to dolutegravir was not observed. Salvage therapy failed in 34.1% of patients; progression to AIDS/death occurred in 8.3% during the first year following LVS. The latter was associated with intravenous drug use, time on raltegravir and lower CD4+ count nadir in patients who started raltegravir-based treatments as salvage regimens. CONCLUSIONS: VF with raltegravir is infrequent, but often associated with major clinical complications in treatment-experienced patients. PMID- 26490728 TI - Improving a Synechocystis-based photoautotrophic chassis through systematic genome mapping and validation of neutral sites. AB - The use of microorganisms as cell factories frequently requires extensive molecular manipulation. Therefore, the identification of genomic neutral sites for the stable integration of ectopic DNA is required to ensure a successful outcome. Here we describe the genome mapping and validation of five neutral sites in the chromosome of Synechocystis sp. PCC 6803, foreseeing the use of this cyanobacterium as a photoautotrophic chassis. To evaluate the neutrality of these loci, insertion/deletion mutants were produced, and to assess their functionality, a synthetic green fluorescent reporter module was introduced. The constructed integrative vectors include a BioBrick-compatible multiple cloning site insulated by transcription terminators, constituting robust cloning interfaces for synthetic biology approaches. Moreover, Synechocystis mutants (chassis) ready to receive purpose-built synthetic modules/circuits are also available. This work presents a systematic approach to map and validate chromosomal neutral sites in cyanobacteria, and that can be extended to other organisms. PMID- 26490730 TI - Does reduced-port laparoscopic surgery for medically uncontrolled ulcerative colitis do more harm than good? AB - INTRODUCTION: Reduced-port laparoscopic surgery is a novel minimally invasive surgery. However, reduced-port surgery for ulcerative colitis (UC) remains controversial. Here, we describe the clinical outcomes of single-incision plus one port laparoscopic surgery (SILS + 1) for medically uncontrolled UC. METHODS: Between May 2011 and September 2014, 10 UC patients underwent SILS + 1 port surgery. All procedures were performed with the use of a SILS port and either a 5 mm or a 12-mm port placed at the planned ileostomy site. RESULTS: The median age of patients was 32 years (range, 22-53 years). Six patients underwent two-stage SILS + 1 port restorative proctocolectomy with ileal pouch-anal anastomosis, two patients underwent SILS + 1 total proctocolectomy, and the remaining two patients underwent SILS + 1 subtotal colectomy with subsequent three-stage SILS + 1 ileal pouch-anal anastomosis. The median operative time was 363.1 min (range, 253-465 min) and the median estimated blood loss was 29 mL (range, 0-100 mL). There were no conversions or additional ports required. Two patients previously underwent SILS + 1 subtotal colectomy, and in one of those patients, SILS + 1 ileal pouch anal anastomosis was performed successfully 6 months after the previous surgery. There were no intra-abdominal adhesions, and no extra wounds were necessary because the previous stoma site had been used to access the SILS port. The median postoperative period was 24 months, during which five patients had their ileostomies closed. No patients reported occasional minor daily soiling or the need to wear a pad. CONCLUSION: Reduced-port laparoscopic surgery for medically uncontrolled UC is a feasible and safe procedure when performed by skilled surgeons. PMID- 26490729 TI - Captured metagenomics: large-scale targeting of genes based on 'sequence capture' reveals functional diversity in soils. AB - Microbial enzyme diversity is a key to understand many ecosystem processes. Whole metagenome sequencing (WMG) obtains information on functional genes, but it is costly and inefficient due to large amount of sequencing that is required. In this study, we have applied a captured metagenomics technique for functional genes in soil microorganisms, as an alternative to WMG. Large-scale targeting of functional genes, coding for enzymes related to organic matter degradation, was applied to two agricultural soil communities through captured metagenomics. Captured metagenomics uses custom-designed, hybridization-based oligonucleotide probes that enrich functional genes of interest in metagenomic libraries where only probe-bound DNA fragments are sequenced. The captured metagenomes were highly enriched with targeted genes while maintaining their target diversity and their taxonomic distribution correlated well with the traditional ribosomal sequencing. The captured metagenomes were highly enriched with genes related to organic matter degradation; at least five times more than similar, publicly available soil WMG projects. This target enrichment technique also preserves the functional representation of the soils, thereby facilitating comparative metagenomics projects. Here, we present the first study that applies the captured metagenomics approach in large scale, and this novel method allows deep investigations of central ecosystem processes by studying functional gene abundances. PMID- 26490731 TI - Utilizing the virus-induced blocking of apoptosis in an easy baculovirus titration method. AB - Baculovirus-mediated protein expression is a robust experimental technique for producing recombinant higher-eukaryotic proteins because it combines high yields with considerable post-translational modification capabilities. In this expression system, the determination of the titer of recombinant baculovirus stocks is important to achieve the correct multiplicity of infection for effective amplification of the virus and high expression of the target protein. To overcome the drawbacks of existing titration methods (e.g., plaque assay, real time PCR), we present a simple and reliable assay that uses the ability of baculoviruses to block apoptosis in their host cells to accurately titrate virus samples. Briefly, after incubation with serial dilutions of baculovirus samples, Sf9 cells were UV irradiated and, after apoptosis induction, they were viewed via microscopy; the presence of cluster(s) of infected cells as islets indicated blocked apoptosis. Subsequently, baculovirus titers were calculated through the determination of the 50% endpoint dilution. The method is simple, inexpensive, and does not require unique laboratory equipment, consumables or expertise; moreover, it is versatile enough to be adapted for the titration of every virus species that can block apoptosis in any culturable host cells which undergo apoptosis under specific conditions. PMID- 26490732 TI - Efficacy and safety of long-acting beta-agonist/long-acting muscarinic antagonist combinations in COPD: a network meta-analysis. AB - BACKGROUND: The place of long-acting beta agonist/long-acting muscarinic antagonist (LABA/LAMA) combinations in stable patients with COPD is not well defined. The purpose of this study was to systematically review the efficacy and safety of LABA/LAMA combinations. METHODS: Several databases and manufacturers' websites were searched for relevant clinical trials. Randomised control trials, at least 12 weeks duration, comparing a LABA/LAMA combination with placebo and/or monotherapy were included. The data were pooled using a network as well as a traditional direct comparison meta-analysis. RESULTS: Twenty-three trials with a total of 27 172 patients were included in the analysis. LABA/LAMA combinations were associated with a greater improvement in lung function, St. George's Respiratory Questionnaire (SGRQ) score, and Transitional Dyspnoea Index (TDI) than monotherapies. LABA/LAMA combinations were associated with a significantly greater proportion of SGRQ and TDI responders than monotherapies (OR 1.23 (95% credible interval (CrI) 1.06-1.39), OR 1.34 (95% CrI 1.19-1.50) versus LABAs and OR 1.24 (95% CrI 1.11-1.36), OR 1.31 (95% CrI 1.18-1.46) versus LAMAs, respectively) and fewer moderate-to-severe exacerbations compared with LABAs (HR 0.82 (95% CrI 0.73-0.93)), but not when compared with LAMAs (HR 0.92 (95% CrI 0.84-1.00)). There were no statistically significant differences associated with LABA/LAMA combinations compared with monotherapies in safety outcomes as well as in severe exacerbations. CONCLUSIONS: The combination therapy was the most effective strategy in improving lung function, quality of life, symptom scores and moderate-to-severe exacerbation rates, and had similar effects on safety outcomes and severe exacerbations as compared with monotherapies. PMID- 26490734 TI - Theory of Mind and social reserve: Alternative hypothesis of progressive Theory of Mind decay during different stages of Alzheimer's disease. AB - Although Theory of Mind (ToM) is thought to be impaired in Alzheimer's disease (AD), it remains unclear whether this impairment is linked to the level of task complexity, the heterogeneity of the studied patients, or the implication of executive dysfunctions. To elucidate this point, 42 AD patients, divided into two subgroups [moderate AD (mAD) patients (n = 19) and early AD (eAD) patients (n = 23)], and 23 matched healthy older subjects (HO) were enrolled. All participants were given (1) a false-belief task (cognitive ToM), (2) a revised version of the "Reading the Mind in the Eyes" test (affective ToM), and (3) a composite task designed to assess ToM abilities with minimal cognitive demands. Participants were also given executive tasks assessing inhibition, shifting, and updating processes. We observed a significant impairment of cognitive and composite ToM abilities in eAD patients compared with mAD patients. There was no impairment of affective ToM. Stepwise regression revealed that measures of global efficiency and executive functions (EFs) were the best predictors of progressive decay of ToM scores. These results indicate that cognitive aspects of ToM are more sensitive to AD progression than affective tasks. They also show that ToM abilities are more affected by dementia severity than by task complexity. One explanation of our results is the presence of compensatory mechanisms (social reserve) in AD. PMID- 26490733 TI - Tomato histone H2B monoubiquitination enzymes SlHUB1 and SlHUB2 contribute to disease resistance against Botrytis cinerea through modulating the balance between SA- and JA/ET-mediated signaling pathways. AB - BACKGROUND: Histone H2B monoubiquitination pathway has been shown to play critical roles in regulating growth/development and stress response in Arabidopsis. In the present study, we explored the involvement of the tomato histone H2B monoubiquitination pathway in defense response against Botrytis cinerea by functional analysis of SlHUB1 and SlHUB2, orthologues of the Arabidopsis AtHUB1/AtHUB2. METHODS: We used the TRV-based gene silencing system to knockdown the expression levels of SlHUB1 or SlHUB2 in tomato plants and compared the phenotype between the silenced and the control plants after infection with B. cinerea and Pseudomonas syringae pv. tomato (Pst) DC3000. Biochemical and interaction properties of proteins were examined using in vitro histone monoubiquitination and yeast two-hybrid assays, respectively. The transcript levels of genes were analyzed by quantitative real time PCR (qRT-PCR). RESULTS: The tomato SlHUB1 and SlHUB2 had H2B monoubiquitination E3 ligases activity in vitro and expression of SlHUB1 and SlHUB2 was induced by infection of B. cinerea and Pst DC3000 and by treatment with salicylic acid (SA) and 1-amino cyclopropane-1-carboxylic acid (ACC). Silencing of either SlHUB1 or SlHUB2 in tomato plants showed increased susceptibility to B. cinerea, whereas silencing of SlHUB1 resulted in increased resistance against Pst DC3000. SlMED21, a Mediator complex subunit, interacted with SlHUB1 but silencing of SlMED21 did not affect the disease resistance to B. cinerea and Pst DC3000. The SlHUB1- and SlHUB2 silenced plants had thinner cell wall but increased accumulation of reactive oxygen species (ROS), increased callose deposition and exhibited altered expression of the genes involved in phenylpropanoid pathway and in ROS generation and scavenging system. Expression of genes in the SA-mediated signaling pathway was significantly upregulated, whereas expression of genes in the jasmonic acid (JA)/ethylene (ET)-mediated signaling pathway were markedly decreased in SlHUB1- and SlHUB2-silenced plants after infection of B. cinerea. CONCLUSION: VIGS-based functional analyses demonstrate that both SlHUB1 and SlHUB2 contribute to resistance against B. cinerea most likely through modulating the balance between the SA- and JA/ET-mediated signaling pathways. PMID- 26490735 TI - Effects of maize cultivation on nitrogen and phosphorus loadings to drainage channels in Central Chile. AB - There are concerns about the impact of maize cultivation with high applications of nitrogen (N) and phosphorus (P) on water quality in surface waters in Mediterranean Central Chile. This study estimated the contribution of N and P from maize fields to nearby drainage channels and evaluated the effects in water quality. An N and P budget was drawn up for three fields managed with a maize fallow system, El Maiten (20.7 ha), El Naranjal (14.9 ha) and El Caleuche (4.2 ha), and water quality variables (pH, EC, dissolved oxygen, total solids, turbidity, NO3-N, NH4-N, PO4(3-), COD, total N, total P and sulphate) were monitored in nearby drainage channels. The N and P balances for the three fields indicated a high risk of N and P non-point source pollution, with fertiliser management, soil texture and climate factors determining the temporal variations in water quality parameters. Elevated levels of NH4-N and PO4(3-) in the drainage channels were usually observed during the winter period, while NO3- concentrations did not show a clear tendency. The results suggest that excessive slurry application during winter represents a very high risk of N and P runoff to drainage channels. Overall, great emphasis must be placed on good agronomic management of fields neighbouring drainage channels, including accurately calculating N and P fertiliser rates and establishing mitigation measures. PMID- 26490736 TI - Hypermethylation of the GATA binding protein 4 (GATA4) promoter in Chinese pediatric acute myeloid leukemia. AB - BACKGROUND: Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature of AML. GATA4 has been suggested to be a tumor suppressor gene regulated by promoter hypermethylation in various types of human cancers although the expression and promoter methylation of GATA4 in pediatric AML is still unclear. METHODS: Transcriptional expression levels of GATA4 were evaluated by semi quantitative and real-time PCR. Methylation status was investigated by methylation-specific PCR (MSP) and bisulfate genomic sequencing (BGS). The prognostic significance of GATA4 expression and promoter methylation was assessed in 105 cases of Chinese pediatric acute myeloid leukemia patients with clinical follow-up records. RESULTS: MSP and BGS analysis showed that the GATA4 gene promoter is hypermethylated in AML cells, such as the HL-60 and MV4-11 human myeloid leukemia cell lines. 5-Aza treatment significantly upregulated GATA4 expression in HL-60 and MV4-11 cells. Aberrant methylation of GATA4 was observed in 15.0 % (3/20) of the normal bone marrow control samples compared to 56.2 % (59/105) of the pediatric AML samples. GATA4 transcript levels were significantly decreased in AML patients (33.06 +/- 70.94; P = 0.011) compared to normal bone marrow/idiopathic thrombocytopenic purpura controls (116.76 +/- 105.39). GATA4 promoter methylation was correlated with patient leukocyte counts (WBC, white blood cells) (P = 0.035) and minimal residual disease MRD (P = 0.031). Kaplan Meier survival analysis revealed significantly shorter overall survival time in patients with GATA4 promoter methylation (P = 0.014). CONCLUSIONS: Epigenetic inactivation of GATA4 by promoter hypermethylation was observed in both AML cell lines and pediatric AML samples; our study implicates GATA4 as a putative tumor suppressor gene in pediatric AML. In addition, our findings imply that GATA4 promoter methylation is correlated with WBC and MRD. Kaplan-Meier survival analysis revealed significantly shorter overall survival in pediatric AML with GATA4 promoter methylation but multivariate analysis shows that it is not an independent factor. However, further research focusing on the mechanism of GATA4 in pediatric leukemia is required. PMID- 26490737 TI - Changes in seasonal climate outpace compensatory density-dependence in eastern brook trout. AB - Understanding how multiple extrinsic (density-independent) factors and intrinsic (density-dependent) mechanisms influence population dynamics has become increasingly urgent in the face of rapidly changing climates. It is particularly unclear how multiple extrinsic factors with contrasting effects among seasons are related to declines in population numbers and changes in mean body size and whether there is a strong role for density-dependence. The primary goal of this study was to identify the roles of seasonal variation in climate driven environmental direct effects (mean stream flow and temperature) vs. density dependence on population size and mean body size in eastern brook trout (Salvelinus fontinalis). We use data from a 10-year capture-mark-recapture study of eastern brook trout in four streams in Western Massachusetts, USA to parameterize a discrete-time population projection model. The model integrates matrix modeling techniques used to characterize discrete population structures (age, habitat type, and season) with integral projection models (IPMs) that characterize demographic rates as continuous functions of organismal traits (in this case body size). Using both stochastic and deterministic analyses we show that decreases in population size are due to changes in stream flow and temperature and that these changes are larger than what can be compensated for through density-dependent responses. We also show that the declines are due mostly to increasing mean stream temperatures decreasing the survival of the youngest age class. In contrast, increases in mean body size over the same period are the result of indirect changes in density with a lesser direct role of climate-driven environmental change. PMID- 26490738 TI - F4+ ETEC infection and oral immunization with F4 fimbriae elicits an IL-17 dominated immune response. AB - Enterotoxigenic Escherichia coli (ETEC) are an important cause of post-weaning diarrhea (PWD) in piglets. Porcine-specific ETEC strains possess different fimbrial subtypes of which F4 fimbriae are the most frequently associated with ETEC-induced diarrhea in piglets. These F4 fimbriae are potent oral immunogens that induce protective F4-specific IgA antibody secreting cells at intestinal tissues. Recently, T-helper 17 (Th17) cells have been implicated in the protection of the host against extracellular pathogens. However, it remains unknown if Th17 effector responses are needed to clear ETEC infections. In the present study, we aimed to elucidate if ETEC elicits a Th17 response in piglets and if F4 fimbriae trigger a similar response. F4(+) ETEC infection upregulated IL-17A, IL-17F, IL-21 and IL-23p19, but not IL-12 and IFN-gamma mRNA expression in the systemic and mucosal immune system. Similarly, oral immunization with F4 fimbriae triggered a Th17 signature evidenced by an upregulated mRNA expression of IL-17F, RORgammat, IL-23p19 and IL-21 in the peripheral blood mononuclear cells (PBMCs). Intriguingly, IL-17A mRNA levels were unaltered. To further evaluate this difference between systemic and mucosal immune responses, we assayed the cytokine mRNA profile of F4 fimbriae stimulated PBMCs. F4 fimbriae induced IL-17A, IL-17F, IL-22 and IL-23p19, but downregulated IL-17B mRNA expression. Altogether, these data indicate a Th17 dominated response upon oral immunization with F4 fimbriae and F4(+) ETEC infection. Our work also highlights that IL-17B and IL-17F participate in the immune response to protect the host against F4(+) ETEC infection and could aid in the design of future ETEC vaccines. PMID- 26490739 TI - Branch-Selective Alkene Hydroarylation by Cooperative Destabilization: Iridium Catalyzed ortho-Alkylation of Acetanilides. AB - An iridium(I) catalyst system, modified with the wide-bite-angle and electron deficient bisphosphine d(F) ppb (1,4-bis(di(pentafluorophenyl)phosphino)butane) promotes highly branch-selective hydroarylation reactions between diverse acetanilides and aryl- or alkyl-substituted alkenes. This provides direct and ortho-selective access to synthetically challenging anilines, and addresses long standing issues associated with related Friedel-Crafts alkylations. PMID- 26490740 TI - Investigation of mucus obtained from different fish species on the acute pain induced with scalpel incision in paw of rats. AB - No comparative study could be found for the analgesic activity of mucuses from the Oncorhynchus mykiss (OM), Salvelinus fontinalis (SF), Salmo coruhensis (SC), Acipenser gueldenstaedtii (AG), and Acipenser baerii (AB) fish species in the literature. We aimed to investigate the effects of mucuses obtained from the abovementioned fish species on scalpel incision-induced pain in the rat paw and to examine the role of oxidant/antioxidant parameters and COX-2 gene expression in the analgesic activities. Animals were divided into groups: SIC (scalpel incision; SI), SIDS (SI+25 mg/kg diclofenac sodium), SOM (SI+25 mg/kg OM mucus), SFM (SI+25 mg/kg SF mucus), SCM (SI+25 mg/kg SC mucus), SAgM (SI+25 mg/kg AG mucus), SAbM (SI+25 mg/kg AB mucus), and HG (healthy). The paw pain thresholds were measured with a Basile algesimeter before and after diclofenac sodium (DS) or mucus administration, and then the rats were euthanized with thiopental sodium. Oxidant/antioxidant and COX-2 gene expression parameters were measured in paw tissues. OM, SC, AG, and AB fish mucuses could not decrease the SI-induced pain. However, SF fish mucus prevented this pain by 69% after the first hour and by 58.3% after the third hour. DS was shown to suppress pain more weakly than SF, preventing the pain by 62.1% and 50.0% after the first and third hours, respectively. SF mucus and DS significantly inhibited increase of COX-2 gene expression, while other fish mucuses could not. None of the fish mucuses except SF mucus in conjunction with DS could significantly inhibit the increase in oxidant parameters and decrease in antioxidants. SF fish mucus should be comparatively assessed in clinical practice for treatment of postoperative pain. PMID- 26490741 TI - Plasticity of adult endothelium: how frequent and to what extent? PMID- 26490743 TI - Correction - A statistical model for measurement error that incorporates variation over time in the target measure, with application to nutritional epidemiology. PMID- 26490742 TI - Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation enhance calcium release. AB - AIMS: In atrial fibrillation (AF), abnormalities in Ca(2+) release contribute to arrhythmia generation and contractile dysfunction. We explore whether ryanodine receptor (RyR) cluster ultrastructure is altered and is associated with functional abnormalities in AF. METHODS AND RESULTS: Using high-resolution confocal microscopy (STED), we examined RyR cluster morphology in fixed atrial myocytes from sheep with persistent AF (N = 6) and control (Ctrl; N = 6) animals. RyR clusters on average contained 15 contiguous RyRs; this did not differ between AF and Ctrl. However, the distance between clusters was significantly reduced in AF (288 +/- 12 vs. 376 +/- 17 nm). When RyR clusters were grouped into Ca(2+) release units (CRUs), i.e. clusters separated by <150 nm, CRUs in AF had more clusters (3.43 +/- 0.10 vs. 2.95 +/- 0.02 in Ctrl), which were more dispersed. Furthermore, in AF cells, more RyR clusters were found between Z lines. In parallel experiments, Ca(2+) sparks were monitored in live permeabilized myocytes. In AF, myocytes had >50% higher spark frequency with increased spark time to peak (TTP) and duration, and a higher incidence of macrosparks. A computational model of the CRU was used to simulate the morphological alterations observed in AF cells. Increasing cluster fragmentation to the level observed in AF cells caused the observed changes, i.e. higher spark frequency, increased TTP and duration; RyR clusters dispersed between Z-lines increased the occurrence of macrosparks. CONCLUSION: In persistent AF, ultrastructural reorganization of RyR clusters within CRUs is associated with overactive Ca(2+) release, increasing the likelihood of propagating Ca(2+) release. PMID- 26490744 TI - Back-calculating the incidence of infection of leprosy in a Bayesian framework. AB - BACKGROUND: The number of new leprosy cases reported annually is falling worldwide, but remains relatively high in some populations. Because of the long and variable periods between infection, onset of disease, and diagnosis, the recently detected cases are a reflection of infection many years earlier. Estimation of the numbers of sub-clinical and clinical infections would be useful for management of elimination programmes. Back-calculation is a methodology that could provide estimates of prevalence of undiagnosed infections, future diagnoses and the effectiveness of control. METHODS: A basic back-calculation model to investigate the infection dynamics of leprosy has been developed using Markov Chain Monte Carlo in a Bayesian context. The incidence of infection and the detection delay both vary with calendar time. Public data from Thailand are used to demonstrate the results that are obtained as the incidence of diagnosed cases falls. RESULTS: The results show that the underlying burden of infection and short-term future predictions of cases can be estimated with a simple model. The downward trend in new leprosy cases in Thailand is expected to continue. In 2015 the predicted total number of undiagnosed sub-clinical and clinical infections is 1,168 (846-1,546) of which 466 (381-563) are expected to be clinical infections. CONCLUSIONS: Bayesian back-calculation has great potential to provide estimates of numbers of individuals in health/infection states that are as yet unobserved. Predictions of future cases provides a quantitative measure of understanding for programme managers and evaluators. We will continue to develop the approach, and suggest that it might be useful for other NTD in which incidence of diagnosis is not an immediate measure of infection. PMID- 26490745 TI - Increased number of volatile organic compounds over malignant glottic lesions. AB - OBJECTIVES/HYPOTHESIS: Electronic noses can identify diseases, including head and neck squamous cell carcinoma (SCC) by the fingerprint of volatile organic compounds (VOCs) in exhaled air. However, whether these VOCs originated from the malignant lesion itself remains unclear. The objective was to test for the presence and properties of VOCs directly over the vocal folds in malignant and benign lesions, as a potential tool for noninvasive screening. STUDY DESIGN: Prospective observational case control study. METHODS: Samples of mucus directly covering vocal fold lesions were analyzed using gas chromatography mass spectrometry for detection of VOCs, and evaluation of the properties and quantity of VOCs in the samples. Additionally, samples of oropharyngeal mucus were analyzed to exclude VOCs found also in the vicinity of the lesion. Benign and malignant lesion groups were compared using a nonparametric (Mann-Whitney) test. RESULTS: We studied 14 patients, six with SCC and eight with benign pathology. We found an increased number of discrete VOC types in patients with SCC both above the lesion (SCC = 4.333 +/- 2.5, benign = 0.875 +/- 0.6; Z=3, P < .001) and directly above the lesion with exclusion of its vicinity (SCC = 3.167 +/- 1.9, benign = 0.5 +/- 0.5; Z = 2.8, P < .003). VOCs detected in SCCs but not in benign samples included the straight-chain fatty acids: butyric acid, pentanoic acid, hexanoic acid, and heptanoic acid. CONCLUSIONS: Compared with benign vocal fold lesions, the environment of vocal folds in SCC is enriched with VOCs. These preliminary findings highlight a unique pattern that may contribute to the development of a future minimally invasive technology for screening vocal fold lesions for malignancy. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1606-1611, 2016. PMID- 26490746 TI - Connexin26 gap junction mediates miRNA intercellular genetic communication in the cochlea and is required for inner ear development. AB - Organ development requires well-established intercellular communication to coordinate cell proliferations and differentiations. MicroRNAs (miRNAs) are small, non-coding RNAs that can broadly regulate gene expression and play a critical role in the organ development. In this study, we found that miRNAs could pass through gap junctions between native cochlear supporting cells to play a role in the cochlear development. Connexin26 (Cx26) and Cx30 are predominant isoforms and co-express in the cochlea. Cx26 deficiency but not Cx30 deficiency can cause cochlear developmental disorders. We found that associated with Cx26 deletion induced the cochlear developmental disorders, deletion of Cx26 but not Cx30 disrupted miRNA intercellular transfer in the cochlea, although inner ear gap junctions still retained permeability after deletion of Cx26. Moreover, we found that deletion of Cx26 but not Cx30 reduced miR-96 expression in the cochlea during postnatal development. The reduction is associated with the cochlear tunnel developmental disorder in Cx26 knockout (KO) mice. These data reveal that Cx26-mediated intercellular communication is required for cochlear development and that deficiency of Cx26 can impair miRNA-mediated intercellular genetic communication in the cochlea, which may lead to cochlear developmental disorders and eventually congenital deafness as previously reported. PMID- 26490747 TI - Electrohydraulic lithotripsy for large bile duct stones under direct cholangioscopy using double-balloon enteroscopy. PMID- 26490748 TI - Ammonia effect on hydrogenotrophic methanogens and syntrophic acetate-oxidizing bacteria. AB - Ammonia-rich substrates can cause inhibition on anaerobic digestion process. Syntrophic acetate-oxidizing bacteria (SAOB) and hydrogenotrophic methanogens are important for the ammonia inhibitory mechanism on anaerobic digestion. The roles and interactions of SAOB and hydrogenotrophic methanogens to ammonia inhibition effect are still unclear. The aim of the current study was to determine the ammonia toxicity levels of various pure strains of SAOB and hydrogenotrophic methanogens. Moreover, ammonia toxicity on the syntrophic-cultivated strains of SAOB and hydrogenotrophic methanogens was tested. Thus, four hydrogenotrophic methanogens (i.e. Methanoculleus bourgensis, Methanobacterium congolense, Methanoculleu thermophilus and Methanothermobacter thermautotrophicus), two SAOB (i.e. Tepidanaerobacter acetatoxydans and Thermacetogenium phaeum) and their syntrophic cultivation were assessed under 0.26, 3, 5 and 7 g NH4 (+)-N L(-1). The results showed that some hydrogenotrophic methanogens were equally, or in some cases, more tolerant to high ammonia levels compared to SAOB. Furthermore, a mesophilic hydrogenotrophic methanogen was more sensitive to ammonia toxicity compared to thermophilic methanogens tested in the study, which is contradicting to the general belief that thermophilic methanogens are more vulnerable to high ammonia loads compared to mesophilic. This unexpected finding underlines the fact that the complete knowledge of ammonia inhibition effect on hydrogenotrophic methanogens is still absent. PMID- 26490749 TI - Dynamic changes in the population structure of Escherichia coli in the Yeongsan River basin of South Korea. AB - Although Escherichia coli has been used as an indicator to examine fecal contamination of aquatic environment, it also has been reported to become naturalized to secondary habitats, including soil, water and beach sand. A total of 2880 E. coli isolates obtained from surface water and sediment samples from the Yeongsan River in 2013 were genotyped by using the horizontal fluorophore enhanced rep-PCR DNA fingerprinting technique. Although different E. coli genotypic groups were observed between surface water and sediments in the dry season, they were mingled and undifferentiated from each other in the rainy season. This indicates that there are frequent sediment resuspension events in the river basin. Moreover, the genotypic composition of the E. coli population in the Yeongsan River basin changes over months and years, implying that genotypic structure of E. coli populations dynamically fluctuates in the river environment. Consequently, our data suggests that the use of E. coli libraries for fecal source tracking needs to be reassessed to account for the changing structure of riverine E. coli populations. PMID- 26490750 TI - Stereoselective total synthesis of (-)-nupharamine utilizing an alpha chlorosulfide and a sulfinimine for C-C bond formation. AB - An efficient stereoselective synthesis of the nuphar alkaloid, (-)-nupharamine, is reported. The key features include the Lewis acid catalyzed reaction of an alpha-chlorosulfide with a silyl ketene acetal for C-C bond formation, creation of the stereocenter at C2 by a diastereoselective reaction of allyl indium with a sulfinimine and reductive amination for the introduction of the C6 stereocenter of the piperidine ring. PMID- 26490752 TI - Resolution of apnoeas in slow wave sleep. PMID- 26490751 TI - [(18)F]FPRGD2 PET/CT imaging of integrin alphavbeta3 levels in patients with locally advanced rectal carcinoma. AB - PURPOSE: Our primary objective was to determine if [(18)F]FPRGD2 PET/CT performed at baseline and/or after chemoradiotherapy (CRT) could predict tumour regression grade (TRG) in locally advanced rectal cancer (LARC). Secondary objectives were to compare baseline [(18)F]FPRGD2 and [(18)F]FDG uptake, to evaluate the correlation between posttreatment [(18)F]FPRGD2 uptake and tumour microvessel density (MVD) and to determine if [(18)F]FPRGD2 and FDG PET/CT could predict disease-free survival. METHODS: Baseline [(18)F]FPRGD2 and FDG PET/CT were performed in 32 consecutive patients (23 men, 9 women; mean age 63 +/- 8 years) with LARC before starting any therapy. A posttreatment [(18)F]FPRGD2 PET/CT scan was performed in 24 patients after the end of CRT (median interval 7 weeks, range 3 - 15 weeks) and before surgery (median interval 4 days, range 1 - 15 days). RESULTS: All LARC showed uptake of both [(18)F]FPRGD2 (SUVmax 5.4 +/- 1.5, range 2.7 - 9) and FDG (SUVmax 16.5 +/- 8, range 7.1 - 36.5). There was a moderate positive correlation between [(18)F]FPRGD2 and FDG SUVmax (Pearson's r = 0.49, p = 0.0026). There was a moderate negative correlation between baseline [(18)F]FPRGD2 SUVmax and the TRG (Spearman's r = -0.37, p = 0.037), and a [(18)F]FPRGD2 SUVmax of >5.6 identified all patients with a complete response (TRG 0; AUC 0.84, 95 % CI 0.68 - 1, p = 0.029). In the 24 patients who underwent a posttreatment [(18)F]FPRGD2 PET/CT scan the response index, calculated as [(SUVmax1 - SUVmax2)/SUVmax1] * 100 %, was not associated with TRG. Post treatment [(18)F]FPRGD2 uptake was not correlated with tumour MVD. Neither [(18)F]FPRGD2 nor FDG uptake predicted disease-free survival. CONCLUSION: Baseline [(18)F]FPRGD2 uptake was correlated with the pathological response in patients with LARC treated with CRT. However, the specificity was too low to consider its clinical routine use. PMID- 26490753 TI - Role of HSP70 in motoneuron survival after excitotoxic stress in a rat spinal cord injury model in vitro. AB - The outcome for gait recovery from paralysis due to spinal lesion remains uncertain even when damage is limited. One critical factor is the survival of motoneurons, which are very vulnerable cells. To clarify the early pathophysiological mechanisms of spinal damage, an in vitro injury model of the rat spinal cord caused by moderate excitotoxicity was used. With this preparation we investigated whether motoneuron survival was dependent on the expression of the neuroprotective protein HSP70. In the present study excitotoxicity evoked by kainate induced delayed (24 h) loss (35%) of motoneurons, which became pyknotic with translocation of the cell death biomarker apoptosis-inducing factor (AIF) to the nucleus. This process was concomitant with suppression of locomotor network electrical activity. Surviving cells showed strong expression of HSP70 without nuclear AIF. The HSP70 inhibitor VER155008 per se induced neurotoxicity similar to that of kainate, while the HSP90 inhibitor geldanamycin did not damage spinal tissue. Electrophysiological recording following kainate or VER155008 indicated depression of motoneuron field potentials, with decreased excitability and impaired synaptic transmission. When these two drugs were applied together, more intense neurotoxicity emerged. Our data indicate that HSP70 was one important contributor to motoneuron survival and suggest that enhancing HSP70 activity is a potential future strategy for neuroprotecting these cells. PMID- 26490754 TI - The impact of nutritional status on treatment outcomes of patients with limb threatening diabetic foot ulcers. AB - AIM: This study aimed to investigate the nutritional status of patients with limb threatening diabetic foot ulcers (DFUs) and its impact on treatment outcomes. METHODS: A total of 478 consecutive patients (mean age, 65.4years) treated for limb-threatening DFUs were enrolled. Nutritional status assessment using the Mini Nutritional Assessment (MNA) and Geriatric Nutritional Risk Index (GNRI) was performed by three qualified dieticians within 48hours of admission. Limb preservation outcomes were stratified into major lower extremity amputation (LEA) (above the ankle, n=33), minor LEA (distal to ankle, n=117) and no amputation (non-LEA, n=328). RESULTS: Most patients were identified as being at risk of malnutrition (70.5%) or malnourished (14.6%) (mean MNA score, 20.6+/-3.4). MNA scores decreased with increasing severity of LEA (mean, 21.1, 20.0, and 17.9, respectively; P for linear trend <0.001), associated inversely with the tendency to require LEA (P for linear trend was 0.001), and associated independently with both major and minor LEA outcomes (adjusted odds ratio [aOR]=0.80, 95% confidence interval [CI], 0.65-0.99, P=0.042 and aOR=0.89, 95% CI, 0.80-0.99, P=0.032, respectively). The predictive value was sustained in patients younger than age 65years. Though GNRI results had similar associations with outcomes, its predictive value was limited in minor LEA and younger population. CONCLUSIONS: Patients' nutritional status was shown to have significant influence on limb preservation outcomes for limb-threatening DFUs. Nutritional assessment of this patient population using the MNA is recommended. PMID- 26490755 TI - The relationship between depressive symptoms, diabetes symptoms, and self management among an urban, low-income Latino population. AB - OBJECTIVE: To investigate the prevalence of depression symptoms among Latinos with diabetes following transition from hospital to home and the relationship of depressive symptoms to diabetes symptom severity and self-management activities. METHODS: 203 Latino patients with diagnosed diabetes completed a survey assessing depressive symptoms (PHQ-9), diabetes symptom severity, and diabetes self management activities (SDSCA). Characteristics and diabetes outcomes between patients with and without probable major depression were compared. Associations between PHQ-9 scores and diabetes outcomes were assessed. Multivariate regression models evaluated the relationship between depressive symptoms and diabetes outcomes and exercise after controlling for patient characteristics. RESULTS: 31.5% of participants indicated probable major depression (PHQ-9>=10). More severe diabetes symptoms and less reported exercise were associated with higher PHQ-9 scores. Regression models showed no relationship between self-management and depression. More severe diabetes symptoms were significantly associated with being female, married, and having probable major depression. Odds of exercising were reduced by 6% for every one-unit increase in PHQ-9 score. CONCLUSIONS: The prevalence of probable depressive symptoms is high in this population. Having depressive symptoms is an indicator of poorer diabetes symptoms. Screening for depressive symptoms may help identify individuals who need additional support with diabetes symptom and self-management. PMID- 26490757 TI - Differentiation between Shallow and Deep Charge Trap States on Single Poly(3 hexylthiophene) Chains through Fluorescence Photon Statistics. AB - Blinking of the photoluminescence (PL) emitted from individual conjugated polymer chains is one of the central observations made by single-molecule spectroscopy (SMS). Important information, for example regarding excitation energy transfer, can be extracted by evaluating dynamic quenching. However, the nature of trap states, which are responsible for PL quenching, often remains obscured. We present a detailed investigation of the photon statistics of single poly(3 hexylthiophene) (P3HT) chains obtained by SMS. The photon statistics provide a measure of the number and brightness of independently emitting areas on a single chain. These observables can be followed during blinking. A decrease in PL intensity is shown to be correlated with either 1) a decrease in the average brightness of the emitting sites; or 2) a decrease in the number of emitting regions. We attribute these phenomena to the formation of 1) shallow charge traps, which can weakly affect all emitting areas of a single chain at once; and 2) deep traps, which have a strong effect on small regions within the single chains. PMID- 26490756 TI - Diabetes distress in adult type 1 diabetes mellitus men and women with disease onset in childhood and in adulthood. AB - THE AIM: To determine whether or not diabetes distress varies by age of type 1 diabetes mellitus (T1DM) onset and/or gender. SUBJECTS AND METHODS: A total of 700 adult T1DM patients were randomly selected from the Lithuanian Diabetes Registry; 214 of them (30.6%) agreed to participate and were recruited for the study. Diabetes distress (emotional burden, physician-related distress, regimen related distress, interpersonal distress) was compared in 105 (42 men and 63 women) patients with T1DM diagnosed during 0-18years of life, and in 109 (61 men and 48 women) with T1DM diagnosed in adulthood, using Diabetes Distress Scale (DDS). RESULTS: Adult childhood-onset T1DM women have higher regimen-related distress (36.3+/-21.3 vs 26.6+/-16.2, p=0.016) than adulthood-onset women. Adult childhood-onset T1DM women experience higher diabetes distress (higher emotional burden (27.0+/-22.0 vs 15.6+/-16.4, p=0.006), physician-related distress (34.4+/ 33.9 vs 20.7+/-29.4, p=0.024), total diabetes distress (41.2+/-13.6 vs 34.8+/ 10.9, p=0.011)) than childhood-onset men. Adulthood-onset T1DM women experience higher physician-related distress (39.2+/-37.6 vs 23.4+/-32.5, p=0.013), but lower regimen-related distress (26.6+/-16.2 vs 35.8+/-21.6, p=0.014) than adulthood-onset men. In conclusion our findings reinforce the interdependence of psychological and biomedical factors in influencing health outcomes and support the need to provide psychological assessment and support to patients with T1DM. PMID- 26490758 TI - Reducing the Risk of Pet-Related Infections to Children. PMID- 26490759 TI - Prebiotic network evolution: six key parameters. AB - The origins of life likely required the cooperation among a set of molecular species interacting in a network. If so, then the earliest modes of evolutionary change would have been governed by the manners and mechanisms by which networks change their compositions over time. For molecular events, especially those in a pre-biological setting, these mechanisms have rarely been considered. We are only recently learning to apply the results of mathematical analyses of network dynamics to prebiotic events. Here, we attempt to forge connections between such analyses and the current state of knowledge in prebiotic chemistry. Of the many possible influences that could direct primordial network, six parameters emerge as the most influential when one considers the molecular characteristics of the best candidates for the emergence of biological information: polypeptides, RNA like polymers, and lipids. These parameters are viable cores, connectivity kinetics, information control, scalability, resource availability, and compartmentalization. These parameters, both individually and jointly, guide the aggregate evolution of collectively autocatalytic sets. We are now in a position to translate these conclusions into a laboratory setting and test empirically the dynamics of prebiotic network evolution. PMID- 26490760 TI - Intra-articular corticosteroid for knee osteoarthritis. AB - BACKGROUND: Knee osteoarthritis is a leading cause of chronic pain, disability, and decreased quality of life. Despite the long-standing use of intra-articular corticosteroids, there is an ongoing debate about their benefits and safety. This is an update of a Cochrane review first published in 2005. OBJECTIVES: To determine the benefits and harms of intra-articular corticosteroids compared with sham or no intervention in people with knee osteoarthritis in terms of pain, physical function, quality of life, and safety. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE (from inception to 3 February 2015), checked trial registers, conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials that compared intra articular corticosteroids with sham injection or no treatment in people with knee osteoarthritis. We applied no language restrictions. DATA COLLECTION AND ANALYSIS: We calculated standardised mean differences (SMDs) and 95% confidence intervals (CI) for pain, function, quality of life, joint space narrowing, and risk ratios (RRs) for safety outcomes. We combined trials using an inverse variance random-effects meta-analysis. MAIN RESULTS: We identified 27 trials (13 new studies) with 1767 participants in this update. We graded the quality of the evidence as 'low' for all outcomes because treatment effect estimates were inconsistent with great variation across trials, pooled estimates were imprecise and did not rule out relevant or irrelevant clinical effects, and because most trials had a high or unclear risk of bias. Intra-articular corticosteroids appeared to be more beneficial in pain reduction than control interventions (SMD 0.40, 95% CI -0.58 to -0.22), which corresponds to a difference in pain scores of 1.0 cm on a 10-cm visual analogue scale between corticosteroids and sham injection and translates into a number needed to treat for an additional beneficial outcome (NNTB) of 8 (95% CI 6 to 13). An I(2) statistic of 68% indicated considerable between-trial heterogeneity. A visual inspection of the funnel plot suggested some asymmetry (asymmetry coefficient -1.21, 95%CI -3.58 to 1.17). When stratifying results according to length of follow-up, benefits were moderate at 1 to 2 weeks after end of treatment (SMD -0.48, 95% CI -0.70 to 0.27), small to moderate at 4 to 6 weeks (SMD -0.41, 95% CI -0.61 to -0.21), small at 13 weeks (SMD -0.22, 95% CI -0.44 to 0.00), and no evidence of an effect at 26 weeks (SMD -0.07, 95% CI -0.25 to 0.11). An I(2) statistic of >= 63% indicated a moderate to large degree of between-trial heterogeneity up to 13 weeks after end of treatment (P for heterogeneity<=0.001), and an I(2) of 0% indicated low heterogeneity at 26 weeks (P=0.43). There was evidence of lower treatment effects in trials that randomised on average at least 50 participants per group (P=0.05) or at least 100 participants per group (P=0.013), in trials that used concomittant viscosupplementation (P=0.08), and in trials that used concomitant joint lavage (P<=0.001).Corticosteroids appeared to be more effective in function improvement than control interventions (SMD -0.33, 95% CI -0.56 to 0.09), which corresponds to a difference in functions scores of -0.7 units on standardised Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability scale ranging from 0 to 10 and translates into a NNTB of 10 (95% CI 7 to 33). An I(2) statistic of 69% indicated a moderate to large degree of between trial heterogeneity. A visual inspection of the funnel plot suggested asymmetry (asymmetry coefficient -4.07, 95% CI -8.08 to -0.05). When stratifying results according to length of follow-up, benefits were small to moderate at 1 to 2 weeks after end of treatment (SMD -0.43, 95% CI -0.72 to -0.14), small to moderate at 4 to 6 weeks (SMD -0.36, 95% CI -0.63 to -0.09), and no evidence of an effect at 13 weeks (SMD -0.13, 95% CI -0.37 to 0.10) or at 26 weeks (SMD 0.06, 95% CI -0.16 to 0.28). An I(2) statistic of >= 62% indicated a moderate to large degree of between-trial heterogeneity up to 13 weeks after end of treatment (P for heterogeneity<=0.004), and an I(2) of 0% indicated low heterogeneity at 26 weeks (P=0.52). We found evidence of lower treatment effects in trials that randomised on average at least 50 participants per group (P=0.023), in unpublished trials (P=0.023), in trials that used non-intervention controls (P=0.031), and in trials that used concomitant viscosupplementation (P=0.06).Participants on corticosteroids were 11% less likely to experience adverse events, but confidence intervals included the null effect (RR 0.89, 95% CI 0.64 to 1.23, I(2)=0%). Participants on corticosteroids were 67% less likely to withdraw because of adverse events, but confidence intervals were wide and included the null effect (RR 0.33, 95% CI 0.05 to 2.07, I(2)=0%). Participants on corticosteroids were 27% less likely to experience any serious adverse event, but confidence intervals were wide and included the null effect (RR 0.63, 95% CI 0.15 to 2.67, I(2)=0%).We found no evidence of an effect of corticosteroids on quality of life compared to control (SMD -0.01, 95% CI -0.30 to 0.28, I(2)=0%). There was also no evidence of an effect of corticosteroids on joint space narrowing compared to control interventions (SMD -0.02, 95% CI -0.49 to 0.46). AUTHORS' CONCLUSIONS: Whether there are clinically important benefits of intra-articular corticosteroids after one to six weeks remains unclear in view of the overall quality of the evidence, considerable heterogeneity between trials, and evidence of small-study effects. A single trial included in this review described adequate measures to minimise biases and did not find any benefit of intra-articular corticosteroids.In this update of the systematic review and meta-analysis, we found most of the identified trials that compared intra-articular corticosteroids with sham or non intervention control small and hampered by low methodological quality. An analysis of multiple time points suggested that effects decrease over time, and our analysis provided no evidence that an effect remains six months after a corticosteroid injection. PMID- 26490762 TI - Pre-gestational overweight in guinea pig sows induces fetal vascular dysfunction and increased rate of large and small fetuses. AB - In humans, obesity before and during pregnancy is associated with both fetal macrosomia and growth restriction, and long-term cardiovascular risk in the offspring. We aimed to determine whether overweighted pregnant guinea pig sows results in an increased fetal weight at term and the effects on the vascular reactivity in fetal systemic and umbilical arteries. Pregnant guinea pigs were classified as control (n=4) or high weight (HWS, n=5) according to their pre mating weight, and their fetuses extracted at 0.9 gestation (~60 days). Segments of fetal femoral and umbilical arteries were mounted in a wire myograph, where the contractile response to KCl (5-125 mM), and the relaxation to nitric oxide synthase-dependent agents (insulin, 10-10-10-7 and acetylcholine, 10-10-10-5) and nitric oxide [sodium nitroprusside (SNP), 10-10-10-5] were determined. Fetuses from HWS (HWSF) were grouped according to their body weight as low (85 g) fetal weight, based on the confidence interval (76.5-84.9 g) of the control group. No HWSF were observed in the normal range. Umbilical arteries from HWSF showed a lower response to KCl and insulin compared with controls, but a comparable response with SNP. Conversely, femoral arteries from HWSF showed an increased response to KCl and acetylcholine, along with a decreased sensitivity to SNP. These data show that overweight sows have altered fetal growth along gestation. Further, large and small fetuses from obese guinea pig sows showed altered vascular reactivity at umbilical and systemic vessels, which potentially associates with long-term cardiovascular risk. PMID- 26490761 TI - Valproic acid modulates radiation-enhanced matrix metalloproteinase activity and invasion of breast cancer cells. AB - PURPOSE: To evaluate matrix metalloproteinase (MMP) activity and invasion after ionizing radiation (IR) exposure and to determine whether MMP could be epigenetically modulated by histone deacetylase (HDAC) inhibition. MATERIAL AND METHODS: Two human breast cancer cell lines (MDA-MB-231 and MCF-7) were cultured in monolayer (2D) and in laminin-rich extracellular matrix (3D). Invasion capability, collagenolytic and gelatinolytic activity, MMP and TIMP protein and mRNA expression and clonogenic survival were analyzed after IR exposure, with and without a HDAC inhibition treatment [1.5 mM valproic acid (VA) or 1 MUM trichostatin-A (TSA)]. RESULTS: IR exposure resulted in cell line-dependent stimulation of invasion capacity. In contrast to MCF-7 cells, irradiated MDA-MB 231 showed significantly enhanced mRNA expression of mmp-1, mmp-3 and mmp-13 and of their regulators timp-1 and timp-2 relative to unirradiated controls. This translated into increased collagenolytic and gelatinolytic activity and could be reduced after valproic acid (VA) treatment. Additionally, VA also mitigated IR enhanced mmp and timp mRNA expression as well as IR-increased invasion capability. Finally, our data confirm the radiosensitizing effect of VA. CONCLUSION: These results suggest that IR cell line-dependently induces upregulation of MMP mRNA expression, which appears to be mechanistically linked to a higher invasion capability that is modifiable by HDAC inhibition. PMID- 26490763 TI - Hygiene quality and presence of ESBL-producing Escherichia coli in raw food diets for dogs. AB - BACKGROUND: Raw food diets are popular among some dog owners, even though there are concerns regarding the infectious disease risk and public health implications. Hence, the two aims of this study were to investigate the hygiene quality of raw food diets for dogs in the Swedish market and if Escherichia coli with transferable resistance to extended spectrum cephalosporins (ESC) was present in such products. METHODS: Samples of raw food diets were suspended and further diluted in 0.9% saline. Appropriate dilutions were 1) cultured on PetrifilmTMSEC to quantify the amount of E. coli in the samples and 2) mixed with cefotaxime to a final concentration of 1 mg/L and cultured on PetrifilmTMSEC to quantify the amount of ESC-resistant E. coli in the samples. Furthermore, undiluted suspensions were mixed 1:1 with double strength MacConkey broth with cefotaxime, enriched overnight and finally cultured on MacConkey agar with cefotaxime (1 mg/L). Suspected ESC-resistant E. coli were screened by PCR for genes encoding extended spectrum beta lactamases and plasmid-mediated AmpC and their susceptibility to a panel of antimicrobials was performed by broth microdilution using VetMIC GN-mo. RESULTS: Escherichia coli was isolated from all samples (n=39) and ESC-resistant E. coli was isolated from nine samples (23%). All ESC-resistant E. coli were PCR-positive for the bla CMY-2 group and only one of them was also resistant to a non-beta-lactam antibiotic. CONCLUSION: The results of this study indicate that raw food diets could be a source of ESC resistant E. coli to dogs and highlight the need for maintaining good hygiene when handling these products to prevent infection. PMID- 26490764 TI - [Diabetes among new cases of pulmonary tuberculosis in Hanoi, Vietnam]. AB - The aim of this study was to analyze all new pulmonary tuberculosis cases and to assess the frequency and consequences of associated diabetes mellitus. Although apparently distinct, these two diseases could be linked, as suspected since decades. The context is the persistent endemicity of tuberculosis and the recent emergence of diabetes, two major health events for developing countries. The study was conducted at National TB hospital in Hanoi, Vietnam, and retrospectively included tuberculosis patients, cases with diabetes and controls without diabetes, collected during a three-year period 2006-2008. Cases associated with HIV infection or other comorbidities potentially affecting mortality were excluded. Among 2867 new pulmonary TB cases, 254 (8.8%) had associated diabetes. Eighty-six cases and 86 matched controls were included. Among cases mean blood glucose at admission was 14.4 mmol/dl, and patients were mostly urban (50% cases vs 32.5% controls, p=0.03). Clinical symptoms were similar in both groups. However, chest X-Ray cavitary images were significantly more frequent among cases (38.3% vs 16.3%, p=0.002, OR=4.1), as did infiltrative images (78% vs 62%, p=0.017, OR=2.55) and positive sputum smears (67.4% vs 47.8%, p=0.014, OR=2.21). In Vietnam, DM is found in quasi 9% of patients with a new diagnosis of primary pulmonary TB. The diabetes-TB patients may have more severe radiologic findings and a higher smear positivity rate. We suggest that in addition to the systematic HIV screening, all new TB patients should also be screened for diabetes. PMID- 26490765 TI - Anti-diabetic potential of Catharanthus roseus Linn. and its effect on the glucose transport gene (GLUT-2 and GLUT-4) in streptozotocin induced diabetic wistar rats. AB - BACKGROUND: Catharanthus roseus is an important Ayurvedic medication in traditional medicine. It is potentially used in countries like India, South Africa, China and Malaysia for the healing of diabetes mellitus. Although, the molecular mechanisms behind this effect are yet to be exclusively explored. Due to the great antidiabetic and hyperlipidemic potential of c. roseus, we hypothesized that the insulin mimetic effect of ethanolic extract of c. roseus might add to glucose uptake through improvement in the expression of genes of the glucose transporter (GLUT) family messenger RNA (mRNA) in liver. METHODS: STZ induced diabetic rats treated by ethanolic extract of c. roseus 100 mg/kg and 200 mg/kg; and one group treated with Metformin (100 mg/kg). After final administration of treatment of 4 weeks, blood samples were collected under fasting conditions, and the body weights (BWs) were measured. Total RNA from liver was extracted with the Qiagen RNEasy Micro kit (GERMANY) as described in the manufacturer's instructions. First-strand complementary DNA (cDNA) was synthesized at 40 degrees C by priming with oligo-dT12-18 (Invitrogen, USA) and using Super ScriptII reverse transcriptase according to the protocol provided by the manufacturer (Invitrogen, USA). Real-time polymerase chain reaction (PCR) amplifications for GLUT-4 (gene ID: 25139) were conducted using Light-Cycler 480 (Roche, USA) with the SyBr(r) I nucleic acid stain (Invitrogen, USA) according to the manufacturer's instructions. Polymerase chain reaction products of beta-actin primer gene were used as an internal standard. RESULTS: The proposed study was framed to look at the antidiabetic efficacy of ethanolic extract of c. roseus and an expression of GLUT-2 and GLUT-4 gene in streptozotocin induced diabetic wistar rats. The doses were administered orally at a rate of 100 and 200 mg/kg and detrain the glucose transport system in liver for 4 weeks. The observed results showed a good positive correlation between intracellular calcium and insulin release levels in isolated islets of Langerhans. The supplementation of ethanolic extract of c. roseus significantly amplified the expression of GLUT gene mRNA by Real Time PCR in liver of diabetic rats. CONCLUSIONS: We conclude that the observed antidiabetic effect of c. roseus on STZ induced diabetes was a result of complex mechanisms of GLUT gene mRNA expression. The findings are very encouraging and greatly advocate its candidature for the design of a novel herbal drug to cure deadly diabetes. PMID- 26490766 TI - Risk prediction model for epithelial ovarian cancer using molecular markers and clinical characteristics. AB - BACKGROUND: A high-quality risk prediction model is urgently needed for the clinical management of ovarian cancer. However most existing models are solely based on clinical parameters, and molecular classifications in recent reports are still being debated. This study aimed to establish a risk prediction model by using both clinicopathological and molecular factors (the synthetic model) for epithelial ovarian cancer. METHODS: A retrospective cohort study was conducted in epithelial ovarian cancer patients (n = 161) treated with primary debulking surgery and adjuvant chemotherapy. The expression level of 15 selected molecular markers were measured using immunohistochemistry. A risk model was developed using COX regression analysis with overall survival as the primary outcome. A simplified scoring system for each prognostic factor was based on its coefficient. Independent validation (n = 40) was conducted to evaluate the performance of the model. RESULTS: A total of 10 out of 15 molecular markers were significantly associated with clinical characteristics and overall survival. The synthetic model performed better than the clinicopathological risk model or the molecular risk model alone, as assessed by analysis of the receiver-operating characteristics curve area and the Youden index. The synthetic model included parity (>3), peritoneal metastasis, stage, tumor type, residual disease, and expression of human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), breast cancer 1 (BRCA1), murine sarcoma viral oncogene homolog B (BRAF) and Kirsten rat sarcoma viral oncogene homolog (KRAS). CONCLUSIONS: Our synthetic risk model may more accurately predict survival of epithelial ovarian cancer patients than current models. PMID- 26490767 TI - Thoracoscopic versus open repair of CDH in cardiovascular stable neonates. AB - BACKGROUND: Thoracoscopic surgery is an increasingly popular surgical technique to repair congenital diaphragmatic hernia (CDH). However, acidosis during surgery and the higher recurrence rate are considerable risk factors. The aim of this retrospective study is to compare the outcome of open versus thoracoscopic repair of the diaphragm in neonates with CDH with the same degree of cardiovascular and pulmonary illness who meet the criteria for thoracoscopic repair. METHODS: Retrospective analysis of all patients of two large national reference centers for CDH born in the years 2008 through 2012, and meeting the criteria for surgical repair on cardiopulmonary and physiological criteria according to the CDH EURO consortium consensus and meeting the criteria for thoracoscopic repair according to the review by Vijfhuize et al. The surgical technical aspects were comparable in both centers. RESULTS: 108 patients were included, of whom 75 underwent thoracoscopic repair and 34 underwent open repair. The gestational age and lung-to-head ratio were significantly lower and stay on the ICU significantly longer in the open-repair group. The operation time was longer (178 vs. 150 min, p = .012) and the recurrence rate higher (18.9 vs. 5.9 %, p = .036) in the thoracoscopic-repair group. The arterial pH, pO2, pCO2 and base excess before and after thoracoscopic repair were all significantly different. CONCLUSION: After critical selection for thoracoscopic repair of left-sided CDH based on the patient's preoperative condition, the outcomes of open repair were almost identical to those of thoracoscopic repair. A notable exception is the recurrence rate, which was significantly higher in the thoracoscopic-repair group. For the time being, thoracoscopic primary closure seems a safe and effective procedure, but efficacy of thoracoscopic patch repair has not been established. PMID- 26490768 TI - Endoscopic band ligation versus endoscopic submucosal dissection and laparoscopic resection for small gastric stromal tumors. AB - BACKGROUND AND AIM: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Previous studies have addressed the safety and feasibility of endoscopic band ligation (EBL) for the treatment of small gastric GISTs. However, published reports comparing EBL with other interventions are limited. This current study evaluates the efficacy of EBL and compares EBL to both endoscopic submucosal dissection (ESD) and laparoscopic resection (LAP) for small gastric GISTs less than 15 mm. METHODS: A total of 339 patients who underwent endoscopic therapy or laparoscopic resection for gastric GISTs between 1998 and 2012 were retrospectively identified and collected from medical records in our hospital. The parameters measured for each procedure type includes clinicopathological characteristics, length of stay, hospitalization expense and surgical outcomes. RESULTS: Among the 147 patients included in our study, 72 (48.98 %) received EBL, 27 (18.37 %) received ESD, and 48 (32.65 %) received LAP. The demographic and clinical characteristics of the patients such as gender, age, tumor site and size were well balanced between the study groups. There was also no significant difference in follow-up time between the study groups. The mean operating time was significantly shorter in the patients receiving EBL than patients receiving ESD and LAP (p < 0.001). The estimated blood loss was significantly different between the three groups (p < 0.001). Complications occurred in 1.39 % of the patients receiving EBL, 18.52 % of the patients receiving ESD and 4.17 % of the patients receiving LAP (p = 0.004), and recurrence rate in 15.00, 9.10 and 11.76 %, respectively (p = 0.705). There was also significant difference about mean hospital stay and hospital cost between three groups (p < 0.001). CONCLUSION: Our results show a significant advantage in the short-term outcome for EBL compared to ESD and LAP. However, long-term randomized controlled trials are needed to compare the three methods for the treatment of small GISTs. PMID- 26490769 TI - Neonatal brain oxygenation during thoracoscopic correction of esophageal atresia. AB - BACKGROUND: Little is known about the effects of carbon dioxide (CO2) insufflation on cerebral oxygenation during thoracoscopy in neonates. Near infrared spectroscopy can measure perioperative brain oxygenation [regional cerebral oxygen saturation (rScO2)]. AIMS: To evaluate the effects of CO2 insufflation on rScO2 during thoracoscopic esophageal atresia (EA) repair. METHODS: This is an observational study during thoracoscopic EA repair with 5 mmHg CO2 insufflation pressure. Mean arterial blood pressure (MABP), arterial oxygen saturation (SaO2), partial pressure of arterial carbon dioxide (paCO2), pH, and rScO2 were monitored in 15 neonates at seven time points: baseline (T0), after anesthesia induction (T1), after CO2-insufflation (T2), before CO2 exsufflation (T3), and postoperatively at 6 (T4), 12 (T5), and 24 h (T6). RESULTS: MABP remained stable. SaO2 decreased from T0 to T2 [97 +/- 3-90 +/- 6 % (p < 0.01)]. PaCO2 increased from T0 to T2 [41 +/- 6-54 +/- 15 mmHg (p < 0.01)]. pH decreased from T0 to T2 [7.33 +/- 0.04-7.25 +/- 0.11 (p < 0.05)]. All parameters recovered during the surgical course. Mean rScO2 was significantly higher at T1 compared to T2 [77 +/- 10-73 +/- 7 % (p < 0.05)]. Mean rScO2 levels never dropped below a safety threshold of 55 %. CONCLUSION: The impact of neonatal thoracoscopic repair of EA with insufflation of CO2 at 5 mmHg was studied. Intrathoracic CO2 insufflation caused a reversible decrease in SaO2 and pH and an increase in paCO2. The rScO2 was higher at anesthesia induction but remained stable and within normal limits during and after the CO2 pneumothorax, which suggest no hampering of cerebral oxygenation by the thoracoscopic intervention. Future studies will focus on the long-term effects of this surgery on the developing brain. PMID- 26490770 TI - The current status of emergent laparoscopic colectomy: a population-based study of clinical and financial outcomes. AB - BACKGROUND: Population-based studies evaluating laparoscopic colectomy and outcomes compared with open surgery have concentrated on elective resections. As such, data assessing non-elective laparoscopic colectomies are limited. Our goal was to evaluate the current usage and outcomes of laparoscopic in the urgent and emergent setting in the USA. METHODS: A national inpatient database was reviewed from 2008 to 2011 for right, left, and sigmoid colectomies in the non-elective setting. Cases were stratified by approach into open or laparoscopic groups. Demographics, perioperative clinical variables, and financial outcomes were compared across each group. RESULTS: A total of 22,719 non-elective colectomies were analyzed. The vast majority (95.8 %) was open. Most cases were performed in an urban setting at non-teaching hospitals by general surgeons. Colorectal surgeons were significantly more likely to perform a case laparoscopic than general surgeons (p < 0.001). Demographics were similar between open and laparoscopic groups; however, the disease distribution by approach varied, with significantly more severe cases in the open colectomy arm (p < 0.001). Cases performed laparoscopically had significantly better mortality and complication rates. Laparoscopic cases also had significantly improved outcomes, including shorter length of stay and hospital costs (all p < 0.001). CONCLUSIONS: Our analysis revealed less than 5 % of urgent and emergent colectomies in the USA are performed laparoscopically. Colorectal surgeons were more likely to approach a case laparoscopically than general surgeons. Outcomes following laparoscopic colectomy in this setting resulted in reduced length of stay, lower complication rates, and lower costs. Increased adoption of laparoscopy in the non-elective setting should be considered. PMID- 26490771 TI - TEP versus Lichtenstein: Which technique is better for the repair of primary unilateral inguinal hernias in men? AB - INTRODUCTION: In the update of the guidelines of the European Hernia Society, open Lichtenstein and endoscopic techniques continue to be recommended as the surgical technique of choice for repair of unilateral primary inguinal hernias in men despite the fact that a meta-analysis had identified a higher recurrence rate for TEP compared with Lichtenstein operation. The Guidelines Group had taken that decision because one surgeon in one of the randomized controlled trials included in the meta-analysis had had a very high recurrence rate. Therefore, this study based on registry data now compares the outcome of TEP versus Lichtenstein repair. PATIENTS AND METHODS: The analysis of the Herniamed Registry compares the prospective data collected for male patients undergoing primary unilateral inguinal hernia repair using either TEP or open Lichtenstein repair. Inclusion criteria were minimum age of 16 years, male patient, primary unilateral inguinal hernia, elective operation, and availability of data on 1-year follow-up. In total, 17,388 patients were enrolled between September 1, 2009, and August 31, 2013. Of these patients, 10,555 (60.70 %) had a Lichtenstein repair and 6833 (39.30 %) a TEP repair. RESULTS: On multivariable analysis, the surgical technique was not found to have had any significant effect on the recurrence rate (p = 0.146) or on the chronic pain rate (p = 0.560). Nor did the complication related reoperation rates differ significantly between the two techniques (p = 0.084). But TEP was found to have benefits as regards the postoperative complication rate (p < 0.001), pain at rest rate (p = 0.011), and pain on exertion rate (p < 0.001). In the present registry study, no significant difference was identified in the recurrence rates between the TEP and Lichtenstein technique. TEP was found to have benefits compared with Lichtenstein repair as regards the postoperative complication rates, pain at rest, and pain on exertion. PMID- 26490772 TI - Liver retraction system by C3-muco-adhesive polymer films for laparoscopic surgery. AB - BACKGROUND: Conventional laparoscopic instruments used for retraction may cause trauma at the retraction site. Alternative retraction/lifting especially of heavy solid organs such as the liver may be obtained by other means. The present study was designed to explore the use of C3-muco-adhesive polymers (C3-MAPs), which exhibit strong binding to the liver shortly after application to the organ and which retain strong adhesion for sufficient time, to enable sustained retraction during laparoscopic operations. METHODS AND MATERIALS: C3-muco-adhesive polymers were produced specifically for the study. In an ex vivo experimental set-up, discs of C3-MAPs were placed on the surface of porcine livers for adhesion and retraction studies involving objective measurements by tensiometry. RESULTS: Experiments were carried out on 14 porcine livers. The force required to detach the C3-MAPs from the liver exceeded 2.0 N 30 s after application. The adhesion force by C3-MAPs files was sufficient to enable sustained retraction force necessary for exposure of the gall bladder, which was achieved by a mean retraction force of 4.85 N (SD = 0.63). This was sustained for a mean of 130 min (range 17.0-240.0). In the adhesion studies, the forces at 30 s required to detach the polymer discs from the liver exceeded 20 N (upper limit of the load cells of the Instron). The duration of the adhesion enabled sustained optimal gall bladder exposure for periods ranging from 17 to 240 min, with a mean of 130 +/- 91 min. CONCLUSIONS: The results of the present study demonstrate that the adhesion and retraction properties of the engineered C3-MAP films are sufficient to enable complete exposure of the gall bladder for a period exceeding 1 h, confirming their potential for atraumatic retraction in laparoscopic and other minimal-access surgical approaches. PMID- 26490773 TI - "Relaparoscopic" management of surgical complications: The experience of an Emergency Center. AB - BACKGROUND/AIM: Laparotomy has been the approach of choice for re-operations in patients with surgical complications. The aim of this retrospective analysis was to evaluate the feasibility and the safety of laparoscopic approach for the management of general abdominal surgery complications. MATERIALS AND METHODS: We report a retrospective review of 75 patients who underwent laparoscopic evaluation for postoperative complications over a 4-year period. Primary outcomes (resolution rate by exclusive laparoscopic approach, conversion rate, further surgery rate) and secondary outcomes (mortality, hospitalization, prolonged ileus, wounds problems and median operative time) were evaluated. RESULTS: Sixty six patients (88 %) were managed with laparoscopic approach without conversion; of these, sixty-three patients (84 %) had no more or further complications and were discharged from hospital between 4 +/- 3 days after "second-look" surgery; three patients (4 %) developed postoperative complications requiring a third surgery. Nine cases (12 %) underwent conversion in open surgery after laparoscopic approach. Two elderly patients (2.7 %) died in intensive care unit, because of multi-organ failure syndrome. Median time elapsed between an intervention and another was about 2.5 +/- 9.5 days. Mean operative time was 90 +/- 150 min. Postoperative hospital stay was between 4.5 and 18 days. DISCUSSION AND CONCLUSION: Laparoscopy has begun to be the preferred method to manage postoperative problems, but only few reports are available actually. Our experience in "relaparoscopic" management of surgical complications seems to suggest that laparoscopy "second look" is an effective tool after open or laparoscopic surgery for the management of postoperative complications and it may avoid diagnostic delay and further laparotomy and related problems. PMID- 26490774 TI - [Semen allergy]. AB - A semen allergy is a type I reaction. Reliable figures about incidence/prevalence are not available. Symptoms can be characterized as local and systemic. After exposure to ejaculate, the patient may experience itching and swelling at points of contact, while systemically it may also lead to generalized urticaria with angioedema or higher grade anaphylaxis. As triggering allergens, substances in seminal plasma (SP) have been identified, which can be SP typical or SP atypical. Reactions against spermatozoa have not yet been clearly proven. With regard to SP typical allergens, prostate-specific antigen (PSA) has been identified, while for SP-atypical allergens, medications or food allergens have been reported, which apparently accumulate in the SP and can then trigger symptoms in women with existing sensitization. The main criteria for the diagnosis of sperm allergy is freedom from symptoms when condoms are used during intercourse. In addition, skin prick tests and determination of allergen-specific IgE are used. In patients with a desire for children, washed, SP-free spermatozoa can be used for insemination. In addition, desensitization may be considered. PMID- 26490775 TI - [Effectiveness of screening programs for skin cancer]. PMID- 26490776 TI - Efficacy of Selective Brain Cooling Using a Nasopharyngeal Method in Piglets. AB - BACKGROUND: Mild hypothermia is an effective neuroprotective strategy for a variety of acute brain injuries. Cooling the nasopharynx may offer the capability to cool the brain selectively due to anatomic proximity of the internal carotid artery to the cavernous sinus. This study investigated the feasibility and efficiency of nasopharyngeal brain cooling by continuously blowing room temperature or cold air at different flow rates into the nostrils of normal newborn piglets. METHODS: Experiments were conducted on thirty piglets (n = 30, weight = 2.7 +/- 1.5 kg). Piglets were anesthetized with 1-2% isoflurane and were randomized to receive one of four different nasopharyngeal cooling treatments: I. Room temperature at a flow rate of 3-4 L min(-1) (n = 6); II. -1 +/- 2 degrees C at a flow rate of 3-4 L min(-1) (n = 6); III. Room temperature at a flow rate of 14-15 L min(-1) (n = 6); IV. -8 +/- 2 degrees C at a flow rate of 14-15 L min( 1) (n = 6). To control for the normal thermal regulatory response of piglets without nasopharyngeal cooling, a control group of piglets (n = 6) had their brain temperature monitored without nasopharyngeal cooling. The duration of treatment was 60 min, with additional 30 min of observation. RESULTS: In group I, median cooling rate was 1.7 +/- 0.9 degrees C/h by setting the flow rate of room temperature air to 3-4 L min(-1). Results of comparing different temperatures and flow rates in the nasopharyngeal cooling approach reveal that the brain temperature could be reduced rapidly at a rate of 5.5 +/- 1.1 degrees C/h by blowing -8 +/- 2 degrees C air at a flow rate of 14-15 L min(-1). CONCLUSIONS: Nasopharyngeal cooling via cooled insufflated air can lower the brain temperature, with higher flows and lower temperatures of insufflated air being more effective. PMID- 26490777 TI - Prolonging Support After Brain Death: When Families Ask for More. AB - BACKGROUND: The manner in which brain death protocols in the United States address family objection to death by neurologic criteria has not been explored. METHODS: Institutional brain death protocols from hospitals in the United States were reviewed to identify if and how the institution addressed situations in which families object to determination of brain death or discontinuation of organ support after brain death. RESULTS: Protocols from 331 institutions in 25 different states and the District of Columbia were reviewed. There was no mention of how to handle a family's objections in 77.9 % (258) of the protocols. Of those that allowed for accommodation, reasons to defer brain death declaration or prolong organ support after brain death declaration included: (1) religion; (2) moral objection; (3) nonspecific social reasons; or (4) awaiting arrival of family. Recommendations to handle these situations included: (1) seek counsel; (2) maintain organ support until cardiac cessation; (3) extubate against the family's wishes; (4) obtain a second opinion; or (5) transfer care of the patient to another practitioner or facility. Protocols differed on indications and length of time to continue organ support, code status while support was continued, and time of death. CONCLUSIONS: The majority of protocols reviewed did not mention how to handle circumstances in which families object to determination of brain death or discontinuation of organ support after brain death. The creation of guidelines on management of these complex situations may be helpful to prevent distress to families and hospital staff. PMID- 26490778 TI - Non-invasive Monitoring of Dynamic Cerebrovascular Autoregulation Using Near Infrared Spectroscopy and the Finometer Photoplethysmograph. AB - BACKGROUND: Near infrared spectroscopy (NIRS) enables continuous monitoring of dynamic cerebrovascular autoregulation, but this methodology relies on invasive blood pressure monitoring (iABP). We evaluated the agreement between a NIRS based autoregulation index calculated from invasive blood pressure monitoring, and an entirely non-invasively derived autoregulation index from continuous non-invasive blood pressure monitoring (nABP) using the Finometer photoplethysmograph. METHODS: Autoregulation was calculated as the moving correlation coefficient between iABP and rSO2 (iTOx) or nABP and rSO2 (nTOx). The blood pressure range where autoregulation is optimal was also determined for invasive (iABPOPT) and non-invasive blood pressure measurements (nABPOPT). RESULTS: 102 simultaneous bilateral measurements of iTOx and nTOx were performed in 19 patients (median 2 per patient, range 1-9) with different acute pathologies (sepsis, cardiac arrest, head injury, stroke). Average iTOx was 0.01 +/- 0.13 and nTOx was 0.01 +/- 0.11. The correlation between iTOx and nTOx was r = 0.87, p < 0.001, 95 % agreement +/- 0.12, bias = 0.005. The interhemispheric asymmetry of autoregulation was similarly assessed with iTOx and nTOx (r = 0.81, p < 0.001). Correlation between iABPOPT and nABPOPT was r = 0.47, p = 0.003, 95 % agreement +/- 32.1 mmHg, bias = 5.8 mmHg. Coherence in the low frequency spectrum between iABP and nABP was 0.86 +/- 0.08 and gain was 1.32 +/- 0.77. CONCLUSIONS: The results suggest that dynamic cerebrovascular autoregulation can be continuously assessed entirely non invasively using nTOx. This allows for autoregulation assessment using spontaneous blood pressure fluctuations in conditions where iABP is not routinely monitored. The nABPOPT might deviate from iABPOPT, likely because of discordance between absolute nABP and iABP readings. PMID- 26490780 TI - Education and Imaging. Gastrointestinal: Emphysematous gastritis. PMID- 26490779 TI - Prompt Recognition and Management of Postoperative Intracranial Hypotension Associated Venous Congestion: A Case Report. AB - BACKGROUND: Postoperative intracranial hypotension-associated venous congestion (PIHV) is an uncommon cause of clinical deterioration after a neurosurgical procedure that is often unrecognized until late in its course. Functional outcomes range from remarkable neurological recovery to death. Little is understood about the reason for deterioration in certain patients compared with improvement in others. A 68-year-old man with a progressive cervical myelopathy underwent an uncomplicated cervical decompression and alignment restoration at our hospital and suffered violent generalized tonic-clonic seizures intraoperatively and postoperatively. A postoperative head CT showed a right parietal hematoma, but no other cranial findings. A subsequent MRI demonstrated what we describe as early PIHV with symmetric T2 signal changes in the bilateral deep gray structures. No diffusion restriction corresponded to these areas. A CT myelogram revealed a considerable CSF collection within the operative bed. Upon returning to the operating room to localize the source of the leak, a large dural tear was identified off of midline with a bone chip alongside the defect. The defect was repaired, and the patient remained comatose for over a week postoperatively. He made a remarkable gradual recovery, and after a month in the hospital and rehabilitation, he returned home with relatively minimal neurological deficits. CONCLUSIONS: We postulate that if caught early and treated aggressively, neurologic injury resulting from PIHV may be reversible despite initially ominous imaging. Neurosurgeons and neurointensivists should therefore be compelled to search for dural defects and return to the operating room for immediate repair. PMID- 26490781 TI - Review blocked by English health secretary backs sugar tax to tackle obesity. PMID- 26490782 TI - Cell Signaling Pathways Involved During Invasion and Syncytialization of Trophoblast Cells. AB - Implantation involves an extensive cross talk between the trophoblast cells and the receptive endometrium through embryonic as well as endometrial-derived factors that regulate the invasion and migration of trophoblast cells and also syncytia formation. Any aberration in this highly regulated process may lead to pregnancy complications such as preeclampsia, intrauterine growth restriction, or even pregnancy failure. How various cytokines and growth factors act by activating various cell signaling pathways leading to the expression of the effector molecules have been reviewed, which control invasion and migration of trophoblast cells and syncytialization. The gaps in our current understanding of the various signaling pathways, activated by different cytokines/growth factors, their possible cross talk for optimized effector function(s), and future prospects in this field have been discussed. PMID- 26490783 TI - Jumping to negative conclusions--a case of study-gathering bias? PMID- 26490784 TI - Congenital lobar emphysema presenting as an airway foreign body. AB - We report here the case of a 15 months old girl presenting with clinical signs and radiological exams highly suggestive of a foreign body (FB) aspiration. Diagnostic endoscopy revealed an overlooked bronchial malformation responsible for a congenital lobar emphysema (CLE). CLE presenting after one year of age is rare and can easily be misdiagnosed. Therefore, the possibility of an overlooked CLE needs to be known and evoked as an alternative diagnosis when dealing with children presenting with suspected FB aspirations. We report on this unexpected, yet misleading presentation of CLE and review the available literature on the subject. PMID- 26490785 TI - Familial and microbiological contribution to the otitis-prone condition. AB - OBJECTIVE: Our group has an ongoing clinical research project investigating the immunology of the otitis-prone (OP) phenotype. In light of evidence that this condition arises from underlying immunological defects, we examined our sample population of stringently defined OP (sOP) children suffering 3 episodes of acute otitis media within 6 months or 4 within a year for a familial association with the sOP phenotype. METHODS: We analyzed the frequency of sOP within and between families and the nasopharyngeal (NP) otopathogen colonization patterns within and between families. RESULTS: The presence of sOP siblings significantly predicted that additional children in the same family would likewise become sOP, with an odds ratio of 3.7 (95% CI 0.77-15.2, 95% lower bound 0.95). We further present evidence for an environmental contribution to this effect by means of prolonged exposure to otopathogens within family units. CONCLUSION: sOP children have a significant familial association. The tendency of siblings to share similar patterns of microbial NP colonization contributes to this association. Further research is necessary to determine whether and to what extent genetics are involved. PMID- 26490786 TI - Incidence of serum sickness after the administration of Australian snake antivenom (ASP-22). AB - CONTEXT: Serum sickness is a delayed immune reaction resulting from the injection of foreign protein or serum. Antivenom is known to cause serum sickness but the incidence and characteristics are poorly defined. OBJECTIVE: To investigate the incidence and clinical features of serum sickness following the administration of Australian snake antivenoms. MATERIALS AND METHODS: This was a prospective cohort study of patients recruited to the Australian Snakebite Project who received snake antivenom from November 2012 to March 2014. Demographics, clinical information, laboratory tests and antivenom treatment were recorded prospectively. Patients administered antivenom were followed up at 7-10 days and 6 weeks' post-antivenom. The primary outcome was the proportion with serum sickness, pre-defined as three or more of: fever, erythematous rash/urticaria, myalgia/arthralgia, headache, malaise, nausea/vomiting 5-20 days post-antivenom. RESULTS: During the 16-month period, 138 patients received antivenom. 23 were not followed up (unable to contact, tourist, child, bee sting) and 6 died in hospital. Of 109 patients followed up, the commonest reason for antivenom was venom induced consumption coagulopathy in 77 patients. An acute systemic hypersensitivity reaction occurred post-antivenom in 25 (23%) and 8 (7%) were severe with hypotension. Serum sickness occurred in 32/109 (29%) patients, including 15/37 (41%) given tiger snake, 6/15 (40%) given polyvalent and 4/23 (17%) given brown snake antivenom. There was no association between the volume of antivenom and serum sickness, p = 0.18. The commonest effects were lethargy, headache, muscle/joint aches and fever. DISCUSSION: The incidence of serum sickness after snake antivenom in Australia was higher than earlier investigations which failed to define symptoms or follow-up patients, but similar to more recent studies of antivenoms in the United States. CONCLUSION: Serum sickness is common with Australian snake antivenom but does not appear to be predictable based on the volume of antivenom administered. PMID- 26490787 TI - Dynamic resource allocation between pre- and postcopulatory episodes of sexual selection determines competitive fertilization success. AB - In polyandrous mating systems, male reproductive success depends on both mate acquisition traits (precopulatory) and sperm competitive abilities (postcopulatory). Empirical data on the interaction between these traits are inconsistent; revealing positive, negative or no relationships. It is generally expected that the investment in pre- and postcopulatory traits is mediated by environmental conditions. To test how dietary resource availability affects sexual ornamentation, sperm quality and their interrelationship in three-spined sticklebacks (Gasterosteus aculeatus), full-sibling groups were raised under three conditions differing in food quantity and/or quality (i.e. carotenoid content): (i) high-quantity/high-quality, (ii) high-quantity/low-quality or (iii) low-quantity/low-quality. After 1 year of feeding, food-restricted males developed a more intense breeding coloration and faster sperm compared with their well-fed brothers, indicating that they allocated relatively more in pre- and postcopulatory traits. Moreover, they outcompeted their well-fed, carotenoid supplemented brothers in sperm competition trials with equal numbers of competing sperm, suggesting that food-restricted males maximize their present reproductive success. This may result in reduced future reproductive opportunities as food restricted males suffered from a higher mortality, had an overall reduced body size, and sperm number available for fertilization. In accordance with theory, a trade-off between the investment in pre- and postcopulatory traits was observed in food-restricted males, whereas well-fed males were able to allocate to both traits resulting in a significantly positive relationship. PMID- 26490788 TI - Losses and recovery of organic carbon from a seagrass ecosystem following disturbance. AB - Seagrasses are among the Earth's most efficient and long-term carbon sinks, but coastal development threatens this capacity. We report new evidence that disturbance to seagrass ecosystems causes release of ancient carbon. In a seagrass ecosystem that had been disturbed 50 years ago, we found that soil carbon stocks declined by 72%, which, according to radiocarbon dating, had taken hundreds to thousands of years to accumulate. Disturbed soils harboured different benthic bacterial communities (according to 16S rRNA sequence analysis), with higher proportions of aerobic heterotrophs compared with undisturbed. Fingerprinting of the carbon (via stable isotopes) suggested that the contribution of autochthonous carbon (carbon produced through plant primary production) to the soil carbon pool was less in disturbed areas compared with seagrass and recovered areas. Seagrass areas that had recovered from disturbance had slightly lower (35%) carbon levels than undisturbed, but more than twice as much as the disturbed areas, which is encouraging for restoration efforts. Slow rates of seagrass recovery imply the need to transplant seagrass, rather than waiting for recovery via natural processes. This study empirically demonstrates that disturbance to seagrass ecosystems can cause release of ancient carbon, with potentially major global warming consequences. PMID- 26490789 TI - Conflict between biotic and climatic selective pressures acting on an extended phenotype in a subarctic, but not temperate, environment. AB - Climatic selective pressures are thought to dominate biotic selective pressures at higher latitudes. However, few studies have experimentally tested how these selective pressures differentially act on traits across latitudes because traits can rarely be manipulated independently of the organism in nature. We overcame this challenge by using an extended phenotype-active bird nests-and conducted reciprocal transplant experiments between a subarctic and temperate site, separated by 14 degrees of latitude. At the subarctic site, biotic selective pressures (nest predation) favoured smaller, non-local temperate nests, whereas climatic selective pressures (temperature) favoured larger local nests, particularly at colder temperatures. By contrast, at the temperate site, climatic and biotic selective pressures acted similarly on temperate and subarctic nests. Our results illustrate a functional trade-off in the subarctic between nest morphologies favoured by biotic versus climatic selective pressures, with climate favouring local nest morphologies. At our temperate site, however, allocative trade-offs in the time and effort devoted to nest construction favour smaller, local nests. Our findings illustrate a conflict between biotic and climatic selective pressures at the northern extremes of a species geographical range, and suggest that trade-offs between trait function and trait elaboration act differentially across latitude to create broad geographic variation in traits. PMID- 26490790 TI - Short-term benefits, but transgenerational costs of maternal loss in an insect with facultative maternal care. AB - A lack of parental care is generally assumed to entail substantial fitness costs for offspring that ultimately select for the maintenance of family life across generations. However, it is unknown whether these costs arise when parental care is facultative, thus questioning their fundamental importance in the early evolution of family life. Here, we investigated the short-term, long-term and transgenerational effects of maternal loss in the European earwig Forficula auricularia, an insect with facultative post-hatching maternal care. We showed that maternal loss did not influence the developmental time and survival rate of juveniles, but surprisingly yielded adults of larger body and forceps size, two traits associated with fitness benefits. In a cross-breeding/cross-fostering experiment, we then demonstrated that maternal loss impaired the expression of maternal care in adult offspring. Interestingly, the resulting transgenerational costs were not only mediated by the early-life experience of tending mothers, but also by inherited, parent-of-origin-specific effects expressed in juveniles. Orphaned females abandoned their juveniles for longer and fed them less than maternally-tended females, while foster mothers defended juveniles of orphaned females less well than juveniles of maternally-tended females. Overall, these findings reveal the key importance of transgenerational effects in the early evolution of family life. PMID- 26490791 TI - A conserved class of queen pheromones? Re-evaluating the evidence in bumblebees (Bombus impatiens). AB - The regulation of reproductive division of labour is a key component in the evolution of social insects. Chemical signals are important mechanisms to regulate worker reproduction, either as queen-produced pheromones that coercively inhibit worker reproduction or as queen signals that honestly advertise her fecundity. A recent study suggested that a conserved class of hydrocarbons serve as queen pheromones across three independent origins of eusociality. In bumblebees (Bombus terrestris), pentacosane (C25) was suggested to serve as a queen pheromone. Here, we repeat these studies using a different species of bumblebee (Bombus impatiens) with a more controlled experimental design. Instead of dequeened colonies, we used same-aged, three-worker queenless groups comprising either experienced or naive workers (with/without adult exposure to queen pheromone). We quantified three hydrocarbons (C23, C25 and C27) on the cuticular surfaces of females and tested their effects on the two worker types. Our results indicate differences in responses of naive and experienced workers, genetic effects on worker reproduction, and general effects of hydrocarbons and duration of egg laying on ovary resorption rates. However, we found no evidence to support the theory that a conserved class of hydrocarbons serve as queen pheromones or queen signals in Bombus impatiens. PMID- 26490792 TI - Continental faunal exchange and the asymmetrical radiation of carnivores. AB - Lineages arriving on islands may undergo explosive evolutionary radiations owing to the wealth of ecological opportunities. Although studies on insular taxa have improved our understanding of macroevolutionary phenomena, we know little about the macroevolutionary dynamics of continental exchanges. Here we study the evolution of eight Carnivora families that have migrated across the Northern Hemisphere to investigate if continental invasions also result in explosive diversification dynamics. We used a Bayesian approach to estimate speciation and extinction rates from a substantial dataset of fossil occurrences while accounting for the incompleteness of the fossil record. Our analyses revealed a strongly asymmetrical pattern in which North American lineages invading Eurasia underwent explosive radiations, whereas lineages invading North America maintained uniform diversification dynamics. These invasions into Eurasia were characterized by high rates of speciation and extinction. The radiation of the arriving lineages in Eurasia coincide with the decline of established lineages or phases of climate change, suggesting differences in the ecological settings between the continents may be responsible for the disparity in diversification dynamics. These results reveal long-term outcomes of biological invasions and show that the importance of explosive radiations in shaping diversity extends beyond insular systems and have significant impact at continental scales. PMID- 26490793 TI - Sex ratio variation shapes the ecological effects of a globally introduced freshwater fish. AB - Sex ratio and sexual dimorphism have long been of interest in population and evolutionary ecology, but consequences for communities and ecosystems remain untested. Sex ratio could influence ecological conditions whenever sexual dimorphism is associated with ecological dimorphism in species with strong ecological interactions. We tested for ecological implications of sex ratio variation in the sexually dimorphic western mosquitofish, Gambusia affinis. This species causes strong pelagic trophic cascades and exhibits substantial variation in adult sex ratios. We found that female-biased populations induced stronger pelagic trophic cascades compared with male-biased populations, causing larger changes to key community and ecosystem responses, including zooplankton abundance, phytoplankton abundance, productivity, pH and temperature. The magnitude of such effects indicates that sex ratio is important for mediating the ecological role of mosquitofish. Because both sex ratio variation and sexual dimorphism are common features of natural populations, our findings should encourage broader consideration of the ecological significance of sex ratio variation in nature, including the relative contributions of various sexually dimorphic traits to these effects. PMID- 26490794 TI - Hidden keys to survival: the type, density, pattern and functional role of emperor penguin body feathers. AB - Antarctic penguins survive some of the harshest conditions on the planet. Emperor penguins breed on the sea ice where temperatures drop below -40 degrees C and forage in -1.8 degrees C waters. Their ability to maintain 38 degrees C body temperature in these conditions is due in large part to their feathered coat. Penguins have been reported to have the highest contour feather density of any bird, and both filoplumes and plumules (downy feathers) are reported absent in penguins. In studies modelling the heat transfer properties and the potential biomimetic applications of penguin plumage design, the insulative properties of penguin plumage have been attributed to the single afterfeather attached to contour feathers. This attribution of the afterfeather as the sole insulation component has been repeated in subsequent studies. Our results demonstrate the presence of both plumules and filoplumes in the penguin body plumage. The downy plumules are four times denser than afterfeathers and play a key, previously overlooked role in penguin survival. Our study also does not support the report that emperor penguins have the highest contour feather density. PMID- 26490797 TI - Anomalous dielectric and thermal properties of Ba-doped PbZrO3 ceramics. AB - The dielectric and thermal properties of an antiferroelectric (AFE) material characterised by an intermediate ferroelectric (FE) phase between the AFE and paraelectric phase in zero field are studied by means of a generalised Landau Kittel model of AFEs. A temperature-dependent coupling of the two sublattices is introduced in accordance with the Rae-Dove (RD) model of re-entrant phase transitions. The sublattice polarisation components are calculated as functions of temperature and the applied electric field by minimising numerically the free energy. The calculated dielectric susceptibility shows anomalies at the boundaries of the intermediate FE phase, characteristic for first-order phase transitions. It is shown that this behaviour is in qualitative agreement with the measured dielectric constant in Ba-doped PbZrO3 ceramics. The model also predicts a negative adiabatic electrocaloric temperature change DeltaT in a broad temperature range in the AFE phase, in qualitative agreement with experiments. The dipolar heat capacity is also predicted to be negative in the intermediate phase in zero field, in analogy with the results of the RD model. PMID- 26490796 TI - Epigenetic screening of salivary gland mucoepidermoid carcinoma identifies hypomethylation of CLIC3 as a common alteration. AB - OBJECTIVES: The role of promoter methylation in the development of mucoepidermoid carcinoma (MEC) has not been fully explored. In this study, we investigated the epigenetic landscape of MEC. METHODS: The Illumina HumanMethylation27 BeadChip array and differential methylation analysis were utilized to screen for epigenetic alterations in 14 primary MEC tumors and 14 matched normal samples. Bisulfite sequencing was used to validate these results, with subsequent quantitative Methylation-Specific PCR (qMSP) to validate chloride intracellular channel protein 3 (CLIC3) in a separate cohort. Furthermore, CLIC3 immunohistochemical (IHC) staining was performed in another separate cohort of MEC. Finally, clinical and pathological characteristics were statistically analyzed for correlation with methylation status of CLIC3 and CLIC3 IHC H-scores by Wilcoxon rank sum, Kruskall-Wallis, and X(2) test tests. RESULTS: We obtained 6 significantly differentially methylated gene candidates demonstrating significant promoter hyper- or hypo-methylation from the array data. Using bisulfite sequencing, we found one gene, CLIC3, which showed differential methylation between MEC tumor and normal samples in a small validation cohort. qMSP analysis of the CLIC3 promoter in a separate validation set showed significantly lower methylation level in tumor than in normal. The level of CLIC3 methylation in MECs was not statistically correlated with clinical or pathological characteristics. However, IHC staining intensity and distribution of CLIC3 were significantly increased in MECs, compared with those of normal salivary gland tissues. CONCLUSIONS: Hypomethylation of CLIC3 promoter and its overexpression are significant events in MEC. Its functional role and potential therapeutic utility in MEC are worthy of further exploration. PMID- 26490798 TI - G-Tetraplex-Induced FRET within Telomeric Repeat Sequences Using (Py) A-(Per) A as Energy Donor-Acceptor Pair. AB - G-tetraplex induced fluorescence resonance energy transfer (FRET) within telomeric repeat sequences has been studied using a nucleoside-tethered FRET pair embedded in the human telomeric G-quadruplex forming sequence (5'-A GGG TT(Py) A GGG TT(Per) A GGG TTA GGG-3', Py=pyrene, Per=perylene). Conformational change from a single strand to an anti-parallel G-quadruplex leads to FRET from energy donor ((Py) A) to acceptor ((Per) A). The distance between the FRET donor/acceptor partners was controlled by changing the number of G-quartet spacer units. The FRET efficiency decreases with increase in G-quartet units. Overall findings indicate that this could be further used for the development of FRET based sensing and measurement techniques. PMID- 26490799 TI - The modifier effects of chymotrypsin and trypsin enzymes on fluorescence lifetime distribution of "N-(1-pyrenyl)maleimide-bovine serum albumin" complex. AB - Chymotrypsin and trypsin are the well known proteolytic enzymes, both of which are synthesized in the pancreas as their precursors - the inactive forms; chymotrypsinogen and trypsinogen - and then are released into the duodenum to cut proteins into smaller peptides. In this paper, the effects of activities of chymotrypsin and trypsin enzymes on fluorescence lifetime distributions of the substrat bovine serum albumin (BSA) modified with N-(1-pyrenyl)maleimide (PM) were examined. In the labeling study of BSA with PM, it is aimed to attach PM to the single free thiol (Cys34) and to all the free amine groups in accessible positions in order to produce excimers of pyrene planes of the possible highest amount to form the lifetime distributions in the widest range, that may show specifically distinguishing changes resulting from the activities of the proteases. The time resolved spectrofluorometer was used to monitor fluorescence decays, which were analyzed by using the exponential series method (ESM) to obtain the changes of lifetime distributions. After the exposure of the synthesized substrat PM-BSA to the enzymes, the fluorescence lifetime distributions exhibited different structures which were attributed to the different activities of the proteases. PMID- 26490800 TI - A combined FTIR and infrared emission spectroscopy investigation of layered double hydroxide as an effective electron donor. AB - A novel method has been presented to characterize electron transfer in layered double hydroxides (LDHs) utilizing an investigation combing FTIR and infrared emission spectroscopy. At room temperature, electron could transfer to interlayer Fe(3+) through monodentate ligand cyanide, and resulted in a reduction of 40% Fe(3+) to Fe(2+). When the environmental temperature increased from 25 to 300 degrees C, reduction of Fe(3+) and Ni(2+) increased to 94% and 42%. Furthermore, electron also transferred to interlayer cation through multidentate ligand EDTA. As a result, LDHs has been proven to be an effective electron donor, and FTIR was a feasible tool in characterizing this property by monitoring the valence state of cations. It was also concluded that octahedral units with OH(-) groups in LDH layer functioned as electron donor centers. Driving force for electron transfer is attributed to the charge density difference between cation layer and probe anion. These results could help to explain the mechanism of various applications of LDHs in catalysis and photocatalysis. PMID- 26490801 TI - Advocate for our patients, advocate for our profession. PMID- 26490802 TI - "I see the light!" trans-carotid balloon valvuloplasty in neonates and small infants utilizing continuous trans-esophageal echo guidance. AB - Continuous echo guidance may add to the safety of neonatal aortic balloon valvuloplasty Trans-carotid access is an alternative route to aortic balloon valvuloplasty in neonates Proof of preferred procedure (surgical or catheter based), procedure setting, and access site remains elusive as the disease is infrequent and single center experience remains small. PMID- 26490803 TI - Too much data, and still not enough information. AB - This analysis of the National Inpatient Sample Database found that Medicare and Medicaid patients with peripheral arterial disease had higher rates of amputation and in-hospital mortality as compared to private pay and Health Maintenance Organization (HMO) patients. Raising awareness of disparities of outcomes among vulnerable populations should lead all healthcare providers to examine gaps in care. Administrative databases are necessarily limited. Prospective registries should be developed to demonstrate that early detection of PAD with simple, cost effective tests like the ankle brachial index can improve outcomes. PMID- 26490804 TI - Transcatheter aortic valve implantation: Watch out for the leak, irrespective of aortic valve disease type. AB - Postprocedural aortic regurgitation (PAR) after transcatheter aortic valve implantation (TAVI) is associated with a worst clinical outcome. The presence of chronic aortic regurgitation in TAVI candidates increases PAR risk but not overall survival. Future valve prototypes will likely reduce the degree and frequency of this complication. PMID- 26490805 TI - Understanding rare comorbidities in TAVR. AB - There seems to be an early morbidity and mortality advantage to TAVR in patients with chronic liver disease. Patients with Childs A and B CLD can be treated with TAVR but we know little about TAVR for sicker patients. Technical issues associated with TAVR (the use of transesophageal echocardiography (TEE) for example) have to be weighed in CLD patients with esophageal varices. PMID- 26490806 TI - A "prospective" and "retrospective" view of the hazards of a career in interventional cardiology. AB - Surveyed interventional cardiologists reported frequent occupation-related health hazards including orthopedic injury (49.4%), radiation-related skin disease (4.8%), cataracts (5.5%), and hematologic and malignant conditions (4.8%) Further advances are needed to increase operator and staff safety to prevent future orthopedic injuries and radiation-related diseases. Each individual interventional cardiologist needs to weigh the hazards of the profession with the benefits which are substantial as well. PMID- 26490807 TI - Radiation dose variation in fluoroscopic imaging: Is What You Get, What You See? AB - Variations in dose exist amongst various imaging systems and in various acquisition angulations; this is not a new finding. Assessment of Image quality should accompany an assessment of dose, as these complement each other. Routine assessment of dose and image quality with potential comparisons amongst operators, laboratories, and imaging systems may prove beneficial for radiation safety in interventional cardiology practice. PMID- 26490808 TI - Keep that radiation off of Me! AB - Radial access may increase operator irradiation if the operator is closer to the X-ray beam. Using appropriate radiation shielding reduces occupational and eye doses without increasing patient irradiation. Reusable shielding can substantially reduce the costs of averting a cancer or cataract relative to the cost of disposables. PMID- 26490809 TI - No syringe is approved as a standalone storage container, FDA says. PMID- 26490810 TI - Get involved in public policy, says 2015 Zellmer Lecturer. PMID- 26490811 TI - Insulin degludec products approved for diabetes. PMID- 26490812 TI - Rolapitant approved for chemotherapy-induced nausea and vomiting. PMID- 26490813 TI - Pharmacy leader Eric T. Hola dies at 60. PMID- 26490815 TI - Integration of investigational drug services in an oncology service line. PMID- 26490816 TI - Development and implementation of an interdisciplinary pulmonary care clinic within an existing clinic program. PMID- 26490817 TI - Emotional intelligence: Not just for leaders. PMID- 26490818 TI - Nivolumab for second-line treatment of metastatic squamous non-small-cell lung cancer. AB - PURPOSE: The pharmacokinetics, pharmacodynamics, efficacy, toxicity, and place in therapy of nivolumab, a novel immunotherapy agent for the treatment of advanced non-small-cell lung cancer (NSCLC) of the squamous cell subtype are reviewed. SUMMARY: Nivolumab is a novel programmed cell death 1 (PD-1) immune checkpoint inhibitor indicated as a second-line treatment for patients with NSCLC whose tumors exhibit squamous cell histology. Nivolumab has high affinity for the PD-1 receptor, and durable responses to treatment have been reported in clinical trials. In a Phase II study evaluating the drug's safety and efficacy in patients who had disease progression despite treatment with platinum-based doublet chemotherapy and at least one additional systemic therapy, nivolumab-treated patients had an objective response rate of 14.5%, with a 17% rate of grade 3 or 4 treatment-related adverse events; overall survival at one year was 40.8%. A head to-head comparison of docetaxel and nivolumab for second-line treatment of squamous cell NSCLC demonstrated superior overall survival and reduced grade 3 or 4 adverse effects in nivolumab-treated patients. CONCLUSION: Nivolumab is a novel PD-1 immune checkpoint inhibitor that is effective for treating advanced squamous NSCLC in patients previously treated with platinum-based doublet chemotherapy or alternative first-line agents. Based on its improved efficacy and lower toxicity relative to docetaxel, nivolumab should be considered standard second-line therapy for this population. PMID- 26490819 TI - Vancomycin dosing and monitoring for patients with end-stage renal disease receiving intermittent hemodialysis. AB - PURPOSE: Vancomycin dosing and monitoring algorithms for patients with end-stage renal disease (ESRD) receiving intermittent hemodialysis are reviewed. SUMMARY: Vancomycin is one of the most commonly administered antimicrobial agents in adult patients with ESRD receiving intermittent hemodialysis. However, despite the availability of many published studies, the single best method of vancomycin administration in this population remains unclear. Many studies evaluating vancomycin dosing in adult patients with ESRD receiving intermittent hemodialysis were limited by a small sample size, inappropriate therapeutic targets, older hemodialysis modalities (e.g., low-flux intermittent hemodialysis), and inconsistencies in the timing of dosing or therapeutic drug monitoring. Pharmacokinetic variables that must be accounted for include a prolonged distribution phase, a redistribution phase and rebound effect after completion of hemodialysis, patient weight, residual renal function, and nonrenal clearance. Optimal vancomycin dosing recommendations are needed, but clinicians should always consider patient-specific variables, the timing of vancomycin administration, the timing of serum vancomycin concentrations, and technical aspects of the dialysis procedure when creating a dosing regimen. CONCLUSION: Individualized vancomycin dosing regimens and therapeutic drug monitoring are necessary for patients with ESRD receiving intermittent hemodialysis to ensure that goal serum vancomycin levels are reached to adequately treat an infection. PMID- 26490820 TI - A probable case of syndrome of inappropriate antidiuretic hormone secretion associated with linezolid. AB - PURPOSE: A probable case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) due to linezolid use is reported. SUMMARY: An 81-year-old Korean woman hospitalized for progressive malignant otitis externa due to methicillin-resistant Staphylococcus aureus infection was started on linezolid therapy (600 mg i.v. twice daily). On day 22 of linezolid use, the patient had severe hyponatremia (serum sodium concentration, 118 meq/L), with stable vital signs and no specific physical findings except for somnolence. The patient's urine sodium concentration was 1183 meq/L, and her serum and urine osmolarity values were 250 and 357 mOsm/kg, respectively; these findings were consistent with SIADH. Hypertonic saline infusion and fluid restriction (<1 L/day) were continued for four days with the aim of achieving a desired serum sodium concentration of 130 meq/L. On day 26 of linezolid therapy, the drug was discontinued due to development of progressive anemia (hemoglobin concentration, 6.7 g/dL). The next day, the patient's serum sodium concentration increased abruptly to 135 meq/L and remained stable until hospital discharge. After multiple alternative etiologies were excluded, drug-induced SIADH due to linezolid use was determined to be the most likely diagnosis. Using the adverse drug reaction probability scale of Naranjo et al., the case was assigned a score of 6, indicating a probable association between linezolid use and SIADH. CONCLUSION: SIADH was observed in a woman who was administered linezolid for more than three weeks, with concurrent development of progressive severe anemia associated with linezolid toxicity. The patient's hyponatremia resolved after cessation of linezolid use. PMID- 26490821 TI - Evaluation of a bedside scoring system for predicting clinical cure and recurrence of Clostridium difficile infections. AB - PURPOSE: The accuracy of a bedside scoring system, ATLAS, for predicting clinical cure and recurrence of Clostridium difficile infections (CDIs) was evaluated. METHODS: A single-center retrospective medical record review was performed for symptomatic adult patients with stool assay-diagnosed CDI treated with metronidazole or vancomycin or both. Multiple logistic regression analysis was performed to assess the potential association of the ATLAS score and other potential factors on achieving cure and 90-day CDI recurrence. ATLAS scores were calculated, and risk factors for severe CDI, severe-complicated CDI, decreased cure rates, and recurrence were recorded. RESULTS: Data from 245 adult patients were assessed. ATLAS scores showed a significant inverse association with the cure rate (p = 0.009) but not with the 90-day recurrence rate (p = 0.901). The only ATLAS component to be independently associated (inversely) with cure was the concomitant use of antibiotics (p = 0.022). Metronidazole was initiated in 97% of patients, with 32% switching to oral vancomycin. Longer courses of vancomycin were associated with a higher cure rate (p = 0.0009) but not with recurrence (p = 0.170). Complicated cases were less likely to be cured (p = 0.027) and more likely to recur within 90 days (p = 0.002). Antibiotics continued after CDI treatment was associated with recurrence (p = 0.055). CONCLUSION: A low ATLAS score was found to correlate with higher cure rates in patients with CDI receiving metronidazole, oral vancomycin, or both. However, the score could not predict CDI recurrence. PMID- 26490822 TI - Development and validation of criteria for classifying severity of drug-related problems in chronic kidney disease: A community pharmacy perspective. AB - PURPOSE: The development and validation of criteria for classifying severity of drug-related problems (DRPs) in chronic kidney disease (CKD) in the community pharmacy setting are described. METHODS: The Severity Categorization for Pharmaceutical Evaluation (SCOPE) criteria were adapted from an existing tool based on the interventions required to manage DRPs in community pharmacy. Ten community pharmacists reviewed the criteria. An expert panel involving community pharmacists, hospital pharmacists, family physicians, and nephrologists scored the relevance of each criterion. The severity of 487 DRPs identified among 168 patients was rated independently by two evaluators and by one evaluator on two occasions. Kappa reliability coefficients were computed. Severity as assessed by implicit judgment and the SCOPE criteria was compared. RESULTS: Three severity categories were defined (mild, moderate, and severe), each including two levels (for a total of six levels). At each level, specific interventions required to manage DRPs in community pharmacy were listed. The test-retest reliability coefficient by level was 0.85 (95% confidence interval [CI], 0.79-0.90), and the interrater reliability coefficient was 0.77 (95% CI, 0.72-0.82). The test-retest coefficient by category was 0.89 (95% CI, 0.84-0.95), and the interrater coefficient was 0.90 (95% CI, 0.86-0.94). A higher level of SCOPE was associated with more severe DRPs as rated by implicit judgment (p < 0.05). CONCLUSION: A set of criteria developed for use in the community pharmacy setting for evaluating the severity of DRPs in CKD proved to be reliable and correlated with clinical implicit judgment. PMID- 26490823 TI - Development of a pharmacy student research program at a large academic medical center. AB - PURPOSE: A program to promote research by pharmacy students created through the collaboration of an academic medical center and a college of pharmacy is described. SUMMARY: In 2009, Midwestern University Chicago College of Pharmacy and Northwestern Memorial Hospital (NMH) expanded their existing partnership by establishing a program to increase opportunities for pharmacy students to conduct clinical-translational research. All professional year 1, 2, or 3 students at the college, as well as professional year 4 students on rotation at NMH, can participate in the program. Central to the program's infrastructure is the mentorship of student leads by faculty- and hospital-based pharmacists. The mentors oversee the student research projects and guide development of poster presentations; student leads mentor junior students and assist with orientation and training activities. Publication of research findings in the peer-reviewed literature is a key program goal. In the first four years after program implementation, participation in a summer research program grew nearly 10-fold (mainly among incoming professional year 2 or 3 students, and student poster presentations at national pharmacy meetings increased nearly 20-fold; the number of published research articles involving student authors increased from zero in 2009 to three in 2012 and two in 2013. CONCLUSION: A collaborative program between an academic medical center and a college of pharmacy has enabled pharmacy students to conduct research at the medical center and has been associated with increases in the numbers of poster presentations and publications involving students. PMID- 26490824 TI - A quantitative study of the emotional intelligence of participants in the ASHP Foundation's Pharmacy Leadership Academy. AB - PURPOSE: Results of a quantitative assessment of emotional intelligence in a sample of pharmacists affiliated with the ASHP Research and Education Foundation's Pharmacy Leadership Academy (PLA) are presented. METHODS: A demographic questionnaire and a validated instrument for assessing emotional intelligence, the Emotional Quotient Inventory, version 2.0 (EQ-i 2.0), were administered to a group of practicing pharmacists who graduated from the PLA during the period 2008-12 (n = 82) and a control group of pharmacists who were accepted into the PLA in 2013 but had not begun leadership training (n = 40). The dependent variables were the mean total EQ-I 2.0 score and mean scores on five EQ i 2.0 composite scales. The independent variables were PLA affiliation status (graduate versus matriculant) and demographic variables. Descriptive and inferential statistics were used to calculate between-group differences in EQ-i 2.0 scores. The relationship of demographic variables to EQ-i 2.0 scores was analyzed via multiple linear regression. RESULTS: Among the 122 pharmacists who completed both assessments, the overall mean total EQ-i 2.0 score was 101.11, which indicated an average level of emotional intelligence. There were significant differences between the PLA graduate group and the control group in total EQ-i 2.0 scores and in EQ-i 2.0 scores for self-expression, decision making, interpersonal skills, and other aspects of emotional intelligence. The evaluated demographic factors were not found to be significant predictors of EQ-i 2.0 scores. CONCLUSION: The study results indicated an average level of emotional intelligence among all PLA affiliates but revealed significant differences in mean total EQ-i 2.0 scores and EQ-i 2.0 composite scale scores favoring PLA graduates. PMID- 26490825 TI - Healthcare-associated pneumonia: Who is truly at risk for multidrug-resistant pathogens? PMID- 26490826 TI - Pilot study comparing simulation-based and didactic lecture-based critical care teaching for final-year medical students. AB - BACKGROUND: Simulation-based medical education has rapidly evolved over the past two decades, despite this, there are few published reports of its use in critical care teaching. We hypothesised that simulation-based teaching of a critical care topic to final-year medical students is superior to lecture-based teaching. METHODS: Thirty-nine final-year medical students were randomly assigned to either simulation-based or lecture-based teaching in the chosen critical care topic. The study was conducted over a 6-week period. Efficacy of each teaching method was compared through use of multiple choice questionnaires (MCQ) - baseline, post teaching and 2 week follow-up. Student satisfaction was evaluated by means of a questionnaire. Feasibility and resource requirements were documented by teachers. RESULTS: Eighteen students were randomised to simulation-based, and 21 to lecture based teaching. There were no differences in age and gender between groups (p > 0.05). Simulation proved more resource intensive requiring specialised equipment, two instructors, and increased duration of teaching sessions (126.7 min (SD = 4.71) vs 68.3 min (SD = 2.36)). Students ranked simulation-based teaching higher with regard to enjoyment (p = 0.0044), interest (p = 0.0068), relevance to taught subject (p = 0.0313), ease of understanding (p = 0.0476) and accessibility to posing questions (p = 0.001). Both groups demonstrated improvement in post teaching MCQ from baseline (p = 0.0002), with greater improvement seen among the simulation group (p = 0.0387), however, baseline scores were higher among the lecture group. The results of the 2-week follow-up MCQ and post-teaching MCQ were not statistically significant when each modality were compared. DISCUSSION: Simulation was perceived as more enjoyable by students. Although there was a greater improvement in post-teaching MCQ among the simulator group, baseline scores were higher among lecture group which limits interpretation of efficacy. Simulation is more resource intensive, as demonstrated by increased duration and personnel required, and this may have affected our results. CONCLUSIONS: The current pilot may be of use in informing future studies in this area. PMID- 26490827 TI - Draft genome sequences of three chemically rich actinomycetes isolated from Mediterranean sponges. AB - Metabolomic analysis has shown the chemical richness of the sponge-associated actinomycetes Streptomyces sp. SBT349, Nonomureae sp. SBT364, and Nocardiopsis sp. SBT366. The genomes of these actinomycetes were sequenced and the genomic potential for secondary metabolism was evaluated. Their draft genomes have sizes of 8.0, 10, and 5.8 Mb having 687, 367, and 179 contigs with a GC content of 71.6, 70.7, and 72.7%, respectively. Moreover, antiSMASH 3.0 predicted 108, 149, and 75 secondary metabolite gene clusters, respectively which highlight the metabolic capacity of the three actinomycete species to produce diverse classes of natural products. PMID- 26490828 TI - Stent-based thrombectomy versus intravenous tissue plasminogen activator in acute ischaemic stroke: A systematic review and meta-analysis. AB - PURPOSE: To date only a few studies have compared the effectiveness and functional outcomes of stent retrievers versus intravenous thrombolysis in acute ischaemic stoke. Our aim was to identify and collate all the available data and to assess for statistical differences in patient outcomes between the two treatments. MATERIALS AND METHODS: We performed a systematic review and meta analysis of studies with a randomised controlled design which utilised stentrievers and intravenous thrombolysis in acute ischaemic stroke. RESULTS: Five randomised controlled studies published in 2015 were identified. Second generation thrombectomy devices constituted at least 80% of thrombectomy devices in the included studies, namely MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME and REVASCAT. No significant heterogeneity was seen in the included studies and the five trials were therefore included in the meta-analysis.A total of 46.10% of patients treated with stentrievers achieved an independent functional outcome (mRS < 2) at 90 days compared with 26.46% of those treated with intravenous thrombolysis with an odds ratio of 2.40 (p < 0.001). The weighted recanalisation mean in the thrombectomy arms was 76.02%.A lower mortality rate was observed with stentrievers compared to intravenous thrombolysis (15.33% vs 18.74%; OR 0.81, p = 0.15). Stentrievers were also associated with a lower risk of symptomatic intracranial haemorrhage (7.86% vs 8.64%; OR 1.02, p = 0.93). The differences in the secondary/safety outcomes were not statistically significant. CONCLUSION: Stentrievers can achieve a high rate of recanalisation and functional independence in acute ischaemic stroke and have a relatively good safety profile. Our meta-analysis demonstrates a clear benefit of an intra-arterial mechanical approach vs standard treatment. PMID- 26490829 TI - Thrombectomy after intravenous thrombolysis is the new standard of care in acute stroke with large vessel occlusion. PMID- 26490830 TI - Mechanical thrombectomy in patients with acute basilar occlusion using stent retrievers. AB - BACKGROUND: Early arterial recanalisation with stent retrievers (SR) has been recently demonstrated to improve clinical outcome of patients with large-vessel occlusion of the anterior circulation. However, the benefit of SR thrombectomy in the setting of acute basilar artery occlusion (BAO) has not been proven yet. This study evaluated a series of consecutive patients with BAO treated with SR, focusing on the efficacy, safety and clinical results. METHODS: We analysed 24 consecutive patients with acute BAO who were treated with SR mechanical thrombectomy. Good clinical outcome at three months was defined as mRS <= 2. Data from patients with good outcome were compared to that from patients with poor outcome. RESULTS: Sufficient recanalisation (TICI 2 b or 3) was achieved in 63% (15/24) of patients. At three months, 33% (8/24) of patients had died; good clinical outcome was obtained in 21% (5/24). Age (46 vs. 60 years old, p = 0.05) and time from symptoms onset to recanalisation (370 vs. 521 minutes, p = 0.048) was significantly lower in patients with good outcome as compared to patients with poor outcome. There were three cases (12.5%) of periprocedural complications, all of them related to arterial wall dissection/perforation. CONCLUSIONS: SR thrombectomy might be an efficient and safe treatment for patients with acute BAO occlusion and might help improve outcome. PMID- 26490831 TI - A stochastic model of acute-care decisions based on patient and provider heterogeneity. AB - The primary cause of preventable death in many hospitals is the failure to recognize and/or rescue patients from acute physiologic deterioration (APD). APD affects all hospitalized patients, potentially causing cardiac arrest and death. Identifying APD is difficult, and response timing is critical - delays in response represent a significant and modifiable patient safety issue. Hospitals have instituted rapid response systems or teams (RRT) to provide timely critical care for APD, with thresholds that trigger the involvement of critical care expertise. The National Early Warning Score (NEWS) was developed to define these thresholds. However, current triggers are inconsistent and ignore patient specific factors. Further, acute care is delivered by providers with different clinical experience, resulting in quality-of-care variation. This article documents a semi-Markov decision process model of APD that incorporates patient and provider heterogeneity. The model allows for stochastically changing health states, while determining patient subpopulation-specific RRT-activation thresholds. The objective function minimizes the total time associated with patient deterioration and stabilization; and the relative values of nursing and RRT times can be modified. A case study from January 2011 to December 2012 identified six subpopulations. RRT activation was optimal for patients in "slightly concerning" health states (NEWS > 0) for all subpopulations, except surgical patients with low risk of deterioration for whom RRT was activated in "concerning" states (NEWS > 4). Clustering methods identified provider clusters considering RRT-activation preferences and estimation of stabilization-related resource needs. Providers with conservative resource estimates preferred waiting over activating RRT. This study provides simple practical rules for personalized acute care delivery. PMID- 26490833 TI - Remote Multiproton Storage within a Pyrrolide-Pincer-Type Ligand. AB - A chemically non-innocent pyrrole-based trianionic (ONO)(3-) pincer ligand within [(pyr-ONO)TiCl(thf)2 ] (2) can access the dianionic [(3H-pyr-ONO)TiCl2 (thf)] (1 THF) and monoanionic [(3H,4H-pyr-ONO)TiCl2 (OEt2 )][B{3,5-(CF3 )2 C6 H3 }4 ] (3 Et2 O) states through remote protonation of the pyrrole gamma-C pi-bonds. The homoleptic [(3H-pyr-ONO)2 Zr] (4) was synthesized and characterized by X-ray diffraction and NMR spectroscopy in solution. The protonation of 4 by [H(OEt2 )2 ][B{C6 H3 (CF3 )2 }4 ] yields [(3H,4H-pyr-ONO)(3H-pyr-ONO)Zr][B{3,5-(CF3 )2 C6 H3 }4 ] (5), thus demonstrating the storage of three protons. PMID- 26490832 TI - Intravitreal treatment in patients with exudative age-related macular degeneration and visual acuity <= 0.05. AB - BACKGROUND: To investigate intravitreal treatment efficiencies in patients suffering from exudative ARMD with a BCVA <= 0.05. METHODS: Retrospective analysis: Analysis parameters were lesion type, BCVA at baseline and at follow up, the intravitreal drug used, and its application frequency. Patients were divided into: 1) following injections of bevacizumab, triamcinolone, their combination, or ranibizumab regardless of their lesion subtype, 2) or by lesion subtype. Statistical tests were performed using Wilcoxon signed-rank tests, Kruskal-Wallis tests and multivariable logistic regressions. RESULTS: Seventy four eyes of 74 patients were analyzed. Follow-up was at 12.0 to 15.7 weeks. Median difference of BCVA (logMAR) between baseline and follow-up was 0.000 ( 0.030, 0.175) in classic (p = 0.105), 0.000 (-1.15, 0.20) in occult (p = 0.005), 0.200 (-1.20, 0.60) in cases with subretinal fluid (p = 0.207), 0.000 (-0.60, 0.30) in pigment epithelial detachment (p = 0.813), and 0.050 (-0.40, 0.70) in Junius Kuhnt maculopathy (p = 0.344). BCVA increased >= 0.2 logMAR in 4 (24 %) classic, 9 (47 %) occult, 6 (33 %) pigment epithelial detachment, 6 (55 %) subretinal fluid, in 29 (39 %) eyes regardless of the lesion type, and reached a BCVA >= 0.05 in 7 (9 %) of those with a baseline BCVA <0.05. CONCLUSIONS: Results indicate that in patients with ARMD and a BCVA lower 0.05, intravitreal treatment may improve visual acuity, most probably in cases with occult lesions. PMID- 26490834 TI - Improving the monitoring of crop productivity using spaceborne solar-induced fluorescence. AB - Large-scale monitoring of crop growth and yield has important value for forecasting food production and prices and ensuring regional food security. A newly emerging satellite retrieval, solar-induced fluorescence (SIF) of chlorophyll, provides for the first time a direct measurement related to plant photosynthetic activity (i.e. electron transport rate). Here, we provide a framework to link SIF retrievals and crop yield, accounting for stoichiometry, photosynthetic pathways, and respiration losses. We apply this framework to estimate United States crop productivity for 2007-2012, where we use the spaceborne SIF retrievals from the Global Ozone Monitoring Experiment-2 satellite, benchmarked with county-level crop yield statistics, and compare it with various traditional crop monitoring approaches. We find that a SIF-based approach accounting for photosynthetic pathways (i.e. C3 and C4 crops) provides the best measure of crop productivity among these approaches, despite the fact that SIF sensors are not yet optimized for terrestrial applications. We further show that SIF provides the ability to infer the impacts of environmental stresses on autotrophic respiration and carbon-use-efficiency, with a substantial sensitivity of both to high temperatures. These results indicate new opportunities for improved mechanistic understanding of crop yield responses to climate variability and change. PMID- 26490835 TI - Infectious salmon anaemia virus (ISAV) mucosal infection in Atlantic salmon. AB - All viruses infecting fish must cross the surface mucosal barrier to successfully enter a host. Infectious salmon anaemia virus (ISAV), the causative agent of the economically important infectious salmon anaemia (ISA) in Atlantic salmon, Salmo salar L., has been shown to use the gills as its entry point. However, other entry ports have not been investigated despite the expression of virus receptors on the surface of epithelial cells in the skin, the gastrointestinal (GI) tract and the conjunctiva. Here we investigate the ISAV mucosal infection in Atlantic salmon after experimental immersion (bath) challenge and in farmed fish collected from a confirmed outbreak of ISA in Norway. We show for the first time evidence of early replication in several mucosal surfaces in addition to the gills, including the pectoral fin, skin and GI tract suggesting several potential entry points for the virus. Initially, the infection is localized and primarily infecting epithelial cells, however at later stages it becomes systemic, infecting the endothelial cells lining the circulatory system. Viruses of low and high virulence used in the challenge revealed possible variation in virus progression during infection at the mucosal surfaces. PMID- 26490836 TI - Maternal anxiety versus depressive disorders: specific relations to infants' crying, feeding and sleeping problems. AB - BACKGROUND: Maternal depression has been associated with excessive infant crying, feeding and sleeping problems, but the specificity of maternal depression, as compared with maternal anxiety remains unclear and manifest disorders prior to pregnancy have been widely neglected. In this prospective longitudinal study, the specific associations of maternal anxiety and depressive disorders prior to, during and after pregnancy and infants' crying, feeding and sleeping problems were investigated in the context of maternal parity. METHODS: In the Maternal Anxiety in Relation to Infant Development (MARI) Study, n = 306 primiparous and multiparous women were repeatedly interviewed from early pregnancy until 16 months post partum with the Composite International Diagnostic Interview for Women (CIDI-V) to assess DSM-IV anxiety and depressive disorders. Information on excessive infant crying, feeding and sleeping problems was obtained from n = 286 mothers during postpartum period via questionnaire and interview (Baby-DIPS). RESULTS: Findings from this study revealed syndrome-specific risk constellations for maternal anxiety and depressive disorders as early as prior to pregnancy: Excessive infant crying (10.1%) was specifically associated with maternal anxiety disorders, especially in infants of younger and lower educated first-time mothers. Feeding problems (36.4%) were predicted by maternal anxiety (and comorbid depressive) disorders in primiparous mothers and infants with lower birth weight. Infant sleeping problems (12.2%) were related to maternal depressive (and comorbid anxiety) disorders irrespective of maternal parity. CONCLUSIONS: Primiparous mothers with anxiety disorders may be more prone to anxious misinterpretations of crying and feeding situations leading to an escalation of mother-infant interactions. The relation between maternal depressive and infant sleeping problems may be better explained by a transmission of unsettled maternal sleep to the fetus during pregnancy or a lack of daily structure and bedtime routine with the infant. Maternal disorders prior to pregnancy require more attention in research and clinical practice. PMID- 26490837 TI - ESCRT (Endosomal Sorting Complex Required for Transport) Machinery Is Essential for Acrosomal Exocytosis in Human Sperm. AB - The sperm acrosome reaction is a unique, regulated exocytosis characterized by the secretion of the acrosomal content and the release of hybrid vesicles formed by patches of the outer acrosomal and plasma membranes. In previous reports, we have shown that inward invaginations of the acrosomal membrane delineate ring shaped membrane microdomains that contact the plasma membrane. We have postulated that the opening and expansion of fusion pores along these rings trigger acrosomal exocytosis. The invaginations of the acrosomal membrane topologically resemble the deformations of the endosomal membrane leading to the assembly of luminal vesicles in multivesicular bodies. In fact, intra-acrosomal vesicles are also formed during acrosomal exocytosis. Endosomal sorting complex required for transport (ESCRT) participates in the organization of membrane microdomains that are invaginated and released as intraluminal vesicles in endosomes. We report here that members of ESCRT I (TSG101), ESCRT III (CHMP4), and the AAA ATPase VPS4 are present in the acrosomal region of the human sperm. Perturbing the function of these factors with antibodies or recombinant proteins inhibited acrosomal exocytosis in permeabilized cells. A similar effect was observed with a dominant negative mutant of VPS4A cross-linked to a cell-penetrating peptide in nonpermeabilized sperm stimulated with a calcium ionophore. When the function of ESCRTs was inhibited, acrosomes showed abnormal deformation of the acrosomal membrane, and SNARE proteins that participate in acrosomal exocytosis failed to be stabilized in neurotoxin-resistant complexes. However, the growing of membrane invaginations was not blocked, and numerous intra-acrosomal vesicles were observed. These observations indicate that ESCRT-mediated processes are essential for acrosomal secretion, implicating these multifunctional complexes in an exocytic event crucial for sperm-egg fusion. PMID- 26490838 TI - Genetic and Pharmacological Modulation of Akt1 for Improving Ovarian Graft Revascularization in a Mouse Model. AB - Ovarian tissue cryopreservation and transplantation is one of a few available treatments for fertility preservation in women diagnosed with cancer. Rapid revascularization is essential for reducing hypoxic damage after grafting and protecting the primordial follicles reserve. Using a mouse model of heterotopic ovarian graft transplantation, we have delineated the role of endothelial Akt1 expression using longitudinal magnetic resonance imaging follow-up to quantify angiogenic response. Endothelial Akt1 activation in ovarian grafts promoted angiogenesis to support the graft during posttransplantation hypoxic period. Similarly, simvastatin therapy activated Akt1 at the transplantation site and improved the revascularization and vascular support of ovarian grafts. These results serve as an important first step toward pharmacological intervention to improve revascularization of ovarian grafts and restoration of fertility in cancer survivors. The pro-angiogenic effects reported here may extend beyond improving ovarian graft reception in fertility preservation and could potentially be used for different organ or tissue transplantation. PMID- 26490839 TI - Progesterone Accelerates the Completion of Sperm Capacitation and Activates CatSper Channel in Spermatozoa from the Rhesus Macaque. AB - During transit through the female reproductive tract, mammalian spermatozoa are exposed to increasing concentrations of progesterone (P4) released by the cumulus oophorus. P4 triggers massive calcium influx into human sperm through activation of the sperm-specific calcium channel CatSper. These properties of human spermatozoa are thought to be unique since CatSper is not progesterone sensitive in rodent sperm. Here, by performing patch clamp recording from spermatozoa from rhesus macaque for the first time, we report that they express P4-sensitive CatSper channel identically to human sperm and react to P4 by inducing responsiveness to zona pellucida, unlike human sperm, which respond directly to P4. We have also determined the physiologic levels of P4 capable of inducing capacitation-associated changes in macaque sperm. Progesterone (1 MUM) induced up to a 3-fold increase in the percentage of sperm undergoing the zona pellucida induced acrosome reaction with the lowest threshold as low as 10 nM of P4. Submicromolar levels of P4 induced a dose-dependent increase in curvilinear velocity and lateral head displacement, while sperm protein tyrosine phosphorylation was not altered. Macaque spermatozoa exposed to 10 MUM of P4 developed fully hyperactivated motility. Similar to human sperm, on approaching cumulus mass and binding to zona pellucida, macaque spermatozoa display hyperactivation and undergo an acrosome reaction that coincides with the rise in the sperm intracellular calcium. Taken together, these data indicate that P4 accelerates the completion of capacitation and provides evidence of spermatozoa "priming" as they move into a gradient of progesterone in search for the oocyte. PMID- 26490840 TI - The Extracellular Calcium-Sensing Receptor (CASR) Regulates Gonadotropins-Induced Meiotic Maturation of Porcine Oocytes. AB - Gonadotropins and epidermal growth factor (EGF) play crucial roles in promoting oocyte maturation. The regulatory network downstream of these key factors is not well understood. The present study was designed to investigate the role of the calcium-sensing receptor (CASR) in porcine oocyte in vitro maturation. CASR expression was up-regulated in oocytes matured in gonadotropin-containing medium. Cortical distribution of CASR was enhanced with gonadotropins but not EGF. Supplementation of a CASR agonist (NPS R-568) in the gonadotropin (FSH and/or LH) containing maturation medium significantly enhanced oocyte nuclear maturation. Addition of NPS2390, a CASR antagonist, compromised oocyte nuclear maturation. Furthermore, increased cortical distribution and decreased expression of CASR was observed after the NPS R-568 treatment. Oocytes treated with NPS R-568 had higher concentration of CYCLIN B1, decreased reactive oxygen species, and increased glutathione levels, indicative of advanced cytoplasmic maturation. In contrast, NPS2390 treatment compromised oocyte cytoplasmic maturation. A higher blastocyst formation rate after parthenogenetic activation was observed when oocytes were matured in the presence of the CASR agonist, NPS R-568. MAPK3/1 phosphorylation was increased during in vitro maturation and after NPS R-568 treatment, and decreased following CASR antagonist supplementation. Taken together, our data showed that the CASR is a gonadotropin-regulated factor that promotes porcine oocyte maturation in a MAPK-dependent manner. PMID- 26490842 TI - Lipid Biochemical and Biophysical Changes in Rat Spermatozoa During Isolation and Functional Activation In Vitro. AB - In spermatozoa isolated from rat epididymis, lipids are differentially modified after in vitro induction of capacitation (Cap) and the acrosomal reaction (AR). This study uses Laurdan fluorescence generalized polarization values (GPv) to evaluate the effect of lipid changes occurring after isolation and functional activation on sperm membrane biophysical properties. In gametes isolated in the presence of a divalent cation chelator, no lipid changes occurred and the GPv were the lowest recorded, indicating maximal membrane lipid mobility. In sperm isolated as rapidly and gently as possible in the absence of chelator, part of the sphingomyelins (SM) were converted into ceramides (Cer), giving rise to higher GPv. In samples incubated as controls for Cap and AR, unchanged cholesterol and reduced glycerophospholipid levels were accompanied by the accumulation of free fatty acids (FFA), leading to even higher GPv. After completion of Cap, the GPv returned to lower levels as a result of the spermatozoa losing part of their cholesterol and FFA. Cap samples became relatively enriched in polyunsaturated fatty acids-containing plasmalogens because hydrolysis affected phosphatidyl rather than plasmenyl glycerophospholipid subclasses. The highest Cer:SM ratio and the highest GPv were found after completion of AR induced by A23187. The degree of SM -> Cer conversion among the samples, including controls, correlated with the extent of AR. FFA and Cer augmented GPv when added to liposomes prepared from the membrane lipid of intact sperm. Our results underscore the importance of hydrolytic changes that affect sperm lipids, especially the decisive lipid SM and Cer pair, not only after inducing sperm functional changes such as Cap and AR, but also under control conditions. PMID- 26490841 TI - Disrupting Cyclin Dependent Kinase 1 in Spermatocytes Causes Late Meiotic Arrest and Infertility in Mice. AB - While cyclin dependent kinase 1 (CDK1) has a critical role in controlling resumption of meiosis in oocytes, its role has not been investigated directly in spermatocytes. Unique aspects of male meiosis led us to hypothesize that its role is different in male meiosis than in female meiosis. We generated a conditional knockout (cKO) of the Cdk1 gene in mouse spermatocytes to test this hypothesis. We found that CDK1-null spermatocytes undergo synapsis, chiasmata formation, and desynapsis as is seen in oocytes. Additionally, CDK1-null spermatocytes relocalize SYCP3 to centromeric foci, express H3pSer10, and initiate chromosome condensation. However, CDK1-null spermatocytes fail to form condensed bivalent chromosomes in prophase of meiosis I and instead are arrested at prometaphase. Thus, CDK1 has an essential role in male meiosis that is consistent with what is known about the role of CDK1 in female meiosis, where it is required for formation of condensed bivalent metaphase chromosomes and progression to the first meiotic division. We found that cKO spermatocytes formed fully condensed bivalent chromosomes in the presence of okadaic acid, suggesting that cKO chromosomes are competent to condense, although they do not do so in vivo. Additionally, arrested cKO spermatocytes exhibited irregular cell shape, irregular large nuclei, and large distinctive nucleoli. These cells persist in the seminiferous epithelium through the next seminiferous epithelial cycle with a lack of stage XII checkpoint-associated cell death. This indicates that CDK1 is required upstream of a checkpoint-associated cell death as well as meiotic metaphase progression in mouse spermatocytes. PMID- 26490843 TI - Bisphenol A and Related Alkylphenols Exert Nongenomic Estrogenic Actions Through a G Protein-Coupled Estrogen Receptor 1 (Gper)/Epidermal Growth Factor Receptor (Egfr) Pathway to Inhibit Meiotic Maturation of Zebrafish Oocytes. AB - Xenobiotic estrogens, such as bisphenol A (BPA), disrupt a wide variety of genomic estrogen actions, but their nongenomic estrogen actions remain poorly understood. We investigated nongenomic estrogenic effects of low concentrations of BPA and three related alkylphenols on the inhibition of zebrafish oocye maturation (OM) mediated through a G protein-coupled estrogen receptor 1 (Gper) dependent epidermal growth factor receptor (Egfr) pathway. BPA (10-100 nM) treatment for 3 h mimicked the effects of estradiol-17beta (E2) and EGF, decreasing spontaneous maturation of defolliculated zebrafish oocytes, an effect not blocked by coincubation with actinomycin D, but blocked by coincubation with a Gper antibody. BPA displayed relatively high binding affinity (15.8% that of E2) for recombinant zebrafish Gper. The inhibitory effects of BPA were attenuated by inhibition of upstream regulators of Egfr, intracellular tyrosine kinase (Src) with PP2, and matrix metalloproteinase with ilomastat. Treatment with an inhibitor of Egfr transactivation, AG1478, and an inhibitor of the mitogen activated protein kinase (MAPK) 3/1 pathway, U0126, increased spontaneous OM and blocked the inhibitory effects of BPA, E2, and the selective GPER agonist, G-1. Western blot analysis showed that BPA (10-200 nM) mimicked the stimulatory effects of E2 and EGF on Mapk3/1 phosphorylation. Tetrabromobisphenol A, 4 nonylphenol, and tetrachlorobisphenol A (5-100 nM) also inhibited OM, an effect blocked by cotreatment with AG1478, as well as with the GPER antagonist, G-15, and displayed similar binding affinities as BPA to zebrafish Gper. The results suggest that BPA and related alkylphenols disrupt zebrafish OM by a novel nongenomic estrogenic mechanism involving activation of the Gper/Egfr/Mapk3/1 pathway. PMID- 26490844 TI - Internet cigarette vendors make tax-free claims and sell cigarettes cheaper than retail outlets. AB - OBJECTIVE: This paper aims to (1) assess whether promotion of tax-free sales among Internet cigarette vendors (ICVs) changed between 2009 and 2011, (2) determine which types of ICVs are most likely to promote tax-free sales (eg, US based, international or mixed location ICVs), and (3) compare the price of cigarettes advertised in ICVs to prices at brick-and-mortar retail outlets. METHODS: We analysed data from the 200 most popular ICVs in 2009, 2010 and 2011 to assess promotion of tax-free sales and the price of Marlboro cigarette cartons. We used Nielsen scanner data from 2009, 2010 and 2011 to measure the price of Marlboro cartons in US grocery stores. FINDINGS: The odds of ICVs claiming tax-free status were higher in 2011 than in 2009 (OR=1.58, p<0.01). Mixed location and international vendors had higher odds of promoting tax-free sales than US-based ICVs (OR=4.95 and 6.23, respectively, both p<0.001). In 2011, the average price of one Marlboro carton was $35.27 online, compared to $52.73 in US grocery stores. We estimated that in 2011, a pack-a-day smoker living in an area with high cigarette prices would save $1508 per year buying cigarettes online. CONCLUSIONS: ICVs commonly promote tax-free sales, and cigarettes are cheaper online compared to US grocery stores. Better enforcement of the Prevent All Cigarette Trafficking Act is needed to address tax-free cigarette sales among ICVs. PMID- 26490845 TI - Consumer preferences for electronic cigarettes: results from a discrete choice experiment. AB - INTRODUCTION: E-cigarettes present a formidable challenge to regulators given their variety and the rapidly evolving nicotine market. The current study sought to examine the influence of e-cigarette product characteristics on consumer perceptions and trial intentions among Canadians. METHODS: An online discrete choice experiment was conducted with 915 Canadians aged 16 years and older in November 2013. An online commercial panel was used to sample 3 distinct subpopulations: (1) non-smoking youth and young adults (n=279); (2) smoking youth and young adults (n=264) and (3) smoking adults (n=372). Participants completed a series of stated-preference tasks, in which they viewed choice sets with e cigarette product images that featured different combinations of attributes: flavour, nicotine content, health warnings and price. For each choice set, participants were asked to select one of the products or indicate 'none of the above' with respect to the following outcomes: interest in trying, less harm and usefulness in quitting smoking. The attributes' impact on consumer choice for each outcome was analysed using multinomial logit regression. RESULTS: Health warning was the most important attribute influencing participants' intentions to try e-cigarettes (42%) and perceived efficacy as a quit aid (39%). Both flavour (36%) and health warnings (35%) significantly predicted perceptions of product harm. CONCLUSIONS: The findings indicate that consumers make trade-offs with respect to e-cigarette product characteristics, and that these trade-offs vary across different subpopulations. Given that health warnings and flavour were weighted most important by consumers in this study, these may represent good targets for e-cigarette regulatory frameworks. PMID- 26490846 TI - Oral cavity squamous cell carcinoma metastatic to central compartment (level 6) lymph nodes. AB - Alterations to drainage pathways in the head and neck as a result of surgical manipulation are not well understood. We present two unusual cases of oral squamous cell carcinoma metastatic to the level 6 nodal compartment following extensive treatment. Both oral squamous cell carcinoma cases exhibited metastases to the central neck compartment following extensive surgery and radiation. Each patient had prior history of multifocal oral cavity disease and recurrent neck metastases requiring salvage lymphadenectomy. Surgical interventions may alter the usual lymphatic drainage patterns. In cases of extensive treatment, all levels of the neck should be monitored for lymph node recurrence. Laryngoscope, 126:1803-1805, 2016. PMID- 26490847 TI - Low to moderate quality evidence demonstrates the potential benefits and adverse events of cannabinoids for certain medical indications. PMID- 26490848 TI - Intra-arterial thrombectomy improves functional outcome when administered up to 6 h after stroke. PMID- 26490849 TI - Longer dual antiplatelet therapy (DAPT) after percutaneous coronary intervention has higher anti-ischaemic efficacy than shorter DAPT but is associated with more frequent bleeding. PMID- 26490851 TI - Human Frontal-Subcortical Circuit and Asymmetric Belief Updating. AB - How humans integrate information to form beliefs about reality is a question that has engaged scientists for centuries, yet the biological system supporting this process is not well understood. One of the most salient attributes of information is valence. Whether a piece of news is good or bad is critical in determining whether it will alter our beliefs. Here, we reveal a frontal-subcortical circuit in the left hemisphere that is simultaneously associated with enhanced integration of favorable information into beliefs and impaired integration of unfavorable information. Specifically, for favorable information, stronger white matter connectivity within this system, particularly between the left inferior frontal gyrus (IFG) and left subcortical regions (including the amygdala, hippocampus, thalamus, putamen, and pallidum), as well as insular cortex, is associated with greater change in belief. However, for unfavorable information, stronger connectivity within this system, particularly between the left IFG and left pallidum, putamen, and insular cortex, is associated with reduced change in beliefs. These novel results are consistent with models suggesting that partially separable processes govern learning from favorable and unfavorable information. SIGNIFICANCE STATEMENT: Beliefs of what may happen in the future are important, because they guide decisions and actions. Here, we illuminate how structural brain connectivity is related to the generation of subjective beliefs. We focus on how the valence of information is related to people's tendency to alter their beliefs. By quantifying the extent to which participants update their beliefs in response to desirable and undesirable information and relating those measures to the strength of white matter connectivity using diffusion tensor imaging, we characterize a left frontal-subcortical system that is associated simultaneously with greater belief updating in response to favorable information and reduced belief updating in response to unfavorable information. This neural architecture may allow valence to be incorporated into belief updating. PMID- 26490852 TI - CaMKII Controls Whether Touch Is Painful. AB - The sensation of touch is initiated when fast conducting low-threshold mechanoreceptors (Abeta-LTMRs) generate impulses at their terminals in the skin. Plasticity in this system is evident in the process of adaption, in which a period of diminished sensitivity follows prior stimulation. CaMKII is an ideal candidate for mediating activity-dependent plasticity in touch because it shifts into an enhanced activation state after neuronal depolarizations and can thereby reflect past firing history. Here we show that sensory neuron CaMKII autophosphorylation encodes the level of Abeta-LTMR activity in rat models of sensory deprivation (whisker clipping, tail suspension, casting). Blockade of CaMKII signaling limits normal adaptation of action potential generation in Abeta LTMRs in excised skin. CaMKII activity is also required for natural filtering of impulse trains as they travel through the sensory neuron T-junction in the DRG. Blockade of CaMKII selectively in presynaptic Abeta-LTMRs removes dorsal horn inhibition that otherwise prevents Abeta-LTMR input from activating nociceptive lamina I neurons. Together, these consequences of reduced CaMKII function in Abeta-LTMRs cause low-intensity mechanical stimulation to produce pain behavior. We conclude that, without normal sensory activity to maintain adequate levels of CaMKII function, the touch pathway shifts into a pain system. In the clinical setting, sensory disuse may be a critical factor that enhances and prolongs chronic pain initiated by other conditions. SIGNIFICANCE STATEMENT: The sensation of touch is served by specialized sensory neurons termed low-threshold mechanoreceptors (LTMRs). We examined the role of CaMKII in regulating the function of these neurons. Loss of CaMKII function, such as occurred in rats during sensory deprivation, elevated the generation and propagation of impulses by LTMRs, and altered the spinal cord circuitry in such a way that low-threshold mechanical stimuli produced pain behavior. Because limbs are protected from use during a painful condition, this sensitization of LTMRs may perpetuate pain and prevent functional rehabilitation. PMID- 26490853 TI - Rapid Feedforward Inhibition and Asynchronous Excitation Regulate Granule Cell Activity in the Mammalian Main Olfactory Bulb. AB - Granule cell-mediated inhibition is critical to patterning principal neuron activity in the olfactory bulb, and perturbation of synaptic input to granule cells significantly alters olfactory-guided behavior. Despite the critical role of granule cells in olfaction, little is known about how sensory input recruits granule cells. Here, we combined whole-cell patch-clamp electrophysiology in acute mouse olfactory bulb slices with biophysical multicompartmental modeling to investigate the synaptic basis of granule cell recruitment. Physiological activation of sensory afferents within single glomeruli evoked diverse modes of granule cell activity, including subthreshold depolarization, spikelets, and suprathreshold responses with widely distributed spike latencies. The generation of these diverse activity modes depended, in part, on the asynchronous time course of synaptic excitation onto granule cells, which lasted several hundred milliseconds. In addition to asynchronous excitation, each granule cell also received synchronous feedforward inhibition. This inhibition targeted both proximal somatodendritic and distal apical dendritic domains of granule cells, was reliably recruited across sniff rhythms, and scaled in strength with excitation as more glomeruli were activated. Feedforward inhibition onto granule cells originated from deep short-axon cells, which responded to glomerular activation with highly reliable, short-latency firing consistent with tufted cell mediated excitation. Simulations showed that feedforward inhibition interacts with asynchronous excitation to broaden granule cell spike latency distributions and significantly attenuates granule cell depolarization within local subcellular compartments. Collectively, our results thus identify feedforward inhibition onto granule cells as a core feature of olfactory bulb circuitry and establish asynchronous excitation and feedforward inhibition as critical regulators of granule cell activity. SIGNIFICANCE STATEMENT: Inhibitory granule cells are involved critically in shaping odor-evoked principal neuron activity in the mammalian olfactory bulb, yet little is known about how sensory input activates granule cells. Here, we show that sensory input to the olfactory bulb evokes a barrage of asynchronous synaptic excitation and highly reliable, short-latency synaptic inhibition onto granule cells via a disynaptic feedforward inhibitory circuit involving deep short-axon cells. Feedforward inhibition attenuates local depolarization within granule cell dendritic branches, interacts with asynchronous excitation to suppress granule cell spike-timing precision, and scales in strength with excitation across different levels of sensory input to normalize granule cell firing rates. PMID- 26490854 TI - Hippocampal Volume Reduction in Humans Predicts Impaired Allocentric Spatial Memory in Virtual-Reality Navigation. AB - The extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated allocentric spatial recall using a virtual environment in a group of patients with severe hippocampal damage (SHD), a group of patients with "moderate" hippocampal damage (MHD), and a normal control group. Through four learning blocks with feedback, participants learned the target locations of four different objects in a circular arena. Distal cues were present throughout the experiment to provide orientation. A circular boundary as well as an intra-arena landmark provided spatial reference frames. During a subsequent test phase, recall of all four objects was tested with only the boundary or the landmark being present. Patients with SHD were impaired in both phases of this task. Across groups, performance on both types of spatial recall was highly correlated with memory quotient (MQ), but not with intelligence quotient (IQ), age, or sex. However, both measures of spatial recall separated experimental groups beyond what would be expected based on MQ, a widely used measure of general memory function. Boundary-based and landmark-based spatial recall were both strongly related to bilateral hippocampal volumes, but not to volumes of the thalamus, putamen, pallidum, nucleus accumbens, or caudate nucleus. The results show that boundary-based and landmark-based allocentric spatial recall are similarly impaired in patients with SHD, that both types of recall are impaired beyond that predicted by MQ, and that recall deficits are best explained by a reduction in bilateral hippocampal volumes. SIGNIFICANCE STATEMENT: In humans, bilateral hippocampal atrophy can lead to profound impairments in episodic memory. Across species, perhaps the most well-established contribution of the hippocampus to memory is not to episodic memory generally but to allocentric spatial memory. However, the extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated spatial recall using a virtual environment in two groups of patients with hippocampal damage (moderate/severe) and a normal control group. The results showed that patients with severe hippocampal damage are impaired in learning and recalling allocentric spatial information. Furthermore, hippocampal volume reduction impaired allocentric navigation beyond what can be predicted by memory quotient as a widely used measure of general memory function. PMID- 26490855 TI - The Periaqueductal Gray Orchestrates Sensory and Motor Circuits at Multiple Levels of the Neuraxis. AB - The periaqueductal gray (PAG) coordinates behaviors essential to survival, including striking changes in movement and posture (e.g., escape behaviors in response to noxious stimuli vs freezing in response to fear-evoking stimuli). However, the neural circuits underlying the expression of these behaviors remain poorly understood. We demonstrate in vivo in rats that activation of the ventrolateral PAG (vlPAG) affects motor systems at multiple levels of the neuraxis through the following: (1) differential control of spinal neurons that forward sensory information to the cerebellum via spino-olivo-cerebellar pathways (nociceptive signals are reduced while proprioceptive signals are enhanced); (2) alterations in cerebellar nuclear output as revealed by changes in expression of Fos-like immunoreactivity; and (3) regulation of spinal reflex circuits, as shown by an increase in alpha-motoneuron excitability. The capacity to coordinate sensory and motor functions is demonstrated in awake, behaving rats, in which natural activation of the vlPAG in fear-conditioned animals reduced transmission in spino-olivo-cerebellar pathways during periods of freezing that were associated with increased muscle tone and thus motor outflow. The increase in spinal motor reflex excitability and reduction in transmission of ascending sensory signals via spino-olivo-cerebellar pathways occurred simultaneously. We suggest that the interactions revealed in the present study between the vlPAG and sensorimotor circuits could form the neural substrate for survival behaviors associated with vlPAG activation. SIGNIFICANCE STATEMENT: Neural circuits that coordinate survival behaviors remain poorly understood. We demonstrate in rats that the periaqueductal gray (PAG) affects motor systems at the following multiple levels of the neuraxis: (1) through altering transmission in spino olivary pathways that forward sensory signals to the cerebellum, reducing and enhancing transmission of nociceptive and proprioceptive information, respectively; (2) by alterations in cerebellar output; and (3) through enhancement of spinal motor reflex pathways. The sensory and motor effects occurred at the same time and were present in both anesthetized animals and behavioral experiments in which fear conditioning naturally activated the PAG. The results provide insights into the neural circuits that enable an animal to be ready and able to react to danger, thus assisting in survival. PMID- 26490857 TI - Decoding Internally and Externally Driven Movement Plans. AB - During movement planning, brain activity within parietofrontal networks encodes information about upcoming actions that can be driven either externally (e.g., by a sensory cue) or internally (i.e., by a choice/decision). Here we used multivariate pattern analysis (MVPA) of fMRI data to distinguish between areas that represent (1) abstract movement plans that generalize across the way in which these were driven, (2) internally driven movement plans, or (3) externally driven movement plans. In a delayed-movement paradigm, human volunteers were asked to plan and execute three types of nonvisually guided right-handed reaching movements toward a central target object: using a precision grip, a power grip, or touching the object without hand preshaping. On separate blocks of trials, movements were either instructed via color cues (Instructed condition), or chosen by the participant (Free-Choice condition). Using ROI-based and whole-brain searchlight-based MVPA, we found abstract representations of planned movements that generalize across the way these movements are selected (internally vs externally driven) in parietal cortex, dorsal premotor cortex, and primary motor cortex contralateral to the acting hand. In addition, we revealed representations specific for internally driven movement plans in contralateral ventral premotor cortex, dorsolateral prefrontal cortex, supramarginal gyrus, and in ipsilateral posterior parietotemporal regions, suggesting that these regions are recruited during movement selection. Finally, we observed representations of externally driven movement plans in bilateral supplementary motor cortex and a similar trend in presupplementary motor cortex, suggesting a role in stimulus-response mapping. SIGNIFICANCE STATEMENT: The way the human brain prepares the body for action constitutes an essential part of our ability to interact with our environment. Previous studies demonstrated that patterns of neuronal activity encode upcoming movements. Here we used multivariate pattern analysis of human fMRI data to distinguish between brain regions containing movement plans for instructed (externally driven) movements, areas involved in movement selection (internally driven), and areas containing abstract movement plans that are invariant to the way these were generated (i.e., that generalize across externally and internally driven movement plans). Our findings extend our understanding of the neural basis of movement planning and have the potential to contribute to the development of brain-controlled neural prosthetic devices. PMID- 26490856 TI - There Is a "U" in Clutter: Evidence for Robust Sparse Codes Underlying Clutter Tolerance in Human Vision. AB - The ability to recognize objects in clutter is crucial for human vision, yet the underlying neural computations remain poorly understood. Previous single-unit electrophysiology recordings in inferotemporal cortex in monkeys and fMRI studies of object-selective cortex in humans have shown that the responses to pairs of objects can sometimes be well described as a weighted average of the responses to the constituent objects. Yet, from a computational standpoint, it is not clear how the challenge of object recognition in clutter can be solved if downstream areas must disentangle the identity of an unknown number of individual objects from the confounded average neuronal responses. An alternative idea is that recognition is based on a subpopulation of neurons that are robust to clutter, i.e., that do not show response averaging, but rather robust object-selective responses in the presence of clutter. Here we show that simulations using the HMAX model of object recognition in cortex can fit the aforementioned single-unit and fMRI data, showing that the averaging-like responses can be understood as the result of responses of object-selective neurons to suboptimal stimuli. Moreover, the model shows how object recognition can be achieved by a sparse readout of neurons whose selectivity is robust to clutter. Finally, the model provides a novel prediction about human object recognition performance, namely, that target recognition ability should show a U-shaped dependency on the similarity of simultaneously presented clutter objects. This prediction is confirmed experimentally, supporting a simple, unifying model of how the brain performs object recognition in clutter. SIGNIFICANCE STATEMENT: The neural mechanisms underlying object recognition in cluttered scenes (i.e., containing more than one object) remain poorly understood. Studies have suggested that neural responses to multiple objects correspond to an average of the responses to the constituent objects. Yet, it is unclear how the identities of an unknown number of objects could be disentangled from a confounded average response. Here, we use a popular computational biological vision model to show that averaging-like responses can result from responses of clutter-tolerant neurons to suboptimal stimuli. The model also provides a novel prediction, that human detection ability should show a U-shaped dependency on target-clutter similarity, which is confirmed experimentally, supporting a simple, unifying account of how the brain performs object recognition in clutter. PMID- 26490858 TI - A Post-Docking Role of Synaptotagmin 1-C2B Domain Bottom Residues R398/399 in Mouse Chromaffin Cells. AB - Synaptotagmin-1 (Syt1) is the principal Ca(2+) sensor for vesicle fusion and is also essential for vesicle docking in chromaffin cells. Docking depends on interactions of the Syt1-C2B domain with the t-SNARE SNAP25/Syntaxin1 complex and/or plasma membrane phospholipids. Here, we investigated the role of the positively charged "bottom" region of the C2B domain, proposed to help crosslink membranes, in vesicle docking and secretion in mouse chromaffin cells and in cell free assays. We expressed a double mutation shown previously to interfere with lipid mixing between proteoliposomes and with synaptic transmission, Syt1 R398/399Q (RQ), in syt1 null mutant cells. Ultrastructural morphometry revealed that Syt1-RQ fully restored the docking defect observed previously in syt1 null mutant cells, similar to wild type Syt1 (Syt1-wt). Small unilamellar lipid vesicles (SUVs) that contained the v-SNARE Synaptobrevin2 and Syt1-R398/399Q also docked to t-SNARE-containing giant vesicles (GUVs), similar to Syt1-wt. However, unlike Syt1-wt, Syt1-RQ-induced docking was strictly PI(4,5)P2-dependent. Unlike docking, neither synchronized secretion in chromaffin cells nor Ca(2+)-triggered SUV-GUV fusion was restored by the Syt1 mutants. Finally, overexpressing the RQ mutant in wild type cells produced no effect on either docking or secretion. We conclude that the positively charged bottom region in the C2B domain--and, by inference, Syt1-mediated membrane crosslinking--is required for triggering fusion, but not for docking. Secretory vesicles dock by multiple, PI(4,5)P2 dependent and PI(4,5)P2-independent mechanisms. The R398/399 mutations selectively disrupt the latter and hereby help to discriminate protein regions involved in different aspects of Syt1 function in docking and fusion. SIGNIFICANCE STATEMENT: This study provides new insights in how the two opposite sides of the C2B domain of Synaptotagmin-1 participate in secretory vesicle fusion, and in more upstream steps, especially vesicle docking. We show that the "bottom" surface of the C2B domain is required for triggering fusion, but not for docking. Synaptotagmin-1 promotes docking by multiple, PI(4,5)P2-dependent and PI(4,5)P2-independent mechanisms. Mutations in the C2B bottom surface (R398/399) selectively disrupt the latter. These mutations help to discriminate protein regions involved in different aspects of Synaptotagmin-1 function in docking and fusion. PMID- 26490860 TI - Congruent Visual Speech Enhances Cortical Entrainment to Continuous Auditory Speech in Noise-Free Conditions. AB - Congruent audiovisual speech enhances our ability to comprehend a speaker, even in noise-free conditions. When incongruent auditory and visual information is presented concurrently, it can hinder a listener's perception and even cause him or her to perceive information that was not presented in either modality. Efforts to investigate the neural basis of these effects have often focused on the special case of discrete audiovisual syllables that are spatially and temporally congruent, with less work done on the case of natural, continuous speech. Recent electrophysiological studies have demonstrated that cortical response measures to continuous auditory speech can be easily obtained using multivariate analysis methods. Here, we apply such methods to the case of audiovisual speech and, importantly, present a novel framework for indexing multisensory integration in the context of continuous speech. Specifically, we examine how the temporal and contextual congruency of ongoing audiovisual speech affects the cortical encoding of the speech envelope in humans using electroencephalography. We demonstrate that the cortical representation of the speech envelope is enhanced by the presentation of congruent audiovisual speech in noise-free conditions. Furthermore, we show that this is likely attributable to the contribution of neural generators that are not particularly active during unimodal stimulation and that it is most prominent at the temporal scale corresponding to syllabic rate (2-6 Hz). Finally, our data suggest that neural entrainment to the speech envelope is inhibited when the auditory and visual streams are incongruent both temporally and contextually. SIGNIFICANCE STATEMENT: Seeing a speaker's face as he or she talks can greatly help in understanding what the speaker is saying. This is because the speaker's facial movements relay information about what the speaker is saying, but also, importantly, when the speaker is saying it. Studying how the brain uses this timing relationship to combine information from continuous auditory and visual speech has traditionally been methodologically difficult. Here we introduce a new approach for doing this using relatively inexpensive and noninvasive scalp recordings. Specifically, we show that the brain's representation of auditory speech is enhanced when the accompanying visual speech signal shares the same timing. Furthermore, we show that this enhancement is most pronounced at a time scale that corresponds to mean syllable length. PMID- 26490859 TI - Multifunctional and Context-Dependent Control of Vocal Acoustics by Individual Muscles. AB - The relationship between muscle activity and behavioral output determines how the brain controls and modifies complex skills. In vocal control, ensembles of muscles are used to precisely tune single acoustic parameters such as fundamental frequency and sound amplitude. If individual vocal muscles were dedicated to the control of single parameters, then the brain could control each parameter independently by modulating the appropriate muscle or muscles. Alternatively, if each muscle influenced multiple parameters, a more complex control strategy would be required to selectively modulate a single parameter. Additionally, it is unknown whether the function of single muscles is fixed or varies across different vocal gestures. A fixed relationship would allow the brain to use the same changes in muscle activation to, for example, increase the fundamental frequency of different vocal gestures, whereas a context-dependent scheme would require the brain to calculate different motor modifications in each case. We tested the hypothesis that single muscles control multiple acoustic parameters and that the function of single muscles varies across gestures using three complementary approaches. First, we recorded electromyographic data from vocal muscles in singing Bengalese finches. Second, we electrically perturbed the activity of single muscles during song. Third, we developed an ex vivo technique to analyze the biomechanical and acoustic consequences of single-muscle perturbations. We found that single muscles drive changes in multiple parameters and that the function of single muscles differs across vocal gestures, suggesting that the brain uses a complex, gesture-dependent control scheme to regulate vocal output. PMID- 26490861 TI - Frizzled3 Controls Axonal Polarity and Intermediate Target Entry during Striatal Pathway Development. AB - The striatum is a large brain nucleus with an important role in the control of movement and emotions. Medium spiny neurons (MSNs) are striatal output neurons forming prominent descending axon tracts that target different brain nuclei. However, how MSN axon tracts in the forebrain develop remains poorly understood. Here, we implicate the Wnt binding receptor Frizzled3 in several uncharacterized aspects of MSN pathway formation [i.e., anterior-posterior guidance of MSN axons in the striatum and their subsequent growth into the globus pallidus (GP), an important (intermediate) target]. In Frizzled3 knock-out mice, MSN axons fail to extend along the anterior-posterior axis of the striatum, and many do not reach the GP. Wnt5a acts as an attractant for MSN axons in vitro, is expressed in a posterior high, anterior low gradient in the striatum, and Wnt5a knock-out mice phenocopy striatal anterior-posterior defects observed in Frizzled3 mutants. This suggests that Wnt5a controls anterior-posterior guidance of MSN axons through Frizzled3. Axons that reach the GP in Frizzled3 knock-out mice fail to enter this structure. Surprisingly, entry of MSN axons into the GP non-cell-autonomously requires Frizzled3, and our data suggest that GP entry may be contingent on the correct positioning of "corridor" guidepost cells for thalamocortical axons by Frizzled3. Together, these data dissect MSN pathway development and reveal (non)cell-autonomous roles for Frizzled3 in MSN axon guidance. Further, they are the first to identify a gene that provides anterior-posterior axon guidance in a large brain nucleus and link Frizzled3 to corridor cell development. SIGNIFICANCE STATEMENT: Striatal axon pathways mediate complex physiological functions and are an important therapeutic target, underscoring the need to define how these connections are established. Remarkably, the molecular programs regulating striatal pathway development remain poorly characterized. Here, we determine the embryonic ontogeny of the two main striatal pathways (striatonigral and striatopallidal) and identify novel (non)cell-autonomous roles for the axon guidance receptor Frizzled3 in uncharacterized aspects of striatal pathway formation (i.e., anterior-posterior axon guidance in the striatum and axon entry into the globus pallidus). Further, our results link Frizzled3 to corridor guidepost cell development and suggest that an abnormal distribution of these cells has unexpected, widespread effects on the development of different axon tracts (i.e., striatal and thalamocortical axons). PMID- 26490863 TI - Internalized Tau Oligomers Cause Neurodegeneration by Inducing Accumulation of Pathogenic Tau in Human Neurons Derived from Induced Pluripotent Stem Cells. AB - Neuronal inclusions of hyperphosphorylated and aggregated tau protein are a pathological hallmark of several neurodegenerative tauopathies, including Alzheimer's disease (AD). The hypothesis of tau transmission in AD has emerged from histopathological studies of the spatial and temporal progression of tau pathology in postmortem patient brains. Increasing evidence in cellular and animal models supports the phenomenon of intercellular spreading of tau. However, the molecular and cellular mechanisms of pathogenic tau transmission remain unknown. The studies described herein investigate tau pathology propagation using human neurons derived from induced pluripotent stem cells. Neurons were seeded with full-length human tau monomers and oligomers and chronic effects on neuronal viability and function were examined over time. Tau oligomer-treated neurons exhibited an increase in aggregated and phosphorylated pathological tau. These effects were associated with neurite retraction, loss of synapses, aberrant calcium homeostasis, and imbalanced neurotransmitter release. In contrast, tau monomer treatment did not produce any measureable changes. This work supports the hypothesis that tau oligomers are toxic species that can drive the spread of tau pathology and neurodegeneration. SIGNIFICANCE STATEMENT: Several independent studies have implicated tau protein as central to Alzheimer's disease progression and cell-to-cell pathology propagation. In this study, we investigated the ability of different tau species to propagate pathology in human neurons derived from induced pluripotent stem cells, which to date has not been shown. We demonstrated that tau oligomers, but not monomers, induce accumulation of pathological, hyperphosphorylated tau. This effect was accompanied with neurite degeneration, loss of synapses, aberrant calcium homeostasis, imbalanced neurotransmitter release, and ultimately with neuronal death. This study bridges various tau pathological phenotypes into a single and relevant induced pluripotent stem cell neuronal model of human disease that can be applied to the discovery of the mechanisms of tau-induced neurodegeneration. PMID- 26490862 TI - Distinct Contributions of Ventromedial and Dorsolateral Subregions of the Human Substantia Nigra to Appetitive and Aversive Learning. AB - The role of neurons in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain in contributing to the elicitation of reward prediction errors during appetitive learning has been well established. Less is known about the differential contribution of these midbrain regions to appetitive versus aversive learning, especially in humans. Here we scanned human participants with high resolution fMRI focused on the SN and VTA while they participated in a sequential Pavlovian conditioning paradigm involving an appetitive outcome (a pleasant juice), as well as an aversive outcome (an unpleasant bitter and salty flavor). We found a degree of regional specialization within the SN: Whereas a region of ventromedial SN correlated with a temporal difference reward prediction error during appetitive Pavlovian learning, a dorsolateral area correlated instead with an aversive expected value signal in response to the most distal cue, and to a reward prediction error in response to the most proximal cue to the aversive outcome. Furthermore, participants' affective reactions to both the appetitive and aversive conditioned stimuli more than 1 year after the fMRI experiment was conducted correlated with activation in the ventromedial and dorsolateral SN obtained during the experiment, respectively. These findings suggest that, whereas the human ventromedial SN contributes to long-term learning about rewards, the dorsolateral SN may be particularly important for long-term learning in aversive contexts. SIGNIFICANCE STATEMENT: The role of the substantia nigra (SN) and ventral tegmental area (VTA) in appetitive learning is well established, but less is known about their contribution to aversive compared with appetitive learning, especially in humans. We used high-resolution fMRI to measure activity in the SN and VTA while participants underwent higher-order Pavlovian learning. We found a regional specialization within the SN: a ventromedial area was selectively engaged during appetitive learning, and a dorsolateral area during aversive learning. Activity in these areas predicted affective reactions to appetitive and aversive conditioned stimuli over 1 year later. These findings suggest that, whereas the human ventromedial SN contributes to long-term learning about rewards, the dorsolateral SN may be particularly important for long-term learning in aversive contexts. PMID- 26490864 TI - The Kruppel-Like Factor Dar1 Determines Multipolar Neuron Morphology. AB - Neurons typically assume multipolar, bipolar, or unipolar morphologies. Little is known about the mechanisms underlying the development of these basic morphological types. Here, we show that the Kruppel-like transcription factor Dar1 determines the multipolar morphology of postmitotic neurons in Drosophila. Dar1 is specifically expressed in multipolar neurons and loss of dar1 gradually converts multipolar neurons into the bipolar or unipolar morphology without changing neuronal identity. Conversely, misexpression of Dar1 or its mammalian homolog in unipolar and bipolar neurons causes them to assume multipolar morphologies. Dar1 regulates the expression of several dynein genes and nuclear distribution protein C (nudC), which is an essential component of a specialized dynein complex that positions the nucleus in a cell. We further show that these genes are required for Dar1-induced multipolar neuron morphology. Dar1 likely functions as a terminal selector gene for the basic layout of neuron morphology by regulating both dendrite extension and the dendrite-nucleus coupling. SIGNIFICANCE STATEMENT: The three basic morphological types of neurons--unipolar, bipolar, and multipolar--are important for information processing and wiring of neural circuits. Little progress has been made toward understanding the molecular and cellular programs that generate these types since their discovery over a century ago. It is generally assumed that basic morphological types of neurons are determined by the number of dendrites growing out from the cell body. Here, we show that this model alone is insufficient. We introduce the positioning of nucleus as a critical factor in this process and report that the transcription factor Dar1 determines multipolar neuron morphology in postmitotic neurons by regulating genes involved in nuclear positioning. PMID- 26490865 TI - Influence of Tinnitus on Auditory Spectral and Temporal Resolution and Speech Perception in Tinnitus Patients. AB - Although cochlear damage is believed to trigger the perception of tinnitus in the central auditory system, its pathophysiological mechanism is still unclear. We aimed to investigate the pathophysiology of tinnitus using psychoacoustic assessments of auditory spectral and temporal resolution and speech perception in noise. Human subjects with tinnitus and symmetric hearing thresholds were divided into three groups: nine unilateral tinnitus subjects with normal hearing thresholds (Group 1), 12 unilateral tinnitus subjects with hearing loss (HL; Group 2), and nine bilateral tinnitus subjects with HL. Fifteen normal-hearing subjects without tinnitus were also tested as a control group. Four different tests were administered: (1) the spectral-ripple discrimination (SRD) test, (2) the temporal modulation detection (TMD) test, (3) the Schroeder-phase discrimination (SPD) test, and (4) the speech recognition threshold (SRT) in noise test. There were no significant differences in SRD, TMD, and SPD between the tinnitus-affected ears (TEs) and non-tinnitus ears (NTEs) in Groups 1 and 2 (p > 0.05). In contrast, the TEs showed poorer SRTs than the NTEs in these two subject groups (p = 0.022 and 0.049). No inferiority of spectral/temporal resolution in TEs compared with NTEs suggests that there may be no more outer hair cell (OHC) damage on the tinnitus side given that damaged OHCs are associated with broadening the auditory filters. The decoupling of the SRT results from the spectral/temporal resolution data could imply that the occurrence of tinnitus does not depend upon the degree of damage to the OHCs, but rather upon different plastic changes in the central auditory system after cochlear damage. SIGNIFICANCE STATEMENT: We can easily find unilateral tinnitus patients who have symmetric hearing thresholds. Our research question was what kind of difference would be responsible for the tinnitus in the tinnitus-affected ears but not in the non-tinnitus ears of subjects with symmetric hearing thresholds. The answer to this fundamental question could help us to understand the pathophysiology of tinnitus. We evaluated the potential influence of tinnitus upon the subjects' auditory spectral and temporal resolution and speech perception in noise by comparing these psychoacoustic performances between tinnitus-affected ears and non-tinnitus ears in the same subjects. PMID- 26490866 TI - Predator Stress-Induced CRF Release Causes Enduring Sensitization of Basolateral Amygdala Norepinephrine Systems that Promote PTSD-Like Startle Abnormalities. AB - The neurobiology of post-traumatic stress disorder (PTSD) remains unclear. Intense stress promotes PTSD, which has been associated with exaggerated startle and deficient sensorimotor gating. Here, we examined the long-term sequelae of a rodent model of traumatic stress (repeated predator exposure) on amygdala systems that modulate startle and prepulse inhibition (PPI), an operational measure of sensorimotor gating. We show in rodents that repeated psychogenic stress (predator) induces long-lasting sensitization of basolateral amygdala (BLA) noradrenergic (NE) receptors (alpha1) via a corticotropin-releasing factor receptor 1 (CRF-R1)-dependent mechanism, and that these CRF1 and NE alpha1 receptors are highly colocalized on presumptive excitatory output projection neurons of the BLA. A profile identical to that seen with predator exposure was produced in nonstressed rats by intra-BLA infusions of CRF (200 ng/0.5 MUl), but not by repeated NE infusions (20 MUg/0.5 MUl). Infusions into the adjacent central nucleus of amygdala had no effect. Importantly, the predator stress- or CRF-induced sensitization of BLA manifested as heightened startle and PPI deficits in response to subsequent subthreshold NE system challenges (with intra BLA infusions of 0.3 MUg/0.5 MUl NE), up to 1 month after stress. This profile of effects closely resembles aspects of PTSD. Hence, we reveal a discrete neural pathway mediating the enhancement of NE system function seen in PTSD, and we offer a model for characterizing potential new treatments that may work by modulating this BLA circuitry. SIGNIFICANCE STATEMENT: The present findings reveal a novel and discrete neural substrate that could underlie certain core deficits (startle and prepulse inhibition) that are observed in post-traumatic stress disorder (PTSD). It is shown here that repeated exposure to a rodent model of traumatic stress (predator exposure) produces a long-lasting sensitization of basolateral amygdala noradrenergic substrates [via a corticotropin-releasing factor (CRF)-dependent mechanism] that regulate startle, which is exaggerated in PTSD. Moreover, it is demonstrated that the sensitized noradrenergic receptors colocalize with CRF1 receptors on output projection neurons of the basolateral amygdala. Hence, this stress-induced sensitization of noradrenergic receptors on basolateral nucleus efferents has wide-ranging implications for the numerous deleterious sequelae of trauma exposure that are seen in multiple psychiatric illnesses, including PTSD. PMID- 26490868 TI - Neuronal Migration Dynamics in the Developing Ferret Cortex. AB - During mammalian neocortical development, newborn excitatory and inhibitory neurons must migrate over long distances to reach their final positions within the cortical plate. In the lissencephalic rodent brain, pyramidal neurons are born in the ventricular and subventricular zones of the pallium and migrate along radial glia fibers to reach the appropriate cortical layer. Although much less is known about neuronal migration in species with a gyrencephalic cortex, retroviral studies in the ferret and primate suggest that, unlike the rodent, pyramidal neurons do not follow strict radial pathways and instead can disperse horizontally. However, the means by which pyramidal neurons laterally disperse remain unknown. In this study, we identified a viral labeling technique for visualizing neuronal migration in the ferret, a gyrencephalic carnivore, and found that migration was predominantly radial at early postnatal ages. In contrast, neurons displayed more tortuous migration routes with a decreased frequency of cortical plate-directed migration at later stages of neurogenesis concomitant with the start of brain folding. This was accompanied by neurons migrating sequentially along several different radial glial fibers, suggesting a mode by which pyramidal neurons may laterally disperse in a folded cortex. These findings provide insight into the migratory behavior of neurons in gyrencephalic species and provide a framework for using nonrodent model systems for studying neuronal migration disorders. SIGNIFICANCE STATEMENT: Elucidating neuronal migration dynamics in the gyrencephalic, or folded, cortex is important for understanding neurodevelopmental disorders. Similar to the rodent, we found that neuronal migration was predominantly radial at early postnatal ages in the gyrencephalic ferret cortex. Interestingly, ferret neurons displayed more tortuous migration routes and a decreased frequency of radial migration at later ages coincident with the start of cortical folding. We found that ferret neurons use several different radial glial fibers as migratory guides, including those belonging to the recently described outer radial glia, suggesting a mechanism by which ferret neurons disperse laterally. It is likely that excitatory neurons horizontally disperse in other gyrencephalic mammals, including the primate, suggesting an important modification to the current model deduced primarily from the rodent. PMID- 26490867 TI - Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance. AB - Misfolded proteins accumulate and aggregate in neurodegenerative disease. The existence of these deposits reflects a derangement in the protein homeostasis machinery. Using a candidate gene screen, we report that loss of RAD-23 protects against the toxicity of proteins known to aggregate in amyotrophic lateral sclerosis. Loss of RAD-23 suppresses the locomotor deficit of Caenorhabditis elegans engineered to express mutTDP-43 or mutSOD1 and also protects against aging and proteotoxic insults. Knockdown of RAD-23 is further neuroprotective against the toxicity of SOD1 and TDP-43 expression in mammalian neurons. Biochemical investigation indicates that RAD-23 modifies mutTDP-43 and mutSOD1 abundance, solubility, and turnover in association with altering the ubiquitination status of these substrates. In human amyotrophic lateral sclerosis spinal cord, we find that RAD-23 abundance is increased and RAD-23 is mislocalized within motor neurons. We propose a novel pathophysiological function for RAD-23 in the stabilization of mutated proteins that cause neurodegeneration. SIGNIFICANCE STATEMENT: In this work, we identify RAD-23, a component of the protein homeostasis network and nucleotide excision repair pathway, as a modifier of the toxicity of two disease-causing, misfolding-prone proteins, SOD1 and TDP 43. Reducing the abundance of RAD-23 accelerates the degradation of mutant SOD1 and TDP-43 and reduces the cellular content of the toxic species. The existence of endogenous proteins that act as "anti-chaperones" uncovers new and general targets for therapeutic intervention. PMID- 26490869 TI - Somatosensory Contribution to the Initial Stages of Human Motor Learning. AB - The early stages of motor skill acquisition are often marked by uncertainty about the sensory and motor goals of the task, as is the case in learning to speak or learning the feel of a good tennis serve. Here we present an experimental model of this early learning process, in which targets are acquired by exploration and reinforcement rather than sensory error. We use this model to investigate the relative contribution of motor and sensory factors to human motor learning. Participants make active reaching movements or matched passive movements to an unseen target using a robot arm. We find that learning through passive movements paired with reinforcement is comparable with learning associated with active movement, both in terms of magnitude and durability, with improvements due to training still observable at a 1 week retest. Motor learning is also accompanied by changes in somatosensory perceptual acuity. No stable changes in motor performance are observed for participants that train, actively or passively, in the absence of reinforcement, or for participants who are given explicit information about target position in the absence of somatosensory experience. These findings indicate that the somatosensory system dominates learning in the early stages of motor skill acquisition. SIGNIFICANCE STATEMENT: The research focuses on the initial stages of human motor learning, introducing a new experimental model that closely approximates the key features of motor learning outside of the laboratory. The finding indicates that it is the somatosensory system rather than the motor system that dominates learning in the early stages of motor skill acquisition. This is important given that most of our computational models of motor learning are based on the idea that learning is motoric in origin. This is also a valuable finding for rehabilitation of patients with limited mobility as it shows that reinforcement in conjunction with passive movement results in benefits to motor learning that are as great as those observed for active movement training. PMID- 26490870 TI - PSD-Zip70 Deficiency Causes Prefrontal Hypofunction Associated with Glutamatergic Synapse Maturation Defects by Dysregulation of Rap2 Activity. AB - Dysregulation of synapse formation and plasticity is closely related to the pathophysiology of psychiatric and neurodevelopmental disorders. The prefrontal cortex (PFC) is particularly important for executive functions such as working memory, cognition, and emotional control, which are impaired in the disorders. PSD-Zip70 (Lzts1/FEZ1) is a postsynaptic density (PSD) protein predominantly expressed in the frontal cortex, olfactory bulb, striatum, and hippocampus. Here we found that PSD-Zip70 knock-out (PSD-Zip70KO) mice exhibit working memory and cognitive defects, and enhanced anxiety-like behaviors. These abnormal behaviors are caused by impaired glutamatergic synapse transmission accompanied by tiny headed immature dendritic spines in the PFC, due to aberrant Rap2 activation, which has roles in synapse formation and plasticity. PSD-Zip70 modulates the Rap2 activity by interacting with SPAR (spine-associated RapGAP) and PDZ-GEF1 (RapGEF) in the postsynapse. Furthermore, suppression of the aberrant Rap2 activation in the PFC rescued the behavioral defects in PSD-Zip70KO mice. Our data demonstrate a critical role for PSD-Zip70 in Rap2-dependent spine synapse development in the PFC and underscore the importance of this regulation in PFC-dependent behaviors. SIGNIFICANCE STATEMENT: PSD-Zip70 deficiency causes behavioral defects in working memory and cognition, and enhanced anxiety due to prefrontal hypofunction. This study revealed that PSD-Zip70 plays essential roles in glutamatergic synapse maturation via modulation of the Rap2 activity in the PFC. PSD-Zip70 interacts with both SPAR (spine-associated RapGAP) and PDZ-GEF1 (RapGEF) and modulates the Rap2 activity in postsynaptic sites. Our results provide a novel Rap2-specific regulatory mechanism in synaptic maturation involving PSD-Zip70. PMID- 26490872 TI - Metabolic Connection of Inflammatory Pain: Pivotal Role of a Pyruvate Dehydrogenase Kinase-Pyruvate Dehydrogenase-Lactic Acid Axis. AB - Pyruvate dehydrogenase kinases (PDK1-4) are mitochondrial metabolic regulators that serve as decision makers via modulation of pyruvate dehydrogenase (PDH) activity to convert pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Metabolic dysregulation and inflammatory processes are two sides of the same coin in several pathophysiological conditions. The lactic acid surge associated with the metabolic shift has been implicated in diverse painful states. In this study, we investigated the role of PDK-PDH-lactic acid axis in the pathogenesis of chronic inflammatory pain. Deficiency of Pdk2 and/or Pdk4 in mice attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivities. Likewise, Pdk2/4 deficiency attenuated the localized lactic acid surge along with hallmarks of peripheral and central inflammation following intraplantar administration of CFA. In vitro studies supported the role of PDK2/4 as promoters of classical proinflammatory activation of macrophages. Moreover, the pharmacological inhibition of PDKs or lactic acid production diminished CFA induced inflammation and pain hypersensitivities. Thus, a PDK-PDH-lactic acid axis seems to mediate inflammation-driven chronic pain, establishing a connection between metabolism and inflammatory pain. SIGNIFICANCE STATEMENT: The mitochondrial pyruvate dehydrogenase (PDH) kinases (PDKs) and their substrate PDH orchestrate the conversion of pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Lactate, the predominant end product of glycolysis, has recently been identified as a signaling molecule for neuron-glia interactions and neuronal plasticity. Pathological metabolic shift and subsequent lactic acid production are thought to play an important role in diverse painful states; however, their contribution to inflammation-driven pain is still to be comprehended. Here, we report that the PDK-PDH-lactic acid axis constitutes a key component of inflammatory pain pathogenesis. Our findings establish an unanticipated link between metabolism and inflammatory pain. This study unlocks a previously ill-explored research avenue for the metabolic control of inflammatory pain pathogenesis. PMID- 26490871 TI - Laminar Profile and Physiology of the alpha Rhythm in Primary Visual, Auditory, and Somatosensory Regions of Neocortex. AB - The functional significance of the alpha rhythm is widely debated. It has been proposed that alpha reflects sensory inhibition and/or a temporal sampling or "parsing" mechanism. There is also continuing disagreement over the more fundamental questions of which cortical layers generate alpha rhythms and whether the generation of alpha is equivalent across sensory systems. To address these latter questions, we analyzed laminar profiles of local field potentials (LFPs) and concomitant multiunit activity (MUA) from macaque V1, S1, and A1 during both spontaneous activity and sensory stimulation. Current source density (CSD) analysis of laminar LFP profiles revealed alpha current generators in the supragranular, granular, and infragranular layers. MUA phase-locked to local current source/sink configurations confirmed that alpha rhythms index local neuronal excitability fluctuations. CSD-defined alpha generators were strongest in the supragranular layers, whereas LFP alpha power was greatest in the infragranular layers, consistent with some of the previous reports. The discrepancy between LFP and CSD findings appears to be attributable to contamination of the infragranular LFP signal by activity that is volume conducted from the stronger supragranular alpha generators. The presence of alpha generators across cortical depth in V1, S1, and A1 suggests the involvement of alpha in feedforward as well as feedback processes and is consistent with the view that alpha rhythms, perhaps in addition to a role in sensory inhibition, may parse sensory input streams in a way that facilitates communication across cortical areas. SIGNIFICANCE STATEMENT: The alpha rhythm is thought to reflect sensory inhibition and/or a temporal parsing mechanism. Here, we address two outstanding issues: (1) whether alpha is a general mechanism across sensory systems and (2) which cortical layers generate alpha oscillations. Using intracranial recordings from macaque V1, S1, and A1, we show alpha band activity with a similar spectral and laminar profile in each of these sensory areas. Furthermore, alpha generators were present in each of the cortical layers, with a strong source in superficial layers. We argue that previous findings, locating alpha generators exclusively in the deeper layers, were biased because of use of less locally specific local field potential measurements. The laminar distribution of alpha band activity appears more complex than generally assumed. PMID- 26490873 TI - Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate alpha-Synuclein Disrupted Gene Expression. AB - alpha-synuclein, a protein enriched in Lewy bodies and highly implicated in neurotoxicity in Parkinson's disease, is distributed both at nerve terminals and in the cell nucleus. Here we show that a nuclear derivative of alpha-synuclein induces more pronounced changes at the gene expression level in mouse primary dopamine (DA) neurons compared to a derivative that is excluded from the nucleus. Moreover, by RNA sequencing we analyzed the extent of genome-wide effects on gene expression resulting from expression of human alpha-synuclein in primary mouse DA neurons. The results implicated the transcription factor Nurr1 as a key dysregulated target of alpha-synuclein toxicity. Forced Nurr1 expression restored the expression of hundreds of dysregulated genes in primary DA neurons expressing alpha-synuclein, and therefore prompted us to test the possibility that Nurr1 can be pharmacologically targeted by bexarotene, a ligand for the retinoid X receptor that forms heterodimers with Nurr1. Although our data demonstrated that bexarotene was ineffective in neuroprotection in rats in vivo, the results revealed that bexarotene has the capacity to coregulate subsets of Nurr1 target genes including the receptor tyrosine kinase subunit Ret. Moreover, bexarotene was able to restore dysfunctional Ret-dependent neurotrophic signaling in alpha synuclein-overexpressing mouse DA neurons. These data highlight the role of the Nurr1-Ret signaling pathway as a target of alpha-synuclein toxicity and suggest that retinoid X receptor ligands with appropriate pharmacological properties could have therapeutic potential in Parkinson's disease. SIGNIFICANCE STATEMENT: How alpha-synuclein, a protein enriched in Lewy bodies in Parkinson's disease, is causing neuropathology in dopamine neurons remains unclear. This study elucidated how alpha-synuclein is influencing gene expression and how Nurr1, a transcription factor known to protect dopamine neurons against alpha-synuclein toxicity, can counteract these effects. Moreover, given the protective role of Nurr1, this study also investigated how Nurr1 could be pharmacologically targeted via bexarotene, a ligand of Nurr1's heterodimerization partner retinoid X receptor (RXR). The results showed that RXR ligands could increase neurotrophic signaling, but provided a mixed picture of its potential in a Parkinson's disease rat model in vivo. However, this study clearly emphasized Nurr1's neuroprotective role and indicated that other RXR ligands could have therapeutic potential in Parkinson's disease. PMID- 26490874 TI - Savings upon Re-Aiming in Visuomotor Adaptation. AB - Sensorimotor adaptation has traditionally been viewed as a purely error-based process. There is, however, growing appreciation for the idea that performance changes in these tasks can arise from the interplay of error-based adaptation with other learning processes. The challenge is to specify constraints on these different processes, elucidating their respective contributions to performance, as well as the manner in which they interact. We address this question by exploring constraints on savings, the phenomenon in which people show faster performance gains when the same learning task is repeated. In a series of five experiments, we demonstrate that error-based learning associated with sensorimotor adaptation does not contribute to savings. Instead, savings reflects improvements in action selection, rather than motor execution. SIGNIFICANCE STATEMENT: Savings is the phenomenon in which people show faster relearning of a previously forgotten memory. In the motor learning domain, this phenomenon has been a puzzle for learning models that operate exclusively on error-based learning processes. We demonstrate, in a series of experiments, that savings selectively reflects improvements in action selection: Participants are more adept in invoking an appropriate aiming strategy when presented with a previously experienced perturbation. Indeed, improvements in action selection appear to be the sole source of savings in visuomotor adaptation tasks. We observe no evidence of savings in implicit error-based adaptation. PMID- 26490875 TI - A Critical Gating Switch at a Modulatory Site in Neuronal Kir3 Channels. AB - Inwardly rectifying potassium channels enforce tight control of resting membrane potential in excitable cells. The Kir3.2 channel, a member of the Kir3 subfamily of G-protein-activated potassium channels (GIRKs), plays several roles in the nervous system, including key responsibility in the GABAB pathway of inhibition, in pain perception pathways via opioid receptors, and is also involved in alcoholism. PKC phosphorylation acts on the channel to reduce activity, yet the mechanism is incompletely understood. Using the heterologous Xenopus oocyte system combined with molecular dynamics simulations, we show that PKC modulation of channel activity is dependent on Ser-196 in Kir3.2 such that, when this site is phosphorylated, the channel is less sensitive to PKC inhibition. This reduced inhibition is dependent on an interaction between phospho-Ser (SEP)-196 and Arg 201, reducing Arg-201 interaction with the sodium-binding site Asp-228. Neutralization of either SEP-196 or Arg-201 leads to a channel with reduced activity and increased sensitivity to PKC inhibition. This study clarifies the role of Ser-196 as an allosteric modulator of PKC inhibition and suggests that the SEP-196/Arg-201 interaction is critical for maintaining maximal channel activity. SIGNIFICANCE STATEMENT: The inwardly rectifying potassium 3.2 (Kir3.2) channel is found principally in neurons that regulate diverse brain functions, including pain perception, alcoholism, and substance addiction. Activation or inhibition of this channel leads to changes in neuronal firing and chemical message transmission. The Kir3.2 channel is subject to regulation by intracellular signals including sodium, G-proteins, ethanol, the phospholipid phosphatidylinositol bis-phosphate, and phosphorylation by protein kinases. Here, we take advantage of the recently published structure of Kir3.2 to provide an in depth molecular view of how phosphorylation of a specific residue previously thought to be the target of PKC promotes channel gating and acts as an allosteric modulator of PKC-mediated inhibition. PMID- 26490876 TI - Reversible Deactivation of Motor Cortex Reveals Functional Connectivity with Posterior Parietal Cortex in the Prosimian Galago (Otolemur garnettii). AB - We examined the functional macrocircuitry of frontoparietal networks in the neocortex of prosimian primates (Otolemur garnettii) using a microfluidic thermal regulator to reversibly deactivate selected regions of motor cortex (M1). During deactivation of either forelimb or mouth/face movement domains within M1, we used long-train intracortical microstimulation techniques to evoke movements from the rostral division of posterior parietal cortex (PPCr). We found that deactivation of M1 movement domains in most instances abolished movements evoked in PPCr. The most common effect of deactivating M1 was to abolish evoked movements in a homotopic domain in PPCr. For example, deactivating M1 forelimb lift domains resulted in loss of evoked movement in forelimb domains in PPCr. However, at some sites, we also observed heterotopic effects; deactivating a specific domain in M1 (e.g., forelimb lift) resulted in loss of evoked movement in a different movement domain in PPCr (e.g., hand-to-mouth or eye-blink). At most sites examined in PPCr, rewarming M1 resulted in a reestablishment of the baseline movement at the same amplitude as that observed before cooling. However, at some sites, reactivation did not result in a return to baseline movement or to the full amplitude of the baseline movement. We discuss our findings in the context of frontoparietal circuits and how they may subserve a repertoire of ecologically relevant behaviors. SIGNIFICANCE STATEMENT: The posterior parietal cortex (PPC) of primates integrates sensory information used to guide movements. Different modules within PPC and motor cortex (M1) appear to control various motor behaviors (e.g., reaching, defense, and feeding). How these modules work together may vary across species and may explain differences in dexterity and even the capacity for tool use. We investigated the functional connectivity of these modules in galagos, a prosimian primate with relatively simple frontoparietal circuitry. By deactivating a reaching module in M1, we interfered with the function of similar PPC modules and occasionally unrelated PPC modules as well (e.g., eye blink). This circuitry in galagos, therefore, is more complex than in nonprimates, indicating that it has been altered with the expansion of primate PPC. PMID- 26490878 TI - Global elimination of leprosy by 2020: are we on track? AB - BACKGROUND: Every year more than 200,000 new leprosy cases are registered globally. This number has been fairly stable over the past 8 years. WHO has set a target to interrupt the transmission of leprosy globally by 2020. The aim of this study is to investigate whether this target, interpreted as global elimination, is feasible given the current control strategy. We focus on the three most important endemic countries, India, Brazil and Indonesia, which together account for more than 80 % of all newly registered leprosy cases. METHODS: We used the existing individual-based model SIMCOLEP to predict future trends of leprosy incidence given the current control strategy in each country. SIMCOLEP simulates the spread of M. leprae in a population that is structured in households. Current control consists of passive and active case detection, and multidrug therapy (MDT). Predictions of leprosy incidence were made for each country as well as for one high-endemic region within each country: Chhattisgarh (India), Para State (Brazil) and Madura (Indonesia). Data for model quantification came from: National Leprosy Elimination Program (India), SINAN database (Brazil), and Netherlands Leprosy Relief (Indonesia). RESULTS: Our projections of future leprosy incidence all show a downward trend. In 2020, the country-level leprosy incidence has decreased to 6.2, 6.1 and 3.3 per 100,000 in India, Brazil and Indonesia, respectively, meeting the elimination target of less than 10 per 100,000. However, elimination may not be achieved in time for the high-endemic regions. The leprosy incidence in 2020 is predicted to be 16.2, 21.1 and 19.3 per 100,000 in Chhattisgarh, Para and Madura, respectively, and the target may only be achieved in another 5 to 10 years. CONCLUSIONS: Our predictions show that although country-level elimination is reached by 2020, leprosy is likely to remain a problem in the high-endemic regions (i.e. states, districts and provinces with multimillion populations), which account for most of the cases in a country. PMID- 26490877 TI - A Luminescent Nitrogen-Containing Polycyclic Aromatic Hydrocarbon Synthesized by Photocyclodehydrogenation with Unprecedented Regioselectivity. AB - We present a nitrogen-containing polycyclic aromatic hydrocarbon (N-PAH), namely 12-methoxy-9-(4-methoxyphenyl)-5,8-diphenyl-4-(pyridin-4-yl)pyreno[1,10,9 h,i,j]isoquinoline (c-TPE-ON), which exhibits high quantum-yield emission both in solution (blue) and in the solid state (yellow). This molecule was unexpectedly obtained by a three-fold, highly regioselective photocyclodehydrogenation of a tetraphenylethylene-derived AIEgen. Based on manifold approaches involving UV/Vis, photoluminescence, and NMR spectroscopy as well as HRMS, we propose a reasonable mechanism for the formation of the disk-like N-PAH that is supported by density functional theory calculations. In contrast to most PAHs that are commonly used, our system does not suffer from entire fluorescence quenching in the solid state due to the peripheral aromatic rings preventing pi-pi stacking interactions, as evidenced by single-crystal X-ray analysis. Moreover, its rod like microcrystals exhibit excellent optical waveguide properties. Hence, c-TPE ON comprises a N-PAH with unprecedented luminescent properties and as such is a promising candidate for fabricating organic optoelectronic devices. Our design and synthetic strategy might lead to a more general approach to the preparation of solution- and solid-state luminescent PAHs. PMID- 26490879 TI - The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans. AB - Behavioural, neurological, and genetic similarities exist in epilepsies, their psychiatric comorbidities, and various psychiatric illnesses, suggesting common aetiological factors. Rodent models of epilepsy are used to characterize the comorbid symptoms apparent in epilepsy and their neurobiological mechanisms. The present study was designed to assess Pavlovian fear conditioning and latent inhibition in a polygenetic rat model of absence epilepsy, i.e. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the non-epileptic control (NEC) strain. Electrophysiological recordings confirmed the presence of spike-wave discharges in young adult GAERS but not NEC rats. A series of behavioural tests designed to assess anxiety-like behaviour (elevated plus maze, open field, acoustic startle response) and cognition (Pavlovian conditioning and latent inhibition) was subsequently conducted on male and female offspring. Results showed that GAERS exhibited significantly higher anxiety-like behaviour, a characteristic reported previously. In addition, using two protocols that differed in shock intensity, we found that both sexes of GAERS displayed exaggerated cued and contextual Pavlovian fear conditioning and impaired fear extinction. Fear reinstatement to the conditioned stimuli following unsignalled footshocks did not differ between the strains. Male GAERS also showed impaired latent inhibition in a paradigm using Pavlovian fear conditioning, suggesting that they may have altered attention, particularly related to previously irrelevant stimuli in the environment. Neither the female GAERS nor NEC rats showed evidence of latent inhibition in our paradigm. Together, the results suggest that GAERS may be a particularly useful model for assessing therapeutics designed to improve the emotional and cognitive disturbances associated with absence epilepsy. PMID- 26490881 TI - Successful treatment of neutropenic MRSA bacteremia with septic superior vena cava thrombus and cerebral embolism using high-dose daptomycin. PMID- 26490882 TI - Venous thromboembolism in adults with sickle cell disease: experience of a single centre in the UK. AB - Venous thromboembolism (VTE) is a recognised complication of sickle cell disease (SCD), long considered to be a hypercoagulable state. While there is a good understanding of arterial thrombosis in SCD, the nature of VTE in SCD is less well-characterised. In this retrospective cohort study, we found that the incidence of VTE in our patient cohort was higher than in the non-SCD black population; patients of all SCD genotypes with VTE had significantly elevated steady-state platelet counts compared to those without. Recent hospitalisation (typically with acute sickle pain) was the commonest precipitating risk factor. These findings suggest consideration of longer VTE prophylaxis for acute hospital admissions in SCD. PMID- 26490883 TI - Factors affecting re-vegetation dynamics of experimentally restored extracted peatland in Estonia. AB - Increasing human activity continues to threaten peatlands, and as the area of natural mires declines, our obligation is to restore their ecosystem functions. Several restoration strategies have been developed for restoration of extracted peatlands, including "The moss layer transfer method", which was initiated on the Tassi extracted peatland in central Estonia in May 2012. Three-year study shows that despite the fluctuating water table, rainfall events can compensate for the insufficient moisture for mosses. Total plant cover on the restoration area attained 70 %, of which ~60 % is comprised of target species-Sphagnum mosses. From restoration treatments, spreading of plant fragments had a significant positive effect on the cover of bryophyte and vascular plants. Higher water table combined with higher plant fragments spreading density and stripping of oxidised peat layer affected positively the cover of targeted Sphagnum species. The species composition in the restoration area became similar to that in the donor site in a natural bog. Based on results, it was concluded that the method approved for restoration in North America gives good results also in the restoration of extracted peatland towards re-establishment of bog vegetation under northern European conditions. PMID- 26490884 TI - Diazinon, an organophosphate pesticide, induces oxidative stress and genotoxicity in cells deriving from large intestine. AB - Diazinon (DZ) (O,O-diethyl-O-[2-isopropyl-6-methyl-4 pyrimidinyl]phosphorothioate) is an organophosphate pesticide which is extensively used to control household insects and fruit and vegetable crops. The exposure to this pesticide has been linked to the development of the serious problem in several experimental animals. The contamination of food by DZ may increase its danger to humans. The aim of this study was to investigate the toxic effect of DZ on intestine using an in vitro model (HCT116). Therefore, we evaluated the cell viability, elucidated the generation of free radicals, measured the mitochondrial membrane potential, and valued DNA fragmentation. Our results showed that DZ is cytotoxic to HCT116. It causes oxidative damage through the generation of free radicals and induces lipid peroxidation and DNA fragmentation. We also demonstrated that such effects can be responsible for DZ induced apoptosis. PMID- 26490885 TI - Removal of the pharmaceuticals ibuprofen and iohexol by four wetland plant species in hydroponic culture: plant uptake and microbial degradation. AB - We aimed at assessing the effects of four wetland plant species commonly used in constructed wetland systems: Typha, Phragmites, Iris and Juncus for removing ibuprofen (IBU) and iohexol (IOH) from spiked culture solution and exploring the mechanisms responsible for the removal. IBU was nearly completely removed by all plant species during the 24-day experiment, whereas the IOH removal varied between 13 and 80 %. Typha and Phragmites were the most efficient in removing IBU and IOH, respectively, with first-order removal rate constants of 0.38 and 0.06 day(-1), respectively. The pharmaceuticals were taken up by the roots and translocated to the aerial tissues. However, at the end of the experiment, plant accumulation constituted only up to 1.1 and 5.7 % of the amount of IBU and IOH spiked initially. The data suggest that the plants mainly function by facilitating pharmaceutical degradation in the rhizosphere through release of root exudates. PMID- 26490886 TI - Indoor second-hand smoking could mediate the associations of foods and adult happiness: Scottish Health Survey, 2012. AB - There has been literature on the relationship of food and happiness, but the role of second-hand smoking is less understood. Therefore, the aim of the present study was to examine if second-hand smoking might mediate the associations of food consumption and subjective happiness in a country-wide and population-based setting. Data was retrieved from the Scottish Health Survey, 2012. Information on demographics, frequency of consuming certain foods and subjective happiness was obtained by household interview. Chi-square test and survey-weighted logistic regression modelling were performed. Of the included Scottish adults aged 16-99 (n = 4815), 15.4 % (n = 677) reported that they were unhappy. It was observed that eating lots of potatoes, some meat, some oily fish and some pastries were inversely associated with unhappiness. People who consumed vegetables and fruits on the day before the health interview were also found to be less unhappy, compared to their counterparts. However, the protective effect from fruits disappeared after additionally adjusting for indoor second-hand smoking while the protective effects from other foods mentioned above have also been lessened. In addition, cumulatively people who consumed more "happy foods" (mentioned above) were more likely to report subjective happiness, compared to those who did not consume any of those. For future research, longitudinally monitoring on the associations among food, household environment and psychological well-being and both the short-term and long-term effects would be suggested. For policy implications, Removal of indoor second-hand smoking to retain the protective effects from happy foods on well-being should be encouraged. PMID- 26490887 TI - Nanoparticle pollution and associated increasing potential risks on environment and human health: a case study of China. AB - The aims of this study are (1) to discuss the mechanism of nanoparticle lifecycle and estimate the impacts of its associated pollution on environment and human health; and (2) to provide recommendation to policy makers on how to leverage nanopollution and human health along with the rapid development of economics in China. Manufactured nanoparticles (MNPs) could either directly or indirectly impair human health and the environment. Exposures to MNP include many ways, such as via inhalation, ingestion, direct contact, or the use of consumer products over the lifecycle of the product. In China, the number of people exposed to MNP has been increasing year by year. To better provide medical care to people exposed to MNP, the Chinese government has established many disease control and prevention centers over China. However, the existing facilities and resources for controlling MNP are still not enough considering the number of people impacted by MNP and the number of ordinary workers in the MNP related industry applying for their occupational identification through the Center for Disease Control and Prevention. China should assess the apparent risk environment and human health being exposed to MNP and develop action plans to reduce the possibility of direct contacts between human beings and the emerging nanomaterials. In addition, we suggest more comprehensive studies on the MNP behavior and the development of quantitative approaches to measure MNP transport, and persistence should be carried out. PMID- 26490888 TI - Comparative sensitivity among early life stages of the South American toad to cypermethrin-based pesticide. AB - Cypermethrin is one of the most widely used pesticides due to its low mammalian and bird toxicity, but it is extremely toxic to aquatic organisms. The aim of the present study was to evaluate the toxicity of a commercial formulation of cypermethrin on the embryo-larval development of Rhinella arenarum. An ecological risk assessment based on the hazard quotient (HQ) approach was performed. The results showed that cypermethrin toxicity was stage-dependent and dramatically increased during the larval period. Thus, larvae were more sensitive than embryos, obtaining at the end of the experiment a 336-h median lethal concentration (LC50) of 0.65 MUg cypermethrin/L. Cypermethrin exposure caused morphological abnormalities such as general underdevelopment, edema, gill malformations, and behavioral alterations as hyperkinesia and spasmodic contractions. The 168-h teratogenic index was 5, implying a high risk for embryos to be malformed in the absence of significant embryonic lethality. Based on the results of the toxicity effects and the ecological risk assessed (HQ for chronic exposure > level of concern), this pesticide should be considered as a direct (effects on survival) or indirect (severe sublethal effects) risk for conservation purposes of this amphibian in agroecosystems. PMID- 26490889 TI - Mercury contamination from historical mining territory at Malachov Hg-deposit (Central Slovakia). AB - Environmental contamination caused by mercury is a serious problem worldwide. The study was conducted in order to identify Hg contamination in soil, technosoil from dumps, groundwater, and surface water in the surroundings of the abandoned Hg deposit of Malachov in Central Slovakia. Soil from the Malachovsky brook valley was classified as cambi-soil (rendzina). The highest Hg concentrations (44.24 mg kg(-1)) were described in the soil from the mining area at the Vel'ka Studna locality. In the groundwater, the maximal Hg content is 0.84 MUg L(-1), and in the surface water it is 394 MUg L(-1). The speciation study proved that in most samples, Hg occurs in the form of cinnabarite. The release of Hg into the environment as a consequence of weathering is limited. PMID- 26490890 TI - Seasonal difference of human adenoviruses in a subtropical river basin based on 1 year monthly survey. AB - In this study, the seasonal difference and the observable presence/absence of human adenovirus (HAdV) in the Puzih River basin in Taiwan was investigated. A total of 288 water samples were collected from 24 sites from March 2014 to February 2015. Human AdV analysis of sample was subjected to viral concentration using a GN-6 Metricel(r) filter, followed by DNA extraction, nested-PCR, and qPCR. Human AdV was detected in 34.3 % (99/288) of the entire river water sample. A higher percentage of HAdV (76.4 %) was obtained during the winter. The HAdV median concentration was relatively high in fall (1.4 * 10(3) copies/L) and winter (2.8 * 10(3) copies/L). Significant difference and correlation were found between the seasonal variation of HAdV and water quality parameters, including heterotrophic plate count, total coliform, water temperature, and turbidity. The most frequently identified HAdV (subgenus F) serotype was 41. Human AdV-41 is the main cause of gastroenteritis and should be considered for associated human health risk potential in the Puzih River basin. PMID- 26490891 TI - Assessing the use of nanoimmobilized laccases to remove micropollutants from wastewater. AB - Enzymes immobilization is a useful way to allow enzyme reuse and increase their stability. A high redox potential laccase from Trametes versicolor (TvL) and a low redox potential, but commercially available low-cost laccase from Myceliophthora thermophila (MtL), were successfully immobilized and co immobilized onto fumed silica nanoparticles (fsNP). Enzyme loads of 1.78 +/- 0.07, 0.69 +/- 0.03, and 1.10 +/- 0.01 U/mg fsNP were attained for the optimal doses of TvL, MtL, and co-immobilized laccases, respectively. In general, the laccase-fsNP conjugates showed a higher resistance against an acidic pH value (i.e., pH 3), and a higher storage stability than free enzymes. In addition, immobilized enzymes exhibited a superior long-term stability than free laccases when incubated in a secondary effluent from a municipal wastewater treatment plant (WWTP). For instance, the residual activity after 2 weeks for the co immobilized laccases and the mixture of free laccases were 40.2 +/- 2.5% and 16.8 +/- 1.0%, respectively. The ability of the laccase-fsNP to remove a mixture of (14)C-bisphenol A (BPA) and (14)C-sodium diclofenac (DCF) from spiked secondary effluents was assessed in batch experiments. The catalytic efficiency was highly dependent on both the microbial source and state of the biocatalyst. The high redox potential TvL in free form attained a four-fold higher percentage of BPA transformation than the free MtL. Compared to free laccases, immobilized enzymes led to much slower rates of BPA transformation. For instance, after 24 h, the percentages of BPA transformation by 1000 U/L of a mixture of free laccases or co immobilized enzymes were 67.8 +/- 5.2 and 27.0 +/- 3.9%, respectively. Nevertheless, the use of 8000 U/L of co-immobilized laccase led to a nearly complete removal of BPA, despite the unfavorable conditions for laccase catalysis (pH ~ 8.4). DCF transformation was not observed for any of the enzymatic systems, showing that this compound is highly recalcitrant toward laccase oxidation under realistic conditions. PMID- 26490892 TI - Levels, distributions and correlations of polybrominated diphenyl ethers in air and dust of household and workplace in Shanghai, China: implication for daily human exposure. AB - Polybrominated diphenyl ethers (PBDEs) were measured in air (TSP and PM2.5) and dust samples collected from 16 households and the corresponding workplaces of eight volunteer citizens in Shanghai, China. The PBDEs concentrations in the workplace air (mean: 281 +/- 126 pg m(-3)) were over two times higher than those in the household (121 +/- 44.0 pg m(-3)), while the mean levels of PBDEs in dust were 995 +/- 547 and 544 +/- 188 ng g(-1) for workplace and household, respectively. BDE209 was the most abundant congener in all samples. PBDEs appeared to be composed of mostly small particles. The C particle/C dust ratios of less brominated PBDEs in PM2.5 were higher than those in TSP, while the values were approximately constant for the more brominated PBDEs. A correlation analysis by network indicated different sources and behavior of the PBDE congeners. The results of a cluster analysis were displayed on a heat map that specified the source and abundance of each PBDE congener. The daily PBDE exposure via dust ingestion was the predominant part of the total intake and was more than 10 times higher than the intake via inhalation. PMID- 26490893 TI - Assessment of the bioavailability and phytotoxicity of sediment spiked with polycyclic aromatic hydrocarbons. AB - Large amounts of sediment are dredged globally every year. This sediment is often contaminated with low concentrations of metals, polycyclic aromatic hydrocarbons, pesticides and other organic pollutants. Some of this sediment is disposed of on land, creating a need for risk assessment of the sediment disposal method, to minimize the degradation of environmental quality and prevent risks to human health. Evaluating the available fractions of certain polycyclic aromatic hydrocarbons is very important, as in the presence of various organisms, they are believed to be easily subject to the processes of bioaccumulation, biosorption and transformation. In order to determine the applicability of applying these methods for the evaluation of pollutant bioavailability in sediments, the desorption kinetics from the sediment of various polycyclic aromatic hydrocarbons in the presence of Tenax and XAD4 were examined over the course of 216 h. Changes in the PAH concentrations in dredged sediments using five different seed plants during a short time of period (10 days) were also followed. Using chemical extraction techniques with Tenax and XAD4, a time of around 24 h is enough to achieve equilibrium for all four PAHs. Results showed good agreement between the seed accumulation and PAH extraction methods with both agents. If we compare the two extraction techniques, XAD4 gave better results for phenanthrene, pyrene and benzo(a)pyrene, and Tenax gave better results for chrysene. PMID- 26490894 TI - Spatial distribution, health risk assessment, and isotopic composition of lead contamination of street dusts in different functional areas of Beijing, China. AB - Street dusts from heavy density traffic area (HDTA), tourism area (TA), residential area (RA), and educational area (EA) in Beijing were collected to explore the distribution, health risk assessment, and source of lead (Pb). The average concentration of Pb in TA was the highest among the four areas. Compared with other cities, Pb concentrations in Beijing were generally at moderate or low levels. The average value (14.05) of ecological risk index (RI) indicated that Pb was at "low pollution risk" status. According to the calculation on hazard index (HI), the ingestion of dust particles of children and adults was the major route of exposure to street dusts in four studied areas, followed by dermal contact. The lower values of HI than 1 further suggested that non-carcinogenic risks of Pb in the street dusts were in the low range. Comparing (206)Pb/(207)Pb and (208)Pb/(207)Pb ratios of street dusts with other environmental samples, it was found that atmospheric deposition of coal combustion dust might be the main pathway for anthropogenic Pb input to the street dusts in four functional areas. PMID- 26490895 TI - Early genotoxic response and accumulation induced by waterborne copper, lead, and arsenic in European seabass, Dicentrarchus labrax. AB - Cu, Pb, and As, which are among the most abundant metals in the aquatic environment, are also among the most health-threatened by causing diverse cellular injuries. The aim of this study was to assess and compare the potential early induction of genotoxic effects after waterborne Cu, Pb, and As exposure in European seabass, Dicentrarchus labrax, a commercial widely cultured fish, using the micronucleus (MN) assay in peripheral blood erythrocytes. Fish were exposed under laboratory conditions to nominal solutions ranging 0-10 mg/L for 24 and 96 h. Furthermore, actual metal ion concentrations were measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES) or differential pulse anodic stripping voltammetry (DPASV) in water and four fish tissues differentially related to environmental exposition and metal accumulation, i.e. the gills, liver, muscle, and brain. Dose-dependent increases of micronuclei (MNi) frequency were observed after these very short exposures; based on measured metal concentrations in water, the genotoxic effect ordered as Cu > As > Pb. Significant genotoxic effect at 0.009 mg/L Cu, 0.57 mg/L Pb, and 0.01 mg/L As was seen. For Cu and Pb these are only slightly higher, but for As it is notably lower than the USEPA criteria of maximum concentration to prevent acute toxicity in aquatic organisms. Furthermore, genotoxicity was differentially related to metal accumulation. MNi frequency correlated positively with the content of Pb in all the organs, with the content of As in liver and gills and only with the content of Cu in the brain. In conclusion, our findings raised environmental concerns because these depicted a genotoxic potential of Cu, Pb, and As after a very short exposure to low but environmentally relevant concentrations, too close to regulatory thresholds. In addition, the MN test in D. labrax could be considered an early biomarker of genotoxicity induced by these metals in fish. PMID- 26490896 TI - Trends in health burden of ambient particulate matter pollution in Iran, 1990 2010: findings from the Global Burden of Disease study 2010. AB - This paper aims to report the assessment of trends in deaths and disability adjusted life years (DALYs) attributed to ambient particulate matter (PM) pollution from 1990 to 2010 by sex and age in Iran. We used the data of the Global Burden of Disease (GBD) 2010 Study, and then we extracted its data on Iran for the years 1990, 2005, and 2010. The proportion of deaths and the DALYs caused by specific risk factors were assessed by using the comparative risk assessment and calculating the attributed burden of exposure level to each risk factor compared with the theoretical minimum level of risk exposure. Uncertainties in distribution of exposure, relative risks, and relevant outcomes calculation were disseminated into the estimates of the attributable deaths and DALYs. We found that the age-standardized death rate attributed to ambient PM pollution decreased to 27.90 cases per 100,000 populations from 1990 to 2010 [86, 95% uncertainty interval (UI) 76-97 to 62; 95% UI 54-71 per 100,000 populations, respectively]. This was mainly because of greater decrease in cardiovascular diseases (CVDs) than in the other diseases attributed to PM pollution. Despite a decrease in the total DALYs and mortality rate attributed to PM pollution, the death percent increased by 6.94%, 95% UI 6.06-7.90% from 1990 to 2010. The number of the DALYs and death in age groups of more than 70 years increased in 2010 compared to that in 1990. The median percent change of the DALYs and death for all age groups shows that the DALYs and death increased by 6% (95% UI 8-19%) and 45% (95% UI 30 60%), respectively, in 2010 in comparison to that in 1990. The increase in the DALYs and mortality attributable to PM pollution emphasizes the necessity of the effective interventions for improving air quality, as well as for increasing the public awareness to reduce the exposure of vulnerable age groups to PM pollution. PMID- 26490897 TI - Urinary heavy metals, phthalates, perchlorate, nitrate, thiocyanate, hydrocarbons, and polyfluorinated compounds are associated with adult hearing disturbance: USA NHANES, 2011-2012. AB - BACKGROUND: Links between environmental chemicals and human health have emerged, but the effects on hearing were less studied. Therefore, the aim of the present study was to investigate the relationships of different sets of environmental chemicals and the hearing conditions in a national and population-based setting. METHODS: Data was retrieved from the US National Health and Nutrition Examination Surveys, 2011-2012 including demographics, serum measurements, lifestyle factors, self-reported hearing conditions, and urinary environmental chemical concentrations. Chi-square test, t test, and survey-weighted logistic regression models were performed. RESULTS: Among the American adults aged 20-69 (n=5560), 462 (8.3 %) people reported their hearing condition as moderate trouble to deaf. They had higher levels of urinary hydrocarbons and polyfluorinated compounds but not heavy metals, phthalates, arsenic, pesticides, phenols, parabens, perchlorate, nitrate, and thiocyanate concentrations. Also, 466 (10.0 %) people had hearing difficulties during conversation. They had higher levels of urinary cobalt (odds ratio (OR) 1.27, 95 % confidence interval (95%CI) 1.00-1.63), molybdemum (OR 1.45, 95%CI 1.04-2.02), strontium (OR 1.56, 95%CI 1.10-2.21), phthalates, perchlorate (OR 1.27, 95%CI 1.05-1.54), nitrate (OR 1.60, 1.03-2.49) and thiocyanate (OR 1.22, 95%CI 1.01-1.48) concentrations but not arsenic, pesticides, phenols, parabens, hydrocarbons, and polyfluorinated compounds. Moreover, people who reported difficulties in following conversation with background noise had higher levels of urinary tin concentrations (OR 1.17, 1.00 1.36). CONCLUSIONS: Urinary heavy metals, phthalates, perchlorate, nitrate, thiocyanate, hydrocarbons, and polyfluorinated compounds were associated with the adult hearing disturbance, although the causality cannot be established. Elimination of these environmental chemicals might need to be considered in future environmental health policy and health intervention programs. PMID- 26490898 TI - Bioavailability and mobility of organic contaminants in soil: new three-step ecotoxicological evaluation. AB - A novel approach was developed for rapid assessment of bioavailability and potential mobility of contaminants in soil. The response of the same test organism to the organic extract, water extract and solid phase of soil was recorded and compared. This approach was designed to give an initial estimate of the total organic toxicity (response to organic extractable fraction), as well as the mobile (response to water extract) and bioavailable fraction (response to solid phase) of soil samples. Eighteen soil samples with different levels of pollution and content of organic carbon were selected to validate the novel three step ecotoxicological evaluation approach. All samples were chemically analysed for priority contaminants, including aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), hexachlorocyclohexane (HCH) and dichlordiphenyltrichloroethane (DDT). The ecotoxicological evaluation involved determination of toxicity of the organic, mobile and bioavailable fractions of soil to the test organism, bacterium Bacillus cereus. We found a good correlation between the chemical analysis and the toxicity of organic extract. The low toxicity of water extracts indicated low water solubility, and thus, low potential mobility of toxic contaminants present in the soil samples. The toxicity of the bioavailable fraction was significantly greater than the toxicity of water-soluble (mobile) fraction of the contaminants as deduced from comparing untreated samples and water extracts. The bioavailability of the contaminants decreased with increasing concentrations of organic carbon in evaluated soil samples. In conclusion, the three-step ecotoxicological evaluation utilised in this study can give a quick insight into soil contamination in context with bioavailability and mobility of the contaminants present. This information can be useful for hazard identification and risk assessment of soil-associated contaminants. Graphical Abstract New three-step ecotoxicological evaluation by using the same organism. PMID- 26490899 TI - Scenario-based analysis of traffic-related PM2.5 concentration: Lisbon case study. AB - Air quality in urban centers constitutes a challenge ahead for most cities. For this reason, the objective of this research work was to evaluate the impacts of changing traffic-related parameters on particulate matter (PM) concentration for several hierarchical street levels using real-world data for the city of Lisbon, Portugal. For that purpose, 2014 data regarding meteorological conditions, traffic volumes, typical vehicle speed, and a vehicle representative of the fleet was used in an air quality dispersion model (CALINE4). The available data allowed building a baseline case for several streets that are representative of the traffic circulation conditions in Lisbon, which was compared with different scenarios: hypothetical introduction of a cordon toll (S1.1 to S1.4) and the implementation of a low emission zone (S2.1 and 2.2). The results indicate that reductions on PM2.5 concentrations from 5 to 42 % may be obtained from the implementation of the scenarios. Overall, this study demonstrates that modeling tools based on real-world data can provide a good approach to study urban policies regarding traffic-related PM exposure. Additionally, implementation of such measures requires an integrated strategy that enables proper enforcement and monitoring, as well as an adequate management of traffic flows between the implementation boundaries. PMID- 26490900 TI - Ligand-enhanced electrokinetic remediation of metal-contaminated marine sediments with high acid buffering capacity. AB - The suitability of electrokinetic remediation for removing heavy metals from dredged marine sediments with high acid buffering capacity was investigated. Laboratory-scale electrokinetic remediation experiments were carried out by applying two different voltage gradients to the sediment (0.5 and 0.8 V/cm) while circulating water or two different chelating agents at the electrode compartments. Tap water, 0.1 M citric acid and 0.1 M ethylenediaminetetraacetic acid (EDTA) solutions were used respectively. The investigated metals were Zn, Pb, V, Ni and Cu. In the unenhanced experiment, the acid front could not propagate due to the high acid buffering capacity of the sediments; the production of OH(-) ions at the cathode resulted in a high-pH environment causing the precipitation of CaCO3 and metal hydroxides. The use of citric acid prevented the formation of precipitates, but solubilisation and mobilisation of metal species were not sufficiently achieved. Metal removal was relevant when EDTA was used as the conditioning agent, and the electric potential was raised up to 0.8 V/cm. EDTA led to the formation of negatively charged complexes with metals which migrated towards the anode compartment by electromigration. This result shows that metal removal from sediments with high acid buffering capacity may be achieved by enhancing the electrokinetic process by EDTA addition when the acidification of the medium is not economically and/or environmentally sustainable. PMID- 26490901 TI - Use of multivariate dispersion to assess water quality based on species composition data. AB - Multivariate dispersion is a powerful approach to determine the variability in species composition of a fauna or a flora and has been considered as a broad beta diversity in global ecological research. To explore the availability of the dispersions based on species composition data for assessing water quality, a dataset of ciliated protozoa in a basin ecosystem, northern China, was studied. Samples were collected from five sampling stations, within a significant heterogeneity of environmental stress. The homogeneity of multivariate dispersions in species composition of the ciliate assemblages represented a clear spatial pattern in response to the environmental stress. Multivariate analysis demonstrated that the spatial variation in species composition of the ciliate was significantly correlated with the changes of environmental variables, especially the nutrients, in combination with the salinity and pH, or alone. Furthermore, the dispersion measure was found to be significantly related to the nutrient. Based on our data, we suggest that multivariate dispersion measures based on species presence/absence data might be used as a potential bioindicator of water quality in marine ecosystems. PMID- 26490902 TI - Toward inline multiplex biodetection of metals, bacteria, and toxins in water networks: the COMBITOX project. PMID- 26490903 TI - Using air, soil and vegetation to assess the environmental behaviour of siloxanes. AB - This study aimed to contribute to the enhancement of the knowledge of levels, trends and behaviour of eight siloxanes (four linear and four cyclic) in the environment. Adding to the prioritised scrutiny of the incidence in the atmosphere through passive samplers (sorbent-impregnated polyurethane foam disks- SIPs), the sampling of pine needles and soil was also performed, thus closing the circle of atmospheric exposure in the areas of study. Two sampling campaigns (one in summer and one in winter) were done in a total of eight sampling points in the Portuguese territory, which covered a wide range of human presence and land uses (urban, industrial, remote and beach areas). By adopting a "green" approach in terms of analytical methods, namely reducing the clean-up steps for the passive air samples and using the quick, easy, cheap, effective, rugged and safe (QuEChERS) technology for soils and pine needles, the results showed total concentration of siloxanes between 5 and 70 ng g(-1) (dry weight) for soils and from 2 to 118 ng g(-1) (dry weight (dw)) for pine needles, with no clear seasonal trend. For SIPs, the levels varied from 0.6 to 7.8 ng m(-3) and were higher in summer than in winter in all sites. Overall, the cyclic siloxanes were found in much higher concentrations, with D5 and D6 being the most predominant in a great majority of cases. Also, the urban and industrial areas had the highest incidence, suggesting a strong anthropogenic fingerprint, in line with their main uses. PMID- 26490904 TI - Investigation of (235)U, (226)Ra, (232)Th, (40)K, (137)Cs, and heavy metal concentrations in Anzali international wetland using high-resolution gamma-ray spectrometry and atomic absorption spectroscopy. AB - Measurements of natural radioactivity levels and heavy metals in sediment and soil samples of the Anzali international wetland were carried out by two HPGe gamma ray spectrometry and atomic absorption spectroscopy techniques. The concentrations of (235)U, (226)Ra, (232)Th, (40)K, and (137)Cs in sediment samples ranged between 1.05 +/- 0.51-5.81 +/- 0.61, 18.06 +/- 0.63-33.36 +/- .0.34, 17.57 +/- 0.38-45.84 +/- 6.23, 371.88 +/- 6.36-652.28 +/- 11.60, and 0.43 +/- 0.06-63.35 +/- 0.94 Bq/kg, while in the soil samples they vary between 2.36 5.97, 22.71-38.37, 29.27-42.89, 472.66-533, and 1.05-9.60 Bq/kg for (235)U, (226)Ra, (232)Th, (40)K, and (137)Cs, respectively. Present results are compared with the available literature data and also with the world average values. The radium equivalent activity was well below the defined limit of 370 Bq/kg. The external hazard indices were found to be less than 1, indicating a low dose. Heavy metal concentrations were found to decrease in order as Fe > Mn > Sr > Zn > Cu > Cr > Ni > Pb > Co > Cd. These measurements will serve as background reference levels for the Anzali wetland. PMID- 26490905 TI - Acute effects of grayanotoxin in rhododendron honey on kidney functions in rats. AB - The aim of the study is to evaluate the acute biochemical and histological changes in rat kidneys after treatment with grayanotoxin (GTX) of rhododendron honey (RH). A total of 60 Sprague-Dawley female rats were divided into five groups of 12 rats each, one being a control group (group 1) and group 2 was treated with 0.015 mg/kg/bw of GTX standard preparation via intraperitoneal injection. Groups 3, 4, and 5 were given RH at doses of 0.1, 0.5, and 2.5 g/kg/bw, respectively, via oral gavage. Compared to the control group, significant increases were observed in glucose, blood urea nitrogen (BUN), and creatinine levels of the GTX-injected groups after 1 h. However, in low dose RH group, such an increase was not observed and had a normal appearance histologically. Therefore, low dose (1 g/kg/bw) of RH produces no acute adverse effects on renal functions of rats. PMID- 26490906 TI - Hydrocarbons and heavy metals in fine particulates in oil field air: possible impacts on production of natural silk. AB - Analyses of fine particulates (PM2.5) from the upper Assam oil fields of India indicated considerable presence of higher hydrocarbons (C22-C35) and heavy metals, Cd, Co, Cr, Cu, Ni, Pb, and Zn. This has raised serious concern for the sustainability of the exotic Muga (Antheraea assama) silk production, which has been a prime activity of a large number of people living in the area. The Muga worm feeds on the leaves of Machilus bombycina plant, and the impacts of air quality on its survival were further investigated by analyzing the leaves of the plant, the plantation soil, and the Muga cocoons. PM2.5 content in the air was much more during the winter due to near calm conditions and high humidity. Fourier transform infrared (FTIR), thermogravimetric analysis (TGA), and gas chromatography-mass spectrometer (GC-MS) analysis of PM2.5 showed the presence of higher alkanes (C22-C35) that could be traced to crude oil. Cr, Ni, and Zn were found in higher concentrations in PM2.5, M. bombycina leaves, and the plantation soil indicating a common origin. The winter has been the best period for production of the silk cocoons, and the unhealthy air during this period is likely to affect the production, which is already reflected in the declining yield of Muga cocoons from the area. SEM and protein analyses of the Muga silk fiber produced in the oil field area have exhibited the deteriorating quality of the silk. This is the first report from India on hydrocarbons and associated metals in PM2.5 collected from an oil field and on their possible effects on production of silk by A. assama. PMID- 26490907 TI - Immobilization of tetracyclines in manure and manure-amended soils using aluminum based drinking water treatment residuals. AB - Veterinary antibiotics (VAs) are emerging contaminants of concern in the environment, mainly due to the potential for development of antibiotic-resistant bacteria and effect on microbiota that could interfere with crucial ecosystem functions such as nutrient cycling and decomposition. High levels of VAs such as tetracyclines (TCs) have been reported in agricultural soils amended with manure, which also has the potential to cause surface and groundwater contamination. Several recent studies have focused on developing methods to immobilize VAs such as composting with straw, hardwood chips, commercial biochar, aeration, mixing, heat treatment, etc. The major shortcomings of these methods include high cost and limited effectiveness. In the current study, we assessed the effectiveness of aluminum-based drinking water treatment residuals (Al-WTR) as a "green" sorbent to immobilize TCs in manure and manure-applied soils with varying physicochemical properties by laboratory incubation study. Results show that Al-WTR is very effective in immobilizing tetracycline (TTC) and oxytetracycline (OTC). The presence of phosphate resulted in significant (p < 0.01) decrease in TTC/OTC sorption by Al-WTR, but the presence of sulfate did not. attenuated total reflection (ATR)-FTIR spectroscopy indicate that TTC and OTC likely forming surface complexes via inner-sphere-type bonds in soils, manure, and manure applied soils amended with Al-WTR. PMID- 26490908 TI - Effects of concentrated leachate injection modes on stabilization of landfilled waste. AB - Injection of concentrated leachate to landfills is a simple and cost-effective technology for concentrated leachate treatment. In this study, the effects of injection mode of concentrated leachate and its hydraulic loading rate on the stabilization of landfilled waste were investigated. Compared with the injection of concentrated leachate, the joint injection of leachate and concentrated leachate (1:1, v/v) was more beneficial to the degradation of landfilled waste and mitigated the discharge amount of pollutants at the hydraulic loading rate of 5.9 L m(-2) day(-1). As the hydraulic loading rate of the joint injection of leachate and concentrated leachate was increased from 5.9 to 17.6 L m(-2) day( 1), the organic matter, biologically degradable matter, and total nitrogen of landfilled waste were degraded more rapidly, with the degradation constant of the first-order kinetics of 0.005, 0.004, and 0.003, respectively. Additionally, NO2( )-N and NO3(-)-N in the concentrated leachate could be well removed in the landfill bioreactors. These results showed that a joint injection of concentrated leachate and raw leachate might be a good way to relieve the inhibitory effect of high concentrations of toxic pollutants in the concentrated leachate and accelerate the stabilization of landfilled waste. PMID- 26490909 TI - Modeling the feedback between aerosol and boundary layer processes: a case study in Beijing, China. AB - Rapid development has led to frequent haze in Beijing. With mountains and sea surrounding Beijing, the pollution is found to be influenced by the mountain plain breeze and sea-land breeze in complex ways. Meanwhile, the presence of aerosols may affect the surface energy balance and impact these boundary layer (BL) processes. The effects of BL processes on aerosol pollution and the feedback between aerosol and BL processes are not yet clearly understood. Thus, the Weather Research and Forecasting model coupled with Chemistry (WRF-Chem) is used to investigate the possible effects and feedbacks during a haze episode on 23 September 2011. Influenced by the onshore prevailing wind, sea-breeze, and upslope breeze, about 45% of surface particulate matter (PM)2.5 in Beijing are found to be contributed by its neighbor cities through regional transport. In the afternoon, the development of upslope breeze suppresses the growth of BL in Beijing by imposing a relatively low thermal stable layer above the BL, which exacerbates the pollution. Two kinds of feedback during the daytime are revealed as follows: (1) as the aerosols absorb and scatter the solar radiation, the surface net radiation and sensible heat flux are decreased, while BL temperature is increased, resulting in a more stable and shallower BL, which leads to a higher surface PM2.5 concentration in the morning and (2) in the afternoon, as the presence of aerosols increases the BL temperature over plains, the upslope breeze is weakened, and the boundary layer height (BLH) over Beijing is heightened, resulting in the decrease of the surface PM2.5 concentration there. PMID- 26490910 TI - Simultaneous acid red 27 decolourisation and bioelectricity generation in a (H type) microbial fuel cell configuration using NAR-2. AB - Microbial fuel cells (MFCs) represent one of the most attractive and eco-friendly technologies that convert chemical bond energy derived from organic matter into electrical power by microbial catabolic activity. This paper presents the use of a H-type MFC involving a novel NAR-2 bacterial consortium consisting of Citrobacter sp. A1, Enterobacter sp. L17 and Enterococcus sp. C1 to produce electricity whilst simultaneously decolourising acid red 27 (AR27) as a model dye, which is also known as amaranth. In this setup, the dye AR27 is mixed with modified P5 medium (2.5 g/L glucose and 5.0 g/L nutrient broth) in the anode compartment, whilst phosphate buffer solution (PBS) pH 7 serves as a catholyte in the cathode compartment. After several electrochemical analyses, the open circuit voltage (OCV) for 0.3 g/L AR27 with 24-h retention time at 30 degrees C was recorded as 0.950 V, whereas (93%) decolourisation was achieved in 220-min operation. The maximum power density was reached after 48 h of operation with an external load of 300 Omega. Scanning electron microscopy (SEM) analysis revealed the surface morphology of the anode and the bacterial adhesion onto the electrode surface. The results of this study indicate that the decolourisation of AR27 dye and electrical power generation was successfully achieved in a MFC operated by a bacterial consortium. The consortium of bacteria was able to utilise AR27 in a short retention time as an electron acceptor and to shuttle the electrons to the anode surface for bioelectricity generation. PMID- 26490911 TI - Biodegradation of benzo(a)pyrene by two freshwater microalgae Selenastrum capricornutum and Scenedesmus acutus: a comparative study useful for bioremediation. AB - A comparative evaluation of the removal of benzo(a)pyrene (BaP) by sorption and degradation by two microalgal species, Selenastrum capricornutum and Scenedesmus acutus was performed. The monitoring of the amount of BaP remaining in the liquid culture media and the biomass along with the appearance of three metabolites (4,5 dihydrodiol-BaP; 7,8-dihydrodiol-BaP; and 9,10 dihydrodiol-BaP) at short time periods (from 0.25 to 72 h) in cultures exposed to BaP was made by high performance liquid chromatography (HPLC) with fluorescence and UV detection. Complete removal of BaP was achieved by the two live microalgal species: S. capricornutum at 15 h of exposure (99%) and S. acutus at 72 h of exposure (95%). Sorption is an important phenomenon for BaP removal by S. capricornutum but biodegradation is the principal means of removing BaP in live cells. The formation of metabolites by S. capricornutum is rapid and seems to be proportional to the amount of the BaP added to cultures. In contrast, in these bioassays, most of the BaP removal of S. acutus is due to sorption rather than degradation. The appearance of metabolites in the cultures is very slow and at a low amount compared to cultures of S. capricornutum. The similarities and differences existing between the two microalgae are important for the establishment of the conditions for bioremediation. PMID- 26490912 TI - Seasonal variations in concentrations, distributions, and air-soil exchange fluxes of dioxin-like polychlorinated biphenyls in Shanghai, China. AB - Dioxin-like polychlorinated biphenyl (dl-PCB) concentrations in ambient air and soil in Shanghai, China, were measured to allow seasonal and spatial differences in the dl-PCB concentrations, profiles, distributions, fugacity fractions, and air-soil fluxes to be determined. The toxic equivalent (TEQ) DL-PCB concentrations in the air were higher in summer (mean 9.46 fg m(-3), range 1.32 26.3 fg m(-3)) than in winter (mean 4.57 fg m(-3), range 1.55-10.9 fg m(-3)). The DL-PCB concentrations in air were different in different areas, and the concentrations decreased in the order industrial areas > commercial and residential areas > suburban areas > rural area. The mean DL-PCB concentration in soil was 0.25 pg TEQ g(-1) dry weight (dw) and the range was 0.05-0.90 pg TEQ g( 1) dw. The highest DL-PCB concentration in soil was found in a sample from a commercial/residential area. The DL-PCB fluxes were negative (-216 pg m(-2) h(-1) in summer and -41.1 pg m(-2) h(-1) in winter), and the fugacity fractions were below 0.5, indicating that dl-PCBs in Shanghai are deposited from the air to the soil in all seasons. The net fluxes were higher in summer than in winter, and the deposition fluxes were higher in industrial areas than in other areas in both summer and winter. PMID- 26490913 TI - Particle-size distribution and phosphorus forms as a function of hydrological forcing in the Yellow River. AB - Samples were collected monthly from January to December in 2010, and daily observations were made during the water-sediment regulation event in June-July 2010. Sequential extractions were applied to determine the forms of P in different particle-size fractions and to assess the potential bioavailability of particulate phosphorus (PP). The results indicated that exchangeable phosphorus, organic phosphorus, authigenic phosphorus, and refractory phosphorus increased with the decreasing of particulate size; conversely, detrital phosphorus decreased with the decreasing of particulate size. The content of bioavailable particulate phosphorus (BAPP) varied greatly in different sizes of particles. In general, the smaller the particle size, the higher the content of bioavailable phosphorus and its proportion in total phosphorous was found in these particles. Hydrological forcing controlled the variability in the major P phases found in the suspended sediments via changes in the sources and the particle grain-size distribution. The variation of particle sizes can be attributed also to different total suspended sediment (TSS) sources. Water-sediment regulation (WSR) mobilized only particulate matter from the riverbed, while during the rainstorm soil erosion and runoff were the main source. The BAPP fluxes associated with the "truly suspended" fraction was approximately 200 times larger than the dissolved inorganic phosphorus (DIP) flux. Thus, the transfer of fine particles to the open sea is most probably accompanied by BAPP release to the DIP and can support greater primary and secondary production. PMID- 26490914 TI - Amazon River dissolved load: temporal dynamics and annual budget from the Andes to the ocean. AB - The aim of the present study is to estimate the export fluxes of major dissolved species at the scale of the Amazon basin, to identify the main parameters controlling their spatial distribution and to identify the role of discharge variability in the variability of the total dissolved solid (TDS) flux through the hydrological cycle. Data are compiled from the monthly hydrochemistry and daily discharge database of the "Programa Climatologico y Hidrologico de la Cuenca Amazonica de Bolivia" (PHICAB) and the HYBAM observatories from 34 stations distributed over the Amazon basin (for the 1983-1992 and 2000-2012 periods, respectively). This paper consists of a first global observation of the fluxes and temporal dynamics of each geomorphological domain of the Amazon basin. Based on mean interannual monthly flux calculations, we estimated that the Amazon basin delivered approximately 272 * 10(6) t year(-1) (263-278) of TDS during the 2003-2012 period, which represents approximately 7 % of the continental inputs to the oceans. This flux is mainly made up by HCO3, Ca and SiO2, reflecting the preferential contributions of carbonate and silicate chemical weathering to the Amazon River Basin. The main tributaries contributing to the TDS flux are the Maranon and Ucayali Rivers (approximately 50 % of the TDS production over 14 % of the Amazon basin area) due to the weathering of carbonates and evaporites drained by their Andean tributaries. An Andes-sedimentary area-shield TDS flux (and specific flux) gradient is observed throughout the basin and is first explained by the TDS concentration contrast between these domains, rather than variability in runoff. This observation highlights that, under tropical context, the weathering flux repartition is primarily controlled by the geomorphological/geological setting and confirms that sedimentary areas are currently active in terms of the production of dissolved load. The log relationships of concentration vs discharge have been characterized over all the studied stations and for all elements. The analysis of the slope of the relationship within the selected contexts reveals that the variability in TDS flux is mainly controlled by the discharge variability throughout the hydrological year. At the outlet of the basin, a clockwise hysteresis is observed for TDS concentration and is mainly controlled by Ca and HCO3 hysteresis, highlighting the need for a sampling strategy with a monthly frequency to accurately determine the TDS fluxes of the basin. The evaporite dissolution flux tends to be constant, whereas dissolved load fluxes released from other sources (silicate weathering, carbonate weathering, biological and/or atmospheric inputs) are mainly driven by variability in discharge. These results suggest that past and further climate variability had or will have a direct impact on the variability of dissolved fluxes in the Amazon. Further studies need to be performed to better understand the processes controlling the dynamics of weathering fluxes and their applicability to present-day concentration-discharge relationships at longer timescales. PMID- 26490915 TI - Prediction of Setschenow constants of N-heteroaromatics in NaCl solutions based on the partial charge on the heterocyclic nitrogen atom. AB - The solubilities of 19 different kinds of N-heteroaromatic compounds in aqueous solutions with different concentrations of NaCl were determined at 298.15 K with a UV-vis spectrophotometry and titration method, respectively. Setschenow constants, Ks, were employed to describe the solubility behavior, and it is found that the higher ring numbers of N-heteroaromatics gave rise to the lower values of Ks. Moreover, Ks showed a good linear relationship with the partial charge on the nitrogen atom (QN) for either QN > 0 or QN < 0 N-heteroaromatics. It further revealed that QN was well-matched in the prediction of salting-out effect for N heteroaromatics compared to the conventional descriptors such as molar volume (VH) and the octanol-water partition coefficient (Kow). The heterocyclic N in N heteroaromatics may interact with Na(+) ions in NaCl solution for QN < 0 and with Cl(-) for QN > 0. PMID- 26490916 TI - Determination of elemental toxicity migration limits, bioaccessibility and risk assessment of essential childcare products. AB - Children especially infants are particularly sensitive to contaminant exposure, they are exposed to toxic substances including heavy metals via multiple pathways, i.e. food, air, water, soil and childcare products. To date, determination of metal bioaccessibility in teethers and feeding teats is missing in the literature; therefore, it is vitally important to assess their metal bioaccessibility and characterise the risk for children. The aim of this study is to determine the migration levels of toxic elements in teethers and feeding teats of different brands as a measure of metal bioaccessibility and characterise the risk for children exposed to these products. The migration limits of several heavy metals (Al, As, Ba, Cd, Co, Cu, Cr, Mn, Ni, Pb, Se, Sr, Zn) in different brands of teethers and feeding teats were determined simultaneously using inductively coupled plasma optical emission spectroscopy (ICP-OES) adopting a protocol in the European standards for safety of toys. With the exception of Pb, the migration limits of all elements in all brands of teethers and feeding teats were below the specified limits. However, in the case of Pb, the migration was above the specified limits in all samples except one brand of feeding teats. Risk assessment expressed as hazard index (HI) was calculated for detected elements and all samples. Although HI was below 1.0 for all samples except one sample, the high Pb concentration would pose a considerable risk to children. Therefore, we recommend a more thorough research and risk characterisation taking into consideration the factors that affect HI values. Graphical Abstract Determination of metal bioaccessibility and risk characterisation of teethers and feeding teats ensure children safety against metal toxicity. PMID- 26490917 TI - Spatial distribution and contamination assessment of six heavy metals in soils and their transfer into mature tobacco plants in Kushtia District, Bangladesh. AB - Although the tobacco production and consumption rate in Bangladesh is very high and a substantial portion of premature deaths is caused by tobacco smoking, the status of heavy metals in tobacco plants has not yet determined. This study, therefore, investigated the concentrations of Cu, Ni, Cd, Pb, Cr, and Zn in tobacco plants and their surrounding agricultural soils in Kushtia District, Bangladesh. The geochemical maps showed a similar spatial distribution pattern of the analyzed metals and identified Shempur, Kharara, Taragunia, and Shantidanga as metal hot spots. Geoanalytical indexes were applied to assess the extent of soil contamination, and the results depicted that the soils of Shempur, Kharara, Taragunia, and Shantidanga were moderately contaminated where Cd contributed the most to contamination degree (C d) in spite of its relative low content. However, other five areas in Kushtia District were suggested as uncontaminated according to both C d and pollution load index (PLI). The hazard quotient (HQ) and hazard index (HI) showed no possible indication of human health risks via ingestion of agricultural soils. This study also determined that human activities such as excess application of commercial fertilizers, animal manures, and metal-based pesticides were the sources of Cu, Ni, Cd, and Cr enrichment in soils and that the metals into tobacco plants were transported from the soils. The present study conclusively suggested that regulation of improper use of agrochemicals and continuous monitoring of heavy metals in tobacco plants are needed to reduce the tobacco-related detrimental health problems in Bangladesh. PMID- 26490918 TI - Use of fallout radionuclides ((7)Be, (210)Pb) to estimate resuspension of Escherichia coli from streambed sediments during floods in a tropical montane catchment. AB - Consumption of water polluted by faecal contaminants is responsible for 2 million deaths annually, most of which occur in developing countries without adequate sanitation. In tropical aquatic systems, streambeds can be reservoirs of persistent pathogenic bacteria and high rainfall can lead to contaminated soils entering streams and to the resuspension of sediment-bound microbes in the streambed. Here, we present a novel method using fallout radionuclides ((7)Be and (210)Pbxs) to estimate the proportions of Escherichia coli, an indicator of faecal contamination, associated with recently eroded soil particles and with the resuspension of streambed sediments. We show that using these radionuclides and hydrograph separations we are able to characterize the proportion of particles originating from highly contaminated soils and that from the resuspension of particle-attached bacteria within the streambed. We also found that although overland flow represented just over one tenth of the total flood volume, it was responsible for more than two thirds of the downstream transfer of E. coli. We propose that data obtained using this method can be used to understand the dynamics of faecal indicator bacteria (FIB) in streams thereby providing information for adapted management plans that reduce the health risks to local populations. Graphical Abstract Graphical abstract showing (1) the main water flow processes (i.e. overland flow, groundwater return flow, blue arrows) and sediment flow components (i.e. resuspension and soil erosion, black arrows) during floods in the Houay Pano catchment; (2) the general principle of the method using fallout radionuclide markers (i.e. (7)Be and (210)Pbxs) to estimate E. coli load from the two main sources (i.e. streambed resuspension vs soil surface washoff); and 3) the main results obtained during the 15 May 2012 storm event (i.e. relative percentage contribution of each process to the total streamflow, values in parentheses). PMID- 26490919 TI - Utilizing a one-dimensional multispecies model to simulate the nutrient reduction and biomass structure in two types of H2-based membrane-aeration biofilm reactors (H2-MBfR): model development and parametric analysis. AB - In this study, a one-dimensional multispecies model (ODMSM) was utilized to simulate NO3(-)-N and ClO4(-) reduction performances in two kinds of H2-based membrane-aeration biofilm reactors (H2-MBfR) within different operating conditions (e.g., NO3(-)-N/ClO4(-) loading rates, H2 partial pressure, etc.). Before the simulation process, we conducted the sensitivity analysis of some key parameters which would fluctuate in different environmental conditions, then we used the experimental data to calibrate the more sensitive parameters MU1 and MU2 (maximum specific growth rates of denitrification bacteria and perchlorate reduction bacteria) in two H2-MBfRs, and the diversity of the two key parameters' values in two types of reactors may be resulted from the different carbon source fed in the reactors. From the simulation results of six different operating conditions (four in H2-MBfR 1 and two in H2-MBfR 2), the applicability of the model was approved, and the variation of the removal tendency in different operating conditions could be well simulated. Besides, the rationality of operating parameters (H2 partial pressure, etc.) could be judged especially in condition of high nutrients' loading rates. To a certain degree, the model could provide theoretical guidance to determine the operating parameters on some specific conditions in practical application. PMID- 26490920 TI - Recent trends in nanomaterials applications in environmental monitoring and remediation. AB - Environmental pollution is one of the greatest problems that the world is facing today, and it is increasing with every passing year and causing grave and irreparable damage to the earth. Nanomaterials, because of their novel physical and chemical characteristics, have great promise to combat environment pollution. Nanotechnology is being used to devise pollution sensor. A variety of materials in their nano form like iron, titanium dioxide, silica, zinc oxide, carbon nanotube, dendrimers, polymers, etc. are increasingly being used to make the air clean, to purify water, and to decontaminate soil. Nanotechnology is also being used to make renewable energy cheaper and more efficient. The use of nanotechnology in agriculture sector will reduce the indiscriminate use of agrochemicals and thus will reduce the load of chemical pollutant. While remediating environment pollution with nanomaterials, it should also be monitored that these materials do not contribute further degradation of the environment. This review will focus broadly on the applications of nanotechnology in the sustainable development with particular emphasis on renewable energy, air-, water , and soil-remediation. Besides, the review highlights the recent developments in various types of nanomaterials and nanodevices oriented toward pollution monitoring and remediation. PMID- 26490921 TI - Partitioning of metals in different binding phases of tropical estuarine sediments: importance of metal chemistry. AB - Distribution of metals in different binding phases of estuarine sediments provides chemically significant description of metal-sediment interactions. This study describes the influences of ligand field stabilization energy (LFSE), Jahn Teller effect, and water exchange rate (k-w) on metal distribution in different binding phases of estuarine sediments. It was found that Cu had highest affinity for organic binding phases in the studied sediments followed by Ni and Pb. However, Pb showed strong association with Fe/Mn oxide phases followed by Ni and Cu. Faster k-w of Cu (II) (1 * 10(9) s(-1)) increased the rate of complex formation of Cu(2+) ion with ligand in the organic phases. The Cu-ligand (from organic phase) complexes gained extra stability by the Jahn-Teller effect. The combined effects of these two phenomena and high ionic potential increased the association of Cu with the organic phases of the sediments than Ni and Pb. The smaller ionic radii of Ni(2+) (0.72 A) than Pb(2+) (1.20 A) increase the stability of Ni-ligand complexes in the organic phase of the sediments. High LFSE of Ni(II) (compared with Pb(2+) ions) also make Ni-organic complexes increasingly stable than Pb. High k-w (7 * 10(9) s(-1)) of Pb did not help it to associate with organic phases in the sediments. The high concentration of Pb in the Fe/Mn oxyhydroxide binding phase was probably due to co-precipitation of Pb(2+) and Fe(3+). High surface area or site availability for Pb(2+) ion on Fe oxyhydroxide phase was probably responsible for the high concentration of Pb in Fe/Mn oxyhydroxide phase. Increasing concentrations of Cu in organic phases with the increasing Cu loading suggest that enough binding sites were available for Cu in the organic binding phases of the sediments. This study also describes the influence of nature of sedimentary organic carbon (terrestrial and marine derived OC) in controlling these metal distribution and speciation in marine sediment. PMID- 26490922 TI - Levels and distributions of polybrominated diphenyl ethers, hexabromocyclododecane, and tetrabromobisphenol A in sediments from Taihu Lake, China. AB - The concentrations and distribution of polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA) were investigated in 28 sediment samples collected from Taihu Lake, Eastern China. The results showed that all three classes of compounds were detected in 28 sediment samples but that PBDEs were the main contaminants in the study area. The total PBDE concentrations ranged from 3.77 to 347 ng/g dry weight (dw) with a mean value of 72.8 ng/g dw, whereas the concentrations ranged from 0.168 to 2.66 and from 0.012 to 1.30 ng/g dw for HBCD and TBBPA, respectively. In all of the sediment samples, BDE-209 was the predominant congener, accounting for 95.9 to 98.6 % of the total PBDEs, which indicated that commercial mixtures of deca-BDEs were the main sources of PBDE contamination. Higher concentrations of PBDEs were found in samples collected from Meiliang Bay and Gonghu Bay near the inflow river, which suggested that inflow runoff might play an important role in the PBDE levels in Taihu Lake sediments. PMID- 26490923 TI - Organic and inorganic components of aerosols over the central Himalayas: winter and summer variations in stable carbon and nitrogen isotopic composition. AB - The aerosol samples were collected from a high elevation mountain site, Nainital, in India (1958 m asl) during September 2006 to June 2007 and were analyzed for water-soluble inorganic species, total carbon, nitrogen, and their isotopic composition (delta(13)C and delta(15)N, respectively). The chemical and isotopic composition of aerosols revealed significant anthropogenic influence over this remote free-troposphere site. The amount of total carbon and nitrogen and their isotopic composition suggest a considerable contribution of biomass burning to the aerosols during winter. On the other hand, fossil fuel combustion sources are found to be dominant during summer. The carbon aerosol in winter is characterized by greater isotope ratios (av. -24.00/00), mostly originated from biomass burning of C4 plants. On the contrary, the aerosols in summer showed smaller delta(13)C values (-26.00/00), indicating that they are originated from vascular plants (mostly of C3 plants). The secondary ions (i.e., SO4 (2-), NH4 (+), and NO3 (-)) were abundant due to the atmospheric reactions during long-range transport in both seasons. The water-soluble organic and inorganic compositions revealed that they are aged in winter but comparatively fresh in summer. This study validates that the pollutants generated from far distant sources could reach high altitudes over the Himalayan region under favorable meteorological conditions. PMID- 26490924 TI - Quantitatively evaluating detoxification of the hepatotoxic microcystin-LR through the glutathione (GSH) pathway in SD rats. AB - Glutathione (GSH) plays crucial roles in antioxidant defense and detoxification metabolism of microcystin-LR (MC-LR). However, the detoxification process of MC LR in mammals remains largely unknown. This paper, for the first time, quantitatively analyzes MC-LR and its GSH pathway metabolites (MC-LR-GSH and MC LR-Cys) in the liver of Sprague-Dawley (SD) rat after MC-LR exposure. Rats received intraperitoneal (i.p.) injection of 0.25 and 0.5 lethal dose 50 (LD50) of MC-LR with or without pretreatment of buthionine-(S,R)-sulfoximine (BSO), an inhibitor of GSH synthesis. The contents of MC-LR-GSH were relatively low during the experiment; however, the ratio of MC-LR-Cys to MC-LR reached as high as 6.65 in 0.5 LD50 group. These results demonstrated that MC-LR-GSH could be converted to MC-LR-Cys efficiently, and this metabolic rule was in agreement with the data of aquatic animals previously reported. MC-LR contents were much higher in BSO + MC-LR-treated groups than in the single MC-LR-treated groups. Moreover, the ratio of MC-LR-Cys to MC-LR decreased significantly after BSO pretreatment, suggesting that the depletion of GSH induced by BSO reduced the detoxification of MCs. Moreover, MC-LR remarkably induced liver damage, and the effects were more pronounced in BSO pretreatment groups. In conclusion, this study verifies the role of GSH in the detoxification of MC-LR and furthers our understanding of the biochemical mechanism for SD rats to counteract toxic cyanobacteria. PMID- 26490925 TI - Levels of dioxin-like PCBs in low-volume serum samples of male patients attending fertility clinics. AB - An accurate and easy method for the extraction, cleanup, and HRGC-HRMS analysis of dioxin-like PCBs (DL-PCBs) in low-volume serum samples (1 mL) was developed. Serum samples were extracted several times using n-hexane and purified by acid washing. Recovery rates of labeled congeners ranged from 70 to 110% and the limits of detection were below 1 pg/g on lipid basis. Although human studies are limited and contradictory, several studies have shown that DL-PCBs can have adverse effects on the male reproductive system. In this way, the present method was applied to 21 serum samples of male patients attending fertility clinics. The total levels obtained for the patients ranged from 6.90 to 84.1 pg WHO-TEQ/g lipid, with a mean value of 20.3 pg WHO-TEQ/g lipid. The predominant PCBs (the sum of PCB 118, 156, and 105) contributed 67% to the mean concentration of total DL-PCBs in the samples analyzed. PMID- 26490926 TI - Bioaccumulation of macro- and trace elements by European frogbit (Hydrocharis morsus-ranae L.) in relation to environmental pollution. AB - The aim of present study was to investigate the level of trace metals and macroelements in Hydrocharis morsus-ranae collected from regions differing in the degree and type of pollution. Concentrations of 17 macro- and microelements were determined in roots and shoots of European frogbit as well as in water and bottom sediments from 30 study sites. Plants differed in concentrations of elements and bioaccumulation capacity depending on the characteristics of dominant anthropogenic activities in the vicinity of the sampling site. Shoots of H. morsus-ranae growing in the vicinity of organic chemistry plants and automotive industry contained particularly high levels of Cd, Co, and S. Plants from area close to heat and power plant, former ferrochrome industry and new highway, were distinguished by the highest concentrations of Cr, Cu, and Pb. European frogbit from both these regions contained more Fe, Hg, Mn, Ni, and Zn than plants from agricultural and recreational areas. The concentrations of alkali metals and Co, Fe, and N in H. morsus-ranae were elevated in relation to the natural content in macrophytes irrespectively to their content in the environment. Based on the values of Bioaccumulation and Translocation Factors, European frogbit is an accumulator for Co, Cr, Cu, Fe, K, Mn, Ni, Pb, and Zn and a good candidate for phytoremediation of water polluted with Co, Cu, Hg, K, Mn, and Ni. The amount of Co and Mn removed from water and accumulated in the plant biomass during the vegetation season was considerably high. PMID- 26490927 TI - Dissipation and transport of quizalofop-p-ethyl herbicide in sunflower cultivation under field conditions. AB - In the present study, the field dissipation and transport of quizalofop-p-ethyl by water and sediment runoff were investigated in sunflower experimental cultivation under Mediterranean conditions. The cultivation was carried out in silty clay soil plots with two different slopes of 1 and 5%. The soil dissipation rate of quizalofop-p-ethyl was fast and can be described by both single first order (SFO) and Gustafson and Holden (first-order multi compartment (FOMC)) kinetics. The half-life of quizalofop-p-ethyl ranged from 0.55 to 0.68 days and from 0.45 to 0.71 days when SFO and FOMC kinetics were applied, respectively. No herbicide residues were detected below the 10-cm soil layer. A single detection of quizalofop-p-ethyl was observed in runoff water (3 days after application (DAA)) at relatively low concentrations (from 1.70 to 2.04 MUg L(-1)). In sediment, it was detected in the samplings of 3 and 25 DAA at concentrations that never exceeded 0.126 MUg g(-1). The estimated total losses of quizalofop-p-ethyl as percentage of the initial applied active ingredient were low both in water and sediment (less than of 0.021 and 0.005%, respectively). Quizalofop-p-ethyl residues were detectable for 18 DAA in the stems and leaves of the plants and 6 DAA in the root system. No herbicide residues were detected in inflorescences and seeds of sunflower plants. Experimental data showed minimal risk for the contamination of soil and adjacent water bodies. PMID- 26490928 TI - Bioaccumulation of polycyclic aromatic hydrocarbons and survival of earthworms (Eisenia andrei) exposed to biochar amended soils. AB - Biochar has a charcoal polycyclic aromatic structure which allows its long half life in soil, making it an ideal tool for C sequestration and for adsorption of organic pollutants, but at the same time raises concerns about possible adverse impacts on soil biota. Two biochars were tested under laboratory-controlled conditions on Eisenia andrei earthworms: a biochar produced at low temperature from wine tree cuttings (WTB) and a commercial low tar hardwood lump charcoal (HLB). The avoidance test (48-h exposure) showed that earthworms avoid biochar treated soil with rates higher than 16 t ha(-1) for HLB and 64 t ha(-1) for WTB. After 42 days, toxic effects on earthworms were observed even at application rates (100 t ha(-1)) that are generally considered beneficial for most crops. The concentration of HLB and WTB required to kill half of earthworms' population (LC50; 95% confidence limits) in the synthetic OECD soil was 338 and 580 t ha( 1), respectively. Accumulation of polycyclic aromatic hydrocarbons (PAH) in earthworms exposed to the two biochar types at 100 t ha(-1) was tested in two soils of different texture. In biochar-treated soils, the average earthworm survival rates were about 64% in the sandy and 78% clay-loam soils. PAH accumulation was larger in the sandy soil and largest in soils amended with HLB. PAH with less than four rings were preferentially scavenged from the soil by biochars, and this behaviour may mask that of the more dangerous components (i.e. four to five rings), which are preferentially accumulated. Earthworms can accumulate PAH as a consequence of exposure to biochar-treated soils and transfer them along the food chain. Soil type and biochar quality are both relevant in determining PAH transfer. PMID- 26490929 TI - Indoor air quality at life and work environments in Rome, Italy. AB - The air quality of three different microenvironments (school, dwelling, and coffee bar) located in the city of Rome, Italy, was assessed. Indoor and outdoor concentrations of polycyclic aromatic hydrocarbons (PAHs) associated with PM2.5 particles were determined during an intensive 3-week sampling campaign conducted in March 2013. In interiors, total particulate PAHs ranged from 1.53 to 4.96 ng/m(3) while outdoor air contained from 2.75 to 3.48 ng/m(3). In addition, gaseous toxicants, i.e., NO2, NOx , SO2, O3, and BTEX (benzene, toluene, ethyl benzene, and xylene isomers), were determined both in internal and external air. To solve the origin of indoor and outdoor PAHs, several source apportionment methods were applied. Multivariate analysis revealed that emissions from motor vehicles, biomass burning for heating purposes, and soil resuspension were the major sources of PAHs in the city. No linear correlation was established between indoor and outdoor values for PM2.5 and BTEX; the respective indoor/outdoor concentration ratios exceed unity except for PM2.5 in the no smoking home and benzene in all school floors. This suggests that important internal sources such as tobacco smoking, cleaning products, and resuspension dust contributed to indoor pollution. Using the monitoring stations of ARPA Lazio regional network as reference, the percentage within PAH group of benzo[a]pyrene, which is the WHO marker for the carcinogenic risk estimates, was ca. 50% higher in all locations investigated. PMID- 26490930 TI - A fusant of Amycolatopsis sp. M3-1 and Pseudomonas sp. Nai8 with high capacity of degrading novel pyrimidynyloxybenzoic herbicide ZJ0273 and naphthalene. AB - ZJ0273 (propyl 4-(2-(4, 6-demethoxy pyrimidin-2-yloxy) benzylamino) benzoate) is a novel pyrimidynyloxybenzoic-based herbicide developed in China for oilseed crop. This study was aimed to construct new strains capable of degrading naphthalene and ZJ0273 by protoplast fusion between Amycolatopsis sp. M3-1 and Pseudomonas sp. Nai8. Eight recombinant strains were successfully produced, and the strains could simultaneously utilize ZJ0273 and naphthalene as the sole carbon and energy source, respectively. One of recombinant strains, MN6 with higher degrading efficiency, was chosen for further study. Under the condition of pH 7.0, 30 degrees C, ZJ0273 and naphthalene degradation percent by the recombinant strain MN6 could reach 65.10% (20 days) and 88.46% (48 h), respectively. According to the identified six metabolites (M1-M6) by LC-MS/MS, biodegradation pathway of ZJ0273 was proposed. ZJ0273 biodegradation catalyzed by the recombinant strain MN6 involved continuous biocatalytic reactions such as de estering, hydrolysis, acylation, C-N cleavage, de-methyl, and ether cleavage reactions. PMID- 26490931 TI - Urban riverine environment is a source of multidrug-resistant and ESBL-producing clinically important Acinetobacter spp. AB - Some Acinetobacter species have emerged as very important opportunistic pathogens in humans. We investigated Acinetobacter spp. from the polluted urban riverine environment in Croatia in regard to species affiliation, antibiotic resistance pattern, and resistance mechanisms. Considerable number of isolates produced acquired extended-spectrum beta-lactamase(s) (ESBLs), CTX-M-15 solely or with TEM 116. By Southern blot hybridization, bla TEM-116 was identified on plasmids ca. 10, 3, and 1.2 kb in Acinetobacter junii, A. gandensis, and A. johnsonii. The bla TEM-116-carrying plasmid in A. gandensis was successfully transferred by conjugation to azide-resistant Escherichia coli J53. A. radioresistens isolate also carried an intrinsic carbapenemase gene bla OXA-133 with ISAba1 insertion sequence present upstream to promote its expression. Majority of ESBL-producing isolates harbored integrases intI1 and/or intI2 and the sulfamethoxazole resistance gene sul1. Almost all isolates had overexpressed resistance-nodulation cell division (RND) efflux system, indicating that this mechanism may have contributed to multidrug resistance phenotypes. This is the first report of environmental CTX-M-15-producing Acinetobacter spp. and the first identification of CTX-M-15 in A. johnsonii, A. junii, A. calcoaceticus, A. gandensis, A. haemolyticus, and A. radioresistens worldwide. We identified, also for the first time, the environmental Acinetobacter-producing TEM ESBLs, highlighting the potential risk for human health, and the role of these bacteria in maintenance and dissemination of clinically important antibiotic resistance genes in community through riverine environments. PMID- 26490933 TI - Phytoscreening-based assessment of mercury in soil. AB - This study was conducted to determine whether phytoscreening techniques could be used to characterize the distribution of Hg in soil at the South River, VA. An estimated 500 to 1000 kg of Hg was released to the South River in the 1930s and 1940s from a synthetic fiber manufacturing plant located in Waynesboro, contaminating the floodplain downstream. Under background conditions (soil Hg <0.03 MUg/g), phytoscreening sample Hg concentrations ranged from 1.9 to 3.9 ng/g. With soil Hg concentrations ranging from 0.1 to 94 MUg/g in the top 30.5 cm of nearby soil, phytoscreening sample Hg concentrations ranged from 5.0 to 145 ng/g. The variability of Hg concentrations in soil solution over the scale of the entire rhizosphere of the large trees sampled was likely high. Furthermore, the mean depth of water uptake and the exact proximity of the soil profile samples for each tree could not be determined. Nevertheless, the phytoscreening results of this study could be used to reliably provide a qualitative delineation of Hg contaminated soil. PMID- 26490932 TI - Serum concentrations of PCBs and OCPs among prepubertal Korean children. AB - Although children are more vulnerable than adults to environmental hazards, due to their physiological and behavioral characteristics, few studies have assessed their internal exposure to persistent organic pollutants (POPs). The objective of this study was to determine the serum levels of certain polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) among pre-pubertal children in Korea and examine their variation with age and gender. We analyzed a total of 51 POPs in 214 children (age range, 7-9 years), using data from the Ewha Birth and Growth Cohort Study. To examine change over time, POP concentrations were measured at both 7 and 9 years of age in a sub-cohort of 26 children. The median and interquartile range (IQR, 25th to 75th percentiles) data for the sum of PCB congeners was 26.44 ng/g lipid (18.27-37.63 ng/g lipid). The median (IQR) concentration for the sum of OCPs was 74.82 ng/g lipid (51.11-112.45 ng/g lipid). Our results showed significant increases in serum concentrations of total PCBs with age (p = 0.0001), no gender dependence of total PCBs (p = 0.38) and total OCPs (p = 0.12), and strong correlations between individual POPs. Childhood exposure to POPs was relatively low compared to other studies carried out in different countries. However, even though the use of POPs has been banned since 2001, our results indicated that children in the general population are still exposed to various POPs. Because long-term, low-level exposure to POPs in the general population remains a concern for human health, future research should examine major routes of exposure and identification of risk factors. PMID- 26490934 TI - Effect of freeze-thaw cycles and 4-nonylphenol on cellular energy allocation in the freeze-tolerant enchytraeid Enchytraeus albidus. AB - Due to climate change and intense anthropogenic activity, organisms from cold regions are often exposed to combined effects of temperature fluctuations and contaminants. In this investigation, we assessed the lipid, protein, and carbohydrate energy budgets; the energy available (Ea); consumed (Ec); and cellular energy allocation (CEA) of the freeze-tolerant Enchytraeus albidus, when exposed to sublethal concentrations of 4-nonylphenol (a lipophilic contaminant) for 7 days, followed by exposure to different temperature regimes (continuous 2 degrees C, continuous -4 degrees C, and daily freeze-thaw cycles (FTC) (2 to -4 degrees C) for additional 10 days. Results showed that a pre-exposure to 4 nonylphenol (4-NP) induced important changes in the worms' energy budgets and CEA and increased mortality with most severe effects observed for the FTC events. For FTC, lipids were the most accumulated energy source, whereas during freezing (-4 degrees C), proteins were the most used. FTC caused the highest Ec, indicating the higher energy requirements for organisms when shifting between freezing and thawing events. This is also in line with the higher mortality observed in FTC compared to continuous -4 degrees C or 2 degrees C. Worms exposed to continuous freezing presented relatively stable and positive levels of Ea and low levels of Ec, possibly related with the decrease in metabolism. PMID- 26490935 TI - Polycyclic aromatic hydrocarbons (PAHs) at traffic and urban background sites of northern Greece: source apportionment of ambient PAH levels and PAH-induced lung cancer risk. AB - Thirteen particle-phase PAHs, including nine >4-ring congeners [Benz[a]anthracene (BaAn), Chrysene (Chry), Benzo[b]fluoranthene (BbF), Benzo[k]fluoranthene (BkF), Benzo[e]pyrene (BeP), Benzo[a]pyrene (BaP), Dibenzo[a,h]anthracene (dBaAn), Benzo[g,h,i]perylene (BghiPe), Indeno(1,2,3-c,d)pyrene (IP)], listed by IARC (International Agency for Research on Cancer) as class 1, class 2A, and 2B carcinogens, plus four <= 4-ring congeners [Phenanthrene (Ph), Anthracene (An), Fluoranthene (Fl), Pyrene (Py)], were concurrently measured in inhalable and respirable particle fractions (PM10 and PM2.5) at a heavy-traffic and an urban background site in Thessaloniki, northern Greece, during the warm and the cold period of the year. Carcinogenic and mutagenic potencies of the PAH-bearing particles were calculated, and the inhalation cancer risk (ICR) for local population was estimated. Finally, Chemical Mass Balance (CMB) modeling was employed for the source apportionment of ambient PAH levels and the estimated lung cancer risk. Resulted inhalation cancer risk during winter was found to be equivalent in the city center and the urban background area suggesting that residential wood burning may offset the benefits from minor traffic emissions. PMID- 26490936 TI - Spatiotemporal patterns of surface-suspended particulate matter in the Three Gorges Reservoir. AB - An investigation was conducted in the Three Gorges Reservoir (TGR) seasonally from September 2010 to June 2011 to screen the distribution pattern of suspended particulate matter (SPM). Concentration of SPM, particulate nitrogen (PN), particulate phosphorus (PP), bioavailable particulate phosphorus (BAPP), and chlorophyll a (Chl a) were determined synchronously. Concentration of SPM was higher in the flood season than in the dry season and higher in the mainstream than in the tributaries. Chl a, PN, PP, and BAPP showed similar temporal pattern with SPM distribution. Particulate elements were significantly correlated with concentrations of SPM (p < 0.05). The proportion of algae-derived SPM in total SPM was higher in the tributaries than that in the mainstream. The results revealed that the spatiotemporal heterogeneity determined by hydrodynamics was the characteristic of SPM distribution. The source of SPM was mostly allochthonous. It could be deduced that SPM was an important factor affecting the water quality and algal growth in TGR by releasing or absorbing particulate nutrient. PMID- 26490937 TI - Changes in gametophyte physiology of Pteris multifida induced by the leaf leachate treatment of the invasive Bidens pilosa. AB - In recent years, the response of fern gametophytes to environment has raised much attention. However, studies on the influence of plant invasion to fern gametophytes are scarce. Allelopathy plays an important role in biological invasion. Hence, it is necessary to study the allelopathic effects of invasive plants on fern gametophytes and elucidate the mechanisms by which invasive plants cause phytotoxicity. As one of the main invasive plants in China, Bidens pilosa exhibits allelopathic effects on spermatophyte growth. Field investigation shows that many ferns are threatened by the invasion of B. pilosa. The distribution of Pteris multifida overlaps with that of B. pilosa in China. To examine the potential involvement of allelopathic mechanisms of B. pilosa leaves, changes in the physiology in P. multifida gametophytes are analyzed. We found that cell membrane and antioxidant enzyme activities as well as photosynthesis pigment contents of the gametophytes were affected by B. pilosa leachates. Gametophytes of P. multifida exposed to B. pilosa had increased damages to cell membranes, expressed in thiobarbituric acid reacting substance (TBARS) concentrations, malondialdehyde (MDA), electrolyte leakage (membrane permeability), and degree of injury. Enzyme activities, assessed by superoxide dismutase (SOD) and catalase (CAT) as well as guaiacol peroxidase (GPX) enhanced with the increase in leachate concentration after 2-day exposure. Meanwhile, lower chlorophyll a (Chl a), chlorophyll b (Chl b), carotenoid (Car), and the total chlorophyll were measured as leachate concentrations increased. At day 10, leaf leachates of B. pilosa exhibited the greatest inhibition. These results suggest that the observed inhibitory or stimulatory effects on the physiology studied can have an adverse effect on P. multifida and that allelopathic interference seems to have involved in this process. PMID- 26490938 TI - Biomarker modulation associated with marine diesel contamination in the Iceland scallop (Chlamys islandica). AB - The decrease of ice cover in the Arctic will lead to an increase of ship traffic in the upcoming decades. Consequently, oil pollution is expected. In this context, the goals of this study were to evaluate the biological impact of marine diesel contamination and, on this basis, to determine analytical tools of interest (biomarkers) for future biomonitoring of diesel spills. Using a 7-day contamination protocol, this study investigated biochemical modulations in the digestive gland of the Iceland scallop (Chlamys islandica). Incorporation of contaminants was verified assessing haemolymph metabolites. Results showed a response of glutathione-S-transferase to contamination suggesting detoxification processes and the suitability of such a tool for diesel spill biomonitoring. The lack of modulation of superoxide dismutase activity and lipid peroxidation suggests no oxidative stress and the unsuitability of these molecular tools for biomonitoring. PMID- 26490939 TI - Effects of sulfate on microcystin production, photosynthesis, and oxidative stress in Microcystis aeruginosa. AB - Increasing sulfate in freshwater systems, caused by human activities and climate change, may have negative effects on aquatic organisms. Microcystis aeruginosa (M. aeruginosa) is both a major primary producer and a common toxic cyanobacterium, playing an important role in the aquatic environment. This study first investigated the effects of sulfate on M. aeruginosa. The experiment presented here aims at analyzing the effects of sulfate on physiological indices, molecular levels, and its influencing mechanism. The results of our experiment showed that sulfate (at 40, 80, and 300 mg L(-1)) inhibited M. aeruginosa growth, increased both intracellular and extracellular toxin contents, and enhanced the mcyD transcript level. Sulfate inhibited the photosynthesis of M. aeruginosa, based on the decrease in pigment content and the down-regulation of photosynthesis-related genes after sulfate exposure. Furthermore, sulfate decreased the maximum electron transport rate, causing the cell to accumulate surplus electrons and form reactive oxygen species (ROS). Sulfate also increased the malondialdehyde (MDA) content, which showed that sulfate damaged the cytomembrane. This damage contributed to the release of intracellular toxin to the culture medium. Although sulfate increased superoxide dismutase (SOD) activities, expression of sod, and total antioxidant capacity in M. aeruginosa, it still overwhelmed the antioxidant system since the ROS level simultaneously increased, and finally caused oxidative stress. Our results indicate that sulfate has direct effects on M. aeruginosa, inhibits photosynthesis, causes oxidative stress, increases toxin production, and affects the related genes expression in M. aeruginosa. PMID- 26490940 TI - Experimental and numerical characterization of floc morphology: role of changing hydraulic retention time under flocculation mechanisms. AB - The formation, breakage, and re-growth of flocs were investigated by using modified flocculation tests and numerical simulation to explore the evolution of floc morphology for different hydraulic retention times. The shorter the aggregation time was, the smaller the flocs produced for the same hydraulic conditions were. Another interesting discovery was that broken flocs that formed in shorter aggregation time had the capacity to completely recover, whereas those formed in a longer amount of time had rather worse reversibility of broken flocs. With the addition of the maximum motion step in the representative two dimensional diffusion-limited aggregation (DLA) model, there was a transition for flocs from isotropic to anisotropic as the maximum motion step increased. The strength of flocs was mainly affected by the distribution of particles near the aggregated core rather than distant particles. A simplified breakage model, which found that broken flocs provided more chances for diffused particles to access the inner parts of flocs and to be uniformly packed around the aggregated core, was first proposed. Moreover, an important result showed that the floc fragments formed with a larger value of the maximum motion step had more growing sites than did those with a smaller msa value, which was a benefit of following the re forming procedure. PMID- 26490941 TI - Characteristics of particle coagulation in an underground parking lot. AB - Particles in vehicle exhaust plumes in underground parking lots have adverse health effects due to the enclosed environment in which they are released and the temperature difference between the tailpipe and ambient environment; at the same time, particle coagulation might be obvious near the tailpipe in an underground parking lot. In the present study, airflow and temperature fields were calculated using the Realizable k-epsilon model, and the Eulerian particle transport model was selected in the numerical simulation of particle concentration dispersion. Polydisperse thermal coagulation due to Brownian collisions was employed to calculate the particle coagulation. The results show that particle coagulation rate and half-time were significant within 1 m from the tailpipe. The variations in the particle coagulation rate and half-time were similar, but their directions were opposite. Air exhaust time was nearly four times longer than averaged half time and 40 times longer than minimum half-time. The peak particle diameter increased approximately 1.43 times due to coagulation. A double particle concentration at the tailpipe caused the fourfold rise in the particle coagulation rate in the distance ranging less than 1 m from the tailpipe. An increase in exhaust velocity at the tailpipe could shorten the obvious range of particle coagulation along the centerline of the tailpipe from 1 to 0.8 m in the study. PMID- 26490942 TI - QSAR models for removal rates of organic pollutants adsorbed by in situ formed manganese dioxide under acid condition. AB - Manganese dioxide formed in oxidation process by potassium permanganate exhibits promising adsorptive capacity which can be utilized to remove organic pollutants in wastewater. However, the structure variances of organic molecules lead to wide difference of adsorption efficiency. Therefore, it is of great significance to find a general relationship between removal rate of organic compounds and their quantum parameters. This study focused on building up quantitative structure activity relationship (QSAR) models based on experimental removal rate (r(exp)) of 25 organic compounds and 17 quantum parameters of each organic compounds computed by Gaussian 09 and Material Studio 6.1. The recommended model is rpre = 0.502-7.742 f(+)x + 0.107 E HOMO + 0.959 q(H(+)) + 1.388 BOx. Both internal and external validations of the recommended model are satisfied, suggesting optimum stability and predictive ability. The definition of applicability domain and the Y-randomization test indicate all the prediction is reliable and no possibility of chance correlation. The recommended model contains four variables, which are closely related to adsorption mechanism. f(+)x reveals the degree of affinity for nucleophilic attack. E HOMO represents the difficulty of electron loss. q(H(+)) reflect the distribution of partial charge between carbon and hydrogen atom. BO x shows the stability of a molecule. PMID- 26490943 TI - Characterizing air quality data from complex network perspective. AB - Air quality depends mainly on changes in emission of pollutants and their precursors. Understanding its characteristics is the key to predicting and controlling air quality. In this study, complex networks were built to analyze topological characteristics of air quality data by correlation coefficient method. Firstly, PM2.5 (particulate matter with aerodynamic diameter less than 2.5 MUm) indexes of eight monitoring sites in Beijing were selected as samples from January 2013 to December 2014. Secondly, the C-C method was applied to determine the structure of phase space. Points in the reconstructed phase space were considered to be nodes of the network mapped. Then, edges were determined by nodes having the correlation greater than a critical threshold. Three properties of the constructed networks, degree distribution, clustering coefficient, and modularity, were used to determine the optimal value of the critical threshold. Finally, by analyzing and comparing topological properties, we pointed out that similarities and difference in the constructed complex networks revealed influence factors and their different roles on real air quality system. PMID- 26490944 TI - Quantitative Proteomics Analysis of Vitreous Humor from Diabetic Retinopathy Patients. AB - Initial triggers for diabetic retinopathy (DR) are hyperglycemia-induced oxidative stress and advanced glycation end-products. The most pathological structural changes occur in retinal microvasculature, but the overall development of DR is multifactorial, with a complex interplay of microvascular, neurodegenerative, genetic/epigenetic, immunological, and secondary inflammation related factors. Although several individual factors and pathways have been associated with retinopathy, a systems level understanding of the disease is lacking. To address this, we performed mass spectrometry based label-free quantitative proteomics analysis of 138 vitreous humor samples from patients with nonproliferative DR or the more severe proliferative form of the disease. Additionally, we analyzed samples from anti-VEGF (vascular endothelial growth factor) (bevacizumab)-treated patients from both groups. In our study, we identified 2482 and quantified the abundancy of 1351 vitreous proteins. Of these, the abundancy of 230 proteins was significantly higher in proliferative retinopathy compared with nonproliferative retinopathy. This specific subset of proteins was linked to inflammation, complement, and coagulation cascade proteins, protease inhibitors, apolipoproteins, immunoglobulins, and cellular adhesion molecules, reflecting the multifactorial nature of the disease. The identification of the key molecules of the disease is critical for the development of new therapeutic molecules and for the new use of existing drugs. PMID- 26490945 TI - Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease. AB - BACKGROUND: Long-acting bronchodilators, comprising long-acting beta2-agonists (LABA) and long-acting anti-muscarinic agents (LAMA, principally tiotropium), are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease (COPD). Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and LABAs for the treatment of COPD are unclear. OBJECTIVES: To compare the relative effects on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in people with COPD randomised to LABA plus tiotropium versus tiotropium alone; or LABA plus tiotropium versus LABA alone. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials and ClinicalTrials.gov up to July 2015. SELECTION CRITERIA: We included parallel-group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to LABA against tiotropium or LABA alone for people with COPD. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials. MAIN RESULTS: This review included 10 trials on 10,894 participants, mostly recruiting participants with moderate or severe COPD. All of the trials compared tiotropium in addition to LABA to tiotropium alone, and four trials additionally compared LAMA plus LABA with LABA alone. Four studies used the LABA olodaterol, three used indacaterol, two used formoterol, and one used salmeterol.Compared to tiotropium alone, treatment with tiotropium plus LABA resulted in a slightly larger improvement in mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) (mean difference (MD) -1.34, 95% confidence interval (CI) -1.87 to -0.80; 6709 participants; 5 studies). The MD was smaller than the four units that is considered clinically important, but a responder analysis indicated that 7% more participants receiving tiotropium plus LABA had a noticeable benefit (greater than four units) from treatment in comparison to tiotropium alone. In the control arm in one study, which was tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with tiotropium plus LABA the improvement was a fall of a further 1.3 units (on average). Most of the data came from studies using olodaterol. High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator forced expiratory volume in one second (FEV1) showed a small mean increase with the addition of LABA over the control arm (MD 0.06, 95% CI 0.05 to 0.07; 9573 participants; 10 studies), which showed a change from baseline ranging from 0.03 L to 0.13 L with tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There was moderate heterogeneity for both exacerbations and withdrawals.This review included data on four LABAs: two administered twice daily (salmeterol, formoterol) and two once daily (indacaterol, olodaterol). The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.Comparing LABA plus tiotropium treatment with LABA alone, there was a small but significant improvement in SGRQ (MD -1.25, 95% CI -2.14 to -0.37; 3378 participants; 4 studies). The data came mostly from studies using olodaterol and, although the difference was smaller than four units, this still represented an increase of 10 people with a clinically important improvement for 100 treated. There was also an improvement in FEV1 (MD 0.07, 95% CI 0.06 to 0.09; 3513 participants; 4 studies), and in addition an improvement in exacerbation rates (odds ratio (OR) 0.80, 95% CI 0.69 to 0.93; 3514 participants; 3 studies). AUTHORS' CONCLUSIONS: The results from this review indicated a small mean improvement in health-related quality of life and FEV1 for participants on a combination of tiotropium and LABA compared to either agent alone, and this translated into a small increase in the number of responders on combination treatment. In addition, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not. Hospital admission and mortality were not altered by adding LABA to tiotropium, although there may not be enough data. While it is possible that this is affected by higher attrition in the tiotropium group, one would expect that participants withdrawn from the study would have had less favourable outcomes; this means that the expected direction of attrition bias would be to reduce the estimated benefit of the combination treatment. The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other. PMID- 26490946 TI - Conjugative transfer of a derivative of the IncP-1alpha plasmid RP4 and establishment of transconjugants in the indigenous bacterial community of poplar plants. AB - The persistence of traits introduced into the indigenous bacterial community of poplar plants was investigated using bioluminescence mediated by the luc gene. Three endophytic bacterial strains provided with the IncP-1alpha plasmid RP4-Tn luc were used to inoculate poplar cuttings at different phenological stages. Screening of isolates by bioluminescence and real-time PCR detection of the luc gene revealed stable persistence for at least 10 weeks. Although the inoculated strains became established with a high population density after inoculation at leaf development (April) and senescence (October), the strains were suppressed by the indigenous bacteria at stem elongation (June). Transconjugants could be detected only at this phenological stage. Indigenous bacteria harbouring RP4-Tn luc became established with densities ranging from 2 * 10(5) to 9 * 10(6) CFU g( 1) fresh weight 3 and 10 weeks after inoculation. The increased colonization of the cuttings by indigenous bacteria at stem elongation seemed to strongly compete with the introduced strains. Otherwise, the phenological stage of the plants as well as the density of the indigenous recipients could serve as the driver for a more frequent conjugative plasmid transfer. A phylogenetic assignment of transconjugants indicated the transfer of RP4-Tn-luc into six genera of Proteobacteria, mainly Sphingomonas, Stenotrophomonas and Xanthomonas. PMID- 26490947 TI - Bacterial production and secretion of water-insoluble fuel compounds from cellulose without the supplementation of cellulases. AB - Achieving economic biofuel production from cellulosic biomass will require significant cost reductions. Enzymatic degradation of cellulosic biomass and distillation of water-soluble fuel compounds substantially increase the cost of biofuel production. Consolidated bioprocessing is a strategy to circumvent expensive biofuel production steps. Clostridium thermocellum is a promising bacterium for consolidated bioprocessing because it does not require the supplementation of lignocellulose-degrading enzymes. To produce water-insoluble fuel compounds, C. thermocellum was engineered to express a fatty acyl-acyl carrier protein reductase and an aldehyde-deformylating oxygenase from Synechococcus elongatus PCC 7942. Expression of the aldehyde-deformylating oxygenase gene was clearly detected, whereas only slight expression of the fatty acyl-acyl carrier protein reductase gene was detected. Cells expressing the fatty acyl-acyl carrier protein reductase and the aldehyde-deformylating oxygenase accumulated fatty aldehydes (higher alcohol precursors). After cultivation with cellulose, the higher alcohols, decanol and dodecanol, were detected in the organic solvent phase of the culture broth, indicating that the strain secreted the higher alcohols. These results suggest that the engineered C. thermocellum strain, expressing fatty acyl-acyl carrier protein reductase and aldehyde deformylating oxygenase genes, directly produces and secretes higher alcohols from cellulose without the supplementation of cellulases. The higher alcohols can be collected by phase separation. PMID- 26490948 TI - Probing the effect of OSCE checklist length on inter-observer reliability and observer accuracy. AB - PURPOSE: The Objective Structured Clinical Examination (OSCE) is a widely employed tool for measuring clinical competence. In the drive toward comprehensive assessment, OSCE stations and checklists may become increasingly complex. The objective of this study was to probe inter-observer reliability and observer accuracy as a function of OSCE checklist length. METHOD: Study participants included emergency physicians and senior residents in Emergency Medicine at Dalhousie University. Participants watched an identical series of four, scripted, standardized videos enacting 10-min OSCE stations and completed corresponding assessment checklists. Each participating observer was provided with a random combination of two 40-item and two 20-item checklists. A panel of physicians scored the scenarios through repeated video review to determine the 'gold standard' checklist scores. RESULTS: Fifty-seven observers completed 228 assessment checklists. Mean observer accuracy ranged from 73 to 93% (14.6 18.7/20), with an overall accuracy of 86% (17.2/20), and inter-rater reliability range of 58-78%. After controlling for station and individual variation, no effect was observed regarding the number of checklist items on overall accuracy (p=0.2305). Consistency in ratings was calculated using intraclass correlation coefficient and demonstrated no significant difference in consistency between the 20- and 40-item checklists (ranged from 0.432 to 0.781, p-values from 0.56 to 0.73). CONCLUSIONS: The addition of 20 checklist items to a core list of 20 items in an OSCE assessment checklist does not appear to impact observer accuracy or inter-rater reliability. PMID- 26490949 TI - Icariin protects rats against 5/6 nephrectomy-induced chronic kidney failure by increasing the number of renal stem cells. AB - BACKGROUND: Chronic kidney disease poses a serious health problem worldwide with increasing prevalence and lack of effective treatment. This study aimed to investigate the mechanism of icariin in alleviating chronic renal failure induced by 5/6 nephrectomy in rats. METHODS: The chronic renal failure model was established by a two-phased 5/6 nephrectomy procedure. The model rats were given daily doses of water or icariin for 8 weeks. The kidney morphology was checked by HE staining. The levels of blood urea nitrogen, serum creatinine, and serum uric acid were measured by colometric methods. The expression of specified genes was analyzed by quantitative real-time PCR and immunohistochemical staining. The number of renal stem/progenitor cells was analyzed by CD133 and CD24 immunohistochemical staining. RESULTS: Icariin protected against CDK-caused damages to kidney histology and improved renal function, significantly reduced levels of BUN, creatinine, and uric acid. Icariin inhibited the expression level of TGF-beta1 whereas upregulated HGF, BMP-7, WT-1, and Pax2 expression. Moreover, ccariin significantly increased the expression of CD24, CD133, Osr1, and Nanog in remnant kidney and the numbers of CD133(+)/CD24(+) renal stem/progenitor cells. CONCLUSIONS: These data demonstrated that icariin effectively alleviated 5/6 nephrectomy induced chronic renal failure through increasing renal stem/progenitor cells. PMID- 26490950 TI - Training in the Conduct of Population-Based Multi-Site and Multi-Disciplinary Studies: the Cancer Research Network's Scholars Program. AB - Expanding research capacity of large research networks within health care delivery systems requires strategically training both embedded and external investigators in necessary skills for this purpose. Researchers new to these settings frequently lack the skills and specialized knowledge conducive to multi site and multi-disciplinary research set in delivery systems. This report describes the goals and components of the Cancer Research Network (CRN) Scholars Program, a 26-month training program developed to increase the capacity for cancer research conducted within the network's participating sites, its progression from training embedded investigators to a mix of internal and external investigators, and the content evolution of the training program. The CRN Scholars program was launched in 2007 to assist junior investigators from member sites develop independent and sustainable research programs within the CRN. Resulting from CRN's increased emphasis on promoting external collaborations, the 2013 Scholars program began recruiting junior investigators from external institutions committed to conducting delivery system science. Based on involvement of this broader population and feedback from prior Scholar cohorts, the program has honed its focus on specific opportunities and issues encountered in conducting cancer research within health care delivery systems. Efficiency and effectiveness of working within networks is accelerated by strategic and mentored navigation of these networks. Investing in training programs specific to these settings provides the opportunity to improve multi disciplinary and multi-institutional collaboration, particularly for early-stage investigators. Aspects of the CRN Scholars Program may help inform others considering developing similar programs to expand delivery system research or within large, multi-disciplinary research networks. PMID- 26490951 TI - Calcium, TRPC channels, and regulation of the actin cytoskeleton in podocytes: towards a future of targeted therapies. AB - With more than 6,000 new pediatric patients with treatment-resistant nephrotic syndrome in the US each year alone, the unmet need for novel, podocyte-specific therapies is substantial. Recently, the established therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) was used as a starting point to gain insight into the pathomechanism of primary podocytopathies. A calcium (Ca(2+))-mediated pathway has been identified that connects the angiotensin type 1 receptor (AT1R) to podocyte cytoskeletal dynamics, essential for a functioning glomerular filtration barrier. This discovery provided an important missing piece in our understanding of the pathomechanism of filter barrier damage, revealing Ca(2+) signaling as critical for podocyte health and disease. The identification of the two Ca(2+) permeant channels TRPC5 and TRPC6 as mediators of this pathway not only bolstered the importance of podocyte cytoskeleton dynamics but also revealed promising drug targets for treatment-resistant nephrotic syndrome. This review will focus on this novel signaling pathway in primary podocytopathies and its implications for next-generation therapies for glomerular disease. PMID- 26490952 TI - Genome-wide association studies in pediatric chronic kidney disease. AB - The genome-wide association study (GWAS) has become an established scientific method that provides an unbiased screen for genetic loci potentially associated with phenotypes of clinical interest, such as chronic kidney disease (CKD). Thus, GWAS provides opportunities to gain new perspectives regarding the genetic architecture of CKD progression by identifying new candidate genes and targets for intervention. As such, it has become an important arm of translational science providing a complementary line of investigation to identify novel therapeutics to treat CKD. In this review, we describe the method and the challenges of performing GWAS in the pediatric CKD population. We also provide an overview of successful GWAS for kidney disease, and we discuss the established pediatric CKD cohorts in North America and Europe that are poised to identify genetic risk variants associated with CKD progression. PMID- 26490953 TI - Long-term fear of recurrence in young breast cancer survivors and partners. AB - BACKGROUND: Fear of a breast cancer recurrence is the most prevalent and disruptive source of distress for long-term survivors and their partners. However, few studies have focused on predictors of fear of recurrence. The aim of this study is to test the efficacy of the Social Cognitive Processing Theory (SCPT) in predicting fear of recurrence in long-term breast cancer survivors diagnosed at age 45 years or younger and their partners. METHODS: In a large cross-sectional study, breast cancer survivors (n = 222) 3-8 years from diagnosis and their partners completed a survey assessing demographic characteristics, fear of recurrence, social constraints, and cognitive processing (intrusive thoughts and cognitive avoidance). Mediation analyses were conducted for survivors and partners separately to determine if cognitive processing would mediate the relationship between social constraints and fear of recurrence. RESULTS: Cognitive processing mediated the relationship between social constraints and fear of recurrence both for survivors [F(3,213) = 47.541, R2 = 0.401, p < 0.001] and partners [F(3,215) = 27.917, R2 = 0.280, p < 0.001). Demographic variables were not significant predictors of fear of recurrence. CONCLUSIONS: As predicted, cognitive processing mediated the relationship between social constraints and fear of recurrence. Results expand the utility of the SCPT in long-term survivors and their partners by supporting its use in intervention design. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26490954 TI - Erratum to: gespeR: a statistical model for deconvoluting off-target-confounded RNA interference screens. PMID- 26490955 TI - Course of cognitive impairment following attempted suicide in older adults. AB - OBJECTIVE: Cognitive impairment has been associated with late-life suicidal behavior. Without longitudinal data it is unclear whether these are transient features of a depressive state or stable impairments. We examined longitudinally the course of cognitive impairment in older adults with depression and a history of suicide attempt. METHODS: We investigated the persistence of cognitive impairment over time in 198 depressed older adults (age >60); 91 suicide attempters, 39 depressed individuals with suicidal ideation (ideators), and 68 non-suicidal depressed adults assessed over a 2-year period at four time points. We used linear mixed effects modeling to examine group differences in trajectories of cognitive decline over 2 years, using the Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale (DRS), and Executive Interview (EXIT). RESULTS: Over the 2-year period, suicide attempters performed significantly worse than both suicide ideators and non-suicidal depressed older adults on the MMSE (mean difference: from ideators: -0.88, p = 0.02; from non suicidal depressed: -1.52, p < 0.01), while on the EXIT and DRS, suicide attempters performed significantly worse than non-suicidal depressed older adults (mean difference: in EXIT: -1.75, p = 0.01; in DRS: 3.04, p < 0.01; in MMSE: 1.15, p < 0.01). Cognitive impairment in suicide attempters partly resolved, as indicated by a group * time interaction on the DRS (p = 0.039), but not the EXIT (p = 0.58) or the MMSE (p = 0.08). CONCLUSIONS: Cognitive impairment in late-life suicidal behavior appears to involve both a stable and a state-related component. PMID- 26490956 TI - Stability of blocked replication forks in vivo. AB - Replication of chromosomal DNA must be carried out to completion in order for a cell to proliferate. However, replication forks can stall during this process for a variety of reasons, including nucleoprotein 'roadblocks' and DNA lesions. In these circumstances the replisome copying the DNA may disengage from the chromosome to allow various repair processes to restore DNA integrity and enable replication to continue. Here, we report the in vivo stability of the replication fork when it encounters a nucleoprotein blockage in Escherichia coli. Using a site-specific and reversible protein block system in conjunction with the temperature sensitive DnaC helicase loader and DnaB replicative helicase, we monitored the disappearance of the Y-shaped DNA replication fork structures using neutral-neutral 2D agarose gels. We show the replication fork collapses within 5 min of encountering the roadblock. Therefore, the stalled replication fork does not pause at a block in a stable confirmation for an extended period of time as previously postulated. PMID- 26490957 TI - SigMol: repertoire of quorum sensing signaling molecules in prokaryotes. AB - Quorum sensing is a widespread phenomenon in prokaryotes that helps them to communicate among themselves and with eukaryotes. It is driven through quorum sensing signaling molecules (QSSMs) in a density dependent manner that assists in numerous biological functions like biofilm formation, virulence factors secretion, swarming motility, bioluminescence, etc. Despite immense implications, dedicated resources of QSSMs are lacking. Therefore, we have developed SigMol (http://bioinfo.imtech.res.in/manojk/sigmol), a specialized repository of these molecules in prokaryotes. SigMol harbors information on QSSMs pertaining to different quorum sensing signaling systems namely acylated homoserine lactones (AHLs), diketopiperazines (DKPs), 4-hydroxy-2-alkylquinolines (HAQs), diffusible signal factors (DSFs), autoinducer-2 (AI-2) and others. Database contains 1382: entries of 182: unique signaling molecules from 215: organisms. It encompasses biological as well as chemical aspects of signaling molecules. Biological information includes genes, preliminary bioassays, identification assays and applications, while chemical detail comprises of IUPAC name, SMILES and structure. We have provided user-friendly browsing and searching facilities for easy data retrieval and comparison. We have gleaned information of diverse QSSMs reported in literature at a single platform 'SigMol'. This comprehensive resource will assist the scientific community in understanding intraspecies, interspecies or interkingdom networking and further help to unfold different facets of quorum sensing and related therapeutics. PMID- 26490958 TI - Slx4 and Rtt107 control checkpoint signalling and DNA resection at double-strand breaks. AB - The DNA damage checkpoint pathway is activated in response to DNA lesions and replication stress to preserve genome integrity. However, hyper-activation of this surveillance system is detrimental to the cell, because it might prevent cell cycle re-start after repair, which may also lead to senescence. Here we show that the scaffold proteins Slx4 and Rtt107 limit checkpoint signalling at a persistent double-strand DNA break (DSB) and at uncapped telomeres. We found that Slx4 is recruited within a few kilobases of an irreparable DSB, through the interaction with Rtt107 and the multi-BRCT domain scaffold Dpb11. In the absence of Slx4 or Rtt107, Rad9 binding near the irreparable DSB is increased, leading to robust checkpoint signalling and slower nucleolytic degradation of the 5' strand. Importantly, in slx4Delta sae2Delta double mutant cells these phenotypes are exacerbated, causing a severe Rad9-dependent defect in DSB repair. Our study sheds new light on the molecular mechanism that coordinates the processing and repair of DSBs with DNA damage checkpoint signalling, preserving genome integrity. PMID- 26490959 TI - Robust expression of vault RNAs induced by influenza A virus plays a critical role in suppression of PKR-mediated innate immunity. AB - Protein kinase R (PKR) is a vital component of host innate immunity against viral infection. However, the mechanism underlying inactivation of PKR by influenza A virus (IAV) remains elusive. Here, we found that vault RNAs (vtRNAs) were greatly induced in A549 cells and mouse lungs after infection with IAV. The viral NS1 protein was shown to be the inducer triggering the upregulation of vtRNAs. Importantly, silencing vtRNA in A549 cells significantly inhibited IAV replication, whereas overexpression of vtRNAs markedly promoted the viral replication. Furthermore, in vivo studies showed that disrupting vtRNA expression in mice significantly decreased IAV replication in infected lungs. The vtRNA knockdown animals exhibited significantly enhanced resistance to IAV infection, as evidenced by attenuated acute lung injury and spleen atrophy and consequently increased survival rates. Interestingly, vtRNAs promoted viral replication through repressing the activation of PKR and the subsequent antiviral interferon response. In addition, increased expression of vtRNAs was required for efficient suppression of PKR by NS1 during IAV infection. Moreover, vtRNAs were also significantly upregulated by infections of several other viruses and involved in the inactivation of PKR signaling by these viruses. These results reveal a novel mechanism by which some viruses circumvent PKR-mediated innate immunity. PMID- 26490960 TI - A non-canonical multisubunit RNA polymerase encoded by a giant bacteriophage. AB - The infection of Pseudomonas aeruginosa by the giant bacteriophage phiKZ is resistant to host RNA polymerase (RNAP) inhibitor rifampicin. phiKZ encodes two sets of polypeptides that are distantly related to fragments of the two largest subunits of cellular multisubunit RNAPs. Polypeptides of one set are encoded by middle phage genes and are found in the phiKZ virions. Polypeptides of the second set are encoded by early phage genes and are absent from virions. Here, we report isolation of a five-subunit RNAP from phiKZ-infected cells. Four subunits of this enzyme are cellular RNAP subunits homologs of the non-virion set; the fifth subunit is a protein of unknown function. In vitro, this complex initiates transcription from late phiKZ promoters in rifampicin-resistant manner. Thus, this enzyme is a non-virion phiKZ RNAP responsible for transcription of late phage genes. The phiKZ RNAP lacks identifiable assembly and promoter specificity subunits/factors characteristic for eukaryal, archaeal and bacterial RNAPs and thus provides a unique model for comparative analysis of the mechanism, regulation and evolution of this important class of enzymes. PMID- 26490961 TI - 5SRNAdb: an information resource for 5S ribosomal RNAs. AB - Ribosomal 5S RNA (5S rRNA) is the ubiquitous RNA component found in the large subunit of ribosomes in all known organisms. Due to its small size, abundance and evolutionary conservation 5S rRNA for many years now is used as a model molecule in studies on RNA structure, RNA-protein interactions and molecular phylogeny. 5SRNAdb (http://combio.pl/5srnadb/) is the first database that provides a high quality reference set of ribosomal 5S RNAs (5S rRNA) across three domains of life. Here, we give an overview of new developments in the database and associated web tools since 2002, including updates to database content, curation processes and user web interfaces. PMID- 26490962 TI - Structural basis for suppression of hypernegative DNA supercoiling by E. coli topoisomerase I. AB - Escherichia coli topoisomerase I has an essential function in preventing hypernegative supercoiling of DNA. A full length structure of E. coli topoisomerase I reported here shows how the C-terminal domains bind single stranded DNA (ssDNA) to recognize the accumulation of negative supercoils in duplex DNA. These C-terminal domains of E. coli topoisomerase I are known to interact with RNA polymerase, and two flexible linkers within the C-terminal domains may assist in the movement of the ssDNA for the rapid removal of transcription driven negative supercoils. The structure has also unveiled for the first time how the 4-Cys zinc ribbon domain and zinc ribbon-like domain bind ssDNA with primarily pi-stacking interactions. This novel structure, in combination with new biochemical data, provides important insights into the mechanism of genome regulation by type IA topoisomerases that is essential for life, as well as the structures of homologous type IA TOP3alpha and TOP3beta from higher eukaryotes that also have multiple 4-Cys zinc ribbon domains required for their physiological functions. PMID- 26490963 TI - Functional coordination and HuR-mediated regulation of mRNA stability during T cell activation. AB - Global mRNA abundance depends on the balance of synthesis and decay of a population of mRNAs. To account for this balance during activation of T cells, we used metabolic labeling to quantify the contributions of RNA transcription and decay over a 4 h time course during activation of leukemia-derived Jurkat T cells. While prior studies suggested more than half of the changes in mRNA abundance were due to RNA stability, we found a smaller but more interesting population of mRNAs changed stability. These mRNAs clustered into functionally related subpopulations that included replicative histones, ribosomal biogenesis and cell motility functions. We then applied a novel analysis based on integrating global protein-RNA binding with concurrent changes in RNA stability at specific time points following activation. This analysis demonstrated robust stabilization of mRNAs by the HuR RNA-binding protein 4 h after activation. Our unexpected findings demonstrate that the temporal regulation of mRNA stability coordinates vital cellular pathways and is in part controlled by the HuR RNA binding protein in Jurkat T cells following activation. PMID- 26490965 TI - Alan Johnson: "utterly charming. Delusional". PMID- 26490964 TI - Solitary Fibrous Tumor of the Liver: a Review of the Current Knowledge and Report of a New Case. AB - INTRODUCTION: Solitary fibrous tumors of the liver (SFTL) are uncommon tumors; to the present day, less than 50 cases has been reported in the English scientific literature, most of which behaved as benign tumors. The present article reports a new case of SFTL and has the main purpose of updating the current knowledge of SFTL because due to its rarity, its clinical presentation, study, treatment, and prognosis are not well known. The clinical presentation, radiologic study, surgical treatment, immunohistochemical study, and prognosis are updated and comprehensively discussed. METHODS: Using the common search engines, a search of the English literature was conducted for "Solitary Fibrous Tumor of The Liver," and the relevant articles were retrieved, reviewed, and analyzed. RESULTS: All published articles reported anecdotal SFTLs, or SFTLs were included in large series analyzing solitary fibrous tumors on different sites. CONCLUSION: The SFTL is an uncommon neoplasm. The clinical presentation is habitually indolent and its behavior is uncertain. In some cases, the SFTL acts as an aggressive sarcoma with poor prognosis. Currently, only surgery offers a therapeutic opportunity for these patients. Due to the lack of current knowledge of long-term behavior of supposedly benign SFTLs and to the lack of specific therapies, methodical long term follow-up is essential to ensure the survival of patients treated for SFTL. PMID- 26490966 TI - Sharp bends of phononic crystal surface modes. AB - Sharp bending of surface waves at the interface of a two-dimensional phononic crystal (PnC) of steel cylinders in air and the method of using a diagonally offset cylindrical scatterer are numerically demonstrated by finite-element method simulations. The radii of the diagonally offset scatterer and the cylinder at the PnC corner, along with the distance between them, are treated as optimization parameters in the genetic algorithm optimization of sharp bends. Surface wave transmittance of at most 5% for the unmodified sharp bend is significantly enhanced to approximately 75% as a result of optimization. A series of transmittance peaks whose maxima increase exponentially, as their widths reduce, with increasing frequency is observed for the optimized sharp bend. The transmittance peaks appear at frequencies corresponding to integer plus half-beat periods, depending on the finite surface length. The optimal parameters are such that the cylinder radius at the PnC corner is not significantly modified, whereas a diagonally offset scatterer having a diameter of almost two periods and a shortest distance of about 0.7 periods between them is required for the strongest transmittance peak. Utilization of PnC surface sharp bends as acoustic ring resonators is demonstrated. PMID- 26490967 TI - Fc Gamma Receptor IIA (CD32A) R131 Polymorphism as a Marker of Genetic Susceptibility to Sepsis. AB - Sepsis is a devastating disease that can affect humans at any time between neonates and the elderly and is associated with mortality rates that range from 30 to 80%. Despite intensive efforts, its treatment has remained the same over the last few decades. Fc receptors regulate multiple immune responses and have been investigated in diverse complex diseases. FcgammaRIIA (CD32A) is an immunoreceptor, tyrosine-based activation motif-bearing receptor that binds immunoglobulin G and C-reactive protein, important opsonins in host defense. We conducted a study of 702 patients (184 healthy individuals, 171 non-infected critically ill patients, and 347 sepsis patients) to investigate if genetic polymorphisms in the CD32A coding region affect the risk of septic shock. All individuals were genotyped for a variant at position 131 of the FcgammaRIIA gene. We found that allele G, associated with the R131 genotype, was significantly more frequent in septic patients than in the other groups (p = 0.05). Our data indicate that FcgammaRIIA genotyping can be used as a marker of genetic susceptibility to sepsis. PMID- 26490968 TI - Toxoplasma gondii Infection Promotes Neuroinflammation Through Cytokine Networks and Induced Hyperalgesia in BALB/c Mice. AB - We hypothesized that in Toxoplasma gondii infection, communication among immune cells promotes neuroinflammation through cytokine networks and induces pain sensitivity under conditions of neuropathic pain. The animal model of Toxoplasma infection was established by the intraperitoneal inoculation of 20-25 tissue cysts from Tehran strain of T. gondii to BALB/c mice. Amitriptyline (20 mg/kg, i.p., 1/day) administrated to animals for 7 days before behavioral tests. Pain behavioral tests including tail flick, hot plate, and formalin test were evaluated in all the groups. The mRNA levels of tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, and IL-6 were examined by real-time PCR. Results revealed that T. gondii induce hyperalgesia in the infected mice, whereas amitriptyline showed a promising effect against the hyperalgesia induced by Toxoplasma infection. The mRNA levels of the aforementioned cytokines significantly (P < 0.05) increased in the infected mice compared to the uninfected ones. Obtained findings suggested that T. gondii infection could promote neuroinflammation through cytokine networks and induced hyperalgesia in BALB/c mice, whereas amitriptyline as an analgesic drug reverses them. PMID- 26490969 TI - Involvement of Prokineticin 2 and Prokineticin Receptor 1 in Lipopolysaccharide Induced Testitis in Rats. AB - Prokineticin 2, a newly discovered proinflammatory peptide, has been amply evidenced to be involved in the occurrence and progress of local and systematical inflammation. Although the presence of Prokineticn 2 in mammal testis has been documented clearly, research targeting the involvement of prokineticin 2 in testicular pathology, especially testitis, is rather scarce. Employing a lipopolysaccharide-induced testitis rat model, we for the first time demonstrated the expression and upregulation of prokineticin 2 in orchitis at several levels. Our effort also addressed the differential expression patterns of prokineticin 2 and interleukin-1beta, a key inflammation indicator, during testitis suggesting Prokineticn 2 serves more than a proinflammatory factor in the context of testitis. Given one of the cognate receptors of prokineticin 2, prokineticin receptor 1 (PKR1) was also significantly upregulated in orchitis as discussed in the current study, it is very likely that PK2/PKR1 signaling contribute to the development of inflammation-related testicular diseases. PMID- 26490970 TI - The social and community opportunities profile social inclusion measure: Structural equivalence and differential item functioning in community mental health residents in Hong Kong and the United Kingdom. AB - INTRODUCTION: China's future major health problem will be the management of chronic diseases - of which mental health is a major one. An instrument is needed to measure mental health inclusion outcomes for mental health services in Hong Kong and mainland China as they strive to promote a more inclusive society for their citizens and particular disadvantaged groups. AIM: To report on the analysis of structural equivalence and item differentiation in two mentally unhealthy and one healthy sample in the United Kingdom and Hong Kong. METHOD: The mental health sample in Hong Kong was made up of non-governmental organisation (NGO) referrals meeting the selection/exclusion criteria (being well enough to be interviewed, having a formal psychiatric diagnosis and living in the community). A similar sample in the United Kingdom meeting the same selection criteria was obtained from a community mental health organisation, equivalent to the NGOs in Hong Kong. Exploratory factor analysis and logistic regression were conducted. RESULTS: The single-variable, self-rated 'overall social inclusion' differs significantly between all of the samples, in the way we would expect from previous research, with the healthy population feeling more included than the serious mental illness (SMI) groups. In the exploratory factor analysis, the first two factors explain between a third and half of the variance, and the single variable which enters into all the analyses in the first factor is having friends to visit the home. All the regression models were significant; however, in Hong Kong sample, only one-fifth of the total variance is explained. CONCLUSION: The structural findings imply that the social and community opportunities profile-Chinese version (SCOPE-C) gives similar results when applied to another culture. As only one-fifth of the variance of 'overall inclusion' was explained in the Hong Kong sample, it may be that the instrument needs to be refined using different or additional items within the structural domains of inclusion. PMID- 26490971 TI - Glucocorticoids inhibit shaft fracture healing but not metaphyseal bone regeneration under stable mechanical conditions. AB - OBJECTIVES: Healing in cancellous metaphyseal bone might be different from midshaft fracture healing due to different access to mesenchymal stem cells, and because metaphyseal bone often heals without a cartilaginous phase. Inflammation plays an important role in the healing of a shaft fracture, but if metaphyseal injury is different, it is important to clarify if the role of inflammation is also different. The biology of fracture healing is also influenced by the degree of mechanical stability. It is unclear if inflammation interacts with stability related factors. METHODS: We investigated the role of inflammation in three different models: a metaphyseal screw pull-out, a shaft fracture with unstable nailing (IM-nail) and a stable external fixation (ExFix) model. For each, half of the animals received dexamethasone to reduce inflammation, and half received control injections. Mechanical and morphometric evaluation was used. RESULTS: As expected, dexamethasone had a strong inhibitory effect on the healing of unstable, but also stable, shaft fractures. In contrast, dexamethasone tended to increase the mechanical strength of metaphyseal bone regenerated under stable conditions. CONCLUSIONS: It seems that dexamethasone has different effects on metaphyseal and diaphyseal bone healing. This could be explained by the different role of inflammation at different sites of injury. Cite this article: Bone Joint Res 2015;4:170-175. PMID- 26490972 TI - Impact of socioeconomic status on mortality and unplanned readmission in septic intensive care unit patients. AB - BACKGROUND: Little is known about the potential association between socioeconomic status (SES) and prognosis after sepsis. We analysed how SES impacted mortality and readmission in septic patients treated at the intensive care unit (ICU) of a university hospital. METHODS: We performed a cohort study including all adult patients admitted to a general tertiary ICU with severe sepsis or septic shock during 2008-2010. Data on SES (educational level, personal income, and cohabitation), comorbidity, readmissions, and mortality were obtained from public registries. We used Cox regression analysis to examine the impact of SES on 30- and 180-day mortality and on first unplanned readmission within 180 days after hospital discharge. RESULTS: A total of 387 patients were included of whom 111 (29%) died within 30 days after ICU admission, and 55 (20%) died within 180 days after hospital discharge. Adjusted for sex, comorbidity and SAPS II, patients with low income had a substantially greater risk of dying within 30 days of admission compared to those with high income (35.7% vs. 23.3%; adjusted hazard ratio (HR) 1.99; 95% confidence interval (CI) 1.24-3.21), and tended to show higher 180-day mortality (25.0% vs. 15.5%; adjusted HR 1.72; 95% CI 0.86-3.45). Among patients discharged from hospital, 125 (45%) were readmitted within 180 days. Patients with low education and low income showed a tendency towards early readmission. CONCLUSIONS: Among septic ICU patients, low income was significantly associated with increased 30-day mortality. There was a trend towards earlier readmission among surviving patients with low educational level and personal income. PMID- 26490973 TI - Reviewing the literature. PMID- 26490975 TI - Autism, an area that needs public attention and investment. PMID- 26490977 TI - Editorial: Pertussis: current problems, challenges and investigations of a re emerging disease. PMID- 26490976 TI - Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism. AB - Autism spectrum disorder (ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones. PMID- 26490974 TI - Immunometabolism within the tuberculosis granuloma: amino acids, hypoxia, and cellular respiration. AB - Tuberculosis (TB) granulomas are compact, organized agglomerations of infected and uninfected macrophages, T cells, neutrophils, and other immune cells. Within the granuloma, several unique metabolic adaptations occur to modify the behavior of immune cells, potentially favoring bacterial persistence balanced with protection against immunopathology. These include the induction of arginase-1 in macrophages to temper nitric oxide (NO) production and block T cell proliferation, inhibition of oxygen-requiring NO production in hypoxic regions, and induction of tryptophan-degrading enzymes that modify T cell proliferation and function. The spatial and time-dependent organization of granulomas further influences immunometabolism, for example through lactate production by activated macrophages, which can induce arginase-1. Although complex, the metabolic changes in and around TB granulomas can be potentially modified by host-directed therapies. While elimination of the TB bacilli is often the goal of any anti-TB therapy, host-directed approaches must also account for the possibility of immunopathologic damage to the lung. PMID- 26490978 TI - Maspin mediates the gemcitabine sensitivity of hormone-independent prostate cancer. AB - Androgen deprivation therapy has constituted the main treatment for prostate cancer; however, tumors ultimately progress to hormone-independent prostate cancer (HIPC), and suitable therapeutic strategies for HIPC are not available. Maspin, which is also known as mammary serine protease inhibitor, has been suggested to be a valuable focus for targeted cancer therapy. Specifically, maspin has been shown to be upregulated after androgen ablation therapy. Gemcitabine is used as a first-line therapy for metastatic castration-resistant prostate cancer, but its disease control rate is low. Furthermore, the role of maspin in the therapeutic efficacy of gemcitabine for HIPC remains unclear. The expression levels of maspin in PC-3 and DU145 cells were determined by real-time PCR and Western blotting. Furthermore, the expression of maspin was silenced using shRNA technology to generate maspin-KD cells. The cytotoxicity of gemcitabine to prostate cancer cells was assessed using 3-[4,5-dimethylthiazol-2 yl]-3,5-diphenyl tetrazolium bromide (MTT) assays, whereas flow cytometry analyses and annexin V-propidium iodide (PI) apoptosis assays were used to assess the ability of gemcitabine to induce apoptosis in maspin-KD and control cells. Additionally, the expression patterns of anti-apoptosis proteins (myeloid cell leukemia 1 (Mcl-1) and B cell lymphoma 2 (Bcl-2)) and pro-apoptosis proteins (Bcl 2-associated death promoter (Bad) and Bcl-2-associated X protein (Bax)) were determined by Western blotting. In this study, PC-3 cells were more resistant to gemcitabine administration than DU145 cells, which correlated with the higher expression levels of maspin observed in PC-3 cells. Furthermore, maspin knockdown enhanced gemcitabine-induced cell death, as evidenced by the increased number of apoptotic cells. Gemcitabine treatment upregulated the levels of anti-apoptosis proteins (Mcl-2 and Bcl-2) in both scrambled control and maspin-KD cells; however, the fold changes in Mcl-1 and Bcl-2 expression were larger in gemcitabine-treated scrambled control cells than in maspin-KD cells. Finally, our findings indicate for the first time that maspin may mediate the therapeutic efficacy of gemcitabine in HIPC. Our results demonstrate that maspin knockdown enhanced the sensitivity of androgen-independent prostate cancer cells to gemcitabine. Therefore, combining gemcitabine with a drug that targets maspin might constitute a valuable strategy for prostate cancer treatment. PMID- 26490979 TI - The roles of mitochondria in radiation-induced autophagic cell death in cervical cancer cells. AB - Mitochondria as the critical powerhouse of eukaryotic cells play important roles in regulating cell survival or cell death. Under numerous stimuli, impaired mitochondria will generate massive reactive oxygen species (ROS) which participate in the regulation of vital signals and could even determine the fate of cancer cells. While the roles of mitochondria in radiation-induced autophagic cell death still need to be elucidated. Human cervical cancer cell line, Hela, was used, and the SOD2 silencing model (SOD2-Ri) was established by gene engineering. Cell viability was detected by methyl thiazolyl tetrazolium (MTT) assays, MitoTracker Green staining was used to detect mitochondrial mass, Western blot was used to detect protein expression, and the level of ROS, autophagy, and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. Ionizing radiation (IR) could induce the increase of MAPLC3-II/MAPLC3-I ratio, Beclin1 expression, and ROS generation but decrease the MMP in a time-dependent manner. After SOD2 silencing, the IR-induced changes of ROS and the MMP were significantly enhanced. Moreover, both the radio sensitivity and autophagy increased in SOD2-Ri cells. Whereas, compared with SOD2-Ri, the opposite results were obtained by NAC, an antioxidant. After the treatment with the inhibitor of mitochondrial electron-transport chain complex II, thenoyltrifluoroacetone (TTFA), the rate of autophagy, ROS, and the total cell death induced by IR increased. In addition, the decrease of MMP was more obvious. However, these results were reversed by cyclosporine A (CsA). IR could induce ROS generation and mitochondrial damage which lead to autophagic cell death in Hela cells. PMID- 26490980 TI - Expression of CDC5L is associated with tumor progression in gliomas. AB - Cell division cycle 5-like (CDC5L) protein is a cell cycle regulator of the G2/M transition and has been reported to participate in the catalytic step of pre messenger RNA (mRNA) splicing and DNA damage repair. Recently, it was also found to act as a candidate oncogene in osteosarcoma and cervical tumors. However, the role of CDC5L expression in tumor biology was still unclear. Here, we analyzed the expression and clinical significance of CDC5L in gliomas. The expression of CDC5L in fresh glioma tissues and paraffin-embedded slices was evaluated by western blot and immunohistochemistry, respectively. We found that CDC5L was highly expressed in glioma tissues. The expression of CDC5L was significantly associated with glioma pathology grade and Ki-67 expression. Univariate and multivariate analyses showed that high CDC5L expression was an independent prognostic factor for glioma patients' survival. To determine whether CDC5L could regulate the proliferation of glioma cells, we transfected glioma cells with interfering RNA target CDC5L, then investigated cell proliferation with cell counting kit (CCK)-8, flow cytometry assays and colony formation analyses. Our results indicated that knockdown of CDC5L would inhibit proliferation of glioma cells. Besides, reduced expression of CDC5L could induce the apoptosis of glioma cells. These findings suggested that CDC5L might play an important role in glioma and thus be a promising therapeutic target of glioma. PMID- 26490981 TI - microRNA-188 is downregulated in oral squamous cell carcinoma and inhibits proliferation and invasion by targeting SIX1. AB - microRNA-188 expression is downregulated in several tumors. However, its function and mechanism in human oral squamous cell carcinoma (OSCC) remains obscure. The present study aims to identify the expression pattern, biological roles, and potential mechanism by which miR-188 dysregulation is associated with oral squamous cell carcinoma. Significant downregulation of miR-188 was observed in OSCC tissues compared with paired normal tissues. In vitro, gain-of-function, loss-of-function experiments were performed to examine the impact of miR-188 on cancer cell proliferation, invasion, and cell cycle progression. Transfection of miR-188 mimics suppressed Detroit 562 cell proliferation, cell cycle progression and invasion, with downregulation of cyclin D1, MMP9, and p-ERK. Transfection of miR-188 inhibitor in FaDu cell line with high endogenous expression exhibited the opposite effects. Using fluorescence reporter assays, we confirmed that SIX1 was a direct target of miR-188 in OSCC cells. Transfection of miR-188 mimics downregulated SIX1 expression. SIX1 siRNA treatment abrogated miR-188 inhibitor induced cyclin D1 and MMP9 upregulation. In addition, we found that SIX1 was overexpressed in 32 of 80 OSCC tissues. In conclusion, this study indicates that miR-188 downregulation might be associated with oral squamous cell carcinoma progression. miR-188 suppresses proliferation and invasion by targeting SIX1 in oral squamous cell carcinoma cells. PMID- 26490982 TI - Far upstream element-binding protein 1 (FUBP1) is a potential c-Myc regulator in esophageal squamous cell carcinoma (ESCC) and its expression promotes ESCC progression. AB - The human far upstream element (FUSE) binding protein 1 (FUBP1) belongs to an ancient family which is required for proper regulation of the c-Myc proto oncogene. Although c-Myc plays an important role in development of various carcinomas, the relevance of FUBP1 and their contribution to esophageal squamous cell carcinoma (ESCC) development remain unclear. In this study, we aimed to investigate the relationship between FUBP1 and c-Myc as well as their contribution to ESCC development. Western blot and immunohistochemical analyses were performed to evaluate FUBP1 expression. Coimmunoprecipitation analysis was performed to explore the correlation between FUBP1 and c-Myc in ESCC. In addition, the role of FUBP1 in ESCC proliferation was studied in ESCC cells through knocking FUBP1 down. The regulation of FUBP1 on proliferation was confirmed by Cell Counting Kit-8 (CCK-8) assay, flow cytometric assays, and clone formation assays. The expressions of FUBP1 and c-Myc were both upregulated in ESCC tissues. In addition to correlation between expression of FUBP1 and tumor grade, we also confirmed the correlation of FUBP1, c-Myc, and Ki-67 expression by twos. Moreover, upregulation of FUBP1 and c-Myc in ESCC was associated with poor survival. FUBP1 was confirmed to activate c-Myc in ESCC tissues and cells. FUBP1 was demonstrated to promote proliferation of ESCC cells. Moreover, downregulation of both FUBP1 and c-Myc was confirmed to inhibit proliferation of ESCC cells. Our results indicated that FUBP1 may potentially stimulate c-Myc expression in ESCC and its expression may promote ESCC progression. PMID- 26490983 TI - Long non-coding RNA PVT1 as a novel biomarker for diagnosis and prognosis of non small cell lung cancer. AB - Accumulating evidence has indicated that long non-coding RNA PVT1 is upregulated in various human cancers. However, it remains unclear whether PVT1 is involved in the development and progression of non-small cell lung cancer (NSCLC). The present study was designed to investigate the expression, biological role, and clinical significance of PVT1 in NSCLC. Our results indicated that PVT1 expression was significantly increased in NSCLC tissues and cell lines, and its upregulation was associated with advanced T-stage and tumor-node-metastasis (TNM) stage and regional lymph node metastasis. PVT1 expression levels were robust in differentiating NSCLC tissues from controls. Kaplan-Meier curve and Cox regression analysis showed that high expression of PVT1 was associated with poor overall survival and disease-free survival in NSCLC patients. The results of 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays indicated that knockdown of PVT1 remarkably inhibited NSCLC cell proliferation, whereas overexpression of PVT1 significantly promoted cellular proliferation. In addition, PVT1 knockdown increased the number of cells in the G0/G1 phase and reduced the number of cells in the S phase, while overexpression of PVT1 could promote cell cycle progression. Furthermore, our findings also revealed that the messenger RNA (mRNA) and protein expression of P15 and P21 was significantly upregulated in NSCLC cells transfected with PVT1 small interfering RNA (siRNA) and downregulated in cells transfected with pcDNA3.1-PVT1. In conclusion, our study demonstrated that PVT1 might serve as a promising biomarker for diagnosis and prognosis of NSCLC, and it could promote the proliferation of NSCLC cells by downregulating p15 and p21 expression. PMID- 26490984 TI - Elevated preoperative neutrophil-to-lymphocyte ratio predicts poor disease-free survival in Chinese women with breast cancer. AB - Inflammation and tumor immune microenviroment are critical factors for prognosis in numerous cancers. The aim of this study was to determine the prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR) in breast cancer. We performed a retrospective analysis of 487 patients diagnosed with primary breast cancer at Shanghai Ruijin hospital from January 2009 to December 2010. Hematological parameters before surgery, clinicopathological data, and survival status were obtained. Survival analysis was used to evaluate the prognostic value of NLR. The optimal cutoff value was determined as 1.93 for NLR and the median follow-up time was 55.0 months. On univariate analysis, patients with high NLR (>1.93) had worse 5-year disease-free survival (DFS) compared to those with low NLR (77.9 vs 88.0 %, p = 0.002). Regarding overall survival, there was no significant difference between patients with high NLR and low NLR, with 5-year overall survival of 90.8 and 91.7 % (p = 0.707). In triple-negative breast cancer, patients with high NLR was associated with worse 5-year DFS compared with patients with low NLR (63.4 vs 84.9 %, p = 0.040). Mutivariate analysis revealed that NLR was an independent prognostic factor for DFS in breast cancer (HR = 1.867, 95 % confidence interval; (95%CI) = 1.155-3.017, p = 0.011). Preoperative NLR is an independent predictor of DFS in breast cancer patients, especially in triple-negative subtype. Further studies are required to validate the prognostic value of NLR before clinical application. PMID- 26490985 TI - Patients with chronic lymphocytic leukaemia (CLL) differ in the pattern of CTLA-4 expression on CLL cells: the possible implications for immunotherapy with CTLA-4 blocking antibody. AB - Recently, systemic administration of a human monoclonal antibody directed against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expressed on circulating T cells in patients with chronic lymphocytic leukaemia (CLL) has been considered. Also, CLL cells have been shown to express CTLA-4, increased levels of which in the leukaemic compartment are a predictor of good clinical outcome. Since both CLL and Treg microenvironment cells can be targeted by the CTLA-4 blocking antibody in this immunotherapy approach, the investigation of the functional effect of CTLA-4 blockade on CLL cells might be of potential clinical relevance. The main aim of this study was to examine the effect of CTLA-4 blockade on proliferation activity and apoptosis of CLL cells in patients with low and high CTLA-4 expression. We found that in the high CTLA-4-expressing CLL group, CTLA-4 blockade on the CLL cell surface resulted in a significant increase in the median percentages of Ki67(+) cells and a tendency to decrease in the proportion of apoptotic cells. In contrast, in the low CTLA-4 expressors, CTLA-4 blockade did not affect the proliferation activity or the frequency of apoptosis. This study reports for the first time the different effect of CTLA-4 blockade on CLL cells in CLL patients depending on the levels of CTLA-4 expression. CTLA-4 blockade seems to induce pro-survival signals in leukaemic cells from CLL patients exhibiting high CTLA-4 expression, suggesting that an immunotherapy approach based on the systemic use of monoclonal anti-CTLA-4 antibodies could be an unfavourable strategy for some CLL patients. PMID- 26490986 TI - SPARCL1 is a novel predictor of tumor recurrence and survival in hilar cholangiocarcinoma. AB - Secreted protein acidic and rich in cysteines-like protein 1 (SPARCL1) has been implicated in tumor initiation, formation, and progression of various cancers, yet its role in hilar cholangiocarcinoma remains largely uncharacterized. In the present study, tissue microarrays containing resected hilar cholangiocarcinoma specimens from 92 patients were used to evaluate the expression of SPARCL1 protein by immunohistochemistry (IHC). In vitro assays were used to determine the effect of SPARCL1 overexpression on cell growth and migration. Loss of SPARCL1 expression was observed in 46 (50.0 %) of the 92 primary tumors. SPARCL1 expression is inversely associated with poorly or undifferentiation specimens (P = 0.030) in addition to lymph node metastasis (P = 0.047). Survival analysis demonstrated that SPARCL1 is an independent factor in predicting the outcome of patients with hilar cholangiocarcinoma. SPARCL1 overexpression suppressed tumor cell migration in vitro by inhibiting MMP-9, MMP-2, Vimentin, and Fibronectin expression, whereas did not inhibit cell proliferation in vitro. Our results suggest that loss of SPARCL1 is involved in the tumorigenesis of hilar cholangiocarcinoma and may serve as a novel molecular biomarker for patients' outcome. PMID- 26490987 TI - MicroRNA-101 polymorphisms and risk of head and neck squamous cell carcinoma in a Chinese population. AB - MicroRNAs (miRNAs) play important roles in regulation of gene expressions and likely have involvement in cancer susceptibility and disease progression. MicroRNA-101 (miR-101) has been well established as a tumor suppressor, and aberrant expression of miR-101 levels has been previously reported in different malignancies including head and neck squamous cell carcinoma (HNSCC). However, the role of single nucleotide polymorphisms (SNPs) of miR-101 in the susceptibility to HNSCC remains unclear. In this study, we genotyped 11 selected SNPs of the miR-101 genes (including miR-101-1 and miR-101-2) in a case-control study including 576 HNSCC cases and 1552 cancer-free controls. For the main effect analysis, none of the 11 selected SNPs was associated with HNSCC risk. However, in the stratification analysis by tumor sites, rs578481 and rs705509 in pri-miR-101-1 were significantly associated with risk of oral squamous cell carcinoma (OSCC) (rs578481: adjusted odds ratio (OR) = 1.19, 95 % confidence interval (CI) 1.01-1.39, P = 0.036; rs705509: adjusted OR = 0.85, 95 % CI 0.73 0.98, P = 0.030). Furthermore, combined analysis of the two SNPs revealed that subjects carrying the risk alleles of rs578481 and rs705509 had increased risk of OSCC in a dose-response manner (P trend = 0.022). Compared with subjects carrying "0-2" risk alleles, subjects carrying "3-4" risk alleles presented a 1.38-fold increased risk of OSCC. In conclusion, our findings suggested that the SNPs rs578481 and rs705509 locating in pri-miR-101-1 may play a role in genetic susceptibility to OSCC, which may improve our understanding of the potential contribution of miRNA SNPs to cancer pathogenesis. PMID- 26490988 TI - The SDF-1/CXCR4 chemokine axis in uveal melanoma cell proliferation and migration. AB - The stromal-cell-derived factor 1 (SDF-1)/chemokine receptor 4 (CXCR4) chemokine axis plays a key role in tumor migration. Here, we analyzed the axis in uveal melanoma (UM) proliferation and migration and investigated the effect of a chemical inhibitor of CXCR4, AMD3100, on UM. We found that CXCR4 was expressed in all five UM cell lines tested as well as the retinal pigment epithelium cell line ARPE-19 cells, while CXCR7 was only detected in OM290 and VUP cell lines. SDF-1 promotes the proliferation and migration of OCM-1 and OCM431 cell lines, while AMD3100 weakens this function. Taken together, our results show that the SDF 1/CXCR4 chemokine axis plays a key role in UM cell proliferation and migration and that AMD3100 can alleviate this function, which may offer a hint for UM treatment. PMID- 26490989 TI - RETRACTED ARTICLE: Identification of microRNAs (miR-203/miR-7) as potential markers for the early detection of lymph node metastases in patients with cervical cancer. PMID- 26490990 TI - The role of miR-145 in stem cell characteristics of human laryngeal squamous cell carcinoma Hep-2 cells. AB - The cancer stem-like cells (CSLCs) are tumorigenic cells promoting initiation, progression, and spread of the tumor. Accumulating evidences suggested the presence of CSLCs in distinct tumors including laryngeal squamous cell carcinoma (LSCC). MicroRNAs have been proposed as significant regulators of carcinogenesis, and several of them have been demonstrated to have direct roles in survival of CSLCs. In this study, we aimed to explore the role of miR-145, which is downregulated in LSCC, on cancer stem cell potency of laryngeal cancer cells. We initially showed the downregulation of miR-145 expression in tumor tissue samples and in CD133-enriched CSLCs. Quantitative reverse-transcription PCR (qRT-PCR) analysis of miR-145-transfected Hep-2 cells demonstrated the inhibitory role of miR-145 on stem cell markers like SOX2, OCT4, KLF4, and ABCG2. We, then, investigated the stem cell features of miR-145-overexpressing Hep-2 cells by sphere formation assay, single-cell cloning assay, and aldehyde dehydrogenase (ALDH) assay, which all demonstrated the inhibition of stem cell potency upon miR 145 overexpression. Further qRT-PCR analysis demonstrated altered expression of epithelial to mesenchymal transition markers in miR-145-overexpressing Hep-2 cells. In conclusion, we demonstrated the regulatory role of miR-145 in stem cell characteristics of Hep-2 cells. Based on these results, we propose that miR-145 might carry crucial roles in LSCC tumorigenesis, prognosis, metastasis, chemoresistance, and recurrence through regulating stem cell properties of tumor cells. PMID- 26490991 TI - The role of liver transplantation or resection for patients with early hepatocellular carcinoma. AB - Liver resection (LR) and liver transplantation (LT) are curative treatments for early hepatocellular carcinoma (HCC), although their performance remains debated. We compared the survival of patients with HCC conforming to the Milan criteria (MC) after LT and LR and analyzed factors affecting clinical outcomes. Between January 2006 and January 2013, 65 and 184 patients received LT and LR for HCCs fulfilling the MC, respectively. Overall survival (OS) and disease-free survival (DFS) rates were compared between the two groups. To investigate effects of liver function and living donor liver transplantation (LDLT) on survival, two subgroup analyses were performed and associations with OS and DFS were examined. We found that OS rates were higher after LT than after LR since 3 years postoperatively. DFS rates were significantly better after LT than after LR. Performance of LR, vascular invasion, and tumor multiplicity were associated with poor DFS, and factors affecting OS included the presence of vascular invasions, liver cirrhosis, and tumor multiplicity. In conclusion, despite of the effects of tumor characteristics on clinical outcomes, LT, including LDLT, should be considered the treatment of choice for patients with HCCs who met the MC. The role of LR is to identify poor prognostic factors through pathological examination. PMID- 26490992 TI - Curcumin induces apoptosis in p53-null Hep3B cells through a TAp73/DNp73 dependent pathway. AB - Curcumin has anticancer functions in various tumors. It has been shown to induce apoptosis through p53-dependent pathways. p73 gene is a member of the p53 family which encodes both a tumor suppressor (transactivation-competent p73 (TAp73)) and a putative oncogene (dominant-negative p73 (DNp73)); the former shares similarity with the tumor suppressor p53, and the latter behaves as dominant-negative proteins that interfere with the activity of TAp73. To understand the p73 dependent mechanisms that are engaged during curcumin-induced apoptosis, we established a p73 overexpression cell models using p53-deficient Hep3B cells (Hep3B(TAp73/DNp73)). Our results demonstrated that curcumin at concentrations of 40 and 80 MUM induced DNA damage, increased TAp73/DNp73 ratio, and also led to apoptosis in the Hep3B(TAp73/DNp73) cells. The apoptotic cell death was concurrent with the loss of mitochondrial membrane potential; release of cytochrome c from mitochondria; and the cleavage of caspase 9, caspase 3, and poly(ADP-ribose) polymerase (PARP). These results demonstrated a p73-dependent mechanism for curcumin-induced apoptosis that involves the mitochondria-mediated pathway. PMID- 26490993 TI - Characterization of exosomes derived from ovarian cancer cells and normal ovarian epithelial cells by nanoparticle tracking analysis. AB - Cellular exosomes are involved in many disease processes and have the potential to be used for diagnosis and treatment. In this study, we compared the characteristics of exosomes derived from human ovarian epithelial cells (HOSEPiC) and three epithelial ovarian cancer cell lines (OVCAR3, IGROV1, and ES-2) to investigate the differences between exosomes originating from normal and malignant cells. Two established colloid-chemical methodologies, electron microscopy (EM) and dynamic light scattering (DLS), and a relatively new method, nanoparticle tracking analysis (NTA), were used to measure the size and size distribution of exosomes. The concentration and epithelial cellular adhesion molecule (EpCAM) expression of exosomes were measured by NTA. Quantum dots were conjugated with anti-EpCAM to label exosomes, and the labeled exosomes were detected by NTA in fluorescent mode. The normal-cell-derived exosomes were significantly larger than those derived from malignant cells, and exosomes were successfully labeled using anti-EpCAM-conjugated quantum dots. Exosomes from different cell lines may vary in size, and exosomes might be considered as potential diagnosis biomarkers. NTA can be considered a useful, efficient, and objective method for the study of different exosomes and their unique properties in ovarian cancer. PMID- 26490994 TI - Neuregulin-1-mediated ErbB2-ErbB3 signalling protects human trophoblasts against apoptosis to preserve differentiation. AB - During placentation, foetal trophoblasts invade deeply into maternal tissue to establish a foeto-maternal circulation. We have previously shown that extravillous trophoblast (EVT) lineage cells express ErbB2 and ErbB3, of which the potential as an oncogenic unit is well established. However, a physiological function of this receptor combination in humans remains a puzzling question. Here, we demonstrate neuregulin 1 (NRG1) expression and secretion by human decidual stromal cells. Stimulation of human primary trophoblasts with exogenous NRG1 induced phosphorylation of ErbB2, ErbB3 and related downstream effectors. Co immunoprecipitation experiments confirmed the formation of ErbB2-ErbB3 dimers upon ligand engagement. Along this line, receptor knockdown and ErbB3 neutralization strongly diminished NRG1-dependent activation of the signalling complex. Functional studies revealed that NRG1 promotes EVT formation in placental explant cultures. Although, in the presence of NRG1, basal and camptothecin-induced trophoblast apoptosis was significantly repressed, this effect was abolished upon ErbB3 inhibition. Notably, camptothecin provoked a strong reduction of trophoblast cell column size, whereas NRG1-treated explants were refractory to the compound. Taken together, our findings newly identify a physiological function of the NRG1-ErbB2-ErbB3 axis in trophoblast survival during human placental development. PMID- 26490996 TI - Drosophila Lipin interacts with insulin and TOR signaling pathways in the control of growth and lipid metabolism. AB - Lipin proteins have key functions in lipid metabolism, acting as both phosphatidate phosphatases (PAPs) and nuclear regulators of gene expression. We show that the insulin and TORC1 pathways independently control functions of Drosophila Lipin (dLipin). Reduced signaling through the insulin receptor strongly enhanced defects caused by dLipin deficiency in fat body development, whereas reduced signaling through TORC1 led to translocation of dLipin into the nucleus. Reduced expression of dLipin resulted in decreased signaling through the insulin-receptor-controlled PI3K-Akt pathway and increased hemolymph sugar levels. Consistent with this, downregulation of dLipin in fat body cell clones caused a strong growth defect. The PAP but not the nuclear activity of dLipin was required for normal insulin pathway activity. Reduction of other enzymes of the glycerol-3 phosphate pathway affected insulin pathway activity in a similar manner, suggesting an effect that is mediated by one or more metabolites associated with the pathway. Taken together, our data show that dLipin is subject to intricate control by the insulin and TORC1 pathways, and that the cellular status of dLipin impacts how fat body cells respond to signals relayed through the PI3K-Akt pathway. PMID- 26490995 TI - Cdc42 regulates epithelial cell polarity and cytoskeletal function during kidney tubule development. AB - The Rho GTPase Cdc42 regulates key signaling pathways required for multiple cell functions, including maintenance of shape, polarity, proliferation, migration, differentiation and morphogenesis. Although previous studies have shown that Cdc42 is required for proper epithelial development and maintenance, its exact molecular function in kidney development is not well understood. In this study, we define the specific role of Cdc42 during murine kidney epithelial tubulogenesis by deleting it selectively at the initiation of ureteric bud or metanephric mesenchyme development. Deletion in either lineage results in abnormal tubulogenesis, with profound defects in polarity, lumen formation and the actin cytoskeleton. Ultimately, these defects lead to renal failure. Additionally, in vitro analysis of Cdc42-null collecting duct cells shows that Cdc42 controls these processes by regulating the polarity Par complex (Par3-Par6 aPKC-Cdc42) and the cytoskeletal proteins N-Wasp and ezrin. Thus, we conclude that the principal role of Cdc42 in ureteric bud and metanephric mesenchyme development is to regulate epithelial cell polarity and the actin cytoskeleton. PMID- 26490997 TI - Wernicke encephalopathy and pellagra in an alcoholic and malnourished patient. AB - Deficiency of multiple vitamins can be identified in alcoholic and malnourished patients. We report a patient with Wernicke encephalopathy, a B1 deficiency and pellagra, a niacin deficiency. A 61-year-old Japanese man presented with generalised weakness. He had drunk alcohol heavily for more than a year without eating adequate meals. Physical examination showed disorientation, eye movement impairment, muscle wasting and a rash over the limbs. Multivitamin supplementations improved all the symptoms. Pellagra causes dementia, diarrhoea, or dermatitis, and can mimic non-specific erythaema in alcoholics. The differential diagnosis between pellagra and non-specific erythaema is important because of the treatability of pellagra by niacin supplementation. PMID- 26490998 TI - Access to essential paediatric surgery in the developing world: a case of imperforate anus with rectovaginal and rectocutaneous fistulas left untreated. AB - Anorectal malformations consist of a wide spectrum of conditions which can affect both sexes and involve the distal anus and rectum as well as the urinary and genital tracts. Patients have the best chance of a good functional outcome if the condition is diagnosed early and efficient anatomic repair is promptly instituted. This report describes a rare case of imperforate anus associated with both rectovaginal and rectocutaneous fistulas in a 6-year-old Filipino girl. The case highlights shortcomings in the healthcare delivery system combined with socio-economic factors that contributed to the delay in both diagnosis and the institution of adequate treatment. Care and preventive measures that can be implemented in low-resource settings to reduce the impact of birth defects are also discussed. PMID- 26490999 TI - Just hypercalcaemia or acute ST elevation myocardial infarction? A review of hypercalcaemia-related electrocardiographic changes. AB - In elderly patients presenting with confusion and recurrent falls, conditions including infection, acute stroke, acute coronary events and electrolyte abnormalities have to be strongly considered as diagnostic possibilities. ECG is a non-invasive test that often serves as a useful tool in suggesting the underlying electrolyte disturbance. However, ECG must be interpreted with caution as it can, at times, be misleading, as in this case of hypercalcaemia seen by us. We discuss the different ECG findings in hypercalcaemic situations. PMID- 26491000 TI - Isolated mammary cysticercosis. PMID- 26491001 TI - A rare case describing catastrophic destruction of the whole skeleton caused by severe hyperparathyroidism. AB - Osteitis fibrosa cystica is a skeletal disorder seen in advanced stages of persistent hyperparathyroidism. Although the measurement of serum Ca and intact parathormone levels provides early diagnosis and decreases the incidence of radiographic bone involvement, progressive major bone lesions may still be seen in developing countries even in the modern era. We aimed to share, by writing up this report, our astonishment after observing how the skeletal system can be ruined by persistent hyperparathyroidism. PMID- 26491002 TI - Bilateral BRVO in a patient with recurrent prostate cancer. AB - Bilateral cases of branch retinal vein occlusions (BRVO) are infrequent and often related to systemic disease. A 72-year-old man with biochemical recurrence of prostate cancer was referred for decreased vision in his left eye. Fundus examination and fluorescein angiography disclosed bilateral BRVO with patches of peripheral non-perfusion and macular oedema in the left eye. A systemic work up revealed elevated fibrinogen and reduced free protein S antigen, consistent with an underlying hypercoagulable state. Cancer is a well-known cause of hypercoagulability. We report the first case of bilateral BRVO related to biochemical recurrence of prostate cancer and a proven coagulation derangement. PMID- 26491003 TI - A challenging central line insertion: where did the contrast go? PMID- 26491004 TI - Herlyn-Werner-Wunderlich and Prader-Willi syndromes: more than a coincidence? AB - A neonate with a prenatal diagnosis of left renal agenesis was born at 33 weeks gestation. A postnatal abdominal ultrasound confirmed the absence of the left kidney and revealed two non-divergent hemiuteri, consistent with the diagnosis of Herlyn-Werner-Wunderlich syndrome. During admission, significant axial hypotonia was noted, warranting additional investigations. Brain ultrasounds and MRI were normal, as were a preliminary metabolic study and comparative genomic hybridisation array. DNA methylation testing confirmed the diagnosis of Prader Willi syndrome. The baby was discharged after 70 days, breast feeding and with modest hypotonia improvement. PMID- 26491005 TI - Isolated small bowel angio-oedema due to ACE inhibitor therapy. PMID- 26491006 TI - Retroperitoneal panniculitis. PMID- 26491007 TI - Dyspnoea in a 72-year-old woman. PMID- 26491008 TI - Analysis of Ribonucleotide Removal from DNA by Human Nucleotide Excision Repair. AB - Ribonucleotides are incorporated into the genome during DNA replication. The enzyme RNase H2 plays a critical role in targeting the removal of these ribonucleotides from DNA, and defects in RNase H2 activity are associated with both genomic instability and the human autoimmune/inflammatory disorder Aicardi Goutieres syndrome. Whether additional general DNA repair mechanisms contribute to ribonucleotide removal from DNA in human cells is not known. Because of its ability to act on a wide variety of substrates, we examined a potential role for canonical nucleotide excision repair in the removal of ribonucleotides from DNA. However, using highly sensitive dual incision/excision assays, we find that ribonucleotides are not efficiently targeted by the human nucleotide excision repair system in vitro or in cultured human cells. These results suggest that nucleotide excision repair is unlikely to play a major role in the cellular response to ribonucleotide incorporation in genomic DNA in human cells. PMID- 26491009 TI - A Second beta-Hexosaminidase Encoded in the Streptococcus pneumoniae Genome Provides an Expanded Biochemical Ability to Degrade Host Glycans. AB - An important facet of the interaction between the pathogen Streptococcus pneumoniae (pneumococcus) and its human host is the ability of this bacterium to process host glycans. To achieve cleavage of the glycosidic bonds in host glycans, S. pneumoniae deploys a wide array of glycoside hydrolases. Here, we identify and characterize a new family 20 glycoside hydrolase, GH20C, from S. pneumoniae. Recombinant GH20C possessed the ability to hydrolyze the beta linkages joining either N-acetylglucosamine or N-acetylgalactosamine to a wide variety of aglycon residues, thus revealing this enzyme to be a generalist N acetylhexosaminidase in vitro. X-ray crystal structures were determined for GH20C in a ligand-free form, in complex with the N-acetylglucosamine and N acetylgalactosamine products of catalysis and in complex with both gluco- and galacto-configured inhibitors O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino N-phenyl carbamate (PUGNAc), O-(2-acetamido-2-deoxy-D-galactopyranosylidene)amino N-phenyl carbamate (GalPUGNAc), N-acetyl-D-glucosamine-thiazoline (NGT), and N acetyl-D-galactosamine-thiazoline (GalNGT) at resolutions from 1.84 to 2.7 A. These structures showed N-acetylglucosamine and N-acetylgalactosamine to be recognized via identical sets of molecular interactions. Although the same sets of interaction were maintained with the gluco- and galacto-configured inhibitors, the inhibition constants suggested preferred recognition of the axial O4 when an aglycon moiety was present (Ki for PUGNAc > GalPUGNAc) but preferred recognition of an equatorial O4 when the aglycon was absent (Ki for GalNGT > NGT). Overall, this study reveals GH20C to be another tool that is unique in the arsenal of S. pneumoniae and that it may implement the effort of the bacterium to utilize and/or destroy the wide array of host glycans that it may encounter. PMID- 26491010 TI - Senescence-associated Long Non-coding RNA (SALNR) Delays Oncogene-induced Senescence through NF90 Regulation. AB - Long non-coding RNAs (lncRNAs) have recently emerged as key players in many physiologic and pathologic processes. Although many lncRNAs have been identified, few lncRNAs have been characterized functionally in aging. In this study, we used human fibroblast cells to investigate genome-wide lncRNA expression during cellular senescence. We identified 968 down-regulated lncRNAs and 899 up regulated lncRNAs in senescent cells compared with young cells. Among these lncRNAs, we characterized a senescence-associated lncRNA (SALNR), whose expression was reduced during cellular senescence and in premalignant colon adenomas. Overexpression of SALNR delayed cellular senescence in fibroblast cells. Furthermore, we found that SALNR interacts with NF90 (nuclear factor of activated T-cells, 90 kDa), an RNA-binding protein suppressing miRNA biogenesis. We demonstrated that NF90 is a SALNR downstream target, whose inhibition led to premature senescence and enhanced expressions of senescence-associated miRNAs. Moreover, our data showed that Ras-induced stress promotes NF90 nucleolus translocation and suppresses its ability to suppress senescence-associated miRNA biogenesis, which could be rescued by SALNR overexpression. These data suggest that lncRNA SALNR modulates cellular senescence at least partly through changing NF90 activity. PMID- 26491011 TI - Evidence for a Functional O-Linked N-Acetylglucosamine (O-GlcNAc) System in the Thermophilic Bacterium Thermobaculum terrenum. AB - Post-translational modification of proteins is a ubiquitous mechanism of signal transduction in all kingdoms of life. One such modification is addition of O linked N-acetylglucosamine to serine or threonine residues, known as O GlcNAcylation. This unusual type of glycosylation is thought to be restricted to nucleocytoplasmic proteins of eukaryotes and is mediated by a pair of O-GlcNAc transferase and O-GlcNAc hydrolase enzymes operating on a large number of substrate proteins. Protein O-GlcNAcylation is responsive to glucose and flux through the hexosamine biosynthetic pathway. Thus, a close relationship is thought to exist between the level of O-GlcNAc proteins within and the general metabolic state of the cell. Although isolated apparent orthologues of these enzymes are present in bacterial genomes, their biological functions remain largely unexplored. It is possible that understanding the function of these proteins will allow development of reductionist models to uncover the principles of O-GlcNAc signaling. Here, we identify orthologues of both O-GlcNAc cycling enzymes in the genome of the thermophilic eubacterium Thermobaculum terrenum. The O-GlcNAcase and O-GlcNAc-transferase are co-expressed and, like their mammalian orthologues, localize to the cytoplasm. The O-GlcNAcase orthologue possesses activity against O-GlcNAc proteins and model substrates. We describe crystal structures of both enzymes, including an O-GlcNAcase.peptide complex, showing conservation of active sites with the human orthologues. Although in vitro activity of the O-GlcNAc-transferase could not be detected, treatment of T. terrenum with an O-GlcNAc-transferase inhibitor led to inhibition of growth. T. terrenum may be the first example of a bacterium possessing a functional O-GlcNAc system. PMID- 26491012 TI - Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics. AB - The pharmacokinetic (PK) behavior of monoclonal antibodies in cynomolgus monkeys (cynos) is generally translatable to that in humans. Unfortunately, about 39% of the antibodies evaluated for PKs in cynos have fast nonspecific (or non-target mediated) clearance (in-house data). An empirical model relating variable region (Fv) charge and hydrophobicity to cyno nonspecific clearance was developed to gauge the risk an antibody would have for fast nonspecific clearance in the monkey. The purpose of this study was to evaluate the predictability of this empirical model on cyno nonspecific clearance with antibodies specifically engineered to have either high or low Fv charge. These amino acid changes were made in the Fv region of two test antibodies, humAb4D5-8 and anti-lymphotoxin alpha. The humAb4D5-8 has a typical nonspecific clearance in cynos, and by making it more positively charged, the antibody acquires fast nonspecific clearance, and making it less positively charged did not impact its clearance. Anti-lymphotoxin alpha has fast nonspecific clearance in cynos, and making it more positively charged caused it to clear even faster, whereas making it less positively charged caused it to clear slower and within the typical range. These trends in clearance were also observed in two other preclinical species, mice and rats. The effect of modifying Fv charge on subcutaneous bioavailability was also examined, and in general bioavailability was inversely related to the direction of the Fv charge change. Thus, modifying Fv charge appears to impact antibody PKs, and the changes tended to correlate with those predicted by the empirical model. PMID- 26491013 TI - Gene Expression Profiling Reveals a Novel Regulatory Role for Sox21 Protein in Mouse Trophoblast Stem Cell Differentiation. AB - Appropriate self-renewal and differentiation of trophoblast stem cells (TSCs) are key factors for proper placental development and function and, in turn, for appropriate in utero fetal growth. To identify novel TSC-specific genes, we performed genome-wide expression profiling of TSCs, embryonic stem cells, epiblast stem cells, and mouse embryo fibroblasts, derived from mice of the same genetic background. Our analysis revealed a high expression of Sox21 in TSCs compared with other cell types. Sox21 levels were high in undifferentiated TSCs and were dramatically reduced upon differentiation. In addition, modulation of Sox21 expression in TSCs affected lineage-specific differentiation, based on both marker analysis and functional assessment. Our results implicate Sox21 specifically in the promotion of spongiotrophoblast and giant cell differentiation and establish a new mechanism through which trophoblast sublineages are specified. PMID- 26491014 TI - Lactate Contributes to Glyceroneogenesis and Glyconeogenesis in Skeletal Muscle by Reversal of Pyruvate Kinase. AB - Phosphoenolpyruvate (PEP) generated from pyruvate is required for de novo synthesis of glycerol and glycogen in skeletal muscle. One possible pathway involves synthesis of PEP from the citric acid cycle intermediates via PEP carboxykinase, whereas another could involve reversal of pyruvate kinase (PK). Earlier studies have reported that reverse flux through PK can contribute carbon precursors for glycogen synthesis in muscle, but the physiological importance of this pathway remains uncertain especially in the setting of high plasma glucose. In addition, although PEP is a common intermediate for both glyconeogenesis and glyceroneogenesis, the importance of reverse PK in de novo glycerol synthesis has not been examined. Here we studied the contribution of reverse PK to synthesis of glycogen and the glycerol moiety of acylglycerols in skeletal muscle of animals with high plasma glucose. Rats received a single intraperitoneal bolus of glucose, glycerol, and lactate under a fed or fasted state. Only one of the three substrates was (13)C-labeled in each experiment. After 3 h of normal awake activity, the animals were sacrificed, and the contribution from each substrate to glycogen and the glycerol moiety of acylglycerols was evaluated. The fraction of (13)C labeling in glycogen and the glycerol moiety exceeded the possible contribution from either plasma glucose or muscle oxaloacetate. The reverse PK served as a common route for both glyconeogenesis and glyceroneogenesis in the skeletal muscle of rats with high plasma glucose. The activity of pyruvate carboxylase was low in muscle, and no PEP carboxykinase activity was detected. PMID- 26491015 TI - alpha/beta Hydrolase Domain-containing 6 (ABHD6) Degrades the Late Endosomal/Lysosomal Lipid Bis(monoacylglycero)phosphate. AB - alpha/beta Hydrolase domain-containing 6 (ABHD6) can act as monoacylglycerol hydrolase and is believed to play a role in endocannabinoid signaling as well as in the pathogenesis of obesity and liver steatosis. However, the mechanistic link between gene function and disease is incompletely understood. Here we aimed to further characterize the role of ABHD6 in lipid metabolism. We show that mouse and human ABHD6 degrade bis(monoacylglycero)phosphate (BMP) with high specific activity. BMP, also known as lysobisphosphatidic acid, is enriched in late endosomes/lysosomes, where it plays a key role in the formation of intraluminal vesicles and in lipid sorting. Up to now, little has been known about the catabolism of this lipid. Our data demonstrate that ABHD6 is responsible for ~ 90% of the BMP hydrolase activity detected in the liver and that knockdown of ABHD6 increases hepatic BMP levels. Tissue fractionation and live-cell imaging experiments revealed that ABHD6 co-localizes with late endosomes/lysosomes. The enzyme is active at cytosolic pH and lacks acid hydrolase activity, implying that it degrades BMP exported from acidic organelles or de novo-formed BMP. In conclusion, our data suggest that ABHD6 controls BMP catabolism and is therefore part of the late endosomal/lysosomal lipid-sorting machinery. PMID- 26491016 TI - Proteomic Analysis Identifies Ribosome Reduction as an Effective Proteotoxic Stress Response. AB - Stress responses are adaptive cellular programs that identify and mitigate potentially dangerous threats. Misfolded proteins are a ubiquitous and clinically relevant stress. Trivalent metalloids, such as arsenic, have been proposed to cause protein misfolding. Using tandem mass tag-based mass spectrometry, we show that trivalent arsenic results in widespread reorganization of the cell from an anabolic to a catabolic state. Both major pathways of protein degradation, the proteasome and autophagy, show increased abundance of pathway components and increased functional output, and are required for survival. Remarkably, cells also showed a down-regulation of ribosomes at the protein level. That this represented an adaptive response and not an adverse toxic effect was indicated by enhanced survival of ribosome mutants after arsenic exposure. These results suggest that a major source of toxicity of trivalent arsenic derives from misfolding of newly synthesized proteins and identifies ribosome reduction as a rapid, effective, and reversible proteotoxic stress response. PMID- 26491017 TI - Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1alpha-TAZ Signaling Pathway in Osteoblasts. AB - Disrupting the protective signals provided by the bone marrow microenvironment will be critical for more effective combination drug therapies for acute myeloid leukemia (AML). Cells of the osteoblast lineage that reside in the endosteal niche have been implicated in promoting survival of AML cells. Here, we investigated how to prevent this protective interaction. We previously showed that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis of AML cells, unless the leukemic cells receive protective signals provided by differentiating osteoblasts (8, 10). We now identify a novel signaling pathway in differentiating osteoblasts that can be manipulated to disrupt the osteoblast mediated protection of AML cells. Treating differentiating osteoblasts with histone deacetylase inhibitors (HDACi) abrogated their ability to protect co cultured AML cells from SDF-1-induced apoptosis. HDACi prominently up-regulated expression of the Nherf1 scaffold protein, which played a major role in preventing osteoblast-mediated protection of AML cells. Protein phosphatase 1alpha (PP1alpha) was identified as a novel Nherf1 interacting protein that acts as the downstream mediator of this response by promoting nuclear localization of the TAZ transcriptional modulator. Moreover, independent activation of either PP1alpha or TAZ was sufficient to prevent osteoblast-mediated protection of AML cells even in the absence of HDACi. Together, these results indicate that HDACi target the AML microenvironment by enhancing activation of the Nherf1-PP1alpha TAZ pathway in osteoblasts. Selective drug targeting of this osteoblast signaling pathway may improve treatments of AML by rendering leukemic cells in the bone marrow more susceptible to apoptosis. PMID- 26491018 TI - Mitochondrial Respiratory Defect Causes Dysfunctional Lactate Turnover via AMP activated Protein Kinase Activation in Human-induced Pluripotent Stem Cell derived Hepatocytes. AB - A defective mitochondrial respiratory chain complex (DMRC) causes various metabolic disorders in humans. However, the pathophysiology of DMRC in the liver remains unclear. To understand DMRC pathophysiology in vitro, DMRC-induced pluripotent stem cells were generated from dermal fibroblasts of a DMRC patient who had a homoplasmic mutation (m.3398T->C) in the mitochondrion-encoded NADH dehydrogenase 1 (MTND1) gene and that differentiated into hepatocytes (DMRC hepatocytes) in vitro. DMRC hepatocytes showed abnormalities in mitochondrial characteristics, the NAD(+)/NADH ratio, the glycogen storage level, the lactate turnover rate, and AMPK activity. Intriguingly, low glycogen storage and transcription of lactate turnover-related genes in DMRC hepatocytes were recovered by inhibition of AMPK activity. Thus, AMPK activation led to metabolic changes in terms of glycogen storage and lactate turnover in DMRC hepatocytes. These data demonstrate for the first time that energy depletion may lead to lactic acidosis in the DMRC patient by reduction of lactate uptake via AMPK in liver. PMID- 26491019 TI - Retinoblastoma-binding Protein 4-regulated Classical Nuclear Transport Is Involved in Cellular Senescence. AB - Nucleocytoplasmic trafficking is a fundamental cellular process in eukaryotic cells. Here, we demonstrated that retinoblastoma-binding protein 4 (RBBP4) functions as a novel regulatory factor to increase the efficiency of importin alpha/beta-mediated nuclear import. RBBP4 accelerates the release of importin beta1 from importin alpha via competitive binding to the importin beta-binding domain of importin alpha in the presence of RanGTP. Therefore, it facilitates importin alpha/beta-mediated nuclear import. We showed that the importin alpha/beta pathway is down-regulated in replicative senescent cells, concomitant with a decrease in RBBP4 level. Knockdown of RBBP4 caused both suppression of nuclear transport and induction of cellular senescence. This is the first report to identify a factor that competes with importin beta1 to bind to importin alpha, and it demonstrates that the loss of this factor can trigger cellular senescence. PMID- 26491020 TI - Genetic Control of Replication through N1-methyladenine in Human Cells. AB - N1-methyl adenine (1-MeA) is formed in DNA by reaction with alkylating agents and naturally occurring methyl halides. The 1-MeA lesion impairs Watson-Crick base pairing and blocks normal DNA replication. Here we identify the translesion synthesis (TLS) DNA polymerases (Pols) required for replicating through 1-MeA in human cells and show that TLS through this lesion is mediated via three different pathways in which Pols iota and theta function in one pathway and Pols eta and zeta, respectively, function in the other two pathways. Our biochemical studies indicate that in the Poliota/Poltheta pathway, Poliota would carry out nucleotide insertion opposite 1-MeA from which Poltheta would extend synthesis. In the Poleta pathway, this Pol alone would function at both the nucleotide insertion and extension steps of TLS, and in the third pathway, Polzeta would extend from the nucleotide inserted opposite 1-MeA by an as yet unidentified Pol. Whereas by pushing 1-MeA into the syn conformation and by forming Hoogsteen base pair with the T residue, Poliota would carry out TLS opposite 1-MeA, the ability of Poleta to replicate through 1-MeA suggests that despite its need for Watson-Crick hydrogen bonding, Poleta can stabilize the adduct in its active site. Remarkably, even though Pols eta and iota are quite error-prone at inserting nucleotides opposite 1-MeA, TLS opposite this lesion in human cells occurs in a highly error free fashion. This suggests that the in vivo fidelity of TLS Pols is regulated by factors such as post-translational modifications, protein-protein interactions, and possibly others. PMID- 26491022 TI - Scanning tunneling microscopy study of the possible topological surface states in BiTeCl. AB - Recently, the non-centrosymmetric bismuth tellurohalides such as BiTeCl are being studied as possible candidates for topological insulators. While some photoemission studies showed that BiTeCl is an inversion asymmetric topological insulator, others showed that it is a normal semiconductor with Rashba splitting. Meanwhile, first-principle calculations have failed to confirm the existence of topological surface states in BiTeCl so far. Therefore, the topological nature of BiTeCl requires further investigation. Here we report a low-temperature scanning tunneling microscopy study on the surface states of BiTeCl single crystals. On the tellurium (Te) -terminated surfaces with relatively low defect density, evidence for topological surface states is observed in the quasi-particle interference patterns, both in the anisotropy of the scattering vectors and the fast decay of the interference near the step edges. Meanwhile, on the samples with much higher defect densities, we observed surface states that behave differently. Our results may help to resolve the current controversy on the topological nature of BiTeCl. PMID- 26491021 TI - Structural Basis for Dimer Formation of Human Condensin Structural Maintenance of Chromosome Proteins and Its Implications for Single-stranded DNA Recognition. AB - Eukaryotic structural maintenance of chromosome proteins (SMC) are major components of cohesin and condensins that regulate chromosome structure and dynamics during cell cycle. We here determine the crystal structure of human condensin SMC hinge heterodimer with ~30 residues of coiled coils. The structure, in conjunction with the hydrogen exchange mass spectrometry analyses, revealed the structural basis for the specific heterodimer formation of eukaryotic SMC and that the coiled coils from two different hinges protrude in the same direction, providing a unique binding surface conducive for binding to single-stranded DNA. The characteristic hydrogen exchange profiles of peptides constituted regions especially across the hinge-hinge dimerization interface, further suggesting the structural alterations upon single-stranded DNA binding and the presence of a half-opened state of hinge heterodimer. This structural change potentially relates to the DNA loading mechanism of SMC, in which the hinge domain functions as an entrance gate as previously proposed for cohesin. Our results, however, indicated that this is not the case for condensins based on the fact that the coiled coils are still interacting with each other, even when DNA binding induces structural changes in the hinge region, suggesting the functional differences of SMC hinge domain between condensins and cohesin in DNA recognition. PMID- 26491023 TI - [Spinal cord stimulation for thalamic pain: Case report and review of the current literature]. AB - BACKGROUND: Spinal cord stimulation (SCS) is an established procedure for treatment of chronic neuropathic pain of peripheral origin. The efficacy of SCS in case of central poststroke pain (CPSP), especially thalamic pain, has not been adequately proven. OBJECTIVES: The efficacy of SCS as an extracranial neurostimulation method for the management of central pain syndrome was investigated. MATERIALS AND METHODS: In this study, relevant pharmacological and nonpharmacological measures for central pain management were reviewed. A case of successful SCS for thalamic pain after ischemic insult is presented. Explanatory approaches of pathophysiological processes and a review of the current literature underline our results. RESULTS: In the case presented, SCS was found effective in the treatment of thalamic pain. CONCLUSION: The efficacy of SCS might be caused by segmental and supraspinal processes and collaboration of activating and inhibiting pathways. The integrity of the spinothalamic tract is mandatory. SCS is a treatment option for central pain syndrome, especially thalamic pain. Comparable studies confirm the potency of this technique. In contrast to other neuromodulation procedures spinal cord stimulation is less invasive, has a lower perioperative risk and is often less expensive. Further studies are needed to define its potential and role in the treatment of thalamic pain. PMID- 26491024 TI - [Course of pain after operative orthopedic interventions: Characterization exemplified by total knee arthroplasty]. AB - BACKGROUND: The number of cases of orthopedic surgery is still increasing and postoperative pain management is of great importance for the patients. Therefore, in this study factors influencing the pain and the developement of pain in general in the first 7 days after total knee arthroplasty were examined. MATERIAL AND METHODS: A total of 28 patients were included in this prospectively designed trial and underwent total knee arthroplasty with psoas compartment and sciatic nerve regional anesthesia and additionally propofol sedation. Postoperative pain scores were documented using a numerical rating scale (NRS) and anthropometric data and perioperative parameters were correlated with the postoperative pain score. RESULTS: Evaluation of the pain values per interval showed that the maximum and the mean postoperative pain levels decreased up to day 4 after surgery and then increased. No significant effects of the analyzed parameters age, body mass index (BMI), duration of surgery and catheter indwelling time could be found. Female patients had significantly more pain than males in this collective. CONCLUSION: The results show that there were no factors which have a significant influence on the degree of postoperative pain. Female patients suffered from more pain than males. There was an increase in pain after postoperative day 4 which might be the effect of more extensive mobilization and reduced effects of regional anesthesia. It is important that pain is treated in the early postoperative period. PMID- 26491025 TI - High Plasma Levels of D-Dimer Are Independently Associated with a Heightened Risk of Deep Vein Thrombosis in Patients with Intracerebral Hemorrhage. AB - Deep venous thrombosis (DVT) is a complication of stroke. Our aim was to determine whether D-dimer plasma levels at admission could be a risk factor for DVT in Chinese patients with acute intracerebral hemorrhage (ICH). From December 2012 to November 2014, all patients with first-ever acute ICH were included. At baseline, the demographical and clinical data were taken. These patients were assessed for DVT using color Doppler ultrasonography (CDUS) on 15 days after ICH and whenever clinically requested. Multivariate analyses were performed using logistic regression models. Receiver operating characteristic (ROC) curves were used to test the overall predictive accuracy of D-dimer and other markers. In our study, acute ICH was diagnosed in 265 patients and 210 completed a 15-day follow up and were included in the analysis. Fifty-four (25.7 %) out of the 210 patients were diagnosed as DVT. Plasma D-dimer levels were significantly higher in ICH patients with DVT as compared to those without DVT (P < 0.0001). Multivariate logistic regression analysis adjusted for common risk factors showed that plasma D-dimer levels >=1.20 mg/L were an independent predictor of DVT [odds ratio (OR) = 12.99, 95 % confidence interval (CI) = 3.17-32.98; P < 0.0001]. With an area under the curve (AUC) of 0.91 (95 % CI = 0.86-0.94), D-dimer showed a significantly greater discriminatory ability to predict DVT as compared with high sensitivity C-reactive protein (Hs-CRP) (AUC = 0.77, 95 % CI = 0.70-0.82; P < 0.01), homocysteine (HCY) (AUC = 0.75, 95 % CI = 0.70-0.81; P < 0.01), and National Institutes of Health Stroke Scale (NIHSS) score (AUC = 0.80, 95 % CI = 0.72-0.85; P < 0.01). The present study suggested that elevated D-dimer plasma levels were independent predictors for DVT in Chinese patients with ICH. PMID- 26491026 TI - SMAD4 Defect Causes Auditory Neuropathy Via Specialized Disruption of Cochlear Ribbon Synapses in Mice. AB - More than 100 genes have been associated with deafness. However, SMAD4 is rarely considered a contributor to deafness in humans, except for its well-defined role in cell differentiation and regeneration. Here, we report that a SMAD4 defect in mice can cause auditory neuropathy, which was defined as a mysterious hearing and speech perception disorder in human for which the genetic background remains unclear. Our study showed that a SMAD4 defect induces failed formation of cochlear ribbon synapse during the earlier stage of auditory development in mice. Further investigation found that there are nearly normal morphology of outer hair cells (OHCs) and post-synapse spiral ganglion nerves (SGNs) in SMAD4 conditional knockout mice (cKO); however, a preserved distortion product of otoacoustic emission (DPOAE) and cochlear microphonic (CM) still can be evoked in cKO mice. Moreover, a partial restoration of hearing detected by electric auditory brainstem response (eABR) has been obtained in the cKO mice using electrode stimuli toward auditory nerves. Additionally, the ribbon synapses in retina are not affected by this SMAD4 defect. Thus, our findings suggest that this SMAD4 defect causes auditory neuropathy via specialized disruption of cochlear ribbon synapses. PMID- 26491029 TI - Social Support and "Playing Around": An Examination of How Older Adults Acquire Digital Literacy With Tablet Computers. AB - This study examines how older adults learn to use tablet computers. Learning to use new technologies can help older adults to be included in today's digital society. However, learning to use new technologies is not always easy, especially for older adults. This study focuses on how older adults learn to use a specific technology, tablet computers, and the role that social support plays in this process. Data for this project are from 21 in-depth interviews with individuals who own tablet computers. We examine how older adults engage with tablet devices and increase their digital literacy. The findings suggest that, for older adults to start to use tablets, social support plays an important role. In addition, a key way that many participants report gaining expertise with the technology is through "playing around" with the tablets. Suggestions for how to help older adults learn to use new technologies are detailed. PMID- 26491027 TI - The Role of Reelin Signaling in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common causes of age-related dementia. It is characterized by the deposition of amyloid-beta peptide and neurofibrillary tangles, as well as neuronal death and synaptic loss. Reelin is an extracellular glycoprotein which performs diverse roles in the developing and adult brain, including regulation of neuronal migration, dendritogenesis, synapse development, hippocampal synaptic plasticity, and learning and memory. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in AD. Accumulating studies have investigated the molecular mechanism by which Reelin, its receptors, and downstream signaling proteins may contribute to the pathophysiology of AD. However, the molecular mechanisms by which Reelin and its downstream signal transduction contribute to the pathogenesis of AD remain still largely unknown. In the present review, we briefly summarize the current knowledge and recent findings related to the molecular link between Reelin dysfunction and AD-related neuropathology. PMID- 26491028 TI - Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Naive First Episode Psychosis. AB - In schizophrenia, genetic and environmental factors affect neurodevelopment and neuroprogressive trajectory. Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression. However, it remains unclear whether circulating levels of cytokines and expression of these genes are associated, and how antipsychotic treatments impact this association. Relationships between messenger RNA (mRNA) expression of 11 schizophrenia-related genes and circulating levels of cytokines (interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha) were analyzed in 174 antipsychotic naive first episode psychosis (FEP) and in 77 healthy controls. A subgroup of 72 patients was reassessed after treatment with risperidone. FEP patients were divided into those with and without depression. FEP patients with depression showed increased COMT expression and decreased NDEL1 expression. Increased IL-6 was associated with lowered AKT1 and DROSHA expression, while increased IL-10 was associated with increased NDEL1, DISC1, and MBP expression. IL-6 levels significantly increased the risperidone-induced expression of AKT1, DICER1, DROSHA, and COMT mRNA. The differential mRNA gene expression in FEP is largely associated with increased cytokine levels. While increased IL-6 may downregulate AKT-mediated cellular functions and dysregulate genes involved in microRNA (miRNA) machinery, increased IL-10 has neuroprotective properties. Increased IL-6 levels may prime the expression of genes (AKT1, DICER1, DROSHA, and COMT) in response to risperidone, suggesting that cytokine * treatment * gene interactions may improve cell function profiles. FEP patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype. PMID- 26491030 TI - Management of chronic hepatitis B infection. AB - Hepatitis B virus (HBV) is a global health problem that can lead to cirrhosis and hepatocellular carcinoma (HCC). Although HBV vaccination has reduced the prevalence Of HBV infection, the burden of disease remains high. Treatment with antiviral drugs reduces the risk of liver disease and the development of HCC, and it can even reverse liver fibrosis. However, challenges remain regarding optimal timing, as well as the modality and duration of treatment. Currently approved drugs include pegylated interferon and nucleos(t)ide analogs. Nucleos(t)ide analogs are better tolerated and provide excellent viral suppression with a low risk of antiviral resistance, but pegylated interferon offers the benefit of a finite duration of treatment. Monitoring of hepatitis B surface antigen (HBsAg) levels may help to predict the likelihood of response to treatment, particularly for pegylated interferon. Prolonged treatment is usually needed with oral antiviral agents, and relapse is common if treatment is discontinued. New treatments that result in sustained clearance of HBV DNA and the clearance of HBsAg are needed. PMID- 26491031 TI - Pulmonary arterial response to hypoxia in survivors of chronic lung disease of prematurity. AB - BACKGROUND: It is unclear whether increased pulmonary arterial (PA) reactivity to hypoxia observed in preterm infants who develop chronic lung disease of prematurity (CLD) persists into childhood. AIM: We assessed and compared PA pulse wave velocity (PWV) in air and after 12% hypoxia using velocity-encoded MRI between children who had CLD in infancy and preterm-born and term-born controls. METHODS: From 67 recruited children, 59 (13 CLD, 21 preterm, 25 term), 9-12-year old children successfully completed the study. Velocity-encoded phase-contrast MR PA images were acquired breathing air and during breathing 12% hypoxia. PA PWV was derived as the ratio of flow to area changes during early systole. RESULTS: There were no differences in mean (SD) PA PWV between the groups breathing air (CLD=1.3 (0.4) m/s, preterm control=1.3 (0.4) m/s, term control=1.3 (0.3) m/s)) but increased following hypoxia to 1.9 (0.7) m/s, 1.6 (0.6) m/s and 1.5 (0.5) m/s in CLD, preterm and term groups, respectively. The mean differences (95% CI) for PA PWV between CLD and the preterm and control groups were 0.37 (0.08 to 0.70) and 0.34 (0.05 to 0.70), respectively. There was no difference for change in PA PWV with hypoxia between the two control groups, mean difference 0.23 (-0.2 to 0.3). CONCLUSIONS: Children who had CLD in infancy had increased pulmonary arterial reactivity during hypoxia, thus long-term follow-up is warranted in this population. PMID- 26491032 TI - Fully parallel write/read in resistive synaptic array for accelerating on-chip learning. AB - A neuro-inspired computing paradigm beyond the von Neumann architecture is emerging and it generally takes advantage of massive parallelism and is aimed at complex tasks that involve intelligence and learning. The cross-point array architecture with synaptic devices has been proposed for on-chip implementation of the weighted sum and weight update in the learning algorithms. In this work, forming-free, silicon-process-compatible Ta/TaOx/TiO2/Ti synaptic devices are fabricated, in which >200 levels of conductance states could be continuously tuned by identical programming pulses. In order to demonstrate the advantages of parallelism of the cross-point array architecture, a novel fully parallel write scheme is designed and experimentally demonstrated in a small-scale crossbar array to accelerate the weight update in the training process, at a speed that is independent of the array size. Compared to the conventional row-by-row write scheme, it achieves >30* speed-up and >30* improvement in energy efficiency as projected in a large-scale array. If realistic synaptic device characteristics such as device variations are taken into an array-level simulation, the proposed array architecture is able to achieve ~95% recognition accuracy of MNIST handwritten digits, which is close to the accuracy achieved by software using the ideal sparse coding algorithm. PMID- 26491033 TI - Return to sport after open and microdiscectomy surgery versus conservative treatment for lumbar disc herniation: a systematic review with meta-analysis. AB - BACKGROUND: Lumbar disc herniation has a prevalence of up to 58% in the athletic population. Lumbar discectomy is a common surgical procedure to alleviate pain and disability in athletes. We systematically reviewed the current clinical evidence regarding athlete return to sport (RTS) following lumbar discectomy compared to conservative treatment. METHODS: A computer-assisted literature search of MEDLINE, CINAHL, Web of Science, PEDro, OVID and PubMed databases (from inception to August 2015) was utilised using keywords related to lumbar disc herniation and surgery. The design of this systematic review was developed using the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA). Methodological quality of individual studies was assessed using the Downs and Black scale (0-16 points). RESULTS: The search strategy revealed 14 articles. Downs and Black quality scores were generally low with no articles in this review earning a high-quality rating, only 5 articles earning a moderate quality rating and 9 of the 14 articles earning a low-quality rating. The pooled RTS for surgical intervention of all included studies was 81% (95% CI 76% to 86%) with significant heterogeneity (I(2)=63.4%, p<0.001) although pooled estimates report only 59% RTS at same level. Pooled analysis showed no difference in RTS rate between surgical (84% (95% CI 77% to 90%)) and conservative intervention (76% (95% CI 56% to 92%); p=0.33). CONCLUSIONS: Studies comparing surgical versus conservative treatment found no significant difference between groups regarding RTS. Not all athletes that RTS return at the level of participation they performed at prior to surgery. Owing to the heterogeneity and low methodological quality of included studies, rates of RTS cannot be accurately determined. PMID- 26491035 TI - Power Relations and Health Care Communication in Older Adulthood: Educating Recipients and Providers. AB - Unequal power relations lie just below the surface in much of today's discourse on health care communication with older adults. Focusing on pathologies or deficits tends to reinforce stereotypes of frailty and dependency, thus framing elders as a vulnerable group requiring special assistance. Implicit stereotyping frequently colors interactions of health care personnel with older clients and their families-interactions likely to affect elders' perceptions and health outcomes. Health care providers need to be attuned to the vast and growing diversity in today's older population, wherein many older adults are exemplars of what it takes to marshal resources and cope with multifaceted challenges. Thus, elders have the potential to teach medical personnel through narratives of resilience as well as tribulation. This potential can be fully realized, however, only in contexts where communication patterns characterized by paternalism, consumerism, and collaboration are mutually recognized and selectively challenged or implemented. Promising interventions to facilitate health care communication in older adulthood might well be directed toward (a) educating both recipients and providers to become more mindful of cues that evoke stereotypical thinking, (b) promoting an institutional culture that normalizes situationally appropriate assertive responses to stereotyping, and (c) formally ratifying older adults' life experience in the training of health care personnel. PMID- 26491034 TI - Genomic and transcriptomic predictors of triglyceride response to regular exercise. AB - AIM: We performed genome-wide and transcriptome-wide profiling to identify genes and single nucleotide polymorphisms (SNPs) associated with the response of triglycerides (TG) to exercise training. METHODS: Plasma TG levels were measured before and after a 20-week endurance training programme in 478 white participants from the HERITAGE Family Study. Illumina HumanCNV370-Quad v3.0 BeadChips were genotyped using the Illumina BeadStation 500GX platform. Affymetrix HG-U133+2 arrays were used to quantitate gene expression levels from baseline muscle biopsies of a subset of participants (N=52). Genome-wide association study (GWAS) analysis was performed using MERLIN, while transcriptomic predictor models were developed using the R-package GALGO. RESULTS: The GWAS results showed that eight SNPs were associated with TG training-response (DeltaTG) at p<9.9*10(-6), while another 31 SNPs showed p values <1*10(-4). In multivariate regression models, the top 10 SNPs explained 32.0% of the variance in DeltaTG, while conditional heritability analysis showed that four SNPs statistically accounted for all of the heritability of DeltaTG. A molecular signature based on the baseline expression of 11 genes predicted 27% of DeltaTG in HERITAGE, which was validated in an independent study. A composite SNP score based on the top four SNPs, each from the genomic and transcriptomic analyses, was the strongest predictor of DeltaTG (R(2)=0.14, p=3.0*10(-68)). CONCLUSIONS: Our results indicate that skeletal muscle transcript abundance at 11 genes and SNPs at a number of loci contribute to TG response to exercise training. Combining data from genomics and transcriptomics analyses identified a SNP-based gene signature that should be further tested in independent samples. PMID- 26491036 TI - Specific CD4+ T-Cell Reactivity and Cytokine Release in Different Clinical Presentations of Leptospirosis. AB - Clinical manifestations of leptospirosis are highly variable: from asymptomatic to severe and potentially fatal. The outcome of the disease is usually determined in the immunological phase, beginning in the second week of symptoms. The underlying mechanisms, predictive factors, and individual immune responses that contribute to clinical variations are not well understood. The aim of this study was to determine the specifics of CD4(+) T-cell reactivity and cytokine release after stimulation with leptospiral antigens in patients with leptospirosis of different disease severities (patients with mild and severe symptoms) and in control subjects (with and without proven exposure to Leptospira). Whole-blood specimens were stimulated with Leptospira antigens in vitro. Subsequently, intracellular staining of cytokines was performed, and flow cytometry was used to assess the expression of CD40 ligand (CD40L) and the production of gamma interferon (IFN-gamma), interleukin-10 (IL-10), IL-2, and tumor necrosis factor alpha (TNF-alpha) by CD4(+) T cells. The production of inflammatory cytokines such as TNF-alpha by CD4(+) T cells after stimulation with leptospiral antigens was highest in patients with severe disease. In contrast, the ratio of IL-10 production to TNF-alpha production was higher in exposed subjects than in patients with mild and severe disease. Levels of proinflammatory cytokines such as TNF-alpha may be useful markers of the severity of the immunological phase of leptospirosis. IL-10 production by T cells after antigen-specific stimulation may indicate a more successful downregulation of the inflammatory response and may contribute to an asymptomatic course of the disease. PMID- 26491038 TI - Selective exfoliation of single-layer graphene from non-uniform graphene grown on Cu. AB - Graphene growth on a copper surface via metal-catalyzed chemical vapor deposition has several advantages in terms of providing high-quality graphene with the potential for scale-up, but the product is usually inhomogeneous due to the inability to control the graphene layer growth. The non-uniform regions strongly affect the reliability of the graphene in practical electronic applications. Herein, we report a novel graphene transfer method that allows for the selective exfoliation of single-layer graphene from non-uniform graphene grown on a Cu foil. Differences in the interlayer bonding energy are exploited to mechanically separate only the top single-layer graphene and transfer this to an arbitrary substrate. The dry-transferred single-layer grapheme showed electrical characteristics that were more uniform than those of graphene transferred using conventional wet-etching transfer steps. PMID- 26491037 TI - Comparative Adjuvant Effects of Type II Heat-Labile Enterotoxins in Combination with Two Different Candidate Ricin Toxin Vaccine Antigens. AB - Type II heat-labile enterotoxins (HLTs) constitute a promising set of adjuvants that have been shown to enhance humoral and cellular immune responses when coadministered with an array of different proteins, including several pathogen associated antigens. However, the adjuvant activities of the four best-studied HLTs, LT-IIa, LT-IIb, LT-IIb(T13I), and LT-IIc, have never been compared side by side. We therefore conducted immunization studies in which LT-IIa, LT-IIb, LT IIb(T13I), and LT-IIc were coadministered by the intradermal route to mice with two clinically relevant protein subunit vaccine antigens derived from the enzymatic A subunit (RTA) of ricin toxin, RiVax and RVEc. The HLTs were tested with low and high doses of antigen and were assessed for their abilities to stimulate antigen-specific serum IgG titers, ricin toxin-neutralizing activity (TNA), and protective immunity. We found that all four HLTs tested were effective adjuvants when coadministered with RiVax or RVEc. LT-IIa was of particular interest because as little as 0.03 MUg when coadministered with RiVax or RVEc proved effective at augmenting ricin toxin-specific serum antibody titers with nominal evidence of local inflammation. Collectively, these results justify the need for further studies into the mechanism(s) underlying LT-IIa adjuvant activity, with the long-term goal of evaluating LT-IIa's activity in humans. PMID- 26491039 TI - A prospective case control comparison of the ZeroGravity system versus a standard lead apron as radiation protection strategy in neuroendovascular procedures. AB - BACKGROUND AND PURPOSE: We aimed to compare the performance of the ZeroGravity (ZG) system (radiation protection system composed by a suspended lead suit) against the use of standard protection (lead apron (LA), thyroid shield, lead eyeglasses, table skirts, and ceiling suspended shield) in neuroangiography procedures. MATERIALS AND METHODS: Radiation exposure data were prospectively collected in consecutive neuroendovascular procedures between December 2014 and February 2015. Operator No 1 was assigned to the use of an LA (plus lead glasses, thyroid shield, and a 1 mm hanging shield at the groin) while operator No 2 utilized the ZG system. Dosimeters were used to measure peak skin dose for the head, thyroid, and left foot. RESULTS: The two operators performed a total of 122 procedures during the study period. The ZG operator was more commonly the primary operator compared with the LA operator (85% vs 71%; p=0.04). The mean anterior posterior (AP), lateral, and cumulative dose area product (DAP) radiation exposure as well as the mean fluoroscopy time were not statistically different between the operators' cases. The peak skin dose to the head of the operator with LA was 2.1 times higher (3380 vs 1600 MUSv), while the thyroid was 13.9 (4460 vs 320 MUSv), the mediastinum infinitely (520 vs 0 MUSv), and the foot 3.3 times higher (4870 vs 1470 MUSv) compared with the ZG operator, leading to an overall accumulated dose 4 times higher. The ratio of cumulative operator received dose/total cumulative DAP was 2.5 higher on the LA operator. CONCLUSIONS: The ZG radiation protection system leads to substantially lower radiation exposure to the operator in neurointerventional procedures. However, substantial exposure may still occur at the level of the lens and thyroid to justify additional protection. PMID- 26491040 TI - Volume versus standard coils in the treatment of intracranial aneurysms. AB - BACKGROUND: Volume coils were developed to improve occlusion rates of intracranial aneurysms. Previous studies have shown increased packing density and comparable occlusion rates, but subgroup analyses of aneurysm size have not been carried out. OBJECTIVE: To evaluate the safety and efficacy of the Penumbra Coil 400 (PC400) system in treating intracranial aneurysms compared with standard diameter coils. METHODS: A monocentric retrospective case review of 260 aneurysms in 233 patients was carried out. In 37 aneurysms the PC400 system was used, while 223 aneurysms were treated with conventional coils. Previously treated aneurysms and aneurysms treated with flow diverters were excluded. Aneurysm and procedure characteristics, packing density, postprocedural and follow-up occlusion grades as well as coil compaction were evaluated. RESULTS: Aneurysms treated with PC400 coils had higher volume (218.9 vs 47.1 mm(3), p<0.001), wider necks (3.0 vs 2.5 mm, p=0.005), and greater dome/neck ratio (2.0 vs 1.6, p=0.001) in comparison with aneurysms treated with conventional coils. Compared with controls, in the PC400 group we achieved higher packing densities (43.2% vs 34.4%, p<0.001; in aneurysms >=7 mm 42.2% vs 27.8%, p<0.001). On follow-up angiography we observed less coil compaction (23.8% vs 64.3%, p=0.003) and less aneurysm recurrence (14.3% vs 40.5%, p=0.046) in aneurysms >=7 mm when using the PC400 system. CONCLUSIONS: Use of the PC400 system as opposed to conventional coils suggests that the PC400 system is safe and effective in treating intracranial aneurysms. Despite having been applied in a potentially more difficult-to-treat group, the use of PC400 was associated with less coil compaction and aneurysm recurrence in aneurysms >=7 mm. PMID- 26491041 TI - Pipeline embolization device for the treatment of vertebral artery aneurysms: the fate of covered branch vessels. AB - INTRODUCTION: Preliminary studies suggest that flow-diverting stents may be suitable for the treatment of aneurysms of the posterior circulation. The safety and efficacy of using flow-diverting stents for vertebral artery (VA) aneurysms is not well defined. OBJECTIVE: To examine the fate of covering the posterior inferior cerebellar artery (PICA) in patients undergoing placement of a flow diverting stent for VA aneurysm. METHODS: Consecutive patients who underwent placement of a Pipeline Embolization Device (PED) for treatment of an aneurysm of the V4 segment of the VA between April 2012 and June 2015 at our institution were retrospectively evaluated. Angiograms were reviewed to determine the patency of the PICA when the vessel origin was covered by the PED. RESULTS: 11 patients with VA aneurysms who underwent treatment with the PED were identified. In each case the device covered the origin of the PICA. Follow-up angiography in eight patients demonstrated thrombosis of the aneurysm with patency of the PICA. CONCLUSIONS: Flow-diverting stents can be used for the treatment of VA aneurysms. When appropriately sized to the vessel wall and positioned in the VA, the device may cover the origin of the PICA without impairing flow through the branching artery. PMID- 26491042 TI - Larval Preference and Performance of Amyelois transitella (Navel Orangeworm, Lepidoptera: Pyralidae) in Relation to the Fungus Aspergillus flavus. AB - The navel orangeworm, Amyelois transitella (Walker), is a polyphagous pest of California nut crops and is responsible for extensive losses in the United States. It directly damages crops by feeding and contaminating nuts with frass and webbing and vectors saprophytic fungi that infect crops. The navel orangeworm is commonly associated with Aspergillus species, including the toxigenic Aspergillus flavus, which causes crop loss by producing carcinogens, including aflatoxin B1. This lepidopteran-fungus association is the most economically serious pest complex in Central Valley orchards, and evidence indicates that this relationship is mutualistic. We assessed preference and performance of navel orangeworm larvae associated with A. flavus in behavioral bioassays in which neonates were allowed to orient within arenas to media with or without fungal tissue, and performance bioassays in which larvae were reared with and without A. flavus on potato dextrose agar (PDA) and a semidefined almond PDA diet to evaluate effects on development and pupal weight. Navel orangeworm larvae were attracted to A. flavus and developed faster in its presence, indicating a nutritional benefit to the caterpillars. Larvae reached pupation ~33% faster on diet containing A. flavus, and pupal weights were ~18% higher for males and ~13% higher for females on this diet. Our findings indicate that A. flavus plays an important role in larval orientation and development on infected hosts. The preference-performance relationship between navel orangeworms and Aspergillus flavus is consistent with a facultative mutualism that has broad implications for pest management efforts and basic understanding of Lepidoptera-plant interactions. PMID- 26491043 TI - Longitudinal Relationship Between Loneliness and Social Isolation in Older Adults: Results From the Cardiovascular Health Study. AB - OBJECTIVE: To understand the longitudinal relationship between loneliness and isolation. METHOD: Participants included 5,870 adults 65 years and older (M = 72.89 +/- 5.59 years) from the first 5 years of the Cardiovascular Health Study. Loneliness was assessed using a dichotomized loneliness question. Social isolation was assessed using six items from the Lubben Social Network Scale. Yearly life events were included to assess abrupt social network changes. Mixed effects logistic regression was employed to analyze the relationship between isolation and loneliness. RESULTS: Higher levels of social isolation were associated with higher odds of loneliness, as was an increase (from median) in level of social isolation. Life events such as a friend dying were also associated with increased odds of loneliness. DISCUSSION: These results suggest that average level of isolation and increases in the level of isolation are closely tied to loneliness, which has implications for future assessment or monitoring of loneliness in older adult populations. PMID- 26491044 TI - Health Expectancies in Adults Aged 50 Years or Older in China. AB - OBJECTIVE: The purpose of this study is to understand the functional health of older adults in China and to assess the potential for advancing healthy and active aging. METHOD: Data of 13,739 older adults aged 50 years and older from the China Health and Retirement Longitudinal Study in 2011 were analyzed. Life expectancy in good perceived health, chronic-disease-free life expectancy, active life expectancy, and severe impairment-free life expectancy were calculated using Sullivan's method. RESULTS: At age 50 years, older adults had a life expectancy in good perceived health of 7.0 and 6.7 years in men and women, respectively. They would remain chronic-disease-free for 8.4 and 8.6 years, without activity limitation for 23.6 and 26.0 years, and severe impairment-free for 21.4 and 24.2 years. DISCUSSION: The world's largest aging population was spending a substantial proportion of remaining life years in suboptimal health and well being, while remaining largely independent in basic self-care without severe impairments. PMID- 26491045 TI - Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes. AB - Mechanical stretch can activate muscle and myotube protein synthesis through mammalian target of rapamycin complex 1 (mTORC1) signaling. While it has been established that tumor-derived cachectic factors can induce myotube wasting, the effect of this catabolic environment on myotube mechanical signaling has not been determined. We investigated whether media containing cachectic factors derived from Lewis lung carcinoma (LLC) can regulate the stretch induction of myotube protein synthesis. C2C12 myotubes preincubated in control or LLC-derived media were chronically stretched. Protein synthesis regulation by anabolic and catabolic signaling was then examined. In the control condition, stretch increased mTORC1 activity and protein synthesis. The LLC treatment decreased basal mTORC1 activity and protein synthesis and attenuated the stretch induction of protein synthesis. LLC media increased STAT3 and AMP-activated protein kinase phosphorylation in myotubes, independent of stretch. Both stretch and LLC independently increased ERK1/2, p38, and NF-kappaB phosphorylation. In LLC treated myotubes, the inhibition of ERK1/2 and p38 rescued the stretch induction of protein synthesis. Interestingly, either leukemia inhibitory factor or glycoprotein 130 antibody administration caused further inhibition of mTORC1 signaling and protein synthesis in stretched myotubes. AMP-activated protein kinase inhibition increased basal mTORC1 signaling activity and protein synthesis in LLC-treated myotubes, but did not restore the stretch induction of protein synthesis. These results demonstrate that LLC-derived cachectic factors can dissociate stretch-induced signaling from protein synthesis through ERK1/2 and p38 signaling, and that glycoprotein 130 signaling is associated with the basal stretch response in myotubes. PMID- 26491046 TI - Nitrotyrosine impairs mitochondrial function in fetal lamb pulmonary artery endothelial cells. AB - Nitration of both protein-bound and free tyrosine by reactive nitrogen species results in the formation of nitrotyrosine (NT). We previously reported that free NT impairs microtubule polymerization and uncouples endothelial nitric oxide synthase (eNOS) function in pulmonary artery endothelial cells (PAEC). Because microtubules modulate mitochondrial function, we hypothesized that increased NT levels during inflammation and oxidative stress will lead to mitochondrial dysfunction in PAEC. PAEC isolated from fetal lambs were exposed to varying concentrations of free NT. At low concentrations (1-10 MUM), NT increased nitration of mitochondrial electron transport chain (ETC) protein subunit complexes I-V and state III oxygen consumption. Higher concentrations of NT (50 MUM) caused decreased microtubule acetylation, impaired eNOS interactions with mitochondria, and decreased ETC protein levels. We also observed increases in heat shock protein-90 nitration, mitochondrial superoxide formation, and fragmentation of mitochondria in PAEC. Our data suggest that free NT accumulation may impair microtubule polymerization and exacerbate reactive oxygen species induced cell damage by causing mitochondrial dysfunction. PMID- 26491047 TI - ATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells. AB - Adenosine triphosphate (ATP) is a ubiquitous extracellular messenger elevated in the tumor microenvironment. ATP regulates cell functions by acting on purinergic receptors (P2X and P2Y) and activating a series of intracellular signaling pathways. We examined ATP-induced Ca(2+) signaling and its effects on antiapoptotic (Bcl-2) and proapoptotic (Bax) proteins in normal human airway epithelial cells and lung cancer cells. Lung cancer cells exhibited two phases (transient and plateau phases) of increase in cytosolic [Ca(2+)] ([Ca(2+)]cyt) caused by ATP, while only the transient phase was observed in normal cells. Removal of extracellular Ca(2+) eliminated the plateau phase increase of [Ca(2+)]cyt in lung cancer cells, indicating that the plateau phase of [Ca(2+)]cyt increase is due to Ca(2+) influx. The distribution of P2X (P2X1-7) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11) receptors was different between lung cancer cells and normal cells. Proapoptotic P2X7 was nearly undetectable in lung cancer cells, which may explain why lung cancer cells showed decreased cytotoxicity when treated with high concentration of ATP. The Bcl-2/Bax ratio was increased in lung cancer cells following treatment with ATP; however, the antiapoptotic protein Bcl-2 demonstrated more sensitivity to ATP than proapoptotic protein Bax. Decreasing extracellular Ca(2+) or chelating intracellular Ca(2+) with BAPTA-AM significantly inhibited ATP-induced increase in Bcl-2/Bax ratio, indicating that a rise in [Ca(2+)]cyt through Ca(2+) influx is the critical mediator for ATP-mediated increase in Bcl-2/Bax ratio. Therefore, despite high ATP levels in the tumor microenvironment, which would induce cell apoptosis in normal cells, the decreased P2X7 and elevated Bcl-2/Bax ratio in lung cancer cells may enable tumor cells to survive. Increasing the Bcl-2/Bax ratio by exposure to high extracellular ATP may, therefore, be an important selective pressure promoting transformation and cancer progression. PMID- 26491048 TI - CUGBP1 and HuR regulate E-cadherin translation by altering recruitment of E cadherin mRNA to processing bodies and modulate epithelial barrier function. AB - The effectiveness and stability of epithelial barrier depend on apical junctional complexes, which consist of tight junctions (TJs) and adherens junctions (AJs). E cadherin is the primary component of AJs, and it is essential for maintenance of cell-to-cell interactions and regulates the epithelial barrier. However, the exact mechanism underlying E-cadherin expression, particularly at the posttranscriptional level, remains largely unknown. RNA-binding proteins CUG binding protein 1 (CUGBP1) and HU antigen R (HuR) are highly expressed in the intestinal epithelial tissues and modulate the stability and translation of target mRNAs. Here, we present evidence that CUGBP1 and HuR interact directly with the 3'-untranslated region of E-cadherin mRNA and regulate E-cadherin translation. CUGBP1 overexpression in Caco-2 cells inhibited E-cadherin translation by increasing the recruitment of E-cadherin mRNA to processing bodies (PBs), thus resulting in an increase in paracellular permeability. Overexpression of HuR exhibited an opposite effect on E-cadherin expression by preventing the translocation of E-cadherin mRNA to PBs and therefore prevented CUGBP1-induced repression of E-cadherin expression. Elevation of HuR also abolished the CUGBP1 induced epithelial barrier dysfunction. These findings indicate that CUGBP1 and HuR negate each other's effects in regulating E-cadherin translation by altering the recruitment of E-cadherin mRNA to PBs and play an important role in the regulation of intestinal barrier integrity under various pathophysiological conditions. PMID- 26491049 TI - Agonist binding to beta-adrenergic receptors on human airway epithelial cells inhibits migration and wound repair. AB - Human airway epithelial cells express beta-adrenergic receptors (beta-ARs), which regulate mucociliary clearance by stimulating transepithelial anion transport and ciliary beat frequency. Previous studies using airway epithelial cells showed that stimulation with isoproterenol increased cell migration and wound repair by a cAMP-dependent mechanism. In the present study, impedance-sensing arrays were used to measure cell migration and epithelial restitution following wounding of confluent normal human bronchial epithelial (NHBE) and Calu-3 cells by electroporation. Stimulation with epinephrine or the beta2-AR-selective agonist salbutamol significantly delayed wound closure and reduced the mean surface area of lamellipodia protruding into the wound. Treatment with the beta-AR bias agonist carvedilol or isoetharine also produced a delay in epithelial restitution similar in magnitude to epinephrine and salbutamol. Measurements of extracellular signal-regulated kinase phosphorylation following salbutamol or carvedilol stimulation showed no significant change in the level of phosphorylation compared with untreated control cells. However, inhibition of protein phosphatase 2A activity completely blocked the delay in wound closure produced by beta-AR agonists. In Calu-3 cells, where CFTR expression was inhibited by RNAi, salbutamol did not inhibit wound repair, suggesting that beta-AR agonist stimulation and loss of CFTR function share a common pathway leading to inhibition of epithelial repair. Confocal images of the basal membrane of Calu-3 cells labeled with anti-beta1-integrin (clone HUTS-4) antibody showed that treatment with epinephrine or carvedilol reduced the level of activated integrin in the membrane. These findings suggest that treatment with beta-AR agonists delays airway epithelial repair by a G protein- and cAMP-independent mechanism involving protein phosphatase 2A and a reduction in beta1-integrin activation in the basal membrane. PMID- 26491050 TI - Inhibition of Notch signaling pathway attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats post-myocardial infarction. AB - Inflammation-dominated sympathetic sprouting adjacent to the necrotic region following myocardial infarction (MI) has been implicated in the etiology of arrhythmias resulting in sudden cardiac death; however, the mechanisms responsible remain to be elucidated. Although being a key immune mediator, the role of Notch has yet to be explored. We investigated whether Notch regulates macrophage responses to inflammation and affects cardiac sympathetic reinnervation in rats undergoing MI. MI was induced by coronary artery ligation. A high level of Notch intracellular domain was observed in the macrophages that infiltrated the infarct area at 3 days post-MI. The administration of the Notch inhibitor N-N-(3,5-difluorophenacetyl-L-alanyl)-S-phenylglycine-t-butyl ester (DAPT) (intravenously 30 min before MI and then daily until death) decreased the number of macrophages and significantly increased the M2 macrophage activation profile in the early stages and attenuated the expression of nerve growth factor (NGF). Eventually, NGF-induced sympathetic hyperinnervation was blunted, as assessed by the immunofluorescence of tyrosine hydroxylase. At 7 days post-MI, the arrhythmia score of programmed electric stimulation in the vehicle-treated infarcted rats was higher than that in rats treated with DAPT. Further deterioration in cardiac function and decreases in the plasma levels of TNF-alpha and IL-1beta were also detected. In vitro studies revealed that LPS/IFN-gamma upregulated the surface expression of NGF in M1 macrophages in a Notch-dependent manner. We concluded that Notch inhibition during the acute inflammatory response phase is associated with the downregulation of NGF, probably through a macrophage dependent pathway, thus preventing the process of sympathetic hyperinnervation. PMID- 26491051 TI - F-actin clustering and cell dysmotility induced by the pathological W148R missense mutation of filamin B at the actin-binding domain. AB - Filamin B (FLNB) is a dimeric actin-binding protein that orchestrates the reorganization of the actin cytoskeleton. Congenital mutations of FLNB at the actin-binding domain (ABD) are known to cause abnormalities of skeletal development, such as atelosteogenesis types I and III and Larsen's syndrome, although the underlying mechanisms are poorly understood. Here, using fluorescence microscopy, we characterized the reorganization of the actin cytoskeleton in cells expressing each of six pathological FLNB mutants that have been linked to skeletal abnormalities. The subfractionation assay showed a greater accumulation of the FLNB ABD mutants W148R and E227K than the wild-type protein to the cytoskeleton. Ectopic expression of FLNB-W148R and, to a lesser extent, FLNB-E227K induced prominent F-actin accumulations and the consequent rearrangement of focal adhesions, myosin II, and septin filaments and results in a delayed directional migration of the cells. The W148R protein-induced cytoskeletal rearrangement was partially attenuated by the inhibition of myosin II, p21-activated protein kinase, or Rho-associated protein kinase. The expression of a single-head ABD fragment with the mutations partially mimicked the rearrangement induced by the dimer. The F-actin clustering through the interaction with the mutant FLNB ABD may limit the cytoskeletal reorganization, preventing normal skeletal development. PMID- 26491053 TI - A coastal and an interior Douglas fir provenance exhibit different metabolic strategies to deal with drought stress. AB - Drought is a major environmental stress affecting growth and vitality of forest ecosystems. In the present study, foliar nitrogen (N) and carbon (C) metabolism of two Douglas fir (Pseudotsuga menziesii) provenances with assumed different drought tolerance were investigated. We worked with 1-year-old seedlings of the interior provenance Fehr Lake (FEHR) originating from a dry environment and the coastal provenance Snoqualmie (SNO) from a more humid origin. Total C and N, structural N and the concentrations of soluble protein, total amino acids (TAAs) and individual amino acids as well as the relative abundance of polar, low molecular-weight metabolites including antioxidants were determined in current year needles exposed either to 42 days of drought or to 42 days drought plus 14 days of rewatering. The seedlings reacted in a provenance-specific manner to drought stress. Coastal provenance SNO showed considerably increased contents of TAAs, which were caused by increased abundance of the quantitatively most important amino acids arginine, ornithine and lysine. Additionally, the polyamine putrescine accumulated exclusively in drought-stressed trees of this provenance. In contrast, the interior provenance FEHR showed the opposite response, i.e., drastically reduced concentrations of these amino acids. However, FEHR showed considerably increased contents of pyruvate-derived and aromatic amino acids, and also higher drought-induced levels of the antioxidants ascorbate and alpha tocopherol. In response to drought, both provenances produced large amounts of carbohydrates, such as glucose and fructose, most likely as osmolytes that can readily be metabolized for protection against osmotic stress. We conclude that FEHR and SNO cope with drought stress in a provenance-specific manner: the coastal provenance SNO was mainly synthesizing N-based osmolytes, a reaction not observed in the interior provenance FEHR; instead, the latter increased the levels of scavengers of reactive oxygen species. Our results underline the importance of provenance-specific reactions to abiotic stress. PMID- 26491052 TI - Regulation of cell proliferation by hypoxia-inducible factors. AB - Hypoxia is a physiological cue that impacts diverse physiological processes, including energy metabolism, autophagy, cell motility, angiogenesis, and erythropoiesis. One of the key cell-autonomous effects of hypoxia is as a modulator of cell proliferation. For most cell types, hypoxia induces decreased cell proliferation, since an increased number of cells, with a consequent increase in O2 demand, would only exacerbate hypoxic stress. However, certain cell populations maintain cell proliferation in the face of hypoxia. This is a common pathological hallmark of cancers, but can also serve a physiological function, as in the maintenance of stem cell populations that reside in a hypoxic niche. This review will discuss major molecular mechanisms by which hypoxia regulates cell proliferation in different cell populations, with a particular focus on the role of hypoxia-inducible factors. PMID- 26491054 TI - Transcriptomic regulatory network underlying morphological and physiological acclimation to nitrogen starvation and excess in poplar roots and leaves. PMID- 26491055 TI - Water availability as dominant control of heat stress responses in two contrasting tree species. AB - Heat waves that trigger severe droughts are predicted to increase globally; however, we lack an understanding of how trees respond to the combined change of extreme temperatures and water availability. Here, we studied the impacts of two consecutive heat waves as well as post-stress recovery in young Pseudotsuga menziesii (Mirb.) Franco (Douglas-fir) and Robinia pseudoacacia L. (black locust) growing under controlled conditions. Responses were compared under water supply close to the long-term average and under reduced irrigation to represent drought. Exposure to high temperatures (+10 degrees C above ambient) and vapour pressure deficit strongly affected the trees in terms of water relations, photosynthesis and growth. Douglas-fir used water resources conservatively, and transpiration decreased in response to mild soil water limitation. In black locust, heat stress led to pronounced tree water deficits (stem diameter shrinkage), accompanied by leaf shedding to alleviate stress on the hydraulic system. The importance of water availability during the heat waves became further apparent by a concurrent decline in photosynthesis and stomatal conductance with increasing leaf temperatures in both species, reaching the lowest rates in the heat-drought treatments. Stress severity determined both the speed and the amount of recovery. Upon release of stress, photosynthesis recovered rapidly in drought-treated black locust, while it remained below control rates in heat (t = -2.4, P < 0.05) and heat-drought stressed trees (t = 2.96, P < 0.05). In Douglas-fir, photosynthesis recovered quickly, while water-use efficiency increased in heat-drought trees because stomatal conductance remained reduced (t = -2.92, P < 0.05). Moreover, Douglas-fir was able to compensate for stem-growth reductions following heat ( 40%) and heat-drought stress (-68%), but most likely at the expense of storage and other growth processes. Our results highlight the importance of studying heat waves alongside changes in water availability. They further suggest that we should look beyond the actual stress event to identify lagged effects and acclimation processes that may determine tree resilience in the long term. PMID- 26491056 TI - Potential Biases Introduced by Conflating Screening and Diagnostic Testing in Colorectal Cancer Screening Surveillance. AB - BACKGROUND: Screening and postsymptomatic diagnostic testing are often conflated in cancer screening surveillance research. We examined the error in estimated colorectal cancer screening prevalence due to the conflation of screening and diagnostic testing. METHODS: Using data from the 2008 National Health Interview Survey, we compared weighted prevalence estimates of the use of all testing (screening and diagnostic) and screening in at-risk adults and calculated the overestimation of screening prevalence across sociodemographic groups. RESULTS: The population screening prevalence was overestimated by 23.3%, and the level of overestimation varied widely across sociodemographic groups (median, 22.6%; mean, 24.8%). The highest levels of overestimation were in non-Hispanic white females (27.4%), adults ages 50-54 years (32.0%), and those with the highest socioeconomic vulnerability [low educational attainment (31.3%), low poverty ratio (32.5%), no usual source of health care (54.4%), and not insured (51.6%); all P < 0.001]. CONCLUSIONS: When the impetus for testing was not included, colorectal cancer screening prevalence was overestimated, and patterns of overestimation often aligned with social and economic vulnerability. These results are of concern to researchers who use survey data from the Behavioral Risk Factor Surveillance System (BRFSS) to assess cancer screening behaviors, as it is currently not designed to distinguish diagnostic testing from screening. IMPACT: Surveillance research in cancer screening that does not consider the impetus for testing risks measurement error of screening prevalence, impeding progress toward improving population health. Ultimately, to craft relevant screening benchmarks and interventions, we must look beyond "what" and "when" and include "why." PMID- 26491057 TI - Development of an implantable synthetic membrane for the treatment of preterm premature rupture of fetal membranes. AB - Preterm premature rupture of fetal membranes is a very common condition leading to premature labour of a non viable fetus. Significant morbidities may occur when preterm premature rupture of fetal membranes management is attempted to prolong the pregnancy for fetal maturation. Reducing the rate of loss of amniotic fluid and providing a barrier to bacterial entry may allow the pregnancy to continue to term, avoiding complications. Our aim is to develop a synthetic biocompatible membrane to form a distensible barrier for cervical closure which acts to reduce fluid loss and provide a surface for epithelial ingrowth to help repair the damaged membranes. Therefore, a bilayer membrane was developed using an electrospinning technique of combining two FDA-approved polymers, poly-L-lactic acid (PLA) and polyurethane (Z3) polymer. This was compared to a plain electrospun Z3 membrane. The physical and mechanical properties were assessed using scanning electron microscope images and a BOSE tensiometer, respectively, and compared to native fetal membranes. The performance of the membranes in preventing fluid loss was assessed by measuring their ability to support a column of water. Finally the ability of the membranes to support cell ingrowth was assessed by culturing adipose-derived stem cells on the membranes for two weeks and assessing metabolic activity after 7 and 14 days. The physical properties of the bilayer were similar to that of the native fetal membranes and it was resistant to fluid penetration. This bilayer membrane presented mechanical properties close to those for fetal membranes and showed elastic distention, which may be crucial for progress of the pregnancy. The membrane was also able to retain surgical sutures. In addition, it also supported the attachment and growth of adipose-derived stem cells for two weeks. In conclusion, this membrane may prove a useful approach in the treatment of preterm premature rupture of fetal membranes and now merits further investigation. PMID- 26491058 TI - An Evaluation of Alternative Markers to Guide Initiation of Anti-retroviral Therapy in HIV-Infected Children in Settings where CD4 Assays are not Available. AB - OBJECTIVES: In settings where CD4 testing is not available, alternative markers to start paediatric anti-retroviral therapy (ART) could be used. A comprehensive evaluation of these markers has not been performed. METHODS: Prospective cross sectional study of HIV-infected Malawian children not eligible for ART based on clinical criteria. Associations between CD4 and alternative markers [haemoglobin, total lymphocyte count (TLC), serum albumin, thrombocytes and growth parameters] were analysed, and accuracy of existing and new cut-offs were evaluated. RESULTS: In all, 417 children were enrolled. Of 261 children aged >=5 years, 155 (59%) qualified to start ART using CD4. In this group, only TLC was associated with CD4 (p < 0.001). Sensitivity for TLC was 21% (95% CI: 15-29%), using World Health Organization cut-offs. Improved cut-offs increased sensitivity to 73% (95% CI: 65 80%), specificity 62% (95% CI: 52-72%). CONCLUSION: Clinical staging alone is an unreliable strategy to start ART in children. TLC is the only alternative marker for CD4, cut-offs need to be revised though. PMID- 26491059 TI - Donning the mask: effects of emotional labour strategies on burnout and job satisfaction in community healthcare. AB - Emotional labour involves management of one's emotions to match the demands of their roles. This emotion display involves just expression (surface-level emotional labour) or experience in addition to expression (deep-level emotional labour) of the desired emotions. Emotional labour is required in the effective, efficient and successful healthcare service delivery. Burnout associated with emotional labour is an important factor that decides how satisfied frontline service providers with their job are. This empirical study investigates the link between surface and deep-level emotional labour, burnout and job satisfaction in women community health workers from India. Our results from the structural equation modelling of 177 accredited social health activists (ASHAs) indicate a negative relation between surface and deep-level emotional labour, clearly demarcating them as two different strategies for performance of emotional labour in community health care setting. Surface-level emotional labour is associated with higher job satisfaction, and burnout partially mediates this relation. Deep level emotional labour is associated with lower job satisfaction; burnout fully mediates this relation. Qualitative post hoc analysis based on interviews of 10 ASHAs was done to understand the findings of the quantitative study. Surface level emotional labour was found to be a more desirable strategy for community health care workers for the effective and efficient performance of their work roles. Our results have a significant contribution to design, redesign, and improvement of employment practices in community healthcare. This study brings forth the neglected issues of emotions and their implications for these healthcare workers in low and middle-income countries who are a vital link that delivers healthcare to weaker section of the society. The findings have relevance not merely for the individual providing this service but the beneficiary and the organization that facilitates this delivery. Interventions based on demographic, community, national and occupational factors have also been presented. PMID- 26491060 TI - Scaling-up essential neuropsychiatric services in Ethiopia: a cost-effectiveness analysis. AB - INTRODUCTION: There is an immense need for scaling-up neuropsychiatric care in low-income countries. Contextualized cost-effectiveness analyses (CEAs) provide relevant information for local policies. The aim of this study is to perform a contextualized CEA of neuropsychiatric interventions in Ethiopia and to illustrate expected population health and budget impacts across neuropsychiatric disorders. METHODS: A mathematical population model (PopMod) was used to estimate intervention costs and effectiveness. Existing variables from a previous WHO CHOICE regional CEA model were substantially revised. Treatments for depression, schizophrenia, bipolar disorder and epilepsy were analysed. The best available local data on epidemiology, intervention efficacy, current and target coverage, resource prices and salaries were used. Data were obtained from expert opinion, local hospital information systems, the Ministry of Health and literature reviews. RESULTS: Treatment of epilepsy with a first generation antiepileptic drug is the most cost-effective treatment (US$ 321 per DALY adverted). Treatments for depression have mid-range values compared with other interventions (US$ 457 1026 per DALY adverted). Treatments for schizophrenia and bipolar disorders are least cost-effective (US$ 1168-3739 per DALY adverted). CONCLUSION: This analysis gives the Ethiopian government a comprehensive overview of the expected costs, effectiveness and cost-effectiveness of introducing basic neuropsychiatric interventions. PMID- 26491061 TI - Paeoniflorin Promotes Non-rapid Eye Movement Sleep via Adenosine A1 Receptors. AB - Paeoniflorin (PF, C23H28O11), one of the principal active ingredients of Paeonia Radix, exerts depressant effects on the central nervous system. We determined whether PF could modulate sleep behaviors and the mechanisms involved. Electroencephalogram and electromyogram recordings in mice showed that intraperitoneal PF administered at a dose of 25 or 50 mg/kg significantly shortened the sleep latency and increased the amount of non-rapid eye movement (NREM). Immunohistochemical study revealed that PF decreased c-fos expression in the histaminergic tuberomammillary nucleus (TMN). The sleep-promoting effects and changes in c-fos induced by PF were reversed by 8-cyclopentyl-1,3 dimethylxanthine (CPT), an adenosine A1 receptor antagonist, and PF-induced sleep was not observed in adenosine A1 receptor knockout mice. Whole-cell patch clamping in mouse brain slices showed that PF significantly decreased the firing frequency of histaminergic neurons in TMN, which could be completely blocked by CPT. These results indicate that PF increased NREM sleep by inhibiting the histaminergic system via A1 receptors. PMID- 26491062 TI - Effects of Acute and Repeated Administration of Oxycodone and Naloxone Precipitated Withdrawal on Intracranial Self-Stimulation in Rats. AB - Incidence of prescription opioid abuse and overdose, often led by oxycodone, continues to increase, producing twice as many overdose deaths as heroin. Surprisingly, preclinical reports relevant to oxycodone's abuse-related effects are relatively sparse considering its history and patient usage. The goal of this study was to characterize dose- and time-dependent effects of acute and repeated oxycodone administration in a frequency-rate intracranial self-stimulation (ICSS) procedure, an assay often predictive of drug-related reinforcing effects, in male Sprague-Dawley rats. We hypothesized that oxycodone would produce a biphasic profile of rate-increasing and rate-decreasing effects maintained by ICSS similar to MU-opioid receptor agonists. Oxycodone (0.03, 0.3, 1, and 3 mg/kg, s.c.) produced dose- and time-dependent alterations on ICSS, with the predicted biphasic profile of rate-increasing effects at lower stimulation frequencies followed by rate-decreasing effects at higher frequencies. Peak effects were observed between 30 and 60 minutes, which were reversed by naloxone pretreatment (30 minutes). Tolerance to rate-decreasing effects was observed over a 5-day period when rats were treated with 1 mg/kg oxycodone twice a day. Subsequently, the dosing regimen was increased to 3 mg/kg twice a day over 10 days, although further marked tolerance did not develop. When then challenged with 10 mg/kg naloxone, a significant suppression below baseline levels of ICSS-maintained responding occurred indicative of dependence that recovered to baseline within 5 hours. The results of this study provide the first report of acute and chronic effects of oxycodone on responding maintained by ICSS presentation and the use of ICSS-maintained responding to characterize its tolerance and dependence effects. PMID- 26491063 TI - Determination of cleavage site of Reelin between its sixth and seventh repeat and contribution of meprin metalloproteases to the cleavage. AB - Reelin is a secreted glycoprotein whose function is regulated by proteolysis. One of the specific cleavage sites of Reelin, called C-t, is located approximately between the sixth and seventh Reelin repeat but its exact site was unknown. We here show that a metalloprotease present in the culture supernatant of cerebellar granular neurons (CGN) cleaves Reelin between Ala2688 and Asp2689. A Reelin mutant in which Asp2689 is replaced by Lys (Reelin-DK) is resistant to C-t cleavage by culture supernatant of CGN. From biochemical characteristics and the cleavage site preference, meprin alpha and meprin beta were suggested candidate proteases and both were confirmed to cleave Reelin at the C-t site. Meprin alpha cleaved Reelin-DK but meprin beta did not. Actinonin, a meprin alpha and meprin beta inhibitor, did not inhibit the Reelin-cleaving activity of CGN and the amount of Reelin fragments in brains of meprin beta knock-out mice was not significantly different from that of the wild-type, indicating that meprin beta does not play a major role in Reelin cleavage under basal conditions. We propose that meprin alpha and meprin beta join the modulators of Reelin signalling as they cleave Reelin at a specific site and are upregulated under specific pathological conditions. PMID- 26491064 TI - Contiguous 2,2,4-triamino-5(2H)-oxazolone obstructs DNA synthesis by DNA polymerases alpha, beta, eta, iota, kappa, REV1 and Klenow Fragment exo-, but not by DNA polymerase zeta. AB - Guanine is the most easily oxidized of the four DNA bases, and contiguous guanines (GG) in a sequence are more readily oxidized than a single guanine in a sequence. Continued oxidation of GGs results in a contiguous oxidized guanine lesion. Two contiguous 2,5-diamino-4H-imidazol-4-ones, an oxidized form of guanine that hydrolyses to 2,2,4-triamino-5(2H)-oxazolone (Oz), are detected following the oxidation of GG. In this study, we analysed translesion synthesis (TLS) across two contiguous Oz molecules (OzOz) using Klenow Fragment exo(-) (KF exo(-)) and DNA polymerases (Pols) alpha, beta, zeta, eta, iota, kappa and REV1. We found that KF exo(-) and Pols alpha, beta, iota and REV1 inserted one nucleotide opposite the 3' Oz of OzOz and stalled at the subsequent extension, and that Pol kappa incorporated no nucleotide. Pol eta only inefficiently elongated the primer up to full-length across OzOz; the synthesis of most DNA strands stalled at the 3' or 5' Oz of OzOz. Surprisingly, however, Pol zeta efficiently extended the primer up to full-length across OzOz, unlike the other DNA polymerases, but catalysed error-prone nucleotide incorporation. We therefore believe that Pol zeta is required for efficient TLS of OzOz. These results show that OzOz obstructs DNA synthesis by DNA polymerases except Pol zeta. PMID- 26491065 TI - Reward Size Informs Repeat-Switch Decisions and Strongly Modulates the Activity of Neurons in Parietal Cortex. AB - Behavior is guided by previous experience. Good, positive outcomes drive a repetition of a previous behavior or choice, whereas poor or bad outcomes lead to an avoidance. How these basic drives are implemented by the brain has been of primary interest to psychology and neuroscience. We engaged animals in a choice task in which the size of a reward outcome strongly governed the animals' subsequent decision whether to repeat or switch the previous choice. We recorded the discharge activity of neurons implicated in reward-based choice in 2 regions of parietal cortex. We found that the tendency to retain previous choice following a large (small) reward was paralleled by a marked decrease (increase) in the activity of parietal neurons. This neural effect is independent of, and of sign opposite to, value-based modulations reported in parietal cortex previously. This effect shares the same basic properties with signals previously reported in the limbic system that detect the size of the recently obtained reward to mediate proper repeat-switch decisions. We conclude that the size of the obtained reward is a decision variable that guides the decision between retaining a choice or switching, and neurons in parietal cortex strongly respond to this novel decision variable. PMID- 26491066 TI - Maturation of Sensori-Motor Functional Responses in the Preterm Brain. AB - Preterm birth engenders an increased risk of conditions like cerebral palsy and therefore this time may be crucial for the brain's developing sensori-motor system. However, little is known about how cortical sensori-motor function matures at this time, whether development is influenced by experience, and about its role in spontaneous motor behavior. We aimed to systematically characterize spatial and temporal maturation of sensori-motor functional brain activity across this period using functional MRI and a custom-made robotic stimulation device. We studied 57 infants aged from 30 + 2 to 43 + 2 weeks postmenstrual age. Following both induced and spontaneous right wrist movements, we saw consistent positive blood oxygen level-dependent functional responses in the contralateral (left) primary somatosensory and motor cortices. In addition, we saw a maturational trend toward faster, higher amplitude, and more spatially dispersed functional responses; and increasing integration of the ipsilateral hemisphere and sensori motor associative areas. We also found that interhemispheric functional connectivity was significantly related to ex-utero exposure, suggesting the influence of experience-dependent mechanisms. At term equivalent age, we saw a decrease in both response amplitude and interhemispheric functional connectivity, and an increase in spatial specificity, culminating in the establishment of a sensori-motor functional response similar to that seen in adults. PMID- 26491067 TI - Healthcare avoidance by people who inject drugs in Bangkok, Thailand. AB - BACKGROUND: Although people who inject drugs (IDU) often contend with various health-related harms, timely access to health care among this population remains low. We sought to identify specific individual, social and structural factors constraining healthcare access among IDU in Bangkok, Thailand. METHODS: Data were derived from a community-recruited sample of IDU participating in the Mitsampan Community Research Project between July and October 2011. We assessed the prevalence and correlates of healthcare avoidance due to one's drug use using multivariate logistic regression. RESULTS: Among 437 participants, 112 (25.6%) reported avoiding health care because they were IDU. In multivariate analyses, factors independently associated with avoiding health care included having ever been drug tested by police [adjusted odds ratio (AOR) = 1.80], experienced verbal abuse (AOR = 3.15), been discouraged from engaging in usual family activities (AOR = 3.27), been refused medical care (AOR = 10.90), experienced any barriers to health care (AOR = 4.87) and received healthcare information and support at a drop-in centre (AOR = 1.92) (all P < 0.05). CONCLUSIONS: These findings highlight the need to address the broader policy environment, which perpetuates the criminalization and stigmatization of IDU, and to expand peer-based interventions to facilitate access to health care for IDU in this setting. PMID- 26491068 TI - IFN-gamma-mediated hematopoietic cell destruction in murine models of immune mediated bone marrow failure. AB - Interferon gamma (IFN-gamma) has been reported to have both negative and positive activity on hematopoietic cells, adding complexity to the interpretation of its pleiotropic functions. We examined the effects of IFN-gamma on murine hematopoietic stem cells (HSCs) and progenitors in vitro and in vivo by using mouse models. IFN-gamma treatment expanded bone marrow (BM) c-Kit(+)Sca1(+)Lin(-) (KSL) cell number but reduced BM KLCD150(+) and KLCD150(+)CD48(-) cells. IFN gamma-expanded KSL cells engrafted poorly when tested by competitive repopulation in vivo. KSL, KLCD150(+), and KLCD150(+)CD48(-) cells from IFN-gamma-treated animals all showed significant upregulation in Fas expression. When cocultured with activated T cells in vitro, KSL and KLCD150(+) cells from IFN-gamma-treated donors showed increased apoptosis relative to those from untreated animals, and infusion of activated CD8 T cells into IFN-gamma-injected animals in vivo led to partial elimination of KSL cells. Exposure of BM cells or KSL cells to IFN-gamma increased expression of Fas, caspases, and related proapoptotic genes and decreased expression of Ets-1 and other hematopoietic genes. In mouse models of BM failure, mice genetically deficient in IFN-gamma receptor expression showed attenuation of immune-mediated marrow destruction, whereas effector lymphocytes from IFN-gamma-deficient donors were much less potent in initiating BM damage. We conclude that the activity of IFN-gamma on murine hematopoiesis is context dependent. IFN-gamma-augmented apoptotic gene expression facilitates destruction of HSCs and progenitors in the presence of activated cytotoxic T cells, as occurs in human BM failure. PMID- 26491069 TI - Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis. AB - Neutrophils play an essential role in the initial stages of inflammation by balancing pro- and antiinflammatory signals. Among these signals are the production of proinflammatory cytokines and the timely initiation of antiinflammatory cell death via constitutive apoptosis. Here we identify ataxia telangiectasia mutated (ATM) kinase as a modulator of these neutrophil functions. Ataxia-telangiectasia (AT) is a pleiotropic multisystem disorder caused by mutations in the gene-encoding ATM, a master regulator of the DNA damage response. In addition to progressive neurodegeneration and high rates of cancer, AT patients have numerous symptoms that can be linked to chronic inflammation. We report that neutrophils isolated from patients with AT overproduce proinflammatory cytokines and have a prolonged lifespan compared with healthy controls. This effect is partly mediated by increases in activation of p38 MAP kinase. Furthermore, we show that the oxidative burst, catalyzed by nicotinamide adenine dinucleotide phosphate oxidase, can activate ATM in neutrophils. Finally, activation of ATM and DNA damage signaling suppress cytokine production and can abrogate the overproduction of IL-8 in ROS-deficient cells. This reveals a novel mechanism for the regulation of cytokine production and apoptosis, establishing DNA damage as a downstream mediator of immune regulation by reactive oxygen species. We propose that deficiencies in the DNA damage response, like deficiencies in the oxidative burst seen in chronic granulomatous disease, could lead to pathologic inflammation. PMID- 26491070 TI - Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9. AB - The congenital sideroblastic anemias (CSAs) are relatively uncommon diseases characterized by defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Here we demonstrate that mutations in HSPA9, a mitochondrial HSP70 homolog located in the chromosome 5q deletion syndrome 5q33 critical deletion interval and involved in mitochondrial Fe-S biogenesis, result in CSA inherited as an autosomal recessive trait. In a fraction of patients with just 1 severe loss-of-function allele, expression of the clinical phenotype is associated with a common coding single nucleotide polymorphism in trans that correlates with reduced messenger RNA expression and results in a pseudodominant pattern of inheritance. PMID- 26491071 TI - Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation. AB - Antigenic stimulation via the B-cell receptor (BCR) is a major driver of the proliferation and survival of chronic lymphocytic leukemia (CLL) cells. However, the precise mechanisms by which BCR stimulation leads to accumulation of malignant cells remain incompletely understood. Here, we investigated the ability of BCR stimulation to increase messenger RNA (mRNA) translation, which can promote carcinogenesis by effects on both global mRNA translation and upregulated expression of specific oncoproteins. Re-analysis of gene expression profiles revealed striking upregulation of pathways linked to mRNA translation both in CLL cells derived from lymph nodes, the major site of antigen stimulation in vivo, and after BCR stimulation in vitro. Anti-IgM significantly increased mRNA translation in primary CLL cells, measured using bulk metabolic labeling and a novel flow cytometry assay to quantify responses at a single-cell level. These translational responses were suppressed by inhibitors of BTK (ibrutinib) and SYK (tamatinib). Anti-IgM-induced mRNA translation was associated with increased expression of translation initiation factors eIF4A and eIF4GI, and reduced expression of the eIF4A inhibitor, PDCD4. Anti-IgM also increased mRNA translation in normal blood B cells, but without clear modulatory effects on these factors. In addition, anti-IgM increased translation of mRNA-encoding MYC, a major driver of disease progression. mRNA translation is likely to be an important mediator of the growth-promoting effects of antigen stimulation acting, at least in part, via translational induction of MYC. Differences in mechanisms of translational regulation in CLL and normal B cells may provide opportunities for selective therapeutic attack. PMID- 26491072 TI - Searching for rigour in the reporting of mixed methods population health research: a methodological review. AB - The environments in which population health interventions occur shape both their implementation and outcomes. Hence, when evaluating these interventions, we must explore both intervention content and context. Mixed methods (integrating quantitative and qualitative methods) provide this opportunity. However, although criteria exist for establishing rigour in quantitative and qualitative research, there is poor consensus regarding rigour in mixed methods. Using the empirical example of school-based obesity interventions, this methodological review examined how mixed methods have been used and reported, and how rigour has been addressed. Twenty-three peer-reviewed mixed methods studies were identified through a systematic search of five databases and appraised using the guidelines for Good Reporting of a Mixed Methods Study. In general, more detailed description of data collection and analysis, integration, inferences and justifying the use of mixed methods is needed. Additionally, improved reporting of methodological rigour is required. This review calls for increased discussion of practical techniques for establishing rigour in mixed methods research, beyond those for quantitative and qualitative criteria individually. A guide for reporting mixed methods research in population health should be developed to improve the reporting quality of mixed methods studies. Through improved reporting, mixed methods can provide strong evidence to inform policy and practice. PMID- 26491074 TI - Enucleation of liver tumors: you do not have to feel blue about it. AB - Enucleation of hepatic tumors is a low-morbidity technique with adequate oncological results that is useful in many clinical settings. Compared with anatomical liver resections, it offers the advantage of maximal hepatic parenchymal preservation. However, some technical adversities may occur during the enucleation of liver tumors, such as difficulty in finding the lesions by intraoperative ultrasonography after hepatic transection or further visually spotting the tumor within the parenchyma if a first specimen is retracted not containing the lesion. We describe an innovative technique that overcomes these possible adversities and makes the enucleation of liver tumors easier and more precise. PMID- 26491073 TI - Effectiveness of and factors related to possession of a mother and child health handbook: an analysis using propensity score matching. AB - BACKGROUND: Mother and Child Health handbooks (MCH handbooks) serve as useful health education tools for mothers and sources of information that allow health care professionals to understand patient status. Therefore, it is necessary to clarify the effectiveness of and identify the factors related to possession of an MCH handbook among parents in rural Western Kenya using propensity score matching (PSM). METHODS: A community-based cross-sectional survey using a structured questionnaire was conducted in rural western Kenya from August to September, 2011. We targeted 2560 mothers with children aged 12-24 months. Both PSM and multivariate logistic analyses were used in this study. RESULTS: Impacts of 5.9, 9.4, and 12.6 percentage points for higher health knowledge and for proper health seeking behavior for fever and diarrhea, respectively, were statistically significant. The significant factors affecting possession of the MCH Handbook were the child's sex, the caregiver's relationship to the child, maternal age, health knowledge, birth interval, household wealth index and CHW performance accordingly. CONCLUSIONS: An MCH handbook was an effective tool for improving both health knowledge and health-seeking behavior in Kenya. The further distribution and utilization of an MCH handbook is expected to be an effective way to improve both maternal and child health. PMID- 26491075 TI - B cells assume the command. AB - A proinflammatory B cell cytokine activates autoimmunity, and B cell depletion treats multiple sclerosis (Li et al., this issue). PMID- 26491076 TI - Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. AB - B cells are not limited to producing protective antibodies; they also perform additional functions relevant to both health and disease. However, the relative contribution of functionally distinct B cell subsets in human disease, the signals that regulate the balance between such subsets, and which of these subsets underlie the benefits of B cell depletion therapy (BCDT) are only partially elucidated. We describe a proinflammatory, granulocyte macrophage colony stimulating factor (GM-CSF)-expressing human memory B cell subset that is increased in frequency and more readily induced in multiple sclerosis (MS) patients compared to healthy controls. In vitro, GM-CSF-expressing B cells efficiently activated myeloid cells in a GM-CSF-dependent manner, and in vivo, BCDT resulted in a GM-CSF-dependent decrease in proinflammatory myeloid responses of MS patients. A signal transducer and activator of transcription 5 (STAT5)- and STAT6-dependent mechanism was required for B cell GM-CSF production and reciprocally regulated the generation of regulatory IL-10-expressing B cells. STAT5/6 signaling was enhanced in B cells of untreated MS patients compared with healthy controls, and B cells reemerging in patients after BCDT normalized their STAT5/6 signaling as well as their GM-CSF/IL-10 cytokine secretion ratios. The diminished proinflammatory myeloid cell responses observed after BCDT persisted even as new B cells reconstituted. These data implicate a proinflammatory B cell/myeloid cell axis in disease and underscore the rationale for selective targeting of distinct B cell populations in MS and other human autoimmune diseases. PMID- 26491077 TI - Identification of broadly conserved cross-species protective Leishmania antigen and its responding CD4+ T cells. AB - There is currently no clinically effective vaccine against leishmaniasis because of poor understanding of the antigens that elicit dominant T cell immunity. Using proteomics and cellular immunology, we identified a dominant naturally processed peptide (PEPCK335-351) derived from Leishmania glycosomal phosphoenolpyruvate carboxykinase (PEPCK). PEPCK was conserved in all pathogenic Leishmania, expressed in glycosomes of promastigotes and amastigotes, and elicited strong CD4(+) T cell responses in infected mice and humans. I-A(b)-PEPCK335-351 tetramer identified protective Leishmania-specific CD4(+) T cells at a clonal level, which comprised ~20% of all Leishmania-reactive CD4(+) T cells at the peak of infection. PEPCK335-351-specific CD4(+) T cells were oligoclonal in their T cell receptor usage, produced polyfunctional cytokines (interleukin-2, interferon gamma, and tumor necrosis factor), and underwent expansion, effector activities, contraction, and stable maintenance after lesion resolution. Vaccination with PEPCK peptide, DNA expressing full-length PEPCK, or rPEPCK induced strong durable cross-species protection in both resistant and susceptible mice. The effectiveness and durability of protection in vaccinated mice support the development of a broadly cross-species protective vaccine against different forms of leishmaniasis by targeting PEPCK. PMID- 26491078 TI - Ultrasound-mediated gastrointestinal drug delivery. AB - There is a significant clinical need for rapid and efficient delivery of drugs directly to the site of diseased tissues for the treatment of gastrointestinal (GI) pathologies, in particular, Crohn's and ulcerative colitis. However, complex therapeutic molecules cannot easily be delivered through the GI tract because of physiologic and structural barriers. We report the use of ultrasound as a modality for enhanced drug delivery to the GI tract, with an emphasis on rectal delivery. Ultrasound increased the absorption of model therapeutics inulin, hydrocortisone, and mesalamine two- to tenfold in ex vivo tissue, depending on location in the GI tract. In pigs, ultrasound induced transient cavitation with negligible heating, leading to an order of magnitude enhancement in the delivery of mesalamine, as well as successful systemic delivery of a macromolecule, insulin, with the expected hypoglycemic response. In a rodent model of chemically induced acute colitis, the addition of ultrasound to a daily mesalamine enema (compared to enema alone) resulted in superior clinical and histological scores of disease activity. In both animal models, ultrasound treatment was well tolerated and resulted in minimal tissue disruption, and in mice, there was no significant effect on histology, fecal score, or tissue inflammatory cytokine levels. The use of ultrasound to enhance GI drug delivery is safe in animals and could augment the efficacy of GI therapies and broaden the scope of agents that could be delivered locally and systemically through the GI tract for chronic conditions such as inflammatory bowel disease. PMID- 26491079 TI - PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2. AB - Cancer cells reprogram their metabolism to meet increased biosynthetic demands, commensurate with elevated rates of replication. Pyruvate kinase M2 (PKM2) catalyzes the final and rate-limiting step in tumor glycolysis, controlling the balance between energy production and the synthesis of metabolic precursors. We report here the synthesis and evaluation of a positron emission tomography (PET) radiotracer, [(11)C]DASA-23, that provides a direct noninvasive measure of PKM2 expression in preclinical models of glioblastoma multiforme (GBM). In vivo, orthotopic U87 and GBM39 patient-derived tumors were clearly delineated from the surrounding normal brain tissue by PET imaging, corresponding to exclusive tumor associated PKM2 expression. In addition, systemic treatment of mice with the PKM2 activator TEPP-46 resulted in complete abrogation of the PET signal in intracranial GBM39 tumors. Together, these data provide the basis for the clinical evaluation of imaging agents that target this important gatekeeper of tumor glycolysis. PMID- 26491080 TI - Impact of guidance documents on translational large animal studies of cartilage repair. AB - Promising therapies for cartilage repair are translated through large animal models toward human application. To guide this work, regulatory agencies publish recommendations ("guidance documents") to direct pivotal large animal studies. These are meant to aid in study design, outline metrics for judging efficacy, and facilitate comparisons between studies. To determine the penetrance of these documents in the field, we synthesized the recommendations of the American Society for Testing and Materials, U.S. Food and Drug Administration, and European Medicines Agency into a scoring system and performed a systematic review of the past 20 years of preclinical cartilage repair studies. Our hypothesis was that the guidance documents would have a significant impact on how large animal cartilage repair studies were performed. A total of 114 publications meeting our inclusion criteria were reviewed for adherence to 24 categories extracted from the guidance documents, including 11 related to study design and description and 13 related to study outcomes. Overall, a weak positive trend was observed over time (P = 0.004, R(2) = 0.07, slope = 0.63%/year), with overall adherence (the sum of study descriptors and outcomes) ranging from 32 +/- 16% to 58 +/- 14% in any individual year. There was no impact of the publication of the guidance documents on adherence (P = 0.264 to 0.50). Given that improved adherence would expedite translation, we discuss the reasons for poor adherence and outline approaches to increase and promote their more widespread adoption. PMID- 26491082 TI - Microfracture produces inferior outcomes to other cartilage repair techniques in chondral injuries in the paediatric knee. AB - INTRODUCTION: Chondral injuries are becoming increasingly common in the paediatric knee. First line surgical therapy is usually microfracture (MF), but the emergence of alternative techniques raises the question of what is the optimal treatment in paediatric patients. SOURCES OF DATA: A comprehensive search of PubMed, OVID, Web of Science, SportDiscus and Cochrane databases was performed using the key words 'autologous chondrocyte implantation, MF, mosaicplasty, juvenile, paediatric'. AREAS OF AGREEMENT: Each technique demonstrated a significant post-surgical improvement in clinical outcome scores. However, MF demonstrated poorer outcomes in larger lesions (>3 cm(2)) and shorter durability. AREA OF CONTROVERSY: The quality of the available literature is poor, and there is a lack of comparative trials. GROWING POINTS: The impact of defect characteristics, mechanism of injury and concomitant surgeries should be investigated. AREAS TIMELY FOR DEVELOPING RESEARCH: Appropriately powered randomized controlled trials with suitably long follow up and condition-specific outcome measures should compare different techniques against each other and placebo. PMID- 26491081 TI - Immune correlates of vaccine protection against HIV-1 acquisition. AB - The partial efficacy reported in the RV144 HIV vaccine trial in 2009 has driven the HIV vaccine field to define correlates of risk associated with HIV-1 acquisition and connect these functionally to preventing HIV infection. Immunological correlates, mainly including CD4(+) T cell responses to the HIV envelope and Fc-mediated antibody effector function, have been connected to reduced acquisition. These immunological correlates place immunological and genetic pressure on the virus. Indeed, antibodies directed at conserved regions of the V1V2 loop and antibodies that mediate antibody-dependent cellular cytotoxicity to HIV envelope in the absence of inhibiting serum immunoglobulin A antibodies correlated with decreased HIV risk. More recently, researchers have expanded their search with nonhuman primate studies using vaccine regimens that differ from that used in RV144; these studies indicate that non-neutralizing antibodies are associated with protection from experimental lentivirus challenge as well. These immunological correlates have provided the basis for the design of a next generation of vaccine regimens to improve upon the qualitative and quantitative degree of magnitude of these immune responses on HIV acquisition. PMID- 26491083 TI - Antibiotic resistance: what, why, where, when and how? AB - BACKGROUND: Antibiotic resistance is a threat to the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi. SOURCES OF DATA: Peer-reviewed journal articles, governmental and professional society publications. AREAS OF AGREEMENT AND CONTROVERSY: There is consensus about the development and spread of antibiotic resistance, the reasons for the development of antibiotic resistance and the clinical impact. There is more debate about the most appropriate way of tackling this increasing problem. GROWING POINTS: This review discusses a number of initiatives (local and global) that are being undertaken to protect the antibiotics we currently have available for use and to encourage the development of newer agents. PMID- 26491086 TI - Amplitudes of SSEP and outcome in cardiac arrest survivors: A prospective cohort study. AB - OBJECTIVE: To investigate the relationship between somatosensory evoked potential (SSEP) amplitudes and neurologic outcome after cardiac arrest. METHODS: We prospectively studied SSEPs, recorded 24 hours to 4 days after cardiac arrest, in patients with targeted temperature management. SSEP amplitude was defined pragmatically as the highest short-latency amplitude of 4 cortical recordings (2 per side, CP3/CP4 vs Fz) at least 4.5 ms after the spinal SSEP. Cerebral performance category (CPC) was determined upon intensive care unit discharge. CPC 1-3 was defined as good, CPC 4-5 as poor outcome. RESULTS: Of 318 patients, 25 had incomplete recordings, no reproducible spinal SSEP, or high noise level. Of the remaining 293 patients, 137 (47%) had poor and 156 (53%) good outcome. The lowest amplitude in a survivor with good outcome was 0.62 MUV. All 78 patients with lower amplitudes had poor outcome. None of 27 patients with CPC 4 (unresponsive wakefulness) had amplitudes above 2.5 MUV. In the majority of 24 patients who died despite amplitudes above 2.5 MUV, clinical course and other prognostic parameters argued against severe hypoxic encephalopathy. CONCLUSIONS: The prognostic value of SSEPs extends beyond an absent/present dichotomy. Absent and very low amplitude SSEPs appear to be highly predictive of poor outcome after cardiac arrest. Prospective external validation of the lower threshold found in our study is necessary. SSEP recordings should not be used for prognostication if noise could mask potentials with critically low amplitudes. High SSEP amplitudes argue against severe hypoxic encephalopathy. PMID- 26491085 TI - Mediterranean diet and brain structure in a multiethnic elderly cohort. AB - OBJECTIVE: To determine whether higher adherence to a Mediterranean-type diet (MeDi) is related with larger MRI-measured brain volume or cortical thickness. METHODS: In this cross-sectional study, high-resolution structural MRI was collected on 674 elderly (mean age 80.1 years) adults without dementia who participated in a community-based, multiethnic cohort. Dietary information was collected via a food frequency questionnaire. Total brain volume (TBV), total gray matter volume (TGMV), total white matter volume (TWMV), mean cortical thickness (mCT), and regional volume or CT were derived from MRI scans using FreeSurfer program. We examined the association of MeDi (scored as 0-9) and individual food groups with brain volume and thickness using regression models adjusted for age, sex, ethnicity, education, body mass index, diabetes, and cognition. RESULTS: Compared to lower MeDi adherence (0-4), higher adherence (5 9) was associated with 13.11 (p = 0.007), 5.00 (p = 0.05), and 6.41 (p = 0.05) milliliter larger TBV, TGMV, and TWMV, respectively. Higher fish (b = 7.06, p = 0.006) and lower meat (b = 8.42, p = 0.002) intakes were associated with larger TGMV. Lower meat intake was also associated with larger TBV (b = 12.20, p = 0.02). Higher fish intake was associated with 0.019 mm (p = 0.03) larger mCT. Volumes of cingulate cortex, parietal lobe, temporal lobe, and hippocampus and CT of the superior-frontal region were associated with the dietary factors. CONCLUSIONS: Among older adults, MeDi adherence was associated with less brain atrophy, with an effect similar to 5 years of aging. Higher fish and lower meat intake might be the 2 key food elements that contribute to the benefits of MeDi on brain structure. PMID- 26491084 TI - Autoimmune post-herpes simplex encephalitis of adults and teenagers. AB - OBJECTIVE: To report 14 patients with immune-mediated relapsing symptoms post herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children. METHODS: Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously. RESULTS: Among the teenage and adult group (8 patients, median age 40 years, range 13-69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6-20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17-296, vs 4 days, range 0-33, p = 0.037). CONCLUSION: In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective. PMID- 26491087 TI - Relapse in herpes simplex virus encephalitis: It's not just about the virus. PMID- 26491089 TI - Double aortic arch and dilated cardiomyopathy in an elderly man. PMID- 26491090 TI - Start mammography at age 45, US guideline recommends. PMID- 26491088 TI - Pisa syndrome in Parkinson disease: An observational multicenter Italian study. AB - OBJECTIVE: To estimate the prevalence of Pisa syndrome (PS) in patients with Parkinson disease (PD) and to assess the association between PS and demographic and clinical variables. METHODS: In this multicenter cross-sectional study, consecutive outpatients with PD attending 21 movement disorders Italian tertiary centers were enrolled and underwent standardized clinical evaluation. PS was defined as trunk lateral deviation >=10 degrees . Patients with PD were compared according to the presence of PS for several demographic and clinical variables. RESULTS: Among 1,631 enrolled patients with PD, PS was detected in 143 patients (8.8%, 95% confidence interval 7.4%-10.3%). Patients with PS were older, had lower body mass index, longer disease duration, higher disease stages, and poorer quality of life. Falls were more frequent in the PS group as well as occurrence of "veering gait" (i.e., the progressive deviation toward one side when patient walked forward and backward with eyes closed). Patients with PS received higher daily levodopa equivalent daily dose and were more likely to be treated with combination of levodopa and dopamine agonists. Osteoporosis and arthrosis were significantly the most frequent associated medical conditions in patients with PS. Multiple explanatory variable logistic regression models confirmed the association of PS with the following variables: Hoehn and Yahr stage, ongoing combined treatment with levodopa and dopamine agonist, associated medical conditions, and presence of veering gait. CONCLUSIONS: Our results suggest that PS is a relatively frequent and often disabling complication in PD, especially in the advanced disease stages. The association is dependent on a number of potentially relevant demographic and clinical variables. PMID- 26491091 TI - Comparison of Ultrasound-Guided Core Needle Biopsy and Endoscopic Ultrasound Guided Fine-Needle Aspiration for Solid Pancreatic Lesions. AB - OBJECTIVES: The objective of our study was to compare the diagnostic yield of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) using a 25-gauge needle and ultrasound (US)-guided core needle biopsy (CNB) using an 18-gauge core needle for diagnosis of solid pancreatic lesions. METHODS: This retrospective study was approved by our Institutional Review Board, and the requirement for informed consent was waived. Patients who underwent either EUS-guided FNA or US guided CNB for a solid pancreatic lesion from January 2008 to December 2012 were included and reviewed. Fine-needle aspirations and CNBs were performed by experienced endoscopists and radiologists. The diagnostic yield, accuracy, technical failure rate, sensitivity, and specificity for malignancy were calculated and compared. RESULTS: A total of 106 biopsy attempts were undertaken in 89 patients (EUS-guided FNA, n = 70; US-guided CNB, n = 36). Biopsy specimens were successfully obtained in 98 biopsy attempts (EUS-guided FNA, n = 63; US guided CNB, n = 35). The accuracy, technical failure rate, sensitivity, and specificity of EUS-guided FNA for malignancy (73.02%, 10.00%, 77.78%, and 44.44%, respectively) was not significantly different from those of US-guided CNB (88.57%, 2.78%, 87.10%, and 100%, respectively; P >= .089). Diagnostic performance did not differ between the modalities according to the size and the location of the lesion in the pancreas. However, the diagnostic yield of US guided CNB (86.11%) was higher than that of EUS-guided FNA (65.71%, P = .035). CONCLUSIONS: The diagnostic yield of US-guided CNB for solid pancreatic lesions is superior to that of EUS-guided FNA. PMID- 26491092 TI - Anatomic Differences in the Sacral Hiatus During Caudal Epidural Injection Using Ultrasound Guidance. AB - OBJECTIVES: The aim of this study was to clarify differences in the anatomic structure of the sacral hiatus and angle of needle insertion during caudal epidural steroid injection using ultrasound guidance in patients according to sex and age. METHODS: A total of 237 patients with low back pain with or without sciatica were included. Sonograms of the sacral hiatus were obtained, and caudal epidural steroid injection using ultrasound guidance was performed in all patients. The intercornual distance, diameter of the sacral canal, thickness of the sacrococcygeal ligament, optimal angle for needle insertion, and actual angle of needle insertion were measured. RESULTS: Between men and women, significant differences were observed for the intercornual distance (17.7 versus 16.5 mm; P< .01) and thickness of the sacrococcygeal ligament (4.3 versus 3.9 mm; P = .02). In all patients, the thickness of the sacrococcygeal ligament (r= 0.28) and diameter of the sacral canal (r= 0.40) were positively correlated with the optimal angle for needle insertion (P < .01). In women, the thickness of the sacrococcygeal ligament (r = -0.24), diameter of the sacral canal (r = -0.27), optimal angle for needle insertion (r = -0.29), and actual angle of needle insertion (r = -0.18) were negatively correlated with age. In men, only the diameter of the sacral canal was negatively correlated with age (r = -0.30). CONCLUSIONS: We found that the sacral hiatus has anatomic differences between patients of different sexes and ages. Understanding these differences, especially in women, may improve the safety and reliability of caudal epidural steroid injection. PMID- 26491093 TI - Effects of an Isolated Complete Right Bundle Branch Block on Mechanical Ventricular Function. AB - OBJECTIVES: The purpose of this study was to investigate the effects of an isolated complete right bundle branch block on mechanical ventricular function. METHODS: Two groups of participants were enrolled in this study: a block group, consisting of 98 patients with isolated complete right bundle branch blocks without structural heart disease, and a control group, consisting of 92 healthy adults. The diameter, end-diastolic area, end-systolic area, and right ventricular (RV) fractional area change were obtained to evaluate morphologic and systolic function by 2-dimensional sonographic technology. Systolic and diastolic velocities and time interval parameters were measured to assess mechanical ventricular performance using pulsed wave tissue Doppler imaging. RESULTS: Although there was no significant difference in the RV fractional area change between the patients with blocks and controls, the diameter, end-diastolic area, and end-systolic area of the RV were significantly larger in the patients with blocks (P < .05). In the patients with blocks, the peak velocities during systole and early diastole and the ratio of the peak velocities during early and late diastole decreased. The block group had a prolonged pre-ejection period, electromechanical delay time, and isovolumic relaxation time, a decreased ejection time, and an increased pre-ejection period/ejection time ratio, and the myocardial performance index (Tei index) at the basal RV lateral wall was significantly increased. There were no significant differences in any echocardiographic parameters at different sites of the left ventricle. CONCLUSIONS: In patients with isolated complete right bundle branch blocks, systolic and diastolic functions are impaired in the RV, and follow-up is needed. PMID- 26491094 TI - Novel Use of Ultrasound Elastography to Quantify Muscle Tissue Changes After Dry Needling of Myofascial Trigger Points in Patients With Chronic Myofascial Pain. AB - OBJECTIVES: To compare a mechanical heterogeneity index derived from ultrasound vibration elastography with physical findings before and after dry-needling treatment of spontaneously painful active myofascial trigger points in the upper trapezius muscle. METHODS: Forty-eight patients with chronic myofascial pain enrolled in a prospective interventional trial of 3 weekly dry-needling treatments for active myofascial trigger points. Trigger points were evaluated at baseline and at treatment completion using palpation, the pressure-pain threshold, and the mechanical heterogeneity index. Thirty patients were reevaluated at 8 weeks. Trigger points that "responded" changed to tissue that was no longer spontaneously painful, with or without the presence of a palpable nodule. Trigger points that "resolved" changed to tissue without a palpable nodule. The mechanical heterogeneity index was defined as the proportion of the upper trapezius muscle that appeared mechanically stiffer on elastography. Statistical significance for comparisons was determined at P < .05. RESULTS: Following 3 dry needle treatments, the mechanical heterogeneity index decreased significantly for the 38 myofascial trigger points (79% of 48) that responded to treatment. Among these, the baseline mechanical heterogeneity index was significantly lower for the 13 trigger points (27% of 38) that resolved, but the decrease after 3 dry needle treatments did not reach significance. The pressure pain threshold improved significantly for both groups. At 8 weeks, the mechanical heterogeneity index decreased significantly for the 22 trigger points (73% of 30) that responded and for the 10 (45% of 22) that resolved. The pressure-pain threshold improvement was significant for trigger points that responded but did not reach significance for resolved trigger points. CONCLUSIONS: The mechanical heterogeneity index identifies changes in muscle tissue properties that correlate with changes in the myofascial trigger point status after dry needling. PMID- 26491095 TI - Contrast-Enhanced Sonographic Features Before and After Interventional Treatment of Ovarian Endometrial Cysts. AB - OBJECTIVES: The purpose of this study was to assess contrast-enhanced sonography features before and after interventional treatment of ovarian endometrial cysts. METHODS: We retrospectively analyzed 53 patients with ovarian endometrial cysts who underwent contrast-enhanced sonography before and after interventional treatment to assess the sonographic features of the cysts at these different times. The sonographic features and quantitative parameters for the cysts were compared before and after treatment. RESULTS: The wash-in mode showed rapid annular enhancement of the cyst wall and slow wash-out with even and uneven enhancement types. Compared to the internal iliac artery, the enhancement intensity was weaker, and the wash-in and wash-out times were longer in the cyst wall; furthermore, all 5 quantitative parameters differed between the cyst wall and internal iliac artery. The wash-in and wash-out characteristics of the cysts before and after interventional treatment were almost identical. The enhancement was primarily even before treatment and uneven after treatment; the enhancement intensity was low in all cases. Although the wash-in time before and after treatment did not differ, the wash-out time for the cysts before treatment was significantly lower than that observed after treatment. Two quantitative parameters differed before and after treatment. CONCLUSIONS: The contrast enhanced sonographic features and quantitative parameters for the walls of ovarian endometrial cysts differed before and after ultrasound-guided interventional treatment. These characteristics could be valuable for evaluating the efficacy of interventional treatment of ovarian endometrial cysts. PMID- 26491096 TI - NICE approval of new hepatitis drug could result in L700m bill for NHS. PMID- 26491097 TI - Genetic identity of thermosensory relay neurons in the lateral parabrachial nucleus. AB - The parabrachial nucleus is important for thermoregulation because it relays skin temperature information from the spinal cord to the hypothalamus. Prior work in rats localized thermosensory relay neurons to its lateral subdivision (LPB), but the genetic and neurochemical identity of these neurons remains unknown. To determine the identity of LPB thermosensory neurons, we exposed mice to a warm (36 degrees C) or cool (4 degrees C) ambient temperature. Each condition activated neurons in distinct LPB subregions that receive input from the spinal cord. Most c-Fos+ neurons in these LPB subregions expressed the transcription factor marker FoxP2. Consistent with prior evidence that LPB thermosensory relay neurons are glutamatergic, all FoxP2+ neurons in these subregions colocalized with green fluorescent protein (GFP) in reporter mice for Vglut2, but not for Vgat. Prodynorphin (Pdyn)-expressing neurons were identified using a GFP reporter mouse and formed a caudal subset of LPB FoxP2+ neurons, primarily in the dorsal lateral subnucleus (PBdL). Warm exposure activated many FoxP2+ neurons within PBdL. Half of the c-Fos+ neurons in PBdL were Pdyn+, and most of these project into the preoptic area. Cool exposure activated a separate FoxP2+ cluster of neurons in the far-rostral LPB, which we named the rostral-to-external lateral subnucleus (PBreL). These findings improve our understanding of LPB organization and reveal that Pdyn-IRES-Cre mice provide genetic access to warm-activated, FoxP2+ glutamatergic neurons in PBdL, many of which project to the hypothalamus. PMID- 26491098 TI - ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause. AB - Premenopausal females are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease onset and severity. However, it is unknown how a fluctuating ovarian hormone environment during the transition from perimenopause to menopause impacts the onset of hypertension, and whether interventions during perimenopause prevent disease onset after menopause. A gradual transition to menopause was induced by repeated daily injections of 4-vinylcyclohexene diepoxide (VCD). ANG II (800 ng.kg(-1).min(-1)) was infused into perimenopausal and menopausal female mice for 14 days. A separate cohort of mice received 17beta-estradiol replacement during perimenopause. ANG II infusion produced significantly higher mean arterial pressure (MAP) in menopausal vs. cycling females, and 17beta-estradiol replacement prevented this increase. In contrast, MAP was not significantly different when ANG II was infused into perimenopausal and cycling females, suggesting that female resistance to ANG II-induced hypertension is intact during perimenopause. ANG II infusion caused a significant glomerular hypertrophy, and hypertrophy was not impacted by hormonal status. Expression levels of aquaporin-2 (AQP2), a collecting duct protein, have been suggested to reflect blood pressure. AQP2 protein expression was significantly downregulated in the renal cortex of the ANG II-infused menopause group, where blood pressure was increased. AQP2 expression levels were restored to control levels with 17beta-estradiol replacement. This study indicates that the changing hormonal environment in the VCD model of menopause impacts the severity of ANG II-induced hypertension. These data highlight the utility of the ovary-intact VCD model of menopause as a clinically relevant model to investigate the physiological mechanisms of hypertension that occur in women during the transition into menopause. PMID- 26491100 TI - Candida glabrata binds to glycosylated and lectinic receptors on the coronary endothelial luminal membrane and inhibits flow sense and cardiac responses to agonists. AB - Candida glabrata (CG) is an opportunistic fungal pathogen that initiates infection by binding to host cells via specific lectin-like adhesin proteins. We have previously shown the importance of lectin-oligosaccharide binding in cardiac responses to flow and agonists. Because of the lectinic-oligosaccharide nature of CG binding, we tested the ability of CG to alter the agonist- and flow-induced changes in cardiac function in isolated perfused guinea pig hearts. Both transmission and scanning electron microscopy showed strong attachment of CG to the coronary endothelium, even after extensive washing. CG shifted the coronary flow vs. auricular-ventricular (AV) delay relationship upward, indicating that greater flow was required to achieve the same AV delay. This effect was completely reversed with mannose, partially reversed with galactose and N acetylgalactosamine, but hyaluronan had no effect. Western blot analysis was used to determine binding of CG to isolated coronary endothelial luminal membrane (CELM) receptors, and the results indicate that flow-sensitive CELM receptors, ANG II type I, alpha-adrenergic 1A receptor, endothelin-2, and VCAM-1 bind to CG. In addition, CG inhibited agonist-induced effects of bradykinin, angiotensin, and phenylephrine on AV delay, coronary perfusion pressure, and left ventricular pressure. Mannose reversed the inhibitory effects of CG on the agonist responses. These results suggest that CG directly binds to flow-sensitive CELM receptors via lectinic-oligosaccharide interactions with mannose and disrupts the lectin oligosaccharide binding necessary for flow-induced cardiac responses. PMID- 26491101 TI - Hepatic fatty acid biosynthesis is more responsive to protein than carbohydrate in rainbow trout during acute stimulations. AB - The link between dietary carbohydrate/protein and de novo lipogenesis (DNL) remains debatable in carnivorous fish. We aimed to evaluate and compare the response of hepatic lipogenic gene expression to dietary carbohydrate intake/glucose and dietary protein intake/amino acids (AAs) during acute stimulations using both in vivo and in vitro approaches. For the in vivo trial, three different diets and a controlled-feeding method were employed to supply fixed amount of dietary protein or carbohydrate in a single meal; for the in vitro trial, primary hepatocytes were stimulated with a low or high level of glucose (3 mM or 20 mM) and a low or high level of AAs (one-fold or four-fold concentrated AAs). In vitro data showed that a high level of AAs upregulated the expression of enzymes involved in DNL [fatty acid synthase (FAS) and ATP citrate lyase (ACLY)], lipid bioconversion [elongation of very long chain fatty acids like-5 (Elovl5), Elovl2, Delta6 fatty acyl desaturase (D6D) and stearoyl-CoA desaturase-1 (SCD1)], NADPH production [glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme (ME)], and transcriptional factor sterol regulatory element binding protein 1-like, while a high level of glucose only elevated the expression of ME. Data in trout liver also showed that high dietary protein intake induced higher lipogenic gene expression (FAS, ACLY, and Elovl2) regardless of dietary carbohydrate intake, while high carbohydrate intake markedly suppressed the expression of acetyl-CoA carboxylase (ACC) and Elovl5. Overall, we conclude that, unlike rodents or humans, hepatic fatty acid biosynthetic gene expression in rainbow trout is more responsive to dietary protein intake/AAs than dietary carbohydrate intake/glucose during acute stimulations. This discrepancy probably represents one important physiological and metabolic difference between carnivores and omnivores. PMID- 26491099 TI - Opposing tissue-specific roles of angiotensin in the pathogenesis of obesity, and implications for obesity-related hypertension. AB - Metabolic disease, specifically obesity, has now become the greatest challenge to improving cardiovascular health. The renin-angiotensin system (RAS) exists as both a circulating hormone system and as a local paracrine signaling mechanism within various tissues including the brain, kidney, and adipose, and this system is strongly implicated in cardiovascular health and disease. Growing evidence also implicates the RAS in the control of energy balance, supporting the concept that the RAS may be mechanistically involved in the pathogenesis of obesity and obesity hypertension. Here, we review the involvement of the RAS in the entire spectrum of whole organism energy balance mechanisms, including behaviors (food ingestion and spontaneous physical activity) and biological processes (digestive efficiency and both aerobic and nonaerobic resting metabolic rates). We hypothesize that opposing, tissue-specific effects of the RAS to modulate these various components of energy balance can explain the apparently paradoxical results reported by energy-balance studies that involve stimulating, versus disrupting, the RAS. We propose a model in which such opposing and tissue specific effects of the RAS can explain the failure of simple, global RAS blockade to result in weight loss in humans, and hypothesize that obesity mediated uncoupling of endogenous metabolic rate control mechanisms can explain the phenomenon of obesity-related hypertension. PMID- 26491102 TI - The utility of Valsalva maneuver in the diagnoses of orthostatic disorders. AB - The objective of this study was to assess hemodynamic responses and baroreflex sensitivity (BRS) indexes during Valsalva maneuver (VM) and head-up tilt (HUT) testing in orthostatic intolerance (OI). Patients with neurogenic orthostatic hypotension (NOH, n = 26), postural tachycardia syndrome (n = 26) and symptomatic OI (n = 14) were compared with healthy population (control, n = 107) and inappropriate sinus tachycardia (n = 7). Hemodynamic assessment included patterning and quantification with vagal and adrenergic BRS (BRSa/BRSa1). In NOH, cardiovagal systolic blood pressure (SBP) decrements in VM and HUT were correlated (r = 0.660, P < 0.001); a "V" pattern of VM indicated alpha-BRSa failure. Yet BRSa1 did not reveal changes vs. control (P > 0.05) or was not applicable in 60% of NOH. In symptomatic OI, compared with control, cardiovagal SBP decrements were larger (P < 0.05); higher BRSa1 contradicted higher adrenergic index (Composite Autonomic Severity Score). Overshoot in phase IV dipped below baseline or dropped >= 10 mmHg over 8 s in postural tachycardia syndrome ("N" pattern), but by 3 s in inappropriate sinus tachycardia ("M" pattern). Visualization of distinct VM patterns allows primary evaluation of autonomic dysfunction and differentiation of the various forms of OI. BRSa1 evaluation is compromised by pathological SBP patterns. VM patterning is a valuable nonpostural supplement to HUT capable of detecting and differentiating OI. PMID- 26491103 TI - Activation of placental insulin and mTOR signaling in a mouse model of maternal obesity associated with fetal overgrowth. AB - Fetal overgrowth is common in obese women and is associated with perinatal complications and increased risk for the child to develop metabolic syndrome later in life. Placental nutrient transport capacity has been reported to be increased in obese women giving birth to large infants; however, the underlying mechanisms are not well established. Obesity in pregnancy is characterized by elevated maternal serum insulin and leptin, hormones that stimulate placental amino acid transporters in vitro. We hypothesized that maternal obesity activates placental insulin/IGF-I/mTOR and leptin signaling pathways. We tested this hypothesis in a mouse model of obesity in pregnancy that is associated with fetal overgrowth. C57BL/6J female mice were fed a control (C) or a high-fat/high-sugar (HF/HS) pelleted diet supplemented by ad libitum access to sucrose (20%) solution. Placentas were collected at embryonic day 18.5. Using Western blot analysis, placental mTOR activity was determined along with energy, inflammatory, leptin, and insulin signaling pathways (upstream modulators of mTOR). Phosphorylation of S6 ribosomal protein (S-235/236), 4E-BP1 (T-37/46), Insulin receptor substrate 1 (Y-608), Akt (T-308), and STAT-3 (Y-705) was increased in obese dams. In contrast, expression of placental caspase-1, IkBalpha, IL-1beta, and phosphorylated-JNK(p46/54-T183/Y185) was unaltered. Fetal amino acid availability is a key determinant of fetal growth. We propose that activation of placental insulin/IGF-I/mTOR and leptin signaling pathways in obese mice stimulates placental amino acid transport and contributes to increased fetal growth. PMID- 26491104 TI - Increased placental fatty acid transporter 6 and binding protein 3 expression and fetal liver lipid accumulation in a mouse model of obesity in pregnancy. AB - Obesity in pregnancy is associated with increased fetal growth and adiposity, which, in part, is determined by transplacental nutrient supply. Trophoblast uptake and intracellular trafficking of lipids are dependent on placental fatty acid transport proteins (FATP), translocase (FAT/CD36), and fatty acid binding proteins (FABP). We hypothesized that maternal obesity in mice leads to increased placental expression of FAT/CD36, FATPs, and FABPs, and lipid accumulation in the fetal liver. C57/BL6J female mice were fed either a control (C; n = 10) or an obesogenic (OB; n = 10) high-fat, high-sugar diet before mating and throughout pregnancy. At E18.5, placentas and fetal livers were collected. Trophoblast plasma membranes (TPM) were isolated from placental homogenates. Expression of FAT/CD36 and FATP (TPM) and FABP (homogenates) was determined by immunoblotting. Gene expression was assessed by RT-quantitative PCR. Sections of fetal livers were stained for Oil Red O, and lipid droplets were quantified. TPM protein expression of FAT/CD36, FATP 2, and FATP 4 was comparable between C and OB groups. Conversely, TPM FATP 6 expression was increased by 35% in OB compared with C placentas without changes in mRNA expression. FABPs 1, 3-5 and PPARgamma were expressed in homogenates, and FABP 3 expression increased 27% in OB compared with C placentas; however, no changes were observed in mRNA expression. Lipid droplet accumulation was 10-fold higher in the livers of fetuses from OB compared with C group. We propose that increased lipid transport capacity in obese mice promotes transplacental fatty acid transport and contributes to excess lipid accumulation in the fetal liver. PMID- 26491105 TI - Comparison of Air Impaction and Electrostatic Dust Collector Sampling Methods to Assess Airborne Fungal Contamination in Public Buildings. AB - Many ailments can be linked to exposure to indoor airborne fungus. However, obtaining a precise measurement of airborne fungal levels is complicated partly due to indoor air fluctuations and non-standardized techniques. Electrostatic dust collector (EDC) sampling devices have been used to measure a wide range of airborne analytes, including endotoxins, allergens, beta-glucans, and microbial DNA in various indoor environments. In contrast, viable mold contamination has only been assessed in highly contaminated environments such as farms and archive buildings. This study aimed to assess the use of EDCs, compared with repeated air impactor measurements, to assess airborne viable fungal flora in moderately contaminated indoor environments. Indoor airborne fungal flora was cultured from EDCs and daily air-impaction samples collected in an office building and a daycare center. The quantitative fungal measurements obtained using a single EDC significantly correlated with the cumulative measurement of nine daily air impactions. Both methods enabled the assessment of fungal exposure, although a few differences were observed between the detected fungal species and the relative quantity of each species. EDCs were also used over a 32-month period to monitor indoor airborne fungal flora in a hospital office building, which enabled us to assess the impact of outdoor events (e.g. ground excavations) on the fungal flora levels on the indoor environment. In conclusion, EDC-based measurements provided a relatively accurate profile of the viable airborne flora present during a sampling period. In particular, EDCs provided a more representative assessment of fungal levels compared with single air-impactor sampling. The EDC technique is also simpler than performing repetitive air-impaction measures over the course of several consecutive days. EDC is a versatile tool for collecting airborne samples and was efficient for measuring mold levels in indoor environments. PMID- 26491107 TI - Sudden cardiac death during exercise in patients with congenital heart disease: the exercise paradox and the challenge of appropriate counselling. PMID- 26491106 TI - Quality markers in cardiology: measures of outcomes and clinical practice--a perspective of the Spanish Society of Cardiology and of Thoracic and Cardiovascular Surgery. PMID- 26491108 TI - Notch-Tnf signalling is required for development and homeostasis of arterial valves. AB - Aims: Congenital anomalies of arterial valves are common birth defects, leading to valvar stenosis. With no pharmaceutical treatment that can prevent the disease progression, prosthetic replacement is the only choice of treatment, incurring considerable morbidity and mortality. Animal models presenting localized anomalies and stenosis of congenital arterial valves similar to that of humans are critically needed research tools to uncover developmental molecular mechanisms underlying this devastating human condition. Methods and results: We generated and characterized mouse models with conditionally altered Notch signalling in endothelial or interstitial cells of developing valves. Mice with inactivation of Notch1 signalling in valvar endothelial cells (VEC) developed congenital anomalies of arterial valves including bicuspid aortic valves and valvar stenosis. Notch1 signalling in VEC was required for repressing proliferation and activating apoptosis of valvar interstitial cells (VIC) after endocardial-to-mesenchymal transformation (EMT). We showed that Notch signalling regulated Tnfalpha expression in vivo, and Tnf signalling was necessary for apoptosis of VIC and post-EMT development of arterial valves. Furthermore, activation or inhibition of Notch signalling in cultured pig aortic VEC-promoted or suppressed apoptosis of VIC, respectively. Conclusion: We have now met the need of critical animal models and shown that Notch-Tnf signalling balances proliferation and apoptosis for post-EMT development of arterial valves. Our results suggest that mutations in its components may lead to congenital anomaly of aortic valves and valvar stenosis in humans. PMID- 26491109 TI - Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54. AB - AIMS: Ticagrelor reduced major adverse cardiovascular event (MACE) by 15-16% in patients with prior myocardial infarction (MI) in PEGASUS-TIMI 54. We hypothesized that patients who recently discontinued P2Y12 inhibition, even years after MI, may be at particular risk of MACE and may derive particular benefit from continuation or reinitiation of therapy. METHODS AND RESULTS: Patients in PEGASUS-TIMI 54 were categorized by time from last P2Y12 inhibitor (days: <=30, >30-360, >360). The risk of MACE and the efficacy of ticagrelor were compared across categories. In the placebo arm, patients who more recently stopped P2Y12 inhibitor therapy had a greater number of risk factors but still had a higher risk of MACE after multivariable adjustment [<=30 days, hazard ratio (HR)adj 1.47, 95% confidence interval (CI) 1.12-1.93, P = 0.0051; 30 days-1 year, HRadj 1.28, 95% CI 0.98-1.67, P = 0.073] compared with those who stopped >1 year prior (P-trend = 0.0097). The benefit of ticagrelor depended on the time from last dose, with HRs (95% CI) for ticagrelor (pooled doses) vs. placebo of 0.73 (0.61 0.87), 0.86 (0.71-1.04), and 1.01 (0.80-1.27), respectively, by category (P-trend for interaction < 0.001). The benefit in those <=30 days of stopping was similar regardless of time from MI (<2 years, HR 0.73, 95% CI 0.60-0.89 vs. >=2 years, HR 0.71, 95% CI 0.50-1.00). CONCLUSION: The benefit of ticagrelor for long-term secondary prevention in patients with prior MI and at least one additional risk factor appeared more marked in patients continuing on or re-starting after only a brief interruption of P2Y12 inhibition, when compared with patients who had proved themselves stable more than 2 years from their MI and off P2Y12 inhibitor therapy for more than a year. The increase in bleeding events with ticagrelor was similar regardless of this time interval. For clinicians considering a strategy of prolonged P2Y12 inhibitor therapy in high-risk patients, these data suggest greater benefit in the continuation of such therapy without interruption after MI, rather than re-initiating such therapy in patients who have remained stable for an extended period. Future analyses may help to clarify further the profile of post-MI patients most likely to benefit from uninterrupted dual antiplatelet therapy. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov NCT01225562. PMID- 26491111 TI - Morphine in myocardial infarction: balancing on the tight rope. PMID- 26491110 TI - A clinical risk score of myocardial fibrosis predicts adverse outcomes in aortic stenosis. AB - AIMS: Midwall myocardial fibrosis on cardiovascular magnetic resonance (CMR) is a marker of early ventricular decompensation and adverse outcomes in aortic stenosis (AS). We aimed to develop and validate a novel clinical score using variables associated with midwall fibrosis. METHODS AND RESULTS: One hundred forty-seven patients (peak aortic velocity (Vmax) 3.9 [3.2,4.4] m/s) underwent CMR to determine midwall fibrosis (CMR cohort). Routine clinical variables that demonstrated significant association with midwall fibrosis were included in a multivariate logistic score. We validated the prognostic value of the score in two separate outcome cohorts of asymptomatic patients (internal: n = 127, follow up 10.3 [5.7,11.2] years; external: n = 289, follow-up 2.6 [1.6,4.5] years). Primary outcome was a composite of AS-related events (cardiovascular death, heart failure, and new angina, dyspnoea, or syncope). The final score consisted of age, sex, Vmax, high-sensitivity troponin I concentration, and electrocardiographic strain pattern [c-statistic 0.85 (95% confidence interval 0.78-0.91), P < 0.001; Hosmer-Lemeshow chi(2) = 7.33, P = 0.50]. Patients in the outcome cohorts were classified according to the sensitivity and specificity of this score (both at 98%): low risk (probability score <7%), intermediate risk (7-57%), and high risk (>57%). In the internal outcome cohort, AS-related event rates were >10-fold higher in high-risk patients compared with those at low risk (23.9 vs. 2.1 events/100 patient-years, respectively; log rank P < 0.001). Similar findings were observed in the external outcome cohort (31.6 vs. 4.6 events/100 patient years, respectively; log rank P < 0.001). CONCLUSION: We propose a clinical score that predicts adverse outcomes in asymptomatic AS patients and potentially identifies high-risk patients who may benefit from early valve replacement. PMID- 26491113 TI - New contract would mean doctors are "overworked, underpaid, undervalued, demoralised". PMID- 26491112 TI - Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. AB - AIMS: The currently available data indicate a drug-drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction. METHODS AND RESULTS: In a single centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0-12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0-12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0-12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine. CONCLUSIONS: Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878. PMID- 26491115 TI - Eltrombopag interference in routine chemistry testing. AB - BACKGROUND: High doses of Eltrombopag have been previously reported to cause bilirubin interference. Following receipt of a sample from a patient receiving high-dose Eltrombopag therapy, the laboratory decided to investigate the effect of this drug on routine chemistry testing. METHODS: Interference studies were performed by spiking Eltrombopag into aliquots of a serum pool to give concentrations ranging from 0 to 500 ug/mL. The following analytes, namely albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, Urea, total calcium, cholesterol, triglycerides, glucose, high-density lipoprotein cholesterol, iron, magnesium, inorganic phosphate, creatinine, bicarbonate, transferrin, ferritin, electrolytes, total and direct bilirubin and serum indices (hemolysis, icterus and lipaemia) were then measured on the Roche Cobas 6000 chemistry analyzer (Roche, Indianapolis, USA). RESULTS: Eltrombopag interference (>10% change of the baseline value) was observed for total cholesterol, triglycerides, inorganic phosphate and high-density lipoprotein cholesterol. Clinical significant interference was observed for total cholesterol, inorganic phosphate and high-density lipoprotein cholesterol CONCLUSIONS: Presence of high Eltrombopag concentrations in blood samples has been demonstrated to cause interference in the measurement of certain spectrophotometric-based assays on the Roche Cobas 6000 analyzer. PMID- 26491116 TI - A Multidisciplinary Sepsis Program Enabled by a Two-Stage Clinical Decision Support System: Factors That Influence Patient Outcomes. AB - Sepsis is an inflammatory response triggered by infection, with risk of in hospital mortality fueled by disease progression. Early recognition and intervention by multidisciplinary sepsis programs may reverse the inflammatory response among at-risk patient populations, potentially improving outcomes. This retrospective study of a sepsis program enabled by a 2-stage sepsis Clinical Decision Support (CDS) system sought to evaluate the program's impact, identify early indicators that may influence outcomes, and uncover opportunities for quality improvement. Data encompassed 16 527 adult hospitalizations from 2014 and 2015. Of 2108 non-intensive care unit patients screened-in by sepsis CDS, 97% patients were stratified by 177 providers. Risk of adverse outcome improved 30% from baseline to year end, with gains materializing and stabilizing at month 7 after sepsis program go-live. Early indicators likely to influence outcomes include patient age, recent hospitalization, electrolyte abnormalities, hypovolemic shock, hypoxemia, patient location when sepsis CDS activated, and specific alert patterns. PMID- 26491118 TI - Moderately Fermentable Potato Fiber Attenuates Signs and Inflammation Associated with Experimental Colitis in Mice. AB - BACKGROUND: Dietary fiber intake leading to short-chain fatty acid (SCFA) production could be a strategy to combat intermittent bouts of inflammation during ulcerative colitis. OBJECTIVE: Our objective was to evaluate dietary potato fiber (PF) in attenuating inflammation using a dextran sodium sulfate (DSS)-induced colitis mouse model. We hypothesized that PF would show anti inflammatory effects compared with cellulose due in part to SCFA production. METHODS: Male C57Bl/6J mice were fed diets containing either 8% cellulose or 14.5% PF for a 22-d feeding study. Starting on study day 14, mice were provided either distilled water (control) or 2% (wt:vol) DSS in drinking water for 5 d (cellulose+control, n = 17; PF+control, n = 16; cellulose+DSS, n = 17; and PF+DSS, n = 16). Body weights and food and water intakes were collected daily from day 14 through day 22. Distal colon tissue was analyzed for histologic outcomes and changes in gene expression, and cecal contents were analyzed for SCFA concentrations. Data were analyzed by ANOVA, with repeated measures applied where necessary. RESULTS: At day 5 post-DSS induction, cellulose+DSS mice exhibited a 2% reduction (P < 0.05) in body weight compared with PF+DSS and PF+ and cellulose+control mice. PF+DSS mice had greater (P < 0.05) cecal butyrate concentrations [24.5 MUmol/g dry matter (DM)] than did cellulose+DSS mice (4.93 MUmol/g DM). Mice fed PF+DSS had lower (P < 0.05) infiltration of leukocytes in the distal colon than did mice fed cellulose+DSS (mean histology scores of 1.22 and 2.30, respectively). Furthermore, mice fed cellulose+DSS exhibited 1.42, 11.5, 8.48, and 35.5 times greater (P < 0.05) colon mRNA expression of tumor necrosis factor alpha (Tnfa) and interleukin (Il) 1b, Il6, and Il17a, respectively, and 7.10 times greater (P < 0.05) expression of C-X-C motif ligand 1 (Cxc1) compared with mice fed PF+DSS. CONCLUSIONS: These results suggest that PF fed to mice before and during DSS colitis attenuates inflammation, potentially through SCFA production; however, future studies are needed to understand the role of dietary fiber intake and immune activation. PMID- 26491117 TI - Zinc Supplementation Increases Procollagen Type 1 Amino-Terminal Propeptide in Premenarcheal Girls: A Randomized Controlled Trial. AB - BACKGROUND: Data have shown that healthy children and adolescents have an inadequate intake of zinc, an essential nutrient for growth. It is unclear whether zinc supplementation can enhance bone health during this rapid period of growth and development. OBJECTIVE: The primary aim of this study was to determine the effect of zinc supplementation on biochemical markers of bone turnover and growth in girls entering the early stages of puberty. The secondary aim was to test moderation by race, body mass index (BMI) classification, and plasma zinc status at baseline. METHODS: One hundred forty seven girls aged 9-11 y (46% black) were randomly assigned to a daily oral zinc tablet (9 mg elemental zinc; n = 75) or an identical placebo (n = 72) for 4 wk. Fasting plasma zinc, procollagen type 1 amino-terminal propeptide (P1NP; a bone formation marker), carboxy terminal telopeptide region of type 1 collagen (ICTP; a bone resorption marker), and insulin-like growth factor I (IGF-I) were assessed at baseline and post-test. Additional markers of bone formation (osteocalcin) and resorption (urinary pyridinoline and deoxypyridinoline) were also measured. RESULTS: Four weeks of zinc supplementation increased plasma zinc concentrations compared with placebo [mean change, 1.8 MUmol/L (95% CI: 1.0, 2.6) compared with 0.2 MUmol/L (95% CI: 0.3, 0.7); P < 0.01]. Zinc supplementation also increased serum P1NP concentrations compared with placebo [mean change, 23.8 MUmol/L (95% CI: -14.9, 62.5) compared with -31.0 MUmol/L (95% CI: -66.4, 4.2); P = 0.04). There was no effect from zinc supplementation on osteocalcin, ICTP, pyridinoline, deoxypyridinoline, or IGF-I. There was no moderation by race, BMI classification, or plasma zinc status at baseline. CONCLUSIONS: Our data suggest that 4 wk of zinc supplementation increases bone formation in premenarcheal girls. Further studies are needed to determine whether supplemental zinc can improve childhood bone strength. This trial was registered at clinicaltrials.gov as NCT01892098. PMID- 26491119 TI - Casein Compared with Whey Proteins Affects the Organization of Dietary Fat during Digestion and Attenuates the Postprandial Triglyceride Response to a Mixed High Fat Meal in Healthy, Overweight Men. AB - BACKGROUND: Postprandial lipemia is a risk factor for cardiovascular disease. The potential impacts of the type/nature of dietary protein on postprandial lipemia and associated dysregulations have been insufficiently investigated. OBJECTIVE: We investigated the postprandial effect of including in a high-fat meal some milk protein fractions that markedly differ in their physicochemical properties and composition [either casein (CAS), whey protein (WHE), or alpha-lactalbumin enriched whey protein (LAC)]. METHODS: The protein fractions were incorporated as 15% energy in a high-fat meal in a 3-period, crossover postprandial study of 10 healthy overweight men with an elevated waist circumference (>94 cm). We measured postprandial changes in plasma lipids, amino acids, glucose, and oxidative stress markers, vascular function (using pulse contour analysis), and low-grade inflammation (using plasma markers). We also characterized in vitro the meal structures, including the size of the fat globule, and possible changes during digestion. RESULTS: The type of protein did not affect postprandial plasma glucose, amino acids, insulin, or nonesterified fatty acids, but, compared with WHE and LAC, which did not differ, CAS markedly reduced postprandial triglycerides (TGs), achieving a 22 +/- 10% reduction in the 6-h area under the curve (P < 0.05). Similar trends were shown for plasma chylomicrons [apolipoprotein (apo)B-48; P < 0.05]. However, there were no significant differences between the meals regarding postprandial oxidative stress (plasma hydroperoxides and malondialdehyde), endothelial dysfunction (salbutamol-induced changes in pulse contour analysis), or low-grade inflammation. In vitro studies showed that when the pH of the meal decreased to stomach pH values, the reduction in the solubility of casein resulted in a phase separation between fat and protein, whereas the proteins in the other meals remained suspended with fat globules. CONCLUSION: In healthy overweight men, casein has specific physical interactions with fat that affect postprandial TGs, leading to the formation of fewer chylomicrons or an increase in chylomicron clearance. This trial was registered at clinicaltrials.gov as NCT00931151. PMID- 26491120 TI - Household Food Insecurity is Associated with Childhood Asthma. AB - BACKGROUND: In 2013, 20% of U.S. households with children experienced food insecurity. Asthma afflicts over 7 million children; prevalence has steadily increased while incidence peaks in young children. Asthma and food insecurity share the determinants of poverty and race that are associated with weight, yet limited research on the relation between food insecurity and asthma exists. OBJECTIVE: The objective of this study was to determine the association between food insecurity and asthma in a diverse sample of children. METHODS: Cross sectional data from grade 3 of the Early Childhood Longitudinal Study Kindergarten Cohort were analyzed (n = 11,099). Food security based on the USDA module and asthma diagnosis were reported by parents; anthropometric factors were measured. Multivariate logistic regression models of food security and asthma were analyzed overall and by race/ethnicity. RESULTS: Children in food-insecure households had a 4% higher adjusted odds of asthma (95% CI: 1.02, 1.06). Adjusted odds of asthma were also higher by 70% for males (95% CI: 1.69, 1.71), 53% for non-Hispanic black (NHB) children (95% CI: 1.51, 1.54), 20% for Hispanic children (95% CI: 1.19, 1.21), 38% for overweight children (95% CI: 1.36, 1.39), 67% for obese children (95% CI: 1.65, 1.68), 23% for low-birth weight children (95% CI: 1.21, 1.24), 24% if mothers had a high school diploma (95% CI: 1.23, 1.26), and 33% if mothers had some college education (95% CI: 1.32, 1.35). High-birth weight children (OR: 0.84; 95% CI: 0.83, 0.85) and those with foreign-born mothers (OR: 0.52; 95% CI: 0.51, 0.53) had lower odds of asthma. Being food-insecure remained positively associated with asthma in non-Hispanic whites and Hispanics but was inversely associated with odds among NHBs. Odds of asthma doubled (OR: 2.00; 95% CI: 1.97, 2.03) for all children in households that were both food-insecure and poor; this relation remained positive in race/ethnicity-specific models. CONCLUSIONS: Food insecurity is positively associated with asthma in U.S. third graders, and household poverty strengthens the association. PMID- 26491121 TI - Dietary Sodium Butyrate Decreases Postweaning Diarrhea by Modulating Intestinal Permeability and Changing the Bacterial Communities in Weaned Piglets. AB - BACKGROUND: The vast majority of substances used as alternatives to antibiotics produce inconsistent results and rarely equal the effectiveness of in-feed antibiotics. OBJECTIVE: This study evaluated the effects of the combined use of sodium butyrate (SB) and reduced antibiotics in a piglet diet in promoting performance and to control weaning diarrhea. METHODS: Piglets weaned at 28 d were randomly assigned to a corn-soybean meal control ration [negative control (NC)]; a similar ration with 50 mg kitasamycin/kg, 20 mg colistin sulfate/kg, and 1000 mg encapsulated SB/kg [reduced antibiotics + SB (ASB)]; or to a ration with 100 mg kitasamycin/kg and 40 mg colistin sulfate/kg [positive control (PC)] for 28 d. Performance, diarrhea incidence, intestinal permeability, and changes in the bacterial communities in the ileum and colon were determined. RESULTS: Weight gain and the ratio of weight gain to feed intake were significantly greater in the ASB and PC piglets than in the NC piglets (P < 0.05). Diarrhea incidence was lower in the ASB and PC piglets than in the NC piglets (P < 0.05). Urinary lactulose to mannitol ratios were 25% and 30% lower, respectively, whereas jejunal and colonic occludin protein expressions were significantly greater in the ASB and PC piglets compared with the NC piglets (P < 0.05). In the intestinal mucosa, malondialdehyde was lower in the ASB and PC piglets (by 42% and 43%, respectively), whereas tumor necrosis factor alpha (TNF-alpha) was 63% lower in the ASB piglets and 59% lower in the PC piglets compared with the NC piglets (P < 0.05). 16S ribosomal RNA gene sequence analysis revealed a higher colonic Shannon index and a lower colonic Simpson index in the ASB and PC piglets than in the NC piglets. In addition, the ASB and PC treatments caused a striking decrease in Lactobacillaceae and a noticeable increase in Clostridiaceae in the ileal and colonic lumen, as well as increases in Ruminococcaceae, Lachnospiraceae, and Bacteroidetes in the colonic lumen. CONCLUSION: Collectively, our results support an important role for SB in improving performance and decreasing diarrhea incidence in weaned piglets by modulation of intestinal permeability and the bacterial communities in the ileum and colon. PMID- 26491122 TI - Promotion of Weight Gain in Early Childhood Does Not Increase Metabolic Risk in Adolescents: A 15-Year Follow-Up of a Cluster-Randomized Controlled Trial. AB - BACKGROUND: A rapid gain in weight for length may put children at a higher risk of noncommunicable diseases later in life. OBJECTIVE: The objective of this study was to assess the long-term effects of nutrition counseling delivered in the first 2 y of life in Pelotas, a city in Southern Brazil. METHODS: The original cluster-randomized controlled trial was conducted in 1998. Nutrition counseling (breastfeeding promotion and increased intake of micronutrient-rich and energy dense foods) was delivered to mothers of children aged 0-17.9 mo attending primary care. Six months later, weight gain was higher in the intervention group than in the control group for children >=12 mo of age at enrollment. In 2013 (mean age 15 y), assessments included anthropometric measurements, body composition (air-displacement plethysmography), body shape (3-dimensional photonic scan), and plasma total, LDL, and HDL cholesterol, triglycerides, C reactive protein, and glucose. RESULTS: A total of 363 of the 424 original participants were assessed. An a priori decision was made to prioritize analyses of subjects aged 12-17.9 mo at enrollment (51 from the intervention group and 45 from the control group). In this subgroup, boys in the intervention group were [mean (95% CI)] 3.4 (0.8, 6.0) cm taller than those in the control group. Systolic blood pressure tended to be 5.2 (-0.8, 11.1) mm Hg higher in male subjects from the intervention group than in those in the control group. Lipid profiles tended to be healthier in the intervention group. The plasma total cholesterol concentration was -17.8 (-29.8, -5.7) mg/dL lower in boys in the intervention group than in those in the control group. The total-to-HDL cholesterol ratio and triglyceride concentration in the girls in the intervention group were -0.4 (-0.6, -0.1) and -26.3 (-46.3, -6.3) mg/dL, respectively, lower than in the control group. There was no difference between the groups in terms of body composition. CONCLUSIONS: Promotion of weight gain in children between 12.0 17.9 mo of age was not associated with higher metabolic risk 15 y later. On the contrary, there was some evidence of reduced metabolic risk in the intervention group. PMID- 26491124 TI - Zinc Intake Is Associated with Lower Cadmium Burden in U.S. Adults. AB - BACKGROUND: Cadmium is a toxic transition metal whose absorption and accumulation might depend on zinc intake. OBJECTIVE: We sought to determine whether zinc intake and serum zinc would be inversely associated with cadmium exposure. METHODS: This study used data from NHANES 2003-2012, from which there were 6678 and 6488 participants with urinary and blood cadmium data, respectively, and 1195 participants with serum zinc data. Mean blood and urinary cadmium were reported by quintiles of zinc intake and by the dose and duration of zinc supplement use. The associations between zinc intake from diet and supplements, serum zinc, and blood and urinary cadmium were determined using multiple regression. Analyses were adjusted for age, body mass index, race/ethnicity, gender, income-to-poverty ratio, education, smoking status, and mean intakes of energy, calcium, and iron. RESULTS: Urinary cadmium concentrations were 0.04 MUg/g creatinine lower among participants in the highest compared with lowest quintile of total zinc intake (P trend = 0.0041). Zinc supplement dose and duration were inversely associated with blood cadmium (P = 0.0372) and serum zinc (P-trend = 0.0017), respectively. In adjusted regression models, a 10% increase in total zinc intake corresponded to a predicted decrease in blood cadmium of 0.42% (95% CI: -0.79%, -0.06%; P = 0.0260) and in urinary cadmium of 0.42% (95% CI: -0.81%, -0.04%; P = 0.0340). A 10% increase in serum zinc was associated with a predicted 1.99% (95% CI: -3.17%, 0.81%; P = 0.0012) decrease in blood cadmium and a predicted 4.09% (95% CI: 2.14%, 6.04%, P = 0.0001) increase in urinary cadmium. CONCLUSIONS: Dietary and serum zinc in US adults are associated with cadmium exposure, presumably by influencing the absorption and accumulation of cadmium. Whether the degree of reduction in cadmium exposure from greater zinc intake and status is causal or relevant from a public health perspective needs further investigation. PMID- 26491123 TI - Acidic Food pH Increases Palatability and Consumption and Extends Drosophila Lifespan. AB - BACKGROUND: Despite the prevalent use of Drosophila as a model in studies of nutrition, the effects of fundamental food properties, such as pH, on animal health and behavior are not well known. OBJECTIVES: We examined the effect of food pH on adult Drosophila lifespan, feeding behavior, and microbiota composition and tested the hypothesis that pH-mediated changes in palatability and total consumption are required for modulating longevity. METHODS: We measured the effect of buffered food (pH 5, 7, or 9) on male gustatory responses (proboscis extension), total food intake, and male and female lifespan. The effect of food pH on germfree male lifespan was also assessed. Changes in fly associated microbial composition as a result of food pH were determined by 16S ribosomal RNA gene sequencing. Male gustatory responses, total consumption, and male and female longevity were additionally measured in the taste-defective Pox neuro (Poxn) mutant and its transgenic rescue control. RESULTS: An acidic diet increased Drosophila gustatory responses (40-230%) and food intake (5-50%) and extended survival (10-160% longer median lifespan) compared with flies on either neutral or alkaline pH food. Alkaline food pH shifted the composition of fly associated bacteria and resulted in greater lifespan extension (260% longer median survival) after microbes were eliminated compared with flies on an acidic (50%) or neutral (130%) diet. However, germfree flies lived longer on an acidic diet (5-20% longer median lifespan) compared with those on either neutral or alkaline pH food. Gustatory responses, total consumption, and longevity were unaffected by food pH in Poxn mutant flies. CONCLUSIONS: Food pH can directly influence palatability and feeding behavior and affect parameters such as microbial growth to ultimately affect Drosophila lifespan. Fundamental food properties altered by dietary or drug interventions may therefore contribute to changes in animal physiology, metabolism, and survival. PMID- 26491125 TI - The Homozygous Hemoglobin EE Genotype and Chronic Inflammation Are Associated with High Serum Ferritin and Soluble Transferrin Receptor Concentrations among Women in Rural Cambodia. AB - BACKGROUND: Ferritin and soluble transferrin receptor (sTfR) concentrations are commonly used to assess iron deficiency (ID); however, they are influenced by multiple factors. OBJECTIVES: We assessed associations between numerous variables and both ferritin and sTfR concentrations in Cambodian women and compared ID prevalence through the use of study-generated correction factors (CFs) for ferritin with those from a published meta-analysis. METHODS: Venous blood from 450 women (aged 18-45 y) was assessed for hemoglobin (Hb), ferritin, sTfR, retinol binding protein, folate, vitamin B-12, C-reactive protein, alpha-1 acid glycoprotein (AGP), and genetic Hb disorders. Linear regression was used to calculate geometric mean ratios (95% CIs) for ferritin and sTfR concentrations. RESULTS: The variant Hb EE genotype was associated with 50% (14%, 96%) and 51% (37%, 66%) higher geometric mean ferritin and sTfR concentrations, respectively, than was the normal Hb AA genotype; a 1-g/L increase in AGP was associated with 99% (50%, 162%) and 48% (33%, 64%) higher concentrations in the same variables, respectively. ID prevalence in nonpregnant women (n = 420) was 2% (n = 9) with the use of ferritin <15 MUg/L and 18% (n = 79) with the use of sTfR >8.3 mg/L as criteria. ID prevalence with the use of sTfR was higher in women with the Hb EE genotype (n = 17; 55%) than in those with the Hb AA genotype (n = 20; 10%); and in women with the Hb AA genotype and chronic inflammation (n = 10; 18%) than in that group of women without chronic inflammation (n = 10; 7%) (P < 0.05). No differences in ID prevalence were found with the use of ferritin between women with Hb EE and AA genotypes (P = 1.0) or by chronic inflammation status (P = 0.32). There were no differences in mean ferritin concentrations among all 450 women when study-generated CFs were compared with those from the meta-analysis (P = 0.87). CONCLUSIONS: Compared with sTfR, ferritin concentrations appear to reflect more accurately true ID in rural Cambodian women. The CFs from a published meta-analysis were appropriate for use in this population with a high prevalence of Hb disorders and inflammation. PMID- 26491127 TI - Impact of Clinical Practice Guideline on the Treatment of Pediatric Femoral Fractures in a Pediatric Hospital. AB - BACKGROUND: Clinical practice guidelines are being developed for a number of topics in medicine to decrease practice variability and to improve evidenced based care. Within orthopaedic surgery, the American Academy of Orthopaedic Surgeons (AAOS) has a dedicated committee that produces these clinical practice guidelines on a variety of issues. One such issue was the treatment of pediatric diaphyseal femoral fractures, with the clinical practice guideline being published in 2009. We performed a retrospective review of the treatment of pediatric diaphyseal femoral fractures at a single institution from 2007 to 2012 to assess the clinical impact of this clinical practice guideline on the treatment of this condition. METHODS: A retrospective review of all patients treated at a single pediatric hospital between 2007 and 2012 for a pediatric diaphyseal femoral fracture was conducted. The 2009 AAOS clinical practice guideline on the treatment of this condition was assessed and each patient record was analyzed to determine if the clinical practice guideline was followed, based on the age-specific recommendations. The percentage of treatment rendered adhering to the clinical practice guideline recommendations was compared in the pre-guideline group (prior to June 2009) and the post-guideline group (after June 2009). RESULTS: A total of 361 patients were treated for a diaphyseal femoral fracture during this time frame and were included in this study. Overall, little change in treatment was found following the publication of this clinical practice guideline. The only significant change noted over this time period was a decrease (p = 0.03) in the percentage of patients between the ages of five and eleven years who were treated with flexible nails, at odds with this specific clinical practice guideline recommendation. CONCLUSIONS: We found little direct clinical impact of the recently published AAOS clinical practice guideline on the treatment of pediatric diaphyseal femoral fractures. This analysis suggests an important role for clinical assessment after guideline publication to identify areas of potentially important future clinical research and to assess the utility of this guideline. PMID- 26491126 TI - Development and Use of a Traditional Mexican Diet Score in Relation to Systemic Inflammation and Insulin Resistance among Women of Mexican Descent. AB - BACKGROUND: Women of Mexican descent are disproportionally affected by obesity, systemic inflammation, and insulin resistance (IR). Available approaches used to give scores to dietary patterns relative to dietary guidelines may not effectively capture traditional diets of Mexicans, who comprise the largest immigrant group in the United States. OBJECTIVES: We characterized an a priori traditional Mexican diet (MexD) score high in corn tortillas, beans, soups, Mexican mixed dishes (e.g., tamales), fruits, vegetables, full-fat milk, and Mexican cheeses and low in refined grains and added sugars and evaluated the association of the MexD score with systemic inflammation and IR in 493 postmenopausal participants in the Women's Health Initiative (WHI) who are of Mexican ethnic descent. METHODS: The MexD score was developed from the baseline (1993-1998) WHI food frequency questionnaire, which included Hispanic foods and was available in Spanish. Body mass index (BMI) was computed from baseline measured weight and height, and ethnicity was self-reported. Outcome variables were high sensitivity C-reactive protein (hsCRP), glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride concentrations measured at follow-up (2012-2013). Multivariable linear and logistic regression models were used to test the associations of the MexD score with systemic inflammation and IR. RESULTS: The mean +/- SD MexD score was 5.8 +/- 2.1 (12 maximum points) and was positively associated with intakes of carbohydrates, vegetable protein, and dietary fiber and inversely associated with intakes of added sugars and total fat (P < 0.01). Women with high compared with low MexD scores, consistent with a more-traditional Mexican diet, had 23% and 15% lower serum hsCRP (P < 0.05) and insulin concentrations, respectively (P < 0.05). Baseline BMI modified these associations such that lower MexD scores were associated with higher insulin and HOMA-IR in overweight/obese women (P interaction <0.05). CONCLUSION: These findings suggest that greater adherence to a traditional Mexican diet could help reduce the future risk of systemic inflammation and IR in women of Mexican descent. PMID- 26491129 TI - Glenoid Bone-Grafting in Revision to a Reverse Total Shoulder Arthroplasty. AB - BACKGROUND: Revision of a shoulder arthroplasty to a reverse shoulder arthroplasty in the presence of glenoid bone loss is especially challenging. The purpose of the present study was to determine the complications and results of glenoid bone-grafting in revision to a reverse shoulder arthroplasty. METHODS: Between 2005 and 2010, 143 consecutive reverse shoulder arthroplasties performed as revision procedures were performed at our institution. Glenoid bone-grafting was performed in forty-one shoulders (29%), with 98% (forty) that had follow-up of more than two years (mean, 3.1 years). The 102 patients who did not undergo grafting served as a control group. RESULTS: Seven patients (18%) required another revision surgery because of glenoid loosening (four patients), instability (two patients), or infection (one patient). The two and five-year implant survival rate free of revision for shoulders that had glenoid bone grafting was 88% and 76%, respectively, which was lower than that for patients who had not required glenoid bone-grafting. The survival rate free of radiographic glenoid loosening at two and five years for the shoulders that had bone-grafting was 92% and 89%, respectively, which was worse than that for those that had not had glenoid bone-grafting. Patients had significant pain relief and improvement in their shoulder range of motion, and they had an increased level of satisfaction compared with the preoperative status. Increased rates of glenoid loosening were seen in patients who had an increased body mass index, an implant with a lateral center of rotation, a previous total shoulder replacement (versus hemiarthroplasty), and in those who were smokers. CONCLUSIONS: Although there were relatively high rates of glenoid loosening and reoperation at mid-term follow-up, glenoid reconstruction with bone graft in the revision setting was able to relieve pain and restore shoulder function and stability. PMID- 26491128 TI - Subacromial Space Width: Does Overuse or Genetics Play a Greater Role in Determining It? An MRI Study on Elderly Twins. AB - BACKGROUND: Age and peripheral microcirculation disorders are the main causes of rotator cuff degeneration. Acromion variants may affect subacromial space width, causing a pathological narrowing of the space that may compromise the cuff integrity. However, it is not clear if the subacromial space width is genetically determined or if it changes according to loading conditions. To clarify this unresolved question, we performed an MRI (magnetic resonance imaging) study with the aim of evaluating the acromiohumeral distance in a group of elderly monozygotic and dizygotic twins, and we analyzed the obtained data using the twin design to separate the contributions of shared and unique environments. METHODS: We identified twenty-nine pairs of elderly twins. On MRI scans, we evaluated the acromiohumeral distance and health status of the rotator cuff tendons. Heritability, defined as the proportion of total variance of a specific characteristic in a particular population due to a genetic cause, was estimated as twice the difference between the intraclass correlation coefficients for monozygotic and dizygotic pairs. The influence of shared environment, due to environmental factors that contribute to twin and sibling similarity, was calculated as the difference between the monozygotic correlation coefficient and the heritability index. One-way ANOVA (analysis of variance) was used to estimate the differences among job categories, both in the total cohort and within zygosity groups. RESULTS: The intraclass correlation coefficient was substantially higher for monozygotic than for dizygotic twins, indicating a high degree of concordance of the acromiohumeral distance in pairs of individuals who shared 100% of their genes. The heritability index was 0.82, and shared and unique environmental contributions were both 0.09. There were no significant differences among subjects in different job categories, either in the total cohort (p = 0.685) or within the monozygotic (p = 0.719) and dizygotic groups (p = 0.957). CONCLUSIONS: The acromiohumeral distance is mainly genetically determined and only marginally influenced by external factors. PMID- 26491130 TI - Lumbar Spine Surgery in Patients with Parkinson Disease. AB - BACKGROUND: Parkinson disease is the second most common neurodegenerative condition. The literature on patients with Parkinson disease and spine surgery is limited, but increased complications have been reported. METHODS: All patients with Parkinson disease undergoing lumbar spine surgery between 2002 and 2012 were identified. Patients' charts, radiographs, and outcome questionnaires were reviewed. Parkinson disease severity was assessed with use of the modified Hoehn and Yahr staging scale. Complications and subsequent surgeries were analyzed. Risk for reoperation was assessed. RESULTS: Ninety-six patients underwent lumbar spine surgery. The mean patient age was 63.0 years. The mean follow-up duration was 30.1 months. The Parkinson disease severity stage was <2 in thirteen patients, 2 in thirty patients, 2.5 in twenty-three patients, and >=3 in thirty patients. The primary indication for surgery was spinal stenosis in seventy-two patients, spondylolisthesis in seventeen patients, and coronal and/or sagittal deformity in seven patients. There were nineteen early complications, including postoperative infections requiring surgical irrigation and debridement and long term antibiotics in ten patients. The visual analog scale for back pain improved from 7.4 cm preoperatively to 1.8 cm postoperatively (p < 0.001). The visual analog scale for lower-limb pain improved from 7.7 cm preoperatively to 2.3 cm postoperatively (p < 0.001). The Oswestry Disability Index score dropped from 54.1 points to 17.7 points at the time of the latest follow-up (p < 0.001). The Short Form-12 Physical Component Summary score improved from 26.6 points preoperatively to 30.5 points postoperatively (p < 0.05). Twenty patients required revision surgery. Risks for further surgery included a Parkinson disease severity stage of >=3 (p < 0.05), a history of diabetes mellitus, treatment for osteoporosis, and a combined anterior and posterior approach. CONCLUSIONS: Despite a higher rate of complications than in the general population, the overall outcome of spine surgery in patients with mild to moderate Parkinson disease is good, with improvement of spine-related pain. A larger prospective study is warranted. PMID- 26491131 TI - Impact of Spinous Process Integrity on Ten to Twelve-Year Outcomes After Posterior Decompression for Lumbar Spinal Stenosis: Study of Open-Door Laminoplasty Using a Spinous Process-Splitting Approach. AB - BACKGROUND: In posterior decompression for lumbar spinal stenosis, preservation of the posterior elements appears to provide patients with long-term favorable outcomes. To confirm this assumption, we evaluated the impact of spinous process integrity, i.e., osseous continuity between the spinous process and the lamina, on short to long-term outcomes. METHODS: As a model for the study of spinous process integrity, we retrospectively reviewed the cases of forty-eight patients who underwent open-door laminoplasty using a spinous process-splitting approach without disrupting attachment sites of the multifidus muscle. In those patients, thirty-nine of the 103 spinous processes achieved spontaneous osseous union with the laminar flap, while the others did not achieve osseous union. The association between the number of ununited spinous processes, as well as baseline characteristics, and the outcomes were analyzed by primary and fully adjusted multivariate linear regression. Outcome measures were the Oswestry Disability Index (ODI) and a numeric rating scale (NRS) for symptoms at two, four, and ten to twelve years. RESULTS: The number of ununited spinous processes was significantly associated with ten to twelve-year scores for the ODI (beta = 0.24, p = 0.030), low back pain NRS (beta = 0.32, p = 0.030), and leg pain NRS (beta = 0.50, p = 0.0012) in the fully adjusted models, but was not associated with two or four-year scores for each scale. The number of decompression levels was significantly associated with ten to twelve-year scores for low back pain and leg pain NRS in the primary models, but was not retained in the fully adjusted models. CONCLUSIONS: Osseous continuity between the spinous processes and the lamina after posterior decompression of the lumbar spine is important for maintaining the positive surgical benefit. Deleterious effects of osseous discontinuity on the outcomes were obvious at ten to twelve years, but not at two or four years. PMID- 26491132 TI - Native Knee Laxities at 0 degrees , 45 degrees , and 90 degrees of Flexion and Their Relationship to the Goal of the Gap-Balancing Alignment Method of Total Knee Arthroplasty. AB - BACKGROUND: Gap-balancing is an alignment method for total knee arthroplasty with the goal of creating uniform tension in the periarticular soft-tissue restraints and equal laxities throughout the arc of flexion. However, there is little evidence that achieving equal laxities prevents either overly tight or overly loose soft-tissue restraints after total knee arthroplasty. Accordingly, the purpose of the present study was to determine whether the laxities at 0 degrees , 45 degrees , and 90 degrees of flexion are equal in the native knee. METHODS: Seven different laxities were measured at 0 degrees , 45 degrees , and 90 degrees of flexion in ten fresh-frozen native cadaveric knees (with intact menisci, cartilage, and ligaments) by applying loads of +/-5 Nm in varus-valgus rotation, +/-3 Nm in internal-external rotation, 100 N in distraction, and +/-45 N in anterior-posterior translation with use of a six-degrees-of-freedom load application system. RESULTS: The mean laxities (and standard deviations) at 45 degrees of flexion were 1.7 degrees +/- 0.6 degrees greater in varus, 0.9 degrees +/- 0.4 degrees greater in valgus, 10.2 degrees +/- 2.7 degrees greater in internal rotation, 10.1 degrees +/- 2.0 degrees greater in external rotation, 1.7 +/- 1.0 mm greater in distraction translation, and 3.3 +/- 1.5 mm greater in anterior translation than those at 0 degrees of flexion. The mean laxities at 90 degrees of flexion were 2.5 degrees +/- 0.8 degrees greater in varus, 1.0 degrees +/- 0.5 degrees greater in valgus, 10.0 degrees +/- 4.6 degrees greater in internal rotation, 10.1 degrees +/- 4.5 degrees greater in external rotation, 1.8 +/- 0.7 mm greater in distraction, and 1.6 +/- 1.2 mm greater in anterior translation than those at 0 degrees of flexion. The mean anterior translation at 90 degrees of flexion was 1.7 +/- 0.9 mm less than that at 45 degrees of flexion. CONCLUSIONS: Because five of the seven laxities were at least 1.7 degrees or 1.6 mm greater at both 45 degrees and 90 degrees of flexion than those at 0 degrees of flexion, the laxities of the native knee measured in this study are unequal at these flexion angles and therefore do not support the goal of gap-balancing in total knee arthroplasty. CLINICAL RELEVANCE: One possible disadvantage of changing the native laxities at 45 degrees and 90 degrees of flexion to match those at 0 degrees of flexion in a total knee arthroplasty is the overly tight soft-tissue restraints relative to those of the native knee, which patients may perceive as pain, stiffness, and/or limited flexion. PMID- 26491133 TI - 25-Hydroxyvitamin-D and Bone Turnover Marker Levels in Patients with Distal Radial Fracture. AB - BACKGROUND: Fragility fractures are a major public health issue with substantial socioeconomic cost. Vitamin-D deficiency and increased bone turnover are associated with higher rates of bone loss and an increased risk of fracture. We hypothesized that patients with a distal radial fracture would have lower levels of 25-hydroxyvitamin D (25[OH]D) and increased levels of serum bone turnover markers than controls without a fracture. METHODS: Postmenopausal women with a recent distal radial fracture (fracture group, n = 105) were prospectively recruited and were compared with individuals without a fracture (control group, n = 150). Outcome variables included serum levels of 25(OH)D and markers of bone formation, including N-terminal extension propeptide of type-I collagen (P1NP), parathyroid hormone (PTH), bone-specific alkaline phosphatase (BSAP), and osteocalcin, as well as a marker of resorption (C-terminal telopeptide of type-I collagen [CTX-1]). Bone mineral density was measured with dual x-ray absorptiometry. RESULTS: The fracture group was slightly older than the control group (mean and standard deviation [SD], 66.8 +/- 10.8 years versus 63.3 +/- 9.0 years, p = 0.008), had a lower body mass index (26.4 +/- 5.9 kg/m(2) versus 28.0 +/- 6.2 kg/m(2), p = 0.05), and more commonly had had a prior fracture (52% versus 31%, p < 0.001). Bone mineral density at the hip was lower in the fracture group than in the control group (0.831 +/- 0.130 g/cm(2) versus 0.917 +/- 0.139 g/cm(2), p < 0.001). The mean 25(OH)D levels were similar in the fracture and control groups (44.4 +/- 14.6 ng/mL versus 41.3 +/- 14.5 ng/mL, p = 0.08). Levels of serum markers of bone formation were significantly higher in the fracture group than in the control group (P1NP: 70.4 +/- 33.2 ng/mL versus 53.2 +/- 25.6 ng/mL, p < 0.001; osteocalcin: 22.3 +/- 9.9 ng/mL versus 20.2 +/- 9.2 ng/mL, p = 0.017). Levels of BSAP, PTH, and CTX-1 were similar in the two groups. Multivariable logistic regression showed independent associations between a distal radial fracture and low total hip bone mineral density (odds ratio [OR] = 2.02 for each decrease of 1 SD, 95% confidence interval [CI] = 1.38 to 3.01, p < 0.001) and a high P1NP level (OR = 2.17 for each 1-SD increase, 95% CI = 1.52 to 3.06, p < 0.001). CONCLUSIONS: In this cohort, 25(OH)D levels were not associated with distal radial fracture and do not appear to affect the risk assessment for distal radial fracture in postmenopausal women. Patients with a distal radial fracture, however, had increased bone turnover as evidenced by high P1NP and osteocalcin levels. Women with both a high P1NP level and low bone mineral density were at particularly high risk for fracture. PMID- 26491134 TI - Defining the "Three-Dimensional Sagittal Plane" in Thoracic Adolescent Idiopathic Scoliosis. AB - BACKGROUND: Obtaining accurate measurements of scoliosis from two-dimensional (2 D) radiographs can be challenging because of the three-dimensional (3-D) nature of the deformity. Previous studies have shown that the sagittal plane, in particular, is misrepresented on 2-D radiographs because of the influence of axial plane rotation. The purpose of the current study was to define a methodology for measuring the 3-D segmental sagittal alignment of the spine in patients with adolescent idiopathic scoliosis (AIS) and to assess the effect of axial plane rotation on differences between 3-D and 2-D measures of deformity. METHODS: Preoperative and postoperative EOS images of 120 consecutive patients with AIS (primary thoracic curves) treated with segmental thoracic pedicle-screw instrumentation were analyzed in the "3-D sagittal plane." The technique measured 3-D kyphosis or lordosis in the specific plane of sagittal motion for each spinal motion segment. The kyphosis (+) and lordosis (-) values of the segments from T5 to T12 were summed to give the 3-D measurement of T5-T12 kyphosis. These values were compared with the standard 2-D measurements of T5-T12 kyphosis on lateral radiographs, and a correlation analysis with regard to axial plane rotation of the apex was performed. RESULTS: The average age (and standard deviation) of the patients was 14 +/- 2 years. The mean preoperative Cobb angle on the standard 2-D view was 55 degrees +/- 10 degrees and on the 3-D view was 52 degrees +/- 9 degrees (p <= 0.001). On the 3-D view, the mean preoperative T5-T12 kyphosis was 6 degrees +/- 14 degrees , and the kyphosis significantly increased to 26 degrees +/- 6 degrees postoperatively (p < 0.001). The T5-T12 kyphosis on the standard 2-D view measured 18 degrees +/- 13 degrees preoperatively and 27 degrees +/- 6 degrees postoperatively (p < 0.001). The difference between the 2 D and 3-D measurements of T5-T12 kyphosis strongly correlated with apical vertebral rotation (r = 0.85; p < 0.01). CONCLUSIONS: Routine 2-D measurements of thoracic kyphosis erroneously underestimate the preoperative loss of kyphosis in AIS because of errors associated with axial plane rotation, an inherent component of thoracic scoliosis. PMID- 26491135 TI - SF-36 Mental Component Summary (MCS) Score Does Not Predict Functional Outcome After Surgery for End-Stage Ankle Arthritis. AB - BACKGROUND: Mental health status has been shown to influence functional outcome in a number of orthopaedic disorders. The purpose of this retrospective cohort study was to assess whether a diminished baseline Mental Component Summary (MCS) score on the Short Form-36 (SF-36) is predictive of less improvement in the Ankle Osteoarthritis Scale (AOS) score at the time of midterm follow-up after arthroplasty or arthrodesis for end-stage ankle arthritis. METHODS: Preoperative and postoperative patient scores on the SF-36 MCS and AOS questionnaires were obtained from the Canadian Orthopaedic Foot and Ankle Society (COFAS) End-Stage Ankle Arthritis Database. The relationship between the preoperative MCS score and the change in the total AOS score at the time of final follow-up was summarized with use of a Pearson correlation coefficient (r). Subgroup analyses according to the type of treatment (ankle arthrodesis versus ankle arthroplasty) and preoperative MCS score (<50 versus >=50) were conducted. RESULTS: Of an initial 372 ankles enrolled, 337 (91%, ninety-five arthrodeses and 242 arthroplasties) were reviewed after a mean duration of follow-up of 5.2 +/- 1.3 years. Analysis revealed no correlation between the preoperative MCS score and the change in the AOS score, from the preoperative baseline to either a mean 5.2 years postoperatively or two years postoperatively (r < 0.1 in both analyses). There was no difference in the change in the AOS score between patients with a preoperative MCS score of <50 and those with a preoperative MCS score of >=50. CONCLUSIONS: In our study of patients with end-stage ankle arthritis treated with arthroplasty or arthrodesis, preoperative mental health status (as measured with the MCS score) did not predict functional outcome (as measured by the change in the AOS score) at the time of intermediate-term postoperative follow-up. AOS scores improved for all patients, regardless of the preoperative MCS score. PMID- 26491136 TI - Scapular Winging: Evaluation and Treatment: AAOS Exhibit Selection. AB - Scapular winging is a rare, underreported, and debilitating disorder that produces abnormal scapulothoracic kinematics, which can lead to shoulder weakness, decreased range of motion, and substantial pain. Although there are numerous underlying etiologies, injuries to the long thoracic nerve or spinal accessory nerve are the most common, with resultant neuromuscular imbalance in the scapulothoracic stabilizing muscles. Early diagnosis followed by initiation of a treatment algorithm is important for successful outcomes. Most cases resolve with nonsurgical management. However, in patients with persistent symptoms despite nonsurgical management, appropriate dynamic muscle transfers can effectively treat the scapular winging, with good clinical outcomes. PMID- 26491137 TI - The American Academy of Orthopaedic Surgeons Evidence-Based Guideline on Detection and Nonoperative Management of Pediatric Developmental Dysplasia of the Hip in Infants up to Six Months of Age. PMID- 26491138 TI - What's New in Shoulder and Elbow Surgery? PMID- 26491139 TI - Is It All in the Genes? Commentary on an article by S. Gumina, MD, PhD, et al.: "Subacromial Space Width: Does Overuse or Genetics Play a Greater Role in Determining It? An MRI Study on Elderly Twins". PMID- 26491140 TI - No Bone? No Problem! Is Bone-Grafting at the Time of Revision to a Reverse Shoulder Arthroplasty a Reasonable Option? Commentary on an article by Eric Wagner, MD, et al.: "Glenoid Bone-Grafting in Revision to a Reverse Total Shoulder Arthroplasty". PMID- 26491141 TI - A Fresh Look at Soft-Tissue Balancing: Commentary on an article by Joshua D. Roth, MS, et al.: "Native Knee Laxities at 0 degrees , 45 degrees , and 90 degrees of Flexion and Their Relationship to the Goal of the Gap-Balancing Alignment Method of Total Knee Arthroplasty". PMID- 26491142 TI - Efficacy of flavonoids in the management of high blood pressure. AB - Plant compounds such as flavonoids have been reported to exert beneficial effects in cardiovascular disease, including hypertension. Information on the effects of isolated individual flavonoids for management of high blood pressure, however, is more limited. This review is focused on the flavonoids, as isolated outside of the food matrix, from the 5 main subgroups consumed in the Western diet (flavones, flavonols, flavanones, flavan-3-ols, and anthocyanins), along with their effects on hypertension, including the potential mechanisms for regulating blood pressure. Flavonoids from all 5 subgroups have been shown to attenuate a rise in or to reduce blood pressure during several pathological conditions (hypertension, metabolic syndrome, and diabetes mellitus). Flavones, flavonols, flavanones, and flavanols were able to modulate blood pressure by restoring endothelial function, either directly, by affecting nitric oxide levels, or indirectly, through other pathways. Quercetin had the most consistent blood pressure-lowering effect in animal and human studies, irrespective of dose, duration, or disease status. However, further research on the safety and efficacy of the flavonoids is required before any of them can be used by humans, presumably in supplement form, at the doses required for therapeutic benefit. PMID- 26491143 TI - Clinical and laboratory characteristics of acute myeloid leukaemia (AML) at relapse and the risk of acute incapacitation. PMID- 26491144 TI - Long-term exposure to diesel engine exhaust induces primary DNA damage: a population-based study. AB - OBJECTIVES: Diesel engine exhaust (DEE) is a ubiquitous environmental pollutant and is carcinogenic to humans. To seek early and sensitive biomarkers for prediction of adverse health effects, we analysed the components of DEE particles, and examined the genetic and oxidative damages in DEE-exposed workers. METHODS: 101 male diesel engine testing workers who were constantly exposed to DEE and 106 matched controls were enrolled in the present study. The components of DEE were analysed, including fine particulate matter (PM2.5), element carbon (EC), nitrogen dioxide (NO2), sulfur dioxide (SO2) and polycyclic aromatic hydrocarbons (PAHs). Postshift urine samples were collected and analysed for 1 hydroxypyrene (1-OHP), an internal exposure marker for DEE. Levels of DNA strand breaks and oxidised purines, defined as formamidopyrimidine-DNA glycosylase (FPG) sites in leucocytes, were measured by medium throughput Comet assay. Urinary 8 hydroxy-2'-deoxyguanosine (8-OHdG) was also used to determine the level of oxidative stress. RESULTS: We found higher levels of PM2.5, EC, NO2, SO2 and PAHs in the diesel engine testing workshop and significantly higher urinary 1-OHP concentrations in exposed subjects (p<0.001). Compared with controls, the levels of parameters in normal Comet and FPG-Comet assay were all significantly higher in DEE-exposed workers (p<0.001), and in a dose-dependent and time-dependent manner. There were no significant differences between DEE-exposed workers and controls in regard to leucocyte FPG sensitive sites and urinary 8-OHdG levels. CONCLUSIONS: These findings suggest that DEE exposure mainly induces DNA damage, which might be used as an early biomarker for risk assessment of DEE exposure. PMID- 26491145 TI - ABA Regulates Subcellular Redistribution of OsABI-LIKE2, a Negative Regulator in ABA Signaling, to Control Root Architecture and Drought Resistance in Oryza sativa. AB - The phytohormone ABA is a key stress signal in plants. Although the identification of ABA receptors led to significant progress in understanding the Arabidopsis ABA signaling pathway, there are still many unsolved mysteries regarding ABA signaling in monocots, such as rice. Here, we report that a rice ortholog of AtABI1 and AtABI2, named OsABI-LIKE2 (OsABIL2), plays a negative role in rice ABA signaling. Overexpression of OsABIL2 not only led to ABA insensitivity, but also significantly altered plant developmental phenotypes, including stomatal density and root architecture, which probably caused the hypersensitivity to drought stress. OsABIL2 interacts with OsPYL1, SAPK8 and SAPK10 both in vitro and in vivo, and the phosphatase activity of OsABIL2 was repressed by ABA-bound OsPYL1. However, unlike many other solely nuclear localized clade A type 2C protein phosphatases (PP2Cs), OsABIL2 is localized in both the nucleus and cytosol. Furthermore, OsABIL2 interacts with and co localized with OsPYL1 mainly in the cytosol, and ABA treatment regulates the nucleus-cytosol distribution of OsABIL2, suggesting a different mechanism for the activation of ABA signaling. Taken together, this study provides significant insights into rice ABA signaling and indicates the important role of OsABIL2 in regulating root development. PMID- 26491146 TI - LEAFY COTYLEDON1-CASEIN KINASE I-TCP15-PHYTOCHROME INTERACTING FACTOR4 Network Regulates Somatic Embryogenesis by Regulating Auxin Homeostasis. AB - Somatic embryogenesis (SE) is an efficient tool for the propagation of plant species and also, a useful model for studying the regulatory networks in embryo development. However, the regulatory networks underlying the transition from nonembryogenic callus to somatic embryos during SE remain poorly understood. Here, we describe an upland cotton (Gossypium hirsutum) CASEIN KINASE I gene, GhCKI, which is a unique key regulatory factor that strongly affects SE. Overexpressing GhCKI halted the formation of embryoids and plant regeneration because of a block in the transition from nonembryogenic callus to somatic embryos. In contrast, defective GhCKI in plants facilitated SE. To better understand the mechanism by which GhCKI regulates SE, the regulatory network was analyzed. A direct upstream negative regulator protein, cotton LEAFY COTYLEDON1, was identified to be targeted to a cis-element, CTTTTC, in the promoter of GhCKI. Moreover, GhCKI interacted with and phosphorylated cotton CINCINNATA-like TEOSINTE BRANCHED1-CYCLOIDEA-PCF transcription factor15 by coordinately regulating the expression of cotton PHYTOCHROME INTERACTING FACTOR4, finally disrupting auxin homeostasis, which led to increased cell proliferation and aborted somatic embryo formation in GhCKI-overexpressing somatic cells. Our results show a complex process of SE that is negatively regulated by GhCKI through a complex regulatory network. PMID- 26491147 TI - Four Isoforms of Arabidopsis 4-Coumarate:CoA Ligase Have Overlapping yet Distinct Roles in Phenylpropanoid Metabolism. AB - The biosynthesis of lignin, flavonoids, and hydroxycinnamoyl esters share the first three enzymatic steps of the phenylpropanoid pathway. The last shared step is catalyzed by 4-coumarate:CoA ligase (4CL), which generates p-coumaroyl CoA and caffeoyl CoA from their respective acids. Four isoforms of 4CL have been identified in Arabidopsis (Arabidopsis thaliana). Phylogenetic analysis reveals that 4CL1, 4CL2, and 4CL4 are more closely related to each other than to 4CL3, suggesting that the two groups may serve different biological functions. Promoter GUS analysis shows that 4CL1 and 4CL2 are expressed in lignifying cells. In contrast, 4CL3 is expressed in a broad range of cell types, and 4CL3 has acquired a distinct role in flavonoid metabolism. Sinapoylmalate, the major hydroxycinnamoyl ester found in Arabidopsis, is greatly reduced in the 4cl1 4cl3 mutant, showing that 4CL1 and 4CL3 function redundantly in its biosynthesis. 4CL1 accounts for the majority of the total 4CL activity, and loss of 4CL1 leads to reduction in lignin content but no growth defect. The 4cl1 4cl2 and 4cl1 4cl2 4cl3 mutants are both dwarf but do not have further reduced lignin than the 4cl1 mutant, indicating that either 4CL1 or 4CL2 is required for normal plant growth. Although 4CL4 has a limited expression profile, it does make a modest contribution to lignin biosynthesis. Together, these data show that the four isoforms of 4CL in Arabidopsis have overlapping yet distinct roles in phenylpropanoid metabolism. PMID- 26491148 TI - Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection. AB - CD4 T cells provide protection against cytomegalovirus (CMV) and other persistent viruses, and the ability to quantify and characterize epitope-specific responses is essential to gain a more precise understanding of their effector roles in this regard. Here, we report the first two I-A(d)-restricted CD4 T cell responses specific for mouse CMV (MCMV) epitopes and use a major histocompatibility complex class II (MHC-II) tetramer to characterize their phenotypes and functions. We demonstrate that MCMV-specific CD4 T cells can express high levels of granzyme B and kill target cells in an epitope- and organ-specific manner. In addition, CD4 T cell epitope vaccination of immunocompetent mice reduced MCMV replication in the same organs where CD4 cytotoxic T lymphocyte (CTL) activity was observed. Together, our studies show that MCMV epitope-specific CD4 T cells have the potential to mediate antiviral defense by multiple effector mechanisms in vivo. IMPORTANCE: CD4 T cells mediate immune protection by using their T cell receptors to recognize specific portions of viral proteins, called epitopes, that are presented by major histocompatibility complex class II (MHC-II) molecules on the surfaces of professional antigen-presenting cells (APCs). In this study, we discovered the first two epitopes derived from mouse cytomegalovirus (MCMV) that are recognized by CD4 T cells in BALB/c mice, a mouse strain commonly used to study the pathogenesis of this virus infection. Here, we report the sequences of these epitopes, characterize the CD4 T cells that recognize them to fight off MCMV infection, and show that we can use the epitopes to vaccinate mice and protect against MCMV. PMID- 26491149 TI - Defensive Perimeter in the Central Nervous System: Predominance of Astrocytes and Astrogliosis during Recovery from Varicella-Zoster Virus Encephalitis. AB - Varicella-zoster virus (VZV) is a highly neurotropic virus that can cause infections in both the peripheral nervous system and the central nervous system. Several studies of VZV reactivation in the peripheral nervous system (herpes zoster) have been published, while exceedingly few investigations have been carried out in a human brain. Notably, there is no animal model for VZV infection of the central nervous system. In this report, we characterized the cellular environment in the temporal lobe of a human subject who recovered from focal VZV encephalitis. The approach included not only VZV DNA/RNA analyses but also a delineation of infected cell types (neurons, microglia, oligodendrocytes, and astrocytes). The average VZV genome copy number per cell was 5. Several VZV regulatory and structural gene transcripts and products were detected. When colocalization studies were performed to determine which cell types harbored the viral proteins, the majority of infected cells were astrocytes, including aggregates of astrocytes. Evidence of syncytium formation within the aggregates included the continuity of cytoplasm positive for the VZV glycoprotein H (gH) fusion-complex protein within a cellular profile with as many as 80 distinct nuclei. As with other causes of brain injury, these results suggested that astrocytes likely formed a defensive perimeter around foci of VZV infection (astrogliosis). Because of the rarity of brain samples from living humans with VZV encephalitis, we compared our VZV results with those found in a rat encephalitis model following infection with the closely related pseudorabies virus and observed similar perimeters of gliosis. IMPORTANCE: Investigations of VZV-infected human brain from living immunocompetent human subjects are exceedingly rare. Therefore, much of our knowledge of VZV neuropathogenesis is gained from studies of VZV-infected brains obtained at autopsy from immunocompromised patients. These are not optimal samples with which to investigate a response by a human host to VZV infection. In this report, we examined both flash-frozen and paraffin-embedded formalin-fixed brain tissue of an otherwise healthy young male with focal VZV encephalitis, most likely acquired from VZV reactivation in the trigeminal ganglion. Of note, the cellular response to VZV infection mimicked the response to other causes of trauma to the brain, namely, an ingress of astrocytes and astrogliosis around an infectious focus. Many of the astrocytes themselves were infected; astrocytes aggregated in clusters. We postulate that astrogliosis represents a successful defense mechanism by an immunocompetent human host to eliminate VZV reactivation within neurons. PMID- 26491150 TI - Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Perturbs the G1-S Cell Cycle Progression via Deregulation of the cyclin D1 Gene. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) infection modulates the host cell cycle to create an environment optimal for its viral-DNA replication during the lytic life cycle. We report here that KSHV vIRF4 targets the beta-catenin/CBP cofactor and blocks its occupancy on the cyclin D1 promoter, suppressing the G1-S cell cycle progression and enhancing KSHV replication. This shows that KSHV vIRF4 suppresses host G1-S transition, possibly providing an intracellular milieu favorable for its replication. PMID- 26491152 TI - Low-Level Expression of the E1B 20-Kilodalton Protein by Adenovirus 14p1 Enhances Viral Immunopathogenesis. AB - Adenovirus 14p1 (Ad14p1) is an emergent variant of Ad serotype 14 (Ad14) that has caused increased severity of respiratory illnesses during globally distributed outbreaks, including cases of acute respiratory distress syndrome and death. We found that human cell infection with Ad14p1 results in markedly decreased expression of the E1B 20-kilodalton (20K) protein compared to that with infection with wild-type (wt) Ad14. This reduced Ad14p1 E1B 20K expression caused a loss-of function phenotype of Ad-infected cell corpses that, in contrast to cells infected with wt Ad14, either failed to repress or increased NF-kappaB-dependent, proinflammatory cytokine responses of responder human alveolar macrophages. A small-animal model of Ad14-induced lung infection was used to test the translational relevance of these in vitro observations. Intratracheal infection of Syrian hamsters with Ad14p1 caused a marked, patchy bronchopneumonia, whereas hamster infection with wt Ad14 caused minimal peribronchial inflammation. These results suggest that this difference in E1B 20K gene expression during Ad14p1 infection and its modulating effect on the interactions between Ad14-infected cells and the host innate immune response could explain the increased immunopathogenic potential and associated increase in clinical illness in some people infected with the Ad14p1 outbreak strain.IMPORTANCE We previously reported that Ad-infected human cells exhibit E1B 19K-dependent repression of virally induced, NF-kappaB-dependent macrophage cytokine responses (J. R. Radke, F. Grigera, D. S. Ucker, and J. L. Cook, J Virol 88:2658-2669, 2014, http://dx.doi.org/10.1128/JVI.02372-13). The more virulent, emergent strain of Ad14, Ad14p1, causes increased cytopathology in vitro, which suggested a possible E1B 20K defect. Whether there is a linkage between these observations was unknown. We show that there is markedly reduced expression of E1B 20K in Ad14p1 infected human cells and that this causes an increased proinflammatory cytokine response of human alveolar macrophages and more severe inflammatory lung disease in infected hamsters. This is the first evidence of a clinical relevance of differential expression of the small Ad E1B gene product. The results suggest that there is a low, critical threshold of E1B 19/20K expression that is needed for viral replication and infection transmission but that a higher level of E1B 19/20K expression is required for the usual repression and control of the Ad triggered host innate immune response. PMID- 26491151 TI - gammadelta T Cells Play a Protective Role in Chikungunya Virus-Induced Disease. AB - Chikungunya virus (CHIKV) is an alphavirus responsible for causing epidemic outbreaks of polyarthralgia in humans. Because CHIKV is initially introduced via the skin, where gammadelta T cells are prevalent, we evaluated the response of these cells to CHIKV infection. CHIKV infection led to a significant increase in gammadelta T cells in the infected foot and draining lymph node that was associated with the production of proinflammatory cytokines and chemokines in C57BL/6J mice. gammadelta T cell(-/-) mice demonstrated exacerbated CHIKV disease characterized by less weight gain and greater foot swelling than occurred in wild type mice, as well as a transient increase in monocytes and altered cytokine/chemokine expression in the foot. Histologically, gammadelta T cell(-/-) mice had increased inflammation-mediated oxidative damage in the ipsilateral foot and ankle joint compared to wild-type mice which was independent of differences in CHIKV replication. These results suggest that gammadelta T cells play a protective role in limiting the CHIKV-induced inflammatory response and subsequent tissue and joint damage. IMPORTANCE: Recent epidemics, including the 2004 to 2007 outbreak and the spread of CHIKV to naive populations in the Caribbean and Central and South America with resultant cases imported into the United States, have highlighted the capacity of CHIKV to cause explosive epidemics where the virus can spread to millions of people and rapidly move into new areas. These studies identified gammadelta T cells as important to both recruitment of key inflammatory cell populations and dampening the tissue injury due to oxidative stress. Given the importance of these cells in the early response to CHIKV, this information may inform the development of CHIKV vaccines and therapeutics. PMID- 26491153 TI - Functional Characterization of Glycoprotein H Chimeras Composed of Conserved Domains of the Pseudorabies Virus and Herpes Simplex Virus 1 Homologs. AB - Membrane fusion is indispensable for entry of enveloped viruses into host cells. The conserved core fusion machinery of the Herpesviridae consists of glycoprotein B (gB) and the gH/gL complex. Recently, crystal structures of gH/gL of herpes simplex virus 2 (HSV-2) and Epstein-Barr virus and of a core fragment of pseudorabies virus (PrV) gH identified four structurally conserved gH domains. To investigate functional conservation, chimeric genes encoding combinations of individual domains of PrV and herpes simplex virus 1 (HSV-1) gH were expressed in rabbit kidney cells, and their processing and transport to the cell surface, as well as activity in fusion assays including gB, gD, and gL of PrV or HSV-1, were analyzed. Chimeric gH containing domain I of HSV-1 and domains II to IV of PrV exhibited limited fusion activity in the presence of PrV gB and gD and HSV-1 gL, but not of PrV gL. More strikingly, chimeric gH consisting of PrV domains I to III and HSV-1 domain IV exhibited considerable fusion activity together with PrV gB, gD, and gL. Replacing PrV gB with the HSV-1 protein significantly enhanced this activity. A cell line stably expressing this chimeric gH supported replication of gH-deleted PrV. Our results confirm the specificity of domain I for gL binding, demonstrate functional conservation of domain IV in two alphaherpesviruses from different genera, and indicate species-specific interactions of this domain with gB. They also suggest that gH domains II and III might form a structural and functional unit which does not tolerate major substitutions. IMPORTANCE: Envelope glycoprotein H (gH) is essential for herpesvirus-induced membrane fusion, which is required for host cell entry and viral spread. Although gH is structurally conserved within the Herpesviridae, its precise role and its interactions with other components of the viral fusion machinery are not fully understood. Chimeric proteins containing domains of gH proteins from different herpesviruses can serve as tools to elucidate the molecular basis of gH function. The present study shows that the C-terminal part of human herpesvirus 1 (herpes simplex virus 1) gH can functionally substitute for the corresponding part of suid herpesvirus 1 (pseudorabies virus) gH, whereas other tested combinations proved to be nonfunctional. Interestingly, the exchangeable fragment included the membrane-proximal end of the gH ectodomain (domain IV), which is most conserved in sequence and structure and might be capable of transient membrane interaction during fusion. PMID- 26491154 TI - Growth and Pathogenic Potential of Naturally Selected Reassortants after Coinfection with Pandemic H1N1 and Highly Pathogenic Avian Influenza H5N1 Viruses. AB - Coinfection of ferrets with H5N1 and pH1N1 viruses resulted in two predominate genotypes in the lungs containing surface genes of highly pathogenic avian influenza H5N1 virus in the backbone of pandemic H1N1 2009 (pH1N1). Compared to parental strains, these reassortants exhibited increased growth and virulence in vitro and in mice but failed to be transmitted indirectly to naive contact ferrets. Thus, this demonstrates a possible natural reassortment following coinfection as well as the pathogenicity of the potential reassortants. PMID- 26491155 TI - Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus. AB - Over the past 2 decades, several novel influenza virus proteins have been identified that modulate viral infections in vitro and/or in vivo. The PB2 segment, which is one of the longest influenza A virus segments, is known to encode only one viral protein, PB2. In the present study, we used reverse transcription-PCR (RT-PCR) targeting viral mRNAs transcribed from the PB2 segment to look for novel viral proteins encoded by spliced mRNAs. We identified a new viral protein, PB2-S1, encoded by a novel spliced mRNA in which the region corresponding to nucleotides 1513 to 1894 of the PB2 mRNA is deleted. PB2-S1 was detected in virus-infected cells and in cells transfected with a protein expression plasmid encoding PB2. PB2-S1 localized to mitochondria, inhibited the RIG-I-dependent interferon signaling pathway, and interfered with viral polymerase activity (dependent on its PB1-binding capability). The nucleotide sequences around the splicing donor and acceptor sites for PB2-S1 were highly conserved among pre-2009 human H1N1 viruses but not among human H1N1pdm and H3N2 viruses. PB2-S1-deficient viruses, however, showed growth kinetics in MDCK cells and virulence in mice similar to those of wild-type virus. The biological significance of PB2-S1 to the replication and pathogenicity of seasonal H1N1 influenza A viruses warrants further investigation. IMPORTANCE: Transcriptome analysis of cells infected with influenza A virus has improved our understanding of the host response to viral infection, because such analysis yields considerable information about both in vitro and in vivo viral infections. However, little attention has been paid to transcriptomes derived from the viral genome. Here we focused on the splicing of mRNA expressed from the PB2 segment and identified a spliced viral mRNA encoding a novel viral protein. This result suggests that other, as yet unidentified viral proteins encoded by spliced mRNAs could be expressed in virus-infected cells. A viral transcriptome including the viral spliceosome should be evaluated to gain new insights into influenza virus infection. PMID- 26491156 TI - Development and Characterization of a Guinea Pig-Adapted Sudan Virus. AB - Infections with Sudan virus (SUDV), a member of the genus Ebolavirus, result in a severe hemorrhagic fever with a fatal outcome in over 50% of human cases. The paucity of prophylactics and therapeutics against SUDV is attributed to the lack of a small-animal model to screen promising compounds. By repeatedly passaging SUDV within the livers and spleens of guinea pigs in vivo, a guinea pig-adapted SUDV variant (SUDV-GA) uniformly lethal to these animals, with a 50% lethal dose (LD50) of 5.3 * 10(-2) 50% tissue culture infective doses (TCID50), was developed. Animals infected with SUDV-GA developed high viremia and died between 9 and 14 days postinfection. Several hallmarks of SUDV infection, including lymphadenopathy, increased liver enzyme activities, and coagulation abnormalities, were observed. Virological analyses and gross pathology, histopathology, and immunohistochemistry findings indicate that SUDV-GA replicates in the livers and spleens of infected animals similarly to SUDV infections in nonhuman primates. These developments will accelerate the development of specific medical countermeasures in preparation for a future disease outbreak due to SUDV. IMPORTANCE: A disease outbreak due to Ebola virus (EBOV), suspected to have emerged during December 2013 in Guinea, with over 11,000 dead and 28,000 infected, is finally winding down. Experimental EBOV vaccines and treatments were administered to patients under compassionate circumstances with promising results, and availability of an approved countermeasure appears to be close. However, the same range of experimental candidates against a potential disease outbreak caused by other members of the genus Ebolavirus, such as Sudan virus (SUDV), is not readily available. One bottleneck contributing to this situation is the lack of a small-animal model to screen promising drugs in an efficient and economical manner. To address this, we have generated a SUDV variant (SUDV-GA) that is uniformly lethal to guinea pigs. Animals infected with SUDV-GA develop disease similar to that of SUDV-infected humans and monkeys. We believe that this model will significantly accelerate the development of life-saving measures against SUDV infections. PMID- 26491157 TI - Structure/Function Studies Involving the V3 Region of the HIV-1 Envelope Delineate Multiple Factors That Affect Neutralization Sensitivity. AB - Antibodies (Abs) specific for the V3 loop of the HIV-1 gp120 envelope neutralize most tier 1 and many tier 2 viruses and are present in essentially all HIV infected individuals as well as immunized humans and animals. Vaccine-induced V3 Abs are associated with reduced HIV infection rates in humans and affect the nature of transmitted viruses in infected vaccinees, despite the fact that V3 is often occluded in the envelope trimer. Here, we link structural and experimental data showing how conformational alterations of the envelope trimer render viruses exceptionally sensitive to V3 Abs. The experiments interrogated the neutralization sensitivity of pseudoviruses with single amino acid mutations in various regions of gp120 that were predicted to alter packing of the V3 loop in the Env trimer. The results indicate that the V3 loop is metastable in the envelope trimer on the virion surface, flickering between states in which V3 is either occluded or available for binding to chemokine receptors (leading to infection) and to V3 Abs (leading to virus neutralization). The spring-loaded V3 in the envelope trimer is easily released by disruption of the stability of the V3 pocket in the unliganded trimer or disruption of favorable V3/pocket interactions. Formation of the V3 pocket requires appropriate positioning of the V1V2 domain, which is, in turn, dependent on the conformation of the bridging sheet and on the stability of the V1V2 B-C strand-connecting loop. IMPORTANCE: The levels of antibodies to the third variable region (V3) of the HIV envelope protein correlate with reduced HIV infection rates. Previous studies showed that V3 is often occluded, as it sits in a pocket of the envelope trimer on the surface of virions; however, the trimer is flexible, allowing occluded portions of the envelope (like V3) to flicker into an exposed position that binds antibodies. Here we provide a systematic interrogation of mechanisms by which single amino acid changes in various regions of gp120 (i) render viruses sensitive to neutralization by V3 antibodies, (ii) result in altered packing of the V3 loop, and (iii) activate an open conformation that exposes V3 to the effects of V3 Abs. Taken together, these and previous studies explain how V3 antibodies can protect against HIV-1 infection and why they should be one of the targets of vaccine-induced antibodies. PMID- 26491158 TI - A Unique Multibasic Proteolytic Cleavage Site and Three Mutations in the HA2 Domain Confer High Virulence of H7N1 Avian Influenza Virus in Chickens. AB - In 1999, after circulation for a few months in poultry in Italy, low-pathogenic (LP) avian influenza (AI) H7N1 virus mutated into a highly pathogenic (HP) form by acquisition of a unique multibasic cleavage site (mCS), PEIPKGSRVRR*GLF (asterisk indicates the cleavage site), in the hemagglutinin (HA) and additional alterations with hitherto unknown biological function. To elucidate these virulence-determining alterations, recombinant H7N1 viruses carrying specific mutations in the HA of LPAI A/chicken/Italy/473/1999 virus (Lp) and HPAI A/chicken/Italy/445/1999 virus (Hp) were generated. Hp with a monobasic CS or carrying the HA of Lp induced only mild or no disease in chickens, thus resembling Lp. Conversely, Lp with the HA of Hp was as virulent and transmissible as Hp. While Lp with a multibasic cleavage site (Lp_CS445) was less virulent than Hp, full virulence was exhibited when HA2 was replaced by that of Hp. In HA2, three amino acid differences consistently detected between LP and HP H7N1 viruses were successively introduced into Lp_CS445. Q450L in the HA2 stem domain increased virulence and transmission but was detrimental to replication in cell culture, probably due to low-pH activation of HA. A436T and/or K536R restored viral replication in vitro and in vivo. Viruses possessing A436T and K536R were observed early in the HPAI outbreak but were later superseded by viruses carrying all three mutations. Together, besides the mCS, stepwise mutations in HA2 increased the fitness of the Italian H7N1 virus in vivo. The shift toward higher virulence in the field was most likely gradual with rapid optimization. IMPORTANCE: In 1999, after 9 months of circulation of low-pathogenic (LP) avian influenza virus (AIV), a devastating highly pathogenic (HP) H7N1 AIV emerged in poultry, marking the largest epidemic of AIV reported in a Western country. The HPAIV possessed a unique multibasic cleavage site (mCS) complying with the minimum motif for HPAIV. The main finding in this report is the identification of three mutations in the HA2 domain that are required for replication and stability, as well as for virulence, transmission, and tropism of H7N1 in chickens. In addition to the mCS, Q450L was required for full virulence and transmissibility of the virus. Nonetheless, it was detrimental to virus replication and required A436T and/or K536R to restore replication, systemic spread, and stability. These results are important for better understanding of the evolution of highly pathogenic avian influenza viruses from low-pathogenic precursors. PMID- 26491159 TI - Characterization of a Herpes Simplex Virus 1 (HSV-1) Chimera in Which the Us3 Protein Kinase Gene Is Replaced with the HSV-2 Us3 Gene. AB - Us3 protein kinases encoded by herpes simplex virus 1 (HSV-1) and 2 (HSV-2) play important roles in viral replication and pathogenicity. To investigate type specific differences between HSV-1 Us3 and HSV-2 Us3 in cells infected by viruses with all the same viral gene products except for their Us3 kinases, we constructed and characterized a recombinant HSV-1 in which its Us3 gene was replaced with the HSV-2 Us3 gene. Replacement of HSV-1 Us3 with HSV-2 Us3 had no apparent effect on viral growth in cell cultures or on the range of proteins phosphorylated by Us3. HSV-2 Us3 efficiently compensated for HSV-1 Us3 functions, including blocking apoptosis, controlling infected cell morphology, and downregulating cell surface expression of viral envelope glycoprotein B. In contrast, replacement of HSV-1 Us3 by HSV-2 Us3 changed the phosphorylation status of UL31 and UL34, which are critical viral regulators of nuclear egress. It also caused aberrant localization of these viral proteins and aberrant accumulation of primary enveloped virions in membranous vesicle structures adjacent to the nuclear membrane, and it reduced viral cell-cell spread in cell cultures and pathogenesis in mice. These results clearly demonstrated biological differences between HSV-1 Us3 and HSV-2 Us3, especially in regulation of viral nuclear egress and phosphorylation of viral regulators critical for this process. Our study also suggested that the regulatory role(s) of HSV-1 Us3, which was not carried out by HSV-2 Us3, was important for HSV-1 cell-cell spread and pathogenesis in vivo. IMPORTANCE: A previous study comparing the phenotypes of HSV-1 and HSV-2 suggested that the HSV-2 Us3 kinase lacked some of the functions of HSV-1 Us3 kinase. The difference between HSV-1 and HSV-2 Us3 kinases appeared to be due to the fact that some Us3 phosphorylation sites in HSV-1 proteins are not conserved in the corresponding HSV-2 proteins. Therefore, we generated recombinant HSV-1 strains YK781 (Us3-chimera) with HSV-2 Us3 and its repaired virus YK783 (Us3-repair) with HSV-1 Us3, to compare the activities of HSV-1 Us3 and HSV-2 Us3 in cells infected by viruses with the same HSV-1 gene products except for their Us3 kinases. We report here that some processes in viral nuclear egress and pathogenesis in vivo that have been attributed to HSV-1 Us3 could not be carried out by HSV-2 Us3. Therefore, our study clarified the biological differences between HSV-1 Us3 and HSV-2 Us3, which may be relevant to viral pathogenesis in vivo. PMID- 26491160 TI - Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interleukin-6 by X-Box Binding Protein 1. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and a subset of multicentric Castleman disease (MCD). The KSHV life cycle has two principal gene repertoires, latent and lytic. KSHV viral interleukin-6 (vIL-6), an analog of human IL-6, is usually lytic; production of vIL-6 by involved plasmablasts is a central feature of KSHV-MCD. vIL-6 also plays a role in PEL and KS. We show that a number of plasmablasts from lymph nodes of patients with KSHV-MCD express vIL-6 but not ORF45, a KSHV lytic gene. We further show that vIL-6 is directly induced by the spliced (active) X-box binding protein-1 (XBP-1s), a transcription factor activated by endoplasmic reticulum (ER) stress and differentiation of B cells in lymph nodes. The promoter region of vIL-6 contains several potential XBP-response elements (XREs), and two of these elements in particular mediate the effect of XBP-1s. Mutation of these elements abrogates the response to XBP-1s but not to the KSHV replication and transcription activator (RTA). Also, XBP-1s binds to the vIL-6 promoter in the region of these XREs. Exposure of PEL cells to a chemical inducer of XBP-1s can induce vIL-6. Patient-derived PEL tumor cells that produce vIL-6 frequently coexpress XBP-1, and immunofluorescence staining of involved KSHV-MCD lymph nodes reveals that most plasmablasts expressing vIL-6 also coexpress XBP-1. These results provide evidence that XBP-1s is a direct activator of KSHV vIL-6 and that this is an important step in the pathogenesis of KSHV-MCD and PEL. IMPORTANCE: Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (KSHV-MCD) is characterized by severe inflammatory symptoms caused by an excess of cytokines, particularly KSHV-encoded viral interleukin-6 (vIL-6) produced by lymph node plasmablasts. vIL-6 is usually a lytic gene. We show that a number of KSHV-MCD lymph node plasmablasts express vIL-6 but do not have full lytic KSHV replication. Differentiating lymph node B cells express spliced (active) X-box binding protein-1 (XBP-1s). We show that XBP-1s binds to the promoter of vIL-6 and can directly induce production of vIL-6 through X-box protein response elements on the vIL-6 promoter region. We further show that chemical inducers of XBP-1s can upregulate production of vIL-6. Finally, we show that most vIL-6-producing plasmablasts from lymph nodes of KSHV-MCD patients coexpress XBP-1s. These results demonstrate that XBP-1s can directly induce vIL-6 and provide evidence that this is a key step in the pathogenesis of KSHV-MCD and other KSHV-induced diseases. PMID- 26491161 TI - A Naturally Occurring Domestic Cat APOBEC3 Variant Confers Resistance to Feline Immunodeficiency Virus Infection. AB - Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) DNA cytosine deaminases can be incorporated into progeny virions and inhibit lentiviral replication. On the other hand, viral infectivity factor (Vif) of lentiviruses antagonizes A3-mediated antiviral activities by degrading A3 proteins. It is known that domestic cat (Felis catus) APOBEC3Z3 (A3Z3), the ortholog of human APOBEC3H, potently suppresses the infectivity of vif-defective feline immunodeficiency virus (FIV). Although a recent report has shown that domestic cat encodes 7 haplotypes (hap I to hap VII) of A3Z3, the relevance of A3Z3 polymorphism in domestic cats with FIV Vif has not yet been addressed. In this study, we demonstrated that these feline A3Z3 variants suppress vif defective FIV infectivity. We also revealed that codon 65 of feline A3Z3 is a positively selected site and that A3Z3 hap V is subject to positive selection during evolution. It is particularly noteworthy that feline A3Z3 hap V is resistant to FIV Vif-mediated degradation and still inhibits vif-proficient viral infection. Moreover, the side chain size, but not the hydrophobicity, of the amino acid at position 65 determines the resistance to FIV Vif-mediated degradation. Furthermore, phylogenetic analyses have led to the inference that feline A3Z3 hap V emerged approximately 60,000 years ago. Taken together, these findings suggest that feline A3Z3 hap V may have been selected for escape from an ancestral FIV. This is the first evidence for an evolutionary "arms race" between the domestic cat and its cognate lentivirus. IMPORTANCE: Gene diversity and selective pressure are intriguing topics in the field of evolutionary biology. A direct interaction between a cellular protein and a viral protein can precipitate an evolutionary arms race between host and virus. One example is primate APOBEC3G, which potently restricts the replication of primate lentiviruses (e.g., human immunodeficiency virus type 1 [HIV-1] and simian immunodeficiency virus [SIV]) if its activity is not counteracted by the viral Vif protein. Here we investigate the ability of 7 naturally occurring variants of feline APOBEC3, APOBEC3Z3 (A3Z3), to inhibit FIV replication. Interestingly, one feline A3Z3 variant is dominant, restrictive, and naturally resistant to FIV Vif-mediated degradation. Phylogenetic analyses revealed that the ancestral change that generated this variant could have been caused by positive Darwinian selection, presumably due to an ancestral FIV infection. The experimental-phylogenetic investigation sheds light on the evolutionary history of the domestic cat, which was likely influenced by lentiviral infection. PMID- 26491162 TI - Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo. AB - Adeno-associated virus 2 (AAV2) and adenovirus 5 (Ad5) are promising gene therapy vectors. Both display liver tropism and are currently thought to enter hepatocytes in vivo through cell surface heparan sulfate proteoglycans (HSPGs). To test directly this hypothesis, we created mice that lack Ext1, an enzyme required for heparan sulfate biosynthesis, in hepatocytes. Ext1(HEP) mutant mice exhibit an 8-fold reduction of heparan sulfate in primary hepatocytes and a 5 fold reduction of heparan sulfate in whole liver tissue. Conditional hepatocyte Ext1 gene deletion greatly reduced AAV2 liver transduction following intravenous injection. Ad5 transduction requires blood coagulation factor X (FX); FX binds to the Ad5 capsid hexon protein and bridges the virus to HSPGs on the cell surface. Ad5.FX transduction was abrogated in primary hepatocytes from Ext1(HEP) mice. However, in contrast to the case with AAV2, Ad5 transduction was not significantly reduced in the livers of Ext1(HEP) mice. FX remained essential for Ad5 transduction in vivo in Ext1(HEP) mice. We conclude that while AAV2 requires HSPGs for entry into mouse hepatocytes, HSPGs are dispensable for Ad5 hepatocyte transduction in vivo. This study reopens the question of how adenovirus enters cells in vivo. IMPORTANCE: Our understanding of how viruses enter cells, and how they can be used as therapeutic vectors to manage disease, begins with identification of the cell surface receptors to which viruses bind and which mediate viral entry. Both adeno-associated virus 2 and adenovirus 5 are currently thought to enter hepatocytes in vivo through heparan sulfate proteoglycans (HSPGs). However, direct evidence for these conclusions is lacking. Experiments presented herein, in which hepatic heparan sulfate synthesis was genetically abolished, demonstrated that HSPGs are not likely to function as hepatocyte Ad5 receptors in vivo. The data also demonstrate that HSPGs are required for hepatocyte transduction by AAV2. These results reopen the question of the identity of the Ad5 receptor in vivo and emphasize the necessity of demonstrating the nature of the receptor by genetic means, both for understanding Ad5 entry into cells in vivo and for optimization of Ad5 vectors as therapeutic agents. PMID- 26491163 TI - A Single Maturation Cleavage Site in Adenovirus Impacts Cell Entry and Capsid Assembly. AB - Proteolytic maturation drives the conversion of stable, immature virus particles to a mature, metastable state primed for cell infection. In the case of human adenovirus, this proteolytic cleavage is mediated by the virally encoded protease AVP. Protein VI, an internal capsid cement protein and substrate for AVP, is cleaved at two sites, one of which is near the N terminus of the protein. In mature capsids, the 33 residues at the N terminus of protein VI (pVIn) are sequestered inside the cavity formed by peripentonal hexon trimers at the 5-fold vertex. Here, we describe a glycine-to-alanine mutation in the N-terminal cleavage site of protein VI that profoundly impacts proteolytic processing, the generation of infectious particles, and cell entry. The phenotypic effects associated with this mutant provide a mechanistic framework for understanding the multifunctional nature of protein VI. Based on our findings, we propose that the primary function of the pVIn peptide is to mediate interactions between protein VI and hexon during virus replication, driving hexon nuclear accumulation and particle assembly. Once particles are assembled, AVP-mediated cleavage facilitates the release of the membrane lytic region at the amino terminus of mature VI, allowing it to lyse the endosome during cell infection. These findings highlight the importance of a single maturation cleavage site for both infectious particle production and cell entry and emphasize the exquisite spatiotemporal regulation governing adenovirus assembly and disassembly. IMPORTANCE: Postassembly virus maturation is a cornerstone principle in virology. However, a mechanistic understanding of how icosahedral viruses utilize this process to transform immature capsids into infection-competent particles is largely lacking. Adenovirus maturation involves proteolytic processing of seven precursor proteins. There is currently no information for the role of each independent cleavage event in the generation of infectious virions. To address this, we investigated the proteolytic maturation of one adenovirus precursor molecule, protein VI. Structurally, protein VI cements the outer capsid shell and links it to the viral core. Functionally, protein VI is involved in endosome disruption, subcellular trafficking, transcription activation, and virus assembly. Our studies demonstrate that the multifunctional nature of protein VI is largely linked to its maturation. Through mutational analysis, we show that disrupting the N-terminal cleavage of preprotein VI has major deleterious effects on the assembly of infectious virions and their subsequent ability to infect host cells. PMID- 26491164 TI - Baculovirus Inhibitor-of-Apoptosis Op-IAP3 Blocks Apoptosis by Interaction with and Stabilization of a Host Insect Cellular IAP. AB - Baculovirus-encoded inhibitor of apoptosis (IAP) proteins likely evolved from their host cell IAP homologs, which function as critical regulators of cell death. Despite their striking relatedness to cellular IAPs, including the conservation of two baculovirus IAP repeat (BIR) domains and a C-terminal RING, viral IAPs use an unresolved mechanism to suppress apoptosis in insects. To define this mechanism, we investigated Op-IAP3, the prototypical IAP from baculovirus OpMNPV. We found that Op-IAP3 forms a stable complex with SfIAP, the native, short-lived IAP of host insect Spodoptera frugiperda. Long-lived Op-IAP3 prevented virus-induced SfIAP degradation, which normally causes caspase activation and apoptosis. In uninfected cells, Op-IAP3 also increased SfIAP steady-state levels and extended SfIAP's half-life. Conversely, SfIAP stabilization was lost or reversed in the presence of mutated Op-IAP3 that was engineered for reduced stability. Thus, Op-IAP3 stabilizes SfIAP and preserves its antiapoptotic function. In contrast to SfIAP, Op-IAP3 failed to bind or inhibit native Spodoptera caspases. Furthermore, BIR mutations that abrogate binding of well-conserved IAP antagonists did not affect Op-IAP3's capacity to prevent virus-induced apoptosis. Remarkably, Op-IAP3 also failed to prevent apoptosis when endogenous SfIAP was ablated by RNA silencing. Thus, Op-IAP3 requires SfIAP as a cofactor. Our findings suggest a new model wherein Op-IAP3 interacts directly with SfIAP to maintain its intracellular level, thereby suppressing virus-induced apoptosis indirectly. Consistent with this model, Op IAP3 has evolved an intrinsic stability that may serve to repress signal-induced turnover and autoubiquitination when bound to its targeted cellular IAP. IMPORTANCE: The IAPs were first discovered in baculoviruses because of their potency for preventing apoptosis. However, the antiapoptotic mechanism of viral IAPs in host insects has been elusive. We show here that the prototypical viral IAP, Op-IAP3, blocks apoptosis indirectly by associating with unstable, autoubiquitinating host IAP in such a way that cellular IAP levels and antiapoptotic activities are maintained. This mechanism explains Op-IAP3's requirement for native cellular IAP as a cofactor and the dispensability of caspase inhibition. Viral IAP-mediated preservation of the host IAP homolog capitalizes on normal IAP-IAP interactions and is likely the result of viral IAP evolution in which degron-mediated destabilization and ubiquitination potential have been reduced. This mechanism illustrates another novel means by which DNA viruses incorporate host death regulators that are modified for resistance to host regulatory controls for the purpose of suppressing host cell apoptosis and acquiring replication advantages. PMID- 26491165 TI - Intricate Roles of Mammalian Sirtuins in Defense against Viral Pathogens. AB - For a number of years, sirtuin enzymes have been appreciated as effective "sensors" of the cellular environment to rapidly transmit information to diverse cellular pathways. Much effort was placed into exploring their roles in human cancers and aging. However, a growing body of literature brings these enzymes to the spotlight in the field of virology. Here, we discuss sirtuin functions in the context of viral infection, which provide regulatory points for therapeutic intervention against pathogens. PMID- 26491166 TI - RNA Silencing May Play a Role in but Is Not the Only Determinant of the Multiplicity of Infection. AB - The multiplicity of infection (MOI), i.e., the number of viral genomes that infect a cell, is an important parameter in virus evolution, which for each virus and environment may have an optimum value that maximizes virus fitness. Thus, the MOI might be controlled by virus functions, an underexplored hypothesis in eukaryote-infecting viruses. To analyze if the MOI is controlled by virus functions, we estimated the MOI in plants coinfected by two genetic variants of Tomato bushy stunt virus (TBSV); by TBSV and a TBSV-derived defective interfering RNA (DI-RNA); or by TBSV and a second tombusvirus, Cymbidium ringspot virus (CymRSV). The MOI was significantly larger in TBSV-CymRSV coinfections (~4.0) than in TBSV-TBSV or TBSV-DI-RNA coinfections (~1.7 to 2.2). Coinfections by CymRSV or TBSV with chimeras in which an open reading frame (ORF) of one virus species was replaced by that of the other identified a role of viral proteins in determining the MOI, which ranged from 1.6 to 3.9 depending on the coinfecting genotypes. However, no virus-encoded protein or genomic region was the sole MOI determinant. Coinfections by CymRSV and TBSV mutants in which the expression of the gene-silencing suppressor protein p19 was abolished also showed a possible role of gene silencing in MOI determination. Taken together, these results demonstrate that the MOI is a quantitative trait showing continuous variation and that as such it has a complex determination involving different virus-encoded functions. IMPORTANCE: The number of viral genomes infecting a cell, or the multiplicity of infection (MOI), is an important parameter in virus evolution affecting recombination rates, selection intensity on viral genes, evolution of multipartite genomes, or hyperparasitism by satellites or defective interfering particles. For each virus and environment, the MOI may have an optimum value that maximizes virus fitness, but little is known about MOI control in eukaryote infecting viruses. We show here that in plants coinfected by two genotypes of Tomato bushy stunt virus (TBSV), the MOI was lower than in plants coinfected by TBSV and Cymbidium ringspot virus (CymRSV). Coinfections by CymRSV or TBSV with TBSV-CymRSV chimeras showed a role of viral proteins in MOI determination. Coinfections by CymRSV and TBSV mutants not expressing the gene-silencing suppressor protein also showed a role of gene silencing in MOI determination. The results demonstrate that the MOI is a quantitative trait with a complex determination involving different viral functions. PMID- 26491167 TI - Divergent Viruses Discovered in Arthropods and Vertebrates Revise the Evolutionary History of the Flaviviridae and Related Viruses. AB - Viruses of the family Flaviviridae are important pathogens of humans and other animals and are currently classified into four genera. To better understand their diversity, evolutionary history, and genomic flexibility, we used transcriptome sequencing (RNA-seq) to search for the viruses related to the Flaviviridae in a range of potential invertebrate and vertebrate hosts. Accordingly, we recovered the full genomes of five segmented jingmenviruses and 12 distant relatives of the known Flaviviridae ("flavi-like" viruses) from a range of arthropod species. Although these viruses are highly divergent, they share a similar genomic plan and common ancestry with the Flaviviridae in the NS3 and NS5 regions. Remarkably, although these viruses fill in major gaps in the phylogenetic diversity of the Flaviviridae, genomic comparisons reveal important changes in genome structure, genome size, and replication/gene regulation strategy during evolutionary history. In addition, the wide diversity of flavi-like viruses found in invertebrates, as well as their deep phylogenetic positions, suggests that they may represent the ancestral forms from which the vertebrate-infecting viruses evolved. For the vertebrate viruses, we expanded the previously mammal-only pegivirus-hepacivirus group to include a virus from the graceful catshark (Proscyllium habereri), which in turn implies that these viruses possess a larger host range than is currently known. In sum, our data show that the Flaviviridae infect a far wider range of hosts and exhibit greater diversity in genome structure than previously anticipated. IMPORTANCE: The family Flaviviridae of RNA viruses contains several notorious human pathogens, including dengue virus, West Nile virus, and hepatitis C virus. To date, however, our understanding of the biodiversity and evolution of the Flaviviridae has largely been directed toward vertebrate hosts and their blood-feeding arthropod vectors. Therefore, we investigated an expanded group of potential arthropod and vertebrate host species that have generally been ignored by surveillance programs. Remarkably, these species contained diverse flaviviruses and related viruses that are characterized by major changes in genome size and genome structure, such that these traits are more flexible than previously thought. More generally, these data suggest that arthropods may be the ultimate reservoir of the Flaviviridae and related viruses, harboring considerable genetic and phenotypic diversity. In sum, this study revises the traditional view on the evolutionary history, host range, and genomic structures of a major group of RNA viruses. PMID- 26491168 TI - Targeting Swine Leukocyte Antigen Class I Molecules for Proteasomal Degradation by the nsp1alpha Replicase Protein of the Chinese Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Strain JXwn06. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a critical pathogen of swine, and infections by this virus often result in delayed, low level induction of cytotoxic T lymphocyte (CTL) responses in pigs. Here, we report that a Chinese highly pathogenic PRRSV strain possessed the ability to downregulate swine leukocyte antigen class I (SLA-I) molecules on the cell surface of porcine alveolar macrophages and target them for degradation in a manner that was dependent on the ubiquitin-proteasome system. Moreover, we found that the nsp1alpha replicase protein contributed to this property of PRRSV. Further mutagenesis analyses revealed that this function of nsp1alpha required the intact molecule, including the zinc finger domain, but not the cysteine protease activity. More importantly, we found that nsp1alpha was able to interact with both chains of SLA-I, a requirement that is commonly needed for many viral proteins to target their cellular substrates for proteasomal degradation. Together, our findings provide critical insights into the mechanisms of how PRRSV might evade cellular immunity and also add a new role for nsp1alpha in PRRSV infection. IMPORTANCE: PRRSV infections often result in delayed, low-level induction of CTL responses in pigs. Deregulation of this immunity is thought to prevent the virus from clearance in an efficient and timely manner, contributing to persistent infections in swineherds. Our studies in this report provide critical insight into the mechanism of how PRRSV might evade CTL responses. In addition, our findings add a new role for nsp1alpha, a critical viral factor involved in antagonizing host innate immunity. PMID- 26491169 TI - Interferon Kappa Inhibits Human Papillomavirus 31 Transcription by Inducing Sp100 Proteins. AB - High-risk human papillomaviruses (hr-HPV) establish persistent infections in keratinocytes, which can lead to cancer of the anogenital tract. Interferons (IFNs) are a family of secreted cytokines that induce IFN-stimulated genes (ISGs), many of which display antiviral activities. Transcriptome studies have indicated that established hr-HPV-positive cell lines display a reduced expression of ISGs, which correlates with decreased levels of interferon kappa (IFN-kappa), a type I IFN constitutively expressed in keratinocytes. Prior studies have also suggested that IFN-beta has anti-hr-HPV activity but the underlying mechanisms are not well understood. The downregulation of IFN-kappa by hr-HPV raises the possibility that IFN-kappa has anti-HPV activity. Using doxycycline-inducible IFN-kappa expression in CIN612-9E cells, which maintain extrachromosomally replicating HPV31 genomes, we demonstrated that IFN-kappa inhibits the growth of these cells and reduces viral transcription and replication. Interestingly, the initiation of viral early transcription was already inhibited at 4 to 6 h after IFN-kappa expression. This was also observed with recombinant IFN-beta, suggesting a common mechanism of IFNs. Transcriptome sequencing (RNA-seq) analysis identified 1,367 IFN-kappa-regulated genes, of which 221 were modulated >2-fold. The majority of those (71%) matched known ISGs, confirming that IFN-kappa acts as a bona fide type I IFN in hr-HPV-positive keratinocytes. RNA interference (RNAi) and cotransfection experiments indicated that the inhibition of viral transcription is mainly due to the induction of Sp100 proteins by IFN-kappa. Consistent with published data showing that Sp100 acts as a restriction factor for HPV18 infection, our results suggest that hr-HPV target IFN-kappa to prevent Sp100 expression and identify Sp100 as an ISG with anti-HPV activity. IMPORTANCE: High-risk HPV can establish persistent infections which may progress to anogenital cancers. hr-HPV interfere with the expression of interferon (IFN)-stimulated genes (ISGs), which is due to reduced levels of IFN kappa, an IFN that is constitutively expressed in human keratinocytes. This study reveals that IFN-kappa rapidly inhibits HPV transcription and that this is due to the induction of Sp100 proteins. Thus, Sp100 represents an ISG for hr-HPV. PMID- 26491170 TI - Viral DNA-Dependent Induction of Innate Immune Response to Hepatitis B Virus in Immortalized Mouse Hepatocytes. AB - Hepatitis B virus (HBV) infects hundreds of millions of people worldwide and causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV is an enveloped virus with a relaxed circular (RC) DNA genome. In the nuclei of infected human hepatocytes, conversion of RC DNA from the incoming virion or cytoplasmic mature nucleocapsid (NC) to the covalently closed circular (CCC) DNA, which serves as the template for producing all viral transcripts, is essential to establish and sustain viral replication. A prerequisite for CCC DNA formation is the uncoating (disassembly) of NCs to expose their RC DNA content for conversion to CCC DNA. We report here that in an immortalized mouse hepatocyte cell line, AML12HBV10, in which RC DNA exposure is enhanced, the exposed viral DNA could trigger an innate immune response that was able to modulate viral gene expression and replication. When viral gene expression and replication were low, the innate response initially stimulated these processes but subsequently acted to shut off viral gene expression and replication after they reached peak levels. Inhibition of viral DNA synthesis or cellular DNA sensing and innate immune signaling diminished the innate response. These results indicate that HBV DNA, when exposed in the host cell cytoplasm, can function to trigger an innate immune response that, in turn, modulates viral gene expression and replication. IMPORTANCE: Chronic infection by hepatitis B virus (HBV) afflicts hundreds of millions worldwide and is sustained by the episomal covalently closed circular (CCC) DNA in the nuclei of infected hepatocytes. Release of viral genomic DNA from cytoplasmic nucleocapsids (NCs) (NC disassembly or uncoating) is a prerequisite for its conversion to CCC DNA, which can also potentially expose the viral DNA to host DNA sensors and trigger an innate immune response. We have found that in an immortalized mouse hepatocyte cell line in which efficient CCC DNA formation was associated with enhanced exposure of nucleocapsid-associated DNA, the exposed viral DNA indeed triggered host cytoplasmic DNA sensing and an innate immune response that was able to modulate HBV gene expression and replication. Thus, HBV can, under select conditions, be recognized by the host innate immune response through exposed viral DNA, which may be exploited therapeutically to clear viral persistence. PMID- 26491171 TI - Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection. AB - Anti-HIV CD8 T cells included in therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Identifying the epitopes that do not accumulate variants but retain immunogenicity depends on both host major histocompatibility complex (MHC) genetics and the likelihood for an epitope to tolerate variation. We previously found that immune escape during acute SIV infection is conditional; the accumulation of mutations in T cell epitopes is limited, and the rate of accumulation depends on the number of epitopes being targeted. We have now tested the hypothesis that conditional immune escape extends into chronic SIV infection and that epitopes with a preserved wild-type sequence have the potential to elicit epitope-specific CD8 T cells. We deep sequenced simian immunodeficiency virus (SIV) from Mauritian cynomolgus macaques (MCMs) that were homozygous and heterozygous for the M3 MHC haplotype and had been infected with SIV for about 1 year. When interrogating variation within individual epitopes restricted by M3 MHC alleles, we found three categories of epitopes, which we called categories A, B, and C. Category B epitopes readily accumulated variants in M3-homozygous MCMs, but this was less common in M3 heterozygous MCMs. We then determined that chronic CD8 T cells specific for these epitopes were more likely preserved in the M3-heterozygous MCMs than M3 homozygous MCMs. We provide evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are homozygous for a set of MHC alleles are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. IMPORTANCE: Anti-HIV CD8 T cells that are part of therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Defining these epitope sequences is a necessary precursor to designing approaches that enhance the functionality of CD8 T cells with the potential to control virus replication during chronic infection or after reactivation of latent virus. Using MHC-homozygous and -heterozygous Mauritian cynomolgus macaques, we have now obtained evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are MHC homozygous are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. Importantly, our findings support the conditional immune escape hypothesis, such that the potential to present a greater number of CD8 T cell epitopes within a single animal can delay immune escape in targeted epitopes. As a result, certain epitope sequences can retain immunogenicity into chronic infection. PMID- 26491172 TI - Env-Specific IgA from Viremic HIV-Infected Subjects Compromises Antibody Dependent Cellular Cytotoxicity. AB - Elucidating the factors that modulate HIV-specific antibody-dependent cellular cytotoxicity (ADCC) will help in understanding its role in HIV immunity. The aim of this study was to determine whether IgA could modify the magnitude of ADCC in HIV infection, abrogating its protective role. Plasma samples from 20 HIV positive (HIV(+)) subjects enrolled during primary HIV infection (PHI), 10 chronically infected subjects (chronic), and 7 elite controllers (EC) were used. ADCC was determined by using a fluorometric ADCC assay, before and after removal of plasma IgA. Data were analyzed by using nonparametric statistics. ADCC was documented in 80% of PHI enrollment samples and in 100% of PHI 12-month, chronic, and EC samples; it peaked after acute infection, reached a plateau in chronic infection, and decreased after initiation of antiretroviral treatment (ART). Significant associations between ADCC and disease progression were found only after removal of plasma IgA from 12-month PHI samples: the magnitude of ADCC not only increased after IgA removal but also correlated with CD4(+) T-cell preservation. This work provides evidence that gp120-specific IgA was capable of modifying ADCC responses during natural HIV infection for the first time and adds to similar evidence provided in other settings. Furthermore, it underscores the complexity of the ADCC phenomenon and will help in an understanding of its underlying mechanisms. IMPORTANCE: Although the induction of ADCC-mediating antibodies in HIV-infected subjects has been extensively documented, the association of these antibodies with protection from disease progression is poorly understood. Here, we demonstrate that plasma IgA is a factor capable of modifying the magnitude of IgG-mediated ADCC in HIV infection, mitigating its beneficial effect. These results help in understanding why previous studies failed to demonstrate correlations between ADCC and disease progression, and they also contribute to the notion that an HIV vaccine should stimulate the production of ADCC-mediating IgG antibodies but not IgA. PMID- 26491173 TI - Neonatal Pasteurella multocida subsp. septica Meningitis Traced to Household Cats: Molecular Linkage Analysis Using Repetitive-Sequence-Based PCR. AB - Pasteurella multocida is a rare cause of neonatal bacterial meningitis. We describe such a case and verify two household cats as the source of infection using repetitive-element PCR (rep-PCR) molecular fingering. PMID- 26491174 TI - Evaluation of the Lyra Direct Strep Assay To Detect Group A Streptococcus and Group C and G Beta-Hemolytic Streptococcus from Pharyngeal Specimens. AB - The Lyra Direct strep assay was compared to culture for its ability to detect Streptococcus group A and beta-hemolytic groups C/G using rapid antigen-negative pharyngeal specimens (n = 161). The Lyra assay correctly detected all beta hemolytic streptococci (group A, n = 19; group C/G, n = 5). In batch mode, the Lyra assay reduced intralaboratory turnaround time by 60% (18.1 h versus 45.0 h) but increased hands-on time by 96% (3 min 16 s versus 1 min 40 s per specimen). PMID- 26491175 TI - Molecular Identification of Zoonotic Tissue-Invasive Tapeworm Larvae Other than Taenia solium in Suspected Human Cysticercosis Cases. AB - Rarely, zoonotic Taenia species other than Taenia solium cause human cysticercosis. The larval stages are morphologically often indistinguishable. We therefore investigated 12 samples of suspected human cysticercosis cases at the molecular level and surprisingly identified one Taenia crassiceps and one Taenia serialis (coenurosis) infection, which were caused by tapeworm larvae normally infecting rodents and sheep via eggs released from foxes and dogs. PMID- 26491177 TI - Cost-Effectiveness of 30- Compared to 20-Milliliter Blood Cultures: a Retrospective Study. AB - The importance of blood culture (BC) volume for detection of bloodstream infections (BSIs) is documented. Recently, improved diagnostic sensitivity was demonstrated for 30- versus 20-ml BCs in adults (Cockerill FR, Wilson JW, Vetter EA, Goodman KM, Torgerson CA, Harmsen WS, Schleck CD, IIstrup DM, Washington JA, Wilson WR. Clin Infect Dis 38:1724-1730, 2004, http://dx.doi.org/10.1128/JCM.01314-11). Hospitals receive higher reimbursement for patients with documented septicemia. We determined the cost-effectiveness of 30-ml versus 20-ml BCs using results from our institution and previously published data. Positive BC results from 292 bacteremic episodes were reviewed. The costs of the reagents, equipment, phlebotomist, and technologist time were determined. The medical records department provided Medicare reimbursement (MR) data for patients with selected ICD-9 codes. These data provided an estimate of the annualized increase in MR versus costs associated with conversion to 30-ml BCs. MR for 464 annual primary BSIs was $24,808/episode. An expected 7.2% increase in BSIs detected using 30-ml BCs would add 34 additional cases annually and increase MR by $843,472. Comparative MR data for cases where septicemia complicated another diagnosis were available for 4 International Classification of Diseases, Ninth Revision (ICD-9) codes: laparoscopic cholecystectomy, biliary tract disorders, pneumonia, and cellulitis. The mean incremental MR was $9,667 per episode, which projected to a $483,350 revenue increase annually. The annual cost associated with conversion to 30-ml BCs was estimated to be $157,798. Thus, the potential net increase in hospital revenue would be $1,169,031 for 30-ml versus 20-ml BCs. Our results suggest that conversion to 30-ml BCs may not only improve patient care by detecting more BSIs but also increase hospital revenue substantially. PMID- 26491176 TI - Development of a TaqMan Array Card for Acute-Febrile-Illness Outbreak Investigation and Surveillance of Emerging Pathogens, Including Ebola Virus. AB - Acute febrile illness (AFI) is associated with substantial morbidity and mortality worldwide, yet an etiologic agent is often not identified. Convalescent phase serology is impractical, blood culture is slow, and many pathogens are fastidious or impossible to cultivate. We developed a real-time PCR-based TaqMan array card (TAC) that can test six to eight samples within 2.5 h from sample to results and can simultaneously detect 26 AFI-associated organisms, including 15 viruses (chikungunya, Crimean-Congo hemorrhagic fever [CCHF] virus, dengue, Ebola virus, Bundibugyo virus, Sudan virus, hantaviruses [Hantaan and Seoul], hepatitis E, Marburg, Nipah virus, o'nyong-nyong virus, Rift Valley fever virus, West Nile virus, and yellow fever virus), 8 bacteria (Bartonella spp., Brucella spp., Coxiella burnetii, Leptospira spp., Rickettsia spp., Salmonella enterica and Salmonella enterica serovar Typhi, and Yersinia pestis), and 3 protozoa (Leishmania spp., Plasmodium spp., and Trypanosoma brucei). Two extrinsic controls (phocine herpesvirus 1 and bacteriophage MS2) were included to ensure extraction and amplification efficiency. Analytical validation was performed on spiked specimens for linearity, intra-assay precision, interassay precision, limit of detection, and specificity. The performance of the card on clinical specimens was evaluated with 1,050 blood samples by comparison to the individual real-time PCR assays, and the TAC exhibited an overall 88% (278/315; 95% confidence interval [CI], 84% to 92%) sensitivity and a 99% (5,261/5,326, 98% to 99%) specificity. This TaqMan array card can be used in field settings as a rapid screen for outbreak investigation or for the surveillance of pathogens, including Ebola virus. PMID- 26491178 TI - Multicenter Evaluation of Anyplex Plus MTB/NTM MDR-TB Assay for Rapid Detection of Mycobacterium tuberculosis Complex and Multidrug-Resistant Isolates in Pulmonary and Extrapulmonary Specimens. AB - The rapid diagnosis of tuberculosis (TB) and the detection of drug-resistant Mycobacterium tuberculosis strains are critical for successful public health interventions. Therefore, TB diagnosis requires the availability of diagnostic tools that allow the rapid detection of M. tuberculosis and drug resistance in clinical samples. Here, we performed a multicenter study to evaluate the performance of the Seegene Anyplex MTB/NTM MDR-TB assay, a new molecular method based on a multiplex real-time PCR system, for detection of Mycobacterium tuberculosis complex (MTBC), nontuberculous mycobacteria (NTM), and genetic determinants of drug resistance. In total, the results for 755 samples (534 pulmonary and 221 extrapulmonary samples) were compared with the results of smears and cultures. For pulmonary specimens, the sensitivities of the Anyplex assay and acid-fast bacillus smear testing were 86.4% and 75.0%, respectively, and the specificities were 99% and 99.4%. For extrapulmonary specimens, the sensitivities of the Anyplex assay and acid-fast bacillus smear testing were 83.3% and 50.0%, respectively, and the specificities of both were 100%. The negative and positive predictive values of the Anyplex assay for pulmonary specimens were 97% and 100%, respectively, and those for extrapulmonary specimens were 84.6% and 100%. The sensitivities of the Anyplex assay for detecting isoniazid resistance in MTBC strains from pulmonary and extrapulmonary specimens were 83.3% and 50%, respectively, while the specificities were 100% for both specimen types. These results demonstrate that the Anyplex MTB/NTM MDR-TB assay is an efficient and rapid method for the diagnosis of pulmonary and extrapulmonary TB and the detection of isoniazid resistance. PMID- 26491179 TI - First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States. AB - Azole resistance in Aspergillus fumigatus is an increasing problem. The TR34 L98H and TR46 Y121F T289A mutations that can occur in patients without previous azole exposure have been reported in Europe, Asia, the Middle East, Africa, and Australia. Here, we report the detection of both the TR34 L98H and TR46 Y121F T289A mutations in confirmed A. fumigatus isolates collected in institutions in the United States. These mutations, other mutations known to cause azole resistance, and azole MICs are reported here. PMID- 26491180 TI - Molecular Epidemiology of Streptococcus uberis Clinical Mastitis in Dairy Herds: Strain Heterogeneity and Transmission. AB - Multilocus sequence typing was successfully completed on 494 isolates of Streptococcus uberis from clinical mastitis cases in a study of 52 commercial dairy herds over a 12-month period. In total, 195 sequence types (STs) were identified. S. uberis mastitis cases that occurred in different cows within the same herd and were attributed to a common ST were classified as potential transmission events (PTEs). Clinical cases attributed to 35 of the 195 STs identified in this study were classified PTE. PTEs were identified in 63% of the herds. PTE-associated cases, which include the first recorded occurrence of that ST in that herd (index case) and all persistent infections with that PTE ST, represented 40% of all the clinical mastitis cases and occurred in 63% of the herds. PTE-associated cases accounted for >50% of all S. uberis clinical mastitis cases in 33% of the herds. Nine STs (ST-5, -6, -20, -22, -24, -35, -233, -361, and -512), eight of which were grouped within a clonal complex (sharing at least four alleles), were statistically overrepresented (OVR STs). The findings indicate that 38% of all clinical mastitis cases and 63% of the PTEs attributed to S. uberis in dairy herds may be caused by the nine most prevalent strains. The findings suggest that a small subset of STs is disproportionally important in the epidemiology of S. uberis mastitis in the United Kingdom, with cow-to-cow transmission of S. uberis potentially occurring in the majority of herds in the United Kingdom, and may be the most important route of infection in many herds. PMID- 26491181 TI - Clinical and Laboratory Testing for Trichomonas vaginalis Infection. AB - Trichomonas vaginalis infection is highly prevalent in the United States and worldwide. Traditional clinical diagnostic methods fail to identify more than half of these infections that, if left untreated, can result in adverse pregnancy outcomes and an exacerbated risk of both acquisition and transmission of HIV. Women bear a disproportionate amount of the burden of these infections, and testing among populations at risk for this disease should be provided. Molecular technologies have expanded our capacity for laboratory-based detection of infection and can be used on samples already being collected for chlamydia/gonorrhea screening. PMID- 26491182 TI - Molecular Characterization of Nonhemolytic and Nonpigmented Group B Streptococci Responsible for Human Invasive Infections. AB - Group B Streptococcus (GBS) is a common commensal bacterium in adults, but is also the leading cause of invasive bacterial infections in neonates in developed countries. The beta-hemolysin/cytolysin (beta-h/c), which is always associated with the production of an orange-to-red pigment, is a major virulence factor that is also used for GBS diagnosis. A collection of 1,776 independent clinical GBS strains isolated in France between 2006 and 2013 was evaluated on specific medium for beta-h/c activity and pigment production. The genomic sequences of nonhemolytic and nonpigmented (NH/NP) strains were analyzed to identify the molecular basis of this phenotype. Gene deletions or complementations were carried out to confirm the genotype-phenotype association. Sixty-three GBS strains (3.5%) were NH/NP, and 47 of these (74.6%) originated from invasive infections, including bacteremia and meningitis, in neonates or adults. The mutations are localized predominantly in the cyl operon, encoding the beta-h/c pigment biosynthetic pathway and, in the abx1 gene, encoding a CovSR regulator partner. In conclusion, although usually associated with GBS virulence, beta-h/c pigment production is not absolutely required to cause human invasive infections. Caution should therefore be taken in the use of hemolysis and pigmentation as criteria for GBS diagnosis in routine clinical laboratory settings. PMID- 26491183 TI - Interlaboratory Collaboration for Optimized Screening for Urinary Tract Infection. AB - As the majority of urine samples submitted for culture yields a negative result, rapid screening that accurately predicts culture outcome benefits clinicians by reducing the time to result and improves the efficiency of the microbiological laboratory. Automated urinalysis using the IRIS Diagnostics iQ200 Elite (iQ200) analyzer permits just such a fast and large-scale screening. We aimed to predict and thus to reduce negative cultures with a screening algorithm based on iQ200 urinalysis in a tertiary university hospital. In parallel, we evaluated the performance of the iQ200 screen compared to that of Gram stain for sample quality. We screened 1,442 samples submitted for bacterial culture using the iQ200 analyzer; of these samples, 357 (24.8%) had a positive culture result. We identified the absence of microorganisms in the iQ200 screen as the strongest solitary predictor for a negative culture, with a sensitivity of 90.5% (323/357). The algorithm was further improved by performing logistic regression on leukocyte counts, which gave a cutoff of 65 leukocytes/MUl to obtain the desired sensitivity of >95% (95.2%; 95% confidence interval [CI], 92.5 to 97.0), a negative predictive value of 97.3% (95% CI, 95.7 to 98.3), and an anticipated culture workload reduction of 44% (95% CI, 41 to 46). Concordance between sample quality based on Gram stain and iQ200 screening was only 72%, which was probably a result of interobserver effect in evaluation of the Gram stain. In conclusion, in our setting, screening by iQ200 proved to be a safe and cost-effective means to provide faster culture results, and it has the added benefit of a more objective evaluation of sample quality. PMID- 26491184 TI - High Incidence of Invasive Group A Streptococcus Disease Caused by Strains of Uncommon emm Types in Thunder Bay, Ontario, Canada. AB - An outbreak of type emm59 invasive group A Streptococcus (iGAS) disease was declared in 2008 in Thunder Bay District, Northwestern Ontario, 2 years after a countrywide emm59 epidemic was recognized in Canada. Despite a declining number of emm59 infections since 2010, numerous cases of iGAS disease continue to be reported in the area. We collected clinical information on all iGAS cases recorded in Thunder Bay District from 2008 to 2013. We also emm typed and sequenced the genomes of all available strains isolated from 2011 to 2013 from iGAS infections and from severe cases of soft tissue infections. We used whole genome sequencing data to investigate the population structure of GAS strains of the most frequently isolated emm types. We report an increased incidence of iGAS in Thunder Bay compared to the metropolitan area of Toronto/Peel and the province of Ontario. Illicit drug use, alcohol abuse, homelessness, and hepatitis C infection were underlying diseases or conditions that might have predisposed patients to iGAS disease. Most cases were caused by clonal strains of skin or generalist emm types (i.e., emm82, emm87, emm101, emm4, emm83, and emm114) uncommonly seen in other areas of the province. We observed rapid waxing and waning of emm types causing disease and their replacement by other emm types associated with the same tissue tropisms. Thus, iGAS disease in Thunder Bay District predominantly affects a select population of disadvantaged persons and is caused by clonally related strains of a few skin and generalist emm types less commonly associated with iGAS in other areas of Ontario. PMID- 26491185 TI - Accuracy of Conventional PCR Targeting the 16S rRNA Gene with the Ot-16sRF1 and Ot-16sRR1 Primers for Diagnosis of Scrub Typhus: a Case-Control Study. AB - We retrospectively evaluated the accuracy of conventional PCR targeting the 16S rRNA gene (16S C-PCR) using the Ot-16sRF1/Ot-16sRR1 primers for diagnosing scrub typhus. The diagnosis of Orientia tsutsugamushi infection by 16S C-PCR presented an increased sensitivity of 87.0% and specificity of 100% compared with those obtained with other targets and is thus a simple and clinically useful method with good diagnostic accuracy. PMID- 26491187 TI - PCR Detection of the Bacteroides fragilis Enterotoxin Gene Relies on Robust Primer Design. PMID- 26491186 TI - Detection of mecA- and mecC-Positive Methicillin-Resistant Staphylococcus aureus (MRSA) Isolates by the New Xpert MRSA Gen 3 PCR Assay. AB - An advanced methicillin-resistant Staphylococcus aureus (MRSA) detection PCR approach targeting SCCmec-orfX along with mecA and mecC was evaluated for S. aureus and coagulase-negative staphylococci. The possession of mecA and/or mecC was correctly confirmed in all cases. All methicillin-susceptible S. aureus strains (n = 98; including staphylococcal cassette chromosome mec element [SCCmec] remnants) and 98.1% of the MRSA strains (n = 160, including 10 mecC positive MRSA) were accurately categorized. PMID- 26491188 TI - Reidentification of Sex Pheromones of Tea Geometrid Ectropis obliqua Prout (Lepidoptera: Geometridae). AB - Tea geometrid Ectropis obliqua Prout (Lepidoptera: Geometridae) is an important defoliator of the tree crop Camellia sinensis L. in China. The sex pheromones of E. obliqua have not been identified, but have potential importance relative to the biological control of this predator. In this study, the female sex pheromones of E. obliqua were identified and evaluated for use in the monitoring and mass trapping of this pest. The sex pheromone extracts were subjected to gas chromatography-electroantennographic detection and gas chromatography-mass spectrometry. The identified chemicals were synthesized and applied to wind tunnel tests and field experiments. (Z,Z,Z)-3,6,9-octadecatriene and 6,7-epoxy (Z,Z)-3,9-octadecadiene were determined to be the primary sex pheromones produced by the female E. obliqua; the latter elicits the strongest electroantennogram responses from male E. obliqua antennae. However, males did not respond to single components in the wind-tunnel tests. The results of a field-trapping experiment indicated that a 4:6 v/v blend of (Z,Z,Z)-3,6,9-octadecatriene and 6,7-epoxy (Z,Z)-3,9-octadecadiene was highly effective in attracting male moths. PMID- 26491189 TI - Reduced Fitness in Adults From Larval, Galleria mellonella (Lepidoptera: Pyralidae) Reared on Media Amended With the Antihelmintic, Mebendazole. AB - Benzimidazole antihelmintics, including mebendazole, have a broad antiparasitic spectrum. These drugs play a major role in the treatments of parasites of intestines or other organs of vertebrates, humans, and other animals.The impact of mebendazole on the biology of the greater wax moth, Galleria mellonella (L.), was assessed by observation of several developmental parameters as follows: survivorship, developmental time, and adult longevity. Sublethal toxicity was measured through reproductive parameters such as fecundity and hatchability.The larvae were reared on artificial diet from first-instar larvae to the adult stage in the laboratory. The diets contained mebendazole at different concentrations of 0.005, 0.05, 0.5, or 1.0%. Control diet did not containme bendazole and produced seventh-instar larvae in 96.6+/-1.67% of cases, whereas the addition of mebendazole into diet at 1.0% significantly decreased survivorship of seventh instar larvae to 79.9+/-4.08%. The diet with the highest concentration of mebendazole decreased survivorship in the adult stage from 79.9+/-2.35 to 56.6+/ 4.73%, and shortened the developmental time for adult emergence from 36.7+/-0.48 to 34.1+/-0.63 d. All mebendazole concentrations shortened adult longevity and significantly decreased fecundity and hatch ability of G. mellonella. The highest dietary concentration of this antihelmintic significantly decreased the egg number to 28.6+/-2.89 and hatching rate to 51.7+/-1.85%. The present study demonstrates that mebendazole exhibits significant adverse effects on greater wax moth, leading to deteriorated life table parameters and decreased adult fitness. PMID- 26491190 TI - Cleanliness is next to godliness: mechanisms for staying clean. AB - Getting dirty is a fundamental problem, and one for which there are few solutions, especially across the enormous range of animal size. How do both a honeybee and a squirrel get clean? In this Review, we discuss two broad types of cleaning, considered from the viewpoint of energetics. Non-renewable cleaning strategies rely upon the organism as an energy source. Examples include grooming motions, wet-dog shaking or the secretion of chemicals. Renewable cleaning strategies depend on environmental sources of energy, such as the use of eyelashes to redirect incoming wind and so reduce deposition onto the eye. Both strategies take advantage of body hair to facilitate cleaning, and honeybees and squirrels, for example, each have around 3 million hairs. This hair mat increases the area on which particles can land by a factor of 100, but also suspends particles above the body, reducing their adhesion and facilitating removal. We hope that the strategies outlined here will inspire energy-efficient cleaning strategies in synthetic systems. PMID- 26491191 TI - Unihemispheric sleep in crocodilians? AB - Reduced vigilance is the conspicuous cost of sleep in most animals. To mitigate against this cost, some birds and aquatic mammals have evolved the ability to sleep with one-half of their brain at a time, a phenomenon known as unihemispheric sleep. During unihemispheric sleep the eye neurologically connected to the 'awake' hemisphere remains open while the other eye is closed. Such unilateral eye closure (UEC) has been observed across avian and non-avian reptiles, but has received little attention in the latter. Here, we explored the use of UEC in juvenile saltwater crocodiles (1) under baseline conditions, and in the presence of (2) other young crocodiles and (3) a human. Crocodiles increased the amount of UEC in response to the human, and preferentially oriented their open eye towards both stimuli. These results are consistent with observations on unihemispherically sleeping cetaceans and birds, and could have implications for our understanding of the evolution of unihemispheric sleep. PMID- 26491192 TI - The rectal complex and Malpighian tubules of the cabbage looper (Trichoplusia ni): regional variations in Na+ and K+ transport and cation reabsorption by secondary cells. AB - In larvae of most Lepidoptera the distal ends of the Malpighian tubules are closely applied to the rectal epithelia and are ensheathed within the perinephric membrane, thus forming the rectal complex. The cryptonephric Malpighian tubules within the rectal complex are bathed in fluid within a functional compartment, the perinephric space, which is separate from the haemolymph. In this study, the scanning ion-selective electrode technique (SIET) was used to measure transport of Na(+) and K(+) across the rectal complex and across multiple regions of the Malpighian tubules of larvae of the cabbage looper Trichoplusia ni. Measurements were made in an intact preparation in which connections of the tubules upstream to the rectal complex and downstream to the urinary bladder and gut remained intact. SIET measurements revealed reabsorption of Na(+) and K(+) across the intact rectal complex and into the bath (haemolymph), with K(+) fluxes approximately twice as large as those of Na(+). Analyses of fluxes in larvae with empty guts, found in recently moulted larvae, versus those with full guts highlighted differences in the rates of K(+) or Na(+) transport within tubule regions that appeared morphologically homogeneous, such as the rectal lead. The distal rectal lead of larvae with empty guts reabsorbed K(+), whereas the same region secreted K(+) in tubules of larvae with full guts. SIET measurements of the ileac plexus also indicated a novel role for secondary (type II) cells in cation reabsorption. Secondary cells reabsorb K(+), whereas the adjacent principal (type I) cells secrete K(+). Na(+) is reabsorbed by both principal and secondary cells, but the rate of reabsorption by the secondary cells is approximately twice the rate in the adjacent principal cells. PMID- 26491193 TI - In vitro strain in human metacarpal bones during striking: testing the pugilism hypothesis of hominin hand evolution. AB - The hands of hominins (i.e. bipedal apes) are distinguished by skeletal proportions that are known to enhance manual dexterity but also allow the formation of a clenched fist. Because male-male physical competition is important in the mating systems of most species of great apes, including humans, we tested the hypothesis that a clenched fist protects the metacarpal bones from injury by reducing the level of strain during striking. We used cadaver arms to measure in vitro strain in metacarpals during forward strikes with buttressed and unbuttressed fist postures and during side slaps with an open palm. If the protective buttressing hypothesis is correct, the clenched fist posture should substantially reduce strain in the metacarpal bones during striking and therefore reduce the risk of fracture. Recorded strains were significantly higher in strikes in which the hand was secured in unbuttressed and slapping postures than in the fully buttressed posture. Our results suggest that humans can safely strike with 55% more force with a fully buttressed fist than with an unbuttressed fist and with twofold more force with a buttressed fist than with an open-hand slap. Thus, the evolutionary significance of the proportions of the hominin hand may be that these are the proportions that improved manual dexterity while at the same time making it possible for the hand to be used as a club during fighting. PMID- 26491194 TI - Fish embryos on land: terrestrial embryo deposition lowers oxygen uptake without altering growth or survival in the amphibious fish Kryptolebias marmoratus. AB - Few teleost fishes incubate embryos out of water, but the oxygen-rich terrestrial environment could provide advantages for early growth and development. We tested the hypothesis that embryonic oxygen uptake is limited in aquatic environments relative to air using the self-fertilizing amphibious mangrove rivulus, Kryptolebias marmoratus, which typically inhabits hypoxic, water-filled crab burrows. We found that adult mangrove rivulus released twice as many embryos in terrestrial versus aquatic environments and that air-reared embryos had accelerated developmental rates. Surprisingly, air-reared embryos consumed 44% less oxygen and possessed larger yolk reserves, but attained the same mass, length and chorion thickness. Water-reared embryos moved their opercula ~2.5 more times per minute compared with air-reared embryos at 7 days post-release, which probably contributed to the higher rates of oxygen uptake and yolk utilization we observed. Genetically identical air- and water-reared embryos from the same parent were raised to maturity, but the embryonic environment did not affect growth, reproduction or emersion ability in adults. Therefore, although aspects of early development were plastic, these early differences were not sustained into adulthood. Kryptolebias marmoratus embryos hatched out of water when exposed to aerial hypoxia. We conclude that exposure to a terrestrial environment reduces the energetic costs of development partly by reducing the necessity of embryonic movements to dispel stagnant boundary layers. Terrestrial incubation of young would be especially beneficial to amphibious fishes that occupy aquatic habitats of poor water quality, assuming low terrestrial predation and desiccation risks. PMID- 26491196 TI - DeVries: the Art of not freezing fish. PMID- 26491195 TI - The mechanosensory lateral line is used to assess opponents and mediate aggressive behaviors during territorial interactions in an African cichlid fish. AB - Fish must integrate information from multiple sensory systems to mediate adaptive behaviors. Visual, acoustic and chemosensory cues provide contextual information during social interactions, but the role of mechanosensory signals detected by the lateral line system during aggressive behaviors is unknown. The aim of this study was first to characterize the lateral line system of the African cichlid fish Astatotilapia burtoni and second to determine the role of mechanoreception during agonistic interactions. The A. burtoni lateral line system is similar to that of many other cichlid fishes, containing lines of superficial neuromasts on the head, trunk and caudal fin, and narrow canals. Astatotilapia burtoni males defend their territories from other males using aggressive behaviors that we classified as non-contact or contact. By chemically and physically ablating the lateral line system prior to forced territorial interactions, we showed that the lateral line system is necessary for mutual assessment of opponents and the use of non-contact fight behaviors. Our data suggest that the lateral line system facilitates the use of non-contact assessment and fight behaviors as a protective mechanism against physical damage. In addition to a role in prey detection, the diversity of lateral line morphology in cichlids may have also enabled the expansion of their social behavioral repertoire. To our knowledge, this is the first study to implicate the lateral line system as a mode of social communication necessary for assessment during agonistic interactions. PMID- 26491197 TI - Antagonizing Peroxisome Proliferator-Activated Receptor alpha Activity Selectively Enhances Th1 Immunity in Male Mice. AB - Females exhibit more robust Th1 responses than males. Our previous work suggested that this sex disparity is a consequence of higher activity of the androgen induced gene peroxisome proliferator-activated receptor alpha (PPARalpha) in male CD4(+) T cells. The objective of this study was to elucidate the cellular and molecular mechanism of how PPARalpha inhibits Th1 responses in male mice. In this study, we found that PPARalpha functions within CD4(+) and CD8(+) T lymphocytes and NKT cells to negatively regulate IFN-gamma responses in male mice and identified Ifng as the gene target of PPARalpha repression. Treatment of male CD4(+) T cells with the PPARalpha agonist fenofibrate induced the recruitment of PPARalpha and the nuclear receptor-interacting protein, nuclear receptor corepressor 1, to specific cis-regulatory elements in the Ifng locus. This recruitment associated with reduced histone acetylation at these sites. Knockdown of nuclear receptor corepressor 1 in primary male T cells abolished the effect of fenofibrate in reducing IFN-gamma production. In contrast, treatment of male T cells with IS001, a novel antagonist of PPARalpha, increased Ifng gene expression and histone acetylation across the Ifng locus. Finally, we investigated the effects of IS001 on IFN-gamma responses in mice during infection with the Th1 associated pathogen Listeria monocytogenes and observed that IS001 enhanced IFN gamma production by NKT, CD4(+), and CD8(+) T cells and improved the survival of male, but not female, mice. Our findings provide a novel mechanism of why IFN gamma responses are more robust in females and introduce a small-molecule IS001 that can be used to enhance Th1 immunity in males. PMID- 26491198 TI - Expression of Cationic Amino Acid Transporter 2 Is Required for Myeloid-Derived Suppressor Cell-Mediated Control of T Cell Immunity. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells that expand during benign and cancer-associated inflammation and are characterized by their ability to inhibit T cell immunity. Increased metabolism of l-Arginine (l-Arg), through the enzymes arginase 1 and NO synthase 2 (NOS2), is well documented as a major MDSC suppressive mechanism. Therefore, we hypothesized that restricting MDSC uptake of l-Arg is a critical control point to modulate their suppressor activity. Using murine models of prostate-specific inflammation and cancer, we have identified the mechanisms by which extracellular l-Arg is transported into MDSCs. We have shown that MDSCs recruited to localized inflammation and tumor sites upregulate cationic amino acid transporter 2 (Cat2), coordinately with Arg1 and Nos2. Cat2 expression is not induced in MDSCs in peripheral organs. CAT2 contributes to the transport of l-Arg in MDSCs and is an important regulator of MDSC suppressive function. MDSCs that lack CAT2 have significantly reduced suppressive ability ex vivo and display impaired capacity for regulating T cell responses in vivo as evidenced by increased T cell expansion and decreased tumor growth in Cat2(-/-) mice. The abrogation of suppressive function is due to low intracellular l-Arg levels, which leads to the impaired ability of NOS2 to catalyze l-Arg-dependent metabolic processes. Together, these findings demonstrate that CAT2 modulates MDSC function. In the absence of CAT2, MDSCs display diminished capacity for controlling T cell immunity in prostate inflammation and cancer models, where the loss of CAT2 results in enhanced antitumor activity. PMID- 26491199 TI - Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses. AB - The MAP3 kinase, TAK1, is known to act upstream of IKK and MAPK cascades in several cell types, and is typically activated in response to cytokines (e.g., TNF, IL-1) and TLR ligands. In this article, we report that in human neutrophils, TAK1 can also be activated by different classes of inflammatory stimuli, namely, chemoattractants and growth factors. After stimulation with such agents, TAK1 becomes rapidly and transiently activated. Blocking TAK1 kinase activity with a highly selective inhibitor (5z-7-oxozeaenol) attenuated the inducible phosphorylation of ERK occurring in response to these stimuli but had little or no effect on that of p38 MAPK or PI3K. Inhibition of TAK1 also impaired MEKK3 (but not MEKK1) activation by fMLF. Moreover, both TAK1 and the MEK/ERK module were found to influence inflammatory cytokine expression and release in fMLF- and GM-CSF-activated neutrophils, whereas the PI3K pathway influenced this response independently of TAK1. Besides cytokine production, other responses were found to be under TAK1 control in neutrophils stimulated with chemoattractants and/or GM CSF, namely, delayed apoptosis and leukotriene biosynthesis. Our data further emphasize the central role of TAK1 in controlling signaling cascades and functional responses in primary neutrophils, making it a promising target for therapeutic intervention in view of the foremost role of neutrophils in several chronic inflammatory conditions. PMID- 26491200 TI - IL-21 and IL-4 Collaborate To Shape T-Dependent Antibody Responses. AB - The selection of affinity-matured Ab-producing B cells is supported by interactions with T follicular helper (Tfh) cells. In addition to cell surface expressed molecules, cytokines produced by Tfh cells, such as IL-21 and IL-4, provide B cell helper signals. In this study, we analyze how the fitness of Th cells can influence Ab responses. To do this, we used a model in which IL-21R sufficient (wild-type [WT]) and -deficient (Il21r(-/-)) Ag-specific Tfh cells were used to help immunodeficient Il21r(-/-) B cells following T-dependent immunization. Il21r(-/-) B cells that had received help from WT Tfh cells, but not from Il21r(-/-) Tfh cells, generated affinity-matured Ab upon recall immunization. This effect was dependent on IL-4 produced in the primary response and associated with an increased fraction of memory B cells. Il21r(-/-) Tfh cells were distinguished from WT Tfh cells by a decreased frequency, reduced conjugate formation with B cells, increased expression of programmed cell death 1, and reduced production of IL-4. IL-21 also influenced responsiveness to IL-4 because expression of both membrane IL-4R and the IL-4-neutralizing soluble (s)IL-4R were reduced in Il21r(-/-) mice. Furthermore, the concentration of sIL-4R was found to correlate inversely with the amount of IgE in sera, such that the highest IgE levels were observed in Il21r(-/-) mice with the least sIL-4R. Taken together, these findings underscore the important collaboration between IL-4 and IL-21 in shaping T-dependent Ab responses. PMID- 26491202 TI - Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma. AB - We reported an 81-year-old woman with metastatic melanoma, in whom myasthenia gravis and rhabdomyolysis developed after nivolumab monotherapy. The first symptom of myasthenia gravis was dyspnea. Ultrasonography detected hypokinesis of the bilateral diaphragm suggesting myasthenia gravis, although there was no abnormal finding of the lungs in computed tomography images. Acetylcholine receptor binding antibodies were low-titer positive in the preserved serum before administration of nivolumab, strongly suggesting that the myasthenia gravis was a nivolumab-related immune adverse event. Despite the remarkable clinical benefits of immune checkpoint inhibitors for patients with advanced melanoma, it is important to recognize unexpected immune-related adverse events. PMID- 26491203 TI - The association between overweight, obesity and ovarian cancer: a meta-analysis. AB - OBJECTIVE: Epidemiological studies have reported an inconsistent association between obesity and ovarian cancer. To update the current knowledge of and further qualify the association between overweight, obesity and ovarian cancer risk, we conducted a meta-analysis of published observational studies. METHODS: Using the PubMed, MEDLINE and EMBASE databases, we performed a literature search of all of the case-control and cohort studies published as original articles in English before March 2015. We included 26 observational studies, of which 13 were case-control studies (7782 cases and 21 854 controls) and 13 were cohort studies (5181 cases). Fixed- and random-effects models were used to compute summary estimates and the corresponding 95% confidence intervals. Subgroup analyses were also performed. RESULTS: The pooled relative risk for overweight and obesity compared with normal weight (body mass index = 18.5-24.9 kg/m(2)) was 1.07 (95% confidence interval: 1.02-1.12) and 1.28 (95% confidence interval: 1.16-1.41), respectively. In subgroup analyses, we found that overweight/obesity increased the risk of ovarian cancer in most groups, except for the postmenopausal group (overweight: pooled relative risk = 0.97, 95% confidence interval: 0.76-1.24; obesity: pooled relative risk = 0.93, 95% confidence interval: 0.61-1.42). There was no evidence of publication bias. CONCLUSIONS: Increased body weight was associated with an increased risk of ovarian cancer; in particular, severe obesity demonstrated a stronger risk effect. No statistically significant association was observed in the postmenopausal period, but was in the premenopausal period. PMID- 26491201 TI - Characterization of Lamprey IL-17 Family Members and Their Receptors. AB - IL-17 is an ancient cytokine implicated in a variety of immune defense reactions. We identified five members of the sea lamprey IL-17 family (IL-17D.1, IL-17D.2, IL-17E, IL-17B, and IL-17C) and six IL-17R genes (IL-17RA.1, IL-17RA.2, IL 17RA.3, IL-17RF, IL-17RE/RC, and IL-17RD), determined their relationship with mammalian orthologs, and examined their expression patterns and potential interactions to explore their roles in innate and adaptive immunity. The most highly expressed IL-17 family member is IL-17D.1 (mammalian IL-17D like), which was found to be preferentially expressed by epithelial cells of skin, intestine, and gills and by the two types of lamprey T-like cells. IL-17D.1 binding to rIL 17RA.1 and to the surface of IL-17RA.1-expressing B-like cells and monocytes of lamprey larvae was demonstrated, and treatment of lamprey blood cells with rIL 17D.1 protein enhanced transcription of genes expressed by the B-like cells. These findings suggest a potential role for IL-17 in coordinating the interactions between T-like cells and other cells of the adaptive and innate immune systems in jawless vertebrates. PMID- 26491204 TI - Randomized, prospective assessment of moisturizer efficacy for the treatment of radiation dermatitis following radiotherapy after breast-conserving surgery. AB - OBJECTIVE: The effect of heparinoid moisturizer use after acute skin damage for patients receiving whole-breast radiotherapy after lumpectomy is understudied. METHODS: A total of 30 patients were randomly assigned to receive heparinoid moisturizer (Group M), and 32 patients comprised the control group (Group C). Patients in Group M were instructed to apply heparinoid moisturizer from 2 weeks following whole-breast radiotherapy, and to continue to use the moisturizer until 3 months after completion of whole-breast radiotherapy. Group C patients were instructed to not apply any topical moisturizer during the study period. The relative ratio of skin water content ratio (RWCR(t) = (It /Nt)/(I0/N0)) between irradiated and non-irradiated field was calculated. Signs and symptoms were also assessed. The primary endpoint was the difference in relative ratio of skin water content ratio between 2 and 4 weeks following whole-breast radiotherapy. RESULTS: In Group C, relative ratio of skin water content ratio dropped to 0.80 +/- 0.15 at 2 weeks and maintained the low level at 4 weeks following whole-breast radiotherapy. Similarly, in Group M, relative ratio of skin water content ratio dropped to 0.81 +/- 0.19 at 2 weeks (prior to application), however, it returned to baseline level (1.05 +/- 0.23) at 4 weeks (2 weeks after application). The arithmetic difference of relative ratio of skin water content ratio in Group M was 0.24 +/- 0.23 and was significantly larger than in Group C (0.06 +/- 0.15; P < 0.01). Skin dryness and desquamation were less severe in Group M. CONCLUSIONS: The application of heparinoid moisturizer for 2 weeks following whole-breast radiotherapy significantly increased water content and helped improve skin dryness and desquamation compared with no use of moisturizer. PMID- 26491205 TI - Selective neck irradiation for supraglottic cancer: focus on Sublevel IIb omission. AB - OBJECTIVE: To estimate selective neck irradiation omitting surgical Sublevel IIb. METHODS: Bilateral necks of 47 patients (94 necks) were subjected to definitive radiotherapy for supraglottic cancer. Sixty-nine and 25 necks were clinically node negative (cN-) and clinically node positive (cN+), respectively. We subdivided Sublevel IIb by the international consensus guideline for radiotherapy into Sublevel IIb/a, directly posterior to the internal jugular vein, and Sublevel IIb/b, which was behind Sublevel IIb/a and coincided with surgical Sublevel IIb. Bilateral (Sub)levels IIa, III, IV and IIb/a were routinely irradiated, whereas Sublevel IIb/b was omitted from the elective clinical target volume in 73/94 treated necks (78%). RESULTS: Two patients presented with ipsilateral Sublevel IIb/a metastases. No Sublevel IIb/b metastasis was observed. Five patients experienced cervical lymph node recurrence; Sublevel IIb/a recurrence developed in two patients, whereas no Sublevel IIb/b recurrence occurred even in the cN- necks of cN+ patients or cN0 patients. The 5-year regional control rates were 91.5% for Sublevel IIb/b-omitted patients and 77.8% for Sublevel IIb/b treated patients. CONCLUSIONS: Selective neck irradiation omitting Sublevel IIb/b did not compromise regional control and could be indicated for cN- neck of supraglottic cancer. PMID- 26491206 TI - A heterobimetallic copper-titanium oxo cluster with a new structural motif. AB - ABSTRACT: Mixed-metal oxo clusters Cu4Ti5O6(OOCR)16 (OOCR = methacrylate, propionate) were obtained by reaction of titanium alkoxides and copper carboxylates with propionic or methacrylic acid. GRAPHICAL ABSTRACT: PMID- 26491207 TI - Euryjanicins E-G, poly-phenylalanine and poly-proline cyclic heptapeptides from the Caribbean sponge Prosuberites laughlini. AB - A new investigation of the active sponge extracts of Prosuberites laughlini collected off the West coast of Puerto Rico has yielded three new cyclic heptapeptides, namely euryjanicins E (1)-G (3), containing multiple phenylalanine and proline residues. In CDCl3 solution, each euryjanicin F (2) and G (3) exists as an inseparable complex mixture of conformational isomers. The molecular structures of 1-3 were elucidated by a combination of chemical degradation, extensive ESI-MS/MS n analyses, and 2D NMR methods. The elucidation of the absolute configuration was achieved by HPLC following analysis of the acid hydrolysates after derivatization with Marfey's reagent. When assayed against the National Cancer Institute 60 tumor cell line panel, the new cyclic peptides did not display significant in vitro cytotoxicity. PMID- 26491208 TI - Quandle colorings of knots and applications. AB - We present a set of 26 finite quandles that distinguish (up to reversal and mirror image) by number of colorings, all of the 2977 prime oriented knots with up to 12 crossings. We also show that 1058 of these knots can be distinguished from their mirror images by the number of colorings by quandles from a certain set of 23 finite quandles. We study the colorings of these 2977 knots by all of the 431 connected quandles of order at most 35 found by Vendramin. Among other things, we collect information about quandles that have the same number of colorings for all of the 2977 knots. For example, we prove that if Q is a simple quandle of prime power order then Q and the dual quandle Q* of Q have the same number of colorings for all knots and conjecture that this holds for all Alexander quandles Q. We study a knot invariant based on a quandle homomorphism f : Q1 -> Q0. We also apply the quandle colorings we have computed to obtain some new results for the bridge index, the Nakanishi index, the tunnel number, and the unknotting number. In an appendix we discuss various properties of the quandles in Vendramin's list. Links to the data computed and various programs in C, GAP and Maple are provided. PMID- 26491209 TI - Measurement of elemental concentration of aerosols using spark emission spectroscopy. AB - A coaxial microelectrode system has been used to collect and analyse the elemental composition of aerosol particles in near real-time using spark emission spectroscopy. The technique involves focused electrostatic deposition of charged aerosol particles onto the flat tip of a microelectrode, followed by introduction of spark discharge. A pulsed spark discharge was generated across the electrodes with input energy ranging from 50 to 300 mJ per pulse, resulting in the formation of controlled pulsed plasma. The particulate matter on the cathode tip is ablated and atomized by the spark plasma, resulting in atomic emissions which are subsequently recorded using a broadband optical spectrometer for element identification and quantification. The plasma characteristics were found to be very consistent and reproducible even after several thousands of spark discharges using the same electrode system. The spark plasma was characterized by measuring the excitation temperature (~7000 to 10 000 K), electron density (~1016 cm-3), and evolution of spectral responses as a function of time. The system was calibrated using particles containing Pb, Si, Na and Cr. Absolute mass detection limits in the range 11 pg to 1.75 ng were obtained. Repeatability of spectral measurements varied from 2 to 15%. The technique offers key advantages over similar microplasma-based techniques such as laser-induced breakdown spectroscopy, as: (i) it does not require any laser beam optics and eliminates any need for beam alignment, (ii) pulse energy from dc power supply in SIBS system can be much higher compared to that from laser source of the same physical size, and (iii) it is quite conducive to compact, field-portable instrumentation. PMID- 26491210 TI - The Relation between eNOS -786 C/T, 4 a/b, MMP-13 rs640198 G/T, Eotaxin 426 C/T, 384 A/G, and 67 G/A Polymorphisms and Long-Term Outcome in Patients with Coronary Artery Disease. AB - AIM: The purpose of this study is to determine the association between eotaxin 426 C/T, -384 A/G, 67 G/A, eNOS -786 T/C, 4 a/b, and MMP-13 rs640198 G/T and prognosis of patients with known CAD. METHODS: From total of 1161 patients referred to coronary angiography, 532 patients with angiographically confirmed CAD were selected. Their long-term outcome was followed up using hospital database. Subsequent events were assessed in this study: death or combined endpoint-myocardial infarction, unstable angina pectoris, revascularization, heart failure hospitalization, and cardioverter-defibrillator implantation. RESULTS: The multivariate Cox regression model identified age, smoking, and 3 vessel disease as significant predictors of all-cause death. Further analysis showed that eotaxin 67 G/A (GA + AA versus GG) and eotaxin -384 A/G (GG versus GA + AA) were significant independent prognostic factors when added into the model: HR (95% CI) 2.81 (1.35-5.85), p = 0.006; HR (95% CI) 2.63 (1.19-5.83), p = 0.017; eotaxin -384 A/G was significantly associated with the event-free survival, but it did not provide the prognostic information above the effect of two- or three vessel disease. CONCLUSION: The A allele in eotaxin 67 G/A polymorphism is associated with worse survival in CAD patients. PMID- 26491211 TI - Identification of Novel Epigenetic Markers of Prostate Cancer by NotI-Microarray Analysis. AB - A significant need for reliable and accurate cancer diagnostics and prognosis compels the search for novel biomarkers that would be able to discriminate between indolent and aggressive tumors at the early stages of disease. The aim of this work was identification of potential diagnostic biomarkers for characterization of different types of prostate tumors. NotI-microarrays with 180 clones associated with chromosome 3 genes/loci were applied to determine genetic and epigenetic alterations in 33 prostate tumors. For 88 clones, aberrations were detected in more than 10% of tumors. The major types of alterations were DNA methylation and/or deletions. Frequent methylation of the discovered loci was confirmed by bisulfite sequencing on selective sampling of genes: FGF12, GATA2, and LMCD1. Three genes (BHLHE40, BCL6, and ITGA9) were tested for expression level alterations using qPCR, and downregulation associated with hypermethylation was shown in the majority of tumors. Based on these data, we proposed the set of potential biomarkers for detection of prostate cancer and discrimination between prostate tumors with different malignancy and aggressiveness: BHLHE40, FOXP1, LOC285205, ITGA9, CTDSPL, FGF12, LOC440944/SETD5, VHL, CLCN2, OSBPL10/ZNF860, LMCD1, FAM19A4, CAND2, MAP4, KY, and LRRC58. Moreover, we probabilistically estimated putative functional relations between the genes within each set using the network enrichment analysis. PMID- 26491212 TI - FGF23 in Acute and Chronic Illness. AB - FGF23 is a bone-derived phosphaturic hormone that may become a useful biomarker for the identification of high-risk patients in chronic but also acute disease. It rises early in chronic kidney disease and is strongly and independently associated with excess morbidity and mortality. Emerging data suggest that FGF23 is also elevated in different scenarios of acute illness. In this review, we give an overview on the role of this interesting disease marker and potential and proven interventional strategies and discuss a blueprint for future research. PMID- 26491213 TI - Roles of NOTCH1 as a Therapeutic Target and a Biomarker for Lung Cancer: Controversies and Perspectives. AB - Lung cancer is one of the most common types of human malignancies and the leading cause of cancer-related death. Patients with surgically resectable early stage lung cancer are more likely curable, but currently only a small population of patients can be diagnosed at such a stage, partly due to our incomplete understanding of the biology of lung cancer and the lack of diagnostic and prognostic biomarkers. Recent studies have shown that NOTCH1 is a critical regulator of human carcinogenesis and has been implicated in multiple steps of cancer development and progression. Herein, we review recent findings about the role of NOTCH1 in lung cancer and discuss its potential usefulness as both a therapeutic target and a biomarker for lung cancer. PMID- 26491215 TI - Assessment of Immunological Biomarkers in the First Year after Heart Transplantation. AB - BACKGROUND: Pharmacodynamic biomarkers that detect changes of immunological functions have been recognized as a helpful tool to increase the efficacy of immunosuppressive drug therapies. However, physiological changes of immunological biomarkers following transplantation are not investigated. Therefore, we assessed frequently used immunological biomarkers of the circulating blood in the first year following heart transplantation (HTx). METHODS: Activation markers CD25 and CD95, intracellular cytokines IL-2 and IFNgamma, chemokines IP10 and MIG, and subsets of dendritic cells as well as antibodies against human leukocyte antigens (HLA) and major histocompatibility complex class I-related chain A (MICA) antigens were analyzed at different time points using flow cytometry and Luminex xMAP technology. RESULTS: Expression of IL-2, IFNgamma, and plasmacytoid dendritic cells (pDCs) significantly increased (p < 0.01) during the first year. Anti-HLA antibodies decreased continuously, while anti-MICA antibodies showed minor increase within the first year. An association between percentage of pDCs and anti-MICA antibody positivity was proven. pDCs, IFNgamma-producing T cells, and IP10 concentration were associated in a stronger way with age and gender of HTx recipients than with antibodies against HLA or MICA. CONCLUSIONS: We conclude that certain immunological biomarkers of the circulating blood change during the first year after HTx. These changes should be considered for interpretation of biomarkers after transplantation. PMID- 26491214 TI - Association of Angiotensin Converting Enzyme Insertion-Deletion Polymorphism with Hypertension in Emiratis with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status. AB - The association of Angiotensin Converting Enzyme (ACE) insertion-deletion (I/D) polymorphism with Type 2 Diabetes Mellitus (T2DM) and hypertension has been extensively studied throughout various ethnic populations but largely with inconsistent findings. We investigated these associations in Emirati population and their interaction with obesity status. Saliva samples were collected from a total of 564 Emiratis (277 T2DM and 297 healthy). DNA was extracted and the samples were genotyped for ACE I/D polymorphism by a PCR based method followed by gel electrophoresis. Upon evaluation of the ACE I/D polymorphism amongst all T2DM, hypertensive patients, and respective controls regardless of obesity status, ACE DD genotype was not found to be associated with either T2DM [odds ratio (OR) = 1.34, p = 0.086] or hypertension [odd ratio (OR) = 1.02, p = 0.93]. When the genetic variants amongst the nonobese and obese population were analyzed separately, the risk genotype ACE DD conferred significantly increased risk of hypertension in nonobese population [odds ratio (OR) = 1.80, p = 0.02] but was found to be protective against the hypertension in the obese group ((OR) = 0.54, p = 0.01). However, there was no effect of obesity status on the association of ACE genotypes with T2DM. The risk of hypertension associated with ACE DD is modulated by obesity status and hence future genetic association studies should take obesity into account for the interpretation of data. We also confirmed that ACE I/D polymorphism is not associated with T2DM risk in Emirati population. PMID- 26491217 TI - Preoperative Diagnostic Angiogram and Endovascular Aortic Stent Placement for Appleby Resection Candidates: A Novel Surgical Technique in the Management of Locally Advanced Pancreatic Cancer. AB - Background. Pancreatic adenocarcinoma of the body and tail usually presents late and is typically unresectable. The modified Appleby procedure allows resection of pancreatic body carcinoma with celiac axis (CA) invasion. Given that the feasibility of this technique is based on the presence of collateral circulation, it is crucial to confirm the presence of an anatomical and functional collateral system. Methods. We here describe a novel technique used in two patients who were candidates for Appleby resection. We present their clinical scenario, imaging, operative findings, and postoperative course. Results. Both patients had a preoperative angiogram for assessment of anatomical circulation and placement of an endovascular stent to cover the CA. We hypothesize that this new technique allows enhancement of collateral circulation and helps minimize intraoperative blood loss when transecting the CA at its takeoff. Moreover, extra length on the CA margin may be gained, as the artery can be transected at its origin without the need for vascular clamp placement. Conclusion. We propose this novel technique in the preoperative management of patients who are undergoing a modified Appleby procedure. While further experience with this technique is required, we believe that it confers significant advantages to the current standard of care. PMID- 26491216 TI - Overview of simulation studies on the enzymatic activity and conformational dynamics of the GTPase Ras. AB - Over the last 40 years, we have learnt a great deal about the Ras onco-proteins. These intracellular molecular switches are essential for the function of a variety of physiological processes, including signal transduction cascades responsible for cell growth and proliferation. Molecular simulations and free energy calculations have played an essential role in elucidating the conformational dynamics and energetics underlying the GTP hydrolysis reaction catalysed by Ras. Here we present an overview of the main lessons from molecular simulations on the GTPase reaction and conformational dynamics of this important anti-cancer drug target. In the first part, we summarise insights from quantum mechanical and combined quantum mechanical/molecular mechanical simulations as well as other free energy methods and highlight consensus viewpoints as well as remaining controversies. The second part provides a very brief overview of new insights emerging from large-scale molecular dynamics simulations. We conclude with a perspective regarding future studies of Ras where computational approaches will likely play an active role. PMID- 26491218 TI - SHARP ENTRYWISE PERTURBATION BOUNDS FOR MARKOV CHAINS. AB - For many Markov chains of practical interest, the invariant distribution is extremely sensitive to perturbations of some entries of the transition matrix, but insensitive to others; we give an example of such a chain, motivated by a problem in computational statistical physics. We have derived perturbation bounds on the relative error of the invariant distribution that reveal these variations in sensitivity. Our bounds are sharp, we do not impose any structural assumptions on the transition matrix or on the perturbation, and computing the bounds has the same complexity as computing the invariant distribution or computing other bounds in the literature. Moreover, our bounds have a simple interpretation in terms of hitting times, which can be used to draw intuitive but rigorous conclusions about the sensitivity of a chain to various types of perturbations. PMID- 26491219 TI - Necroptotic Cell Death Signaling and Execution Pathway: Lessons from Knockout Mice. AB - Under stress conditions, cells in living tissue die by apoptosis or necrosis depending on the activation of the key molecules within a dying cell that either transduce cell survival or death signals that actively destroy the sentenced cell. Multiple extracellular (pH, heat, oxidants, and detergents) or intracellular (DNA damage and Ca(2+) overload) stress conditions trigger various types of the nuclear, endoplasmic reticulum (ER), cytoplasmatic, and mitochondrion-centered signaling events that allow cells to preserve the DNA integrity, protein folding, energetic, ionic and redox homeostasis, thus escaping from injury. Along the transition from reversible to irreversible injury, death signaling is highly heterogeneous and damaged cells may engage autophagy, apoptotic, or necrotic cell death programs. Studies on multiple double- and triple- knockout mice identified caspase-8, flip, and fadd genes as key regulators of embryonic lethality and inflammation. Caspase-8 has a critical role in pro- and antinecrotic signaling pathways leading to the activation of receptor interacting protein kinase 1 (RIPK1), RIPK3, and the mixed kinase domain-like (MLKL) for a convergent execution pathway of necroptosis or regulated necrosis. Here we outline the recent discoveries into how the necrotic cell death execution pathway is engaged in many physiological and pathological outcome based on genetic analysis of knockout mice. PMID- 26491220 TI - Targeting the Mitotic Catastrophe Signaling Pathway in Cancer. AB - Mitotic catastrophe, as defined in 2012 by the International Nomenclature Committee on Cell Death, is a bona fide intrinsic oncosuppressive mechanism that senses mitotic failure and responds by driving a cell to an irreversible antiproliferative fate of death or senescence. Thus, failed mitotic catastrophe can promote the unrestrained growth of defective cells, thereby representing a major gateway to tumour development. Furthermore, the activation of mitotic catastrophe offers significant therapeutic advantage which has been exploited in the action of conventional and targeted anticancer agents. Yet, despite its importance in tumour prevention and treatment, the molecular mechanism of mitotic catastrophe is not well understood. A better understanding of the signals that determine cell fate following failed or defective mitosis will reveal new opportunities to selectively target and enhance the programme for therapeutic benefit and reveal biomarkers to predict patient response. This review is focused on the molecular mechanism of mitotic catastrophe induction and signalling and highlights current strategies to exploit the process in cancer therapy. PMID- 26491221 TI - Endothelial-Leukocyte Interaction in Severe Malaria: Beyond the Brain. AB - Malaria is the most important parasitic disease worldwide, accounting for 1 million deaths each year. Severe malaria is a systemic illness characterized by dysfunction of brain tissue and of one or more peripheral organs as lungs and kidney. The most severe and most studied form of malaria is associated with cerebral complications due to capillary congestion and the adhesion of infected erythrocytes, platelets, and leukocytes to brain vasculature. Thus, leukocyte rolling and adhesion in the brain vascular bed during severe malaria is singular and distinct from other models of inflammation. The leukocyte/endothelium interaction and neutrophil accumulation are also observed in the lungs. However, lung interactions differ from brain interactions, likely due to differences in the blood-brain barrier and blood-air barrier tight junction composition of the brain and lung endothelium. Here, we review the importance of endothelial dysfunction and the mechanism of leukocyte/endothelium interaction during severe malaria. Furthermore, we hypothesize a possible use of adjunctive therapies to antimalarial drugs that target the interaction between the leukocytes and the endothelium. PMID- 26491222 TI - Anti-Inflammatory Effects of a Methanol Extract from the Marine Sponge Geodia cydonium on the Human Breast Cancer MCF-7 Cell Line. AB - Many research groups are working to find new possible anti-inflammatory molecules, and marine sponges represent a rich source of biologically active compounds with pharmacological applications. In the present study, we tested different concentrations of the methanol extract from the marine sponge, Geodia cydonium, on normal human breast epithelial cells (MCF-10A) and human breast cancer cells (MCF-7). Our results show that this extract has no cytotoxic effects on both cell lines whereas it induces a decrease in levels of VEGF and five proinflammatory cytokines (CCL2, CXCL8, CXCL10, IFN-gamma, and TNF-alpha) only in MCF-7 cells in a dose-dependent manner, thereby indicating an anti-inflammatory effect. Moreover, interactomic analysis suggests that all six cytokines are involved in a network and are connected with some HUB nodes such as NF-kB subunits and ESR1 (estrogen receptor 1). We also report a decrease in the expression of two NFKB1 and c-Rel subunits by RT-qPCR experiments only in MCF-7 cells after extract treatment, confirming NF-kB inactivation. These data highlight the potential of G. cydonium for future drug discovery against major diseases, such as breast cancer. PMID- 26491223 TI - Looking for Pyroptosis-Modulating miRNAs as a Therapeutic Target for Improving Myocardium Survival. AB - Pyroptosis is the most recently identified type of regulated cell death with inflammatory response and has characteristics distinct from those of apoptosis or necrosis. Recently, independent studies have reported that small noncoding RNAs termed microRNAs (miRNAs) are involved in the regulation of pyroptosis. Nevertheless, only a handful of empirical data regarding miRNA-dependent regulation of pyroptosis is currently available. This review is aimed to provide a current update on the role of miRNAs in pyroptosis and to offer suggestions for future studies probing miRNAs as a linker connecting pyroptosis to various cardiovascular diseases (CVDs) and their potential as a therapeutic target for preventing excessive cell death of myocardium during CVDs. PMID- 26491224 TI - Cellular Response upon Stress: p57 Contribution to the Final Outcome. AB - Progression through the cell cycle is one of the most important decisions during the life of a cell and several kinds of stress are able to influence this choice. p57 is a cyclin-dependent kinase inhibitor belonging to the CIP/KIP family and is a well-known regulator of the cell cycle during embryogenesis and tissue differentiation. p57 loss has been reported in a variety of cancers and great effort has been spent during the past years studying the mechanisms of p57 regulation and the effects of p57 reexpression on tumor growth. Recently, growing amount of evidence points out that p57 has a specific function in cell cycle regulation upon cellular stress that is only partially shared by the other CIP/KIP inhibitors p21 and p27. Furthermore, it is nowadays emerging that p57 plays a role in the induction of apoptosis and senescence after cellular stress independently of its cell cycle related functions. This review focuses on the contribution that p57 holds in regulating cell cycle arrest, apoptosis, and senescence after cellular stress with particular attention to the response of cancer cells. PMID- 26491225 TI - Downregulation of Lung Toll-Like Receptor 4 Could Effectively Attenuate Liver Transplantation-Induced Pulmonary Damage at the Early Stage of Reperfusion. AB - Acute lung injury (ALI) is a severe complication of orthotopic liver transplantation (OLT) with unclear underline mechanism. Toll-like receptor 4 (TLR4) has been identified as a key receptor mediating inflammation. We hypothesized that TLR4-mediated pulmonary inflammation may contribute to development of ALI during OLT. Patients with or without ALI were observed for serum cytokines and expression of TLR4 on peripheral blood polymorphonuclear leukocytes (PMNs). Next, rats which underwent orthotopic autologous liver transplantation (OALT) were divided into sham and model groups. Pulmonary function and the level of TLR4 expression and cytokines were analyzed. Furthermore, the role of TLR4 in OALT-mediated ALI was assessed in rats treated with TLR4-siRNA before OALT. The PMNs TLR4 expression and the serum TNF-alpha and IL-beta level were higher in patients with ALI than those with non-ALI. Interestingly, lung TLR4 expression was significantly increased after 8 hours of OALT with increased levels of TNF-alpha and IL-beta, which lead to lung pathological damage and an increase of lung myeloperoxidase content. Moreover, knockdown of TLR4 reduced lung cytokines release and reversed the above pathologic changes after OALT and finally improved rats' survival rate. In conclusion, TLR4 overexpression, potentially by stimulating proinflammatory cytokine overproduction, contributes to the development of ALI after OLT. PMID- 26491226 TI - Cancer Microenvironment and Endoplasmic Reticulum Stress Response. AB - Different stressful conditions such as hypoxia, nutrient deprivation, pH changes, or reduced vascularization, potentially able to act as growth-limiting factors for tumor cells, activate the unfolded protein response (UPR). UPR is therefore involved in tumor growth and adaptation to severe environments and is generally cytoprotective in cancer. The present review describes the molecular mechanisms underlying UPR and able to promote survival and proliferation in cancer. The critical role of UPR activation in tumor growth promotion is discussed in detail for a few paradigmatic tumors such as prostate cancer and melanoma. PMID- 26491227 TI - Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms. AB - The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34(+) cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34(+) cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs. PMID- 26491228 TI - Cardiac-Restricted IGF-1Ea Overexpression Reduces the Early Accumulation of Inflammatory Myeloid Cells and Mediates Expression of Extracellular Matrix Remodelling Genes after Myocardial Infarction. AB - Strategies to limit damage and improve repair after myocardial infarct remain a major therapeutic goal in cardiology. Our previous studies have shown that constitutive expression of a locally acting insulin-like growth factor-1 Ea (IGF 1Ea) propeptide promotes functional restoration after cardiac injury associated with decreased scar formation. In the current study, we investigated the underlying molecular and cellular mechanisms behind the enhanced functional recovery. We observed improved cardiac function in mice overexpressing cardiac specific IGF-1Ea as early as day 7 after myocardial infarction. Analysis of gene transcription revealed that supplemental IGF-1Ea regulated expression of key metalloproteinases (MMP-2 and MMP-9), their inhibitors (TIMP-1 and TIMP-2), and collagen types (Col 1alpha1 and Col 1alpha3) in the first week after injury. Infiltration of inflammatory cells, which direct the remodelling process, was also altered; in particular there was a notable reduction in inflammatory Ly6C+ monocytes at day 3 and an increase in anti-inflammatory CD206+ macrophages at day 7. Taken together, these results indicate that the IGF-1Ea transgene shifts the balance of innate immune cell populations early after infarction, favouring a reduction in inflammatory myeloid cells. This correlates with reduced extracellular matrix remodelling and changes in collagen composition that may confer enhanced scar elasticity and improved cardiac function. PMID- 26491229 TI - S-Nitrosoglutathione Reductase Plays Opposite Roles in SH-SY5Y Models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. AB - Oxidative and nitrosative stresses have been reported as detrimental phenomena concurring to the onset of several neurodegenerative diseases. Here we reported that the ectopic modulation of the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR) differently impinges on the phenotype of two SH-SY5Y-based in vitro models of neurodegeneration, namely, Parkinson's disease (PD) and familial amyotrophic lateral sclerosis (fALS). In particular, we provide evidence that GSNOR-knocking down protects SH-SY5Y against PD toxins, while, by contrast, its upregulation is required for G93A-SOD1 expressing cells resistance to NO releasing drugs. Although completely opposite, both conditions are characterized by Nrf2 localization in the nuclear compartment: in the first case induced by GSNOR silencing, while in the second one underlying the antinitrosative response. Overall, our results demonstrate that GSNOR expression has different effect on neuronal viability in dependence on the stimulus applied and suggest that GSNOR could be a responsive gene downstream of Nrf2 activation. PMID- 26491230 TI - Postmitotic Expression of SOD1(G93A) Gene Affects the Identity of Myogenic Cells and Inhibits Myoblasts Differentiation. AB - To determine the role of mutant SOD1 gene (SOD1(G93A)) on muscle cell differentiation, we derived C2C12 muscle cell lines carrying a stably transfected SOD1(G93A) gene under the control of a myosin light chain (MLC) promoter-enhancer cassette. Expression of MLC/SOD1(G93A) in C2C12 cells resulted in dramatic inhibition of myoblast differentiation. Transfected SOD1(G93A) gene expression in postmitotic skeletal myocytes downregulated the expression of relevant markers of committed and differentiated myoblasts such as MyoD, Myogenin, MRF4, and the muscle specific miRNA expression. The inhibitory effects of SOD1(G93A) gene on myogenic program perturbed Akt/p70 and MAPK signaling pathways which promote differentiation cascade. Of note, the inhibition of the myogenic program, by transfected SOD1(G93A) gene expression, impinged also the identity of myogenic cells. Expression of MLC/SOD1(G93A) in C2C12 myogenic cells promoted a fibro adipogenic progenitors (FAPs) phenotype, upregulating HDAC4 protein and preventing the myogenic commitment complex BAF60C-SWI/SNF. We thus identified potential molecular mediators of the inhibitory effects of SOD1(G93A) on myogenic program and disclosed potential signaling, activated by SOD1(G93A), that affect the identity of the myogenic cell population. PMID- 26491231 TI - Hypoxia Inducible Factor Pathway and Physiological Adaptation: A Cell Survival Pathway? AB - Oxygen homeostasis reflects the constant body requirement to generate energy. Hypoxia (0.1-1% O2), physioxia or physoxia (~1-13%), and normoxia (~20%) are terms used to define oxygen concentration in the cellular environment. A decrease in oxygen (hypoxia) or excess oxygen (hyperoxia) could be deleterious for cellular adaptation and survival. Hypoxia can occur under both physiological (e.g., exercise, embryonic development, underwater diving, or high altitude) and pathological conditions (e.g., inflammation, solid tumor formation, lung disease, or myocardial infarction). Hypoxia plays a key role in the pathophysiology of heart disease, cancers, stroke, and other causes of mortality. Hypoxia inducible factor(s) (HIFs) are key oxygen sensors that mediate the ability of the cell to cope with decreased oxygen tension. These transcription factors regulate cellular adaptation to hypoxia and protect cells by responding acutely and inducing production of endogenous metabolites and proteins to promptly regulate metabolic pathways. Here, we review the role of the HIF pathway as a metabolic adaptation pathway and how this pathway plays a role in cell survival. We emphasize the roles of the HIF pathway in physiological adaptation, cell death, pH regulation, and adaptation during exercise. PMID- 26491233 TI - Multidrug Resistance Protein-4 Influences Aspirin Toxicity in Human Cell Line. AB - Overexpression of efflux transporters, in human cells, is a mechanism of resistance to drug and also to chemotherapy. We found that multidrug resistance protein-4 (MRP4) overexpression has a role in reducing aspirin action in patients after bypass surgery and, very recently, we found that aspirin enhances platelet MRP4 levels through peroxisome proliferator activated receptor-alpha (PPARalpha). In the present paper, we verified whether exposure of human embryonic kidney-293 cells (Hek-293) to aspirin modifies MRP4 gene expression and its correlation with drug elimination and cell toxicity. We first investigated the effect of high-dose aspirin in Hek-293 and we showed that aspirin is able to increase cell toxicity dose-dependently. Furthermore, aspirin effects, induced at low dose, already enhance MRP4 gene expression. Based on these findings, we compared cell viability in Hek-293, after high-dose aspirin treatment, in MRP4 overexpressing cells, either after aspirin pretreatment or in MRP4 transfected cells; in both cases, a decrease of selective aspirin cell growth inhibition was observed, in comparison with the control cultures. Altogether, these data suggest that exposing cells to low nontoxic aspirin dosages can induce gene expression alterations that may lead to the efflux transporter protein overexpression, thus increasing cellular detoxification of aspirin. PMID- 26491234 TI - Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI. AB - Drug induced liver injury (DILI) is an idiosyncratic adverse drug reaction leading to severe liver damage. Kupffer cells (KC) sense hepatic tissue stress/damage and therefore could be a tool for the estimation of consequent effects associated with DILI. Aim of the present study was to establish a human in vitro liver model for the investigation of immune-mediated signaling in the pathogenesis of DILI. Hepatocytes and KC were isolated from human liver specimens. The isolated KC yield was 1.2 +/- 0.9 * 10(6) cells/g liver tissue with a purity of >80%. KC activation was investigated by the measurement of reactive oxygen intermediates (ROI, DCF assay) and cell activity (XTT assay). The initial KC activation levels showed broad donor variability. Additional activation of KC using supernatants of hepatocytes treated with hepatotoxic drugs increased KC activity and led to donor-dependent changes in the formation of ROI compared to KC incubated with supernatants from untreated hepatocytes. Additionally, a compound- and donor-dependent increase in proinflammatory cytokines or in anti-inflammatory cytokines was detected. In conclusion, KC related immune signaling in hepatotoxicity was successfully determined in a newly established in vitro liver model. KC were able to detect hepatocyte stress/damage and to transmit a donor- and compound-dependent immune response via cytokine production. PMID- 26491232 TI - Redox Signaling in Diabetic Nephropathy: Hypertrophy versus Death Choices in Mesangial Cells and Podocytes. AB - This review emphasizes the role of oxidative stress in diabetic nephropathy, acting as trigger, modulator, and linker within the complex network of pathologic events. It highlights key molecular pathways and new hypothesis in diabetic nephropathy, related to the interferences of metabolic, oxidative, and inflammatory stresses. Main topics this review is addressing are biomarkers of oxidative stress in diabetic nephropathy, the sources of reactive oxygen species (mitochondria, NADPH-oxidases, hyperglycemia, and inflammation), and the redox sensitive signaling networks (protein kinases, transcription factors, and epigenetic regulators). Molecular switches deciding on the renal cells fate in diabetic nephropathy are presented, such as hypertrophy versus death choices in mesangial cells and podocytes. Finally, the antioxidant response of renal cells in diabetic nephropathy is tackled, with emphasis on targeted therapy. An integrative approach is needed for identifying key molecular networks which control cellular responses triggered by the array of stressors in diabetic nephropathy. This will foster the discovery of reliable biomarkers for early diagnosis and prognosis, and will guide the discovery of new therapeutic approaches for personalized medicine in diabetic nephropathy. PMID- 26491236 TI - Computational Analysis of Amiloride Analogue Inhibitors of Coxsackievirus B3 RNA Polymerase. AB - Coxsackievirus B3 (CVB3) is a picornavirus that is responsible for a significant proportion of human myocarditis. However, no antiviral treatment is currently available to treat this disease or indeed any picornaviral infections. Previously it was shown that amiloride and its derivative 5-(N-ethyl-N-isopropyl)amiloride inhibit the in vitro enzymatic activity of CVB3 RNA polymerase (3Dpol). Here we measure and compare the inhibitory activity of ten amiloride analogues against CVB3 3Dpol. We show that replacement of the 3,5-diaminopyrazinyl moiety of amiloride causes loss of the inhibitory activity, whereas modifications at the 5 amino and guanidino groups increase or decrease potency. Importantly, a combination of substitutions at both the 5-amino and guanidino groups produced a compound that was more potent than its singly modified precursors. The compounds were computationally-docked into available crystal structures of CVB3 3Dpol in order to obtain a structural explanation for the activities of the analogues. To create a robust model which explained the biological activity, optimization of one of the CVB3 3Dpol crystal structures to take into account active site flexibility was necessary, together with the use of consensus docking from two different docking algorithms. This robust predictive 3D atomic model provides insights into the interactions required for inhibitor binding and provides a promising basis for the development of more potent inhibitors against this important therapeutic target. PMID- 26491235 TI - The Link between Fetal Programming, Inflammation, Muscular Strength, and Blood Pressure. AB - Hypertension affects one billion individuals worldwide and is considered the leading cause of cardiovascular death, stroke, and myocardial infarction. This increase in the burden of hypertension and cardiovascular diseases (CVD) is principally driven by lifestyle changes such as increased hypercaloric diets and reduced physical activity producing an increase of obesity, insulin resistance, and low-grade inflammation. Visceral adipocytes are the principal source of proinflammatory cytokines and systemic inflammation participates in several steps in the development of CVD. However, maternal and infant malnutrition also persists as a major public health issue in low- to middle-income regions such as Latin America (LA). We propose that the increased rates of cardiovascular and metabolic diseases in these countries could be the result of the discrepancy between a restricted nutritional environment during fetal development and early life, and a nutritionally abundant environment during adulthood. Maternal undernutrition, which may manifest in lower birth weight offspring, appears to accentuate the relative risk of chronic disease at lower levels of adiposity. Therefore, LA populations may be more vulnerable to the pathogenic consequences of obesity than individuals with similar lifestyles in high-income countries, which may be mediated by higher levels of proinflammatory markers and lower levels of muscle mass and strength observed in low birth weight individuals. PMID- 26491237 TI - Factors Promoting Mental Health of Adolescents Who Have a Parent with Mental Illness: A Longitudinal Study. AB - BACKGROUND: Children of parents with mental illness have an elevated risk of developing a range of mental health and psychosocial problems. Yet many of these children remain mentally healthy. OBJECTIVE: The present study aimed to get insight into factors that protect these children from developing internalizing and externalizing problems. METHODS: Several possible individual, parent-child, and family protective factors were examined cross-sectionally and longitudinally in a sample of 112 adolescents. A control group of 122 adolescents whose parents have no mental illness was included to explore whether the protective factors were different between adolescents with and without a parent with mental illness. RESULTS: Cross-sectional analyses revealed that high self-esteem and low use of passive coping strategies were related to fewer internalizing and externalizing problems. Greater self-disclosure was related to fewer internalizing problems and more parental monitoring was related to fewer externalizing problems. Active coping strategies, parental support, and family factors such as cohesion were unrelated to adolescent problem behavior. Longitudinal analyses showed that active coping, parental monitoring, and self-disclosure were protective against developing internalizing problems 2 years later. We found no protective factors for externalizing problems. Moderation analyses showed that the relationships between possible protective factors and adolescent problem behavior were not different for adolescents with and without a parent with mental illness. CONCLUSIONS: The findings suggest that adolescents' active coping strategies and parent-child communication may be promising factors to focus on in interventions aimed at preventing the development of internalizing problems by adolescents who have a parent with mental illness. PMID- 26491238 TI - A Measure of the Parent-Team Alliance in Youth Residential Psychiatry: The Revised Short Working Alliance Inventory. AB - BACKGROUND: The therapeutic alliance between multidisciplinary teams and parents within youth (semi) residential psychiatry is essential for the treatment process and forms a promising process variable for Routine Outcome Monitoring (ROM). No short evaluative instrument, however, is currently available to assess parent team alliance. OBJECTIVE: In this study, the Working Alliance Inventory-Short Version (WAV-12), a widely used alliance questionnaire, was adjusted to assess parent-team alliance from both a parent and team perspective within a youth residential setting. Psychometric properties, including factor structure and validity of the subscales, were explored. METHODS: A sample of youth with mainly complex developmental disorders admitted to 11 inpatient and day patient units of a child and adolescent psychiatric institute participated in this study. The case manager involved with the youth and the primary caregiver of 87 youth completed the revised WAV-12 (WAV-12R). RESULTS: The team version of the WAV-12R showed a good fit to the original conceptualized model, and distinguished Bond, Task and Goal scales. For the parents' version an adjusted model with Insight, Bond and combined Task/Goal scales had the best fit. The reliability and validity of the scales were shown to be good. CONCLUSIONS: This paper presents preliminary evidence that the parent and treatment team versions of the WAV-12R are psychometrically sound for assessing parent-team alliance within youth (semi) residential psychiatry in the Netherlands. The team and parents' versions of the WAV-12R are recommended instruments to complement outcome measures in ROM. PMID- 26491239 TI - Clinical experience in treatment of diffuse unilateral subretinal neuroretinitis. AB - PURPOSE: To describe the clinical features, management, and outcomes of patients with diffuse unilateral subacute neuroretinitis (DUSN). METHODS: A noncomparative, consecutive analysis of case series from two tertiary care campuses of LV Prasad Eye Institute, India, between January 2011 and April 2014 was performed. Medical records of the patients presenting with DUSN (early or late stage) were reviewed. RESULTS: The current study included 13 patients. The majority (10/13, 76.92%) of the patients were aged 20 years or less. All patients had unilateral eye involvement. Visual acuity at presentation was 20/200 or worse in 9/13 (69.23%) patients. A delay in diagnosis occurred in 6/13 patients, and initial diagnosis in these patients included retinitis pigmentosa (4 patients) and posterior uveitis (2 patients). Clinical features included early presentation (prominent vitritis, localized retinitis, and vasculitis) in 7/13 (53.85%) patients and late presentation (attenuation of vessels, retinal pigment epithelium atrophic changes, and optic atrophy) in 6/13 (46.15%) patients. Worm could not be identified in any of the cases. All the patients received laser photocoagulation of retina and oral albendazole treatment for a period of 30 days. With treatment, visual acuity improved in seven patients (six early stage, one late stage) and remained unchanged in six patients. Mean follow-up period was 8.69 months (range, 1-21 months). The mean central foveal thickness in the affected eye, done by optical coherence tomography, during the late stage of the disease was 188.20+/-40 um (range, 111-242 um), which was significantly thinner than the fellow eye, 238.70+/-36.90 um (range, 186-319 um), P=0.008. CONCLUSION: DUSN is a serious vision threatening disease, which may progress to profound vision loss in the later stage of the disease. Visualization of subretinal worm is usually not possible. Treatment with high-dose albendazole therapy and laser photocoagulation may alter the blood-retinal barrier and may be useful in achieving visual recovery. PMID- 26491240 TI - Impact of surgeon subspecialty training on surgical outcomes in open globe injuries. AB - PURPOSE: The purpose of this study was to evaluate whether subspecialty training of the initial treating surgeon affects visual acuity and surgical outcomes in patients with open globe injuries. DESIGN: This study is a single-institution, retrospective case series. METHODS: The charts of adult patients with open globe injuries requiring surgical repair at the Wilmer Eye Institute between July 1, 2007 and July 1, 2012 were retrospectively reviewed. Clinical findings at presentation were recorded, and details of initial repair and follow-up surgeries were analyzed. Differences in visual acuity and surgical outcomes were compared based on subspecialty training of the initial surgeon. RESULTS: The charts of 282 adult patients were analyzed, and 193 eyes had at least 6 months of follow-up for analysis. Eighty-six eyes (44.6%) required follow-up surgery within the first year, and 39 eyes (20.2%) were enucleated. Eyes initially treated by a vitreoretinal (VR) surgeon were 2.3 times (P=0.003) more likely to improve by one Ocular Trauma Score (OTS) visual acuity category and 1.9 times (P=0.027) more likely to have at least one more follow-up surgery at 6 months compared to eyes treated by non-VR surgeons. Patients with more anterior injuries treated by a VR surgeon were more likely to improve by one OTS visual acuity category compared to those treated by non-VR surgeons (P=0.004 and 0.016 for Zones I and II, respectively). There was no difference in visual acuity outcomes for eyes with posterior injuries (P=0.515 for Zone III). CONCLUSION: Eyes initially treated by a VR surgeon are more likely to improve by one OTS visual acuity category than those initially treated by a non-VR surgeon. However, patients initially treated by a VR surgeon also undergo more follow-up surgical rehabilitation, and improvement in visual acuity is more likely for anterior (Zone I and II injuries) than posterior (Zone III) injuries. PMID- 26491241 TI - Recurrent rates and risk factors associated with recurrent painful bullous keratopathy after primary phototherapeutic keratectomy. AB - OBJECTIVE: To assess the recurrent rate, mean survival time, and risk factors associated with recurrent painful bullous keratopathy (BK) after primary treatment with phototherapeutic keratectomy. METHODS: Medical records from 72 patients (72 eyes) who had phototherapeutic keratectomy for painful BK were evaluated. Data for sex, age, duration of BK, associated ocular and systemic diseases (hypertension, diabetes mellitus, ischemic heart disease, asthma, dyslipidemia, and rheumatoid arthritis), frequency and degree of pain (grade 1 3), visual acuity, corneal thickness, intraocular pressure, and laser setting were extracted and analyzed. RESULTS: The mean age of the patients was 64.2+/ 11.4 years. The mean preoperative duration of BK was 15.0+/-11.0 months. Most patients had pseudophakic BK (69.40%). Majority of the cases had grade 3 degree of pain (48.60%). Glaucoma and hypertension were markedly found among these patients (51.40% and 19.40%, respectively). Preoperative mean intraocular pressure and corneal thickness were 13.70+/-4.95 mmHg and 734.1+/-83.80 um, respectively. The mean laser diameter and depth were 8.36+/-1.22 mm and 38.89+/ 8.81 um, respectively. Systemic disease was significantly associated with the risk for developing recurrent painful BK (P=0.022, hazard ratio [HR] 1.673, 95% confidence interval [CI] 1.08-2.58). The overall recurrent rate was 51%. The average duration time of recurrent painful BK was 17.3+/-12.9 months (range 1-50 months). The median survival time before recurrence was 29.0+/-6.6 months. CONCLUSION: Systemic disease was found to be the only risk factor significantly associated with the development of recurrent painful BK. Low recurrent rate and long mean survival time showed that phototherapeutic keratectomy was effective in relieving recurrent painful BK and can be used as an alternative procedure for patients waiting for corneal transplantation. PMID- 26491242 TI - Cataract surgery: factors influencing decision to treat and implications for training (south-east Scotland 2008-2014). AB - PURPOSE: To describe the population referred for cataract surgery, identify factors that influenced decision to treat, and patients suitable for ophthalmic training. PATIENTS AND METHODS: A total of 2,693 consecutive referrals over 6 years were interrogated using Business Objects software on cataract electronic patient records. RESULTS: A total of 2,693 patients were referred for cataract surgery (group A). Of these patients 2,132 (79%) had surgery (group B) and 561 (21%) did not (group C). Age for group B vs group C: 672 (32%) vs 115 (20%) <=69 years, P<0.001; 803 (38%) vs 225 (40%) 70-79 years, P=0.48; 586 (27%) vs 203 (36%) 80-89 years, P<0.05; 71 (3%) vs 18 (3%) >=90 years, P=1.0. Visual acuity, group B vs group C: 556 (26%) vs 664 (59%) 6/12 or better; 1,275 (60%) vs 367 (33%) 6/18-6/60; 266 (12%) vs 64 (6%) counting fingers or worse, P<0.05. Medical history for group B vs C: cognitive impairment: 55 (2.6%) vs 29 (5.2%), P<0.05; cardiovascular accident: 158 (7.4%) vs 60 (10.7%), P<0.05; diabetes: 372 (17.4%) vs 96 (17.1%), P=0.87; COPD/asthma: 382 (17.9%) vs 93 (16.6%), P=0.53; heart disease: 535 (25.1%) vs 155 (27.6%), P=0.35; hypertension: 971 (45.5%) vs 263 (46.9%), P=0.73. Ocular history for group B vs C was significant (P<0.05) for age related macular degeneration 255 (12.0%) vs 93 (16.6%), other macular pathology 38 (1.8%) vs 25 (4.5%), corneal pathology 92 (4.3%) vs 36 (6.4%), amblyopia 37 (1.7%) vs 22 (3.9%). Detailed data on presenting complaint, ophthalmic history, and social status is discussed. CONCLUSION: We observed that surgery at a younger age with good levels of visual acuity was a factor in deferring cataract surgery. Cognitive impairment, cardiovascular accident, amblyopia, corneal and macular pathology significantly affected decision not to operate. We estimate that 80% of patients would be suitable for ophthalmic training. PMID- 26491243 TI - Stereotactic radiotherapy for wet age-related macular degeneration: current perspectives. AB - Neovascular age-related macular degeneration is a leading cause of blindness in the developed world. Currently, the treatment of choice is intravitreal injections of anti-VEGF medications. These require frequent dosing, up to monthly, and impose a substantial burden on patients and the health economy. Ionizing radiation was proposed as a possible treatment for age-related macular degeneration due to its anti-inflammatory and anti-fibrotic properties. Stereotactic radiotherapy is an outpatient-based radiotherapy platform that provides stereotactic application of low energy X-ray to the retina in three highly collimated beams that cross the inferior sclera to overlap at the macula. A randomized, double-masked, sham-controlled trial of 230 patients (INTREPID) showed that a single dose of stereotactic radiotherapy significantly reduces the number of intravitreal anti-VEGF injections needed over 2 years. A larger randomized controlled trial (STAR) is underway. PMID- 26491244 TI - Glaucoma-service provision in Scotland: introduction and need for Scottish Intercollegiate Guidelines Network guidelines. AB - PURPOSE: To describe the pattern of glaucoma-service delivery in Scotland and identify areas for improvement, taking into account Scottish General Ophthalmic Services (GOS) arrangements and the Eye Care Integration project, and to design Scottish Intercollegiate Guidelines Network (SIGN) guidelines to refine the primary and secondary interface of glaucoma care. MATERIALS AND METHODS: A glaucoma-survey questionnaire was sent to all consultant glaucomatologists in Scotland. The design of SIGN guidelines was based on the results of the questionnaire using SIGN methodology. RESULTS: Over 90% of Scottish glaucoma care is triaged and delivered within hospital services. Despite GOS referral, information is variable. There are no consistent discharge practices to the community. These results led to defined research questions that were answered, thus formulating the content of the SIGN guidelines. The guideline covers the assessment of patients in primary care, referral criteria to hospital, discharge criteria from hospital to community, and monitoring of patients at risk of glaucoma. CONCLUSION: With increasing age and limitations to hospital resources, refining glaucoma pathways between primary and secondary care has become a necessity. Scotland has unique eye care arrangements with both the GOS and Eye Care Integration project. It is hoped that implementation of SIGN guidelines will identify glaucoma at the earliest opportunity and reduce the rate of false positive referrals to hospital. PMID- 26491245 TI - Finding the best glaucoma questionnaire: a qualitative and quantitative evaluation of glaucoma knowledge assessments. AB - OBJECTIVE: The goal of the study was to determine which glaucoma quiz provides the best information about patient glaucoma knowledge to clinicians in clinical practice settings. METHODS: Four glaucoma quizzes were identified from the literature and national eye education programs and were qualitatively analyzed to categorize questions by topic. Quizzes were assessed by 64 glaucoma specialists using an online survey, with descriptive statistics. Comments about the quizzes were analyzed qualitatively using themes and representative quotations. RESULTS: Quizzes covered content that was important for glaucoma diagnosis and management. The National Eye Health Education Program (NEHEP) and Prevent Blindness America quizzes covered primarily diagnosis, screening, and risk factors, and the quizzes from the literature primarily covered causes of glaucoma, vision loss, eye drops, and systemic disease. Overall, the NEHEP quiz was ranked best for clinical practice, ranked first by 38%. Ranked second overall, the Gray quiz was ranked first by 34% and last by 34%. CONCLUSION: The NEHEP quiz was rated most useful for assessing baseline general glaucoma knowledge for a busy clinical practice. The Gray quiz appears to be more useful as part of a comprehensive education program, perhaps in combination with an ophthalmic educator. PMID- 26491246 TI - Prevalence and factors predictive of intraocular fungal infection in patients with fungemia at an academic urban tertiary care center. AB - OBJECTIVE: To report the prevalence and to identify factors predictive of intraocular infection in patients with fungemia receiving prophylactic antifungal therapy. METHODS: A retrospective review of patients who received prophylactic antifungal therapy and a dilated fundus examination at an academic urban tertiary care center from 2000 to 2007. Basic demographic information, fungal species grown, antifungal agent(s) used, number of positive blood culture specimens, visual acuity, visual symptoms, and known risks of disseminated candidiasis were noted. Logistic regression analysis was used to determine the factors significantly associated with intraocular fungal infection. RESULTS: A total of 132 patients with positive fungemia culture were requested to have ophthalmology consults. The prevalence of ocular infection was 6.9% (N=9). All nine patients were infected with Candida species. Undergoing gastrointestinal (GI) surgery within the prior 6 months was significantly related to developing intraocular infection, with an odds ratio of 18.5 (95% confidence interval, 15.1-24.3; P=0.002). Having >=3 positive fungal blood cultures was also a significant risk factor, with an odds ratio of 2.6 (95% confidence interval, 1.8-3.7; P=0.03). Among 40 patients having GI surgery, eight (20.0%) had intraocular fungal disease, compared with one of 92 patients (1.1%) not having GI surgery. Among 125 patients with a negative baseline examination result, two of 32 patients (6.3%), who had recent GI surgery, subsequently developed fungal ocular disease, compared with 0 of 93 patients (0%), who did not have recent GI surgery. CONCLUSION: Recent GI surgery and higher numbers of positive fungal blood culture specimens may be predictive of candida ocular infections. Normal baseline fundoscopy examination results in patients with such risks may require repeat evaluations to detect delayed manifestations. PMID- 26491247 TI - Relocation consequences on an ophthalmology consultation service from an inpatient to outpatient facility. AB - IMPORTANCE: This study shows that relocation of an academic ophthalmology residency program from an inpatient to an outpatient setting in western New York does not affect the consult volume but affects management patterns and follow-up rates. OBJECTIVE: To investigate the effects on the ophthalmology consultation service of an academic program with relocation from a Regional Level-1 Trauma center to an outpatient facility. DESIGN: Consultation notes from 3 years before and 3 years after the University at Buffalo's (UB) Department of Ophthalmology relocation from a Regional Level-1 Trauma center (Erie County Medical Center) to an outpatient facility (Ross Eye Institute) were obtained from hospital electronic medical records and analyzed. SETTING: Hospitalized care and institutional practice. PARTICIPANTS: All inpatient or Emergency Room Ophthalmology consultation patients from the Department of Ophthalmology at UB from 2004 to 2010 (1,379 patients). EXPOSURES: None, this was a retrospective chart review. MAIN OUTCOME MEASURES: Patient demographics, reason for consult, diagnoses, and ophthalmic procedures performed by the UB Department of Ophthalmology before and after its relocation. RESULTS: Relocation to the outpatient facility did not affect consult volume (P=0.15). The number of consults focusing on ophthalmic conditions, as a percentage of the yearly total, rose 460% (P=0.0001), while systemic condition consults with ocular manifestations fell 83% (P=0.0001). Consults for ocular trauma decreased 65% (P=0.0034). Consults ending with a diagnosis of "normal exam" fell, as a percentage of the yearly total (56%, P=0.0023), while diagnoses of new ocular conditions rose 17% (P=0.00065). The percentage of consults for Medicaid patients fell 12% (P=0.0001), while those for privately insured patients rose 15% (P=0.0001). The number of ophthalmic procedures did not change, but postconsult patient follow-up fell from 23% at the Erie County Medical Center clinic to 2% after the move to Ross Eye Institute, a >=97% decrease. CONCLUSION AND RELEVANCE: Relocation of UB's academic Ophthalmology program from an inpatient department to an outpatient facility had no effect on its consultation patient or procedure volume, but it significantly affected the nature of consult diagnoses and decreased outpatient follow-up by >90% at the latter location. Many hospitals are creating separate outpatient facilities that may experience similar obstacles. PMID- 26491248 TI - Toxic anterior segment syndrome and intracameral injection of cefuroxime axetil. PMID- 26491249 TI - Traumatic uveitis in the mid-Atlantic United States. AB - PURPOSE: The purpose of this study was to conduct an in-depth analysis of traumatic uveitis in patients managed in a mid-Atlantic tertiary care center with the goal of better characterizing the clinical features and outcomes of this large and important subset of uveitis patients. METHODS: This was a retrospective, observational study comparing traumatic uveitis patients with nontraumatic uveitis patients seen at the University of Virginia, Charlottesville, VA, USA, from 1984 to 2014. RESULTS: Fifty-four traumatic uveitis patients (55 eyes) were identified. The patient population was 70.4% male, 57.4% Caucasian, and 37.0% African American. Mean age at diagnosis was 31.2 years; mean duration of follow-up was 5.4 years; and mean number of visits to the clinic was 4. The most common treatment modality was local steroids (77.8%). Glaucoma was medically managed in eight patients (14.8%). Cataract surgery was performed in five patients (9.3%). Mean best-corrected visual acuity at baseline for traumatic uveitis patients was 0.33 logMAR (SD 0.42) at the initial visit and 0.16 logMAR (SD 0.33) at the final visit. Mean baseline intraocular pressure (IOP) in the traumatic uveitis group was 15.5 mmHg (SD 7.4) at the initial visit and 14.6 mmHg (SD 4.0) at the final visit. Patients in the traumatic uveitis cohort tended to have better visual outcomes than those in the nontraumatic uveitis cohort. CONCLUSION: In our series, traumatic uveitis patients tended to be young and male and present with unilateral disease, all findings consistent with other reports. Despite relatively good visual outcomes, the traumatic uveitis patients still experienced a high burden of disease, measured both in the number of clinic visits and duration of follow-up. Due to the young mean age of patients, these disease burdens and decreased quality of life are nontrivial, emphasizing the importance of careful management and prompt treatment of this subset of uveitis patients. PMID- 26491250 TI - Intraocular pressure readings obtained through soft contact lenses using four types of tonometer. AB - PURPOSE: To compare the reliability and accuracy of intraocular pressure (IOP) measured while wearing soft contact lenses (SCLs) using a non-contact tonometer (NCT), Goldmann applanation tonometer (GAT), iCare rebound tonometer (RBT) and the Tono-Pen XL. METHODS: Twenty-six healthy subjects were examined. The IOP was measured using NCT, GAT, RBT, and the Tono-Pen XL, while the subjects wore SCLs 5.00 D, -0.50 D and +5.00 D. Bland-Altman plots and a regression analysis were used to compare the IOPs obtained with those instruments and the IOPs of the naked eyes measured using GAT (the standard IOPs in this study). RESULTS: The IOPs obtained by the Tono-Pen XL while the subjects were wearing -5.00 D, -0.50 D, and +5.00 D SCLs were significantly higher than those of the naked eyes obtained using GAT. RBT showed that the IOPs were similar to the GAT standard IOPs under all conditions. The IOPs measured with NCT and GAT while the subjects were wearing -5.00 D and -0.50 D SCLs were similar to the GAT standard IOPs. The IOPs obtained with RBT and NCT while the subjects were wearing -5.00 D and -0.50 D SCLs exhibited a good correlation with the standard IOPs. CONCLUSION: The NCT and RBT are best when measuring IOP through hydrogel SCLs. PMID- 26491251 TI - Role of collagenase clostridium histolyticum in Peyronie's disease. AB - Peyronie's disease is a localized connective tissue disease characterized by an active, inflammatory phase and a stable, quiescent phase, with the eventual development of collagenous plaques within the tunica albuginea of the penis. Risk factors primarily associated with Peyronie's disease include Dupuytren's contracture, penile trauma, and family history. A variety of treatment strategies have been utilized, including oral and topical agents, electromotive drug administration, intralesional injections, extracorporeal shockwave therapy, penile traction, and surgery. However, most of these strategies are ineffective, with surgery being the only definitive treatment. Collagenase clostridium histolyticum is a newly US Food and Drug Administration-approved agent for intralesional injection. It is thought to downregulate many of the disease related genes, cytokines, and growth factors and degrade collagen fibers. It also suppresses cell attachment, spreading, and proliferation. Collagenase clostridium histolyticum has been clinically proven to be a safe and effective therapeutic option, demonstrating decreases in penile curvature and plaque consistency, as well as increases in patient satisfaction. During clinical evaluation, the Peyronie's Disease Questionnaire was validated as an effective tool for assessing treatment outcomes. PMID- 26491252 TI - Systematic review and meta-analysis: bezafibrate in patients with primary biliary cirrhosis. AB - BACKGROUND AND AIM: Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cirrhosis (PBC), but not all cases respond well. Evidence has shown that combination therapy of UDCA with bezafibrate significantly improved liver function. A meta-analysis was performed to assess the efficacy and safety of UDCA and bezafibrate combination therapy in the treatment of PBC. RESULTS: Nine trials, with a total of 269 patients, were included in the analysis. The bias risk of these trials was high. Compared with UDCA alone, the combination with bezafibrate improved the Mayo risk score (mean difference [MD], 0.60; 95% confidence interval [CI], 0.25-0.95; P=0.0008) and liver biochemistry: alkaline phosphatase (MD, -238.21 IU/L; 95% CI, -280.83 to -195.60; P<0.00001); gamma glutamyltransferase (MD, -38.23 IU/L; 95% CI, -50.16 to -25.85; P<0.00001); immunoglobulin M (MD, -128.63 IU/L; 95% CI, -151.55 to -105.71; P<0.00001); bilirubin (MD, -0.20 mg/dL; 95% CI, -0.33 to -0.07; P=0.002); triglycerides (MD, 26.84 mg/dL; 95% CI, -36.51 to -17.17; P<0.0001); total cholesterol (MD, -21.58 mg/dL; 95% CI, -30.81 to -12.34; P<0.0001), and serum alanine aminotransferase (MD, -10.24 IU/L; 95% CI, -12.65 to -78.5; P<0.00001). However, combination therapy showed no significant differences in the incidence of all-cause mortality or pruritus, and may have resulted in more adverse events (risk ratio [RR], 0.22; 95% CI, 0.07-0.67; P=0.008). CONCLUSION: Combination therapy improved liver biochemistry and the prognosis of PBC, but did not improve clinical symptoms or incidence of death. Attention should be paid to adverse events when using bezafibrate. PMID- 26491253 TI - Decreased expression of the APOA1-APOC3-APOA4 gene cluster is associated with risk of Alzheimer's disease. AB - BACKGROUND: Apolipoprotein is genetically associated with the risk of Alzheimer's disease (AD). The APOA1, APOC3, and APOA4 genes are closely linked and located on human chromosome 11. Therefore, this gene cluster may be related to the risk of AD. PATIENTS AND METHODS: A total of 147 AD patients and 160 healthy controls were randomly recruited from June 2013 to August 2014. APOA1, APOC3, and APOA4 levels were measured using real-time quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: APOA1, APOC3 and APOA4 levels were significantly lower in AD patients than controls (P<0.01). APOA1, APOC3, and APOA4 levels were negatively related with the severities of AD determined by Clinical Dementia Rating scores (P<0.01). APOA1, APOC3, and APOA4 levels showed a negative relation with Montgomery-Asberg Depression Rating Scale scores and a positive relation with RAND 36-item health survey scores (P<0.01). There was a decreased trend for levels of APOA1, APOC3, and APOA4 in AD patients. CONCLUSION: Low levels of APOA1, APOC3, and APOA4 are associated with risk of AD. APOA1, APOC3, and APOA4 should be developed as combined drugs for the therapy of AD. PMID- 26491254 TI - A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis. AB - BACKGROUND/AIM: Isoniazid (INH) is an essential component of first-line anti tuberculosis (TB) treatment. However, treatment with INH is complicated by polymorphisms in the expression of the enzyme system primarily responsible for its elimination, N-acetyltransferase 2 (NAT2), and its associated hepatotoxicity. The objective of this study was to develop an individualized INH dosing regimen using a pharmacogenetic-driven model and to apply this regimen in a pilot study. METHODS: A total of 206 patients with TB who received anti-TB treatment were included in this prospective study. The 2-hour post-dose concentrations of INH were obtained, and their NAT2 genotype was determined using polymerase chain reaction and sequencing. A multivariate regression analysis that included the variables of age, sex, body weight, and NAT2 genotype was performed to determine the best model for estimating the INH dose that achieves a concentration of 3.0 6.0 mg/L. This dosing algorithm was then used for newly enrolled 53 patients. RESULTS: Serum concentrations of INH were significantly lower in the rapid acetylators than in the slow-acetylators (2.55 mg/L vs 6.78 mg/L, median, P<0.001). A multivariate stepwise linear regression analysis revealed that NAT2 and body weight independently affected INH concentrations: INH concentration (mg/L) = 13.821-0.1* (body weight, kg) -2.273* (number of high activity alleles of NAT2; 0, 1, 2). In 53 newly enrolled patients, the frequency at which they were within the therapeutic range of 3.0-6.0 mg/L was higher in the model-based treatment group compared to the standard treatment group (80.8% vs 59.3%). CONCLUSION: The use of individualized pharmacogenetic-guided INH dosage regimens that incorporate NAT2 genotype and body weight may help to ensure achievement of therapeutic concentrations of INH in the TB patients. PMID- 26491255 TI - The clinicopathological significance and drug target potential of FHIT in breast cancer, a meta-analysis and literature review. AB - FHIT is a bona fide tumor-suppressor gene and its loss contributes to tumorigenesis of epithelial cancers including breast cancer (BC). However, the association and clinicopathological significance between FHIT promoter hypermethylation and BC remains unclear. The purpose of this study is to conduct a meta-analysis and literature review to investigate the clinicopathological significance of FHIT methylation in BC. A detailed literature search was performed in PubMed, EMBASE, Web of Science, and Google Scholar databases. The data were extracted and assessed by two reviewers independently. Odds ratios with 95% corresponding confidence intervals were calculated. A total of seven relevant articles were available for meta-analysis, which included 985 patients. The frequency of FHIT hypermethylation was significantly increased in invasive ductal carcinoma compared to benign breast disease, the pooled odds ratio was 8.43, P<0.00001. The rate of FHIT hypermethylation was not significantly different between stage I/II and stage III/IV, odds ratio was 2.98, P=0.06. In addition, FHIT hypermethylation was not significantly associated with ER and PR status. FHIT hypermethylation was not significantly correlated with premenopausal and postmenopausal patients with invasive ductal carcinoma. In summary, our meta analysis indicated that the frequency of FHIT hypermethylation was significantly increased in BC compared to benign breast disease. The rate of FHIT hypermethylation in advanced stages of BC was higher than in earlier stages; however, the difference was not statistically significant. Our data suggested that FHIT methylation could be a diagnostic biomarker of BC carcinogenesis. FHIT is a potential drug target for development of demethylation treatment for patients with BC. PMID- 26491257 TI - A novel small-molecule inhibitor of HIV-1 entry. AB - BACKGROUND: Antiretroviral therapy has transformed HIV-1 infection into a managed condition with near-normal life expectancy. However, a significant number of patients remain with limited therapeutic options due to HIV-1 resistance, side effects, or drug costs. Further, it is likely that current drugs will not retain efficacy, due to risks of side effects and transmitted resistance. RESULTS: We describe compound 5660386 (3-ethyl-2-[3-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2 ylidene)-1-propen-1-yl]-1,3-benzothiazol-3-ium) as a novel inhibitor of HIV-1 entry. Compound 5660386 inhibits HIV-1 entry in cell lines and primary cells, binds to HIV-1 envelope protein, and inhibits the interaction of GP120 to CD4. Further, compound 5660386 showed a unique and broad-range activity against primary HIV-1 isolates from different subtypes and geographical areas. CONCLUSION: Development of small-molecule entry inhibitors of HIV-1 such as 5660386 may lead to novel classes of anti-HIV-1 therapeutics. These inhibitors may be particularly effective against viruses resistant to current antiretroviral drugs and could have potential applications in both treatment and prevention. PMID- 26491258 TI - 3-Coumaranone derivatives as inhibitors of monoamine oxidase. AB - The present study examines the monoamine oxidase (MAO) inhibitory properties of a series of 20 3-coumaranone [benzofuran-3(2H)-one] derivatives. The 3-coumaranone derivatives are structurally related to series of alpha-tetralone and 1-indanone derivatives, which have recently been shown to potently inhibit MAO, with selectivity for MAO-B (in preference to the MAO-A isoform). 3-Coumaranones are similarly found to selectively inhibit human MAO-B with half-maximal inhibitory concentration (IC50) values of 0.004-1.05 uM. Nine compounds exhibited IC50<0.05 uM for the inhibition of MAO-B. For the inhibition of human MAO-A, IC50 values ranged from 0.586 to >100 uM, with only one compound possessing an IC50<1 uM. For selected 3-coumaranone derivatives, it is established that MAO-A and MAO-B inhibition are reversible since dialysis of enzyme-inhibitor mixtures almost completely restores enzyme activity. On the basis of the selectivity profiles and potent action, it may be concluded that the 3-coumaranone derivatives are suitable leads for the development of selective MAO-B inhibitors as potential treatment for disorders such as Parkinson's disease and Alzheimer's disease. PMID- 26491256 TI - Maraviroc: a review of its use in HIV infection and beyond. AB - The human immunodeficiency virus-1 (HIV-1) enters target cells by binding its envelope glycoprotein gp120 to the CD4 receptor and/or coreceptors such as C-C chemokine receptor type 5 (CCR5; R5) and C-X-C chemokine receptor type 4 (CXCR4; X4), and R5-tropic viruses predominate during the early stages of infection. CCR5 antagonists bind to CCR5 to prevent viral entry. Maraviroc (MVC) is the only CCR5 antagonist currently approved by the United States Food and Drug Administration, the European Commission, Health Canada, and several other countries for the treatment of patients infected with R5-tropic HIV-1. MVC has been shown to be effective at inhibiting HIV-1 entry into cells and is well tolerated. With expanding MVC use by HIV-1-infected humans, different clinical outcomes post approval have been observed with MVC monotherapy or combination therapy with other antiretroviral drugs, with MVC use in humans infected with dual-R5- and X4 tropic HIV-1, infected with different HIV-1 genotype or infected with HIV-2. This review discuss the role of CCR5 in HIV-1 infection, the development of the CCR5 antagonist MVC, its pharmacokinetics, pharmacodynamics, drug-drug interactions, and the implications of these interactions on treatment outcomes, including viral mutations and drug resistance, and the mechanisms associated with the development of resistance to MVC. This review also discusses available studies investigating the use of MVC in the treatment of other diseases such as cancer, graft-versus host disease, and inflammatory diseases. PMID- 26491259 TI - Crizotinib as a personalized alternative for targeted anaplastic lymphoma kinase rearrangement in previously treated patients with non-small-cell lung cancer. AB - Crizotinib, the first clinically designed and synthesized as a tyrosine kinase inhibitor targeting mesenchymal-epithelial transition factor, indicating marked anticancer activity in patients with advanced, anaplastic lymphoma kinase positive non-small-cell lung cancer, was approved by the US Food and Drug Administration in 2011. In this review, we focus on the efficacy of crizotinib compared with chemotherapy in advanced anaplastic lymphoma kinase-positive lung cancer and present the role of crizotinib as a personalized alternative in previously treated patients with non-small-cell lung cancer. PMID- 26491261 TI - n-Butanol extract from Folium isatidis inhibits lipopolysaccharide-induced inflammatory cytokine production in macrophages and protects mice against lipopolysaccharide-induced endotoxic shock. AB - Sepsis, which is caused by severe infection, is an important cause of mortality, but effective clinical treatment against sepsis is extremely limited. As the main component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS) plays a major role in inflammatory responses. Studies have shown beneficial pharmacological effects for Folium isatidis. The present study further illuminated the effects of n-butanol extract from Folium isatidis in LPS-induced septic shock and identified the main active chemical components. Our study showed that pretreatment with n-butanol extract from Folium isatidis not only significantly inhibited LPS-induced tumor necrosis factor-alpha and interleukin-6 production but also markedly and dose dependently enhanced the recruitment of MyD88, the phosphorylation of extracellular signal-regulated kinase, and the degradation of IkappaB-alpha. Additionally, the extract exhibited dramatic protective effects against lung injury and death in mice with septic shock. Eight main active compounds were identified, including organic acids, glycoside, indolinones, and flavonoids. These findings provide a perspective on the respiratory protection offered by n-butanol extract from Folium isatidis in LPS induced sepsis and outline a novel therapeutic strategy for the treatment of sepsis. PMID- 26491260 TI - Plumbagin suppresses epithelial to mesenchymal transition and stemness via inhibiting Nrf2-mediated signaling pathway in human tongue squamous cell carcinoma cells. AB - Tongue squamous cell carcinoma (TSCC) is the most common malignancy in oral and maxillofacial tumors with highly metastatic characteristics. Plumbagin (5-hydroxy 2-methyl-1, 4-naphthoquinone; PLB), a natural naphthoquinone derived from the roots of Plumbaginaceae plants, exhibits various bioactivities, including anticancer effects. However, the potential molecular targets and underlying mechanisms of PLB in the treatment of TSCC remain elusive. This study employed stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic approach to investigate the molecular interactome of PLB in human TSCC cell line SCC25 and elucidate the molecular mechanisms. The proteomic data indicated that PLB inhibited cell proliferation, activated death receptor mediated apoptotic pathway, remodeled epithelial adherens junctions pathway, and manipulated nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress response signaling pathway in SCC25 cells with the involvement of a number of key functional proteins. Furthermore, we verified these protein targets using Western blotting assay. The verification results showed that PLB markedly induced cell cycle arrest at G2/M phase and extrinsic apoptosis, and inhibited epithelial to mesenchymal transition (EMT) and stemness in SCC25 cells. Of note, N-acetyl-l cysteine (NAC) and l-glutathione (GSH) abolished the effects of PLB on cell cycle arrest, apoptosis induction, EMT inhibition, and stemness attenuation in SCC25 cells. Importantly, PLB suppressed the translocation of Nrf2 from cytosol to nucleus, resulting in an inhibition in the expression of downstream targets. Taken together, these results suggest that PLB may act as a promising anticancer compound via inhibiting Nrf2-mediated oxidative stress signaling pathway in SCC25 cells. This study provides a clue to fully identify the molecular targets and decipher the underlying mechanisms of PLB in the treatment of TSCC. PMID- 26491262 TI - Back to the future - feasibility of recruitment and retention to patient education and telephone follow-up after hip fracture: a pilot randomized controlled trial. AB - OBJECTIVES: Our primary aim of this pilot study was to test feasibility of the planned design, the interventions (education plus telephone coaching), and the outcome measures, and to facilitate a power calculation for a future randomized controlled trial to improve adherence to recovery goals following hip fracture. DESIGN: This is a parallel 1:1 randomized controlled feasibility study. SETTING: The study was conducted in a teaching hospital in Vancouver, BC, Canada. PARTICIPANTS: Participants were community-dwelling adults over 60 years of age with a recent hip fracture. They were recruited and assessed in hospital, and then randomized after hospital discharge to the intervention or control group by a web-based randomization service. Treatment allocation was concealed to the investigators, measurement team, and data entry assistants and analysts. Participants and the research physiotherapist were aware of treatment allocation. INTERVENTION: Intervention included usual care for hip fracture plus a 1-hour in hospital educational session using a patient-centered educational manual and four videos, and up to five postdischarge telephone calls from a physiotherapist to provide recovery coaching. The control group received usual care plus a 1-hour in hospital educational session using the educational manual and videos. MEASUREMENT: Our primary outcome was feasibility, specifically recruitment and retention of participants. We also collected selected health outcomes, including health-related quality of life (EQ5D-5L), gait speed, and psychosocial factors (ICEpop CAPability measure for Older people and the Hospital Anxiety and Depression Scale). RESULTS: Our pilot study results indicate that it is feasible to recruit, retain, and provide follow-up telephone coaching to older adults after hip fracture. We enrolled 30 older adults (mean age 81.5 years; range 61-97 years), representing a 42% recruitment rate. Participants excluded were those who were not community dwelling on admission, were discharged to a residential care facility, had physician-diagnosed dementia, and/or had medical contraindications to participation. There were 27 participants who completed the study: eleven in the intervention group, 15 in the control group, and one participant completed a qualitative interview only. There were no differences between groups for health measures. CONCLUSION: We highlight the feasibility of telephone coaching for older adults after hip fracture to improve adherence to mobility recovery goals. PMID- 26491263 TI - A counselor in your pocket: feasibility of mobile health tailored messages to support HIV medication adherence. AB - PURPOSE: Medication adherence is a major challenge in HIV treatment. New mobile technologies such as smartphones facilitate the delivery of brief tailored messages to promote adherence. However, the best approach for tailoring messages is unknown. Persons living with HIV (PLWH) might be more receptive to some messages than others based on their current psychological state. METHODS: We recruited 37 PLWH from a parent study of motivational states and adherence. Participants completed smartphone-based surveys at a random time every day for 2 weeks, then immediately received intervention or control tailored messages, depending on random assignment. After 2 weeks in the initial condition, participants received the other condition in a crossover design. Intervention messages were tailored to match PLWH's current psychological state based on five variables - control beliefs, mood, stress, coping, and social support. Control messages were tailored to create a mismatch between message framing and participants' current psychological state. We evaluated intervention feasibility based on acceptance, ease of use, and usefulness measures. We also used pilot randomized controlled trial methods to test the intervention's effect on adherence, which was measured using electronic caps that recorded pill-bottle openings. RESULTS: Acceptance was high based on 76% enrollment and 85% satisfaction. Participants found the hardware and software easy to use. However, attrition was high at 59%, and usefulness ratings were slightly lower. The most common complaint was boredom. Unexpectedly, there was no difference between mismatched and matched messages' effects, but each group showed a 10%-15% improvement in adherence after crossing to the opposite study condition. CONCLUSION: Although smartphone-based tailored messaging was feasible and participants had clinically meaningful improvements in adherence, the mechanisms of change require further study. Possible explanations might include novelty effects, increased receptiveness to new information after habituation, or pseudotailoring, three ways in which attentional processes can affect behavior. PMID- 26491264 TI - Fear of driving license withdrawal in patients with insulin-treated diabetes mellitus negatively influences their decision to report severe hypoglycemic events to physicians. AB - BACKGROUND: Under current European Union legislation, two severe hypoglycemic events within 12 months is grounds for driving license withdrawal. The aim of the study reported here was to determine whether fear of such a withdrawal could lead to patients concealing severe hypoglycemia from physicians, which could negatively impact further treatment decisions. METHODS: A total of 663 patients with insulin-treated diabetes were anonymously surveyed about whether they would conceal severe hypoglycemic events from their physicians, if revealing them could result in driving license withdrawal. This investigation utilized an adapted and expanded questionnaire by Graveling et al. RESULTS: Of all diabetic patients surveyed, 26.17% would most likely not report hypoglycemia, and 25.86% were undecided. In a group of patients with type 1 diabetes, 31.83% would likely not report hypoglycemic events, and 25.06% were undecided. The patients least likely to report severe hypoglycemic events were those who indicated that vehicles were partly essential for work, and who also had more than two hypoglycemic events monthly. CONCLUSION: A considerable percentage of diabetic patients would likely conceal severe hypoglycemic events from their physicians due to fear of driving license withdrawal. Patient failure to report severe hypoglycemic events can potentially lead to physicians being misinformed regarding the patient's condition, which could lead to inadequate monitoring and treatment. PMID- 26491265 TI - Depressed patients' preferences for type of psychotherapy: a preliminary study. AB - BACKGROUND: The treatment recommendations for depressed patients by the American Psychiatric Association encourage a focus on the patient's preferences. The focus of this study was the preference of depressed inpatients for the type of psychotherapy. METHODS: Twenty-nine subjects of both sexes who were hospitalized with a major depressive episode were interviewed at 5-day intervals with the same questions after the depressive episode resolved, as indicated by a score less than 7 on the Hamilton Depression Rating Scale (HDRS). The selection of items was performed by expert consensus. RESULTS: The supportive psychotherapy scores were the highest, followed by psychodynamic psychotherapy and cognitive behavioral therapy. The two sessions conducted at 5-day intervals showed no significant difference, which reflected the stability of choices and preferences of patients. CONCLUSION: In this study, the patients preferred supportive psychotherapy as first-line therapy compared to psychodynamic psychotherapy and cognitive behavioral therapy. PMID- 26491266 TI - Predictors of overall satisfaction of cancer patients undergoing radiation therapy. AB - BACKGROUND: Reporting the experiences and satisfaction of patients, as well as their quality of care scores is an emerging recommendation in health care systems. Many aspects of patients' experience determine their overall satisfaction. The aim of this evaluation was to define the main factors contributing to the satisfaction of patients undergoing radiotherapy in an outpatient setting. PATIENTS AND METHODS: A total of 1,710 patients with a histologically proven cancer, who were treated in our department between 2012 and 2014, were recruited for this prospective evaluation. At the end of therapy, each patient was asked to grade the skills and the care provided by radiation therapists, physicians, and physician's assistants, as well as the overall satisfaction during therapy. Statistical analysis was performed to determine which parameters had the greatest influence on overall satisfaction. RESULTS: Overall satisfaction with the provided care was high with a mean satisfaction score of 1.4. Significant correlations were found between overall satisfaction and each of the following survey items: courtesy, protection of privacy, professional skills and care provided by the radiation therapists and physicians, accuracy of provided information, and cleanliness. Linear regression analysis demonstrated that courteous behavior and the protection of privacy were the strongest predictors for overall satisfaction (P<0.001), followed by care and skills of physicians and radiation therapists. Patients suffering from head and neck cancer expressed lower overall satisfaction. CONCLUSION: Based on our prospectively acquired data, we were able to identify and confirm key factors for patient satisfaction in an outpatient radiooncological cancer center. From these results, we conclude that patients want most importantly to be treated with courtesy, protection of privacy and care. PMID- 26491267 TI - Dispensing of non-prescribed antibiotics in Jordan. AB - OBJECTIVE: Current regulations in Jordan state that antibiotics cannot be sold without a medical prescription. This study aimed to assess the percentage of pharmacies that dispense antibiotics without a medical prescription in the Kingdom of Jordan and identify and highlight the extent and seriousness of such practices among Jordanian pharmacies. METHODS: A prospective study was performed, and five different clinical scenarios were simulated at pharmacies investigated including sore throat, otitis media, acute sinusitis, diarrhea, and urinary tract infection in childbearing-aged women. Three levels of demand were used to convince the pharmacists to sell an antibiotic. RESULTS: A total of 202 total pharmacies in Jordan were visited in the present study. The majority of pharmacies (74.3%) dispensed antibiotics without prescription with three different levels of demand. The percentage of pharmacies dispensing antibiotics without a prescription for the sore throat scenario was 97.6%, followed by urinary tract infection (83.3%), diarrhea (83%), and otitis media (68.4%). The lowest percentage of antibiotic dispensing was for the acute sinusitis simulation at 48.5%. Among the pharmacies that dispensed antibiotics, the pharmacists provided an explanation as the number of times per day the drug should be taken in 95.3% of the cases, explained the duration of treatment in 25.7%, and inquired about allergies prior to the sale of the antibiotic in only 17.3%. Only 52 pharmacies (25.7%) refused to dispense any kind of antibiotics, the majority (61.5%) of this refusal response came from acute sinusitis cases, while the minority (2.4%) came from the sore throat cases. CONCLUSION: The results of this study demonstrate that antibiotics continue to be dispensed without prescription in Jordan in violation with national regulations regarding this practice. The findings of this study could provide a layout for governmental health authorities to implement strict enfrorcment of national regulations regarding antibiotic dispensing in order to avoid the serious complications that could arise in the future as a result of such practices. PMID- 26491268 TI - Bridging the gap between patient needs and quality indicators: a qualitative study with chronic heart failure patients. AB - BACKGROUND: The German National Disease Management Guideline (NDMG) on chronic heart failure (CHF) derived nine clinical quality indicators (QIs) to enable assessment of quality of health care in patients with CHF. These QIs epitomize an evidence-based and somatic point of view of guided treatment, but little is known about the experiences and views of patients with their guideline-based treatment across multiple health care sectors. OBJECTIVE: The purpose of this qualitative study was to explore patient perspectives on guided treatment of CHF across multiple health care sectors. Furthermore, it was investigated to what extent patient perspectives are represented by the QIs of the German NDMG. METHODS: Using a qualitative approach, semistructured interviews were carried out with 17 CHF patients. Interviews were audio-recorded and transcribed verbatim. Data were analyzed using qualitative content analysis. RESULTS: Patient-identified needs focused primarily on aspects like the doctor-patient relationship, communication, quality of individual-tailored information, and professional advice. Patients perceived shortcomings in processes of care such as communication and cooperation across health care sectors, especially at the transition between hospital and outpatient care. DISCUSSION: From the patient perspectives, the QIs do represent relevant somatic and clinical aims for quality measurement. However, deficits were identified, especially related to communication and cooperation across health care sectors. Given the fact that the inclusion of patient perspectives in quality improvement processes provides an important contribution to patient centered health care, possible approaches for QI development such as direct and indirect patient involvement or generic vs disease-specific patient-related QIs should be the subject of future discussions. PMID- 26491270 TI - Emerging optical nanoscopy techniques. AB - To face the challenges of modern health care, new imaging techniques with subcellular resolution or detection over wide fields are required. Far field optical nanoscopy presents many new solutions, providing high resolution or detection at high speed. We present a new classification scheme to help appreciate the growing number of optical nanoscopy techniques. We underline an important distinction between superresolution techniques that provide improved resolving power and nanodetection techniques for characterizing unresolved nanostructures. Some of the emerging techniques within these two categories are highlighted with applications in biophysics and medicine. Recent techniques employing wider angle imaging by digital holography and scattering lens microscopy allow superresolution to be achieved for subcellular and even in vivo, imaging without labeling. Nanodetection techniques are divided into four subcategories using contrast, phase, deconvolution, and nanomarkers. Contrast enhancement is illustrated by means of a polarized light-based technique and with strobed phase-contrast microscopy to reveal nanostructures. Very high sensitivity phase measurement using interference microscopy is shown to provide nanometric surface roughness measurement or to reveal internal nanometric structures. Finally, the use of nanomarkers is illustrated with stochastic fluorescence microscopy for mapping intracellular structures. We also present some of the future perspectives of optical nanoscopy. PMID- 26491269 TI - Use of complementary and alternative medicine before and after organ removal due to urologic cancer. AB - OBJECTIVE: Many patients use complementary and alternative medicine (CAM) as primary treatment or symptom relief for a variety of illnesses. This study was designed to investigate the influence of surgical removal of a tumor-bearing urogenital organ on CAM use. METHODS: From 2007 to 2011, 350 patients underwent major urological surgery for kidney, prostate, or bladder cancer at the Goethe University Hospital, Frankfurt, Germany. Data from 172 patients (49%), who returned a questionnaire, were retrospectively evaluated using the hospital information system along with the questionnaire to objectify CAM use 2 years before and after surgery. RESULTS: From the 172 patients returning questionnaires, 56 (33%) used CAM before and/or after surgery and 116 (67%) never used CAM. Of the 56 CAM users, 30 (54%) used CAM presurgery and 53 (95%) used CAM postsurgery, indicating a significant change of mind about CAM use. Patients of German nationality used CAM significantly more than patients of other nationalities. Higher educational status (high-school diploma or higher) was a significant factor in favor of CAM use. The most common type of CAM used before/after surgery was an alternative medical system (63/49%), a manipulative and body-based method (50/19%), and a biological-based therapy (37/32%). Information about CAM, either provided by medical professionals or by other sources, was the main reason determining whether patients used CAM or not. CONCLUSION: The number of patients using CAM almost doubled after surgical removal of a cancer-bearing organ. Better awareness and understanding of CAM use by medical professionals could improve patient counseling. PMID- 26491271 TI - Preferred health behaviors and quality of life of the elderly people in Poland. AB - PURPOSE: The aim of this study was to assess possible differences between a group of residents of public nursing homes (PNH) and a group of members of Universities of the Third Age (UTA) measured using standard psychometric scales. MATERIALS AND METHODS: The research was conducted between January 3, 2013 and February 15, 2014 on a group of 200 residents of PNH and 200 members of the UTA using five psychometric scales: Standardized Satisfaction with Life Scale (SWLS), Standardized Health Behavior Inventory (HBI), Standardized Social Support Scale (SSS), Standardized General Self-efficacy Scale (GSES), and Standardized Multiple Health Locus of Control Scale (MHLC). RESULTS: The average point total in the Standardized Satisfaction with Life Scale (SWLS) in the group of residents of PNH was 18.03 (Me =19) and was significantly higher (P=0.047) in comparison with the group of UTA members (17.08). Similar to residents of PNH, a vast majority of UTA members assessed the support received from the UTA as good, which significantly influenced their satisfaction from life (P=0.028) and their feeling of self efficacy (P=0.048). An observed dependence states that the greater the level of satisfaction from life, the greater the level of various types of support from family. CONCLUSION: This study indicates that biopsychosocial problems decrease quality of life in elderly people. The elderly people require a comprehensive, holistic approach to a variety of problems that occur with aging. In future, extended interdisciplinary research should be carried out on aspects of quality of life in order to optimize comprehensive geriatric assessment. PMID- 26491272 TI - Prevalence of sarcopenia in Germany and the corresponding effect of osteoarthritis in females 70 years and older living in the community: results of the FORMoSA study. AB - BACKGROUND: Although sarcopenia represents a challenging burden for health care systems around the world, its prevalence in the elderly population varies widely. The primary aim of the study was to determine the prevalence of sarcopenia in community-dwelling (CD) German women aged 70 years and older; the secondary aim was to assess the effect of osteoarthritis (OA) on sarcopenia prevalence in this cohort. METHODS: A total of 689 Caucasian females 18-35 years old and 1,325 CD females 70 years+ living in Northern Bavaria, Germany, were assessed during the initial phase of the FORMoSA research project. Anthropometry, total and regional muscle mass, were assessed by segmental multifrequency Bioelectrical Impedance Analysis. Further 10 m walking speed and handgrip strength were evaluated to apply the European Working Group on Sarcopenia in Older People definition of sarcopenia. Covariates were determined by questionnaires and interviews. RESULTS: Applying the algorithm of the European Working Group on Sarcopenia in Older People of two standard deviations below the mean value for appendicular skeletal muscle mass of a reference cohort of the young cohort (5.66 kg/m(2)), low gait speed (<=0.8 m/s), and low grip strength (<20 kg), the prevalence of sarcopenia in CD German females 70 years and older was 4.5% (70-79 years: 2.8% vs >=80 years: 9.9%; P<0.001). Participants with OA at the hip and lower limbs (n=252) exhibited significantly higher rates of sarcopenia (OA: 9.1 vs non-OA: 3.5%). Of importance, anthropometric, demographic, health, and lifestyle parameters (except exercise participation) of our cohorts corresponded with Bavarian or German data for CD women 70 years+. CONCLUSION: The prevalence of sarcopenia in CD German females 70 years+ is relatively low. However, participants with OA at the hip or lower limbs were at increased risk for sarcopenia. PMID- 26491273 TI - Olmesartan vs ramipril in the treatment of hypertension and associated clinical conditions in the elderly: a reanalysis of two large double-blind, randomized studies at the light of the most recent blood pressure targets recommended by guidelines. AB - In this paper, we present the results of a reanalysis of the data of two large randomized, double-blind, parallel group studies with a similar design, comparing the efficacy of an angiotensin-receptor blocker (olmesartan medoxomil) with that of an angiotensin-converting enzyme inhibitor (ramipril), by applying two different blood pressure targets recently recommended by hypertension guidelines for all patients, irrespective of the presence of diabetes (<140/90 mmHg), and for elderly hypertensive patients (<150/90 mmHg). The efficacy of olmesartan was not negatively affected by age, sex, hypertension type, diabetes status or other concomitant clinical conditions, or cardiovascular risk factors. In most cases, olmesartan provided better blood pressure control than ramipril. Olmesartan was significantly more effective than ramipril in male patients, in younger patients (aged 65-69 years), in those with metabolic syndrome, obesity, dyslipidemia, preserved renal function, diastolic +/- systolic hypertension, and, in general, in patients with a high or very high cardiovascular risk. Interestingly, patients previously untreated or treated with two or more antihypertensive drugs showed a significantly larger response with olmesartan than with ramipril. Thus, our results confirm the good efficacy of olmesartan in elderly hypertensives even when new blood pressure targets for antihypertensive treatment are considered. Such results may be relevant for the clinical practice, providing some hint on the possible different response of elderly hypertensive patients to two different drugs acting on the renin-angiotensin system, when patients are targeted according to the blood pressure levels recommended by recent hypertension guidelines. PMID- 26491274 TI - The beneficial effects of honeybee-venom serum on facial wrinkles in humans. AB - Facial wrinkles are an undesirable outcome caused by extrinsic photodamage and intrinsic aging processes. Currently, no effective strategies are known to prevent facial wrinkles. We assessed the beneficial effects of bee-venom serum on the clinical signs of aging skin. Our results show that bee-venom serum treatment clinically improved facial wrinkles by decreasing total wrinkle area, total wrinkle count, and average wrinkle depth. Therefore, bee-venom serum may be effective for the improvement of skin wrinkles. PMID- 26491275 TI - Lower creatinine as a marker of malnutrition and lower muscle mass in hemodialysis patients. PMID- 26491276 TI - The relationship between frailty, anxiety and depression, and health-related quality of life in elderly patients with heart failure. AB - OBJECTIVE: Elderly people constitute over 80% of the population of patients with heart failure (HF). Frailty is a distinct biological syndrome that reflects decreased physiologic reserve and resistance to stressors. Moreover, frailty can serve as an independent predictor of visits to the emergency department, hospitalizations, and mortality. The purpose of this paper was to assess the relationship between frailty, anxiety and depression, and the health-related quality of life (HRQoL) of elderly patients with HF. PATIENTS AND METHODS: The study included 100 patients (53 men and 47 women) with a diagnosis of HF. Frailty was measured using the Tilburg Frailty Indicator (TFI) scale. HRQoL was measured using the 36-Item Short Form Medical Outcomes Study Survey. To determine the prevalence of anxiety and depression, the Hospital Anxiety and Depression Scale was used. RESULTS: Frailty was found in 89% of the studied population. The study showed significant inverse correlations between the values of the physical component scale (PCS) domain results and TFI score, and a significant inverse correlation between the values of the mental component scale (MCS) domain and TFI score. When participants showed increased levels of frailty as measured by the TFI scale, there was also an increase in the levels of anxiety and depression. With increased anxiety and depression, there was deterioration in the quality of life of patients with HF. CONCLUSION: Frailty has a negative impact on the HRQoL results of elderly patients with HF. The assessment of frailty syndrome, and anxiety and depression should be taken into account when estimating risk and making therapeutic decisions for cardiovascular disease treatment and care. PMID- 26491277 TI - Facilitators and barriers to self-management of nursing home residents: perspectives of health-care professionals in Korean nursing homes. AB - PURPOSE: To explore facilitators and barriers to self-management from the viewpoint of staff taking care of nursing home (NH) residents with chronic diseases in South Korea. PATIENTS AND METHODS: A qualitative content analysis was done using the focus group interview method. A total of 23 health-care professionals (16 registered nurses and 7 social workers) were interviewed from three urban NHs, each with more than 100 beds. RESULTS: Five facilitators were identified: grouping the residents; the resident's awareness of his/her current health status; the willingness of residents to engage in self-management; residence in the facility; and support from the staff. Additionally, seven barriers were identified: deterioration of the resident's health; the dependency expectations of the resident; hesitation in asking for help; difference in expectations between the staff and the resident's family; insufficient staffing and time; lack of standardized guidelines; and conservative tendencies of the staff due to rigid policies. CONCLUSION: The findings of this study can help health-care professionals recognize the factors that influence self-management and provide direction for registered nurses and other health professionals involved in supporting self-management programs for NH residents. PMID- 26491278 TI - Investigation of Pneumocystis jirovecii colonization in patients with chronic pulmonary diseases in the People's Republic of China. AB - BACKGROUND: The detection of Pneumocystis jirovecii DNA in respiratory specimen from individuals who do not have signs or symptoms of pneumonia has been defined as colonization. The role of P. jirovecii colonization in the development or progression of various lung diseases has been reported, but little information about P. jirovecii colonization in patients is available in the People's Republic of China. OBJECTIVE: To determine the prevalence of P. jirovecii colonization in patients with various pulmonary diseases, including the acute and stable stage of COPD, interstitial lung diseases, cystic fibrosis, and chronic bronchiectasis. MATERIALS AND METHODS: A loop-mediated isothermal amplification (LAMP) and a conventional polymerase chain reaction (PCR) method for detecting P. jirovecii were developed. Ninety-eight HIV-negative patients who were followed-up and who had undergone bronchoscopy for diagnosis of various underlying respiratory diseases were included in the study. Sputa of these patients were analyzed with LAMP amplification of P. jirovecii gene. In addition, conventional PCR, Giemsa and Gomori's methenamine silver nitrate staining assays were applied to all specimens. RESULTS: The sensitivity and specificity test showed that there was no cross-reaction with other fungi or bacteria in detecting the specific gene of P. jirovecii by LAMP, and the minimum detection limits by LAMP was 50 copies/mL. P. jirovecii DNA was detected in 62 of 98 (63.3%) sputa specimens by LAMP assay and 22.45% (22/98) by conventional PCR. However, no P. jirovecii cysts were found by Giemsa and Gomori's methenamine silver nitrate in all of gene-positive specimens. CONCLUSION: The results of our study showed that prevalence of P. jirovecii colonization is particularly high in patients with chronic pulmonary diseases in the People's Republic of China, and the LAMP method is better for evaluation of the colonization of P. jirovecii in sputum specimen than conventional PCR. PMID- 26491279 TI - Assessment of cognitive impairment in long-term oxygen therapy-dependent COPD patients. AB - BACKGROUND: A number of studies have shown that COPD, particularly in its later and more severe stages, is associated with various cognitive deficits. Thus, the primary goal of the present study was to elucidate the extent of cognitive impairment in patients with long-term oxygen therapy-dependent (LTOTD) COPD. In addition, this study aimed to determine the effectiveness of two cognitive screening tests, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), for COPD patients and the ability of oxygen therapy to mitigate COPD-related deficits in cognitive function. METHODS: The present study enrolled 45 subjects: 24 nonuser and 21 regular-user LTOTD-COPD patients. All subjects had a similar grade of education, and there were no significant differences regarding age or sex. The MoCA (cutoff: <26 points) and MMSE (cutoff: <=24 points) scores were compared between these two groups. RESULTS: The nonuser LTOTD-COPD group had a significantly lower MoCA score than that of the regular user LTOTD-COPD group (19.38+/-2.99 vs 21.68+/-2.14, respectively) as well as a significantly lower MMSE score. Moreover, the absence of supplemental oxygen therapy increased the risk of cognitive impairment (MoCA, P=0.007 and MMSE, P=0.014), and the MoCA and MMSE scores significantly correlated with the number of emergency admissions and the number of hospitalizations in the last year. CONCLUSION: In the present study, the nonuser LTOTD-COPD group exhibited a significant decrease in cognitive status compared with the regular-user LTOTD COPD group. This suggests that the assessment of cognitive function in nonuser LTOTD-COPD patients and the use of protective strategies, such as continuous supplemental oxygen treatment, should be considered during the management of COPD in this population. In addition, the MoCA score was superior to the MMSE score for the determination of cognitive impairment in the nonuser LTOTD-COPD patients. PMID- 26491280 TI - Prevalence and risk factors for COPD in greenhouse farmers: a large, cross sectional survey of 5,880 farmers from northeast China. AB - BACKGROUND: COPD is one of the most common chronic diseases, and more and more farmers who were frequently exposed to greenhouse environments were diagnosed with COPD. However, little information is available on the prevalence of COPD among the greenhouse farmers. This study was conducted to assess the prevalence of COPD and investigate the potential risk factors for COPD among the Chinese greenhouse farmers. METHODS: Cross-sectional studies involving a sample of greenhouse farmers living in northeast China were performed via stratified cluster-random sampling. All subjects were interviewed using a uniform questionnaire and underwent pulmonary function tests between 2006 and 2009, based on the diagnostic criteria of the Global Initiative for Chronic Obstructive Lung Disease. Multiple logistic regression analysis was conducted to examine the risk factors for COPD. RESULTS: Of the 5,880 greenhouse farmers from northeast China who were originally selected for this study, 5,420 questionnaires were completed. The overall prevalence of COPD in greenhouse farmers was 17.5%. The COPD prevalence was significantly higher in elderly subjects (>=50 years), current smokers, in those with lower body mass index (<=18.5 kg/m(2)) and less education, in those who were exposed to mushroom, flowers and poultry, and in those living in mountain and coastal region. Multiple logistic regression analysis revealed that age over 50 years old (odds ratio [OR]=298.69, 95% confidence interval [CI]=121.57-733.84), smoking (OR=2.18, 95% CI=1.84-2.59), planting mushroom and flowers (OR=1.46 and 1.53, 95% CI=1.13-1.87 and 1.24-1.95), and living in mountain and coastal region (OR=1.68 and 1.35, 95% CI=1.37-2.06 and 1.10-1.65) were associated with the development of COPD among greenhouse farmers. CONCLUSION: In northeast China, COPD is highly prevalent among greenhouse farmers, and advanced age, smoking, planting mushroom, and flowers, as well as living in mountain and coastal regions, are potential risk factors for this disease. PMID- 26491281 TI - A real-world evaluation of indacaterol and other bronchodilators in COPD: the INFLOW study. AB - AIM: INFLOW (INdacaterol eFfectiveness and utiLizatiOn in COPD: real World evaluation) was a prospective, noninterventional study assessing the effectiveness and safety of long-acting bronchodilators in patients with chronic obstructive pulmonary disease (COPD) from the Middle East, Asia, and South Africa. METHODS: Patients newly prescribed or switched to indacaterol or other long-acting beta2-agonist (LABA), or tiotropium (monotherapy or in combination) were evaluated over 6 months. The primary endpoint was the clinical COPD questionnaire overall score at the end of the study. RESULTS: Data were analyzed from 1,710 patients (mean postbronchodilator forced expiratory volume in 1 second, 59% predicted) who received indacaterol (n=1,179), other LABA (n=68), tiotropium (n=271), indacaterol plus tiotropium (n=167), or other LABA plus tiotropium (n=25). Across treatments, clinical COPD questionnaire overall score improved from baseline by 0.81-1.26 points (all P<0.0001), 63%-84% of patients were satisfied/very satisfied, and physicians rated effectiveness as good/very good in 63%-80% of cases. The indacaterol inhaler was rated easy/very easy to use by the majority of patients, and physicians considered its use clearly understood by most patients. All treatments had acceptable tolerability. CONCLUSION: In real life clinical practice across a diverse region, indacaterol and other long-acting bronchodilators improved health status and were well regarded by patients and physicians. PMID- 26491282 TI - Lung transplantation in chronic obstructive pulmonary disease: patient selection and special considerations. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and morbidity. Lung transplantation is one of the few treatments available for end stage COPD with the potential to improve survival and quality of life. The selection of candidates and timing of listing present challenges, as COPD tends to progress fairly slowly, and survival after lung transplantation remains limited. Though the natural course of COPD is difficult to predict, the use of assessments of functional status and multivariable indices such as the BODE index can help identify which patients with COPD are at increased risk for mortality, and hence which are more likely to benefit from lung transplantation. Patients with COPD can undergo either single or bilateral lung transplantation. Although many studies suggest better long-term survival with bilateral lung transplant, especially in younger patients, this continues to be debated, and definitive recommendations about this cannot be made. Patients may be more susceptible to particular complications of transplant for COPD, including native lung hyperinflation, and development of lung cancer. PMID- 26491283 TI - Biomarker-based detection of asthma-COPD overlap syndrome in COPD populations. AB - Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) was proposed by the science committees of both Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD). However, the definition of ACOS has remained unclear all over the world, and the prevalence rate of ACOS is basically dependent on the patient's symptoms or the physician's opinion, based on questionnaire testing. In the current case report, we investigated the prevalence rate of COPD patients with high levels of fractional exhaled nitric oxide (FENO) or immunoglobulin E (IgE) as candidate markers of ACOS in COPD, as a multicenter, cross-sectional study. Outpatients with COPD were enrolled from Tohoku University Hospital, Sendai, Japan, and five hospitals (Tohoku University Hospital, Sendai, Japan; NTT East Tohoku Hospital, Sendai, Japan; Wakayama Medical University Hospital, Kimiidera, Japan; Hiraka General Hospital, Yokote, Japan; Iwate Prefectural Isawa Hospital, Oshu, Japan) with pulmonary physicians from March 1, 2013 to February 28, 2014. When they were estimated using 35 ppb as the cutoff value of FENO, the prevalence rate of ACOS was 16.3% in COPD. When estimated by both FENO and IgE, the high-FENO/high-IgE group was 7.8% in COPD. To the best of our knowledge, this study is the first to detect the prevalence rate of ACOS in COPD populations by using objective biomarkers. The results from the current study should be useful to identify the subgroup requiring early intervention by inhaled corticosteroids/long-acting beta agonist combination in COPD in order to improve the long-term management for ACOS. PMID- 26491284 TI - A randomized multicenter Phase II study of perioperative tiotropium intervention in gastric cancer patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Tiotropium, a long-acting inhaled anticholinergic drug, has been widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, the issue of whether perioperative tiotropium improves postoperative outcomes for gastric cancer patients with COPD remains unclear. Thus, the aim of this study was to determine the efficacy of perioperative tiotropium intervention for gastric cancer patients with COPD. PATIENTS AND METHODS: Eighty-four gastric cancer patients with mild-to-moderate COPD were randomly assigned to receive perioperative pulmonary rehabilitation alone (control group) or pulmonary rehabilitation with 18 ug of tiotropium once daily (tiotropium group). The patients in the tiotropium group received tiotropium for more than 1 week before surgery and for 2 weeks after surgery. Spirometry was performed prior to group assignment and at 2 weeks after surgery. Postoperative complications, forced expiratory volume in 1 second, forced vital capacity, and the ratio of forced expiratory volume in second to forced vital capacity (%) were compared between the two groups. RESULTS: There were no significant differences between the two groups in terms of age, body mass index, smoking, gastrectomy incision, operation time, and bleeding volume (all P>0.05). Postoperative complications and pulmonary functions did not differ significantly between the control and tiotropium groups. A subgroup analysis of gastric cancer patients with moderate COPD showed that perioperative tiotropium intervention significantly decreased the rate of postoperative complications compared with the control group (P=0.046). However, even after gastrectomy, many patients with mild COPD in both the control and tiotropium groups showed improved pulmonary function. CONCLUSION: Although perioperative tiotropium intervention had no significant effects in gastric cancer patients with mild COPD, it may be beneficial in those with moderate COPD. Therefore, the next prospective study should further evaluate perioperative tiotropium intervention for gastric cancer patients with moderate-to-severe COPD. PMID- 26491285 TI - Cytotoxicity of various types of gold-mesoporous silica nanoparticles in human breast cancer cells. AB - Recently, gold nanoparticles (AuNPs) have shown promising biological applications due to their unique electronic and optical properties. However, the potential toxicity of AuNPs remains a major hurdle that impedes their use in clinical settings. Mesoporous silica is very suitable for the use as a coating material for AuNPs and might not only reduce the cytotoxicity of cetyltrimethylammonium bromide-coated AuNPs but might also facilitate the loading and delivery of drugs. Herein, three types of rod-like gold-mesoporous silica nanoparticles (termed bare AuNPs, core-shell Au@mSiO2NPs, and Janus Au@mSiO2NPs) were specially designed, and the effects of these AuNPs on cellular uptake, toxic behavior, and mechanism were then systematically studied. Our results indicate that bare AuNPs exerted higher toxicity than the Au@mSiO2NPs and that Janus Au@mSiO2NPs exhibited the lowest toxicity in human breast cancer MCF-7 cells, consistent with the endocytosis capacity of the nanoparticles, which followed the order, bare AuNPs > core-shell Au@mSiO2NPs > Janus Au@mSiO2NPs. More importantly, the AuNPs-induced apoptosis of MCF-7 cells exhibited features that were characteristic of intracellular reactive oxygen species (ROS) generation, activation of c-Jun-N terminal kinase (JNK) phosphorylation, an enhanced Bax-to-Bcl-2 ratio, and loss of the mitochondrial membrane potential. Simultaneously, cytochrome c was released from mitochondria, and the caspase-3/9 cascade was activated. Moreover, both ROS scavenger (N-acetylcysteine) and JNK inhibitor (SP600125) partly blocked the induction of apoptosis in all AuNPs-treated cells. Taken together, these findings suggest that all AuNPs induce apoptosis through the ROS-/JNK-mediated mitochondrial pathway. Thus, Janus Au@mSiO2NPs exhibit the potential for applications in biomedicine, thus aiding the clinical translation of AuNPs. PMID- 26491286 TI - Effect of superparamagnetic iron oxide nanoparticles on fluidity and phase transition of phosphatidylcholine liposomal membranes. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) with multifunctional properties have shown great promise in theranostics. The aim of our work was to compare the effects of SPIONs on the fluidity and phase transition of the liposomal membranes prepared with zwitterionic phosphatidylcholine lipids. In order to study if the surface modification of SPIONs has any influence on these membrane properties, we have used four types of differently functionalized SPIONs, such as: plain SPIONs (primary size was shown to be11 nm), silica-coated SPIONs, SPIONs coated with silica and functionalized with positively charged amino groups or negatively charged carboxyl groups (the primary size of all the surface-modified SPIONs was ~20 nm). Small unilamellar vesicles prepared with 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine lipids and multilamellar vesicles prepared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine lipids were encapsulated or incubated with the plain and surface-modified SPIONs to determine the fluidity and phase transition temperature of the bilayer lipids, respectively. Fluorescent anisotropy and differential scanning calorimetric measurements of the liposomes that were either encapsulated or incubated with the suspension of SPIONs did not show a significant difference in the lipid ordering and fluidity; though the encapsulated SPIONs showed a slightly increased effect on the fluidity of the model membranes in comparison with the incubated SPIONs. This indicates the low potential of the SPIONs to interact with the nontargeted cell membranes, which is a desirable factor for in vivo applications. PMID- 26491287 TI - Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood-brain barrier primary triple coculture model. AB - BACKGROUND: Silver nanoparticles (Ag-NPs) can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood-brain barrier (BBB) and the underlying mechanism(s) of action on the BBB and the brain are not well understood. METHOD: To investigate Ag-NP suspension (Ag-NPS)-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM). Global gene expression of astrocytes was measured using a DNA microarray. RESULTS: A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values >200 Omega.cm(2). After Ag-NPS exposure for 24 hours, the BBB permeability was significantly increased and expression of the tight junction (TJ) protein ZO-1 was decreased. Discontinuous TJs were also observed between microvascular endothelial cells. After Ag-NPS exposure, severe mitochondrial shrinkage, vacuolations, endoplasmic reticulum expansion, and Ag-NPs were observed in astrocytes by TEM. Global gene expression analysis showed that three genes were upregulated and 20 genes were downregulated in astrocytes treated with Ag-NPS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the 23 genes were associated with metabolic processes, biosynthetic processes, response to stimuli, cell death, the MAPK pathway, and so on. No GO term and KEGG pathways were changed in the released-ion or polystyrene NP groups. Ag-NPS inhibited the antioxidant defense of the astrocytes by increasing thioredoxin interacting protein, which inhibits the Trx system, and decreasing Nr4a1 and Dusp1. Meanwhile, Ag-NPS induced inflammation and apoptosis through modulation of the MAPK pathway or B-cell lymphoma-2 expression or mTOR activity in astrocytes. CONCLUSION: These results draw our attention to the importance of Ag-NP-induced toxicity on the neurovascular unit and provide a better understanding of its toxicological mechanisms on astrocytes. PMID- 26491288 TI - Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe. AB - BACKGROUND: The objective of this study was to compare the physicochemical characteristics, solubility, dissolution, and oral bioavailability of an ezetimibe-loaded solid self-nanoemulsifying drug delivery system (SNEDDS), surface modified solid dispersion (SMSD), and solvent evaporated solid dispersion (SESD) to identify the best drug delivery system with the highest oral bioavailability. METHODS: For the liquid SNEDDS formulation, Capryol 90, Cremophor EL, and Tween 80 were selected as the oil, surfactant, and cosurfactant, respectively. The nanoemulsion-forming region was sketched using a pseudoternary phase diagram on the basis of reduced emulsion size. The optimized liquid SNEDDS was converted to solid SNEDDS by spray drying with silicon dioxide. Furthermore, SMSDs were prepared using the spray drying technique with various amounts of hydroxypropylcellulose and Tween 80, optimized on the basis of their drug solubility. The SESD formulation was prepared with the same composition of optimized SMSD. The aqueous solubility, dissolution, physicochemical properties, and pharmacokinetics of all of the formulations were investigated and compared with the drug powder. RESULTS: The drug existed in the crystalline form in SMSD, but was changed into an amorphous form in SNEDDS and SESD, giving particle sizes of approximately 24, 6, and 11 um, respectively. All of these formulations significantly improved the aqueous solubility and dissolution in the order of solid SNEDDS >= SESD > SMSD, and showed a total higher plasma concentration than did the drug powder. Moreover, SESD gave a higher area under the drug concentration time curve from zero to infinity than did SNEDDS and SMSD, even if they were not significantly different, suggesting more improved oral bioavailability. CONCLUSION: Among the various formulations tested in this study, the SESD system would be strongly recommended as a drug delivery system for the oral administration of ezetimibe with poor water solubility. PMID- 26491289 TI - Rapid and quantitative detection of C-reactive protein based on quantum dots and immunofiltration assay. AB - Convenient and rapid immunofiltration assays (IFAs) enable on-site "yes" or "no" determination of disease markers. However, traditional IFAs are commonly qualitative or semi-quantitative and are very limited for the efficient testing of samples in field diagnostics. Here, we overcome these limitations by developing a quantum dots (QDs)-based fluorescent IFA for the quantitative detection of C-reactive proteins (CRP). CRP, the well-known diagnostic marker for acute viral and bacterial infections, was used as a model analyte to demonstrate performance and sensitivity of our developed QDs-based IFA. QDs capped with both polyethylene glycol (PEG) and glutathione were used as fluorescent labels for our IFAs. The presence of the surface PEG layer, which reduced the non-specific protein interactions, in conjunction with the inherent optical properties of QDs, resulted in lower background signal, increased sensitivity, and ability to detect CRP down to 0.79 mg/L with only 5 uL serum sample. In addition, the developed assay is simple, fast and can quantitatively detect CRP with a detection limit up to 200 mg/L. Clinical test results of our QD-based IFA are well correlated with the traditional latex enhance immune-agglutination aggregation. The proposed QD based fluorescent IFA is very promising, and potentially will be adopted for multiplexed immunoassay and in field point-of-care test. PMID- 26491290 TI - Micellar emulsions composed of mPEG-PCL/MCT as novel nanocarriers for systemic delivery of genistein: a comparative study with micelles. AB - Polymeric micelles receive considerable attention as drug delivery vehicles, depending on the versatility in drug solubilization and targeting therapy. However, their use invariably suffers with poor stability both in in vitro and in vivo conditions. Here, we aimed to develop a novel nanocarrier (micellar emulsions, MEs) for a systemic delivery of genistein (Gen), a poorly soluble anticancer agent. Gen-loaded MEs (Gen-MEs) were prepared from methoxy poly(ethylene glycol)-block-(epsilon-caprolactone) and medium-chain triglycerides (MCT) by solvent-diffusion technique. Nanocarriers were characterized by dynamic light scattering, transmission electron microscopy, and in vitro release. The resulting Gen-MEs were approximately 46 nm in particle size with a narrow distribution. Gen-MEs produced a different in vitro release profile from the counterpart of Gen-ME. The incorporation of MCT significantly enhanced the stability of nanoparticles against dilution with simulated body fluid. Pharmacokinetic study revealed that MEs could notably extend the mean retention time of Gen, 1.57- and 7.38-fold as long as that of micelles and solution formulation, respectively, following intravenous injection. Furthermore, MEs markedly increased the elimination half-life (t(1/2beta)) of Gen, which was 2.63 fold larger than that of Gen solution. Interestingly, Gen distribution in the liver and kidney for MEs group was significantly low relative to the micelle group in the first 2 hours, indicating less perfusion in such two tissues, which well accorded with the elongated mean retention time. Our findings suggested that MEs may be promising carriers as an alternative of micelles to systemically deliver poorly soluble drugs. PMID- 26491291 TI - pH-Sensitive carboxymethyl chitosan-modified cationic liposomes for sorafenib and siRNA co-delivery. AB - Combination of chemotherapeutic drug and small interfering RNA (siRNA) can affect multiple disease pathways and has been proven effective in suppressing tumor progression. Co-delivery of drug and siRNA within a same nanocarrier is a vital means in this field. The present study aimed at the development of a pH-sensitive liposome to co-deliver drug and siRNA to tumor region. Driven by the electrostatic interaction, the pH-sensitive material, carboxymethyl chitosan (CMCS), was coated onto the surface of the cationic liposome (CL) preloaded with sorafenib (Sf) and siRNA (Si). To evaluate whether the resulting CMCS-modified Sf and siRNA co-delivery cationic liposome (CMCS-SiSf-CL) enhanced antitumor efficiency after systematic administration, in vitro and in vivo experiments were evaluated in HepG2 cells and the H22 cells-bearing Kunming mice model. The experimental results demonstrated that CMCS-SiSf-CL was able to condense siRNA efficiently and protect siRNA from being degraded by serum and RNase. The release rate of Sf from CMCS-modified liposome exhibited pH-sensitive release behavior. Furthermore, in vitro cellular uptake results showed that CMCS-SiSf-CL yielded higher fluorescence intensity at pH 6.5 than at pH 7.4, and that siRNA could be delivered to tumor site by CMCS-SiSf-CL in vivo. The in vivo antitumor efficacy showed that CMCS-Sf-CL inhibits tumor growth effectively when compared with free Sf solution. In current experimental conditions, this liposomal formulation did not show significant toxicity both in vitro and in vivo. Therefore, co-delivering Sf with siRNA by CMCS-SiSf-CL might provide a promising approach for tumor therapy. PMID- 26491292 TI - An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery. AB - Cell-penetrating peptides (CPPs) as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG) and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL) to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR) to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS) was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into targeted subcellular compartments while remaining inactive and free from opsonins at a maximum extent in systemic circulation. The 4% CPPL as a drug delivery system will have great potential in the clinical application of anticancer drugs in future. PMID- 26491293 TI - Cerium oxide nanoparticle treatment ameliorates peritonitis-induced diaphragm dysfunction. AB - The severe inflammation observed during sepsis is thought to cause diaphragm dysfunction, which is associated with poor patient prognosis. Cerium oxide (CeO2) nanoparticles have been posited to exhibit anti-inflammatory and antioxidative activities suggesting that these particles may be of potential use for the treatment of inflammatory disorders. To investigate this possibility, Sprague Dawley rats were randomly assigned to the following groups: sham control, CeO2 nanoparticle treatment only (0.5 mg/kg iv), sepsis, and sepsis+CeO2 nanoparticles. Sepsis was induced by the introduction of cecal material (600 mg/kg) directly into the peritoneal cavity. Nanoparticle treatment decreased sepsis-associated impairments in diaphragmatic contractile (P(o)) function (sham: 25.6+/-1.6 N/cm(2) vs CeO2: 23.4+/-0.8 N/cm(2) vs Sep: 15.9+/-1.0 N/cm(2) vs Sep+CeO2: 20.0+/-1.0 N/cm(2), P<0.05). These improvements in diaphragm contractile function were accompanied by a normalization of protein translation signaling (Akt, FOXO-1, and 4EBP1), diminished proteolysis (caspase 8 and ubiquitin levels), and decreased inflammatory signaling (Stat3 and iNOS). Histological analysis suggested that nanoparticle treatment was associated with diminished sarcolemma damage and diminished inflammatory cell infiltration. These data indicate CeO2 nanoparticles may improve diaphragmatic function in the septic laboratory rat. PMID- 26491294 TI - Anti-transferrin receptor-modified amphotericin B-loaded PLA-PEG nanoparticles cure Candidal meningitis and reduce drug toxicity. AB - Fatal fungal infections in central nervous system (CNS) can occur through hematogenous spread or direct extension. At present, hydrophobic amphotericin B (AMB) is the most effective antifungal drug in clinical trials. However, AMB is hydrophobic and therefore penetrates poorly into the CNS, and therapeutic levels of AMB are hard to achieve. The transferrin receptor (TfR/CD71) located at the blood-brain barrier mediates transferrin transcytosis. In order to enhance the receptor-mediated delivery of AMB into CNS with therapeutic level, an anti-TfR antibody (OX26)-modified AMB-loaded PLA (poly[lactic acid])-PEG (polyethylene glycol)-based micellar drug delivery system was constructed. The prepared OX26 modified AMB-loaded nanoparticles (OX26-AMB-NPs) showed significant reduction of CNS fungal burden and an increase of mouse survival time. In conclusion, OX26-AMB NPs represent a promising novel drug delivery system for intracerebral fungal infection. PMID- 26491295 TI - Effects of silver nanoparticles on neonatal testis development in mice. AB - BACKGROUND: Metal nanoparticles (MNPs) play an important role in consumer products. An increasing use of MNPs has raised concerns about potential risks for human health. Therefore, in vivo tests of MNPs are urgently required. Using mice as a model animal, the aim of the present study was designed to investigate the effect of biologically synthesized silver nanoparticles (AgNPs) on spermatogenesis in neonatal mice. METHODS: AgNPs were synthesized using Bacillus funiculus. The prepared nanoparticles were characterized using various analytical techniques such as UV-visible spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy. The prepared AgNPs were used to investigate testis development in neonatal mice. Institute of Cancer Research neonatal male mice were used in all experiments and were treated with different doses (0, 1, and 5 mg/kg) of AgNPs five times (interval of 3 days from postnatal day [PND] 8-21) by abdominal subcutaneous injection. RESULTS: The results showed that the sperm abnormalities such as quality and quantity were significantly increased by the synthesized AgNPs. The diameter of the convoluted tubules shrank significantly in mice treated with AgNPs on PND28 and PND42. The results of reverse transcription-quantitative polymerase chain reaction indicated that the E1f1ay, Gsta4, and Fdx1 genes were up-regulated, and the Amh, Cx43, and Claudin-11 genes were down-regulated in response to AgNPs exposure on PND28; however, these genes recovered at PND60. AgNPs had no effect on the recombination levels of chromosomes in germ cells. CONCLUSION: These results demonstrated the adverse effects of AgNPs on the male reproductive tract, particularly spermatogenesis and the quality of sperm. This study suggests that the development of nanomaterials should be safer and non-toxic to the living organisms and the potential reprotoxicity of AgNPs should be investigated more carefully. PMID- 26491296 TI - Reduced graphene oxide-silver nanoparticle nanocomposite: a potential anticancer nanotherapy. AB - BACKGROUND: Graphene and graphene-based nanocomposites are used in various research areas including sensing, energy storage, and catalysis. The mechanical, thermal, electrical, and biological properties render graphene-based nanocomposites of metallic nanoparticles useful for several biomedical applications. Epithelial ovarian carcinoma is the fifth most deadly cancer in women; most tumors initially respond to chemotherapy, but eventually acquire chemoresistance. Consequently, the development of novel molecules for cancer therapy is essential. This study was designed to develop a simple, non-toxic, environmentally friendly method for the synthesis of reduced graphene oxide silver (rGO-Ag) nanoparticle nanocomposites using Tilia amurensis plant extracts as reducing and stabilizing agents. The anticancer properties of rGO-Ag were evaluated in ovarian cancer cells. METHODS: The synthesized rGO-Ag nanocomposite was characterized using various analytical techniques. The anticancer properties of the rGO-Ag nanocomposite were evaluated using a series of assays such as cell viability, lactate dehydrogenase leakage, reactive oxygen species generation, cellular levels of malonaldehyde and glutathione, caspase-3 activity, and DNA fragmentation in ovarian cancer cells (A2780). RESULTS: AgNPs with an average size of 20 nm were uniformly dispersed on graphene sheets. The data obtained from the biochemical assays indicate that the rGO-Ag nanocomposite significantly inhibited cell viability in A2780 ovarian cancer cells and increased lactate dehydrogenase leakage, reactive oxygen species generation, caspase-3 activity, and DNA fragmentation compared with other tested nanomaterials such as graphene oxide, rGO, and AgNPs. CONCLUSION: T. amurensis plant extract-mediated rGO-Ag nanocomposites could facilitate the large-scale production of graphene-based nanocomposites; rGO-Ag showed a significant inhibiting effect on cell viability compared to graphene oxide, rGO, and silver nanoparticles. The nanocomposites could be effective non-toxic therapeutic agents for the treatment of both cancer and cancer stem cells. PMID- 26491297 TI - Physiologically based pharmacokinetic modeling of zinc oxide nanoparticles and zinc nitrate in mice. AB - Zinc oxide nanoparticles (ZnO NPs) have been widely used in consumer products, therapeutic agents, and drug delivery systems. However, the fate and behavior of ZnO NPs in living organisms are not well described. The purpose of this study was to develop a physiologically based pharmacokinetic model to describe the dynamic interactions of (65)ZnO NPs in mice. We estimated key physicochemical parameters of partition coefficients and excretion or elimination rates, based on our previously published data quantifying the biodistributions of 10 nm and 71 nm (65)ZnO NPs and zinc nitrate ((65)Zn(NO3)2) in various mice tissues. The time dependent partition coefficients and excretion or elimination rates were used to construct our physiologically based pharmacokinetic model. In general, tissue partition coefficients of (65)ZnO NPs were greater than those of (65)Zn(NO3)2, particularly the lung partition coefficient of 10 nm (65)ZnO NPs. Sensitivity analysis revealed that 71 nm (65)ZnO NPs and (65)Zn(NO3)2 were sensitive to excretion and elimination rates in the liver and gastrointestinal tract. Although the partition coefficient of the brain was relative low, it increased time dependently for (65)ZnO NPs and (65)Zn(NO3)2. The simulation of (65)Zn(NO3)2 was well fitted with the experimental data. However, replacing partition coefficients of (65)ZnO NPs with those of (65)Zn(NO3)2 after day 7 greatly improved the fitness of simulation, suggesting that ZnO NPs might decompose to zinc ion after day 7. In this study, we successfully established a potentially predictive dynamic model for slowly decomposed NPs. More caution is suggested for exposure to (65)ZnO NPs <10 nm because those small (65)ZnO NPs tend to accumulate in the body for a relatively longer time than 71 nm (65)ZnO NPs and (65)Zn(NO3)2 do. PMID- 26491298 TI - Preparation, optimization, and in vitro simulated inhalation delivery of carvedilol nanoparticles loaded on a coarse carrier intended for pulmonary administration. AB - Carvedilol (CAR) is a potent antihypertensive drug but has poor oral bioavailability (24%). A nanosuspension suitable for pulmonary delivery to enhance bioavailability and bypass first-pass metabolism of CAR could be advantageous. Accordingly, the aim of this work was to prepare CAR nanosuspensions and to use artificial neural networks associated with genetic algorithm to model and optimize the formulations. The optimized nanosuspension was lyophilized to obtain dry powder suitable for inhalation. However, respirable particles must have a diameter of 1-5 um in order to deposit in the lungs. Hence, mannitol was used during lyophilization for cryoprotection and to act as a coarse carrier for nanoparticles in order to deliver them into their desired destination. The bottom-up technique was adopted for nanosuspension formulation using Pluronic stabilizers (F127, F68, and P123) combined with sodium deoxycholate at 1:1 weight ratio, at three levels with two drug loads and two aqueous to organic phase volume ratios. The drug crystallinity was studied using differential scanning calorimetry and powder X-ray diffractometry. The in vitro emitted doses of CAR were evaluated using a dry powder inhaler sampling apparatus and the aerodynamic characteristics were evaluated using an Andersen MKII cascade impactor. The artificial neural networks results showed that Pluronic F127 was the optimum stabilizer based on the desired particle size, polydispersity index, and zeta potential. Results of differential scanning calorimetry combined with powder X-ray diffractometry showed that CAR crystallinity was observed in the lyophilized nanosuspension. The aerodynamic characteristics of the optimized lyophilized nanosuspension demonstrated significantly higher percentage of total emitted dose (89.70%) and smaller mass median aerodynamic diameter (2.80 um) compared with coarse drug powder (73.60% and 4.20 um, respectively). In summary, the above strategy confirmed the applicability of formulating CAR in the form of nanoparticles loaded on a coarse carrier suitable for inhalation delivery. PMID- 26491300 TI - Hyaluronic acid-tagged silica nanoparticles in colon cancer therapy: therapeutic efficacy evaluation. AB - Colon cancer is one of the leading causes of cancer-related death worldwide, and the therapeutic application of 5-fluorouracil (5-FU) is limited due to its nonspecificity, low bioavailability, and overdose. The present study is an attempt to improve the chemotherapeutic efficacy of 5-FU in colon cancers. Therefore, we have prepared 5-FU-loaded hyaluronic acid (HA)-conjugated silica nanoparticles (SiNPs) to target to colon cancer cells. In this study, we have showed the specific binding and intracellular accumulation of targeted nanoparticles based on HA surface modifications in colon carcinoma cells. The particles had spherical shapes with sizes of approximately 130 nm. HA-conjugated nanoparticles showed a sustained release pattern for 5-FU and continuously released for 120 hours. We have further investigated the cytotoxicity potential of targeted and nontargeted nanoparticles in colo-205 cancer cells. IC50 value of 5-FU/hyaluronic acid-conjugated silica nanoparticles (HSNP) was 0.65 ug/mL compared with ~2.8 ug/mL for 5-FU/SNP after 24 hours of incubation. The result clearly showed that HA-conjugated NP was more effective in inducing apoptosis in cancer cells than nontargeted NP. The 5-FU/HSNP showed ~45% of cell apoptosis (early and late apoptosis stage) compared with only 20% for 5-FU/silica nanoparticles (SNP)-treated group. The HA-conjugated nanoparticles provide the possibility of efficient drug transport into tumors that could effectively reduce the side effects in the normal tissues. 5-FU/HSNP was highly efficient in suppressing the tumor growth in xenograft tumor model. The proportion of Ki67 in 5-FU/HSNP-treated group was significantly lower than that of either free drug or nontargeted SiNPs. Altogether, we have showed that conjugation of HA to SiNPs could result in enhanced uptake of 5-FU through CD44-mediated endocytosis uptake and could result in significant antitumor efficacy. Thus, 5-FU/HSNP could be a promising drug delivery system for colon cancer therapy. PMID- 26491299 TI - Para amino benzoic acid-derived self-assembled biocompatible nanoparticles for efficient delivery of siRNA. AB - A number of diseases can result from abnormal gene expression. One of the approaches for treating such diseases is gene therapy to inhibit expression of a particular gene in a specific cell population by RNA interference. Use of efficient delivery vehicles increases the safety and success of gene therapy. Here we report the development of functionalized biocompatible fluorescent nanoparticles from para amino benzoic acid nanoparticles for efficient delivery of short interfering RNA (siRNA). These nanoparticles were non-toxic and did not interfere with progression of the cell cycle. The intrinsic fluorescent nature of these nanoparticles allows easy tracking and an opportunity for diagnostic applications. Human Bcl-2 siRNA was complexed with these nanoparticles to inhibit expression in cells at both the transcriptional and translational levels. Our findings indicated high gene transfection efficiency. These biocompatible nanoparticles allow targeted delivery of siRNA, providing an efficient vehicle for gene delivery. PMID- 26491302 TI - Summary of the National Conference on Challenges in Biomaterials Research jointly organized by VIT and CSIR-CECRI. PMID- 26491301 TI - Attenuation of the macrophage inflammatory activity by TiO2 nanotubes via inhibition of MAPK and NF-kappaB pathways. AB - Biomaterial implantation in a living tissue triggers the activation of macrophages in inflammatory events, promoting the transcription of pro inflammatory mediator genes. The initiation of macrophage inflammatory processes is mainly regulated by signaling proteins of mitogen-activated protein kinase (MAPK) and by nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) pathways. We have previously shown that titania nanotubes modified Ti surfaces (Ti/TiO2) mitigate the immune response, compared with flat Ti surfaces; however, little is known regarding the underlying mechanism. Therefore, the aim of this study is to investigate the mechanism(s) by which this nanotopography attenuates the inflammatory activity of macrophages. Thus, we analyzed the effects of TiO2 nanotubes on the activation of MAPK and NF-kappaB signaling pathways in standard and lipopolysaccharide-evoked conditions. Results showed that the Ti/TiO2 significantly reduce the expression levels of the phosphorylated forms of p38, ERK1/2, c-Jun NH2-terminal kinase (JNK), IKKbeta, and IkB-alpha. Furthermore, a significant reduction in the p65 nuclear accumulation on the nanotubular surface was remarked. Following, by using specific MAPK inhibitors, we observed that lipopolysaccharide-induced production of monocyte chemotactic protein-1 and nitric oxide was significantly inhibited on the Ti/TiO2 surface via p38 and ERK1/2, but not via JNK. However, the selective inhibitor for JNK signaling pathway (SP600125) was effective in reducing tumor necrosis factor alpha release as well as monocyte chemotactic protein-1 and nitric oxide production. Altogether, these data suggest that titania nanotubes can attenuate the macrophage inflammatory response via suppression of MAPK and NF-kappaB pathways providing a potential mechanism for their anti-inflammatory activity. PMID- 26491303 TI - Development of a new carbon nanotube-alginate-hydroxyapatite tricomponent composite scaffold for application in bone tissue engineering. AB - In recent times, tricomponent scaffolds prepared from naturally occurring polysaccharides, hydroxyapatite, and reinforcing materials have been gaining increased attention in the field of bone tissue engineering. In the current work, a tricomponent scaffold with an oxidized multiwalled carbon nanotube (fMWCNT) alginate-hydroxyapatite with the required porosity was prepared for the first time by a freeze-drying method and characterized using analytical techniques. The hydroxyapatite for the scaffold was isolated from chicken bones by thermal calcination at 800 degrees C. The Fourier transform infrared spectra and X-ray diffraction data confirmed ionic interactions and formation of the fMWCNT alginate-hydroxyapatite scaffold. Interconnected porosity with a pore size of 130 170 um was evident from field emission scanning electron microscopy. The total porosity calculated using the liquid displacement method was found to be 93.85%. In vitro biocompatibility and cell proliferation on the scaffold was checked using an MG-63 cell line by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and cell attachment by Hoechst stain assay. In vitro studies showed better cell proliferation, cell differentiation, and cell attachment on the prepared scaffold. These results indicate that this scaffold could be a promising candidate for bone tissue engineering. PMID- 26491304 TI - Biocompatibility evaluation of sputtered zirconium-based thin film metallic glass coated steels. AB - Thin film metallic glasses comprised of Zr48Cu36Al8Ag8 (at.%) of approximately 1.5 MUm and 3 MUm in thickness were prepared using magnetron sputtering onto medical grade 316L stainless steel. Their structural and mechanical properties, in vitro corrosion, and antimicrobial activity were analyzed. The amorphous thin film metallic glasses consisted of a single glassy phase, with an absence of any detectable peaks corresponding to crystalline phases. Elemental composition close to the target alloy was noted from EDAX analysis of the thin film. The surface morphology of the film showed a smooth surface on scanning electron microscopy and atomic force microscopy. In vitro electrochemical corrosion studies indicated that the zirconium-based metallic glass could withstand body fluid, showing superior resistance to corrosion and electrochemical stability. Interactions between the coated surface and bacteria were investigated by agar diffusion, solution suspension, and wet interfacial contact methods. The results indicated a clear zone of inhibition against the growth of microorganisms such as Escherichia coli and Staphylococcus aureus, confirming the antimicrobial activity of the thin film metallic glasses. Cytotoxicity studies using L929 fibroblast cells showed these coatings to be noncytotoxic in nature. PMID- 26491305 TI - Preparation and evaluation of the cytotoxic nature of TiO2 nanoparticles by direct contact method. AB - The purpose of this study is to prepare and evaluate the effect of synthesized titanium dioxide (TiO2) nanoparticles for their biocompatibility on physiological body fluids and the effect of cell toxicity to produce osteointegration when used as implantable materials. For the past few decades, the number of researches done to understand the importance of the biocompatibility of bioceramics, metals, and polymers and their effect on clinical settings of biomedical devices has increased. Hence, the total concept of biocompatibility encourages researchers to actively engage in the investigation of the most compatible materials in living systems by analyzing them using suitable physical, chemical, and biological (bioassay) methods. The ceramic material nano TiO2 was prepared by sol-gel method and analyzed for its functional group and phase formation by Fourier transform infrared spectroscopy and powder X-ray diffraction. Furthermore, the particle size, shape, surface topography, and morphological behavior were analyzed by dynamic light scattering, zeta potential, scanning electron microscopy-energy dispersive X-ray analysis, and transmission electron microscopy analysis. In addition to this, the cytotoxicity and cytocompatibility were determined on MG63 cell lines with varying doses of concentrations such as 1 ug/mL, 10 ug/mL, 25 ug/mL, 50 ug/mL, and 100 ug/mL with different time periods such as 24 hours and 48 hours. The results have not shown any toxicity, whereas, it improved the cell viability/proliferation at various concentrations. Hence, these findings indicate that the nano TiO2 material acts as a good implantable material when used in the biomedical field as a prime surface-modifying agent. PMID- 26491306 TI - Impact of silk fibroin-based scaffold structures on human osteoblast MG63 cell attachment and proliferation. AB - The present study was carried out to investigate the impact of various types of silk fibroin (SF) scaffolds on human osteoblast-like cell (MG63) attachment and proliferation. SF was isolated from Bombyx mori silk worm cocoons after degumming. Protein concentration in the degummed SF solution was estimated using Bradford method. Aqueous SF solution was used to fabricate three different types of scaffolds, viz, electrospun nanofiber mat, sponge, and porous film. The structures of the prepared scaffolds were characterized using optical microscopy and field emission scanning electron microscopy. The changes in the secondary structure of the proteins and the thermal behavior of the scaffolds were determined by Fourier transform infrared spectroscopy and thermo-gravimetric analysis, respectively. The biodegradation rate of scaffolds was determined by incubating the scaffolds in simulated body fluid for 4 weeks. MG63 cells were seeded on the scaffolds and their attachment and proliferation onto the scaffolds were studied. The MTT assay was carried out to deduce the toxicity of the developed scaffolds. All the scaffolds were found to be biocompatible. The amount of collagen produced by the osteoblast-like cells growing on different scaffolds was estimated. PMID- 26491307 TI - Exploration of alginate hydrogel/nano zinc oxide composite bandages for infected wounds. AB - Alginate hydrogel/zinc oxide nanoparticles (nZnO) composite bandage was developed by freeze-dry method from the mixture of nZnO and alginate hydrogel. The developed composite bandage was porous with porosity at a range of 60%-70%. The swelling ratios of the bandages decreased with increasing concentrations of nZnO. The composite bandages with nZnO incorporation showed controlled degradation profile and faster blood clotting ability when compared to the KALTOSTAT(r) and control bandages without nZnO. The prepared composite bandages exhibited excellent antimicrobial activity against Escherichia coli, Staphylococcus aureus, Candida albicans, and methicillin resistant S. aureus (MRSA). Cytocompatibility evaluation of the prepared composite bandages done on human dermal fibroblast cells by Alamar assay and infiltration studies proved that the bandages have a non-toxic nature at lower concentrations of nZnO whereas slight reduction in viability was seen with increasing nZnO concentrations. The qualitative analysis of ex-vivo re-epithelialization on porcine skin revealed keratinocyte infiltration toward wound area for nZnO alginate bandages. PMID- 26491308 TI - Eucalyptus oil nanoemulsion-impregnated chitosan film: antibacterial effects against a clinical pathogen, Staphylococcus aureus, in vitro. AB - Eucalyptus oil (Eucalyptus globulus) nanoemulsion was formulated using low-and high-energy emulsification methods. Development of nanoemulsion was optimized for system parameters such as emulsifier type, emulsifier concentration, and emulsification methods to obtain a lower droplet size with greater stability. The minimized droplet diameter was achieved using the high-energy method of ultrasonication. Tween 80 was more effective in reducing droplet size and emulsion appearance when compared to Tween 20. Stable nanoemulsion was formulated with Tween 80 as a surfactant, and the particle size was found to be 9.4 nm (1:2 v/v). The eucalyptus oil nanoemulsion was impregnated into chitosan (1%) as a biopolymer in varying concentrations. Further, the film was characterized by moisture content, microscopic study, X-ray diffraction, and Fourier transform infrared spectroscopy. Also, the film with and without nanoemulsion was evaluated against Staphylococcus aureus. The nanoemulsion-impregnated chitosan film showed higher antibacterial activity than chitosan film. These results support the inclusion of nanoemulsion-impregnated chitosan film in wound management studies. PMID- 26491309 TI - Antibacterial activity of neem nanoemulsion and its toxicity assessment on human lymphocytes in vitro. AB - Neem (Azadirachta indica) is recognized as a medicinal plant well known for its antibacterial, antimalarial, antiviral, and antifungal properties. Neem nanoemulsion (NE) (O/W) is formulated using neem oil, Tween 20, and water by high energy ultrasonication. The formulated neem NE showed antibacterial activity against the bacterial pathogen Vibrio vulnificus by disrupting the integrity of the bacterial cell membrane. Despite the use of neem NE in various biomedical applications, the toxicity studies on human cells are still lacking. The neem NE showed a decrease in cellular viability in human lymphocytes after 24 hours of exposure. The neem NE at lower concentration (0.7-1 mg/mL) is found to be nontoxic while it is toxic at higher concentrations (1.2-2 mg/mL). The oxidative stress induced by the neem NE is evidenced by the depletion of catalase, SOD, and GSH levels in human lymphocytes. Neem NE showed a significant increase in DNA damage when compared to control in human lymphocytes (P<0.05). The NE is an effective antibacterial agent against the bacterial pathogen V. vulnificus, and it was found to be nontoxic at lower concentrations to human lymphocytes. PMID- 26491310 TI - Biosynthesis characterization of silver nanoparticles using Cassia roxburghii DC. aqueous extract, and coated on cotton cloth for effective antibacterial activity. AB - The present study reports the green synthesis of silver nanoparticles (AgNPs) from silver precursor using a plant biomaterial, Cassia roxburghii DC., aqueous extract. The AgNPs were synthesized from the shade-dried leaf extract and assessed for their stability; they elucidated characteristics under UV-visible spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, high resolution transmission electron microscopy, and energy dispersive X-ray spectroscopy. The synthesized AgNPs exhibited a maximum absorption at 430 nm, and the X-ray diffraction patterns showed that they were crystal in nature. Fourier transform infrared spectroscopy analysis confirmed the conversion of Ag+ ions to AgNPs due to the reduction by capping material of plant extract. The HR-TEM analysis revealed that they are spherical ranging from 10 nm to 30 nm. The spot EDAX analysis showed the presence of silver atoms. In addition, AgNPs were evaluated for their antibacterial activity against six different pathogenic bacteria: three Gram-positive bacteria, Bacillus subtilis, Staphylococcus aureus, and Micrococcus luteus, and three Gram-negative bacteria, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter aerogenes. They were highly sensitive to AgNPs, whereas less sensitive to AgNO3. Furthermore, the green synthesized AgNPs were immobilized on cotton fabrics and screened for antibacterial activity. The immobilized AgNPs on cotton cloth showed high antibacterial activity. Therefore, they could be a feasible alternative source in treating wounds or may help in replacing pharmaceutical band-aids. PMID- 26491311 TI - Preparation and characterization of an iron oxide-hydroxyapatite nanocomposite for potential bone cancer therapy. AB - Recently, multifunctional magnetic nanostructures have been found to have potential applications in biomedical and tissue engineering. Iron oxide nanoparticles are biocompatible and have distinctive magnetic properties that allow their use in vivo for drug delivery and hyperthermia, and as T2 contrast agents for magnetic resonance imaging. Hydroxyapatite is used frequently due to its well-known biocompatibility, bioactivity, and lack of toxicity, so a combination of iron oxide and hydroxyapatite materials could be useful because hydroxyapatite has better bone-bonding ability. In this study, we prepared nanocomposites of iron oxide and hydroxyapatite and analyzed their physicochemical properties. The results suggest that these composites have superparamagnetic as well as biocompatible properties. This type of material architecture would be well suited for bone cancer therapy and other biomedical applications. PMID- 26491312 TI - Enhancement of bioactivity of titanium carbonitride nanocomposite thin films on steels with biosynthesized hydroxyapatite. AB - Thin films of titanium carbonitride (TiCN) were fabricated by DC magnetron sputtering on medical grade steel. The biocompatibility of the coating was further enhanced by growing hydroxyapatite crystals over the TiCN-coated substrates using biologically activated ammonia from synthetic urine. The coatings were characterized using X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy (SEM)-energy dispersive spectroscopy, and Raman spectroscopy. The electrochemical behavior of the coatings was determined in simulated body fluid. In addition, hemocompatibility was assessed by monitoring the attachment of platelets on the coating using SEM. The wettability of the coatings was measured in order to correlate with biocompatibility results. Formation of a coating with granular morphology and the preferred orientation was confirmed by SEM and X-ray diffraction results. The hydroxyapatite coating led to a decrease in thrombogenicity, resulting in controlled blood clot formation, hence demonstrating the hemocompatibility of the coating. PMID- 26491313 TI - Biodegradation and cytotoxicity of ciprofloxacin-loaded hydroxyapatite polycaprolactone nanocomposite film for sustainable bone implants. AB - INTRODUCTION: In recent years there has been a steep increase in the number of orthopedic patients for many reasons. One major reason is osteomyelitis, caused by pyrogenic bacteria, with progressive infection of the bone or bone marrow and surrounding tissues. So antibiotics must be introduced during bone implantation to avoid prolonged infection. AIM: The objective of the study reported here was to prepare a composite film of nanocrystalline hydroxyapatite (HAp) and polycaprolactone (PCL) polymer loaded with ciprofloxacin, a frequently used antibiotic agent for bone infections. METHODS: Nanocrystalline HAp was synthesized by precipitation method using the precursor obtained from eggshell. The nanocomposite film (HAp-PCL-ciprofloxacin) was prepared by solvent evaporation. Drug-release and biodegradation studies were undertaken by immersing the composite film in phosphate-buffered saline solution, while a cytotoxicity test was performed using the fibroblast cell line NIH-3T3 and osteoblast cell line MG-63. RESULTS: The pure PCL film had quite a low dissolution rate after an initial sharp weight loss, whereas the ciprofloxacin-loaded HAp-PCL nanocomposite film had a large weight loss due to its fast drug release. The composite film had higher water absorption than the pure PCL, and increasing the concentration of the HAp increased the water absorption. The in vitro cell-line study showed a good biocompatibility and bioactivity of the developed nanocomposite film. CONCLUSION: The prepared film will act as a sustainable bone implant in addition to controlled drug delivery. PMID- 26491314 TI - Influence of needle-like morphology on the bioactivity of nanocrystalline wollastonite--an in vitro study. AB - In the past 2 decades, wollastonite has been studied thoroughly for its application as a bone implant material due to its biocompatibility, high mechanical strength, and excellent bioactivity when compared to calcium phosphates bioceramics. Wollastonite was prepared through the low-temperature sol gel combustion method using urea as the fuel, nitrate ions and nitric acid as the oxidizer. Calcium nitrate and tetraethyl orthosilicate were taken as the source of calcium and silica. The synthesized wollastonite were characterized by Fourier transform infrared spectroscopy for the identification of characteristic functional group and powder X-ray diffraction for the phase identification. Employing urea as a fuel resulted in needle-like morphology of the particles, which was confirmed by scanning electron microscopy and transmission electron microscopy. It was observed that the needle-like morphology enhances the mechanical properties such as elasticity and compressive strength and also increases the surface area of the material, which could help in a rapid deposition of hydroxyapatite layer. These properties of wollastonite warrant its application as a new artificial bone material in the field of hard tissue engineering. PMID- 26491315 TI - Acute and subchronic toxicity analysis of surface modified paclitaxel attached hydroxyapatite and titanium dioxide nanoparticles. AB - Nanoparticles are widely used for targeted drug delivery applications. Surface modification with appropriate polymer and ligands is carried out to target the drug to the affected area. Toxicity analysis is carried out to evaluate the safety of the surface modified nanoparticles. In this study, paclitaxel attached, folic acid functionalized, polyethylene glycol modified hydroxyapatite and titanium dioxide nanoparticles were used for targeted drug delivery system. The toxicological behavior of the system was studied in vivo in rats and mice. Acute and subchronic studies were carried out. Biochemical, hematological, and histopathological analysis was also done. There were no significant alterations in the biochemical parameters at a low dosage. There was a small change in alkaline phosphatase (ALP) level at a high dosage. The results indicate a safe toxicological profile. PMID- 26491316 TI - Preparation and characterization of cefditoren pivoxil-loaded liposomes for controlled in vitro and in vivo drug release. AB - BACKGROUND: The application of antibiotics has been limited due to weak biodistribution and pharmacokinetics. Encapsulation of these drugs in lipid vesicles might be a good solution for obtaining the required properties. Liposomes are one of the most suitable drug-delivery systems to deliver the drug to the target organ and minimize the distribution of the drug to non-target tissues. OBJECTIVE: The study reported here aimed to develop cefditoren pivoxil liposomes by thin-film hydration, characterize them in terms of physical interactions, and undertake in vitro and in vivo release studies. METHODOLOGY: The pre-formulation studies were carried out using Fourier-transform infrared spectroscopy and differential scanning calorimetry. Cefditoren pivoxil liposomal formulations were formulated by thin-film hydration using biomaterials ie, soya lecithin and cholesterol in different molar ratios. The best molar ratio was determined by in vitro studies such as entrapment efficacy, particle size distribution, and diffusion. RESULTS: From the in vitro release studies, it was found that the formulation that contained soya lecithin and cholesterol in a 1.0:0.6 molar ratio gave good entrapment of 72.33% and drug release of 92.5% at 36 hours. Further, the formulation's zeta potential and surface morphology were examined and stability and in vivo studies were undertaken evaluating the pharmacokinetic parameters, which showed promising results. CONCLUSION: Formulation CPL VI showed the maximum drug-loading capacity of 72.3% with good controlled release and acceptable stability when compared with the other formulations. In vivo studies in rabbits showed that the drug release from the liposomes was successfully retarded with good controlled release behavior which can be used to treat many bacterial infections with a minimal dose. PMID- 26491317 TI - Biobased silver nanocolloid coating on silk fibers for prevention of post surgical wound infections. AB - Bombyx mori silk fibers are an important biomaterial and are used in surgical sutures due to their remarkable biocompatibility. The major drawback to the application of biomaterials is the risk of bacterial invasion, leading to clinical complications. We have developed an easy and cost-effective method for fabrication of antibacterial silk fibers loaded with silver nanoparticles (AgNPs) by an in situ and ex situ process using an aqueous extract of Rhizophora apiculata leaf. Scanning electron microscopy revealed that well dispersed nanoparticles impregnated the silk fibers both in situ and ex situ. The crystalline nature of the AgNPs in the silk fibers was demonstrated by X-ray diffraction. The thermal and mechanical properties of the silk fibers were enhanced after they were impregnated with AgNPs. The silver-coated silk fibers fabricated by the in situ and ex situ method exhibited more than 90% inhibition against Pseudomonas aeruginosa and Staphylococcus aureus. Silk fibers doped with AgNPs were found to be biocompatible with 3T3 fibroblasts. The results obtained represent an important advance towards the clinical application of biocompatible AgNP-loaded silk fibers for prevention of surgical wound infections. PMID- 26491318 TI - Gold nanoparticles-immobilized, hierarchically ordered, porous TiO2 nanotubes for biosensing of glutathione. AB - Glutathione (GSH) is vital for several functions of our human body such as neutralization of free radicals and reactive oxygen compounds, maintaining the active forms of vitamin C and E, regulation of nitric oxide cycle, iron metabolism, etc. It is also an endogenous antioxidant in most of the biological reactions. Given the importance of GSH, a simple strategy is proposed in this work to develop a biosensor for quantitative detection of GSH. This particular biosensor comprises of gold nanoparticles (Au NPs)-immobilized, hierarchically ordered titanium dioxide (TiO2) porous nanotubes. Hexagonally arranged, honeycomb like nanoporous tubular TiO2 electrodes are prepared by using a simple electrochemical anodization process by applying a constant potential of 30 V for 24 hours using ethylene glycol consisting of ammonium fluoride as an electrolytic medium. Structural morphology and crystalline nature of such TiO2 nanotubes are analyzed using field emission scanning electron microscope (FESEM) and X-ray diffraction (XRD). Interestingly, nanocomposites of TiO2 with Au NPs is prepared in an effort to alter the intrinsic properties of TiO2, especially tuning of its band gap. Au NPs are prepared by a well-known Brust and Schiffrin method and are immobilized onto TiO2 electrodes which act as a perfect electrochemical sensing platform for GSH detection. Structural characterization and analysis of these modified electrodes are performed using FESEM, XRD, and UV-visible spectroscopic studies. GSH binding events on Au NPs-immobilized porous TiO2 electrodes are monitored by electrochemical techniques, namely, cyclic voltammetry (CV) and chronoamperometry (CA). Several parameters such as sensitivity, selectivity, stability, limit of detection, etc are investigated. In addition, Au NPs dispersed in aqueous medium are also explored for naked-eye detection of GSH using UV-visible spectroscopy in order to compare the performance of the proposed sensor. Our studies clearly indicate that these materials could potentially be used for GSH sensing applications. PMID- 26491319 TI - One-step, low-temperature fabrication of CdS quantum dots by watermelon rind: a green approach. AB - We investigated the one-step synthesis of CdS nanoparticles via green synthesis that used aqueous extract of watermelon rind as a capping and stabilizing agent. Preliminary phytochemical analysis depicted the presence of carbohydrates which can act as capping and stabilizing agents. Synthesized CdS nanoparticles were characterized using UV-visible, Fourier transform infrared spectroscopy, X-ray diffraction, EDX, dynamic light scattering, transmission electron microscopy, and atomic force microscopy techniques. The CdS nanoparticles were found to be size- and shape-controlled and were stable even after 3 months of synthesis. The results suggest that watermelon rind, an agro-waste, can be used for synthesis of CdS nanoparticles without any addition of stabilizing and capping agents. PMID- 26491320 TI - Structural and magnetic properties of cobalt-doped iron oxide nanoparticles prepared by solution combustion method for biomedical applications. AB - Cobalt-doped iron oxide nanoparticles were prepared by solution combustion technique. The structural and magnetic properties of the prepared samples were also investigated. The average crystallite size of cobalt ferrite (CoFe2O4) magnetic nanoparticle was calculated using Scherrer equation, and it was found to be 16+/-5 nm. The particle size was measured by transmission electron microscope. This value was found to match with the crystallite size calculated by Scherrer equation corresponding to the prominent intensity peak (311) of X-ray diffraction. The high-resolution transmission electron microscope image shows clear lattice fringes and high crystallinity of cobalt ferrite magnetic nanoparticles. The synthesized magnetic nanoparticles exhibited the saturation magnetization value of 47 emu/g and coercivity of 947 Oe. The anti-microbial activity of cobalt ferrite nanoparticles showed better results as an anti bacterial agent. The affinity constant was determined for the nanoparticles, and the cytotoxicity studies were conducted for the cobalt ferrite nanoparticles at different concentrations and the results are discussed. PMID- 26491321 TI - Development of polymer-bound fast-dissolving metformin buccal film with disintegrants. AB - Fast-dissolving drug-delivery systems are considered advantageous over the existing conventional oral dosage forms like tablets, capsules, and syrups for being patient friendly. Buccal films are one such system responsible for systemic drug delivery at the desired site of action by avoiding hepatic first-pass metabolism. Metformin hydrochloride (Met), an antidiabetic drug, has poor bioavailability due to its high solubility and low permeability. The purpose of the study reported here was to develop a polymer-bound fast-dissolving buccal film of metformin to exploit these unique properties. In the study, metformin fast-dissolving films were prepared by the solvent-casting method using chitosan, a bioadhesive polymer. Further, starch, sodium starch glycolate, and microcrystalline cellulose were the disintegrants added to different ratios, forming various formulations (F1 to F7). The buccal films were evaluated for various parameters like weight variation, thickness, folding endurance, surface pH, content uniformity, tensile strength, and percentage of elongation. The films were also subjected to in vitro dissolution study, and the disintegration time was found to be less than 30 minutes for all formulations, which was attributed to the effect of disintegrants. Formulation F6 showed 92.2% drug release within 6 minutes due to the combined effect of sodium starch glycolate and microcrystalline cellulose. PMID- 26491322 TI - Tribological and corrosion behaviors of warm-and hot-rolled Ti-13Nb-13Zr alloys in simulated body fluid conditions. AB - Development of submicrocrystalline structure in biomedical alloy such as Ti-13Nb 13Zr (in wt%) through warm-rolling process has been found to enhance mechanical properties compared to conventional thermomechanical processing routes including hot-rolling process. The present study investigated the tribological and corrosion behaviors of warm-rolled (WR) and hot-rolled Ti-13Nb-13Zr alloys which have not been studied to date. Both tribological and corrosion experiments were carried out in simulated body fluid conditions (Hank's solution at 37 degrees C) based on the fact that the investigated alloys would be used in a human body as orthopedic implants. The WR Ti-13Nb-13Zr demonstrated a submicrocrystalline structure that provided a significant enhancement in hardness, strength, and corrosion resistance. Meanwhile, there was no notable difference in wear resistance between the WR and hot-rolled samples despite the different microstructure and hardness. The present study confirmed the enormous potential of WR Ti-13Nb-13Zr with not only great mechanical properties but also high corrosion resistance in the simulated body fluid. PMID- 26491323 TI - Wear studies on plasma-sprayed Al2O3 and 8mole% of Yttrium-stabilized ZrO2 composite coating on biomedical Ti-6Al-4V alloy for orthopedic joint application. AB - This paper presents the wear characteristics of the composite ceramic coating made with Al2O3-40wt%8YSZ on the biomedical grade Ti-6Al-4V alloy (grade 5) used for total joint prosthetic components, with the aim of improving their tribological behavior. The coatings were deposited using a plasma spraying technique, and optimization of plasma parameters was performed using response surface methodology to obtain dense coating. The tribological behaviors of the coated and uncoated substrates were evaluated using a ball-on-plate sliding wear tester at 37 degrees C in simulated body-fluid conditions. The microstructure of both the titanium alloy and coated specimen were examined using an optical microscope and scanning electron microscope. The hardness of the plasma-sprayed alumina-zirconia composite coatings was 2.5 times higher than that of the Ti-6Al 4V alloy, while the wear rate of Ti-6Al-4V alloy was 253 times higher than that of the composite-coated Ti-6Al-4V alloy. The superior wear resistance of the alumina-zirconia coated alloy is attributed to its enhanced hardness and intersplat bonding strength. Wear-track examination showed that the predominant wear mechanism of Ti-6Al-4V alloy was abrasive and adhesive wear, whereas, in the case of alumina-zirconia composite coated alloy, the wear was dominated by microchipping and microcracking. PMID- 26491324 TI - Influence of thermomechanical processing on biomechanical compatibility and electrochemical behavior of new near beta alloy, Ti-20.6Nb-13.6Zr-0.5V. AB - This paper presents the results for the effect of different methods of thermomechanical processing on the mechanical properties and electrochemical behavior of metastable beta alloy Ti-20.6Nb-13.6Zr-0.5V (TNZV). The thermomechanical processing included hot working, solution heat treatments at different temperatures, and cooling rates in addition to aging. The thermomechanical processing conditions used in the study resulted in attainment of a wide range of microstructures with varying spatial distributions and morphologies of elongated/equiaxed alpha, beta phases, or martensite, as a result of which several tensile properties were achieved. Aging treatment led to an increase in hardness, elastic modulus, and tensile strength and a decrease in ductility (elongation). Electrochemical tests indicated that the TNZV alloy undergoes spontaneous passivation due to spontaneous formation of an oxide film in the environment of the human body. Because the air-cooled samples possessed high hardness and also a fine grain size, they showed a lower corrosion rate than the samples treated under other conditions. PMID- 26491325 TI - Psychosocial functioning in schizophrenia: are some symptoms or demographic characteristics predictors across the functioning domains? AB - This study aimed to examine symptoms/demographic characteristics as predictors for psychosocial functioning among individuals with schizophrenia. The Personal and Social Performance (PSP) scale was used to assess psychosocial functioning. Other measures of interest included were the Clinical Global Impression, Severity scale, and the Marder's five-factor model of the Positive and Negative Syndrome Scale. This study included 199 participants with non-acute stage schizophrenia. Spearman correlation coefficients and stepwise multiple linear regression analyses were applied to determine the correlates and predictors of PSP domain/total scores. Younger age, earlier age of schizophrenia onset, severe illness, positive symptoms, negative symptoms, disorganized thought, hostility/excitement, and anxiety/depression were found to significantly correlate with poor functioning. Severe illness and negative symptoms are the main predictors of greater impairment of socially useful activities, personal and social relationships, and self-care. Further prospective studies in other settings, which would include an increased number of variables such as neurocognitive function and social support, are warranted. PMID- 26491326 TI - A meta-analysis of lipid peroxidation markers in major depression. AB - BACKGROUND: Major depressive disorder (MDD) may be associated with oxidative damage to lipids, which can potentially affect mood-regulating pathways. This meta-analysis summarizes current knowledge regarding lipid peroxidation markers in clinical samples of MDD and the effects of antidepressant pharmacotherapy on those markers. METHODS: MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane Collaboration were searched for original, peer-reviewed articles measuring markers of lipid peroxidation in patients with MDD and nondepressed healthy controls up to April 2015. Standardized mean differences (SMDs) were generated from random effects models summarizing mean (+/- standard deviations) concentrations of selected markers. RESULTS: Lipid peroxidation was greater in MDD than in controls (studies =17, N=857 MDD/782 control, SMD =0.83 [0.56-1.09], z=6.11, P<0.01, I (2)=84.0%) and was correlated with greater depressive symptom severity (B=0.05, df=8, P<0.01). Antidepressant treatment was associated with a reduction in lipid peroxidation in MDD patients (studies=5, N=222, SMD=0.71 [0.40 0.97], P<0.01; I (2)=42.5%). LIMITATIONS: Lipid peroxidation markers were sampled from peripheral blood, included studies comparing MDD to controls were all cross sectional, and only five antidepressant treatment studies were eligible for inclusion. CONCLUSION: Increased lipid peroxidation was associated with MDD and may be normalized by antidepressants. Continued investigation of lipid peroxidation in MDD is warranted. PMID- 26491328 TI - Serotonin syndrome induced by the readministration of escitalopram after a short term interruption in an elderly woman with depression: a case report. AB - BACKGROUND: Serotonin syndrome is a rare but potentially fatal side effect of antidepressants that results from the effects of drug activity on both central and peripheral serotonergic receptors. CASE: A 78-year-old Japanese female with a 2-year history of major depressive disorder was treated with escitalopram (10 mg/d), risperidone (1 mg/d), and nitrazepam (5 mg/d). One month after beginning this drug regimen, she was transferred to the emergency department and immediately hospitalized due to suspicion of a urinary tract infection and dehydration. All psychotropic drugs were discontinued. Five days later, the patient's physical condition had recovered; therefore, the same dose of escitalopram (10 mg/d) was readministered. The patient subsequently developed convulsions accompanied by impaired consciousness, high fever, and myoclonus of both upper extremities. The tendon reflexes of both lower extremities were enhanced. Based on these clinical signs and symptoms, we suspected serotonin syndrome; therefore, escitalopram was discontinued, and a fluid infusion was initiated. The patient recovered from all symptoms within 3 weeks without receiving additional antidepressants. CONCLUSION: This case suggests that the careless readministration of selective serotonin reuptake inhibitors (SSRIs) is harmful to at-risk patients, like those in poor physical condition and the elderly. PMID- 26491327 TI - Etiology of cardiovascular disease in patients with schizophrenia: current perspectives. AB - Cardiovascular morbidity and mortality are important problems among patients with schizophrenia. A wide spectrum of reasons, ranging from genes to the environment, are held responsible for causing the cardiovascular risk factors that may lead to shortening the life expectancy of patients with schizophrenia. Here, we have summarized the etiologic issues related with the cardiovascular risk factors in schizophrenia. First, we focused on heritable factors associated with cardiovascular disease and schizophrenia by mentioning studies about genetics epigenetics, in the first-episode or drug-naive patients. In this context, the association and candidate gene studies about metabolic disturbances in schizophrenia are reviewed, and the lack of the effects of epigenetic/posttranscriptional factors such as microRNAs is mentioned. Increased rates of type 2 diabetes mellitus and disrupted metabolic parameters in schizophrenia are forcing clinicians to struggle with metabolic syndrome parameters and related issues, which are also the underlying causes for the risk of having cardiometabolic and cardiovascular etiology. Second, we summarized the findings of metabolic syndrome-related entities and discussed the influence of the illness itself, antipsychotic drug treatment, and the possible disadvantageous lifestyle on the occurrence of metabolic syndrome (MetS) or diabetes mellitus. Third, we emphasized on the risk factors of sudden cardiac death in patients with schizophrenia. We reviewed the findings on the arrhythmias such as QT prolongation, which is a risk factor for Torsade de Pointes and sudden cardiac death or P-wave prolongation that is a risk factor for atrial fibrillation. For example, the use of antipsychotics is an important reason for the prolongation of QT and some other cardiac autonomic dysfunctions. Additionally, we discussed relatively rare issues such as myocarditis and cardiomyopathy, which are important for prognosis in schizophrenia that may have originated from the use of antipsychotic medication. In conclusion, we considered that the studies and awareness about physical needs of patients with schizophrenia are increasing. It seems logical to increase cooperation and shared care between the different health care professionals to screen and treat cardiovascular disease (CVD)-risk factors, MetS, and diabetes in patients with psychiatric disorders, because some risk factors of MetS or CVD are avoidable or at least modifiable to decrease high mortality in schizophrenia. We suggested that future research should focus on conducting an integrated system of studies based on a holistic biopsychosocial evaluation. PMID- 26491329 TI - Depressogenic medications and other risk factors for depression among Polish patients with epilepsy. AB - PURPOSE: The aim of this study was to assess the prevalence of depression among patients with epilepsy and to establish the risk factors of depression in that group, with special focus on the use of potentially depressogenic medications. PATIENTS AND METHODS: We studied 289 consecutive patients who visited epilepsy outpatient clinic (University Hospital of Krakow) and met inclusion criteria. All patients were screened with Beck Depression Inventory (BDI), and those with BDI score >=12 were further evaluated by a psychiatrist. RESULTS: Mean age of patients was 35.7 years, and mean duration of epilepsy was 14.7 years. Idiopathic generalized epilepsy was diagnosed in 63 patients (21.8%), focal epilepsy was found in 189 subjects (65.4%), and unclassified epilepsy was diagnosed in 37 patients (12.8%). Frequent seizures (>1 per month) were reported in 107 patients (37.0%). Thirty-five patients (12.1%) reported an ongoing treatment with one or more of the predefined potentially depressogenic medication (beta-blockers, combined estrogen and progestogen, corticosteroid, or flunarizine). In a group of 115 patients (39.8%) who scored >=12 points in BDI, depression was finally diagnosed in 84 subjects (29.1%) after psychiatric evaluation. Only 20 of those patients (23.8%) were treated with antidepressant. Independent variables associated with the diagnosis of depression in the logistic regression model included frequent seizures (odds ratio [OR] =2.43 [95% confidence interval, 95% CI =1.38-4.29], P=0.002), use of potentially depression-inducing medications (OR =3.33 [95% CI =1.50-7.39], P=0.003), age (OR =1.03 [95% CI =1.01-1.05] per year], P=0.005), and use of oxcarbazepine (OR =2.26 [95% CI =1.04-4.9], P=0.038). CONCLUSION: The prevalence of depression among consecutive Polish patients with epilepsy reached 29.1%. Less than quarter of them received antidepressant treatment at the moment of evaluation. Independent variables associated with depression included age, frequent seizures, and the use of oxcarbazepine or predefined depressogenic medications. PMID- 26491331 TI - Regulation of proteolytic cleavage of brain-derived neurotrophic factor precursor by antidepressants in human neuroblastoma cells. AB - Evidence has supported the role of brain-derived neurotrophic factor (BDNF) in antidepressant effect. The precursor of BDNF (proBDNF) often exerts opposing biological effects on mature BDNF (mBDNF). Hence, the balance between proBDNF and mBDNF might be critical in total neurotrophic effects, leading to susceptibility to or recovery from depression. In the current study, we measured the protein expression levels of proBDNF, and its proteolytic products, truncated BDNF, and mBDNF, in human SH-SY5Y cells treated with different antidepressants. We found that the treatment significantly increased the production of mBDNF, but decreased the production of truncated BDNF and proBDNF. These results support that antidepressants can promote proBDNF cleavage. Further studies are needed to clarify whether proBDNF cleavage plays a role in antidepressant mechanisms. PMID- 26491330 TI - Psychogenic non-epileptic seizures: so-called psychiatric comorbidity and underlying defense mechanisms. AB - In Diagnostic and Statistical Manual of Mental Disorders, fifth edition, psychogenic non-epileptic seizures (PNES) do not have a unique classification as they can be found within different categories: conversion, dissociative, and somatization disorders. The ICD-10, instead, considers PNES within dissociative disorders, merging the dissociative disorders and conversion disorders, although the underlying defense mechanisms are different. The literature data show that PNES are associated with cluster B (mainly borderline) personality disorders and/or to people with depressive or anxiety disorders. Defense mechanisms in patients with PNES with a prevalence of anxious/depressive symptoms are of "neurotic" type; their goal is to lead to a "split", either vertical (dissociation) or horizontal (repression). The majority of patients with this type of PNES have alexithymia traits, meaning that they had difficulties in feeling or perceiving emotions. In subjects where PNES are associated with a borderline personality, in which the symbolic function is lost, the defense mechanisms are of a more archaic nature (denial). PNES with different underlying defense mechanisms have different prognoses (despite similar severity of PNES) and need usually a different treatment (pharmacological or psychological). Thus, it appears superfluous to talk about psychiatric comorbidity, since PNES are a different symptomatic expression of specific psychiatric disorders. PMID- 26491333 TI - Nomenclature of drug-induced pityriasis rosea-like rashes. PMID- 26491332 TI - Virtual reality exposure-based therapy for the treatment of post-traumatic stress disorder: a review of its efficacy, the adequacy of the treatment protocol, and its acceptability. AB - INTRODUCTION: The essential feature of post-traumatic stress disorder (PTSD) is the development of characteristic symptoms following exposure to one or more traumatic events. According to evidence-based intervention guidelines and empirical evidence, one of the most extensively researched and validated treatments for PTSD is prolonged exposure to traumatic events; however, exposure therapy can present some limitations. Virtual reality (VR) can help to improve prolonged exposure because it creates fictitious, safe, and controllable situations that can enhance emotional engagement and acceptance. OBJECTIVE: In addition to carrying out a review to evaluate the efficacy of VR exposure-based therapy (VR-EBT) for the treatment of PTSD, the aim of this study was to contribute to analyzing the use of VR-EBT by: first, evaluating the adequacy of psychological treatment protocols that use VR-EBT to treat PTSD; and second, analyzing the acceptability of VR-EBT. METHOD: We performed a replica search with descriptors and databases used in two previous reviews and updated to April 2015. Next, we carried out an evaluation of the efficacy, adequacy, and acceptability of VR-EBT protocols. RESULTS: Results showed that VR-EBT was effective in the treatment of PTSD. The findings related to adequacy showed that not all studies using VR-EBT reported having followed the clinical guidelines for evidence-based interventions in the treatment of PTSD. Regarding acceptability, few studies evaluated this subject. However, the findings are very promising, and patients reported high acceptability and satisfaction with the inclusion of VR in the treatment of PTSD. CONCLUSION: The main weaknesses identified in this review focus on the need for more controlled studies, the need to standardize treatment protocols using VR-EBT, and the need to include assessments of acceptability and related variables. Finally, this paper highlights some directions and future perspectives for using VR-EBT in PTSD treatment. PMID- 26491334 TI - Effect of depressive symptoms on the length of hospital stay among patients hospitalized for acute stroke in Japan. AB - BACKGROUND: Depression after stroke is one of the most serious complications of stroke. Although many studies have shown that the length of hospital stay (LOHS) is a measurable and important stroke outcome, research has found limited evidence concerning the effect of depression on LOHS among patients who have experienced acute stroke. The objective of this study was to assess the effect of depression on LOHS among patients hospitalized for acute ischemic stroke in Japan. METHODS: We retrospectively examined 421 patients who had experienced acute ischemic stroke. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS) on the 7th day of hospitalization. On the 10th day of hospitalization, depressive symptoms and functional assessment were assessed by the Japan Stroke Scale (Depression Scale) and the Functional Independence Measure, respectively. A general linear model was employed to assess the effect of probable depression on LOHS. RESULTS: The prevalence of probable depression in the current sample was 16.3% in males and 17.8% in females. The mean LOHS of participants with probable depression (76.4+/-49.2 days) was significantly longer than that of participants without probable depression (44.9+/-39.2 days). An analysis using the general linear model to assess the effect on LOHS revealed a significant interaction between the presence of probable depression and NIHSS scores. CONCLUSION: Depression after stroke was associated with significant increases in LOHS. Early detection and treatment for depression are necessary for patients with ischemic stroke. PMID- 26491335 TI - Analysis of the incidence of postintubation injuries in patients intubated in the prehospital or early hospital conditions of the hospital emergency department and the intensive care unit. AB - BACKGROUND: Intubation is still one of the best methods to secure the airway. In the case of prehospital or early hospital conditions when factors such as urgency, stress, or inaccuracy of the undertaken activities are involved, the risk of causing complications, for instance, edema or postintubation injuries, increases, especially while dealing with a difficult intubation. The risk of improper inflation of the endotracheal tube cuff also increases, which is considered in this study. OBJECTIVE: The aim of this study was to evaluate the prevalence of postintubation complications, such as postintubation injuries or edema, in a research sample, and to examine whether such complications occur more often, for example, while using a guidewire. In this study, we also evaluated the injuries associated with the inflation of the endotracheal tube cuff. MATERIALS AND METHODS: This study was performed on a group of 153 patients intubated in prehospital conditions. The tests were carried out in three clinical sites that received patients from prehospital care. Postintubation injuries were revealed and photographed using videolar-yngoscope, such as the C-MAC and the McGrath series 5. The endotracheal tube cuff pressure was measured using a pressure gage manual (VBM Medizintechnik GmbH). The quantitative analyses of differences between incidence of variables were assessed using chi (2) test for P<0.05. Analyses have been carried out using the Statistica software. RESULTS: In the group of 153 patients, postintubation injuries occurred in 17% of cases. The dependency between using the guidewire and the occurrence of the hematomas and loss of mucosa was statistically significant (P<0.01). In nearly half (42%) of the patients the endotracheal tube cuff pressure was excessively inflated over 30 cm H2O, and in two cases, endotracheal tube displacement was observed on account of poor cuff inflation (<20 cm H2O). CONCLUSION: The highest percentage of overfilled cuffs were observed in the admission room. In the other wards, it was observed in 25% of cases. Even though only six cases of poor cuff inflation were noticed, the relationship between the leakage and the clinical conditions of patients is worth examining. The results would help in taking additional measures to reduce the risk of complications. PMID- 26491336 TI - Surveillance of antibiotic and analgesic use in the Oral Surgery Department of the University Dentistry Clinical Center of Kosovo. AB - BACKGROUND: Because Kosovo has no reliable information on antimicrobial and analgesic use in dental practice, the survey reported here evaluated the antibiotic and analgesic prescriptions in the Oral Surgery Department of the University Dentistry Clinical Center of Kosovo (UDCCK). METHODS: The data of 2,442 registered patients for a 1-year period were screened and analyzed concerning antibiotic and analgesic use as per standards of rational prescription. RESULTS: Dentistry doctors prescribed antibiotics significantly more often than analgesics. Antibiotics were prescribed in 8.11% of all cases, while only 1.35% of total prescriptions were for analgesics. The total consumption of antibiotic drugs in the UDCCK was 4.53 Defined Daily Doses [DDD]/1,000 inhabitants/day, compared with only 0.216 DDD/1,000 inhabitants/day for analgesics. From a total number of 117 patients, 32 patients received combinations of two antibiotics. CONCLUSION: Pharmacotherapy analysis showed that the prescription rates of antibiotics and analgesics in the UDCCK are not rational in terms of the qualitative aspects of treatment. For the qualitative improvement of prescription of these drug groups, we recommend the implementation of treatment guidelines following rational standards. PMID- 26491337 TI - The potential of medical device industry in technological and economical context. AB - The high quality of public health improves not only healthy life expectancy, but also the productivity of labor. The most important part of the health care sector is the medical technology industry. The aim of this study is to analyze the current situation in the medical device industry in Europe, its potential strengths and weaknesses in the context of topical economic and demographic development. The contribution specifies an analysis of the economic state of the medical device industry in the context of demographic development of European Union's macroeconomic indicators and views of experts in the field of medical device development, concerning the opportunities for entities involved in the medical device market. There is fierce competition on the European market. The innovative activity is stable and well regulated by responsible authorities. Worldwide, the medical device market is expected to grow. PMID- 26491338 TI - Anatomic and functional outcomes of retinectomy for the management of complicated retinal detachment with proliferative vitreoretinopathy. AB - The aim of this study is to report the anatomic and functional outcomes of retinectomy for the management of rhegmatogenous retinal detachment complicated by proliferative vitreoretinopathy (PVR), comparing them with previously reported data and determining prognostic factors. Fifty-one eyes of 51 patients with established PVR grade C in which retinectomy was performed were retrospectively enrolled in the study. Primary outcome measures were anatomic success rate and final visual acuity. Secondary outcome measures were intraoperative complications, number of re-operations, and postoperative hypotony. Prognostic factors in relation to retinal re-attachment and final visual acuity were retrospectively analyzed. The rate of complete retinal re-attachment after one operation was 80% and after two operations it was 84%. At the end of the follow up, the macula was attached in 96% of the cases. Mean LogMAR best-corrected visual acuity (BCVA) improved significantly from 2.45+/-0.66 preoperatively to 1.37+/-0.75 at the end of the follow-up (P<0.001). BCVA improved in 37 eyes (72%), remained the same in eleven eyes (22%) and worsened in three eyes (6%). Postoperative hypotony was observed in 2% of cases. Postoperative BCVA was significantly correlated with preoperative BCVA (P<0.001), extension of PVR (P=0.013), preoperative use of gas instead of silicone oil (SO) (P=0.01), and removal of SO (P=0.05). SO was left in situ in 35% of eyes. In conclusion, retinectomy is a surgical option providing good anatomical and reasonable visual outcomes in complicated retinal detachment with PVR. Better preoperative visual acuity, lesser extension of PVR, and the use of gas tamponade during the primary repair are relevant factors for a successful outcome whereas re-proliferation of epiretinal membranes seems to be the main reason of anatomical failure. PMID- 26491339 TI - Acute gastrointestinal injury in the intensive care unit: a retrospective study. AB - BACKGROUND: Acute gastrointestinal injury (AGI) is a common problem in the intensive care unit (ICU). This study is a review of the gastrointestinal function of patients in critical care, with the aim to assess the feasibility and effectiveness of grading criteria developed by the European Society of Intensive Care Medicine (ESICM) Working Group on Abdominal Problems (WGAP). METHODS: Data of patients who were admitted to the ICU of Shenzhen People's Hospital, Shenzhen, People's Republic of China, from January 2010 to December 2011 were reviewed. A total of 874 patients were included into the current study. Their sex, age, ICU admissive causes, complication of diabetes, AGI grade, primary or secondary AGI, mechanical ventilation (MV), and length of ICU stay (days) were recorded as risk factors of death. These risk factors were studied by unconditioned logistic regression analysis. RESULTS: All the risk factors affected mortality rate. Unconditional logistic regression analysis revealed that the mortality rate of secondary AGI was 71 times higher than primary AGI (odds ratio [OR] 4.335, 95% CI [1.652, 11.375]). When the age increased by one year, the mortality probability would increase fourfold. Mortality in patients with MV was 63-fold higher than for patients with non-MV. Mortality rate increased 0.978 times with each additional day of ICU stay. CONCLUSION: Secondary AGI caused by severe systemic conditions can result in worsened clinical outcomes. The 2012 ESICM WGAP AGI recommendations were to some extent feasible and effective in guiding clinical practices, but the grading system lacked the support of objective laboratory outcomes. PMID- 26491340 TI - Study of ambulatory blood pressure in diabetic children: prediction of early renal insult. AB - BACKGROUND: Hypertension is a highly prevalent risk factor for cardiovascular disease in patients with type 1 diabetes mellitus. Elevated blood pressure (BP) promotes the development and progression of microvascular complications, eg, nephropathy and retinopathy. The purpose of this study was to identify and detect early BP changes in diabetic children and adolescents, aiming for the early prediction of future renal and cardiovascular disease risk during childhood. METHODS AND MATERIALS: Ambulatory BP monitoring was undertaken for 40 normotensive type 1 diabetic children with mean age of 11.56+/-2.82 years, and 24 healthy children as control group with matched age and sex. Albumin/creatinine ratio and glycated hemoglobin were tested. BP indices and standard deviation scores were calculated using reference standards. The data were analyzed by SPSS software version 20 using mean and standard deviations for descriptive data. Correlation and regression analysis tests were used to study relations between BP indices and diabetic parameters. RESULTS: All parameters of BP z-scores were highly significantly increased in diabetic patients compared with controlled group (P<0.0001). The frequency of non-dipping was greater and highly significant in microalbuminuric diabetic patients (P<0.0001). Regression analysis revealed that BP parameters were significantly related to albumin/creatinine ratio, glycated hemoglobin, insulin dose, and body mass index. CONCLUSION: Our observation revealed a clear link between the nocturnal BP and microalbuminuria which mandates BP follow-up via ambulatory BP monitoring with therapeutic intervention to prevent renal and cardiovascular diabetic complications in adulthood. PMID- 26491341 TI - Pulse oximetry in bronchiolitis: is it needed? AB - Infants admitted to health-care centers with acute bronchiolitis are frequently monitored with a pulse oximeter, a noninvasive method commonly used for measuring oxygen saturation. The decision to hospitalize children with bronchiolitis has been largely influenced by pulse oximetry, despite its questionable diagnostic value in delineating the severity of the illness. Many health-care providers lack the appropriate clinical fundamentals and limitations of pulse oximetry. This deficiency in knowledge might have been linked to changes in the management of bronchiolitis. The aim of this paper is to provide the current evidence on the role of pulse oximetry in bronchiolitis. We discuss the history, fundamentals of operation, and limitations of the apparatus. A search of the Google Scholar, Embase, Medline, and PubMed databases was carried out for published articles covering the use of pulse oximetry in bronchiolitis. PMID- 26491342 TI - Stroke subtype, age, and baseline NIHSS score predict ischemic stroke outcomes at 3 months: a preliminary study from Central Nepal. AB - BACKGROUND: The combined medications practice of using antithrombotic agents and statins with or without antihypertensive agents is common in the treatment of acute ischemic stroke in Nepal. Short-term outcomes of the current practice have been studied. We aim to explore the predictors of ischemic stroke outcomes at 3 months, with the current combined medications practice. METHODS: The study population (N=56) included acute ischemic stroke patients treated at the Neurology Department of the College of Medical Sciences-Teaching Hospital, Chitwan, Nepal, from May 2014 to August 2014 and followed up at 3 months. Death or disability (modified Rankin scale >2) was defined as poor outcomes. Multivariate logistic regression analysis (P<0.10) using potential variables from bivariate analysis (P<=0.20) was adjusted to predict outcomes at 3 months. RESULTS: At 3 months, 29 (51.8%) patients were independent, eleven (19.6%) were dependent, while 16 (28.6%) died. Stroke subtype and baseline National Institute of Health Stroke Scale (NIHSS) scores were associated with death/disability (27, 48.2%) at 3 months. Regression analysis showed that large-artery stroke (odds ratio [OR] =284.145, 95% confidence interval [CI] =5.221-15,465.136, P=0.006), age (OR =1.113, 95% CI =1.002-1.236, P=0.045), and baseline NIHSS score (OR =1.557, 95% CI =1.194-2.032, P=0.001) were significant predictors of poor outcome at 3 months. CONCLUSION: Stroke subtype, age, and baseline NIHSS score are predictors of ischemic stroke outcomes in Nepalese population treated with the current practice of using combined antithrombotic and statins with or without antihypertensive agents, and these predictors can be used for the improvement of selection of patients for the appropriate treatment. PMID- 26491343 TI - Service users' experiences and views of aggressive situations in mental health care: a systematic review and thematic synthesis of qualitative studies. AB - BACKGROUND: Aggressive situations occurring within mental health services can harm service users, staff, and the therapeutic environment. There is a consensus that the aggression phenomenon is multidimensional, but the picture is still unclear concerning the complex interplay of causal variables and their respective impact. To date, only a small number of empirical studies include users' views of relevant factors. The main objective of this review is to identify and synthesize evidence relating to service users' experiences and views of aggressive situations in mental health settings. METHODS: We included qualitative studies of any design reporting on service users' own experiences of conditions contributing to aggressive situations in mental health care and their views on preventative strategies. Eligible articles were identified through an electronic database search (PsycINFO, PubMed, Ovid Nursing Database, Embase, and CINAHL), hand search, and cross-referencing. Extracted data were combined and interpreted using aspects of thematic synthesis. RESULTS: We reviewed 5,566 records and included 13 studies (ten qualitative and three mixed methods). Service users recognized that both their own mental state and negative aspects of the treatment environment affected the development of aggressive situations. Themes were derived from experiential knowledge and included calls to be involved in questions regarding how to define aggression and relevant triggers, and how to prevent aggressive encounters effectively. The findings suggest that incidents are triggered when users experience staff behavior as custodial rather than caring and when they feel ignored. CONCLUSION: The findings highlight the importance of staffs' knowledge and skills in communication for developing relationships based on sensitivity, respect, and collaboration with service users in order to prevent aggressive situations. An important factor is a treatment environment with opportunities for meaningful activities and a preponderance of trained staff who work continuously on the development of conditions and skills for collaborative interaction with users. PMID- 26491344 TI - Implementing best practice in hospital multidisciplinary nutritional care: an example of using the knowledge-to-action process for a research program. AB - BACKGROUND: Prospective use of knowledge translation and implementation science frameworks can increase the likelihood of meaningful improvements in health care practices. An example of this creation and application of knowledge is the series of studies conducted by and with the Canadian Malnutrition Task Force (CMTF). Following a cohort study and synthesis of evidence regarding best practice for identification, treatment, and prevention of malnutrition in hospitals, CMTF created an evidence-informed, consensus-based pathway for nutritional care in hospitals. The purpose of this paper is to detail the steps taken in this research program, through four studies, as an example of the knowledge-to-action (KTA) process. THE KTA PROCESS: The KTA process includes knowledge creation and action cycles. The steps of the action cycle within this program of research are iterative, and up to this point have been informed by three studies, with a fourth underway. The first study identified the magnitude of the malnutrition problem upon admission to hospital and how it is undetected and undertreated (study 1). Knowledge creation resulted in an evidence-based pathway established to address care gaps (study 2) and the development of monitoring tools (study 3). The study was then adapted to local context: focus groups validated face validate the evidence-based pathway; during the final phase, study site implementation teams will continue to adapt the pathway (studies 2 and 4). Barriers to implementation were also assessed; focus groups and interviews were conducted to inform the pathway implementation (studies 1, 2, and 4). In the next step, specific interventions were selected, tailored, and implemented. In the final study in this research program, plan-do-study-act cycles will be used to make changes and to implement the pathway (study 4). To monitor knowledge use and to evaluate outcomes, audits, staff surveys, patient outcomes, etc will be used to record process evaluations (studies 3 and 4). Finally, a sustainability plan will be incorporated into the final study of the program (study 4) to sustain knowledge use. DISCUSSION: Use of frameworks can increase the likelihood of meaningful and sustainable improvements in health care practice. The example of this program of research demonstrates how existing evidence has been used to identify, create, and adapt knowledge, and how multidisciplinary teams have been used to effect changes in the hospital setting. CONCLUSION: Effective implementation is essential in nutritional health care, and this multidisciplinary program of research provides an example of how the KTA process can facilitate implementation and promote sustainability. PMID- 26491345 TI - Comparative study on individual aromatase inhibitors on cardiovascular safety profile: a network meta-analysis. AB - The third-generation aromatase inhibitors (AIs: anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancer complementing chemotherapy and surgery. Because of the absence of direct head-to-head comparisons of these AIs, an indirect comparison is needed for individual treatment choice. In this network systemic assessment, the cardiovascular (CV) side effects in using anastrozole, letrozole, and exemestane based on original studies on AIs vs placebo or tamoxifen were compared. We integrated all available direct and indirect evidences. The odds ratio (OR) of severe CV events for indirect comparisons between exemestane and anastrozole was 1.41 (95% confidence interval [CI] =0.49-2.78), letrozole and anastrozole was 1.80 (95% CI =0.40 3.92), and letrozole and exemestane was 1.46 (95% CI =0.34-3.4). OR of subgroup risk for AIs and tamoxifen were all >1 except for thrombolism risk subgroup. The results showed that the total and severe CV risk ranking is letrozole, exemestane, and anastrozole in descending order. None of the AIs showed advantages in CV events than tamoxifen except for thromboembolism event incidence. PMID- 26491346 TI - Prognostic role of neutrophil to lymphocyte ratio in lung cancers: a meta analysis including 7,054 patients. AB - BACKGROUND: Neutrophil to lymphocyte ratio (NLR) has recently been reported to be a poor prognostic indicator in lung cancer. However, the prognostic value of the NLR in patients with lung cancer still remains controversial. We performed a meta analysis to evaluate the prognostic value of NLR in patients with lung cancer. METHODS: We performed a comprehensive literature search in PubMed, Ovid, the Cochrane Library, and Web of Science databases in May 2015. Studies were assessed for quality using the Newcastle-Ottawa Scale. RESULTS: Twenty-two studies with a total of 7,054 patients were included in this meta-analysis. The meta-analysis was performed to generate combined hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). Our analysis results indicated that high NLR predicted poorer OS (HR, 1.51; 95% confidence interval [CI], 1.33-1.71; P<0.001) and PFS (HR, 1.33; 95% CI, 1.07-1.67; P=0.012) in patients with lung cancer. High NLR was also associated with poor OS in lung cancer treated by surgical resection (HR, 1.59; 95% CI, 1.26-1.99; P<0.001) and chemotherapy (HR, 1.15; 95% CI, 1.08 1.22; P<0.001). In addition, NLR cut-off value =5 (HR, 1.57; 95% CI, 1.16-2.12; P=0.003) and NLR cut-off value <5 (HR, 1.47; 95% CI, 1.28-1.69; P<0.001). CONCLUSION: This meta-analysis result suggested that NLR should have significant predictive ability for estimating OS and PFS in patients with lung cancer and may be as a significant biomarker in the prognosis of lung cancer. PMID- 26491347 TI - Advanced lung adenocarcinoma with spinal cord metastasis successfully treated with second EGFR-TKI treatment: a case report and literature review. AB - Lung adenocarcinoma can be accompanied by epidermal growth factor receptor (EGFR) mutation. As a consequence, targeted therapy based on screening of tyrosine kinase inhibitors (TKIs) is necessary. Spinal cord metastasis of lung cancer is a serious clinical problem. Here, we report a case of lung adenocarcinoma with severe spinal cord metastasis that was successfully treated with a second administration of an EGFR-TKI. Magnetic resonance imaging showed spinal cord metastasis to the cervical vertebrae. The patient received a second administration of an EGFR-TKI (150 mg/day erlotinib). Four months later, we observed the disappearance of the paravertebral tumor and a reduction in the size of pulmonary tumors in both lungs. These results indicate that EGFR-TKI therapy could be a new strategy for the treatment of advanced lung adenocarcinoma with spinal metastasis. PMID- 26491348 TI - Anti-DR5 mAb inhibits proliferation of human fibroblast-like synovial cells and reduces their cytokine secretion in vitro. AB - BACKGROUND: We have previously reported that anti-death receptor 5 (DR5) monoclonal antibody (mAb) is therapeutically effective in the treatment of rheumatoid arthritis (RA) in a collagen-induced arthritis rat model. However, the molecular mechanism and the effect of anti-DR5 mAb on proapoptotic genes and cytokine secretion in the human fibroblast-like synovial cells (FLS) requires further clarification. This study may provide new evidence for the application of anti-DR5 mAb as a treatment for RA. METHODS: Human FLS were isolated from patients with RA and were treated with anti-DR5 mAb. An MTT assay and flow cytometry were used to detect the induction of apoptosis in vitro. Cytokine secretion by the FLS was detected using the enzyme-linked immunosorbent assay. The mRNA expression was assessed by reverse transcription polymerase chain reaction, and the protein expression was analyzed by Western blot. The apoptotic pathway was investigated further using a caspase inhibition assay. RESULTS: Anti DR5 mAb-induced apoptosis in human RA FLS in vitro. The protein expressions of caspase-8, -3, and -9 were decreased in human anti-DR5 mAb-treated FLS in a dose dependent manner through exposure to a caspase inhibitor, indicating that anti DR5 mAb induction of apoptosis is through the caspase pathway. Decreased levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were detected after treatment with anti-DR5 mAb in vitro. CONCLUSION: Anti-DR5 mAb may induce apoptosis in human FLS through the caspase pathway and through decreased secretions of TNF-alpha and IFN-gamma. PMID- 26491350 TI - Sustained response of malignant pericardial effusion to intrapericardial bevacizumab in an advanced lung cancer patient: a case report and literature review. AB - Malignant pericardial effusion (MPCE) is a common complication of advanced malignant tumors, and interferes severely with patient prognosis and quality of life. The standard treatment for this complication is intracavitary perfusion of chemotherapeutic drugs, which is limited by unsatisfactory therapeutic effects and serious adverse events. We report a patient with MPCE who was treated with bevacizumab by pericardial perfusion, resulting in a complete response. This case supports the use of intrapericardial bevacizumab as a potential treatment for MPCE. PMID- 26491349 TI - Increased risk of developing lung cancer in Asian patients carrying the TERT rs2736098 G>A polymorphism: evidence from 3,354 cases and 3,518 controls. AB - BACKGROUND: The association between telomerase reverse transcriptase (TERT) rs2736098 G>A and risk of lung cancer (LC) remains inconclusive. To explore the association more precisely, we performed a comprehensive search and conducted a meta-analysis on all eligible case-control studies involving 3,354 cases and 3,518 controls. METHODS: The 95% confidence interval (95% CI) and the pooled odds ratio (OR) were calculated using a random or fixed effect model. Publication bias, heterogeneity, and sensitivity analysis were also explored. RESULTS: All studies were case-control studies on LC in patients of Asian descent, consisting of one Korean study and five Chinese studies. Overall, the variant A allele of TERT rs2736098 G>A was found to significantly increase the risk of LC in all genetic models (GA vs GG: OR =1.13, 95% CI =1.02-1.25, P=0.017; AA vs GG: OR =1.78, 95% CI =1.53-2.07, P<0.001; GA/AA vs GG: OR =1.25, 95% CI =1.14-1.38, P<0.001; AA vs GA/GG: OR =1.66, 95% CI =1.45-1.92, P<0.001). In the subgroup analysis, significant associations were found in Chinese group and hospital-based studies. Different genotype test methods showed no influence on the final results. CONCLUSION: Our study identified that TERT rs2736098 G>A polymorphism significantly increased the risk of LC in Asian populations. PMID- 26491351 TI - ESHAP chemotherapy is efficient in refractory/relapsed primary central nervous system lymphoma: report of four cases. AB - Primary central nervous system non-Hodgkin's lymphoma is a rare presentation, almost always of diffuse large B-cell type. Although there is no consensus regarding therapy for this condition, induction regimens are based on high-dose methotrexate and consolidation whole-brain radiotherapy, or, more preferred recently, blood-brain barrier penetrating drugs such as etoposide, cytarabine, and alkylating agents like temozolomide, ifosfamide, and lomustine. We present here four cases of relapsed/refractory primary central nervous system lymphoma treated with ESHAP (etoposide, solumedrol, high-dose cytarabine, and platinum) chemotherapy to complete remission, with the eligible patients proceeding to autologous transplantation. We want to draw attention to this interesting, relatively well tolerated, underused therapeutic option, in a setting where treatment options are scarce and evidence-based recommendations are lacking. PMID- 26491352 TI - Angiogenesis inhibitors rechallenge in patients with advanced non-small-cell lung cancer: a pooled analysis of randomized controlled trials. AB - PURPOSE: Data on the role of angiogenesis inhibitors (AIs) rechallenge in the treatment of advanced non-small-cell lung cancer (NSCLC) patients who previously received bevacizumab remain limited. We aim to investigate the efficacy of AIs in the treatment of advanced NSCLC in this setting. METHODS: Studies from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology meeting up to December 1, 2014 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials evaluating AIs in advanced NSCLC, with survival data on patients who previously received bevacizumab. The end points were overall survival and progression-free survival. Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies. RESULTS: A total of 452 patients with advanced NSCLC who previously received bevacizumab were identified for analysis. The meta-analysis results demonstrated that AI rechallenge significantly improved progression-free survival (hazard ratio: 0.72, 95% confidence interval: 0.58-0.89, P=0.002) when compared to non-AI containing regimens. Additionally, a nonsignificant improvement in overall survival was also observed in advanced NSCLC in this setting (hazard ratio: 0.82, 95% confidence interval: 0.65-1.03, P=0.087). Similar results were also observed in subgroup analysis according to treatment regimens. CONCLUSION: The findings of this study suggest that NSCLC patients who relapsed after a first-line bevacizumab containing chemotherapy obtain improved clinical benefits from AI rechallenge. Prospective clinical trials investigating the role of AI rechallenge in this setting are recommended. PMID- 26491353 TI - Spotlight on decitabine for myelodysplastic syndromes in Chinese patients. AB - Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal hematopoietic stem cell malignancies with advanced median age. The silencing of tumor suppressor genes caused by DNA hypermethylation plays a crucial role in the pathogenesis of MDS. Decitabine, the available hypomethylating agent, is successfully used for the treatment and improves the outcome of MDS, and has become one of the most frequently administered disease-modifying therapies. With an aging population and a growing number of people exposed to benzene, the incidence of MDS has been increasing rapidly. The blinded regimen choice and the lack of a unified strategy create challenges for the treatment of MDS. Here, we present a review of clinical progress and prospects of decitabine treatment of MDS in the People's Republic of China. We also discuss the optimization of therapy issues to improve the cure rate and prolong survival in patients with MDS. PMID- 26491355 TI - Molecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing. AB - A 69-year-old man was diagnosed with IgG lambda-type multiple myeloma (MM), Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients. PMID- 26491354 TI - Association between the COMT Val158Met polymorphism and risk of cancer: evidence from 99 case-control studies. AB - Catechol-O-methyltransferase (COMT) plays a central role in DNA repair and estrogen-induced carcinogenesis. Many recent epidemiologic studies have investigated the association between the COMT Val158Met polymorphism and cancer risk, but the results are inconclusive. In this study, we performed a meta analysis to investigate the association between cancer susceptibility and COMT Val158Met in different genetic models. Overall, no significant associations were found between COMT Val158Met polymorphism and cancer risk (homozygote model: odds ratio [OR] =1.05, 95% confidence interval [CI] = [0.98, 1.13]; heterozygote model: OR =1.01, 95% CI = [0.98, 1.04]; dominant model: OR =1.02, 95% CI [0.97, 1.06], and recessive model: OR =1.03, 95% CI [0.97, 1.09]). In the subgroup analysis of cancer type, COMT Val158Met was significantly associated with increased risks of bladder cancer in recessive model, and esophageal cancer in homozygote model, heterozygote model, and dominant model. Subgroup analyses based on ethnicities, COMT Val158Met was significantly associated with increased risk of cancer in homozygote and recessive model among Asians. In addition, homozygote, recessive, and dominant models were significantly associated with increased cancer risk in the subgroup of allele-specific polymerase chain reaction genotyping. Significant associations were not observed when data were stratified by the source of the controls. In summary, this meta-analysis suggested that COMT Val158Met polymorphism might not be a risk factor for overall cancer risk, but it might be involved in cancer development at least in some ethnic groups (Asian) or some specific cancer types (bladder and esophageal cell cancer). Further evaluations of more preclinical and epidemiological studies are required. PMID- 26491356 TI - Does night-shift work increase the risk of prostate cancer? a systematic review and meta-analysis. AB - BACKGROUND: Night-shift work is suggested to be associated with an increased risk of breast cancer, but its association with prostate cancer is still controversial. We examined this association by conducting a systematic review and meta-analysis. METHODS: Studies were identified by searching PubMed, EMBASE, Ovid, Web of Science, the Cochrane register, and the China National Knowledge Infrastructure databases through December 25, 2014. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random effects or fixed effects model. Heterogeneity and publication bias were also evaluated. RESULTS: A total of 2,459,845 individuals from eight published studies were included in this meta-analysis. Analysis of all studies suggested that night-shift work was associated with a significantly increased risk of prostate cancer (RR: 1.24, 95% CI: 1.05-1.46; P=0.011). Sensitivity analysis showed that the association remained significant when repeating the analysis after removing one study each time. Dose-response meta-analysis suggested that an increase in night-shift work of 5 years duration was statistically significantly associated with a 2.8% (95% CI: 0.3, 5.4%, P=0.030) increase in the risk of prostate cancer. There was no significant publication bias. CONCLUSION: Based on a meta-analysis, night-shift work is associated with an increased risk of prostate cancer. Because of the limited number of included studies and the large level of heterogeneity, further well-designed studies are still warranted to confirm the findings of our analysis. PMID- 26491357 TI - Postoperative intensity-modulated radiation therapy provides favorable local control and low toxicities in patients with soft tissue sarcomas in the extremities and trunk wall. AB - PURPOSE: To investigate the efficacy and toxicity of postoperative intensity modulated radiation therapy (IMRT) for patients with soft tissue sarcomas (STSs) in the extremities and trunk wall. PATIENTS AND METHODS: Eighty patients with localized STSs in the extremities and trunk wall treated with function-conserving surgery and postoperative IMRT were analyzed. The primary locations were in the extremities in 51 patients and in the trunk wall in 29 patients. The margins were positive in nine patients and negative in 71 patients. The median dose of IMRT was 64 Gy. RESULTS: At a median follow-up time of 38 months, eight patients developed local recurrences. The 5-year local control (LC) rate was 88.1%. The patients with negative margins exhibited much better LC than did those with positive margins (90% vs 64.8%, P=0.023). Multivariate analysis revealed that positive margin was an independent risk factor for LC. The 5-year distant metastasis-free survival, disease-free survival, and overall survival rates were 75.2%, 72.6%, and 83.6%, respectively. Large tumor size (>5 cm) was significantly associated with poor overall survival. Edema and joint stiffness were observed in 17.6% and 9.8% of patients with extremity STSs, respectively. CONCLUSION: IMRT provides excellent LC and low toxicity for patients with STSs in the extremities and trunk wall. PMID- 26491358 TI - Role of estrogen in lung cancer based on the estrogen receptor-epithelial mesenchymal transduction signaling pathways. AB - BACKGROUND/AIM: Estrogen is reported to promote the occurrence and development of several human cancers. Increasing evidence shows that most human lung tumors exert estrogen receptor expression. In the present study, we investigated the underlying mechanism of estrogen effect in lung cancer through estrogen receptor epithelial-mesechymal-transition signaling pathways for the first time. MATERIALS AND METHODS: A total of 36 inbred C57BL/6 mice (18 male and 18 female) were injected subcutaneously with human lung adenocarcinoma cell line, Lewis. After the lung tumor model was established, mice with lung adenocarcinoma were randomly divided into three groups for each sex (n=6), such as vehicle group, estrogen group, and estrogen plus tamoxifen group. The six groups of mice were sacrificed after 21 days of drug treatment. Tumor tissue was stripped and weighed, and tumor inhibition rate was calculated based on average tumor weight. Protein and messenger RNA (mRNA) expressions of estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), phosphatidylinositol 3'-kinase (PI3K), AKT, E-cadherin, and vimentin were detected in both tumor tissue and lung tissue by using immunohistochemistry and real-time reverse transcription-polymerase chain reaction. RESULTS: 1) For male mice: in the estrogen group, estrogen treatment significantly increased ERalpha protein and mRNA expressions in tumor tissue and protein expression of PI3K, AKT, and vimentin in both tumor tissue and lung tissue compared with the vehicle-treated group. Besides, mRNA expression of E cadherin was significantly reduced in estrogen-treated tumor tissues than that in vehicle-treated tissues. In the estrogen plus tamoxifen group, protein and mRNA expressions of ERalpha and AKT were dramatically reduced by tamoxifen treatment in tumor tissue compared with the estrogen group; mRNA expression of E-cadherin was increased in tumor tissue; protein expression of vimentin and PI3K were downregulated in tumor tissue; protein expression of E-cadherin increased in lung tissue; protein expression of ERalpha and PI3K were downregulated in lung tissue compared with the estrogen group. 2) For female mice: in the estrogen group, estrogen treatment significantly increased mRNA expression of ERbeta and PI3K, and protein expression of ERbeta, PI3K, AKT, and vimentin in both tumor tissue and lung tissue compared with the vehicle-treated group. mRNA expression of E cadherin was downregulated in tumor tissue, and mRNA expression of AKT was increased in lung tissues compared with the vehicle-treated group. In the estrogen plus tamoxifen group, tamoxifen treatment dramatically reduced protein expression of ERalpha, ERbeta, AKT, and vimentin but significantly increased protein expression of E-cadherin in tumor tissues and lung tissue compared with the estrogen group. mRNA expression of ERbeta, PI3K, and AKT was dramatically reduced by tamoxifen treatment in lung tissues compared with the estrogen group. CONCLUSION: Estrogen promoted lung adenocarcinoma cell metastasis by inducing lung epithelial mesenchymal cells and reducing intercellular adhesion force through PI3K/AKT signaling pathway. PMID- 26491359 TI - Changing attitudes toward needle biopsies of breast cancer in Shanghai: experience and current status over the past 8 years. AB - Diagnostic patterns in breast cancer have greatly changed over the past few decades, and core needle biopsy (CNB) has become a reliable procedure for detecting breast cancer without invasive surgery. To estimate the changing diagnostic patterns of breast cancer in urban Shanghai, 11,947 women with breast lesions detected by preoperative needle biopsy between January 1995 and December 2012 were selected from the Shanghai Cancer Data base, which integrates information from approximately 50% of breast cancer patients in Shanghai. The CNB procedure uses an automated prone unit, biopsy gun, and 14-gauge needles under freehand or ultrasound guidance and was performed by experienced radiologists and surgeons specializing in needle biopsies. Diagnosis and classification for each patient were independently evaluated by pathologists. Over the indicated 8-year period, biopsy type consisted of 11,947 ultrasound-guided core needle biopsies (UCNBs), 2,015 ultrasound-guided vacuum-assisted biopsies (UVABs), and 654 stereotactic X-ray-guided vacuum-assisted biopsies (XVABs). For all the 11,947 women included in this study, image-guided needle biopsy was the initial diagnostic procedure. Approximately 81.0% of biopsied samples were histopathologically determined to be malignant lesions, 5.5% were determined to be high-risk lesions, and 13.5% were determined to be benign lesions. The number of patients choosing UCNB increased at the greatest rate, and UCNB has become a standard procedure for histodiagnosis because it is inexpensive, convenient, and accurate. The overall false-negative rate of CNB was 1.7%, and the specific false negative rates for UCNB, UVAB, and XVAB, were 1.7%, 0%, and 0%, respectively. This study suggests that the use of preoperative needle biopsy as the initial breast cancer diagnostic procedure is acceptable in urban Shanghai. Preoperative needle biopsy is now a standard procedure in the Shanghai Cancer Center because it may reduce the number of surgeries needed to treat breast cancer. PMID- 26491360 TI - Study of internal mammary sentinel lymph node biopsy in breast cancer patients after neoadjuvant chemotherapy. PMID- 26491361 TI - The association of GSTT1 deletion polymorphism with lung cancer risk among Chinese population: evidence based on a cumulative meta-analysis. AB - OBJECTIVE: Previous studies investigating the relationship between glutathione S transferase T1 (GSTT1) gene deletion polymorphism and lung cancer risk among Chinese population produced inconsistent results. To obtain a precise conclusion, we performed this meta-analysis to evaluate the association between GSTT1 deletion polymorphism and lung cancer risk among Chinese population. METHODS: The databases of Medline/PubMed, Embase, Web of Science, Wanfang Med Online, and Chinese National Knowledge Infrastructure were searched. The strength of the association was assessed by odds ratio (OR) with 95% confidence intervals (95% CI). RESULTS: Overall, we found an increased lung cancer risk among subjects carrying GSTT1 null genotype compared with those carrying present genotype (OR =1.31, 95% CI: 1.12-1.52) on the basis of 20 studies with 3,351 cases and 4,683 controls. We also observed an increased risk of lung cancer among subjects carrying GSTT1 null genotype compared with those carrying present genotype in stratified analyses (OR =1.31, 95% CI: 1.11-1.55 for healthy subjects-based control; OR =2.29, 95% CI: 1.84-2.85 for squamous cell carcinoma and OR =1.47, 95% CI: 1.22-1.77 for adenocarcinoma, respectively). CONCLUSION: This meta analysis suggested that GSTT1 deletion polymorphism might contribute to lung cancer risk among Chinese population. PMID- 26491362 TI - Genetic polymorphisms of CYP1A1 and risk of leukemia: a meta-analysis. AB - The associations between CYP1A1 polymorphisms and risk of leukemia have been studied extensively, but the results have been inconsistent. Therefore, in this study, we performed a meta-analysis to clarify associations of three CYP1A1 polymorphisms (T3801C, A2455G, and C4887A) with the risks of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Medline, EMBASE, and China National Knowledge Infrastructure databases were searched to collect relevant studies published up to April 20, 2015. The extracted data were analyzed statistically, and pooled odds ratios with 95% confidence intervals were calculated to quantify the associations. Overall, 26 publications were included. Finally, T3801C was associated with an increased risk of AML in Asians under the dominant model. For A2455G, the risk of ALL was increased among Caucasians in the recessive model and the allele-contrast model; A2455G was also associated with an increased risk of CML among Caucasians under the recessive model, dominant model, and allele-contrast model. For C4887A, few of the included studies produced data. In conclusion, the results suggest that Asians carrying the T3801C C allele might have an increased risk of AML and that Caucasians with the A2455G GG genotype might have an increased risk of ALL. Further investigations are needed to confirm these associations. PMID- 26491363 TI - Clinical effectiveness of dolutegravir in the treatment of HIV/AIDS. AB - Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI), which has now been licensed to be used in different countries including the UK. Earlier studies have demonstrated that DTG when used with nucleoside backbone in treatment-naive and - experienced patients has been well tolerated and demonstrated virological suppression comparable to other INSTIs and superiority against other first-line agents, including efavirenz and boosted protease inhibitors. Like other INSTIs, DTG uses separate metabolic pathways compared to other antiretrovirals and is a minor substrate for CYP-450. It does not appear to have a significant interaction with drugs, which uses the CYP-450 system. Nonetheless, it uses renal solute transporters that may potentially inhibit the transport of other drugs and can have an effect on the elimination of other drugs. However, the impact of this mechanism appears to be very minimal and insignificant clinically. The side effect profiles of DTG are similar to raltegravir and have been found to be well tolerated. DTG has a long plasma half life and is suitable for once daily use without the need for a boosting agent. DTG has all the potential to be used as a first-line drug in combination with other nucleoside backbones, especially in the form of a single tablet in combination with abacavir and lamivudine. The purpose of this review article is to present the summary of the available key information about the clinical usefulness of DTG in the treatment of HIV infection. PMID- 26491365 TI - Combination of new multifunctional molecules for erythematotelangiectatic rosacea disorder. AB - BACKGROUND: Rosacea, a common chronic skin disorder, is currently managed by patient education, pharmacological drugs, medical devices (laser and light therapies), and use of proper skin cares. Unfortunately, none of these actual treatments used alone or in combination is curative, and so we proposed a dermocosmetic active ingredient to mitigate some aspects of the rosacea and particularly for erythematotelangiectatic rosacea. METHODS: Dermocosmetic active ingredient is composed of three glucosylated derivatives of natural plants hydroxybenzoic acid and hydroxycinnamic acids (rosmarinic acid, gallic acid, and caffeic acid). Anti-inflammatory, anti-angiogenesis, and anti-degranulation studies were done on cellular models (keratinocytes, mast cells, and endothelial cells). Efficiency of the active ingredient in comparison to placebo was assessed clinically on human volunteers having erythematotelangiectatic rosacea. The active and placebo were applied topically twice a day for 28 days. Biometrical analyses were done using a siascope tool. RESULTS: We found that the active ingredient decreases inflammation (inhibition of interleukin-8 and tumor necrosis factor release), decreases degranulation of mast cells (inhibition of histamine release), and controls angiogenesis mechanism (inhibition of the production of vascular endothelial growth factor and neovessel formation) on cellular models. Study on human volunteers confirmed macroscopically the efficiency of this active ingredient, as we observed no neovessel formation and less visible vessels. CONCLUSION: Although rosacea is a skin condition disorder that is difficult to heal, the studies have shown that this active ingredient could be a dermocosmetic support, especially for erythematotelangiectatic rosacea armamentarium. The active ingredient was topically applied on the face for 28 days and improved erythematotelangiectatic rosacea symptoms either by decreasing them (vessels are less visible) or by limiting their development (any neovessels). The active ingredient decreases inflammation (inhibition of interleukin-8 and tumor necrosis factor release), decreases degranulation of mast cells (inhibition of histamine release), and limits the angiogenesis process (inhibition of vascular endothelial growth factor production and neovessel formation). PMID- 26491364 TI - Fillers for the improvement in acne scars. AB - Acne is a common inflammatory disease. Scarring is an unwanted end point of acne. Both atrophic and hypertrophic scar types occur. Soft-tissue augmentation aims to improve atrophic scars. In this review, we will focus on the use of dermal fillers for acne scar improvement. Therefore, various filler types are characterized, and available data on their use in acne scar improvement are analyzed. PMID- 26491366 TI - Management of atopic dermatitis: safety and efficacy of phototherapy. AB - Atopic dermatitis (AD) is a common chronic inflammatory skin disease that can affect all age groups. It is characterized by a relapsing course and a dramatic impact on quality of life for patients. Environmental interventions together with topical devices represent the mainstay of treatment for AD, in particular emollients, corticosteroids, and calcineurin inhibitors. Systemic treatments are reserved for severe cases. Phototherapy represents a valid second-line intervention in those cases where non-pharmacological and topical measures have failed. Different forms of light therapy are available, and have showed varying degrees of beneficial effect against AD: natural sunlight, narrowband (NB)-UVB, broadband (BB)-UVB, UVA, UVA1, cold-light UVA1, UVA and UVB (UVAB), full-spectrum light (including UVA, infrared and visible light), saltwater bath plus UVB (balneophototherapy), Goeckerman therapy (coal tar plus UVB radiation), psoralen plus UVA (PUVA), and other forms of phototherapy. In particular, UVA1 and NB-UVB have gained importance in recent years. This review illustrates the main trials comparing the efficacy and safety of the different forms of phototherapy. No sufficiently large randomized controlled studies have been performed as yet, and no light modality has been defined as superior to all. Parameters and dosing protocols may vary, although clinicians mainly refer to the indications included in the American Academy of Dermatology psoriasis guidelines devised by Menter et al in 2010. The efficacy of phototherapy (considering all forms) in AD has been established in adults and children, as well as for acute (UVA1) and chronic (NB UVB) cases. Its use is suggested with strength of recommendation B and level of evidence II. Home phototherapy can also be performed; this technique is recommended with strength C and level of evidence III. Phototherapy is generally considered to be safe and well tolerated, with a low but established percentage of short-term and long-term adverse effects, with the most common being photodamage, xerosis, erythema, actinic keratosis, sunburn, and tenderness. A carcinogenic risk related to UV radiation has not been excluded. Phototherapy also has some limitations related to costs, availability, and patient compliance. In conclusion, phototherapy is an optimal second-line treatment for AD. It can be used as monotherapy or in combination with systemic drugs, in particular corticosteroids. It must be performed conscientiously, especially in children, and must take into account the patient's features and overall condition. PMID- 26491367 TI - Regulation of MT1-MMP/MMP-2/TIMP-2 axis in human placenta. AB - Matrix metalloproteinases (MMPs) and specific endogenous tissue inhibitors of metalloproteinases (TIMPs) mediate rupture of the fetal membranes in both physiological and pathological conditions. MMPs and TIMPs are subject to regulation by DNA methylation in human malignancies and pre-eclampsia. To determine if membrane type 1 MMP (MT1-MMP), MMP2, and TIMP2 are regulated by DNA methylation in human placentas, we employed an in vitro model where human placental tissues were collected at term gestation and cultured with methylation inhibiting agent 5-AZA-2'-deoxycytidine (AZA) and lipopolysaccharide. The results suggest that DNA methylation is not directly involved in the regulation of MT1 MMP in placental tissue; however, remodeling of chromatin by a pharmacologic agent such as AZA potentiates an infection-related increase in MT1-MMP. MT1-MMP is a powerful activator of MMP2 and this action, coupled with either no change or a decrease in TIMP2 concentrations, favors a gelatinolytic state leading to extracellular matrix degradation, which could predispose fetal membranes to rupture prematurely during inflammation. PMID- 26491368 TI - Effect of fluid loading with normal saline and 6% hydroxyethyl starch on stroke volume variability and left ventricular volume. AB - PURPOSE: The aim of this clinical trial was to investigate changes in stroke volume variability (SVV) and left ventricular end-diastolic volume (LVEDV) after a fluid bolus of crystalloid or colloid using real-time three-dimensional transesophageal echocardiography (3D-TEE) and the Vigileo-FloTracTM system. MATERIALS AND METHODS: After obtaining Institutional Review Board approval, and informed consent from the research participants, 22 patients undergoing scheduled peripheral vascular bypass surgery were enrolled in the study. The patients were randomly assigned to receive 500 mL of hydroxyethyl starch (HES; HES group, n=11) or normal saline (Saline group, n=11) for fluid replacement therapy. SVV was measured using the Vigileo-FloTrac system. LVEDV, stroke volume, and cardiac output were measured by 3D-TEE. The measurements were performed over 30 minutes before and after the fluid bolus in both groups. RESULTS: SVV significantly decreased after fluid bolus in both groups (HES group, 14.7%+/-2.6% to 6.9%+/ 2.7%, P<0.001; Saline group, 14.3%+/-3.9% to 8.8%+/-3.1%, P<0.001). LVEDV significantly increased after fluid loading in the HES group (87.1+/-24.0 mL to 99.9+/-27.2 mL, P<0.001), whereas no significant change was detected in the Saline group (88.8+/-17.3 mL to 91.4+/-17.6 mL, P>0.05). Stroke volume significantly increased after infusion in the HES group (50.6+/-12.5 mL to 61.6+/ 19.1 mL, P<0.01) but not in the Saline group (51.6+/-13.4 mL to 54.1+/-12.8 mL, P>0.05). Cardiac output measured by 3D-TEE significantly increased in the HES group (3.5+/-1.1 L/min to 3.9+/-1.3 L/min, P<0.05), whereas no significant change was seen in the Saline group (3.4+/-1.1 L/min to 3.3+/-1.0 L/min, P>0.05). CONCLUSION: Administration of colloid and crystalloid induced similar responses in SVV. A higher plasma-expanding effect of HES compared to normal saline was demonstrated by the significant increase in LVEDV. PMID- 26491369 TI - Superion((r)) InterSpinous Spacer for treatment of moderate degenerative lumbar spinal stenosis: durable three-year results of a randomized controlled trial. AB - PURPOSE: This report provides the 3-year clinical outcomes from the randomized, controlled US Food and Drug Administration Investigational Device Exemption trial of the Superion((r)) for the treatment of moderate degenerative lumbar spinal stenosis. PATIENTS AND METHODS: The Superion((r)) was evaluated in the treatment of subjects aged 45 years or older suffering from symptoms of intermittent neurogenic claudication, secondary to a confirmed diagnosis of moderate degenerative lumbar spinal stenosis at one or two contiguous levels from L1 to L5. Patients were treated between June 2008 and December 2011 at 31 investigational sites. Three hundred ninety-one subjects were included in the randomized study group consisting of 190 Superion((r)) and 201 X-STOP((r)) control subjects. The primary composite endpoint was individual patient success based on four components: improvement in two of three domains of the Zurich Claudication Questionnaire, no reoperations at the index level, no major implant/procedure-related complications, and no clinically significant confounding treatments. RESULTS: At 3 years, the proportion of subjects achieving the primary composite endpoint was greater for Superion((r)) (63/120, 52.5%) than for X-STOP((r)) (49/129, 38.0%) (P=0.023) and the corresponding success rates exceeded 80% for each of the individual components of the primary endpoint in the Superion((r)) group (range: 81%-91%). Improvements in back and leg pain severity as well as back- and disease-specific functional outcomes were also maintained through 36 months. CONCLUSION: The 3-year outcomes from this randomized controlled trial demonstrate durable clinical improvement consistently across all clinical outcomes for the Superion((r)) in the treatment of patients with moderate degenerative lumbar spinal stenosis. PMID- 26491370 TI - Fear of pain potentiates nocebo hyperalgesia. AB - Nocebo hyperalgesia has received sparse experimental attention compared to placebo analgesia. The aim of the present study was to investigate if personality traits and fear of pain could predict experimental nocebo hyperalgesia. One hundred and eleven healthy volunteers (76 females) participated in an experimental study in which personality traits and fear of pain were measured prior to induction of thermal heat pain. Personality traits were measured by the Big-Five Inventory-10. Fear of pain was measured by the Fear of Pain Questionnaire III. Heat pain was induced by a PC-controlled thermode. Pain was measured by a computerized visual analog scale. Stress levels during the experiment were measured by numerical rating scales. The participants were randomized to a Nocebo group or to a no-treatment Natural History group. The results revealed that pain and stress levels were significantly higher in the Nocebo group after nocebo treatment. Mediation analysis showed that higher levels of the Fear of Pain Questionnaire III factor "fear of medical pain" significantly increased stress levels after nocebo treatment and that higher stress levels were associated with increased nocebo hyperalgesic responses. There were no significant associations between any of the personality factors and the nocebo hyperalgesic effect. The results from the present study suggest that dispositional fear of pain might be a useful predictor for nocebo hyperalgesia and emotional states concomitant with expectations of increased pain. Furthermore, measurement of traits that are specific to pain experience is probably better suited for prediction of nocebo hyperalgesic responses compared to broad measures of personality. PMID- 26491371 TI - Cariogram outcome after 90 days of oral treatment with Streptococcus salivarius M18 in children at high risk for dental caries: results of a randomized, controlled study. AB - Dental caries is the most common chronic disease of childhood. Cariogram is a well-recognized algorithm-based software program based on different caries related risk factors and intended to aid clinicians in performing more objective and consistent dental caries risk assessments. This type of approach precedes the diagnosis of caries and allows the dentist to identify at-risk patients and then take appropriate preventive measures before caries develop further. One of the etiological factors favoring the development of dental caries is the mutans streptococci. These acidogenic dental plaque inhabitants can be effectively antagonized by the activity of bacteriocins released by the probiotic Streptococcus salivarius M18 (salivarius M18). Moreover, salivarius M18 after colonizing the human oral mucosa produces the enzymes dextranase and urease that are able to counteract plaque formation and saliva acidity, respectively. Seventy six subjects at high risk of dental caries were randomized and then either treated or not treated for 90 days with an oral formulation containing the oral probiotic salivarius M18 (Carioblis((r))). The results indicate that the use of salivarius M18 increases the chances of avoiding new dental caries development in children, and its application could be proposed as a new tool in the dentist's armory to be adopted in subjects considered at high risk on the basis of their Cariogram outcome. PMID- 26491372 TI - Concurrent sexual partnerships among married Zimbabweans - implications for HIV prevention. AB - BACKGROUND: Concurrent sexual partnerships play a key role in sustaining the HIV epidemic in Zimbabwe. Married couples are at an increased risk of contracting HIV from sexual networks produced by concurrent sexual partnerships. Addressing these partnerships is an international HIV prevention priority. METHODS: Our qualitative study presents the socioeconomic factors that contribute to the occurrence of concurrent sexual partnerships among married people in Zimbabwe. We conducted 36 in-depth interviews and four focus group discussions with married men and women in Zimbabwe in 2008 to understand the organizations of concurrent sexual partnerships. Data were analyzed using framework analysis. RESULTS: Our study indicates that relationship dissatisfaction played a key role in the engagement of concurrent sexual partnerships. Depending on the source of the dissatisfaction, there were four possible types of concurrent sexual relationships that were formed: sex worker, casual partner, regular girlfriend or informal polygyny which was referred to as "small house". These relationships had different levels of intimacy, which had a bearing on practicing safer sex. Participants described three characteristics of hegemonic masculinity that contributed to the sources of dissatisfaction leading to concurrent sexual activity. Similarly, various aspects of emphasized femininity were described as creating opportunities for the occurrence of concurrent sexual relationships. Economic status was also listed as a factor that contributed to the occurrence of concurrent sexual partnerships. CONCLUSION: Marital dissatisfaction was indicated as a contributing factor to the occurrence of concurrent sexual relationships. There were several reports of satisfying marital relationships in which affairs did not occur. Lessons from these marriages can be made part of future HIV prevention interventions targeted at preventing concurrent sexual partnerships by married couples. PMID- 26491373 TI - Adult-onset Kawasaki disease (mucocutaneous lymph node syndrome) and concurrent Coxsackievirus A4 infection: a case report. AB - INTRODUCTION: Kawasaki disease (KD) most commonly develops in infants, although its specific cause is still unclear. We report here a rare case of adult-onset KD which revealed to be concurrently infected by Coxsackievirus A4. CASE PRESENTATION: The patient was a 37-year-old Japanese man who presented with fever, exanthema, changes in the peripheral extremities, bilateral non-exudative conjunctival injection, and changes in the oropharynx, signs that meet the diagnostic criteria for KD defined by the Centers for Disease Control and Prevention. In this case, the patient had a significantly high antibody titer for Coxsackievirus A4, which led us to presume that the occurrence of KD was concurrent Coxsackievirus A4 infection. CONCLUSION: We reported a very rare case of KD which suggests that the disease can be concurrent Coxsackievirus A4 infection. Although KD is an acute childhood disease, with fever as one of the principal features, KD should also be considered in the differential diagnosis when adult patients present with a fever of unknown cause associated with a rash. PMID- 26491374 TI - Onychomycosis treated with a dilute povidone-iodine/dimethyl sulfoxide preparation. AB - BACKGROUND: Povidone-iodine (PVP-I) 10% aqueous solution is a well-known, nontoxic, commonly used topical antiseptic with no reported incidence of fungal resistance. We have been using a low-dose formulation of 1% PVP-I (w/w) in a solution containing dimethyl sulfoxide (DMSO) in our clinical practice for a variety of indications. Presented here is our clinical experience with this novel formulation in a severe case of onychomycosis that was resistant to any other treatment. FINDINGS: A 49-year-old woman who had been suffering from severe onychomycosis for years presented after failing to find any remedy including over the counter (OTC), topical, and systemic oral prescribed therapies. CONCLUSION: The topical povidone-iodine/DMSO system was very effective in this case at alleviating the signs and symptoms of onychomycosis. This novel combination warrants further investigation in randomized, controlled trials to further elucidate its clinical utility. PMID- 26491375 TI - An exploratory, randomized, parallel-group, open-label, relative bioavailability study with an additional two-period crossover food-effect study exploring the pharmacokinetics of two novel formulations of pexmetinib (ARRY-614). AB - BACKGROUND: Pexmetinib (ARRY-614) is a dual inhibitor of p38 mitogen-activated protein kinase and Tie2 signaling pathways implicated in the pathogenesis of myelodysplastic syndromes. Previous clinical experience in a Phase I dose escalation study of myelodysplastic syndrome patients using pexmetinib administered as neat powder-in-capsule (PIC) exhibited high variability in pharmacokinetics and excessive pill burden, prompting an effort to improve the formulation of pexmetinib. METHODS: A relative bioavailability assessment encompassed three parallel treatment cohorts of unique subjects comparing the two new formulations (12 subjects per cohort), a liquid oral suspension (LOS) and liquid-filled capsule (LFC) and the current clinical PIC formulation (six subjects) in a fasted state. The food-effect assessment was conducted as a crossover of the LOS and LFC formulations administered under fed and fasted conditions. Subjects were divided into two groups of equal size to evaluate potential period effects on the food-effect assessment. RESULTS: The geometric mean values of the total plasma exposures based upon area-under-the-curve to the last quantifiable sample (AUClast) of pexmetinib were approximately four- and twofold higher after administration of the LFC and LOS formulations, respectively, than after the PIC formulation, when the formulations were administered in the fasted state. When the LFC formulation was administered in the fed state, pexmetinib AUClast decreased by <5% compared with the fasted state. After administration of the LOS formulation in the fed state, pexmetinib AUClast was 34% greater than observed in the fasted state. CONCLUSION: These results suggest that the LFC formulation of pexmetinib may achieve greater exposures with lower doses due to the greater bioavailability compared to the PIC, and remain unaffected by coadministration with food. PMID- 26491376 TI - Critical review of the responsive neurostimulator system for epilepsy. AB - Patients with medically refractory epilepsy have historically had few effective treatment options. Electrical brain stimulation for seizures has been studied for decades and ongoing technological refinements have made possible the development of an implantable electrical brain stimulator. The NeuroPace responsive neurostimulator was recently approved by the FDA for clinical use and the initial reports are encouraging. This device continually monitors brain activity and delivers an electric stimulus when abnormal activity is detected. Early reports of efficacy suggest that the device is well tolerated and offers a reduction in seizure frequency by approximately half at 2 years. PMID- 26491378 TI - Evaluation and enhancement of medical knowledge competency by monthly tests: a single institution experience. AB - BACKGROUND: In-training examination (ITE) has been used as a predictor of performance at the American Board of Internal Medicine (ABIM) certifying examination. ITE however may not be an ideal modality as it is held once a year and represents snapshots of performance as compared with a trend. We instituted monthly tests (MTs) to continually assess the performance of trainees throughout their residency. OBJECTIVE: To determine the predictors of ABIM performance and to assess whether the MTs can be used as a tool to predict passing the ABIM examination. METHODS: The MTs, core competencies, and ITE scores were analyzed for a cohort of graduates who appeared for the ABIM examination from 2010 to 2013. Logistic regression was performed to identify the predictors of a successful performance at the ABIM examination. RESULTS: Fifty-one residents appeared for the ABIM examination between 2010 and 2013 with a pass rate of 84%. The MT score for the first year (odds ratio [OR] =1.302, CI =1.004-1.687, P=0.04) and second year (OR =1.125, CI =1.004-1.261, P=0.04) were independent predictors of ABIM performance along with the second-year ITE scores (OR =1.248, CI =1.096 1.420, P=0.001). CONCLUSION: The MT is a valuable tool to predict the performance at the ABIM examination. Not only it helps in the assessment of likelihood of passing the certification examination, it also helps to identify those residents who may require more assistance earlier during their residency. It may also highlight the areas of weakness in program curriculum and guide curriculum development. PMID- 26491379 TI - The situational judgement test: a student's worst nightmare. PMID- 26491377 TI - Obstructive sleep apnea as a risk factor for type 2 diabetes mellitus. AB - Obstructive sleep apnea (OSA) is independently associated with cardiovascular and cardiometabolic risk in several large epidemiologic studies. OSA leads to several physiologic disturbances such as intermittent hypoxia, sleep fragmentation, and increase in autonomic tone. These disturbances have been associated with insulin resistance and type 2 diabetes mellitus (T2DM) in animal and human studies. Studies also suggest a bidirectional relationship between OSA and T2DM whereby T2DM itself might contribute to the features of OSA. Moreover, successful treatment of OSA may reduce these risks, although this is controversial. The purpose of this article is to review 1) the links and bidirectional associations between OSA and T2DM; 2) the pathogenic mechanisms that might link these two disease states; 3) the role of continuous positive airway pressure therapy in improving glucose tolerance, sensitivity, and resistance; and 4) the implications for clinical practice. PMID- 26491380 TI - Addressing the need and void of leadership and management development among medical students in the UK. PMID- 26491381 TI - New nomenclature combinations in the green alder species complex (Betulaceae). AB - The name Alnus viridis (Chaix) DC., based on Betula viridis Chaix (1785), has traditionally been attributed to green alders although it is based on a later basionym. Alnus alnobetula (Ehrh.) K. Koch based on Betula alnobetula Ehrh. (1783) is the correct name for green alders. In light of the increasing use and recognition of the name Alnus alnobetula (Ehrh.) K. Koch in the literature. I herein propose new nomenclatural combinations to account for the Japanese and Chinese subspecies respectively: Alnus alnobetula subsp. maximowiczii (Callier ex C.K. Schneid.) J. Chery and Alnus alnobetula subsp. mandschurica (Callier ex C.K. Schneid.) J. Chery. Recent phylogenetic analyses place these two taxa in the green alder species complex, suggesting that they should be treated as infraspecific taxa under the polymorphic Alnus alnobetula. PMID- 26491382 TI - Problematic specimens turn out to be two undescribed species of Bignonia (Bignoniaceae). AB - Bignonia comprises 29 species of lianas characterized by eight phloem wedges, leaves usually 2-foliolate, mostly simple tendrils and opaque seed wings. The analysis of herbarium specimens in preparation for a taxonomic revision of the genus led to the recognition of two new species: (i) Bignonia cararensis from Costa Rica, characterized by a thyrse with lateral compound dichasia and lack of interpetiolar ridge, and (ii) Bignonia sanctae-crucis from Bolivia and Brazil, distinguishable by its membranous leaflets, membranous calyx and small fruits. We provide detailed descriptions, illustrations, distribution maps, initial conservation status assessments, and comparisons of the newly described taxa with closely related species. PMID- 26491383 TI - A new record of the rare alga Pachycladella P. C. Silva (Chlorophyceae) in New England. AB - A rarely reported taxon, the microscopic green alga Pachycladella, was found in a pond in Connecticut. Due to an unresolved taxonomic debate within the genus, the species-level identity of the newly discovered population cannot be determined with absolute certainty. However, according to the currently accepted classification the Connecticut specimens best match Pachycladella zatoriensis, heretofore only known from Europe. The find represents not only the first record of Pachycladella in Connecticut, but also in the entire New England region. This study highlights the need for continuing floristic surveys even in regions previously well explored. PMID- 26491384 TI - Study of phylogenetic relationship of Turkish species of Klasea (Asteraceae) based on ISSR amplification. AB - Klasea is a taxonomically complex genus in which there are many problems, mostly with Klasea kotschyi and Klasea hakkiarica. It is challenging to differentiate the genera based on morphological characters alone. Revision studies performed on the basis of molecular data obtained from studies conducted in recent years have made the phylogenetic relationships and systematic positions of the taxa more apparent and reliable. In this study, Klasea, Serratula, Jurinea and Centaurea species native to Turkey, were collected from different localities of Anatolia and DNA was isolated from the collected samples. The data were analyzed ordination analyses including UPGMA and PCA using NTSYSpc 2.1. The infrageneric and intergeneric phylogenetic relationships between Klasea and other related genera were also characterized. The Klasea species were grouped into three clusters. It was determined that taxa Klasea kotschyi and Klasea hakkiarica are separate but closely related. Moreover, it was observed that the Klasea lasiocephala a separate group within the genera. Clearly the genera Klasea, Serratula, Jurinea and Centaurea are phylogenetically differentiated on the dendogram. PMID- 26491385 TI - A new species of Symplocos (Symplocaceae) from southern Ecuador. AB - A new species from Ecuador, Symplocos limonensis, is here described and illustrated. It resembles Symplocos clethrifolia but differs by having larger leaves with evident (i.e., not concealed) areoles on lower surface, sessile inflorescences, smaller white corollas, and fewer stamens. The species is only known from three collections in the Andean forests of Morona-Santiago Province in southern Ecuador. PMID- 26491386 TI - SIFlore, a dataset of geographical distribution of vascular plants covering five centuries of knowledge in France: Results of a collaborative project coordinated by the Federation of the National Botanical Conservatories. AB - More than 20 years ago, the French Museum National d'Histoire Naturelle (MNHN, Secretariat of the Fauna and Flora) published the first part of an atlas of the flora of France at a 20km spatial resolution, accounting for 645 taxa (Dupont 1990). Since then, at the national level, there has not been any work on this scale relating to flora distribution, despite the obvious need for a better understanding. In 2011, in response to this need, the Federation des Conservatoires Botaniques Nationaux (FCBN, http://www.fcbn.fr) launched an ambitious collaborative project involving eleven national botanical conservatories of France. The project aims to establish a formal procedure and standardized system for data hosting, aggregation and publication for four areas: flora, fungi, vegetation and habitats. In 2014, the first phase of the project led to the development of the national flora dataset: SIFlore. As it includes about 21 million records of flora occurrences, this is currently the most comprehensive dataset on the distribution of vascular plants (Tracheophyta) in the French territory. SIFlore contains information for about 15'454 plant taxa occurrences (indigenous and alien taxa) in metropolitan France and Reunion Island, from 1545 until 2014. The data records were originally collated from inventories, checklists, literature and herbarium records. SIFlore was developed by assembling flora datasets from the regional to the national level. At the regional level, source records are managed by the national botanical conservatories that are responsible for flora data collection and validation. In order to present our results, a geoportal was developed by the Federation des conservatoires botaniques nationaux that allows the SIFlore dataset to be publically viewed. This portal is available at: http://siflore.fcbn.fr. As the FCBN belongs to the Information System for Nature and Landscapes' (SINP), a governmental program, the dataset is also accessible through the websites of the National Inventory of Natural Heritage (http://www.inpn.fr) and the Global Biodiversity Information Facility (http://www.gbif.fr). SIFlore is regularly updated with additional data records. It is also planned to expand the scope of the dataset to include information about taxon biology, phenology, ecology, chorology, frequency, conservation status and seed banks. A map showing an estimation of the dataset completeness (based on Jackknife 1 estimator) is presented and included as a numerical appendix. PURPOSE: SIFlore aims to make the data of the flora of France available at the national level for conservation, policy management and scientific research. Such a dataset will provide enough information to allow for macro-ecological reviews of species distribution patterns and, coupled with climatic or topographic datasets, the identification of determinants of these patterns. This dataset can be considered as the primary indicator of the current state of knowledge of flora distribution across France. At a policy level, and in the context of global warming, this should promote the adoption of new measures aiming to improve and intensify flora conservation and surveys. PMID- 26491387 TI - Dataset of MIGRAME Project (Global Change, Altitudinal Range Shift and Colonization of Degraded Habitats in Mediterranean Mountains). AB - In this data paper, we describe the dataset of the Global Change, Altitudinal Range Shift and Colonization of Degraded Habitats in Mediterranean Mountains (MIGRAME) project, which aims to assess the capacity of altitudinal migration and colonization of marginal habitats by Quercus pyrenaica Willd. forests in Sierra Nevada (southern Spain) considering two global-change drivers: temperature increase and land-use changes. The dataset includes information of the forest structure (diameter size, tree height, and abundance) of the Quercus pyrenaica ecosystem in Sierra Nevada obtained from 199 transects sampled at the treeline ecotone, mature forest, and marginal habitats (abandoned cropland and pine plantations). A total of 3839 occurrence records were collected and 5751 measurements recorded. The dataset is included in the Sierra Nevada Global-Change Observatory (OBSNEV), a long-term research project designed to compile socio ecological information on the major ecosystem types in order to identify the impacts of global change in this mountain range. PMID- 26491388 TI - Dendrochilum hampelii (Coelogyninae, Epidendroideae, Orchidaceae) traded as 'Big Pink' is a new species, not a hybrid: evidence from nrITS, matK and ycf1 sequence data. AB - In 2013, an unidentified species of Dendrochilum appeared in cultivation under the commercial trade name 'Big Pink'. Using sequences of the nuclear ribosomal ITS1-5.8S-ITS2 region and of the plastid matK and ycf1 genes, we examined the phylogenetic relationships between 'Big Pink' and six other species of the phenetically defined Dendrochilum subgen. Platyclinis sect. Eurybrachium. Separate and combined analyses (using Bayesian, Maximum Likelihood and Parsimony inference) showed consistent placement of the unidentified species within a statistically well supported clade. Furthermore, the multi-copy nrITS marker showed clear distinct peaks. Thus, we found no evidence that 'Big Pink' could be a hybrid. Against this background, and further supported by species-specific mutations in (at least) nrITS and ycf1, we formally describe 'Big Pink' as a new species under the name Dendrochilum hampelii. Morphologically, it is most similar to Dendrochilum propinquum, but it differs in a number of characters. Of the two cultivated individuals available for our study, one was of unrecorded provenance. The other allegedly originated from the Philippines. Observations of the species occurring in the wild in the Philippines in the northern provinces of Bukidnon and Misamis Oriental on the island of Mindanao confirmed this. PMID- 26491389 TI - A new subspecies of Seseli gummiferum (Apiaceae) from Ilgaz Mountain National Park, northern Turkey. AB - A new subspecies Seseli gummiferum Pall. ex Sm. subsp. ilgazense A.Duran, O.Cetin & M.Ozturk, subsp. nov. (Apiaceae) is described from Kastamonu province, Turkey. It was collected from the open Pinus sylvestris L. and Abies nordmanniana (Steven) E.Spach. mixed forest in the northern Anatolian region. An endemic apparently confined to the Ilgaz Mountain National Park, the new taxon is closely related to Seseli gummiferum subsp. gummiferum. Diagnostic morphological characters for closely similar taxa are discussed, and a key to the subspecies of Seseli gummiferum is presented. ITS (Internal Transcribed Spacer) region of the nuclear ribozomal DNA of closely related Seseli L. taxa and Pimpinella is used to constract phylogenetic tree by using BioEdit and Seaview Programme. PMID- 26491390 TI - Reinstatement of the Loyalty Islands Sandalwood, Santalum austrocaledonicum var. glabrum (Santalaceae), in New Caledonia. AB - Sandalwoods encompass 19 species restricted to southeast Asia and the Pacific. The species Santalum austrocaledonicum Vieill. (Santalaceae) is endemic to New Caledonia (Grande-Terre, Isle of Pines, Loyalty Islands) and Vanuatu, where several varieties are recognized. The Loyalty Islands sandalwood variety is here reinstated as Santalum austrocaledonicum var. glabrum Hurl. emend. Butaud & P.Firmenich, mut. char. It was previously considered a synonym of the type variety; however, new morphological and genetic studies confirmed its distinctiveness. The key for New Caledonian varieties of Santalum austrocaledonicum has been updated and a short description of its essential oil composition and organoleptic quality is given. PMID- 26491391 TI - A checklist of the Ukrainian Xoridinae (Hymenoptera, Ichneumonidae). AB - The Ukrainian Xoridinae list containing 28 species is reviewed. Four species, Xorides flavotibialis Hilszczanski, 2000, X. hedwigi Clement, 1938, Xorides rufipes (Gravenhorst, 1829), and X. rusticus (Desvignes, 1856) are recorded in the Ukrainian fauna for the first time. Agrilus biguttatus F. is recorded as a host of Ischnoceros caligatus (Gravenhorst, 1829) for the first time. PMID- 26491392 TI - Utilizing online resources for taxonomy: a cybercatalog of Afrotropical apiocerid flies (Insecta: Diptera: Apioceridae). AB - A cybercatalog to the Apioceridae (apiocerid flies) of the Afrotropical Region is provided. Each taxon entry includes links to open-access, online repositories such as ZooBank, BHL/BioStor/BLR, Plazi, GBIF, Morphbank, EoL, and a research web site to access taxonomic information, digitized literature, morphological descriptions, specimen occurrence data, and images. Cybercatalogs as the one presented here will need to become the future of taxonomic catalogs taking advantage of the growing number of online repositories, linked data, and be easily updatable. Comments on the deposition of the holotype of Apiocera braunsi Melander, 1907 are made. PMID- 26491394 TI - A new species of Neossos Malloch (Diptera: Heleomyzidae) from the Yukon Territory, Canada, and a revised key to the Nearctic species. AB - BACKGROUND: The rarely collected genus Neossos Malloch contains three Nearctic and one western European species. Most known specimens have been collected from bird nests. Two specimens of an undescribed species of Neossos were collected by sweeping in subarctic tundra and a mesic meadow in the Yukon Territory, Canada. This represents a significant northward extension of the known Nearctic range of the genus. NEW INFORMATION: Neossos tombstonensis sp. n. is described from the Yukon Territory. This represents the fourth described Nearctic species of Neossos. Although the type specimens were collected by sweeping, the species is predicted to be associated with bird nests, based on habits of other members of the genus. A revised key to the Nearctic species of Neossos is provided. PMID- 26491395 TI - Ecology and phylogeny of birds foraging at outdoor restaurants in Sweden. AB - BACKGROUND: Birds frequently visit the outdoor serving areas of restaurants to feed on scraps of food and leftovers. Although this feeding association between humans and birds is widespread and could have significant effects, both positive and negative, for all taxa involved, the authors know of no published studies that have investigated restaurant bird communities. To lay the foundation for future research, the authors conducted a basic study of birds at 80 outdoor restaurants in Sweden, identifying which species and taxonomic clades of birds visited the restaurants and comparing restaurant birds in urban and rural environments. NEW INFORMATION: Thirteen species of birds visited the outdoor restaurants. Eight of these species were predominant, i.e. accounting for 51% or more of bird presence (sum of minutes of all individual birds) at one or more restaurants. Every restaurant studied had a predominant species, but species often differed from each other in frequency of predominance in different landscapes. No endangered species were seen visiting restaurants. However, three farmland bird species (House Sparrow Passer domesticus, White Wagtail Motacilla alba, Eurasian Tree Sparrow Passer montanus), whose numbers are reported to be declining in the countryside, were predominant at the majority of restaurants in rural areas, suggesting that rural restaurants might be able to contribute to the conservation of these species. The thirteen species of restaurant-visiting birds belonged to five monophyletic clades. Ninety percent of all restaurants had, as their predominant species, birds from either Clade A (Passeridae, Motacillidae, Fringillidae) or Clade C (Corvidae). Statistical testing revealed that Clade A and Clade C were distributed differently in environments along the urban-rural gradient. At all spatial scales measured, birds of Clade C were predominant at the majority of restaurants in urban areas, while birds of Clade A were the predominant clade at the majority of restaurants in rural areas. The authors use this evidence, and observations of birds foraging in association with other primates, to hypothesize that the outdoor serving areas of modern restaurants may be helping to preserve and nurture ancient human-bird symbioses that have been part of human ecology since antiquity. PMID- 26491396 TI - Corrigendum: Three new species of Trigonospila Pokorny (Diptera: Tachinidae), from Area de Conservacion Guanacaste, northwestern Costa Rica, with a key for their identification. AB - [This corrects the article DOI: 10.3897/BDJ.3.e4595.]. PMID- 26491397 TI - Corrigendum to "Outcome of Rhabdomyosarcoma in First Year of Life: Children's Cancer Hospital 57357 Egypt". AB - [This corrects the article DOI: 10.1155/2013/439213.]. PMID- 26491393 TI - PESI - a taxonomic backbone for Europe. AB - BACKGROUND: Reliable taxonomy underpins communication in all of biology, not least nature conservation and sustainable use of ecosystem resources. The flexibility of taxonomic interpretations, however, presents a serious challenge for end-users of taxonomic concepts. Users need standardised and continuously harmonised taxonomic reference systems, as well as high-quality and complete taxonomic data sets, but these are generally lacking for non-specialists. The solution is in dynamic, expertly curated web-based taxonomic tools. The Pan European Species-directories Infrastructure (PESI) worked to solve this key issue by providing a taxonomic e-infrastructure for Europe. It strengthened the relevant social (expertise) and information (standards, data and technical) capacities of five major community networks on taxonomic indexing in Europe, which is essential for proper biodiversity assessment and monitoring activities. The key objectives of PESI were: 1) standardisation in taxonomic reference systems, 2) enhancement of the quality and completeness of taxonomic data sets and 3) creation of integrated access to taxonomic information. NEW INFORMATION: This paper describes the results of PESI and its future prospects, including the involvement in major European biodiversity informatics initiatives and programs. PMID- 26491398 TI - Optimized breeding strategies for multiple trait integration: III. Parameters for success in version testing. AB - Multiple trait integration (MTI) is the process by which a target hybrid (or variety) is converted to add value-added traits to the comprehensive performance package represented by that genotype. The goal is to recover all the attributes of the target hybrid, with the addition of the specified value-added traits. In maize, this process utilizes the backcross breeding method to incorporate transgenic events (or genes) of interest. Thus, MTI involves four main steps: single event introgression, event pyramiding, trait fixation, and version testing to ensure recovery of equivalent performance with at least one version of the converted hybrid. Based on a case study involving conversion of a target hybrid for 15 transgenic events (the female inbred parent was converted for 8 events, and the male inbred parent was converted for 7 events), we explored parameters in version testing to facilitate a high likelihood of recovering at least one version of the hybrid conversion with yield performance equivalency within 3 % of unconverted target hybrid. Using computer simulation, we explored the impact of two factors on the success rate of the MTI outcome: (1) the amount of residual NRP (non-recurrent parent) germplasm remaining in the converted hybrid and (2) the number of versions of each parental line conversion created. A range of residual NRP germplasm from 120 to 180 cM (which represents 95.0-96.6 % germplasm recovery of the target hybrid in maize) and up to 5 versions of each parental conversion were considered, with all possible hybrid combinations of each version of female and male RP (recurrent parent) conversion evaluated for yield. With 5 versions of each RP conversion and testing of 25 hybrid versions, a >95 % rate of success was realized when the amount of residual NRP germplasm in the hybrid conversion was <=180 cM. When hybrid conversions contained <=120-cM residual NRP germplasm, only 4 versions of one of the parental conversions were needed (rather than 5), requiring 20 versions of the hybrid conversion to be yield tested. These results have implications in the strategic design of an overall conversion program and for the upstream MTI process, especially in setting thresholds for the amount of NRP germplasm remaining in RP conversions. Furthermore, these results validate findings of (Peng et al. in Mol Breed 33:189-104, 2014a. doi:10.1007/s11032-013-9936-7, in Mole Breed 33:105-115, 2014b. doi:10.1007/s11032-013-9937-6) which outline effective breeding strategies to optimize earlier steps in MTI (preceding version testing). PMID- 26491399 TI - A quantum-information theoretic analysis of three-flavor neutrino oscillations: Quantum entanglement, nonlocal and nonclassical features of neutrinos. AB - Correlations exhibited by neutrino oscillations are studied via quantum information theoretic quantities. We show that the strongest type of entanglement, genuine multipartite entanglement, is persistent in the flavor changing states. We prove the existence of Bell-type nonlocal features, in both its absolute and genuine avatars. Finally, we show that a measure of nonclassicality, dissension, which is a generalization of quantum discord to the tripartite case, is nonzero for almost the entire range of time in the evolution of an initial electron-neutrino. Via these quantum-information theoretic quantities, capturing different aspects of quantum correlations, we elucidate the differences between the flavor types, shedding light on the quantum-information theoretic aspects of the weak force. PMID- 26491400 TI - Women's decision-making autonomy and children's schooling in rural Mozambique. AB - BACKGROUND: Women's decision-making autonomy in developing settings has been shown to improve child survival and health outcomes. However, little research has addressed possible connections between women's autonomy and children's schooling. OBJECTIVE: To examine the relationship between rural women's decision-making autonomy and enrollment status of primary school-age children living in their households and how this relationship differs by child's gender. METHODS: The analysis uses data from a 2009 survey of rural households in four districts of Gaza province in southern Mozambique. Multilevel logistic models predict the probability of being in school for children between 6 and 14 years old. RESULTS: The results show a positive association of women's decision-making autonomy with the probability of being enrolled in primary school for daughters, but not for sons. The effect of women's autonomy is net of other women's characteristics typically associated with enrollment and does not mediate the effects of those characteristics. CONCLUSIONS: Based on the results, we argue that women with higher levels of decision-making autonomy may have a stronger preference for daughters' schooling and may have a greater say in making and implementing decisions regarding daughters' education, compared to women with lower autonomy levels. Results also illustrate a need for considering a broader set of autonomy related characteristics when examining the effects of women's status on children's educational outcomes. PMID- 26491401 TI - Thomas E. Cataldo, MD, FACS, FASCRS and Deborah Nagle, MD, FACS, FASCRS. PMID- 26491402 TI - Evolving and Emerging Technologies in Colon and Rectal Surgery. PMID- 26491403 TI - Adoption of Laparoscopic Colorectal Surgery: It Was Quite a Journey. AB - The adoption of laparoscopic colorectal surgery has been a slow but steady progress. The first adopters rapidly expanded the application of the technology to all colorectal pathology. Issues related to extraction and port site recurrence of cancer delayed widespread adoption until incontrovertible data from well-powered prospective randomized studies confirmed equipoise with open surgery. Since that time, the data has consistently demonstrated patient-care benefits related to reductions in both short- and long-term complications historically associated with open colectomy. The potential for further improvement related to single-port access, robotic assistance, and natural orifice access for both the surgery and/or extraction will await the test of time. However, it is clear now that laparoscopic colorectal surgery is the new standard of care and a key enabler of enhanced recovery programs. PMID- 26491404 TI - Single-Incision Laparoscopic Colon and Rectal Surgery. AB - Single-incision laparoscopic surgery (SILS) was introduced to further the enhanced outcomes of multiport laparoscopy. Multiple studies have demonstrated the safety and feasibility of SILS for both benign and malignant colorectal disease. SILS provides the potential for improved cosmesis, postoperative outcomes, and patient quality of life. However, widespread use has been limited by technical demands and lack of an evidence and competency-based curriculum. PMID- 26491405 TI - Combined Endoscopic and Laparoscopic Surgery. AB - Benign colon polyps are best treated endoscopically. Colon polyps that are not amenable for endoscopic removals either because they are too large or situated in anatomically difficult locations can pose a clinical dilemma. Traditionally the most common recommendation for these patients has been to offer a colon resection. Although the laparoscopic approach has improved short-term outcomes, morbidities associated with bowel resection are still significant. We may be over treating majority of these patients because of the remote possibility that these polyps may be harboring a cancer. A combined approach using both laparoscopy and colonoscopy (combined endoscopic and laparoscopic surgery) has been described as an alternative to bowel resection in select patients with polyps that cannot be removed endoscopically. Polyp removal using this combined approach may be an effective alternative in select patients. PMID- 26491406 TI - Colorectal Endoscopic Submucosal Dissection: Past, Present, and Factors Impacting Future Dissemination. AB - First performed in the stomach for removal of localized gastric tumors, endoscopic submucosal dissection (ESD) has evolved into a technique that is increasingly being employed to resect colorectal lesions. As opposed to endoscopic mucosal resection (EMR), ESD allows the endoscopist to remove large specimens en bloc to provide accurate pathologic evaluation and lower local recurrence rates. ESD is an ideal technique for resection of lesions without lymph node metastases and is becoming the standard of care in Japan as outcomes data has proven it to be equally efficacious, less invasive, and inexpensive as compared with surgery; however, potential risk for complications is high and the procedure is currently not widely available in the Western world. As more interest, endoscopist training, and data supporting the technique's use mount, ESD will also likely become the standard of care in the Western world for resection of localized colorectal lesions. PMID- 26491407 TI - Emerging and Evolving Technology in Colon and Rectal Surgery. AB - Minimally invasive surgery has changed the way we manage many colon and rectal pathologies. Multiple techniques, from straight laparoscopic procedures, to hand assisted and single-port techniques are available, requiring surgeons to go through various learning curves. Robotic surgery is a relatively novel technique in general surgery which appears to hold most promise for rectal resection. Laparoscopic rectal procedures are difficult, and even in experienced hands, conversion rates are around 17%. Robotic surgery may be a point of difference in these cases, despite a long learning curve and higher costs. This article will describe the role of robotics in colorectal surgery. Room set up, port placement, and docking strategies will be described for common procedures, with emphasis on a hybrid robotic low anterior resection. PMID- 26491408 TI - Enhanced Reality and Intraoperative Imaging in Colorectal Surgery. AB - Colorectal surgery is one of the most common procedures performed around the world with more than 600,000 operations each year in the United States, and more than a million worldwide. In the past two decades, there has been a clear trend toward minimal access and surgeons have embraced this evolution. Widespread adoption of advanced minimally invasive procedures is often limited by procedural complexity and the need for specific technical skills. Furthermore, the loss of 3D vision, limited overview of the surgical field, and diminished tactile sensation make major colorectal procedures more challenging and have an impact on the surgeons' learning curves. New technologies are emerging that can compensate for some of the sensory losses associated with laparoscopy. High-definition picture acquisition, 3D camera systems, and the use of biomarkers will allow improved identification of the target structures and help differentiate them from surrounding tissues. In this article, we describe some of the new technologies available and, in particular, focus on the possible implications of biomarkers and fluorescent laparoscopic imaging. PMID- 26491409 TI - Transanal Endoscopic Microsurgery. AB - Transanal endoscopic microsurgery (TEM) was developed by Professor Gerhard Buess 30 years ago at the dawn of minimally invasive surgery. TEM utilizes a closed proctoscopic system whereby endoluminal surgery is accomplished with high definition magnification, constant CO2 insufflation, and long-shafted instruments. The end result is a more precise excision and closure compared to conventional instrumentation. Virtually any benign lesion can be addressed with this technology; however, proper patient selection is paramount when using it for cancer. PMID- 26491410 TI - Transanal Minimally Invasive Surgery. AB - Transanal minimally invasive surgery (TAMIS) was first described in 2010 as a crossover between single-incision laparoscopic surgery and transanal endoscopic microsurgery (TEM) to allow access to the proximal and mid-rectum for resection of benign and early-stage malignant rectal lesions. The TAMIS technique can also be used for noncurative intent surgery of more advanced lesions in patients who are not candidates for radical surgery. Proper workup and staging should be done before surgical decision-making. In addition to the TAMIS port, instrumentation and set up include readily available equipment found in most operating suites. TAMIS has proven its usefulness in a wide range of applications outside of local excision, including repair of rectourethral fistula, removal of rectal foreign body, control of rectal hemorrhage, and as an adjunct in total mesorectal excision for rectal cancer. TAMIS is an easily accessible, technically feasible, and cost-effective alternative to TEM. PMID- 26491412 TI - MRI Local Staging and Restaging in Rectal Cancer. AB - Magnetic resonance imaging (MRI) with rectal protocol modification is a reliable staging modality which is rapidly replacing transrectal ultrasound for staging. The added information delivered by MRI includes wide circumferential radial margin compromise, distant lymph node metastasis in the pelvis, and level of sphincter compromise in the low rectum. As more information becomes available through ongoing studies, MRI may be able to contribute the decision to treat rectal cancer nonoperatively. PMID- 26491413 TI - A SPECIAL MEETING REVIEW EDITION: Highlights in the Treatment of Hepatitis C Virus From the 2014 Liver Meeting: A Review of Selected Presentations From the 2014 Liver Meeting November 7-11, 2014 * Boston, MassachusettsSpecial Reporting on:* Evaluation of Sofosbuvir and Simeprevir-Based Regimens in the TRIO Network* Safety and Efficacy of New DAA-Based Therapy for Hepatitis C Post-Transplant: Interval Results From the HCV-TARGET Longitudinal, Observational Study* Efficacy and Safety of MK-5172 and MK-8742 +/- Ribavirin in Hepatitis C Genotype 1 Infected Patients With Cirrhosis or Previous Null Response: Final Results of the C-WORTHY Study (Parts A & B)* Safety and Efficacy of Sofosbuvir in Combination With Simeprevir + Ribavirin in Patients With Genotype 1: Interim Results of a Prospective, Observational Study* All-Oral Fixed-Dose Combination Therapy With Daclatasvir/Asunaprevir/BMS-791325, +/- Ribavirin, for Patients With Chronic HCV Genotype 1 Infection and Compensated Cirrhosis: UNITY-2 Phase 3 SVR-12 Results* TURQUOISE-II: Regimens of ABT-450/R/Ombitasvir and Dasabuvir With Ribavirin Achieve High SVR12 Rates in HCV Genotype 1-Infected Patients With Cirrhosis, Regardless of Baseline CharacteristicsPLUS Meeting Abstract Summaries With Expert Commentary by: Ira M. Jacobson, MDChief of the Division of Gastroenterology and HepatologyVincent Astor Distinguished Professor of MedicineWeill Cornell Medical CollegeAttending PhysicianNewYork-Presbyterian HospitalNew York, New York. PMID- 26491411 TI - Shifting Paradigms in Minimally Invasive Surgery: Applications of Transanal Natural Orifice Transluminal Endoscopic Surgery in Colorectal Surgery. AB - Since the advent of laparoscopy, minimally invasive techniques such as single port laparoscopy, robotics, endoscopically assisted laparoscopy, and transanal endoscopic surgery continue to revolutionize the field of colorectal surgery. Transanal natural orifice transluminal endoscopic surgery (NOTES) represents a further paradigm shift by combining the advantages of these earlier techniques to reduce the size and number of abdominal incisions and potentially optimize rectal dissection, especially with respect to performance of an oncologically adequate total mesorectal excision (TME) for rectal cancer. Since the first experimental report of transanal rectosigmoid resection in 2007, the potential impact of transanal NOTES in colorectal surgery has been extensively investigated in experimental models and recently transitioned to clinical application. There have been 14 clinical trials of transanal TME (taTME) for rectal cancer that have demonstrated the feasibility and preliminary oncologic safety of this approach in carefully selected patients, with results comparable to outcomes after laparoscopic and open TME, including cumulative intraoperative and postoperative complication rates of 5.5 and 35.5%, respectively, 97.3% rate of complete or near complete specimens, and 93.6% rate of negative margins. Transanal NOTES has also been safely applied to proctectomy and colectomy for benign indications. The consensus among published series suggests that taTME is most safely performed with transabdominal assistance by surgeons experienced with laparoscopic TME, transanal endoscopic surgery, and sphincter-preserving techniques including intersphincteric resection. Future applications of transanal NOTES may include evolution to a pure endoscopic transanal approach for TME, colectomy, and sentinel lymph node biopsy for rectal cancer, with a potential role for robotic assistance. PMID- 26491414 TI - New Diagnostic Strategies for Detection of Helicobacter pylori Infection in Pediatric Patients. AB - Helicobacter pylori (H pylori) is a common chronic bacterial infection that is an important cause of peptic ulcer disease and gastroduodenal disease in children. H pylori is also associated with extragastric manifestations, including growth reduction, iron-deficiency anemia, and idiopathic thrombocytopenic purpura. Current guidelines recommend endoscopy with biopsy for the definitive demonstration of H pylori infection. In contrast to serology, the fecal antigen test and the urea breath test provide reliable, sensitive, and specific results for detecting active H pylori infection in children before and after treatment. The first-line treatment option for pediatric patients is triple therapy with a proton pump inhibitor and 2 antibiotics, which include amoxicillin and clarithromycin or metronidazole. Decreasing eradication rates and the emergence of antibiotic-resistant strains of H pylori have led to the use of other treatments, such as sequential therapy or triple therapy with newer antibiotics, particularly in geographic areas with high rates of antibiotic resistance. Patients should be tested after treatment to confirm eradication, as the absence of symptoms does not necessarily mean that H pylori is no longer present. This clinical roundtable monograph provides an overview of H pylori infection, as well as expert insight into the diagnosis and management of H pylori infection in children. PMID- 26491415 TI - Emerging Treatment Options in Mild to Moderate Ulcerative Colitis. AB - Ulcerative colitis (UC) is a chronic inflammatory condition associated with rectal bleeding and urgency, tenesmus, and diarrhea. Several medical therapies can be used in the treatment of UC. Aminosalicylates are widely used based on their efficacy in the induction and maintenance of remission. Although corticosteroids are effective in patients with more severe disease, systemic use is associated with significant safety concerns. The newer corticosteroid budesonide has lower systemic bioavailability and, consequently, a more favorable safety profile. A budesonide extended-release formulation allows once-daily dosing and delivers the agent locally throughout the colon. Biologic agents used for the treatment of moderate to severe UC include the tumor necrosis factor inhibitors infliximab, adalimumab, and golimumab, and the integrin inhibitor vedolizumab. Rectally administered therapy can also be useful in the treatment of UC. In October 2014, the US Food and Drug Administration approved a budesonide foam formulation for inducing remission in patients with active mild to moderate distal UC extending up to 40 cm from the anal verge. Budesonide foam rapidly distributes to the sigmoid colon and the rectum and avoids some of the drawbacks of suppositories and enemas. PMID- 26491416 TI - New and Emerging Treatment Options for Irritable Bowel Syndrome. AB - Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with abdominal pain, diarrhea, constipation, or a mix of symptoms. The pathophysiology of IBS is not completely understood but appears to involve genetics, the gut microbiome, immune activation, altered intestinal permeability, and brain-gut interactions. There is no gold standard for diagnosis. Several sets of symptom-based guidelines exist. Treatment strategies for IBS may include both nonpharmacologic and pharmacologic approaches. Lifestyle modifications that aim to improve exercise, sleep, diet, and stress may be warranted. Recent data suggest that a gluten-free diet and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) may benefit some patients. For patients with diarrhea-predominant IBS, treatment options include the synthetic peripheral MU-opioid receptor agonist loperamide, antispasmodic agents, antidepressants, serotonin 5-HT3 antagonists, and the gut-specific antibiotic rifaximin. Ongoing research is evaluating the use of probiotics. For patients with constipation-predominant IBS, therapeutic strategies may include dietary fiber, laxatives, and the prosecretory agents lubiprostone and linaclotide. Research is continuing to optimize the use of available agents and evaluating new approaches to further improve the care of patients with IBS. PMID- 26491417 TI - Fusion of the 1H NMR data of serum, urine and exhaled breath condensate in order to discriminate chronic obstructive pulmonary disease and obstructive sleep apnea syndrome. AB - Chronic obstructive pulmonary disease, COPD, affects the condition of the entire human organism and causes multiple comorbidities. Pathological lung changes lead to quantitative changes in the composition of the metabolites in different body fluids. The obstructive sleep apnea syndrome, OSAS, occurs in conjunction with chronic obstructive pulmonary disease in about 10-20 % of individuals who have COPD. Both conditions share the same comorbidities and this makes differentiating them difficult. The aim of this study was to investigate whether it is possible to diagnose a patient with either COPD or the OSA syndrome using a set of selected metabolites and to determine whether the metabolites that are present in one type of biofluid (serum, exhaled breath condensate or urine) or whether a combination of metabolites that are present in two biofluids or whether a set of metabolites that are present in all three biofluids are necessary to correctly diagnose a patient. A quantitative analysis of the metabolites in all three biofluid samples was performed using 1H NMR spectroscopy. A multivariate bootstrap approach that combines partial least squares regression with the variable importance in projection score (VIP-score) and selectivity ratio (SR) was adopted in order to construct discriminant diagnostic models for the groups of individuals with COPD and OSAS. A comparison study of all of the discriminant models that were constructed and validated showed that the discriminant partial least squares model using only ten urine metabolites (selected with the SR approach) has a specificity of 100 % and a sensitivity of 86.67 %. This model (AUCtest = 0.95) presented the best prediction performance. The main conclusion of this study is that urine metabolites, among the others, present the highest probability for correctly identifying patents with COPD and the lowest probability for an incorrect identification of the OSA syndrome as developed COPD. Another important conclusion is that the changes in the metabolite levels of exhaled breath condensates do not appear to be specific enough to differentiate between patients with COPD and OSAS. PMID- 26491419 TI - Changes in urine headspace composition as an effect of strenuous walking. AB - The present investigation uses proton transfer reaction mass spectrometry (PTR MS) combined with multivariate and univariate statistical analyses to study potential biomarkers for altered metabolism in urine due to strenuous walking. Urine samples, in concurrence with breath and blood samples, were taken from 51 participants (23 controls, 11 type-1 diabetes, 17 type-2 diabetes) during the Dutch endurance walking event, the International Four Days Marches. Multivariate analysis allowed for discrimination of before and after exercise for all three groups (control, type-1 and type-2 diabetes) and on three out of 4 days. The analysis highlighted 12 molecular ions contributing to this discrimination. Of these, acetic acid in urine is identified as a significant marker for exercise effects induced by walking; an increase is observed as an effect of walking. Analysis of acetone concentration with univariate tools resulted in different information when compared to breath as a function of exercise, revealing an interesting effect of time over the 4 days. In breath, acetone provides an immediate snapshot of metabolism, whereas urinary acetone will result from longer term diffusion processes, providing a time averaged view of metabolism. The potential to use PTR-MS measurements of urine to monitor exercise effects is exhibited, and may be utilized to monitor subjects in mass participation exercise events. PMID- 26491418 TI - COordination of Standards in MetabOlomicS (COSMOS): facilitating integrated metabolomics data access. AB - Metabolomics has become a crucial phenotyping technique in a range of research fields including medicine, the life sciences, biotechnology and the environmental sciences. This necessitates the transfer of experimental information between research groups, as well as potentially to publishers and funders. After the initial efforts of the metabolomics standards initiative, minimum reporting standards were proposed which included the concepts for metabolomics databases. Built by the community, standards and infrastructure for metabolomics are still needed to allow storage, exchange, comparison and re-utilization of metabolomics data. The Framework Programme 7 EU Initiative 'coordination of standards in metabolomics' (COSMOS) is developing a robust data infrastructure and exchange standards for metabolomics data and metadata. This is to support workflows for a broad range of metabolomics applications within the European metabolomics community and the wider metabolomics and biomedical communities' participation. Here we announce our concepts and efforts asking for re-engagement of the metabolomics community, academics and industry, journal publishers, software and hardware vendors, as well as those interested in standardisation worldwide (addressing missing metabolomics ontologies, complex-metadata capturing and XML based open source data exchange format), to join and work towards updating and implementing metabolomics standards. PMID- 26491420 TI - Constrained randomization and multivariate effect projections improve information extraction and biomarker pattern discovery in metabolomics studies involving dependent samples. AB - Analytical drift is a major source of bias in mass spectrometry based metabolomics confounding interpretation and biomarker detection. So far, standard protocols for sample and data analysis have not been able to fully resolve this. We present a combined approach for minimizing the influence of analytical drift on multivariate comparisons of matched or dependent samples in mass spectrometry based metabolomics studies. The approach is building on a randomization procedure for sample run order, constrained to independent randomizations between and within dependent sample pairs (e.g. pre/post intervention). This is followed by a novel multivariate statistical analysis strategy allowing paired or dependent analyses of individual effects named OPLS-effect projections (OPLS-EP). We show, using simulated data that OPLS-EP gives improved interpretation over existing methods and that constrained randomization of sample run order in combination with an appropriate dependent statistical test increase the accuracy and sensitivity and decrease the false omission rate in biomarker detection. We verify these findings and prove the strength of the suggested approach in a clinical data set consisting of LC/MS data of blood plasma samples from patients before and after radical prostatectomy. Here OPLS-EP compared to traditional (independent) OPLS-discriminant analysis (OPLS-DA) on constrained randomized data gives a less complex model (3 versus 5 components) as well a higher predictive ability (Q2 = 0.80 versus Q2 = 0.55). We explain this by showing that paired statistical analysis detects 37 unique significant metabolites that were masked for the independent test due to bias, including analytical drift and inter individual variation. PMID- 26491421 TI - Cell-type specific metabolic profiling of Arabidopsis thaliana protoplasts as a tool for plant systems biology. AB - Flow cytometry combined with cell sorting of protoplasts has previously been used successfully for transcript profiling of the Arabidopsis thaliana root. We have developed the technique further, and in this paper we present a robust and reliable method for metabolite profiling in specific cell types isolated from Arabidopsis roots. The method uses a combination of fluorescence-activated cell sorting and gas chromatography-time of flight-mass spectrometry analysis. Cortical and endodermal cells from the green fluorescent protein (GFP)-expressing enhancer trap line J0571 were analysed and compared with non-GFP-expressing cells and intact root tissue. Of the metabolites identified, several showed significant differences in concentration between cell types. Multivariate statistical analysis was used to compare metabolite patterns between cell and tissue types, showing that the patterns differed substantially. Isolation of specific cell populations combined with highly sensitive MS-analysis will be a powerful tool for future studies of plant metabolism, and can also be combined with transcript and protein profiling for in-depth analyses of cellular processes. PMID- 26491422 TI - Biomass composition: the "elephant in the room" of metabolic modelling. AB - Genome-scale stoichiometric models, constrained to optimise biomass production are often used to predict mutant phenotypes. However, for Saccharomyces cerevisiae, the representation of biomass in its metabolic model has hardly changed in over a decade, despite major advances in analytical technologies. Here, we use the stoichiometric model of the yeast metabolic network to show that its ability to predict mutant phenotypes is particularly poor for genes encoding enzymes involved in energy generation. We then identify apparently inefficient energy-generating pathways in the model and demonstrate that the network suffers from the high energy burden associated with the generation of biomass. This is tightly connected to the availability of phosphate since this macronutrient links energy generation and structural biomass components. Variations in yeast's biomass composition, within experimentally-determined bounds, demonstrated that flux distributions are very sensitive to such changes and to the identity of the growth-limiting nutrient. The predictive accuracy of the yeast metabolic model is, therefore, compromised by its failure to represent biomass composition in an accurate and context-dependent manner. PMID- 26491423 TI - LC-MS-based absolute metabolite quantification: application to metabolic flux measurement in trypanosomes. AB - Human African trypanosomiasis is a neglected tropical disease caused by the protozoan parasite, Trypanosoma brucei. In the mammalian bloodstream, the trypanosome's metabolism differs significantly from that of its host. For example, the parasite relies exclusively on glycolysis for energy source. Recently, computational and mathematical models of trypanosome metabolism have been generated to assist in understanding the parasite metabolism with the aim of facilitating drug development. Optimisation of these models requires quantitative information, including metabolite concentrations and/or metabolic fluxes that have been hitherto unavailable on a large scale. Here, we have implemented an LC MS-based method that allows large scale quantification of metabolite levels by using U-13C-labelled E.coli extracts as internal standards. Known amounts of labelled E. coli extract were added into the parasite samples, as well as calibration standards, and used to obtain calibration curves enabling us to convert intensities into concentrations. This method allowed us to reliably quantify the changes of 43 intracellular metabolites and 32 extracellular metabolites in the medium over time. Based on the absolute quantification, we were able to compute consumption and production fluxes. These quantitative data can now be used to optimise computational models of parasite metabolism. PMID- 26491424 TI - Metabolomics profiling of pre-and post-anesthesia plasma samples of colorectal patients obtained via Ficoll separation. AB - 1H NMR spectroscopy was used to investigate the metabolic consequences of general anesthesia in the plasma of two groups of patients with diagnosis for non metastatic colorectal cancer and metastatic colorectal cancer with liver metastasis, respectively. Patients were treated with etomidate or propofol, two frequently used sedation agents. Plasma samples were obtained via Ficoll separation. Here, we demonstrated that this procedure introduces a number of limitations for NMR-based metabolomics studies, due to the appearance of spurious signals. Nevertheless, the comparison of the 1H NMR metabolomic profiles of patients treated with etomidate or propofol at equipotent dose ranges was still feasible and proved that both agents significantly decrease the plasma levels of several NMR-detectable metabolites. Consequently, samples collected during anesthesia are not suitable for metabolic profiling studies aimed at patient stratification, because interpersonal variability are reduced by the overall depression of metabolites levels. On the other hand, this study showed that plasma metabolomics could represent a valuable tool to monitor the effect of different sedation agents and/or the individual metabolic response to anesthesia, providing hints for an appropriate tuning of personalized sedation procedures. In our reference groups, the metabolomic signatures were slightly different in patients anesthetized with etomidate versus propofol. The importance of standardized collection procedures and availability of exhaustive metadata of the experimental design for the accurate evaluation of the significance of the observed changes in metabolites levels are critically discussed. PMID- 26491425 TI - Gender-specific pathway differences in the human serum metabolome. AB - The susceptibility for various diseases as well as the response to treatments differ considerably between men and women. As a basis for a gender-specific personalized healthcare, an extensive characterization of the molecular differences between the two genders is required. In the present study, we conducted a large-scale metabolomics analysis of 507 metabolic markers measured in serum of 1756 participants from the German KORA F4 study (903 females and 853 males). One-third of the metabolites show significant differences between males and females. A pathway analysis revealed strong differences in steroid metabolism, fatty acids and further lipids, a large fraction of amino acids, oxidative phosphorylation, purine metabolism and gamma-glutamyl dipeptides. We then extended this analysis by a network-based clustering approach. Metabolite interactions were estimated using Gaussian graphical models to get an unbiased, fully data-driven metabolic network representation. This approach is not limited to possibly arbitrary pathway boundaries and can even include poorly or uncharacterized metabolites. The network analysis revealed several strongly gender-regulated submodules across different pathways. Finally, a gender stratified genome-wide association study was performed to determine whether the observed gender differences are caused by dimorphisms in the effects of genetic polymorphisms on the metabolome. With only a single genome-wide significant hit, our results suggest that this scenario is not the case. In summary, we report an extensive characterization and interpretation of gender-specific differences of the human serum metabolome, providing a broad basis for future analyses. PMID- 26491427 TI - A rapid method for profiling of volatile and semi-volatile phytohormones using methyl chloroformate derivatisation and GC-MS. AB - Phytohormones are central components of complex signalling networks in plants. The interplay between these metabolites, which include abscisic acid (ABA), auxin (IAA), ethylene, jasmonic acid (JA) and salicylic acid (SA), regulate plant growth and development and modulate responses to biotic and abiotic stress. Few methods of phytohormone profiling can adequately quantify a large range of plant hormones simultaneously and without the requirement for laborious or highly specialised extraction protocols. Here we describe the development and validation of a phytohormone profiling protocol, based on methyl-chloroformate derivatisation of the plant metabolites and analysis by gas chromatography/mass spectrometry (GC-MS). We describe the analysis of 11 metabolites, either plant phytohormones or intermediates of phytohormone metabolism; ABA, azelaic acid, IAA, JA and SA, and the phytohormone precursors 1-aminocyclopropane 1-carboxylic acid, benzoic acid, cinnamic acid, 13-epi-12-oxophytodienoic acid (13-epi-OPDA), linoleic acid and linolenic acid, and validate the isolation from foliar tissue of the model legume Medicago truncatula. The preparation is insensitive to the presence of water, facilitating measurement of the volatile metabolites. Quantitation was linear over four orders of magnitude, and the limits of detection between two and 10 ng/mL for all measured metabolites using a single quadrupole GC-MS. PMID- 26491426 TI - Metabolomic changes during cellular transformation monitored by metabolite metabolite correlation analysis and correlated with gene expression. AB - To investigate metabolic changes during cellular transformation, we used a 1H NMR based metabolite-metabolite correlation analysis (MMCA) method, which permits analysis of homeostatic mechanisms in cells at the steady state, in an inducible cell transformation model. Transcriptomic data were used to further explain the results. Transformed cells showed many more metabolite-metabolite correlations than control cells. Some had intuitively plausible explanations: a shift from glycolysis to amino acid oxidation after transformation was accompanied by a strongly positive correlation between glucose and glutamine and a strongly negative one between lactate and glutamate; there were also many correlations between the branched chain amino acids and the aromatic amino acids. Others remain puzzling: after transformation strong positive correlations developed between choline and a group of five amino acids, whereas the same amino acids showed negative correlations with phosphocholine, a membrane phospholipid precursor. MMCA in conjunction with transcriptome analysis has opened a new window into the metabolome. PMID- 26491428 TI - Challenges for the Modern Science in its Descend Towards Nano Scale. AB - The current rise in the interest in physical phenomena at nano spatial scale is described hereby as a natural consequence of the scientific progress in manipulation with matter with an ever higher sensitivity. The reason behind arising of the entirely new field of nanoscience is that the properties of nanostructured materials may significantly differ from their bulk counterparts and cannot be predicted by extrapolations of the size-dependent properties displayed by materials composed of microsized particles. It is also argued that although a material can comprise critical boundaries at the nano scale, this does not mean that it will inevitably exhibit properties that endow a nanomaterial. This implies that the attribute of "nanomaterial" can be used only in relation with a given property of interest. The major challenges faced with the expansion of resolution of the materials design, in terms of hardly reproducible experiments, are further discussed. It is claimed that owing to an unavoidable interference between the experimental system and its environment to which the controlling system belongs, an increased fineness of the experimental settings will lead to ever more difficulties in rendering them reproducible and controllable. Self-assembly methods in which a part of the preprogrammed scientific design is substituted with letting physical systems spontaneously evolve into attractive and functional structures is mentioned as one of the ways to overcome the problems inherent in synthetic approaches at the ultrafine scale. The fact that physical systems partly owe their properties to the interaction with their environment implies that each self-assembly process can be considered a co-assembly event. PMID- 26491429 TI - Allosteric interactions between receptor site 3 and 4 of voltage-gated sodium channels: a novel perspective for the underlying mechanism of scorpion sting induced pain. AB - BACKGROUND: BmK I, a site-3-specific modulator of voltage-gated sodium channels (VGSCs), causes pain and hyperalgesia in rats, while BmK IT2, a site-4-specific modulator of VGSCs, suppresses pain-related responses. A stronger pain-related effect has been previously attributed to Buthus martensi Karsch (BmK) venom, which points out the joint pharmacological effect in the crude venom. METHODS: In order to detect the joint effect of BmK I and BmK IT2 on ND7-23 cells, the membrane current was measured by whole cell recording. BmK I and BmK IT2 were applied successively and jointly, and the synergistic modulations of VGSCs on ND7 23 cells were detected. RESULTS: Larger peak INa and more negative half activation voltage were elicited by joint application of BmK I and BmK IT2 than by application of BmK I or BmK IT2 alone. Compared to the control, co-applied BmK I and BmK IT2 also significantly prolonged the time constant of inactivation. CONCLUSIONS: Our results indicated that site-4 toxin (BmK IT2) could enhance the pharmacological effect induced by site-3 toxin (BmK I), suggesting a stronger effect elicited by both toxins that alone usually exhibit opposite pharmacological effects, which is related to the allosteric interaction between receptor site 3 and site 4. Meanwhile, these results may bring a novel perspective for exploring the underlying mechanisms of scorpion sting-induced pain. PMID- 26491430 TI - Neural Basis of Intrinsic Motivation: Evidence from Event-Related Potentials. AB - Human intrinsic motivation is of great importance in human behavior. However, although researchers have focused on this topic for decades, its neural basis was still unclear. The current study employed event-related potentials to investigate the neural disparity between an interesting stop-watch (SW) task and a boring watch-stop task (WS) to understand the neural mechanisms of intrinsic motivation. Our data showed that, in the cue priming stage, the cue of the SW task elicited smaller N2 amplitude than that of the WS task. Furthermore, in the outcome feedback stage, the outcome of the SW task induced smaller FRN amplitude and larger P300 amplitude than that of the WS task. These results suggested that human intrinsic motivation did exist and that it can be detected at the neural level. Furthermore, intrinsic motivation could be quantitatively indexed by the amplitude of ERP components, such as N2, FRN, and P300, in the cue priming stage or feedback stage. Quantitative measurements would also be convenient for intrinsic motivation to be added as a candidate social factor in the construction of a machine learning model. PMID- 26491431 TI - Neural Cognition and Affective Computing on Cyber Language. AB - Characterized by its customary symbol system and simple and vivid expression patterns, cyber language acts as not only a tool for convenient communication but also a carrier of abundant emotions and causes high attention in public opinion analysis, internet marketing, service feedback monitoring, and social emergency management. Based on our multidisciplinary research, this paper presents a classification of the emotional symbols in cyber language, analyzes the cognitive characteristics of different symbols, and puts forward a mechanism model to show the dominant neural activities in that process. Through the comparative study of Chinese, English, and Spanish, which are used by the largest population in the world, this paper discusses the expressive patterns of emotions in international cyber languages and proposes an intelligent method for affective computing on cyber language in a unified PAD (Pleasure-Arousal-Dominance) emotional space. PMID- 26491432 TI - Impact of Spleen Size on Outcomes in Laparoscopic Splenectomy in Children. AB - Background. The aim of our study is to compare the efficacy of laparoscopic splenectomy (LS) between enlarged spleens and normal sized spleens. Methods. From June 2006 to September 2012, 50 patients underwent LS. The patients consisted of 24 girls and 26 boys with the mean age of 8.64 years (1-18). The patients are divided into two groups according to spleen's longitudinal length on the ultrasonography. Group I consisted of the normal sized spleens; Group II consisted of spleens that are exceeding the upper limit. Groups are compared in terms of number of ports, operative time, rate of conversion to open procedure, and length of hospital stay. Results. The mean number of ports was 3.27 and 3.46, the mean length of the operation was 116.36 min and 132.17 min, rate of conversion to open procedure was 9.09% and 10.25%, and the mean length of hospital stay was 3.36 days and 3.23 days, respectively, in Group I and Group II. Although there is an increase in the number of the ports, the operative time, rate of conversion to open procedure, and the length of hospital stay, the difference was not significant between groups (P > 0.05). Conclusion. LS is safe and effective in enlarged spleens as well as normal sized spleens. PMID- 26491433 TI - Transumbilical Laparoscopic-Assisted Appendectomy in the Treatment of Acute Uncomplicated Appendicitis in Children. AB - Transumbilical laparoscopic-assisted appendectomy (TULAA) is increasingly being performed worldwide. The authors report their experience in the treatment of acute uncomplicated appendicitis in children with TULAA. From January 2008 to December 2012 all types of acute appendicitis were divided, according to the clinical and ultrasonographic findings, into complicated (appendiceal mass/abscess, diffuse peritonitis) and uncomplicated. Complicated appendicitis was treated by open appendectomy (OA). All patients with the suspicion of uncomplicated appendicitis were offered TULAA by all surgeons of the team. Conversion to open or laparoscopic appendectomy (LA) was performed in case of impossibility to complete TULAA, depending on the choice of surgeon. The histopathologic examination of appendix was always performed. 444 children (252 males) with acute appendicitis were treated. The mean age was 9.2 years (range, 2 to 14 years). Primary OA was performed in 144 cases. In 300 patients a transumbilical laparoscopic-assisted approach was performed. TULAA was completed in 252 patients. Conversion to OA was performed in 45 patients and to LA in 3. Conversion was related to the impossibility to adequately expose the appendix in 47 patients and bleeding in 1. The mean operative time for TULAA was 42 minutes. Histopathologic examination of the appendix removed by TULAA showed a phlegmonous/gangrenous type in 92.8% of cases. Among the 252 TULAA there were 11 cases of umbilical wound infection. TULAA is a feasible and effective procedure for uncomplicated appendicitis in children. It combines the advantages of open and laparoscopic technique (low operative time, low complications rate, and excellent cosmetic results). PMID- 26491434 TI - Targeting AGEs Signaling Ameliorates Central Nervous System Diabetic Complications in Rats. AB - Diabetes is a chronic endocrine disorder associated with several complications as hypertension, advanced brain aging, and cognitive decline. Accumulation of advanced glycation end products (AGEs) is an important mechanism that mediates diabetic complications. Upon binding to their receptor (RAGE), AGEs mediate oxidative stress and/or cause cross-linking with proteins in blood vessels and brain tissues. The current investigation was designed to investigate the effect of agents that decrease AGEs signaling, perindopril which increases soluble RAGE (sRAGE) and alagebrium which cleaves AGEs cross-links, compared to the standard antidiabetic drug, gliclazide, on the vascular and central nervous system (CNS) complications in STZ-induced (50 mg/kg, IP) diabetes in rats. Perindopril ameliorated the elevation in blood pressure seen in diabetic animals. In addition, both perindopril and alagebrium significantly inhibited memory decline (performance in the Y-maze), neuronal degeneration (Fluoro-Jade staining), AGEs accumulation in serum and brain, and brain oxidative stress (level of reduced glutathione and activities of catalase and malondialdehyde). These results suggest that blockade of AGEs signaling after diabetes induction in rats is effective in reducing diabetic CNS complications. PMID- 26491435 TI - Informational Theory of Aging: The Life Extension Method Based on the Bone Marrow Transplantation. AB - The method of lifespan extension that is a practical application of the informational theory of aging is proposed. In this theory, the degradation (error accumulation) of the genetic information in cells is considered a main cause of aging. According to it, our method is based on the transplantation of genetically identical (or similar) stem cells with the lower number of genomic errors to the old recipients. For humans and large mammals, this method can be realized by cryopreservation of their own stem cells, taken in a young age, for the later autologous transplantation in old age. To test this method experimentally, we chose laboratory animals of relatively short lifespan (mouse). Because it is difficult to isolate the required amount of the stem cells (e.g., bone marrow) without significant damage for animals, we used the bone marrow transplantation from sacrificed inbred young donors. It is shown that the lifespan extension of recipients depends on level of their genetic similarity (syngeneity) with donors. We have achieved the lifespan increase of the experimental mice by 34% when the transplantation of the bone marrow with high level of genetic similarity was used. PMID- 26491436 TI - 17beta Estradiol Modulates Perfusion Pressure and Expression of 5-LOX and CYP450 4A in the Isolated Kidney of Metabolic Syndrome Female Rats. AB - Prevalence of metabolic syndrome and progression of nephropathy depend on sex. We examined a protective effect of estradiol against nephropathy in metabolic syndrome through the modulation of the arachidonic acid metabolism by activating the 5-lipoxygenase and cytochrome p450 4A pathways. 28 female Wistar rats were divided into four groups of seven animals each: control, intact metabolic syndrome, ovariectomized metabolic syndrome, and metabolic syndrome ovariectomized plus estradiol. Blood pressure, body weight, body fat, triglycerides, insulin, HOMA-index, albuminuria, and TNF-alpha were increased in ovariectomized metabolic syndrome rats (p < 0.001). The perfusion pressure in isolated kidneys of ovariectomized metabolic syndrome rats in presence of 4 MUg of arachidonic acid was increased. The inhibitors of the arachidonic acid metabolism Baicalein, Miconazole, and Indomethacin in these rats decreased the perfusion pressure by 57.62%, 99.83%, and 108.5%, respectively and they decreased creatinine clearance and the arachidonic acid percentage. Phospholipase A2 expression in the kidney of ovariectomized metabolic syndrome rats was not modified. 5-lipoxygenase was increased in metabolic syndrome ovariectomized rats while cytochrome p450 4A was decreased. In conclusion, the loss of estradiol increases renal damage while the treatment with estradiol benefits renal function by modulating arachidonic acid metabolism through the 5-lipoxygenase and cytochrome p450 4A pathways. PMID- 26491437 TI - Diabetes Burden in Urban and Rural Senegalese Populations: A Cross-Sectional Study in 2012. AB - Diabetes represents a challenging global health issue in the 21st century. Data from sub-Saharan African populations are scarce and are usually restricted to urban settings. The objective of this study was to compare prevalence and risk factors of diabetes in rural and urban areas in Senegal. Methods. In a community based survey between January and May 2012, we included 1027 adults aged >=18 years living in northern Senegal. Sociodemographic, clinical, and biological data were collected during household visits. Multivariate logistic regression was performed to identify factors associated with diabetes. Results. Mean age of participants was 48.0 +/- 16.9 years and 65.7% were female. Participants from urban area represented 55.7%. The age-standardized prevalence of diabetes was 7.6% (6.0% in men versus 9.0% in women). Prevalence of diabetes was higher in urban areas (8.1%) compared to rural areas (4.6%). Disease awareness rate was 43%. After multivariate analysis, age (OR = 1.63, p = 0.001), familial history of diabetes (OR = 1.42, p = 0.001), and abdominal obesity (OR = 1.17, p = 0.05) were associated with diabetes. Conclusion. Diabetes is frequent in urban and rural areas in Senegal. Awareness rate is very low among populations. Age, family history of diabetes, and abdominal obesity are the main risk factors identified. PMID- 26491438 TI - Sodium Valproate Enhances the Urethane-Induced Lung Adenomas and Suppresses Malignization of Adenomas in Ovariectomized Female Mice. AB - In the present study, the possible effect of sodium valproate (NaVP) on urethane induced lung tumors in female mice has been evaluated. BALB/c mice (n = 60; 4-6 weeks old, females) were used in the following groups: (1) urethane-treated; (2) urethane-NaVP-treated; (3) only NaVP-treated; (4) control. In the same groups, ovariectomized female mice (n = 60) were investigated. Urethane was given intraperitoneally, with a total dose of 50 mg/mouse. In NaVP-treated mice groups, 0.4% aqueous solution of NaVP was offered to mice ad libitum. The duration of the experiment was 6 months. The number of tumors per mouse in ovariectomized mice and in those treated with urethane and NaVP was significantly higher than in mice treated with urethane only (8.29 +/- 0.58 versus 6.0 +/- 0.63, p < 0.02). No significant difference in the number of tumors per mouse was revealed while comparing the nonovariectomized urethane- and urethane-NaVP-treated groups (p = 0.13). A significant decrease of adenocarcinoma number in ovariectomized mice treated with a urethane-NaVP as compared with ovariectomized mice treated with urethane only was found (p = 0.031). NaVP together with low estrogen may have a protective effect on the malignization of adenomas in ovariectomized mice. PMID- 26491439 TI - Sex/Gender Differences in Metabolism and Behavior: Influence of Sex Chromosomes and Hormones. PMID- 26491440 TI - Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis. AB - The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis. PMID- 26491442 TI - Role of Sex Hormones in the Development and Progression of Hepatitis B Virus Associated Hepatocellular Carcinoma. AB - Infection with hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC) in developed countries. Epidemiological reports indicate that the incidence of HBV-related HCC is higher in males and postmenopausal females than other females. Increasing evidence suggests that sex hormones such as androgens and estrogens play an important role in the progression of an HBV infection and in the development of HBV-related HCC. While androgen is supposed to stimulate the androgen signaling pathway and cooperate to the increased transcription and replication of HBV genes, estrogen may play a protecting role against the progression of HBV infections and in the development of HBV-related HCC through decreasing HBV RNA transcription and inflammatory cytokines levels. Additionally, sex hormones can also affect HBV-related hepatocarcinogenesis by inducing epigenetic changes such as the regulation of mRNA levels by microRNAs (miRNAs), DNA methylation, and histone modification in liver tissue. This review describes the molecular mechanisms underlying the gender disparity in HBV-related HCC with the aim of improving the understanding of key factors underneath the sex disparity often observed in HBV infections. Furthermore, the review will propose more effective prevention strategies and treatments of HBV-derived diseases. PMID- 26491441 TI - A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings. AB - Gender differences in schizophrenia have been extensively researched and it is being increasingly accepted that gonadal steroids are strongly attributed to this phenomenon. Of the various hormones implicated, the estrogen hypothesis has been the most widely researched one and it postulates that estrogen exerts a protective effect by buffering females against the development and severity of the illness. In this review, we comprehensively analyse studies that have investigated the effects of estrogen, in particular 17beta-estradiol, in clinical, animal, and molecular research with relevance to schizophrenia. Specifically, we discuss the current evidence on estrogen dysfunction in schizophrenia patients and review the clinical findings on the use of estradiol as an adjunctive treatment in schizophrenia patients. Preclinical research that has used animal models and molecular probes to investigate estradiol's underlying protective mechanisms is also substantially discussed, with particular focus on estradiol's impact on the major neurotransmitter systems implicated in schizophrenia, namely, the dopamine, serotonin, and glutamate systems. PMID- 26491444 TI - Serum Bisphenol A Level in Boys with Cryptorchidism: A Step to Male Infertility? AB - Cryptorchidism is the most common congenital birth defect in boys and affects about 2-4% full-term male neonates. Its etiology is multifactorial. Purpose. To evaluate the serum bisphenol A (BPA) levels in boys with cryptorchidism and healthy boys and to assess the risk of environmental exposure to BPA using the authors' questionnaire. The data were acquired from a study on boys with cryptorchidism (n = 98) and a control group (n = 57). Prior to surgery, all patients had BPA serum levels evaluated. The size, position, rigidity of the testis, and abnormality of the epididymis of the undescended testis were assessed. Parents also completed a questionnaire on the risks of exposure to BPA in everyday life. Results. The testes in both groups were similar in size. The turgor of the undescended testis in the group of boys with cryptorchidism was decreased. Free serum BPA level in cryptorchid boys and in the control group was not statistically significant (p > 0.05). The conjugated serum BPA level in cryptorchid boys and in the control group was statistically significant (p <= 0.05). Total serum BPA level in cryptorchid boys and in the control group was statistically significant (p < 0.05). Serum total BPA level was related with a positive answer about problems with conception (p < 0.02). Conclusion. Our study indicated that high serum BPA was associated with cryptorchidism. PMID- 26491446 TI - Oral Lesions Induced by Chronic Khat Use Consist Essentially of Thickened Hyperkeratinized Epithelium. AB - Objectives. The habit of khat chewing is prevalent in many Middle Eastern and African cultures and has been associated with various adverse conditions in humans. This study aimed to describe histological changes induced by chronic khat chewing on the buccal mucosa. Methods. Biopsies of the buccal mucosa from 14 chronic khat chewers, 20 chronic khat chewers who also smoked tobacco, and 8 nonchewers were compared for epithelial thickness, degree and type of keratinization, and connective tissue changes. Results. Tissues from khat chewers depicted abnormal keratinization of the superficial cell layer and showed increased epithelial thickness affecting all layers. Epithelial thickness in control samples was 205 +/- 26 MUm whereas thickness in khat chewers and khat chewers who smoked tobacco was significantly higher measuring 330 +/- 35 MUm and 335 +/- 19 MUm, respectively. Tissues from khat chewers also showed increased intracellular edema, increased melanin pigment deposits, and increased number of rete pegs most of which were thin and deep. Conclusions. These results show that oral lesions induced by chronic chewing of khat in the buccal mucosa present with white and brown discoloration due to increased epithelial thickness, increased keratinization, and melanin deposition. PMID- 26491443 TI - Regulation of Estrogen Receptor alpha Expression in the Hypothalamus by Sex Steroids: Implication in the Regulation of Energy Homeostasis. AB - Sex differences exist in the complex regulation of energy homeostasis that utilizes central and peripheral systems. It is widely accepted that sex steroids, especially estrogens, are important physiological and pathological components in this sex-specific regulation. Estrogens exert their biological functions via estrogen receptors (ERs). ERalpha, a classic nuclear receptor, contributes to metabolic regulation and sexual behavior more than other ER subtypes. Physiological and molecular studies have identified multiple ERalpha-rich nuclei in the hypothalamus of the central nervous system (CNS) as sites of actions that mediate effects of estrogens. Much of our understanding of ERalpha regulation has been obtained using transgenic models such as ERalpha global or nuclei-specific knockout mice. A fundamental question concerning how ERalpha is regulated in wild type animals, including humans, in response to alterations in steroid hormone levels, due to experimental manipulation (i.e., castration and hormone replacement) or physiological stages (i.e., puberty, pregnancy, and menopause), lacks consistent answers. This review discusses how different sex hormones affect ERalpha expression in the hypothalamus. This information will contribute to the knowledge of estrogen action in the CNS, further our understanding of discrepancies in correlation of altered sex hormone levels with metabolic disturbances when comparing both sexes, and improve health issues in postmenopausal women. PMID- 26491445 TI - The Past, Present, and Future in Management of Small Renal Masses. AB - Management of small renal masses (SRMs) is currently evolving due to the increased incidence given the ubiquity of cross-sectional imaging. Diagnosing a mass in the early stages theoretically allows for high rates of cure but simultaneously risks overtreatment. New consensus guidelines and treatment modalities are changing frequently. The multitude of information currently available shall be summarized in this review. This summary will detail the historic surgical treatment of renal cell carcinoma with current innovations, the feasibility and utility of biopsy, the efficacy of ablative techniques, active surveillance, and use of biomarkers. We evaluate how technology may be used in approaching the small renal mass in order to decrease morbidity, while keeping rates of overtreatment to a minimum. PMID- 26491447 TI - Evaluation of Static Friction of Polycrystalline Ceramic Brackets after Conditioning with Different Powers of Er:YAG Laser. AB - This research aimed to reduce the friction between the wire and brackets by Er:YAG laser. To measure the friction between the wires and brackets in 0 degrees and 10 degrees of wire angulations, 40 polycrystalline ceramic brackets (Hubit, South Korea) were divided into 8 study groups and irradiated by 100, 200, and 300 mj/s of Er:YAG laser power. Two groups of brackets were not irradiated. The friction between the wires and brackets was measured with universal testing machine (SANTAM) with a segment of .019 * .025 SS wire pulled out of the slot of bracket. ANOVA and t-test were used for analyzing the results. To evaluate the effect of the laser on surface morphology of the bracket, SEM evaluations were carried out. The mean frictional resistances between the brackets and wires with 0 degrees of angulation by increasing the laser power decreased compared with control group, but, in 10 degrees of angulation, the friction increased regardless of the laser power and was comparable to the friction of nonirradiated brackets. Furthermore, with each laser power, frictional resistance of brackets in 10 degrees of angulation was significantly higher than 0 degrees of angulation. These results were explained by SEM images too. PMID- 26491448 TI - Association of Awake Bruxism with Khat, Coffee, Tobacco, and Stress among Jazan University Students. AB - Objective. The objective is to assess the prevalence of bruxism among the university students and to check its association with their khat chewing habit. Materials and Methods. A cross-sectional descriptive study is designed using cluster random sampling. Pretested questionnaire was administered by a trained interviewer to assess awake bruxism and the use of variables like khat, coffee, tobacco, and stress. Chi-square test at 5% significance was used for assessing the association. Logistic regression was also performed after adjusting for covariates. Results. A high response rate (95%) was obtained as the distribution and collection of questionnaire was within an hour interval. 85% (63%, males; 22%, females) experienced an episode of bruxism at least one time in the past six months. Regression analysis revealed an association of stress (P = 0.00; OR = 5.902, 95% CI 2.614-13.325) and khat use (P = 0.05; OR = 1.629, 95% CI 0.360 7.368) with bruxism. Interestingly, it is observed that the one who chew khat experienced 3.56 times (95% CI; 2.62-11.22) less pain when compared to the nonusers. Conclusion. This study is the first of its kind to assess the association of bruxism with khat chewing. High amount of stress and khat use can be considered as important risk indicators for awake bruxism. PMID- 26491449 TI - Level of Adherence to Prophylactic Osteoporosis Medication amongst Patients with Polymyalgia Rheumatica and Giant Cell Arteritis: A Cross-Sectional Study. AB - Objective. To estimate level of adherence to oral calcium and vitamin D supplementation as well as bisphosphonate amongst patients with PMR and GCA treated with glucocorticoids. Method. A total of 138 patients with the diagnosis of PMR and/or GCA registered in our department in December 2013. In this cross sectional study we interviewed all the patients to measure level of adherence to calcium and vitamin D, as well as bisphosphonates. Results. Out of the 118 included patients, 88.9% of them were adherent to their prescription. Only 2 patients (1.7%) did not take calcium and vitamin D at all and 10 patients (8.5%) took their medication infrequently, 9 and 1 out of 10 patients took the medication 50-100% of the time and less than 50% of the prescribed dose, respectively. Sixty-one patients received additional treatment with bisphosphonate and 96.6% were adherent to this therapy. The remaining 3.4% of the patients did not take the medication at all. Forgetfulness, adverse side effects, and lack of understanding of treatment benefits were the most significant causes for nonadherence to calcium and vitamin D. Conclusions. Contrary to what we expected this study found that adherence to osteoporosis preventive medication in patients with PMR and GCA was high. PMID- 26491450 TI - The Importance of the Monitoring of Resuscitation with Blood Transfusion for Uterine Inversion in Obstetrical Hemorrhage. AB - Objective. The aim of this study was to describe critical care for obstetrical hemorrhage, especially in cases of uterine inversion. Study Design. We extracted data for six patients diagnosed with uterine inversion concerning resuscitation. Results. The shock index on admission of the six patients was 1.6 or more on admission. Four of the six experienced delay in diagnosis and received inadequate fluid replacement. Five of the six experienced delay in transfer. Five of the six underwent simultaneous blood transfusion on admission, and the remaining patient experienced a delay of 30 minutes. All six patients successfully underwent uterine replacement soon after admission. One maternal death occurred due to inappropriate practices that included delay in diagnosis, delay in transfer, inadequate fluid replacement, and delayed transfusion. Two patients experiencing inappropriate practices involving delay in diagnosis, delay in transfer, and inadequate fluid replacement survived. Conclusion. If a delay in diagnosis occurs simultaneously with a delay in transfer and inadequate fluid replacement, failure in providing a prompt blood transfusion may be critical and result in maternal death. The monitoring of resuscitation with blood transfusion for uterine inversion is essential for the improvement of obstetrical care. PMID- 26491451 TI - A Case Report of an Atypical Presentation of IgG4-Related Disease and Idiopathic CD4 Lymphocytopenia. AB - The IgG4-related disease is a fibroinflammatory disease characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and, often but not always, elevated serum levels of IgG4. Idiopathic CD4 lymphocytopenia is a heterogenic and rare syndrome characterized by the detection of a persistent absolute CD4 T cells count <300 cells/mm(3) (or <20% of total T cells) in more than one occasion and no evidence of HIV infection in absence of immunodeficiency or therapy associated with depressed levels of CD4 T cells. We report the case of a 50-year-old man with a multiorgan IgG4-related disease presenting in a temporal association with a profound and symptomatic idiopathic CD4 lymphocytopenia. Both clinical pictures improved after steroid treatment. Idiopathic CD4 lymphocytopenia has been associated with a number of autoimmune conditions but, to the best of our knowledge, this is the first case in which an association with the IgG4-related disease is reported. PMID- 26491452 TI - The Cutaneous Ciliated Cyst in Young Male: The Possibility of Ciliated Cutaneous Eccrine Cyst. AB - Cutaneous ciliated cyst was described as a painless cyst occurring on the lower limbs of women between the ages of 15 and 30 years. The cysts are typically lined by ciliated cuboidal to columnar epithelium with pseudostratified areas and focal squamous metaplasia is occasionally present. Immunohistochemical studies have demonstrated that the cysts are PR and ER positive, similar to the epithelia of the fallopian tubes. However, outliers of cutaneous ciliated cysts, including those in male patients and in unexpected locations such as the scalp, finger, and scapular area, have been reported. Thus, some hypotheses have been proposed including the Mullerian heterotopias, ciliated metaplasia of eccrine sweat glands, and embryonic remnants of the cloacal membrane. We report a rare case of cutaneous ciliated cyst on the left shoulder of a 7-year-old boy and this is the eighth case of cutaneous ciliated cyst in male patients. Moreover, through reviewing the articles, we try to propose the classification of the cutaneous ciliated cysts into the cutaneous Mullerian cysts and the ciliated cutaneous eccrine cysts. PMID- 26491453 TI - Mycological Pattern of Dermatomycoses in a Tertiary Care Hospital. AB - Background. Dermatomycoses are not diseases requiring compulsory notifications; rather they cause cosmetic defacements. Indian subcontinent with a varied topography is favorable for various fungal infections. Objective. To look for the epidemiological and mycological profile of superficial mycoses in North India. Methods. Three hundred and fifty-one clinical samples of skin, hair, and nail were examined to find the fungal etiology of the dermatomycoses. Results. Dermatomycoses were seen in 215/351 (61.2%) of cases. Most common isolates obtained were nondermatophyte molds (NDMs) (36.1%), followed by dermatophytes (13.8%) and yeasts (8.6%). Aspergillus niger (9%) was the most common mold. Trichophyton rubrum (4.6%) was the most common dermatophyte isolated, while amongst the yeasts Non-albicans Candida (NAC) species were more common (6%). Many other NDMs like Syncephalastrum spp., Cunninghamella spp., Rhodotorula spp., A. terreus, Scytalidium spp. and Scopulariopsis spp. were also isolated. Conclusion. Our study reflects an increasing role of NDMs (thought to be normal laboratory or environmental contaminants) as a causative agent of dermatomycoses, replacing the dermatophytes. Clinician's awareness of the demographic profile of the population involved along with more studies on dermatomycoses can help in understanding the etiological profile in area, leading to prevention of disease occurrence and cosmetic disfigurement. PMID- 26491454 TI - Clinical Presentation, Aetiology, and Outcomes of Meningitis in a Setting of High HIV and TB Prevalence. AB - Meningitis causes significant morbidity and mortality globally. The aim of this study was to study the clinical presentation, aetiology, and outcomes of meningitis among adult patients admitted to Queen Mamohato Memorial Hospital in Maseru, Lesotho, with a diagnosis of meningitis. A cross-sectional study was conducted between February and April 2014; data collected included presenting signs and symptoms, laboratory results, and clinical outcomes. Descriptive statistics were used to summarise data; association between variables was analysed using Fisher's exact test. 56 patients were enrolled; the HIV coinfection rate was 79%. The most common presenting symptoms were altered mental status, neck stiffness, headache, and fever. TB meningitis was the most frequent diagnosis (39%), followed by bacterial (27%), viral (18%), and cryptococcal meningitis (16%). In-hospital mortality was 43% with case fatalities of 23%, 40%, 44%, and 90% for TB, bacterial, cryptococcal, and viral meningitis, respectively. Severe renal impairment was significantly associated with mortality. In conclusion, the causes of meningitis in this study reflect the high prevalence of HIV and TB in our setting. Strategies to reduce morbidity and mortality due to meningitis should include improving diagnostic services to facilitate early detection and treatment of meningitis and timely initiation of antiretroviral therapy in HIV-infected patients. PMID- 26491455 TI - Prevalence of Intestinal Protozoa among Saudi Patients with Chronic Renal Failure: A Case-Control Study. AB - It has been hypothesized that chronic renal failure (CRF) predisposes patients to infection with intestinal protozoa. We tested this hypothesis with a matched case control study to determine the prevalence of these protozoa and their diarrhea associated symptoms among 50 patients with CRF (cases) from Taif, western Saudi Arabia. Fifty diarrheal patients without CRF were recruited in the study as controls. Participants were interviewed by a structured questionnaire and stool samples were collected. Samples were thoroughly examined with microscopy and three coproantigens detection kits. Enteric protozoa were detected in 21 cases and 14 controls. Blastocystis spp. were the most predominant parasite (16% in cases versus 8% in controls), followed by Giardia duodenalis (10% in cases versus 12% in controls) and Cryptosporidium spp. (10% in cases versus 6% in controls). Cyclospora cayetanensis was identified in two cases, while Entamoeba histolytica was described in one case and one control. Intestinal parasitism was positively associated with the male gender, urban residence, and travel history. Clinical symptoms of nausea/vomiting and abdominal pain were significantly varied between the parasitized cases and controls (P value <= 0.05). Given the results, we recommend screening all diarrheal feces for intestinal protozoa in the study's population, particularly those with CRF. PMID- 26491456 TI - Amodiaquine and Ciprofloxacin Combination in Plasmodiasis Therapy. AB - Objective. The study was designed to determine the efficacy of combined Amodiaquine and Ciprofloxacin in plasmodiasis therapy. Method. The in vivo antiplasmodial effect of different dosage levels of Amodiaquine, Ciprofloxacin, and their combinations against Plasmodium berghei berghei was evaluated using Swiss albino mice. Results. Amodiaquine (a known antiplasmodial agent) had a fairly significant antiplasmodial effect reducing the parasites for every 100 red blood cells (RBC) from 66 to 16 (75.75%) at the tolerable dosage level of 7.5 mg/kg body weight while Ciprofloxacin (an antibiotic known to have antimalarial effect) showed an insignificant antiplasmodial effect reducing the parasites for every 100 RBC from 65 to 64 (1.53%) at the tolerable dosage level of 10.7 mg/kg body weight. Conversely, the combination therapy of Amodiaquine and Ciprofloxacin had a significant antiplasmodial effect at all the doses administered. The combination of 7.5 mg/kg of Amodiaquine and 12.8 mg/kg of Ciprofloxacin, however, showed the most significant antiplasmodial effect of the doses used reducing the number of parasites per 100 RBC from 60 to 10 (83.33%). Conclusions. Appropriate Amodiaquine and Ciprofloxacin combination will be effective for the treatment of malaria and better than either Amodiaquine or Ciprofloxacin singly at their recommended dosage levels. PMID- 26491457 TI - Perceptions of Yoga Therapy Embedded in Two Inpatient Rehabilitation Hospitals: Agency Perspectives. AB - Inpatient medical rehabilitation has maintained a typical medical-model focus and structure for many years. However, as integrative therapies, such as yoga therapy, emerge as treatments which can enhance the physical and mental health of its participants, it is important to determine if they can be easily implemented into the traditional rehabilitation structure and milieu. Therefore, the purpose of this study was to examine the perceptions of key agency personnel on the feasibility and utility of yoga therapy implemented in inpatient rehabilitation. This study reports the results of focus groups and an individual interview with key stakeholders (administrators and rehabilitation therapists) from two rehabilitation hospitals following the implementation of yoga therapy. Results focused on several key themes: feasibility from the therapist and administrator perspectives, challenges to implementation, and utility and benefit. Overall, the implementation and integration of yoga therapy were positive; however, some programmatic and policy and organizational considerations remain. Implications for practice and future research are provided. PMID- 26491458 TI - Short-Term Effects of Kinesio Taping and Cross Taping Application in the Treatment of Latent Upper Trapezius Trigger Points: A Prospective, Single-Blind, Randomized, Sham-Controlled Trial. AB - Kinesio taping (KT) may be a new treatment in patients with myofascial trigger points (MTrPs). A new method available for taping practitioners is cross taping (CT). The main objective was to determine how CT, KT, and medical adhesive tape (sham group) affect the subjective assessment of resting bioelectrical activity and pain of the upper trapezius muscle (UT) in patients with MTrPs. 105 volunteers were recruited to participate. The primary outcome was resting bioelectrical activity of UT muscle as assessed by surface electromyography (sEMG) in each group and pain intensity on a visual analog scale (VAS). Assessments were collected before and after intervention and after the 24-hours follow-up. No significant differences were observed in bioelectrical activity of UT between pre-, post-, and follow-up results. In three groups patients had significantly lower pain VAS score after the intervention (CT-p < 0.001, KT-p < 0.001, and sham-p < 0.01). The Kruskal-Wallis ANOVA showed no significant differences in almost all measurements between groups. The application of all three types of tapes does not influence the resting bioelectrical activity of UT muscle and may not lead to a reduction in muscle tone in the case of MTrPs. PMID- 26491459 TI - Danhong Promotes Angiogenesis in Diabetic Mice after Critical Limb Ischemia by Activation of CSE-H 2 S-VEGF Axis. AB - The aim of this paper is to investigate effect and mechanism of Danhong injection (DH) on angiogenesis in the diabetic hind limb ischemia mouse model. Thirty diabetic hind limb ischemic model mice and ten normal mice, established by intraperitoneal (i.p.) injection of streptozotocin (STZ) or PBS and ligation/excision of femoral artery, and then twenty diabetic hind limb ischemic model mice of all were evenly randomized to saline (control, n = 10) and DH i.p. injection (2 mL/kg weight for 7 days, n = 10) groups. Limb perfusion recovery and femoral blood hydrogen sulfide (H2S) and vessel regeneration and lower limb vascular endothelial growth factor (VEGF)/cystathionine gamma-lyase (CSE) expression were evaluated during intervention and after euthanasia, respectively. DH i.p. increased ischemic limb perfusion and promoted collateral circulation generation without decreasing blood glucose level. Increased local CSE-H2S-VEGF expression contributed to beneficial effects of DH injection. In conclusion, activation of local CSE-H2S-VEGF axis might participate in proangiogenesis effects of DH injection in diabetic hind limb ischemia model mice, suggesting a potential therapy for diabetic patients with critical limb ischemia. PMID- 26491460 TI - The Expression Patterns of c-Fos and c-Jun Induced by Different Frequencies of Electroacupuncture in the Brain. AB - To investigate patterns of c-Fos and c-Jun expression induced by different frequencies of electroacupuncture (EA) in the brain, goats were stimulated by EA of 0, 2, 60, or 100 Hz at a set of "Baihui, Santai, Ergen, and Sanyangluo" points for 30 min. The pain threshold was measured using the potassium iontophoresis method. The levels of c-Fos and c-Jun were determined with Streptavidin-Biotin Complex immunohistochemistry. The results showed that the pain threshold induced by 60 Hz was 82.2% higher (P < 0.01) than that by 0, 2, or 100 Hz (6.5%, 35.2%, or 40.9%). EA induced increased c-Fos and c-Jun expression in most analgesia related nuclei and areas in the brain. Sixty Hz EA increased more c-Fos or c-Jun expression than 2 Hz or 100 Hz EA in all the measured nuclei and areas except for the nucleus accumbens, the area septalis lateralis, the caudate nucleus, the nucleus amygdala basalis, and the locus coeruleus, in which c-Fos or c-Jun expressions induced by 60 Hz EA did not differ from those by 2 Hz or 100 Hz EA. It was suggested that 60 Hz EA activated more extensive neural circuits in goats, which may contribute to optimal analgesic effects. PMID- 26491461 TI - Are There Benefits from Teaching Yoga at Schools? A Systematic Review of Randomized Control Trials of Yoga-Based Interventions. AB - Introduction. Yoga is a holistic system of varied mind-body practices that can be used to improve mental and physical health and it has been utilized in a variety of contexts and situations. Educators and schools are looking to include yoga as a cost-effective, evidence-based component of urgently needed wellness programs for their students. Objectives. The primary goal of this study was to systematically examine the available literature for yoga interventions exclusively in school settings, exploring the evidence of yoga-based interventions on academic, cognitive, and psychosocial benefits. Methods. An extensive search was conducted for studies published between 1980 and October 31, 2014 (PubMed, PsycInfo, Embase, ISI, and the Cochrane Library). Effect size analysis, through standardized mean difference and Hedges'g, allowed for the comparison between experimental conditions. Results and Conclusions. Nine randomized control trials met criteria for inclusion in this review. Effect size was found for mood indicators, tension and anxiety in the POMS scale, self esteem, and memory when the yoga groups were compared to control. Future research requires greater standardization and suitability of yoga interventions for children. PMID- 26491462 TI - Alleviation of Carbon-Tetrachloride-Induced Liver Injury and Fibrosis by Betaine Supplementation in Chickens. AB - Betaine is a food component with well-reported hepatoprotection effects. However, the effects and mechanisms of betaine on liver fibrosis development are still insufficient. Because metabolic functions of chicken and human liver is similar, we established a chicken model with carbon Tetrachloride- (CCl4-) induced fibrosis for studying antifibrotic effect of betaine in vivo and in vitro. Two week-old male chicks were supplemented with betaine (1%, w/v) in drinking water for 2 weeks prior to the initiation of CCl4 treatment (i.p.) until sacrifice. Primary chicken hepatocytes were treated with CCl4 and betaine to mimic the in vivo supplementation. The supplementation of betaine significantly alleviated liver fibrosis development along with the inhibition of lipid peroxidation, hepatic inflammation cytokine, and transforming growth factor-beta1 expression levels. These inhibitive effects were also accompanied with the attenuation of hepatic stellate cell activation. Furthermore, our in vitro studies confirmed that betaine provides antioxidant capacity for attenuating the hepatocyte necrosis by CCl4. Altogether, our results highlight the antioxidant ability of betaine, which alleviates CCl4-induced fibrogenesis process along with the suppression of hepatic stellate cells activation. Since betaine is a natural compound without toxicity, we suggest betaine can be used as a potent nutritional or therapeutic factor for reducing liver fibrosis. PMID- 26491463 TI - A Bio-Guided Fractionation to Assess the Inhibitory Activity of Calendula officinalis L. on the NF-kappaB Driven Transcription in Human Gastric Epithelial Cells. AB - Calendula officinalis L. has been largely known for its topical anti-inflammatory properties; however, there are no experimental evidences about its antiphlogistic effect at the gastric level. To investigate whether marigold might exert an activity against gastric inflammation, a CH2Cl2 extract obtained from C. officinalis flowers was evaluated in vitro on the NF-kappaB pathway. The lipophilic extract demonstrated a significant inhibitory effect on the NF-kappaB driven transcription. The identification of active compounds was conducted by a bio-guided fractionation of the extract that afforded 16 fractions. Fraction J exhibited a concentration-dependent inhibitory activity on the NF-kappaB driven transcription and significantly contributed to the antiphlogistic effect showed by CH2Cl2 extract. The main components of fraction J were loliolide and the fucoside acetates of beta-eudesmol and viridiflorol. HPLC analysis of fractions D and E led to the identification and isolation of triterpene esters that showed a concentration-dependent inhibition of the NF-kappaB driven transcription, with faradiol-3-myristate and the corresponding aglycone being the most active compounds. The present study provides some experimental evidences that Calendula officinalis L. may exert an anti-inflammatory activity on the gastric district by the inhibition of the NF-kappaB system, identifying the compounds responsible, at least in part, for the observed effect. PMID- 26491464 TI - EEG Signals Analysis Using Multiscale Entropy for Depth of Anesthesia Monitoring during Surgery through Artificial Neural Networks. AB - In order to build a reliable index to monitor the depth of anesthesia (DOA), many algorithms have been proposed in recent years, one of which is sample entropy (SampEn), a commonly used and important tool to measure the regularity of data series. However, SampEn only estimates the complexity of signals on one time scale. In this study, a new approach is introduced using multiscale entropy (MSE) considering the structure information over different time scales. The entropy values over different time scales calculated through MSE are applied as the input data to train an artificial neural network (ANN) model using bispectral index (BIS) or expert assessment of conscious level (EACL) as the target. To test the performance of the new index's sensitivity to artifacts, we compared the results before and after filtration by multivariate empirical mode decomposition (MEMD). The new approach via ANN is utilized in real EEG signals collected from 26 patients before and after filtering by MEMD, respectively; the results show that is a higher correlation between index from the proposed approach and the gold standard compared with SampEn. Moreover, the proposed approach is more structurally robust to noise and artifacts which indicates that it can be used for monitoring the DOA more accurately. PMID- 26491465 TI - A Comparison of Theory-Based and Experimentally Determined Myocardial Signal Intensity Correction Methods in First-Pass Perfusion Magnetic Resonance Imaging. AB - OBJECTIVES: To evaluate the impact of correcting myocardial signal saturation on the accuracy of absolute myocardial blood flow (MBF) measurements. MATERIALS AND METHODS: We performed 15 dual bolus first-pass perfusion studies in 7 dogs during global coronary vasodilation and variable degrees of coronary artery stenosis. We compared microsphere MBF to MBF calculated from uncorrected and corrected MRI signal. Four correction methods were tested, two theoretical methods (Th1 and Th2) and two empirical methods (Em1 and Em2). RESULTS: The correlations with microsphere MBF (n = 90 segments) were: uncorrected (y = 0.47x + 1.1, r = 0.70), Th1 (y = 0.53x + 1.0, r = 0.71), Th2 (y = 0.62x + 0.86, r = 0.73), Em1 (y = 0.82x + 0.86, r = 0.77), and Em2 (y = 0.72x + 0.84, r = 0.75). All corrected methods were not significantly different from microspheres, while uncorrected MBF values were significantly lower. For the top 50% of microsphere MBF values, flows were significantly underestimated by uncorrected SI (31%), Th1 (25%), and Th2 (19%), while Em1 (1%), and Em2 (9%) were similar to microsphere MBF. CONCLUSIONS: Myocardial signal saturation should be corrected prior to flow modeling to avoid underestimation of MBF by MR perfusion imaging. PMID- 26491466 TI - Climate change mitigation effect of harvested wood products in regions of Japan. AB - BACKGROUND: Harvested wood products (HWPs) mitigate climate change through carbon storage, material substitution, and energy substitution. We construct a model to assess the overall climate change mitigation effect (comprising the carbon storage, material substitution, and energy substitution effects) resulting from HWPs in regions of Japan. The model allows for projections to 2050 based on future scenarios relating to the domestic forestry industry, HWP use, and energy use. RESULTS: Using the production approach, a nationwide maximum figure of 2.9 MtC year-1 for the HWP carbon storage effect is determined for 2030. The maximum nationwide material substitution effect is 2.9 MtC year-1 in 2050. For the energy substitution effect, a nationwide maximum projection of 4.3 MtC year-1 in 2050 is established, with at least 50 % of this figure derived from east and west Japan, where a large volume of logging residue is generated. For the overall climate change mitigation effect, a nationwide maximum projection of 8.4 MtC year-1 in 2050 is established, equivalent to 2.4 % of Japan's current carbon dioxide emissions. CONCLUSIONS: When domestic roundwood production and HWP usage is promoted, an overall climate change mitigation effect is consistently expected to be attributable to HWPs until 2050. A significant factor in obtaining the material substitution effect will be substituting non-wooden buildings with wooden ones. The policy of promoting the use of logging residue will have a significant impact on the energy substitution effect. An important future study is an integrated investigation of the climate change mitigation effect for both HWPs and forests. PMID- 26491467 TI - A comparative study of electrochemical oxidation of methidation organophosphorous pesticide on SnO2 and boron-doped diamond anodes. AB - BACKGROUND: Electrochemical oxidation considered to be among the best methods in waste water desalination and removing toxic metals and organic pesticides from wastewater like Methidathion. The objective of this work is to study the electrochemical oxidation of aqueous wastes containing Methidathion using boron doped diamond thin-film electrodes and SnO2, and to determine the calculated partial charge and frontier electron density parameters. RESULTS: Electrolysis parameters such as current density, temperature, supporting electrolyte (NaCl) have been optimized. The influences of the electrode materials on methidathion degradation show that BDD is the best electrode material to oxidize this pesticide organophosphorous. Energetic cost has been determinate for all experiments. The results provide that 2 % of NaCl, 60 mA cm(-2) and 25 oC like the optimized values to carry out the treatment. For BDD the achieved Chemical Oxidation Demand reduction was about 85 %, while for SnO2 it was about 73 %. The BDD anode appears to be the more promising one for the effective electrochemical treatment of methidathion. Finally the theoretical calculation was done by using the calculation program Gaussian 03W, they are a permit to identify the phenomena engaged near the electrode and to completely determine the structures of the products of electrochemical oxidation formed during the degradation and which they are not quantifiable in experiments because of their high reactivity. CONCLUSIONS: The comparison of the results relating to the two electrodes indicates that these materials have a power to reduce the quantity of the organic matter in the electrolyzed solution. But the speed of oxidation of these compounds is different according to the materials of the electrodes used. Graphical abstract:Structural of methidathion [O,O-dimethyl-S-(5-methoxy-1,3,4 thiadiazolinyl-3-methyl) dithiophosphate] used for study the electrochemical oxidation. PMID- 26491468 TI - Synthesis and antibacterial and antifungal activities of N-(tetra-O-acetyl-beta-d glucopyranosyl)thiosemicarbazones of substituted 4-formylsydnones. AB - BACKGROUND: Sydnone is a heterocycle that exhibits remarkable pharmacological activities, including antimicrobial, anti-inflammatory, analgesic, antipyretic and antioxidant activities. Thiosemicarbazones are of compounds that contain the NHCSNHN=C< linkage group and are considerable interest because they exhibit important chemical properties and potentially beneficial biological activities. Similarly, thiosemicarbazones having carbohydrate moieties also exhibit various significant biological activities. RESULTS: The compounds of 3-formyl-4 phenylsydnones were obtained by Vilsmeyer-Haack's formylation reaction and were transformed into thiosemicarbazones by condensation reaction with N-(2,3,4,6 tetra-O-acetyl-beta-d-glucopyranosyl)thiosemicarbazide. Reaction were performed in the presence glacial acetic acid as catalyst using microwave-assisted heating method. Reaction yields were 43-85 %. The antimicrobial activities of these thiosemicarbazones were screened in vitro by using agar well diffusion and MIC methods. Among these thiosemicarbazones, compounds 4k, 4l, 4m and 4n were more active against all tested bacterial strains, especially against S. epidermidis, B. subtilis and E. coli. The MIC values in these cases are 0.156, 0.156 and 0.313 MUg/mL, respectively. All compounds showed weak to moderate antifungal activity against C. albicans and A. niger than nystatin (MIC = 0.156-0.625 MUg/mL vs. MIC = 0.078 MUg/mL of nystatin), and thiosemicarbazones 4l, 4m and 4n exhibited significant activity with MIC = 0.156 MUg/mL. These compounds also had good antifungal activity against F. oxysporum similarly to nystatin (MIC = 0.156 MUg/mL). Among the tested compounds having halogen group 4k, 4l, 4m and 4n showed highest activity against three strains of fungal organisms. CONCLUSIONS: In summary, we have developed a clean and efficient methodology for the synthesis of novel thiosemicarbazone derivatives bearing sydnone ring and d-glucose moiety; the heterocyclic and monosaccharide system being connected via -NH-C(=S)NH-N=C< linker using molecular modification approach. The methodology could be further extended and used for the synthesis of other thiosemicarbazones of biological importance. 4-Formyl-3-arylsydnone N-(2,3,4,6-tetra-O-acetyl-beta-d glucopyranosyl)thiosemicarbazones have been synthesized under microwave-assisted heating conditions. Almost all obtained compounds showed remarkable activities against the tested microorganisms. Among the tested compounds having halogen group 4k, 4l, 4m and 4n showed highest activity against all tested strains of bacterial and fungal organisms. Graphical abstract:Synthesis and antibacterial and antifungal activities of N-(tetra-O-acetyl-beta-D glucopyranosyl)thiosemicarbazones of substituted 4-formylsydnones. PMID- 26491470 TI - Bonebridge Bone Conduction Implant. PMID- 26491469 TI - Site-selective Characterization of Src Homology 3 Domain Molecular Recognition with Cyanophenylalanine Infrared Probes. AB - Local heterogeneity of microenvironments in proteins is important in biological function, but difficult to characterize experimentally. One approach is the combination of infrared (IR) spectroscopy and site-selective incorporation of probe moieties with spectrally resolved IR absorptions that enable characterization within inherently congested protein IR spectra. We employed this method to study molecular recognition of a Src homology 3 (SH3) domain from the yeast protein Sho1 for a peptide containing the proline-rich recognition sequence of its physiological binding partner Pbs2. Nitrile IR probes were introduced at four distinct sites in the protein by selective incorporation of p cyanophenylalanine via the amber codon suppressor method and characterized by IR spectroscopy. Variation among the IR absorption bands reports on heterogeneity in local residue environments dictated by the protein structure, as well as on residue-dependent changes upon peptide binding. The study informs on the molecular recognition of SH3 Sho1 and illustrates the speed and simplicity of this approach for characterization of select microenvironments within proteins. PMID- 26491471 TI - Oral Lesions in Elderly Patients in Referral Centers for Oral Lesions of Bahia. AB - Introduction The aging population phenomenon is occurring on a global scale; aging affects all of the structures of organisms, including the oral cavity. Objective To estimate the frequency of oral lesions, according to the clinical and histopathologic diagnoses, and to describe the sociodemographic profile of the elderly treated at the referral centers of oral lesions of public universities in Bahia, Brazil. Methods A descriptive epidemiologic study with transverse characteristics was conducted with elderly patients between August 2010 and January 2012. A form was used to collect data. The descriptive analysis consisted of calculating the simple and relative frequencies of sociodemographic variables and oral lesions. Results The population was predominantly black women, and the minority of elderly people were retired. Fibroid (13%) and squamous cell carcinoma (145%) were more prevalent clinical diagnoses, with squamous cell carcinoma (30.7%) and fibrous hyperplasia more prevalent histopathologic diagnoses. Conclusion A prevention policy needs to be implemented to reduce new cases of oral lesions in Bahia, Brazil and to aid in early diagnosis and appropriate treatment of oral lesions. PMID- 26491472 TI - Orofacial Praxis Abilities in Children with Speech Disorders. AB - Introduction Phonological development occurs in a gradual manner until the age of 7 years. The phonological system is constructed in a similar way for all children, despite presenting some variations in terms of age, paths taken, or repair strategies used. Objective To compare the orofacial praxis abilities of children with typical phonological development (DFT), children with phonetic phonological impairment (DFoFe), and children with phonological impairment (DF), using two tests to assess the orofacial praxis abilities. Methods The sample consisted of 82 subjects between 4 and 8 years of age who attended public schools (from preschool to the second year of secondary school) in the city of Santa Maria, Brazil. Of these, 29 were diagnosed with DFT, 29 with DF, and 24 with DFoFe; much of this sample was male. Two tests of praxis abilities and assessment of the stomatognathic system were administered. Statistical analysis was performed using the chi-square test, with a significance level of 5%. Results Generally children with DFoFe underperformed in tests of praxis when compared with subjects with DF and DFT. Conclusion The results showed that children with DFoFe have more difficulty in orofacial praxis abilities than subjects in the other groups studied. This result could be expected, because subjects with DFoFe show changes in both phonetic and phonological levels of speech. PMID- 26491473 TI - Is There a Possible Association between Dietary Habits and Benign Paroxysmal Positional Vertigo in the Elderly? The Importance of Diet and Counseling. AB - Introduction Poor diet habits and inadequate intake of nutrients are a concern in the elderly. Nutritional education with guidance may improve the results of the treatment of vertigo. Objective Evaluate the presence of benign paroxysmal positional vertigo (BPPV) associated with feeding habits. Methods Cross-sectional study with elderly people living independently. We evaluated nutritional habits through the method of dietary 24-hour recall and manipulation of Dix-Hallpike. Results Based on a sample of 487 individuals, 117 had BPPV. Among the 117 elderly patients with BPPV, 37 (31.62%) had inadequate feeding. From those 370 individuals without BPPV, 97 (26.21%) had inappropriate feeding. No significant association between nutritional habits and BPPV in the total population was observed (p = 0.3064). However, there was significant relation between BPPV and inadequate carbohydrate intake (p = 0.0419) and insufficient fiber intake (p = 0.03), and the diet of these subjects was rich in polyunsaturated fatty acids (p = 0.0084). Conclusion These data correlate with the dyslipidemia and hypertriglyceridemia status, making it extremely important to reduce the intake of fats and carbohydrates and increase the fiber intake to stabilize triglycerides and thus minimize harmful effects on the inner ear. Food readjustment is suggested in patients with BPPV, along with the work of a multidisciplinary team to improve the quality of the elderly. PMID- 26491474 TI - The Efficacy of Nasal Steroids in Treatment of Otitis Media with Effusion: A Comparative Study. AB - Introduction Otitis media with effusion (OME) continues to be an important pediatric clinical problem, and more studies are needed to decide the proper treatment for it. Objective To assess the efficacy of nasal steroids in the management of OME by comparing its results with that of oral steroid and that of nasal saline spray as placebo. Methods This study was carried on 60 patients with OME who were divided into three groups: in group 1, 20 patients received mometasone furoate spray, one puff in each nostril daily, for 3 months; in group 2, 20 patients received oral prednisolone, 5 mg three times per day for the first 3 weeks; in group 3, 20 patients received nasal saline spray, one puff in each nostril daily for 3 months. Results A highly significant difference between systemic or topical (nasal spray) steroid therapy and saline nasal spray was detected (p < 0.001), and the difference between systemic and topical steroid was nonsignificant (p > 0.05). Conclusion Nasal steroid spray can be used as an effective treatment for OME, giving a significant result similar to systemic steroid. Further studies are needed to investigate its use for longer duration and in recurrent cases. PMID- 26491475 TI - Aspects of Oral Language, Speech, and Written Language in Subjects with Temporal Lobe Epilepsy of Difficult Control. AB - Introduction About 50 million people have epilepsy and 30% of them have epilepsy that does not respond to properly conducted drug treatment. Objective Verify the incidence of language disorders in oral language, speech, and written language of subjects with difficult to control temporal lobe epilepsy (TLE) and compare the occurrence of these disorders in subjects before and after surgery. Methods Cross sectional study with quantitative analysis, exploratory type. A questionnaire for data collection was administered covering the following aspects: oral language, speech complaints, and writing production and comprehension. Criteria for inclusion of subjects were a diagnosis of TLE refractory to drug treatment and at least 4 years of schooling. Results The sample of 63 patients with TLE was divided into two groups: presurgical (n = 31) and postsurgical (n = 32). In the postsurgical group, there was a higher frequency of left lobectomy (75%) than right (25%). Conclusion Statistical analysis was performed with the chi-square test (significance level of 0.05). Complaints related to speech-language attention were more predominant in postsurgical subjects. Analysis of oral language, speech, and written language in subjects with epilepsy who underwent temporal lobectomy or not showed findings consistent with symptoms related to transient aphasia, with the presence of paraphasias, as well as changes in speech prosody and melody. These symptoms appeared more associated with recurrence after having a temporal lobectomy. PMID- 26491476 TI - Open and Endoscopic Management of Fourth Branchial Pouch Sinus - Our Experience. AB - Introduction Acute suppurative neck infections associated with third or fourth branchial arch fistulas are frequently recurrent. Third and fourth branchial arch anomalies are much less common and usually present with recurrent left thyroid lobe abscesses. Objectives The authors present their experience in treating such cases that were observed exclusively in children. Methods The study involved performing a retrospective review of five cases in PSG Institute of Medical Sciences & Research. All cases were evaluated radiologically and with Direct Rigid hypopharyngoscopy. Definitive surgery was performed, including hemithyroidectomy. Results The patients consisted of five children, two boys and three girls. All of them presented with recurrent episodes of neck infection. Investigations performed included computed tomography (CT) fistulography, rigid hypopharyngoscopy and ultrasound, which were useful in preoperatively delineating pyriform sinus fistulous tract. All patients underwent neck exploration with excision of the fistulous tract and hemithyroidectomy. Upon follow-up, all patients are asymptomatic. Conclusions Recurrent neck abscesses in a child should alert the clinician to the possibility of a fourth branchial arch anomaly; therefore, children with this condition require a complete evaluation so the anomaly can be ruled out. PMID- 26491477 TI - Open Reduction and Internal Fixation of Mandibular Fracture without Rigid Maxillomandibular Fixation. AB - Introduction The ability to treat fracture with open reduction and internal fixation (OR/IF) has dramatically revolutionized the approach to mandible fracture. With OR/IF, the postoperative role of rigid maxillomandibular fixation (MMF) has declined, but it is used to maintain proper occlusion until internal fixation of the fracture is achieved. Objective To assess intraoperative manual MMF during OR/IF of selected cases of mandibular fractures. Methods This prospective study was conducted on 80 patients with isolated mandibular fractures managed by OR/IF using two titanium miniplates. The patients were classified into two groups: a control group (40 patients) treated by OR/IF after intraoperative rigid MMF followed by immediate MMF removal, and a study group (40 patients) treated by rigid MMF, which was replaced by temporary intraoperative manual MMF (3MF) until plate fixation. Results There were no significant differences of the postoperative complication and dental occlusion, although a highly significant reduction of operative time was achieved in the 3MF group. Patient who received the 3MF technique had statistically significantly better average intrinsic vertical mouth opening in the early postoperative period (1 week after surgery), and normal mouth opening could be achieved in all cases in both groups 8 weeks after surgery. Conclusions Intraoperative rigid MMF is not mandatory and can be replaced in selected cases of fracture mandible by manual maintenance of proper dental occlusion until hardware fixation, gaining the advantages of shorter operative time and less risk of blood-transmitted diseases to the surgical team and the patient in addition to the benefits of immediate postoperative mandible mobilization. PMID- 26491478 TI - Sternocleidomastoid Muscle Flap after Parotidectomy. AB - Introduction Most patients after either superficial or total parotidectomy develop facial deformity and Frey syndrome, which leads to a significant degree of patient dissatisfaction. Objective Assess the functional outcome and esthetic results of the superiorly based sternocleidomastoid muscle (SCM) flap after superficial or total parotidectomy. Methods A prospective cohort study for 11 patients subjected to parotidectomy using a partial-thickness superiorly based SCM flap. The functional outcome (Frey syndrome, facial nerve involvement, and ear lobule sensation) and the esthetic results were evaluated subjectively and objectively. Results Facial nerve palsy occurred in 5 cases (45%), and all of them recovered completely within 6 months. The Minor starch iodine test was positive in 3 patients (27%), although only 1 (9%) subjectively complained of gustatory sweating. The designed visual analog score completed by the patients themselves ranged from 0 to 3 with a mean of 1.55 +/- 0.93; the scores from the blinded evaluators ranged from 1 to 3 with a mean 1.64 +/- 0.67. Conclusion The partial-thickness superiorly based SCM flap offers a reasonable cosmetic option for reconstruction following either superficial or total parotidectomy by improving the facial deformity. The flap also lowers the incidence of Frey syndrome objectively and subjectively with no reported hazard of the spinal accessory nerve. PMID- 26491479 TI - Auditory Middle Latency Response and Phonological Awareness in Students with Learning Disabilities. AB - Introduction Behavioral tests of auditory processing have been applied in schools and highlight the association between phonological awareness abilities and auditory processing, confirming that low performance on phonological awareness tests may be due to low performance on auditory processing tests. Objective To characterize the auditory middle latency response and the phonological awareness tests and to investigate correlations between responses in a group of children with learning disorders. Methods The study included 25 students with learning disabilities. Phonological awareness and auditory middle latency response were tested with electrodes placed on the left and right hemispheres. The correlation between the measurements was performed using the Spearman rank correlation coefficient. Results There is some correlation between the tests, especially between the Pa component and syllabic awareness, where moderate negative correlation is observed. Conclusion In this study, when phonological awareness subtests were performed, specifically phonemic awareness, the students showed a low score for the age group, although for the objective examination, prolonged Pa latency in the contralateral via was observed. Negative weak to moderate correlation for Pa wave latency was observed, as was positive weak correlation for Na-Pa amplitude. PMID- 26491480 TI - Is There Any Benefit of Drain Placement on Postoperative Complications in Patients Undergoing the Sistrunk Procedure? AB - Introduction Same-day, outpatient Sistrunk procedure is commonly performed to manage thyroglossal duct cyst anomalies and may lead to postoperative complications. Surgical drains are placed to prevent complications, but recent observations show no advantage and rather increased health care costs and patient discomfort. Objective The study evaluated if drain placement in the Sistrunk procedure offers any benefit on postoperative complications. Methods A retrospective analysis of patient records having undergone same-day, outpatient Sistrunk procedure from 2004 to 2014 was done. Of 58 (38 male and 20 female) patients included, 38 did not have drains placed and the remaining 20 had drains placed. Mean and median age of patients was 18.1 and 13.5 years, respectively. Postoperative complications of patients with drains versus those without drains were statistically analyzed. Results Overall, about 10% of patients had hematoma/seroma (H-S), with 6.9% of patients needing aspiration for H-S; 3.4% had wound infections; and 1.7% had pus formation. No statistically significant differences in Sistrunk-related complications between patient groups (with drain or without drain) were seen using Fisher exact (two-sided) test: H-S (p = 0.08); need for aspiration (p = 0.29); wound infection (p > 0.05); and pus formation (p = 0.35). Chi-square test also did not show any significant difference in the groups in terms of number of follow-ups. Conclusion Surgical placement of a drain in the Sistrunk procedure does not seem to offer any advantage in terms of reducing common postoperative complications. Same-day Sistrunk procedure without any drain placement may be a safer alternative without necessitating hospitalization. More studies with larger sample size are needed for further substantiation. PMID- 26491481 TI - Membrane Stress in the Human Labyrinth and Meniere Disease: A Model Analysis. AB - Introduction The nature and extent of membrane damage encountered in Meniere disease remains unexplained. Pressure-induced membrane stress may underlie the characteristic hydropic distention. Analysis of stress in the several vestibular chambers may offer insight into the nature and progression of Meniere disease. Objective Membrane stress levels will be assessed by constructing a specific model of the human membranous labyrinth through the application of human dimensions to an existing generic model of the mammalian labyrinth. Methods Nominal dimensions for a model of the human membranous labyrinth were obtained from fixed human tissue. Stress proclivities were calculated and normalized based on shell theory applied to the various geometric figures comprising the model. Results Normalized peak stress levels were projected to be highest in the saccule (38.8), followed by the utricle (5.4), then ampulla (2.4), and lowest in the canal system (1.0). These results reflect macrostructural variations in membrane shape, size, and thickness among the several chambers of the labyrinth. These decreasing stress proclivities parallel the decreasing frequency of histologic lesions found in documented cases of Meniere disease. Conclusions This model analysis of a human membranous labyrinth indicates that substantial disparities in stress exist among the several vestibular chambers due to macrostructural membrane configuration. Low stress levels in the canals are the result of thick highly curved membranes, and the high levels computed for the saccule reflect its thin and relatively flat membranes. These findings suggest that chamber configuration may be a factor controlling the progression of endolymphatic hydrops in Meniere disease. PMID- 26491482 TI - Active Bone Conduction Prosthesis: Bonebridge(TM). AB - Introduction Bone conduction implants are indicated for patients with conductive and mixed hearing loss, as well as for patients with single-sided deafness (SSD). The transcutaneous technology avoids several complications of the percutaneous bone conduction implants including skin reaction, skin growth over the abutment, and wound infection. The Bonebridge (MED-EL, Austria) prosthesis is a semi implantable hearing system: the BCI (Bone Conduction Implant) is the implantable part that contains the Bone Conduction-Floating Mass Transducer (BC-FMT), which applies the vibrations directly to the bone; the external component is the audio processor Amade BB (MED-EL, Austria), which digitally processes the sound and sends the information through the coil to the internal part. Bonebridge may be implanted through three different approaches: the transmastoid, the retrosigmoid, or the middle fossa approach. Objective This systematic review aims to describe the worlds first active bone conduction implant system, Bonebridge, as well as describe the surgical techniques in the three possible approaches, showing results from implant centers in the world in terms of functional gain, speech reception thresholds and word recognition scores. Data Synthesis The authors searched the MEDLINE database using the key term Bonebridge. They selected only five publications to include in this systematic review. The review analyzes 20 patients that received Bonebridge implants with different approaches and pathologies. Conclusion Bonebridge is a solution for patients with conductive/mixed hearing loss and SSD with different surgical approaches, depending on their anatomy. The system imparts fewer complications than percutaneous bone conduction implants and shows proven benefits in speech discrimination and functional gain. PMID- 26491483 TI - Massive Plexiform Neurofibroma of the Neck and Larynx. AB - Introduction Laryngeal neurofibromas are extremely rare, accounting for only 0.03 to 0.1% of benign tumors of the larynx. Objectives To report the first case of massive neck plexiform neurofibroma with intralaryngeal (supraglottic) extension in a 5-year-old boy with neurofibromatosis type 1 and to describe its treatment. Resumed Report This massive plexiform neurofibroma was surgically removed, relieving its significant respiratory obstructive symptoms without recurrence to date. Conclusion Massive neck plexiform neurofibroma with supraglottic part was found in a child with neurofibromatosis type 1; it should be included in differential diagnosis of stridor and neck mass in children. It was diagnosed and removed in early in childhood without recurrence. PMID- 26491484 TI - An Aggressive Plasmablastic Lymphoma of the Oral Cavity as Primary Manifestation of Acquired Immunodeficiency Syndrome: Case Report and Literature Review. AB - Introduction Plasmablastic lymphoma is a rare entity that was first described in the jaws and the oral cavity of patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Plasmablastic lymphoma is considered as a diffuse, large, B-cell lymphoma with a unique phenotype and a predilection for the oral cavity. Objective The authors describe a case of an aggressive plasmablastic lymphoma of the oral cavity as the primary manifestation of AIDS. Resumed Report We report a case of plasmablastic lymphoma involving only the oral cavity as the first manifestation of AIDS. Diagnosis was confirmed by the oral lesion biopsy and the histopathologic examination that showed a dense infiltrate composed of atypical lymphocytes with numerous plasmocytes that expressed the plasma cell markers MUM-1 and CD138 and that were negative for the B-cell markers CD3, CD20, and CD45. Immunohistochemical and in situ hybridization revealed the Epstein-Barr virus genome in the atypical cells. Polymerase chain reaction was also positive for human herpesvirus-8 RNA. Conclusion The HIV serologic status should be evaluated in all patients with plasmablastic lymphoma of the oral cavity or extraoral sites. PMID- 26491485 TI - Cochlear Implantation in Isolated Large Vestibular Aqueduct Syndrome: Report of Three Cases and Literature Review. AB - Introduction Large vestibular aqueduct syndrome (LVAS) is characterized by the enlargement of the vestibular aqueduct associated with sensorineural hearing loss. It is the most common radiographically detectable inner ear anomaly in congenital hearing loss. LVAS may occur as an isolated anomaly or in association with other inner ear malformations. Objective To report three cases of isolated LVAS with a focus on preoperative assessment, surgical issues, and short-term postoperative follow-up with preliminary auditory habilitation outcomes. Resumed Report One girl and two boys with LVAS were assessed and cochlear implantation was performed for each. Various ways of intraoperative management of cerebrospinal fluid gusher and postoperative care and outcomes are reported. Conclusion Cochlear implantation in the deaf children with LVAS is feasible and effective. PMID- 26491486 TI - Foreign Body in Jugal Mucosa. AB - Introduction Foreign body in the oral cavity may be asymptomatic for long time and only sometimes it can lead to a typical granulomatous foreign body reaction. Some patients may complain of oral pain and present signs of inflammation with purulent discharge. A granuloma is a distinct, compact microscopic structure composed of epithelioid-shaped macrophages typically surrounded by a rim of lymphocytes and filled with fibroblasts and collagen. Nowadays, the increase of cosmetic invasive procedures such as injection of prosthetic materials in lips and cheeks may lead to unusual forms of inflammatory granulomas. Objectives Describe an unusual presentation of a foreign body reaction in the buccal mucosa due to previous injection of cosmetic agent. Resumed Report A 74-year-old woman was referred to the Department of Otorhinolaryngology, Head and Neck Surgery to investigate the presence of multiple painless, bilateral nodules in the buccal mucosa, with progressive growth observed during the previous 2 months. The histologic results showed a foreign body inflammatory reaction. Conclusion Oral granulomatosis lesions represent a challenging diagnosis for clinicians and a biopsy may be necessary. Patients may feel ashamed to report previous aesthetic procedures, and the clinicians must have a proactive approach. PMID- 26491487 TI - Anger, Sadness and Fear in Response to Breaking Crime and Accident News Stories: How Emotions Influence Support for Alcohol-Control Public Policies via Concern about Risks. AB - Prior research shows that discrete emotions, notably anger and fear, can explain effects of news articles on health and alcohol-control policy support. This study advances prior work by coding expressed emotional responses to messages (as opposed to directly manipulated emotions or forced responses), incorporating and controlling for central thoughts, including sadness (a particularly relevant response to tragic stories), and examining concern's mediating role between emotion and policy support. An experiment with a national online adult panel had participants read one of 60 violent crime or accident news stories, each manipulated to mention or withhold alcohol's causal contribution. Multi-group structural equation models suggest that stories not mentioning alcohol had a direct effect on policy support via fear and central thoughts, unmediated by concern. When alcohol was mentioned, sadness and anger affects alcohol-control support through concern. Findings help confirm that emotional responses are key in determining news story effects on public support of health policies. PMID- 26491488 TI - Improving IQ measurement in intellectual disabilities using true deviation from population norms. AB - BACKGROUND: Intellectual disability (ID) is characterized by global cognitive deficits, yet the very IQ tests used to assess ID have limited range and precision in this population, especially for more impaired individuals. METHODS: We describe the development and validation of a method of raw z-score transformation (based on general population norms) that ameliorates floor effects and improves the precision of IQ measurement in ID using the Stanford Binet 5 (SB5) in fragile X syndrome (FXS; n = 106), the leading inherited cause of ID, and in individuals with idiopathic autism spectrum disorder (ASD; n = 205). We compared the distributional characteristics and Q-Q plots from the standardized scores with the deviation z-scores. Additionally, we examined the relationship between both scoring methods and multiple criterion measures. RESULTS: We found evidence that substantial and meaningful variation in cognitive ability on standardized IQ tests among individuals with ID is lost when converting raw scores to standardized scaled, index and IQ scores. Use of the deviation z- score method rectifies this problem, and accounts for significant additional variance in criterion validation measures, above and beyond the usual IQ scores. Additionally, individual and group-level cognitive strengths and weaknesses are recovered using deviation scores. CONCLUSION: Traditional methods for generating IQ scores in lower functioning individuals with ID are inaccurate and inadequate, leading to erroneously flat profiles. However assessment of cognitive abilities is substantially improved by measuring true deviation in performance from standardization sample norms. This work has important implications for standardized test development, clinical assessment, and research for which IQ is an important measure of interest in individuals with neurodevelopmental disorders and other forms of cognitive impairment. PMID- 26491489 TI - A New Horizon of DNP technology: Application to In-vivo 13C Magnetic Resonance Spectroscopy and Imaging. AB - Dynamic nuclear polarization (DNP) is an emerging technique for increasing the sensitivity (>10,000-fold) of magnetic resonance spectroscopy and imaging (MRSI), in particularly for low-gamma nuclei. DNP methodology is based on polarizing nuclear spins in an amorphous solid state at low temperature (ca. 1 K) through coupling of the nuclear spins with unpaired electron spins that are added to the sample via an organic free radical. In an amorphous solid state, the high electron spin polarization can be transferred to the nuclear spins by microwave irradiation. While this technique has been utilized in solid-state research for many years, it is only recently that dissolution methods and the required hardware have been developed to produce the high nuclear polarization provided by DNP to produce injectable hyperpolarized solutions suitable for in vivo studies. It has been applied to a number of 13C-labeled cell metabolites in biological systems and their real-time metabolic conversion has been imaged. This review focuses the DNP methodology briefly and the significant molecules investigated to date in preclinical cancer models, in terms of their downstream metabolism in vivo or the biological processes that they can probe. In particular, conversion between hyperpolarized 13C-labeled pyruvate and lactate, catalyzed by lactate dehydrogenase, has been shown to have a number of potential applications such as diagnosis, staging tumor grade and monitoring therapy response. Strategies for making this technique more viable to use in clinical settings has been discussed. PMID- 26491490 TI - A Classic Case of Tuberous Sclerosis with Multisystem Involvement Including Giant Bilateral Renal Angiomyolipomas Presenting as Massive Hematuria. AB - BACKGROUND: Tuberous Sclerosis (TSC) also known as Bourneville disease is a neurocutaneous syndrome having an autosomal dominant inheritance pattern, though the condition has a high rate of spontaneous mutation. It is the second most common neurocutaneous syndrome after neurofibromatosis. This disease demonstrates a widespread potential for hamartomatous growths in multiple organ systems. CASE REPORT: We report a case of a 36-year-old female with TSC presenting as massive hematuria with underlying giant bilateral renal angiomyolipomas (AML) with estimated total tumor burden of more than 8 kg which is to the best of our knowledge the highest ever reported. The patient also had lymphangioleiomyomatosis and lesions in the brain, skin, teeth and bones. CONCLUSIONS: TSC has a wide variety of clinical and radiologic manifestations. It should be suspected when some of the common radiological manifestations are found, including CNS involvement, renal and hepatic AMLs and LAM, even if clinical signs are not obvious. Renal AMLs in setting of TSC may reach giant proportions and may present with massive hematuria. PMID- 26491491 TI - Advantage of Adding Diffusion Weighted Imaging to Routine MRI Examinations in the Diagnostics of Scrotal Lesions. AB - BACKGROUND: The purpose of the study is to identify the diagnostic value of adding diffusion weighted images (DWI) to routine MRI examinations of the scrotum. MATERIAL/METHODS: The study included 100 testes of 50 patients with a unilateral testicular disease. Fifty normal contralateral testes were used as a control group. All patients underwent conventional MRI and DWI examinations of the scrotum. The results of MRI and DWI of the group of patients treated surgically were correlated with histopathological findings. The MRI and DWI results of non-surgical cases were correlated with the results of clinical, laboratory and other imaging studies. Comparison of the ADC value of normal and pathological tissues was carried out followed by a statistical analysis. RESULTS: There was a significant difference between ADC values of malignant testicular lesions and normal testicular tissues as well as benign testicular lesions (P=0.000). At a cut-off ADC value of <=0.99, it had a sensitivity of 93.3%, specificity of 90%, positive predictive value of 87.5%, and negative predictive value of 94.7% in the characterization of intratesticular masses. CONCLUSIONS: Inclusion of DWI to routine MRI has a substantial value in improving diagnosis in patients with scrotal lesions and consequently can reduce unnecessary radical surgical procedures in these patients. PMID- 26491492 TI - Synovial Hemangioma of the Knee Joint: Magnetic Resonance Imaging Findings. AB - BACKGROUND: Synovial hemangioma is benign tumor of the joints and is seen relatively rare. The most affected joint is knee but should also be seen in other joints. The disease is usually symptomatic. They are classified as juxta articular haemangioma, intra-articular haemangioma or an intermediate type of hemangioma with intra- and extraarticular components. CASE REPORT: A 19-years-old male patient presented with swollen and painful knee. The laboratory findings and physical examination were normal. MRI demonstrated a large lesion that was filling the suprapatellar bursa. CONCLUSIONS: All radiologic examinations should be used in diagnosis but magnetic resonance imaging is the non-invasive method and excellent modality in the evaluation of soft tissues. In this paper, a 19 year-old male patient with the diagnosis of synovial hemangioma is reported and its radiologic findings are mentioned. PMID- 26491493 TI - Palmaris Longus Muscle's Prevalence in Different Nations and Interesting Anatomical Variations: Review of the Literature. AB - The prevalence of the palmaris longus (PL) muscle varies more than any other muscle in the human body. Its absence across the world ranges between 1.5% and 63.9%. It presents with many different anomalies, discovered either clinically, intraoperatively or after anatomical examination of cadavers. This paper includes recent studies and reports about the presence and variations of the PL muscle, thereby illustrating the differences between ethnic groups, as well as emphasizing the different ways of finding it, during daily clinical and surgical practice. PMID- 26491495 TI - Characterization of Older Emergency Department Patients Admitted to Psychiatric Units. AB - BACKGROUND: Many older patients presenting to emergency departments (EDs) with psychiatric complaints require admission to geropsychiatric units (GPUs). The medical evaluation needed prior to this is not understood. Our goal was to understand ED evaluation practices for patients admitted to the GPU through the ED and understand the medical problems identified after admission. METHODS: Via retrospective chart review, we abstracted demographics, medical history, ED complaint, evaluation, length of stay, and diagnosis. The number of patients later transferred from the GPU and the reasons for such transfers were also recorded. RESULTS: Of 100 patients reviewed, the average age was 78 years. Admission diagnoses were agitation/mania (30%), depression/suicidal ideation (28%), change in mental status/confusion (12%) and other (30%). Most had at least one prior psychiatric and medical diagnosis (77%, 60%). Common ED tests ordered were basic metabolic panel (BMP) (96%), complete blood count (CBC) (94%), urinalysis (UA) (89%), electrocardiogram (EKG) (69%), alcohol level (62%), urine toxicology (61%), chest X-ray (51%), and CT scan of the head (71%). Abnormal findings included urinalysis (24.7%), CBC (23.4%), toxicology (23%), BMP (21.9%), head CT (21.1%), chest X-ray (13.7%), ECG changes (10.1%), and alcohol (4.8%). Five of the 100 GPU admissions were later transferred to a medical floor. CONCLUSION: Most GPU admissions have previous psychiatric and medical issues and are admitted for agitation/mania or depression/suicidal ideation. A certain percentage of patients are transferred out due to medical issues despite ED evaluation. However, it is unlikely that further ED testing would reduce this percentage. Further research of medical screening for geropsychiatric patients may elucidate ideal medical clearance procedures. PMID- 26491494 TI - Tiotropium Bromide in Chronic Obstructive Pulmonary Disease and Bronchial Asthma. AB - Inhaled bronchodilators are the mainstay of pharmacological treatment for stable chronic obstructive pulmonary disease (COPD), including beta2-agonists and muscarinic antagonists. Tiotropium bromide, a long-acting antimuscarinic bronchodilator (LAMA), is a treatment choice for moderate-to-severe COPD; its efficacy and safety have been demonstrated in recent trials. Studies also point to a beneficial role of tiotropium in the treatment of difficult-to-control asthma and a potential function in the asthma-COPD overlap syndrome (ACOS). Combination of different bronchodilator molecules and addition of inhaled corticosteroids are viable therapeutic alternatives. A condensation of the latest trials and the rationale behind these therapies will be presented in this article. PMID- 26491496 TI - Physical Activity and Health-Related Quality of Life Among Community Dwelling Elderly. AB - BACKGROUND: Physical activity (PA) and health-related quality of life (HRQoL) are important factors for optimal health in the elderly. Studying the association between PA and HRQoL is becoming more essential as the number of elderly people increases worldwide. This study assesses the association between PA and HRQoL among community dwelling elderly above 60 years old. METHODS: The study included 115 women and 61 men (mean age: 68.15 +/- 6.74 years) recruited from the community and from public centers for the elderly. Data were collected using a background characteristics questionnaire (BCQ), a physical activity socio cultural adapted questionnaire (PA-SCAQ), and the EuroQuol-5Dimensions-5Levels (EQ-5D-5L) questionnaire. Between groups, comparisons were based on the PA-SCAQ by dividing the participants into three PA groups: low (n = 74), moderate (n = 85), and high (n = 17). Kruskal-Wallis tests were performed on the ordinal variables of the three PA groups to determine differences between the groups according to categorical variables such as gender, body mass index (BMI), and the prevalence of comorbid conditions. Mann-Whitney U tests were performed on the ordinal variables of the EuroQuol-5Dimensions (EQ-5D), and the independent sample t-test was performed on the EQ visual analogue scale (EQ-VAS). Spearman's rank correlation coefficient was used to examine the correlation between the EQ-5D and level of PA. RESULTS: Values in all dimensions of HRQoL were significantly higher (P < 0.05) in the moderate and high PA groups compared with the low PA group. Significant correlations were recorded between the five dimensions of HRQoL and the level of PA (P < 0.001). The low PA group showed higher prevalence of hypertension (64%, P < 0.001) and diabetes (50%, P < 0.001). CONCLUSION: There were strong associations between higher levels of PA and all dimensions of HRQoL. Therefore, adopting a PA lifestyle may contribute to better HRQoL among community dwelling elderly above 60 years old. PMID- 26491497 TI - Clinical Significance of Pregnancies Complicated by Velamentous Umbilical Cord Insertion Associated With Other Umbilical Cord/Placental Abnormalities. AB - BACKGROUND: We examined the clinical significance of pregnancies complicated by velamentous cord insertion (VCI) associated with other umbilical cord/placental abnormalities. METHODS: Data were collected from 168 deliveries complicated by VCI and from 16,797 unaffected controls. All placentae were screened identically by trained staff. In this study, we examined the presence of excessively long umbilical cord (longer than 70 cm), vasa previa, single umbilical artery, circumvallate placenta, succenturiate placenta, lobed placenta, placenta previa, low lying placenta and placenta accrete as the other umbilical cord/placental abnormalities. RESULTS: Using a multivariate analysis, the pregnancies complicated by VCI were independently associated with in vitro fertilization use (P < 0.01), maternal smoking (P = 0.03), preterm delivery (P = 0.03), fetal asphyxia (P = 0.01) and small-for-gestational-age infants (P = 0.02). It was also independently associated with vasa previa (P < 0.01), single umbilical artery (P = 0.04), lobed placenta (P = 0.01) and placenta previa (P = 0.03). However, these umbilical cord/placental abnormalities were not associated with the further adverse outcomes of the pregnancies complicated by VCI. CONCLUSION: VCI is associated with an increased risk of adverse perinatal outcomes irrespective of the presence of other umbilical cord/placental abnormalities. Routine identification of the placental cord insertion site should be considered. PMID- 26491498 TI - The Impact of Implementation of Bundle to Reduce Catheter-Related Bloodstream Infection Rates. AB - BACKGROUND: The aim of the study was to investigate how control bundles reduce the rate of central venous catheter-associated bloodstream infections (CVC-BSIs) rates in critically ill patients. METHODS: This is a prospective before-and-after study designed to evaluate whether a set of control measures (bundle) can help prevent CVC-BSI. The bundles included a checklist that aimed to correct practices related to CVC insertion, manipulation, and maintenance based on guidelines of the Center for Disease Control and Prevention (CDC). RESULTS: We examined 123 checklists before and 155 checklists after implementation of the training program. Compared with the pre-intervention period, CVC-BSI rates decreased. Hand hygiene techniques were used correctly. CVC-BSI incidence was 9.3 and 5.1 per 1,000 catheter-days before and after the training program, respectively. CONCLUSIONS: The implementation of a bundle and training program effectively reduces CVC-BSI rates. PMID- 26491499 TI - A Randomized Controlled Trial of Intralesional Glucocorticoid for Treating Pretibial Myxedema. AB - BACKGROUND: Pretibial myxedema (PTM) is an uncommon dermopathy associated with autoimmune thyroid diseases. Now it is thought to be autoimmune and its treatment with glucocorticoid is helpful. However, it has not been evaluated. METHODS: A prospective randomized controlled trial was performed in 110 patients with PTM to evaluate the efficacy and safety of triamcinolone acetonide with intralesional injection once every 3 days and once every 7 days. Randomization was performed with drawing lots and it was also stratified according to variants of PTM lesions. In the follow-up, recurrent rates were observed. The SPSS Statistics 17.0 Software was used in the statistical analysis. RESULTS: The complete response rates were 78.2%, 83.6%, and 87.3% in regimen 1 and 50.9%, 89.1%, and 90.9% in regimen 2 at 3 weeks, 7 weeks and the end of therapy, respectively. Regimen 1 had an earlier efficacy than regimen 2, but at 7 weeks and end of therapy, there were no differences between two regimens. The majority of non severe variants got complete response but severe variants did not. The adverse reaction rates in regimen 1 were higher and earlier than those in regimen 2. Adverse reaction occurring time in regimen 1 was shorter than that in regimen 2. Recurrent rates were 31.25% and 32% in regimens 1 and 2 at 3.5-year follow-up. CONCLUSIONS: For its autoimmune, hyperplasia and disabled features, early treatment of PTM with glucocorticoid is necessary to get complete response. Dosage and frequency of intralesional steroid injection and lesional variants influence the efficacy of PTM. Once every 7 days is a better regimen. PMID- 26491500 TI - Impact of the Absolute Difference in Diastolic Blood Pressure Between Arms in Patients With Coronary Artery Disease. AB - BACKGROUND: We investigated the relationship between the severity and presence of coronary artery disease (CAD) and a difference in systolic and diastolic blood pressure (SBP and DBP) between arms or between lower limbs. METHODS: We enrolled 277 patients who underwent coronary angiography. We calculated the absolute (|right BP (rt. BP) - left BP (lt. BP)|) and relative (rt. BP - lt. BP) differences in SBP or DBP between arms or between lower limbs, and assessed the severity of CAD in terms of the Gensini score. RESULTS: The absolute difference in DBP between arms in the CAD group was significantly lower than that in the non CAD group, whereas the absolute difference in DBP between lower limbs in the CAD group was significantly higher. There were no differences in the absolute or relative difference in SBP between arms or lower limbs between the groups. The absolute difference in DBP between arms decreased as the Gensini score increased. In a logistic regression analysis, the presence of CAD was independently associated with the absolute difference in DBP between arms, in addition to male, family history, dyslipidemia, diabetes mellitus and hypertension. CONCLUSION: The absolute difference in DBP between arms in addition to traditional factors may be a critical risk factor for the presence of CAD. PMID- 26491501 TI - Proton Pump Inhibitors Did Not Increase Risk of Pneumonia in Patients With Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) involves the airways and pneumonia is a major cause of mortality. Proton pump inhibitors (PPIs) were found to have a positive association with pneumonia. The aim of this study was to investigate the impact of PPIs on the risk of pneumonia in patients with COPD. METHODS: This was a nationwide, population-based, case-control study using data from the National Health Insurance Research Database in Taiwan. The enrolled cases were defined as patients with COPD and appearance of pneumonia between 2001 and 2005. The control group was age- and sex-matched 1:2 with the cases without pneumonia. Potential confounders such as coronary artery disease, hypertension, diabetes mellitus, heart failure, chronic kidney disease, and prescriptions of glucocorticoids over 2 weeks, were included in the analysis. Prescriptions for PPIs were identified and entered into the analysis. RESULTS: A total of 10,131 COPD patients, including 3,377 cases with pneumonia and 6,754 without, were identified. There were 213 (5.3%) and 436 (6.5%) cases with concurrent PPIs in the two groups, respectively, and the risk of pneumonia was similar (aOR = 0.96; 95% CI: 0.83 - 1.10). Further subgroup analysis found no differences for younger patients (younger than 70 years old; aOR = 1.04; 95% CI: 0.83 - 1.10), elderly patients (older than 70 years old; aOR = 0.96; 95% CI: 0.81 - 1.15), short-term use of PPIs (less than 30 days; aOR = 1.12; CI: 0.53 - 2.34), medium-term use of PPIs (30 - 90 days; aOR = 0.86; CI: 0.72 - 1.03), or long-term use of PPIs (longer than 90 days; aOR = 0.97; CI: 0.81 - 1.15). CONCLUSION: PPIs did not contribute to a greater occurrence of pneumonia in COPD patients compared with non-users in this population-based case-control study. Further research is required. PMID- 26491502 TI - Combination Therapy With Adalimumab Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis in Patients With Refractory Ulcerative Colitis. AB - BACKGROUND: The efficacy and safety of combination therapy with adalimumab (ADA) plus intensive granulocyte and monocyte adsorptive apheresis (GMA) (two sessions per week) for the treatment of refractory ulcerative colitis (UC) have not been previously evaluated. METHODS: This retrospective study evaluated the 10-week efficacy of combination therapy with ADA plus intensive GMA on refractory UC patients, on clinical outcomes over 52 weeks under subsequent maintenance monotherapy of ADA, and the effect of combined azathioprine (AZA) with ADA at failure to achieve clinical remission at 10 weeks and at flare-up by 52 weeks. Ten patients were given initial combination therapy of ADA (160/80/40 mg every other week) plus intensive GMA. One patient received total colectomy because of poor response. RESULTS: Of nine patients who received this combination therapy, 55.6% displayed cumulative clinical remission at 10 weeks and 33.3% displayed such remission at 52 weeks under subsequent maintenance monotherapy of ADA. The percentage of patients with mucosal healing at 10 weeks (endoscopy subscore <= 1) was 66.7%. Adverse events were observed in three patients (pneumonia, cerebral infarction and headache). CONCLUSION: It was concluded that combination therapy with ADA plus intensive GMA is useful for induction of clinical remission in refractory UC patients, and is well tolerated. PMID- 26491503 TI - Infective Endocarditis Presenting as Complete Heart Block With an Unexpected Finding of a Cardiac Abscess and Purulent Pericarditis. AB - Intracardiac abscess resulting in complete heart block is an infrequent complication of infective endocarditis. Most presentations of endocarditis are limited to valvular and perivalvular structures, with varying degrees of heart block occurring in the minority of cases. We report a case of endocarditis manifesting as chest pain associated with ST segment elevation and complete heart block. The patient expired unexpectedly within a few hours of presentation. Postmortem examination revealed an atrial septal abscess, purulent pericardial collection, and fibrinous pericarditis. Spread of the abscess into the atrial septum was postulated to be the cause of the complete heart block. In endocarditis, the ominous development of heart block and a poor response to antibiotic therapy imply significant extension of the infection. Management therefore requires prompt ventricular pacing with consideration for valve replacement and possible pericardial drainage. PMID- 26491504 TI - Squamous Cell Lung Cancer Associated With Systemic Sclerosis. AB - We here describe a 50-year-old woman diagnosed with squamous cell lung cancer (SqLC) with underlying interstitial lung disease (ILD) 14 years after a diagnosis of systemic sclerosis (SSc). We reviewed the literature and collected 21 well documented cases with SqLC associated with SSc including the present case. Several characteristics of SqLC associated with SSc have been found. First, the average age at diagnosis of SqLC is 57 years, which is much younger than that reported for patients without SSc. Second, SqLC could occur even in never or light smokers, although SqLC usually has a strong association with smoking history. Third, two-thirds of the available cases have ILD. In addition, SqLC developed in the area of ILD in most cases with ILD. Fourth, SqLC generally occurs after a long period from the diagnosis of SSc; the average of this interval reaches 12 years. It would be helpful to know these features so that physicians follow up and treat SSc patients adequately. PMID- 26491505 TI - Zoledronate Therapy for the Pathological Humeral Fracture in Polyostotic Fibrous Dysplasia: A Case Report. AB - Fibrous dysplasia (FD) of bone is a rare skeletal disease often associated with bone pain, deformities and fractures. The bisphosphonate therapies are reported to be useful for bone pain, but seem to be not suitable for fracture repairs of extremities. This is the first report of zoledronate-induced radiological improvement and long bone fracture union in polyostotic FD. A 30-year-old Japanese female had bilateral shepherd's crook deformities typical to FD and right pathological femoral fracture and left humeral fracture nonunion. These fractures occurred without major traumas and the humeral fracture was not united for 1 year with conservative therapy. Laboratory blood test results were notable for elevated serum alkaline phosphatase and urine N-terminal cross-linking telopeptide of type I collagen. Her subtrochanteric femoral fracture was percutaneously fixed using Kirschner wires. After surgery, a hip spica cast was applied for 2 months and the orthosis for the next 2 months. Bony union of the femoral fracture was observed 5 months after surgery. Increased bone turnover and typical radiological features suggested that the constant elbow pain was due to both FD itself and humeral nonunion. Considering the possible side effects of zoledronate delaying acute fracture healing, we initiated zoledronate (Zometa((r)); Novartis, Tokyo, Japan) therapy after femoral fracture union. Intravenous zoledronate acid was administered at a dose of 2 mg, along with supplementation of calcium (600 mg/day) and vitamin D (alfacalcidol 0.5 MUg/day) to limit the risk of osteomalacia and improve the efficacy of bisphosphonate therapy. The patient's elbow pain rapidly resolved 1 week after treatment. Second therapy with same dose was performed after 6 months. No recurrence of elbow pain was reported and bony union was diagnosed after 1 year from the first administration. This patient is currently doing well without recurrence of bone pain. She can also walk for a short distance with crutches. We presented the case of an FD patient with persistent elbow pain due to FD itself and nonunion of humeral fracture, which was ameliorated promptly by intravenous zoledronate therapies. This case illustrated the benefit of zoledronate treatment in patients with extensive polyostotic FD and pathological fractures of extremities. PMID- 26491506 TI - Severe Gastrointestinal Bleeding in a Patient With Subvalvular Aortic Stenosis Treated With Thalidomide and Octreotide: Bridging to Transcoronary Ablation of Septal Hypertrophy. AB - Gastrointestinal bleeding (GB) due to angiodysplasias can cause severe, recurrent bleeding, especially in elderly patients. Angiodysplastic bleedings in the gastrointestinal tract have been associated with aortic stenosis and, more recently, hypertrophic obstructive cardiomyopathy, caused by an acquired coagulopathy known as Heyde's syndrome. Multiple factors are involved in the pathogenesis of angiodysplastic bleeding including genetic factors and increased levels of vascular intestinal growth factor at tissue levels. Endoscopic coagulation therapy is the primary treatment but often fails to resolve bleeding, especially in patients with large numbers of angiodysplasias. In patients with aortic stenosis and GB, the main treatment is aortic valve replacement but the patients may be unfit to undergo surgery due to the complicating anemia. In this case story, we present a patient with severe, GB due to hypertrophic subvalvular obstructive cardiomyopathy. Endoscopic procedures with argon beaming were performed without effect on bleeding. The patient was treated with a combination of both thalidomide and octreotide. Within 3 months, the patient recovered from the anemia and was able to undergo transcoronary ethanol ablation. No further bleeding episodes occurred, and thalidomide and octreotide were arrested. To our knowledge, this case report is the first to describe how this new drug combination therapy is an effective treatment of GB from angiodysplasias and can be used to bridge to surgical or endovascular treatment. PMID- 26491507 TI - Head Loss As an Explanation of the Steal Phenomenon in Microvascular Surgery. AB - Vascular steal has been cited to help explain end-organ ischemia after microvascular reconstruction. Attempts to clarify a mechanism of vascular steal have been made by modeling blood circulation after a simple electrical circuit, suggesting that the free flap provides a path of least resistance for blood flow and thereby compromises end-organ perfusion. We present a case of a posterior medial thigh perforator flap for the reconstruction of a diabetic foot ulcer in a patient with a single vessel providing inflow to the foot. In the context of this case, we provide a novel explanation for the steal phenomenon using the Hagen Poiseuille law and the property of head loss in fluid dynamics and discuss how the vessel size of the free flap may contribute to a steal phenomenon. PMID- 26491508 TI - Efficacy, Safety, and Tolerance of a New Injection Technique for High- and Low Molecular-Weight Hyaluronic Acid Hybrid Complexes. AB - OBJECTIVE: Facial aging is characterized by skin laxity and loss of skin elasticity. Hyaluronic acid, a biological component of the extracellular matrix, whose level decreases during aging, plays structural, rheological, and physiological roles in the skin. Hyaluronic acid may possess different molecular weights: low-molecular-weight hyaluronic acid (from 50 kDa) and high-molecular weight hyaluronic acid (just up to 2 million kDa). This monocentric, retrospective, observational study investigates the efficacy, security, and tolerability of a new injective low- and high-molecular-weight hyaluronic acid for facial skin rejuvenation. METHODS: Eleven women received once a month, for 2 months, 2 mL of the product in the subcutaneous layer of the right and left malar/submalar areas. Facial skin echography, facial skin hydration, elasticity, and transepidermal water loss were assessed before (T 0), after 1 month (T 1), and after 3 months of treatment (T 2). The injective features of the product, physician subjective satisfaction, and patient satisfaction were also reported. RESULTS: Facial face hydration, elasticity, and transepidermal water loss values significantly improved at T 1 and T 2 (P < .01). Patients were very satisfied at the end of the treatment, and the compound's profit evaluated by the physician was optimal in the absence of local side effects. CONCLUSIONS: This treatment represents a good treatment option to restore vitality and turgidity of skin presenting the signs of aging in the absence of intolerance symptoms. PMID- 26491509 TI - Helical Rim Reconstruction: Antia-Buch Flap. PMID- 26491510 TI - [Respiratory signs revealing an amoebic liver abscess]. PMID- 26491511 TI - [Splenic infarction during a severe form of granulomatosis with polyangiitis: report of a case]. PMID- 26491512 TI - A characteristic image in Joubert syndrome: molar tooth sign. PMID- 26491513 TI - [Acute myopericarditis simulating myocardial infarction: report of a case and review of literature]. PMID- 26491514 TI - Macular hole following contusion syndrome. PMID- 26491515 TI - [A small induced vascular malformation]. PMID- 26491516 TI - [Molecular diagnosis of Mycobacterium tuberculosis complex resistant to isoniazid and rifampicin in Burkina Faso]. PMID- 26491517 TI - [Ischemic gangrene of the penis in a diabetic patient: about a case]. PMID- 26491518 TI - Winning the battle and losing the war? Where public health is getting it wrong in the current fight against HIV-AIDS and tuberculosis in Sub-Saharan Africa. AB - Despite the enormous victory that has been recorded in decreasing significantly HIV-TB related mortality and morbidity in Sub-Saharan Africa, enormous challenges continue to obstruct proper and enviable control of these conditions. These range from prioritization, ethics, funding, drug resistance and research gaps. Resistance to these diseases could constitute key treatment and prevention challenges to health care systems and the international community if not handled appropriately and promptly. This paper presents key shortcomings of the current funding, management and research policies and highlights possible action areas to remedy this situation. PMID- 26491519 TI - [Hemophilia B minor revealed by a cerebral hemorrhage: report of a case]. PMID- 26491520 TI - [Eye redness: think of rosacea]. PMID- 26491521 TI - [Pseudomonas aeruginosa infections in the service of infectious diseases at CHU YO, Burkina Faso: about two cases]. PMID- 26491522 TI - Hypoalbuminaemia in haemodialysis patients at Parirenyatwa group of hospitals and Chitungwiza central hospital. AB - INTRODUCTION: Haemodialysis is one of the widely used methods in end stage renal disease. However it has a negative impact on the quality of life of the renal patients. Hypoalbuminaemia occur in haemodialysis patients and it correlates strongly with mortality and morbidity. We sought out to determine the prevalence of hypoalbuminaemia among haemodialysis patients at Parirenyatwa group of hospitals and Chitungwiza central hospital. METHODS: A questionnaire was administered on haemodialysis patients at Parirenyatwa Group of Hospitals and Chitungwiza Central Hospital who consented to participate in the study. Pre dialysis serum samples collected from the patients were used for albumin analysis. The serum from the patients was analysed for serum albumin levels using the Mindray BS120 chemistry analyser using the bromocresol green method. RESULTS: A total of 60 patients were recruited from the two hospitals. The Mean albumin concentration for the entire group was 33.6g/L SD (6.1 g/L). The mean albumin in males was 33.6 g/L, SD (5.9) and in female 33.6, SD (6.6 g/L) and this was not statistically significantly different (p = 0.988). The prevalence of hypoalbuminaemia was 76.7%. CONCLUSION: Hypoalbuminaemia in 76.7% of haemodialysis patients studied is a cause of concern thus monitoring of haemodialysis patients albumin is necessary since its decreased levels has been associated with increased morbidity and mortality. PMID- 26491523 TI - Posterior epidural migration of lumbar intervertebral fragment: case report. AB - Disc fragments are well known to migrate to superior, inferior, or lateral sites in the anterior epidural space, posterior epidural migrated lumbar disc fragments is an extremely rare disorder. Posterior epidural migrated lumbar disc fragments are often confused with other posterior epidural space-occupying lesions (cysts, abscesses, tumors, and hematomas). We reported the case of a 52- year-old man presented with progressive not systematizes bilateral radiculopathy complicated one week before admission a difficulty dorsiflexion prevents the start, and the stared to use crutches. Clinical examination revealed steppage gait and a strength score of 3/5 on dorsiflexion of feet. MR imaging of lumbar spine showed right posterolateral epidural mass that compressed the dural sac at the L3-4 level. Patient underwent surgery using posterior approach, an L3 laminectomy was performed, the extruded disk fragment was gently removed and L3-L4 interspace was explored. Histopathology confirmed the (PEMLIF). Postoperative course was uneventful. PMID- 26491524 TI - [Cushing syndrome during pregnancy: report of a case of adrenal adenoma]. PMID- 26491525 TI - Giant adenoid cystic carcinoma of the sinonasal cavity. PMID- 26491526 TI - [Osteogenesis imperfecta: report of a case]. PMID- 26491527 TI - Budd-chiari syndrome and renal arterial neurysms due to Behcet disease: a rare association. AB - Behcet's disease is a multisystemic vasculitis of unknown etiology with a chronic relapsing course. Vasculitis in Behcet's disease with predominant vascular involvement is the only vasculitis that affects both arteries and veins of any size. Involvement of the renal artery and inferior vena cava is rare among the arteries and veins, respectively. When disease affect the veins, it is in the form of thrombosis. Arterial complications include aneurysms, stenosis and occlusions. Both rupture of arterial aneurysm and occlusion of suprahepatic veins, causing Budd-Chiari syndrome, are associated with a high mortality rate. Vascular involvement is more common in male patients than in female patients. Men and patients with a younger age of onset present with a more severe prognosis. In this case report, we describe a very rare cause of intrarenal arterial aneurysm's rupture with previous Budd-Chiari syndrome due to Behcet's disease and successful angiographic embolization of actively bleeding aneurysm. PMID- 26491528 TI - [Aneurysm of the ascending aorta associated with massive aortic regurgitation: rare and serious complication of Behcet disease]. PMID- 26491529 TI - EUS-guided FNA of a portal vein thrombus in hepatocellular carcinoma. AB - Portal vein thrombosis is a relatively rare but well-known complication of cirrhosis that has a prevalence of between 1% and 5.7%. On the contrary, in case of hepatocellular carcinoma (HCC), it is a much more frequent complication. In this paper, we presented three cases that had liver cirrhosis, mass and portal vein thrombosis in liver. We were not able to diagnose the cases through imaging methods, laboratory results or histopathologically, however, they were diagnosed with endoscopic ultrasonography- fine needle aspiration EUS-FNA from portal vein thrombus. PMID- 26491530 TI - [Pseudotumoral malakoplakia of the breast]. PMID- 26491531 TI - [Desmoid fibromatosis of the breast: a case report on and a review of the literature]. PMID- 26491532 TI - Dermatomyositis revealing breast cancer: report of a case. AB - Dermatomyositis (DM) is a rare connective corresponding to an inflammatory disease of skeletal muscles. Paraneoplastic origin must always be sought, primarily gynecological tumor in women, but the investigations are often made difficult by the fact that a primary tumor is often not detectable at the time of the cutaneous manifestations. This approach includes in addition to the monitoring report at regular intervals of 6 to 12 months for two years after diagnosis. We report a case of Dermatomyositis revealing breast cancer. PMID- 26491533 TI - Amniotic amputation. PMID- 26491534 TI - Proceedings of the African Field Epidemiology Network (AFENET) Scientific Conference 17-22 November 2013 Addis Ababa, Ethiopia: plenaries and oral presentations. AB - Biennially, trainees and graduates of Field Epidemiology and Laboratory Training Programs (FELTPs) are presented with a platform to share investigations and projects undertaken during their two-year training in Applied Epidemiology. The African Field Epidemiology Network (AFENET) Scientific Conference, is a perfect opportunity for public health professionals from various sectors and organizations to come together to discuss issues that impact on public health in Africa. This year's conference was organized by the Ethiopian Health and Nutrition Research Institute in collaboration with the Ethiopia Ministry of Health, Ethiopian Public Health Association (EPHA), Ethiopia Field Epidemiology Training Program (EFETP), Addis Ababa University (AAU), Training Programs in Epidemiology and Public Health Interventions Network (TEPHINET) and AFENET. Participants at this year's conference numbered 400 from over 20 countries including; Angola, Burkina Faso, Cameroon, Central African Republic, Democratic Republic of the Congo, Ethiopia, Ghana, Indonesia, Kenya, Mozambique, Namibia, Nigeria, Rwanda, South Africa, Sudan, Tanzania, Uganda, Yemen and Zimbabwe. The topics covered in the 144 oral presentations included: global health security, emergency response, public health informatics, vaccine preventable diseases, immunization, outbreak investigation, Millennium Development Goals, Non Communicable Diseases, and public health surveillance. The theme for the 5th AFENET Scientific Conference was; "Addressing Public Health Priorities in Africa through FELTPs." Previous AFENET Scientific conferences have been held in: Accra, Ghana (2005), Kampala, Uganda (2007), Mombasa, Kenya (2009) and Dar es Salaam, Tanzania (2011). PMID- 26491535 TI - The Role of Oxygen Sensors, Hydroxylases, and HIF in Cardiac Function and Disease. AB - Ischemic heart disease is the leading cause of death worldwide. Oxygen-sensing proteins are critical components of the physiological response to hypoxia and reperfusion injury, but the role of oxygen and oxygen-mediated effects is complex in that they can be cardioprotective or deleterious to the cardiac tissue. Over 200 oxygen-sensing proteins mediate the effects of oxygen tension and use oxygen as a substrate for posttranslational modification of other proteins. Hydroxylases are an essential component of these oxygen-sensing proteins. While a major role of hydroxylases is regulating the transcription factor HIF, we investigate the increasing scope of hydroxylase substrates. This review discusses the importance of oxygen-mediated effects in the heart as well as how the field of oxygen sensing proteins is expanding, providing a more complete picture into how these enzymes play a multifaceted role in cardiac function and disease. We also review how oxygen-sensing proteins and hydroxylase function could prove to be invaluable in drug design and therapeutic targets for heart disease. PMID- 26491536 TI - Chemotherapy-Induced Cardiotoxicity: Overview of the Roles of Oxidative Stress. AB - Chemotherapy-induced cardiotoxicity is a serious complication that poses a serious threat to life and limits the clinical use of various chemotherapeutic agents, particularly the anthracyclines. Understanding molecular mechanisms of chemotherapy-induced cardiotoxicity is a key to effective preventive strategies and improved chemotherapy regimen. Although no reliable and effective preventive treatment has become available, numerous evidence demonstrates that chemotherapy induced cardiotoxicity involves the generation of reactive oxygen species (ROS). This review provides an overview of the roles of oxidative stress in chemotherapy induced cardiotoxicity using doxorubicin, which is one of the most effective chemotherapeutic agents against a wide range of cancers, as an example. Current understanding in the molecular mechanisms of ROS-mediated cardiotoxicity will be explored and discussed, with emphasis on cardiomyocyte apoptosis leading to cardiomyopathy. The review will conclude with perspectives on model development needed to facilitate further progress and understanding on chemotherapy-induced cardiotoxicity. PMID- 26491537 TI - Allopurinol Protects against Ischemia/Reperfusion-Induced Injury in Rat Urinary Bladders. AB - Bladder ischemia-reperfusion (I/R) injury results in the generation of reactive oxygen species (ROS) and markedly elevates the risk of lower urinary tract symptoms (LUTS). Allopurinol is an inhibitor of xanthine oxidase (XO) and thus can serve as an antioxidant that reduces oxidative stress. Here, a rat model was used to assess the ability of allopurinol treatment to ameliorate the deleterious effects of urinary bladder I/R injury. I/R injury reduced the in vitro contractile responses of longitudinal bladder strips, elevated XO activity in the plasma and bladder tissue, increased the bladder levels of tumor necrosis factor alpha (TNF-alpha), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase, reduced the bladder levels of extracellular regulated kinase (ERK), and decreased and increased the bladder levels of Bcl-2 and Bax, respectively. I/R injury also elevated lipid peroxidation in the bladder. Allopurinol treatment in the I/R injury was generated significantly ameliorating all I/R-induced changes. Moreover, an in situ fluorohistological approach also showed that allopurinol reduces the generation of intracellular superoxides enlarged by I/R injury. Together, the beneficial effects of allopurinol reducing ROS production may be mediated by normalizing the activity of the ERK, JNK, and Bax/Bcl-2 pathways and by controlling TNF-alpha expression. PMID- 26491538 TI - Neurodevelopmental Underpinnings of Angelman Syndrome. PMID- 26491539 TI - CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment. AB - BACKGROUND: Disruptive mutation in the CHD8 gene is one of the top genetic risk factors in autism spectrum disorders (ASDs). Previous analyses of genome-wide CHD8 occupancy and reduced expression of CHD8 by shRNA knockdown in committed neural cells showed that CHD8 regulates multiple cell processes critical for neural functions, and its targets are enriched with ASD-associated genes. METHODS: To further understand the molecular links between CHD8 functions and ASD, we have applied the CRISPR/Cas9 technology to knockout one copy of CHD8 in induced pluripotent stem cells (iPSCs) to better mimic the loss-of-function status that would exist in the developing human embryo prior to neuronal differentiation. We then carried out transcriptomic and bioinformatic analyses of neural progenitors and neurons derived from the CHD8 mutant iPSCs. RESULTS: Transcriptome profiling revealed that CHD8 hemizygosity (CHD8 (+/-)) affected the expression of several thousands of genes in neural progenitors and early differentiating neurons. The differentially expressed genes were enriched for functions of neural development, beta-catenin/Wnt signaling, extracellular matrix, and skeletal system development. They also exhibited significant overlap with genes previously associated with autism and schizophrenia, as well as the downstream transcriptional targets of multiple genes implicated in autism. Providing important insight into how CHD8 mutations might give rise to macrocephaly, we found that seven of the twelve genes associated with human brain volume or head size by genome-wide association studies (e.g., HGMA2) were dysregulated in CHD8 (+/-) neural progenitors or neurons. CONCLUSIONS: We have established a renewable source of CHD8 (+/-) iPSC lines that would be valuable for investigating the molecular and cellular functions of CHD8. Transcriptomic profiling showed that CHD8 regulates multiple genes implicated in ASD pathogenesis and genes associated with brain volume. PMID- 26491540 TI - Poly (3, 4-ethylenedioxythiophene)-ionic liquid coating improves neural recording and stimulation functionality of MEAs. AB - In vivo multi-electrode arrays (MEAs) can sense electrical signals from a small set of neurons or modulate neural activity through micro-stimulation. Electrode's geometric surface area (GSA) and impedance are important for both unit recording and neural stimulation. Smaller GSA is preferred due to enhanced selectivity of neural signal, but it tends to increase electrode impedance. Higher impedance leads to increased electrical noise and signal loss in single unit neural recording. It also yields a smaller charge injection window for safe neural stimulation. To address these issues, poly (3, 4-ethylenedioxythiophene) - ionic liquid (PEDOT-IL) conducting polymers were electrochemically polymerized on the surface of the microelectrodes. The PEDOT-IL coating reduced the electrode impedance modulus by over 35 times at 1 kHz. It also exhibited compelling nanostructure in surface morphology and significant impedance reduction in other physiologically relevant range (100Hz-1000Hz). PEDOT-IL coated electrodes exhibited a Charge Storage Capacity (CSC) that was about 20 times larger than that of bare electrodes. The neural recording performance of PEDOT-IL coated electrodes was also compared with uncoated electrodes and PEDOT-poly (styrenesulfonate) (PSS) coated electrodes in rat barrel cortex (SI). Spontaneous neural activity and sensory evoked neural response were utilized for characterizing the electrode performance. The PEDOT-IL electrodes exhibited a higher unit yield and signal-to-noise ratio (SNR) in vivo. The local field potential recording was benefited from the low impedance PEDOT-IL coating in noise and artifact reduction as well. Moreover, cell culture on PEDOT-IL coating demonstrated that the material is safe for neural tissue and reduces astrocyte fouling. Taken together, PEDOT-IL coating has the potential to benefit neural recording and stimulation electrodes, especially when integrated with novel small GSA electrode arrays designed for high recording density, minimal insertion damage and alleviated tissue reaction. PMID- 26491541 TI - Cognitive-motor integration deficits in young adult athletes following concussion. AB - BACKGROUND: The ability to perform visually-guided motor tasks requires the transformation of visual information into programmed motor outputs. When the guiding visual information does not align spatially with the motor output, the brain processes rules to integrate the information for an appropriate motor response. Here, we look at how performance on such tasks is affected in young adult athletes with concussion history. METHODS: Participants displaced a cursor from a central to peripheral targets on a vertical display by sliding their finger along a touch sensitive screen in one of two spatial planes. The addition of a memory component, along with variations in cursor feedback increased task complexity across conditions. RESULTS: Significant main effects between participants with concussion history and healthy controls without concussion history were observed in timing and accuracy measures. Importantly, the deficits were distinctly more pronounced for participants with concussion history compared to healthy controls, especially when the brain had to control movements having two levels of decoupling between vision and action. A discriminant analysis correctly classified athletes with a history of concussion based on task performance with an accuracy of 94 %, despite the majority of these athletes being rated asymptomatic by current standards. CONCLUSIONS: These findings correspond to our previous work with adults at risk of developing dementia, and support the use of cognitive motor integration as an enhanced assessment tool for those who may have mild brain dysfunction. Such a task may provide a more sensitive metric of performance relevant to daily function than what is currently in use, to assist in return to play/work/learn decisions. PMID- 26491542 TI - Fulminant liver failure associated with delayed identification of thyroid storm due to heterophile antibodies. AB - Hepatic dysfunction during hyperthyroidism frequently occurs with mild abnormalities in liver function tests that are self-limited, improving after treatment of thyroid disease. With the exception of congestive heart failure or secondary hepatic disease, significant hepatic compromise during thyrotoxicosis is rare and often of unexplained origin. This report identifies a novel case of severe hepatic compromise in the setting of thyrotoxicosis that was not initially identified due to a falsely elevated TSH. A 43-year-old African-American man presented to the intensive care unit with severe jaundice, weight loss, thyroid bruit and altered mental status. Initial diagnosis of hyperthyroidism was delayed due to a non-suppressed TSH of 0.20 MUU/mL. Laboratory studies identified dramatic hepatic synthetic dysfunction and elevated transaminases with a total bilirubin of 47.4 mg/dL, AST 259 U/L, and ALT 142 U/L. No toxins, structural or viral causes of liver disease were identified and the patient was prepared for potential liver biopsy. Heterophile antibodies were identified and removed by precipitation, demonstrating an undetectable TSH and free thyroxine 9.0 ng/dL consistent with hyperthyroidism. Subsequent treatment with thionamides, corticosteroids, and potassium iodide improved both thyroid and liver function and avoided unnecessary invasive testing. Heterophile antibodies remain as important interfering factors in TSH immunoassays, and thus, this case demonstrates the importance of matching the clinical picture with available laboratory data. In the absence of a known cause of hepatic dysfunction, hyperthyroidism should be considered as a potential etiology of acute liver failure of unknown origin. PMID- 26491543 TI - Premature Termination Codons Are Recognized in the Nucleus in A Reading-Frame Dependent Manner. AB - mRNAs containing premature termination codons (PTCs) are known to be degraded via nonsense-mediated mRNA decay (NMD). Unexpectedly, we found that mRNAs containing any type of PTC (UAA, UAG, UGA) are detained in the nucleus whereas their wild type counterparts are rapidly exported. This retention is strictly reading-frame dependent. Strikingly, our data indicate that translating ribosomes in the nucleus proofread the frame and detect the PTCs in the nucleus. Moreover, the shuttling NMD protein Upf1 specifically associates with PTC+ mRNA in the nucleus and is required for nuclear retention of PTC+ mRNA. Together, our data lead to a working model that PTCs are recognized in the nucleus by translating ribosomes, resulting in recruitment of Upf1, which in turn functions in nuclear retention of PTC+ mRNA. Nuclear PTC recognition adds a new layer of proofreading for mRNA and may be vital for ensuring the extraordinary fidelity required for protein production. PMID- 26491544 TI - Nanostructured Gas Sensors for Health Care: An Overview. AB - Nanostructured platforms have been utilized for fabrication of small, sensitive and reliable gas sensing devices owing to high functionality, enhanced charge transport and electro-catalytic property. As a result of globalization, rapid, sensitive and selective detection of gases in environment is essential for health care and security. Nonmaterial such as metal, metal oxides, organic polymers, and organic-inorganic hybrid nanocomposites exhibit interesting optical, electrical, magnetic and molecular properties, and hence are found potential gas sensing materials. Morphological, electrical, and optical properties of such nanostructures can be tailored via controlling the precursor concentration and synthesis conditions resulting to achieve desired sensing. This review presents applications of nano-enabling gas sensors to detect gases for environment monitoring. The recent update, challenges, and future vision for commercial applications of such sensor are also described here. PMID- 26491545 TI - Outcomes and Prognostic Factors of Intravitreal Bevacizumab Monotherapy in Zone I Stage 3+ and Aggressive Posterior Retinopathy of Prematurity. AB - Purpose. This study aims to evaluate the regression of retinopathy of prematurity (ROP) after one intravitreal injection of bevacizumab and the factors that influenced it. Methods. This retrospective case series was carried out at the "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania. It includes all the consecutive infants treated for ROP with one intravitreal bevacizumab injection, from January 1, 2009, throughout July 31, 2013. The follow up continued for 60 weeks after injection. We recorded ROP classification, regression, gender, gestational age, birth weight, postnatal age and postmenstrual age at treatment, and pregnancy type. Regression was analyzed according to each of the abovementioned factors, with the program IBM SPSS 20 (Chicago, Illinois, USA). Results. This study includes 74 eyes of 37 infants of which 52 had aggressive posterior ROP (70.27%) and 22 had zone I stage 3+ ROP (29.72%). One week after the bevacizumab injection, ROP regressed in 63 eyes (85.13%), with a statistically significant higher rate in zone I stage 3+ ROP (100%), as compared with aggressive posterior ROP (78.84%) (P = 0.03). We recorded no complications subsequent to the intravitreal injections of bevacizumab. We identified no late retinal detachment. Conclusion. ROP regression rate after one intravitreal bevacizumab injection was 85.13%. This trial is registered with trial registration number IRCT2014101618966N2. PMID- 26491546 TI - Inhibition of Corneal Neovascularization by Subconjunctival Injection of Fc Endostatin, a Novel Inhibitor of Angiogenesis. AB - We assessed the antiangiogenic effects of subconjunctival injection of Fc endostatin (FcE) using a human vascular endothelial growth factor-induced rabbit corneal neovascularization model. Angiogenesis was induced in rabbit corneas through intrastromal implantations of VEGF polymer implanted 2 mm from the limbus. NZW rabbits were separated into groups receiving twice weekly subconjunctival injections of either saline; 25 mg/mL bevacizumab; 2 mg/mL FcE; or 20 mg/mL FcE. Corneas were digitally imaged at 5 time points. An angiogenesis index (AI) was calculated (vessel length (mm) * vessel number score) for each observation. All treatment groups showed a significant decrease in the vessel length and AI compared to saline on all observation days (P < 0.001). By day 15, FcE 2 inhibited angiogenesis significantly better than FcE 20 (P < 0.01). There was no significant difference between FcE 2 and BV, although the values trended towards significantly increased inhibition by BV. BV was a significantly better inhibitor than FcE 20 by day 8 (P < 0.01). FcE was safe and significantly inhibited new vessel growth in a rabbit corneal neovascularization model. Lower concentration FcE 2 exhibited better inhibition than FcE 20, consistent with previous FcE studies referencing a biphasic dose-response curve. Additional studies are necessary to further elucidate the efficacy and clinical potential of this novel angiogenesis inhibitor. PMID- 26491547 TI - Apelin Protects Primary Rat Retinal Pericytes from Chemical Hypoxia-Induced Apoptosis. AB - Pericytes are a population of cells that participate in normal vessel architecture and regulate permeability. Apelin, as the endogenous ligand of G protein-coupled receptor APJ, participates in a number of physiological and pathological processes. To date, the effect of apelin on pericyte is not clear. Our study aimed to investigate the potential protection mechanisms of apelin, with regard to primary rat retinal pericytes under hypoxia. Immunofluorescence staining revealed that pericytes colocalized with APJ in the fibrovascular membranes dissected from proliferative diabetic retinopathy patients. In the in vitro studies, we first demonstrated that the expression of apelin/APJ was upregulated in pericytes under hypoxia, and apelin increased pericytes proliferation and migration. Moreover, knockdown of apelin in pericyte was achieved via lentivirus-mediated RNA interference. After the inhibition of apelin, pericytes proliferation was inhibited significantly in hypoxia culture condition. Furthermore, exogenous recombinant apelin effectively prevented hypoxia-induced apoptosis through downregulating active-caspase 3 expression and increasing the ratio of B cell lymphoma-2 (Bcl-2)/Bcl-2 associated X protein (Bax) in pericytes. These results suggest that apelin suppressed hypoxia-induced pericytes injury, which indicated that apelin could be a potential therapeutic target for retinal angiogenic diseases. PMID- 26491548 TI - Optical Coherence Tomography Angiography in Retinal Vascular Diseases and Choroidal Neovascularization. AB - Purpose. To assess the ability of optical coherence tomography-angiography (OCT A) to show and analyze retinal vascular patterns and the choroidal neovascularization (CNV) in retinal vascular diseases. Methods. Seven eyes of seven consecutive patients with retinal vascular diseases were examined. Two healthy subjects served as controls. All eyes were scanned with the SD-OCT XR Avanti (Optovue Inc, Fremont CA, USA). Split spectrum amplitude decorrelation angiography algorithm was used to identify the blood flow within the tissue. Fluorescein angiography (FA) and indocyanine green angiography (ICGA) with Spectralis HRA + OCT (Heidelberg Engineering GmbH) were performed. Results. In healthy subjects OCT-A visualized major macular vessels and detailed capillary networks around the foveal avascular zone. Patients were affected with myopic CNV (2 eyes), age-related macular degeneration related (2), branch retinal vein occlusion (BRVO) (2), and branch retinal artery occlusion (BRAO) (1). OCT-A images provided distinct vascular patterns, distinguishing perfused and nonperfused areas in BRVO and BRAO and recognizing the presence, location, and size of CNV. Conclusions. OCT-A provides detailed images of retinal vascular plexuses and quantitative data of pathologic structures. Further studies are warranted to define the role of OCT-A in the assessment of retinovascular diseases, with respect to conventional FA and ICG-A. PMID- 26491549 TI - Prognostic Factors for Open Globe Injuries and Correlation of Ocular Trauma Score in Tianjin, China. AB - Purpose. To investigate prognostic factors that influence the final visual acuity (VA) and to correlate the ocular trauma score (OTS) with the final VA in open globe injuries. Methods. A retrospective review of 298 patients with open globe injuries admitted to Tianjin Medical University General Hospital was carried out from January 1, 2010, till December 31, 2014. Prognostic factors influencing the final VA in patients with open globe injuries and the correlation between OTS and the final VA were examined. Results. Three hundred and fourteen eyes from 298 patients with open globe injuries were analyzed. Males had a higher rate of open globe injury than females (83.56% versus 16.44%). Mean age was 45.46 +/- 17.48 years (5-95 years). In a univariate analysis, prognostic factors influencing the final VA included initial VA, relative afferent papillary defect (RAPD), vitreous hemorrhage, lens injury, endophthalmitis, hyphema, retinal detachment, and the zone of injury. In a multiple logistic regression analysis, initial VA, RAPD, and the zone of injury were considered to be independent risk factors. The OTS correlated with final VA (r = 0.988, p = 0.000). Conclusion. In our study, the most important prognostic factors influencing the final VA were initial VA, RAPD, and the zone of injury. The OTS was of great importance for patients and ophthalmologists. PMID- 26491550 TI - Individualized Therapy with Ranibizumab in Wet Age-Related Macular Degeneration. AB - Individualized treatment regimens may reduce patient burden with satisfactory patient outcomes in neovascular age-related macular degeneration. Intravitreal anti-VEGF drugs are the current gold standard. Fixed monthly injections offer the best visual outcome but this regimen is not commonly followed outside clinical trials. A PRN regimen requires monthly visits where the patient is treated in the presence of signs of lesion activity. Therefore, an early detection of reactivation of the disease with immediate retreatment is crucial to prevent visual acuity loss. Several trials suggest that "treat and extend" and other proactive regimens provide a reasonable approach. The rationale of the proactive regimens is to perform treatment anticipating relapses or recurrences and therefore avoid drops in vision while individualizing patient followup. Treat and extend study results in significant direct medical cost savings from fewer treatments and office visits compared to monthly treatment. Current data suggest that, for one year, PRN is less expensive, but treat and extend regimen would likely be less expensive for subsequent years. Once a patient is not a candidate to continue with treatment, he/she should be sent to an outpatient unit with adequate resources to follow nAMD patients in order to reduce the burden of specialized ophthalmologist services. PMID- 26491551 TI - The Measurement of Intraocular Biomarkers in Various Stages of Proliferative Diabetic Retinopathy Using Multiplex xMAP Technology. AB - Purpose. To determine the intraocular levels of growth factors and cytokines in patients with various degrees of severity of proliferative diabetic retinopathy (PDR) using multiplex xMAP technology. Methods. A prospective cohort study of 61 eyes from 56 patients who were divided into 3 groups based on the severity of PDR. Patients in group number 1 are those who presented PDR with no need of repeated surgical intervention; patients in group number 2 had repeated vitreous bleeding; and patients in group number 3 had refractory neovascular glaucoma. The concentrations of proangiogenic, antiangiogenic, inflammatory, and neurotrophic factors were measured in intraocular fluid. The results were also compared with levels of factors measured in 50 eyes from 50 patients prior to senile cataract surgery (control group). Results. Patients with refractory neovascular glaucoma (the highest clinical severity group) had higher levels of interleukin 6 (IL-6) (median1 37.19; median3 384.74; P = .00096), transforming growth factor beta 1 (TGFbeta-1) (median1 49.00; median3 414.40; P = .0017), and vascular endothelial growth factor (VEGF) (median1 211.62; median3 352.82; P = .0454) compared with other PDR patients. Conclusions. Results of our study imply that levels of IL-6, TGFbeta-1, and VEGF correlate with the severity of PDR. PMID- 26491552 TI - Assessment of Full-Eye Response to Osmotic Stress in Mouse Model In Vivo Using Optical Coherence Tomography. AB - NaCl based solutions were applied as osmotic stress agents to alter the hydration state of the mouse eye. Full-eye responses to these osmotic challenges were monitored in vivo using a custom-built optical coherence tomography (OCT) with an extended imaging range of 12.38 mm. Dynamic changes in the mouse eye were quantified based on the OCT images using several parameters, including the central corneal thickness (CCT), the anterior chamber depth (ACD), the crystalline lens thickness (LT), the cornea-retina distance (CRD), the iris curvature (IC), and the lens scattering intensity (LSI). Apparent but reversible changes in the morphology of almost all the ocular components and the light transparency of the lens are exhibited. Particularly, the ocular dehydration induced by the hypertonic challenges resulted in a closing of the iridocorneal angle and an opacification of the lens. Our results indicated that the ocular hydration is an important physiological process which might be correlated with various ocular disorders, such as dry eye, cataract, and angle-closure glaucoma, and would affect the biometry and imaging of the eye. OCT uniquely enables the comprehensive study of the dynamic full-eye responses to the ocular hydration in vivo. PMID- 26491553 TI - Suppression of In Vivo Neovascularization by the Loss of TRPV1 in Mouse Cornea. AB - To investigate the effects of loss of transient receptor potential vanilloid receptor 1 (TRPV1) on the development of neovascularization in corneal stroma in mice. Blocking TRPV1 receptor did not affect VEGF-dependent neovascularization in cell culture. Lacking TRPV1 inhibited neovascularization in corneal stroma following cauterization. Immunohistochemistry showed that immunoreactivity for active form of TGFbeta1 and VEGF was detected in subepithelial stroma at the site of cauterization in both genotypes of mice, but the immunoreactivity seemed less marked in mice lacking TRPV1. mRNA expression of VEGF and TGFbeta1 in a mouse cornea was suppressed by the loss of TRPV1. TRPV1 gene ablation did not affect invasion of neutrophils and macrophage in a cauterized mouse cornea. Blocking TRPV1 signal does not affect angiogenic effects by HUVECs in vitro. TRPV1 signal is, however, involved in expression of angiogenic growth factors in a cauterized mouse cornea and is required for neovascularization in the corneal stroma in vivo. PMID- 26491554 TI - Aqueous Levels of Pigment Epithelium-Derived Factor and Macular Choroidal Thickness in High Myopia. AB - Purpose. To investigate the correlation between aqueous and serum levels of pigment epithelium-derived factor (PEDF) and macular choroidal thickness in high myopia patients, both with and without choroidal neovascularization (CNV). Methods. Serum and aqueous levels of PEDF were measured by enzyme-linked immunosorbent assay in 36 high myopia patients (36 eyes) with no CNV (non-CNV group), 14 high myopia patients (14 eyes) with CNV (CNV group), and 42 nonmyopia patients (42 eyes) (control group). Macular choroidal thickness was measured by enhanced-depth imaging optical coherence tomography. Results. Aqueous levels of PEDF were significantly higher in CNV group compared with non-CNV (P < 0.001) and control (P < 0.001) groups. Macular choroidal thicknesses were significantly decreased in the non-CNV and CNV groups compared with the control (P < 0.001) group. A statistically significant difference (P = 0.012) was found between the CNV and non-CNV groups. There was a positive correlation between aqueous PEDF and macular choroidal thickness in the non-CNV group (P = 0.005), but no correlation with the CNV group. No correlation between serum PEDF and macular choroidal thickness was detected in the three groups. Conclusion. Variations in aqueous PEDF levels coincide with changes in macular choroidal thickness in high myopia patients with no CNV, while no such relationship exists in high myopia patients with CNV. PMID- 26491556 TI - Ocular Angiogenesis. PMID- 26491555 TI - Long-Term Visual Outcome in Wet Age-Related Macular Degeneration Patients Depending on the Number of Ranibizumab Injections. AB - Purpose. To analyse the visual outcome in wet age-related macular degeneration (AMD) patients depending on the number of ranibizumab injections. Methods. 51 naive wet AMD patients were retrospectively recorded. Visual acuity (VA), central retinal thickness (CRT) measured with spectral domain (SD) optical coherence tomography (OCT), and number of intravitreal injections were compared at 6, 12, 18, 24, 30, and 36 months of follow-up. Kaplan-Meier survival rates (SRs) based on VA outcomes were calculated depending on the number of ranibizumab injections performed. Results. VA improved compared with baseline at 6 and 12 months (P < 0.005). No differences were found at 18, 24, 30, and 36 months (P > 0.05). CRT measured with Cirrus OCT decreased (P < 0.001) at all time points analysed. The mean number of injections received was 6.98 +/- 3.69. At 36 months, Kaplan-Meier SR was 76.5% (the proportion of patients without a decrease in vision of more than 0.3 logMAR units). VA remained stable (<=0.01 logMAR units) or improved in 62.7%. Within this group, SR was 92.9% in those who received 7 or more injections versus 51.4% receiving <7 treatments (P = 0.008; log-rank test). Conclusion. Better VA outcomes were found in stable wet AMD patients after 3 years of follow up if they received >=7 ranibizumab injections. PMID- 26491557 TI - Antiproliferative, Apoptotic, and Autophagic Activity of Ranibizumab, Bevacizumab, Pegaptanib, and Aflibercept on Fibroblasts: Implication for Choroidal Neovascularization. AB - Purpose. Choroidal neovascularization (CNV) is one of the most common complications of retinal diseases accompanied by elevated secretion of vascular endothelial growth factor (VEGF). Intravitreal anti-VEGFs (ranibizumab, bevacizumab, pegaptanib, and aflibercept) can suppress neovascularization, decrease vascular permeability and CNV size, and, thereby, improve visual function. The antiproliferative, apoptotic, and autophagic effect of anti-VEGF drugs on fibroblasts found in CNVs has not been yet explored. Methods. Concentration-dependent cellular effects of the four anti-VEGFs were examined in L929 fibroblasts over a 5-day period. The cell survival, mitotic and polykaryocytic indices, the level of apoptosis and autophagy, and the cellular growth kinetics were all assessed. Results. The anti-VEGFs could inhibit the survival, mitotic activity, and proliferation as well as increase the cellular heterogeneity, apoptosis, and autophagy of the fibroblasts in a dose-dependent manner. Cellular growth kinetics showed ranibizumab to be less aggressive, but three other anti-VEGFs showed higher antiproliferative and apoptotic activity and expressed negative cellular growth kinetics. Conclusions. The antiproliferative, apoptotic, and autophagic activity of anti-VEGFs upon fibroblasts may explain the cellular response and the etiology of CNV involution in vivo and serve as a good study model for CNV in vitro. PMID- 26491559 TI - Implications of Renal Denervation Therapy in Patients with Sleep Apnea. AB - Obstructive sleep apnea (OSA) syndrome is a prevalent condition characterized by repeated episodes of obstruction of the upper airway, leading to intermittent hypoxemia and important endothelial and anatomical dysfunctions that cause cardiovascular and cerebrovascular disease. The finding of the relationship between OSA and hypertension, especially resistant hypertension (RHT), has increased the interest in therapeutic strategies that affect renal sympathetic activity in these patients. The observational studies published until now demonstrated that renal denervation therapy can reduce the severity of OSA syndrome. Renal sympathetic denervation (RDN) could be a future therapeutic possibility for conditions other than RHT, such as atrial fibrillation, heart failure, obesity, and OSA syndrome, where renal sympathetic system plays an important physiological role. The aim of this review was to elucidate the implications of renal sympathetic activity in OSA syndrome. PMID- 26491558 TI - Risk Factors Associated with Cognitive Decline after Cardiac Surgery: A Systematic Review. AB - Modern day cardiac surgery evolved upon the advent of cardiopulmonary bypass machines (CPB) in the 1950s. Following this development, cardiac surgery in recent years has improved significantly. Despite such advances and the introduction of new technologies, neurological sequelae after cardiac surgery still exist. Ischaemic stroke, delirium, and cognitive impairment cause significant morbidity and mortality and unfortunately remain common complications. Postoperative cognitive decline (POCD) is believed to be associated with the presence of new ischaemic lesions originating from emboli entering the cerebral circulation during surgery. Cardiopulmonary bypass was thought to be the reason of POCD, but randomised controlled trials comparing with off-pump surgery show contradictory results. Attention has now turned to the growing evidence that perioperative risk factors, as well as patient-related risk factors, play an important role in early and late POCD. Clearly, identifying the mechanism of POCD is challenging. The purpose of this systematic review is to discuss the literature that has investigated patient and perioperative risk factors to better understand the magnitude of the risk factors associated with POCD after cardiac surgery. PMID- 26491560 TI - Robotically Assisted Single Anastomosis Duodenoileal Bypass after Previous Sleeve Gastrectomy Implementing High Valuable Technology for Complex Procedures. AB - Staged bariatric procedures in high risk patients are a common used strategy for morbid obese patients nowadays. After previous sleeve gastrectomy, surgical treatments in order to complete weight loss or comorbidities improvements or resolutions are possible. One strategy is to perform a novel technique named SADI (single anastomosis duodenoileal bypass-sleeve). We present the technique for totally intracorporeal robotically assisted SADI using five ports and a liver retractor. We aim to see if the robotic technology offers more advantageous anastomosis and dissection obtained by the robotic approach in comparison to standard laparoscopy. The safety, feasibility, and reproducibility of a minimally invasive robotic surgical approach to complex abdominal operations such as SADI are discussed. PMID- 26491561 TI - Elevated Risk of Suicidal Ideation in HIV-Positive Persons. AB - Globally, suicide and HIV/AIDS remain two of the greatest healthcare issues, particularly in low- and middle-income countries. Several studies have observed a relationship between suicidal behaviour and HIV/AIDS. Materials and Methods. The main objective of this research was to determine the prevalence of elevated risk of suicidal ideation in HIV-positive persons immediately following voluntary HIV counselling and testing (VCT). The study sample consisted of adult volunteers attending the VCT clinic at a university-affiliated, general state hospital. Participants completed a sociodemographic questionnaire, Beck's Hopeless Scale, and Beck's Depression Inventory. Results. A significantly elevated risk of suicidal ideation was found in 83.1% of the patients who tested seropositive. Despite a wide age range in the cohort studied, the majority of patients with suicidal ideation were males in the younger age group (age < 30 years), consistent with the age-related spread of the disease and an increase in suicidal behaviour in younger people. Relevant associated variables are discussed. Conclusion. The results serve as important markers that could alert healthcare professionals to underlying suicide risks in HIV-positive patients. It is recommended that screening for elevated risk of suicidal ideation and prevention of suicidal behaviour should form a routine aspect of comprehensive patient care at VCT clinics. PMID- 26491562 TI - Comparison of Folate Receptor Targeted Optical Contrast Agents for Intraoperative Molecular Imaging. AB - Background. Intraoperative imaging can identify cancer cells in order to improve resection; thus fluorescent contrast agents have emerged. Our objective was to do a preclinical comparison of two fluorescent dyes, EC17 and OTL38, which both target folate receptor but have different fluorochromes. Materials. HeLa and KB cells lines were used for in vitro and in vivo comparisons of EC17 and OTL38 brightness, sensitivity, pharmacokinetics, and biodistribution. In vivo experiments were then performed in mice. Results. The peak excitation and emission wavelengths of EC17 and OTL38 were 470/520 nm and 774/794 nm, respectively. In vitro, OTL38 required increased incubation time compared to EC17 for maximum fluorescence; however, peak signal-to-background ratio (SBR) was 1.4 fold higher compared to EC17 within 60 minutes (p < 0.001). Additionally, the SBR for detecting smaller quantity of cells was improved with OTL38. In vivo, the mean improvement in SBR of tumors visualized using OTL38 compared to EC17 was 3.3 fold (range 1.48-5.43). Neither dye caused noticeable toxicity in animal studies. Conclusions. In preclinical testing, OTL38 appears to have superior sensitivity and brightness compared to EC17. This coincides with the accepted belief that near infrared (NIR) dyes tend to have less autofluorescence and scattering issues than visible wavelength fluorochromes. PMID- 26491563 TI - A Rationale for Going Back to the Future: Use of Disposable Spacers for Pressurised Metered Dose Inhalers. AB - The introduction of pressurised metered dose inhalers (MDIs) in the mid-1950s completely transformed respiratory treatment. Despite decades of availability and healthcare support and development of teaching aids and devices to promote better use, poor pMDI user technique remains a persistent issue. The main pMDI user aid is the spacer/valved holding chamber (VHC) device. Spacer/chamber features (size, shape, configuration, construction material, and hygiene considerations) can vie with clinical effectiveness (to deliver the same dose as a correctly used pMDI), user convenience, cost, and accessibility. Unsurprisingly, improvised, low-cost alternatives (plastic drink bottles, paper cups, and paper towel rolls) have been pressed into seemingly effective service. A UK law change permitting schools to hold emergency inhalers and spacers has prompted a development project to design a low-cost, user-friendly, disposable, and recyclable spacer. This paper spacer requires neither preuse priming nor washing, and has demonstrated reproducible lung delivery of salbutamol sulphate pMDI, comparable to an industry-standard VHC, an alternative paperboard VHC, and pMDI alone. This new device appears to perform better than these other VHC devices at the low flow rates thought achievable by paediatric patients. The data suggest that this disposable spacer may have a place in the single-use emergency setting. PMID- 26491564 TI - Relationship between Tibial Baseplate Design and Rotational Alignment Landmarks in Primary Total Knee Arthroplasty. AB - This study evaluated the influence of modern tibial baseplate designs when using the anterior tibial cortex as a primary rotational landmark for the tibial baseplate in TKA. Eighty patients undergoing TKA were randomized in two groups. Group 1 included 25 females and 15 males receiving a posterior-stabilized (PS) symmetric tibial baseplate while Group 2 included 24 females and 16 males receiving a PS anatomical tibial component. Identical surgical technique, including the use of the surgical transepicondylar femoral axis (sTEA) and the anterior tibial cortex ("Curve-on-Curve") as rotational alignment landmarks, was used. All patients underwent CT evaluation performed with the knee in full extension. Three observers independently measured the rotational alignment of the tibial component in relation to the sTEA. The rotational alignment of the symmetric baseplate showed an average external rotation of 1.3 degrees (minimum 5 degrees , maximum -1 degrees ): 91% of the knees showed 0 +/- 3 degrees with respect to the surgical sTEA, being internally rotated in 20%. The rotational alignment of the anatomical baseplate showed an average external rotation of 4.1 degrees (minimum 0.4 degrees , maximum 8.9 degrees ): only 47.5% of the knees showed 0 +/- 3 degrees , being externally rotated in 100%. The difference between the two groups was statistically significant. This study confirms the reliability of the "Curve-on-Curve" technique as an adequate rotational alignment anatomical landmark in TKA: the use of an asymmetric tibial baseplate might lead to external rotation of the tibial component when this technique is intraoperatively chosen. PMID- 26491565 TI - Training Family Medicine Residents in Effective Communication Skills While Utilizing Promotoras as Standardized Patients in OSCEs: A Health Literacy Curriculum. AB - Introduction. Future health care providers need to be trained in the knowledge and skills to effectively communicate with their patients with limited health literacy. The purpose of this study is to develop and evaluate a curriculum designed to increase residents' health literacy knowledge, improve communication skills, and work with an interpreter. Materials and Methods. Family Medicine residents (N = 25) participated in a health literacy training which included didactic lectures and an objective structured clinical examination (OSCE). Community promotoras acted as standardized patients and evaluated the residents' ability to measure their patients' health literacy, communicate effectively using the teach-back and Ask Me 3 methods, and appropriately use an interpreter. Pre- and postknowledge, attitudes, and postdidactic feedback were obtained. We compared OSCE scores from the group that received training (didactic group) and previous graduates. Residents reported the skills they used in practice three months later. Results. Family Medicine residents showed an increase in health literacy knowledge (p = 0.001) and scored in the adequately to expertly performed range in the OSCE. Residents reported using the teach-back method (77.8%) and a translator more effectively (77.8%) three months later. Conclusions. Our innovative health literacy OSCE can be replicated for medical learners at all levels of training. PMID- 26491566 TI - Mechanistic Perspectives of Maslinic Acid in Targeting Inflammation. AB - Chronic inflammation drives the development of various pathological diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and cancer. The arachidonic acid pathway represents one of the major mechanisms for inflammation. Prostaglandins (PGs) are lipid products generated from arachidonic acid by the action of cyclooxygenase (COX) enzymes and their activity is blocked by nonsteroidal anti-inflammatory drugs (NSAIDS). The use of natural compounds in regulation of COX activity/prostaglandins production is receiving increasing attention. In Mediterranean diet, olive oil and table olives contain significant dietary sources of maslinic acid. Maslinic acid is arising as a safe and novel natural pentacyclic triterpene which has protective effects against chronic inflammatory diseases in various in vivo and in vitro experimental models. Understanding the anti-inflammatory mechanism of maslinic acid is crucial for its development as a potential dietary nutraceutical. This review focuses on the mechanistic action of maslinic acid in regulating the inflammation pathways through modulation of the arachidonic acid metabolism including the nuclear factor-kappa B (NF-kappaB)/COX-2 expression, upstream protein kinase signaling, and phospholipase A2 enzyme activity. Further investigations may provide insight into the mechanism of maslinic acid in regulating the molecular targets and their associated pathways in response to specific inflammatory stimuli. PMID- 26491567 TI - Perceptions of Participants in a Group, Community, Exercise Programme for People with Multiple Sclerosis. AB - Purpose. The purpose of this study was to explore the perceptions of people with multiple sclerosis of a community based, group exercise programme. Method. A pragmatic programme evaluation approach using qualitative research design was adopted. Focus groups were used to gather data from 14 participants who had taken part in a RCT of community based exercise interventions for PwMS who used at most a stick to walk outdoors. Data were transcribed verbatim and thematic analysis was used to first identify categories and then to group them into themes. Results. Three themes emerged, psychological benefits, physical benefits, and knowledge gained. The psychological benefits included the role of the group as a social and motivational factor, empowerment, confidence, hope, sense of achievement, and pride. Physical benefits were improved energy and reduced fatigue and improved ability and participation. Knowledge gained caused a shift from thoughts that exercise might do harm, to sufficient knowledge that would give participants confidence to exercise themselves. The role of the group was a key element in the positive outcomes. Conclusions. The qualitative analysis supports the findings of the main trial confirming positive effects of community exercise interventions by reducing the impact of MS and fatigue and improving participation. PMID- 26491568 TI - Prediction of Advisability of Returning Home Using the Home Care Score. AB - Purpose. The aim of this study was to assess whether the home care score (HCS), which was developed by the Ministry of Health and Welfare in Japan in 1992, is useful for the prediction of advisability of home care. Methods. Subjects living at home and in assisted-living facilities were analyzed. Binominal logistic regression analyses, using age, sex, the functional independence measure score, and the HCS, along with receiver operating characteristic curve analyses, were conducted. Findings/Conclusions. Only HCS was selected for the regression equation. Receiver operating characteristic curve analysis revealed that the area under the curve (0.9), sensitivity (0.82), specificity (0.83), and positive predictive value (0.84) for HCS were higher than those for the functional independence measure, indicating that the HCS is a powerful predictor for advisability of home care. Clinical Relevance. Comprehensive measurements of the condition of provided care and the activities of daily living of the subjects, which are included in the HCS, are required for the prediction of advisability of home care. PMID- 26491570 TI - Contralateral Metabolic Activation Related to Plastic Changes in the Spinal Cord after Peripheral Nerve Injury in Rats. AB - We have previously reported the crossed-withdrawal reflex in which the rats with nerve injury developed behavioral pain responses of the injured paw to stimuli applied to the contralateral uninjured paw. This reflex indicates that contralateral plastic changes may occur in the spinal cord after unilateral nerve injury. The present study was performed to elucidate the mechanisms and morphological correlates underlying the crossed-withdrawal reflex by using quantitative (14)C-2-deoxyglucose (2-DG) autoradiography which can examine metabolic activities and spatial patterns simultaneously. Under pentobarbital anesthesia, rats were subjected to unilateral nerve injury. Mechanical allodynia was tested for two weeks after nerve injury. After nerve injury, neuropathic pain behaviors developed progressively. The crossed-withdrawal reflex was observed at two weeks postoperatively. Contralateral enhancement of 2-DG uptake in the ventral horn of the spinal cord to electrical stimulation of the uninjured paw was observed. These results suggest that the facilitation of information processing from the uninjured side to the injured side may contribute to the crossed-withdrawal reflex by plastic changes in the spinal cord of nerve-injured rats. PMID- 26491571 TI - Double Ventricular Responses Leading to Reversible Cardiomyopathy as Late Complication after Slow-Pathway Ablation. AB - Double ventricular response is a rare arrhythmia that results from simultaneous antegrade conduction over the fast and slow pathways of AV node. Double ventricular responses may lead to arrhythmia-related cardiomyopathy. As far as we know, there is not any reported reversible cardiomyopathy development that resulted from double ventricular responses to one atrial impulse after slow pathway ablation. We report a unique case of double ventricular response cardiomyopathy that has been developed 5 years after slow pathway ablation. PMID- 26491569 TI - Cortical Excitability Measured with nTMS and MEG during Stroke Recovery. AB - OBJECTIVE: Stroke alters cortical excitability both in the lesioned and in the nonlesioned hemisphere. Stroke recovery has been studied using transcranial magnetic stimulation (TMS). Spontaneous brain oscillations and somatosensory evoked fields (SEFs) measured by magnetoencephalography (MEG) are modified in stroke patients during recovery. METHODS: We recorded SEFs and spontaneous MEG activity and motor threshold (MT) short intracortical inhibition (SICI) and intracortical facilitation (ICF) with navigated TMS (nTMS) at one and three months after first-ever hemispheric ischemic strokes. Changes of MEG and nTMS parameters attributed to gamma-aminobutyrate and glutamate transmission were compared. RESULTS: ICF correlated with the strength and extent of SEF source areas depicted by MEG at three months. The nTMS MT and event-related desynchronization (ERD) of beta-band MEG activity and SICI and the beta-band MEG event-related synchronization (ERS) were correlated, but less strongly. CONCLUSIONS: This first report using sequential nTMS and MEG in stroke recovery found intra- and interhemispheric correlations of nTMS and MEG estimates of cortical excitability. ICF and SEF parameters, MT and the ERD of the lesioned hemisphere, and SICI and ERS of the nonlesioned hemisphere were correlated. Covarying excitability in the lesioned and nonlesioned hemispheres emphasizes the importance of the hemispheric balance of the excitability of the sensorimotor system. PMID- 26491572 TI - Woven Coronary Artery Disease Successfully Managed with Percutaneous Coronary Intervention: A New Case Report. AB - Woven coronary artery is relatively rare and can be complicated in both acute and chronic phases. A few case reports have been published until now. Herein we report a case with right woven coronary artery managed with drug-eluted stent implantation without complication. PMID- 26491573 TI - Laser Phototherapy (660 nm) Can Be Beneficial for Reducing Gingival Inflammation in Prosthodontics. AB - Among the new technologies developed, low power lasers have enabled new approaches to provide conservative treatment. Low power lasers act at cellular level, resulting in reduced pain, modulating inflammation, and improved tissue healing. Clinical application of the low power laser requires specific knowledge concerning laser interaction with biological tissue so that the correct irradiation protocol can be established. The present case report describes the clinical steps involved in an indirect composite resin restoration performed in a 31-year-old patient, in whom low power laser was used for soft tissue biomodulation. Laser therapy was applied with a semiconductor laser 660 nm, spot size of 0.028 cm(2), energy density of 35.7 J/cm(2), mean power of 100 mW, and energy per point as 1 J, in contact mode, on a total of 2 points (mesial and distal), totaling 2 J of energy. The therapy with low power laser can contribute positively to the success of an indirect restorative treatment. PMID- 26491574 TI - Enamel Pearls Implications on Periodontal Disease. AB - Dental anatomy is quite complex and diverse factors must be taken into account in its analysis. Teeth with anatomical variations present an increase in the rate of severity periodontal tissue destruction and therefore a higher risk of developing periodontal disease. In this context, this paper reviews the literature regarding enamel pearls and their implications in the development of severe localized periodontal disease as well as in the prognosis of periodontal therapy. Radiographic examination of a patient complaining of pain in the right side of the mandible revealed the presence of a radiopaque structure around the cervical region of lower right first premolar. Periodontal examination revealed extensive bone loss since probing depths ranged from 7.0 mm to 9.0 mm and additionally intense bleeding and suppuration. Surgical exploration detected the presence of an enamel pearl, which was removed. Assessment of the remaining supporting tissues led to the extraction of tooth 44. Local factors such as enamel pearls can lead to inadequate removal of the subgingival biofilm, thus favoring the establishment and progression of periodontal diseases. PMID- 26491575 TI - Fabrication of Closed Hollow Bulb Obturator Using Thermoplastic Resin Material. AB - Purpose. Closed hollow bulb obturators are used for the rehabilitation of postmaxillectomy patients. However, the time consuming process, complexity of fabrication, water leakage, and discoloration are notable disadvantages of this technique. This paper describes a clinical report of fabricating closed hollow bulb obturator using a single flask and one time processing method for an acquired maxillary defect. Hard thermoplastic resin sheet has been used for the fabrication of hollow bulb part of the obturator. Method. After fabrication of master cast conventionally, bulb and lid part of the defect were formed separately and joined by autopolymerizing acrylic resin to form one sized smaller hollow body. During packing procedure, the defect area was loaded with heat polymerizing acrylic resin and then previously fabricated smaller hollow body was adapted over it. The whole area was then loaded with heat cure acrylic. Further processes were carried out conventionally. Conclusion. This technique uses single flask which reduces laboratory time and makes the procedure simple. The thickness of hollow bulb can be controlled and light weight closed hollow bulb prosthesis can be fabricated. It also minimizes the disadvantages of closed hollow bulb obturator such as water leakage, bacterial infection, and discoloration. PMID- 26491576 TI - Calcitonin-Secreting Neuroendocrine Carcinoma of Larynx with Metastasis to Thyroid. AB - Primary neuroendocrine tumors of the larynx are rare, with moderately differentiated neuroendocrine carcinoma (MDNC) being the most frequent histologic type. We report a MDNC in a 57-year-old gentleman with an enlarging right-sided neck mass. Flexible fiberoptic exam revealed a right arytenoid lesion. Histology from excisional biopsy was concerning for medullary thyroid carcinoma (MTC) versus NET of the larynx. Immunohistochemistry was diffusely positive for calcitonin and CEA and focally positive for TTF-1. Serum calcitonin was elevated. Thyroid ultrasound was unremarkable. The patient underwent laryngectomy, thyroidectomy, and neck dissection. Pathology showed neuroendocrine carcinoma of right arytenoid with positive cervical lymph nodes. A 4 mm deposit of NET was present in right thyroid with adjacent intravascular tumor consistent with thyroidal metastasis from a primary laryngeal NET (MDNC). MDNC and MTC can be microscopically indistinguishable. Both tumors can stain positively for calcitonin and CEA. TTF-1 staining has been useful to help distinguish these tumors as it is strongly and diffusely positive in MTC, but usually negative (or only focally positive) in MDNC. We report the fourth case of primary neuroendocrine carcinoma of the larynx associated with elevated serum calcitonin level and the first such case associated with metastasis to the thyroid. PMID- 26491577 TI - A Case Report on the Progression of Myeloid Sarcoma to Form Multiple Metastatic Deposits without Developing Acute Myeloid Leukaemia. AB - Introduction. Myeloid sarcomas (MS) are rare tumours occurring at extramedullary sites. They are usually associated with other haematology disorders such as acute myeloid leukaemia, myelodysplastic syndrome, and chronic myeloproliferative neoplasms. They frequently occur with a diagnosis of acute myeloid leukaemia (AML) or with relapse of preexisting disease. Patients with myeloid sarcomas without history or evidence of myeloid leukaemia typically progress to form AML. Case Presentation. A case report of a patient diagnosed with an isolated myeloid sarcoma that rarely did not transform to AML but instead spread to form multiple myeloid sarcomas throughout the body. Discussion. This case identifies the risk of metastatic spread of these tumours rather than the development of AML which is poorly documented in the literature, due to the rarity of cases, and may be significant in the investigation and management of isolated myeloid sarcomas. This case highlights the need for clinicians to consider repeat cross-sectional imaging to investigate unexplained clinical decline or symptoms, when there is no sign of AML progression and to consider radiotherapy treatment early. PMID- 26491578 TI - Reverse Pseudohyperkalemia: An Important Clinical Entity in Chronic Lymphocytic Leukemia. AB - Hyperkalemia is a potentially lethal electrolyte derangement commonly seen in patients with hematologic neoplasms with or without renal failure. Pseudohyperkalemia and reverse pseudohyperkalemia also can be seen in this patient population and early recognition and diagnosis of these conditions are vital. Here, we report a case of reverse pseudohyperkalemia in a patient with chronic lymphocytic leukemia (CLL) and provide recommendations regarding diagnostic and therapeutic strategies for management of such patients. Further, we discuss the pathogenesis of this condition and its potential role as a surrogate of favorable prognostic features in patients with CLL. PMID- 26491579 TI - Systemic Sarcoidosis Presenting with Headache and Stroke-Like Episodes. AB - Sarcoidosis is a multisystem granulomatous disorder. Neurological manifestations as a presenting symptom are relatively rare. A 26-year-old male presented with a five-week history of headache suggestive of raised intracranial pressure. He subsequently developed transient episodes of mild right-sided hemiparesis and numbness. Magnetic resonance imaging (MRI) of brain revealed widespread inflammatory white matter lesions, an ischaemic focus in the left corona radiata, and widespread microhaemorrhages consistent with a more diffuse vasculopathy. Serum angiotensin-converting enzyme (ACE) level was normal. Lumbar puncture revealed an elevated opening pressure (36 cmH2O) and inflammatory cerebrospinal fluid (CSF). Computerised tomography (CT) of chest, abdomen, and pelvis revealed widespread lymphadenopathy and biopsy of axillary lymph nodes revealed the presence of noncaseating granulomata in keeping with systemic sarcoidosis. The patient responded well to corticosteroids. This case highlights the importance of considering sarcoidosis to be a rare but potentially treatable cause of stroke in younger patients. PMID- 26491580 TI - A Rare Cause of Reversible Renal Hemosiderosis. AB - Kidney failure secondary to renal hemosiderosis has been reported in diseases with intravascular hemolysis, like paroxysmal nocturnal hemoglobinuria, and valvular heart diseases. We present here a case of hemosiderin induced acute tubular necrosis secondary to intravascular hemolysis from Clostridium difficile infection with possible role of supratherapeutic INR. We discuss the pathophysiology, causes, and prognosis of acute tubular injury from hemosiderosis. PMID- 26491581 TI - Sildenafil Induced Acute Interstitial Nephritis. AB - Acute interstitial nephritis (AIN) is characterized by inflammation of the renal interstitium and usually occurs in a temporal relationship with the medication. We present a case of an Asian male who had nephrotic range proteinuria and presented with acute kidney injury. The patient reported an acute change in physical appearance and symptomatology after the ingestion of a single dose of sildenafil. Renal biopsy was notable for minimal change disease (MCD) with acute and chronic interstitial nephritis. Renal replacement and glucocorticoid therapy were initiated. Renal recovery within six weeks permitted discontinuation of dialysis. AIN superimposed on MCD is a known association of NSAID induced nephropathy. The temporal association and the absence of any new drugs suggest that the AIN was most likely due to the sildenafil. NSAIDs are less likely to have caused the AIN given their remote use. The ease of steroid responsiveness would also suggest another cause as NSAID induced AIN is often steroid resistant. The MCD was most likely idiopathic given the lack of temporal association with a secondary cause. As the number of sildenafil prescriptions increases, more cases of AIN may be identified and physician awareness for this potential drug disease association is necessary. PMID- 26491582 TI - Acquired Hemophilia A with a Rare Presentation of Acute Subdural Hematoma. AB - An 80-year-old man was admitted for acute subdural hematoma caused by a mild brain injury. His coagulation test showed an isolated prolongation of activated partial thromboplastin time (aPTT). Though the subdural hematoma did not progress, oozing bleed from the wound of tracheostomy continued. Failure of correction on aPTT mixing test supported the presence of an inhibitor to a coagulation factor. Once the diagnosis of acquired hemophilia A (AHA) was made, steroid therapy was performed, which leads him to complete remission of AHA. Isolated prolongation of aPTT can be the key to diagnose a rare coagulopathy, such as AHA. PMID- 26491583 TI - A Case of Ovarian Pregnancy Diagnosed by MRI. AB - Ovarian pregnancy is a rare form of ectopic pregnancy, causing a great diagnostic challenge. We report a case of ovarian pregnancy in a 42-year-old woman, in whom MRI successfully demonstrated the implantation in the ovary. Transvaginal ultrasonography showed an echogenic mass in the right ovary but failed to demonstrate tubal pregnancy. T2-weighted MR images disclosed a gestational sac structure in the right ovary, which exhibited heterogeneous high intensity intermingled with punctate foci of distinct low intensity. MRI may be a useful tool for diagnosing ovarian pregnancy, by demonstrating a gestational sac in the ovary. PMID- 26491584 TI - A Rare Case of Meconium Periorchitis Diagnosed in Utero. AB - Meconium periorchitis is a rare disorder caused by fetal meconium peritonitis, with subsequent passage of meconium into the scrotum via a patent processus vaginalis. To date, clinical significance of meconium periorchitis for the prenatal diagnosis of meconium peritonitis and prediction for postnatal surgery remains to be determined. We present a clinical course of a fetus presenting with meconium periorchitis induced by meconium peritonitis. At 28 weeks' gestation, fetal ultrasonography indicated fetal ascites associated with bilateral hydrocele and peritesticular calcification without other signs of meconium peritonitis. The pregnancy was uneventful until delivery and the infant was delivered at 37 weeks' gestation. No abdominal distension was observed at birth, and radiography did not reveal any abdominal calcification except for scrotal calcification. Abdominal distension was observed 3 days after birth and laparotomy was performed. The diagnosis of meconium peritonitis was confirmed at surgery. Our case illustrated that careful examination of the scrotum during fetal life was helpful for prenatal diagnosis of meconium peritonitis as well as postnatal management. PMID- 26491585 TI - Unexpected Leiomyosarcoma 4 Years after Laparoscopic Removal of the Uterus Using Morcellation. AB - Background. Laparoscopic hysterectomies are increasingly popular; a morcellation device is often used. Although there are some clear benefits, morcellation of tissue does have potential risks. Case Presentation. In this case report we present a 55-year-old woman with an abdominal tumour 4 years after a laparoscopic hysterectomy using a morcellation device. Postoperative histological analysis, compromised by morcellated tissue, showed benign myoma. Because of the benign tumour no follow-up was performed. The patient presented now with an abdominal tumour, and she was scheduled for surgical removal of the tumour. During abdominal surgery the tumour appeared malignant and biopsies were taken. Histological analysis showed leiomyosarcoma, and the patient was referred to a third care centre for further treatment. The patient recovered quickly after abdominal removal of the tumour; however, after 7 months the patient had complaints and a CT scan showed a large intra-abdominal tumour with possible lung metastasis. The patient received palliative chemotherapy and died after 10 months. Conclusion. This case shows that although unexpected after a hysterectomy, a leiomyosarcoma has to be considered in case of a suspect tumour in the lower abdomen. PMID- 26491586 TI - Oxaliplatin-Induced Tonic-Clonic Seizures. AB - Oxaliplatin is a common chemotherapy drug used for colon and gastric cancers. Common side effects are peripheral neuropathy, hematological toxicity, and allergic reactions. A rare side effect is seizures which are usually associated with posterior reversible leukoencephalopathy syndrome (PRES). A 50-year-old male patient presented with severe abdominal pain. CT scan of the abdomen showed acute appendicitis. Appendectomy was done and pathology showed mixed adenoneuroendocrine carcinoma. Adjuvant chemotherapy was started with Folinic acid, Fluorouracil, and Oxaliplatin (FOLFOX). During the third cycle of FOLFOX, the patient developed tonic-clonic seizures. Laboratory workup was within normal limits. EEG and MRI of the brain showed no acute abnormality. The patient was rechallenged with FOLFOX but he had tonic-clonic seizures for the second time. His chemotherapy regimen was switched to Folinic acid, Fluorouracil, and Irinotecan (FOLFIRI). After 5 cycles of FOLFIRI, the patient did not develop any seizures, making Oxaliplatin the most likely culprit for his seizures. Oxaliplatin-induced seizures rarely occur in the absence of PRES. One case report has been described in the literature. We present a rare case of tonic-clonic seizures in a patient receiving Oxaliplatin in the absence of PRES. PMID- 26491587 TI - Can Total Wrist Arthroplasty Be an Option for Treatment of Highly Comminuted Distal Radius Fracture in Selected Patients? Preliminary Experience with Two Cases. AB - We present two case reports of successful primary shortening of the forearm and total wrist arthroplasty (TWA) using the new angle-stable Maestro Wrist Reconstructive System (WRS) for treatment of highly comminuted distal radius fracture in selected autonomous patients. In a 56-year-old male patient with adequate bone stock, insertion of the noncemented Maestro WRS was combined with ulnar shortening osteotomy. In an 84-year-old female patient with poor osteoporotic bone stock, insertion of the radial cemented Maestro WRS was combined with ulnar head resection. Both patients could resume their work without additional surgery after TWA. At the 1-year follow-up, there were no changes in position of either implant without signs of loosening, no impingement, and no instability of the distal radioulnar joint or the distal ulna stump. All clinical parameters (DASH score, pain through VAS, and grip strength) were satisfactory. Both patients reported that they would have the same procedure again. Further experience is needed to validate this concept. PMID- 26491588 TI - Acromioclavicular Dislocation Associated with Coracoid Process Fracture: Report of Two Cases and Review of the Literature. AB - Acromioclavicular dislocation associated with coracoid process fracture is a rare injury. Herein we reported two further cases with such combination of injuries and reviewed all previously published cases in current literature. In this review, we discussed the demographic characteristics, mechanism of injury, diagnosis, and treatment options extensively. PMID- 26491589 TI - Talar Neck Fracture after United Tibiotalar Fusion. AB - Tibiotalar arthrodesis is a well-established treatment for tibiotalar arthritis, for example, in younger high demand patients. Talar neck fractures are less common though well-recognised sequelae of foot ankle trauma. Here we present the clinical case of a 69-year-old male who presented to our institution with a nonunion of a talar neck fracture, having undergone a left tibiotalar fusion 24 years previously. To the authors' knowledge, this injury has only been described once previously in the literature. However, the original case described a fracture sustained in the very early postoperative period following tibiotalar fusion, postulated to be secondary to postimmobilisation osteopaenia or stress risers from metalwork. The aetiology in this case is likely due to axial compression transmitted to the talar neck via the calcaneus. The predisposing factors for nonunion are discussed, highlighting the importance of vigilance for this injury in any patient with concomitant tibiotalar fusion and foot trauma. The management of this patient is discussed. PMID- 26491590 TI - Bicruciate Ligament Reconstruction in a Professional Rugby Player: Clinical Presentation and Literature Review. AB - The association of an anterior cruciate ligament (ACL) tear and a posterior cruciate ligament (PCL) injury is rare in athletes, and to our knowledge it has never been described in a professional rugby player. We report the case of a 27 year-old international professional rugby player who presented with an ACL tear associated with chronic posterior laxity on a former PCL tear. The procedure associated arthroscopic ACL and PCL reconstruction in a one-stage operation with two autografts, bone-patellar tendon-bone and hamstring tendon, respectively. At 7 months postoperatively, the patient had returned to playing rugby at the same level of play. The therapeutic strategy successfully met the established goals of returning to sports at the same level of play with excellent functional results after 2 years of follow-up. A literature review was performed via PubMed. The inclusion criteria were the studies in English language, assessing the return-to sport after bicruciate ligament reconstruction in athletes. Eight studies were included in analysis. Only one study has focused on the return-to-sport in 24 competitive athletes and two other studies have included 1 professional athlete each. The overall rate of the return-to-sport after bicruciate reconstruction varied between 100% and 50%. PMID- 26491591 TI - Original Solution for Middle Ear Implant and Anesthetic/Surgical Management in a Child with Severe Craniofacial Dysmorphism. AB - We describe the novel solution adopted in positioning middle ear implant in a child with bilateral congenital aural atresia and craniofacial dysmorphism that have posed a significant challenge for the safe and correct management of deafness. A five-year-old child, affected by a rare congenital disease (Van Maldergem Syndrome), suffered from conductive hearing loss. Conventional skin drive bone-conduction device, attached with a steel spring headband, has been applied but auditory restoration was not optimal. The decision made was to position Vibrant Soundbridge, a middle ear implant, with an original surgical application due to hypoplasia of the tympanic cavity. Intubation procedure was complicated due to child craniofacial deformities. Postoperative hearing rehabilitation involved a multidisciplinary team, showing improved social skills and language development. PMID- 26491592 TI - Spindle Cell Lipoma Occurring in the Buccal Mucosa: An Unusual Location of This Benign Lipomatous Neoplasm. AB - Spindle cell lipoma is a benign lipomatous neoplasm, which rarely occurs in the oral cavity. The aims of this paper are to report a case of spindle cell lipoma located in buccal mucosa and discuss the main clinical, histological, and immunohistochemical findings of this entity. Thus, we report a 4-year history of an asymptomatic smooth surface nodule in an elderly Caucasian man with clinical hypothesis of fibroma. The histopathological examination showed spindle cells, mature adipose tissue, and many mast cells in a stroma of connective tissue presenting ropey collagen fibers bundles. After immunohistochemical analysis, the final diagnosis was spindle cell lipoma. PMID- 26491593 TI - Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases. AB - Introduction. Autism spectrum disorders are defined by behavioral and language atypias. Growing body of evidence indicates inflammatory mediators may contribute to the condition. Palmitoylethanolamide (PEA) is naturally occurring and has been available as a nonprescription medical food supplement in Europe since 2008. PEA has been tested in thousands of human subjects without any noted significant side effects. Here we report the first cases of the administration of PEA to two children with autism. Case Presentations. The first 13-year-old male child (Subject 1) presented with a total IgE of 572 IU/mL (nl < 200) and with low mature CD57(+) natural killer cell counts (32 cells/uL; nl = 60-300 cells/uL) and with significant eczema and allergic stigmata. Expressive language, as measured by mean length of utterance, and overall autism severity as measured by the Childhood Autism Rating Scale, Second Edition, improved significantly. Atopic symptoms diminished. No side effects were reported. The second male child, age 15 (Subject 2), also displayed noticeable and rapid improvements in cognitive, behaviors, and sociability. Conclusion. Currently, there is no definitive treatment for autism condition. Palmitoylethanolamide could be an effective treatment for autism syndrome. We propose appropriate double-blind clinical trials to further explore palmitoylethanolamide efficacy and safety. PMID- 26491594 TI - Pulmonary Nocardiosis in the Immunocompetent Host: Case Series. AB - Pulmonary nocardiosis is commonly recognized as an opportunistic infection in patients with predisposing immunosuppressive conditions. However, reports of pulmonary nocardiosis in the immunocompetent host are rare. Here, we report a case series of four patients with pulmonary nocardiosis without a predisposing condition. PMID- 26491595 TI - Retrograde Transpubic Approach for Percutaneous Radiofrequency Ablation and Cementoplasty of Acetabular Metastasis. AB - We report a case of painful and disabling anterior acetabular bone metastasis treated with bipolar radiofrequency ablation and cementoplasty. Due to the high risk of complications related to the proximity of the femoral neurovascular structures with a direct approach, we successfully performed a retrograde transpubic approach under combined CT and fluoroscopic guidance. In the present report, we describe this approach detailing its indications, advantages, and the technical tips to achieve a safe and satisfactory procedure. PMID- 26491596 TI - Island Latissimus Dorsi Muscle Flap and a Perforator Flap in Repairing Post Gunshot Thoracic Spine CSF Fistula: Case Presentation. AB - Persistent posttraumatic CSF fluid leakage may present a challenge to manage. Failure to address the leakage may result in complications such as meningitis, septicemia, radiculopathy, muscle weakness, and back pains. While the majority of the leakages may be managed conservatively, large dura defects as a result of gunshot wounds or motor vehicle accidents are best managed by surgical interventions. This may range from primary closure of the defect to fascial grafts, adhesive glues, and flaps. We present our experience with the use of flaps in a patient who had sustained such wounds in the thoracic spine. An island latissimus dorsal flap and a perforator fasciocutaneous flap were used to close the defect. Postoperatively the patient recovered well and the wounds healed without any complications. PMID- 26491597 TI - Pediatric Granular Cell Tumor of the Breast: A Case Report and Review of the Literature. AB - Objective. Granular cell tumors arise from neurogenic mesenchymal stem cells and can occur anywhere throughout the body. They rarely present as breast masses and should be included in the differential diagnosis of pediatric breast neoplasms. We report a rare presentation of a pediatric breast granular cell tumor and a review of the literature. Participant. A 15-year-old female presented with an enlarging breast mass. She underwent ultrasound imaging and excisional biopsy, which revealed a granular cell tumor. Granular cell tumors of the breast are difficult to diagnose using ultrasound and mammography due to numerous similarities to other breast masses. Histopathologic staining best differentiates breast granular cell tumors from other breast masses with their positive staining for S100, CD68, and neurospecific enolase. Conclusion. Although rare, granular cell tumors of the breast should be considered as a possible diagnosis for pediatric breast masses to allow for proper management and follow-up for these patients. Although rare, these tumors do have malignant potential necessitating a correct and timely diagnosis. PMID- 26491598 TI - It Suddenly Occurred: Extensive Subcutaneous Emphysema after Bipolar Transurethral Resection of Prostate. AB - Subcutaneous emphysema is a very rare and good-natured complication after transurethral resection of prostate (TURP). It has been reported as colon perforation, diverticulitis, and bladder perforation associated complication previously. We report the first case of a wide subcutaneous emphysema due to microperforations of prostatic capsule, without a bladder perforation after TURP. Any sign of clinic situation should lead to ceasing of the procedure immediately; otherwise, it can cause a life-threatening problem of abdominal compartment syndrome. PMID- 26491599 TI - Urinary Incontinence due to Overactive Detrusor Muscle: A Rare Side Effect of Venlafaxine. AB - We report a case of reemergence of urinary incontinence (UI) in a patient with benign prostatic hyperplasia (BPH) after starting treatment with venlafaxine who was stabilized on tamsulosin and finasteride for about 6 years. A 66-year-old Caucasian male with prior history of major depressive disorder developed UI within a week of starting venlafaxine 75 mg per day. He described symptoms in the form of involuntary leakage of urine both during the day and at night. His symptoms of UI resolved after stopping the venlafaxine. To the best of our knowledge, there are only four case reports of venlafaxine induced urinary incontinence which have been published. PMID- 26491601 TI - Letter from the Editor-in-Chief: Irreproducible Results. PMID- 26491600 TI - Pentoxifylline Neuroprotective Effects Are Possibly Related to Its Anti Inflammatory and TNF-Alpha Inhibitory Properties, in the 6-OHDA Model of Parkinson's Disease. AB - Pentoxifylline (PTX) is a phosphodiesterase inhibitor with anti-TNF-alpha activity, associated with its anti-inflammatory action. Considering Parkinson's disease (PD) as a neuroinflammatory disorder, the objectives were to evaluate PTX neuroprotective properties, in a model of PD. Male Wistar rats, divided into sham operated (SO), untreated 6-OHDA, and 6-OHDA treated with PTX (10, 25, and 50 mg/kg) groups, received a unilateral 6-OHDA injection, except the SO group administered with saline. Treatments started 24 h after surgery and continued for 15 days when the animals were submitted to apomorphine-induced rotations, open field, and forced swimming tests. At the next day, they were euthanized and their striata processed for neurochemical (DA and DOPAC determinations), histological, and immunohistochemical (Fluoro-Jade, TH, DAT, OX-42, TNF-alpha, COX-2, and iNOS) studies. PTX reversed the behavioral changes observed in the untreated 6-OHDA animals. Furthermore, PTX partially reversed the decrease in DA contents and improved neuronal viability. In addition, decreases in immunostaining for TH and dopamine transporter (DAT) were reversed. The untreated 6-OHDA group showed intense OX-42, TNF-alpha, COX-2, and iNOS immunoreactivities, which were attenuated by PTX. In conclusion, we demonstrated a neuroprotective effect of PTX, possibly related to its anti-inflammatory and antioxidant actions, indicating its potential as an adjunct treatment for PD. PMID- 26491602 TI - A Novel Computational Method to Reduce Leaky Reaction in DNA Strand Displacement. AB - DNA strand displacement technique is widely used in DNA programming, DNA biosensors, and gene analysis. In DNA strand displacement, leaky reactions can cause DNA signals decay and detecting DNA signals fails. The mostly used method to avoid leakage is cleaning up after upstream leaky reactions, and it remains a challenge to develop reliable DNA strand displacement technique with low leakage. In this work, we address the challenge by experimentally evaluating the basic factors, including reaction time, ratio of reactants, and ion concentration to the leakage in DNA strand displacement. Specifically, fluorescent probes and a hairpin structure reporting DNA strand are designed to detect the output of DNA strand displacement, and thus can evaluate the leakage of DNA strand displacement reactions with different reaction time, ratios of reactants, and ion concentrations. From the obtained data, mathematical models for evaluating leakage are achieved by curve derivation. As a result, it is obtained that long time incubation, high concentration of fuel strand, and inappropriate amount of ion concentration can weaken leaky reactions. This contributes to a method to set proper reaction conditions to reduce leakage in DNA strand displacement. PMID- 26491603 TI - Three-Dimensional Kinetic Adaptations of Gait throughout Pregnancy and Postpartum. AB - Biomechanical adaptations that occur during pregnancy can lead to changes on gait pattern. Nevertheless, these adaptations of gait are still not fully understood. The purpose was to determine the effect of pregnancy on the biomechanical pattern of walking, regarding the kinetic parameters. A three-dimensional analysis was performed in eleven participants. The kinetic parameters in the joints of the lower limb during gait were compared at the end of the first, second, and third trimesters of pregnancy and in the postpartum period, in healthy pregnant women. The main results showed a reduction in the normalized vertical reaction forces, throughout pregnancy, particularly the third peak. Pregnant women showed, during most of the stance phase, medial reaction forces as a motor response to promote the body stability. Bilateral changes were observed in hip joint, with a decrease in the participation of the hip extensors and in the eccentric contraction of hip flexors. In ankle joint a decrease in the participation of ankle plantar flexors was found. In conclusion, the overall results point to biomechanical adjustments that showed a decrease of the mechanical load of women throughout pregnancy, with exception for few unilateral changes of hip joint moments. PMID- 26491605 TI - Estimating the Risk of ABO Hemolytic Disease of the Newborn in Lagos. AB - Background. ABO hemolytic disease of the newborn is the most common hemolytic consequence of maternofetal blood group incompatibility restricted mostly to non group-O babies of group O mothers with immune anti-A or anti-B antibodies. Aim. We estimated the risk of ABO HDN with view to determining need for routine screening for ABO incompatibility between mother and fetus. Materials and Methods. Prevalence of ABO blood group phenotypes in blood donors at the donor clinic of the Lagos University Teaching Hospital and arithmetic methods were used to determine population prevalence of ABO genes. We then estimated proportion of pregnancies of group O mothers carrying a non-group-O baby and the risk that maternofetal ABO incompatibility will cause clinical ABO HDN. Results. Blood from 9138 donors was ABO typed. 54.3%, 23%, 19.4%, and 3.3% were blood groups O, A, B, and AB, respectively. Calculated gene frequencies were 0.1416, 0.1209, and 0.7375 for A, B, and O genes, respectively. It was estimated that 14.3% of deliveries will result in a blood group O woman giving birth to a child who is non-group-O. Approximately 4.3% of deliveries are likely to suffer ABO HDN with 2.7% prone to suffer from moderately severe to severe hemolysis. PMID- 26491606 TI - Buckysomes: New Nanocarriers for Anticancer Drugs. AB - Buckysomes, liposome-like vesicles comprised of dendritic C60 subunits that self assemble into unilamellar vesicles, are unique nanovectors that have utility in drug delivery. We have prepared paclitaxel-embedded buckysomes (PEBs) and examined biodistriubition profiles with commercially available formulations of the drug. As compared to Abraxane, an albumin-bound formulation of paclitaxel, PEBs showed higher tissue accumulation in the liver and the kidney at 45 and 60 minutes and in the lungs at 30 minutes, making them suitable drug-delivery carriers for short-term therapy to the mentioned organs. These buckysomes can be further functionalized to specifically deliver paclitaxel to the tumor site. PMID- 26491607 TI - Are Serotonin Alterations the Link between Thrombocytopenia and Poor Immune Status among HIV Infected Individuals? AB - OBJECTIVE: Thrombocytopenia (TCP<150 * 103 cells/mm3) has emerged as a relevant factor in the clinical course of HIV. However, the mechanisms mediating such observations have not been well characterized, limiting the possibility of creating targeted interventions. Notably, platelets are the storage and transporter system for serotonin and Brain derived neurotrophic factor (BDNF), which recent laboratory studies associated with viral replication and lymphocyte survival. Thus, we posit that (1) TCP will be associated with reduced levels of BDNF and serotonin (2) That these alterations will lead to poor viro-immune responses to antiretroviral therapy. METHODS: To achieve this goal, a total of 400 people living with HIV were consecutively enrolled to characterize the frequency of thrombocytopenia in hazardous and non-hazardous alcohol user populations in the HAART era. Then, participants underwent immune and laboratory assessments, to determine if TCP was associated with alterations in serotonin (5 HT) and brain derived neurotrophic factor (BDNF). RESULTS: The prevalence of thrombocytopenia in this antiretroviral treated cohort was 14%. Rates were significantly higher in the heavy alcohol users, HAU versus the non HAU group (Heavy: 25% versus HAU: 15% versusnon-HAU: 10%). Multivariate model analyses indicated that having TCP, low BDNF levels (<5000 pg/ml), and number of drinks per day were predictors of serotonin levels. PLWH with TCP had about 2-fold lower PPP-BDNFlevels (5037.4 +/- 381 vs. 9137.5 +/- 7062 pg/ml p=0.0001). Other significant predictors of BDNF levels at the last visit included receiving selective serotonin reuptake inhibitors and PPP serotonin levels. Multivariate analyses also confirmed that altered serotonin levels were associated withhigh viral loadsboth low CD4 cell counts. CONCLUSIONS: Thrombocytopenia is a relatively frequent complication of HIV, andis particularly prevalent among hazardous alcohol users (HAU). These findings suggest that TCP is associated with altered levels of BDNF and serotonin, suggesting that they may be the bridge linking TCP and poor viro-immune responses observed in this group. These results could have important clinical and therapeutic implications. PMID- 26491604 TI - Macrophage Heterogeneity and Plasticity: Impact of Macrophage Biomarkers on Atherosclerosis. AB - Cardiovascular disease (CVD) is a global epidemic, currently representing the worldwide leading cause of morbidity and mortality. Atherosclerosis is the fundamental pathophysiologic component of CVD, where the immune system plays an essential role. Monocytes and macrophages are key mediators in this aspect: due to their heterogeneity and plasticity, these cells may act as either pro- or anti inflammatory mediators. Indeed, monocytes may develop heterogeneous functional phenotypes depending on the predominating pro- or anti-inflammatory microenvironment within the lesion, resulting in classic, intermediate, and non classic monocytes, each with strikingly differing features. Similarly, macrophages may also adopt heterogeneous profiles being mainly M1 and M2, the former showing a proinflammatory profile while the latter demonstrates anti inflammatory traits; they are further subdivided in several subtypes with more specialized functions. Furthermore, macrophages may display plasticity by dynamically shifting between phenotypes in response to specific signals. Each of these distinct cell profiles is associated with diverse biomarkers which may be exploited for therapeutic intervention, including IL-10, IL-13, PPAR-gamma, LXR, NLRP3 inflammasomes, and microRNAs. Direct modulation of the molecular pathways concerning these potential macrophage-related targets represents a promising field for new therapeutic alternatives in atherosclerosis and CVD. PMID- 26491608 TI - AN EXAMINATION OF THE GLUTEAL MUSCLE ACTIVITY ASSOCIATED WITH DYNAMIC HIP ABDUCTION AND HIP EXTERNAL ROTATION EXERCISE: A SYSTEMATIC REVIEW. AB - BACKGROUND: A wide variety of hip abduction and hip external rotation exercises are used for training, both in athletic performance and in rehabilitation programming. Though several different exercises exist, a comprehensive understanding of which exercises best target the gluteus maximus (Gmax) and gluteus medius (Gmed) and the magnitude of muscular activation associated with each exercise is yet to be established. PURPOSE: The purpose of this systematic review was to quantify the electromyographic (EMG) activity of exercises that utilize the Gmax and Gmed muscles during hip abduction and hip external rotation. METHODS: Pubmed, Sports Discuss, Web of Science and Science Direct were searched using the Boolean phrases (gluteus medius OR gluteus maximus) AND (activity OR activation) AND (electromyography OR EMG) AND (hip abduction OR hip external rotation). A systematic approach was used to evaluate 575 articles. Articles that examined injury-free participants of any age, gender or activity level were included. No restrictions were imposed on publication date or publication status. Articles were excluded when not available in English, where studies did not normalize EMG activity to maximum voluntary isometric contraction (MVIC), where no hip abduction or external rotation motion occurred or where the motion was performed with high acceleration. RESULTS: Twenty-three studies met the inclusion criteria and were retained for analysis. The highest Gmax activity was elicited during the lateral step up, cross over step up and rotational single leg squat (ranging from 79 to 113 % MVIC). Gmed activity was highest during the side bridge with hip abduction, standing hip abduction with elastic resistance at the ankle and side lying hip abduction (ranging from 81 to 103 % MVIC). LIMITATIONS: The methodological approaches varied between studies, notably in the different positions used for obtaining MVIC, which could have dramatically impacted normalized levels of gluteal activation, while variation also occurred in exercise technique and/or equipment. CONCLUSIONS: The findings from this review provide an indication for the amount of muscle activity generated by basic strengthening and rehabilitation exercises, which may assist practitioners in making decisions for Gmax and Gmed strengthening and injury rehabilitation programs. PMID- 26491609 TI - THE INFLUENCE OF HIP STRENGTH ON KNEE KINEMATICS DURING A SINGLE-LEGGED MEDIAL DROP LANDING AMONG COMPETITIVE COLLEGIATE BASKETBALL PLAYERS. AB - BACKGROUND: A smaller knee flexion angle and larger knee valgus angle during weight-bearing activities have been identified as risk factors for non-contact anterior cruciate ligament (ACL) injuries. To prevent such injuries, attention has been focused on the role of hip strength in knee motion control. However, gender differences in the relationship between hip strength and knee kinematics during weight-bearing activities in the frontal plane have not been evaluated. HYPOTHESIS/PURPOSE: The purpose of this study was to determine the influence of hip strength on knee kinematics in both genders during a single-legged landing task in the frontal plane. The hypotheses were that 1) subjects with a greater hip strength would demonstrate larger knee flexion and smaller knee valgus and internal rotation angles and 2) no gender differences would exist during the single-legged landing task. METHODS: Forty-three Japanese collegiate basketball players (20 males, 23 females) participated in this study. Three-dimensional motion analysis was used to evaluate knee kinematics during a single-legged medial drop landing (SML). A hand-held dynamometer was used to assess hip extensor (HEXT), abductor (HAB), and external rotator (in two positions: seated position [SHER] and prone [PHER]) isometric strength. Spearman rank correlation coefficients (rho) were determined for correlations between hip strength and knee kinematics at initial contact (IC) and peak (PK) during SML (p < 0.05). RESULTS: Negative correlations were observed between the knee valgus angle at IC and HEXT (rho = -0.48, p = 0.02), HAB (rho = -0.46, p = 0.03) and PHER (rho = -0.44, p = 0.04) strength in females. In addition, a significant positive correlation was observed between the knee flexion angle at PK and HEXT strength (rho = 0.61, p = 0.004) in males. CONCLUSIONS: Significant correlations between hip strength and knee kinematics during SML were observed in both genders. Hip strength may, therefore, play an important role in knee motion control during sports activities, suggesting that increased hip strength may help to prevent non contact ACL injuries in athletes of both genders. Moreover, gender-specific programs may be needed to control abnormal knee motion, as the influence of hip strength on knee kinematics may differ based on gender. LEVEL OF EVIDENCE: 3. PMID- 26491610 TI - Y BALANCE TESTTM ANTERIOR REACH SYMMETRY AT THREE MONTHS IS RELATED TO SINGLE LEG FUNCTIONAL PERFORMANCE AT TIME OF RETURN TO SPORTS FOLLOWING ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION. AB - BACKGROUND: Restoration of symmetrical strength, balance, and power following anterior cruciate ligament reconstruction (ACL-R) are thought to be important factors for successful return to sports. Little information is available regarding early rehabilitation outcomes and achieving suggested limb indices of 90% on functional performance measures at the time of return to sports (RTS). HYPOTHESIS/PURPOSE: To examine the relationship between symmetry of the anterior reach of the Y Balance TestTM at 12 weeks and functional performance measures at time of return to sports after anterior cruciate ligament (ACL) reconstruction. STUDY DESIGN: Retrospective Cohort. METHODS: Forty subjects (mean +/- SD age, 17.2 +/- 3.8 years) who were in the process of rehabilitation following ACL reconstruction. Each subject volunteered and was enrolled in the study during physical therapy following ACL-R. Participants averaged two visits per week in physical therapy until the time of testing for RTS. The Y Balance TestTM was assessed at 12 weeks. Participants completed a battery of tests at RTS (6.4 +/- 1.1 months) including triple hop distance (THD), single hop distance (SHD), isometric knee extension strength (KE), and the Vail Sport TestTM. Side to side difference was calculated for the Y Balance TestTM anterior reach and limb symmetry indices (LSI) were computed for THD, SHD, and KE. Multiple regression models were used to study the relationship between variables at 12 weeks and RTS while controlling for age, gender, type of graft, and pain score. In addition, subjects were dichotomized based on a side-to-side Y Balance anterior reach difference into high risk (>4 cm) or low risk (<=4 cm) categories. A receiver operating characteristic (ROC) curve was used to identify individuals at 12 weeks who do not achieve 90% limb symmetry indices at time of RTS testing. . RESULTS: A statistically significant association was seen between Y Balance ANT at 12 weeks and SHD at RTS (beta = -1.46, p = 0.0005, R(2) = 0.395), THD at RTS (beta = 1.08, p = 0.0011, R(2) = 0.354) and KE at RTS (beta = -1.00, p = 0.0025, R(2) = 0.279) after adjusting for age, gender, type of graft and pain score at week 12. There was no significant association between Y Balance ANT at 12 weeks and Vail Sport Test at RTS (p = 0.273). ROC curves indicated that the Y Balance ANT at 12 weeks identified participants who did not achieve 90% LSI for the SHD (AUC = 0.82 p = 0.02) and THD (AUC=0.85, p = 0.01) at RTS with a sensitivity of 0.96 (SHD) and 0.92 (THD) respectively. CONCLUSIONS: Participants following ACL-R who demonstrated > 4 cm Y Balance ANT deficits at 12 weeks on their involved limb did not tend to achieve 90% LSI for the SHD and THD at time of return to sports. The Y Balance ANT at 12 weeks and Vail Sport TestTM appear to measure different constructs following ACL-R. LEVELS OF EVIDENCE: Level 3. PMID- 26491611 TI - MODIFIED FUNCTIONAL MOVEMENT SCREENING AS A PREDICTOR OF TACTICAL PERFORMANCE POTENTIAL IN RECREATIONALLY ACTIVE ADULTS. AB - BACKGROUND: Failure to meet minimum performance standards is a leading cause of attrition from basic combat training. A standardized assessment such as the Functional Movement ScreenTM (FMSTM) could help identify movement behaviors relevant to physical performance in tactical occupations. Previous work has demonstrated only marginal association between FMSTM tests and performance outcomes, but adding a load challenge to this movement assessment may help highlight performance-limiting behaviors. PURPOSE: The purposes of this investigation were to quantify the effect of load on FMSTM tests and determine the extent to which performance outcomes could be predicted using scores from both loaded and unloaded FMSTM conditions. STUDY DESIGN: Crossover Trial. METHODS: Thirteen female and six male recreationally active college students (21 +/- 1.37 years, 168 +/- 9.8 cm, 66 +/- 12.25 kg) completed the FMSTM under (1) a control condition (FMSTMC), and (2) an 18.10kg weight vest condition (FMSTMW). Balance was assessed using a force plate in double-legged stance and tactical physical performance was evaluated via completion times in a battery of field tests. For each condition, penalized regression was used to select models from the seven FMSTM component tests to predict balance and performance outcomes. Data were collected during a single session lasting approximately three hours per participant. RESULTS: For balance, significant predictors were identified from both conditions but primarily predicted poorer balance with increasing FMSTM scores. For tactical performance, models were retained almost exclusively from FMSTMW and generally predicted better performance with higher item scores. CONCLUSIONS: The current results suggest that FMSTM screening with an external load could help predict performance relevant to tactical occupations. Sports medicine and fitness professionals interested in performance outcomes may consider assessing movement behaviors under a load. LEVEL OF EVIDENCE: 3. PMID- 26491612 TI - OVERHEAD DEEP SQUAT PERFORMANCE PREDICTS FUNCTIONAL MOVEMENT SCREENTM SCORE. AB - BACKGROUND: The Functional Movement Screen (FMSTM) has been suggested for use in predicting injury risk in active populations, but time constraints may limit use of the screening test battery. Identifying one component of the FMSTM that can predict which individuals may perform poorly on the entire test, and therefore should undergo the full group of screening maneuvers, may reduce time constraints and increase pre-participation screening utilization. PURPOSE: The purpose of this study was to determine if performance on the FMSTM overhead deep squat test (DS) could predict performance on the entire FMSTM. STUDY DESIGN: Cohort study. METHODS: One hundred and three collegiate athletes underwent offseason FMSTM testing. The DS and adjusted FMSTM composite scores were dichotomized into low performance and high performance groups with athletes scoring below 2 on the DS categorized as low performance, and athletes with adjusted FMSTM composite scores below 12 categorized as low performance. Scores of 2 or above and 12 or above were considered high performances for the DS test and adjusted FMSTM composite score respectively, and therefore low risk for movement dysfunction and potentially, injury. RESULTS: Individuals categorized as low performance as a result of the DS test had lower adjusted FMSTM composite scores (p < 0.001). DS scores were positively correlated with adjusted FMSTM composite scores (rho = 0.50, p < 0.001). Binomial logistic regression identified an odds ratio of 3.56 (95% CI: 1.24, 10.23, p = 0.018) between DS and FMSTM performance categories. CONCLUSIONS: Performance on the DS test may predict performance on the FMSTM and help identify individuals who require further musculoskeletal assessment. Further research is needed to determine if DS performance can predict asymmetries during the FMSTM. LEVEL OF EVIDENCE: Level 3. PMID- 26491613 TI - RELATIONSHIPS BETWEEN FUNCTIONAL MOVEMENT TESTS AND PERFORMANCE TESTS IN YOUNG ELITE MALE BASKETBALL PLAYERS. AB - PURPOSE/BACKGROUND: Sprinting and jumping are two common and important components of high-level sport performance. The weight-bearing dorsiflexion test (WB-DF) and Star Excursion Balance Test (SEBT) are tools developed to identify athletes at risk for lower extremity injury and may be related to running and jumping performance among athletes. The purposes of the present study were: 1) to identify any relationships between functional movement tests (WB-DF and SEBT) and performance tests (jumping, sprinting and changing direction); 2) to examine any relationships between asymmetries in functional movements and performance tests. STUDY DESIGN: Descriptive cohort study. METHODS: Fifteen elite male basketball players (age: 15.4 +/- 0.9 years) were assessed during a three-week period to determine the reliability of functional screening tools and performance tests and to examine the relationships between these tests. Relative (intraclass correlation coefficient) and absolute (coefficient of variation) reliability were used to assess the reproducibility of the tests. RESULTS: Significant correlations were detected between certain functional movement tests and performance tests. Both left and right excursion composite scores related to slower performance times in sprint testing, demonstrating that greater dynamic reach relates to decreased quickness and acceleration among these elite basketball athletes. The various relationships between dynamic functional movement testing, speed, and jump performance provide guidance for the strength and conditioning professional when conducting and evaluating data in an effort to improve performance and reduce risk of injury. CONCLUSIONS: The results of the present study suggest that these functional and performance tests do not measure the same components of human movement, and could be paired as outcome measures for the clinical and sport assessment of lower extremity function. LEVEL OF EVIDENCE: 2b. PMID- 26491614 TI - THE MINIMUM CLINICALLY IMPORTANT DIFFERENCE ON THE VISA-A AND LEFS FOR PATIENTS WITH INSERTIONAL ACHILLES TENDINOPATHY. AB - STUDY DESIGN: Cohort study of subjects with insertional Achilles tendinopathy (IAT). OBJECTIVES: The purpose of this study was to establish the minimum clinically important difference (MCID) on the Victorian Institute of Sport Assessment - Achilles Questionnaire (VISA-A) and the Lower Extremity Functional Scale (LEFS) for patients with IAT. BACKGROUND: The VISA-A and LEFS are two measures commonly utilized for patients with IAT. Previous authors have estimated the MCID for the VISA-A, but a MCID has not been formally established. The MCID for the LEFS has been established for patients with lower extremity conditions in general, but it is not clear if this MCID is applicable to patients with IAT. METHODS: Fifteen subjects participating in a randomized controlled trial studying the effectiveness of intervention for IAT over a 12-week period were included in this study. Subjects completed the VISA-A and LEFS forms at baseline and 12 weeks after the initiation of treatment. All subjects also completed a 15-point global rating of change (GROC) questionnaire at 12 weeks after the initiation of treatment. Subjects were classified as improved or stable based on their GROC scores. RESULTS: The area under the curve (AUC) for the VISA-A was 0.97 and a MCID of 6.5 points was identified. The AUC for the LEFS was 0.97 and a MCID of 12 points was identified. CONCLUSION: The VISA-A and LEFS are both useful outcome measures to assess response in patients with IAT. LEVEL OF EVIDENCE: 3. PMID- 26491615 TI - ELECTROMYOGRAPHIC ANALYSIS OF SHOULDER GIRDLE MUSCLES DURING COMMON INTERNAL ROTATION EXERCISES. AB - BACKGROUND: High level throwing performance requires the development of effective muscle activation within shoulder girdle muscles particularly during forceful internal rotation (IR) motions. STUDY DESIGN: Controlled Laboratory Descriptive Study. PURPOSE: To investigate activation pattern of 16 shoulder girdle muscles/muscle sub-regions during three common shoulder IR exercises. METHODS: EMG was recorded in 30 healthy subjects from 16 shoulder girdle muscles/muscle sub-regions (surface electrode: anterior, middle and posterior deltoid, upper, middle and lower trapezius, serratus anterior, teres major, upper and lower latissimus dorsi, upper and lower pectoralis major; fine wire electrodes: supraspinatus, infraspinatus, subscapularis and rhomboid major) using a telemetric EMG system. Three IR exercises (standing IR at 0 degrees and 90 degrees of Abduction, and IR at Zero-Position) were studied. EMG amplitudes were normalized to EMGmax (EMG at maximal IR force in a standard position) and compared using one-way repeated-measures analysis of variance (ANOVA). RESULTS: There were significant differences in muscles' activation across IR exercises (p<0.05-p<0.001). Rotator cuff and deltoid muscles were highly activated during IR at 90 degrees of Abduction. Latissimus dorsi exhibited markedly higher activation during IR at Zero-Position. While upper trapezius had the highest activation during IR at Zero-Position, middle and lower trapezius were activated at highest during IR at 90 degrees of Abduction. The highest activation of serratus anterior and rhomboid major occurred in IR at Zero-Position and IR at 90 degrees of Abduction, respectively. CONCLUSIONS: Studied exercises have the potential to effectively activate glenohumeral and scapular muscles involved in throwing motions. Results provide further evidence for developing rehabilitation, injury prevention, and training strategies. LEVEL OF EVIDENCE: 4, Controlled laboratory study. PMID- 26491616 TI - RELIABILITY OF STRENGTH AND PERFORMANCE TESTING MEASURES AND THEIR ABILITY TO DIFFERENTIATE PERSONS WITH AND WITHOUT SHOULDER SYMPTOMS. AB - BACKGROUND: Upper extremity physical performance measures exist but none have been universally accepted as the primary means of gauging readiness to return to activity following rehabilitation. Few reports have described reliability and/or differences in outcome with physical performance measures between individuals with and without shoulder symptoms. HYPOTHESES/PURPOSE: The purpose of this study was to establish the reliability of traditional upper extremity strength testing and the CKCUEST in persons with and without shoulder symptoms as well as to determine if the testing maneuvers could discriminate between individuals with and without shoulder symptoms. The authors hypothesized that strength and physical performance testing would have excellent test/re-test reliability for individuals with and without shoulder symptoms and that the physical performance maneuver would be able to discriminate between individuals with and without shoulder symptoms. METHODS: Male and female subjects 18-50 years of age were recruited for testing. Subjects were screened and placed into groups based on the presence (Symptomatic Group) or absence of shoulder symptoms (Asymptomatic Group). Each subject performed an isometric strength task, a task designed to estimate 1-repetition maximum (RM) lifting in the plane of the scapula, and the closed kinetic chain upper extremity stability test (CKCUEST) during two sessions 7-10 days apart. Test/re-test reliability was calculated for all three tasks. Independent t-tests were utilized for between group comparisons to determine if a performance task could discriminate between persons with and without shoulder symptoms. RESULTS: Thirty-six subjects (18/group) completed both sessions. Test/re-test reliability for each task was excellent for both groups (intraclass correlations >= .85 for all tasks). Neither strength task could discriminate between subjects in either group. Subjects with shoulder symptoms had 3% less touches per kilogram of body weight on the CKCUEST compared to subjects without shoulder symptoms but this was not statistically significantly different (p=.064). CONCLUSIONS: The excellent test/re-test reliability has now been expanded to include individuals with various reasons for shoulder symptoms. Traditional strength testing does not appear to be the ideal assessment method for making discharge and/or return to activity decisions due to the inability to discriminate between the groups. The CKCUEST could be utilized to determine readiness for activity as it was trending towards being discriminatory between known groups. LEVEL OF EVIDENCE: Basic Science Reliability Study, Level 3. PMID- 26491617 TI - EFFECTS OF A SEASON OF SUBCONCUSSIVE CONTACT ON CHILD- SCAT3 SCORES IN 8-12 YEAR OLD MALE ATHLETES. AB - BACKGROUND: Each year, over 173,000 children and adolescents visit emergency departments due to sports and recreation related concussions, an increase of 60% over the last decade due to the rise in the number of children participating in sport. While numerous authors have sought to address the epidemiology of concussions across multiple age groups who participate in contact sports, a recent review of literature did not reveal a substantial amount of published articles that addressed the issue of subconcussive contact. Multiple tools have been developed to assess acute episodes of concussion. Among the assessment protocols many include an assessment of balance, short and long term memory recall, and balance. The Child-SCAT3 was designed specifically to evaluate concussions in children 5-12 years of age. OBJECTIVE: The purpose of this study was to determine the effect of a season of subconcussive contact on Child-SCAT3 scores in 8-12 year old males compared to their age matched peers who participated in non-contact sports. A secondary purpose was to evaluate how scores of the sub- components of the Child-SCAT3 compare between contact and non contact athletes. DESIGN: A prospective cohort study was performed of 71 male athletes (58 football, 13 baseball) ages 8-12 (contact mean age 10.30 years, SD 1.20; non-contact mean age 10.03 years, SD 1.26) over the course of a season. METHODS: Portions of The Child-SCAT3 were administered and scored in pre adolescent athletes prior to and following a season of participation in football (contact sport group) and baseball (non-contact sport group). The outcome measures of interest included the portions related to Cognitive ability, Balance, and Coordination. RESULTS: No statistically significant differences were found in group, time or time and group interaction for any of the utilized portions of the Child-SCAT3. Statistically significant differences were found between groups for preseason cognitive orientation and postseason immediate memory. Cognitive orientation and coordination were also found to be statistically significantly improved across both groups over the course of the season. LIMITATIONS: This study was potentially limited by the number of control subjects tested. CONCLUSIONS: A season of subconcussive contact in football was not detrimental to cognitive and balance scores on the Child-SCAT3. LEVEL OF EVIDENCE: 3. PMID- 26491619 TI - A NOVEL APPROACH TO TREATING PLANTAR FASCIITIS - EFFECTS OF PRIMAL REFLEX RELEASE TECHNIQUE: A CASE SERIES. AB - BACKGROUND/PURPOSE: Plantar fasciitis (PF), a common condition affecting physically active individuals, is typically treated with orthotics, two to four months of stretching programs, and/or surgery. Primal Reflex Release TechniqueTM (PRRT) is thought to reduce over-arousal of the nervous system through down regulation of the primal reflexes. The technique has been suggested as a novel treatment method for patients suffering from PF. The purpose of this case series was to examine the effects of PRRT on patients with PF. DESCRIPTION OF CASES: The PRRT technique was applied in eight consecutive cases of PF in physically active subjects. The Numeric Pain Rating Scale, the Disability in the Physically Active (DPA) Scale, and the Patient Specific Functional Scale (PSFS) were administered to identify patient-reported pain and dysfunction. OUTCOMES: Primal Reflex Release Technique (PRRT) was an effective treatment for subjects with either acute or chronic PF. The use of the PRRT treatment resulted in an average reduction in plantar fascia pain across all subjects that was both statistically significant and clinically following a single treatment. Statistically and clinically significant improvements on averaged measures of function, such as the DPA Scale and PSFS, were also found over the course of treatment. DISCUSSION: In this case series, the use of PRRT produced positive changes in terms of improvements in reported pain and dysfunction and a shorter time to resolution, when compared to traditional treatment methods for PF reported in the literature. Subjects who undergo PRRT treatment for both acute and chronic PF may experience reduction in pain and improvement of function that exceeds what is experienced in traditional conservative therapy programs found in the available literature. Clinicians should consider the regional interdependence model in order to identify underlying related factors when evaluating and treating PF. The autonomic nervous system may play a role in the perception of pain and should be addressed during treatment. LEVEL OF EVIDENCE: Level 4 - case series. PMID- 26491618 TI - PHYSICAL THERAPY INTERVENTION STRATEGIES FOR PATIENTS WITH PROLONGED MILD TRAUMATIC BRAIN INJURY SYMPTOMS: A CASE SERIES. AB - BACKGROUND AND PURPOSE: Although most patients recover from a mild traumatic brain injury (mTBI) within 7-14 days, 10-30% of people will experience prolonged mTBI symptoms. Currently, there are no standardized treatment protocols to guide physical therapy interventions for this population. The purpose of this case series was to describe the unique, multimodal evaluation and treatment approaches for each of the patients with post-concussion syndrome (PCS). CASE DESCRIPTION: Six pediatric athletes with PCS who had participated in physical therapy and fit the inclusion criteria for review were retrospectively chosen for analysis. Patients received a cervical evaluation, an aerobic activity assessment, an oculomotor screen, and postural control assessment. Each patient participated in an individualized physical therapy treatment plan-of-care based on their presentation during the evaluation. OUTCOMES: Patients were treated for a mean of 6.8 treatment sessions over 9.8 weeks. Four of six patients returned to their pre injury level of activity while two returned to modified activity upon completion of physical therapy. Improvements were observed in symptom scores, gaze stability, balance and postural control measures, and patient self-management of symptoms. All patients demonstrated adequate self-management of symptoms upon discharge from physical therapy. DISCUSSION/CONCLUSIONS: Physical therapy interventions for pediatric athletes with PCS may facilitate recovery and improve function. Further research is needed to validate effective tools for assessment of patients who experience prolonged concussion symptoms as well as to establish support for specific post-mTBI physical therapy interventions. LEVEL OF EVIDENCE: Level 4. PMID- 26491620 TI - POSTERIOR STERNOCLAVICULAR JOINT DISLOCATION IN A DIVISION I FOOTBALL PLAYER: A CASE REPORT. AB - Posterior dislocation of the sterno-clavicular (SC) joint is a rare injury in athletes. It normally occurs in high collision sports such as American football or rugby. Acute posterior dislocations of the SC joint can be life-threatening as the posteriorly displaced clavicle can cause damage to vital vascular and respiratory structures such as the aortic arch, the carotid and subclavian arteries, and the trachea. The potential severity of a posterior SC joint dislocation provides multiple challenges for clinicians involved in the emergency care and treatment of this condition. Integration of clinical examination observations, rapid critical thinking, and appropriate diagnostic imaging are often required to provide the best management and outcome for the injured athlete. The criterion for return-to-play and participation in collision sports after suffering a posterior dislocation of the SC joint are unclear due to the rarity of this injury. The purpose of this case report is to describe the management, from the initial on-field evaluation through the return-to-sport, of a collegiate Division I football player following a traumatic sports-related posterior SC joint dislocation. The rehabilitation process and the progression to return to participation are also presented and briefly discussed. LEVEL OF EVIDENCE: 4-Single case report. PMID- 26491621 TI - DIFFERENTIAL DIAGNOSTIC PROCESS AND CLINICAL DECISION MAKING IN A YOUNG ADULT FEMALE WITH LATERAL HIP PAIN: A CASE REPORT. AB - STUDY DESIGN: CASE REPORT: differential diagnosis and clinical decision making. BACKGROUND AND PURPOSE: Young adults with lateral hip pain are often referred to physical therapy (PT). A thorough examination is required to obtain a diagnosis and guide management. The purpose of this case report is to describe the physical therapist's differential diagnostic process and clinical decision making for a subject with the referring diagnosis of trochanteric bursitis. CASE DESCRIPTION: A 29-year-old female presented to PT with limited sitting and running tolerance secondary to right lateral hip pain. Her symptoms began three months prior when she abruptly changed her running intensity and frequency of weight bearing activities, including running and low impact plyometrics for the lower extremity. Physical examination revealed a positive Trendelenburg sign, manual muscle test that was weak and painless of the right hip abductors, and pain elicited when performing a vertical hop on a concrete surface (+single leg hop test), but pain free when performing the same single leg hop on a foam surface. Examination findings warranted discussion with the referring physician for further diagnostic imaging. OUTCOMES: Magnetic resonance imaging revealed a focus of edema in the posterior acetabulum, suspicious for an acetabular stress fracture. The subject was subsequently diagnosed with an acetabular stress fracture and restricted from running and plyometrics for four weeks. DISCUSSION: Thorough examination and appropriate clinical decision making by the physical therapist at the initial examination led to the diagnosis of an acetabular stress fracture in this subject. Clinicians must be aware of symptoms and signs which place the subject at risk for stress fracture for timely referral and management. LEVEL OF EVIDENCE: 4. PMID- 26491622 TI - A NOVEL APPROACH FOR THE REVERSAL OF CHRONIC APPARENT HAMSTRING TIGHTNESS: A CASE REPORT. AB - BACKGROUND AND PURPOSE: Movement dysfunction in the trunk and lower extremity (e.g., apparent hamstring tightness) may produce pain, as well as decrease range of motion, function, and performance in athletes. Novel treatments not frequently studied in the literature, such as Total Motion Release(r) (TMR(r)) and instrument-assisted soft -tissue mobilization (IASTM), have anecdotal claims of immediate, gross gains of mobility that far exceed conventionally reported results. The purpose of this case report was to examine the efficacy of TMR(r) in treating an apparent tissue tightness/extensibility dysfunction and to determine if IASTM would improve outcomes if TMR(r) techniques failed to produce maintained improvement. CASE DESCRIPTION: A 27-year old former competitive speed walker presented with a chronic history of bilateral pain and posterior leg tightness. The patient met the criteria for diagnosis of a bilateral tissue extensibility dysfunction in the posterior lower extremity and was treated with TMR(r) and IASTM (Tecnica Gavilan(r); Tracy, California, United States). OUTCOMES: After the first week of treatment, the patient increased her sit and reach by 5cm and her active straight leg raise (ASLR) by an average of 31.5 degrees bilaterally. Following the second week of treatment, the patient experienced an additional increase in sit and reach and ASLR. At discharge, the patient displayed negative 90/90 Active Knee Extension, Tripod, and Slump tests bilaterally, normalized ASLR and a resolution of her complaints. Follow-up examinations completed at one month and three months post-discharge indicated maintenance of the outcomes without any additional interventions. DISCUSSION: The subject in this case report demonstrated the potential use of TMR(r) in classifying apparent hamstring tightness and provided evidence to support the use of TMR(r) and IASTM in addressing mobility deficits associated with hamstring inflexibility/tightness. Based on these findings, clinicians should consider the use of TMR(r) to improve classification and treatment of patients with a chief complaint of hamstring "tightness." LEVEL OF EVIDENCE: Level 4; single case report. PMID- 26491623 TI - Progress in Making Ras as a Druggable Target. PMID- 26491624 TI - Prevalence and Correlates of Perceived Ethnic Discrimination in the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study. AB - Empirical studies examining perceived ethnic discrimination in Latinos of diverse background groups are limited. This study examined prevalence and correlates of discrimination in a diverse sample of U.S. Latinos (N=5,291) from the multi-site Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and HCHS/SOL Sociocultural Ancillary Study. The sample permitted an examination of differences across seven groups (Central American, Cuban, Dominican, Mexican, Puerto Rican, South American, and Other/Multiple Background). Most participants (79.5%) reported lifetime discrimination exposure and prevalence rates ranged from 64.9% to 98% across groups. Structural Equation Models (SEM) indicated that after adjusting for sociodemographic covariates most group differences in reports of discrimination were eliminated. However, Cubans reported the lowest levels of discrimination, overall among all groups. Furthermore, regional effects were more important than group effects. Participants from Chicago reported the highest levels of discrimination in comparison to other regions. Group differences among Latinos appear to be primarily a function of sociodemographic differences in education, income, and acculturation. In addition, differences in exposure to discrimination may be tied to variables associated with both immigration patterns and integration to U.S. culture. Results highlight the importance of considering historical context and the intersection of discrimination and immigration when evaluating the mental health of Latinos. PMID- 26491625 TI - [International outcomes from attempts to implement a clinical decision support system in gastroenterology]. AB - OBJECTIVE: This study aimed at describing the recent experience acquired with the implementation and use of clinical decision support system in gastroenterology in order to determine the level of development, tests used and advantages that such a system can offer to the medical practice. METHODS: A search in the PubMed, LILACS and ISI Web of Knowledge databases for studies in decision-making support systems in gastroenterology including original papers produced from 2005 to 2010 was performed. A total of 104 scientific papers were retrieved initially. These were analyzed using inclusion and exclusion criteria, thus yielding nine studies for further analysis. RESULTS: The clinical decision support system analyzed in the present study showed a great variety of clinical problems regarding the investigation of a disease and the determination of a diagnosis. Eighty-nine per cent of the studies showed experimental models for clinical decision support system development. Seventy-eight per cent of the studies described the outcomes obtained with artificial intelligence technique. Two studies compared the clinical decision support system performance with that of a doctor, and only one research work described a controlled study evidencing improvements in the medical practice. CONCLUSION: The studies analyzed showed evidence of potential benefits that clinical decision support system can bring to the clinical practice. However, further controlled studies performed in medical day-to-day conditions and environment should be performed in order to provide more clear evidence of the usefulness of clinical decision support system in the medical practice. PMID- 26491628 TI - Turning Spiroketals Inside Out: A Rearrangement Triggered by an Enol Ether Epoxidation. AB - Invited for this month's cover picture is the group of Professor Mark Peczuh at the University of Connecticut. The cover picture compares the rearrangement of a small molecule to the process of turning a stuffed animal inside out. The recycled, inside-out stuffed animals are both artistic and philosophically provocative. They capture the essence of the rearrangement reaction because the compounds themselves turn inside out over the course of the reaction, extending the diversity of products that can arise from simple starting materials. Small molecules often have functional groups with latent reactivity; under the appropriate conditions, those groups can react with other compounds (e.g., reagents) and also with other groups in the same molecule in an intramolecular reaction. The research team found that the epoxidation of some highly functionalized spiroketal compounds promoted rearrangements of their structures that turned them inside out. Some of the features of the products led them to use X-ray crystallography or a combination of computer-assisted structure elucidation, computation, and a new version of the 1,1-ADEQUATE NMR experiment to determine their structures. For more details, see the Communication on p. 577 ff. PMID- 26491629 TI - Graphical Abstract: ChemistryOpen 5/2015. PMID- 26491626 TI - Gated Silica Mesoporous Materials in Sensing Applications. AB - Silica mesoporous supports (SMSs) have a large specific surface area and volume and are particularly exciting vehicles for delivery applications. Such container like structures can be loaded with numerous different chemical substances, such as drugs and reporters. Gated systems also contain addressable functions at openings of voids, and cargo delivery can be controlled on-command using chemical, biochemical or physical stimuli. Many of these gated SMSs have been applied for drug delivery. However, fewer examples of their use in sensing protocols have been reported. The approach of applying SMSs in sensing uses another concept-that of loading pores with a reporter and designing a capping mechanism that is selectively opened in the presence of a target analyte, which results in the delivery of the reporter. According to this concept, we provide herein a complete compilation of published examples of probes based on the use of capped SMSs for sensing. Examples for the detection of anions, cations, small molecules and biomolecules are provided. The diverse range of gated silica mesoporous materials presented here highlights their usefulness in recognition protocols. PMID- 26491630 TI - Corrigendum: Regioisomer-Free C 4h beta-Tetrakis(tert-butyl)metallo phthalocyanines: Regioselective Synthesis and Spectral Investigations. AB - [This corrects the article on p. 102 in vol. 4, PMID: 25969805.]. PMID- 26491632 TI - Spotlights on our sister journals: ChemistryOpen 5/2015. PMID- 26491633 TI - A Focus on Triazolium as a Multipurpose Molecular Station for pH-Sensitive Interlocked Crown-Ether-Based Molecular Machines. AB - The control of motion of one element with respect to others in an interlocked architecture allows for different co-conformational states of a molecule. This can result in variations of physical or chemical properties. The increase of knowledge in the field of molecular interactions led to the design, the synthesis, and the study of various systems of molecular machinery in a wide range of interlocked architectures. In this field, the discovery of new molecular stations for macrocycles is an attractive way to conceive original molecular machines. In the very recent past, the triazolium moiety proved to interact with crown ethers in interlocked molecules, so that it could be used as an ideal molecular station. It also served as a molecular barrier in order to lock interlaced structures or to compartmentalize interlocked molecular machines. This review describes the recently reported examples of pH-sensitive triazolium containing molecular machines and their peculiar features. PMID- 26491634 TI - Turning Spiroketals Inside Out: A Rearrangement Triggered by an Enol Ether Epoxidation. AB - Spiroketals organize small molecule structures into well-defined, three dimensional configurations that make them good ligands of proteins. We recently discovered a tandem cycloisomerization-dimerization reaction of alkynyl hemiketals that delivered polycyclic, enol-ether-containing spiroketals. Here we describe rearrangements of those compounds, triggered by epoxidation of their enol ethers that completely remodel their structures, essentially turning them "inside out". Due to the high level of substitution on the carbon skeletons of the substrates and products, characterization resorted to X-ray crystallography and advanced computation and NMR techniques to solve the structures of representative compounds. In particular, a new proton-detected ADEQUATE NMR experiment (1,1-HD-ADEQUATE) enabled the unequivocal assignment of the carbon skeleton of one of the new compounds. Solution of the structures of the representative compounds allowed for the assignment of product structures for the other compounds in two separate series. Both the rearrangement and the methods used for structural determination of the products are valuable tools for the preparation of characterization of new small molecule compounds. PMID- 26491635 TI - Organocatalyzed Trifluoromethylation of Ketones and Sulfonyl Fluorides by Fluoroform under a Superbase System. AB - Fluoroform (HCF3, HFC-23) is a side product in the manufacture of polytetrafluoroethylene (Teflon). Despite its attractive properties, taming HCF3 for trifluoromethylation is quite problematic owing to its low acidity and the lability of the naked trifluoromethyl carbanion generated from HCF3. Herein we report the organic-superbase-catalyzed trifluoromethylation of ketones and arylsulfonyl fluorides by HCF3. The reactions were carried out by using a newly developed "superbase organocatalyst system" consisting of catalytic amounts of P4 tBu and N(SiMe3)3. A series of aryl and alkyl ketones were converted into the corresponding alpha-trifluoromethyl carbinols in good yields under the organocatalysis conditions in THF. The superbase organocatalytic system can also be applied to the trifluoromethylation of arylsulfonyl fluorides for biologically important aryl triflones in THF or DMF in good yields. Protonated P4-tBu, H[P4 tBu](+), is suggested to be crucial for the catalytic process. This new catalytic methodology using HCF3 is expected to expand the range of synthetic applications of trifluoromethylation. PMID- 26491636 TI - Cellulose-Derived Supercapacitors from the Carbonisation of Filter Paper. AB - Advanced carbon materials are important for the next-generation of energy storage apparatus, such as electrochemical capacitors. Here, the physical and electrochemical properties of carbonised filter paper (FP) were investigated. FP is comprised of pure cellulose and is a standardised material. After carbonisation at temperatures ranging from 600 to 1700 degrees C, FP was contaminant-free, containing only carbon and some oxygenated species, and its primary fibre structure was retained (diameter ~20-40 MUm). The observed enhancement in conductivity of the carbonised FP was correlated with the carbonisation temperature. Electrochemical capacitance in the range of ~1.8-117 F g(-1) was achieved, with FP carbonised at 1500 degrees C showing the best performance. This high capacitance was stable with >87 % retained after 3000 charge-discharge cycles. These results show that carbonised FP, without the addition of composite materials, exhibits good supercapacitance performance, which competes well with existing electrodes made of carbon-based materials. Furthermore, given the lower cost and renewable source, cellulose-based materials are the more eco-friendly option for energy storage applications. PMID- 26491637 TI - A Structurally-Tunable 3-Hydroxyflavone Motif for Visible Light-Induced Carbon Monoxide-Releasing Molecules (CORMs). AB - Molecules that can be used to deliver a controlled amount of carbon monoxide (CO) have the potential to facilitate investigations into the roles of this gaseous molecule in biology and advance therapeutic treatments. This has led to the development of light-induced CO-releasing molecules (photoCORMs). A goal in this field of research is the development of molecules that exhibit a combination of controlled CO release, favorable biological properties (e.g., low toxicity and trackability in cells), and structural tunability to affect CO release. Herein, we report a new biologically-inspired organic photoCORM motif that exhibits several features that are desirable in a next-generation photoCORM. We show that 3-hydroxyflavone-based compounds are easily synthesized and modified to impart changes in absorption features and quantum yield for CO release, exhibit low toxicity, are trackable in cells, and can exhibit both O2-dependent and independent CO release reactivity. PMID- 26491638 TI - Voltammetric Study of the Influence of Various Phosphate Anions on Silver Nanoparticle Oxidation. AB - The antibacterial properties of silver are strongly controlled by the redox couple of silver/silver(I). This work reports the influence of phosphate anions on silver nanoparticle oxidation, which is important given the abundance of phosphate species in biological systems. The three different species of anions were found to have a varying degree of influence on silver oxidation with the order PO4 (3-)>HPO4 (2-)>H2PO4 (-). It was found that in the presence of phosphate anions, the silver oxidation potential shifts to a less positive value, which indicated the increasing ease of the oxidation reaction of silver. Given that the interplay between silver and its cation is crucial to its antibacterial properties and significant concentrations of the HPO4 (2-) anion are present at biological pH (near neutral), it is essential that the influence of the dibasic anion (HPO4 (2-)) on silver oxidation dynamics be considered for biological systems. PMID- 26491639 TI - Electrochemical Nanoparticle Sizing Via Nano-Impacts: How Large a Nanoparticle Can be Measured? AB - The field of nanoparticle (NP) sizing encompasses a wide array of techniques, with electron microscopy and dynamic light scattering (DLS) having become the established methods for NP quantification; however, these techniques are not always applicable. A new and rapidly developing method that addresses the limitations of these techniques is the electrochemical detection of NPs in solution. The 'nano-impacts' technique is an excellent and qualitative in situ method for nanoparticle characterization. Two complementary studies on silver and silver bromide nanoparticles (NPs) were used to assess the large radius limit of the nano-impact method for NP sizing. Noting that by definition a NP cannot be larger than 100 nm in diameter, we have shown that the method quantitatively sizes at the largest limit, the lower limit having been previously reported as ~6 nm.1. PMID- 26491640 TI - Surface Modification of Boron-Doped Diamond with Microcrystalline Copper Phthalocyanine: Oxygen Reduction Catalysis. AB - Surface modification of boron-doped diamond (BDD) with copper phthalocyanine was achieved using a simple and convenient dropcast deposition, giving rise to a microcrystalline structure. Both unmodified and modified BDD electrodes of different surface terminations (namely hydrogen and oxygen) were compared via the electrochemical reduction of oxygen in aqueous solution. A significant lowering of the cathodic overpotential by about 500 mV was observed after modification of hydrogen-terminated (hydrophobic) diamond, while no voltammetric peak was seen on modified oxidised (hydrophilic) diamond, signifying greater interaction between copper phthalocyanine and the hydrogen-terminated BDD. Oxygen reduction was found to undergo a two-electron process on the modified hydrogen-terminated diamond, which was shown to be also active for the reduction of hydrogen peroxide. The lack of a further conversion of the peroxide was attributed to its rapid diffusion away from the triple phase boundary at which the reaction is expected to exclusively occur. PMID- 26491641 TI - Simple and Precise Quantification of Iron Catalyst Content in Carbon Nanotubes Using UV/Visible Spectroscopy. AB - Iron catalysts have been used widely for the mass production of carbon nanotubes (CNTs) with high yield. In this study, UV/visible spectroscopy was used to determine the Fe catalyst content in CNTs using a colorimetric technique. Fe ions in solution form red-orange complexes with 1,10-phenanthroline, producing an absorption peak at lambda=510 nm, the intensity of which is proportional to the solution Fe concentration. A series of standard Fe solutions were formulated to establish the relationship between optical absorbance and Fe concentration. Many Fe catalysts were microscopically observed to be encased by graphitic layers, thus preventing their extraction. Fe catalyst dissolution from CNTs was investigated with various single and mixed acids, and Fe concentration was found to be highest with CNTs being held at reflux in HClO4/HNO3 and H2SO4/HNO3 mixtures. This novel colorimetric method to measure Fe concentrations by UV/Vis spectroscopy was validated by inductively coupled plasma optical emission spectroscopy, indicating its reliability and applicability to asses Fe content in CNTs. PMID- 26491642 TI - Assignment of the Internal Vibrational Modes of C70 by Inelastic Neutron Scattering Spectroscopy and Periodic-DFT. AB - The fullerene C70 may be considered as the shortest possible nanotube capped by a hemisphere of C60 at each end. Vibrational spectroscopy is a key tool in characterising fullerenes, and C70 has been studied several times and spectral assignments proposed. Unfortunately, many of the modes are either forbidden or have very low infrared or Raman intensity, even if allowed. Inelastic neutron scattering (INS) spectroscopy is not subject to selection rules, and all the modes are allowed. We have obtained a new INS spectrum from a large sample recorded at the highest resolution available. An advantage of INS spectroscopy is that it is straightforward to calculate the spectral intensity from a model. We demonstrate that all previous assignments are incorrect in at least some respects and propose a new assignment based on periodic density functional theory (DFT) that successfully reproduces the INS, infrared, and Raman spectra. PMID- 26491643 TI - 2-(Alkylamino)-3-aryl-6,7-dihydrobenzofuran-4(5H)-ones: Improved Synthesis and their Photophysical Properties. AB - Furans are an important class of compounds and exhibit a diverse range of activities and properties. As such, improved synthetic access to furans is an important research goal. In the present report, a solvent- and catalyst-free reaction between 5,5-dimethyl-1,3-cyclohexanedione (dimedone), an aryl aldehyde and an isocyanide under microwave irradiation is presented. This method is significantly improved from previously described protocols in terms of applicability of wide ranging aryl aldehydes, better yields, shorter reaction times, facile work up and essentially no need of column chromatography. The photophysical properties of this series of compounds were studied for their possible applicability in the field of metal ion sensors. In solution, two compounds, 2-(cyclohexylamino)-3-(1H-indol-3-yl)-6,6-dimethyl-6,7 dihydrobenzofuran-4(5H)-one (1 i) and 2-(tert-butylamino)-3-(1H-indol-3-yl)-6,6 dimethyl-6,7-dihydrobenzofuran-4(5H)-one (1 j), underwent an observable color change from yellow to colorless in the presence of aluminum(III) ions. Further studies to investigate the UV absorption and luminescence behavior of these compounds revealed their utility as "naked-eye sensors" for aluminum detection. PMID- 26491644 TI - Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting alphavbeta3 Integrin and VEGF Receptors. AB - A dual-action ligand targeting both integrin alphaVbeta3 and vascular endothelial growth factor receptors (VEGFRs), was synthesized via conjugation of a cyclic peptidomimetic alphaVbeta3 Arg-Gly-Asp (RGD) ligand with a decapentapeptide. The latter was obtained from a known VEGFR antagonist by acetylation at the Lys13 side chain. Functionalization of the precursor ligands was carried out in solution and in the solid phase, affording two fragments: an alkyne VEGFR ligand and the azide integrin alphaVbeta3 ligand, which were conjugated by click chemistry. Circular dichroism studies confirmed that both the RGD and VEGFR ligand portions of the dual-action compound substantially adopt the biologically active conformation. In vitro binding assays on isolated integrin alphaVbeta3 and VEGFR-1 showed that the dual-action conjugate retains a good level of affinity for both its target receptors, although with one order of magnitude (10/20 times) decrease in potency. The dual-action ligand strongly inhibited the VEGF-induced morphogenesis in Human Umbilical Vein Endothelial Cells (HUVECs). Remarkably, its efficiency in preventing the formation of new blood vessels was similar to that of the original individual ligands, despite the worse affinity towards integrin alphaVbeta3 and VEGFR-1. PMID- 26491645 TI - Electronic Structures, Bonding Configurations, and Band-Gap-Opening Properties of Graphene Binding with Low-Concentration Fluorine. AB - To better understand the effects of low-level fluorine in graphene-based sensors, first-principles density functional theory (DFT) with van der Waals dispersion interactions has been employed to investigate the structure and impact of fluorine defects on the electrical properties of single-layer graphene films. The results show that both graphite-2 H and graphene have zero band gaps. When fluorine bonds to a carbon atom, the carbon atom is pulled slightly above the graphene plane, creating what is referred to as a CF defect. The lowest-binding energy state is found to correspond to two CF defects on nearest neighbor sites, with one fluorine above the carbon plane and the other below the plane. Overall this has the effect of buckling the graphene. The results further show that the addition of fluorine to graphene leads to the formation of an energy band (BF) near the Fermi level, contributed mainly from the 2p orbitals of fluorine with a small contribution from the p orbitals of the carbon. Among the 11 binding configurations studied, our results show that only in two cases does the BF serve as a conduction band and open a band gap of 0.37 eV and 0.24 eV respectively. The binding energy decreases with decreasing fluorine concentration due to the interaction between neighboring fluorine atoms. The obtained results are useful for sensor development and nanoelectronics. PMID- 26491646 TI - Influence of Ag(+) on the Magnetic Response of [2.2.2]Paracyclophane: NMR Properties of a Prototypical Organic Host for Cation Binding Based on DFT Calculations. AB - The complexation of metal cations into a host-guest situation is particularly well exemplified by [2.2.2]paracyclophane and Ag(I), which leads to a strong cation-pi interaction with a specific face of the host molecule. Through this study we sought a deeper understanding of the effects the metal center has on the NMR spectroscopic properties of the prototypical organic host, generating theoretical reasons for the observed experimental results with an aim to determine the role of the cation-pi interaction in a host-guest scenario. From an analysis of certain components of the induced magnetic field and the (13)C NMR shielding tensor under its own principal axis system (PAS), the local and overall magnetic behavior can be clearly described. Interestingly, the magnetic response of such a complex exhibits a large axis-dependent behavior, which leads to an overall shielding effect for the coordinating carbon atoms and a deshielding effect for the respective uncoordinated counterparts, evidence that complements previous experimental results. This proposed approach can be useful to gain further insight into the local and overall variation of NMR shifts for host-guest pairs involving both inorganic and organic hosts. PMID- 26491647 TI - Metallacycles Capabilities in Host-Guest Chemistry. PMID- 26491649 TI - Study of relationship between obesity and executive functions among high school students in Bushehr, Iran. AB - BACKGROUND: Obesity is one of the most challenging problems of public health in the present century and can have some serious impacts on cognitive abilities in children and adolescents. This study has tried to investigate the relationship between obesity and executive functioning, particularly in planning- organizing and problem solving among a group of adolescents. METHODS: Some 120 male high school students in the 15 to 18 year age range were included. BMI and executive functions were measured with validetes tools and tests in cases. RESULTS: There is a significant difference between the executive functions such as planning organizing and problem solving in obese, overweight and normal students. CONCLUSIONS: According to our results it seems the obese adolescents have poorer executive functions than normal weight peers. This is important for families and school staff to design and follow some therapeutic plans for weight reduction in adolescents in order to help them improve their skills in some functions such as planning-organizing and problem solving. PMID- 26491648 TI - The role of "bone immunological niche" for a new pathogenetic paradigm of osteoporosis. AB - Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue. The etiology and pathogenetic mechanisms of osteoporosis have not been clearly elucidated. Osteoporosis is linked to bone resorption by the activation of the osteoclastogenic process. The breakdown of homeostasis among pro- and antiosteoclastogenic cells causes unbalanced bone remodeling. The complex interactions among these cells in the bone microenvironment involve several mediators and proinflammatory pathways. Thus, we may consider the bone microenvironment as a complex system in which local and systemic immunity are regulated and we propose to consider it as an "immunological niche." The study of the "bone immunological niche" will permit a better understanding of the complex cell trafficking which regulates bone resorption and disease. The goal of a perfect therapy for osteoporosis would be to potentiate good cells and block the bad ones. In this scenario, additional factors may take part in helping or hindering the proosteoblastogenic factors. Several proosteoblastogenic and antiosteoclastogenic agents have already been identified and some have been developed and commercialized as biological therapies for osteoporosis. Targeting the cellular network of the "bone immunological niche" may represent a successful strategy to better understand and treat osteoporosis and its complications. PMID- 26491650 TI - Arizona Alzheimer's Registry: Strategy and Outcomes of a Statewide Research Recruitment Registry. AB - BACKGROUND: The Arizona Alzheimer's Consortium (AAC) created the Arizona Alzheimer's Registry, a screening and referral process for people interested in participating in Alzheimer's disease related research. The goals of the Registry were to increase awareness of Alzheimer's disease research and accelerate enrollment into AAC research studies. METHODS: Participation was by open invitation to adults 18 and older. Those interested provided consent and completed a written questionnaire. A subset of Registrants underwent an initial telephone cognitive assessment. Referral to AAC sites was based on medical history, telephone cognitive assessment, and research interests. RESULTS: A total of 1257 people consented and 1182 underwent an initial cognitive screening. Earned media (38.7%) was the most effective recruitment strategy. Participants had a mean age of 68.1 (SD 10.6), 97% were Caucasian, had 15.2 (SD 2.7) mean years of education, and 60% were female. 30% reported a family history of dementia and 70% normal cognition. Inter-rater agreement between self-reported memory status and the initial telephone cognitive assessment had a kappa of 0.31 0.43. 301 were referred to AAC sites. CONCLUSION: IThe Registry created an infrastructure and process to screen and refer a high volume of eager Registrants. These methods were found to be effective at prescreening individuals for studies, which facilitated AAC research recruitment. The established infrastructure and experiences gained from the Registry have served as the prototype for the web-based Alzheimer's Prevention Registry, a national registry focusing on Alzheimer's disease prevention research. PMID- 26491651 TI - Double-layered reconstruction of the nasal floor in complete cleft deformity of the primary palate using superfluous lip tissue. AB - After cleft lip repair, many patients suffer from nasolabial fistulas, asymmetrical nasal floor, or an indistinct nostril sill, as well as intraoral wound dehiscence and subsequent scar contracture of surgical wounds leading to vestibular stenosis. For successful primary nasolabial repair of complete cleft deformity of the primary palate, cleft surgeons need special care in reconstructing the sound nasal floor. Especially when the cleft gap is wide or when any type of nasoalveolar molding therapy was not performed, three dimensional reconstruction of the nasal floor is critical for a balanced nasal shape. In this study, the author describes an effective method for reconstructing a double-layered nasal floor using two mucosal flaps from both sides of the fissured upper lip. This is a report of six patients with unilateral or bilateral complete cleft of the primary palate with a detailed description of the surgical technique and a literature review. PMID- 26491652 TI - Accelerating Multiple Compound Comparison Using LINGO-Based Load-Balancing Strategies on Multi-GPUs. AB - Compound comparison is an important task for the computational chemistry. By the comparison results, potential inhibitors can be found and then used for the pharmacy experiments. The time complexity of a pairwise compound comparison is O(n (2)), where n is the maximal length of compounds. In general, the length of compounds is tens to hundreds, and the computation time is small. However, more and more compounds have been synthesized and extracted now, even more than tens of millions. Therefore, it still will be time-consuming when comparing with a large amount of compounds (seen as a multiple compound comparison problem, abbreviated to MCC). The intrinsic time complexity of MCC problem is O(k (2) n (2)) with k compounds of maximal length n. In this paper, we propose a GPU-based algorithm for MCC problem, called CUDA-MCC, on single- and multi-GPUs. Four LINGO based load-balancing strategies are considered in CUDA-MCC in order to accelerate the computation speed among thread blocks on GPUs. CUDA-MCC was implemented by C+OpenMP+CUDA. CUDA-MCC achieved 45 times and 391 times faster than its CPU version on a single NVIDIA Tesla K20m GPU card and a dual-NVIDIA Tesla K20m GPU card, respectively, under the experimental results. PMID- 26491653 TI - Biocompatibility of Novel Type I Collagen Purified from Tilapia Fish Scale: An In Vitro Comparative Study. AB - Type I collagen (COL-1) is the prevailing component of the extracellular matrix in a number of tissues including skin, ligament, cartilage, bone, and dentin. It is the most widely used tissue-derived natural polymer. Currently, mammalian animals, including pig, cow, and rat, are the three major sources for purification of COL-1. To reduce the risk of zoonotic infectious diseases transmission, minimize the possibility of immunogenic reaction, and avoid problems related to religious issues, exploration of new sources (other than mammalian animals) for the purification of type I collagen is highly desirable. Hence, the purpose of the current study was to investigate the in vitro responses of MDPC-23 to type I collagen isolated from tilapia scale in terms of cellular proliferation, differentiation, and mineralization. The results suggested that tilapia scale collagen exhibited comparable biocompatibility to porcine skin collagen, indicating it might be a potential alternative to type I collagen from mammals in the application for tissue regeneration in oral-maxillofacial area. PMID- 26491654 TI - Antioxidant Potential in Different Parts and Callus of Gynura procumbens and Different Parts of Gynura bicolor. AB - Plants from Gynura family was used in this study, namely, Gynura procumbens and Gynura bicolor. Gynura procumbens is well known for its various medicinal properties such as antihyperglycaemic, antihyperlipidaemic, and antiulcerogenic; meanwhile, G. bicolor remains unexploited. Several nonenzymatic antioxidants methods were utilized to study the antioxidant capacity, which include ferric reducing antioxidant power (FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, total flavonoid content, total phenolic content, and ascorbic acid content determination. DPPH assay reveals G. procumbens shoot as the lowest (66.885%) and G. procumbens root as the highest (93.499%) DPPH radical inhibitor. In FRAP assay, reducing power was not detected in G. procumbens leaf callus (0.000 TEAC mg/g FW) whereby G. procumbens root exhibits the highest (1.103 TEAC mg/g FW) ferric reducing power. Total phenolic content and total flavonoid content exhibited similar trend for both the intact plants analysed. In all antioxidant assays, G. procumbens callus culture exhibits very low antioxidant activity. However, G. procumbens root exhibited highest phenolic content, flavonoid content, and ascorbic acid content with 4.957 TEAC mg/g FW, 543.529 QE ug/g FW, and 54.723 ug/g FW, respectively. This study reveals that G. procumbens root extract is a good source of natural antioxidant. PMID- 26491655 TI - Neurorestoratologic Strategies and Mechanisms in the Nervous System. PMID- 26491656 TI - Glu504Lys Single Nucleotide Polymorphism of Aldehyde Dehydrogenase 2 Gene and the Risk of Human Diseases. AB - Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial enzyme that is known for its important role in oxidation and detoxification of ethanol metabolite acetaldehyde. ALDH2 also metabolizes other reactive aldehydes such as 4-hydroxy-2 nonenal and acrolein. The Glu504Lys single nucleotide polymorphism (SNP) of ALDH2 gene, which is found in approximately 40% of the East Asian populations, causes defect in the enzyme activity of ALDH2, leading to alterations in acetaldehyde metabolism and alcohol-induced "flushing" syndrome. Evidence suggests that ALDH2 Glu504Lys SNP is a potential candidate genetic risk factor for a variety of chronic diseases such as cardiovascular disease, cancer, and late-onset Alzheimer's disease. In addition, the association between ALDH2 Glu504Lys SNP and the development of these chronic diseases appears to be affected by the interaction between the SNP and lifestyle factors such as alcohol consumption as well as by the presence of other genetic variations. PMID- 26491657 TI - Genetic Diversity of Mycobacterium tuberculosis Complex Isolated from Tuberculosis Patients in Bahir Dar City and Its Surroundings, Northwest Ethiopia. AB - The knowledge of the diversity of strains of Mycobacterium tuberculosis complex (MTBC) species in a specific geographical region can contribute to the control of tuberculosis (TB). This study was conducted to identify the MTBC isolates to the species and spoligotype international type (SIT) level by spoligotyping. A total of 168 MTBC isolates were recovered from TB patients, spoligotyped, and their patterns were compared with those of the strains registered in the SITVIT2 database. Of 168 isolates spoligotyped, 89 patterns were identified. Ninety-eight isolates were clustered into 19 strain groups with clustering percentage of 58.3%. Forty-four strains matched the preexisting SITs in the SITVIT2 database. The dominant strains were SIT289, SIT134, and SIT3411, comprising 16.7% (28/168), 7.14% (12/168), and 4.76% (8/168) of the isolates, respectively. Euro-American (51.2%), East-African-Indian (34.5%), and M. africanum (9.52%) were the major lineages identified. Two strains of M. bovis were isolated from TB lymphadenitis cases. The high percentage of clustered strains of M. tuberculosis could suggest that a small number of lineages of M. tuberculosis are causing the disease in the area while isolation of M. bovis could suggest its zoonotic potential. Additionally, identification of M. africanum requires further confirmation by tools with a better discriminatory power. PMID- 26491658 TI - Evaluation of APP695 Transgenic Mice Bone Marrow Mesenchymal Stem Cells Neural Differentiation for Transplantation. AB - OBJECTIVE: Even though there is a therapeutic potential to treat Alzheimer's disease (AD) with neural cell replenishment and replacement, immunological rejections of stem cell transplantation remain a challenging risk. Autologous stem cells from AD patients however may prove to be a promising candidate. Therefore, we studied the neuronal differentiation efficiency of bone marrow mesenchymal stem cells (MSCs) from APP695 transgenic mice, which share features of human AD. METHOD: Cultured MSCs from APP695 transgenic mice are used; neuronal differentiation was assessed by immunocytochemistry and Western blot. Correlation with Notch signaling was examined. Autophage flux was assessed by western blot analysis. RESULTS: MSCs from APP695 mice have higher neuronal differentiation efficiency than MSCs from wild type mice (WT MSCs). The expression of Notch-1 signaling decreased during the differentiation process. However, autophagy flux, which is essential for neuronal cell survival and neuronal function, was impaired in the neuronally differentiated counterparts of APP695 MSCs (APP695 MSCs-n). CONCLUSION: These results suggested autologous MSCs of APP690 mice may not be a good candidate for cell transplantation. PMID- 26491659 TI - Determination of Serum Lost Goodwill Target Proteome in Patients with Severe Traumatic Brain Injury. AB - This study investigates the biokinetics of LGT proteome, a potential biomarker of severe TBI, in serum of severe TBI patients. The LGT proteome presents in the serum of severe TBI patients. The abundance diversity of LGT proteome is closely associated with pathologic condition of TBI patients. Serum LGT proteome may be used as a promising marker for evaluating severity of severe TBI. PMID- 26491660 TI - Research Progress on the Role of ABC Transporters in the Drug Resistance Mechanism of Intractable Epilepsy. AB - The pathogenesis of intractable epilepsy is not fully clear. In recent years, both animal and clinical trials have shown that the expression of ATP-binding cassette (ABC) transporters is increased in patients with intractable epilepsy; additionally, epileptic seizures can lead to an increase in the number of sites that express ABC transporters. These findings suggest that ABC transporters play an important role in the drug resistance mechanism of epilepsy. ABC transporters can perform the funcions of a drug efflux pump, which can reduce the effective drug concentration at epilepsy lesions by reducing the permeability of the blood brain barrier to antiepileptic drugs, thus causing resistance to antiepileptic drugs. Given the important role of ABC transporters in refractory epilepsy drug resistance, antiepileptic drugs that are not substrates of ABC transporters were used to obtain ABC transporter inhibitors with strong specificity, high safety, and few side effects, making them suitable for long-term use; therefore, these drugs can be used for future clinical treatment of intractable epilepsy. PMID- 26491662 TI - Past, Present, and Future of Nerve Conduits in the Treatment of Peripheral Nerve Injury. AB - With significant advances in the research and application of nerve conduits, they have been used to repair peripheral nerve injury for several decades. Nerve conduits range from biological tubes to synthetic tubes, and from nondegradable tubes to biodegradable tubes. Researchers have explored hollow tubes, tubes filled with scaffolds containing neurotrophic factors, and those seeded with Schwann cells or stem cells. The therapeutic effect of nerve conduits is improving with increasing choice of conduit material, new construction of conduits, and the inclusion of neurotrophic factors and support cells in the conduits. Improvements in functional outcomes are expected when these are optimized for use in clinical practice. PMID- 26491663 TI - An Update on the Safety and Efficacy of Corneal Collagen Cross-Linking in Pediatric Keratoconus. AB - Keratoconus is a degenerative disease that affects adolescents and young adults and presents with variable thinning and conical deformation of the corneal apex. The resultant irregular astigmatism can progress to levels that can significantly affect everyday activities and overall quality of life. Therefore, stopping the progression of the disease is an essential part in managing patients with keratoconus. Corneal collagen cross-linking is a minimally invasive procedure that stiffens the anterior corneal stroma by creating strong covalent bonds between collagen fibrils. Over the past decade, many studies have proved its safety and efficacy in halting keratoconus progression in adults. This review of the literature highlights the growing trend towards using this treatment in pediatric keratoconic patients. In children, keratoconus tends to be more severe and fast progression is often encountered requiring closer follow-up intervals. Standard cross-linking shows comparable results in children with a good safety efficacy profile during follow-up periods of up to three years. Further research is needed to standardize and evaluate transepithelial and accelerated cross linking protocols as these could be of tremendous help in a population where cooperation and compliance are major issues. PMID- 26491661 TI - Oligodendrocyte Precursor Cells in Spinal Cord Injury: A Review and Update. AB - Spinal cord injury (SCI) is a devastating condition to individuals, families, and society. Oligodendrocyte loss and demyelination contribute as major pathological processes of secondary damages after injury. Oligodendrocyte precursor cells (OPCs), a subpopulation that accounts for 5 to 8% of cells within the central nervous system, are potential sources of oligodendrocyte replacement after SCI. OPCs react rapidly to injuries, proliferate at a high rate, and can differentiate into myelinating oligodendrocytes. However, posttraumatic endogenous remyelination is rarely complete, and a better understanding of OPCs' characteristics and their manipulations is critical to the development of novel therapies. In this review, we summarize known characteristics of OPCs and relevant regulative factors in both health and demyelinating disorders including SCI. More importantly, we highlight current evidence on post-SCI OPCs transplantation as a potential treatment option as well as the impediments against regeneration. Our aim is to shed lights on important knowledge gaps and to provoke thoughts for further researches and the development of therapeutic strategies. PMID- 26491665 TI - Amniotic Mesenchymal Stem Cells Can Enhance Angiogenic Capacity via MMPs In Vitro and In Vivo. AB - The aim of this study was to evaluate the angiogenic capacity and proteolytic mechanism of coculture using human amniotic mesenchymal stem cells (hAMSCs) with human umbilical vein endothelial cells (HUVECs) in vivo and in vitro by comparing to those of coculture using bone marrow mesenchymal stem cells with HUVEC. For the in vivo experiment, cells (HUVEC-monoculture, HUVEC-hAMSC coculture, and HUVEC-BMMSC coculture) were seeded in fibrin gels and injected subcutaneously in nude mice. The samples were collected on days 7 and 14 and histologically analyzed by H&E and CD31 staining. CD31-positive staining percentage and vessel like structure (VLS) density were evaluated as quantitative parameters for angiogenesis. The increases of CD31-positive staining area and VLS density in both HUVEC-hAMSC group and HUVEC-BMMSC group were found between two time points, while obvious decline of those was observed in HUVEC-only group. For the in vitro experiment, we utilized the same 3D culture model to investigate the proteolytic mechanism related to capillary formation. Intensive vascular networks formed by HUVECs were associated with hAMSCs or BMMSCs and related to MMP2 and MMP9. In conclusion, hAMSCs shared similar capacity and proteolytic mechanism with BMMSCs on neovascularization. PMID- 26491664 TI - The Crosstalk between Hypoxia and Innate Immunity in the Development of Obesity Related Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) has become a major health issue in western countries in parallel with the dramatic increase in the prevalence of obesity and all obesity related conditions, including respiratory diseases as obstructive sleep apnea-hypopnea syndrome (OSAHS). Interestingly, the severity of the liver damage in obesity-related NAFLD has been associated with the concomitant presence of OSAHS. In the presence of obesity, the proinflammatory state in these patients together with intermittent episodes of hypoxia, characteristic of OSAHS pathogenesis, may lead to an enhanced inflammatory response mediated by a positive feedback loop mechanism that implicates HIF-1 and NFkappaB. Thus, the severity of liver involvement in obese NAFLD patients with a concomitant diagnosis of OSAHS could be explained. In this review, we focus on the molecular mechanisms underlying the hepatic response to chronic intermittent hypoxia and its interaction with innate immunity in obesity-related NAFLD. PMID- 26491666 TI - Malnutrition and Gut Flora Dysbiosis: Specific Therapies for Emerging Comorbidities in Heart Failure. AB - Chronic heart failure is a complicated multifactorial disease with wide-spread social-economic consequences. In spite of the recent development of new drugs and therapeutic strategies, CHF-related mortality and morbidity remain high. Recent evidence suggests that changes in organs such as skeletal muscle and gut flora may play an important and independent role in CHF prognosis. This paper illustrates these phenomena, proposing how to identify them and presenting current therapies which treat organs all too often underestimated but which have a fundamental role in worsening CHF. PMID- 26491667 TI - Patient Preferences for Receiving Remote Communication Support for Lifestyle Physical Activity Behaviour Change: The Perspective of Patients with Musculoskeletal Disorders from Three Hospital Services. AB - This study examined patients' preference ratings for receiving support via remote communication to increase their lifestyle physical activity. Methods. People with musculoskeletal disorders (n = 221 of 296 eligible) accessing one of three clinics provided preference ratings for "how much" they wanted to receive physical activity support via five potential communication modalities. The five ratings were generated on a horizontal analogue rating scale (0 represented "not at all"; 10 represented "very much"). Results. Most (n = 155, 70%) desired referral to a physical activity promoting intervention. "Print and post" communications had the highest median preference rating (7/10), followed by email and telephone (both 5/10), text messaging (1/10), and private Internet-based social network messages (0/10). Desire to be referred was associated with higher preference for printed materials (coefficient = 2.739, p < 0.001), telephone calls (coefficient = 3.000, p < 0.001), and email (coefficient = 2.059, p = 0.02). Older age was associated with lower preference for email (coefficient = 0.100, p < 0.001), texting (coefficient = -0.096, p < 0.001), and social network messages (coefficient = -0.065, p < 0.001). Conclusion. Patients desiring support to be physically active indicated preferences for interventions with communication via print, email, or telephone calls. PMID- 26491669 TI - The Discriminant Value of Phase-Dependent Local Dynamic Stability of Daily Life Walking in Older Adult Community-Dwelling Fallers and Nonfallers. AB - The present study compares phase-dependent measures of local dynamic stability of daily life walking with 35 conventional gait features in their ability to discriminate between community-dwelling older fallers and nonfallers. The study reanalyzes 3D-acceleration data of 3-day daily life activity from 39 older people who reported less than 2 falls during one year and 31 who reported two or more falls. Phase-dependent local dynamic stability was defined for initial perturbation at 0%, 20%, 40%, 60%, and 80% of the step cycle. A partial least square discriminant analysis (PLS-DA) was used to compare the discriminant abilities of phase-dependent local dynamic stability with the discriminant abilities of 35 conventional gait features. The phase-dependent local dynamic stability lambda at 0% and 60% of the step cycle discriminated well between fallers and nonfallers (AUC = 0.83) and was significantly larger (p < 0.01) for the nonfallers. Furthermore, phase-dependent lambda discriminated as well between fallers and nonfallers as all other gait features combined. The present result suggests that phase-dependent measures of local dynamic stability of daily life walking might be of importance for further development in early fall risk screening tools. PMID- 26491668 TI - Synergistic Inhibitory Effects of Cetuximab and Cisplatin on Human Colon Cancer Cell Growth via Inhibition of the ERK-Dependent EGF Receptor Signaling Pathway. AB - The purpose of this study was to evaluate the anticancer efficacy of cetuximab combined with cisplatin (combination treatment) on colon cancer growth, as well as its underlying action mechanism. Combination treatment synergistically potentiated the effect of cetuximab on cell growth inhibition and apoptosis induction in HCT116 and SW480 cells. Combination treatment further suppressed the expression of the activated form of epidermal growth factor receptor (EGFR) and MAP kinase (p-ERK and p-p38) and also significantly inhibited the activity of activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB). Additionally, the expression of cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) mRNA was significantly reduced by the combination treatment as compared to the expression seen for treatment with cetuximab or cisplatin alone. We found that the synergistic inhibitory effects of cetuximab and cisplatin on AP-1 and NF-kappaB activation, as well as on cell viability, were reversed by pretreatment with an ERK inhibitor. Results demonstrate that combined treatment with cetuximab and cisplatin exerts synergistic anticancer effects on colon cancer cells and also suggest that the ERK pathway plays a critical role in these effects via the suppression of the EGFR signaling pathway, along with the inhibition of COX-2, IL 8, and AP-1 and NF-kappaB. PMID- 26491670 TI - Immunomodulation by Zearalenone in Carp (Cyprinus carpio L.). AB - The mycotoxin zearalenone (ZEN) is a frequent contaminant of animal feeds, but its effects on fish have not yet been investigated extensively. In order to fill this gap a feeding trial with juvenile carp was conducted. Three groups of fish were fed feeds contaminated with ZEN at three concentrations (low: 332 MUg kg( 1), medium: 621 MUg kg(-1), and high: 797 MUg kg(-1) feed) for four weeks. Possible reversible effects of ZEN were evaluated by feeding additional groups with the ZEN-contaminated feeds for four weeks, followed by the uncontaminated diet for two weeks. Immune function of isolated leukocytes from head kidney and trunk kidney was assessed using the assessment of NO production, the respiratory burst assay, the chemiluminescence assay, and the measurement of arginase activities. These investigations frequently revealed increased immune responses after exposure of fish to low ZEN concentrations and reduced immune responses after exposure to high mycotoxin concentrations. Moreover, the feeding of the uncontaminated diet for further two weeks did not improve the immune responses in most cases. These results indicate that cellular immune functions in ZEN contaminated carp are influenced which may be relevant for fish health in aquaculture. PMID- 26491671 TI - Bypassing P-Glycoprotein Drug Efflux Mechanisms: Possible Applications in Pharmacoresistant Schizophrenia Therapy. AB - The efficient noninvasive treatment of neurodegenerative disorders is often constrained by reduced permeation of therapeutic agents into the central nervous system (CNS). A vast majority of bioactive agents do not readily permeate into the brain tissue due to the existence of the blood-brain barrier (BBB) and the associated P-glycoprotein efflux transporter. The overexpression of the MDR1 P glycoprotein has been related to the occurrence of multidrug resistance in CNS diseases. Various research outputs have focused on overcoming the P-glycoprotein drug efflux transporter, which mainly involve its inhibition or bypassing mechanisms. Studies into neurodegenerative disorders have shown that the P glycoprotein efflux transporter plays a vital role in the progression of schizophrenia, with a noted increase in P-glycoprotein function among schizophrenic patients, thereby reducing therapeutic outcomes. In this review, we address the hypothesis that methods employed in overcoming P-glycoprotein in cancer and other disease states at the level of the BBB and intestine may be applied to schizophrenia drug delivery system design to improve clinical efficiency of drug therapies. In addition, the current review explores polymers and drug delivery systems capable of P-gp inhibition and modulation. PMID- 26491672 TI - Multiphysics and Multiscale Analysis for Chemotherapeutic Drug. AB - This paper presents a three-dimensional dynamic model for the chemotherapy design based on a multiphysics and multiscale approach. The model incorporates cancer cells, matrix degrading enzymes (MDEs) secreted by cancer cells, degrading extracellular matrix (ECM), and chemotherapeutic drug. Multiple mechanisms related to each component possible in chemotherapy are systematically integrated for high reliability of computational analysis of chemotherapy. Moreover, the fidelity of the estimated efficacy of chemotherapy is enhanced by atomic information associated with the diffusion characteristics of chemotherapeutic drug, which is obtained from atomic simulations. With the developed model, the invasion process of cancer cells in chemotherapy treatment is quantitatively investigated. The performed simulations suggest a substantial potential of the presented model for a reliable design technology of chemotherapy treatment. PMID- 26491673 TI - Molecular Imaging-Guided Interventional Hyperthermia in Treatment of Breast Cancer. AB - Breast cancer is the most frequent malignancy in women worldwide. Although it is commonly treated via chemotherapy, responses vary among its subtypes, some of which are relatively insensitive to chemotherapeutic drugs. Recent studies have shown that hyperthermia can enhance the effects of chemotherapy in patients with refractory breast cancer or without surgical indications. Recent advances in molecular imaging may not only improve early diagnosis but may also facilitate the development and response assessment of targeted therapies. Combining advanced techniques such as molecular imaging and hyperthermia-integrated chemotherapy should open new avenues for effective management of breast cancer. PMID- 26491675 TI - AR Pathway Is Involved in the Regulation of CX43 in Prostate Cancer. AB - CX43 plays a critical role in tumor progression. Previous studies imply that AR pathway may be involved in regulation of CX43. This study was focused on determining the relationship between AR pathway and CX43. The result showed that the expression of CX43 in malignant cells was higher than that in normal cells, and in nonmalignant and malignant cells, not only is the expression level of CX43 different, but the localization of CX43 can also be changed. After androgen stimulation and inhibition of AR pathway, expression of CX43 can also be changed. Thus, AR pathway plays an important role in regulation of CX43 expression in prostate cancer cells. AR may be the upstream signal of CX43. PMID- 26491674 TI - Osteopontin Involves Cisplatin Resistance and Poor Prognosis in Oral Squamous Cell Carcinoma. AB - BACKGROUND: Osteopontin (OPN) is a multifunctional cytokine involved in cell survival, migration, and adhesion. However, its role in chemosensitivity in locally advanced oral squamous cell carcinoma (OSCC) in humans has not yet been investigated. METHODS: We enrolled 121 patients with locally advanced stage IVA/B OSCC receiving cisplatin-based IC followed by CCRT from January 1, 2006, through January 1, 2012. Immunohistochemistry was used to assess OPN expression in OSCC patients' biopsy specimens from paraffin blocks before treatment. In addition, MTT/colony formation assay was used to estimate the influence of OPN in an oral cancer cell line treated with cisplatin. RESULTS: Of the 121 patients, 94 had positive OPN findings and 52 responded to IC followed by CCRT. Positive osteopontin immunostaining also correlated significantly with positive N status/TNM stage/male gender and smoking. Univariate analyses showed that patients whose tumors had a low expression of OPN were more likely to respond to chemotherapy and have a significantly better OS than those whose tumors had a high expression of OPN. Multivariate analysis revealed that prolonged survival was independently predicted for patients with stage IVA disease, negative lymph nodes, and negative expressions of OPN and for those who received chemotherapy with Docetaxel/cisplatin/fluorouracil (TPF). An oral cancer line stimulated with OPN exhibited a dose-dependent resistance to cisplatin treatment. Conversely, endogenous OPN depletion by OPN-mediated shRNA increased sensitivity to cisplatin. CONCLUSIONS: A positive expression of OPN predicts a poor response and survival in patients with locally advanced stage IVA/B OSCC treated with cisplatin-based IC followed by CCRT. PMID- 26491676 TI - Characteristics of Biological Nitrogen Removal in a Multiple Anoxic and Aerobic Biological Nutrient Removal Process. AB - Two sequencing batch reactors, one with the conventional anoxic and aerobic (AO) process and the other with the multiple AO process, were operated to examine characteristics of biological nitrogen removal, especially of the multiple AO process. The long-term operation showed that the total nitrogen removal percentage of the multiple AO reactor was 38.7% higher than that of the AO reactor. In the multiple AO reactor, at the initial SBR cycle stage, due to the occurrence of simultaneous nitrification and denitrification, no nitrite and/or nitrate were accumulated. In the multiple AO reactor, activities of nitrite oxidizing bacteria were inhibited due to the multiple AO operating mode applied, resulting in the partial nitrification. Denitrifiers in the multiple AO reactor mainly utilized internal organic carbon for denitrification, and their activities were lower than those of denitrifiers in the AO reactor utilizing external organic carbon. PMID- 26491677 TI - A Glimpse to Background and Characteristics of Major Molecular Biological Networks. AB - Recently, biology has become a data intensive science because of huge data sets produced by high throughput molecular biological experiments in diverse areas including the fields of genomics, transcriptomics, proteomics, and metabolomics. These huge datasets have paved the way for system-level analysis of the processes and subprocesses of the cell. For system-level understanding, initially the elements of a system are connected based on their mutual relations and a network is formed. Among omics researchers, construction and analysis of biological networks have become highly popular. In this review, we briefly discuss both the biological background and topological properties of major types of omics networks to facilitate a comprehensive understanding and to conceptualize the foundation of network biology. PMID- 26491678 TI - Medicine Sellers for Prevention and Control of Sexually Transmitted Infections: Effect of a Quasi-Experimental Training Intervention in Bangladesh. AB - This study used a quasi-experimental pre-post design to test whether short training can improve medicine sellers' (MSs) practices and skills for prevention and control of sexually transmitted infections (STIs) in Bangladesh. The training included lectures, printed materials, and identification of referral sites. Difference-in-differences estimation was used to determine the effects of intervention on key primary and secondary outcomes. Advice given by the MSs in intervention group for partner treatment and condoms use increased significantly by 11% and 9%, respectively, after adjusting for baseline differences in education, religion, age, duration of training, and study site. Referral of clients to qualified service providers increased by 5% in the intervention group compared to the comparison group, but this change was not found to be statistically significant. Significantly higher proportion of MSs in the intervention group recognized the recommended medications as per the national syndromic management guidelines in Bangladesh for treatment of urethral discharge and genital ulcer symptoms. Short training intervention was found to be effective in improving MSs' practice of promoting condom use and partner treatment to the clients. We anticipate the need for broad based training programs of MSs to improve their skills for the prevention and control of STI/HIV in Bangladesh. PMID- 26491679 TI - Influence of Ionizing Radiation on Two Generations of Cochlear Implants. AB - The purpose of the present study was to test the behavior of two different generations of cochlear implant systems subjected to a clinical radiotherapy scheme and to determine the maximal acceptable cumulative radiation levels at which the devices show out-of-specification behaviors. Using stereotactic irradiation (Cyberknife, 6 MV photon beam), three Digisonic SP and three Neuro devices were submitted to 5 Gy doses that cumulated to 60 Gy (12 sessions) and 80 Gy (16 sessions), respectively. A follow-up series of irradiation was then applied, in which Digisonic SP devices received two additional fractions of 50 Gy each, cumulating to 160 Gy, and Neuro devices three additional fractions of 20, 40, and 150 Gy, cumulating to 290 Gy. Output current values were monitored during the treatment. At clinical doses, with 60 or 80 Gy cumulative radiation exposure, no single measurement showed more than 10% divergence from the reference measure. The cochlear implants tested in this study showed high resistance to clinically relevant cumulative radiation doses and showed no out-of-bounds behavior up to cumulative doses of 140 or 160 Gy. These observations suggest that cochlear implant users can undergo radiotherapy up to cumulative doses well above those currently used in clinical situations without risk of failure. PMID- 26491680 TI - Are Biodegradable Osteosyntheses Still an Option for Midface Trauma? Longitudinal Evaluation of Three Different PLA-Based Materials. AB - The aim was to evaluate three different biodegradable polylactic acid- (PLA-) based osteosynthesis materials (OM). These OM (BioSorb, LactoSorb, and Delta) were used in 64 patients of whom 55 (85.9%) had fractures of the zygoma, five (7.8%) in the LeFort II level, two of the frontal bone (3.1%), and two of the maxillary sinus wall (3.1%). In addition to routine follow-up (FU) at 3, 6, and 12 months (m) (T1, T2, and T3) all patients were finally evaluated at a mean FU after 14.1 m for minor (e.g., nerve disturbances, swelling, and pain) and major (e.g., infections and occlusal disturbances) complications. Out of all 64 patients 38 presented with complications; of these 28 were minor (43.8%) and 10 major (15.6%) resulting in an overall rate of 59.4%. Differences in minor complications regarding sensibility disturbance at T1 and T3 were statistically significant (P = 0.04). Differences between the OM were not statistically significant. Apart from sufficient mechanical stability for clinical use of all tested OM complications mostly involved pain and swelling probably mainly related to the initial bulk reaction attributable to the drop of pH value during the degradation process. This paper includes a review of the current aspects of biodegradable OM. PMID- 26491681 TI - Genetic and Cultural Reconstruction of the Migration of an Ancient Lineage. AB - A rare R1a1 Y-haplogroup (Y-HG) L657 clade subtype designated as LPKSTR is found in most male members of a clan of "founder" families within the Goud Saraswat Brahmin community in Lotli town in Western India. TMRCA calculations using pairwise comparisons to control cohorts suggested a probable migration history distinct from the canonical narrative for medieval migration of orthodox Brahmin families to South India. Using Y-HG centroid analysis, chi-square analysis of TMRCA distributions and archeological find-spots, and discriminant function analysis we show that the parental Z93 L342.2 subclade in which LPKSTR occurs originated in West Asia and that LPKSTR individuals migrated toward the southeast by a Bolan Pass route distinct from the traditionally presumed route of Brahmin ingress into the Indian subcontinent. The proposed migration route is supported by archeological, toponymic, numismatic, linguistic, iconographic, and literary data. Lastly, we present cultural metrics demonstrating that these LPKSTR lineages retained distinct family practices with respect to literacy, religious practice, and emigration not shared with orthodox Brahmins of canonical geographic origin within the same community, despite centuries of intermarriage. Long-term transmission of differentiated family practices within a patrilineal endogamous community has rarely been documented. PMID- 26491682 TI - Endothelial Progenitor Cell Fraction Contained in Bone Marrow-Derived Mesenchymal Stem Cell Populations Impairs Osteogenic Differentiation. AB - In bone tissue engineering (TE) endothelial cell-osteoblast cocultures are known to induce synergies of cell differentiation and activity. Bone marrow mononucleated cells (BMCs) are a rich source of mesenchymal stem cells (MSCs) able to develop an osteogenic phenotype. Endothelial progenitor cells (EPCs) are also present within BMC. In this study we investigate the effect of EPCs present in the BMC population on MSCs osteogenic differentiation. Human BMCs were isolated and separated into two populations. The MSC population was selected through plastic adhesion capacity. EPCs (CD34(+) and CD133(+)) were removed from the BMC population and the resulting population was named depleted MSCs. Both populations were cultured over 28 days in osteogenic medium (Dex(+)) or medium containing platelet lysate (PL). MSC population grew faster than depleted MSCs in both media, and PL containing medium accelerated the proliferation for both populations. Cell differentiation was much higher in Dex(+) medium in both cases. Real-time RT-PCR revealed upregulation of osteogenic marker genes in depleted MSCs. Higher values of ALP activity and matrix mineralization analyses confirmed these results. Our study advocates that absence of EPCs in the MSC population enables higher osteogenic gene expression and matrix mineralization and therefore may lead to advanced bone neoformation necessary for TE constructs. PMID- 26491683 TI - Cases of Echinococcus granulosus Sensu Stricto Isolated from Polish Patients: Imported or Indigenous? AB - The cases of nine Polish patients with diagnosed cystic echinococcosis (CE) were examined. A total of nine isolates obtained postoperatively were investigated using PCR and sequencing. The mitochondrial region of nad1 gene was amplified. This PCR and sequencing analysis revealed the presence of Echinococcus canadensis G7 in seven patients and E. granulosus G1 in two patients. These data demonstrate that E. canadensis is the predominant causative agent of human cystic echinococcosis in Poland. E. granulosus G1 detection in Polish patients suggests that the parasite was imported; however it does not exclude the possibility that these cases could have been of Polish origin. PMID- 26491684 TI - Lsh Is Essential for Maintaining Global DNA Methylation Levels in Amphibia and Fish and Interacts Directly with Dnmt1. AB - Eukaryotic genomes are methylated at cytosine bases in the context of CpG dinucleotides, a pattern which is maintained through cell division by the DNA methyltransferase Dnmt1. Dramatic methylation losses are observed in plant and mouse cells lacking Lsh (lymphoid specific helicase), predominantly at repetitive sequences and gene promoters. However, the mechanism by which Lsh contributes to the maintenance of DNA methylation is unknown. Here we show that DNA methylation is lost in Lsh depleted frog and fish embryos, both of which exhibit developmental delay. Additionally, we show that both Lsh and Dnmt1 are associated with chromatin and that Lsh knockdown leads to a decreased Dnmt1-chromatin association. Coimmunoprecipitation experiments reveal that Lsh and Dnmt1 are found in the same protein complex, and pulldowns show this interaction is direct. Our data indicate that Lsh is usually diffuse in the nucleus but can be recruited to heterochromatin in a HP1alpha-dependent manner. These data together (a) show that the role of Lsh in DNA methylation is conserved in plants, amphibian, fish, and mice and (b) support a model in which Lsh contributes to Dnmt1 binding to chromatin, explaining how its loss can potentially lead to perturbations in DNA methylation maintenance. PMID- 26491686 TI - Amino Acids in Nine Ligand-Prefer Ramachandran Regions. AB - Several secondary structures, such as pi-helix and left-handed helix, have been frequently identified at protein ligand-binding sites. A secondary structure is considered to be constrained to a specific region of dihedral angles. However, a comprehensive analysis of the correlation between main chain dihedral angles and ligand-binding sites has not been performed. We undertook an extensive analysis of the relationship between dihedral angles in proteins and their distance to ligand-binding sites, frequency of occurrence, molecular potential energy, amino acid composition, van der Waals contacts, and hydrogen bonds with ligands. The results showed that the values of dihedral angles have a strong preference for ligand-binding sites at certain regions in the Ramachandran plot. We discovered that amino acids preceding the ligand-prefer phi/psi box residues are exposed more to solvents, whereas amino acids following ligand-prefer phi/psi box residues form more hydrogen bonds and van der Waals contacts with ligands. Our method exhibited a similar performance compared with the program Ligsite-csc for both ligand-bound structures and ligand-free structures when just one ligand binding site was predicted. These results should be useful for the prediction of protein ligand-binding sites and for analysing the relationship between structure and function. PMID- 26491687 TI - Effects of Caloric Intake on Learning and Memory Function in Juvenile C57BL/6J Mice. AB - Dietary composition may influence neuronal function as well as processes underlying synaptic plasticity. In this study, we aimed to determine the effect of high and low caloric diets on a mouse model of learning and memory and to explore mechanisms underlying this process. Mice were divided into three different dietary groups: normal control (n = 12), high-caloric (HC) diet (n = 12), and low-caloric (LC) diet (n = 12). After 6 months, mice were evaluated on the Morris water maze to assess spatial memory ability. We found that HC diet impaired learning and memory function relative to both control and LC diet. The levels of SIRT1 as well as its downstream effectors p53, p16, and peroxisome proliferator-activated receptor gamma (PPARgamma) were decreased in brain tissues obtained from HC mice. LC upregulated SIRT1 but downregulated p53, p16, and PPARgamma. The expressions of PI3K and Akt were not altered after HC or LC diet treatment, but both LC and HC elevated the levels of phosphorylated-cAMP response element-binding protein (p-CREB) and IGF-1 in hippocampal CA1 region. Therefore, HC diet-induced dysfunction in learning and memory may be prevented by caloric restriction via regulation of the SIRT1-p53 or IGF-1 signaling pathways and phosphorylation of CREB. PMID- 26491688 TI - Significance of Neutrophil Gelatinase-Associated Lipocalin Level-to-Serum Creatinine Ratio for Assessing Severity of Inflammation in Patients with Renal Dysfunction. AB - The aim of this study was to assess the significance of the neutrophil gelatinase associated lipocalin/serum creatinine ratio (NGAL/sCr ratio) in patients with renal dysfunction. The percent difference between plasma NGAL level and the NGAL/sCr ratio was 36.7% (95% CI, 18.4-83.7%) in patients with sCr level >= 1.2 mg/dL. In a multivariate analysis, high sensitivity C-reactive protein (hsCRP) was significantly associated with the NGAL/sCr ratio and plasma NGAL level (r = 0.526 and r = 0.453, resp., P < 0.001). In a receiver operating characteristics curve, the diagnostic ability of the NGAL/sCr ratio to identify hsCRP > 4.0 mg/dL was superior to that of NGAL [0.783 (95% CI, 0.674-0.892) versus 0.733 (95% CI, 0.615-0.852), P = 0.032]. The area under the curve of the NGAL/sCr ratio was larger than that of hsCRP to detect corrected erythrocyte sedimentation rate > 25 mm/h and the neutrophil-to-lymphocyte ratio >4.5 in renal dysfunction. In short, the NGAL/sCr ratio may offer useful information when screening patients with both systemic inflammation and renal dysfunction. PMID- 26491685 TI - Biomaterial Approaches to Enhancing Neurorestoration after Spinal Cord Injury: Strategies for Overcoming Inherent Biological Obstacles. AB - While advances in technology and medicine have improved both longevity and quality of life in patients living with a spinal cord injury, restoration of full motor function is not often achieved. This is due to the failure of repair and regeneration of neuronal connections in the spinal cord after injury. In this review, the complicated nature of spinal cord injury is described, noting the numerous cellular and molecular events that occur in the central nervous system following a traumatic lesion. In short, postinjury tissue changes create a complex and dynamic environment that is highly inhibitory to the process of neural regeneration. Strategies for repair are outlined with a particular focus on the important role of biomaterials in designing a therapeutic treatment that can overcome this inhibitory environment. The importance of considering the inherent biological response of the central nervous system to both injury and subsequent therapeutic interventions is highlighted as a key consideration for all attempts at improving functional recovery. PMID- 26491689 TI - Comparison of Fine Needle Aspiration and Fine Needle Nonaspiration Cytology of Thyroid Nodules: A Meta-Analysis. AB - BACKGROUND: Fine needle aspiration cytology (FNAC) and fine needle nonaspiration cytology (FNNAC) are useful cost-effective techniques for preoperatively assessing thyroid lesions. Both techniques have advantages and disadvantages, and there is controversy over which method is superior. This meta-analysis was performed to evaluate the differences between FNAC and FNNAC for diagnosis of thyroid nodules. METHODS: Primary publications were independently collected by two reviewers from PubMed, Web of Science, Google Scholar, EBSCO, OALib, and the Cochrane Library databases. The following search terms were used: fine needle, aspiration, capillary, nonaspiration, sampling without aspiration, thyroid, and cytology. The last search was performed on February 1, 2015. RESULTS: Sixteen studies comprising 1,842 patients and 2,221 samples were included in this study. No statistically significant difference was observed between FNAC and FNNAC groups with respect to diagnostically inadequate smears, diagnostically superior smears, diagnostic performance (accuracy, sensitivity, specificity, negative predictive value, and positive predictive value), area under the summary receiver operating characteristic curve, average score of each parameter (background blood or clot, amount of cellular material, degree of cellular degeneration, degree of cellular trauma, and retention of appropriate architecture), and total score of five parameters. CONCLUSION: FNAC and FNNAC are equally useful in assessing thyroid nodules. PMID- 26491690 TI - Soluble Receptor for Advanced Glycation End Product: A Biomarker for Acute Coronary Syndrome. AB - The receptor of advanced glycation end products (RAGE) and its ligands are linked to the pathogenesis of coronary artery disease (CAD), and circulating soluble receptor of advanced glycation end products (sRAGE), reflecting the RAGE activity, is suggested as a potential biomarker. Elevated sRAGE levels are reported in relation to acute ischemia and this review focuses on the role of sRAGE as a biomarker for the acute coronary syndrome (ACS). The current studies demonstrated that sRAGE levels are elevated in relation to ACS, however during a very narrow time period, indicating that the time of sampling needs attention. Interestingly, activation of RAGE may influence the pathogenesis and reflection in sRAGE levels in acute and stable CAD differently. PMID- 26491691 TI - T Lymphocyte Inhibition by Tumor-Infiltrating Dendritic Cells Involves Ectonucleotidase CD39 but Not Arginase-1. AB - T lymphocytes activated by dendritic cells (DC) which present tumor antigens play a key role in the antitumor immune response. However, in patients suffering from active cancer, DC are not efficient at initiating and supporting immune responses as they participate to T lymphocyte inhibition. DC in the tumor environment are functionally defective and exhibit a characteristic of immature phenotype, different to that of DC present in nonpathological conditions. The mechanistic bases underlying DC dysfunction in cancer responsible for the modulation of T cell responses and tumor immune escape are still being investigated. Using two different mouse tumor models, we showed that tumor-infiltrating DC (TIDC) are constitutively immunosuppressive, exhibit a semimature phenotype, and impair responder T lymphocyte proliferation and activation by a mechanism involving CD39 ectoenzyme. PMID- 26491692 TI - Effects of Acute Lithium Treatment on Brain Levels of Inflammatory Mediators in Poststroke Rats. AB - Stroke is a leading cause of mortality and morbidity worldwide. Few therapeutic options with proven efficacy are available for the treatment of this disabling disease. Lithium is the gold standard treatment for bipolar disorder. Moreover, lithium has been shown to exhibit neuroprotective effects and therapeutic efficacy as a treatment of other neurological disorders. This study was undertaken to examine the effects of lithium on brain inflammatory mediators levels, fever, and mortality in postischemic stroke rats. Ischemic stroke was induced by occlusion of the mid cerebral artery (MCAO). Pretreatment with a single dose of lithium at 2 hours before MCAO induction significantly reduced the elevation in interleukin- (IL-) 6 and prostaglandin E2 levels in brain of post MCAO rats, as compared to vehicle-treated animals. On the other hand, lithium did not affect the elevation in IL-1alpha, IL-10, IL-12, and tumor necrosis factor alpha levels in brain of post-MCAO rats. Moreover, pretreatment with lithium did not alter post-MCAO fever and mortality. These results suggest that acute pretreatment with a single dose of lithium did not markedly affect post-MCAO morbidity and mortality in rats. PMID- 26491694 TI - Bone and Tooth Regeneration in Maxillofacial Region. PMID- 26491693 TI - Repair of Cranial Bone Defects Using rhBMP2 and Submicron Particle of Biphasic Calcium Phosphate Ceramics with Through-Hole. AB - Recently a submicron particle of biphasic calcium phosphate ceramic (BCP) with through-hole (donut-shaped BCP (d-BCP)) was developed for improving the osteoconductivity. This study was performed to examine the usefulness of d-BCP for the delivery of osteoinductive rhBMP2 and the effectiveness on cranial bone regeneration. The d-BCP was soaked in rhBMP2 solution and then freeze-dried. Scanning electron microscope (SEM), energy dispersive spectroscopy (EDS), and Raman spectroscopy analyses confirmed that rhBMP2 was well delivered onto the d BCP surface and the through-hole. The bioactivity of the rhBMP2/d-BCP composite was validated in MC3T3-E1 cells as an in vitro model and in critical-sized cranial defects in C57BL/6 mice. When freeze-dried d-BCPs with rhBMP2 were placed in transwell inserts and suspended above MC3T3-E1, alkaline phosphatase activity and osteoblast-specific gene expression were increased compared to non-rhBMP2 containing d-BCPs. For evaluating in vivo effectiveness, freeze-dried d-BCPs with or without rhBMP2 were implanted into critical-sized cranial defects. Microcomputed tomography and histologic analysis showed that rhBMP2-containing d BCPs significantly enhanced cranial bone regeneration compared to non-rhBMP2 containing control. These results suggest that a combination of d-BCP and rhBMP2 can accelerate bone regeneration, and this could be used to develop therapeutic strategies in hard tissue healing. PMID- 26491695 TI - Rare Diseases of the Anterior Segment of the Eye: Update on Diagnosis and Management. PMID- 26491696 TI - Roles of Akt and SGK1 in the Regulation of Renal Tubular Transport. AB - A serine/threonine kinase Akt is a key mediator in various signaling pathways including regulation of renal tubular transport. In proximal tubules, Akt mediates insulin signaling via insulin receptor substrate 2 (IRS2) and stimulates sodium-bicarbonate cotransporter (NBCe1), resulting in increased sodium reabsorption. In insulin resistance, the IRS2 in kidney cortex is exceptionally preserved and may mediate the stimulatory effect of insulin on NBCe1 to cause hypertension in diabetes via sodium retention. Likewise, in distal convoluted tubules and cortical collecting ducts, insulin-induced Akt phosphorylation mediates several hormonal signals to enhance sodium-chloride cotransporter (NCC) and epithelial sodium channel (ENaC) activities, resulting in increased sodium reabsorption. Serum- and glucocorticoid-inducible kinase 1 (SGK1) mediates aldosterone signaling. Insulin can stimulate SGK1 to exert various effects on renal transporters. In renal cortical collecting ducts, SGK1 regulates the expression level of ENaC through inhibition of its degradation. In addition, SGK1 and Akt cooperatively regulate potassium secretion by renal outer medullary potassium channel (ROMK). Moreover, sodium-proton exchanger 3 (NHE3) in proximal tubules is possibly activated by SGK1. This review focuses on recent advances in understanding of the roles of Akt and SGK1 in the regulation of renal tubular transport. PMID- 26491697 TI - Targeted Mutation of Nuclear Bone Morphogenetic Protein 2 Impairs Secondary Immune Response in a Mouse Model. AB - We recently identified a nuclear variant of the BMP2 growth factor, called nBMP2. In an effort to understand the function of this variant protein, we generated a mouse line in which BMP2 is expressed and functions normally, but nBMP2 is excluded from the nucleus. This novel mutation allows the study of nBMP2 without compromising BMP2 function. To determine whether nBMP2 plays a role in immune function, we performed a series of experiments in which we compared mouse survival, organ weights, immune cells numbers, and bacterial load in wild type and nBmp2NLS(tm) mice following primary and secondary challenges with Staphylococcus aureus. Following primary challenge with S. aureus, wild type and nBmp2NLS(tm) mice showed no differences in survival or bacterial load and generated similar numbers and types of leukocytes, although mutant spleens were smaller than wild type. Secondary bacterial challenge with S. aureus, however, produced differences in survival, with increased mortality seen in nBmp2NLS(tm) mice. This increased mortality corresponded to higher levels of bacteremia in nBmp2NLS(tm) mice and to a reduced enlargement of mutant spleens in response to the secondary infection. Together, these results suggest that the recently described nuclear variant of BMP2 is necessary for efficient secondary immune responses. PMID- 26491699 TI - Comment on "The Effect of Chromium Picolinate Supplementation on the Pancreas and Macroangiopathy in Type II Diabetes Mellitus Rats". PMID- 26491698 TI - Effects of Glucose Concentration on Propofol Cardioprotection against Myocardial Ischemia Reperfusion Injury in Isolated Rat Hearts. AB - The anesthetic propofol confers cardioprotection against myocardial ischemia reperfusion injury (IRI) by reducing reactive oxygen species (ROS). However, its cardioprotection on patients is inconsistent. Similarly, the beneficial effect of tight glycemic control during cardiac surgery in patients has recently been questioned. We postulated that low glucose (LG) may promote ROS formation through enhancing fatty acid (FA) oxidation and unmask propofol cardioprotection during IRI. Rat hearts were isolated and randomly assigned to be perfused with Krebs Henseleit solution with glucose at 5.5 mM (LG) or 8 mM (G) in the absence or presence of propofol (5 MUg/mL) or propofol plus trimetazidine (TMZ). Hearts were subjected to 35 minutes of ischemia followed by 60 minutes of reperfusion. Myocardial infarct size (IS) and cardiac CK-MB were significantly higher in LG than in G group (P < 0.05), associated with reduced left ventricular developed pressure and increases in postischemic cardiac contracture. Cardiac 15-F2t isoprostane was higher, accompanied with higher cardiac lipid transporter CD36 protein expression in LG. Propofol reduced IS, improved cardiac function, and reduced CD36 in G but not in LG. TMZ facilitated propofol cardioprotection in LG. Therefore, isolated heart with low glucose lost sensitivity to propofol treatment through enhancing FA oxidation and TMZ supplementation restored the sensitivity to propofol. PMID- 26491700 TI - Human Gene Expression in Uncomplicated Plasmodium falciparum Malaria. AB - To examine human gene expression during uncomplicated P. falciparum malaria, we obtained three samples (acute illness, treatment, and recovery) from 10 subjects and utilized each subject's recovery sample as their baseline. At the time of acute illness (day 1), subjects had upregulation of innate immune response, cytokine, and inflammation-related genes (IL-1beta, IL-6, TNF, and IFN-gamma), which was more frequent with parasitemias >100,000 per MUL and body temperatures >= 39 degrees C. Apoptosis-related genes (Fas, BAX, and TP53) were upregulated acutely and for several days thereafter (days 1-3). In contrast, the expression of immune-modulatory (transcription factor 7, HLV-DOA, and CD6) and apoptosis inhibitory (c-myc, caspase 8, and Fas Ligand G) genes was downregulated initially and returned to normal with clinical recovery (days 7-10). These results indicate that the innate immune response, cytokine, and apoptosis pathways are upregulated acutely in uncomplicated malaria with concomitant downregulation of immune modulatory and apoptosis inhibitory genes. PMID- 26491701 TI - Expansion of Circulating T Follicular Helper Cells in Children with Acute Henoch Schonlein Purpura. AB - Henoch-Schonlein purpura (HSP) is a common systemic small vessel vasculitis in children with disorder autoimmune responses. T follicular helper (TFH) cells play crucial roles in regulating immune responses. The aim of our study was to investigate the probable role of TFH cells in the pathogenesis of children with HSP. In this study, the frequency of circulating CXCR5(+)CD4(+)TFH cells with inducible costimulator (ICOS) expression in the children with acute HSP was significantly higher than that in healthy controls (HCs) but not CXCR5(+)CD4(+)TFH cells with programmed death-1 (PD-1) expression. Moreover, serum levels of IL-21 and IL-6 cytokines, IgA, and C3 in HSP children were also significantly higher than those in HCs. A positive correlation was observed between the frequencies of circulating ICOS(+)CXCR5(+)CD4(+)TFH cells and the serum IL-21 or IgA levels of acute HSP children, respectively. Additionally, the mRNA expression levels of interleukin- (IL-) 21, IL-6, and transcriptional factors (B-cell lymphoma-6, Bcl-6) were also significantly increased in peripheral blood from acute HSP children compared to HCs. Taken together, these findings suggest that TFH cells and associated molecules might play critical roles in the pathogenesis of HSP, which are possible therapeutic targets in HSP children. PMID- 26491704 TI - Mincocycline-Induced Discoloration of the Aorta. PMID- 26491702 TI - Altered Traffic of Cardiolipin during Apoptosis: Exposure on the Cell Surface as a Trigger for "Antiphospholipid Antibodies". AB - Apoptosis has been reported to induce changes in the remodelling of membrane lipids; after death receptor engagement, specific changes of lipid composition occur not only at the plasma membrane, but also in intracellular membranes. This paper focuses on one important aspect of apoptotic changes in cellular lipids, namely, the redistribution of the mitochondria-specific phospholipid, cardiolipin (CL). CL predominantly resides in the inner mitochondrial membrane, even if the rapid remodelling of its acyl chains and the subsequent degradation occur in other membrane organelles. After death receptor stimulation, CL appears to concentrate into mitochondrial "raft-like" microdomains at contact sites between inner and outer mitochondrial membranes, leading to local oligomerization of proapoptotic proteins, including Bid. Clustering of Bid in CL-enriched contacts sites is interconnected with pathways of CL remodelling that intersect membrane traffic routes dependent upon actin. In addition, CL association with cytoskeleton protein vimentin was observed. Such novel association also indicated that CL molecules may be expressed at the cell surface following apoptotic stimuli. This observation adds a novel implication of biomedical relevance. The association of CL with vimentin at the cell surface may represent a "new" target antigen in the context of the apoptotic origin of anti-vimentin/CL autoantibodies in Antiphospholipid Syndrome. PMID- 26491703 TI - Emergence of a metalloproteinase / phospholipase A2 axis of systemic inflammation. AB - We review select aspects of the biology of matrix metalloproteinases (MMPs) with a focus on the modulation of inflammatory responses by MMP-2. MMP-2 is a zinc- and calcium-dependent endoprotease with substrates including extracellular matrix proteins, vasoactive peptides and chemokines. Humans and mice with MMP-2 deficiency exhibit a predominantly inflammatory phenotype. Recent research shows that MMP-2 deficient mice display elevated activity of a secreted phospholipase A2 in the heart. Additionally, MMP-2 deficient mice exhibit abnormally high prostaglandin E2 levels in various organs (i.e., the heart, brain and liver), signs of inflammation and exacerbated lipopolysaccharide-induced fever. We briefly review the biology of sPLA2 enzymes to propose the existence of a heart centric MMP-2/sPLA2 axis of systemic inflammation. Moreover, we postulate that PLA2 activation is induced by chemokines, whose ability to signal inflammation is regulated in a tissue-specific fashion by MMPs. Thus, genetic and pharmacologically induced MMP-deficiencies can be expected to perturb PLA2 mediated inflammatory mechanisms. PMID- 26491705 TI - Transcytosis in the blood-cerebrospinal fluid barrier of the mouse brain with an engineered receptor/ligand system. AB - Crossing the blood-brain and the blood-cerebrospinal fluid barriers (BCSFB) is one of the fundamental challenges in the development of new therapeutic molecules for brain disorders because these barriers prevent entry of most drugs from the blood into the brain. However, some large molecules, like the protein transferrin, cross these barriers using a specific receptor that transports them into the brain. Based on this mechanism, we engineered a receptor/ligand system to overcome the brain barriers by combining the human transferrin receptor with the cohesin domain from Clostridium thermocellum, and we tested the hybrid receptor in the choroid plexus of the mouse brain with a dockerin ligand. By expressing our receptor in choroidal ependymocytes, which are part of the BCSFB, we found that our systemically administrated ligand was able to bind to the receptor and accumulate in ependymocytes, where some of the ligand was transported from the blood side to the brain side. PMID- 26491706 TI - Impact of Bioelectronic Medicine on the Neural Regulation of Pelvic Visceral Function. AB - Neuromodulation elicited by electrical stimulation of peripheral or spinal nerves is a U.S. Food and Drug Administered (FDA)-approved therapy for treating disorders of the pelvic viscera, including urinary urgency, urgency-frequency, nonobstructive urinary retention and fecal incontinence. The technique is also being tested experimentally for its efficacy in treating interstitial cystitis, chronic constipation and pelvic pain. The goal of neuromodulation is to suppress abnormal visceral sensations and involuntary reflexes and restore voluntary control. Although detailed mechanisms underlying the effects of neuromodulation are still to be elucidated, it is generally believed that effects are due to stimulation of action potentials in somatic afferent nerves. Afferent nerves project to the lumbosacral spinal cord, where they release excitatory neurotransmitters that activate ascending pathways to the brain or spinal circuits that modulate visceral sensory and involuntary motor mechanisms. Studies in animals revealed that different types of neuromodulation (for example, stimulation of a sacral spinal root, pudendal nerve or posterior tibial nerve) act by releasing different inhibitory and excitatory neurotransmitters in the central nervous system. In addition, certain types of neuromodulation inhibit visceral smooth muscle by initiating reflex firing in peripheral autonomic nerves or excite striated sphincter muscles by initiating reflex firing in somatic efferent nerves. This report will provide a brief summary of (a) neural control of the lower urinary tract and distal bowel, (b) clinical use of neuromodulation in the treatment of bladder and bowel dysfunctions, PMID- 26491707 TI - Research Networking Systems: The State of Adoption at Institutions Aiming to Augment Translational Research Infrastructure. AB - Fostering collaborations across multiple disciplines within and across institutional boundaries is becoming increasingly important with the growing emphasis on translational research. As a result, Research Networking Systems that facilitate discovery of potential collaborators have received significant attention by institutions aiming to augment their research infrastructure. We have conducted a survey to assess the state of adoption of these new tools at the Clinical and Translational Science Award (CTSA) funded institutions. Survey results demonstrate that most CTSA funded institutions have either already adopted or were planning to adopt one of several available research networking systems. Moreover a good number of these institutions have exposed or plan to expose the data on research expertise using linked open data, an established approach to semantic web services. Preliminary exploration of these publically available data shows promising utility in assessing cross-institutional collaborations. Further adoption of these technologies and analysis of the data are needed, however, before their impact on cross-institutional collaboration in research can be appreciated and measured. PMID- 26491708 TI - The Thermogenic Circuit: Regulators of Thermogenic Competency and Differentiation. AB - In mammals, a thermogenic mechanism exists that increases heat production and consumes energy. Recent work has shed light on the cellular and physiological mechanisms that control this thermogenic circuit. Thermogenically active adipocytes, namely brown and closely related beige adipocytes, differentiate from progenitor cells that commit to the thermogenic lineage but can arise from different cellular origins. Thermogenic differentiation shares some features with general adipogenesis, highlighting the critical role that common transcription factors may play in progenitors with divergent fates. However, thermogenic differentiation is also discrete from the common adipogenic program and, excitingly, cells with distinct origins possess thermogenic competency that allows them to differentiate into thermogenically active mature adipocytes. An understanding of this thermogenic differentiation program and the factors that can activate it has led to the development of assays that are able to measure thermogenic activity both indirectly and directly. By combining these assays with appropriate cell models, novel therapeutic approaches to combat obesity and its related metabolic disorders by enhancing the thermogenic circuit can be developed. PMID- 26491709 TI - Insider information: Testing cancer drug sensitivity for personalized therapy. AB - Cancer death is usually caused by incurable drug-resistant and metastatic cancers. Although tremendous progress has been made in anticancer drug development during the past two decades, cancer medicine still faces unprecedented challenges associated with choosing effective treatments for individual patients. Three recent reports have offered encouraging approaches towards potentially personalized cancer drug selection. PMID- 26491710 TI - Dynamic Harmony Search with Polynomial Mutation Algorithm for Valve-Point Economic Load Dispatch. AB - Economic load dispatch (ELD) problem is an important issue in the operation and control of modern control system. The ELD problem is complex and nonlinear with equality and inequality constraints which makes it hard to be efficiently solved. This paper presents a new modification of harmony search (HS) algorithm named as dynamic harmony search with polynomial mutation (DHSPM) algorithm to solve ORPD problem. In DHSPM algorithm the key parameters of HS algorithm like harmony memory considering rate (HMCR) and pitch adjusting rate (PAR) are changed dynamically and there is no need to predefine these parameters. Additionally polynomial mutation is inserted in the updating step of HS algorithm to favor exploration and exploitation of the search space. The DHSPM algorithm is tested with three power system cases consisting of 3, 13, and 40 thermal units. The computational results show that the DHSPM algorithm is more effective in finding better solutions than other computational intelligence based methods. PMID- 26491711 TI - Traffic and Driving Simulator Based on Architecture of Interactive Motion. AB - This study proposes an architecture for an interactive motion-based traffic simulation environment. In order to enhance modeling realism involving actual human beings, the proposed architecture integrates multiple types of simulation, including: (i) motion-based driving simulation, (ii) pedestrian simulation, (iii) motorcycling and bicycling simulation, and (iv) traffic flow simulation. The architecture has been designed to enable the simulation of the entire network; as a result, the actual driver, pedestrian, and bike rider can navigate anywhere in the system. In addition, the background traffic interacts with the actual human beings. This is accomplished by using a hybrid mesomicroscopic traffic flow simulation modeling approach. The mesoscopic traffic flow simulation model loads the results of a user equilibrium traffic assignment solution and propagates the corresponding traffic through the entire system. The microscopic traffic flow simulation model provides background traffic around the vicinities where actual human beings are navigating the system. The two traffic flow simulation models interact continuously to update system conditions based on the interactions between actual humans and the fully simulated entities. Implementation efforts are currently in progress and some preliminary tests of individual components have been conducted. The implementation of the proposed architecture faces significant challenges ranging from multiplatform and multilanguage integration to multievent communication and coordination. PMID- 26491712 TI - Investigating IT Faculty Resistance to Learning Management System Adoption Using Latent Variables in an Acceptance Technology Model. AB - To enhance instruction in higher education, many universities in the Middle East have chosen to introduce learning management systems (LMS) to their institutions. However, this new educational technology is not being used at its full potential and faces resistance from faculty members. To investigate this phenomenon, we conducted an empirical research study to uncover factors influencing faculty members' acceptance of LMS. Thus, in the Fall semester of 2014, Information Technology faculty members were surveyed to better understand their perceptions of the incorporation of LMS into their courses. The results showed that personal factors such as motivation, load anxiety, and organizational support play important roles in the perception of the usefulness of LMS among IT faculty members. These findings suggest adding these constructs in order to extend the Technology acceptance model (TAM) for LMS acceptance, which can help stakeholders of the university to implement the use of this system. This may assist in planning and evaluating the use of e-learning. PMID- 26491713 TI - Medical Dataset Classification: A Machine Learning Paradigm Integrating Particle Swarm Optimization with Extreme Learning Machine Classifier. AB - Medical data classification is a prime data mining problem being discussed about for a decade that has attracted several researchers around the world. Most classifiers are designed so as to learn from the data itself using a training process, because complete expert knowledge to determine classifier parameters is impracticable. This paper proposes a hybrid methodology based on machine learning paradigm. This paradigm integrates the successful exploration mechanism called self-regulated learning capability of the particle swarm optimization (PSO) algorithm with the extreme learning machine (ELM) classifier. As a recent off line learning method, ELM is a single-hidden layer feedforward neural network (FFNN), proved to be an excellent classifier with large number of hidden layer neurons. In this research, PSO is used to determine the optimum set of parameters for the ELM, thus reducing the number of hidden layer neurons, and it further improves the network generalization performance. The proposed method is experimented on five benchmarked datasets of the UCI Machine Learning Repository for handling medical dataset classification. Simulation results show that the proposed approach is able to achieve good generalization performance, compared to the results of other classifiers. PMID- 26491714 TI - Fully Integrated Passive UHF RFID Tag for Hash-Based Mutual Authentication Protocol. AB - Passive radio-frequency identification (RFID) tag has been used in many applications. While the RFID market is expected to grow, concerns about security and privacy of the RFID tag should be overcome for the future use. To overcome these issues, privacy-preserving authentication protocols based on cryptographic algorithms have been designed. However, to the best of our knowledge, evaluation of the whole tag, which includes an antenna, an analog front end, and a digital processing block, that runs authentication protocols has not been studied. In this paper, we present an implementation and evaluation of a fully integrated passive UHF RFID tag that runs a privacy-preserving mutual authentication protocol based on a hash function. We design a single chip including the analog front end and the digital processing block. We select a lightweight hash function supporting 80-bit security strength and a standard hash function supporting 128 bit security strength. We show that when the lightweight hash function is used, the tag completes the protocol with a reader-tag distance of 10 cm. Similarly, when the standard hash function is used, the tag completes the protocol with the distance of 8.5 cm. We discuss the impact of the peak power consumption of the tag on the distance of the tag due to the hash function. PMID- 26491716 TI - Optimization of Electrochemical Treatment Process Conditions for Distillery Effluent Using Response Surface Methodology. AB - Distillery industry is recognized as one of the most polluting industries in India with a large amount of annual effluent production. In this present study, the optimization of electrochemical treatment process variables was reported to treat the color and COD of distillery spent wash using Ti/Pt as an anode in a batch mode. Process variables such as pH, current density, electrolysis time, and electrolyte dose were selected as operation variables and chemical oxygen demand (COD) and color removal efficiency were considered as response variable for optimization using response surface methodology. Indirect electrochemical oxidation process variables were optimized using Box-Behnken response surface design (BBD). The results showed that electrochemical treatment process effectively removed the COD (89.5%) and color (95.1%) of the distillery industry spent wash under the optimum conditions: pH of 4.12, current density of 25.02 mA/cm(2), electrolysis time of 103.27 min, and electrolyte (NaCl) concentration of 1.67 g/L, respectively. PMID- 26491715 TI - Ultrastructural Changes in Clinical and Microbiota Isolates of Klebsiella pneumoniae Carriers of Genes bla SHV, bla TEM, bla CTX-M, or bla KPC When Subject to beta-Lactam Antibiotics. AB - The aim of this study was to characterize the ultrastructural effects caused by beta-lactam antibiotics in Klebsiella pneumoniae isolates. Three K. pneumoniae clinical isolates were selected for the study with resistance profiles for third generation cephalosporins, aztreonam, and/or imipenem and with different resistance genes for extended-spectrum beta-lactamases (ESBL) or Klebsiella pneumoniae carbapenemase (KPC). Two K. pneumoniae isolates obtained from the microbiota, which were both resistant to amoxicillin and ampicillin, were also analyzed. In accordance with the susceptibility profile, the clinical isolates were subjected to subminimum inhibitory concentrations (sub-MICs) of cefotaxime, ceftazidime, aztreonam, and imipenem and the isolates from the microbiota to ampicillin and amoxicillin, for analysis by means of scanning and transmission electron microscopy. The K. pneumoniae isolates showed different morphological and ultrastructural changes after subjection to beta-lactams tested at different concentrations, such as cell filamentation, loss of cytoplasmic material, and deformation of dividing septa. Our results demonstrate that K. pneumoniae isolates harboring different genes that encode for beta-lactamases show cell alterations when subjected to different beta-lactam antibiotics, thus suggesting that they possess residual activity in vitro, despite the phenotypic resistance presented in the isolates analyzed. PMID- 26491717 TI - Exploiting Small Leakages in Masks to Turn a Second-Order Attack into a First Order Attack and Improved Rotating Substitution Box Masking with Linear Code Cosets. AB - Masking countermeasures, used to thwart side-channel attacks, have been shown to be vulnerable to mask-extraction attacks. State-of-the-art mask-extraction attacks on the Advanced Encryption Standard (AES) algorithm target S-Box recomputation schemes but have not been applied to scenarios where S-Boxes are precomputed offline. We propose an attack targeting precomputed S-Boxes stored in nonvolatile memory. Our attack targets AES implemented in software protected by a low entropy masking scheme and recovers the masks with 91% success rate. Recovering the secret key requires fewer power traces (in fact, by at least two orders of magnitude) compared to a classical second-order attack. Moreover, we show that this attack remains viable in a noisy environment or with a reduced number of leakage points. Eventually, we specify a method to enhance the countermeasure by selecting a suitable coset of the masks set. PMID- 26491718 TI - An Efficient Feature Subset Selection Algorithm for Classification of Multidimensional Dataset. AB - Multidimensional medical data classification has recently received increased attention by researchers working on machine learning and data mining. In multidimensional dataset (MDD) each instance is associated with multiple class values. Due to its complex nature, feature selection and classifier built from the MDD are typically more expensive or time-consuming. Therefore, we need a robust feature selection technique for selecting the optimum single subset of the features of the MDD for further analysis or to design a classifier. In this paper, an efficient feature selection algorithm is proposed for the classification of MDD. The proposed multidimensional feature subset selection (MFSS) algorithm yields a unique feature subset for further analysis or to build a classifier and there is a computational advantage on MDD compared with the existing feature selection algorithms. The proposed work is applied to benchmark multidimensional datasets. The number of features was reduced to 3% minimum and 30% maximum by using the proposed MFSS. In conclusion, the study results show that MFSS is an efficient feature selection algorithm without affecting the classification accuracy even for the reduced number of features. Also the proposed MFSS algorithm is suitable for both problem transformation and algorithm adaptation and it has great potentials in those applications generating multidimensional datasets. PMID- 26491719 TI - Optimization and Prediction of Ultimate Tensile Strength in Metal Active Gas Welding. AB - We investigated the effect of welding parameters on ultimate tensile strength of structural steel, ST37-2, welded by Metal Active Gas welding. A fractional factorial design was used for determining the significance of six parameters: wire feed rate, welding voltage, welding speed, travel angle, tip-to-work distance, and shielded gas flow rate. A regression model to predict ultimate tensile strength was developed. Finally, we verified optimization of the process parameters experimentally. We achieved an optimum tensile strength (558 MPa) and wire feed rate, 19 m/min, had the greatest effect, followed by tip-to-work distance, 7 mm, welding speed, 200 mm/min, welding voltage, 30 V, and travel angle, 60 degrees . Shield gas flow rate, 10 L/min, was slightly better but had little effect in the 10-20 L/min range. Tests showed that our regression model was able to predict the ultimate tensile strength within 4%. PMID- 26491720 TI - A New Arbiter PUF for Enhancing Unpredictability on FPGA. AB - In general, conventional Arbiter-based Physically Unclonable Functions (PUFs) generate responses with low unpredictability. The N-XOR Arbiter PUF, proposed in 2007, is a well-known technique for improving this unpredictability. In this paper, we propose a novel design for Arbiter PUF, called Double Arbiter PUF, to enhance the unpredictability on field programmable gate arrays (FPGAs), and we compare our design to conventional N-XOR Arbiter PUFs. One metric for judging the unpredictability of responses is to measure their tolerance to machine-learning attacks. Although our previous work showed the superiority of Double Arbiter PUFs regarding unpredictability, its details were not clarified. We evaluate the dependency on the number of training samples for machine learning, and we discuss the reason why Double Arbiter PUFs are more tolerant than the N-XOR Arbiter PUFs by evaluating intrachip variation. Further, the conventional Arbiter PUFs and proposed Double Arbiter PUFs are evaluated according to other metrics, namely, their uniqueness, randomness, and steadiness. We demonstrate that 3-1 Double Arbiter PUF archives the best performance overall. PMID- 26491721 TI - Determining Cut-Off Points for the Dental Fear Survey. AB - OBJECTIVE: To determine a high fear cut-off point score for the Dental Fear Survey (DFS) using a single-item self-report questionnaire. METHODS: The DFS, a 20-item questionnaire assessing fear of dental treatment, was completed by 1,256 participants with a mean age of 22.3 years (SD = 5.1). Another self-report questionnaire was used to collect data on previous dental experiences. A high fear cut-off point score was determined by calculating the receiver operating characteristic (ROC) curve for the DFS. Descriptive statistics and multinomial logistic regression were calculated; a significance level of p < 0.05 was used for all tests. RESULTS: The ROC curve indicated that a DFS score >= 53 corresponds to a sensitivity of 88.9% and a specificity of 92.5%. Most participants (n = 895; 71.5%) reported no fear of going to the dentist. There was significant association between DFS score and fear assessed with the question "Are you fearful of going to the dentist?" (p < 0.001). CONCLUSION: A cut-off point of 53 on the DFS total score represents the best compromise between sensitivity and specificity and can be used to predict high dental fear. PMID- 26491722 TI - Amniotic Tissues for the Treatment of Chronic Plantar Fasciosis and Achilles Tendinosis. AB - Introduction. Allogeneic amniotic tissue and fluid may be used to treat chronic plantar fasciosis and Achilles tendinosis. This innovative approach involves delivering a unique allograft of live human cells in a nonimmunogenic structural tissue matrix to treat chronic tendon injury. These tissues convey very positive regenerative attributes; procurement is performed with maternal consent during elective caesarian birth. Materials and Methods. In the present investigation all patients were unresponsive to multiple standard therapies for a minimum of 6 months and were treated with one implantation of PalinGen SportFLOW around the plantar fascia and/or around the Achilles paratenon. The patients were given a standard protocol for postimplant active rehabilitation. Results. The analogue pretreatment pain score (VAS) of 8. By the fourth week after treatment, all patients had significantly reduced self-reported pain. Twelve weeks following the procedure the average pain level had reduced to only 2. No adverse reactions were reported in any of the patients. Conclusion. All patients in this study experienced heel or Achilles pain, unresponsive to standard therapy protocols. After treatment all patients noted significant pain reduction, indicating that granulized amniotic membrane and amniotic fluid can be successfully used to treat both chronic plantar fasciosis and Achilles tendinosis. PMID- 26491723 TI - To Investigate the Effect of Colchicine in Prevention of Adhesions Caused by Serosal Damage in Rats. AB - Introduction and Aim. Adhesion formation is a process which starts with an inflammation caused by a number of factors and eventually results in fibrosis. Colchicine prevents adhesion formation which is antifibrous process. The effectivity of colchicine in the prevention of adhesions was investigated. Materials and Methods. A total of 36 rats were equally divided into three groups: (I) control group 1 (n = 12), (II) abrasion group 2 (n = 12), and (III) abrasion + colchicine group 3 (n = 12). Group 1 underwent laparotomy and was orally given physiological serum 2 cc/day for 10 days. In Group 2, injury was created in the cecum serosa following laparotomy and they were orally given physiological serum 2 cc/day for 10 days. In Group 3, injury was created in the cecum serosa following laparotomy and the rats were orally given colchicine 50 mcg kg/day mixed with physiological serum 2 cc/day for 10 days. Laparotomy was performed and adhesions were examined both macroscopically and microscopically. Both macroscopic and microscopic examinations were performed using Zuhlke's score. Results. A significant difference was observed among the adhesion scores of the groups both macroscopically and microscopically. Macroscopic score was lower in group 3 than group 2. Microscopic score was lower in group 3 than group 2. Conclusion. Oral administration of colchicine is effective in the prevention of adhesions. PMID- 26491724 TI - Will Septal Correction Surgery for Deviated Nasal Septum Improve the Sense of Smell? A Prospective Study. AB - Background and Objectives. Nasal obstruction due to deviated nasal septum is a common problem bringing a patient to an otorhinolaryngologist. Occasionally, these patients may also complain of olfactory impairment. We proposed to study the effect of septal deviation on the lateralised olfactory function and the change in olfaction after surgery of the septum (septoplasty). Methods. Forty-one patients with deviated nasal septum were evaluated for nasal airflow, olfactory score, and nasal symptomatology. Septoplasty was done under local anesthesia. Pre and postoperative olfactory scores, airflow and olfactory scores, and nasal symptomatology and olfactory scores were compared and correlated. Results. The range of preoperative composite olfactory score (COS) on the side of septal deviation was 4-14 (mean 7.90 +/- 2.234) and on the nonobstructed side was 9-18 (mean 14.49 +/- 2.378). Severity of deviated nasal septum and preoperative COS of diseased side were correlated and the correlation was found to be significant (rho = -0.690, p = 0.000 (<0.001)). The preoperative mean COS (7.90 +/- 2.234) was compared with the postoperative mean COS (12.39 +/- 3.687) and the improvement was found to be statistically significant (p = 0.000 (<0.001)). Conclusion. We found improvement in olfactory function in 70.6% patients after surgery, no change in 20.1%, and reduced function in 7.6%. With the limitation of a small sample size and a potential repeat testing bias, we would conclude that correction of nasal septal deviation may lead to improvement in sense of smell. PMID- 26491725 TI - Autoregulated paracellular clearance of amyloid-beta across the blood-brain barrier. AB - The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-beta (Abeta) peptide is a central event in the pathogenesis of Alzheimer's disease (AD). Whereas transport of Abeta across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Abeta has not been described. We show that soluble human Abeta(1-40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Abeta(1-40) levels were significantly increased, brain Abeta(1-40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Abeta can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Abeta movement across the BBB and identify both claudin 5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Abeta from the brain. PMID- 26491727 TI - A silica coated paper substrate: development and its application in paper spray mass spectrometry for rapid analysis of pesticides in milk. AB - A novel silica coated paper substrate is developed through a facile vacuum filtration method by using the commercially available silica particles as the coating material and corn starch as the adhesive agent. Unlike the commercial silica coated paper (namely grade SG81 paper), the resulting paper substrate was covered by a layer of silica particles on the top side of the paper, and no cellulosic fibers were exposed at its surface. After loading a solution sample on its surface, the coated silica particles allowed the target analytes to remain at the top side rather than penetration through the substrate. Owing to this effect and the special interactions with analytes, the as-prepared silica coated paper demonstrated superior performance in the analysis of different pesticides in milk using paper spray mass spectrometry to the uncoated filter paper and grade SG81 paper. Compared to the other two papers, paper spray analysis using the as prepared paper improved the estimated lower limit of quantitation of seven pesticides (alachlor, acetochlor, pretilachlor, butachlor, metolachlor, napropamid and benzeneacetamide) in milk by a factor of 2 to 19-fold depending on the pesticide. This study offers a novel paper substrate for paper spray in high sensitivity analysis of target analytes in a complex foodstuff matrix without any pretreatment. PMID- 26491726 TI - Ethanol, Neurodevelopment, Infant and Child Health (ENRICH) prospective cohort: Study design considerations. AB - BACKGROUND: While intervention is the leading factor in reducing long-term disabilities in children with fetal alcohol spectrum disorder (FASD), early identification of children affected by prenatal alcohol exposure (PAE) remains challenging. Deficits in higher-order cognitive domains (e.g. executive function) might be more specific to FASD than global neurodevelopmental tests, yet these functions are not developed in very young children. Measures of early sensorimotor development may provide early indications of atypical brain development during the first two years of life. METHODS: This paper describes the novel methodology of the Ethanol, Neurodevelopment, Infant and Child Health (ENRICH) prospective cohort study of 120 maternal-infant pairs with a goal to identify early indices of functional brain impairment associated with PAE. The cohort is established by recruiting women early in pregnancy and classifying them into one of three study groups: patients on opioid-maintenance therapy who consume alcohol during pregnancy (Group 1), patients on opioid-maintenance therapy who abstain from alcohol during pregnancy (Group 2), and healthy controls (Group 3). After the initial prenatal assessment (Visit 1), patients are followed to Visit 2 occurring at delivery, and two comprehensive assessments of children at six (Visit 3) and 20 months (Visit 4) of age. ENRICH recruitment started in November 2013 and 87 women were recruited during the first year. During Year 1, the biospecimen (maternal whole blood, serum, urine, dry blood spots of a newborn) collection rate was 100% at Visit 1, and 97.6% for those who completed Visit 2. DISCUSSION: The tiered screening approach, evaluation of confounders, neurocognitive and magneto-/electro-encephalography (MEG/EEG) outcomes, and ethical considerations are discussed. PMID- 26491728 TI - [IMPORTANCE OF THE METHODOLOGY REPORT IN ELECTRICAL BIOIMPEDANCE ON BODY COMPOSITION STUDIES]. PMID- 26491729 TI - Protocols in In Vitro Hepatocyte Research. Preface. PMID- 26491730 TI - [The family physician and the travel card]. PMID- 26491731 TI - [50.000 Danes are at risk of developing drug-induced headache]. PMID- 26491732 TI - A window into cutaneous adult T-cell leukemia/lymphoma. PMID- 26491734 TI - [Whole-genome data directly into the faroese electronic health records]. PMID- 26491735 TI - [The regional chairman's vertical orders of a useless treatment]. PMID- 26491736 TI - In this issue... PMID- 26491737 TI - Variations in selective nerve root block technique. PMID- 26491738 TI - Obstruction of an ileal urinary conduit in an incarcerated right inguinal hernia. AB - We present the case of a 72-year-old man with a history of anuria from his ileal conduit 15 months following its formation. That conduit had become incarcerated in a right-sided ingunial hernia. The patient presented with anuria and an acute kidney injury. A clincal diagnosis of an incarcerated hernia was made, and he was taken to theatre for reduction and repair of the hernia. On removal of the conduit from the hernial sac, it began to drain immediately. He made a full recovery, with normalisation of his renal function. PMID- 26491739 TI - Reply: To PMID 26270071. PMID- 26491740 TI - [Be careful with data and diagnostic codes]. PMID- 26491741 TI - [Unfair criticism of the Danish National Survey of Patient Experiences]. PMID- 26491742 TI - [Reply: Our criticism is relevant]. PMID- 26491743 TI - [Dear Else Smith!]. PMID- 26491744 TI - [Else Smith replies to Lotte Hvas: You do not break secrecy]. PMID- 26491745 TI - [Practitioners were ready to hand over provider numbers]. PMID- 26491746 TI - [Bruno Melgaard: The price was too high]. PMID- 26491747 TI - What Does it Really Mean for Florida Dentists Now That a Judge Has Ruled Florida Unlawfully Restricted Care for Kids on Medicaid? PMID- 26491748 TI - Stay Healthy and Fit While You Travel for Business or Pleasure. PMID- 26491749 TI - Fruits and Vegetables in the Prevention of Disease. PMID- 26491750 TI - My Great First-year LCD Experience: A Much Needed Position in Organized Dentistry. PMID- 26491751 TI - Diagnostic Discussion. Subpontic osseous hyperplasia. PMID- 26491752 TI - Dr.Robert Hayling ... A Lifetime of Dedication. PMID- 26491753 TI - Tenacious D. why beta cells are no match for the relentless persistence of type 2 diabetes. PMID- 26491754 TI - THRIVE Guide for Young Adults. PMID- 26491785 TI - Preparation of Antimalarial Endoperoxides by a Formal [2 + 2 + 2] Cycloaddition. AB - A formal [2 + 2 + 2] cycloaddition reaction between a 1,3-dione, an olefin, and molecular oxygen mediated by light is reported, which delivers endoperoxides in good yield through the formation of two C-O and one C-C bond in one step. The resulting 1,2-dioxanes are stable compounds and can be further derivatized at the hemiacetal position via alkylation or acetylation. All compounds have been evaluated against Plasmodium falciparum, and the best compound displayed an IC50 value of 180 nM. A potential mechanistic rationale for the formation of these compounds is presented. PMID- 26491786 TI - Evidence of Negative Capacitance in Piezoelectric ZnO Thin Films Sputtered on Interdigital Electrodes. AB - The scaling paradigm known as Moore's Law, with the shrinking of transistors and their doubling on a chip every two years, is going to reach a painful end. Another less-known paradigm, the so-called Koomey's Law, stating that the computing efficiency doubles every 1.57 years, poses other important challenges, since the efficiency of rechargeable energy sources is substantially constant, and any other evolution is based on device architecture only. How can we still increase the computational power/reduce the power consumption of our electronic environments? A first answer to this question comes from the quest for new functionalities. Within this aim, negative capacitance (NC) is becoming one of the most intriguing and studied phenomena since it can be exploited for reducing the aforementioned limiting effects in the downscaling of electronic devices. Here we report the evidence of negative capacitance in 80 nm thick ZnO thin films sputtered on Au interdigital electrodes (IDEs). Highly (002)-oriented ZnO thin films, with a fine-grained surface nanostructure and the desired chemical composition, are deposited at room temperature on different IDEs structures. Direct-current electrical measurements highlighted the semiconducting nature of ZnO (current density in the order of 1 * 10(-3) A/cm(2)). When turned into the alternating current regime (from 20 Hz to 2 MHz) the presence of NC values is observed in the low-frequency range (20-120 Hz). The loss of metal/semiconductor interface charge states under forward bias conditions, together with the presence of oxygen vacancies and piezoelectric/electrostriction effects, is believed to be at the basis of the observed negative behavior, suggesting that ZnO thin-film based field-effect transistors can be a powerful instrument to go beyond the Boltzmann limit and the downscaling of integrated circuit elements required for the fabrication of portable and miniaturized electronic devices, especially for electric household appliances working in the low 50 Hz utility frequency. PMID- 26491788 TI - Novel biomarkers for cardiovascular risk assessment: current status and future directions. AB - Cardiovascular disease (CVD) is the leading cause of mortality in the modern world. Traditional risk algorithms may miss up to 20% of CVD events. Therefore, there is a need for new cardiac biomarkers. Many fields of research are dedicated to improving cardiac risk prediction, including genomics, transcriptomics and proteomics. To date, even the most promising biomarkers have only demonstrated modest associations and predictive ability. Few have undergone randomized control trials. A number of biomarkers are targets to new therapies aimed to reduce cardiovascular risk. Currently, some of the most promising risk prediction has been demonstrated with panels of multiple biomarkers. This article reviews the current state and future of proteomic biomarkers and aggregate biomarker panels. PMID- 26491787 TI - A Comparative Analysis of Synthetic Quorum Sensing Modulators in Pseudomonas aeruginosa: New Insights into Mechanism, Active Efflux Susceptibility, Phenotypic Response, and Next-Generation Ligand Design. AB - Quorum sensing (QS) is a chemical signaling mechanism that allows bacterial populations to coordinate gene expression in response to social and environmental cues. Many bacterial pathogens use QS to initiate infection at high cell densities. Over the past two decades, chemical antagonists of QS in pathogenic bacteria have attracted substantial interest for use both as tools to further elucidate QS mechanisms and, with further development, potential anti-infective agents. Considerable recent research has been devoted to the design of small molecules capable of modulating the LasR QS receptor in the opportunistic pathogen Pseudomonas aeruginosa. These molecules hold significant promise in a range of contexts; however, as most compounds have been developed independently, comparative activity data for these compounds are scarce. Moreover, the mechanisms by which the bulk of these compounds act are largely unknown. This paucity of data has stalled the choice of an optimal chemical scaffold for further advancement. Herein, we submit the best-characterized LasR modulators to standardized cell-based reporter and QS phenotypic assays in P. aeruginosa, and we report the first comprehensive set of comparative LasR activity data for these compounds. Our experiments uncovered multiple interesting mechanistic phenomena (including a potential alternative QS-modulatory ligand binding site/partner) that provide new, and unexpected, insights into the modes by which many of these LasR ligands act. The lead compounds, data trends, and mechanistic insights reported here will significantly aid the design of new small molecule QS inhibitors and activators in P. aeruginosa, and in other bacteria, with enhanced potencies and defined modes of action. PMID- 26491789 TI - Laparoscopic simulation training in gynaecology: Current provision and staff attitudes - a cross-sectional survey. AB - The objectives of this study were to explore current provision of laparoscopic simulation training, and to determine attitudes of trainers and trainees to the role of simulators in surgical training across the UK. An anonymous cross sectional survey with cluster sampling was developed and circulated. All Royal College of Obstetricians and Gynaecologists (RCOG) Training Programme Directors (TPD), College Tutors (RCT) and Trainee representatives (TR) across the UK were invited to participate. One hundred and ninety-six obstetricians and gynaecologists participated. Sixty-three percent of hospitals had at least one box trainer, and 14.6% had least one virtual-reality simulator. Only 9.3% and 3.6% stated that trainees used a structured curriculum on box and virtual-reality simulators, respectively. Respondents working in a Large/Teaching hospital (p = 0.008) were more likely to agree that simulators enhance surgical training. Eighty-nine percent agreed that simulators improve the quality of training, and should be mandatory or desirable for junior trainees. Consultants (p = 0.003) and respondents over 40 years (p = 0.011) were more likely to hold that a simulation test should be undertaken before live operation. Our data demonstrated, therefore, that availability of laparoscopic simulators is inconsistent, with limited use of mandatory structured curricula. In contrast, both trainers and trainees recognise a need for greater use of laparoscopic simulation for surgical training. PMID- 26491790 TI - Pregnancy diets, migration, and birth outcomes. AB - Women in low- and middle-income countries are known to make changes to their diets during pregnancy. We set out to explore the subject of traditional pregnancy diets with a view to finding out if migrant women follow these practices, and if such information might help explain differences in birth outcomes between migrant women and destination-country-born women. This review found that traditional pregnancy diets vary from region to region, that migrant women may follow some of these practices, and that there is a dearth of studies looking into the impact of pregnancy diets on birth outcomes. PMID- 26491792 TI - UV and IR Spectroscopy of Cold H2O(+)-Benzo-Crown Ether Complexes. AB - The H2O(+) radical ion, produced in an electrospray ion source via charge transfer from Eu(3+), is encapsulated in benzo-15-crown-5 (B15C5) or benzo-18 crown-6 (B18C6). We measure UV photodissociation (UVPD) spectra of the (H2O.B15C5)(+) and (H2O.B18C6)(+) complexes in a cold, 22-pole ion trap. These complexes show sharp vibronic bands in the 35 700-37 600 cm(-1) region, similar to the case of neutral B15C5 or B18C6. These results indicate that the positive charge in the complexes is localized on H2O, giving the forms H2O(+).B15C5 and H2O(+).B18C6, in spite of the fact that the ionization energy of B15C5 and B18C6 is lower than that of H2O. The formation of the H2O(+) complexes and the suppression of the H3O(+) production through the reaction of H2O(+) and H2O can be attributed to the encapsulation of hydrated Eu(3+) clusters by B15C5 and B18C6. On the contrary, the main fragment ions subsequent to the UV excitation of these complexes are B15C5(+) and B18C6(+) radical ions; the charge transfer occurs from H2O(+) to B15C5 and B18C6 after the UV excitation. The position of the band origin for the H2O(+).B18C6 complex (36323 cm(-1)) is almost the same as that for Rb(+).B18C6 (36315 cm(-1)); the strength of the intermolecular interaction of H2O(+) with B18C6 is similar to that of Rb(+). The spectral features of the H2O(+).B15C5 complex also resemble those of the Rb(+).B15C5 ion. We measure IR-UV spectra of these complexes in the CH and OH stretching region. Four conformers are found for the H2O(+).B15C5 complex, but there is one dominant form for the H2O(+).B18C6 ion. This study demonstrates the production of radical ions by charge transfer from multivalent metal ions, their encapsulation by host molecules, and separate detection of their conformers by cold UV spectroscopy in the gas phase. PMID- 26491791 TI - Combined Mulberry Leaf and Fruit Extract Improved Early Stage of Cutaneous Wound Healing in High-Fat Diet-Induced Obese Mice. AB - Obesity is a pandemic that causes many health challenges, including difficulties in achieving proper wound healing without complications. The current study investigated the role of NLRP3 inflammasome in the early stages of cutaneous wound healing and the effect of combined mulberry leaf and fruit extract (MLFE) on cutaneous NLRP inflammasome involvement in delayed wound healing mice with high-fat diet (HFD)-induced obesity. After obesity was induced by HFD for 10 weeks, the mice were supplemented with MLFE (at a dose of 500 mg/kg containing 333.3 mg/kg of mulberry leaf extract and 166.7 mg/kg of mulberry fruit extract) by gavage, 5 days/week for 12 weeks. MLFE supplementation ameliorated delayed wound closure in obese mice. While wound size was positively correlated with fasting blood glucose level during the early stage of wound healing, it was strongly correlated with body weight gain and body fat mass during the later stage of wound healing. Under obese conditions, the levels of NLRP3 inflammasome and its related markers (pro-caspase-1 and precursor/mature interleukin 1 beta) were increased at a basal level, but the NLRP3 inflammasome was suppressed during the inflammatory stage of cutaneous wound healing. However, MLFE supplementation stimulated cutaneous NLRP3 inflammasome in HFD-induced obese mice (day 3). Taken together, stimulating the NLRP3 inflammasome might be beneficial in the early inflammatory stage of cutaneous wound healing and MLFE could be a potential therapeutic intervention in delayed wound healing through activation of the NLRP3 inflammasome in obesity. PMID- 26491793 TI - Prehospital airway technique does not influence incidence of ventilator associated pneumonia in trauma patients. AB - BACKGROUND: The relationship between the prehospital airway device used and later development of ventilator-associated pneumonia (VAP) is unknown. We sought to determine if the prehospital airway device choice is associated with an increased risk of VAP in risk-adjusted critically injured patients. METHODS: We performed a retrospective analysis of all trauma patients requiring definitive airway placement before intensive care unit admission at a Level I trauma center from 2008 to 2012. Prehospital airway management strategies were classified as extraglottic device placement, endotracheal intubation, bag-valve mask ventilation (BVM), or lack of a prehospital airway with subsequent intubation at the trauma center. Patients were excluded if they were hospital transfers, were dead on arrival, died in the emergency department, or did not require at least 48 hours of mechanical ventilation. The primary end point was the development of VAP as determined by institutional guidelines for diagnosis. Logistic regression was used to determine risk factors for VAP. RESULTS: A total of 317 patients met inclusion criteria. The median age was 37 years (interquartile range, 25-51 years), 75% were male, 78% sustained a blunt injury, and the median Injury Severity Score (ISS) was 29 (interquartile range, 21-34). Ninety-seven patients (30.6%) developed VAP. Prehospital airway strategies were as follows: 17 (5.4%) had extraglottic device placement, 28 (8.8%) had BVM, 84 (26.5%) had endotracheal intubation, and 188 (59.3%) had no prehospital airway placement and were intubated after arrival. The type of prehospital airway was not statistically significant in terms of VAP development (range, 26.1-42.9%; p = 0.15). The only statistically significant predictor of VAP was length of mechanical ventilation (univariate: odds ratio, 1.14; 95% confidence interval, 1.10-1.18; p <= 0.01; multivariate: odds ratio, 1.15; 95% confidence interval, 1.10-1.20; p <= 0.01). CONCLUSION: Our data suggest that the prehospital airway device used was not associated with the development of VAP. LEVEL OF EVIDENCE: Therapeutic study, level IV; epidemiologic study, level III. PMID- 26491795 TI - Thoracolumbar spine clearance: Clinical examination for patients with distracting injuries. AB - BACKGROUND: The purpose of this study was to prospectively assess the sensitivity of clinical examination to screen for thoracolumbar spine (TLS) injury in awake and alert blunt trauma patients with distracting injuries. METHODS: From December 2012 to June 2014, all blunt trauma patients older than 13 years were prospectively evaluated as per standard TLS examination protocol at a Level 1 trauma center. Awake and alert patients with Glasgow Coma Scale (GCS) score of 14 or greater underwent clinical examination of the TLS. Clinical examination was performed regardless of distracting injuries. Patients with no complaints of pain or tenderness on examination of the TLS were considered clinically cleared of injury. Patients with distracting injuries, including those clinically cleared and those with complaints of TLS pain or tenderness, underwent computed tomographic scan of the entire TLS. Patients with minor distracting injuries were not considered to have a distracting injury. RESULTS: A total of 950 blunt trauma patients were entered, 530 (56%) of whom had at least one distracting injury. Two hundred nine patients (40%) with distracting injuries had a positive TLS clinical examination result, of whom 50 (25%) were diagnosed with TLS injury. Three hundred twenty-one patients (60%) with distracting injuries were initially clinically cleared, in whom 17 (5%) TLS injuries were diagnosed. There were no missed injuries that required surgical intervention, with only four injuries receiving TLS orthotic bracing. This yielded an overall clinical clearance sensitivity for injury of 75% and sensitivity for clinically significant injury of 89%. CONCLUSION: In awake and alert blunt trauma patients with distracting injuries, clinical examination is a sensitive screening method for significant TLS injury. Radiologic assessment may be unnecessary for safe clearance of the asymptomatic TLS in patients with distracting injuries. These findings suggest significant potential reduction of both health care cost and patient radiation exposure. LEVEL OF EVIDENCE: Diagnostic study, level IV; therapeutic/care management study, level IV. PMID- 26491794 TI - Trauma-induced heterotopic bone formation and the role of the immune system: A review. AB - Extremity trauma, spinal cord injuries, head injuries, and burn injuries place patients at high risk of pathologic extraskeletal bone formation. This heterotopic bone causes severe pain, deformities, and joint contractures. The immune system has been increasingly implicated in this debilitating condition. This review summarizes the various roles immune cells and inflammation play in the formation of ectopic bone and highlights potential areas of future investigation and treatment. Cell types in both the innate and adaptive immune system such as neutrophils, macrophages, mast cells, B cells, and T cells have all been implicated as having a role in ectopic bone formation through various mechanisms. Many of these cell types are promising areas of therapeutic investigation for potential treatment. The immune system has also been known to also influence osteoclastogenesis, which is heavily involved in ectopic bone formation. Chronic inflammation is also known to have an inhibitory role in the formation of ectopic bone, whereas acute inflammation is necessary for ectopic bone formation. PMID- 26491796 TI - Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. AB - BACKGROUND: Trauma-induced coagulopathy (TIC) is associated with a fourfold increased risk of mortality. Hyperfibrinolysis is a component of TIC, but its mechanism is poorly understood. Plasminogen activation inhibitor (PAI-1) degradation by activated protein C has been proposed as a mechanism for deregulation of the plasmin system in hemorrhagic shock, but in other settings of ischemia, tissue plasminogen activator (tPA) has been shown to be elevated. We hypothesized that the hyperfibrinolysis in TIC is not the result of PAI-1 degradation but is driven by an increase in tPA, with resultant loss of PAI-1 activity through complexation with tPA. METHODS: Eighty-six consecutive trauma activation patients had blood collected at the earliest time after injury and were screened for hyperfibrinolysis using thrombelastography (TEG). Twenty-five hyperfibrinolytic patients were compared with 14 healthy controls using enzyme linked immunosorbent assays for active tPA, active PAI-1, and PAI-1/tPA complex. Blood was also subjected to TEG with exogenous tPA challenge as a functional assay for PAI-1 reserve. RESULTS: Total levels of PAI-1 (the sum of the active PAI-1 species and its covalent complex with tPA) are not significantly different between hyperfibrinolytic trauma patients and healthy controls: median, 104 pM (interquartile range [IQR], 48-201 pM) versus 115 pM (IQR, 54-202 pM). The ratio of active to complexed PAI-1, however, was two orders of magnitude lower in hyperfibrinolytic patients than in controls. Conversely, total tPA levels (active + complex) were significantly higher in hyperfibrinolytic patients than in controls: 139 pM (IQR, 68-237 pM) versus 32 pM (IQR, 16-37 pM). Hyperfibrinolytic trauma patients displayed increased sensitivity to exogenous challenge with tPA (median LY30 of 66.8% compared with 9.6% for controls). CONCLUSION: Depletion of PAI-1 in TIC is driven by an increase in tPA, not PAI-1 degradation. The tPA challenged TEG, based on this principle, is a functional test for PAI-1 reserves. Exploration of the mechanism of up-regulation of tPA is critical to an understanding of hyperfibrinolysis in trauma. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level II. PMID- 26491797 TI - Inhibition of histone deacetylase 6 restores innate immune cells in the bone marrow in a lethal septic model. AB - BACKGROUND: We have previously demonstrated that Tubastatin A, a selective inhibitor of histone deacetylase 6 (HDAC6), improves survival and increases circulating monocyte count and bacterial clearance in a lethal model of cecal ligation and puncture (CLP) in mice. The aim of the present study was to characterize the effects of inhibition of HDAC6 on the bone marrow cell population. METHODS: C57BL/6J mice were subjected to CLP and, 1 hour later, given an intraperitoneal injection of either Tubastatin A (70 mg/kg) dissolved in DMSO or DMSO alone (n = 9 per group). Sham-operated animals were treated in an identical fashion, without CLP. Forty-eight hours later, bone marrow cells were flushed out from the femurs and tibias. Erythrocytes were lysed, and a single cell suspension was made for analysis. Cells were washed; blocked with antimouse CD16/32; stained with antimouse B220 PE-Cy7, CD3 APC-eFluor 780, CD11b FITC, Gr-1 PerCP-Cy5.5, and F4/80 Antigen APC; and subjected to flow cytometry. Data were acquired on an LSRII Flow Cytometer (BD Biosciences, San Jose, CA) and analyzed with FlowJo (Flowjo, LLC, Ashland, OR). RESULTS: In comparison with the sham group, CLP animals showed decreased percentage of innate immune cells (CD11b, 62.1% +/- 3.1% vs. 32.9% +/- 4.9%, p = 0.0025) and macrophages (CD11bF4/80, 44.6% +/- 3.4% vs. 19.8% +/- 2.6%, p = 0.0002) as well as increased percentage of T lymphocytes (CD3, 1.1% +/- 0.2% vs. 3.3% +/- 0.4%, p = 0.0082) in the bone marrow 48 hours after CLP. Treatment with Tubastatin A restored the innate immune cells (32.9% +/- 4.9% vs. 54.0% +/- 4.1%, p = 0.0112) and macrophages (19.8% +/- 2.6% vs. 47.1% +/- 4.6%, p = 0.0001) and increased the percentage of neutrophils (CD11bGr-1, 28.4% +/- 3.9% vs. 48.0% +/- 4.0%, p = 0.0075). The percentages of B (B220) and T lymphocytes were not significantly altered by Tubastatin A, compared with the vehicle-treated CLP animals. CONCLUSION: Selective inhibition of HDAC6 in this lethal septic model restored the innate immune cell and macrophage populations and increased the neutrophil composition in the bone marrow. These results may explain the previously reported beneficial effects of Tubastatin A treatment in a septic model. PMID- 26491798 TI - Incidence, characteristics, and long-term follow-up of sternoclavicular injuries: An epidemiologic analysis of 92 cases. AB - BACKGROUND: The majority of published studies concerning sternoclavicular injuries are case series or systematic reviews. Prospective studies on the subject are hindered by the low incidence of these lesions. The aims of the present study were to provide an overview of this rare entity compared with those described in the literature and to present the long-term clinical outcome. METHODS: We performed a retrospective data analysis of all sternoclavicular injuries treated at a single Level I trauma center from 1992 to 2011. Long-term clinical outcome was assessed using the ASES [American Shoulder and Elbow Surgeons], SST [Simple Shoulder Test], UCLA [University of California-Los Angeles] Shoulder Scale, and VAS [Visual Analog Scale] at latest follow-up. RESULTS: We detected an overall incidence of 0.9% of sternoclavicular injuries related to all shoulder-girdle lesions. Ninety-two patients (52 males and 40 females) with a mean (SD) age of 39.2 (19.5) years (median, 41 years; range, 4-92 years) were included in this study. The main trauma mechanism was fall. Classification was performed according to Allman, the time point of treatment after initial trauma, and the direction of the dislocation. Nine patients of the 15 Grade III lesions were treated conservatively by closed reduction and immobilization, while four patients were treated surgically by open reduction and internal fixation. Forty-nine percent of the patients were available for long term follow-up at a median of 11.3 years (range, 5.3-22.6 years) with a mean ASES score of 96.21, SST score of 11.69, UCLA score of 31.89, and VAS score of 0.47. CONCLUSION: We found an overall incidence of 0.9% of sternoclavicular joint injuries related to all shoulder-girdle lesions and of 1.1% related to all dislocations, which is slightly lower compared with those described in the literature. Furthermore, we observed a high number of physeal sternoclavicular injuries with a percentage of 16% and overall good-to-excellent results at long term follow-up. LEVEL OF EVIDENCE: Epidemiologic study, level IV. PMID- 26491799 TI - The incidence of ARDS and associated mortality in severe TBI using the Berlin definition. AB - BACKGROUND: The incidence of adult respiratory distress syndrome (ARDS) in severe traumatic brain injury (TBI) is poorly reported. Recently, a new definition for ARDS was proposed, the Berlin definition. The percentage of patients represented by TBI in the Berlin criteria study is limited. This study describes the incidence and associated mortality of ARDS in TBI patients. METHODS: The study was an analysis of the safety of erythropoietin administration and transfusion threshold on the incidence of ARDS in severe TBI patients. Three reviewers independently assessed all patients enrolled in the study for acute lung injury/ARDS using the Berlin and the American-European Consensus Conference (AECC) definitions. A Cox proportional hazards model was used to assess the relationship between ARDS and mortality and 6-month Glasgow Outcome Scale (GOS) score. RESULTS: Two hundred patients were enrolled in the study. Of the patients, 21% (41 of 200) and 26% (52 of 200) developed ARDS using the AECC and Berlin definitions, respectively, with a median time of 3 days (interquartile range, 3) after injury. ARDS by either definition was associated with increased mortality (p = 0.04) but not with differences in functional outcome as measured by the GOS score at 6 months. Adjusted analysis using the Berlin criteria showed an increased mortality associated with ADS (p = 0.01). CONCLUSION: Severe TBI is associated with an incidence of ARDS ranging from 20% to 25%. The incidence is comparable between the Berlin and AECC definitions. ARDS is associated with increased mortality in severe TBI patients, but further studies are needed to validate these findings. LEVEL OF EVIDENCE: Epidemiologic study, level II. PMID- 26491800 TI - The old man and the C-spine fracture: Impact of halo vest stabilization in patients with blunt cervical spine fractures. AB - BACKGROUND: Placement of a halo vest for cervical spine fractures is presumed to be less morbid than operative fixation. However, restrictions imposed by the halo vest can be detrimental, especially in older patients. The purpose of this study was to evaluate the impact of halo vest placement on outcomes by age in patients with cervical spine fractures without spinal cord injury. METHODS: All patients with blunt cervical spine fractures managed over an 18-year period were identified. Those with spinal cord injury and severe traumatic brain injury were excluded. Patients were stratified by age, sex, halo vest, injury severity, and severity of shock. Outcomes included intensive care unit length of stay, ventilator days, ventilator-associated pneumonia, functional status, and mortality. Multivariable logistic regression was performed to determine whether halo vest was an independent predictor of mortality in older patients. RESULTS: A total of 3,457 patients were identified: 69% were male, with a mean Injury Severity Score (ISS) and Glasgow Coma Scale (GCS) score of 19 and 13, respectively. Overall mortality was 5.3%. One hundred seventy-nine patients were managed with a halo vest, 133 of those 54 years and older and 46 of those younger than 54 years. Both mortality (13% vs. 0%, p < 0.001) and intensive care unit length of stay (4 days vs. 2 days, p = 0.02) were significantly increased in older patients despite less severe injury (admission GCS score of 15 vs. 14 and ISS of 14 vs. 17, p = 0.03). Multivariable logistic regression identified halo vest as an independent predictor of mortality after adjusting for injury severity and severity of shock (odds ratio, 2.629; 95% confidence interval, 1.056-6.543) in older patients. CONCLUSION: The potential risk of operative stabilization must be weighed against that of halo vest placement for older patients with cervical spine fractures following blunt trauma. Patient age should be strongly considered before placement of a halo vest for cervical spine stabilization. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 26491801 TI - Acute care surgery: Is it time for a "victory lap"? PMID- 26491802 TI - Isolated blunt severe traumatic brain injury in Bern, Switzerland, and the United States: A matched cohort study. AB - BACKGROUND: The ideal prehospital management of patients with severe traumatic brain injury (TBI) including the impact of endotracheal intubation (ETI) and physicians on scene is unclear. Prehospital management differs substantially in Switzerland and the United States: in Switzerland, there is usually a physician on scene who may provide ETI and other advanced life support procedures, whereas in the United States, prehospital management (including ETI) is performed by paramedics. METHODS: This is a retrospective cohort-matched study of patients with isolated blunt severe TBI (head Abbreviated Injury Scale [AIS] score, 4-5) and no major extracranial injuries, using Bern University Hospital data from the Swiss PEBITA [Patient-relevant Endpoints after Brain Injury from Traumatic Accidents] (TBI-specific) database and the US National Trauma Data Bank from 2009 to 2010. A 1:4 cohort matching of Bern and US patients was performed. Matching criteria were sex, age (+/-10 years), exact field Glasgow Coma Scale (GCS) score, exact head AIS score, and injury type (subdural hematoma, epidural hematoma, intraparenchymal hemorrhage, intraventricular hemorrhage, brain edema/swelling, brain stem injury). The matched cohorts were compared with univariable analysis (Fisher's exact test and Mann-Whitney U-test). RESULTS: Matching of the Bern (n = 128) and US (n = 86,375) cohort resulted in 355 matched cases (71 Bern and 284 US patients). Bern patients had significantly longer scene times (median, 23.0 minutes vs. 9.0 minutes, p < 0.001) and more frequent prehospital ETI (31.0% vs. 18.7%, p = 0.034) and air transportation (39.4% vs. 19.4%, p < 0.001). No significant difference in procedures (craniotomy/craniectomy, intracranial pressure monitoring, tracheotomy), intensive care unit and total hospital lengths of stay, ventilator days, and in-hospital mortality (14.1% vs. 15.8%, p = 0.855) was found between the two cohorts. CONCLUSION: When taking into account the limitation that patient- and injury-related factors, but not in-hospital treatment variables, were matched, the more frequent prehospital ETI and presence of a physician on scene in the Swiss cohort compared with the US cohort had no significant effect on outcomes, including intensive care unit and total hospital lengths of stay, ventilator days, and in-hospital mortality. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 26491803 TI - Field intubation in civilian patients with hemorrhagic shock is associated with higher mortality. AB - BACKGROUND: Field intubation (FI) by emergency medical service personnel on severely injured trauma patients remains a contentious practice. Clinical studies suggest an association between FI and adverse outcomes in patients with traumatic brain injury. Military tactical emergency casualty care recommends deferring intubation and providing supplemental oxygenation until reaching a more equipped destination. In addition, animal models with penetrating hemorrhagic shock demonstrate increased acidosis with intubation before resuscitation. The purpose of this study was to evaluate the impact of FI on outcomes in trauma patients with hemorrhagic shock requiring massive transfusion. METHODS: The Los Angeles County Trauma System Database was retrospectively queried for all trauma patients 16 years or older with hemorrhagic shock requiring massive transfusion (>=6 U packed red blood cells in the first 24 hours) between January 1, 2012, and June 30, 2014. Demographics, clinical and transfusion data, and outcomes were compared between patients who received FI and those who did not (NO-FI). Multivariate regression analysis was used to adjust for confounders. RESULTS: Of 552 trauma patients meeting inclusion criteria, 63 (11%) received FI, and the remaining 489 (89%) were NO-FI. Age, sex, and incidence of blunt injury were similar between the FI and the NO-FI group. The FI cohort presented with a lower median Glasgow Coma Scale (GCS) score (3 vs. 14, p < 0.001), a lower median systolic blood pressure (86 mm Hg vs. 104 mm Hg, p < 0.001), and a higher median Injury Severity Score (ISS) (41 vs. 29, p < 0.001). Mortality was significantly higher in FI patients (83% vs. 43%, p < 0.001). Transfusion patterns and total field times were similar in both groups. After adjusting for confounders, FI patients had increased odds of mortality (adjusted odds ratio, 2.89; 95% confidence interval, 1.08-7.78; p = 0.035). In addition, FI was identified as an independent predictor of mortality (adjusted odds ratio, 3.41; 95% confidence interval, 1.35-8.59; p = 0.009). CONCLUSION: FI may be associated with higher mortality in trauma patients with hemorrhagic shock requiring massive transfusion. Less invasive airway interventions and rapid transport might improve outcomes for these patients. LEVEL OF EVIDENCE: Therapeutic study, level IV; epidemiologic study, level III. PMID- 26491804 TI - Presence of a dedicated trauma center physiatrist improves functional outcomes following traumatic brain injury. AB - BACKGROUND: Maximizing long-term recovery following traumatic brain injury (TBI) is an important end point. We hypothesized that the addition of a dedicated physiatrist specializing in brain injury medicine to the trauma team would lead to improved functional outcomes. METHODS: Data from the Northern NJ TBI Model Systems were queried for all patients admitted to rehabilitation from four regional trauma centers, one with a full-time TBI physiatrist (PHYS) and three without (NO-PHYS). Patient demographics, mechanism of injury, Glasgow Coma Scale (GCS) score, length of posttraumatic amnesia, length of stay, and Functional Independence Measure (FIM) were abstracted. TBI severity was determined by GCS score and length of posttraumatic amnesia. FIM motor and cognitive scores at rehabilitation admission and discharge were the primary outcome measure. TBI medications (stimulants, sleep, and neurodepressants) administered in acute care were reviewed to evaluate prescription patterns. RESULTS: A total of 148 patients treated at four trauma centers and discharged to a single acute inpatient rehabilitation center between 2005 to 2013 were divided into two groups, PHYS with 44 patients and NO-PHYS with 104 patients. Compared with those in the NO PHYS group, patients from the PHYS group had significant improvement in FIM motor and cognitive scores (p < 0.05). Prescription patterns differed. Patients from the PHYS group received significantly more neurostimulants (p < 0.001) and sleep medications (p = 0.02) compared with the NO-PHYS group. Analysis of covariance was conducted to examine FIM (motor and cognitive) changes from rehabilitation admission to discharge based on medications initiated in acute care. Those who received neither a neurostimulant nor a sleep medication had significantly lower FIM motor scores compared with those who received at least one of these medications (p = 0.047) and compared with those who received both types of medication (p = 0.17). No significant differences were found in FIM cognitive scores. CONCLUSION: The addition of a dedicated physiatrist providing early specialized care to patients who sustained a moderate or severe TBI was associated with improved functional outcomes upon discharge from rehabilitation. The presence of a dedicated trauma center physiatrist, trained in TBI rehabilitation, was also associated with a change in neuroprotective medication management in the acute care setting. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 26491805 TI - Firearm injuries in the pediatric population: A tale of one city. AB - BACKGROUND: Firearm-related injuries are a significant cause of morbidity and mortality in children. To determine current trends and assess avenues for future interventions, we examined the epidemiology and outcome of pediatric firearm injuries managed at our region's two major pediatric trauma centers. METHODS: Following institutional review board approval, we conducted a 5-year retrospective review of all pediatric firearm victims, 16 years or younger, treated at either of the region's two Level 1 pediatric trauma centers, St. Louis Children's Hospital and Cardinal Glennon Children's Medical Center. RESULTS: There were 398 children treated during a 5-year period (2008-2013) for firearm related injuries. Of these children, 314 (78.9%) were black. Overall, there were 20 mortalities (5%). Although most (67.6%) patients were between 14 years and 16 years of age, younger victims had a greater morbidity and mortality. The majority of injuries were categorized as assault/intentional (65%) and occurred between 6:00 pm and midnight, outside the curfew hours enforced by the city. Despite a regional decrease in the overall incidence of firearm injuries during the study period, the rate of accidental victims per year remained stable. Most accidental shootings occurred in the home (74.2%) and were self-inflicted (37.9%) or caused by a person known to the victim (40.4%). CONCLUSION: Despite a relative decrease in intentional firearm-related injuries, a constant rate of accidental shootings suggest an area for further intervention. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level IV. PMID- 26491806 TI - Smart(phone) Medicine. PMID- 26491807 TI - Validation of a brief, two-question depression screen in trauma patients. AB - BACKGROUND: Increasingly, depression following traumatic injury is recognized as a complication of injury. Unlike mandated screening for risky alcohol use in trauma centers, screening for psychological risks is not required by the American College of Surgeons' Committee on Trauma. Limited resources and time constraints are commonly given reasons against routine screening. The purpose of this study was to determine if a two-item screen was as valid as an eight-question screen for depression. METHODS: A total of 421 patients were given the Patient Health Questionnaire 8 (PHQ-8) during initial hospitalization to assess depression in a prospective study at a Level I trauma center. A cutoff score of 10 or higher (possible range, 0-24) on the PHQ-8 is used as diagnostic for depression. The PHQ 2 (possible range, 0-6) is derived from the first two questions of the PHQ-8 and contains items assessing sad mood and loss of interest/pleasure during the previous 2 weeks. A cutoff score of 3 or higher was considered to be a positive screen result. Discriminatory ability of the PHQ-2 was calculated. RESULTS: The sample was predominantly male (65%) and white (67%). The majority (85%) sustained a blunt trauma, and the primary cause of injury was motor vehicle collision (37%), with a mean Injury Severity Score (ISS) of 11.6. A total of 142 patients (34%) were positive for depression on the PHQ-8. When comparing the PHQ-2 with the PHQ-8, a sensitivity of 76.1 and a specificity of 92.8 were found, as well as a positive predictive value of 84.4. CONCLUSION: The result of our study confirms that depression is a frequent condition (34%) among individuals who sustain physical injury. The PHQ-2 seems to have acceptable sensitivity and specificity to identify depression in this population. The use of a two-item screening questionnaire is a minimal addition to the evaluation of patients after injury, allowing for earlier intervention and better outcomes. LEVEL OF EVIDENCE: Diagnostic study, level IV; prognostic/epidemiologic study, level III. PMID- 26491808 TI - Helicopter interfacility transport of pediatric trauma patients: Are we overusing a costly resource? AB - BACKGROUND: Helicopter emergency medical services (HEMS) provide an important service to decrease interfacility transport times compared with ground ambulances. Although transport via HEMS is typically faster, the decreased transportation time comes at the expense of increased risks to the patient and flight crew and higher costs. Therefore, it is important to balance the immediate patient needs with the risk and expense of HEMS transport. Our objective was to determine how frequently pediatric patients who are interfacility transported to a Level 1 pediatric trauma center (PTC) receive a time-sensitive intervention. METHODS: This was a 4-year (2008-2012) retrospective study of children aged 0 year to 18 years who were interfacility transported to a single Level 1 PTC by HEMS. Patients were identified using the trauma registry at the PTC. A previously published outcome was used to determine if patients received time-sensitive interventions. Driving distance to the PTC was determined using Google Maps. Data were analyzed using descriptive statistics. RESULTS: A total of 207 cases were identified (median age, 7 years; interquartile range, 2-12 years; 29% female; median Injury Severity Score [ISS], 11; median Revised Trauma Score [RTS], 8). Forty-three percent (90 patients; 95% confidence interval, 37-50%) of patients received a time-sensitive intervention; these cases had a median age of 6 years (interquartile range, 2-11 years; 32% female; median ISS, 13; median RTS, 8). Of the 117 patients who did not receive time-sensitive interventions, 81% were within 120 driving miles of the PTC and 49% were within 60 miles. CONCLUSION: This study suggests an overuse of HEMS for interfacility transfer of injured pediatric patients to a PTC. Although these patients likely required the resources of a PTC, they could perhaps have been transported by ground ambulance without detriment. Further research is needed to investigate how interfacility transport modes are selected and if these decisions can be improved without increasing evaluation times at transferring facilities. LEVEL OF EVIDENCE: Epidemiologic study, level V. PMID- 26491809 TI - Potentially Important Extracolonic Findings at Screening CT Colonography: Incidence and Outcomes Data From a Clinical Screening Program. AB - OBJECTIVE: The effect of detection of extracolonic findings at screening CT colonography (CTC) remains controversial. Our objective is to analyze the incidence and outcomes of unsuspected potentially significant (CT Colonography Reporting and Data System [C-RADS] extracolonic category E4) findings in a population undergoing clinical CTC screening. SUBJECTS AND METHODS: Over the course of 99 months (April 1, 2004, through June 30, 2012), 7952 consecutive asymptomatic adults (3675 men and 4277 women; mean [+/- SD] age, 56.7 +/- 7.3 years) underwent first-time screening CTC. Examinations were prospectively interpreted by radiologists within our abdominal imaging section, and extracolonic findings were recorded and categorized. Potentially significant (i.e., C-RADS extracolonic category E4) findings were retrospectively reviewed with additional analysis of follow-up (range, 2-10 years) and ultimate clinical outcome. RESULTS: Overall, 2.5% (202/7952) of patients had a potentially significant (C-RADS category E4) extracolonic finding for which further imaging (56%; 113/202) or clinical follow-up (44%; 89/202) was recommended. No patients had multiple category E4 findings. Twenty-two patients were lost to follow-up. Of the remaining 180 patients, 68% (123/180) proved to have clinically significant disease, including 23% (42/180) with malignant or potentially malignant neoplasms and 32% (57/180) with abdominal aortic or other visceral artery aneurysms requiring treatment or surveillance. The most commonly involved organs and systems included the vascular system (26%; 53/202), the genitourinary system (18%; 36/202), the liver (15%; 30/202), the gastrointestinal system (9.9%; 20/202), the lungs (9.4%; 19/202), and the gynecologic system (6.9%; 14/202). CONCLUSION: Potentially significant extracolonic findings in asymptomatic adults at screening CTC are uncommon (2-3% of cases). However, most of these findings (68%) will prove to be clinically significant, including a number of malignancies and aneurysms requiring treatment or surveillance. PMID- 26491811 TI - Flash Points of Secondary Alcohol and n-Alkane Mixtures. AB - The flash point is one of the most important characteristics used to assess the ignition hazard of mixtures of flammable liquids. To determine the flash points of mixtures of secondary alcohols with n-alkanes, it is necessary to calculate the activity coefficients. In this paper, we use a model that allows us to obtain enthalpy of fusion and enthalpy of vaporization data of the pure components to calculate the liquid-solid equilibrium (LSE) and vapor-liquid equilibrium (VLE). Enthalpy of fusion and enthalpy of vaporization data of secondary alcohols in the literature are limited; thus, the prediction of these characteristics was performed using the method of thermodynamic similarity. Additionally, the empirical models provided the critical temperatures and boiling temperatures of the secondary alcohols. The modeled melting enthalpy and enthalpy of vaporization as well as the calculated LSE and VLE flash points were determined for the secondary alcohol and n-alkane mixtures. PMID- 26491810 TI - Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin. AB - The dynorphin (Dyn) A analogue zyklophin ([N-benzyl-Tyr(1)-cyclo(d Asp(5),Dap(8))]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR)-selective antagonist in vitro, is active in vivo, and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogues to explore the structure-activity relationships of this peptide. The synthesis of selected analogues required modification to introduce the N-terminal amino acid due to poor solubility and/or to avoid epimerization of this residue. Among the N terminal modifications, the N-phenethyl and N-cyclopropylmethyl substitutions resulted in analogues with the highest KOR affinities. Pharmacological results for the alanine-substituted analogues indicated that Phe(4) and Arg(6), but interestingly not the Tyr(1) phenol, are important for zyklophin's KOR affinity and that Arg(7) was important for KOR antagonist activity. In the GTPgammaS assay, while all of the cyclic analogues exhibited negligible KOR efficacy, the N cyclopropylmethyl-Tyr(1) and N-benzyl-Phe(1) analogues were 28- and 11-fold more potent KOR antagonists, respectively, than zyklophin. PMID- 26491812 TI - Modified-Atmospheric Pressure-Matrix Assisted Laser Desorption/Ionization Identification of Friction Modifier Additives Oleamide and Ethoxylated Tallow Amines on Varied Metal Target Materials and Tribologically Stressed Steel Surfaces. AB - For many tasks in failure and damage analysis of surfaces deteriorated in heavy tribological contact, the detailed characterization of used lubricants and their additives is essential. The objective of the presented work is to establish accessibility of tribostressed surfaces for direct characterization via modified atmospheric pressure-matrix assisted laser desorption/ionization-mass spectrometry (m-AP-MALDI-MS). Special target holders were constructed to allow target samples of differing shape and form to fit into the desorption/ionization chamber. The best results of desorption and ionization on different target materials and varying roughnesses were achieved on smooth surfaces with low matrix/substrate interaction. M-AP-MALDI characterization of tribologically stressed steel surfaces after pin-on-disc sliding wear tests (SRV-tribotests) yielded positive identification of used friction modifier additives. Further structure elucidation by electrospray ionization mass spectrometry (ESI-MS) and measurements of worn surfaces by time-of-flight-secondary ion mass spectrometry (TOF-SIMS) accompanied findings about additive behavior and deterioration during tribological contact. Using m-AP-MALDI for direct offline examinations of worn surfaces may set up a quick method for determination of additives used for lubrication and general characterization of a tribological system. PMID- 26491814 TI - Using Diverse Communication Strategies to Re-Engage Relapsed Tobacco Quitline Users in Treatment, New York State, 2014. AB - INTRODUCTION: Most smoking cessation programs lack strategies to reach relapsed participants and encourage a new quit attempt. We used a multimodal intervention to encourage past quitline registry participants to recycle into services. METHODS: We invited 3,510 past quitline participants back to quitline services, using messages consecutively delivered through Interactive Voice Response (IVR), followed by postcard and email reminders, 2 Short Messaging Services (SMS) texts, and a final cycle of IVR. The primary study outcome was recycling into a new quitline-assisted quit attempt. We used statistical analyses to assess rates and predictors of recycling (socioeconomic, health- and tobacco-related variables) with study participants and compared the study sample with registry participants not selected for the study (comparison group). RESULTS: Quitline services were re initiated by 12.2% of the intervention sample and 1.9% of the comparison group (z = 6.03, P < .001, effect size of 0.44). Most re-enrollments were done via direct IVR-transfer to the quitline. Predictors of re-enrollment were age (odds ratio [OR] = 1.45 for every 10 years of age; 95% confidence interval [CI], 1.34-1.57), number of years smoking (OR = 1.27; 95% CI, 1.18-1.36), and reporting cancer (OR = 2.32; 95% CI, 1.47-3.68) or chronic obstructive pulmonary disease (OR = 1.55; 95% CI, 1.16-2.10). Living with other smokers was correlated with a lower chance of recycling into treatment (OR = 0.72; 95% CI, 0.57-0.91). CONCLUSION: Recycling previous quitline participants using a proactive, IVR-based intervention is effective in reinitiating quitline-assisted quit attempts. Older, long-term smokers reporting chronic conditions are more likely than younger smokers to re engage in quitline support when these methods are used. PMID- 26491813 TI - Prevention of Filipino Youth Behavioral Health Disparities: Identifying Barriers and Facilitators to Participating in "Incredible Years," an Evidence-Based Parenting Intervention, Los Angeles, California, 2012. AB - INTRODUCTION: Evidence-based interventions for training parents are proven to prevent onset and escalation of childhood mental health problems. However, participation in such programs is low, especially among hard-to-reach, underserved populations such as Filipino Americans. Filipinos, the largest Asian subgroup in California, have significant behavioral health disparities compared with non-Hispanic whites and other Asian subgroups. The purpose of this study was to learn about Filipinos' barriers and facilitators to participating in "Incredible Years" (IY), a parenting program. METHODS: We conducted 4 focus groups in Los Angeles, California, in 2012; the groups consisted of 20 Filipino parents of children aged 6 to 12 years who recently completed the IY parenting program, which was offered as a prevention workshop. Three reviewers, including two co-authors (A.S., J.J.) and a research assistant used content analysis to independently code the interview transcripts and extract subthemes. Grounded theory analytic methods were used to analyze interview transcripts. RESULTS: Parents' perceived benefits of participation in IY were learning more effective parenting techniques, networking with other parents, improved spousal relationships, and improvements in their children's behavior. Parents' most common motivating factor for enrollment in IY was to improve their parenting skills and their relationships with their children. The most common barriers to participation were being uncomfortable sharing problems with others and the fear of being stigmatized by others judging their parenting skills. Participants said that parent testimonials would be the most effective way to promote IY. Many recommended outreach at schools, pediatricians' offices, and churches. CONCLUSION: Increasing Filipino American parent enrollment in IY in culturally relevant ways will reduce the incidence of mental health disorders among children in this growing population. PMID- 26491817 TI - Silver Ion-Mediated Heterometallic Three-Fold Interpenetrating Uranyl-Organic Framework. AB - A unique case of a uranyl-silver heterometallic 3-fold interpenetrating network (U-Ag-2,6-DCPCA) from a multifunctionalized organic ligand, 2,6 dichloroisonicotinic acid, in the presence of uranyl and silver ions is reported. It is the first report of a heterometallic uranyl-organic interpenetrating network or framework. Notably, a (4,4)-connected uranyl building unit in U-Ag-2,6 DCPCA, which is available through combined influences of structural halogenation and silver ion additive on uranyl coordination, plays a vital role in the formation of a 3-fold interpenetrating network. Halogen substitution effectively changes structural features and coordination behaviors of isonicotinate ligand and contributes to the control of uranyl coordination. Meanwhile, it exerts influence on the stabilization of 3-fold interpenetrating networks by halogen halogen interactions. Theoretical calculation suggests that the silver ion should mainly serve as an inductive factor of uranyl species through strong Ag-N binding affinity, directly leading to the formation of a (4,4)-connected uranyl building unit and finally a heterometallic 3-fold interpenetrating network. Related experimental results, especially an interesting postsynthetic metalation, afford further evidence of this induction effect. PMID- 26491815 TI - Long-Term Impact of a Community Health Worker Intervention on Diabetes Control in American Samoa. AB - INTRODUCTION: Diabetes Care in American Samoa (DCAS) was a randomized controlled trial of a 12-month intervention facilitated by community health workers (CHWs) that demonstrated improved HbA1c levels compared with usual care at trial completion. We sought to evaluate the long-term impact of this intervention on diabetes control. METHODS: We retrospectively collected HbA1c measurements from medical records of DCAS participants (n = 268). The study group received the intervention during the trial, and the control group received the intervention after the trial. We used mixed-effects longitudinal regression models to assess change in HbA1c within each trial arm during 3 time periods: DCAS (12 months of the study group's intervention), the first year after DCAS (control group's intervention), and the second year after DCAS. Models were adjusted for baseline characteristics that differed significantly for participants with a low number of HbA1c measurements from those with a high number of HbA1c measurements. RESULTS: After adjustment for confounders, the experiment group experienced a decrease in HbA1c of 0.28 units per year (95% confidence interval [CI], -0.64 to 0.07) during DCAS (intervention). HbA1c decreased by 0.88 units per year (95% CI, -1.31 to 0.45) during the year after the intervention. No significant change was observed the following year. HbA1c of the control group did not significantly change during DCAS (usual care) but decreased by 1.31 units per year (95% CI, -1.72 to 0.91) during its intervention. During the year after the control group's intervention, HbA1c increased by 1.18 units per year (95% CI, 0.42 to 1.93). CONCLUSION: Both groups had initial improvements in glycemic control, but HbA1c later plateaued or increased. These results suggest that time-limited CHW programs improve diabetes control in the short term, but ongoing programs are needed for sustained impact. PMID- 26491816 TI - Farm to Work: Development of a Modified Community-Supported Agriculture Model at Worksites, 2007-2012. AB - BACKGROUND: The Farm to Work program is a modified community-supported agriculture model at worksites in Texas. COMMUNITY CONTEXT: The objective of the Farm to Work program is to increase fruit and vegetable intake among employees and their households by decreasing cost, improving convenience, and increasing access while also creating a new market for local farmers at worksites. The objectives of this article were to describe the development, implementation, and outcome of a 5-year participation trend analysis and to describe the community relationships that were formed to enable the successful implementation of the program. METHODS: The Farm to Work program began in November 2007 as a collaborative effort between the nonprofit Sustainable Food Center, the Texas Department of State Health Services, the Web development company WebChronic Consulting LLC, and Naegelin Farm. The program provides a weekly or biweekly opportunity for employees to order a basket of produce online to be delivered to the worksite by a local farmer. A 5-year participation trend analysis, including seasonal variation and sales trends, was conducted using sales data from November 2007 through December 2012. OUTCOME: The total number of baskets delivered from November 2007 through December 2012 was 38,343; of these, 37,466 were sold and 877 were complimentary. The total value of sold and complimentary baskets was $851,035 and $21,925, respectively. Participation in the program increased over time and was highest in 2012. INTERPRETATION: The Farm to Work program increased access to locally grown fruits and vegetables for employees and created a new market for farmers. Increased program participation indicates that Farm to Work can increase employees' fruit and vegetable consumption and thus help prevent chronic diseases in this population. PMID- 26491818 TI - Recent progress in urinary proteome analysis for prostate cancer diagnosis and management. AB - Prostate cancer (PCa) is fifth leading cause of cancer-associated deaths in men worldwide. Although the application of the serum prostate-specific antigen (PSA) screening test resulted in an increase in the PCa diagnosed cases, it demonstrated a negligible benefit regarding the associated mortality. Treatment options vary, with active surveillance to be preferable for patients with low risk PCa and therapy of advanced castration-resistant PCa to rely on alpha emitters and cytotoxic chemotherapy. Although recent developments have led to the approval of novel drugs for the treatment of castration-resistant PCa, the optimal sequence and timing of medication have not been yet determined. New screening modalities could improve the discriminatory accuracy between tumors with favorable clinical prognosis. Implementation of proteomic-based biomarkers appears to be a promising improvement, which could enable a more accurate diagnosis, guide treatment and improve patient outcome. Reviewed here are urinary proteome-based approaches for detection of PCa and patient management. PMID- 26491819 TI - Technological Considerations for the Delivery of Real-Time Child Telemental Healthcare. AB - OBJECTIVE: In recent years, rapid advances in the sophistication and accessibility of new technologies for consumer use have been leveraged to meaningfully expand the scope of mental health services for youth. However, despite many potential benefits inherent in applying new technologies to improve the accessibility and quality of care, organizations and private providers looking to expand their services with telemental health (TMH) service options may find the broad range of software packages and hardware options daunting. METHODS: We summarize key considerations for adopting a videoteleconferencing (VTC) system, and provide recommendations for institutions and providers planning to launch TMH services at varying levels. RESULTS: Although there is currently no single combination of VTC software and equipment that works best for every provider, certain factors such as cost, ease of use, and system functionality contribute to the setup that may serve as the "best fit" for practitioners' and clients' needs. CONCLUSIONS: Careful consideration of these system characteristics and their bearing on institutional functioning, quality of services, and client satisfaction and privacy prior to VTC installation can proactively reduce difficulties after TMH implementation. PMID- 26491820 TI - Crystallization-induced dynamic resolution R-epimer from 25-OCH3-PPD epimeric mixture. AB - 25-OCH3-PPD is a promising antitumor dammarane sapogenin isolated from the total saponin-hydrolyzed extract of Panax ginseng berry and Panax notoginseng leaves. 20(R)-25-OCH3-PPD was more potent as an anti-cancer agent than 20(S)-25-OCH3-PPD and epimeric mixture of 25-OCH3-PPD. This paper describes the rapid separation process of the R-epimer of 25-OCH3-PPD from its epimeric mixture by crystallization-induced dynamic resolution (CIDR). The optimized CIDR process was based on single factor analysis and nine well-planned orthogonal design experiments (OA9 matrix). A rapid and sensitive reverse phase high-performance liquid chromatographic (HPLC) method with evaporative light-scattering detector (ELSD) was developed and validated for the quantitation of 25-OCH3-PPD epimeric mixture and crystalline product. Separation and quantitation were achieved with a silica column using a mobile phase consisting of methanol and water (87:13, v/v) at a flow rate of 1.0mL/min. The ELSD detection was performed at 50 degrees C and 3L/min. Under conditions involving 3mL of 95% ethanol, 8% HCl, and a hermetically sealed environment for 72h, the maximum production of 25(R)-OCH3-PPD was achieved with a chemical purity of 97% and a total yield of 87% through the CIDR process. The 25(R)-OCH3-PPD was nearly completely separated from the 220mg 25-OCH3-PPD epimeric mixture. Overall, a simple and steady small-batch purification process for the large-scale production of 25(R)-OCH3-PPD from 25-OCH3-PPD epimeric mixture was developed. PMID- 26491821 TI - Association among diameter and volume of follicles, oocyte maturity, and competence in intracytoplasmic sperm injection cycles. AB - AIM: The follicular size has been considered for years as an index for oocyte maturity in stimulated ovulation cycles so that the time of initiating human chorionic gonadotropin (HCG) has been formerly determined by the ultrasonography measurement of larger follicles. The other studies have demonstrated that there was no significant difference between fertility of oocytes aspirated from follicles with various sizes. The objective of this study to explore the associations among the size and volume of extracted follicles at the time of oocyte collection with the rate of collection, oocyte maturity, and oocyte competence in the intracytoplasmic sperm injection (ICSI) therapeutic cycles. METHODS: This prospective study was performed on 412 stimulated ovulation cycles of 340 patients visiting the infertility center of Tehran Mirzakouchakkhan Hospital from September 2011 to February 2013, so that a total of 2324 follicles were investigated. The follicular diameter and fluid volume were measured then the follicles were classified into four groups regarding the aforesaid spatial dimensions. The association among the size and volume of follicles with the probability of oocytes collection, oocytes maturity, fertility competence, cleavage rate, and embryo quality was assessed. RESULTS: The majority of follicles (38%) were categorized in the group C with the follicle diameter of 16 20 mm and volume of 1-3 mm3. No significant difference was observed between these four follicle groups in terms of oocyte collection rate. There was a significant difference (P<0.05) between the group A (diameter>21 mm; volume>5 mm3) and group D (diameter<12 mm; volume<=1 mm3) regarding oocyte maturity and collection rate of metaphase II (MII) oocyte. Conversely, this difference was not significant between groups A, B (diameter=16-20 mm; volume=3-5 mm3), and C (diameter=12-15 mm; volume=1-3 mm3). The fertility rate of oocytes aspirated from small follicles was 55%, which is significantly lower than the fertility rate of oocytes obtained from follicles larger than 12 mm and volume of more than 1 mm3. However, the oocytes aspirated from smaller follicles continue to cleaved, and the quality of embryos did not significantly differ from that embryos cultivated from larger follicles. CONCLUSION: This study showed that the size of follicles and the oocytes maturity in stimulated ovaries are not considerably associated, thus might be independent factors. The development competence of oocytes from smaller follicles was similar to oocytes aspirated from larger follicles. Thus follicles smaller than 12 mm in size and 1 mm3 in volume should be also aspirated. Moreover, this study suggests initiating HCG at the phase with follicles equal to or larger than 16 mm to save time and expense for the patient. PMID- 26491822 TI - [Counseling about folate intake during pregnancy]. AB - AIM: In gynecology, the importance of an adequate folate intake in the periconceptional period and during pregnancy is widely accepted. Its purpose is to decrease the risk of maternal and fetal diseases, such as neural tube defects (NTD), so that Italy strongly recommends that women who are pregnant or are planning to become pregnant receive folate supplementation (i.e. 0.4 or 4-5 mg per day, as needed). Despite that, recent studies show women's low awareness of the importance of folate supplementation, above all during the periconceptional period. Basing on these considerations, we surveyed pregnant women to investigate their awareness and the real use of folate. METHODS: From January to October 2014 we surveyed 650 pregnant women. We used a questionnaire with closed and semi closed questions. RESULTS: The mean age of the enrolled women was 32.8 (+/-2.9). The survey showed that a significant proportion of women knew folate benefits in pregnancy (about 70%) and they used it during gestational period (89.8%), whereas folate supplementation during periconceptional period was inadequate, used by only the 16.9% of women and often at a lower than recommended amount. CONCLUSION: Awareness and use of folate can be promoted through informational campaigns among general practitioners and obstetricians/gynecologists, through preconceptional and prenatal counseling, and through a risk assessment addressed to choose the appropriate folate type and dosage. PMID- 26491823 TI - Chronic pelvic pain, quality of life and sexual health of women treated with palmitoylethanolamide and alpha-lipoic acid. AB - AIM: The aim of this paper was to evaluate the effects of the association between palmitoylethanolamide (PEA) and alpha-lipoic acid (LA) on quality of life (QoL) and sexual function in women affected by endometriosis-associated pelvic pain. METHODS: Fifty-six women constituted the study group and were given PEA 300 mg and LA 300mg twice daily To define the endometriosis-associated pelvic pain, the visual analogic scale (VAS) was used. The Short Form-36 (SF-36), the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) were used to assess the QoL, the sexual function and the sexual distress, respectively. The study included three follow-ups at 3, 6 and 9 months. RESULTS: No changes were observed in pain, QoL and sexual function at the 3rd month follow up (P=NS). By the 6th and 9th month, pain symptoms (P<0.001) and all categories of the QoL (P<0.001) improved. The FSFI and the FSDS scores did not change at the 3rd month follow-up (P=ns). On the contrary, at the 3rd and 9th months follow-ups they improved with respect to the baseline (P<0.001). CONCLUSION: The progressive reduction of the pain syndrome reported by women over the treatment period could contribute to improve the QoL and sexual life of women on PEA and LA. PMID- 26491824 TI - Polycystic ovary syndrome (PCOS) and hyperandrogenism: the role of a new natural association. AB - AIM: Polycystic ovary syndrome (PCOS) affects 5-10% of women of childbearing age and manifests itself through oligomenorrhea, anovulation, hirsutism, micro polycystic ovaries. Insulin resistance is a characteristic of PCOS patients and is more pronounced in obese patients. Insulin resistance and consequent hyperinsulinemia are related to many aspects of the syndrome such as hyperandrogenism, reproductive disorders, acne and hirsutism. In the long-term it may increase the risk of cardiovascular disease and negatively affect lipid profile and blood pressure. Changes in lifestyle and diet can partially improve these aspects. The use of insulin-sensitizing drugs such as metformin often normalises the menstrual cycle, improving hyperandrogenism and, subsequently, the response to ovulation induction therapies. New molecules have recently been marketed, that produce the same results, but without the side-effects. One of these is myo-inositol, a new insulin-sensitizing molecule which has been successfully administered to women suffering from PCOS. Associations between inositol and other compounds that can increase the therapeutic effect have been proposed. Of these, we found to be interesting the association with monacolin K, a natural statin that reduces cholesterol levels starting point of the synthesis of steroids, including androgens, and lipoic acid, known for its anti inflammatory, antioxidant and insulin-sensitizing activity. We decided to assess the efficacy of the product. METHODS: We recruited 30 women aged between 24 and 32 years suffering from PCOS with insulin resistance, HOMA index>2.5 and no other endocrine diseases. The following were assessed: Body Mass Index (BMI), characteristics of menstrual cycles, lipid profile (total cholesterol, and HDL), androgens (total testosterone and androstenedione). The patients were also assessed for the degree of hirsutism using the Ferriman-Gallwey Score>8. The subjects were divided into two groups: Group A, treated with an association of 1 g myo-inositol, 5 mg monacolin K and 400 mg lipoic acid for 6 months; Group B, treated with a double dosage of 2 g myo-inositol, 10 mg monacolin K, 800 mg lipoic acid for 6 months. RESULTS: The results have shown good efficacy of both dosages, although women treated with a double dosage of myo-inositol, monacolin K and lipoic acid showed a significantly greater improvement in terms of lipid parameters and those connected with hyperandrogenism. CONCLUSION: This new myo inositol, monacolin K and lipoic acid association contains appropriate substances to contrast various etiopathogenic elements responsible for the onset of PCOS and the symptoms of hyperandrogenism and dyslipidemia related to it. PMID- 26491825 TI - [Use of alpha-lipoic acid and omega-3 in postpartum pain treatment]. AB - Postpartum pain is a frequent condition that negatively affects women's quality of life, interferring with everyday life. Analgesic drugs and surgery are often contraindicated in pregnancy and during breast feeding. This review of the literature aims to evaluate the rational of the association of lipoic acid and omega-3 employ in the management of postpartum pain. Lipoic acid is a cofactor essential in mitochondrial metabolism with antioxidant and anti-inflammatory activity. Lipoic acid has been shown to be effective in neuropatic pain treatment in patients with sciatica, carpal tunnel syndrome and diabetic neuropathy. Omega 3 are known for their anti-inflammatory and neurotrophic activity. The peripheral and central activity of both substances allows to act on neuroinflammation mechanisms thus reducing cronicization of pain and also determining a potential improvement of women's emotional status. The preliminary data here presented confirm the positive effect of this association on the treatment of postpartum perineal pain. The supplementation of lipoic acid in association with omega-3 seems effective and safe for the treatment of chronic postpartum pain, allowing a pathogenetic approach to neuroinflammation, thus reducing the consumption of analgesic drugs, often contraindicated during breast-feeding. PMID- 26491827 TI - Myo-inositol: from induction of ovulation to menopausal disorder management. PMID- 26491826 TI - [Preliminary data on the effectiveness of resveratrol in a new formulation in treatment of hot flushes]. AB - AIM: We conducted a pilot study to evaluate the effectiveness of resveratrol absorbed orally, conveyed through a new patented technology that increases the absorption through the oral mucosa in treatment of hot flushes (HF) during menopause. METHODS: This is a randomized controlled double-blind study with crossover design. From October 2012 to July 2014 we considered the first 50 patients enrolled at the Center for Menopause Maggiore Hospital of Charity of Novara, with diagnosis of physiological or surgical menopause. Each woman received a diary in which she indicated the weekly number of HF and the perceived intensity, in a 0-10 Scale (Visual Analogue Scale, VAS). RESULTS: Reduction of the monthly number of vasomotor episodes. Resveratrol 16/28 (57.1%); P2/22 placebo (9.1%) <0.001. The resveratrol group gets a positive result 6.28 times more compared to the placebo arm (95% CI: 1.61-24.49). Improvement of the intensity of symptoms and improving quality of life: resveratrol 22/28 (78.6%); placebo 4/22 P (18.2%) <0.001. Resveratrol group obtained a positive result 4:32 times more than the placebo arm (95% CI: 1.74-10.71). CONCLUSION: Resveratrol is effective in reducing the number of episodes vasomotor and the intensity of HF, with the transition from moderate/severe to mild symptoms in 78.6% of patients. Resveratrol has the characteristics to be an alternative therapy in the treatment of HF in menopause. PMID- 26491828 TI - A novel hemostatic technique during cesarean section for placenta previa: combining "cervical inversion" and "holding the cervix". PMID- 26491829 TI - Hydrogelation Induced by Fmoc-Protected Peptidomimetics. AB - Four new low molecular weight hydrogelators (LMWGs) have been prepared in multigram scale and their attitude to form hydrogels has been tested. The gelation trigger is pH variation. The resulting gels have been characterized with several techniques: measurement of the melting points (T(gel)), transparency, gelation time, and viscoelastic properties, together with ECD analysis. Among them, Fmoc-L-Tyr-D-Oxd-OH 1 is an excellent gelator that leads to the preparation of strong, transparent, and viscoelastic gels, by pH variation. UV-visible analyses have demonstrated that the gels obtained with the LMWG 1 possess high transparency, with a transmittance up to 25.6% at a wavelength of 600 nm. Results of the amplitude sweep experiments showed that the elastic response component (G') was approximately an order of magnitude larger than the viscous component, indicating an elastic rather than viscous attitude of the gels, confirmed by the frequency independence of G' and G" values, in the range from 0.1 to 100 rad.s( 1). The thermal behavior of gel obtained from Fmoc-L-Tyr-D-Oxd-OH 1 was characterized performing an "ad hoc" rheological temperature sweep experiment, that indicated that G' remained almost constant from 23 degrees C up to about 65 degrees C while G" increased in the same temperature range. At higher temperatures, both G' and G" values started to slightly decrease without displaying a crossover point. PMID- 26491830 TI - Erratum: Vol. 64, No. 18. PMID- 26491831 TI - Antimalarial activity of ruthenium(II) and osmium(II) arene complexes with mono- and bidentate chloroquine analogue ligands. AB - Eight new ruthenium and five new osmium p-cymene half-sandwich complexes have been synthesized, characterized and evaluated for antimalarial activity. All complexes contain ligands that are based on a 4-chloroquinoline framework related to the antimalarial drug chloroquine. Ligands HL(1-8) are salicylaldimine derivatives, where HL(1) = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7 chloroquinolin-4-amine, and HL(2-8) contain non-hydrogen substituents in the 3 position of the salicylaldimine ring, viz. F, Cl, Br, I, NO2, OMe and (t)Bu for HL(2-8), respectively. Ligand HL(9) is also a salicylaldimine-containing ligand with substitutions in both 3- and 5-positions of the salicylaldimine moiety, i.e. N-(2-((2-hydroxy-3,5-di-tert-butylphenyl)methyl-imino)ethyl)-7-chloroquinolin-4 amine, while HL(10) is N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7 chloroquinolin-4-amine) The half sandwich metal complexes that have been investigated are [Ru(eta(6)-cym)(L(1-8))Cl] (Ru-1-Ru-8, cym = p-cymene), [Os(eta(6)-cym)(L(1-3,5,7))Cl] (Os-1-Os-3, Os-5, and Os-7), [M(eta(6) cym)(HL(9))Cl2] (M = Ru, Ru-HL(9); M = Os, Os-HL(9)) and [M(eta(6) cym)(L(10))Cl]Cl (M = Ru, Ru-10; M = Os, Os-10). In complexes Ru-1-Ru-8 and Ru 10, Os-1-Os-3, Os-5 and Os-7 and Os-10, the ligands were found to coordinate as bidentate N,O- and N,N-chelates, while in complexes Ru-HL(9) and Os-HL(9), monodentate coordination of the ligands through the quinoline nitrogen was established. The antimalarial activity of the new ligands and complexes was evaluated against chloroquine sensitive (NF54 and D10) and chloroquine resistant (Dd2) Plasmodium falciparum malaria parasite strains. Coordination of ruthenium and osmium arene moieties to the ligands resulted in lower antiplasmodial activities relative to the free ligands, but the resistance index is better for the ruthenium complexes compared to chloroquine. Overall, osmium complexes appeared to be less active than the corresponding ruthenium complexes. PMID- 26491832 TI - Identification of a homozygous mutation of SLC24A5 (OCA6) in two patients with oculocutaneous albinism from French Guiana. PMID- 26491833 TI - The effect of domain-general inhibition-related training on language switching: An ERP study. AB - Previous studies have demonstrated that inhibitory control ability could be improved by training, and the Inhibitory Control (IC) Model implies that enhanced domain-general inhibition may elicit certain changes in language switch costs. In the present study, we aimed to examine the effects of domain-general inhibition training on performance in a language switching task, including which phase of domain-general inhibitory control benefits from training during an overt picture naming task in L1 and L2, using the event-related brain potentials (ERPs). Results showed that the language switch costs of bilinguals with high inhibitory control (high-IC) were symmetrical in both pretest and posttest, and those of bilinguals with low inhibitory control (low-IC) were asymmetrical in the pretest, but symmetrical in the posttest. Moreover, the high-IC group showed a larger LPC (late positive component) for L2 switch trials than for L1 trials in both pretest and posttest. In contrast, the low-IC group only exhibited a similar pattern of LPC in the posttest, but not in the pretest. These results indicate that inhibition training could increase the efficiency of language switching, and inhibitory control may play a key role during the lexical selection response phase. Overall, the present study is the first one to provide electrophysiological evidence for individual differences in the domain-general inhibition impact on language switching performance in low-proficient bilinguals. PMID- 26491834 TI - Fast automated counting procedures in addition problem solving: When are they used and why are they mistaken for retrieval? AB - Contrary to a widespread assumption, a recent study suggested that adults do not solve very small additions by directly retrieving their answer from memory, but rely instead on highly automated and fast counting procedures (Barrouillet & Thevenot, 2013). The aim of the present study was to test the hypothesis that these automated compiled procedures are restricted to small quantities that do not exceed the size of the focus of attention (i.e., 4 elements). For this purpose, we analyzed the response times of ninety adult participants when solving the 81 additions with operands from 1 to 9. Even when focusing on small problems (i.e. with sums ?10) reported by participants as being solved by direct retrieval, chronometric analyses revealed a strong size effect. Response times increased linearly with the magnitude of the operands testifying for the involvement of a sequential multistep procedure. However, this size effect was restricted to the problems involving operands from 1 to 4, whereas the pattern of response times for other small problems was compatible with a retrieval hypothesis. These findings suggest that very fast responses routinely interpreted as reflecting direct retrieval of the answer from memory actually subsume compiled automated procedures that are faster than retrieval and deliver their answer while the subject remains unaware of their process, mistaking them for direct retrieval from long-term memory. PMID- 26491835 TI - A multimodal parallel architecture: A cognitive framework for multimodal interactions. AB - Human communication is naturally multimodal, and substantial focus has examined the semantic correspondences in speech-gesture and text-image relationships. However, visual narratives, like those in comics, provide an interesting challenge to multimodal communication because the words and/or images can guide the overall meaning, and both modalities can appear in complicated "grammatical" sequences: sentences use a syntactic structure and sequential images use a narrative structure. These dual structures create complexity beyond those typically addressed by theories of multimodality where only a single form uses combinatorial structure, and also poses challenges for models of the linguistic system that focus on single modalities. This paper outlines a broad theoretical framework for multimodal interactions by expanding on Jackendoff's (2002) parallel architecture for language. Multimodal interactions are characterized in terms of their component cognitive structures: whether a particular modality (verbal, bodily, visual) is present, whether it uses a grammatical structure (syntax, narrative), and whether it "dominates" the semantics of the overall expression. Altogether, this approach integrates multimodal interactions into an existing framework of language and cognition, and characterizes interactions between varying complexity in the verbal, bodily, and graphic domains. The resulting theoretical model presents an expanded consideration of the boundaries of the "linguistic" system and its involvement in multimodal interactions, with a framework that can benefit research on corpus analyses, experimentation, and the educational benefits of multimodality. PMID- 26491836 TI - Relationship between adaptation and cardiovascular response to tonic cold and heat pain Adaptability to tonic pain and cardiovascular responses. AB - BACKGROUND: The mechanisms of adaptation to tonic pain are not elucidated. We hypothesized that the adaptability to tonic pain is related to the cardiovascular system. METHODS: Twenty-six subjects received over two sessions in a random order: tonic cold (7 +/- 0.2 degrees C) and heat pain (47.5 +/- 0.5 degrees C) on the hand for 5 min. Pain intensity, blood pressure (BP), and heart rate (HR) were continuously monitored. RESULTS: Pain experience during the heat (HIT) and cold (CIT) immersion tests exhibited different average time courses, being approximated with a linear and cubic function, respectively. In each test, two groups of participants could be identified based on the time course of their tonic thermal pain: one-third of participants were pain adaptive and two-thirds non adaptive. The adaptive group exhibited higher initial pain, lower last pain, and shorter latency to peak pain than the non-adaptive one. Interestingly, some participants were adaptive to both pain stimuli, most were not. HIT as well as CIT produced a stable elevation of BP. However, BP was higher during CIT than HIT (p = 0.034). HR was also increased during CIT and HIT, but the two tests differed with respect to the time course of responses. Finally, the intensity and time course of pain rating to both HIT and CIT correlated with neither BP nor HR responses. CONCLUSIONS: These results suggest that individual sensitivity and adaptability to tonic thermal pain is related to the intensity of initial pain rating and the latency to peak pain but not to cardiovascular responses. PMID- 26491838 TI - Anesthesiologists Are Affiliated with Many Hospitals Only Reporting Anesthesia Claims Using Modifier QZ for Medicare Claims in 2013. AB - We examined hospitals that exclusively used the billing modifier QZ in anesthesia claims for a 5% sample of Medicare beneficiaries in 2013. We used a national Medicare provider file to identify physician anesthesiologists and nurse anesthetists affiliated with these hospitals. Among the 538 hospitals that exclusively reported the modifier QZ, 47.5% had affiliated physician anesthesiologists. These hospitals accounted for 60.4% of the cases. Our results illustrate the challenges of using modifier QZ to describe anesthesia practice arrangements in hospitals. The modifier QZ does not seem to be a valid surrogate for no anesthesiologist being involved in the care provided. PMID- 26491839 TI - Unexplained Profound Hypoglycemia After Vocal Fold Lipoinjection. AB - Vocal fold injection is used for the management of glottal incompetence from various causes. The procedure is well tolerated and has few reported complications. We present a case of a 66-year-old man with long-lasting hoarseness secondary to vocal fold atrophy, who underwent an uneventful bilateral vocal fold injection with autologous fat. While in the recovery area, he experienced profuse sweating approximately 30 minutes after the surgical procedure. His blood glucose value was measured at 24 mg/dL, and plasmatic insulin level was 246 mU/L. To our knowledge, this is the first reported case of a systemic side effect after vocal fold lipoinjection. PMID- 26491840 TI - The Resident Academic Project Program: A Structured Approach to Inspiring Academic Development During Residency Training. AB - We report the successful implementation of structured resident academic projects in our Department of Anesthesiology at the Penn State Hershey Medical Center. Beginning with the graduating class of 2010, we adopted an expectation that each resident complete a project that results in a manuscript of publishable quality. Defining a clear timeline for all steps in the project and providing research education, as well as the necessary infrastructure and ongoing support, has helped grow the academic productivity of our anesthesia residents. PMID- 26491841 TI - Intraoperative Management of Increased Intraocular Pressure in a Patient with Glaucoma Undergoing Robotic Prostatectomy in the Trendelenburg Position. AB - Patients with primary open angle glaucoma have decreased outflow through the trabecular meshwork of the eye, resulting in increased intraocular pressure (IOP). It is known that the Trendelenburg position causes increased IOP, but there are no current guidelines for monitoring and treating patients with glaucoma undergoing surgical procedures while in the Trendelenburg position. We describe a case of successful intraoperative management of increased IOP in a patient with glaucoma undergoing robotic radical prostatectomy while in steep Trendelenburg position. PMID- 26491842 TI - Radiofrequency Scanning for Retained Surgical Items Can Cause Electromagnetic Interference and Pacing Inhibition if an Asynchronous Pacing Mode Is Not Applied. AB - Radiofrequency (RF) scanning is an increasingly popular method of detecting retained surgical items. RF systems are generally regarded as safe but have the potential to cause electrical interference with pacemakers. This may lead to serious adverse events, including asystole. We present a case of an RF system used with a temporary pacemaker resulting in asystole. With the use of RF devices becoming widespread, it is important for all operating room personnel to recognize the potential for pacemaker interference from RF scanning devices and the requirements for asynchronous pacing when these devices are in use. PMID- 26491843 TI - Analysis of mandipropamid residual levels through systematic method optimization against the matrix complexity of sesame leaves using HPLC/UVD. AB - An analytical method was developed to detect mandipropamid residues in sesame leaves using high-performance liquid chromatography-ultraviolet detection. Samples were extracted with acetonitrile and were prepurified using a solid-phase extraction (SPE) cartridge with an additional dispersive-SPE (d-SPE) sorbent application. The method was validated using an external calibration curve prepared using pure solvent. The linearity was excellent with determination coefficient = 1. The limits of detection and quantification were 0.003 and 0.01 mg/kg, respectively. Recoveries at three spiking levels - 0.1, 0.5, and 1.0 mg/kg - were in the range 80.3-90.7% with relative standard deviations <2%. This method was applied to field-treated samples collected from two different areas, Gwangju and Muan, in the Republic of Korea and the half-lives were similar, 5.10 and 5.41 days, respectively. The pre-harvest residue limit was also predicted for both sites. The proposed method is sensitive and able to quantify trace amounts of mandipropamid in leafy vegetables. The combination of SPE and d-SPE effectively removed the matrix components in sesame leaves. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26491844 TI - Is technology the best medicine? Three practice theoretical perspectives on medication administration technologies in nursing. AB - Even though it is often presumed that the use of technology like medication administration technology is both safer and more effective, the importance of nurses' know-how is not to be underestimated. In this article, we accordingly try to argue that nurses' labor, including their different forms of knowledge, must play a crucial role in the development, implementation and use of medication administration technology. Using three different theoretical perspectives ('heuristic lenses') and integrating this with our own ethnographic research, we will explore how nursing practices change through the use of medication technology. Ultimately, we will argue that ignoring (institutional) complexity and the various types of important knowledge that nurses have, will seriously complicate the implementation of medication administration technology. PMID- 26491846 TI - Matching and Minimizing Movement Time in Speed-Accuracy Tasks. AB - The goal of present experiment was to test whether different speed-accuracy paradigms outcomes (time minimization and time matching) were due to different temporal and spatial task constraints. Fifteen participants twice performed 100 trials of time minimization and time matching tasks with the yoked temporal and spatial requirements (criterion time and target width). The results showed that performing an aiming movement under the same spatial and temporal constraints resulted in similar outcomes with distributional properties (skewness and kurtosis) being slightly affected by practice effects. There was a trade-off in the information entropy for space and time (temporal information entropy decreased as spatial information entropy increased) with practice. Nevertheless, the joint space-time entropy of outcome did not change across tasks and conditions-revealing a common level of space-time entropy between these two categories of aiming tasks. These findings support the hypothesis that under the same spatial and temporal constraints the movement speed-accuracy function shares the same properties independent of task category. PMID- 26491845 TI - Critical role of c-jun N-terminal protein kinase in promoting mitochondrial dysfunction and acute liver injury. AB - The mechanism by which c-Jun N-terminal protein kinase (JNK) promotes tissue injury is poorly understood. Thus we aimed at studying the roles of JNK and its phospho-target proteins in mouse models of acute liver injury. Young male mice were exposed to a single dose of CCl4 (50mg/kg, IP) and euthanized at different time points. Liver histology, blood alanine aminotransferase, and other enzyme activities were measured in CCl4-exposed mice without or with the highly-specific JNK inhibitors. Phosphoproteins were purified from control or CCl4-exposed mice and analyzed by differential mass-spectrometry followed by further characterizations of immunoprecipitation and activity measurements. JNK was activated within 1h while liver damage was maximal at 24h post-CCl4 injection. Markedly increased phosphorylation of many mitochondrial proteins was observed between 1 and 8h following CCl4 exposure. Pretreatment with the selective JNK inhibitor SU3327 or the mitochondria-targeted antioxidant mito-TEMPO markedly reduced the levels of p-JNK, mitochondrial phosphoproteins and liver damage in CCl4-exposed mice. Differential proteomic analysis identified many phosphorylated mitochondrial proteins involved in anti-oxidant defense, electron transfer, energy supply, fatty acid oxidation, etc. Aldehyde dehydrogenase, NADH-ubiquinone oxidoreductase, and alpha-ketoglutarate dehydrogenase were phosphorylated in CCl4 exposed mice but dephosphorylated after SU3327 pretreatment. Consistently, the suppressed activities of these enzymes were restored by SU3327 pretreatment in CCl4-exposed mice. These data provide a novel mechanism by which JNK, rapidly activated by CCl4, promotes mitochondrial dysfunction and acute hepatotoxicity through robust phosphorylation of numerous mitochondrial proteins. PMID- 26491847 TI - Pre- and Posttreatment Glioma: Comparison of Amide Proton Transfer Imaging with MR Spectroscopy for Biomarkers of Tumor Proliferation. AB - PURPOSE: To correlate and compare diagnostic performance with amide proton transfer (APT) imaging as a tumor proliferation index with that with magnetic resonance (MR) spectroscopy in subgroups of patients with pre- and posttreatment glioma. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. In 40 patients with pretreatment glioma and 25 patients with posttreatment glioma, correlation between APT asymmetry and the choline-to-creatine and choline-to-N-acetylaspartate ratios in corresponding voxels of interest was determined, and the 90% histogram cutoff of APT asymmetry values (APT90) for the entire solid portion of gliomas was calculated for diagnostic performance. Area under the receiver operating characteristic curve (AUC), leave-one-out cross validation, and intraclass correlation coefficients were analyzed. RESULTS: The APT asymmetry values showed a moderate correlation (r = 0.49, P < .001) with the choline-to-creatine ratios and a mild correlation with the choline-to-N-acetyl-aspartate ratios (r = 0.32, P = .011) in the corresponding lesions. The APT90 showed comparable diagnostic accuracy for grading of gliomas (AUC, 0.81-0.84 vs 0.86; P = .582-.864) and superior accuracy for differentiation of tumor progression from treatment-related change (AUC, 0.89 0.90 vs 0.60; P = .031-.046) compared with those with MR spectroscopy. The cross validated area under the curve and accuracy of the APT90 in posttreatment gliomas were 0.89-0.90 and 72%, respectively. The interreader agreement for APT90 was excellent in both pretreatment and posttreatment gliomas (intraclass correlation coefficient, 0.95 and 0.96, respectively). CONCLUSION: APT imaging used as a tumor proliferation index showed moderate correlation with MR spectroscopic values and is a superior imaging method to MR spectroscopy, particularly for assessment of posttreatment gliomas. PMID- 26491848 TI - Primary palliative care in the delivery room: patients' and medical personnel's perspectives. AB - OBJECTIVE: To investigate circumstances of primary palliative care (PPC) in the delivery room (DR), medical personnel's experience with neonates who died under PPC in the DR and perceived sources of care-related distress in DR staff. STUDY DESIGN: Retrospective chart review of all neonates who were cared for under PPC in the DR during the years 2000-2010 at Charite University Medical Center Berlin, and structured face-to-face interviews with DR nursing staff and physicians. RESULT: Neonates undergoing PPC could be grouped as preterm infants at the limits of viability with a gestational age between 22 (0)/7 and 23 (6)/7 weeks (n=86, 76%) and newborn infants with complex chronic conditions (n=27, 24%). The median age of neonates at death was 59 min (interquartile range [IQR] 28-105 min). Most of DR staff did not report relevant signs of distress in dying neonates, and providing palliative care was not named as a relevant care-related source of distress by medical personnel. However, half of the participants reported on high degrees of caregiver's emotional distress in PPC situations, identifying insecurity of how to communicate with parents and to provide emotional support as the most common source of distress. CONCLUSION: Caregiver's emotional distress primarily originates from providing support to parents and not from providing medical care to the dying newborn. Implications for future practice include the need for structured education to improve DR staff's communication and counselling skills related to parents in PPC situations. PMID- 26491849 TI - Assessment of G6PD screening program in premature infants in a NICU. AB - OBJECTIVE: Targeted screening for glucose-6-phosphate dehydrogenase deficiency (G6PDdef) using fluorescent spot test (FST) is done in our newborn nursery (NN) and now in our NICU. Premature infants have higher G6PD levels than term infants. FST may result in under diagnosis of G6PDdef in preterms. We sought to determine if FST is appropriate for diagnosis of G6PDdef at<35 weeks and assess screening in NICU. STUDY DESIGN: Retrospective chart review of male, inborn infants<35 weeks in NICU from 2008 to 2011. Difference in G6PDdef incidence<5% between NN and NICU was acceptable for equivalence. RESULTS: Out of 679 subjects, 442 were screened for G6PDdef and 11.3% had abnormal results. Binomial testing comparing 11.3% (95% confidence interval (CI) 8.5 to 14.6) incidence of G6PDdef in NICU and reported incidence in NN (11%) demonstrated no difference. 12.2% of Black/African American males were not screened. CONCLUSION: FST is appropriate for screening all at-risk newborns. A number of at-risk premature males were not screened. PMID- 26491851 TI - Second trimester dilation and evacuation: a risk factor for preterm birth? AB - OBJECTIVE: To evaluate whether second trimester pregnancy termination with dilation and evacuation (D&E) vs induction of labor (IOL) affects subsequent risk of preterm birth. STUDY DESIGN: Our cohort was a retrospective cohort of women undergoing second trimester pregnancy termination for fetal anomalies, fetal death or previable premature rupture of membranes. We analyzed the rates of spontaneous delivery <37 weeks in the first pregnancy following the termination. We also compared preterm birth rates in our cohort with national averages and analyzed by the total number of prior procedures. RESULT: There were 173 women in our cohort. Women who had undergone a D&E (n=130) were less likely to have a subsequent preterm birth (6.9 vs 30.2%; P<0.01). This held true for a low risk subset without obstetric risk factors. There was no statistical difference in preterm birth rates for women who had undergone a D&E as compared with national averages, nor between the rates of preterm birth for women with 0, 1, 2 or 3 or more prior first or second trimester procedures. CONCLUSION: We did not find that D&E was a risk factor for preterm delivery when compared with women with a prior IOL or national rates. PMID- 26491850 TI - Timing of induction of labor and association with nighttime delivery: a retrospective cohort. AB - OBJECTIVE: To assess the risk of nighttime delivery associated with timing and method of labor induction. STUDY DESIGN: We reviewed records of 692 patients undergoing full, late or post-term labor induction at two large hospitals. Primary independent variables were start time (morning or evening) and method (prostaglandin or oxytocin). Relative risk was assessed for the primary outcome of nighttime delivery. RESULT: Two hundred and ninety-seven (42.9%) patients experienced nighttime delivery. The relative risk of nighttime delivery adjusted for age in multiparous women using oxytocin in the morning compared with oxytocin inductions in the evening was 0.31 (95% confidence interval (CI): 0.22 to 0.45). Among nulliparous women in the same group, the adjusted relative risk was 0.65 (95% CI: 0.36 to 1.19). For prostaglandin inductions, there was no difference in the risk of nighttime delivery based on timing of the induction in the evening (relative risk: 0.89; 95% CI: 0.71 to 1.10). CONCLUSION: The method used and the time at which induction is started affect risk of nighttime delivery. For multiparous patients receiving oxytocin, morning induction carries lower risk of nighttime delivery. For prostaglandins, timing of initiation did not affect risk of nighttime delivery. PMID- 26491853 TI - Can fetal pulmonary artery Doppler indices predict neonatal respiratory distress syndrome? AB - OBJECTIVE: To study whether fetal main pulmonary artery (MPA) Doppler indices can predict the development of neonatal respiratory distress syndrome (RDS). STUDY DESIGN: This prospective cross-sectional study included pregnant women between 34 and 38+6 weeks gestation. The diagnostic accuracy of MPA Doppler measurements (systolic/diastolic (S/D) ratio, peak systolic velocity (PSV), pulsatility index (PI), resistance index (RI) and acceleration time/ejection time (At/Et)) for diagnosis of neonatal RDS was tested. RESULT: Of the 698 eligible fetuses, 55 (7.87%) developed neonatal RDS. PSV, PI, RI and At/Et were positively correlated with gestational age. The strongest correlation was found with At/Et (r=0.602, P<0.001). PI and RI were significantly higher, whereas At/Et and PSV were significantly lower in fetuses that developed RDS. A cutoff value of 0.305 for At/Et predicted the development of RDS (sensitivity: 76.4%; specificity: 91.6%). CONCLUSION: Development of neonatal RDS can be predicted using the MPA At/Et with high sensitivity and specificity. PMID- 26491854 TI - Tissue Doppler Imaging-derived Diastolic Function Assessment in Children With Sickle Cell Disease and Its Relation With Ferritin. AB - Diastolic dysfunction has been shown to occur earlier than systolic dysfunction in iron overload states in adult patients with sickle cell disease (SCD). Tissue Doppler imaging (TDI)-derived E/E' has emerged as a noninvasive marker of diastolic function. We sought to determine diastolic function in children with SCD and study its relation with iron overload. A retrospective review of medical records of 225 pediatric patients with SCD who received an echocardiogram between January 2008 and December 2012 was performed. Echocardiographic measures including M-mode, spectral Doppler, and TDI-derived E/E' were compared with previously published data in healthy children. The left ventricular end-diastolic and end-systolic dimensions were significantly higher in SCD (P<0.0001) and the shortening fraction was similar (P=0.66). E/E' ratio was significantly higher in SCD at the mitral annulus, septum, and tricuspid annulus. In 54% of subjects, the septal E/E' was >8, indicating elevated left ventricular filling pressure. However, there was no significant correlation between ferritin level and E/E' ratios. Pediatric patients with SCD have a high prevalence of elevated estimated left ventricular filling pressure, but this does not correlate with ferritin levels. PMID- 26491852 TI - Sildenafil and retinopathy of prematurity risk in very low birth weight infants. AB - OBJECTIVE: To examine the effect of sildenafil therapy on development of severe retinopathy of prematurity (ROP) requiring surgical intervention in premature infants. STUDY DESIGN: We identified premature infants who were discharged from Pediatrix Medical Group neonatal intensive care units from 2003 to 2012 and who received an ophthalmologic exam. We matched each infant exposed to sildenafil before first eye exam to three nonexposed infants using propensity scoring to control for differences in baseline infant characteristics. We evaluated the association between sildenafil exposure and development of severe ROP using conditional logistic regression. RESULT: Of the 57 815 infants meeting inclusion criteria, 88 were exposed to sildenafil. We matched 81/88 (92%) sildenafil exposed with 243 nonexposed infants. There was no difference in the proportion of infants who developed severe ROP in the sildenafil-exposed vs nonexposed groups (17/81 (21%) vs 38/243 (16%), P=0.27). On adjusted analysis, there was no difference in severe ROP in the sildenafil-exposed vs nonexposed infants (odds ratio=1.46, 95% confidence interval=0.76 to 2.82, P=0.26). CONCLUSION: We did not observe an association between risk of severe ROP and sildenafil exposure before first eye exam in this cohort of premature infants. PMID- 26491855 TI - A Simple Diagnostic Test to Confirm Correct Placement of Dysfunctional Central Venous Catheters Before Chemotherapy in Children. AB - BACKGROUND: In children undergoing intravenous chemotherapy, partial dysfunction of the central venous catheter (CVC) is common. Fluids can be infused into the catheter; however, blood cannot be aspirated. In those situations, chemotherapy is withheld and a catheter investigation is performed. Usually, a radiographic study with contrast media or therapy with thrombolytic drugs followed by rechecking for blood return is undertaken. AIM: To evaluate if a previously described method using dilute sodium bicarbonate injection and the resultant rise in measured end-tidal carbon dioxide tracing can confirm correct intravascular placement of a dysfunctional CVC in children at the bedside. PATIENTS: Cohort group of 22 children scheduled for chemotherapy with partial dysfunction of a CVC in a tertiary hematology-oncology care facility. RESULTS: All children with a partial dysfunctional CVC that was proven to be intravascular after venogram or thrombolytic therapy had a distinct and predictable increase in end-tidal carbon dioxide response to injected bicarbonate. CONCLUSION: Injection of 1 mL/kg (maximum 20 mL) of 4.2% dilute sodium bicarbonate is a quick, simple, bedside test allowing confirmation of intravascular location of dysfunctional CVC. PMID- 26491856 TI - Successful Use of Eltrombopag in a Child With Hurler Syndrome After Haploidentical Hematopoietic Stem Cell Transplantation. PMID- 26491857 TI - Interictal Infraslow Activity in Stereoelectroencephalography: From Focus to Network. AB - PURPOSE: Infraslow activity (ISA) occurring during the interictal state in focal epilepsy is largely unstudied. In this exploratory analysis, the authors aimed to characterize features of interictal ISA in a cohort of patients studied by stereoelectroencephography. METHODS: The interictal stereoelectroencephography records for 15 consecutive adult patients were retrospectively analyzed, after application of both conventional (1.6-70 Hz) and infraslow (0.01-0.1 Hz) bandpass filters. Visual analysis was complemented by time-frequency analysis to quantify the change in ISA power over hours. Linear correlation coefficient (R) calculations were used to map interictal connectivity in the infraslow band. RESULTS: Interictal ISA background fluctuations were present throughout the interictal state in all patients, manifesting as recurrent and stereotyped oscillations. These oscillations had an apparent modulatory effect on conventional-band activities and spikes ("spike-crested oscillations"). In the infraslow band, the correlations between electrode contacts were shown to have a stable structure over time. CONCLUSIONS: Infraslow activity exists as a fundamental component of wideband cortical dynamics in focal epilepsy, with features suggestive of scale-free (1/f) dynamics: evidence of phase-amplitude coupling and functional connectivity in the infraslow band. Rather than viewed as a focal paroxysmal activity, interictal ISA may be better understood as a network process, although this requires further study. PMID- 26491858 TI - Identification of peptides derived from the C-terminal domain of fibulin-7 active for endothelial cell adhesion and tube formation disruption. AB - Despite the research done on pathological angiogenesis, there is still a need for the development of new therapies against angiogenesis-related diseases. Fibulin-7 (Fbln7) is a member of the extracellular matrix fibulin protein family. The Fbln7 C-terminal fragment, Fbln7-C, binds to endothelial cells and inhibits their tube formation in culture. In this study, we screened 12 synthetic peptides, covering the fibulin-globular domain of Fbln7-C, to identify active sites for endothelial cell adhesion and in vitro antiangiogenic activity. Three peptides, fc10, fc11, and fc12, promoted Human Umbilical Vein Endothelial Cells (HUVECs) adhesion, and the morphology of HUVECs on fc10 was similar to that on Fbln7-C. EDTA and the anti-integrin beta1 function-blocking antibody inhibited HUVECs adhesion to both fc10 and fc12, and heparin inhibited HUVECs adhesion to both fc11 and fc12. fc10 and fc11 inhibited HUVECs tube formation. Our results suggest that three peptides from Fbln7-C are biologically active for endothelial cell adhesion and disrupt the tube formation, suggesting a potential therapeutic use of these peptides for angiogenesis-related diseases. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 184-195, 2016. PMID- 26491859 TI - Effects of Oxygen Concentrations on Postresuscitation Myocardial Oxidative Stress and Myocardial Function in a Rat Model of Cardiopulmonary Resuscitation. AB - OBJECTIVE: Lipid peroxidation induced by free-radical species plays a prominent role in myocardial injury following ischemia and reperfusion. However, there is a lack of data in different oxygen concentrations on myocardial lipid peroxidation during the early phase of reperfusion. In this study, we investigated whether ventilation with medium or normal concentration of oxygen would decrease the severity of myocardial lipid peroxidation and postresuscitation myocardial dysfunction. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University-affiliated animal research institution. SUBJECTS: Sixty-three healthy male Sprague-Dawley rats. INTERVENTIONS: Animals were randomized into three groups: 1) 100% group, 2) 50% group, and 3) 21% group. Ventricular fibrillation was induced and untreated for 8 minutes, and defibrillation was attempted after 8 minutes of cardiopulmonary resuscitation. Ventilation with 100%, 50%, or 21% oxygen was initiated in all groups during cardiopulmonary resuscitation and 1 hour following the return of spontaneous circulation. Normoxic ventilation was maintained thereafter. MEASUREMENTS AND MAIN RESULTS: Myocardial function, including ejection fraction and myocardial performance index, were measured at baseline, 4, or 72 hours after resuscitation. Blood samples were drawn at baseline, 15 minutes, 1, 4, or 72 hours after resuscitation for the measurements of blood gas or biomarkers. Significantly better myocardial function and longer duration of survival were observed in the 50% group. Compared with the 21% and 100% groups, a mild hyperoxia and greater oxygen extraction with lower 8-iso-prostaglandin F2alpha were observed in the 50% group. Pearson correlation analysis confirmed that 8-iso-prostaglandin F2alpha was positively correlated with myocardial performance index at 4 hours postresuscitation. CONCLUSIONS: In a rat model of cardiac arrest and resuscitation, ventilation with 50% inspired oxygen during early postischemic reperfusion phase contributed to a decreased lipid peroxidation and a better myocardial function and duration of survival. PMID- 26491860 TI - Targeted Inhibition of Leucine-Rich Repeat and Immunoglobulin Domain-Containing Protein 1 in Transplanted Neural Stem Cells Promotes Neuronal Differentiation and Functional Recovery in Rats Subjected to Spinal Cord Injury. AB - OBJECTIVE: Leucine-rich repeat and immunoglobulin domain-containing protein (LINGO)-1 is expressed in neural stem cells, and its neutralization results in sustained neuronal immaturity. Thus, targeted inhibition of LINGO-1 via RNA interference may enhance transplanted neural stem cell survival and neuronal differentiation in vivo. Furthermore, LINGO-1 RNA interference in neural stem cells represents a potential therapeutic strategy for spinal cord injury. DESIGN: Department of Spine Surgery, First Affiliated Hospital of Sun Yat-sen University. SETTING: Translational Medicine Center Research Laboratory, First Affiliated Hospital of Sun Yat-sen University. SUBJECTS: Female Sprague-Dawley rats. INTERVENTIONS: The animals were divided into three groups that underwent laminectomy and complete spinal cord transection accompanied by transplantation of control-RNA interference-treated or LINGO-1-RNA interference-treated neural stem cells at the injured site in vivo. In vitro, neural stem cells were divided into four groups for the following treatments: control, control RNA interference lentivirus, LINGO-1 RNA interference lentivirus and LINGO-1 complementary DNA lentivirusand the Key Projects of the Natural Science Foundation of Guangdong Province (No. S2013020012818). MEASUREMENTS AND MAIN RESULTS: Neural stem cells in each treatment group were examined for cell survival and neuronal differentiation in vitro and in vivo via immunofluorescence and Western blot analysis. Axonal regeneration and tissue repair were assessed via retrograde tracing using Fluorogold, electron microscopy, hematoxylin-eosin staining and MRI. Rats were also examined for functional recovery based on the measurement of spinal cord-evoked potentials and the Basso-Beattie-Bresnahan score. LINGO-1-RNA interference-treated neural stem cell transplantation increased tissue repair and functional recovery of the injured spinal cord in rats. Similarly, LINGO-1 RNA interference increased neural stem cell survival and neuronal differentiation in vitro. The mechanism underlying the effect of LINGO-1 RNA interference on the injured rat spinal cord may be that the significant inhibition of LINGO-1 expression in neural stem cells inactivated the RhoA and Notch signaling pathways, which act downstream of LINGO-1. CONCLUSIONS: Our findings indicate that transplantation of LINGO-1-RNA interference-treated neural stem cells facilitates functional recovery after spinal cord injury and represents a promising potential strategy for the repair of spinal cord injury. PMID- 26491861 TI - Mortality of Septic Mice Strongly Correlates With Adrenal Gland Inflammation. AB - OBJECTIVES: Sepsis and septic shock are commonly present in the ICU and accompanied by significant morbidity, mortality, and cost. The frequency of secondary adrenal insufficiency in sepsis remains open to debate and a challenge to identify and treat appropriately. Animal models of sepsis using genetic or surgical initiation of adrenal insufficiency resulted in increased mortality, but the mechanisms are still unclear. The present study investigates the impact of adrenal inflammation in septic mice challenged with cecal ligation and puncture. DESIGN: Prospective experimental study. SETTING: University laboratory. SUBJECTS: C57BL/6N wild-type mice. INTERVENTIONS: Sepsis, induced by cecal ligation and puncture for 24 and 48 hours. MEASUREMENTS AND MAIN RESULTS: Both septic and control mice were carefully monitored (every 30 min) for up to 48 hours and divided into survivors and nonsurvivors. We observed a significant and massive increase of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha in adrenal protein extracts of nonsurvivors compared with sham animals and survivors. This pattern was partly reflected in liver and lung but not in plasma samples. Notably, a significant increase in nonsurvivors compared with survivors was only found for lung interleukin-6. In line with these findings, we detected a higher degree of leukocyte infiltration and hemorrhage in the adrenal glands of deceased mice. Evaluation of the hypothalamic-pituitary-adrenal axis response in these animals revealed an increase of adrenocorticotropic hormone, which was only partly reflected in the corticosterone level. Notably, using the adrenocorticotropic hormone stimulation test, we found an impaired adrenocorticotropic hormone response, particularly in nonsurvivors, which significantly correlated with the number of infiltrated leukocytes. CONCLUSIONS: Cecal ligation and puncture-induced murine sepsis induces a strong inflammatory response in the adrenal glands, which is accompanied by cell death and hemorrhage. Our data suggest that mortality and adrenal incapacitation are associated with the degree of adrenal inflammation, thereby underscoring the importance of adrenal function on survival. PMID- 26491862 TI - Population Pharmacokinetics of Fentanyl in the Critically Ill. AB - OBJECTIVE: To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. DESIGN: Prospective cohort study. SETTING: Medical and surgical ICUs in a large tertiary care hospital in the United States. PATIENTS: Patients with acute respiratory failure and/or shock who received fentanyl during the first 5 days of their ICU stay. MEASUREMENTS AND MAIN RESULTS: We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to 5 days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 MUg/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found that fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92 kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance, intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35 L/hr (95% CI, 32-39 L/hr), 55 L/hr (95% CI, 42-68 L/hr), 203 L (95% CI, 140-266 L), and 523 L (95% CI, 428 618 L), respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart diseases were included. CONCLUSIONS: In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients. PMID- 26491863 TI - A Donation After Circulatory Death Program Has the Potential to Increase the Number of Donors After Brain Death. AB - OBJECTIVES: Donation after circulatory death has been responsible for 75% of the increase in the numbers of deceased organ donors in the United Kingdom. There has been concern that the success of the donation after circulatory death program has been at the expense of donation after brain death. The objective of the study was to ascertain the impact of the donation after circulatory death program on donation after brain death in the United Kingdom. DESIGN: Retrospective cohort study. SETTING: A national organ procurement organization. PATIENTS: Patients referred and assessed as donation after circulatory death donors in the United Kingdom between October and December 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 257 patients were assessed for donation after circulatory death. Of these, 193 were eligible donors. Three patients were deemed medically unsuitable following surgical inspection, 56 patients did not proceed due to asystole, and 134 proceeded to donation. Four donors had insufficient data available for analysis. Therefore, 186 cases were analyzed in total. Organ donation would not have been possible in 79 of the 130 actual donors if donation after circulatory death was not available. Thirty-six donation after circulatory death donors (28% of actual donors) were judged to have the potential to progress to brain death if withdrawal of life-sustaining treatment had been delayed by up to a further 36 hours. A further 15 donation after circulatory death donors had brain death confirmed or had clinical indications of brain death with clear mitigating circumstances in all but three cases. We determined that the maximum potential donation after brain death to donation after circulatory death substitution rate observed was 8%; however due to mitigating circumstances, only three patients (2%) could have undergone brain death testing. CONCLUSIONS: The development of a national donation after circulatory death program has had minimal impact on the number of donation after brain death donors. The number of donation after brain death donors could increase with changes in end-of-life care practices to allow the evolution of brain death and increasing the availability of ancillary testing. PMID- 26491864 TI - Inhibition of Adenosine Kinase Attenuates Acute Lung Injury. AB - OBJECTIVES: Extracellular adenosine has tissue-protective potential in several conditions. Adenosine levels are regulated by a close interplay between nucleoside transporters and adenosine kinase. On the basis of the evidence of the role of adenosine kinase in regulating adenosine levels during hypoxia, we evaluated the effect of adenosine kinase on lung injury. Furthermore, we tested the influence of a pharmacologic approach to blocking adenosine kinase on the extent of lung injury. DESIGN: Prospective experimental animal study. SETTING: University-based research laboratory. SUBJECTS: In vitro cell lines, wild-type and adenosine kinase+/- mice. INTERVENTIONS: We tested the expression of adenosine kinase during inflammatory stimulation in vitro and in a model of lipopolysaccharide inhalation in vivo. Studies using the adenosine kinase promoter were performed in vitro. Wild-type and adenosine kinase+/- mice were subjected to lipopolysaccharide inhalation. Pharmacologic inhibition of adenosine kinase was performed in vitro, and its effect on adenosine uptake was evaluated. The pharmacologic inhibition was also performed in vivo, and the effect on lung injury was assessed. MEASUREMENTS AND MAIN RESULTS: We observed the repression of adenosine kinase by proinflammatory cytokines and found a significant influence of nuclear factor kappa-light-chain-enhancer of activated B-cells on regulation of the adenosine kinase promoter. Mice with endogenous adenosine kinase repression (adenosine kinase+/-) showed reduced infiltration of leukocytes into the alveolar space, decreased total protein and myeloperoxidase levels, and lower cytokine levels in the alveolar lavage fluid. The inhibition of adenosine kinase by 5-iodotubercidin increased the extracellular adenosine levels in vitro, diminished the transmigration of neutrophils, and improved the epithelial barrier function. The inhibition of adenosine kinase in vivo showed protective properties, reducing the extent of pulmonary inflammation during lung injury. CONCLUSIONS: Taken together, these data show that adenosine kinase is a valuable target for reducing the inflammatory changes associated with lung injury and should be pursued as a therapeutic option. PMID- 26491865 TI - Interhospital Transfer Delays Appropriate Treatment for Patients With Severe Sepsis and Septic Shock: A Retrospective Cohort Study. AB - OBJECTIVE: To test the hypothesis that interhospital transfer causes significant delays in the administration of appropriate antibiotics and compliance with the completion of Surviving Sepsis Bundle elements. DESIGN: Single-center retrospective cohort study. SETTING: A comprehensive 60,000-visit emergency department at a 711-bed Midwestern academic medical center. PATIENTS: Patients with severe sepsis and septic shock treated between 2009 and 2014 were identified by International Classification of Diseases,9th Revision, Clinical Modification, codes, then divided into two cohorts: 1) transfer patients who arrived at the tertiary academic center after receiving care in a local community hospital and 2) control patients who presented directly to the tertiary academic center emergency department. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: One hundred ninety-three patients were included. Transfer patients were more likely to require surgery in the hospital (p < 0.001) and require ICU care (p = 0.001) but had similar illness severity based on (Acute Physiology and Chronic Health Evaluation II, 17.7 vs 17.5; p = 0.662). Antibiotic administration at 1 and 3 hours was comparable between the two cohorts, but initial antibiotic appropriateness was lower in transfer patients (34% vs 79%; p < 0.001). Transfer patients were less likely to have fluid resuscitation started by 3 hours (54% vs 89%; p < 0.001), but they were not less likely to receive an adequate fluid bolus (30 mL/kg) by the time of hospital admission (p = 0.056). There were no differences in ICU length of stay or mortality. CONCLUSIONS: Interhospital transfer significantly delays administration of appropriate initial antibiotics and resuscitation therapy. Future studies are needed to identify strategies of providing regional sepsis care prior to transfer to tertiary centers and to continue care pathways during the interhospital transfer process. PMID- 26491866 TI - Ineffective erythropoiesis and regulation of iron status in iron loading anaemias. AB - The definition 'iron loading anaemias' encompasses a group of inherited and acquired anaemias characterized by ineffective erythropoiesis, low hepcidin levels, excessive iron absorption and secondary iron overload. Non-transfusion dependent beta-thalassaemia is the paradigmatic example of these conditions that include dyserythropoietic and sideroblastic anaemias and some forms of myelodysplasia. Interrupting the vicious cycle between ineffective erythropoiesis and iron overload may be of therapeutic benefit in all these diseases. Induction of iron restriction by means of transferrin infusions, minihepcidins or manipulation of the hepcidin pathway prevents iron overload, redistributes iron from parenchymal cells to macrophage stores and partially controls anaemia in beta-thalassaemic mice. Inhibition of ineffective erythropoiesis by activin ligand traps improves anaemia and iron overload in the same models. Targeting iron loading or ineffective erythropoiesis shows promise in preclinical studies; activin ligand traps are in clinical trials with promising results and may be useful in patients with ineffective erythropoiesis. PMID- 26491867 TI - Different Blood-Borne Human Osteoclast Precursors Respond in Distinct Ways to IL 17A. AB - Osteoclasts are bone-degrading cells that are formed through fusion of their monocytic precursors. Three distinct subsets of monocytes have been identified in human peripheral blood: classical, intermediate, and non-classical monocytes. They are known to play different roles in physiology and pathology, but their capacity to differentiate into osteoclasts and whether inflammatory cytokines influence this differentiation is unknown. We hypothesized that classical, intermediate, and non-classical monocytes generate functionally different osteoclasts and that they respond in different ways to the inflammatory cytokine interleukin-17A (IL-17A). To investigate this, the different monocyte subsets were isolated from human peripheral blood and osteoclastogenesis was induced with the cytokines M-CSF and RANKL, with or without IL-17A. We found that all subsets are able to differentiate into osteoclasts in vitro, and that both osteoclastogenesis and subsequent bone resorption was distinctly affected by IL 17A. Osteoclastogenesis and bone resorption by osteoclasts derived from classical monocytes remained unaffected by IL-17A, while osteoclast formation from intermediate monocytes was inhibited by the cytokine. Surprisingly, bone resorption by osteoclasts derived from intermediate monocytes remained at similar levels as control cultures, indicating an increased bone resorbing activity by these osteoclasts. Limited numbers of osteoclasts were formed from non-classical monocytes on bone and no bone resorption was detected, which suggest that these cells belong to a cell lineage different from the osteoclast. By providing more insight into osteoclast formation from human blood monocytes, this study contributes to the possible targeting of specific osteoclast precursors as a therapeutic approach for diseases associated with inflammatory bone loss. PMID- 26491868 TI - Mild Joint Symptoms Are Associated with Lower Risk of Falls than Asymptomatic Individuals with Radiological Evidence of Osteoarthritis. AB - Osteoarthritis (OA) exacerbates skeletal muscle functioning, leading to postural instability and increased falls risk. However, the link between impaired physical function, OA and falls have not been elucidated. We investigated the role of impaired physical function as a potential mediator in the association between OA and falls. This study included 389 participants [229 fallers (>=2 falls or one injurious fall in the past 12 months), 160 non-fallers (no history of falls)], age (>=65 years) from a randomized controlled trial, the Malaysian Falls Assessment and Intervention Trial (MyFAIT). Physical function was assessed using Timed Up and Go (TUG) and Functional Reach (FR) tests. Knee and hip OA were diagnosed using three methods: Clinical, Radiological and Self-report. OA symptom severity was assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). The total WOMAC score was categorized to asymptomatic, mild, moderate and severe symptoms. Individuals with radiological OA and 'mild' overall symptoms on the WOMAC score had reduced risk of falls compared to asymptomatic OA [OR: 0.402(0.172-0.940), p = 0.042]. Individuals with clinical OA and 'severe' overall symptoms had increased risk of falls compared to those with 'mild' OA [OR: 4.487(1.883-10.693), p = 0.005]. In individuals with radiological OA, mild symptoms appear protective of falls while those with clinical OA and severe symptoms have increased falls risk compared to those with mild symptoms. Both relationships between OA and falls were not mediated by physical limitations. Larger prospective studies are needed for further evaluation. PMID- 26491869 TI - Patterns of Methylphenidate Use and Assessment of Its Abuse among the General Population and Individuals with Drug Dependence. AB - PURPOSE: The aim of this study was to describe the extent of methylphenidate (MPH) abuse and characterize its patterns by following several cases involving intravenous administration of crushed MPH tablets. METHODS: First, a drug reimbursement database (covering 4 million inhabitants) was explored to assess the magnitude of MPH abuse among the general population, and second, a specific study based on individuals with drug dependence was performed to describe abusers' characteristics (n = 64), patterns of abuse and clinical implications. RESULTS: From 2005 to 2011, the number of patients who were dispensed MPH at least once increased by 166%. The patients with 'deviant' patterns of MPH consumption were mainly male adults with opiate maintenance treatment reimbursements. MPH abusers had precarious living conditions. Half of them consumed MPH daily by intravenous route and reported amphetamine-like effects (cardiovascular events, weight loss, psychiatric adverse events). CONCLUSION: Given the increase of MPH use, it is important to warn the scientific community about possible MPH abuse, especially in individuals with drug dependence. This study has facilitated public health intervention and dissemination of information related to MPH abuse among health care professionals at local and national levels. PMID- 26491870 TI - A Preliminary Study Examining the Binding Capacity of Akkermansia muciniphila and Desulfovibrio spp., to Colonic Mucin in Health and Ulcerative Colitis. AB - BACKGROUND: Akkermansia muciniphila and Desulfovibrio spp. are commensal microbes colonising the mucus gel layer of the colon. Both species have the capacity to utilise colonic mucin as a substrate. A. muciniphila degrades colonic mucin, while Desulfovibrio spp. metabolise the sulfate moiety of sulfated mucins. Altered abundances of these microorganisms have been reported in ulcerative colitis (UC). However their capacity to bind to human colonic mucin, and whether this binding capacity is affected by changes in mucin associated with UC, remain to be defined. METHODS: Mucin was isolated from resected colon from control patients undergoing resection for colonic cancer (n = 7) and patients undergoing resection for UC (n = 5). Isolated mucin was purified and printed onto mucin microarrays. Binding of reference strains and three clinical isolates of A. muciniphila and Desulfovibrio spp. to purified mucin was investigated. RESULTS: Both A. muciniphila and Desulfovibro spp. bound to mucin. The reference strain and all clinical isolates of A. muciniphila showed increased binding capacity for UC mucin (p < .005). The Desulfovibrio reference strain showed increased affinity for UC mucin. The mucin binding profiles of clinical isolates of Desulfovibrio spp. were specific to each isolate. Two isolates showed no difference in binding. One UC isolate bound with increased affinity to UC mucin (p < .005). CONCLUSION: These preliminary data suggest that differences exist in the mucin binding capacity of isolates of A. muciniphila and Desulfovibrio spp. This study highlights the mucin microarray platform as a means of studying the ability of bacteria to interact with colonic mucin in health and disease. PMID- 26491871 TI - Panitumumab Use in Metastatic Colorectal Cancer and Patterns of KRAS Testing: Results from a Europe-Wide Physician Survey and Medical Records Review. AB - BACKGROUND: From 2008-2013, the European indication for panitumumab required that patients' tumor KRAS exon 2 mutation status was known prior to starting treatment. To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer (mCRC), two European multi-country, cross-sectional, observational studies were initiated in 2012: a physician survey and a medical records review. The first two out of three planned rounds for each study are reported. METHODS: The primary objective in the physician survey was to estimate the prevalence of KRAS testing, and in the medical records review, it was to evaluate the effect of test results on patterns of panitumumab use. The medical records review study also included a pathologists' survey. RESULTS: In the physician survey, nearly all oncologists (299/301) were aware of the correct panitumumab indication and the need to test patients' tumor KRAS status before treatment with panitumumab. Nearly all oncologists (283/301) had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status. In the medical records review, 97.5% of participating oncologists (77/79) conducted a KRAS test for all of their patients prior to prescribing panitumumab. Four patients (1.3%) did not have tumor KRAS mutation status tested prior to starting panitumumab treatment. Approximately one-quarter of patients (85/306) were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy; of these, 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment. All 56 referred laboratories that participated used a Conformite Europeenne-marked or otherwise validated KRAS detection method, and nearly all (55/56) participated in a quality assurance scheme. CONCLUSIONS: There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients' tumors as being wild-type KRAS prior to treatment with panitumumab, with or without concurrent oxaliplatin-containing therapy. PMID- 26491872 TI - Efficient Mating-Type Switching in Candida glabrata Induces Cell Death. AB - Candida glabrata is an apparently asexual haploid yeast that is phylogenetically closer to Saccharomyces cerevisiae than to Candida albicans. Its genome contains three MAT-like cassettes, MAT, which encodes either MATa or MATalpha information in different strains, and the additional loci, HML and HMR. The genome also contains an HO gene homolog, but this yeast has never been shown to switch mating types spontaneously, as S. cerevisiae does. We have recently sequenced the genomes of the five species that, together with C. glabrata, make up the Nakaseomyces clade. All contain MAT-like cassettes and an HO gene homolog. In this work, we express the HO gene of all Nakaseomyces and of S. cerevisiae in C. glabrata. All can induce mating-type switching, but, despite the larger phylogenetic distance, the most efficient endonuclease is the one from S. cerevisiae. Efficient mating-type switching in C. glabrata is accompanied by a high cell mortality, and sometimes results in conversion of the additional cassette HML. Mortality probably results from the cutting of the HO recognition sites that are present, in HML and possibly HMR, contrary to what happens naturally in S. cerevisiae. This has implications in the life-cycle of C. glabrata, as we show that efficient MAT switching is lethal for most cells, induces chromosomal rearrangements in survivors, and that the endogenous HO is probably rarely active indeed. PMID- 26491873 TI - Rationally Targeted Mutations at the V1V2 Domain of the HIV-1 Envelope to Augment Virus Neutralization by Anti-V1V2 Monoclonal Antibodies. AB - HIV-1 envelope glycoproteins (Env) are the only viral antigens present on the virus surface and serve as the key targets for virus-neutralizing antibodies. However, HIV-1 deploys multiple strategies to shield the vulnerable sites on its Env from neutralizing antibodies. The V1V2 domain located at the apex of the HIV 1 Env spike is known to encompass highly variable loops, but V1V2 also contains immunogenic conserved elements recognized by cross-reactive antibodies. This study evaluates human monoclonal antibodies (mAbs) against V2 epitopes which overlap with the conserved integrin alpha4beta7-binding LDV/I motif, designated as the V2i (integrin) epitopes. We postulate that the V2i Abs have weak or no neutralizing activities because the V2i epitopes are often occluded from antibody recognition. To gain insights into the mechanisms of the V2i occlusion, we evaluated three elements at the distal end of the V1V2 domain shown in the structure of V2i epitope complexed with mAb 830A to be important for antibody recognition of the V2i epitope. Amino-acid substitutions at position 179 that restore the LDV/I motif had minimal effects on virus sensitivity to neutralization by most V2i mAbs. However, a charge change at position 153 in the V1 region significantly increased sensitivity of subtype C virus ZM109 to most V2i mAbs. Separately, a disulfide bond introduced to stabilize the hypervariable region of V2 loop also enhanced virus neutralization by some V2i mAbs, but the effects varied depending on the virus. These data demonstrate that multiple elements within the V1V2 domain act independently and in a virus-dependent fashion to govern the antibody recognition and accessibility of V2i epitopes, suggesting the need for multi-pronged strategies to counter the escape and the shielding mechanisms obstructing the V2i Abs from neutralizing HIV-1. PMID- 26491874 TI - Evidence of Selection against Complex Mitotic-Origin Aneuploidy during Preimplantation Development. AB - Whole-chromosome imbalances affect over half of early human embryos and are the leading cause of pregnancy loss. While these errors frequently arise in oocyte meiosis, many such whole-chromosome abnormalities affecting cleavage-stage embryos are the result of chromosome missegregation occurring during the initial mitotic cell divisions. The first wave of zygotic genome activation at the 4-8 cell stage results in the arrest of a large proportion of embryos, the vast majority of which contain whole-chromosome abnormalities. Thus, the full spectrum of meiotic and mitotic errors can only be detected by sampling after the initial cell divisions, but prior to this selective filter. Here, we apply 24-chromosome preimplantation genetic screening (PGS) to 28,052 single-cell day-3 blastomere biopsies and 18,387 multi-cell day-5 trophectoderm biopsies from 6,366 in vitro fertilization (IVF) cycles. We precisely characterize the rates and patterns of whole-chromosome abnormalities at each developmental stage and distinguish errors of meiotic and mitotic origin without embryo disaggregation, based on informative chromosomal signatures. We show that mitotic errors frequently involve multiple chromosome losses that are not biased toward maternal or paternal homologs. This outcome is characteristic of spindle abnormalities and chaotic cell division detected in previous studies. In contrast to meiotic errors, our data also show that mitotic errors are not significantly associated with maternal age. PGS patients referred due to previous IVF failure had elevated rates of mitotic error, while patients referred due to recurrent pregnancy loss had elevated rates of meiotic error, controlling for maternal age. These results support the conclusion that mitotic error is the predominant mechanism contributing to pregnancy losses occurring prior to blastocyst formation. This high-resolution view of the full spectrum of whole-chromosome abnormalities affecting early embryos provides insight into the cytogenetic mechanisms underlying their formation and the consequences for human fertility. PMID- 26491876 TI - Periconception Maternal Folate Status and Human Embryonic Cerebellum Growth Trajectories: The Rotterdam Predict Study. AB - We aimed to investigate whether periconceptional maternal folate status affects human embryonic cerebellar size and growth trajectories. In a prospective periconceptional cohort participants filled out questionnaires and received weekly transvaginal 3D-ultrasounds between 7+0 and 12+6 weeks gestational age (GA). Viable non-malformed singleton pregnancies were selected for cerebellar measurements; transcerebellar diameter, (TCD), left and right cerebellar diameters (LCD, RCD). Linear mixed models were performed to estimate associations between questionnaire data on the timing of maternal folic acid supplement initiation and longitudinal cerebellar measurements as a function of crown-rump length (CRL) and GA. Maternal red blood cell folate concentrations were analysed before 8 weeks GA to validate the associations. A total of 263 serial high quality three-dimensional ultrasound scans of 135 pregnancies were studied. Preconceptional compared to postconceptional initiation of folic acid use was associated with slightly larger cerebellar diameters per millimetre increase of CRL (TCD: beta = 0.260mm, 95%CI = 0.023-0.491, p<0.05; LCD: beta = 0.171mm, 95%CI = 0.038-0.305, p<0.05; RCD: beta = 0.156mm, 95%CI = 0.032-0.280, p<0.05) and with proportional cerebellar growth (TCD/CRL:beta = 0.015mm/mm, 95%CI = 0.005-0.024, p<0.01; LCD/CRL:beta = 0.012mm/mm, 95%CI = 0.005-0.018, p<0.01; RCD/CRL:beta = 0.011mm/mm, 95%CI = 0.005-0.017, p<0.01). Cerebellar growth was significantly highest in the third quartile of maternal red blood cell folate levels (1538-1813 nmol/L). These first findings show that periconceptional maternal folate status is associated with human embryonic cerebellar development. Implications of these small but significant variations for fetal cerebellar growth trajectories and the child's neurodevelopmental outcome are yet unknown and warrant further investigation. PMID- 26491875 TI - Dengue Virus Infection of Aedes aegypti Requires a Putative Cysteine Rich Venom Protein. AB - Dengue virus (DENV) is a mosquito-borne flavivirus that causes serious human disease and mortality worldwide. There is no specific antiviral therapy or vaccine for DENV infection. Alterations in gene expression during DENV infection of the mosquito and the impact of these changes on virus infection are important events to investigate in hopes of creating new treatments and vaccines. We previously identified 203 genes that were >=5-fold differentially upregulated during flavivirus infection of the mosquito. Here, we examined the impact of silencing 100 of the most highly upregulated gene targets on DENV infection in its mosquito vector. We identified 20 genes that reduced DENV infection by at least 60% when silenced. We focused on one gene, a putative cysteine rich venom protein (SeqID AAEL000379; CRVP379), whose silencing significantly reduced DENV infection in Aedes aegypti cells. Here, we examine the requirement for CRVP379 during DENV infection of the mosquito and investigate the mechanisms surrounding this phenomenon. We also show that blocking CRVP379 protein with either RNAi or specific antisera inhibits DENV infection in Aedes aegypti. This work identifies a novel mosquito gene target for controlling DENV infection in mosquitoes that may also be used to develop broad preventative and therapeutic measures for multiple flaviviruses. PMID- 26491877 TI - Laminar Neural Field Model of Laterally Propagating Waves of Orientation Selectivity. AB - We construct a laminar neural-field model of primary visual cortex (V1) consisting of a superficial layer of neurons that encode the spatial location and orientation of a local visual stimulus coupled to a deep layer of neurons that only encode spatial location. The spatially-structured connections in the deep layer support the propagation of a traveling front, which then drives propagating orientation-dependent activity in the superficial layer. Using a combination of mathematical analysis and numerical simulations, we establish that the existence of a coherent orientation-selective wave relies on the presence of weak, long range connections in the superficial layer that couple cells of similar orientation preference. Moreover, the wave persists in the presence of feedback from the superficial layer to the deep layer. Our results are consistent with recent experimental studies that indicate that deep and superficial layers work in tandem to determine the patterns of cortical activity observed in vivo. PMID- 26491878 TI - The London Exercise And Pregnant smokers (LEAP) trial: a randomised controlled trial of physical activity for smoking cessation in pregnancy with an economic evaluation. AB - BACKGROUND: Smoking during pregnancy is the main preventable cause of poor birth outcomes. Improved methods are needed to help women to stop smoking during pregnancy. Pregnancy provides a compelling rationale for physical activity (PA) interventions as cessation medication is contraindicated or ineffective, and an effective PA intervention could be highly cost-effective. OBJECTIVE: To examine the effectiveness and cost-effectiveness of a PA intervention plus standard behavioural support for smoking cessation relative to behavioural support alone for achieving smoking cessation at the end of pregnancy. DESIGN: Multicentre, two group, pragmatic randomised controlled trial and economic evaluation with follow up at the end of pregnancy and 6 months postnatally. Randomisation was stratified by centre and a computer-generated sequence was used to allocate participants using a 1 : 1 ratio. SETTING: 13 hospitals offering antenatal care in the UK. PARTICIPANTS: Women between 10 and 24 weeks' gestation smoking five or more cigarettes a day before pregnancy and one or more during pregnancy. INTERVENTIONS: Participants were randomised to behavioural support for smoking cessation (control) or behavioural support plus a PA intervention consisting of supervised treadmill exercise plus PA consultations. Neither participants nor researchers were blinded to treatment allocation. MAIN OUTCOME MEASURES: The primary outcome was self-reported, continuous smoking abstinence between a quit date and end of pregnancy, validated by expired carbon monoxide and/or salivary cotinine. Secondary outcomes were maternal weight, depression, birth outcomes, withdrawal symptoms and urges to smoke. The economic evaluation investigated the costs of the PA intervention compared with the control intervention. RESULTS: In total, 789 women were randomised (n = 394 PA, n = 395 control). Four were excluded post randomisation (two had been enrolled twice in sequential pregnancies and two were ineligible and randomised erroneously). The intention-to treat analysis comprised 785 participants (n = 392 PA, n = 393 control). There was no significant difference in the rate of abstinence at the end of pregnancy between the PA group (7.7%) and the control group (6.4%) [odds ratio for PA group abstinence 1.21, 95% confidence interval (CI) 0.70 to 2.10]. For the PA group compared with the control group, there was a 33% (95% CI 14% to 56%), 28% (95% CI 7% to 52%) and 36% (95% CI 12% to 65%) significantly greater increase in self reported minutes of moderate- and vigorous-intensity PA from baseline to 1 week, 4 weeks and 6 weeks respectively. Accelerometer data showed that there was no significant difference in PA levels between the groups. There were no significant differences between the groups for change in maternal weight, depression, withdrawal symptoms or urges to smoke. Adverse events and birth outcomes were similar between the groups except for there being significantly more caesarean births in the control group than in the PA group (28.7% vs. 21.3%; p < 0.023). The PA intervention was less costly than the control intervention by L35 per participant. This was mainly attributable to increased health-care usage in the control group. However, there was considerable statistical uncertainty around this estimate. CONCLUSIONS: During pregnancy, offering an intervention combining supervised exercise and PA counselling does not add to the effectiveness of behavioural support for smoking cessation. Only 10% of participants had PA levels accessed by accelerometer and it is, therefore, unclear whether or not the lack of an effect on the primary outcome is the result of insufficient increases in PA. Research is needed to identify the smoking populations most suitable for PA interventions and methods for increasing PA adherence. TRIAL REGISTRATION: Current Controlled Trials ISRCTN48600346. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 84. See the NIHR Journals Library website for further project information. PMID- 26491879 TI - Mechanics of Viral Chromatin Reveals the Pressurization of Human Adenovirus. AB - Tight confinement of naked genomes within some viruses results in high internal pressure that facilitates their translocation into the host. Adenovirus, however, encodes histone-like proteins that associate with its genome resulting in a confined DNA-protein condensate (core). Cleavage of these proteins during maturation decreases core condensation and primes the virion for proper uncoating via unidentified mechanisms. Here we open individual, mature and immature adenovirus cages to directly probe the mechanics of their chromatin-like cores. We find that immature cores are more rigid than the mature ones, unveiling a mechanical signature of their condensation level. Conversely, intact mature particles demonstrate more rigidity than immature or empty ones. DNA-condensing polyamines revert the mechanics of mature capsid and cores to near-immature values. The combination of these experiments reveals the pressurization of adenovirus particles induced by maturation. We estimate a pressure of ~30 atm by continuous elasticity, which is corroborated by modeling the adenovirus mini chromosome as a confined compact polymer. We propose this pressurization as a mechanism that facilitates initiating the stepwise disassembly of the mature particle, enabling its escape from the endosome and final genome release at the nuclear pore. PMID- 26491880 TI - Visible-Light-Promoted Photoredox Syntheses of alpha,beta-Epoxy Ketones from Styrenes and Benzaldehydes under Alkaline Conditions. AB - A range of styrenes and benzaldehydes were smoothly combined to form alpha,beta epoxy ketones under the synergistic actions of photocatalyst Ru(bpy)3Cl2, tert butyl hydroperoxide (t-BuOOH), cesium carbonate (Cs2CO3), and visible light irradiation. The process likely proceeds through visible-light-enabled photocatalytic generations of acyl radicals as key intermediates. PMID- 26491881 TI - Phosphonic Acid-Functionalized Polyurethane Dispersions with Improved Adhesion Properties. AB - A facile route to phosphorus-functionalized polyurethane dispersions (P-PUDs) with improved adhesion properties is presented. (Bis)phosphonic acid moieties serve as adhesion promoting sites that are covalently attached via an end-capping reaction to isocyanate-reactive polyurethane particles under aqueous conditions. The synthetic approach circumvents solubility issues, offers great flexibility in terms of polyurethane composition, and allows for the synthesis of semicrystalline systems with thermomechanical response due to reversible physical cross-linking. Differential scanning calorimetry (DSC) is used to investigate the effect of functionalization on the semicrystallinity. The end-capping conversion was determined via inductively-coupled plasma optical emission spectroscopy (ICP OES) and was surprisingly found to be almost independent of the stoichiometry of reaction, suggesting an adsorption-dominated process. Particle charge detection (PCD) experiments reveal that a dense surface coverage of phosphonic acid groups can be attained and that, at high functionalization degrees, the phosphonic adhesion moieties are partially dragged inside the colloidal P-PUD particle. Quartz crystal microbalance with dissipation (QCMD) investigations conducted with hydroxyapatite (HAP) and stainless steel sensors as model surfaces show a greatly enhanced affinity of the aqueous P-PUDs and furthermore indicate polymer chain rearrangements and autonomous film formation under wet conditions. Due to their facile synthesis, significantly improved adhesion, and variable film properties, P-PUD systems such as the one described here are believed to be of great interest for multiple applications, e.g., adhesives, paints, anticorrosion, or dentistry. PMID- 26491882 TI - Intramolecular Direct Arylation of 3-Halo-2-pyrones and 2-Coumarins. AB - Direct arylation represents a favorable alternative to traditional cross-coupling and has found widespread use with simple aryls and robust heterocycles. Herein a direct arylation protocol has been optimized and applied to 2-pyrones, which are delicate and privileged biological motifs. Regioselective halogenation at the 3 position allows intramolecular coupling by activation of a pyrone C-Br or C-Cl bond and a phenoxy C-H bond. Importantly, electron-poor phenoxy substrates also worked well. The methodology was extended to 2-coumarins and applied to the synthesis of flemichapparin C and a novel analogue. Deuterium isotope effects, typical of a concerted metalation-deprotonation (CMD) mechanism, were observed in the case of a bromopyrone, but a highly unusual, inverse kinetic isotope effect was evident using a chlorocoumarin, implying that a different mechanism is operating. PMID- 26491883 TI - Quantifying the pi-Stacking Interactions in Nitroarene Binding Sites of Proteins. AB - Stacking interactions in nitroarene binding sites of proteins were studied through analyses of structures in the protein data bank (PDB), as well as DFT and ab initio computations applied to model systems. Stacked dimers of mono-, di-, and trinitrobenzene with the amino acid side chains histidine (His), phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp) were optimized at the B97-D/TZV(2d,2p) level of theory. Binding energies for the global minimum dimer geometries were further refined at the estimated CCSD(T)/aug-cc-pVTZ level of theory. The results show that the interactions between aromatic amino acids and nitroarenes are very strong (up to -14.6 kcal mol(-1)), and the regiochemistry of the nitro substituents plays a significant role in the relative monomer orientations and strength of the interaction. In contrast to model stacked benzene dimers, effects of nitro substituents in stacking complexes with aromatic amino acid side chains are not perfectly additive. This is attributed to direct interactions of the nitro substituents with functional groups in the amino acid side chain. Overall, the strength of stacking interactions with these nitrobenzenes follows the order Trp > Tyr > Phe ~ His. We also analyzed nitroarene binding sites in the PDB. Out of 216 selected crystal structures containing nitroarene ligands, 191 have nearby aromatic residues, providing 65 examples of pi-stacking interactions involving a nitroarene. Of these, the representations of the different aromatic amino acids (Trp > Tyr > Phe > His) are correlated with the strength of model complexes of nitroarenes, with the exception of His. B97-D computations applied to complexes extracted from these crystal structures reveal that pi-stacking interactions between the nitroarene and aromatic amino acid side chains exhibit a broad range of strengths, with many contributing significantly to binding. PMID- 26491884 TI - Beyond Single-Wavelength SHG Measurements: Spectrally-Resolved SHG Studies of Tetraphosphonate Ester Coordination Polymers. AB - Powder second-harmonic generation (SHG) efficiencies are usually measured at single wavelengths. In the present work, we provide a proof of concept of spectrally resolved powder SHG measured for a newly obtained series of three non centrosymmetric coordination polymers (CPs). CPs are constructed from tetrahedral linker-tetraphenylmethane-based tetraphosphonate octaethyl ester and cobalt(II) ions of mixed, octahedral (Oh), and tetrahedral (Td), geometries and different sets of donors (CoO6 vs CoX3O). Isostructurality of the obtained materials allowed for the determination of anion-dependent tunability of SHG optical spectra and their relationship with solid-state absorption spectra. PMID- 26491885 TI - Phospholipid Topography of Whole-Body Sections of the Anopheles stephensi Mosquito, Characterized by High-Resolution Atmospheric-Pressure Scanning Microprobe Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging. AB - High-resolution atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) has been employed to study the molecular anatomical structure of rodent malaria vector Anopheles stephensi mosquitoes. A dedicated sample preparation method was developed which suits both, the special tissue properties of the sample and the requirements of high-resolution MALDI imaging. Embedding in 5% carboxymethylcellulose (CMC) was used to maintain the tissue integrity of the whole mosquitoes, being very soft, fragile, and difficult to handle. Individual lipid compounds, specifically representing certain cell types, tissue areas, or organs, were detected and imaged in 20 MUm-thick whole-body tissue sections at a spatial resolution of 12 MUm per image pixel. Mass spectrometric data and information quality were based on a mass resolution of 70,000 (at m/z 200) and a mass accuracy of better than 2 ppm in positive-ion mode on an orbital trapping mass spectrometer. A total of 67 imaged lipids were assigned by database search and, in a number of cases, identified via additional MS/MS fragmentation studies directly from tissue. This is the first MSI study at 12 MUm spatial resolution of the malaria vector Anopheles. The study provides insights into the molecular anatomy of Anopheles stephensi and the distribution and localization of major classes of glycerophospholipids and sphingolipids. These data can be a basis for future experiments, investigating, e.g., the metabolism of Plasmodium-infected and uninfected Anopheles mosquitoes. PMID- 26491888 TI - Bimodal Latex Effect on Spin-Coated Thin Conductive Polymer-Single-Walled Carbon Nanotube Layers. AB - We synthesize two differently sized poly(methyl methacrylate-co-tert-butyl acrylate) latexes by emulsion polymerization and mix these with a sonicated single-walled carbon nanotube (SWCNT) dispersion, in order to prepare 3% SWCNT composite mixtures. We spin-coat these mixtures at various spin-speed rates and spin times over a glass substrate, producing a thin, transparent, solid, conductive layer. Keeping the amount of SWCNTs constant, we vary the weight fraction of our smaller 30-nm latex particles relative to the larger 70-nm-sized ones. We find a maximum in the electrical conductivity up to 370 S/m as a function of the weight fraction of smaller particles, depending on the overall solid content, the spin speed, and the spin time. This maximum occurs at 3-5% of the smaller latex particles. We also find a more than 2-fold increase in conductivity parallel to the radius of spin-coating than perpendicular to it. Atomic force microscopy points at the existence of lanes of latex particles in the spin-coated thin layer, while large-area transmission electron microscopy demonstrates that the SWCNTs are aligned over a grid fixed on the glass substrate during the spin-coating process. We extract the conductivity distribution on the surface of the thin film and translate this into the direction of the SWCNTs in it. PMID- 26491886 TI - Concise Enantioselective Synthesis of Oxygenated Steroids via Sequential Copper(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions. AB - A new scalable enantioselective approach to functionalized oxygenated steroids is described. This strategy is based on chiral bis(oxazoline) copper(II) complex catalyzed enantioselective and diastereoselective Michael reactions of cyclic ketoesters and enones to install vicinal quaternary and tertiary stereocenters. In addition, the utility of copper(II) salts as highly active catalysts for the Michael reactions of traditionally unreactive beta,beta'-enones and substituted beta,beta'-ketoesters that results in unprecedented Michael adducts containing vicinal all-carbon quaternary centers is also demonstrated. The Michael adducts subsequently undergo base-promoted diastereoselective aldol cascade reactions resulting in the natural or unnatural steroid skeletons. The experimental and computational studies suggest that the torsional strain effects arising from the presence of the Delta(5)-unsaturation are key controlling elements for the formation of the natural cardenolide scaffold. The described method enables expedient generation of polycyclic molecules including modified steroidal scaffolds as well as challenging-to-synthesize Hajos-Parrish and Wieland-Miescher ketones. PMID- 26491887 TI - Quantitative Proteomics Reveals That the Inhibition of Na(+)/K(+)-ATPase Activity Affects S-Phase Progression Leading to a Chromosome Segregation Disorder by Attenuating the Aurora A Function in Hepatocellular Carcinoma Cells. AB - Many studies have shown the Na(+)/K(+)-ATPase (NKA) might be a potential target for anticancer therapy. Cardiac glycosides (CGs), as a family of naturally compounds, inhibited the NKA activity. The present study investigates the antitumor effect of ouabain and elucidates the pharmacological mechanisms of CG activity in liver cancer HepG2 cell using SILAC coupled to LC-MS/MS method. Bioinformatics analysis of 330 proteins that were changed in cells under treatment with 0.5 MUmol/L ouabain showed that the biological processes are associated with an acute inflammatory response, cell cycle, oxidation reduction, chromosome segregation, and DNA metabolism. We confirmed that ouabain induced chromosome segregation disorder and S-cell cycle block by decreasing the expression of AURKA, SMC2, Cyclin D, and p-CDK1 as well as increasing the expression of p53. We found that the overexpression or inhibition of AURKA significantly reduced or enhanced the ouabain-mediated the anticancer effects. Our findings suggest that AURKA is involved in the anticancer mechanisms of ouabain in HepG2 cells. PMID- 26491889 TI - Impact of Ialuril Soft Gels in reducing urinary toxicity during radical hypofractionated radiotherapy in prostate cancer: a preliminary experience. AB - BACKGROUND: The aim of this study was to evaluate the impact of Ialuril Soft Gels in reducing acute genito-urinary (GU) toxicity in patients with prostate cancer treated with volumetric-modulated arc radiotherapy. METHODS: Forty patients were prospectively recruited. A moderate hypofractionation in 28 fractions ("hypo moderate") was prescribed in 20 patients, while an extreme hypofractionation ("hypo-extreme") in 5 fractions was prescribed in 20 patients. The International Prostate Symptom Score (IPSS) questionnaire was administered in all cases before and after radiotherapy (RT). GU toxicity was evaluated according to CTCAE v4.0. Patients of each group ("hypo-moderate" and "hypo-extreme") were randomized (1:1) to receive RT alone or RT combined with Ialuril Soft Gels. RESULTS: In "hypo moderate" patients treated with Ialuril Soft Gels the following GU toxicity was reported: G0 3, G1 6, G2 1, G3 0. In the arm treated without Ialuril Soft Gels: G0 0, G1 7, G2 2, G3 1. In "hypo-extreme" arm treated with Ialuril Soft Gels the following GU toxicity was recorded: G0 7, G1 2, G2 1, G3 in 0; while in the arm treated without Ialuril Soft Gels: G0 5, G1 2, G2 2, G3 1. IPSS was unchanged in "hypo-moderate" and "hypo-extreme" groups and patients treated with Ialuril Soft Gels, with a median value of 6 and 5 respectively. In patients treated without Ialuril Soft Gels an increased IPSS was reported in "hypo-moderate" and "hypo extreme" from 6 to 8 and from 3.5 to 4.5, respectively. At statistical analysis (Fisher's exact text) Ialuril Soft Gels was associated with IPSS improvement (P=0.03). CONCLUSION: Ialuril Soft Gels seems to have a beneficial role in reducing GU toxicity without worsening the IPSS. PMID- 26491890 TI - Developing Rapport and Therapeutic Alliance During Telemental Health Sessions with Children and Adolescents. AB - OBJECTIVE: The purpose of this study was to describe the special considerations for building rapport and establishing a therapeutic alliance when conducting mental health evaluations for children and adolescents via videoconferencing. METHODS: The authors review the literature and describe their experience in conducting mental health evaluations, developing rapport, and establishing a therapeutic alliance during telemental health practice. RESULTS: Clinical need and shortages of clinicians with expertise in evaluating mental conditions for children and adolescents in underserved communities have stimulated the rapid expansion of telemental health programs while the research base continues to develop. The emerging evidence base and clinical experience suggest that teleclinicians can, and do, build rapport and establish a therapeutic alliance during telemental health sessions with youth and families. Families may be more accepting of telemental health approaches than clinicians. The impact that technology, equipment, site staff, community supports, cultural identification, and teleclinicians' characteristics have on building rapport and establishing a therapeutic alliance should be considered when establishing a telemental health service. Staff at the patient site and referring providers have a valuable role in supporting the therapeutic alliance between telemental health providers and their patients, and ultimately supporting the success of a telemental health program. CONCLUSIONS: Teleclinicians are creative in transcending the videoconferencing technology to evaluate patients using guideline-based care. Further research is needed to determine how clinicians build rapport and establish a therapeutic alliance during telemental health sessions, and whether the therapeutic alliance is associated with the accuracy of evaluation and outcomes. PMID- 26491891 TI - High-Resolution 3-T Endorectal Prostate MRI: A Multireader Study of Radiologist Preference and Perceived Interpretive Quality of 2D and 3D T2-Weighted Fast Spin Echo MR Images. AB - OBJECTIVE: The goal of this study was to compare the perceived quality of 3-T axial T2-weighted high-resolution 2D and high-resolution 3D fast spin-echo (FSE) endorectal MR images of the prostate. MATERIALS AND METHODS: Six radiologists independently reviewed paired 3-T axial T2-weighted high-resolution 2D and 3D FSE endorectal MR images of the prostates of 85 men in two sessions. In the first session (n = 85), each reader selected his or her preferred images; in the second session (n = 28), they determined their confidence in tumor identification and compared the depiction of the prostatic anatomy, tumor conspicuity, and subjective intrinsic image quality of images. A meta-analysis using a random effects model, logistic regression, and the paired Wilcoxon rank-sum test were used for statistical analyses. RESULTS: Three readers preferred the 2D acquisition (67-89%), and the other three preferred the 3D images (70-80%). The option for one of the techniques was not associated with any of the predictor variables. The 2D FSE images were significantly sharper than 3D FSE (p < 0.001) and significantly more likely to exhibit other (nonmotion) artifacts (p = 0.002). No other statistically significant differences were found. CONCLUSION: Our results suggest that there are strong individual preferences for the 2D or 3D FSE MR images, but there was a wide variability among radiologists. There were differences in image quality (image sharpness and presence of artifacts not related to motion) but not in the sequences' ability to delineate the glandular anatomy and depict a cancerous tumor. PMID- 26491892 TI - Breast Imaging: A Paradigm for Accountable Care Organizations. AB - OBJECTIVE: Accountable care organizations (ACOs) are being promoted by the Centers of Medicare Services as alternative payment models for radiology reimbursement. Because of its clinical orientation, focus on prevention, standardized reporting, quality orientation through mandatory accreditation, and value demonstration through established outcome metrics, breast imaging offers a unique paradigm for the ACO model in radiology. CONCLUSION: In radiology, breast imaging represents the paradigm for ACOs. PMID- 26491893 TI - Imaging of Conductive Hearing Loss With a Normal Tympanic Membrane. AB - OBJECTIVE: This article presents an approach to imaging conductive hearing loss in patients with normal tympanic membranes and discusses entities that should be checked as the radiologist evaluates this potentially complicated issue. CONCLUSION: Conductive hearing loss in a patient with a normal tympanic membrane is a complicated condition that requires a careful imaging approach. Imaging should focus on otosclerosis, and possible mimics and potential surgical considerations should be evaluated. The radiologist should examine the ossicular chain and the round window and keep in mind that a defect in the superior semicircular canal can disturb the hydraulic integrity of the labyrinth. PMID- 26491895 TI - Imaging of Cerebrovascular Disease in Pregnancy and the Puerperium. AB - OBJECTIVE: The purpose of this article is to review the unique physiologic changes that characterize pregnancy and the puerperium, some that substantially affect the cerebrovascular system. Conditions that can cause neurologic deterioration and share features with preeclampsia-eclampsia include postpartum angiopathy, reversible cerebral vasoconstriction syndrome, posterior reversible encephalopathy syndrome, and amniotic fluid embolism. Other conditions not specific to this patient group include cerebral venous thrombosis, cervicocephalic arterial dissection, ischemic stroke, and hemorrhagic stroke, which can pose specific diagnostic and therapeutic challenges. CONCLUSION: Radiologists must be familiar with the imaging findings of cerebrovascular complications and pathologic entities encountered during pregnancy and the puerperium. Ongoing improvements in understanding of molecular changes during pregnancy and the puerperium and advances in diagnostic tests should allow radiologists to continue to make important contributions to the care of this patient population. PMID- 26491896 TI - An unusual complication of vesicoamniotic shunt: coiling of the shunt around lower extremity associated with dislodgement. PMID- 26491894 TI - Current Status of Hybrid PET/MRI in Oncologic Imaging. AB - OBJECTIVE: This review article explores recent advancements in PET/MRI for clinical oncologic imaging. CONCLUSION: Radiologists should understand the technical considerations that have made PET/MRI feasible within clinical workflows, the role of PET tracers for imaging various molecular targets in oncology, and advantages of hybrid PET/MRI compared with PET/CT. To facilitate this understanding, we discuss clinical examples (including gliomas, breast cancer, bone metastases, prostate cancer, bladder cancer, gynecologic malignancy, and lymphoma) as well as future directions, challenges, and areas for continued technical optimization for PET/MRI. PMID- 26491897 TI - Rapid isolation of dengue-neutralizing antibodies from single cell-sorted human antigen-specific memory B-cell cultures. AB - Monitoring antigen-specific memory B cells and the antibodies they encode is important for understanding the specificity, breadth and duration of immune response to an infection or vaccination. The antibodies isolated could further help design vaccine antigens for raising relevant protective immune responses. However, developing assays to measure and isolate antigen-specific memory B cells is technically challenging due to the low frequencies of these cells that exist in the circulating blood. Here, we describe a flow cytometry method to identify and isolate dengue envelope-specific memory B cells using a labeled dengue envelope protein. We enumerated dengue-envelope specific memory B cells from a cohort of dengue seropositive donors using this direct flow cytometry assay. A more established and conventional assay, the cultured B ELISPOT, was used as a benchmark comparator. Furthermore, we were able to confirm the single-sorted memory B-cell specificity by culturing B cells and differentiating them into plasma cells using cell lines expressing CD40L. The culture supernatants were assayed for antigen binding and the ability of the antibodies to neutralize the cognate dengue virus. Moreover, we successfully isolated the heavy and light Ig sequences and expressed them as full-length recombinant antibodies to reproduce the activity seen in culture supernatants. Mapping of these antibodies revealed a novel epitope for dengue 2 virus serotype. In conclusion, we established a reproducible methodology to enumerate antigen-specific memory B cells and assay their encoded antibodies for functional characterization. PMID- 26491899 TI - Vulvar Cancer with Bilateral Axillary Lymph Node Metastasis. PMID- 26491898 TI - FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12-ATG5 conjugate, leading to the delay of cartilage development in achondroplasia. AB - FGFR3 (fibroblast growth factor receptor 3) is a negative regulator of endochondral ossification. Gain-of-function mutations in FGFR3 are responsible for achondroplasia, the most common genetic form of dwarfism in humans. Autophagy, an evolutionarily conserved catabolic process, maintains chondrocyte viability in the growth plate under stress conditions, such as hypoxia and nutritional deficiencies. However, the role of autophagy and its underlying molecular mechanisms in achondroplasia remain elusive. In this study, we found activated FGFR3 signaling inhibited autophagic activity in chondrocytes, both in vivo and in vitro. By employing an embryonic bone culture system, we demonstrated that treatment with autophagy inhibitor 3-MA or chloroquine led to cartilage growth retardation, which mimics the effect of activated-FGFR3 signaling on chondrogenesis. Furthermore, we found that FGFR3 interacted with ATG12-ATG5 conjugate by binding to ATG5. More intriguingly, FGFR3 signaling was found to decrease the protein level of ATG12-ATG5 conjugate. Consistently, using in vitro chondrogenic differentiation assay system, we showed that the ATG12-ATG5 conjugate was essential for the viability and differentiation of chondrocytes. Transient transfection of ATG5 partially rescued FGFR3-mediated inhibition on chondrocyte viability and differentiation. Our findings reveal that FGFR3 inhibits the autophagic activity by decreasing the ATG12-ATG5 conjugate level, which may play an essential role in the pathogenesis of achondroplasia. PMID- 26491900 TI - Confidence and connectedness: Indigenous Maori women's views on personal safety in the context of intimate partner violence. AB - Maori (New Zealand) women, similar to women belonging to Indigenous and minority groups globally, have high levels of lifetime abuse, assault, and homicide, and are over-represented in events that compromise their safety. We sought insights into how Maori women view safety. Twenty Maori women's narratives revealed safety as a holistic concept involving a number of different elements. We found women had developed an acute sense of the concept of safety. They had firm views and clear strategies to maintain their own safety and that of their female family and friends. These women also provided insights into their experiences of feeling unsafe. PMID- 26491902 TI - A Surrogate Technique for Investigating Deterministic Dynamics in Discrete Human Movement. AB - Entropy is an effective tool for investigation of human movement variability. However, before applying entropy, it can be beneficial to employ analyses to confirm that observed data are not solely the result of stochastic processes. This can be achieved by contrasting observed data with that produced using surrogate methods. Unlike continuous movement, no appropriate method has been applied to discrete human movement. This article proposes a novel surrogate method for discrete movement data, outlining the processes for determining its critical values. The proposed technique reliably generated surrogates for discrete joint angle time series, destroying fine-scale dynamics of the observed signal, while maintaining macro structural characteristics. Comparison of entropy estimates indicated observed signals had greater regularity than surrogates and were not only the result of stochastic but also deterministic processes. The proposed surrogate method is both a valid and reliable technique to investigate determinism in other discrete human movement time series. PMID- 26491903 TI - Clinical, Radiographic, and Pathologic Findings in Patients Undergoing Reoperation Following Radiation Therapy and Temozolomide for Newly Diagnosed Glioblastoma. AB - PURPOSE: Patients with glioblastoma (GBM) frequently deteriorate clinically and radiographically after chemoradiation and may require repeat surgical intervention. We attempted to correlate pathologic findings with preoperative clinical characteristics and survival in patients undergoing reoperation for GBM. MATERIALS AND METHODS: Patients eligible for this retrospective analysis had pathologically confirmed GBM diagnosed between 2005 and 2010, received standard radiation and temozolomide, and underwent repeat resection within 18 months of diagnosis. RESULTS: Thirty-eight patients were identified. Median age was 56 years (range, 30 to 80 y), 55% were male, and 66% had baseline performance status >=90%. Median survival was 16.3 months (95% confidence interval [CI], 13.3-19.8) from initial surgery. At reoperation, 21% of patients had no pathologically evident tumor. Median time from initial diagnosis to second surgery was similar in patients with and without evident tumor (8.5 vs. 8.8 mo, respectively). Patients without evident tumor tended to have a worse performance status. Median overall survival from second surgery was 7 months (95% CI, 4.2-10.1) and 9.1 months (95% CI, 2.1-25.3) for patients with and without evident tumor, respectively. Multivariate proportional hazards analysis showed a hazard ratio for death of 0.61 (95% CI, 0.25-1.49) for patients without evident tumor after adjusting for Karnofsky performance status and second surgical procedure. CONCLUSIONS: GBM patients with and without disease recurrence have similar clinical characteristics at the time of second surgical resection. Pathologic outcomes were not correlated with specific clinical or radiologic characteristics, including the time from diagnosis to reoperation. There was a trend toward improved overall survival among patients without evident tumor at reoperation. PMID- 26491904 TI - Expression of Sex Determining Region Y-Box 2 and Pancreatic and Duodenal Homeobox 1 in Pancreatic Neuroendocrine Tumors. AB - OBJECTIVE: The World Health Organization 2010 classification divides pancreatic neuroendocrine tumors (p-NETs) entity to well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC) by Ki-67 index. The aim of this study is elucidate the pathophysiology and tumor biology of p-NETs. METHODS: We assessed the expression of transcription factors sex determining region Y-box 2 (SOX2) and pancreatic and duodenal homeobox 1 (Pdx1)) essential for the normal fetal development of pancreatic neuroendocrine cells in 46 surgically resected p-NETs by immunohistochemistry. The relationship of expression levels of these factors and clinicopathological factors were analyzed. RESULTS: SOX2 was positive in 6 p-NETs (13.0%). Five of 7 NEC patients showed positive for SOX2. SOX2 was highly (sensitivity 71%) and specifically (specificity 97%) expressed in NEC. Patients with SOX2 positive p-NET showed the significantly shorter disease-free and overall survival than patients with SOX2 negative p-NET. High Pdx1 expression was seen in 25 p-NET patients (54.3%). None of the NEC patients showed high Pdx1 expression. There was a significant reverse correlation between SOX2 and Pdx1 expression. CONCLUSIONS: The expression patterns of SOX2 and Pdx1 highly correlated with prognosis of p-NETs. These expression patterns may represent the biological and pathophysiological difference of p-NETs and indicate the origin of tumor. PMID- 26491905 TI - Surgery for Localized Pancreatic Cancer: The Trend Is Not Improving. AB - OBJECTIVES: The aim of this study was to examine the trend in the use of surgery for localized pancreatic adenocarcinoma for the past 2 decades using the Surveillance, Epidemiology, and End Results database. METHODS: We identified a cohort of patients who received a diagnosis of localized pancreatic adenocarcinoma between 1988 and 2010 in the United States. Univariate and multivariate methods were used to determine factors associated with not receiving surgery. Cox proportional hazards regression modeling was used to determine factors associated with survival. RESULTS: Of 6742 patients with a diagnosis of localized pancreatic adenocarcinoma, 1715 patients (25.4%) underwent surgery. There was no significant change in use of surgery over time. Patients were less likely to undergo surgery if they were older than 50 years, black, unmarried, and located outside the East and had pancreatic head or body lesions, higher tumor grades, or tumor size greater than 2 cm (P < 0.0001). Receiving surgery had the most significant impact on the hazard of disease-specific death (hazards ratio, 1.41; 95% confidence interval, 1.29-1.53; P < 0.0001). CONCLUSIONS: In contrast to recent studies that suggest an increasing use of surgery, the present study demonstrates that there has been no change in the rate of use of surgery in patients with localized pancreatic disease. PMID- 26491906 TI - Double Filtration Plasma Apheresis Shortens Hospital Admission Duration of Patients With Severe Hypertriglyceridemia-Associated Acute Pancreatitis. AB - OBJECTIVES: The treatment effectiveness of double filtration plasma apheresis (DFPP) on severe hypertriglyceridemia-associated acute pancreatitis (STAP) has been questioned because the currently defined serum triglyceride level--1000 mg/dL--is too low for STAP. Given this, we aimed to investigate DFPP effectiveness when we elevated STAP definition to 5000 mg/dL serum triglyceride. METHODS: We performed nested case-control studies for STAP patients and divided them into groups "with" or "without" DFPP. We further recruited outpatient asymptomatic hypertriglyceridemia patients with STAP history, then divided them into groups "with" or "without" prophylactic DFPP once every 3 to 6 months for 2 years. We observed hospitalization duration and STAP recurrence between patients with and patients without DFPP. RESULTS: Twelve STAP patients receiving DFPP had a median hospitalization of 5 days, whereas 24 patients without DFPP had 10 days (P = 0.009). Six outpatient referrals with STAP history receiving prophylactic DFPP showed no STAP recurrences whereas 6 without DFPP showed 3 recurrences (P = 0.046). For the 25 patients whose serum triglyceride exceeded 5000 mg/dL, 11 receiving DFPP had median hospitalization of 5 days while 14 without DFPP had 11 days (P = 0.012). CONCLUSIONS: When applied to serum triglyceride in excess of 5000 mg/dL, DFPP removes oxidized and inflammatory lipoproteins, shortens hospitalization duration, and minimizes STAP recurrence. PMID- 26491907 TI - Mitogen-Activated Protein Kinases Are Activated in Placental Injury in Rat Model of Acute Pancreatitis in Pregnancy. AB - OBJECTIVES: To establish a rat model of acute pancreatitis in pregnancy (APIP) and evaluate its general presentations, assess placental injury, and discuss possible mechanisms. METHODS: The APIP rat model was induced by sodium taurocholate in Sprague-Dawley rats of later gestation. Normal and sham-operated (SO) rats in later gestation were set as controls, 3 time points were set in SO and APIP groups to determine optimal modeling time. Histological changes of pancreas and placenta were assessed. Placental injury was determined by immunohistochemistry stain of caspase-3. Serum levels of amylase, lipase, and Ca; proinflammatory cytokines as tumor necrosis factor-alpha, interleukin-1beta (IL 1beta), IL-6, and anti-inflammatory cytokine IL-10 by enzyme-linked immunosorbent assay; mitogen-activated protein kinases and their phosphorylated forms by Western blotting. RESULTS: Pancreatic necrotizing and placental injury occurred in time-dependent patterns. Serum levels of amylase and lipase significantly increased but Ca decreased; tumor necrosis factor-alpha, IL-1beta, IL-6, and IL 10 were all increased in the APIP group; c-Jun N-terminal kinase, p38, and ERK1/2 were activated but with different distributing patterns in the placenta. CONCLUSIONS: Placental injury is involved in the rat model of APIP, and a modeling time of 6 hours is optimal and conducive to further studies; c-Jun N terminal kinase and p38 may play important roles in placental injury during APIP. PMID- 26491908 TI - T1-weighted Dynamic Contrast-enhanced MR Imaging of the Lung in Asthma: Semiquantitative Analysis for the Assessment of Contrast Agent Kinetic Characteristics. AB - PURPOSE: To evaluate the contrast agent kinetics of dynamic contrast material enhanced (DCE) magnetic resonance (MR) imaging in healthy lungs and asthmatic lungs by using non-model-based semiquantitative parameters and to explore the relationships with pulmonary function testing and eosinophil level. MATERIALS AND METHODS: The study was approved by the National Research Ethical Committee (reference no. 11/NW/0387), and written informed consent was obtained from all individuals. Ten healthy subjects and 30 patients with asthma underwent pulmonary function tests, blood and sputum eosinophil counts, and 1.5-T DCE MR imaging within 7 days. Semiquantitative parameters of contrast agent kinetics were calculated from the relative signal intensity-time course curves on a pixel-by pixel basis and were summarized by using whole-lung median values. The distribution heterogeneity was assessed by using the regional coefficient of variation. DCE MR imaging readouts were compared between groups by using one-way analysis of variance, and the relationships with pulmonary function testing and eosinophil counts were assessed by using Pearson correlation analysis. RESULTS: Asthmatic patients showed significantly lower peak enhancement (P < .001) and initial areas under the relative signal intensity curve in the first 60 seconds (P = .002) and significantly reduced late-phase washout slope (P = .002) when compared with healthy control subjects. The distribution heterogeneity of bolus arrival time (P = .029), time to peak (P = .008), upslope of the first-pass peak (P = .011), and late-phase washout slope (P = .032), estimated by using the median coefficient of variation, were significantly higher in asthmatic patients than in healthy control subjects. These imaging readouts also showed significant linear correlations with measurements of pulmonary function testing but not with eosinophil level in patients with asthma. CONCLUSION: The contrast agent kinetic characteristics of T1-weighted DCE MR images of asthmatic lungs are different from those of healthy lungs and are related to measurements of pulmonary function testing but not to eosinophil level. PMID- 26491910 TI - Predictors of Recurrent Patellar Instability in Children and Adolescents After First-time Dislocation. AB - BACKGROUND: Patellar dislocations are one of the most common knee injuries in children and adolescents and are challenging to treat. Recurrence rates are relatively high and many patients have functional limitations, even in the absence of a recurrent instability episode. The purpose of this study was to examine the risk factors in patients with first-time patellofemoral dislocations to develop a prediction model of recurrence. METHODS: A single institution retrospective review of all patients with a first-time patellofemoral dislocation from 2002 to 2013 was performed. Demographic risk factors (age, sex, laterality, mechanism of injury, and history of contralateral patellar dislocation) and radiographic risk factors (increased patella height, trochlear dysplasia, and skeletal immaturity) were examined. Patella height was measured using Caton Deschamps index (CDI). Trochlear dysplasia was assessed using the 2-grade Dejour classification and skeletal immaturity was assessed based on the distal femur and proximal tibia physis (open, closing, or closed). RESULTS: In total, 266 knees in 250 patients were included in the study. Of these, 222 (83.5%) were treated nonoperatively and 44 (16.5%) were treated surgically. Of the knees treated nonoperatively, 77 (34.7%) had a recurrence. Significant risk factors for recurrence on univariate analysis were age 14 years and below, history of contralateral patellar dislocation, trochlear dysplasia, skeletal immaturity, and a CDI>1.45. Multivariate analysis was performed and trochlear dysplasia and skeletal immaturity were the most significant factors with odds ratios of 3.56 and 2.23, respectively. The presence of all 4 multivariate risk factors (CDI>1.45, history of contralateral patellar dislocation, trochlear dysplasia, and skeletal immaturity) had a predicted risk of recurrence of 88%. The presence of any 3 risk factors had a predicted risk of about 75% and the presence of any 2 risk factors had a predicted risk of about 55%. CONCLUSIONS: Trochlear dysplasia, skeletal immaturity, CDI>1.45, and a history of contralateral patellar dislocation were all significant risk factors for recurrence in patients with first-time patellar dislocations. A predictive model for calculation of recurrence risk was developed for any combination of the different risk factors. This information is useful when counseling patients and their families after first-time patellar dislocation about prognosis and potential outcomes. LEVEL OF EVIDENCE: Level IV-retrospective case series. PMID- 26491909 TI - Fully Automated Quantitative Estimation of Volumetric Breast Density from Digital Breast Tomosynthesis Images: Preliminary Results and Comparison with Digital Mammography and MR Imaging. AB - PURPOSE: To assess a fully automated method for volumetric breast density (VBD) estimation in digital breast tomosynthesis (DBT) and to compare the findings with those of full-field digital mammography (FFDM) and magnetic resonance (MR) imaging. MATERIALS AND METHODS: Bilateral DBT images, FFDM images, and sagittal breast MR images were retrospectively collected from 68 women who underwent breast cancer screening from October 2011 to September 2012 with institutional review board-approved, HIPAA-compliant protocols. A fully automated computer algorithm was developed for quantitative estimation of VBD from DBT images. FFDM images were processed with U.S. Food and Drug Administration-cleared software, and the MR images were processed with a previously validated automated algorithm to obtain corresponding VBD estimates. Pearson correlation and analysis of variance with Tukey-Kramer post hoc correction were used to compare the multimodality VBD estimates. RESULTS: Estimates of VBD from DBT were significantly correlated with FFDM-based and MR imaging-based estimates with r = 0.83 (95% confidence interval [CI]: 0.74, 0.90) and r = 0.88 (95% CI: 0.82, 0.93), respectively (P < .001). The corresponding correlation between FFDM and MR imaging was r = 0.84 (95% CI: 0.76, 0.90). However, statistically significant differences after post hoc correction (alpha = 0.05) were found among VBD estimates from FFDM (mean +/- standard deviation, 11.1% +/- 7.0) relative to MR imaging (16.6% +/- 11.2) and DBT (19.8% +/- 16.2). Differences between VDB estimates from DBT and MR imaging were not significant (P = .26). CONCLUSION: Fully automated VBD estimates from DBT, FFDM, and MR imaging are strongly correlated but show statistically significant differences. Therefore, absolute differences in VBD between FFDM, DBT, and MR imaging should be considered in breast cancer risk assessment. PMID- 26491911 TI - Preoperative Computer Simulation and Patient-specific Guides are Safe and Effective to Correct Forearm Deformity in Children. AB - BACKGROUND: Posttraumatic and congenital forearm deformities in children can be difficult to appreciate in all planes. In cases of distal radioulnar joint instability and loss of forearm rotation, surgical correction is challenging. Advances in 3-dimensional printing allow creation of custom guides at a reasonable cost, enabling precise correction of the deformity in all planes. METHODS: Nineteen children with deformity of the forearm had corrective osteotomies performed using preoperative 3-dimensional computer modeling and patient-specific surgical guides. Surgicase software was used for 3-dimensional planning of the corrective osteotomy, by superimposing a mirror image of the unaffected side as a template. Based upon this planning, patient-specific surgical guides were manufactured. Radiographic and clinical outcomes were assessed. RESULTS: Three patients had a diagnosis of multiple hereditary exostoses, and one of Madelung's deformity. The remaining 15 patients had a diagnosis of fracture malunion. Average preoperative angulation of both the radius and ulna was 23 degrees. For the patients with fracture malunions, the time from injury to surgery ranged from 6 months to 8 years. Twelve patients underwent osteotomies of both the radius and ulna, 5 had osteotomies of the radius alone, and 2 had a single osteotomy of the ulna only. All osteotomies went on to unite and no patient lost range of motion. Preoperative arc of forearm rotation averaged 101 degrees (range 0 to 180 degrees). Postoperatively, this improved to 133 degrees (range 85 to 180 degrees). Eight patients had distal radioulnar instability preoperatively, all of which normalized after surgery. There were 4 complications: 1 hypertrophic scar, 1 subject with extensor pollicis longus weakness, and 2 transient sensory losses in the superficial radial nerve distribution. CONCLUSIONS: This case series demonstrates that 3-dimensional computer modeling permits complex and multiple osteotomies to be done safely to achieve deformity correction in children. Limitations in forearm rotation and distal radioulnar malalignment can be reliably improved using this technique. LEVEL OF EVIDENCE: Level IV-retrospective case series. PMID- 26491912 TI - Delay in the Diagnosis of Stable Slipped Capital Femoral Epiphysis. AB - INTRODUCTION: Delays in the diagnosis of stable slipped capital femoral epiphysis (SCFE) is common due to the vague symptomatology and the lack of awareness of this entity by healthcare providers. Delays in the diagnosis of this condition can lead to poor outcomes for the patients. This study was designed to identify factors that contributed to delays in the diagnosis or the treatment of patients with SCFE seen at our institution. METHODS: A retrospective chart review of patients with the diagnosis of a stable SCFE who had undergone screw stabilization between 1989 and 2010 at our hospital was performed. For each patient, demographic data, the date of initial onset of symptoms, the date of the first visit to the medical provider, the type of provider seen initially (orthopaedic surgeon or not), the date of diagnosis of SCFE, the type of physician who made the diagnosis (orthopaedic surgeon or not), and the date of surgery were recorded. For each patient, the presenting symptom was recorded as hip, thigh, or knee pain. The effect of demographic data, presenting symptoms, and the type of initial provider seen on the delay to diagnosis was studied using 2 Cox models. RESULTS: A total of 149 patients with 196 stable SCFE were included. The average time from the first physician visit to diagnosis was 94 days in the group seen by a nonorthopaedic provider compared with an average of 2.9 days in the group seen by an orthopaedist (P<0.05). Diagnosis was made in 1 week only in 19% of the group seen by a nonorthopaedic provider versus 97% in the group seen by orthopaedic surgeons. It took significantly longer to be diagnosed with SCFE in patients who presented with initial knee pain (P=0.0097) compared with those who presented with hip pain at the initial visit. CONCLUSIONS: This study shows a significant delay in the diagnosis of SCFE in the United States, particularly in patients seen by nonorthopaedic providers initially. LEVEL OF EVIDENCE: Level III-prognostic. PMID- 26491913 TI - Long-term Outcome of Internal Tibial Derotation Osteotomies in Children With Cerebral Palsy. AB - BACKGROUND: External tibial torsion (ETT) is a common bony deformity in children with cerebral palsy (CP). The current recommended treatment is tibial derotation osteotomy (TDO) to improve gait biomechanics. Satisfactory short-term results after TDO have been reported but long-term results have not been studied. The purpose of this study was to evaluate the long-term outcome following TDO to correct ETT in ambulatory children with CP. METHODS: Following IRB approval, gait kinematics and passive range of motion measurements were retrospectively evaluated in children with spastic CP who underwent TDO due to ETT comparing preoperative (E0), short-term postoperative (E1; 1 to 3 y post), and long-term postoperative (E2; >5 y post) results. Limbs were categorized as corrected, undercorrected, or overcorrected at both E1 and E2, by comparing mean tibial rotation (MTR) in gait to a group of typically developing children. Age at surgery, E0 MTR, E0 gait velocity, gross motor function classification system (GMFCS) score, and foot deformity were evaluated to determine their influence on long-term results. RESULTS: The study sample consisted of 43 legs (with E0 and E2) and 22 legs (with E0, E1, and E2). The mean age at surgery was 10.3+/-3.4 years (range, 6 to 19.2 y). In the group MTR trended toward improvement moving from -26+/-17 degrees (E0, external negative) to -16+/-16 degrees (E1) and relapsed to -23+/-17 degrees at the long term (P=0.071, E0/E1; P=0.589, E0/E2). Improvement was also seen in the transmalleolar axis (P=0.074), mean ankle rotation, and mean foot orientation (P<0.05, E0/E2). At the long-term evaluation, 16 legs (37%) were found to be in the kinematic corrected group, 25 legs (58%) in the kinematic undercorrected group, and 2 legs (5%) in the kinematic overcorrected group. There were no significant differences between the corrected and undercorrected groups of children with respect to age at surgery, GMFCS, E0 MTR, gait velocity, or foot deformity. CONCLUSIONS: Although internal TDO improves ETT in the short term, recurrence is frequent with an apparent developmental trend toward external rotation of the tibia. LEVELS OF EVIDENCE: Level IV-therapeutic study. PMID- 26491915 TI - Ultrasound Examination for Infants Born Breech by Elective Cesarean Section With a Normal Hip Exam for Instability. AB - INTRODUCTION: Because of the risk of developmental dysplasia of the hip in infants born breech-despite a normal physical exam-the American Academy of Pediatrics (AAP) guidelines recommend ultrasound (US) hip imaging at 6 weeks of age for breech females and optional imaging for breech males. The purpose of this study is to report US results and follow-up of infants born breech with a normal physical exam. METHODS: The electronic medical record for children born at 1 hospital from 2008 to 2011 was reviewed. Data were analyzed for sex, birth weight, breech position, birth order, ethnicity, US and x-ray results, follow-up, and cost. RESULTS: A total of 237 infants were born breech with a normal physical examination, all delivered by cesarean section. Of the infants, 55% were male and 45% female. About 151 breech infants (64%) with a normal Barlow and Ortolani exam had a precautionary hip US as recommended by the AAP performed at an average of 7 weeks of age. Eighty-six breech infants (35%) did not have an US and were followed clinically. Of the 151 infants that had an US, 140 (93%) were read as normal. None had a dislocated hip. Two patients had a normal physical exam but laxity on US. These 2 patients were the only infants treated in a Pavlik harness. A pediatric orthopaedic surgeon followed those with subtle US findings and no laxity until normal. CONCLUSIONS: The decision by the AAP to recommend US screening at 6 weeks of age for infants with a normal physical exam but breech position was based on an extensive literature review and expert opinion. Not all pediatricians are following the AAP guidelines. The decision to perform an US should be done on a case-by-case basis by the examining physician. A more practical, cost-effective strategy would be to skip the US if the physical exam is normal and simply obtain an AP pelvis x-ray at 4 months. LEVEL OF EVIDENCE: Level III-this is a case-control study investigating the outcomes of infants on data drawn from the electronic medical record. PMID- 26491914 TI - Long-term Outcome of External Tibial Derotation Osteotomies in Children With Cerebral Palsy. AB - BACKGROUND: Internal tibial torsion (ITT) is a common boney deformity in children with cerebral palsy (CP). The current recommended treatment is tibial derotation osteotomy (TDO) to improve gait biomechanics. Satisfactory short-term results after TDO have been reported but long-term results have not been studied. The purpose of this study was to evaluate the long-term outcome after external TDO performed to correct ITT in ambulatory children with CP. METHODS: Following IRB approval, gait kinematics and passive range of motion measurements were retrospectively evaluated in children with spastic CP who underwent TDO due to ITT comparing preoperative (E0), short-term postoperative (E1; 1 to 3 y post), and long-term postoperative (E2; >5 y post) results. Limbs were categorized as corrected, undercorrected, or overcorrected at both E1 and E2, by comparing the subjects mean tibial rotation (MTR) in gait to a group of typically developing children. Age at surgery, preop MTR (at E0), preop gait velocity (at E0), gross motor function classification system score, and foot deformity were evaluated to determine their influence on long-term results. RESULTS: The study sample consisted of 36 legs (with E0 and E2) and 17 legs (with E0, E1, and E2). The mean age at surgery was 7.4+/-2.8 (range, 4 to 16.6) years. Comparing the changes over time, kinematic MTR improved from 17+/-11 degrees initially (E0) to -10+/-14 degrees short term (E1) and progressed to -23+/-13 degrees long term (E2) (P<0.05 E0/E1/E2; internal rotation is positive). At E2, 16 legs (44%) were found to be in the kinematic corrected group and 20 legs (56%) in the kinematic overcorrected group. There were no significant differences between the corrected and overcorrected groups of children in respect to age of surgery, gross motor function classification system, E0 MTR, gait velocity, or foot deformity. CONCLUSIONS: Although external TDO is an accepted form of treatment in children with CP, in the long term a tendency to move into external tibial torsion is common. Therefore, caution is warranted with children who initially present with ITT to avoid overcorrection. LEVEL OF EVIDENCE: Level IV-therapeutic study. PMID- 26491916 TI - An Unusual Presentation of Myositis Ossificans in a Pediatric Patient. AB - BACKGROUND: Myositis ossificans (MO) is a rare, non-neoplastic lesion characterized by heterotopic ossification of soft tissue. The condition is predominantly seen in young adults and adolescents and is most commonly secondary to trauma. Although the exact etiology remains unclear, patients typically present with pain and restricted range of motion following trauma or overuse. MO rarely presents in the popliteal fossa of adult patients and has not been previously reported in that of a pediatric patient. METHODS: We present a 12-year old patient with no history of direct trauma with MO in the right popliteal fossa, a highly unusual location. Initial x-rays failed to show the lesion; however, later radiographs showed an ossified mass. At peak dimensions, the ossification measured 3.8 cm anteroposterior*2.5 cm transverse*3.2 cm craniocaudal. After 14 months of observation and conservative therapy, the mass was excised. RESULTS: The patient was ultimately able to return to full activity. Radiographs taken 14 months after the excision showed no signs of recurrence of the lesion. CONCLUSIONS: To our knowledge, this is the first reported case of MO excised from the popliteal fossa of a pediatric patient and followed for >1 year. LEVEL OF EVIDENCE: Level IV-case report. PMID- 26491917 TI - Two Techniques for Retrograde Flexible Intramedullary Fixation of Pediatric Femur Fractures: All-Lateral Entry Versus Medial and Lateral Entry Point. AB - BACKGROUND: Multiple techniques for flexible intramedullary nailing (FIMN) of pediatric femur fractures have been described. To our knowledge, no study has compared combined medial-lateral (ML) entry versus all-lateral (AL) entry retrograde nailing. This study compares surgical outcomes, radiographic outcomes, and complication rates between these 2 techniques. METHODS: A retrospective review of a consecutive series of patients treated by retrograde, dual FIMN of femur fractures was performed from 2005 to 2012. Demographics and operative data were recorded. Radiographs were analyzed for fracture pattern, fracture location, percent canal fill by the nails, as well as shortening and angulation at the time of osseous union. Rates of symptomatic implants and their removal were noted. Data were compared between patients treated with medial and lateral entry (ML group) nailing and those treated with all-lateral entry (AL group) nailing using the Student t test and correlation statistics. RESULTS: Of the 244 children with femoral shaft fractures treated with retrograde FIMN using Ender stainless steel nails, 156 were in the ML group and 88 were in the AL group. There were no statistical differences in sex (74% vs. 82% males), age (8.0 vs. 8.6 y), weight (29.4 vs. 31.1 kg), or fracture pattern between the 2 groups. The average total anesthesia time was less in the AL group (133 vs. 103 min) (P<0.0001). There was no difference between the techniques in shortening (3.9 vs. 3.0 mm), coronal angulation (2.9 vs. 2.6 degrees), or sagittal angulation (3.3 vs. 2.7 degrees) at union. In the AL group, there was a correlation between canal fill and reduced shortening at union. No differences were found in the presence or degree of varus alignment, procurvatum deformity, or recurvatum angulation between the constructs. There were 5 malunions in the AL group and 9 malunions in the ML group (5.7% vs. 5.8%, P=1). The incidence of having a healed femur fracture with >10 degrees of valgus was higher in the AL group (0% vs. 3.4%) (P=0.04). There were no differences between the groups in the rate of symptomatic implant removal or surgical complications. CONCLUSIONS: The AL entry technique for FIMN of pediatric femur fractures is 30 minutes faster without worse final fracture alignment, additional complications, or increased rates of symptomatic implants. When using the AL technique, specific attention should be paid to percentage of canal fill and ensuring that the fracture is not reduced in a valgus position. LEVEL OF EVIDENCE: Level III-therapeutic. PMID- 26491918 TI - Classification of Computer-Aided Design-Computer-Aided Manufacturing Applications for the Reconstruction of Cranio-Maxillo-Facial Defects. AB - PURPOSE: To gain insight into the methodology of different computer-aided design computer-aided manufacturing (CAD-CAM) applications for the reconstruction of cranio-maxillo-facial (CMF) defects. METHODS: We reviewed and analyzed the available literature pertaining to CAD-CAM for use in CMF reconstruction. RESULTS: We proposed a classification system of the techniques of implant and cutting, drilling, and/or guiding template design and manufacturing. The system consisted of 4 classes (I-IV). These classes combine techniques used for both the implant and template to most accurately describe the methodology used. CONCLUSIONS: Our classification system can be widely applied. It should facilitate communication and immediate understanding of the methodology of CAD CAM applications for the reconstruction of CMF defects. PMID- 26491919 TI - The Psychologic and Psychosocial Impact of Otoplasty on Children and Adults. AB - BACKGROUND: In previous studies, our research group already evaluated the impact of aesthetic surgery on "quality of life" (QoL). This study evaluates QoL factors and perceptions of well-being after otoplasty as a single indication. METHODS: Eighty-one patients who underwent otoplasty were divided into three age groups: Youth 1 (Y1) = 8-12 years (n = 17), Youth 1 (Y2) = 13-17 years (n = 13), and Adult >=18 years (n = 51). For competitive analysis, 2 groups of tests were used: a standardized self-assessment test on life satisfaction (FLZ(M)), the Glasgow Benefit Inventory (GBI), the standardized Rosenberg Self-Esteem Scale (RSES), the standardized Freiburg Personality Inventory (FPI-R), the Patient Health Questionnaire 4 (PHQ-4), and a self-developed and indication-specific questionnaire for "Adult" group. The tools for the groups Y1 and Y2 were: PHQ-4, KINDL(R), the Glasgow Child Benefit Inventory (GCBI), and a self-developed and indication-specific questionnaire either. RESULTS: Our data bared numerous significant improvements on patients' QoL. In the items "friends" (P = 0.036) and "freedom of anxiety" (P = 0.034) of the FLZ(M), important improvements were found. In section "satisfaction with appearance" (body image), the items "hair" (P = 0.003) and "ear" (P = 0.034) were to point out. The RSES (P = 0.001) and the FPI-R (P = 0.035) data indicated a well-balanced emotional stability. The results of the GBI/GCBI (P = 0.000/P = 0.000) showed a higher QoL of postsurgery patients. The data of the KINDL questionnaire provided increasing values in the modules "friends" (P = 0.033) and "total score" (P = 0.040) for boys of the ages 8 to 12. For all age groups, there was a less affinity to depression (PHQ-4) and a high satisfaction with the aesthetical result (indication-specific questionnaire). CONCLUSIONS: This study showed higher QoL in all age groups by using standardized tools in comparison with the norm data. The knowledge of postoperative psychologic benefits, such as "satisfaction with appearance" (body image) and "different areas of life," self-confidence, and self-esteem as well as lower level of depression support meaningfulness of otoplasty. LEVEL OF EVIDENCE: Therapeutic, III: Retrospective cohort or comparative study. PMID- 26491922 TI - Fabrication of Patient Specific Titanium Implants for Correction of Cranial Defects: A Technique to Improve Anatomic Contours and Accuracy. AB - Hard tissue cranial defects may result from traumatic or iatrogenic etiology and warrants adequate reconstruction to provide protection to the underlying brain and cosmesis. Various techniques have been described in the literature for fabrication of patient specific titanium cranial implants. The process of fabrication of titanium patient specific implants (PSI) can be broadly classified into indirect and direct techniques. With the improvements in the medical imaging and computational modeling, direct technique of computer assisted prefabricated patient specific implants have gained popularity. However indirect method of PSI fabrication hold some specific advantage. Here we describe a technique for fabrication of titanium PSI by combining the principles of direct and indirect methods for reconstruction of cranial defects. PMID- 26491923 TI - Comparative Finite Element Analysis of Short Implants and Lateralization of the Inferior Alveolar Nerve With Different Prosthesis Heights. AB - The lateralization of the inferior alveolar nerve (LIAN) and short implants are efficient options for rehabilitation of the posterior atrophic mandible. However, the loss of bone leads to prosthesis with greater height and lever effect that in turn can have different impact on treatments. Through the finite element method, the present study tests the hypothesis that conventional implants placed under LIAN and short implants have similar risk of bone loss regarding variable height of the crown and that crown-to-implant ratio is not a reliable resource to evaluate risk in these treatments. Computed tomography scans of mandibles were processed and implants and prosthetic components were reverse engineered for reconstruction of three-dimensional models to simulate 3 elements fixed partial dentures supported by 2 osseointegrated implants. The models of implants were based on MK III implants (Nobel Biocare, Zurich, Switzerland) with 4 mm in diameter by 7 mm in length representing short implants, and 15 mm in length representing implants used in LIAN. The implant/crown ratio for short implants was 1:1.5, 1:2, and 1:2.5 and LIAN models were modeled with exactly the same prosthesis, resulting in implant/crown ratios of 1:0.67, 1:0.89, and 1:1.12. The results partially rejected the hypothesis that LIAN and short implants have similar risk of bone loss, showing that although LIAN results were better in the models evaluated, the variations in height had proportionally similar impact on both treatments and accepted the hypothesis that crown-to-implant ratio was not a reliable resource to evaluate risk. PMID- 26491927 TI - The Precise Repositioning Instrument for Genioplasty. AB - To improve the surgical precision of genioplasty, the authors develop and validate the precise repositioning instrument for genioplasty, which can guide the precise repositioning of chin bone segment truncated during genioplasty. The patent application for the precise repositioning instrument for genioplasty is already submitted (Patent No. 201410032051. 2, China). The accuracy of genioplasty can be improved significantly by using the precise repositioning instrument to locate the chin bone segment truncated. And this method is quick, simple, and safe. PMID- 26491930 TI - Cleft and Craniofacial Care in Palestine: Breaking From the Cycle of the Past. AB - The history of cleft care in the Palestinian territories has largely been sporadic and dependent on foreign practitioners. This article discusses the recent history and the current status of cleft care in Palestine, including the quality of training among Palestinian cleft practitioners and limitations in operating room capacity. The discussion concludes with a future model of cleft care that focuses on carefully crafted programs to train surgeons (this is broadly applicable to other disciplines involved in cleft care), working in partnership with a designated National Cleft Organization, operationalized within a centrally located and accessible Cleft Center. PMID- 26491931 TI - Three-Dimensional Printing Technology for Medial Orbital Wall Fractures. PMID- 26491932 TI - Complete Mulberry Hypertrophy and Conchachoanal Polyp of Inferior Turbinate. PMID- 26491934 TI - A Simple Method of Neonatal Ear Molding for Treatment of Stahl Ear Deformity. PMID- 26491935 TI - The Diagnostic Accuracy of Gluteal Trigger Points to Differentiate Radicular From Nonradicular Low Back Pain. AB - OBJECTIVES: Low back pain (LBP) is highly prevalent and costly to the society. Previous studies have shown an association between radicular LBP and trigger points (TrPs) in the superior-lateral quadrant of the gluteal area (GTrP). The objective of current study was to evaluate the diagnostic value of GTrP to predict nerve root involvement among patients with LBP. MATERIALS AND METHODS: In a prospective, diagnostic accuracy study 325 consecutive patients with LBP were recruited. At first step, patients were evaluated for the presence or absence of the GTrP. A different investigator, blinded to the GTrP findings, then performed history taking and physical examination. Subsequently, all patients underwent a lumbar spine magnetic resonance imaging and, when indicated, electrodiagnostic tests. On the basis of the clinical and ancillary tests findings, a multidisciplinary panel of experts (the "reference standard"), blinded to the GTrP evaluation, allocated patients to radicular versus nonradicular LBP groups. The agreement between the GTrP findings, as a diagnostic test and the reference standard allocation was evaluated in a 2 by 2 contingency table. RESULTS: The specificity of the GTrP test was 91.4% and its sensitivity was 74.1%. The area under the receiver operating characteristic curve was 0.827 (0.781 to 0.874). Positive likelihood ratio was 8.62 and negative likelihood ratio was 0.28. Positive and negative predictive values were 91.9% and 72.7%, respectively. DISCUSSION: As a clinical finding, TrPs in superior-lateral quadrant of gluteal area are highly specific indicators for radicular LBP. Incorporating these TrPs evaluation in routine physical examination of patients with LBP could decrease the need for more costly, time-consuming, and invasive diagnostic tests. PMID- 26491936 TI - Anticonvulsants or Antidepressants in Combination Pharmacotherapy for Treatment of Neuropathic Pain in Cancer Patients: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To investigate the efficacy of anticonvulsants or antidepressants in combination pharmacotherapy for treatment of neuropathic pain in cancer patients. MATERIALS AND METHODS: We systematically searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and the metaRegister of Controlled Trials for randomized controlled trials that compared anticonvulsants or antidepressants in combination pharmacotherapy (experimental group) with treatments without anticonvulsants or antidepressants (control group) for neuropathic pain in cancer patients. Risk of bias was evaluated in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was a mean difference (MD) in change in global pain analyzed by a random-effects model. RESULTS: Eight trials met the inclusion criteria with a total of 1359 participants of whom 698 received an experimental intervention. The MD in change in global pain suggested a favorable association with anticonvulsants or antidepressants in combination pharmacotherapy compared with control groups (MD, -0.41; 95% confidence interval, -0.70 to -0.12) with no heterogeneity across trials (I=0%). The MD in change estimated in all sensitivity analyses ranged from -0.36 to -0.47, suggesting that these effects were consistent across different study designs and statistical assumptions. CONCLUSIONS: Anticonvulsants or antidepressants in combination pharmacotherapy reduce neuropathic pain in cancer patients compared with treatments without anticonvulsants or antidepressants. Limited evidence precludes a recommendation on specific adjuvants in combination pharmacotherapy. PMID- 26491937 TI - The Course of the Spatial Extent of Pain in Nonspecific Chronic Back Pain: A Prospective Population-based Cohort Study With Clinical Evaluation. AB - OBJECTIVES: Longitudinal population-based studies on the natural course of nonspecific chronic back pain (nsCBP) concerning the spatial extent of pain are scarce. This study aims to assess the natural course of nsCBP patients concerning their spatial extent of pain and physical impairment over time. METHODS: Analyses were based on a prospective, population-based survey with clinical evaluation. A representative population-based sample of 4000 German adults was sent a pain questionnaire. Patients mentioning nsCBP in the questionnaire were invited to a comprehensive clinical evaluation, including 1- and 2-year follow-ups. On the basis of pain drawings, the course of the spatial extent of pain over time was classified as "constant-local," "constant-widespread," "constant-amelioration," "constant-spreading," or "variable." Physical impairment was assessed by the Back Performance Scale as an objective clinical assessment tool that measures self reported activity limitation in daily functioning caused by nsCBP. RESULTS: Pain drawings and physical assessment from 3 visits were available from 165 patients. The course of the spatial extent of pain was constant-local in 39.4% and constant widespread in 18.2% of all patients, whereas 11.5% reported a variable course. Constant-amelioration was observed in 18.2% and constant-spreading was observed in 12.7%. Physical impairment remained unchanged over the time in all groups and was worst in the constant-widespread group. DISCUSSION: Most nsCBP patients report a stable pain extent over the time of the study, whereas a constant spread of pain is observed only in a minority of nsCBP patients. These findings challenge the concept of a continuous transition from local to widespread pain. PMID- 26491939 TI - Halocuprate(I) zigzag chain structures with N-methylated DABCO cations--bright metal-centered luminescence and thermally activated color shifts. AB - Two compounds 1,4-dimethyl-1,4-diazoniabicyclo[2.2.2]octane catena-tetra-MU-halo dicuprate(I) with DABCOMe2 Cu2X4 (1: X = Br, 2: X = I) were synthesized by hydrothermal reaction of copper(I) halides with the corresponding 1,4 diazoniabicyclo[2.2.2]octane (DABCO) dihydrohalides in an acetonitrile/methanol mixture. Both compounds crystallize monoclinically, 1 with a = 9.169(4) A, b = 10.916(6) A, c = 15.349(6) A, beta = 93.93(2) degrees , V = 1533(1) A(3), Z = 4, space group P2(1)/n (no. 14) and 2 with a = 15.826(9) A, b = 9.476(5) A, c = 22.90(2) A, beta = 90.56(5) degrees , V = 3434(5) A(3), Z = 8, space group P2(1) (no. 4), respectively (lattice constants refined from powder diffraction data measured at 293 K). The cations in both compounds are formed by in situ N methylation of DABCOH2(2+) cations by methanol in a S(N)2 reaction. Both compounds contain an anionic copper(I) halide chain structure consisting of trans edge-sharing CuX4 tetrahedra. The chains are strongly kinked at every 2(nd) junction thus forming a zigzag structure. The shortest halide-halide distances are observed between the halide ions of adjacent tetrahedra which are approaching each other due to the kinking. This structure type shows a specific luminescence behavior. Under optical excitation, the compounds exhibit yellow (1) and green (2) emission with photoluminescence quantum yields of Phi(PL) = 52 and 4%, respectively, at ambient temperature. According to DFT and TDDFT calculations, the emission is assigned to be a phosphorescence essentially involving a metal centered transition between the HOMO consisting mainly of copper 3d and halide p orbitals and the LUMO consisting mainly of copper 4s and 4p orbitals. The temperature dependence of the emission spectra, decay times, and quantum yields has been investigated in detail, especially for 1. From the resulting trends it can be concluded that the emission for T<= 100 K stems from energetically lower lying copper halide segments. Such segments represent the structural motif of the halocuprate(I) chains. With increasing temperature energetically higher lying segments are populated which also emit, but open the pathway for thermally activated energy transfer to quenching defects. PMID- 26491938 TI - The Pelvis and Beyond: Musculoskeletal Tender Points in Women With Chronic Pelvic Pain. AB - OBJECTIVE: To determine the feasibility of a detailed pain sensitivity assessment using body-wide musculoskeletal tender points (TPs) in women with different types of chronic pelvic pain (CPP) and compare phenotypic differences. MATERIALS AND METHODS: Seventy women with CPP and 35 pain-free women underwent musculoskeletal evaluation of TPs in the pelvic floor, abdomen, groin, inner thigh, and all 18 fibromyalgia TPs. Patients scored elicited pain on a numeric rating scale. TP pain scores were used for intergroup comparison and intragroup correlation. RESULTS: Women with CPP were grouped as having either bladder pain syndrome (BPS, n=24) or myofascial pelvic pain (MPP, n=11) singularly or both concomitantly (BPS+MPP, n=35). TP pain scores for all evaluations were higher in women with CPP compared with healthy women (P<0.001). Women with BPS+MPP had elevated TP pain for each evaluation compared with women with BPS alone. Pelvic floor and fibromyalgia TP scores correlated strongly in the MPP group, moderately in the BPS+MPP group, and weakly in the BPS alone group. Although some moderate and strong correlations between different body locations were present in all 3 groups, only the BPS+MPP group showed moderate to strong correlations between all body TPs. CONCLUSIONS: Detailed musculoskeletal evaluation of women with CPP is feasible and well tolerated. Careful phenotyping differentiated BPS, MPP, and BPS+MPP groups. Attending to the differences between these groups clinically may lead to more effective treatment strategies and improved outcomes for patients with CPP. PMID- 26491941 TI - FaceTime validation study: Low-cost streaming video for cytology adequacy assessment. AB - BACKGROUND: Adequacy assessment for fine-needle aspiration procedures is a standard of care in large medical centers. Although the benefits of this approach include higher adequacy rates with fewer passes, it costs cytopathologist time and affects other clinical responsibilities. The objective of the current study was to evaluate the use of mobile video streaming (FaceTime) technology with the help of smartphone adapters attached to microscopes for remote adequacy assessment of cytologic samples. METHODS: The study consisted of 2 phases: Phase 1 was a retrospective assessment of 25 samples by a primary pathologist with simultaneous streaming to a second pathologist using a smartphone (iPhone/iPad) FaceTime connection. Data on the adequacy of each sample and preliminary diagnoses were recorded. In phase 2, live cases were assessed prospectively by an onsite primary pathologist and by a remote pathologist using an iPhone/iPad FaceTime connection. The testing phase involved prospective assessment of additional samples with a resident or cytotechnologist as the slide driver. RESULTS: In phase 1, retrospective evaluation of 25 samples yielded considerable agreement (22 of 25 samples; 88%) between onsite and remote adequacy assessments. Three samples (12%) yielded results that did not agree, including 2 samples that were read as adequate in the onsite evaluation that were assessed as indeterminate using FaceTime. In phase 2 and in the testing phase, 14 samples exhibited considerable agreement on both adequacy and preliminary diagnosis (6 samples in phase 2 and 8 samples in the testing phase) and are currently available for reporting. Problems encountered include software version standardization, camera alignment, and (rarely) comprehension of the audio stream. CONCLUSIONS: The current data indicate that iPhone/iPad FaceTime technology can be used to perform remote adequacy assessments of fine-needle aspirations and can help save valuable time for pathologists. PMID- 26491942 TI - Developmental compartments in the larval trachea of Drosophila. AB - The Drosophila tracheal system is a branched tubular network that forms in the embryo by a post-mitotic program of morphogenesis. In third instar larvae (L3), cells constituting the second tracheal metamere (Tr2) reenter the cell cycle. Clonal analysis of L3 Tr2 revealed that dividing cells in the dorsal trunk, dorsal branch and transverse connective branches respect lineage restriction boundaries near branch junctions. These boundaries corresponded to domains of gene expression, for example where cells expressing Spalt, Delta and Serrate in the dorsal trunk meet vein-expressing cells in the dorsal branch or transverse connective. Notch signaling was activated to one side of these borders and was required for the identity, specializations and segregation of border cells. These findings suggest that Tr2 is comprised of developmental compartments and that developmental compartments are an organizational feature relevant to branched tubular networks. PMID- 26491944 TI - Expression signature based on TP53 target genes doesn't predict response to TP53 MDM2 inhibitor in wild type TP53 tumors. AB - A number of TP53-MDM2 inhibitors are currently under investigation as therapeutic agents in a variety of clinical trials in patients with TP53 wild type tumors. Not all wild type TP53 tumors are sensitive to such inhibitors. In an attempt to improve selection of patients with TP53 wild type tumors, an mRNA expression signature based on 13 TP53 transcriptional target genes was recently developed (Jeay et al. 2015). Careful reanalysis of TP53 status in the study validation data set of cancer cell lines considered to be TP53 wild type detected TP53 inactivating alterations in 23% of cell lines. The subsequent reanalysis of the remaining TP53 wild type cell lines clearly demonstrated that unfortunately the 13-gene signature cannot predict response to TP53-MDM2 inhibitor in TP53 wild type tumors. PMID- 26491943 TI - Dna2 nuclease-helicase structure, mechanism and regulation by Rpa. AB - The Dna2 nuclease-helicase maintains genomic integrity by processing DNA double strand breaks, Okazaki fragments and stalled replication forks. Dna2 requires ssDNA ends, and is dependent on the ssDNA-binding protein Rpa, which controls cleavage polarity. Here we present the 2.3 A structure of intact mouse Dna2 bound to a 15-nucleotide ssDNA. The nuclease active site is embedded in a long, narrow tunnel through which the DNA has to thread. The helicase domain is required for DNA binding but not threading. We also present the structure of a flexibly tethered Dna2-Rpa interaction that recruits Dna2 to Rpa-coated DNA. We establish that a second Dna2-Rpa interaction is mutually exclusive with Rpa-DNA interactions and mediates the displacement of Rpa from ssDNA. This interaction occurs at the nuclease tunnel entrance and the 5' end of the Rpa-DNA complex. Hence, it only displaces Rpa from the 5' but not 3' end, explaining how Rpa regulates cleavage polarity. PMID- 26491945 TI - Modulation of pain via expectation of its location. AB - BACKGROUND: The spatial precision of expectancy effects on pain is unclear. We hypothesized that expecting nociceptive stimuli at particular skin sites would have an analgesic effect on nociceptive stimuli presented between them (middle zone). METHODS: Laser stimuli (evoking pin-prick pain) were delivered to three discrete skin zones on the forearm, under two conditions. During 'Localization', participants' expectation of stimuli was spatially divided between two locations (expected stimuli in only the outer two skin zones): pain intensity and stimulus location were judged. During 'No-localization' (control condition), participants had no expectation concerning stimulus location; only pain intensity was rated. Additional experiments assessed the importance of the actual location on the forearm by: shifting all skin zones proximally towards the elbow (control for joint proximity, Experiment 2); adding a fourth zone distally (control for interaction between joint proximity and enhanced distal inhibition, Experiment 3). RESULTS: All experiments demonstrated spatially specific pain modulation, but only Experiment 2 (near elbow) supported our hypothesis: middle zone pain intensity was significantly lower (p = 0.02) during Localization than No localization. Experiment 1 (near wrist) found reduced pain intensity during Localization only for the distal zone (p = 0.04). Experiment 3 confirmed this effect: reduced pain during Localization occurred only for the most distal zone (p = 0.046). CONCLUSION: Expecting a painful stimulus in non-adjacent skin sites has spatially specific effects on pain modulation, but this reflects an interaction between the expected location of stimulation and the actual location. This suggests a more complex connection between somatotopic maps and nociceptive modulation than previously thought; several distinct mechanisms likely contribute. PMID- 26491946 TI - Saltwater Upconing Due to Cyclic Pumping by Horizontal Wells in Freshwater Lenses. AB - This article deals with the quantification of saltwater upconing below horizontal wells in freshwater lenses using analytical solutions as a computationally fast alternative to numerical simulations. Comparisons between analytical calculations and numerical simulations are presented regarding three aspects: (1) cyclic pumping; (2) dispersion; and (3) finite horizontal wells in a finite domain (a freshwater lens). Various hydrogeological conditions and pumping regimes within a dry half year are considered. The results show that the influence of elastic and phreatic storage (which are not taken into account in the analytical solutions) on the upconing of the interface is minimal. Furthermore, the analytical calculations based on the interface approach compare well with numerical simulations as long as the dimensionless interface upconing is below 1/3, which is in line with previous studies on steady pumping. Superimposing an analytical solution for mixing by dispersion below the well over an analytical solution based on the interface approach is appropriate in case the vertical flow velocity around the interface is nearly constant but should not be used for estimating the salinity of the pumped groundwater. The analytical calculations of interface upconing below a finite horizontal well compare well with the numerical simulations in case the distance between the horizontal well and the initial interface does not vary significantly along the well and in case the natural fluctuation of the freshwater lens is small. In order to maintain a low level of salinity in the well during a dry half year, the dimensionless analytically calculated interface upconing should stay below 0.25. PMID- 26491947 TI - Household Air Pollution, Intermediate Outcomes, and Major Adverse Cardiovascular Events. PMID- 26491949 TI - Direct C-H Bond Arylation of Thienyl Thioamides Catalyzed by Pd-Phenanthroline Complexes. AB - A direct C-H bond arylation method for thienyl thioamides catalyzed by [Pd(phen)2](PF6)2 was developed. This reaction selectively afforded 2 monoarylated products, while the corresponding amide thiophene derivatives furnished 2,5-diarylated products. Mechanistic studies revealed that a Pd(II) bisthioamide complex should be the active species for the reaction of thienyl thioamides in the presence of catalytic amounts of [Pd(phen)2](PF6)2. Similar to the reaction with amides, the reaction with thioamides selectively generated the 2,5-diarylated products when a preformed Pd(phen)PhI complex was used. PMID- 26491948 TI - From CLL to Multiple Myeloma - Spleen Tyrosine Kinase (SYK) influences multiple myeloma cell survival and migration. PMID- 26491950 TI - Effects of Sex Hormones on Ocular Surface Epithelia: Lessons Learned From Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality in women of reproductive age. Although its clinical consequences have been known for a long time to extend beyond the reproductive system, with type-2 diabetes and obesity being the most common, the involvement of the ocular surface in PCOS has been described only more recently. The ocular surface is a morphofunctional unit comprising eyelid margin, tear film, cornea, and conjunctiva. Increasing evidence indicates that these structures are under a sex hormone control and relevant diseases such as ocular allergy and dry eye are often caused by alterations in circulating or local steroid hormones levels. Novel treatments targeting sex hormone receptors on ocular surface epithelial cells are also being developed. In this review we aim to describe the current knowledge on the effects of sex hormones at the ocular surface, with a special focus on the effects of androgen imbalance in PCOS. PMID- 26491951 TI - Long-term assessment of effectiveness and quality of life of OnabotulinumtoxinA injections in provoked vestibulodynia. AB - BACKGROUND: Provoked vestibulodynia is a relatively common condition that affects sexual activity. Multidisciplinary care is indicated and OnabotulinumtoxinA injections are safe and effective treatment in this indication. AIMS: To assess the long-term efficacy of OnabotulinumtoxinA in provoked vestibulodynia. MATERIALS AND METHODS: Twenty-one patients treated with OnabotulinumtoxinA injections (50U in each bulbospongiosus muscle) 24 months prior to the study were included. Data on pain [assessed using a visual analogue scale (VAS)], quality of life [measured by the Dermatology Life Quality Index (DLQI)] and quality of sex life [assessed using the Female Sexual Function Index (FSFI)] were collected before treatment, and 3 and 24 months after injection. RESULTS: Nineteen patients participated in the study and 37% had no pain after 24 months. Significant improvements were noted in the VAS, DLQI and FSFI scores between baseline and 24 months post treatment (P < 0.0001). After 24 months, 18 patients (95%) were able to have sexual intercourse. This study was open and non-controlled. DISCUSSION AND CONCLUSION: 100U OnabotulinumtoxinA injections constitute an effective treatment in provoked vestibulodynia with results maintained after 2 years. They significantly improve pain, and have a positive impact on patient quality of life and sex life. Beneficial effects continue in the long-term, allowing patients to resume sexual activity. PMID- 26491952 TI - In Vitro and in Vivo Demonstration of Photodynamic Activity and Cytoplasm Imaging through TPE Nanoparticles. AB - We synthesized novel tetraphenylethene (TPE) conjugates, which undergo unique self-assembly to form spherical nanoparticles that exhibited aggregation induced emission (AIE) in the near-infrared region. These nanoparticles showed significant singlet oxygen generation efficiency, negligible dark toxicity, rapid cellular uptake, efficient localization in cytoplasm, and high in vitro photocytotoxicity as well as in vivo photodynamic activity against a human prostate tumor animal model. This study demonstrates, for the first time, the power of the self-assembled AIE active tetraphenylethene conjugates in aqueous media as a nanoplatform for future therapeutic applications. PMID- 26491953 TI - Construction of Spirocyclopropane-Linked Heterocycles Containing Both Pyrazolones and Oxindoles through Michael/Alkylation Cascade Reactions. AB - An effective diastereoselective Michael/alkylation cascade reaction of arylidenepyrazolones with 3-chlorooxindoles catalyzed by DIPEA was developed. A variety of highly functionalized spiro-pyrazolone-cyclopropane-oxindoles were obtained in excellent yields (up to 99%) with good to excellent diastereoselectivities (up to >25:1 dr). Moreover, the squaramide-catalyzed asymmetric reactions of arylidenepyrazolones with 3-chlorooxindoles afforded the corresponding chiral spirocyclic heterocycles in excellent yields (up to 99%) with moderate diastereoselectivities (up to 87:13 dr) and moderate to high enantioselectivities (up to 74% ee). PMID- 26491954 TI - Hepatoprotective Activity of Easter Lily (Lilium longiflorum Thunb.) Bulb Extracts. AB - The hepatoprotective activities of two different extracts, a hydroethanolic crude bulb extract (CB) and a steroidal glycoside-rich 1-butanol extract (BuOH), prepared from the bulbs of Easter lily (Lilium longiflorum Thunb.), were evaluated in a 24 week study in the female KK.Cg-A(y)/J Type 2 diabetic mouse model. Animals were divided into six groups (n = 16): control mice received Easter lily bulb extract-free drinking water together with a low- or high-fat diet (diabetic control); drinking water for the remaining groups was supplemented with CB extract (1%), BuOH extract (0.1 or 0.2%), and reference drug Metformin (0.001%), together with a high-fat diet. Both CB and BuOH extract treatment groups exhibited significantly improved liver function based on comparisons of triglycerides [diabetic 219 +/- 34 mg/dL, CB 131 +/- 27 mg/dL, BuOH(0.2%) 114 +/- 35 mg/dL], CB total cholesterol (TC) (diabetic 196 +/- 12 mg/dL, CB 159 +/- 5 mg/dL), average liver mass [diabetic 2.96 +/- 0.13 g, CB 2.58 +/- 0.08 g, BuOH(0.1%) 2.48 +/- 0.13 g], alanine transferase [diabetic 74 +/- 5 units/L, CB 25 +/- 1 units/L, BuOH(0.1%) 45 +/- 1 units/L], and histological examinations. Glucose metabolism was improved only in CB, which was confirmed by oral glucose tolerance tests (OGTT) in diet-induced obese C57BL/6J mice exposed to CB extract. These data suggest that steroidal glycosides 1-5 might play a role in the hepatoprotective activity of the BuOH extracts, while the results of the TC measurements and OGTT study indicate that other constituents present in the CB extract are responsible for its hypocholesterolemic and hypoglycemic activity. PMID- 26491955 TI - Comprehensive Screen of Metal Oxide Nanoparticles for DNA Adsorption, Fluorescence Quenching, and Anion Discrimination. AB - Although DNA has been quite successful in metal cation detection, anion detectioin remains challenging because of the charge repulsion. Metal oxides represent a very important class of materials, and different oxides might interact with anions differently. In this work, a comprehensive screen of common metal oxide nanoparticles (MONPs) was carried out for their ability to adsorb DNA, quench fluorescence, and release adsorbed DNA in the presence of target anions. A total of 19 MONPs were studied, including Al2O3, CeO2, CoO, Co3O4, Cr2O3, Fe2O3, Fe3O4, In2O3, ITO, Mn2O3, NiO, SiO2, SnO2, a-TiO2 (anatase), r-TiO2 (rutile), WO3, Y2O3, ZnO, ZrO2. These MONPs have different DNA adsorption affinity. Some adsorb DNA without quenching the fluorescence, while others strongly quench adsorbed fluorophores. They also display different affinity toward anions probed by DNA desorption. Finally, CeO2, Fe3O4, and ZnO were used to form a sensor array to discriminate phosphate, arsenate, and arsenite from the rest using linear discriminant analysis. This study not only provides a solution for anion discrimination using DNA as a signaling molecule but also provides insights into the interface of metal oxides and DNA. PMID- 26491956 TI - From ribbons to networks: hierarchical organization of DNA-grafted supramolecular polymers. AB - DNA-grafted supramolecular polymers (SPs) allow the programmed organization of DNA in a highly regular, one-dimensional array. Oligonucleotides are arranged along the edges of pyrene-based helical polymers. Addition of complementary oligonucleotides triggers the assembly of individual nanoribbons resulting in the development of extended supramolecular networks. Network formation is enabled by cooperative coaxial stacking interactions of terminal GC base pairs. The process is accompanied by structural changes in the pyrene polymer core that can be followed spectroscopically. Network formation is reversible, and disassembly into individual ribbons is realized either via thermal denaturation or by addition of a DNA separator strand. PMID- 26491957 TI - Photoinduced, Copper-Catalyzed Carbon-Carbon Bond Formation with Alkyl Electrophiles: Cyanation of Unactivated Secondary Alkyl Chlorides at Room Temperature. AB - We have recently reported that, in the presence of light and a copper catalyst, nitrogen nucleophiles such as carbazoles and primary amides undergo C-N coupling with alkyl halides under mild conditions. In the present study, we establish that photoinduced, copper-catalyzed alkylation can also be applied to C-C bond formation, specifically, that the cyanation of unactivated secondary alkyl chlorides can be achieved at room temperature to afford nitriles, an important class of target molecules. Thus, in the presence of an inexpensive copper catalyst (CuI; no ligand coadditive) and a readily available light source (UVC compact fluorescent light bulb), a wide array of alkyl halides undergo cyanation in good yield. Our initial mechanistic studies are consistent with the hypothesis that an excited state of [Cu(CN)2](-) may play a role, via single electron transfer, in this process. This investigation provides a rare example of a transition metal-catalyzed cyanation of an alkyl halide, as well as the first illustrations of photoinduced, copper-catalyzed alkylation with either a carbon nucleophile or a secondary alkyl chloride. PMID- 26491958 TI - Improving Detection of Metastatic Neuroblastoma in Bone Marrow Core Biopsies: A Proposed Immunohistochemical Approach. AB - Bone marrow (BM) nvolvement is common in stage 4/M neuroblastoma patients and profoundly impacts clinical decision-making and predicts outcomes, but to our knowledge no standard exists for immunohistochemical evaluation of staging BMs. We examined the use of three immuno-stains-synaptophysin, tyrosine hydroxylase (TH), and PGP9.5-in detecting metastatic neuroblastoma in BM. We retrospectively selected 174 BM core biopsies from 41 neuroblastoma patients. Immunohistochemistry for synaptophysin, TH, and PGP9.5 was performed. These slides and the hematoxylin and eosin (H&E)-stained slide from each BM were randomized and independently scored by three pathologists as positive, negative, or indeterminate. Cohen's kappa coefficients (interobserver agreement), McNemar's test (for frequencies of positive/indeterminate interpretations), and sensitivities for each stain/combination were calculated. Interobserver agreement was higher for all immunostains (synaptophysin, 78%-90%, kappa = 0.548-0.787; TH, 77%-92%, kappa = 0.481-0.788; and PGP9.5, 83%-90%, kappa = 0.601-0.740) than for H&Es (77%-84%, kappa = 0.434-0.572). Indeterminate interpretations were more frequent with H&Es (8.9%) and synaptophysin (6.0%) than with PGP9.5 (3.5%) or TH (3.3%). TH (76%) and PGP9.5 (70%) were the immunostains most likely to correctly resolve indeterminate H&E interpretation. Mean sensitivity among all three pathologists for detection of metastasis compared to the consensus diagnosis was 42.5% for H&E alone, 70.7% to 78.8% for H&E plus one immunostain, and 81.6% to 85% for H&E plus two immunostains. Immunohistochemistry enhanced sensitivity for tumor detection particularly dramatically in cases of prior chemotherapy. PGP9.5 and TH showed good interobserver agreement, fewer indeterminate interpretations, and resolved indeterminate H&E diagnoses at the highest frequencies. Therefore, we recommend H&E and two immunostains, specifically PGP9.5 and TH, for optimal detection of metastatic neuroblastoma in BM. PMID- 26491959 TI - The effect of fluphenazine decanoate on glucocorticoid production, reproductive cyclicity, and the behavioral stress response in the Persian onager (Equus hemionus onager). AB - Artificial insemination, performed to maximize genetic diversity in populations of zoo-housed animals, requires intensive management and has been associated with low success rates in fractious species. In these species, stressors, such as frequent handling, may impact fertility. Long-acting neuroleptic pharmaceuticals (LANs) can attenuate the stress response to handling, but may also disrupt ovulation in some species, compromising their use for artificial insemination. Therefore, the goal of this study was to determine whether LANs may be used to mitigate stress during reproductive management in wild equids without inhibiting ovulation. Six female Persian onagers (Equus hemionus onager) were treated with fluphenazine decanoate (FD; 0.1 mg/kg IM) or saline control in a random crossover design study. Urinary cortisol, progesterone, estrogen metabolites and behavior were monitored, and follicular dynamics were examined using ultrasonography until ovulation. Onagers demonstrated significantly lower cortisol concentrations (P = 0.03) when treated with FD (6.61 +/- 3.26 ng/mg creatinine) compared to saline (9.73 +/- 3.19 ng/mg creatinine). Overall, there were no differences in peak estrogen (P = 0.51) or progesterone (P = 0.38) concentrations between the two groups, and all animals ovulated within the expected time frame following FD treatment. However, some onagers exhibited only minor reductions in cortisol secretion and one treated female demonstrated a suppressed luteal progesterone peak, indicating a possible reproductive cost to FD administration. While FD may be useful for highly fractious equids for which the stress of handling delays or inhibits ovulation, these results warrant further investigation of dosing. PMID- 26491960 TI - Maternal Buprenorphine Dose at Delivery and Its Relationship to Neonatal Outcomes. AB - BACKGROUND/AIMS: To determine whether there is a dose-response relationship between maternal dose of buprenorphine at delivery and neonatal outcomes. METHODS: This retrospective cohort study of 155 maternal-infant dyads exposed to buprenorphine during pregnancy examines the relationship between maternal dose of buprenorphine at delivery and gestational age, birthweight, method of delivery, Apgar scores at 1 and 5 min, duration of infant hospital stay, peak neonatal abstinence syndrome (NAS) score, duration of NAS and incidence of pharmacologic treatment of NAS. RESULTS: Analyses failed to support any relationship between maternal dose of buprenorphine at delivery and any of the 9 clinical outcomes (all p values >0.093). CONCLUSIONS: This study failed to provide any evidence to support limiting or reducing maternal dose of buprenorphine during pregnancy in order to reduce possible adverse outcomes to the infant. Findings suggest that healthcare providers can focus medication decisions on maternal opioid cravings to reduce the risk of relapse to illicit opioid use rather than out of concern for adverse infant outcomes. PMID- 26491961 TI - Micrometeorological measurements over 3 years reveal differences in N2 O emissions between annual and perennial crops. AB - Perennial crops can deliver a wide range of ecosystem services compared to annual crops. Some of these benefits are achieved by lengthening the growing season, which increases the period of crop water and nutrient uptake, pointing to a potential role for perennial systems to mitigate soil nitrous oxide (N2 O) emissions. Employing a micrometeorological method, we tested this hypothesis in a 3-year field experiment with a perennial grass-legume mixture and an annual corn monoculture. Given that N2 O emissions are strongly dependent on the method of fertilizer application, two manure application options commonly used by farmers for each crop were studied: injection vs. broadcast application for the perennial; fall vs. spring application for the annual. Across the 3 years, lower N2 O emissions (P < 0.001) were measured for the perennial compared to the annual crop, even though annual N2 O emissions increased tenfold for the perennial after ploughing. The percentage of N2 O lost per unit of fertilizer applied was 3.7, 3.1 and 1.3 times higher for the annual for each consecutive year. Differences in soil organic matter due to the contrasting root systems of these crops are probably a major factor behind the N2 O reduction. We found that a specific manure management practice can lead to increases or reductions in annual N2 O emissions depending on environmental variables. The number of freeze-thaw cycles during winter and the amount of rainfall after fertilization in spring were key factors. Therefore, general manure management recommendations should be avoided because interannual weather variability has the potential to determine if a specific practice is beneficial or detrimental. The lower N2 O emissions of perennial crops deserve further research attention and must be considered in future land-use decisions. Increasing the proportion of perennial crops in agricultural landscapes may provide an overlooked opportunity to regulate N2 O emissions. PMID- 26491962 TI - Quantification of Borrelia burgdorferi Membrane Proteins in Human Serum: A New Concept for Detection of Bacterial Infection. AB - The Borrelia burgdorferi spirochete is the causative agent of Lyme disease, the most common tick-borne disease in the United States. The low abundance of bacterial proteins in human serum during infection imposes a challenge for early proteomic detection of Lyme disease. To address this challenge, we propose to detect membrane proteins released from bacteria due to disruption of their plasma membrane triggered by the innate immune system. These membrane proteins can be separated from the bulk of serum proteins by high-speed centrifugation causing substantial sample enrichment prior to targeted protein quantification using multiple reaction monitoring mass spectrometry. This new approach was first applied to detection of B. burgdorferi membrane proteins supplemented in human serum. Our results indicated that detection of B. burgdorferi membrane proteins, which are ~10(7) lower in abundance than major serum proteins, is feasible. Therefore, quantitative analysis was also carried out for serum samples from three patients with acute Lyme disease. We were able to demonstrate the detection of ospA, the major B. burgdorferi lipoprotein at the level of 4.0 fmol of ospA/mg of serum protein. The results confirm the concept and suggest that the proposed approach can be expanded to detect other bacterial infections in humans, particularly where existing diagnostics are unreliable. PMID- 26491963 TI - Intracellular Information Processing through Encoding and Decoding of Dynamic Signaling Features. AB - Cell signaling dynamics and transcriptional regulatory activities are variable within specific cell types responding to an identical stimulus. In addition to studying the network interactions, there is much interest in utilizing single cell scale data to elucidate the non-random aspects of the variability involved in cellular decision making. Previous studies have considered the information transfer between the signaling and transcriptional domains based on an instantaneous relationship between the molecular activities. These studies predict a limited binary on/off encoding mechanism which underestimates the complexity of biological information processing, and hence the utility of single cell resolution data. Here we pursue a novel strategy that reformulates the information transfer problem as involving dynamic features of signaling rather than molecular abundances. We pursue a computational approach to test if and how the transcriptional regulatory activity patterns can be informative of the temporal history of signaling. Our analysis reveals (1) the dynamic features of signaling that significantly alter transcriptional regulatory patterns (encoding), and (2) the temporal history of signaling that can be inferred from single cell scale snapshots of transcriptional activity (decoding). Immediate early gene expression patterns were informative of signaling peak retention kinetics, whereas transcription factor activity patterns were informative of activation and deactivation kinetics of signaling. Moreover, the information processing aspects varied across the network, with each component encoding a selective subset of the dynamic signaling features. We developed novel sensitivity and information transfer maps to unravel the dynamic multiplexing of signaling features at each of these network components. Unsupervised clustering of the maps revealed two groups that aligned with network motifs distinguished by transcriptional feedforward vs feedback interactions. Our new computational methodology impacts the single cell scale experiments by identifying downstream snapshot measures required for inferring specific dynamical features of upstream signals involved in the regulation of cellular responses. PMID- 26491964 TI - Diversity of Active States in TMT Opsins. AB - Opn3/TMT opsins belong to one of the opsin groups with vertebrate visual and non visual opsins, and are widely distributed in eyes, brains and other internal organs in various vertebrates and invertebrates. Vertebrate Opn3/TMT opsins are further classified into four groups on the basis of their amino acid identities. However, there is limited information about molecular properties of these groups, due to the difficulty in preparing the recombinant proteins. Here, we successfully expressed recombinant proteins of TMT1 and TMT2 opsins of medaka fish (Oryzias latipes) in cultured cells and characterized their molecular properties. Spectroscopic and biochemical studies demonstrated that TMT1 and TMT2 opsins functioned as blue light-sensitive Gi/Go-coupled receptors, but exhibited spectral properties and photo-convertibility of the active state different from each other. TMT1 opsin forms a visible light-absorbing active state containing all-trans-retinal, which can be photo-converted to 7-cis- and 9-cis-retinal states in addition to the original 11-cis-retinal state. In contrast, the active state of TMT2 opsin is a UV light-absorbing state having all-trans-retinal and does not photo-convert to any other state, including the original 11-cis-retinal state. Thus, TMT opsins are diversified so as to form a different type of active state, which may be responsible for their different functions. PMID- 26491965 TI - Chronic Cigarette Smoking Impairs Erectile Function through Increased Oxidative Stress and Apoptosis, Decreased nNOS, Endothelial and Smooth Muscle Contents in a Rat Model. AB - Cigarette use is an independent risk factor for the development of erectile dysfunction (ED). While the association between chronic smoking and ED is well established, the fundamental mechanism(s) of cigarette-related ED are incompletely understood, partly due to no reliable animal model of smoking induced ED. The present study was designed to validate an in vivo rat model of chronic cigarette-induced ED. Forty 12-week old male Sprague-Dawley rats were divided into 4 groups. Ten rats served as control group and were exposed only to room air. The remaining 30 rats were passively exposed to cigarette smoke (CS) for 4 weeks (n = 10), 12 weeks (n = 10), and 24 weeks (n = 10). At the 24-week time point all rats were assessed with intracavernous pressure (ICP) during cavernous nerve electrostimulation. Blood and urine were collected to measure serum testosterone and oxidative stress, respectively. Corporal tissue was assessed by Western blot for neuronal nitric oxide synthase (nNOS). Penile tissues were subjected to immunohistochemistry for endothelial, smooth muscle, and apoptotic content. Mean arterial pressure (MAP) was significantly higher in 24-week cigarette exposed animals compared to the control animals. Mean ICP/MAP ratio and cavernosal smooth muscle/endothelial contents were significantly lower in the 12- and 24-week rats compared to control animals. Oxidative stress was significantly higher in the 24-week cigarette exposed group compared to control animals. Mean nNOS expression was significantly lower, and apoptotic index significantly higher, in CS-exposed animals compared to control animals. These findings indicate that the rat model exposure to CS increases apoptosis and oxidative stress and decreases nNOS, endothelial and smooth muscle contents, and ICP in a dose dependent fashion. The rat model is a useful tool for further study of the molecular and cellular mechanisms of CS-related ED. PMID- 26491967 TI - A Novel Byte-Substitution Architecture for the AES Cryptosystem. AB - The performance of Advanced Encryption Standard (AES) mainly depends on speed, area and power. The S-box represents an important factor that affects the performance of AES on each of these factors. A number of techniques have been presented in the literature, which have attempted to improve the performance of the S-box byte-substitution. This paper proposes a new S-box architecture, defining it as ultra low power, robustly parallel and highly efficient in terms of area. The architecture is discussed for both CMOS and FPGA platforms, and the pipelined architecture of the proposed S-box is presented for further time savings and higher throughput along with higher hardware resources utilization. A performance analysis and comparison of the proposed architecture is also conducted with those achieved by the existing techniques. The results of the comparison verify the outperformance of the proposed architecture in terms of power, delay and size. PMID- 26491966 TI - Quercetin Suppresses Twist to Induce Apoptosis in MCF-7 Breast Cancer Cells. AB - Quercetin is a dietary flavonoid which exerts anti-oxidant, anti-inflammatory and anti-cancer properties. In this study, we investigated the anti-proliferative effect of quercetin in two breast cancer cell lines (MCF-7 and MDA-MB-231), which differed in hormone receptor. IC50 value (37MUM) of quercetin showed significant cytotoxicity in MCF-7 cells, which was not observed in MDA-MB-231 cells even at 100MUM of quercetin treatment. To study the response of cancer cells to quercetin, with respect to different hormone receptors, both the cell lines were treated with a fixed concentration (40MUM) of quercetin. MCF-7 cells on quercetin treatment showed more apoptotic cells with G1 phase arrest. In addition, quercetin effectively suppressed the expression of CyclinD1, p21, Twist and phospho p38MAPK, which was not observed in MDA-MB-231 cells. To analyse the molecular mechanism of quercetin in exerting an apoptotic effect in MCF-7 cells, Twist was over-expressed and the molecular changes were observed after quercetin administration. Quercetin effectively regulated the expression of Twist, in turn p16 and p21 which induced apoptosis in MCF-7 cells. In conclusion, quercetin induces apoptosis in breast cancer cells through suppression of Twist via p38MAPK pathway. PMID- 26491968 TI - Population Genetics and Reproductive Strategies of African Trypanosomes: Revisiting Available Published Data. AB - Trypanosomatidae are a dangerous family of Euglenobionta parasites that threaten the health and economy of millions of people around the world. More precisely describing the population biology and reproductive mode of such pests is not only a matter of pure science, but can also be useful for understanding parasite adaptation, as well as how parasitism, specialization (parasite specificity), and complex life cycles evolve over time. Studying this parasite's reproductive strategies and population structure can also contribute key information to the understanding of the epidemiology of associated diseases; it can also provide clues for elaborating control programs and predicting the probability of success for control campaigns (such as vaccines and drug therapies), along with emergence or re-emergence risks. Population genetics tools, if appropriately used, can provide precise and useful information in these investigations. In this paper, we revisit recent data collected during population genetics surveys of different Trypanosoma species in sub-Saharan Africa. Reproductive modes and population structure depend not only on the taxon but also on the geographical location and data quality (absence or presence of DNA amplification failures). We conclude on issues regarding future directions of research, in particular vis-a-vis genotyping and sampling strategies, which are still relevant yet, too often, neglected issues. PMID- 26491969 TI - Smoking in Relation to Coronary Atherosclerotic Plaque Burden, Volume and Composition on Intravascular Ultrasound. AB - BACKGROUND: This study aimed to evaluate the relationship between cigarette smoking and coronary atherosclerotic burden, volume and composition as determined in-vivo by grayscale and virtual histology (VH) intravascular ultrasound (IVUS). METHODS AND RESULTS: Between 2008 and 2011, (VH-)IVUS of a non-culprit coronary artery was performed in 581 patients undergoing coronary angiography. To account for differences in baseline characteristics, current smokers were matched to never smokers by age, gender and indication for catheterization, resulting in 280 patients available for further analysis. Coronary atherosclerotic plaque volume, burden, composition (fibrous, fibro-fatty, dense calcium and necrotic core) and high-risk lesions (VH-IVUS derived thin-cap fibroatheroma (TCFA), plaque burden >=70%, minimal luminal area <=4.0 mm2) were assessed. Cigarette smoking showed a tendency towards higher coronary plaque burden (mean+/-SD, 38.6+/-12.5% in current versus 36.4+/-11.0% in never smokers, p = 0.080; and odds ratio (OR) of current smoking for plaque burden above versus below the median 1.69 (1.04-2.75), p = 0.033). This effect was driven by an association in patients presenting with an acute coronary syndrome (ACS) (current smokers, plaque burden 38.3+/-12.8% versus never smokers, plaque burden 35.0+/-11.2%, p = 0.049; OR 1.88 (1.02-3.44), p = 0.042). Fibrous tissue tended to be lower in current smokers (mean+/-SD, 57.7+/-10.5% versus 60.4+/-12.6%, p = 0.050) and fibro-fatty tissue was higher in current smokers (median[IQR], 9.6[6.0-13.7]% versus 8.6[5.8-12.2]%, p = 0.039). However, differences in percentage necrotic core and dense calcium could not be demonstrated. Also, no differences were found with regard to high-risk lesions. CONCLUSIONS: An association between smoking and degree of coronary atherosclerosis was present in patients undergoing coronary angiography who presented with ACS. Although smoking was associated with higher fibro-fatty percentage, no associations could be demonstrated with percentage necrotic core, nor with VH-IVUS derived TCFA lesions. Since the magnitude of the differences in both degree and composition of atherosclerosis was modest, clinical relevance of the findings may be questioned. PMID- 26491970 TI - Crystal Structures of a Piscine Betanodavirus: Mechanisms of Capsid Assembly and Viral Infection. AB - Betanodaviruses cause massive mortality in marine fish species with viral nervous necrosis. The structure of a T = 3 Grouper nervous necrosis virus-like particle (GNNV-LP) is determined by the ab initio method with non-crystallographic symmetry averaging at 3.6 A resolution. Each capsid protein (CP) shows three major domains: (i) the N-terminal arm, an inter-subunit extension at the inner surface; (ii) the shell domain (S-domain), a jelly-roll structure; and (iii) the protrusion domain (P-domain) formed by three-fold trimeric protrusions. In addition, we have determined structures of the T = 1 subviral particles (SVPs) of (i) the delta-P-domain mutant (residues 35-217) at 3.1 A resolution; and (ii) the N-ARM deletion mutant (residues 35-338) at 7 A resolution; and (iii) the structure of the individual P-domain (residues 214-338) at 1.2 A resolution. The P-domain reveals a novel DxD motif asymmetrically coordinating two Ca2+ ions, and seems to play a prominent role in the calcium-mediated trimerization of the GNNV CPs during the initial capsid assembly process. The flexible N-ARM (N-terminal arginine-rich motif) appears to serve as a molecular switch for T = 1 or T = 3 assembly. Finally, we find that polyethylene glycol, which is incorporated into the P-domain during the crystallization process, enhances GNNV infection. The present structural studies together with the biological assays enhance our understanding of the role of the P-domain of GNNV in the capsid assembly and viral infection by this betanodavirus. PMID- 26491971 TI - Quantifying Multistate Cytoplasmic Molecular Diffusion in Bacterial Cells via Inverse Transform of Confined Displacement Distribution. AB - Single-molecule tracking (SMT) of fluorescently tagged cytoplasmic proteins can provide valuable information on the underlying biological processes in living cells via subsequent analysis of the displacement distributions; however, the confinement effect originated from the small size of a bacterial cell skews the protein's displacement distribution and complicates the quantification of the intrinsic diffusive behaviors. Using the inverse transformation method, we convert the skewed displacement distribution (for both 2D and 3D imaging conditions) back to that in free space for systems containing one or multiple (non)interconverting Brownian diffusion states, from which we can reliably extract the number of diffusion states as well as their intrinsic diffusion coefficients and respective fractional populations. We further demonstrate a successful application to experimental SMT data of a transcription factor in living E. coli cells. This work allows a direct quantitative connection between cytoplasmic SMT data with diffusion theory for analyzing molecular diffusive behavior in live bacteria. PMID- 26491972 TI - Do All Dinoflagellates have an Extranuclear Spindle? AB - The syndinean dinoflagellates are a diverse assemblage of alveolate endoparasites that branch basal to the core dinoflagellates. Because of their phylogenetic position, the syndineans are considered key model microorganisms in understanding early evolution in the dinoflagellates. Closed mitosis with an extranuclear spindle that traverses the nucleus in cytoplasmic grooves or tunnels is viewed as one of the morphological features shared by syndinean and core dinoflagellates. Here we describe nuclear morphology and mitosis in the syndinean dinoflagellate Amoebophrya sp. from Akashiwo sanguinea, a member of the A. ceratii complex, as revealed by protargol silver impregnation, DNA specific fluorochromes, and transmission electron microscopy. Our observations show that not all species classified as dinoflagellates have an extranuclear spindle. In Amoebophrya sp. from A. sanguinea, an extranuclear microtubule cylinder located in a depression in the nuclear surface during interphase moves into the nucleoplasm via sequential membrane fusion events and develops into an entirely intranuclear spindle. Results suggest that the intranuclear spindle of Amoebophrya spp. may have evolved from an ancestral extranuclear spindle and indicate the need for taxonomic revision of the Amoebophryidae. PMID- 26491973 TI - Janus Silica Hollow Spheres Prepared via Interfacial Biosilicification. AB - A poly(ethylene glycol)-b-poly(L-lysine)-b-poly(styrene) (PEG-PLL-PS) triblock copolymer, which contains a cationic PLL block as the middle block, is synthesized via a combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The PEG-PLL-PS (ELS) triblock is employed as a macromolecular surfactant to form a stable oil-in-water (O/W) emulsion, which is subsequently used as the template to prepare Janus silica hollow spheres (JHS) via a one-pot biosilicification reaction. For the emulsion template, the middle PLL block assembles at the O/W interface and directs the biomimetic silica synthesis in the presence of phosphate buffer and silicic acid precursors. This biosilicification process takes place only in the intermediate layer between water and the organic interior phase, leading to the formation of silica JHSs with hydrophobic PS chains tethered to the inner surface and PEG attached to the outer surface. The three-layer JHSs, namely, PEG/silica-polylysine/PS composites, were verified by electron microscopy. Upon further breaking these JHSs into species, polymer-grafted Janus silica nanoplates (JPLs) can be obtained. Our studies provide an efficient one-step method for preparing hybrid silica Janus structures within minutes. PMID- 26491974 TI - Recent advances in the management of AL Amyloidosis. AB - Immunoglobulin light chain (AL) amyloidosis, the most common of the systemic amyloidosis, is characterized by the deposition of amyloid fibrils that derive from the aggregation of misfolded monoclonal immunoglobulin light chains. Amyloid fibrils disrupt tissue architecture and the pre-fibril oligomers are directly toxic to myocardiac cells, causing cardiac dysfunction. The lethal consequences of AL amyloidosis are due to the toxic product and not due to the malignant behaviour of the plasma cell clone; however, the characteristics of this clone are associated with long-term prognosis. Early and accurate diagnosis is the key to effective management, but is challenging. Modern chemotherapy options (including autologous transplantation, bortezomib, lenalidomide) have improved the outcomes of patients at low or intermediate risk, but the prognosis of patients with severe cardiac dysfunction is still poor. Therapies targeting amyloid deposits and the amyloidogenic process are under investigation and offer promise for better future treatments. PMID- 26491975 TI - Modulation of the Innate Immune Response through the Vagus Nerve. AB - The innate immune system is a defense mechanism that is of vital importance to our survival. However, excessive or unwanted activation of the innate immune system, which can occur in major surgery, sepsis, trauma, ischemia-reperfusion injury and autoimmune diseases, can lead to damage of the kidneys and other organs. Therefore, therapeutic approaches aimed at attenuating the innate immune response could have beneficial effects in these conditions. The vagus nerve exerts anti-inflammatory effects through the so-called cholinergic anti inflammatory pathway. Since its discovery, numerous animal studies have shown beneficial effects of stimulation of this pathway in models of inflammatory diseases, either through (electrical) stimulation of the vagus nerve or pharmacological approaches. However, human data are very scarce. In this review, we present an overview of the molecular and anatomical bases of the cholinergic anti-inflammatory pathway, but mainly focus on human studies. We discuss the difficulties and drawbacks associated with investigating this pathway in humans, and finally, we provide future perspectives. PMID- 26491976 TI - Genomic and Proteomic Characterization of Acute Kidney Injury. AB - The incidence and severity of acute kidney injury (AKI) is rising globally, and the associated morbidity and mortality remain high despite promising advances in experimental therapeutics. The reasons include (a) an incomplete understanding of the complex pathophysiology, (b) an inability to reliably identify risk factors for AKI and (c) a lack of biomarkers for the early prediction of AKI and its outcomes. Functional genomics, bioinformatics and proteomics have begun to uncover candidates that are emerging as biomarkers and therapeutic targets. This review will update the reader on current technologies in genomics (including targeted sequencing, genome wide association studies and transcriptome profiling) and proteomics (including gel electrophoresis and mass spectrometry methods) and their application on human AKI. PMID- 26491977 TI - "Of and beyond medical consequences": Exploring health information scanning and seeking behaviors of Filipino domestic service workers in Hong Kong. AB - The increasing trend for women in developing countries to engage in international and temporary labor migration has exposed female migrant workers to health inequities. In this article, we problematize the impact of international and temporary labor migration on the health of Filipino domestic workers in Hong Kong by exploring their general patterns of health information acquisition. Through a series of focus group discussions with Filipino domestic workers in Hong Kong, we found that employers serve as stakeholders in migration health, social networking sites can be a platform for participatory health promotion, and religious beliefs and behaviors can promote favorable health behaviors. PMID- 26491978 TI - Novel 5-carboxy-8-HQ based histone demethylase JMJD2A inhibitors: introduction of an additional carboxyl group at the C-2 position of quinoline. AB - A series of JMJD2A inhibitors had been designed by analyzing the binding mode of 5-carboxy-8-hydroxyquinoline (5-carboxy-8-HQ) with JMJD2A. The inhibitory activity of the synthesized compounds against JMJD2A was determined, followed by docking simulations to understand the structure-activity relationships. Compounds with potent JMJD2A inhibitory activity demonstrated outstanding selectivity for JMJD2A over PHD2. Several potent compounds were selected to evaluate their anti proliferative activity on tumor cell lines. Among them, compound 6p displayed the best anti-proliferative activity. Based on these in vitro biological data, seven compounds were chosen to determine their physicochemical properties. Compound 6p displayed good aqueous solubility and better permeability than 5-carboxy-8-HQ. Our data recognized that compound 6p could be considered as a starting point for development of new JmjC inhibitors. PMID- 26491980 TI - Synthesis and anticancer activity of 6-heteroarylcoumarins. AB - A series of novel 7-hydroxy-8-methyl-coumarins with indole, pyrimidine, pyrazole, pyran, tetrazolo[1,5-a]pyrimidine, pyrimido[1,2-a]benzimidazol, 2-oxo-1,2 dihydropyridine and dihydropyrazolo[3,4-b]pyridine moieties at C6 position of heterocyclic core have been synthesized. Anticancer activity screening on NCI60 cell lines allowed identification of 6-(6-fluoro-1H-indol-2-yl)-7-hydroxy-4,8 dimethyl-2H-chromen-2-one (23) with the highest level of antimitotic activity with mean GI50/TGI values of 3.28/13.24 MUM and certain sensitivity profile towards the Non-Small Cell Lung Cancer cell line NOR-92 (GI50/TGI/LC50 values 0.95/4.17/29.9 MUM). PMID- 26491979 TI - Synthesis of novel flavone hydrazones: in-vitro evaluation of alpha-glucosidase inhibition, QSAR analysis and docking studies. AB - Thirty derivatives of flavone hydrazone (5-34) had been synthesized through a five-step reaction and screened for their alpha-glucosidase inhibition activity. Chalcone 1 was synthesized through aldol condensation then subjected through oxidative cyclization, esterification, and condensation reaction to afford the final products. The result for baker's yeast alpha-glucosidase (EC 3.2.1.20) inhibition assay showed that all compounds are active with reference to the IC50 value of the acarbose (standard drug) except for compound 3. Increase in activity observed for compounds 2 to 34 clearly highlights the importance of flavone, hydrazide and hydrazone linkage in suppressing the activity of alpha-glucosidase. Additional functional group on N-benzylidene moiety further enhances the activity significantly. Compound 5 (15.4 +/- 0.22 MUM), a 2,4,6-trihydroxy substituted compound, is the most active compound in the series. Other compounds which were found to be active are those having chlorine, fluorine, and nitro substituents. Compounds with methoxy, pyridine, and methyl substituents are weakly active. Further studies showed that they are not active in inhibiting histone deacetylase activity and do not possess any cytotoxic properties. QSAR model was being developed to further identify the structural requirements contributing to the activity. Using Discovery Studio (DS) 2.5, various 2D descriptors were being used to develop the model. The QSAR model is able to predict the pIC50 and could be used as a prediction tool for compounds having the same skeletal framework. Molecular docking was done for all compounds using homology model of alpha glucosidase to identify important binding modes responsible for inhibition activity. PMID- 26491981 TI - Inhibition of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase from Mycobacterium tuberculosis: in silico screening and in vitro validation. AB - Tuberculosis, caused by Mycobacterium tuberculosis, remains a serious global health threat, highlighting the urgent need for novel antituberculosis drugs. The shikimate pathway, responsible for aromatic amino acid biosynthesis, is required for the growth of Mycobacterium tuberculosis and is a potential drug target. 3 deoxy-D-arabino-heptulosonate 7-phosphate synthase (mtDAH7Ps) catalyzes the first step in shikimate pathway. E-pharmacophore models for inhibitors of mtDAH7Ps - tyrosine, phenylalanine, phosphoenolpyruvate and (2S)-2,7 bis(phosphonooxy)heptanoic acid were screened against ZINC synthetic and natural compounds databases. The shortlisted compounds were subjected to induce fit docking and validated by Prime/Molecular Mechanics Generalized Born Surface Area calculation to predict ligand binding energy and ligand strain energy for ligand and receptor. The lead compounds were screened for their inhibitory activity against purified mtDAH7Ps enzyme. Lead compounds inhibited mtDAH7Ps in a concentration-dependent manner; with an IC50 value of 21 MUM, 42 MUM and 54 MUM for alpha-Tocopherol, rutin and 3-Pyridine carboxyaldehyde respectively. Molecular Dynamics analysis for 50 ns of the active compounds-mtDAH7Ps complexes showed that the backbone of mtDAH7Ps was stable. These results suggest that alpha tocopherol, 3 - Pyridine carboxyaldehyde and rutin could be novel drug leads to inhibit mtDAH7Ps in M. tuberculosis. PMID- 26491982 TI - A click chemistry approach for the synthesis of mono and bis aryloxy linked coumarinyl triazoles as anti-tubercular agents. AB - A series of mono and bis-triazole coumarin hybrids 6a-u and 9a-f respectively have been synthesized using 4-(azidomethyl)-2H-chromen-2-ones 5a-i and aryl propargyl ethers 2a-c/8 employing Click chemistry modified protocol for Azide Alkyne cycloadditions(CuAAC). Anti-tubercular screening showed moderate activity for mono aryloxy compounds 6a-u with MIC 50-100 MUg/mL, whereas the bis compounds 9a-f were more effective with MICs between 0.2 and 12.5 MUg/mL. Molecular modeling and 3D-QSAR measurements using CoMFA and Topomer CoMFA further supported the observed results. The bis compound 9b showed excellent activity with MIC value as low as 0.2 MUg/mL. PMID- 26491983 TI - Ecto-5'-Nucleotidase Overexpression Reduces Tumor Growth in a Xenograph Medulloblastoma Model. AB - BACKGROUND: Ecto-5'-nucleotidase/CD73 (ecto-5'-NT) participates in extracellular ATP catabolism by converting adenosine monophosphate (AMP) into adenosine. This enzyme affects the progression and invasiveness of different tumors. Furthermore, the expression of ecto-5'-NT has also been suggested as a favorable prognostic marker, attributing to this enzyme contradictory functions in cancer. Medulloblastoma (MB) is the most common brain tumor of the cerebellum and affects mainly children. MATERIALS AND METHODS: The effects of ecto-5'-NT overexpression on human MB tumor growth were studied in an in vivo model. Balb/c immunodeficient (nude) 6 to 14-week-old mice were used for dorsal subcutaneous xenograph tumor implant. Tumor development was evaluated by pathophysiological analysis. In addition, the expression patterns of adenosine receptors were verified. RESULTS: The human MB cell line D283, transfected with ecto-5'-NT (D283hCD73), revealed reduced tumor growth compared to the original cell line transfected with an empty vector. D283hCD73 generated tumors with a reduced proliferative index, lower vascularization, the presence of differentiated cells and increased active caspase-3 expression. Prominent A1 adenosine receptor expression rates were detected in MB cells overexpressing ecto-5'-NT. CONCLUSION: This work suggests that ecto-5'-NT promotes reduced tumor growth to reduce cell proliferation and vascularization, promote higher differentiation rates and initiate apoptosis, supposedly by accumulating adenosine, which then acts through A1 adenosine receptors. Therefore, ecto-5'-NT might be considered an important prognostic marker, being associated with good prognosis and used as a potential target for therapy. PMID- 26491984 TI - Ecotoxicity monitoring and bioindicator screening of oil-contaminated soil during bioremediation. AB - A series of toxicity bioassays was conducted to monitor the ecotoxicity of soils in the different phases of bioremediation. Artificially oil-contaminated soil was inoculated with a petroleum hydrocarbon-degrading bacterial consortium containing Burkholderia cepacia GS3C, Sphingomonas GY2B and Pandoraea pnomenusa GP3B strains adapted to crude oil. Soil ecotoxicity in different phases of bioremediation was examined by monitoring total petroleum hydrocarbons, soil enzyme activities, phytotoxicity (inhibition of seed germination and plant growth), malonaldehyde content, superoxide dismutase activity and bacterial luminescence. Although the total petroleum hydrocarbon (TPH) concentration in soil was reduced by 64.4%, forty days after bioremediation, the phytotoxicity and Photobacterium phosphoreum ecotoxicity test results indicated an initial increase in ecotoxicity, suggesting the formation of intermediate metabolites characterized by high toxicity and low bioavailability during bioremediation. The ecotoxicity values are a more valid indicator for evaluating the effectiveness of bioremediation techniques compared with only using the total petroleum hydrocarbon concentrations. Among all of the potential indicators that could be used to evaluate the effectiveness of bioremediation techniques, soil enzyme activities, phytotoxicity (inhibition of plant height, shoot weight and root fresh weight), malonaldehyde content, superoxide dismutase activity and luminescence of P. phosphoreum were the most sensitive. PMID- 26491985 TI - Long-term use of an ultrapotent topical steroid for the treatment of vulval lichen sclerosus is safe. PMID- 26491986 TI - When the Label Matters: Adsorption of Labeled and Unlabeled Proteins on Charged Surfaces. AB - Fluorescent labels are often attached to proteins to monitor binding and adsorption processes. Docking simulations for native hen egg white lysozyme (HEWL) and HEWL labeled with fluorescein isothiocyanate show that these adsorb differently on charged surfaces. Attachment of even a small label can significantly change the interaction properties of a protein. Thus, the results of experiments with fluorescently labeled proteins should be interpreted by modeling the structures and computing the interaction properties of both labeled and unlabeled species. PMID- 26491988 TI - Environmental Contributions to Social and Mental Health Outcomes Following Pediatric Stroke. AB - Mental health and social outcomes following acquired brain injury (ABI) in children are often considered to be due to brain insult, but other factors, such as environment, may also play a role. We assessed mental health and social function in children with chronic illness, with and without stroke (a form of ABI), and typically developing (TD) controls to examine environmental influences on these outcomes. We recruited 36 children diagnosed with stroke, 15 with chronic asthma, and 43 TD controls. Children and parents completed questionnaires rating child mental health and social function and distal and proximal environment. TD children had significantly less internalizing and social problems than stroke and asthma groups, and engaged in more social activities than children with stroke. Poorer parent mental health predicted more internalizing and social problems and lower social participation. Family dysfunction was associated with internalizing problems. Lower parent education contributed to children's social function. Children with chronic illness are at elevated risk of poorer mental health and social function. Addition of brain insult leads to poorer social participation. Quality of home environment contributes to children's outcomes, suggesting that supporting parent and family function provides an opportunity to optimize child mental health and social outcomes. PMID- 26491987 TI - The role of age and executive function in auditory category learning. AB - Auditory categorization is a natural and adaptive process that allows for the organization of high-dimensional, continuous acoustic information into discrete representations. Studies in the visual domain have identified a rule-based learning system that learns and reasons via a hypothesis-testing process that requires working memory and executive attention. The rule-based learning system in vision shows a protracted development, reflecting the influence of maturing prefrontal function on visual categorization. The aim of the current study was twofold: (a) to examine the developmental trajectory of rule-based auditory category learning from childhood through adolescence and into early adulthood and (b) to examine the extent to which individual differences in rule-based category learning relate to individual differences in executive function. A sample of 60 participants with normal hearing-20 children (age range=7-12years), 21 adolescents (age range=13-19years), and 19 young adults (age range=20-23years) learned to categorize novel dynamic "ripple" sounds using trial-by-trial feedback. The spectrotemporally modulated ripple sounds are considered the auditory equivalent of the well-studied "Gabor" patches in the visual domain. Results reveal that auditory categorization accuracy improved with age, with young adults outperforming children and adolescents. Computational modeling analyses indicated that the use of the task-optimal strategy (i.e., a conjunctive rule-based learning strategy) improved with age. Notably, individual differences in executive flexibility significantly predicted auditory category learning success. The current findings demonstrate a protracted development of rule-based auditory categorization. The results further suggest that executive flexibility coupled with perceptual processes play important roles in successful rule-based auditory category learning. PMID- 26491990 TI - From the Editors. PMID- 26491989 TI - Reward-Related Neural Activity and Adolescent Antisocial Behavior in a Community Sample. AB - Behavioral research has found evidence supporting reward dominance in adolescence with externalizing disorders, but findings from neuroimaging studies have been largely heterogeneous. We examined the Feedback-Related Negativity (FRN) and P3b in relation to self-reported externalizing behavior among 78 adolescents (11-18 yrs) during a monetary gambling task with concurrent high-density electroencephalogram. As expected, the P3b and the FRN demonstrated greater evoked activity to reward and punishment, respectively. Further, high externalizing behavior was associated with greater P3b difference and reduced FRN difference in response to reward and punishment, suggesting that externalizing behaviors may be associated with both reward dominance and reduced feedback monitoring. PMID- 26491991 TI - Introduction to the Special Series on Risk, Perception, and Response. PMID- 26491992 TI - Overcoming Learning Aversion in Evaluating and Managing Uncertain Risks. AB - Decision biases can distort cost-benefit evaluations of uncertain risks, leading to risk management policy decisions with predictably high retrospective regret. We argue that well-documented decision biases encourage learning aversion, or predictably suboptimal learning and premature decision making in the face of high uncertainty about the costs, risks, and benefits of proposed changes. Biases such as narrow framing, overconfidence, confirmation bias, optimism bias, ambiguity aversion, and hyperbolic discounting of the immediate costs and delayed benefits of learning, contribute to deficient individual and group learning, avoidance of information seeking, underestimation of the value of further information, and hence needlessly inaccurate risk-cost-benefit estimates and suboptimal risk management decisions. In practice, such biases can create predictable regret in selection of potential risk-reducing regulations. Low-regret learning strategies based on computational reinforcement learning models can potentially overcome some of these suboptimal decision processes by replacing aversion to uncertain probabilities with actions calculated to balance exploration (deliberate experimentation and uncertainty reduction) and exploitation (taking actions to maximize the sum of expected immediate reward, expected discounted future reward, and value of information). We discuss the proposed framework for understanding and overcoming learning aversion and for implementing low-regret learning strategies using regulation of air pollutants with uncertain health effects as an example. PMID- 26491993 TI - Changes in the Clinical Capacity of Local Health Departments and Continuity of Reproductive Health Services. AB - OBJECTIVE: The role of local health departments (LHDs) as a clinical service provider remains a salient topic of discussion. As local and state health departments continue to migrate away from clinical services, there is need to understand the impact on these transitions on access to care in a given community. The purpose of this study was to examine the impact of clinical capacity reductions in LHDs on receipt of annual family planning visits among South Carolina women. DESIGN: A rolling panel of women eligible for Medicaid between 2001 and 2012 was created. Receipt of an annual visit for each year of Medicaid eligibility was tracked over time. A typology reflecting changes in county capacity for clinical services was used as the independent variable. We estimated multivariate generalized estimating equation models, which examined changes in population-averaged probabilities (marginal means) of annual family planning visits over time by level of county typology. RESULTS: Approximately 325 269 unduplicated women were included in the panel, with 25.18% receiving an annual visit in a given year. On average, receipt of annual visits in counties with notable reductions in LHD clinical capacity tended to be fewer over time ( 0.022; 95% CI [confidence interval], -0.028 to -0.017) as among counties with reduced capacity that included a specific clinic closing (-0.032; 95% CI, -0.037 to -0.028). However, the magnitude of observed differences between county typologies was relatively small. CONCLUSIONS: Evidence of service discontinuity was present. However, differences occurred later in the study period following the economic recession. Our findings suggest that counties that reduced capacity did not lose ground but were unable to meet increasing demand from the economic recession relative to those that did not reduce capacity even when closing a clinic. As LHDs discontinue or significantly reduced clinical services, fulfilling the assurance role is important for transitioning women to other sources of care. PMID- 26491994 TI - Owning your mistakes. AB - Most scientists admit to their errors but, as Eve Marder explains, the scientific community as a whole needs to rethink the way it recognizes achievement. PMID- 26491995 TI - Sociodemographic and Clinical Features of Disruptive Mood Dysregulation Disorder: A Chart Review. AB - OBJECTIVE: Disruptive mood dysregulation disorder (DMDD) is a novel diagnosis listed in Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) to encompass chronic and impairing irritability in youth, and to help its differentiation from bipolar disorders. Because it is a new entity, treatment guidelines, as well as its sociodemographic and clinical features among diverse populations, are still not elucidated. Here, DMDD cases from three centers in Turkey are reported and the implications are discussed. METHODS: The study was conducted at the Abant Izzet Baysal University Medical Faculty Department of Child and Adolescent Psychiatry (Bolu), and American Hospital and Bengi Semerci Institute (Istanbul) between August 2014 and October 2014. Records of patients were reviewed and features of patients who fulfilled criteria for DMDD were recorded. Data were analyzed with SPS Version 17.0 for Windows. Descriptive analyses, chi(2) test, and Mann-Whitney U test were used for analyses. Diagnostic consensus was determined via Cohen's kappa constants. p was set at 0.01. RESULTS: Thirty-six patients (77.8 % male) fulfilled criteria for DMDD. kappa value for consensus between clinicians was 0.68 (p = 0.00). Mean age of patients was 9.0 years (S.D. = 2.5) whereas the mean age of onset for DMDD symptoms was 4.9 years (S.D. = 2.2). Irritability, temper tantrums, verbal rages, and physical aggression toward family members were the most common presenting complaints. CONCLUSIONS: Diagnostic consensus could not be reached for almost one fourth of cases. Most common reasons for lack of consensus were problems in clarification of moods of patients in between episodes, problems in differentiation of normality and pathology (i.e., symptoms mainly reported in one setting vs. pervasiveness), and inability to fulfill frequency criterion for tantrums. PMID- 26491996 TI - In vivo dual-targeted chemotherapy of drug resistant cancer by rationally designed nanocarrier. AB - Multidrug resistance is one of major obstacles to the effective cancer chemotherapy. To address this issue, we developed the effective circumvention of multidrug resistance in cancer cells by a yolk-shell Fe3O4@MgSiO3 nanoplatform with the polymerpoly(ethylene glycol) and folic acid modifications can achieve active targeted delivery of anti-cancer drug by using combined magnetic and ligand targeting. The direct intracellular drug delivery of doxorubicin by nanocarrier was much more effectively than free DOX for multidrug resistant Hep G2/MDR cancer cells. Besides the excellent biocompatibility, high drug loading efficiency, dual-targeting delivery, and controlled releasing behavior, in vivo experiments demonstrate that this nanocarrier can specifically deliver and concentrate doxorubicin hydrochloride in tumor sites to overcome drug resistance. It follows an alternative strategy for effective chemotherapy against drug resistant cancers by using rationally designed nanomaterial. PMID- 26491997 TI - Development and evaluation of in vivo tissue engineered blood vessels in a porcine model. AB - BACKGROUND: There's a large clinical need for novel vascular grafts. Tissue engineered blood vessels (TEBVs) have great potential to improve the outcome of vascular grafting procedures. Here, we present a novel approach to generate autologous TEBV in vivo. Polymer rods were engineered and implanted, evoking an inflammatory response that culminates in encapsulation by a fibrocellular capsule. We hypothesized that, after extrusion of the rod, the fibrocellular capsule differentiates into an adequate vascular conduit once grafted into the vasculature. METHODS AND RESULTS: Rods were implanted subcutaneously in pigs. After 4 weeks, rods with tissue capsules grown around it were harvested. Tissue capsules were grafted bilaterally as carotid artery interposition. One and 4-week patency were evaluated by angiography whereupon pigs were sacrificed. Tissue capsules before and after grafting were evaluated on tissue remodeling using immunohistochemistry, RNA profiling and mechanical testing. Rods were encapsulated by thick, well-vascularized tissue capsules, composed of circumferentially aligned fibroblasts, collagen and few leukocytes, with adequate mechanical strength. Patency was 100% after 1 week and 87.5% after 4 weeks. After grafting, tissue capsules remodeled towards a vascular phenotype. Gene profiles of TEBVs gained more similarity with carotid artery. Wall thickness and alphaSMA positive area significantly increased. Interestingly, a substantial portion of (myo)fibroblasts present before grafting expressed smooth muscle cell markers. While leukocytes were hardly present anymore, the lumen was largely covered with endothelial cells. Burst pressure remained stable after grafting. CONCLUSIONS: Autologous TEBVs were created in vivo with sufficient mechanical strength enabling vascular grafting. Grafts differentiated towards a vascular phenotype upon grafting. PMID- 26491998 TI - Phenylboronic acid-sugar grafted polymer architecture as a dual stimuli responsive gene carrier for targeted anti-angiogenic tumor therapy. AB - We present a cationic polymer architecture composed of phenylboronic acid (PBA), sugar-installed polyethylenimine (PEI), and polyethylene glycol (PEG). The chemical bonding of PBA with the diol in the sugar enabled the crosslinking of low-molecular-weight (MW) PEI to form high-MW PEI, resulting in strong interaction with anionic DNA for gene delivery. Inside the cell, the binding of PBA and sugar was disrupted by either acidic endosomal pH or intracellular ATP, so gene payloads were released effectively. This dual stimuli-responsive gene release drove the polymer to deliver DNA for high transfection efficiency with low cytotoxicity. In addition, PBA moiety with PEGylation facilitated the binding of polymer/DNA polyplexes to sialylated glycoprotein which is overexpressed on the tumor cell membrane, and thus provided high tumor targeting ability. Therapeutic application of our polymer was demonstrated as an anti-angiogenic gene delivery agent for tumor growth inhibition. Our judicious designed polymer structure based on PBA provides enormous potential as a gene delivery agent for effective gene therapy by stimuli-responsiveness and tumor targeting. PMID- 26492000 TI - Hard-luck Scheele. PMID- 26491999 TI - Schwann cells promote endothelial cell migration. AB - Directed cell migration is a crucial orchestrated process in embryonic development, wound healing, and immune response. The underlying substrate can provide physical and/or chemical cues that promote directed cell migration. Here, using electrospinning we developed substrates of aligned poly(lactic-co-glycolic acid) nanofibres to study the influence of glial cells on endothelial cells (ECs) in a 3-dimensional (3D) co-culture model. ECs build blood vessels and regulate their plasticity in coordination with neurons. Likewise, neurons construct nerves and regulate their circuits in coordination with ECs. In our model, the neuro vascular cross-talk was assessed using a direct co-culture model of human umbilical vein endothelial cells (HUVECs) and rat Schwann cells (rSCs). The effect of rSCs on ECs behavior was demonstrated by earlier and higher velocity values and genetic expression profiles different of those of HUVECs when seeded alone. We observed 2 different gene expression trends in the co-culture models: (i) a later gene expression of angiogenic factors, such as interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), and (ii) an higher gene expression of genes involved in actin filaments rearrangement, such as focal adhesion kinase (FAK), Mitogen-activated protein kinase-activated protein kinase 13 (MAPKAPK13), Vinculin (VCL), and Profilin (PROF). These results suggested that the higher ECs migration is mainly due to proteins involved in the actin filaments rearrangement and in the directed cell migration rather than the effect of angiogenic factors. This co-culture model provides an approach to enlighten the neurovascular interactions, with particular focus on endothelial cell migration. PMID- 26492001 TI - Fullerene stability: One rule for the electron-rich... PMID- 26492002 TI - Foldamers: Biomimetic and built to order. PMID- 26492003 TI - Natural products: Emulation illuminates biosynthesis. PMID- 26492004 TI - Light harvesting: Strike while the iron is cold. PMID- 26492005 TI - Palladium-catalysed norbornene-mediated C-H functionalization of arenes. AB - The Catellani reaction--a palladium-catalysed C-H functionalization reaction mediated by norbornene--was first reported in 1997. The capacity to functionalize both the ortho and ipso positions of aryl halides in a single transformation held great appeal. We reported an annulative Catellani reaction in 2000. Since then, our two groups have explored the synthetic utility of this reaction and dramatic progress has been made by a number of groups in the past five years. Whereas the original Catellani reaction uses Pd(0) catalysts, recent studies have shown that Pd(II) catalysts can be used in combination with norbornene to effect (1) direct 2-alkylation of indoles and pyrroles and (2) selective meta-C-H functionalization of arenes bearing commonly used ortho-directing groups, thereby opening new avenues for future research. We describe the most recent developments concerning the Pd-catalysed norbornene-mediated C-H functionalization of arenes, including applications in natural products synthesis. We outline challenges and future opportunities. PMID- 26492006 TI - Shaping quaternary assemblies of water-soluble non-peptide helical foldamers by sequence manipulation. AB - The design and construction of biomimetic self-assembling systems is a challenging yet potentially highly rewarding endeavour that contributes to the development of new biomaterials, catalysts, drug-delivery systems and tools for the manipulation of biological processes. Significant progress has been achieved by engineering self-assembling DNA-, protein- and peptide-based building units. However, the design of entirely new, completely non-natural folded architectures that resemble biopolymers ('foldamers') and have the ability to self-assemble into atomically precise nanostructures in aqueous conditions has proved exceptionally challenging. Here we report the modular design, formation and structural elucidation at the atomic level of a series of diverse quaternary arrangements formed by the self-assembly of short amphiphilic alpha-helicomimetic foldamers that bear proteinaceous side chains. We show that the final quaternary assembly can be controlled at the sequence level, which permits the programmed formation of either discrete helical bundles that contain isolated cavities or pH responsive water-filled channels with controllable pore diameters. PMID- 26492007 TI - An eight-step synthesis of epicolactone reveals its biosynthetic origin. AB - Epicolactone is a recently isolated fungal metabolite that is highly complex for its size, and yet racemic. With its array of quaternary stereocentres, high degree of functionalization and intricate polycyclic structure, it poses a considerable challenge to synthesis, a challenge that can be met by understanding its biosynthetic origin. If drawn in a certain way, epicolactone reveals a pattern that resembles purpurogallin, the archetype of ubiquitous natural colourants formed via oxidative dimerization. Based on this insight, we designed a biomimetic synthesis of epicolactone that proceeds in only eight steps from vanillyl alcohol. We have isolated a key intermediate that supports our biosynthetic hypothesis and anticipate that an isomer of epicolactone stemming from our synthetic efforts could also be found as a natural product. PMID- 26492008 TI - Iron sensitizer converts light to electrons with 92% yield. AB - Solar energy conversion in photovoltaics or photocatalysis involves light harvesting, or sensitization, of a semiconductor or catalyst as a first step. Rare elements are frequently used for this purpose, but they are obviously not ideal for large-scale implementation. Great efforts have been made to replace the widely used ruthenium with more abundant analogues like iron, but without much success due to the very short-lived excited states of the resulting iron complexes. Here, we describe the development of an iron-nitrogen-heterocyclic carbene sensitizer with an excited-state lifetime that is nearly a thousand-fold longer than that of traditional iron polypyridyl complexes. By the use of electron paramagnetic resonance, transient absorption spectroscopy, transient terahertz spectroscopy and quantum chemical calculations, we show that the iron complex generates photoelectrons in the conduction band of titanium dioxide with a quantum yield of 92% from the (3)MLCT (metal-to-ligand charge transfer) state. These results open up possibilities to develop solar energy-converting materials based on abundant elements. PMID- 26492009 TI - Unidirectional rotary motion in achiral molecular motors. AB - Control of the direction of motion is an essential feature of biological rotary motors and results from the intrinsic chirality of the amino acids from which the motors are made. In synthetic autonomous light-driven rotary motors, point chirality is transferred to helical chirality, and this governs their unidirectional rotation. However, achieving directional rotary motion in an achiral molecular system in an autonomous fashion remains a fundamental challenge. Here, we report an achiral molecular motor in which the presence of a pseudo-asymmetric carbon atom proved to be sufficient for exclusive autonomous disrotary motion of two appended rotor moieties. Isomerization around the two double bonds enables both rotors to move in the same direction with respect to their surroundings--like wheels on an axle--demonstrating that autonomous unidirectional rotary motion can be achieved in a symmetric system. PMID- 26492010 TI - Co-assembly, spatiotemporal control and morphogenesis of a hybrid protein-peptide system. AB - Controlling molecular interactions between bioinspired molecules can enable the development of new materials with higher complexity and innovative properties. Here we report on a dynamic system that emerges from the conformational modification of an elastin-like protein by peptide amphiphiles and with the capacity to access, and be maintained in, non-equilibrium for substantial periods of time. The system enables the formation of a robust membrane that displays controlled assembly and disassembly capabilities, adhesion and sealing to surfaces, self-healing and the capability to undergo morphogenesis into tubular structures with high spatiotemporal control. We use advanced microscopy along with turbidity and spectroscopic measurements to investigate the mechanism of assembly and its relation to the distinctive membrane architecture and the resulting dynamic properties. Using cell-culture experiments with endothelial and adipose-derived stem cells, we demonstrate the potential of this system to generate complex bioactive scaffolds for applications such as tissue engineering. PMID- 26492011 TI - Stable, crystalline, porous, covalent organic frameworks as a platform for chiral organocatalysts. AB - The periodic layers and ordered nanochannels of covalent organic frameworks (COFs) make these materials viable open catalytic nanoreactors, but their low stability has precluded their practical implementation. Here we report the synthesis of a crystalline porous COF that is stable against water, strong acids and strong bases, and we demonstrate its utility as a material platform for structural design and functional development. We endowed a crystalline and porous imine-based COF with stability by incorporating methoxy groups into its pore walls to reinforce interlayer interactions. We subsequently converted the resulting achiral material into two distinct chiral organocatalysts, with the high crystallinity and porosity retained, by appending chiral centres and catalytically active sites on its channel walls. The COFs thus prepared combine catalytic activity, enantioselectivity and recyclability, which are attractive in heterogeneous organocatalysis, and were shown to promote asymmetric C-C bond formation in water under ambient conditions. PMID- 26492012 TI - O-GlcNAc modification blocks the aggregation and toxicity of the protein alpha synuclein associated with Parkinson's disease. AB - Several aggregation-prone proteins associated with neurodegenerative diseases can be modified by O-linked N-acetyl-glucosamine (O-GlcNAc) in vivo. One of these proteins, alpha-synuclein, is a toxic aggregating protein associated with synucleinopathies, including Parkinson's disease. However, the effect of O GlcNAcylation on alpha-synuclein is not clear. Here, we use synthetic protein chemistry to generate both unmodified alpha-synuclein and alpha-synuclein bearing a site-specific O-GlcNAc modification at the physiologically relevant threonine residue 72. We show that this single modification has a notable and substoichiometric inhibitory effect on alpha-synuclein aggregation, while not affecting the membrane binding or bending properties of alpha-synuclein. O GlcNAcylation is also shown to affect the phosphorylation of alpha-synuclein in vitro and block the toxicity of alpha-synuclein that was exogenously added to cells in culture. These results suggest that increasing O-GlcNAcylation may slow the progression of synucleinopathies and further support a general function for O GlcNAc in preventing protein aggregation. PMID- 26492013 TI - Molecular hydrogen interacts more strongly when rotationally excited at low temperatures leading to faster reactions. AB - The role of internal molecular degrees of freedom, such as rotation, has scarcely been explored experimentally in low-energy collisions despite their significance to cold and ultracold chemistry. Particularly important to astrochemistry is the case of the most abundant molecule in interstellar space, hydrogen, for which two spin isomers have been detected, one of which exists in its rotational ground state whereas the other is rotationally excited. Here we demonstrate that quantization of molecular rotation plays a key role in cold reaction dynamics, where rotationally excited ortho-hydrogen reacts faster due to a stronger long range attraction. We observe rotational state-dependent non-Arrhenius universal scaling laws in chemi-ionization reactions of para-H2 and ortho-H2 by He(2(3)P2), spanning three orders of magnitude in temperature. Different scaling laws serve as a sensitive gauge that enables us to directly determine the exact nature of the long-range intermolecular interactions. Our results show that the quantum state of the molecular rotor determines whether or not anisotropic long-range interactions dominate cold collisions. PMID- 26492014 TI - Cage connectivity and frontier pi orbitals govern the relative stability of charged fullerene isomers. AB - Fullerene anions and cations have unique structural, electronic, magnetic and chemical properties that make them substantially different from neutral fullerenes. Although much theoretical effort has been devoted to characterizing and predicting their properties, this has been limited to a fraction of isomeric forms, mostly for fullerene anions, and has practically ignored fullerene cations. Here we show that the concepts of cage connectivity and frontier pi orbitals allow one to understand the relative stability of charged fullerene isomers without performing elaborate quantum chemistry calculations. The latter is not a trivial matter, as the number of possible isomers for a medium-sized fullerene is many more than 100,000. The model correctly predicts the structures observed experimentally and explains why the isolated pentagon rule is often violated for fullerene anions, but the opposite is found for fullerene cations. These predictions are relevant in fields as diverse as astrophysics, electrochemistry and supramolecular chemistry. PMID- 26492016 TI - Strontium's scarlet sparkles. PMID- 26492015 TI - Rhodium-catalysed asymmetric allylic arylation of racemic halides with arylboronic acids. AB - Csp(2)-Csp(2) cross-coupling reactions between arylboronic acid and aryl halides are widely used in both academia and industry and are strategically important in the development of new agrochemicals and pharmaceuticals. Csp(2)-Csp(3) cross coupling reactions have been developed, but enantioselective variations are rare and simply retaining the stereochemistry is a problem. Here we report a highly enantioselective Csp(2)-Csp(3) bond-forming method that couples arylboronic acids to racemic allyl chlorides. Both enantiomers of a cyclic chloride are converted into a single enantiomer of product via a dynamic kinetic asymmetric transformation. This Rh-catalysed method uses readily available and inexpensive building blocks and is mild and broadly applicable. For electron-deficient, electron-rich or ortho-substituted boronic acids better results are obtained with racemic allyl bromides. Oxygen substitution in the allyl halide is tolerated and the products can be functionalized to provide diverse building blocks. The approach fills a significant gap in the methods for catalytic asymmetric synthesis. PMID- 26492017 TI - Science to Practice: What Light through Yonder Tumor Breaks: Noninvasive Staging of Cancer--Shining a Light on Disease. AB - Photoacoustic imaging imparts the ability to distinguish materials according to their differences in optical absorption (ie, their color) with the high spatial and temporal resolution of ultrasonography (US). Experiments in rats show the advantages this approach would have in the clinically important noninvasive determination of the presence of tumor in the lymph nodes draining a tumor, providing the ability to achieve the results of total axillary lymph node dissection without the risks of surgery or even percutaneous sentinel node biopsy. The coupling of this technique to a conventional US imaging system gives the promise of rapid translation to clinical use. PMID- 26492019 TI - "Error Bars" in Medical Imaging: Stealth and Treacherous. AB - Given the critical role that diagnostic radiology has in patient care, it is important for providers and patients to understand the level of certainty associated with imaging. Over-reliance on imaging and failure to appreciate its limitations can lead to unforeseen consequences. Further, there are uncertainties and inconsistencies in the manner in which imaging-based information is considered, communicated, and applied. There are opportunities to alter practice to maximize comprehension of radiologic reports and thus optimize the manner in which imaging-based information is applied clinically. PMID- 26492020 TI - Cardiac MR Imaging and the Specter of Double-Strand Breaks. PMID- 26492021 TI - Communicating Nonroutine Radiologic Findings to the Ordering Physician: Will (Should) Information Technology-assisted Communication Replace Direct Voice Contact? PMID- 26492022 TI - Multidetector CT for Penetrating Torso Trauma: State of the Art. AB - The use of computed tomography (CT) for hemodynamically stable victims of penetrating torso trauma continues to increase but remains less singular to the work-up than in blunt trauma. Research in this area has focused on the incremental benefits of CT within the context of evolving diagnostic algorithms and in conjunction with techniques such as laparoscopy, endoscopy, and angiographic intervention. This review centers on the current state of multidetector CT as a triage tool for penetrating torso trauma and the primacy of trajectory evaluation in diagnosis, while emphasizing diagnostic challenges that have lingered despite tremendous technological advances since CT was first used in this setting 3 decades ago. As treatment strategies have also changed considerably over the years in parallel with advances in CT, current management implications of organ-specific injuries depicted at multidetector CT are also discussed. PMID- 26492026 TI - Case 223: Arytenoid Dislocation. AB - A 71-year-old man with a history of atrial fibrillation refractory to medical therapy and lung cancer status after left upper lobectomy presented to our hospital for elective cardioversion and rate control with tikosyn. Overnight, the patient became unresponsive and was found to be in a state of cardiogenic shock. A code was called, and he was stabilized after cardioversion and bedside intubation. His stay in the intensive care unit was complicated by ventilator associated pneumonia. The patient subsequently underwent multiple failed extubation attempts, requiring two additional reintubations. He was finally extubated 18 days after his initial admission to the intensive care unit. After he was discharged, he reported a hoarse voice and was only able to whisper. His voice varied in timbre and volume, and it became hoarser with use. Otolaryngology evaluation, including laryngoscopy and video stroboscopy, showed immobility of the right vocal cord. He was referred for speech therapy, and a computed tomographic (CT) examination of the neck was ordered. PMID- 26492027 TI - Assessment of BI-RADS Category 4 Lesions or How Some Flaws in a Study Put into Question the Credibility of the Study Results. PMID- 26492028 TI - Splenic Switch-Off for Stress Cardiovascular MR Imaging and Dipyridamole. PMID- 26492029 TI - Lipid and Metabolite Deregulation in BRCA1 and BRCA2 Genetic Mutations. PMID- 26492030 TI - Clinical Value of Coronary CT Angiography before Transcatheter Aortic Valve Replacement. PMID- 26492034 TI - 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV. PMID- 26492033 TI - Neuroanatomical, Clinical and Cognitive Correlates of Post-Stroke Dysphagia. AB - BACKGROUND AND PURPOSE: About half of the dysphagic stroke patients have persistent swallowing dysfunction after 7 days from symptom onset. The aim of the study was to evaluate incidence, prognosis, clinical and neuroradiological correlates of post-stroke dysphagia. METHODS: We prospectively examined consecutive patients with acute ischemic or hemorrhagic stroke. Patients' clinical and neuroradiological data were collected. Swallowing function was assessed by the water swallow test upon admission and after 14 days; patients were then classified as persistent dysphagic, non-persistent dysphagic or non dysphagic. RESULTS: We recruited 275 patients, 121 of whom were dysphagic upon admission and 254 patients attended follow-up at 14 days; 141 never presented dysphagia, 21 had a non-persistent pattern of dysphagia and 92 had a persistent one. Stroke type, leukoaraiosis degree, previous cognitive impairment and stroke severity upon admission independently predicted the occurrence of dysphagia after stroke and its persistence as well. At receiver operating characteristic (ROC) analysis, the National Institutes of Health Stroke Scale (NIHSS) score of 11.5 was the best predictive value of persistent dysphagia, with a specificity of 90.1% and a sensitivity of 72.4%. CONCLUSION: Stroke severity is an important predictor of a persistent pattern of dysphagia, with a suggested NIHSS cutoff value of >=12. An independent correlation was observed with leukoaraiosis and with previous cognitive impairment. PMID- 26492035 TI - MET18 Connects the Cytosolic Iron-Sulfur Cluster Assembly Pathway to Active DNA Demethylation in Arabidopsis. AB - DNA demethylation mediated by the DNA glycosylase ROS1 helps determine genomic DNA methylation patterns and protects active genes from being silenced. However, little is known about the mechanism of regulation of ROS1 enzymatic activity. Using a forward genetic screen, we identified an anti-silencing (ASI) factor, ASI3, the dysfunction of which causes transgene promoter hyper-methylation and silencing. Map-based cloning identified ASI3 as MET18, a component of the cytosolic iron-sulfur cluster assembly (CIA) pathway. Mutation in MET18 leads to hyper-methylation at thousands of genomic loci, the majority of which overlap with hypermethylated loci identified in ros1 and ros1dml2dml3 mutants. Affinity purification followed by mass spectrometry indicated that ROS1 physically associates with MET18 and other CIA components. Yeast two-hybrid and split luciferase assays showed that ROS1 can directly interact with MET18 and another CIA component, AE7. Site-directed mutagenesis of ROS1 indicated that the conserved iron-sulfur motif is indispensable for ROS1 enzymatic activity. Our results suggest that ROS1-mediated active DNA demethylation requires MET18 dependent transfer of the iron-sulfur cluster, highlighting an important role of the CIA pathway in epigenetic regulation. PMID- 26492037 TI - Frugivory in Canopy Plants in a Western Amazonian Forest: Dispersal Systems, Phylogenetic Ensembles and Keystone Plants. AB - Frugivory is a widespread mutualistic interaction in which frugivores obtain nutritional resources while favoring plant recruitment through their seed dispersal services. Nonetheless, how these complex interactions are organized in diverse communities, such as tropical forests, is not fully understood. In this study we evaluated the existence of plant-frugivore sub-assemblages and their phylogenetic organization in an undisturbed western Amazonian forest in Colombia. We also explored for potential keystone plants, based on network analyses and an estimate of the amount of fruit going from plants to frugivores. We carried out diurnal observations on 73 canopy plant species during a period of two years. During focal tree sampling, we recorded frugivore identity, the duration of each individual visit, and feeding rates. We did not find support for the existence of sub assemblages, such as specialized vs. generalized dispersal systems. Visitation rates on the vast majority of canopy species were associated with the relative abundance of frugivores, in which ateline monkeys (i.e. Lagothrix and Ateles) played the most important roles. All fruiting plants were visited by a variety of frugivores and the phylogenetic assemblage was random in more than 67% of the cases. In cases of aggregation, the plant species were consumed by only primates or only birds, and filters were associated with fruit protection and likely chemical content. Plants suggested as keystone species based on the amount of pulp going from plants to frugivores differ from those suggested based on network approaches. Our results suggest that in tropical forests most tree frugivore interactions are generalized, and abundance should be taken into account when assessing the most important plants for frugivores. PMID- 26492036 TI - Biomarkers of Endothelial Activation Are Associated with Poor Outcome in Critical Illness. AB - BACKGROUND: Endothelial activation plays a role in organ dysfunction in the systemic inflammatory response syndrome (SIRS). Angiopoietin-1 (Ang-1) promotes vascular quiescence while angiopoietin-2 (Ang-2) mediates microvascular leak. Circulating levels of Ang-1 and Ang-2 in patients with SIRS could provide insight on risks for organ dysfunction and death distinct from inflammatory proteins. In this study, we determined if biomarkers of endothelial activation and inflammation exhibit independent associations with poor outcomes in SIRS. METHODS: We studied 943 critically ill patients with SIRS admitted to an Intensive Care Unit (ICU) of an academic medical center. We measured plasma levels of endothelial markers (Ang-1, Ang-2, soluble vascular cell adhesion molecule-1 (sVCAM-1)) and inflammatory markers (interleukin-6 (IL-6), interleukin 8 (IL-8), granulocyte-colony stimulating factor (G-CSF), soluble tumor necrosis factor receptor-1 (sTNFR-1)) within 24 hours of enrollment. We tested for associations between each marker and 28 day mortality, shock, and day 3 sequential organ failure assessment (SOFA) score. For 28 day mortality, we performed sensitivity analysis for those subjects with sepsis and those with sterile inflammation. We used multivariate models to adjust for clinical covariates and determine if associations identified with endothelial activation markers were independent of those observed with inflammatory markers. RESULTS: Higher levels of all biomarkers were associated with increased 28 day mortality except levels of Ang-1 which were associated with lower mortality. After adjustment for comorbidities and sTNFR-1 concentration, a doubling of Ang-1 concentration was associated with lower 28 day mortality (Odds ratio (OR) = 0.81; p<0.01), shock (OR = 0.82; p<0.001), and SOFA score (beta = -0.50; p<0.001), while Ang-2 concentration was associated with increased mortality (OR = 1.55; p<0.001), shock (OR = 1.51; p<0.001), and SOFA score (beta = +0.63; p<0.001). sVCAM-1 was not independently associated with SIRS outcomes. CONCLUSIONS: In critically ill patients with SIRS, early measurements of Ang-1 and Ang-2 are associated with death and organ dysfunction independently of simultaneously measured markers of inflammation. PMID- 26492038 TI - Summary of Notifiable Infectious Diseases and Conditions - United States, 2013. AB - The Summary of Notifiable Infectious Diseases and Condition-United States, 2013 (hereafter referred to as the summary) contains the official statistics, in tabular and graphic form, for the reported occurrence of nationally notifiable infectious diseases and conditions in the United States for 2013. Unless otherwise noted, data are final totals for 2013 reported as of June 30, 2014. These statistics are collected and compiled from reports sent by U.S. state and territory, New York City, and District of Columbia health departments to the National Notifiable Diseases Surveillance System (NNDSS), which is operated by CDC in collaboration with the Council of State and Territorial Epidemiologists (CSTE). This summary is available at http://www.cdc.gov/mmwr/mmwr_nd/index.html. This site also includes summary publications from previous years. PMID- 26492039 TI - Decline in Clinical Efficacy of Oral Miltefosine in Treatment of Post Kala-azar Dermal Leishmaniasis (PKDL) in India. AB - BACKGROUND: Recent studies have shown significant decline in the final cure rate after miltefosine treatment in visceral leishmaniasis. This study evaluates the efficacy of miltefosine in the treatment of post kala-azar dermal leishmaniasis (PKDL) patients recruited over a period of 5 years with 18 months of follow-up. METHODOLOGY: In this study 86 confirmed cases of PKDL were treated with two different dosage regimens of miltefosine (Regimen I- 50mg twice daily for 90 days and Regimen II- 50 mg thrice for 60 days) and the clinical outcome assessed monthly. Cure/relapse was ascertained by clinical and histopathological examination, and measuring parasite burden by quantitative real-time PCR. In vitro susceptibility of parasites towards miltefosine was estimated at both promastigote and amastigote stages. RESULTS: Seventy three of eighty six patients completed the treatment and achieved clinical cure. Approximately 4% (3/73) patients relapsed by the end of 12 months follow-up, while a total of 15% (11/73) relapsed by the end of 18 months. Relapse rate was significantly higher in regimen II (31%) compared to regimen I (10.5%)(P<0.005). Parasite load at the pre treatment stage was significantly higher (P<0.005) in cases that relapsed compared to the cases that remained cured. In vitro susceptibility towards miltefosine of parasites isolated after relapse was significantly lower (>2 fold) in comparison with the pre-treatment isolates (P<0.005). CONCLUSION: Relapse rate in PKDL following miltefosine treatment has increased substantially, indicating the need of introducing alternate drugs/ combination therapy with miltefosine. PMID- 26492040 TI - Rhodopsin Forms Nanodomains in Rod Outer Segment Disc Membranes of the Cold Blooded Xenopus laevis. AB - Rhodopsin forms nanoscale domains (i.e., nanodomains) in rod outer segment disc membranes from mammalian species. It is unclear whether rhodopsin arranges in a similar manner in amphibian species, which are often used as a model system to investigate the function of rhodopsin and the structure of photoreceptor cells. Moreover, since samples are routinely prepared at low temperatures, it is unclear whether lipid phase separation effects in the membrane promote the observed nanodomain organization of rhodopsin from mammalian species. Rod outer segment disc membranes prepared from the cold-blooded frog Xenopus laevis were investigated by atomic force microscopy to visualize the organization of rhodopsin in the absence of lipid phase separation effects. Atomic force microscopy revealed that rhodopsin nanodomains form similarly as that observed previously in mammalian membranes. Formation of nanodomains in ROS disc membranes is independent of lipid phase separation and conserved among vertebrates. PMID- 26492042 TI - Correction: Metabolomic Profiling of the Nectars of Aquilegia pubescens and A. Canadensis. PMID- 26492041 TI - Modulation of the Surface Proteome through Multiple Ubiquitylation Pathways in African Trypanosomes. AB - Recently we identified multiple suramin-sensitivity genes with a genome wide screen in Trypanosoma brucei that includes the invariant surface glycoprotein ISG75, the adaptin-1 (AP-1) complex and two deubiquitylating enzymes (DUBs) orthologous to ScUbp15/HsHAUSP1 and pVHL-interacting DUB1 (type I), designated TbUsp7 and TbVdu1, respectively. Here we have examined the roles of these genes in trafficking of ISG75, which appears key to suramin uptake. We found that, while AP-1 does not influence ISG75 abundance, knockdown of TbUsp7 or TbVdu1 leads to reduced ISG75 abundance. Silencing TbVdu1 also reduced ISG65 abundance. TbVdu1 is a component of an evolutionarily conserved ubiquitylation switch and responsible for rapid receptor modulation, suggesting similar regulation of ISGs in T. brucei. Unexpectedly, TbUsp7 knockdown also blocked endocytosis. To integrate these observations we analysed the impact of TbUsp7 and TbVdu1 knockdown on the global proteome using SILAC. For TbVdu1, ISG65 and ISG75 are the only significantly modulated proteins, but for TbUsp7 a cohort of integral membrane proteins, including the acid phosphatase MBAP1, that is required for endocytosis, and additional ISG-related proteins are down-regulated. Furthermore, we find increased expression of the ESAG6/7 transferrin receptor and ESAG5, likely resulting from decreased endocytic activity. Therefore, multiple ubiquitylation pathways, with a complex interplay with trafficking pathways, control surface proteome expression in trypanosomes. PMID- 26492043 TI - Uncovering Spatiotemporal Characteristics of Human Online Behaviors during Extreme Events. AB - In response to an extreme event, individuals on social media demonstrate interesting behaviors depending on their backgrounds. By making use of the large scale datasets of posts and search queries collected from Twitter and GoogleTrends, we first identify the distinct categories of human collective online concerns and durations based on the distributions of solo tweets and new incremental tweets about events. Such a characterization enables us to gain a better understanding of dynamic changes in human behaviors corresponding to different types of events. Next, we observe the heterogeneity of individual responses to events through measuring the fraction of event-related tweets relative to the tweets released by an individual, and thus empirically confirm the heterogeneity assumption as adopted in the meta-population models for characterizing collective responses to events. Finally, based on the correlations of information entropy in different regions, we show that the observed distinct responses may be caused by their different speeds in information propagation. In addition, based on the detrended fluctuation analysis, we find that there exists a self-similar evolution process for the collective responses within a region. These findings have provided a detailed account for the nature of distinct human behaviors on social media in presence of extreme events. PMID- 26492044 TI - Corrigendum. PMID- 26492046 TI - Heterobimetallic Ti/Co Complexes That Promote Catalytic N-N Bond Cleavage. AB - Treatment of the tris(phosphinoamide) titanium precursor ClTi(XylNP(i)Pr2)3 (1) with CoI2 leads to the heterobimetallic complex (eta(2) (i)Pr2PNXyl)Ti(XylNP(i)Pr2)2(MU-Cl)CoI (2). One-electron reduction of 2 affords (eta(2)-(i)Pr2PNXyl)Ti(XylNP(i)Pr2)2CoI (3), which can be reduced by another electron under dinitrogen to generate the reduced diamagnetic complex (THF)Ti(XylNP(i)Pr2)3CoN2 (4). The removal of the dinitrogen ligand from 4 under vacuum affords (THF)Ti(XylNP(i)Pr2)3Co (5), which features a Ti-Co triple bond. Treatment of 4 with hydrazine or methyl hydrazine results in N-N bond cleavage and affords the new diamagnetic complexes (L)Ti(XylNP(i)Pr2)3CoN2 (L = NH3 (6), MeNH2 (7)). Complexes 4, 5, and 6 have been shown to catalyze the disproportionation of hydrazine into ammonia and dinitrogen gas through a mechanism involving a diazene intermediate. PMID- 26492045 TI - In Vitro and Sensory Evaluation of Capsaicin-Loaded Nanoformulations. AB - Capsaicin has known health beneficial and therapeutic properties. It is also able to enhance the permeability of drugs across epithelial tissues. Unfortunately, due to its pungency the oral administration of capsaicin is limited. To this end, we assessed the effect of nanoencapsulation of capsaicin, under the hypothesis that this would reduce its pungency. Core-shell nanocapsules with an oily core and stabilized with phospholipids were used. This system was used with or without chitosan coating. In this work, we investigated the in vitro release behavior of capsaicin-loaded formulations in different physiological media (including simulated saliva fluid). We also evaluated the influence of encapsulation of capsaicin on the cell viability of buccal cells (TR146). To study the changes in pungency after encapsulation we carried out a sensory analysis with a trained panel of 24 students. The in vitro release study showed that the systems discharged capsaicin slowly in a monotonic manner and that the chitosan coating had an effect on the release profile. The cytotoxic response of TR146 cells to capsaicin at a concentration of 500 MUM, which was evident for the free compound, was reduced following its encapsulation. The sensory study revealed that a chitosan coating results in a lower threshold of perception of the formulation. The nanoencapsulation of capsaicin resulted in attenuation of the sensation of pungency significantly. However, the presence of a chitosan shell around the nanoformulations did not mask the pungency, when compared with uncoated systems. PMID- 26492047 TI - Organ Donation and Transplantation: The View From Canada. PMID- 26492049 TI - All in (IL-) 1? PMID- 26492050 TI - Single-Cell Analysis by LA-ICP-MS. PMID- 26492051 TI - Robert S. Schwartz, MD: The Dawn of Immunosuppression. PMID- 26492052 TI - Induction Therapy in Repeat Kidney Transplantation. PMID- 26492053 TI - High Incidence of Paralytic Ileus After Bortezomib Treatment of Antibody-Mediated Rejection in Kidney Transplant Recipients: Report of 2 Cases. PMID- 26492054 TI - Behavioral Science Strategies to Boost Organ Donor Consent. PMID- 26492055 TI - Does Statistics Matter? PMID- 26492056 TI - Response to A reassessment of the Survival Advantage of Simultaneous Kidney Pancreas Versus Kidney-Alone Transplantation. PMID- 26492057 TI - Successful Heart Transplantation for Unreversible Endomyocardial Fibrosis Related to FIP1L1-PDGFRA Chronic Eosinophilic Leukemia. PMID- 26492058 TI - Intraoperative Steroid Use and Outcomes Following the Norwood Procedure: An Analysis of the Pediatric Heart Network's Public Database. AB - OBJECTIVE: Data supporting the use of perioperative steroids during cardiac surgery are conflicting, and most pediatric studies have been limited by small sample sizes and/or diverse cardiac diagnoses. The objective of this study was to determine if intraoperative steroid administration improved outcomes following the Norwood procedure. DESIGN: A retrospective analysis was performed on the 549 neonates who underwent a Norwood procedure in the publicly available datasets from the Pediatric Heart Network's Single Ventricle Reconstruction trial. Groups were compared to determine if outcomes differed between intraoperative steroid recipients (n = 498, 91%) and nonrecipients (n = 51, 9%). SETTING: Fifteen North American centers. SUBJECTS: Infants enrolled in the Single Ventricle Reconstruction trial. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics and intraoperative variables were similar between groups with the exception of a shorter duration of cross clamp and cardiopulmonary bypass time in the group that received steroids. Subjects who did not receive intraoperative steroids had improved hospital survival (94% vs 83%, p = 0.03) but longer ICU stays (16 d; interquartile range, 12-33 vs 14 d; interquartile range, 9-28; p = 0.04) and hospital stays (29 d; interquartile range, 21-50 vs 23 d; interquartile range, 15-40; p = 0.01) than steroid recipients. In multivariate analysis, lengths of stay associations were no longer significant, but hospital survival trended toward favoring the nonsteroid group with an odds ratio of 3.52 (95% CI, 0.98-12.64; p = 0.054). CONCLUSIONS: In the large multicentered Single Ventricle Reconstruction trial, there was widespread use of intraoperative steroids. Intraoperative steroid administration was not associated with an improvement in outcomes and may be associated with a reduction in hospital survival in neonates undergoing the Norwood procedure. This study highlights the need for a randomized control trial. PMID- 26492059 TI - The Pediatric Risk of Mortality Score: Update 2015. AB - OBJECTIVES: Severity of illness measures have long been used in pediatric critical care. The Pediatric Risk of Mortality is a physiologically based score used to quantify physiologic status, and when combined with other independent variables, it can compute expected mortality risk and expected morbidity risk. Although the physiologic ranges for the Pediatric Risk of Mortality variables have not changed, recent Pediatric Risk of Mortality data collection improvements have been made to adapt to new practice patterns, minimize bias, and reduce potential sources of error. These include changing the outcome to hospital survival/death for the first PICU admission only, shortening the data collection period and altering the Pediatric Risk of Mortality data collection period for patients admitted for "optimizing" care before cardiac surgery or interventional catheterization. This analysis incorporates those changes, assesses the potential for Pediatric Risk of Mortality physiologic variable subcategories to improve score performance, and recalibrates the Pediatric Risk of Mortality score, placing the algorithms (Pediatric Risk of Mortality IV) in the public domain. DESIGN: Prospective cohort study from December 4, 2011, to April 7, 2013. MEASUREMENTS AND MAIN RESULTS: Among 10,078 admissions, the unadjusted mortality rate was 2.7% (site range, 1.3-5.0%). Data were divided into derivation (75%) and validation (25%) sets. The new Pediatric Risk of Mortality prediction algorithm (Pediatric Risk of Mortality IV) includes the same Pediatric Risk of Mortality physiologic variable ranges with the subcategories of neurologic and nonneurologic Pediatric Risk of Mortality scores, age, admission source, cardiopulmonary arrest within 24 hours before admission, cancer, and low-risk systems of primary dysfunction. The area under the receiver operating characteristic curve for the development and validation sets was 0.88 +/- 0.013 and 0.90 +/- 0.018, respectively. The Hosmer-Lemeshow goodness of fit statistics indicated adequate model fit for both the development (p = 0.39) and validation (p = 0.50) sets. CONCLUSIONS: The new Pediatric Risk of Mortality data collection methods include significant improvements that minimize the potential for bias and errors, and the new Pediatric Risk of Mortality IV algorithm for survival and death has excellent prediction performance. PMID- 26492060 TI - Procalcitonin to Detect Suspected Bacterial Infections in the PICU. AB - OBJECTIVES: Nonspecific clinical symptoms frequently lead to suspicion of bacterial infection in critically ill children. Clinicians send bacterial cultures for suspected infection and begin an empiric course of antibiotics while microbiology results are pending. We investigated whether the biomarker procalcitonin could be useful to predict confirmed bacterial infection in critically ill children in the PICU, before culture results are available. DESIGN: Prospective, blinded single-center study. SETTING: Tertiary PICU and cardiothoracic ICU. PATIENTS: There were one hundred forty-four patients with suspected bacterial infections that had bacterial cultures sent by clinicians. INTERVENTIONS: Procalcitonin samples were obtained at three time intervals: as close to the time of the initial culture as possible (up to 12 hr after) and 24 and 72 hours after the initial culture. Patients were stratified into clinical outcome groups based on microbiology results and clinical symptoms using Centers for Disease Control and Prevention criteria. These assignments were blinded to procalcitonin levels. Primary outcome was the presence of culture-proven bacterial infection. MEASUREMENTS AND MAIN RESULTS: There was a statistically significant difference in initial and subsequent median procalcitonin values between patients with confirmed bacterial infections and patients with low suspicion of bacterial infection (p < 0.02). However, there was extremely high variability in procalcitonin values among all groups. Procalcitonin had only a fair ability to predict bacterial infection, with area under the curve of receiver operating characteristic plots ranging between 0.63 and 0.71. When using serial procalcitonin values to predict bacterial infection, positive likelihood ratios were near 1 and negative likelihood ratios were between 0.3 and 0.4. CONCLUSIONS: Procalcitonin levels were higher in children with documented confirmed bacterial infection as compared with those with low suspicion of infection. However, neither single nor serial procalcitonin measurements were able to predict the presence or absence of confirmed bacterial infection with enough certainty to be clinically useful as to recommend initiating or withholding antibiotics. PMID- 26492061 TI - The Morbidity and Mortality Conference in Pediatric Intensive Care as a Means for Improving Patient Safety. AB - OBJECTIVES: To present our experience in an interdisciplinary and interprofessional morbidity and mortality conference, with special emphasis on its usefulness in improving patient safety. DESIGN: Retrospective analysis. SETTING: Tertiary interdisciplinary neonatal PICU. PATIENTS: Morbidity and mortality conference minutes on 48 patients (newborns to 17 yr), January 2009 to June 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors' PICU implemented a morbidity and mortality conference guideline in 2009 using a system based approach to identify medical errors, their contributing factors, and possible solutions. In the subsequent 5.5 years, there were 44 mortality conferences (of 181 deaths [27%] over the same period) and four morbidity conferences. The median death/morbidity event-morbidity and mortality conference interval was 90 days (range, 7 d to 1.5 yr). The median age of patients was 4 months (range, newborn to 17 years). In six cases, the primary reason for PICU admission was a treatment complication. Unsafe processes/medical errors were identified and discussed in 37 morbidity and mortality conferences (77%). In seven cases, new autopsy findings prompted the discussion of a possible error. The 48 morbidity and mortality conferences identified 50 errors, including 30 in which an interface problem was a contributing factor. Fifty-four improvements were identified in 34 morbidity and mortality conferences. Four morbidity and mortality conferences discussed specific ethical issues. CONCLUSIONS: From our experience, we have found that the interdisciplinary and interprofessional morbidity and mortality conference has the potential to reveal unsafe processes/medical errors, in particular, diagnostic and communication errors and interface problems. When formatted as a nonhierarchical tool inviting contributions from all staff levels, the morbidity and mortality conference plays a key role in the system approach to medical errors. PMID- 26492062 TI - Transforming the Morbidity and Mortality Conference to Promote Safety and Quality in a PICU. AB - OBJECTIVE: Determine the effectiveness of a structured systems-oriented morbidity and mortality conference in improving the process of reviewing and responding to adverse events in a PICU. DESIGN: Prospective time series analysis before and after implementation of a systems-oriented morbidity and mortality conference. SETTING: Single tertiary referral PICU in Baltimore, MD. PATIENTS: Thirty-three patients discussed before and 31 patients after implementation of a systems oriented morbidity and mortality conference over a total of 20 morbidity and mortality conferences, from April 2013 to March 2014. INTERVENTIONS: Systems oriented morbidity and mortality conference incorporating elements of medical incident analysis. MEASUREMENTS AND MAIN RESULTS: There was a significant increase in meeting attendance (mean, 12 vs 31 attendees per morbidity and mortality conference; p < 0.001) after the systems-oriented morbidity and mortality conference was instituted. There was no significant difference in the mean number of cases suggested (4.2 vs 4.6) or discussed (3.3 vs 3.1) per morbidity and mortality conference. There was also no significant difference in the mean number of adverse events identified per morbidity and mortality conference (3.4 vs 4.3). However, there was an increase in the proportion of cases discussed using a standard case review tool, but this did not reach statistical significance (27% vs 45%; p = 0.231). Nevertheless, we observed a significant increase in the mean number of quality improvement interventions suggested (2.4 vs 5.6; p < 0.001) and implemented (1.7 vs 4.4; p < 0.001) per morbidity and mortality conference. All adverse event categories identified had corresponding interventions suggested after the systems-oriented morbidity and mortality conference was instituted compared with before (80% vs 100%). Intervention-to-adverse event ratios per category were also higher (mean, 0.6 vs 1.5). CONCLUSIONS: A structured systems-oriented PICU morbidity and mortality conference incorporating elements of medical incident analysis improves the process of reviewing and responding to adverse events by significantly increasing quality improvement interventions suggested and implemented. Future work would involve testing locally adapted versions of the systems-oriented morbidity and mortality conference in multiple inpatient settings. PMID- 26492063 TI - ICU-Acquired Weakness Is Associated With Differences in Clinical Outcomes in Critically Ill Children. AB - OBJECTIVE: ICU-acquired weakness, comprised critical illness myopathy and critical illness neuropathy, occurs in a significant proportion of critically ill adults and is associated with high morbidity and mortality. Little is known about ICU-acquired weakness among critically ill children. We investigated the incidence of ICU-acquired weakness among PICUs participating in the Virtual PICU Systems database. We also sought to identify associated risk factors for ICU acquired weakness and evaluate the hypothesis that ICU-acquired weakness is associated with poor clinical outcomes. DESIGN: Retrospective cohort study. SETTING: PICU. MEASUREMENTS AND MAIN RESULTS: Virtual PICU System was queried for critical illness myopathy and critical illness neuropathy between January 2009 and November 2013. Demographic, admission, and clinical outcome variables including mechanical ventilation days, PICU length of stay, and discharge disposition were analyzed. The Pediatric Index of Mortality-2 was used to evaluate and control for illness severity and risk of mortality. Among 203,875 admissions, there were 55 cases of critical illness myopathy reported and no cases of critical illness neuropathy, resulting in an incidence of 0.02%. Mechanical ventilation days were higher among patients with ICU-acquired weakness versus those who did not develop ICU-acquired weakness (31.6 +/- 28.9 vs 9.3 +/- 20.6; p < 0.001). In our multivariable analysis, when controlling for Pediatric Index of Mortality-2, ICU-acquired weakness was more frequently reported in those with admission diagnoses of respiratory illness and infection and the need for mechanical ventilation, renal replacement therapy, extracorporeal life support, and tracheostomy. ICU-acquired weakness was associated with a longer PICU length of stay, episodes requiring mechanical ventilation, and discharge to an intermediate, chronic care, and rehabilitation care unit. ICU-acquired weakness was not independently associated with mortality. CONCLUSIONS: ICU-acquired weakness is uncommonly diagnosed among PICU patients reported in Virtual PICU System. ICU-acquired weakness is associated with critical care therapies, invasive procedures, and resource utilization. Limitations of our retrospective study include underrecognition of ICU-acquired weakness and lack of standardized diagnostic criteria within Virtual PICU System. Prospective studies are needed to better understand the true incidence, risk factors, and clinical course for patients who develop ICU-acquired weakness. PMID- 26492064 TI - Rapid onsite evaluation: A comparison of cytopathologist and pulmonologist performance. AB - BACKGROUND: Rapid onsite evaluation (ROSE) has several potential benefits but also can prolong procedures if one must wait for a cytopathologist, and it can involve a considerable time commitment on the part of the cytopathologist. At the University of Arkansas for Medical Sciences, interventional pulmonologists have routinely reviewed cytology specimens. This study was performed to determine prospectively how accurately pulmonologists could perform ROSE and whether they could contribute to the efficiency of the process. METHODS: For sequential cases, the procedural pulmonologist documented a ROSE reading before the reading by the cytopathologist. Readings were compared between the two for agreement and for accuracy. The time commitment for the cytopathologist was also recorded. RESULTS: One hundred sixty-four sites were biopsied in 102 patients. With respect to onsite adequacy, there was a high level of concordance between pulmonology and cytopathology as evidenced by the kappa score ( +/- standard error) of 0.72 +/- 0.15 and by disagreement in only 3 cases (2%). For the diagnostic category, there was once again a high level of concordance; there was agreement in 141 of the 164 cases (86%), and the weighted kappa score was 0.89 +/- 0.02. The cytopathologist's time in the endoscopy suite averaged 4.02 +/- 6.9 minutes per procedure. CONCLUSIONS: Procedural pulmonologists can effectively learn enough cytology to be able to make ROSE a collaborative process and to greatly increase the efficiency of the cytopathologist. PMID- 26492065 TI - Health-related Quality of Life and Survival in Pulmonary Arterial Hypertension. AB - RATIONALE: Pulmonary arterial hypertension is a progressive disease with high morbidity and mortality despite advances in medical therapy. The relationship between patient-related outcomes, such as health-related quality of life (HRQOL), and survival is not well described. OBJECTIVE: To assess the relationship between HRQOL and outcomes in patients with pulmonary arterial hypertension. METHODS: Consecutive patients with right heart catheterization-proven pulmonary arterial hypertension who completed the Medical Outcomes Survey Short Form-36 survey (SF 36) were included. Demographic, clinical, physiological, and hemodynamic data were collected at baseline. Survival was assessed from the time of diagnosis of pulmonary arterial hypertension. Cox proportional hazard models were constructed to assess the relationship between HRQOL and transplant-free survival. MEASUREMENTS AND MAIN RESULTS: Eighty-seven patients with pulmonary arterial hypertension were enrolled and followed prospectively for a median of 3.8 years. At baseline, HRQOL was significantly worse than U.S. normal values for six of eight domains of the SF-36. Several domains demonstrated moderate correlation (r value >= 0.40) with 6-minute-walk distance and World Health Organization functional class; there were no significant associations with hemodynamics. In univariable Cox proportional hazard models, six of eight domains and both summary scores were significantly associated with survival. In multivariable models, adjusted for age, disease type, and cardiac function, these relationships largely persisted. CONCLUSIONS: In this cohort of patients with pulmonary arterial hypertension, HRQOL, as assessed by the SF-36, was strongly associated with transplant-free survival. These relationships persisted when controlling for potential confounders such as disease type and disease severity. These findings suggest that HRQOL may be an important predictor of outcomes in pulmonary arterial hypertension and therefore a target for future therapeutic interventions. PMID- 26492066 TI - Long-term opioid therapy for chronic non-cancer pain in Germany. AB - BACKGROUND: No data are available on the prevalence and predictors of (high-dose) long-term opioid therapy (LTOT) and on abuse/addiction of prescribed opioids by patients with chronic non-cancer pain (CNCP) outside North America and Scandinavia. METHODS: We analysed randomly selected claims records of 870,000 persons (10% of insureds) in a large German medical health insurance organization during the fiscal year 2012. RESULTS: The prevalence of LTOT prescriptions (defined by at least one opioid prescription per quarter for at least three consecutive quarters) for CNCP was 1.3% of all insureds. The mean daily dosage of LTOT was 58 (SD 79; minimum 0.3, maximum 2010) mg morphine equivalent/day. The percentage of insureds with high-dose opioid prescriptions (>=100 mg morphine equivalent/day) among LTOT insureds was 15.5%. High-dose LTOT (compared to traditional dose) prescription was associated with younger age, male gender, diagnoses of chronic pain disease, somatoform pain disorder, depression and prescription of anticonvulsants. The pooled 1-year prevalence of abuse/addiction of prescribed opioids (defined by hospital stays because of mental and behavioural disorders due to alcohol, opioids, tranquilizers, multiple substances and intoxications by narcotic agents) was 0.56%. Abuse/addiction of prescribed opioids was associated with younger age, diagnoses of somatoform pain disorder, depression and prescription of tranquilizers. CONCLUSIONS: The study found no signals of an 'opioid epidemic' in Germany. However, careful selection of patients with CNCP considered for LTOT and continuous evaluation during LTOT are warranted. PMID- 26492067 TI - The cytoprotective effects of ethanol extract of Ecklonia cava against oxidative stress are associated with upregulation of Nrf2-mediated HO-1 and NQO-1 expression through activation of the MAPK pathway. AB - The aim of the present study was to examine the cytoprotective effect of Ecklonia cava against oxidative stress in C2C12 myoblasts. The ethanol extract of E. cava (EEEC) prevented hydrogen peroxide (H2O2)-induced inhibition of the growth of C2C12 myoblasts and exhibited scavenging activity against intracellular reactive oxygen species (ROS) induced by H2O2. EEEC treatment attenuated H2O2-induced comet tail formation and phospho-histone gammaH2A.X expression. Furthermore, EEEC treatment enhanced the level of the phosphorylated form of nuclear factor erythroid 2- related factor 2 (Nrf2) and its nuclear translocation, which was associated with the induction of heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase 1 (NQO-1). Zinc protoporphyrin IX, a HO-1 competitive inhibitor, significantly abolished the protective effects of EEEC against H2O2-induced ROS generation and growth inhibition in C2C12 myoblasts. Transient transfection with Nrf2-specific small interfering RNA restored the elevated HO-1 and NQO-1 expression and the phosphorylation of Nrf2 to near normal levels. The EEEC treatment also induced the activation of mitogen-activated protein kinases (MAPKs), and specific inhibitors of MAPKs abolished upregulated HO-1 and NQO-1, as well as the phosphorylation of Nrf2. Taken together, these data suggest that EEEC attenuates oxidative stress by activating Nrf2-mediated HO-1 and inducing NQO-1 via the activation of MAPK signaling pathways. PMID- 26492068 TI - Cardioprotective effect of postconditioning against ischemia-reperfusion injury is lost in heart of 8-week diabetic rat. AB - Although ischemic preconditioning (IPC) and ischemic postconditioning (IPost) result in protection against ischemia-reperfusion (I/R) injury in healthy hearts, pathological conditions such as diabetes can modify the protective effects of IPC and IPost. There are a few studies concerning the effect of IPost only in diabetic hearts which have similar or decreased tolerance to I/R injury. In the present study we investigated the effects of IPost in diabetic hearts which had increased tolerance to I/R injury. Isolated hearts from control and diabetic rats were subjected to global ischemia (40 min) followed by reperfusion (40 min). IPost was induced by six cycles (10 s) of reperfusion and ischemia after the global ischemia. After I/R, cardiac recovery in diabetic hearts was better than that in control hearts. IPost did not produce any further protection in the diabetic hearts whereas it resulted in a significant recovery in the control hearts. Similarly, the decreased troponin I (TnI) levels of diabetic hearts did not change after IPost. However, IPost significantly lowered the increase in TnI levels of control hearts. In conclusion, these results show that IPost can not produce a further protection in the hearts of 8-week diabetic rats which have increased tolerance to I/R injury. PMID- 26492069 TI - Recent advances in iPSC technologies involving cardiovascular and neurodegenerative disease modeling. AB - Cardiovascular and neurodegenerative diseases are the most common health threats in developed countries. Limited cell derivation and cell number in cardiac tissue makes it difficult to study the cardiovascular disease using the existing cardiac cell model. Regarding the neurodegenerative disorders, the most potential sources of cell therapeutics such as fetal-derived primary neurons and human embryonic stem cells (ESCs) are associated with ethical or technical limitations. The successful derivation of human-induced pluripotent stem cells (iPSCs) by de differentiation of somatic cells offers significant potential to overcome hurdles in the field of the replacement therapy. Human iPSCs are functionally similar to human embryonic stem cells, and can be derived autologously without the ethical challenges associated with human ESCs. The iPSCs can, in turn, be differentiated into all cell types including neurons, cardiac cells, blood and liver cells, etc. Recently, target tissues derived from human iPSCs such as cardiomyocytes (CMs) or neurons have been used for new disease modeling and regenerative medicine therapies. Diseases models could be advantageous in the development of personalized medicine of various pathological conditions. This paper reviews efforts aimed at both the practical development of iPSCs, differentiation to neural/cardiac lineages, and the further use of these iPSCs-derived cells for disease modeling, as well as drug toxicity testing. PMID- 26492070 TI - Concept of relative variability of cardiac action potential duration and its test under various experimental conditions. AB - Beat-to-beat variability of action potential duration (short-term variability, SV) is an intrinsic property of mammalian myocardium. Since the majority of agents and interventions affecting SV may modify also action potential duration (APD), we propose here the concept of relative SV (RSV), where changes in SV are normalized to changes in APD and these data are compared to the control SV-APD relationship obtained by lengthening or shortening of action potentials by inward and outward current injections. Based on this concept the influence of the several experimental conditions like stimulation frequency, temperature, pH, redox-state and osmolarity were examined on RSV in canine ventricular myocytes using sharp microelectrodes. RSV was increased by high stimulation frequency (cycle lengths <0.7 s), high temperature (above 37oC), oxidative agents (H2O2), while it was decreased by reductive environment. RSV was not affected by changes in pH (within the range of 6.4-8.4) and osmolarity of the solution (between 250 350 mOsm). The results indicate that changes in beat-to-beat variability of APD must be evaluated exclusively in terms of RSV; furthermore, some experimental conditions, including the stimulation frequency, redox-state and temperature have to be controlled strictly when analyzing alterations in the short-term variability of APD. PMID- 26492071 TI - The effect of aerobic exercise on hepatotoxicity induced by intratracheal instillation of iron oxide nanoparticles in Wistar rats. AB - Iron oxide nanoparticles (IONPs) can cause significant health problems due to their unique physicochemical properties and environmental characteristics. They are found as ultrafine particles in ambient air. After inhalation, these particles move from the lung to phagocytosis tissues, especially the liver. The aim of present study was to investigate the effect of concurrent aerobic exercise and IONPs on liver enzymes and histological hepatic appearance. 48 rats were divided into six groups: experimental 1 (aerobic exercise), experimental 2 (nanoparticle, anesthesia), experimental 3 (aerobic exercise, nanoparticles, anesthesia), placebo 4 (distilled water, anesthesia), placebo 5 (aerobic exercise, anesthesia), and control group. In groups 2 and 3, 40 mg/kg/b.w. of IONPs was injected via intratracheal installation every other day for 14 days. Groups 1, 3, and 5 [corrected] run on treadmill for 30 minutes with the intensity of 35-40% VO2max (maximal oxygen consumption) every day. ALT was increased in group 1 but decreased in groups 2 and 3. AST was not significant in any of the groups, while ALP was reduced significantly in groups 2 and 3 (p < 0.05). Histological examination of the liver showed that, in groups 2 and 3, hepatic cells were damaged and also the congestion, inflammation, mononuclear cell infiltration, and ballooning degeneration were occurred. Tissue injuries in group 3 were less than those of group 2. These findings indicated that hepatotoxicity was caused by iron oxide nanoparticles; however, low-intensity aerobic exercise could decrease the damage somewhat. PMID- 26492072 TI - The influence of zinc on the blood serum of cadmium-treated rats through the rheological properties. AB - The blood rheological properties serve as an important indicator for the early detection of many diseases. This study aimed to investigate the influence of zinc (Zn) on blood serum of cadmium (Cd) intoxication-treated male rats through the rheological properties. The rheological parameters were measured in serum of control, Cd, and Cd+Zn groups at wide range of shear rates (225-1875 s(-1)). The rat blood serum showed a non-significant change in cadmium-treated rats' %torque and shear stress at the lower shear rates (200-600 s(-1)) while a significant increase was observed at the higher shear rates (650-1875 s(-1)) compared with the control. The rat blood serum viscosity increased significantly in the Cd treated group at each shear rate compared with the control. The viscosity and shear rate exhibited a non-Newtonian behavior for all groups. The increase in blood serum viscosity in Cd-treated male rats might be attributed to destruction or changes in the non-clotting proteins, and other blood serum components. In Cd+Zn-treated rats, the rat blood serum viscosity values returned nearer to the control values at each shear rate. Our results confirmed that Zn displaced Cd or compete with the binding sites for Cd uptake. PMID- 26492075 TI - Porphyrin cosensitization for a photovoltaic efficiency of 11.5%: a record for non-ruthenium solar cells based on iodine electrolyte. AB - Dye-sensitized solar cells (DSSCs) are promising for utilizing solar energy. To achieve high efficiencies, it is vital to synergistically improve the photocurrent (Jsc) and the photovoltage (Voc). In this respect, conjugation framework extension and cosensitization are effective for improving the absorption and the Jsc, which, however, is usually accompanied by undesirably decreased Voc. Herein, based on a rationally optimized porphyrin dye, we develop a targeted coadsorption/cosensitization approach for systematically improving the Voc from 645 to 727, 746, and 760 mV, with synergistical Jsc enhancement from 18.83 to 20.33 mA cm(-2). Thus, the efficiency has been dramatically enhanced to 11.5%, which keeps the record for nonruthenium DSSCs using the I2/I3(-) electrolyte. These results compose an alternative approach for developing highly efficient DSSCs with relatively high Voc using traditional iodine electrolyte. PMID- 26492073 TI - Mre11 and Blm-Dependent Formation of ALT-Like Telomeres in Ku-Deficient Ustilago maydis. AB - A subset of human cancer cells uses a specialized, aberrant recombination pathway known as ALT to maintain telomeres, which in these cells are characterized by complex aberrations including length heterogeneity, high levels of unpaired C strand, and accumulation of extra-chromosomal telomere repeats (ECTR). These phenotypes have not been recapitulated in any standard budding or fission yeast mutant. We found that eliminating Ku70 or Ku80 in the yeast-like fungus Ustilago maydis results initially in all the characteristic telomere aberrations of ALT cancer cells, including C-circles, a highly specific marker of ALT. Subsequently the ku mutants experience permanent G2 cell cycle arrest, accompanied by loss of telomere repeats from chromosome ends and even more drastic accumulation of very short ECTRs (vsECTRs). The deletion of atr1 or chk1 rescued the lethality of the ku mutant, and "trapped" the telomere aberrations in the early ALT-like stage. Telomere abnormalities are telomerase-independent, but dramatically suppressed by deletion of mre11 or blm, suggesting major roles for these factors in the induction of the ALT pathway. In contrast, removal of other DNA damage response and repair factors such as Rad51 has disparate effects on the ALT phenotypes, suggesting that these factors process ALT intermediates or products. Notably, the antagonism of Ku and Mre11 in the induction of ALT is reminiscent of their roles in DSB resection, in which Blm is also known to play a key role. We suggest that an aberrant resection reaction may constitute an early trigger for ALT telomeres, and that the outcomes of ALT are distinct from DSB because of the unique telomere nucleoprotein structure. PMID- 26492074 TI - Utilization of an Eilat Virus-Based Chimera for Serological Detection of Chikungunya Infection. AB - In December of 2013, chikungunya virus (CHIKV), an alphavirus in the family Togaviridae, was introduced to the island of Saint Martin in the Caribbean, resulting in the first autochthonous cases reported in the Americas. As of January 2015, local and imported CHIKV has been reported in 50 American countries with over 1.1 million suspected cases. CHIKV causes a severe arthralgic disease for which there are no approved vaccines or therapeutics. Furthermore, the lack of a commercially available, sensitive, and affordable diagnostic assay limits surveillance and control efforts. To address this issue, we utilized an insect specific alphavirus, Eilat virus (EILV), to develop a diagnostic antigen that does not require biosafety containment facilities to produce. We demonstrated that EILV/CHIKV replicates to high titers in insect cells and can be applied directly in enzyme-linked immunosorbent assays without inactivation, resulting in highly sensitive detection of recent and past CHIKV infection, and outperforming traditional antigen preparations. PMID- 26492076 TI - Progress in the reduction of carbon monoxide levels in major urban areas in Korea. AB - Long-term trends in observed carbon monoxide (CO) concentrations were analyzed in seven major South Korean cities from 1989 to 2013. Temporal trends were evident on seasonal and annual timescales, as were spatial gradients between the cities. As CO levels in the most polluted cities decreased significantly until the early 2000s, the data were arbitrarily divided into two time periods (I: 1989-2000 and II: 2001-2013) for analysis. The mean CO concentration of period II was about 50% lower than that of period I. Long-term trends of annual mean CO concentrations, examined using the Mann-Kendall (MK) method, confirm a consistent reduction in CO levels from 1989 to 2000 (period I). The abrupt reduction in CO levels was attributed to a combination of technological improvements and government administrative/regulatory initiatives (e.g., emission mitigation strategies and a gradual shift in the fuel/energy consumption mix away from coal and oil to natural gas and nuclear power). PMID- 26492077 TI - Cross-talk modulation between ABA and ethylene by transcription factor SlZFP2 during fruit development and ripening in tomato. AB - The stress hormone ABA not only regulates stress response, but is also required for plant development and growth. Some evidences indicate that ABA plays a pivotal role in the ripening process of non climacteric as well as climacteric fruits. In a recent study, we showed that the tomato (Solanum lycopersicum) transcription factor SlZFP2 fine tunes ABA biosynthesis during fruit development through direct suppression of ABA biosynthetic genes and it also regulates fruit ripening through transcriptional suppression of the ripening regulator CNR. This indicates that SlZFP2 likely modulates the cross-talk between ABA and ethylene in regulation of fruit development and ripening in tomato. Gene expression analysis using ABA deficient mutants sit and flc as well as the SlZFP2 RNAi lines of high fruit ABA production showed that ethylene biosynthetic genes LeACS1A, LeACS1 and LeACO1 were positively regulated by ABA during early fruit growth. We reason that ABA promotes basal ethylene biosynthesis in system 1 during fruit growth and likely plays a minor role in ripening regulation after the onset of ripening process. PMID- 26492078 TI - Perspectives on safer conception practices and preconception counseling among women living with HIV. AB - Pregnancies are frequently unplanned, and higher rates of unplanned pregnancies occur among HIV-infected women. Reviewers examined reproductive decision making, conception practices, and patient-provider communication among women living with HIV. Qualitative interviews were conducted with 19 HIV-infected sexually active women aged 18-45 in southern Florida, USA. Using thematic analysis, we found decisions to conceive were influenced by women and partners; knowledge and use of safer conception practices were low. Discussion and support from partners, family, and providers was limited and diminished by stigma and nondisclosure. Preconception counseling discussions in HIV care should be comprehensive and initiated frequently by all health care providers. PMID- 26492079 TI - Clinical Potential of Effective Noninvasive Exclusion of KEL1-Positive Fetuses in KEL1-Negative Pregnant Women. AB - BACKGROUND: The clinical importance of assessing the fetal KEL genotype is to exclude 'K'-positive fetuses (genotype KEL1/KEL2) in 'K'-alloimmunized pregnant women (genotype KEL2/KEL2). Noninvasive assessment of the fetal KEL genotype is not yet available in the Czech Republic. OBJECTIVE: The aim of this study was to assess the fetal KEL1/KEL2 genotype from cell-free fetal DNA in the plasma of KEL2/KEL2 pregnant women. METHODS: The fetal genotype was assessed by minisequencing (a dilution series including control samples). A total of 138 pregnant women (between the 8th and 23rd gestational week) were tested by minisequencing. The fetal genotype was further verified by analysis of a buccal swab from the newborn. RESULTS: Minisequencing proved to be a reliable method. In 2.2% (3/138) of the examined women, plasma sample testing failed; 94.8% (128/135) had the KEL2/KEL2 genotype, and a total of 3.1% of fetuses (4/128) had the KEL1/KEL2 genotype. Sensitivity and specificity reached 100% (p < 0.0001). CONCLUSION: Minisequencing is a reliable method for the assessment of the fetal KEL1 allele from the plasma of KEL2/KEL2 pregnant women. PMID- 26492080 TI - Rv3351c, a Mycobacterium tuberculosis gene that affects bacterial growth and alveolar epithelial cell viability. AB - Despite the interactions known to occur between various lower respiratory tract pathogens and alveolar epithelial cells (AECs), few reports examine factors influencing the interplay between Mycobacterium tuberculosis bacilli and AECs during infection. Importantly, in vitro studies have demonstrated that the M. tuberculosis hbha and esxA gene products HBHA and ESAT6 directly or indirectly influence AEC survival. In this report, we identify Rv3351c as another M. tuberculosis gene that impacts the fate of both the pathogen and AEC host. Intracellular replication of an Rv3351c mutant in the human AEC type II pneumocyte cell line A549 was markedly reduced relative to the complemented mutant and parent strain. Deletion of Rv3351c diminished the release of lactate dehydrogenase and decreased uptake of trypan blue vital stain by host cells infected with M. tuberculosis bacilli, suggesting attenuated cytotoxic effects. Interestingly, an isogenic hbha mutant displayed reductions in AEC killing similar to those observed for the Rv3351c mutant. This opens the possibility that multiple M. tuberculosis gene products interact with AECs. We also observed that Rv3351c aids intracellular replication and survival of M. tuberculosis in macrophages. This places Rv3351c in the same standing as HBHA and ESAT6, which are important factors in AECs and macrophages. Defining the mechanism(s) by which Rv3351c functions to aid pathogen survival within the host may lead to new drug or vaccine targets. PMID- 26492081 TI - Deformation of the Outer Hair Cells and the Accumulation of Caveolin-2 in Connexin 26 Deficient Mice. AB - BACKGROUND: Mutations in GJB2, which encodes connexin 26 (Cx26), a cochlear gap junction protein, represent a major cause of pre-lingual, non-syndromic deafness. The degeneration of the organ of Corti observed in Cx26 mutant-associated deafness is thought to be a secondary pathology of hearing loss. Here we focused on abnormal development of the organ of Corti followed by degeneration including outer hair cell (OHC) loss. METHODS: We investigated the crucial factors involved in late-onset degeneration and loss of OHC by ultrastructural observation, immunohistochemistry and protein analysis in our Cx26-deficient mice (Cx26f/fP0Cre). RESULTS: In ultrastructural observations of Cx26f/fP0Cre mice, OHCs changed shape irregularly, and several folds or notches were observed in the plasma membrane. Furthermore, the mutant OHCs had a flat surface compared with the characteristic wavy surface structure of OHCs of normal mice. Protein analysis revealed an increased protein level of caveolin-2 (CAV2) in Cx26f/fP0Cre mouse cochlea. In immunohistochemistry, a remarkable accumulation of CAV2 was observed in Cx26f/fP0Cre mice. In particular, this accumulation of CAV2 was mainly observed around OHCs, and furthermore this accumulation was observed around the shrunken site of OHCs with an abnormal hourglass-like shape. CONCLUSIONS: The deformation of OHCs and the accumulation of CAV2 in the organ of Corti may play a crucial role in the progression of, or secondary OHC loss in, GJB2-associated deafness. Investigation of these molecular pathways, including those involving CAV2, may contribute to the elucidation of a new pathogenic mechanism of GJB2-associated deafness and identify effective targets for new therapies. PMID- 26492084 TI - Self-Assembly of Asymmetrically Interacting ABC Star Triblock Copolymer Melts. AB - The phase behavior of asymmetrically interacting ABC star triblock copolymer melts is investigated by the self-consistent field theory (SCFT). Motivated by the experimental systems, in this study, we focus on the systems in which the Flory-Huggins interaction parameters satisfy chiAC > chi BC ~ chiAB. Using various initialization strategies, a large number of periodic structures have been obtained in our calculations. A fourth-order pseudospectral algorithm combined with Anderson mixing method is used to compute the free energy of candidate structures carefully. The stability has been analyzed in detail by splitting the free energy into internal and entropic parts. A complete and complex triangular phase diagram is presented for a model with chiAC > chiBC = chiAB in which 15 ordered phases, including two- and three-dimensional structures, have been predicted to be stable from the SCFT calculations. Generally speaking, with the asymmetrical interactions, the hierarchical structures tend to be formed near the B-rich corner of the triangular phase diagram. This work broadens the previous theoretical results from equal interaction systems to unequal interaction systems. The predicted phase behavior is in good agreement with experimental observations and previous theoretical results. PMID- 26492083 TI - Self-Assembling NanoLuc Luciferase Fragments as Probes for Protein Aggregation in Living Cells. AB - Given the clear role of protein aggregation in human disease, there is a critical need for assays capable of quantifying protein aggregation in living systems. We hypothesized that the inherently low background and biocompatibility of luminescence signal readouts could provide a potential solution to this problem. Herein, we describe a set of self-assembling NanoLuc luciferase (Nluc) fragments that produce a tunable luminescence readout that is dependent upon the solubility of a target protein fused to the N-terminal Nluc fragment. To demonstrate this approach, we employed this assay in bacteria to assess mutations known to disrupt amyloid-beta (Abeta) aggregation as well as disease-relevant mutations associated with familial Alzheimer's diseases. The luminescence signal from these experiments correlates with the reported aggregation potential of these Abeta mutants and reinforces the increased aggregation potential of disease-relevant mutations in Abeta1-42. To further demonstrate the utility of this approach, we show that the effect of small molecule inhibitors on Abeta aggregation can be monitored using this system. In addition, we demonstrate that aggregation assays can be ported into mammalian cells. Taken together, these results indicate that this platform could be used to rapidly screen for mutations that influence protein aggregation as well as inhibitors of protein aggregation. This method offers a novel, genetically encodable luminescence readout of protein aggregation in living cells. PMID- 26492082 TI - The Effects of Acute Dopamine Precursor Depletion on the Cognitive Control Functions of Performance Monitoring and Conflict Processing: An Event-Related Potential (ERP) Study. AB - Studies using medications and psychiatric populations implicate dopamine in cognitive control and performance monitoring processes. However, side effects associated with medication or studying psychiatric groups may confound the relationship between dopamine and cognitive control. To circumvent such possibilities, we utilized a randomized, double-blind, placebo-controlled, within subjects design wherein participants were administered a nutritionally-balanced amino acid mixture (BAL) and an amino acid mixture deficient in the dopamine precursors tyrosine (TYR) and phenylalanine (PHE) on two separate occasions. Order of sessions was randomly assigned. Cognitive control and performance monitoring were assessed using response times (RT), error rates, the N450, an event-related potential (ERP) index of conflict monitoring, the conflict slow potential (conflict SP), an ERP index of conflict resolution, and the error related negativity (ERN) and error positivity (Pe), ERPs associated with performance monitoring. Participants were twelve males who completed a Stroop color-word task while ERPs were collected four hours following acute PHE and TYR depletion (APTD) or balanced (BAL) mixture ingestion in two separate sessions. N450 and conflict SP ERP amplitudes significantly differentiated congruent from incongruent trials, but did not differ as a function of APTD or BAL mixture ingestion. Similarly, ERN and Pe amplitudes showed significant differences between error and correct trials that were not different between APTD and BAL conditions. Findings indicate that acute dopamine precursor depletion does not significantly alter cognitive control and performance monitoring ERPs. Current results do not preclude the role of dopamine in these processes, but suggest that multiple methods for dopamine-related hypothesis testing are needed. PMID- 26492085 TI - Novel Function of Lysine Methyltransferase G9a in the Regulation of Sox2 Protein Stability. AB - G9a is a lysine methyltransferase (KMTase) for histone H3 lysine 9 that plays critical roles in a number of biological processes. Emerging evidence suggests that aberrant expression of G9a contributes to tumor metastasis and maintenance of a malignant phenotype in cancer by inducing epigenetic silencing of tumor suppressor genes. Here, we show that G9a regulates Sox2 protein stability in breast cancer cells. When G9a lysine methyltransferase activity was chemically inhibited in the ER(+) breast cancer cell line MCF7, Sox2 protein levels were decreased. In addition, ectopic overexpression of G9a induced accumulation of Sox2. Changes in cell migration, invasion, and mammosphere formation by MCF7 cells were correlated with the activity or expression level of G9a. Ectopic expression of G9a also increased Sox2 protein levels in another ER(+) breast cancer cell line, ZR-75-1, whereas it did not affect Sox2 expression in MDA-MB 231 cells, an ER(-) breast cancer cell line, or in glioblastoma cell lines. Furthermore, treatment of mouse embryonic stem cells with a KMT inhibitor, BIX 01294, resulted in a rapid reduction in Sox2 protein expression despite increased Sox2 transcript levels. This finding suggests that G9a has a novel function in the regulation of Sox2 protein stability in a cell type-dependent manner. PMID- 26492086 TI - Formal Synthesis of (+)-Lasubine II and (-)-Subcosine II via Organocatalytic Michael Addition of a Ketone to an alpha-Nitrostyrene. AB - The first examples of an organocatalytic Michael addition of a ketone to in situ generated alpha-nitrostyrenes are reported. A suitably functionalized gamma nitroketone obtained from the organocatalyzed Michael addition was converted into (+)-2-epi-lasubine II, the immediate synthetic precursor of (+)-lasubine II and ( )-subcosine II (enantiomers of the natural quinolizidine alkaloids). Two of the three stereocenters in (+)-2-epi-lasubine II are set by the Michael reaction. PMID- 26492087 TI - Archeal lectins: An identification through a genomic search. AB - Forty-six lectin domains which have homologues among well established eukaryotic and bacterial lectins of known three-dimensional structure, have been identified through a search of 165 archeal genomes using a multipronged approach involving domain recognition, sequence search and analysis of binding sites. Twenty-one of them have the 7-bladed beta-propeller lectin fold while 16 have the beta-trefoil fold and 7 the legume lectin fold. The remainder assumes the C-type lectin, the beta-prism I and the tachylectin folds. Acceptable models of almost all of them could be generated using the appropriate lectins of known three-dimensional structure as templates, with binding sites at one or more expected locations. The work represents the first comprehensive bioinformatic study of archeal lectins. The presence of lectins with the same fold in all domains of life indicates their ancient origin well before the divergence of the three branches. Further work is necessary to identify archeal lectins which have no homologues among eukaryotic and bacterial species. PMID- 26492088 TI - Phospholipase D2 Modulates the Secretory Pathway in RBL-2H3 Mast Cells. AB - Phospholipase D (PLD) hydrolyses phosphatidylcholine to produce phosphatidic acid (PA) and choline. It has two isoforms, PLD1 and PLD2, which are differentially expressed depending on the cell type. In mast cells it plays an important role in signal transduction. The aim of the present study was to clarify the role of PLD2 in the secretory pathway. RBL-2H3 cells, a mast cell line, transfected to overexpress catalytically active (PLD2CA) and inactive (PLD2CI) forms of PLD2 were used. Previous observations showed that the Golgi complex was well organized in CA cells, but was disorganized and dispersed in CI cells. Furthermore, in CI cells, the microtubule organizing center was difficult to identify and the microtubules were disorganized. These previous observations demonstrated that PLD2 is important for maintaining the morphology and organization of the Golgi complex. To further understand the role of PLD2 in secretory and vesicular trafficking, the role of PLD2 in the secretory process was investigated. Incorporation of sialic acid was used to follow the synthesis and transport of glycoconjugates in the cell lines. The modified sialic acid was subsequently detected by labeling with a fluorophore or biotin to visualize the localization of the molecule after a pulse-chase for various times. Glycoconjugate trafficking was slower in the CI cells and labeled glycans took longer to reach the plasma membrane. Furthermore, in CI cells sialic acid glycans remained at the plasma membrane for longer periods of time compared to RBL-2H3 cells. These results suggest that PLD2 activity plays an important role in regulating glycoconjugate trafficking in mast cells. PMID- 26492089 TI - Optimized (31)P MRS in the human brain at 7 T with a dedicated RF coil setup. AB - The design and construction of a dedicated RF coil setup for human brain imaging ((1)H) and spectroscopy ((31)P) at ultra-high magnetic field strength (7 T) is presented. The setup is optimized for signal handling at the resonance frequencies for (1)H (297.2 MHz) and (31)P (120.3 MHz). It consists of an eight channel (1)H transmit-receive head coil with multi-transmit capabilities, and an insertable, actively detunable (31)P birdcage (transmit-receive and transmit only), which can be combined with a seven-channel receive-only (31)P array. The setup enables anatomical imaging and (31)P studies without removal of the coil or the patient. By separating transmit and receive channels and by optimized addition of array signals with whitened singular value decomposition we can obtain a sevenfold increase in SNR of (31)P signals in the occipital lobe of the human brain compared with the birdcage alone. These signals can be further enhanced by 30 +/- 9% using the nuclear Overhauser effect by B1-shimmed low-power irradiation of water protons. Together, these features enable acquisition of (31)P MRSI at high spatial resolutions (3.0 cm(3) voxel) in the occipital lobe of the human brain in clinically acceptable scan times (~15 min). PMID- 26492090 TI - Phase I Dose-Escalation and Pharmacokinetic Study of Intravenous Aflibercept in Combination with Docetaxel, Cisplatin, and 5-Fluorouracil in Patients with Advanced Solid Malignancies. AB - PURPOSE: This phase I study (EudraCT No. 2006-001177-25) investigated aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received 2, 4, or 6 mg/kg of intravenous aflibercept with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 5-fluorouracil 750 mg/m2 in 3-week cycles until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLTs) during cycle 1 and to determine the recommended phase II dose. Pharmacokinetics, tolerability, and antitumor activity were also investigated. RESULTS: Forty-four patients were enrolled and treated (29 patients in a dose escalation phase and 15 patients in an expansion cohort). Following three cases of febrile neutropenia in patients receiving aflibercept at 4 mg/kg, the protocol was amended to allow earlier granulocyte colony-stimulating factor support (from day 6) and prophylactic use of ciprofloxacin. Subsequently, there were two DLTs: febrile neutropenia (2 mg/kg) and grade 4 pulmonary embolism (6 mg/kg). An excess of free over VEGF-bound aflibercept was observed at 6 mg/kg. The most frequent grade 3/4 adverse events (AEs) were neutropenia (54.5%), lymphopenia (47.7%), and stomatitis (38.6%). AEs associated with VEGF blockade (any grade) included epistaxis (61.4%), dysphonia (40.9%), hypertension (38.6%), and proteinuria (11.4%). There were 15 partial responses, including 9 in patients with gastroesophageal cancers. Thirteen patients had stable disease. CONCLUSION: Aflibercept 6 mg/kg administered every 3 weeks in combination with docetaxel, cisplatin, and 5- fluorouracil is the recommended dose for further clinical development based on tolerability, pharmacokinetics, and antitumor activity. PMID- 26492091 TI - Vulnerability of the Oceanic Whitetip Shark to Pelagic Longline Fisheries. AB - A combination of fisheries dependent and independent data was used to assess the vulnerability of the oceanic whitetip shark to pelagic longline fisheries. The Brazilian tuna longline fleet, operating in the equatorial and southwestern Atlantic, is used as a case study. Fisheries dependent data include information from logbooks (from 1999 to 2011) and on-board observers (2004 to 2010), totaling 65,277 pelagic longline sets. Fisheries independent data were obtained from 8 oceanic whitetip sharks tagged with pop-up satellite archival tags in the area where longline fleet operated. Deployment periods varied from 60 to 178 days between 2010 and 2012. Tagging and pop-up sites were relatively close to each other, although individuals tended to travel long distances before returning to the tagging area. Some degree of site fidelity was observed. High utilization hotspots of tagged sharks fell inside the area under strongest fishing pressure. Despite the small sample size, a positive correlation between tag recorded information and catch data was detected. All sharks exhibited a strong preference for the warm and shallow waters of the mixed layer, spending on average more than 70% of the time above the thermocline and 95% above 120 m. Results indicate that the removal of shallow hooks on longline gear might be an efficient mitigation measure to reduce the bycatch of this pelagic shark species. The work also highlights the potential of tagging experiments to provide essential information for the development of spatio-temporal management measures. PMID- 26492092 TI - Histology of Pericardial Tissue Substitutes Used in Congenital Heart Surgery. AB - Pericardium is used as a tissue substitute during pediatric heart surgery. However, little is known about the histological characteristics of pericardial tissue substitutes. We searched our clinical and Pathology databases to identify cases in which glutaraldehyde-preserved autologous pericardium, PhotoFix bovine pericardium, or Peri-Guard Repair Patch glutaraldehyde-preserved bovine pericardium was used as patch material during cardiac surgery and in which explanted tissue substitute was available for histologic examination. Tissue sections were stained with hematoxylin and eosin, Masson trichrome, and Movat pentachrome, and were graded for inflammation, tissue substitute degeneration, neointima formation, and calcification. Nonparametric statistical methods were used to test differences between groups because of small sample size. The eight patients who received PhotoFix pericardium were older (median 10 months vs 10 days, P < 0.05) and the material was in situ longer (median 14 vs 2.5 months, P < 0.05) compared to the eight who received autologous pericardium. Only three patients received glutaraldehyde-preserved bovine pericardium precluding statistical comparison. Inflammation and tissue degeneration were greater in PhotoFix pericardium compared to autologous pericardium but were no more than moderate. Neointima formation and calcification did not differ significantly between the two groups. PhotoFix bovine pericardium is associated with more inflammation and material degeneration but calcification, and neointima formation are similar to autologous pericardium. Although the short-term outcomes are acceptable, calcification and degeneration seen in some cases suggest that long term outcomes and performance at certain anatomic locations need further study. PMID- 26492093 TI - Comparing concentration-based (AOT40) and stomatal uptake (PODY) metrics for ozone risk assessment to European forests. AB - Tropospheric ozone (O3) produces harmful effects to forests and crops, leading to a reduction of land carbon assimilation that, consequently, influences the land sink and the crop yield production. To assess the potential negative O3 impacts to vegetation, the European Union uses the Accumulated Ozone over Threshold of 40 ppb (AOT40). This index has been chosen for its simplicity and flexibility in handling different ecosystems as well as for its linear relationships with yield or biomass loss. However, AOT40 does not give any information on the physiological O3 uptake into the leaves since it does not include any environmental constraints to O3 uptake through stomata. Therefore, an index based on stomatal O3 uptake (i.e. PODY), which describes the amount of O3 entering into the leaves, would be more appropriate. Specifically, the PODY metric considers the effects of multiple climatic factors, vegetation characteristics and local and phenological inputs rather than the only atmospheric O3 concentration. For this reason, the use of PODY in the O3 risk assessment for vegetation is becoming recommended. We compare different potential O3 risk assessments based on two methodologies (i.e. AOT40 and stomatal O3 uptake) using a framework of mesoscale models that produces hourly meteorological and O3 data at high spatial resolution (12 km) over Europe for the time period 2000-2005. Results indicate a remarkable spatial and temporal inconsistency between the two indices, suggesting that a new definition of European legislative standard is needed in the near future. Besides, our risk assessment based on AOT40 shows a good consistency compared to both in-situ data and other model-based datasets. Conversely, risk assessment based on stomatal O3 uptake shows different spatial patterns compared to other model-based datasets. This strong inconsistency can be likely related to a different vegetation cover and its associated parameterizations. PMID- 26492094 TI - A systematic study comparing aspirate versus trephine for quantifying plasma cell infiltration in newly-diagnosed myeloma. PMID- 26492095 TI - Prototype Development of the Intelligent Hydrogel Wound Dressing and Its Efficacy in the Detection of Model Pathogenic Wound Biofilms. AB - The early detection of wound infection in situ can dramatically improve patient care pathways and clinical outcomes. There is increasing evidence that within an infected wound the main bacterial mode of living is a biofilm: a confluent community of adherent bacteria encased in an extracellular polymeric matrix. Here we have reported the development of a prototype wound dressing, which switches on a fluorescent color when in contact with pathogenic wound biofilms. The dressing is made of a hydrated agarose film in which the fluorescent dye containing vesicles were mixed with agarose and dispersed within the hydrogel matrix. The static and dynamic models of wound biofilms, from clinical strains of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis, were established on nanoporous polycarbonate membrane for 24, 48, and 72 h, and the dressing response to the biofilms on the prototype dressing evaluated. The dressing indicated a clear fluorescent/color response within 4 h, only observed when in contact with biofilms produced by a pathogenic strain. The sensitivity of the dressing to biofilms was dependent on the species and strain types of the bacterial pathogens involved, but a relatively higher response was observed in strains considered good biofilm formers. There was a clear difference in the levels of dressing response, when dressings were tested on bacteria grown in biofilm or in planktonic cultures, suggesting that the level of expression of virulence factors is different depending of the growth mode. Colorimetric detection on wound biofilms of prevalent pathogens (S. aureus, P. aeruginosa, and E. faecalis) is also demonstrated using an ex vivo porcine skin model of burn wound infection. PMID- 26492097 TI - Effects of Caffeic Acid Phenethyl Ester and 4-Vinylcatechol on the Stabilities of Oil-in-Water Emulsions of Stripped Soybean Oil. AB - Caffeic acid phenethyl ester (CAPE) and 4-vinylcatechol (4-VC) were prepared for studying their antioxidative activities in emulsion. Oil-in-water emulsions of stripped soybean oil containing 200 ppm of CAPE, 4-VC, or alpha-tocopherol were stored at 40 degrees C in the dark for 50 days, and proton nuclear magnetic resonance ((1)H NMR) was used to identify and quantify the oxidation products. Emulsion droplet sizes, peroxide values, and levels of primary oxidation products (i.e., hydroperoxides) and secondary oxidation products (i.e., aldehydes) were determined. The results showed that CAPE (200 ppm) and 4-VC (200 ppm) had significantly greater antioxidant activities on the oxidation of stripped soybean oil-in-water emulsions than alpha-tocopherol (200 ppm). The peroxide values of CAPE (8.4 mequiv/L emulsion) and 4-VC (15.0 mequiv/L emulsion) were significantly lower than that of alpha-tocopherol (33.4 mequiv/L emulsion) (p < 0.05) on 36 days. In addition, the combinations of CAPE + alpha-tocopherol (100 + 100 ppm) or 4-VC + alpha-tocopherol (100 + 100 ppm) had better antioxidant activities than alpha-tocopherol (200 ppm). For CAPE + alpha-tocopherol, 4-VC + alpha-tocopherol, and alpha-tocopherol, the amounts of conjugated diene forms were 16.67, 13.72, and 16.32 mmol/L emulsion, and the concentrations of aldehydes were 2.15, 1.13, and 4.26 mmol/L emulsion, respectively, after 50 days of storage. PMID- 26492096 TI - What's in a name? The pharmacy of vitamin K. PMID- 26492098 TI - Polybrominated diphenyl ethers and new polybrominated flame retardants in tree bark from western areas of China. AB - Tree bark samples were collected from 15 sites across western China in 2013, and the polybrominated diphenyl ether (PBDE) and new polybrominated flame retardant (NBFR) concentrations in the samples were determined. The mean total PBDE concentration was 51.8 ng/g lipid weight, which was 85.2% to 99.4% lower than in Chinese eastern coastal areas and the E-waste recycling areas. The dominant PBDE congener was BDE209, and its mean concentration was 49 ng/g lipid weight. The mean 2,3,5,6-tetrabromo-p-xylene, pentabromobenzene, pentabromotoluene, and hexabromobenzene concentrations were 0.61 ng/g, 0.97 ng/g, 0.68 ng/g, and 0.68 ng/g lw, respectively. The PBDE and NBFR concentrations in the air at the sampling sites were estimated from the concentrations in the tree bark samples. The estimated mean total PBDE and total NBFR concentrations in air were 58.5 pg/m(3) and 2.76 pg/m(3) , respectively. The sources of NBFR emissions were found to be different from the sources of PBDE emissions, as no relationship was found between the NBFR and PBDE concentrations, and it appeared that sources of measured hexabromobenzene, pentabromobenzene, and pentabromotoluene in tree bark in western China include industrial activity related to the aluminum industry. Environ Toxicol Chem 2016;35:1364-1370. (c) 2015 SETAC. PMID- 26492099 TI - Enhanced Electrorheological Properties of Elastomers Containing TiO2/Urea Core Shell Particles. AB - Polar molecule-coated core-shell particles have been used to prepare electrorheological (ER) fluids with high performance. Inspired by those studies, TiO2/urea core-shell structured particles were fabricated and used to prepare novel ER elastomers, whose properties were compared with the ER elastomers with bare TiO2 particles. Particles characterization results illustrate the TiO2/urea particles present little change in size, morphology and crystal structure with respect to the bare amorphous TiO2 particles, while clear core-shell structure is observed. Compared with the bare TiO2 particles filled elastomer, the TiO2/urea particles filled elastomer presents higher dielectric constant, indicating enhanced polarization. The viscoelastic properties of the two elastomers under different strain amplitude, frequency and electric field were tested. The results indicate that the TiO2/urea particles filled elastomer shows higher storage modulus G' and higher relative ER effect within the low field strength region from 0 to 2 kV/mm. Coating polar molecules is an effective method to improve the ER performance for ER elastomers. PMID- 26492100 TI - Twelve tips for early career medical educators. AB - The first 10 years of career development pose unique challenges for MD- and PhD trained faculty members working in medical education. These may include publishing peer-reviewed articles, winning grant funding, teaching, maintaining a clinical practice, and supporting professional communities both within and external to their institution. As the inaugural and current leaders of the ECME group in Canada, we have actively sought to better understand the challenges ECME faculty members face. We developed this understanding by surveying and tracking the qualitative reports of our ECME members, reviewing the (limited) literature available on ECME faculty members' experiences, and learning from our own experiences as ECME faculty and the advice shared by our own mentors. In this paper, we consolidate this knowledge into 12 tips for ECME faculty members. We suggest these tips will benefit both MD- and PhD-trained ECME faculty members as they strive for professional success. PMID- 26492101 TI - Effect of Different Sprint Training Methods on Sprint Performance Over Various Distances: A Brief Review. AB - Linear sprinting speed is an essential physical quality for many athletes. There are a number of different training modalities that can be used to improve sprint performance. Strength and conditioning coaches must select the most appropriate modalities for their athletes, taking into consideration the sprint distances that typically occur during competition. The study purpose was to perform a brief review as to the effect of specific (free sprinting; resisted sprinting by sleds, bands, or incline running; assisted sprinting with a towing device or a downhill slope), nonspecific (resistance and plyometric training), and combined (a combination of specific and nonspecific) training methods on different sprint distances (0-10, 0-20, 0-30, and 31+ m). A total of 48 studies fulfilled the inclusion criteria, resulting in 1,485 subjects from a range of athletic backgrounds. The training effects associated with specific sprint training were classified as moderate (effect size [ES] = -1.00; %change = -3.23). Generally, the effect of specific sprint training tended to decrease with distance, although the largest training effects were observed for the 31+ m distance. The greatest training effects (ES = -0.43; %change = -1.65) of nonspecific training were observed for the 31+ m distance. The combined training revealed greatest effects (ES = -0.59; %change = -2.81) for the 0-10 m distance. After this review, specific sprint training methods seem the most beneficial over the investigated distances. However, the implementation of nonspecific training methods (e.g., strength and power training) could also benefit speed and athletic performance. PMID- 26492102 TI - Observed Dietary Practices of Recreational Ultraendurance Cyclists in the Heat. AB - Dietary approaches for optimizing exercise performance have been debated in the literature for years. For endurance athletes, various position stands focus on recommendations for high-carbohydrate diets to maximize performance in events. However, theories of low-carbohydrate diets and their ability to provide more fuel may prove beneficial to ultraendurance athletes. Therefore, the purpose of this research was to observe the food and fluid consumption of successful recreational ultraendurance cyclists on the day before (ED-1), Event Day, and the day after (ED+1), a 162 km endurance event in a hot environment, and subsequently compare dietary intakes to recommendations and other observed dietary practices. Twenty men (age, 48 +/- 8 years; mass, 85.1 +/- 13.4 kg; height, 178.2 +/- 7.4 cm) recorded all dietary items during ED-1, Event Day, and ED+1. Diet composition and the relationships between carbohydrate and caloric intake with finish time were examined. Results show athletes consumed a high-carbohydrate diet on ED-1 (384 g.d), Event Day (657 g.d), and ED+1 (329 g.d). However, there were no significant associations between carbohydrate (p > 0.05), or caloric intake (p > 0.05), and finish time. This study results great variation in diets of recreational endurance cyclists, although most consume within nationally recognized dietary recommendation ranges. Because there is great variation and lack of correlation with performance, these findings suggest that current high carbohydrate dietary recommendations for general endurance athletes may not be sport specific or individualized enough for recreational ultraendurance cyclists, and that individualized dietary macronutrient composition manipulations may improve performance outcomes. PMID- 26492103 TI - Concurrent Strength and Interval Endurance Training in Elite Water Polo Players. AB - This study compared the effects of different high-intensity interval training (HIIT) intervals performed concurrently with strength and specific water polo training on performance indices of elite players. During the precompetition season, 2 water polo clubs were assigned to either HIIT of 4 * 4 minutes (n = 7, HIIT4 * 4) or HIIT of 16 * 100-m swimming efforts (n = 7, HIIT16 * 100). Both clubs applied the swimming (6% above the speed corresponding to blood lactate concentration of 4.0 mmol . L) and strength training (85-90% of 1 repetition maximum, 5 repetitions, 4 sets) twice per week concurrently with specific water polo training. Before and after the 8-week intervention period, maximal bench press strength was measured and a speed-lactate test (5 * 200 m) was performed to determine the speed corresponding to lactate concentration of 4.0, 5.0, and 10.0 mmol . L(-1). Maximal strength was improved in both groups (HIIT4 * 4: 14 +/- 4% vs. HIIT16 * 100: 19 +/- 10%). Improvements in speed corresponding to 4.0, 5.0, and 10.0 mmol . L(-1) were shown only after HIIT4 * 4 (9 +/- 5, 8 +/- 3, 7 +/- 2%, respectively; p < 0.01). However, HIIT16 * 100 was more effective in the differential velocity between 10.0 and 5.0 mmol . L(-) development (19 +/- 20%, p = 0.03). During the precompetition season, HIIT and strength training together with specific water polo training performed concurrently improves muscle strength and allows specific adaptations enhancing swimming performance of elite water polo players. PMID- 26492104 TI - Preliminary neurocognitive outcomes in Jeavons syndrome. AB - Jeavons syndrome (JS, eyelid myoclonia with absences [EMA]) consists of a triad of symptoms including eyelid myoclonia that may be accompanied by absence seizures, eye closure-induced EEG paroxysms or seizures, and photosensitivity. The age of onset ranges between 2 and 14 years with symptoms peaking between 6 and 8 years of age. Though investigation of the clinical, EEG, and neurological features of JS has occurred, neurocognitive functioning has not been well delineated despite suggestion that a subtype of the syndrome is characterized in part by cognitive impairment. The purpose of this study was to define neurocognitive functioning in a more detailed manner by examining global IQ and relevant neurocognitive domains (i.e., verbal and nonverbal reasoning, attention, executive functioning, memory) in pediatric patients. The sample (N=6, 4 females) ranged in age from 8 to 15 years (M=11, SD=2.82). All participants completed neuropsychological evaluations. Statistical analyses revealed performance that was below average on measures of global IQ, processing speed and rote, verbal learning coupled with average nonverbal reasoning, and sustained attention. There was also evidence of impaired higher-level verbal reasoning. While global IQ ranged from low average to borderline impaired, no participant could be accurately described as impaired or having intellectual disability (ID) given the consistently average performance noted on some higher-order tasks including nonverbal reasoning. PMID- 26492106 TI - Sinking myoma: A case of one-step cold loop hysteroscopic myomectomy. PMID- 26492105 TI - Mitochondrial Dysfunction and Ca(2+) Overload Contributes to Hesperidin Induced Paraptosis in Hepatoblastoma Cells, HepG2. AB - Paraptosis is a programmed cell death which is morphologically and biochemically different from apoptosis. In this study, we have investigated the role of Ca(2+) in hesperidin-induced paraptotic cell death in HepG2 cells. Increase in mitochondrial Ca(2+) level was observed in hesperidin treated HepG2 cells but not in normal liver cancer cells. Inhibition of inositol-1,4,5-triphosphate receptor (IP3 R) and ryanodine receptor also block the mitochondrial Ca(2+) accumulation suggesting that the release of Ca(2+) from the endoplasmic reticulum (ER) may probably lead to the increase in mitochondrial Ca(2+) level. Pretreatment with ruthenium red (RuRed), a Ca(2+) uniporter inhibitor inhibited the hesperidin induced mitochondrial Ca(2+) overload, swelling of mitochondria, and cell death in HepG2 cells. It has also been demonstrated that mitochondrial Ca(2+) influxes act upstream of ROS and mitochondrial superoxide production. The increased ROS production further leads to mitochondrial membrane loss in hesperidin treated HepG2 cells. Taken together our results show that IP3 R and ryanodine receptor mediated release of Ca(2+) from the ER and its subsequent influx through the uniporter into mitochondria contributes to hesperidin-induced paraptosis in HepG2 cells. PMID- 26492107 TI - Contribution of different antiretroviral regimens containing zidovudine, lamivudine and ritonavir-boosted lopinavir on HIV viral load reduction during pregnancy. AB - BACKGROUND: Antiretroviral (ARV) regimens used for the prevention of mother-to child transmission of HIV have evolved over time. We evaluated the contribution of different ARV regimens on the reduction of the plasma HIV RNA viral load (VL) during pregnancy. METHODS: A total of 1,833 VL measurements from ARV-naive pregnant women participating in perinatal prevention trials in Thailand were included. Women received either zidovudine (ZDV) monotherapy, ZDV plus lopinavir/ritonavir (LPV/r), or ZDV plus lamivudine (3TC) plus LPV/r. VL time course during pregnancy was described as a function of pretreatment VL and treatment duration using an Emax non-linear mixed-effect model. VL reduction and median time to achieve a VL<50 copies/ml were estimated for each regimen. RESULTS: Among 745 women, 279 (37%), 145 (20%) and 321 (43%) received ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. The predicted VL reduction from baseline to delivery after a median of 10 weeks of treatment were 0.5, 2.7 and 2.9 log10 copies/ml with ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. At delivery, 1%, 57% and 63% of women receiving ZDV monotherapy, ZDV+LPV/r or ZDV+3TC+LPV/r had a VL<50 copies/ml. The addition of 3TC to ZDV+LPV/r reduced the time to achieve a VL<50 copies/ml and the higher the pretreatment VL, the larger the effect 3TC had on reducing the time to VL<50 copies/ml. CONCLUSIONS: The addition of 3TC to ZDV+LPV/r was associated with a slight further VL reduction but the time to reach a VL<50 copies/ml was shorter. This beneficial effect of 3TC is crucial for prevention of mother-to-child transmission in women who receive ARVs late and with high pretreatment VL. PMID- 26492108 TI - Structural Transformation of Diblock Copolymer/Homopolymer Assemblies by Tuning Cylindrical Confinement and Interfacial Interactions. AB - In this study, we report the controllable structural transformation of block copolymer/homopolymer binary blends in cylindrical nanopores. Polystyrene-b poly(4-vinylpyridine)/homopolystyrene (SVP/hPS) nanorods (NRs) can be fabricated by pouring the polymers into an anodic aluminum oxide (AAO) channel and isolated by selective removal of the AAO membrane. In this two-dimensional (2D) confinement, SVP self-assembles into NRs with concentric lamellar structure, and the internal structure can be tailored with the addition of hPS. We show that the weight fraction and molecular weight of hPS and the diameter of the channels can significantly affect the internal structure of the NRs. Moreover, mesoporous materials with tunable pore shape, size, and packing style can be prepared by selective solvent swelling of the structured NRs. In addition, these NRs can transform into spherical structures through solvent-absorption annealing, triggering the conversion from 2D to 3D confinement. More importantly, the transformation dynamics can be tuned by varying the preference property of surfactant to the polymers. It is proven that the shape and internal structure of the polymer particles are dominated by the interfacial interactions governed by the surfactants. PMID- 26492109 TI - Carrier Mobility Enhancement of Tensile Strained Si and SiGe Nanowires via Surface Defect Engineering. AB - Changes in the carrier mobility of tensile strained Si and SiGe nanowires (NWs) were examined using an electrical push-to-pull device (E-PTP, Hysitron). The changes were found to be closely related to the chemical structure at the surface, likely defect states. As tensile strain is increased, the resistivity of SiGe NWs deceases in a linear manner. However, the corresponding values for Si NWs increased with increasing tensile strain, which is closely related to broken bonds induced by defects at the NW surface. Broken bonds at the surface, which communicate with the defect state of Si are critically altered when Ge is incorporated in Si NW. In addition, the number of defects could be significantly decreased in Si NWs by incorporating a surface passivated Al2O3 layer, which removes broken bonds, resulting in a proportional decrease in the resistivity of Si NWs with increasing strain. Moreover, the presence of a passivation layer dramatically increases the extent of fracture strain in NWs, and a significant enhancement in mobility of about 2.6 times was observed for a tensile strain of 5.7%. PMID- 26492110 TI - Update in vitamin D and multiple sclerosis. AB - Multiple sclerosis (MS) is a common neurological disease, and its etiology remains unknown. In recent years, increasing attention has been paid to the possible association between MS and vitamin D deficiency. Here, we review the current literature between MS and vitamin D, showing clear evidence that vitamin D deficiency is a risk factor for MS despite the lack of direct evidence for the effects of vitamin D in MS progression. PMID- 26492111 TI - The relationship between Willis-Ekbom disease and serum ferritin levels among children in Northwestern Turkey. AB - OBJECTIVE: To examine the incidence of restless legs syndrome (RLS) among children with iron deficiency, or iron deficiency anemia, or both, and the relationship between RLS prevalence and serum ferritin levels. METHODS: This prospective, cross-sectional, case controlled study was carried out between January and June 2013, and included 98 iron deficiency and/or iron deficiency anemia, and 102 healthy children referred to the Neurology and Pediatric Departments of the Medical Faculty of Bezmialem Vakif University, Istanbul, Turkey. Both groups were evaluated according to the International Restless Legs Syndrome Study Group diagnostic criteria. RESULTS: The range of ferritin levels was 0.01-12 mg/ml in patients while it was 12.3-91.8 mg/mL in the control group. Restless legs syndrome was detected in 61.2% of children with iron deficiency anemia, and in 37.3% of children with normal biochemistry values. A statistically significant correlation was found between serum ferritin levels and frequency of RLS. In patients with serum ferritin levels higher than 50 ng/ml, 92.3% had no RLS, while 55.2% of patients with serum ferritin levels lower than 50 ng/ml had RLS. The patients with serum ferritin levels of > 50 ng/ml had a significantly higher incidence of RLS. Serum ferritin levels were significantly different between the 2 groups. CONCLUSION: The incidence of RLS, also known as Willis Ekbom Disease, is high in children aged between 8-18 years with iron deficiency, or iron deficiency anemia, or both. This finding supports the importance of iron replacement therapy especially during the growth and development of children. PMID- 26492112 TI - Serum levels of zinc and copper in epileptic children during long-term therapy with anticonvulsants. AB - OBJECTIVE: To evaluate the serum levels of zinc and copper in epileptic children during the long-term treatment of anticonvulsant drugs and correlate this with healthy subjects. METHODS: A hospital-based group matched case-control study was conducted in the Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt between November 2013 and October 2014. Ninety patients aged 7.1 +/- 3.6 years were diagnosed with epilepsy by a neurologist. The control group was selected from healthy individuals and matched to the case group. Serum zinc and copper were measured by the calorimetric method using a colorimetric method kit. RESULTS: The mean zinc level was 60.1 +/- 22.6 ug/dl in the cases, and 102.1 +/- 18 ug/dl in the controls (p<0.001). The mean copper level was 180.1 +/- 32.4 ug/dl in cases compared with 114.5 +/- 18.5 ug/dl in controls (p<0.001). CONCLUSION: Serum zinc levels in epileptic children under drug treatment are lower compared with healthy children. Also, serum copper levels in these patients are significantly higher than in healthy people. No significant difference in the levels of serum copper and zinc was observed in using one drug or multiple drugs in the treatment of epileptic patients. PMID- 26492113 TI - Maternal knowledge of acute seizures. AB - OBJECTIVE: To study maternal knowledge -of, and behavior during acute seizures. METHODS: A cross sectional study conducted from September 2013 to January 2014 included consecutive mothers presenting at the Pediatric Neurology Clinics of King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia. A structured 30-item questionnaire was designed to examine their demographics, knowledge, and behavior on acute seizures. RESULTS: A total of 92 mothers were interviewed and 41% witnessed at least one acute seizure in their affected child (range 1-15 years, mean 4.5). Up to 26% felt not knowledgeable at all regarding the acute care and management of seizure. Mothers with higher education (college or university degree) were more likely to feel very knowledgeable (19% versus 11%, p=0.02). Only 10% were aware of an antiepileptic drug that could be used at home to stop prolonged seizures, and 35% mentioned that they would wait for 15 minutes before taking the child to the emergency department. Most mothers (93%) wanted more information. Those who felt strongly regarding that (66%), were more likely to be younger (<27 years) (p=0.01), and have at least 3 out of 7 mismanagement decisions (p=0.003). CONCLUSION: Maternal level of knowledge and behavior during acute seizures needs improvement. Many mothers have significant misinformation, negative behavior, and poor management practices. Increased awareness and educational programs are needed. PMID- 26492114 TI - Depression and anxiety among parents of phenylketonuria children. AB - OBJECTIVE: To investigate the existence of depression and/or anxiety with underlying risk factors among parents of children with classical phenylketonuria (PKU). METHODS: This cross-sectional study was conducted in the Division of Pediatric Metabolism, Ankara Children's Hospital, Dokuz Eylul University, Kirikkale University, and Erzurum Local Research Hospital, Turkey, between January and July 2014. Parents of 61 patients and 36 healthy controls completed the self-report questionnaires. We used Beck Depression Inventory (BDI) to assess the parental depression and State-Trait Anxiety Inventory S-T (STAI S-T) to assess parental anxiety. RESULTS: Depression and anxiety scores were significantly higher in the case group (BDI: 12.3 +/- 9.1; STAI-S: 38.2 +/- 9.6; STAI-T: 43.2 +/- 6.9) than controls (BDI: 5.4 +/- 4.1 p=0.000; STAI-S: 31.8 +/- 7.6 p=0.001; STAI-T: 37.0 +/- 7.2 p=0.000). Mothers of the patients had higher scores than the other parental groups (BDI: p=0.000, STAI-S: p=0.001 and STAI-T: p=0.000). Logistic regression analysis showed that low educational level of the parent was the only independent factor for depression (OR: 9.96, 95% CI: 1.89 52.35, p=0.007) and state anxiety (OR: 6.99, 95% CI: 1.22-40.48, p=0.030) in the case group. CONCLUSION: A subset of parents with PKU patients have an anxiety or depressive disorder. Supportive services dealing with the parents of chronically ill children such as PKU are needed in order to reduce the level of anxiety. PMID- 26492115 TI - The efficacy and safety of low-molecular-weight heparin and unfractionated heparin in the treatment of cerebral venous sinus thrombosis. AB - OBJECTIVE: To compare the efficacy and safety of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in the treatment of patients with cerebral venous sinus thrombosis (CVST), and to provide an appropriate treatment option in these patients. METHODS: This is a randomized double blind clinical trial conducted between December 2013 and December 2014. The subjects were selected among patients referred to Neurology Department, Imam Reza Hospital; affiliated to Kermanshah University of Medical Sciences, Kermanshah, Iran. Fifty two cases of CVST were included in this study and randomly divided into 2 groups. Twenty-six cases received LMWH and the other 26 cases received UFH. The primary outcomes include hospital mortality rate and neurologic deficits as assessed by the National Institutes of Health Stroke Scale (NIHSS). The secondary end point was disability as measured by the Modified Rankin Scale (MRS). RESULTS: We observed the rate of mortality and neurological deficits and disability based on NIHSS, and the MRS did not differ between the 2 groups. CONCLUSION: The efficacy of LMWH and UFH in reduction of neurologic deficit and functional disability in patients with CVST are similar. PMID- 26492116 TI - Surgical outcome of posterior fixation, including fractured vertebra, for thoracolumbar fractures. AB - OBJECTIVE: To evaluate the role of posterior fixation including the fractured vertebra (PFFV) for the treatment of thoracolumbar vertebral fractures. METHODS: Sixty-seven patients that sustained a single-level thoracolumbar fracture were included in this retrospective study carried out in the Wuxi People's Hospital, Wuxi, China between August 2010 and June 2013. Thirty-two cases were treated with PFFV, and 35 cases were treated with traditional short-segment fixation (TSSF). All patients were periodically followed-up with clinical and radiologic evaluation. Cobb's angle and vertebral body height were analyzed and compared, and the operational time, intra-operational blood loss, and the Denis pain scale scores were also compared. RESULTS: Compared with preoperative angles, the Cobb's angles were reduced and the vertebral body height of the fractured vertebra was increased after operation at a statistically significant level. Twelve months post-operative, the loss of Cobb's angle and vertebral body height in the PFFV group was significantly less than that in the TSSF group. There was no statistical significance in the Denis pain scale score 12 months post-operatively between the 2 groups. CONCLUSION: Selective adoption of PFFV is helpful not only for stabilization of fractures and restoration of anatomy, but also maintaining the effectiveness of the restoration with good functional outcome. PMID- 26492117 TI - Parry-Romberg syndrome. Physical, clinical, and imaging features. AB - Progressive hemifacial atrophy also known as Parry-Romberg syndrome is an acquired, slowly progressive disorder, occurring more in women, primarily affecting one side of the face, mainly characterized by unilateral atrophy, and loss of skin and subcutaneous tissues of face, muscles, and bones. Ocular and neurologic involvements are common. The possible etiology is unclear without any known cure. We report a rare case of Parry-Romberg syndrome with classical features. The clinical features, radiological imaging findings, differential diagnosis, and available treatment options are discussed in this report. PMID- 26492118 TI - Acute cervical cord infarction in anterior spinal artery territory with acute swelling mimicking myelitis. AB - Acute infarction of the cervical segment of the spinal cord is extremely uncommon. Patients may present with signs and symptoms mimicking that of acute myelitis. On imaging, both conditions may present as a hyperintense area on T-2 weighted MRI. History of sudden onset is essential in establishing the diagnosis. We report a case of cervical spinal cord infarction in a 40-year-old man who was diagnosed with acute transverse myelitis, and was treated with high dose intravenous corticosteroids followed by 5 sessions of plasma exchange. An MRI of the spine revealed abnormal high T2 signal intensity extending from the C2 to C7 level involving the anterior two-thirds of the cord with more central involvement. The findings were consistent with anterior spinal artery territory cervical cord infarction. PMID- 26492119 TI - Tardive dyskinesia occurring in a young woman after withdrawal of an atypical antipsychotic drug. AB - Tardive dyskinesia (TD) is one of the most serious and disturbing side-effects of dopamine receptor antagonists. It affects 20-50% of patients on long-term antipsychotic therapy. The pathophysiology of TD remains poorly understood, and treatment is often challenging. Here, we present a 32-year-old woman presenting with a 9-month history of TD occurring after risperidone withdrawal, and characterized almost exclusively by tongue protrusion. After being seen by different specialties and undergoing multiple investigations, she was eventually correctly diagnosed with TD by a specialist team and successfully treated with amantadine. Vigilance and awareness of this condition and its risk factors are required to make the correct diagnosis, especially in cases with unusual presentations caused by atypical antipsychotics, and treatment can be challenging. PMID- 26492120 TI - A rare case of nonenhancing primary central nervous system lymphoma mimic multiple sclerosis. AB - Primary central nervous system lymphoma (PCNSL) is reported to have increased in the last decades. Early diagnosis is crucial for proper management of this tumor. We report a case of a 48-year-old man who was initially diagnosed with multiple sclerosis. Magnetic resonance imaging of the brain revealed multiple lesions with hyper-signals in the bilateral basal ganglia and brain stem in T2-weighted image and non-enhancement, while positron emission tomography showed a low uptake of 18F-fluorodeoxyglucose in the affected brain, indicative of demyelination. However, this individual was correctly diagnosed with PCNSL after biopsy and further histological analysis. Primary central nervous system lymphoma must be considered even when nonenhancing, diffuse lesions are seen on MRI. A visible tumor on imaging is essential to ensure an early brain biopsy and histological diagnosis. PMID- 26492121 TI - Dyke-Davidoff-Masson Syndrome. An unusual cause of status epilepticus. AB - The Dyke-Davidoff-Masson Syndrome (DDMS) results from an insult to the growing brain in utero or early infancy, which lead to loss of neurons compromising the growth of the brain. Clinical presentation includes seizures, hemiparesis, facial asymmetry, and learning disability. Radiological findings include cerebral atrophy on one side. Here, we present a case with status epilepticus who had underlying DDMS. It is a rare syndrome and uncommon cause for status epilepticus. Infections of CNS, hypoxic ischemic encephalopathy, intracranial bleed, trauma, congenital vascular malformations are the common causes of this syndrome. Diagnosis is established after clinical history, examination, and MRI. Intractable seizures can be controlled with appropriate anticonvulsants. Subsequently, these children may require physiotherapy, speech therapy, and occupational therapy in addition to the anticonvulsant medication. Outcome is better if the seizures are controlled. PMID- 26492122 TI - Advanced case of glioblastoma multiforme and pregnancy. An ethical dilemma. AB - Glioblastoma multiforme (GBM) is the most common and malignant form of the glial tumors. Advanced and treated GBM is rarely associated with pregnancy for many reasons. Glioblastoma multiforme presenting during pregnancy carries unique challenges to the patient, baby, family, and health care providers. We describe an unusual case of advanced GBM that was treated with maximum doses of chemotherapy and radiations, and she became pregnant and presented at eighteenth weeks of gestation. Her medical management was associated with a significant ethical dilemma. We managed to deliver the baby safely through cesarean section at week 28 despite the critical condition of the mother. Unfortunately, the mother died 2 weeks post delivery. We concluded that although recurrent and treated GBM is rarely associated with pregnancy and carries dismal prognosis, but if it occurs, it can still be carried, and a multidisciplinary team work is the key for successful outcome. PMID- 26492123 TI - Survey of h-index for neurosurgeons in Saudi Arabia. AB - OBJECTIVE: To calculate the h-index for neurosurgeons in the Kingdom of Saudi Arabia (KSA), and to assess its association with a number of features relating to neurosurgical practice in KSA. METHODS: The h-index for 84 neurosurgeons that worked in KSA during 1990-2013 was evaluated using Google Scholar during the period September to October 2014. The correlation between the h-index and a number of neurosurgeon and neurosurgical center characteristics was determined and examined statistically. RESULTS: The median h-index was 2.5 (range 0-33) and the mean was 5.04. The h-index was significantly higher for neurosurgeons who obtained their certification before 2001 and those working at the King Faisal Specialist Hospital, Riyadh, KSA. The h-index was also higher, but without reaching significance, for non-Saudi neurosurgeons, those with international certification and those working at the university hospitals. Additionally, the h index was significantly lower for neurosurgeons working in the Ministry of Health hospitals. CONCLUSION: Application of the h-index to KSA neurosurgeons revealed a significant correlation with the duration after certification and with certain centers. Evaluation of the h-index should be included in the consideration for academic positions in KSA. Saudi neurosurgeons should be encouraged to publish in journals with high impact factor. PMID- 26492124 TI - Axillary nerve course and position in the fetal period. An anatomic dissection study for surgical practice. AB - OBJECTIVE: To examine the fetal axillary nerve to reveal and compare its morphometric features within the second and third trimester. METHODS: This study was conducted at the Anatomy Department, School of Medicine, Mersin University, Mersin, Turkey. Thirty-five fetal shoulders were studied to provide anatomic data and to describe its position with regard to certain landmarks around the shoulder. RESULTS: The shortest distance between the axillary nerve and the glenoid labrum was found 2.27 mm and 2.89 mm in the second and third trimester fetuses, respectively. The shortest distances between the anterior and posterior acromial tips and the axillary nerve were also measured and were used with arm length measurements to define the anterior and posterior indexes. CONCLUSION: The indexes show that the distance between the axillary nerve and the anterior/posterior acromial tips are approximately one-fourth of the arm length in both the second and third trimester fetuses. The data presented in this study will be of use to surgeons, particularly to pediatric and orthopedic surgeons who will undertake surgical procedures in the axilla and arm in the newborn or early childhood. PMID- 26492125 TI - Ipsilaterality serves contralaterality. An explanation for the ipsilateral pathways of the retinal fibers of the binocular vision. PMID- 26492126 TI - An adult with focal neurological deficits and inter-arm blood pressure difference. PMID- 26492127 TI - Neurophobia among medical students. PMID- 26492130 TI - Camel Milk: Potential Utility as an Adjunctive Therapy to Peg-IFN/RBV in HCV-4 Infected Patients in Egypt. AB - The present prospective study aims to investigate the potential therapeutic effect and the underlying mechanisms of drinking camel milk for 60 days as an adjunctive therapy to the standard treatment PEG/RBV. Twenty-five hepatitis C virus (HCV)-infected Egyptian patients, with mild to moderate parenchymal affection to mild cirrhosis were enrolled in this study after proper history taking and clinical examination. Their biomarkers were evaluated before and after the addition of camel milk. The improving effect of camel milk was reflected on the marked inhibition of the serum levels of the proinflammatory markers, viz., tumor necrosis factor-alpha, monocyte chemotactic protein-1, hyaluronic acid, and TGF-beta1, besides PCR, AST, ALT, GGT, bilirubin, prothrombin time, INR, and alpha-fetoprotein. In addition, camel milk elevated significantly (P < 0.001) the serum levels of albumin, the antiapoptotic protein BCL-2, the total antioxidant capacity, interleukin-10, and vitamin D. In conclusion, our study revealed a regulatory function of camel milk on multiple parameters of inflammatory mediators, immunomodulators, antiapoptosis, and antioxidants, giving insight into the potential therapeutic benefit underlying the anti-HCV actions of camel milk. The limitations of the current study include the small sample size recruited and the failure to test it on cohorts with severe stages of hepatitis; like Child Pugh stage C, and hepatocellular carcinoma. PMID- 26492128 TI - Depression and Anxiety as Risk Factors for Morbidity and Mortality After Organ Transplantation: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Depression and anxiety are common mental health problems in transplant populations. There is mixed evidence concerning whether they increase morbidity and mortality risks after transplantation. If such associations exist, additional risk reduction strategies may be needed. METHODS: Four bibliographic databases were searched from 1981 through September 2014 for studies prospectively examining whether depression or anxiety (determined with diagnostic evaluations or standardized symptom scales) affected risk for posttransplant mortality, graft loss, acute graft rejection, chronic rejection, cancer, infection, and rehospitalization. RESULTS: Twenty-seven studies (10 heart, total n = 1738; 6 liver, n = 1063; 5 kidney, n = 49515; 4 lung, n = 584; 1 pancreas, n = 80; 1 mixed recipient sample, n = 205) were identified. In each, depression and/or anxiety were typically measured before or early after transplantation. Follow-up for outcomes was a median of 5.8 years (range, 0.50-18.0). Depression increased the relative risk (RR) of mortality by 65% (RR, 1.65; 95% confidence interval [95% CI], 1.34-2.05; 20 studies). Meta-regression indicated that risk was stronger in studies that did (vs did not) control for potential confounders (P = .032). Risk was unaffected by type of transplant or other study characteristics. Depression increased death-censored graft loss risk (RR, 1.65; 95% CI, 1.21-2.26, 3 studies). Depression was not associated with other morbidities (each morbidity was assessed in 1-4 studies). Anxiety did not significantly increase mortality risk (RR, 1.39; 95% CI, 0.85-2.27, 6 studies) or morbidity risks (assessed in single studies). CONCLUSIONS: Depression increases risk for posttransplant mortality. Few studies considered morbidities; the depression-graft loss association suggests that linkages with morbidities deserve greater attention. Depression screening and treatment may be warranted, although whether these activities would reduce posttransplant mortality requires study. PMID- 26492129 TI - Gaps in the hepatitis C continuum of care among sex workers in Vancouver, British Columbia: Implications for voluntary hepatitis C virus testing, treatment and care. AB - BACKGROUND: Hepatitis C virus (HCV) eradication leads to reduced morbidity, mortality and transmission. Despite the disproportionate burden of HCV among sex workers, data regarding the HCV care continuum in this population remain negligible. METHODS: Using baseline data from an ongoing cohort of women sex workers in Vancouver (An Evaluation of Sex Workers' Health Access, January 2010 to August 2013), the authors assessed HCV prevalence and engagement in the HCV care continuum within the past year. Multivariable logistic regression analyses were used to evaluate associations with recent (ie, in the past year) HCV testing. RESULTS: Among 705 sex workers, 302 (42.8%) were HCV seropositive. Of these, 22.5% were previously unaware of their HCV status, 41.7% had accessed HCV related care, 13.9% were offered treatment and only 1.0% received treatment. Among 552 HCV-seronegative sex workers, only one-half (52.9%) reported a recent HCV test. In multivariable analysis, women who self-identified as a sexual/gender minority (adjusted OR [aOR] 1.89 [95% CI 1.11 to 3.24]), resided in the inner city drug use epicentre (aOR 3.19 [95%CI 1.78 to 5.73]) and used injection (aOR 2.00 [95% CI 1.19 to 3.34]) or noninjection drugs (aOR 1.95 [95% CI 1.00 to 3.78]) had increased odds of undergoing a recent HCV test, while immigrant participants (aOR 0.24 [95% CI 0.12 to 0.48]) had decreased odds. CONCLUSIONS: Despite a high burden of HCV among sex workers, large gaps in the HCV care continuum remain. Particularly concerning are the low access to HCV testing, with one-fifth of women living with HCV being previously unaware of their status, and the exceptionally low prevalence of HCV treatment. There is a critical need for further research to better understand and address barriers to engage in the HCV continuum for sex workers. PMID- 26492131 TI - The Chlamydomonas reinhardtii alternative oxidase 1 is regulated by heat stress. AB - The alternative oxidase (AOX) is a non-energy conserving terminal oxidase that has emerged as an important mitochondrial component of the cell stress responses. Although the most studied abiotic condition in relation to Chlamydomonas reinhardtii is high temperature, changes in AOX capacity of the alga were studied only under oxidative stress and cold. To examine whether elevated temperatures affected AOX1 expression, we applied quantitative real-time PCR and pharmaceutical approaches. In this work, we demonstrated a sharp increase in AOX1 transcript and protein abundance under heat stress. Furthermore, C. reinhardtii cells displayed a large increase in alternative respiration in response to high temperature. Feeding with the protein kinase inhibitor staurosporine strongly retarded the AOX1 transcription. Finally, the addition of the calcium chelator EGTA prevented heat-induced AOX1 expression. Together, our results imply that heat-inducible Ca(2+) influx and protein kinase(s) may mediate AOX1 expression at elevated temperatures. Characterization of heat-induced AOX1 regulation in the green alga C. reinhardtii provides a framework for a more complete understanding of the function of this conserved protein. PMID- 26492132 TI - Functional characterization of a dehydrin protein from Fagus sylvatica seeds using experimental and in silico approaches. AB - A strong increase in the level of dehydrin/response ABA transcripts expression reported from the 14th week after flowering coincident with the accumulation of 26 and 44 kDa dehydrins in the embryonic axes of developing beech (Fagus sylvatica L.) seeds. Both transcript and protein levels were strongly correlated with maturation drying. These results suggest that the 44-kDa dehydrin protein is a putative dimer of dehydrin/response ABA protein migrating as a 26-kDa protein. Dehydrins and dehydrin-like proteins form large oligomeric complexes under native conditions and are shown as several spots differing in pI through isoelectrofocusing analyses. Detailed prediction of specific sites accessible for various post-translational modifications (PTMs) in the dehydrin/response ABA protein sequence revealed sites specific to acetylation, amidation, glycosylation, methylation, myristoylation, nitrosylation, O-linked beta-N acetylglucosamination and Yin-O-Yang modification, palmitoylation, phosphorylation, sumoylation, sulfation, and ubiquitination. Thus, these results suggest that specific PTMs might play a role in switching dehydrin function or activity, water binding ability, protein-membrane interactions, transport and subcellular localization, interactions with targeted molecules, and protein stability. Despite the ability of two Cys residues to form a disulfide bond, -SH groups are likely not involved in dimer arrangement. His-rich regions and/or polyQ-tracts are potential candidates as spatial organization modulators. Dehydrin/response ABA protein is an intrinsically disordered protein containing low complexity regions. The lack of a fixed structure and exposition of amino acids on the surface of the protein structure enhances the accessibility to 40 predicted PTM sites, thereby facilitating dehydrin multifunctionality, which is discussed in the present study. PMID- 26492133 TI - Cytological, molecular mechanisms and temperature stress regulating production of diploid male gametes in Dianthus caryophyllus L. AB - In plant evolution, because of its key role in sexual polyploidization or whole genome duplication events, diploid gamete formation is considered as an important component in diversification and speciation. Environmental stress often triggers unreduced gamete production. However, the molecular, cellular mechanisms and adverse temperature regulating diplogamete production in carnation remain poorly understood. Here, we investigate the cytological basis for 2n male gamete formation and describe the isolation and characterization of the first gene, DcPS1 (Dianthus Caryophyllus Parallel Spindle 1). In addition, we analyze influence of temperature stress on diploid gamete formation and transcript levels of DcPS1. Cytological evidence indicated that 2n male gamete formation is attributable to abnormal spindle orientation at male meiosis II. DcPS1 protein is conserved throughout the plant kingdom and carries domains suggestive of a regulatory function. DcPS1 expression analysis show DcPS1 gene probably have a role in 2n pollen formation. Unreduced pollen formation in various cultivation was sensitive to high or low temperature which was probably regulated by the level of DcPS1 transcripts. In a broader perspective, these findings can have potential applications in fundamental polyploidization research and plant breeding programs. PMID- 26492134 TI - Progress Toward Global Eradication of Dracunculiasis, January 2014-June 2015. AB - Dracunculiasis (Guinea worm disease) is caused by Dracunculus medinensis, a parasitic worm. Approximately 1 year after a person acquires infection from contaminated drinking water, the worm emerges through the skin, usually on the lower limb. Pain and secondary bacterial infection can cause temporary or permanent disability that disrupts work and schooling. The campaign to eradicate dracunculiasis worldwide began in 1980 at CDC. In 1986, the World Health Assembly called for dracunculiasis elimination, and the global Guinea Worm Eradication Program, led by the Carter Center and supported by the World Health Organization (WHO), United Nations Children's Fund (UNICEF), CDC, and other partners, began assisting ministries of health in countries where dracunculiasis was endemic. In 1986, an estimated 3.5 million cases occurred each year in 20 countries in Africa and Asia. Since then, although the goal of eradicating dracunculiasis has not been achieved, considerable progress has been made. Compared with the 1986 estimate, the annual number of reported cases in 2015 has been reduced by 99% and cases are confined to four endemic countries. This report updates published and unpublished surveillance data reported by ministries of health and describes progress toward dracunculiasis eradication from January 2014 through June 2015. During 2014, a total of 126 cases were reported from four countries (Chad [13 cases], Ethiopia [three], Mali [40], and South Sudan [70]), compared with 148 cases reported in 2013, from the same four countries. The overall 15% reduction in cases during 2013-2014 was less than that experienced in recent years, but the rate of decline increased again to 70% in the first 6 months of 2015 compared with the same period during 2014. Continued active surveillance with aggressive detection and appropriate management of cases are essential program components; however, epidemiologic challenges and civil unrest and insecurity pose potential barriers to eradication. PMID- 26492135 TI - Preparation of a cyanine-based fluorescent probe for highly selective detection of glutathione and its use in living cells and tissues of mice. AB - Glutathione (GSH) is a major endogenous antioxidant that has a central role in cellular defense against toxins and free radicals. This protocol describes the preparation of CPDSA, a cyanine-based near-infrared (NIR) fluorescent probe for the detection of GSH in cells and in vivo. CPDSA is prepared with high yield through a simple two-step process. The first step is to react commercially available IR-780 iodide with excess anhydrous piperazine in anhydrous N,N dimethyl formamide at 85 degrees C to form cyanine-piperazine (CP). The second step is the sulfonylation of CP with dansyl chloride in anhydrous dichloromethane. CPDSA selectively detects GSH in cells, and it has been shown to not react with other biothiols such as cysteine (Cys) and homocysteine (Hcy). This probe can also be used to monitor the GSH level of mouse bone marrow-derived neutrophils (BMDNs). The preparation of probe CPDSA takes 2 d, and experiments in cells and mice take 12-13 d. PMID- 26492136 TI - Using the GEMM-ESC strategy to study gene function in mouse models. AB - Preclinical in vivo validation of target genes for therapeutic intervention requires careful selection and characterization of the most suitable animal model in order to assess the role of these genes in a particular process or disease. To this end, genetically engineered mouse models (GEMMs) are typically used. However, the appropriate engineering of these models is often cumbersome and time consuming. Recently, we and others described a modular approach for fast-track modification of existing GEMMs by re-derivation of embryonic stem cells (ESCs) that can be modified by recombinase-mediated transgene insertion and subsequently used for the production of chimeric mice. This 'GEMM-ESC strategy' allows for rapid in vivo analysis of gene function in the chimeras and their offspring. Moreover, this strategy is compatible with CRISPR/Cas9-mediated genome editing. This protocol describes when and how to use the GEMM-ESC strategy effectively, and it provides a detailed procedure for re-deriving and manipulating GEMM-ESCs under feeder- and serum-free conditions. This strategy produces transgenic mice with the desired complex genotype faster than traditional methods: generation of validated GEMM-ESC clones for controlled transgene integration takes 9-12 months, and recombinase-mediated transgene integration and chimeric cohort production takes 2-3 months. The protocol requires skills in embryology, stem cell biology and molecular biology, and it is ideally performed within, or in close collaboration with, a transgenic facility. PMID- 26492137 TI - Mapping ribonucleotides in genomic DNA and exploring replication dynamics by polymerase usage sequencing (Pu-seq). AB - Ribonucleotides are frequently misincorporated into DNA during replication, and they are rapidly repaired by ribonucleotide excision repair (RER). Although ribonucleotides in template DNA perturb replicative polymerases and can be considered as DNA damage, they also serve positive biological functions, including directing the orientation of mismatch repair. Here we describe a method for ribonucleotide identification by high-throughput sequencing that allows mapping of the location of ribonucleotides across the genome. When combined with specific mutations in the replicative polymerases that incorporate ribonucleotides at elevated frequencies, our ribonucleotide identification method was adapted to map polymerase usage across the genome. Polymerase usage sequencing (Pu-seq) has been used to define, in unprecedented detail, replication dynamics in yeasts. Although other methods that examine replication dynamics provide direct measures of replication timing and indirect estimates of origin efficiency, Pu-seq directly ascertains origin efficiency. The Pu-seq protocol can be completed in 12-14 d. PMID- 26492138 TI - Imaging the beating heart in the mouse using intravital microscopy techniques. AB - Real-time microscopic imaging of moving organs at single-cell resolution represents a major challenge in studying complex biology in living systems. Motion of the tissue from the cardiac and respiratory cycles severely limits intravital microscopy by compromising ultimate spatial and temporal imaging resolution. However, significant recent advances have enabled single-cell resolution imaging to be achieved in vivo. In this protocol, we describe experimental procedures for intravital microscopy based on a combination of thoracic surgery, tissue stabilizers and acquisition gating methods, which enable imaging at the single-cell level in the beating heart in the mouse. Setup of the model is typically completed in 1 h, which allows 2 h or more of continuous cardiac imaging. This protocol can be readily adapted for the imaging of other moving organs, and it will therefore broadly facilitate in vivo high-resolution microscopy studies. PMID- 26492139 TI - Precision-engineering the Pseudomonas aeruginosa genome with two-step allelic exchange. AB - Allelic exchange is an efficient method of bacterial genome engineering. This protocol describes the use of this technique to make gene knockouts and knock ins, as well as single-nucleotide insertions, deletions and substitutions, in Pseudomonas aeruginosa. Unlike other approaches to allelic exchange, this protocol does not require heterologous recombinases to insert or excise selective markers from the target chromosome. Rather, positive and negative selections are enabled solely by suicide vector-encoded functions and host cell proteins. Here, mutant alleles, which are flanked by regions of homology to the recipient chromosome, are synthesized in vitro and then cloned into allelic exchange vectors using standard procedures. These suicide vectors are then introduced into recipient cells by conjugation. Homologous recombination then results in antibiotic-resistant single-crossover mutants in which the plasmid has integrated site-specifically into the chromosome. Subsequently, unmarked double-crossover mutants are isolated directly using sucrose-mediated counter-selection. This two step process yields seamless mutations that are precise to a single base pair of DNA. The entire procedure requires ~2 weeks. PMID- 26492142 TI - Increasing Staff Pride and Patient Connection. AB - This column is presented by a nurse educator at the Princess Alexandra Hospital. The author reinforces the value of our professional identity as nurses. The project described in this article focused on the presence of a visible name tag and a professional introduction of the nurse to the patient to promote the development of trust. PMID- 26492140 TI - Efficient delivery of nuclease proteins for genome editing in human stem cells and primary cells. AB - Targeted nucleases, including zinc-finger nucleases (ZFNs), transcription activator-like (TAL) effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9), have provided researchers with the ability to manipulate nearly any genomic sequence in human cells and model organisms. However, realizing the full potential of these genome-modifying technologies requires their safe and efficient delivery into relevant cell types. Unlike methods that rely on expression from nucleic acids, the direct delivery of nuclease proteins to cells provides rapid action and fast turnover, leading to fewer off-target effects while maintaining high rates of targeted modification. These features make nuclease protein delivery particularly well suited for precision genome engineering. Here we describe procedures for implementing protein-based genome editing in human embryonic stem cells and primary cells. Protocols for the expression, purification and delivery of ZFN proteins, which are intrinsically cell-permeable; TALEN proteins, which can be internalized via conjugation with cell-penetrating peptide moieties; and Cas9 ribonucleoprotein, whose nucleofection into cells facilitates rapid induction of multiplexed modifications, are described, along with procedures for evaluating nuclease protein activity. Once they are constructed, nuclease proteins can be expressed and purified within 6 d, and they can be used to induce genomic modifications in human cells within 2 d. PMID- 26492143 TI - The Academic Progression in Nursing Initiative: The Halfway Point. AB - This column, presented by the American Organization of Nurse Executives, discusses the results of the initial 9 state-funded coalition grants to increase the levels of education among RNs and smooth academic transition. PMID- 26492144 TI - Regulating the Flow of Change to Reduce Fontline Nurse Stress and Burnout. AB - The nursing workforce is at the center of many changes associated with care delivery transformation. To achieve this transformation, frontline nursing staff must be engaged in their work, committed to their organization's mission, and capable of delivering high-quality care. To identify top opportunities for driving nursing engagement, researchers from The Advisory Board Company analyzed engagement survey responses from more than 343 000 employees at 575 healthcare organizations. In this article, the authors describe 3 strategies for addressing 1 of the greatest opportunities for improving nurse engagement: ensuring nurses feel their organization helps them reduce stress and burnout. PMID- 26492145 TI - Using Consultants in the Design, Construction, and Occupancy of New Healthcare Facilities. AB - Nurse leaders are critical players in the design, construction, and occupancy of new healthcare facilities or renovation projects. While most hospitals and healthcare systems have internal resources needed to manage large projects, there is often a recognized need for expertise of external consultants during various phases of design and construction. The purpose of this article is to provide an overview of types of external consultants that can be contracted to ensure the success of the project from concept through initial occupancy. PMID- 26492146 TI - Growing and Sustaining the Clinical Nurse Leader Initiative: Shifting the Focus From Pioneering Innovation to Evidence-Driven Integration Into Healthcare Delivery. AB - The Clinical Nurse Leader (CNL) initiative has been characterized by innovation. While an innovation framework for diffusing CNL practice remains relevant, generalizable evidence of effectiveness is necessary to sustain nationwide momentum. A framework is proposed in this department for a national-level CNL research collaborative linking research, policy, education, and practice stakeholders in an ongoing partnership to advance CNL evidence, education, policy, and practice. PMID- 26492141 TI - Whole-body tissue stabilization and selective extractions via tissue-hydrogel hybrids for high-resolution intact circuit mapping and phenotyping. AB - To facilitate fine-scale phenotyping of whole specimens, we describe here a set of tissue fixation-embedding, detergent-clearing and staining protocols that can be used to transform excised organs and whole organisms into optically transparent samples within 1-2 weeks without compromising their cellular architecture or endogenous fluorescence. PACT (passive CLARITY technique) and PARS (perfusion-assisted agent release in situ) use tissue-hydrogel hybrids to stabilize tissue biomolecules during selective lipid extraction, resulting in enhanced clearing efficiency and sample integrity. Furthermore, the macromolecule permeability of PACT- and PARS-processed tissue hybrids supports the diffusion of immunolabels throughout intact tissue, whereas RIMS (refractive index matching solution) grants high-resolution imaging at depth by further reducing light scattering in cleared and uncleared samples alike. These methods are adaptable to difficult-to-image tissues, such as bone (PACT-deCAL), and to magnified single cell visualization (ePACT). Together, these protocols and solutions enable phenotyping of subcellular components and tracing cellular connectivity in intact biological networks. PMID- 26492147 TI - Defining Peer-to-Peer Accountability From the Nurse's Perspective. AB - OBJECTIVE: The aim of this study was to define and create a conceptual model for peer-to-peer accountability (P to PA). BACKGROUND: Many organizations cite the importance of peer accountability (PA) as essential in ensuring patient safety. Professionalism in nursing requires self-regulation of practice and PA. Although discussed in the literature, P to PA is not conceptually defined. METHODS: A grounded theory study design with constant comparative data collection and analysis was used to explore nurses' definitions of P to PA and their perceptions of motivators and barriers to engaging in P to PA. Transcripts of digital recordings of all interviews were analyzed using line-by-line coding until identified themes emerged. RESULTS: P to PA was defined as the act of speaking up when one observes a peer not practicing to acceptable standards. A conceptual model illustrates the antecedents, attributes, and consequences of P to PA. CONCLUSIONS: P to PA is the professional responsibility of every nurse and healthcare provider and is essential for safe patient care. The conceptual definition facilitates actualization of P to PA in practice. PMID- 26492148 TI - Patient Satisfaction With Nursing Care: Measuring Outcomes in an International Setting. AB - OBJECTIVE: The purpose of this study was to assess patient satisfaction with nursing care. BACKGROUND: Patients' satisfaction with nursing care is considered an important factor in explaining patients' perceptions of service quality. METHODS: The study was conducted in a major tertiary hospital in Riyadh, Saudi Arabia. An exploratory approach utilizing cross-sectional survey design was used. Data were collected from 424 patients through patients' interviews using the Arabic version of the Newcastle Satisfaction With Nursing Scale. RESULTS: The results showed a high level of satisfaction among patients in all hospital areas. Female patients were significantly more satisfied than males with no differences among other groups. CONCLUSION: Patient satisfaction with nursing care remains an important factor in explaining patients' perceptions of service quality. International healthcare settings should systematically monitor the relationship between nursing care and experience to support quality care provision. PMID- 26492149 TI - Implications of the Patient-Centered Medical Home for Nursing Practice. AB - OBJECTIVE: The experiences of RNs and licensed practical nurses (LPNs) implementing a patient-centered medical home (PCMH) in the Department of Veterans Affairs (VA) primary care clinics were examined to understand model implications for nursing practice and professional identity. BACKGROUND: National implementation of the PCMH model, called patient-aligned care teams (PACTs) in VA, emphasizes areas of nursing expertise, yet little is known about the effect of medical homes on the day-to-day work of nurses. METHODS: As part of a formative evaluation to identify barriers and facilitators to PACT implementation, we interviewed 18 nurses implementing PACT. RESULTS: Challenges to nurse's organizational and professional roles were experienced differently by RNs and LPNs in the following areas: (1) diversified modes of care and expanded clinical duties, (2) division of labor among PACT nurses, and (3) interprofessional status in the team. CONCLUSIONS: Healthcare managers implementing PCMH should consider its inherent cultural and practice transformations. PMID- 26492150 TI - Chief Nursing Officer Sustainment: A Phenomenological Inquiry. AB - OBJECTIVE: The study explored factors leading to chief nursing officer (CNO) sustainment in the professional practice of nurse executive leadership. BACKGROUND: CNOs are expected to lead adaptations in care delivery in this current era of healthcare reform, requiring a multitude of new leadership skills. Exploration is needed to understand barriers to longevity, which prevent consistency of leadership and execution of vision. METHODS: Twenty CNOs were interviewed to determine the lived experience related to the phenomena of role sustainment. An interpretative phenomenological analysis approach was used. RESULTS: Six themes emerged describing sustainment. These are as follows: loving the profession, having a broader impact, reflecting on one's own work, learning to manage conflict, maintaining work/life balance, and working with supportive leaders. CONCLUSIONS: The desire and passion for nurse executive leadership must be enhanced through education and competencies that emerged in this study and include strategic processing, mindful reflection, and resiliency training. PMID- 26492151 TI - Achieving 80% BSN by 2020: Chief Nurse Executive Role and ANCC Influence. AB - OBJECTIVES: The aim of this study was to understand current education level of hospital nurses and strategies used by Kentucky's chief nurse executives (CNEs) to encourage academic progression in their RN workforce. BACKGROUND: The Institute of Medicine and American Nurses Credentialing Center called for 80% of RNs to be educated with a minimum of a BSN. CNEs have a key role in achieving that goal. METHODS: An electronic survey was administered in fall 2013. Fifty-two Kentucky CNEs responded. RESULTS: No hospitals in Kentucky met the BSN target. Sixty-two percent of CNEs planned to achieve 80% BSN nurses by 2020. Teaching status, hiring preferences, goals for increasing percentage of BSN nurses, and processes to facilitate advancement of nurses prepared at the associate degree level were associated with pursuit or achievement of Pathway to Excellence(r) or Magnet(r) designation. In addition to policies to support increasing educational levels, incentives offered included tuition reimbursement, career advancement, time off, and academic partnerships. CONCLUSION: Increasing the proportion of BSN prepared nurses should be a priority for CNEs. Strategies to facilitate that goal are explored. From these data, a large number of CNEs (38%) do not have a goal to achieve the recommended levels of BSN nurses. Further education and support in the rural hospitals in Kentucky are indicated to support this recommendation. PMID- 26492152 TI - A small yet comprehensive subset of human experimental pain models emerging from correlation analysis with a clinical quantitative sensory testing protocol in healthy subjects. AB - BACKGROUND: Picturing the complexity of pain in human experimental settings has increased the predictivity for clinical pain but requires increasingly complex test batteries. This raises problems in studies in which time is objectively limited, for example by the course of action of an analgesic drug. We addressed the selection of a small yet comprehensive set of pain tests for the use in such a situation. METHOD: Nineteen different pain measures from 'classical' pain models (n = 9) and a clinically established QST-pain test battery (n = 10), were obtained from 72 healthy volunteers (34 men). The nonparametric correlation structure among the various pain measures was analysed using Ward clustering. RESULTS: Four clusters emerged, each consisting of highly correlated pain measures. The pain model groups emerged comprised (I) pain thresholds and tolerances to blunt pressure or electrical pain; (II) pain thresholds to thermal stimuli; (III) pain measures obtained following application of punctate mechanical, intranasal CO2 chemical or cutaneous laser heat stimuli; and (IV) detection thresholds to thermal stimuli. The first three clusters agreed with an immediate mechanistic interpretation as reflecting C-fibre mediated pain, thermal pain and Adelta-fibre mediated pain, respectively, whereas the last cluster contained non-painful measures and was disregarded. CONCLUSIONS: When basing a selection of a small comprehensive set of pain models on the assumption that highly correlated pain measures account for redundant results and therefore, one member of each group suffices an economic yet comprehensive pain study, results suggest inclusion of established C-fibre, Adelta-fibre mediated and thermal pain measures. PMID- 26492153 TI - DFT Investigation of the Mechanism of Action of Organoiridium(III) Complexes As Anticancer Agents. AB - The potential use of synthetic metal complexes able to catalyze chemical transformations in living organisms is currently attracting a great deal of attention. Recently, organometallic ruthenium and iridium complexes have revealed an unexpected ability to modulate the redox status of cancer cells. In particular, half-sandwich organoiridium(III) cyclopentadienyl complexes of general formula [(eta(5)-Cp(x))Ir(III)(X(?)Y)Z](0/+), where Cp(x) = Cp*, Cp(xph) (tetramethyl-(phenyl)cyclopentadienyl) or Cp(xbiph) (tetramethyl(biphenyl) cyclopentadienyl), X(?)Y = bidentate ligand with nitrogen, oxygen, and/or carbon donor atoms, and Z = Cl, H2O, or pyridine (py) have shown promising antiproliferative activity toward cancer cells, higher potency than cisplatin, and a different mechanism of action due to the increase of the oxidative stress in cells. As such, complexes can belong to the class of DNA interacting compounds and attack on DNA can represent a secondary mechanism of action. We have explored here by means of density functional calculations (M06-L) and with the support of experimental observations for both [(eta(5)-Cp(xbiph))Ir-(phpy) (Cl)], 1-Cl, and [(eta(5)-Cp(xbiph))Ir-(phpy) (py)], 1-py, complexes the mechanistic aspects of the hydrolysis reaction, H2O2 ROS production by assisted hydride transfer from NADH to molecular oxygen, interaction with purine nucleobases adenine and guanine as well as gluthatione, that is highly abundant in cells, alongside the reaction mechanism for the oxidation of the formed sulfur-coordinated thiolate to the corresponding sulfenato complex. The comparison between kinetic and thermodynamic parameters calculated for all the involved processes shows that, according to the hypothesis based on experimental findings, the interaction with the tripeptide glutathione causes deactivation of 1-Cl, whereas 1-py, in both its aquated and nonaquated form, can induce cell apoptosis in a dual manner: DNA damage and H2O2 ROS production to increase oxidative stress. PMID- 26492154 TI - Multigas Leakage Correction in Static Environmental Chambers Using Sulfur Hexafluoride and Raman Spectroscopy. AB - In static environmental chamber experiments, the precision of gas flux measurements can be significantly improved by a thorough gas leakage correction to avoid under- or overestimation of biological activity such as respiration or photosynthesis. Especially in the case of small biological net gas exchange rates or gas accumulation phases during long environmental monitoring experiments, gas leakage fluxes could distort the analysis of the biogenic gas kinetics. Here we propose and demonstrate a general protocol for online correction of diffusion driven gas leakage in plant chambers by simultaneous quantification of the inert tracer sulfur hexafluoride (SF6) and the investigated biogenic gases using enhanced Raman spectroscopy. By quantifying the leakage rates of carbon dioxide (CO2), methane (CH4), and hydrogen (H2) simultaneously with SF6 in the test chamber, their effective diffusivity ratios of approximately 1.60, 1.96, and 5.65 were determined, each related to SF6. Because our experiments suggest that the effective diffusivity ratios are reproducible for an individual static environmental chamber, even under varying concentration gradients and slight changes of the chamber sealing, an experimental method to quantify gas leakage fluxes by using effective diffusivity ratios and SF6 leakage fluxes is proposed. The method is demonstrated by quantifying the CO2 net exchange rate of a plant soil ecosystem (Mirabilis jalapa). By knowing the effective chamber diffusivity ratio CO2/SF6 and the measured SF6 leakage rate during the experiment, the leakage contribution to the total CO2 exchange rate could be calculated and the biological net CO2 concentration change within the chamber atmosphere determined. PMID- 26492155 TI - Cell-penetrating peptide-siRNA conjugate loaded YSA-modified nanobubbles for ultrasound triggered siRNA delivery. AB - Due to the absence of effective in vivo delivery systems, the employment of small interference RNA (siRNA) in the clinic has been hindered. In this paper, a new siRNA targeting system for EphA2-positive tumors was developed, based on ultrasound-sensitive nanobubbles (NBs) and cell-permeable peptides (CPPs). Here, a CPP-siRNA conjugate (CPP-siRNA) was entrapped in an ephrin mimetic peptide (YSA peptide)-modified NB (CPP-siRNA/YSA-NB) and the penetration of the CPP-siRNA was temporally masked; local ultrasound stimulation triggered the release of CPP siRNA from the NBs and activated its penetration. Subsequent research demonstrated that the CPP-siRNA/YSA-NBs had particle sizes of approximately 200 nm and a siRNA entrapment efficiency of more than 85%. The in vitro release results showed that over 90% of the encapsulated CPP-siRNA released from the NBs in the presence of ultrasound, while less than 1.5% of that (30 min) released without ultrasound. Cell experiments showed a the higher CPP-siRNA cellular uptake of CPP-siRNA/YSA-NB among the various formulations in human breast adenocarcinoma cells (MCF-7, EphA2 positive cells). Additionally, after systemic administration in mice, CPP-siRNA/YSA-NB accumulated in the tumor, augmented c Myc silencing and delayed tumor progression. In conclusion, the application of CPP-siRNA/YSA-NB with ultrasound may provide a strategy for the selective and efficient delivery of siRNA. PMID- 26492156 TI - Solid lipid nanoparticles of clotrimazole silver complex: An efficient nano antibacterial against Staphylococcus aureus and MRSA. AB - New and effective strategies to transform current antimicrobials are required to address the increasing issue of microbial resistance and declining introduction of new antibiotic drugs. In this context, metal complexes of known drugs and nano delivery systems for antibiotics are proving to be promising strategies. The aim of the study was therefore to synthesize a silver complex of clotrimazole and formulate it into a nano delivery system for enhanced and sustained antibacterial activity against susceptible and resistant Staphylococcus aureus. A silver complex of clotrimazole was synthesized, characterized and further encapsulated into solid lipid nanoparticles to evaluate its antibacterial activity against S. aureus and methicillin-resistant S. aureus (MRSA). An in vitro cytotoxicity study was performed on HepG2 cell lines to assess the overall biosafety of the synthesized clotrimazole silver complex to mammalian cells, and was found to be non-toxic to mammalian cells (cell viability >80%). The minimum inhibitory concentrations (MIC) of clotrimazole and clotrimazole-silver were 31.25 and 9.76 MUg/mL against S. aureus, and 31.25 and 15.62 against MRSA, respectively. Clotrimazole SLNs exhibited MIC values of 104 and 208 MUg/mL against both MSSA and MRSA at the end of 18 and 36 h, respectively, but thereafter completely lost its antibacterial activity. Clotrimazole-silver SLNs had an MIC value of 52 MUg/mL up to 54 h, after which the MIC value was 104 MUg/mL against both strains at the end of 72 h. Thus, clotrimazole-silver SLNs was found to be an efficient nanoantibiotic. PMID- 26492157 TI - Molecular dynamics simulations of the Escherichia coli HPPK apo-enzyme reveal a network of conformational transitions. AB - 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes the first reaction in the folate biosynthetic pathway. Comparison of its X-ray and nuclear magnetic resonance structures suggests that the enzyme undergoes significant conformational change upon binding to its substrates, especially in three catalytic loops. Experimental research has shown that even when confined by crystal contacts, loops 2 and 3 remain rather flexible when the enzyme is in its apo form, raising questions about the putative large-scale induced-fit conformational change of HPPK. To investigate the loop dynamics in a crystal-free environment, we performed conventional molecular dynamics simulations of the apo enzyme at two different temperatures (300 and 350 K). Our simulations show that the crystallographic B-factors considerably underestimate the loop dynamics; multiple conformations of loops 2 and 3, including the open, semi-open, and closed conformations that an enzyme must adopt throughout its catalytic cycle, are all accessible to the apo-enzyme. These results revise our previous view of the functional mechanism of conformational change upon MgATP binding and offer valuable structural insights into the workings of HPPK. In this paper, conformational network analysis and principal component analysis related to the loops are discussed to support the presented conclusions. PMID- 26492158 TI - A low observed-to-expected postoperative mortality ratio in a Swiss high-standard peri-operative care environment - an observational study. AB - QUESTIONS UNDER STUDY/PRINCIPLES: The objective was to assess observed-to expected in-hospital postoperative 30-day mortality and to identify associated risks. METHODS: A single centre, retrospective study was performed in Geneva University Hospitals, Switzerland. Hospitalised adult surgical patients who received anaesthesia and stayed in the Post Anaesthesia Care Unit - Intermediate Care Unit (PACU-IMC) between July 2008 and June 2011 were included. Outcome measure was in-hospital 30-day mortality. Expected probabilities of in-hospital death were estimated with the surgical mortality probability model (S-MPM). Descriptive statistics were calculated. Univariate and multivariate logistic regressions (odds ratio [OR] with 95% confidence interval [95% CI]) were used to identify risk factors of mortality. RESULTS: Overall in-hospital mortality was 0.8% (176/24 160 patients). Observed 30-day in-hospital mortality was 0.7%; expected mortality from the S-MPM was 1.2%. Independent risk factors were age (OR 1.05, 95% CI 1.03-1.06), American Society of Anesthesiologists Physical Status score (ASA PS 3-5 vs ASA PS 1-2: OR 5.48, 95% CI 3.12-9.63), nonelective surgery (vs elective surgery) (OR 3.15, 95% CI 2.04-4.86), head surgery (OR 2.83, 95% CI 1.41-5.67) and duration of PACU-IMC stay (OR 1.00, 95% CI 1.00-1.00). A protective factor was a high body mass index (OR 0.92, 95% CI 0.89-0.96). The procedural risk, type and time of anaesthesia and day of intervention were not independent risk factors of mortality. CONCLUSION: The postoperative observed-to expected mortality ratio was favourable. Independent postoperative risk factors for mortality were well-established factors such as age, ASA PS, non elective surgery but also duration of PACU-IMC stay which was considered as a surrogate of postoperative complications. PMID- 26492159 TI - Temporal trends of stress myocardial perfusion imaging: Influence of diabetes, gender and coronary artery disease status. AB - INTRODUCTION: Temporal trends of myocardial perfusion imaging (MPI) among diabetics and non-diabetics and the influence of gender and prior coronary artery disease (CAD) status has not been previously investigated. MATERIALS AND METHODS: Consecutive patients who underwent clinically indicated stress-MPI over a 17-year period (1996 through 2012) were studied. Data were collected prospectively as a part of the ongoing clinical databases. Study patients were divided into 4 temporal subgroups (1996 to 2000, 2001 to 2004, 2005 to 2008 and 2009 to 2012) to compare the trends of cardiac risk factors and the frequency of abnormal and ischemic MPI. RESULTS: Of 78,344 total stress MPI studies, 30.2% were in diabetics. The frequency of abnormal MPI studies, while substantially higher in diabetics, significantly declined over time both in diabetics (53.6% in 1996 to 39.8% in 2012) and non-diabetics (37% in 1996 to 27.4% in 2012), despite an increase in the cardiac risk factor profile. Furthermore, among patients with no known CAD, the temporal prevalence of abnormal MPI was highest in diabetic men (57.5% in 1996 to 31.9% in 2012), lowest in non-diabetic women (18.8% in 1996 to 11% in 2012), and both intermediate and comparable in non-diabetic men and diabetic women (36.4% and 35.7% in 1996 and 20.7% and 17.5% in 2012, respectively). CONCLUSIONS: Despite a temporal reduction in the prevalence of abnormal studies from 1996 through 2012, stress MPI continues to play an important clinical role, particularly in diabetics, men and patients with known CAD. PMID- 26492160 TI - The danger of epigenetics misconceptions (epigenetics and stuff...). AB - Within the past two decades, the fields of chromatin structure and function and transcription regulation research started to fuse and overlap, as evidence mounted to support a very strong regulatory role in gene expression that was associated with histone post-translational modifications, DNA methylation, as well as various chromatin-associated proteins (the pillars of the "Epigenetics" building). The fusion and convergence of these complementary fields is now often simply referred to as "Epigenetics". During these same 20 years, numerous new research groups have started to recognize the importance of chromatin composition, conformation, and its plasticity. However, as the field started to grow exponentially, its growth came with the spreading of several important misconceptions, which have unfortunately led to improper or hasty conclusions. The goal of this short "opinion" piece is to attempt to minimize future misinterpretations of experimental results and ensure that the right sets of experiment are used to reach the proper conclusion, at least as far as epigenetic mechanisms are concerned. PMID- 26492161 TI - Atherosclerotic Plaque Destabilization in Mice: A Comparative Study. AB - Atherosclerosis-associated diseases are the main cause of mortality and morbidity in western societies. The progression of atherosclerosis is a dynamic process evolving from early to advanced lesions that may become rupture-prone vulnerable plaques. Acute coronary syndromes are the clinical manifestation of life threatening thrombotic events associated with high-risk vulnerable plaques. Hyperlipidemic mouse models have been extensively used in studying the mechanisms controlling initiation and progression of atherosclerosis. However, the understanding of mechanisms leading to atherosclerotic plaque destabilization has been hampered by the lack of proper animal models mimicking this process. Although various mouse models generate atherosclerotic plaques with histological features of human advanced lesions, a consensus model to study atherosclerotic plaque destabilization is still lacking. Hence, we studied the degree and features of plaque vulnerability in different mouse models of atherosclerotic plaque destabilization and find that the model based on the placement of a shear stress modifier in combination with hypercholesterolemia represent with high incidence the most human like lesions compared to the other models. PMID- 26492162 TI - Spectroscopic studies, DFT calculations, and cytotoxic activity of novel silver(I) complexes of hydroxy ortho-substituted-nitro-2H-chromen-2-one ligands and a phenanthroline adduct. AB - Silver(I) complexes of coumarin-based ligands and one of their phenanthroline (phen) adducts have been prepared and characterized using microanalytical data, molar conductivity, IR, (1)H and (13)C NMR, UV-Vis, and atomic absorption (AAS) spectroscopies. The binding modes of the coumarin-based ligands and the most probable structure of their Ag(I) complexes were predicted by means of molecular modeling and calculations of their IR, NMR, and absorption spectra using density functional theory (DFT). The cytotoxicity of the compounds studied against human derived hepatic carcinoma cells (Hep-G2) and a renal cancer cell line (A498) showed that the complexes were more cytotoxic than the clinically used chemotherapeutic, mitoxantrone. The compounds showed little interaction with DNA and also did not show nuclease activity but manifested excellent superoxide dismutase activity which may indicate that their mechanism of action is quite different to many metal-based therapeutics. PMID- 26492164 TI - Excellent outcomes of liver transplantation using severely steatotic grafts from brain-dead donors. PMID- 26492163 TI - Suppressing NRIP1 inhibits growth of breast cancer cells in vitro and in vivo. AB - Earlier age at menarche is a major risk factor for breast cancer. Our previous study identified Nrip1 (also known as Rip140) as a candidate gene for delaying female sexual maturation (FSM) and found that knocking out Nrip1 could significantly delay FSM in mice. To investigate the effects of NRIP1 in breast cancer we used human cell lines and tissue arrays along with an in vivo study of DMBA-induced carcinogenesis in Nrip1 knockout mice. Analysis of tissue arrays found that NRIP1 is elevated in tumors compared to cancer adjacent normal tissue. Interestingly, in benign tumors NRIP1 levels are higher in the cytosol of stromal cells, but NRIP1 levels are higher in the nuclei of epithelial cells in malignancies. We also found overexpression of NRIP1 in breast cancer cell lines, and that suppression of NRIP1 by siRNA in these cells significantly induced apoptosis and inhibited cell growth. Furthermore, in vivo data suggests that NRIP1 is upregulated in DMBA-induced breast cancer. Importantly, we found that DMBA-induced carcinogenesis is suppressed in Nrip1 knockdown mice. These findings suggest that NRIP1 plays a critical role in promoting the progression and development of breast cancer and that it may be a potential therapeutic target for the new breast cancer treatments. PMID- 26492165 TI - Hair testing in postmortem diagnosis of substance abuse: An unusual case of slow release oral morphine abuse in an adolescent. AB - Morphine sulfate misuse is essentially observed among regular heroin injectors. To our knowledge, primary addiction to morphine sulfate is exceptional, especially among young adolescents. A 13-year-old girl, with no history of addiction, was found dead with three empty blisters of Skenan((r)) LP 30 mg at her side. Opiates were detected in biological fluids and hair by chromatographic methods. Blood analyses confirmed morphine overdose (free morphine: 428 ng/mL; total morphine: 584 ng/mL) and segmental hair analysis confirmed regular exposure over several months (maximum morphine concentration 250 pg/mg). Suspecting the victim's mother of recreational use of Skenan((r)), the magistrate ordered analysis of her hair, with negative results. From an epidemiological viewpoint, this case of oral morphine sulfate abuse in an adolescent with no previous history suggests the emergence of a new trend of morphine sulfate consumption. From a toxicological viewpoint, it demonstrates the value of hair testing, which documented the victim's regular exposure and made an important contribution to the police investigation. PMID- 26492166 TI - A Genetic Cascade of let-7-ncl-1-fib-1 Modulates Nucleolar Size and rRNA Pool in Caenorhabditis elegans. AB - Ribosome biogenesis takes place in the nucleolus, the size of which is often coordinated with cell growth and development. However, how metazoans control nucleolar size remains largely unknown. Caenorhabditis elegans provides a good model to address this question owing to distinct tissue distribution of nucleolar sizes and a mutant, ncl-1, which exhibits larger nucleoli than wild-type worms. Here, through a series of loss-of-function analyses, we report that the nucleolar size is regulated by a circuitry composed of microRNA let-7, translation repressor NCL-1, and a major nucleolar pre-rRNA processing protein FIB 1/fibrillarin. In cooperation with RNA binding proteins PUF and NOS, NCL-1 suppressed the translation of FIB-1/fibrillarin, while let-7 targeted the 3'UTR of ncl-1 and inhibited its expression. Consequently, the abundance of FIB-1 is tightly controlled and correlated with the nucleolar size. Together, our findings highlight a novel genetic cascade by which post-transcriptional regulators interplay in developmental control of nucleolar size and function. PMID- 26492167 TI - Endometrioma size is a relevant factor in selection of the most appropriate surgical technique: a prospective randomized preliminary study. AB - OBJECTIVES: To assess and compare the ovarian reserve in patients with different sized endometriomas undergoing cystectomy or ablative surgery in order to determine the best surgical approach to safeguard healthy ovarian tissue. STUDY DESIGN: Prospective randomized study on 48 patients with unilateral single ovarian endometriomas. Patients were allocated into two groups based on endometrioma size: <5cm (n=26, Group A, small endometriomas) and >=5cm (n=22, Group B, large endometriomas). Each group was randomized to coagulation or excision treatment (1:1 ratio) before the procedure. Anti-Mullerian hormone (AMH) levels were evaluated before surgery and 3 months after surgery. RESULTS: Both ablation and excision resulted in a significant reduction in AMH level regardless of endometrioma size. A significant interaction effect was observed between endometrioma size and type of surgical technique (analysis of covariance p for interaction=0.039): in Group A, no significant difference was found between the two surgical techniques (-17.6+/-4.7% vs -18.2+/-10.6%), whereas in Group B, the excision group showed a significantly greater percentage decrease in AMH level compared with the ablation group (-24.1+/-9.3% vs -14.8+/-6.7%, p=0.011). CONCLUSIONS: Both ablative and excision treatment of endometriomas have a negative effect on ovarian function. Endometrioma size is associated with the magnitude of ovarian reserve damage following excision treatment, but in the case of ablative treatment, the decrease in AMH serum level is independent of the size of the cyst. In surgical treatment of large endometriomas, the decrease in AMH level is more consistent and much more severe following cystectomy than ablation. PMID- 26492168 TI - Toward understanding the molecular mechanism of a geminivirus C4 protein. AB - Geminiviruses are ssDNA plant viruses that cause significant agricultural losses worldwide. The viruses do not encode a polymerase protein and must reprogram differentiated host cells to re-enter the S-phase of the cell cycle for the virus to gain access to the host-replication machinery for propagation. To date, 3 Beet curly top virus (BCTV) encoded proteins have been shown to restore DNA replication competency: the replication-initiator protein (Rep), the C2 protein, and the C4 protein. Ectopic expression of the BCTV C4 protein leads to a severe developmental phenotype characterized by extensive hyperplasia. We recently demonstrated that C4 interacts with 7 of the 10 members of the Arabidopsis thaliana SHAGGY-like protein kinase gene family and characterized the interactions of C4 and C4 mutants with AtSKs. Herein, we propose a model of how C4 functions. PMID- 26492169 TI - Economic evaluation of technology for a new generation biofuel production using wastes. AB - An economic evaluation of an integrated technology for industrial scale new generation biofuel production using whey, vinasse, and lignocellulosic biomass as raw materials is reported. Anaerobic packed-bed bioreactors were used for organic acids production using initially synthetic media and then wastes. Butyric, lactic and acetic acid were predominately produced from vinasse, whey, and cellulose, respectively. Mass balance was calculated for a 16,000L daily production capacity. Liquid-liquid extraction was applied for recovery of the organic acids using butanol-1 as an effective extraction solvent which serves also as the alcohol for the subsequent enzyme-catalyzed esterification. The investment needed for the installation of the factory was estimated to about 1.7million? with depreciation excepted at about 3months. For cellulosics, the installation investment was estimated to be about 7-fold higher with depreciation at about 1.5years. The proposed technology is an alternative trend in biofuel production. PMID- 26492170 TI - Insights to the effects of free cells on community structure of attached cells and chalcopyrite bioleaching during different stages. AB - The effects of free cells on community structure of attached cells and chalcopyrite bioleaching by Acidithiobacillus sp. during different stages were investigated. The attached cells of Acidithiobacillus thiooxidans owned the community advantage from 14thd to the end of bioprocess in the normal system. The community structure of attached cells was greatly influenced in the free cells deficient systems. Compared to A. thiooxidans, the attached cells community of Acidithiobacillus ferrooxidans had a higher dependence on its free cells. Meanwhile, the analysis of key biochemical parameters revealed that the effects of free cells on chalcopyrite bioleaching in different stages were diverse, ranging from 32.8% to 64.3%. The bioleaching contribution of free cells of A. ferrooxidans in the stationary stage (8-14thd) was higher than those of A. thiooxidans, while the situation was gradually reversed in the jarosite passivation inhibited stage (26-40thd). These results may be useful in guiding chalcopyrite bioleaching. PMID- 26492171 TI - Effect of biological pretreatment of Agropyron elongatum 'BAMAR' on biogas production by anaerobic digestion. AB - The aim of this work was to analyze the impact of three different moisture contents (MC), at 45% MC, 65% MC, 75% MC, on the degradation of cellulose, hemicellulose, and lignin during fungi treatment by Flammulina velutipes of Agropyron elongatum 'BAMAR' and on biogas production. The analysis of chemical composition shown that F. velutipes had greater selectivity for lignin biodegradation with the highest hemicellulose and lignin removal at 29.1% and 35.4%, respectively, and lowest cellulose removal (20.48%) at 65% MC. F. velutipes cultivated at 65% MC increased biogas production of 398.07Ndm(3)kg( 1)VS(-1), which was 120% higher than the untreated sample. These treatment conditions resulted in 134% more methane yield compared with untreated sample. The results of this study suggested that A. elongatum is a potential biomass for biogas production in agriculture biogas plant and white-rot fungus F. velutipes provides an effective methods for improve biodegradation of A. elongatum. PMID- 26492172 TI - Is torrefaction of polysaccharides-rich biomass equivalent to carbonization of lignin-rich biomass? AB - Waste biomass species such as lignin-rich hazelnut shell (HS) and polysaccharides rich sunflower seed shell (SSS) were subjected to torrefaction at 300 degrees C and carbonization at 600 degrees C under nitrogen. The structural variations in torrefied and carbonized biomasses were compared. Also, the burning characteristics under dry air and pure oxygen (oxy-combustion) conditions were investigated. It was concluded that the effects of carbonization on HS are almost comparable with the effects of torrefaction on SSS in terms of devolatilization and deoxygenation potentials and the increases in carbon content and the heating value. Consequently, it can be proposed that torrefaction does not provide efficient devolatilization from the lignin-rich biomass while it is relatively more efficient for polysaccharides-rich biomass. Heat-induced variations in biomass led to significant changes in the burning characteristics under both burning conditions. That is, low temperature reactivity of biomass reduced considerably and the burning shifted to higher temperatures with very high burning rates. PMID- 26492173 TI - Evaluation of the inhibitory effects of heavy metals on anammox activity: A batch test study. AB - This study evaluated the interactive effect of Cu(II) and Zn(II) on anaerobic ammonium oxidation (anammox) activity using response surface methodology with a central composite design. A regression model equation was developed and validated to predict the normalized anammox activity (NAA) of anammox granules exposed to various heavy metal concentrations. The joint inhibitory effect tended to exacerbate initially and reversed as the concentrations increased and then moderated again. The most severe inhibition, resulting in a NAA of 20.1%, occurred at Cu(II) and Zn(II) concentrations of 16.3 and 20.0mgL(-1), respectively. Notably, the cumulative toxicity was mitigated with the aid of intermittent exposure acclimatization. Additionally, pre-exposure to Cu(II) in the absence of substrates strongly inhibited anammox activity. However, the presence of NO2(-) significantly enhanced Cu(II) inhibition. Therefore, such conditions should be avoided to minimize the disturbance of the anammox process. PMID- 26492174 TI - Changes in microbial community during biohydrogen production using gamma irradiated sludge as inoculum. AB - The changes in microbial community structures during fermentative hydrogen production process were investigated by analyzing 16S rDNA gene sequences using gamma irradiated sludge as inoculum. The experimental results showed that the microbial community structure of untreated sludge was very rich in diversity. After gamma irradiation, lots of species were inhibited, and species with high survival rates under radiation conditions became dominant. After fermentation, Clostridium butyrium and a sequence closely related to Clostridium perfringens ATCC 13124(T) (CP000246) became predominant, which were all common hydrogen producers. Microbial distribution analysis indicated that gamma irradiation was a good pretreatment method for enriching hydrogen-producing strains from digested sludge. PMID- 26492175 TI - Degradation and toxicity reduction of the endocrine disruptors nonylphenol, 4 tert-octylphenol and 4-cumylphenol by the non-ligninolytic fungus Umbelopsis isabellina. AB - Nonylphenol (NP), 4-tert-octylphenol (4-t-OP) and 4-cumylphenol (4-CP) are pollutants that are known as endocrine disruptors mainly due to their estrogen mimicking activity. These phenolic substances are used in a wide range of industrial and commercial applications. In the present study, biodegradation of tNP, 4-t-OP and 4-CP using the non-ligninolytic fungus Umbelopsis isabellina was investigated. After 12h of incubation, more than 90% of initially applied tNP, 4 t-OP and 4-CP (25mgL(-1)) were eliminated. GC-MS analysis revealed several derivatives mainly (hydroxyalkyl)phenols. Moreover, xenobiotic biotransformation led to the formation of intermediates with less harmful effects than the parent compounds. For all xenobiotics, a decrease in growth medium toxicity was observed, using Artemia franciscana and Daphnia magna as bioindicators. The results indicate that U. isabellina has potential in the degradation and detoxification of contaminants with endocrine activity. Moreover, this is the first report demonstrating that a microorganism is capable of effective 4-CP elimination. PMID- 26492176 TI - Kinetics of biogas production in Anaerobic Filters. AB - This study investigates methane production kinetics from individual volatile fatty acids (VFA) in an Upflow Anaerobic Filter (AF). 1gCOD in the form of acetic (HAc), propionic (HPr) or butyric acid (HBu) was injected into the AF while operating at an organic loading rate (OLRCOD) of 3.5gL(-1)d(-1). A new method is introduced to separate gas production of the baseload from the product formation of VFA degradation after the injection. The lag phase, fractional rate of gas production and half-life has been determined for the methane production of the three VFAs. The half-lives were in the order HAc10 kDa) was markedly different to that of the low molecular weight fraction (<10 kDa). The former was dominated by a broad peak, which is consistent with P bound by phosphomonoester linkages of supra-/macro-molecular structures, whereas the latter contained all of the sharp peaks that were present in unfractionated extracts, along with some broad signal. Overall, phosphomonoesters in supra-/macro-molecular structures were found to account for the majority (61% to 73%) of soil organic P across the five diverse soils. These soil phosphomonoesters will need to be integrated within current models of the inorganic-organic P cycle of soil-plant terrestrial ecosystems. PMID- 26492191 TI - Multiplex Brain Proteomic Analysis Revealed the Molecular Therapeutic Effects of Buyang Huanwu Decoction on Cerebral Ischemic Stroke Mice. AB - Stroke is the second-leading cause of death worldwide, and tissue plasminogen activator (TPA) is the only drug used for a limited group of stroke patients in the acute phase. Buyang Huanwu Decoction (BHD), a traditional Chinese medicine prescription, has long been used for improving neurological functional recovery in stroke. In this study, we characterized the therapeutic effect of TPA and BHD in a cerebral ischemia/reperfusion (CIR) injury mouse model using multiplex proteomics approach. After the iTRAQ-based proteomics analysis, 1310 proteins were identified from the mouse brain with <1% false discovery rate. Among them, 877 quantitative proteins, 10.26% (90/877), 1.71% (15/877), and 2.62% (23/877) of the proteins was significantly changed in the CIR, BHD treatment, and TPA treatment, respectively. Functional categorization analysis showed that BHD treatment preserved the integrity of the blood-brain barrier (BBB) (Alb, Fga, and Trf), suppressed excitotoxicity (Grm5, Gnai, and Gdi), and enhanced energy metabolism (Bdh), thereby revealing its multiple effects on ischemic stroke mice. Moreover, the neurogenesis marker doublecortin was upregulated, and the activity of glycogen synthase kinase 3 (GSK-3) and Tau was inhibited, which represented the neuroprotective effects. However, TPA treatment deteriorated BBB breakdown. This study highlights the potential of BHD in clinical applications for ischemic stroke. PMID- 26492193 TI - Seven-Membered Ring Nucleoside Analogues: Stereoselective Synthesis and Studies on Their Conformational Properties. AB - The synthesis of a novel series of seven-membered ring nucleoside analogues as candidates for biological screening and gene silencing applications is described. The key step in the synthetic approach is a stereoselective synthesis of an epoxide that is used as a common synthetic intermediate to prepare functionalized oxepane nucleoside derivatives. The conformational landscape and preferred ring puckering of selected oxepane nucleosides was also studied by NMR, X-ray crystallography, and quantum mechanical calculations. PMID- 26492194 TI - Analysis of free modeling predictions by RBO aleph in CASP11. AB - The CASP experiment is a biannual benchmark for assessing protein structure prediction methods. In CASP11, RBO Aleph ranked as one of the top-performing automated servers in the free modeling category. This category consists of targets for which structural templates are not easily retrievable. We analyze the performance of RBO Aleph and show that its success in CASP was a result of its ab initio structure prediction protocol. A detailed analysis of this protocol demonstrates that two components unique to our method greatly contributed to prediction quality: residue-residue contact prediction by EPC-map and contact guided conformational space search by model-based search (MBS). Interestingly, our analysis also points to a possible fundamental problem in evaluating the performance of protein structure prediction methods: Improvements in components of the method do not necessarily lead to improvements of the entire method. This points to the fact that these components interact in ways that are poorly understood. This problem, if indeed true, represents a significant obstacle to community-wide progress. Proteins 2016; 84(Suppl 1):87-104. (c) 2015 Wiley Periodicals, Inc. PMID- 26492195 TI - Myocardial Integrated Backscatter in Obese Adolescents: Associations with Measures of Adiposity and Left Ventricular Deformation. AB - BACKGROUND: Myocardial fibrosis has been proposed to play an important pathogenetic role in left ventricular (LV) dysfunction in obesity. This study tested the hypothesis that calibrated integrated backscatter (cIB) as a marker of myocardial fibrosis is altered in obese adolescents and explored its associations with adiposity, LV myocardial deformation, and metabolic parameters. METHODS/PRINCIPAL FINDINGS: Fifty-two obese adolescents and 38 non-obese controls were studied with conventional and speckle tracking echocardiography. The average cIB of ventricular septum and LV posterior wall was measured. In obese subjects, insulin resistance as estimated by homeostasis model assessment (HOMA-IR) and glucose tolerance were determined. Compared with controls, obese subjects had significantly greater cIB of ventricular septum (-16.8+/-7.8 dB vs -23.2+/-7.8 dB, p<0.001), LV posterior wall (-20.5+/-5.6 dBvs -25.0+/-5.1 dB, p<0.001) and their average (-18.7+/-5.7 dB vs -24.1+/-5.0 dB, p<0.001). For myocardial deformation, obese subjects had significantly reduced LV longitudinal systolic strain rate (SR) (p = 0.045) and early diastolic SR (p = 0.015), and LV circumferential systolic strain (p = 0.008), but greater LV longitudinal late diastolic SR (p<0.001), and radial early (p = 0.037) and late (p = 0.002) diastolic SR than controls. For the entire cohort, myocardial cIB correlated positively with body mass index (r = 0.45, p<0.001) and waist circumference (r = 0.45, p<0.001), but negatively with LV circumferential systolic strain (r = 0.23, p = 0.03) and systolic SR (r = -0.25, p = 0.016). Among obese subjects, cIB tended to correlate with HOMA-IR (r = 0.26, p = 0.07). CONCLUSION: Obese adolescents already exhibit evidence of increased myocardial fibrosis, which is associated with measures of adiposity and impaired LV circumferential myocardial deformation. PMID- 26492197 TI - Developments in the field of allergy in 2014 through the eyes of Clinical and Experimental Allergy. AB - The pathogenesis of asthma continues to be a major topic of interest to our authors with reviews and original papers on the role of viruses, mechanisms of inflammation, biomarkers, and phenotypes of asthma being major topics. A number of papers described new treatments for asthma focusing on blocking the Th2 response reflecting the fact that two decades of work in this area is finally bearing fruit. The pathogenesis of chronic rhinosinusitis is a growing area of interest, but there has been less on the genetics of airways disease than in previous years possibly reflecting the degree of rigour (and therefore a smaller body of work), with which these sorts of studies are now being undertaken. There continues to be a wide range of papers dealing with mechanisms of allergic disease ranging from clinical-based studies to basic research and the use of in vivo animal models especially mice. As before, mechanisms and new approaches to immunotherapy are common themes. Several were published in the allergens section investigating modification of allergens to increase their effectiveness and reduce the risk of adverse events. Risk factors for allergic disease was a common theme in the epidemiology section and food allergy a common theme in clinical allergy with papers on the development of protocols to induce tolerance and attempts to find biomarkers to distinguish sensitization from allergic disease. This was another exciting year for the editors, and we hope the readers of the journal. PMID- 26492196 TI - Stakeholder Engagement to Identify Priorities for Improving the Quality and Value of Critical Care. AB - BACKGROUND: Large amounts of scientific evidence are generated, but not implemented into patient care (the 'knowledge-to-care' gap). We identified and prioritized knowledge-to-care gaps in critical care as opportunities to improve the quality and value of healthcare. METHODS: We used a multi-method community based participatory research approach to engage a Network of all adult (n = 14) and pediatric (n = 2) medical-surgical intensive care units (ICUs) in a fully integrated geographically defined healthcare system serving 4 million residents. Participants included Network oversight committee members (n = 38) and frontline providers (n = 1,790). Network committee members used a modified RAND/University of California Appropriateness Methodology, to serially propose, rate (validated 9 point scale) and revise potential knowledge-to-care gaps as priorities for improvement. The priorities were sent to frontline providers for evaluation. Results were relayed back to all frontline providers for feedback. RESULTS: Initially, 68 knowledge-to-care gaps were proposed, rated and revised by the committee (n = 32 participants) over 3 rounds of review and resulted in 13 proposed priorities for improvement. Then, 1,103 providers (62% response rate) evaluated the priorities, and rated 9 as 'necessary' (median score 7-9). Several factors were associated with rating priorities as necessary in multivariable logistic regression, related to the provider (experience, teaching status of ICU) and topic (strength of supporting evidence, potential to benefit the patient, potential to improve patient/family experience, potential to decrease costs). CONCLUSIONS: A community-based participatory research approach engaged a diverse group of stakeholders to identify 9 priorities for improving the quality and value of critical care. The approach was time and cost efficient and could serve as a model to prioritize areas for research quality improvement across other settings. PMID- 26492199 TI - Placenta Accreta and Placenta Increta: An Approach to Pathogenesis Based on the Trophoblastic Differentiation Pathway. AB - Morbid adherence remains a puzzling disease. This paper suggests that normal and morbidly adherent placentation may be viewed best in terms of trophoblastic stem cells and the mutually exclusive branches of the trophoblastic differentiation pathway-villous trophoblast (VT), interstitial and endovascular nonvillous trophoblast (NVT) at the implantation site, and a positional variation in the chorion. Based on cases of hysterectomies for morbid adherence seen over 30 years at a community hospital, analyzed with routine keratin stains, with actin and trichrome stains as indicated, and with attempts at ultrasonography-pathology correlation, we present selected observations. In true accreta, the site of morbid adherence was to dilated basal plate vessels infiltrated by endovascular NVT, with scant interstitial NVT, and normal myometrium. It appeared that excess blood flow into the placenta was due to excessively deep keratin-positive endovascular NVT that spread-independently of interstitial NVT-in an angiocentric fashion in both accreta and increta. Retroplacental abnormalities were due to myometrial destruction by interstitial NVT in increta, sometimes requiring actin stains for detection; and to an admixture of markedly dilated endometrial glands and vessels in true accreta, best appreciated with keratin stains. Variations of depth and extent in increta may be due to variations in myometrial tone, and in the protease-antiprotease balance. Morbidly adherent fetal membranes are described, and the role of caesarean section scars in incretas is addressed. PMID- 26492198 TI - Cardiovirus Leader proteins bind exportins: Implications for virus replication and nucleocytoplasmic trafficking inhibition. AB - Cardiovirus Leader proteins (LX) inhibit cellular nucleocytoplasmic trafficking by directing host kinases to phosphorylate Phe/Gly-containing nuclear pore proteins (Nups). Resolution of the Mengovirus LM structure bound to Ran GTPase, suggested this complex would further recruit specific exportins (karyopherins), which in turn mediate kinase selection. Pull-down experiments and recombinant complex reconstitution now confirm that Crm1 and CAS exportins form stable dimeric complexes with encephalomyocarditis virus LE, and also larger complexes with LE:Ran. shRNA knockdown studies support this idea. Similar activities could be demonstrated for recombinant LS and LT from Theiloviruses. When mutations were introduced to alter the LE zinc finger domain, acidic domain, or dual phosphorylation sites, there was reduced exportin selection. These regions are not involved in Ran interactions, so the Ran and Crm1 binding sites on LE must be non-overlapping. The involvement of exportins in this mechanism is important to viral replication and the observation of trafficking inhibition by LE. PMID- 26492200 TI - Whole-building decontamination of Bacillus anthracis Sterne spores by methyl bromide fumigation. AB - AIMS: To evaluate the field inactivation of Bacillus anthracis Sterne spores with methyl bromide (MB) using commercial fumigation techniques. METHODS AND RESULTS: Eighty-seven wood and 87 glass coupons each containing ca. 1 * 10(6) B. anthracis Sterne spores, were placed in 22 locations inside a 1444 m(3) conference building. Four additional 12-coupon sets (six wood, six glass) were removed from the building at 16, 24, 32 and 40 h during fumigation. The building was sealed under two tarpaulins and fumigated with MB at >=225 g m(-3) mean concentration for 48 h at 28 degrees C and 83% RH. All B. anthracis spores fumigated for more than 16 h were inactivated. A single wood coupon from the 16-h set yielded ca. 2 * 10(3) CFU. No damage to the building or its contents was observed. CONCLUSIONS: MB fumigation is a rapid, economical and effective whole-structure decontamination method for B. anthracis spores. SIGNIFICANCE AND IMPACT OF THE STUDY: MB fumigation offers a method of whole-structure B. anthracis decontamination without removal of materials, damage to sensitive electronics, costly indoor retrofitting. PMID- 26492201 TI - Colour Vision in Stargardt Disease. AB - PURPOSE: To investigate the type and severity of acquired colour vision deficiencies (CVDs) in molecularly proven Stargardt disease (STD) and to establish whether a relationship exists between best-corrected visual acuity (BCVA) and full-field electroretinography (ffERG), and the degree of CVD. METHODS: A retrospective, cross-sectional study of 73 patients with a molecularly proven diagnosis of STD, who underwent extensive colour vision evaluation, using pseudo-isochromatic and arrangement tests. Thirteen patients underwent Nagel anomaloscopy. RESULTS: Normal colour vision was found in almost 20% of patients. Red/green (R/G) CVDs increased as BCVA declined. About 45% of all R/G CVDs were of the deutan type, although protan type CVDs became progressively apparent when moving from the high to the low BCVA group. An additional blue/yellow CVD was noted in about 25% of patients. In 10/13 patients, a pseudoprotanomaly was noted on anomaloscopy. Severe CVDs leading to scotopization were noted in patients with low BCVA and/or long-standing disease. No statistically significant differences in ERG results were found between groups with or without a CVD. CONCLUSIONS: The degree and type of colour vision deficiency in STD patients correlate better with BCVA than with ffERG results. The presence of specific CVDs may help to establish a diagnosis of STD. A battery of colour vision tests is required to properly evaluate CVDs in STD. PMID- 26492202 TI - Laboratory measurement of the direct oral anticoagulants. AB - Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor, dabigatran, and the direct factor Xa (FXa) inhibitors, rivaroxaban, apixaban and edoxaban, are approved for thromboembolism prevention and treatment. These drugs do not require routine coagulation monitoring but, in some circumstances, measurement of drug level or anticoagulant effect may be necessary. Although traditional coagulation tests lack analytical sensitivity and specificity, they are widely available and inexpensive, and can provide useful information regarding the residual anticoagulant effect of DOACs. Hemoclot(r) and ecarin based assays can be used to quantify dabigatran level and calibrated chromogenic anti-FXa assays are suitable for measuring rivaroxaban, apixaban and edoxaban levels, but these tests are not yet widely available. PMID- 26492203 TI - Amplified Singlet Oxygen Generation in Semiconductor Polymer Dots for Photodynamic Cancer Therapy. AB - This paper described the energy-transfer amplified singlet oxygen generation in semiconductor polymer dots (Pdots) for in vitro and in vivo photodynamic therapy. Hydrophobic photosensitizer tetraphenylporphyrin was facilely doped in the nanoparticles consisting of densely packed semiconductor polymers. Optical characterizations indicated that the fluorescence of Pdots was completely quenched by the photosensitizer, yielding an energy transfer efficiency of nearly 100% and singlet-oxygen generation quantum yield of ~50%. We evaluated the cellular uptake, dark toxicity, and photodynamic therapy of the Pdot photosensizer in human gastric adenocarcinoma cells. The in vitro studies indicated that cancer cells were efficiently destroyed at very low dose of the Pdots such as 1 MUg/mL by using the light dose of 90 J/cm(2), which is considerably less than that in clinical practice. The antitumor effect of the Pdots was further evaluated in vivo with human gastric adenocarcinoma xenografts in Balb/c nude mice, which show that the xenograft tumors were significantly inhibited and eradicated in some cases. Our results indicate the energy transfer amplified Pdot platforms have great therapeutic potential for treating malignant cancers. PMID- 26492204 TI - Correction: An Oriental Medicine, Hyungbangpaedok-San Attenuates Motor Paralysis in an Experimental Model of Multiple Sclerosis by Regulating the T Cell Response. PMID- 26492206 TI - Enhanced Dissipation of Triazole and Multiclass Pesticide Residues on Grapes after Foliar Application of Grapevine-Associated Bacillus Species. AB - Disease management in vineyards with fungicides sometimes results in undesirable residue accumulations in grapes at harvest. Bioaugmentation of the grape fructosphere can be a useful approach for enhancing the degradation rate and reducing the residues to safe levels. This paper reports the in vitro and in vivo biodegradation of three triazole fungicides commonly used in Indian vineyards, by Bacillus strains, namely, DR-39, CS-126, TL-171, and TS-204, which were earlier found to enhance the dissipation rate of profenophos and carbendazim. The strains utilized the triazoles as carbon source and enhanced their in vitro rate of degradation. Myclobutanil, tetraconazole, and flusilazole were applied in separate vineyard plots at field doses of 0.40 g L(-1), 0.75 mL L(-1), and 0.125 mL L(-1), respectively. Residue analysis of field samples from the treated fields reflected 87.38 and >99% degradations of myclobutanil and tetraconazole, respectively, by the strain DR-39, and 90.82% degradation of flusilazole by the strain CS-126 after 15-20 days of treatment. In the respective controls, the corresponding percent degradations were 72.07, 58.88, and 54.28, respectively. These Bacillus strains could also simultaneously degrade the residues of profenofos, carbendazim, and tetraconazole on the grape berries and can be useful in multiclass pesticide residue biodegradation. PMID- 26492205 TI - Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia. AB - The prognostic value of minimal residual disease (MRD) assessed by multi parameter flow cytometry (MFC) was investigated among 340 adult patients with B cell acute lymphoblastic leukaemia (B-ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15-84). Median white blood cell count (WBC) was 9.35 * 10(9) /l (range, 0.4-658.1 *1 0(9) /l). MRD by MFC was initially assessed with a sensitivity of 0.01%, using a 15-marker, 4-colour panel and subsequently a 6-colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease-free survival (DFS) and overall survival (OS) (P = 0.004 and P = 0.03, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P = 0.004 and P < 0.0001, respectively) and OS (P = 0.004 and P < 0.0001, respectively). Multivariate analysis including age, WBC at presentation, cytogenetics (standard versus high risk) and MRD status at CR, 3 and 6 months, indicated that MRD negative status at CR was an independent predictor of DFS (P < 0.05). Achievement of an MRD negative state assessed by MFC is an important predictor of DFS and OS in adult patients with ALL. PMID- 26492207 TI - Silica Foams for Fire Prevention and Firefighting. AB - We report the new development of fire-extinguishing agents employing the latest technology of fighting and preventing fires. The in situ technology of fighting fires and explosions involves using large-scale ultrafast-gelated foams, which possess new properties and unique characteristics, in particular, exceptional thermal stability, mechanical durability, and full biocompatibility. We provide a detailed description of the physicochemical processes of silica foam formation at the molecular level and functional comparison with current fire-extinguishing and fire-fighting agents. The new method allows to produce controllable gelation silica hybrid foams in the range from 2 to 30 s up to 100 Pa.s viscosity. Chemical structure and hierarchical morphology obtained by scanning electron microscopy and transmission electron microscopy images develop thermal insulation capabilities of the foams, reaching a specific heat value of more than 2.5 kJ/(kg. degrees C). The produced foam consists of organized silica nanoparticles as determined by X-ray photoelectron spectroscopy and X-ray diffraction analysis with a narrow particle size distribution of ~10-20 nm. As a result of fire extinguishing tests, it is shown that the extinguishing efficiency exhibited by silica-based sol-gel foams is almost 50 times higher than that for ordinary water and 15 times better than that for state-of-the-art firefighting agent aqueous film forming foam. The biodegradation index determined by the time of the induction period was only 3 d, while even for conventional foaming agents this index is several times higher. PMID- 26492209 TI - Maternal Characteristics, Pregnancy Complications, and Adverse Birth Outcomes Among Women With Disabilities. AB - OBJECTIVES: The objective of this study is to describe the maternal characteristics, pregnancy complications, and birth outcomes among a representative sample of Rhode Island women with disabilities who recently gave birth. METHODS: Data from the 2002-2011 Rhode Island Pregnancy Risk Assessment Monitoring System survey were analyzed. RESULTS: Approximately 7% of women in Rhode Island reported a disability. Women with disabilities reported significant disparities in their health care utilization, health behaviors, and health status before and during pregnancy and during the postpartum period. Compared with nondisabled women, they were significantly more likely to report stressful life events and medical complications during their most recent pregnancy, were less likely to receive prenatal care in the first trimester, and more likely to have preterm births (13.4%; 95% CI, 11.6-15.6 compared with 8.9%; 95% CI, 8.5-9.3 for women without disabilities) and low-birth-weight babies (10.3%; 95% CI, 9.4-11.2 compared with 6.8%; 95% CI, 6.8-6.9). There was no difference in the rates of cesarean section between women with and without disabilities. CONCLUSIONS: These findings support the need for clinicians providing care to pregnant women with disabilities to be aware of the increased risk for medical problems during pregnancy and factors that increase the risk for poor infant outcomes. PMID- 26492208 TI - Highly differentiated human airway epithelial cells: a model to study host cell parasite interactions in pertussis. AB - BACKGROUND: Bordetella pertussis colonizes the human respiratory mucosa. Most studies on B. pertussis adherence have relied on cultured mammalian cells that lack key features present in differentiated human airway cells or on animal models that are not natural hosts of B. pertussis. The objectives of this work were to evaluate B. pertussis infection in highly differentiated human airway cells in vitro and to show the role of B. pertussis fimbriae in cell adherence. METHODS: Primary human airway epithelial (PHAE) cells from human bronchi and a human bronchial epithelial (HBE) cell line were grown in vitro under air-liquid interface conditions. RESULTS: PHAE and HBE cells infected with B. pertussis wild type strain revealed bacterial adherence to the apical surface of cells, bacteria induced cytoskeleton changes, and cell detachment. Mutations in the major fimbrial subunits Fim2/3 or in the minor fimbrial adhesin subunit FimD affected B. pertussis adherence to predominantly HBE cells. This cell model recapitulates the morphologic features of the human airway infected by B. pertussis and confirms the role of fimbriae in B. pertussis adherence. Furthermore, HBE cells show that fimbrial subunits, and specifically FimD adhesin, are critical in B. pertussis adherence to airway cells. CONCLUSIONS: The relevance of this model to study host-parasite interaction in pertussis lies in the striking physiologic and morphologic similarity between the PHAE and HBE cells and the human airway ciliated and goblet cells in vivo. These cells can proliferate in vitro, differentiate, and express the same genetic profile as human respiratory cells in vivo. PMID- 26492210 TI - Serious Mental Illness and Risk for Hospitalizations and Rehospitalizations for Ambulatory Care-sensitive Conditions in Denmark: A Nationwide Population-based Cohort Study. AB - BACKGROUND: Hospitalizations for ambulatory care-sensitive conditions (ACSCs) and early rehospitalizations increase health care costs. OBJECTIVES: To determine if individuals with serious mental illnesses (SMIs) (eg, schizophrenia or bipolar disorder) are at increased risk for hospitalizations for ACSCs, and rehospitalization for the same or another ACSC, within 30 days. RESEARCH DESIGN: Population-based cohort study. PARTICIPANTS: A total of 5.9 million Danish persons aged 18 years and older between January 1, 1999 and December 31, 2013. MEASURES: The Danish Psychiatric Central Register provided information on SMI diagnoses and the Danish National Patient Register on hospitalizations for ACSCs and 30-day rehospitalizations. RESULTS: SMI was associated with increased risk for having any ACSC-related hospitalization after adjusting for demographics, socioeconomic factors, comorbidities, and prior primary care utilization [incidence rate ratio (IRR): 1.41; 95% confidence interval (95% CI), 1.37-1.45]. Among individual ACSCs, SMI was associated with increased risk for hospitalizations for angina (IRR: 1.14, 95% CI, 1.04-1.25), chronic obstructive pulmonary disease/asthma exacerbation (IRR: 1.87; 95% CI, 1.74-2.00), congestive heart failure exacerbation (IRR: 1.25; 95% CI, 1.16-1.35), and diabetes (IRR: 1.43; 95% CI, 1.31-1.57), appendiceal perforation (IRR: 1.49; 95% CI, 1.30-1.71), pneumonia (IRR: 1.72; 95% CI, 1.66-1.79), and urinary tract infection (IRR: 1.70; 95% CI, 1.62-1.78). SMI was also associated with increased risk for rehospitalization within 30 days for the same (IRR: 1.28; 95% CI, 1.18-1.40) or for another ACSC (IRR: 1.62; 95% CI, 1.49-1.76). CONCLUSION: Persons with SMI are at increased risk for hospitalizations for ACSCs, and after discharge, are at increased risk for rehospitalizations for ACSCs within 30 days. PMID- 26492211 TI - High Intensity of End-of-Life Care Among Adolescent and Young Adult Cancer Patients in the New York State Medicaid Program. AB - BACKGROUND: Little is known about the care that adolescent and young adult (AYA) cancer patients receive at the end of life (EOL). OBJECTIVE: To evaluate use of intensive measures and hospice and location of death of AYA cancer patients insured by Medicaid in New York State. DESIGN: Using linked patient-level data from the New York State Cancer Registry and state Medicaid program, we identified 705 Medicaid patients who were diagnosed with cancer between the ages of 15 and 29 in the years 2004-2011, who subsequently died, and who were continuously enrolled in Medicaid in the last 60 days of life. We evaluated use of intensive EOL measures (chemotherapy within 14 d of death; intensive care unit care, >1 emergency room visit, and hospitalizations in the last 30 d of life), hospice use, and location of death (inpatient hospice, long-term care facility, acute care facility, home with hospice, home without hospice). RESULTS: 75% of AYA Medicaid decedents used at least 1 aspect of intensive EOL care. 38% received chemotherapy in the last 2 weeks of life; 21% received intensive care unit care, 44% had >1 emergency room visit, and 64% were hospitalized in the last month of life. Only 23% used hospice. 65% of patients died in acute care settings, including the inpatient hospital or emergency room. CONCLUSIONS: Given the high rates of intensive measures and low utilization of hospice at the EOL among AYA Medicaid enrollees, opportunities to maximize the quality of EOL care in this high-risk group should be prioritized. PMID- 26492212 TI - Predictors of Emergency Department Visits and Inpatient Admissions Among Homeless and Unstably Housed Adolescents and Young Adults. AB - BACKGROUND: Individuals under age 25 years are estimated to comprise one third of the homeless population nationally. Understanding the reasons for utilization of hospitals by homeless youth is important for optimizing disposition planning. OBJECTIVES: Objectives of the present study were to: (1) report prevalence of emergency department (ED) and inpatient admissions among homeless and unstably housed youth; (2) describe demographic characteristics of those youth who seek hospital care; (3) describe their patterns of injury, illness, psychiatric, and substance use conditions; and (4) identify demographic and diagnostic predictors of ED visit or hospital readmission. METHODS: Retrospective cohort study of 15-25 year-olds (N=402) who were admitted to the ED or inpatient floors of 2 urban teaching hospitals in King County, WA between July 1, 2009 and June 30, 2012 and whose address was "homeless" or "none" or a homeless shelter or service agency (ie, homeless or unstably housed), during any recorded encounter between July 1, 2009 and June 30, 2012. RESULTS: A total of 1151 ED visits and 227 inpatient admissions were documented. Fifty percent of patients had an ED visit or hospital readmission within 1 year, with 43.1% receiving care within 30 days of discharge. Cox regression showed that female individuals with an injury diagnosis (hazard ratio=1.74, 95% confidence interval=1.06, 2.85) and male individuals with an acute medical condition (hazard ratio=1.59, 95% confidence interval=1.09, 2.32) at index visit were more likely to have an ED visit or hospital readmission during the following year, as were patients who provided a private address at their index visit. CONCLUSIONS: Homeless young people who seek hospital care demonstrate a high rate of ED visits and hospital readmissions, with unique predictors of utilization associated with sex and housing status. Additional research is necessary to determine how best to transition these young people from hospital-based to community-based care. PMID- 26492213 TI - Reexamining the Relationship of Breast Cancer Hospital and Surgical Volume to Mortality: An Instrumental Variable Analysis. AB - OBJECTIVE: To reexamine the relationship of hospital and surgical volume to all cause and breast cancer-specific mortality, taking into account the potential selection bias in patients treated at high-volume centers or by high-volume surgeons. DATA SOURCES: Elderly (65+) women with early-stage, incident breast cancer surgery in 2003. STUDY DESIGN: A population-based, prospective survey study. METHODS: Two-stage, instrumental variable regression models. PRINCIPAL FINDINGS: Women treated in high-volume hospitals were significantly less likely to die of any cause by 5 years after surgery, even after adjustments for self selection and a number of other factors. The relationship was larger and more significant for breast cancer-specific mortality. Although the general pattern of better mortality outcomes held for moderately sized hospitals, the relationships were not statistically significant. In contrast, there was no relationship of surgeon volume with all-cause or breast cancer-specific mortality. CONCLUSIONS: Hospital volume, but not surgeon volume, is associated with better survival among women with breast cancer. The magnitude of the potential improvement was substantial and comparable with the benefit conferred by many systemic therapies. These findings highlight the importance of accounting for patient self-selection in volume-outcome analyses, and provide support for policy initiatives aimed at regionalizing breast cancer care in the United States. PMID- 26492214 TI - A Time Trade-off-derived Value Set of the EQ-5D-5L for Canada. AB - BACKGROUND: The 5-level version of the EQ-5D (EQ-5D-5L) was recently developed. A number of preference-based scoring systems are being developed for several countries around the world. OBJECTIVE: To develop a value set for the EQ-5D-5L based on societal preferences in Canada. METHODS: We used age, sex, and education quota sampling from the general population from 4 cities across Canada. Composite time trade-off (cTTO) and traditional time trade-off (tTTO) were used as the main elicitation technique. A total of 86 EQ-5D-5L health states grouped into 10 blocks were valued using cTTO, whereas a subset of 18 severe states was also valued using tTTO. Participants meeting predefined inconsistency criteria were excluded from the analyses. For the value set development, we used tTTO and positive cTTO values, while censoring negative and zero cTTO values at zero. Models with the main effects presented using linear terms combined with various additional terms were estimated. The preferred model was selected based primarily on logically ordered coefficients, and secondly model fit. RESULTS: Of the 1209 participants who completed the interview, 136 met criteria that excluded them from the primary analyses. The demographics and socioeconomic status of the remaining 1073 participants were similar to the Canadian general population. The preferred model has 5 linear terms for the main effects, a term for level 4 or 5 for each dimension, and a term for the squared total number of level 4 or 5 beyond the first. For this preferred model, the health utilities ranged from 0.148 for the worst (55555) to 0.949 for the best (11111) EQ-5D-5L states. CONCLUSIONS: This is the first TTO-based value set of the EQ-5D-5L for Canada. It can be used to support the health utility estimation in economic evaluations for reimbursement decision making in Canada. PMID- 26492215 TI - Mortality Among Older Adults Before Versus After Hospital Transition to Intensivist Staffing. AB - BACKGROUND: A large body of research suggests that hospitals with intensive care units staffed by board-certified intensivists have lower mortality rates than those that do not. OBJECTIVE: To determine whether hospitals can reduce their mortality by adopting an intensivist staffing model. DESIGN: Retrospective, longitudinal study using 2003-2010 Medicare data and the Leapfrog Group Hospital surveys. SETTING AND PATIENTS: In total, 2,916,801 Medicare patients at 488 US hospitals. MEASUREMENTS: We studied 30-day and in-hospital mortality among patients with several common medical and surgical conditions. We first compared risk-adjusted mortality rates of 3 groups of hospitals: those that were intensivist staffed throughout this time period, those that were not intensivist staffed, and those that transitioned to intensivist staffing somewhere during the period. We then examined rates of mortality improvement within each of the 3 groups and used difference-in-differences techniques to assess the independent effect of intensivist staffing among the subset of hospitals that transitioned. RESULTS: Hospitals with intensivist staffing at the beginning of our study period had lower mortality rates than those without. However, hospitals that adopted intensivist staffing during the study period did not substantially improve their mortality rates. In our difference-in-differences analysis, there was no significant independent improvement in mortality after transitioning to intensivist staffing either overall [relative risk (RR), 0.96; 95% confidence interval (CI), 0.90-1.02] or in the medical (RR, 0.95; 95% CI, 0.89-1.02) or surgical populations (RR, 0.97; 95% CI, 0.84-1.10). LIMITATIONS: Risk adjustment was based on administrative data. Categorization of exposure was by survey response at the hospital level. CONCLUSIONS: Adoption of an intensivist staffing model was not associated with improved mortality in Medicare beneficiaries. These findings suggest that the lower mortality rates previously observed at hospitals with intensivist staffing may be attributable to other factors. PMID- 26492216 TI - Do Health Care Delivery System Reforms Improve Value? The Jury Is Still Out. AB - BACKGROUND: Widespread restructuring of health delivery systems is underway in the United States to reduce costs and improve the quality of health care. OBJECTIVE: To describe studies evaluating the impact of system-level interventions (incentives and delivery structures) on the value of US health care, defined as the balance between quality and cost. RESEARCH DESIGN: We identified articles in PubMed (2003 to July 2014) using keywords identified through an iterative process, with reference and author tracking. We searched tables of contents of relevant journals from August 2014 through 11 August 2015 to update our sample. SUBJECTS: We included prospective or retrospective studies of system-level changes, with a control, reporting both quality and either cost or utilization of resources. MEASURES: Data about study design, study quality, and outcomes was extracted by one reviewer and checked by a second. RESULTS: Thirty reports of 28 interventions were included. Interventions included patient centered medical home implementations (n=12), pay-for-performance programs (n=10), and mixed interventions (n=6); no other intervention types were identified. Most reports (n=19) described both cost and utilization outcomes. Quality, cost, and utilization outcomes varied widely; many improvements were small and process outcomes predominated. Improved value (improved quality with stable or lower cost/utilization or stable quality with lower cost/utilization) was seen in 23 reports; 1 showed decreased value, and 6 showed unchanged, unclear, or mixed results.Study limitations included variability among specific endpoints reported, inconsistent methodologies, and lack of full adjustment in some observational trials. Lack of standardized MeSH terms was also a challenge in the search. CONCLUSIONS: On balance, the literature suggests that health system reforms can improve value. However, this finding is tempered by the varying outcomes evaluated across studies with little documented improvement in outcome quality measures. Standardized measures of value would facilitate assessment of the impact of interventions across studies and better estimates of the broad impact of system change. PMID- 26492217 TI - Disparities in 30-Day Rehospitalization Rates Among Medicare Skilled Nursing Facility Residents by Race and Site of Care. AB - OBJECTIVES: To examine racial and site-of-care disparities in all-cause and potentially avoidable 30-day rehospitalization rates among a national cohort of Medicare skilled nursing facility (SNF) residents. METHODS: We analyzed the 2012 Minimum Data Set, Medicare inpatient claims, and other data. Multivariable logistic regressions were used to adjust for resident demographic, functional, and diagnostic characteristics, as well as observed SNF and geographic factors. Conditional fixed effects for SNFs were further used to adjust for both observed and unobserved factors. Independent effects of black race and site-of-care groups were estimated, where sites were defined using proportions of black Medicare admissions to the SNF. RESULTS: The 30-day all-cause and potentially avoidable rehospitalization rates were 21.9% and 8.8%, respectively, for black residents (n=120,508), and 17.7% and 7.9% for white residents (n=1,182,003). Racial disparities persisted after adjustment for resident characteristics. Moreover, risk-adjusted disparities were essentially related to the type of SNFs to which residents were admitted; after controlling for SNF sites, significant racial disparity disappeared for potentially available rehospitalizations. Black residents and white residents admitted to SNFs with high proportions of black admissions (>25%) were 31% and 19%, respectively, more likely to be rehospitalized than white residents admitted to SNFs caring for only a small percentage of black postacute residents (<3%). CONCLUSIONS: Compared with white SNF residents, black SNF residents are more likely to be rehospitalized even after adjusting for patient risk factors. Black-white disparities, especially in potentially preventable rehospitalizations, are largely due to the fact that black residents tend to be admitted to the small number of SNFs with very high rehospitalization rates. PMID- 26492218 TI - Is there an effect of thyroid autoimmunity on the outcomes of assisted reproduction? AB - We aimed to evaluate the role of thyroid autoantibodies (TAA) on the outcomes of intracytoplasmic sperm injection-embryo transfer (ICSI-ET). A prospective case control study was conducted in the in vitro fertilisation (IVF) centre of Suleymaniye Maternity Training and Research Hospital, Istanbul, Turkey between July 2013 and March 2014. A total of 49 (19.52%) TAA-positive and 202 TAA negative patients were enrolled. Demographic characteristics and laboratory parameters were recorded. All patients underwent ICSI-ET. Thirty-one TAA-positive patients (32 cycles) and 121 TAA-negative patients (126 cycles) completed the study. Mean female age, body mass index (BMI), type of infertility, duration of infertility, antral follicle count (AFC), anti-Mullerian hormone (AMH), basal follicle stimulating hormone (bFSH), luteinising hormone (bLH), and oestradiol (bE2), prolactin and thyroid hormone profiles, male age and aetiology of infertility of both groups were similar (p > 0.05). There was no significant difference between groups in terms of duration and dose of gonadotropin (Gn) therapy, day of human chorionic Gn (hCG) administration, serum E2 and progesterone levels, number of collected oocytes, ratio of fertilisation, number of available embryos, positive pregnancy test, biochemical pregnancy, clinical pregnancy, ratio of miscarriage and ongoing pregnancy (p > 0.05). In conclusion, we failed to demonstrate a significant role of TAA on the outcomes of ICSI-ET in euthyroid patients. Further studies with larger numbers of participants are required to clarify these data. PMID- 26492219 TI - Combination therapy with lopinavir/ritonavir, ribavirin and interferon-alpha for Middle East respiratory syndrome. AB - Since the first report of Middle East respiratory syndrome (MERS) in 2012 in Saudi Arabia, no standard treatment guideline has been set despite the virulence of MERS-coronavirus (CoV) and the high case-fatality rate. The outbreak in South Korea in 2015 demonstrates that MERS outbreaks can occur outside of the Middle East. The combination of ribavirin and interferon-alpha has been the most widely used therapy for this infection. However, due to the varying results of treatment with these drugs, a new antiviral combination regimen is urgently needed. This is a case report of use of lopinavir/ritonavir-based combination antiviral therapy for a patient with MERS-CoV infection. PMID- 26492220 TI - Tailor-Made Fluorinated Copolymer/Clay Nanocomposite by Cationic RAFT Assisted Pickering Miniemulsion Polymerization. AB - Fluorinated polymers in emulsion find enormous applications in hydrophobic surface coating. Currently, lots of efforts are being made to develop specialty polymer emulsions which are free from surfactants. This investigation reports the preparation of a fluorinated copolymer via Pickering miniemulsion polymerization. In this case, 2,2,3,3,3-pentafluoropropyl acrylate (PFPA), methyl methacrylate (MMA), and n-butyl acrylate (nBA) were copolymerized in miniemulsion using Laponite-RDS as the stabilizer. The copolymerization was carried out via reversible addition-fragmentation chain transfer (RAFT) process. Here, a cationic RAFT agent, S-1-dodecyl-S'-(methylbenzyltriethylammonium bromide) trithiocarbonate (DMTTC), was used to promote polymer-Laponite interaction by means of ionic attraction. The polymerization was much faster when Laponite content was 30 wt % or above with 1.2 wt % RAFT agent. The stability of the miniemulsion in terms of zeta potential was found to be dependent on the amount of both Laponite and RAFT agent. The miniemulsion had particle sizes in the range of 200-300 nm. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) analyses showed the formation of Laponite armored spherical copolymer particles. The fluorinated copolymer films had improved surface properties because of polymer-Laponite interaction. PMID- 26492221 TI - Magnetocaloric properties of TbN, DyN and HoN nanopowders prepared by the plasma arc discharge method. AB - We report for the first time the synthesis of nanopowders of TbN, DyN and HoN crystallized in a cubic structure by the plasma arc discharge (PAD) method and investigate their magnetocaloric properties for magnetic refrigeration applications. The nitridization of terbium, dysprosium and holmium was obtained using a mixture of nitrogen and argon gas inside a discharge chamber with 4 kPa pressure. The structural and microstructural properties of these rare earth nitrides were investigated by using X-ray diffraction and transmission electron microscopy. The studied nitrides undergo a second-order ferromagnetic to paramagnetic phase transition at Curie temperatures of 35.7, 19.9 and 14.2 K for TbN, DyN and HoN, respectively. The magnetocaloric effects were estimated by calculating the magnetic entropy changes from the magnetization data sets measured at the different applied magnetic fields and temperatures. The changes in entropy -DeltaSM were found to be 12.0, 13.6 and 24.5 J kg(-1) K(-1) at an applied magnetic field of 5 T. PMID- 26492222 TI - Simultaneous Purification and Perforation of Low-Grade Si Sources for Lithium-Ion Battery Anode. AB - Silicon is regarded as one of the most promising candidates for lithium-ion battery anodes because of its abundance and high theoretical capacity. Various silicon nanostructures have been heavily investigated to improve electrochemical performance by addressing issues related to structure fracture and unstable solid electrolyte interphase (SEI). However, to further enable widespread applications, scalable and cost-effective processes need to be developed to produce these nanostructures at large quantity with finely controlled structures and morphologies. In this study, we develop a scalable and low cost process to produce porous silicon directly from low grade silicon through ball-milling and modified metal-assisted chemical etching. The morphology of porous silicon can be drastically changed from porous-network to nanowire-array by adjusting the component in reaction solutions. Meanwhile, this perforation process can also effectively remove the impurities and, therefore, increase Si purity (up to 99.4%) significantly from low-grade and low-cost ferrosilicon (purity of 83.4%) sources. The electrochemical examinations indicate that these porous silicon structures with carbon treatment can deliver a stable capacity of 1287 mAh g(-1) over 100 cycles at a current density of 2 A g(-1). This type of purified porous silicon with finely controlled morphology, produced by a scalable and cost effective fabrication process, can also serve as promising candidates for many other energy applications, such as thermoelectrics and solar energy conversion devices. PMID- 26492223 TI - Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients. AB - BACKGROUND: Metastatic renal cell carcinoma (mRCC) prognostic models may be improved by incorporating treatment-induced toxicities. METHODS: In sunitinib treated mRCC patients (N=770), baseline prognostic factors and treatment-induced toxicities (hypertension (systolic blood pressure ?140 mm Hg), neutropenia (grade ?2), thrombocytopenia (grade ?2), hand-foot syndrome (grade >0), and asthenia/fatigue (grade >0)) were analysed in multivariate analyses of progression-free survival (PFS) and overall survival (OS) end points. RESULTS: On treatment neutropenia and hypertension were associated with longer PFS (P=0.0276 and P<0.0001, respectively) and OS (P=0.0014 and P<0.0001, respectively), independent of baseline prognostic factors, including International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. By 12-week landmark analysis, neutropenia was significantly associated with longer PFS and OS (P=0.013 and P=0.0122, respectively) and hypertension or hand-foot syndrome with longer OS (P=0.0036 and P=0.0218, respectively). The concordance index was 0.65 (95% CI: 0.63-0.67) for IMDC classification alone and 0.72 (95% CI: 0.70-0.74) when combined with hypertension and neutropenia. Considering hypertension and neutropenia (developing both vs neither) changed IMDC-predicted median OS in each IMDC risk group (favourable: 45.3 vs 19.5 months; intermediate: 32.5 vs 8.0 months; poor: 21.1 vs 4.8 months). CONCLUSIONS: On-treatment neutropenia and hypertension are independent biomarkers of sunitinib efficacy and may add prognostic accuracy to the IMDC model. PMID- 26492224 TI - Big Data: the challenge for small research groups in the era of cancer genomics. AB - In the past decade, cancer research has seen an increasing trend towards high throughput techniques and translational approaches. The increasing availability of assays that utilise smaller quantities of source material and produce higher volumes of data output have resulted in the necessity for data storage solutions beyond those previously used. Multifactorial data, both large in sample size and heterogeneous in context, needs to be integrated in a standardised, cost effective and secure manner. This requires technical solutions and administrative support not normally financially accounted for in small- to moderate-sized research groups. In this review, we highlight the Big Data challenges faced by translational research groups in the precision medicine era; an era in which the genomes of over 75,000 patients will be sequenced by the National Health Service over the next 3 years to advance healthcare. In particular, we have looked at three main themes of data management in relation to cancer research, namely (1) cancer ontology management, (2) IT infrastructures that have been developed to support data management and (3) the unique ethical challenges introduced by utilising Big Data in research. PMID- 26492225 TI - Berberine and Curcumin Target Survivin and STAT3 in Gastric Cancer Cells and Synergize Actions of Standard Chemotherapeutic 5-Fluorouracil. AB - Aberrantly expressed survivin and STAT3 signaling have emerged as major determinants of chemoresistance in gastric cancer. We evaluated effects of potent herbal derivatives curcumin, berberine, and quercetin on STAT3 signaling, survivin expression, and response to 5-fluorouracil (5-FU) treatment in gastric cancer cells (AGS). Cytotoxic and inhibitory effects of berberine, curcumin, and quercetin alone or in combination with 5-FU were examined by MTT assay, and their effect on survivin, STAT3, and the phosphorylated active STAT3 (pSTAT3) expression was examined by western blotting. Effect of these herbal derivatives on STAT3 DNA binding activity was measured by electrophoretic mobility shift assay. Curcumin, berberine, and quercetin effectively downregulated pSTAT3 levels, survivin expression, and gastric cancer cells viability in a dose dependent manner (with corresponding IC50 values of 40.3MUM, 29.2MUM and 37.5MUM, respectively). Berberine was more effective in inhibiting survivin expression as compared to other herbal agents. 5-FU in combination with berberine or curcumin showed a synergistic inhibition of survivin and STAT3 level resulting in enhanced cell death in gastric cancer cells. Overall, our data suggest use of berberine and curcumin as adjunct therapeutics to overcome chemoresistance during treatment of gastric malignancies. PMID- 26492226 TI - Effect of Three Training Systems on Grapes in a Wet Region of China: Yield, Incidence of Disease and Anthocyanin Compositions of Vitis vinifera cv. Cabernet Sauvignon. AB - Grapevine training systems determine the suitability for grape varieties in a specific growing region. We evaluated the influence of three training systems, Single Guyot (SG), Spur-pruned Vertical Shoot-Positioned (VSP), and Four-Arm Kniffin (4AK), on the performance of grapes and vines of Vitis vinifera L. cv. Cabernet Sauvignon in the 2012 and 2013 growing seasons in a wet region of central China. 4AK was the most productive system in comparison to SG and VSP. SG and VSP had lower disease infections of leaves and berries, especially in the mid and final stage of berry ripening. Three training systems had no impact on berry maturity. PLS-DA (Partial Least Squares-Discriminant) analysis showed that the relatively dry vintage could well discriminate three training systems, but the wet vintage was not. A wet vintage of 2013 had more accumulation of 3'5' substituted and acylated anthocyanins, including malvidin-3-O-(6-O-acetyl) glucoside, malvidin-3-O-glucoside, and petunidin-3-O-(cis-6-O-coumaryl) glucoside, etc. With regard to the effect of training systems, 4AK grapes had the lowest concentrations of total anthocyanins and individual anthocyanins, SG and VSP differed according to the different vintages, and showed highest concentration of total individual anthocyanins in 2012 and 2013, respectively. Generally, VSP benefited the most, contributing to significantly highest levels of total individual anthocyanins, and major anthocyanin, including malvidin-3-O glucoside and malvidin-3-O-(6-O-acetyl)-glucoside, and the grapes obtained from VSP presented significantly highest proportion of 3'5'-substituted anthocyanins. With regard to the ratios of 3'5'/3'-substituted, methoxylated/non-methoxylated and acylated/non-acylated anthocyanins, the significantly higher levels were also shown in VSP system. In summary, VSP was the best training system for Cabernet Sauvignon to accumulate relatively stable individual anthocyanins in this wet region of China and potentially in other rainy regions. PMID- 26492227 TI - Validated LC-MS/MS Method for the Determination of Scopoletin in Rat Plasma and Its Application to Pharmacokinetic Studies. AB - A rapid, sensitive and selective liquid chromatography-electrospray ionization tandem mass spectrometric method was developed and validated for the quantification of scopoletin in rat plasma. After the addition of the internal standard xanthotoxin, plasma samples were pretreated by a simple one-step protein precipitation with acetonitrile-methanol (2:1, v/v). Chromatographic separation was achieved on a Diamonsil ODS chromatography column using gradient elution with the mobile phase consisting of acetonitrile and 0.1% formic acid. The determination was performed by positive ion electrospray ionization in multiple reaction monitoring mode. The calibration curve was linear over the concentration range of 5-1000 ng/mL (r = 0.9996). The intra- and inter-day precision (RSD%) was less than 6.1%, and the accuracy (RE%) was from -3.0%-2.5%. This method was successfully applied to the pharmacokinetic research of scopoletin in rats after intravenous (5 mg/kg) or oral (5, 10 and 20 mg/kg) administration. The result showed that oral bioavailability with a dose of 5 mg/kg was 6.62% +/- 1.72%, 10 mg/kg, 5.59% +/- 1.16%, and 20 mg/kg, 5.65% +/- 0.75%. PMID- 26492228 TI - The Occurrence of Propyl Lactate in Chinese Baijius (Chinese Liquors) Detected by Direct Injection Coupled with Gas Chromatography-Mass Spectrometry. AB - As one of the oldest distillates in the world, flavor compounds of Chinese Baijiu (Chinese liquor) were extremely complex. Propyl lactate was firstly detected by direct injection and gas chromatography-mass spectrometry (GC-MS) in 72 Chinese Baijius. The objectives were to detect the contents of propyl lactate and evaluate its contribution to the aroma of Chinese Baijiu based on odor activity values (OAVs). The levels of propyl lactate in these distillates were determined by internal standard method and selective ion monitoring (SIM), which ranged from 0.050 to 1.900 mg?L(-1) under investigation. Its detection threshold was determined by Three-Alternative Forced-Choice (3-AFC) and curve fitting (CF), which was 0.740 mg?L(-1) in 38% ethanol solution. The contribution of propyl lactate on the aroma of these distillate drinks was evaluated by their odor activity values (OAVs), which varied from 0.066 to 4.440. The OAVs of propyl lactate were found to exceed 1 in 13 Chinese Baijius, including 50 degrees Jingzhi Guniang 5 years (4.440), 52 degrees Jingzhi Guniang 10 years (3.024), Jingyanggang (2.568), Xianghe Ronghe Shaofang (2.313), and 1956 Laolang (1.431), which indicated that propyl lactate was one of odor-active components in these Chinese Baijius. PMID- 26492229 TI - Oligomeric Procyanidins Interfere with Glycolysis of Activated T Cells. A Novel Mechanism for Inhibition of T Cell Function. AB - Procyanidins, which are flavonoids that are found in a variety of plant species, reduce or prevent immune disorders, such as allergy and autoimmune diseases, through an unknown mechanism. In the present study, we investigated the effects of procyanidins on the T cell receptor (TCR)-mediated responses of CD4+ T cells in vitro. Apple procyanidins strongly suppressed the proliferation of splenic CD4+ T cells that were stimulated by an anti-CD3epsilon antibody, as well as splenocytes stimulated by antigen, but did not alter interleukin (IL)-2 secretion from these cells. Furthermore, we found that oligomeric procyanidins strongly suppressed, in a degree of polymerization dependent manner, the proliferation of activated CD4+ T cells, as well as their production of effector cytokines, including glycolysis associated-cytokines, without affecting IL-2 secretion. Additionally, we investigated the inhibitory effects of oligomeric procyanidins on the glycolytic activity of activated CD4+ T cells. We show that pentameric procyanidin suppressed L-lactate production and glucose uptake in activated CD4+ T cells. These results suggest that oligomeric procyanidins suppress the functions of activated CD4+ T cells by interfering with glycolysis. PMID- 26492230 TI - miRNA Stability in Frozen Plasma Samples. AB - MicroRNAs (miRNAs) represent a family of small non-coding ribonucleic acids that post-transcriptionally inhibits the expression of their target messenger RNAs (mRNAs), thereby acting as general gene repressors. In this study we examined the relative quantity and stability of miRNA subjected to a long period of freezing; we compared the stability of eight miRNAs in the plasma of five human healthy controls before freezing and after six and 12 months of storage at -80 degrees C. In addition, we examined the plasma frozen for 14 years and the amount of miRNA still available. Using a Life Technologies protocol to amplify and quantify plasma miRNAs from EDTA (Ethylene Diamine Tetraacetic Acid)-treated blood, we analyzed the stability of eight miRNAs, (miR-125b-5p, miR-425-5p, miR-200b-5p, miR-200c-3p, miR-579-3p, miR-212-3p, miR-126-3p, and miR-21-5p). The miRNAs analyzed showed a high stability and long frozen half-life. PMID- 26492231 TI - Thermal Influence of CNT on the Polyamide 12 Nanocomposite for Selective Laser Sintering. AB - The thermal influence of carbon nanotubes (CNTs) on the PA12 in the laser sintering process was assessed by physical experiments and a three dimensional simulation model. It appears that, by adding the CNTs into the PA12 matrix, the thermal conductivity increased. A double ellipsoidal heat flux model was applied to input a three dimensional, continuous moving, volumetric laser heat source. The predicted three dimensional temperature distributions suggested that the laser heat was conducted wider and deeper in the PA12-CNT sample than PA12. Greater heat conduction can reduce the interspace between two successive layers, and result in the increase of the parts' density and properties. PMID- 26492232 TI - Antioxidant Properties of Essential Oil Extracted from Pinus morrisonicola Hay Needles by Supercritical Fluid and Identification of Possible Active Compounds by GC/MS. AB - Pine (Pinus morrisonicola Hay, PM) needles have been used as folk medicine for their antihypertension and lipid-lowering effects. As supercritical fluid extraction (SFE) is considered an ideal technique for the extraction of essential oil from plant materials, the present work investigated the optimal SFE conditions and the protective effects of different resulting fractions of PM needles on lipid peroxidation and foam cell production in macrophages. Nine PM needle extracts (PME1-9) were obtained in 1%-4% yields using different SFE conditions, of which PME1 had the lowest yield (1.1%) and PME3 the highest (3.9%). PME3 exhibited lower cytotoxic effects and stronger inhibition of lipid peroxidation and formation of foam cell in RAW 264.7 macrophages than those of other PME extracts. PME3-1 purified from PME3 by column and thin layer chromatography inhibited LDL oxidation more effectively than did PME3 in a cell free system oxidized by Cu(2+). PME3-1 dose-dependently (25-100 MUg/mL) decreased conjugated diene levels and foam cell formation induced by ox-LDL. GC/MS analyses revealed that 1-docosene, neophytadiene, and methyl abietate were increased 5.2-, 1.7- and 4.3-fold in PME3-1 relative to PME3. A new hydrocarbon compound, cedrane 8,13-diol, was identified in PME3-1. Overall, the present study demonstrates the optimal extraction conditions of SFE of PM and identifies the most potent antioxidant fractions and possible active compounds in PM. PMID- 26492233 TI - Synthesis and Evaluation of New Pyrazoline Derivatives as Potential Anticancer Agents. AB - New pyrazoline derivatives were synthesized and evaluated for their cytotoxic effects on AsPC-1 human pancreatic adenocarcinoma, U87 and U251 human glioblastoma cell lines. 1-[((5-(4-Methylphenyl)-1,3,4-oxadiazol-2 yl)thio)acetyl]-3-(2-thienyl)-5-(4-chlorophenyl)-2-pyrazoline (11) was found to be the most effective anticancer agent against AsPC-1 and U251 cell lines, with IC50 values of 16.8 uM and 11.9 uM, respectively. Tumor selectivity of compound 11 was clearly seen between Jurkat human leukemic T-cell line and human peripheral blood mononuclear cells (PBMC). Due to its promising anticancer activity, compound 11 was chosen for apoptosis/necrosis evaluation and DNA cleavage analysis in U251 cells. Compound 11-treated U251 cells exhibited apoptotic phenotype at low concentration (1.5 uM). DNA-cleaving efficiency of this ligand was more significant than cisplatin and was clearly enhanced by Fe(II)-H2O2-ascorbic acid systems. This result pointed out the relationship between the DNA cleavage and the cell death. PMID- 26492234 TI - Lupanine Improves Glucose Homeostasis by Influencing KATP Channels and Insulin Gene Expression. AB - The glucose-lowering effects of lupin seeds involve the combined action of several components. The present study investigates the influence of one of the main quinolizidine alkaloids, lupanine, on pancreatic beta cells and in an animal model of type-2 diabetes mellitus. In vitro studies were performed with insulin secreting INS-1E cells or islets of C57BL/6 mice. In the in vivo experiments, hyperglycemia was induced in rats by injecting streptozotocin (65 mg/kg body weight). In the presence of 15 mmol/L glucose, insulin secretion was significantly elevated by 0.5 mmol/L lupanine, whereas the alkaloid did not stimulate insulin release with lower glucose concentrations. In islets treated with l-arginine, the potentiating effect of lupanine already occurred at 8 mmol/L glucose. Lupanine increased the expression of the Ins-1 gene. The potentiating effect on secretion was correlated to membrane depolarization and an increase in the frequency of Ca(2+) action potentials. Determination of the current through ATP-dependent K+ channels (KATP channels) revealed that lupanine directly inhibited the channel. The effect was dose-dependent but, even with a high lupanine concentration of 1 mmol/L or after a prolonged exposure time (12 h), the KATP channel block was incomplete. Oral administration of lupanine did not induce hypoglycemia. By contrast, lupanine improved glycemic control in response to an oral glucose tolerance test in streptozotocin-diabetic rats. In summary, lupanine acts as a positive modulator of insulin release obviously without a risk for hypoglycemic episodes. PMID- 26492235 TI - Stress Sensitivity Is Associated with Differential Accumulation of Reactive Oxygen and Nitrogen Species in Maize Genotypes with Contrasting Levels of Drought Tolerance. AB - Drought stress decreases crop growth, yield, and can further exacerbate pre harvest aflatoxin contamination. Tolerance and adaptation to drought stress is an important trait of agricultural crops like maize. However, maize genotypes with contrasting drought tolerances have been shown to possess both common and genotype-specific adaptations to cope with drought stress. In this research, the physiological and metabolic response patterns in the leaves of maize seedlings subjected to drought stress were investigated using six maize genotypes including: A638, B73, Grace-E5, Lo964, Lo1016, and Va35. During drought treatments, drought-sensitive maize seedlings displayed more severe symptoms such as chlorosis and wilting, exhibited significant decreases in photosynthetic parameters, and accumulated significantly more reactive oxygen species (ROS) and reactive nitrogen species (RNS) than tolerant genotypes. Sensitive genotypes also showed rapid increases in enzyme activities involved in ROS and RNS metabolism. However, the measured antioxidant enzyme activities were higher in the tolerant genotypes than in the sensitive genotypes in which increased rapidly following drought stress. The results suggest that drought stress causes differential responses to oxidative and nitrosative stress in maize genotypes with tolerant genotypes with slower reaction and less ROS and RNS production than sensitive ones. These differential patterns may be utilized as potential biological markers for use in marker assisted breeding. PMID- 26492236 TI - PARP Inhibitor PJ34 Suppresses Osteogenic Differentiation in Mouse Mesenchymal Stem Cells by Modulating BMP-2 Signaling Pathway. AB - Poly(ADP-ribosyl)ation is known to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, genomic stability and cell differentiation by poly(ADP-ribose) polymerase (PARP). While PARP inhibitors are presently under clinical investigation for cancer therapy, little is known about their side effects. However, PARP involvement in mesenchymal stem cell (MSC) differentiation potentiates MSC-related side effects arising from PARP inhibition. In this study, effects of PARP inhibitors on MSCs were examined. MSCs demonstrated suppressed osteogenic differentiation after 1 uM PJ34 treatment without cytotoxicity, while differentiation of MSCs into chondrocytes or adipocytes was unaffected. PJ34 suppressed mRNA induction of osteogenic markers, such as Runx2, Osterix, Bone Morphogenetic Protein-2, Osteocalcin, bone sialoprotein, and Osteopontin, and protein levels of Bone Morphogenetic Protein 2, Osterix and Osteocalcin. PJ34 treatment also inhibited transcription factor regulators such as Smad1, Smad4, Smad5 and Smad8. Extracellular mineralized matrix formation was also diminished. These results strongly suggest that PARP inhibitors are capable of suppressing osteogenic differentiation and poly(ADP ribosyl)ation may play a physiological role in this process through regulation of BMP-2 signaling. Therefore, PARP inhibition may potentially attenuate osteogenic metabolism, implicating cautious use of PARP inhibitors for cancer treatments and monitoring of patient bone metabolism levels. PMID- 26492237 TI - Metabolomics to Decipher the Chemical Defense of Cereals against Fusarium graminearum and Deoxynivalenol Accumulation. AB - Fusarium graminearum is the causal agent of Fusarium head blight (FHB) and Gibberella ear rot (GER), two devastating diseases of wheat, barley, and maize. Furthermore, F. graminearum species can produce type B trichothecene mycotoxins that accumulate in grains. Use of FHB and GER resistant cultivars is one of the most promising strategies to reduce damage induced by F. graminearum. Combined with genetic approaches, metabolomic ones can provide powerful opportunities for plant breeding through the identification of resistant biomarker metabolites which have the advantage of integrating the genetic background and the influence of the environment. In the past decade, several metabolomics attempts have been made to decipher the chemical defense that cereals employ to counteract F. graminearum. By covering the major classes of metabolites that have been highlighted and addressing their potential role, this review demonstrates the complex and integrated network of events that cereals can orchestrate to resist to F. graminearum. PMID- 26492238 TI - Antiproliferative Activity and in Vivo Toxicity of Double-Point Modified Analogs of 1,25-Dihydroxyergocalciferol. AB - Analogs of 1,25-dihydroxyergocalciferol, modified in the side-chain and in the A ring, were tested for their antiproliferative activity against a series of human cancer cell lines in vitro and in vivo toxicity. The proliferation inhibition caused by the analogs was higher than that of the parent compounds, while the toxicity, measured as the serum calcium level, was lower. All analogs were able to induce, in HL-60 and MV4-11 leukemic cells, G0/G1 cell cycle arrest and differentiation expressed as morphological signs typical for monocytes. The analogs also induced the expression of CD11b and/or CD14 cell-differentiation markers. The most potent analogs, PRI-5105, PRI-5106, PRI-5201 and PRI-5202, were also able to induce vitamin D receptor (VDR) protein expression, mainly in the cytoplasmic fraction of HL-60 or MV4-11 cells. The most active analogs were the 19-nor ones with an extended and rigidified side-chain (PRI-5201 and PRI-5202), as in the former analogs PRI-1906 and PRI-1907. Epimerization at C-24 (PRI-5101) or introduction of an additional hydroxyl at C-23 (PRI-5104) reduced the toxicity of the analog with retained antiproliferative activity. PMID- 26492240 TI - High-Throughput Screening in Protein Engineering: Recent Advances and Future Perspectives. AB - Over the last three decades, protein engineering has established itself as an important tool for the development of enzymes and (therapeutic) proteins with improved characteristics. New mutagenesis techniques and computational design tools have greatly aided in the advancement of protein engineering. Yet, one of the pivotal components to further advance protein engineering strategies is the high-throughput screening of variants. Compartmentalization is one of the key features allowing miniaturization and acceleration of screening. This review focuses on novel screening technologies applied in protein engineering, highlighting flow cytometry- and microfluidics-based platforms. PMID- 26492239 TI - MicroRNAs Regulate Mitochondrial Function in Cerebral Ischemia-Reperfusion Injury. AB - Cerebral ischemia-reperfusion injury involves multiple independently fatal terminal pathways in the mitochondria. These pathways include the reactive oxygen species (ROS) generation caused by changes in mitochondrial membrane potential and calcium overload, resulting in apoptosis via cytochrome c (Cyt c) release. In addition, numerous microRNAs are associated with the overall process. In this review, we first briefly summarize the mitochondrial changes in cerebral ischemia reperfusion and then describe the possible molecular mechanism of miRNA-regulated mitochondrial function, which likely includes oxidative stress and energy metabolism, as well as apoptosis. On the basis of the preceding analysis, we conclude that studies of microRNAs that regulate mitochondrial function will expedite the development of treatments for cerebral ischemia-reperfusion injury. PMID- 26492241 TI - The Osteogenesis Effect and Underlying Mechanisms of Local Delivery of gAPN in Extraction Sockets of Beagle Dogs. AB - A plastic and biodegradable bone substitute consists of poly (L-lactic-co glycolic) acid and 30 wt % beta-tricalcium phosphate has been previously fabricated, but its osteogenic capability required further improvement. We investigated the use of globular adiponectin (gAPN) as an anabolic agent for tissue-engineered bone using this scaffold. A qualitative analysis of the bone regeneration process was carried out using MUCT and histological analysis 12 weeks after implantation. CBCT (Cone Beam Computed Tomography) superimposition was used to characterise the effect of the different treatments on bone formation. In this study, we also explored adiponectin's (APN) influence on primary cultured human jaw bone marrow mesenchymal stem cells gene expressions involved in the osteogenesis. We found OPEN ACCESS Int. J. Mol. Sci. 2015, 16 24947 that composite scaffolds loaded with gAPN or bone morphogenetic protein 2 (BMP2) exhibited significantly increased bone formation and mineralisation following 12 weeks in the extraction sockets of beagle dogs, as well as enhanced expression of osteogenic markers. In vitro investigation revealed that APN also promoted osteoblast differentiation of primary cultured human jaw bone marrow mesenchymal stem cells (h-JBMMSCs), accompanied by increased activity of alkaline phosphatase, greater mineralisation, and production of the osteoblast differentiated genes osteocalcin, bone sialoprotein and collagen type I, which was reversed by APPL1 siRNA. Therefore, the composite scaffold loaded with APN exhibited superior activity for guided bone regeneration compared with blank control or Bio-Oss(r) (a commercially available product). The composite scaffold with APN has significant potential for clinical applications in bone tissue engineering. PMID- 26492242 TI - miR-223 Inhibits Lipid Deposition and Inflammation by Suppressing Toll-Like Receptor 4 Signaling in Macrophages. AB - Atherosclerosis and its complications rank as the leading cause of death with the hallmarks of lipid deposition and inflammatory response. MicroRNAs (miRNAs) have recently garnered increasing interests in cardiovascular disease. In this study, we investigated the function of miR-223 and the underlying mechanism in atherosclerosis. In the atherosclerotic ApoE-/- mice models, an obvious increase of miR-223 was observed in aortic atherosclerotic lesions. In lipopolysaccharide (LPS) activated macrophages, its expression was decreased. The miR-223 overexpression significantly attenuated macrophage foam cell formation, lipid accumulation and pro-inflammatory cytokine production, which were reversed by anti-miR-223 inhibitor transfection. Mechanism assay corroborated that miR-223 negatively regulated the activation of the toll-like receptor 4 (TLR4)-nuclear factor-kappaB (NF-kappaB) pathway. Pretreatment with a specific inhibitor of NF kappaB (pyrrolidinedithiocarbamate, PDTC) strikingly abrogated miR-223 silence induced lipid deposition and inflammatory cytokine production. Furthermore, PI3K/AKT was activated by miR-223 up-regulation. Pretreatment with PI3K/AKT inhibitor LY294002 strikingly ameliorated the inhibitory effects of miR-223 on the activation of TLR4 and p65, concomitant with the increase in lipid deposition and inflammatory cytokine production. Together, these data indicate that miR-223 up-regulation might abrogate the development of atherosclerosis by blocking TLR4 signaling through activation of the PI3K/AKT pathway, and provides a promising therapeutic avenue for the treatment of atherosclerosis. PMID- 26492243 TI - (-)-Epicatechin-3-O-beta-D-allopyranoside from Davallia formosana, Prevents Diabetes and Hyperlipidemia by Regulation of Glucose Transporter 4 and AMP Activated Protein Kinase Phosphorylation in High-Fat-Fed Mice. AB - The purpose of this experiment was to determine the antidiabetic and lipid lowering effects of (-)-epicatechin-3-O-beta-D-allopyranoside (BB) from the roots and stems of Davallia formosana in mice. Animal treatment was induced by high-fat diet (HFD) or low-fat diet (control diet, CD). After eight weeks of HFD or CD exposure, the HFD mice were treating with BB or rosiglitazone (Rosi) or fenofibrate (Feno) or water through gavage for another four weeks. However, at 12 weeks, the HFD-fed group had enhanced blood levels of glucose, triglyceride (TG), and insulin. BB treatment significantly decreased blood glucose, TG, and insulin levels. Moreover, visceral fat weights were enhanced in HFD-fed mice, accompanied by increased blood leptin concentrations and decreased adiponectin levels, which were reversed by treatment with BB. Muscular membrane protein levels of glucose transporter 4 (GLUT4) were reduced in HFD-fed mice and significantly enhanced upon administration of BB, Rosi, and Feno. Moreover, BB treatment markedly increased hepatic and skeletal muscular expression levels of phosphorylation of AMP-activated (adenosine monophosphate) protein kinase (phospho-AMPK). BB also decreased hepatic mRNA levels of phosphenolpyruvate carboxykinase (PEPCK), which are associated with a decrease in hepatic glucose production. BB-exerted hypotriglyceridemic activity may be partly associated with increased mRNA levels of peroxisome proliferator activated receptor alpha (PPARalpha), and with reduced hepatic glycerol-3-phosphate acyltransferase (GPAT) mRNA levels in the liver, which decreased triacylglycerol synthesis. Nevertheless, we demonstrated BB was a useful approach for the management of type 2 diabetes and dyslipidemia in this animal model. PMID- 26492244 TI - Folic Acid Inhibits Amyloid beta-Peptide Production through Modulating DNA Methyltransferase Activity in N2a-APP Cells. AB - Alzheimer's disease (AD) is a common neurodegenerative disease resulting in progressive dementia, and is a principal cause of dementia among older adults. Folate acts through one-carbon metabolism to support the methylation of multiple substrates. We hypothesized that folic acid supplementation modulates DNA methyltransferase (DNMT) activity and may alter amyloid beta-peptide (Abeta) production in AD. Mouse Neuro-2a cells expressing human APP695 were incubated with folic acid (2.8-40 MUmol/L), and with or without zebularine (the DNMT inhibitor). DNMT activity, cell viability, Abeta and DNMTs expression were then examined. The results showed that folic acid stimulated DNMT gene and protein expression, and DNMT activity. Furthermore, folic acid decreased Abeta protein production, whereas inhibition of DNMT activity by zebularine increased Abeta production. The results indicate that folic acid induces methylation potential dependent DNMT enzymes, thereby attenuating Abeta production. PMID- 26492245 TI - MyoD Is a Novel Activator of Porcine FIT1 Gene by Interacting with the Canonical E-Box Element during Myogenesis. AB - Fat-induced transcript 1 (FIT1/FITM1) gene is a member of the conserved gene family important for triglyceride-rich lipid droplet accumulation. FIT1 gene displays a similar muscle-specific expression across pigs, mice, and humans. Thus pigs can act as a useful model of many human diseases resulting from misexpression of FIT1 gene. Triglyceride content in skeletal muscle plays a key role in pork meat quality and flavors. An insertion/deletion mutation in porcine FIT1 coding region shows a high correlation with a series of fat traits. To gain better knowledge of the potential role of FIT1 gene in human diseases and the correlations with pork meat quality, our attention is given to the region upstream of the porcine FIT1 coding sequence. We cloned ~1 kb of the 5'-flanking region of porcine FIT1 gene to define the role of this sequence in modulating the myogenic expression. A canonical E-box element that activated porcine FIT1 promoter activity during myogenesis was identified. Further analysis demonstrated that promoter activity was induced by overexpression of MyoD1, which bound to this canonical E-box during C2C12 differentiation. This is the first evidence that FIT1 as the direct novel target of MyoD is involved in muscle development. PMID- 26492247 TI - An accurate projector calibration method based on polynomial distortion representation. AB - In structure light measurement systems or 3D printing systems, the errors caused by optical distortion of a digital projector always affect the precision performance and cannot be ignored. Existing methods to calibrate the projection distortion rely on calibration plate and photogrammetry, so the calibration performance is largely affected by the quality of the plate and the imaging system. This paper proposes a new projector calibration approach that makes use of photodiodes to directly detect the light emitted from a digital projector. By analyzing the output sequence of the photoelectric module, the pixel coordinates can be accurately obtained by the curve fitting method. A polynomial distortion representation is employed to reduce the residuals of the traditional distortion representation model. Experimental results and performance evaluation show that the proposed calibration method is able to avoid most of the disadvantages in traditional methods and achieves a higher accuracy. This proposed method is also practically applicable to evaluate the geometric optical performance of other optical projection system. PMID- 26492246 TI - Comparative Mitogenomics of the Genus Odontobutis (Perciformes: Gobioidei: Odontobutidae) Revealed Conserved Gene Rearrangement and High Sequence Variations. AB - To understand the molecular evolution of mitochondrial genomes (mitogenomes) in the genus Odontobutis, the mitogenome of Odontobutis yaluensis was sequenced and compared with those of another four Odontobutis species. Our results displayed similar mitogenome features among species in genome organization, base composition, codon usage, and gene rearrangement. The identical gene rearrangement of trnS-trnL-trnH tRNA cluster observed in mitogenomes of these five closely related freshwater sleepers suggests that this unique gene order is conserved within Odontobutis. Additionally, the present gene order and the positions of associated intergenic spacers of these Odontobutis mitogenomes indicate that this unusual gene rearrangement results from tandem duplication and random loss of large-scale gene regions. Moreover, these mitogenomes exhibit a high level of sequence variation, mainly due to the differences of corresponding intergenic sequences in gene rearrangement regions and the heterogeneity of tandem repeats in the control regions. Phylogenetic analyses support Odontobutis species with shared gene rearrangement forming a monophyletic group, and the interspecific phylogenetic relationships are associated with structural differences among their mitogenomes. The present study contributes to understanding the evolutionary patterns of Odontobutidae species. PMID- 26492248 TI - Balancing energy consumption with hybrid clustering and routing strategy in wireless sensor networks. AB - Multi-hop data collection in wireless sensor networks (WSNs) is a challenge issue due to the limited energy resource and transmission range of wireless sensors. The hybrid clustering and routing (HCR) strategy has provided an effective solution, which can generate a connected and efficient cluster-based topology for multi-hop data collection in WSNs. However, it suffers from imbalanced energy consumption, which results in the poor performance of the network lifetime. In this paper, we evaluate the energy consumption of HCR and discover an important result: the imbalanced energy consumption generally appears in gradient k = 1, i.e., the nodes that can communicate with the sink directly. Based on this observation, we propose a new protocol called HCR-1, which includes the adaptive relay selection and tunable cost functions to balance the energy consumption. The guideline of setting the parameters in HCR-1 is provided based on simulations. The analytical and numerical results prove that, with minor modification of the topology in Sensors 2015, 15 26584 gradient k = 1, the HCR-1 protocol effectively balances the energy consumption and prolongs the network lifetime. PMID- 26492249 TI - Research on the rapid and accurate positioning and orientation approach for land missile-launching vehicle. AB - Getting a land vehicle's accurate position, azimuth and attitude rapidly is significant for vehicle based weapons' combat effectiveness. In this paper, a new approach to acquire vehicle's accurate position and orientation is proposed. It uses biaxial optical detection platform (BODP) to aim at and lock in no less than three pre-set cooperative targets, whose accurate positions are measured beforehand. Then, it calculates the vehicle's accurate position, azimuth and attitudes by the rough position and orientation provided by vehicle based navigation systems and no less than three couples of azimuth and pitch angles measured by BODP. The proposed approach does not depend on Global Navigation Satellite System (GNSS), thus it is autonomous and difficult to interfere. Meanwhile, it only needs a rough position and orientation as algorithm's iterative initial value, consequently, it does not have high performance requirement for Inertial Navigation System (INS), odometer and other vehicle based navigation systems, even in high precise applications. This paper described the system's working procedure, presented theoretical deviation of the algorithm, and then verified its effectiveness through simulation and vehicle experiments. The simulation and experimental results indicate that the proposed approach can achieve positioning and orientation accuracy of 0.2 m and 20" respectively in less than 3 min. PMID- 26492250 TI - Securing health sensing using integrated circuit metric. AB - Convergence of technologies from several domains of computing and healthcare have aided in the creation of devices that can help health professionals in monitoring their patients remotely. An increase in networked healthcare devices has resulted in incidents related to data theft, medical identity theft and insurance fraud. In this paper, we discuss the design and implementation of a secure lightweight wearable health sensing system. The proposed system is based on an emerging security technology called Integrated Circuit Metric (ICMetric) that extracts the inherent features of a device to generate a unique device identification. In this paper, we provide details of how the physical characteristics of a health sensor can be used for the generation of hardware "fingerprints". The obtained fingerprints are used to deliver security services like authentication, confidentiality, secure admission and symmetric key generation. The generated symmetric key is used to securely communicate the health records and data of the patient. Based on experimental results and the security analysis of the proposed scheme, it is apparent that the proposed system enables high levels of security for health monitoring in resource optimized manner. PMID- 26492251 TI - Maximum measurement range and accuracy of SAW reflective delay line sensors. AB - In a surface acoustic wave (SAW) wireless sensor with a reflective delay line structure, three reflectors are often used to eliminate 2pi ambiguity of phase measurement. The maximum range of the measured parameter and the maximum accuracy have recently been attracting much research attention. In this paper, an analytical formula for all the factors influencing the measurement range and accuracy of the delay line SAW sensor are deduced for the first time. The factors include: the sensor sensitivity, the topology of the delay line, the available wireless bandwidth and the allowed maximum phase measuring error of the reading system, which is easier to retrieve and more fully describes the possible noises than SNR. Additionally, many designers believe that increasing the reflector could improve accuracy continuously or realize multi-resolution measurement. However, they ignore some certain criteria that the reflector location must satisfy. The reachable maximum accuracy by every increase of a reflector is also presented. A SAW temperature sensor system using 128 degrees YX-LiNbO3 is designed to verify the above theoretical analysis. PMID- 26492252 TI - A biologically-inspired framework for contour detection using superpixel-based candidates and hierarchical visual cues. AB - Contour detection has been extensively investigated as a fundamental problem in computer vision. In this study, a biologically-inspired candidate weighting framework is proposed for the challenging task of detecting meaningful contours. In contrast to previous models that detect contours from pixels, a modified superpixel generation processing is proposed to generate a contour candidate set and then weigh the candidates by extracting hierarchical visual cues. We extract the low-level visual local cues to weigh the contour intrinsic property and mid level visual cues on the basis of Gestalt principles for weighting the contour grouping constraint. Experimental results tested on the BSDS benchmark show that the proposed framework exhibits promising performances to capture meaningful contours in complex scenes. PMID- 26492254 TI - A Cultivated Form of a Red Seaweed (Chondrus crispus), Suppresses beta-Amyloid Induced Paralysis in Caenorhabditis elegans. AB - We report here the protective effects of a methanol extract from a cultivated strain of the red seaweed, Chondrus crispus, against beta-amyloid-induced toxicity, in a transgenic Caenorhabditis elegans, expressing human Abeta1-42 gene. The methanol extract of C. crispus (CCE), delayed beta-amyloid-induced paralysis, whereas the water extract (CCW) was not effective. The CCE treatment did not affect the transcript abundance of amy1; however, Western blot analysis revealed a significant decrease of Abeta species, as compared to untreated worms. The transcript abundance of stress response genes; sod3, hsp16.2 and skn1 increased in CCE-treated worms. Bioassay guided fractionation of the CCE yielded a fraction enriched in monogalactosyl diacylglycerols (MGDG) that significantly delayed the onset of beta-amyloid-induced paralysis. Taken together, these results suggested that the cultivated strain of C. crispus, whilst providing dietary nutritional value, may also have significant protective effects against beta-amyloid-induced toxicity in C. elegans, partly through reduced beta-amyloid species, up-regulation of stress induced genes and reduced accumulation of reactive oxygen species (ROS). PMID- 26492253 TI - Tetrodotoxin, an Extremely Potent Marine Neurotoxin: Distribution, Toxicity, Origin and Therapeutical Uses. AB - Tetrodotoxin (TTX) is a potent neurotoxin responsible for many human intoxications and fatalities each year. The origin of TTX is unknown, but in the pufferfish, it seems to be produced by endosymbiotic bacteria that often seem to be passed down the food chain. The ingestion of contaminated pufferfish, considered the most delicious fish in Japan, is the usual route of toxicity. This neurotoxin, reported as a threat to human health in Asian countries, has spread to the Pacific and Mediterranean, due to the increase of temperature waters worldwide. TTX, for which there is no known antidote, inhibits sodium channel producing heart failure in many cases and consequently death. In Japan, a regulatory limit of 2 mg eq TTX/kg was established, although the restaurant preparation of "fugu" is strictly controlled by law and only chefs qualified are allowed to prepare the fish. Due to its paralysis effect, this neurotoxin could be used in the medical field as an analgesic to treat some cancer pains. PMID- 26492255 TI - Salt Effect on the Antioxidant Activity of Red Microalgal Sulfated Polysaccharides in Soy-Bean Formula. AB - Sulfated polysaccharides produced by microalgae, which are known to exhibit various biological activities, may potentially serve as natural antioxidant sources. To date, only a few studies have examined the antioxidant bioactivity of red microalgal polysaccharides. In this research, the effect of different salts on the antioxidant activities of two red microalgal sulfated polysaccharides derived from Porphyridium sp. and Porphyridium aerugineum were studied in a soy bean-based infant milk formula. Salt composition and concentration were both shown to affect the polysaccharides' antioxidant activity. It can be postulated that the salt ions intefer with the polysaccharide chains' interactions and alter their structure, leading to a new three-dimensional structure that better exposes antiooxidant sites in comparison to the polysaccharide without salt supplement. Among the cations that were studied, Ca(2+) had the strongest enhancement effect on antioxidant activities of both polysaccharides. Understanding the effect of salts on polysaccharides' stucture, in addition to furthering knowledge on polysaccharide bioactivities, may also shed light on the position of the antioxidant active sites. PMID- 26492256 TI - Assessment of the Antimicrobial Activity of Algae Extracts on Bacteria Responsible of External Otitis. AB - External otitis is a diffuse inflammation around the external auditory canal and auricle, which is often occurred by microbial infection. This disease is generally treated using antibiotics, but the frequent occurrence of antibiotic resistance requires the development of new antibiotic agents. In this context, unexplored bioactive natural candidates could be a chance for the production of targeted drugs provided with antimicrobial activity. In this paper, microbial pathogens were isolated from patients with external otitis using ear swabs for over one year, and the antimicrobial activity of the two methanol extracts from selected marine (Dunaliella salina) and freshwater (Pseudokirchneriella subcapitata) microalgae was tested on the isolated pathogens. Totally, 114 bacterial and 11 fungal strains were isolated, of which Staphylococcus spp. (28.8%) and Pseudomonas aeruginosa (P. aeruginosa) (24.8%) were the major pathogens. Only three Staphylococcus aureus (S. aureus) strains and 11 coagulase negative Staphylococci showed resistance to methicillin. The two algal extracts showed interesting antimicrobial properties, which mostly inhibited the growth of isolated S. aureus, P. aeruginosa, Escherichia coli, and Klebsiella spp. with MICs range of 1.4 * 108 to 2.2 * 10(10) cells/mL. These results suggest that the two algae have potential as resources for the development of antimicrobial agents. PMID- 26492257 TI - Effect of Solvent System on Extractability of Lipidic Components of Scenedesmus obliquus (M2-1) and Gloeothece sp. on Antioxidant Scavenging Capacity Thereof. AB - Microalgae are well known for their biotechnological potential, namely with regard to bioactive lipidic components-especially carotenoids and polyunsaturated fatty acids (PUFA), well-known for therapeutic applications based on their antioxidant capacity. The aim of this work was to evaluate the influence of four distinct food-grade solvents upon extractability of specific lipidic components, and on the antioxidant capacity exhibited against both synthetic (2,2-diphenyl-1 picrylhydrazyl (DPPH(*)) and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS(+*))) and biological reactive species (O2(*)- and (*)NO-). A eukaryotic microalga (Scenedesmus obliquus (M2-1)) and a prokaryotic one (Gloeothece sp.) were used as case studies. Concerning total antioxidant capacity, the hexane:isopropanol (3:2) and acetone extracts of Sc. obliquus (M2 1) were the most effective against DPPH(*) and ABTS(+*), respectively. Gloeothece sp. ethanol extracts were the most interesting scavengers of O2(*)-, probably due the high content of linolenic acid. On the other hand, acetone and hexane:isopropanol (3:2) extracts were the most interesting ones in (*)NO- assay. Acetone extract exhibited the best results for the ABTS assay, likely associated to its content of carotenoids, in both microalgae. Otherwise, ethanol stood out in PUFA extraction. Therefore, profiles of lipidic components extracted are critical for evaluating the antioxidant performance-which appears to hinge, in particular, on the balance between carotenoids and PUFAs. PMID- 26492258 TI - Wealth Inequality and Mental Disability Among the Chinese Population: A Population Based Study. AB - In the study described herein, we investigated and explored the association between wealth inequality and the risk of mental disability in the Chinese population. We used nationally represented, population-based data from the second China National Sample Survey on Disability, conducted in 2006. A total of 1,724,398 study subjects between the ages of 15 and 64, including 10,095 subjects with mental disability only, were used for the analysis. Wealth status was estimated by a wealth index that was derived from a principal component analysis of 10 household assets and four other variables related to wealth. Logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for mental disability for each category, with the lowest quintile category as the referent. Confounding variables under consideration were age, gender, residence area, marital status, ethnicity, education, current employment status, household size, house type, homeownership and living arrangement. The distribution of various types and severities of mental disability differed significantly by wealth index category in the present population. Wealth index category had a positive association with mild mental disability (p for trend <0.01), but had a negative association with extremely severe mental disability (p for trend <0.01). Moreover, wealth index category had a significant, inverse association with mental disability when all severities of mental disability were taken into consideration. This study's results suggest that wealth is a significant factor in the distribution of mental disability and it might have different influences on various types and severities of mental disability. PMID- 26492259 TI - Investigation of Legionella Contamination in Bath Water Samples by Culture, Amoebic Co-Culture, and Real-Time Quantitative PCR Methods. AB - We investigated Legionella contamination in bath water samples, collected from 68 bathing facilities in Japan, by culture, culture with amoebic co-culture, real time quantitative PCR (qPCR), and real-time qPCR with amoebic co-culture. Using the conventional culture method, Legionella pneumophila was detected in 11 samples (11/68, 16.2%). Contrary to our expectation, the culture method with the amoebic co-culture technique did not increase the detection rate of Legionella (4/68, 5.9%). In contrast, a combination of the amoebic co-culture technique followed by qPCR successfully increased the detection rate (57/68, 83.8%) compared with real-time qPCR alone (46/68, 67.6%). Using real-time qPCR after culture with amoebic co-culture, more than 10-fold higher bacterial numbers were observed in 30 samples (30/68, 44.1%) compared with the same samples without co culture. On the other hand, higher bacterial numbers were not observed after propagation by amoebae in 32 samples (32/68, 47.1%). Legionella was not detected in the remaining six samples (6/68, 8.8%), irrespective of the method. These results suggest that application of the amoebic co-culture technique prior to real-time qPCR may be useful for the sensitive detection of Legionella from bath water samples. Furthermore, a combination of amoebic co-culture and real-time qPCR might be useful to detect viable and virulent Legionella because their ability to invade and multiply within free-living amoebae is considered to correlate with their pathogenicity for humans. This is the first report evaluating the efficacy of the amoebic co-culture technique for detecting Legionella in bath water samples. PMID- 26492260 TI - Modeling Occurrence of Urban Mosquitos Based on Land Use Types and Meteorological Factors in Korea. AB - Mosquitoes are a public health concern because they are vectors of pathogen, which cause human-related diseases. It is well known that the occurrence of mosquitoes is highly influenced by meteorological conditions (e.g., temperature and precipitation) and land use, but there are insufficient studies quantifying their impacts. Therefore, three analytical methods were applied to determine the relationships between urban mosquito occurrence, land use type, and meteorological factors: cluster analysis based on land use types; principal component analysis (PCA) based on mosquito occurrence; and three prediction models, support vector machine (SVM), classification and regression tree (CART), and random forest (RF). We used mosquito data collected at 12 sites from 2011 to 2012. Mosquito abundance was highest from August to September in both years. The monitoring sites were differentiated into three clusters based on differences in land use type such as culture and sport areas, inland water, artificial grasslands, and traffic areas. These clusters were well reflected in PCA ordinations, indicating that mosquito occurrence was highly influenced by land use types. Lastly, the RF represented the highest predictive power for mosquito occurrence and temperature-related factors were the most influential. Our study will contribute to effective control and management of mosquito occurrences. PMID- 26492262 TI - Raising Public Awareness: The Role of the Household Sector in Mitigating Climate Change. AB - In addition to greenhouse gas emissions from the industrial, transportation and commercial sectors, emissions from the household sector also contribute to global warming. By examining residents of Taiwan (N = 236), this study aims to reveal the factors that influence households' intention to purchase energy-efficient appliances. The assessment in this study is based on the theory of planned behavior (TPB), and perceived benefit or cost (BOC) is introduced as an independent variable in the proposed efficiency action toward climate change (ECC) model. According to structural equation modeling, most of the indicators presented a good fit to the corresponding ECC model constructs. The analysis indicated that BOC is a good complementary variable to the TPB, as the ECC model explained 61.9% of the variation in intention to purchase energy-efficient appliances, which was higher than that explained by the TPB (58.4%). This result indicates that the ECC model is superior to the TPB. Thus, the strategy of promoting energy-efficient appliances in the household sector should emphasize global warming and include the concept of BOC. PMID- 26492261 TI - Sedentary Behavior in Preschoolers: How Many Days of Accelerometer Monitoring Is Needed? AB - The reliability of accelerometry for measuring sedentary behavior in preschoolers has not been determined, thus we determined how many days of accelerometry monitoring are necessary to reliably estimate daily time spent in sedentary behavior in preschoolers. In total, 191 and 150 preschoolers (three to five years) wore ActiGraph accelerometers (15-s epoch) during the in-school (>=4 days) and the total-day (>=6 days) period respectively. Accelerometry data were summarized as time spent in sedentary behavior (min/h) using three different cutpoints developed for preschool-age children (<37.5, <200, and <373 counts/15 s). The intraclass correlations (ICCs) and Spearman-Brown prophecy formula were used to estimate the reliability of accelerometer for measuring sedentary behavior. Across different cutpoints, the ICCs ranged from 0.81 to 0.92 for in school sedentary behavior, and from 0.75 to 0.81 for total-day sedentary behavior, respectively. To achieve an ICC of >=0.8, two to four days or six to nine days of monitoring were needed for in-school sedentary behavior and total day sedentary behavior, respectively. These findings provide important guidance for future research on sedentary behavior in preschool children using accelerometry. Understanding the reliability of accelerometry will facilitate the conduct of research designed to inform policies and practices aimed at reducing sedentary behavior in preschool children. PMID- 26492263 TI - Spatio-Temporal Trends and Identification of Correlated Variables with Water Quality for Drinking-Water Reservoirs. AB - It is widely accepted that characterizing the spatio-temporal trends of water quality parameters and identifying correlated variables with water quality are indispensable for the management and protection of water resources. In this study, cluster analysis was used to classify 56 typical drinking water reservoirs in Zhejiang Province into three groups representing different water quality levels, using data of four water quality parameters for the period 2006-2010. Then, the spatio-temporal trends in water quality were analyzed, assisted by geographic information systems (GIS) technology and statistical analysis. The results indicated that the water quality showed a trend of degradation from southwest to northeast, and the overall water quality level was exacerbated during the study period. Correlation analysis was used to evaluate the relationships between water quality parameters and ten independent variables grouped into four categories (land use, socio-economic factors, geographical features, and reservoir attributes). According to the correlation coefficients, land use and socio-economic indicators were identified as the most significant factors related to reservoir water quality. The results offer insights into the spatio-temporal variations of water quality parameters and factors impacting the water quality of drinking water reservoirs in Zhejiang Province, and they could assist managers in making effective strategies to better protect water resources. PMID- 26492264 TI - Sequence and Structure Analysis of Distantly-Related Viruses Reveals Extensive Gene Transfer between Viruses and Hosts and among Viruses. AB - The origin and evolution of viruses is a subject of ongoing debate. In this study, we provide a full account of the evolutionary relationships between proteins of significant sequence and structural similarity found in viruses that belong to different classes according to the Baltimore classification. We show that such proteins can be found in viruses from all Baltimore classes. For protein families that include these proteins, we observe two patterns of the taxonomic spread. In the first pattern, they can be found in a large number of viruses from all implicated Baltimore classes. In the other pattern, the instances of the corresponding protein in species from each Baltimore class are restricted to a few compact clades. Proteins with the first pattern of distribution are products of so-called viral hallmark genes reported previously. Additionally, this pattern is displayed by the envelope glycoproteins from Flaviviridae and Bunyaviridae and helicases of superfamilies 1 and 2 that have homologs in cellular organisms. The second pattern can often be explained by horizontal gene transfer from the host or between viruses, an example being Orthomyxoviridae and Coronaviridae hemagglutinin esterases. Another facet of horizontal gene transfer comprises multiple independent introduction events of genes from cellular organisms into otherwise unrelated viruses. PMID- 26492265 TI - Diagnosis of Dengue Infection Using Conventional and Biosensor Based Techniques. AB - Dengue is an arthropod-borne viral disease caused by four antigenically different serotypes of dengue virus. This disease is considered as a major public health concern around the world. Currently, there is no licensed vaccine or antiviral drug available for the prevention and treatment of dengue disease. Moreover, clinical features of dengue are indistinguishable from other infectious diseases such as malaria, chikungunya, rickettsia and leptospira. Therefore, prompt and accurate laboratory diagnostic test is urgently required for disease confirmation and patient triage. The traditional diagnostic techniques for the dengue virus are viral detection in cell culture, serological testing, and RNA amplification using reverse transcriptase PCR. This paper discusses the conventional laboratory methods used for the diagnosis of dengue during the acute and convalescent phase and highlights the advantages and limitations of these routine laboratory tests. Subsequently, the biosensor based assays developed using various transducers for the detection of dengue are also reviewed. PMID- 26492267 TI - Longitudinal Study of Cytokine Expression, Lipid Profile and Neuronal Growth Factors in Human Breast Milk from Term and Preterm Deliveries. AB - Breast milk (BM) is considered as a reference for infant nutrition. The role of bioactive components, such as cytokines, hormones, growth factors (GFs) and fatty acids (FAs) is poorly known, but they might be implicated in immune response development. The aim of this study was to identify the lipid profile and the spectrum of cytokines and neuronal GF in BM samples and analyse the influence of gestational age and lactation time on these components. This study used a longitudinal prospective method for the characterization of cytokines, FAs and GFs global profiles in 120 BM samples from 40 healthy mothers (20 preterm and 20 term) collected as colostrum, transitional and mature milk. The cytokines were analysed by protein array (Ray Bio(r) Human Cytokine Array G6. Ray Biotech, Inc. Norcross, GA, USA) and the FAs were analysed by gas chromatography. The FA profile was similar between the term and the preterm BM samples. Omega-3-alpha linoleic and docosahexaenoic acid (DHA) and omega-6-linoleic acid were the most abundant in the term and preterm samples during lactation. Omega-3 ETA and omega 3 EPA we observed exclusively in the preterm samples. The cytokine profile showed a different trend based on gestational age. A significantly higher expression of neurotrophic factors was found in the mature preterm milk samples as compared to the mature term samples. Our study is the first to identify the influence and interactions of perinatal factors on cytokine, GFs and FAs in human milk. PMID- 26492266 TI - Perspective of Use of Antiviral Peptides against Influenza Virus. AB - The threat of a worldwide influenza pandemic has greatly increased over the past decade with the emergence of highly virulent avian influenza strains. The increased frequency of drug-resistant influenza strains against currently available antiviral drugs requires urgent development of new strategies for antiviral therapy, too. The research in the field of therapeutic peptides began to develop extensively in the second half of the 20(th) century. Since then, the mechanisms of action for several peptides and their antiviral prospect received large attention due to the global threat posed by viruses. Here, we discussed the therapeutic properties of peptides used in influenza treatment. Peptides with antiviral activity against influenza can be divided into three main groups. First, entry blocker peptides such as a Flupep that interact with influenza hemagglutinin, block its binding to host cells and prevent viral fusion. Second, several peptides display virucidal activity, disrupting viral envelopes, e.g., Melittin. Finally, a third set of peptides interacts with the viral polymerase complex and act as viral replication inhibitors such as PB1 derived peptides. Here, we present a review of the current literature describing the antiviral activity, mechanism and future therapeutic potential of these influenza antiviral peptides. PMID- 26492268 TI - Association of Proton Pump Inhibitor (PPI) Use with Energy Intake, Physical Activity, and Weight Gain. AB - Studies suggest proton pump inhibitor (PPI) use impacts body weight regulation, though the effect of PPIs on energy intake, energy extraction, and energy expenditure is unknown. We used data on 3073 eligible adults from the National Health and Nutrition Examination Survey (NHANES). Medication use, energy intake, diet composition, and physical activity were extracted from NHANES. Multivariate regression models included confounding variables. Daily energy intake was similar between PPI users and non-users (p = 0.41). Diet composition was similar between the two groups, except that PPI users consumed a slightly greater proportion of calories from fat (34.5% vs. 33.2%; p = 0.02). PPI users rated themselves as being as physically active as their age/gender-matched peers and reported similar frequencies of walking or biking. However, PPI users were less likely to have participated in muscle-strengthening activities (OR: 0.53; 95% CI: 0.30-0.95). PPI users reported similar sedentary behaviors to non-users. Male PPI users had an increase in weight (of 1.52 +/- 0.59 kg; p = 0.021) over the previous year compared to non-users, while female PPI users had a non-significant increase in weight. The potential mechanisms for PPI-associated weight gain are unclear as we did not find evidence for significant differences in energy intake or markers of energy expenditure. PMID- 26492269 TI - Four Models Including Fish, Seafood, Red Meat and Enriched Foods to Achieve Australian Dietary Recommendations for n-3 LCPUFA for All Life-Stages. AB - Populations are not meeting recommended intakes of omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA). The aim was (i) to develop a database on n-3 LCPUFA enriched products; (ii) to undertake dietary modelling exercise using four dietary approaches to meet the recommendations and (iii) to determine the cost of the models. Six n-3 LCPUFA enriched foods were identified. Fish was categorised by n-3 LCPUFA content (mg/100 g categories as "excellent" "good" and "moderate"). The four models to meet recommended n-3 LCPUFA intakes were (i) fish only; (ii) moderate fish (with red meat and enriched foods); (iii) fish avoiders (red meat and enriched foods only); and (iv) lacto-ovo vegetarian diet (enriched foods only). Diets were modelled using the NUTTAB2010 database and n-3 LCPUFA were calculated and compared to the Suggested Dietary Targets (SDT). The cost of meeting these recommendations was calculated per 100 mg n-3 LCPUFA. The SDT were achieved for all life-stages with all four models. The weekly food intake in number of serves to meet the n-3 LCPUFA SDT for all life-stages for each dietary model were: (i) 2 "excellent" fish; (ii) 1 "excellent" and 1 "good" fish, and depending on life-stage, 3-4 lean red meat, 0-2 eggs and 3-26 enriched foods; (iii) 4 lean red meat, and 20-59 enriched foods; (iv) 37-66 enriched foods. Recommended intakes of n-3 LCPUFA were easily met by the consumption of fish, which was the cheapest source of n-3 LCPUFA. Other strategies may be required to achieve the recommendations including modifying the current food supply through feeding practices, novel plant sources and more enriched foods. PMID- 26492270 TI - High Sensitivity of Aged Mice to Deoxynivalenol (Vomitoxin)-Induced Anorexia Corresponds to Elevated Proinflammatory Cytokine and Satiety Hormone Responses. AB - Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos) and adult (3 mos) mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg) and dietary (1, 2.5, 10 ppm) DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes. PMID- 26492271 TI - A Magnetic Nanoparticle Based Enzyme-Linked Immunosorbent Assay for Sensitive Quantification of Zearalenone in Cereal and Feed Samples. AB - A novel enzyme-linked immunosorbent assay based on magnetic nanoparticles and biotin/streptavidin-HRP (MNP-bsELISA) was developed for rapid and sensitive detection of zearalenone (ZEN). The detection signal was enhanced and the sensitivity of the assay was improved by combined use of antibody-conjugated magnetic nanoparticles and biotin-streptavidin system. Under the optimized conditions, the regression equation for quantification of ZEN was y = -0.4287x + 0.3132 (R2 = 0.9904). The working range was 0.07-2.41 ng/mL. The detection limit was 0.04 ng/mL and IC50 was 0.37 ng/mL. The recovery rates of intra-assay and inter-assay ranged from 92.8%-111.9% and 91.7%-114.5%, respectively, in spiked corn samples. Coefficients of variation were less than 10% in both cases. Parallel analysis of cereal and feed samples showed good correlation between MNP bsELISA and liquid chromatograph-tandem mass spectrometry (R2 = 0.9283). We conclude that this method is suitable for rapid detection of zearalenone in cereal and feed samples in relevant laboratories. PMID- 26492272 TI - UV-B Exposure Affects the Biosynthesis of Microcystin in Toxic Microcystis aeruginosa Cells and Its Degradation in the Extracellular Space. AB - Microcystins (MCs) are cyclic hepatotoxic heptapeptides produced by cyanobacteria that can be toxic to aquatic and terrestrial organisms. MC synthesis and degradation are thought to be influenced by several different physical and environmental parameters. In this study, the effects of different intensities of UV-B radiation on MC biosynthesis in Microcystis cells and on its extracellular degradation were investigated by mRNA analysis and degradation experiments. Exposure to UV-B at intensities of 1.02 and 1.45 W/m2 not only remarkably inhibited the growth of Microcystis, but also led to a decrease in the MC concentration. In addition, mcyD transcription was decreased under the same UV-B intensities. These results demonstrated that the effects of UV-B exposure on the biosynthesis of MCs in Microcystis cells could be attributed to the regulation of mcy gene transcription. Moreover, the MC concentration was decreased significantly after exposure to different intensities of UV-B radiation. Of the three MC variants (MC-LR, -RR and -YR, L, R and Y are abbreviations of leucine, arginine and tyrosine), MC-LR and MC-YR were sensitive to UV-B radiation, whereas MC-RR was not. In summary, our results showed that UV-B radiation had a negative effect on MC production in Microcystis cells and MC persistence in the extracellular space. PMID- 26492273 TI - Aberrant MUC1-TRIM46-KRTCAP2 Chimeric RNAs in High-Grade Serous Ovarian Carcinoma. AB - High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. By analyzing the mRNA-seq reads from The Cancer Genome Atlas (TCGA), we uncovered a novel cancer-enriched chimeric RNA as the result of splicing between MUC1, a highly glycosylated transmembrane mucin, TRIM46, a tripartite motif containing protein, and KRTCAP2, a keratinocyte associated protein. Experimental analyses by RT-PCR (reverse transcription PCR) and Sanger sequencing using an in house cohort of 59 HGSC patient tumors revealed a total of six MUC1-TRIM46 KRTCAP2 isoforms joined by different annotated splice sites between these genes. These chimeric isoforms are not detected in non-cancerous ovaries, yet are present in three out of every four HGSC patient tumors, a significant frequency given the exceedingly heterogeneous nature of this disease. Transfection of the cDNA of MUC1-TRIM46-KRTCAP2 isoforms in mammalian cells led to the translation of mutant MUC1 fusion proteins that are unglycosylated and cytoplasmically localized as opposed to the cell membrane, a feature resembling the tumor-associated MUC1. Because the parental MUC1 is overexpressed in 90% of HGSC tumors and has been proposed as a clinical biomarker and therapeutic target, the chimeric MUC1-TRIM46 KRTCAP2 isoforms identified in this report could represent significantly better MUC1 variants for the same clinical utilities. PMID- 26492274 TI - Transcriptome Changes during the Life Cycle of the Red Sponge, Mycale phyllophila (Porifera, Demospongiae, Poecilosclerida). AB - Sponges are an ancient metazoan group with broad ecological, evolutionary, and biotechnological importance. As in other marine invertebrates with a biphasic life cycle, the developing sponge undergoes a significant morphological, physiological, and ecological transformation during settlement and metamorphosis. In this study, we compare new transcriptome datasets for three life cycle stages of the red sponge (Mycale phyllophila) to test whether gene expression (as in the model poriferan, Amphimedon queenslandica) also varies more after settlement and metamorphosis. In contrast to A. queenslandica, we find that the transcriptome of M. phyllophila changes more during the earlier pre-competent larva/post-larva transition that spans these defining events. We also find that this transition is marked by a greater frequency of significantly up-regulated Gene Ontology terms including those for morphogenesis, differentiation, and development and that the transcriptomes of its pre-competent larvae and adult are distinct. The life cycle transcriptome variation between M. phyllophila and A. queenslandica may be due to their long separate evolutionary histories and corresponding differences in developmental rates and timing. This study now calls for new transcriptome datasets of M. phyllophila and other sponges, which will allow for tests of the generality of our life cycle expression differences and for the greater exploitation of poriferans in both basic and applied research. PMID- 26492275 TI - Recorded Behavior as a Valuable Resource for Diagnostics in Mobile Phone Addiction: Evidence from Psychoinformatics. AB - Psychologists and psychiatrists commonly rely on self-reports or interviews to diagnose or treat behavioral addictions. The present study introduces a novel source of data: recordings of the actual problem behavior under investigation. A total of N = 58 participants were asked to fill in a questionnaire measuring problematic mobile phone behavior featuring several questions on weekly phone usage. After filling in the questionnaire, all participants received an application to be installed on their smartphones, which recorded their phone usage for five weeks. The analyses revealed that weekly phone usage in hours was overestimated; in contrast, numbers of call and text message related variables were underestimated. Importantly, several associations between actual usage and being addicted to mobile phones could be derived exclusively from the recorded behavior, but not from self-report variables. The study demonstrates the potential benefit to include methods of psychoinformatics in the diagnosis and treatment of problematic mobile phone use. PMID- 26492276 TI - Nanodelivery Systems as New Tools for Immunostimulant or Vaccine Administration: Targeting the Fish Immune System. AB - Fish disease treatments have progressed significantly over the last few years and have moved from the massive use of antibiotics to the development of vaccines mainly based on inactivated bacteria. Today, the incorporation of immunostimulants and antigens into nanomaterials provide us with new tools to enhance the performance of immunostimulation. Nanoparticles are dispersions or solid particles designed with specific physical properties (size, surface charge, or loading capacity), which allow controlled delivery and therefore improved targeting and stimulation of the immune system. The use of these nanodelivery platforms in fish is in the initial steps of development. Here we review the advances in the application of nanoparticles to fish disease prevention including: the type of biomaterial, the type of immunostimulant or vaccine loaded into the nanoparticles, and how they target the fish immune system. PMID- 26492277 TI - HIV-1 Recruits UPF1 but Excludes UPF2 to Promote Nucleocytoplasmic Export of the Genomic RNA. AB - Unspliced, genomic HIV-1 RNA (vRNA) is a component of several ribonucleoprotein complexes (RNP) during the viral replication cycle. In earlier work, we demonstrated that the host upframeshift protein 1 (UPF1), a key factor in nonsense-mediated mRNA decay (NMD), colocalized and associated to the viral structural protein Gag during viral egress. In this work, we demonstrate a new function for UPF1 in the regulation of vRNA nuclear export. OPEN ACCESS Biomolecules 2015, 5 2809 We establish that the nucleocytoplasmic shuttling of UPF1 is required for this function and demonstrate that UPF1 exists in two essential viral RNPs during the late phase of HIV-1 replication: the first, in a nuclear export RNP that contains Rev, CRM1, DDX3 and the nucleoporin p62, and the second, which excludes these nuclear export markers but contains Gag in the cytoplasm. Interestingly, we observed that both UPF2 and the long isoform of UPF3a, UPF3aL, but not the shorter isoforms UPF3aS and UPF3b, are excluded from the UPF1-Rev-CRM1-DDX3 complex as they are negative regulators of vRNA nuclear export. In silico protein-protein docking analyses suggest that Rev binds UPF1 in a region that overlaps the UPF2 binding site, thus explaining the exclusion of this negative regulatory factor by HIV-1 that is necessary for vRNA trafficking. This work uncovers a novel and unique regulatory circuit involving several UPF proteins that ultimately regulate vRNA nuclear export and trafficking. PMID- 26492280 TI - Progress Toward Poliomyelitis Eradication--Afghanistan, January 2014-August 2015. AB - Despite recent progress toward global polio eradication, endemic transmission of wild poliovirus (WPV) continues to be reported in Afghanistan and Pakistan. The Afghanistan program must overcome many challenges to remain on track toward achieving the objectives set in the 2013-2018 strategic plan of the Global Polio Eradication Initiative (GPEI). Cross-border transmission of WPV type 1 (WPV1) continues to occur among children traveling to and from Pakistan. The country's routine immunization system remains weak and unable to reach recommended benchmarks in most regions; hence, the national Polio Eradication Initiative (PEI) relies mainly on providing children aged <5 years with oral poliovirus vaccine (OPV), administered during supplementary immunization activities (SIAs). Because of ongoing conflict and insecurity, some children continue to be missed during SIAs in areas not under government control; however, the majority of missed children live in accessible areas and are often unreached because of a failure to plan, implement, and supervise SIAs efficiently. This report describes polio eradication activities and progress in Afghanistan during January 2014 August 2015 and updates previous reports. During 2014, a total of 28 WPV1 cases were reported in Afghanistan, compared with 14 cases in 2013; nine cases were reported during January-August 2015, the same number as during the same period in 2014. To eliminate poliovirus transmission in Afghanistan, emergency operations centers (EOCs) need to be established at the national level and in critical regions without delay to improve overall coordination and oversight of polio eradication activities. The recently revised National Emergency Action Plan for polio eradication needs to be fully implemented, including detailed microplanning and enhanced monitoring and supervision of SIAs, as well as improved cross-border coordination with Pakistan. PMID- 26492279 TI - Personal UVR exposure of farming families in four European countries. AB - BACKGROUND: The main risk factor for skin cancer is ultraviolet radiation (UVR). Farming families living in rural areas with easy outdoor access may experience excessive UVR exposure. Differences between countries in latitude, altitude and sun behaviour could result in different personal UVR exposures. However, no studies have examined this until now. OBJECTIVES: To determine personal UVR exposure in work and leisure situations among farming families in Europe. METHODS: Prospective cohort study of farmers, their partners (spouses) and children in Denmark (DK), Poland (PL), Austria (AT), and Spain (ES) from 2009 to 2011. Personal UVR exposure and sun behaviour were recorded by dosimetry and diaries. RESULTS: Farmers' average daily UVR exposure on working days ranged from 1.4 SED (DK, AT) to 2.7 SED (ES). Corresponding figures for partners were: 0.6 SED (DK) to 1.9 SED (PL), and for children (day-care/school days): 0.7 SED (ES) to 1.3 SED (PL). DISCUSSION AND CONCLUSIONS: Farmers' UVR exposure was comparable to that of outdoor workers in previous studies and exceeded the recommended UVR exposure limits on 36% (DK, AT), 29% (PL) and 56% (ES) of their working days. Attention to sun protection for outdoor workers across Europe in preventing UVR induced skin cancer is still needed. PMID- 26492278 TI - Chronic Ethanol Exposure: Pathogenesis of Pulmonary Disease and Dysfunction. AB - Ethanol (EtOH) is the world's most commonly used drug, and has been widely recognized as a risk factor for developing lung disorders. Chronic EtOH exposure affects all of the organ systems in the body and increases the risk of developing pulmonary diseases such as acute lung injury and pneumonia, while exacerbating the symptoms and resulting in increased mortality in many other lung disorders. EtOH and its metabolites inhibit the immune response of alveolar macrophages (AMs), increase airway leakage, produce damaging reactive oxygen species (ROS), and disrupt the balance of antioxidants/oxidants within the lungs. In this article, we review the role of EtOH exposure in the pathogenesis and progression of pulmonary disease. PMID- 26492281 TI - Child abuse research 2015: it's time for breakthroughs. PMID- 26492283 TI - B-cell hyperfunction in children with immune thrombocytopenic purpura persists after splenectomy. AB - BACKGROUND: Immune thrombocytopenic purpura (ITP) is characterized by reduced platelet count secondary to immune-mediated destruction, this results in an increased bleeding risk. Autoantibodies binding to platelets tag them for premature destruction in the spleen. For this reason, splenectomy is often performed as treatment of chronic forms of disease that are resistant to pharmacological therapy. METHODS: We studied 30 patients with ITP and compared them with age-matched controls. RESULTS: We show that B cells of patients with chronic ITP are intrinsically hyperreactive, producing more than normal IgG in vivo and plasma cells in vitro. In normal individuals after splenectomy, a significant depletion of memory B cells is observed, associated with loss of reactivity to CpG oligodeoxynucleotide and consequent inability to form antibody producing cells. In Enzyme-Linked ImmunoSpot Methods, we compared three splenectomized ITP patients relapsing after surgery, 30 healthy controls, and 37 individuals splenectomized for trauma, spherocytosis, thalassemia, nonhematological tumor, and other diseases. CONCLUSIONS: We confirmed that B cells of ITP patients remain hyperreactive in vitro and form high numbers of antibody-producing cells after splenectomy. Thus, chronic ITP may be associated with intrinsic B-cell hyperfunction, leading to the production of antibodies with multiple specificities including that against platelets. PMID- 26492282 TI - Dynamic regulation of plasma matrix metalloproteinases in human diabetic ketoacidosis. AB - BACKGROUND: Diabetic ketoacidosis (DKA) in children is associated with cerebrovascular-related complications. We recently reported that DKA facilitates leukocyte adherence to the brain microvascular endothelium. Adhered leukocytes can release enzymes that instigate vascular dysfunction. Our aims were to measure plasma levels of leukocyte-derived matrix metalloproteinases (MMPs) from DKA patients and to correlate plasma MMP concentrations with DKA severity. METHODS: Plasma was obtained from children with type 1 diabetes, either in DKA (n = 16) or insulin controlled (CON; n = 16). Antibody microarray and gelatin zymography were used to quantify plasma MMPs and their endogenous tissue inhibitors (TIMPs). MMP concentrations were correlated with DKA severity (blood pH). Quantitative PCR of leukocyte mRNA was used to help determine the origin of plasma MMPs. RESULTS: DKA was associated with altered plasma levels of ?MMP-2 (P < 0.001), ?MMP-8 (P < 0.001), ?MMP-9 (P < 0.05), and ?TIMP-4 (P < 0.001), as compared with CON. Elevated MMP-8 and MMP-9 were both positively correlated with DKA severity (P < 0.05). DKA was associated with increased leukocyte mRNA for MMP-8, MMP-9, and TIMP-4 (P < 0.005). CONCLUSION: MMPs are dynamically regulated during DKA. Plasma MMP-8 and MMP-9 concentrations correlate with DKA severity and are known to degrade brain microvascular endothelial cell tight junctions. Thus, leukocyte derived MMPs might contribute to DKA-associated cerebrovascular complications. PMID- 26492284 TI - Effect of 22q11.2 deletion on bleeding and transfusion utilization in children with congenital heart disease undergoing cardiac surgery. AB - BACKGROUND: Postsurgical bleeding causes significant morbidity and mortality in children undergoing surgery for congenital heart defects (CHD). 22q11.2 deletion syndrome (DS) is the second most common genetic risk factor for CHD. The deleted segment of chromosome 22q11.2 encompasses the gene encoding glycoprotein (GP) Ibbeta, which is required for expression of the GPIb-V-IX complex on the platelet surface, where it functions as the receptor for von Willebrand factor (VWF). Binding of GPIb-V-IX to VWF is important for platelets to initiate hemostasis. It is not known whether hemizygosity for the gene encoding GPIbbeta increases the risk for bleeding following cardiac surgery for patients with 22q11.2 DS. METHODS: We performed a case-control study of 91 pediatric patients who underwent cardiac surgery with cardiopulmonary bypass from 2004 to 2012 at Children's Hospital of Wisconsin. RESULTS: Patients with 22q11.2 DS had larger platelets and lower platelet counts, bled more excessively, and received more transfusion support with packed red blood cells in the early postoperative period relative to control patients. CONCLUSION: Presurgical genetic testing for 22q11.2 DS may help to identify a subset of pediatric cardiac surgery patients who are at increased risk for excessive bleeding and who may require more transfusion support in the postoperative period. PMID- 26492285 TI - Simvastatin attenuates oleic acid-induced oxidative stress through CREB-dependent induction of heme oxygenase-1 in renal proximal tubule cells. AB - BACKGROUND: Statins elicit antioxidant effects independently of their lipid lowering properties. Heme oxygenase-1 (HO-1) induction may be a part of these pleiotropic effects, which are insufficiently described in the kidney. We hypothesize that simvastatin (SIM) transcriptionally activates HO-1 that protects renal proximal tubule cells from lipotoxic injury. METHODS: Impact of SIM on 100 MUmol/l oleic acid (OA)-mediated reactive oxygen species (ROS) production and consequent oxidative stress (4-hydroxynonenal (HNE) content) as well as cell injury/apoptosis (lactate dehydrogenase (LDH) release, caspase-3 activation) were determined in cultured renal proximal tubule (NRK52E) cells. Effect of SIM on the HO-1 promoter and its enhancer elements (antioxidant response element (ARE), CCAAT, AP1, and cAMP response element (CRE)) was also determined in reporter luciferase assays. Dominant-negative (dnMEK, M1CREB) and pharmacologic (H89) approaches were used to inhibit activation of extracellular signal regulated kinase (ERK), CREB, and protein kinase A (PKA), respectively. RESULTS: SIM dose dependently activated the HO-1 promoter that was essential for protection against OA-dependent ROS production/oxidative stress and LDH release/caspase-3 activation. We found that the HO-1 promoter was induced through ERK and PKA dependent activation of the CRE by SIM. CONCLUSION: SIM may protect the kidney from adverse effects of circulating fatty acids by upregulating the antioxidant HO-1, aside from its well-described lipid-lowering effects. PMID- 26492286 TI - Perfluoroalkyl and polyfluoroalkyl substances and indicators of immune function in children aged 12-19 y: National Health and Nutrition Examination Survey. AB - BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are immunotoxic in laboratory studies. Human studies of immune effects are inconsistent. Using the US National Health and Nutrition Examination Survey (NHANES), we examined PFAS serum concentration and indicators of prevalent immune function among 12-19 y-old children. METHODS: In this cross-sectional study, we examined PFAS serum concentration in relation to measles, mumps, and rubella antibody concentrations in NHANES 1999-2000 and 2003-2004 (n = 1,191) and to allergic conditions and allergic sensitization in NHANES 2005-2006 (n = 640). RESULTS: In adjusted, survey-weighted models, a doubling of perfluorooctane sulfonate (PFOS) concentration among seropositive children was associated with a 13.3% (95% confidence interval (CI): -19.9, -6.2) decrease in rubella antibody concentration and a 5.9% decrease in mumps antibody concentration (95% CI: -9.9, -1.6). We observed no adverse association between exposure and current allergic conditions, including asthma. Children with higher PFOS concentration were less likely to be sensitized to any allergen (odds ratio (OR): 0.74; 95% CI: 0.58, 0.95). CONCLUSION: Increased exposure to several PFAS was associated with lower levels to mumps and rubella antibody concentrations, especially among seropositive individuals. These lower antibody concentrations may indicate a less robust response to vaccination or greater waning of vaccine-derived immunity over time. PMID- 26492288 TI - Anesthetic Management of a Case of Posterior Fossa Tumor With An Intracardiac Mass. PMID- 26492287 TI - Airway and alveolar nitric oxide production, lung function, and pulmonary blood flow in sickle cell disease. AB - BACKGROUND: Children with sickle cell disease (SCD) often have obstructive lung function abnormalities which could be due to asthma or increased pulmonary blood volume; it is important to determine the underlying mechanism to direct appropriate treatment. In asthmatics, exhaled nitric oxide (FeNO) is elevated. FeNO, however, can also be raised due to increased alveolar production. Our aim, therefore, was to determine if airway or alveolar NO production differed between SCD children and ethnic and age-matched controls. METHODS: Lung function, airway NO flux and alveolar NO production, and effective pulmonary blood flow were assessed in 18 SCD children and 18 ethnic and age-matched controls. RESULTS: The SCD children compared to the controls had a higher respiratory system resistance (P = 0.0008), alveolar NO production (P = 0.0224), and pulmonary blood flow (P < 0.0001), but not airway NO flux. There was no significant correlation between FeNO and respiratory system resistance in either group, but in the SCD children, there were correlations between alveolar NO production (P = 0.0006) and concentration (P < 0.0001) and pulmonary blood flow. CONCLUSION: Airway NO flux was not elevated in the SCD children nor correlated with airways obstruction, suggesting that airways obstruction, at least in some SCD children, is not due to asthma. PMID- 26492289 TI - Meta-areas of the Trigeminocardiac Reflex Within the Skull Base: A Neuroanatomic "Thinking" Model. PMID- 26492290 TI - Attenuation of pain behaviour by local administration of alpha-2 adrenoceptor antagonists to dorsal root ganglia in a rat radiculopathy model. AB - BACKGROUND: There were several reports suggesting alpha-adrenoceptor antagonists are effective to treat neuropathic pain. The aims of this study were as follows: (1) to introduce drug delivery system for dorsal root ganglion (DRG) neurons; (2) to elucidate the effects of alpha-adrenoceptor antagonists in acute, subacute or chronic phase and (3) to determine which subtype of adrenoceptor was mainly involved. METHOD: We used 130 male Sprague-Dawley rats. After root constriction, rats received three local injections of alpha-adrenoceptor antagonists around DRG. We administered the non-selective alpha-adrenoceptor antagonist phentolamine for 3 consecutive days from day 0, 4 or 11 after the surgery, and the alpha1 adrenoceptor antagonist prazosin, the alpha1-adrenoceptor antagonist silodosin, the more preferred alpha1-adrenoceptor than prazosin and the alpha2-adrenoceptor antagonist yohimbine for 3 consecutive days from day 0 after the surgery. RESULTS: Phentolamine and yohimbine continually attenuated pain behaviour. Prazosin at high dose attenuated pain behaviour, however, prazosin at low dose did not attenuate pain behaviour every experimental day. Silodosin had no analgesic effect. Phentolamine injections from day 4 after surgery attenuated pain behaviour that had been established on the 3rd experimental day until the 28th post-operative day, although effect of phentolamine wore off. Phentolamine injections from day 11 after surgery temporarily attenuated pain behaviour that had been established on the 3rd, 7th and 10th experimental days. CONCLUSIONS: This study showed alpha-adrenoceptor antagonists could suppress pain behaviour via alpha2-adrenoceptor in acute phase and temporary attenuate pain behaviour in chronic phase. These findings presented potentials sympathetic nerve blockade contributed to treat neuropathic pain. PMID- 26492291 TI - Ti2-Containing 18-Tungsto-2-Arsenate(III) Monolacunary Host and the Incorporation of a Phenylantimony(III) Guest. AB - The novel Ti2-containing, sandwich-type 18-tungsto-2-arsenate(III) [(Ti(IV)O)2(alpha-As(III)W9O33)2](14-) (1) was successfully synthesized by the reaction of [TiO](2+) species with [alpha-As(III)W9O33](9-). The monolacunary polyanion 1 is solution-stable, and a further reaction with 1 equiv of phenylantimony(III) dichloride resulted in [C6H5Sb(III)(Ti(IV)O)2(alpha As(III)W9O33)2](12-) (2). Both polyanions 1 and 2 were structurally characterized in the solid state and solution. Electrochemical studies were also performed on both polyanions. PMID- 26492292 TI - Can a single dose response predict the effect of montelukast on exercise-induced bronchoconstriction? AB - RATIONALE: Exercise-induced bronchoconstriction (EIB) can be prevented by a single dose of montelukast (MLK). The effect is variable, similar to the variable responsiveness observed after daily treatment with MLK. We hypothesized that the effect of a single MLK-dose (5 or 10 mg) on EIB could predict the clinical effectiveness of longer term once daily treatment. METHODS: This was a prospective, open-label study. Twenty-four asthmatic adolescents (12-17 years) suboptimally controlled by low-dose inhaled corticosteroids, with >=10% post exercise fall in FEV1 , were included. They performed an exercise test at baseline, 20 hr after a single MLK-dose and 40-44 hr after the last dose of 4 weeks once daily treatment. The correlations between the effect of a single dose and 4 weeks treatment on area under the curve (AUC) and maximum % fall in FEV1 were calculated. RESULTS: AUC0-20 min decreased significantly after a single MLK dose (P = 0.001, CI: 64.9-218.2), but not after 4 weeks of treatment (P = 0.080, CI: -12.2 to 200.4). There was a moderate correlation between the effect of a single MLK-dose and 4 weeks treatment on AUC0-20 min , r = 0.49 (P = 0.011), and maximum % fall in FEV1 , r = 0.40 (P = 0.035). CONCLUSION: The protection provided by a single MLK-dose against EIB only modestly predicts the effect of regular treatment against EIB in adolescent asthmatics on low-dose inhaled corticosteroids. If used on a daily base, MLK offered clinically significant protection against EIB in two thirds of adolescents suboptimally controlled by low-dose ICS. PMID- 26492293 TI - Transoral endoscopic surgical resection of a giant pedunculated polyp. PMID- 26492294 TI - Nonexposure endoscopic full-thickness resection with two flexible endoscopes equipped with a suturing device: ex vivo study. PMID- 26492295 TI - MINDful polypectomy: a quality improvement initiative to improve complete resection of colorectal polyps. PMID- 26492296 TI - Diagnosis and preoperative tagging of duodenal gastrinoma by endoscopic ultrasound. PMID- 26492297 TI - Endoscopic management of coloanal anastomotic disruption: a pilot case. PMID- 26492298 TI - A tablet of clopidogrel remaining in the lower esophagus after primary percutaneous coronary intervention for acute myocardial infarction. PMID- 26492299 TI - Epiphrenic diverticulum of the esophagus after peroral endoscopic myotomy. PMID- 26492300 TI - Peroral endoscopic myotomy for achalasia after distal gastrectomy. PMID- 26492301 TI - Underwater endoscopic resection of a neuroendocrine rectal tumor. PMID- 26492302 TI - Synthesis of a Polyhistidine-bearing Amphipol and its Use for Immobilizing Membrane Proteins. AB - Amphipols (APols) are short amphipathic polymers that stabilize membrane proteins (MPs) in aqueous solutions. In the present study, A8-35, a polyacrylate-based APol, was grafted with hexahistidine tags (His6-tags). The synthesis and characterization of this novel functionalized APol, named HistAPol, are described. Its ability to immobilize MPs on nickel ion-bearing surfaces was tested using two complementary methods, immobilized metal affinity chromatography (IMAC) and surface plasmon resonance (SPR). Compared to a single His6-tag fused at one extremity of a MP, the presence of several His6-tags carried by the APol belt surrounding the transmembrane domain of a MP increases remarkably the affinity of the protein/APol complex for nickel ion-bearing SPR chips, whereas it does not show such a strong effect on an IMAC resin. HistAPol-mediated immobilization, which allows reversibility of the interaction and easy regeneration of the supports and dispenses with any genetic modification of the target protein, provides a novel, promising tool for attaching MPs onto solid supports while stabilizing them. PMID- 26492303 TI - Rare complication of left main intervention with bioabsorbable everolimus-eluting scaffolds implantation. PMID- 26492304 TI - Echocardiographic diagnosis of left subclavian artery stenosis before coronary artery bypass grafting (CABG). PMID- 26492305 TI - Childhood metabolic syndrome, inflammation and carotid intima-media thickness. The Aboriginal Birth Cohort Study. AB - BACKGROUND/OBJECTIVES: We evaluated whether atherosclerotic changes associated with MetS in Australian Aboriginals are reversible in childhood. In addition, we investigated whether heightened inflammation is mediating the adverse effects of MetS. METHODS: The study cohort comprised of 351 children from the Aboriginal Birth Cohort Study (a longitudinal study based in the Northern Territory of Australia) aged 9-13 years at baseline examination who were followed up 6 years later. MetS was defined by at least three of the following parameters within the extreme sex- and age-specific quartile: highest quartile for waist circumference, blood pressure, triglycerides, and glucose, and lowest quartile for HDL cholesterol. Carotid intima-media thickness (IMT) and C-reactive protein (CRP) were assessed at follow-up. RESULTS: Individuals with MetS at baseline or follow up had increased carotid IMT at follow-up (mean +/- SEM 539 +/- 3 vs. 561 +/- 8 MUm, P=0.007; and 537 +/- 3 vs. 567 +/- 8 MUm, P<0.0001 respectively). In combined analyses from baseline and follow-up studies, those individuals with MetS only at baseline had partially improved vascular status; their IMT was not significantly increased compared to those without MetS at both time-points (534 +/- 3 vs. 550 +/- 10 MUm, P=0.09). At the follow-up examination, MetS status was associated with increased IMT levels only among individuals with CRP levels above the median (>= 2.1mg/l) (536 +/- 5 vs. 573 +/- 9 MUm, P<0.0001, P for interaction 0.01). CONCLUSIONS: MetS in childhood is associated with subclinical atherosclerosis in an Australian Aboriginal population and the effects appear to be mediated by increased inflammation. The extent of atherosclerosis was partially reduced if metabolic status improved during the follow-up. PMID- 26492306 TI - Paradoxical low flow/low gradient aortic stenosis: Can cardiopulmonary exercise test help in identifying it? PMID- 26492307 TI - Tako-tsubo syndrome and myocarditis: Two sides of the same coin or same side for two different coins? PMID- 26492308 TI - Value of cardiac magnetic resonance imaging in the setting of familiar cardiomyopathy: A step toward pre-clinical diagnosis. PMID- 26492309 TI - Impact of reduced creatinine clearance on early heart transplantation outcomes: A propensity score adjusted analysis. PMID- 26492310 TI - Left atrial appendage occlusion in atrial fibrillation for stroke prevention: A systemic review. AB - BACKGROUND: Atrial fibrillation (AF) is an arrthymia characterized by increased risk of ventricle arrthymias and thromboembolism especially ischemic stroke. Most thrombus originated in the left atrial appendage, thus left atrial occlusion (LAAO) may be an effective alternative for stroke prevention in atrial fibrillation. OBJECTIVE: To assess the effect and safety of left atrial occlusion for stroke prevention in atrial fibrillation. METHODS AND RESULTS: We searched Pub Med, CENTRAL in The Cochrane Library, Embase, CBM-Disk, CNKI for published trials, ClinicalTrials.gov, ISI Proceedings for conference abstracts, and WHO International Clinical Trial registration Platform for ongoing studies. The search results were extracted, and then the quality of included studies was assessed. By RevMan 5.3, meta analysis was used if there was low heterogeneity. Three randomized controlled clinical trials involving 1165 participants were included (percutaneous 1114 in 2 trials, surgical 51 in 1 trial). The current data suggest that left atrial occlusion may be as efficacious as warfarin in stroke prevention (RR 0.78 [0.33, 1.84]) and mortality reduction (RR 0.68 [0.40, 1.16]) for AF. CONCLUSION: In contrast to warfarin left atrial occlusion with Watchman device may have the same effectivity in stroke reduction. Surgical LAAO may also get positive outcomes compared with warfarin, but owing to the small sample size the evidence is less powerful. Total outcomes of percutaneous and surgical LAAO support this approach. PMID- 26492311 TI - Beta-blockers treatment in heart failure with atrial fibrillation--Who should we believe? PMID- 26492312 TI - Ross procedure is a safe treatment option for aortic valve endocarditis: Long term follow-up of 42 patients. AB - BACKGROUND: Aortic root replacement with a pulmonary autograft (Ross procedure) can be performed as a treatment of aortic valve endocarditis, avoiding prosthetic valve implantation in septic context. We sought to assess long-term outcomes of the Ross procedure in this indication. METHODS: From April 1992 to March 2009, the intervention was performed in 42 patients (mean age 34 +/- 8 years) suffering from an active or ancient aortic valve endocarditis. 36% of the patients had extensive perivalvular involvement, and surgery was urgent in 18 patients (43%). We performed a prospective clinical and echocardiographic follow-up of this population. RESULTS: Median follow-up was 10 years (4-21 years). Overall survival at 10 and 15 years was respectively 87 +/- 5% and 81 +/- 8%. Perioperative mortality was 4.7% (2 patients) and no late cardiac death was reported. Eight patients (19%) underwent repeat surgery for autograft and/or homograft dysfunction at a median time of 8.4 years (3 months-18 years). Rate of recurrent endocarditis was low (7%-3 patients), including 1 in a context of persistent intravenous drug abuse. Clinical follow-up showed good functional status for all patients with NYHA <= II, and less than 25% of patients requiring cardiovascular medication. Late echocardiographic follow-up demonstrated well-functioning autograft and homograft, with only one severe aortic regurgitation, and one significant increase in pulmonary mean gradient. CONCLUSION: The Ross procedure in aortic valve endocarditis is an interesting alternative to prosthetic valvular replacement in a selected population, with a high rate of survival free from any cardiovascular event or medication requirement. PMID- 26492313 TI - High evening salivary cortisol is an independent predictor of increased mortality risk in patients with systolic heart failure. AB - AIMS: Serum cortisol independently predicts mortality risk in patients with systolic heart failure. Salivary cortisol may provide advantages as it better reflects the biologically active free compound. Furthermore, sampling is non invasive and may easily be performed in outpatients. We comparatively evaluated associations of morning (MSC) vs. evening salivary cortisol (ESC) and all-cause mortality risk. METHODS AND RESULTS: MSC (8 am) and ESC (9 pm) were determined in 229 patients with heart failure participating in the Interdisciplinary Network for Heart Failure program (66 +/- 13 years; 21% female; 37% New York Heart Association (NYHA) class III/IV, median left ventricular ejection fraction 33%). The association of cortisol with mortality risk was determined by univariate and Cox multivariable regression analyses adjusting for age, sex, NYHA class, and N terminal pro-hormone B-type natriuretic peptide. Compared to ESC, MSC was significantly higher and exhibited a higher variance: median 0.59 ng/ml (interquartile range 0.41-0.93) vs. 0.25 ng/ml (0.15-0.48), p<0.001. During 18 months of follow-up, 25 (11%) patients died. In univariate and multivariable models mortality risk was not increased in the highest MSC quartile: crude hazard ratio (HR) 1.81 (95% confidence interval 0.79-4.14, p=0.160), adjusted HR 1.26 (0.51-3.13, p=0.616). However, patients in the highest ESC quartile had a significantly increased mortality risk, suggesting that associations of high ESC and increased mortality were independent of disease severity: crude HR 3.33 (1.50 7.42, p=0.003), adjusted HR 2.49 (1.01-6.14, p=0.047). ESC alone proved the best predictor of mortality. CONCLUSION: High ESC but not MSC levels independently predict increased mortality risk in heart failure. PMID- 26492314 TI - Could dexmedetomidine have a role in patients admitted with Takotsubo syndrome? PMID- 26492316 TI - Modeling of inter-sample variation in flow cytometric data with the joint clustering and matching procedure. AB - We present an algorithm for modeling flow cytometry data in the presence of large inter-sample variation. Large-scale cytometry datasets often exhibit some within class variation due to technical effects such as instrumental differences and variations in data acquisition, as well as subtle biological heterogeneity within the class of samples. Failure to account for such variations in the model may lead to inaccurate matching of populations across a batch of samples and poor performance in classification of unlabeled samples. In this paper, we describe the Joint Clustering and Matching (JCM) procedure for simultaneous segmentation and alignment of cell populations across multiple samples. Under the JCM framework, a multivariate mixture distribution is used to model the distribution of the expressions of a fixed set of markers for each cell in a sample such that the components in the mixture model may correspond to the various populations of cells, which have similar expressions of markers (that is, clusters), in the composition of the sample. For each class of samples, an overall class template is formed by the adoption of random-effects terms to model the inter-sample variation within a class. The construction of a parametric template for each class allows for direct quantification of the differences between the template and each sample, and also between each pair of samples, both within or between classes. The classification of a new unclassified sample is then undertaken by assigning the unclassified sample to the class that minimizes the distance between its fitted mixture density and each class density as provided by the class templates. For illustration, we use a symmetric form of the Kullback Leibler divergence as a distance measure between two densities, but other distance measures can also be applied. We show and demonstrate on four real datasets how the JCM procedure can be used to carry out the tasks of automated clustering and alignment of cell populations, and supervised classification of samples. PMID- 26492315 TI - Loss of PTEN Facilitates Rosiglitazone-Mediated Enhancement of Platinum(IV) Complex LA-12-Induced Apoptosis in Colon Cancer Cells. AB - We demonstrated for the first time an outstanding ability of rosiglitazone to mediate a profound enhancement of LA-12-induced apoptosis associated with activation of mitochondrial pathway in human colon cancer cells. This effect was preferentially observed in the G1 cell cycle phase, independent on p53 and PPARgamma proteins, and accompanied with significant changes of selected Bcl-2 family protein levels. Further stimulation of cooperative synergic cytotoxic action of rosiglitazone and LA-12 was demonstrated in the cells deficient for PTEN, where mitochondrial apoptotic pathway was more stimulated and G1-phase associated dying was reinforced. Our results suggest that combined treatment with rosiglitazone and LA-12 might be promising anticancer strategy in colon-derived tumours regardless of their p53 status, and also favourable in those defective in PTEN function. PMID- 26492317 TI - Ultralow-dose CT with tin filtration for detection of solid and sub solid pulmonary nodules: a phantom study. AB - OBJECTIVES: To investigate the diagnostic performance of advanced modelled iterative reconstruction (ADMIRE) to filtered back projection (FBP) when using an ultralow-dose protocol for the detection of solid and subsolid pulmonary nodules. METHODS: Single-energy CT was performed at 100 kVp with tin filtration in an anthropomorphic chest phantom with solid and subsolid pulmonary nodules (2-10 mm, attenuation, 20 to -800 HU at 120 kVp). The mean volume CT dose index (CTDIvol) of the standard chest protocol was 2.2 mGy. Subsequent scans were obtained at 1/8 (0.28 mGy), 1/20 (0.10 mGy) and 1/70 (0.03 mGy) dose levels by lowering tube voltage and tube current. Images were reconstructed with FBP and ADMIRE. One reader measured image noise; two readers determined image quality and assessed nodule localization. RESULTS: Image noise was significantly reduced using ADMIRE compared with FBP (ADMIRE at a strength level of 5 : 70.4% for 1/20; 71.6% for 1/8; p < 0.001). Interobserver agreement for image quality was excellent (k = 0.88). Image quality was considered diagnostic for all images at 1/20 dose using ADMIRE. Sensitivity of nodule detection was 97.1% (100% for solid, 93.8% for subsolid nodules) at 1/20 dose and 100% for both nodule entities at 1/8 dose using ADMIRE 5. Images obtained with 1/70 dose had moderate sensitivity (overall 85.7%; solid 95%; subsolid 73.3%). CONCLUSION: Our study suggests that with a combination of tin filtration and ADMIRE, the CTDIvol of chest CT can be lowered considerably, while sensitivity for nodule detection remains high. For solid nodules, CTDIvol was 0.10 mGy, while subsolid nodules required a slightly higher CTDIvol of 0.28 mGy. ADVANCES IN KNOWLEDGE: Detection of subsolid nodules is feasible with ultralow-dose protocols. PMID- 26492318 TI - Peanut witches' broom (PnWB) phytoplasma-mediated leafy flower symptoms and abnormal vascular bundles development. AB - The peanut witches' broom (PnWB) phytoplasma causes virescence symptoms such as phyllody (leafy flower) in infected peanuts. However, the obligate nature of phytoplasma limits the study of host-pathogen interactions, and the detailed anatomy of PnWB-infected plants has yet to be reported. Here, we demonstrate that 4',6'-diamidino-2-phenylindole (DAPI) staining can be used to track PnWB infection. The DAPI-stained phytoplasma cells were observed in phloem/internal phloem tissues, and changes in vascular bundle morphology, including increasing pith rays and thinner cell walls in the xylem, were found. We also discerned the cell types comprising PnWB in infected sieve tube members. These results suggest that the presence of PnWB in phloem tissue facilitates the transmission of phytoplasma via sap-feeding insect vectors. In addition, PnWB in sieve tube members and changes in vascular bundle morphology might strongly promote the ability of phytoplasmas to assimilate nutrients. These data will help further an understanding of the obligate life cycle and host-pathogen interactions of phytoplasma. PMID- 26492319 TI - Topology preserving non-rigid image registration using time-varying elasticity model for MRI brain volumes. AB - In this paper, we present a new non-rigid image registration method that imposes a topology preservation constraint on the deformation. We propose to incorporate the time varying elasticity model into the deformable image matching procedure and constrain the Jacobian determinant of the transformation over the entire image domain. The motion of elastic bodies is governed by a hyperbolic partial differential equation, generally termed as elastodynamics wave equation, which we propose to use as a deformation model. We carried out clinical image registration experiments on 3D magnetic resonance brain scans from IBSR database. The results of the proposed registration approach in terms of Kappa index and relative overlap computed over the subcortical structures were compared against the existing topology preserving non-rigid image registration methods and non topology preserving variant of our proposed registration scheme. The Jacobian determinant maps obtained with our proposed registration method were qualitatively and quantitatively analyzed. The results demonstrated that the proposed scheme provides good registration accuracy with smooth transformations, thereby guaranteeing the preservation of topology. PMID- 26492320 TI - A probabilistic approach for automated discovery of perturbed genes using expression data from microarray or RNA-Seq. AB - BACKGROUND: In complex diseases, alterations of multiple molecular and cellular components in response to perturbations are indicative of disease physiology. While expression level of genes from high-throughput analysis can vary among patients, the common path among disease progression suggests that the underlying cellular sub-processes involving associated genes follow similar fates. Motivated by the interconnected nature of sub-processes, we have developed an automated methodology that combines ideas from biological networks, statistical models, and game theory, to probe connected cellular processes. The core concept in our approach uses probability of change (POC) to indicate the probability that a gene's expression level has changed between two conditions. POC facilitates the definition of change at the neighborhood, pathway, and network levels and enables evaluation of the influence of diseases on the expression. The 'connected' disease-related genes (DRG) identified display coherent and concomitant differential expression levels along paths. RESULTS: RNA-Seq and microarray breast cancer subtyping expression data sets were used to identify DRG between subtypes. A machine-learning algorithm was trained for subtype discrimination using the DRG, and the training yielded a set of biomarkers. The discriminative power of the biomarkers was tested using an unseen data set. Biomarkers identified overlaps with disease-specific identified genes, and we were able to classify disease subtypes with 100% and 80% agreement with PAM50, for microarray and RNA-Seq data set respectively. CONCLUSIONS: We present an automated probabilistic approach that offers unbiased and reproducible results, thus complementing existing methods in DRG and biomarker discovery for complex diseases. PMID- 26492321 TI - Preparation of 68Ga-labelled DOTA-peptides using a manual labelling approach for small-animal PET imaging. AB - (68)Ga-DOTA-peptides are a promising PET radiotracers used in the detection of different tumours types due to their ability for binding specifically receptors overexpressed in these. Furthermore, (68)Ga can be produced by a (68)Ge/(68)Ga generator on site which is a very good alternative to cyclotron-based PET isotopes. Here, we describe a manual labelling approach for the synthesis of (68)Ga-labelled DOTA-peptides based on concentration and purification of the commercial (68)Ga/(68)Ga generator eluate using an anion exchange-cartridge. (68)Ga-DOTA-TATE was used to image a pheochromocytoma xenograft mouse model by a microPET/CT scanner. The method described provides satisfactory results, allowing the subsequent (68)Ga use to label DOTA-peptides. The simplicity of the method along with its implementation reduced cost, makes it useful in preclinical PET studies. PMID- 26492322 TI - Effect of correction methods of radiochromic EBT2 films on the accuracy of IMRT QA. AB - Radiochromic films are dosimeters with more favorable characteristics than other two-dimensional (2D) radiation detectors. Transmission film scanners using a linear charge-coupled device (CCD) array have a drawback of variation in response along the detector array, which may result in a nonuniform transmission of signal over the scanned image. This study uses 2D gamma index analysis to compare two methods for correcting the nonuniform response of EBT2: the first method was based on the new red:blue method proposed by the manufacturer (to compensate for small nonuniformities in the film coating) and the second method, proposed by Menegotti et al. (2008), was based on dose-dependent matrix correction factors. The gamma index analysis shows that both the methods are comparably accurate for all the criteria values used for evaluation (1 mm/1%, 2 mm/2%, 3 mm/3%). Centers around the world use both the methods to correct EBT2 local heterogeneities, but it is important to note that the former method has several advantages such as less time consumption and easy implementation. PMID- 26492323 TI - Optimal timing of [18F]Mefway PET for imaging the serotonin 1A receptor in healthy male subjects. AB - To determine the optimal acquisition time of [(18)F]Mefway PET, we examined the regional specific-to-nonspecific binding ratios and evaluated the relationship between distribution volume ratios (DVRs) and standardized uptake value ratios (SUVRs) in various time windows. The specific-to-nonspecific binding ratios peaked after 40 min and there was a strong correlation between DVR and SUVR in the 60-80 min. Therefore, we recommend the use of a single time point between 60 and 80 min for [(18)F]Mefway static PET. PMID- 26492324 TI - Application of spectrum shifting methodology to restore NaI(Tl)-recorded gamma spectra, shifted due to temperature variations in the environment. AB - A method has been standardized for restoring a shifted differential pulse height spectrum from a scintillator based gamma ray spectrometer recorded at measurement temperature, to the position of a desired spectrum, recorded at a reference temperature. The method is based on the assumption that the spectrum obtained at measurement temperature represents the same statistical distribution as that at reference temperature but with different energy scales. A computer program has been developed for calculation of the transformation between the energy scales and for the restoration of the shifted spectrum. The method developed has been successfully applied for the restoration of gamma spectra measured at different temperatures. PMID- 26492325 TI - Quantitative nanoscopy: Tackling sampling limitations in (S)TEM imaging of polymers and composites. AB - Sampling limitations in electron microscopy questions whether the analysis of a bulk material is representative, especially while analyzing hierarchical morphologies that extend over multiple length scales. We tackled this problem by automatically acquiring a large series of partially overlapping (S)TEM images with sufficient resolution, subsequently stitched together to generate a large area map using an in-house developed acquisition toolbox (TU/e Acquisition ToolBox) and stitching module (TU/e Stitcher). In addition, we show that quantitative image analysis of the large scale maps provides representative information that can be related to the synthesis and process conditions of hierarchical materials, which moves electron microscopy analysis towards becoming a bulk characterization tool. We demonstrate the power of such an analysis by examining two different multi-phase materials that are structured over multiple length scales. PMID- 26492327 TI - Editorial Transition at Alzheimer's Disease and Associated Disorders. PMID- 26492326 TI - DNA Methylation Landscapes of Human Fetal Development. AB - Remodelling the methylome is a hallmark of mammalian development and cell differentiation. However, current knowledge of DNA methylation dynamics in human tissue specification and organ development largely stems from the extrapolation of studies in vitro and animal models. Here, we report on the DNA methylation landscape using the 450k array of four human tissues (amnion, muscle, adrenal and pancreas) during the first and second trimester of gestation (9,18 and 22 weeks). We show that a tissue-specific signature, constituted by tissue-specific hypomethylated CpG sites, was already present at 9 weeks of gestation (W9). Furthermore, we report large-scale remodelling of DNA methylation from W9 to W22. Gain of DNA methylation preferentially occurred near genes involved in general developmental processes, whereas loss of DNA methylation mapped to genes with tissue-specific functions. Dynamic DNA methylation was associated with enhancers, but not promoters. Comparison of our data with external fetal adrenal, brain and liver revealed striking similarities in the trajectory of DNA methylation during fetal development. The analysis of gene expression data indicated that dynamic DNA methylation was associated with the progressive repression of developmental programs and the activation of genes involved in tissue-specific processes. The DNA methylation landscape of human fetal development provides insight into regulatory elements that guide tissue specification and lead to organ functionality. PMID- 26492328 TI - Same Ages, Same Genes: Same Brains, Same Pathologies?: Dementia Timings, Co Occurring Brain Pathologies, ApoE Genotypes in Identical and Fraternal Age matched Twins at Autopsy. PMID- 26492329 TI - Errors in Self-Reports of Health Services Use: Impact on Alzheimer Disease Clinical Trial Designs. PMID- 26492330 TI - Don't Shoot the Messenger. PMID- 26492331 TI - Configuring bonds between first-row transition metals. AB - Alfred Werner, who pioneered the field of coordination chemistry, envisioned coordination complexes as a single, transition metal atom at the epicenter of a vast ligand space. The idea that the locus of a coordination complex could be shared by multiple metals held together with covalent bonds would eventually lead to the discovery of the quadruple and quintuple bond, which have no analogues outside of the transition metal block. Metal-metal bonding can be classified into homometallic and heterometallic groups. Although the former is dominant, the latter is arguably more intriguing because of the inherently larger chemical space in which metal-metal bonding can be explored. In 2013, Lu and Thomas independently reported the isolation of heterometallic multiple bonds with exclusively first-row transition metals. Structural and theoretical data supported triply bonded Fe-Cr and Fe-V cores. This Account describes our continued efforts to configure bonds between first-row transition metals from titanium to copper. Double-decker ligands, or binucleating platforms that brace two transition metals in proximity, have enabled the modular synthesis of diverse metal-metal complexes. The resulting complexes are also ideal for investigating the effects of an "ancillary" metal on the properties and reactivities of an "active" metal center. A total of 38 bimetallic complexes have been compiled comprising 18 unique metal-metal pairings. Twenty-one of these bimetallics are strictly isostructural, allowing for a systematic comparison of metal-metal bonding. The nature of the chemical bond between first-row metals is remarkably variable and depends on two primary factors: the total d-electron count, and the metals' relative d-orbital energies. Showcasing the range of covalent bonding are a quintuply bonded (d-d)(10) Mn-Cr heterobimetallic and the singly bonded late late pairings, e.g., Fe-Co, which adopt unusually high spin states. A long-term goal is to rationally tailor the properties and reactivities of the bimetallic complexes. In some cases, synergistic redox and magnetic properties were found that are different from the expected sum of the individual metals. Intermetal charge transfer was shown in a Co-M series, for M = Mn to Cu, where the transition energy decreases as M is varied across the first-row period. The potential of using metal-metal complexes for multielectron reduction of small molecules is addressed by N2 binding studies and a mechanistic study of a dicobalt catalyst in reductive silylation of N2 to N(SiMe3)3. Finally, metal-ion exchange reactions with metal-metal complexes can be selective under appropriate reaction conditions, providing an alternative synthetic route to metal-metal species. PMID- 26492333 TI - Atmospheric Oxidation of Squalene: Molecular Study Using COBRA Modeling and High Resolution Mass Spectrometry. AB - Squalene is a major component of skin and plant surface lipids and is known to be present at high concentrations in indoor dust. Its high reactivity toward ozone makes it an important ozone sink and a natural protectant against atmospheric oxidizing agents. While the volatile products of squalene ozonolysis are known, the condensed-phase products have not been characterized. We present an analysis of condensed-phase products resulting from an extensive oxidation of squalene by ozone probed by electrospray ionization (ESI) high-resolution mass spectrometry (HR-MS). A complex distribution of nearly 1300 peaks assignable to molecular formulas is observed in direct infusion positive ion mode ESI mass spectra. The distribution of peaks in the mass spectra suggests that there are extensive cross coupling reactions between hydroxy-carbonyl products of squalene ozonolysis. To get additional insights into the mechanism, we apply a Computational Brewing Application (COBRA) to simulate the oxidation of squalene in the presence of ozone, and compare predicted results with those observed by the HR-MS experiments. The system predicts over one billion molecular structures between 0 and 1450 Da, which correspond to about 27 000 distinct elemental formulas. Over 83% of the squalene oxidation products inferred from the mass spectrometry data are matched by the simulation. The simulation indicates a prevalence of peroxy groups, with hydroxyl and ether groups being the second-most important O containing functional groups formed during squalene oxidation. These highly oxidized products of squalene ozonolysis may accumulate on indoor dust and surfaces and contribute to their redox capacity. PMID- 26492332 TI - Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer. AB - BACKGROUND: Lung cancer is the most common cancer that is caused by perturbation of regulatory pathways rather than dysfunction of a single gene. Cisplatin (CDDP; cis-diamminedichloroplatinum II) is the first member of a class of platinum containing anti-cancer medication, which binds to DNA and triggers apoptosis. CDDP-based chemotherapy is used to treat various types of cancers. However, the efficacy of CDDP in the treatment of non-small-cell lung cancer (NSCLC) is limited by acquired drug resistance. MicroRNAs have recently emerged as key regulators of cancers, and miR-26a is one of down-regulated miRNAs in A549/CDDPres cell line. This study aimed to investigate the role of miR-26a in CDDP resistance in NSCLC as well as the underlying mechanisms. METHODS: In this study, we analyzed expressional profiles of CDDP resistance-related mRNA, miRNA, and transcription factors (TF) that regulate miRNA expression in NSCLC. A549 cells were treated with CDDP, miR-26a mimic, or miR-26a inhibitor, and followed by biological analysis including drug sensitivity assay, colony formation assay, terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) assay, and cell cycle analysis. Luciferase assay was used to determine the target of miR 26a. The regulation of miR-26a in Akt pathway was measured by western blot. RESULTS: High mobility group A (HMGA) 2 was identified as the target of miR-26a. Overexpression of miR-26a in A549 cells inhibited G1-S transition, increased cell death in response to CDDP treatment, and decreased the colony formation of A549 cells. MiR-26a significantly decreased the expression of E2F1, diminished Akt phosphorylation, and downregulated Bcl2 expression. Cell growth was suppressed by inhibiting HMGA2-mediated E2F1-Akt pathway. CONCLUSION: MiR-26a is responsible for A549 cell sensitivity in the treatment of CDDP through regulating HMGA2 mediated E2F1-Akt pathway. PMID- 26492334 TI - The Intervention of CRAC Channels Alleviates Inflammatory Responses in Nasal Polyps. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with Th2-dominant inflammation. However, effective treatments for CRSwNP have not yet been found. This study aimed to investigate the expression of Orai1 in nasal polyps (NP) and the influence on them of the intervention of Ca2+ release activated Ca2+ (CRAC) channels. MATERIALS AND METHODS: Nasal samples were obtained from normal subjects or subjects with CRSwNP. We studied the distribution of Orai1 protein in NP and normal mucosa (normal group) using immunohistochemistry. These tissues in cultures were then maintained in the absence (control group) or presence of 2-aminoethoxydiphenyl borate (2-APB) for 24 h. Orai1 was examined by means of enzyme-linked immunosorbent assay (ELISA) and real-time reverse transcription-polymerase chain reaction (RT-PCR). The Ca2+ mean fluorescence intensity (MFI) was evaluated by flow cytometry, and the inflammatory mediators, including interleukin (IL)-4, IL-5, IL-13, Dermatophagoides pteronyssinus-specific IgE, leukotriene C4 and eosinophil cation protein in cultures, were analyzed with ELISA and real-time RT-PCR. RESULTS: The expression of Orai1 was localized to the cytoplasmic membrane of inflammatory cells, and upregulated in NP compared to that in the normal group. However, Orai1 protein was decreased in polyp tissues after the 2-APB treatment. The levels of Ca2+ MFI and above inflammatory mediators were also elevated in NP, and reduced after the 2-APB administration compared to those in the control group. CONCLUSIONS: Orai1 and CRAC channels may play a crucial role in NP formation and development, and the 2-APB intervention of Orai1 protein may alleviate inflammatory responses in NP. PMID- 26492335 TI - Toward decrypting the allosteric mechanism of the ryanodine receptor based on coarse-grained structural and dynamic modeling. AB - The ryanodine receptors (RyRs) are a family of calcium (Ca) channels that regulate Ca release by undergoing a closed-to-open gating transition in response to action potential or Ca binding. The allosteric mechanism of RyRs gating, which is activated/regulated by ligand/protein binding >200 A away from the channel gate, remains elusive for the lack of high-resolution structures. Recent solution of the closed-form structures of the RyR1 isoform by cryo-electron microscopy has paved the way for detailed structure-driven studies of RyRs functions. Toward elucidating the allosteric mechanism of RyRs gating, we performed coarse-grained modeling based on the newly solved closed-form structures of RyR1. Our normal mode analysis captured a key mode of collective motions dominating the observed structural variations in RyR1, which features large outward and downward movements of the peripheral domains with the channel remaining closed, and involves hotspot residues that overlap well with key functional sites and disease mutations. In particular, we found a key interaction between a peripheral domain and the Ca-binding EF hand domain, which may allow for direct coupling of Ca binding to the collective motions as captured by the above mode. This key mode was robustly reproduced by the normal mode analysis of the other two closed-form structures of RyR1 solved independently. To elucidate the closed-to-open conformational changes in RyR1 with amino-acid level of details, we flexibly fitted the closed-form structures of RyR1 into a 10-A cryo-electron microscopy map of the open state. We observed extensive structural changes involving the peripheral domains and the central domains, resulting in the channel pore opening. In sum, our findings have offered unprecedented structural and dynamic insights to the allosteric mechanism of RyR1 via modulation of the key collective motions involved in RyR1 gating. The predicted hotspot residues and open-form conformation of RyR1 will guide future mutational and functional studies. PMID- 26492336 TI - Functional Impairment of Myeloid Dendritic Cells during Advanced Stage of HIV-1 Infection: Role of Factors Regulating Cytokine Signaling. AB - INTRODUCTION: Severely immunocompromised state during advanced stage of HIV-1 infection has been linked to functionally defective antigen presentation by dendritic cells (DCs). The molecular mechanisms behind DC impairment are still obscure. We investigated changes in DC function and association of key regulators of cytokine signaling during different stages of HIV-1 infection and following antiretroviral therapy (ART). METHODS: Phenotypic and functional characteristics of circulating myeloid DCs (mDCs) in 56 ART-naive patients (23 in early and 33 in advanced stage of disease), 36 on ART and 24 healthy controls were evaluated. Sixteen patients were studied longitudinally prior-to and 6 months after the start of ART. For functional studies, monocyte-derived DCs (Mo-DCs) were evaluated for endocytosis, allo-stimulation and cytokine secretion. The expression of suppressor of cytokine signaling (SOCS)-1 and other regulators of cytokine signaling was evaluated by real-time RT-PCR. RESULTS: The ability to respond to an antigenic stimulation was severely impaired in patients in advanced HIV-1 disease which showed partial recovery in the treated group. Mo-DCs from patients with advanced HIV-disease remained immature with low allo-stimulation and reduced cytokine secretion even after TLR-4 mediated stimulation ex-vivo. The cells had an increased expression of negative regulatory factors like SOCS-1, SOCS-3, SH2-containing phosphatase (SHP)-1 and a reduced expression of positive regulators like Janus kinase (JAK)2 and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB)1. A functional recovery after siRNA mediated silencing of SOCS-1 in these mo-DCs confirms the role of negative regulatory factors in functional impairment of these cells. CONCLUSIONS: Functionally defective DCs in advanced stage of HIV-1 infection seems to be due to imbalanced state of negative and positive regulatory gene expression. Whether this is a cause or effect of increased viral replication at this stage of disease, needs further investigation. The information may be useful in design of novel therapeutic targets for better management of disease. PMID- 26492337 TI - Activation of Transducin by Bistable Pigment Parapinopsin in the Pineal Organ of Lower Vertebrates. AB - Pineal organs of lower vertebrates contain several kinds of photosensitive molecules, opsins that are suggested to be involved in different light-regulated physiological functions. We previously reported that parapinopsin is an ultraviolet (UV)-sensitive opsin that underlies hyperpolarization of the pineal photoreceptor cells of lower vertebrates to achieve pineal wavelength discrimination. Although, parapinopsin is phylogenetically close to vertebrate visual opsins, it exhibits a property similar to invertebrate visual opsins and melanopsin: the photoproduct of parapinopsin is stable and reverts to the original dark states, demonstrating the nature of bistable pigments. Therefore, it is of evolutionary interest to identify a phototransduction cascade driven by parapinopsin and to compare it with that in vertebrate visual cells. Here, we showed that parapinopsin is coupled to vertebrate visual G protein transducin in the pufferfish, zebrafish, and lamprey pineal organs. Biochemical analyses demonstrated that parapinopsins activated transducin in vitro in a light dependent manner, similar to vertebrate visual opsins. Interestingly, transducin activation by parapinopsin was provoked and terminated by UV- and subsequent orange-lights irradiations, respectively, due to the bistable nature of parapinopsin, which could contribute to a wavelength-dependent control of a second messenger level in the cell as a unique optogenetic tool. Immunohistochemical examination revealed that parapinopsin was colocalized with Gt2 in the teleost, which possesses rod and cone types of transducin, Gt1, and Gt2. On the other hand, in the lamprey, which does not possess the Gt2 gene, in situ hybridization suggested that parapinopsin-expressing photoreceptor cells contained Gt1 type transducin GtS, indicating that lamprey parapinopsin may use GtS in place of Gt2. Because it is widely accepted that vertebrate visual opsins having a bleaching nature have evolved from non-bleaching opsins similar to parapinopsin, these results implied that ancestral bistable opsins might acquire coupling to the transducin-mediated cascade and achieve light-dependent hyperpolarizing response of the photoreceptor cells. PMID- 26492338 TI - Patient rehabilitation after cancer: is it time to adjust our approach? PMID- 26492339 TI - Patterns of practice in oncology: is progress reaching our practice? PMID- 26492340 TI - Unveiling the photoelectrocatalytic inactivation mechanism of Escherichia coli: Convincing evidence from responses of parent and anti-oxidation single gene knockout mutants. AB - This study investigated photoelectrocatalytic (PEC) inactivation mechanism of bacteria using parental Escherichia coli (E. coli) BW25113 and its isogenic mutants deficient in catalase HPI (katG(-), JW3914-1) and Mn-SOD (sodA(-), JW3879 1). BW25113 in the mid-log phase was less susceptible to PEC inactivation than those in early-log and stationary phases, consistent with the peak activities of catalase and superoxide dismutase (SOD) at mid-log phase (30.6 and 13.0 Unit/ml/OD600). For different strains all in mid-log phase, PEC inactivation efficiency followed the order katG(-) > sodA(-) > BW25113, with the duration of 60, 60 and 90 min for complete inactivation of ~2 * 10(7) CFU mL(-1) bacteria, respectively. Correspondingly, catalase and SOD levels of BW25113 were also higher than the mutants by 5.9 and 11.7 Unit/mL/OD600, respectively. Reactive oxygen species (ROSs) concentrations in PEC systems revealed that the inactivation performance coincided with H2O2 levels, rather than OH. Moreover, pre-incubation with H2O2 elevated catalase activities and PEC inactivation resistance of BW25113 were positively correlated. The above results indicated that H2O2 was the dominant PEC generated bactericide, and anti-oxidative enzymes especially catalase contributed greatly to the bacterial PEC resistance capacity. Further tests revealed that PEC treatment raised the intracellular ROSs concentration by more than 3 times, due to the permeated H2O2 and its intracellular derivative, OH. However, oxidative stress response of E. coli, such as increased catalase or SOD were not observed, perhaps because the ROSs overwhelmed the bacterial protective capacity. The accumulated ROSs subsequently caused oxidative damages to E. coli cells, including membrane damage, K(+) leakage, and protein oxidation. Compared with BW25113, the mutants experienced damages earlier and at higher levels, confirming the essential roles of catalase and SOD in the bacterial PEC resistance. PMID- 26492341 TI - Membrane fouling and anti-fouling strategies using RO retentate from a municipal water recycling plant as the feed for osmotic power generation. AB - RO retentate from a municipal water recycling plant is considered as a potential feed stream for osmotic power generation in this paper. The feasibility of using RO retentate from a municipal water recycling plant was examined from two aspects: (a) the membrane fouling propensity of RO retentate, and (b) the efficacy of anti-fouling strategies. The membranes used in this study were the inner selective thin film composite polyethersulfone (TFC/PES) hollow fiber membranes, which possessed a high water permeability and good mechanical strength. Scaling by phosphate salts was found to be one possible inorganic fouling on the innermost layer of the PES membrane, whereas silica fouling was observed to be the governing fouling on the outmost surface of the PES membrane. Two anti-fouling pretreatments, i.e., pH adjustment and anti-scalant pre treatment for the feed stream, were studied and found to be straightforward and effective. Using RO retentate at pH 7.2 as the feed and 1 M NaCl as the draw solution, the average power density was 7.3 W/m(2) at 20 bar. The average power density increased to 12.6 W/m(2) by modifying RO retentate with an initial pH value of 5.5 using HCl and to 13.4 W/m(2) by adding 1.1 mM ethylenediaminetetraacetic acid (EDTA). Moreover, the flux recovery of the fouled membranes, without the indicated pretreatments, reached 84.9% using deionized (DI) water flushing and 95.0% using air bubbling under a high crossflow velocity of 23.3 cm/s (Re = 2497) for 30 min. After pretreatment by pH adjustment, the flux recovery increased to 94.6% by DI water flushing and 100.0% by air bubbling. After pretreatment by adding 1.1 mM EDTA into RO retentate, flux was almost fully restored by physical cleaning by DI water flushing and air bubbling. These results provide insight into developing an effective pretreatment by either pH adjustment or EDTA addition before PRO and physical cleaning methods by DI water flushing and air bubbling for membrane used in osmotic power generation. PMID- 26492342 TI - Impact of liming and drying municipal sewage sludge on the amount and availability of (14)C-acetyl sulfamethoxazole and (14)C-acetaminophen residues. AB - Acetyl Sulfamethoxazole (AC-SMX) and acetaminophen (ACM) can be found in municipal sewage sludge, and their content and availability may be influenced by sludge treatments, such as drying and liming. A sludge similarly centrifuged with/without a flocculant was spiked with (14)C-labelled AC-SMX or ACM. Then, it was either limed (20% CaO) or/and dried under different laboratory conditions (1 week at ambient temperature; and 48 h at 40 or 80 degrees C). The total amount and distribution of the (14)C-compounds among several chemical fractions, based on the sludge floc definition, were assessed at the end of the treatments. All the (14)C-activity brought initially was recovered in the limed and/or dried sludges for AC-SMX but only between 44.4 and 84.9% for ACM, with the highest rate obtained for the limed sludge. Drying at 80 degrees C or liming increased the percentage of the sludge total organic carbon recovered in the extracts containing soluble extracellular polymeric substances (S-EPS) and the percentage of the total (14)C-activity extracted simultaneously. The non-extractable residues represented only 3.9-11.6% of the total (14)C-activity measured in the treated sludges for AC-SMX and 16.9-21.8% for ACM. The presence of AC-SMX and ACM residues in the treated sludges, after liming and drying under different conditions, was shown using some (14)C-labelled molecules. At this time scale and according to the extraction method selected, most of the (14)C-residues remained soluble and easily extractable for both compounds. This result implies that certain precautions should be taken when storing sludges before being spread on the field. Sludge piles, particularly the limed sludge, should be protected from rain to limit the production of lixiviates, which may contain residues of AC-SMX and ACM. PMID- 26492343 TI - Conservation of acquired morphology and community structure in aged biofilms after facing environmental stress. AB - The influence of growth history on biofilm morphology and microbial community structure is poorly studied despite its important role for biofilm development. Here, biofilms were exposed to a change in hydrodynamic conditions at different growth stages and we observed how biofilm age affected the change in morphology and bacterial community structure. Biofilms were developed in two bubble column reactors, one operated under constant shear stress and one under variable shear stress. Biofilms were transferred from one reactor to the other at different stages in their development by withdrawing and inserting the support medium from one reactor to the other. The developments of morphology and microbial community structure were followed by image analysis and molecular tools. When transferred early in biofilm development, biofilms adapted to the new hydrodynamic conditions and adopted features of the biofilm already developed in the receiving reactor. Biofilms transferred at a late state of biofilm development continued their initial trajectories of morphology and community development even in a new environment. These biofilms did not immediately adapt to their new environment and kept features acquired during their early growth phase, a property we called memory effect. PMID- 26492344 TI - Clinical course of hepatitis B surface antigen positive subjects following screening: A retrospective observational study from April 2008 to January 2013. AB - AIM: Determination of the percentage of hepatitis B surface antigen (HBsAg) positive participants who undergo screening and treatment may reduce the development of hepatocellular carcinoma. This study assessed the percentages of HBsAg positive participants detected by free screening at medical institutions in Saga Prefecture who underwent detailed examinations and antiviral treatment. METHODS: Participants were screened for HBsAg positivity at medical institutions in Saga Prefecture from April 2008 to January 2013, with some visiting physicians for detailed examinations and applying for reimbursement. Participants in the database of the Health Promotion Division of Saga Prefecture and results of detailed examinations were analyzed retrospectively. RESULTS: Screening revealed 193 eligible participants, 105 men (54%) and 88 women (46%), of a mean age of 55.5 +/- 14.9 years. Of these 193 participants, 147 (76%) visited physicians for detailed examinations, 24 (16%) were regarded as needing treatment and seven (3.6%) were reimbursed for antiviral treatments. The 46 participants who did not undergo detailed examinations were significantly younger than the 147 examined participants (50.9 +/- 13.2 vs 56.9 +/- 15.2 years, P = 0.018). Of the 110 participants thought to require observation, 68 (62%) were assigned to this group without determination of alanine aminotransferase or hepatitis B virus DNA concentration, and 15 (14%) had indications for antiviral treatment according to the 2014 guidelines of the Japanese Society of Hepatology. CONCLUSION: The proportion of HBsAg positive participants receiving antiviral treatment was lower than that of participants undergoing detailed examinations. PMID- 26492345 TI - Stillbirth: Correlations Between Brain Injury and Placental Pathology. AB - Chronic placental pathologic processes such as fetal thrombotic vasculopathy have been linked to brain injury in neonates. We hypothesize that using stillbirth as a model, placental pathology can predict risk for hypoxic-ischemic brain injury. From a single institutional database of stillbirths >=23 weeks' gestational age, we included cases with full autopsy and neuropathology examination. Bivariable analyses were performed to identify whether there was an association between placental pathologic findings and neuropathologic findings. Logistic regression was used to control for potential confounders. Among 97 potential cases, adequate tissue was analyzable from 79 cases (mean gestational age = 33 weeks). Acute central nervous system hemorrhage and acute neuronal necrosis were the most common neuropathologic processes seen in this cohort (57% for each). Maternal vascular underperfusion was the most common placental pathology but was not significantly associated with a specific neuropathologic finding. High-grade chronic villitis (HGCV) and fetal thrombotic vasculopathy (FTV) were significantly associated with increased risk for pontosubicular necrosis (odds ratios, 15.73 and 3.79, respectively). These associations persisted after controlling for potential confounders. Chronic placental pathologies, specifically HGCV and FTV, were associated with pontosubicular necrosis, suggesting that placental pathology involving the fetal vasculature and altered fetoplacental blood flow carry the greatest likelihood of hypoxic/ischemic brain injury. PMID- 26492346 TI - Structure-Activity Relationship of Synthetic 2-Phenylnaphthalenes with Hydroxyl Groups that Inhibit Proliferation and Induce Apoptosis of MCF-7 Cancer Cells. AB - In this study, six 2-phenylnaphthalenes with hydroxyl groups were synthesized in high yields by the demethylation of the corresponding methoxy-2 phenylnaphthalenes, and one 2-phenylnaphthalene with an amino group was obtained by hydrogenation. All of the 2-phenylnaphthalene derivatives were evaluated for cytotoxicity, and the structure-activity relationship (SAR) against human breast cancer (MCF-7) cells was also determined. The SAR results revealed that cytotoxicity was markedly promoted by the hydroxyl group at the C-7 position of the naphthalene ring. The introduction of hydroxyl groups at the C-6 position of the naphthalene ring and the C-4' position of the phenyl ring fairly enhanced cytotoxicity, but the introduction of a hydroxyl group at the C-3' position of the phenyl ring slightly decreased cytotoxicity. Overall, 6,7-dihydroxy-2-(4' hydroxyphenyl)naphthalene (PNAP-6h) exhibited the best cytotoxicity, with an IC50 value of 4.8 MUM against the MCF-7 cell line, and showed low toxicity toward normal human mammary epithelial cells (MCF-10A). PNAP-6h led to cell arrest at the S phase, most likely due to increasing levels of p21 and p27 and decreasing levels of cyclin D1, CDK4, cyclin E, and CDK2. In addition, PNAP-6h decreased CDK1 and cyclin B1 expression, most likely leading to G2/M arrest, and induced morphological changes, such as nuclear shrinkage, nuclear fragmentation, and nuclear hypercondensation, as observed by Hoechst 33342 staining. PNAP-6h induced apoptosis, most likely by the promotion of Fas expression, increased PARP activity, caspase-7, caspase-8, and caspase-9 expression, the Bax/Bcl-2 ratio, and the phosphorylation of p38, and decreased the phosphorylation of ERK. This study provides the first demonstration of the cytotoxicity of PNAPs against MCF-7 cells and elucidates the mechanism underlying PNAP-induced cytotoxicity. PMID- 26492347 TI - Blood donations: justifying blood donor restrictions. PMID- 26492348 TI - DNA Barcoding through Quaternary LDPC Codes. AB - For many parallel applications of Next-Generation Sequencing (NGS) technologies short barcodes able to accurately multiplex a large number of samples are demanded. To address these competitive requirements, the use of error-correcting codes is advised. Current barcoding systems are mostly built from short random error-correcting codes, a feature that strongly limits their multiplexing accuracy and experimental scalability. To overcome these problems on sequencing systems impaired by mismatch errors, the alternative use of binary BCH and pseudo quaternary Hamming codes has been proposed. However, these codes either fail to provide a fine-scale with regard to size of barcodes (BCH) or have intrinsic poor error correcting abilities (Hamming). Here, the design of barcodes from shortened binary BCH codes and quaternary Low Density Parity Check (LDPC) codes is introduced. Simulation results show that although accurate barcoding systems of high multiplexing capacity can be obtained with any of these codes, using quaternary LDPC codes may be particularly advantageous due to the lower rates of read losses and undetected sample misidentification errors. Even at mismatch error rates of 10(-2) per base, 24-nt LDPC barcodes can be used to multiplex roughly 2000 samples with a sample misidentification error rate in the order of 10(-9) at the expense of a rate of read losses just in the order of 10(-6). PMID- 26492349 TI - Iodine seed- versus wire-guided localization in breast-conserving surgery for non palpable ductal carcinoma in situ. AB - BACKGROUND: Breast-conserving surgery for isolated non-palpable ductal carcinoma in situ (DCIS) is associated with high rates of incomplete surgical resection in comparison with unifocal invasive breast cancer. Therefore, accurate preoperative localization of the lesion is very important to facilitate adequate resection. Wire-guided localization (WGL) remains the standard for localization of DCIS. Recently, iodine-125 seed-guided localization (I-125 GL) was introduced as an alternative localization technique. The aim of this study was to compare the efficacy of these localization techniques in the resection of DCIS by breast conserving surgery. METHODS: Between March 2006 and June 2013, 169 patients with non-palpable DCIS were treated with breast-conserving surgery. Only patients with pure DCIS on both preoperative core biopsy and definitive pathology were included. RESULTS: WGL was performed in 78 patients and I-125 GL in 91 patients. The groups did not differ with respect to age, size of DCIS or type of imaging used. Patients in the I-125 GL group had a significantly lower risk of extensively involved resection margins than those in the WGL group (4 versus 13 per cent respectively; P = 0.048). CONCLUSION: In patients treated with breast conserving surgery for non-palpable DCIS, localization with iodine-125 seeds is superior to the WGL technique in reducing the risk of extensively involved resection margins. PMID- 26492350 TI - DNA Aptamer Raised against Advanced Glycation End Products Prevents Abnormalities in Electroretinograms of Experimental Diabetic Retinopathy. AB - PURPOSE: Abnormalities in electroretinograms (ERG), such as reduced amplitudes and delayed implicit times of a- and b-wave and oscillatory potentials (OPs), are one of the earliest features of diabetic retinopathy prior to obvious vascular changes in diabetic retinas. We have previously shown that serum levels of advanced glycation end products (AGEs) are correlated with a delayed latency of OPs in type 2 diabetic rats. However, the pathological role of AGEs in ERG abnormalities remains unclear. We examined here whether high-affinity DNA aptamer directed against AGEs (AGE-aptamer) prevents ERG abnormalities in experimental type 1 diabetic retinopathy. METHODS: Streptozotocin-induced diabetic rats or control rats received continuous intraperitoneal infusion of either AGE-aptamer or control aptamer via an osmotic mini pump for 16 weeks. Anthropometric, metabolic, and hemodynamic variables were measured, and an ERG was performed. RESULTS: Although AGE-aptamer did not affect body weight, fasting and random blood glucose, HbA1c, blood pressure, or lipid parameters, it completely prevented the increase in serum AGE levels as well as the reduction of a- and b wave and OP amplitudes in diabetic rats. CONCLUSION: The present study demonstrated for the first time that AGE-aptamer prevents abnormalities in ERG in experimental diabetic retinopathy probably by blocking the harmful effects of AGEs. PMID- 26492351 TI - Probabilistic Exposure Assessment for Applicators during Treatment of the Fungicide Kresoxim-methyl on an Apple Orchard by a Speed Sprayer. AB - Probabilistic exposure and risk assessment of kresoxim-methyl were conducted for agricultural applicators during preparation of spray suspension and application with a speed sprayer on an apple orchard. The preparation and application of 1000 L of spray suspension were repeated 30 times. Several exposure matrices, including patches, cotton gloves, socks, masks, and XAD-2 resin, were used to measure the potential exposure for workers. The analytical methods were fully validated to guarantee the precision and accuracy of analysis. The exposure amount on hands for mixer/loader was 0.7 mg [95% confidence interval (CI) from 0.02 to 2.4], taking 0.0005% (95% CI from 1.2 * 10(-5) to 0.001) of total prepared active ingredient. During application of kresoxim-methyl, the amount of dermal exposure was 17.5 mg (95% CI from 9.3 to 28.9), corresponding to 0.010% (95% CI from 0.006 to 0.017) of total applied active ingredient. The major exposure parts of the body were thighs and shins, with correlation coefficients of 0.53 and 0.43, respectively. The inhalation exposure during application were estimated as 6.8 ng (95% CI from 0.4 to 17.0), being 0.04% (95% CI from 0.004 to 0.06) of the dermal exposure. The calculated absorbable quantities of exposures for mixer/loader and applicator were 2.1 * 10(-4) mg/day (95% CI from 5.0 * 10( 6) to 7.2 * 10(-4)) and 2.3 mg/day (95% CI from 1.2 to 3.8), respectively. For risk assessment, the margin of safety of all working activities was much higher than 1, indicating that the possibility of risk to kresoxim-methyl was unlikely. PMID- 26492352 TI - Origin of Mechanoluminescence from Cu-Doped ZnS Particles Embedded in an Elastomer Film and Its Application in Flexible Electro-mechanoluminescent Lighting Devices. AB - Mechanically driven light emission from particles embedded in elastomer films has recently attracted interest as a strong candidate for next-generation light sources on display devices because it is nondestructive, reproducible, real-time, environmentally friendly, and reliable. The origin of mechanoluminescence (ML) obtained from particles embedded in elastomer films have been proposed as the trapping of drifting charge carriers in the presence of a piezoelectric field. However, in this study, we propose a new origin of ML through the study of the microstructure of a Cu-doped ZnS particles embedded in an elastomer composite film with high brightness using transmission electron microscopy (TEM) to clearly demonstrate the origin of ML with respect to the microstructure of ML composite films. The TEM characterization of the ML composite film demonstrated that the Cu doped ZnS particles were fully encapsulated by a 500 nm thick Al layer, which acts as an electron source for ML emission. Furthermore, we fabricated a flexible electro-mechanoluminescence (EML) device using a Cu-doped ZnS particles embedded in a flexible elastomer composite film. Our research results on a new emission mechanism for ML and its application in flexible light generating elastomer films represent an important step toward environmentally benign and ecofriendly flexible electro-mechanoluminescent lighting devices. PMID- 26492353 TI - Correction: Efficacy and Safety Assessment of the Addition of Bevacizumab to Adjuvant Therapy Agents in Cancer Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PMID- 26492354 TI - Systemic symptoms predict presence or development of severe sepsis and septic shock. AB - BACKGROUND: Severe sepsis is a major cause of mortality and morbidity globally. As the time to adequate treatment is directly linked to outcome, early recognition is of critical importance. Early, accessible markers for severe sepsis are desirable. The systemic inflammatory response in sepsis leads to changes in vital signs and biomarkers and to symptoms unrelated to the focus of infection. This study investigated whether the occurrence of any of six systemic symptoms could predict severe sepsis in a cohort of patients admitted to hospital for suspected bacterial infections. METHODS: A retrospective, consecutive study was conducted. All adult patients admitted during 1 month to a 550-bed secondary care hospital in western Sweden and given intravenous antibiotics for suspected community-acquired infection were included (n = 289). Symptoms (fever/chills, muscle weakness, localised pain, dyspnea, altered mental status and gastrointestinal symptoms) were registered along with age, sex, vital signs and laboratory values. Patients who fulfilled criteria of severe sepsis within 48 h were compared with patients who did not. Odds ratios for severe sepsis were calculated, adjusted for age, sex and comorbidities. RESULTS: Criteria for severe sepsis were fulfilled by 90/289 patients (31.1%). Altered mental status (OR = 4.29, 95% CI = 2.03-9.08), dyspnea (OR = 2.92, 95% CI = 1.69-5.02), gastrointestinal symptoms (OR = 2.31, 95% CI = 1.14-4.69) and muscle weakness (OR = 2.24, 95% CI = 1.06-4.75) were more common in patients who had or later developed severe sepsis. CONCLUSIONS: Systemic symptoms in combination with other signs of infection should be considered warning signs of severe sepsis. PMID- 26492356 TI - Interprofessional Education Using a Palliative Care Simulation. AB - This quasi-experimental pretest-posttest study measured self-efficacy, attitudes toward physician-nurse collaboration, and interprofessional competencies as outcomes of a palliative care simulation. Based on experience level, teams of participants, 1 consisting of nursing/medical students and the other of nursing/medical health care professionals, completed a palliative care simulation as part of their education. Self-efficacy and attitudes toward physician-nurse collaboration were measured before and after simulation. Interprofessional competency was measured during the simulation. The results revealed a significant improvement in the previously mentioned measures, and interprofessional competency scores varied by profession and evaluator. PMID- 26492355 TI - Myeloproliferative neoplasms: A decade of discoveries and treatment advances. AB - Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR-ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, "driver" mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. PMID- 26492357 TI - Joint preserved reconstruction after curettage in giant cell tumor of bone arising in the distal radius: Case report. AB - INTRODUCTION: Giant cell tumor of bone is a locally aggressive tumor. Preserved joint reconstruction for tumors in the distal radius is challenging, especially when there is extraosseous extension and less subarticular bone. PRESENTATION OF CASE: To preserve the joint, we developed a new reconstruction technique using beta-tricalcium phosphate (TCP) with strong compressive resistance. DISCUSSION AND CONCLUSION: Giant cell tumor of bone in the distal radius was treated by curettage and bone grafting, plus the use of beta-TCP. This new method will preserve joint junction. PMID- 26492358 TI - Intrathoracic esophageal rupture distal to the carina after blunt chest trauma: Case-report. AB - INTRODUCTION: Esophageal rupture caused by blunt chest trauma is a very rare entity, with an incidence of 0.001%. Eighty two percent of the esophageal perforation secondary to blunt chest trauma occur above the level of the carina, with the lowest reported incidence in the intrathoracic region distal to the carina. PRESENTATION OF CASE: We report on the case of a 48-year-old Hispanic male with intrathoracic esophageal rupture. Exploration revealed a right lateral, mid esophageal, longitudinal 1.5cm perforation. The defect was repaired using a double-layered primary closure reinforced with an intercostal muscle flap. The patient tolerated the procedure and the recovery was complicated by a pneumonic process which was treated accordingly. No leakage was found. DISCUSSION: A five year retrospective review (2009-2013) at our institution identified 5586 trauma cases with only one case with esophageal rupture. This represents a 0.0002% of incidence of blunt esophageal rupture. This estimate is consistent with what has been previously reported in the medical literature. Our case represents a uniquely rare presentation of traumatic esophageal rupture due to the underline mechanism of injury and its anatomical location. A high index of suspicion and early intervention are critical in assuring a favorable outcome. CONCLUSION: Diagnosis and surgical intervention with primary repair completed in the first twenty-four hours after presentation is fundamental to achieve a good outcome after esophageal rupture. PMID- 26492359 TI - Conventional fascial technique versus mesh repair for advanced pelvic organ prolapse: Analysis of recurrences in treated and untreated compartments. AB - 117 women with severe pelvic organ prolapse (POP; stage > 2) were enrolled to elucidate a 24-month outcome of POP surgery, using conventional or mesh repair with 3 techniques. 59 patients underwent conventional repair and 58 underwent mesh repair. Two types of mesh were used: a trocar-guided transobturator polypropylene (Avaulta, Bard Inc.) and a porcine dermis mesh (Pelvisoft, Bard Inc.). Women with recurrences, who underwent previous unsuccessful conventional repair, were randomised. Primary outcome was the evaluation of anatomic failures (prolapse stage > 1) in treated and untreated compartments. Anatomic failure was observed in 11 of 58 patients (19%; CI 8.9-29) in the mesh group and in 16 of 59 patients (27.1%; p value = 0.3) in the conventional group. 9 of 11 failures in the mesh group (15.5%; CI 6.2-24.8) were observed in the untreated compartment (de novo recurrences), 14.3% in Pelvisoft and 16.7% in Avaulta arm, while only 1 recurrence in the untreated compartment (1.7%) was observed in the conventional group (odds ratio 10.6, p = 0.03). PMID- 26492360 TI - Spray-On Polyaniline/Poly(acrylic acid) Electrodes with Enhanced Electrochemical Stability. AB - Polyaniline (PANI)-based electrodes are promising candidates for energy storage, but their cycle life remains poor. Recent work suggests that secondary interactions may enhance polyaniline's electrochemical stability and cycle life, but evidence to date is not conclusive. Here, we investigate spray-assisted layer by-layer assemblies containing polyaniline nanofibers (PANI NFs) or conventional PANI and poly(acrylic acid) (PAA), which provides hydrogen bonding and electrostatic interactions. This spray-on approach may be suitable for the deposition of PANI onto a variety of surfaces. The effects of PANI type, PAA pH, and PAA molecular weight on the growth behavior, conductivity, and electrochemical performance are examined. It is shown that LbL films with PANI NFs, higher molecular weight PAA, and lower PAA pH yield the thickest films, whereas the thinnest films come from conventional PANI assembled under similar conditions. Electron microscopy imaging and density measurements show that LbL films containing PANI NFs are very porous, whereas those containing conventional PANI are very dense (0.28 vs 1.33 g/cm(3), respectively). The difference in density dramatically affects the electrochemical properties in terms of capacity and long-term cycling behavior. Upon extended cycling, PANI NFs alone rapidly lose their electrochemical activity. On the other hand, PANI NF-based LbL films exhibited somewhat enhanced stability, and PANI-based LbL films were exceptionally stable, maintaining 94.7% of their capacity after 1000 cycles when cycled up to 4.2 V vs Li/Li(+). These results show that secondary interactions from PAA enhance stability, as does the selection of PANI type and the electrode's density. PMID- 26492361 TI - Ruthenium and osmium complexes of dihydroperimidine-based N-heterocyclic carbene pincer ligands. AB - The reactions of N,N'-bis(phosphinomethyl)dihydroperimidine pro-ligands H2C(NCH2PR2)2C10H6 (R = Cy 1a, R = Ph 1b) with [RuCl2(PPh3)3] give markedly different products. Chelate-assisted double C-H activation in the former affords the perimidinylidene-based N-heterocyclic carbene (per-NHC) pincer complex [RuCl2(OC4H8){kappa(3)-P,C,P'-C(NCH2PCy2)2C10H6}] (2), while the latter reaction provides the asymmetric PNP-coordinated complex [RuCl2(PPh3){kappa(3)-P,N,P' CH2(NCH2PPh2)2C10H6}] (3), in which no C-H activation has occurred. Subsequent reactions of the per-NHC complex 2 with carbon monoxide and mesityl isocyanide readily displaced the labile THF ligand to afford the complexes [RuCl2(CA){kappa(3)-P,C,P'-C(NCH2PCy2)2C10H6}] (A = O 4, A = NC6H2Me35). Double C H activation of 1a and 1b was significantly more facile on reaction with [OsCl2(PPh3)3], providing the per-NHC complexes [OsHCl(PPh3){kappa(3)-P,C,P' C(NCH2PR2)2C10H6}] (R = Cy 7a, R = Ph 7b, respectively), each as two isomers. The reactions of 1b with [Ru2(MU-Cl)2Cl2(eta-C6H3Me3)2] or [AuCl(THT)] (THT = tetrahydrothiophene) provide the bimetallic complexes [Ru2{MU H2C(NCH2PPh2)2C10H6}Cl4(eta-C6H3Me3)2] (8) and [Au2{MU-H2C(NCH2PPh2)2C10H6}Cl2] (9) without C-H activation occurring. PMID- 26492362 TI - Ferroelectric Polarization-Enhanced Photoelectrochemical Water Splitting in TiO2 BaTiO3 Core-Shell Nanowire Photoanodes. AB - The performances of heterojunction-based electronic devices are extremely sensitive to the interfacial electronic band structure. Here we report a largely enhanced performance of photoelectrochemical (PEC) photoanodes by ferroelectric polarization-endowed band engineering on the basis of TiO2/BaTiO3 core/shell nanowires (NWs). Through a one-step hydrothermal process, a uniform, epitaxial, and spontaneously poled barium titanate (BTO) layer was created on single crystalline TiO2 NWs. Compared to pristine TiO2 NWs, the 5 nm BTO-coated TiO2 NWs achieved 67% photocurrent density enhancement. By numerically calculating the potential distribution across the TiO2/BTO/electrolyte heterojunction and systematically investigating the light absorption, charge injection and separation properties of TiO2 and TiO2/BTO NWs, the PEC performance gain was proved to be a result of the increased charge separation efficiency induced by the ferroelectric polarization of the BTO shell. The ferroelectric polarization could be switched by external electric field poling and yielded PEC performance gain or loss based on the direction of the polarization. This study evidence that the piezotronic effect (ferroelectric or piezoelectric potential-induced band structure engineering) holds great promises in improving the performance of PEC photoelectrodes in addition to chemistry and structure optimization. PMID- 26492363 TI - Activation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatin-resistant cancer cells. AB - Platinum-based drugs remain as the cornerstone of cancer chemotherapy; however, development of multidrug resistance presents a therapeutic challenge. This study aims at understanding the molecular mechanisms underlying resistance to cisplatin and unraveling surrogate signaling networks that could revert sensitivity to apoptosis stimuli. We made use of three different sets of cell lines, A549 and H2030 non-small-cell lung cancer (NSCLC) and A2780 ovarian cancer cells and their cisplatin-resistant variants. Here we report that cisplatin-resistant cell lines displayed a multidrug-resistant phenotype. Changes in mitochondrial metabolism and defective mitochondrial signaling were unraveled in the resistant cells. More interestingly, a marked increase in sensitivity of the resistant cells to death receptor-induced apoptosis, in particular TRAIL (TNF-related apoptosis-inducing ligand)-mediated execution, was observed. Although this was not associated with an increase in gene transcription, a significant increase in the localization of TRAIL death receptor, DR4, to the lipid raft subdomains of plasma membrane was detected in the resistant variants. Furthermore, exposure of cisplatin-resistant cells to TRAIL resulted in upregulation of inducible nitric oxide synthase (iNOS) and increase in nitric oxide (NO) production that triggered the generation of peroxynitrite (ONOO(-)). Scavenging ONOO(-) rescued cells from TRAIL-induced apoptosis, thereby suggesting a critical role of ONOO(-) in TRAIL-induced execution of cisplatin-resistant cells. Notably, preincubation of cells with TRAIL restored sensitivity of resistant cells to cisplatin. These data provide compelling evidence for employing strategies to trigger death receptor signaling as a second-line treatment for cisplatin-resistant cancers. PMID- 26492364 TI - The RCAN1 inhibits NF-kappaB and suppresses lymphoma growth in mice. AB - Nuclear factor-kappaB (NF-kappaB) has a vital role in cell survival. Inhibition of NF-kappaB has been proven to be an efficient therapeutic pathway for various cancers. Activation of NF-kappaB is mainly through serine residues' phosphorylation of inhibitor of kappaBalpha (IkappaBalpha) by IKK complex. Phosphorylation at tyrosine 42 is an alternative pathway in regulation of IkappaBalpha and NF-kappaB signaling, though little is known about the underlying mechanism. Here we identified regulator of calcineurin 1 (RCAN1) as a novel endogenous inhibitor of NF-kappaB signaling pathway. RCAN1 can interact with IkappaBalpha and affect the phosphorylation of IkappaBalpha at tyrosine 42. Overexpression of RCAN1 by adenovirus reduced cell viability in lymphoma Raji cells and restrained the growth of lymphoma transplants in mice. We further found that N terminus 1-103aa of RCAN1 is sufficient to inhibit NF-kappaB and reduce cell viability of lymphoma cells. Our study implicated a novel therapeutic approach for lymphoma by RCAN1 through inhibition of NF-kappaB signaling. PMID- 26492366 TI - Paracrine regulation in mesenchymal stem cells: the role of Rap1. PMID- 26492365 TI - Early effects of the antineoplastic agent salinomycin on mitochondrial function. AB - Salinomycin, isolated from Streptomyces albus, displays antimicrobial activity. Recently, a large-scale screening approach identified salinomycin and nigericin as selective apoptosis inducers of cancer stem cells. Growing evidence suggests that salinomycin is able to kill different types of non-stem tumor cells that usually display resistance to common therapeutic approaches, but the mechanism of action of this molecule is still poorly understood. Since salinomycin has been suggested to act as a K(+) ionophore, we explored its impact on mitochondrial bioenergetic performance at an early time point following drug application. In contrast to the K(+) ionophore valinomycin, salinomycin induced a rapid hyperpolarization. In addition, mitochondrial matrix acidification and a significant decrease of respiration were observed in intact mouse embryonic fibroblasts (MEFs) and in cancer stem cell-like HMLE cells within tens of minutes, while increased production of reactive oxygen species was not detected. By comparing the chemical structures and cellular effects of this drug with those of valinomycin (K(+) ionophore) and nigericin (K(+)/H(+) exchanger), we conclude that salinomycin mediates K(+)/H(+) exchange across the inner mitochondrial membrane. Compatible with its direct modulation of mitochondrial function, salinomycin was able to induce cell death also in Bax/Bak-less double-knockout MEF cells. Since at the concentration range used in most studies (around 10 MUM) salinomycin exerts its effect at the level of mitochondria and alters bioenergetic performance, the specificity of its action on pathologic B cells isolated from patients with chronic lymphocytic leukemia (CLL) versus B cells from healthy subjects was investigated. Mesenchymal stromal cells (MSCs), proposed to mimic the tumor environment, attenuated the apoptotic effect of salinomycin on B-CLL cells. Apoptosis occurred to a significant extent in healthy B cells as well as in MSCs and human primary fibroblasts. The results indicate that salinomycin, when used above MUM concentrations, exerts direct, mitochondrial effects, thus compromising cell survival. PMID- 26492367 TI - Implication of different domains of the Leishmania major metacaspase in cell death and autophagy. AB - Metacaspases (MCAs) are cysteine peptidases expressed in plants, fungi and protozoa, with a caspase-like histidine-cysteine catalytic dyad, but differing from caspases, for example, in their substrate specificity. The role of MCAs is subject to debate: roles in cell cycle control, in cell death or even in cell survival have been suggested. In this study, using a Leishmania major MCA deficient strain, we showed that L. major MCA (LmjMCA) not only had a role similar to caspases in cell death but also in autophagy and this through different domains. Upon cell death induction by miltefosine or H2O2, LmjMCA is processed, releasing the catalytic domain, which activated substrates via its catalytic dyad His/Cys and a proline-rich C-terminal domain. The C-terminal domain interacted with proteins, notably proteins involved in stress regulation, such as the MAP kinase LmaMPK7 or programmed cell death like the calpain-like cysteine peptidase. We also showed a new role of LmjMCA in autophagy, acting on or upstream of ATG8, involving Lmjmca gene overexpression and interaction of the C-terminal domain of LmjMCA with itself and other proteins. These results allowed us to propose two models, showing the role of LmjMCA in the cell death and also in the autophagy pathway, implicating different protein domains. PMID- 26492368 TI - Proteasomal inhibition sensitizes cervical cancer cells to mitomycin C-induced bystander effect: the role of tumor microenvironment. AB - Inaccessibility of drugs to poorly vascularized strata of tumor is one of the limiting factors in cancer therapy. With the advent of bystander effect (BE), it is possible to perpetuate the cellular damage from drug-exposed cells to the unexposed ones. However, the role of infiltrating tumor-associated macrophages (TAMs), an integral part of the tumor microenvironment, in further intensifying BE remains obscure. In the present study, we evaluated the effect of mitomycin C (MMC), a chemotherapeutic drug, to induce BE in cervical carcinoma. By using cervical cancer cells and differentiated macrophages, we demonstrate that MMC induces the expression of FasL via upregulation of PPARgamma in both cell types (effector cells) in vitro, but it failed to induce bystander killing in cervical cancer cells. This effect was primarily owing to the proteasomal degradation of death receptors in the cervical cancer cells. Pre-treatment of cervical cancer cells with MG132, a proteasomal inhibitor, facilitates MMC-mediated bystander killing in co-culture and condition medium transfer experiments. In NOD/SCID mice bearing xenografted HeLa tumors administered with the combination of MMC and MG132, tumor progression was significantly reduced in comparison with those treated with either agent alone. FasL expression was increased in TAMs, and the enhanced level of Fas was observed in these tumor sections, thereby causing increased apoptosis. These findings suggest that restoration of death receptor mediated apoptotic pathway in tumor cells with concomitant activation of TAMs could effectively restrict tumor growth. PMID- 26492369 TI - Reactivation of p53 via MDM2 inhibition. PMID- 26492370 TI - Discovering in vitro spermatogenesis stimulating factors. PMID- 26492371 TI - Impact of the combined loss of BOK, BAX and BAK on the hematopoietic system is slightly more severe than compound loss of BAX and BAK. AB - It is well established that BAX and BAK play crucial, overlapping roles in the intrinsic pathway of apoptosis. Gene targeted mice lacking both BAX and BAK have previously been generated, but the majority of these animals died perinatally. BOK is a poorly studied relative of BAX and BAK that shares extensive amino acid sequence homology to both proteins, but its function remains largely unclear to date. To determine whether BOK plays an overlapping role with BAX and BAK, we utilized a hematopoietic reconstitution model where lethally irradiated wild type mice were transplanted with Bok(-/-)Bax(-/-)Bak(-/-) triple knockout (TKO) fetal liver cells, and compared alongside mice reconstituted with a Bax(-/-)Bak(-/-) double knockout (DKO) hematopoietic compartment. We report here that mice with a TKO and DKO hematopoietic system died at a similar rate and much earlier than control animals, mostly due to severe autoimmune pathology. Both TKO and DKO reconstituted mice also had altered frequencies of various leukocyte subsets in the thymus, bone marrow and spleen, displayed leukocyte infiltrates and autoimmune pathology in multiple tissues, as well as elevated levels of anti nuclear autoantibodies. Interestingly, the additional deletion of BOK (on top of BAX and BAK loss) led to a further increase in peripheral blood lymphocytes, as well as enhanced lymphoid infiltration in some organs. These findings suggest that BOK may have some functions that are redundant with BAX and BAK in the hematopoietic system. PMID- 26492373 TI - Muscle Lim Protein (MLP)/CSRP3 at the crossroad between mechanotransduction and autophagy. PMID- 26492372 TI - Development of a neuroprotective peptide that preserves survival pathways by preventing Kidins220/ARMS calpain processing induced by excitotoxicity. AB - Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), has a central role in the coordination of receptor crosstalk and the integration of signaling pathways essential for neuronal differentiation, survival and function. This protein is a shared downstream effector for neurotrophin- and ephrin-receptors signaling that also interacts with the N-methyl-d-aspartate type of glutamate receptors (NMDARs). Failures in neurotrophic support and glutamate signaling are involved in pathologies related to excitotoxicity and/or neurodegeneration, where different components of these dynamic protein complexes result altered by a combination of mechanisms. In the case of Kidins220/ARMS, overactivation of NMDARs in excitotoxicity and cerebral ischemia triggers its downregulation, which contributes to neuronal death. This key role in neuronal life/death decisions encouraged us to investigate Kidins220/ARMS as a novel therapeutic target for neuroprotection. As the main mechanism of Kidins220/ARMS downregulation in excitotoxicity is proteolysis by calpain, we decided to develop cell-penetrating peptides (CPPs) that could result in neuroprotection by interference of this processing. To this aim, we first analyzed in detail Kidins220/ARMS cleavage produced in vitro and in vivo, identifying a major calpain processing site in its C-terminal region (between amino acids 1669 and 1670) within a sequence motif highly conserved in vertebrates. Then, we designed a 25-amino acids CPP (Tat-K) containing a short Kidins220/ARMS sequence enclosing the identified calpain site (amino acids 1668-1681) fused to the HIV-1 Tat protein basic domain, able to confer membrane permeability to attached cargoes. Transduction of cortical neurons with Tat-K reduced Kidins220/ARMS calpain processing in a dose- and time dependent manner upon excitotoxic damage and allowed preservation of the activity of pERK1/2 and pCREB, signaling molecules central to neuronal survival and functioning. Importantly, these effects were associated to a significant increase in neuronal viability. This Kidins220/ARMS-derived peptide merits further research to develop novel neuroprotective therapies for excitotoxicity-associated pathologies. PMID- 26492374 TI - SAG-UPS regulates malignant transformation--from chronic inflammation to pro tumorigenesis to liver cancer. PMID- 26492375 TI - Autophagy-induced RelB/p52 activation mediates tumour-associated macrophage repolarisation and suppression of hepatocellular carcinoma by natural compound baicalin. AB - The plasticity of tumour-associated macrophages (TAMs) has implicated an influential role in hepatocellular carcinoma (HCC). Repolarisation of TAM towards M1 phenotype characterises an immune-competent microenvironment that favours tumour regression. To investigate the role and mechanism of TAM repolarisation in suppression of HCC by a natural compound baicalin, Orthotopic HCC implantation model was used to investigate the effect of baicalin on HCC; liposome-clodronate was introduced to suppress macrophage populations in mice; bone marrow-derived monocytes (BMDMs) were induced to unpolarised, M1-like, M2-like macrophages and TAM using different conditioned medium. We observed that oral administration of baicalin (50 mg/kg) completely blocked orthotopic growth of implanted HCC. Suppression of HCC by baicalin was diminished when mice macrophage was removed by clodronate treatment. Baicalin induced repolarisation of TAM to M1-like phenotype without specific toxicity to either phenotype of macrophages. Baicalin initiated TAM reprogramming to M1-like macrophage, and promoted pro-inflammatory cytokines production. Co-culturing of HCC cells with baicalin-treated TAMs resulted in reduced proliferation and motility in HCC. Baicalin had minimal effect on derivation of macrophage polarisation factors by HCC cells, while directly induced repolarisation of TAM and M2-like macrophage. This effect was associated with elevated autophagy, and transcriptional activation of RelB/p52 pathway. Suppression of autophagy or RelB abolished skewing of baicalin-treated TAM. Autophagic degradation of TRAF2 in baicalin-treated TAM might be responsible for RelB/p52 activation. Our findings unveil the essential role of TAM repolarisation in suppressive effect of baicalin on HCC, which requires autophagy-associated activation of RelB/p52. PMID- 26492377 TI - Theoretical Impact of Replacing Whole Cow's Milk by Young-Child Formula on Nutrient Intakes of UK Young Children: Results of a Simulation Study. AB - BACKGROUND: Research into the role of young-child formulae (YCF) in a child's diet is limited and there is no consensual recommendation on its use. We evaluated the theoretical nutritional impact of replacing the existing practice of consuming cow's milk by YCF. METHODS: From the UK Diet and Nutrition Survey of Infants and Young Children, whole cow's milk consumers, aged 12-18 months (n = 591) were selected for simulation scenarios. In Scenario 1, we tested the replacement of all whole cow's milk (434 +/- 187 ml/day) by a matching volume of YCF, and in Scenario 2, all whole cow's milk was replaced by the on-pack recommended daily intake of 300 ml. Nutrient intakes before and after simulation scenarios were compared and evaluated against nutrient recommendations. RESULTS: Intakes of protein and saturated fatty acids were significantly decreased, whereas essential fatty acid intakes were increased. The prevalence of nutrient inadequacy before simulation was 95.2% for vitamin D and 53.8% for iron. After simulation, inadequacy decreased to 4.9% (Scenario 1) and 0% (Scenario 2) for vitamin D and to 2.7% (Scenario 1) and 1.1% (Scenario 2) for iron. CONCLUSIONS: Replacement of habitual cow's milk intake by a matching volume or 300 ml of YCF may lead to nutritional intakes more in line with recommendations in young children. PMID- 26492376 TI - Pur-alpha functionally interacts with FUS carrying ALS-associated mutations. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to motor neuron loss. Fused in sarcoma (FUS) protein carrying ALS-associated mutations localizes to stress granules and causes their coalescence into larger aggregates. Here we show that Pur-alpha physically interacts with mutated FUS in an RNA-dependent manner. Pur-alpha colocalizes with FUS carrying mutations in stress granules of motoneuronal cells differentiated from induced pluripotent stem cells and that are derived from ALS patients. We observe that both Pur-alpha and mutated FUS upregulate phosphorylation of the translation initiation factor eukaryotic translation initiation factor 2 alpha and consistently inhibit global protein synthesis. In vivo expression of Pur-alpha in different Drosophila tissues significatively exacerbates the neurodegeneration caused by mutated FUS. Conversely, the downregulation of Pur-alpha in neurons expressing mutated FUS significatively improves fly climbing activity. All these findings suggest that Pur-alpha, through the control of mRNA translation, might be involved in the pathogenesis of ALS associated with the mutation of FUS, and that an alteration of protein synthesis may be directly implicated in the disease. Finally, in vivo RNAi-mediated ablation of Pur-alpha produced locomotion defects in Drosophila, indicating a pivotal role for this protein in the motoneuronal function. PMID- 26492380 TI - Association Between IL-10 Gene Polymorphism and Diabetic Retinopathy. AB - BACKGROUND: Genetic and environmental factors both play important roles in the occurrence and progression of diabetic retinopathy (DR). IL-10 592 gene polymorphism is associated with diabetes pathogenesis. This study analyzed the relationship between IL-10 gene promoter-592 loci polymorphism (SNP) in a diabetic model rats with DR. MATERIAL AND METHODS: Streptozotocin (STZ) was injected through the tail vein to establish a diabetic rat model. The rats were randomly divided into 2 groups for 3 months' feeding, including 100 rats in the diabetes-positive control group and 100 rats only injected with citric acid buffer as the blank control group. Fundus fluorescein angiography (FFA) was used to observe retinal vascular changes. Polymerase chain reaction-restriction fragment polymorphisms assay (PCR-RFLP) was used to detect IL-10 gene promoter 592 loci polymorphism in DNA samples. Enzyme-linked immunosorbent assay (ELISA) was performed to test serum IL-10 concentration. RESULTS: Serum IL-10 level in DR rats was 33.18+/-5.0 pg/mL and in the control rats it was 53.33+/-4.16 pg/mL in (P<0.01). Diabetes susceptibility with IL-10-592 genotype frequency and gene frequency analysis showed that IL-10-592 genotype frequency and allele frequency were significantly different in the DR group compared with the control group (P<0.01). CONCLUSIONS: IL-10 592 polymorphism was associated with DR susceptibility, suggesting that the gene polymorphism might be a risk factor for DR. PMID- 26492381 TI - Use of Serogroup B Meningococcal Vaccines in Adolescents and Young Adults: Recommendations of the Advisory Committee on Immunization Practices, 2015. AB - At its June 2015 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended that adolescents and young adults aged 16-23 years may be vaccinated with a serogroup B meningococcal (MenB) vaccine to provide short-term protection against most strains of serogroup B meningococcal disease. This report summarizes the deliberations of ACIP, the rationale for its decision, and recommendations for use of MenB vaccines in adolescents and young adults. Two MenB vaccines have recently been licensed by the Food and Drug Administration (FDA) for use in the United States and approved for use in persons aged 10-25 years: MenB-FHbp (Trumenba, Wyeth Pharmaceuticals, Inc.) and MenB-4C (Bexsero, Novartis Vaccines). Both MenB vaccines were licensed based on statutory regulations for accelerated approval, which enabled FDA to approve the MenB vaccines for serious or life threatening diseases based on safety and demonstration that vaccine effectiveness, as measured by bactericidal antibody responses with assays using several MenB test strains that were representative of prevalent strains in the United States, is reasonably likely to predict clinical benefit. As a requirement for accelerated approval, confirmatory studies in the postmarketing period will be conducted to verify and further describe the effectiveness of the vaccines against an extended number of MenB strains that represent a broader diversity of endemic disease. Additional postlicensure safety data are also needed and will be reviewed by ACIP as they become available. PMID- 26492383 TI - Length of Disability and Medical Costs in Low Back Pain: Do State Workers' Compensation Policies Make a Difference? AB - OBJECTIVE: The aim of the study was to examine the impact of state workers' compensation (WC) policies regarding wage replacement and medical benefits on medical costs and length of disability (LOD) in workers with low back pain (LBP). METHODS: Retrospective cohort analysis of LBP claims from 49 states (n = 59,360) filed between 2002 and 2008, extracted from a large WC administrative database. RESULTS: Longer retroactive periods and state WC laws allowing treating provider choice were associated with higher medical costs and longer LOD. Limiting the option to change providers and having a fee schedule were associated with longer LOD, except that allowing a one-time treating provider change was associated with lower medical costs and shorter LOD. CONCLUSIONS: WC policies about wage replacement and medical treatment appear to be associated with WC LBP outcomes, and might represent opportunities to improve LOD and reduce medical costs in occupational LBP. PMID- 26492382 TI - Sickle cell detection using a smartphone. AB - Sickle cell disease affects 25% of people living in Central and West Africa and, if left undiagnosed, can cause life threatening "silent" strokes and lifelong damage. However, ubiquitous testing procedures have yet to be implemented in these areas, necessitating a simple, rapid, and accurate testing platform to diagnose sickle cell disease. Here, we present a label-free, sensitive, and specific testing platform using only a small blood sample (<1 MUl) based on the higher density of sickle red blood cells under deoxygenated conditions. Testing is performed with a lightweight and compact 3D-printed attachment installed on a commercial smartphone. This attachment includes an LED to illuminate the sample, an optical lens to magnify the image, and two permanent magnets for magnetic levitation of red blood cells. The sample is suspended in a paramagnetic medium with sodium metabisulfite and loaded in a microcapillary tube that is inserted between the magnets. Red blood cells are levitated in the magnetic field based on equilibrium between the magnetic and buoyancy forces acting on the cells. Using this approach, we were able to distinguish between the levitation patterns of sickle versus control red blood cells based on their degree of confinement. PMID- 26492384 TI - The association of total and central body fat with pain, fatigue and the impact of fibromyalgia in women; role of physical fitness. AB - BACKGROUND: The relationship between estimates of total and central body fat with fibromyalgia pain, fatigue and overall impact has not been fully described. We aimed to assess the individual and combined association of body fat (total and central) with pain, fatigue and the overall impact in fibromyalgia women; and to study the possible mediation role of physical fitness in these associations. METHODS: A total of 486 fibromyalgia women with a mean (standard deviation) age of 52.2 (8.0) years participated. Pain was measured with self-reported measures and algometry, whereas fatigue with the Multidimensional Fatigue Inventory. The impact of fibromyalgia was measured with the Revised Fibromyalgia Impact Questionnaire (FIQR) total score. Total and central body fat were assessed by means of bioelectrical impedance and waist circumference, respectively. The Functional Senior Fitness Test battery and the handgrip strength test were used to assess physical fitness. RESULTS: Total and central body fat were positively associated with pain- and fatigue-related measures and the FIQR total score (beta from 0.10 to 0.25; all, p < 0.05). A combined effect of total and central body fat was observed on pain (FIQR and 36-item Short-Form Health Survey), general and physical-related fatigue and FIQR total score (all, overall p < 0.05), so that the group with no total and central obesity had more favourable results than those with total and central obesity. Cardiorespiratory fitness partially mediated (between 22-40% of the total effect) the associations between total and central body fat with pain, general fatigue, physical fatigue and reduced activity, and largely mediated (80%) the association of central body fat with the FIQR total score. CONCLUSIONS: Physical fitness might potentially explain the association between obesity and fibromyalgia symptoms. PMID- 26492385 TI - Organometallic Complexes Anchored to Conductive Carbon for Electrocatalytic Oxidation of Methane at Low Temperature. AB - Low-temperature direct methane fuel cells (DMEFCs) offer the opportunity to substantially improve the efficiency of energy production from natural gas. This study focuses on the development of well-defined platinum organometallic complexes covalently anchored to ordered mesoporous carbon (OMC) for electrochemical oxidation of methane in a proton exchange membrane fuel cell at 80 degrees C. A maximum normalized power of 403 MUW/mg Pt was obtained, which was 5 times higher than the power obtained from a modern commercial catalyst and 2 orders of magnitude greater than that from a Pt black catalyst. The observed differences in catalytic activities for oxidation of methane are linked to the chemistry of the tethered catalysts, determined by X-ray photoelectron spectroscopy. The chemistry/activity relationships demonstrate a tangible path for the design of electrocatalytic systems for C-H bond activation that afford superior performance in DMEFC for potential commercial applications. PMID- 26492386 TI - Diagnostic and Therapeutic Challenges. PMID- 26492387 TI - Aggregation-Induced Emission: Together We Shine, United We Soar! PMID- 26492388 TI - Oleoyl and linoleoyl esters of fumonisin B1 are differently produced by Fusarium verticillioides on maize and rice based media. AB - Fatty acid esters of fumonisins, namely oleoyl- and linoleoyl esters of fumonisin B1 (EFB1OA and EFB1LA, respectively), are modified forms of fumonisins whose formation and occurrence have been reported so far in naturally infected maize and in artificially inoculated rice. There is a lack of knowledge about the mechanism of formation, mainly in relation to the role played by the substrate. Therefore, in this work we studied the dynamics of accumulation of the toxin and its esters, together with their precursor, in maize and rice based media inoculated with different strains of F. verticillioides and incubated at 25 degrees C for 7-45 days. The production pattern of FB1 and its modified forms was significantly influenced by growth media, reaching a higher concentration in cornmeal compared to rice based medium. Similarly, cornmeal was more supportive for the conversion of FB1 by considering the esterification rate, with a prevalence of linoleoyl esters compared to oleoyl esters resembling the OA/LA rate in both media. The conversion of FB1 into fatty acid esters was also shown as strain-related. Results, thus, strongly support the hypothesis that fatty acid esters of FB1 are produced by the fungus itself at a late stage of growth, or at a certain point of FB1 accumulation in the medium, using fatty acids from the substrate. PMID- 26492389 TI - [What is Men's Health? A definition]. AB - Target of the study: Men's Health is increasingly coming into focus of health research, epidemiology, health care organization, and health policy. Over the past 10-15 years have been published by some countries and the EU Men's Health reports where problems of health noted in men. Starting point for a scientific study of men's health is the definition of "Men's Health". A group of German experts in the field of men's health has taken on this task. METHODOLOGY: A literature review in international and national databases was performed for the years 1990-2014 by selected MeSH terms and for "experts for men's health". Another research concerned "gray literature" in Germany, especially health reports and web pages. This was followed by a conference of experts to define "Men's Health" using a modified Delphi method according to W. Zinn. From the expert group minimum criteria for a definition "Men's Health" were created and discussed, which must comply with the new definition of men's health. This definition was created in the third round of the Delphi method. RESULTS: The international literature review yielded 7 definitions of "Men's Health" in the English-speaking and 5 definitions in the German inkl. in the "gray" literature. Due to the developed by the Expert Group 7 minimum criteria 15 relevant topics were listed, of which by weighting 8 subject areas were considered relevant for a new definition. In comparison with the previous definitions none could fulfill these 8 criteria. Therefore, in the next step of the expert group a new definition "Men's Health" was elaborated. The definition has reference to the WHO concept of "health" and includes dimensions of health and disease, risk and protective factors that require special prevention and care services for all phases of life. All participants in the expert group agreed on the definition developed. CONCLUSIONS: The definition of Men's Health is a basis for further scientific work and practice to improve men's health in Germany and other countries. PMID- 26492390 TI - [Self-Medication, Health and Online Orders: An Online Survey]. AB - Background: The intensive use of Internet as health guide is proved by a current representative survey. Online orders of OTC pharmaceuticals and prescription medicine represent a special way of utillisation. Intention: The aim of the following study is to investigate motives and backgrounds of self-medication in coherency of health and ordering of OTC pharmaceuticals via Internet. Method: With an online questionnaire developed in particular for this thesis N=104 internet users (mean age M=32,7; SD=11,1 consisting of 73 female and 31 male participants) were questioned concerning the relevant topics. Furthermore, the subjects were interviewed with regard to identification of their quality of life (with the German version of the EUROHIS-QOL 8 item index), their well-being (by using the German version of the WHO-5 well-being index, version II). Results: The wish for (especially temporal) independence from a physicians treatment and the idea of a faster convalescence or prevention of worse ailment could be identified as motives for self-medication. The most frequently selected advantages of ordering drugs via internet were the lower price, organisational aspects such as direct home delivery or saving time without a consultation. In contrast, the lack of advice was often mentioned as a possible disadvantage, just like the risk of undetected and undiagnosed diseases. Compared to participants who did not do any Internet orders, participants who ordered their non-prescription drugs on the Internet were less aware of possible risks and they also used painkillers available without prescription more frequently. However, there were no differences in the total amount of applied OTC medications, which made a drug abuse less likely. Overall, self-medication of the users of Internet forums interviewed within this thesis seemed to be quantitatively and qualitatively appropriate. Conclusion: Self-medication by Internet users in this study seems to be reasonable in a quantitative and qualitative way. PMID- 26492391 TI - [Different Regions, Differently Insured Populations? Socio-demographic and Health related Differences Between Insurance Funds]. AB - Objectives: Analyses of health insurance claims data are getting more important in public health and health services research. Since there are several different health insurance funds in Germany, the specific characteristics of regional and socio-demographic population covered by a single fund has to be considered. The aim of this study is to evaluate the differences in socio-demographic and health related variables between health insurance funds. Methods: This study is based on the GEDA-Study 2009 and 2010, 2 representative cross-sectional telephone surveys (n=42 534). We included socio-economic factors as well as information on area of residence and health-related variables to health status, health behavior and cardiovascular diseases. Results: There are fewer privately insured persons in the eastern regions of Germany. Insurants of the public health insurances have a lower socio-economic status and many have a migration background. Similar results can be found for smoking, obesity and cardiovascular factors. These differences between funds were found in many regional analyses. Conclusions: Especially differences in socio-economic factors are constant between insurance funds and regions. Therefore, the results show that analyses of one single health insurance fund cannot be generalized to the whole population. To ensure precise estimates on health services, morbidity or quality monitoring, we need data sets that integrate more funds. PMID- 26492392 TI - [Association of Deployment and Tobacco Dependence among Soldiers]. AB - OBJECTIVE: Smoking is a highly preventable risk factor. The present study investigates whether military operations abroad, as compared to deployment preparation, increase the risk of starting to smoke, enhance tobacco dependence and moderator variables can be identified on smoking behavior. METHOD: The study was conducted at 2 mechanized infantry battalions with N=264 soldiers. The task force completed a deployment in Afghanistan, the control group performed a deployment training. Assessments of tobacco dependence, posttraumatic symptoms, depression and stress were done before (t1) and after (t3) deployment. In addition, one assessment was done at mid-point (t2) during deployment and during the pre-deployment training, respectively. RESULTS: The prevalence rate of smoking soldiers was 56,4%. 51,1% (n=135) of all examined soldiers smoked more than 20 cigarettes per day. The results show a significant increase of tobacco dependence in the task force from t1 to t3 (p=0,040) as compared to the control group. For both groups, there was no increase in starting to smoke during the period of investigation (chi2<1; n. s.). Moderator variables on smoking were not found, but there was a significant increase in posttraumatic stress symptoms in the deployed group (p=0,006). CONCLUSIONS: Perhaps the increase in tobacco dependence in the experimental group can be attributed to the specific burdens of deployment. If high smoking rates were to be found also in other branches of the armed services, effective smoking cessation programs should be offered more widely. PMID- 26492393 TI - Cancer Specific Long Noncoding RNAs Show Differential Expression Patterns and Competing Endogenous RNA Potential in Hepatocellular Carcinoma. AB - Long noncoding RNAs (lncRNAs) regulate gene expression by acting with microRNAs (miRNAs). However, the roles of cancer specific lncRNA and its related competitive endogenous RNAs (ceRNA) network in hepatocellular cell carcinoma (HCC) are not fully understood. The lncRNA profiles in 372 HCC patients, including 372 tumor and 48 adjacent non-tumor liver tissues, from The Cancer Genome Atlas (TCGA) and NCBI GEO omnibus (GSE65485) were analyzed. Cancer specific lncRNAs (or HCC related lncRNAs) were identified and correlated with clinical features. Based on bioinformatics generated from miRcode, starBase, and miRTarBase, we constructed an lncRNA-miRNA-mRNA network (ceRNA network) in HCC. We found 177 cancer specific lncRNAs in HCC (fold change >= 1.5, P < 0.01), 41 of them were also discriminatively expressed with gender, race, tumor grade, AJCC tumor stage, and AJCC TNM staging system. Six lncRNAs (CECR7, LINC00346, MAPKAPK5 AS1, LOC338651, FLJ90757, and LOC283663) were found to be significantly associated with overall survival (OS, log-rank P < 0.05). Collectively, our results showed the lncRNA expression patterns and a complex ceRNA network in HCC, and identified a complex cancer specific ceRNA network, which includes 14 lncRNAs and 17 miRNAs in HCC. PMID- 26492394 TI - Control of Immune Response to Allogeneic Embryonic Stem Cells by CD3 Antibody Mediated Operational Tolerance Induction. AB - Implantation of embryonic stem cells (ESCs) and their differentiated derivatives into allogeneic hosts triggers an immune response that represents a hurdle to clinical application. We established in autoimmunity and in transplantation that CD3 antibody therapy induces a state of immune tolerance. Promising results have been obtained with CD3 antibodies in the clinic. In this study, we tested whether this strategy can prolong the survival of undifferentiated ESCs and their differentiated derivatives in histoincompatible hosts. Recipients of either mouse ESC-derived embryoid bodies (EBs) or cardiac progenitors received a single short tolerogenic regimen of CD3 antibody. In immunocompetent mice, allogeneic EBs and cardiac progenitors were rejected within 20-25 days. Recipients treated with CD3 antibody showed long-term survival of implanted cardiac progenitors or EBs. In due course, EBs became teratomas, the growth of which was self-limited. Regulatory CD4(+)FoxP3(+) T cells and signaling through the PD1/PDL1 pathway played key roles in the CD3 antibody therapeutic effect. Gene profiling emphasized the importance of TGF-beta and the inhibitory T cell coreceptor Tim3 to the observed effect. These results demonstrate that CD3 antibody administered alone promotes prolonged survival of allogeneic ESC derivatives and thus could prove useful for enhancing cell engraftment in the absence of chronic immunosuppression. PMID- 26492395 TI - Source term estimation and the isotopic ratio of radioactive material released from the WIPP repository in New Mexico, USA. AB - After almost 15 years of operations, the Waste Isolation Pilot Plant (WIPP) had one of its waste drums breach underground as a result of a runaway chemical reaction in the waste it contained. This incident occurred on February 14, 2014. Moderate levels of radioactivity were released into the underground air. A small portion of the contaminated underground air also escaped to the surface through the ventilation system and was detected approximately 1 km away from the facility. According to the source term estimation, the actual amount of radioactivity released from the WIPP site was less than 1.5 mCi. The highest activity detected on the surface was 115.2 MUBq/m(3) for (241)Am and 10.2 MUBq/m(3) for (239+240)Pu at a sampling station located 91 m away from the underground air exhaust point and 81.4 MUBq/m(3) of (241)Am and 5.8 MUBq/m(3) of (239+240)Pu at a monitoring station located approximately 1 km northwest of the WIPP facility. The dominant radionuclides released were americium and plutonium, in a ratio that matches the content of the breached drum. Air monitoring across the WIPP site intensified following the first reports of radiation detection underground to determine the extent of impact to WIPP personnel, the public, and the environment. In this paper, the early stage monitoring data collected by an independent monitoring program conducted by the Carlsbad Environmental Monitoring & Research Center (CEMRC) and an oversight monitoring program conducted by the WIPP's management and operating contractor, the Nuclear Waste Partnership (NWP) LLC were utilized to estimate the actual amount of radioactivity released from the WIPP underground. The Am and Pu isotope ratios were measured and used to support the hypothesis that the release came from one drum identified as having breached that represents a specific waste stream with this radionuclide ratio in its inventory. This failed drum underwent a heat and gas producing reaction that overpowered its vent and lifted its lid to allow release of waste into the underground air. PMID- 26492396 TI - Effects of soil water content on the external exposure of fauna to radioactive isotopes. AB - Within a recent model intercomparison about radiological risk assessment for contaminated wetlands, the influence of soil saturation conditions on external dose rates was evidenced. This issue joined concerns of assessors regarding the choice of the soil moisture value to input in radiological assessment tools such as the ERICA Tool. Does it really influence the assessment results and how? This question was investigated under IAEA's Modelling and Data for Radiological Impacts Assessments (MODARIA) programme via 42 scenarios for which the soil water content varied from 0 (dry soil) to 100% (saturated soil), in combination with other parameters that may influence the values of the external dose conversion coefficients (DCCs) calculated for terrestrial organisms exposed in soil. A set of alpha, beta, and gamma emitters was selected in order to cover the range of possible emission energies. The values of their external DCCs varied generally within a factor 1 to 1.5 with the soil water content, excepted for beta emitters that appeared more sensitive (DCCs within a factor of about 3). This may be of importance for some specific cases or for upper tiers of radiological assessments, when refinement is required. But for the general purpose of screening assessment of radiological impact on fauna and flora, current approaches regarding the soil water content are relevant. PMID- 26492397 TI - Pre- and post-accident (129)I and (137)Cs levels, and (129)I/(137)Cs ratios in soil near the Fukushima Dai-ichi Nuclear Power Plant, Japan. AB - To evaluate the deposition density and extent of subsurface infiltration of (129)I and (137)Cs in the restricted area that was highly contaminated by the accident of Fukushima Dai-ichi Nuclear Power Plant, cumulative inventories of (129)I and (137)Cs, concentrations of (129)I and (137)Cs, and (129)I/(137)Cs ratio in 30-cm-long soil columns were compared with pre-accident levels from the same area. The cores were collected before and after the accident from locations of S-1 (4 km west of FDNPP) and S-2 (8 km west of FDNPP). Deposition densities of (129)I and (137)Cs in the soil following the accident were 0.90-2.33 Bq m(-2) and 0.80-4.04 MBq m(-2), respectively, which were 14-39 and 320-510 times larger than the pre-accident levels of (129)I (59.3-63.3 mBq m(-2)) and (137)Cs (2.51-7.88 kBq m(-2)), respectively. Approximately 90% of accident-derived (129)I and (137)Cs deposited in the 30-cm soil cores was concentrated in the surface layer from 0 to 44-95 kg m(-2) of mass depth (0-4.3-6.2 cm depth) and from 0 to 16-25 kg m(-2) of mass depth (0-1.0-3.1 cm depth), respectively. The relaxation mass depths (h0) of 10.8-11.2 kg m(-2) for (129)I estimated in the previous study were larger than those of 8.1-10.6 kg m(-2) for (137)Cs at both sites, owing to the larger infiltration depth of radioiodine mainly by the gravitational water penetration in the surface soil in our study sites. Approximately 7-9% of the accident-derived (129)I was present in the lower layer from 44 to 100 kg m(-2) (4.3-8.6 cm depth) at S-1, and from 95 to 160 kg m(-2) (6.2-10.2 cm depth) at S 2. Approximately 1% of (137)Cs seems to infiltrate deeper than (129)I in the lower layer at each site in contrast to the surface layer. PMID- 26492398 TI - Chronic pulmonary accumulation of iron oxide nanoparticles induced Th1-type immune response stimulating the function of antigen-presenting cells. AB - Although there is growing evidence that suggests that pulmonary exposure to nanoparticles causes adverse health effects by modulating immune system of the body, available information is very limited. In this study, we investigated immune response following chronic pulmonary accumulation of iron oxide nanoparticles (FeNPs, Fe2O3). FeNPs have a needle-like shape in suspension (101.3+/-4.2 nm). On day 90 after a single intratracheal instillation (0.5, 1, and 2 mg/kg), the FeNPs remained in the lung and particle-laden macrophages were clearly observed in the BAL fluid of the treated-mice. The number of total cells and proportions of neutrophils and lymphocytes significantly increased at 2 mg/kg dose, and the percentage of apoptotic cells and LDH release increased in a dose dependent manner. We also found that Th1-polarized inflammatory response was induced in the lung of the treated group accompanying the elevated secretion of chemokines, including GM-CSF, MCP-1, and MIP-1. Additionally, FeNPs enhanced the expression of antigen presentation-related proteins, including CD80, CD86, and MHC class II, on antigen-presenting cells in BAL fluid. Taken together, we suggest that chronic pulmonary accumulation of FeNPs may induce Th1-polarized immune response augmenting the function of antigen-presenting cells in the lung. PMID- 26492399 TI - Association of prenatal exposure to maternal smoking and postnatal exposure to household smoking with dental caries in 3-year-old Japanese children. AB - BACKGROUND: Epidemiological studies of the association between smoking exposure and dental caries are limited. OBJECTIVE: The purpose of this cross-sectional study was to examine the association between prenatal and postnatal secondhand smoke (SHS) exposure and the prevalence of dental caries in primary dentition in young Japanese children. METHODS: Study subjects were 6412 children aged 3 years. Information on exposure to maternal smoking during pregnancy and postnatal SHS exposure at home was collected via parent questionnaire. Children were classified as having dental caries if one or more primary teeth had decayed or had been filled. RESULTS: Compared with never smoking during pregnancy, maternal smoking in the first trimester of pregnancy was significantly associated with an increased prevalence of dental caries in children (adjusted odds ratio=1.37, 95% confidence interval: 1.03-1.80). Postnatal SHS exposure was also positively associated with dental caries, with a significant positive exposure-response relationship. Compared with children not exposed to prenatal maternal smoking or postnatal SHS at home, those exposed to both prenatal and postnatal smoking had higher odds of dental caries (adjusted odds ratio=1.62, 95% confidence interval: 1.23-2.11). CONCLUSION: Our findings suggest that maternal smoking during pregnancy and postnatal SHS exposure may be associated with an increased prevalence of dental caries in primary dentition. PMID- 26492400 TI - Long-term exposure to residential traffic noise and changes in body weight and waist circumference: A cohort study. AB - BACKGROUND: Traffic noise can act as a stressor and disturb sleep, and has been associated with cardiovascular disease. Recent studies suggest a possible association to metabolic outcomes and adiposity through biological mechanisms related to physiological stress and sleep disturbance. OBJECTIVES: We aimed to investigate the association between long-term residential traffic noise and changes in adiposity. MATERIALS AND METHODS: The study was based on 39,720 middle aged Danish men and women from a cohort, with information on weight and waist circumference at two points in time. Residential exposure to traffic noise was calculated for all participants' present and historical addresses using the Nordic prediction method. The associations between traffic noise and changes in adiposity measures after a mean follow-up of 5.3 years were analyzed by linear and logistic regression with adjustments for age, sex, socioeconomic position and lifestyle factors in three models with increasing adjustment. RESULTS: In linear models adjusted for sex, age, socioeconomic position and competing noise sources we found road traffic noise to be significantly associated with small gains in both weight and waist circumference. For example, time-weighted mean exposure 5 years preceding follow-up was associated with a yearly weight gain of 15.4 g (95% confidence interval (CI): 2.14; 28.7) and a yearly increase in waist circumference of 0.22 mm (95% CI: 0.018; 0.43) per 10dB. Similarly, in Poisson regression models we found an 10% increased risk for gaining more than 5 kg body weight during follow-up (95% CI: 1.04; 1.15) per 10 dB higher 5 years exposure preceding follow-up. Exposure to railway noise above 55 dB was associated with weight gain (39.9 g/year (95% CI: 10.2; 69.6)), but not with a significant change in waist circumference. We found baseline BMI (p<0.001) and waist circumference (p=0.001) to be significant effect modifiers for the association between road traffic noise and waist circumference, with gain in waist circumference only among the obese (BMI>=30) participants (1.20 mm/year (95% CI: 0.68; 1.72)) and participants with a large waist circumference (0.83 mm/year (95% CI: 0.42; 1.23)). CONCLUSION: The findings supports previous studies suggesting that traffic noise may be associated with development of adiposity. However, the potential effects are small and suggest an effect mainly among obese participants. PMID- 26492401 TI - Heavy metals in cigarettes for sale in Spain. AB - The aim of the present study was to determine the concentrations of eight metals (Al, Cd, Co, Cr, Mn, Ni, Pb, Sr) in 33 cigarette brands for sale in Spain. Samples were analysed by Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). Mean values obtained were 428 ug Al/g, 0.810 ug Cd/g, 0.558 ug Co/g, 1.442 ug Cr/g, 112.026 ug Mn/g, 2.238 ug Ni/g, 0.602 ug Pb/g and 82.206 ug Sr/g. Statistically significant differences were observed with respect to concentrations of Co (0.004), Cr (0.045), Mn (0.005) and Sr (0.005) between black and blond tobacco and between levels of Mn (0.027) among manufacturers. Considering a Cd inhalation rate of 10% and a Cd absorption rate of 50%, absorption of Cd for smokers of 30 cigarettes/day was estimated at 0.75 ug Cd/day. An inhalation rate of 2-6% and an absorption rate of 86% were considered for Pb, Pb absorption in smokers of 30 cigarettes/day was therefore 0.18-0.54 MUg/day. In view of the significant toxic effects of these metals, quantification and control of their concentrations in this drug are of the utmost importance. PMID- 26492403 TI - Job satisfaction in nursing: a concept analysis study. AB - AIM: This study aims to undertake a concept analysis of job satisfaction in the nursing profession. BACKGROUND: Around current global shortage of nurses, it is important to stabilize the nursing workforce. Nurses' job satisfaction has been found to be related to intention to leave. INTRODUCTION: In the nursing profession, there is a lack of evidence to support the attributes of nurses' job satisfaction. METHODS: Walker and Avant's approach of concept analysis was used. RESULTS: The main attributes of job satisfaction from this study are (1) fulfillment of desired needs within the work settings, (2) happiness or gratifying emotional responses towards working conditions, and (3) job value or equity. These attributes are influenced by antecedent conditions like demographic, emotional, work characteristics and environmental variables. Additionally, the consequences of nurses' job satisfaction have a significant impact on both nurses and patients. DISCUSSION: This study integrated both the content and process of motivational theories to generate the attributes of job satisfaction in nursing that overcome the limitation of the previous studies, which looked only at the definitions of nurses' job satisfaction based on content motivational theories. CONCLUSION AND IMPLICATIONS FOR NURSING AND HEALTH POLICY: The findings of this study can facilitate both nursing researchers to develop a cultural adaption instrument and policy makers to improve clinical nursing practice. This analysis provides nurse managers with a new perspective to deal with nurses' job satisfaction by taking into account all the attributes that influence it in the nursing field. PMID- 26492402 TI - Clinical impact of IMPORT HIGH trial (CRUK/06/003) on breast radiotherapy practices in the United Kingdom. AB - OBJECTIVE: IMPORT HIGH is a multicentre randomized UK trial testing dose escalated intensity-modulated radiotherapy (IMRT) after tumour excision in females with early breast cancer and higher than average local recurrence risk. A survey was carried out to investigate the impact of this trial on the adoption of advanced breast radiotherapy (RT) techniques in the UK. METHODS: A questionnaire was sent to all 26 IMPORT HIGH recruiting RT centres to determine whether the trial has influenced non-trial breast RT techniques in terms of volume delineation, dosimetry, treatment delivery and verification. In order to compare the clinical practice of breast RT between IMPORT HIGH and non-IMPORT HIGH centres, parts of the Royal College of Radiologists (RCR) breast RT audit result were used in this study. RESULTS: 26/26 participating centres completed the questionnaire. After joining the trial, the number of centres routinely using tumour bed clips to guide whole-breast RT rose from 5 (19%) to 21 (81%). 20/26 (77%) centres now contour target volumes and organs at risk (OARs) in some or all patients compared with 14 (54%) before the trial. 14/26 (54%) centres offer inverse-planned IMRT for selected non-trial patients with breast cancer, and 10/14 (71%) have adopted the IMPORT HIGH trial protocol for target volume and OARs dose constraints. Only 2/26 (8%) centres used clip information routinely for breast treatment verification prior to IMPORT HIGH, a minority that has since risen to 7/26 (27%). Data on 1386 patients was included from the RCR audit. This suggested that more cases from IMPORT HIGH centres had surgical clips implanted (83 vs 67%), were treated using CT guided planning with full three-dimensional dose compensation (100 vs 75%), and were treated with photon boost RT (30 vs 8%). CONCLUSION: The study suggests that participation in the IMPORT HIGH trial has played an important part in providing the guidance and support networks needed for the safe integration of advanced RT techniques, where appropriate, as a standard of care for breast cancer patients treated at participating cancer centres. ADVANCES IN KNOWLEDGE: We investigated the impact of the IMPORT HIGH trial on the adoption of advanced breast RT techniques in the UK and the trial has influenced non-trial breast RT techniques in terms of volume delineation, dosimetry, treatment delivery and verification. PMID- 26492404 TI - beta-Cell Function and Insulin Sensitivity in Normal Glucose-Tolerant Subjects Stratified by 1-Hour Plasma Glucose Values. AB - AIM: This study was designed to assess beta-cell function and insulin sensitivity indices among normal glucose tolerance (NGT) subjects stratified by 1-h plasma glucose (1hPG) values during an oral glucose tolerance test (OGTT). MATERIALS AND METHODS: One hundred sixty-six NGT subjects underwent a five-point OGTT, and glucose and insulin levels were estimated. We calculated the following indices: (a) beta-cell function (homeostasis assessment model-beta-cell function [HOMA beta] and Insulinogenic Index [IGI]) and (b) insulin sensitivity (homeostasis assessment model-insulin resistance [HOMA-IR], Matsuda Index, and Insulin Sensitivity Index [ISI]). RESULTS: NGT subgroups with elevated 1hPG values (i.e., 1hPG >=143 to <155 mg/dL and 1hPG >=155 mg/dL) did not differ from those with 1hPG <143 mg/dL by HOMA-beta (P = 0.236) but had significantly lower IGIs (367 +/ 239 vs. 257 +/- 243 vs. 246 +/- 239; P = 0.019). With respect to ISIs, HOMA-IR was not significantly different among the groups (P = 0.103). However, the Matsuda Index (11.2 +/- 5.0 vs. 7.4 +/- 4.8 vs. 5.5 +/- 4.9; P < 0.001) and ISI (0.015 +/- 0.010 vs. 0.012 +/- 0.006 vs. 0.011 +/- 0.011; P = 0.028) were significantly lower in subjects with elevated 1hPG values. CONCLUSIONS: NGT subjects with elevated 1hPG levels have alterations in beta-cell function and insulin sensitivity compared with those with normal 1hPG levels. PMID- 26492407 TI - Lanthanide ion and tetrathiafulvalene-based ligand as a "magic" couple toward luminescence, single molecule magnets, and magnetostructural correlations. AB - The synthesis of molecules featuring different properties is a perpetual challenge for the chemists' community. The coexistence and even more the synergy of those properties open new perspectives in the field of molecular devices and molecular electronics. In that sense, coordination chemistry contributed to the development of new functional molecules through, for instance, single-molecule magnets (SMMs) and light emitting molecules with potential applications in high capacity data storage and OLEDs, respectively. The appealing combination of both electronic properties into one single object may offer the possibility to have magnetized luminescent entities at nanometric scale. To that end, lanthanides seem to be one of the key ingredients since their peculiar electronic structures endow them with specific magnetic and luminescence properties. Indeed, lanthanides cover a wide range of emission wavelengths, from infrared to UV, which add up to a large variety of magnetic behaviors, from the fully isotropic spin (e.g., Gd(III)) to highly anisotropic magnetic moments (e.g., Dy(III)). In lanthanide complexes, ligands play a fundamental role because on one hand they govern the orientation of the magnetic moment of anisotropic lanthanides and on the other hand they can sensitize efficiently the luminescence. The design of appropriate organic ligands to elaborate such chemical objects with the desired property appears to be essential but remains a perpetual challenge. In this Account, we describe the design of lanthanide-based complexes that emit light, behave as SMMs, or combine both properties. We have paid peculiar attention to the design of ligands based on the tetrathiafulvalene (TTF) moiety. TTF and its derivatives are well-known chemical entities, stable at different oxidation states, and employed mainly in the synthesis of molecular conductors and superconductors. In addition to their redox properties, TTF-based derivatives act as organic chromophores for the sensitization of visible and near-infrared (NIR) luminescence of lanthanides. The mechanism of sensitization involves either antenna effect (energy transfer from the excited state) or photoinduced electron transfer. TTF-based ligands act also as structural agents in the conception of SMM in crystals. Such objects are obtained with the highly anisotropic Dy(III) ion in crystalline phase as well as in frozen solution with magnetic memory at helium-4 temperature (4 K). We highlight the influence of the magnetic dilution (both in amorphous solution and in diamagnetic crystalline matrix) and, particular case of dysprosium based SMMs, the effect of metal-centered isotope enrichment on the SMM properties. Our aim is not only to realize functional molecules but to rationalize both luminescence and magnetic properties on the basis of the structure of the molecules. These two properties are intimately intricate and governed by the electronic structure, which can be calculated and interpreted using modern quantum chemistry tools. PMID- 26492405 TI - Loss of a Conserved tRNA Anticodon Modification Perturbs Plant Immunity. AB - tRNA is the most highly modified class of RNA species, and modifications are found in tRNAs from all organisms that have been examined. Despite their vastly different chemical structures and their presence in different tRNAs, occurring in different locations in tRNA, the biosynthetic pathways of the majority of tRNA modifications include a methylation step(s). Recent discoveries have revealed unprecedented complexity in the modification patterns of tRNA, their regulation and function, suggesting that each modified nucleoside in tRNA may have its own specific function. However, in plants, our knowledge on the role of individual tRNA modifications and how they are regulated is very limited. In a genetic screen designed to identify factors regulating disease resistance and activation of defenses in Arabidopsis, we identified SUPPRESSOR OF CSB3 9 (SCS9). Our results reveal SCS9 encodes a tRNA methyltransferase that mediates the 2'-O ribose methylation of selected tRNA species in the anticodon loop. These SCS9 mediated tRNA modifications enhance during the course of infection with the bacterial pathogen Pseudomonas syringae DC3000, and lack of such tRNA modification, as observed in scs9 mutants, severely compromise plant immunity against the same pathogen without affecting the salicylic acid (SA) signaling pathway which regulates plant immune responses. Our results support a model that gives importance to the control of certain tRNA modifications for mounting an effective immune response in Arabidopsis, and therefore expands the repertoire of molecular components essential for an efficient disease resistance response. PMID- 26492406 TI - The Potential for a Blood Test for Scabies. AB - BACKGROUND: Scabies afflicts millions of people worldwide, but it is very difficult to diagnose by the usual skin scrape test, and a presumptive diagnosis is often made based on clinical signs such as rash and intense itch. A sensitive and specific blood test to detect scabies would allow a physician to quickly make a correct diagnosis. OBJECTIVE: Our objective was to profile the mite-specific antibodies present in the sera of patients with ordinary scabies. METHODS: Sera of 91 patients were screened for Ig, IgD, IgE, IgG and IgM antibodies to S. scabiei, as well as to the house dust mites Dermatophagoides farinae, D. pteronyssinus and Euroglyphus maynei. RESULTS: 45%, 27% and 2.2% of the patients had measurable amounts of mixed Ig, IgG and IgE that recognized scabies mite antigens. However, 73.6% of the scabies patients had serum IgM that recognized scabies proteins, and all except two of them also had IgM that recognized all of the three species of dust mites. No patient had serum antibody exclusively reactive to scabies mite antigens. CONCLUSIONS: Co-sensitization or cross reactivity between antigens from scabies and house dust mites confounds developing a blood test for scabies. PMID- 26492409 TI - Interplay of Zero-Field Splitting and Excited State Geometry Relaxation in fac Ir(ppy)3. AB - The lowest energy triplet state, T1, of organometallic complexes based on iridium(III) is of fundamental interest, as the behavior of molecules in this state determines the suitability of the complex for use in many applications, e.g., organic light-emitting diodes. Previous characterization of T1 in fac Ir(ppy)3 suggests that the trigonal symmetry of the complex is weakly broken in the excited state. Here we report relativistic time dependent density functional calculations of the zero-field splitting (ZFS) of fac-Ir(ppy)3 in the ground state (S0) and lowest energy triplet (T1) geometries and at intermediate geometries. We show that the energy scale of the geometry relaxation in the T1 state is large compared to the ZFS. Thus, the natural analysis of the ZFS and the radiative decay rates, based on the assumption that the structural distortion is a small perturbation, fails dramatically. In contrast, our calculations of these quantities are in good agreement with experiment. PMID- 26492411 TI - Bacteria Endosymbiont, Wolbachia, Promotes Parasitism of Parasitoid Wasp Asobara japonica. AB - Wolbachia is the most widespread endosymbiotic bacterium that manipulates reproduction of its arthropod hosts to enhance its own spread throughout host populations. Infection with Wolbachia causes complete parthenogenetic reproduction in many Hymenoptera, producing only female offspring. The mechanism of such reproductive manipulation by Wolbachia has been extensively studied. However, the effects of Wolbachia symbiosis on behavioral traits of the hosts are scarcely investigated. The parasitoid wasp Asobara japonica is an ideal insect to investigate this because symbiotic and aposymbiotic strains are available: Wolbachia-infected Tokyo (TK) and noninfected Iriomote (IR) strains originally collected on the main island and southwest islands of Japan, respectively. We compared the oviposition behaviors of the two strains and found that TK strain females parasitized Drosophila melanogaster larvae more actively than the IR strain, especially during the first two days after eclosion. Removing Wolbachia from the TK strain wasps by treatment with tetracycline or rifampicin decreased their parasitism activity to the level of the IR strain. Morphological and behavioral analyses of both strain wasps showed that Wolbachia endosymbionts do not affect development of the host female reproductive tract and eggs, but do enhance host-searching ability of female wasps. These results suggest the possibility that Wolbachia endosymbionts may promote their diffusion and persistence in the host A. japonica population not only at least partly by parthenogenesis but also by enhancement of oviposition frequency of the host females. PMID- 26492410 TI - Early High-Frequency Oscillatory Ventilation in Pediatric Acute Respiratory Failure. A Propensity Score Analysis. AB - RATIONALE: The use of high-frequency oscillatory ventilation (HFOV) for acute respiratory failure in children is prevalent despite the lack of efficacy data. OBJECTIVES: To compare the outcomes of patients with acute respiratory failure managed with HFOV within 24-48 hours of endotracheal intubation with those receiving conventional mechanical ventilation (CMV) and/or late HFOV. METHODS: This is a secondary analysis of data from the RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure) study, a prospective cluster randomized clinical trial conducted between 2009 and 2013 in 31 U.S. pediatric intensive care units. Propensity score analysis, including degree of hypoxia in the model, compared the duration of mechanical ventilation and mortality of patients treated with early HFOV matched with those treated with CMV/late HFOV. MEASUREMENTS AND MAIN RESULTS: Among 2,449 subjects enrolled in RESTORE, 353 patients (14%) were ever supported on HFOV, of which 210 (59%) had HFOV initiated within 24-48 hours of intubation. The propensity score model predicting the probability of receiving early HFOV included 1,064 patients (181 early HFOV vs. 883 CMV/late HFOV) with significant hypoxia (oxygenation index >= 8). The degree of hypoxia was the most significant contributor to the propensity score model. After adjusting for risk category, early HFOV use was associated with a longer duration of mechanical ventilation (hazard ratio, 0.75; 95% confidence interval, 0.64-0.89; P = 0.001) but not with mortality (odds ratio, 1.28; 95% confidence interval, 0.92-1.79; P = 0.15) compared with CMV/late HFOV. CONCLUSIONS: In adjusted models including important oxygenation variables, early HFOV was associated with a longer duration of mechanical ventilation. These analyses make supporting the current approach to HFOV less convincing. PMID- 26492412 TI - "You're Really Gonna Kick Us All Out?" Sustaining Safe Spaces for Community-Based HIV Prevention and Control among Black Men Who Have Sex with Men. AB - Black men who have sex with men (BMSM) experience among the highest rates of HIV infection in the United States. We conducted a community-based ethnography in New York City to identify the structural and environmental factors that influence BMSMs vulnerability to HIV and their engagement with HIV prevention services. Methods included participant observation at community-based organizations (CBOs) in New York City, in-depth interviews with 31 BMSM, and 17 key informant interviews. Our conceptual framework shows how creating and sustaining safe spaces could be a critical environmental approach to reduce vulnerability to HIV among BMSM. Participant observation, in-depth and key informant interviews revealed that fear and mistrust characterized men's relation to social and public institutions, such as churches, schools, and the police. This fear and mistrust created HIV vulnerability among the BMSM in our sample by challenging engagement with services. Our findings suggest that to be successful, HIV prevention efforts must address these structural and environmental vulnerabilities. Among the CBOs that we studied, "safe spaces" emerged as an important tool for addressing these environmental vulnerabilities. CBOs used safe spaces to provide social support, to address stigma, to prepare men for the workforce, and to foster a sense of community among BMSM. In addition, safe spaces were used for HIV and STI testing and treatment campaigns. Our ethnographic findings suggest that safe spaces represent a promising but so far under-utilized part of HIV prevention infrastructure. Safe spaces seem integral to high impact comprehensive HIV prevention efforts, and may be considered more appropriately as part of HIV capacity-building rather than being nested within program-specific funding structures. PMID- 26492413 TI - Influence of Substrates on the Surface Characteristics and Membrane Proteome of Fibrobacter succinogenes S85. AB - Although Fibrobacter succinogenes S85 is one of the most proficient cellulose degrading bacteria among all mesophilic organisms in the rumen of herbivores, the molecular mechanism behind cellulose degradation by this bacterium is not fully elucidated. Previous studies have indicated that cell surface proteins might play a role in adhesion to and subsequent degradation of cellulose in this bacterium. It has also been suggested that cellulose degradation machinery on the surface may be selectively expressed in response to the presence of cellulose. Based on the genome sequence, several models of cellulose degradation have been suggested. The aim of this study is to evaluate the role of the cell envelope proteins in adhesion to cellulose and to gain a better understanding of the subsequent cellulose degradation mechanism in this bacterium. Comparative analysis of the surface (exposed outer membrane) chemistry of the cells grown in glucose, acid swollen cellulose and microcrystalline cellulose using physico-chemical characterisation techniques such as electrophoretic mobility analysis, microbial adhesion to hydrocarbons assay and Fourier transform infra-red spectroscopy, suggest that adhesion to cellulose is a consequence of an increase in protein display and a concomitant reduction in the cell surface polysaccharides in the presence of cellulose. In order to gain further understanding of the molecular mechanism of cellulose degradation in this bacterium, the cell envelope associated proteins were enriched using affinity purification and identified by tandem mass spectrometry. In total, 185 cell envelope-associated proteins were confidently identified. Of these, 25 proteins are predicted to be involved in cellulose adhesion and degradation, and 43 proteins are involved in solute transport and energy generation. Our results supports the model that cellulose degradation in F. succinogenes occurs at the outer membrane with active transport of cellodextrins across for further metabolism of cellodextrins to glucose in the periplasmic space and inner cytoplasmic membrane. PMID- 26492415 TI - Pulmonary Arterial Hypertension-Specific Drug Therapy in COPD Patients with Severe Pulmonary Hypertension and Mild-to-Moderate Airflow Limitation. AB - BACKGROUND: Patients with severe pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD) present a poor outcome. Specific PH treatment could improve the clinical and hemodynamic status of these patients but may worsen arterial blood gases. OBJECTIVES: Our study retrospectively included 28 patients with severe precapillary PH (mean pulmonary arterial pressure >35 mm Hg) associated with mild-to-moderate COPD [forced expiratory volume in 1 s (FEV1) >50% predicted]. All patients underwent specific pulmonary arterial hypertension (PAH) treatment as mono-, bi- or triple therapy. METHODS: Our single-center study was conducted based on retrospective data of 537 right heart catheterizations (RHCs) performed on patients with COPD from January 2004 to June 2014. An echocardiography, comprehensive blood tests, pulmonary function tests, and a high resolution computed tomography were performed before the RHCs. All patients underwent RHC with a Swan-Ganz catheter. RESULTS: Compared to baseline, patients treated with specific PAH drugs showed a significant increase in cardiac index at long term (2.5 +/- 0.7 liters/min/m2 at baseline vs. 3.2 +/- 0.6 liters/min/m2 at 6/12 months; p = 0.003) as well as a decrease in pulmonary vascular resistance in the long term (8.4 +/- 4.2 Wood units at baseline vs. 5 +/- 1.7 Wood units at 6/12 months; p = 0.008). There was a slight decrease in arterial oxygen tension (PaO2) after 3 months of treatment (-2.4 +/- 7.21 mm Hg; p = 0.066). During a median follow-up of 3 years, 12 patients (42.8%) died (including all causes of death). CONCLUSIONS: This preliminary report suggests that the use of specific PH therapy in severe PH associated with mild-to-moderate COPD can improve pulmonary hemodynamic parameters, with worsening of PaO2, which had no clinical significance and did not lead to specific PAH therapy withdrawal in any patient. PMID- 26492416 TI - Anabaena sp. DyP-type peroxidase is a tetramer consisting of two asymmetric dimers. AB - DyP-type peroxidases are a newly discovered family of heme peroxidases distributed from prokaryotes to eukaryotes. Recently, using a structure-based sequence alignment, we proposed the new classes, P, I and V, as substitutes for classes A, B, C, and D [Arch Biochem Biophys 2015;574:49-55]. Although many class V enzymes from eukaryotes have been characterized, only two from prokaryotes have been reported. Here, we show the crystal structure of one of these two enzymes, Anabaena sp. DyP-type peroxidase (AnaPX). AnaPX is tetramer formed from Cys224 Cys224 disulfide-linked dimers. The tetramer of wild-type AnaPX was stable at all salt concentrations tested. In contrast, the C224A mutant showed salt concentration-dependent oligomeric states: in 600 mM NaCl, it maintained a tetrameric structure, whereas in the absence of salt, it dissociated into monomers, leading to a reduction in thermostability. Although the tetramer exhibits non-crystallographic, 2-fold symmetry in the asymmetric unit, two subunits forming the Cys224-Cys224 disulfide-linked dimer are related by 165 degrees rotation. This asymmetry creates an opening to cavities facing the inside of the tetramer, providing a pathway for hydrogen peroxide access. Finally, a phylogenetic analysis using structure-based sequence alignments showed that class V enzymes from prokaryotes, including AnaPX, are phylogenetically closely related to class V enzymes from eukaryotes. PMID- 26492414 TI - Application of the pMHC Array to Characterise Tumour Antigen Specific T Cell Populations in Leukaemia Patients at Disease Diagnosis. AB - Immunotherapy treatments for cancer are becoming increasingly successful, however to further improve our understanding of the T-cell recognition involved in effective responses and to encourage moves towards the development of personalised treatments for leukaemia immunotherapy, precise antigenic targets in individual patients have been identified. Cellular arrays using peptide-MHC (pMHC) tetramers allow the simultaneous detection of different antigen specific T cell populations naturally circulating in patients and normal donors. We have developed the pMHC array to detect CD8+ T-cell populations in leukaemia patients that recognise epitopes within viral antigens (cytomegalovirus (CMV) and influenza (Flu)) and leukaemia antigens (including Per Arnt Sim domain 1 (PASD1), MelanA, Wilms' Tumour (WT1) and tyrosinase). We show that the pMHC array is at least as sensitive as flow cytometry and has the potential to rapidly identify more than 40 specific T-cell populations in a small sample of T-cells (0.8-1.4 x 10(6)). Fourteen of the twenty-six acute myeloid leukaemia (AML) patients analysed had T cells that recognised tumour antigen epitopes, and eight of these recognised PASD1 epitopes. Other tumour epitopes recognised were MelanA (n = 3), tyrosinase (n = 3) and WT1(126-134) (n = 1). One of the seven acute lymphocytic leukaemia (ALL) patients analysed had T cells that recognised the MUC1(950-958) epitope. In the future the pMHC array may be used provide point of care T-cell analyses, predict patient response to conventional therapy and direct personalised immunotherapy for patients. PMID- 26492417 TI - Time for Chocolate: Current Understanding and New Perspectives on Cacao Witches' Broom Disease Research. PMID- 26492418 TI - Outcomes in emergency general surgery following the introduction of a consultant led unit. AB - BACKGROUND: Patients presenting with emergency surgical conditions place significant demands on healthcare services globally. The need to improve emergency surgical care has led to establishment of consultant-led emergency surgery units. The aim of this study was to determine the effect of a changed model of service on outcomes. METHODS: A retrospective observational study of all consecutive emergency general surgical admissions in 2009-2012 was performed. A 2 year time frame before and after the establishment of the emergency general surgery (EGS) service was used to determine the number of admissions and operations, emergency department and hospital length of stay, as well as complication rates. RESULTS: The study included 7233 acute admissions. The EGS service managed 4468 patients (61.6 per cent increase) and performed 1804 operations (41.0 per cent increase). The most common diagnoses during the EGS period included acute appendicitis (532, 11.9 per cent), biliary disease (361, 8.1 per cent) and abdominal pain (561, 12.6 per cent). Appendicectomy (536, 29.7 per cent), cholecystectomy (239, 13.2 per cent) and laparotomy (226, 12.5 per cent) were the most commonly performed procedures. In the EGS period, time in the emergency department was reduced (from 8.0 to 6.0 h; P < 0.001), as was length of hospital stay (from 3.0 to 2.0 days; P < 0.001). The number of complications was reduced by 46.8 per cent, from 172 (6.2 per cent) to 147 (3.3 per cent) (P < 0.001), with a 53 per cent reduction in the number of deaths in the EGS period, from 29 (16.9 per cent) to seven (8 per cent) (P = 0.039). CONCLUSION: The establishment of a consultant-led emergency surgical service has been associated with improved provision of care, resulting in timely management and improved clinical outcomes. PMID- 26492419 TI - New recognition of the natural history and growth pattern of hepatic hemangioma in adults. AB - AIM: Surgical indications for hepatic hemangiomas are still not clearly defined due to limited data on their natural history. This study aimed to investigate the natural history and growth pattern of hepatic hemangiomas in adults. METHODS: From April 2010 to March 2013, adult patients with hepatic hemangioma who had no prior treatment were enrolled. A routine follow up was performed to observe the natural history of the lesions and their tendency to cause complications. RESULTS: A total of 236 patients were enrolled in the study. The median size of hemangiomas was 4.5 cm (range, 0.6-19.2). During a median follow-up period of 48 months (range, 3-266), 61.0% patients had hemangiomas that increased in size, 23.7% patients had stable lesions and 8.5% patients had hemangiomas that decreased in size. The peak growth period of hemangiomas was in patients of less than 30 years of age (0.46 +/- 0.41 cm/year) and the growth rate decreased significantly after 50 years of age (0.21 +/- 0.40 cm/year). Hemangiomas of less than 2 cm had the lowest growth rate (0.16 +/- 0.42 cm/year). The peak growth rate of hemangioma size was 8-10 cm (0.80 +/- 0.62 cm/year), then decreased rapidly to 0.47 +/- 0.91 cm/year while the hemangiomas were of more than 10 cm. Only nine patients had severe symptoms caused by hemangioma. No patients presented with hemangioma-related complications. CONCLUSION: The majority of hepatic hemangiomas have the tendency to increase in size but rarely cause complications. All the hemangiomas can be safely managed by observation, and surgery is only considered for patients with severe complications. PMID- 26492420 TI - Meconium-Associated Umbilical Vascular Myonecrosis: Correlations with Adverse Outcome and Placental Pathology. AB - Intrauterine passage of meconium is common, occurring in approximately 10-15% of term births. Uncommonly, long-standing meconium exposure is associated with umbilical vascular myonecrosis, but few studies have evaluated specific clinical and pathologic features. This is a retrospective study of 481 term placentas: 139 with meconium-associated myonecrosis, 139 with meconium in fetal membranes, only 62 with meconium in the cord without myonecrosis, and 139 controls without meconium. We studied clinical factors, including clinical evidence of meconium discharge, fetal distress, APGAR scores, intrauterine growth restriction (IUGR), and intrauterine fetal demise (IUFD), and histologic factors, including acute chorioamnionitis, umbilical cord complications, uteroplacental malperfusion, fetal thrombosis, chorangiosis, and fetal nucleated red blood cells. Meconium myonecrosis was significantly associated with clinical meconium, fetal distress, IUGR, IUFD, acute chorioamnionitis, cord complications, fetal thrombosis, chorangiosis, and nucleated red blood cells when compared to controls (P < 0.05). Compared to cases with meconium in the membranes only, clinical meconium, fetal distress, IUGR, chorioamnionitis, thrombosis, chorangiosis, and nucleated red blood cells remained significant. Compared to cases with meconium in the cord without myonecrosis, only chorioamnionitis retained significance. In conclusion, myonecrosis was associated with adverse clinical outcome and placental lesions associated with hypoxia. Chorioamnionitis was significantly more common in all meconium groups compared to controls. As myonecrosis is an important lesion, a clinical history of meconium should trigger a meticulous search for meconium and specifically myonecrosis. PMID- 26492421 TI - Solution-Processable Organic Molecule for High-Performance Organic Solar Cells with Low Acceptor Content. AB - A new planar D2-A-D1-A-D2 structured organic molecule with bithienyl benzodithiophene (BDT) as central donor unit D1 and fluorine-substituted benzothiadiazole (BTF) as acceptor unit and alkyl-dithiophene as end group and donor unit D2, BDT-BTF, was designed and synthesized for the application as donor material in organic solar cells (OSCs). BDT-BTF shows a broad absorption in visible region, suitable highest occupied molecular orbital energy level of -5.20 eV, and high hole mobility of 1.07 * 10(-2) cm(2)/(V s), benefitted from its high coplanarity and strong crystallinity. The OSCs based on BDT-BTF as donor (D) and PC71BM as acceptor (A) at a D/A weight ratio of 3:1 without any extra treatment exhibit high photovoltaic performance with Voc of 0.85 V, Jsc of 10.48 mA/cm(2), FF of 0.66, and PCE of 5.88%. The morphological study by transmission electron microscopy reveals that the blend of BDT-BTF and PC71BM (3:1, w/w) possesses an appropriate interpenetrating D/A network for the exciton separation and charge carrier transport, which agrees well with the good device performance. The optimized D/A weight ratio of 3:1 is the lowest acceptor content in the active layer reported so far for the high-performance OSCs, and the organic molecules with the molecular structure like BDT-BTF could be promising high-performance donor materials in solution-processable OSCs. PMID- 26492422 TI - Distribution and health risk assessment of organochlorine pesticides (OCPs) residue in edible cattle tissues from northeastern part of Egypt: High accumulation level of OCPs in tongue. AB - Food consumption is an important route of human exposure to organochlorine pesticides (OCPs). In order to assess the potential human health risks associated with OCPs, edible cattle tissues (liver, kidney and tongue) were collected from three slaughter houses in Mansoura, Zagazig and Ismailia cities, Egypt. Levels of 22 OCPs such as hexachlorocyclohexanes (HCHs), dichlorodiphenyltrichloroethanes (DDTs), aldrin, dieldrin and endrin (Drins), chlordanes (CHLs), heptachlors (HPTs) and hexachlorobenzene (HCB) residues were investigated. Among the investigated OCPs, HCHs represented the most dominant group with high proportions of gamma-HCH isomer (53-91% of total HCHs). Mansoura city had the highest OCPs contamination load ranged from 0.1 to 2827 ng g(-1) lw (lipid weight). Surprisingly, tongue samples collected from Mansoura showed the highest concentration of HCHs (448 ng g(-1) lw) in comparison to liver (152 ng g(-1) lw) and kidney (266 ng g(-1) lw). Generally, contamination pattern of OCPs was in the order of HCHs > Drins > CHLs > DDTs ? HCB and HPTs. Estimated daily intakes (EDIs) through dietary consumption of cattle tissues were lower than the recommended acceptable daily intakes (ADIs) established by FAO/WHO. However, the hazard ratios (HRs) based on cancer risk were greater than 1.0 for HCHs based on the average and 95th centile concentrations, indicating carcinogenic effects to consumers through cattle tissues consumption. PMID- 26492423 TI - Investigation of fixed wavelength fluorescence results for biliary metabolites of polycyclic aromatic hydrocarbons formed in Atlantic cod (Gadus morhua). AB - Fixed wavelength fluorescence (FF) and synchronous fluorescence scanning (SFS) of fish bile are commonly used methods to analyze for exposure to polycyclic aromatic hydrocarbons (PAHs) from petrogenic and pyrogenic sources. A range of conjugated oxidation products from petrogenic PAHs are normally accumulated in the bile. Therefore their detection is important. In the present study, phenanthrene and naphthalene metabolites, formed in vivo in Atlantic cod (Gadus morhua), were used to study the response of these compounds in both FF and SFS analyses. The selected synthetic metabolites were (-)-(1R,2R)-1,2 dihydrophenanthrene-1,2-diol and (-)-(1R,2R)-1,2-dihydronaphthalene-1,2-diol. The study findings showed that the recommended excitation and emission wavelengths for FF analysis do not comprise the maximum emission wavelengths for these metabolites, providing an incorrect estimation of the PAH exposure. A method developed in our laboratory for the synthesis of (-)-(1R,2R)-1,2 dihydrophenanthrene-1,2-diol is also described. PMID- 26492424 TI - Crabs tell the difference--Relating trace metal content with land use and landscape attributes. AB - Heavy metal concentration in a given locality depends upon its natural characteristics and level of anthropogenic pressure. Volcanic sites have a different heavy metal footprint from agriculture soils and both differ from urban centres. Different animal species absorb heavy metals differently according to their feeding behaviour and physiology. Depending on the capability to accumulate heavy metals, some species can be used in biomonitoring programs for the identification of disturbed areas. Crabs are included in these species and known to accumulate heavy metals. The present study investigates the potential of Pachygrapsus marmoratus (Fabricius, 1787), a small crab abundant in the Azores intertidal, as an indicator of the presence of heavy metals in Azorean coastal environments, comparing hydrothermal vent locations, urban centres and locations adjacent to agricultural activity. Specimens were collected in the same period and had their hepatopancreas removed, dried and analysed for heavy metals. Results revealed differences in concentration of the studied elements between all sampling sites, each one revealing a distinct heavy metal content. Fe, Cu, Mn, Zn and Cd are the metals responsible for separating the various sites. The concentration levels of the heavy metals recorded in the present study reflect the environmental available metals where the organisms live. This, associated to the large availability of P. marmoratus specimens in the Azores, and to the fact that these animals are easy to capture and handle, suggests this species as a potential bioindicator for heavy metal concentration in Azorean coastal areas, both humanized and naturally disturbed. PMID- 26492425 TI - Estimating the use of antibiotics for humans across China. AB - The present study aimed to propose a method to estimate the spatially resolved dataset for human-use antibiotics, which are highly needed in exposure models dealing with regions of various environmental characteristics. In this study, a regression model describing the relationship between the use of antibiotics and a set of socio-economic determinants was developed. It has been demonstrated that economic status (expressed using per capita gross domestic production) dominates the antibiotic use at least in China. Linear regression analysis was used to build the model, resulting in high goodness-of-fit, R(2) (>0.75). Internal and external validations along with residue plot indicated that the model was robust and predictive. The model was successfully applied to allocate the use of antibiotics in China in 2011 at national-, provincial-, prefectural-, and county level, which are comparable to that back-calculated from the available data of wastewater analysis in some cities. Antibiotic uses were higher in East China than other regions and it was found that uses of total antibiotics vary among Chinese counties on four orders of magnitude (0.186-1645 t antibiotics per year per county). Also management practice could be worked out according to our exploration of the impact transition of social-economic factors on antibiotic uses. To our knowledge, this is the first endeavor to explore this economic dominated relationship for estimating spatially resolved use map of antibiotics in China. PMID- 26492426 TI - Discrimination of hexabromocyclododecane from new polymeric brominated flame retardant in polystyrene foam by nuclear magnetic resonance. AB - Hexabromocyclododecane (HBCDD) is a brominated flame retardant (BFR) and major additive to polystyrene foam thermal insulation that has recently been listed as a persistent organic pollutant by the Stockholm Convention. During a 2013/2014 field analytical survey, we measured HBCDD content ranging from 0.2 to 2.4% by weight in 98 polystyrene samples. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses indicated that expandable (EPS) and extruded (XPS) polystyrene foams significantly differed in the alpha/gamma HBCDD isomer ratio, with a majority of alpha and gamma isomers in XPS and EPS, respectively. Interestingly, this technique indicated that some recent materials did not contain HBCDD, but demonstrated bromine content when analysed with X-ray fluorescence (XRF). Further investigation by Nuclear Magnetic Resonance (NMR) was able to discriminate between the BFRs present. In addition to confirming the absence or presence of HBCDD in polystyrene samples, high-field NMR spectroscopy provided evidence of the use of brominated butadiene styrene (BBS) as copolymer in the production of polystyrene. Use of this alternative flame retardant is expected to cause fewer health and environmental concerns. Our results highlight a trend towards the use of copolymerized BFRs as an alternative to HBCDD in polystyrene foam boards. In addition to providing a rapid NMR method to identify polymeric BFR, our analytical approach is a simple method to discriminate between flame-retardants in polystyrene foam insulating materials. PMID- 26492427 TI - Impact of runoff water from an experimental agricultural field applied with Vertimec(r) 18EC (abamectin) on the survival, growth and gill morphology of zebrafish juveniles. AB - Edge-of-field waterbodies in tropical agroecosystems have been reported to be especially prone to pesticide contamination through runoff resulting from intensive irrigation practices and tropical rainfall. In the present study, the effects of runoff from an experimental agricultural field applied with Vertimec((r)) 18EC (active ingredient: abamectin) on zebrafish were evaluated. To this end, the experimental field was applied with the Vertimec((r)) 18EC dose recommended for strawberry crop in Brazil, whereas another field was treated with water only to serve as control. No effects of runoff water from either plot were recorded on survival. Water from the treated field led to increased growth and gill alterations. In general, these alterations were of the first and second degree, including proliferation of cells between the secondary lamellae, dilation at the lamellar apex, detachment of the respiratory epithelium and aneurism. These results confirm the high toxic potential of Vertimec((r)) 18EC and provide evidence that environmental risks are likely to occur in areas subject to runoff containing this pesticide. PMID- 26492428 TI - Multisession Radiosurgery for Sellar and Parasellar Benign Meningiomas: Long-term Tumor Growth Control and Visual Outcome. AB - BACKGROUND: Concern about radiation-induced optic neuropathy (RION) has governed recent thinking about the role of radiation therapy in the treatment of meningiomas involving the anterior optic pathways. Despite this concern, during the last few years, the use of radiosurgery for such lesions has increased steadily. OBJECTIVE: To define both the tumor control rate and the risk of RION over a long-term follow-up period in a large cohort of patients treated with multisession radiosurgery. METHODS: The local control and visual outcome of 143 patients who underwent multisession radiosurgery (mRS) were evaluated. Neurological outcome was also analyzed. The data for the present study were obtained from a prospectively maintained database. RESULTS: The mean follow-up was 44 months (range, 12-113 months). All patients underwent mRS. The median prescription dose was 25 Gy delivered in 3 to 5 fractions. The prescription isodose, which typically encompassed at least 95% of the tumor, ranged from 65% to 86% (median, 80%). The mean tumor volume was 11.0 cm (range, 0.1-126.3 cm; median, 8 cm). The progression-free survival at 3, 5, and 8 years was 100%, 93%, and 90%, respectively. Compared with baseline, visual function improved in 36% of patients, whereas 7.4% experienced a worsening in visual function (5.1% excluding the patients with progressive disease). CONCLUSION: Good local control rate and a low risk of RION indicate that mRS is a safe and effective treatment option in cases of large meningiomas. PMID- 26492429 TI - Endovascular Treatment of Intracranial Aneurysms in Patients With Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND: Little is known about the outcome of endovascular treatment for intracranial aneurysms in patients with autosomal dominant polycystic kidney disease (ADPKD). OBJECTIVE: To present clinical outcomes in terms of safety, effectiveness, and renal functions to assess contrast-induced nephropathy in endovascular coil embolization for intracranial aneurysms in ADPKD patients. METHODS: Nineteen ADPKD patients (female:male, 15:4; mean age, 49.8 years; range, 20-67 years) had 26 aneurysms (mean size, 5.86 mm; range, 2.5-11.6 mm) and underwent 22 endovascular treatment sessions from 2001 to 2013. Four patients presented with ruptured aneurysms. Periprocedural complications, clinical outcomes with modified Rankin Scale scores, laboratory findings, and chronic kidney disease (CKD) stage before and after treatment were documented. Acute renal impairment was defined as serum creatinine (Cr) elevation by >= 0.5 mg/dL or 25% relative to baseline. RESULTS: Symptomatic periprocedural complications developed after 1 endovascular procedure (1 of 22, 4.5%), and good clinical outcomes (modified Rankin Scale scores, 0-1) were achieved in 90% of patients (17 of 19). Overall, acute renal impairment occurred in 9.1% of treatment sessions (2 of 22). Acute renal impairment developed in 25% of high-risk patients (baseline Cr > 2.0 mg/dL) and 33.3% of baseline CKD stage 5 sessions but in none of the low risk patients (baseline Cr <= 2.0 mg/dL) and in no CKD stage 1 to 4 sessions. CONCLUSION: With appropriate management, coil embolization may be safe and effective for intracranial aneurysms in ADPKD. There is a concern about contrast induced nephropathy in patients with CKD stage 5 or high serum Cr level (>2.0 mg/dL). PMID- 26492430 TI - Endovascular Management vs Intravenous Thrombolysis for Acute Stroke Secondary to Carotid Artery Dissection: Local Experience and Systematic Review. AB - BACKGROUND: Little is known regarding the endovascular management of acute ischemic stroke (AIS) related to carotid artery dissection (CAD). OBJECTIVE: To report our interventional experience in AIS from CAD and to compare it with conservative treatment of CAD with intravenous thrombolysis (IVT) via systematic review. METHODS: Retrospective analysis of consecutive high-grade steno-occlusive CAD with National Institutes of Health Stroke Scale (NIHSS) >5 and <=12 hours of last seen normal from 2 tertiary centers. A systematic review for studies on IVT in the setting of CAD via PubMed was performed for comparison. RESULTS: Of 1112 patients treated with endovascular interventions within the study period, 21 met the inclusion criteria. Mean age was 52.0 +/- 10.9 years, 76% were male, NIHSS was 17.4 +/- 5.8, 52% received IVT before intervention, and 90% had tandem occlusions. Mean time from last-known-normal to puncture was 4.8 +/- 2.1 hours and procedure length 1.8 +/- 1.0 hours. Stents were used in 52% of cases, and reperfusion (modified Treatment in Cerebral Ischemia 2b-3) achieved in 95%. No parenchymal hemorrhages were observed and 71% achieved good outcome (90-day modified Rankin Scale 0-2). The literature review identified 8 studies concerning thrombolysis in the CAD setting fitting inclusion criteria (n = 133). Our endovascular experience compared with the pooled IVT reports indicated that, despite presenting with higher NIHSS (17 vs 14; P = .04) and experiencing a longer time to definitive therapy (287 vs 162 minutes; P < .01), patients treated intra-arterially had similar rates of symptomatic cerebral/European Cooperative Acute Stroke Study-parenchymal hematoma 2 hemorrhage (0% vs 6%; P = .43) and good outcomes (71% vs 52%; P = .05). CONCLUSION: Our study provides evidence that the endovascular management of AIS in the setting of CAD is a feasible, safe, and promising strategy. PMID- 26492431 TI - Letter: Survival With Glioblastoma Multiforme and the Timing of Chemoradiation. PMID- 26492432 TI - In Reply: Survival With Glioblastoma Multiforme and the Timing of Chemoradiation. PMID- 26492433 TI - Management of polycythaemia vera: a critical review of current data. AB - Polycythaemia vera (PV) is a chronic blood cancer; its clinical features are dominated by myeloproliferation (erythrocytosis, often leucocytosis and/or thrombocytosis) and a tendency for thrombosis and transformation to myelofibrosis or acute myeloid leukaemia. In the past 10 years the pathophysiology of this condition has been defined as JAK/STAT pathway activation, almost always due to mutations in JAK2 exons 12 or 14 (JAK2 V617F). In the same time period our understanding of the optimal management of PV has expanded, most recently culminating in the approval of JAK inhibitors for the treatment of PV patients who are resistant or intolerant to therapy with hydroxycarbamide. It has also been demonstrated that life expectancy for many patients with PV is not normal, nor is their quality of life. We critically explore these findings and discuss their impact. In addition, we highlight persisting gaps in our current management strategy; for example, what is the optimal first line cytoreductive therapy and, indeed, which patients need cytoreductive drugs. PMID- 26492434 TI - The influence of landscape configuration and environment on population genetic structure in a sedentary passerine: insights from loci located in different genomic regions. AB - The study of the factors structuring genetic variation can help to infer the neutral and adaptive processes shaping the demographic and evolutionary trajectories of natural populations. Here, we analyse the role of isolation by distance (IBD), isolation by resistance (IBR, defined by landscape composition) and isolation by environment (IBE, estimated as habitat and elevation dissimilarity) in structuring genetic variation in 25 blue tit (Cyanistes caeruleus) populations. We typed 1385 individuals at 26 microsatellite loci classified into two groups by considering whether they are located into genomic regions that are actively (TL; 12 loci) or not (NTL; 14 loci) transcribed to RNA. Population genetic differentiation was mostly detected using the panel of NTL. Landscape genetic analyses showed a pattern of IBD for all loci and the panel of NTL, but genetic differentiation estimated at TL was only explained by IBR models considering high resistance for natural vegetation and low resistance for agricultural lands. Finally, the absence for IBE suggests a lack of divergent selection pressures associated with differences in habitat and elevation. Overall, our study shows that markers located in different genomic regions can yield contrasting inferences on landscape-level patterns of realized gene flow in natural populations. PMID- 26492435 TI - Effects of kinesiologic taping on epidermal-dermal distance, pain, edema and inflammation after experimentally induced soft tissue trauma. AB - PURPOSE: In sports medicine, the use of kinesiologic tape has recently gained popularity. Although widely used, there is no study examining the effects of kinesiologic tape on soft tissue after a contusion injury. The aim of this study was to examine the effects of kinesiologic taping on epidermal-dermal distance, edema, pain and inflammation after experimentally induced contusion injury. METHODS: Twelve adult female Wistar albino rats were divided into two groups: (1) 30 min group: n = 6, weight range: 182.0-199.4 g; and (2) 6 h group: n = 6, weight range: 186.9-200.8 g. After soft-tissue trauma, tape was applied to the right sides of each rat. In one group, tape was applied for 30 min while 6 h in the other. To assess the epidermal-dermal distance and edematous area, tissue sections were stained with hematoxylin and eosin and examined. Tissue sections were stained with nerve growth factor (NGF) and B-cell lymphoma 2 (Bcl-2) immunohistochemically to evaluate the effect of taping on pain and inflammation respectively. RESULTS: Epidermal-dermal distances were found to be significantly higher than controls' in both groups (p < 0.05). Notable decreases were seen in edematous areas in both groups (p < 0.05). NGF and Bcl-2 immune reactivity were decreased in all tape applied sides. CONCLUSIONS: After soft-tissue trauma, it was histologically shown that kinesiologic taping increases epidermal-dermal distance, and may reduce the sensation of pain, edema and inflammation. For better, faster and comfortable tissue healing with protection of soft-tissue integrity, kinesiologic taping may be a valuable treatment after contusion injury. However, these results should be supported by clinical studies. PMID- 26492437 TI - Integration of Ligand and Structure Based Approaches for CSAR-2014. AB - The prediction of binding poses and affinities is an area of active interest in computer-aided drug design (CADD). Given the documented limitations with either ligand or structure based approaches, we employed an integrated approach and developed a rapid protocol for binding mode and affinity predictions. This workflow was applied to the three protein targets of Community Structure-Activity Resource-2014 (CSAR-2014) exercise: Factor Xa (FXa), Spleen Tyrosine Kinase (SYK), and tRNA (guanine-N(1))-methyltransferase (TrmD). Our docking and scoring workflow incorporates compound clustering and ligand and protein structure based pharmacophore modeling, followed by local docking, minimization, and scoring. While the former part of the protocol ensures high-quality ligand alignments and mapping, the subsequent minimization and scoring provides the predicted binding modes and affinities. We made blind predictions of docking pose for 1, 5, and 14 ligands docked into 1, 2, and 12 crystal structures of FXa, SYK, and TrmD, respectively. The resulting 174 poses were compared with cocrystallized structures (1, 5, and 14 complexes) made available at the end of CSAR. Our predicted poses were related to the experimentally determined structures with a mean root-mean-square deviation value of 3.4 A. Further, we were able to classify high and low affinity ligands with the area under the curve values of 0.47, 0.60, and 0.69 for FXa, SYK, and TrmD, respectively, indicating the validity of our approach in at least two of the three systems. Detailed critical analysis of the results and CSAR methodology ranking procedures suggested that a straightforward application of our workflow has limitations, as some of the performance measures do not reflect the actual utility of pose and affinity predictions in the biological context of individual systems. PMID- 26492438 TI - Real-Time Evaluation of Live Cancer Cells by an in Situ Surface Plasmon Resonance and Electrochemical Study. AB - This work presents a new strategy of the combination of surface plasmon resonance (SPR) and electrochemical study for real-time evaluation of live cancer cells treated with daunorubicin (DNR) at the interface of the SPR chip and living cancer cells. The observations demonstrate that the SPR signal changes could be closely related to the morphology and mass changes of adsorbed cancer cells and the variation of the refractive index of the medium solution. The results of light microscopy images and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide studies also illustrate the release or desorption of HepG2 cancer cells, which were due to their apoptosis after treatment with DNR. It is evident that the extracellular concentration of DNR residue can be readily determined through electrochemical measurements. The decreases in the magnitudes of SPR signals were linearly related to cell survival rates, and the combination of SPR with electrochemical study could be utilized to evaluate the potential therapeutic efficiency of bioactive agents to cells. Thus, this label-free, real time SPR-electrochemical detection technique has great promise in bioanalysis or monitoring of relevant treatment processes in clinical applications. PMID- 26492439 TI - The value of occlusive balloons in the management of abnormal placentation: A retrospective study. AB - Abnormal placentation is a potential cause of maternal morbidity and mortality from massive postpartum bleeding. The objective of this study was to investigate the efficacy of occlusive balloons when used as an adjunct to surgery in reducing blood loss and transfusion requirements. A retrospective study of 42 patients was performed involving consecutive cases of abnormal placentation who delivered with either conventional surgery with preoperatively placed occlusive balloons or conventional surgery alone. No differences were noted between the control group and the group of patients who had occlusive balloons with regard to estimated blood loss (P = 0.767), packed red blood cells transfused (P = 0.799), amount of crystalloids infused (P = 0.435), total procedure duration (P = 0.076), and length of ICU stay (P = 0.315) or total hospital stay (P = 0.254). Prophylactic intravascular balloon catheters did not benefit women with abnormal placentation when compared with conventional surgery alone. PMID- 26492440 TI - Predictors for Pancreatic Cancer Diagnosis Following New-Onset Diabetes Mellitus. AB - OBJECTIVES: New-onset diabetes mellitus (NODM) in adults is often an early manifestation of pancreatic cancer (PaCa), but the incidence of PaCa in this cohort is rather low. We evaluated whether combining other patient factors such as age, smoking history, the absence of obesity, the presence of chronic pancreatitis (CP), and gallstone disease can result in a more enriched cohort. METHODS: After a washout period of 2 years to exclude pre-existing PaCa or DM, 507,378 non-diabetic patients in the veterans' administration healthcare system were identified. Patients <40 years (n=54,465) and those with PaCa diagnosed before the diagnosis of diabetes (n=22) were excluded. A total of 452,804 veterans were followed for development of DM or PaCa. RESULTS: 73,811 patients (16.3%) developed NODM during the follow-up period. One hundred and eighty-three NODM patients (0.25%) were diagnosed with PaCa within 3 years. In comparison, 434 of 378,993 remaining patients (0.11%) developed PaCa in 3 years following inclusion into the study [relative risk (RR)=2.27, 95% confidence intervals (CI) 1.96, 2.63; P<0.0001]. The risk of PaCa diagnosis was higher among patients who were non-obese (RR=1.51), were >=65 years old (RR=2.01), were heavy smokers (RR=1.55), and had a history of CP (RR=4.72) or gallstone disease (RR=2.02). Using a combination of these risk factors in NODM patients resulted in up to 0.72% three-year risk of PaCa but captured only 17% of patients with PaCa. CONCLUSIONS: Based on our findings, the likelihood of PaCa in adults with NODM even after adjusting for other potential risk factors for PaCa including age, body mass index, smoking, gallstones, and CP is probably not high enough to recommend routine evaluation for all these patients for underlying PaCa. PMID- 26492441 TI - Ruthenium-Porphyrin-Catalyzed [4 + 2] Cycloaddition of alpha,beta-Unsaturated Imines and Aldehydes. AB - A new efficient synthetic route to unsymmetrically substituted dihydropyridine scaffolds via dehydrative [4 + 2] cycloaddition of N-tosylated alpha,beta unsaturated imines with aldehydes has been developed. This transformation is enabled by (i) the remarkable catalytic ability of the cationic Ru(IV) porphyrin complex to activate both the imino and carbonyl groups and (ii) the hydrophobic nature of the porphyrin ligand, which helps realize robust Lewis acidity in the dehydrative cycloaddition. PMID- 26492442 TI - Relationships between thrill seeking, speeding attitudes, and driving violations among a sample of motorsports spectators and drivers. AB - BACKGROUND: Motor racing includes high speed driving and risky maneuvers and can result in negative outcomes for both spectators and drivers. Interest in motorsports is also associated with risky driving attitudes and behaviors on public roads as well as with individual difference variables, such as sensation seeking. However, whether the links between motorsports involvement and risky driving tendencies differ for spectators and drivers has remained mainly unexamined. The aim of this study was to investigate the relationships between thrill seeking, attitudes toward speeding, and self-reported driving violations among a sample of motorsports spectators and drivers. METHOD: A web-based survey was conducted and sampled 408 members and visitors of car club and racing websites in Ontario, Canada. The questionnaire included measures of (i) motorsports involvement, (ii) thrill seeking (Driver Thrill Seeking Scale), (iii) attitudes (Attitudes toward Speed Limits on Roadways and Competitive Attitudes toward Driving Scale); (iv) self-reported driving violations (adapted from Driver Behaviour Questionnaire), and (v) background variables. Path analysis was performed to test the relationships among the variables. RESULTS: For both spectators and drivers, thrill seeking directly predicted driving violations; competitive attitudes toward driving further mediated this relationship. Attitudes toward speed limits, however, mediated the relationship between thrill seeking and violations only for drivers. DISCUSSION: We observed significant relationships among individual difference measures, motorsports involvement, speeding attitudes and violations that may inform road safety interventions, including differences in the relationships among thrill seeking, speeding attitudes, and violations for motorsports spectators and drivers. PMID- 26492443 TI - Factor V Leiden. AB - Factor V Leiden (FVLeiden ) is a common hereditary thrombophilia that causes activated protein C (APC) resistance. This review describes many of the most fascinating features of FVLeiden , including background features, mechanisms of hypercoagulability, the founder mutation concept, the "FVLeiden paradox," synergistic interaction with other thrombotic risk factors, the intertwined relationship between FVLeiden and APC resistance testing, and other, uncommon mutations implicated in causing APC resistance. In addition, there are several conditions where laboratory tests for APC resistance and FVLeiden are or can be discrepant, including lupus anticoagulants, anticoagulants such as direct thrombin inhibitors (dabigatran, argatroban, and bivalirudin) and rivaroxaban, as well as pseudohomozygous, pseudo-wildtype, liver transplant, and bone marrow transplant patients. The laboratory test error rate for FVLeiden is also presented. PMID- 26492444 TI - Use of oral contraceptives in three European countries: a population-based multi database study. AB - OBJECTIVES: The aim of the study was to assess the prevalence of oral contraceptive (OC) use, user characteristics and prescribing patterns by accessing health care databases of three European countries. METHODS: A retrospective study was performed from 2009 to 2010 in three general practice (GP) databases from the Netherlands, UK and Italy and in one database of linked pharmacy and hospitalisation data in the Netherlands. The presence of selected chronic conditions and diagnoses of diseases associated with OC use were assessed, as were switches, discontinuations and types of OC used during the study period. RESULTS: Among 2.16 million women aged 15 to 49 years, 16.0% were using an OC on 1 January 2010. The prevalence ranged from 19.7% in a Dutch database to 2.6% in the Italian database. During 2009 and 2010, mainly second generation progestogens were prescribed in the Netherlands (79.4% and 78.3% of users), both second- (57.9%) and third-generation progestogens (43.6%) were prescribed in the UK, and mainly third-generation progestogens in Italy (61.8%). Most switches were to third- or fourth-generation pills. The prevalence of chronic diseases tended to be higher among OC users, and the proportions of women with a history of disease associated with OC use tended to be lower than among non-users. CONCLUSIONS: Second-generation OCs were most frequently prescribed in the Netherlands. In the UK, and even more so in Italy, many women used third- or fourth-generation OCs. Preparation switches were mainly to third- or fourth generation OCs. Among OC users, a somewhat higher prevalence of chronic diseases was observed; however, information bias cannot be ruled out. PMID- 26492445 TI - Formamide-Free Genomic in situ Hybridization Allows Unambiguous Discrimination of Highly Similar Parental Genomes in Diploid Hybrids and Allopolyploids. AB - Polyploidy and hybridization play an important role in plant diversification and speciation. The application of genomic in situ hybridization (GISH) allows the identification of parental genomes in hybrids, thus elucidating their origins and allowing for analysis of their genomic evolution. The performance of GISH depends on the similarity of the parental genomes and on the age of hybrids. Here, we present the formamide-free GISH (ff-GISH) protocol applied to diploid and polyploid hybrids of monocots (Prospero, Hyacinthaceae) and dicots (Melampodium, Asteraceae) differing in similarity of the parental genomes and in chromosome and genome sizes. The efficiency of the new protocol is compared to the standard GISH protocol. As a result, ff-GISH allowed efficient labeling and discrimination of the parental chromosome sets in diploid and allopolyploid hybrids in Prospero autumnale species complex. In contrast, the standard GISH protocol failed to differentiate the parental genomes due to high levels of similar repetitive DNA. Likewise, an unambiguous identification of parental genomes in allotetraploid Melampodium nayaritense (Asteraceae) was possible after ff-GISH, whereas the standard GISH hybridization performance was suboptimal. The modified method is simple and non-toxic and allows the discrimination of very similar parental genomes in hybrids. This method lends itself to modifications and improvements and can also be used for FISH. PMID- 26492446 TI - Combination of STOP-Bang Score with Mallampati Score fails to improve specificity in the prediction of sleep-disordered breathing. AB - BACKGROUND: Sleep-disordered breathing (SDB) is closely associated with perioperative complications. STOP-Bang score was validated for preoperative screening of SDB. However, STOP-Bang Score lacks adequately high specificity. We aimed to improve it by combining it with the Mallampati Score. METHODS: The study included 347 patients, in which we assessed both STOP-Bang and Mallampati scores. Overnight oxygen saturation was measured to calculate ODI4%. We calculated the sensitivity and specificity for AHI and ODI4% of both scores separately and in combination. RESULTS: We found that STOP-Bang Score >=3 was present in 71%, ODI>=5/h (AHI >=5/h) in 42.6% (39.3%) and ODI>=15/h (AHI >=15/h) in 13.5% (17.8%). For ODI4%>=5/h (AHI >=5/h) we observed in men a response rate for sensitivity and specificity of STOP-Bang of 94.5% and 17.1% (90.9% and 12.5%) and in women 66% and 51% (57.8% and 46.9%). For ODI4%>=15/h (AHI>=15/h) it was 92% and 12% (84.6% and 10.3%) and 93% and 49% (75% and 49.2%). For ODI4%>=5 (AHI>=5) sensitivity and specificity of Mallampati score were in men 38.4% and 78.6% (27.3% and 68.2%) and in women 25% and 82.7% (21.9% and 81.3%), for ODI>=15 (AHI >=15/h) 38.5% and 71.8% (26.9% and 69.2%) and 33.3% and 81.4% (17.9% and 79.6%). In combination, for ODI4%>=15/h, we found sensitivity in men to be 92.3% and in women 93.3%, specificity 10.3% and 41.4%. CONCLUSIONS: STOP-Bang Score combined with Mallampati Score fails to increase specificity. Low specificity should be considered when using both scores for preoperative screening of SDB. PMID- 26492447 TI - Nutrition in critically ill patients: where do we stand? AB - Both the optimal caloric intake and the best route of delivery of nutrition to critically ill patients fuel an intense debate. Recently, two large pragmatic, multicenter, controlled, randomized clinical trials evaluated these issues in large cohorts of patients. In the CALORIES Study, the authors compared the parenteral with the enteral route as the most effective way to deliver early (e.g. within 36 hours from admission) nutritional support in critically ill adults in 33 English ICUs (N.=2388). The primary endpoint, 30-day mortality (33.1% in the parenteral group and 34.2% in the enteral group), as well as the infection rate, were similar in both groups, while patients of the parenteral group experienced less hypoglycemia and vomiting than the enteral group. In the PermiT Study, 894 enterally fed patients from 7 ICUs were randomized to a restrictive strategy for non-protein calories (e.g. "permissive underfeeding" - 40% to 60% of energy expenditure) or to standard feeding (70 to 100% of energy expenditure) for up to 2 weeks. The primary endpoint (90-day mortality) was similar in both groups (27.2% in the permissive-underfeeding group and 28.9% in the standard-feeding group) without significant differences in feeding intolerance, diarrhea or ICU-acquired infections. We herein discuss how these studies should be interpreted with regard to the existing evidence and propose some practical suggestions for nutrition management in the critically ill patient. PMID- 26492448 TI - Incidence and laryngoscopic grade of adult patients with Mallampati class zero airway. PMID- 26492449 TI - Chemopreventive activity of grape juice concentrate (G8000TM) on rat colon carcinogenesis induced by azoxymethane. AB - Colorectal cancer is the third most common cancer worldwide in both sexes, with similar geographic patterns between genders. This neoplasm has good prognosis if the disease is diagnosed at early stages. The aim of this study was to evaluate the effect of red grape juice on the expression of COX-2 and Ki-67 expression following colon carcinogenesis induced by azoxymethane (AOM). Thirty-five rats were randomly distributed into seven groups (n=5 per group): G1: SHAM or negative control received only saline; G2 (positive control): animals received 15 mg/kg AOM; G3: animals received 1% red grape juice 2 weeks before the administration of AOM; G4: animals received 2% red grape juice 2 weeks before the administration of AOM; G5: animals received 1% red grape juice 4 weeks after the last administration of AOM; G6: animals received 2% red grape juice 4 weeks after the last administration of AOM; G7: animals received only 2% red grape juice. COX-2 mRNA expression was reduced in animals treated with 1% red grape juice before AOM induction or 2% red grape juice after AOM induction. COX-2 immunoexpression was also reduced to groups treated with red grape juice at 1% before and after AOM induction or 2% red grape juice after AOM induction. Decreased immunoexpression of Ki-67 positive cells was observed in animals treated with 1% grape juice before AOM-treated animals. Taken together, grape juice concentrate is able to exert some chemopreventive activity on rat colon carcinogenesis. PMID- 26492450 TI - Application of the yeast-based reporter gene bioassay for the assessment of estrogenic activity in cow's milk from Poland. AB - Milk contain compounds acting through the estrogen receptor signaling. The still open question whether such estrogens pose a risk for human health, encouraged us to measure the overall estrogenic activity of cow's milk in the in vitro yeast reporter bioassay. First, we assessed the ability of the bioassay to detect estrogens frequently detected in milk. The relative potencies of 16 compounds descended in the order: 17beta-estradiol (17beta-E2), 17alpha-ethinylestradiol, diethylstilbestrol, dienestrol, 17alpha-E2, estrone, zearalenone, estriol, equol, genistein, 17beta-E2 glucuronide, bisphenol A, apigenin, daidzein. Flavone, 4-n nonylphenol and 4-t-octylphenol shown no activity in the bioassay.The estrogenic activities of milk samples without hydrolysis were below the detection limit, whereas in 50% of the deconjugated samples they varied between 0.29 and 0.49 ng EEQ mL(-1). We also compared the estrogenic activity in raw cow's milk collected from rural and industrial locations in Poland. In our pilot study we did not observe statistically significant difference in estrogenic activities in milk collected from the two locations. We found that the daily intake of estrogens with milk may be higher than estrogen levels in human serum. Further studies are warranted to evaluate the significance of milk and dairy as a source of estrogens for humans. PMID- 26492451 TI - QSAR analyses of organophosphates for insecticidal activity and its in-silico validation using molecular docking study. AB - The present work was carried out to design and develop novel QSAR models using 2D QSAR and 3D-QSAR with CoMFA methodology for prediction of insecticidal activity of organophosphate (OP) molecules. The models were validated on an entirely different external dataset of in-house generated combinatorial library of OPs, by completely different computational approach of molecular docking against the target AChE protein of Musca domestica. The dock scores were observed to be in good correlation with 2D-QSAR and 3D-QSAR with CoMFA predicted activities and had the correlation coefficients (r(2)) of -0.62 and -0.63, respectively. The activities predicted by 2D-QSAR and 3D-QSAR with CoMFA were also observed to be highly correlated with r(2)=0.82. Also, the combinatorial library molecules were screened for toxicity in non-target organisms and degradability using USEPA-EPI Suite. The work was first step towards computer aided design and development of novel OP pesticide candidates with good insecticidal property but lower toxicity in non-targeted organisms and having biodegradation potential. PMID- 26492452 TI - Mycobacterium chelonae Eye Infections Associated with Humidifier Use in an Outpatient LASIK Clinic--Ohio, 2015. AB - Laser-assisted in situ keratomileusis (LASIK) eye surgery is increasingly common, with approximately 600,000 procedures performed each year in the United States. LASIK eye surgery is typically performed in an outpatient setting and involves the use of a machine-guided laser to reshape the lens of the eye to correct vision irregularities. Clinic A is an ambulatory surgery center that performs this procedure on 1 day each month. On February 5, 2015, the Toledo-Lucas County Health Department (TLCHD) in Ohio was notified of eye infections in two of the six patients who had undergone LASIK procedures at clinic A on January 9, 2015. The two patients experienced eye pain after the procedures and received diagnoses of infection with Mycobacterium chelonae, an environmental organism found in soil and water. PMID- 26492453 TI - Does Health Reform Change Femoral Neck Fracture Care? A Natural Experiment in the State of Massachusetts. AB - OBJECTIVES: To determine whether hospital processes and hospital quality associated with the care of femoral neck fractures were significantly altered by the implementation of healthcare reform in Massachusetts. DESIGN: Pre-post retrospective study. SETTING: Massachusetts Statewide Inpatient Dataset (SID). PATIENTS/PARTICIPANTS: Patients treated for femoral neck fracture (n = 23,485) in the periods prehealth (2003-06) and posthealth reform (2008-10). INTERVENTION: Differences in hospital processes for fracture care and quality measures were assessed for the periods before and after health reform. OUTCOME MEASUREMENTS: Differences in hospital processes for fracture care (type of surgical intervention, length of stay, and discharge disposition) and quality metrics [mortality, complications, re-operation, and failure to rescue (FTR)] in the periods before and after health reform were assessed using regression techniques to adjust for differences in case mix and the type of surgical intervention. RESULTS: There were no significant differences in the type of surgical intervention performed prereform and postreform (P = 0.27). After adjustment for case mix and surgical intervention, length of stay was significantly reduced {regression coefficient -0.07 [95% confidence interval (CI), -0.09 to -0.06]} as were the odds of FTR [odds ratio 0.73 (95% CI, 0.59-0.92)]. Discharges to skilled nursing facilities significantly increased in the postreform period [relative risk ratio 1.15 (95% CI, 1.03-1.30)]. Findings associated with FTR were driven by changes in the detection of surveillance sensitive complications. CONCLUSIONS: Health reform in Massachusetts led to no clinically meaningful differences in hospital processes for femoral neck fracture care. Although some differences in quality measures were noted, these cannot necessarily be attributed to health care reform. PMID- 26492454 TI - External Fixation Using a Locking Plate: A Reliable Way in Treating Distal Tibial Fractures. AB - The surgical treatment of distal tibial fractures is still challenging. The purpose of this study was to evaluate the clinical and radiographic results associated with the use of a precontoured distal femoral locking plate as an external fixator in treating distal tibial fractures. From August 2011 to October 2012, 28 patients with distal tibial fractures were consecutively enrolled in this study. There were 9 OTA 43.A1, 9 43.A2, and 10 43.A3, including 21 closed and 7 open fractures. The precontoured distal femoral locking plate was placed on the anteromedial aspect of the tibia as an external fixator. All patients were followed for an average of 16 months. The mean surgical duration was 38 (25-60) minutes. The mean time until fracture healing was 16.7 (12-24) weeks. At final follow-up, the mean American Orthopaedic Foot and Ankle Society score was 93 (88 100). There were no nonunions, deep infections, or implant fractures. Three patients had transient superficial pin site infection, but these did not change the clinical outcome. External fixation using a precontoured distal femoral locking plate is a reliable option in treating distal tibial fracture. The procedure is easy to perform, is less invasive, and the low profile plate can be concealed under stockings and can be conveniently removed. PMID- 26492456 TI - Are individual levels of pain anxiety related to negative interpretation bias? An examination using an ambiguous word priming task. AB - BACKGROUND: Cognitive processes like attentional and interpretation biases have been suggested to play a vital role in the onset and exacerbation of chronic pain. Research consistently supports the occurrence of interpretation bias (IB) in pain patients and healthy individuals high in pain anxiety. Nevertheless, studies on the indirect assessment of IB or the relation between IB and responses to pain are limited. The present studies examined the association between indirect assessed IB and pain anxiety, while Study 2 additionally examined IB as a mediator in the relation between pain anxiety and pain responses. METHOD: In Study 1 (N = 125) and Study 2 (N = 73), anxiety sensitivity, injury/illness sensitivity (IS) and pain catastrophizing were assessed with questionnaires. IB was indirectly derived from performance on an ambiguous word priming task. In Study 2, an experimental heat pain induction was used to assess pain responses (i.e. tolerance and subjective pain experience). RESULTS: Results showed a positive correlation between pain anxiety and IB, albeit that the strength of the observed associations differed between both studies. Furthermore, IB was inversely related to pain tolerance, and found to mediate the relation between IS and pain tolerance in Study 2. CONCLUSIONS: Current findings underscore the importance of interpretational processes in the context of physical health threat. Furthermore, the ambiguous word priming task is proposed as a suitable paradigm for further research on the indirect assessment of IB. Nevertheless, further research is warranted to deepen our understanding of IB and its contribution to the experience of (chronic) pain. PMID- 26492455 TI - Largest known Mesozoic multituberculate from Eurasia and implications for multituberculate evolution and biology. AB - A new multituberculate, Yubaartar zhongyuanensis gen. and sp. nov., is reported from the Upper Cretaceous of Luanchuan County, Henan Province, China. The holotype of the new taxon is a partial skeleton with nearly complete cranium and associated lower jaws with in situ dentitions. The new species is the southern most record of a Late Cretaceous multituberculate from outside of the Mongolian Plateau in Asia and represents the largest known Mesozoic multituberculate from Eurasia. The new specimen displays some intriguing features previously unknown in multituberculates, such as the first evidence of replacement of the ultimate upper premolar and a unique paleopathological case in Mesozoic mammals in which the animal with a severely broken right tibia could heal and survive in natural condition. The phylogenetic analysis based on craniodental characters places Yubaartar as the immediate outgroup of Taeniolabidoidea, a group consisting of a North American clade and an Asian clade. This relationship indicates at least a faunal interchange of multituberculates before the K-Pg transition. The new evidence further supports the hypothesis that disparity in dental complexity, which relates to animal diets, increased with generic richness and disparity in body size, and that an adaptive shift towards increased herbivory across the K-Pg transitional interval. PMID- 26492457 TI - Laparoscopic Total Gastrectomy in the Western Patient Population: Tips, Techniques, and Evidence-based Practice. AB - Gastric cancer is the second most common malignancy worldwide, and surgical resection is the only curative treatment. Traditionally, open total gastrectomy has been the procedure of choice for large and proximal carcinomas. Over the past decade, however, laparoscopic gastrectomy has emerged and an oncologically safe and feasible alternative to open surgery, and its use has become particularly widespread in Japan and Korea. Patients in the United States have important biological and anatomic distinctions from East Asian patients, and these become important factors when considering minimally invasive resection techniques. The goal of this paper is to describe the technique we have developed for laparoscopic total gastrectomy in our 10-year experience with a western patient population. PMID- 26492458 TI - Palliative Stent Insertion for Acute Malignant Colorectal Obstruction: Long-term Patency and Survival. AB - PURPOSE: To investigate the long-term outcome of palliative stent insertion for acute malignant colorectal obstruction. METHODS: From May 2009 to February 2015, consecutive patients with acute malignant colorectal obstruction underwent palliative stent insertion in our center. Technical success, clinical success, and long-term outcomes were analyzed retrospectively. RESULTS: A total of 45 patients with acute malignant colorectal obstruction underwent palliative stent insertion. Technical success was achieved in 42 of 45 patients. Clinical success was achieved in 41 of 42 patients. During a follow-up of 5 days to 25 months (mean, 6.9+/-4.5 mo), the cumulative 6- and 12-month patency rates were 88.6% and 72.7%, respectively. The cumulative 6- and 12-month survival rates were 60.1% and 14.3%, respectively. The independent predictor of prolonging survival was subsequent chemotherapy after stenting (P=0.017). CONCLUSION: Palliative colorectal stent insertion can provide a good long-term outcome in patients with malignant colorectal obstruction. PMID- 26492459 TI - Intergenerational transmission of the healthy immigrant effect (HIE) through birth weight: A systematic review and meta-analysis. AB - This review examines intergenerational differences in birth weight among children born to first-generation and second-generation immigrant mothers and the extent to which they vary by country of origin and receiving country. We searched MEDLINE, EMBASE, Web of Science, PubMed, and ProQuest from inception to October 2014 for articles that recorded the mean birth weight (in grams) or odds of low birth weight (LBW) of children born to immigrant mothers and one subsequent generation. Studies were analyzed descriptively and meta-analyzed using Review Manager 5.3 software. We identified 10 studies (8 retrospective cohort and 2 cross-sectional studies) including 158,843 first and second-generation immigrant women. The United States and the United Kingdom represented the receiving countries with the majority of immigrants originating from Mexico and South Asia. Six studies were meta-analyzed for mean birth weight and seven for low birth weight. Across all studies, there was found to be no statistically significant difference in mean birth weight between first and second-generation children. However, the odds of being LBW were 1.21 [95% CI, 1.15, 1.27] times greater among second-generation children. Second-generation children of Mexican descent in particular were at increased odds of LBW (OR = 1.47 [95% CI, 1.28, 1.69]). In the United States, second-generation children were at 34% higher odds of being LBW (OR = 1.34 [95% CI, 1.13, 1.58]) when compared to their first-generation counterparts. This effect was slightly smaller in the United Kingdom (OR = 1.18 [95% CI, 1.13, 1.23]). In conclusion, immigration to a new country may differentially influence low birth weight over generations, depending on the mother's nativity and the country she immigrates to. PMID- 26492460 TI - [Pulmonary embolism - legal significance and difficult diagnosis]. PMID- 26492461 TI - Reduced Baseline Sensitivity to Maraviroc Inhibition Among R5 HIV-1 Isolates From Individuals With Severe Immunodeficiency. PMID- 26492463 TI - A Convenient Synthesis of Hydroxytyrosol Monosulfate Metabolites. AB - The growing interest in the bioactivity of natural polyphenols and of their metabolites requires metabolites to be used in bioassays and as standards in research protocols. We report here on the synthesis of several hydroxytyrosol metabolite monosulfates achieved using a simplified protocol with improved yields. A synthetic solution based on avoidance of high temperature conditions during the synthesis and of low pressure conditions during purification has been established. Monosulfates of several phenolic compounds, namely, hydroxytyrosol, hydroxytyrosol acetate, homovanillyl alcohol, homovanillyl alcohol acetate, homovanillic acid, ferulic acid, and 3,4-dihydroxyphenylethanoic acid, were efficiently synthesized in 1-2 steps in good yield and isolated using simple procedures. The proposed protocol was shown to be relatively rapid, efficient, cheap, and widely applicable to a number of catechol scaffolds. PMID- 26492462 TI - Changes in Antibody Levels during and following an Episode of Acute Adenolymphangitis (ADL) among Lymphedema Patients in Leogane, Haiti. AB - INTRODUCTION: Episodes of acute adenolymphangitis (ADL) are often the first clinical sign of lymphatic filariasis (LF). They are often accompanied by swelling of the affected limb, inflammation, fever, and general malaise and lead to the progression of lymphedema. Although ADL episodes have been studied for a century or more, questions still remain as to their etiology. We quantified antibody levels to pathogens that potentially contribute to ADL episodes during and after an episode among lymphedema patients in Leogane, Haiti. We estimated the proportion of ADL episodes hypothesized to be attributed to specific pathogens. METHODS: We measured antibody levels to specific pathogens during and following an ADL episode among 41 lymphedema patients enrolled in a cohort study in Leogane, Haiti. We calculated the absolute and relative changes in antibody levels between the ADL and convalescent time points. We calculated the proportion of episodes that demonstrated a two-fold increase in antibody level for several bacterial, fungal, and filarial pathogens. RESULTS: Our results showed the greatest proportion of two-fold changes in antibody levels for the carbohydrate antigen Streptococcus group A, followed by IgG2 responses to a soluble filarial antigen (BpG2), Streptococcal Pyrogenic Exotoxin B, and an antigen for the fungal pathogen Candida. When comparing the median antibody level during the ADL episode to the median antibody level at the convalescent time point, only the antigens for Pseudomonas species (P-value = 0.0351) and Streptolysin O (P-value = 0.0074) showed a significant result. CONCLUSION: Although our results are limited by the lack of a control group and few antibody responses, they provide some evidence for infection with Streptococcus A as a potential contributing factor to ADL episodes. Our results add to the current evidence and illustrate the importance of determining the causal role of bacterial and fungal pathogens and immunological antifilarial response in ADL episodes. PMID- 26492464 TI - Switching Rho GTPase activation into effective antibacterial defenses requires the caspase-1/IL-1beta signaling axis. AB - The monitoring of the activation state of Rho GTPases has emerged as a potent innate immune mechanism for detecting pathogens. In the March issue of PLOS Pathogens, we show that the activation of Rho GTPases by the CNF1 toxin during E. coli-triggered bacteremia leads to a GR1(+)cell-mediated efficient bacterial clearing and improves host survival. Host alarm requires the Caspase-1/IL-1beta signaling axis. Furthermore, we discover that pathogenic bacteria have the capacity to block immune responses via the expression of the alpha-hemolysin pore forming toxin. In this commentary, we will comment on these findings and highlight the questions raised by this example of attack-defense mechanisms used alternatively by the pathogen and the host during blood infection. PMID- 26492465 TI - Measuring environmental sustainability in agriculture: A composite environmental impact index approach. AB - The present study develops a composite environmental impact index (CEII) to evaluate the extent of environmental degradation in agriculture after successfully validating its flexibility, applicability and relevance as a tool. The CEII tool is then applied to empirically measure the extent of environmental impacts of High Yield Variety (HYV) rice cultivation in three districts of north western Bangladesh for a single crop year (October, 2012-September, 2013). Results reveal that 27 to 69 per cent of the theoretical maximum level of environmental damage is created due to HYV rice cultivation with significant regional variations in the CEII scores, implying that policy interventions are required in environmentally critical areas in order to sustain agriculture in Bangladesh. PMID- 26492466 TI - Pre-operative sentinel lymph node localization in breast cancer with superparamagnetic iron oxide MRI: the SentiMAG Multicentre Trial imaging subprotocol. AB - OBJECTIVE: Sentinel lymph node biopsy (SLNB) with a superparamagnetic iron oxide (SPIO) tracer was shown to be non-inferior to the standard combined technique in the SentiMAG Multicentre Trial. The MRI subprotocol of this trial aimed to develop a magnetic alternative for pre-operative lymphoscintigraphy (LS). We evaluated the feasibility of using MRI following the administration of magnetic tracer for pre-operative localization of sentinel lymph nodes (SLNs) and its potential for non-invasive identification of lymph node (LN) metastases. METHODS: Patients with breast cancer scheduled to undergo SLNB were recruited for pre operative LS, single photon emission CT (SPECT)-CT and SPIO MRI. T1 weighted turbo spin echo and T2 weighted gradient echo sequences were used before and after interstitial injection of magnetic tracer into the breast. SLNs on MRI were defined as LNs with signal drop and direct lymphatic drainage from the injection site. LNs showing inhomogeneous SPIO uptake were classified as metastatic. During surgery, a handheld magnetometer was used for SLNB. Blue or radioactive nodes were also excised. The number of SLNs and MR assessment of metastatic involvement were compared with surgical and histological outcomes. RESULTS: 11 patients were recruited. SPIO MRI successfully identified SLNs in 10 of 11 patients vs 11 of 11 patients with LS/SPECT-CT. One patient had metastatic involvement of four LNs, and this was identified in one node on pre-operative MRI. CONCLUSION: SPIO MRI is a feasible technique for pre-operative localization of SLNs and, in combination with intraoperative use of a handheld magnetometer, provides an entirely radioisotope-free technique for SLNB. Further research is needed for the evaluation of MRI characterization of LN involvement using subcutaneous injection of magnetic tracer. ADVANCES IN KNOWLEDGE: This study is the first to demonstrate that an interstitially administered magnetic tracer can be used both for pre operative imaging and intraoperative SLNB, with equal performance to imaging and localization with radioisotopes. PMID- 26492467 TI - Gordon's model applied to nursing care of people with depression. AB - BACKGROUND: Psychiatric nurses should consider the patient's biological, psychological and social aspects. Marjory Gordon's Functional Health Pattern Model ensures a holistic approach for the patient. AIM: To examine the effectiveness of Gordon's Functional Health Pattern Model in reducing depressive symptoms, increasing self-efficacy, coping with depression and increasing hope in people with depression. DESIGN: A quasi-experimental two-group pre-test and post test design was adopted. METHODS: Data were collected from April 2013 to May 2014 from people with depression at the psychiatry clinic of a state hospital in Turkey; they were assigned to the intervention (n = 34) or control group (n = 34). The intervention group received nursing care according to Gordon's Functional Health Pattern Model and routine care, while the control group received routine care only. The Beck Depression Inventory, Beck Hopelessness Scale and Depression Coping Self-Efficacy Scale were used. RESULTS: The intervention group had significantly lower scores on the Beck Depression Inventory and Beck Hopelessness Scale at the post-test and 3-month follow-up; they had higher scores on the Depression Coping Self-Efficacy Scale at the 3 month follow-up when compared with the control group. LIMITATION: The study was conducted at only one psychiatry clinic. The intervention and control group patients were at the clinic at the same time and influenced each other. Moreover, because clinical routines were in progress during the study, the results cannot only be attributed to nursing interventions. DISCUSSION: Nursing models offer guidance for the care provided. Practices based on the models return more efficient and systematic caregiving results with fewer health problems. CONCLUSION: Gordon's Functional Health Pattern Model was effective in improving the health of people with depression and could be introduced as routine care with ongoing evaluation in psychiatric clinics. More research is needed to evaluate Gordon's Nursing Model effect on people with depression. Future studies could focus on the effects of this nursing model on people with other psychiatric disorders. IMPLICATIONS FOR NURSING AND HEALTH POLICY: This study highlighted that psychiatric nurses' role decreased depressive symptoms and hopelessness, and increased coping and self-efficacy in people with depression. PMID- 26492468 TI - Fluorescence biosensing strategy based on mercury ion-mediated DNA conformational switch and nicking enzyme-assisted cycling amplification for highly sensitive detection of carbamate pesticide. AB - Pesticides are of great importance in agricultural and biological fields, but pesticide residues may harm the environment and human health. A highly sensitive fluorescent biosensor for the detection of carbamate pesticide has been developed based on acetylcholinesterase (AChE)-catalyzed hydrolysis product triggered Hg(2+) release coupled with subsequent nicking enzyme-induced cleavage of a duplex DNA for cycling amplification. In this protocol, two DNA probes, an unmodified single-stranded helper DNA probe 1 (HP1) and a quencher-fluorophore probe (QFP) are ingeniously designed. HP1 can be folded into hairpin configuration through T-Hg(2+)-T base pair formation. QFP, labeled with FAM and BHQ1 at its two terminals, contains the recognition sequence and the cleavage site of the nicking enzyme. In the presence of carbamate pesticide, the activity of AChE is inhibited, and the amount of the product containing the thiol group generated by the hydrolysis reaction of acetylthiocholine chloride (ACh) decreases, resulting in the release of a low concentration of Hg(2+). The number of HP1 that can be selectively unfolded would be reduced and the subsequent nicking enzyme-assisted cleavage processes would be affected, resulting in decreased fluorescence signals. The fluorescence intensity further decreases with the increase of the pesticide concentration. Therefore, the pesticide content can be easily obtained by monitoring the fluorescence signal change, which is inversely proportional to the logarithm of the pesticide concentration. The detection limit of aldicarb, the model analyte, is 3.3 MUgL(-1), which is much lower than the Chinese National Standards or those previously reported. The as proposed method has also been applied to detect carbamate pesticide residues in fresh ginger and artificial lake water samples with satisfactory results, which demonstrates that the method has great potential for practical application in biological or food safety field. PMID- 26492469 TI - A dual amplification fluorescent strategy for sensitive detection of DNA methyltransferase activity based on strand displacement amplification and DNAzyme amplification. AB - DNA methyltransferase (MTase) plays a critical role in many biological processes and has been regarded as a predictive cancer biomarker and a therapeutic target in cancer treatment. Sensitive detection of DNA MTase activity is essential for early cancer diagnosis and therapeutics. Here, we developed a dual amplification fluorescent strategy for sensitive detection of DNA MTase activity based on strand displacement amplification (SDA) and DNAzyme amplification. A trifunctional double-stranded DNA (dsDNA) probe was designed including a methylation site for DNA MTase recognition, a complementary sequence of 8-17 DNAzyme for synthesizing DNAzyme, and a nicking site for nicking enzyme cleavage. Firstly, the trifunctional dsDNA probe was methylated by DNA MTase to form the methylated dsDNA. Subsequently, HpaII restriction endonuclease specifically cleaved the residue of unmethylated dsDNA. Next, under the action of polymerase and nicking enzyme, the methylared dsDNA initiated SDA, releasing numbers of 8-17 DNAzymes. Finally, the released 8-17 DNAzymes triggered DNAzyme amplification reaction to induce a significant fluorescence enhancement. This strategy could detect DNA MTase activity as low as 0.0082U/mL. Additionally, the strategy was successfully applied for evaluating the inhibitions of DNA MTase using two anticancer drugs, 5-azacytidine and 5-aza-2'-deoxycytidine. The results indicate the proposed strategy has a potential application in early cancer diagnosis and therapeutics. PMID- 26492471 TI - Nighttime Administration of Nicotine Improves Hepatic Glucose Metabolism via the Hypothalamic Orexin System in Mice. AB - Nicotine is known to affect the metabolism of glucose; however, the underlying mechanism remains unclear. Therefore, we here investigated whether nicotine promoted the central regulation of glucose metabolism, which is closely linked to the circadian system. The oral intake of nicotine in drinking water, which mainly occurred during the nighttime active period, enhanced daily hypothalamic prepro orexin gene expression and reduced hyperglycemia in type 2 diabetic db/db mice without affecting body weight, body fat content, and serum levels of insulin. Nicotine administered at the active period appears to be responsible for the effect on blood glucose, because nighttime but not daytime injections of nicotine lowered blood glucose levels in db/db mice. The chronic oral treatment with nicotine suppressed the mRNA levels of glucose-6-phosphatase, the rate-limiting enzyme of gluconeogenesis, in the liver of db/db and wild-type control mice. In the pyruvate tolerance test to evaluate hepatic gluconeogenic activity, the oral nicotine treatment moderately suppressed glucose elevations in normal mice and mice lacking dopamine receptors, whereas this effect was abolished in orexin deficient mice and hepatic parasympathectomized mice. Under high-fat diet conditions, the oral intake of nicotine lowered blood glucose levels at the daytime resting period in wild-type, but not orexin-deficient, mice. These results indicated that the chronic daily administration of nicotine suppressed hepatic gluconeogenesis via the hypothalamic orexin-parasympathetic nervous system. Thus, the results of the present study may provide an insight into novel chronotherapy for type 2 diabetes that targets the central cholinergic and orexinergic systems. PMID- 26492470 TI - Embryonic Poly(A)-Binding Protein (EPAB) Is Required for Granulosa Cell EGF Signaling and Cumulus Expansion in Female Mice. AB - Embryonic poly(A)-binding protein (EPAB) is the predominant poly(A)-binding protein in Xenopus, mouse, and human oocytes and early embryos before zygotic genome activation. EPAB is required for translational activation of maternally stored mRNAs in the oocyte and Epab(-/-) female mice are infertile due to impaired oocyte maturation, cumulus expansion, and ovulation. The aim of this study was to characterize the mechanism of follicular somatic cell dysfunction in Epab(-/-) mice. Using a coculture system of oocytectomized cumulus oophorus complexes (OOXs) with denuded oocytes, we found that when wild-type OOXs were cocultured with Epab(-/-) oocytes, or when Epab(-/-) OOXs were cocultured with WT oocytes, cumulus expansion failed to occur in response to epidermal growth factor (EGF). This finding suggests that oocytes and cumulus cells (CCs) from Epab(-/-) mice fail to send and receive the necessary signals required for cumulus expansion. The abnormalities in Epab(-/-) CCs are not due to lower expression of the oocyte-derived factors growth differentiation factor 9 or bone morphogenetic protein 15, because Epab(-/-) oocytes express these proteins at comparable levels with WT. Epab(-/-) granulosa cells (GCs) exhibit decreased levels of phosphorylated MEK1/2, ERK1/2, and p90 ribosomal S6 kinase in response to lutenizing hormone and EGF treatment, as well as decreased phosphorylation of the EGF receptor. In conclusion, EPAB, which is oocyte specific, is required for the ability of CCs and GCs to become responsive to LH and EGF signaling. These results emphasize the importance of oocyte-somatic communication for GC and CC function. PMID- 26492472 TI - Long-Acting PASylated Leptin Ameliorates Obesity by Promoting Satiety and Preventing Hypometabolism in Leptin-Deficient Lep(ob/ob) Mice. AB - Body weight loss of Lep(ob/ob) mice in response to leptin is larger than expected from the reduction in energy intake alone, suggesting a thermogenic action of unknown magnitude. We exploited the superior pharmacological properties of a novel long-acting leptin prepared via PASylation to study the contribution of its anorexigenic and thermogenic effects. PASylation, the genetic fusion of leptin with a conformationally disordered polypeptide comprising 600 Pro/Ala/Ser (PAS) residues, provides a superior way to increase the hydrodynamic volume of the fusion protein, thus retarding kidney filtration and extending plasma half-life. Here a single PAS(600)-leptin injection (300 pmol/g) resulted in a maximal weight reduction of 21% 6 days after application. The negative energy balance of 300 kJ/(4 d) was driven by a decrease in energy intake, whereas energy expenditure remained stable. Mice that were food restricted to the same extent showed an energy deficit of only 220 kJ/(4 d) owing to recurring torpor bouts. Therefore, the anorexigenic effect of PAS(600)-leptin contributes 75% to weight loss, whereas the thermogenic action accounts for 25% by preventing hypometabolism. In a second experiment, just four injections of PAS(600)-leptin (100 pmol/g) administered in 5- to 6-day intervals rectified the Lep(ob/ob) phenotype. In total, 16 nmol of PAS(600)-leptin per mouse triggered a weight loss of 43% within 20 days and normalized hypothermia and glucose homeostasis as well as hepatic steatosis. The beneficial properties of PAS(600)-leptin are substantiated by a comparison with previous studies in which approximately 400 nmol (~25-fold) unmodified leptin was mandatory to achieve similar improvements. PMID- 26492473 TI - Three-Dimensional Adipocyte Culture: The Next Frontier for Adipocyte Biology Discovery. PMID- 26492476 TI - Resolution of Inflammation by Resolvin D1 Is Essential for Peroxisome Proliferator-activated Receptor-gamma-mediated Analgesia during Postincisional Pain Development in Type 2 Diabetes. AB - BACKGROUND: The wound healing process following acute inflammation after surgery is impaired in diabetes. Altered macrophage functions are linked to delayed tissue repair and pain development in diabetes. Although peroxisome proliferator activated receptor (PPAR)-gamma agonists are used to treat diabetes, their postoperative analgesic effects in diabetes have not been evaluated. METHODS: The PPARgamma agonist rosiglitazone (rosi) was injected at the incision site of diabetic (db/db) mice with resolvin (Rv) D1, a lipid mediator involved in resolution of inflammation. Pain-related behavior, neutrophil infiltration, phagocytosis, and macrophage polarity were assessed for 7 days postoperatively. RESULTS: Rosiglitazone and RvD1 alleviated mechanical hyperalgesia in db/db (db) mice, whereas rosiglitazone alone did not alter mechanical thresholds on days 4 (db rosi + RvD1 vs. db rosi: 0.506 +/- 0.106 vs. 0.068 +/- 0.12) and 7 (0.529 +/- 0.184 vs. 0.153 +/- 0.183) after incision (n = 10 per group). In control m/m mice, the rosiglitazone-induced analgesic effects were reversed by knockdown with arachidonate 5-lipoxygenase small interfering RNA, but these were restored by addition of RvD1. In db/db mice treated with rosiglitazone and RvD1, local infiltration of neutrophils was markedly reduced, with an associated decrease in total TdT-mediated dUTP nick-end labeling cells. Acceleration of rosiglitazone induced phenotype conversion of infiltrated macrophages from M1 to M2 was impaired in db/db mice, but it was effectively restored by RvD1 in db/db wounds. CONCLUSIONS: In diabetes, exogenous administration of RvD1 is essential for PPARgamma-mediated analgesia during development of postincisional pain. Resolution of inflammation accelerated by RvD1 might promote PPARgamma-mediated macrophage polarization to the M2 phenotype. PMID- 26492475 TI - Minor Postoperative Increases of Creatinine Are Associated with Higher Mortality and Longer Hospital Length of Stay in Surgical Patients. AB - BACKGROUND: Surgical patients frequently experience postoperative increases in creatinine levels. The authors hypothesized that even small increases in postoperative creatinine levels are associated with adverse outcomes. METHODS: The authors examined the association of postoperative changes from preoperative baseline creatinine with all-cause in-hospital mortality and hospital length of stay (HLOS) in a retrospective analysis of surgical patients at a single tertiary care center between January 2006 and June 2012. RESULTS: The data of 39,369 surgical patients (noncardiac surgery n = 37,345; cardiac surgery n = 2,024) were analyzed. Acute kidney injury (AKI)-by definition of the Kidney Disease: Improving Global Outcome group-was associated with a five-fold higher mortality (odds ratio [OR], 4.8; 95% CI, 4.1 to 5.7; P < 0.001) and a longer HLOS of 5 days (P < 0.001) after adjusting for age, sex, comorbidities, congestive heart failure, preoperative hemoglobin, preoperative creatinine, exposure to radiocontrast agent, type of surgery, and surgical AKI risk factors. Importantly, even minor creatinine increases (Deltacreatinine 25 to 49% above baseline but < 0.3 mg/dl) not meeting AKI criteria were associated with a two-fold increased risk of death (OR, 1.7; 95% CI, 1.3 to 2.4; P < 0.001) and 2 days longer HLOS (P < 0.001). This was more pronounced in noncardiac surgery patients. Patients with minor creatinine increases had a five-fold risk of death (OR, 5.4; 95% CI, 1.5 to 20.3; P < 0.05) and a 3-day longer HLOS (P < 0.01) when undergoing noncardiac surgery. CONCLUSIONS: Even minor postoperative increases in creatinine levels are associated with adverse outcomes. These results emphasize the importance to find effective therapeutic approaches to prevent or treat even mild forms of postoperative kidney dysfunction to improve surgical outcomes. PMID- 26492477 TI - Oral Midodrine Hydrochloride for Prevention of Orthostatic Hypotension during Early Mobilization after Hip Arthroplasty: A Randomized, Double-blind, Placebo controlled Trial. AB - BACKGROUND: Early postoperative mobilization is essential for rapid recovery but may be impaired by orthostatic intolerance (OI) and orthostatic hypotension (OH), which are highly prevalent after major surgery. Pathogenic mechanisms include an insufficient postoperative vasopressor response. The oral alpha-1 agonist midodrine hydrochloride increases vascular resistance, and the authors hypothesized that midodrine would reduce the prevalence of OH during mobilization 6 h after total hip arthroplasty relative to placebo. METHODS: This double-blind, randomized trial allocated 120 patients 18 yr or older and scheduled for total hip arthroplasty under spinal anesthesia to either 5 mg midodrine hydrochloride or placebo orally 1 h before mobilization at 6 and 24 h postoperatively. The primary outcome was the prevalence of OH (decrease in systolic or diastolic arterial pressures of > 20 or 10 mmHg, respectively) during mobilization 6 h after surgery. Secondary outcomes were OI and hemodynamic responses to mobilization at 6 and 24 h. RESULTS: At 6 h, 14 (25%; 95% CI, 14 to 38%) versus 23 (39.7%; 95% CI, 27 to 53%) patients had OH in the midodrine and placebo group, respectively, relative risk 0.63 (0.36 to 1.10; P = 0.095), whereas OI was present in 15 (25.0%; 15 to 38%) versus 22 (37.3%; 25 to 51%) patients, relative risk 0.68 (0.39 to 1.18; P = 0.165). At 24 h, OI and OH prevalence did not differ between groups. CONCLUSIONS: Preemptive use of oral 5 mg midodrine did not significantly reduce the prevalence of OH during early postoperative mobilization compared with placebo. However, further studies on dose and timing are warranted since midodrine is effective in chronic OH conditions. PMID- 26492478 TI - Bedside Ultrasound: A Tool for Assessment of IV Functionality. PMID- 26492479 TI - Differential Efficacy of Ketamine in the Acute versus Chronic Stages of Complex Regional Pain Syndrome in Mice. AB - BACKGROUND: Complex regional pain syndrome (CRPS) is a painful, disabling, and often chronic condition, where many patients transition from an acute phase with prominent peripheral neurogenic inflammation to a chronic phase with evident central nervous system changes. Ketamine is a centrally acting agent believed to work through blockade of N-methyl-D- aspartate receptors and is being increasingly used for the treatment of refractory CRPS, although the basis for the drug's effects and efficacy at different stages of the syndrome remains unclear. METHODS: The authors used a mouse model of CRPS (n = 8 to 12/group) involving tibia fracture/cast immobilization to test the efficacy of ketamine (2 mg kg day; 7 days) or vehicle infusion during acute (3 weeks after fracture) and chronic (7 weeks after fracture) stages. RESULTS: Acute-phase fracture mice displayed increased limb temperature, edema, and nociceptive sensitization that were not reduced by ketamine. Fracture mice treated with ketamine during the chronic phase showed reduced nociceptive sensitization that persisted beyond completion of the infusion. During this chronic phase, ketamine also reduced latent nociceptive sensitization and improved motor function at 18 weeks after fracture. No side effects of the infusions were identified. These behavioral changes were associated with altered spinal astrocyte activation and expression of pain-related proteins including N-methyl-D-aspartate receptor 2b, Ca/calmodulin-dependent protein kinase II, and brain-derived neurotrophic factor. CONCLUSIONS: Collectively, these results demonstrate that ketamine is efficacious in the chronic, but not acute, stage of CRPS, suggesting that the centrally acting drug is relatively ineffective in early CRPS when peripheral mechanisms are more critical for supporting nociceptive sensitization. PMID- 26492480 TI - Resolvin D1: A New Path to Unleash the Analgesic Potential of Peroxisome Proliferator-activated Receptor-gamma for Postoperative Pain in Patients with Diabetes. PMID- 26492481 TI - Perioperative Mortality, 2010 to 2014: A Retrospective Cohort Study Using the National Anesthesia Clinical Outcomes Registry. AB - BACKGROUND: The National Anesthesia Clinical Outcomes Registry collects demographic and outcome data from anesthesia cases, with the goal of improving safety and quality across the specialty. The authors present a preliminary analysis of the National Anesthesia Clinical Outcomes Registry database focusing on the rates of and associations with perioperative mortality (within 48 h of anesthesia induction). METHODS: The authors retrospectively analyzed 2,948,842 cases performed between January 1, 2010, and May 31, 2014. Cases without procedure information and vaginal deliveries were excluded. Mortality and other outcomes were reported by the anesthesia provider. Hierarchical logistic regression was performed on cases with complete information for patient age group, sex, American Society of Anesthesiologists physical status, emergency case status, time of day, and surgery type, controlling for random effects within anesthesia practices. RESULTS: The final analysis included 2,866,141 cases and 944 deaths (crude mortality rate, 33 per 100,000). Increasing American Society of Anesthesiologists physical status, emergency case status, cases beginning between 4:00 PM and 6:59 AM, and patient age less than 1 yr or greater than or equal to 65 yr were independently associated with higher perioperative mortality. A post hoc subgroup analysis of 279,154 patients limited to 22 elective case types, post hoc models incorporating either more granular estimate of surgical risk or work relative value units, and a post hoc propensity score-matched cohort confirmed the association with time of day. CONCLUSIONS: Several factors were associated with increased perioperative mortality. A case start time after 4:00 PM was associated with an adjusted odds ratio of 1.64 (95% CI, 1.22 to 2.21) for perioperative death, which suggests a potentially modifiable target for perioperative risk reduction. Limitations of this study include nonstandardized mortality reporting and limited ability to adjust for missing data. PMID- 26492482 TI - Properties of Schottky Barrier Diodes on (In(x)Ga(1-x))2O3 for 0.01 <= x <= 0.85 Determined by a Combinatorial Approach. AB - We investigated properties of an (In(x)Ga(1-x))2O3 thin film with laterally varying cation composition that was realized by a large-area offset pulsed laser deposition approach. Within a two inch diameter thin film, the composition varies between 0.01 <= x <= 0.85, and three crystallographic phases (cubic, hexagonal, and monoclinic) were identified. We observed a correlation between characteristic parameters of Schottky barrier diodes fabricated on the thin film and its chemical and structural material properties. The highest Schottky barriers and rectification of the diodes were found for low indium contents. The thermal stability of the diodes is also best for Ga-rich parts of the sample. Conversely, the series resistance is lowest for large In content. Overall, the (In(x)Ga(1 x))2O3 alloy is well-suited for potential applications such as solar-blind photodetectors with a tunable absorption edge. PMID- 26492484 TI - Cochrane Reviews on Deworming and the Right to a Healthy, Worm-Free Life. PMID- 26492485 TI - Remarkably Intense Emission from Ruthenium(II) Complexes with Multiple Borane Centers. AB - The electrochemical, spectroscopic, and phophysical properties of a series of Ru(II) complexes having a triarylborane-appended 2,2'-bipyridine (bpy) ligand(s) (RuBbpys: [Ru(Bbpy)n(bpy)(3-n)](2+) (B1n) and [Ru(B2bpy)n(bpy)(3-n)](2+) (B2n), B = (dimesityl)boryldurylethynyl group(s) at the 4- or 4,4'-position(s) in bpy, n = 1-3) are described. In the excited states of the complexes, the intramolecular charge transfer transitions between the pi-orbital of the aryl group and the vacant p-orbital on the boron atom (pi(aryl)-p(B) CT) synergistically interact with the metal-to-ligand charge transfer (MLCT) transitions. The molar absorption coefficient of the MLCT band (epsilon(MLCT)) of the complex increased with increasing n, and B23 showed extremely intense absorption with epsilon(MLCT) = 5.6 * 10(4) M(-1) cm(-1) at 488 nm. Furthermore, B23 showed the highest emission quantum yield (0.43) among those of the polypyridine Ru(II) complexes hitherto reported. As one of the interesting results, we report that the radiative rate constant of B2n shows the correlation with epsilon(MLCT). The effects of the synergistic MLCT/pi(aryl)-p(B) CT interactions on the spectroscopic and photophysical characteristics of RuBbpys are discussed in detail. PMID- 26492483 TI - Modulation of Ambient Temperature-Dependent Flowering in Arabidopsis thaliana by Natural Variation of FLOWERING LOCUS M. AB - Plants integrate seasonal cues such as temperature and day length to optimally adjust their flowering time to the environment. Compared to the control of flowering before and after winter by the vernalization and day length pathways, mechanisms that delay or promote flowering during a transient cool or warm period, especially during spring, are less well understood. Due to global warming, understanding this ambient temperature pathway has gained increasing importance. In Arabidopsis thaliana, FLOWERING LOCUS M (FLM) is a critical flowering regulator of the ambient temperature pathway. FLM is alternatively spliced in a temperature-dependent manner and the two predominant splice variants, FLM-beta and FLM-delta, can repress and activate flowering in the genetic background of the A. thaliana reference accession Columbia-0. The relevance of this regulatory mechanism for the environmental adaptation across the entire range of the species is, however, unknown. Here, we identify insertion polymorphisms in the first intron of FLM as causative for accelerated flowering in many natural A. thaliana accessions, especially in cool (15 degrees C) temperatures. We present evidence for a potential adaptive role of this structural variation and link it specifically to changes in the abundance of FLM beta. Our results may allow predicting flowering in response to ambient temperatures in the Brassicaceae. PMID- 26492487 TI - Comorbidities and inhibitors in adult patients with haemophilia: issues, costs and management strategies. AB - Along with greater life expectancy in patients with haemophilia has been an increase in associated haemophilia-related (arthropathy, osteoporosis, viral infections) and age-related (cardiovascular disease, renal disease, cancer and others) comorbidities, many of which are only just emerging as the population ages. At present, experience in managing these comorbidities is limited. As the demographic shift continues, haemophilia care centres can expect to encounter more patients with greater levels of complexity. In the absence of evidence-based information to guide the management of adult patients with haemophilia, it is important that the scientific position be reviewed on a regular basis. To this end, several topics relevant to the clinical management of adult patients with haemophilia were examined in a symposium entitled Comorbidities and inhibitors in adult patients with haemophilia: issues, costs and management strategies held on 11 February 2015 in Helsinki, Finland, in conjunction with the 8th Annual Congress of the European Association for Haemophilia and Allied Disorders. This article is a summary of that event. PMID- 26492486 TI - Development of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis. AB - RATIONALE: Cystic fibrosis (CF) is characterized by early structural lung disease caused by pulmonary infections. The nasopharynx of infants is a major ecological reservoir of potential respiratory pathogens. OBJECTIVES: To investigate the development of nasopharyngeal microbiota profiles in infants with CF compared with those of healthy control subjects during the first 6 months of life. METHODS: We conducted a prospective cohort study, from the time of diagnosis onward, in which we collected questionnaires and 324 nasopharynx samples from 20 infants with CF and 45 age-matched healthy control subjects. Microbiota profiles were characterized by 16S ribosomal RNA-based sequencing. MEASUREMENTS AND MAIN RESULTS: We observed significant differences in microbial community composition (P < 0.0002 by permutational multivariate analysis of variance) and development between groups. In infants with CF, early Staphylococcus aureus and, to a lesser extent, Corynebacterium spp. and Moraxella spp. dominance were followed by a switch to Streptococcus mitis predominance after 3 months of age. In control subjects, Moraxella spp. enrichment occurred throughout the first 6 months of life. In a multivariate analysis, S. aureus, S. mitis, Corynebacterium accolens, and bacilli were significantly more abundant in infants with CF, whereas Moraxella spp., Corynebacterium pseudodiphtericum and Corynebacterium propinquum and Haemophilus influenzae were significantly more abundant in control subjects, after correction for age, antibiotic use, and respiratory symptoms. Antibiotic use was independently associated with increased colonization of gram-negative bacteria such as Burkholderia spp. and members of the Enterobacteriaceae bacteria family and reduced colonization of potential beneficial commensals. CONCLUSIONS: From diagnosis onward, we observed distinct patterns of nasopharyngeal microbiota development in infants with CF under 6 months of age compared with control subjects and a marked effect of antibiotic therapy leading toward a gram-negative microbial composition. PMID- 26492489 TI - Cost-benefit analysis of an enhanced recovery protocol for pancreaticoduodenectomy. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) programmes have been shown to decrease complications and hospital stay. The cost-effectiveness of such programmes has been demonstrated for colorectal surgery. This study aimed to assess the economic outcomes of a standard ERAS programme for pancreaticoduodenectomy. METHODS: ERAS for pancreaticoduodenectomy was implemented in October 2012. All consecutive patients who underwent pancreaticoduodenectomy until October 2014 were recorded. This group was compared in terms of costs with a cohort of consecutive patients who underwent pancreaticoduodenectomy between January 2010 and October 2012, before ERAS implementation. Preoperative, intraoperative and postoperative real costs were collected for each patient via the hospital administration. A bootstrap independent t test was used for comparison. ERAS-specific costs were integrated into the model. RESULTS: The groups were well matched in terms of demographic and surgical details. The overall complication rate was 68 per cent (50 of 74 patients) and 82 per cent (71 of 87 patients) in the ERAS and pre-ERAS groups respectively (P = 0.046). Median hospital stay was lower in the ERAS group (15 versus 19 days; P = 0.029). ERAS-specific costs were ?922 per patient. Mean total costs were ?56 083 per patient in the ERAS group and ?63 821 per patient in the pre-ERAS group (P = 0.273). The mean intensive care unit (ICU) and intermediate care costs were ?9139 and ?13 793 per patient for the ERAS and pre-ERAS groups respectively (P = 0.151). CONCLUSION: ERAS implementation for pancreaticoduodenectomy did not increase the costs in this cohort. Savings were noted in anaesthesia/operating room, medication and laboratory costs. Fewer patients in the ERAS group required an ICU stay. PMID- 26492490 TI - Does Prison Crowding Predict Higher Rates of Substance Use Related Parole Violations? A Recurrent Events Multi-Level Survival Analysis. AB - OBJECTIVE: This administrative data-linkage cohort study examines the association between prison crowding and the rate of post-release parole violations in a random sample of prisoners released with parole conditions in California, for an observation period of two years (January 2003 through December 2004). BACKGROUND: Crowding overextends prison resources needed to adequately protect inmates and provide drug rehabilitation services. Violence and lack of access to treatment are known risk factors for drug use and substance use disorders. These and other psychosocial effects of crowding may lead to higher rates of recidivism in California parolees. METHODS: Rates of parole violation for parolees exposed to high and medium levels of prison crowding were compared to parolees with low prison crowding exposure. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using a Cox model for recurrent events. Our dataset included 13070 parolees in California, combining individual level parolee data with aggregate level crowding data for multilevel analysis. RESULTS: Comparing parolees exposed to high crowding with those exposed to low crowding, the effect sizes from greatest to least were absconding violations (HR 3.56 95% CI: 3.05-4.17), drug violations (HR 2.44 95% CI: 2.00-2.98), non-violent violations (HR 2.14 95% CI: 1.73-2.64), violent and serious violations (HR 1.88 95% CI: 1.45-2.43), and technical violations (HR 1.86 95% CI: 1.37-2.53). CONCLUSIONS: Prison crowding predicted higher rates of parole violations after release from prison. The effect was magnitude-dependent and particularly strong for drug charges. Further research into whether adverse prison experiences, such as crowding, are associated with recidivism and drug use in particular may be warranted. PMID- 26492491 TI - Exemplar-Based Image Inpainting Using a Modified Priority Definition. AB - Exemplar-based algorithms are a popular technique for image inpainting. They mainly have two important phases: deciding the filling-in order and selecting good exemplars. Traditional exemplar-based algorithms are to search suitable patches from source regions to fill in the missing parts, but they have to face a problem: improper selection of exemplars. To improve the problem, we introduce an independent strategy through investigating the process of patches propagation in this paper. We first define a new separated priority definition to propagate geometry and then synthesize image textures, aiming to well recover image geometry and textures. In addition, an automatic algorithm is designed to estimate steps for the new separated priority definition. Comparing with some competitive approaches, the new priority definition can recover image geometry and textures well. PMID- 26492488 TI - Frequency of and Risk Factors for Depression among Participants in the Swiss HIV Cohort Study (SHCS). AB - OBJECTIVES: We studied the incidence and prevalence of, and co-factors for depression in the Swiss HIV Cohort Study. METHODS: Depression-specific items were introduced in 2010 and prospectively collected at semiannual cohort visits. Clinical, laboratory and behavioral co-factors of incident depression among participants free of depression at the first two visits in 2010 or thereafter were analyzed with Poisson regression. Cumulative prevalence of depression at the last visit was analyzed with logistic regression. RESULTS: Among 4,422 participants without a history of psychiatric disorders or depression at baseline, 360 developed depression during 9,348 person-years (PY) of follow-up, resulting in an incidence rate of 3.9 per 100 PY (95% confidence interval (CI) 3.5-4.3). Cumulative prevalence of depression during follow-up was recorded for 1,937/6,756 (28.7%) participants. Incidence and cumulative prevalence were higher in injection drug users (IDU) and women. Older age, preserved work ability and higher physical activity were associated with less depression episodes. Mortality (0.96 per 100 PY, 95% CI 0.83-1.11) based upon 193 deaths over 20,102 PY was higher among male IDU (2.34, 1.78-3.09), female IDU (2.33, 1.59-3.39) and white heterosexual men (1.32, 0.94-1.84) compared to white heterosexual women and homosexual men (0.53, 0.29-0.95; and 0.71, 0.55-0.92). Compared to participants free of depression, mortality was slightly elevated among participants with a history of depression (1.17, 0.94-1.45 vs. 0.86, 0.71-1.03, P = 0.033). Suicides (n = 18) did not differ between HIV transmission groups (P = 0.50), but were more frequent among participants with a prior diagnosis of depression (0.18 per 100 PY, 95%CI 0.10-0.31; vs. 0.04, 0.02-0.10; P = 0.003). CONCLUSIONS: Depression is a frequent co-morbidity among HIV-infected persons, and thus an important focus of care. PMID- 26492492 TI - Silicone Y-Stent Placement on the Secondary Left Carina. AB - BACKGROUND: The silicone Y-stent has mainly been used for the treatment of lesions around the main carina, and only a few case reports have been published on the technique for the lesions around the secondary left carina (LC2). OBJECTIVES: We investigated the feasibility, efficacy and safety of a stenting technique using a silicone Y-stent for patients with airway stenosis around LC2. METHODS: Patients who underwent airway stent placement between December 2010 and September 2014 in a single center were retrospectively reviewed. Under general anesthesia, using rigid and flexible bronchoscopes, the airway lumen was re established followed by Y-stent placement on LC2. RESULTS: We performed 274 airway stenting procedures for 253 patients during the study period. Twelve of them (7 with lung cancer, 3 with esophageal cancer/carcinosarcoma, 1 with thyroid cancer and 1 with renal cancer) underwent a Y-stent placement on LC2. Respiratory symptoms were relieved in all patients. Six of 7 patients with supplemental oxygen, including the mechanically ventilated patient before stent placement, could be discharged without supplemental oxygen. The chest radiograph after the procedure showed increased lung volume in all 7 patients with partial or complete atelectasis. Median survival after stenting was 197 days at the time of data collection. Retention of secretions occurred in 1 and hemoptysis in another patient. CONCLUSIONS: Silicone Y-stent placement on LC2 is technically feasible, effective and acceptably safe. PMID- 26492494 TI - Konjac Glucomannan Dietary Supplementation Causes Significant Fat Loss in Compliant Overweight Adults. AB - OBJECTIVES: Changes in body composition and blood chemistries between overweight adult subjects receiving a supplement containing either 3 g of konjac glucomannan/300 mg calcium carbonate or a placebo containing only 300 mg of calcium carbonate were compared as the primary objective. A secondary objective was to compare outcome differences between compliant and partially compliant subjects. METHODS: A total of 83 overweight adults (66 women and 17 men) completed a randomized, double-blind, placebo-controlled protocol in which they received either a glucomannan or placebo supplement for 60 days. Dual-energy x ray absorptiometry (DEXA) total body scans and a 42-measurement blood test were completed at baseline and 60 days later. Compliance was assessed by rating self reports of (1) how many tablets were taken, (2) adherence to taking the tablets 30 minutes before eating, and (3) a sum of the ratings for (1) and (2). An anonymous poststudy questionnaire and telephone calls were also completed by 80 (96%) of the participants who were used as the study cohort. RESULTS: No statistically significant differences were found between the groups on changes from baseline on the DEXA and blood tests. However, when subjects were classified as either compliant or partially compliant using the compliance measures, statistically significant reductions in scale weight, percentage body fat, fat mass, total cholesterol, and low-density lipoprotein (LDL) cholesterol were found in the glucomannan group compared to the placebo group. CONCLUSIONS: This study supports the efficacy glucomannan supplementation to reduce body weight, body fat, and circulating cholesterol levels without the concomitant loss of lean mass and bone density often associated with weight loss. However, these positive outcomes were not observable until corrections for compliance were applied. PMID- 26492493 TI - Association Study between the FTCDNL1 (FONG) and Susceptibility to Osteoporosis. AB - Osteoporosis is a systemic skeletal disease characterized by a decreased bone mineral density that results in an increased risk of fragility fractures. Previous studies indicated that genetic factors are involved in the pathogenesis of osteoporosis. Polymorphisms of the FONG (FTCDNL1) gene (rs7605378) were reported to be associated with the risk of osteoporosis in a Japanese population. To assess whether polymorphisms of the FTCDNL1 gene contribute to the susceptibility and severity of osteoporosis in a Taiwanese population, 326 osteoporosis patients and 595 controls of a Taiwanese population were included in this study. Our results indicated that rs10203122 was significantly associated with osteoporosis susceptibility among female. Our findings provide evidence that rs10203122 in FTCDNL1 is associated with a susceptibility to osteoporosis. PMID- 26492495 TI - Preparing for the Next Epidemic with Basic Virology. PMID- 26492496 TI - Removal of epulis fissuratum by Er,Cr:YSGG laser in comparison with the conventional method. AB - OBJECTIVE: The present study aimed to compare clinical outcomes during the recovery period after soft tissue surgery performed by an erbium, chromium:yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser with those after surgery with the conventional method, in which a scalpel was used. METHODS: A total of 44 epulis fissuratum removal surgeries were performed in 30 healthy volunteers using either an Er,Cr:YSGG laser (laser group) or a scalpel (conventional group), with the same number of lesions in each group. Both groups were controlled postoperatively on days 2, 7, 14, and 30. The visual analog scale (VAS) pain scores of the patients and healing, erythema, and suppuration in the surgical area were recorded with scores between 0 and 3. Total wound surface was measured by a ruler according to the Bates-Jensen Wound Assessment Tool. RESULTS: The results of the present study demonstrated that there were no significant differences between the conventional group using analgesic and the laser group in terms of the VAS scores (p = 0.744) and edema (p = 0.206). Evaluation of wound surface revealed healing without any problem as of the 2nd day at a rate of 82% in the laser group and 59% in the conventional group. CONCLUSIONS: In conclusion, Er,Cr:YSGG laser was superior to scalpel regarding clinical outcomes, and led to a difference in the use of analgesic and local anesthetic. PMID- 26492498 TI - Soy Protein Isolate As Fluid Loss Additive in Bentonite-Water-Based Drilling Fluids. AB - Wellbore instability and formation collapse caused by lost circulation are vital issues during well excavation in the oil industry. This study reports the novel utilization of soy protein isolate (SPI) as fluid loss additive in bentonite water based drilling fluids (BT-WDFs) and describes how its particle size and concentration influence on the filtration property of SPI/BT-WDFs. It was found that high pressure homogenization (HPH)-treated SPI had superior filtration property over that of native SPI due to the improved ability for the plugging pore throat. HPH treatment also caused a significant change in the surface characteristic of SPI, leading to a considerable surface interaction with BT in aqueous solution. The concentration of SPI had a significant impact on the dispersion state of SPI/BT mixtures in aquesous solution. At low SPI concentrations, strong aggregations were created, resulting in the formation of thick, loose, high-porosity and high-permeability filter cakes and high fluid loss. At high SPI concentrations, intercatlated/exfoliated structures were generated, resulting in the formation of thin, compact, low-porosity and low permeability filter cakes and low fluid loss. The SPI/BT-WDFs exhibited superior filtration property than pure BT-WDFs at the same solid concentraion, demonstrating the potential utilization of SPI as an effective, renewable, and biodegradable fluid loss reducer in well excavation applications. PMID- 26492497 TI - European AIDS Clinical Society Standard of Care meeting on HIV and related coinfections: The Rome Statements. AB - OBJECTIVES: The objective of the 1st European AIDS Clinical Society meeting on Standard of Care in Europe was to raise awareness of the European scenario and come to an agreement on actions that could be taken in the future. METHODS: Data driven presentations were given on specific topics followed by interactive panel discussions. RESULTS: In Eastern European countries, the epidemic is largely driven by injecting drug use, in contrast with Western Europe where the infection mainly occurs through heterosexual contact. A high proportion of people living with HIV remain unaware of their infection. Substantial differences exist in Eastern Europe and Central Asia with respect to treatment coverage, regimen availability and continuity of drug supply. In 2012, tuberculosis case notification rates were 5-10 times higher in Eastern Europe compared with Western Europe, with an alarming proportion of newly diagnosed multi-drug-resistant cases. Hepatitis C is widespread in selected geographical areas and risk groups. CONCLUSIONS: The key conclusion from the meeting was that a high-priority group of actions could be identified, including: increasing HIV awareness and testing, improving training for health care providers, ensuring equitable patient access to treatments and diagnostics for HIV and comorbidities, and implementing best practices in infection control and treatment of HIV-infected patients coinfected with tuberculosis and hepatitis C virus, for whom direct acting antiviral treatment. should be considered. PMID- 26492499 TI - Redesigning a falls prevention standard of practice. PMID- 26492500 TI - AACN CSI Academy, part 3: Introducing the Massachusetts CSI Nursing Delirium Collaborative. AB - In the final installment of our three-part series, we reveal how the Boston cohort of the American Association of Critical-Care Nurses (AACN) Clinical Scene Investigator (CSI) Academy launched a collective to improve patient safety and quality outcomes related to delirium. PMID- 26492502 TI - Patient safety and IT trends. PMID- 26492503 TI - Improving hand hygiene through a multimodal approach. PMID- 26492504 TI - Patient teaching: Short peripheral I.V. catheters. PMID- 26492505 TI - A prevention initiative to decrease HAPUs at two acute care hospitals. PMID- 26492506 TI - Outcomes of a comprehensive nurse residency program. PMID- 26492508 TI - Blogging as a tool to address communication challenges among nurses. PMID- 26492509 TI - Safety: More than a quality model. PMID- 26492510 TI - Parental effects and the evolution of phenotypic memory. AB - Despite growing evidence for nongenetic inheritance, the ecological conditions that favour the evolution of heritable parental or grandparental effects remain poorly understood. Here, we systematically explore the evolution of parental effects in a patch-structured population with locally changing environments. When selection favours the production of a mix of offspring types, this mix differs according to the parental phenotype, implying that parental effects are favoured over selection for bet-hedging in which the mixture of offspring phenotypes produced does not depend on the parental phenotype. Positive parental effects (generating a positive correlation between parental and offspring phenotype) are favoured in relatively stable habitats and when different types of local environment are roughly equally abundant, and can give rise to long-term parental inheritance of phenotypes. By contrast, unstable habitats can favour negative parental effects (generating a negative correlation between parental and offspring phenotype), and under these circumstances, even slight asymmetries in the abundance of local environmental states select for marked asymmetries in transmission fidelity. PMID- 26492511 TI - The challenge of antibiotic resistance in haematology patients. AB - Bacterial infections were once a major obstacle to the treatment of acute leukaemia. Improvement in management strategies, including the use of broad spectrum antibacterial drugs targeting Gram-negative bacteria, has reduced the mortality in neutropenic patients developing blood stream infections and other severe infections. In many countries these achievements are threatened by development of multi-resistant bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. This review addresses the epidemiology, clinical importance and possible management of these multi-resistant organisms. PMID- 26492513 TI - Comments from the New Editor: Perspectives on Radiation Research. PMID- 26492512 TI - Adaptive immune response to therapy in hmgcr autoantibody myopathy. AB - INTRODUCTION: We evaluated the response to immunosuppression in a case of 3 hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)-autoantibody myopathy. METHODS: T- and B-cell subsets were determined by flow cytometry pre- and posttherapy. RESULTS: Baseline immune profiling demonstrated strikingly elevated T-follicular helper (Tfh) cells and plasmablasts. Immunosuppression resulted in clinical improvement and decreased Tfh cells, plasmablasts, and autoantibodies. CONCLUSIONS: Immune profiling in HMGCR-autoantibody myopathy suggests a B-cell mediated disease. Tfh cells and plasmablasts may be therapeutic biomarkers. PMID- 26492514 TI - Probing the S2' Subsite of the Anthrax Toxin Lethal Factor Using Novel N Alkylated Hydroxamates. AB - The lethal factor (LF) enzyme secreted by Bacillus anthracis is a zinc hydrolase that is chiefly responsible for anthrax-related cell death. Although many studies of the design of small molecule LF inhibitors have been conducted, no LF inhibitor is yet available as a therapeutic agent. Inhibitors with considerable chemical diversity have been developed and investigated; however, the LF S2' subsite has not yet been systematically explored as a potential target for lead optimization. Here we present synthesis, experimental evaluation, modeling, and structural biology for a novel series of sulfonamide hydroxamate LF inhibitor analogues specifically designed to extend into, and probe chemical preferences of, this S2' subsite. We discovered that this region accommodates a wide variety of chemical functionalities and that a broad selection of ligand structural modifications directed to this area can be incorporated without significant deleterious alterations in biological activity. We also identified key residues in this subsite that can potentially be targeted to improve inhibitor binding. PMID- 26492515 TI - Mechanistic Insight into DNA-Guided Control of Nanoparticle Morphologies. AB - Although shapes and surface characteristics of nanoparticles are known to play important roles in defining their properties, it remains challenging to fine-tune the morphologies systematically and predictably. Recently, we have shown that DNA molecules can serve as programmable ligands to fine-tune the morphologies of nanomaterials. Despite this discovery, the mechanism of how the morphology can be controlled and the roles of the DNA molecules in contributing to such control are not understood. We herein report mechanistic investigation of DNA-mediated morphological evolution of gold nanoprism seeds into nonagon, hexagon, and six pointed stars, some of which display rough surfaces, in the presence of homo oligomeric T30, G20, C30, and A30. The growth, elucidated through various analytical methods including UV-vis, SEM, TEM, zeta potential, fluorescence, and cyclic voltammetry, is found to occur in two stages: control of shape, followed by control of thickness. A careful analysis of diffraction patterns of the nanoprism seeds as well as the resulting intermediate shapes by TEM allowed us to deduce the exact sequence of shape evolution. Through systematic comparison of the nanoparticle growth process, the DNA molecules were found to play important roles by influencing diffusion of the Au precursor to the seed and modulating the growth through differences in DNA desorption, density, and mobility on the seed surface. These insights into the mechanism of DNA-guided control of nanomaterial morphologies provide deeper understanding of the interactions between the DNA and nanomaterials and will allow better control of the shapes and surface properties of many nanomaterials. PMID- 26492516 TI - Improvement of CH3NH3PbI3 Formation for Efficient and Better Reproducible Mesoscopic Perovskite Solar Cells. AB - High-performance perovskite solar cells (PSCs) are obtained through optimization of the formation of CH3NH3PbI3 nanocrystals on mesoporous TiO2 film, using a two step sequential deposition process by first spin-coating a PbI2 film and then submerging it into CH3NH3I solution for perovskite conversion (PbI2 + CH3NH3I -> CH3NH3PbI3). It is found that the PbI2 morphology from different film formation process (thermal drying, solvent extraction, and as-deposited) has a profound effect on the CH3NH3PbI3 active layer formation and its nanocrystalline composition. The residual PbI2 in the active layer contributes to substantial photocurrent losses, thus resulting in low and inconsistent PSC performances. The PbI2 film dried by solvent extraction shows enhanced CH3NH3PbI3 conversion as the loosely packed disk-like PbI2 crystals allow better CH3NH3I penetration and reaction in comparison to the multicrystal aggregates that are commonly obtained in the thermally dried PbI2 film. The as-deposited PbI2 wet film, without any further drying, exhibits complete conversion to CH3NH3PbI3 in MAI solution. The resulting PSCs reveal high power conversion efficiency of 15.60% with a batch-to batch consistency of 14.60 +/- 0.55%, whereas a lower efficiency of 13.80% with a poorer consistency of 11.20 +/- 3.10% are obtained from the PSCs using thermally dried PbI2 films. PMID- 26492517 TI - Maternal pre-pregnancy BMI and adverse pregnancy outcomes among Chinese women: Results from the C-ABCS. AB - The aim of this study was to investigate associations between pre-pregnancy body mass index (BMI) and adverse pregnancy outcomes among Chinese pregnant women. A prospective population-based cohort study was performed using data collected as part of the China-Anhui Birth Cohort Study or C-ABCS. A total of 13,121 pregnant women who received the first prenatal visit were enrolled from November 2008 to October 2010. Logistic regression analysis was used to calculate associations between pre-pregnancy BMI and pregnancy outcomes. Results indicated that the increased pre-pregnancy BMI was associated with a number of adverse pregnancy outcomes such as hypertensive disorder (adjusted relative risk (ARR) 2.3, 95% confidence interval [CI] 1.5-3.6), gestational diabetes (ARR 3.5, 95% CI 2.3 5.2), caesarean delivery (ARR 2.0, 95% CI 1.6-2.4), and medically indicated preterm delivery (ARR 1.8, 95% CI 1.1-2.9). Women with pre-pregnancy BMI above the normal range pose an increased risk of adverse pregnancy outcomes. PMID- 26492518 TI - KIR haplotypes are associated with late-onset type 1 diabetes in European American families. AB - Classical human leukocyte antigens (HLA) genes confer the strongest, but not the only, genetic susceptibility to type 1 diabetes. Killer cell immunoglobulin-like receptors (KIR), on natural killer (NK) cells, bind ligands including class I HLA. We examined presence or absence, with copy number, of KIR loci in 1698 individuals, from 339 multiplex type 1 diabetes families, from the Human Biological Data Interchange, previously genotyped for HLA. Combining family data with KIR copy number information allowed assignment of haplotypes using identity by descent. This is the first disease study to use KIR copy number typing and unambiguously define haplotypes by gene transmission. KIR A1 haplotypes were positively associated with T1D in the subset of patients without the high T1D risk HLA genotype, DR3/DR4 (odds ratio=1.29, P=0.0096). The data point to a role for KIR in type 1 diabetes risk in late-onset patients. In the top quartile (age of onset>14), KIR A2 haplotype was overtransmitted (63.4%, odds ratio=1.73, P=0.024) and KIR B haplotypes were undertransmitted (41.1%, odds ratio=0.70, P=0.0052) to patients. The data suggest that inhibitory 'A' haplotypes are predisposing and stimulatory 'B' haplotypes confer protection in both DR3/DR4 negative and late-onset patient groups. PMID- 26492519 TI - The association between the HLA-G 14-bp insertion/deletion polymorphism and type 1 diabetes. AB - Type 1 diabetes (T1D) is a multifactorial disease that has a strong genetic component. The HLA-G is a nonclassical HLA class I locus that is associated with immunomodulatory functions, including downregulation of innate and adaptive immune responses and induction of immune tolerance. However, there is currently limited information about the involvement of HLA-G in T1D susceptibility. This case-control study aims to investigate the T1D susceptibility association of alleles and genotypes of a widely investigated 14-bp insertion/deletion polymorphism in the HLA-G and to provide further evidence of the frequency distribution of class II HLA-DR-DQ-risk genotypes in T1D children and adolescents in the Brazilian population. The deletion allele and the homozygous deletion genotype are associated with susceptibility to T1D and the insertion allele and the heterozygous deletion/insertion genotype are associated with protection from T1D. We also confirm that genetic susceptibility to T1D is associated with the DRB1*03:01-DQA1*05:01-DQB1*02:01 and DRB1*04-DQA1*03:01-DQB1*03:02 haplotypes in Brazilian northeast region. The DR3-DQ2/DR4-DQ8 genotype conferred the highest detected risk for T1D. Our results identify a novel association of the 14-bp deletion allele and the homozygous deletion genotype with T1D development and provide additional evidence of the importance of HLA class II heterozygous DR3 DQ2/DR4-DQ8 genotype in T1D susceptibility. PMID- 26492521 TI - CitSci.org: A New Model for Managing, Documenting, and Sharing Citizen Science Data. AB - Citizen science projects have the potential to advance science by increasing the volume and variety of data, as well as innovation. Yet this potential has not been fully realized, in part because citizen science data are typically not widely shared and reused. To address this and related challenges, we built CitSci.org (see www.citsci.org), a customizable platform that allows users to collect and generate diverse datasets. We hope that CitSci.org will ultimately increase discoverability and confidence in citizen science observations, encouraging scientists to use such data in their own scientific research. PMID- 26492520 TI - Personalized risk prediction for event-free survival at 24 months in patients with diffuse large B-cell lymphoma. AB - We recently defined event-free survival at 24 months (EFS24) as a clinically relevant outcome for patients with DLBCL. Patients who fail EFS24 have very poor overall survival, while those who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. Here, we develop and validate a clinical risk calculator (IPI24) for EFS24. Model building was performed on a discovery dataset of 1,348 patients with DLBCL and treated with anthracycline-based immunochemotherapy. A multivariable model containing age, Ann Arbor stage, normalized serum LDH, ALC, ECOG performance status, bulky disease, and sex was identified. The model was then applied to an independent validation dataset of 1,177 DLBCL patients. The IPI24 score estimates the probability of failing to achieve the EFS24 endpoint for an individual patient. The IPI24 model showed superior discriminatory ability (c-statistic = 0.671) in the validation dataset compared to the IPI (c-statistic = 0.649) or the NCCN-IPI (c-statistic = 0.657). After recalibration of the model on the combined dataset, the median predicted probability of failing to achieve EFS24 was 36% (range, 12-88%), and the IPI24 showed an EFS24 gradient in all IPI groups. The IPI24 also identified a significant percentage of patients with high risk disease, with over 20% of patients having a 50% or higher risk of failing to achieve EFS24. The IPI24 provides an individual patient level probability of achieving the clinically relevant EFS24 endpoint. It can be used via electronic apps. PMID- 26492522 TI - FAM3A Protects HT22 Cells Against Hydrogen Peroxide-Induced Oxidative Stress Through Activation of PI3K/Akt but not MEK/ERK Pathway. AB - BACKGROUND/AIMS: Oxidative stress-induced cell damage is involved in many neurological diseases. FAM3A is the first member of family with sequence similarity 3 (FAM3) gene family and its biological function remains largely unknown. METHODS: This study aimed to determine its role in hydrogen peroxide (H2O2) induced injury in neuronal HT22 cells. The protective effects were measured by cell viability, lactate dehydrogenase (LDH) release and apoptosis, and oxidative stress was assayed by reactive oxygen species (ROS) generation, ATP synthesis and lipid peroxidation. By using selective inhibitors, the involvement of PI3K/Akt and MEK/ERK pathways were also investigated. RESULTS: The results of fluorescence staining revealed that H2O2 significantly decreased the expression of FAM3A protein, which was shown to be subcellularly located in mitochondria. Up regulation of FAM3A by lentivirus transfection markedly increased cell viability and decreased LDH release after H2O2 treatment. The anti-apoptotic activity of FAM3A was demonstrated by the reduced mitochondrial cytochrome c release, decreased activation of caspase-3 and the results of flow cytometry. Overexpression of FAM3A attenuated intracellular ROS generation and loss of ATP production induced by H2O2, and subsequently inhibited lipid peroxidation. In addition, overexpression of FAM3A significantly increased the activation of Akt and ERK in H2O2 injured HT22 cells. By using Akt and ERK specific inhibitors, we found that inhibition of PI3K/Akt, but not MEK/ERK pathway, partially prevented FAM3A-induced protection against H2O2. CONCLUSION: These results suggest that FAM3A has protective effects against H2O2-induced oxidative stress by reducing ROS accumulation and apoptosis, and these protective effects are dependent on the activation of PI3K/Akt pathway. PMID- 26492523 TI - IL-1beta-induced MCP-1 expression and secretion of human dental pulp cells is related to TAK1, MEK/ERK, and PI3K/Akt signaling pathways. AB - OBJECTIVE: Interleukin-1beta (IL-1beta) is an inflammatory molecule of the dental pulp. IL-1beta stimulates cyclooxygenase-2 (COX-2) and prostaglandins production of pulp cells and affects the pulpal inflammation and repair. However, the effects of IL-1beta on Monocyte Chemotactic Factor-1 (MCP-1) of dental pulp cells and its relation to transforming growth factor beta-activated kinase-1 (TAK1), PI3K/Akt, and MEK/ERK signaling and COX activation are not fully clear. DESIGN: Human dental pulp cells were exposed to IL-1beta with/without pretreatment and co incubation by aspirin (a COX inhibitor), 5z-7-oxozeaenol (a TAK1 inhibitor), LY294002 (a PI3K/Akt inhibitor) or U0126 (a MEK/ERK inhibitor). Viable cell number was evaluated by MTT assay. MCP-1 mRNA expression was tested by reverse transcriptase-polymerase chain reaction (RT-PCR). MCP-1 and COX-2 protein expression was studied by western blot. MCP-1 in the culture medium was measure by ELISA. RESULTS: IL-1beta showed little cytotoxicity to pulp cells. It stimulated MCP-1 mRNA and protein expression and MCP-1 secretion. Aspirin, U0126, LY294002 and 5z-7-oxozeaenol attenuated the IL-1beta-induced MCP-1 expression. In addition, 5z-7-oxozeaenol, LY294002, U0126 and aspirin prevented the IL-1beta induced MCP-1 secretion of pulp cells. CONCLUSION: These results indicate that IL 1beta may be involved in the pulpal inflammatory and healing processes by inducing MCP-1 expression and secretion. These events are related to differential activation of TAK1, PI3K/Akt and MEK/ERK 1/2 signaling and COX activation. These results are important for future pharmacologic intervention of pulpal inflammatory diseases. PMID- 26492524 TI - Onlay bone augmentation on mouse calvarial bone using a hydroxyapatite/collagen composite material with total blood or platelet-rich plasma. AB - OBJECTIVE: The aim of this study was to assess newly formed onlay bone on mouse calvarial bone using a new artificial bone material, a hydroxyapatite/collagen composite, with total blood or platelet-rich plasma. DESIGN: The hydroxyapatite/collagen composite material with normal saline, total blood or platelet-rich plasma was transplanted on mouse calvarial bone. The mice were sacrificed and the specimens were harvested four weeks after surgery. The newly formed bone area was measured on hematoxylin and eosin stained specimens using Image J software. RESULTS: The hydroxyapatite/collagen composite materials with total blood or platelet-rich plasma induced a significantly greater amount of newly formed bone than that with normal saline. Moreover, bone marrow was observed four weeks after surgery in the transplanted materials with total blood or platelet-rich plasma but not with normal saline. However, there were no significant differences in the amount of newly formed bone between materials used with total blood versus platelet-rich plasma. CONCLUSIONS: The hydroxyapatite/collagen composite material was valid for onlay bone augmentation and this material should be soaked in total blood or platelet-rich plasma prior to transplantation. PMID- 26492526 TI - A programmable Y-shaped junction scaffold-mediated modular and cascade amplification strategy for the one-step, isothermal and ultrasensitive detection of target DNA. AB - The programmable DNA polymerization across the two branches of the assembled Y shaped junction was ingeniously manipulated for modular target recycling and cascade lambda exonuclease cleavage, which afforded the one-pot, isothermal and ultrasensitive detection of target DNA. A low detection limit of 28.2 fM of target DNA with an excellent selectivity could be obtained. PMID- 26492525 TI - An Ornithopod-Dominated Tracksite from the Lower Cretaceous Jiaguan Formation (Barremian-Albian) of Qijiang, South-Central China: New Discoveries, Ichnotaxonomy, Preservation and Palaeoecology. AB - The historically-famous Lotus Fortress site, a deep 1.5-3.0-meter-high, 200-meter long horizonal notch high up in near-vertical sandstone cliffs comprising the Cretaceous Jiaguan Formation, has been known since the 13th Century as an impregnable defensive position. The site is also extraordinary for having multiple tetrapod track-bearing levels, of which the lower two form the floor of part of the notch, and yield very well preserved asseamblages of ornithopod, bird (avian theropod) and pterosaur tracks. Trackway counts indicate that ornithopods dominate (69%) accounting for at least 165 trackmakers, followed by bird (18%), sauropod (10%), and pterosaur (3%). Previous studies designated Lotus Fortress as the type locality of Caririchnium lotus and Wupus agilis both of which are recognized here as valid ichnotaxa. On the basis of multiple parallel trackways both are interpreted as representing the trackways of gregarious species. C. lotus is redescribed here in detail and interpreted to indicate two age cohorts representing subadults that were sometimes bipedal and larger quadrupedal adults. Two other previously described dinosaurian ichnospecies, are here reinterpreted as underprints and considered nomina dubia. Like a growing number of significant tetrapod tracksites in China the Lotus Fortress site reveals new information about the composition of tetrapod faunas from formations in which the skeletal record is sparse. In particular, the site shows the relatively high abundance of Caririchium in a region where saurischian ichnofaunas are often dominant. It is also the only site known to have yielded Wupus agilis. In combination with information from other tracksites from the Jiaguan formation and other Cretaceous formations in the region, the track record is proving increasingly impotant as a major source of information on the vertebrate faunas of the region. The Lotus Fortress site has been developed as a spectacular, geologically-, paleontologically- and a culturally-significant destination within Qijiang National Geological Park. PMID- 26492527 TI - Analgesic effects of mambalgin peptide inhibitors of acid-sensing ion channels in inflammatory and neuropathic pain. AB - Mambalgins are 57-amino acid peptides isolated from snake venom that evoke naloxone-resistant analgesia after local (intraplantar) and central (intrathecal) injections through inhibition of particular subtypes of acid-sensing ion channels (ASICs). We now show that mambalgins also have an opioid-independent effect on both thermal and mechanical inflammatory pain after systemic intravenous (i.v.) administration and are effective against neuropathic pain. By combining the use of knockdown and knockout animals, we show the critical involvement of peripheral ASIC1b-containing channels, along with a contribution of ASIC1a-containing channels, in the i.v. effects of these peptides against inflammatory pain. The potent analgesic effect on neuropathic pain involves 2 different mechanisms depending on the route of administration, a naloxone-insensitive and ASIC1a independent effect associated with i.v. injection and an ASIC1a-dependent and partially naloxone-sensitive effect associated with intrathecal injection. These data further support the role of peripheral and central ASIC1-containing channels in pain, demonstrate their participation in neuropathic pain, and highlight differences in the repertoire of channels involved in different pain conditions. They also strengthen the therapeutic potential of mambalgin peptides that are active in a broader range of experimental pain models and through i.v. systemic delivery. PMID- 26492528 TI - The Case for Mass Treatment of Intestinal Helminths in Endemic Areas. AB - Two articles published earlier this year in the International Journal of Epidemiology [1,2] have re-ignited the debate over the World Health Organization's long-held recommendation of mass-treatment of intestinal helminths in endemic areas. In this note, we discuss the content and relevance of these articles to the policy debate, and review the broader research literature on the educational and economic impacts of deworming. We conclude that existing evidence still indicates that mass deworming is a cost-effective health investment for governments in low-income countries where worm infections are widespread. PMID- 26492529 TI - Latest advances in the pathological understanding of cholangiocarcinomas. AB - Cholangiocarcinomas (CCAs) are anatomically classified into intrahepatic, perihilar, and distal types. The gross pathological classification of intrahepatic CCAs divides them into mass-forming, periductal-infiltrating, and intraductal-growth types; and perihilar/distal CCAs into flat- and nodular infiltrating and papillary types. Unique preinvasive lesions appear to precede individual gross types of CCA. Biliary intraepithelial neoplasia, a flat lesion, precedes periductal-, flat-, and nodular-infiltrating CCAs, whereas intraductal papillary neoplasm of the bile duct (IPNB) precedes the intraductal-growth and papillary type of CCAs. IPNBs are heterogeneous in their histological and pathological profiles along the biliary tree. Hepatobiliary cystadenomas/adenocarcinomas are reclassified as cystic IPNBs and hepatic mucinous cystic neoplasms. Peribiliary glands may participate in the development of CCAs. These latest findings present a new challenge for understanding the pathology of CCAs. PMID- 26492530 TI - Tetra-n-butylammonium Iodide Catalyzed C-H Azidation of Aldehydes with Thermally Stable Azidobenziodoxolone. AB - Tetra-n-butylammonium iodide can efficiently catalyze direct azidation of aldehyde C-H bonds with thermally stable azidobenziodoxolone at room temperature. Compared to conventional methods, which require excessive amounts of highly explosive azide sources, this is a safe and convenient procedure. PMID- 26492531 TI - Evaluation of alternative airway management strategies in surgical repair of severe cranio-maxillofacial trauma. AB - BACKGROUND: Severe cranio-maxillofacial trauma requires the utilization of alternative airway management techniques when oral and nasal routes of tracheal intubation are either not possible or contraindicated. METHODS: This retrospective study evaluated the techniques of submental intubation, retromolar intubation and tracheostomy in terms of their frequency of use, time required, costs involved and associated complications in a total of 200 patients. RESULTS: Frequency of utilization of alternative airway management techniques was 3.63%. Tracheostomy was associated with the most severe complications, took the most time to establish and was the most expensive technique. Although retromolar intubation was not associated with any complications, it was not suitable in adults with erupted third molars and interfered with the surgical field. Submental intubation was associated with minor complications, was suitable in all cases and did not interfere with surgical access. CONCLUSIONS: Retromolar intubation must be considered as a first choice alternative in patients with unerupted third molars provided the surgeon is adept at working in the presence of an oral tube. Submental intubation is a good second choice when retromolar intubation is not possible or is not acceptable to the surgeon. Tracheostomy is only indicated in patients who require long term control of the airway. PMID- 26492532 TI - The Rise and Fall of an Evolutionary Innovation: Contrasting Strategies of Venom Evolution in Ancient and Young Animals. AB - Animal venoms are theorized to evolve under the significant influence of positive Darwinian selection in a chemical arms race scenario, where the evolution of venom resistance in prey and the invention of potent venom in the secreting animal exert reciprocal selection pressures. Venom research to date has mainly focused on evolutionarily younger lineages, such as snakes and cone snails, while mostly neglecting ancient clades (e.g., cnidarians, coleoids, spiders and centipedes). By examining genome, venom-gland transcriptome and sequences from the public repositories, we report the molecular evolutionary regimes of several centipede and spider toxin families, which surprisingly accumulated low-levels of sequence variations, despite their long evolutionary histories. Molecular evolutionary assessment of over 3500 nucleotide sequences from 85 toxin families spanning the breadth of the animal kingdom has unraveled a contrasting evolutionary strategy employed by ancient and evolutionarily young clades. We show that the venoms of ancient lineages remarkably evolve under the heavy constraints of negative selection, while toxin families in lineages that originated relatively recently rapidly diversify under the influence of positive selection. We propose that animal venoms mostly employ a 'two-speed' mode of evolution, where the major influence of diversifying selection accompanies the earlier stages of ecological specialization (e.g., diet and range expansion) in the evolutionary history of the species-the period of expansion, resulting in the rapid diversification of the venom arsenal, followed by longer periods of purifying selection that preserve the potent toxin pharmacopeia-the period of purification and fixation. However, species in the period of purification may re enter the period of expansion upon experiencing a major shift in ecology or environment. Thus, we highlight for the first time the significant roles of purifying and episodic selections in shaping animal venoms. PMID- 26492533 TI - Laser-evoked potentials mediated by mechano-insensitive nociceptors in human skin. AB - OBJECTIVES: Laser-evoked potentials (LEP) were assessed after peripheral nerve block of the lateral femoral cutaneous nerve (LFCN) in healthy volunteers from partially anesthetized skin areas to differentially stimulate mechano-insensitive nociceptors. METHODS: An ultrasound-guided nerve block of the LFCN was performed in 12 healthy male subjects with Ropivacain 1%. After 30 min, the nerve block induced significantly larger anesthetic areas to mechanical stimuli than to electrical stimuli revealing an area of differential sensitivity. LEPs, reaction times and pain ratings were recorded in response to the laser stimuli of (1) completely anesthetic skin, (2) mechano-insensitive, but electrically excitable skin ('differential sensitivity'), (3) normal skin. RESULTS: LEP latencies in the area of differential sensitivity were increased compared to unaffected skin (228 +/- 8.5 ms, vs. 181 +/- 3.6 ms, p < 0.01) and LEP amplitudes were reduced (14.8 +/- 1.2 MUV vs. 24.6 +/- 1.7 MUV, p < 0.01). Correspondingly, psychophysically assessed response latencies in the differentially anesthetic skin were increased (649 ms vs. 427 ms, p < 0.01) and pain ratings reduced (1.5/10 vs. 5/10 NRS, p < 0.01). CONCLUSION: The increase in LEP latency suggests that mechano-insensitive heat-sensitive Adelta nociceptors (MIA, type II) have a slower conduction velocity or higher utilization time than mechano-sensitive type II Adelta nociceptors. Moreover, widely branched, slowly conducting and mechano-insensitive branches of Adelta nociceptors can explain our finding. LEPs in the differentially anesthetized skin provide specific information about a mechanically insensitive but heat-sensitive subpopulation of Adelta nociceptors. These findings support the concept that A-fibre nociceptors exhibit a similar degree of modality specificity as C-fibre nociceptors. PMID- 26492534 TI - Quantitative DNA Analyses for Airborne Birch Pollen. AB - Birch trees produce large amounts of highly allergenic pollen grains that are distributed by wind and impact human health by causing seasonal hay fever, pollen related asthma, and other allergic diseases. Traditionally, pollen forecasts are based on conventional microscopic counting techniques that are labor-intensive and limited in the reliable identification of species. Molecular biological techniques provide an alternative approach that is less labor-intensive and enables identification of any species by its genetic fingerprint. A particularly promising method is quantitative Real-Time polymerase chain reaction (qPCR), which can be used to determine the number of DNA copies and thus pollen grains in air filter samples. During the birch pollination season in 2010 in Mainz, Germany, we collected air filter samples of fine (<3 MUm) and coarse air particulate matter. These were analyzed by qPCR using two different primer pairs: one for a single-copy gene (BP8) and the other for a multi-copy gene (ITS). The BP8 gene was better suitable for reliable qPCR results, and the qPCR results obtained for coarse particulate matter were well correlated with the birch pollen forecasting results of the regional air quality model COSMO-ART. As expected due to the size of birch pollen grains (~23 MUm), the concentration of DNA in fine particulate matter was lower than in the coarse particle fraction. For the ITS region the factor was 64, while for the single-copy gene BP8 only 51. The possible presence of so-called sub-pollen particles in the fine particle fraction is, however, interesting even in low concentrations. These particles are known to be highly allergenic, reach deep into airways and cause often severe health problems. In conclusion, the results of this exploratory study open up the possibility of predicting and quantifying the pollen concentration in the atmosphere more precisely in the future. PMID- 26492535 TI - [Successful Management of a Massive Bronchopleural Fistula with Endobronchial Valves in a Case of Perforated Central Lung Cancer: a Case Report]. PMID- 26492536 TI - [Strategies for the treatment of postoperative sternal infections]. AB - Postoperative sternal infections are associated with significant morbidity and mortality. An incidence of up to 8 % has to be expected. Typically, a highly inflammatory acute infection with a marked soft tissue component is observed. However, the infection may also be present as a less symptomatic reaction and localised chronic osteomyelitis with fistula formation. The treatment strategy for a deep sternal wound infection consists of several steps. A radical debridement of the wound requires the opening of all abscesses, the resection of non-vital bone and the removal of all infected allomaterial. This is followed by a period of VAC therapy (Vacuum-Assisted Closure Therapy) for infection treatment and conditioning of the wound. Secondary closure of the wound may be planned only after the infection is completely controlled. The sternum is stabilised by osteosynthesis. Sternal defects are covered. In most cases adequate soft tissue coverage is achieved by mobilisation of both pectoral muscles together with the precostal soft tissues. Following resection of the sternum, the reconstruction of the thoracic wall requires the implantation of material for stabilisation as well as soft tissue coverage. For complicated or large defects various muscle flaps and the omentum majus have been advocated. The latissimus dorsi muscle with skin is the muscle flap most frequently used. PMID- 26492538 TI - Ammonium Sulfate Improves Detection of Hydrophilic Quaternary Ammonium Compounds through Decreased Ion Suppression in Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry. AB - Hydrophilic quaternary ammonium compounds (QACs) include derivatives of carnitine (Car) or choline, which are known to have essential bioactivities. Here we developed a technique for improving the detection of hydrophilic QACs using ammonium sulfate (AS) in matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS). In MALDI mass spectrometry for brain homogenates, the addition of AS greatly increased the signal intensities of Car, acetylcarnitine (AcCar), and glycerophosphocholine (GPC) by approximately 300-, 700-, and 2500 fold. The marked improvement required a higher AS concentration than that needed for suppressing the potassium adduction on phosphatidylcholine and 2,5 dihydroxybenzoic acid. Adding AS also increased the signal intensities of Car, AcCar, and GPC by approximately 10-, 20-, and 40-fold in MALDI-IMS. Consequently, the distributions of five hydrophilic QACs (Car, AcCar, GPC, choline, and phosphocholine) were simultaneously visualized by this technique. The distinct mechanism from other techniques such as improved matrix application, derivatization, or postionization suggests the great potential of AS addition to achieve higher sensitivity of MALDI-IMS for various analytes. PMID- 26492539 TI - Simulation of Human Plasma Concentrations of Thalidomide and Primary 5 Hydroxylated Metabolites Explored with Pharmacokinetic Data in Humanized TK-NOG Mice. AB - Plasma concentrations of thalidomide and primary 5-hydroxylated metabolites including 5,6-dihydroxythalidomide and glutathione (GSH) conjugate(s) were investigated in chimeric mice with highly "humanized" liver cells harboring cytochrome P450 3A5*1. Following oral administration of thalidomide (100 mg/kg), plasma concentrations of GSH conjugate(s) of 5-hydroxythalidomide were higher in humanized mice than in controls. Simulation of human plasma concentrations of thalidomide were achieved with a simplified physiologically based pharmacokinetic model in accordance with reported thalidomide concentrations. The results indicate that the pharmacokinetics in humans of GSH conjugate and/or catechol primary 5-hydroxylated thalidomide contributing in vivo activation can be estimated for the first time. PMID- 26492540 TI - DOES CLINICAL INERTIA VARY BY PERSONALIZED A1C GOAL? A STUDY OF PREDICTORS AND PREVALENCE OF CLINICAL INERTIA IN A U.S. MANAGED-CARE SETTING. AB - OBJECTIVE: Clinical inertia is defined as failure to initiate or intensify therapy despite an inadequate treatment response. We assessed the prevalence and identified the predictors of clinical inertia among patients with type 2 diabetes (T2DM) based on personalized goals. METHODS: Three hemoglobin A1c (A1C) targets (American Diabetes Association A1C <7.0%; modified Ismail-Beigi et al; and Healthcare Effectiveness Data and Information Set) were used when identifying adult patients with T2DM who experienced above-target A1C values during the index period (July 1, 2008 to June 30, 2012) in a U.S. managed-care claims database (IMPACTTM). Clinical inertia was defined as no intensification of treatment during the response period. Demographic and clinical characteristics were analyzed to identify predictors of treatment intensification. RESULTS: Irrespective of A1C target, the majority of patients with T2DM (70.4 to 72.8%) experienced clinical inertia in the 6 months following the index event, with 5.3 to 6.2% of patients intensifying treatment with insulin. Patients with a lower likelihood of intensification were older, used >1 oral antidiabetes drug during the baseline period, and had an above-target A1C more recently. Treatment intensification was associated with patients who had point-of-service insurance, mental illness, an endocrinologist visit in the baseline period, or higher index A1C. CONCLUSION: The prevalence of clinical inertia among patients with T2DM in a U.S. managed-care setting is high and has increased over more recent years. Factors predicting increased risk of clinical inertia may help identify "at-risk" populations and assist in developing strategies to improve their management. PMID- 26492541 TI - HOSPITAL INSULIN PROTOCOL AIMS FOR GLUCOSE CONTROL IN GLUCOCORTICOID-INDUCED HYPERGLYCEMIA. AB - OBJECTIVE: To compare the effectiveness of 2 insulin protocols to treat glucocorticoid-induced hyperglycemia in the nonintensive care hospital setting. METHODS: A randomized, open-label, parallel-arm study was conducted comparing standard recommended care of complete insulin orders (CIO) (i.e., 3-part insulin regimen of long-acting basal [background], rapid-acting bolus [mealtime], and rapid-acting correction factor) to an experimental group following a regimen of Neutral Protamine Hagedorn (NPH) plus CIO (NPH-CIO). The primary outcome was mean blood glucose (BG), and the secondary outcome was percent of BG in target range of 70 to 180 mg/dL. Hypoglycemia was also evaluated. RESULTS: Sixty-one patients completed 2 to 5 consecutive inpatient days (31 CIO; 30 NPH-CIO). Baseline mean BG results were 237.2 +/- 50.2 and 221.9 +/- 35.8 mg/dL (P = .30) in the CIO and NPH-CIO groups, respectively. No significant difference in overall mean BG between the 2 groups was detected; however, a significant difference arose on day 3: mean BG 181.8 +/- 32.6 mg/dL (CIO) versus 157.2 +/- 6.1 mg/dL (NPH-CIO) (P = .03). Moreover, the total daily doses (TDDs) of insulin did not differ: 34.8 +/- 43.0 units (CIO) versus 35.8 +/- 25.0 units (NPH-CIO) (P = .13). Percent of BG in target was 54.6% (CIO) and 62% (NPH-CIO) (P = .24). Incidence of severe hypoglycemia (<50 mg/dL) was the same in both groups (0.1%). CONCLUSION: NPH added to 3-part insulin regimen (CIO) may be an effective way to a combat glucocorticoid-induced hyperglycemia, though further research is needed in a larger population. PMID- 26492542 TI - RADIOACTIVE IODINE THERAPY WITHOUT RECENT ANTITHYROID DRUG PRETREATMENT FOR HYPERTHYROIDISM COMPLICATED BY SEVERE HYPERBILIRUBINEMIA DUE TO HEPATIC DYSFUNCTION: EXPERIENCE OF A CHINESE MEDICAL CENTER. AB - OBJECTIVE: The objective of this work is to report our experience with (131)I therapy without recent antithyroid drug (ATD) pretreatment for refractory severe hyperthyroidism complicated by hyperbilirubinemia due to hepatic dysfunction. METHODS: Five patients with refractory severe hyperthyroidism were treated with (131)I at 90 to 120 MUCi/g-thyroid (total activity, 6.2 to 10.1 mCi). The patients previously had received ATD treatment from 2 months to 12 years and discontinued ATDs from 2 months to 4 years before (131)I treatment due to treatment failure or severe jaundice. Prior to (131)I therapy, the patients were asked to take a low-iodine diet and were treated with bisoprolol fumarate, digoxin, furosemide, S-adenosylmethionine, polyene phosphatidylcholine, and plasma exchange as supportive treatment for related clinical conditions. Four of the patients also received lithium carbonate in conjunction with their (131)I treatment. The patients were followed for 4 to 9 years after (131)I therapy. RESULTS: After (131)I treatment, jaundice disappeared completely within 3 to 4 months in all patients, and liver function tests returned to normal. Concurrent atrial fibrillation and heart failure, leukopenia and thrombocytopenia, or thrombocytopenia and left cardiac enlargement improved remarkably in 3 patients during the follow-up period. Three to 45 months after (131)I treatment, hypothyroidism was noted in the patients and they were treated with L-thyroxine replacement therapy. CONCLUSION: (131)I therapy without recent ATD pretreatment for refractory severe hyperthyroidism complicated by serious jaundice appears to be safe and effective, with good long-term results. It may be the preferred therapy for such patients and should be used as early as possible. PMID- 26492543 TI - AN AGGRESSIVE TEMPORAL BONE SDHC PARAGANGLIOMA ASSOCIATED WITH INCREASED HIF 2alpha SIGNALING. AB - OBJECTIVE: To describe a patient with a germline succinate dehydrogenase (SDHC) gene mutation presenting with primary hyperparathyroidism and a large catecholamine-producing temporal bone paraganglioma (PGL). METHODS: Evaluation of a SDHC mutation-positive PGL tumor biology using staining for tyrosine hydroxylase (TH), hypoxia-inducible factors 1alpha (HIF-1alpha) and 2alpha (HIF 2alpha). RESULTS: A 66-year-old man was noted to have a lytic skull base mass during work-up for his primary hyperparathyroidism. Biochemical evaluation with 24-hour urine catecholamines and metanephrines revealed marked elevation of norepinephrine and normetanephrine. Genetic testing revealed a germline SDHC mutation. A partial excision of skull base tumor was performed, which upon further examination revealed PGL. Immunohistochemistry of skull base PGL demonstrated heavy expression of TH and HIF-2alpha but reduced expression of HIF 1alpha. The remaining skull base PGL was treated with adjuvant radiation therapy. The patient's normetanephrine levels significantly decreased after surgery and radiation. CONCLUSION: Here, we report an unusual case of a patient presenting with a germline SDHC mutation-related functional PGL along with concomitant primary hyperparathyroidism. The present case illustrates that overexpression of HIF-2alpha but not of HIF-1alpha is linked to the pathogenesis of SDHC mutation related PGL, and it may be responsible for the aggressive clinical behavior of a usually indolent course of SDHC-related PGLs. PMID- 26492544 TI - ASSOCIATION BETWEEN HYPOGLYCEMIA AND FALL-RELATED FRACTURES AND HEALTH CARE UTILIZATION IN OLDER VETERANS WITH TYPE 2 DIABETES. AB - OBJECTIVE: To examine the association between hypoglycemia and fall-related outcomes in older patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective cohort study used electronic medical records of T2DM patients (>=65 years) from the Veterans Integrated Service Network 16 (VISN 16) data warehouse (01/01/2004-06/30/2010). Patients in nonhypoglycemia group (non-HG) were 1:1 randomly matched with patients in hypoglycemia group (HG) by age (+/-5 years), sex, race, and medical center location. Fall-related events (i.e., fractures and head injuries) were identified, with a fall being the external cause within +/-2 days. McNemar tests and generalized estimating equation (GEE) models were used to compare fall-related events in the 1-year outcome period after the index date (i.e., date of first hypoglycemic episode). We also examined fall-related healthcare utilization. RESULTS: A total of 4,215 patients in each group were studied, with the mean age of 76.5 years (SD: 5.85). The mean Charlson comorbidity index (CCI) scores were 5.73 (SD: 2.95) in the HG and 4.34 (SD: 2.40) in the non-HG. The HG had significantly higher rates of fall-related events than non-HG, 27 (0.64%) versus 1 (0.02%) and 89 (2.11%) versus 21 (0.50%) events within 30 days and 1 year, respectively. GEE models confirmed the elevated risk of fall-related events after controlling for sociodemographic and clinical characteristics, comorbidities, and medication use (adjusted odds ratio [aOR]: 2.70; 95% confidence interval [CI]: 1.64-4.47). The HG patients were more likely to have emergency department (ED) visits, hospital admissions, and long-term care placement compared to their counterparts. CONCLUSION: Hypoglycemia is associated with worse fall-related outcomes among the elderly veterans. PMID- 26492545 TI - HIGH-PRECISION CONFORMAL FRACTIONATED RADIOTHERAPY IS EFFECTIVE IN ACHIEVING REMISSION IN PATIENTS WITH ACROMEGALY AFTER FAILED TRANSSPHENOIDAL SURGERY. AB - OBJECTIVE: Variable efficacy of pituitary radiotherapy in acromegaly is reported. Here we sought to assess the efficacy of high-precision conformal fractionated radiotherapy (CRT) in patients with acromegaly after failed TSS. METHODS: A retrospective analysis was conducted a in tertiary care referral center between 1999 to 2013 on 36 acromegaly patients (M: 16, F: 20; median age: 36.0 years) with macroadenoma and mean growth hormone (GH) and insulin-like growth factor-1 (IGF1) upper limits of normal (ULN) of 15.9 +/- 14.3 ng/mL and 1.74 +/- 0.43, respectively. The cohort was divided into 2 groups: 30 patients (M: 13, F: 17) who were medical treatment naive, and 6 patients (M: 3, F: 3) who received medical treatment after CRT. RESULTS: Normalization of GH (fasting GH <1 ng/mL), normalization of IGF1 (ULN <1), and remission (normalization of GH and IGF1) were achieved in 20 (55%), 23 (63%) and 20 (55%) patients, respectively. The mean time required to achieve remission was 63 +/- 33.4 months. Follow-up duration was the only predictor of achieving remission. GH level declined exponentially by 65% and 89% at 2 and 5 years, respectively. New onset hypopituitarism was noted in 33% of patients. Tumor control was achieved in 100% of patients. In groups 1 and 2, 18 (60%) and 2 (33.3%) achieved remission post-CRT, and the mean times required to achieve remission were 58.6 +/- 30.7 months and 102 +/- 42.4 months, respectively. CONCLUSION: High-precision CRT is an effective modality to achieve remission in patients with acromegaly after failed TSS. PMID- 26492546 TI - Emerging innovative therapeutic approaches targeting PCSK9 to lower lipids. AB - Statins are established therapies for cardiovascular disease prevention and ezetimibe has recently been shown to modestly reduce cardiovascular events when added to background statin therapy. Yet here remains a clear unmet need for additional therapies aimed at lowering low density lipoprotein cholesterol (LDL C) to further reduce cardiovascular risk. Multiple strategies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have emerged as effective modalities for LDL-C lowering. PCSK9 monoclonal antibodies are the farthest along in clinical development and alirocumab and evolocumab were approved for clinical use by regulatory agencies in 2015. In addition to robust LDL-C lowering (nearly 50-65% from baseline), they improve other lipid parameters as well. Adverse events associated with these medications are minimal. Importantly, they improve clinical cardiovascular disease outcomes, although long term study results are awaited. Cost may be an important limiting factor in their use and we propose two possible solutions which can potentially curtail cost. PMID- 26492547 TI - Outcome of Patients with Interstitial Lung Disease Treated with Extracorporeal Membrane Oxygenation for Acute Respiratory Failure. AB - RATIONALE: Patients with interstitial lung disease and acute respiratory failure have a poor prognosis especially if mechanical ventilation is required. OBJECTIVES: To investigate the outcome of patients with acute respiratory failure in interstitial lung disease undergoing extracorporeal membrane oxygenation (ECMO) as a bridge to recovery or transplantation. METHODS: This was a retrospective analysis of all patients with interstitial lung disease and acute respiratory failure treated with or without ECMO from March 2012 to August 2015. MEASUREMENTS AND MAIN RESULTS: Forty patients with interstitial lung disease referred to our intensive care unit for acute respiratory failure were included in the analysis. Twenty-one were treated with ECMO. Eight patients were transferred by air from other hospitals within a range of 320 km (linear distance) for extended intensive care including the option of lung transplant. In total, 13 patients were evaluated, and eight were finally found to be suitable for lung transplantation from an ECMO bridge. Four patients from external hospitals were de novo listed during acute respiratory failure. Six patients underwent lung transplant, and two died on the waiting list after 9 and 63 days on ECMO, respectively. A total of 14 of 15 patients who did not undergo lung transplantation (93.3%) died after 40.3 +/- 27.8 days on ECMO. Five out of six patients (83.3%) receiving a lung transplant could be discharged from hospital. CONCLUSIONS: ECMO is a lifesaving option for patients with interstitial lung disease and acute respiratory failure provided they are candidates for lung transplantation. ECMO is not able to reverse the poor prognosis in patients that do not qualify for lung transplantation. PMID- 26492548 TI - Transformation with TT8 and HB12 RNAi Constructs in Model Forage (Medicago sativa, Alfalfa) Affects Carbohydrate Structure and Metabolic Characteristics in Ruminant Livestock Systems. AB - Lignin, a phenylpropanoid polymer present in secondary cell walls, has a negative impact on feed digestibility. TT8 and HB12 genes were shown to have low expression levels in low-lignin tissues of alfalfa, but to date, there has been no study on the effect of down-regulation of these two genes in alfalfa on nutrient chemical profiles and availability in ruminant livestock systems. The objectives of this study were to investigate the effect of transformation of alfalfa with TT8 and HB12 RNAi constructs on carbohydrate (CHO) structure and CHO nutritive value in ruminant livestock systems. The results showed that transformation with TT8 and HB12 RNAi constructs reduced rumen, rapidly degraded CHO fractions (RDCA4, P = 0.06; RDCB1, P < 0.01) and totally degraded CHO fraction (TRDCHO, P = 0.08). Both HB12 and TT8 populations had significantly higher in vitro digestibility of neutral detergent fiber (NDF) at 30 h of incubation (ivNDF30) compared to the control (P < 0.01). The TT8 populations had highest ivDM30 and ivNDF240. Transformation of alfalfa with TT8 and HB12 RNAi constructs induced molecular structure changes. Different CHO functional groups had different sensitivities and different responses to the transformation. The CHO molecular structure changes induced by the transformation were associated with predicted CHO availability. Compared with HB12 RNAi, transformation with TT8 RNAi could improve forage quality by increasing the availability of both NDF and DM. Further study is needed on the relationship between the transformation induced structure changes at a molecular level and nutrient utilization in ruminant livestock systems when lignification is much higher. PMID- 26492549 TI - Predictors of Discharge Disposition in Older Adults With Burns: A Study of the Burn Model Systems. AB - Older patients with burn injury have a greater likelihood for discharge to nursing facilities. Recent research indicates that older patients discharged to nursing facilities are two to three times as likely to die within a 3-year period relative to those discharged to home. In light of these poor long-term outcomes, we conducted this study to identify predictors for discharge to independent vs nonindependent living status in older patients hospitalized for burns. We retrospectively reviewed all older adults (age >= 55 years) who were prospectively enrolled in a longitudinal multicenter study of outcomes from 1993 to 2011. Patient, injury, and treatment outcomes data were analyzed. Recognizing that transfer to inpatient rehabilitation may have impacted final hospital discharge disposition: we assessed the likelihood of inpatient rehabilitation stay, based on identified predictors of inpatient rehabilitation. We subsequently performed a logistic regression analysis on the clustered, propensity-matched cohort to assess associations of burn and injury characteristics on the primary outcome of final discharge status. A total of 591 patients aged >=55 years were treated and discharged alive from three participating U.S. burn centers during the study period. Mean burn size was 14.8% (SD 11.2%) and mean age was 66.7 years (SD 9.3 years). Ninety-three patients had an inpatient rehabilitation stay before discharge (15.7%). Significant factors predictive of inpatient rehabilitation included a burn >20% TBSA, mechanical ventilation, older age, range of motion deficits at acute care discharge, and study site. These factors were included in the propensity model. Four hundred seventy-one patients (80%) were discharged to independent living status. By matched propensity analysis, older age was significantly associated with a higher likelihood of discharge to nonindependent living (P < .01 in both the 65-74 age group and the oldest age group when compared with the 55-64 age group). Comorbidity (P < .01) and history of alcohol abuse (P < 0.01) were also predictive patient factors. Furthermore, clinical practice variations among the three study sites also constituted a significant factor in discharge disposition (both P < .01 when compared with the index study site). Older age remains an important risk factor for discharge to nonindependent living status, even after accounting for inpatient rehabilitation stay. This analysis, however, reveals significant variations in discharge disposition practices among the three participating study sites. We believe that these variations among burn centers need to be elucidated to better understand discharge disposition status in older patients with burns. PMID- 26492550 TI - A Simple Method for Immunohistochemical Staining of Zebrafish Brain Sections for c-fos Protein Expression. AB - Immediate early genes (IEGs) are transcription factors whose own transcription is initiated rapidly, for example, in the brain in response to environmental stimuli. c-fos is an IEG often used as a marker of neuronal activation. c-fos mRNA expression has started to be quantified and localized in the zebrafish brain following environmental manipulations but analysis of the expression of c-fos protein in the zebrafish brain has rarely been attempted. Here, we describe an immunofluorescence staining method for quantifying c-fos protein expression in different regions of the zebrafish brain. In addition, we expose zebrafish to caffeine, a positive control for c-fos activation in the brain. To confirm cell nucleus specific binding of the c-fos antibody, we counterstained brain sections with the nuclear fluorescent stain DAPI. Furthermore, we describe a method for reducing background autofluorescence often observed in zebrafish brain tissue. Our analysis showed that exposure to caffeine increased the number of c-fos protein-positive cells in specific zebrafish brain regions detected by the immunofluorescence method. Our results demonstrate the feasibility of immunofluorescence-based methods in the analysis of neuronal activation in the zebrafish brain, and reinforce the utility of the zebrafish in behavioral neuroscience research. PMID- 26492551 TI - Cation Exchange in Dynamic 3D Porous Magnets: Improvement of the Physical Properties. AB - We report two novel three-dimensional porous coordination polymers (PCPs) of formulas Li4{Mn4[Cu2(Me3mpba)2]3}.68H2O (2) and K4{Mn4[Cu2(Me3mpba)2]3}.69H2O (3) obtained-via alkali cation exchange in a single-crystal to single-crystal process from the earlier reported anionic manganese(II)-copper(II) PCP of formula Na4{Mn4[Cu2(Me3mpba)2]3}.60H2O (1) [Me3mpba(4-) = N,N'-2,4,6-trimethyl-1,3 phenylenebis(oxamate)]. This postsynthetic process succeeds where the direct synthesis in solution from the corresponding building blocks fails and affords significantly more robust PCPs with enhanced magnetic properties [long-range 3D magnetic ordering temperatures for the dehydrated phases (1'-3') of 2.0 (1'), 12.0 (2'), and 20.0 K (3')]. Changes in the adsorptive properties upon postsynthetic exchange suggest that the nature, electrostatic properties, mobility, and location of the cations within the framework are crucial for the enhanced structural stability. Overall, these results further confirm the potential of postsynthetic methods (including cation exchange) to obtain PCPs with novel or enhanced physical properties while maintaining unaltered their open framework structures. PMID- 26492552 TI - Gas-Phase Acidities of Phosphorylated Amino Acids. AB - Gas-phase acidities and heats of formation have been predicted at the G3(MP2)/SCRF-COSMO level of theory for 10 phosphorylated amino acids and their corresponding amides, including phospho-serine (pSer), -threonine (pThr), and tyrosine (pTyr), providing the first reliable set of these values. The gas-phase acidities (GAs) of the three named phosphorylated amino acids and their amides have been determined using proton transfer reactions in a Fourier transform ion cyclotron mass spectrometer. Excellent agreement was found between the experimental and predicted GAs. The phosphate group is the deprotonation site for pSer and pThr and deprotonation from the carboxylic acid generated the lowest energy anion for pTyr. The infrared spectra were calculated for six low energy anions of pSer, pThr, and pTyr. For deprotonated pSer and pThr, good agreement is found between the experimental IRMPD spectra and the calculated spectra for our lowest energy anion structure. For pTyr, the IR spectra for a higher energy phosphate deprotonated structure is in good agreement with experiment. Additional experiments tested electrospray ionization (ESI) conditions for pTyr and determined that variations in solvent, temperature, and voltage can result in a different experimental GA value, indicating that ESI conditions affect the conformation of the pTyr anion. PMID- 26492553 TI - Halocyclization of Unsaturated Guanidines Mediated by Koser's Reagent and Lithium Halides. AB - The synthesis of halogenated cyclic guanidines through iodine(III)-mediated umpolung of halide salts is described. Cyclic guanidines of various sizes can be obtained with generally excellent regioselectivities through either a chloro- or a bromocyclization, using Koser's reagent and the corresponding lithium salt. PMID- 26492555 TI - Chemoselective N-deacetylation of protected nucleosides and nucleotides promoted by Schwartz's reagent. AB - Protection and deprotection strategies involving the N-acetyl group are widely utilized in nucleoside and nucleotide chemistry. Herein, we present a mild and selective N-deacetylation methodology, applicable to purine and pyrimidine nucleosides, by means of Schwartz's reagent, compatible with most of the common protecting groups used in nucleoside chemistry. PMID- 26492557 TI - Fourteenth International Kidney Cancer Symposium Miami Marriott Biscayne Bay, Miami, Florida 6-7 November 2015. PMID- 26492556 TI - A survey on the correlation between sexual satisfaction and depressive symptoms during infertility. AB - This cross-sectional study has been conducted in a descriptive, correlational design in order to determine the correlation between sexual satisfaction and depressive symptoms. In this respect, sexual satisfaction and depression scores were assessed in 102 infertile couples in a Turkish university hospital. There was a positive and meaningful correlation between Beck Depression scores and educational status and monthly income of infertile women on the one hand, and among marriage, infertility, infertility treatment durations, and the number of assisted-reproduction treatments on the other hand. It was found that there were more sexual dysfunctions in women than in men and that they were affected more deeply. As a result, it might be suggested that infertile couples receive proper guidance from health professionals in the course of treatment. PMID- 26492558 TI - Seagrass Herbivory Levels Sustain Site-Fidelity in a Remnant Dugong Population. AB - Herds of dugong, a largely tropical marine megaherbivore, are known to undertake long-distance movements, sequentially overgrazing seagrass meadows in their path. Given their drastic declines in many regions, it is unclear whether at lower densities, their grazing is less intense, reducing their need to travel between meadows. We studied the effect of the feeding behaviour of a small dugong population in the Andaman and Nicobar archipelago, India to understand how small isolated populations graze seagrasses. In the seven years of our observation, all recorded dugongs travelled either solitarily or in pairs, and their use of seagrasses was limited to 8 meadows, some of which were persistently grazed. These meadows were relatively large, contiguous and dominated by short-lived seagrasses species. Dugongs consumed approximately 15% of meadow primary production, but there was a large variation (3-40% of total meadow production) in consumption patterns between meadows. The impact of herbivory was relatively high, with shoot densities c. 50% higher inside herbivore exclosures than in areas exposed to repeated grazing. Our results indicate that dugongs in the study area repeatedly graze the same meadows probably because the proportion of primary production consumed reduces shoot density to levels that are still above values that can trigger meadow abandonment. This ability of seagrasses to cope perhaps explains the long-term site fidelity shown by individual dugongs in these meadows. The fact that seagrass meadows in the archipelago are able to support dugong foraging requirements allows us to clearly identify locations where this remnant population persists, and where urgent management efforts can be directed. PMID- 26492559 TI - A Retrospective Evaluation of Critical Care Blood Culture Yield - Do Support Services Contribute to the "Weekend Effect"? AB - BACKGROUND: The "weekend effect" describes an increase in adverse outcomes for patients admitted at the weekend. Critical care units have moved to higher intensity working patterns to address this with some improved outcomes. However, support services have persisted with traditional working patterns. Blood cultures are an essential diagnostic tool for patients with sepsis but yield is dependent on sampling technique and processing. We therefore used blood culture yield as a surrogate for the quality of support service provision. We hypothesized that blood culture yields would be lower over the weekend as a consequence of reduced support services. METHODS: We performed a retrospective observational study examining 1575 blood culture samples in a university hospital critical care unit over a one-year period. RESULTS: Patients with positive cultures had, on average, higher APACHE II scores (p = 0.015), longer durations of stay (p = 0.03), required more renal replacement therapy (p<0.001) and had higher mortality (p = 0.024). Blood culture yield decreased with repeated sampling with an increased proportion of contaminants. Blood cultures were 26.7% less likely to be positive if taken at the weekend (p = 0.0402). This effect size is the equivalent to the impact of sampling before and after antibiotic administration. CONCLUSIONS: Our study demonstrates that blood culture yield is lower at the weekend. This is likely caused by delays or errors in incubation and processing, reflecting the reduced provision of support services at the weekend. Reorganization of services to address the "weekend effect" should acknowledge the interdependent nature of healthcare service delivery. PMID- 26492560 TI - Immunological effects in patients with steroid-refractory graft-versus-host disease following treatment with basiliximab, a CD25 monoclonal antibody. AB - Steroid-refractory graft-versus-host disease (GvHD) is a complication following an allogeneic stem cell transplantation with limited therapeutic options. Studies have shown a response in up to 80% of patients with this condition after treatment with the CD25 monoclonal antibody, basiliximab. Despite the good responses to treatment, around 50% of the patients experience recurrence of their GvHD symptoms 4-6 wk following cessation of therapy. The in vivo changes in the following treatment with this antibody have not been elucidated so far. We treated 14 patients with severe steroid-refractory GvHD with basiliximab weekly for 4 wk and monitored the changes in the T-, B-, NK- and dendritic cell subsets over this time period. The overall response to treatment was 92% (13/14) with 50% (7/14) achieving a complete response. Fifty four percentage (7/13) of the patients who responded showed recurrence of their GvHD symptoms. Contrary to expectations, our observations showed a significant depletion of the regulatory T cell subset following treatment. Our findings suggest that the undesirable depletion of the regulatory T cells along with the CD25(+) acute inflammatory cells might be responsible for the high incidence of GvHD recurrence in this cohort of patients. PMID- 26492561 TI - Formation, Removal, and Reformation of Surface Coatings on Various Metal Oxide Surfaces Inspired by Mussel Adhesives. AB - Mussels survive by strongly attaching to a variety of different surfaces, primarily subsurface rocks composed of metal oxides, through the formation of coordinative interactions driven by protein-based catechol repeating units contained within their adhesive secretions. From a chemistry perspective, catechols are known to form strong and reversible complexes with metal ions or metal oxides, with the binding affinity being dependent on the nature of the metal ion. As a result, catechol binding with metal oxides is reversible and can be broken in the presence of a free metal ion with a higher stability constant. It is proposed to exploit this competitive exchange in the design of a new strategy for the formation, removal, and reformation of surface coatings and self assembled monolayers (SAM) based on catechols as the adhesive unit. In this study, catechol-functionalized tri(ethylene oxide) (TEO) was synthesized as a removable and recoverable self-assembled monolayer (SAM) for use on oxides surfaces. Attachment and detachment of these catechol derivatives on a variety of surfaces was shown to be reversible and controllable by exploiting the high stability constant of catechol to soluble metal ions, such as Fe(III). This tunable assembly based on catechol binding to metal oxides represents a new concept for reformable coatings with applications in fields ranging from friction/wettability control to biomolecular sensing and antifouling. PMID- 26492562 TI - French Maritime Pine Bark Extract (Pycnogenol(r)) Effects on Human Skin: Clinical and Molecular Evidence. AB - Nutritional strategies to benefit skin health are of growing importance. Current approaches mainly involve nutritional supplements containing antioxidants which were initially designed to protect human skin against ultraviolet radiation induced damage. Within recent years, however, a growing number of studies suggests that the beneficial effects of these products clearly extend beyond photoprotection. In this review we take the nutritional supplement Pycnogenol(r), which is based on an extract prepared from French marine pine bark extract, as an example to illustrate this development. Accordingly, the existing data provide compelling evidence that Pycnogenol(r) intake does not only provide photoprotection, but may be used to (i) reduce hyperpigmentation of human skin and (ii) improve skin barrier function and extracellular matrix homeostasis. PMID- 26492564 TI - Incidence and prognostic factors of chronic pain after isolated musculoskeletal extremity injury. AB - BACKGROUND: Chronic pain in patients is usually related to an episode of pain following acute injury, emphasizing the need to prevent progression from acute to chronic pain. Multiple factors in the acute phase might be responsible for perpetuating the pain. The presentation of patients at the emergency department (ED) presents a prime opportunity to identify patients at high risk for chronic pain and to start appropriate treatment. METHODS: The PROTACT study is a prospective follow-up study aiming to estimate the incidence and prognostic factors responsible for the development of chronic pain after musculoskeletal injury. Data including sociodemographic, pain, clinical, injury- or treatment related and psychological factors of 435 patients were collected from registries and questionnaires at ED visit, 6-week, 3- and 6-month follow-up. RESULTS: At 6 months post-injury, 43.9% of the patients had some degree of pain (Numeric Rating Scale (NRS) >=1) and 10.1% had chronic pain (NRS >=4). Patients aged over 40 years, in poor physical health, with pre-injury chronic pain, pain catastrophizing, high urgency level and severe pain at discharge were found to be at high risk for chronic pain. CONCLUSIONS: Two prognostic factors, severe pain at discharge and pain catastrophizing, are potentially modifiable. The implementation of a pain protocol in the ED and the use of cognitive-behavioural techniques involving reducing catastrophizing might be useful. PMID- 26492563 TI - TIM-3 Suppresses Anti-CD3/CD28-Induced TCR Activation and IL-2 Expression through the NFAT Signaling Pathway. AB - TIM-3 (T cell immunoglobulin and mucin-domain containing protein 3) is a member of the TIM family of proteins that is preferentially expressed on Th1 polarized CD4+ and CD8+ T cells. Recent studies indicate that TIM-3 serves as a negative regulator of T cell function (i.e. T cell dependent immune responses, proliferation, tolerance, and exhaustion). Despite having no recognizable inhibitory signaling motifs, the intracellular tail of TIM-3 is apparently indispensable for function. Specifically, the conserved residues Y265/Y272 and surrounding amino acids appear to be critical for function. Mechanistically, several studies suggest that TIM-3 can associate with interleukin inducible T cell kinase (ITK), the Src kinases Fyn and Lck, and the p85 phosphatidylinositol 3-kinase (PI3K) adaptor protein to positively or negatively regulate IL-2 production via NF-kappaB/NFAT signaling pathways. To begin to address this discrepancy, we examined the effect of TIM-3 in two model systems. First, we generated several Jurkat T cell lines stably expressing human TIM-3 or murine CD28-ECD/human TIM-3 intracellular tail chimeras and examined the effects that TIM-3 exerts on T cell Receptor (TCR)-mediated activation, cytokine secretion, promoter activity, and protein kinase association. In this model, our results demonstrate that TIM-3 inhibits several TCR-mediated phenotypes: i) NF-kB/NFAT activation, ii) CD69 expression, and iii) suppression of IL-2 secretion. To confirm our Jurkat cell observations we developed a primary human CD8+ cell system that expresses endogenous levels of TIM-3. Upon TCR ligation, we observed the loss of NFAT reporter activity and IL-2 secretion, and identified the association of Src kinase Lck, and PLC-gamma with TIM-3. Taken together, our results support the conclusion that TIM-3 is a negative regulator of TCR-function by attenuating activation signals mediated by CD3/CD28 co-stimulation. PMID- 26492566 TI - Photodissociation Dynamics of Diacetylene Rydberg States. AB - The state-selective photodissociation of diacetylene (C4H2) was studied in the wavelength range of 127.5-164.4 nm by high-resolution Rydberg H atom time-of flight spectroscopy measurements. In the wavelength region, two Rydberg series nR and nR' were state-selectively excited using tunable vacuum-ultraviolet laser radiation. In all photolysis wavelengths, two decay channels with different dissociation dynamics were observed. In one channel, the characteristic and isotropic translational energy distributions with a peak around 1800 cm(-1) can be found, suggesting statistical dissociation through internal conversion (IC) from the Rydberg state to the ground state and then dissociation on the ground state surface. In contrast to this, in the second channel, nonstatistical and anisotropic translational energy distributions were observed, possibly through IC to the excited repulsive state. The vibrational progressions of C4H (A(2)Pi) products have also been observed and assigned to the CCC bend and C=C stretch progressions in the second channel at 3R Rydberg states. PMID- 26492565 TI - The Fungal Exopolysaccharide Galactosaminogalactan Mediates Virulence by Enhancing Resistance to Neutrophil Extracellular Traps. AB - Of the over 250 Aspergillus species, Aspergillus fumigatus accounts for up to 80% of invasive human infections. A. fumigatus produces galactosaminogalactan (GAG), an exopolysaccharide composed of galactose and N-acetyl-galactosamine (GalNAc) that mediates adherence and is required for full virulence. Less pathogenic Aspergillus species were found to produce GAG with a lower GalNAc content than A. fumigatus and expressed minimal amounts of cell wall-bound GAG. Increasing the GalNAc content of GAG of the minimally pathogenic A. nidulans, either through overexpression of the A. nidulans epimerase UgeB or by heterologous expression of the A. fumigatus epimerase Uge3 increased the amount of cell wall bound GAG, augmented adherence in vitro and enhanced virulence in corticosteroid-treated mice to levels similar to A. fumigatus. The enhanced virulence of the overexpression strain of A. nidulans was associated with increased resistance to NADPH oxidase-dependent neutrophil extracellular traps (NETs) in vitro, and was not observed in neutropenic mice or mice deficient in NADPH-oxidase that are unable to form NETs. Collectively, these data suggest that cell wall-bound GAG enhances virulence through mediating resistance to NETs. PMID- 26492568 TI - Ultrasound visualization of nerve remodeling after strenuous exercise. AB - INTRODUCTION: The aim of this case study is to describe the use of nerve ultrasound to visualize the morphological changes that occur during conduction velocity alterations after strenuous exercise. METHODS: A 32-year-old, healthy runner underwent clinical, electrophysiological, and ultrasound evaluation 24 hours before, 30 minutes after, and 24 hours after a marathon. RESULTS: An increase in motor conduction velocity of the median, ulnar, radial, and tibial nerves and sensory conduction velocity of the median and ulnar nerves was found between pre- and post-marathon studies. An increase in the cross-sectional area of the median (carpal tunnel), ulnar (Guyon canal and elbow), fibular (fibular head), and tibial (ankle) nerves was documented. No changes in the MRC sum scale score of the various peripheral nerves were detected. CONCLUSION: The case described shows the morphological changes that occur in healthy peripheral nerves during conduction velocity alterations. PMID- 26492567 TI - Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601. AB - Bortezomib is active in mantle cell lymphoma (MCL), with approval in upfront and relapsed settings. Given inevitable recurrence following induction chemoimmunotherapy, maintenance approaches are a rational strategy to improve clinical outcomes. We conducted a phase II study to evaluate the safety and efficacy of six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus bortezomib (1.3 mg/m2 days 1 and 4 of 21 d cycles) followed by bortezomib maintenance (1.3 mg/m2 days 1, 4, 8, and 11 every 3 months for 2 years). Sixty-five eligible patients were enrolled. The treatment was well tolerated and toxicities were mainly haematological. The rate of grade >=3 peripheral neuropathy was low (5%). With a median follow-up of 6.8 years, 2-year progression-free survival (PFS) was 62%, and 2-year overall survival (OS) was 85%. At 5 years, PFS was 28% and OS was 66%. MCL International Prognostic Index scores were significantly associated with 2-year PFS, but did not predict long term (>=5-year) PFS. Baseline Ki-67 index was significantly associated with survival. Combination R-CHOP with bortezomib followed by maintenance bortezomib appears to improve outcomes compared historically with R-CHOP alone, with prolonged remissions in a subset of patients. These results suggest that inclusion of bortezomib with induction chemotherapy and/or maintenance is promising in MCL and warrants further exploration. PMID- 26492569 TI - Nondermatomal somatosensory deficits in chronic pain are associated with cerebral grey matter changes. AB - OBJECTIVES: Widespread sensory deficits occur in 20-40% of chronic pain patients on the side of pain, independent of pain aetiology, and are known as nondermatomal sensory deficits (NDSDs). NDSDs can occur in absence of central or peripheral nervous system lesions. We hypothesised that NDSDs were associated with cerebral grey matter changes in the sensory system and in pain processing regions, detectable with voxel-based morphometry. METHODS: Twenty-five patients with NDSDs, 23 patients without NDSDs ("pain-only"), and 29 healthy controls were studied with high resolution structural MRI of the brain. A comprehensive clinical and psychiatric evaluation based on Diagnostic and Statistical Manual was performed in all patients. RESULTS: Patients with NDSDs and "pain-only" did not differ concerning demographic data and psychiatric diagnoses, although anxiety scores (HADS-A) were higher in patients with NDSDs. In patients with NDSDs, grey matter increases were found in the right primary sensory cortex, thalamus, and bilaterally in lateral temporal regions and the hippocampus/fusiform gyrus. "Pain-only" patients showed a bilateral grey matter increase in the posterior insula and less pronounced changes in sensorimotor cortex. CONCLUSIONS: Dysfunctional sensory processing in patients with NDSDs is associated with complex changes in grey matter volume, involving the somatosensory system and temporal regions. PMID- 26492572 TI - Water Permeability across Symmetric and Asymmetric Droplet Interface Bilayers: Interaction of Cholesterol Sulfate with DPhPC. AB - Cellular membranes employ a variety of strategies for controlling the flow of small molecules into the cytoplasmic space, including incorporation of sterols for modulation of permeability and maintenance of lipid asymmetry to provide both sides of the membrane with differing biophysical properties. The specific case of cholesterol asymmetry, especially, is known to have profound effects in neurological cellular systems. Synthetic membrane models that can readily determine valuable physical parameters, such as water transport rates, for sterol containing membranes of defined lipid composition remain in demand. We report the use of the droplet interface bilayer (DIB), composed of adherent aqueous droplets surrounded by a lipid monolayer and immersed in a hydrophobic medium, for measurement of water permeability across the membrane, with rapid visualization and ease of experimental setup. We studied droplet bilayer membranes composed of the prototypical synthetic membrane lipid (i.e., the archaeal lipid DPhPC) as well as of symmetric and asymmetric DIBs formed by DPhPC and sodium cholesterol sulfate (S-Chol). The presence of S-Chol in DPhPC in symmetric DIB reduced the passive water permeability rate (P(f)) at all concentrations and increased the activation energy (E(a)) to 17-18 kcal/mol. When only one side of the DIB contains S-Chol (asymmetric DIB), an E(a) of 14-15 kcal/mol was obtained, a value intermediate that of pure lipid and symmetrical DIB containing lipid and S-Chol. Our data are consistent with a capability for regulation of water transport by one leaflet independent of the other. The engineering of our various systems is believed to have implications for garnering detailed knowledge regarding the transport of small moieties across bilayers in a wide variety of lipid systems. PMID- 26492573 TI - Inverted Quantum-Dot Light Emitting Diode Using Solution Processed p-Type WOx Doped PEDOT:PSS and Li Doped ZnO Charge Generation Layer. AB - Quantum dots (QDs) are a promising material for emissive display with low-cost manufacturing and excellent color purity. In this study, we report colloidal quantum-dot light emitting diodes (QLEDs) with an inverted architecture with a solution processed charge generation layer (CGL) of p-type polymer (tungsten oxide doped poly(ethylenedioxythiophene)/polystyrenesulfonate, PEDOT: PSS:WOx) and n-type metal oxide (lithium doped zinc oxide, LZO). The effective charge generation in solution processed p-n junction was confirmed by capacitance voltage (C-V) and current density-electric field characteristics. It is also demonstrated that the performances of CGL based QLEDs are very similar when various substrates with different work functions are used. PMID- 26492570 TI - Metabolic Signaling to Chromatin. AB - There is a dynamic interplay between metabolic processes and gene regulation via the remodeling of chromatin. Most chromatin-modifying enzymes use cofactors, which are products of metabolic processes. This article explores the biosynthetic pathways of the cofactors nicotinamide adenine dinucleotide (NAD), acetyl coenzyme A (acetyl-CoA), S-adenosyl methionine (SAM), alpha-ketoglutarate, and flavin adenine dinucleotide (FAD), and their role in metabolically regulating chromatin processes. A more detailed look at the interaction between chromatin and the metabolic processes of circadian rhythms and aging is described as a paradigm for this emerging interdisciplinary field. PMID- 26492574 TI - Qualitative and Quantitative Protein Complex Prediction Through Proteome-Wide Simulations. AB - Despite recent progress in proteomics most protein complexes are still unknown. Identification of these complexes will help us understand cellular regulatory mechanisms and support development of new drugs. Therefore it is really important to establish detailed information about the composition and the abundance of protein complexes but existing algorithms can only give qualitative predictions. Herein, we propose a new approach based on stochastic simulations of protein complex formation that integrates multi-source data--such as protein abundances, domain-domain interactions and functional annotations--to predict alternative forms of protein complexes together with their abundances. This method, called SiComPre (Simulation based Complex Prediction), achieves better qualitative prediction of yeast and human protein complexes than existing methods and is the first to predict protein complex abundances. Furthermore, we show that SiComPre can be used to predict complexome changes upon drug treatment with the example of bortezomib. SiComPre is the first method to produce quantitative predictions on the abundance of molecular complexes while performing the best qualitative predictions. With new data on tissue specific protein complexes becoming available SiComPre will be able to predict qualitative and quantitative differences in the complexome in various tissue types and under various conditions. PMID- 26492575 TI - MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2. AB - BACKGROUND/AIMS: There have been many studies on the etiology of osteoarthritis (OA) with regard to the function of inflammatory cytokines, the process of cartilage degradation, the function of miR-146a, hypoxia stimulation and autophagy in OA chondrocytes, but there have been no reports on the relationship between miR-146a and autophagy in cartilage, especially under hypoxia. This study aimed to confirm the relationship of miR-146a and autophagy in cartilage under hypoxia. METHODS: Chondrocytes were treated by hypoxia gradients, and the main factors including HIF-1alpha, HIF-2alpha, miR-146a and Bcl-2 and autophagy markers ULK-1, ATG-5 were detected by quantitative PCR (Q-PCR) and western blotting. The autophagy marker LC-3 was detected by immunofluorescence. The reciprocal effects between miR-146a and Bcl-2 were confirmed by several combinations of shRNAs and adenovirus-gene systems followed by Q-PCR and western blot detection. RESULTS: Hypoxia maintained the chondrocytes phenotype and promoted autophagy and miR-146a expression via HIF-1alpha, but not HIF-2alpha, while miR-146a did not reversely affect HIF-1alpha. The autophagy induced by hypoxia through HIF-1alpha, miR-146a and Bcl-2. Simply, hypoxia induced HIF 1alpha, and HIF-1alpha increased miR-146a, but miR-146a suppressed Bcl-2, an autophagy inhibitor. While Bcl-2 affected neither HIF-1alpha nor miR-146a. The absence of both HIF-1alpha and miR-146a or Bcl-2 over-expression inhibited hypoxia-induced autophagy. CONCLUSION: HIF-1alpha, miR-146a and Bcl-2 play crucial roles during hypoxia-induced autophagy, Hypoxia, HIF-1alpha and miR-146a promote chondrocytes autophagy via depressing Bcl-2. We conclude that miR-146a may serve as a novel therapeutic target for protecting cartilage from degeneration in OA. PMID- 26492576 TI - Ligand-Orientation Based Fragment Selection in STD NMR Screening. AB - While saturation transfer difference (STD) is a widely used NMR method for ligand screening, the selection of specific binders requires the validation of the hits through competition experiments or orthogonal biophysical techniques. We show here that the quantitative STD analysis is a reliable and robust approach to discriminate between specific and nonspecific ligands, allowing selection of fragments that bind proteins with a privileged binding mode, in the absence of any structural data for the protein. PMID- 26492571 TI - Oligodendrocyte Development and Plasticity. AB - Oligodendrocyte precursor cells (OPCs) originate in the ventricular zones (VZs) of the brain and spinal cord and migrate throughout the developing central nervous system (CNS) before differentiating into myelinating oligodendrocytes (OLs). It is not known whether OPCs or OLs from different parts of the VZ are functionally distinct. OPCs persist in the postnatal CNS, where they continue to divide and generate myelinating OLs at a decreasing rate throughout adult life in rodents. Adult OPCs respond to injury or disease by accelerating their cell cycle and increasing production of OLs to replace lost myelin. They also form synapses with unmyelinated axons and respond to electrical activity in those axons by generating more OLs and myelin locally. This experience-dependent "adaptive" myelination is important in some forms of plasticity and learning, for example, motor learning. We review the control of OL lineage development, including OL population dynamics and adaptive myelination in the adult CNS. PMID- 26492577 TI - A Novel Method for Assessment of Natural Killer Cell Cytotoxicity Using Image Cytometry. AB - Natural killer (NK) cells belong to the innate arm of the immune system and though activated NK cells can modulate immune responses through the secretion of cytokines, their primary effector function is through target cell lysis. Accordingly, cytotoxicity assays are central to studying NK cell function. The 51Chromium release assay, is the "gold standard" for cytotoxicity assay, however, due to concerns over toxicity associated with the use and disposal of radioactive compounds there is a significant interest in non-radioactive methods. We have previously used the calcein release assay as a non-radioactive alternative for studying NK cell cytotoxicity. In this study, we show that the calcein release assay varies in its dynamic range for different tumor targets, and that the entrapped calcein could remain unreleased within apoptotic bodies of lysed tumor targets or incompletely released resulting in underestimation of percent specific lysis. To overcome these limitations, we developed a novel cytotoxicity assay using the Cellometer Vision Image Cytometer and compared this method to standard calcein release assay for measuring NK cell cytotoxicity. Using tumor lines K562, 721.221, and Jurkat, we demonstrate here that image cytometry shows significantly higher percent specific lysis of the target cells compared to the standard calcein release assay within the same experimental setup. Image cytometry is able to accurately analyze live target cells by excluding dimmer cells and smaller apoptotic bodies from viable target cell counts. The image cytometry-based cytotoxicity assay is a simple, direct and sensitive method and is an appealing option for routine cytotoxicity assay. PMID- 26492579 TI - Retraction notice for: "Validation of a multiplex genotyping platform using a novel genomic database approach". PMID- 26492580 TI - A dedicated undergraduate gynaecology teaching clinic: The Keele experience. AB - Much discussion in the literature centres on how best to teach medical students the intricacies of gynaecological assessment and the subsequent formulation of a management plan. At Keele University skills are initially developed in a simulated setting and then transferred to the workplace where students continue to develop their skills. A dedicated undergraduate gynaecology teaching clinic has been developed and comprises of 2-3 students and a tutor. All 38 students rotating through the department between January and June 2013 were invited to complete an anonymous questionnaire to evaluate this clinic and 36 (95%) of them responded. Respondents felt significantly more comfortable taking a gynaecology history, ensuring privacy during examination and formulating a management plan post-clinic (all p < 0.001), with female students feeling significantly more comfortable than their male counterparts (p = 0.04). The use of this clinic shows great promise to help students learn an unfamiliar and challenging skill. PMID- 26492578 TI - Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing. AB - PURPOSE: Homozygosity mapping is an effective approach for detecting molecular defects in consanguineous families by delineating stretches of genomic DNA that are identical by descent. Constant developments in next-generation sequencing created possibilities to combine whole-exome sequencing (WES) and homozygosity mapping in a single step. METHODS: Basic optimization of homozygosity mapping parameters was performed in a group of families with autosomal-recessive (AR) mutations for which both single-nucleotide polymorphism (SNP) array and WES data were available. We varied the criteria for SNP extraction and PLINK thresholds to estimate their effect on the accuracy of homozygosity mapping based on WES. RESULTS: Our protocol showed high specificity and sensitivity for homozygosity detection and facilitated the identification of novel mutations in GAN, GBA2, and ZFYVE26 in four families affected by hereditary spastic paraplegia or Charcot Marie-Tooth disease. Filtering and mapping with optimized parameters was integrated into the HOMWES (homozygosity mapping based on WES analysis) tool in the GenomeComb package for genomic data analysis. CONCLUSION: We present recommendations for detection of homozygous regions based on WES data and a bioinformatics tool for their identification, which can be widely applied for studying AR disorders.Genet Med 18 6, 600-607. PMID- 26492581 TI - Pulmonary platelet thrombi and vascular pathology in acute chest syndrome in patients with sickle cell disease. AB - A growing body of evidence suggests a role for platelets in sickle cell disease (SCD). Despite the proinflammatory, occlusive nature of platelets, a role for platelets in acute chest syndrome (ACS), however, remains understudied. To provide evidence and potentially describe contributory factors for a putative link between ACS and platelets, we performed an autopsy study of 20 SCD cases-10 of whom died from ACS and 10 whose deaths were not ACS-related. Pulmonary histopathology and case history were collected. We discovered that disseminated pulmonary platelet thrombi were present in 3 out of 10 of cases with ACS, but none of the matched cases without ACS. Those cases with detected thrombi were associated with significant deposition of endothelial vWF and detection of large vWF aggregates adhered to endothelium. Potential clinical risk factors were younger age and higher platelet count at presentation. However, we also noted a sharp and significant decline in platelet count prior to death in each case with platelet thrombi in the lungs. In this study, neither hydroxyurea use nor perimortem transfusion was associated with platelet thrombi. Surprisingly, in all cases, there was profound pulmonary artery remodeling with both thrombotic and proliferative pulmonary plexiform lesions. The severity of remodeling was not associated with a severe history of ACS, or hydroxyurea use, but was inversely correlated with age. We thus provide evidence of undocumented presence of platelet thrombi in cases of fatal ACS and describe clinical correlates. We also provide novel correlates of pulmonary remodeling in SCD. PMID- 26492582 TI - Reverse Electron Transfer Completes the Catalytic Cycle in a 2,3,5 Trifluorotyrosine-Substituted Ribonucleotide Reductase. AB - Escherichia coli class Ia ribonucleotide reductase is composed of two subunits (alpha and beta), which form an alpha2beta2 complex that catalyzes the conversion of nucleoside 5'-diphosphates to deoxynucleotides (dNDPs). beta2 contains the essential tyrosyl radical (Y122(*)) that generates a thiyl radical (C439(*)) in alpha2 where dNDPs are made. This oxidation occurs over 35 A through a pathway of amino acid radical intermediates (Y122 -> [W48] -> Y356 in beta2 to Y731 -> Y730 > C439 in alpha2). However, chemistry is preceded by a slow protein conformational change(s) that prevents observation of these intermediates. 2,3,5 Trifluorotyrosine site-specifically inserted at position 122 of beta2 (F3Y(*) beta2) perturbs its conformation and the driving force for radical propagation, while maintaining catalytic activity (1.7 s(-1)). Rapid freeze-quench electron paramagnetic resonance spectroscopy and rapid chemical-quench analysis of the F3Y(*)-beta2, alpha2, CDP, and ATP (effector) reaction show generation of 0.5 equiv of Y356(*) and 0.5 equiv of dCDP, both at 30 s(-1). In the absence of an external reducing system, Y356(*) reduction occurs concomitant with F3Y reoxidation (0.4 s(-1)) and subsequent to oxidation of all alpha2s. In the presence of a reducing system, a burst of dCDP (0.4 equiv at 22 s(-1)) is observed prior to steady-state turnover (1.7 s(-1)). The [Y356(*)] does not change, consistent with rate-limiting F3Y reoxidation. The data support a mechanism where Y122(*) is reduced and reoxidized on each turnover and demonstrate for the first time the ability of a pathway radical in an active alpha2beta2 complex to complete the catalytic cycle. PMID- 26492584 TI - Realisation and advanced engineering of true optical rugate filters based on nanoporous anodic alumina by sinusoidal pulse anodisation. AB - This study is the first realisation of true optical rugate filters (RFs) based on nanoporous anodic alumina (NAA) by sinusoidal waves. An innovative and rationally designed sinusoidal pulse anodisation (SPA) approach in galvanostatic mode is used with the aim of engineering the effective medium of NAA in a sinusoidal fashion. A precise control over the different anodisation parameters (i.e. anodisation period, anodisation amplitude, anodisation offset, number of pulses, anodisation temperature and pore widening time) makes it possible to engineer the characteristic reflection peaks and interferometric colours of NAA-RFs, which can be finely tuned across the UV-visible-NIR spectrum. The effect of the aforementioned anodisation parameters on the photonic properties of NAA-RFs (i.e. characteristic reflection peaks and interferometric colours) is systematically assessed in order to establish for the first time a comprehensive rationale towards NAA-RFs with fully controllable photonic properties. The experimental results are correlated with a theoretical model (Looyenga-Landau-Lifshitz - LLL), demonstrating that the effective medium of these photonic nanostructures can be precisely described by the effective medium approximation. NAA-RFs are also demonstrated as chemically selective photonic platforms combined with reflectometric interference spectroscopy (RIfS). The resulting optical sensing system is used to assess the reversible binding affinity between a model drug (i.e. indomethacin) and human serum albumin (HSA) in real-time. Our results demonstrate that this system can be used to determine the overall pharmacokinetic profile of drugs, which is a critical aspect to be considered for the implementation of efficient medical therapies. PMID- 26492585 TI - Management of functional, hepatic damage after chemotherapy with Liverubin (pharma-standard silymarin). AB - : Mild, temporary hepatic failure (MTHF) after chemotherapy is a common clinical problem; in case of repeated episodes MTHF may cause chronic impairment. This registry has evaluated post- chemotherapy (PC)-MTHF in subjects using Liverubin (standardized Silymarin) for 8 weeks (3 capsules/day). METHODS: PC-MTHF was evaluated in a registry study. Hepatitis markers were negative at inclusion and at end-registry. In the final registry there were results concerning 18 Liverubin supplemented patients and 19 controls completing the 8-week period. Signs/symptoms. The distribution of the most common symptoms and signs with ultrasound scans were comparable. Symptoms were mostly minimal or subclinical. Most symptoms observed at inclusion were completely disappeared or greatly attenuated after 8 weeks. The improvement produced by Liverubin induced a better and faster disappearance of symptoms. The results of the blood tests (at inclusion and at 8 weeks showed the increase in albumin, significantly (P<0.05) faster with the final values higher in the supplement group. Total bilirubin was reduced with the supplement better than in controls (P<0.05). Direct bilirubin values improved more in the supplement (P<0.05) group. The decrease in SGPT and AST-ASAT was more evident with the supplement (P<0.05). Improvement in controls was more limited. Alkaline phosphatase was significantly lower (than in controls) with Liverubin at 8 weeks (p<0.05). Gamma GT also decreased more and faster with the supplement. The ESR (erythrocytes sedimentation rate) was decreased in both groups, more in ?the Liverubin group (P<0.05). There was a more limited decrease in controls with persisting higher values at 8 weeks. The white cell count was also better at 3 months (with a larger decrease with the supplement; P<0.05). Oxidative stress. Plasma free radicals (PFR) were elevated in both groups at inclusion. A more significant decrease in the supplement group was observed at 8 weeks. Persisting elevation in values was seen in controls (P<0.05). Platelets values improved better with Liverubin (P<0.05). Safety and tolerability were optimal (no side effect was registered). In conclusion, results from this pilot registry indicate a significant activity of Liverubin associated with a very good safety profile, in patients with post-chemotherapy hepatic failure. The recovery of hepatic function is faster and more effective with Liverubin in comparison with the best "standard" management. PMID- 26492583 TI - Transitioning Adolescents and Young Adults With Sickle Cell Disease From Pediatric to Adult Health Care: Provider Perspectives. AB - The transition from pediatric to adult health care is often challenging for adolescents and young adults with sickle cell disease (SCD). Our study aimed to identify (1) measures of success for the transition to adult health care; and (2) barriers and facilitators to this process. We interviewed 13 SCD experts and asked them about their experiences caring for adolescents and young adults with SCD. Our interview guide was developed based on Social-Ecological Model of Adolescent and Young Adult Readiness to Transition framework, and interviews were coded using the constant comparative method. Our results showed that transition success was measured by health care utilization, quality of life, and continuation on a stable disease trajectory. We also found that barriers to transition include negative experiences in the emergency department, sociodemographic factors, and adolescent skills. Facilitators include a positive relationship with the provider, family support, and developmental maturity. Success in SCD transition is primarily determined by the patients' quality of relationships with their parents and providers and their developmental maturity and skills. Understanding these concepts will aid in the development of future evidence-based transition care models. PMID- 26492586 TI - Management of osteoarthritis (OA) with the pharma-standard supplement FlexiQule (Boswellia): a 12-week registry. AB - : This registry study assessed the pharma-standard supplement FlexiQule (Boswellia extract in capsules) in the management of symptoms associated to osteoarthritis (OA) also managed with the 'standard management' (SM) in comparison with a group of patients managed only with SM. The 12- week registry included patients with symptomatic knee arthrosis. They were able to walk on a treadmill for a walking test and to complete the WOMAC questionnaire. RESULTS: 32 patients used the supplement and 34 acted as controls (SM). No safety problems were observed. At 12 weeks, the Karnofsky scale was significantly improved in both groups: the variation was higher (p<0.05) in the supplement group. The WOMAC score was decreased significantly more in the supplement+SM group in comparison with controls considering pain, stiffness and physical functions (p<0.05). For social and emotional functions the decrease in score was also more evident in the supplement group (p<0.05). Both groups improved in pain-free and total walking distance at 12 weeks. Pain-free walking distance (treadmill) was higher (p<0.05) with the supplement (from 93.4;11.6 m to 271.3;19.3 m) than in controls (from 90.5;13.5 m to 158.3;22.3)(p<0.05). The improvement in total walking distance was also higher in the supplement group (p<0.05) (from 164.3;23.2 to 322.3;22.3 m) in comparison with the SM- only group ( from 158.3;18,4 to 240.2;19.3 m). The need for concomitant drugs and medical attention during the registry was reduced more in the supplement group (p<0.05). In conclusion the difference between SM and the Flexiqule+SM was in favor of the management with the supplement for all target measurements. The product is safe and well tolerated. PMID- 26492587 TI - Phyto-relief CC: prevention of cold episodes. Control of signs/symptoms and complications. AB - : The aim of this supplement, registry study was to evaluate the effects of the use of standardized, oral supplement (Phyto-Relief CC, Alchem). Phyto-Relief CC includes anti-inflammatory, anti-oxidant and anti- edema natural compounds. Increased salivation produced by ginger is useful in the prevention of cold episodes and on signs and symptoms associated to the episodes by increasing saliva and its content (i.e. lysozyme). Main targets of the study were the evaluation of the occurrence of episodes and the reduction of signs/symptoms, the reduction of days of disease, the reduction in the use of other treatments and the control of cold-related complications. RESULTS: The two resulting registry groups were comparable. There were 5 full episodes (lasting at least 3 days) of cold in 61 registry subjects (8.1%) in comparison with 17 cases in 63 subjects (26.98%) in controls. Phyto-Relief CC subjects - even in this time-limited and small study population registry - had 30.1% of the episodes of the control group with a reduction of 69.88% of the cold episodes (p<0.0221). Also in the following, continuation, third week only 3 episodes of cold were recorded in the Phyto- Relief CC group vs 6 (50% reduction) observed in controls. All the other chosen parameters were better in the supplement group (p<0.05). Affected days (2.9;1.1 vs 4.6; 1.2 in controls), lost working days (0.58;0.5 vs 1.02;0.43 in controls. The use of any other OTC product, nasal drops, aspirin, Vit C, antihistamines, aerosols, the number of complications after 4 days were better in the Phyto-Relief CC group. Disease 'extension' (to >4 days), particularly tracheal and bronchial extension were significantly less frequent (p<0.05) with the supplement. No safety or tolerability problem was observed. In conclusion this preliminary study shows that Phyto-Relief CC may help the evolution of cold if used early, when initial symptoms could be identified. More specific evaluations and larger prevention studies are needed. PMID- 26492588 TI - Supplementary management of benign prostatic hypertrophy with Prostaquil. An 8 week registry. AB - : The aim of this registry was to evaluate the management of initial symptoms of benign prostatic hyperthrophy (BPH) in otherwise healthy subjects, using Prostaquil(r) (Alchem) in a 8-week registry. Prostaquil was used at the dosage of 200 mg/day. The product includes Pygeum extract (100 mg) and Saw palmetto oil (35 mg). The two resulting groups standard management and supplement) were comparable. RESULTS: No side effects or comparability problems were observed and compliance was optimal with more than 95% of the capsules correctly used. Empting, frequency, intermittency, urgency, weak flow, straining, nocturia were all significantly improved with Prostaquil (p<0.05) and the improvement - globally and evaluating any single item - was significantly superior to the one observed in controls (p<0.05). Quality of life with the supplement was also significantly better in comparison with controls (p<0.05). The residual vescical volume was 94.7;5,8 ml in the supplement group at inclusion and decreased to 39.3;5 ml (p<0.05) at 8 weeks. This decrease was equivalent to a reduction of 58.5%(vs a decrease of 27.9% in controls)(p<0.05; ANOVA). In conclusion, the most common symptoms of BPH are controlled by Prostaquil a new standardized supplement including Pygeum. PMID- 26492589 TI - Miraqule-C and mild heart failure: an 8-week registry. AB - : The aim of this registry study was the evaluation of possible benefits of a supplement including CoenzymeQ10 and a grape seed combination (MiraQule C, Alchem) in stable, moderate, heart failure patients. RESULTS: The mean age of the 18 supplemented patients was 60.1;2 years (the age of the 22 controls was 61.1;2.2). The two groups were comparable. There were no dropouts in the two groups. In the 8 weeks of the registry, all supplemented patients remained in the NYHA class while 7 out of 22 in controls increased the level of heart failure passing into Class III. Systolic- diastolic pressure, heart rate, respiratory rate were minimally (non significantly lowered) with the supplement without differences controls. Ultrasound-derived ejection fraction was increased by supplementation (median of 2.7%) in the CoQ10 group (p<0.05) while there were minimal, non- significant differences in controls. Walking distance on treadmill was also significantly increased with the supplement (p<0.05) and only marginally in controls. The microcirculation (laser Doppler parameters and transcutaneous PO2, PCO2) improved significantly in the MQ-C group (p<0.05) and only marginally in controls. Oxidative stress was significantly decreased (p<0.05) with the CoQ10 preparation while there were minimal. Non-significant changes were observed in in controls. Tolerability and compliance were optimal (with more than 95% of the capsules correctly used). In conclusion in this supplement registry Miraqule-C seem to help patients with moderate heart failure and should be considered for larger studies. PMID- 26492590 TI - Hand 'stress' arthritis in young subjects: effects of Flexiqule (pharma-standard Boswellia extract). A preliminary case report. AB - This case report (supplement registry study) evaluated subjects with painful 'stress' arthritis of the hand mainly localized at the joints. The patients received a suggestion to follow a rehabilitation plan (standard management; SM). A second group also used the same SM in association with the oral, pharma standard supplement FlexiQule (Alchem) a new standardized, phytosomal preparation manufactured from the Boswellia plant, which can be used for self-management in inflammatory conditions (150 mg / 3 times daily). The two resulting registry groups included 12 subjects using SM+Flexiqule and and 11 controls (SM only). The groups were comparable. Serology showed no significant alterations: only ESR was slightly elevated (minimal elevation). After 2 weeks, the ESR was normal in the supplement group and mildly elevated in controls (p<0.05%). The decrease in hypertermic areas was greater/faster (p<0.05) in the supplement group. The identification of a working stress and the localization to the dominant hand was comparable in both groups. At 2 weeks, the decrease in pain was significantly faster and more important with the supplement (p<0.05). The hand became more usable in time and the score was better with the supplement (p<0.05). No supplemented patient had to use other drugs, while in the control group 3 subjects eventually used NSAIDs to control pain and stiffness and one used corticosteroids. In conclusion, the natural extract Flexiqule was effective in controlling work-related stress arthritis (without inflammaitory signs) over a 2 weeks period, better than only Standard Management. More prolonged and larger studies are needed. PMID- 26492591 TI - The role of mental imagery in non-clinical paranoia. AB - BACKGROUND & OBJECTIVES: Cognitive models of paranoia incorporate many of the processes implicated in the maintenance of anxiety disorders. Despite this, the role of mental imagery in paranoia remains under-researched. The current study examined the impact of a self-imagery manipulation in people with high non clinical paranoia. METHODS: We used a mixed design with one between-subjects variable (type of self-imagery) and one within-subjects variable (time--pre and post imagery manipulation). Thirty participants with high trait paranoia were allocated alternately to a positive or negative self-imagery condition. Scripts were used to elicit positive and negative self-imagery. All participants completed self-report state measures of paranoia, mood, self-esteem and self compassion. RESULTS: Group by time interaction effects were found for each of the dependent variables. Positive imagery led to less state paranoia, anxiety and negative affect, and more positive affect, self-esteem and self-compassion, compared with the negative imagery group. LIMITATIONS: This was a non-blind study, limited by allocation method and a brief time-frame which did not allow us to assess longevity of effects. We recruited a relatively small and predominantly female sample of people with high non-clinical paranoia. The study did not include a neutral control condition, a low paranoia comparison group, or a manipulation check following the imagery task. CONCLUSIONS: Self-imagery manipulations may affect paranoia, mood and self-beliefs. If the findings are replicated with clinical groups, and maintained over a longer period, this would suggest that imagery-based interventions targeting persecutory delusions might be usefully examined. PMID- 26492592 TI - Cobalt(III)-Catalyzed C-H Alkynylation with Bromoalkynes under Mild Conditions. AB - Expedient cobalt-catalyzed C-H alkynylation was achieved under exceedingly mild reaction conditions. Thus, chelation-assisted direct alkynylations of heteroarenes occurred with 1-bromoalkynes and ample substrate scope. The optimized catalytic system allowed for step-economical C-H functionalizations with a mild base K2CO3 at reaction temperatures as low as 25 degrees C. PMID- 26492593 TI - Statins and myositis: the role of anti-HMGCR antibodies. AB - Muscle toxicity is a recognized adverse effect of statin use. Recently, a new myositis syndrome was described in association with antibodies directed against the pharmacologic target of statins, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR antibody). The patient's genetic background, characteristic histologic patterns (immune-mediated necrotizing myopathy), and presence of anti HMGCR antibodies define the syndrome. In most patients, statin discontinuation is insufficient to reverse the myositis symptoms, and immunosuppressive therapy is needed. The mechanisms by which these antibodies may lead to disease are not fully elucidated. Several important questions remain unsolved and warrant further research. PMID- 26492594 TI - Bortezomib for refractory acute antibody-mediated rejection in kidney transplant recipients: A single-centre case series. AB - AIM: Acute antibody-mediated rejection (ABMR) after kidney transplantation (KT) is associated with poor allograft survival. Current therapies for ABMR are able to deplete B-lymphocytes but do not target plasma cells. Bortezomib is a proteasome inhibitor that can eliminate plasma cells and has demonstrated utility in the treatment of ABMR. METHODS: A retrospective study was carried out from 2010 to 2014, including all patients with ABMR refractory to conventional treatment who received bortezomib. Bortezomib (1.3 mg/m(2) ) was administered intravenously on days 1, 4, 8, and 11. Renal function, graft survival, follow-up biopsies, and donor-specific antibodies (DSA) were recorded. RESULTS: We identified seven patients. Of these, high immunological risk was found in 6 of 7, preformed DSA were found in 5 of 7, flow cytometry crossmatch was positive in 4 of 7, and desensitization before KTx was provided in 6 of 7 patients. ABMR was diagnosed at a median of 90 days (8-167) post-KT. After bortezomib therapy, renal function improved or stabilized in 5 of 7 patients and progressively deteriorated in 2 of 7, leading to haemodialysis after 7 and 11 months, respectively. Follow up kidney biopsies showed persistence of ABMR in 2 of 7, chronic active ABMR 3 of 7 and inactive chronic lesions in 2 of 7. DSA titres significantly decreased after treatment (P = 0.028). All patients experienced mild adverse events. After a follow-up of 22 +/- 18 months, three grafts were lost (42%) and four remained functioning. CONCLUSION: Bortezomib could be useful as an adjuvant therapy for ABMR refractory to conventional treatment with acceptable mid-term outcomes in these severe cases. More research is needed to develop strategies to better preserve graft function after refractory ABMR. PMID- 26492595 TI - Pressure behavior of different PEEK materials for dental implants. AB - Due to its mechanical properties, the biocompatible high-performance material PEEK (polyetheretherketone) and PEEK-based compounds may represent viable alternatives to titanium in the field of dental implantology. Therefore we performed static pressure tests with 11 PEEK materials (two unfilled grades, two grades filled with titanium-dioxide-powder, two grades filled with barium-sulfate powder, two grades reinforced with short carbon fibers, one grade reinforced with glass fibers and two grades reinforced with continuous carbon fibers) in the form of cylindrical specimens with a diameter of 4, 5 and 6mm. The specimens had a height to diameter ratio of 2:1 and were therefore 8, 10 and 12mm high. The parameters elastic modulus, elastic limit and pressure strength were evaluated. The elastic moduli ranged between 2.65+/-0.03GPa for specimens of a titanium dioxide-filled grade and 106.71+/-14.83GPa for specimens reinforced with continuous carbon fibers. The elastic limits ranged between 808.1+/-42.44N for specimens of a barium-sulfate-filled grade and 7256.4+/-519.86N for specimens reinforced with continuous carbon fibers. The lowest pressure strength of 122.77MPa was observed for specimens of an unfilled grade, whereas the highest pressure strength of 712.67+/-66.02MPa could be evaluated for specimens containing continuous carbon fibers. Regarding the maximum bite force of a first molar, all tested materials seem to be suitable for the use as dental implants. PMID- 26492596 TI - False discovery rate estimation for large-scale homogeneous discrete p-values. AB - Large-scale homogeneous discrete p-values are encountered frequently in high throughput genomics studies, and the related multiple testing problems become challenging because most existing methods for the false discovery rate (FDR) assume continuous p-values. In this article, we study the estimation of the null proportion and FDR for discrete p-values with common support. In the finite sample setting, we propose a novel class of conservative FDR estimators. Furthermore, we show that a broad class of FDR estimators is simultaneously conservative over all support points under some weak dependence condition in the asymptotic setting. We further demonstrate the significant improvement of a newly proposed method over existing methods through simulation studies and a case study. PMID- 26492599 TI - Human papillomavirus type 2 associated with pyogenic granuloma in patients without clinical evidence of warts. AB - BACKGROUND: Pyogenic granuloma is a non-neoplastic lesion that frequently occurs in the skin and mucous membranes of children and pregnant women. The anatomical sites of pyogenic granulomas overlap with those of wart infections caused by the human papillomavirus (HPV). OBJECTIVE: This study assessed the presence of HPV DNA in pyogenic granuloma samples by polymerase chain reaction. METHODS: Eighteen pyogenic granuloma biopsies from patients without a clinical history or evidence of verruca in the studied area were tested for the presence of the HPV genome. The presence of HPV DNA was screened by three independent polymerase chain reaction reactions using standard consensus primer sets targeted to the L1 or E1 consensus regions of HPV genome. The HPV DNA-positive samples were genotyped using methodologies enabling the identification of up to 30 HPVs, including oncogenic, nononcogenic, and cutaneous viral types. RESULTS: The HPV DNA was detected in 44.4% (eight of 18) of the samples, with HPV-2 being the only type in the eight HPV DNA-positive samples. Contamination with HPV-2 sequences throughout the entire process was reliably eliminated. CONCLUSION: This report is the first to suggest an association between HPV-2 and pyogenic granuloma. This relationship is similar to that observed between HPV-2 and nongenital warts. PMID- 26492598 TI - TNF-alpha/TNFR2 Regulatory Axis Stimulates EphB2-Mediated Neuroregeneration Via Activation of NF-kappaB. AB - HIV-1 infected individuals are at high risk of developing HIV-associated neurocognitive disorders (HAND) as HIV infection leads to neuronal injury and synaptic loss in the central nervous system (CNS). The neurotoxic effects of HIV 1 are primarily a result of viral replication leading to the production of inflammatory chemokines and cytokines, including TNF-alpha. Given an important role of TNF-alpha in regulating synaptic plasticity, we investigated the effects of TNF-alpha on the development of neuronal processes after mechanical injury, and we showed that TNF-alpha treatment stimulates the regrowth of neuronal processes. To investigate transcriptional effects of TNF-alpha on synaptic plasticity, we analyzed both human neurosphere and isolated neuronal cultures for the regulation of genes central to synaptic alterations during learning and memory. TNF-alpha treatment upregulated Ephrin receptor B2 (EphB2), which is strongly involved in dendritic arborization and synaptic integrity. TNF-alpha strongly activates the NF-kappaB pathway, therefore, we propose that TNF-alpha induced neurite regrowth occurs primarily through EphB2 signaling via stimulation of NF-kappaB. EphB2 promoter activity increased with TNF-alpha treatment and overexpression of NF-kappaB. Direct binding of NF-kappaB to the EphB2 promoter occurred in the ChIP assay, and site-directed mutagenesis identified binding sites involved in TNF-alpha-induced EphB2 activation. TNF-alpha induction of EphB2 was determined to occur specifically through TNF-alpha receptor 2 (TNFR2) activation in human primary fetal neurons. Our observations provide a new avenue for the investigation on the impact of TNF-alpha in the context of HIV-1 neuronal cell damage as well as providing a potential therapeutic target in TNFR2 activation of EphB2. PMID- 26492600 TI - An Alternative Technique for External Fixation of Traumatic Intra-articular Fractures of Proximal and Middle Phalanx. AB - BACKGROUND: Intra-articular fractures of the proximal interphalangeal (PIP) joint are commonly treated with dynamic external fixation. Most commonly used is the Suzuki modification of the pins and rubber traction system (PRTS). There are a few other modifications of the PRTS external fixators. We present an alternative pin external fixator that is simple and effective. METHODS: Under a suitable anesthesia and image intensification a true lateral view of the head of the proximal phalanx is obtained. A K-wire construct holds the affected digit out to length with the fracture reduced and Jurgan pin-balls hold the construct into position. Under image intensification the whole device is checked to ensure the joint and fracture is reduced and the joint is not over distracted. The PIP joint is also checked to ensure good range of motion. The device was checked in clinic at 1 week with radiographs. The wires are removed at 4 weeks followed by intensive hand physiotherapy. RESULTS: Over 20 patients with intra-articular fractures of the proximal and middle phalangeal were treated with this technique. In all cases the fracture healed with good joint congruency. All patients achieved good range of motion of the PIP joint but with some restriction of full flexion (mean, 20 degrees). There was no loss of position or pin-site infections. There was good compliance with the treatment. DISCUSSION: The main advantages of the technique we describe are: (1) the compact design, making it less cumbersome for the patient compared with other PRTS external fixators; (2) it is straightforward to assemble and the device is easy to adjust in clinic if there is any loss of reduction; (3) the pin-balls prevent sharp ends of the wire protruding causing morbidity to the patient; (4) there is less chance of loss of traction compared with traction devices using rubber bands. It is a dynamic device, which allows mobilization of the joints reducing stiffness. PMID- 26492601 TI - Pulmonary Lung Cancer Subspecialty Training. PMID- 26492602 TI - Are Inhaled Corticosteroids Safe for Large Airways?: A New Paradigm? PMID- 26492603 TI - Endobronchial Ultrasound-guided Transvascular Needle Aspiration: A Single-Center Experience. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is well established for the staging and diagnosis of lung cancer and mediastinal lymphadenopathy. Central mediastinal vascular structures may preclude EBUS-TBNA access to lymph nodes in the aortopulmonary window and certain centrally located parenchymal lesions. Thus, a transvascular approach is necessitated. Few such reports exist in the literature. METHODS: We retrospectively analyzed the results of endobronchial ultrasound-guided transvascular needle aspiration (EBUS-TVNA) performed over 1 year to sample mediastinal lymph nodes (stations: 5) and lung lesions inaccessible by standard bronchoscopy or EBUS-TBNA. Data regarding the indication, location, size, and relationship to adjacent blood vessels, the number of transvascular passes, EBUS TVNA diagnosis, the final diagnosis, procedural images, and complications were collected. Patients' charts were reviewed for 6 months after the procedure for evidence of late complications, including mediastinitis or mediastinal hemorrhage. RESULTS: Of 865 EBUS-TBNA procedures, 10 were performed by traversing the pulmonary artery or its branches. Nine were for left-sided lesions, 3 for hilar parenchymal nodules, 6 for hilar or mediastinal LN, and the remainder for a right-sided mass. Rapid-onsite evaluation was either diagnostic or positive for lymphoid cells in 9 patients and the final cytopathology was diagnostic in 9 patients: 5 non-small cell lung cancer, 1 small cell cancer, 1 metastatic colon cancer, and 2 normal lymphoid tissue. One patient had necrosis and required video assisted thoracoscopic surgery to diagnose histoplasmosis. Bleeding was insignificant, with no short-term/long-term complications. CONCLUSIONS: From our single-center experience, we conclude that in experienced hands, EBUS-TVNA is feasible, with a high yield, but without complications. Larger prospective trials are warranted to explore its diagnostic potential. PMID- 26492604 TI - Experimental Pilot Study of a Novel Endobronchial Drug Delivery Catheter. AB - BACKGROUND: An endobronchial infusion catheter introduced through a flexible bronchoscope channel has not been previously described. The aim of this study was to evaluate the technical feasibility of a new device. METHODS: Four porcine models underwent bronchoscopy with the infusion catheter. In the first experiment, methylene blue was injected into airway in volumes of 0.1, 0.3, or 1.0 mL into 2 animals. One animal was killed at 1 hour and the other at 24 hours after the procedure and gross dye diffusion was visually assessed. In the second experiment, a mixture of 80% sterile normal saline and 20% contrast media was injected into the airway in volumes of 0.3, 1.0, and 3.0 mL into 2 animals. One animal was killed at 7 days and the other at 20 days. Histologic evaluations were performed according to a bronchial damage scoring system. RESULTS: There was no perioperative morbidity. In the first experiment, infusion volumes of 0.1, 0.3, and 1.0 mL resulted in dye surrounding 67%+/-29%, 55%+/-17%, and 80%+/-20% of the infusion-site circumference, and longitudinal distribution of 4.0+/-1.7, 8.1+/ 4.1, and 18.0+/-3.0 mm each, respectively. In the second experiment, infusion of 0.3 to 3.0 mL resulted in mild injury, inflammation, and hemorrhage/fibrin/thrombus at 7 and 20 days after surgery. CONCLUSIONS: Endobronchial infusion of dye and contrast media by the endobronchial drug delivery catheter showed that the media spread in a dose-dependent manner macroscopically and histologically. Further investigation will be required to assess the catheter as a new tool for localized drug delivery into the airway. PMID- 26492605 TI - A Novel, Adaptable Laryngeal Mask to Facilitate a Percutaneous Dilatational Tracheostomy: Proof-of-Concept Prototype Demonstration on a Mannequin Model and Cadaver. AB - BACKGROUND: Most percutaneous dilatational tracheostomy (PDT) mortalities result from airway-related complications. Improved airway pressure management and gas delivery are targets for innovation. This study describes an adaptable laryngeal mask (ALM) designed to remove the bronchoscope from the endotracheal tube (ETT) and place it in a separate lumen. Airflow and device efficacy were evaluated during PDTs with an ALM on mannequins and cadavers, respectively. METHODS: Procedures were completed by a single physician using an 8.0 mm ETT and the Ciaglia Blue Rhino method on simulation mannequins (TruCorp AirSim Traci) and fresh-frozen cadavers. Mannequin simulation tested the respiratory capabilities of an ALM utilizing a BioPac spirometer and a Maquet Servo ventilator. Qualitative analysis on device efficacy was performed on 2 fresh-frozen cadavers (1 male, 1 female). RESULTS: Preliminary ventilation testing on a PDT-able mannequin using the ALM showed an increase in airflow reaching the lungs compared with a deflated ETT. During mannequin and cadaver testing, the ALM was placed over the in situ ETT effectively, thereby removing the bronchoscope from the ETT while maintaining a continuous visual of the incision site. Both mannequin and cadaveric testing using an ALM enabled a single physician to safely perform the PDT procedure with minimal assistance. CONCLUSIONS: Initial testing using an ALM during PDT on mannequins and cadavers showed an improvement in airflow and the removal of the bronchoscope from the ETT, respectively. Further studies using the ALM in a patient population compared with standard techniques would be useful. PMID- 26492606 TI - Endobronchial Involvement in Idiopathic Hypereosinophilic Syndrome. PMID- 26492607 TI - Diagnosis of Pulmonary Hydatid Cyst by Bronchoscopy. AB - Hydatid cyst is a parasitic infestation caused by Echinococcus granulosus. Lungs are the second most common site of involvement after liver. The diagnosis of complicated pulmonary hydatid cysts may not be easy because hydatid cyst disease mimics tuberculosis, lung cancer, empyema, or abscess. Fiberoptic bronchoscopy can be a valuable tool in the diagnosis of the infestation by visualization of hydatid cyst membrane. Here, we report the case of a 33-year-old woman who presented with hemoptysis and chest discomfort and was diagnosed with a hydatid cyst by fiberoptic bronchoscopy. PMID- 26492608 TI - Transesophageal Bronchoscopic Ultrasound-guided Fine-needle Aspiration (EUS-B FNA) in a 3-Year-Old Child. AB - Evaluation of mediastinal lymphadenopathy in children is challenging and surgical procedures (mediastinoscopy/thoracotomy) are usually performed wherever tissue sampling is required. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a widely utilized and minimally invasive modality for evaluation of mediastinum (lymphadenopathy, masses, and nodal staging in patients with lung cancer) in adults. Smaller size of pediatric trachea potentially limits the use of EBUS. The EBUS bronchoscope can also be introduced into the esophagus for mediastinal evaluation and sampling, a technique described as transesophageal bronchoscopic ultrasound-guided fine-needle aspiration (EUS-B-FNA). We herein report the successful utilization of EUS-B-FNA to obtain diagnostic mediastinal lymph node sampling in a 3-year-old child. The procedure was accomplished under moderate conscious sedation without any procedural complications. EUS-B-FNA, by obviating entry of EBUS scope into small pediatric trachea and reduced anesthesia requirement can evolve into an extremely useful modality for evaluation of pediatric mediastinal lymphadenopathy. PMID- 26492609 TI - Pulmonary Neuroendocrine Tumors: Part II. Treatment. AB - Pulmonary neuroendocrine tumors that arise from Kulchitzky cells of the bronchial mucosa consist of a spectrum of histologic features leading to a variable prognosis. Although typical carcinoid represents the most benign course, small cell cancer has the grimmest outcome. Therefore, differentiating the spectrum of neuroendocrine tumors helps one not only to determine the prognosis, but also to guide the treatment options. In this part, we aim to discuss the treatment options in pulmonary neuroendocrine tumors except for small-cell lung cancer. PMID- 26492610 TI - Vanished: Is This for Real? AB - Spontaneous regression (SR) of lung cancer is especially rare. We report a case of an early endobronchial squamous cell carcinoma that exhibited complete radiologic and pathologic SR soon after diagnosis. The patient was monitored radiologically and bronchoscopically at regular intervals and to date, the biopsy samples have been negative. Remarkably, SR has been maintained 6 years after diagnosis, without local recurrence or distant metastases. Many hypotheses abound to explain how complete SR was achieved and maintained despite the lack of treatment. PMID- 26492611 TI - Montgomery T-tube Migration: A Rare and Life-threatening Complication. PMID- 26492612 TI - Distal Airway Stenting: How Far Is Too Far? PMID- 26492613 TI - Pulmonary Tumor Embolism Diagnosed by Endobronchial Ultrasound. PMID- 26492614 TI - Transarterial EBUS-TBNA in the Diagnosis of Hilar Lesions. PMID- 26492615 TI - Whole genome sequencing of fecal samples as a tool for the diagnosis and genetic characterization of norovirus. AB - BACKGROUND: Norovirus is a major cause of gastroenteritis, causing yearly epidemics and hospital outbreaks resulting in a high burden on health care. Detection and characterization of norovirus directly from clinical samples could provide a powerful tool in infection control and norovirus epidemiology. OBJECTIVES: To determine whether next-generation sequencing directly on fecal samples can accurately detect and characterize norovirus. STUDY DESIGN: Whole genome sequencing was performed on fecal samples from 10 patients with gastro enteritis. Norovirus infection had previously been confirmed by RT-PCR. Genotyping was performed using phylogenetic analysis. RESULTS: From all clinical samples sufficient amounts of RNA were retrieved to perform whole-transcriptome sequencing for the detection of RNA-viruses. Complete genomic norovirus sequences were obtained from all clinical samples, permitting accurate genotyping by phylogenetic analysis. In addition, a complete coxsackie B1 virus genome was isolated. CONCLUSION: Detailed information on viral content can be obtained from fecal samples in a single-step approach, supporting clinical and epidemiological purposes. Next-generation sequencing performed directly on clinical samples can become a powerful tool in patient care and infection control. PMID- 26492616 TI - The Potential Role of Solvation in Antibody Recognition of the Lewis Y Antigen. AB - Solvents play an important role in protein folding, protein-protein associations, stability, and specificity of recognition as in the case of antibody-antigen interactions through hydrogen bonds. One of the underappreciated features of protein-associated waters is that it weakens inter- and intra-molecular interactions by modulating electrostatic interactions and influencing conformational changes. Such observations demonstrate the direct relationship between macroscopic solvent effects on protein-protein interactions and atom scale solvent-protein interactions. Although crystallographic solvents do explain some aspects of solvent-mediated interactions, molecular simulation allows the study of the dynamic role of solvents. Thus, analysis of conformations from molecular simulations are employed to understand the role of solvent on the inherent polyspecificity of a Lewis Y reactive germline gene relative to its expanded hybridomas and a humanized anti-Lewis Y antibody. Our analysis reveals that solvent mediates critical contacts through charged residues to facilitate cross-reactivity to carbohydrate antigens, but also increases the flexibility of some anti-Lewis Y antibodies concomitant with mutations (amino acid substitutions) to the germline antibody. Such flexibility might better allow for recognition and binding of internal structures of extended carbohydrate structures on tumor cells. PMID- 26492617 TI - Production of Recombinant Human scFv Against Tetanus Toxin Heavy Chain by Phage Display Technology. AB - Tetanus, as a major cause of death in developing countries, is caused by tetanus neurotoxin. Recombinant antibodies against tetanus neurotoxin can be useful in tetanus management. Phage display of antibody fragments from immune human antibody libraries with single chain constructs combining the variable fragments (scFv) has been one of the most prominent technologies in antibody engineering. The aim of this study was the generation of a single chain fragment of variable region (scFv) library and selection of specific antibodies with high affinity against tetanus toxin. Immune human single chain fragment variable (HuscFv) antibody phagemid library was displayed on pIII of filamentous bacteriophage. Selection of scFv clones was performed against tetanus toxin antigens after three rounds of panning. The selected scFv clones were analyzed for inhibition of tetanus toxin binding to ganglioside GT1b. After the third round of panning, over 35 HuscFv phages specific for tetanus toxin were isolated from this library of which 15 clones were found to bind specifically to tetanus toxin. The selected HuscFv phages expressed as a soluble HuscFv peptide and some clones showed positive signals against tetanus toxin. We found that six HuscFv clones inhibit toxin binding to ganglioside GT1b. These selected antibodies can be used in the management of tetanus. PMID- 26492618 TI - Monoclonal Antibody LpMab-9 Recognizes O-glycosylated N-Terminus of Human Podoplanin. AB - Podoplanin (PDPN) induces cell invasion and cancer metastasis, and its expression in cancer cells or cancer-associated fibroblasts has been reported to be involved in poor prognosis of several cancers including malignant gliomas and lung cancers. PDPN is also expressed in normal cells such as lymphatic endothelial cells, lung type I alveolar cells, and kidney podocytes. Many anti-PDPN monoclonal antibodies (MAbs) have been established; however, almost all anti-PDPN MAbs recognize a platelet aggregation-inducing (PLAG) domain, because the PLAG domain is known to be highly immunogenic. Here, we developed and characterized LpMab-9, a novel anti-PDPN MAb. LpMab-9 reacted with LN319 glioblastoma cells, but did not react with LN319/PDPN knock-out cells. LpMab-9 showed slight reaction with sialylated O-glycan-deficient PDPN. We identified the minimum epitope of LpMab-9 as Thr25-Asp31, which is the N-terminus of human PDPN, using Western blot analysis. Furthermore, Thr25, Gly26, Gln27, and Pro28 were shown to be critical for LpMab-9-binding to PDPN using flow cytometry. Antibody-overlay lectin microarray using LpMab-9 demonstrated that PDPN reacts with sialic acid +/- core1 binders and sialo-mucin binders. Taken together, these results indicate that LpMab-9 recognizes O-glycosylation of Thr25 in the N-terminus of PDPN. LpMab-9 could be useful for uncovering the physiological function of O-glycosylated N terminus of human PDPN. PMID- 26492619 TI - Development of Monoclonal Antibody LpMab-10 Recognizing Non-glycosylated PLAG1/2 Domain Including Thr34 of Human Podoplanin. AB - Podoplanin (PDPN) is a type-I transmembrane sialoglycoprotein that possesses a platelet aggregation-stimulating (PLAG) domain in the N-terminus. PLAG domain includes three tandem repeats of eight amino acids: PLAG1, PLAG2, and PLAG3. Among the three PLAG domains, O-glycan on Thr52 of PLAG3 is critical for binding with C-type lectin-like receptor-2 (CLEC-2) and is essential for platelet aggregating activity of PDPN. In contrast, the glycosylation of Thr34 of PLAG1 of human PDPN remains to be clarified. Herein, we developed and characterized a novel anti-PDPN monoclonal antibody, LpMab-10, which targets PLAG1/2 domain. LpMab-10 detects endogenous PDPN of cancer cells and normal cells independently of glycosylation. The minimum epitope of LpMab-10 was identified as Glu33-Gly45 of PDPN using Western blot and flow cytometry. The Thr34 of PLAG1 is critical for LpMab-10 recognition, and O-glycan is not included in LpMab-10 epitope, indicating that Thr34 of PLAG1 is not O-glycosylated. In immunocytochemical and immunohistochemical analyses, LpMab-10 strongly detected PDPN-expressing tumor cells. By using monoclonal antibodies against different Ser/Thr, including epitopes of PDPN, it becomes possible to determine whether Ser/Thr residues of PDPN are O-glycosylated. PMID- 26492620 TI - Prokaryotic Expression of Truncated S1 Protein of Porcine Epidemic Diarrhea Virus and Production of Monoclonal Antibodies to Recombinant Protein. AB - Monoclonal antibodies are known to have several applications in clinical diagnosis and therapy. In the present study, the truncated S1 gene, encoding the exterior of the viral spike protein of porcine epidemic diarrhea virus (PEDV), was subcloned into prokaryotic expression vector pET32a (+) and expressed as a recombinant protein in Escherichia coli BL21(DE3). Female BALB/c mice were immunized with the purified recombinant truncated S1 protein, and three monoclonal antibodies (MAb designated as E3, G8, and G9) against the truncated S1 protein obtained by hydridoma technique. Further characterization demonstrated that the three MAbs (E2, G8, and G9) belong to IgG1 subclass and have different affinities (G9 > G8 > E3). Furthermore, all of the three MAbs reacted with PEDV in the fluorescent antibody assay. Our study suggests that purified truncated S1 protein and the three developed MAbs could be useful in the development of a diagnostic assay for anti-PEDV antibodies and PEDV antigen, respectively. PMID- 26492621 TI - Preparation and Identification of a Monoclonal Antibody Against Cystatin C. AB - Cystatin C (Cys C) has been shown to be an excellent marker of renal function, especially when evaluating the early stages of acute kidney injury. It is less affected by age, gender, muscle mass, and ethnicity. The detection of Cys C is important and has broad application prospects. Therefore, we have developed a panel of monoclonal antibodies against Cys C that can be used to establish an enzyme-linked immunosorbent assay (ELISA) kit and paired for further use in other methods of detecting Cys C. This study describes the preparation, application, and characterization of monoclonal antibodies used in ELISA. The antibodies were developed by PEG fusion of the SP2/0 cells with splenic B cells from Cys C immunized BALB/c mice. Antibody-producing cells were identified by ELISA and Western blot analysis. By way of cloning and screening, four hybridoma cell lines were established. Simultaneously large-scale monoclonal antibodies produced in mice ascites were prepared. The results showed that the cell clone 8D12 could be used in immunohistochemical staining. With the ELISA additivity test, we got a preliminarily finding that the monoclonal antibodies were not on the same epitope. The antibody matching test showed that 5D7 and 7A8 successfully paired with 8D12, and the optimal reaction conditions were initially identified. PMID- 26492622 TI - Development of ELISA and Colloidal Gold-PAb Conjugate-Based Immunochromatographic Assay for Detection of Abrin-a. AB - When abrin-a was combined with several polyclonal antibodies (PAb), the detection limit could be increased. In this way, a monoclonal antibody (capture) and polyclonal antibody (detection) sandwich enzyme-linked immunosorbent assay (ELISA) and a colloidal gold-PAb conjugate-based immunochromatographic assay for detection of abrin-a were developed. The ELISA had a detection limit of 3.9 ng/mL for abrin-a in standard solution and 7.8 ng/mL in soybean milk, and was more sensitive than polyclonal antibody (capture) and monoclonal antibody (detection) ELISA, which had a detection limit of 15.6 ng/mL. The test strip had a detection range of 50 to 500 ng/mL for abrin-a and a detection limit in standard solution or soybean milk samples of 50 ng/mL. However, the test strip had a reduced detection capability compared with a colloidal gold-monoclonal antibody conjugate based immunochromatographic assay test strip, which had a lower detection limit of 10 ng/mL. The developed ELISAs and test strip show the specificity towards abrin-a and have no cross-reactivity towards abrin-b, -c, -d, ricin, or the agglutinins from either castor beans or rosary peas. PMID- 26492623 TI - Development of Monoclonal Antibodies and Characterization of an ELISA Platform Against Kallikrein-Related Peptidase 6 as a Tumor Biomarker. AB - Kallikrein-related peptidase 6 (KLK6) is a serine protease, and one of fifteen kallikrein members located on chromosome 19. KLK6 is associated with the regulation of axonal growth following spinal injury, tumor cell metastasis, and alpha synuclein aggregate pathologies like Parkinson's, making KLK6 a potentially important biomarker. We generated a KLK6 expression vector for large-scale expression in Escherichia coli. After affinity chromatography purification and SDS-PAGE confirmation, mice were immunized with the purified protein for development of monoclonal B cell populations. Our immunizations generated five hybridomas (1D8, 2E3, 3B7, 5G8, and 5H12) against KLK6. Isotyping analysis revealed that clone 2E3 was IgG2b, while the other four clones were IgG1. Further studies found that clone 5G8 could be used to visualize specific KLK6 bands by Western blot analysis from ovarian cancer patient serum and plasma, and also in mouse liver lysates. Finally, we established a sandwich ELISA pair and determined their sensitivity for KLK6 to be 10 ng/mL. These findings establish an essential tool for the detection and analysis of KLK6. PMID- 26492624 TI - Preparation, Purification, and Identification of a Monoclonal Antibody Against NRP2 b1b2 Domain. AB - First identified as a high-affinity kinase-deficient receptor for class-3 semaphorins and vascular endothelial growth factor (VEGF) families, Neuropilin2 (NRP2) is a transmembrane non-tyrosine-kinase glycoprotein that has a vital function in neuronal patterning. Furthermore, NRP2 expression is often upregulated in cancer tissues and correlated with poor prognosis. In the present study, we report the establishment of a monoclonal antibody specific for NRP2b1b2 domain (NRP2 MAb) through hybridoma method. NRP2 MAb is measured to have a titer of 5.12 * 10(5) against NRP2b1b2 in indirect ELISA. Western blotting, flow cytometry, and immunofluorescence analysis indicate that NRP2 MAb can combine full-length NRP2 in LoVo and SW480 cells. Besides helping further understand NRP2 related pathological mechanisms and cell-signaling pathways, NRP2 MAb may act as a therapeutic agent for cancer in the future. PMID- 26492625 TI - Protection Against H7 Subtype Influenza Virus Infection in Mice by Passive Transfer of Neutralizing Monoclonal Antibody. AB - H7 subtype influenza viruses pose serious threats to both the poultry industry and public health. Recent human infections of avian H7N9 influenza viruses with substantial morbidity and mortality have raised concerns about this virus becoming a potential pandemic pathogen. Neutralizing antibodies have been proven to be highly effective in blocking influenza virus infections. In this study, in order to develop an antibody-based immunoprophylaxis against H7 subtype influenza virus, we first generated a neutralizing monoclonal antibody (MAb) by using a pseudotyped lentiviral vector carrying the hemagglutinin protein of H7 subtype influenza virus. In vitro studies demonstrated that this neutralizing MAb completely inhibited the infection of an H7 subtype influenza virus to cells. The protective efficacy of this MAb was then further tested in a mouse model. It was shown that passive immunization of this MAb protected mice from local virus challenge. Results of the current study lay a foundation for the development of neutralizing MAb-mediated prophylactic strategies to combat human H7 influenza virus infections. PMID- 26492626 TI - Comparison of Gold Nanoparticle Conjugated Secondary Antibody with Non-Gold Secondary Antibody in an ELISA Kit Model. AB - In this study, gold nanoparticles (AuNPs) were used as carriers of the signaling anti-chicken antibody peroxidase in comparison with anti-chicken antibody peroxidase without gold nanoparticle in a commercial avian influenza kit. AuNPs enhanced the absorbance and shortened the assay time. AuNPs act as a carrier of many enzymes and multiply the effect of enzyme when reacting with substrate. They amplify optical signal, while keeping low background signals. PMID- 26492628 TI - Comprehensive assessment of microcirculation after primary percutaneous intervention in ST-segment elevation myocardial infarction: insight from thermodilution-derived index of microcirculatory resistance and coronary flow reserve. AB - OBJECTIVES: A pathophysiological mechanism of microvascular dysfunction in ST segment elevation myocardial infarction (STEMI) is multifactorial; thus, multiple modalities were needed to precisely evaluate a microcirculation. METHODS: We complementarily assessed microcirculation in STEMI by the index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) immediately after a primary percutaneous intervention in 89 STEMI patients. Cardiovascular and cerebrovascular events (MACCE) including cardiovascular death, target vessel failure, heart failure, and stroke were assessed during a mean follow-up period of 3.0 years. RESULTS: The microcirculation of enrolled patients was classified into four groups using cutoff CFR and IMR values (CFR>2 and mean IMR): group-1 (n=23, CFR>2 and IMR <= 27); group-2 (n=31, CFR <= 2 and IMR <= 27); group-3 (n=9, CFR>2 and IMR>27); and group-4 (n=26, CFR<2 and IMR>27). On echocardiography 3 months later, improvement in the wall motion score index was shown in group-1 (P<0.01), group-2 (P<0.01), and group-3 (P=0.04), whereas group 4 did not show improvement in wall motion score index (P=0.06). During clinical follow-up, there were no MACCE in group-1 and the patients in group-2 and group-3 showed significantly lower MACCE compared with group-4 (group-1=0%, group-2, and group-3=10%, group-4=23.1%, P=0.04). CONCLUSION: Complimentary assessment of microcirculation by the IMR and CFR may be useful to evaluate myocardial viability and the long-term prognosis of STEMI patients. PMID- 26492629 TI - The effect of patient-practitioner communication on pain: a systematic review. AB - BACKGROUND AND OBJECTIVE: Communication between patients and health care practitioners is expected to benefit health outcomes. The objective of this review was to assess the effects of experimentally varied communication on clinical patients' pain. DATABASES AND DATA TREATMENT: We searched in July 2012, 11 databases supplemented with forward and backward searches for (quasi-) randomized controlled trials in which face-to-face communication was manipulated. We updated in June 2015 using the four most relevant databases (CINAHL, Cochrane Central, Psychinfo, PubMed). RESULTS: Fifty-one studies covering 5079 patients were included. The interventions were separated into three categories: cognitive care, emotional care, procedural preparation. In all but five studies the outcome concerned acute pain. We found that, in general, communication has a small effect on (acute) pain. The 19 cognitive care studies showed that a positive suggestion may reduce pain, whereas a negative suggestion may increase pain, but effects are small. The 14 emotional care studies showed no evidence of a direct effect on pain, although four studies showed a tendency for emotional care lowering patients' pain. Some of the 23 procedural preparation interventions showed a weak to moderate effect on lowering pain. CONCLUSIONS: Different types of communication have a significant but small effect on (acute) pain. Positive suggestions and informational preparation seem to lower patients' pain. Communication interventions show a large variety in quality, complexity and methodological rigour; they often used multiple components and it remains unclear what the effective elements of communication are. Future research is warranted to identify the effective components. PMID- 26492630 TI - Risk factor analysis of cerebral white matter hyperintensities in children with sickle cell disease. AB - Sickle cell disease (SCD) is complicated by silent cerebral infarcts, visible as white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI). Both local vaso-occlusion, elicited by endothelial dysfunction, and insufficiency of cerebral blood flow (CBF) have been proposed to be involved in the aetiology. We performed an explorative study to investigate the associations between WMHs and markers of endothelial dysfunction and CBF by quantifying WMH volume on 3.0 Tesla MRI. We included 40 children with HbSS or HbSbeta(0) thalassaemia, with a mean age of 12.1 +/- 2.6 years. Boys demonstrated an increased risk for WMHs (odds ratio 4.5, 95% confidence interval 1.2-17.4), unrelated to glucose-6-phosphate dehydrogenase deficiency. In patients with WMHs, lower fetal haemoglobin (HbF) was associated with a larger WMH volume (regression coefficient = -0.62, R2 = 0.5, P = 0.04). Lower ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) levels were associated with lower CBF in the white matter (regression coefficient = 0.07, R2 = 0.15, P = 0.03), suggesting that endothelial dysfunction could potentially hamper CBF. The findings of our explorative study suggest that a high level of HbF may be protective for WMHs and that endothelial dysfunction may contribute to the development of WMHs by reducing CBF. PMID- 26492631 TI - Current controversies in prenatal diagnosis 1: should NIPT routinely include microdeletions/microduplications? PMID- 26492632 TI - Cardiovascular and Metabolic Responses to On-Water Upwind Sailing in Optimist Sailors. AB - PURPOSE: To explore the cardiovascular and metabolic responses of 9 Optimist sailors (12.7 +/- 0.8 y, 153 +/- 9 cm, 41 +/- 6 kg, sailing career 6.2 +/- 1 y, peak oxygen uptake [VO2peak] 50.5 +/- 4.5 mL . min-1 . kg-1) during on-water upwind sailing with various wind intensities (W). METHODS: In a laboratory session, peak VO2, beat-by-beat cardiac output (Q),mean arterial blood pressure (MAP), and heart rate (fH) were measured using a progressive cycle ramp protocol. Steady-state VO2, Q, MAP, and fH at 4 submaximal workloads were also determined. During 2 on-water upwind sailing tests (constant course and with tacks), W, Q, MAP, and fH were measured for 15 min. On-water VO2 was estimated on the basis of steady-state fH measured on water and of the individual DeltaVO2/DeltafH relationship obtained in the laboratory. RESULTS: VO2, fH, and Q expressed as percentage of the corresponding peak values were linearly related with W; exercise intensity during on-water sailing corresponded to 46-48% of VO2peak. MAP and total vascular peripheral resistance (TPR = MAP/Q) were larger (P < .005) during on-water tests (+39% and +50%, respectively) than during cycling, and they were correlated with W. These responses were responsible for larger values of the double (DP) and triple (TP) products of the heart during sailing than during cycling (P < .005) (+37% and +32%, respectively). CONCLUSIONS: These data indicate that the cardiovascular system was particularly stressed during upwind sailing even though the exercise intensity of this activity was not particularly high. PMID- 26492633 TI - Ten Simple Rules for Creating a Good Data Management Plan. PMID- 26492634 TI - Autologous bone marrow stromal cells are promising candidates for cell therapy approaches to treat bone degeneration in sickle cell disease. AB - Osteonecrosis of the femoral head is a frequent complication in adult patients with sickle cell disease (SCD). To delay hip arthroplasty, core decompression combined with concentrated total bone marrow (BM) treatment is currently performed in the early stages of the osteonecrosis. Cell therapy efficacy depends on the quantity of implanted BM stromal cells. For this reason, expanded bone marrow stromal cells (BMSCs, also known as bone marrow derived mesenchymal stem cells) can be used to improve osteonecrosis treatment in SCD patients. In this study, we quantitatively and qualitatively evaluated the function of BMSCs isolated from a large number of SCD patients with osteonecrosis (SCD-ON) compared with control groups (patients with osteonecrosis not related to SCD (ON) and normal donors (N)). BM total nuclear cells and colony-forming efficiency values (CFE) were significantly higher in SCD-ON patients than in age and sex-matched controls. The BMSCs from SCD-ON patients were similar to BMSCs from the control groups in terms of their phenotypic and functional properties. SCD-ON patients have a higher frequency of BMSCs that retain their bone regeneration potential. Our findings suggest that BMSCs isolated from SCD-ON patients can be used clinically in cell therapy approaches. This work provides important preclinical data that is necessary for the clinical application of expanded BMSCs in advanced therapies and medical products. PMID- 26492636 TI - Effect of Performance Level on the Prediction of Middle-Distance-Running Performances Using a Nomogram. AB - PURPOSE: This study examined the effect of performance level on the validity and accuracy of middle-distance running-performance predictions obtained from the nomogram of Mercier et al in male runners. METHODS: Official French track-running rankings for the 3000-, 5000-, and 10,000-m events from 2006 to 2014 were examined. The performance level was determined from the official reference table of the Federation Francaise d'Athletisme, and the runners were divided in 3 groups (ie, low, moderate, and high levels). Only male runners who performed in the 3 distance events within the same year were included (N = 443). Each performance over any distance was predicted using the nomogram from the 2 other performances. RESULTS: No difference was found in low- and moderate-performance level athletes (0.02 <= effect size [ES] <= 0.06, 95% limits of agreement [LoA] <= 6%). By contrast, a small difference in high-performance-level athletes (P < .01, 0.23 <= ES <= 0.45, 95% LoA <= 11.6%) was found. CONCLUSION: The study confirms the validity of the nomogram to predict track-running performance with a high level of accuracy, except for male runners with high performance level (ie, national or international). Consequently, the predictions from the nomogram may be used in training programs (eg, to prescribe tempo runs with realistic training velocities) and competitions (eg, to plan realistic split times to reach the best performance). PMID- 26492635 TI - Depression, immune function, and early adrenarche in children. AB - Despite consistent findings of an association between depression and immunity in adult and adolescent populations, little is known about the nature of this relationship at earlier ages. Studies of children have yielded mixed results, suggesting methodological confounds and/or the presence of significant moderating factors. Timing of adrenarche, the first phase of puberty that occurs during late childhood, is a plausible moderator of the depression-immunity relationship in late childhood due to its associations with both the immune system and psychological wellbeing. We hypothesized that: (1) a depression-immunity association exists in children, (2) this association is moderated by adrenarcheal timing, and, (3) this association is also moderated by gender. Data were drawn from a nested study of 103 participants (62 females, Mage=9.5, age range: 8.67 10.21 years) participating in a population based cohort study of the transition from childhood to adolescence (across puberty). Participants in this nested study completed the Children's Depression Inventory 2 (CDI-2) and provided morning saliva samples to measure immune markers (i.e., C-reactive protein, CRP; and secretory immunoglobulin A, SIgA). Using hierarchical regression, inflammation measured by CRP was positively associated with the negative mood/physical symptoms (NM/PS) subscale (beta=0.23, t=2.33, p=0.022) of the CDI-2. A significant interaction effect of SIgA x adrenarcheal timing was found for NM/PS (beta=-0.39, t=-2.19, p=0.031) and Interpersonal Problems (beta=-0.47, t=-2.71, p=0.008). SIgA and NM/PS were positively associated for relatively late developers. SIgA and Interpersonal Problems were positively associated for late developers, and negatively associated for early developers. We suggest that both sets of findings might be partially explained by the immunosuppressive effect of the hormonal changes associated with earlier adrenarche, namely testosterone. These results also suggest that adrenarcheal timing has an effect on the association between depression and immunity, and is therefore an important measure in research with younger populations. Future research should utilize longitudinal designs to demonstrate direction of influence of variables, and use a broader range of pro- and anti-inflammatory markers. PMID- 26492637 TI - Electrostatic and Small-Signal Analysis of CMUTs With Circular and Square Anisotropic Plates. AB - Traditionally, capacitive micromachined ultrasonic transducers (CMUTs) are modeled using the isotropic plate equation, and this leads to deviations between analytical calculations and finite element modeling (FEM). In this paper, the deflection is calculated for both circular and square plates using the full anisotropic plate equation. It is shown that the anisotropic calculations match excellently with FEM, whereas an isotropic approach causes up to 10% deviations in deflection. For circular plates, an exact solution can be found. For square plates using the Galerkin method, and utilizing the symmetry of the silicon crystal, a compact and accurate expression for the deflection can be obtained. The deviation from FEM in center deflection is <0.1%. The theory of multilayer plates is also applied to the CMUT. The deflection of a square plate was measured on fabricated CMUTs using a white light interferometer. Fitting the plate parameter for the anisotropic calculated deflection to the measurement, a deviation of 0.07% is seen. Electrostatic and small-signal dynamic analysis are performed using energy considerations including anisotropy. The stable position, effective spring constant, pullin distance, and pull-in voltage are found for both circular and square anisotropic plates, and the pressure dependence is included by comparison with the corresponding analysis for a parallel plate. Measurements on fabricated devices with both circular and square plates subjected to increasing bias voltage are performed, and it is observed that the models including anisotropic effects are within the uncertainty interval of the measurements. Finally, a lumped element small-signal model for both circular and square anisotropic plates is derived to describe the dynamics of the CMUT. PMID- 26492638 TI - Reply: To PMID 25970376. PMID- 26492639 TI - Quantitative analysis of flavanones and chalcones from willow bark. AB - Willow bark extracts are used for the treatment of fever, pain and inflammation. Recent clinical and pharmacological research revealed that not only the salicylic alcohol derivatives, but also the polyphenols significantly contribute to these effects. Quantitative analysis of the European Pharmacopoeia still focuses on the determination of the salicylic alcohol derivatives. The objective of the present study was the development of an effective quantification method for the determination of as many flavanone and chalcone glycosides as possible in Salix purpurea and other Salix species as well as commercial preparations thereof. As Salix species contain a diverse spectrum of the glycosidated flavanones naringenin, eriodictyol, and the chalcone chalconaringenin, a subsequent acidic and enzymatic hydrolysis was developed to yield naringenin and eriodictyol as aglycones, which were quantified by HPLC. The 5-O-glucosides were cleaved with 11.5% TFA before subsequent hydrolysis of the 7-O-glucosides with an almond beta glucosidase at pH 6-7. The method was validated with regard to LOD, LOQ, intraday and interday precision, accuracy, stability, recovery, time of hydrolysis, robustness and applicability to extracts. All 5-O- and 7-O-glucosides of naringenin, eriodictyol and chalconaringenin were completely hydrolysed and converted to naringenin and eriodictyol. The LOD of the HPLC method was 0.77 MUM of naringenin and 0.45 MUM of eriodictyol. The LOQ was 2.34 MUM of naringenin and 1.35 MUM for eriodictyol. The method is robust with regard to sample weight, but susceptible concerning enzyme deterioration. The developed method is applicable to the determination of flavanone and chalcone glycosides in willow bark and corresponding preparations. PMID- 26492640 TI - Quantitative determination of the beta-methyl carbapenem doripenem in powder for injection by a stability-indicating capillary zone electrophoresis method. AB - A capillary zone electrophoresis method for quantitative determination of doripenem in synthetic matrix was developed. The stability-indicating capability was performed applying stress testing protocols. The selected analytical conditions include 100 mM sodium borate buffer (pH 8.0) as run electrolyte, voltage of +15 kV, hydrodynamic injection of 5s (50 mBar), detection at 298 nm and temperature of analysis of 25 degrees C. The electrophoretic separation was carried out in a fused silica capillary (effective length 40 cm, 50 MUm i.d.), using procainamide hydrochloride as internal standard. The proposed method showed quickness and reproducibility, with an analytical run in a total time of 5 min. The percentage of drug amount estimated was 101.33% (RSD = 0.80), with satisfactory intra-day and inter-day precision. In the recovery test, the method was found to be reliable and accurate in the drug quantitation (mean recovery = 101.86%). The robustness was performed applying the Plackett-Burman experimental design which confirmed the assay reliability. Based on results from forced degradation study, the stability-indicating capability was established, being observed a major degradation in alkaline, photolytic and thermal conditions. In comparison to HPLC method previously developed, the proposed capillary electrophoresis assay is statistically equivalent. PMID- 26492641 TI - Influence of formulation on photoinactivation of bacteria by lumichrome. AB - Lumichrome, a photodegradation product of riboflavin, is an endogenous compound in humans. The compound is more photostable and a more efficient photogenerator of singlet oxygen than riboflavin. It absorbs radiation in the UVA and blue-light region, which can be an advantage in antibacterial photodynamic therapy (aPDT) of superficial infections. The aim of this study was to investigate the in vitro aPDT effect of various lumichrome pharmaceutical formulations. Solutions of lumichrome (10(-5) - 10(-3)M) were prepared in plain phosphate buffered saline (PBS) or in PBS solutions containing cyclodextrins, DMSO, PEG 400 or polyoxamers (Pluronic). Supersaturated solutions of lumichrome in PBS were prepared via the cosolvent and solvent evaporation method. Phototoxic effects of selected lumichrome preparations were studied in planktonic Gram-positive (E. faecalis) and Gram-negative (E. coli) bacteria models. The UVA/blue light source emitted mainly in the range 340-440 nm. Lumichrome was up to tenfold more phototoxic against Gram-positive than to Gram-negative bacteria. Bacterial eradication was induced after exposure of lumichrome formulations (PBS, PEG 400 and HPgammaCD) combined with 24J/cm2 UVA/blue light. Increasing the concentration of lumichrome did not enhance the phototoxic effect, probably due to radiation attenuation in the highly absorbing solution (inner filter effect). Cyclodextrins were efficient enhancers of the lumichrome solubility in aqueous solutions, but inhibited the phototoxic effect. The study demonstrates that assuming the use of an optimized formulation, lumichrome has potential as a UVA/blue light photosensitizer in aPDT. PMID- 26492642 TI - Analysis of Niemann-Pick C1-like 1 (NPC1L1) genetic polymorphisms and haplotypes in Chinese Han population. AB - Niemann-Pick C1-like 1 (NPC1L1i) protein is the key transporter responsible for dietary cholesterol absorption. Recent studies indicated that several functional polymorphisms of NPC1L1 were associated with coronary heart disease (CHD) and response to ezetimibe therapy. The aim of the present study was to analyze the allele frequency and haplotype distribution of NPC1L1 polymorphisms in Chinese Hans and to compare them with those of other ethnic populations reported before. Blood samples were collected from 424 unrelated Chinese Hans (246 males and 178 females). Ten NPC1L1 polymorphisms (-762T > C, -133A > G, -18C > A, 1721C > T, 1735C > G, 1764T > C, 1767G > A, 27677T > C, 25342A > C and 28650A > G) were genotyped by direct sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Among the variants, the minor allele frequency of -762T > C and 1735C > G were 35.0% and 37.0%, respectively. Furthermore, these two polymorphisms were highly linked with a D' value of 0.80. The observed frequencies of two major haplotypes were 59.1% for T-762/C1735 and 30.1% for C-762/G1735, respectively. The frequencies of the rest variants were extremely low (1.8% for - 133G, 1.5% for -18A, 0.9% for 1721T and only 0.2% for 27677C allele, respectively) or even not detected (1764T > C, 1767G > A, 25342A > C and 28650A > G) in our study population. Comparison with other ethnic populations revealed a remarkable genetic variability in the incidences of NPC1L1 polymorphisms. The frequencies of NPC1L1 polymorphisms in Chinese Hans are comparable to Japanese population but totally different from Caucasians, African Americans and Hispanic individuals. This is the first study to report the ethnic difference in the frequencies of NPC1L1 functional polymorphisms in detail. -762T > C and 1735C > G are two prevalent NPC1L1 variants which need further studies to explore their clinical impact on CHD prevalence and response to ezetimibe therapy in Chinese Hans. PMID- 26492643 TI - Characterization of endonuclease G and mitochondria-sarcoplasmic reticulum related proteins during cardiac hypertrophy. AB - Endonuclease G (Endo G) is a novel determinant of cardiac hypertrophy. Here, we report the characterization of Endo G and mitochondria-sarcoplasmic reticulum related proteins during cardiac hypertrophy, and hypothesize that Endo G regulate mitochondrial function partly through Mfn2 and Jp2 during cardiac hypertrophy. Our results show that Endo G levels gradually increased at the beginning of phenylephrine-induced cardiac hypertrophy, accompanied by an abnormal mitochondrial membrane potential. The up-regulation of Mfn2, Jp2, and Endo G appeared at an early stage of cardiac hypertrophy, whereas PGC1alpha was not up regulated until a later stage. Abolishing Endo G with siRNA led to the uncoupling of the mitochondrial electron transport chain from ATP production and decreased PGC1alpha expression, likely by affecting the juxtaposition of the mitochondria and the sarcoplasmic reticulum via Mfn2 and Jp2. Furthermore, abolishing Jp2 altered the expression of Endo G expression and induced mitochondrial dysfunction, suggesting that mitochondrial abnormalities in cardiac hypertrophy are most likely caused by Endo G. Taken together, our study established a link between Endo G and mitochondrial function during cardiac hypertrophy, partly through the effects of Endo G on Mfn2 and Jp2, and revealed a role for Endo G in the crosstalk between the processes controlled by Mfn2 and Jp2 in maladaptive cardiac hypertrophy. PMID- 26492644 TI - Cardioprotective effect of breviscapine: inhibition of apoptosis in H9c2 cardiomyocytes via the PI3K/Akt/eNOS pathway following simulated ischemia/reperfusion injury. AB - Breviscapine (BE) is a standardized Chinese herbal medicine extracted from Erigeron breviscapus (Vant.) Hand.-Mazz. It has been widely used to treat cardiovascular and cerebrovascular diseases. However, there are no reports on the protective effects and underlying molecular mechanisms of BE action on myocardial ischemia/reperfusion (MI/R)-induced cardiomyocyte apoptosis. In the present study, we aimed to confirm the cardioprotective effect of BE from MI/R injury in vivo, and investigate the potential molecular mechanisms against simulated ischemia/reperfusion (SI/R)-induced cardiomyocyte apoptosis in vitro. The rat model of MI/R injury was induced by 30 min of transient vessel occlusion followed by 3 h of reperfusion. BE significantly reduced the myocardium infarct size and production of cardiac troponin (cTnl) in serum. In an in vitro experiment, H9c2 cardiomyocytes were incubated with vehicle or ischemic buffer during hypoxia; then, they were reoxygenated with or without BE. BE markedly improved the cell viability and decreased lactate dehydrogenase (LDH) release. We confirmed the anti-apoptotic effect of BE with the Hoechst 33258 staining assay, and this effect was associated with an increase in Bcl-2 and a decrease in active caspase 3 expression. Western blot analysis also showed that BE increased the phosphorylation of Akt and eNOS in H9c2 cells, and the protective effects of BE were partially inhibited by the phosphatidylinositol 3'-kinase (PI3K) specific inhibitor LY294002. Our results suggested that BE could provide significant cardioprotection against MI/R injury, and the potential mechanisms might involve suppression of cardiomyocyte apoptosis through activating the PI3K/Akt/eNOS signaling pathway. PMID- 26492645 TI - Suppression of MAPK and NF-kappa B pathways by schisandrin B contributes to attenuation of DSS-induced mice model of inflammatory bowel disease. AB - Schisandrin B (Sch B), the most abundant dibenzocyclooctadiene lignan isolated from the traditional Chinese medicinal herb Schisandra chinensis (Turcz.) Baill, possesses various biological activities, such as hepatic protection, anti-tumor, anti-inflammatory and anti-cardiovascular properties. However, the effect of Sch B on inflammatory bowel disease (IBD) is not yet known. The aim of this study was to investigate whether Sch B has protective effect against dextran sulfate sodium (DSS)-induced colitis in a mouse model. The acute mouse model of IBD was induced by drinking 2.5% DSS water for 5 days. Sch B was administered orally in doses of 10, 40, and 100 mg/kg respectively. It significantly reduced concentration of TNF alpha, IL-1beta, INF-gamma and IL-6 in colon tissue as well as the mRNA expression levels. In addition, we demonstrated that Sch B blocked the phosphorylation of IkappaBalpha, nuclear factor-kappaB (NF-kappaB) p65, p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, and extracellular signal regulated kinase in DSS-induced acute colitis. In conclusion, these results indicated that Sch B could exert beneficial effects on experimental IBD induced by DSS and may represent a novel treatment strategy for IBD. PMID- 26492646 TI - Chronic rapamycin treatment exacerbates metabolism and does not down-regulate mTORC2/Akt signaling in diabetic mice induced by high-fat diet and streptozotocin. AB - Rapamycin, a classical inhibitor of the mammalian target of rapamycin (mTOR), has been intensively studied for its role in metabolism and verified to induce metabolic defects through mTORC2/Akt pathway. However, disparity of the results exists depending on the differences of the animal models or the detailed procedures. Moreover, data regarding the effect of rapamycin treatment in diabetic models are sparse. Therefore, we investigated its influence on glucose and lipid metabolism, and further analyzed its effect on the mTORC2/Akt pathway in a high-fat diet- and streptozotocin-induced diabetic mice model. Three-weeks old C57BL/6J mice were fed with a high fat diet (60 kcal% fat) and intraperitoneally injected with streptozotocin (100 mg/kg) at 6 weeks of age. Rapamycin (2 mg/kg) was orally given to the mice daily for consecutive 6 weeks. Body weight, blood lipid parameters and HbA(1c)% values were evaluated. Oral glucose test and insulin tolerance test were performed. Furthermore, western blot assay was applied to investigate the protein epression levels of Akt and PKCalpha, two key targets of the mTORC2/Akt pathway. Rapamycin-treated diabetic mice demonstrated less weight gain, more profound symptoms of polydipsia, polyphagia and polyuria, significant liver fat accumulation and exacerbated metabolic disorders including insulin resistance, hyperglycemia and dyslipidemia. Contrary to what have been expected, though significantly inhibiting mTORC1/S6K1 signaling, chronic rapamycin treatment failed to down-regulate mTORC2/Akt pathway. Our findings provide evidence that chronic rapamycin treatment may exacerbate metabolism in diabetic subjects and does not down-regulate mTORC2/Akt signialing in a high-fat diet- and streptozotocin-induced diabetic mice model. PMID- 26492647 TI - In vitro anti-cancer effects of the actin-binding natural compound rhizopodin. AB - Several natural compound interfere with microtubules or the actin cytoskeleton. Compounds interfering with the microtubules like Vinca-alkaloids or taxanes, are extensively used for cancer therapy. In contrast, knowledge about pharmacological properties of actin binding drugs is poor and drugs interfering with actin are far from clinical use. Rhizopodin is a natural compound that strongly affects the actin cytoskeleton at nanomolar concentrations. Initial work revealed interesting anti-bacterial and cytotoxic effects, but the cellular effects and pharmacological properties of rhizopodin have not been characterized. We hypothesized that rhizopodin might exert anti-cancer activity. Therefore, the aim of this study was to characterize the cellular and pharmacological effects of rhizopodin in cancer. Effects of rhizopodin demonstrated prominent effects on the actin cytoskeleton as shown in the actin-pyrene assay and by immunostaining of cancer cells. To investigate cellular effects of rhizopodin, we analyzed cell proliferation, cell death induction by propidium iodide exclusion and western blot, as well as migration by impedance measurement using the xCELLligence device in MDA-MB-231 breast cancer and T24 bladder cancer cell lines. Rhizopodin inhibited proliferation and induced cell death of MDA-MB-231 and T24 cells at nanomolar concentrations. PARP cleavage by rhizopodin suggests caspase-dependent cell death induction. Importantly, rhizopodin potently inhibited MDA-MB-231 and T24 cancer cell migration at subtoxic doses where no actin aggregation was observed, indicating a specific underlying signaling of rhizopodin. In summary, our study elucidates rhizopodin as actin-binding natural compound that exerts potent anti-cancer effects. Therefore, our work provides the basis for further in depth characterization of rhizopodin as an antitumoral agent. PMID- 26492648 TI - Ethnopharmacological information from the botanical correspondence of Berthold Seemann (1825 - 1871)--a pilot study. AB - Historical research may be able to contribute to the exploration of traditional knowledge about medicinal plants and promising attempts have been made investigating Byzantine texts, Early Modern herbals, and writings of Christian missionaries. In this pilot study it should be explored if publications, travel reports, diaries or correspondence of the botanical explorers of the 19th and early 20th centuries may serve a source of ethnopharmacological information as well and may be able to guide modern phytopharmacological research. Writings of Berthold Seemann (1825-1871), a German investigator exploring the botany of Middle America, the Fiji islands and other regions, are investigated as a first example. It could be shown that Seemann's heritage mainly kept at Kew Garden Archives, does contain ethnopharmacological information which in part has already been confirmed by recent study results indicating some reliability of his observations. However, there are also reports about traditional medicinal plants scarcely investigated so far, including Schultesia stenophylla Mart. (syn. S. guainensis (Aubl.) Malme), Trixis inula Crantz, Waltheria glomerata Presl., Gonophlebium attenuatum (Humb. & Bonpl. Es Wil?d) C. Presl., or Pseudoelephantopus spicatus (Juss ex Aubl.) C.F. Baker. It is suggested to further explore their potential as medicinal plants. In general, as Seemann's example has shown, publications and correspondence of botanical explorers of the past seem to be a valuable and hitherto almost neglected source of information to be considered in further historical and ethnopharmacological research. PMID- 26492649 TI - "Everyone can reap the rewards of revalidation". PMID- 26492650 TI - Private firms aim to cash in on revalidation sign off. PMID- 26492651 TI - New RCN chief 'frustrated' by those who look to nursing past. PMID- 26492652 TI - Lack of 'vital' protection for district nurses working alone. PMID- 26492653 TI - Review will assess support for student whistleblowers. PMID- 26492654 TI - New overseas nurse crackdown prompts nurses to quit the NHS. PMID- 26492655 TI - Manchester trust recruits over 250 Indian nurses. PMID- 26492656 TI - Thousands sign petition to exempt nursing from immigration rules. PMID- 26492657 TI - Trusts will be able to breach spending cap on agency staff. PMID- 26492658 TI - "Cancer CNSs are not only cost effective, but also invaluable". PMID- 26492659 TI - "Nursing needs to find a better way of protecting itself". PMID- 26492660 TI - Life outside the NHS. PMID- 26492661 TI - "Learning disability nursing is still genuine nursing". PMID- 26492662 TI - Rehabilitating patients after critical care. AB - Many people survive critical illness but experience problems such as post traumatic stress disorder, after discharge from the critical care unit. This article aims to help intensive care and ward-based nurses, as well as the wider multidisciplinary team, understand the importance of promoting rehabilitation for patients after critical illness. It outlines how critical illness and admission to intensive care affects patients and families, and details rehabilitation strategies that have been adopted and proved beneficial. PMID- 26492663 TI - Do care homes increase risk of dehydration? PMID- 26492664 TI - Reducing dehydration in residents of care homes. AB - Dehydration can have serious consequences for older people and is a particular problem for residents of nursing and care homes. This article, the second in a two-part series, describes how a specialist care home for people with dementia in Great Yarmouth introduced high-quality hydration care to frail residents. By involving all staff and ensuring residents take a litre of fluid by the end of a relaxed and extended breakfast, staff have reduced anxiety and aggression and created a calmer and more sociable atmosphere. This has benefitted residents, visitors and staff, and is reflected in low levels of unplanned hospital admissions and paramedic call-outs. PMID- 26492665 TI - Improving upper limb function after stroke. PMID- 26492666 TI - A new model of reflection for clinical practice. AB - Reflection is a tool that is commonly used as part of student nurse education and in clinical practice, and is often supported by the use of reflective models. It can help demonstrate everyday learning and is also useful for processing thoughts after a critical incident. This article describes a new model of reflection that ensures a thorough reflective process is followed and yet is easy to remember: users do not need textbooks to remind them what each stage covers and what they are required to do. PMID- 26492667 TI - 60 seconds with Sarah Richardson. PMID- 26492668 TI - Five decades in nursing. PMID- 26492669 TI - Help your boss tackle bullying. PMID- 26492670 TI - [The Formulaires of Magendie (1821-1840) of the chemical pharmacy to pharmacology]. AB - With nine consecutive issues published from 1821 to 1836, the Formulaire concepted by Magendie as a usual tool for the medical precriptions, was first dedicated to the new chemical pharmaceuticals, mainly the pure alcaloids, strychnine, quinine and morphine, extracted from raw products. As well he included mineral chemicals, hydrocyanates, iodine and bromide, all supported by newly achieved works, from Pelletier, Caventou and others. Magendie perfectly skilled in animal experimentation, developped and standardized the as far as to evaluate the activity and safety degrees of these new components. It clearly anticipated the evaluation plan determined by the law for the registration of the new drugs in the twentieth century. PMID- 26492671 TI - [Raspail, propagandist himself from the "warnings" of the manual of health, between 1845 and 1878]. AB - During the last thirty years of his life, between 1845 and 1878, Francois-Vincent Raspail (1794-1878) published each year a new edition of his Manuel de sante (Manual of Health), which was intended as a practical guide to prevent and treat, using in particular camphor, major human diseases. Each edition was accompanied by a preamble, as an annual forum where the "revered teacher" applied to give information on his family, his trial, his stays in prison, his resentment, his exile, his publications, schedules consultations, etc. As a libertarian protester against the powers wether medical, political or judicial, Raspail was a tireless defender of the poor and weak, and this attitude earned him his reputation and his popularity. This positive image of "secular saint" was built from an effective propaganda, where the Manuel de sante and its preambles played a central rol. PMID- 26492672 TI - [Raspail, Don Quixote of camphor!]. AB - Francois Vincent Raspail (1794-1878) was a chemist and a politician who practised medicine illegally : for him, all pathologies were almost exclusively caused by "parasites" and he treated them all thanks to the beneficial effects of camphor. Raspail did not invent nor discover that substance, which was broadly used in the 18th century, but he codified the use of its various pharmaceutical forms thanks to what would be later called "Raspail's method": camphor to eat (lumps), to snuff (powder), to smoke (cigarettes), brandy and 32 degrees camphored alcohol, camphored oil and sedative water... Since Raspail lavished his patients with many hygiene pieces of advice and moral principles, this method--that was actually a prolongation of his political action in favour of the very poor--was a complete success among the population. But this success was also due to the simplicity of the remedy, its relative harmlessness and, above all, to an incredibly efficient advertising since he enjoyed the support of many important people and also published a very successful book, his Manuel annuaire de Sante, that was re edited 77 times. PMID- 26492673 TI - [A quarantine of plague at the lazaret of Frioul in 1901]. AB - In September 1901, a cruise for work and pleasure is organized in Mediterranean including VIP all firstclass (politicals, scientists, clergymen...) These were 174 passengers on the ship Senegal. After a departure from Marseille, the ship must quickly turn and go back on account of a sailor in the crew might be sicked with plague. A quarantine was organised in the lazaret of Frioul's island. This man died but an another actually ill will be cured. All the conference participents landed in the Frioul lazaret stayed only seven days on place and remained uninjured. This misadventure will be studied by scientific people and given to authorities. So, Pr Jules Buckoy' communication to the french Academy of medicine. Adrien Proust gave a report. In this doctoral thesis in 1902 Joseph Pellissier reported all the cases of plague cured in the Frioul lazaret. The physician Charles Leroux made an epidemiologic study about effects and troubles with plague serums. A lot of orig- inal and beautiful photographs, notably those by the famous passenger, Leon Gaumont, are joined in our presentation. PMID- 26492674 TI - [Ludwig Wittgenstein (1889-1951) and the "wound shock"]. AB - Ludwig Wittgenstein was born in 1889 in Vienna. As a scholar in Cambdrige University, his philosophical achievements are still major regarding the foundations of mathematics and language. In 1939, he took a job as a porter at London Guys' Hospital then under the Blitz. Wittgenstein met Drs. Grant and Reeve who worked in a dedicated "traumatic shock" under the auspices of the Medical Research Council unit, a unit which then moved to the Royal Victoria Infirmary in Newcastle; Wittgenstein followed them as a technician and improved the preparation of fine pieces of histology fixed by paraffin. He also invented a new device to record pulse pressure and paradoxical pulse search in laboratory rats. At the end of the war, he returned to Cambridge until 1949 and died in 1951. PMID- 26492675 TI - [The daily life of patients at the Hotel-Dieu in Lyon in the nineteenth century]. AB - In 1802 the Hotel-Dieu in Lyons was incorporated in the so-called Hospices Civils de Lyon. This allowed the expansion and renovation of buildings, as well as the improvement of the conditions of hygiene and comfort of the patients. This hospital was devoted only to the most severely ill or injured adults. 1100 patients were treated by seven doctors, a main surgeon and his deputy, residents and sisters. Broadly speaking the evolution of surgery can be divided into two periods: that of before anesthesia and septic surgery and that of antiseptic and aseptic surgery. We have to mention Gensoul and the resection of the maxillary before anesthesia, Bonnet and Ollier who were devoted to osteo-articular surgery (Ollier's disease), Poncet who built the first aseptic theater, Jaboulay and the resident Carrel who were transplantation's pioneers, Bouveret (paroxysmal tachycardia and Bouveret syndrome), Destot who did the first medical use of X rays in 1895. PMID- 26492676 TI - [The Liege School of Physiology in the nineteenth and twentieth centuries]. AB - A short history of the "Ecole liegeoise" of physiology, its great men (Schwann, Van Beneden Fredericq, Florkin and Bacq) and the position of physiology in the future. PMID- 26492677 TI - [Simenon and medicine: a close and complex relationship]. AB - Both as a Leodiensis citizen and as a novelist, Simenon had strong and complex links with medecine and medical men. PMID- 26492678 TI - [The research on medicine in Greco-Roman Egypt in the Centre de Documentation de Papyrologie Litteraire (CEDOPAL) of the University of Liege]. AB - The paper presents the research on medicine in Greco-Roman Egypt conducted in the last forty years at the Centre de Documentation de Papyrologie Litteraire (CEDOPAL) at the University of Liege. It describes the main results obtained by deciphering, editing, translating and commenting Greek and Latin medical papyri, be they literary, documentary or magical. PMID- 26492679 TI - [Anonymous Londinensis and the Greek documentary papyrus of medicine at the CEDOPAL]. AB - The present paper proposes an account of my research on human and veterinary medicine in Graeco-Roman and Byzantine Egypt, undertaken since 2008 at the CEDOPAL at the University of Liege. This research focuses on literary papyri, particularly on the Anonymus Londiniensis (Hermopolis?, 2d half of the 1st). PMID- 26492680 TI - [The pharmacopeia in the Austrian Netherlands: an unpublished book in the Archives of Namur]. AB - Pharmacopeia in the Austrian Netherlands: an unpublished medical book in the Archives of Namur (Belgium); a codicological study and a study of the content. PMID- 26492681 TI - [The uncertain construction of a medical discourse on the effects of zinc in the nineteenth century]. AB - What about the pathological effects of zinc mining in the region of Liege during the 19th century. PMID- 26492682 TI - [The former medical faculty of Reims, famous place of medical training for students of Liege and the region of Liege]. AB - The author, taking advantage of this meeting between the French Society of Medicine and the Centre for the history of Science and Technology in the city of Liege, provides us with a rectified list of all the Doctors in Medicine in Liege and its province who were promoted to the former Faculty of Medicine in Reims. New controls have been made thanks to the contribution of two registration books which give previous education establishments for the medical doctorate. This research has also been checked on the list established in the masterful work written by Marcel Florkin et Jean Kelecom, namely Kelecom Le monde medical liegeois avant la Revolution (Liege Medical World before the French Revolution). PMID- 26492684 TI - "Nurses need support to discuss end-of-life care". PMID- 26492683 TI - [Meyerbeer, spa curist, biography of J. -F. Struensee, physician and man of the modernist state]. AB - In 1757, Struensee (1737-1772) graduated in medicine at Halle-Saale university, as his father a high dignitary in the lutherian church was, and supported by the presence of his grand-father the physician and scientist Samuel Carl. The family moved to Altona where he was nominated as physician in the city council. Then he largely dealt with medical and social items, for orphans and disabled, and attempted to prevent infectious deseases, small pox, typhus, scabies ans dysenteric syndroms. For sure when he practised his investigations on water samples with microscopy, Struensee acted as a pioneer to suspect microrganisms to be responsible for infectious diseases. Later on, he started his medical service dedicated to the Danish king Christian VII. This part of his life demonstrated the ambitious but highly capable man he was when running the whole government load for Denmark, in a liberal and advanced way. We link the drama of his death when he was condamned, to the symphony composed by Meyerbeer (1791-1864), known as an incidental music for Michael Beer's play Struensee, 1846. PMID- 26492685 TI - Concerns over skill mix and recruitment in A&E. PMID- 26492686 TI - Election result means tough time ahead for nurses, say academics. PMID- 26492687 TI - Patient views offer 'important messages' for end-of-life care. PMID- 26492688 TI - Nurse jobs 'safe' after trust takes over GP services. PMID- 26492689 TI - Nurses celebrate their profession. PMID- 26492690 TI - Nursing quality scheme piloted in Scotland. PMID- 26492691 TI - Nurse shortage leaves agency unable to fill majority of shifts. PMID- 26492693 TI - "Involving nurses in purchasing will make the NHS greener". PMID- 26492692 TI - Relaxation steps help nurses 'cut stress by 40%'. PMID- 26492694 TI - "What the Tories' victory means for the NHS's future". PMID- 26492695 TI - "Specialists are uniquely positioned to share knowledge". PMID- 26492696 TI - Screening for antibiotic-resistant infection. AB - Cases of carbapenemase-producing enterobacteriaceae (CPEs) are rising in the UK and around the world. Guidelines from Public Heath England outline methods for screening and managing CPEs, although the implementation is costly. Managing CPEs effectively relies on early detection and management of colonised or infected people. This article describes how an acute London trust designed a management programme for CPEs that involved increased screening. It began with a trustwide point-prevalence study to determine the most likely entrance points of the infection. Coupled with yearly reviews, this will enable targeted screening and more efficient use of resources. PMID- 26492697 TI - Assessing knowledge of antimicrobial stewardship. AB - The Scottish Antimicrobial Prescribing Group (SAPG) is a national clinical multidisciplinary forum that coordinates and delivers antimicrobial stewardship (AS). This work includes ensuring health professionals have the necessary knowledge to contribute to improving the use of antimicrobials and to develop and implement education resources if required. The SAPG undertook a survey to scope the current understanding and learning needs among nurses and midwives in a range of care settings across Scotland. This article reports on the results, which have been used to help develop a dedicated AS education programme for this group of health professionals. PMID- 26492698 TI - How NHS managers are perceived by nurses. AB - BACKGROUND: The introduction of business principles into the NHS to increase efficiency and value for money has involved bringing in managers who are not necessarily experienced in healthcare, but can offer the right business skills. AIM: To learn more about frontline nurses' perception of senior managers and any areas of potential conflict. METHOD: Interviews with 31 frontline NHS nurses in a Scottish hospital between July and September 2010 to explore their perceptions of the managers' role. RESULTS: Many participants had a poor understanding of senior managers' role. They believed the non-clinical background of some managers meant they cannot understand the pressures at the front line. DISCUSSION: One way to increase staff engagement could be for managers to spend time at the front line experiencing what it is like to give patient care. This could increase their credibility to frontline staff as leaders. CONCLUSIONS: Tensions can arise between managers and nurses because of perceived differences in priorities. Understanding the relationship between senior managers and frontline nursing staff, and involving nurses in decision making, can lead to shared goals. PMID- 26492700 TI - Perceptions of a "good death" in acute hospitals. AB - BACKGROUND: Despite the fact that half of all deaths occur in hospital, there is a lack of literature on general nurses' experiences of caring for end-of-life patients on general hospital wards. AIM: To ascertain general nurses' perceptions and experiences of a good death in an acute hospital setting. METHOD: In-depth interviews were conducted with 13 general nurses working in an acute hospital. RESULTS: Six themes were identified as important in facilitating a good death: good communication/awareness of expected death; time (to care); environment; support; knowledge; symptom management. CONCLUSION: Participants felt that failing to communicate a diagnosis of dying adversely affected the quality of death. As such the focus of future end-of-life care education needs to include how general nurses can facilitate communication and handle difficult questions to enable a good death for patients and their families. PMID- 26492701 TI - 60 seconds with Peter Gill. PMID- 26492702 TI - Diagnosis, step by step. PMID- 26492703 TI - [The memory of prof. Andrew Miecznikowski, the Nestor of Polish gynecology, obstetrics and gynecology oncology]. PMID- 26492704 TI - Montelukast is effective in preventing of ovarian hyperstimulation syndrome; an experimental study. AB - OBJECTIVES: To determine the efficacy of montelukast in comparison with cabergoline in the prevention of ovarian hyperstimulation syndrome (OHSS) in rats. MATERIAL AND METHODS: An experimental OHSS model was formed in 35 female Wistar rats. Rats (22 days old) were randomized into 5 groups, each containing 7 animals. The control group received no therapy; the mild OHSS group was administered pregnant mare serum gonadotropin (PMSG) 10 IU for 4 days, hCG 10 IU on the 5th day; the severe OHSS group received PMSG 10 IU for 4 days, hCG 30 IU on the 5th day The montelukast group: received montelukast 10 mg/kg/day and the cabergoline group was administered cabergollne 100 microg/kg/day via oral gavage for 6 days (days 22-27), in addition to those of severe OHSS. All groups were sacrificed on 28th day Body weight, ovarian diameter and weight, vascular permeability vascular endothelial growth factor (VEGF), semiquantitative VEGF receptor-1, and VEGF receptor-2 (VEGFR-2) immunohistochemistry were evaluated. RESULTS: Ovarian diameter and VEGF expression were significantly lower in the montelukast and cabergoline groups than in the severe OHSS group. While montelukast was more effective in limiting vascular permeability in the severe OHSS, cabergoline was superior to montelukast with respect to the limiting effect on increased body weight and VEGFR-2 expression. CONCLUSIONS: The VEGF/VEGFR-2 interaction plays an important role in OHSS pathogenesis. Montelukast limits VEGF expression, and cabergoline reduces both VEGF and VEGFR-2 expressions; they are both effective therapies for the prevention of severe OHSS. PMID- 26492705 TI - Primary ovarian clear cell carcinoma of the abdominal wall--a systematic review of the literature to establish optimal surgical management. AB - Primary ovarian clear cell carcinoma of the abdominal wall (AW-OCCC) is an extremely rare occurrence. Therefore, data on the prognosis and treatment regime remain limited. OBJECTIVES: The aim of the study was to provide an evidence-based review of the available case reports to establish optimal surgical management. MATERIAL AND METHODS: A literature search according to PRISMA guidelines was performed using PubMed database (from 01.01.1990 to 31.12.2013) with the terms: "clear cell carcinoma" and "abdominal wall". A total of 17 case reports on 18 patients with full text available were identified. RESULTS: All AW-OCCC's appeared after previous laparotomy for gynecological reasons, with cesarean section as the predominant intervention (15/18, 83%). Median age was 46 years (range 37-56) and median time elapsed between the initial laparotomy and the cancer was 19 years (range 9-30). Data on the course of the disease were available for 17 cases. The overall median follow-up was 11 months (range 1-60). No cases of metastatic spread to the ovaries or the intraperitoneal cavity were observed. Eight patients experienced recurrence (8/17, 47.1%). Metastatic lymph nodes appeared in 6 of the 8 relapsed women and local recurrence in the remaining 2 subjects. There were 4 fatal cases (4/17, 23.5%), including 3 with lymphatic cancer spread. The women with treatment failure (recurrence or death) more frequently developed lymph node metastases than the curable cases (p=0.002). CONCLUSIONS: Radical resection of the tumor with concomitant pelvic lymph nodes dissection seems to be the most suitable surgical approach. The need for comprehensive intraperitoneal surgical staging for ovarian cancer is questionable. PMID- 26492706 TI - [Efficacy and costs of ovarian cancer therapy in Poland--regional approach]. AB - Ovarian cancer (OC) affects over 3 000 women in Poland annually The efficacy of the therapy remains relatively low due to challenges of systematic improvement in the early detection OC rates. International comparisons indicate a positive correlation between health expenditures and 5-year survival rates of cancer patients. To the best of our knowledge, our study has been the first to present a correlation between the 5-year survival rates (SRs) and the cost of ovarian cancer therapy in particular regions of Poland. MATERIAL AND METHODS: The study was based on the National Health Fund (NHF) data, available in the Disease Treatment Registry The analysis included approximately 13,000 OC patients who started their treatment between 2005 and 2008 to allow for the evaluation of long term therapy results. The 5-year survival rates were analyzed in relation to average NHF expenditures in various regions of Poland, distinguishing the population of patients aged 45-64 years. RESULTS: The 5-year survival rate in the cohorts diagnosed in 2005 and 2008 changed marginally from 42% to 43%, maintaining relatively large differences between the regions (from 35% to 53% in patients diagnosed in 2008). The NHF expenditures in particular regions differed significantly: mean cost for the entire treatment cycle ranged from 31.600 PLN do 58.000 PLNperperson among patients diagnosed in 2008. No significant correlation between the survival and the cost was found. CONCLUSIONS: SRs of OC patients in particular regions of Poland are not correlated with average treatment cost. Thus, the differences in SRs between various regions of Poland have their source in other factors, e.g., clinical stage at diagnosis, or prevailing treatment patterns in the given region. Further studies may decrease regional discrepancies in patient care and SRs in OC subjects. PMID- 26492707 TI - [Conization and radical vaginal trachelectomy with laparoscopic lymphadenectomy in fertility-sparing surgical treatment of cervical cancer]. AB - INTRODUCTION: In the mid-80's and 90's of the last century uterine-sparing surgical treatment methods were proposed to women wishing to preserve their fertility. OBJECTIVES: The aim of the study was to assess practical application of conization or radical vaginal trachelectomy with laparoscopic lymphadenectomy in women with squamous cell cervical cancer (FIGO stages IA and IB1) who want to retain their ability to procreate. Material and methods: A total of 119 women (aged 25-43 years) were included in the study Ninety-six women (60 - IA1 and 36 - IA2) were deemed eligible for conization and 23 women with stages IA2 and IB1 with neoplastic changes of <2cm in diameter were qualified for radical vaginal trachelectomy with laparoscopic lymphadenectomy RESULTS: Conization was not radical in 9 cases and these women were reoperated. A 5-year follow-up in patients after conization revealed disease recurrence (CIN) in 3 IA1 cases (6.5%), and 2 IA2 cases (9.1%). In patients with follow-up of <5 years, no recurrence was observed in 9 out of 10 A1 cases. Similarly there was no recurrence in 7 out of 9 lA2 cases. A 5-year follow-up in patients after trachelectomy confirmed disease recurrence (CIN) in 1 IA2 case (6.25%). There was no disease recurrence in 2 IA1 cases and 4 IB1 cases. Out of 8 subjects staged 1A2 with a follow-up of <5 years, no disease recurrence was observed in 7 (87.5%) patients. During the same follow-up time, no disease recurrence was detected in 3 patients staged IB1. CONCLUSIONS: Proper uterine-sparing treatment with appropriate qualification guarantees adequate control of the treatment process in women with cervical cancer stages IA and IB1 (<2 cm in diameter) according to FIGO. PMID- 26492708 TI - Trends in prenatal diagnosis of non-specific multiple malformations disorders with reference to the own experience and research study on Smith-Lemli-Opitz syndrome. AB - AIM OF THE STUDY: Biochemical diagnosis of fetuses with multiple malformations- an attempt to determine the frequency of prenatal Smith-Lemli-Opitz syndrome. Discussion on trends in prenatal diagnosis of non-specific multiple malformations disorders. MATERIAL AND METHODS: A total of 117 fetal samples were obtained. They were analyzed with gas chromatography/mass spectrometry (GC/MS) method to assess the concentration of 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) in amniotic fluid samples and (or) to establish 7-dehydroestriol/estriol and 8 dehydropregnanetriol/pregnanetrio ratios in maternal urine. RESULTS: In 4 cases Smith-Lemll-Opitz syndrome was confirmed. CONCLUSIONS: Biochemical GC/MS sterol analyses of amniotic fluid or maternal urinary metabolites toward Smith- Lemli Opitz syndrome, as cheap tests, should be performed in all pregnancies with suggestive ultrasound features (holoprosencephaly and(or) atrioventricular canal and(or) genital anomalies), especially when nuchal translucency is increased >3 mm, and after exclusion of chromosomal aberration in routine karyotyping or even arrayCGH. PMID- 26492709 TI - [Umbilical cord blood as a source of nerve and stem cells]. AB - OBJECTIVES: The aim of the study was to assess proliferative ability of the stem cells in the umbilical cord blood and their potential to differentiate in in vitro culture. MATERIAL AND METHODS: The material consisted of 14 samples of umbilical cord blood collected from the umbilical cord vein. Mononuclear cells were isolated using the method of density gradient medium. Next, CD34 cells were isolated from the interphase with the use of the VarioMACS sorter and anti-CD34 antibodies. Long-term cultures were conducted on Iscove's modified Dulbecco medium (IMDM) with addition of granulocyte-macrophage colony stimulating factor (GM-CSF) and nerve growth factor (NGF). Qualitative identification was performed using the May-Grunwald-Giemsy staining method, taking photographs with a confocal microscope, and with the immunoenzymatic method. RESULTS: In our research, CD34+ stem cells constituted 1.16% of the mononuclear cells, and after centrifugation in medium 0.37% of leukocytes in whole umbilical cord blood. Even after 60 days of culture without addition of the growth factors, CD34+ cells were present in the fraction of adherent cells. After stimulation with GM-CSF and NGF a part of the umbilical cord blood cells were transformed into nerve cells (presence of neuron-specific enolase was shown) and into cells morphologically similar to fibroblast and dendritic cells. CONCLUSIONS: After stimulation with GM-CSF and NGF cytokines, the umbilical cord blood cells proliferate in long-term medium, transform into nerve cells and into cells similar to fibroblast and dendritic cells. PMID- 26492710 TI - Biochemical markers in screening for preeclampsia and intrauterine growth restriction. AB - OBJECTIVES: The aim of the study was to evaluate the relationship between the concentrations of substances released by the placenta: placental growth factor (PIGF), pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) and the risk of early and late preeclampsia (PE) and intrauterine fetal growth restriction (IUGR). MATERIAL AND METHODS: A total of 180 pregnant women between 11+0 and 13+6 weeks gestation were recruited for a case-control study Twenty-two patients suffered from early PE, 29 patients from late PE. Data analyzed during the study included maternal histoty and concentrations of PAPP-A, PlGF beta-hCG. RESULTS: The multiple of the median (MoM) value of the PAPP-A concentrations was 1.01 in the control group (interquartile range (1QR), 0.65-1.55), 0.67 (1QR, 0.382-0.82) in the group of patients with early preeclampsia and 0.74 (IQ, 0.33-1.09) in the group of patients suffering from late preeclampsia. MoM value of the PIGF concentrations was 1.21 in the control group (IQR, 0.93-1.57), 0.62 (IQR, 0.51-0.96) in the group of patients with early preeclampsia and 0.92 (lQR, 0.63-1.09) in the group of patients suffering from late preeclampsia. MoM value of beta-hCG concentrations was 1.14 in the control group (IQR, 0.75-1.49), 1.08(IQR, 0.74 1.23) in the group of patients with early preeclampsia and 1,25(IQR, 1,05-1,49) in the group of patients suffering from late preeclampsia. The performance of screening was determined by the areas under the curve and detection rates, with a fixed false-positive rate of 10%. CONCLUSIONS: Decreased levels of PAPP-A and PIGF are related to an increased risk of preeclampsia and its complications. PMID- 26492711 TI - [Analysis of screening tests for Streptococcus agalactiae in pregnant women from the West Pomeranian region]. AB - OBJECTIVE: The aim of the study was to determine the degree of colonization Streptococcus agalactiae (GBS--Group B Streptococcus) in women at 35.-37. weeks of pregnancy and to evaluate drug susceptibility of the isolated strains. MATERIAL AND METHODS: We analyzed the results of 1111 tests for GBS colonization performed between 2010-2013 in pregnant women (aged 16-40) from the West Pomeranian region. Swabs were taken from the vagina and the anus of the study subjects at 35.-37. weeks of pregnancy Materials were cultured on Granada Agar and in selective Todd-Hewitt broth, which was next cultured on Granada Agar The degree of GBS colonization was determined by the semi-quantitative method on solid media. The strains were tested for susceptibility to penicillin, erythromycin and clindamycin by disc diffusion method according to the EUCAST standards. RESULTS: Positive cultures for S. agalactiae were found in 22.5% of the pregnant women. The highest (25.4%) and the lowest (15.9%) rates of GBS colonization were observed in the age groups of 31-35 and 16-20 years, respectively Massive GBS colonization was detected in 68.4% of pregnant subjects, with the highest and the lowest rates in the age groups of 31-35 and 16-20 years, (75.3% and 50.0%, respectively). All isolated GBS strains were sensitive to penicillin. Macrolide, lincosamide and streptogramin B resistance (MLSB) was found in 28% of the isolates, resistance only to erythromycin (phenotype M) in 2% of the strains. There were no significant differences in the degree of GBS colonization and drug sensitivity of GBS strains versus the year of our examination. CONCLUSIONS: Monitoring for GBS colonization in the last weeks of pregnancy seems to be necessary for effective prevention of S. agalactiae infections. PMID- 26492712 TI - [Fetal programming and the etiology of osteoporosis]. AB - Osteoporosis is a multifactorial skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in increased risk of fracture. Peak bone mass is an important predictor of later risk of osteoporosis. Epidemiological studies revealed that the risk of osteoporosis might be modified by exposure to environmental factors during intrauterine life and early postnatal period. This review summarizes the influence of fetal programming on the development of osteoporosis based on the epidemiological studies and potential mechanisms of epigenetic regulation of gene expression. PMID- 26492713 TI - [The use of Doppler in the second half of pregnancy]. AB - The article is a review of the literature on the use and clinical applicability of Doppler examination in the second half of pregnancy Nowadays, despite its accessibility Doppler ultrasound in pregnancy is often contraindicated. At the same time, the is no evidence of clinical utility of Doppler studies in a low risk pregnancy The main indications for Doppler examinations in pregnancy include intrauterine growth restriction (IUGR), suspicion of fetal anemia, and complications of monochorionic twin pregnancy As far as IUGR is concerned, Doppler allows to diagnose IUGR associated with placental insufficiency and to differentiate IUGR from small for gestational age fetuses (SGA). Doppler is also very useful in making the decision about the time of delivery of IUGR fetuses. The assessment of the peak systolic velocity in the middle cerebral artery (PSV MVA) reduced the rate of invasive procedures due to fetal anemia by approximately 70%. Complications of the second half of pregnancy which are indications for Doppler ultrasound include selective IUGR, TTTS and TAPS. Similarly to the first trimester, the mid-trimester assessment of the blood flow in the uterine arteries plays an important role in the prediction of preeclampsia and IUGR, especially early-onset forms of these complications. PMID- 26492714 TI - Successful treatment of Placenta Percreta through a combinatorial treatment involving a Bakri Balloon and Methotrexate--a case report. AB - Placental percreta is a complication involving an abnormally deep placental attachment to the myometrium, resulting in obstetric hemorrhage and peripartum hysterectomy A 38-year-old pregnant woman, with a history of 2 Cesarean births, myomectomy 9 pregnancies, and 6 spontaneous abortions, was admitted after experiencing intrauterine fetal death, which occurred at 19 weeks gestation. The patient was referred to our institution after 8 days of unsuccessful medical treatment. Doppler ultrasonography and vacuum curettage revealed possible signs of abnormal placentation. Because of the unsuccessful separation of the placenta and massive bleeding, we used a Bakri Balloon to treat excessive bleeding during the acute phase, followed by the conservative administration of parenteral methotrexate to treat the spontaneous involution of the placenta at 7 weeks of conservative therapy Bakri Balloon and methotrexate application to treat bleeding after curettage is a useful choice in placenta percreta and hemorrhage after abortion. PMID- 26492715 TI - [Polish Gynecological Society--Ultrasound Section Guidelines on ultrasound screening in gynecology--2015]. PMID- 26492716 TI - Top Standards Compliance Data for First Half of 2015. PMID- 26492717 TI - Living Better in the Built Environment. Make Sure the Environment of Care Is Both Safe and Comfortable for Patients, Visitors, and Staff . PMID- 26492718 TI - Theoretical approaches to lightness and perception. AB - Theories of lightness, like theories of perception in general, can be categorized as high-level, low-level, and mid-level. However, I will argue that in practice there are only two categories: one-stage mid-level theories, and two-stage low high theories. Low-level theories usually include a high-level component and high level theories include a low-level component, the distinction being mainly one of emphasis. Two-stage theories are the modern incarnation of the persistent sensation/perception dichotomy according to which an early experience of raw sensations, faithful to the proximal stimulus, is followed by a process of cognitive interpretation, typically based on past experience. Like phlogiston or the ether, raw sensations seem like they must exist, but there is no clear evidence for them. Proximal stimulus matches are postperceptual, not read off an early sensory stage. Visual angle matches are achieved by a cognitive process of flattening the visual world. Likewise, brightness (luminance) matches depend on a cognitive process of flattening the illumination. Brightness is not the input to lightness; brightness is slower than lightness. Evidence for an early (< 200 ms) mosaic stage is shaky. As for cognitive influences on perception, the many claims tend to fall apart upon close inspection of the evidence. Much of the evidence for the current revival of the 'new look' is probably better explained by (1) a natural desire of (some) subjects to please the experimenter, and (2) the ease of intuiting an experimental hypothesis. High-level theories of lightness are overkill. The visual system does not need to know the amount of illumination, merely which surfaces share the same illumination. This leaves mid-level theories derived from the gestalt school. Here the debate seems to revolve around layer models and framework models. Layer models fit our visual experience of a pattern of illumination projected onto a pattern of reflectance, while framework models provide a better account of illusions and failures of constancy. Evidence for and against these approaches is reviewed. PMID- 26492719 TI - Comments and responses to "Theoretical approaches to lightness and perception". PMID- 26492720 TI - The staircase Gelb stimulus. PMID- 26492721 TI - Anchoring? PMID- 26492722 TI - Reply to comments. PMID- 26492723 TI - Differential processing of vertical interfeature relations due to real-life experience with personally familiar faces. AB - Identification of personally familiar faces is possibly the most complex and likewise efficient task achieved by the human visual system, yet to date the mechanisms underlying this extreme proficiency remain largely unknown. Building on empirical evidence from unfamiliar face processing in healthy populations and neuropsychological patients, the present work aimed to determine the type of information processed differently due to repeated, real-life experience with faces. A modulatory effect of familiarity was observed for processing of vertical interfeature distances, which have been suggested to rely on holistic processing skills. Contrariwise, no such effect was found for processing of information that can be discriminated locally (ie featural cues, interocular distances). The results indicate that familiarity-related advantages in face processing may arise from more efficient, or increased, holistic processing. PMID- 26492724 TI - The Poggendorff illusion before Poggendorff. AB - This paper is about the Poggendorff illusion in pictorial artworks. In particular, it deals with the role played by the Poggendorff illusion in the making of the geometrical misalignments in the mosaic known as Lunetta di San Lorenzo in Ravenna (Italy) and in Rubens's oil on panel Descent from the Cross in Antwerp (Belgium). Three experiments are presented. Experiment 1 tested the role of viewing distance in perceived collinearity in the mosaic by asking participants to adjust two ends of a cross in silhouette renderings of the saint projected so to mimic its original size. Results confirm an effect of viewing distance and support the hypothesis that the author of the mosaic became aware of the illusion and attempted to 'fix' it. Experiment 2 aimed at verifying perceived collinearity in a book-size version of Rubens's Descentfrom the Cross by employing a similar adjustment method. Results demonstrate that the Poggendorff illusion affects perceived collinearity in the painting, but perceptual collinearity does not agree with the actual geometrical misalignment in book-size reproductions of the masterpiece. Experiment 3 tested the role of viewing distance in a classic Poggendorff illusion configuration by employing the same setup as in experiment 1. Contrary to what was found in experiment 1, viewing distance did not modulate the magnitude of the illusion in the classic display, suggesting that the outcome of perceived collinearity is sensitive to the complexity of the visual scene. The difference in results between experiments 1 and 3 underscore the necessity of new tests before any reasonable conclusion can be drawn about the whys and wherefores of Rubens's misalignment. PMID- 26492725 TI - Catching objects thrown to oneself: Testing control strategies for object interception in a novel domain. AB - A considerable amount of research has been performed to determine the strategies people use to intercept moving objects. Much of this research has been done using target objects such as baseballs and Frisbees that are launched to people from distances ranging from 10 m to 50 m. This research has qualified the range of domains in which each strategy is effective, but there is still controversy regarding which strategy has the most general application. The present research sought to further reduce the range of possible domains in which these strategies work by testing object interception in a situation that had never been tested before, where people launch the target objects to themselves. A strategy based on controlling optical velocity--acting to keep the optical velocity of the object at zero--provided the best match to catcher ground movements and optical trajectories. These results suggest that control of optical velocity is currently the best explanation of effective interception of both other- and self-launched objects. PMID- 26492726 TI - Mo' money, mo' problems: Monetary motivation can exacerbate the attentional blink. AB - The attentional blink (AB) is a compelling psychological phenomenon wherein observers are less likely to identify a second target (T2) when it appears approximately 200 ms after a first target (T1) in a rapidly presented stream of items. The present investigation examined how monetary motivation could impact the AB when participants were differentially motivated to identify T1 versus T2. Participants completed one of three conditions where the only difference across conditions was a motivational manipulation: a standard AB task (control condition), a motivated condition with T1 worth double the points of T2, or a motivated condition with T1 worth half the points of T2 (points in the motivated conditions were linked to a possible monetary bonus). Motivation had an expected influence on overall performance as both motivated conditions had higher overall T1 accuracy relative to the control condition. More specific to the question at hand, the AB was exacerbated (ie T2 performance was worse shortly after T1) when T1 was worth more than T2. This finding suggests that participants overallocated attentional resources to T1 processing at the expense of T2 processing, and it supports current theories of the AB. PMID- 26492727 TI - Idealism and materialism in perception. AB - Koenderink (2014, Perception, 43, 1-6) has said most Perception readers are deluded, because they believe an 'All Seeing Eye' observes an objective reality. We trace the source of Koenderink's assertion to his metaphysical idealism, and point to two major weaknesses in his position-namely, its dualism and foundationalism. We counter with arguments from modern philosophy of science for the existence of an objective material reality, contrast Koenderink's enactivism to his idealism, and point to ways in which phenomenology and cognitive science are complementary and not mutually exclusive. PMID- 26492728 TI - The nonvisual illusion of self-touch: Misaligned hands and anatomical implausibility. AB - The self-touch illusion is elicited when the participant (with eyes closed) administers brushstrokes to a prosthetic hand while the examiner administers synchronous brushstrokes to the participant's other (receptive) hand. In three experiments we investigated the effects of misalignment on the self-touch illusion. In experiment 1 we manipulated alignment (0 degrees, 45 degrees, 90 degrees, 135 degrees, 180 degrees) of the prosthetic hand relative to the participant's receptive hand. The illusion was equally strong at 0 degrees and 45 degrees: the two conditions in which the prosthetic hand was in an anatomically plausible orientation. To investigate whether the illusion was diminished at 90 degrees (and beyond) by anatomical implausibility rather than by misalignment, in experiment 2 hand positioning was changed. The illusion was equally strong at 0 degrees, 45 degrees, and 90 degrees, but diminished at 135 degrees despite the prosthetic hand now being in an anatomically plausible orientation. Thus the illusion is diminished with misalignment of 135 degrees, irrespective of anatomical plausibility. Having demonstrated that the illusion was equally strong with the hands aligned (0 degrees) or misaligned by 45 degrees, in experiment 3 we demonstrated that participants did not detect a 45 degrees misalignment. Large degrees of misalignment prevent a compelling experience of the self-touch illusion, and the self-touch illusion prevents detection of small degrees of misalignment. PMID- 26492729 TI - Testing the mechanisms underlying improved distance judgments in virtual environments. AB - Virtual environments (VEs) presented via head-mounted displays are typically perceived as smaller in scale than intended. Visual-motor experience in VEs can reduce this underestimation of distance, though the mechanisms underlying this improved accuracy of distance estimates are unknown. To address this question, we created a mismatch between biomechanical and visual indicators of self-movement within the VE, and assessed the effect on distance and size judgments. Our results suggest that visual-motor feedback influences subsequent distance judgments by recalibrating perceptual-motor relationships, but we found no evidence that perceived size, which was substantially underestimated, changed as a function of this feedback. In contrast to recent studies that suggest that feedback in VEs causes a broad rescaling ofvirtual space, our results are consistent with a visual-motor recalibration account for much of the improvement in distance judgments following VE experience. PMID- 26492730 TI - Editorial. PMID- 26492731 TI - Improving Ourselves for the Sake of Others: Our Baldrige Journey. AB - In today's healthcare environment, healthcare organizations are trying to balance one foot in each oftwo boats: one for traditional fee-for-service reimbursement and one for population health and pay-for-quality reimbursement. The Baldrige Performance Excellence Program and its associated Criteria will help healthcare leaders navigate this changing environment and improve healthcare outcomes for patients while improving financial performance, enhancing the patient experience, and creating a positive work environment. This balanced approach, grounded in behaviors identified in high-performing organizations, provides leaders and their teams with the key to realizing strategic goals and long-term sustainability. The Baldrige Criteria alone will not improve an organization; rather, it is the unique and disciplined application of the Criteria to each organization that makes the difference. A Baldrige journey is not a sprint, but rather a marathon; it requires a long-term commitment to improvement at all levels of the organization. At Hill Country Memorial (HCM) Hospital in Fredericksburg, Texas, we selected the Baldrige Framework to guide our team as we embarked on a performance excellence climb that would take us from merely average to the national top io percent of performance as evaluated on important organizational metrics. HCM did not achieve overnight success; instead, we achieved year-over year improvement in finance and growth, patient experience, quality of care, and workforce environment and engagement. The story of our climb is one of perseverance, willingness to learn from our mistakes, pursuit of innovative best practices both inside and outside of healthcare, and a team committed to providing the highest-quality service to our customers--our patients and our community. PMID- 26492732 TI - Small-Town Touch, Big-City Innovation, World-Class Aspirations. AB - The healthcare system in the United States is at a critical crossroads. Costs are rising, measures of healthcare quality are well below those of other industrialized nations, and public and regulatory scrutiny is increasing. Healthcare leaders are searching for more effective, efficient, and sustainable operational models to address the mounting challenges they face. We at Schneck Medical Center in Seymour, Indiana, chose the Baldrige Excellence Framework to guide our organization, to accelerate our performance improvement journey, and to create sustainable results in our core services. The Baldrige Framework uses a systematic approach to innovation and improvement in seven key management areas. These seven areas were leadership; strategic planning; customer focus; measurement, analysis, and knowl- edge management; workforce focus; operations focus; and results (Baldrige Performance Excellence Program 2015). In this article, we describe our Baldrige journey. We address why we chose to use the Framework, how we engaged our key stakeholders, and what challenges we faced and lessons we learned along the way. In addition, we detail how Schneck's focus on performance improvement has resulted in significant returns to the organization. Throughout the article, we refer to our pursuit of performance excellence as a "journey," and it is indeed just that. Quality improvement takes time, because it is a transformation with many steps. World-class performance is attainable only with years of work and constant refinement. PMID- 26492733 TI - Can Baldrige Build Learning Organizations? PMID- 26492734 TI - Sharing Leadership Insights on Our Baldrige Journey to Excellence. PMID- 26492735 TI - A Framework for Performance Excellence and Success. PMID- 26492736 TI - Looking past today. PMID- 26492737 TI - Organized medicine versus MOC. PMID- 26492738 TI - Physicians and education: A life-long pursuit. PMID- 26492739 TI - Physicians respond to MOC. PMID- 26492740 TI - An update on the Ebola virus disease. PMID- 26492741 TI - Georgia's innovative response to GME expansion. PMID- 26492742 TI - Where we practice: Thomasville. PMID- 26492744 TI - Georgia Campus--Philadelphia College of Osteopathic Medicine. PMID- 26492743 TI - Emory University School of Medicine. PMID- 26492745 TI - Medical College of Georgia at GRU. PMID- 26492746 TI - Mercer University School of Medicine. PMID- 26492747 TI - Morehouse School of Medicine. PMID- 26492749 TI - Professionalism, TV and the social contract. PMID- 26492748 TI - ACIP's new recommendation for pneumococcal vaccines for all adults 65 years and older. PMID- 26492750 TI - The Interstate Compact, Part II. PMID- 26492751 TI - Professional education after training. PMID- 26492752 TI - Ten traps recent medical graduates should avoid in physician employment agreements. PMID- 26492753 TI - Physician's cognitive and communication failures result in cancer treatment delay. PMID- 26492754 TI - Five things providers need to know about cybersecurity. PMID- 26492755 TI - Life lessons: continued. PMID- 26492756 TI - Medicare's 'dramatic change' in how it pays for care. PMID- 26492757 TI - Hospital-physician practice mergers hinge on finding common ground. PMID- 26492758 TI - Payment reform a primer for taking on risk. AB - To reduce unnecessary care and improve patient outcomes through bundled payments or population health management, healthcare organizations must define both the population for which they are assuming risk and the services that they will provide. Organizations also must be able to manage variations in cost and quality and demonstrate both the economic and clinical value they provide to the populations they serve. To effectively coordinate care across a patient population, providers--including physicians, hospitals, and postacute care facilities--must be willing to collaborate on efforts to reengineer care delivery. PMID- 26492759 TI - Taking smart steps toward clinical integration. AB - Health systems should take five key steps in the early phases of establishing a clinically integrated network (CIN): Establish the operating model and implementation timeline. Identify who to include. Define what's in it for the physicians. Agree on the tenets that will make the CIN stick. Understand when to say no. PMID- 26492760 TI - Finance leadership imperatives in clinical redesign. AB - As physicians embrace their roles in managing healthcare costs and quality, finance leaders should seize the opportunity to engage physicians in clinical care redesign to ensure both high-quality performance and efficient resource use. Finance leaders should strike a balance between risk and reward to achieve a portfolio of clinical initiatives that is organizationally sustainable and responsive to current external drivers of payment changes. Because these initiatives should be driven by physicians, the new skill set of finance leaders should include an emphasis on relationship building to achieve consensus and drive change across an organization. PMID- 26492761 TI - Discussing cost with clinicians. AB - To overcome communication barriers, finance executives and caregivers must better understand the other side's concerns so they can find common ground. Building trust among financial, clinical, and other staff is a critical success factor. Finance leaders can play a transformative role by cultivating their own receptivity to the perspectives of clinicians and other staff. PMID- 26492762 TI - Lessons learned from implementation of gainsharing. AB - Gainsharing offers a hospital a way to control costs by using incentive payments to engage physicians in efforts to improve cost and quality performance. Author John Kotter's eight stages of change management can serve as a framework for understanding how the New Jersey Hospital Association and the Greater New York Hospital Association have guided the successful implementation of gainsharing. Successful gainsharing fosters a culture of improvement that capitalizes on the creativity, knowledge, and problem-solving ability of physicians to implement change and create added value. PMID- 26492763 TI - Implementing a trustworthy cost-accounting model. AB - Hospitals and health systems can develop an effective cost-accounting model and maximize the effectiveness of their cost-accounting teams by focusing on six key areas: Implementing an enhanced data model. Reconciling data efficiently. Accommodating multiple cost-modeling techniques. Improving transparency of cost allocations. Securing department manager participation. Providing essential education and training to staff members and stakeholders. PMID- 26492764 TI - Getting a handle on DNFB strategies for boosting performance. AB - Keeping tabs on DNFB requires a commitment from multiple departments, including clinical documentation, health information management, utilization management, and patient financial services. Monitoring DNFB performance daily, weekly, and monthly can help an organization quickly resolve short-term problems and also identify and respond to more systemic issues. By leveraging historical and comparison data, including performance information from peer organizations, hospitals and health systems can set more realistic targets and further highlight improvement opportunities. PMID- 26492765 TI - Improving revenue cycle performance in medical labs. PMID- 26492766 TI - An overlooked argument in favor of hospital consolidation. PMID- 26492767 TI - Measure quality to create value. PMID- 26492768 TI - State data point to increased Medicaid admissions, with shorter ALOS and lower charges. PMID- 26492769 TI - [CLINICAL AND DIAGNOSTIC SIGNIFICANCE OF IMMUNOGLOBULIN G SUBCLASSES IN IMMUNODEFICIENCY VERIFICATION]. AB - In general practice of clinical immunologists must be use the detection of immunoglobulin G subclasses in cases with symptoms of recurrent and chronic infectious diseases with normal serum IgG. Thus, these patients are not examined and they are under treatment. Over the years, these patients has a sharp decrease in IgG subclasses, which is accompanied by a long course of various infectious processes and complications. Therefore; early diagnosis, early treatment and prevention of complications immunodeficiency knowledge-based clinical immunologists and general practitioners of modern diagnostic methods. PMID- 26492770 TI - [INFORMATIVITY ANALYSIS OF IMMUNOLOGIC MARKERS OF SLOWLY PROGRESSIVE AUTOIMMUNE DIABETES IN ADULTS (LADA)]. AB - A survey of 116 patients with slowly progressive autoimmune diabetes of adults. (LADA) substantiates the need to define at least two kinds of antibodies for final verification of the diagnosis. It's been found that GAD ab and/or IA-2A ab are 'the most conclusive. Gender and age-specific rate of antibodies have been defined. In persons under 45 years ICA ab positive titer was detected significantly less frequently than in patients of middle age (45-59 years), a positive titer IA-2A ab detected more often in younger patients than in middle aged persons. In women, the frequency of a positive titer ICA ab is significantly higher than that of men, but the incidence of positive titer IA-2A ab. is significantly higher in men than in women. The obtained data on the gender and age particularities of antibody in patients with LADA can be used while defining purposeful examination of the patients. PMID- 26492771 TI - [CHAPERONES FUNCTION HSP60 AND HSP90 AND THEIR ROLE IN CARDIAC PATHOLOGY]. AB - In review provides information about the function oft the body of chaperones and their role in the development of pathological processes, including- atherosclerosis and coronary heart disease. Marked comminications systems chaperones to the immune and endocrine systems, and inflammation. PMID- 26492772 TI - [HYALURONIC ACID: STRUCTURE, FUNCTIONS, THE POSSIBILITES OF APPLYING IN THE COMPLEX TREATMENT OF THE TEMPOROMANDIBULAR JOINT DISEASES. A REWIEW]. AB - Over the last decade the use of hyaluronic acid has become increasingly important in treatment of degenerative disorders of the temporomandibular joint. Urgency is caused by numerous studies in biology and pharmacology on structure and function of hyaluronic acid and its influence on the processes of repair damaged bone and articular cartilage restoration, as well as the positive long-term results of treatment in this group of patients. PMID- 26492773 TI - [CHANGES OF GLOBAL AND LOCAL MYOCARDIAL CONTRACTILITY OF CHERNOBYL ACCIDENT CLEAN UP WORKERS WITH STABLE ANGINA]. AB - Changes of global and local myocardial contractility of Chernobyl accident clean up workers (ChA CW) with stable angina were investigated. There were discovered that regular long-term treatment of ChA CW with stable angina using of antiischemic and metabolic drugs promoted to stabilization of global and local myocardial contractility indexes. Ejection fraction, degree of contraction of front-rear systolic left ventricle size, systolic thickness of interventricular septum sufficiently increased. Step-by-step worsening of global and local myocardial contractility indexes in cases of non-regular treatment was taken place. Sufficient differences between indexes of ejection fraction, left ventricle end-diastolic volume, systolic thickness and excursion of interventricular septum in stable angina patients of general population and ChA CW were discovered. Results of global and local myocardial contractility monitoring in ChA CW with stable angina substantiate the advisability of long term supporting treatment using evidence-based drugs. PMID- 26492774 TI - [ANTIPLATELET THERAPY INFLUENCE ON IMMUNOLOGICAL STATUS OF PROGRESSIVE ANGINA PATIENTS]. AB - The study involved 65 progressive angina patients (PA) aged 67 to 73 years. Determination of lymphocytes population and subpopulation was performed by monoclonal antibodies. Immunoglobulin G, A, M and circulating immune complexes (CIC) determination in the blood serum was performed by the Mancini method. The results showed that the clopidogrel with aspirin (aspihrel) combination in the basic treatment of PA patients is more effective than the basic treatment that included only clopidogrel, as evidenced by the positive trend of more indicators of immune status of patients. PMID- 26492775 TI - [CLINICAL PERSPECTIVES OF COMPLEX APPLICATION OF PERCUTANEOUS CORONARY INTERVENTION AND DRUG REVASCULARIZATION IN ACUTE CORONARY SYNDROME]. AB - The article presents the evaluation of the influence of complex application of monopril, propranolol and heparin and percutaneous coronary intervention (PCI); monopril, propranolol with methylase in combination with PCI and PCI only on hemddynamics, cardiohemodynamics and clinical course in acute myocardial infarction (MI), as well as the monitoring of these patients. A comparison of the results of the complex medical and mechanical revascularization. The study involved 63 patients with acute coronary syndrome (ACS): anterior MI with Q wave and ST-segment with the rise in age from 30 to 70 years, the average age (56.7 +/ 1.2) years old, who were randomly divided into three groups with 21 in each. Patients in group I received heparin, propranolol with monopril and PCI; II- methylase (tenakteplaza) and propranolol, monopril and after 1 day they performed PCI; group III patients performed only PCI. With the help of echocardiography and Doppler echocardiometry values studied endsystolic (ESV) and end-diastolic (EDV) volume, ejection fraction (EF), stroke (SI) and heart (HI) index, index of local contractility disturbance of the left ventricle (LV ILCD) as well as the dynamics of systolic, (SBP) and diastolic (PBP) blood pressure, clinical features of myocardial infarction during follow-up. Injection of methylase, infusion of propranolol, receiving per os of monopril and conduct after 1 day of PCI accelerate the stabilization of central hemodynamics. ESV, EDV and ILCD reduce, systolic function of LV improves, ejection fraction increases. When there was no restenosis, myocardial infarction relapse and mortality 1 patient on 5th day was recorded acute heart failure (AHF). When treating by monopril, propranolol and heparin and conduct of PCI also stabilize central hemodynamics. ESV, EDV and ILCD reduce, EF increases and systolic function of LV improves (I group). However, in one patient on the 3rd day were recorded acute heart failure (AHF). Restenosis, recurrent myocardial infarction, and mortality were not observed. During the PCI only treatment 4 patients relapsed MI, 4 patients had restenosis, 2 patients had AHF and 2 patients died. Observations have shown that the combined application of drug therapy with PCI provides a positive predictive as opposed to using only PCI. PMID- 26492776 TI - [THE CHANGES IN THE STRUCTURAL REMODELING OF THE CAROTID ARTERY IN PATIENTS WITH HYPERTENSION AND HEART VALVE CALCIFICATION UNDER THE INFLUENCE OF TREATMENT]. AB - In patients with essential hypertension (EH) and heart valves calcification (HVC) were studied the dynamics of the structural remodeling of the carotid artery under the influence of different variants of lipid-lowering therapy. Significant decrease in the thickness of the intimamedia, the frequency of new atherosclerotic plaques have been seen in patients with EH and HVC using high dose atorvastatin compared with less. PMID- 26492777 TI - [THE BALANCE OF EICOSANOIDS WITH VIBRATION DISEASED PATIENTS IN CONJUNCTION WITH HYPERTENSION DISEASE]. AB - The status of vasodilatational and vasoconstrictoral eicosanoids in patients with vibration disease combined with hypertension disease are presented. The increase of the concentration vasodilators observed in patients with vibration disease. The maximum growth vasoconstrictoral eicosanoids observed in groups with comorbidity. PMID- 26492778 TI - [IMMUNOMODULATORY ACTIVITY OF NEW GALACTOSE-CONTAING POLYSACCHARIDES]. AB - The immunomodulatory properties of perspective prebiotics--beta-galactose containing--polysaccharides arabinogalactan, arabinogalactan with flavonoids, carrageenan, galaktomannan have been studied. It was established that oral administration of the studied beta-polysaccharides to experimental animals leads to a significant activation of immune cells and the synthesis of humoral factors in their organism which significantly increases the cytotoxic activity of blood serum. The most pronounced immunomodulatory effect exhibits arabinogalactan with flavonoids and carrageenan. PMID- 26492779 TI - [A NEW APPROACH TO TREATMENT LIVER CIRRHOSIS IN CONNECTION WITH INTESTINAL DYSBIOSIS]. AB - In order to increase the effectiveness of treatment of the liver cirrhosis were examined 65 patients, we studied the effect on the features flow of intestine microbiocenosis and were are included to the combined treatment the synbiotic medications "Bifilakt extra". Inclusion to the combined treatment of the examined patients with liver cirrhosis synbiotic medications "Bifilakt extra" probably led to better reduction of subjective and objective signs of cirrhosis and intensity of functional biochemical syndromes, symptoms of hepatic encephalopathy. PMID- 26492780 TI - [THE ROLE OF VEGETATIVE DYSREGULATION IN THE FORMING OF BRONCHIAL ASTHMA IN CHILDREN]. AB - To study the heart rate variability (HRV) in bronchial asthma (BA) examined 107 children aged 10 to 18 years old with asthma exacerbation. As a result of the application of asthma control test (GINA, 2011) on the level of controlled asthma children were distributed as follows: 34 (31.8%)--with controlled (CBA), 47 (43.9%)--is partly controlled (PCBA) and 26 (24.3%)--with uncontrolled asthma (UCBA). The control group consisted of 10 healthy children of similar age. All investigated HRV measured on the device "KardyLab BCC" (Kharkov, 2009) with holding orthostatic test to assess the type of autonomic regulation, changes in autonomic balance and adaptive reserves. Analyzed time (SDNN, IN, IWT) and spectral (TP, HF, LF, VLF, LF/HF) HRV indices. Investigation of heart rate variability in children with different degrees of severity of asthma indicated presence of autonomic dysfunction syndrome. It is shown that changes in the autonomic nervous system patients differ depending on the degree controlled asthma. Thus, in children with CBA tendency to sympathicotonia in patients with UCBA often reveals signs of parasympathetic and autonomic imbalance. Severe asthma accompaniedby signs. of autonomic dysfunction: increase vagotonia, the reaction to stress and'rapid depletion of compensatory mechanisms in the restoration of homeostasis against parasympathetic dominance. PMID- 26492781 TI - [PREDICTION OF RECURRENT PYELONEPHRITIS BY AN INDEX OF OXIDATIVE STRESS]. AB - We examined the indicators of oxidant/antioxidant (O/A) balance in the blood of, 118 women with chronic pyelonephritis. (PN), aged 18 to 69 years (mean 36.0 +/- 7.9 years) and 30 conventionally healthy donors: 82 (69.5%) of patients had the recurrent PN, 36 (30.5%) of women had the sporadic PN. The malondialdehyde in serum, ceruloplasmin, transferrin and the number of sulfhydryl groups, which allowed to calculate the index of oxidative stress (IOS) were included into the complex research of O/A balance. IOS was significantly increased in patients with recurrent PN 4.27 2.06 vs. 2.30 +/- 1.06 for sporadic PN (P < 0;001). It allowed us to conduct the multivaiate analysis using binary logistic regression. The analysis demonstrated alhigh quality (>80 %) of regression model chi2 = 74.3; P < 0.001, odds ratio (OR) = 7.5, 95% CI 3.3-7.1. We have created an additional examinational sample to confirm the adequacy of this model which included the test results of 23 pa- tients with acute PN in 6 (26%) of them have developed recurrent PN. We defined a high quality of examinational model chi2 = 11.2; P = 0.0008, OR =3.34, 95% CI 1.3-10.3. The optimal criteria for IOS was > 3, sensitivity 100%, and for specificity 94%. Thus, for the prediction of recurrent PN can be evaluated the IOS. The development of recurrent PN can be predicted with probability 97.6% if value of IOS > 2.5; this will optimize the rehabilitation program of patients Vith acute PN. PMID- 26492782 TI - [PROGNOSTIC RISK FACTORS FOR NEWLY DIAGNOSED PATIENTS WITH ADVANCED STAGES CLASSICAL HODGKIN'S LYMPHOMA]. AB - Determination the complex of new prognostic risk factors will optimize and improve treatment and survival of patients with primary Hodgkin's Lymphoma. PMID- 26492783 TI - [DIFFERENTIATED THERAPY IN PATIENTS WITH URTICARIA]. AB - The actuality is in quite a high proportion of the dermatoses structure. Unclear etiological factors and pathogenesis, the polymorphism of clinical progression, torpid to traditional methods and therapy agents are often observed. The aim of the research is the development of a differentiated treatment of the patients with urticaria, taking into account the functional state of the thyroid gland and its participation in the formation. of autoimmune processes. 127 patients with chronic idiopathic urticarial aged 15-67 were observed (49 of them were men and 78--women). 20 healthy individuals formed the control group. The levels of thyroxine, thyroid peroxidise and thyroglobulin in the blood serum were determined. Dysfunctional state of the thyroid gland and its association with autoimmune processes were specified. The results obtained allowed to justify, develop and implement into the clinical practice the differentiated (depending upon the severity of dermatosis) treatment of the patients with urticaria using the narrow spectroscopic photo and balneo acupuncture which allows to limit the pathologic process. PMID- 26492784 TI - [MORFOHISTOHIMICHNA EVALUATION OF REHABILITATION PATIENTS WITH GENERALIZED PERIODONTAL DISEASE AGAINST CORONARY HEART DISEASE]. AB - Un the basis of morphological studies examined the effectiveness of complex pathogenetic treatment of generalized periodontal disease with the use of products based on natural ingredients: dental paste "Fitopasta-3K" and drug "plantain juice" for the local treatment and drugs "Granules quercetin" and "Energoton" for systemic treatment. Established that one of the important mechanisms of complex pathogenetic treatment is the effect on energy metabolism of periodontal tissues, including the reduction of tissue hypoxia, metabolic stabilization was observed structural changes navkolozubnyh tissues. It should be noted positive effects of integrated treatment on the whole body. PMID- 26492785 TI - [ASSESSMENT OF POSTOPERATIVE PAIN SYNDROME AT SINGLE-PORT TRANSUMBILICAL LAPAROSCOPIC CHOLECYSTECTOMY COMPARED TO TRADITIONAL LAPAROSCOPIC CHOLECYSTECTOMY]. AB - The article analyzes the dynamics of postoperative pain at single-port transumbilical laparoscopic cholecystectomy compared to traditional laparoscopic cholecystectomy. It is shown that the intensity of pain in patients who have undergone laparoscopic procedures through a single transumbilical access was significantly less than in patients with traditional laparoscopic intervention. Furthermore, the use of a single-port transumbilical laparoscopic cholecystectomy accompanied by a smaller increase in the concentration of proinflammatory cytokines compared with patients who had laparoscopic procedures through four trocar accesses. PMID- 26492786 TI - [PREDICTORS OF FORMATION OF NEW FORMS--OF BRONCHOPULMONARY DYSPLASIA AT THE PRENATAL STAGE]. AB - The analysis of history in 116 premature infants, of which 74 children formed a new form of bronchopulmionary dysplasia. The analysis revealed that predictors of the formation of new forms of bronchopulmonary dysplasia are the pregnant woman, accompanied by hypoxia (jeopardy throughout pregnancy, fetoplacental insufficiency, hypotension, pregnancy, anemia) or infectious inflammation (presence of IgG to a pregnant ureaplasma, chorioamnionitis, polyhydramnios). PMID- 26492787 TI - [EVALUETION OF THE CLINICAL EFFICACY OF SUSTAINED RELEASE THEOPHILLINE IN A COMPLEX BASIC THERAPY OF EOSINOPHILIC PHENOTYPE OF BRONCHIAL ASTHMA IN SCHOOL AGE CHILDREN]. AB - Based on a complex examination of 11 school age children with eosinophilic phenotype of bronchial asthma, it has been demonstrated that combination of inhaled corticosteroids with oral sustained release theophillines were more effective as a basic anti-inflammatory asthma therapy, in comparison with monotherapy by inhaled corticosteroids. The usage of such combined anti-relapsing asthma treatment has been reduced both the relative risk (RR = 57%) and the attributable risk (AR = 36.3%) of insufficient control of bronchial asthma in children with eosinophilic type of airways inflammation. At the same time, the minimum number of patients, which have to be treated by such method with the object of preventing at least one case of poor asthma control, came to 3 children. PMID- 26492788 TI - [THE ROLE OF ADIPOCYTOKINES IN THE FORMATION OF INSULIN RESISTANCE IN PATIENTS WITH PRIMARY HYPOTHYROIDISM]. AB - The aim of the study was to investigate the levels of adiponectin and indexes of insulin resistance in patients with primary hypothyroidism. In this article published data and personal data about the role of adiponectin in formation insulin resistance in patients with primary hypothyroidism are shown. The study involved 72 patients with primary hypothyroidism. arising on the background of endemic goiter, including 42 women and 30 men. A direct linear correlation between indexes HOMA IR and TSH was established. We found significantly lower levels of adiponectin in all patients with manifest and subclinical hypothyroidism compared with the control group. Low levels of adiponectin may be an independent factor in the development of insulin resistance in hypothyroidism, cardiovascular diseases and can be considered to be the marker of hypothyroidism with components of metabolic syndrome. PMID- 26492789 TI - [INVESTIATION OF ELECTROMYOGRAPHIC ACTIVITY OF TEMPORAL AND MASSETER MUSCLES AFTER ORTHODONTIC TREATMENT OF MALOCCLUSION COMPLICATED BY DENTAL CROWDING]. AB - The results of investigation showed that it is necessary to use complex methods of orthodontic treatment in patients with malocclusion complicated by dental crowding. Orthodontic appliance therapy should be accompanied by differentiated massage and mioymnastics to improve functional state of masseter and temporal muscles. It was found that after the treatment electromyographic potential amplitude of temporal muscles is on the average in 1.5 times lower as compared with pretreatment records (P < 0.05). It was observed increase on the average in 1.5 times in electromyographic potential oscillation amplitude of masseter muscles during clenching after the treatment of maxillary and mandibular dental crowding (P < 0.05). Treatment of dental crowding resulted in restoration of masseter muscles functional symmetry. During clenching index MASI(MM) significantly decreased in all groups in comparison with pretreatment indices (P < 0.05). PMID- 26492790 TI - [THE SPONTANEOUS PNEUMOTHORAX INTERPRETATION, DIFFICULTIES DURING HISTIOCYTOSIS X]. AB - Since spontaneous pneumothorax can be a complication, and sometimes a manifestation of significant amount of intrathoracic and extrathoracic diseases, verifying the process can be very difficult. One of these diseases is the local (pulmonary) histiocytosis X. Authors cite the etiological diagnosis experience of spontaneous pneumothorax during current pathology. According to their data, spontaneous pneumothorax on the histiocytosis X background found in 3 patients. Complications developed during the disease later stages, and therefore the verification was complex and based on morphological data, consistent with the clinical and radiographic changes. PMID- 26492791 TI - [PUBLIC ADMINISTRATION OF PERSONNEL POLICY IN REFORMING OF UKRAINIAN HEALTH CARE SYSTEM USING THE EXAMPLE OF DERMATOVENEREOLOGICAL SERVICE]. AB - The health care system, its modernization and optimization are among the most important functions of the modern Ukrainian state. The main goal of the reforms in the field of healthcare is to improve the health of the population, equal and fair access for all to health services of adequate quality. Important place in the health sector reform belongs to optimizing the structure and function of dermatovenereological service. The aim of this work is to address the issue of human resources management of dermatovenereological services during health sector reform in Ukraine, taking into account the real possibility of disengagement dermatovenereological providing care between providers of primary medical care level (general practitioners) and providers of secondary (specialized) and tertiary (high-specialized) medical care (dermatovenerologists and pediatrician dermatovenerologists), and coordinating interaction between these levels. During research has been found, that the major problems of human resources of dermatovenereological service are insufficient staffing and provision of health care providers;,growth in the number of health workers of retirement age; sectoral and regional disparity of staffing; the problem of improving the skills of medical personnel; regulatory support personnel policy areas and create incentives for staff motivation; problems of rational use of human resources for health care; problems of personnel training for dermatovenereological service. Currently reforming health sector should primarily serve the needs of the population in a fairly effective medical care at all levels, to ensure that there must be sufficient qualitatively trained and motivated health workers. To achieve this goal directed overall work of the Ministry of Health of Uktaine, the National Academy of Medical Sciences of Ukraine, medical universities, regional health authorities, professional medical associations. Therefore Ukrainian dermatovenereological care, in particular fixed, needs a deep and objective medical and social audit. A necessary condition for the harmonious development of dermatovenereological service is adequate staffing to ensure it to reflect changes in the structure of the provision of the assistance at various levels, as well as their effective coordination throughout the natient's medical route. PMID- 26492792 TI - [THE RESULTS OF SCREENING OF DONATED BLOOD IN THE UKRAINE THE PRESENCE OF MARKERS HEMOTRANSMISYVNYH INFECTIONS IN 2010-2012 YEARS]. AB - Prevalence level of HIV markers among blood and blood coMponent donors in European region of WHO increased from 8.3 to 10.3 positive cases per: 100,000 donations diring 2001-2006. In Ukraine from 2.1 to 112.3 positive cases per 100,000 donations in 2012. In 2010 and .2012 prevalence level of blood borne infections among Ukrainian donors was the following: HIV infection--112.3 positive cases per 100,000 donations; HCV--1498.1 cases and 1207.7 cases; HBsAg (hepatitis B surface antigen)--690.4 and 546.6 and antibodies to Tr. Pallidum- 747 seropositive cases per 100,000 and 672.5 respectively. Specific weight of truly positive donations for HIV varied on test systems of different manufactures from 28.3% to 58.3% in 2010, from 12.2% to 61.8% in 2011 and from 20.7% to 63% in 2012. Significant fluctuation of results of confirmatory tests and high prevalence of HIV and HCV markers among Ukrainian donors displays a tendency to HIV prevalence which requires to define screening strategy of donated blood taking into consideration epidemiological studies and available state resources. PMID- 26492793 TI - [ANALYSIS OF RADIATION IN THE DEPLOYMENT OF MILITARY UNITS OF THE MINISTRY OF DEFENSE OF UKRAINE]. AB - There were observed radiation hazardous objects and zone of possibie rauioactive contaminationof the area with military units, and also possibility of influence of adverse factors (radiation) on the human organism. There is also available characteristic of Ukrainian nuclear Powers, number of population, that lives on the area with different pollution degree. PMID- 26492794 TI - [OPTIMIZATION THE LEVEL OF INTENSIVELY IN PHYSICAL EDUCATION FOR PUPILS OF THE SPECIAL MEDICAL CONTINGENT]. AB - This article describes an original technique, designed tooptimize the level of intensity of physical activity used in the course of routine physical edication in classes for pupils of the specialized medical groups. The basis of this technique is the principles evaluate the response of students of special medical group to progressively increasing exercise test with which sets the optimal level of activity for each of the students with the features of the state of his health. The practical application of this method allows you to install exactly the level of exercise used in the course of the lessons of physical education in special medical groups, which improves the health of students with variations in health status, and does not increase the likelihood of any complications of their diseases. PMID- 26492795 TI - Missed Opportunities for Intervention in a Patient With Prolonged Postoperative Delirium. AB - PURPOSE: Postoperative delirium is a common and costly state of brain dysfunction that complicates postsurgical management in some patients. The purpose of this report was to describe a case of prolonged postoperative delirium and to review the appropriate identification and management of this condition. METHODS: A 56 year-old female patient who presented with newly diagnosed diabetes mellitus and dry gangrene underwent a vascular bypass procedure while under general anesthesia. After extubation, the patient became disoriented and agitated. FINDINGS: The delirium continued in a hypoactive form for 10 days before it progressed to severe agitation. During the patient's 2-month hospitalization, she underwent 6 additional surgeries. Eventually, the delirium improved with the use of antipsychotic agents, and the patient was discharged to a skilled nursing facility. IMPLICATIONS: This patient's history, medications, and anesthetic and surgical exposure placed her at high risk for postoperative delirium. Her exceptionally prolonged course of postoperative delirium was likely perpetuated by a multitude of factors, including the continued use of high-risk medications, the stress of repeated surgeries, urinary issues, and infection. CONCLUSION: In this high-risk patient, a proactive approach to the prevention and treatment of delirium may have avoided or mitigated the prolonged delirium and, potentially, long-term cognitive deficits. PMID- 26492796 TI - Why we need a core outcome set for trials of interventions for prevention and management of caries. PMID- 26492797 TI - Priority oral health research identification for clinical decision-making. AB - The Cochrane Library is a core resource for clinical decision-making globally, by clinicians, guideline developers, healthcare providers and patients.The publication of Cochrane Library systematic reviews concerning oral health conditions has grown exponentially to over 215 individual titles (as of 20 June 2015) during the past 20 years.Consequently, maintaining updates of the most clinically important reviews to provide up-to-date and accurate sources of evidence for decision-making has become a pressing concern for the editorial group behind their production, Cochrane Oral Health Group.To identify priority research required by oral health decision-makers, the Cochrane OHG embarked on a consultation process across eight defined areas of dentistry (periodontology, operative (including endodontics) and prosthodontics, paediatric dentistry, dental public health, oral and maxillofacial surgery, oral medicine, orthodontics, cleft lip and/or palate) with existing authors (by email), with members of the public (by online survey), and established internationally clinically expert panels for each area of defined area of dentistry to discuss and ratify (by teleconference) a core portfolio of priority evidence to be produced and maintained on the Cochrane Library.The resulting portfolio of priority research encompasses 81 existing titles to be maintained, and an additional 15 new systematic reviews to be developed by the Cochrane OHG in due course.The Cochrane OHG has actively responded to the outcomes of this prioritisation process by allocating resources to primarily supporting the maintenance of identified priority evidence for the Cochrane Library. PMID- 26492798 TI - Association between developmental defects of enamel and dental caries. PMID- 26492799 TI - Professional mechanical plaque removal alone may not be enough to maintain gingival health. PMID- 26492800 TI - Low-quality evidence for the effectiveness of interdental brushing. PMID- 26492801 TI - Review finds periodontal treatment has short term benefits for diabetics. PMID- 26492802 TI - Metal or fibre posts and root fractures. PMID- 26492803 TI - Nonsurgical retreatment vs. endodontic microsurgery: assessing success. PMID- 26492804 TI - Platform switching of implants may decrease bone loss. PMID- 26492805 TI - Does orthodontic treatment improve oral health-related quality of life? PMID- 26492806 TI - Insufficient evidence to recommend a treatment to stop non-nutritive sucking habits in children. PMID- 26492807 TI - Limited research on surgical interventions to accelerate orthodontic treatment. PMID- 26492808 TI - Congenital bleeding disorders and dental surgery. PMID- 26492809 TI - Oral contraceptives use may increase incidence of dry sockets. PMID- 26492810 TI - Oral healthcare protocols in a nursing home. PMID- 26492813 TI - Implications of co-infection of Leptomonas in visceral leishmaniasis in India. AB - Protozoan parasites Leishmania donovani (family: Trypanosomatidae) cause fatal visceral leishmaniasis (VL) and the infection relapses in apparently cured population as post kala-azar dermal leishmaniasis (PKDL) in the Indian subcontinent. In recent years co-infection of another Trypanosomatid parasite Leptomonas with L. donovani during VL/PKDL in this region has become prominent. The observation of clinically lesser-known insect parasite, Leptomonas in leishmaniasis is intriguing to researchers. The presence of Leishmania look alike Leptomonas in the cultures of clinical isolates of Leishmania has been worrisome to those, who prefer to work with pure Leishmania cultures for drug and vaccine development or immune response studies. The exact implications of such a co habitation, which might lead to a delay in the diagnostics of VL and elevate mortality, need a thorough investigation. Also whether Leptomonas is involved in leishmaniasis manifestation needs to be ascertained. Thus we are currently witnessing a new paradigm of a parasitic co-infection in VL/PKDL cases in India and this review outlines various opportunities for further research in understanding such emerging co-infection. PMID- 26492814 TI - A thermochemical-biochemical hybrid processing of lignocellulosic biomass for producing fuels and chemicals. AB - Thermochemical-biological hybrid processing uses thermochemical decomposition of lignocellulosic biomass to produce a variety of intermediate compounds that can be converted into fuels and chemicals through microbial fermentation. It represents a unique opportunity for biomass conversion as it mitigates some of the deficiencies of conventional biochemical (pretreatment-hydrolysis fermentation) and thermochemical (pyrolysis or gasification) processing. Thermochemical-biological hybrid processing includes two pathways: (i) pyrolysis/pyrolytic substrate fermentation, and (ii) gasification/syngas fermentation. This paper provides a comprehensive review of these two hybrid processing pathways, including the characteristics of fermentative substrates produced in the thermochemical stage and microbial utilization of these compounds in the fermentation stage. The current challenges of these two biomass conversion pathways include toxicity of the crude pyrolytic substrates, the inhibition of raw syngas contaminants, and the mass-transfer limitations in syngas fermentation. Possible approaches for mitigating substrate toxicities are discussed. The review also provides a summary of the current efforts to commercialize hybrid processing. PMID- 26492816 TI - Epigenomic functional characterization of genetic susceptibility variants in systemic vasculitis. AB - Systemic vasculitides are poorly understood inflammatory diseases of the blood vessels that are frequently associated with significant organ damage. Genetic risk variants contribute to the susceptibility of vasculitis, but functional consequences of these genetic variants are largely unknown. Most genetic risk variants in immune-mediated diseases, including systemic vasculitis, are localized to non-coding genetic regions suggesting they might increase disease risk by influencing regulatory elements within the genome. Long range regulatory interactions pose an additional obstacle in localizing functional consequences associated with risk variants to specific genes or cell types. We used cell-type specific enrichment patterns of histone changes that mark poised, primed, and active enhancers, and DNase hypersensitivity to identify specific immune cells mediating genetic risk in vasculitis. Our data suggest that genetic risk variants in ANCA-associated vasculitis are significantly enriched in enhancer elements in Th17 cells, supporting a role for Th17 cells in this disease. Primed and active enhancer elements in B cells can be potentially affected by genetic risk variants associated with Kawasaki disease. Genetic risk in Behcet's disease and Takayasu arteritis might affect enhancer elements in multiple cell types, possibly explained by influencing enhancers in hematopoietic stem cells. Interestingly, our analyses indicate a role for B cells in Kawasaki disease, Behcet's disease, and Takayasu arteritis, and suggest that further work to characterize the involvement of B cells in these diseases is warranted. PMID- 26492815 TI - Structural insights on mouse L-threonine dehydrogenase: A regulatory role of Arg180 in catalysis. AB - Mouse L-threonine dehydrogenase (mTDH), which belongs to the short-chain dehydrogenase/reductase (SDR) superfamily and mediates threonine catabolism, plays pivotal roles in both powerful biosynthesis and signaling in mouse stem cells and has a regulatory residue Arg180. Here we determined three crystal structures of mTDH: wild-type (WT) in the apo form; in complex with NAD(+) and a substrate analog, glycerol, or with only NAD(+); as well as the R180K variant with NAD(+). This is the first description of a structure for mammalian SDR-type TDH. Structural comparison revealed the structural basis for SDR-type TDH catalysis remains strictly conserved in bacteria and mammals. Kinetic enzyme assays, and isothermal titration calorimetry (ITC) measurements indicated the R180K mutation has little effect on NAD(+) binding affinity, whereas affects the substrate's affinity for the enzyme. The crystal structure of R180K with NAD(+), biochemical and spectroscopic studies suggested that the R180K mutant should bind NAD(+) in a similar way and have a similar folding to the WT. However, the R180K variant may have difficulty adopting the closed form due to reduced interaction of residue 180 with a loop which connects a key position for mTDH switching between the closed and open forms in mTDH catalysis, and thereby exhibited a significantly decreased kcat/Km value toward the substrate, L-Thr. In sum, our results suggest that activity of GalE-like TDH can be regulated by remote interaction, such as hydrogen bonding and hydrophobic interaction around the Arg180 of mTDH. PMID- 26492817 TI - Rationale, Design, and Methodological Aspects of the BUDAPEST-GLOBAL Study (Burden of Atherosclerotic Plaques Study in Twins-Genetic Loci and the Burden of Atherosclerotic Lesions). AB - The heritability of coronary atherosclerotic plaque burden, coronary geometry, and phenotypes associated with increased cardiometabolic risk are largely unknown. The primary aim of the Burden of Atherosclerotic Plaques Study in Twins Genetic Loci and the Burden of Atherosclerotic Lesions (BUDAPEST-GLOBAL) study is to evaluate the influence of genetic and environmental factors on the burden of coronary artery disease. By design this is a prospective, single-center, classical twin study. In total, 202 twins (61 monozygotic pairs, 40 dizygotic same-sex pairs) were enrolled from the Hungarian Twin Registry database. All twins underwent non-contrast-enhanced computed tomography (CT) for the detection and quantification of coronary artery calcium and for the measurement of epicardial fat volumes. In addition, a single non-contrast-enhanced image slice was acquired at the level of L3-L4 to assess abdominal fat distribution. Coronary CT angiography was used for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. For the primary analysis, we will assess the presence and volume of atherosclerotic plaques. Furthermore, the 3 dimensional coronary geometry will be assessed based on the coronary CT angiography datasets. Additional phenotypic analyses will include per-patient epicardial and abdominal fat quantity measurements. Measurements obtained from monozygotic and dizygotic twin pairs will be compared to evaluate the genetic or environmental effects of the given phenotype. The BUDAPEST-GLOBAL study provides a unique framework to shed some light on the genetic and environmental influences of cardiometabolic disorders. PMID- 26492818 TI - Demographic and infection characteristics of patients with carbapenem-resistant Enterobacteriaceae in a community hospital: Development of a bedside clinical score for risk assessment. AB - BACKGROUND: The objective of this study was to identify risk factors associated with the presence of carbapenem-resistant Enterobacteriaceae (CRE) infections to develop a clinical prediction model that can be used at patient bedside to identify subjects likely infected with a CRE pathogen. METHODS: This case-control study included patients aged >=18 years admitted to Novant Health Forsyth Medical Center between January 1, 2012, and December 31, 2013, with CRE infections (cases) or non-CRE infections (controls). Controls were matched to their corresponding resistant case (3:1) based on pathogen, place of likely acquisition, isolate source, year of admission, and level of care. A risk prediction model was developed using variables independently associated with CRE isolation. Sensitivities and specificities were obtained at various point cutoffs, and a determination of the receiver operator characteristic (ROC) area under the curve (AUC) was performed. RESULTS: A total of 164 subjects were included. Independent risk factors for CRE included recent antibiotic therapy, recent immunosuppression, and Charlson Comorbidity Index score >=4. Adjusted odds ratios were 13.37 (95% confidence interval [CI], 4.16-61.19), 6.69 (95% CI, 1.85 29.65), and 3.30 (95% CI, 1.34-8.40), respectively. Diagnostic performance of various score cutoffs for the model indicated a score >=5 correlated with the highest accuracy (79%). The ROC AUC was 0.83. CONCLUSION: The risk prediction model displayed good discrimination and was an excellent predictor of CRE infection. PMID- 26492819 TI - How and when nurses collect urine cultures on catheterized patients: A survey of 5 hospitals. AB - BACKGROUND: Obtaining a specimen for urine culture is a key element in evaluating for catheter-associated urinary tract infections (CAUTIs). Evaluating nurses' knowledge regarding appropriate reasons and methods to obtain urine culture specimens are the first steps to improving practice. METHODS: Nurses at 5 hospitals completed a 40-question survey regarding their knowledge, training, and practices of appropriate reasons for obtaining urine cultures. The survey included different scenarios of patients with urinary catheters and when they would expect to obtain urine cultures. A 12-point scoring system calculated responses regarding urine collection appropriateness. RESULTS: There were 394 nurses who responded to the survey. Of them, 76.1% reported receiving education on CAUTI risk reduction within the last 12 months. Although 327 (83%) of all nurses surveyed reported that they never collect urine samples by draining directly from the drainage bag, only 58.4% viewed others to be fully compliant with that standard (P < .001). Nurses who considered their knowledge to be above average to excellent had similar knowledge assessment scores (out of 12 points) for triggers to obtain urine cultures (mean score, 4.9 +/- 1.72) compared with those that reported average to poor knowledge (mean score, 4.64 +/- 1.78; P = .15). CONCLUSIONS: Important opportunities exist for nurses to optimize the decisions to obtain urine cultures and the process for obtaining them. Addressing nurses' knowledge and practice may lead to more appropriate use of urine cultures. PMID- 26492820 TI - Direct observation of ultrafast coherent exciton dynamics in helical pi-stacks of self-assembled perylene bisimides. AB - Ever since the discovery of dye self-assemblies in nature, there have been tremendous efforts to exploit biomimetic supramolecular assemblies for tailored artificial photon processing materials. This feature necessarily has resulted in an increasing demand for understanding exciton dynamics in the dye self assemblies. In a sharp contrast with J-type aggregates, however, the detailed observation of exciton dynamics in H-type aggregates has remained challenging. In this study, as we succeed in measuring transient fluorescence from Frenkel state of pi-stacked perylene tetracarboxylic acid bisimide dimer and oligomer aggregates, we present an experimental demonstration on Frenkel exciton dynamics of archetypal columnar pi-pi stacks of dyes. The analysis of the vibronic peak ratio of the transient fluorescence spectra reveals that unlike the simple pi stacked dimer, the photoexcitation energy in the columnar pi-stacked oligomer aggregates is initially delocalized over at least three molecular units and moves coherently along the chain in tens of femtoseconds, preceding excimer formation process. PMID- 26492821 TI - Reactive gliosis in the adult zebrafish retina. AB - In contrast to mammals, zebrafish posses the remarkable ability to regenerate retinal neurons. Damage to the zebrafish retina induces Muller glia to act as stem cells, generating retinal progenitors for regeneration. In contrast, injury in the mammalian retina results in Muller glial reactive gliosis, a characteristic gliotic response that is normally detrimental to vision. Understanding the signaling pathways that determine how Muller glia respond to injury is a critical step toward promoting regeneration in the mammalian retina. Here we report that zebrafish Muller glia exhibit signs of reactive gliosis even under normal regenerative conditions and that cell cycle inhibition increases this response. Persistently reactive Muller glia increase their neuroprotective functions, temporarily saving photoreceptors from a cytotoxic light lesion. However, the absence of a sustained proliferation response results in a significant inhibition of retinal regeneration. Interestingly, when cell cycle inhibition is released, a partial recovery of regeneration is observed. Together, these data demonstrate that zebrafish Muller glia possess both gliotic and regenerative potential. PMID- 26492822 TI - Region-specific effects of repeated ketamine administration on the presynaptic GABAergic neurochemistry in rat brain. AB - A growing body of evidence indicates that clinical use of ketamine as a promising antidepressant can be accompanied by psychotic-like side effects. Although, the generation of such effects is thought to be attributed to dysfunction of prefrontal GABAergic interneurons, the mechanism underlying ketamine's propsychotic-like action is not fully understood. Due to wide spectrum of behavioral abnormalities, it is hypothesized that ketamine action is not limited to only cortical GABA metabolism but may also involve alterations in other functional brain areas. To test it, we treated rats with ketamine (30 mg/kg, i.p.) for 5 days, and next we analyzed GABA metabolizing enzymes in cortex, cerebellum, hippocampus and striatum. Our results demonstrated that diminished GAD67 expression in cortex, cerebellum (by ~60%) and in hippocampus (by ~40%) correlated with lowered protein level in these areas. The expression of GAD65 isoform decreased by ~45% in striatum, but pronounced increase by ~90% was observed in hippocampus. Consecutively, reduction in glutamate decarboxylase activity and GABA concentration were detected in cortex, cerebellum and striatum, but not in hippocampus. Ketamine administration decreased GABA transaminase protein in cortex and striatum (by ~50% and 30%, respectively), which was reflected in diminished activity of the enzyme. Also, a significant drop in succinic semialdehyde dehydrogenase activity in cortex, cerebellum and striatum was present. These data suggest a reduced utilization of GABA for energetic purposes. In addition, we observed synaptic GABA release to be reduced by ~30% from striatal terminals. It correlated with lowered KCl-induced Ca(2+) influx and decreased amount of L-type voltage-dependent calcium channel. Our results indicate that unique changes in GABA metabolism triggered by chronic ketamine treatment in functionally distinct brain regions may be involved in propsychotic like effects of this drug. PMID- 26492823 TI - Molecular detection and genetic identification of Babesia bigemina, Theileria annulata, Theileria orientalis and Anaplasma marginale in Turkey. AB - Babesia spp., Theileria spp. and Anaplasma spp. are significant tick-borne pathogens of livestock globally. In this study, we investigated the presence and distribution of Babesia bigemina, Theileria annulata, Theileria orientalis and Anaplasma marginale in cattle from 6 provinces of Turkey using species-specific PCR assays. The PCR were conducted using the primers based on the B. bigemina rhoptry-associated protein 1a (BbiRAP-1a), T. annulata merozoite surface antigen 1 (Tams-1), T. orientalis major piroplasm surface protein (ToMPSP) and A. marginale major surface protein 4 (AmMSP4) genes, respectively. Fragments of B. bigemina internal transcribed spacer (BbiITS), T. annulata internal transcribed spacer (TaITS), ToMPSP and AmMSP4 genes were sequenced for phylogenetic analysis. PCR results revealed that the overall infections of A. marginale, T. annulata, B. bigemina and T. orientalis were 29.1%, 18.9%, 11.2% and 5.6%, respectively. The co-infection of two or three pathogens was detected in 29/196 (15.1%) of the cattle samples. The results of sequence analysis indicated that BbiRAP-1a, BbiITS, Tams-1, ToMPSP and AmMSP4 were conserved among the Turkish samples, with 99.76%, 99-99.8%, 99.34-99.78%, 96.9-99.61% and 99.42-99.71% sequence identity values, respectively. In contrast, the Turkish TaITS gene sequences were relatively diverse with 92.3-96.63% identity values. B. bigemina isolates from Turkey were found in the same clade as the isolates from other countries in phylogenetic analysis. On the other hand, phylogenetic analysis based on T. annulata ITS sequences revealed significant differences in the genotypes of T. annulata isolates from Turkey. Additionally, the T. orientalis isolates from Turkish samples were classified as MPSP type 3 genotype. This is the first report of type 3 MPSP in Turkey. Moreover, AmMSP4 isolates from Turkey were found in the same clade as the isolates from other countries. This study provides important data for understanding the epidemiology of tick-borne diseases and it is expected to improve approach for diagnosis and control of tick-borne diseases in Turkey. PMID- 26492824 TI - Potent and Selective Inhibitors of Trypanosoma cruzi Triosephosphate Isomerase with Concomitant Inhibition of Cruzipain: Inhibition of Parasite Growth through Multitarget Activity. AB - Triosephosphate isomerase (TIM) is an essential Trypanosoma cruzi enzyme and one of the few validated drug targets for Chagas disease. The known inhibitors of this enzyme behave poorly or have low activity in the parasite. In this work, we used symmetrical diarylideneketones derived from structures with trypanosomicidal activity. We obtained an enzymatic inhibitor with an IC50 value of 86 nm without inhibition effects on the mammalian enzyme. These molecules also affected cruzipain, another essential proteolytic enzyme of the parasite. This dual activity is important to avoid resistance problems. The compounds were studied in vitro against the epimastigote form of the parasite, and nonspecific toxicity to mammalian cells was also evaluated. As a proof of concept, three of the best derivatives were also assayed in vivo. Some of these derivatives showed higher in vitro trypanosomicidal activity than the reference drugs and were effective in protecting infected mice. In addition, these molecules could be obtained by a simple and economic green synthetic route, which is an important feature in the research and development of future drugs for neglected diseases. PMID- 26492825 TI - Ancestral state reconstruction of ontogeny supports a bilaterian affinity for Dickinsonia. AB - Despite numerous attempts, classification of the Precambrian fossil Dickinsonia has eluded scientific consensus. This is largely because Dickinsonia and its relatives are structurally simple, lacking morphological synapomorphies to clarify their relationship to modern taxa. However, there is increasing precedence for using ontogeny to constrain enigmatic fossils, and growth of the type species Dickinsonia costata is well understood. This study formalizes the connection between ontogeny in Dickinsonia-which grows by the addition of metameric units onto one end of its primary axis-with terminal addition, defined as growth and patterning from a posterior, subtermial growth zone. We employ ancestral state reconstruction and stochastic character mapping to conclude that terminal addition is a synapomorphy of bilaterian animals. Thus, terminal addition allies Dickinsonia with the bilaterians, providing evidence that large stem- or crown-group bilaterians made up a significant proportion of the Precambrian biota. This study also illustrates the potential for combining developmental and phylogenetic data in constraining the placement of ancient problematic fossil taxa on the evolutionary tree. PMID- 26492826 TI - Evidence of duplicated Hox genes in the most recent common ancestor of extant scorpions. AB - Scorpions (order Scorpiones) are unusual among arthropods, both for the extreme heteronomy of their bauplan and for the high gene family turnover exhibited in their genomes. These phenomena appear to be correlated, as two scorpion species have been shown to possess nearly twice the number of Hox genes present in most arthropods. Segmentally offset anterior expression boundaries of a subset of Hox paralogs have been shown to correspond to transitions in segmental identities in the scorpion posterior tagmata, suggesting that posterior heteronomy in scorpions may have been achieved by neofunctionalization of Hox paralogs. However, both the first scorpion genome sequenced and the developmental genetic data are based on exemplars of Buthidae, one of 19 families of scorpions. It is therefore not known whether Hox paralogy is limited to Buthidae or widespread among scorpions. We surveyed 24 high throughput transcriptomes and the single whole genome available for scorpions, in order to test the prediction that Hox gene duplications are common to the order. We used gene tree parsimony to infer whether the paralogy was consistent with a duplication event in the scorpion common ancestor. Here we show that duplicated Hox genes in non-buthid scorpions occur in six of the ten Hox classes. Gene tree topologies and parsimony-based reconciliation of the gene trees are consistent with a duplication event in the most recent common ancestor of scorpions. These results suggest that a Hox paralogy, and by extension the model of posterior patterning established in a buthid, can be extended to non Buthidae scorpions. PMID- 26492828 TI - Evolutionarily divergent thermal sensitivity of germline development and fertility in hermaphroditic Caenorhabditis nematodes. AB - Thermal developmental plasticity represents a key organismal adaptation to maintain reproductive capacity in contrasting and fluctuating temperature niches. Although extensively studied, research on thermal plasticity has mainly focused on phenotypic outcomes, such as adult life history, rather than directly measuring plasticity of underlying developmental processes. How thermal plasticity of developmental phenotypes maps into plasticity of resulting final phenotypes, and how such mapping relationships evolve, thus remain poorly understood. Here we address these questions by quantifying thermal plasticity of Caenorhabditis hermaphrodite germline development. We integrate measurements of germline development and fertility at the upper thermal range in isolates of C. briggsae, C. elegans, and C. tropicalis. First, we compare intra- and interspecific variation in thermal germline plasticity with plasticity in reproductive output. Second, we ask whether the developmental errors leading to fertility break-down at upper thermal limits are evolutionarily conserved. We find that temperature variation modulates spermatogenesis, oogenesis and germ cell progenitor pools, yet the thermal sensitivity of these processes varies among isolates and species, consistent with evolutionary variation in upper thermal limits of hermaphrodite fertility. Although defective sperm function is a major contributor to heat-induced fertility break-down, high temperature also significantly perturbs oogenesis, germline integrity, and mitosis-meiosis progression. Remarkably, the occurrence and frequency of specific errors are strongly species- and genotype-dependent, indicative of evolutionary divergence in thermal sensitivity of distinct processes in germline development. Therefore, the Caenorhabditis reproductive system displays complex genotype-by-temperature interactions at the developmental level, which may remain masked when studying thermal plasticity exclusively at the life history level. PMID- 26492827 TI - Making maxillary barbels with a proximal-distal gradient of Wnt signals in matrix bound mesenchymal cells. AB - The evolution of specific appendages is made possible by the ontogenetic deployment of general cell signaling pathways. Many fishes, amphibians and reptiles have unique skin appendages known as barbels, which are poorly understood at the cellular and molecular level. In this study, we examine the cell arrangements, cell division patterns, and gene expression profiles associated with the zebrafish maxillary barbel, or ZMB. The earliest cellular organization of the ZMB is an internal whorl of mesenchymal cells in the dermis of the maxilla; there is no epithelial placode, nor any axially-elongated epithelial cells as expected of an apical ectodermal ridge (AER). As the ZMB develops, cells in S-phase are at first distributed randomly throughout the appendage, gradually transitioning to a proliferative population concentrated at the distal end. By observing ZMB ontogenetic stages in a Wnt-responsive transgenic reporter line, TCFsiam, we identified a strongly fluorescent mesenchymal cell layer within these developing appendages. Using an in vitro explant culture technique on developing barbel tissues, we co-localized the fluorescent label in these cells with the mitotic marker EdU. Surprisingly, the labeled cells showed little proliferation, indicating a slow-cycling subpopulation. Transmission electron microscopy of the ZMB located these cells in a single, circumferential layer within the barbel's matrix core. Morphologically, these cells resemble fibroblasts or osteoblasts; in addition to their matrix bound location, they are identified by their pancake-shaped nuclei, abundant rough endoplasmic reticulum, and cytoplasmic extensions into the surrounding extracellular matrix. Taken together, these features define a novel mesenchymal cell population in zebrafish, the "TCF(+) core cells." A working model of barbel development is proposed, in which these minimally mitotic mesodermal cells produce collagenous matrix in response to ectodermally-derived Wnt signals deployed in a proximal-distal gradient along the appendage. This documents a novel mechanism of vertebrate appendage outgrowth. Similar genetic signals and cell behaviors may be responsible for the independent and repeated evolution of barbel structures in other fish species. PMID- 26492829 TI - Satisfaction of undergraduate students at University of Jordan after root canal treatment of posterior teeth using rotary or hand preparation. AB - The aim of this study was to report the satisfaction of fifth year undergraduate students on the clinical use of rotary endodontic preparation compared with stainless steel standard technique and to evaluate the impact of rotary nickel titanium instruments on undergraduate teaching. This study was carried out by the fifth year undergraduate students attending peer review sessions as a part of their training program using a questionnaire to assess their satisfaction with these two techniques. The overall results indicated a statistically significant satisfaction of the undergraduate students with the use of the nickel-titanium system (P < 0.001) compared to stainless steel standard technique. Under the conditions of this study, the results showed a positive acceptance and consensus among novice dental students regarding the use of ProTaper rotary files and the need for undergraduate teaching of rotary nickel-titanium systems in Jordan. PMID- 26492830 TI - Differential vascular permeability along the forebrain ventricular neurogenic niche in the adult murine brain. AB - Adult neurogenesis is influenced by blood-borne factors. In this context, greater or lesser vascular permeability along neurogenic niches would expose differentially neural stem cells (NSCs), transit amplifying cells (TACs), and neuroblasts to such factors. Here we evaluate endothelial cell morphology and vascular permeability along the forebrain neurogenic niche in the adult brain. Our results confirm that the subventricular zone (SVZ) contains highly permeable, discontinuous blood vessels, some of which allow the extravasation of molecules larger than those previously reported. In contrast, the rostral migratory stream (RMS) and the olfactory bulb core (OBc) display mostly impermeable, continuous blood vessels. These results imply that NSCs, TACs, and neuroblasts located within the SVZ are exposed more readily to blood-borne molecules, including those with very high molecular weights, than those positioned along the RMS and the OBc, subregions in which every stage of neurogenesis also takes place. These observations suggest that the existence of specialized vascular niches is not a precondition for neurogenesis to occur; specialized vascular beds might be essential for keeping high rates of proliferation and/or differential differentiation of neural precursors located at distinct domains. PMID- 26492832 TI - Tyrosine Kinase Inhibitors and Diabetes: A Novel Treatment Paradigm? AB - Deregulation of protein tyrosine kinase (PTK) activity is implicated in various proliferative conditions. Multi-target tyrosine kinase inhibitors (TKIs) are increasingly used for the treatment of different malignancies. Recently, several clinical cases of the reversal of both type 1 and 2 diabetes mellitus (T1DM, T2DM) during TKI administration have been reported. Experimental in vivo and in vitro studies have elucidated some of the mechanisms behind this effect. For example, inhibition of Abelson tyrosine kinase (c-Abl) results in beta cell survival and enhanced insulin secretion, while platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) inhibition leads to improvement in insulin sensitivity. In addition, inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) reduces the degree of islet cell inflammation (insulitis). Therefore, targeting several PTKs may provide a novel approach for correcting the pathophysiologic disturbances of diabetes. PMID- 26492831 TI - The miRNA Interactome in Metabolic Homeostasis. AB - Global expression analyses demonstrate that alterations in miRNA levels correlate with various metabolic diseases. miRNAs regulate central metabolic pathways and thus play vital roles in maintaining organismal energy balance and metabolic homeostasis. Here we highlight novel sequencing technologies used to comprehensively define the target spectrum of miRNAs in metabolic disease that complement recent literature reporting physiologic roles for miRNAs in the regulation of glucose and lipid metabolism in peripheral tissues of animal models of metabolic dysfunction. These emerging technologies help decipher the complexity of the miRNA interactome and enrich our understanding of how miRNAs mediate physiologic effects by targeting a spectrum of gene transcripts simultaneously. miRNA-based therapeutics emerge as a viable strategy for treating metabolic diseases. PMID- 26492833 TI - One-step large-scale deposition of salt-free DNA origami nanostructures. AB - DNA origami nanostructures have tremendous potential to serve as versatile platforms in self-assembly -based nanofabrication and in highly parallel nanoscale patterning. However, uniform deposition and reliable anchoring of DNA nanostructures often requires specific conditions, such as pre-treatment of the chosen substrate or a fine-tuned salt concentration for the deposition buffer. In addition, currently available deposition techniques are suitable merely for small scales. In this article, we exploit a spray-coating technique in order to resolve the aforementioned issues in the deposition of different 2D and 3D DNA origami nanostructures. We show that purified DNA origamis can be controllably deposited on silicon and glass substrates by the proposed method. The results are verified using either atomic force microscopy or fluorescence microscopy depending on the shape of the DNA origami. DNA origamis are successfully deposited onto untreated substrates with surface coverage of about 4 objects/mm(2). Further, the DNA nanostructures maintain their shape even if the salt residues are removed from the DNA origami fabrication buffer after the folding procedure. We believe that the presented one-step spray-coating method will find use in various fields of material sciences, especially in the development of DNA biochips and in the fabrication of metamaterials and plasmonic devices through DNA metallisation. PMID- 26492834 TI - Strategies and Molecular Design Criteria for 3D Printable Hydrogels. PMID- 26492836 TI - Early postoperative outcome of bipolar transurethral enucleation and resection of the prostate. AB - OBJECTIVES: To report the early postoperative outcome of bipolar transurethral enucleation and resection of the prostate. Our results were compared with those published from various centres. SETTING: Regional hospital, Hong Kong. PATIENTS: A total of 28 consecutive patients who had undergone bipolar transurethral enucleation and resection of the prostate by a single surgeon between January and June 2014. All patients were evaluated preoperatively by physical examination, digital rectal examination, transrectal ultrasonography, and laboratory studies, including measurement of haemoglobin, sodium, and prostate-specific antigen levels. Patients were assessed perioperatively and at 4 weeks and 3 months postoperatively. RESULTS: The mean resected specimen weight of prostatic adenoma in 28 patients was 48.2 g with a mean enucleation and resection time of 13.6 and 47.7 minutes, respectively. There was a mean decrease in serum prostate-specific antigen by 85.9% (from 6.4 ng/mL to 0.9 ng/mL) postoperatively. Prostate volume was decreased by 68.2% (from 71.9 cm(3) to 22.9 cm(3)) at 4 weeks postoperatively. The mean postoperative haemoglobin drop was 11.5 g/L. The rate of transient urinary incontinence at 3 months was 3.6%. Patients who underwent bipolar transurethral enucleation and resection of the prostate had a short catheterisation time and hospital stay, which is comparable to conventional transurethral resection of the prostate. CONCLUSIONS: Bipolar transurethral enucleation and resection of the prostate should become the endourological equivalent to open adenomectomy with fewer complications and short convalescence. The technique of bipolar transurethral enucleation and resection of the prostate can be acquired safely with a relatively short learning curve. PMID- 26492835 TI - Aetiological bases of 46,XY disorders of sex development in the Hong Kong Chinese population. AB - OBJECTIVE: Disorders of sex development are due to congenital defects in chromosomal, gonadal, or anatomical sex development. The objective of this study was to determine the aetiology of this group of disorders in the Hong Kong Chinese population. SETTING: Five public hospitals in Hong Kong. PATIENTS: Patients with 46,XY disorders of sex development under the care of paediatric endocrinologists between July 2009 and June 2011. MAIN OUTCOME MEASURES: Measurement of serum gonadotropins, adrenal and testicular hormones, and urinary steroid profiling. Mutational analysis of genes involved in sexual differentiation by direct DNA sequencing and multiplex ligation-dependent probe amplification. RESULTS: Overall, 64 patients were recruited for the study. Their age at presentation ranged from birth to 17 years. The majority presented with ambiguous external genitalia including micropenis and severe hypospadias. A few presented with delayed puberty and primary amenorrhea. Baseline and post-human chorionic gonadotropin-stimulated testosterone and dihydrotestosterone levels were not discriminatory in patients with or without AR gene mutations. Of the patients, 22 had a confirmed genetic disease, with 11 having 5alpha-reductase 2 deficiency, seven with androgen insensitivity syndrome, one each with cholesterol side-chain cleavage enzyme deficiency, Frasier syndrome, NR5A1-related sex reversal, and persistent Mullerian duct syndrome. CONCLUSIONS: Our findings suggest that 5alpha-reductase 2 deficiency and androgen insensitivity syndrome are possibly the two most common causes of 46,XY disorders of sex development in the Hong Kong Chinese population. Since hormonal findings can be unreliable, mutational analysis of the SRD5A2 and AR genes should be considered the first line tests for these patients. PMID- 26492837 TI - Bone health status of postmenopausal Chinese women. AB - OBJECTIVES: To evaluate the prevalence of osteoporosis in treatment-naive postmenopausal women, their treatment adherence, and the risk factors for osteoporosis. DESIGN: Cross-sectional study of bone density reports, a self administered health checklist, and computerised consultation records. SETTING: Primary care sexual and reproductive health service in Hong Kong. PARTICIPANTS: Postmenopausal Chinese women who had never received osteoporosis treatment or hormone replacement therapy. INTERVENTION: Each woman completed a checklist of risk factors for osteoporosis, menopause age, history of hormone replacement therapy, and osteoporosis treatment prior to undergoing bone mineral density measurement at the postero-anterior lumbar spine and left femur. The consultation records of those with osteoporosis were reviewed to determine their treatment adherence. MAIN OUTCOME MEASURES: T-score at the spine and hip, presence or absence of risk factors for osteoporosis, and treatment adherence. RESULTS: Between January 2008 and December 2011, 1507 densitometries were performed for eligible women; 51.6% of whom were diagnosed with osteopenia and 25.7% with osteoporosis. The mean age of women with normal bone mineral density, osteopenia, and osteoporosis was 57.0, 58.0, and 59.7 years, respectively. Approximately half of them had an inadequate dietary calcium intake, performed insufficient weight bearing exercise, or had too little sun exposure. Logistic regression analysis revealed that age, body mass index of <18.5 kg/m(2), parental history of osteoporosis or hip fracture, and duration of menopause were significant risk factors for osteoporosis. Among those with osteoporosis, 42.9% refused treatment, 30.7% complied with treatment, and 26.3% discontinued treatment or defaulted from follow-up. Those who refused treatment were significantly older. CONCLUSIONS: Osteoporosis is prevalent in postmenopausal women. Only 50% adopted primary prevention strategies. Almost 70% refused treatment or stopped prematurely. PMID- 26492838 TI - Common variants in QPCT gene confer risk of schizophrenia in the Han Chinese population. AB - Schizophrenia (SCZ) is a common and severe mental disorder, its etiology has not been elucidated completely. In one previous genome-wide association study (GWAS) of SCZ in the Caucasian population, the QPCT has been reported as susceptible gene for SCZ. The QPCT gene encodes Glutaminyl cyclase (QC), an enzyme which is involved in the post translational modification by converting N-terminal glutamate of protein to pyroglutamate, which is resistant to protease degradation, more hydrophobic, and prone to aggregation and neurotoxic. To further investigate the role of this gene in the pathogenesis of schizophrenia in the Han Chinese population, we conducted this study in 1,248 (Mean age +/- S.D, 36.44 years +/- 9.0) SCZ cases, 1,248 (Mean age +/- S.D, 30.62 years +/- 11.35) healthy control samples for a case control study. We genotyped six SNPs in this study, including one positive SNP of the previous study, using the Sequenom MassARRAY platform. We found that rs2373000 was significantly associated with SCZ before correction [rs2373000: P allele = 0.016, chi(2) = 5.784, OR [95%CI] = 0.861 [0.762-0.972], P genotype = 0.018, chi(2) = 0.069]. After permutation correction for multiple testing, rs2373000 [rs2373000: P Allele corrected = 0.063, P genotype corrected = 0.069] showed marginal association with SCZ. Additionally, one pathogenic haplotype (TGT) containing rs2373000 was also significantly associated with SCZ. Our results are consistent with the findings of previous study and the genetic risk of QPCT gene for SCZ also exists in the Han Chinese population. PMID- 26492839 TI - Patient reported outcomes following stereotactic ablative radiotherapy or surgery for stage IA non-small-cell lung cancer: Results from the ROSEL multicenter randomized trial. AB - We report quality of life and indirect costs from patient reported outcomes from the ROSEL randomized control trial comparing stereotactic ablative radiotherapy (SABR, also known as stereotactic body radiotherapy or SBRT) versus surgical resection for medically operable stage IA non-small cell lung cancer. ROSEL closed prematurely after accruing and randomizing 22 patients. This exploratory analysis found the global health related quality of life and indirect costs to be significantly favorable and cheaper, with SABR. PMID- 26492840 TI - How can individual differences in autobiographical memory distributions of older adults be explained? AB - The reminiscence bump phenomenon has frequently been reported for the recall of autobiographical memories. The present study complements previous research by examining individual differences in the distribution of word-cued autobiographical memories. More importantly, we introduce predictor variables that might account for individual differences in the mean (location) and the standard deviation (scale) of individual memory distributions. All variables were derived from different theoretical accounts for the reminiscence bump phenomenon. We used a mixed location-scale logitnormal model, to analyse the 4602 autobiographical memories reported by 118 older participants. Results show reliable individual differences in the location and the scale. After controlling for age and gender, individual proportions of first-time experiences and individual proportions of positive memories, as well as the ratings on Openness to new Experiences and Self-Concept Clarity accounted for 29% of individual differences in location and 42% of individual differences in scale of autobiographical memory distributions. Results dovetail with a life-story account for the reminiscence bump which integrates central components of previous accounts. PMID- 26492841 TI - Direct Synthesis of Carbon-Doped TiO2-Bronze Nanowires as Anode Materials for High Performance Lithium-Ion Batteries. AB - Carbon-doped TiO2-bronze nanowires were synthesized via a facile doping mechanism and were exploited as active material for Li-ion batteries. We demonstrate that both the wire geometry and the presence of carbon doping contribute to the high electrochemical performance of these materials. Direct carbon doping for example reduces the Li-ion diffusion length and improves the electrical conductivity of the wires, as demonstrated by cycling experiments, which evidenced remarkably higher capacities and superior rate capability over the undoped nanowires. The as prepared carbon-doped nanowires, evaluated in lithium half-cells, exhibited lithium storage capacity of ~306 mA h g(-1) (91% of the theoretical capacity) at the current rate of 0.1C as well as excellent discharge capacity of ~160 mAh g( 1) even at the current rate of 10 C after 1000 charge/discharge cycles. PMID- 26492843 TI - Underuse and Overuse of Colonoscopy for Repeat Screening and Surveillance in the Veterans Health Administration. AB - BACKGROUND & AIMS: Regular screening with colonoscopy lowers colorectal cancer incidence and mortality. We aimed to determine patterns of repeat and surveillance colonoscopy and identify factors associated with overuse and underuse of colonoscopy. METHODS: We analyzed data from participants in a previous Veterans Health Administration (VHA) study who underwent outpatient colonoscopy at 25 VHA facilities between October 2007 and September 2008 (n = 1455). The proportion of patients who received a follow-up colonoscopy was calculated for 3 risk groups, which were defined on the basis of the index colonoscopy: no adenoma, low-risk adenoma, or high-risk adenoma. RESULTS: Colonoscopy was overused (used more frequently than intervals recommended by guidelines) by 16% of patients with no adenomas, 26% with low-risk adenomas, and 29% with high-risk adenomas. Most patients with high-risk adenomas (54%) underwent colonoscopy after the recommended interval or did not undergo colonoscopy. Patients who received a follow-up recommendation that was discordant with guidelines were more likely to undergo colonoscopy too early (no adenoma odds ratio [OR], 3.80; 95% confidence interval [CI], 2.31-6.25 and low-risk adenoma OR, 5.28; 95% CI, 1.88-14.83). Receipt of colonoscopy at nonacademic facilities was associated with overuse among patients without adenomas (OR, 5.26; 95% CI, 1.96-14.29) or with low-risk adenomas (OR, 3.45; 95% CI, 1.52-7.69). Performance of colonoscopies by general surgeons vs gastroenterologists (OR, 2.08; 95% CI, 1.02-4.23) and female sex of the patient (OR, 3.28; 95% CI, 1.06 10.16) were associated with overuse of colonoscopy for patients with low-risk adenomas. No factors examined were associated with underuse of colonoscopy among patients with high-risk adenomas. CONCLUSIONS: In an analysis of patients in the VHA system, more than one fourth of patients with low-risk adenomas received follow-up colonoscopies too early, whereas more than one half of those with high risk adenomas did not undergo surveillance colonoscopy as recommended. Our findings highlight the need for system-level improvements to facilitate the appropriate delivery of colonoscopy that is based on individual risk. PMID- 26492842 TI - Airway Hypersensitivity, Reflux, and Phonation Contribute to Chronic Cough. AB - BACKGROUND & AIMS: Although chronic cough is common, its etiology is often elusive, making patient management a challenge. Gastroesophageal reflux and airway hypersensitivity can cause chronic cough. We explored the relationship between reflux, phonation, and cough in patients with idiopathic chronic cough. METHODS: We performed a blinded, cross-sectional study of nonsmoking patients with chronic cough (duration, >8 weeks) refractory to reflux treatment referred to the Digestive Disease Center at Vanderbilt University. All underwent 24-hour acoustic recording concurrently and temporally synchronized with ambulatory pH impedance monitoring. Cough, phonation, and pH-impedance events were recorded. We evaluated the temporal relationship between cough and phonation or reflux events using Poisson and logistic regression. RESULTS: Seventeen patients met the inclusion criteria (88% female; 100% white; median age, 63 years [interquartile age range, 52-66 years]; mean body mass index, 30.6 [interquartile range, 27.9 34.0]); there were 2048 analyzable coughing events. The probability of subsequent coughing increased with higher burdens of preceding cough, reflux, or phonation. Within the first 15 minutes after a cough event, the cough event itself was the main trigger of subsequent cough events. After this period, de novo coughing occurred with increases of 1.46-fold in association with reflux alone (95% confidence interval, 1.17-1.82; P < .001) and 1.71-fold in association with the combination of phonation and reflux events. CONCLUSIONS: Antecedent phonation and reflux increased the rate of cough events in patients with idiopathic chronic cough. Reflux events were more strongly associated with increased rate of coughing. Our findings support the concept that airway hypersensitivity is a cause of chronic cough, and that the vocal folds may be an effector in chronic cough ClinicalTrials.gov number: NCT01263626. PMID- 26492844 TI - Safety and Effectiveness of Early Colonoscopy in Management of Acute Lower Gastrointestinal Bleeding on the Basis of Propensity Score Matching Analysis. AB - BACKGROUND & AIMS: We investigated the safety and effectiveness of early colonoscopy (performed within 24 hours of hospital admission) for acute lower gastrointestinal bleeding (LGIB) vs elective colonoscopy (performed 24 hours after admission). METHODS: We conducted a retrospective study by using a database of endoscopies performed at the National Center for Global Health and Medicine in Tokyo, Japan from January 2009 through December 2014. We analyzed data from 538 patients emergently hospitalized for acute LGIB. We used propensity score matching to adjust for differences between patients who underwent early colonoscopy vs elective colonoscopy. Outcomes included rates of adverse events during bowel preparation and colonoscopy procedures, stigmata of recent hemorrhage, endoscopic therapy, blood transfusion requirement, 30-day rebleeding and mortality, and length of hospital stay. RESULTS: We selected 163 pairs of patients for analysis on the basis of propensity matching. We observed no significant differences between the early and elective colonoscopy groups in bowel preparation-related rates of adverse events (1.8% vs 1.2%, P = .652), colonoscopy-related rates of adverse events (none in either group), blood transfusion requirement (27.6% vs 27.6%, P = 1.000), or mortality (1.2% vs 0, P = .156). The early colonoscopy group had higher rates than the elective group for stigmata of recent hemorrhage (26.4% vs 9.2%, P < .001) and endoscopic therapy (25.8% vs 8.6%, P < .001), including clipping (17.8% vs 4.9%, P < .001), band ligation (6.1% vs 1.8%, P = .048), and rebleeding (13.5% vs 7.4%, P = .070). Patients in the early colonoscopy group stayed in the hospital for a shorter mean time (10 days) than patients in the elective colonoscopy group (13 days) (P < .001). CONCLUSIONS: Early colonoscopy for patients with acute LGIB is safe, allows for endoscopic therapy because it identifies the bleeding source, and reduces hospital stay. However, compared with elective colonoscopy, early colonoscopy does not reduce mortality and may increase the risk for rebleeding. PMID- 26492845 TI - Nonalcoholic Steatohepatitis Is Associated With Increased Mortality in Obese Patients Undergoing Bariatric Surgery. AB - BACKGROUND & AIMS: Bariatric surgery is associated with improved outcomes in subjects with severe obesity. We investigated the prognostic relevance of nonalcoholic steatohepatitis (NASH) and liver gene expression patterns in patients undergoing bariatric surgery. METHODS: We performed a retrospective analysis of 492 subjects who underwent gastric bypass bariatric surgery at a single center in Switzerland from January 1997 through December 2004; routine perioperative liver biopsies were collected, analyzed histologically, and RNA was isolated. We collected data on overall survival and clinical and biochemical parameters and compared these with data from propensity score-matched subjects participating in the third National Health and Nutrition Examination Survey (NHANES III). We used liver biopsies to identify bariatric surgery patients with NASH; NHANES III participants with NASH were identified based on a hyperechogenic liver at ultrasound and increased alanine transaminase levels. We analyzed a 32 gene signature associated with NAFLD severity in the liver tissues collected from 47 bariatric surgery patients with NASH, and assessed its prognostic features using nearest template prediction and survival analysis. RESULTS: At baseline, the median body mass index of patients who underwent bariatric surgery was 43.6 kg/m2; based on histologic findings, 12% had NASH and 16% had fibrosis. During a median follow-up of 10.2 years after the surgery, 4.2% of the subjects died. In multivariable Cox regression, the presence of NASH (hazard ratio [HR], 2.9; P = .02) and arterial hypertension (HR, 3.9; P = .02) were associated with overall mortality. When bariatric surgery patients were matched with NHANES III participants, bariatric surgery reduced the risk of death during the follow-up period (HR, 0.54; P = .04). However, bariatric surgery patients with NASH did not have a reduced risk of death compared with NHANES III participants with NASH (HR, 0.90; P = .85). We identified an expression pattern of 32 genes in liver tissues from patients with NASH that was associated with increased risk of death in multivariable analysis (HR, 7.7; P = .045). CONCLUSIONS: Histologically proven NASH is associated with increased risk of death within a median follow-up of 10.2 years after bariatric surgery, compared with patients who undergo bariatric surgery without NASH. The survival benefit of bariatric surgery in subjects with NASH may be reduced. A 32-gene expression pattern identified patients with NASH who underwent bariatric surgery and had shorter survival times. PMID- 26492846 TI - Efficacy of 6-Mercaptopurine as Second-Line Treatment for Patients With Autoimmune Hepatitis and Azathioprine Intolerance. AB - BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that requires long-term immunosuppressive therapy. Although most patients have an excellent response to standard therapy (azathioprine in combination with corticosteroids), approximately 10%-15% have intolerance or an insufficient response to azathioprine treatment. We investigated whether 6-mercaptopurine (6 MP) is an effective second-line therapy for patients with AIH. METHODS: We performed a retrospective study of 22 patients with AIH who were switched to 6-MP therapy after treatment with the combination of azathioprine and prednisolone at 2 tertiary care institutions in Europe (Germany and the United Kingdom) before November 15, 2014. We performed statistical analyses of data on clinical and biochemical responses collected 4 weeks after 6-MP treatment and then at regular physician visits. RESULTS: A total of 15 of 20 patients with prior azathioprine intolerance (75%) responded to 6-MP treatment; 8 of these patients had a complete response and 7 had partial remission, based on biochemical features. In these 15 patients, 6-MP was well tolerated, whereas the 5 remaining patients had to be switched to different immunosuppressive regimes because of 6-MP intolerance. The 2 patients with insufficient response to azathioprine treatment also showed no response to 6-MP. CONCLUSIONS: In patients with AIH and azathioprine intolerance, 6-MP seems to be an effective and well-tolerated second-line treatment. 6-MP might be ineffective in patients with insufficient response to azathioprine. PMID- 26492847 TI - Lactulose Challenge Determines Visceral Sensitivity and Severity of Symptoms in Patients With Irritable Bowel Syndrome. AB - BACKGROUND & AIMS: Patients with irritable bowel syndrome (IBS) can be assigned to groups with different gastrointestinal (GI) symptoms based on results from a combined nutrient and lactulose challenge. We aimed to identify factors that predict outcomes to this challenge and to determine whether this can be used in noninvasive assessment of visceral sensitivity in patients with IBS. METHODS: We performed a prospective study of 100 patients with IBS diagnosed according to Rome III criteria (all subtypes) and seen at a secondary or tertiary care center. After an overnight fast, subjects were given a liquid breakfast (400 mL; Nutridrink) that contained 25 g lactulose. Before the challenge, we assessed visceral sensitivity (via rectal barostat), oro-anal transit time, and fecal microbiota composition (via 16S ribosomal RNA pyrosequencing); we determined IBS severity using questionnaires. The intensity of 8 GI symptoms, the level of digestive comfort, and the amount of exhaled H2 and CH4 in breath were measured before and during a 4-hour period after the liquid breakfast. RESULTS: Based on the intensity of 8 GI symptoms and level of digestive comfort during the challenge, patients were assigned to groups with high-intensity GI symptoms (HGS; n = 39) or low-intensity GI symptoms (LGS; n = 61); patients with HGS had more severe IBS (P < .0001), higher somatization (P < .01), and lower quality of life (P < .05-.01) than patients with LGS. Patients with HGS also had significantly higher rectal sensitivity to random phasic distensions (P < .05-.001, compared with patients with LGS). There were no significant differences between groups in fecal microbiota composition, exhaled gas in breath, or oro-anal transit time. CONCLUSIONS: We found, in a prospective study, that results from a lactulose challenge test could be used to determine visceral sensitivity and severity of IBS. The intensity of patient symptoms did not correlate with the composition of the fecal microbiota. The lactulose challenge test may help better characterize patients with IBS and evaluate the efficacy of new treatments. ClinicalTrial.gov no: NCT01252550. PMID- 26492848 TI - Delivery of Instructions via Mobile Social Media App Increases Quality of Bowel Preparation. AB - BACKGROUND & AIMS: Bowel preparation is closely linked to the quality of colonoscopy. We investigated whether delivery of instructions via a social media app increases the quality of colonoscopy by improving adequacy of bowel preparation. METHODS: We performed a prospective study at 3 endoscopic centers in China of 770 colonoscopy outpatients (18-80 years old) with convenient access to Wechat (a widely used mobile social media app) from May through November 2014. Patients were randomly assigned to groups that received standard education along with delivery of interactive information via Wechat (n = 387) or standard education (controls, n = 383). The primary outcome was proportion of patients with adequate bowel preparation (Ottawa score <6). Secondary outcomes included rates of adenoma detection and cecal intubation, cecal intubation time, rates of incomplete compliance with instructions, and patient willingness to repeat bowel preparation. RESULTS: Demographic features were comparable between the groups. A higher proportion of patients in the group that received social media instruction had adequate bowel preparation than the control group (82.2% vs 69.5%, P < .001). Among patients with successful colonoscopies, the group that received social media instruction had lower mean total and segmental Ottawa scores (P < .05). A higher proportion of patients receiving social media instruction also had cecal intubation (97.2% vs 93.2% in controls, P = .014) and were found to have adenomas (18.6% vs 12.0% in controls, P = .012). CONCLUSIONS: Instruction via a mobile social media app, in conjunction with regular instruction, increases subjective measures of adequacy of bowel preparation. Use of the app significantly increased the proportion of patients with successful cecal intubation and in whom adenomas were detected, indicating increased quality of colonoscopy. ClinicalTrials.gov number: NCT02140827. PMID- 26492849 TI - beta-thalassemia patients and gynecological approach: review and clinical experience. AB - Significant improvements in therapy and life expectancy of beta-thalassemia patients in last decades result in the need of commitment for gynecologists and obstetricians as the complexity of organ impairment needs a specific multidisciplinary approach. After a review of clinical manifestations of beta thalassemia from a gynecologic point of view, we present the experience of a gynecologic center in treating beta-thalassemia patients from more than 20 years. PMID- 26492850 TI - Identification of a phosphinothricin-resistant mutant of rice glutamine synthetase using DNA shuffling. AB - To date, only bar/pat gene derived from Streptomyces has been used to generate the commercial PPT-resistant crops currently available in the market. The limited source of bar/pat gene is probably what has caused the decrease in PPT-tolerance, which has become the main concern of those involved in field management programs. Although glutamine synthetase (GS) is the target enzyme of PPT, little study has been reported about engineering PPT-resistant plants with GS gene. Then, the plant-optimized GS gene from Oryza sativa (OsGS1S) was chemically synthesized in the present study by PTDS to identify a GS gene for developing PPT-tolerant plants. However, OsGS1S cannot be directly used for developing PPT-tolerant plants because of its poor PPT-resistance. Thus, we performed DNA shuffling on OsGS1S, and one highly PPT-resistant mutant with mutations in four amino acids (A63E, V193A, T293A and R295K) was isolated after three rounds of DNA shuffling and screening. Among the four amino acids substitutions, only R295K was identified as essential in altering PPT resistance. The R295K mutation has also never been previously reported as an important residue for PPT resistance. Furthermore, the mutant gene has been transformed into Saccharomyces cerevisiae and Arabidopsis to confirm its potential in developing PPT-resistant crops. PMID- 26492851 TI - Structural characterization of procentrioles in Drosophila spermatids. AB - Male gametogenesis in insects is unusual in that the centrioles do not duplicate during the second meiosis and the differentiating spermatids inherit only one centriole. Here it is showed that a distinct procentriole is assembled close to the proximal region of the centriole in early S13 spermatids at the onion stage, confirming previous reports of a proximal centriole-like structure at the proximal end of the spermatid centriole. However, the procentrioles of Drosophila spermatids do not behave like true procentrioles, but their development is blocked at an early stage before the assembly of a complete A-tubule set. Therefore, they may represent early frozen stages of procentriole assembly that do not develop further and eventually disappear in late spermatids. PMID- 26492852 TI - Rapid and Efficient Conversion of (11) CO2 to (11) CO through Silacarboxylic Acids: Applications in Pd-Mediated Carbonylations. AB - Herein, we present a new rapid, efficient, and low-cost radiosynthetic protocol for the conversion of (11) CO2 to (11) CO and its subsequent application in Pd mediated reactions of importance for PET applications. This room-temperature methodology, using readily available chemical reagents, is carried out in simple glass vials, thus eliminating the need for expensive and specialized high temperature equipment to access (11) CO. With this fast and near-quantitative conversion of (11) CO2 into (11) CO, aryl and heteroaryl iodides were easily converted into a broad selection of biologically active amides in radiochemical yields ranging from 29-84 %. PMID- 26492853 TI - Endoscopic butterfly cartilage myringoplasty. AB - CONCLUSION: Based on the results of this study, it is believed that, in appropriate patients with tympanic membrane perforation, the endoscopic butterfly cartilage myringoplasty can be applied, with a shorter operation time, high graft success rate, and low risk of complications. OBJECTIVE: The aim of this study was to evaluate the results of the endoscopic butterfly cartilage myringoplasty in terms of the graft success rate and hearing gain. METHODS: Forty-five ears of the 42 patients who were subjected to endoscopic butterfly cartilage myringoplasty surgery between January 2013 and December 2014 were included in this study. The archival records of the patients were reviewed retrospectively, evaluating the pre-operative and post-operative hearing results and post-operative graft success rates in the early and late periods. RESULTS: The graft success rates were 97.8% (44/45 ears) and 95.6% (43/45 ears) at the post-operative 1- and 6-month follow ups, respectively. When the post-operative air conduction hearing thresholds were compared, significant improvement was seen at post-operative 1- and 6-month follow-ups in the hearing thresholds, when compared to the pre-operative levels (p < 0.001). PMID- 26492854 TI - Recent developments and future prospects on bio-based polyesters derived from renewable resources: A review. AB - A significantly growing interest is to design a new strategy for development of bio-polyesters from renewable resources due to limited fossil fuel reserves, rise of petrochemicals price and emission of green house gasses. Therefore, this review aims to present an overview on synthesis of biocompatible, biodegradable and cost effective polyesters from biomass and their prospective in different fields including packaging, coating, tissue engineering, drug delivery system and many more. Isosorbide, 2,4:3,5-di-O-methylene-d-mannitol, bicyclic diacetalyzed galactaric acid, 2,5-furandicarboxylic acid, citric, 2,3-O-methylene l-threitol, dimethyl 2,3-O-methylene l-threarate, betulin, dihydrocarvone, decalactone, pimaric acid, ricinoleic acid and sebacic acid, are some important monomers derived from biomass which are used for bio-based polyester manufacturing, consequently, replacing the petrochemical based polyesters. The last part of this review highlights some recent advances in polyester blends and composites in order to improve their properties for exceptional biomedical applications i.e. skin tissue engineering, guided bone regeneration, bone healing process, wound healing and wound acceleration. PMID- 26492855 TI - Extraction, characterization and gelling behavior enhancement of pectins from the cladodes of Opuntia ficus indica. AB - Total Pectins Fraction (TPF) was extracted at room temperature from dried cladodes of Opuntia ficus indica. TPF is constituted of three pectic fractions WSP, CSP and ASP, which are made up of 66.6%, 44.3% and 81.1% (w/w) of galacturonic acid, respectively. The antioxidant ability of TPF increased with the concentration increasing. It scavenged hydroxyl radical by 90% and chelated 90% of ferrous ions at 5 g/L. FTIR study was carried out. Strong characteristic absorption peaks at 1,618 cm(-1) assigned to the vibration of COO(-) group of galacturonic acid. In the fingerprint region, we noticed three well-defined peaks at 1054, 1085, and 1,154 cm(-1) characteristic of pectic polysaccharides. TPF are non-gelling pectins. The co-crosslinking of TPF with carrageenan was carried out and the gelling behavior was successfully improved. Thermo-sensitive hydrogel was obtained with 82% of TPF and 18% of carrageenan (w/w). PMID- 26492856 TI - A General Strategy for the Separation of Immiscible Organic Liquids by Manipulating the Surface Tensions of Nanofibrous Membranes. AB - Oil/water separation membranes with different wettability towards water are attractive for their economic efficiency and convenience. The key factor for the separation process is the roughness-enhanced wettability of membranes based on the intrinsic wetting threshold (IWT) of water, that is, the limitation of the wettability caused by hydrophobicity and hydrophilicity. However, the separation of organic liquids (OLs) remains a challenge. Herein, we manipulate the surface tensions of nanofibrous membranes to lie between the IWTs of the two OLs to be separated so that the nanofibrous membranes can be endowed with superlyophobicity and superlyophilicity for the two liquids, and thus lead to successful separation. Our investigations provide a general strategy to separate any immiscible liquids efficiently, and may lead to the development of membranes with a large capacity, high flux, and high selectivity for organic reactions or liquid extraction in chemical engineering. PMID- 26492857 TI - The origin of beta-strand bending in globular proteins. AB - BACKGROUND: Many beta-strands are not flat but bend and/or twist. However, although almost all beta-strands have a twist, not all have a bend, suggesting that the underlying force(s) driving beta-strand bending is distinct from that for the twist. We, therefore, investigated the physical origin(s) of beta-strand bends. METHODS: We calculated rotation, twist and bend angles for a four-residue short frame. Fixed-length fragments consisting of six residues found in three consecutive short frames were used to evaluate the twist and bend angles of full length beta-strands. RESULTS: We calculated and statistically analyzed the twist and bend angles of beta-strands found in globular proteins with known three dimensional structures. The results show that full-length beta-strand bend angles are related to the nearby aromatic residue content, whereas local bend angles are related to the nearby aliphatic residue content. Furthermore, it appears that beta-strands bend to maximize their hydrophobic contacts with an abutting hydrophobic surface or to form a hydrophobic side-chain cluster when an abutting hydrophobic surface is absent. CONCLUSIONS: We conclude that the dominant driving force for full-length beta-strand bends is the hydrophobic interaction involving aromatic residues, whereas that for local beta-strand bends is the hydrophobic interaction involving aliphatic residues. PMID- 26492858 TI - Surmounting the barrier: advances and challenges in transdermal drug delivery. PMID- 26492859 TI - High-level aminoglycoside resistance in Enterococcus faecalis and Enterococcus faecium causing invasive infection: Twelve-year surveillance in the Minami Ibaraki Area. AB - We examined prevalence of high-level aminoglycoside resistance (HLAR) in Enterococcus faecalis and Enterococcus faecium causing invasive infection in the Minami Ibaraki Area. Ten strains of both species each, recovered from the blood or the cerebrospinal fluid between 2003 and 2014, were randomly selected every year. High-level resistance to gentamicin (HLR-GM) and streptomycin (HLR-SM) was detected in 34% (41 of 120 strains) and 18% (21) of E. faecalis and 9% (11) and 39% (48) of E. faecium, respectively. In comparisons of the proportions among three four-year periods, HLR-SM among E. faecium was significantly lower in the 2011-2014 period. All strains with HLR-GM were positive for the aac(6')-Ie aph(2")-Ia gene. The ant(6')-Ia gene was detected in all with HLR-SM except for one E. faecalis strain. The present study showed that prevalence of HLR-GM among E. faecalis and E. faecium causing invasive infection in this area was nearly equivalent to that described in previous studies in Japan and that proportions of strains with HLAR did not vary during the study period except for that of HLR-SM among E. faecium. PMID- 26492860 TI - Pneumonia Caused by Klebsiella spp. in 46 Horses. AB - BACKGROUND: Klebsiella spp. are implicated as a common cause of bacterial pneumonia in horses, but few reports describe clinical presentation and disease progression. HYPOTHESIS/OBJECTIVES: To describe the signalment, clinicopathologic data, radiographic and ultrasonographic findings, antimicrobial susceptibility, outcome, and pathologic lesions associated with Klebsiella spp. pneumonia in horses. ANIMALS: Forty-six horses from which Klebsiella spp. was isolated from the lower respiratory tract. METHODS: Retrospective study. Medical records from 1993 to 2013 at the William R. Pritchard Veterinary Medical Teaching Hospital, University of California, Davis were reviewed. Exact logistic regression was performed to determine if any variables were associated with survival to hospital discharge. RESULTS: Survival in horses <1 year old was 73%. Overall survival in adults was 63%. For adults in which Klebsiella pneumoniae was the primary isolate, survival was 52%. Mechanical ventilation preceded development of pneumonia in 11 horses. Complications occurred in 25/46 horses, with thrombophlebitis and laminitis occurring most frequently. Multi-drug resistance was found in 47% of bacterial isolates. Variables that significantly impacted survival included hemorrhagic nasal discharge, laminitis, and thoracic radiographs with a sharp demarcation between marked caudal pulmonary alveolar infiltration and more normal-appearing caudodorsal lung. CONCLUSIONS AND CLINICAL IMPORTANCE: Klebsiella spp. should be considered as a differential diagnosis for horses presenting with hemorrhagic pneumonia and for horses developing pneumonia after mechanical ventilation. Multi-drug resistance is common. Prognosis for survival generally is fair, but is guarded for adult horses in which K. pneumoniae is isolated as the primary organism. PMID- 26492861 TI - MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery. AB - Drug delivery across the blood-brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non-invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam bridged peptidomimetic MiniAp-4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human-cell-based BBB model. Furthermore, MiniAp-4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice. PMID- 26492862 TI - The post-vaccine microevolution of invasive Streptococcus pneumoniae. AB - The 7-valent pneumococcal conjugated vaccine (PCV7) has affected the genetic population of Streptococcus pneumoniae in pediatric carriage. Little is known however about pneumococcal population genomics in adult invasive pneumococcal disease (IPD) under vaccine pressure. We sequenced and serotyped 349 strains of S. pneumoniae isolated from IPD patients in Nijmegen between 2001 and 2011. Introduction of PCV7 in the Dutch National Immunization Program in 2006 preluded substantial alterations in the IPD population structure caused by serotype replacement. No evidence could be found for vaccine induced capsular switches. We observed that after a temporary bottleneck in gene diversity after the introduction of PCV7, the accessory gene pool re-expanded mainly by genes already circulating pre-PCV7. In the post-vaccine genomic population a number of genes changed frequency, certain genes became overrepresented in vaccine serotypes, while others shifted towards non-vaccine serotypes. Whether these dynamics in the invasive pneumococcal population have truly contributed to invasiveness and manifestations of disease remains to be further elucidated. We suggest the use of whole genome sequencing for surveillance of pneumococcal population dynamics that could give a prospect on the course of disease, facilitating effective prevention and management of IPD. PMID- 26492863 TI - Assessing the visual vertical: how many trials are required? AB - BACKGROUND: The visual vertical (VV) consists of repeated adjustments of a luminous rod to the earth vertical. How many trials are required to reach consistency in this measure? This question has never been addressed despite the widespread clinical use of the measurement in stroke rehabilitation. METHODS: VV perception was assessed (10 trials) in 117 patients undergoing rehabilitation after a first hemisphere stroke. The intraclass correlation coefficient (ICC) and standard error of measurement (SEM) were calculated for each patient category: with contralesional VV bias (n = 48), ipsilesional VV bias (n = 17) and normal VV (n = 52). RESULTS: For patients with VV biases, 6 trials were required to reach high inter-trial reliability (contralesional: ICC = 0.9, SEM = 1.36 degrees ; ipsilesional: ICC = 0.896, SEM = 0.96 degrees ). For patients with normal VV, a minimum of 10 trials was required (ICC = .728, SEM = 1.13 degrees ). A set of 6 trials correctly classified 96 % of patients. CONCLUSIONS: In the literature, 10 is the most frequently used number of trials used to assess VV orientation. Our study shows that 10 trials are required to adequately measure VV orientation in non-selected subacute stroke patients. For complex protocols imposing a decrease in the number of trials in each condition, 6 trials are needed to identify VV biases in most patients. PMID- 26492864 TI - The readability and suitability of sexual health promotion leaflets. AB - OBJECTIVE: To investigate the readability and suitability of sexual health promotion leaflets. METHOD: Application of SMOG, FRY and SAM tests to assess the readability and suitability of a selection of sexual health leaflets. RESULTS: SMOG and FRY scores illustrate an average reading level of grade 9. SAM scores indicate that 59% of leaflets are superior in design and 41% are average in design. Leaflets generally perform well in the categories of content, literacy demand, typography and layout. They perform poorly in use of graphics, learning stimulation/motivation and cultural appropriateness. CONCLUSION: Sexual health leaflets have a reading level that is too high. Leaflets perform well on the suitability scores indicating they are reasonably suitable. There are a number of areas where sexual health leaflets could improve their design. PRACTICE IMPLICATIONS: Numerous practical techniques are suggested for improving the readability and suitability of sexual health leaflets. PMID- 26492865 TI - Marriage, Separation and Beyond: A Longitudinal Study of Families of Children with Intellectual and Developmental Disabilities in a Norwegian Context. AB - BACKGROUND: This study addresses family structure in families raising a child with disabilities in Norway. The aims are to add to the literature on termination of parental relationships and to explore family research topics that are rarely discussed in disability research, such as cohabitation versus marriage and repartnering. METHODS: Longitudinal survey data on families of children with intellectual and developmental disabilities who were born 1993-1995 were compared with register data on all families of same-aged children (five waves 1999-2012). RESULTS: Parents of children with disabilities had slightly lower termination rates and formalized their partnerships earlier. Furthermore, the rate of repartnering among divorced/separated mothers of young children with disabilities was similar to that of other mothers but decreases later in the child's life course. CONCLUSIONS: Results support the view that findings diverge and are most likely dependent on context. PMID- 26492866 TI - Measurement of Function Post Hip Fracture: Testing a Comprehensive Measurement Model of Physical Function. AB - BACKGROUND: Measurement of physical function post hip fracture has been conceptualized using multiple different measures. PURPOSE: This study tested a comprehensive measurement model of physical function. DESIGN: This was a descriptive secondary data analysis including 168 men and 171 women post hip fracture. METHODS: Using structural equation modeling, a measurement model of physical function which included grip strength, activities of daily living, instrumental activities of daily living, and performance was tested for fit at 2 and 12 months post hip fracture, and among male and female participants. Validity of the measurement model of physical function was evaluated based on how well the model explained physical activity, exercise, and social activities post hip fracture. FINDINGS: The measurement model of physical function fit the data. The amount of variance the model or individual factors of the model explained varied depending on the activity. CONCLUSION: Decisions about the ideal way in which to measure physical function should be based on outcomes considered and participants. CLINICAL RELEVANCE: The measurement model of physical function is a reliable and valid method to comprehensively measure physical function across the hip fracture recovery trajectory. PMID- 26492868 TI - Intrinsic and Extrinsic Cardiac Pseudotumors: Echocardiographic Evaluation and Review of the Literature. AB - Echocardiography is the most common imaging modality for the assessment of cardiovascular tumors, followed by more advanced imaging modalities, such as cardiac computed tomography or cardiac magnetic resonance imaging. Non-neoplastic lesions that may simulate a true neoplasm on imaging are termed "cardiac pseudotumors." As echocardiography is the initial imaging modality where pseudotumors are identified, it is imperative to have a fundamental understanding of pseudotumors evaluation using echocardiography. There is paucity of the literature describing the different kinds of pseudotumors. This review is an attempt to describe common cardiac pseudotumors and to classify them based on their origin. The tumors arising from cardiac structures, such as epicardium, endocardium, or myocardium, were termed as "intrinsic" while the pseudotumors with no cardiac origin were termed as "extrinsic." The more common pseudotumors are described in detail with pertinent echocardiographic features and examples. PMID- 26492867 TI - Generalized anxiety disorder in primary care: mental health services use and treatment adequacy. AB - PURPOSE: Generalized Anxiety Disorder (GAD) is a common mental disorder in the primary care setting, marked by persistent anxiety and worries. The aims of this study were to: 1) examine mental health services utilisation in a large sample of primary care patients; 2) explore detection of GAD and minimal standards for pharmacological and psychological treatment adequacy based on recommendation from clinical practice guidelines; 3) examine correlates of treatment adequacy, i.e. predisposing, enabling and needs factors according to the Behavioural Model of Health Care Use. METHODS: A sample of 373 adults meeting DSM-IV criteria for Generalized Anxiety Disorder in the past 12 months took part in this study. Data were drawn from the "Dialogue" project, a large primary care study conducted in 67 primary care clinics in Quebec, Canada. Following a mental health screening in medical clinics (n = 14833), patients at risk of anxiety or depression completed the Composite International Diagnostic Interview-Simplified (CIDIS). Multilevel logistic regression models were developed to examine correlates of treatment adequacy for pharmacological and psychological treatments. RESULTS: Results indicate that 52.5 % of participants were recognized as having GAD by a healthcare professional in the past 12 months, and 36.2 % of the sample received a pharmacological (24.4 %) and/or psychological treatment (19.2 %) meeting indicators based on clinical practice guidelines recommendations. The detection of GAD by a health professional and the presence of comorbid depression were associated with overall treatment adequacy. CONCLUSIONS: This study suggests that further efforts towards GAD detection could lead to an increase in the delivery of evidence-based treatments. Key targets for improvement in treatment adequacy include regular follow up of patients with a GAD medication and access to psychotherapy from the primary care setting. PMID- 26492870 TI - Synthetic cannabinoid presentations decline following ban. PMID- 26492869 TI - Genome-wide identification of copy number variations between two chicken lines that differ in genetic resistance to Marek's disease. AB - BACKGROUND: Copy number variation (CNV) is a major source of genome polymorphism that directly contributes to phenotypic variation such as resistance to infectious diseases. Lines 63 and 72 are two highly inbred experimental chicken lines that differ greatly in susceptibility to Marek's disease (MD), and have been used extensively in efforts to identify the genetic and molecular basis for genetic resistance to MD. Using next generation sequencing, we present a genome wide assessment of CNVs that are potentially associated with genetic resistance to MD. METHODS: Three chickens randomly selected from each line were sequenced to an average depth of 20*. Two popular software, CNVnator and Pindel, were used to call genomic CNVs separately. The results were combined to obtain a union set of genomic CNVs in the two chicken lines. RESULTS: A total of 5,680 CNV regions (CNVRs) were identified after merging the two datasets, of which 1,546 and 1,866 were specific to the MD resistant or susceptible line, respectively. Over half of the line-specific CNVRs were shared by 2 or more chickens, reflecting the reduced diversity in both inbred lines. The CNVRs fixed in the susceptible lines were significantly enriched in genes involved in MAPK signaling pathway. We also found 67 CNVRs overlapping with 62 genes previously shown to be strong candidates of the underlying genes responsible for the susceptibility to MD. CONCLUSIONS: Our findings provide new insights into the genetic architecture of the two chicken lines and additional evidence that MAPK signaling pathway may play an important role in host response to MD virus infection. The rich source of line-specific CNVs is valuable for future disease-related association studies in the two chicken lines. PMID- 26492871 TI - Mesoporous Foam TiO2 Nanomaterials for Effective Hydrogen Production. AB - Hydrolysis of TiCl4 in a diether-functionalized imidazolium ionic liquid (IL), namely 1-methyl-3-[2-(2-methoxy(ethoxy)ethyl]imidazolium methane sulfonate (M(MEE)I?CH3 SO3 ), results in a heterostructured organic/inorganic and sponge like porous TiO2 material. The thermal treatment (300 degrees C) followed by calcination (500 degrees C) affords highly porous TiO2 . The characterization of the obtained samples (with and without IL, before and after calcination) by XRD, SEM, and TEM reveals TiO2 anatase crystalline phases and irregular-shaped particles with different porous structures. These hierarchical-structured mesoporous TiO2 nanomaterials were employed as efficient photocatalysts in the water-splitting process, yielding up to 1304 MUmol g(-1) on hydrogen production. PMID- 26492872 TI - A New Image Analysis Method Based on Morphometric and Fractal Parameters for Rapid Evaluation of In Situ Mammalian Mast Cell Status. AB - Apart from their effector functions in allergic disorders, tissue-resident mast cells (MC) are gaining recognition as initiators of inflammatory events through their distinctive ability to secrete many bioactive molecules harbored in cytoplasmic granules. Activation triggers mediator release through a regulated exocytosis named degranulation. MC activation is still substantiated by measuring systemic levels of MC-restricted mediators. However, identifying the anatomical location of MC activation is valuable for disease diagnosis. We designed a computer-assisted morphometric method based on image analysis of methylene blue (MB)-stained normal mouse skin tissue sections that quantitates actual in situ MC activation status. We reasoned MC cytoplasm could be viewed as an object featuring unique relative mass values based on activation status. Integrated optical density and area (A) ratios were significantly different between intact and degranulated MC (p<0.001). The examination of fractal characteristics is of translational diagnostic/prognostic value in cancer and readily applied to quantify cytoskeleton morphology and vasculature. Fractal dimension (D), a measure of their comparative space filling capacity and structural density, also differed significantly between intact and degranulated MC (p<0.001). Morphometric analysis provides a reliable and reproducible method for in situ quantification of MC activation status. PMID- 26492873 TI - Serology describes a profile of declining malaria transmission in Farafenni, The Gambia. AB - BACKGROUND: Malaria morbidity and mortality has declined in recent years in a number of settings. The ability to describe changes in malaria transmission associated with these declines is important in terms of assessing the potential effects of control interventions, and for monitoring and evaluation purposes. METHODS: Data from five cross-sectional surveys conducted in Farafenni and surrounding villages on the north bank of River Gambia between 1988 and 2011 were compiled. Antibody responses to MSP-119 were measured in samples from all surveys, data were normalized and expressed as seroprevalence and seroconversion rates (SCR) using different mathematical models. RESULTS: Results showed declines in serological metrics with seroprevalence in children aged one to 5 years dropping from 19 % (95 % CI 15-23 %) in 1988 to 1 % (0-2 %) in 2011 (p value for trend in proportions < 0.001) and the SCR dropping from 0.069 year(-1) (0.059 0.080) to 0.022 year(-1) (0.017-0.028; p = 0.004). The serological data were consistent with previously described drops in both parasite prevalence in children aged 1-5 years (62 %, 57-66 %, in 1988 to 2 %, 0-4 %, in 2011; p < 0.001), and all-cause under five mortality rates (37 per 1000 person-years, 34 41, in 1990 to 17, 15-19, in 2006; p = 0.059). CONCLUSIONS: This analysis shows accurate reconstruction of historical malaria transmission patterns in the Farafenni area using anti-malarial antibody responses. Demonstrating congruence between serological measures, and conventional clinical and parasitological measures suggests broader utility for serology in monitoring and evaluation of malaria transmission. PMID- 26492874 TI - Chronic infection phenotypes of Pseudomonas aeruginosa are associated with failure of eradication in children with cystic fibrosis. AB - Early eradication treatment with inhaled tobramycin is successful in the majority of children with cystic fibrosis (CF) with incident Pseudomonas aeruginosa infection. However, in 10-40 % of cases, eradication fails and the reasons for this are poorly understood. The purpose of this study was to determine whether specific microbial characteristics could explain eradication treatment failure. This was a cross-sectional study of CF patients (aged 0-18 years) with incident P. aeruginosa infection from 2011 to 2014 at the Hospital for Sick Children, Toronto, Canada. Phenotypic assays were done on all incident P. aeruginosa isolates, and eradicated and persistent isolates were compared using the Mann Whitney test or the two-sided Chi-square test. A total of 46 children with CF had 51 incident P. aeruginosa infections. In 72 % (33/46) of the patients, eradication treatment was successful, while 28 % failed eradication therapy. Persistent isolates were less likely to be motile, with significantly less twitch motility (p=0.001), were more likely to be mucoid (p=0.002), and more likely to have a tobramycin minimum inhibitory concentration (MIC) >= 128 MUg/mL (p=0.02) compared to eradicated isolates. Although biofilm production was similar, there was a trend towards more persistent isolates with deletions in quorum-sensing genes compared with eradicated isolates (p=0.06). Initial acquisition of P. aeruginosa with characteristics of chronic infection is associated with failure of eradication treatment. PMID- 26492875 TI - Mixed-mode resins: taking shortcut in downstream processing of raw-starch digesting alpha-amylases. AB - Bacillus licheniformis 9945a alpha-amylase is known as a potent enzyme for raw starch hydrolysis. In this paper, a mixed mode Nuvia cPrimeTM resin is examined with the aim to improve the downstream processing of raw starch digesting amylases and exploit the hydrophobic patches on their surface. This resin combines hydrophobic interactions with cation exchange groups and as such the presence of salt facilitates hydrophobic interactions while the ion-exchange groups enable proper selectivity. alpha-Amylase was produced using an optimized fed-batch approach in a defined media and significant overexpression of 1.2 g L( 1) was achieved. This single step procedure enables simultaneous concentration, pigment removal as well as purification of amylase with yields of 96% directly from the fermentation broth. PMID- 26492876 TI - Patterns of Allergic Sensitization in High IgE Syndromes. AB - Dramatic elevations in the serum IgE level are seen both in polygenic allergic diseases such as atopic dermatitis and food allergy, and in a growing list of monogenic primary immune deficiencies (PIDs). Although the IgE produced in patients with PID has generally been considered to be driven by dysregulated IL-4 production and thus lack antigen specificity, in fact allergen-specific IgE can be detected by skin and serum testing in many of these patients. However, perhaps not surprisingly given the distinct immunologic pathways involved, the patterns of allergic disease and atopic sensitization vary widely between syndromes, leading to strikingly different clinical phenotypes. PMID- 26492877 TI - Indoor Fungal Exposure and Allergic Respiratory Disease. AB - A gathering body of evidence has repeatedly revealed associations between indoor fungi and initiation, promotion, and exacerbation of allergic respiratory disease. The relationship between the exposure and outcome are complicated by the difficulties in measuring both exposure and outcome, the multifactorial nature of the disease, and the wide range of potential confounders. New technologies are becoming available that may enable better measurement of exposure and tighter case definitions so as to build more confidence in the associations discovered. The growing strength of the evidence base will aid the design of future public health interventions and generate new hypotheses on the cause of the rapid increase in allergic respiratory disease prevalence. PMID- 26492878 TI - The Role of Bitter and Sweet Taste Receptors in Upper Airway Immunity. AB - Over the past several years, taste receptors have emerged as key players in the regulation of innate immune defenses in the mammalian respiratory tract. Several cell types in the airway, including ciliated epithelial cells, solitary chemosensory cells, and bronchial smooth muscle cells, all display chemoresponsive properties that utilize taste receptors. A variety of bitter products secreted by microbes are detected with resultant downstream inflammation, increased mucous clearance, antimicrobial peptide secretion, and direct bacterial killing. Genetic variation of bitter taste receptors also appears to play a role in the susceptibility to infection in respiratory disease states, including that of chronic rhinosinusitis. Ongoing taste receptor research may yield new therapeutics that harness innate immune defenses in the respiratory tract and may offer alternatives to antibiotic treatment. The present review discusses taste receptor-protective responses and analyzes the role these receptors play in mediating airway immune function. PMID- 26492880 TI - Videofluoroscopic Predictors of Penetration-Aspiration in Parkinson's Disease Patients. AB - Parkinson's disease (PD) patients show a high prevalence of swallowing disorders and tracheal aspiration of food. The videofluoroscopic study of swallowing (VFSS) allows clinicians to visualize the visuoperceptual and temporal parameters associated with swallowing disorders in an attempt to predict aspiration risk. However, this subject remains understudied in PD populations. Our aim was to identify the predictors of penetration-aspiration in PD patients using the VFSS. Consecutive patients were evaluated using VFSS with different consistencies and volumes of food. A speech-language pathologist measured the type of intra-oral bolus organization, loss of bolus control, bolus location at the initiation of the pharyngeal swallow, the presence of multiple swallows, piecemeal deglutition, bolus residue in the pharyngeal recesses and temporal measures. Scores >=3 on the penetration-aspiration scale (PAS) indicated the occurrence of penetration aspiration. Using logistic marginal regression, we found that residue in the vallecula, residue in the upper esophageal sphincter and piecemeal deglutition were associated with penetration-aspiration (odds ratio (OR) = 4.09, 2.87 and 3.83; P = 0.0040, 0.0071 and 0.0009, respectively). Penetration/aspiration occurred only with fluids (both of thin and thick consistency), and no significant differences were observed between fluid types or food volumes. The mechanisms underlying dysphagia and penetration/aspiration in PD patients and indications for further studies are discussed. PMID- 26492879 TI - Treatment of traumatised refugees with basic body awareness therapy versus mixed physical activity as add-on treatment: Study protocol of a randomised controlled trial. AB - BACKGROUND: Treatment of traumatised refugees is one of the fields within psychiatry, which has received little scientific attention. Evidence based treatment and knowledge on the efficiency of the treatment for this complex patient group is therefore scarce. This leads to uncertainty as to which treatment should be offered and potentially lowers the quality of life for the patients. Chronic pain is very common among traumatised refugees and it is believed to maintain the mental symptoms of trauma. Hence, treating chronic pain is believed to be of high clinical value for this patient group. In clinical studies, physical activity has shown a positive effect on psychiatric illnesses such as depression and anxiety and for patients with chronic pain. However, scientific knowledge about physical activity as part of the treatment for traumatised refugees is very limited and no guidelines exist on this topic. METHODS/DESIGN: This study will include approximately 310 patients, randomised into three groups. All three groups receive psychiatric treatment as usual for the duration of 6-7 months, consisting of consultations with a medical doctor including pharmacological treatment and manual-based Cognitive Behavioural Therapy. The first group only receives treatment as usual while the second and the third groups receive either Basic-Body Awareness Therapy or mixed physical activity as add-on treatments. Each physical activity is provided for an individual 1-hour consultation per week, for the duration of 20 weeks. The study is being conducted at the Competence Centre for Transcultural Psychiatry, Mental Health Centre Ballerup in the Capital Region of Denmark. The primary endpoint of the study is symptoms of Post Traumatic Stress Disorder; the secondary endpoints are depression and anxiety as well as quality of life, functional capacity, coping with pain, body awareness and physical fitness. DISCUSSION: This study will examine the effect of physical activity for traumatised refugees. This has not yet been done in a randomised controlled setting on such a large scale before. Hereby the study will contribute to important knowledge that is expected to be used in future clinical guidelines and reference programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01955538 . Date of registration: 18 September 2013. PMID- 26492881 TI - Management of tibial non-unions according to a novel treatment algorithm. AB - Tibial non-unions represent a spectrum of conditions that are challenging to treat. The optimal management remains unclear despite the frequency with which these diagnoses are encountered. The aim of this study was to determine the outcome of tibial non-unions managed according to a novel tibial non-union treatment algorithm. One hundred and eighteen consecutive patients with 122 uninfected tibial non-unions were treated according to our proposed tibial non union treatment algorithm. All patients were followed-up clinically and radiologically for a minimum of six months after external fixator removal. Four patients were excluded because they did not complete the intended treatment process. The final study population consisted of 94 men and 24 women with a mean age of 34 years. Sixty-seven non-unions were stiff hypertrophic, 32 mobile atrophic, 16 mobile oligotrophic and one true pseudoarthrosis. Six non-unions were classified as type B1 defect non-unions. Bony union was achieved after the initial surgery in 113/122 (92.6%) tibias. Nine patients had failure of treatment. Seven persistent non-unions were successfully retreated according to the tibial non-union treatment algorithm. This resulted in final bony union in 120/122 (98.3%) tibias. The proposed tibial non-union treatment algorithm appears to produce high union rates across a diverse group of tibial non-unions. Tibial non-unions however, remain difficult to treat and should be referred to specialist units where advanced reconstructive techniques are practiced on a regular basis. PMID- 26492883 TI - Early versus delayed application of Thomas splints in patients with isolated femur shaft fractures: The benefits quantified. AB - AIMS: To investigate and quantify the clinical benefits of early versus delayed application of Thomas splints in patients with isolated femur shaft fractures. MATERIALS AND METHODS: Level IV retrospective clinical and radiological analysis of patients presenting from January to December 2012 at a Level 1 Trauma Unit. All skeletally mature patients with isolated femur shaft fractures independently of their mechanism of injury were included. Exclusion criteria were: ipsilateral fracture of the lower limb, neck and supracondylar femur fractures, periprosthetic and incomplete fractures. Their clinical records were analysed for blood transfusion requirements, pulmonary complications, surgery time, duration of hospital stay and analgesic requirements. RESULTS: A total of 106 patients met our inclusion criteria. There were 74 males and 32 females. Fifty seven (54%) patients were in the 'early splinted' group and 49 patients (46%) were in the 'delayed splinted' group (P>0.05). The need for blood transfusion was significantly reduced in the 'early splinted' group (P=0.04). There was a significantly higher rate of pulmonary complications in the 'delayed splinted' group (P=0.008). All other parameters were similar between the two groups. CONCLUSION: The early application of Thomas splints for isolated femur fractures in non-polytraumatised patients has a clinically and statistically significant benefit of reducing the need for blood transfusions and the incidence of pulmonary complications. PMID- 26492882 TI - District-level hospital trauma care audit filters: Delphi technique for defining context-appropriate indicators for quality improvement initiative evaluation in developing countries. AB - INTRODUCTION: Prospective clinical audit of trauma care improves outcomes for the injured in high-income countries (HICs). However, equivalent, context-appropriate audit filters for use in low- and middle-income country (LMIC) district-level hospitals have not been well established. We aimed to develop context-appropriate trauma care audit filters for district-level hospitals in Ghana, was well as other LMICs more broadly. METHODS: Consensus on trauma care audit filters was built between twenty panellists using a Delphi technique with four anonymous, iterative surveys designed to elicit: (i) trauma care processes to be measured; (ii) important features of audit filters for the district-level hospital setting; and (iii) potentially useful filters. Filters were ranked on a scale from 0 to 10 (10 being very useful). Consensus was measured with average percent majority opinion (APMO) cut-off rate. Target consensus was defined a priori as: a median rank of >=9 for each filter and an APMO cut-off rate of >=0.8. RESULTS: Panellists agreed on trauma care processes to target (e.g. triage, phases of trauma assessment, early referral if needed) and specific features of filters for district-level hospital use (e.g. simplicity, unassuming of resource capacity). APMO cut-off rate increased successively: Round 1--0.58; Round 2--0.66; Round 3- 0.76; and Round 4--0.82. After Round 4, target consensus on 22 trauma care and referral-specific filters was reached. Example filters include: triage--vital signs are recorded within 15 min of arrival (must include breathing assessment, heart rate, blood pressure, oxygen saturation if available); circulation--a large bore IV was placed within 15 min of patient arrival; referral--if referral is activated, the referring clinician and receiving facility communicate by phone or radio prior to transfer. CONCLUSION: This study proposes trauma care audit filters appropriate for LMIC district-level hospitals. Given the successes of similar filters in HICs and obstetric care filters in LMICs, the collection and reporting of prospective trauma care audit filters may be an important step towards improving care for the injured at district-level hospitals in LMICs. PMID- 26492884 TI - Peri-operative radiation exposure: Are overweight patients at increased risks? AB - The aim of this study was to identify if there was a correlation between body mass index (BMI) and intra-operative radiation exposure. A retrospective review of 81 patients who had sliding hip screw fixation for femoral neck fractures in one year was completed, recording body mass index (BMI), screening time, dose area product (DAP), American Society of Anesthesiologists (ASA) grade, seniority of operating surgeon and complexity of the fracture configuration. There was a statistically significant correlation between dose area product and BMI. There was no statistically significant relationship between screening time and BMI. There was no statistical difference between ASA grade, seniority of surgeon, or complexity of fracture configuration and dose area product. Simulated stochastic risks were increased for overweight patients. Overweight patients are exposed to increased doses of radiation regardless of length of screening time. Surgeons and theatre staff should be aware of the increased radiation exposure during fixation of fractures in overweight patients and, along with radiographers, ensure steps are taken to minimise these risks. Whilst such radiation dosages may have little adverse effect for individual patients, these findings may be of more relevance and concern to staff that will be exposed to increased radiation. PMID- 26492885 TI - Hepatitis E virus infection activates signal regulator protein alpha to down regulate type I interferon. AB - Hepatitis E virus (HEV) is a major cause of enterically transmitted acute hepatitis worldwide. However, the mechanism of HEV replication is unclear. Type I interferon is the first defense line of host against viral infection. Signal regulator protein alpha (SIRP-alpha) plays an important role in negative regulation of innate immunity. In the present study, HEV infection significantly activated the expression of SIRP-alpha and down-regulated phosphorylation of IRF3, consequently resulted in suppression of type I interferon (IFN-beta). In conclusion, HEV exploited SIRP-alpha to negative regulated IFN-beta of the host innate immune system to promote viral infection. It suggested that interfering with the functions of SIRP-alpha should be considered as a potential therapeutic approach to the prevention and treatment of HEV infection. PMID- 26492886 TI - Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) for Conformational Space Search of Peptide and Miniprotein. AB - Protein and peptide structure predictions are of paramount importance for understanding their functions, as well as the interactions with other molecules. However, the use of molecular simulation techniques to directly predict the peptide structure from the primary amino acid sequence is always hindered by the rough topology of the conformational space and the limited simulation time scale. We developed here a new strategy, named Multiple Simulated Annealing-Molecular Dynamics (MSA-MD) to identify the native states of a peptide and miniprotein. A cluster of near native structures could be obtained by using the MSA-MD method, which turned out to be significantly more efficient in reaching the native structure compared to continuous MD and conventional SA-MD simulation. PMID- 26492887 TI - Identification of invasion proteins of Cryptosporidium parvum. AB - Host cell interactions and invasion by Cryptosporidium is a complex process mediated by zoites ligand-host cell receptors. Knowledge of proteins involved in this process will enable entry level inhibitors to be tried as therapeutic agents. In the present study, invasion proteins of Cryptosporidium parvum were studied in vitro. Cryptosporidium sporozoites membrane proteins were isolated and Cy5 dye labelled. They were then allowed to interact with the intact host cells. The interacting proteins were identified using 2-dimensional gel electrophoresis followed by mass spectrometry analysis. Sixty-one proteins were identified including twenty-seven previously reported invasion proteins. The newly identified proteins such as serine/threonine protein kinase, PI4 kinase, Hsp105 and coiled coil may have their roles in the parasitic invasion process. Thus, a new approach was used in the study to identify the probable proteins involved in invasion and/or host-parasite interactions. The advantage of this method is that it takes only a months' time instead of decades to identify these proteins involved in invasion process. PMID- 26492888 TI - Bacterial succession and the dynamics of volatile compounds during the fermentation of Chinese rice wine from Shaoxing region. AB - Shaoxing rice wine is one of the most typical representatives of Chinese rice wine. It is brewed under non-sterile condition with various microorganism growing at the same time and forms a special flavor. The aims of this study was to monitor the bacterial succession by MiSeq pyrosequencing and the volatile compound dynamics by HS-SPME/GC-MS during brewing process. Moreover, the volatile compounds and bacterial community were analyzed by partial least squares regression to evaluate the effect of bacteria on volatile compounds formation. The results showed that there were ten dominating genera during Shaoxing rice wine fermentation process. Ten genera, Bacillus, Leuconostoc, Lactococcus, Weissella, Thermoactinomyces, Pseudomonas, Saccharopolyspora, Staphylococcus, Enterobacter and Lactobacillus, were identified as the main bacteria. The Bacillus and Lactobacillus dominated the Chinese rice wine ecosystems. In addition, a total of 64 volatile compounds were identified, mainly esters, alcohols, carbonyl compound and phenols. Pseudomonas were involved in synthesis of a wide variety of volatile compounds. Thermoactinomyces, Bacillus and Lactococcus also played critical roles in the formation of volatile compounds. PMID- 26492889 TI - Gene expression signature in mouse thyroid tissue after (131)I and (211)At exposure. AB - BACKGROUND: (131)I and (211)At are used in nuclear medicine and accumulate in the thyroid gland and may impact normal thyroid function. The aim of this study was to determine transcriptional profile variations, assess the impact on cellular activity, and identify genes with biomarker properties in thyroid tissue after (131)I and (211)At administration in mice. METHODS: To further investigate thyroid tissue transcriptional responses to (131)I and (211)At administration, we generated a new transcriptional dataset that includes re-evaluated raw intensity values from our previous (131)I and (211)At studies. Differential transcriptional profiles were identified by comparing treated and mock-treated samples using Nexus Expression 3.0 software. Further data analysis was performed using R/Bioconductor and IPA. RESULTS: A total of 1144 genes were regulated. Hierarchical clustering subdivided the groups into two clusters containing the lowest and highest absorbed dose levels, respectively, and revealed similar transcriptional regulation patterns for many kallikrein-related genes. Twenty seven of the 1144 genes were recurrently regulated after (131)I and (211)At exposure and divided into six clusters. Several signalling pathways were affected, including calcium, integrin-linked kinase, and thyroid cancer signalling, and the peroxisomal proliferator-activated receptor network. CONCLUSIONS: Substantial changes in transcriptional regulation were shown in (131)I and (211)At-treated samples, and 27 genes were identified as potential biomarkers for (131)I and (211)At exposure. Clustering revealed distinct differences between transcriptional profiles of both similar and different exposures, demonstrating the necessity for better understanding of radiation induced effects on cellular activity. Additionally, ionizing radiation-induced changes in kallikrein gene expression and identified canonical pathways should be further assessed. PMID- 26492890 TI - Behavioural flexibility of the chemical defence in the parasitoid wasp Leptopilina heterotoma. AB - Many insects use chemical defence mechanisms to defend themselves against predators. However, defensive secretions are costly to produce and should thus only be used in cases of real danger. This would require that insects are able to discriminate between predators to adjust their chemical defence. Here, we show that females of the parasitoid wasp Leptopilina heterotoma adjust the intensity of their chemical defence to differently sized predators. If attacked by Myrmica ants, the females always released their defensive secretion, which consists mainly of (-)-iridomyrmecin. However, if attacked by smaller Cardiocondyla ants, most females did not release any defensive spray, irrespective of the duration of the ant's aggression. When in contact with non-aggressive Nasonia wasps, the females of L. heterotoma did not release any defensive secretion. Our data show that females of L. heterotoma are able to discriminate between two predators and suggest that a predator of a certain size or strength is necessary to trigger the chemical defence mechanism of L. heterotoma. PMID- 26492892 TI - Protective Factors Against Child Victimization in the School and Community: An Exploratory Systematic Review of Longitudinal Predictors and Interacting Variables. AB - Protective factors against the victimization of children and young people within the school and community environments (extrafamilial victimization) have received less attention than risk factors. To date, there has been no systematic review on protective factors. This systematic review therefore aimed to synthesize the prospective longitudinal research findings on the protective factors against extrafamilial victimization. A systematic search of multiple sources led to the identification of 19,053 studies. Following application of a predefined inclusion and quality assessment criteria, 13 studies exploring protective factors against peer victimization and exposure to violence were included in this review. Across these studies, 19 protective factors were explored: 9 individual factors and 10 contextual factors. Four studies also explored the impact of mediating and moderating variables on the relationship between predictors and extrafamilial victimization. Findings highlight inconsistencies in the definition and measurement of victimization, along with bias in a number of areas. Nevertheless, a small number of variables (perceptions of social competence, physical strength, and aggression) were identified as potential protective factors against extrafamilial victimization. Additionally, mediating and moderating variables were identified, and the interaction between individual and contextual protective and risk factors were highlighted. These findings are explored under the theoretical framework of the ecological systems theory and their practical and research-based implications are discussed. PMID- 26492891 TI - Are Single-Item Global Ratings Useful for Assessing Health Status? AB - The research performance of the single-item self-rating In general, would you say your health is: excellent, very good, good, fair, or poor? was evaluated relative to the SF-36 General Health Scale that contains this item, using data for a sample of psychiatric outpatients who had co-occurring chronic physical conditions (N = 177). The scale was more robust than the single-item in cross sectional validity tests and for predicting 2-year outcomes, but the single-item had stronger discriminant validity as a measure of physical health, especially in post-baseline analyses. Single-item and scale were both sensitive enough to detect change in perceived health over 2 years and a conditional experimental effect on health self-perceptions in a randomized trial. These findings demonstrate that a global single-item can be as valid, reliable, and sensitive as a multi-item scale for longitudinal research purposes, even if the scale performs better in cross-sectional surveys or as a screening measure. PMID- 26492893 TI - Impact of potentially inappropriate medication and continuity of care in a sample of Taiwan elderly patients with diabetes mellitus who have also experienced heart failure. AB - AIMS: Continuity of care (COC) and potentially inappropriate medication (PIM) can affect the elderly healthcare outcome. We evaluated the COC and PIM effects in older diabetes mellitus (DM) patients with heart failure (HF). METHODS: The Longitudinal Health Insurance Database of 2005 was multiple-year claim data collected from 2005 to 2010 in Taiwan. There were both 823 DM and non-DM subjects aged 65 years and older in this observational study. The COC index and 2012 Beers criteria were applied to evaluate the COC and HF-PIM in older DM patients with heart failure. The dependent variables were either hospital admissions or emergency department visits. Generalized estimating equation was used to adjust all covariates. RESULTS: During 2005-2010, the rate of HF-PIM in the elderly DM group was 86.1%, the mean COC index was 0.28 +/- 0.19, the admission rate was 31.9% and the emergency department rate was 38.8 %. Lower COC index was associated with HF-PIM and HF-PIM duration in older DM patients with HF. Lower COC index was associated with hospitalizations (OR 0.07, 95% CI 0.05-0.11) and ED visits (OR 0.10, 95% CI 0.07-0.13), but HF-PIM was not significant. The duration of HF-PIM was related with poor health outcomes over 90 and 180 days for hospitalization and emergency department visit, respectively. CONCLUSION: Among elderly DM patients with HF, COC had positive effects on healthcare outcomes. Improving COC and reducing PIM duration for elderly DM patients with HF seems warranted. Geriatr Gerontol Int 2016; 16: 1117-1126. PMID- 26492894 TI - Right ventricular function in dilated cardiomyopathy: women are the stronger sex! PMID- 26492895 TI - Antivirals, pandemic planning, and failure to heed calls for trial data. PMID- 26492896 TI - Brazilian Valuation of EQ-5D-3L Health States: Results from a Saturation Study. AB - BACKGROUND: Most EQ-5D-3L valuation studies include the same sample of health states that was used in the protocol of the original UK Measurement and Valuation of Health (MVH) study. Thus far, no studies using a time tradeoff utility elicitation method have been carried out using all 243 EQ-5D health states. Because the values and preferences regarding health outcomes differ among countries, it is essential to have country-specific data to enable local high level decisions regarding resource allocation. This study developed a country specific set of values for EQ-5D-3L health states. METHODS: A multicentric study was conducted in 4 Brazilian areas. A probabilistic sample of the general population, aged 18 to 64 y, stratified by age and gender, was surveyed. The interview followed a revised version of the MVH protocol, in which all 243 health states were valued. Each respondent ranked and valued 7 health states using the TTO in a home interview. RESULTS: Data were collected from 9148 subjects. The best-fitting regression model was an individual-level mixed-effects model without any interaction terms. The dimensions "Mobility" and "Usual Activities" were associated with higher losses in health state utility value. The "Anxiety/Depression" dimension was the domain that contributed to lower losses in health state utility value. CONCLUSIONS: This study generated significant insight into the Brazilian population's health preferences that can be applied to health technology assessment and economic analyses in Brazil. This information represents an important new tool that can be used in Brazilian health policy creation and evaluation. PMID- 26492897 TI - Diversity and Distribution of Aquatic Fungal Communities in the Ny-Alesund Region, Svalbard (High Arctic): Aquatic Fungi in the Arctic. AB - We assessed the diversity and distribution of fungi in 13 water samples collected from four aquatic environments (stream, pond, melting ice water, and estuary) in the Ny-Alesund Region, Svalbard (High Arctic) using 454 pyrosequencing with fungi specific primers targeting the internal transcribed spacer (ITS) region of the ribosomal rRNA gene. Aquatic fungal communities in this region showed high diversity, with a total of 43,061 reads belonging to 641 operational taxonomic units (OTUs) being found. Of these OTUs, 200 belonged to Ascomycota, 196 to Chytridiomycota, 120 to Basidiomycota, 13 to Glomeromycota, and 10 to early diverging fungal lineages (traditional Zygomycota), whereas 102 belonged to unknown fungi. The major orders were Helotiales, Eurotiales, and Pleosporales in Ascomycota; Chytridiales and Rhizophydiales in Chytridiomycota; and Leucosporidiales and Sporidiobolales in Basidiomycota. The common fungal genera Penicillium, Rhodotorula, Epicoccum, Glaciozyma, Holtermanniella, Betamyces, and Phoma were identified. Interestingly, the four aquatic environments in this region harbored different aquatic fungal communities. Salinity, conductivity, and temperature were important factors in determining the aquatic fungal diversity and community composition. The results suggest the presence of diverse fungal communities and a considerable number of potentially novel fungal species in Arctic aquatic environments, which can provide reliable data for studying the ecological and evolutionary responses of fungi to climate change in the Arctic ecosystem. PMID- 26492899 TI - An author's guide to submission, revision and rejection. PMID- 26492900 TI - An evidence-based approach to red blood cell transfusions in asymptomatically anaemic patients. AB - INTRODUCTION: Surgeons and physicians encounter blood transfusions on a daily basis but a robust evidence-based strategy on indications and timing of transfusion in asymptomatic anaemic patients is yet to be determined. For judicious use of blood products, the risks inherent to packed red blood cells, the patient's co-morbidities and haemoglobin (Hb)/haematocrit levels should be considered. This review critiques and summarises the latest available evidence on the indications for transfusions in healthy and cardiac disease patients as well as the timing of transfusions relative to surgery. METHODS: An electronic literature search of the MEDLINE((r)), Google ScholarTM and Trip databases was conducted for articles published in English between January 2006 and January 2015. Studies discussing timing and indications of transfusion in medical and surgical patients were retrieved. Bibliographies of studies were checked for other pertinent articles that were missed by the initial search. FINDINGS: Six level 1 studies (randomised controlled trials or systematic reviews) and six professional society guidelines were included in this review. In healthy patients without cardiac disease, a restrictive transfusion trigger of Hb 70-80g/l is safe and appropriate whereas in cardiac patients, the trigger is Hb 80-100g/l. The literature on timing of transfusions relative to surgery is limited. For the studies available, preoperative transfusions were associated with a decreased incidence of subsequent transfusions and timing of transfusions did not affect the rates of colorectal cancer recurrence. PMID- 26492901 TI - Acute surgical unit safely reduces unnecessary after-hours cholecystectomy. AB - INTRODUCTION: The acute surgical model has been trialled in several institutions with mixed results. The aim of this study was to determine whether the acute surgical model provides better outcomes for patients with acute biliary presentation, compared with the traditional emergency surgery model of care. METHODS: A retrospective review was carried out of patients who were admitted for management of acute biliary presentation, before and after the establishment of an acute surgical unit (ASU). Outcomes measured were time to operation, operating time, after-hours operation (6pm - 8am), length of stay and surgical complications. RESULTS: A total of 342 patients presented with acute biliary symptoms and were managed operatively. The median time to operation was significantly reduced in the ASU group (32.4 vs 25.4 hours, p=0.047), as were the proportion of operations performed after hours (19.5% vs 2.5%, p<0.001) and the median length of stay (4 vs 3 days, p<0.001). The median operating time, rate of conversion to open cholecystectomy and wound infection rates remained similar. CONCLUSIONS: Implementation of an ASU can lead to objective differences in outcomes for patients who present with acute cholecystitis. In our study, the ASU significantly reduced time to operation, the number of operations performed after hours and length of stay. PMID- 26492902 TI - UK national survey of management of breast lobular carcinoma in situ. AB - INTRODUCTION: There is no national standard treatment for patients with breast lobular carcinoma in situ (LCIS). Association of Breast Surgery guidelines for the management of breast cancer suggest that lesions containing LCIS should be excised for definitive diagnosis and recommend close surveillance after excision biopsy. The aim of this study was to form a picture of the current management of LCIS by UK breast surgeons. METHODS: A questionnaire about the management of LCIS was sent to 490 UK breast surgeons. RESULTS: Of 490 questionnaires sent out, 173 (35%) were returned. When LCIS is present in a core biopsy, 61% of breast surgeons perform surgical excision, 22% would not excise but would continue follow-up and the remainder perform neither or set no clear management plan. Over half (54%) follow patients up with five years of annual mammography. If classic LCIS were found at the margins of wide local excision, 92% would not re-excise. Conversely, if pleomorphic LCIS were found, 71% would achieve clear margins. Respondents were split evenly regarding management of classic LCIS with a family history as 54% would not alter management whereas 43% would treat the disease more aggressively. CONCLUSIONS: Our survey has shown that in cases where LCIS is found at core biopsy, most surgeons follow Association of Breast Surgery guidance, obtaining further histological samples to exclude pleomorphic LCIS, ductal carcinoma in situ or invasive cancer, whereas others opt for annual surveillance and some discharge the patient. This study highlighted the huge variability in LCIS management, and the need for randomised controlled trials and input into national audits such as the Sloane Project to establish evidence-based national standard guidelines. PMID- 26492903 TI - Adequacy of diagnostic tests and surgical management of symptomatic invasive lobular carcinoma of the breast. AB - INTRODUCTION: Invasive lobular carcinoma (ILC) presents diagnostic and therapeutic challenges as it produces subtle radiological changes. It has been suggested that it is not suitable for breast conserving surgery (BCS). The aim of this study was to ascertain the diagnostic adequacy of modern mammography and ultrasonography in the context of a fast track symptomatic diagnostic clinic in the UK. It also sought to compare the mastectomy, re-excision and BCS rates for ILC with those for invasive ductal carcinoma (IDC). METHODS: A retrospective analysis of prospectively collected data was carried out on all new symptomatic cancers presenting to the one-stop diagnostic clinic of a single breast unit between 1998 and 2007. RESULTS: Compared with IDC, ILC was significantly larger at presentation (46mm vs 25mm), needed re-excision after BCS more often (38.8% vs 22.3%) and required mastectomy more frequently (58.8% vs 40.8%). Although mammography performs poorly in diagnosing ILC compared with IDC, when combined with ultrasonography, sensitivity of the combined imaging was not significantly different between these two histological types. CONCLUSIONS: Provided ultrasonography is performed, standard radiological imaging is adequate for initial diagnosis of symptomatically presenting ILC but some additional preoperative workup should clearly be employed to reduce the higher number of reoperations for this histological type. PMID- 26492904 TI - No association between seniority of surgeon and postoperative recurrence of chronic subdural haematoma. AB - INTRODUCTION: Neurosurgical trainees should achieve competency in chronic subdural haematoma (CSDH) drainage at an early stage in training. The effect of surgeon seniority on recurrence following surgical drainage of CSDH was examined. METHODS: All CSDH cases performed at St George's Hospital in London between March 2009 and March 2012 were analysed. Recurrence was defined as clinical deterioration with computed tomography evidence of CSDH requiring reoperation within six months. The following risk factors were considered: seniority of primary and supervising surgeons, timing of surgery (working hours, outside working hours), patient related factors (age, antiplatelets, warfarin) and operative factors (general vs local anaesthesia, burr holes vs craniotomy, drain use). For recurrent cases, we examined the distance of the cranial opening from the thickest part of the CSDH. RESULTS: A total of 239 patients (median age: 79 years, range: 33-98 years) had 275 CSDH drainage operations. The overall recurrence rate was 13.1%. The median time between the initial procedure and reoperation was 16 days (range: 1-161 days). The only statistically significant risk factor for recurrence was antiplatelets (odds ratio: 2.62, 95% confidence interval: 1.13-6.10, p<0.05). Warfarin, grade of surgeon, timing of surgery, type of anaesthesia, type of operation and use of drains were not significant risk factors. In 26% of recurrent CSDH cases, the burr holes or craniotomy flaps were placed with borderline accuracy. CONCLUSIONS: CSDH drainage is a suitable case for neurosurgical trainees to perform without increasing the chance of recurrence. PMID- 26492905 TI - Determination of a safe INR for joint injections in patients taking warfarin. AB - INTRODUCTION: With an increase in life expectancy in 'developed' countries, the number of elderly patients receiving joint injections for arthritis is increasing. There are legitimate concerns about an increased risk of thromboembolism if anticoagulation is stopped or reversed for such an injection. Despite being a common dilemma, the literature on this issue is scarce. METHODS: We undertook 2,084 joint injections of the knee and shoulder in 1,714 patients between August 2008 and December 2013. Within this cohort, we noted 41 patients who were taking warfarin and followed them immediately after joint injection in the clinic or radiology department, looking carefully for complications. Then, we sought clinical follow-up, correspondence, and imaging evidence for 4 weeks, looking for complications from these joint injections. We recorded International Normalised Ratio (INR) values before injection. RESULTS: No complications were associated with the procedure after any joint injection. The radiologists who undertook ultrasound-guided injections to shoulders re-scanned the joints looking for haemarthroses: they found none. A similar outcome was noted clinically after injections in the outpatient setting. CONCLUSION: With a mean INR of 2.77 (range, 1.7-5.5) and a maximum INR within this group of 5.5, joint injections to the shoulder and knee can be undertaken safely in primary or secondary care settings despite the patient taking warfarin. PMID- 26492906 TI - Litigation costs of wrong-site surgery and other non-technical errors in orthopaedic operating theatres. AB - INTRODUCTION: This study reviews the litigation costs of avoidable errors in orthopaedic operating theatres (OOTs) in England and Wales from 1995 to 2010 using the National Health Service Litigation Authority Database. MATERIALS AND METHODS: Litigation specifically against non-technical errors (NTEs) in OOTs and issues regarding obtaining adequate consent was identified and analysed for the year of incident, compensation fee, cost of legal defence, and likelihood of compensation. RESULTS: There were 550 claims relating to consent and NTEs in OOTs. Negligence was related to consent (n=126), wrong-site surgery (104), injuries in the OOT (54), foreign body left in situ (54), diathermy and skin preparation burns (54), operator error (40), incorrect equipment (25), medication errors (15) and tourniquet injuries (10). Mean cost per claim was L40,322. Cumulative cost for all cases was L20 million. Wrong-site surgery was error that elicited the most successful litigation (89% of cases). Litigation relating to implantation of an incorrect prosthesis (eg right-sided prosthesis in a left knee) cost L2.9 million. Prevalence of litigation against NTEs has declined since 2007. CONCLUSIONS: Improved patient-safety strategies such as the World Health Organization Surgical Checklist may be responsible for the recent reduction in prevalence of litigation for NTEs. However, addition of a specific feature in orthopaedic surgery, an 'implant time-out' could translate into a cost benefit for National Health Service hospital trusts and improve patient safety. PMID- 26492907 TI - Contemporary surgical treatment of primary hyperparathyroidism without intraoperative parathyroid hormone measurement. AB - INTRODUCTION: Primary hyperparathyroidism (pHPT) is usually the result of a single adenoma that can often be accurately located preoperatively and excised by a focused operation. Intraoperative parathyroid hormone (IOPTH) measurement is used occasionally to detect additional abnormal glands. However, it remains controversial as to whether IOPTH monitoring is necessary. This study presents the results of a large series of focused parathyroidectomy without IOPTH measurement. METHODS: Data from 2003 to 2014 were collected on 180 consecutive patients who underwent surgical treatment for pHPT by a single surgeon. Preoperative ultrasonography and sestamibi imaging was performed routinely, with computed tomography (CT) and/or selective venous sampling in selected cases. The preferred procedure for single gland disease was a focused lateral approach guided by on-table surgeon performed ultrasonography. Frozen section was used selectively and surgical cure was defined as normocalcaemia at the six-month follow-up appointment. RESULTS: Focused surgery was undertaken in 146 patients (81%) and 97% of these cases had concordant results with two imaging modalities. In all cases, an abnormal gland was discovered at the predetermined site. Of the 146 patients, 132 underwent a focused lateral approach (11 of which were converted to a collar incision), 10 required a collar incision and 4 underwent a mini-sternotomy. At 6 months following surgery, 142 patients were normocalcaemic (97% primary cure rate). Three of the four treatment failures had subsequent surgery and are now biochemically cured. There were no complications or cases of persistent hypocalcaemia. CONCLUSIONS: This study provides further evidence that in the presence of concordant preoperative imaging, IOPTH measurement can be safely omitted when performing focused parathyroidectomy for most cases of pHPT. PMID- 26492908 TI - Inconsistent reporting of minimally invasive surgery errors. AB - INTRODUCTION: Minimally invasive surgery (MIS) is a complex task requiring dexterity and high level cognitive function. Unlike surgical 'never events', potentially important (and frequent) manual or cognitive slips ('technical errors') are underresearched. Little is known about the occurrence of routine errors in MIS, their relationship to patient outcome, and whether they are reported accurately and/or consistently. METHODS: An electronic survey was sent to all members of the Association of Surgeons of Great Britain and Ireland, gathering demographic information, experience and reporting of MIS errors, and a rating of factors affecting error prevalence. RESULTS: Of 249 responses, 203 completed more than 80% of the questions regarding the surgery they had performed in the preceding 12 months. Of these, 47% reported a significant error in their own performance and 75% were aware of a colleague experiencing error. Technical skill, knowledge, situational awareness and decision making were all identified as particularly important for avoiding errors in MIS. Reporting of errors was variable: 15% did not necessarily report an intraoperative error to a patient while 50% did not consistently report at an institutional level. Critically, 12% of surgeons were unaware of the procedure for reporting a technical error and 59% felt guidance is needed. Overall, 40% believed a confidential reporting system would increase their likelihood of reporting an error. CONCLUSION: These data indicate inconsistent reporting of operative errors, and highlight the need to better understand how and why technical errors occur in MIS. A confidential 'no blame' reporting system might help improve patient outcomes and avoid a closed culture that can undermine public confidence. PMID- 26492909 TI - Power-assisted endoscopic adenoidectomy using a 120 degrees reverse-viewing telescope. PMID- 26492910 TI - Harvesting cortical temporal bone to close attic defects using a TraumadriveTM. PMID- 26492911 TI - The twisted double loop mattress suture. PMID- 26492912 TI - Use of additional absorbent pad in the skin preparation and draping of breast patients to reduce rates of contact dermatitis. PMID- 26492914 TI - de winters ECG changes and anterior myocardial infarction. PMID- 26492915 TI - Asymmetric Weighting to Optimize Regional Sensitivity in Combined fMRI-MEG Maps. AB - Functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) are neuroimaging techniques that measure inherently different physiological processes, resulting in complementary estimates of brain activity in different regions. Combining the maps generated by each technique could thus provide a richer understanding of brain activation. However, present approaches to integration rely on a priori assumptions, such as expected patterns of brain activation in a task, or use fMRI to bias localization of MEG sources, diminishing fMRI-invisible sources. We aimed to optimize sensitivity to neural activity by developing a novel method of integrating data from the two imaging techniques. We present a data-driven method of integration that weights fMRI and MEG imaging data by estimates of data quality for each technique and region. This method was applied to a verbal object recognition task. As predicted, the two imaging techniques demonstrated sensitivity to activation in different regions. Activity was seen using fMRI, but not MEG, throughout the medial temporal lobes. Conversely, activation was seen using MEG, but not fMRI, in more lateral and anterior temporal lobe regions. Both imaging techniques were sensitive to activation in the inferior frontal gyrus. Importantly, integration maps retained activation from individual activation maps, and showed an increase in the extent of activation, owing to greater sensitivity of the integration map than either fMRI or MEG alone. PMID- 26492916 TI - Active auditory mechanics in female black-horned tree crickets (Oecanthus nigricornis). AB - The acoustic signalling behaviour of many tree cricket species is easily observed and has been well described. Very little is known, however, about the receivers in these communication loops. The exception to this is a single Indian species (Oecanthus henryi) which employs active auditory mechanics to enhance female sensitivity to quiet sounds at male calling frequencies. In most species, male calls have been described, but whether or not sender-receiver matching is present is uncertain. Here we investigate auditory mechanics in females of the North American black-horned tree cricket (Oecanthus nigricornis). The response of the anterior tympanal membrane is nonlinear, exhibiting a lack of tuning at high amplitudes (60 dB and above) but as stimulus amplitude decreases, the membrane becomes tuned to around 4.3 kHz. The tuning of the membrane falls within the frequency range of male calls indicating sender-receiver matching at low amplitudes, which could aid localisation of the highly directional calls of males. The extent of active auditory mechanics in tympanal insects is not yet known, but this paper provides an indication that this may indeed be widespread in at least the Oecanthinae. PMID- 26492918 TI - The Skin Microbiome in Atopic Dermatitis and Its Relationship to Emollients. AB - BACKGROUND: Human-associated bacterial communities on the skin, skin microbiome, likely play a central role in development of immunity and protection from pathogens. In atopic patients, the skin bacterial diversity is smaller than in healthy subjects. OBJECTIVE: To review treatment strategies for atopic dermatitis in Canada, taking the skin microbiome concept into account. METHODS: An expert panel of 8 Canadian dermatologists explored the role of skin microbiome in clinical dermatology, specifically looking at atopic dermatitis. RESULTS: The panel reached consensus on the following: (1) In atopic patients, the skin microbiome of lesional atopic skin is different from nonlesional skin in adjacent areas. (2) Worsening atopic dermatitis and smaller bacterial diversity are strongly associated. (3) Application of emollients containing antioxidant and antibacterial components may increase microbiome diversity in atopic skin. CONCLUSION: The skin microbiome may be the next frontier in preventive health and may impact the approach to atopic dermatitis treatment. PMID- 26492917 TI - EglN2 associates with the NRF1-PGC1alpha complex and controls mitochondrial function in breast cancer. AB - The EglN2/PHD1 prolyl hydroxylase is an important oxygen sensor contributing to breast tumorigenesis. Emerging studies suggest that there is functional cross talk between oxygen sensing and mitochondrial function, both of which play an essential role for sustained tumor growth. However, the potential link between EglN2 and mitochondrial function remains largely undefined. Here, we show that EglN2 depletion decreases mitochondrial respiration in breast cancer under normoxia and hypoxia, which correlates with decreased mitochondrial DNA in a HIF1/2alpha-independent manner. Integrative analyses of gene expression profile and genomewide binding of EglN2 under hypoxic conditions reveal nuclear respiratory factor 1 (NRF1) motif enrichment in EglN2-activated genes, suggesting NRF1 as an EglN2 binding partner. Mechanistically, by forming an activator complex with PGC1alpha and NRF1 on chromatin, EglN2 promotes the transcription of ferridoxin reductase (FDXR) and maintains mitochondrial function. In addition, FDXR, as one of effectors for EglN2, contributes to breast tumorigenesis in vitro and in vivo. Our findings suggest that EglN2 regulates mitochondrial function in ERalpha-positive breast cancer. PMID- 26492919 TI - The Use of the PlasmaBlade and Acellular Dermal Matrix in Rhinophyma Surgery: A Case Report. AB - BACKGROUND: Rhinophyma is a rare, disfiguring disease characterized by a slow progressive overgrowth of the soft tissue of the nose associated with end-stage severe acne rosacea. OBJECTIVE: We present a case of severe rhinophyma treated successfully using PlasmaBlade and acellular dermal matrix with split-thickness skin graft. METHODS: This procedure combines deep excision with PlasmaBlade followed by coverage with an acellular dermal matrix for dermal substitution and split-thickness skin graft. RESULTS: Functional and aesthetic results were satisfactory. CONCLUSION: We offer a new approach to surgical treatment of rhinophyma. Total excision of phymatous tissue and single session replacement of epidermal-dermal components is an effective treatment for patients with severe rhinophyma, resulting in satisfactory functional and aesthetic outcome. This combined treatment modality prevents the recurrence of rhinophyma. It should be considered an appropriate alternative in cases of severe rhinophyma. PMID- 26492920 TI - Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis. AB - Epidermal growth factor receptor (EGFR) and ERBB3 have been implicated in hepatocellular carcinogenesis (HCC). However, it is not known whether altering the activity of either EGFR or ERBB3 affects HCC development. We now show that Egfr(Dsk5) mutant mice, which have a gain-of-function allele that increases basal EGFR kinase activity, develop spontaneous HCC by 10 mo of age. Their tumors show increased activation of EGFR, ERBB2, and ERBB3 as well as AKT and ERK1,2. Hepatocyte-specific models of EGFR and ERBB3 gene ablation were generated to evaluate how the loss of these genes affected tumor progression. Loss of either receptor tyrosine kinase did not alter liver development or regenerative liver growth following carbon tetrachloride injection. However, using a well characterized model of HCC in which N-nitrosodiethylamine is injected into 14-day old mice, we discovered that loss of hepatocellular ERBB3 but not EGFR, which occurred after tumor initiation, retarded liver tumor formation and cell proliferation. We found no evidence that this was due to increased apoptosis or diminished phosphatidylinositol-3-kinase activity in the ERBB3-null cells. However, the relative amount of phospho-STAT3 was diminished in tumors derived from these mice, suggesting that ERBB3 may promote HCC through STAT3 activation. PMID- 26492921 TI - Cephalic phase secretion of insulin and other enteropancreatic hormones in humans. AB - Enteropancreatic hormone secretion is thought to include a cephalic phase, but the evidence in humans is ambiguous. We studied vagally induced gut hormone responses with and without muscarinic blockade in 10 glucose-clamped healthy men (age: 24.5 +/- 0.6 yr, means +/- SE; body mass index: 24.0 +/- 0.5 kg/m(2); HbA1c: 5.1 +/- 0.1%/31.4 +/- 0.5 mmol/mol). Cephalic activation was elicited by modified sham feeding (MSF, aka "chew and spit") with or without atropine (1 mg bolus 45 min before MSF + 80 ng.kg(-1).min(-1) for 2 h). To mimic incipient prandial glucose excursions, glucose levels were clamped at 6 mmol/l on all days. The meal stimulus for the MSF consisted of an appetizing breakfast. Participants (9/10) also had a 6 mmol/l glucose clamp without MSF. Pancreatic polypeptide (PP) levels rose from 6.3 +/- 1.1 to 19.9 +/- 6.8 pmol/l (means +/- SE) in response to MSF and atropine lowered basal PP levels and abolished the MSF response. Neither insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), nor glucagon-like peptide-1 (GLP-1) levels changed in response to MSF or atropine. Glucagon and ghrelin levels were markedly attenuated by atropine prior to and during the clamp: at t = 105 min on the atropine (ATR) + clamp (CLA) + MSF compared with the saline (SAL) + CLA and SAL + CLA + MSF days; baseline subtracted glucagon levels were -10.7 +/- 1.1 vs. -4.0 +/- 1.1 and -4.7 +/- 1.9 pmol/l (means +/- SE), P < 0.0001, respectively; corresponding baseline subtracted ghrelin levels were 303 +/- 36 vs. 39 +/- 38 and 3.7 +/- 21 pg/ml (means +/- SE), P < 0.0001. Glucagon and ghrelin levels were unaffected by MSF. Despite adequate PP responses, a cephalic phase response was absent for insulin, glucagon, GLP-1, GIP, and ghrelin. PMID- 26492922 TI - Nkx2.2 is expressed in a subset of enteroendocrine cells with expanded lineage potential. AB - There are two major stem cell populations in the intestinal crypt region that express either Bmi1 or Lgr5; however, it has been shown that other populations in the crypt can regain stemness. In this study, we demonstrate that the transcription factor NK2 homeobox 2 (Nkx2.2) is expressed in enteroendocrine cells located in the villus and crypt of the intestinal epithelium and is coexpressed with the stem cell markers Bmi1 and Lgr5 in a subset of crypt cells. To determine whether Nkx2.2-expressing enteroendocrine cells display cellular plasticity and stem cell potential, we performed genetic lineage tracing of the Nkx2.2-expressing population using Nkx2.2(Cre/+);R26RTomato mice. These studies demonstrated that Nkx2.2+ cells are able to give rise to all intestinal epithelial cell types in basal conditions. The proliferative capacity of Nkx2.2 expressing cells was also demonstrated in vitro using crypt organoid cultures. Injuring the intestine with irradiation, systemic inflammation, and colitis did not enhance the lineage potential of Nkx2.2-expressing cells. These findings demonstrate that a rare mature enteroendocrine cell subpopulation that is demarcated by Nkx2.2 expression display stem cell properties during normal intestinal epithelial homeostasis, but is not easily activated upon injury. PMID- 26492923 TI - Long-term CD4 lymphopenia is associated with accelerated decline of kidney allograft function. AB - BACKGROUND: Persistent CD4 T-cell lymphopenia after kidney transplantation has been associated with an increased occurrence of opportunistic infections, malignancies and even mortality, but studies have focussed only on the first few years after kidney transplantation. In this study, we investigated the risk factors and clinical significance of long-term profound CD4 lymphopenia detected >=10 years after renal transplantation. METHODS: Between 2007 and 2010, 6206 CD4 T-cell counts, including 1507 counts <300/mm(3), were identified in an active cohort of 1876 kidney transplant patients. We identified 27 HIV-negative lymphopenic kidney transplant recipients out of 513 patients with graft survival over 10 years. We compared this cohort to 54 non-lymphopenic controls matched for the date of kidney transplantation. RESULTS: The prevalence of CD4 lymphopenia 10 years after transplantation was 5.3%. CD4 T-cell lymphopenia was associated with significantly lower thymic output and with B-cell lymphopenia (P < 0.05). The duration of pre-transplant dialysis, but not the use of lymphopenic induction or recipient age, was significantly associated with a persistent CD4 lymphopenia (6.1 versus 3.0 years, P = 0.008). CD4 lymphopenia was associated with a higher frequency of cancer (50 versus 29.6%, P = 0.047). Most strikingly, long-term lymphopenia was significantly and independently associated with an accelerated decline in renal allograft function (P = 0.005), despite a similar rate of biopsy proven acute rejection and comparable immunosuppression. CONCLUSIONS: Our study shows an association between long-term CD4 T-cell lymphopenia in kidney recipients and malignancy and an accelerated decline of kidney allograft function. PMID- 26492924 TI - Haemodiafiltration and mortality in end-stage kidney disease patients: a pooled individual participant data analysis from four randomized controlled trials. AB - BACKGROUND: Mortality rates remain high for haemodialysis (HD) patients and simply increasing the HD dose to remove more small solutes does not improve survival. Online haemodiafiltration (HDF) provides additional clearance of larger toxins compared with standard HD. Randomized controlled trials (RCTs) comparing HDF with conventional HD on all-cause and cause-specific mortality in end-stage kidney disease (ESKD) patients reported inconsistent results and were at high risk of bias. We conducted a pooled individual participant data analysis of RCTs to provide the most reliable evidence to date on the effects of HDF on mortality outcomes in ESKD patients. METHODS: Individual participant data were used from four trials that compared online HDF with HD and were designed to examine the effects of HDF on mortality endpoints. Bias by informative censoring of patients was resolved. Hazard ratios (HRs) and 95% confidence intervals (95% CI) comparing the effect of online HDF versus HD on all-cause and cause-specific mortality were calculated using the Cox proportional hazard regression models. The relationship between convection volume and the study outcomes was examined by delivered convection volume standardized to body surface area. RESULTS: After a median follow-up of 2.5 years (Q1-Q3: 1.9-3.0), 769 of the 2793 participants had died (292 cardiovascular deaths). Online HDF reduced the risk of all-cause mortality by 14% (95% CI: 1%; 25%) and cardiovascular mortality by 23% (95% CI: 3%; 39%). There was no evidence for a differential effect in subgroups. The largest survival benefit was for patients receiving the highest delivered convection volume [>23 L per 1.73 m(2) body surface area (BSA) per session], with a multivariable-adjusted HR of 0.78 (95% CI: 0.62; 0.98) for all-cause mortality and 0.69 (95% CI: 0.47; 1.00) for cardiovascular disease mortality. CONCLUSIONS: This pooled individual participant analysis on the effects of online HDF compared with conventional HD indicates that online HDF reduces the risk of mortality in ESKD patients. This effect holds across a variety of important clinical subgroups of patients and is most pronounced for those receiving a higher convection volume normalized to BSA. PMID- 26492925 TI - Differences in survival on chronic dialysis treatment between ethnic groups in Denmark: a population-wide, national cohort study. AB - BACKGROUND: In Western countries, black and Asian dialysis patients experience better survival compared with white patients. The aim of this study is to compare the survival of native Danish dialysis patients with that of dialysis patients originating from other countries and to explore the association between the duration of residence in Denmark before the start of dialysis and the mortality on dialysis. METHODS: We performed a population-wide national cohort study of incident chronic dialysis patients in Denmark (>=18 years old) who started dialysis between 1995 and 2010. RESULTS: In total, 8459 patients were native Danes, 344 originated from other Western countries, 79 from North Africa or West Asia, 173 from South or South-East Asia and 54 from sub-Saharan Africa. Native Danes were more likely to die on dialysis compared with the other groups (crude incidence rates for mortality: 234, 166, 96, 110 and 53 per 1000 person-years, respectively). Native Danes had greater hazard ratios (HRs) for mortality compared with the other groups {HRs for mortality adjusted for sociodemographic and clinical characteristics: 1.32 [95% confidence interval (CI) 1.14-1.54]; 2.22 [95% CI 1.51-3.23]; 1.79 [95% CI 1.41-2.27]; 2.00 [95% CI 1.10-3.57], respectively}. Compared with native Danes, adjusted HRs for mortality for Western immigrants living in Denmark for <=10 years, >10 to <=20 years and >20 years were 0.44 (95% CI 0.27-0.71), 0.56 (95% CI 0.39-0.82) and 0.86 (95% CI 0.70-1.04), respectively. For non-Western immigrants, these HRs were 0.42 (95% CI 0.27-0.67), 0.52 (95% CI 0.33-0.80) and 0.48 (95% CI 0.35-0.66), respectively. CONCLUSIONS: Incident chronic dialysis patients in Denmark originating from countries other than Denmark have a better survival compared with native Danes. For Western immigrants, this survival benefit declines among those who have lived in Denmark longer. For non-Western immigrants, the survival benefit largely remains over time. PMID- 26492926 TI - Association between pregnancy-associated plasma protein-A levels in the first trimester and gestational diabetes mellitus in Chinese women. AB - INTRODUCTION: Several studies have shown that women with pre-existing diabetes mellitus have significantly lower pregnancy-associated plasma protein-A levels than those without. This study aimed to evaluate whether first-trimester pregnancy-associated plasma protein-A multiple of median is associated with gestational diabetes mellitus in Chinese pregnant women. METHODS: This prospectively collected case series was conducted in a regional hospital in Hong Kong. All consecutive Chinese women with a singleton pregnancy who attended the hospital for their first antenatal visit (before 14 weeks' gestation) from April to July 2014 were included. Pregnancy-associated plasma protein-A multiple of median was compared between the gestational diabetic (especially for early-onset gestational diabetes) and non-diabetic groups. The correlation between pregnancy associated plasma protein-A level and glycosylated haemoglobin level in women with gestational diabetes was also examined. RESULTS: Of the 520 women recruited, gestational diabetes was diagnosed in 169 (32.5%). Among them, 43 (25.4%) had an early diagnosis, and 167 (98.8%) with the disease were managed by diet alone. The gestational diabetic group did not differ significantly to the non-diabetic group in pregnancy-associated plasma protein-A (0.97 vs 0.99, P=0.40) or free beta human chorionic gonadotrophin multiple of median (1.05 vs 1.02, P=0.29). Compared with the non-gestational diabetic group, women with early diagnosis of gestational diabetes had a non-significant reduction in pregnancy-associated plasma protein-A multiple of median (median, interquartile range: 0.86, 0.57-1.23 vs 0.99, 0.67-1.44; P=0.11). Pregnancy-associated plasma protein-A and glycosylated haemoglobin levels were not correlated in women with gestational diabetes (r=0.027; P=0.74). CONCLUSIONS: Chinese women with non-insulin-dependent gestational diabetes did not exhibit significant changes to pregnancy-associated plasma protein-A multiple of median nor a correlation between pregnancy associated plasma protein-A with glycosylated haemoglobin levels. Pregnancy associated plasma protein-A multiple of median was not predictive of non-insulin dependent gestational diabetes or early onset of gestational diabetes. There was a high prevalence of gestational diabetes in the Chinese population. PMID- 26492928 TI - Guidelines on PML risk stratification and diagnosis in patients with MS treated with natalizumab: so far so good? PMID- 26492927 TI - Partial nephrectomy for T1 renal cancer can achieve an equivalent oncological outcome to radical nephrectomy with better renal preservation: the way to go. AB - INTRODUCTION: Patients who undergo partial nephrectomy have been shown to be at decreased risk of renal impairment compared with radical nephrectomy. We examined the oncological outcome of patients in our centre who underwent partial or radical nephrectomy for T1 renal cancer (7 cm or smaller), and compared the likelihood of developing chronic kidney disease. METHODS: This historical cohort study with internal comparison was conducted in a tertiary hospital in Hong Kong. A cohort of 86 patients with solitary T1 renal cancer and a normal contralateral kidney who underwent radical (38 patients) or partial (48 patients) nephrectomy between January 2005 and December 2010 was included. The overall and cancer-free survival, change in glomerular filtration rate, and new onset of chronic kidney disease were compared between the radical and partial nephrectomy groups. RESULTS: A total of 32 (84%) radical nephrectomy patients and 43 (90%) partial nephrectomy patients were alive by 31 December 2012. The mean follow-up was 43.5 (standard deviation, 22.4) months. There was no significant difference in overall survival (P=0.29) or cancer-free survival (P=0.29) between the two groups. Both groups enjoyed good oncological outcome with no recurrence in the partial nephrectomy group. Overall, 18 (21%) patients had pre-existing chronic kidney disease. The partial nephrectomy group had a significantly smaller median reduction in glomerular filtration rate (12.6% vs 35.4%; P<0.001), and radical nephrectomy carried a significantly higher risk of developing chronic kidney disease (hazard ratio=5.44; 95% confidence interval, 1.26-23.55; P=0.02). CONCLUSIONS: Compared with radical nephrectomy, partial nephrectomy can prevent chronic kidney disease and still achieve an excellent oncological outcome for T1 renal tumours, in particular T1a tumours and tumours with a low R.E.N.A.L. score. PMID- 26492929 TI - In two minds: executive functioning versus theory of mind in behavioural variant frontotemporal dementia. AB - BACKGROUND: The relationship of executive function (EF) and theory of mind (ToM) deficits in neurodegeneration is still debated. There is contradicting evidence as to whether these cognitive processes are overlapping or distinct, which has clear clinical relevance for the evaluation of their associated clinical symptoms. AIM: To investigate the relationship of EF and ToM deficits via a data driven approach in a large sample of patients with behavioural variant frontotemporal dementia (bvFTD). METHODS: Data of 46 patients with bvFTD were employed in a hierarchical cluster analysis to determine the similarity of variance between different EF measures (verbal abstraction, verbal initiation, motor programming, sensitivity to interference, inhibitory control, visual abstraction, flexibility, working memory/attention) and ToM (faux pas). RESULTS: Overall results showed that EF measures were clustered separately from the ToM measure. A post hoc analysis revealed a more complex picture where selected ToM subcomponents (empathy; intention) showed a relationship to specific EF measures (verbal abstraction; working memory/attention), whereas the remaining EF and ToM subcomponents were separate. CONCLUSIONS: Taken together, these findings suggest that EF and ToM are distinct components; however, ToM empathy and intention subcomponents might share some functions with specific EF processes. This has important implications for guiding diagnostic assessment of these deficits in clinical conditions. PMID- 26492930 TI - Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. AB - The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naive patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk. PMID- 26492931 TI - Characterizing social environment's association with neurocognition using census and crime data linked to the Philadelphia Neurodevelopmental Cohort. AB - BACKGROUND: The contribution of 'environment' has been investigated across diverse and multiple domains related to health. However, in the context of large scale genomic studies the focus has been on obtaining individual-level endophenotypes with environment left for future decomposition. Geo-social research has indicated that environment-level variables can be reduced, and these composites can then be used with other variables as intuitive, precise representations of environment in research. METHOD: Using a large community sample (N = 9498) from the Philadelphia area, participant addresses were linked to 2010 census and crime data. These were then factor analyzed (exploratory factor analysis; EFA) to arrive at social and criminal dimensions of participants' environments. These were used to calculate environment-level scores, which were merged with individual-level variables. We estimated an exploratory multilevel structural equation model (MSEM) exploring associations among environment- and individual-level variables in diverse communities. RESULTS: The EFAs revealed that census data was best represented by two factors, one socioeconomic status and one household/language. Crime data was best represented by a single crime factor. The MSEM variables had good fit (e.g. comparative fit index = 0.98), and revealed that environment had the largest association with neurocognitive performance (beta = 0.41, p < 0.0005), followed by parent education (beta = 0.23, p < 0.0005). CONCLUSIONS: Environment-level variables can be combined to create factor scores or composites for use in larger statistical models. Our results are consistent with literature indicating that individual-level socio-demographic characteristics (e.g. race and gender) and aspects of familial social capital (e.g. parental education) have statistical relationships with neurocognitive performance. PMID- 26492932 TI - Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. AB - Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families. PMID- 26492933 TI - Discordance in lymphoid tissue recovery following stem cell transplantation in rhesus macaques: an in vivo imaging study. AB - Ionizing irradiation is used routinely to induce myeloablation and immunosuppression. However, it has not been possible to evaluate the extent of ablation without invasive biopsy. For lymphoid recovery, peripheral blood (PB) lymphocytes (PBLs) have been used for analysis, but they represent <2% of cells in lymphoid tissues (LTs). Using a combination of single-photon emission computed tomography imaging and a radiotracer ((99m)Tc-labeled rhesus immunoglobulin G1 anti-CD4R1 (Fab')2), we sequentially imaged CD4(+) cell recovery in rhesus macaques following total body irradiation (TBI) and reinfusion of vector transduced, autologous CD34(+) cells. Our results present for the first time a sequential, real-time, noninvasive method to evaluate CD4(+) cell recovery. Importantly, despite myeloablation of circulating leukocytes following TBI, total depletion of CD4(+) lymphocytes in LTs such as the spleen is not achieved. The impact of TBI on LTs and PBLs is discordant, in which as few as 32.4% of CD4(+) cells were depleted from the spleen. In addition, despite full lymphocyte recovery in the spleen and PB, lymph nodes have suboptimal recovery. This highlights concerns about residual disease, endogenous contributions to recovery, and residual LT damage following ionizing irradiation. Such methodologies also have direct application to immunosuppressive therapy and other immunosuppressive disorders, such as those associated with viral monitoring. PMID- 26492934 TI - Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease free survival in IGHV-mutated chronic lymphocytic leukemia. AB - Accurate identification of patients likely to achieve long-progression-free survival (PFS) after chemoimmunotherapy is essential given the availability of less toxic alternatives, such as ibrutinib. Fludarabine, cyclophosphamide, and rituximab (FCR) achieved a high response rate, but continued relapses were seen in initial reports. We reviewed the original 300 patient phase 2 FCR study to identify long-term disease-free survivors. Minimal residual disease (MRD) was assessed posttreatment by a polymerase chain reaction-based ligase chain reaction assay (sensitivity 0.01%). At the median follow-up of 12.8 years, PFS was 30.9% (median PFS, 6.4 years). The 12.8-year PFS was 53.9% for patients with mutated immunoglobulin heavy chain variable (IGHV) gene (IGHV-M) and 8.7% for patients with unmutated IGHV (IGHV-UM). 50.7% of patients with IGHV-M achieved MRD negativity posttreatment; of these, PFS was 79.8% at 12.8 years. A plateau was seen on the PFS curve in patients with IGHV-M, with no relapses beyond 10.4 years in 42 patients (total follow-up 105.4 patient-years). On multivariable analysis, IGHV-UM (hazard ratio, 3.37 [2.18-5.21]; P < .001) and del(17p) by conventional karyotyping (hazard ratio, 7.96 [1.02-61.92]; P = .048) were significantly associated with inferior PFS. Fifteen patients with IGHV-M had 4-color MRD flow cytometry (sensitivity 0.01%) performed in peripheral blood, at a median of 12.8 years posttreatment (range, 9.5-14.7). All were MRD-negative. The high rate of very long-term PFS in patients with IGHV-M after FCR argues for the continued use of chemoimmunotherapy in this patient subgroup outside clinical trials; alternative strategies may be preferred in patients with IGHV-UM, to limit long term toxicity. PMID- 26492935 TI - Anti-mouse FcgammaRIV antibody 9E9 also blocks FcgammaRIII in vivo. PMID- 26492936 TI - Synthesis of a Novel Quinoline Skeleton Introduced Cationic Polyfluorene Derivative for Multimodal Antimicrobial Application. AB - A new functional polyfluorene derivative containing quinoline skeleton and quarternary ammonium group (QAG) modified side chains (PFPQ) was synthesized and characterized. The multimodal antimicrobial effect toward Gram-negative E. coli was achieved by the dark toxicity resulting from the quinoline skeleton, QAG, and light toxicity resulting from reactive oxygen species (ROS) produced by the main backbone of PFPQ under white light. The mechanism of interaction between PFPQ and bacteria was also demonstrated. PFPQ bound to E. coli mainly through electrostatic interactions causing nearly 50% bacterial death in the absence of light irradiation, and the huge capability of PFPQ to generate ROS under white light opened another bactericidal mode. The killing efficiency was more than 99% upon relatively mild irradiation under white light (400-800 nm) with a light dose of 18 J.cm(-2). PFPQ with the incorporation of quinoline into the backbones will provide a new versatile strategy to achieve the multimodal antimicrobial effect to fight against resistant bacteria. PMID- 26492937 TI - Discovery of Chemical Inhibitors of Human Bromodomains. PMID- 26492938 TI - Characteristics of clinical studies of summer acupoint herbal patching: a bibliometric analysis. AB - BACKGROUND: Summer acupoint herbal patching (SAHP) has been widely used in China for thousands of years. This bibliometric analysis aims to provide a comprehensive review of the characteristics of clinical studies on SAHP for any condition. METHODS: We included clinical studies such as randomized clinical trials (RCTs), controlled clinical studies (CCTs), case series (CSs), case reports (CRs), and cross-sectional studies on SAHP for any condition. Six databases were searched from date of inception to March 2015. Bibliometric information and study details such as study type, characteristics of participants, details of the intervention and comparison, and outcome were extracted and analyzed. RESULTS: A total of 937 clinical studies were identified and which were published between 1977 and 2015. This included 404 RCTs, 52 CCTs, 458 CSs, 19 CRs and 4 cross-sectional studies and involved 232,138 participants aged 2 to 90 years from two countries. Almost all studies were from China (936, 99.89%). The five conditions most commonly treated by SAHP were asthma (401, 42.80%), chronic bronchitis (146, 15.58%), allergic rhinitis (117, 12.49%), chronic obstructive pulmonary disease (73, 7.79%), and recurrent respiratory tract infection (42, 4.48%). Among 502 controlled studies, the majority compared SAHP alone with different controls (16 categories, 275 comparisons). The most commonly used controls were western medicine, placebo, traditional Chinese medicine, no treatment and non-pharmaceutical traditional Chinese therapies. Composite outcome measures were the most frequently reported outcome (512, 69.19%). CONCLUSION: A substantial amount of research on SAHP has been published in China and which predominantly focuses on respiratory conditions. The findings from this study can be used to inform further research by highlighting areas of greatest impact for SAHP. PMID- 26492940 TI - Formation of protective deposits by anti-erosive toothpastes-A microscopic study on enamel with artificial defects. AB - This study investigated formation of protective deposits on the enamel surface after application of several anti-erosive toothpastes with different active ingredients. NaF-containing Sensodyne Pronamel, SnCl2 /F-based Elmex Erosion Protection and calcium phosphate-based BioRepair Plus Sensitivity Control, SensiShield and Enamel Care toothpastes with claimed anti-erosive properties were tested. Artificial saliva and Elmex Erosion Protection mouth rinse served as control groups. The toothpastes were applied 30 times by a toothbrush for 2 min per day, mouth rinse for 30 s on polished enamel of thirty five human molars (n = 5) with series of five rhomboid-shaped indents of various length prepared by a Knoop indentor. After 15 and 30 applications, the shape of the indents and surface morphology was characterised using light and scanning electron microscopy. At the end of treatment, the samples were exposed to 0.2 wt. % citric acid (pH 3.30) to test resistance of the treated enamel to erosion. Pronounced differences were observed between protective properties of the toothpastes. While Sensodyne Pronamel and BioRepair Plus Sensitivity Control did not produce any protective deposits, Enamel Care formed a compact layer of deposits which protected the enamel surface against erosion. With Elmex Erosion Protection and SensiShield fractured indent edges and scratches on the treated enamel suggested that their abrasive properties prevailed over ability of active ingredients to form deposits. These results revealed that toothpastes with strong potential to form acid-resistant deposits on the enamel surface and of low abrasivity should be used for effective prevention of enamel erosion. SCANNING 38:380-388, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26492939 TI - Low free drug concentration prevents inhibition of F508del CFTR functional expression by the potentiator VX-770 (ivacaftor). AB - BACKGROUND AND PURPOSE: The most common cystic fibrosis (CF) mutation F508del inhibits the gating and surface expression of CFTR, a plasma membrane anion channel. Optimal pharmacotherapies will probably require both a 'potentiator' to increase channel open probability and a 'corrector' that improves folding and trafficking of the mutant protein and its stability at the cell surface. Interaction between CF drugs has been reported but remains poorly understood. EXPERIMENTAL APPROACH: CF bronchial epithelial cells were exposed to the corrector VX-809 (lumacaftor) and potentiator VX-770 (ivacaftor) individually or in combination. Functional expression of CFTR was assayed as the forskolin stimulated short-circuit current (Isc ) across airway epithelial monolayers expressing F508del CFTR. KEY RESULTS: The potentiated Isc response during forskolin stimulation was increased sixfold after pretreatment with VX-809 alone and reached ~11% that measured across non-CF monolayers. VX-770 (100 nM) and genistein (50 MUM) caused similar levels of potentiation, which were not additive and were abolished by the CFTR inhibitor CFTRinh -172. The unbound fraction of VX 770 in plasma was 0.13 +/- 0.04%, which together with previous measurements in patients given 250 mg p.o. twice daily, suggests a peak free plasma concentration of 1.5-8.5 nM. Chronic exposure to high VX-770 concentrations (>1 MUM) inhibited functional correction by VX-809 but not in the presence of physiological protein levels (20-40 mg.mL(-1) ). Chronic exposure to a low concentration of VX-770 (100 nM) together with VX-809 (1 MUM) also did not reduce the forskolin-stimulated Isc , relative to cells chronically exposed to VX-809 alone, provided it was assayed acutely using the same, clinically relevant concentration of potentiator. CONCLUSIONS AND IMPLICATIONS: Chronic exposure to clinically relevant concentrations of VX-770 did not reduce F508del CFTR function. Therapeutic benefit of VX-770 + VX-809 (Orkambi) is probably limited by the efficacy of VX 809 rather than by inhibition by VX-770. PMID- 26492941 TI - Synthesis and Evaluation of Hybrid Structures Composed of Two Glucosylceramide Synthase Inhibitors. AB - Glucosylceramide metabolism and the enzymes involved have attracted significant interest in medicinal chemistry, because aberrations in the levels of glycolipids that are derived from glucosylceramide are causative in a range of human diseases including lysosomal storage disorders, type 2 diabetes, and neurodegenerative diseases. Selective modulation of one of the glycoprocessing enzymes involved in glucosylceramide metabolism-glucosylceramide synthase (GCS), acid glucosylceramidase (GBA1), or neutral glucosylceramidase (GBA2)-is therefore an attractive research objective. In this study we took two established GCS inhibitors, one based on deoxynojirimycin and the other a ceramide analogue, and merged characteristic features to obtain hybrid compounds. The resulting 39 compound library does not contain new GCS inhibitors; however, a potent (200 nm) GBA1 inhibitor was identified that has little activity toward GBA2 and might therefore serve as a lead for further biomedical development as a selective GBA1 modulator. PMID- 26492942 TI - Concentration-mediated multicolor fluorescence polymer carbon dots. AB - Polymer dots (PDs) showing concentration-mediated multicolor fluorescence were first prepared from sulfuric acid-treated dehydration of Pluronic(r) F-127 in a single step. Pluronic-based PDs (P-PDs) showed high dispersion stability in solvent media and exhibited a fluorescence emission that was widely tunable from red to blue by adjusting both the excitation wavelengths and the P-PD concentration in an aqueous solution. This unique fluorescence behavior of P-PDs might be a result of cross-talk in the fluorophores of the poly(propylene glycol) rich core inside the P-PD through either energy transfer or charge transfer. Reconstruction of the surface energy traps of the P-PDs mediated through aggregation may lead to a new generation of carbon-based nanomaterials possessing a fluorescence emission and tunable by adjusting the concentration. These structures may be useful in the design of multifunctional carbon nanomaterials with tunable emission properties according to a variety of internal or external stimuli. PMID- 26492943 TI - Secondary prevention after ischaemic stroke: the ASPIRE-S study. AB - BACKGROUND: Survivors of ischaemic stroke (IS) are at high-risk for future vascular events. Comprehensive information on the adequacy of secondary prevention after IS is lacking despite the knowledge that appropriate secondary prevention improves long-term patient outcomes. ASPIRE-S (Action on Secondary Prevention Interventions and Rehabilitation in Stroke) aimed to prospectively assess secondary prevention in patients 6 months following IS. METHODS: Consenting patients admitted with IS to three Dublin hospitals were recruited over 1 year, from October 2011. At 6 months post IS a comprehensive assessment was completed, modelled on the EUROASPIRE protocol for evaluation of the adequacy of secondary prevention in post-discharge cardiac patients. This assessment included measurements of blood pressure, body mass index and fasting lipid and glucose profiles. Secondary preventive medications and smoking status were also documented. RESULTS: Three hundred two patients (58 % male) participated, of whom 256 (85 %) were followed-up at 6 months. Mean age was 69 years (range 22-95). At follow-up, 68 % of patients had a BMI >25 kg/m(2) and 16.4 % were still smoking. Almost two-thirds (63.4 %) had a blood pressure >140/90 and 23 % had low-density lipoprotein >2.5 mmol/L. 28 % of diabetic patients had HbA1c >= 7 %. Ninety seven percent of patients were on anti-platelet and/or anticoagulant therapy. Of those with atrial fibrillation, 82 % were anti-coagulated (mean INR of 2.4). Ninety five percent were on lipid-lowering therapy and three-quarters were on anti hypertensive therapy. CONCLUSION: This prospective multi-centre survey of IS patients demonstrated a high prevalence of remaining modifiable risk factors at 6 months post stroke, despite the widespread prescription of secondary preventive medications. There is scope to improve preventive measures after IS (in particular blood pressure) by incorporating evidence-based guidelines into quality assurance cycles in stroke care. PMID- 26492945 TI - Identification, modeling, and characterization studies of Tetrahymena thermophila myosin FERM domains suggests a conserved core fold but functional differences. AB - Myosins (MYO) define a superfamily of motor proteins which facilitate movement along cytoskeletal actin filaments in an ATP-dependent manner. To date, over 30 classes of myosin have been defined that vary in their roles and distribution across different taxa. The multidomain tail of myosin is responsible for the observed functional differences in different myosin classes facilitating differential binding to different cargos. One domain found in this region, the FERM domain, is found in several diverse proteins and is involved in many biological functions ranging from cell adhesion and actin-driven cytoskeleton assembly to cell signaling. Recently, new classes of unconventional myosin have been identified in Tetrahymena thermophila. In this study, we have identified, modeled, and characterized eight FERM domains from the unconventional T. thermophila myosins as their complete functional MyTH4-FERM cassettes. Our results reveal notable sequence, structural, and electrostatic differences between T. thermophila and other characterized FERM domains. Specifically, T. thermophila FERM domains contain helical inserts or extensions, which contribute to significant differences in surface electrostatic profiles of T. thermophila myosin FERMs when compared to the conventional FERM domains. Analyses of the modeled domains reveal differences in key functional residues as well as phosphoinositide-binding signatures and affinities. The work presented here broadens the scope of our understanding of myosin classes and their inherent functions, and provides a platform for experimentalists to design rational experimental studies to test the functional roles for T. thermophila myosins. PMID- 26492946 TI - Clinical perspectives on osteogenesis imperfecta versus non-accidental injury. AB - Although non-accidental injuries (NAI) are more common in cases of unexplained fractures than rare disorders such as osteogenesis imperfecta (OI), ruling out OI and other medical causes of fracture is always indicated. The majority of OI patients can be diagnosed with the help of family history, physical examination, and radiographic findings. In particular, there are a few radiological findings which are seen more commonly in NAI than in OI which may help guide clinician considerations regarding the probability of either of these diagnoses. At the same time, molecular testing still merits careful consideration in cases with unexplained fractures without obvious additional signs of abuse. PMID- 26492944 TI - Intravenous thrombolysis for acute ischaemic stroke in the elderly: data from the Baden-Wuerttemberg stroke registry. AB - BACKGROUND AND PURPOSE: In Europe intravenous thrombolysis (IVT) for ischaemic stroke is still not approved for patients aged >80 years. However, elderly patients are frequently treated based on individual decision making. In a retrospective observational study a consecutive and prospective stroke registry in southwest Germany was analysed. METHODS: The data registry collected 101,349 patients with ischaemic stroke hospitalized from January 2008 to December 2012. Of these, 38,575 (38%) were aged 80 years and older and 10 286 (10.1%) underwent IVT. Favourable outcome at discharge was defined as modified Rankin Scale (mRS) <=1 or not worse than prior to stroke. Multiple logistic regression models stratified by 10-year age groups were used to assess the relationship between IVT and mRS at discharge, adjusted for patient characteristics, admitting facility and length of hospital stay. RESULTS: The highest IVT rate was 15% in patients aged <50 years, with a continuous decline down to 8% in patients aged >=90 years. Adjusted odds ratios and 95% confidence intervals for patients 80-89 years of age were 2.20 (1.95-2.47) (P < 0.0001) and 1.25 (0.88-1.78) (P = 0.21) for patients >90 years of age, compared to patients of the same age decade not treated with IVT. CONCLUSIONS: The evidence from routine hospital care in southwest Germany indicates that IVT is an effective treatment also for aged patients with ischaemic stroke in an age range between 80 and 89 years. Although no clear evidence for the effectiveness of IVT beyond 90 years was found, treatment should also be carefully considered in these patients. High age should not discourage from treatment. PMID- 26492948 TI - The Renaissance of an Old Problem: Highly Regioselective Carboxylation of 2 Alkynyl Bromides with Carbon Dioxide. AB - A steric effect-controlled, zinc-mediated carboxylation of different 2-alkynyl bromides under an atmospheric pressure of CO2 has been developed by careful tuning of different reaction parameters, including the metal, solvent, temperature, and additive. 2-Substituted 2,3-allenoic acids were afforded from primary 2-alkynyl bromides, whereas the carboxylation of secondary 2-alkynyl bromides yielded 3-alkynoic acids in decent yields. A rationale for the observed regioselectivity has been proposed. PMID- 26492947 TI - Spectral Doppler of the Hepatic Veins in Rate, Rhythm, and Conduction Disorders. AB - Doppler interrogation of blood flow in the hepatic veins (HVs) provides valuable information regarding a wide spectrum of pathological processes that affect the right heart. Systematic analysis of the direction, velocity, and phasicity of the HV waveforms allows one to distinguish normal from abnormal patterns and provides important diagnostic information. Abnormalities in heart rate, rhythm, and intracardiac conduction are commonly encountered during echocardiographic studies. Sinus bradycardia and tachycardia, bradyarrhythmias and tachyarrhythmias as well as atrioventricular conduction disturbances influence the flow pattern in the HVs and may pose a challenge to the correct interpretation of the HV Doppler. Alterations in HV flow that are induced by the electrical abnormalities may mimic right heart pathology. Awareness of these alterations allows one to avoid misinterpretation of the HV signal, helps diagnose the underlying rhythm or conduction abnormality, and permits assessment of the impact on right heart hemodynamics. PMID- 26492949 TI - Surface-Specific Functionalization of Nanoscale Metal-Organic Frameworks. AB - A method for modifying the external surfaces of a series of nanoscale metal organic frameworks (MOFs) with 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) is presented. A series of zirconium-based nanoMOFs of the same topology (UiO-66, UiO 67, and BUT-30) were synthesized, isolated as aggregates, and then conjugated with DOPA to create stably dispersed colloids. BET surface area analysis revealed that these structures maintain their porosity after surface functionalization, providing evidence that DOPA functionalization only occurs on the external surface. Additionally, dye-labeled ligand loading studies revealed that the density of DOPA on the surface of the nanoscale MOF correlates to the density of metal nodes on the surface of each MOF. Importantly, the surface modification strategy described will allow for the general and divergent synthesis and study of a wide variety of nanoscale MOFs as stable colloidal materials. PMID- 26492951 TI - Single-photon non-linear optics with a quantum dot in a waveguide. AB - Strong non-linear interactions between photons enable logic operations for both classical and quantum-information technology. Unfortunately, non-linear interactions are usually feeble and therefore all-optical logic gates tend to be inefficient. A quantum emitter deterministically coupled to a propagating mode fundamentally changes the situation, since each photon inevitably interacts with the emitter, and highly correlated many-photon states may be created. Here we show that a single quantum dot in a photonic-crystal waveguide can be used as a giant non-linearity sensitive at the single-photon level. The non-linear response is revealed from the intensity and quantum statistics of the scattered photons, and contains contributions from an entangled photon-photon bound state. The quantum non-linearity will find immediate applications for deterministic Bell state measurements and single-photon transistors and paves the way to scalable waveguide-based photonic quantum-computing architectures. PMID- 26492950 TI - Pycnogenol attenuates atherosclerosis by regulating lipid metabolism through the TLR4-NF-kappaB pathway. AB - Atherosclerosis is a leading cause of death worldwide and is characterized by lipid-laden foam cell formation. Recently, pycnogenol (PYC) has drawn much attention because of its prominent effect on cardiovascular disease (CVD). However, its protective effect against atherosclerosis and the underlying mechanism remains undefined. Here PYC treatment reduced areas of plaque and lipid deposition in atherosclerotic mice, concomitant with decreases in total cholesterol and triglyceride levels and increases in HDL cholesterol levels, indicating a potential antiatherosclerotic effect of PYC through the regulation of lipid levels. Additionally, PYC preconditioning markedly decreased foam cell formation and lipid accumulation in lipopolysaccharide (LPS)-stimulated human THP 1 monocytes. A mechanistic analysis indicated that PYC decreased the lipid related protein expression of adipose differentiation-related protein (ADRP) and adipocyte lipid-binding protein (ALBP/aP2) in a dose-dependent manner. Further analysis confirmed that PYC attenuated LPS-induced lipid droplet formation via ADRP and ALBP expression through the Toll-like receptor 4 (TLR4) and nuclear factor-kappaB (NF-kappaB) pathway, because pretreatment with anti-TLR4 antibody or a specific inhibitor of NF-kappaB (PDTC) strikingly mitigated the LPS-induced increase in ADRP and ALBP. Together, our results provide insight into the ability of PYC to attenuate bacterial infection-triggered pathological processes associated with atherosclerosis. Thus PYC may be a potential lead compound for the future development of antiatherosclerotic CVD therapy. PMID- 26492952 TI - Metformin Attenuates Testosterone-Induced Prostatic Hyperplasia in Rats: A Pharmacological Perspective. AB - Benign prostatic hyperplasia (BPH) is uncontrolled proliferation of prostate tissue. Metformin, a widely prescribed anti-diabetic agent, possesses anticancer activity through induction of apoptotic signaling and cell cycle arrest. This study aimed to investigate the protective effect of metformin against experimentally-induced BPH in rats. Treatment with 500 and 1000 mg/kg metformin orally for 14 days significantly inhibited testosterone-mediated increase in the prostate weight &prostate index (prostate weight/body weight [mg/g]) and attenuated the pathological alterations induced by testosterone. Mechanistically, metformin significantly protected against testosterone-induced elevation of estrogen receptor-alpha (ER-alpha) and decrease of estrogen receptor-beta (ER beta) expression, with no significant effect of androgen receptor (AR) and 5alpha reductase expression. It decreased mRNA expression of IGF-1 and IGF-1R and protein expression ratio of pAkt/total Akt induced by testosterone. Furthermore, it significantly ameliorated testosterone-induced reduction of mRNA expression Bax/Bcl-2 ratio, P21 and phosphatase and tensin homolog (PTEN) and AMPK [PT-172] activity. In conclusion, these findings elucidate the effectiveness of metformin in preventing testosterone-induced BPH in rats. These results could be attributed, at least partly, to its ability to enhance expression ratio of ER beta/ER-alpha, decrease IGF-1, IGF-1R and pAkt expressions, increase P21, PTEN, Bax/Bcl-2 expressions and activate AMPK with a subsequent inhibition of prostate proliferation. PMID- 26492953 TI - The association of thiol/disulphide homeostasis and lipid accumulation index with cardiovascular risk factors in overweight adolescents with polycystic ovary syndrome. AB - OBJECTIVE: To assess thiol/disulphide homeostasis and lipid accumulation product index, and to determine whether they are associated with increased cardiovascular disease (CVD) risk or not in overweight adolescents with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: Education and Research Hospital. PATIENTS: Group 1: 43 overweight+PCOS, Group 2: 45 normal weight+PCOS, Group 3: 27 overweight adolescents and Group 4: 96 age-matched, normal weight healthy controls. INTERVENTIONS: Serum lipid profiles, hormonal parameters and thiol/disulphide homeostasis were measured. Lipid accumulation index (LAP index) and homeostasis model assessment (HOMA-IR) were calculated. MAIN OUTCOME MEASURES: The relation between thiol/disulphide homeostasis and LAP index, and increased CVD risk were evaluated in overweight adolescents with PCOS. RESULTS: Native and total thiol levels were significantly lower in overweight+PCOS adolescents when compared with both normal weight PCOS and control adolescents (P = 0.002). LAP index values were significantly higher in Group 1 when compared separately with the rest of the three groups (P < 0.001). Multivariable logistic regression analysis revealed serum total thiol levels of lower than 405.45 MUmol/l were independently associated with increased risk of CVD in overweight PCOS adolescents (OR: 1.019, 95% CI: 1.001-1.036). In addition, a LAP index greater than 21.54 was also associated with increased CVD risk in overweight PCOS adolescents (OR: 1.270, 95% CI: 1.174-1.374). CONCLUSION: In conclusion, we suggest that increased LAP index and decreased total thiol levels may contribute to the increased CVD risk in overweight adolescents with PCOS. PMID- 26492954 TI - Intensive insulin therapy implementation by means of planned versus emergent change approach. AB - BACKGROUND: Nurses' participation in decisions about new care procedures and protocols is potentially of benefit for patient outcomes. Whether nurses' participation in decisions is allowed in the implementation of innovations depends on the implementation approach used for the introduction. A planned change implementation approach does not allow it, an emergent change implementation approach does. AIM: To compare a planned change and an emergent change implementation approach to introduce an intensive insulin therapy to an intensive care unit (ICU). DESIGN: A prospective comparative study in an ICU in the Netherlands of two teams of nurses using either implementation approach. METHODS: Pre-introduction of the comparability of the two teams was assessed. The nurse compliance to the protocol was assessed as being nurses' behaviour according to the protocol and leading to acceptable glucose values. The effectiveness of the implementation was assessed by measuring the percentage of patients' glucose values within the target range, the occurrence of hypoglycaemic events and the time to glucose value normalization. Data were collected from December 2007 till January 2009. RESULTS: In the emergent change approach team there was better nurse compliance measurements than in the planned change approach team (83.5% vs 66,8% conform protocol), a better percentage of glucose values in the target range (53,5% vs 52.8%) and a shorter time to glucose value normalization. CONCLUSION: The implementation approach allowing nurse participation was associated with better nurse compliance and patient outcome measurements. The implementation approach did not conflict with introducing an evidence-based innovation. It was also associated with more effective adaptation of the protocol to changing circumstances. RELEVANCE FOR CLINICAL PRACTICE: When a new treatment requires adaptability to changing circumstances to be most effective, nurses' participation in decisions about the implementation of the treatment should be considered. PMID- 26492955 TI - Lewis Superacidic Ionic Liquids with Tricoordinate Borenium Cations. AB - The first examples of ionic liquids based on borenium cations, [BCl2 L](+), are reported. These compounds form highly Lewis acidic liquids under solvent-free conditions. Their acidity was quantified by determining the Gutmann acceptor number (AN). Extremely high ANs were recorded (up to AN = 182, delta31P = 120 ppm), demonstrating that these borenium ionic liquids are the strongest Lewis superacids reported to date, with the acidity enhanced by the ionic liquid environment. PMID- 26492956 TI - Pricing and sales tax collection policies for e-cigarette starter kits and disposable products sold online. AB - BACKGROUND: Previous studies have examined marketing characteristics of e cigarettes sold online and others have examined e-cigarettes pricing in retail (non-Internet) settings. This study expands on these findings by examining pricing and marketing characteristics of interest among e-cigarette online vendors. METHODS: Structured web searches were conducted from August-September 2014 to identify popular e-cigarette Internet vendors. We then collected pricing data (e-cigarette starter kits and disposables), sales tax collection policies and other vendor marketing characteristics. Average price for each product category was then compared with marketing characteristics using linear regression for continuous variables and independent t-tests for binary variables. RESULTS: Our searches yielded 44 e-cigarette Internet vendors of which 77% (n = 34) sold a total of 238 starter kit offerings (Mprice = $55.89). Half (n = 22) sold disposable types of e-cigarettes (Mprice = $7.17 p/e-cigarette) at a price lower than reported elsewhere in retail settings. Average disposable e-cigarette prices were also significantly higher for vendors displaying more health warning notices (P = 0.001). Only 46% disclosed sales tax collection policies and only 39% collected sales tax in their state of business. CONCLUSIONS: This study expands on current understanding of e-cigarette pricing and availability online and finds variation in e-cigarette pricing may be influenced by type of product, use of online health warnings and vendor sales tax collection policies. It also finds that e-cigarette online access and availability may be impacted by a combination of pricing and marketing strategies uniquely different from e-cigarette retail settings that requires further study and targeted policy-making. [Cuomo RE, Miner A, Mackey TK. Pricing and sales tax collection policies for e-cigarette starter kits and disposable products sold online. Drug Alcohol Rev 2015]. PMID- 26492957 TI - Ba(Zn(1-2x)MnxCux)2As2: A Bulk Form Diluted Ferromagnetic Semiconductor with Mn and Cu Codoping at Zn Sites. AB - We report the synthesis and characterization of a bulk form diluted magnetic semiconductor Ba(Zn(1-2x)MnxCux)2As2 (0.025 <= x <= 0.2) with the crystal structure identical to that of "122" family iron based superconductors and the antiferromagnet BaMn2As2. No ferromagnetic order occurs with (Zn, Mn) or (Zn, Cu) substitution in the parent compound BaZn2As2. Only when Zn is substituted by both Mn and Cu simultaneously, can the system undergo a ferromagnetic transition below TC ~ 70 K, followed by a magnetic glassy transition at Tf ~ 35 K. AC susceptibility measurements for Ba(Zn0.75Mn0.125Cu0.125)2As2 reveal that Tf strongly depends on the applied frequency with [formula in text] and a DC magnetic field dependence of [formula in text], demonstrating that a spin glass transition takes place at Tf. As large as -53% negative magnetoresistance has been observed in Ba(Zn(1-2x)MnxCux)2As2, enabling its possible application in memory devices. PMID- 26492958 TI - A new mutually reinforcing network node and link ranking algorithm. AB - This study proposes a novel Normalized Wide network Ranking algorithm (NWRank) that has the advantage of ranking nodes and links of a network simultaneously. This algorithm combines the mutual reinforcement feature of Hypertext Induced Topic Selection (HITS) and the weight normalization feature of PageRank. Relative weights are assigned to links based on the degree of the adjacent neighbors and the Betweenness Centrality instead of assigning the same weight to every link as assumed in PageRank. Numerical experiment results show that NWRank performs consistently better than HITS, PageRank, eigenvector centrality, and edge betweenness from the perspective of network connectivity and approximate network flow, which is also supported by comparisons with the expensive N-1 benchmark removal criteria based on network efficiency. Furthermore, it can avoid some problems, such as the Tightly Knit Community effect, which exists in HITS. NWRank provides a new inexpensive way to rank nodes and links of a network, which has practical applications, particularly to prioritize resource allocation for upgrade of hierarchical and distributed networks, as well as to support decision making in the design of networks, where node and link importance depend on a balance of local and global integrity. PMID- 26492959 TI - Impact of health literacy, accessibility and coordination of care on patient's satisfaction with primary care in Germany. AB - BACKGROUND: Although health policy makers call for the transformation of health care organizations to health literacy responsive ones, there is limited evidence on the care experiences of patients with limited health literacy skills (HL) in respect to health care quality. We explored if HL and patient-reported experiences regarding access to care and support in care-coordination in primary care organizations (PCO) have an impact on patients satisfaction with the care received by their personal general practitioner (GP). METHODS: A nationwide representative survey was administered in a random sample of 1125 German adults. Binary logistic regression analyses were performed to determine whether HL and perceived access to and coordination of care were associated with satisfaction with care received in primary care adjusting for demographics and health status. RESULTS: In the unadjusted as well as adjusted model, better accessibility of the primary care practice (beta= 1.858; 2.032 p < 0.001) frequent support in care coordination by the general practitioner (beta = 2.680; 2.820 p < 0.001) as well as sufficient HL (beta = 0.888; 1.228 p < 0.05) were independent predictors of a higher satisfaction with care received in the general practice. CONCLUSION: German adults with sufficient HL and positive experiences regarding care coordination and access to care are more satisfied with care received by their personal general practitioner. This result is from major importance for primary care organizations intending to transform their processes and structures to respond to the health literacy needs of their patients more effectively. PMID- 26492960 TI - Molecular and phylogenetic characterization of the homoeologous EPSP Synthase genes of allohexaploid wheat, Triticum aestivum (L.). AB - BACKGROUND: 5-Enolpyruvylshikimate-3-phosphate synthase (EPSPS) is the sixth and penultimate enzyme in the shikimate biosynthesis pathway, and is the target of the herbicide glyphosate. The EPSPS genes of allohexaploid wheat (Triticum aestivum, AABBDD) have not been well characterized. Herein, the three homoeologous copies of the allohexaploid wheat EPSPS gene were cloned and characterized. METHODS: Genomic and coding DNA sequences of EPSPS from the three related genomes of allohexaploid wheat were isolated using PCR and inverse PCR approaches from soft white spring "Louise'. Development of genome-specific primers allowed the mapping and expression analysis of TaEPSPS-7A1, TaEPSPS-7D1, and TaEPSPS-4A1 on chromosomes 7A, 7D, and 4A, respectively. Sequence alignments of cDNA sequences from wheat and wheat relatives served as a basis for phylogenetic analysis. RESULTS: The three genomic copies of wheat EPSPS differed by insertion/deletion and single nucleotide polymorphisms (SNPs), largely in intron sequences. RT-PCR analysis and cDNA cloning revealed that EPSPS is expressed from all three genomic copies. However, TaEPSPS-4A1 is expressed at much lower levels than TaEPSPS-7A1 and TaEPSPS-7D1 in wheat seedlings. Phylogenetic analysis of 1190-bp cDNA clones from wheat and wheat relatives revealed that: 1) TaEPSPS-7A1 is most similar to EPSPS from the tetraploid AB genome donor, T. turgidum (99.7 % identity); 2) TaEPSPS-7D1 most resembles EPSPS from the diploid D genome donor, Aegilops tauschii (100 % identity); and 3) TaEPSPS-4A1 resembles EPSPS from the diploid B genome relative, Ae. speltoides (97.7 % identity). Thus, EPSPS sequences in allohexaploid wheat are preserved from the most two recent ancestors. The wheat EPSPS genes are more closely related to Lolium multiflorum and Brachypodium distachyon than to Oryza sativa (rice). CONCLUSIONS: The three related EPSPS homoeologues of wheat exhibited conservation of the exon/intron structure and of coding region sequence, but contained significant sequence variation within intron regions. The genome specific primers developed will enable future characterization of natural and induced variation in EPSPS sequence and expression. This can be useful in investigating new causes of glyphosate herbicide resistance. PMID- 26492961 TI - Chronic pain: the burden of disease and treatment innovations. AB - Musculoskeletal conditions are the most frequent cause of chronic pain and affect around 1 in 5 adults in Europe. When chronic pain occurs, it becomes disease itself, with substantial clinical, social and economic impact. Efficacy and tolerability problems are encountered with all therapeutic strategies available to treat musculoskeletal pain. This often limits effective analgesia and patients' long term compliance, with the result that chronic pain is persistently underestimated and undertreated. Tapentadol is a novel, centrally acting analgesic that has been recently commercialized for the treatment of chronic pain. This new molecule, by combining two distinct mechanisms of action, MU opioid receptor agonism (MOR) and noradrenaline reuptake inhibition (NRI), introduces a new pharmacological class called MOR-NRI. Several studies demonstrated promising results in the management of both nociceptive and neuropathic pain and good tolerability profile, particularly concerning side effects, compared to traditional opioids. This novel analgesic represents a possible therapeutic option also in the rheumatologic field, particularly in the treatment of osteoarthritis and low back pain. PMID- 26492962 TI - The economic burden of musculoskeletal disorders on the Italian social security pension system estimated by a Monte Carlo simulation. AB - The aim of the study is to estimate the pension costs incurred for patients with musculoskeletal disorders (MDs) and specifically with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in Italy between 2009 and 2012. We analyzed the database of the Italian National Social Security Institute (Istituto Nazionale Previdenza Sociale i.e. INPS) to estimate the total costs of three types of social security benefits granted to patients with MDs, RA and AS: disability benefits (for people with reduced working ability), disability pensions (for people who cannot qualify as workers) and incapacity pensions (for people without working ability). We developed a probabilistic model with a Monte Carlo simulation to estimate the total costs for each type of benefit associated with MDs, RA and AS. We also estimated the productivity loss resulting from RA in 2013. From 2009 to 2012 about 393 thousand treatments were paid for a total of approximately ?2.7 billion. The annual number of treatments was on average 98 thousand and cost in total ?674 million per year. In particular, the total pension burden was about ?99 million for RA and ?26 million for AS. The productivity loss for AR in 2013 was equal to ?707,425,191 due to 9,174,221 working days lost. Our study is the fi rst to estimate the burden of social security pensions for MDs based on data of both approved claims and benefits paid by the national security system. From 2009 to 2012, in Italy, the highest indirect costs were associated with disability pensions (54% of the total indirect cost), followed by disability benefits (44.1% of cost) and incapacity pensions (1.8% of cost). In conclusion, MDs are chronic and highly debilitating diseases with a strong female predominance and very significant economic and social costs that are set to increase due to the aging of the population. PMID- 26492963 TI - Influenza vaccination is safe and effective in patients suffering from fibromyalgia syndrome. AB - The fibromyalgia syndrome (FMS) is considered to result from the exposure of a genetically susceptible individual to various triggers, such as physical trauma, stress, viral infections etc. A possible role of vaccination in FMS etiology has been suspected. Our objective was to evaluate the efficacy and safety of influenza vaccination in FMS patients. Nineteen FMS patients underwent physical and dolorimetric examinations and answered the fibromyalgia impact questionnaire (FIQ), the widespread pain index (WPI) checklist and the symptoms severity scale (SSS), which are part of the 2010 diagnostic criteria. Thirty-eight healthy subjects were recruited as controls. All participants were vaccinated with the inactivated split virion influenza vaccine. Serum was collected for antibody titration. Six weeks after vaccination, sera were tested by hemagglutination (HI) against A/California (H1N1), A/Perth (H3N2) and B/Brisbane. Humoral response was defined as either a fourfold or greater increase in titer, or an increase from a non-protective baseline level of <1/40 to a level of 1/40. No severe vaccination reactions were observed. No significant change was observed between WPI, SSS and FIQ values before and after vaccination, indicating no worsening of FMS symptoms. Vaccine immunogenicity: Six weeks after vaccination, FMS patients showed a significant increase in geometric mean titers of HI antibody. The rates of sero protection increased from 22.9% for H1N1 to 89.5% post-vaccination. A significant increase in HI antibody titers was also demonstrated among healthy controls. Influenza vaccination was both safe and effective in FMS patients. In view of these results, FMS patients should be encouraged to undergo influenza vaccination according to the standard WHO recommendations. PMID- 26492964 TI - Joint involvement in patients affected by systemic lupus erythematosus: application of the swollen to tender joint count ratio. AB - Joint involvement is a common manifestation in systemic lupus erythematosus (SLE). According to the SLE disease activity index 2000 (SLEDAI-2K), joint involvement is present in case of >=2 joints with pain and signs of inflammation. However this definition could fail to catch all the various features of joint involvement. Alternatively the Swollen to Tender joint Ratio (STR) could be used. This new index, which was originally proposed for rheumatoid arthritis (RA) patients, is based on the count of 28 swollen and tender joints. Our study is, therefore, aimed to assess joint involvement in a SLE cohort using the STR. SLE patients with joint symptoms (>=1 tender joint) were enrolled over a period of one month. Disease activity was assessed by SLEDAI-2K. We performed the swollen and tender joint count (0-28) and calculated the STR. Depending on the STR, SLE patients were grouped into three categories of disease activity: low (STR1.0). We also calculated the disease activity score based on a 28-joint count and the erythrocyte sedimentation rate (DAS28-ESR). We enrolled 100 SLE patients [F/M 95/5, mean+/-standard deviation (SD) age 46.3+/-10.6 years, mean+/-SD disease duration 147.1+/-103.8 months]. The median of tender and swollen joints was 4 (IQR 7) and 1 (IQR 2.5), respectively. The median STR value was 0.03 (IQR 0.6). According to the STR, disease activity was low in 70 patients, moderate in 23 and high in 7. A significant correlation was identified between STR values and DAS28 (r=0.33, p=0.001). The present study suggests a correlation between STR and DAS28, allowing an easier and faster assessment of joint involvement with the former index. PMID- 26492965 TI - Magnetic resonance imaging features of hip disorders in an Egyptian pediatric population. AB - Hip disorders in a pediatric population are a diagnostic challenge. The aim of the study is to assess the role of magnetic resonance imaging (MRI) in the evaluation of non-traumatic hip disorders in a series of Egyptian patients and to review the literature on the most common hip conditions. Seventy two consecutive patients [40 males (55.6%) and 32 females (44.4)] with acute onset of hip complaints unrelated to trauma or falls were recruited. All patients underwent an initial full clinical assessment and blood tests as well as contrast enhanced MRI of both hips. The most common diagnosis in this group of Egyptian patients was transient synovitis in 29 (40.3%) cases, followed by seronegative enthesopathy and arthropathy syndrome in 8 (11.1%), septic arthritis in 10 (13.9%), tuberculous arthritis in 4 (5.6%), sickle-cell disease in 7 (9.7%), complicated with septic arthritis in 3 (4.2%), transient bone marrow edema (BME) in 3 (4.2%), osteomyelitis in 2 (2.8%), osteosarcoma in 2 (2.8%), sciatic nerve injury in 1 (1.4%), leukemia with BME in 1 (1.4%), coxa vara of both hips and L5/S1 facet joint ankylosis in 1 (1.4%), and a benign bone cyst in 1 (1.4%). MRI studies showed hip effusion in a total of 51 patients (70.8%), joint space narrowing in 9 (12.5%), and BME in 15(20.8%). MRI is a sensitive tool for assessing hip disorders in a pediatric population and can play an important role in both diagnosis and management of different hip disorders, irrespective of the underlying pathology. PMID- 26492966 TI - Sarcoidosis presenting as orbital pseudotumor. AB - Sarcoidosis is a systemic multiorgan disorder of unknown etiology characterized by a non-caseating granuloma reaction. Ocular involvement has been reported in 25 60% of the patients. Seven percent of the patients with sarcoidosis may first see an ophthalmologist due to ocular complaints. This report aims to present our diagnostic and treatment approach to a female patient with significant unilateral lacrimal gland swelling and musculoskeletal involvement, who was diagnosed with sarcoidosis on the basis of tests and histological studies. PMID- 26492967 TI - Massive lower gastrointestinal bleeding associated with solitary rectal ulcer in a patient with Behcet's disease. AB - Solitary rectal ulcer syndrome is a rare benign disorder that has a wide range of clinical presentations and variable endoscopic findings which makes it difficult to diagnose and treat. The clinical and endoscopic picture in this condition can also mimic malign ulceration, malignancy or Crohn's disease. Behcet's disease can affect the gastrointestinal tract. However to the best of our knowledge, no case with solitary rectal ulceration has been reported so far in literature. We herein present a patient diagnosed with Behcet's disease admitted to our clinic with rectal bleeding due to solitary rectal ulceration. PMID- 26492969 TI - Spontaneous symmetry breaking in vortex systems with two repulsive lengthscales. AB - Scanning Hall probe microscopy (SHPM) has been used to study vortex structures in thin epitaxial films of the superconductor MgB2. Unusual vortex patterns observed in MgB2 single crystals have previously been attributed to a competition between short-range repulsive and long-range attractive vortex-vortex interactions in this two band superconductor; the type 1.5 superconductivity scenario. Our films have much higher levels of disorder than bulk single crystals and therefore both superconducting condensates are expected to be pushed deep into the type 2 regime with purely repulsive vortex interactions. We observe broken symmetry vortex patterns at low fields in all samples after field-cooling from above Tc. These are consistent with those seen in systems with competing repulsions on disparate length scales, and remarkably similar structures are reproduced in dirty two band Ginzburg-Landau calculations, where the simulation parameters have been defined by experimental observations. This suggests that in our dirty MgB2 films, the symmetry of the vortex structures is broken by the presence of vortex repulsions with two different lengthscales, originating from the two distinct superconducting condensates. This represents an entirely new mechanism for spontaneous symmetry breaking in systems of superconducting vortices, with important implications for pinning phenomena and high current density applications. PMID- 26492968 TI - Molecular incidence and clearance of Plasmodium falciparum infection. AB - BACKGROUND: Although the epidemiology of malaria has been based primarily on microscopy and rapid diagnostic tests, molecular methods are necessary to understand the complexity of natural infection in regions where transmission is intense and simultaneous infection with multiple parasite genotypes is common such as sub-Saharan Africa. METHODS: To compare microscopic and molecular estimates of the incidence and clearance of Plasmodium falciparum infection, we followed 80 children monthly for 1 year in the village of Bancoumana in Mali. RESULTS AND DISCUSSION: Similar seasonal patterns were observed with both methods (rainy season peak, dry season nadir), although molecular methods detected more infections than microscopy (571 vs 331 in 906 specimens), more new infections (311 vs 104 during 829 person-months) and spontaneous clearance events (317 vs 116) and found higher incidence (0.38 vs 0.13 new genotypes/person/month, p < 0.001) and spontaneous clearance rates (0.38 vs 0.14 genotypes cleared/person/month, p < 0.001). These differences were greatest for persistently-infected subjects in whom neither new infections nor the clearance of old infections could be detected by microscopy (0.71 new infections and 0.73 cleared infections per month using molecular methods vs 0.000 by microscopy, p < 0.001). CONCLUSIONS: Molecular methods provide information about genetic diversity, the intensity of transmission and spontaneous clearance in the absence of drug treatment that cannot be obtained by microscopy. They will be necessary to evaluate the efficacy of vaccines, drugs and other control strategies for diseases such as malaria in which simultaneous infection with more than one organism (genotype) is common. PMID- 26492971 TI - Interdisciplinary intervention reduced the risk of being persistently depressive among older patients with hip fracture. AB - AIM: To assess the effects of an interdisciplinary intervention on the trajectories of depressive symptoms among older patients during 2 years after hip fracture surgery. METHODS: A secondary analysis of data from a randomized controlled trial that contrasted usual care with an interdisciplinary program. Whereas usual care (n = 77) entailed only in-hospital rehabilitation and occasional discharge planning, the interdisciplinary program (n = 76) consisted of geriatric consultation, in-hospital rehabilitation, discharge planning and rehabilitation at home for 3 months after hospitalization. Depressive symptoms were assessed by using the Chinese version of the Geriatric Depression Scale short-form, before discharge, and 1, 3, 6, 12, 18 and 24 months after discharge. Covariates included demographic attributes, pre-fracture performance of activities of daily living (Chinese Barthel Index) and cognitive functioning (Mini-Mental State Examination). RESULTS: Changes in depressive symptoms can be characterized by three trajectory groups, including a non-depressive group (n = 58, 37.8%), a marginally depressive group (n = 46, 30.7%) and a persistently depressive group (n = 49, 31.5%). Relative to those who received usual care, participants in the interdisciplinary program had a significantly lower risk of being in the persistently depressive group (odds ratio 0.23, P < 0.05). In addition, women and those physically and cognitively more impaired were more likely to be in the marginally and persistently depressive groups. CONCLUSIONS: Our interdisciplinary intervention reduced older persons' likelihood of having persistent depressive symptoms after hip fracture surgery. Geriatr Gerontol Int 2016; 16: 1145-1152. PMID- 26492970 TI - The LRR receptor Islr2 is required for retinal axon routing at the vertebrate optic chiasm. AB - BACKGROUND: In the visual system of most binocular vertebrates, the axons of retinal ganglion cells (RGCs) diverge at the diencephalic midline and extend to targets on both ipsi- and contralateral sides of the brain. While a molecular mechanism explaining ipsilateral guidance decisions has been characterized, less is known of how RGC axons cross the midline. RESULTS: Here, we took advantage of the zebrafish, in which all RGC axons project contralaterally at the optic chiasm, to characterize Islr2 as an RGC receptor required for complete retinal axon midline crossing. We used a systematic extracellular protein-protein interaction screening assay to identify two Vasorin paralogs, Vasna and Vasnb, as specific Islr2 ligands. Antibodies against Vasna and Vasnb reveal cellular populations surrounding the retinal axon pathway, suggesting the involvement of these proteins in guidance decisions made by axons of the optic nerve. Specifically, Vasnb marks the membranes of a cellular barricade located anteriorly to the optic chiasm, a structure termed the "glial knot" in higher vertebrates. Loss of function mutations in either vasorin paralog, individually or combined, however, do not exhibit an overt retinal axon projection phenotype, suggesting that additional midline factors, acting either independently or redundantly, compensate for their loss. Analysis of Islr2 knockout mice supports a scenario in which Islr2 controls the coherence of RGC axons through the ventral midline and optic tract. CONCLUSIONS: Although stereotypic guidance of RGC axons at the vertebrate optic chiasm is controlled by multiple, redundant mechanisms, and despite the differences in ventral diencephalic tissue architecture, we identify a novel role for the LRR receptor Islr2 in ensuring proper axon navigation at the optic chiasm of both zebrafish and mouse. PMID- 26492972 TI - Analysis of factors in successful nasal endoscopic resection of nasopharyngeal angiofibroma. AB - CONCLUSIONS: Endoscopic resection of nasopharyngeal angiofibroma is less traumatic, causes less bleeding, and provides a good curative effect. Using pre operative embolization and controlled hypotension, reasonable surgical strategies and techniques lead to successful resection tumors of a maximum Andrews-Fisch classification stage of III. OBJECTIVE: To investigate surgical indications, methods, surgical technique, and curative effects of transnasal endoscopic resection of nasopharyngeal angiofibroma, this study evaluated factors that improve diagnosis and treatment, prevent large intra-operative blood loss and residual tumor, and increase the cure rate. METHODS: A retrospective analysis was performed of the clinical data and treatment programs of 23 patients with nasopharyngeal angiofibroma who underwent endoscopic resection with pre-operative embolization and controlled hypotension. The surgical method applied was based on the size of tumor and extent of invasion. Curative effects were observed. RESULTS: No intra-operative or perioperative complications were observed in 22 patients. Upon removal of nasal packing material 3-7 days post-operatively, one patient experienced heavy bleeding of the nasopharyngeal wound, which was treated compression hemostasis using post-nasal packing. Twenty-three patients were followed up for 6-60 months. Twenty-two patients experienced cure; one patient experienced recurrence 10 months post-operatively, and repeat nasal endoscopic surgery was performed and resulted in cure. PMID- 26492973 TI - Filling in the gaps: using testing and restudy to promote associative learning. AB - Although testing has been shown to potentiate subsequent learning [Izawa, C. (1966). Reinforcement-test sequences in paired-associate learning. Psychological Reports, 18, 879-919.], the mechanisms that influence this effect are not entirely understood. The present research examined the relationship between associative binding and test-potentiation effects. We hypothesised that test potentiation effects would be most pronounced when participants could easily extract the relationship among word groupings. Towards that end, we compared three-word groupings, or triads, that were either semantically related or unrelated. Participants engaged in repeated study, repeated testing, or engaged in interpolated study and test prior to a final test. Final test performance was greatest for participants who engaged in interpolated study and test on related triads. The results support three primary conclusions: (1) testing aids in associative binding; (2) associative binding is facilitated by retrieval practice and restudy pairings; and (3) pre-existing associations facilitate test potentiation effects. PMID- 26492975 TI - Endosulfan splenic pathology and amelioration by vitamin C in New Zealand rabbit. AB - Endosulfan, a chlorinated hydrocarbon insecticide/acaricide, is a member of a cyclodiene sub-group of poisons to a wide variety of insects and mites. It is also toxic to humans and animals, but there is limited knowledge about endosulfan related splenic and overall immunotoxicity. The aim of this study was to review pathological findings of endosulfan toxicity in the spleen and to examine potential protective effects of the anti-oxidant Vitamin C (Vit C). Here, after 6 week exposures, the spleens of New Zealand White rabbits were examined grossly and histopathologically and tissue caspase-3 activity was assessed immunohistochemically. Rabbits in four groups were used: Group END were given by oral gavage a sub-lethal dose of endosulfan (1 mg/kg) in corn oil daily for 6 weeks; Group END + C received the same dose of endosulfan daily and Vit C (20 mg/kg) every other day by gavage during this period; Group Vit C received oral corn oil daily and 20 mg/kg Vit C every other day; and Group OIL received corn oil daily for 6 weeks. Analyses of the tissues collected 1 week after the final dosing revealed lymphocyte depletion and necrosis in spleens of the hosts that received the pesticide (END only and END + C); hemorrhage and slight neutrophilic infiltration was also noted. Caspase-3 immunoreactivity was marked in lymphocytes in all spleens of rabbits in both END groups. Overall, these toxicities were mitigated by Vit C co-treatment; in END + C hosts, markedly decreased depletion of lymphocytes, inflammation and caspase-3 immunoreactivity were observed. However, even with mitigation, the level of toxicity present was still greater than any seen in the spleens of hosts that received OIL or Vit C alone. These results revealed endosulfan could cause toxicity in the rabbit spleen, characterized by depletion of lymphocytes, inflammation, necrosis and hemorrhage, and that this toxicity could begin to be mitigated by Vit C co-treatment. PMID- 26492976 TI - Detection of parathyroid hormone-like hormone in cancer cell cultures by gold nanoparticle-based lateral flow immunoassays. AB - Parathyroid hormone-like hormone (PTHLH) exerts relevant roles in progression and dissemination of several tumors. However, factors influencing its production and secretion have not been fully characterized. The main limitation is the lack of specific, sensitive and widely available techniques to detect and quantify PTHLH. We have developed a lateral flow immunoassay using gold nanoparticles label for the fast and easy detection of PTHLH in lysates and culture media of three human cell lines (HaCaT, LA-N-1, SK-N-AS). Levels in culture media and lysates ranged from 11 to 20 ng/mL and 0.66 to 0.87 MUg/mL respectively. Results for HaCaT are in agreement to the previously reported, whereas LA-N-1 and SK-N-AS have been evaluated for the first time. The system also exhibits good performance in human serum samples. This methodology represents a helpful tool for future in vitro and in vivo studies of mechanisms involved in PTHLH production as well as for diagnostics. From the Clinical Editor: Parathyroid Hormone-like Hormone (PTHLH) is known to be secreted by some tumors. However, the detection of this peptide remains difficult. The authors here described their technique of using gold nanoparticles as label for the detection of PTHLH by Lateral-flow immunoassays (LFIAs). The positive results may also point a way to using the same technique for the rapid determination of other relevant cancer proteins. PMID- 26492974 TI - Epigenetic Histone Modifications Involved in Profibrotic Gene Regulation by 12/15 Lipoxygenase and Its Oxidized Lipid Products in Diabetic Nephropathy. AB - AIMS: Epigenetic mechanisms, including histone post-translational modifications and DNA methylation, are implicated in the pathogenesis of diabetic nephropathy (DN), but the mediators are not well known. Moreover, although dyslipidemia contributes to DN, epigenetic changes triggered by lipids are unclear. In diabetes, increased expression of 12/15-lipoxygenase (12/15-LO) enhances oxidized lipids such as 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which promote oxidant stress, glomerular and mesangial cell (MC) dysfunction, and fibrosis, and mediate the actions of profibrotic growth factors. We hypothesized that 12/15-LO and its oxidized lipid products can regulate epigenetic mechanisms mediating profibrotic gene expression related to DN. RESULTS: 12(S)-HETE increased profibrotic gene expression and enrichment of permissive histone lysine modifications at their promoters in MCs. 12(S)-HETE also increased protein levels of SET7, a histone H3 lysine 4 methyltransferase, and promoted its nuclear translocation and enrichment at profibrotic gene promoters. Furthermore, SET7 (Setd7) gene silencing inhibited 12(S)-HETE-induced profibrotic gene expression. 12/15-LO (Alox15) gene silencing or genetic knockout inhibited transforming growth factor-beta1 (TGF-beta1)-induced expression of Setd7 and profibrotic genes and histone modifications in MCs. Furthermore, 12/15-LO knockout in mice ameliorated key features of DN and abrogated increases in renal SET7 and profibrotic genes. Additionally, 12/15-LO siRNAs in vivo blocked increases in renal SET7 and profibrotic genes in diabetic mice. INNOVATION AND CONCLUSION: These novel results demonstrate for the first time that 12/15-LO-derived oxidized lipids regulate histone modifications associated with profibrotic gene expression in MCs, and 12/15-LO can mediate similar actions of TGF-beta1 and diabetes. Targeting 12/15-LO might be a useful strategy to inhibit key epigenetic mechanisms involved in DN. PMID- 26492978 TI - Adsorption-Driven Heat Pumps: The Potential of Metal-Organic Frameworks. PMID- 26492977 TI - Anxiety and anxious-depression in Parkinson's disease over a 4-year period: a latent transition analysis. AB - BACKGROUND: Depression and anxiety in Parkinson's disease are common and frequently co-morbid, with significant impact on health outcome. Nevertheless, management is complex and often suboptimal. The existence of clinical subtypes would support stratified approaches in both research and treatment. METHOD: Five hundred and thirteen patients with Parkinson's disease were assessed annually for up to 4 years. Latent transition analysis (LTA) was used to identify classes that may conform to clinically meaningful subgroups, transitions between those classes over time, and baseline clinical and demographic features that predict common trajectories. RESULTS: In total, 64.1% of the sample remained in the study at year 4. LTA identified four classes, a 'Psychologically healthy' class (approximately 50%), and three classes associated with psychological distress: one with moderate anxiety alone (approximately 20%), and two with moderate levels of depression plus moderate or severe anxiety. Class membership tended to be stable across years, with only about 15% of individuals transitioning between the healthy class and one of the distress classes. Stable distress was predicted by higher baseline depression and psychiatric history and younger age of onset of Parkinson's disease. Those with younger age of onset were also more likely to become distressed over the course of the study. CONCLUSIONS: Psychopathology was characterized by relatively stable anxiety or anxious-depression over the 4-year period. Anxiety, with or without depression, appears to be the prominent psychopathological phenotype in Parkinson's disease suggesting a pressing need to understanding its mechanisms and improve management. PMID- 26492979 TI - Dosimetric variations in permanent breast seed implant due to patient arm position. AB - PURPOSE: Planning and delivery for permanent breast seed implant (PBSI) are performed with the ipsilateral arm raised; however, changes in implant geometry can be expected because of healing and anatomical motion as the patient resumes her daily activities. The purpose of this study is to quantify the effect of ipsilateral arm position on postplan dosimetry. METHODS AND MATERIALS: Twelve patients treated at the Tom Baker Cancer Centre were included in this study. Patients underwent two postimplant CT scans on the day of implant (Day 0) and two scans approximately 8 weeks later (Day 60). One scan at each time was taken with the ipsilateral arm raised, recreating the planning scan position, and the other with both arms down in a relaxed position beside the body, recreating a more realistic postimplant arm position. Postplans were completed on all four scans using deformable image registration (MIM Maestro). RESULTS: On the Day 0 scan, the V200 for the evaluation planning target volume was significantly increased in the arm-down position compared with the arm-up position. Lung, rib, and chest wall dose were significantly reduced at both time points. Left anterior descending coronary artery, heart, and skin dose showed no significant differences at either time point. CONCLUSIONS: Although some dosimetric indices show significant differences between the arm-up and arm-down positions, the magnitude of these differences is small and the values remain indicative of implant quality. Despite the delivery of the majority of dose with the arm down, it is reasonable to use CT scans taken in the arm-up position for postplanning. PMID- 26492980 TI - Radiological prognostication in patients with head trauma requiring decompressive craniectomy: Analysis of optic nerve sheath diameter and Rotterdam CT Scoring System. AB - INTRODUCTION: Optic nerve sheath diameter (ONSD) measured on CT scan has been shown to predict outcomes of patients with severe traumatic brain injury. No such relation has been studied in patients undergoing decompressive craniectomy (DC). We evaluated ONSD on admission CT scan to predict outcomes of patients undergoing DC along with Rotterdam CT Score (RCTS). MATERIALS AND METHODS: This retrospective cohort study was approved by the institutional ethics committee. All the consecutive patients undergoing DC with available images and records were included. We measured ONSD 3mm behind the eyeball and calculated RCTS. Glasgow Outcome Scale (GOS) was measured at last follow-up. We analyzed the data on SPSS v 19. Receiver operator curve analysis (ROC) was done to measure the predictive values of ONSD and RCTS for mortality and unfavorable outcomes. RESULTS: One hundred and seventeen patients were included. Twenty patients had bilateral DC. Mean GCS at presentation was 8.5+/-3.5. Mean follow-up was 7.5+/-1.2 months. Thirty-day mortality was 19%. Mean ONSD of both eyes was 6.73+/-0.89mm. Area under the curve (AUC) for bilateral mean ONSD as predictor of mortality was 0.49 [95%CI: 0.36-0.62]. AUC for RCTS was as a predictor of 30-day mortality was significant, i.e. 0.67 [95%CI: 0.572-0.820]. The difference of mean ONSD was also not significantly different between survivor and non-survivors. CONCLUSION: Admission ONSD in DC patients is high but does not predict mortality and unfavorable outcomes. RCTS has a better prognostic value for predicting mortality and unfavorable outcomes in DC patients. PMID- 26492981 TI - Neonatal propofol anesthesia modifies activity-dependent processes and induces transient hyperlocomotor response to d-amphetamine during adolescence in rats. AB - This study examined the influence of propofol anesthesia on the expression of activity-regulated molecules (BDNF and c-Fos) and synaptic plasticity markers (synaptophysin, GAP-43, drebrin) in the frontal cortex and thalamus of 7-day-old (P7) rats. Although these brain regions are the main targets of anesthetic action, they are contained in the cortico-striato-thalamo-cortical feedback loops, involved in naturally occurring and drug-induced psychoses. Therefore, functional integrity of these loops was examined in adolescent and adult rats through d-amphetamine-induced hyperactivity. Propofol treatment (25mg/kg) decreased exon-specific and total BDNF mRNA expression in the frontal cortex and thalamus, in a time-dependent manner. BDNF protein level was increased in the frontal cortex and decreased in the thalamus, which was accompanied by the change of phospho-TrkB expression. Similarly to BDNF, the expression of c-Fos was decreased in the frontal cortex while it was changed only at the protein level in the thalamus. Synaptic plasticity markers changed in a time- and region-specific manner, indicating increased synaptogenesis in the frontal cortex and synapse elimination in the thalamus in P7 rats after the propofol anesthesia exposure. These early molecular changes were followed by time-related, increased motor reaction to d-amphetamine in adolescent, but not in adult rats. Our study revealed that exposure of immature brain to propofol anesthesia during the critical phase of development provoked immediate changes in activity-dependent processes and synaptic adjustment, influencing brain capacity to integrate later developmental events and resulting in temporary altered response to acute psychotropic stimulation during adolescence. PMID- 26492982 TI - Withanolides and Sucrose Esters from Physalis neomexicana. AB - Four withanolides (1-4) and two sucrose esters (5, 6) were isolated from the aerial parts of Physalis neomexicana. The structures of 1-6 were elucidated through a variety of spectroscopic techniques. Cytotoxicity studies of the isolates revealed that 2 inhibited human breast cancer cell lines (MDA-MB-231 and MCF-7) with IC50 values of 1.7 and 6.3 MUM, respectively. PMID- 26492983 TI - A pH- and Temperature-Responsive Magnetic Composite Adsorbent for Targeted Removal of Nonylphenol. AB - A pH- and temperature-responsive magnetic adsorbent [poly(N-isopropylacrylamide) grafted chitosan/Fe3O4 composite particles, CN-MCP], was synthesized for the removal of the endocrine-disrupting chemical nonylphenol. According to the structural characteristics (changeable surface-charge and hydrophilic/hydrophobic properties) of the targeted contaminant, CN-MCP was designed owning special structure (pH- and temperature-responsiveness for the changeable surface-charge and adjustable hydrophilic/hydrophobic properties, respectively). Compared to chitosan magnetic composite particles without grafting modification (CS-MCP) and several other reported adsorbents, CN-MCP exhibited relatively high adsorption capacity for nonylphenol under corresponding optimal conditions (123 mg/g at pH 9 and 20 degrees C; 116 mg/g at pH 5 and 40 degrees C). Meanwhile, high selectivity of the novel adsorbent in selective adsorption of nonylphenol from bisolute solution of nonylphenol and phenol was found. Effects of grafting ratio of the grafted polymer branches and coexisting inorganic salts on the adsorption were systematically investigated. Moreover, CN-MCP demonstrated desired reusability during 20 times of adsorption-desorption recycling. The high adsorption capacity, high selectivity, and desired reusability aforementioned revealed the significant application potential of CN-MCP in the removal of NP. On the basis of the adsorption behaviors, isotherms equilibrium, thermodynamics and kinetics studies, and instrumental analyses including X-ray photoelectron spectroscopy, BET specific surface area, zeta potential, and static water contact angle measurements, distinct adsorption mechanisms were found under various conditions: charge attraction between CN-MCP and the contaminant, as well as binding between polymeric branches of CN-MCP and nonyls, contributed to the adsorption at pH 9 and 20 degrees C; whereas hydrophobic interaction between CN MCP and nonylphenol played a dominant role at pH 5 and 40 degrees C. The current study provided a strategy for the structural design of adsorbents according to the features of targeted emerging contaminants, and the continuity of the work was discussed and proposed. PMID- 26492984 TI - [Acute myocardial infarction in Morocco: FES-AMI registry data]. AB - BACKGROUND: Acute myocardial infarction is the most dangerous complication of coronary atherothrombosis. There are several disparities in regard to its management around the world. The aim of this study is to analyze the specificities of management of acute myocardial infarction in Morocco. METHODS: FES-AMI (Fes Acute Myocardial Infarction) is a prospective monocentric registry conducted in cardiology department of Hassan II university hospital in Fes. In this registry, we enrolled patients with acute myocardial infarction who presented within 5 days after symptom onset. RESULTS: From January 2005 to August 2015, we enrolled 1835 patients. Seventy-five percent of patients were males and mean age was 60 years old. Fifty-one percent of patients were smokers, 27% were hypertensives and 14% were diabetics. Sixty-six percent of patients had more than 2 risk factors. Time from symptom onset to hospital admission was less than six hours for 40% of the patients. Thirty-six percent of patients were admitted more than twelve hours after the onset of chest pain. Only 37% of patients received reperfusion therapy, 31% with in-hospital thrombolysis and 6% with primary angioplasty. In-hospital mortality was 7.6%. CONCLUSION: The patients enrolled in our registry have late presentation of acute myocardial infarction and less rate of reperfusion therapy. Furthermore, the majority of our patients have multiple risk factors and this result underlines the failure of preventive interventions. PMID- 26492985 TI - [Coronary stent evaluation with cardiac CT: Literature review]. AB - Since the introduction of the 64-generation scanners, the accuracy and robustness of the diagnosis of coronary artery disease has progressed. The main advantage of cardiac CT is the exclusion of coronary artery disease by its excellent negative predictive value. Currently, cardiac CT applications extend thanks to innovations both in terms of technological development systems scanner or stents implanted. This is a literature review of stent evaluation with cardiac CT. PMID- 26492986 TI - [High pressure trap]. AB - Pheochromocytoma is a rare tumor potentially life-threatening and associated with non specific and diverse symptomatology. Cardiac symptoms may mislead diagnosis; they could manifest as myocardial sideration concomitant to a hypertensive peak or supraventricular arythmia. We report a case of pheochromocytoma associated with hypokaliemia revealed by a myocardial ischemia with acute cardiac failure and severe left ventricular depression and complete reversal after surgery. PMID- 26492988 TI - Does impotence improve after parathyroidectomy in men with primary hyperparathyroidism? AB - BACKGROUND: Erectile dysfunction (ED) is a common diagnosis associated with age, hypertension, cardiovascular disease, and diabetes. Primary hyperparathyroidism (PHP) is also seen with these comorbidities, but its association with ED has yet to be studied. We evaluated the rate and resolution of impotence after curative surgery for PHP. METHODS: Prospectively collected data, including a self-reported questionnaire of symptoms, were reviewed for men who had curative parathyroid exploration for sporadic PHP from July 2010 to January 2014. Data were compared with an age-matched cohort of men who had thyroidectomy during the same period. RESULTS: Among 160 men with PHP and mean age of 60 years (range, 19-88), preoperative ED was reported by 13%, and this group was older than patients without ED (mean age, 70 vs 58 years, P < .01). Self-reported resolution of ED after parathyroidectomy occurred in 67% compared with 43% of patients in a thyroidectomy cohort. Preoperative mean arterial blood pressure was less in men with postoperative resolution of ED (96.6 vs 105.4 mm Hg, P = .03). Among 3 of 21 men on specific ED medications, 2 no longer required them postoperatively. CONCLUSION: Impotence is reported often by men undergoing parathyroidectomy for PHP. After curative surgery, 67% of those affected may self-report ED resolution, which may be more pronounced in those patients with a lesser preoperative mean arterial blood pressure. PMID- 26492987 TI - Motor behavior reflects reduced hemispheric asymmetry in the psychosis risk period. AB - BACKGROUND: A body of work focusing on brain connectivity, language dominance, and motor laterality research suggests that reduced hemispheric asymmetry is a core feature in schizophrenia. However, there is little consensus about whether reduced dominance is present in those at ultrahigh risk (UHR) for psychosis. METHODS: A total of 94 demonstrated right-handed neuroleptic free participants (38 UHR and 56 matched healthy controls) were assessed with structured clinical interviews and completed an innovative handwriting task using a digital tablet computer. A laterality quotient (LQ) was calculated using kinematic variables from the participant's left and right hands. A subset of the sample (26 UHR and 29 controls) returned after 12-months to complete clinical interviews in order to examine relationships between handwriting laterality and progression of psychosis risk symptoms. RESULTS: The UHR group showed decreased dextrality compared to healthy controls. At the 12-month follow-up, decreased dextrality accounted for 8% of the variance in worsened positive symptoms within the UHR group. CONCLUSION: The current results suggest that disrupted cerebral dominance is also present in the ultrahigh risk period and that decreased dextrality may serve as a novel biomarker for the progression of psychosis risk. PMID- 26492989 TI - Discussion. PMID- 26492990 TI - Cysteine is not a substrate but a specific modulator of human ASCT2 (SLC1A5) transporter. AB - The Alanine Serine Cysteine Transporter 2 (ASCT2) is involved in balancing the intracellular amino acid pool. This function is allowed by the antiport mechanism and the asymmetric specificity towards different neutral amino acids, distinctive of this transporter. In the present work, the interaction of the putative substrate Cys with the human ASCT2 has been studied using the recombinant hASCT2 over-produced in Pichia pastoris and the native ASCT2 extracted from HeLa in both proteoliposomes and intact cells. It was found that Cys is a potent competitive inhibitor of hASCT2 but is not a substrate. Moreover, Cys binding to a second site, different from that of substrate, triggers a protein-mediated unidirectional Gln efflux. PMID- 26492991 TI - Effects of adjuvant MontanideTM ISA 763 A VG in rainbow trout injection vaccinated against Yersinia ruckeri. AB - Enteric redmouth disease (ERM) caused by the fish pathogen Yersinia ruckeri is a major threat to freshwater production of rainbow trout (Oncorhynchus mykiss) throughout all life stages. Injection vaccination of rainbow trout against Y. ruckeri infection has been shown to confer better protection compared to the traditionally applied immersion vaccination. It may be hypothesized, based on experience from other vaccines, that adjuvants may increase the protective level of ERM injection vaccines even more. Controlled comparative vaccination studies have been performed to investigate effects of the oil adjuvant MontanideTM ISA 763 A VG (Seppic) when added to an experimental Y. ruckeri bacterin (containing both biotype 1 and 2 of serotype O1). A total of 1000 fish with mean weight 19 g was divided into five different groups (in duplicated tanks 2 * 100 fish per group) 1) non-vaccinated control fish (NonVac), 2) fish injected with a commercial vaccine (AquaVac((r)) ReleraTM) (ComVac), 3) fish injected with an experimental vaccine (ExpVac), 4) fish injected with an experimental vaccine + adjuvant (ExpVacAdj) and 5) fish injected with adjuvant alone (Adj). Injection of the experimental vaccine (both adjuvanted and non-adjuvanted) induced a significantly higher antibody (IgM) level, increased occurrence of IgM(+) cells in spleen tissue and significant up-regulation of several immune genes. Additional experiments using a higher challenge dosage suggested an immune enhancing effect of the adjuvant as the challenge produced 100% mortality in the NonVac group, 60% mortality in both of ComVac and Adj groups and only 13 and 2.5% mortalities in the ExpVac and the ExpVacAdj groups, respectively. PMID- 26492992 TI - Molecular cloning, immunohistochemical localization, characterization and expression analysis of caspase-8 from the blunt snout bream (Megalobrama amblycephala) exposed to ammonia. AB - Caspase-8 is an initiator caspase that plays a crucial role in some cases of apoptosis by extrinsic and intrinsic pathways. Caspase-8 structure and function have been extensively studied in mammals, but in fish the characterization of that initiator caspase is still scarce. In this study, we isolated the caspase-8 gene from Megalobrama amblycephala, one of the most important industrial aquatic animals in China using rapid amplification of cDNA ends (RACE). The 2034 bp full length M. amblycephala caspase-8 cDNA sequence contained an ORF of 1467 bp encoding a polypeptide of 489 amino acid residues, a 5'-UTR of 102 bp and a 3' UTR of 462 bp. The caspase-8 amino acid sequences contained two highly conservative death effector domains (DEDs) at N-terminal, the caspase family domains P20 and P10, caspase-8 active-site pentapeptide and potential aspartic acid cleavage sites. Phylogenetic analysis revealed that M. amblycephala caspase 8 were clustered with the caspase-8 from other vertebrate. Real-time quantitative PCR analysis revealed that caspase-8 transcripts were detected in liver after exposure to ammonia. Meanwhile using Western blot analysis, caspase-8 cleaved fragment was detected and significant alteration of procaspase-8 level was found with the same ammonia treatment condition. Furthermore, the result of immunohistochemical detection showed that remarkable changes of immunopositive staining were observed after ammonia treatment. Accordingly, the results signify that caspase-8 of fish may play an essential role in ammonia induced apoptosis. PMID- 26492993 TI - The effects of a thermophile metabolite, tryptophol, upon protecting shrimp against white spot syndrome virus. AB - White spot syndrome virus (WSSV) is a shrimp pathogen responsible for significant economic loss in commercial shrimp farms and until now, there has been no effective approach to control this disease. In this study, tryptophol (indole-3 ethanol) was identified as a metabolite involved in bacteriophage-thermophile interactions. The dietary addition of tryptophol reduced the mortality in shrimp Marsupenaeus japonicus when orally challenged with WSSV. Our results revealed that 50 mg/kg tryptophol has a better protective effect in shrimp than 10 or 100 mg/kg tryptophol. WSSV copies in shrimp were reduced significantly (P < 0.01) when supplemented with 50 mg/kg tryptophol, indicating that virus replication was inhibited by tryptophol. Consequently, tryptophol represents an effective antiviral dietary supplement for shrimp, and thus holds significant promise as a novel and efficient therapeutic approach to control WSSV in shrimp aquaculture. PMID- 26492994 TI - Cloning and gene expression of signal transducers and activators of transcription (STAT) homologue provide new insights into the immune response and nucleus graft of the pearl oyster Pinctada fucata. AB - The signal transducers and activators of the transcription (STAT) family play an important role in regulatory and cellular functions by regulating the expression of a variety of genes, including cytokines and growth factors. In the present study, a Pinctada fucata STAT protein, termed PfSTAT, was described. The deduced amino acid sequence of PfSTAT contains the conserved STAT_bind domain and the SH2 domain, and the additional Bin/Amphiphysin/Rvs (BAR) domain, but does not have STAT_alpha and STAT_int domains. Multiple sequence alignments revealed that PfSTAT showed relatively low identity with vertebrate and other invertebrate STATs, and phylogenetic analysis indicated that the evolution of STAT may have been more complex and ancient. Gene expression analysis revealed that PfSTAT is involved in the immune response to polyinosinic-polycytidylic acid (poly I:C) stimulation and in the nucleus insertion operation. This study contributes to a better understanding of PfSTAT in protecting the pearl oyster from disease or injury caused by grafting. PMID- 26492995 TI - Characterization of two types of vascular endothelial growth factor from Litopenaeus vannamei and their involvements during WSSV infection. AB - Vascular endothelial growth factors (VEGFs) are important signaling proteins in VEGF signaling pathway which play key roles in inducing endothelial cell proliferation, migration, angiogenesis, vascular permeability, inhibition of apoptosis and virus infection. In the present study, we isolated and characterized two VEGF genes, LvVEGF1 and LvVEGF2 from Litopenaeus vannamei. The deduced amino acid sequences of both LvVEGF1 and LvVEGF2 contained a signal peptide, a typical PDGF/VEGF domain and a cysteine knot motif (CXCXC). Tissue distribution analysis showed that LvVEGF1 was predominantly expressed in lymphoid organ (Oka) while LvVEGF2 was mainly detected in gill and hemocytes. The transcriptional levels of LvVEGF1 in Oka and LvVEGF2 in gill or hemocytes were apparently up-regulated during WSSV infection. Double-stranded RNA interference was used for further functional studies. The data showed that silencing of LvVEGF1 and LvVEGF2 caused a decrease of the copy numbers of the virus in WSSV infected shrimp and a reduction of the cumulative mortality rate of shrimp during WSSV infection. The present study indicated that LvVEGF1 and LvVEGF2 might facilitate WSSV infection, which provided new evidence to understand the function of VEGF signaling pathway during WSSV infection in shrimp. PMID- 26492996 TI - Transcription expression of immune-related genes from Caligus rogercresseyi evidences host-dependent patterns on Atlantic and coho salmon. AB - The transcriptomic response of the sea louse Caligus rogercresseyi during the infestation on Atlantic salmon (Salmo salar) and coho salmon (Oncorhynchus kisutch) was evaluated using 27 genes related to immune response, antioxidant system and secretome. Results showed early responses of TLR/IMD signaling pathway in sea lice infesting Atlantic salmon. Overall, genes associated with oxidative stress responses were upregulated in both host species. This pattern suggests that reactive oxygen species emitted by the host as a response to the infestation, could modulate the sea louse antioxidant system. Secretome-related transcripts evidenced upregulation of trypsins and serpins, mainly associated to Atlantic salmon than coho salmon. Interestingly, cathepsins and trypsin2 were downregulated at 7 days post-infection (dpi) in coho salmon. The principal component analysis revealed an inverse time-dependent pattern based on the different responses of C. rogercresseyi infecting both salmon species. Here, Atlantic salmon strongly modulates the transcriptome responses at earlier infection stages; meanwhile coho salmon reveals a less marked modulation, increasing the transcription activity during the infection process. This study evidences transcriptome differences between two salmon host species and provides pivotal knowledge towards elaborating future control strategies. PMID- 26492997 TI - Paclitaxel-coated versus plain balloon angioplasty in the treatment of infrainguinal vein bypass stenosis. AB - OBJECTIVE: The aim of this study was to compare the clinical and hemodynamic outcomes of plain vs paclitaxel-coated percutaneous transluminal angioplasty (PTA) in patients with infrainguinal vein bypass stenosis. METHODS: A single center retrospective analysis was conducted of consecutive patients treated by infrainguinal bypass PTA. Primary study end points were primary and assisted primary patency. Secondary end points were clinical and hemodynamic improvement, limb salvage, and survival. Society for Vascular Surgery reporting standards were applied. RESULTS: From April 2008 to November 2014, 83 infrainguinal vein bypasses were treated for graft stenosis by plain (group A, n = 41) or by paclitaxel-coated PTA (group B, n = 42). The groups did not differ significantly in mean age (71.9 years for both groups; P = .99), hypertension (P = 1.0), hyperlipidemia (P = .5), diabetes (P = .6), coronary artery disease (P = 1.0), smoking (P = 1.0), preoperative ankle-brachial index (P = .08), or bypass characteristics (below-knee, P = .82). Technical success rate was 100% for both groups. Mean follow-up was 2.9 years for group A patients and 2.2 years for group B patients (P = .08). No patient was lost to follow-up. Primary patency rates were 88% vs 87% and 73% vs 75% (P = .19) and assisted primary patency rates were 88% vs 90% and 77% vs 84% (P = .76) for group A and B patients at 1 and 2 years, respectively. Repeat target lesion revascularization rates were 22% vs 14% (P = .17). At the last follow-up, there were eight vs seven bypass occlusions (P = .74) for group A and B patients, respectively. In univariate analysis, proximal in-graft stenosis (Cox F, P = .041), bypass failure <6 months after bypass surgery (Cox F, P = .013), more than one bypass stenosis per graft (Cox F, P = .047), and redo bypass procedure (Cox F, P = .0001) were significantly related to assisted primary bypass patency. Immediate hemodynamic and sustained clinical improvement rates were 88% vs 86% and 70% vs 73% for group A and B patients, respectively. There were three vs one major amputations (P = .36) and eight vs seven deaths (P = .78) in group A and B patients, respectively. CONCLUSIONS: Paclitaxel-coated and plain angioplasty of significant infrainguinal vein bypass stenoses performed equally well in clinical and hemodynamic improvement and in primary and assisted primary bypass patency rates. PMID- 26492998 TI - Discussion. PMID- 26492999 TI - Revision using distal inflow is a safe and effective treatment for ischemic steal syndrome and pathologic high flow after access creation. AB - OBJECTIVE: Ischemic steal syndrome (ISS) and pathologic high flow (HF) are a complications after hemodialysis access creation. Their management is complex and varied with most requiring surgical revision for correction of symptoms. Revision using distal inflow (RUDI) has been described in small series for the treatment of ISS. We present our experience with RUDI for the treatment of ISS and pathologic HF. METHODS: We retrospectively reviewed consecutive patients who underwent RUDI for ISS from April, 2010 to March, 2014. Data collection included demographic characteristics, medical histories, subsequent procedures, volume flows, access usage, limb salvage, and patient survival. RESULTS: We performed 29 RUDI procedures in 28 patients (16 women, 12 men). Indications for surgery were pathologic HF in 13 and ISS in 19. Ten percent had previous banding for ISS or HF. Sixty-nine percent of patients had a history of diabetes. Fifty-two percent had a history of atherosclerotic disease. Mean time to intervention from creation was 40 months (range, 6-88 months). Accesses included 1 upper arm graft and 27 brachial artery-based fistulas. Outflow included 25 cephalic veins and 3 basilic veins. Distalization targets were 19 radial arteries and 10 ulnar arteries. Mean flow reduction was 1191 mL/min. Primary assisted patency at 1 year was 74%. Secondary patency at 1 year was 87%. A single access was ligated for continued heart failure after RUDI. ISS symptom resolution was reported as complete in 69% and partial in 31%. CONCLUSIONS: RUDI is an effective and durable treatment of ISS and HF comparable with reported experiences with distal revascularization interval ligation, proximalization of the arterial inflow, and banding. Patient selection is key for optimizing relief of symptoms and maintaining use of the access. PMID- 26493000 TI - The formation and function of the sclerosis rim in the femoral head: A biomechanical point of view. AB - Sclerosis rim surrounding the necrotic area is commonly found in necrotic femoral head, but the biomechanical function of sclerosis rim has received relatively little attention. Little is known about the formation and natural history of sclerosis rim. In the present work, we assume that the necrotic change may trigger bone remodeling process in the femoral head, which took place according to Huiskes' bone remodeling model incorporated with the FE simulations as described earlier. We then investigate the function of sclerosis rim as a mechanical supporter in delaying further collapse of the femoral head based on our sclerotic rim model. The main tasks of this study are: (1) simulation of the density distribution in the necrotic femoral head after bone remodeling; (2) calculation of maximal von Mises stress in the subchondral bone of the weight bearing area of the femoral head over the necrotic area before and after bone remodeling. Results show that the sclerotic rim is, from the biomechanical point of view, an adaptive response to the decrease in elastic modulus of the femoral head, and that the sclerotic rim that acts as a compensatory structural reinforcement can usually significantly reduce the maximal stress in the subchondral bone when the lesion is small, but not when the lesion is large. PMID- 26493001 TI - Subchronic (13-week) toxicity and prenatal developmental toxicity studies of dietary astaxanthin in rats. AB - Two studies examined the effects of dietary astaxanthin on Hanlbm Wistar (SPF) rats. Male and female rats receiving astaxanthin concentrations up to 1.52% of the feed for 13 weeks showed no evidence of toxicity; no effects were noted in the offspring of female rats exposed to astaxanthin at up to 1.39% of the feed during the period of organogenesis (GD 7-16). Discoloration of the feces and yellow pigmentation of adipose tissue was seen in the 13-week study, an intrinsic property of the substance, and not a sign of toxicity. Differences between the control and astaxanthin groups, some of which reached statistical significance, were generally sporadic (i.e., transient and/or not related to astaxanthin concentration) and not considered of biological or toxicological significance. Blood cholesterol levels, for example, were greater in animals receiving astaxanthin for 13 weeks, but remained within the normal range. The highest dietary concentration of astaxanthin in each of the studies is proposed as a no observable-adverse-effect level (NOAEL). Specifically, 1.52% for the 13-week study, corresponding to a mean intake of 1033 mg/kg bw/day (range: 880-1240 mg/kg bw/day), and 1.39% for the developmental toxicity study, corresponding to a mean intake of approximately 830 mg/kg bw/day (range: 457-957 mg/kg bw/day). PMID- 26493002 TI - Contrasting directions and directives on hazard identification for formaldehyde carcinogenicity. PMID- 26493003 TI - Transgenic proteins in agricultural biotechnology: The toxicology forum 40th annual summer meeting. AB - During the 40th Annual Meeting of The Toxicology Forum, the current and potential future science, regulations, and politics of agricultural biotechnology were presented and discussed. The range of current commercial crops and commercial crop traits related to transgenic proteins were reviewed and example crop traits discussed, including insecticidal resistance conferred by Bt proteins and the development of nutritionally enhanced food such as Golden Rice. The existing regulatory framework in the USA, with an emphasis on US FDA's role in evaluating the safety of genetically engineered crops under the regulatory umbrella of the FD&C Act was reviewed. Consideration was given to the polarized politics surrounding agricultural biotechnology, the rise of open access journals, and the influence of the internet and social media in shaping public opinion. Numerous questions related to misconceptions regarding current products and regulations were discussed, highlighting the need for more scientists to take an active role in public discourse to facilitate public acceptance and adoption of new technologies and to enable science-based regulations. PMID- 26493004 TI - Consideration of non-linear, non-threshold and threshold approaches for assessing the carcinogenicity of oral exposure to hexavalent chromium. AB - A non-linear approach, consistent with available mode of action (MOA) data, is most scientifically defensible for assessing the carcinogenicity of oral exposure to hexavalent chromium (CrVI). Accordingly, the current paper builds upon previous studies (Haney, 2015a, 2015b) to first develop a non-linear, non threshold approach as well as a non-linear threshold approach for assessing the oral carcinogenicity of CrVI, and then utilizes available MOA analyses and information for selection of the most scientifically-supported approach. More specifically, a non-linear, non-threshold dose-response function was developed that adequately describes the non-linearity predicted for potential human excess risk versus oral dose due to the sub-linear relationship between oral dose and internal dose (added mg Cr/kg target tissue) across environmentally-relevant doses of regulatory interest. Additionally, benchmark dose modeling was used to derive a reference dose (RfD of 0.003 mg/kg-day) with cytotoxicity-induced regenerative hyperplasia as a key precursor event to carcinogenesis in the mouse small intestine. This RfD value shows remarkable agreement with that published previously (0.006 mg/kg-day) based on a more scientifically-sophisticated, physiologically-based pharmacokinetic modeling approach (Thompson et al., 2013b). The RfD approach is the most scientifically-defensible approach based on the weight-of-evidence of available MOA information and analyses conducted for the most scientifically-supported MOA. PMID- 26493005 TI - Serological evidence of avian encephalomyelitis virus infection associated with vertical transmission in chicks. AB - Avian encephalomyelitis virus (AEV) can be transmitted both horizontally and vertically. In the present study, we report a typical case of AEV infection in broiler breeder chickens and their progeny identified by clinical survey of the disease, antibody detection, and reverse transcription (RT)-polymerase chain reaction (PCR) assay. PMID- 26493006 TI - Comparative efficacy of virus like particle (VLP) vaccine of foot-and-mouth disease virus (FMDV) type O adjuvanted with poly I:C or CpG in guinea pigs. AB - Foot-and-mouth disease (FMD) is one of the most contagious and economically important diseases of cloven-hoofed livestock. Currently used inactivated FMD vaccines have short lived immunity besides risk of handling live virus. We studied recombinant FMD virus like particles (VLPs) encoded by FMDV type O/IND/R2/75 polyprotein genes expressed in Sf9 cells and adjuvanted with CpG or Poly I:C in inducing protective immune response in guinea pigs. Guinea pigs immunized with VLP + CpG vaccine had shown markedly higher cell mediated immunity (CMI) in comparison to the conventional vaccine group as evident from higher levels of IgG2 than IgG1. Although the humoral response was less in VLP + CpG compared to conventional vaccine, the lymphocyte stimulation index was more in VLP + CpG compared to conventional and VLP + Poly I:C vaccine groups. Finally the challenge experiments on 28 and 56 dpv had shown 75% protection in VLP + CpG immunized guinea pigs primary and boosted animals, while 50% and 62% protection in VLP + Poly I:C in primary and boosted animals, respectively. In conclusion, CpG adjuvant was found to be superior followed by ISA206 and Poly I:C in eliciting protection in VLP based FMD vaccines in guinea pigs. PMID- 26493008 TI - Duplex formation and secondary structure of gamma-PNA observed by NMR and CD. AB - Peptide nucleic acids (PNAs) are non-natural oligonucleotides mimics, wherein the phosphoribose backbone has been replaced by a peptidic moiety (N-(2 aminoethyl)glycine). This peptidic backbone lends itself to substitution and the gamma-position has proven to yield oligomers with enhanced hybridization properties. In this study, we use Nuclear Magnetic Resonance (NMR) and Circular Dichroism (CD) to explore the properties of the supramolecular duplexes formed by these species. We show that standard Watson-Crick base pair as well as non standard ones are formed in solution. The duplexes thus formed present marked melting transition temperatures substantially higher than their nucleic acid homologs. Moreover, the presence of a chiral group on the gamma-peptidic backbone increases further this transition temperature, leading to very stable duplexes. PNA duplexes with a chiral backbone present a marked chiral secondary structure, observed by CD, and showing a common folding pattern for all studied structures. Nevertheless small differences are observed depending on the details of the nucleobase sequence. PMID- 26493007 TI - 3-Amidocoumarins as Potential Multifunctional Agents against Neurodegenerative Diseases. AB - Monoamine oxidase (MAO) generates reactive oxygen species (ROS), which cause neuronal cell death, causing neurodegeneration. Agents that are able to concurrently inhibit MAO and scavenge free radicals represent promising multifunctional neuroprotective agents that could be used to delay or slow the progression of neurodegenerative diseases. In this work, variously substituted 3 amidocoumarins are described that exert neuroprotection in vitro against hydrogen peroxide in rat cortical neurons, as well as antioxidant activity in a 1,1 diphenyl-2-picrylhydrazyl (DPPH?) radical scavenging assay. Selective and reversible inhibitors of the MAO-B isoform were identified. Interestingly, in the case of the 3-benzamidocoumarins, substitution at position 4 with a hydroxy group abolishes MAO-B activity, but the compounds remain active in the neuroprotection model. Further evaluation of 3-heteroarylamide derivatives indicates that it is the nature of the heterocycle that determines the neuroprotective effects. Evaluation in a parallel artificial membrane permeability assay (PAMPA) highlighted the need to further improve the blood-brain barrier permeability of this compound class. However, the compounds described herein adhere to Lipinski's rule of five, suggesting that this novel scaffold has desirable properties for the development of potential drug candidates. PMID- 26493009 TI - Indications, outcome and complications with axial pattern skin flaps in dogs and cats: 73 cases. AB - OBJECTIVE: To determine the indications, frequency of complications and long term outcome associated with axial pattern flaps used to repair wound defects in dogs and cats. METHODS: Medical records from two independent referral centres for dogs and cats undergoing wound repair with an axial pattern flap were reviewed. RESULTS: Seventy-three animals were included, 49 dogs: 24 cats. Indications for axial pattern flaps were chronic wounds (43/73; 59%) and closure following tumour resection (30/73; 41%). Axial pattern flaps used were: thoracodorsal, caudal superficial epigastric, reverse saphenous conduit, superficial brachial, deep circumflex iliac, superficial cervical, caudal auricular, lateral thoracic, cranial superficial epigastric, genicular and superficial temporal. Postoperative complications occurred in 64 patients (89%) and 8 patients (11%) had no complications. Complications were: dehiscence, swelling of the flap, necrosis, infection, discharge and seroma. Flap outcome was excellent in 16 patients (23%), good in 29 (41%), fair in 21 (30%) and poor in 5 (7%). CLINICAL SIGNIFICANCE: There is a high complication rate associated with axial pattern flaps but these are usually easily managed and long term outcome is excellent, in either species. PMID- 26493011 TI - The efficacy of automated breast volume scanning over conventional ultrasonography among patients with breast lesions. AB - OBJECTIVE: To compare the efficacy of automated breast volume scanning (ABVS) with that of conventional ultrasonography in the detection of breast cancer lesions. METHODS: In a retrospective study, patients aged 18-78 years who had breast cancer, had undergone screening using ABVS and conventional ultrasonography, and provided a biopsy sample at a center in Changsha, China, between July 22, 2011, and September 20, 2014, were identified. Results of ultrasonography and ABVS were compared. RESULTS: A total of 417 lesions were detected among 300 patients. Ultrasonography detected 326 lesions, whereas ABVS detected all 417 (P<0.001). ABVS detected all 32 malignant lesions and ultrasonography detected 31 (P=0.158). Conventional ultrasonography identified microcalcifications in only two cases, whereas ABVS reported these in eight cases (P<0.001). CONCLUSION: ABVS detects significantly more breast lesions than conventional ultrasonography does. PMID- 26493010 TI - Activity of botulinum toxin type A in cranial dura: implications for treatment of migraine and other headaches. AB - BACKGROUND AND PURPOSE: Although botulinum toxin type A (BoNT/A) is approved for chronic migraine treatment, its mechanism of action is still unknown. Dural neurogenic inflammation (DNI) commonly used to investigate migraine pathophysiology can be evoked by trigeminal pain. Here, we investigated the reactivity of cranial dura to trigeminal pain and the mechanism of BoNT/A action on DNI. EXPERIMENTAL APPROACH: Because temporomandibular disorders are highly comorbid with migraine, we employed a rat model of inflammation induced by complete Freund's adjuvant, followed by treatment with BoNT/A injections or sumatriptan p.o. DNI was assessed by Evans blue-plasma protein extravasation, cell histology and RIA for CGRP. BoNT/A enzymatic activity in dura was assessed by immunohistochemistry for cleaved synaptosomal-associated protein 25 (SNAP-25). KEY RESULTS: BoNT/A and sumatriptan reduced the mechanical allodynia and DNI, evoked by complete Freund's adjuvant. BoNT/A prevented inflammatory cell infiltration and inhibited the increase of CGRP levels in dura. After peripheral application, BoNT/A-cleaved SNAP-25 colocalized with CGRP in intracranial dural nerve endings. Injection of the axonal transport blocker colchicine into the trigeminal ganglion prevented the formation of cleaved SNAP-25 in dura. CONCLUSIONS AND IMPLICATIONS: Pericranially injected BoNT/A was taken up by local sensory nerve endings, axonally transported to the trigeminal ganglion and transcytosed to dural afferents. Colocalization of cleaved SNAP-25 and the migraine mediator CGRP in dura suggests that BoNT/A may prevent DNI by suppressing transmission by CGRP. This might explain the effects of BoNT/A in temporomandibular joint inflammation and in migraine and some other headaches. PMID- 26493012 TI - Oncologic and reproductive outcomes after fertility-sparing management with oral progestin for women with complex endometrial hyperplasia and endometrial cancer. AB - OBJECTIVE: To investigate the oncologic and reproductive outcomes after progestin treatment of complex endometrial hyperplasia (CEH) and grade 1 endometrial carcinoma (EC). METHODS: In a retrospective study, data were obtained for patients aged 20-42years with CEH or grade 1 EC at presumed stage IA (without myometrial invasion) who wished to preserve fertility and were treated at the Peking Union Medical College Hospital, China, between January 1, 2000, and December 31, 2011. Patients had received oral medroxyprogesterone acetate (250 500mg/day) or megestrol acetate (160-480mg/day) for at least 6months. Response to progestin treatment was assessed histologically. RESULTS: Among 53 included patients, 39 (74%) achieved complete response after a median period of 6 (3-24) months. Complete response was less frequent among obese than nonobese patients (4/12 [33%] vs 35/41 [85%]; P=0.001). Disease recurrence was recorded in 10 (26%) patients with complete response; the 5-year recurrence-free survival rate was 71%. Among the 33 patients who retained a desire to conceive, 17 (52%) became pregnant. CONCLUSION: Fertility-sparing management with oral progestin is effective. Obesity is associated with a lower probability of long-term success. PMID- 26493013 TI - Obstetric care of women with female genital mutilation attending a specialized clinic in a tertiary center. AB - OBJECTIVE: To study the obstetric outcomes of women attending a specialized clinic for women with female genital mutilation (FGM). METHODS: The medical charts of women with FGM who consecutively attended a specialized clinic between 2010 and 2012 were reviewed retrospectively. The present study focused on women attending for obstetric reasons. The outcome measures were type of delivery, reason for cesarean delivery or assisted delivery, blood loss, episiotomy, perineal tear, duration of the second stage of labor, postpartum complications, weight of the neonate, and Apgar score. Outcomes were compared between women with FGM type III who underwent defibulation, and patients with FGM type I and II. RESULTS: The clinic was attended by 129 women, 84 perinatally. Obstetric outcomes were similar to average outcomes for women without FGM presenting at the same department and in Switzerland generally. Specifically, 20 women had a cesarean delivery. An assisted delivery was performed for 18 patients; among these, only eight had experienced obstructed labor. No statistically significant differences were found for the outcome measures when women with FGM type III were compared to FGM type I and II. CONCLUSIONS: Routine obstetric follow-up combined with specialized care for women with FGM, including defibulation, can avoid inappropriate obstetric practices and reduce obstetric complications known to be associated with FGM. PMID- 26493014 TI - Transforming growth factor beta (CiTGF-beta) gene expression is induced in the inflammatory reaction of Ciona intestinalis. AB - Transforming growth factor (TGF-beta) is a well-known component of a regulatory cytokines superfamily that has pleiotropic functions in a broad range of cell types and is involved, in vertebrates, in numerous physiological and pathological processes. In the current study, we report on Ciona intestinalis molecular characterisation and expression of a transforming growth factor beta homologue (CiTGF-beta). The gene organisation, phylogenetic tree and modelling supported the close relationship with the mammalian TGF suggesting that the C. intestinalis TGF-beta gene shares a common ancestor in the chordate lineages. Functionally, real-time PCR analysis showed that CiTGF-beta was transcriptionally upregulated in the inflammatory process induced by LPS inoculation, suggesting that is involved in the first phase and significant in the secondary phase of the inflammatory response in which cell differentiation occurs. In situ hybridisation assays revealed that the genes transcription was upregulated in the pharynx, the main organ of the ascidian immune system, and expressed by cluster of hemocytes inside the pharynx vessels. These data supported the view that CiTGF-beta is a potential molecule in immune defence systems against bacterial infection. PMID- 26493017 TI - Announcing the appointment of Mike Belosevic as Coeditor-in-Chief. PMID- 26493015 TI - Molecular characterization and expression analysis of mitochondrial antiviral signaling protein gene in sea perch, Lateolabrax japonicus. AB - The mitochondrial antiviral signaling protein (MAVS) is vital for host defenses against viral infection by inducing expression of type I interferon. Here, the MAVS of sea perch (Lateolabrax japonicus) (LjMAVS) was cloned and analyzed. The complete cDNA sequence of LjMAVS was 3207 bp and encoded a polypeptide of 601 amino acids. LjMAVS contains an N-terminal CARD-like domain, a central proline rich domain and a C-terminal transmembrane domain. Phylogenetic analysis indicated that LjMAVS exhibited the closest relationship to O. fasciatus MAVS. LjMAVS was ubiquitously expressed in all tested tissues of healthy fish. The expression of LjMAVS was significantly increased post nervous necrosis virus (NNV) infection in vivo in all the selected tissues. Furthermore, time course analysis showed that LjMAVS transcripts significantly increased in the brain, spleen and kidney tissues after NNV infection. LjMAVS mRNA expression was significantly up-regulated in vitro after poly I:C stimulation. The viral gene transcription of RGNNV was significantly decreased in LjMAVS over-expressing LJB cells. These findings provide useful information for further elucidating the function ofLjMAVS in antiviral innate immune against NNV in sea perch. PMID- 26493016 TI - Akirin interacts with Bap60 and 14-3-3 proteins to regulate the expression of antimicrobial peptides in the kuruma shrimp (Marsupenaeus japonicus). AB - Akirin is a recently discovered nuclear factor that plays important roles in innate immune responses. Akirin is a positive regulator of the NF-kappaB factor of the Drosophila immune deficiency (IMD) pathway, which shares extensive similarities with the mammalian tumor necrosis factor receptor (TNFR) signaling pathway. However, some studies found that the NF-kappaB transcriptional targets were also strongly repressed in akirin2 knockout mice following TLR, IL-1beta and TNFalpha treatment. Therefore, the function of Akirin in the immune response requires further clarification. In this study, an Akirin homolog in the kuruma shrimp (Marsupenaeus japonicus) was identified. It was mainly expressed in hemocytes, heart and intestines. The expression of Akirin was upregulated by challenge with the Gram-negative bacterium Vibrio anguillarum, but was not significantly influenced by challenge with the Gram-positive bacterium Staphylococcus aureus. Knockdown of Akirin suppressed the expression of several IMD-Relish target effectors (antimicrobial peptides, AMPs). The limited regulating spectrum of Akirin might be associated with Bap60, a component of the Brahma (SWI/SNF) ATP-dependent chromatin-remodeling complex. In addition, Akirin also interacts with 14-3-3, which inhibited the expression of Akirin-target AMPs. The results suggested that Akirin is involved in the IMD-Relish pathway by interacting with Relish. The interaction of Akirin with Bap60 positively regulated the Akirin-Relish function, and its interaction with 14-3-3 negatively regulated the Akirin-Relish function. PMID- 26493018 TI - Generation of N-Heterocycles via Tandem Reactions of N '-(2 Alkynylbenzylidene)hydrazides. AB - As a powerful synthon, N '-(2-alkynylbenzylidene)hydrazides have been utilized efficiently for the construction of N-heterocycles. Since N '-(2 alkynylbenzylidene)hydrazides can easily undergo intramolecular 6-endo cyclization promoted by silver triflate or electrophiles, the resulting isoquinolinium-2-yl amides can proceed through subsequent transformations including [3 + 2] cycloaddition, nucleophilic addition, and [3 + 3] cycloaddition. Several unexpected rearrangements via radical processes were observed in some cases, which afforded nitrogen-containing heterocycles with molecular complexity. Reactive partners including internal alkynes, arynes, ketenimines, ketenes, allenoates, and activated alkenes reacted through [3 + 2] cycloaddition and subsequent aromatization, leading to diverse H-pyrazolo[5,1 a]isoquinolines with high efficiency. Nucleophilic addition to the in situ generated isoquinolinium-2-yl amide followed by aromatization also produced H pyrazolo[5,1-a]isoquinoline derivatives when terminal alkynes, carbonyls, enamines, and activated methylene compounds were used as nucleophiles. Isoquinoline derivatives were obtained when indoles or phosphites were employed as nucleophiles in the reactions of N '-(2-alkynylbenzylidene)hydrazides. A tandem 6-endo cyclization and [3 + 3] cycloaddition of cyclopropane-1,1 dicarboxylates with N '-(2-alkynylbenzylidene)hydrazides was observed as well. Small libraries of these compounds were constructed. Biological evaluation suggested that some compounds showed promising activities for inhibition of CDC25B, TC-PTP, HCT-116, and PTP1B. PMID- 26493019 TI - Ion strength limit of computed excess functions based on the linearized Poisson Boltzmann equation. AB - The linearized Poisson-Boltzmann (L-PB) equation is examined for its kappa-range of validity (kappa, Debye reciprocal length). This is done for the Debye-Huckel (DH) theory, i.e., using a single ion size, and for the SiS treatment (D. Fraenkel, Mol. Phys. 2010, 108, 1435), which extends the DH theory to the case of ion-size dissimilarity (therefore dubbed DH-SiS). The linearization of the PB equation has been claimed responsible for the DH theory's failure to fit with experiment at > 0.1 m; but DH-SiS fits with data of the mean ionic activity coefficient, gamma+/- (molal), against m, even at m > 1 (kappa > 0.33 A(-1) ). The SiS expressions combine the overall extra-electrostatic potential energy of the smaller ion, as central ion-Psia>b (kappa), with that of the larger ion, as central ion-Psib>a (kappa); a and b are, respectively, the counterion and co-ion distances of closest approach. Psia>b and Psib>a are derived from the L-PB equation, which appears to conflict with their being effective up to moderate electrolyte concentrations (~1 m). However, the L-PB equation can be valid up to kappa >= 1.3 A(-1) if one abandons the 1/kappa criterion for its effectiveness and, instead, use, as criterion, the mean-field electrostatic interaction potential of the central ion with its ion cloud, at a radial distance dividing the cloud charge into two equal parts. The DH theory's failure is, thus, not because of using the L-PB equation; the lethal approximation is assigning a single size to the positive and negative ions. PMID- 26493020 TI - Replication study of MATR3 in familial and sporadic amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by an extensive loss of motor neurons in the primary motor cortex, brainstem, and spinal cord. Genetic studies report a high heritability of ALS. Recently, whole-exome sequencing analysis of familial ALS (FALS) patients allowed the identification of missense variations within the MATR3 gene. MATR3 was previously associated to distal myopathy 2 and encodes for a nuclear matrix and DNA/RNA binding protein that has been shown to interact with TDP43 in an RNA dependent manner. Here, we assessed the MATR3 mutation frequency in French Canadian ALS and control individuals (nFALS = 83, sporadic ALS [nSALS] = 164, and ncontrols = 162) and showed that MATR3 mutations were found in 0%, 1.8%, and 0% of FALS, SALS, and controls, respectively. Interestingly, among the mutations identified in SALS, the splicing mutation c.48+1G>T was found to result in the insertion of 24 amino acids in MATR3 protein. These findings further support the role of MATR3 in ALS, and more studies are needed to shed more light on MATR3 proteinopathy. PMID- 26493021 TI - A retrospective study on perineal lacerations in vaginal delivery and the individual performance of experienced mifwives. AB - BACKGROUND: Medical staff's influence on patient outcomes has become a subject of interest. We evaluated experienced midwives and compared their performance concerning perineal lacerations (PL). METHODS: In a retrospective cohort study, 1937 women with singleton pregnancies who had delivered spontaneously with a cephalic presentation by experienced midwives in the Medical University of Vienna from January 2009 to April 2014 were included. As predictive parameters, we included basic patient-, pregnancy- and delivery-related characteristics including the individual midwife who delivered the child. The incidence of PL was the main outcome measure. RESULTS: Overall PL and severe PL were found in 508/1937 (26.2%) and 19/1937 women (1.0%), respectively. In a multivariate analysis for PL of any degree, maternal age (beta = 0.170 +/- 0.080), gestational age at delivery (beta = 0.190 +/- 0.320), and birth weight (beta = 0.002 +/- 0.000) significantly increased the risk, whereas multiparity (beta = -0.379 +/- 0.141) and mediolateral episiotomy (beta = -1.514 +/- 0.284) decreased it (p < 0.05). In addition, the individual midwife who delivered the child was a significant influencing factor, with beta-values ranging from -0.028 to 0.899 compared to the reference midwife. For severe PL, the midwife was not of significant influence. CONCLUSIONS: The individual midwife is an independent factor that influences the risk for overall PL, not for severe PL. Other risk factors include maternal age, gestational age at delivery, birth weight, parity and episiotomy. PMID- 26493022 TI - Filgrastim versus TBO-filgrastim to reduce the duration of neutropenia after autologous hematopoietic stem cell transplantation: TBO, or not TBO, that is the question. AB - After a hospital-wide formulary change resulted in the replacement of filgrastim with TBO-filgrastim for all on- and off-label indications, we performed a retrospective comparison of patients with myeloma receiving 200 mg/m(2) melphalan with autologous hematopoietic stem cell transplantation to see whether the type of growth factor used post-transplant made a difference. One hundred and eighty two consecutive patients with myeloma were studied, 91 receiving filgrastim immediately prior to the change and 91 receiving TBO-filgrastim afterward. The CD34(+) cell dose was comparable, as were other characteristics. Although the overall time to neutrophil recovery was similar for both groups, early engraftment (<= 12 d) occurred more often (p = 0.05), and late engraftment (>= 14 d) less often (p = 0.09) in filgrastim-treated patients. The number of documented infections was significantly less in the TBO-filgrastim group. Day 100 mortality and hospital stay were similar for the two groups. These data indicate that there is no material difference between filgrastim and TBO-filgrastim in this clinical setting. PMID- 26493023 TI - Uric acid, carotid intima-media thickness and body composition in prepubertal children. AB - BACKGROUND: Increased uric acid is an independent biomarker for cardiovascular disease in obese adolescents and adults. OBJECTIVE: We investigated whether uric acid relates to carotid intima-media thickness (cIMT) in prepubertal children, and whether body mass index (BMI) and preperitoneal fat modulate this association. METHODS: 359 asymptomatic prepubertal Caucasian children were stratified according to BMI categories (171 with BMI-SDS < 0; 188 with BMI-SDS >= 0) and according to preperitoneal fat levels (180 with preperitoneal fat <50th centile; 179 with preperitoneal fat >50th centile). Uric acid levels, insulin resistance (homeostasis model assessment insulin resistance; HOMA-IR), C-reactive protein (CRP), triacylglycerol (TG), systolic blood pressure (SBP), abdominal fat and cIMT (both by ultrasound) were assessed. RESULTS: Uric acid was associated with several cardiovascular risk factors, namely higher HOMA-IR, CRP, TG, BMI, waist, SBP, preperitoneal fat and cIMT (all P < 0.001 to P < 0.0001). Significant BMI and preperitoneal fat interactions were documented in the relationship between uric acid and cIMT (both P < 0.05), as uric acid was preferentially related to cIMT in heavier children (beta = 0.247, P < 0.001, r(2) = 9.1%) and in children with more preperitoneal fat (beta = 0.263, P < 0.0001, r(2) = 11.9%). CONCLUSIONS: Serum uric acid is associated with cIMT in asymptomatic prepubertal children. Both higher BMI and preperitoneal fat aggravate the potential risk of atherosclerotic disease imposed by higher concentrations of uric acid. PMID- 26493024 TI - Prolonged silencing of diacylglycerol acyltransferase-1 induces a dedifferentiated phenotype in human liver cells. AB - Diacylglycerol acyltransferase-1 (DGAT1), a key enzyme in triglyceride (TG) biogenesis, is highly associated with metabolic abnormalities, such as obesity and type 2 diabetes. However, the effects of DGAT1 silencing in the human liver have not been elucidated. To investigate the effects of DGAT1 silencing in human liver cells, we compared the cellular behaviours of DGAT1-deficient Huh-7.5 cell lines with those of control Huh-7.5 cells. DGAT1-deficient cells acquired dedifferentiated and stem cell-like characteristics, such as formation of aggregates in the presence of high levels of growth factors, high proliferation rates and loss of albumin secretion. In relation to aggregate formation, the expression level of various adhesion molecules was significantly altered in DGAT1 deficient cells. Microarray data analysis and immunostaining of patient tissue samples clearly showed decreased expression levels of DGAT1 and integrin beta1 in patients who have nodular cirrhosis without fatty degeneration. PMID- 26493025 TI - Optimum number of procedures required to achieve procedural skills competency in internal medicine residents. AB - BACKGROUND: Procedural skills training forms an essential, yet difficult to assess, component of an Internal Medicine Residency Program. We report the development of process of documentation and assessment of procedural skills training. METHOD: An explanatory sequential mixed methods design was adopted where both quantitative and qualitative information was collected sequentially. A survey was conducted within the Department of Internal Medicine at The Aga Khan University Hospital, Karachi, Pakistan to determine the optimum number of procedures needed to be performed by residents at each year of residency. Respondents included both faculty and the residents in the Department. Thereafter, all responses were compiled and later scrutinized by a focus group comprising of a mix of faculty from various subspecialties and resident representatives. RESULTS: A total of 64 responses were obtained. A significant difference was found in eight procedural skills' status between residents and faculty, though none of these were significant after accounting for multiple consecutive testing. However, the results were reviewed and a consensus for the procedures needed was developed through a focus group. A finalized procedural list was generated to determine: (a) the minimum number of times each procedure needed to be performed by the resident before deemed competent; (b) the level of competency for each procedure for respective year of residency. CONCLUSION: We conclude that the opinion of both the residents and the faculty as key stakeholders is vital to determine the number of procedures to be performed during an Internal Medicine Residency. Documentation of procedural competency development during the training would make the system more objective and hence reproducible. A log book was designed consisting of minimum number of procedures to be performed before attaining competency. PMID- 26493026 TI - Echocardiographic Assessment of Mantle Radiation Mitral Stenosis. AB - The long-term sequelae of mantle radiotherapy include lung disease and cardiac disorders. Dyspnea on exertion is a common complaint and can be due to one or more pathologies. We describe a case of mantle radiotherapy-induced mitral stenosis, characterized by aorto-mitral continuity calcification and absent commissural fusion which precludes balloon valvotomy. The latency period is long, and this patient presented 42 years after radiotherapy. Importantly, as previously described with radiation-induced valve disease, significant mitral stenosis developed 10 years after surgery for significant aortic stenosis. Two dimensional and three-dimensional transthoracic and transesophageal echocardiography should be considered during assessment of symptomatic survivors of Hodgkin's disease where the index of suspicion for valvular stenosis increases over time. Given the natural history of mantle radiation valvular disease, a lower threshold for surgical intervention in radiation-induced mitral stenosis may need to be considered if cardiac surgery is planned for other reasons in order to avoid repeated sternotomy in patients with prior irradiation. PMID- 26493027 TI - Relationship of functional disability after a recent stroke with recurrent stroke risk. AB - BACKGROUND AND PURPOSE: Post-stroke disability status is primarily focused on recovery prognostication but the influence of post-stroke disability on future vascular risk is unknown. The relationship between functional disability after an index stroke and risk of recurrent vascular events was examined. METHODS: A cohort analysis of 3680 recent non-cardioembolic, non-to-moderate disabled [modified Rankin Scale (mRS) <=3] stroke patients aged >=35 years and followed for 2 years was reviewed. The mRS measured at a median of 35 days after the index stroke was analyzed as a dichotomous variable (mRS 3 vs. <=2) and in a stepwise manner. Independent associations of post-stroke disability by mRS score with ischaemic stroke (primary outcome), stroke/coronary heart disease/vascular death as major vascular events (secondary outcome) and all-cause death (tertiary outcome) were analyzed. RESULTS: Amongst study participants, 435 (11.8%) had an mRS of 3. Compared with mRS <=2 as no/slight disability, mRS 3 as moderate disability was associated with a higher risk of stroke (adjusted hazard ratio 1.45, 95% confidence interval 1.06-1.99). Compared with mRS 0, there was a progressively higher independent risk for each of the study outcomes: stroke, mRS 1 (1.42, 0.97-2.08), mRS 2 (1.46, 0.97-2.20), mRS 3 (1.89, 1.20-2.97); major vascular events, mRS 1 (1.31, 1.01-1.70), mRS 2 (1.31, 0.99-1.74), mRS 3 (1.46, 1.06-2.01); and all-cause death, mRS 1 (1.75, 1.03-2.98), mRS 2 (2.49, 1.44 4.31), mRS 3 (2.72, 1.43-5.19). CONCLUSION: Compared with no/slight disability, moderate disability after a recent stroke is linked to a higher risk of recurrent stroke. PMID- 26493028 TI - Genetic characterization of T-PLL reveals two major biologic subgroups and JAK3 mutations as prognostic marker. AB - T-cell prolymphocytic leukemia (T-PLL) is a rare post-thymic T-cell neoplasm with aggressive clinical course and short overall survival. So far, due to the rareness of this disease, genetic data are available only from individual cases or small cohorts. In our study, we aimed at performing a comprehensive cytogenetic and molecular genetic characterization of T-PLL comprising the largest cohort of patients with T-PLL analyzed so far, including correlations between the respective markers and their impact on prognosis. Genetic abnormalities were found in all 51 cases with T-PLL, most frequently involving the TCRA/D locus (86%). Deletions were detected for ATM (69%) and TP53 (31%), whereas i(8)(q10) was observed in 61% of cases. Mutations in ATM, TP53, JAK1, and JAK3 were detected in 73, 14, 6, and 21% of patients, respectively. Additionally, BCOR mutations were observed for the first time in a lymphoid malignancy (8%). Two distinct genetic subgroups of T-PLL were identified: A large subset (86% of patients) showed abnormalities involving the TCRA/D locus activating the proto oncogenes TCL1 or MTCP1, while the second group was characterized by a high frequency of TP53 mutations (4/7 cases). Further, analyses of overall survival identified JAK3 mutations as important prognostic marker, showing a significant negative impact. PMID- 26493029 TI - Eupalitin induces apoptosis in prostate carcinoma cells through ROS generation and increase of caspase-3 activity. AB - Prostate cancer is the second most common malignancy in the human reproductive system. Eupalitin is one of the O-methylated flavonol-exhibited enhanced cancer chemopreventive agents. The current study highlights the structural determination of eupalitin and aims to explore the antitumor activity of eupalitin in human prostate cancer cell (PC3) and its underlying mechanism. Eupalitin structure was determined by using FTIR, (1)H NMR, and (13)C NMR. PC3 cells were treated with increasing concentrations of eupalitin, followed by analysis of the cell viability with an MTT assay. The results demonstrated that eupalitin markedly inhibited the proliferation of PC3 cells in a concentration-dependent manner. The results from fluorescent microscopic analysis of nuclear condensation and intracellular ROS generation determined that eupalitin significantly induced ROS level lead to nuclear apoptosis. Cell cycle analysis revealed that eupalitin induced cell cycle progression as a percentage of cells in G0/G1 phase decreased whereas S phase increased. Caspase-3 immunofluorescence analysis confirms the efficacy of eupalitin-inducing apoptotic pathway and cell death. Thus, our study is helpful in understanding the mechanism underlying these effects in prostate cancer and it may provide novel molecular targets for prostate cancer therapy. PMID- 26493030 TI - S-nitrosylation triggers ABI5 degradation to promote seed germination and seedling growth. AB - Plant survival depends on seed germination and progression through post germinative developmental checkpoints. These processes are controlled by the stress phytohormone abscisic acid (ABA). ABA regulates the basic leucine zipper transcriptional factor ABI5, a central hub of growth repression, while the reactive nitrogen molecule nitric oxide (NO) counteracts ABA during seed germination. However, the molecular mechanisms by which seeds sense more favourable conditions and start germinating have remained elusive. Here we show that ABI5 promotes growth via NO, and that ABI5 accumulation is altered in genetic backgrounds with impaired NO homeostasis. S-nitrosylation of ABI5 at cysteine-153 facilitates its degradation through CULLIN4-based and KEEP ON GOING E3 ligases, and promotes seed germination. Conversely, mutation of ABI5 at cysteine-153 deregulates protein stability and inhibition of seed germination by NO depletion. These findings suggest an inverse molecular link between NO and ABA hormone signalling through distinct posttranslational modifications of ABI5 during early seedling development. PMID- 26493031 TI - Prolonged organ culture reduces the incidence of endothelial immune reactions. AB - PURPOSE The number of antigen-presenting cells decreases during organ culture of corneoscleral discs. This might result in a decrease of immune reactions with increasing duration of organ culture. To investigate this hypothesis, we performed a retrospective analysis of all penetrating keratoplasties that were consecutively performed over the last 5 years.PATIENTS AND METHODS All cases of penetrating keratoplasties (n=1006) were divided into two groups, with the division made at the median of the storage time (21 days). These two groups were compared by a Cox proportional hazards survival model regarding the incidence of endothelial immune reactions, clear graft survival, and chronic endothelial cell loss following penetrating keratoplasty considering patient's age, donor's age, and risk situation as co-variates.RESULTS We observed statistically significantly fewer endothelial immune reactions (20.1% (95% confidence interval 15.5-24.5%) after 2 years) in the group with a storage time of more than 21 days compared with the group with a storage time of <21 days (26.5% (95% confidence interval 21.6-31.2%) after 2 years). However, the duration of organ culture did not have a statistically significant effect on clear graft survival or chronic endothelial cell loss.CONCLUSION Our results demonstrate that an increased duration of organ culture leads to a lower incidence of endothelial immune reactions following penetrating keratoplasty. However, we do not recommend increased storage times in general as overall graft survival did not improve. The reason for this apparent paradox may be that the endothelial cell count decreases during storage time. PMID- 26493032 TI - South Asian diabetic macular oedema treated with ranibizumab (ADMOR)-real-life experience. AB - PURPOSE Diabetic macular oedema (DMO) is a leading cause for visual impairment in the working age population in the UK. Ranibizumab has been shown to be effective in treatment of DMO in studies based on mainly Caucasian populations. This study reports the 12-month outcome in a cohort of South Asian subjects with DMO treated with ranibizumab.MethodsDMO in 51 eyes of 41 South Asian patients was treated with ranibizumab 0.5 mg according to the modified DRCRnet protocol I. Visual acuity (VA) and central macular thickness (CMT) were recorded at baseline, 3, 6, and 12 months. Results were compared for eyes with different baseline visual acuities and different baseline macular thicknesses.RESULTS Over the 12-month period, the mean ETDRS VA increased from 55.3+/-13.4 letters to 63.8+/-15.2 letters for all eyes. At 12 months, 70.6% eyes gained 5 or more letters acuity and 17.6% eyes gained 15 letters or more. During the same period, the mean CMT decreased from 532+/-129 to 318+/-136 MUm. Eyes that had received previous laser treatments had a mean letter gain of 9.2 letters, compared with 8.5 for all eyes at 12 months.CONCLUSIONS Ranibizumab 0.5 mg is safe and effective at reversing vision loss due to DMO in patients of South Asian origin at 12 months. Ranibizumab treatment appears to be effective in patients with longstanding DMO who received prior laser treatments. Further studies are needed to define the long-term outcome in patients of different ethnicity and DMO. PMID- 26493033 TI - Complement pathway biomarkers and age-related macular degeneration. AB - In the age-related macular degeneration (AMD) 'inflammation model', local inflammation plus complement activation contributes to the pathogenesis and progression of the disease. Multiple genetic associations have now been established correlating the risk of development or progression of AMD. Stratifying patients by their AMD genetic profile may facilitate future AMD therapeutic trials resulting in meaningful clinical trial end points with smaller sample sizes and study duration. PMID- 26493034 TI - The Royal College of Ophthalmologists' National Ophthalmology Database Study of cataract surgery: report 2, relationships of axial length with ocular copathology, preoperative visual acuity, and posterior capsule rupture. AB - PURPOSE: To describe the relationships of axial length with ocular copathology, preoperative visual acuity, and posterior capsule rupture rates in patients undergoing cataract surgery.DesignThe Royal College of Ophthalmologists' National Ophthalmology Database (NOD) study. METHODS: Anonymised data on 180 114 eyes from 127 685 patients undergoing cataract surgery between August 2006 and November 2010 were collected prospectively from 28 sites. Data parameters included: demographics, biometry, ocular copathology, visual acuity measurements, and surgical complications including posterior capsule rupture, or vitreous loss or both (PCR). RESULTS: Consultant surgeons performed a higher proportion of operations on eyes whose axial length were at the extremes. Glaucoma and age related macular degeneration were more common in eyes with shorter axial lengths, whilst previous vitrectomy was associated with longer axial lengths. Eyes with brunescent or white cataracts or amblyopia were more common at both axial length extremes. Preoperative visual acuities were similar for eyes with axial length measurements up to approximately 28 mm and worse for eyes with longer axial length measurements. PCR rates showed little change with axial length (overall mean 1.95%, 95% CI: 1.89 to 2.01%), except for a borderline increase in eyes with axial length <20.0 mm where rates were 3.6% (95% CI: 2.0 to 6.3%). The likelihood of PCR in eyes with axial length <20.0 mm was 1.88 times higher than those of >=20.0 mm (P=0.0373). CONCLUSION: Rates of ocular comorbidities vary by axial length. PCR rates in eyes with very short or long axial lengths were lower than expected. PMID- 26493035 TI - A rare penetrant TIMP3 mutation confers relatively late onset choroidal neovascularisation which can mimic age-related macular degeneration. AB - PURPOSE: To perform a genotype-phenotype correlation for three patients heterozygous for a missense mutation in the tissue inhibitor of metalloproteinase 3 (TIMP3) gene. METHODS: Retrospective, observational case series. The medical records and photographs were reviewed for three patients diagnosed at the time with neovascular age-related macular degeneration (AMD). All were later found to carry a predicted C113G mutation in the TIMP3 gene, other known mutations in which are associated with Sorsby's fundus dystrophy. RESULTS: All three patients developed drusen and bilateral choroidal neovascularisation with subsequent disciform scarring and atrophy. Visual acuity rapidly deteriorated to <6/60 in both eyes. The age of onset varied from 56 to 64 years and the interval to contralateral eye involvement varied from 4 to 6 years. Two of the three patients had a family history of AMD. All three patients were heterozygous for the C113G nucleotide change, resulting in a Ser38Cys change at the N terminus of the TIMP3 protein. CONCLUSION: This case series suggests the C113G TIMP3 variant may represent a novel highly penetrant mutation causing choroidal neovascularisation of relatively late onset for Sorsby's fundus dystrophy, mimicking early onset AMD. PMID- 26493036 TI - Primary posterior continuous curvilinear capsulorhexis combined with diffractive multifocal intraocular lens implantation. AB - PurposeTo evaluate the effect of mild posterior capsule opacity (PCO) on visual acuity (VA) in eyes implanted with a diffractive multifocal intraocular lens (IOL) compared with a monofocal IOL, and the effect of posterior continuous curvilinear capsulorhexis (PCCC) combined with diffractive multifocal IOL implantation.MethodsFor the initial evaluation, we compared charge-coupled device (CCD) camera photographs taken through both a monofocal IOL-loaded model eye and a diffractive IOL-loaded model eye under the conditions of both with and without an opaque filter for the simulation of mild PCO. The clinical evaluation involved 20 patients who underwent bilateral implantation of the same diffractive multifocal IOL. In all 20 cases, PCCC was performed in 1 eye (PCCC group) and not performed in the fellow eye (NCCC group). Postoperative clinical results were then compared between the two groups.ResultsThe CCD photographs revealed that the diffractive IOL-loaded eye was more strongly affected by the simulated PCO than was the monofocal IOL-loaded eye. In the clinical setting, the PCCC group registered better results than NCCC group in distance and near VA, low-contrast VA, and contrast sensitivity testing.ConclusionsDiffractive multifocal IOLs tend to be more influenced by mild PCO than do monofocal IOLs, and PCCC prior to IOL implantation can contribute to the avoidance of this effect. PMID- 26493037 TI - Depth evaluation of intended vs actual intacs intrastromal ring segments using optical coherence tomography. AB - PurposeEvaluation of actual vs intended intrastromal corneal ring segments (ICRS) implantation depth as measured by anterior segment optical coherence tomography (OCT)MethodsProspective study evaluating 30 Intacs segments implanted manually in 19 eyes of 15 patients suffering from keratoconus. Segment depth evaluation was performed using anterior segment OCT. Measurements were performed above and below the segment at 3 points in relation to the incision site. Statistical analysis was performed using the SAS software for ANOVA, matched t-test, and GLIMMIX procedure.ResultsIntacs segment depth was 153-MUm shallower than intended (58% vs 80%). Segment layout demonstrated the proximal and distal portions to be 13-MUm shallower and 12-MUm deeper (on average), respectively. Intacs segment thickness does not influence implantation depth. Intacs segments implanted in the same eye do not share similar implantation depths. Stromal compression is likely to occur.ConclusionIntacs are implanted at a shallower depth than intended. The 'pocketing' stage prior to implantation most likely has a stronger effect on the segment's final implantation depth than does the incisions' depth. PMID- 26493038 TI - A randomized clinical trial comparing fixed vs pro-re-nata dosing of Ozurdex in refractory diabetic macular oedema (OZDRY study). AB - OBJECTIVE: To compare the clinical effectiveness and safety of 5-monthly fixed dosing vs pro-re-nata (PRN) Ozurdex treatment in patients with refractory diabetic macular oedema (DMO). DESIGN: Prospective, multicentre, randomized active-controlled non-inferiority clinical trial. PARTICIPANTS: Participants were 100 patients who attended Medical Retina Clinics for management of centre involving refractory DMO. INTERVENTIONS: Participants were randomized 1 : 1 to either 5-monthly fixed dosing or optical coherence tomography (OCT)-guided PRN regimen of Ozurdex therapy for DMO. Data were collected on best-corrected visual acuity (BCVA), patient-reported outcome measures (PROM), macular thickness and morphology, diabetic retinopathy status, number of injections and adverse events from baseline for a period of 12 months.Main outcome measuresThe primary outcome was the difference between arms in change in BCVA from baseline to 12 months. The prespecified non-inferiority margin was five ETDRS letters. Key secondary outcomes included change in PROM scores, change in macular thickness, change in retinopathy and macular morphology, and safety profile. RESULTS: The mean change in BCVA was +1.48 (SD 14.8) in the fixed arm vs -0.17 (SD 13.1) in the PRN arm, with adjusted effect estimate +0.97, 90% confidence interval (-4.01, +5.95), P=0.02 (per protocol analysis). The conclusions of the ITT analysis were primarily supportive, -0.34 (-5.49, 4.81) P=0.07, but sensitive to an alternative assumption on missing data, +0.28 (-4.72, 5.27) P=0.04. CONCLUSIONS: The mean change in BCVA with 5-monthly fixed dosing of Ozurdex was non-inferior to OCT guided PRN Ozurdex therapy for refractory DMO based on a per protocol analysis. PMID- 26493039 TI - High-hyperopia database, part I: clinical characterisation including morphometric (biometric) differentiation of posterior microphthalmos from nanophthalmos. AB - PURPOSE To characterise and differentiate posterior microphthalmos (PM) and nanophthalmos (NO) using morphometric parameters.Patients and methodsConsecutive case database of patients with hyperopia >+7.00 D sphere was analysed retrospectively for clinical and biometric characterisation. Thirty-eight consecutive high-hyperopic subjects (75 eyes) with axial lengths <20.5 mm underwent uniform comprehensive ocular evaluation. Twenty-five subjects were diagnosed as PM and 13 as NO based on the horizontal corneal diameter. Parameters analysed included visual acuity, refraction, horizontal corneal diameter, anterior chamber depth, lens thickness, axial length, fundus changes, and associated ocular pathology. PRIMARY OUTCOME MEASURES: ocular biometry difference between PM and NO. SECONDARY OUTCOME MEASURES: differences in associated ocular pathologies between PM and NO.RESULTS Hyperopia ranged from +7 to +17 D and was similar in the two groups. Lens thickness was statistically more in NO than in PM group (4.53+/-0.75 mm vs 3.82+/-0.48 mm, P <0.001), whereas anterior chamber depth was more in the PM than in NO group (3.26+/-0.36 mm, vs 2.59+/-0.37 mm, P<0.001). NO had higher association with angle-closure glaucoma (66.7% vs 0%) and pigmentary retinopathy (38.5 vs 8.0%) but lesser association with macular folds (0% vs 24%) as compared with PM. NO was associated with poorer visual acuity.CONCLUSION PM and NO have significant differences in lens thickness, anterior chamber depth, prevalence of glaucoma, pigmentary retinopathy, macular pathology, and visual acuity while being similar in hyperopic refraction. PMID- 26493040 TI - Retinal vessel structure measurement using spectral-domain optical coherence tomography. AB - PURPOSE: To assess the reliability and validity of spectral-domain optical coherence tomography (SD-OCT) measurements of retinal vessel lumen diameters and wall thicknesses. METHODS: SD-OCT was used to characterize the circular region around the optic disc of 40 eyes (20 subjects). The inner and outer sides (vitreal and choroidal sides) of the vessel wall and the luminal diameter were measured using intensity graphs. RESULTS: Mean arterial and venous luminal diameters were 95.1+/-16.1 and 132.6+/-17.8 MUm, respectively. The wall thicknesses of inner and outer sides of the artery were 23.9+/-4.9 and 21.2+/-3.5 MUm, respectively. The wall thicknesses of the inner and outer sides of the vein were 20.7+/-4.2 and 16.3+/-4.3 MUm, respectively. There were significant differences between the inner and outer wall thicknesses in both the artery and vein (P<0.01). Intra- and interobserver intraclass correlation coefficients (ICCs) for lumen measurements were >0.95, and for wall thicknesses were >0.85, except for the outer wall thickness measurements. The mean value of outer and inner wall thicknesses showed good reproducibility, with ICCs of >0.85. CONCLUSION: Intensity graph-assisted measurements using SD-OCT provided more objective information in finding boundaries of vessels. Luminal diameters and wall thicknesses obtained with OCT showed good overall reproducibility, with inner wall thicknesses being thicker, and with better reproducibility compared with outer wall thicknesses, where ICC values were the lowest among the inner wall thicknesses, mean thicknesses of inner and outer walls, and luminal diameters. When using SD-OCT measurements, caution is therefore advised when using only the outer wall as representative of the wall thicknesses. PMID- 26493041 TI - A load of mice to hypergravity causes AMPKalpha repression with liver injury, which is overcome by preconditioning loads via Nrf2. AB - An understanding of the effects of hypergravity on energy homeostasis is necessary in managing proper physiological countermeasures for aerospace missions. This study investigated whether a single or multiple load(s) of mice to hypergravity has an effect on molecules associated with energy metabolism. In the liver, AMPKalpha level and its signaling were repressed 6 h after a load to +9 Gz hypergravity for 1 h, and then gradually returned toward normal. AMPKalpha level was restored after 3 loads to +9 Gz, suggestive of preconditioning adaptation. In cDNA microarray analyses, 221 genes were differentially expressed by +9 Gz, and the down-regulated genes included Nrf2 targets. Nrf2 gene knockout abrogated the recovery of AMPKalpha elicited by 3 loads to +9 Gz, indicating that Nrf2 plays a role in the adaptive increase of AMPKalpha. In addition, +9 Gz stress decreased STAT3, FOXO1/3 and CREB levels, which was attenuated during the resting time. Similarly, apoptotic markers were enhanced in the liver, indicating that the liver may be vulnerable to hypergravity stress. Preconditioning loads prevented hepatocyte apoptosis. Overall, a load of mice to +9 Gz hypergravity causes AMPKalpha repression with liver injury, which may be overcome by multiple loads to hypergravity as mediated by Nrf2. PMID- 26493042 TI - Effect of acute and chronic glucocorticoid therapy on insulin sensitivity and postprandial vascular function. AB - OBJECTIVE: Postprandial hyperglycaemia is associated with increased arterial stiffness and cardiovascular events. Low-dose prednisolone causes insulin resistance that typically manifests as postprandial hyperglycaemia. We investigated whether prednisolone causes postprandial vascular dysfunction in a cohort of patients with rheumatoid arthritis. DESIGN: An open interventional and cross-sectional study was undertaken. PATIENTS AND MEASUREMENTS: Eighteen subjects with rheumatoid arthritis who had not taken oral glucocorticoids for >=6 months were studied before and after prednisolone 6 mg/day for 7 days to determine the acute effects of prednisolone. Pre-prednisolone data were compared to 18 subjects with rheumatoid arthritis taking long-term (>6 months) prednisolone (6.5 +/- 1.8 mg/day) to assess the chronic effects of prednisolone. Augmentation index (by applanation tonometry) and reactive hyperaemia index (by peripheral artery tonometry) were measured before and after a mixed-meal (10 kcal/kg, 45% carbohydrate, 15% protein, 40% fat). Insulin sensitivity was estimated by the Matsuda index and sympathetic nervous system activity from urinary noradrenaline excretion. RESULTS: Matsuda index was lower after acute (2.0 +/- 1.0 vs 3.6 +/- 1.1, P = 0.01) and chronic (1.9 +/- 1.0 vs 3.6 +/- 1.1, P = 0.04) prednisolone. Postprandial augmentation index was lower after acute prednisolone (2551 +/- 197 vs 2690 +/- 272%*min, P <= 0.001), but not chronic prednisolone. There were no significant differences in reactive hyperaemia index with acute or chronic prednisolone. Noradrenaline excretion was lower after acute (54 +/- 8 vs 93 +/- 23 nmol/6 h, P = 0.02), but not chronic, prednisolone. CONCLUSIONS: Prednisolone-induced insulin resistance is not associated with postprandial vascular dysfunction in patients with rheumatoid arthritis. Reduced sympathetic activity may contribute to the reduction in postprandial arterial stiffness with acute prednisolone. PMID- 26493043 TI - Optimal support techniques when providing mechanical ventilation to patients with acute respiratory distress syndrome. AB - BACKGROUND: Adult respiratory distress syndrome (ARDS) is a type of acute diffuse lung injury characterized by severe inflammation, increased pulmonary vascular permeability and a loss of aerated lung tissue. The effects of high fraction of inspired oxygen (FiO2 ) include oxygen toxicity manifested by damage to the lung parenchyma in the acute phase of lung injury. There is still a high mortality rate among this group of patients, so clinically sensitive evidence-based interventions are paramount to maximize survival chances during critical care. AIMS AND OBJECTIVES: The aim of this article is to explore the current opinion concerning optimal mechanical ventilation support techniques for patients with acute respiratory distress syndrome. SEARCH STRATEGY, INCLUSION AND EXCLUSION CRITERIA: A literature search of clinical trials and observation studies, reviews, discussion papers, meta-analyses and clinical guidelines written in English up to 2015, derived from the databases of Scopus, CINAHL, Cochrane Library databases and PubMed was conducted. CONCLUSIONS: Low tidal volume, pressure limitation and prone positioning in severe ARDS patients appear to be of some benefit. More research is required and further development and use of standardized protocols is an important strategy for reducing practice variations across disciplines, as well as giving clear guidelines to nurses practising in critical care. There is also evidence that this syndrome is under-diagnosed and the utilization of lung protective ventilation is still variable. RELEVANCE TO CLINICAL PRACTICE: It is important that nurses have underlying knowledge of both aetiology of ARDS and ventilation management, and that they monitor patients very closely. The adoption of a low tidal ventilation protocol, which is based on quality evidence guidelines, the value of rescue therapies and patient observation practices in the overall patient management, and the need to place emphasis on long-term patient outcomes, all these emerge as key factors for consideration and future research. However, there is also a need for more research that would explore the unique contribution of nurses in the management of this patient group, as it is difficult to discern this in the current literature. PMID- 26493044 TI - Total Synthesis of Crotophorbolone. AB - The complex ABC-tricyclic structure of crotophorbolone, a derivative of the tigliane diterpenoids, was assembled by coupling of simple fragments. The six membered C-ring fragment, having five contiguous stereocenters, was stereoselectively constructed from (R)-carvone. After attachment of the five membered A-ring through the pi-allyl Stille coupling reaction, the alpha-alkoxy bridgehead radical reaction effected the endo-cyclization of the seven-membered B ring by forming the sterically congested bond at C9 and C10 stereospecifically and stereoselectively, respectively. Finally, the functional groups on the 5/7/6 membered ring system were manipulated by rhodium-catalyzed C2 olefin isomerization, C13 decarboxylative oxidation, and C4 hydroxylation, thus completing the first total synthesis of crotophorbolone. PMID- 26493045 TI - Dynamics of quantum correlation between separated nitrogen-vacancy centers embedded in plasmonic waveguide. AB - We investigate the dynamics of quantum correlation between two separated nitrogen vacancy centers (NVCs) placed near a one-dimensional plasmonic waveguide. As a common medium of the radiation field of NVCs propagating, the plasmonic waveguide can dynamically induce quantum correlation between the two NVCs. It is interesting to find that such dynamically induced quantum correlation can be preserved in the long-time steady state by locally applying individual driving on the two NVCs. In particular, we also show that a large degree of quantum correlation can be established by this scheme even when the distance between the NVCs is much larger than their operating wavelength. This feature may open new perspectives for devising active decoherence-immune solid-state optical devices and long-distance NVC-based quantum networks in the context of plasmonic quantum electrodynamics. PMID- 26493047 TI - Prenatal education for congenital toxoplasmosis. AB - BACKGROUND: Congenital toxoplasmosis is considered a rare but potentially severe infection. Prenatal education about congenital toxoplasmosis could be the most efficient and least harmful intervention, yet its effectiveness is uncertain. OBJECTIVES: To assess the effects of prenatal education for preventing congenital toxoplasmosis. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2015), and reference lists of relevant papers, reviews and websites. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials of all types of prenatal education on toxoplasmosis infection during pregnancy. Cluster-randomized trials were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: Two cluster-randomized controlled trials (RCTs) (involving a total of 5455 women) met the inclusion criteria. The two included trials measured the effectiveness of the intervention in different ways, which meant that meta analysis of the results was not possible. The overall quality of the two studies, as assessed using the GRADE approach, was low, with high risk of detection and attrition bias in both included trials.One trial (432 women enrolled) conducted in Canada was judged of low methodological quality. This trial did not report on any of the review's pre-specified primary outcomes and the secondary outcomes reported results only as P values. Moreover, losses to follow-up were high (34%, 147 out of 432 women initially enrolled). The authors concluded that prenatal education can effectively change pregnant women's behavior as it increased pet, personal and food hygiene. The second trial conducted in France was also judged of low methodological quality. Losses to follow-up were also high (44.5%, 2233 out of 5023 women initially enrolled) and differential (40% in the intervention group and 52% in the control group). The authors concluded that prenatal education for congenital toxoplasmoses has a significant effect on improving women's knowledge, whereas it has no effect on changing women's behavior. In this trial 17/3949 pregnant women seroconverted for toxoplasmosis: 13/2591 (0.5%) in the intervention group and 4/1358 (0.3%) in the control group. The rate of seroconversion detected during the study did not differ between groups (risk ratio (RR) 1.70, 95% confidence interval (CI) 0.56 to 5.21; participants = 3949; studies = one, low quality evidence). The number of events was too small to reach conclusions about the effect of prenatal education on seroconversion rate during pregnancy.No other randomized trials on the effect of prenatal education on congenital toxoplasmosis rate, or toxoplasmosis seroconversion rate during pregnancy were detected. AUTHORS' CONCLUSIONS: Even though primary prevention of congenital toxoplasmosis is considered a desirable intervention, given the lack of related risks compared to secondary and tertiary prevention, its effectiveness has not been adequately evaluated. There is very little evidence from RCTs that prenatal education is effective in reducing congenital toxoplasmosis even though evidence from observational studies suggests it is. Given the lack of good evidence supporting prenatal education for congenital toxoplasmosis prevention, further RCTs are needed to confirm any potential benefits and to further quantify the impact of different sets of educational intervention. PMID- 26493046 TI - TUBA1A mutation can cause a hydranencephaly-like severe form of cortical dysgenesis. AB - TUBA1A mutations cause a wide spectrum of lissencephaly and brain malformations. Here, we report two patients with severe cortical dysgeneses, one with an extremely thin cerebral parenchyma apparently looking like hydranencephaly and the other with lissencephaly accompanied by marked hydrocephalus, both harbouring novel de novo missense mutations of TUBA1A. To elucidate how the various TUBA1A mutations affect the severity of the phenotype, we examined the capacity of the mutant protein to incorporate into the endogenous microtubule network in transfected COS7 cells by measuring line density using line extraction in an immunofluorescence study. The mutants responsible for severe phenotypes were found to incorporate extensively into the network. To determine how each mutant alters the microtubule stability, we examined cold-induced microtubule depolymerisation in fibroblasts. The depolymerisation of patients' fibroblasts occurred earlier than that of control fibroblasts, suggesting that microtubules bearing mutated tubulins are unstable. Both mutations are predicted to participate in lateral interactions of microtubules. Our data suggest that the TUBA1A mutations disrupting lateral interactions have pronounced dominant negative effects on microtubule dynamics that are associated with the severe end of the lissencephaly spectrum. PMID- 26493048 TI - Detecting the existence of an invisibility cloak using temporal steering. AB - An invisibility cloak provides a way to hide an object under the detection of waves. A good cloak guides the incident waves through the cloaking shell with few distortion. Even if one day a nearly perfect cloak is built, some important quantum effects, such as dephasing of the electron spin or photon polarization, may still remain. In this work, we consider the possibility that using the temporal steering of these degrees of freedom to detect the existence of an invisibility cloak. PMID- 26493049 TI - New In Vitro Studies on the Bioprofile of Genista tenera Antihyperglycemic Extract. AB - The inhibition of alpha-glucosidase and glucose-6-phosphatase, two enzymes involved in the carbohydrate metabolism, is an important target to control glycaemia on individuals with type 2 diabetes. In this work we report for the first time the inhibition of both enzymes by the antihyperglycemic n-butanol extract from Genista tenera (Fabaceae). This extract decreased alpha-glucosidase and glucose-6-phosphatase activities to 0.97 and 80.25 %, respectively, being more effective than acarbose, and phlorizin, the positive controls, which reduced enzymes activities only to 17.39 and 96.06 %. Once inflammation and oxidative stress are related to diabetic impairments, the anti-inflammatory activity of the extract was also evaluated, through its inhibitory activity over COX-1 enzyme (47.5 % inhibition). Moreover, after induction of oxidative stress by UV radiation, the viability of irradiated rat liver hepatoma cells exposed to the extract was significantly higher (67.82 %) than that promoted by ascorbic acid, the positive control (45.05 %). In addition, the stability of the extract under gastrointestinal conditions was evaluated by HPLC-DAD-ESI-MS/MS. Flavonoid diglycosides were identified as the main constituents of the extract, and no alterations in the chemical composition nor in the antioxidant activity were observed after in vitro digestion with artificial gastric and pancreatic juices. PMID- 26493050 TI - Hybrid Sex Pheromones of the Hibiscus Flower-bud Borer, Rehimena surusalis. AB - The sex pheromone of the hibiscus flower borer Rehimena surusalis (Walker) (Lepidoptera: Crambidae) was analyzed by gas chromatography with electroantennographic detection (GC-EAD) and GC-mass spectrometry (GC/MS). Three EAD-active components were found in crude pheromone gland extracts of calling females. GC/MS and GC analyses using synthetic chemicals and derivatization of the extracts identified three components as (10E,12Z)-hexadeca-10,12-dienal (E10,Z12-16:Ald,), (10E,12E)-hexadeca-10,12-dienyl acetate (E10,Z12-16:OAc), and (3Z,6Z,9Z)-tricosa-3,6,9-triene (Z3,Z6,Z9-23:HC). In field tests, male moths were strongly attracted to a ternary blend of E10,Z12-16:Ald, E10,Z12-16:OAc, and Z3,Z6,Z9-23:HC at a ratio of 1:5:14, but single and binary blends showed only weak or no attraction. PMID- 26493051 TI - Age and sex differences in the taste sensitivity of young adult, young-old and old-old Japanese. AB - AIM: The present study examined sex and age differences in taste sensitivity among young adult, young-old and old-old Japanese. METHODS: Participants were divided into three groups comprising 477 men and 519 women in the young-old group (aged 69-71 years), 449 men and 500 women in the old-old group (aged 79-81 years), and 35 men and 35 women in the young adult group (aged 24-32 years). Recognition thresholds for the four basic tastes were measured using the 1-mL whole mouth gustatory test, in which taste solutions of the four basic tastes were tested in five concentrations. RESULTS: Young adults showed significantly lower recognition thresholds than the young-old group, and the young-old group showed significantly lower recognition thresholds than the old-old group. Among the young-old and old-old groups, women showed significantly lower recognition thresholds than males for sour, salty and bitter tastes, but there was no sex difference in the sweet taste threshold between the two groups. CONCLUSIONS: The present study confirmed that there are age and sex differences in taste sensitivity for the four basic tastes among young adult, young-old, and old-old Japanese, and that the sensitivity of sweet taste is more robust than the other tastes. Geriatr Gerontol Int 2016; 16: 1281-1288. PMID- 26493052 TI - Image quality of Zr-89 PET imaging in the Siemens microPET Focus 220 preclinical scanner. AB - PURPOSE: Zr-89 positron emission tomography (PET) is a valuable tool for understanding the biodistribution and pharmacokinetics of antibody-based therapeutics. We compared the image quality of Zr-89 PET and F-18 PET in the Siemens microPET Focus 220 preclinical scanner using different reconstruction methods. PROCEDURES: Image quality metrics were measured in various Zr-89 and F 18 PET phantoms, including the NEMA NU 4-2008 image quality phantom. Images were reconstructed using various algorithms. RESULTS: Zr-89 PET had greater image noise, inferior spatial resolution, and greater spillover than F-18 PET, but comparable recovery coefficients for cylinders of various diameters. Of the reconstruction methods, OSEM3D resulted in the lowest noise, highest recovery coefficients, best spatial resolution, but also the greatest spillover. Scatter correction results were found to be sensitive to varying object sizes. CONCLUSIONS: Zr-89 PET image quality was inferior to that of F-18, and no single reconstruction method was superior in all aspects of image quality. PMID- 26493053 TI - Non-invasive PET Imaging of PARP1 Expression in Glioblastoma Models. AB - PURPOSE: The current study presents [(18)F]PARPi as imaging agent for PARP1 expression. PROCEDURES: [(18)F]PARPi was generated by conjugating a 2H-phthalazin 1-one scaffold to 4-[(18)F]fluorobenzoic acid. Biochemical assays, optical in vivo competition, biodistribution analysis, positron emission tomography (PET)/X ray computed tomography, and PET/magnetic resonance imaging studies were performed in subcutaneous and orthotopic mouse models of glioblastoma. RESULTS: [(18)F]PARPi shows suitable pharmacokinetic properties for brain tumor imaging (IC50 = 2.8 +/- 1.1 nM; logPCHI = 2.15 +/- 0.41; plasma-free fraction = 63.9 +/- 12.6 %) and accumulates selectively in orthotopic brain tumor tissue. Tracer accumulation in subcutaneous brain tumors was 1.82 +/- 0.21 %ID/g, whereas in healthy brain, the uptake was only 0.04 +/- 0.01 %ID/g. CONCLUSIONS: [(18)F]PARPi is a selective PARP1 imaging agent that can be used to visualize glioblastoma in xenograft and orthotopic mouse models with high precision and good signal/noise ratios. It offers new opportunities to non-invasively image tumor growth and monitor interventions. PMID- 26493054 TI - Sacrococcygeal ependymoblastoma. PMID- 26493056 TI - Neurosurgical training with simulators: a novel neuroendoscopy model. AB - PURPOSE: The aim of this study is to present a novel neuroendoscopy simulation model in live animals, with the objective of enhancing patient safety with realistic surgical training. METHODS: A simulation model using live Wistar rats was designed after the approval of the Institutional Committee for the Care and Use of Laboratory Animals. Under anesthesia, a hydroperitoneum was created in order to simulate a cavity with mesenteric membranes and vessels, viscera, and a solid and bleeding tumor (the liver) floating in a liquid environment. For validation purposes, we evaluated trainees' basal and final skills for each neuroendoscopic procedure, and we also acknowledged trainees' and instructors' opinion on the model's realism. RESULTS: This model is simple and low cost effective for complete and real-life training in neuroendoscopy, with the possibility of performing all the basic and advanced endoscopic procedures, such as endoscopic exploration, membrane fenestration, vessel coagulation, hematoma evacuation, and endoscopic tumor biopsy and resection using a ventricular neuroendoscopy set. Although the model does not represent human ventricular anatomy, a reliable simulation is possible in real living tissue in a liquid environment. Trainees' skills improvements were notorious. CONCLUSION: Minimally invasive endoscopic techniques require specific training. Simulation training can improve and accelerate the learning curve. The presented training model allows simulating the different neuroendoscopic procedures. We believe that due to its practical possibilities, its simplicity, low cost, reproducibility, and reality, being live animal tissue, it can be considered a fundamental model within a complete training program on neuroendoscopy. PMID- 26493055 TI - Meta-analysis of vagus nerve stimulation treatment for epilepsy: correlation between device setting parameters and acute response. AB - BACKGROUND: Vagus nerve stimulation (VNS) is an adjunctive neurophysiological treatment for those patients who have pharmacoresistant or surgically resistant partial onset epilepsy. OBJECTIVE: The aim of this study is to determine the effects of high and low stimulation paradigms on a responder rate of >=50 and >=75% reduction in seizure frequency and associated adverse effects in adults and children. METHOD: A literature search was performed using Medline, PubMed, EMBASE, and Cochrane library for studies using vagus nerve stimulation published from January 1980 until July 2014 for medically or surgically resistant partial onset seizures, in children and adults. No restrictions on languages were imposed. DATA COLLECTION AND ANALYSIS: Four authors reviewed and selected studies for inclusion and exclusion. The search identified five randomized control trials that fit with our inclusion criteria. The following outcomes were evaluated: 50% or greater reduction in total seizure frequency, 75% or greater reduction in total seizure frequency, and adverse effects. RESULTS: Four randomized controlled trials were analyzed in this meta-analysis. Results indicate high stimulation is more effective in adult patients who experienced >=50 and >=75% reduction in seizure frequency with a significant difference within both high and low stimulation groups. In children, there was no significant difference between the two groups and patients with >=50 % reduction in seizures. Adverse effects such as hoarseness and dyspnea were more common in the high stimulation group where the remaining side effects were not statistically different among both groups. CONCLUSION: High stimulation is more effective than low stimulation in producing a greater reduction in seizure frequency in patients with medically and surgically resistant epilepsy. PMID- 26493057 TI - [Value and acceptance of risk assessment for Alzheimer's disease]. AB - BACKGROUND: It is quite common that people suffering from cognitive impairment only visit a doctor when the symptoms have already reached an advanced stage. This is often due to a fear of Alzheimer's disease or a dread of exhausting diagnostic procedures and exposure of personal details; however, an early diagnosis and therapy increases the chance of preserving the quality of life for a longer period of time. OBJECTIVES: Evaluation of a risk assessment for Alzheimer's disease by magnetic resonance imaging (MRI) with respect to the acceptance and value by participants. METHODS: In this prospective preventive study 106 subjects between the age of 39 and 89 years (median age 68 years) with general risk factors were included and underwent a risk assessment for Alzheimer's disease by standard MRI of the brain using a 1 T open MRI with subsequent hippocampal volumetry. Participants were stratified into two distinct subgroups according to the individual hippocampal atrophy status, one with elevated and the other with reduced risk. All participants were thoroughly interviewed regarding anxieties and mental well-being before and after the risk assessment. RESULTS: As expected, participants with a reduced risk had a significant improvement in well-being and a reduction of fears and worries after the examination. Neither a significant deterioration of the mental situation nor an increase of fears and worries was found for participants with an elevated risk. Of the participants 90% stated that MRI-based risk stratification generated positive perspectives for the future. The assessment revealed a high acceptance by most of the participants (94%). CONCLUSION: An MRI-based risk assessment is beneficial to the patient's quality of life and as a low threshold approach may induce more individuals with concerns to take advantage of an early diagnosis of Alzheimer's disease. PMID- 26493058 TI - [Mental comorbidities of alcohol-related disorders]. AB - BACKGROUND: Alcohol-related disorders have a high comorbidity with mental disorders and vice versa, alcohol consumption plays an important role in affective disorders and schizophrenic psychoses. In developing the current S3 guidelines evidence-based knowledge on the rate and significance of comorbid disorders in alcohol use disorders has been compiled to generate recommendations for treatment. METHODS: In preparation for the guidelines, previous international guidelines and a systematic literature search were taken into consideration. Recommendations for various and specific clinical situations were derived from these sources based on evidence grading. Evidence and recommendations were subdivided into psychotherapy, pharmacotherapy and combination therapy, each having differential efficacies in the treatment of psychiatric symptoms and alcohol consumption behavior. Furthermore, a separate treatment pathway was developed for a stepwise approach to affective disorders for both comorbidities. CONCLUSION: Appearing for the first time in guidelines are specific treatment recommendations for comorbid mental diseases in alcohol use disorders. These recommendations extend to different treatment approaches including diagnostics and settings, affording clinicians more pragmatic relevance. PMID- 26493059 TI - [Do the areas of nursing and specialist therapy have sufficient personnel?]. PMID- 26493060 TI - [Is delusion a reasonable scientific term? Reflections on psychopathology in the psychiatry of the twenty-first century]. AB - Delusion is a central but difficult and controversial term in psychiatry. Similar to the term schizophrenia at the nosological level, the basic questions in the specialty are linked in the debate on delusion at the clinical psychopathological level, beginning with epistemological and methodological aspects up to concrete embodiment of the physician-patient relationship. The text of this article reflects this development from the nineteenth century up to the present day and makes reference to the lively discussion on the future directions of psychiatric research triggered by the research domain criteria (RDoC). Under certain prerequisites, including in particular an extensive understanding of psychopathology, delusion is considered to be a reasonable scientific term, also in the future. PMID- 26493061 TI - Solid Serous Adenoma of Pancreas, Misdiagnosed as Neuroendocrine Tumor, a Rare Case Report and Review of the Literature. PMID- 26493062 TI - Proposed Radiation Induced Hormone Crisis in a Patient with Glucagonoma. PMID- 26493063 TI - Novel Approaches to Targeting Visceral and Hepatic Adiposities in HIV-Associated Lipodystrophy. AB - Visceral and hepatic adiposities have been associated with both cardiovascular and liver disease and are of concern in HIV-infected persons in the modern era of combination antiretroviral therapy (ART). The development of therapeutic targets to reduce visceral and hepatic adiposities in HIV-infected persons has been slow, because of early reports that attributed the excess adiposity to specific antiretroviral drugs. Visceral adiposity was initially thought to occur as part of a protease inhibitor-induced "HIV-associated lipodystrophy syndrome." Subsequent studies show that visceral adiposity is likely a result of effective ART, recovery of health, and the normal aging process. Visceral adiposity is an established risk factor for hepatic adiposity. Identifying drug targets for non alcoholic fatty liver disease is under active investigation. The present review summarizes the recent literature on the pathogenesis of visceral and hepatic adiposities in HIV-infected persons, current therapeutic strategies, and novel interventions in HIV-infected and uninfected persons. PMID- 26493065 TI - Synthesis and characterization of MFe2O4 (M = Co, Ni, Mn) magnetic nanoparticles for modulation of angiogenesis in chick chorioallantoic membrane (CAM). AB - In this study, we report the synthesis and characterization studies of amine functionalized MFe2O4 (Co, Ni, Mn) nanoparticles. The synthesis process was accomplished by refluxing metal chloride precursors in ethylene glycol in the presence of sodium acetate and ethanolamine. The average crystallite sizes of the synthesized particles are found to be in the range of 8-10 nm. The synthesized particles are characterized using X-ray diffraction, Brunauer-Emmett-Teller technique, FTIR, dynamic light scattering, Raman and UV-visible spectroscopy for crystal structure, average size, surface area, pore diameter and hydrodynamic diameter, phase and functional group determination. The surface morphology and elemental composition were studied by scanning electron microscope and X-ray fluorescence respectively. Magnetic behavior up to fields of 3 T at room temperature measured in Quantum Design Physical Property Measurement System (QD PPMS) magnetometer showed the superparamagnetic behavior of these particles. Modulation of angiogenesis by the nanoparticles was studied in a chick embryo chorioallantoic membrane model by analysis of blood vessel development and effect on hemoglobin level using imaging and colorimetric methods. An enhancement in the angiogenesis compared to the saline control was observed for all the ferrite nanoparticles with a relatively optimal activity in case of CoFe2O4 nanoparticles. PMID- 26493064 TI - Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor positive, HER2-negative early breast cancer: TEXT and SOFT trials. AB - The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally assessed levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 expression in women with HER2-negative disease. Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2-) disease had ER, PgR, and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional, or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology. In this HR+/HER2- population, the median ER, PgR, and Ki-67 expressions were 95, 90, and 18 % immunostained cells. As most patients had strongly ER-positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels, though there was a greater 5-year absolute benefit of exemestane + ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67. Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane + OFS versus tamoxifen + OFS or tamoxifen alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2- early breast cancer. PMID- 26493066 TI - In vitro spectroscopic study of piperine-encapsulated nanosize liposomes. AB - Black pepper is a source of effective antioxidants. It contains several powerful antioxidants and is thus one of the most important spices for preventing and curtailing oxidative stress. There is considerable interest in the development of a drug-delivery systems that would result in the selective delivery of antioxidants to tissues in sufficient concentrations to ameliorate oxidant induced tissue injuries. Liposomes are biocompatible, biodegradable and nontoxic artificial phospholipid vesicles that offer the possibility of carrying hydrophilic, hydrophobic and amphiphilic molecules. This article focuses on the use of liposomes for the delivery of antioxidants in the prevention or treatment of pathological conditions related to oxidative stress. Liposome formulations of piperine were analyzed with various spectroscopic methods. The formulation with the highest entrapment efficiency (90.5%) was formulated with an L-alpha phosphatidylcholine dipalmitoyl (DPPC):piperine, 30:1 molar ratio, and total lipid count of 19.47 mg/ml in the final liposomal preparation. The liposome formulation was found to be stable after storage at 4 degrees C, protected from light, for a minimum of 3 weeks. The incremental process of piperine penetration through the phospholipid membrane was analyzed using the FT-IR, UV-Vis and NMR methods. Temperature stability studies carried out at 37 degrees C showed the highest percentage of piperine release in the first 3 h of incubation. PMID- 26493068 TI - Epigenetics mechanisms in renal development. AB - Appreciation for the role of epigenetic modifications in the diagnosis and treatment of diseases is fast gaining attention. Treatment of chronic kidney disease stemming from diabetes or hypertension as well as Wilms tumor will all profit from knowledge of the changes in the epigenomic landscapes. To do so, it is essential to characterize the epigenomic modifiers and their modifications under normal physiological conditions. The transcription factor Pax2 was identified as a major epigenetic player in the early specification of the kidney. Notably, the progenitors of all nephrons that reside in the cap mesenchyme display a unique bivalent histone signature (expressing repressive epigenetic marks alongside activation marks) on lineage-specific genes. These cells are deemed poised for differentiation and commitment to the nephrogenic lineage. In response to the appropriate inducing signal, these genes lose their repressive histone marks, which allow for their expression in nascent nephron precursors. Such knowledge of the epigenetic landscape and the resultant cell fate or behavior in the developing kidney will greatly improve the overall success in designing regenerative strategies and tissue reprogramming methodologies from pluripotent cells. PMID- 26493067 TI - The multifaceted role of the renal microvasculature during acute kidney injury. AB - Pediatric acute kidney injury (AKI) represents a complex disease process for clinicians as it is multifactorial in cause and only limited treatment or preventatives are available. The renal microvasculature has recently been implicated in AKI as a strong therapeutic candidate involved in both injury and recovery. Significant progress has been made in the ability to study the renal microvasculature following ischemic AKI and its role in repair. Advances have also been made in elucidating cell-cell interactions and the molecular mechanisms involved in these interactions. The ability of the kidney to repair post AKI is closely linked to alterations in hypoxia, and these studies are elucidated in this review. Injury to the microvasculature following AKI plays an integral role in mediating the inflammatory response, thereby complicating potential therapeutics. However, recent work with experimental animal models suggests that the endothelium and its cellular and molecular interactions are attractive targets to prevent injury or hasten repair following AKI. Here, we review the cellular and molecular mechanisms of the renal endothelium in AKI, as well as repair and recovery, and potential therapeutics to prevent or ameliorate injury and hasten repair. PMID- 26493069 TI - Favorable outcome in children with idiopathic steroid-resistant nephrotic syndrome due to mesangial hypercellularity: A distinct disease entity? PMID- 26493070 TI - Ability of a novel system for neonatal extracorporeal renal replacement therapy with an ultra-small volume circuit to remove solutes in vitro. AB - BACKGROUND: We automated our manual, syringe-driven extracorporeal renal replacement therapy (eRRT) system with an ultra-small volume circuit (3.2 ml) that is suitable for neonates without blood priming. Our objective was to determine the solute clearance and water balance of the automated and manual systems in vitro. METHODS: Stored whole blood samples containing exogenous urea, creatinine (Cr), potassium (K), and ammonia (NH3) to imitate acute kidney injury (AKI) and hyperammonemia were dialyzed for 3 h (blood flow, 4.0 ml/min; dialysate flow, 600 ml/h) with a continuous infusion of heparin. Solute clearance and sample weight were then compared with values before dialysis. RESULTS: The median clearance of blood urea nitrogen, Cr, K, and NH3 ranged from 1.7 to 2.3 and from 2.4 to 2.6 ml/min, and the median weight of the samples was decreased by 3.8 g and increased by 8.3 g after 3 h of dialysis using the manual and automated systems, respectively. CONCLUSIONS: The automated system effectively cleared solutes, but safety concerns were associated with platelet consumption and fluid balance. Additional studies are needed to establish the safety and accuracy of this novel system for clinical use in neonates and preterm infants. PMID- 26493071 TI - Cognitive and Behavioral Risk Factors for Unintentional Drowning Among Rural Chinese Children. AB - BACKGROUND: Unintentional drowning is among the top causes of pediatric death worldwide and the leading cause of death for children under age 14 in China. Environmental factors such as abundant bodies of water and psychosocial factors such as lack of parental supervision contribute to heightened risk of pediatric drowning in rural China, but little is known about the role of individual characteristics such as knowledge and perceived vulnerability in the drowning risk of rural Chinese children. PURPOSE: The present study aimed to explore the cognitive and behavioral risk factors for unintentional drowning among school aged rural Chinese children. METHOD: Two hundred and eighty children (mean age = 10.03 years, range 8-13) enrolled at an elementary school in rural Zhejiang Province, China completed self-report assessments of knowledge about drowning prevention, perceived vulnerability toward drowning, and history of non-fatal drowning experiences, as well as demographic information. A simulation task using a dollhouse assessed children's anticipated behaviors with water. RESULTS: Fifty two percent of the sample reported exposure to water sources at least once daily, and 21 % of the sample reported at least one non-fatal drowning experience in their lifetime. Regression analysis showed that male gender, better swimming ability, less safety knowledge, and lower levels of perceived vulnerability were associated with more self-reported risky practice in/near water. More safety knowledge also predicted safer behaviors in the dollhouse simulation task. None of the risk factors predicted self-reported history of non-fatal drowning incidents. CONCLUSION: High exposure to water sources and non-fatal drowning experiences were found among school-aged children in rural China. Drowning risk factors included demographic, cognitive, and behavioral characteristics of children. Results offer evidence for developing interventions in both Zhejiang Province and other regions with similar geographic and population characteristics. PMID- 26493072 TI - Measuring empathic, person-centred communication in primary care nurses: validity and reliability of the Consultation and Relational Empathy (CARE) Measure. AB - BACKGROUND: Empathic patient-centred care is central to high quality health encounters. The Consultation and Relational Empathy (CARE) Measure is a patient rated experience measure of the interpersonal quality of healthcare encounters. The measure has been extensively validated and is widely used by doctors in primary care but has not been validated in nursing. This study assessed the validity and reliability of the CARE Measure in routine nurse consultations in primary care. METHODS: Seventeen nurses from nine general medical practices located in three Scottish Health Boards participated in the study. Consecutive patients (aged 16 years or older) were asked to self-complete a questionnaire containing the CARE Measure immediately after their clinical encounter with the nurse. Statistical analysis included Spearman's correlation and principal component analysis (construct validity), Cronbach's alpha (internal consistency), and Generalisability theory (inter-rater reliability). RESULTS: A total of 774 patients (327 male and 447 female) completed the questionnaire. Almost three out of four patients (73 %) felt that the CARE Measure items were very important to their current consultation. The number of 'not applicable' responses and missing values were low overall (5.7 and 1.6 % respectively). The mean CARE Measure score in the consultations was 45.9 and 48 % achieved the maximum possible score of 50. CARE Measure scores correlated in predicted ways with overall satisfaction and patient enablement in support of convergent and divergent validity. Factor analysis found that the CARE Measure items loaded highly onto a single factor. The measure showed high internal consistency (Cronbach's alpha coefficient = 0.97) and acceptable inter-rater reliability (G = 0.6 with 60 patients ratings per nurse). The scores were not affected by patients' age, gender, self-perceived overall health, living arrangements, employment status or language spoken at home. CONCLUSIONS: The CARE Measure has high face and construct validity, and internal reliability in nurse consultations in primary care. Its ability to discriminate between nurses is sufficient for educational and quality improvement purposes. PMID- 26493073 TI - Round window application of an active middle ear implant (AMEI) system in congenital oval window atresia. AB - CONCLUSION: Application of the Vibrant Soundbridge to the round window (RW) membrane can be utilized as an efficient therapy for congenital oval window (OW) atresia. OBJECTIVE: To report the surgical technique and auditory outcome of an active middle ear implant (AMEI) system used in patients with congenital OW atresia. METHODS: Nine subjects with congenital OW atresia (six males and three females, ranging in age from 5.5 to 25 years, average 12.5 years) were implanted with an AMEI (Vibrant Soundbridge) at the round window (RW-Vibroplasty). Five cases were diagnosed as having isolated congenital OW atresia while four patients presented with combined external/middle ear malformation. RESULTS: An improvement of 30 dB in average pure-tone air conduction thresholds (0.5-4 kHz) was achieved, with the high frequencies showing greater results. The subjects achieved postoperative speech recognition scores of 80-100% on the Computerized Mandarin Speech Test System (CMSTS) sentence test. Bone conduction thresholds were confirmed as stable in all subjects postoperatively. Decline in auditory benefit was noticed in two subjects, who then underwent revision surgery. One of these revision surgery patients then experienced stable hearing recovery, while the other patient's hearing declined. PMID- 26493074 TI - Genome-wide variation in the pinewood nematode Bursaphelenchus xylophilus and its relationship with pathogenic traits. AB - BACKGROUND: Bursaphelenchus xylophilus is an emerging pathogenic nematode that is responsible for a devastating epidemic of pine wilt disease across Asia and Europe. In this study, we report the first genome-wide variation analysis of the nematode with an aim to obtain a full picture of its diversity. METHODS: We sequenced six key B. xylophilus strains using Illumina HiSeq sequencer. All the strains were isolated in Japan and have been widely used in previous studies. Detection of genomic variations were done by mapping the reads to the reference genome. RESULTS: Over 3 Mb of genetic variations, accounting for 4.1 % of the total genome, were detected as single nucleotide polymorphisms or small indels, suggesting multiple introductions of this invaded species from its native area into the country. The high level of genetic diversity of the pine wood nematode was related to its pathogenicity and ecological trait differences. Moreover, we identified a gene set affected by genomic variation, and functional annotation of those genes indicated that some of them had potential roles in pathogenesis. CONCLUSIONS: This study provides an important resource for understanding the population structure, pathogenicity and evolutionary ecology of the nematode, and further analysis based on this study with geographically diverse B. xylophilus populations will greatly accelerate our understanding of the complex evolutionary/epidemic history of this emerging pathogen. PMID- 26493075 TI - Cortisol response and psychological distress predict susceptibility to false memories for a trauma film. AB - For eyewitness testimony to be considered reliable, it is important to ensure memory remains accurate following the event. As many testimonies involve traumatic, as opposed to neutral, events, it is important to consider the role of distress in susceptibility to false memories. The aim of this study was to investigate whether cortisol response following a stressor would be associated with susceptibility to false memories. Psychological distress responses were also investigated, specifically, dissociation, intrusions, and avoidance. Participants were allocated to one of three conditions: those who viewed a neutral film (N = 35), those who viewed a real trauma film (N = 35), and a trauma "reappraisal" group where participants were told the film was not real (N = 35). All received misinformation about the film in the form of a narrative. Participants provided saliva samples (to assess cortisol) and completed distress and memory questionnaires. Cortisol response was a significant predictor of the misinformation effect. Dissociation and avoidance were related to confabulations. In conclusion, following a stressor an individual may differ with regard to their psychological response to the event, and also whether they experience a cortisol increase. This may affect whether they are more distressed later on, and also whether they remember the event accurately. PMID- 26493076 TI - Epidemiology of the epidemic of bovine anaemia associated with Theileria orientalis (Ikeda) between August 2012 and March 2014. AB - AIMS: To describe the epidemiology of the epidemic of bovine anaemia associated with Theileria orientalis infection (TABA) in New Zealand between 30 August 2012 and 4 March 2014. METHODS: Blood samples and associated data were obtained from cases of TABA. The case definition for TABA was met when piroplasms were present on blood smears and the haematocrit was <=0.24 L/L. Samples were analysed using quantitative PCR (qPCR) assays for the detection of T. orientalis Ikeda type. Only cases that were positive in the qPCR assays were included in the analysis. A case herd was defined as a herd that had >=1 animal positive for T. orientalis Ikeda. Movement records for farms were accessed through the national animal identification and tracing scheme. The OR for cattle movements onto a case farm compared to a non-case farm was estimated using a generalised estimating equation model and the geodesic distance for movements onto case and non-case farms compared using Student's t-test. The kernel-smoothed risk of disease at the farm level was calculated using an extraction map and the clustering of diseased farms in time and space was measured using the spatial temporal inhomogeneous pair correlation function. RESULTS: In the first 18 months there were 496 case herds; 392 (79%) were dairy and 104 (21%) beef herds. Of 882 individual cases, 820 (93.0%) were positive for T. orientalis Ikeda in the qPCR assays. Case herds were initially clustered in the Northland, then the Waikato regions. The OR for a case farm compared to a non-case farm having >=1 inward cattle movements was 2.03 (95% CI=1.52-2.71) and the distance moved was 26 (95% CI=20.8-31.3) km greater for case farms. The risk of disease was highest in a north, north-eastern to south, south-western belt across the Waikato region. The spatial-temporal analysis showed significant clustering of infected herds within 20-30 days and up to 15 km distant from a case farm. CONCLUSIONS: Theileria orientalis Ikeda type is likely to have been introduced into regions populated with naive cattle by the movement of parasitaemic cattle from affected areas. Local spread through dispersed ticks then probably became more important for disease transmission between herds once the disease established in a new area. CLINICAL RELEVANCE: Dairy and beef farming in the North Island of New Zealand will be significantly changed in the coming years by the incursion of this new disease. PMID- 26493077 TI - Management of acute paracetamol poisoning. PMID- 26493078 TI - First-trimester medical abortion service in Hong Kong. AB - Research on medical abortion has been conducted in Hong Kong since the 1990s. It was not until 2011 that the first-trimester medical abortion service was launched. Mifepristone was registered in Hong Kong in April 2014 and all institutions that are listed in the Gazette as a provider for legal abortion can purchase mifepristone from the local provider. This article aimed to share our 3 year experience of this service with the local medical community. Our current protocol is safe and effective, and advocates 200-mg mifepristone and 400-ug sublingual misoprostol 24 to 48 hours later, followed by a second dose of 400-ug sublingual misoprostol 4 hours later if the patient does not respond. The complete abortion rate is 97.0% and ongoing pregnancy rate is 0.4%. Some minor side-effects have been reported and include diarrhoea, fever, abdominal pain, and allergy. There have been no serious adverse events such as heavy bleeding requiring transfusion, anaphylactic reaction, septicaemia, or death. PMID- 26493079 TI - Use of robotic-assisted laparoscopic Mitrofanoff appendicovesicostomy in a paediatric patient: problem encountered. AB - This report is of robotic-assisted laparoscopic Mitrofanoff appendicovesicostomy in a 12-year-old patient with detrusor underactivity and hereditary sensory neuropathy. The whole operation was performed in 555 minutes with no open conversion. The patient experienced one episode of stomal stenosis, which required dilatation. At 3-year follow-up, the patient had both stomal and urinary continence. This is a safe and effective procedure to create a means of urinary catheterisation with avoidance of a large unsightly scar and comparable clinical outcome to an open procedure. PMID- 26493080 TI - A lucky and reversible cause of 'ischaemic bowel'. AB - An 81-year-old man was admitted with an infective exacerbation of chronic obstructive pulmonary disease. He also had clinical and radiological features suggestive of ileus. On day 6 after admission, he developed generalised abdominal pain. Urgent computed tomography of the abdomen showed presence of portovenous gas and dilated small bowel with pneumatosis intestinalis and whirl sign. Emergency laparotomy was performed, which showed a 7-mm perforated ulcer over the first part of the duodenum and small bowel volvulus. Omental patch repair and reduction of small bowel volvulus were performed. No bowel resection was required. The patient had a favourable outcome. Clinicians should suspect small bowel volvulus as a cause of ischaemic bowel. Presence of portovenous gas and pneumatosis intestinalis are normally considered to be signs of frank ischaemic bowel. The absence of bowel ischaemia at laparotomy in this patient shows that this is not necessarily the case and prompt surgical treatment could potentially save the bowels and lives of these patients. PMID- 26493081 TI - The dark side of the moon. PMID- 26493082 TI - MERS = SARS? PMID- 26493083 TI - Emphasise the importance of adequate water intake. PMID- 26493084 TI - Endophthalmitis caused by Bacillus cereus: a devastating ophthalmological emergency. PMID- 26493085 TI - 'Cleft sign' of severe lipohypertrophy. PMID- 26493086 TI - HMGB1 as a Key Mediator of Immune Mechanisms in Ischemic Stroke. AB - SIGNIFICANCE: Stroke is the leading cause of morbidity and mortality worldwide. Inflammatory cascades have a major impact on outcome and regeneration after ischemic stroke. High-mobility group box 1 (HMGB1) has come into the focus of experimental and clinical stroke research because it is released from necrotic brain tissue and its differential redox forms attract and activate immune cells after ischemic brain injury. HMGB1 is a potent inducer of inflammatory cascades, and thereby, secondary deterioration of neurological outcome. RECENT ADVANCES: The role of HMGB1 in sterile inflammation is well established. Emerging evidence suggests that HMGB1 modulates neuroinflammation after experimental brain ischemia and that it may be a useful prognostic biomarker for stroke patients. CRITICAL ISSUES: HMGB1 is instantly released from necrotic cells in the ischemic core and activates an early inflammatory response. In addition, brain-released HMGB1 can be redox modified in the circulation and activate peripheral immune cells. HMGB1 concentrations correlate with disease severity and outcome after brain injury. This is the first review depicting the crucial role of HMGB1 in the initiation and perpetuation of secondary immune alterations after experimental and clinical stroke. FUTURE DIRECTIONS: HMGB1-dependent signaling pathways are on the verge and have the potential to become a central topic in experimental stroke research. Current and upcoming projects in this field will be paving the way for future translational approaches targeting the center of poststroke inflammation to improve stroke recovery and long-term outcome. PMID- 26493087 TI - Mevalonate inhibits acid sphingomyelinase activity, increases sphingomyelin levels and inhibits cell proliferation of HepG2 and Caco-2 cells. AB - BACKGROUND: Sphingomyelin (SM) and cholesterol are two types of lipid closely related biophysically. Treating the cells with exogenous sphingomyelinase (SMase) induces trafficking of cholesterol from membrane to intracellular pools and inhibition of cholesterol synthesis. In the present work, we address a question whether increased cholesterol synthesis affects hydrolysis of SM by endogenous SMases. METHODS: Both HepG2 and Caco-2 cells were incubated with mevalonate. The SMase activity was determined and its mRNA examined by qPCR. The cellular levels of cholesterol, SM, and phosphatidylcholine (PC) were determined and cell proliferation rate assayed. RESULTS: We found that mevalonate dose-dependently decreased acid but not neutral SMase activity in both HepG2 and Caco-2 cells with HepG2 cells being more sensitive to mevalonate. Kinetic examination in HepG2 cells revealed that acid SMase activity was increasing with cell proliferation, and such an increase was reversed by mevalonate treatment. Acid SMase mRNA was not significantly decreased and Western blot showed signs of proteolysis of acid SMase by mevalonate. After mevalonate treatment, the levels of cholesterol were significantly increased associated with increases in SM and PC. The cell growth was retarded by mevalonate and the effect was more obvious in HepG2 cells than in Caco-2 cells. CONCLUSION: Mevalonate can trigger a mechanism to enhance SM levels by inhibition of acid SMase. The effect may ensure the coordinate changes of SM and cholesterol in the cells. Mevalonate also affects cell growth with mechanism required further characterization. PMID- 26493089 TI - The hybrid doctor-patient relationship in the age of technology - Telepsychiatry consultations and the use of virtual space. AB - The doctor-patient relationship is evolving and changing through the impact of many technological, social and environmental factors. These factors will be examined, especially the impact of changing attitudes among younger generations of physicians and patients who live in an information-driven networked world. Telepsychiatry is already over 50 years old and has a strong evidence base which suggests that it is a better form of practice compared with the traditional in person consultation for certain patient groups. In particular, telepsychiatry encourages intimacy in relationships through the use of the 'virtual space' in the consultation, better collaboration between psychiatrists and primary care physicians, and improved patient satisfaction. The practice of psychiatry will change through the use of mobile devices, asynchronous consultations, and the opportunities that automated interpretation and translation bring to work across cultures. The future will likely bring many psychiatrists working increasingly in a hybrid model, both in-person, and online, using the strengths of both approaches to improve patient care. PMID- 26493088 TI - Lumbar Imaging With Reporting Of Epidemiology (LIRE)--Protocol for a pragmatic cluster randomized trial. AB - BACKGROUND: Diagnostic imaging is often the first step in evaluating patients with back pain and likely functions as a "gateway" to a subsequent cascade of interventions. However, lumbar spine imaging frequently reveals incidental findings among normal, pain-free individuals suggesting that treatment of these "abnormalities" may not be warranted. Our prior work suggested that inserting the prevalence of imaging findings in patients without back pain into spine imaging reports may reduce subsequent interventions. We are now conducting a pragmatic cluster randomized clinical trial to test the hypothesis that inserting this prevalence data into lumbar spine imaging reports for studies ordered by primary care providers will reduce subsequent spine-related interventions. METHODS/DESIGN: We are using a stepped wedge design that sequentially randomizes 100 primary care clinics at four health systems to receive either standard lumbar spine imaging reports, or reports containing prevalence data for common imaging findings in patients without back pain. We capture all outcomes passively through the electronic medical record. Our primary outcome is spine-related intervention intensity based on Relative Value Units (RVUs) during the following year. Secondary outcomes include subsequent prescriptions for opioid analgesics and cross-sectional lumbar spine re-imaging. DISCUSSION: If our study shows that adding prevalence data to spine imaging reports decreases subsequent back-related RVUs, this intervention could be easily generalized and applied to other kinds of testing, as well as other conditions where incidental findings may be common. Our study also serves as a model for cluster randomized trials that are minimal risk and highly pragmatic. PMID- 26493090 TI - The acute and medium-term effects of treatment with electroconvulsive therapy on memory in patients with major depressive disorder. AB - BACKGROUND: Current literature provides insufficient information on the degree of cognitive impairment during and after electroconvulsive therapy (ECT), mostly due to the fact that applied tests lacked sensitivity and flexibility. Our goal was to evaluate cognitive functioning in adult depressed patients treated with bi temporal ECT, using tests sensitive for detection of possible acute and medium term memory changes. METHOD: Thirty adult patients with major depressive disorder, treated with a course of bi-temporal ECT, underwent clinical and cognitive measurements three times: at baseline, immediately after a course of ECT, and 1 month later. For cognition assessment, we used learning and visual, spatial and figural memory tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: Bi-temporal ECT has proven to be an effective treatment. The linear mixed model, used to analyze changes in depression severity and patients' cognitive performances over time and to assess dynamic correlations between aforementioned features, did not show any significant memory impairment as a potential acute or medium-term ECT effect. However, it yielded significant improvement on visual memory and learning at the follow-up, which positively correlated with the improvement of depression. CONCLUSION: Good progress is being made in the search for ECT-related acute and medium-term cognitive side-effects by using the tests sensitive to detect memory dysfunction with parallel forms of the tasks (to counter practice effects on repeat testing). Our results on learning and memory in relation to ECT during treatment of depression did not bring forth any prolonged and significant bi temporal ECT-related memory deficit. PMID- 26493091 TI - Erratum to: Studies of trypanosomiasis in the Luangwa valley, north-eastern Zambia. AB - Unfortunately, the original version of this article [1] contained a mistake. The spelling of Yasuyuki Goto's name was incorrectly given as Yasuhuki Goto. The correct spelling is Yasuyuki Goto and is included correctly in the author list of this article. In addition, some author affiliations were assigned incorrectly. Yasuyuki Goto additionally belongs to affiliation 3, which should be listed as 'Laboratory of Molecular Immunology' and not 'Department of Molecular Immunology'. Masahito Asada was incorrectly assigned to affiliation number 3, but belongs to affiliation 1. This has been corrected in the affiliation list of this article. PMID- 26493092 TI - Denial of risk: The effects of positive impression management on risk assessments for psychopathic and nonpsychopathic offenders. AB - Risk assessments for offenders often combine past records with current clinical findings from observations, interviews, and test data. Conclusions based on these risk assessments are highly consequential, sometimes resulting in increased criminal sentences or prolonged hospitalization. Therefore, many offenders are motivated to intentionally minimize risk factors and their negative consequences. Positive impression management (PIM) is especially likely to occur in offenders with high psychopathic traits because goal-directed deception is reflected in several of psychopathy's core traits of the disorder, such as manipulativeness, glibness, and superficial charm. However, this connection appears to be based on the conceptual understanding of psychopathy, and has rarely been examined empirically for either frequency of or success at deception. The current study examined the ability of a jail sample to intentionally minimize risk factors and related criminal attributes using a repeated measures, simulation design. In general, offenders were able to effectively use PIM to lower scores on the HCR-20 and the Self-Appraisal Questionnaire (SAQ), while the Psychological Inventory of Criminal Thinking Styles (PICTS), as a measure of cognitive styles, was more resistant to such minimization. Psychopathic traits, especially high Factor 1 scores (i.e., affective/interpersonal), were associated with greater PIM. Important differences in the willingness and ability to use deception were found based on the (a) mode of administration (i.e., interview vs. self-report) and (b) level of psychopathy as measured by the Psychopathy Checklist - Revised (PCL-R). The important implications of this research are discussed for risk assessment procedures regarding likely areas of deception and its detection. The current research also informs the growing literature on the connection between psychopathic traits and deception. PMID- 26493094 TI - Identifying treatment effect heterogeneity in clinical trials using subpopulations of events: STEPP. AB - BACKGROUND: Investigators conducting randomized clinical trials often explore treatment effect heterogeneity to assess whether treatment efficacy varies according to patient characteristics. Identifying heterogeneity is central to making informed personalized healthcare decisions. Treatment effect heterogeneity can be investigated using subpopulation treatment effect pattern plot (STEPP), a non-parametric graphical approach that constructs overlapping patient subpopulations with varying values of a characteristic. Procedures for statistical testing using subpopulation treatment effect pattern plot when the endpoint of interest is survival remain an area of active investigation. METHODS: A STEPP analysis was used to explore patterns of absolute and relative treatment effects for varying levels of a breast cancer biomarker, Ki-67, in the phase III Breast International Group 1-98 randomized clinical trial, comparing letrozole to tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor positive breast cancer. Absolute treatment effects were measured by differences in 4-year cumulative incidence of breast cancer recurrence, while relative effects were measured by the subdistribution hazard ratio in the presence of competing risks using O-E (observed-minus-expected) methodology, an intuitive non parametric method. While estimation of hazard ratio values based on O-E methodology has been shown, a similar development for the subdistribution hazard ratio has not. Furthermore, we observed that the subpopulation treatment effect pattern plot analysis may not produce results, even with 100 patients within each subpopulation. After further investigation through simulation studies, we observed inflation of the type I error rate of the traditional test statistic and sometimes singular variance-covariance matrix estimates that may lead to results not being produced. This is due to the lack of sufficient number of events within the subpopulations, which we refer to as instability of the subpopulation treatment effect pattern plot analysis. We introduce methodology designed to improve stability of the subpopulation treatment effect pattern plot analysis and generalize O-E methodology to the competing risks setting. Simulation studies were designed to assess the type I error rate of the tests for a variety of treatment effect measures, including subdistribution hazard ratio based on O-E estimation. This subpopulation treatment effect pattern plot methodology and standard regression modeling were used to evaluate heterogeneity of Ki-67 in the Breast International Group 1-98 randomized clinical trial. RESULTS: We introduce methodology that generalizes O-E methodology to the competing risks setting and that improves stability of the STEPP analysis by pre-specifying the number of events across subpopulations while controlling the type I error rate. The subpopulation treatment effect pattern plot analysis of the Breast International Group 1-98 randomized clinical trial showed that patients with high Ki-67 percentages may benefit most from letrozole, while heterogeneity was not detected using standard regression modeling. CONCLUSION: The STEPP methodology can be used to study complex patterns of treatment effect heterogeneity, as illustrated in the Breast International Group 1-98 randomized clinical trial. For the subpopulation treatment effect pattern plot analysis, we recommend a minimum of 20 events within each subpopulation. PMID- 26493096 TI - Discharge delays reach eight year high as social care budgets are squeezed. PMID- 26493093 TI - A review of the carcinogenic potential of bisphenol A. AB - The estrogenic properties of bisphenol A (BPA), a ubiquitous synthetic monomer that can leach into the food and water supply, have prompted considerable research into exposure-associated health risks in humans. Endocrine-disrupting properties of BPA suggest it may impact developmental plasticity during early life, predisposing individuals to disease at doses below the oral reference dose (RfD) established by the Environmental Protection Agency in 1982. Herein, we review the current in vivo literature evaluating the carcinogenic properties of BPA. We conclude that there is substantial evidence from rodent studies indicating that early-life BPA exposures below the RfD lead to increased susceptibility to mammary and prostate cancer. Based on the definitions of "carcinogen" put forth by the International Agency for Research on Cancer and the National Toxicology Program, we propose that BPA may be reasonably anticipated to be a human carcinogen in the breast and prostate due to its tumor promoting properties. PMID- 26493095 TI - Pathology concordance levels for meningioma classification and grading in NRG Oncology RTOG Trial 0539. AB - BACKGROUND: With advances in the understanding of histopathology on outcome, accurate meningioma grading becomes critical and drives treatment selection. The 2000 and 2007 WHO schema greatly increased the proportion of grade II meningiomas. Although associations with progression-free survival (PFS) and overall survival (OS) have been independently validated, interobserver concordance has not been formally assessed. METHODS: Once mature, NRG Oncology RTOG-0539 will report PFS and OS in variably treated low-, intermediate-, and high-risk cohorts. We address concordance of histopathologic assessment between enrolling institutions and central review, performed by a single pathologist (AP), who is also involved in developing current WHO criteria. RESULTS: The trial included 170 evaluable patients, 2 of whom had 2 eligible pathology reviews from different surgeries, resulting in 172 cases for analysis. Upon central review, 76 cases were categorized as WHO grade I, 71 as grade II, and 25 as grade III. Concordance for tumor grade was 87.2%. Among patients with WHO grades I, II, and III meningioma, respective concordance rates were 93.0%, 87.8%, and 93.6% (P values < .0001). Moderate to substantial agreement was encountered for individual grading criteria and were highest for brain invasion, >=20 mitoses/10 high powered field [HPF], and spontaneous necrosis, and lowest for small cells, sheeting, and >=4 mitoses/10 HPF. In comparison, published concordance for gliomas in clinical trials have ranged from 8%-74%. CONCLUSION: Our data suggest that current meningioma classification and grading are at least as objective and reproducible as for gliomas. Nevertheless, reproducibility remains suboptimal. Further improvements may be anticipated with education and clarification of subjective criteria, although development of biomarkers may be the most promising strategy. PMID- 26493097 TI - Evolution of Quantitative MALDI-TOF Mass Spectrometry for Clinical Applications. PMID- 26493098 TI - A Delicate Balance When Substituting a Small Hydrophobe onto Low Molecular Weight Polyethylenimine to Improve Its Nucleic Acid Delivery Efficiency. AB - High molecular weight (HMW) polyethylenimine (PEI) is one of the most versatile nonviral gene vectors that was extensively investigated over the past two decades. The cytotoxic profile of HMW PEI, however, encouraged a search for safer alternatives. Because of lack of cytotoxicity of low molecular weight (LMW) PEI, enhancing its performance via hydrophobic modifications has been pursued to this end. Since the performance of modified PEIs depends on the nature and extent of substituents, we systematically investigated the effect of hydrophobic modification of LMW (1.2 kDa) PEI with a short propionic acid (PrA). Moderate enhancements in PEI hydrophobicity resulted in enhanced cellular uptake of polyplexes and siRNA-induced silencing efficacy, whereas further increase in PrA substitution abolished the uptake as well as the silencing. We performed all-atom molecular dynamics simulations to elucidate the mechanistic details behind these observations. A new assembly mechanism was observed by the presence of hydrophobic PrA moieties, where PrA migrated to core of the polyplex. This phenomenon caused higher surface hydrophobicity and surface charge density at low substitutions, and it caused deleterious effects on surface hydrophobicity and cationic charge at higher substitutions. It is evident that an optimal balance of hydrophobicity/hydrophilicity is needed to achieve the desired polyplex properties for an efficient siRNA delivery, and our mechanistic findings should provide valuable insights for the design of improved substituents on nonviral carriers. PMID- 26493099 TI - Determining the reliability of a custom built seated stadiometry set-up for measuring spinal height in participants with chronic low back pain. AB - Indirect measurement of disc hydration can be obtained through measures of spinal height using stadiometry. However, specialised stadiometers for this are often custom-built and expensive. Generic wall-mounted stadiometers alternatively are common in clinics and laboratories. This study examined the reliability of a custom set-up utilising a wall-mounted stadiometer for measurement of spinal height using custom built wall mounted postural rods. Twelve participants with non-specific chronic low back pain (CLBP; females n = 5, males n = 7) underwent measurement of spinal height on three separate consecutive days at the same time of day where 10 measurements were taken at 20 s intervals. Comparisons were made using repeated measures analysis of variance for 'trial' and 'gender'. There were no significant effects by trial or interaction effects of trial x gender. Intra individual absolute standard error of measurement (SEM) was calculated for spinal height using the first of the 10 measures, the average of 10 measures, the total shrinkage, and the rate of shrinkage across the 10 measures examined as the slope of the curve when a linear regression was fitted. SEMs were 3.1 mm, 2.8 mm, 2.6 mm and 0.212, respectively. Absence of significant differences between trials and the reported SEMs suggests this custom set-up for measuring spinal height changes is suitable use as an outcome measure in either research or clinical practice in participants with CLBP. PMID- 26493100 TI - The Economic Burden of Fetal Alcohol Spectrum Disorder in Canada in 2013. AB - AIM: To estimate the economic burden and cost attributable to Fetal Alcohol Spectrum Disorder (FASD) in Canada in 2013. METHODS: This cost-of-illness study examined the impact of FASD on the material welfare of the Canadian society in 2013 by analyzing the direct costs of resources expended on health care, law enforcement, children and youth in care, special education, supportive housing, long-term care, prevention and research, as well as the indirect costs of productivity losses of individuals with FASD due to their increased morbidity and premature mortality. RESULTS: The costs totaled approximately $1.8 billion (from about $1.3 billion as the lower estimate up to $2.3 billion as the upper estimate). The highest contributor to the overall FASD-attributable cost was the cost of productivity losses due to morbidity and premature mortality, which accounted for 41% ($532 million-$1.2 billion) of the overall cost. The second highest contributor to the total cost was the cost of corrections, accounting for 29% ($378.3 million). The third highest contributor was the cost of health care at 10% ($128.5-$226.3 million). CONCLUSIONS: FASD is a significant public health and social problem that consumes resources, both economic and societal, in Canada. Many of the costs could be reduced with the implementation of effective social policies and intervention programs. PMID- 26493102 TI - Clinical trial transparency: many gains but access to evidence for new medicines remains imperfect. AB - BACKGROUND: Although selective and incomplete publication is widely acknowledged to be a problem, full access to clinical trial data remains illusive. SOURCES OF DATA: Authors' personal files, key documents from Food and Drug Administration and European Medicines Agency and focussed searches of PubMed. AREAS OF AGREEMENT: Existing sources of information provide an incomplete overview of scientific research. AREAS OF CONTROVERSY: Persistent arguments about commercial confidentiality and the potential difficulties in de-identifying raw data can block important progress. Current industry efforts are voluntary and only partially satisfy the need for complete data. GROWING POINTS: Requirements for trial registration are increasing. Important regulatory changes in particular in Europe have the potential to result in the release of more information. AREAS TIMELY FOR DEVELOPING RESEARCH: Documenting the effects of prospective trial registration and requirements for proactive clinical trial publication on healthcare decisions, public health and rational resource allocation. PMID- 26493101 TI - Marginal zone B cells emerge as a critical component of pregnancy well-being. AB - The success of eutherian mammal evolution was certainly supported by the ability of the already existing immune system to adapt to the presence of the semi allogeneic fetus without losing the capability to defend the mother against infections. This required the acquisition of highly regulated and coordinated immunological mechanisms. Failures in the development of these strategies not only lead to the interruption of pregnancy but also compromise maternal health. Alongside changes on the cytokine profile - expansion of tolerogenic dendritic and regulatory T cells - a profound adaptation of the B cell compartment during pregnancy was recently described. Among others, the suppression of B cell lymphopoiesis and B cell lymphopenia were proposed to be protective mechanisms tending to reduce the occurrence of autoreactive B cells that might recognize fetal structures and put pregnancy on risk. On the other hand, expansion of the pre-activated marginal zone (MZ) B cell phenotype was described as a compensatory strategy launched to overcome B cell lymphopenia thus ensuring a proper defense. In this work, using an animal model of pregnancy disturbances, we demonstrated that the suppression of B cell lymphopoiesis as well as splenic B cell lymphopenia occur independently of pregnancy outcome. However, only animals undergoing normal pregnancies, but not those suffering from pregnancy disturbances, could induce an expansion and activation of the MZ B cells. Hence, our results clearly show that MZ B cells, probably due to the production of natural protective antibodies, participate in the fine balance of immune activation required for pregnancy well-being. PMID- 26493103 TI - Skin surface imaging of psoriasis vulgaris by using an electron paramagnetic resonance spin probe. PMID- 26493104 TI - Human DNA repair disorders in dermatology: A historical perspective, current concepts and new insight. AB - Products of DNA damage, such as cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4 PPs), are continually formed in genomes after exposure to UV radiation. When these DNA damages remain unrepaired in essential DNA sites for prolonged periods, DNA replication and transcription are hampered or mutation is induced, which may cause cell death, cellular senescence, and carcinogenesis of the skin. To protect against such UV-induced DNA damage, living organisms nicely retain "DNA repair systems", which can efficiently repair "harmful" DNA damage through precise mechanisms by the integrated functions of many proteins. In humans, the failure of DNA repair systems causes a variety of disorders. Dermatological conditions such as hereditary photodermatoses, xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are caused by congenital functional defects in the nucleotide excision repair (NER) system or the translesion synthesis (TLS) system. In this review, we describe the historical progress, recent findings, and future prospects of studies of human diseases associated with DNA-repair defects. PMID- 26493105 TI - Striate palmoplantar keratoderma: Report of a novel DSG1 mutation and atypical clinical manifestations. PMID- 26493106 TI - APC controls asymmetric Wnt/beta-catenin signaling and cardiomyocyte proliferation gradient in the heart. AB - AIMS: Cardiomyocyte (CM) proliferation increases from the inner trabecular to outer compact myocardium in fetal hearts. We determined if canonical Wnt signaling has directional and graded activity to maintain this CM proliferation gradient. Moreover, we investigated whether perturbation of Wnt signaling intensity could modulate CM proliferative activity. METHODS AND RESULTS: With confocal microscopy and image analysis we found that the Wnt effector, beta catenin, formed a signaling gradient which positively correlated with CM proliferative activity across ventricular walls of wild type (WT) embryos at embryonic day (E) 13.5 and 17.5. Negative Wnt regulators, adenomatosis polyposis coli (APC), had a reverse distribution pattern. The activation of canonical Wnt/beta-catenin signaling by deletion of Apc in CMs led to ventricular hyperplasia with no adverse effects on fetal survival or CM differentiation. In contrast, cardiac deletion of beta-catenin resulted in ventricular hypoplasia and fetal demise by E14.5. We further revealed differential distribution and regulation of three cyclin Ds in fetal hearts. Cyclin D1 was mainly expressed in endothelial cells. Although both cyclin D2 and D3 were present in CMs, only cyclin D2 was regulated by Wnt signaling perturbation: downregulation by beta catenin deletion and upregulation by Apc knockout. CONCLUSION: Canonical Wnt signaling is asymmetrical and graded across ventricular walls and positively regulates CM proliferation via cyclin D2. PMID- 26493107 TI - miRNA-34a reduces neointima formation through inhibiting smooth muscle cell proliferation and migration. AB - AIMS: We have recently reported that microRNA-34a (miR-34a) regulates vascular smooth muscle cell (VSMC) differentiation from stem cells in vitro and in vivo. However, little is known about the functional involvements of miR-34a in VSMC functions and vessel injury-induced neointima formation. In the current study, we aimed to establish the causal role of miR-34a and its target genes in VSMC proliferation, migration and neointima lesion formation. METHODS AND RESULTS: Various pathological stimuli regulate miR-34a expression in VSMCs through a transcriptional mechanism, and the P53 binding site is required for miR-34a gene regulation by these stimuli. miR-34a over-expression in serum-starved VSMCs significantly inhibited VSMC proliferation and migration, while knockdown of miR 34a dramatically promoted VSMC proliferation and migration, respectively. Notch homolog 1 (Notch1), a well-reported regulator in VSMC functions and arterial remodeling, was predicted as one of the top targets of miR-34a by using several computational miRNA target prediction tools, and was negatively regulated by miR 34a in VSMCs. Luciferase assay showed miR-34a substantially repressed wild type Notch1-3'-UTR-luciferase activity in VSMCs, but not mutant Notch1-3'-UTR luciferease reporter, confirming the Notch1 is the functional target of miR-34a in VSMCs. Data from co-transfection experiments also revealed that miR-34a inhibited VSMC proliferation and migration through modulating Notch gene expression levels. Importantly, the expression level of miR-34a was significantly down-regulated in injured arteries, and miR-34a perivascular over-expression significantly reduced Notch1 expression levels, decreased VSMC proliferation, and inhibited neointima formation in wire-injured femoral arteries. CONCLUSION: Our data have demonstrated that miR-34a is an important regulator in VSMC functions and neointima hyperplasia, suggesting its potential therapeutic application for vascular diseases. PMID- 26493110 TI - Therapeutic potential and mechanism of thymol action against ethanol-induced gastric mucosal injury in rat model. AB - In this study, we investigated the potential of thymol and its mode of action to protect against the gastric mucosal injury induced by ethanol consumption in an in vivo model. Moreover, we determined the role of thymol in regulation of matrix metalloproteinase-9 (MMP-9), an enzyme belonging to the metalloproteinase group, which is responsible for the remodeling of injured tissues. Sprague-Dawley rats pretreated with thymol (10 mg/kg body weight) or normal saline were subjected to intragastric administration of 95% ethanol (5 mL/kg body weight). Morphological examination included ulcer index as a measurement of hemorrhages, and hematoxylin and eosin (H&E) staining was performed to analyze severity of gastric mucosal damage. Gelatinase zymography of tissue extract and in situ zymography were performed to demonstrate MMP-9 activity. Results of macroscopic examination suggested that thymol significantly protected gastric mucosa from damage induced by alcohol, which was severe in the case of alcohol-only treatment. H&E data demonstrated necrosis of the corpus region in alcohol-treated rats, which was abrogated in rats pretreated with thymol. Further, thymol protected against the constriction of small arteries and neutrophil infiltration in lymphatic vessels. Expression of antioxidant enzymes increased in the thymol-pretreated group, and downregulation of MMP-9 protein expression was observed by gelatin zymography as well as in situ zymography. The results of this study suggest that thymol protects against gastric mucosa injury induced by ethanol consumption by upregulating the secretion of antioxidant enzymes and downregulating the expression of the MMP-9 protein. PMID- 26493108 TI - Fitness, but not physical activity, is related to functional integrity of brain networks associated with aging. AB - Greater physical activity and cardiorespiratory fitness are associated with reduced age-related cognitive decline and lower risk for dementia. However, significant gaps remain in the understanding of how physical activity and fitness protect the brain from adverse effects of brain aging. The primary goal of the current study was to empirically evaluate the independent relationships between physical activity and fitness with functional brain health among healthy older adults, as measured by the functional connectivity of cognitively and clinically relevant resting state networks. To build context for fitness and physical activity associations in older adults, we first demonstrate that young adults have greater within-network functional connectivity across a broad range of cortical association networks. Based on these results and previous research, we predicted that individual differences in fitness and physical activity would be most strongly associated with functional integrity of the networks most sensitive to aging. Consistent with this prediction, and extending on previous research, we showed that cardiorespiratory fitness has a positive relationship with functional connectivity of several cortical networks associated with age-related decline, and effects were strongest in the default mode network (DMN). Furthermore, our results suggest that the positive association of fitness with brain function can occur independent of habitual physical activity. Overall, our findings provide further support that cardiorespiratory fitness is an important factor in moderating the adverse effects of aging on cognitively and clinically relevant functional brain networks. PMID- 26493109 TI - The impact of micronutrient supplementation in alcohol-exposed pregnancies on information processing skills in Ukrainian infants. AB - The potential of micronutrients to ameliorate the impact of prenatal alcohol exposure (PAE) was explored in a clinical trial conducted in Ukraine. Cardiac orienting responses (ORs) during a habituation/dishabituation learning paradigm were obtained from 6 to 12 month-olds to assess neurophysiological encoding and memory. Women who differed in prenatal alcohol use were recruited during pregnancy and assigned to a group (No study-provided supplements, multivitamin/mineral supplement, or multivitamin/mineral supplement plus choline supplement). Heart rate was collected for 30 s prior to stimulus onset and 12 s post-stimulus onset. Difference values (?HR) for the first 3 trials of each condition were aggregated for analysis. Gestational blood samples were collected to assess maternal nutritional status and changes as a function of the intervention. Choline supplementation resulted in a greater ?HR on the visual habituation trials for all infants and for the infants with no PAE on the dishabituation trials. The latency of the response was reduced in both conditions for all infants whose mothers received choline supplementation. Change in gestational choline level was positively related to ?HR during habituation trials and levels of one choline metabolite, dimethylglycine (DMG), predicted ?HR during habituation trials and latency of responses. A trend was found between DMG and ?HR on the dishabituation trials and latency of the response. Supplementation did not affect ORs to auditory stimuli. Choline supplementation when administered together with routinely recommended multivitamin/mineral prenatal supplements during pregnancy may provide a beneficial impact to basic learning mechanisms involved in encoding and memory of environmental events in alcohol-exposed pregnancies as well as non- or low alcohol-exposed pregnancies. Changes in maternal nutrient status suggested that one mechanism by which choline supplementation may positively impact brain development is through prevention of fetal alcohol-related depletion of DMG, a metabolic nutrient that can protect against overproduction of glycine, during critical periods of neurogenesis. PMID- 26493111 TI - Neuroinflammation in Lewy body dementia. AB - Neuroinflammation is increasingly recognized as a key factor in the pathogenesis of neurodegenerative conditions. However, it remains unclear whether it has a protective or damaging role. Studies of Alzheimer's disease and Parkinson's disease have provided much of the evidence for inflammatory pathology in neurodegeneration. Here we review the evidence for inflammation in dementia with Lewy bodies and Parkinson's disease dementia. Neuroinflammation has been confirmed in vivo using PET imaging, with microglial activation seen in Parkinson's disease dementia and recently in dementia with Lewy bodies. In Parkinson's disease and Parkinson's disease dementia, microglial activation suggests a chronic inflammatory process, although there is also evidence of its association with cognitive ability and neuronal function. Alpha-synuclein in various conformations has also been linked to activation of microglia, with a broad range of components of the innate and adaptive immune systems associated with this interaction. Evidence of neuroinflammation in Lewy body dementia is further supported by pathological and biomarker studies. Genetic and epidemiological studies support a role for inflammation in Parkinson's disease, but have yet to provide the same for Lewy body dementia. This review highlights the need to identify whether the nature and extent of microglial activation in Lewy body dementia can be linked to structural change, progression of domain specific cognitive symptoms and peripheral inflammation as a marker of central microglial pathology. Answers to these questions will enable the evaluation of immunotherapies as potential therapeutic options for prevention or treatment of dementia with Lewy bodies and Parkinson's disease dementia. PMID- 26493112 TI - Diagnostic accuracy of different caries risk assessment methods. A systematic review. AB - OBJECTIVES: To evaluate the accuracy of different methods used to identify individuals with increased risk of developing dental coronal caries. DATA: Studies on following methods were included: previous caries experience, tests using microbiota, buffering capacity, salivary flow rate, oral hygiene, dietary habits and sociodemographic variables. QUADAS-2 was used to assess risk of bias. Sensitivity, specificity, predictive values, and likelihood ratios (LR) were calculated. Quality of evidence based on >=3 studies of a method was rated according to GRADE. SOURCES: PubMed, Cochrane Library, Web of Science and reference lists of included publications were searched up to January 2015. STUDY SELECTION: From 5776 identified articles, 18 were included. Assessment of study quality identified methodological limitations concerning study design, test technology and reporting. No study presented low risk of bias in all domains. Three or more studies were found only for previous caries experience and salivary mutans streptococci and quality of evidence for these methods was low. Evidence regarding other methods was lacking. For previous caries experience, sensitivity ranged between 0.21 and 0.94 and specificity between 0.20 and 1. Tests using salivary mutans streptococci resulted in low sensitivity and high specificity. For children with primary teeth at baseline, pooled LR for a positive test was 3 for previous caries experience and 4 for salivary mutans streptococci, given a threshold >=10(5) CFU/ml. CONCLUSIONS: Evidence on the validity of analysed methods used for caries risk assessment is limited. As methodological quality was low, there is a need to improve study design. CLINICAL SIGNIFICANCE: Low validity for the analysed methods may lead to patients with increased risk not being identified, whereas some are falsely identified as being at risk. As caries risk assessment guides individualized decisions on interventions and intervals for patient recall, improved performance based on best evidence is greatly needed. PMID- 26493114 TI - Unusual outer ear swelling: Childhood auricular rhabdomyosarcoma. AB - INTRODUCTION: Rhabdomyosarcoma (RMS) is the most frequent soft-tissue sarcoma in children and makes up 5% of all pediatric malignant tumors. The main head and neck locations are the base of the skull, nasopharynx, nasal cavity and orbit. An outer ear location is considered extremely rare. We present 3 cases of children, aged 6 to 14 years, presenting with auricular RMS. CASE REPORTS: The first child, aged 6, was managed by 4 chemotherapy cycles followed by surgical resection of the tumor bed, completed by 5 further cycles of chemotherapy. The second, aged 14, was managed by 4 chemotherapy cycles followed by external radiation therapy of the tumor bed and lymph node areas, completed by 5 further cycles of chemotherapy. The third, aged 13, was managed by 4 chemotherapy cycles followed by surgery, completed by 5 further cycles of chemotherapy. DISCUSSION: In these 3 patients, the treatment program achieved complete disease control. Prognosis was good, thanks to good surgical access. Diagnosis should be considered in case of unusual progressive swelling in the outer ear. PMID- 26493115 TI - Time dependent gender differences in suicide risk among Operation Enduring Freedom and Operation Iraqi Freedom veterans. PMID- 26493113 TI - Head and neck adenoid cystic carcinoma: A prospective multicenter REFCOR study of 95 cases. AB - OBJECTIVES: To describe the clinical, histological and therapeutic characteristics of a prospective multicenter series of 95 head and neck adenoid cystic carcinoma patients, and to determine any prognostic factors for disease free survival. PATIENTS AND METHODS: Ninety-five patients with adenoid cystic carcinoma were included in the Reseau d'Expertise Francais Des Cancers ORL Rares (REFCOR, French Rare Head and Neck Cancer Expert Network) database between 2009 and 2012. The primary site was the salivary glands in 39 cases, sinus cavities (including hard palate) in 36 cases, pharynx-larynx-trachea in 14 cases, and lips and oral cavity in 4 cases. The tumor was stage I in 15% of cases, stage II in 23%, stage III in 26% and stage IV in 36%. Nine patients had cervical lymph node involvement and 5 had metastases at diagnosis. Fifty-six percent of patients were managed by surgery with postoperative radiation therapy. During follow-up, 3 patients died, 9 developed metastases and 12 showed recurrence or local progression. RESULTS: Mean follow-up was 18 months. On univariate analysis, disease-free survival correlated with T stage (P=0.05), N stage (P=0.003), resection margins (P=0.04), lymph node involvement on histology (P=0.01), and absence of chemotherapy (P=0.03). On multivariate analysis, disease-free survival correlated with T stage (P=0.01), N stage (P=0.09) and surgery (P=0.005). CONCLUSION: The essential issue in adenoid cystic carcinoma is long-term control. The present results confirm that the reference attitude is radical surgical resection for optimal local control. Adjuvant radiation therapy did not emerge as a prognostic factor. This study also provides a starting-point for translational studies in pathology and genetics. PMID- 26493116 TI - Preimplantation genetic screening (PGS) is an excellent tool, but not perfect: a guide to counseling patients considering PGS. PMID- 26493117 TI - Relationship between sperm aneuploidy, sperm DNA integrity, chromatin packaging, traditional semen parameters, and recurrent pregnancy loss. AB - OBJECTIVE: To study the possible relationship between sperm aneuploidy, sperm DNA integrity, chromatin packaging, traditional semen parameters, and recurrent pregnancy loss (RPL). DESIGN: Descriptive study. SETTING: University-affiliated tertiary teaching. PATIENT(S): A total of 22 couples with history of RPL and 20 fertile men. INTERVENTION(S): Semen samples from case and control men were examined for differences in semen parameters, DNA fragmentation, chromatin condensation, and sperm aneuploidy. MAIN OUTCOME MEASURE(S): Sperm DNA and chromatin integrity and sperm aneuploidy. RESULT(S): Sperm progressive motility (30.2% vs. 51.5%) was significantly lower and abnormal morphology (74.8% vs. 54.2%) was significantly higher in the RPL group versus the control group, respectively. The percentage of fragmented DNA was significantly increased in the RPL group (17.1% vs. 10.2%) as well as the rate of spermatozoa with nuclear chromatin decondensation (23.6% vs. 11.8%). There was a significantly higher sperm aneuploidy rate among the RPL group as well. CONCLUSION(S): The increase in abnormal sperm parameters, sperm DNA fragmentation, nuclear chromatin decondensation, and sperm aneuploidy suggest possible causes of unexplained RPL. PMID- 26493118 TI - Second live birth after undergoing assisted reproductive technology in women operated on for endometriosis. AB - OBJECTIVE: To determine prognostic factors for a second live birth, after a first child obtained through assisted reproductive techniques (ART). DESIGN: Observational study from January 2004 to December 2014. SETTING: Tertiary care university hospital and ART center. PATIENT(S): A total of 164 infertile patients with endometriosis, who underwent laparoscopy surgery and had a first baby obtained by ART, were included and 65 wished a second baby. INTERVENTION(S): No iterative surgery. MAIN OUTCOME MEASURE(S): Spontaneous pregnancy rate (PR) according to endometriosis fertility index. RESULT(S): Among the cohort, 27 patients (41.5%) gave birth to a second child through spontaneous pregnancy, whereas 23 patients (35.3%) required ART to obtain a second live birth. No difference was observed between patients regarding age, endometriosis staging, complete removal of endometriosis lesions and pelvic adhesion, except for the least function score, and the endometriosis fertility index. Taking into account irrespective of both mode of conception a total of 78% of patients obtained a second child, with a median conception time of 17 months. CONCLUSION(S): The second live birth rate in infertile patients with endometriosis and with surgical treatment was high (78%). Spontaneous PR was 54%. Endometriosis fertility index could be considered as a predictive factor for a spontaneous second pregnancy in fertility management. Our results need to be confirmed in larger prospective studies. PMID- 26493119 TI - Maternal microbiome and pregnancy outcomes. AB - Alterations of the human microbiome are a known characteristic of various inflammatory disease states and have been linked to spontaneous preterm birth and other adverse pregnancy outcomes. Recent advances in metagenomic research have proven that the placenta harbors its own rich diverse microbiome, even in clinically healthy pregnancies, and preterm birth may be a result of hematogenous infection rather than exclusively ascending infection as previously hypothesized. In this review, we describe the microbiome in healthy nongravid and gravid women to contrast it with the alterations of the microbiome associated with spontaneous preterm birth. We also discuss the importance of host gene-environment interactions and the potential for microbiota-specific targeted therapies to reduce the risk of adverse pregnancy outcomes. PMID- 26493120 TI - Novel fumarate hydratase mutation in a family with atypical uterine leiomyomas and hereditary leiomyomatosis and renal cell cancer. AB - OBJECTIVE: To describe a novel mutation in the fumarate hydratase (FH) gene in a family with atypical uterine leiomyomas. DESIGN: Case report and review of the literature. SETTING: Academic community hospital. PATIENT(S): Three sisters who presented as nulligravidas aged 27-30 years with large atypical uterine leiomyomas. INTERVENTION(S): Abdominal myomectomy, robotic myomectomy, hysterectomy, gene sequencing. MAIN OUTCOME MEASURE(S): Identification of a family with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome and a novel mutation in the FH gene. RESULT(S): Two of the three sisters tested positive for a novel FH mutation p.Leu99Glufsx6. The eldest sister was clinically diagnosed with HLRCC. The patients' father also carries the same mutation in the FH gene. The patients and their father are now undergoing yearly screening for renal cancer. CONCLUSION(S): Patients with HLRCC are at risk for developing renal cancer as well as losing their fertility via early hysterectomy. Physicians must be aware of this condition and refer at-risk individuals for genetic testing. PMID- 26493121 TI - Beneficial value of testicular sperm extraction-AgarCyto in addition to the standard testicular biopsy for diagnosis of testicular germ cell tumors in nonobstructive azoospermia. AB - OBJECTIVE: To study whether immunohistochemical detection of germ cell neoplasia in situ (GCNIS) in AgarCytos, made of the remnants of the testicular sperm extraction (TESE) specimen, is equally accurate as in a standard testicular biopsy. DESIGN: Prospective cohort study performed between January 2013 and May 2014. SETTING: University hospital. PATIENT(S): All men with nonobstructive azoospermia (n = 197) undergoing a urological work-up followed by a unilateral or bilateral TESE for fertility treatment were consecutively included. INTERVENTION(S): An AgarCyto was made of the remnants of these TESE biopsies. Simultaneously a standard testicular biopsy was performed. For all cases a routine hematoxylin-eosin (H & E) staining was performed as well as immunohistochemistry (PLAP and OCT3/4) to detect GCNIS. MAIN OUTCOME MEASURE(S): The presence or absence of GCNIS in the TESE-AgarCyto and standard testicular biopsy. RESULT(S): Six men (3.0%) were diagnosed with a germ cell (pre)malignancy by immunohistochemistry. No cases were encountered in which the TESE-AgarCyto was negative, whereas the standard testicular biopsy was positive for GCNIS. In one case the TESE-AgarCyto detected a premalignancy that was missed by standard testicular biopsy. Unfortunately a standard testicular biopsy was not available for direct comparison in 50% of the GCNIS-positive patients due to various reasons. CONCLUSION(S): Because GCNIS is heterogeneously distributed in the testis, the TESE-AgarCyto can diagnose GCNIS even when the standard testicular biopsy is negative. Direct comparison of accuracy, however, is not reliable due to the low prevalence of GCNIS and the lack of a standard biopsy when an orchidectomy was performed simultaneously with TESE. PMID- 26493123 TI - Prediction modelling for trauma using comorbidity and 'true' 30-day outcome. AB - BACKGROUND: Prediction models for trauma outcome routinely control for age but there is uncertainty about the need to control for comorbidity and whether the two interact. This paper describes recent revisions to the Trauma Audit and Research Network (TARN) risk adjustment model designed to take account of age and comorbidities. In addition linkage between TARN and the Office of National Statistics (ONS) database allows patient's outcome to be accurately identified up to 30 days after injury. Outcome at discharge within 30 days was previously used. METHODS: Prospectively collected data between 2010 and 2013 from the TARN database were analysed. The data for modelling consisted of 129 786 hospital trauma admissions. Three models were compared using the area under the receiver operating curve (AuROC) for assessing the ability of the models to predict outcome, the Akaike information criteria to measure the quality between models and test for goodness-of-fit and calibration. Model 1 is the current TARN model, Model 2 is Model 1 augmented by a modified Charlson comorbidity index and Model 3 is Model 2 with ONS data on 30 day outcome. RESULTS: The values of the AuROC curve for Model 1 were 0.896 (95% CI 0.893 to 0.899), for Model 2 were 0.904 (0.900 to 0.907) and for Model 3 0.897 (0.896 to 0.902). No significant interaction was found between age and comorbidity in Model 2 or in Model 3. CONCLUSIONS: The new model includes comorbidity and this has improved outcome prediction. There was no interaction between age and comorbidity, suggesting that both independently increase vulnerability to mortality after injury. PMID- 26493122 TI - Association study of androgen signaling pathway genes in polycystic ovary syndrome. AB - OBJECTIVE: To evaluate genes involved in androgen receptor (AR) signaling as candidate genes for polycystic ovary syndrome (PCOS). DESIGN: Two groups of women with PCOS and control women (discovery and replication cohorts), were genotyped for single-nucleotide polymorphisms (SNPs) in eight genes for AR chaperones and co-chaperones: HSPA1A, HSPA8, ST13, STIP1, PTGES3, FKBP4, BAG1, and STUB1. Single nucleotide polymorphisms were tested for association with PCOS status and with androgenic and metabolic parameters. SETTING: Tertiary referral center. PATIENT(S): Discovery cohort: 354 women with PCOS and 161 control women. Replication cohort: 397 women with PCOS and 306 control women. INTERVENTION(S): Phenotypic and genotypic assessment. MAIN OUTCOME MEASURE(S): Single-nucleotide polymorphism genotypes, association with PCOS status, and androgenic and metabolic parameters. RESULT(S): In the discovery cohort, FKBP4 SNPs rs2968909 and rs4409904 were associated with lower odds of PCOS. This finding was not confirmed in the replication cohort analysis; however, when combining the two cohorts, rs4409904 was associated with lower odds of PCOS. In subjects with PCOS in the replication cohort as well as in the combined cohort, rs2968909 was associated with lower body mass index. CONCLUSION(S): Single-nucleotide polymorphisms in FKBP4, which codes for the AR co-chaperone FKBP52, may be associated with PCOS and body mass index in patients with PCOS. The remaining genes studied do not seem to be major contributors to the development of PCOS. These findings warrant confirmation in future studies, and genes encoding other androgen pathway components remain to be studied. PMID- 26493124 TI - Challenging the dogma of traumatic cardiac arrest management: a military perspective. AB - Attempts to resuscitate patients in traumatic cardiac arrest (TCA) have, in the past, been viewed as futile. However, reported outcomes from TCA in the past five years, particularly from military series, are improving. The pathophysiology of TCA is different to medical causes of cardiac arrest, and therefore, treatment priorities may also need to be different. This article reviews recent literature describing the pathophysiology of TCA and describes how the military has challenged the assumption that outcome is universally poor in these patients. PMID- 26493125 TI - Immunomodulatory properties and in vivo osteogenesis of human dental stem cells from fresh and cryopreserved dental follicles. AB - In our previous study, dental follicle tissues from extracted wisdom teeth were successfully cryopreserved for use as a source of stem cells. The goals of the present study were to investigate the immunomodulatory properties of stem cells from fresh and cryopreserved dental follicles (fDFCs and cDFCs, respectively) and to analyze in vivo osteogenesis after transplantation of these DFCs into experimental animals. Third passage fDFCs and cDFCs showed similar expression levels of interferon-gamma receptor (CD119) and major histocompatibility complex class I and II (MHC I and MHC II, respectively), with high levels of CD119 and MHC I and nearly no expression of MHC II. Both fresh and cryopreserved human DFCs (hDFCs) were in vivo transplanted along with a demineralized bone matrix scaffold into mandibular defects in miniature pigs and subcutaneous tissues of mice. Radiological and histological evaluations of in vivo osteogenesis in hDFC transplanted sites revealed significantly enhanced new bone formation activities compared with those in scaffold-only implanted control sites. Interestingly, at 8 weeks post-hDFC transplantation, the newly generated bones were overgrown compared to the original size of the mandibular defects, and strong expression of osteocalcin and vascular endothelial growth factor were detected in the hDFCs transplanted tissues of both animals. Immunohistochemical analysis of CD3, CD4, and CD8 in the ectopic bone formation sites of mice showed significantly decreased CD4 expression in DFCs-implanted tissues compared with those in control sites. These findings indicate that hDFCs possess immunomodulatory properties that involved inhibition of the adaptive immune response mediated by CD4 and MHC II, which highlights the usefulness of hDFCs in tissue engineering. In particular, long-term preserved dental follicles could serve as an excellent autologous or allogenic stem cell source for bone tissue regeneration as well as a valuable therapeutic agent for immune diseases. PMID- 26493126 TI - Abnormal adaptation over time of motor network recruitment in multiple sclerosis patients with fatigue. AB - OBJECTIVES: Using functional magnetic resonance imaging (fMRI) during a motor task, we investigated the functional correlates of central fatigue in multiple sclerosis (MS), and adaptation of motor network recruitment during a prolonged effort. METHODS: Motor fMRI was obtained from 79 MS patients (50 fatigued (F), 29 non-fatigued (nF)) and 26 matched healthy controls (HC). Cognitive and physical fatigue were rated using the Modified Fatigue Impact Scale (MFIS). RESULTS: Compared to HC and nF patients, F-MS patients experienced reduced activations of the left middle temporal gyrus, left supplementary motor area (SMA), bilateral superior frontal gyrus, left postcentral gyrus and basal ganglia regions. They also showed increased activation of the right middle frontal gyrus (MFG). Time modulation analysis showed a reduced activity of the SMA and right precentral gyrus, and increased activity of the basal ganglia in HC. Such a trend was impaired in F-MS patients. In MS patients, increased MFG activity was related to MFIS scores. Physical MFIS score was related to a reduced recruitment of the right thalamus and SMA. CONCLUSIONS: Abnormalities and impaired timing of activation between different areas of the motor and executive networks occur in F MS patients. The dysfunction of critical cortical areas contributes to the occurrence of central fatigue. PMID- 26493127 TI - Deregulation of microRNA-181c in cerebrospinal fluid of patients with clinically isolated syndrome is associated with early conversion to relapsing-remitting multiple sclerosis. AB - BACKGROUND: MiRNA-181c, miRNA-633 and miRNA-922 have been reported to be deregulated in multiple sclerosis. OBJECTIVES: To investigate the association between miRNA-181c, miRNA-633 and miRNA-922 and conversion from clinically isolated syndrome (CIS) to relapsing-remitting multiple sclerosis (RRMS); and to compare microRNAs in cerebrospinal fluid (CSF) and serum with regard to dysfunction of the blood-CSF barrier. METHODS: CSF and serum miRNA-181c, miRNA 633 and miRNA-922 were retrospectively determined by quantitative real-time polymerase chain reaction in CIS patients with (CIS-RRMS) and without (CIS-CIS) conversion to RRMS within 1 year. RESULTS: Thirty of 58 CIS patients developed RRMS. Cerebrospinal fluid miRNA-922, serum miRNA-922 and cerebrospinal fluid miRNA-181c were significantly higher in CIS-RRMS compared to CIS-CIS (P=0.027, P=0.048, P=0.029, respectively). High levels of cerebrospinal fluid miRNA-181c were independently associated with conversion from CIS to RRMS in multivariate Cox regression analysis (hazard ratio 2.99, 95% confidence interval 1.41-6.34, P=0.005). A combination of high cerebrospinal fluid miRNA-181c, younger age and more than nine lesions on magnetic resonance imaging showed the highest specificity (96%) and positive predictive value (94%) for conversion from CIS to RRMS. MiRNA-181c was higher in serum than in cerebrospinal fluid (P <0.001), while miRNA-633 and miRNA-922 were no different in cerebrospinal fluid and serum. Cerebrospinal fluid/serum albumin quotients did not correlate with microRNAs in cerebrospinal fluid (all P>0.711). CONCLUSIONS: Cerebrospinal fluid miRNA-181c might serve as a biomarker for early conversion to RRMS. Moreover, our data suggest an intrathecal origin of microRNAs detected in the cerebrospinal fluid. PMID- 26493128 TI - Evaluation of owner experiences and adherence to home-cooked diet recipes for dogs. AB - OBJECTIVES: To evaluate owner experiences and adherence to home-cooked diet recipes for dogs. METHODS: Clients of a veterinary teaching hospital clinical nutrition service who had a home-cooked diet recipe formulated for their dogs between March 2011 and December 2013 were given a survey by email, postal mail and telephone. Survey questions addressed motivations, positive and negative aspects of feeding home-cooked diets and current feeding practices. Responses were compared to animals' medical records to determine adherence. RESULTS: Of the 93 owners who were contacted, 53 (57%) completed the survey. Of the 53 respondents, 43 owners (81%) reported that they were still feeding an home-cooked diet or had fed an home-cooked diet until the time of their dogs' deaths. The most common motivation for feeding a home-cooked diet was suitability for specific medical needs. Of the 30 surveys that included a complete diet history, only four (13%) demonstrated exact adherence to home-cooked diet recipes. CLINICAL SIGNIFICANCE: Most respondents liked and continued to feed a home-cooked diet, but few owners adhered to prescribed recipes and many dogs required recipe modifications. It is important to counsel dog owners about benefits and drawbacks of feeding home-cooked diets, importance of recipe adherence and necessity for follow-up after diet formulation with a board-certified veterinary nutritionist. PMID- 26493130 TI - Effectiveness of motivational interviewing on lifestyle modification and health outcomes of clients at risk or diagnosed with cardiovascular diseases: A systematic review. AB - BACKGROUND AND OBJECTIVE: Clinically, there is an increasing trend in using motivational interviewing as a counseling method to help clients with cardiovascular diseases to modify their unhealthy lifestyle in order to decrease the risk of disease occurrence. As motivational interviewing has gained increased attention, research has been conducted to examine its effectiveness. This review attempts to identify the best available evidence related to the effectiveness of motivational interviewing on lifestyle modification, physiological and psychological outcomes for clients at risk of developing or with established cardiovascular diseases. DESIGN: Systematic review of studies incorporating motivational interviewing in modifying lifestyles, improving physiological and psychological outcomes for clients at risk of or diagnosed with cardiovascular diseases. DATA SOURCES: Major English and Chinese electronic databases were searched to identify citations that reported the effectiveness of motivational interviewing. The searched databases included MEDLINE, British Nursing Index, CINAHL Plus, PsycINFO, SCOPUS, CJN, CBM, HyRead, WanFang Data, Digital Dissertation Consortium, and so on. REVIEW METHOD: Two reviewers independently assessed the relevance of citations based on the inclusion criteria. Full texts of potential citations were retrieved for more detailed review. Critical appraisal was conducted by using the standardized critical appraisal checklist for randomized and quasi-randomized controlled studies from the Joanna Briggs Institute - Meta Analysis of Statistics Assessment and Review Instrument (JBI MAStaRI). RESULTS: After eligibility screening, 14 articles describing 9 studies satisfied the inclusion criteria and were included in the analysis. Only certain outcomes in certain studies were pooled for meta-analysis because of the large variability of the studies included, other findings were presented in narrative form. For lifestyle modification, the review showed that motivational interviewing could be more effective than usual care on altering smoking habits. For physiological outcomes, the review showed that motivational interviewing positively improved client's systolic and diastolic blood pressures but the result was not significant. For psychological outcomes, the review showed that motivational interviewing might have favorable effect on improving clients' depression. For other outcomes, the review showed that motivational interviewing did not differ from usual care or usual care was even more effective. CONCLUSIONS: The review showed that motivational interviewing might have favorable effects on changing clients' smoking habits, depression, and three SF 36 domains. For the other outcomes, most of the results were inconclusive. Further studies should be performed to identify the optimal format and frequency of motivational interviewing. Primary research on the effectiveness of motivational interviewing on increasing clients' motivation and their actual changes in healthy behavior is also recommended. PMID- 26493131 TI - How new graduate nurses experience patient death: A systematic review and qualitative meta-synthesis. AB - BACKGROUND: Patient death is an emotional and demanding experience for nurses, especially for new graduate nurses who are unprepared to deliver end-of-life care. Understanding new graduate nurses' experience of death and dying will inform the design of training programs and interventions for improvements in the quality of care and support of new graduates. OBJECTIVE: To summarize new graduate nurses' experience with patient death by examining the findings of existing qualitative studies. DESIGN: Systematic review methods incorporating meta-synthesis were used. METHODS: A comprehensive search was conducted in 12 databases from January 1990 to December 2014. All qualitative and mixed-method studies in English and Chinese that explored new graduate nurses' experience of patient death were included. Two independent reviewers selected the studies for inclusion and assessed each study quality. Meta-aggregation was performed to synthesize the findings of the included studies. RESULTS: Five primary qualitative studies and one mix-method study met inclusion and quality criteria. Six key themes were identified from the original findings: emotional experiences, facilitating a good death, support for family, inadequacy on end-of-life care issues, personal and professional growth and coping strategies. New graduate nurses expressed a variety of feelings when faced with patient death, but still they tried to facilitate a good death for dying patients and provide support for their families. The nurses benefited from this challenging encounter though they lacked of coping strategies. PMID- 26493129 TI - Mirabegron relaxes urethral smooth muscle by a dual mechanism involving beta3 adrenoceptor activation and alpha1 -adrenoceptor blockade. AB - LINKED ARTICLE: This article is commented on by Michel, M. C., pp. 429-430 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.13379. BACKGROUND AND PURPOSE: Mirabegron is the first beta3 -adrenoceptor agonist approved for treatment of overactive bladder syndrome. This study aimed to investigate the effects of beta3 -adrenoceptor agonist mirabegron in mouse urethra. The possibility that mirabegron also exerts alpha1 -adrenoceptor antagonism was also tested in rat smooth muscle preparations presenting alpha1A - (vas deferens and prostate), alpha1D - (aorta) and alpha1B -adrenoceptors (spleen). EXPERIMENTAL APPROACH: Functional assays were carried out in mouse and rat isolated tissues. Competition assays for the specific binding of [(3) H]prazosin to membrane preparations of HEK-293 cells expressing each of the human alpha1 -adrenoceptors, as well as beta-adrenoceptor mRNA expression and cyclic AMP measurements in mouse urethra, were performed. KEY RESULTS: Mirabegron produced concentration-dependent urethral relaxations that were shifted to the right by the selective beta3 -adrenoceptor antagonist L-748,337 but unaffected by beta1 - and beta2 -adrenoceptor antagonists (atenolol and ICI-118,551 respectively). Mirabegron-induced relaxations were enhanced by the PDE4 inhibitor rolipram, and the agonist stimulated cAMP synthesis. Mirabegron also produced rightward shifts in urethral contractions induced by the alpha1 -adrenoceptor agonist phenylephrine. Schild regression analysis revealed that mirabegron behaves as a competitive antagonist of alpha1 -adrenoceptors in urethra, vas deferens and prostate (alpha1A -adrenoceptor, pA2 ? 5.6) and aorta (alpha1D adrenoceptor, pA2 ? 5.4) but not in spleen (alpha1B -adrenoceptor). The affinities estimated for mirabegron in functional assays were consistent with those estimated in radioligand binding with human recombinant alpha1A - and alpha1D -adrenoceptors (pKi ? 6.0). CONCLUSION AND IMPLICATIONS: The effects of mirabegron in urethral smooth muscle are the result of beta3 -adrenoceptor agonism together with alpha1A and alpha1D -adrenoceptor antagonism. PMID- 26493132 TI - Nonsymbiotic hemoglobins and stress tolerance in plants. AB - Hemoglobins (Hbs) are heme containing proteins found in most organisms including animals, bacteria, and plants. Their structure, size, and function are quite diverse among the different organisms. There are three different types of hemoglobins in plants: symbiotic (sHb), nonsymbiotic (nsHb), and truncated hemoglobins (trHb). The nonsymbiotic hemoglobins are divided into: class 1 hemoglobins (nsHb-1s), which have a very high affinity for oxygen: and class 2 hemoglobins (nsHb-2s), which have lower affinity for oxygen, are similar to the sHbs. nsHb-1s are expressed under hypoxia, osmotic stress, nutrient deprivation, cold stress, rhizobial infection, nitric oxide exposure, and fungal infection. Tolerance to stress is very important for the survival of the plant. Hemoglobins are one of many different strategies that plants have evolved to overcome stress conditions and survive. Hbs also react with NO produced under different stress conditions. Class 1 nsHbs are involved in a metabolic pathway involving NO. Those hemoglobins provide an alternative type of respiration to mitochondrial electron transport under limiting oxygen concentrations. Class 1 nsHbs in hypoxic plants act as part of a soluble, terminal, NO dioxygenase system, yielding nitrate from the reaction of oxyHb with NO. The overall reaction sequence, referred to as the nsHb/NO cycle, consumes NADH and maintains ATP levels via an as yet unknown mechanism. Class 2 nsHbs seem to scavenge NO in a similar fashion as class 1 Hbs and are involved in reducing flowering time in Arabidopsis. nsHbs also show peroxidase-like activity and NO metabolism and possibly protect against nitrosative stress in plant-pathogen interaction and in symbiotic interactions. nsHbs may be involved in other stress conditions such as osmotic, nutrient and cold stress together with NO and the function of nsHbs can be in NO metabolism and signal transduction. However, other possible functions cannot be precluded as Hbs have many different functions in other organisms. PMID- 26493133 TI - Rethinking metabolic control. AB - Modulation of metabolic fluxes in plants is usually not a successful business. The main reason is our limited understanding of metabolic plasticity and metabolic control, with the latter still largely influenced by the idea that each pathway has a rate limiting step controlling the flux. Not only is experimental evidence for such steps lacking for most pathways, despite intensive search, but there are also theoretical arguments against the idea that highly regulated enzymes catalyzing reactions far from equilibrium must be considered a priori rate limiting. Conversely, it is argued that reactions close to equilibrium need a lot of enzyme to be maintained close to equilibrium and, contrary to accepted wisdom, begin to limit flux when reduced. Using a few key examples of plant metabolic pathways as case studies, I draw some general conclusions. The approach of augmenting flux by pushing a pathway from above is well exemplified by the attempts at increasing starch content in potato tubers, where several different approaches failed. Also pulling at the other end (close to the end product) has yielded little improvement, while targeting a reaction close to equilibrium (ADP/ATP translocation at the plastid envelope) successfully increased starch content. Rethinking control is equally well applicable to photosynthesis, with prime examples of 'neglected', unregulated enzymes exerting significant control and overprized 'limiting' enzymes having little control in normal conditions like rubisco. In this new paradigm, the role of most control mechanisms is also challenged: feedback inhibition and post-translational modification of enzymes are relevant to metabolite homeostasis rather than flux control, with moiety conservation being a major reason for this constraint. I advocate a more extensive use of control circuitry elements (e.g. sensors like riboswitches), metabolic shortcuts and transcription factors in metabolic engineering. PMID- 26493135 TI - Mago Nashi is involved in meristem organization, pollen formation, and seed development in Arabidopsis. AB - Mago Nashi (Mago) is involved in several processes related to mRNA physiology in animal cells, including mRNA export from the nucleus, cytoplasmic mRNA localization, non-sense mediated mRNA decay, and translation. These cellular roles are visible as defects in development when Mago gene expression is modified in mutant model animal systems. Mago gene orthologs exist in plants, however, their functional roles in growth and development have not been well studied. Using an RNA interference (RNAi) approach, we produced transgenic Arabidopsis plants that had reduced levels of AtMago mRNA. RNAi-AtMago plants were delayed in their overall development, produced a greater number of leaves, and possessed short and occasionally fasciated stems. The leaves were small in size and demonstrated enhanced curling along their length. Shoot meristems of RNAi-AtMago plants lacked the cellular organization of wildtype meristems. Shoot meristematic cells were extensively vacuolated and large intercellular spaces were evident. RNAi-AtMago plants produced short lateral roots that lacked normal cell profiles and demonstrated premature root hair differentiation. The arrangement of microspore tetrads in RNAi-AtMago plants was aberrant, and microspores were extensively vacuolated. Pollen production and pollen germination rates were also reduced. RNAi-AtMago plants occasionally produced aborted seeds, or demonstrated delayed seed development that resulted in non-viable seed. The range of developmental defects visible in RNAi-AtMago plants and the ubiquitous expression of AtMago indicates that Mago has essential functions in most, if not all plant cell types. PMID- 26493134 TI - Variation in intron length in caffeic acid O-methyltransferase (COMT) in Vanilla species (Orchidaceae). AB - Variation in intron length in caffeic acid O-methyltransferase (COMT) in Vanilla was studied and demonstrated that COMT genes in Vanilla are organized with four exons and three introns. At least two to four different versions (either allelic or paralogous) of the COMT multigenic family in the genus Vanilla (in terms of intron sizes) were detected. The three introns were differentially variable, with intron-1 being the most length-polymorphic. Patterns of variations were in accordance with known phylogenetic relationships in the genus obtained with neutral markers. In particular, the genus displayed a strong Old World versus New World differentiation with American fragrant species being characterized by a specific 99bp intron-1 size-variant and a unique 226bp intron-3 variant. Conversely, leafless species of the genus displayed unexpected variations in intron lengths. Due to their role in primary (lignin) and secondary (phenolics, e.g., vanillin, alkaloids) metabolisms, COMT genes might not be neutral markers, and represent candidate functional markers for resistance, aromatic or medicinal properties of Vanilla species. Investigating the orthologous/paralogous status of the different genes revealed (in terms of intron size) will allow the evolution of the COMT genes to be studied. PMID- 26493136 TI - Color recovery in berries of grape (Vitis vinifera L.) 'Benitaka', a bud sport of 'Italia', is caused by a novel allele at the VvmybA1 locus. AB - Color mutations in grape berry skin are relatively frequent events, and can be easily seen in the vineyard. Both light-red-skinned 'Ruby Okuyama' and more intense and uniform rosy-skinned 'Benitaka' (Vitis vinifera L.) are bud sports of white-skinned 'Italia'. Previously, we reported that 'Ruby Okuyama' was caused by the recovery of VvmybA1 expression, which may have occurred as a result of intra LTR (long terminal repeat) recombination within a retrotransposon, Gret1. However, the molecular basis of the color recovery in 'Benitaka' has not been elucidated so far. Here, we found that the VvmybA1 locus of 'Benitaka' is heterozygous for the VvmybA1a allele (non-functional) and a novel VvmybA1(BEN) allele, and that VvmybA1(BEN) restored VvmybA1 transcripts. We hypothesized that VvmybA1(BEN) allele was caused by homologous recombination between VvmybA1a and VvmybA3. In addition, the content and composition of anthocyanins in berry skins differed greatly between 'Ruby Okuyama' and 'Benitaka'. The levels of expression of the genes for flavonoid 3',5'-hydroxylase (F3'5'H), O-methyltransferase (OMT), and glutathione-S-transferase (GST) were associated with differences in the anthocyanin content and composition between the two cultivars. PMID- 26493137 TI - Improving phosphorus acquisition of white clover (Trifolium repens L.) by transgenic expression of plant-derived phytase and acid phosphatase genes. AB - Phosphate is one of the least available macronutrients restricting crop production in many ecosystems. A phytase gene (MtPHY1) and a purple acid phosphatase gene (MtPAP1), both isolated from the model legume Medicago truncatula, were introduced into white clover (Trifolium repens L.) by Agrobacterium-mediated transformation. The transgenes were driven by the constitutive CaMV35S promoter or the root-specific MtPT1 promoter. Transcripts were detected in roots of the transgenic plants. Phytase or acid phosphatase (APase) activities in root apoplasts of the transgenic plants were increased up to three-fold compared to the wild type control. After the plants were grown 80 days in sand pots supplied with organic phosphorus (Po) as the sole P source, dry weights of shoot tissues of the best performing transgenic plants almost doubled that of the control and were comparable to the counterparts supplied with inorganic phosphorus (Pi). Relative biomass production of the transgenics under Po treatment was over 90% and 80% of that from the Pi treatment when the plants were grown in hydroponics (40 days) and sand pots (80 days), respectively. In contrast, biomass of the wild type controls under Po treatment was only about 50% of the Pi treatment in either hydroponic cultures or sand pots. In addition, shoot P concentrations of the transgenic plants were significantly increased compared to the control. Transgenic plants accumulated much higher amounts of total P (up to 2.6-fold after 80 days of growth) than the control in Po supplied sand pots. The results showed that transgenic expression of MtPHY1 or MtPAP1 in white clover plants increased their abilities of utilizing organic phosphorus in response to P deficiency. PMID- 26493138 TI - A stable cytosolic expression of VH antibody fragment directed against PVY NIa protein in transgenic potato plant confers partial protection against the virus. AB - The expression of recombinant antibodies in transgenic plants has been proved to be an efficient approach for large-scale production. However, the stability of these molecules and their accumulation level depend on their molecular properties and cellular targeting. The expression of single-domain antibody fragment (VH) can be advantageous since it offers small length, high expression, solubility and stability. It can therefore be preferred to other antibody derivatives avoiding the expression difficulties related to immunoglobulin domain folding via the formation of disulfide bridge. This report describes the production of transgenic potato plants expressing a VH antibody directed against the NIa protease of potato virus Y. The antibody was driven by the constitutive CaMV 35S RNA promoter. The expression cassette was transferred into potato plants via Agrobacterium tumefaciens mediated transformation. All transgenic lines showed detectable levels of VH protein confirming the efficient translation and stability of this protein. The cellular localisation of the VH antibody was investigated. Transgenic and control plants were transferred in the greenhouse and mechanically inoculated by PVY(o) suspension. Some of the transgenic lines showed delayed symptoms at the first period post inoculation and then displayed a recovery phenomenon while the virions were still detected in the leaves. PMID- 26493139 TI - The apoplastic pH and its significance in adaptation to salinity in maize (Zea mays L.): Comparison of fluorescence microscopy and pH-sensitive microelectrodes. AB - The apoplastic ionic milieu contains essential determinants for cell expansion and plant growth. Since pH is a multifunctional basic component of this extracellular space, the knowledge of its behaviour during stress situations is of major importance. In detached leaves of maize (Zea mays L. cvs. Pioneer 3906 and SR 03) the effect of salinity on apoplastic pH was measured to investigate its adaptive role to salt stress applying two different methods: an optical approach using pH-sensitive fluorescent dyes (fluorescein isothiocyanate-dextran (FITC), fluorescein tetramethylrhodamine-dextran (FTMR) and Oregon Green((r)) 488), and an electrophysiological technique, pH-sensitive microelectrodes. Both approaches yielded similar results. In the presence of 100mM NaCl, which was added to the growth medium, apoplastic pH of the salt-sensitive maize genotype Pioneer 3906 leaves increased in maximum by 0.4 units (pH microelectrodes) and by 0.3 units (fluorescent dyes); the salt-resistant SR 03 hardly responded. The same treatment reduced leaf growth by 60% in Pioneer 3906, but only by 40% in SR 03. Since according to acid growth considerations apoplastic pH is an important factor in elongation growth, we suggest that this pH increase is a main cause for reduced leaf growth under salt stress conditions. PMID- 26493140 TI - AFLP-based molecular characterization of an elite germplasm collection of Jatropha curcas L., a biofuel plant. AB - Amplified fragment length polymorphism (AFLP) was employed to assess the diversity in the elite germplasm collection of Jatropha curcas, which has gained tremendous significance as a biofuel plant in India and many other countries recently. Forty-eight accessions, collected from six different states of India, were used with seven AFLP primer combinations that generated a total of 770 fragments with an average of 110 fragments per primer combination. A total of 680 (88%) fragments showed polymorphism in the germplasm analyzed, of which 59 (8.7%) fragments were unique (accession specific) and 108 (15.9%) fragments were rare (present in less than 10% accessions). In order to assess the discriminatory power of seven primer combinations used, a variety of marker attributes like polymorphism information content (PIC), marker index (MI) and resolving power (RP) values were calculated. Although the PIC values ranged from 0.20 (E-ACA/M CAA) to 0.34 (E-ACT/M-CTT) with an average of 0.26 per primer combination and the MI values were observed in the range of 17.60 (E-ACA/M-CAA) to 32.30 (E-ACT/M CTT) with an average of 25.13 per primer combination, the RP was recognized the real attribute for AFLP to determine the discriminatory power of the primer combination. The RP values for different primer combinations varied from 23.11 (E ACA/M-CAA) to 46.82 (E-ACT/M-CTT) with an average of 35.21. Genotyping data obtained for all 680 polymorphic fragments were used to group the accessions analyzed using the UPGMA-phenogram and principal component analysis (PCA). Majority of groups obtained in phenogram and PCA contained accessions as per geographical locations. In general, accessions coming from Andhra Pradesh were found diverse as these were scattered in different groups, whereas accessions coming from Chhattisgarh showed occurrence of higher number of unique/rare fragments. Molecular diversity estimated in the present study combined with the datasets on other morphological/agronomic traits will be very useful for selecting the appropriate accessions for plant improvement through conventional as well as molecular breeding approaches. PMID- 26493141 TI - QTL analysis of seed-flooding tolerance in soybean (Glycine max [L.] Merr.). AB - In soybean (Glycine max [L.] Merr.), varieties with seed-flooding tolerance at the geminating stage are desirable for breeding in countries with much rainfall at sowing time. Our study revealed great intervarietal variation in seed-flooding tolerance as evaluated by germination rate (GR) and normal seedling rate (NS). Pigmented seed coat and small seed weight tended to give a positive effect on seed-flooding tolerance. Subsequently, QTL analysis of GR and NS were performed and a total of four QTLs were detected. Among them, Sft1 on the linkage group H (LG_H) exhibited a large effect on GR after a 24-h treatment; however, Sft2 near the I locus on LG_A2 involved in seed coat pigmentation exhibited the largest effect on seed-flooding tolerance. Sft1, Sft3 and Sft4 were independent of seed coat color and seed weight. Based on the results, we discussed the physiological effects of genetic factors responsible for seed-flooding tolerance in soybean. PMID- 26493142 TI - Establishment of a high efficiency Agrobacterium-mediated transformation system of rice (Oryza sativa L.). AB - Technologies for transformation of rice have been developed to meet the requirements of functional genomics in order to enable the production of transgenic rice plants with useful agricultural characters. However, many rice varieties are not efficiently transformed by Agrobacterium. We have succeeded in establishing a highly efficient transformation system in rice by co-cultivating rice calli with Agrobacterium on three filter papers moistened with enriched N6 or DKN media instead of using solid media. Rice calli immersed in Agrobacterium suspension (EHA101, Agrobacterium concentration of OD600=0.04) were co-cultured on three pieces of filter paper (9cm in diameter) moistened with 5.5mL of N6 or DKN liquid co-cultivation medium supplemented with 2,4-d (2mg/L), proline (10mM), casein hydrolysate (300mg/L), sucrose (30g/L), glucose (5g/L), l-cysteine (100mg/L) and acetosyringone (15mg/L) at 25 degrees C for 3 days in the dark. Compared with the transformation efficiency of calli co-cultivated on solid media, transformation efficiency was increased by about fivefold by using the filter paper method for many varieties of rice, including those that previously yielded much poor transformation rates. PMID- 26493143 TI - Functional analysis of the rice metallothionein gene OsMT2b promoter in transgenic Arabidopsis plants and rice germinated embryos. AB - In this paper, the promoter of a type 2 metallothionein gene OsMT2b was cloned in indica rice Jiayu948 and its function was analyzed in transgenic Arabidopsis plant and rice germinated embryo aided by a GUS reporter gene. The result shows that the full promoter drives GUS expression predominantly in the vascular tissues of Arabidopsis, and the expression undergoes a unimodal pattern during the development, with peaking in the mature tissues in leaves and floral organs. Further promoter deletion analysis in Arabidopsis displays different function regions that are crucial for regulating gene expression: the -212/-21 region for keeping the minimal promoter activity and the expression in the initiation site of lateral root; the -924/-213 region for the expression in vegetative and reproductive organs; the -1227/-925 region for confining high expression in silique; and the -1502/-1228 and -1227/-925 regions for the balanceable control of high expression in embryo. And by using a transient expression system in rice germinated embryo, the similar promoter region-based regulation was observed. In addition, from studying the promoter activities under different stress conditions such as ABA, GA, ZT, PEG, cold, hot, NaCl, Cu, Zn and wounding, it is proposed that environmental stresses may regulate OsMT2b expression through the promoter cis-acing elements. PMID- 26493144 TI - 1-MCP application suppresses ethylene biosynthesis and retards fruit softening during cold storage of 'Tegan Blue' Japanese plum. AB - Plum is a highly perishable fruit and postharvest fruit softening limits its cold storage life. To investigate the role of 1-methylcyclopropene (1-MCP) in ethylene biosynthesis and fruit softening during cold storage, Japanese plum (Prunus salicina Lindl. cv. Tegan Blue) as harvested at commercial fruit maturity and exposed to 1-MCP (0.0, 0.5, 1.0 and 2.0MULL(-1)) at 20+/-1 degrees C for 24h. Following 1-MCP treatments, fruit were stored at 0+/-1 degrees C and 90+/-5% RH for 0, 3 and 6 weeks. 1-MCP treatments significantly reduced endogenous ethylene production in plum fruit after 3 and 6 weeks of cold storage when compared to untreated fruit. Fruit treated with 1-MCP (1.0 and 2.0MULL(-1)) were more firm (31% and 33.5% respectively) when compared untreated fruit. Activities of 1 aminocyclopropane-1-carboxylic acid synthase (ACS) and 1-aminocyclopropane-1 carboxylic acid oxidase (ACO) enzymes during cold storage also decreased in 1-MCP treated fruit skin and pulp tissues and 1-aminocyclopropane-1-carboxylic acid (ACC) content was not detected in the skin and pulp tissues of fruit treated with 1.0 and 2.0MULL(-1) 1-MCP. Activities of exo-polygalacturonase (exo-PG) and endo polygalacturonase (endo-PG) enzymes in the fruit skin tissues were not affected by 1-MCP whereas activities of exo-PG and endo-PG enzymes in fruit pulp tissues, and activities of pectin esterase (PE) and endo-1,4-beta-d-glucanase (EGase) enzymes in both fruit skin and pulp tissues were significantly reduced during cold storage. Activities of ethylene biosynthesis and fruit softening enzymes were concentration dependent, and both were reduced with increased concentrations of 1-MCP. In conclusion, 1-MCP application extends cold storage life of 'Tegan Blue' plum by suppressing ethylene biosynthesis and reducing fruit softening. PMID- 26493145 TI - Involvement of lignification and membrane permeability in the tomato root response to boron toxicity. AB - To gain an insight into the role of lignification and membrane permeability in the root response to boron (B) toxicity, lignification-related enzymes and a number of physiological and oxidative stress parameters were analyzed in two tomato (Solanum lycopersicum L.) cultivars (Kosaco and Josefina) subjected to 0.05 (control), 0.5 and 2mM B during 16 days. 2mM B supply inhibited root growth and increased the root B concentration in both tomato cultivars. Although excess B increased the hydrogen peroxide (H2O2) concentration in Kosaco, no major changes were observed in other oxidative-stress-related parameters. High levels of B supply also induced higher lignin deposition in Kosaco roots but did not in Josefina ones. The latter result was associated with an increase of the polyphenol oxidase (PPO), guaiacol peroxidase (GPOX) and soluble syringaldazine peroxidase (SPOX) activity in Kosaco roots. Boron toxicity did not induce lipid peroxidation but increased the leakage of K(+) and the passive efflux of B in tomato roots. We conclude that high concentrations of B do not cause major oxidative or membrane damage in tomato roots. The data also indicate that high levels of B supply induce a higher lignin deposition in Kosaco roots but not in Josefina ones. This phenomenon suggests that lignification is not an essential factor reducing root growth in tomato plants, however, it proves that exist a high genotypic variation in response to excess B at root level. PMID- 26493146 TI - Metabolomics of Daucus carota cultured cell lines under stressing conditions reveals interactions between phenolic compounds. AB - A metabolomic approach followed by principal components and partial least square analysis was used for investigating the effect of environmental factors on two Daucus carota L. cv. Flakkese cell lines (R3M and R4G), selected for their ability to produce anthocyanins in the light and the dark, respectively. A positive correlation between total anthocyanin, hydroxycinnamic and hydroxybenzoic acid accumulation was found in both lines. Furthermore, the experimental design and the combination of biochemical and statistical analyses allowed us to unravel complex relationships between environmental factors and phenylpropanoid composition. Among these, the induction by mechanical stress of overproduction of all anthocyanins, hydroxycinnamic and hydroxybenzoic acids except sinapic acid derivatives, whose accumulation was inhibited. PMID- 26493147 TI - Suppression and overexpression of ubiquitin extension protein S27a affects cell proliferation and in vitro regeneration in Nicotiana benthamiana. AB - Ubiquitin is a highly conserved 76-amino-acid protein found in all eukaryotic cells. Ubiquitin's expression is encoded and expressed as multimeric head-to-tail repeats (polyubiquitins) that are post-translationally cleaved into monomers, or fused with ribosomal proteins S27a and L40. S27a is highly expressed in meristematic tissues, pollen and ovules and its ubiquitin moiety is thought to act as a chaperone in ribosome biogenesis prior to cleavage. This study suggests that the ribosomal protein S27a plays a critical role in the allocation of meristematic cells that differentiate into lateral structures such as leaves and flowers. S27a was also found to regulate floral meristem development, possibly through the control of cell proliferation as well as cell identity. Overexpression of S27a was correlated with increased proliferation of undifferentiated cells and arrest of morphologically "normal" shoot and leaf development. The ubiquitin moiety did not affect the localization of S27a, but it did affect its protein level: expression of S27a without the ubiquitin moiety caused a severe reduction in S27a protein level. PMID- 26493148 TI - Effects of salt and waterlogging stresses and their combination on leaf photosynthesis, chloroplast ATP synthesis, and antioxidant capacity in wheat. AB - The objective of this study was to investigate the effects of salt (ST) and waterlogging (WL) stresses and their combination (SW) on leaf photosynthesis, chloroplast ATP synthesis, and antioxidant capacity in wheat (Triticum aestivum L.). Two winter wheat cultivars, Huaimai 17 and Yangmai 12, differing in their tolerance to ST and WL stresses were used. The plants were grown in pots and were subjected to ST, WL, and SW from 7 days after anthesis (DAA). The WL and SW treatments lasted for 5 days, while the ST treatment was continuously imposed during the grain filling stage. Significant decrease in net photosynthetic rate (PN) of the flag leaf was observed under the ST and SW treatments from 10 DAA in Yangmai 12 and at 18 DAA in both cultivars, which could be stomatal closure related. At 18 DAA, clear reduction in PN under the ST and SW treatments was observed, which was associated with chlorosis, damages to the photosystem II (PSII), enhanced lipid peroxidation, and depressed ATP synthesis in the chloroplasts of the flag leaf. Whereas, WL treatment alone had slightly negative effect on PN, which was mainly attributed to leaf chlorosis and waste in harvested energy by the PSII reaction center dispersed via non-photochemical approaches. PMID- 26493149 TI - Genome-wide survey and expression profiling of heat shock proteins and heat shock factors revealed overlapped and stress specific response under abiotic stresses in rice. AB - Heat shock proteins (Hsps) are molecular chaperons, which function in protein folding and assembly, protein intracellular localization and secretion, and degradation of misfolded and truncated proteins. Heat shock factors (Hsfs) are the transcriptional activators of Hsps. It has been reported that Hsps and Hsfs are widely involved in response to various abiotic stresses such as heat, drought, salinity and cold. To elucidate the function and regulation of rice Hsp and Hsf genes, we examined a global expression profiling with heat stressed rice seedling, and then compared our results with the previous rice data under cold, drought and salt stresses. The comparison revealed that, while most Hsfs and Hsps had highly similar and overlapped response and regulation patterns under different stresses, some of those genes showed significantly specific response to distinct stress. We also found that heat-responsive gene profiling differed largely from those under cold/drought/salt stresses, and that drought treatment was more effective to up-regulate Hsf expression in rice than in Arabidopsis. Overall, our data suggests that Hsps and Hsfs might be important elements in cross-talk of different stress signal transduction networks. PMID- 26493150 TI - Alternative splicing of two translesion synthesis DNA polymerases from Arabidopsis thaliana. AB - DNA damages can be removed by different repair processes, but lesions sometimes remain and block DNA replication. Specialized polymerases are needed to overcome this difficulty. In Arabidopsis, AtPOLH and AtREV1 genes code for two polymerases that are involved in replication of damaged DNA. Alternative splicing was detected in both genes. Complementation analysis of the alternative splicing forms in Saccharomycescerevisiae showed that the C-terminal extreme of AtPOLH protein is essential for recovering wild type UV viability in Rad30 deficient strain. None of the alternative AtREV1 forms recovered the yeast wild type phenotype of Rev1 deficient yeast strains after UV light irradiation or methyl methane sulphonate exposition, suggesting that AtREV1 may not be able to interact with other yeast specific proteins needed for DNA translesion synthesis. PMID- 26493151 TI - Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1alpha signaling pathway. AB - The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of PGC-1alpha and its downstream targets, i.e. NRF-1, NRF-2 and Tfam in mitochondrial biogenesis. Aluminium lactate (10mg/kg b.wt./day) was administered intragastrically to rats, which were pre-treated with quercetin 6h before aluminium (10mg/kg b.wt./day, intragastrically) for 12 weeks. We found a decrease in ROS levels, mitochondrial DNA oxidation and citrate synthase activity in the hippocampus (HC) and corpus striatum (CS) regions of rat brain treated with quercetin. Besides this an increase in the mRNA levels of the mitochondrial encoded subunits - ND1, ND2, ND3, Cyt b, COX1, COX3 and ATPase6 along with increased expression of nuclear encoded subunits COX4, COX5A and COX5B of electron transport chain (ETC). In quercetin treated group an increase in the mitochondrial DNA copy number and mitochondrial content in both the regions of rat brain was observed. The PGC 1alpha was up regulated in quercetin treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1alpha. Electron microscopy results revealed a significant decrease in the mitochondrial cross-section area, mitochondrial perimeter length and increase in mitochondrial number in case of quercetin treated rats as compared to aluminium treated ones. Therefore it seems quercetin increases mitochondrial biogenesis and makes it an almost ideal flavanoid to control or limit the damage that has been associated with the defective mitochondrial function seen in many neurodegenerative diseases. PMID- 26493152 TI - Intranasal administration of rotenone in mice attenuated olfactory functions through the lesion of dopaminergic neurons in the olfactory bulb. AB - Many environmental chemicals are thought to affect brain function. It was reported that chemicals in the nasal cavity directly reach the brain through the connection between olfactory neurons and the olfactory bulb (OB). In this 'olfactory transport,' xenobiotics absorbed at the nasal mucosa reach the brain by bypassing some physical barriers and defenses, and thus olfactory transport is suspected to be a vulnerable mechanism of the brain against invasion threats of environmental chemicals. In this study, we focused on the neuronal toxicity of rotenone administered intranasally to mice. The results showed that the mice that were administered rotenone had attenuated olfactory functions. We also found that intranasally administered rotenone induced acute mitochondrial stress at the OB. The repeated administration of rotenone resulted in a decrease in the number of dopaminergic neurons, which are inhibitory interneurons in the OB. Taken together, our findings suggest that the inhalation of environmental toxins induces the neurodegeneration of cranial neurons through olfactory transport, and that olfactory dysfunction may be induced as an earliest symptom of neurodegeneration caused by inhaled neurotoxins. PMID- 26493153 TI - Approaches toward High-Mannose-Type Glycan Libraries. AB - Asparagine-linked (N-linked) sugar chains are widely found in the rough endoplasmic reticulum (ER), which has attracted renewed attention because of its participation in the glycoprotein quality control process. In the ER, newly formed glycoproteins are properly folded to higher-order structures by the action of a variety of lectin chaperones and processing enzymes and are transported into the Golgi, while terminally misfolded glycoproteins are carried into the cytosol for degradation. A group of proteins related to this system are known to recognize subtle differences in the high-mannose-type oligosaccharide structures of glycoproteins; however, their molecular foundations are still unclear. In order to gain a more precise understanding, our group has established a strategy for the systematic synthesis of high-mannose-type glycans. More recently, we have developed "top-down" chemoenzymatic approaches that allow expeditious access to theoretically all types of high-mannose glycans. This strategy comprehensively delivered 37 high-mannose-type glycans, including G1M9-M3 glycans, and opened up the possibility of the elucidation of structure-function relationships with a series of high-mannose-type glycans. PMID- 26493154 TI - Free energy simulations with the AMOEBA polarizable force field and metadynamics on GPU platform. AB - The free energy calculation library PLUMED has been incorporated into the OpenMM simulation toolkit, with the purpose to perform enhanced sampling MD simulations using the AMOEBA polarizable force field on GPU platform. Two examples, (I) the free energy profile of water pair separation (II) alanine dipeptide dihedral angle free energy surface in explicit solvent, are provided here to demonstrate the accuracy and efficiency of our implementation. The converged free energy profiles could be obtained within an affordable MD simulation time when the AMOEBA polarizable force field is employed. Moreover, the free energy surfaces estimated using the AMOEBA polarizable force field are in agreement with those calculated from experimental data and ab initio methods. Hence, the implementation in this work is reliable and would be utilized to study more complicated biological phenomena in both an accurate and efficient way. (c) 2015 Wiley Periodicals, Inc. PMID- 26493155 TI - What can dissaving tell us about catastrophic costs? Linear and logistic regression analysis of the relationship between patient costs and financial coping strategies adopted by tuberculosis patients in Bangladesh, Tanzania and Bangalore, India. AB - BACKGROUND: Tuberculosis (TB) is a major global public health problem which affects poorest individuals the worst. A high proportion of patients incur 'catastrophic costs' which have been shown to result in severe financial hardship and adverse health outcomes. Data on catastrophic cost incidence is not routinely collected, and current definitions of this indicator involve several practical and conceptual barriers to doing so. We analysed data from TB programmes in India (Bangalore), Bangladesh and Tanzania to determine whether dissaving (the sale of assets or uptake of loans) is a useful indicator of financial hardship. METHODS: Data were obtained from prior studies of TB patient costs in Bangladesh (N = 96), Tanzania (N = 94) and Bangalore (N = 891). These data were analysed using logistic and linear multivariate regression to determine the association between costs (absolute and relative to income) and both the presence of dissaving and the amounts dissaved. RESULTS: After adjusting for covariates such as age, sex and rural/urban location, we found a significant positive association between the occurrence of dissaving and total costs incurred in Tanzania and Bangalore. We further found that, for patients in Bangalore an increase in dissaving of $10 USD was associated with an increase in the cost-income ratio of 0.10 (p < 0.001). For low-income patients in Bangladesh, an increase in dissaving of $10 USD was associated with an increase in total costs of $7 USD (p <0.001). CONCLUSIONS: Dissaving is potentially a convenient proxy for catastrophic costs that does not require usage of complex patient cost questionnaires. It also offers an informative indicator of financial hardship in its own right, and could therefore play an important role as an indicator to monitor and evaluate the impact of financial protection and service delivery interventions in reducing hardship and facilitating universal health coverage. Further research is required to understand the patterns and types of dissaving that have the strongest relationship with financial hardship and clinical outcomes in order to move toward evidence-based policy making. PMID- 26493156 TI - 'Thin people ... they're healthy': young children's understanding of body weight change. AB - BACKGROUND: While research has investigated negative stereotyping of fat body shapes, little has focused on young children's understanding of the mechanisms, motivations and consequences of weight change. OBJECTIVES: To investigate children's understanding of how weight change is achieved, people's motivation for weight change, and the consequences of weight loss or weight gain. METHODS: One hundred children (mean age 5.2, 38 girls) read a book in which one of the main characters (male/female according to the child's sex) was either healthy weight or overweight. Afterwards, this character was described as gaining or losing weight, and drawings which depicted the child in the story as either healthy weight or overweight were presented to the child and discussed. An audio recorded semi-structured interview followed and transcripts were analysed using thematic analysis. RESULTS: Nearly all children described the weight/shape change and attributed this to food more frequently than exercise. Weight loss was viewed positively and both motivations and consequences grouped under two master themes (physical and social reasons). No clear gender differences were observed in these responses. CONCLUSIONS: Talking with 5-year-olds showed them to be observant and knowledgeable, especially about motivations for and consequences of weight change. For those working to improve children's health literacy, this suggests receptiveness to early and fact-based education. PMID- 26493157 TI - A Flexible Electrode Based on Iron Phosphide Nanotubes for Overall Water Splitting. AB - The design of cheap and efficient water splitting systems for sustainable hydrogen production has attracted increasing attention. A flexible electrode, based on carbon cloth substrate and iron phosphide nanotubes coated with an iron oxide/phosphate layer, is shown to catalyze overall water splitting. The as prepared flexible electrode demonstrates remarkable electrocatalytic activity for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) at modest overpotentials. The surface iron oxide/phosphate, which is formed in situ, is proposed to improve the HER activity by facilitating the water dissociation step and serves directly as the catalytically-active component for the OER process. PMID- 26493159 TI - Predictors of Future Atrial Fibrillation Development in Patients with Hypertrophic Cardiomyopathy: A Prospective Follow-Up Study. AB - BACKGROUND: We evaluated whether left atrial (LA) phasic functions, P-wave dispersion (PWD), and plasma NT-proBNP levels could predict future development of atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM). METHODS: Seventy patients with HCM were evaluated. The LA phasic functions including the LA total emptying volume (LATEV), LA total emptying fraction (LATEF), LA active emptying volume (LAAEV), LA active emptying fraction (LAAEF), LA passive emptying volume (LAPEV), and LA passive emptying fraction (LAPEF) were evaluated. P-wave dispersion was calculated. Plasma NT-proBNP levels were measured on the same day with echocardiographic study. RESULTS: Patients were followed up 53.09 +/- 1.87 months. Patients who developed AF (n = 18) had significantly higher PWD values, NT-proBNP levels, LAVI, E/E' av, and resting LVOT gradients and significantly lower LATEF and LAAEF. In multivariate analysis, LATEF (P = 0.002), LAAEF (P = 0.007), logNT-proBNP level (P = 0.022), and PWD (P = 0.018) were associated with AF development. The results of receiver operating characteristic analysis revealed that a LATEF cutoff value 49% with 72% sensitivity and 81% specificity, a LAAEF cutoff value of 36% with 72% sensitivity and 71% specificity, and an NT-proBNP cutoff value of 720 pg/mL predicted future AF development with 72% sensitivity and 60% specificity. A PWD cutoff value of 47.5 msecond predicted future AF development with 78% sensitivity and 72% specificity. CONCLUSION: In patients with HCM, LA phasic functions, PWD, and NT proBNP levels predict future development of AF. Assessment of LA phasic functions during routine echocardiographic evaluation and measuring NT-proBNP levels and PWD values of patients with HCM during daily practice may provide important data in predicting those at high risk of AF occurrence. PMID- 26493158 TI - Macrophage-mediated cholesterol handling in atherosclerosis. AB - Formation of foam cells is a hallmark at the initial stages of atherosclerosis. Monocytes attracted by pro-inflammatory stimuli attach to the inflamed vascular endothelium and penetrate to the arterial intima where they differentiate to macrophages. Intimal macrophages phagocytize oxidized low-density lipoproteins (oxLDL). Several scavenger receptors (SR), including CD36, SR-A1 and lectin-like oxLDL receptor-1 (LOX-1), mediate oxLDL uptake. In late endosomes/lysosomes of macrophages, oxLDL are catabolysed. Lysosomal acid lipase (LAL) hydrolyses cholesterol esters that are enriched in LDL to free cholesterol and free fatty acids. In the endoplasmic reticulum (ER), acyl coenzyme A: cholesterol acyltransferase-1 (ACAT1) in turn catalyses esterification of cholesterol to store cholesterol esters as lipid droplets in the ER of macrophages. Neutral cholesteryl ester hydrolases nCEH and NCEH1 are involved in a secondary hydrolysis of cholesterol esters to liberate free cholesterol that could be then out-flowed from macrophages by cholesterol ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 and SR-BI. In atherosclerosis, disruption of lipid homoeostasis in macrophages leads to cholesterol accumulation and formation of foam cells. PMID- 26493160 TI - A multi-center, multinational age- and gender-adjusted normative dataset for immunofluorescent intraepidermal nerve fiber density at the distal leg. AB - BACKGROUND AND PURPOSE: Quantification of intraepidermal nerve fibers (IENFs) in skin biopsies is now the tool of choice to diagnose small fiber neuropathies. An adequate normative dataset, necessary to assess normality cutoffs, is available for brightfield microscopy but not for immunofluorescence. METHODS: Intraepidermal nerve fiber density data in distal leg skin samples processed with immunofluorescence were collected from 528 healthy individuals from four experienced laboratories worldwide. In all laboratories skin samples were collected, processed and analyzed according to standard procedures. Quantile regression analysis was employed to tailor the fit of the 5 degrees percentile as the normal cutoff value and to test and measure the effect of age, gender, body mass index, race, biopsy site (lateral distal lower leg or medial posterior mid-calf) and participating laboratory as possible influential variables. RESULTS: Age, gender and biopsy site showed an independent linear correlation with IENF density. For each decade the 5 degrees quantile IENF cutoff showed a 0.54 fibers/mm decrease, whilst females exhibited a 1.0 fiber/mm cutoff greater than males. Compared to the lateral distal lower leg, biopsies from the calf showed a 3.4 fibers/mm lower 5 degrees percentile cutoff, documenting a variation linked by site. CONCLUSIONS: An age- and gender-adjusted normative dataset for IENF density at the lateral distal lower leg obtained with indirect immunofluorescence is presented for the first time by sharing data from four experienced laboratories worldwide. This dataset can be used as reference for laboratories processing skin biopsies with this technique. PMID- 26493161 TI - A functional magnetic resonance imaging study of cognitive control and neurosensory deficits in mild traumatic brain injury. AB - Mild traumatic brain injury patients (mTBI) frequently report symptoms of increased distractability and sensory disturbances during mutisensory stimulation. These common post-concussive symptoms could putatively result from dysfunction within the cognitive control network (CCN; top-down) or from unisensory cortex (bottom-up) itself. Functional magnetic resonance imaging (fMRI) and high-resolution structural data were therefore prospectively collected during a multisensory (audio-visual) cognitive control task from 46 mTBI patients within 3 weeks of injury and 46 matched healthy controls (HC), with a subset of participants returning at 4 months. Multisensory stimuli were presented at two frequencies to manipulate cognitive and perceptual load. Patients self-reported more cognitive, emotional, somatic, vestibular and visual symptoms relative to HC, which improved, but did not entirely resolve, over the 4 month follow-up period. There were no group differences in behavior or functional activation during cognitive control (incongruent--congruent trials). In contrast, patients exhibited abnormal activation within different regions of visual cortex that depended on whether attention was focused on auditory or visual information streams. Patients also exhibited increased activation within bilateral inferior parietal lobules during higher cognitive/perceptual loads, suggesting a compensatory mechanism to achieve similar levels of behavioral performance. Functional abnormalities within the visual cortex and inferior parietal lobules were only partially resolved at 4 months post-injury, suggesting that neural abnormalities may take longer to resolve than behavioral measures used in most clinical settings. In summary, current results indicate that abnormalities within unisensory cortex (particularly visual areas) following mTBI, which likely contribute to deficits commonly reported during multisensory stimulation. PMID- 26493162 TI - Regional specificity of aberrant thalamocortical connectivity in autism. AB - Preliminary evidence suggests aberrant (mostly reduced) thalamocortical (TC) connectivity in autism spectrum disorder (ASD), but despite the crucial role of thalamus in sensorimotor functions and its extensive connectivity with cerebral cortex, relevant evidence remains limited. We performed a comprehensive investigation of region-specific TC connectivity in ASD. Resting-state functional MRI and diffusion tensor imaging (DTI) data were acquired for 60 children and adolescents with ASD (ages 7-17 years) and 45 age, sex, and IQ-matched typically developing (TD) participants. We examined intrinsic functional connectivity (iFC) and anatomical connectivity (probabilistic tractography) with thalamus, using 68 unilateral cerebral cortical regions of interest (ROIs). For frontal and parietal lobes, iFC was atypically reduced in the ASD group for supramodal association cortices, but was increased for cingulate gyri and motor cortex. Temporal iFC was characterized by overconnectivity for auditory cortices, but underconnectivity for amygdalae. Occipital iFC was broadly reduced in the ASD group. DTI indices (such as increased radial diffusion) for regions with group differences in iFC further indicated compromised anatomical connectivity, especially for frontal ROIs, in the ASD group. Our findings highlight the regional specificity of aberrant TC connectivity in ASD. Their overall pattern can be largely accounted for by functional overconnectivity with limbic and sensorimotor regions, but underconnectivity with supramodal association cortices. This could be related to comparatively early maturation of limbic and sensorimotor regions in the context of early overgrowth in ASD, at the expense of TC connectivity with later maturing cortical regions. PMID- 26493163 TI - Reliability correction for functional connectivity: Theory and implementation. AB - Network properties can be estimated using functional connectivity MRI (fcMRI). However, regional variation of the fMRI signal causes systematic biases in network estimates including correlation attenuation in regions of low measurement reliability. Here we computed the spatial distribution of fcMRI reliability using longitudinal fcMRI datasets and demonstrated how pre-estimated reliability maps can correct for correlation attenuation. As a test case of reliability-based attenuation correction we estimated properties of the default network, where reliability was significantly lower than average in the medial temporal lobe and higher in the posterior medial cortex, heterogeneity that impacts estimation of the network. Accounting for this bias using attenuation correction revealed that the medial temporal lobe's contribution to the default network is typically underestimated. To render this approach useful to a greater number of datasets, we demonstrate that test-retest reliability maps derived from repeated runs within a single scanning session can be used as a surrogate for multi-session reliability mapping. Using data segments with different scan lengths between 1 and 30 min, we found that test-retest reliability of connectivity estimates increases with scan length while the spatial distribution of reliability is relatively stable even at short scan lengths. Finally, analyses of tertiary data revealed that reliability distribution is influenced by age, neuropsychiatric status and scanner type, suggesting that reliability correction may be especially important when studying between-group differences. Collectively, these results illustrate that reliability-based attenuation correction is an easily implemented strategy that mitigates certain features of fMRI signal nonuniformity. PMID- 26493164 TI - Intravenous infusion of H2-saline suppresses oxidative stress and elevates antioxidant potential in Thoroughbred horses after racing exercise. AB - Upon intensive, exhaustive exercise, exercise-induced reactive oxygen species may exceed the antioxidant defence threshold, consequently resulting in muscular damage or late-onset chronic inflammation. Recently, the therapeutic antioxidant and anti-inflammatory effects of molecular hydrogen (H2) for human rheumatoid arthritis have been demonstrated. However, it is also important to clarify the effects of administrating H2 in large animals other than humans, as H2 is thought to reach the target organ by passive diffusion upon delivery from the blood flow, indicating that the distance from the administration point to the target is critical. However, data on the effects of H2 on oxidative stress in real-life exhaustive exercise in large animals are currently lacking. We here investigated 13 Thoroughbred horses administered intravenous 2-L saline with or without 0.6 ppm H2 (placebo, N = 6; H2, N = 7) before participating in a high-intensity simulation race. Intravenous H2-saline significantly suppressed oxidative stress immediately, 3 h, and 24 h after the race, although the antioxidant capability was not affected throughout the study. The serum creatine kinase, lactate, and uric acid levels were increased in both groups. Taken together, these results indicate that intravenous H2-saline can significantly and specifically suppress oxidative stress induced after exhaustive racing in Thoroughbred horses. PMID- 26493166 TI - Large magnetocaloric effect and adiabatic demagnetization refrigeration with YbPt2Sn. AB - Adiabatic demagnetization is currently gaining strong interest in searching for alternatives to (3)He-based refrigeration techniques for achieving temperatures below 2 K. The main reasons for that are the recent shortage and high price of the rare helium isotope (3)He. Here we report the discovery of a large magnetocaloric effect in the intermetallic compound YbPt2Sn, which allows adiabatic demagnetization cooling from 2 K down to 0.2 K. We demonstrate this with a home-made refrigerator. Other materials, for example, paramagnetic salts, are commonly used for the same purpose but none of them is metallic, a severe limitation for low-temperature applications. YbPt2Sn is a good metal with an extremely rare weak magnetic coupling between the Yb atoms, which prevents them from ordering above 0.25 K, leaving enough entropy free for use in adiabatic demagnetization cooling. The large volumetric entropy capacity of YbPt2Sn guarantees also a good cooling power. PMID- 26493165 TI - GREM1 and POLE variants in hereditary colorectal cancer syndromes. AB - Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high-penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy-number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease-causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease-causing mutations in hereditary CRC syndromes. PMID- 26493167 TI - Piera Aulagnier, an introduction: Some elements of her intellectual biography. PMID- 26493168 TI - Birth of a body, origin of a history. PMID- 26493169 TI - On Piera Aulagnier's 'Birth of a Body, Origin of a History'. PMID- 26493170 TI - On: Hijab and homosexuality--a case report and review of the literature. PMID- 26493171 TI - On: An "Intradisciplinary" comparison of psychoanalytic theorizations. PMID- 26493172 TI - Paenibacillus terreus sp. nov., isolated from forest soil. AB - A Gram-stain-positive, rod-shaped, endospore-forming, motile bacterium, designated D33T, was isolated from a forest soil sample. The strain grew optimally at 30-37 degrees C, pH 8.0 and with 1 % (w/v) NaCl. The 16S rRNA gene sequence of the isolate showed similarities lower than 97 % with respect to species of the genus Paenibacillus. Strain D33T contained meso-diaminopimelic acid in the cell-wall peptidoglycan, and ribose and lower amounts of glucose and galactose as the whole-cell sugars. The major cellular fatty acid was anteiso-C15 : 0, and menaquinone-7 (MK-7) was the only respiratory quinone. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylmethylethanolamine, two glycolipids and an unknown lipid. The DNA G+C content was 51.1 mol%. The low DNA-DNA relatedness values between strain D33T and recognized species of the genus Paenibacillus, together with many phenotypic properties supported the classification of strain D33T as representative of a novel species of the genus Paenibacillus, for which the name Paenibacillus terreus sp. nov. is proposed. The type strain is D33T ( = KACC 18491T = DSM 100035T = CCTCC AB 2015273T). PMID- 26493174 TI - Carl W. Schaefer (September 06, 1934 - April 29, 2015). PMID- 26493173 TI - Cancer Worry, Perceived Risk and Cancer Screening in First-Degree Relatives of Patients with Familial Gastric Cancer. AB - Currently, there is a lack of evidence evaluating the psychological impact of cancer-related risk perception and worry in individuals at high risk for gastric cancer. We examined the relationships between perceived risk, cancer worry and screening behaviors among first-degree relatives (FDRs) of patients with familial gastric cancer. FDRs of patients diagnosed with familial gastric cancer with a non-informative genetic analysis were identified and contacted. Participants completed a telephone interview that assessed socio-demographic information, cancer risk perception, cancer worry, impact of worry on daily functioning, and screening behaviors. Twenty-five FDRs completed the telephone interview. Participants reported high levels of comparative and absolute cancer risk perception, with an average perceived lifetime risk of 54 %. On the other hand, cancer-related worry scores were low, with a significant minority (12 %) experiencing high levels of worry. Study participants exhibited high levels of confidence (median = 70 %) in the effectiveness of screening at detecting a curable cancer. Participants that had undergone screening in the past showed significantly lower levels of cancer-related worry compared to those that had never undergone screening. In conclusion, individuals at high-risk for gastric cancer perceived a very high personal risk of cancer, but reported low levels of cancer worry. This paradoxical result may be attributed to participants' high levels of confidence in the effectiveness of screening. These findings highlight the importance for clinicians to discuss realistic risk appraisals and expectations towards screening with unaffected members of families at risk for gastric cancer, in an effort to help mitigate anxiety and help with coping. PMID- 26493175 TI - Pitfall Traps and Mini-Winkler Extractor as Complementary Methods to Sample Soil Coleoptera. AB - We compared abundance, species richness, and capture efficiency with pitfall traps and mini-Winkler extractors to examine their use as complementary methods for sampling soil Coleoptera during dry (2010) and high water seasons (2011) in three areas, including inundated and non-inundated regions, in the Pantanal of Pocone, Mato Grosso, Brazil. We paired treatments with two 10 * 10 m plots in inundated and non-inundated locations that were repeated three times in each location for a total of 18 plots. In each plot, we used nine pitfall traps and collected 2 m(2) of leaf litter and surface soil samples with mini-Winkler extractors. We collected a total of 4260 adult beetles comprising 36 families, 113 genera, and 505 species. Most were caught in pitfalls (69%) and the remainder in the mini-Winkler extractors (31%). Each method provided distinct information about the beetle community: 252 species were captured only in pitfall traps, 147 using only the mini-Winkler extractors, and these methods shared another 106 species. Pitfall and mini-Winkler contribute in different ways for the sampling of the soil beetle community, and so they should be considered complementary for a more thorough assessment of community diversity. PMID- 26493176 TI - A Versatile Microarray Platform for Capturing Rare Cells. AB - Analyses of rare events occurring at extremely low frequencies in body fluids are still challenging. We established a versatile microarray-based platform able to capture single target cells from large background populations. As use case we chose the challenging application of detecting circulating tumor cells (CTCs)- about one cell in a billion normal blood cells. After incubation with an antibody cocktail, targeted cells are extracted on a microarray in a microfluidic chip. The accessibility of our platform allows for subsequent recovery of targets for further analysis. The microarray facilitates exclusion of false positive capture events by co-localization allowing for detection without fluorescent labelling. Analyzing blood samples from cancer patients with our platform reached and partly outreached gold standard performance, demonstrating feasibility for clinical application. Clinical researchers free choice of antibody cocktail without need for altered chip manufacturing or incubation protocol, allows virtual arbitrary targeting of capture species and therefore wide spread applications in biomedical sciences. PMID- 26493177 TI - Extracapillary proliferation and arteriolar hyalinosis are associated with long term kidney survival in IgA nephropathy. AB - BACKGROUND: The Oxford classification of IgA nephropathy consists of four markers as prognosticators. We retrospectively examined the relevance of extracapillary proliferation involving cellular and fibrocellular crescents (Ex) and arteriolar hyalinosis (A) on the long-term outcome of renal function. METHODS: A total of 314 Japanese patients who were diagnosed with IgA nephropathy, with 12 months or more of follow-up period were included in this study. A total of 186 patients were with UP >= 0.5 g/day. Patients with diabetes mellitus or severe kidney injury (eGFR < 30 ml/min/1.73 m(2)) were excluded. The presence of Ex and A were scored 0 in the absence, and 1 in the presence, of each lesion. The end point was determined as a 50 % reduction in initial eGFR or end-stage renal disease defined as eGFR < 15 ml/min/1.73 m(2). RESULTS: In univariate analyses, the kidney survival rate was significantly lower in patients with Ex1 and A1 if UP >= 0.5 g/day. In the patients with UP < 0.5/day, none of the clinical and pathological parameters was determined as a risk factor. In the multivariate model including pathological parameters, Ex1 and A1 were independent risk factors for renal outcome if UP >= 0.5 g/day. In those patients treated with RAS-blocker or treated before introduction of methylprednisolone pulse therapy, Ex was the only independent risk factor. In multivariate analysis including clinical parameters, eGFR alone was a risk factor, due to strong correlation with other parameters. CONCLUSION: Ex and A would be associated with the renal outcome of the patients with UP >= 0.5 g/day. PMID- 26493178 TI - Clinical value of ambulatory blood pressure: Is it time to recommend for all patients with hypertension? AB - Hypertension is a very common disease, and office measurements of blood pressure are frequently inaccurate. Ambulatory Blood Pressure Monitoring (ABPM) offers a more accurate diagnosis, more detailed readings of average blood pressures, better blood pressure measurement during sleep, fewer false positives by detecting more white-coat hypertension, and fewer false negatives by detecting more masked hypertension. ABPM offers better management of clinical outcomes. For example, based on more accurate measurements of blood pressure variability, ABPM demonstrates that taking antihypertensive medication at night leads to better controlled nocturnal blood pressure, which translates into less end organ damage and fewer clinical complications of hypertension. For these reasons, albeit some shortcomings which were discussed, ABPM should be considered as a first-line tool for diagnosing and managing hypertension. PMID- 26493179 TI - Towards identification of immune and genetic correlates of severe influenza disease in Indigenous Australians. AB - Indigenous populations, including Indigenous Australians, are highly susceptible to severe influenza disease and the underlying mechanisms are unknown. We studied immune and genetic factors that could predicate severe influenza disease in Indigenous Australians enrolled in the LIFT study: looking into influenza T-cell immunity. To examine CD8(+) T-cell immunity, we characterised human leukocyte antigen (HLA) profiles. HLA typing confirmed previous studies showing predominant usage of HLA-A*02:01, 11:01, 24:02, 34:01 and HLA-B*13:01, 15:21, 40:01/02, 56:01/02 in Indigenous Australians. We identified two new HLA alleles (HLA A*02:new and HLA-B*56:new). Modelling suggests that variations within HLA A*02:new (but not HLA-B56:new) could affect peptide binding. There is a relative lack of known influenza epitopes for the majority of these HLAs, with the exception of a universal HLA-A*02:01-M158 epitope and proposed epitopes presented by HLA-A*11:01/HLA-A*24:02. To dissect universal CD8(+) T-cell responses, we analysed the magnitude, function and T-cell receptor (TCR) clonality of HLA A*02:01-M158(+)CD8(+) T cells. We found comparable IFN-gamma, TNF and CD107a and TCRalphabeta characteristics in Indigenous and non-Indigenous Australians, suggesting that the ~15% of Indigenous people that express HLA-A*02:01 have universal influenza-specific CD8(+) T-cell immunity. Furthermore, the frequency of an influenza host risk factor, IFITM3-C/C, was comparable between Indigenous Australians and Europeans, suggesting that expression of this allele does not explain increased disease severity at a population level. Our study indicates a need to identify novel influenza-specific CD8(+) T-cell epitopes restricted by HLA-A and HLA-B alleles prevalent in Indigenous populations for the rational design of universal T-cell vaccines. PMID- 26493181 TI - Analogues of Cis- and Transplatin with a Rich Solution Chemistry: cis-[PtCl2 (NH3 )(1-MeC-N3)] and trans-[PtI2 (NH3 )(1-MeC-N3)]. AB - Mono(nucleobase) complexes of the general composition cis-[PtCl2 (NH3 )L] with L=1-methylcytosine, 1-MeC (1 a) and L=1-ethyl-5-methylcytosine, as well as trans [PtX2 (NH3 )(1-MeC)] with X=I (5 a) and X=Br (5 b) have been isolated and were characterized by X-ray crystallography. The Pt coordination occurs through the N3 atom of the cytosine in all cases. The diaqua complexes of compounds 1 a and 5 a, cis-[Pt(H2 O)2 (NH3 )(1-MeC)](2+) and trans-[Pt(H2 O)2 (NH3 )(1-MeC)](2+) , display a rich chemistry in aqueous solution, which is dominated by extensive condensation reactions leading to MU-OH- and MU-(1-MeC(-) -N3,N4)-bridged species and ready oxidation of Pt to mixed-valence state complexes as well as diplatinum(III) compounds, one of which was characterized by X-ray crystallography: h,t-[{Pt(NH3 )2 (OH)(1-MeC(-) -N3,N4)}2 ](NO3 )2 ?2 [NH4 ](NO3 )?2 H2 O. A combination of (1) H NMR spectroscopy and ESI mass spectrometry was applied to identify some of the various species present in solution and the gas phase, respectively. As it turned out, mass spectrometry did not permit an unambiguous assignment of the structures of +1 cations due to the possibilities of realizing multiple bridging patterns in isomeric species, the occurrence of different tautomers, and uncertainties regarding the Pt oxidation states. Additionally, compound 1 a was found to have selective and moderate antiproliferative activity for a human cervix cancer line (SISO) compared to six other human cancer cell lines. PMID- 26493180 TI - Laser treatment of drusen to prevent progression to advanced age-related macular degeneration. AB - BACKGROUND: Drusen are amorphous yellowish deposits beneath the sensory retina. People with drusen, particularly large drusen, are at higher risk of developing age-related macular degeneration (AMD). The most common complication in AMD is choroidal neovascularisation (CNV), the growth of new blood vessels in the centre of the macula. The risk of CNV is higher among people who are already affected by CNV in one eye.It has been observed clinically that laser photocoagulation of drusen leads to their disappearance and may prevent the occurrence of advanced disease (CNV or geographic atrophy) associated with visual loss. OBJECTIVES: To examine the effectiveness and adverse effects of laser photocoagulation of drusen in AMD. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 7), Ovid MEDLINE, Ovid MEDLINE In Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2015), EMBASE (January 1980 to August 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 August 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) of laser treatment of drusen in AMD in which laser treatment had been compared with no intervention or sham treatment. Two types of trials were included. Some trials studied one eye of each participant (unilateral studies); other studies recruited participants with bilateral drusen and randomised one eye to photocoagulation or control and the fellow eye to the other group. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We pooled data from unilateral and bilateral studies using a random-effects model. For the bilateral studies, we estimated the within-person correlation coefficient from one study and assumed it was valid for the others. MAIN RESULTS: The update of this review found two additional studies, totaling 11 studies that randomised 2159 participants (3580 eyes) and followed them up to two years, of which six studies (1454 participants) included people with one eye randomised to treatment and one to control. Studies were conducted in Australia, Europe and North America.Overall, the risk of bias in the included studies was low, particularly for the larger studies and for the primary outcome development of CNV. Photocoagulation did not reduce the development of CNV at two years' follow-up (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.79 to 1.46, 11 studies, 2159 participants (3580 eyes), high quality evidence). This estimate means that, given an overall occurrence of CNV of 8.3% in the control group, we estimated an absolute risk reduction by no more than 1.4% in the laser group, according to the lower CI limit. Only two studies investigated the effect on the development of geographic atrophy and could not show a difference, but estimates were imprecise (OR 1.30, 95% CI 0.38 to 4.51, two studies, 148 participants (148 eyes), low quality evidence).Among secondary outcomes, photocoagulation led to drusen reduction (OR 9.16, 95% CI 6.28 to 13.4, three studies, 570 participants (944 eyes), high quality evidence) but was not shown to limit loss of 3 or more lines of visual acuity (OR 0.99, 95% CI 0.81 to 1.22, nine studies, 2002 participants (2386 eyes), moderate quality evidence).In a subgroup analysis, no difference could be shown for conventional visible (eight studies) versus subthreshold invisible (four studies) photocoagulation for the primary outcomes (P value = 0.29). The effect in the subthreshold group did not suggest a relevant benefit (OR 1.27, 95% CI 0.82 to 1.98). No study used micropulse subthreshold photocoagulation.No other adverse effects (apart from development of CNV, geographic atrophy or visual loss) were reported. AUTHORS' CONCLUSIONS: The trials included in this review confirm the clinical observation that laser photocoagulation of drusen leads to their disappearance. However, treatment does not result in a reduction in the risk of developing CNV, and was not shown to limit the occurrence of geographic atrophy or visual acuity loss.Ongoing studies are being conducted to assess whether the use of extremely short laser pulses (i.e. nanosecond laser treatment) cannot only lead to drusen regression but also prevent neovascular AMD. PMID- 26493182 TI - Health-related quality of life in patients treated for nonfunctioning pituitary adenomas during the years 2000-2010. AB - OBJECTIVE: The published data on health-related quality of life (HRQoL) after treatment of nonfunctioning pituitary adenomas (NFPAs) are conflicting. We evaluated HRQoL in a recent series of patients who had surgery for an NFPA. DESIGN: Cross-sectional study including a large control population. PATIENTS AND MEASUREMENTS: A HRQoL questionnaire (15D) was sent to all patients (n = 161) having undergone transsphenoidal surgery for NFPA in the years 2000-2010 at the Helsinki University Hospital. The 15D score and dimension scores of the study population (n = 137) were compared with those of a large (n = 4967) gender- and age-standardized control population. Possible independent predictors of HRQoL in the patients were estimated with multivariate regression analysis. RESULTS: Postoperatively, 57% of the patients had normal visual function. After a mean follow-up of 7.4 +/- 3.2 years (mean +/- SD), 62% suffered from hypopituitarism. Overall, HRQoL was near-normal in patients compared to controls (15D scores 0.885 +/- 0.114 vs 0.903 +/- 0.093, respectively, P = 0.07). On single dimensions, patients had impaired vision and sexual activity (both P < 0.0005), more depression and distress (both P < 0.005) and less discomfort and symptoms (P < 0.05). Age, body mass index, diabetes, depression and reoperation were independent predictors of impaired HRQoL (all P < 0.05). Thyroxine substitution was associated with impaired and hydrocortisone and testosterone substitution (males only) with better HRQoL (all P < 0.05). CONCLUSIONS: This recent series of NFPA patients demonstrates that overall HRQoL is near-normal after medium term follow-up; the most impaired dimensions were in vision and sexual activity. Comorbidities are strong predictors of impaired HRQoL. PMID- 26493183 TI - A Gibbs Sampler for the (Extended) Marginal Rasch Model. AB - In their seminal work on characterizing the manifest probabilities of latent trait models, Cressie and Holland give a theoretically important characterization of the marginal Rasch model. Because their representation of the marginal Rasch model does not involve any latent trait, nor any specific distribution of a latent trait, it opens up the possibility for constructing a Markov chain - Monte Carlo method for Bayesian inference for the marginal Rasch model that does not rely on data augmentation. Such an approach would be highly efficient as its computational cost does not depend on the number of respondents, which makes it suitable for large-scale educational measurement. In this paper, such an approach will be developed and its operating characteristics illustrated with simulated data. PMID- 26493184 TI - Characterizing novel endogenous retroviruses from genetic variation inferred from short sequence reads. AB - From Illumina sequencing of DNA from brain and liver tissue from the lion, Panthera leo, and tumor samples from the pike-perch, Sander lucioperca, we obtained two assembled sequence contigs with similarity to known retroviruses. Phylogenetic analyses suggest that the pike-perch retrovirus belongs to the epsilonretroviruses, and the lion retrovirus to the gammaretroviruses. To determine if these novel retroviral sequences originate from an endogenous retrovirus or from a recently integrated exogenous retrovirus, we assessed the genetic diversity of the parental sequences from which the short Illumina reads are derived. First, we showed by simulations that we can robustly infer the level of genetic diversity from short sequence reads. Second, we find that the measures of nucleotide diversity inferred from our retroviral sequences significantly exceed the level observed from Human Immunodeficiency Virus infections, prompting us to conclude that the novel retroviruses are both of endogenous origin. Through further simulations, we rule out the possibility that the observed elevated levels of nucleotide diversity are the result of co-infection with two closely related exogenous retroviruses. PMID- 26493186 TI - Peritumoral adipose tissue as a source of inflammatory and angiogenic factors in colorectal cancer. AB - PURPOSE: Obesity is a risk factor for the development of human colorectal cancer (CC). The aim of this work is to report the inflammatory and angiogenic scenario in lean (BMI < 25 kg/m2) and obese (BMI > 30 kg/m2) patients with and without CC and to assess the role of peritumoral adipose tissue in CC-induced inflammation. MATERIAL AND METHODS: Patients were divided in four experimental groups: obese patients with CC (OB-CC), lean patients with CC (LEAN-CC), obese patients without CC (OB), and lean patients without CC (LEAN). RESULTS: Plasma levels of pro inflammatory cytokines (interleukin (IL)-6, IL-4, IL-8) and granulocyte macrophage colony-stimulating factor (GM-CSF) were increased in OB-CC patients. Peritumoral adipose tissue (TF) explants and cultured mature adipocytes secreted higher amounts of nitrites and nitrates than did control and non-tumoral (NTF) adipose tissue both alone and in response to lipopolysaccharide (LPS). Nitrite and nitrate secretion was also increased in TF explants from OB-CC patients compared with that from LEAN-CC patients. Gene expression of adiponectin, tumor necrosis factor alpha (TNF-alpha), insulin-like growth factor type I (IGF-I), cyclooxygenase-2 (COX-2), and peroxisome proliferator-activated receptor gamma (PPAR-gamma) was increased in TF explants from CC patients. LPS increased the gene expression of IL-6, IL-10, TNF-alpha, vascular endothelial growth factor (VEGF), and COX-2 in OB and in TF explants from OB-CC patients. COX-2 and PPAR gamma inhibition further increased LPS-induced release of nitrites and nitrates in TF explants and adipocytes from OB-CC patients. CONCLUSIONS: In conclusion, OB CC patients have increased plasma levels of pro-inflammatory and angiogenic factors. TF from OB-CC patients shows an increased secretion of inflammatory markers compared with both TF from LEAN-CC and non-tumoral adipose tissue (AT) through a COX-2- and PPAR-gamma-independent mechanism. PMID- 26493187 TI - Initial retrocolic endoscopic tunnel approach (IRETA) for complete mesocolic excision (CME) with central vascular ligation (CVL) for right colonic cancers: technique and pathological radicality. AB - INTRODUCTION: The concept of complete mesocolic excision (CME) with central vascular ligation (CVL) for treatment of right colon cancer evolved over last one decade. It decreases local recurrences and improves the survival rates. We describe our novel technique which involves first posterior sharp dissection between planes of parietal and visceral fascia of mesocolon followed by ligation of ileocolic, right colic and middle colic pedicles at their origin. We highlight the technical variations with various techniques and advantages over conventional medial to lateral approach in current study. AIM: The outcomes were measured in terms of technical feasibility, short-term outcomes and pathological radicality of current laparoscopic technique (IRETA) for CME with CVL. MATERIALS AND METHODS: Two hundred twelve patients (163 males) who underwent laparoscopic CME for right colon cancer over the period of January 2009 to December 2013 were analysed via prospectively maintained database. RESULTS: 97.16 % of patients (n = 206) underwent laparoscopic CME while six patients required open conversion. Mean operative time was 142 +/- 28.4 min with median hospital stay of 5 days (range 4 11). The median count of lymph node harvested were 24 (range 10-42). The complete mesocolic excision plane was achieved in 93.8 % patients. 84.4 % (n = 179) of our patients were having (T3, N+) disease on pathological examination. The overall morbidity (<30 days) was 9.9 %. CONCLUSION: Laparoscopic initial retrocolic endoscopic tunnel approach (IRETA) for CME with CVL in right colonic cancers is safe, simpler and feasible laparoscopic approach with minimal complications. Creation of retro colic tunnel is key highlight of IRETA approach. This approach becomes especially useful in patients with late presentations where complete mesocolic excision remains essential to enhance oncological radicality as per evidence available. PMID- 26493188 TI - Isolation of human monoclonal autoantibodies derived from pancreatic lymph node and peripheral blood B cells of islet autoantibody-positive patients. AB - AIMS/HYPOTHESIS: Autoantibodies against pancreatic islets and infections by enteroviruses are associated with type 1 diabetes, but the specificity of immune responses within the type 1 diabetic pancreas is poorly characterised. We investigated whether pancreatic lymph nodes could provide a source of antigen specific B cells for analysis of immune responses within the (pre)diabetic pancreas. METHODS: Human IgG antibodies were cloned from single B lymphocytes sorted from pancreatic lymph node cells of three organ donors positive for islet autoantibodies, and from the peripheral blood of a patient with type 1 diabetes. Antibodies to insulinoma-associated antigen 2 (IA-2), GAD65, zinc transporter 8 (ZnT8) and Coxsackie B virus proteins were assayed by immunoprecipitation and by immunofluorescence on pancreatic sections. RESULTS: Human IgG antibodies (863) were successfully cloned and produced from 4,092 single B cells from lymph nodes and peripheral blood. Reactivity to the protein tyrosine phosphatase domain of the IA-2 autoantigen was detected in two cloned antibodies: one derived from a pancreatic lymph node and one from peripheral blood. Epitopes for these two antibodies were similar to each other and to those for circulating antibodies in type 1 diabetes. The remaining 861 antibodies were negative for reactivity to IA 2, GAD65 or ZnT8 by both assays tested. Reactivity to a Coxsackie viral protein 2 was detected in one antibody derived from a peripheral blood B cell, but not from lymph nodes. CONCLUSIONS/INTERPRETATION: We show evidence for the infrequent presence of autoantigen-specific IgG+ B lymphocytes in the pancreatic-draining lymph nodes of islet autoantibody-positive individuals. PMID- 26493189 TI - Disturbance maintains alternative biome states. AB - Understanding the mechanisms controlling the distribution of biomes remains a challenge. Although tropical biome distribution has traditionally been explained by climate and soil, contrasting vegetation types often occur as mosaics with sharp boundaries under very similar environmental conditions. While evidence suggests that these biomes are alternative states, empirical broad-scale support to this hypothesis is still lacking. Using community-level field data and a novel resource-niche overlap approach, we show that, for a wide range of environmental conditions, fire feedbacks maintain savannas and forests as alternative biome states in both the Neotropics and the Afrotropics. In addition, wooded grasslands and savannas occurred as alternative grassy states in the Afrotropics, depending on the relative importance of fire and herbivory feedbacks. These results are consistent with landscape scale evidence and suggest that disturbance is a general factor driving and maintaining alternative biome states and vegetation mosaics in the tropics. PMID- 26493190 TI - Early-life experience affects honey bee aggression and resilience to immune challenge. AB - Early-life social experiences cause lasting changes in behavior and health for a variety of animals including humans, but it is not well understood how social information ''gets under the skin'' resulting in these effects. Adult honey bees (Apis mellifera) exhibit socially coordinated collective nest defense, providing a model for social modulation of aggressive behavior. Here we report for the first time that a honey bee's early-life social environment has lasting effects on individual aggression: bees that experienced high-aggression environments during pre-adult stages showed increased aggression when they reached adulthood relative to siblings that experienced low-aggression environments, even though all bees were kept in a common environment during adulthood. Unlike other animals including humans however, high-aggression honey bees were more, rather than less, resilient to immune challenge, assessed as neonicotinoid pesticide susceptibility. Moreover, aggression was negatively correlated with ectoparasitic mite presence. In honey bees, early-life social experience has broad effects, but increased aggression is decoupled from negative health outcomes. Because honey bees and humans share aspects of their physiological response to aggressive social encounters, our findings represent a step towards identifying ways to improve individual resiliency. Pre-adult social experience may be crucial to the health of the ecologically threatened honey bee. PMID- 26493192 TI - A retrospective study on post-operative hearing of middle ear cholesteatoma patients with labyrinthine fistula. AB - CONCLUSIONS: There is no significant change in bone conduction threshold after operation, so the tympanoplasty can be done to maintain hearing when conditions allow. OBJECTIVE: To study the impact of surgical treatment on hearing of cholesteatoma patients with labyrinthine fistula. METHODS: The clinical data of 35 patients (35 ears) with labyrinthine fistula, which were caused by cholesteatoma, were analyzed retrospectively. The hearing of 21 patients was followed up. RESULTS: Three months to 5 years follow-up of 21 patients were accomplished by pure tone audiometry and other details. There was no recurrent cholesteatoma in the patients. Compared with pre-operative average bone conduction at 0.5, 1, 2, 4, and 8 kHz, 12 cases had a difference less than 5 dB, three patients' hearing improved (more than 10 dB), and five cases declined (more than 10 dB). One patient received cochlear implantation 3 months after the surgery. The average bone and air conduction thresholds at 0.5, 1, 2, 4, and 8 kHz had no obvious change (p > 0.05) in 11 patients managed by a canal wall down mastoidectomy with tympanoplasty. PMID- 26493191 TI - Hypoxia and Dark Adaptation in Diabetic Retinopathy: Interactions, Consequences, and Therapy. AB - In diabetes, retinal blood flow is compromised, and retinal hypoxia is likely to be further intensified during periods of darkness. During dark adaptation, rod photoreceptors in the outer retina are maximally depolarized and continuously release large amounts of the neurotransmitter glutamate-an energetically demanding process that requires the highest oxygen consumption per unit volume of any tissue of the body. In complete darkness, even more oxygen is consumed by the outer retina, producing a steep fall in the retinal oxygen tension curve which reaches a nadir at the depth of the mitochondrial-rich rod inner segments. In contrast to the normal retina, the diabetic retina cannot meet the added metabolic load imposed by the dark-adapted rod photoreceptors; this exacerbates retinal hypoxia and stimulates the overproduction of vascular endothelial growth factor (VEGF). The use of nocturnal illumination to prevent dark adaptation, specifically reducing the rod photoreceptor dark current, should ameliorate diabetic retinopathy. PMID- 26493193 TI - DNA repair system and renal cell carcinoma prognosis: under the influence of NBS1. AB - Nibrin (NBS1) is a protein involved in the maintenance of genomic stability and in DNA repair mechanisms. The NBS1 E185Q polymorphism (rs1805794) has been investigated in several studies, including its influence in the pathogenesis of renal cell carcinoma (RCC), although its prognostic value is still not determined for these patients. The purpose of the present work was to determine the role of NBS1 E185Q polymorphism as a prognostic factor/genetic marker of survival in patients with RCC. We conducted a hospital-based study analyzing 172 caucasian patients with histopathological diagnosis of RCC, for which polymorphism genotyping was performed by TaqMan((r)) Allelic Discrimination methodology. In this study, we have found that male patients, non-metastatic at diagnosis and NBS1 C allele carriers (GC/CC) showed a lower 5-years survival when compared with GG genotype patients (P = 0.045). Furthermore, for carriers of low-activity NBS1 C allele, multivariate Cox regression analysis revealed almost a fourfold increase in risk of death at 5 years, after adjustment for age, histological type, Fuhrman's grade, tumor size and vascular permeation (HR 3.92; 95 % CI 1.33 11.57; P = 0.013). There were no statistically significant differences between the NBS1 E185Q genotypes and the assessed patients' clinical-pathological characteristics. Our results demonstrate for the first time the impact of NBS1 E185Q polymorphism in RCC prognosis suggesting that, for RCC male patients non metastatic at diagnosis, this polymorphism might be a putative genetic marker in the clinical outcome. PMID- 26493194 TI - Problems with the pathological diagnosis of osteonecrosis. PMID- 26493196 TI - Corrigendum. PMID- 26493195 TI - Blood flow characteristics in the ascending aorta after TAVI compared to surgical aortic valve replacement. AB - Ascending aortic blood flow characteristics are altered after aortic valve surgery, but the effect of transcatheter aortic valve implantation (TAVI) is unknown. Abnormal flow may be associated with aortic and cardiac remodeling. We analyzed blood flow characteristics in the ascending aorta after TAVI in comparison to conventional stented aortic bioprostheses (AVR) and healthy subjects using time-resolved three-dimensional flow-sensitive cardiovascular magnetic resonance imaging (4D-flow MRI). Seventeen patients with TAVI (Edwards Sapien XT), 12 with AVR and 9 healthy controls underwent 4D-flow MRI of the ascending aorta. Target parameters were: severity of vortical and helical flow pattern (semiquantitative grading from 0 = none to 3 = severe) and the local distribution of systolic wall shear stress (WSSsystole). AVR revealed significantly more extensive vortical and helical flow pattern than TAVI (p = 0.042 and p = 0.002) and controls (p < 0.001 and p = 0.001). TAVI showed significantly more extensive vortical flow than controls (p < 0.001). Both TAVI and AVR revealed marked blood flow eccentricity (64.7 and 66.7%, respectively), whereas controls showed central blood flow (88.9%). TAVI and AVR exhibited an asymmetric distribution of WSSsystole in the mid-ascending aorta with local maxima at the right anterior aortic wall and local minima at the left posterior wall. In contrast, controls showed a symmetric distribution of WSSsystole along the aortic circumference. Blood flow was significantly altered in the ascending aorta after TAVI and AVR. Changes were similar regarding WSSsystole distribution, while TAVI resulted in less helical and vortical blood flow. PMID- 26493197 TI - Interactive effects of glutamine and gamma-aminobutyric acid on growth performance and skeletal muscle amino acid metabolism of 22-42-day-old broilers exposed to hot environment. AB - The present experiment was conducted to investigate the interactive effects between dietary glutamine (Gln, 0 and 5 g/kg) and gamma-aminobutyric acid (GABA, 0 and 100 mg/kg) on growth performance and amino acid (AA) metabolism of broilers under hot environment. A total of 360 22-day-old Arbor Acres male chickens were randomly assigned to five treatment groups under thermoneutral chamber (PC, 23 degrees C) and cyclic heat stress (HS, 30-34 degrees C cycling) conditions. Compared with the PC group, cyclic HS decreased (P < 0.05) daily weight gain (DWG), daily feed consumption (DFC), the concentrations of Gln, glutamate (Glu), and GABA, and the activities of glutaminase and glutamic acid decarboxylase (GAD) in breast muscle at 28, 35, and 42 days, while it increased (P < 0.05) the activities of glutamine synthetase (GS) and gamma-aminobutyric acid transaminase (GABA-T) at 28, 35, and 42 days. Dietary Gln and GABA improved (P < 0.05) DWG and DFC of broilers under cyclic HS during 28-42 days. In breast muscle, the Gln supplementation increased (P < 0.05) the concentrations of Gln (28, 35, and 42 days), Glu (28, 35, and 42 days), and GABA (42 days) and the activities of glutaminase (28, 35, and 42 days) and GAD (28, 35, and 42 days) but decreased (P < 0.05) GS activities at 28, 35, and 42 days and GABA-T activities at 28 days. The addition of GABA increased (P < 0.05) the concentrations of Gln and Glu and activities of glutaminase and GAD, while it decreased (P < 0.05) GABA-T activities at 28, 35, and 42 days. Significant interactions (P < 0.05) between Gln and GABA were found on breast skeletal muscle Gln concentrations, glutaminase activities, GS activities at 28 and 35 days, and DWG, GABA concentrations, and GABA-T activities at 28, 35, and 42 days in broilers under cyclic HS. In conclusion, the present results indicated that the interactions of exogenous Gln and GABA could offer a potential nutritional strategy to prevent HS-related depression in skeletal muscle Gln and GABA metabolism of broilers. PMID- 26493198 TI - An agro-climatic approach to determine citrus postbloom fruit drop risk in Southern Brazil. AB - Postbloom fruit drop (PFD) causes lesions on the petals of citrus flowers and induces fruit abscission causing severe damage to production when the flowering period coincides with intense rainfall. The aims of this study were to develop a phenological-climatological model for citrus PFD occurrence and, together with weather data series from several locations, to determine and map the agro climatic favorability of PFD occurrence in the state of Sao Paulo, Southern Brazil. A phenological flowering model was developed to identify when citrus flowering occurs. The flowering starts after when a temperature below 10 degrees C in the months of June or July is reached followed by cumulative rainfall within 5 days of at least 20 mm, and then 96 degrees C days. Between the beginning of flowering and its peak, 147 degrees C days are required, and between the peak and its end, approximately 229 degrees C days, being 206 degrees C days from the peak to the moment when flowers remaining are about 50 % of total. The relationship between PFD incidence and accumulated rainfall during the critical period (between flowering peak and 50 % of flowers remaining) was adjusted by the Gompertz model (R (2) = 0.99, p < 0.05). After its validation, this model was used to estimate PFD incidence for 29 locations in the state, from 1993 to 2013, which allowed to map the PFD climatic favorability for the state through a Geographical Information System using linear models based on latitude, longitude, and altitude. The obtained map showed a trend of PFD incidence increasing from the northwest of the state of Sao Paulo towards the south and the coastal region, with medium to very high favorability in the center of the state. The results of this study can be used by growers as a guide for disease control planning as well as for defining the regions where the climatic conditions are likely to escape this disease. PMID- 26493199 TI - Impact of temperature variation between adjacent days on childhood hand, foot and mouth disease during April and July in urban and rural Hefei, China. AB - Previous studies have found that both high temperature and low temperature increase the risk of childhood hand, foot and mouth disease (HFMD). However, little is known about whether temperature variation between neighboring days has any effects on childhood HFMD. A Poisson generalized linear regression model, combined with a distributed lag non-linear model, was applied to examine the relationship between temperature change and childhood HFMD in Hefei, China, from 1st January 2010 to 31st December 2012. Temperature change was defined as the difference of current day's mean temperature and previous day's mean temperature. Late spring and early summer (April-July) were chosen as the main study period due to it having the highest childhood HFMD incidence. There was a statistical association between temperature change between neighboring days and childhood HFMD. The effects of temperature change on childhood HFMD increased below a temperature change of 0 degrees C (temperature drop). The temperature change has the greatest adverse effect on childhood HFMD at 7 days lag, with 4 % (95 % confidence interval 2-7 %) increase per 3 degrees C drop of temperature. Male children and urban children appeared to be more vulnerable to the effects of temperature change. Temperature change between adjacent days might be an alternative temperature indictor for exploring the temperature-HFMD relationship. PMID- 26493200 TI - High-definition endoscopy with digital chromoendoscopy for histologic prediction of distal colorectal polyps. AB - BACKGROUND: Distal diminutive colorectal polyps are common and accurate endoscopic prediction of hyperplastic or adenomatous polyp histology could reduce procedural time, costs and potential risks associated with the resection. Within this study we assessed whether digital chromoendoscopy can accurately predict the histology of distal diminutive colorectal polyps according to the ASGE PIVI statement. METHODS: In this prospective cohort study, 224 consecutive patients undergoing screening or surveillance colonoscopy were included. Real time histology of 121 diminutive distal colorectal polyps was evaluated using high definition endoscopy with digital chromoendoscopy and the accuracy of predicting histology with digital chromoendoscopy was assessed. RESULTS: The overall accuracy of digital chromoendoscopy for prediction of adenomatous polyp histology was 90.1 %. Sensitivity, specificity, positive and negative predictive values were 93.3, 88.7, 88.7, and 93.2 %, respectively. In high-confidence predictions, the accuracy increased to 96.3 % while sensitivity, specificity, positive and negative predictive values were calculated as 98.1, 94.4, 94.5, and 98.1 %, respectively. Surveillance intervals with digital chromoendoscopy were correctly predicted with >90 % accuracy. CONCLUSIONS: High-definition endoscopy in combination with digital chromoendoscopy allowed real-time in vivo prediction of distal colorectal polyp histology and is accurate enough to leave distal colorectal polyps in place without resection or to resect and discard them without pathologic assessment. This approach has the potential to reduce costs and risks associated with the redundant removal of diminutive colorectal polyps. TRIAL REGISTRATION: ClinicalTrials NCT02217449. PMID- 26493201 TI - Excitability tuning of axons in the central nervous system. AB - The axon is a long neuronal process that originates from the soma and extends towards the presynaptic terminals. The pioneering studies on the squid giant axon or the spinal cord motoneuron established that the axon conducts action potentials faithfully to the presynaptic terminals with self-regenerative processes of membrane excitation. Recent studies challenged the notion that the fundamental understandings obtained from the study of squid giant axons are readily applicable to the axons in the mammalian central nervous system (CNS). These studies revealed that the functional and structural properties of the CNS axons are much more variable than previously thought. In this review article, we summarize the recent understandings of axon physiology in the mammalian CNS due to progress in the subcellular recording techniques which allow direct recordings from the axonal membranes, with emphasis on the hippocampal mossy fibers as a representative en passant axons typical for cortical axons. PMID- 26493202 TI - Effects of food diameter on bite size per mouthful and chewing behavior. AB - Obesity is well known to be associated with a wide variety of illnesses, and is an increasing problem not only in developed countries but also in developing countries. It is well known that large bite size contributes to excess energy intake and obesity, whereas an increased number of chews before swallowing the food bolus is associated with suppression of obesity. However, the effect of food diameter on bite size per mouthful and on chewing behavior remains poorly understood. Here, we examined the effects of food diameter on bite size and chewing behavior using a masticatory counter during the mastication of stick-type biscuits having the same length (10 cm) and ingredients, but with four different diameters (3.0, 3.5, 4.0, and 8.0 mm). Bite length and bite weight per mouthful were similar among the 3.0, 3.5, and 4.0 mm groups. However, bite length in the 8.0 mm group was significantly smaller, whereas bite weight was significantly greater than in the 3.0/3.5 mm groups. Further, the number of chews gradually increased, whereas the number of chews per bite weight gradually decreased, with an increase of biscuit diameter. These results indicate that a smaller biscuit diameter is associated with a smaller bite weight per mouthful and a greater number of chews per bite weight. This is the first report to quantity the effect of food diameter on bite weight per mouthful and on chewing behavior; these results should be helpful in the design of effective, safe, and low-cost behavioral modification therapy to combat obesity. PMID- 26493204 TI - Fast Patch-Based Pseudo-CT Synthesis from T1-Weighted MR Images for PET/MR Attenuation Correction in Brain Studies. AB - Attenuation correction in hybrid PET/MR scanners is still a challenging task. This paper describes a methodology for synthesizing a pseudo-CT volume from a single T1-weighted volume, thus allowing us to create accurate attenuation correction maps. METHODS: We propose a fast pseudo-CT volume generation from a patient-specific MR T1-weighted image using a groupwise patch-based approach and an MRI-CT atlas dictionary. For every voxel in the input MR image, we compute the similarity of the patch containing that voxel to the patches of all MR images in the database that lie in a certain anatomic neighborhood. The pseudo-CT volume is obtained as a local weighted linear combination of the CT values of the corresponding patches. The algorithm was implemented in a graphical processing unit (GPU). RESULTS: We evaluated our method both qualitatively and quantitatively for PET/MR correction. The approach performed successfully in all cases considered. We compared the SUVs of the PET image obtained after attenuation correction using the patient-specific CT volume and using the corresponding computed pseudo-CT volume. The patient-specific correlation between SUV obtained with both methods was high (R(2) = 0.9980, P < 0.0001), and the Bland-Altman test showed that the average of the differences was low (0.0006 +/- 0.0594). A region-of-interest analysis was also performed. The correlation between SUVmean and SUVmax for every region was high (R(2) = 0.9989, P < 0.0001, and R(2) = 0.9904, P < 0.0001, respectively). CONCLUSION: The results indicate that our method can accurately approximate the patient-specific CT volume and serves as a potential solution for accurate attenuation correction in hybrid PET/MR systems. The quality of the corrected PET scan using our pseudo-CT volume is comparable to having acquired a patient-specific CT scan, thus improving the results obtained with the ultrashort-echo-time-based attenuation correction maps currently used in the scanner. The GPU implementation substantially decreases computational time, making the approach suitable for real applications. PMID- 26493203 TI - Comparison of Prostate-Specific Membrane Antigen-Based 18F-DCFBC PET/CT to Conventional Imaging Modalities for Detection of Hormone-Naive and Castration Resistant Metastatic Prostate Cancer. AB - Conventional imaging modalities (CIMs) have limited sensitivity and specificity for detection of metastatic prostate cancer. We examined the potential of a first in-class radiofluorinated small-molecule inhibitor of prostate-specific membrane antigen (PSMA), N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-l cysteine ((18)F-DCFBC), to detect metastatic hormone-naive (HNPC) and castration resistant prostate cancer (CRPC). METHODS: Seventeen patients were prospectively enrolled (9 HNPC and 8 CRPC); 16 had CIM evidence of new or progressive metastatic prostate cancer and 1 had high clinical suspicion of metastatic disease. (18)F-DCFBC PET/CT imaging was obtained with 2 successive PET scans starting at 2 h after injection. Patients were imaged with CIM at approximately the time of PET. A lesion-by-lesion analysis of PET to CIM was performed in the context of either HNPC or CRPC. The patients were followed with available clinical imaging as a reference standard to determine the true nature of identified lesions on PET and CIM. RESULTS: On the lesion-by-lesion analysis, (18)F-DCFBC PET was able to detect a larger number of lesions (592 positive with 63 equivocal) than CIM (520 positive with 61 equivocal) overall, in both HNPC and CRPC patients. (18)F-DCFBC PET detection of lymph nodes, bone lesions, and visceral lesions was superior to CIM. When intrapatient clustering effects were considered, (18)F-DCFBC PET was estimated to be positive in a large proportion of lesions that would be negative or equivocal on CIM (0.45). On follow-up, the sensitivity of (18)F-DCFBC PET (0.92) was superior to CIM (0.71). (18)F-DCFBC tumor uptake was increased at the later PET time point (~2.5 h after injection), with background uptake showing a decreasing trend on later PET. CONCLUSION: PET imaging with (18)F-DCFBC, a small-molecule PSMA-targeted radiotracer, detected more lesions than CIM and promises to diagnose and stage patients with metastatic prostate cancer more accurately than current imaging methods. PMID- 26493205 TI - Quantitative Comparison of 124I PET/CT and 131I SPECT/CT Detectability. AB - Radioiodine therapy with (131)I is used for treatment of suspected recurrence of differentiated thyroid carcinoma. Pretherapeutic (124)I PET/CT with a low activity (~1% of (131)I activity) can be performed to determine whether uptake of (131)I, and thereby the desired therapeutic effect, may be expected. However, false-negative (124)I PET/CT results as compared with posttherapeutic (131)I SPECT/CT have been reported by several groups. The purpose of this study was to investigate whether the reported discrepancies may be ascribed to a difference in lesion detectability between (124)I PET/CT and (131)I SPECT/CT and, hence, whether the administered (124)I activity is sufficient to achieve equal detectability. METHODS: Phantom measurements were performed using the National Electrical Manufacturers Association 2007 image-quality phantom. As a measure of detectability, the contrast-to-noise ratio was calculated. The (124)I activity was expressed as the percentage of (131)I activity required to achieve the same contrast-to-noise ratio. This metric was defined as the detectability equivalence percentage (DEP). RESULTS: Because lower DEPs were obtained for smaller spheres, a relatively low (124)I activity was sufficient to achieve similar lesion detectability between (124)I PET/CT and (131)I SPECT/CT. DEP was 1.5%, 1.9%, 1.9%, 4.4%, 9.0%, and 16.2% for spheres with diameters of 10, 13, 17, 18, 25, and 37 mm, respectively, for attenuation- and scatter-corrected SPECT versus point spread function (PSF) model-based and time-of-flight (TOF) PET. For no-PSF no-TOF PET, DEP was 3.6%, 2.1%, 3.5%, 7.8%, 15.1%, and 23.3%, respectively. CONCLUSION: A relatively low (124)I activity of 74 MBq (~1% of (131)I activity) is sufficient to achieve similar lesion detectability between (124)I PSF TOF PET/CT and (131)I SPECT/CT for small spheres (<=10 mm), since the reported DEPs are close to 1%. False-negative (124)I PET/CT results as compared with posttherapeutic (131)I SPECT/CT may be ascribed to differences in detectability for large lesions (>10 mm) and for no-PSF no-TOF PET, since DEPs are greater than 1%. On the basis of DEPs of 3.5% for lesion diameters of up to 17 mm on no-PSF no-TOF PET, (124)I activities as high as 170 MBq may be warranted to obtain equal detectability. PMID- 26493206 TI - Multicenter Clinical Trials Using 18F-FDG PET to Measure Early Response to Oncologic Therapy: Effects of Injection-to-Acquisition Time Variability on Required Sample Size. AB - Uptake time (interval between tracer injection and image acquisition) affects the SUV measured for tumors in (18)F-FDG PET images. With dissimilar uptake times, changes in tumor SUVs will be under- or overestimated. This study examined the influence of uptake time on tumor response assessment using a virtual clinical trials approach. METHODS: Tumor kinetic parameters were estimated from dynamic (18)F-FDG PET scans of breast cancer patients and used to simulate time-activity curves for 45-120 min after injection. Five-minute uptake time frames followed 4 scenarios: the first was a standardized static uptake time (the SUV from 60 to 65 min was selected for all scans), the second was uptake times sampled from an academic PET facility with strict adherence to standardization protocols, the third was a distribution similar to scenario 2 but with greater deviation from standards, and the fourth was a mixture of hurried scans (45- to 65-min start of image acquisition) and frequent delays (58- to 115-min uptake time). The proportion of out-of-range scans (<50 or >70 min, or >15-min difference between paired scans) was 0%, 20%, 44%, and 64% for scenarios 1, 2, 3, and 4, respectively. A published SUV correction based on local linearity of uptake-time dependence was applied in a separate analysis. Influence of uptake-time variation was assessed as sensitivity for detecting response (probability of observing a change of >=30% decrease in (18)F-FDG PET SUV given a true decrease of 40%) and specificity (probability of observing an absolute change of <30% given no true change). RESULTS: Sensitivity was 96% for scenario 1, and ranged from 73% for scenario 4 (95% confidence interval, 70%-76%) to 92% (90%-93%) for scenario 2. Specificity for all scenarios was at least 91%. Single-arm phase II trials required an 8%-115% greater sample size for scenarios 2-4 than for scenario 1. If uptake time is known, SUV correction methods may raise sensitivity to 87%-95% and reduce the sample size increase to less than 27%. CONCLUSION: Uptake-time deviations from standardized protocols occur frequently, potentially decreasing the performance of (18)F-FDG PET response biomarkers. Correcting SUV for uptake time improves sensitivity, but algorithm refinement is needed. Stricter uptake time control and effective correction algorithms could improve power and decrease costs for clinical trials using (18)F-FDG PET endpoints. PMID- 26493207 TI - Evaluation of Atlas-Based Attenuation Correction for Integrated PET/MR in Human Brain: Application of a Head Atlas and Comparison to True CT-Based Attenuation Correction. AB - Attenuation correction (AC) for integrated PET/MR imaging in the human brain is still an open problem. In this study, we evaluated a simplified atlas-based AC (Atlas-AC) by comparing (18)F-FDG PET data corrected using either Atlas-AC or true CT data (CT-AC). METHODS: We enrolled 8 patients (median age, 63 y). All patients underwent clinically indicated whole-body (18)F-FDG PET/CT for staging, restaging, or follow-up of malignant disease. All patients volunteered for an additional PET/MR of the head (additional tracer was not injected). For each patient, 2 AC maps were generated: an Atlas-AC map registered to a patient specific liver accelerated volume acquisition-Flex MR sequence and using a vendor provided head atlas generated from multiple CT head images and a CT-based AC map. For comparative AC, the CT-AC map generated from PET/CT was superimposed on the Atlas-AC map. PET images were reconstructed from the list-mode raw data from the PET/MR imaging scanner using each AC map. All PET images were normalized to the SPM5 PET template, and (18)F-FDG accumulation was quantified in 67 volumes of interest (VOIs; automated anatomic labeling atlas). Relative difference (%diff) between images based on Atlas-AC and CT-AC was calculated, and averaged difference images were generated. (18)F-FDG uptake in all VOIs was compared using Bland-Altman analysis. RESULTS: The range of error in all 536 VOIs was -3.0% 7.3%. Whole-brain (18)F-FDG uptake based on Atlas-AC was slightly underestimated (%diff = 2.19% +/- 1.40%). The underestimation was most pronounced in the regions below the anterior/posterior commissure line, such as the cerebellum, temporal lobe, and central structures (%diff = 3.69% +/- 1.43%, 3.25% +/- 1.42%, and 3.05% +/- 1.18%), suggesting that Atlas-AC tends to underestimate the attenuation values of the skull base bone. CONCLUSION: When compared with the gold-standard CT-AC, errors introduced using Atlas-AC did not exceed 8% in any brain region investigated. Underestimation of (18)F-FDG uptake was minor (<4%) but significant in regions near the skull base. PMID- 26493208 TI - DECKO: Single-oligo, dual-CRISPR deletion of genomic elements including long non coding RNAs. AB - BACKGROUND: CRISPR genome-editing technology makes it possible to quickly and cheaply delete non-protein-coding regulatory elements. We present a vector system adapted for this purpose called DECKO (Double Excision CRISPR Knockout), which applies a simple two-step cloning to generate lentiviral vectors expressing two guide RNAs (gRNAs) simultaneously. The key feature of DECKO is its use of a single 165 bp starting oligonucleotide carrying the variable sequences of both gRNAs, making it fully scalable from single-locus studies to complex library cloning. RESULTS: We apply DECKO to deleting the promoters of one protein-coding gene and two oncogenic lncRNAs, UCA1 and the highly-expressed MALAT1, focus of many previous studies employing RNA interference approaches. DECKO successfully deleted genomic fragments ranging in size from 100 to 3000 bp in four human cell lines. Using a clone-derivation workflow lasting approximately 20 days, we obtained 9 homozygous and 17 heterozygous promoter knockouts in three human cell lines. Frequent target region inversions were observed. These clones have reductions in steady-state MALAT1 RNA levels of up to 98 % and display reduced proliferation rates. CONCLUSIONS: We present a dual CRISPR tool, DECKO, which is cloned using a single starting oligonucleotide, thereby affording simplicity and scalability to CRISPR knockout studies of non-coding genomic elements, including long non-coding RNAs. PMID- 26493209 TI - Clinical characteristics, surgical and neuropsychological outcomes in drug resistant tumoral temporal lobe epilepsy. AB - INTRODUCTION: Glioneuronal tumors are found in nearly one third patients who undergo surgery for pharmacoresistant epilepsy with temporal lobe being the most common location. Few studies, however have concentrated on the neurological and neuropsychological outcomes after surgery, hitherto none from India. METHODS: We studied 34 patients with temporal lobe tumors and drug resistant epilepsy. These patients underwent anterior temporal lobectomy or lesionectomy based on the involvement of the hippocampus and mesial temporal structures. The clinical history, EEG, neuropsychology profile and MRI were compared. Seizure outcome was categorized using Engel's classification. RESULTS: At a mean follow up of 62 months, 85.29% of the patients were seizure free (Engel's Class I). All 8 patients with intraoperative electrocorticography (ECoG) guided resection were seizure free. DISCUSSION: Presence of a residual lesion was significantly associated with persistence of seizures post surgery (p = 0.002). Group analysis revealed no significant shifts in IQ and memory scores postoperatively. There was a significant improvement in the quality of life scores (total and across all subdomains) in all patients (p < 0.001). Postoperative EEG abnormalities predicted unfavorable seizure outcome. CONCLUSION: Surgery for temporal lobe tumors and refractory epilepsy offers complete seizure freedom in majority. Complete surgical excision of the epileptogenic zone is of paramount importance in achieving seizure freedom. Intraoperative electrocorticography (EcoG) is a useful adjunct to ensure complete removal of epileptogenic zone, thus achieving optimal seizure freedom. There is a significant improvement in the quality of life scores (p < 0.001) with no negative impact of surgery on memory and intelligence. Even the patients who are not seizure free can achieve worthwhile improvement post surgery. PMID- 26493211 TI - Best evidence topic: What is the best management of the appendix-stump in acute appendicitis: Simple ligation or stump invagination? AB - A best evidence topic has been constructed using a described protocol. The three part question addressed was: for patients undergoing appendicectomy for complicated acute appendicitis is simple ligation or invagination of the appendix stump safer? Using the reported search, 587 papers were found. Five studies were deemed to be suitable to answer the question. In conclusion, the literature is more in favour of the appendix stump being managed with simple ligation rather than stump invagination. All 5 studies assessed are prospective, randomised studies, though overall the quality of these studies is poor. The outcomes assessed were incidence of post-operative complications (pyrexia, wound infection, abscess, caecal fistula and post-operative ileus), post-operative length of stay and mean operating time. The analysis indicates no significant difference between the groups in rates of post-operative pyrexia, intra-abdominal abscess or caecal fistula. Only one study showed a significant difference in rates of wound infection in favour of simple ligation. One study demonstrated a significant difference in favour of simple ligation when comparing rates of post operative ileus. Overall, simple ligation was found to reduce patient length of stay when compared with stump invagination; one study found this difference to be significant. Simple ligation also produced shorter operating times compared with stump invagination--a risk factor for the development of post-operative ileus. All studies suffered limitations that make the quality of the evidence assessed poor. Although this evidence does favour simple ligation of the stump as compared to invagination, higher quality randomised studies are needed to answer the question definitively. PMID- 26493210 TI - Splenectomy is associated with a higher risk for venous thromboembolism: A prospective cohort study. AB - BACKGROUND: Thrombocytosis following splenectomy is a common occurrence. Whether this thrombocytosis leads to a higher risk for venous thromboembolism (VTE) remains unclear. This investigation aimed to determine if splenectomy increases the risk for VTE. METHODS: This was a prospective study conducted in the SICU between 1/2011 and 11/2013 investigating the VTE risk in patients undergoing a splenectomy compared with those undergoing any other abdominal procedure. RESULTS: In total 2503 patients were admitted to the SICU: 37 (2%) after a splenectomy and 638 (26%) after any other abdominal surgery. Splenectomy patients had a higher incidence of VTE compared to patients undergoing any other abdominal procedure (29.7% vs. 12.1%, p < 0.01). After adjustment, splenectomy was associated with a higher adjusted risk for VTE compared to the no-splenectomy group (AOR [95% CI]: 2.6 [1.2, 5.9], p = 0.02). Reactive thrombocytosis did not predict the development of VTE. CONCLUSION: Splenectomy increases the risk for VTE, however reactive thrombocytosis is not associated with this higher incidence. Further investigations are required to characterize the pathophysiologic mechanisms of VTE development following splenectomy. PMID- 26493212 TI - Bicycle trauma and alcohol intoxication. AB - INTRODUCTION: As bicycling has become more popular, admissions after bicycle trauma are on the rise. The impact of alcohol use on bicycle trauma has not been well studied. The aim of this study was to examine the effect of alcohol intoxication on injury burden following bicycle-related crashes. METHODS: A retrospective review of trauma patients presenting to a Level I trauma center after bicycle-related crashes from January 2002 to December 2011 was conducted. Demographics, injury data, alcohol intoxication, helmet use, and clinical outcomes were reviewed. Blood alcohol level (BAL) was considered positive if >0.01 g/dL. Variables were compared between patients based on BAL: negative, 0.01 0.16 g/dL, and >0.16 g/dL. RESULTS: During the 10 year study period, 563 patients met study criteria; mean age was 33.5 +/- 16.5 years, 87% were male, and mortality was 1%. On average, bicycle crashes increased over the study period by 4.4 collisions per year. BAL was tested in 211 (38%) patients. Mean BAL was 0.24 g/dL, with 37% of these patients being intoxicated (BAL >= 0.010 g/dL). Intoxicated patients were significantly less likely to wear a helmet (4.7% vs. 22.2%, p = 0.002) and to be involved in motor vehicle crash (59.0% vs. 81.2%, p < 0.001). There was no difference noted in the injury burden including ISS >= 16 (14.3% vs. 19.5%, p = 0.335) and AIS Head >= 3 (17.9% vs. 21.8%, p = 0.502). When comparing patients according to their BAL, there was a decreasing risk of motor vehicle collision with increasing BAL (81.2% for undetected, 76.5% for BAL <= 0.16 g/dL and 54.1% for BAL >0.16 g/dL, p < 0.001). The risk for a severe head injury (AIS Head >= 3) was significantly lower in helmeted patients (8.4% vs. 15.8%, p = 0.035). CONCLUSIONS: The incidence of bicycle-related crashes is increasing and more than a third of patients tested for alcohol after bicycle related crashes are found to be intoxicated. The injury burden in intoxicated patients, including head trauma, was not different compared to non-intoxicated patients. In addition, the risk for a collision with a motor vehicle was significantly lower. Nonetheless, these patients rarely utilize a helmet. The findings from this study can be used for the development and implementation of preventive strategies to minimize the injury burden associated with bicycle crashes and intoxicated cyclists. PMID- 26493213 TI - A Multicenter Longitudinal Study of Hospital-Onset Bacteremia: Time for a New Quality Outcome Measure? AB - BACKGROUND: Central-line-associated bloodstream infection (CLABSI) rate is an important quality measure, but it suffers from subjectivity and interrater variability, and decreasing national CLABSI rates may compromise its power to discriminate between hospitals. This study evaluates hospital-onset bacteremia (HOB, ie, any positive blood culture obtained 48 hours post admission) as a healthcare-associated infection-related outcome measure by assessing the association between HOB and CLABSI rates and comparing the power of each to discriminate quality among intensive care units (ICUs). METHODS: In this multicenter study, ICUs provided monthly CLABSI and HOB rates for 2012 and 2013. A Poisson regression model was used to assess the association between these 2 rates. We compared the power of each measure to discriminate between ICUs using standardized infection ratios (SIRs) with 95% confidence intervals (CIs). A measure was defined as having greater power to discriminate if more of the SIRs (with surrounding CIs) were different from 1. RESULTS: In 80 ICUs from 16 hospitals in the United States and Canada, a total of 663 CLABSIs, 475,420 central line days, 11,280 HOBs, and 966,757 patient days were reported. An absolute change in HOB of 1 per 1,000 patient days was associated with a 2.5% change in CLABSI rate (P<.001). Among the 80 ICUs, 20 (25%) had a CLABSI SIR and 60 (75%) had an HOB SIR that was different from 1 (P<.001). CONCLUSION: Change in HOB rate is strongly associated with change in CLABSI rate and has greater power to discriminate between ICU performances. Consideration should be given to using HOB to replace CLABSI as an outcome measure in infection prevention quality assessments. PMID- 26493214 TI - A framework of ethics for telepsychiatry practice. AB - Psychiatrists who provide telepsychiatric services must uphold the standards of ethics and professionalism expected in in-person interactions. Psychiatrists' fundamental ethical responsibilities do not change when they take up a new form of practice. But as in other areas of medicine, the introduction of a new technology - here, Internet use and videoconferencing - raises new ethical challenges, requiring a fresh look at clinical practice and social issues such as equitable access. This review discusses these new challenges under six headings: providing competent, safe care, ensuring informed consent, promoting privacy and confidentiality, managing boundaries, encouraging continuity of care, and addressing health equity. Ethical guidelines for in-person practice have emerged from decades of clinical discussion and carefully observed treatment in the office and hospital setting. New observations, clinical reports, and shared discussion and learning must do the same for telepsychiatry in the years to come. PMID- 26493215 TI - The laforin/malin E3-ubiquitin ligase complex ubiquitinates pyruvate kinase M1/M2. AB - BACKGROUND: Lafora disease (LD, OMIM 254780) is a fatal neurodegenerative disorder produced mainly by mutations in two genes: EPM2A, encoding the dual specificity phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. Although it is known that laforin and malin may form a functional complex, the underlying molecular mechanisms of this pathology are still far from being understood. METHODS: In order to gain information about the substrates of the laforin/malin complex, we have carried out a yeast substrate-trapping screening, originally designed to identify substrates of protein tyrosine phosphatases. RESULTS: Our results identify the two muscular isoforms of pyruvate kinase (PKM1 and PKM2) as novel interaction partners of laforin. CONCLUSIONS: We present evidence indicating that the laforin/malin complex is able to interact with and ubiquitinate both PKM1 and PKM2. This post-translational modification, although it does not affect the catalytic activity of PKM1, it impairs the nuclear localization of PKM2. PMID- 26493217 TI - DNA-based identification of Peucedanum ostruthium specimens and detection of common adulterants by high-resolution melting curve analysis. AB - Masterwort (Peucedanum ostruthium, syn. Imperatoria ostruthium, Apiaceae) is an old economic plant in Alpine countries cultivated as ornamental plant and used for spirits and in folk medicine. P. ostruthium is a species that has often been confused with related Apiaceae species or morphologically similar roots or tubers resulting in products of minor quality. Masterwort can be distinguished from other Apiaceae species by nrDNA (ITS1 and ITS2). The analysed chloroplast markers (trnK 5' intron, trnT-trnL, and psbA-trnH), however, showed no species-specific mutations. With the application of two primer pairs amplifying parts of ITS and developed for high-resolution melting curve analysis (HRM) the target species was distinguishable from the other Peucedanum and Apiaceae species of our reference set. A multiplex PCR/HRM was developed to detect adulterations with Gentiana spp., Aconitum napellus and Veratrum album. PMID- 26493216 TI - Glucose availability determines silver nanoparticles toxicity in HepG2. AB - BACKGROUND: The increasing body of evidence suggest that nanomaterials toxicity is associated with generation of oxidative stress. In this paper we investigated the role of respiration in silver nanoparticles (AgNPs) generated oxidative stress and toxicity. Since cancer cells rely on glucose as the main source of energy supply, glucose availability might be an important determinant of NPs toxicity. METHODS: AgNPs of 20 nm nominal diameter were used as a model NPs. HepG2 cells were cultured in the media with high (25 mM) or low (5.5 mM) glucose content and treated with 20 nm AgNPs. AgNPs-induced toxicity was tested by neutral red assay. Generation of H2O2 in mitochondria was evaluated by use of mitochondria specific protein indicator HyPer-Mito. Expression of a 77 oxidative stress related genes was assessed by qPCR. The activity of antioxidant enzymes was estimated colorimetrically by dedicated methods in cell homogenates. RESULTS: AgNPs-induced dose-dependent generation of H2O2 and toxicity was observed. Toxicity of AgNPs towards cells maintained in the low glucose medium was significantly lower than the toxicity towards cells growing in the high glucose concentration. Scarceness of glucose supply resulted in upregulation of the endogenous antioxidant defence mechanisms that in turn alleviated AgNPs dependent ROS generation and toxicity. CONCLUSION: Glucose availability can modify toxicity of AgNPs via elevation of antioxidant defence triggered by oxidative stress resulted from enhanced oxidative phosphorylation in mitochondria and associated generation of ROS. Presented results strengthen the idea of strong linkage between NPs toxicity and intracellular respiration and possibly other mitochondria dependent processes. PMID- 26493218 TI - The prevalence of vertebral fractures in spondyloarthritis: relation to disease characteristics, bone mineral density, syndesmophytes and history of back pain and trauma. AB - INTRODUCTION: An increased risk of vertebral fracture (VF) is one of the extra articular manifestations of spondyloarthropathy (SpA). The prevalence of moderate to severe VFs visualized by radiography (Rx) in patients with SpA in daily practice is unknown until imaging of the full spine is available, as most VFs do not present with clinical signs and symptoms of an acute fracture. METHODS: We evaluated the prevalence of VFs (>25% loss in height) on available Rx and dual energy X-ray absorptiometry (DXA) images in 390 consecutive patients with SpA in daily practice. We assessed their association with disease characteristics, bone mineral density, the modified Stoke Ankylosing Spondylitis Spinal Score, and history of trauma. RESULTS: Forty-six patients (11.8%) had Rx VF (56.4% men, 93.5% in the thoracic spine), and 44.5% had multiple VFs. Compared with patients without VF, patients with VF were older (52.2 vs. 47.3 years, p < 0.01; range 25 84 years), had lower femoral neck T-scores (-1.1 vs. -0.7; p < 0.05), and had a marginally higher modified Stoke Ankylosing Spondylitis Spinal Score (11.7 vs. 7.0; p = 0.06). Among patients with VFs, 15.2% had a history of trauma with acute back pain (p < 0.001 vs. no VF). The reliability of DXA for diagnosing radiographic VFs was high (kappa 0.90). CONCLUSIONS: Moderate to severe VFs are found in more than 10% of patients with SpA before the age of 40 years in 5% of women and 9% in men. Most VFs are located in the thoracic region, are related to low femoral neck bone mineral density and to stiffening of the spine, and are only rarely related to trauma history. DXA is a useful alternative for diagnosing VFs. PMID- 26493219 TI - The Effectiveness of Measures Aimed at Noise Reduction in an Intensive Care Unit. AB - Noise is a significant problem for both hospitalized patients and health care workers. This study aimed to determine the effectiveness of noise reduction strategies in an intensive care unit. Noise was measured in two phases. In the first phase, the unit's present level of noise was established over 3 weeks between January 1, 2012, and February 1, 2012. During the month following initial measurements, noise reduction interventions, including staff education and physical space arrangement, were initiated, and device alarms were checked. The second phase of measurement was conducted during another 3-week period (between June 1, 2012, and July 1, 2012). The noise levels before and after noise reduction interventions were calculated as 67.6 dB-A and 56 dB-A; the difference between the two levels was statistically significant (p<.05). The interventions were effective in reducing noise in intensive care units; the interventions are relatively easy and low cost. PMID- 26493220 TI - Restructured abstracts for research in The BMJ. PMID- 26493221 TI - Single-Cell, Time-Resolved Antimicrobial Effects of a Highly Cationic, Random Nylon-3 Copolymer on Live Escherichia coli. AB - Synthetic random copolymers based on the nylon-3 (beta-peptide) backbone show promise as inexpensive antimicrobial agents resistant to proteolysis. We present a time-resolved observational study of the attack of a particular copolymer MM63:CHx37 on single, live Escherichia coli cells. The composition and chain length of MM63:CHx37 (63% cationic subunits, 37% hydrophobic subunits, 35-subunit average length) were optimized to enhance antibacterial activity while minimizing lysis of human red blood cells. For E. coli cells that export GFP to the periplasm, we obtain alternating phase-contrast and green fluorescence images with a time resolution of 12 s over 60 min following initiation of copolymer flow. Within seconds, cells shrink and exhibit the same plasmolysis spaces that occur following abrupt external osmotic upshift. The osmoprotection machinery attempts to replenish cytoplasmic water, but recovery is interrupted by permeabilization of the cytoplasmic membrane (CM) to GFP. Evidently, the highly cationic copolymer and its counterions rapidly translocate across the outer membrane without permeabilizing it to GFP. The CM permeabilization event is spatially localized. Cells whose CM has been permeabilized never recover growth. The minimum inhibitory concentration (MIC) for cells lacking the osmolyte importer ProP is 4-fold smaller than for normal cells, suggesting that osmoprotection is an important survival strategy. In addition, at the time of CM permeabilization, we observe evidence of oxidative stress. The MIC under anaerobic conditions is at least 8-fold larger than under aerobic conditions, further implicating oxidative damage as an important bacteriostatic effect. Once the copolymer reaches the periplasm, multiple growth-halting mechanisms proceed in parallel. PMID- 26493223 TI - A new paradigm for rectal cancer: Organ preservation: Introducing the International Watch & Wait Database (IWWD). PMID- 26493222 TI - The Structural Basis of Actin Organization by Vinculin and Metavinculin. AB - Vinculin is an essential adhesion protein that links membrane-bound integrin and cadherin receptors through their intracellular binding partners to filamentous actin, facilitating mechanotransduction. Here we present an 8.5-A-resolution cryo electron microscopy reconstruction and pseudo-atomic model of the vinculin tail (Vt) domain bound to F-actin. Upon actin engagement, the N-terminal "strap" and helix 1 are displaced from the Vt helical bundle to mediate actin bundling. We find that an analogous conformational change also occurs in the H1' helix of the tail domain of metavinculin (MVt) upon actin binding, a muscle-specific splice isoform that suppresses actin bundling by Vt. These data support a model in which metavinculin tunes the actin bundling activity of vinculin in a tissue-specific manner, providing a mechanistic framework for understanding metavinculin mutations associated with hereditary cardiomyopathies. PMID- 26493224 TI - Molecular phylogenetics and the morphology of the Lycopodiaceae subfamily Huperzioideae supports three genera: Huperzia, Phlegmariurus and Phylloglossum. AB - The generic classification of huperzioid Lycopodiaceae was tested using Bayesian inference and Maximum likelihood phylogenetic analyses of DNA sequences from four chloroplast loci for 119 taxa and optimisation of 29 morphological characteristics onto the phylogeny. Consistent with previous studies, the subfamilies Lycopodioideae and Huperzioideae are monophyletic and diagnosable by synapomorphies that correlate with differences in their life-histories. Within the Huperzioideae, the monophyly of the widely adopted genus Huperzia (excl. Phylloglossum) is poorly supported. Three clades of huperzioid Lycopodiaceae were recovered in all analyses of molecular data: Phylloglossum drummondii, Huperzia sensu stricto and Phlegmariurus sensu lato. These clades are strongly supported by morphological characters, including differences in spores, gametophytes, sporophyte macro-morphology, as well as growth habit and life-histories. Our findings indicate that either a one-genus (Huperzia s.l.) or a three-genus (Phylloglossum, Huperzia s.s. and Phlegmariurus s.l.) classification of huperzioid Lycopods are equally supported by molecular evidence, but a two-genus system (Huperzia s.l.+Phylloglossum) is not. We recommend recognising three genera in the huperzioid Lycopodiaceae, as this classification best reflects evolutionary, ecological, and morphological divergence within the lineage. PMID- 26493226 TI - Evolutionary history of PEPC genes in green plants: Implications for the evolution of CAM in orchids. AB - The phosphoenolpyruvate carboxylase (PEPC) gene is the key enzyme in CAM and C4 photosynthesis. A detailed phylogenetic analysis of the PEPC family was performed using sequences from 60 available published plant genomes, the Phalaenopsis equestris genome and RNA-Seq of 15 additional orchid species. The PEPC family consists of three distinct subfamilies, PPC-1, PPC-2, and PPC-3, all of which share a recent common ancestor in chlorophyte algae. The eudicot PPC-1 lineage separated into two clades due to whole genome duplication (WGD). Similarly, the monocot PPC-1 lineage also divided into PPC-1M1 and PPC-1M2 through an ancient duplication event. The monocot CAM- or C4-related PEPC originated from the clade PPC-1M1. WGD may not be the major driver for the performance of CAM function by PEPC, although it increased the number of copies of the PEPC gene. CAM may have evolved early in monocots, as the CAM-related PEPC of orchids originated from the monocot ancient duplication, and the earliest CAM-related PEPC may have evolved immediately after the diversification of monocots, with CAM developing prior to C4. Our results represent the most complete evolutionary history of PEPC genes in green plants to date and particularly elucidate the origin of PEPC in orchids. PMID- 26493227 TI - Phylogenetic placement of enigmatic percomorph families (Teleostei: Percomorphaceae). AB - Percomorphs are a large and diverse group of spiny-finned fishes that have come to be known as the "bush at the top" due to their persistent lack of phylogenetic resolution. Recently, the broader Euteleost Tree of Life project (EToL) inferred a well-supported phylogenetic hypothesis that groups the diversity of percomorphs into nine well-supported series (supraordinal groups): Ophidiaria, Batrachoidaria, Gobiaria, Syngnatharia, Pelagiaria, Anabantaria, Carangaria, Ovalentaria, and Eupercaria. The EToL also provided, for the first time, a monophyletic definition of Perciformes - the largest order of vertebrates. Despite significant progress made in accommodating the diversity of percomorph taxa into major clades, some 62 families (most previously placed in "Perciformes", as traditionally defined) were not examined by the EToL. Here, we provide evidence for the phylogenetic affinities of 10 of those 62 families, seven of which have largely remained enigmatic. This expanded taxonomic sampling also provides further support for the nine EToL supraordinal series. We examined sequences from 21 genes previously used by the EToL and added two fast-evolving mitochondrial markers in an attempt to increase resolution within the rapid percomorph radiations. We restricted the taxonomic sampling to 1229 percomorph species, including expanded sampling from recent studies. Results of maximum likelihood analysis revealed that bathyclupeids (Bathyclupeidae), galjoen fishes (Dichistiidae), kelpfishes (Chironemidae), marblefishes (Aplodactylidae), trumpeters (Latridae), barbeled grunters (Hapalogenyidae), slopefishes (Symphysanodontidae), and picarel porgies (formerly Centracanthidae) are members of the series Eupercaria ("new bush at the top"). The picarel porgies and porgies (Sparidae) are now placed in the same family (Sparidae). Our analyses suggest a close affinity between the orders Spariformes (including Lethrinidae, Nemipteridae and Sparidae) and Lobotiformes (including the tripletails or Lobotidae, the barbeled grunters, and tigerperches or Datnioididae), albeit support for this group is low. None of the newly examined families belong in the order Perciformes, as recently defined. Finally, we confirm results from other recent studies that place the Australasian salmons (Arripidae) within Pelagiaria, and the false trevallies (Lactariidae) close to flatfishes, jacks, and trevallies, within Carangaria. PMID- 26493225 TI - Emergence and evolution of Zfp36l3. AB - In most mammals, the Zfp36 gene family consists of three conserved members, with a fourth member, Zfp36l3, present only in rodents. The ZFP36 proteins regulate post-transcriptional gene expression at the level of mRNA stability in organisms from humans to yeasts, and appear to be expressed in all major groups of eukaryotes. In Mus musculus, Zfp36l3 expression is limited to the placenta and yolk sac, and is important for overall fecundity. We sequenced the Zfp36l3 gene from more than 20 representative species, from members of the Muridae, Cricetidae and Nesomyidae families. Zfp36l3 was not present in Dipodidae, or any families that branched earlier, indicating that this gene is exclusive to the Muroidea superfamily. We provide evidence that Zfp36l3 arose by retrotransposition of an mRNA encoded by a related gene, Zfp36l2 into an ancestral rodent X chromosome. Zfp36l3 has evolved rapidly since its origin, and numerous modifications have developed, including variations in start codon utilization, de novo intron formation by mechanisms including a nested retrotransposition, and the insertion of distinct repetitive regions. One of these repeat regions, a long alanine rich sequence, is responsible for the full-time cytoplasmic localization of Mus musculus ZFP36L3. In contrast, this repeat sequence is lacking in Peromyscus maniculatus ZFP36L3, and this protein contains a novel nuclear export sequence that controls shuttling between the nucleus and cytosol. Zfp36l3 is an example of a recently acquired, rapidly evolving gene, and its various orthologues illustrate several different mechanisms by which new genes emerge and evolve. PMID- 26493228 TI - Advances in Dendrobium molecular research: Applications in genetic variation, identification and breeding. AB - Orchids of the genus Dendrobium are of great economic importance in global horticultural trade and in Asian traditional medicine. For both areas, research yielding solid information on taxonomy, phylogeny, and breeding of this genus are essential. Traditional morphological and cytological characterization are used in combination with molecular results in classification and identification. Markers may be useful when used alone but are not always reliable in identification. The number of species studied and identified by molecular markers is small at present. Conventional breeding methods are time-consuming and laborious. In the past two decades, promising advances have been made in taxonomy, phylogeny and breeding of Dendrobium species due to the intensive use of molecular markers. In this review, we focus on the main molecular techniques used in 121 published studies and discuss their importance and possibilities in speeding up the breeding of new cultivars and hybrids. PMID- 26493229 TI - Cost effectiveness of an antimicrobial stewardship programme. PMID- 26493230 TI - Mediterranean diet is associated with reduced brain shrinkage in older people, study finds. PMID- 26493231 TI - Investigating the contribution of the upper and lower lumbar spine, relative to hip motion, in everyday tasks. AB - BACKGROUND: It is commonplace for clinicians to measure range of motion (ROM) in the assessment of the lumbar spine. Traditional single 'joint' models afford measuring only a limited number of regions along the spine and may, therefore, over-simplify the description of movement. It remains to be determined if additional, useful information can be gleaned by considering the traditional 'lumbar region' as two regions. OBJECTIVE: The aim of this study was to determine whether modelling the lumbar spine as two separate regions (i.e. upper and lower), yields a different understanding of spinal movement relative to hip motion, than a traditional single-joint model. This study is unique in adopting this approach to evaluate a range of everyday tasks. METHOD: Lumbar spine motion was measured both by being considered as a whole region (S1 to T12), and where the lumbar spine was modelled as two regions (the upper (L3-T12) and lower (S1 L3)). RESULTS: A significant difference was evident between the relative contribution from the lower and upper spine across all movements, with the lower lumbar spine consistently contributing on average 63% of the total ROM. A significant difference was also evident between the whole lumbar spine-hip ratio, and the lower lumbar spine-hip ratio, for the movement of lifting only. The lower lumbar spine achieved greater velocity for all tasks, when compared to the upper lumbar spine. CONCLUSION: This study has consistently demonstrated differences in the contribution of the upper and lower spinal regions across a range of everyday tasks; hence, it would appear that greater focus should be given to performing more detailed assessments to fully appreciate spinal movement. PMID- 26493232 TI - Current practice of target temperature management post-cardiac arrest in The Netherlands, a post-TTM trial survey. PMID- 26493233 TI - [Results following the implementation of a clinical pathway in the process of care to elderly patients with osteoporotic hip fracture in a second level hospital]. AB - PURPOSE: To evaluate the efficiency of a clinical pathway in the management of elderly patients with fragility hip fracture in a second level hospital in terms of length of stay time to surgery, morbidity, hospital mortality, and improved functional outcome. MATERIAL AND METHODS: A comparative and prospective study was carried out between two groups of patients with hip fracture aged 75 and older prior to 2010 (n=216), and after a quality improvement intervention in 2013 (n=196). A clinical pathway based on recent scientific evidence was implemented. The degree of compliance with the implemented measures was quantified. RESULTS: The characteristics of the patients in both groups were similar in age, gender, functional status (Barthel Index) and comorbidity (Charlson Index). Median length of stay was reduced by more than 45% in 2013 (16.61 vs. 9.08 days, p=.000). Also, time to surgery decreased 29.4% in the multidisciplinary intervention group (6.23 vs. 4.4 days, p=.000). Patients assigned to the clinical pathway group showed higher medical complications rate (delirium, malnutrition, anaemia and electrolyte disorders), but a lower hospital mortality (5.10 vs. 2.87%, p>.005). The incidence of surgical wound infection (p=.031) and functional efficiency (p=.001) also improved in 2013. An increased number of patients started treatment for osteoporosis (14.80 vs. 76.09%, p=.001) after implementing the clinical pathway. CONCLUSION: The implementation of a clinical pathway in the care process of elderly patients with hip fracture reduced length of stay and time to surgery, without a negative impact on associated clinical and functional outcomes. PMID- 26493234 TI - Muscle stiffness estimation using a system identification technique applied to evoked mechanomyogram during cycling exercise. AB - The aims of this study were to develop a method to extract the evoked mechanomyogram (MMG) during cycling exercise and to clarify muscle stiffness at various cadences, workloads, and power. Ten young healthy male participants were instructed to pedal a cycle ergometer at cadences of 40 and 60 rpm. The loads were 4.9, 9.8, 14.7, and 19.6 N, respectively. One electrical stimulus per two pedal rotations was applied to the vastus lateralis muscle at a knee angle of 80 degrees in the down phase. MMGs were measured using a capacitor microphone, and the MMGs were divided into stimulated and non-stimulated sequences. Each sequence was synchronously averaged. The synchronously averaged non-stimulated MMG was subtracted from the synchronously averaged stimulated MMG to extract an evoked MMG. The evoked MMG system was identified and the poles of the transfer function were calculated. The poles and mass of the vastus lateralis muscle were used to estimate muscle stiffness. Results showed that muscle stiffness was 186-626 N /m and proportional to the workloads and power. In conclusion, our method can be used to assess muscle stiffness proportional to the workload and power. PMID- 26493235 TI - Diagnosis disclosure in dementia: Understanding the experiences of clinicians and patients who have recently given or received a diagnosis. AB - Diagnosis disclosure in dementia is a complex area that results in positive and negative outcomes for both clinicians and patients. Eight clinicians and seven patients were interviewed about their recent experience of either giving or receiving a diagnosis of dementia. Interview transcripts were analysed using interpretative phenomenological analysis. The analysis revealed two higher order themes: Hiding from the Truth and The Social Environment: Help or Hindrance? Both clinicians and patients experience avoidance in relation to the diagnosis. The results support a psychosocial model of dementia and highlight the need for flexible follow up interventions that both recognise patients' use of avoidance and denial as coping strategies and facilitate social support. The social environment can also assist and hamper clinicians' efforts to help their patients. Future research is needed to elucidate optimal conditions for facilitating patients' uptake of positive coping strategies. PMID- 26493236 TI - Qualitative assessment of self-identity in people with advanced dementia. AB - This study aimed to understand the preserved elements of self-identity in persons with moderate to severe dementia attributable to Alzheimer's disease. A semi structured interview was developed to explore the narrative self among residents with dementia in a residential care facility, and residents without dementia in an independent living setting. The interviews were transcribed verbatim from audio recordings and analyzed for common themes, while being sensitive to possible differences between the groups. The participants with dementia showed evidence of self-reference even though losses in explicit memory were evident. The most noticeable difference between the two groups was time frame reference. Nonetheless, all participants showed understanding of their role in relationships and exhibited concrete preferences. Our findings suggest that memory loss and other cognitive deficits associated with moderate to severe dementia do not necessarily lead to a loss of "self." PMID- 26493237 TI - Multistimuli-Responsive Luminescence Switching of Pyrazine Derivative Based Donor Acceptor-Donor Luminophores. AB - Three symmetrical donor-acceptor-donor (D-A-D) luminophores (C1, C2, and C3) with pyrazine derivatives as electron-withdrawing groups have been developed for multistimuli-responsive luminescence switching. For comparison, reference compounds R1 and R2 without the pyrazine moiety have also been synthesized. Intramolecular charge transfer (ICT) interactions can be found for all D-A-D luminophores owing to the electron-withdrawing properties of the two imine nitrogen atoms in the pyrazine ring and the electron-donating properties of the other two amine nitrogen atoms in the two triphenylamine units. Moreover, luminophores C1, C2, and C3 exhibit "on-off-on" luminescence switching properties in mixtures of water/tetrahydrofuran with increasing water content, which is different from the "on-off" switching for typical aggregation-caused quenching (ACQ) materials and "off-on" switching for traditional aggregation-induced emission (AIE) materials. Additionally, upon grinding the pristine samples, luminophores C1, C2, and C3 display bathochromically shifted photoluminescence maxima that can be recovered by either solvent fuming or thermal annealing treatments. The piezofluorochromic (PFC) properties are more pronounced than those for reference compounds R1 and R2, which indicates that D-A molecules have the ability to amplify the PFC effect by tuning the ICT interactions upon tiny structural changes under pressure. Furthermore, the target luminophores demonstrate acid-responsive photoluminescence spectra that can be recovered in either basic or ambient environments. These results suggest that D-A complexes are potential candidates for multistimuli-responsive luminescence switching because their ICT profiles can be facilely tuned with tiny external stimuli. PMID- 26493238 TI - Doppler Characteristics of Cavernosal-Spongiosal Communications in Patients with Erectile Dysfunction. AB - The goal of this work was to characterize the blood flow in cavernosal-spongiosal communications (CSCs) in patients with erectile dysfunction using color Doppler ultrasound. Peak systolic velocity was measured in the CSCs, cavernosal artery and urethral artery in 72 erectile dysfunction patients of the Han ethnic group in southern China. Blood in the CSCs was observed to flow from the cavernosal artery to the urethral artery in all except 5 patients with arteriogenic insufficiency whose blood flow was bidirectional. Peak systolic velocity in erectile dysfunction patients with normal vascular function or veno-occlusive dysfunction was significantly lower in the CSCs than in the cavernosal artery (p < 0.01), but significantly higher than in the urethral artery (p < 0.05). Peak systolic velocities in CSCs in patients with arteriogenic insufficiency were significantly lower than those in the cavernosal (p < 0.01) and urethral (p < 0.01) arteries. The direction of blood flow in the CSCs is determined by the pressure gradient between the cavernosal and urethral arteries. PMID- 26493239 TI - Ultrasound and Biochemical Diagnostic Tools for the Characterization of Vulnerable Carotid Atherosclerotic Plaque. AB - Stroke is a leading cause of morbidity and mortality worldwide, and characterization of vulnerable carotid plaque remains the spearhead of scientific research. Plaque destabilization, the key factor that induces the series of events leading to the clinical symptoms of carotid artery disease, is a consequence of complex mechanical, structural and biochemical processes. Novel imaging and molecular markers have been studied as predictors of disease outcome with promising results. The aim of this review is to present the current state of research on the association between ultrasound-derived echogenicity indices and blood parameters indicative of carotid plaque stability and activity. Bibliographic research revealed that there are limited available data. Among the biomarkers studied, those related to oxidative stress, lipoproteins and diabetes/insulin resistance are associated with echolucent plaques, whereas adipokines are associated with echogenic plaques. Biomarkers of inflammation and coagulation have not exhibited any conclusive relationship with plaque echogenicity, and it is not possible to come to any conclusion regarding calcification-, apoptosis- and neo-angiogenesis-related parameters because of the extremely limited bibliographic data. PMID- 26493240 TI - Prognostic impact of extra-nodal extension in thyroid cancer: A meta-analysis. AB - BACKGROUND AND OBJECTIVES: Lymph node involvement is common in thyroid cancer, but the system of staging does not consider the histological features of lymph node metastases. We conducted a meta-analysis to investigate the prognostic role of extranodal extension (ENE) in thyroid cancer patients. METHODS: We ran PubMed and SCOPUS searches without language restrictions. Prospective studies reporting data on overall mortality, cancer-specific mortality, or disease recurrence including thyroid cancer patients, in which cases with ENE (ENE+) were compared with those with only intranodal disease (ENE-) were eligible. Data were summarized using risk ratios (RR) for number of deaths/recurrences, and hazard ratios (HR) for time-dependent risks related to ENE+ status, adjusted for potential confounders. RESULTS: Of 414 hits, 23 studies were eligible and included. Compared to ENE-, patients who were ENE+ had significantly higher rates of all-cause mortality (studies = 8; RR = 3.25; 95%CI: 1.35-2.64, I(2) = 83%) and recurrence (studies = 17; RR = 2.64, 95%CI: 1.93-3.60, I(2) = 73%). Using HRs adjusted for potential confounders, ENE+ status carried a significantly higher risk of all-cause and cancer-specific mortality and disease recurrence. CONCLUSION: It becomes mandatory to consider ENE in the histopathological examination of surgical samples in thyroid cancer patients, and this factor should be included in future oncological staging systems. PMID- 26493241 TI - Functional, electrophysiological and molecular docking analysis of the modulation of Cav 1.2 channels in rat vascular myocytes by murrayafoline A. AB - BACKGROUND AND PURPOSE: The carbazole alkaloid murrayafoline A (MuA) enhances contractility and the Ca(2+) currents carried by the Cav 1.2 channels [ICa1.2 ] of rat cardiomyocytes. As only few drugs stimulate ICa1.2 , this study was designed to analyse the effects of MuA on vascular Cav 1.2 channels. EXPERIMENTAL APPROACH: Vascular activity was assessed on rat aorta rings mounted in organ baths. Cav 1.2 Ba(2+) current [IBa1.2 ] was recorded in single rat aorta and tail artery myocytes by the patch-clamp technique. Docking at a 3D model of the rat, alpha1c central pore subunit of the Cav 1.2 channel was simulated in silico. KEY RESULTS: In rat aorta rings MuA, at concentrations <=14.2 MUM, increased 30 mM K(+) -induced tone and shifted the concentration-response curve to K(+) to the left. Conversely, at concentrations >14.2 MUM, it relaxed high K(+) depolarized rings and antagonized Bay K 8644-induced contraction. In single myocytes, MuA stimulated IBa1.2 in a concentration-dependent, bell-shaped manner; stimulation was stable, incompletely reversible upon drug washout and accompanied by a leftward shift of the voltage-dependent activation curve. MuA docked at the alpha1C subunit central pore differently from nifedipine and Bay K 8644, although apparently interacting with the same amino acids of the pocket. Neither Bay K 8644-induced stimulation nor nifedipine-induced block of IBa1.2 was modified by MuA. CONCLUSIONS AND IMPLICATIONS: Murrayafoline A is a naturally occurring vasoactive agent able to modulate Cav 1.2 channels and dock at the alpha1C subunit central pore in a manner that differed from that of dihydropyridines. PMID- 26493243 TI - Electronic Health Record Patient Portals in CKD and Hypertension Management: Meaningfully Used? PMID- 26493242 TI - Disparities in Electronic Health Record Patient Portal Use in Nephrology Clinics. AB - BACKGROUND AND OBJECTIVES: Electronic health record (EHR) patient portals allow individuals to access their medical information with the intent of patient empowerment. However, little is known about portal use in nephrology patients. We addressed this gap by characterizing adoption of an EHR portal, assessing secular trends, and examining the association of portal adoption and BP control (<140/90 mmHg). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients seen between January 1, 2010, and December 31, 2012, at any of four university-affiliated nephrology offices who had at least one additional nephrology follow-up visit before June 30, 2013, were included. Sociodemographic characteristics, comorbidities, clinical measurements, and office visits were abstracted from the EHR. Neighborhood median household income was obtained from the American Community Survey 2012. RESULTS: Of 2803 patients, 1098 (39%) accessed the portal. Over 87% of users reviewed laboratory results, 85% reviewed their medical information (e.g., medical history), 85% reviewed or altered appointments, 77% reviewed medications, 65% requested medication refills, and 31% requested medical advice from their renal provider. In adjusted models, older age, African-American race (odds ratio [OR], 0.50; 95% confidence interval [95% CI], 0.39 to 0.64), Medicaid status (OR, 0.53; 95% CI, 0.36 to 0.77), and lower neighborhood median household income were associated with not accessing the portal. Portal adoption increased over time (2011 versus 2010: OR, 1.38 [95% CI, 1.09 to 1.75]; 2012 versus 2010: OR, 1.95 [95% CI, 1.44 to 2.64]). Portal adoption was correlated with BP control in patients with a diagnosis of hypertension; however, in the fully adjusted model this was somewhat attenuated and no longer statistically significant (OR, 1.11; 95% CI, 0.99 to 1.24). CONCLUSION: While portal adoption appears to be increasing, greater attention is needed to understand why vulnerable populations do not access it. Future research should examine barriers to the use of e-health technologies in underserved patients with CKD, interventions to address them, and their potential to improve outcomes. PMID- 26493244 TI - Cervical vertebrae maturation method and craniofacial growth. PMID- 26493245 TI - Percutaneous Transcatheter Assessment of the Left Main Coronary Artery: Current Status and Future Directions. AB - Accurate assessment of the left main coronary artery (LMCA) is critical in determining treatment strategies and delineating revascularization options to improve prognosis. There has been an evolution in invasive techniques that allow detailed assessment of both function and anatomy. As technologies advance, there is an increasing amount of evidence supporting the use of percutaneous coronary intervention for the LMCA. This state-of-the-art paper provides an in-depth exploration of intravascular ultrasound, fractional flow reserve, and optical coherence tomography. A discussion is provided that explores the basis for application of these technologies, the body of evidence for each modality and its use in LMCA assessment, and the potential role in post-PCI optimization in what is a dynamically changing field. PMID- 26493246 TI - A Clinical and Angiographic Scoring System to Predict the Probability of Successful First-Attempt Percutaneous Coronary Intervention in Patients With Total Chronic Coronary Occlusion. AB - OBJECTIVES: This study sought to develop a scoring model predicting percutaneous coronary intervention (PCI) success in chronic total occlusions. BACKGROUND: Coronary chronic total occlusion is the lesion subtype in which angioplasty is most likely to fail. Chronic total occlusion for PCI (CTO-PCI) failure is associated with higher 1-year mortality and major adverse cardiac events compared with successful CTO-PCI. Although several independent predictors of final procedural success have been identified, no study has yet produced a model predicting final procedural outcome. METHODS: Data from 1,657 consecutive patients who underwent a first-attempt CTO-PCI were prospectively collected. The scoring model was developed in a derivation cohort of 1,143 patients (70%) using a multivariable stepwise analysis to identify independent predictors of CTO-PCI failure. The model was then validated in the remaining 514 (30%). RESULTS: The overall procedural success rate was 72.5%. Independent predictors of CTO-PCI failure were identified and included in the clinical and lesion-related score (CL score) as follows: previous coronary artery bypass graft surgery +1.5 (odds ratio [OR]: 2.49, 95% confidence interval [CI]: 1.56 to 3.96), previous myocardial infarction +1 (OR: 1.6, 95% CI: 1.17 to 2.2), severe lesion calcification +2 (OR: 2.72, 95% CI :1.78 to 4.16), longer CTOs +1.5 (>=20 mm OR: 2.04, 95% CI: 1.54 to 2.7), non-left anterior descending coronary artery location +1 (OR: 1.56, 95% CI: 1.14 to 2.15), and blunt stump morphology +1 (OR: 1.39, 95% CI: 1.05 to 1.81). Score values of 0 to 1, >1 and <3, >=3 and <5, and >=5 identified subgroups at high, intermediate, low, and very low probability, respectively, of CTO-PCI success (derivation cohort: 84.9%, 74.9%, 58%, and 31.9%; p < 0,0001; validation cohort: 88.3%, 73.1%, 59.4%, and 46.2%; p < 0.0001). CONCLUSIONS: This clinical and angiographic score predicted the final CTO-PCI procedural outcome of our study population. PMID- 26493247 TI - Do We Need Another Predictive Scoring Tool for Chronic Total Occlusion Percutaneous Coronary Intervention? PMID- 26493248 TI - Stent Thrombosis in Drug-Eluting or Bare-Metal Stents in Patients Receiving Dual Antiplatelet Therapy. AB - OBJECTIVES: This study sought to compare rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE) (composite of death, myocardial infarction, or stroke) after coronary stenting with drug-eluting stents (DES) versus bare-metal stents (BMS) in patients who participated in the DAPT (Dual Antiplatelet Therapy) study, an international multicenter randomized trial comparing 30 versus 12 months of dual antiplatelet therapy in subjects undergoing coronary stenting with either DES or BMS. BACKGROUND: Despite antirestenotic efficacy of coronary DES compared with BMS, the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Many clinicians perceive BMS to be associated with fewer adverse ischemic events and to require shorter-duration dual antiplatelet therapy than DES. METHODS: Prospective propensity-matched analysis of subjects enrolled into a randomized trial of dual antiplatelet therapy duration was performed. DES- and BMS-treated subjects were propensity-score matched in a many-to-one fashion. The study design was observational for all subjects 0 to 12 months following stenting. A subset of eligible subjects without major ischemic or bleeding events were randomized at 12 months to continued thienopyridine versus placebo; all subjects were followed through 33 months. RESULTS: Among 10,026 propensity-matched subjects, DES-treated subjects (n = 8,308) had a lower rate of stent thrombosis through 33 months compared with BMS-treated subjects (n = 1,718, 1.7% vs. 2.6%; weighted risk difference -1.1%, p = 0.01) and a noninferior rate of MACCE (11.4% vs. 13.2%, respectively, weighted risk difference -1.8%, p = 0.053, noninferiority p < 0.001). CONCLUSIONS: DES-treated subjects have long-term rates of stent thrombosis that are lower than BMS-treated subjects. (The Dual Antiplatelet Therapy Study [DAPT study]; NCT00977938). PMID- 26493249 TI - Prasugrel in Clopidogrel Nonresponders: A Way to Improve Secondary Prevention in Patients After Percutaneous Coronary Intervention? PMID- 26493250 TI - Impact of Glycoprotein IIb/IIIa Inhibition in Contemporary Percutaneous Coronary Intervention for Acute Coronary Syndromes: Insights From the National Cardiovascular Data Registry. AB - OBJECTIVES: This study investigates the effects of glycoprotein IIb/IIIa inhibitors (GPIs) on outcomes after percutaneous coronary intervention (PCI). BACKGROUND: Ischemic complications are reduced after PCI when a GPI is added to heparin. However, there are limited data on the safety and efficacy in contemporary PCI. METHODS: We used the National Cardiovascular Data Registry CathPCI Registry data to assess the association between GPI use and PCI outcomes for acute coronary syndrome between July 2009 and September 2011. The primary outcome was all-cause in-hospital mortality. The secondary outcome was major bleeding. To adjust for potential bias, we used multivariable logistic regression, propensity-matched (PM) analysis, and instrumental variable analysis (IVA). RESULTS: There were 970,865 patients included; 326,283 (33.6%) received a GPI. Unadjusted mortality and major bleeding were more common with a GPI (2.4% vs. 1.4% and 3.7% vs. 1.5%, respectively; p < 0.001 for both). In contrast, GPI use was associated with lower mortality on adjusted analyses; relative risks range from 0.72 (95% confidence interval [CI]: 0.50 to 0.97) with IVA to 0.90 (95% CI: 0.86 to 0.95) with PM. The association of GPI use with bleeding remained in adjusted analyses (multivariable relative risk: 1.93, 95% CI: 1.83 to 2.04; PM relative risk: 1.83, 95% CI: 1.74 to 1.92; and IVA relative risk: 1.53, 95% CI: 1.27 to 2.13). Subgroup analysis revealed enhanced risk reduction with ST-segment elevation myocardial infarction, high predicted mortality, and heparin-based anticoagulation. CONCLUSIONS: In unselected acute coronary syndrome patients undergoing PCI, GPI use was associated with reduced in-hospital mortality and increased bleeding. In the modern era of PCI, there may still be a role for the judicious use of GPIs. PMID- 26493251 TI - What Role for Glycoprotein IIb/IIIa Inhibition in Contemporary Coronary Intervention? PMID- 26493252 TI - Prevention of Acute Kidney Injury With the RenalGuard System in Patients Undergoing Transcatheter Aortic Valve Replacement: The PROTECT-TAVI Trial (PROphylactic effecT of furosEmide-induCed diuresis with matched isotonic intravenous hydraTion in Transcatheter Aortic Valve Implantation). PMID- 26493253 TI - Paclitaxel-Coated Balloon in Infrapopliteal Arteries: 12-Month Results From the BIOLUX P-II Randomized Trial (BIOTRONIK'S-First in Man study of the Passeo-18 LUX drug releasing PTA Balloon Catheter vs. the uncoated Passeo-18 PTA balloon catheter in subjects requiring revascularization of infrapopliteal arteries). AB - OBJECTIVES: The aim of BIOLUX P-II (BIOTRONIK'S-First in Man study of the Passeo 18 LUX drug releasing PTA Balloon Catheter vs. the uncoated Passeo-18 PTA balloon catheter in subjects requiring revascularization of infrapopliteal arteries) trial was to compare the safety and efficacy of a novel paclitaxel-coated drug eluting balloon (DEB) versus an uncoated balloon (percutaneous transluminal angioplasty [PTA]) in de novo or native restenotic lesions of the infrapopliteal arteries in patients with claudication and critical limb ischemia. BACKGROUND: DEB have shown promising results in femoropopliteal lesions, but data for infrapopliteal lesions are scarce. METHODS: In this prospective, multicenter, randomized first-in-man study, 72 patients were randomized 1:1 to either a Passeo 18 Lux DEB (Biotronik AG, Buelach, Switzerland) (n = 36) or Passeo-18 PTA (n = 36). Follow-up assessments were scheduled at 1, 6, and 12 months, with angiographic assessment at 6 months. Adverse events were adjudicated by an independent clinical events committee, and angiographic parameters were assessed by an independent core laboratory. RESULTS: The primary safety endpoint (a composite of all-cause mortality, target extremity major amputation, target lesion thrombosis, and target vessel revascularization at 30 days) was 0% in the DEB group versus 8.3% in the PTA group (p = 0.239). The primary performance endpoint (patency loss at 6 months) was 17.1% in the DEB group versus 26.1% in the PTA group (p = 0.298), and major amputations of the target extremity occurred in 3.3% versus 5.6% of the patients at 12 months, respectively. CONCLUSIONS: The Passeo-18 Lux DEB has been proven to be safe and effective in infrapopliteal lesions with comparable outcomes to PTA. PMID- 26493254 TI - Missing the Forest for the Trees?: Drug-Eluting Balloon Treatment for Infrapopliteal Disease. PMID- 26493255 TI - Reply: Sympathetic and Autonomic Effects of Renal Denervation on Atrial Remodeling and Atrial Arrhythmias. PMID- 26493256 TI - Sympathetic and Autonomic Effects of Renal Denervation on Atrial Remodeling and Atrial Arrhythmias. PMID- 26493257 TI - Post-Percutaneous Coronary Intervention Angina: A New Performance Measure? PMID- 26493258 TI - Reply: Post-Percutaneous Coronary Intervention Angina: A New Performance Measure? PMID- 26493259 TI - Endovascular Bariatrics: First in Humans Study of Gastric Artery Embolization for Weight Loss. PMID- 26493260 TI - How Did Andreas Get Here? PMID- 26493261 TI - Right Ventricular Free Wall Hematoma: Contemporary Multimodal Imaging. PMID- 26493262 TI - Severe Generalized Resistant Spasm of the Right Coronary Artery Causing Hemodynamic Collapse After Stenting. PMID- 26493263 TI - "Protruding Myocardium" as a Target for Percutaneous Transluminal Septal Myocardial Ablation in a Case of Hypertrophic Obstructive Cardiomyopathy. PMID- 26493264 TI - Thiazolidinediones and Parkinson Disease: A Cohort Study. AB - Thiazolidinediones, a class of medications indicated for the treatment of type 2 diabetes mellitus, reduce inflammation and have been shown to provide a therapeutic benefit in animal models of Parkinson disease. We examined the association between treatment with thiazolidinediones and the onset of Parkinson disease in older individuals. We performed a cohort study of 29,397 Medicare patients enrolled in state pharmaceutical benefits programs who initiated treatment with thiazolidinediones or sulfonylureas during the years 1997 through 2005 and had no prior diagnosis of Parkinson disease. New users of thiazolidinediones were propensity score matched to new users of sulfonylureas and followed to determine whether they were diagnosed with Parkinson disease. We used Cox proportional hazards models to compare time to diagnosis of Parkinson disease in the propensity score-matched populations. To assess the association with duration of use, we performed several analyses that required longer continuous use of medications. In the primary analysis, thiazolidinedione users had a hazard ratio for a diagnosis of Parkinson disease of 1.09 (95% confidence interval: 0.71, 1.66) when compared with sulfonylurea users. Increasing the duration-of-use requirements to 10 months did not substantially change the association; the hazard ratios ranged from 1.00 (95% confidence interval: 0.49, 2.05) to 1.17 (95% confidence interval: 0.60, 2.25). Thiazolidinedione use was not associated with a longer time to diagnosis of Parkinson disease than was sulfonylurea use, regardless of duration of exposure. PMID- 26493266 TI - Epidemiology: Then and Now. AB - Twenty-five years ago, on the 75th anniversary of the Johns Hopkins Bloomberg School of Public Health, I noted that epidemiologic research was moving away from the traditional approaches used to investigate "epidemics" and their close relationship with preventive medicine. Twenty-five years later, the role of epidemiology as an important contribution to human population research, preventive medicine, and public health is under substantial pressure because of the emphasis on "big data," phenomenology, and personalized medical therapies. Epidemiology is the study of epidemics. The primary role of epidemiology is to identify the epidemics and parameters of interest of host, agent, and environment and to generate and test hypotheses in search of causal pathways. Almost all diseases have a specific distribution in relation to time, place, and person and specific "causes" with high effect sizes. Epidemiology then uses such information to develop interventions and test (through clinical trials and natural experiments) their efficacy and effectiveness. Epidemiology is dependent on new technologies to evaluate improved measurements of host (genomics), epigenetics, identification of agents (metabolomics, proteomics), new technology to evaluate both physical and social environment, and modern methods of data collection. Epidemiology does poorly in studying anything other than epidemics and collections of numerators and denominators without specific hypotheses even with improved statistical methodologies. PMID- 26493265 TI - Smoking and Risk of Breast Cancer in a Racially/Ethnically Diverse Population of Mainly Women Who Do Not Drink Alcohol: The MEC Study. AB - We prospectively examined the association between smoking and the risk of breast cancer in a racially/ethnically diverse population comprising mainly women who did not drink alcohol. From 1993 to 2010, we followed 83,300 women who were enrolled in the Multiethnic Cohort Study at 45-75 years of age. We identified cancer cases via linkage to the Surveillance, Epidemiology, and End Results Program cancer registries that covered the states of Hawaii and California through December 2010. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals while adjusting for confounders that were decided a priori. During a mean follow-up of 15 years, 4,484 women developed invasive breast cancer. Compared with parous never smokers, women who had smoked for more than 20 pack-years and initiated smoking more than 5 years before their first childbirth had an overall risk of breast cancer that was 35% higher (hazard ratio = 1.35, 95% confidence interval: 1.13, 1.63). Among women who did not drink alcohol, the risk was 40% higher (hazard ratio = 1.40, 95% confidence interval: 1.08, 1.81). This higher risk did not significantly differ among racial/ethnic groups (P(interaction) = 0.82). We found that various measures of smoking exposure were associated with a higher risk of breast cancer, especially smoking initiated many years before first childbirth, and that risk did not differ by alcohol consumption (yes vs. no) or racial/ethnic group. PMID- 26493267 TI - Randomized phase II study of paclitaxel/carboplatin intercalated with gefitinib compared to paclitaxel/carboplatin alone for chemotherapy-naive non-small cell lung cancer in a clinically selected population excluding patients with non smoking adenocarcinoma or mutated EGFR. AB - BACKGROUND: Considering cell cycle dependent cytotoxicity, intercalation of chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) may be a treatment option in non-small cell lung cancer (NSCLC). This randomized phase 2 study compared the efficacy of paclitaxel and carboplatin (PC) intercalated with gefitinib (G) versus PC alone in a selected, chemotherapy naive population of advanced NSCLC patients with a history of smoking or wild type EGFR. METHODS: Eligible patients were chemotherapy-naive advanced NSCLC patients with Eastern Cooperative Oncology Group performance status of 0-2. Non smoking patients with adenocarcinoma or patients with activating EGFR mutation were excluded because they could benefit from gefitinib alone. Eligible patients were randomized to one of the following treatment arms: PCG, P 175 mg/m(2), and C AUC 5 administered intravenously on day 1 intercalated with G 250 mg orally on days 2 through 15 every 3 weeks for four cycles followed by G 250 mg orally until progressive disease; or PC, same dosing schedule for four cycles only. The primary endpoint was the objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity profile. RESULTS: A total of 90 patients participated in the study. The ORRs were 41.9 % (95 % confidence interval (CI) 27.0-57.9 %) for the PCG arm and 39.5 % (95 % CI 25.0-55.6 %) for the PC arm (P = 0.826). No differences in PFS (4.1 vs. 4.1 months, P = 0.781) or OS (9.3 vs. 10.5 months, P = 0.827) were observed between the PCG and PC arms. Safety analyses showed a similar incidence of drug-related grade 3/4 toxicity. Rash and pruritus were more frequent in the PCG than in the PC arm. CONCLUSIONS: PCG did not improve ORR, PFS, and OS compared to PC chemotherapy alone for NSCLC in a clinically selected population excluding non-smoking adenocarcinoma or mutated EGFR. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov ( NCT01196234 ). Registration date is 08/09/2010. PMID- 26493268 TI - Gender differences in the use of psychiatric outpatient specialist services in Tromso, Norway are dependent on age: a population-based cross-sectional survey. AB - BACKGROUND: Overall, men are less likely than women to seek health care services for mental health problems, but differences between genders in higher age groups are equivocal. The aim of the current study was to investigate the association between gender and the use of psychiatric outpatient specialist services in Norway, both in a general population and in a subpopulation with self-reported anxiety and/or depression. METHODS: Using questionnaires from 12,982 participants (30-87 years) in the cross-sectional sixth Tromso Study (2007-8) we estimated proportions reporting anxiety/depression, and proportions using psychiatric outpatient specialist services in a year. By logistic regressions we studied the association between gender and the use of psychiatric outpatient specialist services. Analyses were adjusted for age, marital status, income, education, self reported degree of anxiety/depression, and GP visits last year. Analyses were also performed for genders separately. RESULTS: Anxiety/depression was reported by 21.5 % of women and 12.3 % of men in the general population. Visits to psychiatric outpatient services during one year were reported by 4.6 % of women and 3.3 % of men. The general population's probability of a visit was significantly lower among men compared to women in ages 30-49 years (odds ratio [OR] 0.58, confidence interval [CI] 0.39-0.84, p-value [p] = 0.004), whereas men used services slightly more than women in ages 50 years and over (OR 1.36, CI 1.00-1.83, p = 0.047). Among those with anxiety/depression 13.5 % of women and 10.5 % of men visited psychiatric outpatient services in a year. We found no statistically significant gender differences in the use of services in this subgroup. Other factors associated with services use in women with anxiety/depression were higher education, more severe anxiety/depression, and GP visits the last year, whereas in men only a more severe anxiety/depression was associated with psychiatric outpatient visits. Overall, the use of services decreased with higher age. CONCLUSIONS: Most people with self-reported anxiety/depression did not visit specialist outpatient clinics. This applies in particular to men aged 30-49 years, older individuals, and individuals with lower education. Gender differences in the use of services in the general population were dependent on age, whereas in the subgroup with anxiety/depression gender differences were not confirmed. PMID- 26493270 TI - The imaging findings of infratentorial primitive neuroectodermal tumour: A case report. AB - Central primitive neuroectodermal tumour (cPNET), a rare malignant neoplasm of embryonal origin, often occurs in children younger than 15 years. This is the first case report of the imaging findings of an infratentorial cPNET to be reported in a patient. Here, is reported the case of a 6-year-old boy presenting with symptoms of diplopia for 14 days. Magnetic resonance imaging revealed a solid mass in the fourth ventricle. The postoperative pathological diagnosis was cPNET. To conclude, whenever a child is diagnosed to have an infratentorial solid tumour in the fourth ventricle, cPNET should always be considered despite its rarity. PMID- 26493269 TI - Differences in the variability of cerebral proton magnetic resonance spectroscopy (1H-MRS) measurements within three HIV-infected cohorts. AB - INTRODUCTION: Cerebral functional impairment remains prevalent in effectively treated HIV-infected subjects. As the results of formal cognitive testing are highly variable, surrogate markers to accurately measure cerebral function parameters are needed. Such markers include measurement of cerebral metabolite ratios (CMR) using proton magnetic resonance spectroscopy (1H-MRS). However, data on the inter-subject variability of CMR are sparse. Our aim was to assess inter subject variability in CMRs within three different HIV-infected cohorts. METHODS: Cerebral 1H-MRS was performed using a Phillips AchievaTM 1.5 Tesla magnetic resonance scanner in HIV-infected subjects as follows: 12 subjects before (group 1) and after intensification of antiretroviral therapy with maraviroc (group 2) and 13 subjects with acute viral hepatitis C (HCV) co-infection (group 3). The coefficients of variation (CV) for CMRs in each group were determined and compared using non-parametric tests to determine whether the inter-subject variability differed significantly. All baseline characteristics between the groups were similar. RESULTS: Overall CVs for all CMRs in groups 1, 2 and 3 were 32.3%, 33.2% and 23.4%, respectively (group 1 vs. 2, p=0.863; group 1 vs. 3, p=0.076). On testing for differences in variability between individual CMRs, two metabolites in the right basal ganglia (RBG) had statistically significantly different CVs when comparing group 1 with group 3: N-acetyl aspartate/creatine (NAA/Cr), p=0.029 and myo-Inositol/creatine (mI/Cr), p=0.016. CONCLUSION: The variability of 1H MRS-measurable CMRs in HIV-infected individuals was lower in those with acute HCV co-infection (group 3).We can conclude that the use of these CMRs in 1H MRS imaging in patients with HIV/acute HCV co-infection is more reliable to assess cerebral function than in patients with HIV infection alone. This has implications for future sample size estimations. PMID- 26493271 TI - A fatal case of healthcare associated Crimean-Congo haemorrhagic fever with severe disease and multi-organ failure. PMID- 26493272 TI - Acute and sub-lethal exposure to copper oxide nanoparticles causes oxidative stress and teratogenicity in zebrafish embryos. AB - Nano-copper oxides are a versatile inorganic material. As a result of their versatility, the immense applications and usage end up in the environment causing a concern for the lifespan of various beings. The ambiguities surround globally on the toxic effects of copper oxide nanoparticles (CuO-NPs). Hence, the present study endeavored to study the sub-lethal acute exposure effects on the developing zebrafish embryos. The 48 hpf LC50 value was about 64 ppm. Therefore, we have chosen the sub-lethal dose of 40 and 60 ppm for the study. Accumulation of CuO NPs was evidenced from the SEM-EDS and AAS analyzes. The alterations in the AChE and Na(+)/K(+)-ATPase activities disrupted the development process. An increment in the levels of oxidants with a concomitant decrease in the antioxidant enzymes confirmed the induction of oxidative stress. Oxidative stress triggered apoptosis in the exposed embryos. Developmental anomalies were observed with CuO-NPs exposure in addition to oxidative stress in the developing embryos. Decreased heart rate and hatching delay hindered the normal developmental processes. Our work has offered valuable data on the connection between oxidative stress and teratogenicity leading to lethality caused by CuO-NPs. A further molecular mechanism unraveling the uncharted connection between oxidative stress and teratogenicity will aid in the safe use of CuO-NPs. PMID- 26493273 TI - Changes in different parameters, lymphocyte proliferation and hematopoietic progenitor colony formation in EAE mice treated with myelin oligodendrocyte glycoprotein. AB - Myelin oligodendrocyte glycoprotein (MOG) is an antigen of the myelin sheath, which may trigger immune cell responses and the production of auto-antibodies in multiple sclerosis (MS). In this study, we used MOG(35-55) -induced experimental autoimmune encephalomyelitis (EAE), a model of human MS, to assess the production of catalytically active immunoglobulin G (IgG) antibodies or abzymes which have been shown to be present in sera of patients with several autoimmune diseases. Here, we show that IgGs from the sera of control C57BL/6 mice are catalytically inactive. During development of EAE, a specific reorganization of the immune system of mice occurred leading to a condition which was associated with the generation of catalytically active IgGs hydrolysing DNA, myelin basic protein (MBP) and MOG which was associated with increased proteinuria, changes in differentiation of mice bone marrow hematopoietic stem cells (HSCs) and an increase in proliferation of lymphocytes in bone marrow, spleen and thymus as well as a significant suppression of cell apoptosis in these organs. The strongest alterations were found in the early disease phase (18-24 days after immunization) and were less pronounced in later EAE stages (40 days after EAE induction). We conclude that a significant increase in DNase and proteolytic activities of antibodies may be considered the earliest statistically significant marker of MOG-induced EAE in mice. The possible differences in immune system reorganizations during preclinical phases of the disease, acute and late EAE, leading to production of different auto-antibodies and abzymes as well other changes are discussed. PMID- 26493274 TI - A novel prediction model for human papillomavirus-associated oropharyngeal squamous cell carcinoma using p16 and subcellular beta-catenin expression. AB - BACKGROUND: p16 overexpression is a highly sensitive yet moderately specific biomarker for predicting human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Nuclear beta-catenin translocation has been linked to HPV-positive OPSCC. However, whether the strategy of combining beta catenin with p16 can better predict HPV-associated OPSCC remains unknown. METHODS: We evaluated the expression of p16 and beta-catenin (nuclear and membrane) by immunohistochemistry staining in 101 OPSCC tissues and HPV status by HPV DNA in situ hybridization. Logistic regression models were used to evaluate single or multiple biomarkers for HPV prediction. The prediction power, sensitivity, and specificity were determined by receiver operating characteristic (ROC) analyses. RESULTS: Our data showed that upon univariate analysis, p16 and nuclear beta-catenin were positively correlated with HPV status, while membrane beta-catenin was inversely correlated with HPV status (P < 0.01). p16 showed the highest HPV predictive power, with area under the curve (AUC) of 0.9074 compared to 0.6762 for nuclear beta-catenin and 0.7635 for membrane beta-catenin, respectively, indicating differential accuracies for HPV prediction. Multivariable analysis showed that p16 was significantly correlated with HPV, while nuclear and membrane beta-catenin showed marginal significance. The three biomarker model was similarly sensitive (98.9% vs. 100%) but more specific (88.9% vs. 81%) than p16 alone, which also showed a good predictive value for overall (P = 0.0002) survival and disease-free (P = 0.0158) survival. CONCLUSION: Our study suggests a novel model of combining p16 and subcellular beta-catenin for prediction of HPV-associatred OPSCC, and this finding deserves further validation. PMID- 26493276 TI - Cytologic findings in stratified mucin-producing intraepithelial lesion of the cervix: A report of 34 cases. AB - BACKGROUND: Stratified mucin-producing intraepithelial lesion (SMILE) is an uncommon variant of in situ carcinoma of the cervix. This study aimed to identify the cytologic features of SMILE since these have not been well documented previously. METHODS: The study group comprised 34 consecutive cases of SMILE encountered at a single institution in which a corresponding Papanicolaou smear, taken up to 12 months before histologic diagnosis, was available for review. The presence of associated cervical neoplastic lesions including cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS), and invasive carcinoma was recorded. The linear extent and distribution of the SMILEs was also noted. RESULTS: Most Pap smears had been reported to show possible or definite high-grade CIN although 3 cases reported the presence of a high-grade glandular abnormality. No case had a prospective cytologic diagnosis of SMILE. Histology revealed concurrent CIN and/or AIS in all cases, and 1 specimen (3%) showed invasive adenocarcinoma. Following smear review, 23 of the 31 cases that included endocervical material showed recurrent cytologic features that appeared consistent with SMILE. These included three dimensional cell clusters with nuclear stratification and crowding, mild nuclear atypia, cytoplasmic vacuoles, mitotic figures, and apoptosis. CONCLUSION: SMILE is almost always associated with additional HPV-related neoplastic lesions although only one patient (3%) had invasive carcinoma, a lower rate than recorded in other studies. Consistent cytologic features associated with SMILE were identified but these were relatively subtle. However, increased awareness of these features may permit prospective diagnosis and this could influence patient management. PMID- 26493277 TI - How should we address the diagnosis of overactive bladder in women? AB - OBJECTIVE: Determine the degree of completion, agreement and diagnostic performance of various instruments for assessing the presence and intensity of urgency and other symptoms of idiopathic overactive bladder (OAB) and determine which is the best diagnostic combination. MATERIAL AND METHODS: Observational, noninterventional, cross-sectional multicentre study on 247 women aged 18 years or older, with a clinical diagnosis of OAB, evaluated in 55 functional urology and urodynamic units. The women completed the Patient Perception of Intensity of Urgency Scale questionnaire, an independent bladder control self-assessment questionnaire (B-SAQ), the Overactive Bladder Questionnaire Short-Form and a 3 day voiding diary (VD3d), and they underwent a urodynamic study (UDS). The degree of completion and agreement among the instruments was assessed using the Kappa index (95% CI) and Cramer's V. The diagnostic performance of each tool and their combination was studied using absolute frequencies of positive cases for each OAB symptom. RESULTS: The patients mean age was 57.66 years (SD, 13.43). There was a high degree of completion (>85%). The agreement among the instruments was poor or moderate, and there was no agreement with the UDS. The best combination of tools for the diagnosis of OAB in women was the B-SAQ and VD3d. CONCLUSIONS: The degree of completion of all instruments was high, the agreement between them was poor moderate and not significant for the UDS. The instruments that had the best diagnostic performance for assessing urgency and other OAB symptoms, providing data on their severity and discomfort, were the B-SAQ and the VD3d. PMID- 26493278 TI - Correlation of Left Atrial Strain and Doppler Measurements with Invasive Measurement of Left Ventricular End-Diastolic Pressure in Patients Stratified for Different Values of Ejection Fraction. AB - BACKGROUND: This study aimed at exploring the correlation of left atrial longitudinal function by speckle tracking echocardiography (left atrial strain) and Doppler measurements (E/E' ratio) with direct measurements of left ventricular (LV) end-diastolic pressure (LVEDP) in patients stratified for different values of ejection fraction. METHODS: The study population was 80 stable patients with sinus rhythm undergoing cardiac catheterization. This population was selected in order to have four groups of 20 patients each with different LV ejection fraction (>55%, 45-54%, 30-44%, and <30%). LVEDP was obtained during cardiac catheterization; peak atrial longitudinal strain (PALS) and mean E/E' ratio were measured in all subjects. RESULTS: Similar correlations with LVEDP of global PALS and E/E' ratio were recorded in patients with preserved (r = -0.79 vs. r = 0.72, respectively; P < 0.0001 for both) or mildly reduced ejection fraction (r = -0.75 vs. r = 0.73, respectively; P < 0.0001 for both). A closer correlation of global PALS compared to E/E' ratio was evident in patients with moderate (r = -0.78 P < 0.0001; vs. r = 0.47 P = 0.01, respectively) and severe reduction (r = -0.74 P < 0.0001; vs. r = 0.19 ns, respectively) of LV ejection fraction. In multivariate analysis of all measurements, global PALS emerged as a determinant of the LVEDP, independent on other confounding factors and, with the cutoff value of 18.0% presented the best diagnostic accuracy to predict a LVDP above 12 mmHg (AUC 0.87). CONCLUSIONS: In patients with preserved or mildly reduced LV ejection fraction, global PALS and mean E/E' ratio presented good correlations with LVEDP. In patients with moderate or severe reduction of ejection fraction, E/E' ratio correlated poorly with invasively obtained LV filling pressures. Global PALS provided an overall better estimation of LV filling pressures. PMID- 26493275 TI - Atypically rightward cerebral asymmetry in male adults with autism stratifies individuals with and without language delay. AB - In humans, both language and fine motor skills are associated with left hemisphere specialization, whereas visuospatial skills are associated with right hemisphere specialization. Individuals with autism spectrum conditions (ASC) show a profile of deficits and strengths that involves these lateralized cognitive functions. Here we test the hypothesis that regions implicated in these functions are atypically rightward lateralized in individuals with ASC and, that such atypicality is associated with functional performance. Participants included 67 male, right-handed adults with ASC and 69 age- and IQ-matched neurotypical males. We assessed group differences in structural asymmetries in cortical regions of interest with voxel-based analysis of grey matter volumes, followed by correlational analyses with measures of language, motor and visuospatial skills. We found stronger rightward lateralization within the inferior parietal lobule and reduced leftward lateralization extending along the auditory cortex comprising the planum temporale, Heschl's gyrus, posterior supramarginal gyrus, and parietal operculum, which was more pronounced in ASC individuals with delayed language onset compared to those without. Planned correlational analyses showed that for individuals with ASC, reduced leftward asymmetry in the auditory region was associated with more childhood social reciprocity difficulties. We conclude that atypical cerebral structural asymmetry is a potential candidate neurophenotype of ASC. PMID- 26493279 TI - Quasi-steady-state air plasma channel produced by a femtosecond laser pulse sequence. AB - A long air plasma channel can be formed by filamentation of intense femtosecond laser pulses. However, the lifetime of the plasma channel produced by a single femtosecond laser pulse is too short (only a few nanoseconds) for many potential applications based on the conductivity of the plasma channel. Therefore, prolonging the lifetime of the plasma channel is one of the key challenges in the research of femtosecond laser filamentation. In this study, a unique femtosecond laser source was developed to produce a high-quality femtosecond laser pulse sequence with an interval of 2.9 ns and a uniformly distributed single-pulse energy. The metre scale quasi-steady-state plasma channel with a 60-80 ns lifetime was formed by such pulse sequences in air. The simulation study for filamentation of dual femtosecond pulses indicated that the plasma channel left by the previous pulse was weakly affected the filamentation of the next pulse in sequence under our experimental conditions. PMID- 26493280 TI - Cognitive and affective functions in Alzheimer's disease patients with metabolic syndrome. AB - BACKGROUND AND PURPOSE: The influence of metabolic syndrome (MetS) on cognitive and affective functions in patients with Alzheimer's disease (AD) was examined. METHODS: A total of 570 AD patients were divided into two subgroups depending on waist circumference (WC) (normal versus achieving Japanese diagnostic criteria of MetS). Afterwards, the AD control subgroup was defined as those normal WC patients with no vascular risk factors (VRFs). The AD with MetS (AD-MetS) subgroup was defined as the MetS WC group who had two or more VRFs to qualify as having MetS. Cognitive and affective functions, insulin resistance, vascular endothelial function and white matter changes between AD-MetS and AD controls were compared. RESULTS: Scores on the Mini-Mental State Examination, Hasegawa Dementia Score-Revised, Frontal Assessment Battery and Montreal Cognitive Assessment were worse in the AD-MetS group than in AD controls, but the difference was not significant. Some analyses were conducted twice, once including all patients and once including only late-elderly patients. Scores on the Geriatric Depression Scale were found to be significantly higher for AD-MetS than for AD controls (all ages, late-elderly), as were those for apathy (late elderly). Furthermore, both the homeostasis model assessment of insulin resistance and reactive hyperemia index scores were significantly worse in AD MetS than in AD controls, whilst white matter changes showed a tendency to be worse. CONCLUSIONS: Greater cognitive and affective decline occurs in patients with AD-MetS than in those without. Further, insulin resistance and vascular endothelial dysfunction are strongly correlated with AD-MetS before pathological white matter changes can be observed. PMID- 26493281 TI - Female sexual dysfunction in multiple sclerosis: Results of a survey among Dutch urologists and patients. AB - AIMS: The objective of this study was to determine the prevalence of female sexual dysfunction (FSD) in patients with Multiple Sclerosis (MS) in one of the leading MS centers in the Netherlands. Furthermore, we evaluated the practice patterns of members of the Dutch Urological Association (DUA) with respect to FSD. METHODS: A self-administered Web-based questionnaire for physicians was mailed to all 467 members of the DUA. The questions covered different topics in female sexuality. For the patient survey the Female Sexual Function Index (FSFI) was used. RESULTS: The response rate of the physicians survey was 42% (n = 194). Sixty-one percent of the responders reported to ask their female patients about their sexual function. Thirty-nine percent of the physicians did not ask their patients about sexuality. The majority indicated that they lacked knowledge on FSD or found discussing sexuality not relevant for their practice. The response rate of the patient survey was 28% (n = 85). According to the FSFI questionnaire 32% of the sexually active MS patients experienced FSD. Women with FSD scored low on all subdomains of the FSFI questionnaire. In particular, desire, arousal, lubrication, and the ability to achieve orgasm were affected. CONCLUSIONS: The prevalence of FSD in MS patients in our center is about 32%. Overall, many members of the DUA do not screen for sexual dysfunction in female patients because of lack of knowledge on FSD. Better and more structured education of urologists and residents in urology on FSD in The Netherlands is urgently needed. Neurourol. Urodynam. 36:116-120, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26493282 TI - Microsecond-sustained lasing from colloidal quantum dot solids. AB - Colloidal quantum dots have grown in interest as materials for light amplification and lasing in view of their bright photoluminescence, convenient solution processing and size-controlled spectral tunability. To date, lasing in colloidal quantum dot solids has been limited to the nanosecond temporal regime, curtailing their application in systems that require more sustained emission. Here we find that the chief cause of nanosecond-only operation has been thermal runaway: the combination of rapid heat injection from the pump source, poor heat removal and a highly temperature-dependent threshold. We show microsecond sustained lasing, achieved by placing ultra-compact colloidal quantum dot films on a thermally conductive substrate, the combination of which minimizes heat accumulation. Specifically, we employ inorganic-halide-capped quantum dots that exhibit high modal gain (1,200 cm(-1)) and an ultralow amplified spontaneous emission threshold (average peak power of ~50 kW cm(-2)) and rely on an optical structure that dissipates heat while offering minimal modal loss. PMID- 26493283 TI - A Multifunctional Subphthalocyanine Nanosphere for Targeting, Labeling, and Killing of Antibiotic-Resistant Bacteria. AB - Developing a material that can combat antibiotic-resistant bacteria, a major global health threat, is an urgent requirement. To tackle this challenge, we synthesized a multifunctional subphthalocyanine (SubPc) polymer nanosphere that has the ability to target, label, and photoinactivate antibiotic-resistant bacteria in a single treatment with more than 99 % efficiency, even with a dose as low as 4.2 J cm(-2) and a loading concentration of 10 nM. The positively charged nanosphere shell composed of covalently linked SubPc units can increase the local concentration of photosensitizers at therapeutic sites. The nanosphere shows superior performance compared to corresponding monomers presumably because of their enhanced water dispersibility, higher efficiency of singlet-oxygen generation, and phototoxicity. In addition, this material is useful in fluorescence labeling of living cells and shows promise in photoacoustic imaging of bacteria in vivo. PMID- 26493284 TI - Mutations in genes encoding PI3K-AKT and MAPK signaling define anogenital papillary hidradenoma. AB - Papillary hidradenoma (a.k.a. hidradenoma papilliferum) is a benign tumor of the anogenital region that almost exclusively arises in middle-aged Caucasian women. These tumors may recur and rare cases of malignant development have been reported. The genetic basis of papillary hidradenoma is currently unknown. Hence, we employed targeted high-coverage next generation sequencing interrogating 50 cancer-related genes and conventional Sanger sequencing to investigate the mutational landscape in a cohort of 15 cases. Additionally, we analyzed the HPV status of these tumors. Thirteen cases (87%) harbored mutations in cancer-related genes. Recurrent mutations in PIK3CA and AKT1 were present in 10 of the cases (67%). One PIK3CA mutated case had a concomitant STK11 mutation. Three cases harbored mutually exclusive mutations in BRAF, APC and ERBB4. The remaining two cases showed no mutations. None of the cases harbored DNA of human papilloma virus. Our results also provide evidence that--just as BRAF V600E mutations in hyperplastic polyps and benign nevi- a mutated driver gene does not imply malignant behavior per se but may set the basis for malignant transformation. The latter point may explain why rare cases of papillary hidradenoma have been reported to take a malignant course. Lastly, our genetic data may suggest treatment avenues beyond conventional surgery for some of these tumors. PMID- 26493285 TI - The origins and destinies of the idea of thirdness in contemporary psychoanalysis. AB - The central aim that animates this paper is to present and discuss the idea of thirdness or analytic third in psychoanalysis, from its origins to the concepts formulated by Andre Green and Thomas Ogden. The contributions of Winnicott, Reik and the Baranger couple are discussed, as are their influences to contemporary psychoanalysis. In order to promote the clarification and to distinguish different psychoanalytic conceptions of the third, ten figures referring to the meaning of thirdness that appear in different theories are presented, without necessarily their being mutually exclusive. As a final consideration, the article seeks to reorder in four dimensions the ten figures originally presented, emphasizing the central elements in Ogden and Green's constructions. These dimensions are at the same time conceptual and clinical, insofar as they create possibilities of operating the idea of thirdness in the transference/ countertransference dynamics. PMID- 26493286 TI - Insulin Fibrillization at Acidic and Physiological pH Values is Controlled by Different Molecular Mechanisms. AB - Formation of amyloid-like fibrils by insulin was studied at different insulin concentrations, pH and temperatures. At low pH (pH 2.5) the insulin fibrillization occurred only at high ([10 lM) peptide concentrations, whereas at physiological pH values the fibril formation is inhibited at higher insulin concentrations. The enthalpy of activation Ea of the fibril growth at pH 2.5 equals to 33 kJ/mol, which is considerably lower than 84 kJ/mol at physiological pH. The fibrillization rate of insulin decreases with increasing pH at high, 250 lM concentration, which was opposite to the pH effect observed in 2.5 lM insulin solutions. The latter effect indicates that protonation of histidine residues seems to be important for the fibrillization of monomeric insulin, whereas the pH effect at high concentration may result from off-pathway oligomerization propensity. Together, the different effect of environmental factors on the insulin fibrillization suggest that the reaction rate is controlled by different molecular events in acidic conditions and at physiological pH values. PMID- 26493287 TI - Optimization of Expression and Purification of Recombinant Archeoglobus fulgidus F420H2:NADP+ Oxidoreductase, an F420 Cofactor Dependent Enzyme. AB - Methanogens play a critical role in carbon cycling and contain a number of intriguing biosynthetic pathways. One unusual cofactor found in methanogenic and sulfate reducing archaea is Factor 420 (F420), which can be interconverted between its reduced and oxidized forms by the F420H2:NADP(+) oxidoreductase (Fno) through hydride transfer mechanisms. Here, we report an optimized expression and purification method for recombinant Fno derived from the extreme thermophile Archeoglobus fulgidus. An expression vector that is codon-optimized for heterologous expression in Escherichia coli, modified growth conditions, and a modified purification protocol involving a key polyethyleneimine precipitation step results in a highly purified, homogeneous preparation of Fno that displays high catalytic activity with a truncated F420 analog. This method should accelerate studies on how Fno uses the unusual F420 cofactor during catalysis. PMID- 26493288 TI - Pharmacologic targeting of regulatory T cells for solid organ transplantation: current and future prospects. AB - The last three decades have witnessed significant advances in the development of immunosuppressive medications used in kidney transplantation leading to a remarkable gain in short-term graft function and outcomes. Despite these major breakthroughs, improvements in long-term outcomes lag behind due to a stalemate between drug-related nephrotoxicity and chronic rejection typically due to donor specific antibodies. Regulatory T cells (Tregs) have been shown to modulate the alloimmune response and can exert suppressive activity preventing allograft rejection in kidney transplantation. Currently available immunosuppressive agents impact Tregs in the alloimmune milieu with some of these interactions being deleterious to the allograft while others may be beneficial. Variable effects are seen with common antibody induction agents such that basiliximab, an IL-2 receptor blocker, decreases Tregs while lymphocyte depleting agents such as antithymocyte globulin increase Tregs. Calcineurin inhibitors, a mainstay of maintenance immunosuppression since the mid-1980s, seem to suppress Tregs while mammalian targets of rapamycin (less commonly used in maintenance regimens) expand Tregs. The purpose of this review is to provide an overview of Treg biology in transplantation, identify in more detail the interactions between commonly used immunosuppressive agents and Tregs in kidney transplantation and lastly describe future directions in the use of Tregs themselves as therapy for tolerance induction. PMID- 26493290 TI - Comment on "Does the position of shoulder immobilization after reduced anterior glenohumeral dislocation affect coaptation of a Bankart lesion? An arthrographic comparison." by Momenzadeh O R et al. PMID- 26493291 TI - Polymorphisms of RAD50, IL33 and IL1RL1 are associated with atopic asthma in Chinese population. AB - Genetic architecture of asthma remains obscure. This study aimed to investigate whether the genetic polymorphisms of CDHR3 (rs6967330), GSDMB (rs2305480), IL33 rs928413, RAD50 (rs6871536) and IL1RL1 (rs1558641) are associated with the development of atopic asthma in Chinese population. Genotype and allele frequencies were compared between 516 patients and 552 controls by Chi-square test. Patients were found to have significantly higher allele G of rs928413 and allele C of rs6871536 (9.5% vs 6.2%, P = 0.004 for rs928413; 26.1% vs 19.9%, P < 0.001 for rs6871536). Besides, patients were found to have significantly lower frequency of allele A of rs1558641 (17.2% vs 21.7%, P = 0.007). This is the first study validating that IL33, IL1R1, and RAD50 genes are associated with the risk of asthma in Chinese population. PMID- 26493292 TI - Phosphatidic Acid (PA) can Displace PPARalpha/LXRalpha Binding to The EGFR Promoter Causing its Transrepression in Luminal Cancer Cells. AB - The expression of the epidermal growth factor receptor (EGFR) is highly regulated in normal cells, whereas some cancer cells have high constitutive levels. Understanding naturally-occurring ways of downregulating EGFR in cancer cells was investigated. Phosphatidic acid (PA) or Nuclear Receptors (NR) PPARalpha/RXRalpha/LXRalpha, enhance EGFR expression, mediated by the promoter region -856(A) to -226(T). Unexpectedly, the combination of NRs and PA caused repression. PA induces a conformational change in the nuclear receptor PPARalpha (increase of alpha-helices at the expense of decreasing beta-sheets), as evidenced by circular dichroism. This represses the naturally-enhancing capability of PPARalpha on EGFR transcription. PPARalpha-overexpressing cells in the presence of PA > 300 nM or the enzyme that produces it, phospholipase D (PLD), downregulate EGFR expression. The reasons are two-fold. First, PA displaces PPARalpha binding to the EGFR promoter at those concentrations. Second, NR heterodimer-dependent promoter activity is weakened in the presence of PA in vivo. Since other genes considered (beta-catenin, cyclin D3, PLD2 and ACOX-1) are also downregulated with a PA + PPARalpha combination, the transrepression appears to be a global phenomenon. Lastly, the reported effect is greater in MCF-7 than in MDA-MB-231 breast cancer cells, which could provide a novel basis for regulating excessive expression of EGFR in luminal cancer cells. PMID- 26493289 TI - Laparoscopic surgery: a narrative review of pharmacotherapy in pain management. AB - Laparoscopic surgery is widespread, and an increasing number of surgeries are performed laparoscopically. Early pain after laparoscopy can be similar or even more severe than that after open surgery. Thus, proactive pain management should be provided. Pain after laparoscopic surgery is derived from multiple origins; therefore, a single agent is seldom sufficient. Pain is most effectively controlled by a multimodal, preventive analgesia approach, such as combining opioids with non-opioid analgesics and local anaesthetics. Wound and port site local anaesthetic injections decrease abdominal wall pain by 1-1.5 units on a 0 10 pain scale. Inflammatory pain and shoulder pain can be controlled by NSAIDs or corticosteroids. In some patient groups, adjuvant drugs, ketamine and alpha2 adrenergic agonists can be helpful, but evidence on gabapentinoids is conflicting. In the present review, the types of pain that need to be taken into account while planning pain management protocols and the wide range of analgesic options that have been assessed in laparoscopic surgery are critically assessed. Recommendations to the clinician will be made regarding how to manage acute pain and how to prevent persistent postoperative pain. It is important to identify patients at the highest risk for severe and prolonged post-operative pain, and to have a proactive strategy in place for these individuals. PMID- 26493293 TI - The RNA helicase, eIF4A-1, is required for ovule development and cell size homeostasis in Arabidopsis. AB - eIF4A is a highly conserved RNA-stimulated ATPase and helicase involved in the initiation of mRNA translation. The Arabidopsis genome encodes two isoforms, one of which (eIF4A-1) is required for the coordination between cell cycle progression and cell size. A T-DNA mutant eif4a1 line, with reduced eIF4A protein levels, displays slow growth, reduced lateral root formation, delayed flowering and abnormal ovule development. Loss of eIF4A-1 reduces the proportion of mitotic cells in the root meristem and perturbs the relationship between cell size and cell cycle progression. Several cell cycle reporter proteins, particularly those expressed at G2/M, have reduced expression in eif4a1 mutant meristems. Single eif4a1 mutants are semisterile and show aberrant ovule growth, whereas double eif4a1 eif4a2 homozygous mutants could not be recovered, indicating that eIF4A function is essential for plant growth and development. PMID- 26493294 TI - Right handed chiral superstructures from achiral molecules: self-assembly with a twist. AB - The induction and development of chiral supramolecular structures from hierarchical self-assembly of achiral compounds is closely related to the evolution of life and the chiral amplification found in nature. Here we show that the combination of achiral tetraphenylethene (TPE) an AIE-active luminophore bearing four long alkyl chains via amide linkage allows the entire process of induction and control of supramolecular chirality into well-defined uniform right handed twisted superstructures via solvent composition and polarity, i.e. solvophobic effect. We showed that the degree of twist and the pitch of the ribbons can be controlled to one-handed helical structure via solvophobic effects. The twisted superstructure assembly was visualised by scanning electron microscope (SEM) and transmission electron microscopy (TEM), furthermore, circular dichroism (CD) confirms used to determine controlled right-handed assembly. This controlled assembly of an AIE-active molecule can be of practical value; for example, as templates for helical crystallisation, catalysis and a chiral mechanochromic luminescent superstructure formation. PMID- 26493295 TI - The phylogenetic structure of plant-pollinator networks increases with habitat size and isolation. AB - Similarity among species in traits related to ecological interactions is frequently associated with common ancestry. Thus, closely related species usually interact with ecologically similar partners, which can be reinforced by diverse co-evolutionary processes. The effect of habitat fragmentation on the phylogenetic signal in interspecific interactions and correspondence between plant and animal phylogenies is, however, unknown. Here, we address to what extent phylogenetic signal and co-phylogenetic congruence of plant-animal interactions depend on habitat size and isolation by analysing the phylogenetic structure of 12 pollination webs from isolated Pampean hills. Phylogenetic signal in interspecific interactions differed among webs, being stronger for flower visiting insects than plants. Phylogenetic signal and overall co-phylogenetic congruence increased independently with hill size and isolation. We propose that habitat fragmentation would erode the phylogenetic structure of interaction webs. A decrease in phylogenetic signal and co-phylogenetic correspondence in plant pollinator interactions could be associated with less reliable mutualism and erratic co-evolutionary change. PMID- 26493296 TI - Comparison of translocation methods to conserve metallophyte communities in the Southeastern D.R. Congo. AB - In southeastern Democratic Republic of Congo, unique metallophyte communities supporting numerous endemic species occurred on the highly mineralized copper cobalt (Cu-Co) hills throughout the province. These hills are economically valuable mineral reserves; mining activities represent therefore a threat to the long-term persistence of these communities. Ex situ conservation program was set up by a mining company to rescue and conserve the diversity of Cu-Co communities until restoration activities are initiated. Two kinds of Cu-Co communities: the steppe and the steppic savanna, were translocated using topsoil spreading and whole-turf translocation. In this study, we assessed the effectiveness of these two techniques in conserving Cu-Co communities and their potential use in future restoration programs. More than 2 years after the translocation, whole-turf translocation appeared to be the better technique for ex situ conservation of endemic Cu-Co species. Not only did whole-turf successfully translocate numerous target species that were not present in the topsoil areas, but it also resulted in fewer ruderal and non-target species compared to topsoil spreading. Topsoil spreading recorded low seedling emergence from seed bank due to large proportions of dormant seeds or the absence of a seed bank, especially for the steppic savanna. Restoration of the steppe is currently more successful than for steppic savanna where the lack of dominant and structuring species likely contributed to divergence in species composition compared to reference ecosystem. Our study stresses the fact that tropical old-growth grasslands, which require probably several centuries to assemble, are difficult to restore or translocate. PMID- 26493297 TI - Effects of drip irrigation on migration and distribution of heavy metals in soil profile. AB - Drip irrigation systems have been widely applied in semiarid and arid regions of China. However, little is known about the migration of heavy metals in cultivated soil under drip irrigation. Therefore, the concentrations of Cd, Cr, Cu, Ni, Pb, and Zn in soil were determined. The mean contents of Cd, Cr, Cu, Pb, Zn, and Ni in surface soil subjected to irrigation with low and high amounts of water (W1 and W2) were 0.11, 117.50, 37.51, 13.53, 78.10, and 38.41 mg/kg and 0.20, 94.45, 29.71, 22.48, 63.00, and 36.62 mg/kg, respectively. Metal concentrations in deep soil varied slightly between W1 and W2. Among different distances from the dropper, the metal levels in surface soil varied widely, while they varied slightly in deep soil. The Igeo (geo-accumulation index) values indicated that the soil was usually contaminated by Cr, Cu, and Cd. Under W1, Cd and Cu usually accumulated in surface soil near the dropper, while the other metals leached into subsurface soil. Moreover, the metals generally accumulated in soil away from the dropper. However, significant leaching of metals to the subsurface and deep soil was observed near the dropper under W2. Away from the dropper, Cd, Cr, Cu, Ni, and Pb usually accumulated in surface and deep soil. This suggested that heavy metals generally migrated to the soil away from the dropper when subjected to lower amounts of irrigation, while metals usually moved to surface soil and deep soil under high irrigation amounts. These findings indicate that drip irrigation greatly affected the distribution and migration of heavy metals in soil, with irrigation with lower amounts of irrigation water significantly affecting the horizontal migration of heavy metals and higher amounts influencing the vertical movement of heavy metals. PMID- 26493298 TI - Environment and air pollution like gun and bullet for low-income countries: war for better health and wealth. AB - The objective of the study is to examine the impact of environmental indicators and air pollution on "health" and "wealth" for the low-income countries. The study used a number of promising variables including arable land, fossil fuel energy consumption, population density, and carbon dioxide emissions that simultaneously affect the health (i.e., health expenditures per capita) and wealth (i.e., GDP per capita) of the low-income countries. The general representation for low-income countries has shown by aggregate data that consist of 39 observations from the period of 1975-2013. The study decomposes the data set from different econometric tests for managing robust inferences. The study uses temporal forecasting for the health and wealth model by a vector error correction model (VECM) and an innovation accounting technique. The results show that environment and air pollution is the menace for low-income countries' health and wealth. Among environmental indicators, arable land has the largest variance to affect health and wealth for the next 10-year period, while air pollution exerts the least contribution to change health and wealth of low-income countries. These results indicate the prevalence of war situation, where environment and air pollution become visible like "gun" and "bullet" for low income countries. There are required sound and effective macroeconomic policies to combat with the environmental evils that affect the health and wealth of the low-income countries. PMID- 26493299 TI - Degradation of organic pollutants and microorganisms from wastewater using different dielectric barrier discharge configurations--a critical review. AB - The growing global drinking water crisis requires the development of novel advanced, sustainable, and cost-effective water treatment technologies to supplement the existing conventional methods. One such technology is advanced oxidation based on dielectric barrier discharge (DBD). DBD such as single and double planar and single and double cylindrical dielectric barrier configurations have been utilized for efficient degradation of recalcitrant organic pollutants. The overall performance of the different DBD system varies and depends on several factors. Therefore, this review was compiled to give an overview of different DBD configurations vis-a-viz their applications and the in situ mechanism of generation of free reactive species for water and wastewater treatment. Our survey of the literature indicated that application of double cylindrical dielectric barrier configuration represents an ideal and viable route for achieving greater water and wastewater purification efficiency. PMID- 26493300 TI - Monitoring PAHs in the petrochemical area of Tarragona County, Spain: comparing passive air samplers with lichen transplants. AB - The levels of 16 polycyclic aromatic hydrocarbons (PAHs) were determined in 8 passive air samples (PAS) and 6 lichen transplants (Ramalina fastigiata) deployed for a period of 2 months in different zones of Tarragona County (Catalonia, Spain), an area with an important number of chemical and petrochemical industries. The accumulated amount of the sum of the 16 PAHs ranged between 1363 to 7866 ng/sample in air samples. The highest concentration was found in the neighborhood of Puigdelfi (village of Perafort), in the vicinity of a big oil refinery and well under the potential influence of the petrochemical emissions. In lichen samples, the sum of the 16 PAHs ranged between 247 and 841 ng/g (dry weight), being the greatest value also observed in Puigdelfi. Data on the levels and profiles of PAHs in both passive monitoring methods were compared. A significant positive linear correlation was found between the concentrations of low molecular weight PAHs in lichens and the amounts accumulated in passive air samples (R = 0.827, P < 0.05), being especially significant the correlation of 4 ring PAHs (R = 0.941, P < 0.05). These results strongly suggest that lichens can be used to monitor gas-phase PAHs, providing data that can be quantitatively translated into equivalents for air. PMID- 26493301 TI - Effects of N-Methylated Amyloid-beta30-40 Peptides on the Fibrillation of Amyloid beta1-40. AB - Alzheimer's disease is a neurodegenerative disorder associated with amyloid-beta (Abeta) fibrillation. N-Methylated amyloid-beta peptides are potent inhibitors of amyloid-beta fibrillation. We investigated the inhibitory effect of N-Methylated Abeta30-40 peptides on Abeta1-40 fibrillation. N-Methylated Abeta30-40 peptides affected the fibrillation, and this effect was dependent on the concentration of N-Methylated peptide and the number and position of N-Methylated groups. N Methylated Abeta30-40 peptides were co-aggregated with Abeta1-40 . Spectroscopic technique was adopted to investigate an origin of the observed dependence. Suppression of thioflavin T (ThT) fluorescence count was correlated with the dissociation constant Kd of monomer-dimer equilibrium of each N-Methylated Abeta30-40 peptide. Monomeric N-Methylated peptides decreased ThT fluorescence count during Abeta1-40 fibrillation. Secondary structure content was not largely different between Abeta1-40 fibrils and co-aggregates. These results suggested that N-Methylated Abeta30-40 peptides disrupted the regular beta-sheet structure of Abeta1-40 fibrils and affected the ThT fluorescence count. The monomer-dimer equilibrium of N-Methylated peptides was (partly) responsible for the observed dependence of their inhibitory effect on the concentration of N-Methylated peptide and the number and position of N-Methylated groups. Our study provides a hint to design new N-Methylated inhibitor peptides of fibrillation. PMID- 26493302 TI - Genetic analysis of capsular polysaccharide synthesis gene clusters in 79 capsular types of Klebsiella spp. AB - A total of 79 capsular types have been reported in Klebsiella spp., whereas capsular polysaccharide synthesis (cps) regions were available in only 22 types. Due to the limitations of serotyping, complete repertoire of cps will be helpful for capsular genotyping. We therefore resolved the rest 57 cps and conducted comparative analysis. Clustering results of 1,515 predicted proteins from cps loci categorized proteins which share similarity into homology groups (HGs) revealing that 77 Wzy polymerases were classified into 56 HGs, which indicate the high specificity of wzy between different types. Accordingly, wzy-based capsular genotyping could differentiate capsule types except for those lacking wzy (K29 and K50), those sharing identical wzy (K22 vs. K37); and should be carefully applied in those exhibited high similarity (K12 vs. K41, K2 vs. K13, K74 vs. K80, K79 vs. KN1 and K30 vs. K69). Comparison of CPS structures in several capsular types that shared similarity in their gene contents implies possible functions of glycosyltransferases. Therefore, our results provide complete set of cps in various types of Klebsiella spp., which enable the understandings of relationship between genes and CPS structures and are useful for identification of documented or new capsular types. PMID- 26493303 TI - Which ear should we choose for cochlear implantation in the elderly: The poorer or the better? Audiometric outcomes, quality of sound, and quality-of-life results. AB - CONCLUSIONS: Cochlear implantation in the poorer ear of an elderly patient does not predict poorer post-operative audiological, quality-of-life (QoL), and quality of sound results. OBJECTIVES: To determine whether choosing the 'better' or the 'poorer' ear for cochlear implantation impacts performance outcome in an elderly population. METHODS: Forty-two out of 73 elderly (>= 60 years) cochlear implant users with some residual hearing in at least one ear were selected. Three criteria were used to group the patients as 'better' or 'poorer' ear implanted; (C1) based on previous use of hearing aid, (C2) pre-operative PTA, and (C3) pre operative speech discrimination. The Glasgow Benefit Inventory (GBI) and the Hearing Implant Sound Quality Index (HISQUI) were used to measure QoL and quality of sound, respectively. RESULTS: The mean post-operative PTA was 38.7 +/- 7.2 dBHL. In quiet, the mean disyllabic SDS at 65dBSPL was 75.4 +/- 18.5, whereas the discrimination of sentences was 95.0% +/- 6.9. The mean total GBI score was 30.9 +/- 21.8, 92.9% of patients reporting a positive score. The mean HISQUI score was 111.3 +/- 36.0, which corresponds to 'moderate' sound quality. No significant differences were found between both groups in terms of audiological outcomes, HISQUI scores or GBI scores when considering each of the three criteria. PMID- 26493304 TI - Morphine interaction with prasugrel: a double-blind, cross-over trial in healthy volunteers. AB - BACKGROUND: Morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction. OBJECTIVES: To clarify whether more potent P2Y12-inhibitors may provide an effective alternative, we examined drug-drug interactions between morphine and prasugrel. METHODS: Twelve healthy volunteers received 60 mg prasugrel with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests. RESULTS: Morphine neither diminished total drug exposure (AUC), which was the primary endpoint, nor significantly delayed drug absorption of prasugrel. However, morphine reduced maximal plasma concentrations (C max) of prasugrel active metabolite by 31 % (p = 0.019). Morphine slightly, but not significantly, delayed the onset of maximal inhibition of platelet plug formation under high shear rates (30 vs. 20 min). Whole blood aggregation was not influenced. CONCLUSIONS: Although morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers. However, it should be considered that the observed decrease in C max of prasugrel active metabolite caused by morphine co-administration may gain relevance in STEMI patients. CLINICAL TRIAL REGISTRATION: NCT01369186, EUDRA-CT#: 2010-023761-22. PMID- 26493306 TI - Complete encapsulation of a leadless cardiac pacemaker. PMID- 26493305 TI - Effects of catheter-based renal denervation on cardiac sympathetic activity and innervation in patients with resistant hypertension. AB - OBJECTIVES: To investigate, whether renal denervation (RDN) has a direct effect on cardiac sympathetic activity and innervation density. BACKGROUND: RDN demonstrated its efficacy not only in reducing blood pressure (BP) in certain patients, but also in decreasing cardiac hypertrophy and arrhythmias. These pleiotropic effects occur partly independent from the observed BP reduction. METHODS: Eleven patients with resistant hypertension (mean office systolic BP 180 +/- 18 mmHg, mean antihypertensive medications 6.0 +/- 1.5) underwent I-123-mIBG scintigraphy to exclude pheochromocytoma. We measured cardiac sympathetic innervation and activity before and 9 months after RDN. Cardiac sympathetic innervation was assessed by heart to mediastinum ratio (H/M) and sympathetic activity by wash out ratio (WOR). Effects on office BP, 24 h ambulatory BP monitoring, were documented. RESULTS: Office systolic BP and mean ambulatory systolic BP were significantly reduced from 180 to 141 mmHg (p = 0.006) and from 149 to 129 mmHg (p = 0.014), respectively. Cardiac innervation remained unchanged before and after RDN (H/M 2.5 +/- 0.5 versus 2.6 +/- 0.4, p = 0.285). Cardiac sympathetic activity was significantly reduced by 67 % (WOR decreased from 24.1 +/- 12.7 to 7.9 +/- 25.3 %, p = 0.047). Both, responders and non-responders experienced a reduction of cardiac sympathetic activity. CONCLUSION: RDN significantly reduced cardiac sympathetic activity thereby demonstrating a direct effect on the heart. These changes occurred independently from BP effects and provide a pathophysiological basis for studies, investigating the potential effect of RDN on arrhythmias and heart failure. PMID- 26493308 TI - Backbone and side chain chemical shift assignments of apolipophorin III from Galleria mellonella. AB - Apolipophorin III, a 163 residue monomeric protein from the greater wax moth Galleria mellonella (abbreviated as apoLp-IIIGM), has roles in upregulating expression of antimicrobial proteins as well as binding and deforming bacterial membranes. Due to its similarity to vertebrate apolipoproteins there is interest in performing atomic resolution analysis of apoLp-IIIGM as part of an effort to better understand its mechanism of action in innate immunity. In the first step towards structural characterization of apoLp-IIIGM, 99 % of backbone and 88 % of side chain (1)H, (13)C and (15)N chemical shifts were assigned. TALOS+ analysis of the backbone resonances has predicted that the protein is composed of five long helices, which is consistent with the reported structures of apolipophorins from other insect species. The next stage in the characterization of apoLp-III from G. mellonella will be to utilize these resonance assignments in solving the solution structure of this protein. PMID- 26493307 TI - Social and psychological contributions to the co-occurrence of sub-threshold psychotic experiences and suicidal behavior. AB - PURPOSE: Psychotic experiences and suicidal behavior commonly co-occur in the general population, which can have implications for suicide prevention approaches. However, little is known about the nature of this relation in non clinical samples. This cross-sectional study aimed to address a research gap by testing whether the relation between psychotic experiences and suicide-related outcomes (ideation, intent, and attempts) is explained by common social and psychological factors. METHODS: Young adult college students (N = 590) were assessed for psychotic experiences, suicidal behavior, and a comprehensive set of 24 potential shared risk factors selected through review of past epidemiological studies and meta-analyses. Nonparametric bootstrapped regression models were used to examine whether these factors attenuated or eliminated the associations between psychotic experiences and suicide-related outcomes. RESULTS: Psychotic experiences were associated with greater risk for suicidal ideation and behaviors. Adjustment for psychosocial factors, particularly those contributing to cumulative stress, accounted for the associations between psychotic experiences and suicide-related outcomes, except broadly defined suicidal ideation. CONCLUSIONS: These results suggest that the robust associations between psychotic experiences and suicidal behavior demonstrated in past studies may be primarily explained by shared risk factors, rather than by causal relations. In our sample, suicidal behavior and sub-threshold psychosis appear to be trans diagnostic clinical outcomes that share common causes, notably cumulative stress, but do not cause one another. PMID- 26493309 TI - Endogenous TSH levels at the time of 131I ablation do not influence ablation success, recurrence-free survival or differentiated thyroid cancer-related mortality. AB - PURPOSE: Based on a single older study it is established dogma that TSH levels should be >=30 mU/l at the time of postoperative 131I ablation in differentiated thyroid cancer (DTC) patients. We sought to determine whether endogenous TSH levels, i.e. after levothyroxine withdrawal, at the time of ablation influence ablation success rates, recurrence-free survival and DTC-related mortality. METHODS: A total of 1,873 patients without distant metastases referred for postoperative adjuvant 131I therapy were retrospectively included from 1991 onwards. Successful ablation was defined as stimulated Tg <1 MUg/l. RESULTS: Age, gender and the presence of lymph node metastases were independent determinants of TSH levels at the time of ablation. TSH levels were not significantly related to ablation success rates (p = 0.34), recurrence-free survival (p = 0.29) or DTC elated mortality (p = 0.82), but established risk factors such as T-stage, lymph node metastases and age were. Ablation was successful in 230 of 275 patients (83.6 %) with TSH <30 mU/l and in 1,359 of 1,598 patients (85.0 %) with TSH >=30 mU/l. The difference was not significant (p = 0.55). Of the whole group of 1,873 patients, 21 had recurrent disease. There were no significant differences in recurrence rates between patients with TSH <30 mU/l and TSH >=30 mU/l (p = 0.16). Ten of the 1,873 patients died of DTC. There were no significant differences in DTC-specific survival between patients with TSH <30 mU/l and TSH >=30 mU/l (p = 0.53). CONCLUSION: The precise endogenous TSH levels at the time of 131I ablation are not related to the ablation success rates, recurrence free survival and DTC related mortality. The established dogma that TSH levels need to be >=30 mU/l at the time of 131I ablation can be discarded. PMID- 26493310 TI - Prostate-specific antigen and radiolabelled choline PET/CT for the assessment of response to therapy: synergy or conflicting? PMID- 26493311 TI - Development of cellular hypertrophy by 8-hydroxyeicosatetraenoic acid in the human ventricular cardiomyocyte, RL-14 cell line, is implicated by MAPK and NF kappaB. AB - Recent studies have established the role of mid-chain hydroxyeicosatetraenoic acids (mid-chain HETEs) in the development of cardiovascular disease. Among these mid-chains, 8-HETE has been reported to have a proliferator and proinflammatory action. However, whether 8-HETE can induce cardiac hypertrophy has never been investigated before. Therefore, the overall objectives of the present study are to elucidate the potential hypertrophic effect of 8-HETE in the human ventricular cardiomyocytes, RL-14 cells, and to explore the mechanism(s) involved. Our results showed that 8-HETE induced cellular hypertrophy in RL-14 cells as evidenced by the induction of cardiac hypertrophy markers ANP, BNP, alpha-MHC, and beta-MHC in a concentration- and time-dependent manner as well as the increase in cell surface area. Mechanistically, 8-HETE was able to induce the NF kappaB activity as well as it significantly induced the phosphorylation of ERK1/2. The induction of cellular hypertrophy was associated with a proportional increase in the formation of dihydroxyeicosatrienoic acids (DHETs) parallel to the increase of soluble epoxide hydrolase (sEH) enzyme activity. Blocking the induction of NF-kappaB, ERK1/2, and sEH signaling pathways significantly inhibited 8-HETE-induced cellular hypertrophy. Our study provides the first evidence that 8-HETE induces cellular hypertrophy in RL-14 cells through MAPK- and NF-kappaB-dependent mechanism PMID- 26493312 TI - Oxidative damage induced by retching; antiemetic and neuroprotective role of Sambucus ebulus L. AB - Nausea and vomiting are the most common symptoms in different diseases. Medicinal plants are considered as a reliable source of new drugs to control these symptoms. In this study, we evaluated the antiemetic and neuroprotective effects of the methanolic extract of Sambucus ebulus L. fruit and relationship between emesis (retching) and oxidative stress biomarkers in the mitochondria brain of young chickens. Emesis was induced by ipecac and copper sulphate (60 and 600 mg/kg, orally), respectively, and the methanolic extracts (50, 100, 200 mg/kg) were injected intraperitoneally (i.p.). The extract showed a significant antiemetic activity against ipecac and copper sulphate-induced emesis at all doses (p<0.001; percentages of retching inhibition 46, 96.5 and 83% against ipecac and 73, 79.5 and 69.2% against copper sulphate, respectively). Lipid peroxidation (LPO) was significantly decreased (p<0.001) at all doses of extract in retching induced by copper sulphate, and catalase (CAT) activity significantly increased (p<0.05) in the extract (50 mg/kg) and metoclopromide groups in retching induced by ipecac in the chickens' brain mitochondria. Protein carbonyl (PC) contents significantly (p<0.05) decreased only in extract (100 mg/kg) group in retching induced by ipecac. Mitochondria function (MTT assay) significantly increased by extract (100 mg/kg) as compared to control group in retching induced by ipecac. The results of this study suggests that the extract has protective effects, possibly by central and peripheral mechanisms, and neuroprotective effect by increasing plasma antioxidants or scavenging of free radicals induced by retching. It seems that extract could prevent protein modification and improve oxidative stress in the early stages. PMID- 26493313 TI - Validity of the portuguese version of the mini nutritional assessment in brazilian elderly. AB - BACKGROUND: Malnutrition is common and affects negatively the health of the older adult. The Mini Nutritional Assessment (MNA), a nutritional assessment tool allows to identify elders malnourished and at risk of malnutrition. The aim of this study is to validate the Portuguese version of the MNA. METHODS: Cross sectional study with 344 Brazilian elderly. The full version of the MNA was performed, also calf circumference (CC), mid arm circumference (MAC) and body fat (BF). Psychometric evaluation was carried out and correlation, diagnostic accuracy and ROC curves were generated. RESULTS: Construct validity was supported, all four questionnaire dimensions were evidenced in the Principal Component Analysis and also significant Spearman correlation (P < 0.001) were demonstrated. Criterion validity was also evidenced with relevant sensitivity (MAC = 82.8; CI95% = 64.2-94.2) and specificity (CC = 80.0; CI95% = 74.0-85.1). In the ROC curve AUC was excellent (MAC = 0.832; CI95% =0.785-0.873). CONCLUSIONS: The full MNA demonstrated significant results and sufficient exploratory psychometric properties that supported its validity. It seems to be valid tool to access nutritional status of Brazilian elderly. PMID- 26493314 TI - Outcome measures and quality markers for perioperative blood loss and transfusion in cardiac surgery. AB - PURPOSE: The purpose of this narrative review is to address perioperative bleeding and transfusion as determinants of adverse outcomes after cardiac surgery. PRINCIPAL FINDINGS: The relationship between postoperative bleeding and adverse outcomes is non-linear, with an increase in the risk of mortality only in cases of severe perioperative bleeding. When perioperative bleeding is used as an outcome variable, it should be dichotomized according to the existing definitions. In retrospective observational studies, red blood cell transfusions have been associated with an increase in morbidity and mortality, which points to restriction of transfusion as a potential benefit. Nevertheless, randomized controlled trials have not confirmed that restrictive transfusion policies are associated with better outcomes. Additionally, a transfusion policy that is too restrictive may actually increase postoperative mortality in cardiac surgery patients. CONCLUSION: Perioperative bleeding itself is a complex syndrome that can be classified as an outcome measure. Red blood cell transfusion has limitations when considered as an outcome variable and can be biased by many confounders. Its relationship with clinical outcome remains uncertain. In addition to being potential outcome measures, transfusion rates and the number of allogeneic blood products transfused may also be considered as quality-of-care markers. PMID- 26493315 TI - De novo assembly and sex-specific transcriptome profiling in the sand fly Phlebotomus perniciosus (Diptera, Phlebotominae), a major Old World vector of Leishmania infantum. AB - BACKGROUND: The phlebotomine sand fly Phlebotomus perniciosus (Diptera: Psychodidae, Phlebotominae) is a major Old World vector of the protozoan Leishmania infantum, the etiological agent of visceral and cutaneous leishmaniases in humans and dogs, a worldwide re-emerging diseases of great public health concern, affecting 101 countries. Despite the growing interest in the study of this sand fly species in the last years, the development of genomic resources has been limited so far. To increase the available sequence data for P. perniciosus and to start studying the molecular basis of the sexual differentiation in sand flies, we performed whole transcriptome Illumina RNA sequencing (RNA-seq) of adult males and females and de novo transcriptome assembly. RESULTS: We assembled 55,393 high quality transcripts, of which 29,292 were unique, starting from adult whole body male and female pools. 11,736 transcripts had at least one functional annotation, including full-length low abundance salivary transcripts, 981 transcripts were classified as putative long non-coding RNAs and 244 transcripts encoded for putative novel proteins specific of the Phlebotominae sub-family. Differential expression analysis identified 8590 transcripts significantly biased between sexes. Among them, some show relaxation of selective constraints when compared to their orthologs of the New World sand fly species Lutzomyia longipalpis. CONCLUSIONS: In this paper, we present a comprehensive transcriptome resource for the sand fly species P. perniciosus built from short-read RNA-seq and we provide insights into sex-specific gene expression at adult stage. Our analysis represents a first step towards the identification of sex-specific genes and pathways and a foundation for forthcoming investigations into this important vector species, including the study of the evolution of sex-biased genes and of the sexual differentiation in phlebotomine sand flies. PMID- 26493316 TI - Tubulin cytoskeleton during microsporogenesis in the male-sterile genotype of Allium sativum and fertile Allium ampeloprasum L. AB - KEY MESSAGE: Microsporogenesis in garlic. The male-sterile Allium sativum (garlic) reproduces exclusively in the vegetative mode, and anthropogenic factors seem to be the cause of the loss of sexual reproduction capability. There are many different hypotheses concerning the causes of male sterility in A.sativum; however, the mechanisms underlying this phenomenon have not been comprehensively elucidated.Numerous attempts have been undertaken to understand the causes of male sterility, but the tubulin cytoskeleton in meiotically dividing cells during microsporogenesis has never been investigated in this species. Using sterile A.sativum genotype L13 and its fertile close relative A. ampeloprasum (leek), we have analysed the distribution of the tubulin cytoskeleton during microsporogenesis. We observed that during karyokinesis and cytokinesis, in both meiotic divisions I and II, the microtubular cytoskeleton in garlic L13 formed configurations that resembled tubulin arrangement typical of monocots. However, the tubulin cytoskeleton in garlic was distinctly poorer (composed of a few MT filaments) compared with that found in meiotically dividing cells in A. ampeloprasum. These differences did not affect the course of karyogenesis, chondriokinesis, and cytokinesis, which contributed to completion of microsporogenesis, but there was no further development of the male gametophyte. At the very beginning of the successive stage of development of fertile pollen grains, i.e. gametogenesis, there were disorders involving the absence of a normal cortical cytoskeleton and dramatically progressive degeneration of the cytoplasm in garlic. Therefore,we suggest that, due to disturbances in cortical cytoskeleton formation at the very beginning of gametogenesis, the intracellular transport governed by the cytoskeleton might be perturbed, leading to microspore decay in the male-sterile garlic genotype. PMID- 26493317 TI - AlloPred: prediction of allosteric pockets on proteins using normal mode perturbation analysis. AB - BACKGROUND: Despite being hugely important in biological processes, allostery is poorly understood and no universal mechanism has been discovered. Allosteric drugs are a largely unexplored prospect with many potential advantages over orthosteric drugs. Computational methods to predict allosteric sites on proteins are needed to aid the discovery of allosteric drugs, as well as to advance our fundamental understanding of allostery. RESULTS: AlloPred, a novel method to predict allosteric pockets on proteins, was developed. AlloPred uses perturbation of normal modes alongside pocket descriptors in a machine learning approach that ranks the pockets on a protein. AlloPred ranked an allosteric pocket top for 23 out of 40 known allosteric proteins, showing comparable and complementary performance to two existing methods. In 28 of 40 cases an allosteric pocket was ranked first or second. The AlloPred web server, freely available at http://www.sbg.bio.ic.ac.uk/allopred/home, allows visualisation and analysis of predictions. The source code and dataset information are also available from this site. CONCLUSIONS: Perturbation of normal modes can enhance our ability to predict allosteric sites on proteins. Computational methods such as AlloPred assist drug discovery efforts by suggesting sites on proteins for further experimental study. PMID- 26493319 TI - Risk environments facing potential users of a supervised injection site in Ottawa, Canada. AB - BACKGROUND: Supervised injection sites (SISs) have been effective in reducing health risks among people who inject drugs (PWID), including those who face issues of homelessness, mental health illness, interactions with local policing practices, and HIV infection. We investigate the risk behaviours and risk environments currently faced by potential users of an SIS in Ottawa to establish the need for such a service and to contribute to the design of an SIS that can address current health risks and reduce harm. METHODS: The PROUD cohort is a community-based participatory research (CBPR) project that examines the HIV risk environment among people who use drugs in Ottawa. From March to October 2013, 593 people who reported using injection drugs or smoking crack cocaine were enrolled through street-based recruitment in the ByWard Market neighbourhood, an area of the city with a high concentration of public drug use and homelessness. Participants completed a demographic, behavioural, and risk environment questionnaire and were offered HIV point-of-care testing. We undertook descriptive and univariate analyses to estimate potential use of an SIS by PWID in Ottawa and to explore risk behaviours and features of the risk environment faced by potential users of the service. RESULTS: Of those participants who reported injecting drugs in the previous 12 months (n = 270), 75.2 % (203) reported a willingness to use an SIS in Ottawa. Among potential SIS users, 24.6 % had recently injected with a used needle, 19.0 % had trouble accessing new needles, 60.6 % were unstably housed, 49.8 % had been redzoned by the police, and 12.8 % were HIV positive. Participants willing to use an SIS more frequently injected in public (OR = 1.98, 95 % CI = 1.06-3.70), required assistance to inject (OR = 1.84, 95 % CI = 1.00-3.38), were hepatitis C positive (OR = 2.13, 95 % CI = 1.16-3.91), had overdosed in the previous year (OR = 2.00, 95 % CI = 1.02 3.92), and identified as LGBTQ (OR = 5.61, 95 % CI = 1.30-24.19). CONCLUSION: An SIS in Ottawa would be well-positioned to reach its target group of highly marginalized PWID and reduce drug-related harms. The application of CBPR methods to a large-scale quantitative survey supported the mobilization of communities of PWID to identify and advocate for their own service needs, creating an enabling environment for harm reduction action. PMID- 26493318 TI - New discoveries in schizophrenia genetics reveal neurobiological pathways: A review of recent findings. AB - Schizophrenia research has undergone a recent transformation. By leveraging large sample sizes, genome-wide association studies of common genetic variants have approximately tripled the number of candidate genetic loci. Rare variant studies have identified copy number variants that are schizophrenia risk loci. Among these, the 3q29 microdeletion is now known to be the single largest schizophrenia risk factor. Next-generation sequencing studies are increasingly used for rare variant association testing, and have already facilitated identification of large effect alleles. Collectively, recent findings implicate voltage-gated calcium channel and cytoskeletal pathways in the pathogenesis of schizophrenia. Taken together, these results suggest the possibility of imminent breakthroughs in the molecular understanding of schizophrenia. PMID- 26493321 TI - Aurantiacicella marina gen. nov., sp. nov., a myxol-producing bacterium from surface seawater. AB - A Gram-stain-negative, non-motile, mesophilic, aerobic, rod-shaped bacterium, strain 2A-8T, was isolated from surface seawater at Muroto city, Kochi prefecture, Japan. The strain produced myxol as a major carotenoid. Phylogenetic analyses based on 16S rRNA gene sequences showed that the strain fell within the family Flavobacteriaceae and was related most closely to the genus Aquimarina (91.0-94.4 % 16S rRNA gene sequence similarity to the type strains of species of this genus). The DNA G+C content was 35 mol%. The major fatty acids were iso-C15 : 0 and iso-C17 : 0 3-OH. The major polar lipids were phosphatidylethanolamine, an unidentified aminolipid and five unidentified lipids. Menaquinone 6 was detected as the sole isoprenoid quinone. On the basis of phenotypic, genotypic and chemotaxonomic data, strain 2A-8T represents a novel genus and species, for which the name Aurantiacicella marina gen. nov., sp. nov. is proposed. The type strain of Aurantiacicella marina is 2A-8T ( = NBRC 111187T = KCTC 42676T). PMID- 26493320 TI - Methotrexate polyglutamates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis: an observational, cross-sectional study. AB - INTRODUCTION: Methotrexate (MTX) is a cornerstone of treatment in a wide variety of inflammatory conditions, including juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM). However, owing to its narrow therapeutic index and the considerable interpatient variability in clinical response, monitoring of adherence to MTX is important. The present study demonstrates the feasibility of using methotrexate polyglutamates (MTXPGs) as a biomarker to measure adherence to MTX treatment in children with JIA and JDM. METHODS: Data were collected prospectively from a cohort of 48 children (median age 11.5 years) who received oral or subcutaneous (SC) MTX therapy for JIA or JDM. Dried blood spot samples were obtained from children by finger pick at the clinic or via self- or parent led sampling at home, and they were analysed to determine the variability in MTXPG concentrations and assess adherence to MTX therapy. RESULTS: Wide fluctuations in MTXPG total concentrations (>2.0-fold variations) were found in 17 patients receiving stable weekly doses of MTX, which is indicative of nonadherence or partial adherence to MTX therapy. Age (P = 0.026) and route of administration (P = 0.005) were the most important predictors of nonadherence to MTX treatment. In addition, the study showed that MTX dose and route of administration were significantly associated with variations in the distribution of MTXPG subtypes. Higher doses and SC administration of MTX produced higher levels of total MTXPGs and selective accumulation of longer-chain MTXPGs (P < 0.001 and P < 0.0001, respectively). CONCLUSIONS: Nonadherence to MTX therapy is a significant problem in children with JIA and JDM. The present study suggests that patients with inadequate adherence and/or intolerance to oral MTX may benefit from SC administration of the drug. The clinical utility of MTXPG levels to monitor and optimise adherence to MTX in children has been demonstrated. TRIAL REGISTRATION: ISRCTN Registry identifier: ISRCTN93945409 . Registered 2 December 2011. PMID- 26493322 TI - Glutathionyl systems and metabolic dysfunction in obesity. AB - Oxidative stress is associated with obesity. However, glutathione (GSH), one of the body's most abundant antioxidants, plays dual and seemingly contradictory roles in the development of obesity and its comorbidities. Glutathione has complex metabolic and biochemical fates and is a cofactor for several enzymes that function in modifying obesity-related responses. For example, depletion of GSH increases energy metabolism and reduces adipose accretion, while elevation of GSH peroxidase activity induces insulin resistance. This review summarizes the literature linking GSH and its related enzymes, GSH peroxidase, glutaredoxins, and glutathione S-transferases, to obesity and its pertinent endpoints (e.g., energy metabolism, inflammation, and insulin resistance). PMID- 26493323 TI - Therapeutic engagement: Perspectives from adolescents with eating disorders. AB - This study aimed to identify factors that adolescents with eating disorders (ED) consider important for therapeutic engagement, and to examine similarities and differences in the number of identified factors considered important for therapeutic engagement based on diagnostic status and readiness and motivation to change dietary restriction behaviors. Treatment seeking adolescent females (n=34, Mage=16.33, SD=1.34) with an ED were prompted to generate responses to 4 constructs related to therapeutic engagement: (1) Trust, (2) Agreement on therapeutic goals, (3) Confidence in Ability to Change and (4) Feelings of Inclusion in therapeutic decisions. A coding scheme for each construct was developed using a random sample of responses, and each category within a construct was rated as present or absent for each participant. Frequencies and percentages of participants who reported each category within each construct are reported. Additionally, findings indicate that the top two out of three categories reported within each construct were the same between participants with AN versus EDNOS, and between participants high and low in readiness and motivation to change dietary restriction behaviors. This study is a first step in identifying aspects of therapeutic engagement that are important to adolescents with ED, which may differ from adults. PMID- 26493324 TI - Meaning in life and non-suicidal self-injury: A follow-up study with participants with Borderline Personality Disorder. AB - Non-suicidal self-injury (NSSI) is considered one of the defining features of people diagnosed with Borderline Personality Disorder (BPD). Longitudinal studies are needed to identify factors predicting future NSSI in BPD participants. Several studies have shown that low meaning in life is associated with mental health problems, addiction problems, depression, hopelessness, and suicide. The purpose of this paper is to examine whether meaning in life predicts the frequency of NSSI behaviors during the one-year follow-up. The sample was composed up of 80 participants with a BPD diagnosis. We assessed the frequency of NSSI behaviors over a 12-month follow-up period. The results suggest that the participants who had low meaning in life had more frequency of NSSI, depression, and hopelessness at baseline, and more frequency of NSSI during the follow-up, than participants with high meaning in life. The predictor variables: Frequency of NSSI at base line, depression, hopelessness, and meaning in life, significantly predicted the frequency of NSSI during the one-year follow-up. Therefore, meaning in life was the only predictor of NSSI during the follow-up period. PMID- 26493325 TI - Diagnostic accuracy and feasibility of a net-based application for diagnosing common psychiatric disorders. AB - A net-based application, which enables users to diagnose and manage common psychiatric disorders independently, was developed. Diagnostic accuracy and reliability of the application were compared with the Mini International Neuropsychiatric Interview among 274 adult outpatients. The screening sub-module of the application had high sensitivity, specificity and negative predictive values for most disorders, but low positive predictive values for several disorders. The criteria-based diagnostic sub-module demonstrated moderate to substantial agreement (kappa>0.50) for all 4 broad categories and 10 of the 18 individual disorders included. Diagnostic agreement was, however, low (kappa<0.4) for most of the disorders comprising the broad category of 'neurotic and stress related disorders'. Low sensitivity was also observed among these disorders, though specificity, and positive and negative predictive values were high for most disorders. Inter-rater reliability of the application's diagnoses was high. Symptom-severity and functional status scores correlated significantly with those on standard scales. Average time taken was 5min for screening and 20min for detailed diagnostic assessment. A majority of the patients, their relatives and interviewers were satisfied with the assessment. The results suggest that with further refinement the application could be suitable for use as a net-based diagnostic tool for psychiatric disorders. PMID- 26493326 TI - Diabetes care in England improves little, NAO report shows. PMID- 26493327 TI - Anomalous Stretchable Conductivity Using an Engineered Tricot Weave. AB - Robust electric conduction under stretching motions is a key element in upcoming wearable electronic devices but is fundamentally very difficult to achieve because percolation pathways in conductive media are subject to collapse upon stretching. Here, we report that this fundamental challenge can be overcome by using a parameter uniquely available in textiles, namely a weaving structure. A textile structure alternately interwoven with inelastic and elastic yarns, achieved via a tricot weave, possesses excellent elasticity (strain up to 200%) in diagonal directions. When this textile is coated with conductive nanomaterials, proper textile engineering allows the textile to obtain an unprecedented 7-fold conductivity increase, with conductivity reaching 33,000 S cm(-1), even at 130% strain, due to enhanced interyarn contacts. The observed stretching conductivity can be described well using a modified 3D percolation theory that reflects the weaving effect and is also utilized for stretchable electronic interconnects and supercapacitors with high performance. PMID- 26493328 TI - Recent advances in microbiology: towards new horizons? PMID- 26493329 TI - IFT88 influences chondrocyte actin organization and biomechanics. AB - OBJECTIVES: Primary cilia are microtubule based organelles which control a variety of signalling pathways important in cartilage development, health and disease. This study examines the role of the intraflagellar transport (IFT) protein, IFT88, in regulating fundamental actin organisation and mechanics in articular chondrocytes. METHODS: The study used an established chondrocyte cell line with and without hypomorphic mutation of IFT88 (IFT88(orpk)). Confocal microscopy was used to quantify F-actin and myosin IIB organisation. Viscoelastic cell and actin cortex mechanics were determined using micropipette aspiration with actin dynamics visualised in live cells transfected with LifeACT-GFP. RESULTS: IFT88(orpk) cells exhibited a significant increase in acto-myosin stress fibre organisation relative to wild-type (WT) cells in monolayer and an altered response to cytochalasin D. Rounded IFT88(orpk) cells cultured in suspension exhibited reduced cortical actin expression with reduced cellular equilibrium modulus. Micropipette aspiration resulted in reduced membrane bleb formation in IFT88(orpk) cells. Following membrane blebbing, IFT88(orpk) cells exhibited slower reformation of the actin cortex. IFT88(orpk) cells showed increased actin deformability and reduced cortical tension confirming that IFT regulates actin cortex mechanics. The reduced cortical tension is also consistent with the reduced bleb formation. CONCLUSIONS: This study demonstrates for the first time that the ciliary protein IFT88 regulates fundamental actin organisation and the stiffness of the actin cortex leading to alterations in cell deformation, mechanical properties and blebbing in an IFT88 chondrocyte cell line. This adds to the growing understanding of the role of primary cilia and IFT in regulating cartilage biology. PMID- 26493330 TI - Culture expanded primary chondrocytes have potent immunomodulatory properties and do not induce an allogeneic immune response. AB - OBJECTIVE: Allogeneic cell therapies, such as mesenchymal stromal cells (MSC), which have potent regenerative and anti-inflammatory potential are being investigated as a therapy for osteoarthritis (OA) and cartilage injury. Here we describe another potential source of regenerative and anti-inflammatory allogeneic cells, culture expanded primary chondrocytes (CEPC). In direct comparison to allogeneic MSC, we extensively assess the immunological interactions of CEPC in an allogeneic setting. METHODS: Chondrocytes were isolated from rat articular cartilage and cultured in normoxic or hypoxic conditions. In vitro co-culture assays with allogeneic lymphocytes and macrophages were used to assess the immunomodulatory capacities of the chondrocytes, followed by immune response analysis by flow cytometry, ELISA and qPCR. RESULTS: CEPC showed reduced induction of proliferation, activation and cytotoxic granzyme B expression in allogeneic T cells. Importantly, exposure to pro-inflammatory cytokines did not increase CEPC immunogenicity despite increases in MHC-I. Furthermore, CEPC had a potent ability to suppress allogeneic T cell proliferation, which was dependent on nitric oxide production. This suppression was contact independent in hypoxia cultured CEPC. Finally, chondrocytes were shown to have the capacity to modulate pro-inflammatory macrophage activity by reducing MHC-II expression and TNF-alpha secretion. CONCLUSION: These data indicate the potential use of allogeneic chondrocytes in OA and cartilage defects. The lack of evident immunogenicity, despite exposure to a pro inflammatory environment, coupled with the immunomodulatory ability indicates that these cells have the potential to evade the host immune system and suppress inflammation, thus potentially facilitating the resolution of OA induced inflammation and cartilage regeneration. PMID- 26493331 TI - Ubiquitylation of CD98 limits cell proliferation and clonal expansion. AB - CD98 heavy chain (SLC3A2) facilitates lymphocyte clonal expansion that enables adaptive immunity; however, increased expression of CD98 is also a feature of both lymphomas and leukemias and represents a potential therapeutic target in these diseases. CD98 is transcriptionally regulated and ectopic expression of the membrane-associated RING-CH (MARCH) E3 ubiquitin ligases MARCH1 or MARCH8 leads to ubiquitylation and lysosomal degradation of CD98. Here, we examined the potential role of ubiquitylation in regulating CD98 expression and cell proliferation. We report that blocking ubiquitylation by use of a catalytically inactive MARCH or by creating a ubiquitylation-resistant CD98 mutant, prevents MARCH-induced CD98 downregulation in HeLa cells. March1-null T cells display increased CD98 expression. Similarly, T cells expressing ubiquitylation-resistant CD98 manifest increased proliferation in vitro and clonal expansion in vivo. Thus, ubiquitylation and the resulting downregulation of CD98 can limit cell proliferation and clonal expansion. PMID- 26493333 TI - A Prospective Nonrandomized Study on Carotid Surgery Performed under General Anesthesia without Intraoperative Cerebral Monitoring. AB - BACKGROUND: The purpose of this study was to assess our experience of carotid surgery habitually performed under general anesthesia without intraoperative intracerebral monitoring, and following a pre-established perioperative protocol, which includes extensive use of an intraoperative shunt (IOS). METHODS: This study included 311 consecutive carotid operations performed over 32 months. This patient cohort represents 14% of our total experience in carotid surgery (2219 operations, major stroke/mortality rate: 1.4%). The IOS was inserted routinely in the presence of intraoperative blood pressure instability during cross-clamping and when the predictable clamping time might have exceeded 20 minutes. A moderate and stable hypertension was maintained throughout surgery without IOS. RESULTS: Overall, 120 (38.6%) endarterectomies were performed with primary closure, 73 (23.5%) with eversion technique, 113 (36.3%) with patch angioplasty, and 5 (1.6%) with other techniques. Out of 113 patch angioplasties, 111 (98.2%) were performed with an IOS. This was utilized in only 3 cases of direct carotid reconstructions or other carotid endarterectomy techniques (1.5%). Overall, the IOS placement rate was 36.7%. Postoperatively, 2 major strokes (.64%), 2 minor strokes (.64%), 4 hyperperfusion syndromes (1.3%), and no mortality were recorded. No cases of cross-clamp ischemia/shunt-related perioperative strokes were observed. CONCLUSIONS: The low perioperative stroke rate reported in this prospective study proves the advantages of wide use of IOS during carotid surgery. This coupled with a large experience in carotid surgery and close monitoring and support of blood pressure, are the major determinants of these results that demonstrate the low risk of shunt-related complications for surgeons who regularly utilize an IOS. PMID- 26493332 TI - Stress-induced inhibition of translation independently of eIF2alpha phosphorylation. AB - Exposure of fission yeast cells to ultraviolet (UV) light leads to inhibition of translation and phosphorylation of the eukaryotic initiation factor-2alpha (eIF2alpha). This phosphorylation is a common response to stress in all eukaryotes. It leads to inhibition of translation at the initiation stage and is thought to be the main reason why stressed cells dramatically reduce protein synthesis. Phosphorylation of eIF2alpha has been taken as a readout for downregulation of translation, but the role of eIF2alpha phosphorylation in the downregulation of general translation has not been much investigated. We show here that UV-induced global inhibition of translation in fission yeast cells is independent of eIF2alpha phosphorylation and the eIF2alpha kinase general control nonderepressible-2 protein (Gcn2). Also, in budding yeast and mammalian cells, the UV-induced translational depression is largely independent of GCN2 and eIF2alpha phosphorylation. Furthermore, exposure of fission yeast cells to oxidative stress generated by hydrogen peroxide induced an inhibition of translation that is also independent of Gcn2 and of eIF2alpha phosphorylation. Our findings show that stress-induced translational inhibition occurs through an unknown mechanism that is likely to be conserved through evolution. PMID- 26493334 TI - Influence of Diabetes Mellitus and Cigarette Smoking on Variability of the Clopidogrel-Induced Antiplatelet Effect and Efficacy of Active Management of the Target P2Y12 Reaction Unit Range in Patients Undergoing Neurointerventional Procedures. AB - BACKGROUND: Optimal antiplatelet inhibition is essential in patients undergoing neurointerventional procedures; however, variability in response to clopidogrel can contribute to thromboembolic and hemorrhagic complications. The present study evaluated the influence of diabetes mellitus and cigarette smoking on clopidogrel reactivity. METHODS: Between 2011 and 2013, 71 consecutive patients underwent aneurysmal coil embolization (CE) or carotid artery stenting (CAS) and received clopidogrel (75 mg daily) and aspirin (100 mg daily) before the treatment. The patients were divided into 2 groups: CE (n = 31) and CAS (n = 40). The patients underwent prospective assessment of preoperative platelet function using VerifyNow assay and received adjunctive cilostazol (200 mg daily, triple antiplatelet therapy) in case of clopidogrel hyporesponse. Patients with clopidogrel hyper-response underwent clopidogrel dose reduction (clopidogrel, 12.5-50 mg daily). RESULTS: Clopidogrel resistance was noted in 15 patients (37.5%) in the CAS group and in 4 patients (12.9%) in the CE group (P = .031). Clopidogrel hyper-response was noted in 2 patients (5%) in the CAS group and in 11 patients (54.8%) in the CE group (P < .001). There was a significant difference in the baseline clinical characteristics between the 2 groups. In the multivariate logistic regression analysis, diabetes and age were independent predictors of clopidogrel hyporesponse, whereas current smoker was an independent predictor of clopidogrel hyper-response. CONCLUSIONS: Significant differences in baseline clinical characteristics were present when comparing patients undergoing endovascular treatment of unruptured cerebral aneurysms and carotid artery stenosis. Diabetes mellitus and current smoker status were independent factors related to reactivity to clopidogrel. PMID- 26493335 TI - Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer. AB - BACKGROUND: Resistance to chemotherapy is common in gastroesophageal cancer. Mechanisms of resistance are incompletely characterised and there are no predictive biomarkers in clinical practice for cytotoxic drugs. We used new cell line models to characterise novel chemotherapy resistance mechanisms and validated them in tumour specimens to identify new targets and biomarkers for gastroesophageal cancer. METHODS: Cell lines were selected for resistance to oxaliplatin, cisplatin and docetaxel and gene expression examined using Affymetrix Exon 1.0 ST arrays. Leads were validated by qRT-PCR and HPLC of tumour metabolites. Protein expression and pharmacological inhibition of lead target SPHK1 was evaluated in independent cell lines, and by immunohistochemistry in gastroesophageal cancer patients. RESULTS: Genes with differential expression in drug resistant cell lines compared to the parental cell line they were derived from, were identified for each drug resistant cell line. Biological pathway analysis of these gene lists, identified over-represented pathways, and only 3 pathways - lysosome, sphingolipid metabolism and p53 signalling- were identified as over-represented in these lists for all three cytotoxic drugs investigated. The majority of genes differentially expressed in chemoresistant cell lines from these pathways, were involved in metabolism of glycosphingolipids and sphingolipids in lysosomal compartments suggesting that sphingolipids might be important mediators of cytotoxic drug resistance in gastroeosphageal cancers . On further investigation, we found that drug resistance (IC50) was correlated with increased sphingosine kinase 1(SPHK1) mRNA and also with decreased sphingosine-1 phosphate lysase 1(SGPL1) mRNA. SPHK1 and SGPL1 gene expression were inversely correlated. SPHK1:SGPL1 ratio correlated with increased cellular sphingosine-1 phosphate (S1P), and S1P correlated with drug resistance (IC50). High SPHK1 protein correlated with resistance to cisplatin (IC50) in an independent gastric cancer cell line panel and with survival of patients treated with chemotherapy prior to surgery but not in patients treated with surgery alone. Safingol a SPHK1 inhibitor, was cytotoxic as a single agent and acted synergistically with cisplatin in gastric cancer cell lines. CONCLUSION: Agents that inhibit SPHK1 or S1P could overcome cytotoxic drug resistance in gastroesophageal cancer. There are several agents in early phase human trials including Safingol that could be combined with chemotherapy or used in patients progressing after chemotherapy. PMID- 26493336 TI - Ceftiofur hydrochloride affects the humoral and cellular immune response in pigs after vaccination against swine influenza and pseudorabies. AB - BACKGROUND: Cephalosporins are a class of antibiotics that are active against many Gram-positive and some Gram-negative bacteria. Beyond their antibacterial activity, they are reported to have various immunomodulatory properties. It has been shown that they reduce the secretion of cytokines as well as influence the humoral and cellular immune response. In the field conditions antibiotics are frequently administered at the same time as vaccines in pigs and, in the view of their potential immunomodulatory properties, it is important to examine their effect on the development and persistence of the post-vaccinal immune response. Ceftiofur is a very popular veterinary medicine third-generation cephalosporin with a broad spectrum of activity. It has been shown that it can inhibit cytokines secretion and in this way can potentially affect host immune response. The influence of ceftiofur on the immune response has not yet been investigated in pigs. In the present study we evaluated the influence of therapeutic doses of ceftiofur hydrochloride on the post-vaccinal immune response after vaccination with two model vaccines (live and inactivated). METHODS: Seventy pigs were divided into five groups: control, unvaccinated (C), control vaccinated against swine influenza (SI-V), control vaccinated against pseudorabies (PR-V), vaccinated against SI during ceftiofur administration (SI-CEF) and vaccinated against PR during ceftiofur administration (PR-CEF). Pigs from SICEF and PR-CEF groups received therapeutic dose of ceftiofur for five days. Pigs from SI-CEF, PR CEF, SIV and PR-V groups were vaccinated against SI and PR. Antibodies to PRV were determined with the use of blocking ELISA tests (IDEXX Laboratories, USA). Humoral responses to SIV were assessed based on haemagglutination inhibition assay. T-cell response was analyzed with the use of proliferation test. The concentrations of IFN- gamma and IL-4 in culture supernatant were determined with the use of ELISA kits Invitrogen Corporation, USA). RESULTS: The significant delay in the development of humoral response against pseudorabies virus (PRV) as well as a significant suppression of production of antibodies against swine influenza virus (SIV) was found in pigs receiving ceftiofur hydrochloride at the time of vaccination. The cellular immune response against PRV was also significantly affected by ceftiofur. In contrast, there were no significant differences between vaccinated groups with regard to the T-cell response against SIV. From day 28 of study to day 70, the concentration of INF-gamma in culture supernatants were significantly lower in group treated with ceftiofur after restimulation with PRV. While, no significant differences were observed after restimulation of PBMC with H3N2 SIV. CONCLUSIONS: The effect of an antibiotic therapy with ceftiofur hydrochloride on the humoral and cellular post-vaccinal immune responses in pigs was investigated. Ceftiofur hydrochloride was given in therapeutic doses. The results of the present study indicate that both, humoral and cell-mediated post-vaccinal immune responses can be modulated by treatment with ceftiofur hydrochloride. The results of our study point out that caution should be taken when administered this antibiotic during vaccination of pigs. PMID- 26493338 TI - Athletic Performance at the NFL Scouting Combine After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Anterior cruciate ligament (ACL) injuries are common and potentially career ending in the National Football League (NFL). Although statistical performance has been demonstrated after ACL reconstruction, functional performance is not well defined. PURPOSE/HYPOTHESIS: The purpose of this study was to determine the functional performance of NFL combine participants after ACL reconstruction compared with an age-, size-, and position-matched control group. The hypothesis was that there would be no difference between players after ACL reconstruction as compared with controls in functional athletic performance. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 98 NFL caliber athletes who had undergone primary ACL reconstruction and participated in the NFL scouting combine between 2010 and 2014 were reviewed and compared with an age-, size-, and position-matched control group. Data recorded for each player included a 40-yard dash, vertical leap, broad jump, shuttle drill, and 3-cone drill. RESULTS: With regard to speed and acceleration, the mean 40-yard dash time for ACL-reconstructed players was 4.74 seconds (range, 4.33-5.55 seconds) compared with controls at 4.74 seconds (range, 4.34-5.38 seconds; P = .96). Jumping performance was also similar, with a mean vertical leap for ACL reconstructed players of 33.35 inches (range, 23-43 inches) and broad jump of 113.9 inches (range, 96-136 inches) compared with respective values for the controls of 33.22 inches (range, 23.5-43.5 inches; P = .84) and 113.9 inches (range, 92-134 inches; P = .99). Agility and quickness testing measures also did not show a statistically significantly difference, with ACL-reconstructed players performing the shuttle drill in 4.37 seconds (range, 4.02-4.84 seconds) and the 3 cone drill in 7.16 seconds (range, 6.45-8.14 seconds), respectively, compared with respective times for the controls of 4.37 seconds (range, 3.96-5.00 seconds; P = .91) and 7.18 seconds (range, 6.64-8.24 seconds; P = .75). CONCLUSION: This study suggests that after ACL reconstruction, high-caliber athletes can achieve equivalent levels of performance with no statistically significant differences compared with matched controls. This information is unique when advising high level athletes on athletic performance after ACL reconstruction, suggesting that those who fully recover and return to play appear to have no decrement in athletic performance. PMID- 26493337 TI - Decreased Knee Joint Loading Associated With Early Knee Osteoarthritis After Anterior Cruciate Ligament Injury. AB - BACKGROUND: Anterior cruciate ligament (ACL) injury predisposes individuals to early-onset knee joint osteoarthritis (OA). Abnormal joint loading is apparent after ACL injury and reconstruction. The relationship between altered joint biomechanics and the development of knee OA is unknown. HYPOTHESIS: Altered knee joint kinetics and medial compartment contact forces initially after injury and reconstruction are associated with radiographic knee OA 5 years after reconstruction. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Individuals with acute, unilateral ACL injury completed gait analysis before (baseline) and after (posttraining) preoperative rehabilitation and at 6 months, 1 year, and 2 years after reconstruction. Surface electromyographic and knee biomechanical data served as inputs to an electromyographically driven musculoskeletal model to estimate knee joint contact forces. Patients completed radiographic testing 5 years after reconstruction. Differences in knee joint kinetics and contact forces were compared between patients with and those without radiographic knee OA. RESULTS: Patients with OA walked with greater frontal plane interlimb differences than those without OA (nonOA) at baseline (peak knee adduction moment difference: 0.00 +/- 0.08 N.m/kg.m [nonOA] vs -0.15 +/- 0.09 N.m/kg.m [OA], P = .014; peak knee adduction moment impulse difference: -0.001 +/ 0.032 N.m.s/kg.m [nonOA] vs -0.048 +/- 0.031 N.m.s/kg.m [OA], P = .042). The involved limb knee adduction moment impulse of the group with osteoarthritis was also lower than that of the group without osteoarthritis at baseline (0.087 +/- 0.023 N.m.s/kg.m [nonOA] vs 0.049 +/- 0.018 N.m.s/kg.m [OA], P = .023). Significant group differences were absent at posttraining but reemerged 6 months after reconstruction (peak knee adduction moment difference: 0.02 +/- 0.04 N.m/kg.m [nonOA] vs -0.06 +/- 0.11 N.m/kg.m [OA], P = .043). In addition, the OA group walked with lower peak medial compartment contact forces of the involved limb than did the group without OA at 6 months (2.89 +/- 0.52 body weight [nonOA] vs 2.10 +/- 0.69 body weight [OA], P = .036). CONCLUSION: Patients who had radiographic knee OA 5 years after ACL reconstruction walked with lower knee adduction moments and medial compartment joint contact forces than did those patients without OA early after injury and reconstruction. PMID- 26493339 TI - Threats, rewards, and attention deployment in anxious youth and adults: An eye tracking study. AB - The current study examines anxiety and age associations with attention allocation and physiological response to threats and rewards. Twenty-two healthy-adults, 20 anxious-adults, 26 healthy-youth, and 19 anxious-youth completed two eye-tracking tasks. In the Visual Scene Task (VST), participants' fixations were recorded while they viewed a central neutral image flanked by two threatening or two rewarding stimuli. In the Negative Words Task (NWT), physiological response was measured by means of pupil diameter change while negative and neutral words were presented. For both tasks, no interaction was found between anxiety and age group. In the VST, anxious participants avoided the threatening images when groups were collapsed across age. Similarly, adults but not adolescents avoided the threatening images when collapsed across anxiety. No differences were found for rewarding images. In NWT, all subjects demonstrated increase in pupil dilation after word presentation. Only main effect of age emerged with stronger pupil dilation in adults than children. Finally, maximum pupil change was correlated with threat avoidance bias in the scene task. Gaze patterns and pupil dilation show that anxiety and age are associated with attention allocation to threats. The relations between attention and autonomic arousal point to a complex interaction between bottom-up and top-down processes as they relate to attention allocation. PMID- 26493340 TI - Surprising sequential effects on MMN. AB - The mismatch negativity (MMN) is conceptualized as a confidence-weighted error signal elicited when a deviation violates the predicted next-state based on regularity. The mechanisms underpinning its generation remain contentious. Smaller MMN response is a robust finding in schizophrenia and reduced amplitude may implicate impairment in prediction-error signalling. An enriched understanding of factors that influence MMN size in healthy people is a prerequisite for translating the relevance of reduced MMN in schizophrenia. This paper features two studies designed to explore factors that impact MMN in healthy individuals. Study 1 confirms that MMN amplitude does not faithfully reflect transition statistics and is susceptible to order-driven bias. In study 2, we demonstrate that an order-driven bias remains despite repeated encounters with sound sequences. These data demonstrate that factors that impact on MMN size in non-clinical groups are not fully understood and that some mechanisms driving relevance filtering are likely influenced by 'top-down' expectations. PMID- 26493341 TI - Retrograde Intramedullary Nailing for Femoral Shaft Fractures in Elderly Patients with Previous Ipsilateral Dynamic Hip Screw Fixation. AB - PURPOSE: We present our experience in managing femoral shaft fractures in elderly patients with previous ipsilateral dynamic hip screw fixation for extracapsular neck of femur fractures using retrograde intramedullary nailing implants. METHODS: This was a prospective consecutive study of patients presenting with a femoral shaft fracture and an ipsilateral dynamic hip screw fixation treated with unreamed retrograde femoral nailing. The Wilde modification of the Neer knee score was used as a primary outcome measure. RESULTS: A total of 16 patients were included (5 males, 11 females), with a mean age of 82 years (range 74-101). All fractures were closed and were due to low-energy trauma. There were 7 patients with 32-A1 fractures, 5 patients with 32-A2 fractures and 4 patients with 32-B1 fractures. All patients had an ipsilateral 4-hole plate dynamic hip screw implant. Minor surgical complications were recorded in 5 patients. Two patients died due to medical complications and were excluded from the final analysis. All remaining 14 patients achieved satisfactory outcomes at 12 months of follow-up with a mean Wilde modification of the Neer knee score of 15.5 (SD 2.53; range 13 20). CONCLUSIONS: Unreamed retrograde femoral nailing can achieve good functional recovery in elderly patients with a femoral shaft fracture and a previous ipsilateral dynamic hip screw fixation. PMID- 26493342 TI - The association between myometrial electrical activity and time to delivery in threatened preterm labor. AB - OBJECTIVE: To assess the association between myometrial electrical activity and time-to-delivery in preterm labor using uterine electromyography. METHODS: Myometrial electrical activity was measured via the electrical uterine monitor (EUM) device. Data was prospectively collected among women admitted due to suspected preterm labor, prior to 34 weeks of gestation. EUM-Index was defined as the mean electrical activity of the uterine muscle over a period of 10 minutes measured in units of microjoule (MUJ, microwatt second). The association between the EUM-Index at admission to time-to-delivery and delivery prior to 34 weeks of gestation was calculated. RESULTS: Overall, 45 women were included in the study. EUM-Index combined with cervical dilatation, demonstrated significant correlation to time-to-delivery (R(2 )= 0.49, p = 0.005), which was strengthened for women presenting prior to 28 weeks of gestation. EUM-Index above the median (>3.05 MJ) was significantly associated with a shorter latency period for delivery (36.0 +/- 19.4 vs. 50.2 +/- 25.9 days, p = 0.04). For delivery prior to 34 weeks, the EUM Index showed an AUC = 0.65 (95% CI 0.48-0.82), and a cutoff of 2.5 MJ provided 91.7% sensitivity and 93.3% negative predictive value. CONCLUSION: EUM-Index at time of admission due to suspected preterm labor is inversely correlated with time-to-delivery and may effectively rule out preterm delivery prior to 34 weeks. PMID- 26493343 TI - Religious Participation is Associated with Increases in Religious Social Support in a National Longitudinal Study of African Americans. AB - This study reports on the association between religious beliefs and behaviors and the change in both general and religious social support using two waves of data from a national sample of African Americans. The Religion and Health in African Americans (RHIAA) study is a longitudinal telephone survey designed to examine relationships between various aspects of religious involvement and psychosocial factors over time. RHIAA participants were 3173 African American men (1281) and women (1892). A total of 1251 men (456) and women (795) participated in wave 2 of data collection. Baseline religious behaviors were associated with increased overall religious social support from baseline to wave 2 (p < .001) and with increased religious social support from baseline to wave 2 in each of the following religious social support subscales: emotional support received (p < .001), emotional support provided (p < .001), negative interaction (p < .001), and anticipated support (p < .001). Religious beliefs did not predict change in any type of support, and neither beliefs nor behaviors predicted change in general social support. African Americans who are active in faith communities showed increases in all types of religious social support, even the negative aspects, over a relatively modest longitudinal study period. This illustrates the strength of the church as a social network and the role that it plays in people's lives. PMID- 26493344 TI - The growth of railway ground vibration problems - A review. AB - Ground-borne noise and vibration from railway lines can cause human distress/annoyance, and also negatively affect real estate property values. Therefore this paper analyses a collection of technical ground-borne noise and vibration reports, detailing commercial vibration assessments undertaken at 1604 railway track sections, in 9 countries across the world. A wide range of rail projects are considered including light rail, tram lines, underground/tunnelled lines, freight, conventional rail and high speed rail. It documents the rise in ground-borne vibration problems and trends in the prediction industry, with the aim of informing the current research area. Firstly, the reports are analysed chronologically and it is found that railway vibration is a growing global concern, and as such, assessments have become more prevalent. International assessment metrics are benchmarked and it is found that velocity decibels (VdB), vibration dose value (VDV) and peak particle velocity (PPV) are the most commonly used methods of assessment. Furthermore, to predict vibration levels, the physical measurement of frequency transfer functions is preferential to numerical modelling. Results from the reports show that ground vibration limits are exceeded in 44% of assessments, and that ground-borne noise limits are exceeded in 31%. Moreover, mitigation measures were required on approximately 50% of projects, revealing that ground-borne noise and vibration is a widespread railroad engineering challenge. To solve these problems, the most commonly used abatement strategy is a modification of the railtrack structure (active mitigation), rather than the implementation of a more passive solution in the far field. PMID- 26493345 TI - Application of fault tree approach for the causation mechanism of urban haze in Beijing--Considering the risk events related with exhausts of coal combustion. AB - Haze weather has become a serious environmental pollution problem which occurs in many Chinese cities. One of the most critical factors for the formation of haze weather is the exhausts of coal combustion, thus it is meaningful to figure out the causation mechanism between urban haze and the exhausts of coal combustion. Based on above considerations, the fault tree analysis (FAT) approach was employed for the causation mechanism of urban haze in Beijing by considering the risk events related with the exhausts of coal combustion for the first time. Using this approach, firstly the fault tree of the urban haze causation system connecting with coal combustion exhausts was established; consequently the risk events were discussed and identified; then, the minimal cut sets were successfully determined using Boolean algebra; finally, the structure, probability and critical importance degree analysis of the risk events were completed for the qualitative and quantitative assessment. The study results proved that the FTA was an effective and simple tool for the causation mechanism analysis and risk management of urban haze in China. PMID- 26493346 TI - On the load-sharing along the ligamentous lumbosacral spine in flexed and extended postures: Finite element study. AB - A harmonic synergy between the load-bearing and stabilizing components of the spine is necessary to maintain its normal function. This study aimed to investigate the load-sharing along the ligamentous lumbosacral spine under sagittal loading. A 3D nonlinear detailed Finite Element (FE) model of lumbosacral spine with realistic geometry was developed and validated using wide range of numerical and experimental (in-vivo and in-vitro) data. The model was subjected to 500 N compressive Follower Load (FL) combined with 7.5 Nm flexion (FLX) or extension (EXT) moments. Load-sharing was expressed as percentage of total internal force/moment developed along the spine that each spinal component carried. These internal forces and moments were determined at the discs centres and included the applied load and the resisting forces in the ligaments and facet joints. The contribution of the facet joints and ligaments in supporting bending moments produced additional forces and moments in the discs. The intervertebral discs carried up to 81% and 68% of the total internal force in case of FL combined with FLX and EXT, respectively. The ligaments withstood up to 67% and 81% of the total internal moment in cases of FL combined with EXT and FLX, respectively. Contribution of the facet joints in resisting internal force and moment was noticeable at levels L4-S1 only particularly in case of FL combined with EXT and reached up 29% and 52% of the internal moment and force, respectively. This study demonstrated that spinal load-sharing depended on applied load and varied along the spine. PMID- 26493347 TI - Contact mechanics of reverse engineered distal humeral hemiarthroplasty implants. AB - Erosion of articular cartilage is a concern following distal humeral hemiarthroplasty, because native cartilage surfaces are placed in contact with stiff metallic implant components, which causes decreases in contact area and increases in contact stresses. Recently, reverse engineered implants have been proposed which are intended to promote more natural contact mechanics by reproducing the native bone or cartilage shape. In this study, finite element modeling is used in order to calculate changes in cartilage contact areas and stresses following distal humeral hemiarthroplasty with commercially available and reverse engineered implant designs. At the ulna, decreases in contact area were -34+/-3% (p=0.002), -27+/-1% (p<0.001) and -14+/-2% (p=0.008) using commercially available, bone reverse engineered and cartilage reverse engineered designs, respectively. Peak contact stresses increased by 461+/-57% (p=0.008), 387+/-127% (p=0.229) and 165+/-16% (p=0.003). At the radius, decreases in contact area were -21+/-3% (p=0.013), -13+/-2% (p<0.006) and -6+/-1% (p=0.020), and peak contact stresses increased by 75+/-52% (p>0.999), 241+/-32% (p=0.010) and 61+/ 10% (p=0.021). Between the three different implant designs, the cartilage reverse engineered design yielded the largest contact areas and lowest contact stresses, but was still unable to reproduce the contact mechanics of the native joint. These findings align with a growing body of evidence indicating that although reverse engineered hemiarthroplasty implants can provide small improvements in contact mechanics when compared with commercially available designs, further optimization of shape and material properties is required in order reproduce native joint contact mechanics. PMID- 26493348 TI - Treatment of lithium intoxication: facing the need for evidence. AB - Lithium has been used as the gold standard in the treatment of major depressive and bipolar disorders for decades. Due to its narrow therapeutic index, lithium toxicity is a common clinical problem. Although risk factors for lithium intoxication seem to be well-described, lacking patient education and inexperience of treatment are assumed to contribute to the probability of lithium intoxication. A review of literature shows that the treatment of lithium intoxication has not been adequately studied or standardized. The aim of this literature review is to compile and present current evidence on the treatment of lithium intoxication and contribute to a standardization regarding general treatment recommendations as well as evidence on indication for extracorporeal methods. Against the background of this common and potentially life-threatening condition, the standardization of the treatment of lithium intoxication is definitely a task for the future. PMID- 26493349 TI - MMSA-1 expression pattern in multiple myeloma and its clinical significance. AB - Multiple myeloma-associated antigen-1 (MMSA-1) is a novel multiple myeloma (MM) associated antigen which has been recently identified. Herein, we have tried to examine its clinical significance by studying the relationship between its expression and selected clinicopathological features. We extracted mononuclear cells from the bone marrow of MM patients and healthy donors and compared the MMSA-1 expression by RT-PCR and Western blot analysis. In addition, we also analyzed MMSA-1 expression in patients that were grouped based on selected clinical parameters. Moreover, the impact of MMSA-1 on patients' survival was also explored. MMSA-1 mRNA and protein were significantly upregulated in MM patients in comparison with healthy donors. Moreover, among the newly diagnosed and relapsed/refractory patients, the MMSA-1 expression was higher in relapsed/refractory patients. In addition, MMSA-1 mRNA expression not only showed significantly higher correlation with clinical parameters such as age, Durie and Salmon stage, bone lesion condition, albumin, creatinine and lactate dehydrogenase but also has a close relationship with myeloma bone disease-related cytokines, genetic abnormalities and treatment response. Multivariate COX analysis predicted MMSA-1 and LDH levels to be independently associated with a poor progression-free survival and overall survival in myeloma patients. Our findings provide initial proof of concept that MMSA-1 is a potent gene that is specifically expressed in MM patients and could be a feasible biomarker and independent prognostic factor. PMID- 26493350 TI - TGF-beta/BMP proteins as therapeutic targets in renal fibrosis. Where have we arrived after 25 years of trials and tribulations? AB - The understanding of renal fibrosis in chronic kidney disease (CKD) remains as a challenge. More than 10% of the population of developed countries suffer from CKD. Proliferation and activation of myofibroblasts and accumulation of extracellular matrix proteins are the main features of kidney fibrosis, a process in which a large number of cytokines are involved. Targeting cytokines responsible for kidney fibrosis development might be an important strategy to face the problem of CKD. The increasing knowledge of the signaling pathway network of the transforming growth factor beta (TGF-beta) superfamily members, such as the profibrotic cytokine TGF-beta1 or the bone morphogenetic proteins (BMPs), and their involvement in the regulation of kidney fibrosis, has stimulated numerous research teams to look for potential strategies to inhibit profibrotic cytokines or to enhance the anti-fibrotic actions of other cytokines. The consequence of all these studies is a better understanding of all these canonical (Smad-mediated) and non-canonical signaling pathways. In addition, the different receptors involved for signaling of each cytokine, the different combinations of type I-type II receptors, and the presence and function of co receptors that can influence the biological response have been also described. However, are these studies leading to suitable strategies to block the appearance and progression of kidney fibrosis? In this review, we offer a critical perspective analyzing the achievements using the most important strategies developed up till now: TGF-beta antibodies, chemical inhibitors of TGF-beta receptors, miRNAs and signaling pathways and BMP agonists with a potential role as therapeutic molecules against kidney fibrosis. PMID- 26493352 TI - A Cluster-Randomized Controlled Trial of the Catheter Reminder and Evaluation Program. PMID- 26493351 TI - Association of the variants and haplotypes in the DOCK7, PCSK9 and GALNT2 genes and the risk of hyperlipidaemia. AB - Little is known about the association between the single nucleotide polymorphisms (SNPs) and haplotypes of the dedicator of cytokinesis 7 (DOCK7), pro-protein convertase subtilisin/kexin type 9 (PCSK9) and polypeptide N acetylgalactosaminyltransferase 2 (GALNT2) and serum lipid traits in the Chinese populations. This study was to determine the association between nine SNPs in the three genes and their haplotypes and hypercholesterolaemia (HCH)/hypertriglyceridaemia (HTG), and to identify the possible gene-gene interactions among these SNPs. Genotyping was performed in 733 HCH and 540 HTG participants. The haplotype of C-C-G-C-T-G-C-C-G [in the order of DOCK7 rs1168013 (G>C), rs10889332 (C>T); PCSK9 rs615563 (G>A), rs7552841 (C>T), rs11206517 (T>G); and GALNT2 rs1997947 (G>A), rs2760537 (C>T), rs4846913 (C>A) and rs11122316 (G>A) SNPs] was associated with increased risk of HCH and HTG. The haplotypes of C-C-G C-T-G-C-C-A and G-C-G-T-T-G-T-C-G were associated with a reduced risk of HCH and HTG. The haplotypes of G-C-G-C-T-G-C-C-A and G-C-G-C-T-G-T-C-G were associated with increased risk of HCH. The haplotypes of C-T-G-C-T-G-C-C-G, G-C-A-C-T-G-C-C G and G-C-G-C-T-G-C-C-A were associated with an increased risk of HTG. The haplotypes of G-C-G-C-T-G-T-C-A and G-C-G-T-T-G-T-C-G were associated with a reduced risk of HTG. In addition, possible inter-locus interactions among the DOCK7, PCSK9 and GALNT2 SNPs were also noted. However, further functional studies of these genes are still required to clarify which SNPs are functional and how these genes actually affect the serum lipid levels. PMID- 26493353 TI - Cognitive training approaches to remediate attention and executive dysfunction after traumatic brain injury: A single-case series. AB - Attentional deficits are common following traumatic brain injury (TBI) and interfere with daily functioning. This study employed a single-case design to examine the effects of individualised strategy training on attention beyond the effects of computerised training using Attention Process Training 3 (APT-3), and to examine the participants' subjective experience of these approaches. An ABCA (baseline, APT-3, strategy training, follow-up) design was repeated across three participants with severe TBI. Outcomes were measured on alternate versions of the oral Symbol Digit Modalities Test (SDMT) and cancellation tasks; generalisation with the Test of Everyday Attention (TEA) and self and significant other (SO) ratings on the Rating Scale of Attentional Behaviour (RSAB); and participant experiences with semi-structured interviews. Planned Tau-U analyses revealed improvements in speed of processing on the SDMT and the automatic condition of the cancellation task after APT-3 and at follow-up, but with most improvement after strategy training. Limited generalisation was evident on TEA subtests and self-RSAB ratings. SO-RSAB ratings were mixed after APT-3, but demonstrated improvement after strategy training. Variability in attentional deficits and everyday attentional requirements between patients required individualised goals and approaches to rehabilitation. This study highlights the need for individualised rehabilitation of attention to improve everyday functioning after TBI. PMID- 26493354 TI - [Haut Conseil de la Sante Publique (HCSP). Guidance on the prioritization of antiviral drugs in case of seasonal influenza epidemics (March 3, 2015)]. PMID- 26493355 TI - Exanthema, fever and arthralgia in a pregnant woman. PMID- 26493356 TI - [Laboratory diagnosis of Clostridium difficile infection]. AB - Clostridium difficile is the leading cause of nosocomial diarrhoea in developed countries, and is one of the main aetiologic agents of community diarrhea. The eruption of the hypervirulent strain BI/NAP1/027 has given rise to an increase in the morbidity and mortality of C.difficile infection (CDI). This document aims to review the main clinical pictures of CDI and the laboratory diagnosis, including sampling, transport and storage of specimens, specimen processing, diagnostic procedures, antimicrobial susceptibility testing, and molecular characterisation of the isolates. The main purpose of the article is to develop a practical document that provides answers to the main questions that arise in the laboratory diagnosis of CDI. PMID- 26493357 TI - Paralympic athletes with cerebral palsy display altered pacing strategies in distance-deceived shuttle running trials. AB - This study investigated performance and physiology to understand pacing strategies in elite Paralympic athletes with cerebral palsy (CP). Six Paralympic athletes with CP and 13 able-bodied (AB) athletes performed two trials of eight sets of 10 shuttles (total 1600m). One trial was distance-deceived (DEC, 1000 m + 600 m) one trial was nondeceived (N-DEC, 1600 m). Time (s), heart rate (HR, bpm), ratings of perceived exertion (RPE, units), and electromyography of five bilateral muscles (EMG) were recorded for each set of both trials. The CP group ran slower than the AB group, and pacing differences were seen in the CP DEC trial, presenting as a flat pacing profile over the trial (P < 0.05). HR was higher and RPE was lower in the CP group in both trials (P < 0.05). EMG showed small differences between groups, sides, and trials. The present study provides evidence for a possible pacing strategy underlying exercise performance and fatigue in CP. The results of this study show (1) underperformance of the CP group, and (2) altered pacing strategy utilization in the CP group. We proposed that even at high levels of performance, the residual effects of CP may negatively affect performance through selection of conservative pacing strategies during exercise. PMID- 26493359 TI - Practical aspects of backward bifurcation in a mathematical model for tuberculosis. AB - In this work, we examine practical aspects of backward bifurcation for a data based model of tuberculosis that incorporates multiple features which have previously been shown to produce backward bifurcation (e.g. exogenous reinfection and imperfect vaccination) and new considerations such as the treatment of latent TB infection (LTBI) and the BCG vaccine's interference with detecting LTBI. Understanding the interplay between these multiple factors and backward bifurcation is particularly timely given that new diagnostic tests for LTBI detection could dramatically increase rates of both LTBI detection and vaccination in the coming decades. By establishing analytic thresholds for the existence of backward bifurcation, we identify those aspects of TB's complicated pathology that make backward bifurcation more or less likely to occur. We also examine the magnitude of the backward bifurcation produced by the model and its sensitivity to various model parameters. We find that backward bifurcation is unlikely to occur. While increased vaccine coverage and/or increased detection and treatment of LTBI can push the threshold for backward bifurcation into the region of biological plausibility, the resulting bifurcations may still be too small to have any noticeable epidemiological impact. PMID- 26493358 TI - Design, synthesis, and characterization of nucleosomes containing site-specific DNA damage. AB - How DNA damaged is formed, recognized, and repaired in chromatin is an area of intense study. To better understand the structure activity relationships of damaged chromatin, mono and dinucleosomes containing site-specific damage have been prepared and studied. This review will focus on the design, synthesis, and characterization of model systems of damaged chromatin for structural, physical, and enzymatic studies. PMID- 26493360 TI - In silico identification of putative bifunctional Plk1 inhibitors by integrative virtual screening and structural dynamics approach. AB - Polo like kinase (Plk1) is a master regulator of cell cycle and considered as next generation antimitotic target in human. As Plk1 predominantly expresses in the dividing cells with a much higher expression in cancerous cells, it serves as a discriminative target for cancer therapeutics. Here we implied a novel and promising integrative strategy to identify "bifunctional" Plk1 inhibitors that compete simultaneously with ATP and substrate for their binding sites. We integrated structure-based virtual screening (SBVS) and molecular dynamics simulations with emphasis on unique structural properties of Plk1. Through screening of 20,000 compounds, nearly ~2000 hits were enriched and subjected to SBVS against ATP and substrate binding sites of Plk1. Subsequently, on the basis of their binding abilities to Plk1 kinase and polo box domains, filtration of candidate hits resulted in the isolation of 26 compounds. By exclusion of close analogs or isomers, 10 unique compounds were selected for detailed study. A representative compound was subjected to molecular dynamics simulation assay to have deep structural insights and to gauge critical structural crunch for inhibitor binding against kinase and polo box domains. Our integrative approach may complement high-throughput screening and identify bifunctional Plk1 inhibitors that may contribute in selective targeting of Plk1 to elicit desired biological process. PMID- 26493361 TI - Modeling nanoparticle delivery of TB drugs to granulomas. AB - Tuberculosis, which typically presents as a pulmonary disease, has a complex pathology. The primary site of infection, the Ghon focus, recruits immune cells and a granuloma forms. At earlier stages the granuloma is still vascularized, offering the best opportunity for drug treatment. In the more progressive state blood flow is reduced and a distinct caseous structure develops. Effective delivery of drugs to bacilli in the core of the granuloma becomes very difficult. It is perceivable that granuloma cores could create conditions where bacilli persist and develop resistance. In this study we analyze drug delivery to granulomas by means of a nanoparticle delivery system. The model consists of two parts; the overall distribution of the nanoparticles is described by a simple circulatory model and this result is used in the second part, focusing on transport in a capillary lined with macrophages. Nanoparticles enter the macrophages where they are metabolized and the drugs are released. The model reveals significant differences in drug concentrations between the plasma and macrophages. Based on the results of the model, strategies for improved drug delivery are proposed. PMID- 26493363 TI - Dioxygen-Mediated Decarbonylative C-H Alkylation of Heteroaromatic Bases with Aldehydes. AB - An operationally simple and economical method for the direct alkylation of heteroaromatic bases employing readily available aldehydes as alkyl radical precursors and molecular oxygen as a reagent is presented. This simple transformation demonstrates a broad substrate scope with respect to aldehydes and nitrogen heterocycles, enabling the introduction of several medicinally important yet challenging alkyl moieties, such as ethyl, isopropyl, tert-butyl, and cyclohexyl to the different classes of heterocyclic bases in good to excellent yields. PMID- 26493362 TI - How Schizophrenia Develops: Cognitive and Brain Mechanisms Underlying Onset of Psychosis. AB - Identifying cognitive and neural mechanisms involved in the development of schizophrenia requires longitudinal observation of individuals prior to onset. Here recent studies of prodromal individuals who progress to full psychosis are briefly reviewed in relation to models of schizophrenia pathophysiology. Together, this body of work suggests that disruption in brain connectivity, driven primarily by a progressive reduction in dendritic spines on cortical pyramidal neurons, may represent a key triggering mechanism. The earliest disruptions appear to be in circuits involved in referencing experiences according to time, place, and agency, which may result in a failure to recognize particular cognitions as self-generated or to constrain interpretations of the meaning of events based on prior experiences, providing the scaffolding for faulty reality testing. PMID- 26493364 TI - Integrated multi-omics analyses reveal the pleiotropic nature of the control of gene expression by Puf3p. AB - The PUF family of RNA-binding proteins regulate gene expression post transcriptionally. Saccharomyces cerevisiae Puf3p is characterised as binding nuclear-encoded mRNAs specifying mitochondrial proteins. Extensive studies of its regulation of COX17 demonstrate its role in mRNA decay. Using integrated genome wide approaches we define an expanded set of Puf3p target mRNAs and quantitatively assessed the global impact of loss of PUF3 on gene expression using mRNA and polysome profiling and quantitative proteomics. In agreement with prior studies, our sequencing of affinity-purified Puf3-TAP associated mRNAs (RIP seq) identified mRNAs encoding mitochondrially-targeted proteins. Additionally, we also found 720 new mRNA targets that predominantly encode proteins that enter the nucleus. Comparing transcript levels in wild-type and puf3? cells revealed that only a small fraction of mRNA levels alter, suggesting Puf3p determines mRNA stability for only a limited subset of its target mRNAs. Finally, proteomic and translatomic studies suggest that loss of Puf3p has widespread, but modest, impact on mRNA translation. Taken together our integrated multi-omics data point to multiple classes of Puf3p targets, which display coherent post-transcriptional regulatory properties and suggest Puf3p plays a broad, but nuanced, role in the fine-tuning of gene expression. PMID- 26493365 TI - Defective titanium dioxide single crystals exposed by high-energy {001} facets for efficient oxygen reduction. AB - The cathodic material plays an essential role in oxygen reduction reaction for energy conversion and storage systems. Titanium dioxide, as a semiconductor material, is usually not recognized as an efficient oxygen reduction electrocatalyst owning to its low conductivity and poor reactivity. Here we demonstrate that nano-structured titanium dioxide, self-doped by oxygen vacancies and selectively exposed with the high-energy {001} facets, exhibits a surprisingly competitive oxygen reduction activity, excellent durability and superior tolerance to methanol. Combining the electrochemical tests with density functional calculations, we elucidate the defect-centred oxygen reduction reaction mechanism for the superiority of the reductive {001}-TiO2-x nanocrystals. Our findings may provide an opportunity to develop a simple, efficient, cost-effective and promising catalyst for oxygen reduction reaction in energy conversion and storage technologies. PMID- 26493366 TI - The prevalence of developmental delay among children aged 3-60 months in Izmir, Turkey. AB - BACKGROUNDS: Developmental delay is defined as delays in speech and language development, motor development, social-emotional development and cognitive development. On a global scale, the prevalence estimations in paediatric population range between 5% and 15%. However, no prevalence studies on developmental delay have been conducted in primary care in Turkey. The aim of this study was to determine the prevalence of developmental delay among children aged 3-60 months in Izmir. METHODS: This cross-sectional, descriptive study involved 1514 children aged 3-60 months, who were at 12 primary health centres for various reasons in Izmir between 1 November 2013 and 31 January 2014. The questionnaire and age-specific Turkish version of the Ages and Stages Questionnaires were applied to mothers via face-to-face interview. RESULTS: The prevalence of developmental delay was 6.4% (95% confidence interval 5.2-7.7). The prevalence for age groups varied between 3.3% and 12.1%. Significant associations were found between developmental delay and maternal age, maternal/paternal education, socio-economic level of the family and the presence of consanguineous marriage. CONCLUSIONS: Identifying developmental delay in children earlier by a validated, reliable, parent-completed questionnaire like Ages and Stages Questionnaires and detecting risk factors for delay are crucial for primary care where their growth and development are monitored. Identifying developmental delay and early referral to rehabilitation services may help improve children's quality of life. PMID- 26493368 TI - Solid-State Chemistry on the Nanoscale: Ion Transport through Interstitial Sites or Vacancies? AB - How can ion-exchange process occur in nanocrystals without the size and shape changing and why is the ion transport much faster than in classical interdiffusion processes in macrocrystalline solids? We have investigated these processes at the molecular level by means of high-resolution and analytical electron microscopy in temperature-dependent kinetic experiments for several model reactions. The results clearly show a diffusion process that proceeds exclusively through the interstitial lattice positions with a subsequent "kick out" to remove individual ions from lattice sites without the formation of vacancies. This mechanism has not been observed in nanocrystalline systems before. PMID- 26493369 TI - Serviceable and consistent: The goal of metapsychology. PMID- 26493370 TI - Cardiopulmonary resuscitation: Time for all of us to feel the pressure. PMID- 26493371 TI - Neurodegeneration and Cancer: Where the Disorder Prevails. AB - It has been reported that genes up-regulated in cancer are often down-regulated in neurodegenerative disorders and vice versa. The fact that apparently unrelated diseases share functional pathways suggests a link between their etiopathogenesis and the properties of molecules involved. Are there specific features that explain the exclusive association of proteins with either cancer or neurodegeneration? We performed a large-scale analysis of physico-chemical properties to understand what characteristics differentiate classes of diseases. We found that structural disorder significantly distinguishes proteins up regulated in neurodegenerative diseases from those linked to cancer. We also observed high correlation between structural disorder and age of onset in Frontotemporal Dementia, Parkinson's and Alzheimer's diseases, which strongly supports the role of protein unfolding in neurodegenerative processes. PMID- 26493372 TI - The Dialogue Continues: The Future of Public Health Nursing. AB - This editorial reflects upon the current discussion among nursing academics and educators about the division between individual level care and population health and its implications for the subdiscipline of public health nursing, from the perspective of a current practitioner in the field. PMID- 26493373 TI - The Preparation of Community/Public Health Nurses: Amplifying the Impact. AB - In summary, improved population health, population focused care, and community based networks are the objectives of health care delivery systems. Community/public health nursing education, practice, and research must be re examined, re-focused, and re-designed to address the challenges of an expanding 21st century health care delivery to populations and communities. Common standards are in place to be utilized by academia, practice and research. With a unified front, C/PHN can collectively play an important transformative role and go forward to meet the ever expanding challenges of the 21st century populations and communities. The Association of Public Health Nurses (APHN) and the Association of Community Health Nurse Educator (ACHNE) have a joint meeting planned in June 2016 in Indianapolis. Please bring your colleagues, stakeholders, and community partners to join the voices of C/PHN to make a positive impact on the changing health care environment through our education, practice and work. PMID- 26493374 TI - Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding. AB - BACKGROUND AND PURPOSE: Although the ongoing clinical trials of ABT-263 and ABT 199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge. EXPERIMENTAL APPROACH: The LD50 values of ABT-737, ABT-263 and ABT-199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl-2 family proteins, including phosphorylated Bcl-2 (pBcl-2) and their interactions were measured by immunoblotting and co immunoprecipitation. In vitro binding assays were performed by isothermal titration calorimetry and ELISA. BH3 profiling in isolated mitochondria was analysed. KEY RESULTS: The ratio of (Mcl-1 + pBcl-2) to Bcl-2 expression provided the most significant predictive marker for the cytotoxic potential of ABT-737, ABT-263 and ABT-199 in the panel of CLL samples. Mechanistically, pBcl-2 inhibited the effects of the ABT compounds on the displacement of Bax and Bim from Bcl-2, thereby suppressing mitochondrial apoptosis. The ABT compounds exhibited 100-300-fold lower binding affinity to the glutamic acid, phosphomimetic, mutant of Bcl-2 (T69E, S70E and S87E; EEE-Bcl-2). BH3 peptides exhibited different rank orders of binding affinities to full-length WT-Bcl-2 and full-length EEE-Bcl-2. CONCLUSIONS AND IMPLICATIONS: Our study suggested that a structural alteration in the BH3-binding groove was induced by phosphorylation of Bcl-2. Our data also provided a framework to overcome resistance of CLL cells to the ABT compounds by combining pBcl-2 kinase inhibitors with the ABT compounds. PMID- 26493375 TI - Light exposure before learning improves memory consolidation at night. AB - Light is recently recognized as a modulator able to activate the hippocampus and modulate memory processing, but little is known about the molecular mechanisms. Here, we report that in mice, a short pulse of white light before learning dramatically improves consolidation of contextual fear memory during the night. The light exposure increases hippocampal active p21-activated kinase 1 (PAK1) and CA1 long-term potentiation (LTP). These light effects are abolished in PAK1 knockout and dominant-negative transgenic mice, but preserved by expression of constitutively active PAK1 in the hippocampus. Our results indicate that light can act as a switch of PAK1 activity that modulate CA1 LTP and thereby memory consolidation without affecting learning and short-term memory. PMID- 26493376 TI - Heart rate and suicide: findings from two cohorts of 533 000 Taiwanese and 75 000 Norwegian adults. AB - OBJECTIVE: To investigate the association of resting heart rate with suicide in two large cohorts. METHOD: The MJ cohort (Taiwan) included 532 932 adults from a health check-up programme (1994-2008). The HUNT cohort (Norway) included 74 977 adults in the Nord-Trondelag County study (1984-1986), followed up to 2004. In both cohorts heart rate was measured at baseline, and suicide was ascertained through linkage to cause-of-death registers. Risk of suicide was estimated using Cox proportional hazards models. RESULTS: There were 569 and 188 suicides (average follow-up period of 8.1 and 16.9 years) in the MJ and HUNT cohorts respectively. Sex- and age-adjusted hazard ratio for every 10 beat increase in heart rate per minute was 1.08 (95% Confidence Interval 1.00-1.16) and 1.24 (1.12 1.38) in the MJ and HUNT cohorts, respectively. In the MJ cohort this association was confined to individuals with a history of heart diseases vs. those without such a history (P for interaction = 0.008). In the HUNT cohort the association did not differ by history of heart diseases and was robust to adjustment for health-related life style, medication use, and symptoms of anxiety and depression. CONCLUSION: Elevated resting heart rate may be a marker of increased suicide risk. PMID- 26493377 TI - A comprehensive compartmental model of blood glucose regulation for healthy and type 2 diabetic subjects. AB - We have expanded a former compartmental model of blood glucose regulation for healthy and type 2 diabetic subjects. The former model was a detailed physiological model which considered the interactions of three substances, glucose, insulin and glucagon on regulating the blood sugar. The main drawback of the former model was its restriction on the route of glucose entrance to the body which was limited to the intravenous glucose injection. To handle the oral glucose intake, we have added a model of glucose absorption in the gastrointestinal tract to the former model to address the resultant variations of blood glucose concentrations following an oral glucose intake. Another model representing the incretins production in the gastrointestinal tract along with their hormonal effects on boosting pancreatic insulin production is also added to the former model. We have used two sets of clinical data obtained during oral glucose tolerance test and isoglycemic intravenous glucose infusion test from both type 2 diabetic and healthy subjects to estimate the model parameters and to validate the model results. The estimation of model parameters is accomplished through solving a nonlinear optimization problem. The results show acceptable precision of the estimated model parameters and demonstrate the capability of the model in accurate prediction of the body response during the clinical studies. PMID- 26493378 TI - Outcomes of acute kidney injury patients with and without cancer. AB - Incidence of AKI in hospitalized patients with cancer is increasing, but there have been few studies on AKI in patients with cancer. We conducted a retrospective cohort study in a South Korean tertiary care hospital. A total of 2211 consecutive patients (without cancer 61.5%; with cancer 38.5%) were included over a 140-month period. Predictors of all-cause death were examined using the Kaplan-Meier method and the Cox proportional hazards model. The main contributing factors of AKI were sepsis (31.1%) and ischemia (52.7%). AKI was multifactorial in 78% of patients with cancer and in 71% of patients without cancer. Hospital mortality rates were higher in patients with cancer (42.8%) than in patients without cancer (22.5%) (p = 0.014). In multivariate analyses, diabetes mellitus (DM) and cancer diagnosis were associated with hospital mortality. Cancer diagnosis was independently associated with mortality [odds ratio = 3.010 (95% confidence interval, 2.340-3.873), p = 0.001]. Kaplan-Meier analysis revealed that subjects with DM and cancer (n = 146) had lower survival rates than subjects with DM and without cancer (n = 687) (log rank test, p = 0.001). The presence of DM and cancer was independently associated with mortality in AKI patients both with and without cancer. Studies are warranted to determine whether proactive measures may limit AKI and improve outcomes. PMID- 26493379 TI - Extraoral cutaneous sinus tracts of dental origin in the paediatric patient. A report of three cases and a review of the literature. AB - BACKGROUND: An extraoral sinus of odontogenic origin within the face and neck region is normally the consequence of long-standing chronic infection due to caries, trauma or periodontal infection. There is little reported literature on the prevalence of extraoral cutaneous sinus lesions in the paediatric dental patient as presentation is often delayed resulting in misdiagnosis and consequential mismanagement. CASE REPORT: The cases discussed concentrate on the aetiology, history, presentation and diagnosis of extraoral sinus lesions that presented in children referred to the Child Dental Health Department at the University Dental Hospital of Manchester over a six-month period. CONCLUSIONS: The importance of correct diagnosis and treatment management of an extra oral cutaneous sinus in the paediatric patient only occurred when the child attended a specialist led paediatric dental clinic for consultation. PMID- 26493380 TI - Comparison of 10,11-Dehydrocurvularin Polyketide Synthases from Alternaria cinerariae and Aspergillus terreus Highlights Key Structural Motifs. AB - Iterative type I polyketide synthases (PKSs) from fungi are multifunctional enzymes that use their active sites repeatedly in a highly ordered sequence to assemble complex natural products. A phytotoxic macrolide with anticancer properties, 10,11-dehydrocurvularin (DHC), is produced by cooperation of a highly reducing (HR) iterative PKS and a non-reducing (NR) iterative PKS. We have identified the DHC gene cluster in Alternaria cinerariae, heterologously expressed the active HR PKS (Dhc3) and NR PKS (Dhc5) in yeast, and compared them to corresponding proteins that make DHC in Aspergillus terreus. Phylogenetic analysis and homology modeling of these enzymes identified variable surfaces and conserved motifs that are implicated in product formation. PMID- 26493381 TI - Lumazine Synthase Protein Nanoparticle-Gd(III)-DOTA Conjugate as a T1 contrast agent for high-field MRI. AB - With the applications of magnetic resonance imaging (MRI) at higher magnetic fields increasing, there is demand for MRI contrast agents with improved relaxivity at higher magnetic fields. Macromolecule-based contrast agents, such as protein-based ones, are known to yield significantly higher r1 relaxivity at low fields, but tend to lose this merit when used as T1 contrast agents (r1/r2 = 0.5 ~ 1), with their r1 decreasing and r2 increasing as magnetic field strength increases. Here, we developed and characterized an in vivo applicable magnetic resonance (MR) positive contrast agent by conjugating Gd(III)-chelating agent complexes to lumazine synthase isolated from Aquifex aeolicus (AaLS). The r1 relaxivity of Gd(III)-DOTA-AaLS-R108C was 16.49 mM(-1)s(-1) and its r1/r2 ratio was 0.52 at the magnetic field strength of 7 T. The results of 3D MR angiography demonstrated the feasibility of vasculature imaging within 2 h of intravenous injection of the agent and a significant reduction in T1 values were observed in the tumor region 7 h post-injection in the SCC-7 flank tumor model. Our findings suggest that Gd(III)-DOTA-AaLS-R108C could serve as a potential theranostic nanoplatform at high magnetic field strength. PMID- 26493383 TI - Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use. AB - Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome characterized by cardiovascular, metabolic, and pro inflammatory diseases associated with advanced age and extracardiac comorbidities. All of these conditions finally lead to impairment of myocardial structure and function. The large phenotypic heterogeneity of HFpEF from pathophysiological underpinnings presents a major hurdle to HFpEF therapy. The new therapeutic approach in HFpEF should be targeted to each HF phenotype, instead of the 'one-size-fits-all' approach, which has not been successful in clinical trials. Unless the structural and biological determinants of the failing heart are deeply understood, it will be impossible to appropriately differentiate HFpEF patients, identify subtle myocardial abnormalities, and finally reverse abnormal cardiac function. Based on evidence from endomyocardial biopsies, some of the specific cardiac structural phenotypes to be targeted in HFpEF may be represented by myocyte hypertrophy, interstitial fibrosis, myocardial inflammation associated with oxidative stress, and coronary disease. Once the diagnosis of HFpEF has been established, a potential approach could be to use a panel of biomarkers to identify the main cardiac structural HFpEF phenotypes, guiding towards more appropriate therapeutic strategies. Accordingly, the purpose of this review is to investigate the potential role of biomarkers in identifying different cardiac structural HFpEF phenotypes and to discuss the merits of a biomarker-guided strategy in HFpEF. PMID- 26493382 TI - Gliomatosis cerebri: no evidence for a separate brain tumor entity. AB - Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification. PMID- 26493384 TI - The bitter truth about bitter taste receptors: beyond sensing bitter in the oral cavity. AB - The bitter taste receptor (TAS2R)-family of G-protein-coupled receptors has been identified on the tongue as detectors of bitter taste over a decade ago. In the last few years, they have been discovered in an ever growing number of extra-oral tissues, including the airways, the gut, the brain and even the testis. In tissues that contact the exterior, protective functions for TAS2Rs have been proposed, in analogy to their function on the tongue as toxicity detector. However, TAS2Rs have also been found in internal organs, suggesting other roles for these receptors, perhaps involving as yet unidentified endogenous ligands. The current review gives an overview of the different proposed functions for TAS2Rs in tissues other than the oral cavity; from appetite regulation to the treatment of asthma, regulation of gastrointestinal motility and control of airway innate immunity. PMID- 26493385 TI - Benzodiazepine-associated delirium dosing strategy or cumulative dose? PMID- 26493386 TI - Hospitalized patients at risk of dying: an Intensive Care Medicine call for papers. PMID- 26493387 TI - BCOR internal tandem duplication and YWHAE-NUTM2B/E fusion are mutually exclusive events in clear cell sarcoma of the kidney. AB - Clear cell sarcoma of the kidney (CCSK) is the second most common pediatric renal tumor. Two recurrent genetic aberrations have been described in CCSK. One is a fusion of YWHAE and NUTM2B/E, the other is an internal tandem duplication (ITD) in the BCOR gene. Here it is shown that YWHAE-NUTM2B/E fusion and the BCOR ITD are mutually exclusive events and activated different downstream signaling systems. This has important diagnostic implications and opens up for further mechanistic studies of CCSK pathogenesis. PMID- 26493388 TI - Assessment of branch pulmonary artery stenosis in children after repair of tetralogy of Fallot using lung perfusion scintigraphy comparison with echocardiography. AB - PURPOSE: The aim of this study was to compare the usefulness of lung perfusion scintigraphy and echocardiogram in the evaluation of the branch pulmonary arteries stenosis in children with tetralogy of Fallot (TOF). MATERIALS AND METHODS: From February 2006 to November 2008, 74 children (mean age 7.8 years, range 1-18 years) who underwent repair of TOF at ages from 10 months to 13 years were suspected to have unilateral or bilateral branch pulmonary artery stenosis. In all patients, cardiac angiography was performed to confirm the diagnosis of branch pulmonary artery stenosis. Lung perfusion scintigraphy and two-dimensional transthoracic echocardiography were performed in all patients to compare their abilities to diagnose branch pulmonary artery stenosis. RESULTS: Of the 74 patients, 51 cases were found to have branch pulmonary artery stenosis by cardiac angiography. There was agreement between the scintigraphic and angiographic findings in 44 (86%) patients and there were discrepancies in 11 (15%) patients. The positive predictive value of our lung perfusion scintigraphy in detecting the branch pulmonary artery stenosis was 92 %. The positive and negative likelihood ratios of lung perfusion scintigraphy were 4.96 and 0.17, respectively. There was conformity between the echocardiographic and angiographic findings in 40 (78%) patients with discrepancies in 16 (21%) patients. The positive predictive value of our echocardiography in detecting the branch pulmonary artery stenosis was 89%. The positive and negative likelihood ratios of echocardiography were 3.61 and 0.28, respectively. CONCLUSIONS: Lung perfusion scintigraphy is a valuable, non-invasive screening tool in the assessment of branch pulmonary artery stenosis in children after TOF. PMID- 26493389 TI - Secondary patella resurfacing in painful non-resurfaced total knee arthroplasties : A study of survival and clinical outcome from the Norwegian Arthroplasty Register (1994-2011). AB - PURPOSE: In Norway, 19 % of revisions of non-resurfaced total knee arthroplasties done for knee pain between 1994 and 2011 were Secondary Patella Resurfacing (SPR). It is, however, unclear whether SPR actually resolves the pain. The aim was to investigate prostheses survival and clinical outcomes following SPR. METHOD: A total of 308 knees (301 patients) with SPR were used to assess implant survival, and a sub-cohort (n = 114 out of 301 patients) with Patient Reported Outcome Measures (PROMs) data were used to assess the clinical outcomes. The EuroQol (EQ-5D), the Knee Injury and Osteoarthritis Outcome Score, and Visual Analogue Scales on satisfaction and pain were used to collect PROM data. Outcomes were analysed by Kaplan-Meier, Cox regression, and multiple linear regression. RESULTS: The five- and ten-year Kaplan-Meier survival percentages were 91 % and 87 %, respectively. Overall, 35 knees were re-revised at a median follow-up of eight years and pain alone (10 knees) was the main cause of re-revision. Younger patients (<60 years) had nearly nine times higher risk of re-revision compared to older patients (>70 years) (RR = 8.6; p < 0.001). Mean EQ-5D index score had improved from 0.41 (SD 0.21) preoperative to 0.56 (SD 0.25) postoperative following SPR. A total of 63 % of patients with PROM data were satisfied with the outcomes of SPR. CONCLUSION: The long-term prostheses survival following SPR was satisfactory, although not as good as for primary knee replacement. Patients' health related quality of life improved significantly following SPR. Still, more than a third of patients with PROMs data were dissatisfied with the outcomes of the SPR procedure. PMID- 26493390 TI - Treatment of the trapeziometacarpal osteoarthritis by arthroplasty with a pyrocarbon implant. AB - PURPOSE: Trapeziometacarpal (TM) osteoarthritis is the most common type of arthritis of the hand. To date, among surgical alternatives proposed, no one type has been proven superior to others. In this prospective study we evaluated the efficacy of treating arthroplasty with a latest-generation pyrocarbon implant (Pyrocardan). METHODS: Thirty-six patients with TM arthritis were treated using Pyrocardan implant arthroplasty. Results were evaluated through thumb radial and palmar abduction assessment, key pinch strength evaluation, thumb opposition assessment according to Kapandji classification, the visual analogue scale, the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and the Patient's Satisfaction Index. RESULTS: There was substantial pain reduction and a satisfying increase in range of motion and strength (p < 0.01) and improvement in DASH score (p < 0.01). Average Patient's Satisfaction Index was 8 out of 10. CONCLUSIONS: TM arthroplasty with Pyrocardan implantation is a suitable option in treating Eaton-Littler grade II or III TM osteoarthritis. PMID- 26493391 TI - Sleep Disordered Breathing: Hypertension and Cardiac Structure and Function. AB - Obstructive sleep apnea (OSA) is a common form of sleep disordered breathing and has a relatively high prevalence in the general population. The frequency and severity of OSA is associated with age, male sex, and obesity, and OSA has been linked to cardiovascular complications and death. Importantly, OSA has a strong association with both prevalent and incidental hypertension and has a particularly high prevalence in patients with resistant hypertension. In these patients, CPAP and other OSA-directed treatments have been proposed as therapy to help control blood pressure (BP), especially in patients who have not attained optimal BP control despite maximum pharmacological therapy. OSA has also been associated with alterations in cardiac structure and function, although most studies are small and highly limited in study design. Existing data suggest an association between OSA greater left ventricle (LV) mass and hypertrophy that appears independent of confounders including hypertension and obesity. Although less clear and more controversial, OSA severity has been linked to LV systolic and diastolic function, pulmonary hypertension, and right ventricular hypertrophy. Further studies are needed to confirm the potential causal role of OSA in these observed associations with cardiac abnormalities. PMID- 26493392 TI - Parental Involvement in Infant Sleep Routines Predicts Differential Sleep Patterns in Children With and Without Anxiety Disorders. AB - This study compared parents' retrospective reports of their involvement in infant settling strategies and their relation to current sleep patterns among children (N = 84, ages 7-11) with generalized anxiety disorder (GAD) and healthy controls. Parents of children with GAD were significantly more likely to report rocking their infants to sleep and putting infants down when they were already asleep than parents of healthy controls, even when accounting for infant health-related factors and parental anxiety. Greater involvement in infant sleep routines also predicted sleep patterns (measured via actigraphy) during childhood, though opposite relationships were observed in the two groups. Early involvement was related to poorer sleep in control children but better sleep for children with GAD even after controlling for current parenting practices. Findings suggest differential effects of early sleep-related parenting for children with and without later anxiety disorders with possible implications for early intervention. PMID- 26493393 TI - Psychometric Properties of the Original and Short Form of the Inventory of Callous-Unemotional Traits in Detained Female Adolescents. AB - This study examines the psychometric properties of the self-report version of the Inventory of Callous-Unemotional Traits in 191 detained female adolescents (M = 15.76, SD = 1.02). Evidence supporting the validity of the ICU scores was generally weak, largely due to poor functioning of the Unemotional subscale. Results from confirmatory factor analyses demonstrated support for a recently proposed shortened version of the ICU consisting of two subscales (Callousness and Uncaring). Both subscales showed acceptable to good internal consistency. This short-form version also improved criterion validity, though some issues regarding its convergent validity need further consideration. In conclusion, this study suggests that a short-form version of the ICU that includes a subset of the original items may hold promise as an efficient and valid method for assessing CU traits. PMID- 26493395 TI - Enriching the Toxicology Experience through Twitter. PMID- 26493394 TI - Improving hospital hygiene to reduce the impact of multidrug-resistant organisms in health care--a prospective controlled multicenter study. AB - BACKGROUND: Nosocomial infections are the most common complication during inpatient hospital care. An increasing proportion of these infections are caused by multidrug-resistant organisms (MDROs). This report describes an intervention study which was designed to address the practical problems encountered in trying to avoid and treat infections caused by MDROs. The aim of the HARMONIC (Harmonized Approach to avert Multidrug-resistant Organisms and Nosocomial Infections) study is to provide comprehensive support to hospitals in a defined study area in north-east Germany, to meet statutory requirements. To this end, a multimodal system of hygiene management was implemented in the participating hospitals. METHODS/DESIGN: HARMONIC is a controlled intervention study conducted in eight acute care hospitals in the 'Health Region Baltic Sea Coast' in Germany. The intervention measures include the provision of written recommendations on methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) and multi-resistant Gram-negative bacteria (MRGN), supplemented by regional recommendations for antibiotic prescriptions. In addition, there is theoretical and practical training of health care workers (HCWs) in the prevention and handling of MDROs, as well as targeted and critically gauged applications of antibiotics. The main outcomes of the implementation and analysis of the HARMONIC study are: (i) screening rates for MRSA, VRE and MRGN in high risk patients, (ii) the frequency of MRSA decolonization, (iii) the level of knowledge of HCWs concerning MDROs, and (iv) specific types and amounts of antibiotics used. The data are predominantly obtained by paper-based questionnaires and documentation sheets. A computer-assisted workflow-based documentation system was developed in order to provide support to the participating facilities. The investigation includes three nested studies on risk profiles of MDROs, health-related quality of life, and cost analysis. A six-month follow-up study investigates the quality of life after discharge, the long-term costs of the treatment of infections caused by MDROs, and the sustainability of MRSA eradication. DISCUSSION: The aim of this study is to implement and evaluate an area-wide harmonized hygiene program to control the nosocomial spreading of MDROs. Comparability between the intervention and control group is ensured by matching the hospitals according to size (number of discharges per year/number of beds) and level of care (standard or maximum). The results of the study may provide important indications for the implementation of regional MDRO management programs. PMID- 26493396 TI - Caudal extradural catheterization in pediatric renal transplant and its effect on perioperative hemodynamics and pain scoring: a prospective randomized study. AB - PURPOSE: 'Hockey stick incision' used in renal transplant is large enough to cause severe postoperative morbidity especially in pediatric recipients. Although epidural analgesia is known to be effective in pain control, the resulting sympathectomy might affect hemodynamics interfering with the transplant process. In our study, we evaluated the feasibility and safety of inserting an epidural catheter to the thoracic level via the caudal route, and the effect of using epidural local anesthetics at low concentrations on hemodynamics. METHODS: After approval from the ethical committee at Kasr Al Ainy University Hospital and consent from parents/legal guardians, sixty patients aged 3-12 years who were scheduled for renal transplant were randomly divided into two equal groups. Group I (epidural group) received continuous caudal epidural bupivacaine 0.125 % with fentanyl together with intravenous (IV) fentanyl and paracetamol. Group II (control group) received only IV fentanyl and paracetamol. Intraoperative data included heart rate (HR), mean arterial blood pressure (MAP) and central venous pressure (CVP). Postoperative variables included HR, MAP, CVP, pain score and complications. RESULTS: Threading failure via the caudal route occurred in 6.67 % of cases. Intraoperative differences in hemodynamics and CVP were not clinically significant between groups. Postoperative HR, MAP, and CVP were generally higher in the control group. Pain control was more satisfactory and postoperative complications were less in the epidural group. CONCLUSION: Caudal epidural anesthesia in pediatric renal transplant is a valuable addition to general anesthesia as it provides stable perioperative hemodynamics, excellent postoperative analgesia and is associated with fewer complications than narcotic dependent analgesia. CLINICAL TRIAL REGISTRATION NUMBER: NCT02037802. PMID- 26493397 TI - Teaching basic fiberoptic intubation skills in a simulator: initial learning and skills decay. AB - PURPOSE: Generally, novices are taught fiberoptic intubation on patients by attending anesthesiologists; however, this approach raises patient safety concerns. Patient safety should improve if novice learners are trained for basic skills on simulators. In this educational study, we assessed the time and number of attempts required to train novices in fiberoptic bronchoscopy and fiberoptic intubation on simulators. Because decay in skills is inevitable, we also assessed fiberoptic bronchoscopy and fiberoptic intubation skill decay and the amount of effort required to regain fiberoptic bronchoscopy skill. METHODS: First, we established attempt- and duration-based quantitative norms for reaching skill proficiency for fiberoptic bronchoscopy and fiberoptic intubation by experienced anesthesiologists (n = 8) and prepared an 11-step checklist and a 5-point global rating scale for assessment. Novice learners (n = 15) were trained to reach the established skill proficiency in a Virtual Reality simulator for fiberoptic bronchoscopy skills and a Human Airway Anatomy Simulator for fiberoptic intubation skills. Two months later, novices were reassessed to determine decay in learned skills and the required time to retrain them to fiberoptic bronchoscopy proficiency level. RESULTS: Proficiency in fiberoptic bronchoscopy skill level was achieved with 11 +/- 5 attempts and after 658 +/- 351 s. After 2 months without practice, the time taken by the novices to successful fiberoptic bronchoscopy on the Virtual Reality simulator increased from 41 +/- 8 to 68 +/- 31 s (P = 0.0138). Time and attempts required to retrain them were 424 +/- 230 s and 9.1 +/- 4.6 attempts, respectively. CONCLUSION: Novices were successfully trained to proficiency skill level. Although fiberoptic bronchoscopy skills started to decay within 2 months, the re-training time was shorter. PMID- 26493398 TI - The distribution and impact of common copy-number variation in the genome of the domesticated apple, Malus x domestica Borkh. AB - BACKGROUND: Copy number variation (CNV) is a common feature of eukaryotic genomes, and a growing body of evidence suggests that genes affected by CNV are enriched in processes that are associated with environmental responses. Here we use next generation sequence (NGS) data to detect copy-number variable regions (CNVRs) within the Malus x domestica genome, as well as to examine their distribution and impact. METHODS: CNVRs were detected using NGS data derived from 30 accessions of M. x domestica analyzed using the read-depth method, as implemented in the CNVrd2 software. To improve the reliability of our results, we developed a quality control and analysis procedure that involved checking for organelle DNA, not repeat masking, and the determination of CNVR identity using a permutation testing procedure. RESULTS: Overall, we identified 876 CNVRs, which spanned 3.5 % of the apple genome. To verify that detected CNVRs were not artifacts, we analyzed the B- allele-frequencies (BAF) within a single nucleotide polymorphism (SNP) array dataset derived from a screening of 185 individual apple accessions and found the CNVRs were enriched for SNPs having aberrant BAFs (P < 1e-13, Fisher's Exact test). Putative CNVRs overlapped 845 gene models and were enriched for resistance (R) gene models (P < 1e-22, Fisher's exact test). Of note was a cluster of resistance gene models on chromosome 2 near a region containing multiple major gene loci conferring resistance to apple scab. CONCLUSION: We present the first analysis and catalogue of CNVRs in the M. x domestica genome. The enrichment of the CNVRs with R gene models and their overlap with gene loci of agricultural significance draw attention to a form of unexplored genetic variation in apple. This research will underpin further investigation of the role that CNV plays within the apple genome. PMID- 26493399 TI - Iterative reconstruction of three-dimensional models of human chromosomes from chromosomal contact data. AB - BACKGROUND: The entire collection of genetic information resides within the chromosomes, which themselves reside within almost every cell nucleus of eukaryotic organisms. Each individual chromosome is found to have its own preferred three-dimensional (3D) structure independent of the other chromosomes. The structure of each chromosome plays vital roles in controlling certain genome operations, including gene interaction and gene regulation. As a result, knowing the structure of chromosomes assists in the understanding of how the genome functions. Fortunately, the 3D structure of chromosomes proves possible to construct through computational methods via contact data recorded from the chromosome. We developed a unique computational approach based on optimization procedures known as adaptation, simulated annealing, and genetic algorithm to construct 3D models of human chromosomes, using chromosomal contact data. RESULTS: Our models were evaluated using a percentage-based scoring function. Analysis of the scores of the final 3D models demonstrated their effective construction from our computational approach. Specifically, the models resulting from our approach yielded an average score of 80.41%, with a high of 91%, across models for all chromosomes of a normal human B-cell. Comparisons made with other methods affirmed the effectiveness of our strategy. Particularly, juxtaposition with models generated through the publicly available method Markov chain Monte Carlo 5C (MCMC5C) illustrated the outperformance of our approach, as seen through a higher average score for all chromosomes. Our methodology was further validated using two consistency checking techniques known as convergence testing and robustness checking, which both proved successful. CONCLUSIONS: The pursuit of constructing accurate 3D chromosomal structures is fueled by the benefits revealed by the findings as well as any possible future areas of study that arise. This motivation has led to the development of our computational methodology. The implementation of our approach proved effective in constructing 3D chromosome models and proved consistent with, and more effective than, some other methods thereby achieving our goal of creating a tool to help advance certain research efforts. The source code, test data, test results, and documentation of our method, Gen3D, are available at our sourceforge site at: http://sourceforge.net/projects/gen3d/. PMID- 26493400 TI - The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetry. AB - Vertebrate left-right (LR) asymmetry originates at a transient left-right organizer (LRO), a ciliated structure where cilia play a crucial role in breaking symmetry. However, much remains unknown about the choreography of cilia biogenesis and resorption at this organ. We recently identified a mutation affecting NEK2, a member of the NIMA-like serine-threonine kinase family, in a patient with congenital heart disease associated with abnormal LR development. Here, we report how Nek2 acts through cilia to influence LR patterning. Both overexpression and knockdown of nek2 in Xenopus result in abnormal LR development and reduction of LRO cilia count and motility, phenotypes that are modified by interaction with the Hippo signaling pathway. nek2 knockdown leads to a centriole defect at the LRO, consistent with the known role of Nek2 in centriole separation. Nek2 overexpression results in premature ciliary resorption in cultured cells dependent on function of the tubulin deacetylase Hdac6. Finally, we provide evidence that the known interaction between Nek2 and Nup98, a nucleoporin that localizes to the ciliary base, is important for regulating cilium resorption. Together, these data show that Nek2 is a switch balancing ciliogenesis and resorption in the development of LR asymmetry. PMID- 26493401 TI - New markers for tracking endoderm induction and hepatocyte differentiation from human pluripotent stem cells. AB - The efficient generation of hepatocytes from human pluripotent stem cells (hPSCs) requires the induction of a proper endoderm population, broadly characterized by the expression of the cell surface marker CXCR4. Strategies to identify and isolate endoderm subpopulations predisposed to the liver fate do not exist. In this study, we generated mouse monoclonal antibodies against human embryonic stem cell-derived definitive endoderm with the goal of identifying cell surface markers that can be used to track the development of this germ layer and its specification to a hepatic fate. Through this approach, we identified two endoderm-specific antibodies, HDE1 and HDE2, which stain different stages of endoderm development and distinct derivative cell types. HDE1 marks a definitive endoderm population with high hepatic potential, whereas staining of HDE2 tracks with developing hepatocyte progenitors and hepatocytes. When used in combination, the staining patterns of these antibodies enable one to optimize endoderm induction and hepatic specification from any hPSC line. PMID- 26493402 TI - Expression of an S phase-stabilized version of the CDK inhibitor Dacapo can alter endoreplication. AB - In developing organisms, divergence from the canonical cell division cycle is often necessary to ensure the proper growth, differentiation, and physiological function of a variety of tissues. An important example is endoreplication, in which endocycling cells alternate between G and S phase without intervening mitosis or cytokinesis, resulting in polyploidy. Although significantly different from the canonical cell cycle, endocycles use regulatory pathways that also function in diploid cells, particularly those involved in S phase entry and progression. A key S phase regulator is the Cyclin E-Cdk2 kinase, which must alternate between periods of high (S phase) and low (G phase) activity in order for endocycling cells to achieve repeated rounds of S phase and polyploidy. The mechanisms that drive these oscillations of Cyclin E-Cdk2 activity are not fully understood. Here, we show that the Drosophila Cyclin E-Cdk2 inhibitor Dacapo (Dap) is targeted for destruction during S phase via a PIP degron, contributing to oscillations of Dap protein accumulation during both mitotic cycles and endocycles. Expression of a PIP degron mutant Dap attenuates endocycle progression but does not obviously affect proliferating diploid cells. A mathematical model of the endocycle predicts that the rate of destruction of Dap during S phase modulates the endocycle by regulating the length of G phase. We propose from this model and our in vivo data that endo S phase-coupled destruction of Dap reduces the threshold of Cyclin E-Cdk2 activity necessary to trigger the subsequent G-S transition, thereby influencing endocycle oscillation frequency and the extent of polyploidy. PMID- 26493403 TI - ATAF2 integrates Arabidopsis brassinosteroid inactivation and seedling photomorphogenesis. AB - The Arabidopsis thaliana hypocotyl is a robust system for studying the interplay of light and plant hormones, such as brassinosteroids (BRs), in the regulation of plant growth and development. Since BRs cannot be transported between plant tissues, their cellular levels must be appropriate for given developmental fates. BR homeostasis is maintained in part by transcriptional feedback regulation loops that control the expression of key metabolic enzymes, including the BR inactivating enzymes BAS1 (CYP734A1, formerly CYP72B1) and SOB7 (CYP72C1). Here, we find that the NAC transcription factor (TF) ATAF2 binds the promoters of BAS1 and SOB7 to suppress their expression. ATAF2 restricts the tissue-specific expression of BAS1 and SOB7 in planta. ATAF2 loss- and gain-of-function seedlings have opposite BR-response phenotypes for hypocotyl elongation. ATAF2 modulates hypocotyl growth in a light-dependent manner, with the photoreceptor phytochrome A playing a major role. The photomorphogenic phenotypes of ATAF2 loss- and gain of-function seedlings are suppressed by treatment with the BR biosynthesis inhibitor brassinazole. Moreover, the disruption of BAS1 and SOB7 abolishes the short-hypocotyl phenotype of ATAF2 loss-of-function seedlings in low fluence rate white light, demonstrating an ATAF2-mediated connection between BR catabolism and photomorphogenesis. ATAF2 expression is suppressed by both BRs and light, which demonstrates the existence of an ATAF2-BAS1/SOB7-BR-ATAF2 feedback regulation loop, as well as a light-ATAF2-BAS1/SOB7-BR-photomorphogenesis pathway. ATAF2 also modulates root growth by regulating BR catabolism. As it is known to regulate plant defense and auxin biosynthesis, ATAF2 therefore acts as a central regulator of plant defense, hormone metabolism and light-mediated seedling development. PMID- 26493404 TI - ClearSee: a rapid optical clearing reagent for whole-plant fluorescence imaging. AB - Imaging techniques for visualizing and analyzing precise morphology and gene expression patterns are essential for understanding biological processes during development in all organisms. With the aid of chemical screening, we developed a clearing method using chemical solutions, termed ClearSee, for deep imaging of morphology and gene expression in plant tissues. ClearSee rapidly diminishes chlorophyll autofluorescence while maintaining fluorescent protein stability. By adjusting the refractive index mismatch, whole-organ and whole-plant imaging can be performed by both confocal and two-photon excitation microscopy in ClearSee treated samples. Moreover, ClearSee is applicable to multicolor imaging of fluorescent proteins to allow structural analysis of multiple gene expression. Given that ClearSee is compatible with staining by chemical dyes, the technique is useful for deep imaging in conjunction with genetic markers and for plant species not amenable to transgenic approaches. This method is useful for whole imaging for intact morphology and will help to accelerate the discovery of new phenomena in plant biological research. PMID- 26493405 TI - Cytoreduction and HIPEC in the treatment of "unconventional" secondary peritoneal carcinomatosis. AB - BACKGROUND: Peritoneal metastasis (PM) is considered a terminal and incurable disease. In the last 30 years, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) radically changed the therapeutic approach for these patients and is regarded as the standard of care for pseudomyxoma peritonei from appendiceal cancer and peritoneal mesotheliomas. Improved survival has also been reported in treating PM from ovarian, gastric, and colorectal cancers. However, PM often seriously complicates the clinical course of patients with other primary digestive and non-digestive cancers. There is increasing literature evidence that helped to identify not only the primary tumors for which CRS and HIPEC showed a survival advantage but also the patients who may benefit form this treatment modality for the potential lethal complications. Our goal is to report our experience with cytoreduction and HIPEC in patients with PM from rare or unusual primary tumors, discussing possible "unconventional" indications, outcome, and the peculiar issues related to each tumor. METHODS: From a series of 253 consecutive patients with a diagnosis of peritoneal carcinomatosis and treated by CRS and HIPEC, we selected only those with secondary peritoneal carcinomatosis from rare or unusual primary tumors, excluding pseudomyxoma peritonei, peritoneal mesotheliomas, ovarian, gastric, and colorectal cancers. Complications and adverse effects were graded from 0 to 5 according to the WHO Common Toxicity Criteria for Adverse Events (CTCAE). Survival was expressed as mean and median. RESULTS: We admitted and treated by CRS and HIPEC 28 patients with secondary peritoneal carcinomatosis from rare or unusual primary tumors. Morbidity and mortality rates were in line with those reported for similar procedures. Median survival for the study group was 56 months, and 5-year overall survival reached 40.3 %, with a difference between patients with no (CC0) and minimal (CC1) residual disease (52.3 vs. 25.7), not reaching statistical significance. Ten patients are alive disease-free, and eight are alive with disease. CONCLUSIONS: Cytoreduction and HIPEC should not be excluded "a priori" for the treatment of peritoneal metastases from unconventional primary tumors. This combined therapeutic approach, performed in an experienced center, is safe and can provide a survival benefit over conventional palliative treatments. PMID- 26493406 TI - Laccase-mediated synthesis of a phenoxazine compound with antioxidative and dyeing properties--the optimisation process. AB - This study demonstrates the optimisation of the main parameters of the laccase mediated biosynthesis of high-intensity-coloured orange phenoxazine compound, 2 amino-3-oxo-3H-phenoxazine-8-sulfonic acid, and the antioxidative and dyeing properties. Among optimised parameters were the pH value, the activity of laccase, and the high concentration of the precursor as the necessary step in terms of dye synthesis scale-up. The high concentration of the precursor of ca. 10 g/L can be transformed totally by laccase at the activity of 30 U/g during 12 hours, in an optimised and standardised process in nearly 100% yield of synthesis. The obtained dye exhibited good dyeing properties determined according to the ISO standards. Antioxidative activities were detected for phenoxazinone dye using two independent methods, the chemiluminescence assay and the ABTS free radical-scavenging test, with the values of EC50 for the tested phenoxazine dye amounting 189.8 MUg/mL and 1428 MUg/mL, respectively. Despite the presence of the phenoxazine core in the structure of this dye, no antibacterial capacity was noted. PMID- 26493407 TI - Exposure of pregnant women to persistent organic pollutants and cord sex hormone levels. AB - STUDY QUESTION: Is prenatal exposure to persistent organic pollutants (POPs) associated with variations of sex hormone levels in cord blood? SUMMARY ANSWER: Prenatal exposure to a number of POPs is associated with a disruption of hormone levels in cord blood, with sex specificities. WHAT IS KNOWN ALREADY: Epidemiological studies have reported disorders of reproductive health, in relation with POPs exposure during early life and the endocrine disruption properties of these chemicals have been suggested as possible mechanisms. STUDY DESIGN, SIZE, DURATION: A subset of 282 mother-child pairs was selected from the prospective population-based PELAGIE birth cohort (n = 3421, 2002-2006, Brittany, France). Pregnant women were recruited before 19 weeks of gestation and followed until delivery. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sex hormone levels including sex hormone-binding globulin (SHBG), estradiol (E2), total testosterone (T), free testosterone (fT = T/SHBG) and the aromatase index (AI = T/E2) were measured in 282 cord blood samples. Anti-Mullerian hormone (AMH) was measured in male newborns only. Pesticide concentrations of alpha-endosulfan, beta hexachlorocyclohexane (beta-HCH), gamma-HCH, dieldrin, pp' dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), heptachlor epoxide (HCE), as well as PCBs (congeners 153, 187 and the sum of anti-estrogenic PCBs 118, 138, and 170) and decabrominated diphenyl ether (BDE209) were also measured in cord blood. Associations between sex hormones and POPs exposure were explored using multiple linear regressions adjusted for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: High PCB levels were associated with an increase of SHBG (P-trend < 0.01) and AMH (P-trend < 0.05) and a decrease of fT (P-trend < 0.05) and AI (P-trend < 0.01). High pesticide levels, particularly alpha-endosulfan and HCE, were associated with an increase of SHBG (P < 0.05) and E2 (P < 0.01) and a decrease of fT (P < 0.05) and AI (P < 0.01). Several of these associations were stronger, or specific, among male or female newborns. The associations were not altered in the sensitivity analyses. LIMITATIONS, REASONS FOR CAUTION: The study population was of relatively small sample size, and some compounds rarely detected in cord blood. The high level of correlation between POPs makes it difficult to identify the most contributing POPs. Hormone measurements were performed at birth (in cord blood) and may not adequately represent the infant endocrine system. Multiple statistical testing may have led to false-positive associations. WIDER IMPLICATIONS OF THE FINDINGS: Our results are in discordance with those reported in the only published study of the kind but in accordance with studies about prenatal exposure to other endocrine disruptors such as phthalates. These findings may help understanding the pathways involved in adverse reproductive outcomes associated with POPs exposure. STUDY FUNDING/COMPETING INTERESTS: The PELAGIE cohort is funded by Inserm, French Ministry of Health, French Ministry of Labor, InVS, ANR, ANSES, and French Ministry of Ecology. None of the authors has any competing interest to declare. PMID- 26493408 TI - Evidence from the very beginning: endoglandular trophoblasts penetrate and replace uterine glands in situ and in vitro. AB - STUDY QUESTION: How is histiotrophic nutrition of the embryo secured during the first trimester of pregnancy? SUMMARY ANSWER: Rather than specifically focusing on invasion into spiral arteries, extravillous trophoblasts also invade into uterine glands (endoglandular trophoblast) from the very beginning and open them toward the intervillous space. WHAT IS KNOWN ALREADY: Extravillous trophoblasts can be found in close contact and within the lumen of uterine glands, sometimes replacing glandular epithelial cells. STUDY DESIGN, SIZE, DURATION: As well as extensive screening of specimens from first trimester placentation sites in situ we used a previously established three-dimensional co-culture in vitro model system of first trimester villous explants with non-invaded decidua parietalis. PARTICIPANTS/MATERIALS, SETTING, METHODS: First trimester placentas were obtained from elective terminations of pregnancies (n = 48) at 5-11 weeks of gestational age. A subset was processed for confrontation co-culture (n = 31). Invaded decidua basalis was obtained from 20 placentas. All tissues were sectioned, subsequently immunostained and immunodoublestained with antibodies against keratin 7 (KRT7), major histocompatibility complex, class I, G (HLA-G), matrix metallopeptidase 9 (MMP9), von Willebrand factor (VWF) and the appropriate Immunoglobulin G (IgG) negative controls. Replacement of endothelial/epithelial cells by extravillous trophoblasts was quantified semi-quantitatively. Additionally, hematoxylin and eosin-stained archival specimens from early implantation sites were assessed. MAIN RESULTS AND THE ROLE OF CHANCE: The earliest available specimen was from around Day 10 after conception; already at this stage trophoblasts had penetrated into uterine glands and had started to replace the epithelium of the glands. Endoglandular trophoblasts replaced uterine glands in vitro and in situ and could be found in the lumen of invaded glands. Quantitative analysis revealed significantly more replacement of epithelial cells in glands (63.8 +/- 22.1%) compared with endothelial cells in vessels (26.4 +/- 8.8%). Accumulated detached glandular epithelial cells could be repeatedly observed in the lumen of invaded glands. Additionally, in areas of trophoblast invasion the glandular epithelium seemed to be completely disintegrated compared with glandular epithelium in the non-invaded parts of the decidua. Whole tissue specimens were used in vitro and in situ instead of cell lines; these systems mostly maintain the context of the in vivo situation. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive study supported by in vitro experiments. However, a histological section will always only be a snapshot and quantification from histological sections has its limitations. WIDER IMPLICATIONS OF THE FINDINGS: This study further strengthens the hypothesis of histiotrophic nutrition of the embryo prior to the establishment of the maternal blood flow toward the placenta. Invasion of uterine glands by endoglandular trophoblasts may have more impact on the outcome of early pregnancy than assumed up to now. PMID- 26493410 TI - Cardiac myxoma imaging features and tissue characteristics at cardiovascular magnetic resonance. PMID- 26493409 TI - Anemia in a middle aged female with aortitis: a case report. AB - BACKGROUND: Idiopathic aortitis is among the most common causes of non-infectious aortitis, which rarely presents with anemia. CASE PRESENTATION: Here we report a case of a 49-year-old muhajir female who presented with shortness of breath and easy fatigability for the past 6 months. Physical examination revealed pallor and a diastolic murmur in the aortic region. Echocardiography showed thickened and calcified aortic and mitral valves, severe aortic regurgitation and dilatation of ascending aorta. She was advised aortic valve replacement and was referred to a haematologist due to concomitant anemia. Complete blood counts revealed haemoglobin: 7.7 gm/dl, mean corpuscular volume (MCV): 78 fl, mean corpuscular haemoglobin (MCH):23 pg, total white cell count: 9.0 * 10(9)/L and platelet count: 227 * 10(9)/L. Erythrocyte sedimentation rate (ESR) was 100 mm/hr. There was suspicion of myelodysplastic syndrome, but could not be confirmed as the patient refused bone marrow and cytogenetic studies. She was given erythropoietin, folic acid and ferrous sulphate. Following relatively prolonged therapy, her haemoglobin level increased to approximately 9.0 gm/dL. She was transfused with packed red cells and underwent aortic valve and ascending aorta replacement. The ascending aorta was dilated and aortic wall markedly thick and irregular. Histopathology of the resected aorta revealed granulomatous aortitis. She was prescribed prednisolone, which resulted in further incremental rise of haemoglobin to 13.1 gm/dL. One month later, she developed complaints of blurred vision in the right eye and was diagnosed with central retinal vein occlusion. She was treated with antiplatelet agents and her vision improved. After 3 months, she was asymptomatic and her haemoglobin level rose to 11.2 gm/dL without hematinic therapy or blood transfusion. She was begun on anticoagulant therapy and remains clinically stable. CONCLUSION: We report a case of idiopathic aortitis with presumed diagnosis of anemia of chronic disease exhibiting a transient response towards steroid therapy post-valvuloplasty. PMID- 26493411 TI - Quality Management Systems Implementation Compared With Organizational Maturity in Hospital. AB - BACKGROUND: A quality management system can provide a framework for continuous improvement in order to increase the probability of customers and other stakeholders' satisfaction. The test maturity model helps organizations to assess the degree of maturity in implementing effective and sustained quality management systems; plan based on the current realities of the organization and prioritize their improvement programs. OBJECTIVES: We aim to investigate and compare the level of organizational maturity in hospitals with the status of quality management systems implementation. MATERIALS & METHODS: This analytical cross sectional study was conducted among hospital administrators and quality experts working in hospitals with over 200 beds located in Tehran. In the first step, 32 hospitals were selected and then 96 employees working in the selected hospitals were studied. The data were gathered using the implementation checklist of quality management systems and the organization maturity questionnaire derived from ISO 10014. The content validity was calculated using Lawshe method and the reliability was estimated using test - retest method and calculation of Cronbach's alpha coefficient. The descriptive and inferential statistics were used to analyze the data using SPSS 18 software. RESULTS: According to the table, the mean score of organizational maturity among hospitals in the first stage of quality management systems implementation was equal to those in the third stage and hypothesis was rejected (p-value = 0.093). In general, there is no significant difference in the organizational maturity between the first and third level hospitals (in terms of implementation of quality management systems). CONCLUSIONS: Overall, the findings of the study show that there is no significant difference in the organizational maturity between the hospitals in different levels of the quality management systems implementation and in fact, the maturity of the organizations cannot be attributed to the implementation of such systems. As a result, hospitals should make changes in the quantity and quality of quality management systems in an effort to increase organizational maturity, whereby they improve the hospital efficiency and productivity. PMID- 26493412 TI - Study of Relationship Between Depression and Quality of Life in Patients With Chronic Schizophrenia. AB - Depression is among the personality traits of schizophrenic patients, which results from psychotic features or is a consequence of a period of psychosis. Depression in schizophrenic patients is one of the important factors affecting their quality of life. The study population of this descriptive and analytic study consists of patients with chronic schizophrenia in Zahedan in 2014. The sample included 60 patients who simultaneously suffered from depression and were selected using random sampling (30 males and 30 females). The research instruments included the Schizophrenia Quality of Life Scale (SQLS) and the Beck Depression Inventory (the inventory was filled out by the tester). In order to form a statistics analysis, we used Pearson correlation and regression multivariate. Investigating the study hypotheses showed that there was a negative correlation between the high level of depression and low quality of life. the relationship between depression and the quality of life subscales showed that in women, the variable of symptoms and complications was a significant predictor; however, the other two variables (energy and motivation and psychosocial) were not significant predictors. In case of men, psychosocial variable was a significant predictor; however, the other two variables (energy and motivation and symptoms and complications) were not significant predictors. In general, depression on these patients makes discontent of life on them; therefore, elimination of their depression on their treatment is necessary. PMID- 26493413 TI - The Determination of Predictive Construct of Physical Behavior Change on Osteoporosis Prevention Women Aged 30-50: A Trans-Theoretical Method Study. AB - Osteoporosis is a major public health priority in Iran and throughout the world. The prevention of osteoporosis has recently become the ultimate goal of many health professionals. Behavior change is one of the most powerful strategies to prevent osteoporosis. This study aimed to determine the predictive construct of physical preventive behavior of osteoporosis in women aged 30-50 in Khorramabad, west of Iran. This study included 269 women selected from all the health centers of Khorramabad city according to the inclusion criteria of the study and through random cluster and systematic sampling. The data gathering tools were valid and reliable questionnaires of demographic information, stages of change, decisional balance, self-efficacy, and physical activity. Data were analyzed using descriptive and inferential statistics. The mean of the subjects' age was 38.72+/ 7.003, and the mean of light weekly physical activity was 38.83+/-56.400. The results showed that the construct of self-efficacy had the highest predictive power of the preventive behavior. The results also showed that self-efficacy among the constructs of the Trans-theoretical Model was the only predictive construct for osteoporosis prevention behavior. Therefore, the findings of this study can serve as a base for educational interventions in behavioral changes to prevent of osteoporosis by health authorities. PMID- 26493414 TI - Marriage Patterns and Childbearing: Results From a Quantitative Study in North of Iran. AB - Social changes have rapidly removed arranged marriages and it seems the change in marriage pattern has played a role in childbearing. On the other hand, there is a great reduction in population in many countries which requires a comprehensive policy to manage the considerable drop in population. To achieve this goal, initially, the factors affecting fertility must be precisely identified. This study aims to examine the role of marriage patterns in childbearing. In this cross-sectional quantitative study, 880 married women 15-49 years old, living in the north of Iran were studied using a cluster sampling strategy. The results showed that there are no significant differences in reproductive behaviors of three patterns of marriage in Bobol city of Iran. It seems there is a convergence in childbearing due to the different patterns of marriage and Policymakers should pay attention to other determinants of reproductive behaviors in demographic planning. PMID- 26493415 TI - Quality of Life for Saudi Patients With Heart Failure: A Cross-Sectional Correlational Study. AB - INTRODUCTION: Heart failure is a major public health issue and a growing concern in developing countries, including Saudi Arabia. Most related research was conducted in Western cultures and may have limited applicability for individuals in Saudi Arabia. Thus, this study assesses the quality of life of Saudi patients with heart failure. MATERIALS & METHODS: A cross-sectional correlational design was used on a convenient sample of 103 patients with heart failure. Data were collected using the Short Form-36 and the Medical Outcomes Study-Social Support Survey. RESULTS: Overall, the patients' scores were low for all domains of Quality of Life. The Physical Component Summary and Mental Component Summary mean scores and SDs were (36.7+/-12.4, 48.8+/-6.5) respectively, indicating poor Quality of Life. Left ventricular ejection fraction was the strongest predictor of both physical and mental summaries. CONCLUSION: Identifying factors that impact quality of life for Saudi heart failure patients is important in identifying and meeting their physical and psychosocial needs. PMID- 26493416 TI - The Relationship Between the Customer Relationship Management and Patients' Loyalty to Hospitals. AB - BACKGROUND & AIM: Customer Relationship Management (CRM) with its various components has been considered as a tool causing customers' loyalty. The present study aims to investigate the relationship between the various components of customer relationship management and patients' loyalty to the place of their treatment. METHODS: This cross sectional and descriptive-analytical study was conducted among nurses and hospitalized patients in inpatient wards in selected hospitals in 2014. Using the stratified random sampling method, 224 valid and reliable researcher-drafted questionnaires were completed for CRM by nurses and 359 questionnaires were completed by patients for patients' loyalty in the studied wards. Data were analyzed using the SPSS(20) software. RESULTS: There was no statistically significant relationship between the level of patients' loyalty and organizational indicators, information technology and knowledge management (P Value>0.05). However, there was a statistically significant relationship between loyalty and the dimensions of the service process (P Value=0.04), human resources (P Value=0.002) and CRM (P Value=0.038). The strength of these relationships were 34, 40 and 36 percent, respectively all of which were positive. CONCLUSION: Customer Relationship Management is a tool for improving influencing factors on patients' satisfaction and loyalty. Therefore, attempts to implement customer relationship management as a process for improving hospitals performance and improving communication between service providers in hospitals and customers leading to enhance patients' loyalty should be taken into account by managers and policy makers in the health sectors. PMID- 26493417 TI - Incidence Trend and Epidemiology of Common Cancers in the Center of Iran. AB - INTRODUCTION: Cancer is a major public health problem in Iran and many other parts of the world. The cancer incidence is different in various countries and in country provinces. Geographical differences in the cancer incidence lead to be important to conduct an epidemiological study of the disease. This study aimed to investigate cancer epidemiology and trend in the province of Qom, located in center of Iran. METHOD: This is an analytical cross-sectional study carried out based on re-analysis cancer registry report and the disease management center of health ministry from 2004 to 2008 in the province of Qom. To describe incidence time trends, we carried out join point regression analysis using the software Join point Regression Program, Version 4.1.1.1. RESULTS: There were 3,029 registered cases of cancer during 5 years studied. Sex ratio was 1.32 (male to female). Considering the frequency and mean standardized incidence, the most common cancer in women were breast, skin, colorectal, stomach, and esophagus, respectively while in men the most common cancers included skin, stomach, colorectal, bladder, and prostate, respectively. There was an increasing and significant trend, according to the annual percentage change (APC) equal to 8.08% (CI: 5.1-11.1) for all site cancer in women. CONCLUSION: The incidence trend of all cancers was increasing in this area. Hence, planning for identifying risk factors and performing programs for dealing with the disease are essential. PMID- 26493418 TI - The Effectiveness of Mindfulness-Based Cognitive Group Therapy on Marital Satisfaction and General Health in Woman With Infertility. AB - Infertility affects around 80 million people around the world and it has been estimated that psychological problems in infertile couples is within the range of 25-60%. The purpose of this study was to determine the effectiveness of Mindfulness-based cognitive group therapy on consciousness regarding marital satisfaction and general health in woman with infertility. Recent work is a clinical trial with a pre/posttest plan for control group. Covering 60 women who were selected by in access method and arranged randomly in interference (30) and control (30) groups. Before and after implementation of independent variable, all subjects were measured in both groups using Enrich questionnaire and marital satisfaction questionnaire. Results of covariance analysis of posttest, after controlling the scores of pretest illustrated the meaningful difference of marital satisfaction and mental health scores in interference and control groups after treatment and the fact that MBCT treatment in infertile women revealed that this method has an appropriate contribution to improvement of marital satisfaction and mental health. Necessary trainings for infertile people through consultation services can improve their mental health and marital satisfaction and significantly help reducing infertile couples' problems. PMID- 26493419 TI - Functional Status Assessment of COPD Based on Ability to Perform Daily Living Activities: A Systematic Review of Paper and Pencil Instruments. AB - CONTEXT: Activity of daily living (ADL) is an important predictor of mortality in patients with chronic obstructive pulmonary disease (COPD). Increasing ADL is important in patients with COPD and assessment of ADL is one of the best ways to evaluate the status of COPD patients. OBJECTIVES: The objective of this systematic review was to provide an overview of the psychometric properties of paper and pencil instruments measuring ADL in patients with COPD. DATA SOURCES: English papers published from 1980 to 2014 regarding ADL in patients with COPD were searched in Web of Science, MEDLINE, Google Scholar, Cochrane, PubMed, ProQuest, and CINAHL databases using the following keywords: "COPD", "ADL", "activities of daily living", "daily activities", "instrument", "questionnaire", "paper-and-pencil instruments", and "measure". Following the Internet search, manual search was also done to find article references. STUDY SELECTION: A total of 186 articles were found. Of those, 31 met the inclusion criteria. Full texts of articles meeting the inclusion criteria were studied. Consensus-based standards for the selection of health measurement instruments"(COSMIN) were used to assess the quality of the studies. DATA EXTRACTION: Data extraction form based on research aims developed by researchers and psychometric experts, with 17 questions was used. RESULTS: In these articles, 14 pen and paper instruments were identified for examining ADL in patients with COPD; of which, 4 dealt directly with ADL while 9 assessed other criteria i.e. dyspnea as ADL indicator. The majority of instruments only dealt with two main dimensions of ADL: Basic Activities of Daily Living (BADL) and Instrumental Activities of Daily Living (IADL), and did not consider Advanced Activities of Daily Living (AADL), which is influenced by cultural and motivational factors. CONCLUSION: Despite several ADL instruments identified, complete psychometric processes have only been done in a few of them. Selection of the appropriate instrument should focus on the aim of the study and the target construct. PMID- 26493420 TI - Dysfunctional Metacognitive Beliefs in Body Dysmorphic Disorder. AB - The present study aims to examine the correlation of body dysmorphic disorder, with metacognitive subscales, metaworry and thought-fusion. The study was conducted in a correlation framework. Sample included 155 high school students in Isfahan, Iran in 2013-2014, gathered through convenience sampling. To gather data about BDD, Yale-Brown Obsessive Compulsive Scale Modified for BDD was applied. Then, Meta Cognitive Questionnaire, Metaworry Questionnaire, and Thought-Fusion Inventory were used to assess metacognitive subscales, metaworry and thought fusion. Data obtained from this study were analyzed using Pearson correlation and multiple regressions in SPSS 18. Result indicated YBOCS-BDD scores had a significant correlation with scores from MCQ (P<0.05), MWG (P<0.05), and TFI (P<0.05). Also, multiple regressions were run to predict YBOCS from TFI, MWQ, and MCQ-30. These variables significantly predicted YBOCS [F (3,151) =32.393, R(2)=0.57]. Findings indicated that body dysmorphic disorder was significantly related to metacognitive subscales, metaworry, and thought fusion in high school students in Isfahan, which is in line with previous studies. A deeper understanding of these processes can broaden theory and treatment of BDD, thereby improve the lives of sufferers and potentially protect others from developing this devastating disorder. PMID- 26493421 TI - Characteristics of Inpatient Falls not Reported in an Incident Reporting System. AB - An incident reporting system is the most commonly used method to identify patient safety incidents in a hospital. However, non-reporting of incidents for various reasons is a serious problem. We studied the rate of inpatient falls that were not reported in an incident reporting system but were recorded in medical charts and we evaluated characteristics of those falls by comparing with the falls reported in incident reports in a Japanese acute care hospital setting. Falls recorded in medical charts were detected by using a text mining method followed by a manual chart review. About 25% of the recorded falls were not reported in incident reports. Male patients, first fall, long lag time until recording, no witness at the time of the fall and physician profession were shown to be significant factors associated with non-reporting. Our results show that the rate of non-reporting of inpatient falls in a Japanese acute care hospital is compable to that shown in previous studies in other conutries and that the same barriers to incident reporting as those found in previous studies exist in the medical staff. PMID- 26493422 TI - Comparing Intelligence Quotient (IQ)among 3 to 7-year-old strabismic and nonstrabismic children in an Iranian population. AB - This study was designed to compare the Intelligence Quotient (IQ) among 3 to 7 year-old strabismic and nonstrabismic children in an Iranian population. In this cross-sectional study, 108 preschool children with equal numbers of strabismic/non-strabismic disorder (age 3-7 years) were randomly selected from exceptional strabismus clinics of Ahvaz and were evaluated with the preschool and primary scale of intelligence versions of Wechsler (WPPSI). In the current study, 108 children were evaluated. In strabismic patients the mean performance, verbal and total IQ were 89.46+/-19.79, 89.57+/-21.57 and 91.54+/-22.08 respectively.These mean scores in normal children were 91.89+/-47.53 , 87.56+/ 15.6 and 89.96+/-17.62 consecuently. The results showed that these three different IQ subscales were not significantly different among 3 to 7 years old strabismic and nonstrabismic children ((P>0.05 for all comparisons). There was no significant difference in IQ between two sexes (P>0.05) while Persian tribe children had greater IQ score compared to other tribes (P<0.05). Also, higher paternal educational status of children related to higher IQ score. IQ score was better in combined deviations and was higher in exotropes than esotropes; however, these differences were not statistically significant.(p>0.05) In this evaluation, we did not found a significant negative interference of strabismus on IQ score of preschool children. It can be concluded that paternal educational level and tribe have a significant effect on intelligent quotient, while this is not the case on sex and ocular deviation. PMID- 26493423 TI - Predictors of Mortality in Patients Undergoing Mitral Valve Replacement. AB - OBJECTIVE: Although mitral valve replacement is frequently performed in patients of all age groups, there are few studies available which determine the causes of operative mortality in mitral valve replacement especially in our region. Therefore, the objective of this study was to identify factors that are significantly associated with operative mortality in mitral valve replacement. METHODS: From August 2012 to March 2013, 80 consecutive patients undergoing mitral valve replacement in a single tertiary hospital were included. Patients with a history of previous coronary artery bypass graft surgery or congenital heart problems were excluded from the sample. The included patients were observed for a period of 30 days. Pre and post-operative variables were used to identify significant predictors of mortality. RESULTS: The overall hospital mortality (30 days) was 15%. High post-perative creatinine (P =0.05), high ASO titre (P=0.03), young age (P=0.011), low cardiac output (P=0.0001), small mitral valve size (P=0.002) and new onset of atrial fibrillation (P=0.007) were the significant independent predictors of operative morality. CONCLUSION: Mitral valve replacement can be performed in third world countries with limited resources with low mortality. However, optimal selection of mitral valve size can help to improve operative mortality. PMID- 26493424 TI - Self Management Behaviors in Rheumatoid Arthritis Patients and Associated Factors in Tehran 2013. AB - INTRODUCTION: Rheumatoid Arthritis (RA) is a systemic, autoimmune and inflammatory disease with an unknown etiology that is associated with progressive joint degeneration, limitation of physical activity and disability. The aim of the study was to evaluate self-management behaviors and their associated factors in RA patients. MATERIAL & METHOD: This cross-sectional study was performed in 2013 on185 patients in Iran. Data were selected through convenient sampling. The collected data included demographic variables, disease related variables, Arthritis Impact Measurement Scale 2 (AIMS-2SF), and Self-Management Behaviors (SMB). Data were analyzed by SPSS17 using Spearman correlation and logistic regression test. RESULT: In this study drug management, regular follow-up, and food supplement were used as the most frequently applied SMB and aquatic exercise, diet, massage therapy, and relaxation were the least common SMBs. Age, education, health status, occupation, marital status, sex, DAS28 (Disease Activity Score 28 joints), and PGA (Physician Global Assessment) were significantly related with SMB. CONCLUSION: The result of the study highlight the influence of demographic variables, health status, and disease related data on SMB. Thus, more studies are required to find factors influencing SMB in order to improve SMB. PMID- 26493425 TI - Effectiveness of Acceptance and Commitment Therapy on Interpersonal Problems and Psychological Flexibility in Female High School Students With Social Anxiety Disorder. AB - Social anxiety is a psychological disorder which has devastative and pernicious effects on interpersonal relationships and one's psychological flexibility. The aim of this research was to determine the effectiveness of Acceptance and Commitment Therapy on interpersonal problems and psychological flexibility in female high school students with social anxiety disorder. With a semi experimental design, the subjects were assessed using the Social Anxiety Scale and clinical interview. The statistical population of the research was high school female students studying in 5 areas of Isfahan. 30 individuals were purposively selected as the sample. The subjects of the research were randomly assigned to the experimental and control groups. Acceptance and Commitment Therapy was given in 10 sessions of 90 minutes in the experimental group and the control group did not receive any treatment. Pre-test and post-test scores of Inventory of Interpersonal Problems, and Acceptance and Action Questionnaire were analyzed using multivariate analysis of variance & the results showed that after the intervention, there was a significant difference between the scores of the subjects in the experimental and control groups. This means that Acceptance and Commitment Therapy can influence interpersonal problems and their six dimensions and psychological flexibility as well. PMID- 26493426 TI - Survey of Nursery Errors in Healthcare Centers, Isfahan, Iran. AB - BACKGROUND & AIM: Nurse's mistakes usually have a strong effect on the patients trust and satisfaction in the health services systems, and it can also lead to stress and moral contradicts among nurses. This study has aimed to survey the rate of nurses' mistakes, according to documents in the Isfahan Province during 2007-2012. METHODS: The study was a descriptive cross-sectional study. The sample population consisted of all complaints concerning nursing services provided in hospitals, private clinics and other health service centers between 2007 and 2012, submitted to the Forensic Medicine Commission Office, in Isfahan. The data were collected by a cheklist and analyzed using SPSS version 16.0 software. RESULTS: Out of 708 complaints, 70 (9.8%) cases were related to nurses. Twenty four cases led to awards. The age range of nurses was 35-40 (25.7%). Out of 70 nurses with a record, 75% (53 people) were female and the rest were male. Sixty four nurses (91.4%) were working in hospitals. Negligence was the first basis of the court rulings (16 cases out of 24). Nurses' recklessness in providing services was due to their convictions among 66.7% of the cases. CONCLUSION: Although efforts to reduce and control nurses' faults and mistakes depends on using a system for studying and removing the factors which lead to faults, human error is inevitable in every occupation and a 100% accurate operation is unreachable. PMID- 26493427 TI - Decomposing Cost Efficiency in Regional Long-term Care Provision in Japan. AB - Many developed countries face a growing need for long-term care provision because of population ageing. Japan is one such example, given its population's longevity and low birth rate. In this study, we examine the efficiency of Japan's regional long-term care system in FY2010 by performing a data envelopment analysis, a non parametric frontier approach, on prefectural data and separating cost efficiency into technical, allocative, and price efficiencies under different average unit costs across regions. In doing so, we elucidate the structure of cost inefficiency by incorporating a method for restricting weight flexibility to avoid unrealistic concerns arising from zero optimal weight. The results indicate that technical inefficiency accounts for the highest share of losses, followed by price inefficiency and allocation inefficiency. Moreover, the majority of technical inefficiency losses stem from labor costs, particularly those for professional caregivers providing institutional services. We show that the largest share of allocative inefficiency losses can also be traced to labor costs for professional caregivers providing institutional services, while the labor provision of in-home care services shows an efficiency gain. However, although none of the prefectures gains efficiency by increasing the number of professional caregivers for institutional services, quite a few prefectures would gain allocative efficiency by increasing capital inputs for institutional services. These results indicate that preferred policies for promoting efficiency might vary from region to region, and thus, policy implications should be drawn with care. PMID- 26493428 TI - Hydroxyurea: Clinical and Hematological Effects in Patients With Sickle Cell Anemia. AB - BACKGROUND & AIM: it is well known that hydroxyurea impacts on clinical and hematologic indices in sickle cell disease (SCD), we aimed to evaluate the effect of hydroxyurea on clinical and hematological improvement of sickle cell anemia. METHODS & MATERIALS: In this cohort study 48 patients with sickle cell disease were enrolled and pain crisis, severity of pain, acute chest syndrome, the number of hospitalization, the rate of transfusion, spleen size, total Hb, HbF levels, MCV, MCH were compared before and after treatment with HU 10 mg/kg/day/for one year. RESULTS: In patients with Sickle cell disease Hu significantly decreased the rate of transfusion, hospitalization, spleen size and significantly increased Hb, RBC indices and HbF. Furthermore, we did not find any remarkable adverse effect related to HU during the one year follow up in patients. CONCLUSION: We demonstrated that in the course of one year hydroxyurea 10 mg/kg/day can significantly increase HbF, total hemoglobin and RBC indices without any notable side effect in patients with SCD. PMID- 26493429 TI - Effect of Nurse-Led Telephone Follow ups (Tele-Nursing) on Depression, Anxiety and Stress in Hemodialysis Patients. AB - INTRODUCTION: Depressive and anxious patients on hemodialysis have a higher risk of death and hospitalizations. The aim of this study was to evaluate the effect of nurse-led telephone follow ups (tele-nursing) on depression, anxiety and stress in hemodialysis patients. METHOD & MATERIAL: The subjects of the study who were selected based on double blind randomized clinical trial consisted of 60 patients with advanced chronic renal disease treated with hemodialysis. The patients were placed in two groups of 30 individuals. Before the intervention, a questionnaire was completed by patients. There was no telephone follow up in the control group and the patients received only routine care in the hospital. The participants allocated to the intervention group received telephone follow-up 30 days after dialysis shift, in addition to conventional treatment. Every session lasted 30 minutes, as possible. Then the DASS scale was filled out by the patients after completion of study by two groups. RESULT: Significant differences were observed between the two groups in the posttest regarding the dimensions scores of DASS scale. CONCLUSION: The result of this trial is expected to provide new knowledge to support the effective follow-up for hemodialysis patient in order to improve their emotional and health status. PMID- 26493430 TI - Comparison of the Effects of Maternal Supportive Care and Acupressure (at BL32 Acupoint) on Labor Length and Infant's Apgar Score. AB - BACKGROUND & OBJECTIVES: Prolonged labor leads to increase of cesarean deliveries, reduction of fetal heart rate, and maternal as well as infantile complications. Therefore, many women tend to use pharmacological or non pharmacological methods for reduction of labor length. The present study aimed to compare the effects of maternal supportive care and acupressure (at BL32 acupoint) on labor length and infant's Apgar score. METHODS: In this clinical trial, 150 women with low-risk pregnancy were randomly divided into supportive care, acupressure, and control groups each containing 50 subjects. The data were collected using a questionnaire including demographic and pregnancy characteristics. Then, the data were analyzed using Chi-square test and one-way ANOVA. RESULTS: The mean length of the first and second stages of labor was respectively 157.0+/-29.5 and 58.9+/-5.8 minutes in the supportive care group, 161.7+/-37.3 and 56.1+/-31.4 minutes in the acupressure group, ad 281.0+/-9.8 and 128.4+/-44.9 minutes in the control group. The difference between the length of labor stages was significant in the three study groups (P<0.001). Moreover, the frequency of Apgar score>8 in the first and 5th minutes was higher in the supportive care and acupressure groups compared to the control group, and the difference was statistically significant (P<0.001). CONCLUSION: Continuous support and acupressure could reduce the length of labor stages and increase the infants' Apgar scores. Therefore, these methods, as effective non-pharmacological strategies, can be introduced to the medical staff to improve the delivery outcomes. PMID- 26493432 TI - Knowledge, Attitude and Practice of Nurses about Standard Precautions for Hospital-Acquired Infection in Teaching Hospitals Affiliated to Zabol University of Medical Sciences (2014). AB - BACKGROUND & OBJECTIVES: Hospital-acquired infection (HAI) is one of the common problems and difficulties faced by hospitals in all countries around the world. Since nurses are part of the healthcare team that plays a unique role in the control of hospital infection, this study is conducted to analyze the knowledge and practice of healthcare personnel about standard precautions for hospital infection. MATERIALS & METHODS: This descriptive study was conducted on 170 nurses worked in medical surgical wards, pediatric wards, dialysis units of two teaching hospitals in Zabol city, Iran, in 2014. The sample population was selected through simple random sampling. The data collection instrument is composed of a researcher-made questionnaire titled "Hospital-acquired infection Control" based on precautions posited by the World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC). Data were fed into the SPSS software v.20 and were analyzed using descriptive and inferential statistics. RESULTS: The results show that 43% of the participants in this study had poor knowledge, 42% had average practice, and 37% had a moderate attitude about hospital infection. There was a significant relationship between knowledge and gender (r = 00.8 p = 0.02). However, the variables of age, marital status, employment, work experience, education, and place of work did not establish a significant relationship with the independent variables (p>0.05). CONCLUSION: As the results indicate a low level of awareness among the personnel about hospital infection, it is suggested to provide training sessions on the prevention and control of HAI to increase the awareness of personnel and hold practical courses for practicing these principles. PMID- 26493431 TI - Health Promotion Behaviors and Chronic Diseases of Aging in the Elderly People of Iranshahr*- IR Iran. AB - INTRODUCTION & AIM: Aging is considered as the phenomenon of the day in the health arena of the world and Iran. It is anticipated that there will be an explosion of aging population in Iran in about 2031 and 20-25% of the population will be aged over 60 years. With aging, chronic diseases also increase and diminish the functional ability of older people. On the other hand, increased healthcare costs should be also added to this issue. Health promotion is a concept of process that continues throughout life. As much as health promotion is important in children and adults, it is equally important in older people. In fact, the elderlies, as a group, also acquire many benefits from health promotion behaviors. Due to the increasing elderly population, geriatric health promotion and enhancing the health level of older people is proposed as a health priority that should be properly planned. Hence, the present study has been conducted in this regard and aims to identify behaviors of health promotion and chronic diseases of aging in the elderly people of Iranshahr-Iran. MATERIALS & METHODS: The present research is a cross-sectional descriptive study whose population consists of 425 elderly people aged 60 years and over, who lived in the city of Iranshahr*, IR Iran. The random cluster sampling method has been used to select the research samples. The required information was collected using a questionnaire which was distributed among the older people through visiting their homes; then, the collected data was statistically analyzed using the statistical software of SPSS version 13. FINDINGS: the research findings show that the mean age of older people is and the highest frequency belongs to the age group of 60 years and the maximum age is 92 years. 69.5% of the older people were in the age group of the young elderly (60-69 years) and 44% of them lived with their married children; also 55.8%, 81.9%, 70.5%, and 74.4% of them were respectively female, illiterate, married, and unemployed. The mean score of geriatric health promotion behaviors was in the range of 0-11 and 54.9% of them got the score of the inappropriate health promotion behavior. The most frequent chronic diseases of older people were respectively joint problems (78.9%), sensory problems (64.1%), and hypertension (56.6%). No significant relationship was observed between the score of health promotion behaviors and "the gender, lifestyle and marital status of the older people", but there was statistically a significant relationship between the score of health promotion behaviors and "the age, education, and job of the older people". CONCLUSION: Providing training programs for health promotion behaviors in elderly people can improve these behaviors and enhance their health and quality of life and reduce the incidence of chronic diseases in them. The goal of health promotion behaviors is to maintain performance, independence and quality of life; and many studies have demonstrated that the elderly people who aged 60 years and over benefit from health promotion behaviors more than middle-aged people. PMID- 26493433 TI - Histological Stains: A Literature Review and Case Study. AB - The history of histology indicates that there have been significant changes in the techniques used for histological staining through chemical, molecular biology assays and immunological techniques, collectively referred to as histochemistry. Early histologists used the readily available chemicals to prepare tissues for microscopic studies; these laboratory chemicals were potassium dichromate, alcohol and the mercuric chloride to harden cellular tissues. Staining techniques used were carmine, silver nitrate, Giemsa, Trichrome Stains, Gram Stain and Hematoxylin among others. The purpose of this research was to assess past and current literature reviews, as well as case studies, with the aim of informing ways in which histological stains have been improved in the modern age. Results from the literature review has indicated that there has been an improvement in histopathology and histotechnology in stains used. There has been a rising need for efficient, accurate and less complex staining procedures. Many stain procedures are still in use today, and many others have been replaced with new immunostaining, molecular, non-culture and other advanced staining techniques. Some staining methods have been abandoned because the chemicals required have been medically proven to be toxic. The case studies indicated that in modern histology a combination of different stain techniques are used to enhance the effectiveness of the staining process. Currently, improved histological stains, have been modified and combined with other stains to improve their effectiveness. PMID- 26493434 TI - Looking for a Taste of Home: A Qualitative Study of the Health Implications of the Diets of Australian - Based Southeast Asian Students. AB - PURPOSE: To investigate potential dietary changes among Southeast Asian international students living in self-catered accommodation while studying abroad and to consider implications for their health. DESIGN: Participants were interviewed about their food preferences and behaviours in their home countries and during their undergraduate studies at the Australian National University. SETTING: A university in Australia. PARTICIPANTS: Study participants were full time undergraduate students over 18 years of age from Southeast Asian countries studying at the Australian National University for at least one year, and living at self-catered accommodation. METHODS: Thirty-one, in-depth, face-to-face qualitative interviews concerning usual diets were collected over a three month period in 2013. Interviews were coded and analysed with the aid of a computer program Atlas.ti. RESULTS: The macro-nutrient content of Southeast Asian international students' diets did not change a great deal when they moved to Australia. Most students replaced some preferred foods on occasions because they either could not afford them, they were not available or they lacked the time to prepare them. These dietary changes were not necessarily reflected in changes to students' weights and most students considered that they were as healthy as when they lived at home. CONCLUSION: As students' adapt to a new food environment they reflexively manage potential health risks. Strong student networks and an accessible and healthy food environment would support students to make healthy dietary choices although additional information about healthy diets could facilitate this further. PMID- 26493435 TI - Clinical Factors Influencing the Efficacy of Systemic Moxifloxacin in the Therapy of Patients With Generalized Aggressive Periodontitis: A Multilevel Analysis From a Clinical Trial. AB - BACKGROUND: It has been reported that clinical results of mechanical periodontal treatment could differ between subjects and among different sites of the tooth in the patient. The objective of this multilevel analysis is to investigate clinical factors at subject and sites of the tooth that influence variations in clinical attachment (CAL) increase and probing depth (PD) diminution of adjunctive moxifloxacin (MOX) at six months post-treatment in generalized aggressive periodontitis. METHODS: This clinical trial included 40 patients randomly distributed to two therapy protocols: scaling and root planing alone or combined with MOX. Multilevel linear models for continuous variables were formulated to evaluate the clinical impact of the hierarchical configuration of periodontal data. RESULTS: Six months following therapy, the divergences between both protocols were statistically significant in PD diminution and CAL increase, favouring the MOX therapy (p<0.001). Besides, the multilevel analysis revealed that adjunctive MOX at the subject level, non-molar and the interaction non-molar x MOX at the tooth level, interproximal sites and the interaction interproximal sites x MOX at the site level, were statistically significant factors in determining CAL increase and PD diminution. CONCLUSIONS: The main cause of variability in CAL gain and PD reduction following adjunctive MOX was attributable to the tooth level. Adjunctive MOX and their interactions with non molar and interproximal sites showed higher clinical benefits at the tooth and site levels which could be essential for PD reduction and CAL gain in generalized aggressive periodontitis subjects. PMID- 26493436 TI - Rabies Epidemiology and Control in Ecuador. AB - OBJECTIVE: Describe the epidemiology and the control effort for rabies in Ecuador. METHODS: This observational study included data from the Ecuadorian National Institute of Census and Statistics (INEC), and mortality and morbidity data reported by the Ministry of Public Health and the National Institute for Social Security. We conducted a phylogeny analyses to compare the N gene from the Challenge Virus Standard (CVS) vaccine strain used in Ecuador with published Cosmopolitan, Asian and Sylvatic strains. Descriptive and inferential statistics were used to determine the significance of the data. RESULTS: In 1996 Ecuador suffered the highest rate of rabies per capita in the Americas, with an incidence rate of 0.56 cases per 100 000 people per year. Human and canine rabies showed a sharp decline until 2012. Between 1994 and 2014, we found a correlation of 0.925 (p<0.01) between annual cases of dog and human rabies. In 2011, there was an epidemic of sylvatic rabies transmitted to people by vampire bats (Desmodus rotundus) in the Amazon region, specifically in Morona Santiago, leading to 11 fatalities. Phylogenetic analyses of the CVS vaccine N gene showed an association with urban canine rabies strains (the Cosmopolitan lineage and Asian strains), whereas sylvatic rabies, like those reported in the Amazon region, were found to be grouped in a different clade represented mainly by bat-derived strains. CONCLUSIONS: This study presents the first compilation of epidemiological data on rabies in Ecuador. The incidence of human and canine rabies, also known as urban rabies, has clearly decreased due to massive canine vaccination campaigns. Phylogenetic analysis of the prevailing vaccine used in the country showed a clear separation from bat-derived rabies, the source of recent rabies outbreaks. Efforts are ongoing to develop rabies vaccines that are highly specific to the rabies virus genotype circulating in the region, including sylvatic rabies. These efforts include the implementation of reverse genetics to generate recombinant virus coding for the prevailing glycoprotein gene. PMID- 26493437 TI - Prevalence and Reporting of Needle Stick Injuries: A Survey of Surgery Team Members in Kermanshah University of Medical Sciences in 2012. AB - BACKGROUND: Surgeons are one of the groups, most highly exposed to the risk of needle stick injuries at work. The present study aims to determine the prevalence and reporting of needle stick injuries during the first 6 months of 2012, in faculty surgeons affiliated to the Kermanshah University of Medical Sciences. METHODS: In a cross-sectional descriptive-analytical survey, 29 surgeons were studied based on the census method. A reliable and valid questionnaire was used as a research instrument to collect the data. Data was analyzed using SPSS v.16 and based on descriptive and inferential statistics. RESULTS: Among 29 recruited surgeons, 5 (17.2%) had needle stick injuries during the 6 months, only one of whom had followed the established guidelines about reporting and following treatment. The most common instrument causing injury was the suture needle (60%). Significant differences were found in both groups of the injured and non-injured in term of gender (X(2)=5.612, P= 0.003), and number of patients (Z= 2.40, P=0.016) and daily working hours (Z=2.85, P=0.04). CONCLUSIONS: In relation to the relatively high prevalence of needle stick injuries among the surgeons and their lack of reporting, it is suggested that the Safety Guidelines in the operating room are carefully observed. Moreover, safer and lower risk surgical Instruments should be used. PMID- 26493438 TI - Detection of Hydroxychloroquine Retinal Toxicity by Automated Perimetry in 60 Rheumatoid Arthritis Patients with Normal Fundoscopic Findings. AB - Hydroxychloroquine (HCQ) is an antimalarial drug used extensively in treatment of autoimmune diseases such as rheumatoid arthritis. Retinal toxicity is the most important side effects of this drug. Even after the drug is discontinued, retinal degeneration from HCQ can continue to progress. Consequently, multiple ophthalmic screening tests have been developed to detect early retinopathy. The aim of the current study was to evaluate the value of central 2-10 perimetry method in early detection of retinal toxicity. This prospective cross-sectional investigation was carried out on 60 rheumatoid arthritis patients, who had been receiving HCQ for at least 6 months and still were on their medication (HCQ intake) at the time of enrollment. An ophthalmologist examined participants using direct and indirect ophthalmoscopy. Visual field testing with automated perimetry technique (central 2-10 perimetry with red target) was performed on all included subjects twice in 6 months interval: The first one at the time of enrollment and the second one 6 months later. Males and females did not show any significant difference in terms of age, duration of therapy, daily and cumulative HCQ dose, anterior or posterior segment abnormalities, hypertension, body mass index, and best corrected visual acuity. Anterior segment was abnormal in 9 individuals including 3 subjects with macular pigmentary changes, 4 individuals with cataract and 2 cases with dry eyes. Moreover, 12 subjects had retinal pigmented epithelium (RPE) in their posterior segments. After 6 months, depressive changes appeared in 12 subjects. Additionally, HCQ therapy worsened significantly the perimetric results of 5 (55.6%) patients with abnormal anterior segment. A same trend was observed in perimetric results of 6 (50.0%) subjects with abnormal posterior segments (P=0.009). The daily dose of HCQ (P=0.035) as well as the cumulative dose of hydroxychloroquine (P=0.021) displayed statistically significant associations with perimetric results. Central 2-10 perimetry is a useful method for early detection of HCQ retinal toxicity, but more comprehensive studies, with larger sample size, longer-term follow-up and more precise techniques are mandatory to confirm HCQ retinal toxicity. PMID- 26493439 TI - Concept of Educational Assistance to Health Protection of the Individual. AB - The article describes the theoretical and practical need for the development of the concept of assistance to health protection of the individual in order to address the problem of health protection of students and teachers in the conditions of a higher pedagogical education. The problem of studying human health, its entirety, systemacity and connection with the environment attracts particular attention in recent years. This was one of the reasons to study the problem of "healthy lifestyle" as the qualitative characteristic of a human life aimed at health, due to the fact that a healthy lifestyle is one of the determinants of health. This is made possible with the use of specific health protecting technologies aimed at searching for ways and means of protection and conservation of health of students and teachers in the conditions of the educational process and using educational tools, which is currently included into the priorities of education. PMID- 26493440 TI - An Exploration of the Role of Hospital Committees to Enhance Productivity. AB - Productivity is the main concern of hospitals as organizations providing health services. As the role of hospital committees is increasing and their productivity and performance improvement is very important, the present study was performed to identify weaknesses and strengths of committee sessions. This analytical descriptive study was conducted cross- sectional from January to April in 2012. Summary of 405 committee session's agendas related to 11 kinds of committees in 8 hospitals (out of 23 hospitals) of capital cities in 3 provinces of Sistan and Balouchestan, South Khorasan and Khorasan Razavi in Iran were extracted. Data was collected through a form and was analyzed by SPSS16 software using descriptive statistics and variance analysis and content analysis technique. This study showed that the number of hospital committee's sessions holding in 2012 was more than 2011.The differences between public and private hospitals in terms of the following subjects were significant (P-Value < 0.001). In terms of the number of selected policies, participants of the committees, and the duration of the sessions the public hospitals had better conditions. And regarding documentation process, feedback of decisions to personnel and the implementation of the formulated policies in the committees, private hospitals performed better. According to the results of this study, to improve the productivity of hospital committees, it is suggested to motivate senior, tactical and operational managers to appropriately participate in the committees and necessary planning for the committees in advance is mandatory. PMID- 26493441 TI - Dorsal medial prefrontal cortex contributes to conditioned taste aversion memory consolidation and retrieval. AB - The medial prefrontal cortex (mPFC) is known for its role in decision making and memory processing, including the participation in the formation of extinction memories. However, little is known regarding its contribution to aversive memory consolidation. Here we demonstrate that neural activity and protein synthesis are required in the dorsal mPFC for memory formation of a conditioned taste aversion (CTA) task and that this region is involved in the retrieval of recent and remote long-term CTA memory. In addition, both NMDA receptor and CaMKII activity in dorsal mPFC are needed for CTA memory consolidation, highlighting the complexity of mPFC functions. PMID- 26493442 TI - Nanoscale Surface Creasing Induced by Post-polymerization Modification. AB - Creasing in soft polymeric films is a result of substantial compressive stresses that trigger instability beyond a critical strain and have been directly related to failure mechanisms in different materials. However, it has been shown that programming these instabilities into soft materials can lead to new applications, such as particle sorting, deformable capillaries, and stimuli-responsive interfaces. In this work, we present a method for fabricating reproducible nanoscale surface instabilities using reactive microcontacting printing (MUCP) on activated ester polymer brush layers of poly(pentafluorophenyl acrylate). The sizes and structures of the nanoscale creases can be modulated by varying the grafting density of the brush substrate and pressure applied during MUCP. Stress is generated in the film under confinement due to the molecular weight increase of the side chains during post-polymerization modification, which results in substantial in-plane growth in the film and leads to the observed nanoscale creases. PMID- 26493443 TI - Molecular alterations of the blood-brain barrier under inflammatory conditions: The role of endothelial to mesenchymal transition. AB - Impairment of the protective properties of the blood-brain barrier (BBB) is a key event during numerous neurological diseases, including multiple sclerosis (MS). Under these pathological conditions, the specialized brain endothelial cells (BECs) lose their protective function leading to neuroinflammation and neurodegeneration. To date, underlying mechanisms for this loss of function remain unclear. Endothelial to mesenchymal transition (EndoMT) is a dynamic process by which endothelial cells (ECs) dedifferentiate into mesenchymal cells and as a result lose their specific phenotype and function. As yet, little is known about the involvement of this process in the impaired function of the BECs under pathological conditions such as MS. Interestingly, several signaling pathways that can induce EndoMT are also involved in different central nervous system (CNS) pathologies associated with BBB dysfunction. In this review, we first discuss the structure and function of the BBB highlighting the changes that occur during MS. Next, we will summarize recent findings on the pathways underlying EndoMT, and finally, we will discuss the potential role of EndoMT during BBB dysfunction in neurological disorders. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26493445 TI - Glial cell response after aneurysmal subarachnoid hemorrhage - Functional consequences and clinical implications. PMID- 26493446 TI - The plasminogen activation system in neuroinflammation. AB - The plasminogen activation (PA) system consists in a group of proteases and protease inhibitors regulating the activation of the zymogen plasminogen into its proteolytically active form, plasmin. Here, we give an update of the current knowledge about the role of the PA system on different aspects of neuroinflammation. These include modification in blood-brain barrier integrity, leukocyte diapedesis, removal of fibrin deposits in nervous tissues, microglial activation and neutrophil functions. Furthermore, we focus on the molecular mechanisms (some of them independent of plasmin generation and even of proteolysis) and target receptors responsible for these effects. The description of these mechanisms of action may help designing new therapeutic strategies targeting the expression, activity and molecular mediators of the PA system in neurological disorders involving neuroinflammatory processes. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26493444 TI - Comparative effects of diet and carcinogen on microRNA expression in the stem cell niche of the mouse colonic crypt. AB - There is mounting evidence that noncoding microRNAs (miRNA) are modulated by select chemoprotective dietary agents. For example, recently we demonstrated that the unique combination of dietary fish oil (containing n-3 fatty acids) plus pectin (fermented to butyrate in the colon) (FPA) up-regulates a subset of putative tumor suppressor miRNAs in intestinal mucosa, and down-regulates their predicted target genes following carcinogen exposure as compared to control (corn oil plus cellulose (CCA)) diet. To further elucidate the biological effects of diet and carcinogen modulated miR's in the colon, we verified that miR-26b and miR-203 directly target PDE4B and TCF4, respectively. Since perturbations in adult stem cell dynamics are generally believed to represent an early step in colon tumorigenesis and to better understand how the colonic stem cell population responds to environmental factors such as diet and carcinogen, we additionally determined the effects of the chemoprotective FPA diet on miRNAs and mRNAs in colonic stem cells obtained from Lgr5-EGFP-IRES-creER(T2) knock-in mice. Following global miRNA profiling, 26 miRNAs (P<0.05) were differentially expressed in Lgr5(high) stem cells as compared to Lgr5(negative) differentiated cells. FPA treatment up-regulated miR-19b, miR-26b and miR-203 expression as compared to CCA specifically in Lgr5(high) cells. In contrast, in Lgr5(negative) cells, only miR-19b and its indirect target PTK2B were modulated by the FPA diet. These data indicate for the first time that select dietary cues can impact stem cell regulatory networks, in part, by modulating the steady-state levels of miRNAs. To our knowledge, this is the first study to utilize Lgr5(+) reporter mice to determine the impact of diet and carcinogen on miRNA expression in colonic stem cells and their progeny. PMID- 26493447 TI - The effect of surgical approach on performance of lymphadenectomy and perioperative morbidity for radical nephroureterectomy. AB - OBJECTIVES: To examine the effect of surgical approach on regional lymphadenectomy (LND) performance and inpatient complications for radical nephroureterectomy (NU) using a national administrative database. METHODS: The National Inpatient Sample (2009-2012) was used to identify patients who underwent NU for urothelial carcinoma. Cohorts were stratified by performance of LND. Covariates included patient demographics, comorbidity, hospital characteristics, hospital volume, performance of LND, surgical approach (open [ONU], laparoscopic [LNU], or robotic [RNU]), and complications. Multivariable logistic regression was used to identify factors associated with LND performance and complications. RESULTS: A weighted population of 14,059 (85%) without LND and 2,560 (15%) with LND was identified. LND was more common in RNU (27%) compared with ONU (15%) and LNU (10%) (P<0.01). On multivariable analysis, when compared with ONU, RNU was associated with increased odds of LND performance (odds ratio [OR] = 1.9, 95% CI: [1.3-2.8]; P = 0.001), whereas LNU was associated with decreased odds of LND performance (OR = 0.6, 95% CI: [0.4-0.8]; P = 0.004). Multivariable analysis of risk factors for complications demonstrated lower odds of complications with RNU (OR = 0.6, 95% CI: [0.4-0.8]; P = 0.001), whereas performance of LND increased the risk of complications (OR = 1.3, 95% CI: [1.001-1.7]; P = 0.049). CONCLUSIONS: When compared with ONU, RNU increased the odds of LND performance and had a lower inpatient complication rate, whereas LNU reduced the odds of LND performance and had no significant effect on inpatient complication rates. Performance of LND was independently associated with higher inpatient complication rates. PMID- 26493448 TI - Randomized controlled trials in testicular cancer: A demographic and quality assessment. AB - BACKGROUND: Randomized controlled trials (RCT) provide the strongest evidence to justify interventions in patients. However, trials with inadequate methods are associated with bias and exaggerated treatment effects. A search of the literature was conducted to review RCTs in testicular cancer (TC) to assess demographic and trial reporting quality patterns over time. METHODS: MEDLINE and CENTRAL were queried for TC RCTs from 1989 to 2014. Demographic information was abstracted and reporting quality score was evaluated using the Consolidated Standards of Reporting Trials criteria. Linear regression was used to assess the trend in reporting quality over time. RESULTS: A total of 39 RCTs were identified, of which 25 were published from 1989 to 2001 and 14 were published from 2002 to 2014. Most (59%) of the RCTs involved chemotherapy as the intervention, had a medical oncologist as the first author (87%), and took place in Europe (59%). RCTs published between 2002 and 2014 had longer enrollment periods (mean = 6.1 [2.7] vs. 3.7 [1.5] years, P = 0.007), whereas the number of patients randomized, median follow-up, or time from manuscript submission to acceptance were not significantly different between the periods. For each increasing year of publication, there was a significant improvement of 1.34% points (95% CI: 0.86-1.83, P<0.0001) in the Consolidated Standards of Reporting Trials score. CONCLUSIONS: Fewer RCTs in TC were published in the recent 13-year period. Although the quality of trial reporting improved compared with the preceding 13-year period, deficiencies remain. Urologists can play an important role in trial design, recruitment, and execution, and ensuring trial methodology and reporting quality is prioritized. PMID- 26493449 TI - Prevalence and management of prostate cancer among East Asian men: Current trends and future perspectives. AB - OBJECTIVES: Previously East Asian men had been considered less likely to develop or die of prostate cancer. Emerging research and the onset of prostate-specific antigen screening in East Asian countries suggests that this may not be the case. We sought to analyze epidemiology and molecular genetic data and recent trends in the management of prostate cancer among East Asian men. METHODS AND MATERIALS: We performed literature searches using PubMed, Embase, and Google Scholar to examine current literature on prostate cancer in East Asian men. Additionally, articles were searched for further references related to the topic. RESULTS: Recent studies have reported increasing incidence of prostate cancer identified in East Asian men. Prostate cancer mortality has increased and is currently the fourth leading cause of death among men in Shanghai, China. Although prostate cancer was considered less aggressive among East Asian men, studies suggest that it is similarly aggressive to prostate cancer in Western populations. Molecular markers such as the TEMPRESS:ERG fusion gene and PTEN loss may provide novel methods of screening East Asian men for prostate cancer. National-level guidelines for prostate cancer screening and management are only available in Japan. CONCLUSIONS: The prevalence of prostate cancer in East Asian men is likely similar to that in Western male populations. East Asian men present at higher stages of prostate cancer, likely because of a lack of standardized screening protocols. Urologists in Western countries should screen East Asian men for prostate cancer using the same standards as used for Western men. PMID- 26493451 TI - Obama outlines plan to curb prescription drug and heroin misuse. PMID- 26493452 TI - Oxalate induces breast cancer. AB - BACKGROUND: Microcalcifications can be the early and only presenting sign of breast cancer. One shared characteristic of breast cancer is the appearance of mammographic mammary microcalcifications that can routinely be used to detect breast cancer in its initial stages, which is of key importance due to the possibility that early detection allows the application of more conservative therapies for a better patient outcome. The mechanism by which mammary microcalcifications are formed is still largely unknown but breast cancers presenting microcalcifications are more often associated with a poorer prognosis. METHODS: We combined Capillary Electrochromatography, histology, and gene expression (qRT-PCR) to analyze patient-matched normal breast tissue vs. breast tumor. Potential carcinogenicity of oxalate was tested by its inoculation into mice. All data were subjected to statistical analysis. RESULTS: To study the biological significance of oxalates within the breast tumor microenvironment, we measured oxalate concentration in both human breast tumor tissues and adjoining non-pathological breast tissues. We found that all tested breast tumor tissues contain a higher concentration of oxalates than their counterpart non pathological breast tissue. Moreover, it was established that oxalate induces proliferation of breast cells and stimulates the expression of a pro-tumorigenic gene c-fos. Furthermore, oxalate generates highly malignant and undifferentiated tumors when it was injected into the mammary fatpad in female mice, but not when injected into their back, indicating that oxalate does not induce cancer formation in all types of tissues. Moreover, neither human kidney-epithelial cells nor mouse fibroblast cells proliferate when are treated with oxalate. CONCLUSIONS: We found that the chronic exposure of breast epithelial cells to oxalate promotes the transformation of breast cells from normal to tumor cells, inducing the expression of a proto-oncogen as c-fos and proliferation in breast cancer cells. Furthermore, oxalate has a carcinogenic effect when injected into the mammary fatpad in mice, generating highly malignant and undifferentiated tumors with the characteristics of fibrosarcomas of the breast. As oxalates seem to promote these differences, it is expected that a significant reduction in the incidence of breast cancer tumors could be reached if it were possible to control oxalate production or its carcinogenic activity. PMID- 26493453 TI - Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice. AB - Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with beta-cell dysfunction. A genome-wide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 (SUR1) and Kcnj11 (Kir6.2). The NZO Abcc8 allele was associated with a ~211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8/Kcnj11 genes and displayed significant improvements in early-phase glucose-mediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving beta-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to beta-cell dysfunction in T2D. PMID- 26493454 TI - Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes. AB - BACKGROUND: A hallmark of chronic liver disease is the impairment of the liver's innate regenerative ability. In this work we use a computational approach to unravel the principles underlying control of liver repair following an acute physiological challenge. METHODS: We used a mathematical model of inter- and intra-cellular interactions during liver regeneration to infer key molecular factors underlying the dysregulation of multiple regeneration modes, including delayed, suppressed, and enhanced regeneration. We used model analysis techniques to identify organizational principles governing the cellular regulation of liver regeneration. We fit our model to several published data sets of deficient regeneration in rats and healthy regeneration in humans, rats, and mice to predict differences in molecular regulation in disease states and across species. RESULTS: Analysis of the computational model pointed to an important balance involving inflammatory signals and growth factors, largely produced by Kupffer cells and hepatic stellate cells, respectively. Our model analysis results also indicated an organizational principle of molecular regulation whereby production rate of molecules acted to induce coarse-grained control of signaling levels while degradation rate acted to induce fine-tuning control. We used this computational framework to investigate hypotheses concerning molecular regulation of regeneration across species and in several chronic disease states in rats, including fructose-induced steatohepatitis, alcoholic steatohepatitis, toxin induced cirrhosis, and toxin-induced diabetes. Our results indicate that altered non-parenchymal cell activation is sufficient to explain deficient regeneration caused by multiple disease states. We also investigated liver regeneration across mammalian species. Our results suggest that non-invasive measures of liver regeneration taken at 30 days following resection could differentiate between several hypotheses about how human liver regeneration differs from rat regeneration. CONCLUSIONS: Overall, our results provide a new computational platform integrating a wide range of experimental information, with broader utility in exploring the dynamic patterns of liver regeneration across species and over multiple chronic diseases. PMID- 26493455 TI - Fitness predicts long-term survival after a cardiovascular event: a prospective cohort study. AB - OBJECTIVES: To identify the role of fitness, fitness change, body mass index and other factors in predicting long-term (>5 years) survival in patients with coronary heart disease. DESIGN: Cohort study of patients with coronary heart disease recruited from 1 January 1993 to 31 December 2002, followed up to March 2011 (1 day to 18 years 3 months, mean 10.7 years). SETTING: A community-based National Health Service (NHS) cardiac rehabilitation programme serving the Basingstoke and Alton area in Hampshire, UK. PARTICIPANTS: An unselected cohort of NHS patients, 2167 men and 547 women aged 28-88 years, who attended the rehabilitation programme following acute myocardial infarction, an episode of angina or revascularisation, and had a baseline fitness test. MAIN OUTCOME MEASURES: Cardiovascular mortality and all-cause mortality. RESULTS: A high level of fitness (VO2>=22 mL/kg/min for men, VO2>=19 mL/kg/min for women) at completion of the programme was associated with decreased all-cause death, as was a prescription for statins or aspirin, and female gender. Increase in all-cause mortality was associated with higher age and ACE inhibitors prescription. Higher risk of cardiovascular mortality was associated with increasing age, prescriptions for ACE inhibitor, and diagnosis of myocardial infarction or angina as compared with the other diagnoses. CONCLUSIONS: Prior fitness and fitness improvement are strong predictors of long-term survival in patients who have experienced a cardiac event or procedure. Some secondary prevention medications make a significant contribution to reducing all-cause mortality and cardiovascular mortality in these patients. This study supports public health messages promoting fitness for life. PMID- 26493456 TI - Comparative effectiveness of inhaled corticosteroids for paediatric asthma: protocol for a systematic review and Bayesian network meta-analysis. AB - INTRODUCTION: Use of inhaled corticosteroid (ICS) is the mainstream maintenance therapy for paediatric asthma. Several forms of ICS are available, but the relative effectiveness among ICS has not been well investigated in published, randomised, controlled trials. The paucity of direct comparisons between ICS may have resulted in insufficient estimation in former systematic reviews/meta analyses. To supplement the information on the comparative effectiveness of ICS for paediatric asthma, we plan to conduct a network meta-analysis that will enable summary of direct and indirect evidence. METHODS AND ANALYSIS: We will retrieve randomised, controlled trials that examined the effectiveness of ICS for paediatric asthma from the PubMed and Cochrane Central Register of Controlled Trials. After one author scans the title and abstract for eligible studies, two authors will independently review study data and assess the quality of the study. Studies of children (<=18 years old) with chronic asthma or recurrent wheezing episodes will be included if they used ICS for >=4 weeks. We will define a priori core outcomes and supplemental outcomes of paediatric asthma, including exacerbation, healthcare use and pulmonary function. Studies reporting a minimum of one core outcome will be entered into the systematic review. After the systematic review is performed, extracted data of relevant studies will be synthesised in the Bayesian framework using a random-effects model. ETHICS AND DISSEMINATION: The results will be disseminated through peer-reviewed publications and conference presentations. PROTOCOL REGISTRATION NUMBER: UMIN (000016724) and PROSPERO (CRD42015025889). PMID- 26493457 TI - Rapid diagnostic pathways for suspected colorectal cancer: views of primary and secondary care clinicians on challenges and their potential solutions. AB - OBJECTIVES: To ascertain the challenges associated with implementation of the 2 week wait referral criteria and waiting time targets for colorectal cancer and to identify recommendations for improvements to the pathway. DESIGN: Qualitative research using semistructured interviews and applying thematic analysis using the method of constant comparison. SETTING: 10 primary care surgeries and 6 secondary care centres from 3 geographical areas in the England. PARTICIPANTS: Purposive sample of 24 clinicians (10 general practitioners (GPs), 7 oncologists and 7 colorectal surgeons). RESULTS: GPs and specialists highlighted delays in patient help-seeking, difficulties applying the colorectal cancer referral criteria due to their low predictive value, and concerns about the stringent application of targets because of potential impact on individual care and associated penalties for breaching. Promoting patient awareness and early presentation, clarifying predictive symptoms, allowing flexibility, optimising resources and maximising care coordination were suggested as improvements. CONCLUSIONS: Challenges during diagnosis and treatment persist, with guidelines and waiting time targets producing the perception of unintended harms at individual and organisational levels. This has led to variations in how guidelines are implemented. These require urgent evaluation, so that effective practices can be adopted more widely. PMID- 26493458 TI - Patients who discontinued statin treatment: a protocol for cohort study using primary care data. AB - INTRODUCTION: Risk thresholds for using statins to prevent cardiovascular disease (CVD) have recently been lowered, so an increasing number of patients are now prescribed these drugs. Although the safety of long-term statin use has been generally established, concerns about the balance of risks and benefits of statins still exist for some medical professionals and patients, and issues concerning their side effects are occasionally widely publicised. This study will report the rates of stopping for statins and also identify any patient groups more likely to stop using statins, so possibly increasing their risk of cardiovascular events. METHODS AND ANALYSIS: A prospective open cohort study between 1 January 2002 and 30 September 2014 will be based on the general population of people prescribed statins, using records from UK general practices contributing to the Clinical Practice Research Database (CPRD). Participants aged 25-84 years will enter the cohort on the date of their first prescription for a statin and leave on the earliest date of: a cardiovascular event; death; leaving the practice; the last practice upload date or the study end date. If there are no prescriptions within 90 days after the expected finishing date of a prescription, a patient will be defined as a stopper with the discontinuation outcome date as the expected finishing date. Rates of statin discontinuation will be calculated by calendar year, type and dose of statin, age, and morbidities. Cox proportional regression analyses will be run to identify the most important factors associated with discontinuation. Analyses will be run separately for patients without CVD (primary prevention) and with diagnosed CVD (secondary prevention). ETHICS AND DISSEMINATION: The protocol has been reviewed and approved by Independent Scientific Advisory Committee for MHRA Database Research. The results will be published in a peer-reviewed journal. PMID- 26493459 TI - Adaptation and uptake evaluation of an SMS text message smoking cessation programme (MiQuit) for use in antenatal care. AB - OBJECTIVES: To adapt a tailored short message service (SMS) text message smoking cessation intervention (MiQuit) for use without active health professional endorsement in routine antenatal care settings, to estimate 'real-world' uptake and test the feasibility of its use. DESIGN: Single-site service evaluation. SETTING: A Nottinghamshire (UK) antenatal clinic. PARTICIPANTS: Pregnant women accessing the antenatal clinic (N=1750) over 6 months. INTERVENTION: A single sheet A5 leaflet provided in the women's maternity notes folder describing the MiQuit text service. Similar materials were left on clinic desks and noticeboards. OUTCOME MEASURES: MiQuit activation requests and system interactions were logged for two time frames: 6 months (strict) and 8 months (extended). Local hospital data were used to estimate the denominator of pregnant smokers exposed to the materials. RESULTS: During the strict and extended time frames, 13 and 25 activation requests were received, representing 3% (95% CI 2% to 5%) and 4% (95% CI 3% to 6%) of estimated smokers, respectively. Only 11 (44%) of the 25 requesting activation sent a correctly formatted initiation text. Of those activating MiQuit, and invited to complete tailoring questions (used to tailor support), 6 (67%) completed all 12 questions by text or website and 5 (56%) texted a quit date to the system. Of the 11 activating MiQuit, 5 (45%, 95% CI 21% to 72%) stopped the programme prematurely. CONCLUSIONS: A low-intensity, cheap cessation intervention promoted at very low cost, resulted in a small but potentially impactful uptake rate by pregnant smokers. PMID- 26493460 TI - Interventions to improve antimicrobial prescribing of doctors in training: the IMPACT (IMProving Antimicrobial presCribing of doctors in Training) realist review. AB - INTRODUCTION: Antimicrobial resistance has been described as a global crisis-more prudent prescribing is part of the solution. Behaviour change interventions are needed to improve prescribing practice. Presently, the literature documents that context impacts on prescribing decisions, yet insufficient evidence exists to enable researchers and policymakers to determine how local tailoring should take place. Doctors in training are an important group to study, being numerically the largest group of prescribers in UK hospitals. Unfortunately very few interventions specifically targeted this group. METHODS AND ANALYSIS: Our project aims to understand how interventions to change antimicrobial prescribing behaviours of doctors in training produce their effects. We will recruit a project stakeholder group to advise us throughout. We will synthesise the literature using the realist review approach-a form of theory-driven interpretive systematic review approach often used to make sense of complex interventions. Interventions to improve antimicrobial prescribing behaviours are complex-they are context dependent, have long implementation chains, multiple non-linear interactions, emergence and depend on human agency. Our review will iteratively progress through 5 steps: step 1--Locate existing theories; step 2--Search for evidence; step 3--Article selection; step 4--Extracting and organising data; and step 5--Synthesising the evidence and drawing conclusions. Data analysis will use a realist logic of analysis to describe and explain what works, for whom, in what circumstances, in what respects, how and why to improve antimicrobial prescribing behaviour of doctors in training. ETHICS AND DISSEMINATION: Ethical approval was not required for our review. Our dissemination strategy will be participatory and involve input from our stakeholder group. Tailored project outputs will be targeted at 3 audiences: (1) doctors in training; (2) clinical supervisors/trainers and medical educators; and (3) policy, decision makers, regulators and royal societies. PMID- 26493461 TI - Evaluating the effectiveness of a home-based exercise programme delivered through a tablet computer for preventing falls in older community-dwelling people over 2 years: study protocol for the Standing Tall randomised controlled trial. AB - INTRODUCTION: In order to prevent falls, older people should exercise for at least 2 h per week for 6 months, with a strong focus on balance exercises. This article describes the design of a randomised controlled trial to evaluate the effectiveness of a home-based exercise programme delivered through a tablet computer to prevent falls in older people. METHODS AND ANALYSIS: Participants aged 70 years or older, living in the community in Sydney will be recruited and randomly allocated to an intervention or control group. The intervention consists of a tailored, home-based balance training delivered through a tablet computer. Intervention participants will be asked to complete 2 h of exercises per week for 2 years. Both groups will receive an education programme focused on health related information relevant to older adults, delivered through the tablet computer via weekly fact sheets. Primary outcome measures include number of fallers and falls rate recorded in weekly fall diaries at 12 months. A sample size of 500 will be necessary to see an effect on falls rate. Secondary outcome measures include concern about falling, depressive symptoms, health-related quality of life and physical activity levels (in all 500 participants); and physiological fall risk, balance, functional mobility, gait, stepping and cognitive performance (in a subsample of 200 participants). Adherence, acceptability, usability and enjoyment will be recorded in intervention group participants over 2 years. Data will be analysed using the intention-to-treat principle. Secondary analyses are planned in people with greater adherence. Economic analyses will be assessed from a health and community care provider perspective. ETHICS AND DISSEMINATION: Ethical approval was obtained from UNSW Ethics Committee in December 2014 (ref number HC#14/266). Outcomes will be disseminated through publication in peer-reviewed journals and presentations at international conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN)12615000138583. PMID- 26493462 TI - Frequency-selective REDOR and spin-diffusion relays in uniformly labeled whole cells. AB - Solid-state NMR is a powerful and non-perturbative method to measure and define chemical composition and architecture in bacterial cell walls, even in the context of whole cells. Most NMR studies on whole cells have used selectively labeled samples. Here, we introduce an NMR sequence relay using frequency selective REDOR (fsREDOR) and spin diffusion elements to probe a unique amine contribution in uniformly (13)C- and (15)N-labeled Staphylococcus aureus whole cells that we attribute to the d-alanine of teichoic acid. In addition to the primary peptidoglycan structural scaffold, cell walls can contain significant amounts of teichoic acid that contribute to cell-wall function. When incorporated into teichoic acid, d-alanine is present as an ester, connected via its carbonyl to a ribitol carbon, and thus has a free amine. Teichoic acid d-Ala is removed during cell-wall isolations and can only be detected in the context of whole cells. The sequence presented here begins with fsREDOR and a chemical shift evolution period for 2D data acquisition, followed by DARR spin diffusion and then an additional fsREDOR period. fsREDOR elements were used for (13)C observation to avoid complications from (13)C-(13)C couplings due to uniform labeling and for (15)N dephasing to achieve selectivity in the nitrogens serving as dephasers. The results show that the selected amine nitrogen of interest is near to teichoic acid ribitol carbons and also the methyl group carbon associated with alanine. In addition, its carbonyl is not significantly dephased by amide nitrogens, consistent with the expected microenvironment around teichoic acid. PMID- 26493463 TI - Is osteonecrosis of the lunate bone an underestimated feature of systemic sclerosis? A case series of nine patients and review of literature. AB - Osteonecrosis of the lunate bone, also known as Kienbock's disease, is a very rare disease of unknown cause. Until today, only six cases of osteonecrosis of the lunate bone in patients with systemic sclerosis (SSc) have been reported in the literature. It is unknown whether these few cases reflect only a coincidence of two rare diseases or whether osteonecrosis of the lunate bone is a potential currently underestimated disease-associated feature of SSc. In this study, we report the clinical course of nine SSc patients with magnetic resonance imaging proven osteonecrosis of the lunate bone and discuss associated disease characteristics and potential underlying pathophysiological mechanisms. Overall, our observations suggest that osteonecrosis of the lunate bone is a frequent and so far under-recognized manifestation of SSc which might be linked to SSc-related vasculopathy. It is important to distinguish osteonecrosis of the lunate bone from wrist arthritis in SSc patients because the clinical treatment is different. In general, the clinical progression of osteonecrosis of the lunate bone seems to be slow in SSc patients. As most of the patients have only minor complaints, watchful waiting in combination with analgesic therapy seems to be a feasible treatment approach in most patients whether an operative intervention might be necessary in rapid progressive cases. PMID- 26493464 TI - Exercise for ankylosing spondylitis: An evidence-based consensus statement. AB - OBJECTIVE: Despite Level 1b evidence and international consensus that exercise is beneficial in ankylosing spondylitis (AS), there is a paucity of detailed information to guide exercise prescription, including the type and dosage of exercise required for the most benefit. This collaborative project, combining evidence with clinical expertise, was established to develop practical recommendations to guide sustainable exercise prescription for individuals with AS. METHODS: Using a modified Delphi technique, 10 clinical questions were generated and a systematic literature review was conducted for each. Draft recommendations were developed at a 2-day meeting, based on the integration of evidence summaries and expert opinion. Feedback was obtained from patient and health professional groups prior to finalisation. RESULTS: Recommendations and practice points were developed for the following areas: assessment; monitoring; safety; disease management; AS-specific exercise; physical activity; dosage, adherence and setting. A framework was developed that could also be adapted for exercise in other chronic musculoskeletal conditions. Feedback suggests that the final consensus statement provides useful information for those seeking to provide best practice exercise prescription for people with AS. CONCLUSION: The recommendations provide an up-to-date, evidence-based approach to the full range of issues related to the use of exercise in AS, as well as identifying evidence gaps for further research. Most importantly, this includes investigation of aspects of exercise programme design required to produce the largest effect, long term adherence with exercise programs and the specific exercise requirements of sub-groups of people with AS. Widespread dissemination and implementation of the guidelines will be required to optimise exercise outcomes. PMID- 26493465 TI - Ameliorative potential of gingerol: Promising modulation of inflammatory factors and lipid marker enzymes expressions in HFD induced obesity in rats. AB - Obesity, generally linked to hyperlipidemia, has been occurring of late with distressing alarm and has now become a global phenomenon casting a huge economic burden on the health care system of countries around the world. The present study investigated the effects of gingerol over 30 days on the changes in HFD-induced obese rats in marker enzymes of lipid metabolism such as fatty-acid synthase (FAS), Acetyl CoA Carboxylase (ACC), Carnitine Palmitoyl Transferase-1(CPT-1), HMG co-A Reductase (HMGR), Lecithin Choline Acyl Transferase (LCAT) and Lipoprotein Lipase (LPL) and inflammatory markers (TNF-alpha and IL-6). The rats were treated orally with gingerol (75 mg kg(-1)) once daily for 30 days with a lorcaserin-treated group (10 mg kg(-1)) included for comparison. Changes in body weight, glucose, insulin resistance and expressions of lipid marker enzymes and inflammatory markers in tissues were observed in experimental rats. The administration of gingerol resulted in a significant reduction in body weight gain, glucose and insulin levels, and insulin resistance, which altered the activity, expressions of lipid marker enzymes and inflammatory markers. It showed that gingerol had significantly altered these parameters when compared with HFD control rats. This study confirms that gingerol prevents HFD-induced hyperlipidemia by modulating the expression of enzymes important to cholesterol metabolism. PMID- 26493466 TI - Low plasma levels of brain derived neurotrophic factor are potential risk factors for diabetic retinopathy in Chinese type 2 diabetic patients. AB - Previous studies suggested that neurotrophins play a role in the diabetic retinopathy (DR). We therefore evaluated the role of plasma brain derived neurotrophic factor (BDNF) levels in Chinese type 2 diabetic patients with and without diabetic retinopathy (DR). Plasma levels of BDNF were determined in type 2 diabetic patients (N=344). At baseline, the demographical and clinical data were taken. Multivariate analyses were performed using logistic regression models. Receiver operating characteristic curves (ROC) was used to test the overall predict accuracy of BDNF and other markers. Diabetic patients with DR and vision-threatening diabetic retinopathy (VTDR) had significantly lower BDNF levels on admission (P<0.0001 both). BDNF improved the area under the receiver operating characteristic curve of the diabetes duration for DR from 0.76 (95% confidence interval [CI], 0.71-0.82) to 0.89 (95% CI, 0.82-0.95; P<0.01) and for VDTR from 0.84 (95% CI, 0.78-0.92) to 0.95 (95% CI, 0.90-0.98; P<0.01). Multivariate logistic regression analysis adjusted for common risk factors showed that plasma BDNF levels<=12.4 ng/mL(1(rd) quartiles) was an independent marker of DR (OR=3.92; 95%CI: 2.31-6.56) and VTDR (OR=4.88; 95%CI: 2.21-9.30). The present study demonstrated that decreased plasma levels of BDNF were independent markers for DR and VDTR in Chinese type 2 diabetic patients, suggesting a possible role of BDNF in the pathogenesis of DR complications. PMID- 26493467 TI - Multicentre analysis of incidental findings on low-resolution CT attenuation correction images: an extended study. AB - OBJECTIVE: To review new incidental findings detected on low-resolution CT attenuation correction (CTAC) images acquired during single-photon emission CT-CT myocardial perfusion imaging as an extension to our initial study. METHODS: CTAC images acquired as part of myocardial perfusion imaging performed using single photon emission CT at four UK nuclear medicine centres were evaluated as part of a multicentre study. New incidental findings that were considered to be clinically significant were evaluated further. Positive-predictive value (PPV) was determined at the time of definitive diagnosis. RESULTS: Out of 3485 patients, 962 (28%) patients had a positive finding on the CTAC image, of which 824 (24%) were new findings. 84 (2.4%) patients had findings that were considered clinically significant at the time of the CTAC report and which had not been previously diagnosed. However, only 10 (0.29%) of these had findings that were confirmed as clinically significant, with the potential to be detrimental to patient outcome, after follow-up and definitive diagnosis. CONCLUSION: The overall PPV from all centres over the 2-year period was 12%. Each centre achieved what we considered to be low PPVs with no significant difference between the present and initial studies. The additional data from the combined studies show that, statistically, there is no significant difference between the PPVs from any of the centres. We conclude that routine reporting of CTAC images is not beneficial. ADVANCES IN KNOWLEDGE: This study combined with the previous study offers a unique evaluation of new clinically significant incidental findings on low-resolution CT images in an attempt to determine the benefit of reporting the CTAC images. PMID- 26493468 TI - The incremental impact of cardiac MRI on clinical decision-making. AB - OBJECTIVE: Despite a significant expansion in the use of cardiac MRI (CMR), there is inadequate evaluation of its incremental impact on clinical decision-making over and above other well-established modalities. We sought to determine the incremental utility of CMR in routine practice. METHODS: 629 consecutive CMR studies referred by 44 clinicians from 9 institutions were evaluated. Pre-defined algorithms were used to determine the incremental influence on diagnostic thinking, influence on clinical management and thus the overall clinical utility. Studies were also subdivided and evaluated according to the indication for CMR. RESULTS: CMR provided incremental information to the clinician in 85% of cases, with incremental influence on diagnostic thinking in 85% of cases and incremental impact on management in 42% of cases. The overall incremental utility of CMR exceeded 90% in 7 out of the 13 indications, whereas in settings such as the evaluation of unexplained ventricular arrhythmia or mild left ventricular systolic dysfunction, this was <50%. CONCLUSION: CMR was frequently able to inform and influence decision-making in routine clinical practice, even with analyses that accepted only incremental clinical information and excluded a redundant duplication of imaging. Significant variations in yield were noted according to the indication for CMR. These data support a wider integration of CMR services into cardiac imaging departments. ADVANCES IN KNOWLEDGE: These data are the first to objectively evaluate the incremental value of a UK CMR service in clinical decision-making. Such data are essential when seeking justification for a CMR service. PMID- 26493469 TI - The effect of labor and delivery on white blood cell count. AB - OBJECTIVE: To explore post-partum white blood cell (WBC) count, and possible factors affecting it. STUDY DESIGN: Retrospective cohort analysis of 12 079 healthy women, delivering a singleton term fetus with an uncomplicated course of labor, delivery and puerperium. All women delivered in a single tertiary, university-affiliated medical center from 2009 to 2014. Student's t-test, Mann Whitney's U-test, chi(2) test and ANOVA were used to compare between variables. Multiple variable analyses was performed to allow adjustment for potential covariates and confounders. The main outcome measures included post-partum WBC count and the difference in the post-partum versus ante-partum WBC count, in association to mode of delivery, type of analgesia, timing of cesarean delivery and perineal trauma. RESULTS: The mean post-partum WBC count was 13.39 +/- .24 * 10(9)/L (range 1.20-37.30 * 10(9)/L). There is a significant increase in the WBC after delivery (2.1 9 +/- 3.33 * 10(9)/L) with significant differences according to mode of delivery (2.34 +/- 3.48, 3.32 +/- 3.69 and 1.6 0 +/- 2.87 * 10(9)/L for spontaneous, assisted and cesarean deliveries. Multiple variables can affect post-partum leukocytosis, including: age, parity, gestational age, mode of delivery, type of anesthesia, timing of cesarean delivery in relation to labor onset and the extent of perineal trauma. CONCLUSIONS: Post-partum leukocytosis is a physiological phenomenon with a wide normal variation and multiple contributing factors. As a single parameter, post-partum leukocytosis should not prompt further work up. PMID- 26493470 TI - Long-term water stress leads to acclimation of drought sensitivity of photosynthetic capacity in xeric but not riparian Eucalyptus species. AB - BACKGROUND AND AIMS: Experimental drought is well documented to induce a decline in photosynthetic capacity. However, if given time to acclimate to low water availability, the photosynthetic responses of plants to low soil moisture content may differ from those found in short-term experiments. This study aims to test whether plants acclimate to long-term water stress by modifying the functional relationships between photosynthetic traits and water stress, and whether species of contrasting habitat differ in their degree of acclimation. METHODS: Three Eucalyptus taxa from xeric and riparian habitats were compared with regard to their gas exchange responses under short- and long-term drought. Photosynthetic parameters were measured after 2 and 4 months of watering treatments, namely field capacity or partial drought. At 4 months, all plants were watered to field capacity, then watering was stopped. Further measurements were made during the subsequent 'drying-down', continuing until stomata were closed. KEY RESULTS: Two months of partial drought consistently reduced assimilation rate, stomatal sensitivity parameters (g1), apparent maximum Rubisco activity (V'(cmax)) and maximum electron transport rate (J'(max)). Eucalyptus occidentalis from the xeric habitat showed the smallest decline in V'(cmax) and J'(max); however, after 4 months, V'(cmax) and J'(max) had recovered. Species differed in their degree of V'(cmax) acclimation. Eucalyptus occidentalis showed significant acclimation of the pre-dawn leaf water potential at which the V'(cmax) and 'true' V(cmax) (accounting for mesophyll conductance) declined most steeply during drying-down. CONCLUSIONS: The findings indicate carbon loss under prolonged drought could be over-estimated without accounting for acclimation. In particular, (1) species from contrasting habitats differed in the magnitude of V'(cmax) reduction in short-term drought; (2) long-term drought allowed the possibility of acclimation, such that V'(cmax) reduction was mitigated; (3) xeric species showed a greater degree of V'(cmax) acclimation; and (4) photosynthetic acclimation involves hydraulic adjustments to reduce water loss while maintaining photosynthesis. PMID- 26493471 TI - Cox regression with missing covariate data using a modified partial likelihood method. AB - Missing covariate values is a common problem in survival analysis. In this paper we propose a novel method for the Cox regression model that is close to maximum likelihood but avoids the use of the EM-algorithm. It exploits that the observed hazard function is multiplicative in the baseline hazard function with the idea being to profile out this function before carrying out the estimation of the parameter of interest. In this step one uses a Breslow type estimator to estimate the cumulative baseline hazard function. We focus on the situation where the observed covariates are categorical which allows us to calculate estimators without having to assume anything about the distribution of the covariates. We show that the proposed estimator is consistent and asymptotically normal, and derive a consistent estimator of the variance-covariance matrix that does not involve any choice of a perturbation parameter. Moderate sample size performance of the estimators is investigated via simulation and by application to a real data example. PMID- 26493472 TI - Thermodynamic modelling of hydrophobic interaction chromatography of biomolecules in the presence of salt. AB - Hydrophobic interaction chromatography (HIC) is a useful method for isolation and purification of macromolecules. HIC separates proteins on the basis of surface hydrophobicity while generally retaining the activity of proteins. Aqueous mobile phases with high salt concentrations are often used to adsorb the proteins on a mildly hydrophobic support. In this research, the thermodynamic model of Chen and Sun, which predicts the adsorption isotherms of protein in presence of different type of salts, was modified by substitution the protein and salt activities in the mobile phase instead of their concentrations. In addition, model was examined for studying the adsorption of BSA, HSA, alpha-lactalbumin and Trypsinogen on different sepharose gels. The model parameters of Chen and Sun are adsorption equilibrium constant (KP), protein dehydration equilibrium constant (Ks), salt coefficient (alpha) and number of ligand binding (n). By substitution activity instead of salt and protein concentration, two other parameters (c1 and As), which related to the activity coefficients, are added to the model. The parameters of this nonlinear model are calculated by genetic algorithm (GA). The maximum average absolute percentage deviation (AAD) for the data which are obtained from the adsorption isotherm of BSA on phenyl sepharose gel, in the presence of different concentration of NaCl was 4.8%, while for Chen and Sun model, was 22.0%. Also maximum ADD for HSA, alpha-lactalbumin, and Trypsinogen adsorption was 7.8, 6.9, and 8.4, respectively. The results indicate that the modified model has adequate accuracy to predict protein HIC behaviour. PMID- 26493473 TI - Asymmetric flow field-flow fractionation coupled to inductively coupled plasma mass spectrometry for the quantification of quantum dots bioconjugation efficiency. AB - Hyphenation of asymmetric flow field-flow fractionation (AF4) to an on-line elemental detection (inductively coupled plasma-mass spectrometry, ICP-MS) is proposed as a powerful diagnostic tool for quantum dots bioconjugation studies. In particular, conjugation effectiveness between a "model" monoclonal IgG antibody (Ab) and CdSe/ZnS core-shell Quantum Dots (QDs), surface-coated with an amphiphilic polymer, has been monitored here by such hybrid AF4-ICP-MS technique. Experimental conditions have been optimized searching for a proper separation between the sought bioconjugates from the eventual free reagents excesses employed during the bioconjugation (QDs and antibodies). Composition and pH of the carrier have been found to be critical parameters to ensure an efficient separation while ensuring high species recovery from the AF4 channel. An ICP-MS equipped with a triple quadropole was selected as elemental detector to enable sensitive and reliable simultaneous quantification of the elemental constituents, including sulfur, of the nanoparticulated species and the antibody. The hyphenated technique used provided nanoparticle size-based separation, elemental detection, and composition analysis capabilities that turned out to be instrumental in order to investigate in depth the Ab-QDs bioconjugation process. Moreover, the analytical strategy here proposed allowed us not only to clearly identify the bioconjugation reaction products but also to quantify nanoparticle:antibodies bioconjugation efficiency. This is a key issue in future development of analytical and bioanalytical photoluminescent QDs applications. PMID- 26493474 TI - Sedimentation field-flow fractionation for characterization of citric acid modified Hbeta zeolite particles: Effect of particle dispersion and carrier composition. AB - In this study, sedimentation field-flow fractionation (SdFFF) was, for the first time, applied for determination of size distribution of Hbeta zeolite particles modified by citric acid (CA-Hbeta). Effects of the particle dispersion and the carrier liquid composition (type of dispersing reagent (surfactant) and salt added in the carrier liquid, ionic strength, and pH) on SdFFF elution behavior of CA-Hbeta zeolite particles were systematically investigated. Also the SdFFF separation efficiency of the particles was discussed in terms of the forces such as van der Waals, hydrophobic, and induced-dipole interactions. Results reveal that the type of salt and pH of the carrier liquid significantly affect the SdFFF separation efficiency of the zeolite particles. It was found that addition of a salt (NaN3) into the carrier liquid affects the characteristic of the SdFFF channel surface. It was found that the use of an acidic medium (pH 3.2) leads to a particle-channel interaction, while the use of a basic medium (pH 10.6) promotes an inter-particle hydrophobic interaction. Result from SdFFF was compared with those from scanning electron microscopy (SEM) and dynamic light scattering (DLS). It seems that, once the experimental conditions are optimized, SdFFF becomes a valuable tool for size characterization of the zeolite particles. PMID- 26493475 TI - Ocular myasthenia gravis induced by human acetylcholine receptor epsilon subunit immunization in HLA DR3 transgenic mice. AB - Extraocular muscles (EOM) are preferentially involved in myasthenia gravis (MG) and acetylcholine receptor (AChR) antibody positive MG patients may occasionally present with isolated ocular symptoms. Although experimental autoimmune myasthenia gravis (EAMG) induced by whole AChR immunization closely mimics clinical and immunopathological aspects of MG, EOM are usually not affected. We have previously developed an EAMG model, which imitates EOM symptoms of MG by immunization of human leukocyte antigen (HLA) transgenic mice with alpha or gamma subunits of human AChR (H-AChR). To investigate the significance of the epsilon subunit in ocular MG, we immunized HLA-DR3 and HLA-DQ8 transgenic mice with recombinant H-AChR epsilon-subunit expressed in Escherichia coli. HLA-DR3 transgenic mice showed significantly higher clinical ocular and generalized MG severity scores and lower grip strength values than HLA-DQ8 mice. H-AChR epsilon subunit-immunized HLA-DR3 transgenic mice had higher serum anti-AChR antibody (IgG, IgG1, IgG2b, IgG2c and IgM) levels, neuromuscular junction IgG and complement deposit percentages than epsilon-subunit-immunized HLA-DQ8 transgenic mice. Control mice immunized with E. coli extract or complete Freund adjuvant (CFA) did not show clinical and immunopathological features of ocular and generalized EAMG. Lymph node cells of epsilon-subunit-immunized HLA-DR3 mice showed significantly higher proliferative responses than those of epsilon-subunit immunized HLA-DQ8 mice, crude E. coli extract-immunized and CFA-immunized transgenic mice. Our results indicate that the human AChR epsilon-subunit is capable of inducing myasthenic muscle weakness. Diversity of the autoimmune responses displayed by mice expressing different HLA class II molecules suggests that the interplay between HLA class II alleles and AChR subunits might have a profound impact on the clinical course of MG. PMID- 26493476 TI - Selection of population controls for a Salmonella case-control study in the UK using a market research panel and web-survey provides time and resource savings. AB - Timely recruitment of population controls in infectious disease outbreak investigations is challenging. We evaluated the timeliness and cost of using a market research panel as a sampling frame for recruiting controls in a case control study during an outbreak of Salmonella Mikawasima in the UK in 2013. We deployed a web-survey by email to targeted members of a market research panel (panel controls) in parallel to the outbreak control team interviewing randomly selected public health staff by telephone and completing paper-based questionnaires (staff controls). Recruitment and completion of exposure history web-surveys for panel controls (n = 123) took 14 h compared to 15 days for staff controls (n = 82). The average staff-time cost per questionnaire for staff controls was L13.13 compared to an invoiced cost of L3.60 per panel control. Differences in the distribution of some exposures existed between these control groups but case-control studies using each group found that illness was associated with consumption of chicken outside of the home and chicken from local butchers. Recruiting market research panel controls offers time and resource savings. More rapid investigations would enable more prompt implementation of control measures. We recommend that this method of recruiting controls is considered in future investigations and assessed further to better understand strengths and limitations. PMID- 26493477 TI - Selection of the method to appraise and compare health systems using risk stratification: the ASSEHS approach. AB - To face the challenge of active and healthy ageing, European Health Systems and services should move towards proactive, anticipatory and integrated care. The comparison of methods to combine results across studies and to determine an overall effect was undertaken by the EU project ASSEHS (Activation of Stratification Strategies and Results of the interventions on frail patients of Healthcare Services, EU project (No. 2013 12 04). The questions raised in ASSEHS are broad and involve a complex body of literature. Thus, systematic reviews are not appropriate. The most appropriate method appears to be scoping studies. In this paper, an updated method of scoping studies has been used to determine the questions needed to appraise the health systems and services for frailty in the ageing population. Three objectives were set (i) to detect a relevant number of risk stratification tools for frailty and identify the best-in-class, (ii) to understand the feasibility of introducing stratification tools and identify the difficulties of the process and (iii) to find evidence on the impact of risk stratification in Health Services. This novel approach may provide greater clarity about scoping study methodology and help enhance the methodological rigor with which authors undertake and report scoping studies. PMID- 26493478 TI - Effects of the Mediterranean diet and exercise in subjects with coronary artery disease. AB - INTRODUCTION: The association of the Mediterranean diet and exercise appears to have a protective role, reducing cardiovascular risk. This study investigated the effects of education sessions on the Mediterranean diet and an exercise program in modifying eating behaviors, body composition and abdominal fat. METHODS: An experimental study was performed on 20 subjects with known coronary heart disease randomly assigned to experimental (n=10) and control (n=10) groups. Both groups received education sessions on the Mediterranean diet, but the experimental group also followed an eight-week program of specific exercises. A semiquantitative food frequency questionnaire was administered to analyze food intake, bioimpedance was used to measure weight, fat mass and lean mass, and waist circumference was measured to calculate waist-to-height ratio. RESULTS: After eight weeks, protein (p<0.05) and cholesterol (p<0.05) intake in the experimental group had decreased significantly compared with the control group. Between the beginning and end of the study, there were significant decreases in the control group in carbohydrate (p<0.05) and saturated fat intake (p<0.05). In both groups the percentage of total fat (p<0.05) and fat mass (p<0.05) was significantly decreased. In the experimental group the waist-to-height ratio was significantly reduced (p<0.05). CONCLUSION: The Mediterranean diet reduced carbohydrate and saturated fat intake, reflected in reduced fat mass. The association of the exercise program showed additional benefits in reduction of protein and cholesterol intake and abdominal fat. PMID- 26493479 TI - Palmitoylacyltransferase Zdhhc9 inactivation mitigates leukemogenic potential of oncogenic Nras. PMID- 26493481 TI - [Background and practical use of the assessment of identity development in adolescence (AIDA)]. AB - A paradigm shift towards early detection and intervention of personality disorders in adolescence to prevent persistent and chronic suffering is currently taking place. Aside further distinct areas of impaired psychosocial integrity, disturbed identity development is seen as one core component of personality disorders. Thus, the detection of early antecedents of impaired identity development is an important step to allow for early intervention. The self-report questionnaire Assessment of Identity Development in Adolescence (AIDA) is a reliable and valid diagnostic instrument to detect disturbed identity development. This questionnaire allows for global assessment of identity and a differentiation in fundamental subdomains as well and distinguishes between identity diffusion on one side and consolidated and stable identity on the other. In clinical practice, it supports the differentiation between severely disturbed identity as the core component of personality disorders and identity crisis or stable identity development that can be found in other mental disorders. PMID- 26493482 TI - [Visual perceptual abilities of children with low motor abilities--a pilot study]. AB - The results of many studies show visual perceptual deficits in children with low motor abilities. This study aims to indicate the correlation between visual perceptual and motor abilities. The correlation of visual-perceptual and motor abilities of 41 children is measured by using the German versions of the Developmental Test of Visual Perception--Adolescent and Adult (DTVP-A) and the Movement Assessment Battery for Children--Second Edition (M-ABC-2). The visual perceptual abilities of children with low motor abilities (n=21) are also compared to the visual-perceptual abilities of children with normal motor abilities (the control group, n=20). High correlations between the visual perceptual and motor abilities are found. The perceptual abilities of the groups differ significantly. Nearly half of the children with low motor abilities show visual-perceptual deficits. Visual perceptual abilities of children suffering coordination disorders should always be assessed. The DTVP-A is useful, because it provides the possibilities to compare motor-reduced visual-perceptual abilities and visualmotor integration abilities and to estimate the deficit's degree. PMID- 26493483 TI - [Frequency and Type of Traumatic Events in Children and Adolescents with a Posttraumatic Stress Disorder]. AB - The risk for children and adolescents to be exposed to a potentially traumatic event (PTE) is high. The present study examines the frequency of PTEs in children and adolescents with Posttraumatic Stress Disorder (PTSD), the type of index trauma, and its relation to PTSD symptom severity and gender. A clinical sample of 159 children and adolescents between 7-16 years was assessed using the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA). All reported PTEs from the checklist were analyzed according to frequency. The index events were categorized according to the following categories: cause (random vs. intentional), relation to offender (intrafamilial vs. extrafamilial), patient's role (victim, witness or vicarious traumatization), and type of PTE (physical or sexual violence). Relation between categories and PTSD symptom severity and sex were analyzed with inferential statistics. On average participants reported five PTEs, most frequently physical violence without weapons (57.9%), loss of loved person through death (45.9%), and sexual abuse/assaults (44%). The most frequent index traumata were intentional (76.7%). Regarding trauma type, there was a significant difference concerning higher symptom severity in children and adolescents who experienced sexual abuse/assault compared to physical violence (t=-1.913(109), p=0.05). A significantly higher symptom severity was found for girls compared to boys for the trauma categories extrafamilial offender (z=-2,27, p=0.02), victim (z=-2,11, p=0,04), and sexual abuse/assault (z=-2,43, p=0,01). Clinical and diagnostic implications are discussed in relation to the amendments of PTSD diagnostic criteria in DSM-5. PMID- 26493489 TI - Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142. AB - JBIR-141 (1) and JBIR-142 (2) were discovered as potent Foxo3a inhibitors that consist of three quite unique substructures, a 1-((dimethylamino)ethyl)-5-methyl 4,5-dihydrooxazole-4-carboxylic acid that is originated from Ala-Thr amino acid residues, a 3-acetoxy-4-amino-7-(hydroxy(nitroso)amino)-2,2-dimethylheptanoic acid, and an alpha-acyl tetramic acid fused with a 2-methylpropan-1-ol moiety. Their structures involving absolute configurations were determined by spectroscopic data, chemical degradation, anisotropy methods, and LC-MS analyses of diastereomeric derivatives. Compounds 1 and 2 exhibited specific inhibition against Foxo3a transcriptional activity with IC50 values of 23.1 and 166.2 nM, respectively. PMID- 26493488 TI - Functional analyses of the plant-specific C-terminal region of VPS9a: the activating factor for RAB5 in Arabidopsis thaliana. AB - Recent studies demonstrated that endosomal transport played important roles in various plant functions. The RAB GTPase regulates the tethering and fusion steps of vesicle trafficking to target membranes in each trafficking pathway by acting as a molecular switch. RAB GTPase activation is catalyzed by specific guanine nucleotide exchange factors (GEFs) that promote the exchange of GDP on the RAB GTPase with GTP. RAB5 is a key regulator of endosomal trafficking and is uniquely diversified in plants; the plant-unique RAB5 group ARA6 was acquired in addition to conventional RAB5 during evolution. In Arabidopsis thaliana, conventional RAB5, ARA7 and RHA1 regulate the endosomal/vacuolar trafficking pathways, whereas ARA6 acts in the pathway from the endosome to the plasma membrane. Despite their distinct functions, all RAB5 members are activated by the common GEF VACUOLAR PROTEIN SORTING 9a (VPS9a). VPS9a consists of an N-terminal conserved domain and C-terminal region (CTR) with no similarity to known functional domains. In this study, we investigated the function of the CTR by generating truncated versions of VPS9a and found that it was specifically responsible for ARA6 regulation; moreover, the CTR was required for the oligomerization and correct localization of VPS9a. The oligomerization of VPS9a was mediated by a distinctive region consisting of 36 amino acids in the CTR that was conserved in plant RAB5 GEFs. Thus the VPS9a CTR plays an important role in the regulation of the two RAB5 groups in plants. PMID- 26493490 TI - Electromyographic adjustments during continuous and intermittent incremental fatiguing cycling. AB - We studied the sensitivity of electromyographic (EMG) variables to load and muscle fatigue during continuous and intermittent incremental cycling. Fifteen men attended three laboratory sessions. Visit 1: lactate threshold, peak power output, and VO2max . Visits 2 and 3: Continuous (more fatiguing) and intermittent (less fatiguing) incremental cycling protocols [20%, 40%, 60%, 80% and 100% of peak power output (PPO)]. During both protocols, multichannel EMG signals were recorded from vastus lateralis: muscle fiber conduction velocity (MFCV), instantaneous mean frequency (iMNF), and absolute and normalized root mean square (RMS) were analyzed. MFCV differed between protocols (P < 0.001), and only increased consistently with power output during intermittent cycling. RMS parameters were similar between protocols, and increased linearly with power output. However, only normalized RMS was higher during the more fatiguing 100% PPO stage of the continuous protocol [continuous-intermittent mean difference (95% CI): 45.1 (8.5% to 81.7%)]. On the contrary, iMNF was insensitive to load changes and muscle fatigue (P = 0.14). Despite similar power outputs, continuous and intermittent cycling influenced MFCV and normalized RMS differently. Only normalized RMS was sensitive to both increases in power output (in both protocols) and muscle fatigue, and thus is the most suitable EMG parameter to monitor changes in muscle activation during cycling. PMID- 26493491 TI - High frequency bone conduction auditory evoked potentials in the guinea pig: Assessing cochlear injury after ossicular chain manipulation. AB - Permanent high frequency (>4 kHz) sensorineural hearing loss following middle ear surgery occurs in up to 25% of patients. The aetiology of this loss is poorly understood and may involve transmission of supra-physiological forces down the ossicular chain to the cochlea. Investigating the mechanisms of this injury using animal models is challenging, as evaluating cochlear function with evoked potentials is confounded when ossicular manipulation disrupts the normal air conduction (AC) pathway. Bone conduction (BC) using clinical bone vibrators in small animals is limited by poor transducer output at high frequencies sensitive to trauma. The objectives of the present study were firstly to evaluate a novel high frequency bone conduction transducer with evoked auditory potentials in a guinea pig model, and secondly to use this model to investigate the impact of middle ear surgical manipulation on cochlear function. We modified a magnetostrictive device as a high frequency BC transducer and evaluated its performance by comparison with a calibrated AC transducer at frequencies up to 32 kHz using the auditory brainstem response (ABR), compound action potential (CAP) and summating potential (SP). To mimic a middle ear traumatising stimulus, a rotating bur was brought in to contact with the incudomalleal complex and the effect on evoked cochlear potentials was observed. BC-evoked potentials followed the same input-output function pattern as AC potentials for all ABR frequencies. Deterioration in CAP and SP thresholds was observed after ossicular manipulation. It is possible to use high frequency BC to evoke responses from the injury sensitive basal region of the cochlea and so not rely on AC with the potential confounder of conductive hearing loss. Ongoing research explores how these findings evolve over time, and ways in which injury may be reduced and the cochlea protected during middle ear surgery. PMID- 26493492 TI - Saracatinib as a metastasis inhibitor in metastatic castration-resistant prostate cancer: A University of Chicago Phase 2 Consortium and DOD/PCF Prostate Cancer Clinical Trials Consortium Study. AB - BACKGROUND: Fyn is a kinase that is upregulated in a subset of metastatic castration-resistant prostate cancer. Saracatinib potently inhibits Fyn activation. We have noted a relationship between Fyn expression and directional motility, a cellular process related to metastasis. As such we hypothesized that treatment with saracatinib would increase the time required to develop new metastatic lesions. METHODS: Patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel were eligible for enrollment. This study was executed as a randomized discontinuation trial. During a lead-in phase of two 28-Day cycles, all patients received saracatinib. Afterward, patients with radiographically stable disease were randomized to either saracatinib or placebo. Patients continued treatment until evidence of new metastasis. RESULTS: Thirty-one patients were treated. Only 26% of patients had stable disease after 8 weeks and thus proceeded to randomization. This required early termination of the study for futility. The 70% of patients who progressed after the lead-in phase exhibited expansion of existing lesions or decompensation due to clinical progression without new metastatic lesions. Fatigue was reported in more than 25% of patients (all grades) with only two patients experiencing grade 3 toxicity. Other grade 3 adverse events included dehydration, thrombocytopenia, and weakness. CONCLUSIONS: This study was unable to determine if saracatinib had potential as metastasis inhibitor. Metastasis inhibition by saracatinib may still be viable in an earlier time in the disease history. PMID- 26493493 TI - Single-cell high resolution melting analysis: A novel, generic, pre-implantation genetic diagnosis (PGD) method applied to cystic fibrosis (HRMA CF-PGD). AB - BACKGROUND: Institutions offering CF-PGD face the challenge of developing and optimizing single cell genotyping protocols that should cover for the extremely heterogeneous CF mutation spectrum. Here we report the development and successful clinical application of a generic CF-PGD protocol to facilitate direct detection of any CFTR nucleotide variation(s) by HRMA and simultaneous confirmation of diagnosis through haplotype analysis. METHODS: A multiplex PCR was optimized supporting co-amplification of any CFTR exon-region, along with 6 closely linked STRs. Single cell genotypes were established through HRM analysis following melting of the 2nd round PCR products and were confirmed by STR haplotype analysis of the 1st PCR products. The protocol was validated pre-clinically, by testing 208 single lymphocytes, isolated from whole blood samples from 4 validation family trios. Fifteen PGD cycles were performed and 103 embryos were biopsied. RESULTS: In 15 clinical PGD cycles, genotypes were achieved in 88/93 (94.6%) embryo biopsy samples, of which 57/88 (64.8%) were deemed genetically suitable for embryo transfer. Amplification failed at all loci for 10/103 blastomeres biopsied from poor quality embryos. Six clinical pregnancies were achieved (2 twin, 4 singletons). PGD genotypes were confirmed following conventional amniocentesis or chorionic villus sampling in all achieved pregnancies. CONCLUSIONS: The single cell HRMA CF-PGD protocol described herein is a flexible, generic, low cost and robust genotyping method, which facilitates the analysis of any CFTR genotype combination. Single-cell HRMA can be beneficial to other clinical settings, for example the detection of single nucleotide variants in single cells derived from clinical tumor samples. PMID- 26493494 TI - Artificial Urinary Sphincter Mechanical Failures-Is it Better to Replace the Entire Device or Just the Malfunctioning Component? AB - PURPOSE: We evaluate the characteristics of artificial urinary sphincter mechanical failures and compare outcomes based on the surgical revision strategy, replacing only the failed component or the entire device. MATERIALS AND METHODS: A total of 1,802 male patients with stress urinary incontinence underwent artificial urinary sphincter procedures from 1983 to 2011 at our institution, of which 1,082 were primary placements. Of these patients 125 experienced mechanical device malfunction. Multiple clinical and surgical variables were evaluated for a potential association with device malfunction. In addition, we evaluated for predictors of failure of the revised device, including time from primary artificial urinary sphincter to revision surgery and surgical revision strategy (single component vs entire device), with failure defined as any tertiary surgery. RESULTS: At a median followup of 4.2 years (IQR 0.8, 7.9) 125 patients experienced device malfunction. The urethral cuff was the most common component failure (46.1%), followed by abdominal reservoir (22.6%), tubing (21.7%) and pump (9.6%). There was no association of time from primary surgery to revision for mechanical failure (HR 0.89, p=0.33) or revision strategy (HR 0.47, p=0.15) with the risk of tertiary surgery. Additionally, as there was no significant interaction between these variables (HR 1.11, p=0.39), no cutoff could be identified at which one revision technique produced significantly improved device survival compared to another. However, there was a trend toward improved 3-year device survival after replacement of the entire device vs a single component (76% vs 60%, p=0.11). CONCLUSIONS: No cutoff in time to mechanical failure could be identified to guide decision making in the management of mechanical artificial urinary sphincter failure. Likewise, it is unclear if replacing the entire device, rather than the single malfunctioning component, alters device survival. As such, further studies are needed. However, given the current trend toward improved overall device survival, the limited additional risk and the lack of adequate clinical predictors for tertiary surgery, we would advocate for replacement of the entire device when possible. PMID- 26493495 TI - Intracranial EEG analysis in tumor-related epilepsy: Evidence of distant epileptic abnormalities. AB - OBJECTIVE: In patients with tumor-related epilepsy (TRE), surgery traditionally focuses on tumor resection; but identification and removal of associated epileptogenic zone may improve seizure outcome. Here, we study spatial relationship of tumor and seizure onset and early spread zone (SOSz). We also perform quantitative analysis of interictal epileptiform activities in patients with both TRE and non-lesional epilepsy in order to better understand the electrophysiological basis of epileptogenesis. METHODS: Twenty-five patients (11 with TRE and 14 with non-lesional epilepsy) underwent staged surgery using intracranial electrodes. Tumors were outlined on MRI and images were coregistered with post-implantation CT images. For each electrode, distance to the nearest tumor margin was measured. Electrodes were categorized based on distance from tumor and involvement in seizure. Quantitative EEG analysis studying frequency, amplitude, power, duration and slope of interictal spikes was performed. RESULTS: At least part of the SOSz was located beyond 1.5 cm from the tumor margin in 10/11 patients. Interictally, spike frequency and power were higher in the SOSz and spikes near tumor were smaller and less sharp. Interestingly, peritumoral electrodes had the highest spike frequencies and sharpest spikes, indicating greatest degree of epileptic synchrony. A complete resection of the SOSz resulted in excellent seizure outcome. CONCLUSIONS: Seizure onset and early spread often involves brain areas distant from the tumor. SIGNIFICANCE: Utilization of epilepsy surgery approach for TRE may provide better seizure outcome and study of the intracranial EEG may provide insight into pathophysiology of TRE. PMID- 26493497 TI - Identification and analysis of anthocyanin components in fruit color variation in Schisandra chinensis. AB - BACKGROUND: Fruit color is an important index and parameter for measuring fruit quality. As an important pigment, anthocyanin is a determinant which appears in all sorts of colors of fruits in nature. RESULTS: Color parameters were measured using a spectrometer and used as a basis to divide the materials into three groups: reddish-orange, orange and yellow. A validated high-performance liquid chromatographic-electrospray ionization-mass spectrometric method was used for the analysis of anthocyanin in Schisandra chinensis and for determining major anthocyanin components in S. chinensis fruits, i.e. cyanidin xylosyl-glucoside (CyXylGlu), cyanidin glucosyl-rutinoside (CyGluRutin), cyanidin rutinoside (CyRutin) and cyanidin xylosyl-rutinoside (CyXylRutin). The anthocyanin contents vary obviously in different colored fruits in S. chinensis. The impact of anthocyanin on coloration of fruits was investigated by multiple regression analysis between color parameters and anthocyanin components, which indicated that CyRutin is the primary cause of fruit color variation in S. chinensis. CONCLUSION: The content and type of anthocyanin determine fruit coloration in S. chinensis, laying the early foundations for systematically interpreting the mechanism of fruit coloration in S. chinensis. (c) 2015 Society of Chemical Industry. PMID- 26493496 TI - Immune Endophenotypes in Children With Autism Spectrum Disorder. AB - BACKGROUND: Autism spectrum disorder (ASD) is characterized by social communication deficits and restricted, repetitive patterns of behavior. Varied immunological findings have been reported in children with ASD. To address the question of heterogeneity in immune responses, we sought to examine the diversity of immune profiles within a representative cohort of boys with ASD. METHODS: Peripheral blood mononuclear cells from male children with ASD (n = 50) and from typically developing age-matched male control subjects (n = 16) were stimulated with either lipopolysaccharide or phytohemagglutinin. Cytokine production was assessed after stimulation. The ASD study population was clustered into subgroups based on immune responses and assessed for behavioral outcomes. RESULTS: Children with ASD who had a proinflammatory profile based on lipopolysaccharide stimulation were more developmentally impaired as assessed by the Mullen Scales of Early Learning. They also had greater impairments in social affect as measured by the Autism Diagnostic Observation Schedule. These children also displayed more frequent sleep disturbances and episodes of aggression. Similarly, children with ASD and a more activated T cell cytokine profile after phytohemagglutinin stimulation were more developmentally impaired as measured by the Mullen Scales of Early Learning. CONCLUSIONS: Children with ASD may be phenotypically characterized based upon their immune profile. Those showing either an innate proinflammatory response or increased T cell activation/skewing display a more impaired behavioral profile than children with noninflamed or non-T cell activated immune profiles. These data suggest that there may be several possible immune subphenotypes within the ASD population that correlate with more severe behavioral impairments. PMID- 26493498 TI - Efficacy of Anodal Transcranial Direct Current Stimulation is Related to Sensitivity to Transcranial Magnetic Stimulation. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) has become an important non-invasive brain stimulation tool for basic human brain physiology and cognitive neuroscience, with potential applications in cognitive and motor rehabilitation. To date, tDCS studies have employed a fixed stimulation level, without considering the impact of individual anatomy and physiology on the efficacy of the stimulation. This approach contrasts with the standard procedure for transcranial magnetic stimulation (TMS) where stimulation levels are usually tailored on an individual basis. OBJECTIVE/HYPOTHESIS: The present study tests whether the efficacy of tDCS-induced changes in corticospinal excitability varies as a function of individual differences in sensitivity to TMS. METHODS: We performed an archival review to examine the relationship between the TMS intensity required to induce 1 mV motor-evoked potentials (MEPs) and the efficacy of (fixed-intensity) tDCS over the primary motor cortex (M1). For the latter, we examined tDCS-induced changes in corticospinal excitability, operationalized by comparing MEPs before and after anodal or cathodal tDCS. For comparison, we performed a similar analysis on data sets in which MEPs had been obtained before and after paired associative stimulation (PAS), a non-invasive brain stimulation technique in which the stimulation intensity is adjusted on an individual basis. RESULTS: MEPs were enhanced following anodal tDCS. This effect was larger in participants more sensitive to TMS as compared to those less sensitive to TMS, with sensitivity defined as the TMS intensity required to produce MEPs amplitudes of the size of 1 mV. While MEPs were attenuated following cathodal tDCS, the magnitude of this attenuation was not related to TMS sensitivity nor was there a relationship between TMS sensitivity and responsiveness to PAS. CONCLUSION: Accounting for variation in individual sensitivity to non-invasive brain stimulation may enhance the utility of tDCS as a tool for understanding brain behavior interactions and as a method for clinical interventions. PMID- 26493499 TI - New aspects in the phase behaviour of poly-N-isopropyl acrylamide: systematic temperature dependent shrinking of PNiPAM assemblies well beyond the LCST. AB - We investigate the phase behaviour of aqueous dispersions of poly-N-isopropyl acrylamide (PNiPAM) microgels above their lower critical solution temperature (LCST) and find that beyond a well-defined concentration the systems exhibit a peculiar behaviour: the microgels assemble into space-spanning gels that shrink in time while maintaining the shape of the container in which they have been formed. Over a wide range of concentrations this shrinking behaviour is independent of PNiPAM concentration, but systematically depends on temperature in a temperature range significantly exceeding the LCST. The overall shrinking characteristics are consistent with those expected for scaffolds made of materials that exhibit thermal contraction. However, for the PNiPAM assemblies contraction is irreversible and can be as large as 90%. Such characteristics disclose complex interactions between fully collapsed PNiPAM and water well beyond the LCST, the origin of which has yet to be elucidated. PMID- 26493501 TI - The nature of peer-directed behaviours in children with profound intellectual and multiple disabilities and its relationship with social scaffolding behaviours of the direct support worker. AB - BACKGROUND: The multiple and complex disabilities of persons with profound intellectual and multiple disabilities (PIMD) form a barrier for peer interactions and peer-directed behaviours. In this study, we further explore the nature of peer-directed behaviours in persons with PIMD and its relationship with social scaffolding behaviour of direct support workers (DSWs). METHODS: Fourteen dyads of children with PIMD, who knew each other for at least 12 months, participated. They were sitting in close proximity while they were filmed with and without the presence of the DSW. Video recordings were coded continuously making use of observation schemes for the peer-directed behaviours of the children and the peer interaction influencing behaviours of the DSW. RESULTS: Significantly more singular peer-directed behaviour (without DSW: 18.00%; with DSW: 3.81%) was observed than multiple peer-directed behaviour (without DSW: 4.01%; with DSW: 0.52%). The amount of time the singular and multiple peer directed behaviours were observed was significantly lower in the presence of a DSW. When the DSW shows peer interaction influencing behaviour, it was mostly social scaffolding behaviour (2.17%). The conditional probability of observing social scaffolding behaviour in the 10 s following on singular peer-directed behaviour was 0.02 with a Yule's Q of 0.04 and following on multiple peer directed behaviour 0.04 with a Yule's Q of 0.33. CONCLUSION: The way in which peer interactions in children with PIMD are defined could have an impact on the amount of observed peer-directed behaviours and on the effect of the social scaffolding behaviours presented by DSW. PMID- 26493502 TI - [Role of Gastroenterologists in Management of Obesity]. AB - Obesity is a serious disorder that increases morbidity and mortality. Primary intervention with life style modification and medication is not always effective for obese patients. Endoscopic management of obesity may be a less invasive, more cost-effective, and relatively safer option than bariatric surgery. Moreover, therapeutic endoscopy is considered to be the primary modality for managing complications that occur after bariatric surgery. In the near future, role of gastroenterologists will be more important in the management of obesity and its related problems. PMID- 26493503 TI - [Colonoscopic Tattooing of Colonic Lesions]. AB - With the development of minimal invasive surgery including laparoscopic and robot surgery, colonoscopic tattooing of colonic lesions is becoming more important to ensure easy localization of the lesion during surgery. Lack of accurate lesion identification during minimal invasive surgery may lead to resection of wrong segment of the bowel. In this article, some topics including proper materials, injection technique, and safety of colonoscopic tattooing are reviewed. PMID- 26493500 TI - Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. AB - Human-pluripotent-stem-cell-derived kidney cells (hPSC-KCs) have important potential for disease modelling and regeneration. Whether the hPSC-KCs can reconstitute tissue-specific phenotypes is currently unknown. Here we show that hPSC-KCs self-organize into kidney organoids that functionally recapitulate tissue-specific epithelial physiology, including disease phenotypes after genome editing. In three-dimensional cultures, epiblast-stage hPSCs form spheroids surrounding hollow, amniotic-like cavities. GSK3beta inhibition differentiates spheroids into segmented, nephron-like kidney organoids containing cell populations with characteristics of proximal tubules, podocytes and endothelium. Tubules accumulate dextran and methotrexate transport cargoes, and express kidney injury molecule-1 after nephrotoxic chemical injury. CRISPR/Cas9 knockout of podocalyxin causes junctional organization defects in podocyte-like cells. Knockout of the polycystic kidney disease genes PKD1 or PKD2 induces cyst formation from kidney tubules. All of these functional phenotypes are distinct from effects in epiblast spheroids, indicating that they are tissue specific. Our findings establish a reproducible, versatile three-dimensional framework for human epithelial disease modelling and regenerative medicine applications. PMID- 26493504 TI - [Primary Non-ampullary Duodenal Adenocarcinoma: A Single-center Experience for 15 Years]. AB - BACKGROUND/AIMS: Primary non-ampullary duodenal adenocarcinomas (PNADAs) comprise =2 mg/dL (OR, 85.28; 95% CI, 3.77-1,938.79; p=0.005) and distant metastasis (OR, 26.74; 95% CI, 3.13-2,328.14; p=0.003) at the time of diagnosis were independent poor prognostic factors. CONCLUSIONS: The majority of patients were diagnosed at an advanced stage. Presence of distant metastasis was independent prognostic factor of PNADA together with elevated total bilirubin. PMID- 26493506 TI - Timing of Cholecystectomy after Percutaneous Cholecystostomy for Acute Cholecystitis. AB - BACKGROUND/AIMS: Laparoscopic cholecystectomy is the standard treatment for acute cholecystitis. Percutaneous cholecystostomy is an alternative treatment to resolve acute inflammation in patients with severe comorbidities. The purpose of this study is to determine the optimal timing of laparoscopic cholecystectomy after percutaneous cholecystostomy for the patients with acute cholecystitis. METHODS: This retrospective study was conducted in patients who underwent cholecystectomy after percutaneous cholecystostomy from January 2010 through November 2014. Seventy-four patients were included in this study. The patients were divided into two groups by the operation timing. Group I patients underwent cholecystectomy within 10 days after percutaneous cholecystostomy (n=30) and group II patients underwent cholecystectomy at more than 10 days after percutaneous cholecystostomy (n=44). RESULTS: There was no significant difference between groups in conversion rate to open surgery, operation time, perioperative complications rate, and days of hospital stay after operation. However, complications related to cholecystostomy such as catheter dislodgement occurred significantly more often in group II than group I (group I:group II=0%:18.2%; p=0.013). CONCLUSIONS: Timing of laparoscopic cholecystectomy after percutaneous cholecystostomy did not influence postoperative outcomes. However, late surgery caused more complications related to cholecystostomy than early surgery. Therefore, early laparoscopic cholecystectomy should be considered over late surgery after percutaneous cholecystostomy insertion. PMID- 26493505 TI - Uric Acid Is a Risk Indicator for Metabolic Syndrome-related Colorectal Adenoma: Results in a Korean Population Receiving Screening Colonoscopy. AB - BACKGROUND/AIMS: An association between serum uric acid and cancer risk has been noted over the past few decades. There is ongoing debate about whether hyperuricemia represents an independent risk factor for colorectal neoplasm. We investigated the association between serum uric acid and prevalence of colorectal adenoma considering numerous confounding factors. METHODS: A cross-sectional study was performed with individuals who underwent a routine health check-up examination, including a screening colonoscopy and blood chemistry. The association between serum uric acid and prevalence of colorectal adenoma was estimated from the results of a logistic regression analysis. RESULTS: Of the 1,066 participants, 402 had colorectal adenoma (37.7%). In univariate models, the prevalence of colorectal adenoma was higher in participants in the fourth quartile uric acid level, compared to those in the first quartile uric acid level (OR, 1.67; 95% CI, 1.17-2.42; p=0.004). However, no significant association was detected between serum uric acid and prevalence of colorectal adenoma in multiple logistic regression analysis. A number of metabolic syndrome components exhibited a strong association with the prevalence of colorectal adenoma in the multivariate model (OR, 3.46 for highest vs. lowest; 95% CI, 1.30-9.20; p=0.021). Moreover, serum uric acid was strongly associated with metabolic syndrome associated variables, including waist circumference, fasting blood glucose, systolic blood pressure, diastolic blood pressure, triglyceride, and high-density lipoprotein. CONCLUSIONS: Uric acid is not an independent risk factor for colorectal adenoma but is a risk indicator for metabolic syndrome-related colorectal adenoma. PMID- 26493507 TI - MicroRNA-200c as a Prognostic Biomarker for Pancreatic Cancer. AB - BACKGROUND/AIMS: MicroRNA (miRNA) regulates messenger RNA stability and translation. In cancer biology, miRNA affects the growth and metastasis of cancer cells by controlling epithelial-mesenchymal transition (EMT). MiR-200 family (200a/200b/ 200c/141) and miR-205 are associated with the regulation of EMT. We investigated the prognostic role of EMT-related miRNAs in pancreatic cancer. METHODS: We analyzed miR-200 family and miR-205 expression in tissue samples of 84 patients who underwent radical resection for pancreatic cancer. RESULTS: Patients were followed from the date of diagnosis until death or censoring. The mean overall survival was 25.0 +/- 2.0 months (2-140 months). The R0 resection rate was obtained in 84.5% (n=71) of patients. The relative expressions of miR 200a/200b/200c/141 and miR-205 were 266.9 +/- 57.3/18.5 +/- 2.2/0.7 +/- 0.1/27.2 +/- 6.6 folds and 0.1 +/- 0.1 compared with human pancreatic ductal epithelial cells, respectively. Overall survival was longer in the low miR-200c expression group than in the high expression group (35 vs. 19 months, p=0.013). Multivariate analysis confirmed that patients with low miR-200c expression survived longer than the high expression group (hazard ratio, 1.771; 95% CI, 1.081-2.900; p=0.023). There was a trend toward longer disease-free survival in low miR-200c group without statistical significance (p=0.061). CONCLUSIONS: The expression of miR-200c may be an important prognosis factor in pancreatic cancer, and it could be a novel therapeutic target of pancreatic cancer. PMID- 26493508 TI - [A Case of Advanced Gastric Cancer Presenting as Multiple Colonic Lymphoid Hyperplasia]. AB - Gastric cancer frequently disseminates to the liver, lung, and bone via hematogeneous, lymphatic, or peritoneal routes. However, gastric adenocarcinoma that metastasize to the colon and that shows typical linea platisca pattern on colonofiberscopy has rarely been reported. Recently, the authors experience a case of advanced gastric cancer with colonic metastases in a 55-year-old female patient. Multiple colonic lymphoid hyperplasias were detected on colonofiberscopy and biopsy revealed metastatic gastric cancer to the colonic wall. She was treated with mFOLFOX (5-FU, oxaliplatin, leucovorin) and has achieved stable disease status without disease progression. Herein, we report a rare case of signet ring-cell gastric cancer which metastasized to the colon in the form of multiple colonic lymphoid hyperplasias. PMID- 26493509 TI - [A Case of Primary Gastric Amyloidosis with Fulminant Heart Failure]. AB - A 53-year-old woman was admitted with epigastric discomfort and weakness. Laboratory examination at admission showed mild anemia and proteinuria. Esophagogastroduodenoscopy revealed marked mucosal atrophy, diffuse nodularity and granular appearance with mucosal friability. Biopsy was performed on the antrum and body of the stomach. On the next day, the patient began to complain of severe dyspnea, and hypoxia was present on pulse oximetry. Therefore, emergency echocardiography was conducted and it showed restrictive cardiomyopathy along with thrombus in the left atrium. With time, heart failure was aggravated despite intensive management. The result of gastric biopsy revealed amyloid deposits which stained positively with Congo red. On immunohistochemistry study, kappa and lambda chain were present. In addition, kappa chain was significantly elevated in urine and serum on electrophoresis. Although the patient was finally diagnosed as having primary gastric amyloidosis with restrictive cardiomyopathy, her general condition rapidly deteriorated and died at 12th hospital day. When obscure gastric lesion is encountered, performing gastric biopsy is strongly recommended since it be primary gastric amyloidosis. Herein, we present an unusual case of primary gastric amyloidosis. PMID- 26493510 TI - [A Case of Crohn's Disease Showing Favorable Response to Induction and Maintenance Therapy with Methotrexate after Failure of Anti-tumor Necrosis Factor Therapy]. AB - Thanks to the introduction of immumomodulators and biologics, therapeutic approaches in Crohn's disease have changed significantly during the past decade. Although new biologic therapy has dramatically improved the treatment of Crohn's disease, a substantial number of patients are refractory to these therapies or lose their initial response. Methotrexate (MTX) is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid to the enzyme dihydrofolate reductase and has been widely used as immunomodulator in rheumatology area for patients with rheumatoid arthritis and psoriasis. Although MTX has also been shown to be an effective agent for remission induction and maintenance of remission in Crohn's disease, the use of MTX in Crohn's disease has not yet been reported in Korea. Herein, we report a case of Crohn's disease patient who was successfully treated with MTX after treatment failure with thiopurine and anti-tumor necrosis factor. PMID- 26493511 TI - [A Case of Delayed-onset Multiple Metastatic Infection following Liver Abscess]. AB - Klebsiella pneumoniae liver abscess has a tendency to spread to distant sites early in the course of disease and to involve multiple organs synchronously. A 59 year-old male was admitted because of liver abscess accompanied by fever and abdominal pain. The patient underwent percutaneous catheter drainage and received intravenous antibiotics. Symptom relief was achieved after the treatment as well as marked reduction in the size of the abscess. Despite proper treatment of the liver abscess, however, patient developed multiple metastatic infections in a non concurrent manner: left and right endophthalmitis, psoas abscess, and infectious spondylitis at 5, 23, 30 and 65 days after initial manifestations of liver abscess, respectively. Each infectious episode followed one another after resolution of the former one. For each episode of metastatic infections, the patient promptly underwent treatment with systemic and local antibiotics, interventional abscess drainage, and surgical treatments as needed. The patient fully recovered without sequelae after the use of intravenous antibiotics for an extended period of time. Herein, we report a case of K. pneumoniae liver abscess complicated with delayed-onset multiple metastatic infections. PMID- 26493512 TI - Scope and Mechanisms of Frustrated Lewis Pair Catalyzed Hydrogenation Reactions of Electron-Deficient C=C Double Bonds. AB - Several phosphonium and ammonium triarylborohydrides, which are intermediates in hydrogenation reactions catalyzed by frustrated Lewis pairs, were synthesized in high yield under mild conditions from triaryl boranes, ammonium or phosphonium halides, and triethylsilane. The kinetics and mechanisms of the reactions of these hydridoborate salts with benzhydrylium ions, iminium ions, quinone methides, and Michael acceptors were investigated, and their nucleophilicity was determined and compared with that of other hydride donors. PMID- 26493515 TI - A Highly Efficient Heterogenized Iridium Complex for the Catalytic Hydrogenation of Carbon Dioxide to Formate. AB - A heterogenized catalyst on a highly porous covalent triazine framework was synthesized and characterized to have a coordination environment similar to that of its homogeneous counterpart. The catalyst efficiently converted CO2 into formate through hydrogenation with a turnover number of 5000 after 2 h and an initial turnover frequency of up to 5300 h(-1) ; both of these values are the highest reported to date for a heterogeneous catalyst, which makes it attractive toward industrial application. Furthermore, the synthesized catalyst was found to be stable in air and was recycled by simple filtration without significant loss of catalytic activity. PMID- 26493516 TI - Adolescents' co-rumination and stress predict affective changes in a daily-diary paradigm. AB - Co-rumination has been related to both high quality friendship and depressive symptoms. However, little is known regarding the extent to which co-rumination may be detrimental, its distinction from rumination and potential gender differences in co-rumination. This study used a modified version of Rose's Co rumination Questionnaire (Rose, 2002) to examine the behaviour of daily co rumination with daily stress and negative affect among adolescents. Results demonstrated that co-rumination did not have a main effect in predicting negative affect, but did evidence a significant interaction with life stress. Additionally, co-rumination demonstrated incremental utility above that of rumination. Finally, gender differences were not supported. In conclusion, this investigation revealed that co-rumination exacerbates the effects of life stress and is predictive of increased internalising symptoms. PMID- 26493517 TI - Metabolic consequences of knocking out UGT85B1, the gene encoding the glucosyltransferase required for synthesis of dhurrin in Sorghum bicolor (L. Moench). AB - Many important food crops produce cyanogenic glucosides as natural defense compounds to protect against herbivory or pathogen attack. It has also been suggested that these nitrogen-based secondary metabolites act as storage reserves of nitrogen. In sorghum, three key genes, CYP79A1, CYP71E1 and UGT85B1, encode two Cytochrome P450s and a glycosyltransferase, respectively, the enzymes essential for synthesis of the cyanogenic glucoside dhurrin. Here, we report the use of targeted induced local lesions in genomes (TILLING) to identify a line with a mutation resulting in a premature stop codon in the N-terminal region of UGT85B1. Plants homozygous for this mutation do not produce dhurrin and are designated tcd2 (totally cyanide deficient 2) mutants. They have reduced vigor, being dwarfed, with poor root development and low fertility. Analysis using liquid chromatography-mass spectrometry (LC-MS) shows that tcd2 mutants accumulate numerous dhurrin pathway-derived metabolites, some of which are similar to those observed in transgenic Arabidopsis expressing the CYP79A1 and CYP71E1 genes. Our results demonstrate that UGT85B1 is essential for formation of dhurrin in sorghum with no co-expressed endogenous UDP-glucosyltransferases able to replace it. The tcd2 mutant suffers from self-intoxication because sorghum does not have a feedback mechanism to inhibit the initial steps of dhurrin biosynthesis when the glucosyltransferase activity required to complete the synthesis of dhurrin is lacking. The LC-MS analyses also revealed the presence of metabolites in the tcd2 mutant which have been suggested to be derived from dhurrin via endogenous pathways for nitrogen recovery, thus indicating which enzymes may be involved in such pathways. PMID- 26493518 TI - Functional Characterization of PhapLEAFY, a FLORICAULA/LEAFY Ortholog in Phalaenopsis aphrodite. AB - The plant-specific transcription factor LEAFY (LFY) is considered to be a master regulator of flower development in the model plant, Arabidopsis. This protein plays a dual role in plant growth, integrating signals from the floral inductive pathways and acting as a floral meristem identity gene by activating genes for floral organ development. Although LFY occupies an important position in flower development, the functional divergence of LFY homologs has been demonstrated in several plants including monocots and gymnosperms. In particular, the functional roles of LFY genes from orchid species such as Phalaenopsis that contain unique floral morphologies with distinct expression patterns of floral organ identity genes remain elusive. Here, PhapLFY, an ortholog of Arabidopsis LFY from Phalaenopsis aphrodite subsp. formosana, a Taiwanese native monopodial orchid, was isolated and characterized through analyses of expression and protein activity. PhapLFY transcripts accumulated in the floral primordia of developing inflorescences, and the PhapLFY protein had transcriptional autoactivation activity forming as a homodimer. Furthermore, PhapLFY rescues the aberrant floral phenotypes of Arabidopsis lfy mutants. Overexpression of PhapLFY alone or together with PhapFT1, a P. aphrodite subsp. formosana homolog of Arabidopsis FLOWERING LOCUS T (FT) in rice, caused precocious heading. Consistently, a higher Chl content in the sepals and morphological changes in epidermal cells were observed in the floral organs of PhapLFY knock-down orchids generated by virus induced gene silencing. Taken together, these results suggest that PhapLFY is functionally distinct from RICE FLORICAULA/LEAFY (RFL) but similar to Arabidopsis LFY based on phenotypes of our transgenic Arabidopsis and rice plants. PMID- 26493519 TI - Down the Rabbit Hole: Emergency Department Medical Clearance of Patients with Psychiatric or Behavioral Emergencies. AB - Patients presenting with behavior or psychiatric complaints may have an underlying medical disorder causing or worsening their symptoms. Misdiagnosing a medical illness as psychiatric can lead to increased morbidity and mortality. A thorough history and physical examination, including mental status, are important to identify these causes and guide further testing. Laboratory and ancillary testing should be guided by what is indicated based on clinical assessment. Certain patient populations and signs and symptoms have a higher association with organic causes of behavioral complaints. Many medical problems can present with or exacerbate psychiatric symptoms, and a thorough medical assessment is imperative. PMID- 26493520 TI - Stabilization and Management of the Acutely Agitated or Psychotic Patient. AB - Acutely agitated or psychotic patients are particularly challenging to manage in the emergency department. Often these patients present with little or no history, and an adequate assessment may initially be difficult because of the condition of the patient. This article discusses basic concepts regarding agitation, and the related management goals and strategies. PMID- 26493521 TI - Stabilizing and Managing Patients with Altered Mental Status and Delirium. AB - Present in all patient populations, altered mental status (AMS) is a common, but nonspecific emergency department (ED) presentation that can signify serious underlying pathology. Delirium is a more defined mental status change caused by another medical condition that carries a high morbidity and mortality if missed. However, ED physicians miss the condition in more than 50% of cases. The ED physician should maintain a high index of suspicion for delirium, because if missed in the ED, delirium is more likely to be missed on the floors as well. Management of delirium is directed toward treating the underlying course. PMID- 26493522 TI - Depression and the Suicidal Patient. AB - Depression is the most common psychiatric illness in the general community, with 3% to 4% of depressives dying by suicide today. Studies have shown that depression has considerable morbidity and mortality. This article focuses on depressed patients and their management within the emergency department. Understanding the intricacies of the interview process and identifying which patients need immediate attention are important skills for the emergency physician. PMID- 26493523 TI - New Drugs of Abuse and Withdrawal Syndromes. AB - New drugs of abuse continue to emerge, including synthetic cannabinoids, synthetic cathinones, and hallucinogens. It is important to recognize their individual psychopharmacologic properties, symptoms of intoxication, and symptoms of withdrawal. Providers must be vigilant of acute medical or psychiatric complications that may arise from use of these substances. Treatment of the patient also includes recognition of any substance use disorders as well as comorbid psychiatric disorders. Although pharmacologic treatments for substance use disorder (of the drugs included in this article) are limited, there are a variety of psychotherapeutic modalities that may be of some benefit. PMID- 26493524 TI - Shift, Interrupted: Strategies for Managing Difficult Patients Including Those with Personality Disorders and Somatic Symptoms in the Emergency Department. AB - Difficult patients are often those who present with a mix of physical and psychiatric symptoms, and seem refractory to usual treatments or reassurance. such patients can include those with personality disorders, those with somatization symptoms; they can come across as entitled, drug-seeking, manipulative, or simply draining to the provider. Such patients are often frequent visitors to Emergency Departments. Other reasons for difficult encounters could be rooted in provider bias or countertransference, rather than sole patient factors. Emergency providers need to have high awareness of these possibilities, and be prepared to manage such situations, otherwise workup can be sub-standard and dangerous medical mistakes can be made. PMID- 26493525 TI - Special Considerations in Pediatric Psychiatric Populations. AB - Proper treatment of the pediatric psychiatric population can be challenging. Emergency department (ED) boarding, availability of child and adolescent psychiatrists, lack of parental understanding, and inexperience working with children with special needs are just some of the obstacles the ED physician will encounter. We discuss the risk stratification and interventions necessary when dealing with children and adolescents presenting with suicidal ideation and violent behavior. In addition, we discuss the unique approaches to patients with autism spectrum disorders and attention deficit hyperactivity disorder. PMID- 26493526 TI - Psychiatric Emergencies in the Elderly. AB - With the increasing life expectancy, the geriatric population has been increasing over the past few decades. By the year 2050, it is projected to compose more than a fifth of the entire population, representing a 147% increase in this age group. There has been a steady increase in the number of medical and psychiatric disorders, and a large percentage of geriatric patients are now presenting to the emergency department with such disorders. The management of our progressively complex geriatric patient population will require an integrative team approach involving emergency medicine, psychiatry, and hospitalist medicine. PMID- 26493527 TI - Psychiatric Emergencies in Pregnant Women. AB - Psychiatric emergencies in pregnancy can be difficult to manage. The authors (both practicing psychiatrists and emergency clinicians) review the evaluation and treatment of common mental health diagnoses in pregnancy. PMID- 26493528 TI - Special Considerations in Trauma Patients. AB - The emergent management of a traumatic injury can be an extremely intense situation. These assessments can be even more difficult when patients have an underlying psychiatric condition. After a protocoled evaluation of the traumatic injuries, the psychological manifestation of diseases can be addressed. The appropriate use of physical or chemical restraints to facilitate the work-up is paramount in the ability of the provider to protect patients and staff from agitated and traumatized patients. The emergency medicine provider should have a low threshold for including psychiatry in the treatment plans, as the long-term sequelae of these entities require specialized treatment. PMID- 26493529 TI - Ethical Issues in Emergency Psychiatry. AB - The care of patients with a psychiatric emergency is fraught with ethical challenges. Applying ethical reasoning to clinical challenges may help to improve care. Emergency providers should assess decision-making capacity using 4 criteria: communication, understanding, appreciation, and reasoning. Maintaining patient confidentiality is a strong imperative for emergency physicians and should be protected unless compelling additional concerns take precedence. The goal of involuntary treatment should be to protect patients from harm that they would not be exposed to were they capable of autonomous decision making, not dangerous, or not impaired by their psychiatric illness using the least restrictive means possible. PMID- 26493530 TI - Health Policy Considerations in Treating Mental and Behavioral Health Emergencies in the United States. AB - In recent years, health care providers have sounded the call that the US mental health system is in crisis. With decreases in funding and eroding access to care, the availability of psychiatric services has become increasingly limited, failing to meet growing needs. This article provides a brief history of mental health services in the United States and describes the current landscape of US psychiatric care; it touches upon some of the most important policy considerations, describing some of the glaring issues in US mental health care today. Last, it offers some potential remedies to improve care in acute behavioral emergencies. PMID- 26493531 TI - Behavioral and Psychiatric Emergencies. PMID- 26493532 TI - The Hidden Costs of Behavioral and Psychiatric Emergencies. PMID- 26493533 TI - Super-strengthening and stabilizing with carbon nanotube harnessed high density nanotwins in metals by shock loading. AB - CNTs reinforced metal composites has great potential due to their superior properties, such as light weight, high strength, low thermal expansion and high thermal conductivity. The current strengthening mechanisms of CNT/metal composite mainly rely on CNTs' interaction with dislocations and CNT's intrinsic high strength. Here we demonstrated that laser shock loading the CNT/metal composite results in high density nanotwins, stacking fault, dislocation around the CNT/metal interface. The composites exhibit enhanced strength with excellent stability. The results are interpreted by both molecular dynamics simulation and experiments. It is found the shock wave interaction with CNTs induces a stress field, much higher than the applied shock pressure, surrounding the CNT/metal interface. As a result, nanotwins were nucleated under a shock pressure much lower than the critical values to generate twins in metals. This hybrid unique nanostructure not only enhances the strength, but also stabilize the strength, as the nanotwin boundaries around the CNTs help pin the dislocation movement. PMID- 26493534 TI - Erratum to Center-out echo-planar spectroscopic imaging with correction of gradient-echo phase and time Shifts (Magn Reson Med 2013;70:16-24). PMID- 26493535 TI - Erratum to Myelin water mapping by spatially regularized longitudinal relaxographic imaging at high magnetic fields (Magn Reson Med 2014;71:375-387). PMID- 26493538 TI - Single-Walled Carbon Nanotubes in Highly Viscous Media: A Comparison between the Dispersive Agents [BMIM][BF4 ], L121, and Triton X-100. AB - Dispersions of single-walled carbon nanotubes (SWNTs) have been prepared by using the room-temperature ionic liquid [BMIM][BF4 ] (1-butyl-3-methylimidazolium tetrafluoroborate), the triblock copolymer Pluronic L121 [poly(ethylene oxide)5 poly(propylene oxide)68 -poly(ethylene oxide)5 ] and the non-ionic surfactant Triton X-100 (TX100) in the pure state. The size of the SWNTs aggregates and the dispersion degree in the three viscous systems depend on the sonication time, as highlighted by UV/Vis/NIR spectroscopy and optical microscopy analysis. A nonlinear increase in conductivity can be observed as a function of the SWNTs loading, as suggested by electrochemical impedance spectroscopy. The generation of a three-dimensional network of SWNTs showing a viscoelastic gel-like behavior above a critical percolation concentration has been found at 25 degrees C in all the investigated systems by oscillatory rheology measurements. PMID- 26493541 TI - First discovery of Holocene cryptotephra in Amazonia. AB - The use of volcanic ash layers for dating and correlation (tephrochronology) is widely applied in the study of past environmental changes. We describe the first cryptotephra (non-visible volcanic ash horizon) to be identified in the Amazon basin, which is tentatively attributed to a source in the Ecuadorian Eastern Cordillera (0-1 degrees S, 78-79 degrees W), some 500-600 km away from our field site in the Peruvian Amazon. Our discovery 1) indicates that the Amazon basin has been subject to volcanic ash fallout during the recent past; 2) highlights the opportunities for using cryptotephras to date palaeoenvironmental records in the Amazon basin and 3) indicates that cryptotephra layers are preserved in a dynamic Amazonian peatland, suggesting that similar layers are likely to be present in other peat sequences that are important for palaeoenvironmental reconstruction. The discovery of cryptotephra in an Amazonian peatland provides a baseline for further investigation of Amazonian tephrochronology and the potential impacts of volcanism on vegetation. PMID- 26493539 TI - Enhanced serelaxin signalling in co-cultures of human primary endothelial and smooth muscle cells. AB - BACKGROUND AND PURPOSE: In the phase III clinical trial, RELAX-AHF, serelaxin caused rapid and long-lasting haemodynamic changes. However, the cellular mechanisms involved are unclear in humans. EXPERIMENTAL APPROACH: This study examined the effects of serelaxin in co-cultures of human primary endothelial cells (ECs) and smooth muscle cells (SMCs) on cAMP and cGMP signalling. KEY RESULTS: Stimulation of HUVECs or human coronary artery endothelial cells (HCAECs) with serelaxin, concentration-dependently increased cGMP accumulation in co-cultured SMCs to a greater extent than in monocultures of either cell type. This was not observed in human umbilical artery endothelial cells (HUAECs) that do not express the relaxin receptor, RXFP1. Treatment of ECs with l-N(G) -nitro arginine (NOARG; 30 MUM, 30 min) inhibited serelaxin-mediated (30 nM) cGMP accumulation in HUVECs, HCAECs and co-cultured SMCs. In HCAECs, but not HUVECs, pre-incubation with indomethacin (30 MUM, 30 min) also inhibited cGMP accumulation in SMCs. Pre-incubation of SMCs with the guanylate cyclase inhibitor ODQ (1 MUM, 30 min) had no effect on serelaxin-mediated (30 nM) cGMP accumulation in HUVECs and HCAECs but inhibited cGMP accumulation in SMCs. Serelaxin stimulation of HCAECs, but not HUVECs, increased cAMP accumulation concentration dependently in SMCs. Pre-incubation of HCAECs with indomethacin, but not l-NOARG, abolished cAMP accumulation in co-cultured SMCs, suggesting involvement of prostanoids. CONCLUSIONS AND IMPLICATIONS: In co-cultures, treatment of ECs with serelaxin caused marked cGMP accumulation in SMCs and with HCAEC also cAMP accumulation. Responses involved EC-derived NO and with HCAEC prostanoid production. Thus, serelaxin differentially modulates vascular tone in different vascular beds. PMID- 26493540 TI - Mixed methods evaluation of targeted selective anthelmintic treatment by resource poor smallholder goat farmers in Botswana. AB - Due to the threat of anthelmintic resistance, livestock farmers worldwide are encouraged to selectively apply treatments against gastrointestinal nematodes (GINs). Targeted selective treatment (TST) of individual animals would be especially useful for smallholder farmers in low-income economies, where cost effective and sustainable intervention strategies will improve livestock productivity and food security. Supporting research has focused mainly on refining technical indicators for treatment, and much less on factors influencing uptake and effectiveness. We used a mixed method approach, whereby qualitative and quantitative approaches are combined, to develop, implement and validate a TST system for GINs in small ruminants, most commonly goats, among smallholder farmers in the Makgadikgadi Pans region of Botswana, and to seek better understanding of system performance within a cultural context. After the first six months of the study, 42 out of 47 enrolled farmers were followed up; 52% had monitored their animals using the taught inspection criteria and 26% applied TST during this phase. Uptake level showed little correlation with farmer characteristics, such as literacy and size of farm. Herd health significantly improved in those herds where anthelmintic treatment was applied: anaemia, as assessed using the five-point FAMACHA((c)) scale, was 0.44-0.69 points better (95% confidence interval) and body condition score was 0.18-0.36 points better (95% C.I., five-point scale) in treated compared with untreated herds. Only targeting individuals in greatest need led to similar health improvements compared to treating the entire herd, leading to dose savings ranging from 36% to 97%. This study demonstrates that TST against nematodes can be implemented effectively by resource-poor farmers using a community-led approach. The use of mixed methods provides a promising system to integrate technical and social aspects of TST programmes for maximum uptake and effect. PMID- 26493542 TI - Low-intensity extracorporeal shockwave therapy in the treatment of postprostatectomy erectile dysfunction: a pilot study. AB - OBJECTIVE: The objective was to investigate the effect and feasibility of low intensity extracorporeal shockwave therapy (LI-ESWT) as a treatment for erectile dysfunction (ED) after bilateral nerve-sparing radical prostatectomy (RP). MATERIALS AND METHODS: Patients who had undergone robot-assisted bilateral nerve sparing RP more than a year before entering this pilot study, had no preoperative ED and were suffering from mild to severe postoperative ED were invited to participate. Six treatments were given over a 6 week period, using the Duolith(r) SD1 T-Top machine. The effect of the treatment was evaluated 1 month (t1) and 1 year (t2) after the final treatment. The main outcome measure was changes in the five-item International Index of Erectile Function (IIEF-5) scores. RESULTS: Eighteen patients were included in the study. However, two patients breached the protocol and consequently 16 patients were included in the analysis at t1 and 15 patients were included in the analysis at t2. At baseline the median age was 62 years (range 51 to 70 years) and the median time since surgery was 24 months (range 12 to 54 months). The median preoperative IIEF-5 score was 25 (range 22 to 25) and the median baseline IIEF-5 score was 9.5 (range 5 to 20). The median change in IIEF-5 scores was +3.5 (range -1 to 8; p = 0.0049) and +1 (range -3 to 14; p = 0.046) at t1 and t2, respectively. No severe side-effects were reported. CONCLUSIONS: LI-ESWT may improve erectile function after bilateral nerve-sparing RP. Based on these results, further studies in patients with ED after nerve sparing RP are justified. PMID- 26493544 TI - Short- and Long-Term Optimal Control of a Mathematical Model for HIV Infection of CD4+T Cells. AB - The main goal of this study was to develop a theoretical short- and long-term optimal control treatment of HIV infection of [Formula: see text] cells. The aim of the mathematical model used herein is to make the free HIV virus particles in the blood decrease, while administering a treatment that is less toxic to patients. Pontryagin's classical control theory is applied to a mathematical model of HIV infection of [Formula: see text] cells characterized by a system of nonlinear differential equations with the following unknown functions: the concentration of susceptible [Formula: see text] cells, [Formula: see text] cells infected by the HIV viruses and free HIV virus particles in the blood. PMID- 26493543 TI - Clinical evaluation of the IONA test: a non-invasive prenatal screening test for trisomies 21, 18 and 13. AB - OBJECTIVE: To evaluate the clinical accuracy of the IONA(r) test for aneuploidy screening. METHODS: This was a multicenter blinded study in which plasma samples from pregnant women at increased risk of trisomy 21 underwent cell-free DNA analysis utilizing the IONA test. For each sample, the IONA software generated a likelihood ratio and a maternal age-adjusted probability risk score for trisomies 21, 18 and 13. All results from the IONA test were compared against accepted diagnostic karyotyping. RESULTS: A total of 442 maternal samples were obtained, of which 437 had test results available for analysis and assessment of clinical accuracy. The IONA test had a detection rate of 100% for trisomies 21 (n = 43; 95% CI, 87.98-100%), 18 (n = 10; 95% CI, 58.72-100%) and 13 (n = 5; 95% CI, 35.88 100%) with cut-offs applied to likelihood ratio (cut-off > 1 considered high risk for trisomy) and probability risk score incorporating adjustment for maternal age (cut-off >= 1/150 considered high risk for trisomy). The false-positive rate (FPR) was 0% for trisomies 18 and 13 with both analysis outputs. For trisomy 21, a FPR of 0.3% was observed for the likelihood ratio, but became 0% with adjustment for maternal age. CONCLUSION: This study indicates that the IONA test is suitable for trisomy screening in a high-risk screening population. The result interpretation feature of the IONA software should facilitate wider implementation, particularly in local laboratories, and should be a useful addition to the current screening methods for trisomies 21, 18 and 13. PMID- 26493545 TI - Novel Abscisic Acid Antagonists Identified with Chemical Array Screening. AB - Abscisic acid (ABA) signaling is involved in multiple processes in plants, such as water stress control and seed dormancy. Major regulators of ABA signaling are the PYR/PYL/RCAR family receptor proteins, group A protein phosphatases 2C (PP2Cs), and subclass III of SNF1-related protein kinase 2 (SnRK2). Novel ABA agonists and antagonists to modulate the functions of these proteins would not only contribute to clarification of the signaling mechanisms but might also be used to improve crop yields. To obtain small molecules that interact with Arabidopsis ABA receptor PYR1, we screened 24 275 compounds from a chemical library at the RIKEN Natural Products Depository by using a chemical array platform. Subsequent SnRK2 and PP2C assays narrowed down the candidates to two molecules. One antagonized ABA in a competitive manner and inhibited the formation of the PYR1-ABA-PP2C ternary complex. These compounds might have potential as bioprobes to analyze ABA signaling. PMID- 26493546 TI - Inverse relationship between chitobiase and transglycosylation activities of chitinase-D from Serratia proteamaculans revealed by mutational and biophysical analyses. AB - Serratia proteamaculans chitinase-D (SpChiD) has a unique combination of hydrolytic and transglycosylation (TG) activities. The TG activity of SpChiD can be used for large-scale production of chito-oligosaccharides (CHOS). The multiple activities (hydrolytic and/or chitobiase activities and TG) of SpChiD appear to be strongly influenced by the substrate-binding cleft. Here, we report the unique property of SpChiD substrate-binding cleft, wherein, the residues Tyr28, Val35 and Thr36 control chitobiase activity and the residues Trp160 and Trp290 are crucial for TG activity. Mutants with reduced (V35G and T36G/F) or no (SpChiDDelta30-42 and Y28A) chitobiase activity produced higher amounts of the quantifiable even-chain TG product with degree of polymerization (DP)-6, indicating that the chitobiase and TG activities are inversely related. In addition to its unprecedented catalytic properties, unlike other chitinases, the single modular SpChiD showed dual unfolding transitions. Ligand-induced thermal stability studies with the catalytically inactive mutant of SpChiD (E153A) showed that the transition temperature increased upon binding of CHOS with DP2-6. Isothermal titration calorimetry experiments revealed the exceptionally high binding affinities for E153A to CHOS with DP2-6. These observations strongly support that the architecture of SpChiD substrate-binding cleft adopted to control chitobiase and TG activities, in addition to usual chitinase-mediated hydrolysis. PMID- 26493547 TI - Tacrolimus interaction with dexmedetomidine--a case report. AB - Drugs and xenobiotics that inhibit the CYP-450 isoenzyme 3A4 are associated with increased serum tacrolimus levels. We sought to determine whether there was a temporal association between initiation of dexmedetomidine and increased serum tacrolimus levels. An interaction has not been previously documented. We reviewed tacrolimus levels and dosing in a pediatric patient aged 8 months who had undergone deceased-donor liver transplantation for biliary atresia and later required sedation with dexmedetomidine continuous infusion during the POD (212 216). Serum tacrolimus trough levels increased 4-fold from 3.4 to 13.1 ng/mL (tacrolimus regimen: 1 mg every 12 h) within 21 h of initiating dexmedetomidine. During dexmedetomidine infusion, serum tacrolimus trough levels were maintained with doses that were 25% of baseline tacrolimus dose. Tacrolimus trough levels decreased to below goal range within 30-40 h of discontinuation of dexmedetomidine. Data submitted to the U.S. Food and Drug Administration demonstrate that dexmedetomidine inhibits CYP 3A4 and may produce adequate liver concentrations that could interfere with tacrolimus metabolism. We suggest that tacrolimus levels should be carefully monitored in children receiving prolonged infusions of dexmedetomidine to avoid adverse events associated with elevated tacrolimus levels. PMID- 26493548 TI - Prospective case-control study of efficacy of bilateral selective neck dissection in primary surgical treatment of supraglottic laryngeal cancers with clinically negative cervical findings (N0). AB - OBJECTIVE: To evaluate the efficacy of bilateral selective neck dissection of levels II-IV in elective and therapeutic management of the neck as a part of primary surgical treatment of patients with supraglottic laryngeal cancer and clinically negative cervical findings (N0). DESIGN: Institutional, observational, case-control study with historic control of patients who underwent primary supraglottic tumour surgery, and a prospective cohort of patient, who underwent, besides the operation of primary tumour, bilateral selective neck dissection (level II-IV). SETTING: University, tertiary level hospital, national referral centre. PARTICIPANTS: The study included 193 patients with supraglottic cancer and without palpable or ultrasound positive cervical findings who were surgically treated from 1988 to 2005. Besides the operation of primary tumour, all patients in the study group underwent bilateral selective neck dissection (level II-IV). Patients in the control group (N = 51) underwent primary tumour operation only and were followed up regularly. In cases with postoperative regional recurrences, the radical neck dissection was performed. All patients with histopathological confirmation of occult metastases were administered radiotherapy treatment (60 Gy) in the postoperative period. MAIN OUTCOME MEASURES: Five-year overall survival rate. RESULTS: Occult cervical metastases were found in 18% of patients. They were present in level II in 77.5%, in level III in 20% of cases and in one patient in level IV (2.5%); the extracapsular spread was observed in 20% of cases. Postoperative regional metastases were found in 4.15% of cases in the study group, and in 11.8% in the control group, which proved to be significantly higher. The five-year overall survival rate showed no significant difference between the study group and the control group. CONCLUSION: The incidence of postoperative regional recurrences could be reduced by performing bilateral selective neck dissection simultaneously with primary tumour operation, but with no influence on the survival rate. PMID- 26493549 TI - Medium-term outcomes of mosaicplasty versus arthroscopic microfracture with or without platelet-rich plasma in the treatment of osteochondral lesions of the talus. AB - PURPOSE: This study aimed to compare medium-term functional effects of three different treatment modalities in patients with osteochondral lesions of the talus (OLT). METHODS: Fifty-four patients undergoing arthroscopic surgery for osteochondral lesion of the talus were included in this study. Patients were assigned to one of the three treatment groups: microfracture surgery (n = 19), microfracture surgery plus platelet-rich plasma (PRP) (n = 22), and mosaicplasty (n = 13). Function was assessed using the American Orthopedic Foot and Ankle Society (AOFAS) scoring system and VAS scores for pain, before and after surgery. In addition, the Foot and Ankle Ability Measure (FAAM) tests for pain and 15-min walking were done at follow-up visits. RESULTS: The median duration of follow-up was 42 months (range 12-84 months). All groups showed significant improvements in AOFAS and VAS pain scores at the last follow-up visit, when compared to baseline. The groups did not differ with regard to change in baseline AOFAS score; however, improvement in VAS pain scores was significantly better in the mosaicplasty group when compared to the microfracture group (change from baseline, -5.8 +/- 1.0 vs. 3.2 +/- 2.9, p = 0.018). CONCLUSIONS: All the three treatment modalities resulted in good medium-term functional results. However, mosaicplasty procedure seems to be a promising option and it might be preferred particularly in patients where pain control is important. LEVEL OF EVIDENCE: II. PMID- 26493550 TI - A meta-analysis of clinical and radiographic outcomes of posterior horn medial meniscus root repairs. AB - PURPOSE: Although interest in medial meniscus posterior root tear (MMPRT) repair has increased, few case series have been reported. This meta-analysis aimed to examine the clinical and radiological effects of MMPRT repair by pooling pre- and post-operative data from case-series reports. METHODS: A literature search was performed using MEDLINE/PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE databases. Pre- and post-operative data were pooled to investigate the effects of MMPRT repair, including the Lysholm score improvement, meniscal extrusion (mm) reduction, progression of the Kellgren-Lawrence (K-L) grade, and cartilage status according to the Outerbridge classification. Treatment effects included paired standardized mean differences (difference in the pre- and post-operative mean outcomes divided by the standard deviation) for the Lysholm score and meniscal extrusion, as well as the pooled event rates of progression of K-L grade and cartilage status. RESULTS: As treatment effects, the Lysholm score increased by as much as 3.675 (P < 0.001), whereas meniscus extrusion was not reduced (n.s.). The overall pooled event rates of progression of K-L grade and cartilage status were 10.6 and 17.3 % (P < 0.001), respectively. CONCLUSIONS: According to the current literature, MMPRT repair resulted in significant improvements in the post-operative clinical subjective scores compared with the preoperative status. However, meniscus extrusion was not reduced. Considering the occurrence of progression of K-L grade and cartilage status, it did not prevent the progression of arthrosis completely. Based on these results, repair results in favourable outcomes for MMPRT. LEVEL OF EVIDENCE: Meta-analysis, Level IV. PMID- 26493551 TI - Comparing ovarian reserve after laparoscopic excision of endometriotic cysts and hemostasis achieved either by bipolar coagulation or suturing: a randomized clinical trial. AB - PURPOSE: This study aimed to compare ovarian reserve between laparoscopic suturing and bipolar coagulation techniques in women with unilateral endometrioma. METHODS: In a prospective randomized clinical trial, 109 patients with unilateral endometrioma underwent laparoscopic cystectomy. Patients were then randomized to undergo hemostasis with either bipolar coagulation (n = 57) or suturing (n = 52) technique. We evaluated the impact of surgery and hemostasis techniques on ovarian reserve using serum levels of anti-Mullerian hormone (AMH) and follicle-stimulating hormone (FSH) that were measured preoperatively and at 3 months postoperatively. RESULTS: Baseline characteristics such as age and preoperative AMH and FSH levels were similar between the two study groups. At 3 month follow-up, in both groups, postoperative AMH levels were significantly lower and FSH levels were significantly higher than before surgery. The decline rate of AMH levels was significantly greater in the bipolar coagulation (53.42 +/ 15.28) group than in the suturing group (15.94 +/- 18.55). Furthermore, patients in the suturing group had higher AMH and lower FSH as compared with the other group (p < 0.001). CONCLUSION: After laparoscopic stripping of endometrioma, intracorporeal suturing showed less damage on ovarian reserve as compared with bipolar electrocoagulation. Therefore, hemostatic suturing technique may be considered as a better choice after laparoscopic ovarian cystectomy. PMID- 26493552 TI - Some clarifications on the Avicenna's nationality. PMID- 26493553 TI - p53 Arg72Pro polymorphism confers the susceptibility to endometriosis among Asian and Caucasian populations. AB - PURPOSE: Findings from studies on the association between the p53 Arg72Pro polymorphism and endometriosis susceptibility have so far been inconsistent. Therefore, we undertook a meta-analysis to clarify the association of p53 Arg72Pro polymorphism with the risk of endometriosis. METHODS: Relevant studies were chosen by searching PubMed, Embase, the Cochrane Library databases, CNKI, Wanfang database, and CBM for articles published before and up to April 30, 2015. Two independent reviewers performed the eligibility evaluation and data extraction. The odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated for the overall risk estimate. RESULTS: Eleven case-control studies involving 1834 endometriosis cases and 2331 controls were included. Pooled data analysis suggested that the p53 72Pro variant is a significant endometriosis risk factors in comparison to the 72Arg variant (Pro vs. Arg: OR = 1.298, 95 % CI 1.082-1.558; Pro/Pro vs. Arg/Arg: OR = 1.751, 95 % CI 1.130-2.711; Pro/Arg vs. Arg/Arg: OR = 1.530, 95 % CI 1.174-1.994), which was strengthened in the dominant model (Pro/Pro + Arg/Pro vs. Arg/Arg: OR = 1.570, 95 % CI = 1.181-2.087). In the stratified analysis by ethnicity and Hardy-Weinberg equilibrium (HWE) in the controls, we found strong associations in Asians and in studies that were consistent with HWE. However, the analyses of the revised American Fertility Society (rAFS) stage and the menopausal status subgroup did not reveal any significant associations. CONCLUSION: In conclusion, the p53 Arg72Pro polymorphism was closely related to the risk of endometriosis, especially in Asian populations. PMID- 26493554 TI - Perinatal survival and procedure-related complications after intrauterine transfusion for red cell alloimmunization. AB - OBJECTIVES: To study the perinatal survival and procedure-related (PR)complications after intrauterine transfusions in red cell alloimmunization. METHODS: Prospective data of 102 women with Rh-alloimmunized pregnancy undergoing intrauterine intravascular transfusion for fetal anemia, from January 2011 to October 2014 were analyzed. Main outcome measures were perinatal survival and procedure-related (PR) complications. RESULTS: A total of 303 intrauterine transfusions were performed in 102 women. Of 102 fetuses, 22 were hydropic at first transfusion. The mean period of gestation and hematocrit at first transfusion was 26.9 +/- 3.3 weeks (range 19.7-33.8 weeks) and 17 +/- 7.82 % (range 5.7-30 %), respectively. Average number of transfusions was 2.97 (range 1 7) per patient. Overall survival was 93 % and mean period of gestation at delivery was 34.5 +/- 1.94 (range 28.3-37.4) weeks. Mean hematocrit at delivery was 36.9 +/- 8.77 % (range 10-66 %). Fetal death occurred in four cases (3PR), neonatal death occurred in three cases (2PR). Emergency cesarean delivery after transfusion was performed in four pregnancies. The total PR complication rate was 2.97 %, resulting in overall PR loss in 1.65 % per procedure. CONCLUSION: Our results compare favorably with other studies published in the literature. Intravascular transfusion is a safe procedure improving perinatal survival in fetuses with anemia due to Rh-alloimmunization. PMID- 26493556 TI - Late-Life Exercise and Difficulty with Activities of Daily Living: an 8-Year Nationwide Follow-up Study in Taiwan. AB - BACKGROUND: Many studies have shown that low levels of exercise in later life are associated with the progression of difficulties with activities of daily living. However, few have assessed the independent effect of exercise components on difficulty in performing activities of daily living and explored whether the relationship between exercise and activities of daily living is reciprocal. PURPOSES: This study aimed to examine, in a nationally representative sample of older Taiwanese, the independent effect of the frequency, duration, and intensity of exercise on difficulty with activities of daily living. A secondary objective was to explore the degree to which the relationship of late-life exercise with activities of daily living is bi-directional. METHODS: Data from a fixed cohort (n = 1268, aged 70+) in 1999 with 8 years of follow-up were analyzed. Generalized estimating equation models with multivariate adjustment were performed. RESULTS: Participants engaging in higher levels of exercise had less difficulty with subsequent activities of daily living. Among the components of exercise, only duration, especially 30 min or more per session, was associated with fewer difficulties with activities of daily living. The relationship between exercise and activities of daily living was reciprocal, although the influence of activities of daily living on subsequent exercise levels was weaker. CONCLUSIONS: Exercise in later life may be able to minimize the difficulties in activities of daily living and help maintain the mobility and independence of older adults. PMID- 26493555 TI - Anger Expression, Momentary Anger, and Symptom Severity in Patients with Chronic Disease. AB - BACKGROUND: Anger expression styles are associated with physical health, and may affect health by modulating anger experience in daily life. Research examining this process in the daily lives of clinically relevant populations, such as patients with chronic disease, is needed. METHOD: Community adults with asthma (N = 97) or rheumatoid arthritis (RA; N = 31) completed measures of trait-level anger expression styles (anger-in and anger-out), followed by ecological momentary assessments of anger and physical health five times daily for 7 days. RESULTS: High anger-in predicted greater momentary anger, physical limitations, and greater asthma symptoms. High anger-out predicted reduced RA symptoms. Momentary anger was robustly associated with more severe symptoms in daily life. Three-way interactions showed that anger-in moderated these momentary anger symptom associations more consistently in men. CONCLUSIONS: Anger expression styles, particularly anger-in, may affect the day-to-day adjustment of patients with chronic disease in part by altering the dimensions of everyday anger experience, in ways that appear to differ by gender. PMID- 26493557 TI - The Efficacy and Safety of Lidocaine-Containing Hyaluronic Acid Dermal Filler for Treatment of Nasolabial Folds: A Multicenter, Randomized Clinical Study. AB - BACKGROUND: The use of injectable hyaluronic acid-based gel is well established in aesthetic facial procedures especially on the nasolabial fold (NLF). OBJECTIVE: To compare the efficacy and safety of PP-501-A-Lidocaine dermal filler with RestylaneLidocaine((r)) when administered to the NLF. METHODS: Sixty-six subjects seeking correction of NLFs, with moderate or severe wrinkle severity, were recruited for this multicenter, randomized, patient and evaluator-blind, matched pairs, and active-controlled design clinical study. PP-501-A-Lidocaine and RestylaneLidocaine((r)) were injected into the deep layer of the dermis and/or subcutis of the NLF. The first validity evaluation variable was the average wrinkle severity rating scale (WSRS), as scored by independent blinded evaluators at week 24. The second validity evaluation variable including the global aesthetic improvement scale (GAIS), the WSRS, and adverse event reporting at weeks 8, 16, and 24 were also performed. RESULTS: The mean improvement in the WSRS from baseline was 1.58 +/- 0.68 for the PP-501-A-Lidocaine and 1.51 +/- 0.66 for the RestylaneLidocaine((r)) at week 24. The average value at week 8 after the final application was 1.62 +/- 0.78 and 1.60 +/- 0.75 in parts subject to PP-501 A-Lidocaine and RestylaneLidocaine((r)), respectively, and 1.58 +/- 0.70 and 1.57 +/- 0.68 at week 16, respectively. Both improvement and duration of the treatment effect were similar between the two groups. GAIS data rated by the treating investigator and participants showed no statistically significant differences. Both fillers were well tolerated and adverse reactions were mild and transient in most cases. CONCLUSION: PP-501-A-Lidocaine showed an equivalent efficacy and safety observed after 6 months of follow-up compared to RestylaneLidocaine((r)). LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26493558 TI - Neurological Complications of Bariatric Surgery. AB - Obesity has attained pandemic proportions, and bariatric surgery is increasingly being employed resulting in turn to more neurological complications which must be recognized and managed. Neurological complications may result from mechanical or inflammatory mechanisms but primarily result from micro-nutritional deficiencies. Vitamin B12, thiamine, and copper constitute the most frequent deficiencies. Neurological complications may occur at reasonably predictable times after bariatric surgery and are associated with the type of surgery used. During the early post-operative period, compressive or stretch peripheral nerve injury, rhabdomyolysis, Wernicke's encephalopathy, and inflammatory polyradiculoneuropathy may occur. Late complications ensue after months to years and include combined system degeneration (vitamin B12 deficiency) and hypocupric myelopathy. Bariatric surgery patients require careful nutritional follow-up with routine monitoring of micronutrients at 6 weeks and 3, 6, and 12 months post operatively and then annually after surgery and multivitamin supplementation for life. Sustained vigilance for common and rare neurological complications is essential. PMID- 26493559 TI - A qualitative study on health workers' and community members' perceived sources, role of information and communication on malaria treatment, prevention and control in southeast Nigeria. AB - BACKGROUND: It has been widely acknowledged that well-planned and executed communication programmes can contribute to achieving malaria prevention and treatment goals. This however requires a good understanding of current sources and roles of information used by both health workers and communities. The study aimed at determining health workers' and community members' sources, value and use of information on malaria prevention and treatment in Nigeria. METHODS: Qualitative data was collected from six selected communities (three urban and three rural) in Enugu state, southeast Nigeria. A total of 18 Focus Group Discussions (FGDs) with 179 community members and 26 in-depth interviews (IDIs) with health workers in public and private health facilities were used to collect data on where people receive treatment for malaria and access information on malaria. The FGDS and IDIs also provided data on the values, uses and effects of information and communication on malaria treatment seeking and provision of services. RESULTS: The findings revealed that the major sources of information on malaria for health workers and community members were advertisements in the mass media, workshops and seminars organized by donor agencies, facility supervision, posters, other health workers, television and radio adverts. Community involvement in the design and delivery of information on malaria control was seen as a strong strategy for improving both consumer and provider knowledge. Information from the different sources catalyzed appropriate provision and consumption of malaria treatment amongst health workers and community members. CONCLUSION: Health workers and consumers receive information on malaria prevention and treatment from multiple sources of communication and information, which they find useful. Harnessing these information sources to encourage consistent and accurate messages around malaria prevention and treatment is a necessary first step in the design and implementation of malaria communication and behaviour change interventions and ultimately for the sustained control of malaria. PMID- 26493560 TI - Phylogenomics and sequence-structure-function relationships in the GmrSD family of Type IV restriction enzymes. AB - BACKGROUND: GmrSD is a modification-dependent restriction endonuclease that specifically targets and cleaves glucosylated hydroxymethylcytosine (glc-HMC) modified DNA. It is encoded either as two separate single-domain GmrS and GmrD proteins or as a single protein carrying both domains. Previous studies suggested that GmrS acts as endonuclease and NTPase whereas GmrD binds DNA. METHODS: In this work we applied homology detection, sequence conservation analysis, fold recognition and homology modeling methods to study sequence-structure-function relationships in the GmrSD restriction endonucleases family. We also analyzed the phylogeny and genomic context of the family members. RESULTS: Results of our comparative genomics study show that GmrS exhibits similarity to proteins from the ParB/Srx fold which can have both NTPase and nuclease activity. In contrast to the previous studies though, we attribute the nuclease activity also to GmrD as we found it to contain the HNH endonuclease motif. We revealed residues potentially important for structure and function in both domains. Moreover, we found that GmrSD systems exist predominantly as a fused, double-domain form rather than as a heterodimer and that their homologs are often encoded in regions enriched in defense and gene mobility-related elements. Finally, phylogenetic reconstructions of GmrS and GmrD domains revealed that they coevolved and only few GmrSD systems appear to be assembled from distantly related GmrS and GmrD components. CONCLUSIONS: Our study provides insight into sequence-structure function relationships in the yet poorly characterized family of Type IV restriction enzymes. Comparative genomics allowed to propose possible role of GmrD domain in the function of the GmrSD enzyme and possible active sites of both GmrS and GmrD domains. Presented results can guide further experimental characterization of these enzymes. PMID- 26493561 TI - Identification of novel mutations by targeted exome sequencing and the genotype phenotype assessment of patients with achromatopsia. AB - BACKGROUND: Achromatopsia (ACHM) is a severe congenital autosomal recessive retinal disorder caused by loss of cone photoreceptors. Here, we aimed to determine the underlying genetic lesions and phenotypic correlations in two Chinese families with ACHM. METHODS: Medical history and clinical evaluation were obtained from both families. Targeted exome sequencing (TES) was performed on 201 disease-causing genes of inherited retinal dystrophies to screen for ACHM causative mutations in the two probands. RESULTS: The compound heterozygous mutations in CNGA3 (c.1074G > A, p.W358X; c.1706G > A, p.R569H) were identified in the first proband, and a novel homozygous mutation (c.968C > A, p.A323D) was detected in the other pedigree. The proposed topological model of the CNGA3 polypeptide suggested that the missense mutations primarily affected the transmembrane helix 5 and the cGMP-binding domain, respectively. Crystal structure modeling of the cyclic nucleotide-gated cation channel alpha-3 (CNGA3) protein encoded by the CNGA3 gene revealed an abnormal combined structure generated by R569H. CONCLUSIONS: We firstly used the TES approach to identify genetic alterations in patients with ACHM. We uncovered three mutations in CNGA3, including one novel mutation. Our results not only expand the genotypic spectrum for CNGA3 mutations, but also demonstrate that the TES approach is a valuable tool for molecular diagnosis. PMID- 26493562 TI - Novel method to detect microRNAs using chip-based QuantStudio 3D digital PCR. AB - BACKGROUND: Research efforts for the management of cancer, in particular for lung cancer, are directed to identify new strategies for its early detection. MicroRNAs (miRNAs) are a new promising class of circulating biomarkers for cancer detection, but lack of consensus on data normalization methods has affected the diagnostic potential of circulating miRNAs. There is a growing interest in techniques that allow an absolute quantification of miRNAs which could be useful for early diagnosis. Recently, digital PCR, mainly based on droplets generation, emerged as an affordable technology for precise and absolute quantification of nucleic acids. RESULTS: In this work, we described a new interesting approach for profiling circulating miRNAs in plasma samples using a chip-based platform, the QuantStudio 3D digital PCR. The proposed method was validated using synthethic oligonucleotide at serial dilutions in plasma samples of lung cancer patients and in lung tissues and cell lines. CONCLUSION: Given its reproducibility and reliability, our approach could be potentially applied for the identification and quantification of miRNAs in other biological samples such as circulating exosomes or protein complexes. As chip-digital PCR becomes more established, it would be a robust tool for quantitative assessment of miRNA copy number for diagnosis of lung cancer and other diseases. PMID- 26493564 TI - Implications and Management of Central Nervous System Involvement before Allogeneic Hematopoietic Cell Transplantation in Acute Lymphoblastic Leukemia. AB - Acute lymphoblastic leukemia (ALL) with a history of central nervous system (CNS) involvement, either at diagnosis or relapse, poses challenges when the decision is made to proceed with allogeneic hematopoietic cell transplantation (alloHCT), as there is no evidence-based consensus on the best peri-transplantation approach to reduce subsequent CNS relapse risk. Here, we retrospectively analyzed outcomes of 87 patients with ALL and a history of CNS involvement who later underwent alloHCT. Patients with pretransplantation CNS involvement had higher risk of CNS relapse after transplantation (2-year CNS relapse: 9.6% versus 1.4%, P < .0001), inferior event-free survival (EFS) (hazard ratio [HR], 1.52; P = .003), and worse overall survival (OS) (HR, 1.55; P = .003) compared with patients without pretransplantation CNS involvement (n = 543). There was no difference in post transplantation CNS relapse, EFS, or OS among patients presenting with CNS involvement at diagnosis, those with isolated CNS relapse, and those with combined bone marrow and CNS relapse before HCT. Interestingly, neither pretransplantation cranial irradiation, use of total body irradiation-based conditioning, nor post-transplantation prophylactic intrathecal chemotherapy were associated with a reduction of CNS relapse risk after transplantation. Thus, among the patients in the cohort studied, there was no clear benefit of CNS directed therapy in the peri-transplantation period among patients who had prior CNS involvement and underwent subsequent alloHCT. PMID- 26493563 TI - Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors. AB - The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (P = .03), dynamic international prognostic scoring system score (P = .003), and donor type (P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose >=6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation. PMID- 26493566 TI - A tribute to Massimo Gallucci. PMID- 26493565 TI - Comparison of pain neurophysiology knowledge among health sciences students: a cross-sectional study. AB - BACKGROUND: A key tool for use in approaching chronic pain treatment is educating patients to reconceptualize pain. Thus, health professionals are fundamental to the transmission of pain information to patients. Because their understanding of pain is acquired during the educational process, the aim of this study was to compare the knowledge about pain neurophysiology in first and final-year students from three different health science programs at a single University to determine their gain in knowledge using a well-known questionnaire designed to evaluate the understanding of pain. METHODS: The Neurophysiology of Pain Questionnaire (19 closed-ended questions) was administered to students in their first and final years of study in Medicine, Physiotherapy, or Nutrition. The percentage of correct responses was determined and comparisons of the results were analyzed between the programs as well as between the first and final years of study within each program. For all tests, p-values were two-sided, and results with p-values below 0.05 were considered statistically significant. RESULTS: The participation rate was greater than 51% (n = 285). The mean percentage of correct responses, reported as mean (SD), among the first year students was 42.14 (12.23), without significant statistical differences detected between the programs. The mean percentages of correct responses for students in their final year were as follows: Medicine, 54.38 (13.87); Physiotherapy, 68.92 (16.22); Nutrition, 42.34 (10.11). We found statistically significant differences among all three programs and between the first and final years in Medicine and Physiotherapy. A question by-question analysis showed that the percentage of correct responses for questions related to the biopsychosocial aspects of pain was higher for students in Physiotherapy than those in Medicine. CONCLUSIONS: Students in their final years of Medicine and Physiotherapy programs know more about the neurophysiology of pain than students in their first years of these programs, however there are some questions where first years students have better results. Physiotherapy students have greater knowledge of neurophysiology of pain than Medicine students, especially the biopsychosocial aspects. Even so, their understanding may not be sufficient and does not guarantee an approach to chronic pain that will help patients reconceptualize their pain. PMID- 26493567 TI - Contingency management effects on delay discounting among patients receiving smoking cessation treatment. AB - BACKGROUND: Increasing evidence suggests that delay discounting may change following effective interventions. Nonetheless, previous studies that assessed the effect of contingency management (CM) on delay discounting are scarce, and their results are mixed. The current study assessed whether CM in conjunction with a cognitive-behavioral treatment (CBT) for smoking cessation was associated with changes in delay discounting at end-of-treatment and at 6-month follow-up compared to CBT alone. METHOD: One hundred and sixteen treatment-seeking smokers were randomly assigned either to CM + CBT (n = 69) or to CBT alone (n = 47). Participants completed delay discounting assessments at the intake, at end-of treatment, and at 6-month follow-up. We evaluated CM’s effect on discounting with parametric and nonparametric methods. RESULTS: Between-group analyses showed that none of the interventions changed delay discounting from intake to end-of-treatment or to 6-month follow-up. Nonetheless, some within group analyses showed that the CM + CBT condition evidenced some degree of reduction. CONCLUSIONS: The current results suggest that CM intervention is not robustly associated with delay discounting changes. Future studies should address treatments that may potentially change delay discounting. PMID- 26493568 TI - [2013 research ranking of Spanish public universities]. AB - BACKGROUND: The evaluation of research production and productivity is becoming increasingly necessary for universities. Having reliable and clear data is extremely useful in order to uncover strengths and weaknesses. The objective of this article is to update the research ranking of Spanish public universities with the 2013 data. METHOD: Assessment was carried out based on articles in journals indexed in the JCR, research periods, R+D projects, doctoral theses, FPU grants, doctoral studies awarded with a citation of excellence, and patents, providing a rating, both for each individual indicator and globally, in production and productivity. The same methodology as previous editions was followed. RESULTS: In the global ranking, the universities with a higher production are Barcelona, Complutense of Madrid, and Granada. In productivity, the first positions are held by the universities Pompeu Fabra, Pablo de Olavide, and the Autonomous University of Barcelona. CONCLUSIONS: Differences can be found between the universities in production and productivity, while there are also certain similarities with regard to the position of Spanish universities in international rankings. PMID- 26493569 TI - Justification beliefs of violence, myths about love and cyber dating abuse. AB - BACKGROUND: Distorted beliefs about violence and love are often associated with the presence of violence in dating relationships. This study analyzes the relationship between beliefs that justify violence and myths about love in two types of cyber dating abuse (control and direct aggression). METHOD: The sample consisted of 656 young people between the ages of 18 and 30 years (79.5% women). RESULTS: Regression analysis showed that justification of cyber dating abuse was significantly associated with a higher likelihood of direct aggression in online dating relationships. Myths about love were associated with a greater likelihood of control in online dating relationships. Furthermore, the relationship between justification of cyber dating abuse and perpetration of direct aggression was stronger in women. The relationship between myths about love and perpetration of online control was stronger among the youngest individuals. CONCLUSION: The justification of abuse and myths about love are important aspects in the development of different kinds of online abuse among young couples. This finding has important implications for the prevention of and intervention in these behaviors. PMID- 26493570 TI - Predicting approach to homework in Primary school students. AB - BACKGROUND: The goal of this research was to study the weight of student variables related to homework (intrinsic homework motivation, perceived homework instrumentality, homework attitude, time spent on homework, and homework time management) and context (teacher feedback on homework and parental homework support) in the prediction of approaches to homework. METHOD: 535 students of the last three courses of primary education participated in the study. Data were analyzed with hierarchical regression models and path analysis. RESULTS: The results obtained suggest that students’ homework engagement (high or low) is related to students´ level of intrinsic motivation and positive attitude towards homework. Furthermore, it was also observed that students who manage their homework time well (and not necessarily those who spend more time) are more likely to show the deepest approach to homework. CONCLUSIONS: Parental support and teacher feedback on homework affect student homework engagement through their effect on the levels of intrinsic homework motivation (directly), and on homework attitude, homework time management, and perceived homework instrumentality (indirectly). Data also indicated a strong and significant relationship between parental and teacher involvement. PMID- 26493571 TI - Adaptation of the Evidence-Based Practices Attitude Scale in Spanish child welfare professionals. AB - BACKGROUND: Implementation of evidence-based practices (EBPs) into real-world settings represents an organizational change that may be limited or facilitated by provider attitudes towards the adoption of new interventions and practices. The objective of the present study was to analyze psychometric properties of the Evidence Based Practices Attitude Scale (EBPAS) Spanish version in Child Welfare professionals. METHOD: The EBPAS 50-item version was administered to a sample of professionals (N = 240) providing services to children/adolescents and their families in Child Welfare Services from three Spanish regions. RESULTS: Most of the dimensions measured by the EBPAS (50 items) were confirmed in the Spanish version administrated to Child Welfare professionals. Internal consistency reliabilities were fair to excellent. Provider attitudes varied by professional discipline and organizational context. CONCLUSIONS: The EBPAS Spanish version is an adequate instrument to be used as a measure of attitudes toward implementation of evidence-based practices. PMID- 26493572 TI - Explicative factors of face-to-face harassment and cyberbullying in a sample of primary students. AB - BACKGROUND: Research has shown that there is a co-occurrence between bullying and cyberbullying in relation to certain variables that describe and explain them. The present study aims to examine the differential influence of individual and contextual variables on perception of the role played in the involvement in both phenomena. METHOD: Participants were 1278 schoolchildren (47.7 % girls) of primary education, aged 10 to 14 years ( M =11.11, SD = 0.75). RESULTS: Logistic regression analysis indicated that social adjustment, normative adjustment, disruptiveness, gender, and self-esteem explain a substantial part of the involvement in both violent phenomena as victims, aggressors, and bully/victims. CONCLUSIONS: The results are discussed regarding the weight that must attributed to individual versus contextual factors, concluding that the explicative weight of the immediate social elements and educational context may make the difference. PMID- 26493573 TI - Assessing teamwork competence. AB - BACKGROUND: In recent years, organizations of all types have undergone major changes, and teamwork is one of them. This way of working generates greater profits for an organization. This article aims to assess the teamwork competence of the employees of various Spanish companies in order to determine how effective the team members are in their professional actions. METHOD: We contacted 55 teams from different organizations and obtained a non-probabilistic sample comprised of 55 participants (subjects tested) and 218 observers (evaluators: coordinators and co-workers). The instrument used for data collection was the Teamwork Rubric (Torrelles, 2011) and data analysis was based on 360o feedback. RESULTS: 80% of the teams analyzed obtained median scores for teamwork competence that were greater than 3, whereas 20% obtained scores between 2 and 3. CONCLUSIONS: The results showed that the workers in the companies studied had not fully acquired teamwork competence. It is necessary to find training solutions to improve their level of acquisition, particularly the dimensions of performance and regulation. PMID- 26493574 TI - An overall decline both in recollection and familiarity in healthy aging. AB - BACKGROUND: In the area of recognition memory, the experimental data have been inconsistent about whether or not familiarity declines in healthy aging. A recent meta-analysis concluded that familiarity is impaired when estimated with the remember-know procedure, but not with the process-dissociation procedure. METHOD: We present an associative recognition experiment with remember-know judgments that allow us to estimate both recollection and familiarity using both procedures in the same task and with the same participants (a sample of healthy older people and another sample of young people). Moreover, we performed a within-subjects manipulation of the type of materials (pairs of words or pairs of pictures), and the repetition or not of the pairs during the study phase. RESULTS: The results show that familiarity, estimated using both estimation procedures, declines significantly with age, although the effect size obtained with the process dissociation procedure is significantly smaller than the one obtained with the remember-know procedure. CONCLUSIONS: Our results show that aging is associated with significant decreases both in recollection and, to a lesser extent, familiarity. PMID- 26493575 TI - Enhancing emotion-based learning in decision-making under uncertainty. AB - BACKGROUND: The Iowa Gambling Task (IGT) is widely used to study decision-making differences between several clinical and healthy populations. Unlike the healthy participants, clinical participants have difficulty choosing between advantageous options, which yield long-term benefits, and disadvantageous options, which give high immediate rewards but lead to negative profits. However, recent studies have found that healthy participants avoid the options with a higher frequency of losses regardless of whether or not they are profitable in the long run. The aim of this study was to control for the confounding effect of the frequency of losses between options to improve the performance of healthy participants on the IGT. METHOD: Eighty healthy participants were randomly assigned to the original IGT or a modified version of the IGT that diminished the gap in the frequency of losses between options. RESULTS: The participants who used the modified IGT version learned to make better decisions based on long-term profit, as indicated by an earlier ability to discriminate good from bad options, and took less time to make their choices. CONCLUSIONS: This research represents an advance in the study of decision making under uncertainty by showing that emotion-based learning is improved by controlling for the loss-frequency bias effect. PMID- 26493576 TI - Factors involved in making post-performance judgments in mathematics problem solving. AB - BACKGROUND: This study examines the impact of executive functions, affective motivational variables related to mathematics, mathematics achievement and task characteristics on fifth and sixth graders’ calibration accuracy after completing two mathematical problems. METHOD: A sample of 188 students took part in the study. They were divided into two groups as function of their judgment accuracy after completing the two tasks (accurate= 79, inaccurate= 109). Differences between these groups were examined. The discriminative value of these variables to predict group membership was analyzed, as well as the effect of age, gender, and grade level. RESULTS: The results indicated that accurate students showed better levels of executive functioning, and more positive feelings, beliefs, and motivation related to mathematics. They also spent more time on the tasks. Mathematics achievement, perceived usefulness of mathematics, and time spent on Task 1 significantly predicted group membership, classifying 71.3% of the sample correctly. CONCLUSIONS: These results support the relationship between academic achievement and calibration accuracy, suggesting the need to consider a wide range of factors when explaining performance judgments. PMID- 26493577 TI - Gender and cultural effects on perception of psychological violence in the partner. AB - BACKGROUND: Studies reporting similar figures of couple (man-woman) violence and works questioning the validity of the instruments employed have generated controversy about the conceptualization of this construct. One of the critical issues is the different ways of perceiving violence between men and women, as well as its nature in the cultural context. This may affect self-reported answers. METHOD: A questionnaire evaluating the degree of violence perceived in ten kinds of psychological partner abuse was applied. 1750 students from Spain and Mexico, all of them randomly selected, completed it. RESULTS: Through MANOVA, greater perception of violence in the Spanish sample than in the Mexican one was obtained; in both countries, there was a greater perception in women than in men. Effects of gender-culture interaction were obtained in four dimensions: Isolation, Sexual Pressure, Emotional Manipulation, and Dominance. Multidimensional scaling showed two perceived dimensions: (1) "Proactive-Passive Tactics", stronger in the Spanish culture and (2) "Punitive-Emotional Tactics", stronger in the Mexican culture. CONCLUSIONS: These results confirm gender culture effects in perception of psychological violence in the partner. PMID- 26493578 TI - Guidelines based on validity criteria for the development of multiple choice items. AB - BACKGROUND: Many different guidelines have been presented for the construction of multiple choice items. Those guidelines have been based on the observation of errors when constructing items but not on any clear scientific criterion. Our main objective was to draw up guidelines for the development of multiple choice items based on validity criteria. METHOD: We used the properties of adjustment, precision, and differentiation, applying them to three basic phases of instrument construction: the definition of the objective and its context; their expression in the instrument and item stem; and the elaboration of response options. RESULTS: We have combined these properties and phases to give nine general guidelines with a firm theoretical footing. CONCLUSIONS: Finally, we have written a checklist with twenty-four points to check how far the measurement instruments comply with the proposed guidelines. PMID- 26493579 TI - Psychometric evaluation of the Self-Appraisal Questionnaire in a Spanish sample of offenders. AB - BACKGROUND: The Self-Appraisal Questionnaire (SAQ) is a self-report instrument designed to predict recidivism among adult criminal offenders. The aim of this study was to evaluate the psychometric properties of this self-report in a Spanish sample of offenders. METHOD: The questionnaire was administered to 276 offenders recruited from various prisons in Madrid (Spain). RESULTS: Confirmatory factor analyses showed that the underlying structure of SAQ was best explained by a one-factor solution. SAQ total scores exhibited high levels of internal consistency (.92). Correlations of the instrument with violence risk measures were statistically significant and had a moderate magnitude, indicating a reasonable degree of concurrent validity. CONCLUSIONS: After examination of its psychometric properties, it was concluded that the SAQ total score is a reliable and valid measure to estimate violence risk in Spanish offenders. PMID- 26493580 TI - Psychometric properties of the Spanish version of the Passion Scale. AB - BACKGROUND: Passion has been shown to be involved in psychological processes that emerge in diverse human activities like physical activity and sports, work, leisure, videogaming, pathological gambling, and interpersonal relationships. We aimed to present evidence of validity and internal consistency of the Passion Scale in Spanish based on the Dualistic Model of Passion, comprising harmonious and obsessive dimensions. METHOD: The sample comprised 1,007 participants (350 females and 657 males), aged 16-65 (Md= 30.0 years). Exploratory Structural Equation Modeling (ESEM), measurement invariance and Multiple-Cause-Multiple Indicator models (MIMIC) were used. RESULTS: Fit for the ESEM 2-factor solution was acceptable. Near full or partial measurement invariance across sex, type of activity, and age was supported. Relationships between both harmonious and obsessive dimensions and the external variables considered (age, sex, and criterion items) reasonably replicated those found in previous studies. Both scale scores showed adequate internal consistency (α = .81). CONCLUSIONS: Empirical evidence for the validity and internal consistency of the Spanish version of the Passion Scale is satisfactory and reveals that the scale is comparable to the English and French versions. Therefore, the Passion Scale can be used in research conducted in Spanish. PMID- 26493581 TI - Validation of the General Self-Efficacy Scale in psychiatric outpatient care. AB - BACKGROUND: Self-efficacy has been used to explain and predict human characteristics in different domains, including health behavior. The aim of this paper is to study the internal consistency, components, and convergent validity of the Spanish version of the General Self-Efficacy Scale (GSE) in psychiatric outpatients. METHODS: A convenience sample of 966 consecutive psychiatric out patients completed in 2014 the Spanish versions of the General Self-Efficacy Scale (GSE), Form C of the Multidimensional Health Locus of Control Scale (MHLC C), the Hong Psychological Reactance Scale (HPRS), the Drug Attitude Inventory (DAI-10), and a questionnaire including socio-demographic and clinical variables. RESULTS: The GSE scale attained high internal consistency. Principal component analysis produced a general one-component solution. This structure accounted for more than 50% of the common variance. Further analyses yielded significant results with health locus of control dimensions, attitudes toward psychiatric treatment, age, and affective psychological reactance, but not with other socio demographic or clinical variables. CONCLUSIONS: The structure of the General Self efficacy Scale is unidimensional, homogenous and positively related to the constructs examined. The scale is a reliable and valid measure of the perception of self-efficacy in psychiatric outpatient care. PMID- 26493582 TI - Further validity evidence of the Behavioral Inhibition Observation System (BIOS). AB - BACKGROUND: The Behavioral Inhibition Observation System (BIOS) is a brief clinician-report scale for detecting behavioral inhibition (BI) from direct observation. This study aims to compare the validity coefficients obtained in the natural context of use of the BIOS (i.e., a clinical situation) with those obtained using the BIOS after standardized observation. METHOD: The participants were 74 randomly selected preschool children who were exposed to systematic observation. RESULTS: The results indicate excellent internal consistency (alpha = .91) and moderate to good inter-rater reliability for all items (ICC from .55 to .88). The correlations with observational measures of BI ranged from .40 to .70, and were mostly equivalent to those of the previous study. The correlations with parents', teachers', and clinicians' measures of BI and related constructs ranged from .30 to .60, and were also equivalent to those obtained in the natural context of use of the BIOS (i.e., clinical situation). CONCLUSIONS: The validity coefficients obtained with the BIOS in a non-structured natural observation are mostly equivalent to those obtained in an experimental situation, thus supporting that the BIOS is a cost-efficient instrument for measuring BI from observation in a clinical situation. PMID- 26493583 TI - Cooperative Self-Assembly Transfer from Hierarchical Supramolecular Polymers to Gold Nanoparticles. AB - The transfer of information encoded by molecular subcomponents is a key phenomenon that regulates the biological inheritance in living organisms, yet there is a lack of understanding of related transfer mechanisms at the supramolecular level in artificial multicomponent systems. Our contribution to tackle this challenge has focused on the design of a thiolated pi-conjugated linking unit, whose hierarchical, cooperative self-assembly in nonpolar media can be efficiently transferred from the molecular to the nanoscopic level, thereby enabling the reversible self-assembly of gold nanoparticle (AuNP) clusters. The transfer of supramolecular information by the linking pi-system can only take place when a specific cooperative nucleation-elongation mechanism is operative, whereas low-ordered noncooperative assemblies formed below a critical concentration do not suffice to extend the order to the AuNP level. To the best of our knowledge, our approach has allowed for the first time a deep analysis of the hierarchy levels and thermodynamics involved in the self-assembly of AuNPs. PMID- 26493585 TI - Quantitative aspects of drug permeation across in vitro and in vivo barriers. AB - The kinetics of permeation across epithelial and endothelial cell sheets and across cell membranes is determinant for the pharmacokinetics of a drug. In vitro transport experiments with cultured cells or artificial barriers have tremendously improved the predictability of the in vivo behaviour of tested compounds. This article focuses on the parameters and calculation methods that are used to describe permeation quantitatively, with a focus on in vitro experiments and the prediction of intestinal absorption and blood-brain barrier passage. It shows under which in vitro experimental conditions standard calculations are adequate and under which conditions equations should be adapted to the experimental details. The impact of volume differences between donor and receiver compartments, pH gradients, addition of albumin, accumulation in the barrier and unidirectional transport by an efflux transporter on the results is shown in simulations. The article should make researchers aware of experimental factors that affect the outcome of a permeation experiment and how to account for this during data analysis. Finally, strategies to predict the in vivo behaviour of a compound based on the in vitro data are discussed. The goal of the article is to support researchers in choosing experimental conditions and calculation methods that deliver appropriate and reproducible results in permeation studies in vitro. PMID- 26493584 TI - Licensing failure in the European decentralised procedure. AB - The majority of the licensing applications in the European Union are submitted via the decentralised procedure. Little is known about licensing failure (i.e. refusal or withdrawal of a marketing authorisation application) in the EU decentralised procedure compared to the EU centralised procedure and the approval procedure in the United States. The study aim was to determine the frequency of and determinants for licensing failure of marketing authorisation applications submitted via this procedure. We assessed procedures that failed between 2008 and 2012 with The Netherlands as leading authority and assessed the remaining major objections. In total 492 procedures were completed, of which 48 (9.8%) failed: 8 refused, 40 withdrawn. A wide variety of major objections was identified and included both quality (48 major objections) and clinical (45 major objections) issues. The low failure rate may be related to the regular interaction between competent authorities and applicants during the procedure. Some degree of licensing failure may be inevitable, as it may also be affected by the financial feasibility or willingness to resolve major objections, as well as other reasons to withdraw an application besides the raised major objections. PMID- 26493586 TI - Mitigating unwanted amorphisation: A screening method for the selection of suitable excipients. AB - Co-processing an active pharmaceutical ingredient (API) with a low Tg excipient has been previously reported to be an effective strategy for preventing drug amorphisation on milling. This technique relies on the ability of the excipient to form a molecular dispersion with the amorphous API during the milling process. The presence of the excipient within the amorphous phase induces a reduction of the Tg. Hence, the molecular dispersion becomes less stable than the amorphous API alone and recrystallises upon milling. The objective of this study was to develop a screening method for the selection of suitable excipients to prevent amorphisation, based on two criteria: the Tg of the excipient and the solubility of the excipient in the amorphous API. The ability of the excipients to induce Tg reduction was first assessed by measuring the Tg of the amorphous composite by thermal analysis and comparing it with that of the pure API (griseofulvin). A predicted ability for mitigation of amorphisation upon milling was then deduced from these observations for each excipient and assessed against experimental results. The same excipients were then studied with regard to their expected solubility in another amorphous API (budesonide) by Hildebrand solubility parameter calculations in order to evaluate their capacity to form an amorphous composite with the drug. The predicted effects of the excipients on comilling were compared with the amorphous content of the processed API. The screening method as applied to both APIs showed good agreement with the experimental results and were shown to be efficient for the selection of the most appropriate excipient. This approach revealed that the two key parameters involved are the Tg of the excipient and the ability of the API to form an amorphous molecular dispersion with the excipients. This work confirms and completes our previously published results on the mitigation of the amorphisation by comilling with low Tg excipients and constitutes the first report of the use of a polymeric additive for this purpose. PMID- 26493587 TI - A comprehensive Candida albicans PeptideAtlas build enables deep proteome coverage. AB - To provide new and expanded proteome documentation of the opportunistically pathogen Candida albicans, we have developed new protein extraction and analysis routines to provide a new, extended and enhanced version of the C. albicans PeptideAtlas. Two new datasets, resulting from experiments consisting of exhaustive subcellular fractionations and different growing conditions, plus two additional datasets from previous experiments on the surface and the secreted proteomes, have been incorporated to increase the coverage of the proteome. High resolution precursor mass spectrometry (MS) and ion trap tandem MS spectra were analyzed with three different search engines using a database containing allele specific sequences. This approach, novel for a large-scale C. albicans proteomics project, was combined with the post-processing and filtering implemented in the Trans Proteomic Pipeline consistently used in the PeptideAtlas project and resulted in 49,372 additional peptides (3-fold increase) and 1630 more proteins (1.6-fold increase) identified in the new C. albicans PeptideAtlas with respect to the previous build. A total of 71,310 peptides and 4174 canonical (minimal non redundant set) proteins (4115 if one protein per pair of alleles is considered) were identified representing 66% of the 6218 proteins in the predicted proteome. This makes the new PeptideAtlas build the most comprehensive C. albicans proteomics resource available and the only large-scale one with detections of individual alleles. PMID- 26493588 TI - Bevacizumab and Combination Chemotherapy in rectal cancer Until Surgery (BACCHUS): a phase II, multicentre, open-label, randomised study of neoadjuvant chemotherapy alone in patients with high-risk cancer of the rectum. AB - BACKGROUND: In locally advanced rectal cancer (LARC) preoperative chemoradiation (CRT) is the standard of care, but the risk of local recurrence is low with good quality total mesorectal excision (TME), although many still develop metastatic disease. Current challenges in treating rectal cancer include the development of effective organ-preserving approaches and the prevention of subsequent metastatic disease. Neoadjuvant systemic chemotherapy (NACT) alone may reduce local and systemic recurrences, and may be more effective than postoperative treatments which often have poor compliance. Investigation of intensified NACT is warranted to improve outcomes for patients with LARC. The objective is to evaluate feasibility and efficacy of a four-drug regimen containing bevacizumab prior to surgical resection. METHODS/DESIGN: This is a multi-centre, randomized phase II trial. Eligible patients must have histologically confirmed LARC with distal part of the tumour 4-12 cm from anal verge, no metastases, and poor prognostic features on pelvic MRI. Sixty patients will be randomly assigned in a 1:1 ratio to receive folinic acid + flurourcil + oxaliplatin (FOLFOX) + bevacizumab (BVZ) or FOLFOX + irinotecan (FOLFOXIRI) + BVZ, given in 2 weekly cycles for up to 6 cycles prior to TME. Patients stop treatment if they fail to respond after 3 cycles (defined as >= 30 % decrease in Standardised Uptake Value (SUV) compared to baseline PET/CT). The primary endpoint is pathological complete response rate. Secondary endpoints include objective response rate, MRI tumour regression grade, involved circumferential resection margin rate, T and N stage downstaging, progression-free survival, disease-free survival, overall survival, local control, 1-year colostomy rate, acute toxicity, compliance to chemotherapy. DISCUSSION: In LARC, a neoadjuvant chemotherapy regimen - if feasible, effective and tolerable would be suitable for testing as the novel arm against the current standards of short course preoperative radiotherapy (SCPRT) and/or fluorouracil (5FU)-based CRT in a future randomised phase III trial. TRIAL REGISTRATION: Clinical trial identifier BACCHUS: NCT01650428. PMID- 26493590 TI - Information about Sexual Health on Crisis Pregnancy Center Web Sites: Accurate for Adolescents? AB - STUDY OBJECTIVE: The objective of this study was to evaluate the quality and accuracy of sexual health information on crisis pregnancy center Web sites listed in state resource directories for pregnant women, and whether these Web sites specifically target adolescents. DESIGN: A survey of sexual health information presented on the Web sites of crisis pregnancy centers. SETTING: Internet. PARTICIPANTS: Crisis pregnancy center Web sites. INTERVENTIONS: Evaluation of the sexual health information presented on crisis pregnancy center Web sites. MAIN OUTCOME MEASURES: Themes included statements that condoms are not effective, promotion of abstinence-only education, availability of comprehensive sexual education, appeal to a young audience, provision of comprehensive sexual health information, and information about sexually transmitted infections (STIs). RESULTS AND CONCLUSION: Crisis pregnancy center Web sites provide inaccurate and misleading information about condoms, STIs, and methods to prevent STI transmission. This information might be particularly harmful to adolescents, who might be unable to discern the quality of sexual health information on crisis pregnancy center Web sites. Listing crisis pregnancy centers in state resource directories might lend legitimacy to the information on these Web sites. States should be discouraged from listing Web sites as an accurate source of information in their resource directories. PMID- 26493589 TI - Precision of spinal radiographs as a screening test for intervertebral disc calcification in Dachshunds. AB - Among dog breeds, the Dachshund has the highest lifetime incidence of intervertebral disc disease (IVDD). Intervertebral disc (IVD) calcification is an indicator of severe degeneration that predisposes to disc herniation. IVDD is heritable in Dachshunds, and in some countries, breeding candidates are screened to reduce IVDD occurrence by selecting dogs according to their score of radiographically detectable intervertebral disc calcification (RDIDC) and excluding dogs with >=5 RDIDCs from breeding. This study evaluated the precision of scoring spinal radiographs for IVD calcification and subsequent classification of Dachshund dogs for breeding based on their RDIDC score. Digital radiographs of the spine were obtained in 19 clinically healthy, young adult Dachshunds, and scored for RDIDC independently by five scorers with varying levels of experience, three times each. Within scorer (repeatability) and between scorer (reproducibility) variability was estimated both at the individual IVD level and at the whole dog level for breeding classification purposes. At the IVD level, some degree of scorer effect was supported by the pairwise repeatability (92.3%; 95% CI: 88.8-94.7%) being marginally higher than the reproducibility (89.2%; 95% CI: 85.7-91.8%). Scorer-specific patterns confirmed the presence of scorer subjectivity. Repeatability significantly increased with scorer experience but the reproducibility did not. RDIDC scoring repeatability and reproducibility substantially decreased at the cervicothoracic spine region, likely due to anatomical superimpositions. At the dog level, a breeding classification could be repeated by the same scorer for 83.6% (95% CI: 73.8-90.2%) of the dogs, and was reproduced between two scorers for 80.2% (95% CI: 66.6-89.1%) of the dogs. The repeatability of breeding classification also seemed to increase with scorer experience but not the reproducibility. Overall, RDIDC scoring revealed some degree of inconsistency explained by scorer subjectivity and inexperience, and anatomical superimpositions. Scorer training and experience is strongly recommended to improve test precision and ensure appropriate classification of Dachshunds for breeding. PMID- 26493591 TI - Systematic Review of Inspiratory Muscle Training After Cerebrovascular Accident. AB - This systematic review examines levels of evidence and recommendation grades of various therapeutic interventions of inspiratory muscle training in people who have had a stroke. Benefits from different levels of force and resistance in respiratory muscles are shown in this population. This review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses) directives and was completed in November 2014. The search limits were studies published in English between 2004 and 2014. Relevant studies were searched for in MEDLINE, PEDro, OAIster, Scopus, PsycINFO, Web of Knowledge, CINAHL, SPORTDiscus, DOAJ, Cochrane, Embase, Academic Search Complete, Fuente Academica, and MedicLatina. Initially, 20 articles were identified. After analyzing all primary documents, 14 studies were excluded. Only 6 studies were relevant to this review. Three different types of interventions were found (maximum inspiratory training, controlled training, and nonintervention) in 3 different groups. One specific study compared 3 inspiratory muscle training groups with a group of breathing exercises (diaphragmatic exercises with pursed lips) and a control group. Future long-term studies with larger sample sizes are needed. It is necessary to apply respiratory muscle training as a service of the national health system and to consider its inclusion in the conventional neurological program. PMID- 26493592 TI - A Comprehensive Review of Prone Position in ARDS. AB - Prone position (PP) has been used since the 1970s to treat severe hypoxemia in patients with ARDS because of its effectiveness at improving gas exchange. Compared with the supine position (SP), placing patients in PP effects a more even tidal volume distribution, in part, by reversing the vertical pleural pressure gradient, which becomes more negative in the dorsal regions. PP also improves resting lung volume in the dorsocaudal regions by reducing the superimposed pressure of both the heart and the abdomen. In contrast, pulmonary perfusion remains preferentially distributed to the dorsal lung regions, thus improving overall alveolar ventilation/perfusion relationships. Moreover, the larger tissue mass suspended from a wider dorsal chest wall effects a more homogeneous distribution of pleural pressures throughout the lung that reduces abnormal strain and stress development. This is believed to ameliorate the severity or development of ventilator-induced lung injury and may partly explain why PP reduces mortality in severe ARDS. Over 40 years of clinical trials have consistently reported improved oxygenation in approximately 70% of subjects with ARDS. Early initiation of PP is more likely to improve oxygenation than initiation during the subacute phase. Maximal oxygenation improvement occurs over a wide time frame ranging from several hours to several days. Meta-analyses of randomized controlled trials suggest that PP provides a survival advantage only in patients with relatively severe ARDS (PaO2 /FIO2 < 150 mm Hg). Moreover, survival is enhanced when patients are managed with a smaller tidal volume (<= 8 mL/kg), higher PEEP (10-13 cm H2O), and longer duration of PP sessions (> 10-12 h/session). Combining adjunctive therapies (high PEEP, recruitment maneuvers, and inhaled vasodilators) with PP has an additive effect in improving oxygenation and may be particularly helpful in stabilizing gas exchange in very severe ARDS. PMID- 26493593 TI - Recruitment Maneuvers and PEEP Titration. AB - The injurious effects of alveolar overdistention are well accepted, and there is little debate regarding the importance of pressure and volume limitation during mechanical ventilation. The role of recruitment maneuvers is more controversial. Alveolar recruitment is desirable if it can be achieved, but the potential for recruitment is variable among patients with ARDS. A stepwise recruitment maneuver, similar to an incremental PEEP titration, is favored over sustained inflation recruitment maneuvers. Many approaches to PEEP titration have been proposed, and the best method to choose the most appropriate level for an individual patient is unclear. A PEEP level should be selected that balances alveolar recruitment against overdistention. The easiest approach to select PEEP might be according to the severity of the disease: 5-10 cm H2O PEEP in mild ARDS, 10-15 cm H2O PEEP in moderate ARDS, and 15-20 cm H2O PEEP in severe ARDS. Recruitment maneuvers and PEEP should be used within the context of lung protection and not just as a means of improving oxygenation. PMID- 26493594 TI - Why Use Anything But a Standard Spontaneous Breathing Trial to Determine Readiness for Ventilator Discontinuation? PMID- 26493595 TI - Noninvasive Ventilatory Support: The Detail Lies in the Interface. PMID- 26493596 TI - Capnography: A Feasible Tool in Clinical and Experimental Settings. PMID- 26493599 TI - Empagliflozin in diabetes: A therapeutic light at the end of the cardiovascular tunnel? PMID- 26493598 TI - High metallothionein predicts poor survival in glioblastoma multiforme. AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor. Even with vigorous surgery, radiation and chemotherapy treatment, survival rates of GBM are very poor and predictive markers for prognosis are currently lacking. METHODS: We performed whole genome expression studies of 67 fresh frozen untreated GBM tumors and validated results by 210 GBM samples' expression data from The Cancer Genome Atlas. RESULTS AND DISCUSSION: Here we show that in GBM patients, high metallothionein (MT) expression is associated with poor survival whereas low MT levels correspond to good prognosis. Furthermore we show that in U87 GBM cell line, p53 is found to be in an inactive mutant-like conformation concurrently with more than 4 times higher MT3 expression level than normal astrocytes and U251GBM cell line. We then show that U87- p53 inactivity can be rescued by zinc (Zn). CONCLUSIONS: Taken together, these data suggest that MT expression may be a potential novel prognostic biomarker for GBM, and that U87 cells may be a good model for patients with non active WT p53 resulting from high levels of MTs. PMID- 26493600 TI - Seven days in medicine: 17-23 October. PMID- 26493602 TI - Is Breast-conserving Therapy Really a Good Option for BRCA1/2 Mutation Carriers? PMID- 26493601 TI - The Sensitivity to Change and Responsiveness of the Adult Responses to Children's Symptoms in Children and Adolescents With Chronic Pain. AB - OBJECTIVE: To examine the sensitivity to change and responsiveness of the Adult Responses to Children's Symptoms (ARCS) among parents of youth with chronic pain. METHODS: Participants included 330 youth (89 children aged 7-11 years, 241 children aged 12-17 years) and their parents who participated in randomized controlled trials of family-based cognitive-behavioral therapy for chronic pain. Child pain and disability, parental emotional functioning, and parental responses to child pain were assessed at baseline and posttreatment. RESULTS: The Protect and Monitor scales of the ARCS were sensitive to change following intervention for both developmental groups, with clinically meaningful reductions in these behaviors, thereby demonstrating responsiveness. Among the adolescent sample, greater change on some ARCS scales was associated with better parental emotional functioning and lower child pain at posttreatment. CONCLUSIONS: Findings support the sensitivity to change and responsiveness of the Protect and Monitor scales among parents of youth with chronic pain. PMID- 26493603 TI - Thrombin generation and international normalized ratio in inherited thrombophilia patients receiving thromboprophylactic therapy. AB - BACKGROUND: Thrombin generation assay (TGA) is useful as a global functional test for assessing bleeding or thrombotic risk and its modification with therapy. We investigated TGA to assess anticoagulation status compared with the international normalized ratio (INR) system in patients with primary thrombophilia receiving and not undergoing thromboprophylaxis. MATERIALS AND METHODS: We studied 50 patients with at least one thrombotic event and a confirmed diagnosis of inherited thrombophilia. Thrombin generation was measured in platelet-poor plasma by calibrated automated thrombography (CAT). RESULTS: Patients in optimal anticoagulation (INR: 2.0-3.0) showed an endogenous thrombin potential (ETP) of 14-56% of normal and a peak of 18-55% of normal. A significant inverse relationship between INR and thrombin generation parameters (ETP, peak and velocity index) and a linear correlation for lag time was found in patients treated with vitamin-K antagonists (VKA). Receiver-operating characteristics (ROC) analysis showed that the optimal cutoff for ETP was 1600.2 nM . min (111.6% of normal, with a sensitivity of 96.6% and a specificity of 92.9%) and for the peak was 298.3 nM (112.1% of normal, with a sensitivity of 96.4% and a specificity of 100%). According to this analysis, ETP was able to identify patients with increased thrombotic and hemorrhagic risk, correlating with severe clinical complications. CONCLUSION: TGA showed excellent sensitivity and specificity for assessing anticoagulation status in patients with primary thrombophilia receiving VKA, with significant advantages with regard to INR. Clinical data strongly support ETP as a valuable indicator of thrombotic or hemorrhagic risk in patients receiving or not receiving thromboprophylaxis. PMID- 26493604 TI - Severe hepatic dysfunction is associated with venous thromboembolic events in phase 1 clinical trials. AB - INTRODUCTION: Venous thromboembolic events (VTEs) are a significant cause of death in patients with cancer. The incidence of VTE is not well characterized in early phase clinical trials of novel antineoplastic agents, or in hepatic dysfunction studies designed for patients with varying degrees of liver test abnormalities. We compared the incidences of VTE in phase 1 clinical trials (P1CTs) and hepatic dysfunction trials (HDCTs) sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) of the United States. MATERIALS & METHODS: We reviewed individual patient records of 1841 subjects for symptomatic VTE diagnosed while on study: 1328 subjects on 42 P1CTs, and 513 subjects on 9 HDCTs. The NCI's Organ Dysfunction Working Group definitions were used to categorize patients. The incidences of VTEs between patients were compared by the Chi square test. Confounders were evaluated with the Cochran Mantel-Haenszel method. RESULTS & CONCLUSIONS: There were 43 VTEs identified among all subjects (2.3%). There were significantly more VTE observed in the subjects on P1CTs (n=38, 2.9%) than in the subjects on HDCTs (n=5, 1.0%; RR 0.341, 95% 0.13-0.86, p=0.015). For patients on HDCTs, those with severe dysfunction had a high incidence of VTE (RR 10.5 (1.12-93.6), p=0.021) that remained significant in a multivariate model. VTEs were observed less frequently in patients who were enrolled in HDCT than those who were enrolled in P1CT; however, patients with severe hepatic dysfunction were more likely to experience VTE. Severe liver test abnormalities may not be protective against VTE in patients with malignancies receiving chemotherapy. PMID- 26493605 TI - Neuronal-glial populations form functional networks in a biocompatible 3D scaffold. AB - Monolayers of neurons and glia have been employed for decades as tools for the study of cellular physiology and as the basis for a variety of standard toxicological assays. A variety of three dimensional (3D) culture techniques have been developed with the aim to produce cultures that recapitulate desirable features of intact. In this study, we investigated the effect of preparing primary mouse mixed neuron and glial cultures in the inert 3D scaffold, Alvetex. Using planar multielectrode arrays, we compared the spontaneous bioelectrical activity exhibited by neuroglial networks grown in the scaffold with that seen in the same cells prepared as conventional monolayer cultures. Two dimensional (monolayer; 2D) cultures exhibited a significantly higher spike firing rate than that seen in 3D cultures although no difference was seen in total signal power (<50Hz) while pharmacological responsiveness of each culture type to antagonism of GABAAR, NMDAR and AMPAR was highly comparable. Interestingly, correlation of burst events, spike firing and total signal power (<50Hz) revealed that local field potential events were associated with action potential driven bursts as was the case for 2D cultures. Moreover, glial morphology was more physiologically normal in 3D cultures. These results show that 3D culture in inert scaffolds represents a more physiologically normal preparation which has advantages for physiological, pharmacological, toxicological and drug development studies, particularly given the extensive use of such preparations in high throughput and high content systems. PMID- 26493607 TI - Critical role of androgen receptor in the postnatal period in male sexual behavior in rats. AB - Gonadal hormones have a developmental role in organization of the nervous system that regulates sexually dimorphic behavior. It is well known that androgen secreted from testes in the perinatal period is converted to estrogen by aromatase in rodent brain, and that estrogen and its receptor play a pivotal role in masculinization of brain structure and function. Treatment with flutamide, an androgen receptor (AR) antagonist, during the perinatal period inhibits development of malespecific brain structure and function, suggesting that androgen signaling via AR also influences brain masculinization. In this study, we investigated which stage during the postnatal period is critical for androgen signaling in brain masculinization. The postnatal period was designated as postnatal days (PD) 0-22, and divided into stages I (PD 0-7), II (PD 8-14), and III (PD 15-22). Newborn male rats were given flutamide subcutaneously in each stage. After adulthood, the effects of postnatal flutamide treatment on brain masculinization were evaluated byanalysis of male sexual behavior. Continuous inhibition of AR throughout stages I and II caused a robust reduction of the intromission ratio and ejaculation frequency compared with other groups. AR inhibition in stage I, II, or III did not cause any change. AR inhibition had no effect onmount behavior. These results show that stage-specific AR activation in the first two postnatal weeks may contribute to brain masculinization mediating male sexual behavior in adulthood. PMID- 26493606 TI - Fronto-temporal regions encode the manner of motion in spatial language. AB - When describing spatial events, dynamic actions can be decomposed into the path of motion (where the object moves), and the manner of motion (how the object moves). These components may be instantiated in two processing streams in the human brain, wherein dorsal parietal areas process path-related information, while ventral temporal regions process manner information. Previous research showed this pattern during the observation of videos showing animate characters in motion [15]. It is unknown whether reading language describing path and manner information - a level of abstraction beyond the perception of visual motion - relies on similar mechanisms. Here, we use functional neuroimaging to show that the left pMTG processes the manner of motion during reading. We also demonstrate the involvement of other ventral fronto-temporal regions in the understanding of manner of motion in spatial language. PMID- 26493608 TI - The persistent and broadly distributed EEG synchronization might inhibit the normal processing capability of the human brain. AB - Synchrony in the brain functioning describes the mode that the components are interacted and reflect the collective behaviour of neuronal assemblies. Nevertheless, the excessive and prolonged coupling among brain sites is relevant with disturbed information routing. In the present study we investigated the possibility that the sustained oscillatory states and the common mode in which several brain sites vary their functional connectivity inhibit the ability of the brain in perceiving and processing information. The hypothesis, that in many interacting systems, greater regularity-rhythmicity corresponds to grater component self-organization and isolation, is investigated in the case of thought blocks (under persistent auditory verbal hallucinations) and epileptic absences (under spike wave discharges). Our findings indicate that the observed common mode of coupling significantly restrains the normal flow of mental processes. This erroneous "connectivity mode" in the presence of symptoms such as thought blocks and absences respectively, was found to eliminate the spontaneous synchrony variability, essentially needed for the information processing, by fixating the functional specificity of the respected brain sites. PMID- 26493609 TI - Predicting the Movement Speeds of Animals in Natural Environments. AB - An animal's movement speed affects all behaviors and underlies the intensity of an activity, the time it takes to complete it, and the probability of successfully completing it, but which factors determine how fast or slow an animal chooses to move? Despite the critical importance of an animal's choice of speed (hereafter designated as "speed-choice"), we still lack a framework for understanding and predicting how fast animals should move in nature. In this article, we develop a framework for predicting speed that is applicable to any animal-including humans-performing any behavior where choice of speed occurs. To inspire new research in this area, we (1) detail the main factors likely to affect speed-choice, including organismal constraints (i.e., energetic, physiological, and biomechanical) and environmental constraints (i.e., predation intensity and abiotic factors); (2) discuss the value of optimal foraging theory in developing models of speed-choice; and (3) describe how optimality models might be integrated with the range of potential organismal and environmental constraints to predict speed. We show that by utilizing optimality theory it is possible to provide quantitative predictions of optimal speeds across different ecological contexts. However, the usefulness of any predictive models is still entirely dependent on being able to provide relevant mathematical functions to insert into such models. We still lack basic knowledge about how an animal's speed affects its motor control, maneuverability, observational skills, and vulnerability to predators. Studies exploring these gaps in knowledge will help facilitate the field of optimal performance and allow us to adequately parameterize models predicting the speed-choice of animals, which represents one of the most basic of all behavioral decisions. PMID- 26493610 TI - Introduction to the Symposium: Towards a General Framework for Predicting Animal Movement Speeds in Nature. AB - Speed of movement is fundamental to animal behavior-defining the intensity of a task, the time needed to complete it, and the likelihood of success-but how does an animal decide how fast to move? Most studies of animal performance measure maximum capabilities, but animals rarely move at their maximum in the wild. It was the goal of our symposium to develop a conceptual framework to explore the choices of speed in nature. A major difference between our approach and previous work is our move toward understanding optimal rather than maximal speeds. In the following series of papers, we provide a starting point for future work on animal movement speeds, including a conceptual framework, a simple optimality model, an evolutionary context, and an exploration of the various biomechanical and energetic constraints on speed. By applying a cross-disciplinary approach to the study of the choice of speed-as we have done here-we can reveal much about the way animals use habitats, interact with conspecifics, avoid predators, obtain food, and negotiate human-modified landscapes. PMID- 26493611 TI - Reference ranges for the uterine arteries Doppler and cervical length measurement at 11-13(+6) weeks of gestation in a Brazilian population. AB - OBJECTIVE: To establish references ranges for the uterine arteries (UtA) Doppler and cervical length (CL) measurements at 11-13(+6) weeks of gestation in a Brazilian population. METHODS: We performed a retrospective cross-sectional study with singleton low-risk pregnant women who underwent first trimester ultrasound exams of fetuses with crown-rump length (CRL) ranging from 45 to 84 mm. The mean UtA Doppler and CL measurements were performed by transvaginal route. The mean pulsatility index (PI) of uterine arteries was obtained with color Doppler at the level of cervico-corporeal junction. The CL was obtained in a sagittal view using the cervical gland area as landmark. We determined mean +/- standard deviation (SD), ranges for mean PI of UtA and CL in each gestational age. Polynomial regression was performed to establish reference values. RESULTS: We have assessed 598 first-trimester pregnancies: the CL measurement was obtained from 497, while the mean PI UtA Doppler was available in 450 pregnant women. The mean CL ranged from 33.41 to 35.58 mm while the PI UtA Doppler ranged from 1.89 to 1.45. The best fit curves were: CL = 30.790 + 0.057 * CRL and UtA PI = 2.411-0.011 * CRL. CONCLUSION: References ranges for the mean UtA PI Doppler and CL measurement at 11-13(+6) weeks of gestation in a Brazilian population were established. PMID- 26493612 TI - The developmental emergence of unconscious fear processing from eyes during infancy. AB - From early in life, emotion detection plays an important role during social interactions. Recently, 7-month-old infants have been shown to process facial signs of fear in others without conscious perception and solely on the basis of their eyes. However, it is not known whether unconscious fear processing from eyes is present before 7months of age or only emerges at around 7months. To investigate this question, we measured 5-month-old infants' event-related potentials (ERPs) in response to subliminally presented fearful and non-fearful eyes and compared these with 7-month-old infants' ERP responses from a previous study. Our ERP results revealed that only 7-month-olds, but not 5-month-olds, distinguished between fearful and non-fearful eyes. Specifically, 7-month-olds' processing of fearful eyes was reflected in early visual processes over occipital cortex and later attentional processes over frontal cortex. This suggests that, in line with prior work on the conscious detection of fearful faces, the brain processes associated with the unconscious processing of fearful eyes develop between 5 and 7months of age. More generally, these findings support the notion that emotion perception and the underlying brain processes undergo critical change during the first year of life. Therefore, the current data provide further evidence for viewing infancy as a formative period in human socioemotional functioning. PMID- 26493613 TI - Phosphatidylinositol kinase activities in Trypanosoma cruzi epimastigotes. AB - Phosphatidylinositol (PtdIns) metabolism through phosphatidylinositol kinase (PIKs) activities plays a central role in different signaling pathways. In Trypanosoma cruzi, causative agent of Chagas disease, PIKs have been proposed as target for drug design in order to combat this pathogen. In this work, we studied the classes of PI4K, PIPK and PI3K that could participate in signaling pathways in T. cruzi epimastigote forms. For this reason, we analyzed their enzymatic parameters and detailed responses to avowed kinase inhibitors (adenosine, sodium deoxycholate, wortmannin and LY294002) and activators (Ca(2+), phosphatidic acid, spermine and heparin). Our results suggest the presence and activity of a class III PI4K, a class I PIPK, a class III PI3K previously described (TcVps34) and a class I PI3K. Class I PI3K enzyme, here named TcPI3K, was cloned and expressed in a bacterial system, and their product was tested for kinase activity. The possible participation of TcPI3K in central cellular events of the parasite is also discussed. PMID- 26493614 TI - Subcutaneous Infection Associated with Trichosporon ovoides: A Case Report and Review of Literature. AB - Trichosporon species are opportunistic yeasts which can cause infections, especially in immunocompromised patients. This is a report of Trichosporon ovoides that caused subcutaneous infection in a patient with underlying ischemic heart disease. The identification of fungal isolate was confirmed by PCR sequencing of ITS and large subunit regions in rRNA gene. In vitro susceptibility study showed that the isolate was susceptible to amphotericin B, fluconazole and voriconazole, and resistant to caspofungin, anidulafungin and itraconazole. The lesion improved after treatment with oral fluconazole and topical miconazole. PMID- 26493615 TI - One Health approach to controlling a Q fever outbreak on an Australian goat farm. AB - A recent outbreak of Q fever was linked to an intensive goat and sheep dairy farm in Victoria, Australia, 2012-2014. Seventeen employees and one family member were confirmed with Q fever over a 28-month period, including two culture-positive cases. The outbreak investigation and management involved a One Health approach with representation from human, animal, environmental and public health. Seroprevalence in non-pregnant milking goats was 15% [95% confidence interval (CI) 7-27]; active infection was confirmed by positive quantitative PCR on several animal specimens. Genotyping of Coxiella burnetii DNA obtained from goat and human specimens was identical by two typing methods. A number of farming practices probably contributed to the outbreak, with similar precipitating factors to the Netherlands outbreak, 2007-2012. Compared to workers in a high efficiency particulate arrestance (HEPA) filtered factory, administrative staff in an unfiltered adjoining office and those regularly handling goats and kids had 5.49 (95% CI 1.29-23.4) and 5.65 (95% CI 1.09-29.3) times the risk of infection, respectively; suggesting factory workers were protected from windborne spread of organisms. Reduction in the incidence of human cases was achieved through an intensive human vaccination programme plus environmental and biosecurity interventions. Subsequent non-occupational acquisition of Q fever in the spouse of an employee, indicates that infection remains endemic in the goat herd, and remains a challenge to manage without source control. PMID- 26493617 TI - Assessment of experimental thermal, numerical, and mandibular drilling factors in implantology. AB - The main factors that cause an increase in the temperature of the jaw during drilling when implanting teeth are the geometric measurements of the surgical drill, its rotational speed, and its feed rate (cutting speed). Using finite element modelling we analysed the effect of the three variables - the angle of the head of the drill bit, the rotational speed, and the feed rate - on the increase in the temperature of the bone at the point of the drill. This showed that drilling with the angle of the head of the drill bit at 70 degrees generates a lower temperature than when it is at 90 degrees or 118 degrees . The same is true when the drill bit is set at 200 rotations/minute (rpm) compared with 400,800, or 1200rpm. When the feed rate of the drill bit is 120mm/minute it generates less heat than when it is at 90 or 60mm/minute. An increase in temperature during drilling of the jaw has a direct relation with the rotational speed of the drill bit, and a reverse relation to its feed rate. The sharper the drill bit, the lower the temperature during drilling. PMID- 26493616 TI - A Source-based Measurement Database for Occupational Exposure Assessment of Electromagnetic Fields in the INTEROCC Study: A Literature Review Approach. AB - INTRODUCTION: To date, occupational exposure assessment of electromagnetic fields (EMF) has relied on occupation-based measurements and exposure estimates. However, misclassification due to between-worker variability remains an unsolved challenge. A source-based approach, supported by detailed subject data on determinants of exposure, may allow for a more individualized exposure assessment. Detailed information on the use of occupational sources of exposure to EMF was collected as part of the INTERPHONE-INTEROCC study. To support a source-based exposure assessment effort within this study, this work aimed to construct a measurement database for the occupational sources of EMF exposure identified, assembling available measurements from the scientific literature. METHODS: First, a comprehensive literature search was performed for published and unpublished documents containing exposure measurements for the EMF sources identified, a priori as well as from answers of study subjects. Then, the measurements identified were assessed for quality and relevance to the study objectives. Finally, the measurements selected and complementary information were compiled into an Occupational Exposure Measurement Database (OEMD). RESULTS: Currently, the OEMD contains 1624 sets of measurements (>3000 entries) for 285 sources of EMF exposure, organized by frequency band (0 Hz to 300 GHz) and dosimetry type. Ninety-five documents were selected from the literature (almost 35% of them are unpublished technical reports), containing measurements which were considered informative and valid for our purpose. Measurement data and complementary information collected from these documents came from 16 different countries and cover the time period between 1974 and 2013. CONCLUSION: We have constructed a database with measurements and complementary information for the most common sources of exposure to EMF in the workplace, based on the responses to the INTERPHONE-INTEROCC study questionnaire. This database covers the entire EMF frequency range and represents the most comprehensive resource of information on occupational EMF exposure. It is available at www.crealradiation.com/index.php/en/databases. PMID- 26493619 TI - TCL1 expression patterns in Waldenstrom macroglobulinemia. AB - The oncogenic role of TCL1 in chronic lymphocytic leukemia is well established in transgenic mice. TCL1 expression in other B-cell malignancies has been also described: post-germinal center-derived malignancies, such as multiple myeloma, classically do not express TCL1. Waldenstrom macroglobulinemia is a post-germinal center malignancy that is known to be similar to chronic lymphocytic leukemia in terms of its gene expression profile. TCL1 expression has not been so far assessed in Waldenstrom macroglobulinemia. Transcriptomic explorations show that TCL1A expression is linked to signaling pathways and biological functions that are known to be involved in Waldenstrom macroglobulinemia as well as to gene signatures of interest in B-cell malignancies. We investigated TCL1 expression at the protein level in the bone marrow of a series of 59 patients with Waldenstrom macroglobulinemia: 76% of patients expressed TCL1, which appeared to be associated with a pejorative prognostic impact. TCL1 could have an oncogenic role in Waldenstrom macroglobulinemia, and deserves further exploration. PMID- 26493620 TI - Vinylogous Mukaiyama-Michael Reactions of Dihydropyridinones. AB - An In(III)-catalyzed vinylogous addition of O-silyl vinylketene acetals to 2,3 dihydro-4-pyridinones has been developed. The method features the unprecedented employment of supersilyl groups to influence the gamma versus alpha regiochemical control of vinylogous Mukaiyama-Michael (vM-Michael) reactions when gamma substituted O-silyl vinylketene acetals are used. We also demonstrate that these reactions allow facile access to quinolizidine-based alkaloids such as deoxynupharidine and well as lasubine I and II. PMID- 26493618 TI - The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma. AB - Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n=25, 29%), hemizygous NF2 loss (n=30, 35%), and/or loss of BAP1 protein expression (n=49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progression-free survival (P<0.02) and poor overall survival (P<0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (P<0.01) and overall survival rate of 18% with a median of 8 months (P<0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma. PMID- 26493621 TI - Atrial fibrillation and low vitamin D levels are associated with severe vascular calcifications in hemodialysis patients. AB - BACKGROUND/AIMS: Vascular calcifications (VCs) and fractures are major complications of chronic kidney disease. Hemodialysis patients have a high prevalence of atrial fibrillation (AF) and an increased risk of thromboembolism, which should be prevented with warfarin, a drug potentially causing increased risk of VCs and fractures. Aim of this study is evaluating, in hemodialysis patients with and without AF, the prevalence of VCs and fractures, as well as identifying the associated risk factors. METHODS: A total of 314 hemodialysis patients were recruited, 101 with documented AF and 213 without AF. Comorbidities, chronic kidney disease mineral and bone disorder blood tests and therapies were collected. Vertebral quantitative morphometry was carried out centrally for the detection of fractures, defined as vertebral body reduction by >=20 %. In the same radiograph, the length of aortic calcification was also measured. Logistic regression models were applied for evaluating the independent predictors of presence of VCs and vertebral fractures. RESULTS: In our population VCs were very common (>85 %). Severe VCs (>10 cm) were more common in patients with AF (76 %) than in patients without (33 %). Vertebral fractures were present in 54 % of patients. Multivariable analysis showed that AF (OR 5.41, 95 % CI 2.30 12.73) and 25(OH) vitamin D <20 ng/mL (OR 2.05, 95 % CI 1.10-3.83) were independent predictors of VCs. Age (OR 1.04/year, 95 % CI 1.01-1.07) and male gender (OR 1.76, 95 % CI 1.07-2.90) predicted vertebral fractures. CONCLUSIONS: Hemodialysis patients had an elevated prevalence of severe VCs, especially when affected by AF. Low vitamin D levels were strongly associated with severe VCs. Prevalence of vertebral fractures was also remarkably high and associated with older age and male gender. PMID- 26493622 TI - Percutaneous endoscopic cecostomy (introducer method) in chronic intestinal pseudo-obstruction: Report of two cases and literature review. AB - We report on two patients with recurrent episodes of chronic intestinal pseudo obstruction (CIPO). A 50-year-old woman with severe multiple sclerosis and an 84 year-old man with Parkinson's disease and dementia had multiple hospital admissions because of pain and distended abdomen. Radiographic and endoscopic findings showed massive dilation of the colon without any evidence of obstruction. Conservative management resolved symptoms only for a short period of time. As these patients were poor candidates for any surgical treatment we carried out percutaneous endoscopic colostomy by placing a 20-Fr tube in the cecum with the introducer method. The procedure led to durable symptom relief without complications. We present these two cases and give a review through the existing literature of the procedure in CIPO. PMID- 26493623 TI - A pilot study of photoacoustic imaging system for improved real-time visualization of neurovascular bundle during radical prostatectomy. AB - BACKGROUND: Photoacoustic imaging, a noninvasive imaging based on optical excitation and ultrasonic detection, enables one to visualize the distribution of hemoglobin and acquire a map of microvessels without using contrast agents. We examined whether it helps visualize periprostatic microvessels and improves visualization of the neurovascular bundle. METHODS: We developed a photoacoustic imaging (PAI) system with a hand-held probe combining optical illumination and a conventional linear array ultrasound probe. In experiments with a phantom model, it was able to visualize vessels with diameters as small as 300 MUm within a depth of 10 mm. We also developed a TRUS type probe for our photoacoustic imaging system and used it to intraoperatively monitor periprostatic tissues in seven patients with clinically organ-confined prostate cancer who were undergoing non nerve-sparing retropubic radical prostatectomy. Images of periprostatic tissues from resected prostatectomy specimens were also obtained using the linear photoacoustic probe, and the consistency of the microvessel distribution and co existence of nerve fibers was examined by double immunostaining of paraffin embedded sections with anti-CD31 and anti-S-100 antibodies. RESULTS: Intraoperative monitoring of periprostatic tissues with the TRUS photoacoustic probe showed substantial signals on the posterolateral surface of the prostate and clearly demonstrated the location and extent of the neurovascular bundle better than does TRUS alone. Photoacoustic images of the periprostatic tissues in resected specimens also showed substantial signals that were especially strong on the posterolateral surface of the prostate. Nerve fibers were closely co localized with periprostatic microvessels and the pattern of their distribution was consistent with that of PAI signals. CONCLUSIONS: The intraoperative photoacoustic imaging located the microvascular complex in the neurovascular bundle. Moreover, the neurovascular bundle was easier to identify by PAI than by TRUS alone, suggesting that PAI could be helpful in nerve-sparing radical prostatectomy. PMID- 26493624 TI - Invasion of the Fungal Pathogen Batrachochytrium dendrobatidis on California Islands. AB - Batrachochytrium dendrobatidis (Bd), an amphibian fungal pathogen, has infected >500 species and caused extinctions or declines in >200 species worldwide. Despite over a decade of research, little is known about its invasion biology. To better understand this, we conducted a museum specimen survey (1910-1997) of Bd in amphibians on 11 California islands and found a pattern consistent with the emergence of Bd epizootics on the mainland, suggesting that geographic isolation did not prevent Bd invasion. We propose that suitable habitat, host diversity, and human visitation overcome isolation from the mainland and play a role in Bd invasion. PMID- 26493625 TI - Essay: Evidence-based medicine (EBM): New paradigm or integration? PMID- 26493626 TI - PNPLA3 rs738409 and TM6SF2 rs58542926 variants increase the risk of hepatocellular carcinoma in alcoholic cirrhosis. AB - BACKGROUND: PNPLA3 rs738409 polymorphism is associated with fatty liver disease, alcoholic or non-alcoholic (NAFLD) and hepatocellular carcinoma (HCC). TM6SF2 rs58542926 is clearly associated with NAFLD, but it is not clearly associated with HCC. The relationship between TM6SF2 rs58542926 and HCC and the potential synergistic effect of TM6SF2 and PNPLA3 variants in modifying the risk of HCC are not known. AIM: This study assessed the interaction between PNPLA3 rs738409 and TM6SF2 rs58542926 variants in the conditioning of HCC development. METHODS: A total of 511 cirrhotic patients (44% alcohol-related, 56% viral, 57.5% liver transplanted) were retrospectively investigated for HCC occurrence. PNPLA3 rs734809 and TM6SF2 rs58542926 were genotyped using restriction fragment length polymorphism and real-time allelic discrimination polymerase chain reaction methods. RESULTS: Patients with HCC were more likely to be PNPLA3 rs734809 G/G homozygotes (41/150 vs. 60/361, p=0.009) or TM6SF2 rs58542926 C/T-T/T (27/150 vs. 41/361, p=0.044). The presence of either PNPLA3 G/G or TM6SF2*/T identified high risk genotypes for HCC, which were strongly associated with HCC (64/150 vs. 93/361, p=0.0002). This association was evident in alcohol-related (p=0.0007) but not in viral cirrhosis. CONCLUSION: TM6SF2 C/T or T/T in conjunction with PNPLA3 G/G variants may be potential genetic risk factors for developing HCC in alcohol related cirrhosis. PMID- 26493627 TI - Health-related quality of life is a prognostic factor for survival in older patients after colorectal cancer diagnosis: A population-based study. AB - BACKGROUND: Studies carried out in the context of clinical trials have shown a relationship between survival and health-related quality of life in colorectal cancer patients. AIMS: We assessed the prognostic value of health-related quality of life at diagnosis and of its longitudinal evolution on survival in older colorectal cancer patients. METHODS: All patients aged >=65 years, diagnosed with new colorectal cancer between 2003 and 2005 and registered in the Digestive Cancer Registry of Burgundy were eligible. Patients were asked to complete the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 at inclusion, three, six and twelve months after. Multivariate regression models were used to evaluate the prognostic value of health-related quality of life scores at diagnosis and their deterioration on relative survival. RESULTS: In multivariate analysis, a role functioning dimension lower than median was predictive of lower survival (hazard ratio=3.1, p=0.015). After three and six months of follow-up, patients with greater appetite loss were more likely to die, with hazard ratios of 4.7 (p=0.013) and 3.7 (p=0.002), respectively. CONCLUSIONS: Health-related quality of life assessments at diagnosis are independently associated with older colorectal cancer patients' survival. Its preservation should be a major management goal for older cancer patients. PMID- 26493628 TI - Krill oil reduces intestinal inflammation by improving epithelial integrity and impairing adherent-invasive Escherichia coli pathogenicity. AB - BACKGROUND: Krill oil is a marine derived oil rich in phospholipids, astaxanthin and omega-3 fatty acids. Several studies have found benefits of krill oil against oxidative and inflammatory damage. AIMS: We aimed at assessing the ability of krill oil to reduce intestinal inflammation by improving epithelial barrier integrity, increasing cell survival and reducing pathogenicity of adherent invasive Escherichia coli. METHODS: CACO2 and HT29 cells were exposed to cytomix (TNFalpha and IFNgamma) to induce inflammation and co-exposed to cytomix and krill oil. E-cadherin, ZO-1 and F-actin levels were analyzed by immunofluorescence to assess barrier integrity. Scratch test was performed to measure wound healing. Cell survival was analyzed by flow cytometry. Adherent invasive Escherichia coli LF82 was used for adhesion/invasion assay. RESULTS: In inflamed cells E-cadherin and ZO-1 decreased, with loss of cell-cell adhesion, and F-actin polymerization increased stress fibres; krill oil restored initial conditions and improved wound healing, reduced bacterial adhesion/invasion in epithelial cells and survival within macrophages; krill oil reduced LF82-induced mRNA expression of pro-inflammatory cytokines. CONCLUSIONS: Krill oil improves intestinal barrier integrity and epithelial restitution during inflammation and controls bacterial adhesion and invasion to epithelial cells. Thus, krill oil may represent an innovative tool to reduce intestinal inflammation. PMID- 26493629 TI - Early and delayed complications of polypectomy in a community setting: The SPoC prospective multicentre trial. AB - BACKGROUND: Colonoscopic polypectomy is effective in reducing the incidence of and mortality from colorectal cancer, but is not complication-free. AIMS: To evaluate the incidence of early and delayed polypectomy complications and factors associated with their occurrence in a community setting. METHODS: Web-database collection of patients' and polyp's features in consecutive colonic polypectomies during a 3-month period in 18 endoscopy centres. RESULTS: Data on 5178 polypectomies in 2692 patients (54.3% males, mean age 59 years) were collected. The majority of the polyps were <10mm (83.5%). Antithrombotic agents were taken by 22.7% of patients, 57.3% of which withheld them before the procedure. Overall, 5 patients experienced perforations (0.2%) and 114 had bleeding (4.2%); the overall complication rate was 4.4%. Early complications were observed in 87 (3.2%); delayed complications (all major bleedings) occurred in 32 (1.2%). At multivariate analysis polyp size (size >10mm: OR 4.35, 95% CI 5.53-7.48) and, inversely, right-sided location (OR 0.58, 95% CI 0.36-0.94) were correlated with bleeding events. The use of antithrombotics was associated with 5-fold increased risk of delayed bleeding. CONCLUSIONS: In the community setting, polypectomy was associated with a 1.4% risk of major complications. Polyp size and, inversely, right-sided location were associated with early bleeding; the use of antithrombotics increased the risk of delayed events. PMID- 26493630 TI - A variant in the nuclear dot protein 52kDa gene increases the risk for spontaneous bacterial peritonitis in patients with alcoholic liver cirrhosis. AB - BACKGROUND: Spontaneous bacterial peritonitis is frequently a fatal infection in patients with liver cirrhosis. We investigated if nuclear dot protein 52kDa (NDP52), a negative regulator of toll-like receptor (TLR) signalling and autophagy adaptor protein, might be involved. METHODS: Two cohorts comprising 152 (derivation cohort) and 198 patients (validation cohort) with decompensated liver cirrhosis and 168 healthy controls were genotyped for the rs2303015 polymorphism in the NDP52 gene and prospectively followed-up for spontaneous bacterial peritonitis. RESULTS: Overall, 57 (38%) patients in the derivation cohort and 77 (39%) in the validation cohort had spontaneous bacterial peritonitis. Cirrhosis was due to alcohol abuse in 57% of the derivation and 66% of the validation cohort. In patients with alcoholic cirrhosis, patients with spontaneous bacterial peritonitis had an increased frequency of the NDP52 rs2303015 minor variant in the derivation (p=0.04) and in the validation cohort (p=0.01). Multivariate analysis confirmed this minor variant (odds ratio 4.7, p=0.002) and the TLR2 16934 TT variant (odds ratio 2.5, p=0.008) as risk factors for spontaneous bacterial peritonitis. In addition, presence of the NDP52 minor variant affected survival negatively. CONCLUSION: Presence of the NDP52 rs2303015 minor variant increases the risk for spontaneous bacterial peritonitis in patients with alcoholic cirrhosis. PMID- 26493632 TI - De novo transcriptome analysis of Inonotus baumii by RNA-seq. AB - Inonotus baumii, a basidiomycete white rot fungus, has been widely used as traditional herbal medicine in China, Korea, Japan and other Asian countries for many years. Its extract is of great medicinal importance and plays a valuable role in the immune response and disease resistance. However, limited genetic resources for I. baumii have hindered exploration of this species. In order to gain a molecular understanding of this fungus, Illumina high-throughput technology was used to sequence and analyze the transcriptome of I. baumii, and 280,691 contigs, 43,890 scaffolds and 30,051 unigenes were obtained. Additionally, based on similarity search with known proteins, unigenes were annotated with gene descriptions, gene ontology (GO), clusters of orthologous group (COG), and database of protein families (Pfam) terms. According to the annotation of unigenes, a total of 12 candidate genes involved in the triterpenoid biosynthesis pathway and 21 putative FOLymes (fungal oxidative lignin enzymes) and 176 CAZymes (carbohydrate-active enzymes) were obtained using homology-based BlastX. Moreover, for better understanding of the transcripts function, the BlastX algorithm was used to search for homologous sequences against the Yeast genome. This is the first study on transcriptome analyses of I. baumii, which provided a dataset for functional gene mining and laid a basis for further functional genomics studies of I. baumii. PMID- 26493633 TI - Epistasis effects of multiple ancestral-consensus amino acid substitutions on the thermal stability of glycerol kinase from Cellulomonas sp. NT3060. AB - Thermostable variants of the Cellulomonas sp. NT3060 glycerol kinase have been constructed by through the introduction of ancestral-consensus mutations. We produced seven mutants, each having an ancestral-consensus amino acid residue that might be present in the common ancestors of both bacteria and of archaea, and that appeared most frequently at the position of 17 glycerol kinase sequences in the multiple sequence alignment. The thermal stabilities of the resulting mutants were assessed by determining their melting temperatures (Tm), which was defined as the temperature at which 50% of the initial catalytic activity is lost after 15 min of incubation, as well as when the half-life of the catalytic activity occurs at a temperature of 60 degrees C (t1/2). Three mutants showed increased stabilities compared to the wild-type protein. We then produced five more mutants with multiple amino acid substitutions. Some of the resulting mutants showed thermal stabilities much greater than those expected given the stabilities of the respective mutants with single mutations. Therefore, the effects of mutations are not always simply additive and some amino acid substitutions, which do not affect or only slightly improve stability when individually introduced into the protein, show substantial stabilizing effects in combination with other mutations. PMID- 26493631 TI - Caffeine stimulates locomotor activity in the mammalian spinal cord via adenosine A1 receptor-dopamine D1 receptor interaction and PKA-dependent mechanisms. AB - Caffeine is a potent psychostimulant that can have significant and widely variable effects on the activity of multiple neuronal pathways. The most pronounced caffeine-induced behavioral effect seen in rodents is to increase locomotor activity which has been linked to a dose-dependent inhibition of A1 and A(2A) receptors. The effects of caffeine at the level of the lumbar spinal central pattern generator (CPG) network for hindlimb locomotion are lacking. We assessed the effects of caffeine to the locomotor function of the spinal CPG network via extracellular ventral root recordings using the isolated neonatal mouse spinal cord preparation. Addition of caffeine and of an A1 receptor antagonist significantly decreased the cycle period accelerating the ongoing locomotor rhythm, while decreasing burst duration reversibly in most preparations suggesting the role of A1 receptors as the primary target of caffeine. Caffeine and an A1 receptor antagonist failed to stimulate ongoing locomotor activity in the absence of dopamine or in the presence of a D1 receptor antagonist supporting A1/D1 receptor-dependent mechanism of action. The use of caffeine or an A1 receptor blocker failed to stimulate an ongoing locomotor rhythm in the presence of a blocker of the cAMP-dependent protein kinase (PKA) supporting the need of this intracellular pathway for the modulatory effects of caffeine to occur. These results support a stimulant effect of caffeine on the lumbar spinal network controlling hindlimb locomotion through the inhibition of A1 receptors and subsequent activation of D1 receptors via a PKA-dependent intracellular mechanism. PMID- 26493634 TI - Antioxidant, immunomodulatory and antiproliferative effects of gelatin hydrolysate from unicorn leatherjacket skin. AB - BACKGROUND: The in vitro cellular bioactivities including, antioxidant, immunomodulatory and antiproliferative effects of a gelatin hydrolysate (GH) prepared from unicorn leatherjacket skin, using partially purified glycyl endopeptidase, were investigated in order to optimize the use of fish skin waste products as functional food ingredients. RESULTS: GH under the tested concentrations (750-1500 ug mL(-1) ) protected against H2 O2 -induced DNA damage in U937 cells. GH also protected against the H2 O2 -induced reduction in cellular antioxidant enzyme activities, superoxide dismutase and catalase, in HepG2 cells. GH demonstrated immunomodulatory potential by reducing pro-inflammatory cytokine (interleukin-6 (IL-6) and IL-1beta) production and nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. Cell proliferation in human colon cancer (Caco-2) cells was significantly reduced in a dose-dependent manner following incubation with GH. CONCLUSION: These results indicate that GH has several bioactivities which support its potential as a promising functional food ingredient with various health benefits. (c) 2015 Society of Chemical Industry. PMID- 26493635 TI - Passive immunotherapy targeting amyloid-beta reduces cerebral amyloid angiopathy and improves vascular reactivity. AB - Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-beta isoform(s) (predominantly amyloid-beta40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-beta40 selective antibody, to attenuate amyloid-beta accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-beta accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-beta biochemically. We hypothesized that the reduction in vascular amyloid-beta40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-beta40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid beta40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-beta species that may otherwise be detrimental to normal vessel function. PMID- 26493636 TI - Reply: The challenges for research on deep brain stimulation and memory. PMID- 26493638 TI - The cross-sectional association between severity of non-cognitive disability and self-reported worsening memory. AB - BACKGROUND: Research has demonstrated a clear association between cognitive decline and non-cognitive disability; however, all of these studies focus on disability as a correlate or result of some level of cognitive impairment or dysfunction. The relationship between disability and cognition is likely a complex one, that is currently incompletely described in the literature. OBJECTIVES: Our objective was to estimate the prevalence of long-term, non cognitive disability using a population-representative sample of adults aged 18 and older, and then estimate the association between long-term, non-cognitive disability and self-reported worsening memory. METHODS: Using the 2009 Florida Behavioral Risk Factor Surveillance System (BRFSS), we measured the relationship between non-cognitive disability and worsening memory using multivariable logistic regression analysis weighted to account for the complex sampling design of the BRFSS. We also estimated the adjusted odds of worsening memory by disability severity, classified according to the types of assistance needed. RESULTS: Approximately 18% (95% confidence interval = (16%, 19%)) of Floridians were living with a long-term, non-cognitive disability in 2009. Among adults with no disability during or prior to the last year, only 5% reported worsening memory. The proportion of Floridians reporting worsening memory increases with increasing severity of disability-related limitations. In a multivariable logistic regression model, odds of worsening memory increased significantly with severity of disability-related limitations. CONCLUSIONS: These results highlight the association between non-cognitive disability and subsequent increased odds of worsening memory, independent of several other known risk factors, and a dose response association with disability-related limitations. PMID- 26493639 TI - Crystal structure, equation of state, and elasticity of phase H (MgSiO4H2) at Earth's lower mantle pressures. AB - Dense hydrous magnesium silicate (DHMS) phases play a crucial role in transporting water in to the Earth's interior. A newly discovered DHMS, phase H (MgSiO4H2), is stable at Earth's lower mantle, i.e., at pressures greater than 30 GPa. Here we report the crystal structure and elasticity of phase H and its evolution upon compression. Using first principles simulations, we have explored the relative energetics of the candidate crystal structures with ordered and disordered configurations of magnesium and silicon atoms in the octahedral sites. At conditions relevant to Earth's lower mantle, it is likely that phase H is able to incorporate a significant amount of aluminum, which may enhance the thermodynamic stability of phase H. The sound wave velocities of phase H are ~2 4% smaller than those of isostructural delta-AlOOH. The shear wave impedance contrast due to the transformation of phase D to a mixture of phase H and stishovite at pressures relevant to the upper part of the lower mantle could partly explain the geophysical observations. The calculated elastic wave velocities and anisotropies indicate that phase H can be a source of significant seismic anisotropy in the lower mantle. PMID- 26493637 TI - Disrupted sensorimotor and social-cognitive networks underlie symptoms in childhood-onset schizophrenia. AB - Schizophrenia is increasingly recognized as a neurodevelopmental disorder with altered connectivity among brain networks. In the current study we examined large scale network interactions in childhood-onset schizophrenia, a severe form of the disease with salient genetic and neurobiological abnormalities. Using a data driven analysis of resting-state functional magnetic resonance imaging fluctuations, we characterized data from 19 patients with schizophrenia and 26 typically developing controls, group matched for age, sex, handedness, and magnitude of head motion during scanning. This approach identified 26 regions with decreased functional correlations in schizophrenia compared to controls. These regions were found to organize into two function-related networks, the first with regions associated with social and higher-level cognitive processing, and the second with regions involved in somatosensory and motor processing. Analyses of across- and within-network regional interactions revealed pronounced across-network decreases in functional connectivity in the schizophrenia group, as well as a set of across-network relationships with overall negative coupling indicating competitive or opponent network dynamics. Critically, across-network decreases in functional connectivity in schizophrenia predicted the severity of positive symptoms in the disorder, such as hallucinations and delusions. By contrast, decreases in functional connectivity within the social-cognitive network of regions predicted the severity of negative symptoms, such as impoverished speech and flattened affect. These results point toward the role that abnormal integration of sensorimotor and social-cognitive processing may play in the pathophysiology and symptomatology of schizophrenia. PMID- 26493640 TI - Therapeutic resistance: Multiple mechanisms to keep going. PMID- 26493645 TI - Centrosomes and cancer: revisiting a long-standing relationship. AB - Over a century ago, centrosome aberrations were postulated to cause cancer by promoting genome instability. The mechanisms governing centrosome assembly and function are increasingly well understood, allowing for a timely reappraisal of this postulate. This Review discusses recent advances that shed new light on the relationship between centrosomes and cancer, and raise the possibility that centrosome aberrations contribute to this disease in different ways than initially envisaged. PMID- 26493646 TI - Functional and genetic deconstruction of the cellular origin in liver cancer. AB - During the past decade, research on primary liver cancers has particularly highlighted the uncommon plasticity of differentiated parenchymal liver cells (that is, hepatocytes and cholangiocytes (also known as biliary epithelial cells)), the role of liver progenitor cells in malignant transformation, the importance of the tumour microenvironment and the molecular complexity of liver tumours. Whereas other reviews have focused on the landscape of genetic alterations that promote development and progression of primary liver cancers and the role of the tumour microenvironment, the crucial importance of the cellular origin of liver cancer has been much less explored. Therefore, in this Review, we emphasize the importance and complexity of the cellular origin in tumour initiation and progression, and attempt to integrate this aspect with recent discoveries in tumour genomics and the contribution of the disrupted hepatic microenvironment to liver carcinogenesis. PMID- 26493650 TI - Carbon-Free Cathodes: A Step Forward in the Development of Stable Lithium-Oxygen Batteries. AB - Lithium-oxygen (Li-O2 ) batteries are receiving considerable interest owing to their potential for higher energy densities than current Li-ion systems. However, the lack stability of carbon-based oxygen electrodes is believed to promote carbonate formation leading to capacity fade and limiting the cycling performance of the battery. To improve the stability and cyclability of these systems, alternative electrode materials are required. Metal oxides are mainly utilized at low current densities, whereas noble metals show outstanding performance at high current densities. Carbides appear to provide a good compromise between electrochemical performance and cost, which makes them interesting materials for further investigations. Here, a critical review of current carbon-free electrode research is provided with the goal of identifying routes to its successful optimization. PMID- 26493651 TI - MERS epidemiological investigation to detect potential mode of transmission in the 178th MERS confirmed case in Pyeongtaek, Korea. AB - Most cases of Middle East Respiratory Syndrome (MERS) infection in Korea (outbreak: May 11-July 4, 2015) occurred in hospital settings, with uncertain transmission modes in some cases. We performed an in-depth investigation epidemiological survey on the 178th case to determine the precise mode of transmission. A 29- year-old man living in Pyeongtaek presented on June 16 with a febrile sensation, chills, and myalgia. Upon confirmatory diagnosis on June 23, he was treated in an isolation room and discharged on July 2 after cure. An epidemiological investigation of all possible infection routes indicated two likely modes of transmission: exposure to MERS in Pyeongtaek St. Mary's Hospital during a visit to his hospitalized father (May 18-29), and infection through frequent contact with his father between the latter's referral to Pyeongtaek Good Samaritan Bagae Hospital for treatment without confirmatory diagnosis until his death (May 29-June 6). Although lack of clear proof or evidence to the contrary does not allow a definitive conclusion, all other possibilities could be excluded by epidemiological inferences. While it is impossible to trace back the modes of transmission of all cases in a large-scale outbreak, case-by-case tracking and isolation of infected individuals and those in close contact with them is important in preventing the spread. Efforts should be made to establish a methodology for rapid tracking of all possible contacts and elimination-based identification of the precise modes of transmission. PMID- 26493648 TI - Directly targeting transcriptional dysregulation in cancer. AB - Drugs that target intracellular signalling pathways have markedly improved progression-free survival of patients with cancers who were previously regarded as untreatable. However, the rapid emergence of therapeutic resistance, as a result of bypass signalling or downstream mutation within kinase-mediated signalling cascades, has curtailed the benefit gained from these therapies. Such resistance mechanisms are facilitated by the linearity and redundancy of kinase signalling pathways. We argue that, in each cancer, the dysregulation of key transcriptional regulators not only defines the cancer phenotype but is essential for its development and maintenance. Furthermore, we propose that, as therapeutic targets, these transcriptional regulators are less prone to bypass by alternative mutational events or clonal heterogeneity, and therefore we must rekindle our efforts to directly target transcriptional regulation across a broad range of cancers. PMID- 26493652 TI - "The Duty to Prevent" during an epidemic situation like 2015 Korean MERS outbreak. PMID- 26493653 TI - Changing trends in colorectal cancer in the Republic of Korea: contrast with Japan. AB - Colorectal cancer has a high worldwide incidence. Japan, a country that is geographically and culturally similar to the Republic of Korea (here after Korea), has recently reported a decreasing trend in the incidence of colorectal cancer. However, Korea had the highest incidence of colorectal cancer among Asian countries in 2012. Our aim was to observe the changing trends in incidence and mortality of colorectal cancer in Korea and to compare them to those in Japan. Incidence data were collected from the Korean Central Cancer Registry and mortality data were collected from Korean Statistical Information Service. Incidence and mortality data on colorectal cancer in Japan were acquired from the National Cancer Center in Japan. Age-standardized incidence and mortality rates were determined based on Segi's world population. Screening data from both countries were collected from the national cancer center in each country. In Korea, the age-standardized incidence rate of colorectal cancer in both sexes was 20.9 to 38.0 per 100,000 from 1999 to 2012 and the rate in males increased more dramatically than in females. In addition, the increase between 2002 and 2012 was first observed in the age group over 40. In Japan, the incidence of colorectal cancer has been more constant over recent years than in Korea. The age standardized mortality rate of colorectal cancer in both sexes in Korea was 8.5 to 9.3 per 100,000 from 2000 to 2013, and the trend in mortality was constant during this period. In Japan, the mortality rate decreased slightly during the same period. Crude screening rates were increased overall in both Korea and Japan during the period studied. Since the incidence of colorectal cancer has increased in Korea, the control of this cancer is an important public health issue. As Japan has achieved a reduction in colorectal cancer, adjustment of Korea's current systems for screening and treatment of colorectal cancer according to those of Japan may contribute to improved colorectal cancer control in Korea. PMID- 26493647 TI - Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. AB - High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015. PMID- 26493654 TI - Strengthening epidemiologic investigation of infectious diseases in Korea: lessons from the Middle East Respiratory Syndrome outbreak. AB - The recent outbreak of Middle East Respiratory Syndrome (MERS) coronavirus infection in Korea resulted in large socioeconomic losses. This provoked the Korean government and the general public to recognize the importance of having a well-established system against infectious diseases. Although epidemiologic investigation is one of the most important aspects of prevention, it has been pointed out that much needs to be improved in Korea. We review here the current status of the Korean epidemiologic service and suggest possible supplementation measures. We examine the current national preventive infrastructure, including human resources such as Epidemic Intelligence Service officers, its governmental management, and related policies. In addition, we describe the practical application of these resources to the recent MERS outbreak and the progress in preventive measures. The spread of MERS demonstrated that the general readiness for emerging infectious diseases in Korea is considerably low. We believe that it is essential to increase society's investment in disease prevention. Fostering public health personnel, legislating management policies, and establishing research centers for emerging infectious diseases are potential solutions. Evaluating international preventive systems, developing cooperative measures, and initiating improvements are necessary. We evaluated the Korean epidemiologic investigation system and the public preventive measures against infectious diseases in light of the recent MERS outbreak. We suggest that governmental authorities in Korea enforce preventive policies, foster the development of highly qualified personnel, and increase investment in the public health domain of infectious disease prevention. PMID- 26493655 TI - Comparative Performance of ATRIA, CHADS2, and CHA2DS2-VASc Risk Scores Predicting Stroke in Patients With Atrial Fibrillation: Results From a National Primary Care Database. AB - BACKGROUND: Previous studies report that CHADS2 and CHA2DS2-VASc risk scores have similar discriminating ability (C statistic ~0.6). Recently a clinically based risk score, the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study risk score, was developed and validated. OBJECTIVES: This study compared predictive ability of CHA2DS2-VASc and CHADS2 ischemic stroke risk scores with ATRIA stroke risk score and their implications for anticoagulant treatment in patients with atrial fibrillation (AF). METHODS: Patients with AF not using warfarin were included from the Clinical Practice Research Datalink database, 1998 to 2012. Patients were followed from AF diagnosis until occurrence of ischemic stroke, prescription of warfarin, death, or the study's end. Independent predictors of ischemic stroke were identified and the c-index and net reclassification improvement were calculated. RESULTS: A total of 60,594 patients with AF were included. Annualized stroke rate was 2.99%. Event rates for moderate and high-risk categories for CHA2DS2-VASc were lower than those of the ATRIA and CHADS2. Age and previous stroke most strongly predicted ischemic stroke. C statistics for the full point scores were 0.70 (95% confidence interval [CI]: 0.69 to 0.71) for the ATRIA risk score, 0.68 (95% CI: 0.67 to 0.69) for CHADS2, and 0.68 (95% CI: 0.67 to 0.69) for CHA2DS2-VASc risk score. The net reclassification improvement was 0.23 (95% CI: 0.22 to 0.25) for ATRIA compared with CHA2DS2-VASc. CONCLUSIONS: The ATRIA score performed better in the U.K. Clinical Practice Research Datalink AF cohort. It more accurately identified low risk patients than the CHA2DS2-VASc score, which assigned these patients to higher-risk categories. Such reclassification of stroke risk could prevent overuse of anticoagulants in very low stroke risk patients with AF. PMID- 26493656 TI - Stroke Risk Stratification in Patients With Atrial Fibrillation: Comme Ci, Comme Ca, Plus Ca Change.... PMID- 26493657 TI - Trends in the Use of Nonstatin Lipid-Lowering Therapy Among Patients With Coronary Heart Disease: A Retrospective Cohort Study in the Medicare Population 2007 to 2011. AB - BACKGROUND: Nonstatin lipid-lowering therapy is adjunctive therapy for high-risk individuals on statins or monotherapy among those who cannot tolerate statins. OBJECTIVES: This study determined time trends between 2007 and 2011 for statin and nonstatin lipid-lowering therapy (niacin, fibrates, bile acid sequestrants, and ezetimibe) use among Medicare beneficiaries with coronary heart disease (CHD) in light of emerging clinical trial evidence. METHODS: We conducted a retrospective cohort study using the national 5% random sample of Medicare beneficiaries (n = 310,091). We created 20 cohorts of individuals with CHD, representing calendar quarters from 2007 through 2011, to assess trends in use of statins and nonstatin lipid-lowering medications. RESULTS: Statin use increased from 53.1% to 58.8% between 2007 and 2011. Ezetimibe use peaked at 12.1% and declined to 4.6% by the end of 2011, declining among both patients on statins (18.4% to 6.2%) and not on statins (5.0% to 2.4%). Fibrate use increased from 4.2% to 5.0%, bile acid sequestrants did not change significantly, and niacin use increased from 1.5% to 2.4% and then declined in late 2011. Use of nonstatin lipid-lowering therapy was less common at older age, among African Americans, patients with heart failure, and patients with a higher Charlson comorbidity score. Nonstatin lipid-lowering therapy use was more common among men and patients with diabetes, those who had cardiologist visits, and among those taking statins. CONCLUSIONS: Declining ezetimibe and niacin use but not fibrate therapy among Medicare beneficiaries with CHD coincides with negative clinical trial results for these agents. PMID- 26493658 TI - Treatment of Dyslipidemia in Elderly Patients With Coronary Heart Disease: There Are Miles to Go Before We Sleep. PMID- 26493659 TI - Cardiorespiratory Fitness in Middle Age and Health Care Costs in Later Life. AB - BACKGROUND: Low cardiovascular risk factor burdens in middle age are associated with lower health care costs in later life. However, there are few data regarding the effect of cardiorespiratory fitness on health care costs independent of these risk factors. OBJECTIVES: This study sought to evaluate the association of health care costs in later life with cardiorespiratory fitness in midlife after adjustment for cardiovascular risk factors. METHODS: We studied 19,571 healthy individuals in the Cooper Center Longitudinal Study who underwent cardiorespiratory fitness assessment at a mean age of 49 years and received Medicare coverage from 1999 to 2009 at an average age of 71 years. Cardiorespiratory fitness was estimated by maximal metabolic equivalents (METs) calculated from treadmill time. The primary outcome was average annual health care costs obtained from Medicare standard analytical files. RESULTS: Over 126,388 person-years of follow-up, average annual health care costs were significantly lower forparticipants aged 65 years or older with high midlife fitness than with low midlife fitness in both men($7,569 vs. $12,811; p < 0.001) and women ($6,065 vs. $10,029; p < 0.001). [corrected].In a generalized linear model adjusted for cardiovascular risk factors, average annual health care costs in later life were incrementally lower per MET achieved in midlife in men (6.8% decrease in costs per MET achieved; 95% confidence interval: 5.7% to 7.8%; p < 0.001) and women (6.7% decrease in costs per MET achieved; 95% confidence interval: 4.1% to 9.3%; p < 0.001). These associations persisted when participants were separated into those who died during Medicare follow-up and those who survived. CONCLUSIONS: Higher cardiorespiratory fitness in middle age is strongly associated with lower health care costs at an average of 22 years later in life, independent of cardiovascular risk factors. These findings may have important implications for health policies directed at improving physical fitness. PMID- 26493660 TI - Fiscal Fitness? Exercise Capacity and Health Care Costs. PMID- 26493661 TI - Household Disposable Income and Long-Term Survival After Cardiac Surgery: A Swedish Nationwide Cohort Study in 100,534 Patients. AB - BACKGROUND: Lower socioeconomic groups face higher mortality risk, possibly due to a higher burden of cardiovascular risk factors. The independent association between income and survival following cardiac surgery is not known. OBJECTIVES: This study sought to investigate the association between household disposable income and long-term mortality after cardiac surgery. METHODS: In a Swedish nationwide population-based analysis, we included all patients who underwent cardiac surgery between 1999 and 2012 using a large national registry. Information regarding income, education, marital status, medical history, and cardiovascular risk factors was obtained from data managed by the National Board of Health and Welfare and Statistics Sweden. The adjusted risk for all-cause mortality was estimated using Cox regression by quintiles of household disposable income. RESULTS: We included 100,534 patients and, during a mean follow-up of 7.3 years, 29,176 (29%) patients died. There was a stepwise inverse association between household disposable income and all-cause mortality: the adjusted hazard ratio was 0.93 (95% confidence interval [CI]: 0.89 to 0.96), 0.87 (95% CI: 0.84 to 0.91), 0.78 (95% CI: 0.75 to 0.82), and 0.71 (95% CI: 0.67 to 0.75), for the second, third, fourth, and fifth income quintiles, respectively, compared to the first (and lowest) income quintile. The inverse association between income and mortality was consistent through the study period and in selected subgroups, although it was slightly attenuated in older patients. CONCLUSIONS: We found a strong inverse association between income and mortality following cardiac surgery in Sweden that was independent of other socioeconomic status variables, comorbidities, and cardiovascular risk profile. Ways to better implement secondary prevention measures should be explored in low-income patient groups. (HeAlth-data Register sTudies of Risk and Outcomes in Cardiac Surgery [HARTROCS]; NCT02276950). PMID- 26493662 TI - Merits and Pitfalls of Using Observational "Big Data" to Inform Our Understanding of Socioeconomic Outcome Disparities. PMID- 26493663 TI - Very Late Scaffold Thrombosis: Intracoronary Imaging and Histopathological and Spectroscopic Findings. AB - BACKGROUND: Bioresorbable scaffolds provide transient lumen support followed by complete resorption. OBJECTIVES: This study examined whether very late scaffold thrombosis (VLScT) occurs when resorption is presumed to be nearly complete. METHODS: Patients with VLScT at 3 tertiary care centers underwent thrombus aspiration followed by optical coherence tomography (OCT). Thrombus aspirates were analyzed by histopathological and spectroscopic examination. RESULTS: Between March 2014 and February 2015, 4 patients presented with VLScT at 44 (case 1), 19 (cases 2 and 4), and 21 (case 3) months, respectively, after implantation of an Absorb Bioresorbable Vascular Scaffold 1.1 (Abbott Laboratories, Abbott Park, Illinois). At the time of VLScT, all patients were taking low-dose aspirin, and 2 patients were also taking prasugrel. OCT showed malapposed scaffold struts surrounded by thrombus in 7.1%, 9.0%, and 8.9% of struts in cases 1, 2, and 4, respectively. Scaffold discontinuity with struts in the lumen center was the cause of malapposition in cases 2 and 4. Uncovered scaffold struts with superimposed thrombus were the predominant findings in case 3. OCT percent area stenosis at the time of VLScT was high in case 1 (74.8%) and case 2 (70.9%) without evidence of excessive neointimal hyperplasia. Spectroscopic thrombus aspirate analysis showed persistence of intracoronary polymer fragments in case 1. CONCLUSIONS: VLScT may occur at advanced stages of scaffold resorption. Potential mechanisms specific for VLScT include scaffold discontinuity and restenosis during the resorption process, which appear delayed in humans; these findings suggest an extended period of vulnerability for thrombotic events. PMID- 26493664 TI - Very Late Thrombosis After Bioresorbable Scaffolds: Cause for Concern? PMID- 26493666 TI - Mitral Annulus Calcification. AB - Mitral annulus calcification (MAC) is a chronic, degenerative process in the fibrous base of the mitral valve. Although MAC was initially thought to be an age related degenerative process, there is accumulating evidence that other mechanisms, such as atherosclerosis and abnormal calcium-phosphorus metabolism, also contribute to the development of MAC. Despite its frequency, the clinical relevance of MAC is grossly underappreciated. Indeed, MAC is associated with an increased incidence of cardiovascular disease, mitral valve disease, arrhythmias, and mortality. MAC also influences the outcomes of cardiac surgery and interventions, and its clinical relevance may well increase substantially in the forthcoming era of transcatheter mitral valve replacement. In this paper, we review the available published data to provide a consistent, clinically relevant description of MAC on the basis of contemporary imaging. We describe the pathophysiological mechanisms contributing to the formation of MAC and the clinical implications of this disease entity. PMID- 26493667 TI - Telomere Maintenance Is a Critical Determinant in the Physiopathology of Pulmonary Hypertension. PMID- 26493668 TI - Is Caffeine Abstention Necessary Before Adenosine-Induced Fractional Flow Reserve Measurement? PMID- 26493665 TI - Emergence of Nonobstructive Coronary Artery Disease: A Woman's Problem and Need for Change in Definition on Angiography. AB - Recognition of ischemic heart disease (IHD) is often delayed or deferred in women. Thus, many at risk for adverse outcomes are not provided specific diagnostic, preventive, and/or treatment strategies. This lack of recognition is related to sex-specific IHD pathophysiology that differs from traditional models using data from men with flow-limiting coronary artery disease (CAD) obstructions. Symptomatic women are less likely to have obstructive CAD than men with similar symptoms, and tend to have coronary microvascular dysfunction, plaque erosion, and thrombus formation. Emerging data document that more extensive, nonobstructive CAD involvement, hypertension, and diabetes are associated with major adverse events similar to those with obstructive CAD. A central emerging paradigm is the concept of nonobstructive CAD as a cause of IHD and related adverse outcomes among women. This position paper summarizes currently available knowledge and gaps in that knowledge, and recommends management options that could be useful until additional evidence emerges. PMID- 26493669 TI - Going Over LEGACY With a Pinch of Salt. PMID- 26493670 TI - Reply: Going Over LEGACY With a Pinch of Salt. PMID- 26493671 TI - Secondary Mitral Regurgitation. PMID- 26493672 TI - Reply: Secondary Mitral Regurgitation. PMID- 26493673 TI - Cerebral Fat Embolism: A Case of Rapid-Onset Coma. PMID- 26493674 TI - Time-Resolved C-Arm Computed Tomographic Angiography Derived From Computed Tomographic Perfusion Acquisition: New Capability for One-Stop-Shop Acute Ischemic Stroke Treatment in the Angiosuite. AB - BACKGROUND AND PURPOSE: Multimodal imaging using cone beam C-arm computed tomography (CT) may shorten the delay from ictus to revascularization for acute ischemic stroke patients with a large vessel occlusion. Largely because of limited temporal resolution, reconstruction of time-resolved CT angiography (CTA) from these systems has not yielded satisfactory results. We evaluated the image quality and diagnostic value of time-resolved C-arm CTA reconstructed using novel image processing algorithms. METHODS: Studies were done under an Institutional Review Board approved protocol. Postprocessing of data from 21 C-arm CT dynamic perfusion acquisitions from 17 patients with acute ischemic stroke were done to derive time-resolved C-arm CTA images. Two observers independently evaluated image quality and diagnostic content for each case. ICC and receiver-operating characteristic analysis were performed to evaluate interobserver agreement and diagnostic value of this novel imaging modality. RESULTS: Time-resolved C-arm CTA images were successfully generated from 20 data sets (95.2%, 20/21). Two observers agreed well that the image quality for large cerebral arteries was good but was more limited for small cerebral arteries (distal to M1, A1, and P1). receiver-operating characteristic curves demonstrated excellent diagnostic value for detecting large vessel occlusions (area under the curve=0.987-1). CONCLUSIONS: Time-resolved CTAs derived from C-arm CT perfusion acquisitions provide high quality images that allowed accurate diagnosis of large vessel occlusions. Although image quality of smaller arteries in this study was not optimal ongoing modifications of the postprocessing algorithm will likely remove this limitation. Adding time-resolved C-arm CTAs to the capabilities of the angiography suite further enhances its suitability as a one-stop shop for care for patients with acute ischemic stroke. PMID- 26493675 TI - Time From Symptoms to Carotid Endarterectomy or Stenting and Perioperative Risk. AB - BACKGROUND AND PURPOSE: Prior meta-analysis showed that carotid endarterectomy benefits decline with increasing surgical delay following symptoms. For symptomatic patients in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), we assessed if differences in time between symptoms and carotid endarterectomy or carotid artery stenting are associated with differences in risk of periprocedural stroke or death. METHODS: We analyzed the 1180 symptomatic patients in CREST who received their assigned procedure and had clearly defined timing of symptoms. Patients were classified into 3 groups based on time from symptoms to procedure: <15, 15 to 60, and >60 days. RESULTS: For carotid endarterectomy, risk of periprocedural stroke or death was not significantly different for the 2 later time periods relative to the earliest time period (hazard ratio, 0.74; 95% confidence interval, 0.22-2.49 for 15-60 days and hazard ratio, 0.91; 95% confidence interval, 0.25-3.33 for >60 days; P=0.89). For carotid artery stenting, risk of periprocedural stroke or death was also not significantly different for later time periods relative to the earliest time period (hazard ratio, 1.12; 95% confidence interval, 0.53-2.40 for 15-60 days and hazard ratio, 1.15; 95% confidence interval, 0.48-2.75 for >60 days; P=0.93). CONCLUSIONS: Time from symptoms to carotid endarterectomy or carotid artery stenting did not alter periprocedural safety, supporting early revascularization regardless of modality. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732. PMID- 26493676 TI - Shear-Activated Nanoparticle Aggregates Combined With Temporary Endovascular Bypass to Treat Large Vessel Occlusion. AB - BACKGROUND AND PURPOSE: The goal of this study is to combine temporary endovascular bypass (TEB) with a novel shear-activated nanotherapeutic (SA-NT) that releases recombinant tissue-type plasminogen activator (r-tPA) when exposed to high levels of hemodynamic stress and to determine if this approach can be used to concentrate r-tPA at occlusion sites based on high shear stresses created by stent placement. METHODS: A rabbit model of carotid vessel occlusion was used to test the hypothesis that SA-NT treatment coupled with TEB provides high recanalization rates while reducing vascular injury. We evaluated angiographic recanalization with TEB alone, intra-arterial delivery of soluble r-tPA alone, or TEB combined with 2 doses of intra-arterial infusion of either the SA-NT or soluble r-tPA. Vascular injury was compared against stent-retriever thrombectomy. RESULTS: Shear-targeted delivery of r-tPA using the SA-NT resulted in the highest rate of complete recanalization when compared with controls (P=0.0011). SA-NT (20 mg) had a higher likelihood of obtaining complete recanalization as compared with TEB alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), intra-arterial r-tPA alone (odds ratio 65.019, 95% confidence interval 1.77, >1000; P=0.0231), or TEB with soluble r-tPA (2 mg; odds ratio 18.78, 95% confidence interval 1.28, 275.05; P=0.0322). Histological analysis showed circumferential loss of endothelium restricted to the area where the TEB was deployed; however, there was significantly less vascular injury using a TEB as compared with stent-retriever procedure (odds ratio 12.97, 95% confidence interval 8.01, 21.02; P<0.0001). CONCLUSIONS: A novel intra-arterial, nanoparticle-based thrombolytic therapy combined with TEB achieves high rates of complete recanalization. Moreover, this approach reduces vascular trauma as compared with stent-retriever thrombectomy. PMID- 26493677 TI - Beneficial Effects of Implementing Stroke Protocols Require Establishment of a Geographically Distinct Unit. AB - BACKGROUND AND PURPOSE: Usefulness of multidisciplinary stroke units in acute stroke patients is well established. There is extensive western literature on usefulness of stroke units in outcome, but limited evidence from the rest of the world. We aim to evaluate the impact of establishing a stroke unit on outcome in patients presenting to a tertiary care facility. METHODS: This is a retrospective study of 1003 patients with acute stroke admitted to Hamad General Hospital, Qatar, between January 2014 and February 2015. Patients directly admitted to intensive care unit (132) were excluded. We compared outcomes of pre- and poststroke ward (SW) establishment and in SW patients versus those of general medical wards. RESULTS: Before the establishment of the SW, 175 patients were admitted to the hospital. From April 2014 to February 2015, 696 patients were admitted (SW, 545; medical ward, 151). There was a significant reduction in length of stay from 14.7+/-27.7 to 6.2+/-20.2 days (P=0.0001) and incidence of complications (23.6% versus 6.4%, P=0.0001) after implementation of stroke specific protocols. Prognosis at discharge (modified Rankin Scale 0-2 in 56.0% versus 70.4%, P=0.001) and at 90 days (modified Rankin Scale 0-2 in 70.6% versus 95.0%, P=0.001) also significantly improved. Compared with medical ward patients, outcome was significantly better in SW patients with fewer complications (10.9% versus 5.0%, P=0.013) and shorter length of stay (8.9+/-30.7 versus 5.4+/-16.1 days, P=0.05). CONCLUSIONS: Establishing a distinct SW is essential for achieving full benefits of stroke protocols implementation. SW patients have significantly fewer complications and better prognosis when compared with patients in medical wards. PMID- 26493678 TI - Silencing NADPH-cytochrome P450 reductase results in reduced acaricide resistance in Tetranychus cinnabarinus (Boisduval). AB - Cytochrome P450 monooxygenases (P450s) are involved in metabolic resistance to insecticides and require NADPH cytochrome P450 reductase (CPR) to transfer electrons when they catalyze oxidation reactions. The carmine spider mite, Tetranychus cinnabarinus is an important pest mite of crop and vegetable plants worldwide, and its resistance to acaricides has quickly developed. However, the role of CPR on the formation of acaricide-resistance in T. cinnabarinus is still unclear. In this study, a full-length cDNA encoding CPR was cloned and characterized from T. cinnabarinus (designated TcCPR). TcCPR expression was detectable in all developmental stages of T. cinnabarinus, but it's much lower in eggs. TcCPR was up-regulated and more inducible with fenpropathrin treatment in the fenpropathrin-resistant (FeR) strain compared with the susceptible SS strain. Feeding of double-strand RNA was effective in silencing the transcription of TcCPR in T. cinnabarinus, which resulted in decreasing the activity of P450s and increasing the susceptibility to fenpropathrin in the FeR strain but not in the susceptible strain. The current results provide first evidence that the down regulation of TcCPR contributed to an increase of the susceptibility to fenpropathrin in resistant mites. TcCPR could be considered as a novel target for the development of new pesticides. PMID- 26493679 TI - CREB, AP-1, ternary complex factors and MAP kinases connect transient receptor potential melastatin-3 (TRPM3) channel stimulation with increased c-Fos expression. AB - BACKGROUND AND PURPOSE: The rise in intracellular Ca(2+) stimulates the expression of the transcription factor c-Fos. Depending on the mode of entry of Ca(2+) into the cytosol, distinct signal transducers and transcription factors are required. Here, we have analysed the signalling pathway connecting a Ca(2+) influx via activation of transient receptor potential melastatin-3 (TRPM3) channels with enhanced c-Fos expression. EXPERIMENTAL APPROACH: Transcription of c-Fos promoter/reporter genes that were integrated into the chromatin via lentiviral gene transfer was analysed in HEK293 cells overexpressing TRPM3. The transcriptional activation potential of c-Fos was measured using a GAL4-c-Fos fusion protein. KEY RESULTS: The signalling pathway connecting TRPM3 stimulation with enhanced c-Fos expression requires the activation of MAP kinases. On the transcriptional level, three Ca(2+) -responsive elements, the cAMP-response element and the binding sites for the serum response factor (SRF) and AP-1, are essential for the TRPM3-mediated stimulation of the c-Fos promoter. Ternary complex factors are additionally involved in connecting TRPM3 stimulation with the up-regulation of c-Fos expression. Stimulation of TRPM3 channels also increases the transcriptional activation potential of c-Fos. CONCLUSIONS AND IMPLICATIONS: Signalling molecules involved in connecting TRPM3 with the c-Fos gene are MAP kinases and the transcription factors CREB, SRF, AP-1 and ternary complex factors. As c-Fos constitutes, together with other basic region leucine zipper transcription factors, the AP-1 transcription factor complex, the results of this study explain TRPM3-induced activation of AP-1 and connects TRPM3 with the biological functions regulated by AP-1. PMID- 26493680 TI - Hamartomatous polyposis in tuberous sclerosis complex: Case report and review of the literature. AB - Tuberous sclerosis complex (TSC) is a genetic disorder with multisystem involvement that is due to autosomal-dominantly inherited or sporadic mutations in TSC1 and TSC2 genes. Involvement of the gastrointestinal tract is rare. We report the case of a 51-year-old woman with diagnosis of TSC established by genetic testing, who presented with colorectal hamartomatous polyposis. Multiple small polyps were found scattered through the left colon and rectum. Histology revealed a distinct spindle cell proliferation in the lamina propria, originating from the muscularis mucosae. The cells lacked atypia or mitotic activity and were diffusely positive for smooth muscle actin and negative for S100 protein. Genetic testing proved a disease causing frameshift mutation in the TSC1 gene. Although gastrointestinal involvement is rare in TSC, hamartomatous polyps can be the initial manifestation of this syndrome. Genetic testing should be considered in every case for which TSC is clinically suspected. PMID- 26493681 TI - Detecting Lateral Motion using Light's Orbital Angular Momentum. AB - Interrogating an object with a light beam and analyzing the scattered light can reveal kinematic information about the object, which is vital for applications ranging from autonomous vehicles to gesture recognition and virtual reality. We show that by analyzing the change in the orbital angular momentum (OAM) of a tilted light beam eclipsed by a moving object, lateral motion of the object can be detected in an arbitrary direction using a single light beam and without object image reconstruction. We observe OAM spectral asymmetry that corresponds to the lateral motion direction along an arbitrary axis perpendicular to the plane containing the light beam and OAM measurement axes. These findings extend OAM-based remote sensing to detection of non-rotational qualities of objects and may also have extensions to other electromagnetic wave regimes, including radio and sound. PMID- 26493682 TI - Sparse Markov chain-based semi-supervised multi-instance multi-label method for protein function prediction. AB - Automated assignment of protein function has received considerable attention in recent years for genome-wide study. With the rapid accumulation of genome sequencing data produced by high-throughput experimental techniques, the process of manually predicting functional properties of proteins has become increasingly cumbersome. Such large genomics data sets can only be annotated computationally. However, automated assignment of functions to unknown protein is challenging due to its inherent difficulty and complexity. Previous studies have revealed that solving problems involving complicated objects with multiple semantic meanings using the multi-instance multi-label (MIML) framework is effective. For the protein function prediction problems, each protein object in nature may associate with distinct structural units (instances) and multiple functional properties (class labels) where each unit is described by an instance and each functional property is considered as a class label. Thus, it is convenient and natural to tackle the protein function prediction problem by using the MIML framework. In this paper, we propose a sparse Markov chain-based semi-supervised MIML method, called Sparse-Markov. A sparse transductive probability graph is constructed to encode the affinity information of the data based on ensemble of Hausdorff distance metrics. Our goal is to exploit the affinity between protein objects in the sparse transductive probability graph to seek a sparse steady state probability of the Markov chain model to do protein function prediction, such that two proteins are given similar functional labels if they are close to each other in terms of an ensemble Hausdorff distance in the graph. Experimental results on seven real-world organism data sets covering three biological domains show that our proposed Sparse-Markov method is able to achieve better performance than four state-of-the-art MIML learning algorithms. PMID- 26493683 TI - Modeling the heterogeneity of p53 dynamics in DNA damage response. AB - The tumor suppressor p53 can be activated by DNA damage and exhibits undamped pulses. Recent reports have demonstrated a non-threshold mechanism for p53 dynamics. However, no related theoretical studies have been proposed. Here, we constructed a refined DNA damage repair model that incorporated both intrinsic and extrinsic DNA lesions. We proposed that the basal DNA damage may trigger significant fractions of p53 pulses. We also reproduced the heterogeneity of p53 dynamics in experiments. The number of p53 pulses showed no correlations with DNA damage. We also replicated the linear correlation between DNA damage and the probability of igniting a pulse. Our model has unraveled the heterogeneous p53 responses. PMID- 26493684 TI - An MRI-compatible platform for one-dimensional motion management studies in MRI. AB - PURPOSE: Abdominal MRI remains challenging because of respiratory motion. Motion compensation strategies are difficult to compare clinically because of the variability across human subjects. The goal of this study was to evaluate a programmable system for one-dimensional motion management MRI research. METHODS: A system comprised of a programmable motorized linear stage and computer was assembled and tested in the MRI environment. Tests of the mutual interference between the platform and a whole-body MRI were performed. Organ trajectories generated from a high-temporal resolution scan of a healthy volunteer were used in phantom tests to evaluate the effects of motion on image quality and quantitative MRI measurements. RESULTS: No interference between the motion platform and the MRI was observed, and reliable motion could be produced across a wide range of imaging conditions. Motion-related artifacts commensurate with motion amplitude, frequency, and waveform were observed. T2 measurement of a kidney lesion in an abdominal phantom showed that its value decreased by 67% with physiologic motion, but could be partially recovered with navigator-based motion compensation. CONCLUSION: The motion platform can produce reliable linear motion within a whole-body MRI. The system can serve as a foundation for a research platform to investigate and develop motion management approaches for MRI. Magn Reson Med 76:702-712, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26493685 TI - A {Nb6 P2 W12 }-Based Hexameric Manganese Cluster with Single-Molecule Magnet Properties. AB - By deliberately using a metastable polyanion [(NbO2 )6 P2 W12 O56 ](12-) (1), which was formed in situ, we have discovered the unprecedented hexameric cluster {Mn15 (Nb6 P2 W12 O62 )6 } (2), in which the six polyanions [Nb6 P2 W12 O61 ](10 ) are alternately connected by four intriguing trinuclear {Mn(III) 3 } moieties and four {Mn(II) } linkers. This discovery is the first in which the phosphoniobotungstate has been made accessible by using transition-metal ions; furthermore, polyanion 2 represents the largest niobotungstate cluster reported to date. Analysis by means of electrospray ionization mass spectrometry (ESI-MS) provides insight into the self-assembly process, and the peaks observed relate to the different charge states of the parent cluster, thus confirming the stability of 2. In addition, magnetic-susceptibility measurements reveal that each {Mn(III) 3 } subunit is a separate single-molecule magnet (SMM). This discovery results from the exploration of the reverse effect of metastable polyanion 1 possessing high reactivity, thereby turning a disadvantage into an advantage. This finding could define a new synthetic strategy for the design and synthesis of magnetic polyoxometalate (POM) clusters. PMID- 26493686 TI - Operating room nurses' positioning of anesthetized surgical patients. AB - AIMS AND OBJECTIVES: To describe the incidence of problems associated with the positioning of anaesthetised surgical patients. BACKGROUND: The positioning of the anaesthetised surgical patient is a complex task. The interdisciplinary nature with several professional groups in a surgical team may lead to conflict between the positioning standards and individual consideration for the patient. Existing knowledge of the relationship between the different positioning forms, surgical team competences and the applicability and availability of positioning equipment is sparse. DESIGN: A descriptive cross-sectional study. METHOD: An electronic questionnaire was sent to 833 OR nurses employed at four public university hospitals. With 481 responses, a response rate of 57.7% was achieved. Descriptive statistical analyses were performed using the spss software package (version 19.00). RESULTS: Positioning of the patient was found to be particularly difficult for the prone (43.8%), lithotomy (53.4%) and lateral (65.5%) positions. Lack of positioning competences and equipment for arm support, standardised equipment for leg support and standard sizes of OR beds seemed to complicate positioning. CONCLUSION: Lack of appropriate positioning equipment and positioning competences in surgical teams, combined with the poor availability of positioning equipment in ORs were found to cause problems. RELEVANCE TO CLINICAL PRACTICE: There is a need for innovative solutions to develop modern forms of positioning equipment allowing individual consideration of the patient. Further research is required on positioning equipment, optimisation of continuity and the establishment of permanent surgical teams. PMID- 26493687 TI - Photocontrolled Exposure of Pro-apoptotic Peptide Sequences in LOV Proteins Modulates Bcl-2 Family Interactions. AB - LOV domains act as biomolecular sensors for light, oxygen or the environment's redox potential. Conformational changes upon the formation of a covalent cysteinyl flavin adduct are propagated through hydrogen-bonding networks in the core of designed hybrid phototropin LOV2 domains that incorporate the Bcl homology region 3 (BH3) of the key pro-apoptotic protein BH3-interacting-domain death agonist (BID). The resulting change in conformation of a flanking amphiphilic alpha-helix creates a light-dependent optogenetic tool for the modulation of interactions with the anti-apoptotic B-cell leukaemia-2 (Bcl-2) family member Bcl-xL . PMID- 26493688 TI - High-resolution computed tomography and rheumatoid arthritis: semi-quantitative evaluation of lung damage and its correlation with clinical and functional abnormalities. AB - BACKGROUND: We aimed to establish risk factors for radiological lung damage associated with rheumatoid arthritis (RA) and determine whether clinical findings and pulmonary function test were correlated with Warrick score calculated on the basis of high-resolution computed tomography or not. METHODS: One hundred thirty RA patients who were followed at rheumatology outpatient clinic were included through retrospective screening. To evaluate radiological involvement, the semi quantitative evaluation proposed by Warrick was used to assign a score for each lesion based on the severity and extent of the pulmonary damage. In addition to the total score, indices for alveolitis and fibrosis were created. The correlations between each score and clinical and functional parameters were tested for all patients. RESULTS: We showed that age was an independent explanatory variable of radiological lung damage. Percentage of predicted lung diffusion capacity for carbon monoxide (DLco) below 75 % and presence of respiratory symptoms were found to contribute more to radiological lung damage. Warrick score was positively correlated with age at study onset (r = 0.43, p < 0.001). In addition, a negative correlation was found between Warrick score and DLco % predicted (r = -0.357, p = 0.001). Alveolitis index was negatively correlated with DLco % predicted (r = -0.321, p = 0.003). CONCLUSIONS: It is considered that this semi-quantitative method may have added value in early diagnosis, appropriate treatment decisions and follow-up when taken into account together with risk factors associated with pulmonary damage in RA. PMID- 26493690 TI - Factors that influence outcomes in cochlear implantation in adults, based on patient-related characteristics - a retrospective study. AB - OBJECTIVE: Outcomes in speech perception following cochlear implantation in adults vary widely. Many studies have been carried out to identify and quantify factors that influence outcomes. This study adds a new dimension to pre-existing literature. DESIGN: Single-centre retrospective cohort study. SETTING: University Medical Center Utrecht, the Netherlands. PARTICIPANTS: A total of 428 adults with bilateral severe-to-profound sensorineural hearing loss, unilaterally implanted between February 1988 and March 2014. MAIN OUTCOME MEASURES: Univariable and multivariable linear regression analyses were carried out to identify factors that may influence outcome after cochlear implantation. Consonant-vowel-consonant word scores were recorded pre- and post-implant and were used as outcome measure in two groups of patients (prelingually and postlingually deafened adults). As an added dimension, multiple imputation was implemented and evaluated to tackle 4% (17/407) missing data. RESULTS: For postlinguals, pre-implant speech perception score and age at onset of deafness are positive predictors and meningitis and otosclerosis as cause of deafness are negative predictors of post-implant speech perception. This model accounted for 26% of variance. For prelinguals, pre implant speech perception score is the only strong positive predictor (beta 0.524; P < 0.001). This model accounted for 31% of variance. Age at implantation was not a significant predictor in either group. CONCLUSIONS: Speech perception is predicted by pre-implant speech perception, age at onset of deafness and aetiology (meningitis and otosclerosis) for postlinguals and solely pre-implant speech perception for prelinguals. Age at implantation is of lesser importance in predicting speech perception outcome post-implant. Multiple imputation is a useful statistical technique when analysing incomplete data sets. PMID- 26493689 TI - Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer. AB - TIM-3 functions to enforce CD8+ T cell exhaustion, a dysfunctional state associated with the tolerization of tumor microenvironment. Here we report apoptosis of IFN-gamma competent TIM-3+ population of tumor-infiltrating CD8+ T cells in colon cancer. In humans suffering from colorectal cancer, TIM-3+ population is higher in cancer tissue-resident relative to peripheral blood CD8+ T cells. Both the TIM-3+ and TIM-3- cancer tissue-resident CD8+ T cells secrete IFN-gamma of comparable levels, although apoptotic cells are more in TIM-3+ compared to TIM-3- population. In mouse CT26 colon tumor model, majority of tumor infiltrating CD8+ T cells express TIM-3 and execute cytolysis function with higher effector cytokine secretion and apoptosis in TIM-3+ compared to TIM-3- population. The tumor cells secrete galectin-9, which increases apoptosis of tumor-infiltrating CD8+ T cells. Galectin-9/TIM-3 signaling blockade with anti TIM-3 antibody reduces the apoptosis and in addition, inhibits tumor growth in mice. The blockade increases therapeutic efficacy of cyclophosphamide to treat tumor in mice as well. These results reveal a previously unexplored role of TIM-3 on tumor-infiltrating CD8+ T cells in vivo. PMID- 26493691 TI - Hematopoietic stem cell transplantation from non-sibling matched family donors for patients with thalassemia major in Jordan. AB - There are limited data on the outcome of patients with thalassemia receiving HSCT from non-sibling matched family donors. Of the 341 patients with thalassemia major that underwent donor search at our center from January 2003 to December 2011, 236 (69.2%) had fully matched family donor of which 28 patients (8.2%) had non-sibling matched family donors identified. We report on seven patients with a median age of eight yr (4-21) who underwent myeloablative (n = 4) or RIC (n = 3) HSCT. The median age of the donors was 33 yr (4-47), three were parents, two first cousins, one paternal uncle, and one paternal aunt. All patients achieved primary neutrophil and platelet engraftment at a median of 18 (13-20) and 16 days (11-20), respectively. One patient developed grade II acute GVHD, and two patients developed limited chronic GVHD. One patient experienced secondary GF requiring a second transplant. At a median follow-up of 69 months (7-110), all patients are alive and thalassemia free. Our data emphasize the need for extended family HLA typing for patients with thalassemia major in regions where there is high rate of consanguinity. Transplant from non-sibling matched family donor can result in excellent outcome. PMID- 26493692 TI - Can we predict and prevent pelvic floor dysfunction? PMID- 26493693 TI - The formation of adipocere in model aquatic environments. AB - An examination of the chemistry of adipocere formation in aquatic systems provides insight into how environmental factors affect the decomposition processes of human remains. Gas chromatography-mass spectrometry (GC-MS) and inductively coupled plasma-mass spectrometry (ICPMS) have been employed to monitor the changes to the chemistry of adipocere formed in aquatic environments used to model seawater, river and chlorinated water systems. Seawater was shown to inhibit adipocere formation, and a distinctively different elemental composition was produced in this environment due to the high concentrations of salts. By comparison, river water has been shown to accelerate the formation of adipocere. Chlorinated water appears to significantly enhance adipocere formation, based on a comparison with established fatty acid concentration values. However, a competing reaction to form chlorohydrins in chlorinated water is believed to be responsible for the unusual findings in this environment. The application of the chemical characterization of adipocere to an understanding of how this particular decomposition product forms in different water environments has been demonstrated, and there is potential to utilise this approach to identify the environment in which a body has been immersed. PMID- 26493694 TI - Oxygen: The Missing Element in Low-Income Countries. PMID- 26493695 TI - The Prediction of Sonographic features and BRAF Mutation for Central Lymph Node Metastasis in Papillary Thyroid Microcarcinoma: Reply. PMID- 26493696 TI - Neutrophil-Lymphocyte Ratio as a Prognostic Marker for Lung Adenocarcinoma After Complete Resection. AB - BACKGROUNDS: The neutrophil-lymphocyte ratio (NLR) is a simple and low-cost index that may be a benchmark for systemic inflammatory response and antitumor immunity. The goal of the study was to investigate the prognostic value of preoperative NLR in patients with lung adenocarcinoma after complete resection. METHODS: The subjects were 361 consecutive patients with lung adenocarcinoma who underwent complete resection between 2000 and 2009. Perioperative clinical and laboratory data were evaluated retrospectively. The cohort was divided using the cut-off value for preoperative NLR identified in receiver operating characteristic analysis. Correlations of NLR with clinicopathological characteristics and prognosis were examined. RESULTS: A high NLR was significantly correlated with a smoking history >10 pack-years (p = 0.023), pathological stage II or III (p < 0.001), lymphatic invasion (p = 0.003), and pleural invasion (p = 0.039). In univariate analysis, the high NLR group had significantly lower 5-year overall survival (86.0 vs. 77.1 %, p < 0.001) and 5 year recurrence-free survival (75.1 vs. 59.9 %, p < 0.001). Multivariate analysis showed that NLR was an independent prognostic factor (hazard ratio 1.822, 95 % confidence interval 1.133-2.931, p = 0.013). CONCLUSION: These results show that preoperative NLR is an independent prognostic factor in patients with lung adenocarcinoma after complete resection. NLR may reflect host immunity and systemic inflammation that facilitates tumor growth. PMID- 26493697 TI - Chordoma: an update on the pathophysiology and molecular mechanisms. AB - Chordoma is a rare low-grade primary malignant skeletal tumor, which is presumed to derive from notochord remnants. The pathogenesis of chordoma has not been fully elucidated. However, recent advances in the molecular biology studies have identified brachyury underlying the initiation and progression of chordoma cells. More efforts have been made on accumulating evidence of the notochordal origin of chordoma, discovering signaling pathways and identifying crucial targets in chordomagenesis. In this review, we summarize the most recent research findings and focus on the pathophysiology and molecular mechanisms of chordoma. PMID- 26493699 TI - Variation in dry grassland communities along a heavy metals gradient. AB - The aim of this study was to investigate the variation in plant communities growing on metal-enriched sites created by historical Zn-Pb mining. The study sites were 65 small heaps of waste rock covered by grassland vegetation and scattered mostly over agricultural land of southern Poland. The sites were described in terms of plant coverage, species richness and composition, and the composition of plant traits. They were classified using phytosociological methods and detrended correspondence analysis. Identified plant communities were compared for vegetation parameters and habitat properties (soil characteristics, distance from the forest) by analysis of variance. The variation in plant community parameters was explained by multiple regression, in which the predictors were properties of the habitat selected on the basis of factor analysis. Grasslands that developed at low and high concentrations of heavy metals in soil were similar to some extent: they were composed on average of 17-20 species (per 4 m(2)), and their total coverage exceeded 90%. The species composition changed substantially with increasing contamination with heavy metals; metal-sensitive species withdrew, while the metal-tolerant became more abundant. Other important predictors of community structure were: proximity to the forest (responsible for the encroachment of competitive forest species and ruderals), and the thickness of the surface soil (shallow soil favored the formation of the heavy metal grassland). The heavy metal grassland was closely related to the dry calcareous grasslands. The former was an earlier succession stage of the latter at low contamination with heavy metals. PMID- 26493698 TI - Review of the Uses of Vagal Nerve Stimulation in Chronic Pain Management. AB - Recent human and animal studies provide growing evidence that vagal nerve stimulation (VNS) can deliver strong analgesic effects in addition to providing therapeutic efficacy in the treatment of refractory epilepsy and depression. Analgesia is potentially mediated by vagal afferents that inhibit spinal nociceptive reflexes and transmission and have strong anti-inflammatory properties. The purpose of this review is to provide pain practitioners with an overview of VNS technology and limitations. It specifically focuses on clinical indications of VNS for various chronic pain syndromes, including fibromyalgia, pelvic pain, and headaches. We also present potential mechanisms for VNS modulation of chronic pain by reviewing both animal and human studies. PMID- 26493700 TI - Feasibility of a birth cohort study dedicated to assessing acute infections using symptom diaries and parental collection of biomaterials. AB - BACKGROUND: A birth cohort dedicated to studying infections in early childhood may be assisted by parental recording of symptoms on a daily basis and a collection of biomaterials. We aimed at testing the feasibility of this approach for use in a long-term study focusing on infections in children in Germany. METHODS: Parents of 1- to 3-year-old children (n = 75) were recruited in nursery schools. They were asked to complete a symptom diary on a daily basis and to take monthly and symptom-triggered nasal swabs and stool samples from their child over the study period of three months. Feasibility was measured by means of the return proportions of symptom diaries and bio samples; acceptance was assessed by a questionnaire delivered to participants at the end of the study. RESULTS: The majority of the participants filled in the symptom diary during the three months study for 75 or more days (77.3%), and provided the monthly nasal swabs (62.7%) and stool samples (65.3%). The time needed for the tasks was acceptable for most participants (symptom diary: 92.3%, nasal swabs: 98.5%, stool samples: 100.0%). In 64.3% of the symptom-triggered nasal swabs, respiratory viruses were found compared to 55.5% in throat swabs taken by health-care professionals within the "ARE surveillance Lower Saxony", a special project by the Governmental Institute of Public Health of Lower Saxony to investigate causal pathogens for acute respiratory infections in children. CONCLUSIONS: The parental assessment of symptoms and collection of biomaterials in a birth cohort dedicated to studying infections appears feasible in a middle class German population. The success of the study will depend on the ability to maintain these activities over a long time period. PMID- 26493701 TI - A large-scale conformation sampling and evaluation server for protein tertiary structure prediction and its assessment in CASP11. AB - BACKGROUND: With more and more protein sequences produced in the genomic era, predicting protein structures from sequences becomes very important for elucidating the molecular details and functions of these proteins for biomedical research. Traditional template-based protein structure prediction methods tend to focus on identifying the best templates, generating the best alignments, and applying the best energy function to rank models, which often cannot achieve the best performance because of the difficulty of obtaining best templates, alignments, and models. METHODS: We developed a large-scale conformation sampling and evaluation method and its servers to improve the reliability and robustness of protein structure prediction. In the first step, our method used a variety of alignment methods to sample relevant and complementary templates and to generate alternative and diverse target-template alignments, used a template and alignment combination protocol to combine alignments, and used template-based and template free modeling methods to generate a pool of conformations for a target protein. In the second step, it used a large number of protein model quality assessment methods to evaluate and rank the models in the protein model pool, in conjunction with an exception handling strategy to deal with any additional failure in model ranking. RESULTS: The method was implemented as two protein structure prediction servers: MULTICOM-CONSTRUCT and MULTICOM-CLUSTER that participated in the 11th Critical Assessment of Techniques for Protein Structure Prediction (CASP11) in 2014. The two servers were ranked among the best 10 server predictors. CONCLUSIONS: The good performance of our servers in CASP11 demonstrates the effectiveness and robustness of the large-scale conformation sampling and evaluation. The MULTICOM server is available at: http://sysbio.rnet.missouri.edu/multicom_cluster/. PMID- 26493702 TI - Effects of a multidisciplinary programme on postural stability in patients with chronic recurrent low back pain: preliminary findings. AB - PURPOSE: This longitudinal study investigated the effects of a multidisciplinary rehabilitation programme on postural stability in patients with low back pain. While the consequences of such rehabilitation programme have been described for pain, mobility, strength, and functional disability, the effects on postural stability have not been examined so far. METHODS: Thirty-four patients suffering from chronic low back pain were included to participate in a multidisciplinary rehabilitation programme. We assessed postural stability, pain, strength of the lumbar extensor muscles, and functional disability. The examinations were performed before the intervention, after 20 training sessions ("half-way point"), and at the end of the rehabilitation programme. RESULTS: All outcome measures improved significantly from baseline to the first follow-up evaluation and remained constant until completion of the rehabilitation programme. CONCLUSIONS: A multidisciplinary outpatient rehabilitation programme may improve postural stability, muscle strength, pain, and functional disability in patients with chronic low back pain. PMID- 26493703 TI - Second messenger - Sensing riboswitches in bacteria. AB - Signal sensing in bacteria has traditionally been attributed to protein-based factors. It is however becoming increasingly clear that bacteria also exploit RNAs to serve this role. This review discusses how key developmental processes in bacteria, such as community formation, choice of a sessile versus motile lifestyle, or vegetative growth versus dormant spore formation may be governed by signal sensing RNAs. The signaling molecules that affect these processes, the RNAs that sense these molecules and the underlying molecular basis for specific signal-response are discussed here. PMID- 26493704 TI - Physico-chemical and biological considerations for membrane wound evolution and repair in animal cells. AB - Membrane damage is a daily threat to the life of a cell, especially cells from muscles, gut, epidermis and vasculature, tissues that are particularly subjected to mechanical stress. Damages can come from different sources and give rise to different holes in terms of size and nature. For example, while some holes are simply scratches in the lipid bilayer, others are delimited by pore forming proteins. It is thus expectable that these wounds will not evolve similarly in a cellular context, and that repair mechanisms will differ to a certain extent. It would therefore be misleading to fully generalize cell membrane damage and repair, and consider it as one universal phenomenon. Indeed, damage has been observed in cells ranging from the rather small mammalian cells (~30MUm) to the very big Urchin egg (~100MUm). Moreover, the wounds observed or artificially induced in eukaryotic cells range from some nanometers to several micrometers, and can be delimited by particular molecules as mentioned before. This chapter aims at reviewing the different physico-chemical and biological parameters that can influence wound evolution in cells and to conciliate the different repair mechanisms that have been described by evaluating them in their cellular and wound type context. PMID- 26493706 TI - Developmental regulation and evolution of muscle-specific microRNAs. AB - MicroRNAs (miRs) are a group of small RNAs that play a major role in post transcriptional regulation of gene expression. In animals, many of the miRs are expressed in a conserved spatiotemporal manner. Muscle tissues, the major cellular systems involved in the locomotion and physiological functions of animals, have been one of the main sites for verification of miR targets and analysis of their developmental functions. During the determination and differentiation of muscle cells, numerous miRs bind to and repress target mRNAs in a highly specific but redundant manner. Interspecific comparisons of the sequences and expression of miRs have suggested that miR regulation became increasingly important during the course of vertebrate evolution. However, the detailed molecular interactions that have led to the highly complex morphological structures still await investigation. In this review, we will summarize the recent findings on the functional and developmental characteristics of miRs that have played major roles in vertebrate myogenesis, and discuss how the evolution of miRs is related to the morphological complexity of the vertebrates. PMID- 26493705 TI - Non-coding functions of alternative pre-mRNA splicing in development. AB - A majority of messenger RNA precursors (pre-mRNAs) in the higher eukaryotes undergo alternative splicing to generate more than one mature product. By targeting the open reading frame region this process increases diversity of protein isoforms beyond the nominal coding capacity of the genome. However, alternative splicing also frequently controls output levels and spatiotemporal features of cellular and organismal gene expression programs. Here we discuss how these non-coding functions of alternative splicing contribute to development through regulation of mRNA stability, translational efficiency and cellular localization. PMID- 26493707 TI - Fine mapping of a large-effect QTL conferring Fusarium crown rot resistance on the long arm of chromosome 3B in hexaploid wheat. AB - BACKGROUND: Fusarium crown rot (FCR) is a major cereal disease in semi-arid areas worldwide. Of the various QTL reported, the one on chromosome arm 3BL (Qcrs.cpi 3B) has the largest effect that can be consistently detected in different genetic backgrounds. Nine sets of near isogenic lines (NILs) for this locus were made available in a previous study. To identify markers that could be reliably used in tagging the Qcrs.cpi-3B locus, a NIL-derived population consisting of 774 F10 lines were generated and exploited to assess markers selected from the existing linkage map and generated from sequences of the 3B pseudomolecule. RESULTS: This is the first report on fine mapping a QTL conferring FCR resistance in wheat. By three rounds of linkage mapping using the NILs and the NIL-derived population, the Qcrs.cpi-3B locus was mapped to an interval of 0.7 cM covering a physical distance of about 1.5 Mb. Seven markers co-segregating with the locus were developed. This interval contains a total of 63 gene-coding sequences based on the 3B pseudomolecule, and six of them were known to encode disease resistance proteins. Several of the genes in this interval were among those responsive to FCR infection detected in an earlier study. CONCLUSIONS: The accurate localization of the Qcrs.cpi-3B locus and the development of the markers co segregating with it should facilitate the incorporation of this large-effect QTL conferring FCR resistance into breeding programs as well as the cloning of the gene(s) underlying the QTL. PMID- 26493709 TI - Palladium-catalyzed carbonylative couplings of vinylogous enolates: application to statin structures. AB - The first Pd-catalyzed carbonylative couplings of aryl and vinyl halides with vinylogous enolates are reported generating products derived from C-C bond formation exclusively at the gamma-position. Good results were obtained with a dienolate derivative of acetoacetate (1,3-dioxin-4-one). These transformations occurred at room temperature and importantly with only stoichiometric carbon monoxide in a two-chamber reactor. The methodology was applied to the synthesis of two members of the statin family generating the cis-3,5-diol acid motif by a gamma-selective carbonylation followed by a cis-stereoselective reduction of the 3,5-dicarbonyl acid intermediates. PMID- 26493708 TI - Depression literacy of undergraduates in a non-western developing context: the case of Sri Lanka. AB - BACKGROUND: Research examining the depression literacy of undergraduates in non western developing countries is limited. This study explores this among undergraduates in Sri Lanka. METHODS: A total of 4671 undergraduates responded to a survey presenting a vignette of a depressed undergraduate. They were asked to identify the problem, describe their intended help-seeking actions if affected by it and rate the helpfulness of a range of help-providers and interventions for dealing with it. Mental health experts also rated these options, providing a benchmark for assessing the undergraduates' responses. RESULTS: Only 17.4% of undergraduates recognised depression, but this was significantly lower among those responding in Sinhala compared to English (3.5 vs 36.8%). More undergraduates indicated intentions of seeking informal help, such as from friends and parents, than from professionals, such as psychiatrists and counsellors. However, a majority rated all these help-providers as 'helpful', aligning with expert opinion. Other options recommended by experts and rated as 'helpful' by a large proportion of undergraduates included counselling/psychological therapy and self-help strategies such as doing enjoyable activities and meditation/yoga/relaxation exercises. However, a low proportion of undergraduates rated "western medicine to improve mood" as 'helpful', deviating from expert opinion. Although not endorsed by experts, undergraduates indicated intentions of using religious strategies, highly endorsing these as 'helpful'. Labelling the problem as depression and using mental health-related labels were both associated with higher odds of endorsing professional help, with the label 'depression' associated with endorsing a wider range of professional options. CONCLUSIONS: The recognition rate of depression might be associated with the language used to label it. These undergraduates' knowledge about the use of medication for depression needs improvement. Health promotion interventions for depressed undergraduates must be designed in light of the prevalent socio-cultural backdrop, such as the undergraduates' high endorsement of informal and culturally relevant help-seeking. Improving their ability to recognise the problem as being mental health-related might trigger their use of professional options of help. PMID- 26493710 TI - Advances in Dental Materials through Nanotechnology: Facts, Perspectives and Toxicological Aspects. AB - Nanotechnology is currently driving the dental materials industry to substantial growth, thus reflecting on improvements in materials available for oral prevention and treatment. The present review discusses new developments in nanotechnology applied to dentistry, focusing on the use of nanomaterials for improving the quality of oral care, the perspectives of research in this arena, and discussions on safety concerns regarding the use of dental nanomaterials. Details are provided on the cutting-edge properties (morphological, antibacterial, mechanical, fluorescence, antitumoral, and remineralization and regeneration potential) of polymeric, metallic and inorganic nano-based materials, as well as their use as nanocluster fillers, in nanocomposites, mouthwashes, medicines, and biomimetic dental materials. Nanotoxicological aspects, clinical applications, and perspectives for these nanomaterials are also discussed. PMID- 26493711 TI - Vault Nanoparticles Packaged with Enzymes as an Efficient Pollutant Biodegradation Technology. AB - Vault nanoparticles packaged with enzymes were synthesized as agents for efficiently degrading environmental contaminants. Enzymatic biodegradation is an attractive technology for in situ cleanup of contaminated environments because enzyme-catalyzed reactions are not constrained by nutrient requirements for microbial growth and often have higher biodegradation rates. However, the limited stability of extracellular enzymes remains a major challenge for practical applications. Encapsulation is a recognized method to enhance enzymatic stability, but it can increase substrate diffusion resistance, lower catalytic rates, and increase the apparent half-saturation constants. Here, we report an effective approach for boosting enzymatic stability by single-step packaging into vault nanoparticles. With hollow core structures, assembled vault nanoparticles can simultaneously contain multiple enzymes. Manganese peroxidase (MnP), which is widely used in biodegradation of organic contaminants, was chosen as a model enzyme in the present study. MnP was incorporated into vaults via fusion to a packaging domain called INT, which strongly interacts with vaults' interior surface. MnP fused to INT and vaults packaged with the MnP-INT fusion protein maintained peroxidase activity. Furthermore, MnP-INT packaged in vaults displayed stability significantly higher than that of free MnP-INT, with slightly increased Km value. Additionally, vault-packaged MnP-INT exhibited 3 times higher phenol biodegradation in 24 h than did unpackaged MnP-INT. These results indicate that the packaging of MnP enzymes in vault nanoparticles extends their stability without compromising catalytic activity. This research will serve as the foundation for the development of efficient and sustainable vault-based bioremediation approaches for removing multiple contaminants from drinking water and groundwater. PMID- 26493712 TI - Toxicity evaluation of nanocarriers for the oral delivery of macromolecular drugs. AB - Oral administration is the most commonly used and accepted route for drug administration. However, two of the main concerns are the poor intestinal epithelium permeability and rapid degradation, which limit absorption of drugs. In this context, nanocarriers have shown great potential for oral drug delivery. Nevertheless, special importance should be given to the possible toxic effect of these nanocarriers, such as their bioaccumulation in different tissues of the body, as well as, the different physicochemical parameters influencing their properties and so their potential toxic effect. This review describes first some aspects related to the behavior of nanosystems within the gastrointestinal tract and then some aspects of nanotoxicology and its evaluation, including the most popular techniques and approaches used for in vitro and in vivo toxicity studies. It also reviews the physicochemical characteristics of polymeric nanoparticles that may influence the development of toxicological effects, and finally it summarizes the toxicity results that have been published regarding polymeric nanocarriers. PMID- 26493713 TI - Simultaneous determination of active component and vehicle penetration from F DPPC liposomes into porcine skin layers. AB - Liposomes have been used as innovative delivery vehicles on skin for a number of years due to their positive influence on skin penetration. However, until now it is not entirely clear how and by which mechanism enhancement is achieved. In the present study, the skin permeation of a model substance incorporated into liposomes and a control formulation was compared to study the influence of the vehicle in Franz-type diffusion cell experiments. Furthermore, the penetration depths of both components were studied by simultaneous determination of the active substance and the vehicle component during tape stripping studies and horizontal sectioning. For these purposes we prepared liposomes with 1-palmitoyl 2-(16-fluoropalmitoyl)-sn-glycero-3-phosphocholine (F-DPPC), the monofluorinated analogue of dipalmitoylphosphaditylcholine (DPPC) loaded with sodium fluorescein (SoFl). A sodium-fluorescein solution was used as control formulation. While the semi-solid F-DPPC liposomes and the SoFl-solution performed equally well with similar permeation profiles during skin diffusion experiments, superior penetrated amounts of SoFl into the stratum corneum (SC) from F-DPPC liposomes compared to the SoFl-solution were observed possibly due to a "push" exerted by the vehicle F-DPPC. We also showed that SoFl penetrated through SC into the viable epidermis. PMID- 26493714 TI - Junior Seau: An Illustrative Case of Chronic Traumatic Encephalopathy and Update on Chronic Sports-Related Head Injury. AB - BACKGROUND: Few neurologic diseases have captured the nation's attention more completely than chronic traumatic encephalopathy (CTE), which has been discovered in the autopsies of professional athletes, most notably professional football players. The tragic case of Junior Seau, a Hall of Fame, National Football League linebacker, has been the most high-profile confirmed case of CTE. Here we describe Seau's case, which concludes an autopsy conducted at the National Institutes of Health that confirmed the diagnosis. CASE DESCRIPTION: Since 1990, Junior Seau had a highly distinguished 20-year career playing for the National Football League as a linebacker, from which he sustained multiple concussions. He committed suicide on May 2, 2012, at age 43, after which an autopsy confirmed a diagnosis of CTE. His clinical history was significant for a series of behavioral disturbances. Seau's history and neuropathologic findings were used to better understand the pathophysiology, diagnosis, and possible risk factors for CTE. CONCLUSIONS: This high-profile case reflects an increasing awareness of CTE as a long-term consequence of multiple traumatic brain injuries. The previously unforeseen neurologic risks of American football have begun to cast doubt on the safety of the sport. PMID- 26493715 TI - Human Brain-to-Brain Interface: Prelude to Telepathy. PMID- 26493716 TI - Omental Approach to Functional Recovery After Cerebrovascular Disease. AB - OBJECTIVE: To review and synthesize the clinical literature regarding risks and benefits of omentum transplantation and transposition surgery in patients with ischemic stroke of other etiology (non-MMD) and Moyamoya disease (MMD), and to evaluate the evidence for biological underpinnings of the presumed physiologic effects of omentum transplantation and transposition on vascularization of brain parenchyma. METHODS: Articles were searched on scientific databases using predefined key terms. Data abstraction was based on the clinical course as reported in the articles. For further analysis, patients were divided into groups according to their diagnosis (MMD or non-MMD). Descriptive statistics were computed for better integration of the results. RESULTS: The final literature review contained 15 articles (11 case series, 4 single case studies) with data on 93 patients (29 non-MMD, 64 MMD). At post-assessment 56% of patients showed substantial gains in functional domains (24% in the non-MMD group, 71% in the MMD group) and 92% demonstrated improvements of cerebral vascularization (55% in the non-MMD group, 98% in the MMD group). Differences in improvement became apparent with regard to the initial symptomatology wherein transient ischemic attacks were related to superior recovery rates and language pathologies showed least improvement. CONCLUSIONS: Surgical revascularization using omental tissue has shown good success rates, particularly for recurrent transient ischemic attacks and prevention of further strokes and should be considered as treatment option for selected patients. Experimental data on the physiologic basis for postoperative improvement delivered convincing evidence for its arteriogenic potential and recent developments in omental stem cell research suggest a role in recovery from long-standing neurological deficits. PMID- 26493717 TI - Effects of black adzuki bean (Vigna angularis, Geomguseul) extract on body composition and hypothalamic neuropeptide expression in rats fed a high-fat diet. AB - BACKGROUND: Obesity is often considered to result from either excessive food intake or insufficient physical activity. Adzuki beans have been evaluated as potential remedies for various health conditions, and recent studies have reported their effects on the regulation of lipid metabolism, but it remains to be determined whether they may be effective in overcoming obesity by regulating appetite and satiety. OBJECTIVE: This study investigated the effect of black adzuki bean (BAB) extract on body composition and hypothalamic neuropeptide expression in Sprague Dawley rats (Rattus norvegicus) fed a high-fat diet. DESIGN: The rats were fed for 8 weeks with a control diet containing 10 kcal% from fat (CD), a high-fat diet containing 60 kcal% from fat (HD), or a high-fat diet with 1% or 2% freeze-dried ethanolic extract powder of BAB (BAB-1 and BAB 2). RESULTS: The body weights and epididymal fat weights were significantly reduced and the serum lipid profiles were improved in the group fed the diet containing BAB compared to the HD group. The expression of AGRP mRNA significantly decreased in the BAB groups, and treatment with BAB-2 resulted in a marked induction of the mRNA expression of POMC and CART, which are anorexigenic neuropeptides that suppress food intake. Furthermore, mRNA expression levels of ObRb, a gene related to leptin sensitivity in the hypothalamus, were significantly higher in the BAB groups than in the HD group. CONCLUSIONS: These results suggest that supplementation with BAB has a significant effect on body weight via regulation of hypothalamic neuropeptides. PMID- 26493718 TI - Combination of videolaryngoscope and tracheal tube introducer for difficult infant airway management. PMID- 26493719 TI - Combined inhibition of Hsp90 and heme oxygenase-1 induces apoptosis and endoplasmic reticulum stress in melanoma. AB - Heat shock proteins are ubiquitous molecular chaperones involved in post translational folding, stability, activation and maturation of many proteins that are essential mediators of signal transduction and cell cycle progression. Heat shock protein 90 (Hsp90) has recently emerged as an attractive therapeutic target in cancer treatment since it may act as a key regulator of various oncogene products and cell-signaling molecules. Heme oxygenase-1 (HO-1; also known as Hsp32) is an inducible enzyme participating in heme degradation and involved in oxidative stress resistance. Recent studies indicate that HO-1 activation may play a role in tumor development and progression. In the present study we investigated the chemotherapic effects of combining an Hsp90 inhibitor (NMS E973) and an HO-1 inhibitor (SnMP) on A375 melanoma cells. NMS E973 treatment was able to reduce cell viability and induce endoplasmic reticulum (ER) stress (i.e. Ire1alpha, ERO1, PDI, BIP and CHOP). Interestingly, no significant effect was observed in reactive oxygen species (ROS) formation. Finally, NMS E973 treatment resulted in a significant HO-1 overexpression, which in turn serves as a possible chemoresistance molecular mechanism. Interestingly, the combination of NMS E973 and SnMP produced an increase of ROS and reduced cell viability compared to NMS E973 treatment alone. The inhibitors combination exhibited higher ER stress, apoptosis as evidenced by bifunctional apoptosis regulator (BFAR) mRNA expression and lower phosphorylation of Akt when compared to NMS E973 alone. In conclusion, these data suggest that HO-1 inhibition potentiates NMS E973 toxicity and may be exploited as a strategy for melanoma treatment. PMID- 26493720 TI - Localization and distribution of neurons that co-express xeroderma pigmentosum-A and epidermal growth factor receptor within Rosenthal's canal. AB - Xeroderma pigmentosum-A (XPA) is a C4-type zinc-finger scaffolding protein that regulates the removal of bulky-helix distorting DNA damage products from the genome. Phosphorylation of serine residues within the XPA protein is associated with improved protection of genomic DNA and cell death resistance. Therefore, kinase signaling is one important mechanism for regulating the protective function of XPA. Previous experiments have shown that spiral ganglion neurons (SGNs) may mobilize XPA as a general stress response to chemical and physical ototoxicants. Therapeutic optimization of XPA via kinase signaling could serve as a means to improve DNA repair capacity within neurons following injury. The kinase signaling activity of the epidermal growth factor receptor (EGFR) has been shown in tumor cell lines to increase the repair of DNA damage products that are primarily repaired by XPA. Such observations suggest that EGFR may regulate the protective function of XPA. However, it is not known whether SGNs in particular or neurons in general could co-express XPA and EGFR. In the current study gene and protein expression of XPA and EGFR were determined from cochlear homogenates. Immunofluorescence assays were then employed to localize neurons expressing both EGFR and XPA within the ganglion. This work was then confirmed with double immunohistochemistry. Rosenthal's canal served as the reference space in these experiments and design-based stereology was employed in first-order stereology quantification of immunoreactive neurons. The results confirmed that a population of SGNs that constitutively express XPA may also express the EGFR. These results provide the basis for future experiments designed to therapeutically manipulate the EGFR in order to regulate XPA activity and restore gene function in neurons following DNA damage. PMID- 26493721 TI - Delayed entry into HIV medical care in a nationally representative sample of HIV infected adults receiving medical care in the USA. AB - Before widespread antiretroviral therapy (ART), an estimated 17% of people delayed HIV care. We report national estimates of the prevalence and factors associated with delayed care entry in the contemporary ART era. We used Medical Monitoring Project data collected from June 2009 through May 2011 for 1425 persons diagnosed with HIV from May 2004 to April 2009 who initiated care within 12 months. We defined delayed care as entry >three months from diagnosis. Adjusted prevalence ratios (aPRs) were calculated to identify risk factors associated with delayed care. In this nationally representative sample of HIV infected adults receiving medical care, 7.0% (95% confidence interval [CI]: 5.3 8.8) delayed care after diagnosis. Black race was associated with a lower likelihood of delay than white race (aPR 0.38). Men who have sex with women versus women who have sex with men (aPR 1.86) and persons required to take an HIV test versus recommended by a provider (aPR 2.52) were more likely to delay. Among those who delayed 48% reported a personal factor as the primary reason. Among persons initially diagnosed with HIV (non-AIDS), those who delayed care were twice as likely (aPR 2.08) to develop AIDS as of May 2011. Compared to the pre ART era, there was a nearly 60% reduction in delayed care entry. Although relatively few HIV patients delayed care entry, certain groups may have an increased risk. Focus on linkage to care among persons who are required to take an HIV test may further reduce delayed care entry. PMID- 26493723 TI - Basic leucine zipper (bZIP) transcription factors involved in abiotic stresses: A molecular model of a wheat bZIP factor and implications of its structure in function. AB - BACKGROUND: Basic leucine zipper (bZIP) genes encode transcription factors (TFs) that control important biochemical and physiological processes in plants and all other eukaryotic organisms. SCOPE OF REVIEW: Here we present (i) the homo-dimeric structural model of bZIP consisting of basic leucine zipper and DNA binding regions, in complex with the synthetic Abscisic Acid-Responsive Element (ABREsyn); (ii) discuss homo- and hetero-dimerisation patterns of bZIP TFs; (iii) summarise the current progress in understanding the molecular mechanisms of function of bZIP TFs, including features determining the specificity of their binding to DNA cis-elements, and (iv) review information on interaction partners of bZIPs during plant development and stress response, as well as on types and roles of post-translational modifications, and regulatory aspects of protein degradation mediated turn-over. Finally, we (v) recapitulate on the recent advances regarding functional roles of bZIP factors in major agricultural crops, and discuss the potential significance of bZIP-based genetic engineering in improving crop yield and tolerance to abiotic stresses. MAJOR CONCLUSIONS: An accurate analysis and understanding of roles of plant bZIP TFs in different biological processes requires the knowledge of interacting partners, time and location of expression in plant organs, and the information on mechanisms of homo and hetero-dimerisation of bZIP TFs. GENERAL SIGNIFICANCE: Studies on molecular mechanisms of plant bZIP TFs at the atomic levels will provide novel insights into the regulatory processes during plant development, and responses to abiotic and biotic stresses. PMID- 26493722 TI - Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design. AB - BACKGROUND: Cytochrome P450 sterol 14alpha-demethylase (CYP51) is an essential enzyme for sterol biosynthesis and a target for anti-parasitic drug design. However, the design of parasite-specific drugs that inhibit parasitic CYP51 without severe side effects remains challenging. The active site of CYP51 is situated in the interior of the protein. Here, we characterize the potential ligand egress routes and mechanisms in Trypanosoma brucei and human CYP51 enzymes. METHODS: We performed Random Acceleration Molecular Dynamics simulations of the egress of four different ligands from the active site of models of soluble and membrane-bound T. brucei CYP51 and of soluble human CYP51. RESULTS: In the simulations, tunnel 2f, which leads to the membrane, was found to be the predominant ligand egress tunnel for all the ligands studied. Tunnels S, 1 and W, which lead to the cytosol, were also used in T. brucei CYP51, whereas tunnel 1 was the only other tunnel used significantly in human CYP51. The common tunnels found previously in other CYPs were barely used. The ligand egress times were shorter for human than T. brucei CYP51, suggesting lower barriers to ligand passage. Two gating residues, F105 and M460, in T. brucei CYP51 that modulate the opening of tunnels 2f and S were identified. CONCLUSIONS: Although the main egress tunnel was the same, differences in the tunnel-lining residues, ligand passage and tunnel usage were found between T. brucei and human CYP51s. GENERAL SIGNIFICANCE: The results provide a basis for the design of selective anti parasitic agents targeting the ligand tunnels. PMID- 26493724 TI - CacyBP/SIP--Structure and variety of functions. AB - BACKGROUND: CacyBP/SIP (Calcyclin-Binding Protein and Siah-1 Interacting Protein) is a small modular protein implicated in a wide range of cellular processes. It is expressed in different tissues of mammals but homologs are also found in some lower organisms. In mammals, a high level of CacyBP/SIP is present in tumor cells and in neurons. CacyBP/SIP binds several target proteins such as members of the S100 family, components of a ubiquitin ligase complex, and cytoskeletal proteins. SCOPE OF REVIEW: CacyBP/SIP has been shown to be involved in protein de phosphorylation, ubiquitination, cytoskeletal dynamics, regulation of gene expression, cell proliferation, differentiation, and tumorigenesis. This review focuses on very recent reports on CacyBP/SIP structure and function in these important cellular processes. MAJOR CONCLUSIONS: CacyBP/SIP is a multi-domain and multi-functional protein. Altered levels of CacyBP/SIP in several cancers implicate its involvement in the maintenance of cell homeostasis. Changes in CacyBP/SIP subcellular localization in neurons of AD brains suggest that this protein is strongly linked to neurodegenerative diseases. Elucidation of CacyBP/SIP structure and cellular function is leading to greater understanding of its role in normal physiology and disease pathologies. GENERAL SIGNIFICANCE: The available results suggest that CacyBP/SIP is a key player in multiple biological processes. Detailed characterization of the physical, biochemical and biological properties of CacyBP/SIP will provide better insight into the regulation of its diverse functions in vivo, and given the association with specific diseases, will help clarify the potential of therapeutic targeting of this protein. PMID- 26493726 TI - Brain tumour classification and abnormality detection using neuro-fuzzy technique and Otsu thresholding. AB - Brain tumour is one of the main causes for an increase in transience among children and adults. This paper proposes an improved method based on Magnetic Resonance Imaging (MRI) brain image classification and image segmentation approach. Automated classification is encouraged by the need of high accuracy when dealing with a human life. The detection of the brain tumour is a challenging problem, due to high diversity in tumour appearance and ambiguous tumour boundaries. MRI images are chosen for detection of brain tumours, as they are used in soft tissue determinations. First of all, image pre-processing is used to enhance the image quality. Second, dual-tree complex wavelet transform multi-scale decomposition is used to analyse texture of an image. Feature extraction extracts features from an image using gray-level co-occurrence matrix (GLCM). Then, the Neuro-Fuzzy technique is used to classify the stages of brain tumour as benign, malignant or normal based on texture features. Finally, tumour location is detected using Otsu thresholding. The classifier performance is evaluated based on classification accuracies. The simulated results show that the proposed classifier provides better accuracy than previous method. PMID- 26493725 TI - Systems biology evaluation of cell-free amniotic fluid transcriptome of term and preterm infants to detect fetal maturity. AB - BACKGROUND: Amniotic fluid (AF) is a proximal fluid to the fetus containing higher amounts of cell-free fetal RNA/DNA than maternal serum, thereby making it a promising source for identifying novel biomarkers that predict fetal development and organ maturation. Our aim was to compare AF transcriptomic profiles at different time points in pregnancy to demonstrate unique genetic signatures that would serve as potential biomarkers indicative of fetal maturation. METHODS: We isolated AF RNA from 16 women at different time points in pregnancy: 4 from 18 to 24 weeks, 6 from 34 to 36 weeks, and 6 from 39 to 40 weeks. RNA-sequencing was performed on cell-free RNA. Gene expression and splicing analyses were performed in conjunction with cell-type and pathway predictions. RESULTS: Sample-level analysis at different time points in pregnancy demonstrated a strong correlation with cell types found in the intrauterine environment and fetal respiratory, digestive and external barrier tissues of the fetus, using high-confidence cellular molecular markers. While some RNAs and splice variants were present throughout pregnancy, many transcripts were uniquely expressed at different time points in pregnancy and associated with distinct neonatal co-morbidities (respiratory distress and gavage feeding), indicating fetal immaturity. CONCLUSION: The AF transcriptome exhibits unique cell/organ selective expression patterns at different time points in pregnancy that can potentially identify fetal organ maturity and predict neonatal morbidity. Developing novel biomarkers indicative of the maturation of multiple organ systems can improve upon our current methods of fetal maturity testing which focus solely on the lung, and will better inform obstetrical decisions regarding delivery timing. PMID- 26493728 TI - NHS values should be preserved, but institutions changed, former health secretary tells conference. PMID- 26493727 TI - DNA damage-induced apoptosis suppressor (DDIAS), a novel target of NFATc1, is associated with cisplatin resistance in lung cancer. AB - In a previous study, we reported that DNA damage induced apoptosis suppressor (DDIAS; hNoxin), a human homolog of mouse Noxin, functions as an anti-apoptotic protein in response to DNA repair. Here we reveal that DDIAS is a target gene of nuclear factor of activated T cells 2 (NFATc1) and is associated with cisplatin resistance in lung cancer cells. In the DDIAS promoter analysis, we found that NFATc1 activated the transcription of DDIAS through binding to NFAT consensus sequences in the DDIAS promoter. In addition, tissue array immunostaining revealed a correlation between DDIAS and NFATc1 expression in human lung tumors. NFATc1 knockdown or treatment with the NFAT inhibitor cyclosporine A induced apoptosis and led to growth inhibition of lung cancer cells, indicating the functional relevance of both the proteins. In contrast, DDIAS overexpression overcame this NFATc1 knockdown-induced growth inhibition, supporting the cancer specific role of DDIAS as a target gene of NFATc1. NFATc1 or DDIAS inhibition clearly enhanced apoptosis induced by cisplatin in NCI-H1703 and A549 cells. Conversely, DDIAS overexpression rescued NCI-H1703 cells from cisplatin-mediated cell death and caspase-3/7 activation. These results suggest that NFATc1-induced DDIAS expression contributes to cisplatin resistance, and targeting DDIAS or NFATc1 impairs the mechanism regulating cisplatin resistance in lung cancer cells. Taken together, DDIAS is a target of NFATc1 and is associated with cisplatin resistance in lung cancer cells. PMID- 26493729 TI - Patient-Reported Outcomes and Return to Activity After Peroneus Brevis Repair. AB - BACKGROUND: There is limited data on functional outcomes after primary repair of partial peroneal tendon tears. Previous reports have been limited by small cohorts, duration of follow-up, and often included both tenodesis and primary repair. The purpose of this study was to report the functional outcomes and return to activity in the largest cohort to date with partial peroneal tendon tears treated with primary repair. METHODS: A chart review identified all patients who underwent primary repair of the peroneus brevis tendon from 2008 to 2012. Demographic data, magnetic resonance imaging findings, and postoperative complications were reviewed. Patients were asked to complete a follow-up questionnaire, Foot and Ankle Ability Measure (FAAM), and Foot Function Index (FFI). There were 201 patients who underwent primary repair of the peroneus brevis tendon. The average age at time of operation was 44.3 years. Seventy-one patients returned the follow-up questionnaires with an average follow-up of 4.6 years. Fifty-two patients completed the FFI questionnaire preoperatively and postoperatively. RESULTS: Fifty-nine patients (83.1%) reported a return to regular exercise and sports at final follow-up. At 1 year postoperatively, 76.5% of patients returned to the same preinjury activities, and 62.3% returned to the same level of preinjury activity. Furthermore, 85.9% of patients were satisfied with their outcome, and 91.4% of patients reported they would choose to undergo the same procedure again. The mean FAAM score was 85.2 at follow-up. The mean preoperative and postoperative FFI score was 41.1 and 12.2, respectively. There was a significant improvement in the FFI score of 28.9 after primary peroneus brevis tendon repair (P < .001). CONCLUSION: Primary repair of peroneus brevis tendon provided consistent improvement in functional outcomes in the majority of patients, as measured by a validated scoring system, the FFI. FAAM scores demonstrated good function compared to historical controls. The majority of patients were able to return to preinjury activity. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26493730 TI - Outbreak of hospital-acquired gastroenteritis and invasive infection caused by Listeria monocytogenes, Finland, 2012. AB - During one week in July 2012, two patients from the same ward at the municipal hospital in Vaasa, Finland, were diagnosed with septicaemia caused by Listeria monocytogenes. An outbreak investigation revealed eight concomitant cases of febrile gastroenteritis caused by L. monocytogenes on the same ward. Median age of the cases was 82 years and median incubation time for listerial gastroenteritis was 21 h (range 9-107). An additional 10 cases of invasive listeriosis caused by the same outbreak strain were identified across the whole country during the summer of 2012. Environmental investigation at the affected municipal hospital ward revealed ready-sliced meat jelly as the suspected source of the infection. During inspection of the meat jelly production plant, one pooled sample taken from a floor drain and a trolley wheel in the food processing environment was positive for the outbreak strain of L. monocytogenes. After the producer stopped the production of meat jelly, no further cases of listeriosis with the outbreak strain were identified via nationwide surveillance. PMID- 26493731 TI - Effects of Exercise on Falls, Balance, and Gait Ability in Parkinson's Disease: A Meta-analysis. AB - Postural instability and falls are complex and disabling features of Parkinson's disease (PD) and respond poorly to anti-Parkinsonian medication. There is an imperative need to evaluate the effectiveness of exercise interventions in enhancing postural stability and decreasing falls in the PD population. The objectives of our study were to determine the effects of exercise training on the enhancement of balance and gait ability and reduction in falls for people with PD and to investigate potential factors contributing to the training effects on balance and gait ability of people with PD. We included 25 randomized control trials of a moderate methodological quality in our meta-analysis. The trials examined the effects of exercise training on balance and gait ability and falls against no intervention and placebo intervention. The results showed positive effects of exercise intervention on enhancing balance and gait performance (Hedges' g = 0.303 over the short-term in 24 studies and 0.419 over the long-term in 12 studies; P < .05) and reducing the fall rate (rate ratio = 0.485 over the short-term in 4 studies and 0.413 over the long-term in 5 studies; P < .05). The longest follow-up duration was 12 months. There was no evidence that training decreased the number of fallers over the short- or long-term (P > .05). The results of our metaregression and subgroup analysis showed that facility-based training produced greater training effects on improving PD participants' balance and gait ability (P < .05). The findings support the application of exercise training to improve balance and gait ability and prevent falls in people with PD. PMID- 26493732 TI - Prefrontal Cortex Activation While Walking Under Dual-Task Conditions in Stroke: A Multimodal Imaging Study. AB - Background Walking while performing another task (eg, talking) is challenging for many stroke survivors, yet its neural basis are not fully understood. Objective To investigate prefrontal cortex activation and its relationship to gait measures while walking under single-task (ST) and dual-task (DT) conditions (ie, walking while simultaneously performing a cognitive task) in stroke survivors. Methods We acquired near-infrared spectroscopy (NIRS) data from the prefrontal cortex during treadmill walking in ST and DT conditions in chronic stroke survivors and healthy controls. We also acquired functional magnetic resonance imaging (fMRI) and NIRS during simulated walking under these conditions. Results NIRS revealed increased oxygenated hemoglobin concentration in DT-walking compared with ST-walking for both groups. For simulated walking, NIRS showed a significant effect of group and group * task, being greater on both occasions, in stroke survivors. A greater increase in brain activation observed from ST to DT walking/ simulated walking was related to a greater change in motor performance in stroke survivors. fMRI revealed increased activity during DT relative to ST conditions in stroke patients in areas including the inferior temporal gyri, superior frontal gyri and cingulate gyri bilaterally, and the right precentral gyrus. The DT-related increase in fMRI activity correlated with DT-related change in behavior in stroke participants in the bilateral inferior temporal gyrus, left cingulate gyrus, and left frontal pole. Conclusion Our results provide novel evidence that enhanced brain activity changes relate to dual task motor decrements. PMID- 26493733 TI - Analysis of muscle synergies and activation-deactivation patterns in subjects with anterior cruciate ligament deficiency during walking. AB - BACKGROUND: The knowledge of muscle activation patterns when doing a certain task in subjects with anterior cruciate ligament deficiency could help to improve their rehabilitation treatment. The goal of this study is to identify differences in such patterns between anterior cruciate ligament-deficient and healthy subjects during walking. METHODS: Electromyographic data for eight muscles were measured in a sample of eighteen subjects with anterior cruciate ligament deficiency, in both injured (ipsilateral group) and non-injured (contralateral group) legs, and a sample of ten healthy subjects (control group). The analysis was carried out at two levels: activation-deactivation patterns and muscle synergies. Muscle synergy components were calculated using a non-negative matrix factorization algorithm. FINDINGS: The results showed that there was a higher co contraction in injured than in healthy subjects. Although all muscles were activated similarly since all subjects developed the same task (walking), some differences could be observed among the analyzed groups. INTERPRETATION: The observed differences in the synergy components of injured subjects suggested that those individuals alter muscle activation patterns to stabilize the knee joint. This analysis could provide valuable information for the physiotherapist to identify alterations in muscle activation patterns during the follow-up of the subject's rehabilitation. PMID- 26493734 TI - Seizure Freedom in Children With Pathology-Confirmed Focal Cortical Dysplasia. AB - OBJECTIVE: We evaluated the temporal course of seizure outcome in children with pathology-confirmed focal cortical dysplasia and explored predictors of sustained seizure freedom. METHODS: We performed a single-center retrospective study of children <= 18 years who underwent resective surgery from January 1, 2000 through December 31, 2012 and had pathology-proven focal cortical dysplasia. Surgical outcome was classified as seizure freedom (Engel class I) or seizure recurrence (Engel classes II-IV). Fisher exact and nonparametric Wilcoxon ranksum tests were used, as appropriate. Survival analysis was based on seizure-free outcome. Patients were censored at the time of seizure recurrence or seizure freedom at last follow-up. RESULTS: Thirty-eight patients were identified (median age at surgery, 6.5 years; median duration of epilepsy, 3.3 years). Median time to last follow-up was 13.5 months (interquartile range, 7-41 months). Twenty patients (53%) were seizure free and 26 patients (68%) attained seizure freedom for a minimum of 3 months. Median time to seizure recurrence was 38 months (95% confidence interval, 6-109 months), and the cumulative seizure-free rate was 60% at 12 months (95% confidence interval, 43%-77%). Clinical features associated with seizure freedom at last follow-up included older age at seizure onset (P = .02), older age at surgery (P = .04), absent to mild intellectual disability before surgery (P = .05), and seizure freedom for a minimum of 3 months (P < .001). CONCLUSION: Favorable clinical features associated with sustained seizure freedom included older age at seizure onset, older age at surgery, absent or mild intellectual disability at baseline, and seizure freedom for a minimum of 3 months. PMID- 26493735 TI - Too Old for a Diaper! A Child With Diaper Changing-Induced Seizures. PMID- 26493736 TI - Exaggerated Startle. PMID- 26493737 TI - Commentary: The salience of socioeconomic status in assessing cardiovascular disease and risk in low- and middle-income countries. PMID- 26493738 TI - Coral record of southeast Indian Ocean marine heatwaves with intensified Western Pacific temperature gradient. AB - Increasing intensity of marine heatwaves has caused widespread mass coral bleaching events, threatening the integrity and functional diversity of coral reefs. Here we demonstrate the role of inter-ocean coupling in amplifying thermal stress on reefs in the poorly studied southeast Indian Ocean (SEIO), through a robust 215-year (1795-2010) geochemical coral proxy sea surface temperature (SST) record. We show that marine heatwaves affecting the SEIO are linked to the behaviour of the Western Pacific Warm Pool on decadal to centennial timescales, and are most pronounced when an anomalously strong zonal SST gradient between the western and central Pacific co-occurs with strong La Nina's. This SST gradient forces large-scale changes in heat flux that exacerbate SEIO heatwaves. Better understanding of the zonal SST gradient in the Western Pacific is expected to improve projections of the frequency of extreme SEIO heatwaves and their ecological impacts on the important coral reef ecosystems off Western Australia. PMID- 26493739 TI - Erratum to: Predictors of recurrence in the management of chordoid meningioma. PMID- 26493740 TI - Clinical outcome and prognostic factors for central neurocytoma: twenty year institutional experience. AB - Central neurocytomas are uncommon intraventricular neoplasms whose optimal management remains controversial due to their rarity. We assessed outcomes for a historical cohort of neurocytoma patients and evaluated effects of tumor atypia, size, resection extent, and adjuvant radiotherapy. Progression-free survival (PFS) was measured by Kaplan-Meier and Cox proportional hazards methods. A total of 28 patients (15 males, 13 females) were treated between 1995 and 2014, with a median age at diagnosis of 26 years (range 5-61). Median follow-up was 62.2 months and 3 patients were lost to follow-up postoperatively. Thirteen patients experienced recurrent/progressive disease and 2-year PFS was 75% (95% CI 53-88%). Two-year PFS was 48% for MIB-1 labeling >4% versus 90% for <=4% (HR 5.4, CI 2.2 27.8, p = 0.0026). Nine patients (32%) had gross total resections (GTR) and 19 (68%) had subtotal resections (STR). PFS for >80% resection was 83 versus 67% for <=80% resection (HR 0.67, CI 0.23-2.0, p = 0.47). Three STR patients (16%) received adjuvant radiation which significantly improved overall PFS (p = 0.049). Estimated 5-year PFS was 67% for STR with radiotherapy versus 53% for STR without radiotherapy. Salvage therapy regimens were diverse and resulted in stable disease for 54% of patients and additional progression for 38 %. Two patients with neuropathology-confirmed atypical neurocytomas died at 4.3 and 113.4 months after initial surgery. For central neurocytomas, MIB-1 labeling index >4% is predictive of poorer outcome and our data suggest that adjuvant radiotherapy after STR may improve PFS. Most patients requiring salvage therapy will be stabilized and multiple modalities can be effectively utilized. PMID- 26493741 TI - Nursing assessment of older people who are in hospital: exploring registered nurses' understanding of their assessment skills. AB - BACKGROUND: Nurses worldwide are expected to take a leading role in caring for older people. Considerable literature dedicated to the range and application of assessment skills used by nurses vary. There is limited knowledge of registered nurses' (RNs) views of their assessment of older adults. AIM: The aim of this project was to explore RNs current perceptions of nursing assessment, and the core skills they identified as necessary. DESIGN: A qualitative descriptive design study was conducted in three inpatient units in one regional hospital in Victoria. METHOD: Date were collected through participant observation of RNs (n = 13) followed by 1:1 semi-structured interviews. Data were analysed thematically. CONCLUSION: This research has illuminated that an ill-defined repertoire of skills was used by RNs when assessing older persons. Skills identified appeared to be based on years of personal-professional experience. Differences were noted between the descriptions nurses gave and what was observed during interactions with older persons. PMID- 26493742 TI - Organocatalyzed One-Step Synthesis of Functionalized N-Alkyl-Pyridinium Salts from Biomass Derived 5-Hydroxymethylfurfural. AB - An efficient and scalable method has been developed for the synthesis of N alkylpyridinium salts from biomass derived 5-hydroxymethylfurfural and alkyl amines using a catalytic amount of formic acid. This protocol is also extended to various diamines providing the exclusive formation of mono-N-alkylpyridinium salts. In addition, the mechanism for the formation of pyridinium salts was studied by DFT and using H2(18)O isotope labeled experiments showing no incorporation of (18)O in the product. PMID- 26493743 TI - Observing real-time images during ultrasound-guided procedures improves patients' experience. PMID- 26493744 TI - An argument for early genomic sequencing in atypical cases: a WISP3 variant leads to diagnosis of progressive pseudorheumatoid arthropathy of childhood. PMID- 26493745 TI - Qualitative Analyses of Protein Phosphorylation in Bovine Pluripotent Stem Cells Generated from Embryonic Fibroblasts. AB - Pluripotent stem cells (PSCs) generated from somatic cells via ectopic expression of specific transcription factors provide an unlimited cell resource for regenerative medicine and transgenic breeding. Here, we describe the successful generation of bovine induced PSCs (biPSCs) from foetal fibroblasts by lentivirus mediated delivery of bovine pluripotency reprogramming factors (PRFs) OCT3/4, SOX2, KLF4, c-MYC, NANOG and LIN28. The generated biPSCs resembled embryonic stem cells (ESCs) in their gene expression profiles, self-renewal capabilities and proliferation, as well as maintenance of a normal karyotype and differentiation into diverse cell types of all three germ layers both in vitro and in vivo. Qualitative phosphoproteomics of biPSCs revealed a large number of phosphorylated proteins, which might be related to the control of biPSCs status. The successful generation of biPSCs and the analysis of their phosphoproteome would further our understanding of the epigenetic mechanisms underlying iPSC pluripotency, thus promoting their application in bovine transgenic breeding and marking avenues for future research. PMID- 26493746 TI - Involvement of Potassium Channels and Calcium-Independent Mechanisms in Hydrogen Sulfide-Induced Relaxation of Rat Mesenteric Small Arteries. AB - Endogenous hydrogen sulfide (H2S) is involved in the regulation of vascular tone. We hypothesized that the lowering of calcium and opening of potassium (K) channels as well as calcium-independent mechanisms are involved in H2S-induced relaxation in rat mesenteric small arteries. Amperometric recordings revealed that free [H2S] after addition to closed tubes of sodium hydrosulfide (NaHS), Na2S, and GYY4137 [P-(4-methoxyphenyl)-P-4-morpholinyl-phosphinodithioic acid] were, respectively, 14%, 17%, and 1% of added amount. The compounds caused equipotent relaxations in isometric myographs, but based on the measured free [H2S], GYY4137 caused more relaxation in relation to released free H2S than NaHS and Na2S in rat mesenteric small arteries. Simultaneous measurements of [H2S] and tension showed that 15 uM of free H2S caused 61% relaxation in superior mesenteric arteries. Simultaneous measurements of smooth muscle calcium and tension revealed that NaHS lowered calcium and caused relaxation of NE-contracted arteries, while high extracellular potassium reduced NaHS relaxation without corresponding calcium changes. In NE-contracted arteries, NaHS (1 mM) lowered the phosphorylation of myosin light chain, while phosphorylation of myosin phosphatase target subunit 1 remained unchanged. Protein kinase A and G, inhibitors of guanylate cyclase, failed to reduce NaHS relaxation, whereas blockers of voltage-gated KV7 channels inhibited NaHS relaxation, and blockers of mitochondrial complex I and III abolished NaHS relaxation. Our findings suggest that low micromolar concentrations of free H2S open K channels followed by lowering of smooth muscle calcium, and by another mechanism involving mitochondrial complex I and III leads to uncoupling of force, and hence vasodilation. PMID- 26493747 TI - New Multi-target Antagonists of alpha1A-, alpha1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure. AB - Benign prostatic hyperplasia (BPH) is characterized by stromal cell proliferation and contraction of the periurethral smooth muscle, causing lower urinary tract symptoms. Current BPH treatment, based on monotherapy with alpha1A-adrenoceptor antagonists, is helpful for many patients, but insufficient for others, and recent reports suggest that stimulation of alpha1D-adrenoceptors and 5 hydroxytryptamine (serotonin) (5-HT)1A receptors contributes to cell proliferation. In this study, we investigated the potential of three N phenylpiperazine derivatives (LDT3, LDT5, and LDT8) as multi-target antagonists of BPH-associated receptors. The affinity and efficacy of LDTs were estimated in isometric contraction and competition-binding assays using tissues (prostate and aorta) and brain membrane samples enriched in specific on- or off-target receptors. LDTs' potency was estimated in intracellular Ca(2+) elevation assays using cells overexpressing human alpha1-adrenoceptor subtypes. The antiproliferative effect of LDTs on prostate cells from BPH patients was evaluated by viable cell counting and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays. We also determined LDTs' effects on rat intraurethral and arterial pressure. LDT3 and LDT5 are potent antagonists of alpha1A-, alpha1D adrenoceptors, and 5-HT1A receptors (Ki values in the nanomolar range), and fully inhibited phenylephrine- and 5-HT-induced proliferation of BPH cells. In vivo, LDT3 and LDT5 fully blocked the increase of intraurethral pressure (IUP) induced by phenylephrine at doses (ED50 of 0.15 and 0.09 MUg.kg(-1), respectively) without effect on basal mean blood pressure. LDT3 and LDT5 are multi-target antagonists of key receptors in BPH, and are capable of triggering both prostate muscle relaxation and human hyperplastic prostate cell growth inhibition in vitro. Thus, LDT3 and LDT5 represent potential new lead compounds for BPH treatment. PMID- 26493749 TI - Novel Direct Assay for Acetyl-CoA:alpha-Glucosaminide N-Acetyltransferase Using BODIPY-Glucosamine as a Substrate. AB - Heparan sulfate acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT) catalyzes the transmembrane acetylation of heparan sulfate in lysosomes required for its further catabolism. Inherited deficiency of HGSNAT in humans results in lysosomal storage of heparan sulfate and causes severe neurodegenerative disease, mucopolysaccharidosis III type C (MPS IIIC). MPS IIIC patients can potentially benefit from a therapeutic approach based on active site-specific inhibitors of HGSNAT used as pharmacological chaperons to modify the folding of the mutant protein in the patient's cells. This research however was hampered by the absence of the assay suitable for high-throughput screening of drug libraries for HGSNAT inhibitors. The existing method utilizing 4-methylumbelliferyl-beta-D glucosaminide (MU-betaGlcN) requires the sequential action of two enzymes, HGSNAT and beta-hexosaminidase, whereas the radioactive assay with [C14]-AcCoA is complicated and expensive. We describe a novel direct method to assay HGSNAT enzymatic activity using fluorescent BODIPY-glucosamine as a substrate. The specificity of the assay was tested using cultured fibroblasts of MPS IIIC patients, which showed a profound deficiency of HGSNAT activity as compared to normal controls as well as to MPS IIIA and D patients known to have normal HGSNAT activity. Known competitive HGSNAT inhibitor, glucosamine, had similar inhibition constants for MU-betaGlcN and BODIPY-glucosamine acetylation reactions. Altogether our data show that novel HGSNAT assay is specific and potentially applicable for the biochemical diagnosis of MPS IIIC and high-throughput screening for HGSNAT inhibitors. PMID- 26493748 TI - Visual features as stepping stones toward semantics: Explaining object similarity in IT and perception with non-negative least squares. AB - Object similarity, in brain representations and conscious perception, must reflect a combination of the visual appearance of the objects on the one hand and the categories the objects belong to on the other. Indeed, visual object features and category membership have each been shown to contribute to the object representation in human inferior temporal (IT) cortex, as well as to object similarity judgments. However, the explanatory power of features and categories has not been directly compared. Here, we investigate whether the IT object representation and similarity judgments are best explained by a categorical or a feature-based model. We use rich models (>100 dimensions) generated by human observers for a set of 96 real-world object images. The categorical model consists of a hierarchically nested set of category labels (such as "human", "mammal", and "animal"). The feature-based model includes both object parts (such as "eye", "tail", and "handle") and other descriptive features (such as "circular", "green", and "stubbly"). We used non-negative least squares to fit the models to the brain representations (estimated from functional magnetic resonance imaging data) and to similarity judgments. Model performance was estimated on held-out images not used in fitting. Both models explained significant variance in IT and the amounts explained were not significantly different. The combined model did not explain significant additional IT variance, suggesting that it is the shared model variance (features correlated with categories, categories correlated with features) that best explains IT. The similarity judgments were almost fully explained by the categorical model, which explained significantly more variance than the feature-based model. The combined model did not explain significant additional variance in the similarity judgments. Our findings suggest that IT uses features that help to distinguish categories as stepping stones toward a semantic representation. Similarity judgments contain additional categorical variance that is not explained by visual features, reflecting a higher-level more purely semantic representation. PMID- 26493750 TI - Elevated Circulating S100A12 Associates with Vascular Disease and Worse Clinical Outcome in Peritoneal Dialysis Patients. AB - ? BACKGROUND: The pro-inflammatory receptor of advanced glycation end-products (RAGE)-ligand S100A12 is thought to promote, whereas anti-inflammatory soluble RAGE (sRAGE) may protect against, vascular disease. We evaluated circulating S100A12 and sRAGE in relation to vascular disease, inflammation, nutritional status, and mortality risk in peritoneal dialysis (PD) patients. ? METHODS: Plasma S100A12 and sRAGE, biomarkers of inflammation, nutritional status, and comorbidities were analyzed in 82 prevalent PD patients (median age 65 years; 70% men; median vintage 12 months) and, for comparative analysis, also in 190 hemodialysis (HD) patients and 50 control subjects. Associations between mortality risk and concentrations of S100A12 and sRAGE were assessed in PD and HD patients after a mean follow-up period of 31 and 29 months respectively using a competing risk Cox regression model. ? RESULTS: In PD patients, median S100A12, sRAGE and S100A12/sRAGE were markedly higher than in controls, and S100A12 was 1.9 times higher and median sRAGE 14% lower compared with HD patients. In PD patients, S100A12 associated with C-reactive protein (rho = 0.46; p < 0.001) and interleukin-6 (rho = 0.38; p < 0.001), and, negatively, with s-albumin (rho = 0.27; p < 0.05) whereas sRAGE associated negatively with body mass index (rho = 0.37; p < 0.001), fat body mass index (rho = -0.34; p < 0.001), and lean body mass index (rho = -0.36; p < 0.001). Peripheral vascular disease or cerebrovascular disease (PCVD) was present in 28% of PD patients and, in multivariate analysis, associated mainly with high S100A12 (odds ratio [OR] 3.52, p = 0.04). In both PD and HD patients, the highest versus other tertiles of S100A12 associated with increased mortality. In contrast, sRAGE did not associate with PCVD or mortality in PD and HD patients. ? CONCLUSIONS: Plasma S100A12 and sRAGE are markedly elevated in PD patients. Soluble RAGE was inversely related to body mass indices while S100A12 associated with increased inflammation, PCVD, and mortality, suggesting that S100A12 may identify PD patients at high risk for vascular disease and increased mortality. PMID- 26493751 TI - Erythrocytes as Volume Markers in Experimental PD Show that Albumin Transport in the Extracellular Space Depends on PD Fluid Osmolarity. AB - ? BACKGROUND: Macromolecules, when used as intraperitoneal volume markers, have the disadvantage of leaking into the surrounding tissue. Therefore, (51)Cr labeled erythrocytes were evaluated as markers of intraperitoneal volume and used in combination with (125)I-labeled bovine serum albumin to study albumin transport into peritoneal tissues in a rat model of peritoneal dialysis (PD). ? METHODS: Single dwells of 20 mL of lactate-buffered filter-sterilized PD fluid at glucose concentrations of 0.5%, 2.5%, and 3.9% were performed for 1 or 4 hours. Tissue biopsies from abdominal muscle, diaphragm, liver, and intestine, and blood and dialysate samples, were analyzed for radioactivity. ? RESULTS: The dialysate distribution volume of labeled erythrocytes, measured after correction for lymphatic clearance to blood, was strongly correlated with, but constantly 3.3 mL larger than, drained volumes. Erythrocyte activity of rinsed peritoneal tissue biopsies corresponded to only 1 mL of dialysate, supporting our utilization of erythrocytes as markers of intraperitoneal volume. The difference between the distribution volumes of albumin and erythrocytes was analyzed to represent the albumin loss into the peritoneal tissues, which increased rapidly during the first few minutes of the dwell and then leveled out at 2.5 mL. It resumed when osmotic ultrafiltration turned into reabsorption and, at the end of the dwell, it was significantly lower for the highest osmolarity PD fluid (3.9% glucose). Biopsy data showed the lowest albumin accumulation and edema formation in abdominal muscle for the 3.9% fluid. ? CONCLUSION: Labeled erythrocytes are acceptable markers of intraperitoneal volume and, combined with labeled albumin, provided novel kinetic data on albumin transport in peritoneal tissues. PMID- 26493752 TI - Peritoneal Dialysis Fluid and Some of Its Components Potentiate Fibrocyte Differentiation. AB - Long-term peritoneal dialysis (PD) often results in the development of peritoneal fibrosis. In many other fibrosing diseases, monocytes enter the fibrotic lesion and differentiate into fibroblast-like cells called fibrocytes. We find that peritoneal tissue from short-term PD patients contains few fibrocytes, while fibrocytes are readily observed in the peritoneal membrane of long-term PD patients. The PD fluid Dianeal (Baxter Healthcare Corporation, Deerfield, IL, USA) contains dextrose, a number of electrolytes including sodium chloride, and sodium lactate. We find that PD fluid potentiates human fibrocyte differentiation in vitro and implicates sodium lactate in this potentiation. The plasma protein serum amyloid P (SAP) inhibits fibrocyte differentiation. Peritoneal dialysis fluid and sodium chloride decrease the ability of human SAP to inhibit human fibrocyte differentiation in vitro Together, these results suggest that PD fluid contributes to the development of peritoneal fibrosis by potentiating fibrocyte differentiation. PMID- 26493753 TI - Stability of Antibiotics for Intraperitoneal Administration in Extraneal 7.5% Icodextrin Peritoneal Dialysis Bags (STAB Study). AB - ? BACKGROUND AND OBJECTIVES: Patients with peritoneal dialysis (PD)-associated peritonitis may be advised to store PD-bags with pre-mixed antibiotics at home, although there is a paucity of antibiotic stability studies in the commonly used icodextrin solutions. The purpose of this study was to assess the stability of various antibiotics in PD-bags when stored at different temperatures over a 14 day period. ? METHODS: 7.5% icodextrin PD-bags were dosed with gentamicin 20 mg/L (n = 9), vancomycin 1,000 mg/L (n = 9), cefazolin 500 mg/L (n = 9) and ceftazidime 500 mg/L (n = 9) as for intermittent dosing. Combinations of gentamicin/vancomycin (n = 9), cefazolin/ceftazidime (n = 9), and cefazolin/gentamicin (n = 9) were also tested. Nine drug-free bags were used as controls. Bags were stored in triplicate at 37 degrees C, room-temperature (25 degrees C), and refrigeration (4 degrees C). Antibiotic concentrations were quantified at various time intervals using validated chromatography. Storage duration was considered unstable if the concentration of the antibiotic dropped <= 90% of the initial value. ? RESULTS: Gentamicin was stable for 14 days at all temperatures. Vancomycin was stable for 4 days at 37 degrees C and for 14 days at both 25 degrees C and 4 degrees C. The gentamicin and vancomycin combination was stable for 4 days at 37 degrees C and for 14 days at 25 degrees C and 4 degrees C. Cefazolin alone was stable for 24 hours at 37 degrees C, 7 days at 25 degrees C, and 14 days at 4 degrees C. Ceftazidime alone was stable for only 6 hours at 37 degrees C, 2 days at 25 degrees C, and 14 days at 4 degrees C. The cefazolin and ceftazidime combination was stable for 24 hours at 37 degrees C, 2 days at 25 degrees C, and 14 days at 4 degrees C. The cefazolin and gentamicin combination was stable for 1 day at 37 degrees C, 4 days at 25 degrees C, and 14 days at 4 degrees C. ? CONCLUSIONS: Antibiotics premixed in icodextrin PD-bags have varying stabilities with stability generally least at 37 degrees C and best at 4(o)C, permitting storage for 14 days when refrigerated and prewarming to body temperature prior to administration. Further research confirming the sterility of these antibiotic-containing bags is recommended. PMID- 26493754 TI - Catheter Insertion and Perioperative Practices Within the ISPD North American Research Consortium. AB - ? BACKGROUND: In general, efforts to standardize care based on group consensus practice guidelines have resulted in lower morbidity and mortality. Although there are published guidelines regarding insertion and perioperative management of peritoneal dialysis (PD) catheters, variation in practice patterns between centers may exist. The objective of this study is to understand variation in PD catheter insertion practices in preparation for conducting future studies. ? METHODS: An electronic survey was developed by the research committee of the International Society for Peritoneal Dialysis - North American Research Consortium (ISPD-NARC) to be completed by physicians and nurses involved in PD programs across North America. It consisted of 45 questions related to 1) organizational characteristics; 2) PD catheter insertion practices; 3) current quality-improvement initiatives; and 4) interest in participation in PD studies. Invitation to participate in the survey was given to nephrologists and nurses in centers across Canada and the United States (US) identified by participation in the inaugural meeting of the ISPD-NARC. Descriptive statistics were applied to analyze the data. ? RESULTS: Fifty-one ISPD-NARC sites were identified (45% in Canada and 55% in the US) of which 42 responded (82%). Center size varied significantly, with prevalent PD population ranging from 6 - 300 (median: 60) and incident PD patients in the year prior to survey administration ranging from 3 - 180 (median: 20). The majority of centers placed fewer than 19 PD catheters/year, with a range of 0 - 50. Availability of insertion techniques varied significantly, with 83% of centers employing more than 1 insertion technique. Seventy-one percent performed laparoscopic insertion with advanced techniques (omentectomy, omentopexy, and lysis of adhesions), 62% of sites performed open surgical dissection, 10% performed blind insertion via trocar, and 29% performed blind placement with the Seldinger technique. Use of double-cuff catheters was nearly universal, with a near even distribution of catheters with pre-formed bend versus straight inter-cuff segments. There was also variation in the choice of perioperative antibiotics and perioperative flushing practices. Although 86% of centers had quality-improvement initiatives, there was little consensus as to appropriate targets. ? CONCLUSIONS: There is marked variability in PD catheter insertion techniques and perioperative management. Large multicenter studies are needed to determine associations between these practices and catheter and patient outcomes. This research could inform future trials and guidelines and improve practice. The ISPD-NARC is a network of PD units that has been formed to conduct multicenter studies in PD. PMID- 26493756 TI - Pernicious Emboli: An Uncommon Cause of a Common Problem. PMID- 26493755 TI - Burkholderia cepacia Exit-Site Infection in Peritoneal Dialysis Patients-Clinical Characteristics and Treatment Outcomes. AB - ? BACKGROUND: Burkholderia cepacia is a hardy bacterium with intrinsic resistance to multiple antibiotics and high transmissibility. Opportunistic healthcare associated B. cepacia infections among immunocompromised or critically ill patients have been reported, but there is limited data on the clinical characteristics and treatment outcomes of exit-site infection (ESI) in peritoneal dialysis (PD) patients. ? PATIENTS AND METHODS: Patients who suffered from B. cepacia ESI from 1 January 2004 to 31 December 2014 were reviewed. The clinical characteristics and treatment outcomes of the patients and the antibiotic susceptibility patterns of the bacterial isolates were analyzed. ? RESULTS: Twenty-two patients were included for analysis. Eight patients (36.4%) had medical conditions which impaired host immunity, while 7 (31.8%) had pre-existing skin abnormalities. Three patients (13.6%) progressed to tunnel-tract infection and another 3 patients (13.6%) developed associated peritonitis. Fifteen patients (68.2%) responded to medical treatment while 7 (31.8%) required catheter removal. Eleven patients (50.0%) had recurrent B. cepacia ESI, which occurred at 7.8 months (95% confidence interval [CI] 0.1 - 19.4 months) after the first episode. Most B. cepacia strains were susceptible to ceftazidime (95.5%), piperacillin/tazobactam (95.5%), and piperacillin (90.9%). Besides aminoglycosides (80 - 100%), high rates of resistance were also observed for ticarcillin/clavulanate (90.9%). ? CONCLUSION: Burkholderia cepacia ESI is associated with low rates of tunnel-tract infection or peritonitis, but the risk of recurrence is high. Most cases can be managed with medical treatment alone, although one third of patients might require catheter removal. PMID- 26493757 TI - Intraductal papillary neoplasm of the bile duct (IPN-B): also a disease of western Caucasian patients. A literature review and case series. AB - Cholangiocarcinoma (CCa) is an aggressive malignancy, which often presents with advanced, inoperable disease. Early detection of any premalignant condition could improve the dismal prognosis of cholangiocarcinoma (5% 5-year survival). There are two premalignant precursors of CCa: biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPN-B). BilIN is only visible microscopically; imaging has no role in identification. IPN-B is a recent diagnostic entity, arising from a World Health Organization (WHO) reclassification of tumours. IPN-B is visible macroscopically, and can be identified on imaging. With its propensity to spread preferentially along the biliary epithelium, only infiltrating the duct wall at a late stage, it may be more amenable to complete resection than typical CCa. The lead time with early detection, during which dysplasia could progress to invasive carcinoma, is an opportunity where resection may be curative. The literature on IPN-B has originated from Asia, but awareness of this condition in the western world is limited. We report a case series of IPN-B occurring in Caucasian patients from the UK, with radiological-pathological correlation. The protean imaging appearances present a unique challenge, but also a great opportunity, for radiologists. Early identification and resection of lesions, even in asymptomatic or minimally symptomatic patients, should be considered. PMID- 26493758 TI - Splenic Preservation Versus Splenectomy During Distal Pancreatectomy: A Systematic Review and Meta-analysis. AB - BACKGROUND: Studies have been published comparing spleen-preserving distal pancreatectomy (SPDP) with distal pancreatectomy with splenectomy (DPS), but the results remain inconsistent. The aim of this study was to compare SPDP with DPS by conducting a systematic review and meta-analysis. METHODS: Literature searches of the Medline/PubMed, Embase, and Cochrane Library databases were performed to identify relevant studies published before April 30,2015. Perioperative outcomes of SPDP and DPS were evaluated. The meta-analysis was performed in random- or fixed-effects models, as appropriate. A subanalysis was conducted to compare the two techniques of splenic preservation: splenic vessel preservation (SVP) and Warshaw technique (WT). RESULTS: Eighteen studies and 1156 patients were included in the comparison between SPDP and DPS. A total of 502 of these patients underwent SPDP and 654 underwent DPS. Meta-analysis showed the SPDP group had significantly fewer infectious complications (odds ratio [OR] 0.57, P = 0.006), less operative blood loss (P<0.0001), lower overall morbidity rate (OR 0.66, P = 0.002), and lower clinical pancreatic fistula rate (OR 0.42, P = 0.002) than the DPS group. Subanalysis indicated the SVP group had significantly lower rate of spleen infarction (OR 0.12, P<0.00001) and fewer secondary splenectomies (OR 0.13, P = 0.008) than the WT group. CONCLUSIONS: SPDP was a safe procedure associated with better short-term outcomes than DPS. SVP could provide more sufficient blood perfusion for the conserved spleen than WT. However, the evidence is limited, and more randomized controlled trials are warranted. PMID- 26493759 TI - [Minimally invasive tricuspid valve replacement using percutaneous endocaval occlusion in patients with previous cardiac surgery]. PMID- 26493760 TI - Influence of the hydrophilic head size and hydrophobic tail length of surfactants on the ability of micelles to stabilize citral. AB - BACKGROUND: Surfactant-made micelles can control the rate of chemical degradation of poorly water-soluble food flavors. To evaluate how the molecular structure of surfactant has an influence on the chemical decomposition rate of citral, micelles were prepared with polyoxyethylene alkyl ether-type surfactants that had similar molecular structures but various hydrophilic head sizes and hydrophobic tail lengths. RESULTS: At a critical 20* micelle concentration of surfactant, there was no significant difference in the chemical degradation rate of citral in micelles in neutral pH, regardless of the hydrophilic head size or hydrophobic tail length. In an acidic environment, the degradation rate constant of citral generally increased proportionally with increasing hydrophilic head size of surfactant (0.1563 and 0.2217 for surfactants with 23 and 100 oxyethylene units, respectively) but the length of hydrophobic tail did not affect the citral stability. Also, little difference (0.2217 and 0.2265 for surfactant having 100 oxyethylene units with and without Fe(3+) ) in degradation rate constant of citral between simple micellar solution and micellar solution containing iron suggested that iron ions could not accelerate citral degradation in micelles, regardless of the form of iron (Fe(2+) and Fe(3+) ). CONCLUSION: This work concludes that although the concentration of surfactant could be relevant, if its concentration could be controlled in the same manner as the critical micelle concentration, then a polyethylene alkyl ether-type surfactant with a small hydrophilic head could more efficiently stabilize citral at an acidic pH. (c) 2015 Society of Chemical Industry. PMID- 26493761 TI - Ectopic thyroid tissue in the adrenal gland: CT and MRI findings. PMID- 26493762 TI - Multidetector-row computed tomography (MDCT) features of small bowel obstruction (SBO) caused by Meckel's diverticulum. AB - OBJECTIVES: To report the multidetector-row computed tomography (MDCT) findings of small bowel obstruction (SBO) caused by Meckel's diverticulum. MATERIALS AND METHODS: Ten patients (9 men and 1 woman; age range, 2-44 years; median age, 21years) with surgical proven Meckel's diverticulum who presented SBO on the preoperative MDCT were included in the study. RESULTS: On MDCT, all patients presented with SBO, either high-grade (n=6) or low-grade obstruction (n=4). Meckel's diverticulum was identified in five patients (n=5, 50%) on preoperative MDCT. In the five patients in whom a diverticulum was not seen on preoperative MDCT, MDCT showed a transition site on ileum with dilated proximal loops (n=3), pneumoperitoneum (n=1), jejuno-jejunal intussusception (n=1). Transition zone was located near midline in four patients (4/5, 80%). CONCLUSION: The diagnosis of Meckel's diverticulum complicated SBO can be made with certainty when the diverticulum is visualized on preoperative MDCT. However, the preoperative diagnosis is difficult if the Meckel's diverticulum is not noted on the MDCT. When the obstructive processes are visualized in the lower abdomen or pelvis, particularly near the midline, one should keep in mind that SBO may be caused by Meckel's diverticulum without prior surgical history. PMID- 26493763 TI - Retrieval of a dislocated coil and stent-assisted coiling by Solitaire((r)) stent during endovascular treatment of an intracranial aneurysm. PMID- 26493764 TI - Unique Separation Behavior of a C60 Fullerene-Bonded Silica Monolith Prepared by an Effective Thermal Coupling Agent. AB - Herein, we report a newly developed C60 fullerene-bonded silica monolith in a capillary with unique retention behavior due to the structure of C60 fullerene. N Hydroxysuccinimide (NHS)-conjugated C60 fullerene was successfully synthesized by a thermal coupling agent, perfluorophenyl azide (PFPA), and assigned by spectroscopic analyses. Then, NHS-PFPA-C60 fullerene was attached onto the surface of a silica monolith in a capillary. The capillary provided specific separation ability for polycyclic aromatic hydrocarbons in liquid chromatography by an effective pi-pi interaction. Furthermore, corannulene, which has a hemispherical structure, was selectively retained in the capillary based on the specific structural recognition due to the spherical C60 fullerene. This is the first report revealing the spherical recognition ability by C60 fullerene in liquid chromatographic separation. PMID- 26493765 TI - Comparison of medetomidine, thiopental and ketamine/midazolam anesthesia in chick embryos for in ovo Magnetic Resonance Imaging free of motion artifacts. AB - Non-invasive assessment of the perfusion capacity of tissue engineered constructs grown on the chorioallantoic membrane by MRI is often hampered by motion artifacts. Therefore, we examined the suitability of three anesthetic regimes for sufficient sedation of the chick embryo. Medetomidine at a dosage of 0.3 mg/kg, was compared to thiopental at 100 mg/kg and ketamine/midazolam at 50 mg/kg and 1 mg/kg, respectively. These soluble anesthetics were applied by dropping a total volume of 0.3 mL onto the surface of the CAM. Motion was videotaped through the window of the eggshell and scored semi-quantitatively. Medetomidine performed best in terms of reduced motion; onset of anesthesia occurred within 10 minutes and for the following 30 minutes, allowing proper in vivo MRI measurements. The other regimen were not sedating deep enough (ketamine/midazolam) and not long enough (thiopental). In sum, medetomidine allows proper sedation for MRI assessment of the perfusion capacity in a tissue engineered construct placed on the CAM. PMID- 26493769 TI - Total Synthesis of (+)-MPC1001B. AB - The first total synthesis of an epidithiodiketopiperazine alkaloid, (+)-MPC1001B, was accomplished. This synthesis features a tetra-n-butylammonium fluoride mediated intramolecular aldol reaction for forming the 15-membered macrolactone ring, and the construction of an epidithiodiketopiperazine substructure through a stepwise sulfenylation reaction involving a novel trityl trisulfide (TrSSS)-group transfer. PMID- 26493768 TI - A population database study of outcomes associated with vitamin K antagonists in atrial fibrillation before DOAC. AB - AIMS: This study aimed to describe the real-life incidence of bleeding, arterial thrombotic events and death during vitamin K antagonist (VKA) treatment in atrial fibrillation (AF). METHODS: This was a cohort study in Echantillon Generaliste de Beneficiaires, the 1/97 sample of the French national healthcare claims and hospitalization database, of new VKA users with definite or probable AF and no other indication, and of patients without AF, from 2007 to 2011. Prespecified outcomes were all-cause death, hospitalization for bleeding, arterial thrombotic event (ATE), or acute coronary syndrome (ACS) or any of the above (composite outcome). RESULTS: Of 8894 new VKA users, 3345 had probable or certain AF, 51.7% were male, mean age was 75.1 years, 87.1% had a CHA2 DS2 -VASc score >= 2 and 11.6% a HAS-BLED score > 3. Among AF patients, during VKA exposure the incidence rate of bleeding was 2.8 [95% confidence interval (CI) 2.2, 3.4] per 100 patient years, including 0.6 (95% CI 0.3, 0.8) cerebral, 1.0 (95% CI 0.7, 1.3) digestive and 1.4 (95% CI 1.0, 1.7) other bleeds. There were 1.6 (95% CI 1.2, 2.0) ACS, 1.5 (95% CI 1.1, 1.8) ATE and 3.8 (95% CI 3.2, 4.4) deaths per 100 patient-years. The incidence rate of the composite outcome was 9.1 per 100 patient-years (95% CI 8.2, 10.0). When patients stopped VKA, bleeding decreased (RR 0.67, 95% CI 0.43, 1.04)), but death or thrombosis increased (RR 3.06, 95% CI 2.46, 3.81 and 1.75, 95% CI 1.14, 2.70, respectively). During VKA exposure non-AF patients had similar rates of bleeding, but fewer deaths, ACS and ischaemic events. CONCLUSIONS: Real life rates for bleeding, arterial thrombotic events, ACS and deaths in AF patients treated with VKA were similar to those observed in clinical trials. PMID- 26493767 TI - Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void? AB - Concern over antibiotic resistance is growing, and new classes of antibiotics, particularly against Gram-negative bacteria, are needed. However, even if the scientific hurdles can be overcome, it could take decades for sufficient numbers of such antibiotics to become available. As an interim solution, antibiotic resistance could be 'broken' by co-administering appropriate non-antibiotic drugs with failing antibiotics. Several marketed drugs that do not currently have antibacterial indications can either directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics and/or modulate host defence through effects on host innate immunity, in particular by altering inflammation and autophagy. This article discusses how such 'antibiotic resistance breakers' could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation. PMID- 26493766 TI - Complement, a target for therapy in inflammatory and degenerative diseases. AB - The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies. PMID- 26493770 TI - Non-Oxidative Dehydrogenation Pathways for the Conversion of C2 -C4 Alcohols to Carbonyl Compounds. AB - Gold nanoparticles (NPs) supported on hydrotalcite (Au/HT) are highly active and selective catalysts for the continuous, gas-phase, non-oxidative dehydrogenation of bioderived C2 -C4 alcohols. A sharp increase in turn over frequency (TOF) is noted when the size of Au NPs is less than 5 nm relating to the strong synergy between metallic Au NPs and the acid-base groups on the support surface. It is shown that catalytic activity depends critically on Au NP size, support composition, and support pretreatments. A reaction pathway elucidated from kinetic isotope effects suggests that the abstraction of beta-H by Au NPs (C-H activation) is the rate-determining step in the dehydrogenation of bioderived C2 C4 alcohols. PMID- 26493771 TI - The SUMO Protease SENP3 Orchestrates G2-M Transition and Spindle Assembly in Mouse Oocytes. AB - Oocyte meiosis is a transcription quiescence process and the cell-cycle progression is coordinated by multiple post-translational modifications, including SUMOylation. SENP3 an important deSUMOylation protease has been intensively studied in ribosome biogenesis and oxidative stress. However, the roles of SENP3 in cell-cycle regulation remain enigmatic, particularly for oocyte meiotic maturation. Here, we found that SENP3 co-localized with spindles during oocyte meiosis and silencing of SENP3 severely compromised the M phase entry (germinal vesicle breakdown, GVBD) and first polar body extrusion (PBI). The failure in polar body extrusion was due to the dysfunction of gamma-tubulin that caused defective spindle morphogenesis. SENP3 depletion led to mislocalization and a substantial loss of Aurora A (an essential protein for MTOCs localization and spindle dynamics) while irregularly dispersed distribution of Bora (a binding partner and activator of Aurora A) in cytoplasm instead of concentrating at spindles. The SUMO-2/3 but not SUMO-1 conjugates were globally decreased by SENP3 RNAi. Additionally, the spindle assembly checkpoint remained functional upon SENP3 RNAi. Our findings renew the picture of SENP3 function by exploring its role in meiosis resumption, spindle assembly and following polar body emission during mouse oocyte meiotic maturation, which is potentially due to its proteolytic activity that facilitate SUMO-2/3 maturation. PMID- 26493772 TI - Judging trustworthiness from faces: Emotion cues modulate trustworthiness judgments in young children. AB - By adulthood, people judge trustworthiness from appearances rapidly and reliably. However, we know little about these judgments in children. This novel study investigates the developmental trajectory of explicit trust judgments from faces, and the contribution made by emotion cues across age groups. Five-, 7-, 10-year olds, and adults rated the trustworthiness of trustworthy and untrustworthy faces with neutral expressions. The same participants also rated faces displaying overt happy and angry expressions, allowing us to investigate whether emotion cues modulate trustworthiness judgments similarly in children and adults. Results revealed that the ability to evaluate the trustworthiness of faces emerges in childhood, but may not be adult like until 10 years of age. Moreover, we show that emotion cues modulate trust judgments in young children, as well as adults. Anger cues diminished the appearance of trustworthiness for participants from 5 years of age and happy cues increased it, although this effect did not consistently emerge until later in childhood, that is, 10 years of age. These associations also extended to more subtle emotion cues present in neutral faces. Our results indicate that young children are sensitive to facial trustworthiness, and suggest that similar expression cues modulate these judgments in children and adults. PMID- 26493773 TI - Visual Identification of Light-Driven Breakage of the Silver-Dithiocarbamate Bond by Single Plasmonic Nanoprobes. AB - Insight into the nature of metal-sulfur bond, a meaningful one in life science, interface chemistry and organometallic chemistry, is interesting but challenging. By utilizing the localized surface plasmon resonance properties of silver nanoparticles, herein we visually identified the photosensitivity of silver dithiocarbamate (Ag-DTC) bond by using dark field microscopic imaging (iDFM) technique at single nanoparticle level. It was found that the breakage of Ag-DTC bond could be accelerated effectively by light irradiation, followed by a pH dependent horizontal or vertical degradation of the DTC molecules, in which an indispensable preoxidation process of the silver was at first disclosed. These findings suggest a visualization strategy at single plasmonic nanoparticle level which can be excellently applied to explore new stimulus-triggered reactions, and might also open a new way to understand traditional organic reaction mechanisms. PMID- 26493774 TI - [Etiologic diagnosis in meningitis and encephalitis molecular biology techniques]. AB - INTRODUCTION: The aetiological study of infections of the central nervous system has traditionally been performed using bacterial cultures and, more recently, using polymerase chain reaction (PCR) for herpes simplex virus (HSV). Bacterial cultures may not have good performance, especially in the context of patients who have received antibiotics prior to sampling, and a request for HSV only by PCR reduces the information to only one aetiological agent. The aim of this study is to determine the infectious causes of meningitis and encephalitis, using traditional microbiology and molecular biology to improve the aetiological diagnosis of these diseases. PATIENTS AND METHOD: A prospective study was conducted on 19 patients with suspected meningitis, admitted to the Luis Calvo Mackenna Hospital in Santiago, Chile, from March 1, 2011 to March 30, 2012. After obtaining informed consent, the CSF samples underwent cytochemical study, conventional culture, multiplex PCR for the major producing bacterial meningitis (N. meningitidis, S. pneumoniae, H. influenzae), real-time single PCR for HSV-1 and 2, VZV, EBV, CMV, HHV-6 and enterovirus. Clinical and epidemiological data were also collected from the clinical records. RESULTS: Of the 19 patients analysed, 2 were diagnosed by conventional methods and 7 by adding molecular biology (increase to 37%). Three patients had meningitis due to S. pneumoniae, one due to Enterobacter cloacae, 2 patients meningoencephalitis HSV-1, and one VZV meningitis. CONCLUSIONS: The addition of PCR to conventional diagnostic methods in CNS infections increases the probability of finding the causal agent. This allows a more adequate, timely and rational management of the disease. PMID- 26493775 TI - Do the tuberculin skin test and the QuantiFERON-TB Gold in-tube test agree in detecting latent tuberculosis among high-risk contacts? A systematic review and meta-analysis. AB - OBJECTIVES: The QuantiFERON-TB Gold in-tube test (QFT-GIT) and the tuberculin skin test (TST) are used to diagnose latent tuberculosis infection (LTBI). However, conclusive evidence regarding the agreement of these two tests among high risk contacts is lacking. This systematic review and meta-analysis aimed to estimate the agreement between the TST and the QFT-GIT using kappa statistics. METHODS: According to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines, scientific databases including PubMed, Scopus, and Ovid were searched using a targeted search strategy to identify relevant studies published as of June 2015. Two researchers reviewed the eligibility of studies and extracted data from them. The pooled kappa estimate was determined using a random effect model. Subgroup analysis, Egger's test and sensitivity analysis were also performed. RESULTS: A total of 6,744 articles were retrieved in the initial search, of which 24 studies had data suitable for meta-analysis. The pooled kappa coefficient and prevalence-adjusted bias-adjusted kappa were 0.40 (95% confidence interval [CI], 0.34 to 0.45) and 0.45 (95% CI, 0.38 to 0.49), respectively. The results of the subgroup analysis found that age group, quality of the study, location, and the TST cutoff point affected heterogeneity for the kappa estimate. No publication bias was found (Begg's test, p=0.53; Egger's test, p=0.32). CONCLUSIONS: The agreement between the QFT-GIT and the TST in diagnosing LTBI among high-risk contacts was found to range from fair to moderate. PMID- 26493776 TI - Test-retest reliability of health behavior items in the Community Health Survey in South Korea. AB - OBJECTIVES: Responses to health-related items on the Community Health Survey (CHS) provide evidence that is used to develop community-based health policy. This study aimed to assess the test-retest reliability of selected health behavioral items on the CHS according to item category, response period, and response scale. METHODS: A sample of 159 men and women 20 to 69 years of age participated in a test-retest with an interval of 14 to 21 days. A total of 28 items relating to smoking, alcohol consumption, diet and weight control, and mental health were selected. We evaluated the test-retest reliability of the items using kappa statistics. RESULTS: Kappa values ranged from 0.44 to 0.93. Items concerning habits had higher kappa values (mean, 0.7; standard error, 0.05) than items concerning awareness or attitudes (p=0.012). The kappa value of items with two- to four-point scales was 0.63, which was higher than the value of 0.59 for items with scales involving five or more points, although this difference was not statistically significant. Different kappa values were observed for each reference period, but no statistically significant differences were noted. CONCLUSIONS: The test-retest reliability of the CHS items that we studied was associated with item category. Further study of the relationship between item category and reliability in domains other than health behaviors is required. PMID- 26493777 TI - Risk factors for amputation in patients with diabetic foot ulcer in southwest Iran: a matched case-control study. AB - OBJECTIVES: Amputation is a multifactorial complication in diabetic patients. The aim of this study was to determine the risk factors associated with amputation in patients with diabetic foot ulcers. METHODS: This matched case-control study was conducted based on new cases of amputation from March 2012 to November 2014. We selected new cases who had undergone amputation, and the control group was chosen from the cities or areas where the cases resided. Each case was matched with two controls based on the duration of diabetes and location. Conditional logistic regression was used to evaluate the associations between potential risk factors and amputation. RESULTS: A total of 131 cases were compared with 262 controls. The results of the adjusted model showed that sex (odds ratio [OR], 8.66; 95% confidence interval [CI], 2.68 to 27.91), fewer than two hemoglobin A1c (HbA1c) tests per year (OR, 13.97; 95% CI, 4.97 to 39.26), unsuitable shoes (OR, 5.50; 95% CI, 2.20 to 13.77), smoking (OR, 3.44; 95% CI, 1.45 to 8.13), and body mass index (OR, 1.20; 95% CI, 1.03 to 1.41) were associated with amputation in diabetic patients. CONCLUSIONS: The most important factors associated with amputation were females, irregular monitoring of HbA1c levels, improper footwear, and smoking. Developing educational programs and working to ensure a higher quality of care for diabetic patients are necessary steps to address these issues. PMID- 26493778 TI - Trends in health-related behaviors of Korean adults: study based on data from the 2008-2014 Community Health Surveys. AB - Unhealthy lifestyle behaviors such as smoking, alcohol consumption, and physical inactivity (multiple risks) often lead to serious health consequence and impaired health status. The purpose of this study was to investigate the trend in health related behavioral factors over time among adults in South Korea (hereafter Korea). The data of 1,595,842 Koreans older than 19 years who participated in the 2008-2014 Korea Community Health Survey were analyzed to assess the trend in the prevalence of behavioral risk factors. Individual or clustering health-related behaviors were assessed according to sex, age, and region among 228,712 adults who participated in the 2014 survey. From 2008 to 2014, the age-adjusted prevalence of obesity and high-risk alcohol use increased the prevalence of male current smoking and marginally decreased walking ability. Over 7 years, the percentage of adults who reported having all three healthy behaviors (i.e., currently not smoking, not consuming alcohol or having high-risk alcohol use, and engaging in walking) decreased from 35.2% in 2008 to 29.6% in 2014. Increased efforts to emphasize multiple health-related behavioral risk factors, including reducing alcohol use and smoking, and to encourage walking are needed in the thirties and forties age groups in Korea. PMID- 26493779 TI - [Formula: see text]Gestational age and gender influence on executive control and its related neural structures in preterm-born children at 6 years of age. AB - Within preterm-born children, being born male and at a lower gestational age (GA) have both been associated with a heightened risk for developmental difficulties. However, in this population little is known about the combined effect and the influence of these risk factors on cortical structures and executive control. In the present study, 58 preterm-born children (GA ranging from 24.0 to 35.1 weeks) were administered the computerized Child Attention Network Task at 6 years of age. Brain magnetic resonance imaging was performed and analyzed using Voxel Based Morphometry (VBM) in all children. At a behavioral level, boys born <28 weeks of GA had significantly less executive control than preterm-born girls <28 weeks (p = .001) and preterm-born boys >=28 (p = .003). The reduced executive control in preterm-born boys <28 weeks gestation was related to lower cortical densities in the inferior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC). The current study links the higher incidence of reduced executive control in preterm-born boys to a higher degree of prematurity (low GA) and identifies brain structural abnormalities in the prefrontal cortex related to these deficits. The implications of these results are discussed. PMID- 26493780 TI - Oxidation and beta-Alkylation of Alcohols Catalysed by Iridium(I) Complexes with Functionalised N-Heterocyclic Carbene Ligands. AB - The borrowing hydrogen methodology allows for the use of alcohols as alkylating agents for C?C bond forming processes offering significant environmental benefits over traditional approaches. Iridium(I)-cyclooctadiene complexes having a NHC ligand with a O- or N-functionalised wingtip efficiently catalysed the oxidation and beta-alkylation of secondary alcohols with primary alcohols in the presence of a base. The cationic complex [Ir(NCCH3 )(cod)(MeIm(2- methoxybenzyl))][BF4 ] (cod=1,5-cyclooctadiene, MeIm=1-methylimidazolyl) having a rigid O-functionalised wingtip, shows the best catalyst performance in the dehydrogenation of benzyl alcohol in acetone, with an initial turnover frequency (TOF0 ) of 1283 h(-1) , and also in the beta-alkylation of 2-propanol with butan-1-ol, which gives a conversion of 94 % in 10 h with a selectivity of 99 % for heptan-2-ol. We have investigated the full reaction mechanism including the dehydrogenation, the cross aldol condensation and the hydrogenation step by DFT calculations. Interestingly, these studies revealed the participation of the iridium catalyst in the key step leading to the formation of the new C?C bond that involves the reaction of an O bound enolate generated in the basic medium with the electrophilic aldehyde. PMID- 26493781 TI - Semiparametric Allelic Tests for Mapping Multiple Phenotypes: Binomial Regression and Mahalanobis Distance. AB - Binary phenotypes commonly arise due to multiple underlying quantitative precursors and genetic variants may impact multiple traits in a pleiotropic manner. Hence, simultaneously analyzing such correlated traits may be more powerful than analyzing individual traits. Various genotype-level methods, e.g., MultiPhen (O'Reilly et al. []), have been developed to identify genetic factors underlying a multivariate phenotype. For univariate phenotypes, the usefulness and applicability of allele-level tests have been investigated. The test of allele frequency difference among cases and controls is commonly used for mapping case-control association. However, allelic methods for multivariate association mapping have not been studied much. In this article, we explore two allelic tests of multivariate association: one using a Binomial regression model based on inverted regression of genotype on phenotype (Binomial regression-based Association of Multivariate Phenotypes [BAMP]), and the other employing the Mahalanobis distance between two sample means of the multivariate phenotype vector for two alleles at a single-nucleotide polymorphism (Distance-based Association of Multivariate Phenotypes [DAMP]). These methods can incorporate both discrete and continuous phenotypes. Some theoretical properties for BAMP are studied. Using simulations, the power of the methods for detecting multivariate association is compared with the genotype-level test MultiPhen's. The allelic tests yield marginally higher power than MultiPhen for multivariate phenotypes. For one/two binary traits under recessive mode of inheritance, allelic tests are found to be substantially more powerful. All three tests are applied to two different real data and the results offer some support for the simulation study. We propose a hybrid approach for testing multivariate association that implements MultiPhen when Hardy-Weinberg Equilibrium (HWE) is violated and BAMP otherwise, because the allelic approaches assume HWE. PMID- 26493782 TI - From light-harvesting to photoprotection: structural basis of the dynamic switch of the major antenna complex of plants (LHCII). AB - Light-Harvesting Complex II (LHCII) is largely responsible for light absorption and excitation energy transfer in plants in light-limiting conditions, while in high-light it participates in photoprotection. It is generally believed that LHCII can change its function by switching between different conformations. However, the underlying molecular picture has not been elucidated yet. The available crystal structures represent the quenched form of the complex, while solubilized LHCII has the properties of the unquenched state. To determine the structural changes involved in the switch and to identify potential quenching sites, we have explored the structural dynamics of LHCII, by performing a series of microsecond Molecular Dynamics simulations. We show that LHCII in the membrane differs substantially from the crystal and has the signatures that were experimentally associated with the light-harvesting state. Local conformational changes at the N-terminus and at the xanthophyll neoxanthin are found to strongly correlate with changes in the interactions energies of two putative quenching sites. In particular conformational disorder is observed at the terminal emitter resulting in large variations of the excitonic coupling strength of this chlorophyll pair. Our results strongly support the hypothesis that light harvesting regulation in LHCII is coupled with structural changes. PMID- 26493783 TI - Rhinovirus-associated pulmonary exacerbations show a lack of FEV1 improvement in children with cystic fibrosis. AB - BACKGROUND: Respiratory viral infections lead to bronchial inflammation in patients with cystic fibrosis, especially during pulmonary exacerbations. The aim of this study was to determine the impact of viral-associated pulmonary exacerbations in children with cystic fibrosis and failure to improve forced expiratory volume in 1 s (FEV1 ) after an appropriate treatment. METHODS: We lead a pilot study from January 2009 until March 2013. Children with a diagnosis of cystic fibrosis were longitudinally evaluated three times: at baseline (Visit 1), at the diagnosis of pulmonary exacerbation (Visit 2), and after exacerbation treatment (Visit 3). Nasal and bronchial samples were analyzed at each visit with multiplex viral respiratory PCR panel (qualitative detection of 16 viruses). Pulmonary function tests were recorded at each visit, in order to highlight a possible failure to improve them after treatment. Lack of improvement was defined by an increase in FEV1 less than 5% between Visit 2 and Visit 3. RESULTS: Eighteen children were analyzed in the study. 10 patients failed to improve by more than 5% their FEV1 between Visit 2 and Visit 3. Rhinovirus infection at Visit 2 or Visit 3 was the only risk factor significantly associated with such a failure (OR, 12; 95% CI, 1.3-111.3), P = 0.03. CONCLUSIONS: Rhinovirus infection seems to play a role in the FEV1 recovery after pulmonary exacerbation treatment in children with cystic fibrosis. Such an association needs to be confirmed by a large-scale study because this finding may have important implications for pulmonary exacerbation management. PMID- 26493784 TI - Predictors of costs from the hospital perspective of primary pulmonary embolism. AB - The objective of this study was to estimate the total hospital cost per patient admitted through the emergency department with a primary diagnosis of pulmonary embolism (PE), and to identify the main components and predictors of costs.Actual costs of care of 652 consecutive patients hospitalised in 10 general hospitals in Belgium, including 31 outlier patients in terms of length of stay (4.8%), were obtained by aggregating all cost components contributing to care of each patient.In both inlier and outlier patients, the mean total cost per patient increased linearly with the degree of severity of illness classes related to the All Patient Refined Diagnosis Related Group (p<0.0001). Medical procedures, nursing activities and hospitalisation accommodation were the main cost components. We identified six independent predictors of costs in inliers: age group, chronic pulmonary heart disease, heart failure, admission to intensive care unit, initial thrombolysis treatment and type of hospital. There was a statistically significant linear trend between age groups and costs (p<0.0001).An increasing burden of comorbid illness was strongly associated with increasing actual cost for caring hospitalised patients for PE. Increasing age was associated with an increase in all main cost components. PMID- 26493785 TI - Circulating free DNA concentration is an independent prognostic biomarker in lung cancer. AB - Plasma circulating cell-free (cf)DNA is of interest in oncology because it has been shown to contain tumour DNA and may thus be used as liquid biopsy. In nonsmall cell lung cancer (NSCLC), cfDNA quantification has been proposed for the monitoring and follow-up of patients. However, available studies are limited and need to be confirmed by studies with larger sample sizes and including patients who receive more homogenous treatments. Our objective was to assess the predictive and prognostic value of plasma cfDNA concentration in a large series of patients with NSCLC and treated with a standard chemotherapy regimen.We included samples from lung cancer patients recruited into the Pharmacogenoscan study. The cfDNA of 218 patients was extracted and quantified by fluorometry before and after two or three cycles of platinum-based chemotherapy. The association between baseline and post-chemotherapy concentrations and treatment response, assessed by RECIST (response evaluation criteria in solid tumours) or patient survival was analysed.Patients with high cfDNA concentrations (highest tertile) at baseline had a significantly worse disease-free and overall survival than those with lower concentrations (lowest and middle tertiles) (median overall survival 10 months (95% CI 10.7-13.9) versus 14.2 months (95% CI 12.6-15.8), respectively; p=0.001). In multivariate analysis, increased baseline concentration of cfDNA was an independent prognostic factor. However, we did not find any association between cfDNA concentration and response to treatment.cfDNA may be a biomarker for the assessment of prognosis in NSCLC. However, total concentration of cfDNA does not appear to predict chemotherapy response. PMID- 26493786 TI - Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN. AB - In SERAPHIN, a long-term, randomised, controlled trial (NCT00660179) in pulmonary arterial hypertension (PAH), macitentan significantly reduced the risk of morbidity/mortality and PAH-related death/hospitalisation. We evaluated disease progression and the effect of macitentan in treatment-naive incident and prevalent cohorts.Patients allocated to placebo, or macitentan 3 mg or 10 mg were classified by time from diagnosis to enrolment as incident (<=6 months; n=110) or prevalent (>6 months; n=157). The risk of morbidity/mortality and PAH-related death/hospitalisation was determined using Cox regression.The risk of morbidity/mortality (Kaplan-Meier estimates at month 12: 54.4% versus 26.7%; p=0.006) and PAH-related death/hospitalisation (Kaplan-Meier estimates at month 12: 47.3% versus 19.9%; p=0.006) were significantly higher for incident versus prevalent patients receiving placebo, respectively. There was no significant difference in the risk of all-cause death between incident and prevalent cohorts (p=0.587). Macitentan 10 mg significantly reduced the risk of morbidity/mortality and PAH-related death/hospitalisation versus placebo in incident and prevalent cohorts.Incident patients had a higher risk for PAH progression compared with prevalent patients but not a higher risk of death. Macitentan delayed disease progression in both incident and prevalent PAH patients. PMID- 26493787 TI - Bile acid aspiration in people with cystic fibrosis before and after lung transplantation. PMID- 26493788 TI - Functional evidence for continued alveolarisation in former preterms at school age? AB - Prematurity is the most common disruptor of lung development. The aim of our study was to examine the function of the more vulnerable peripheral airways in former preterm children by multiple-breath washout (MBW) measurements.86 school aged children, born between 24 and 35 weeks of gestation and 49 term-born children performed nitrogen MBW. Lung clearance index (LCI), and slope III derived Scond and Sacin were assessed as markers for global, convection-dependent and diffusion-convection-dependent ventilation inhomogeneity, respectively.We analysed the data of 77 former preterm (mean (range) age 9.5 (7.2-12.8) years) and 46 term-born children (mean age 9.9 (6.0-15.9) years). LCI and Sacin did not differ between preterm and term-born children. Scond was significantly elevated in preterm compared to term-born participants (mean difference z-score 1.74, 95% CI 1.17-2.30; p<0.001), with 54% of former preterm children showing elevated Scond. In multivariable regression analysis Scond was significantly related only to gestational age (R(2)=0.37).Normal Sacin provides evidence for a functionally normal alveolar compartment, while elevated Scond indicates impaired function of more proximal conducting airways. Together, our findings support the concept of continued alveolarisation, albeit with "dysanaptic" lung growth in former preterm children. PMID- 26493789 TI - Tuberculosis screening using ability to provide sputum in an endemic emergency department. PMID- 26493790 TI - Pulmonary artery diameter to predict pulmonary hypertension in pulmonary sarcoidosis. PMID- 26493791 TI - Exertional dyspnoea and cortical oxygenation in patients with COPD. AB - This study was designed to investigate the association of perceived dyspnoea intensity with cortical oxygenation and cortical activation during exercise in patients with chronic obstructive pulmonary disease (COPD) and exertional hypoxaemia.Low-intensity exercise was performed at a constant work rate by patients with COPD and exertional hypoxaemia (n=11) or no hypoxaemia (n=16), and in control participants (n=11). Cortical oxyhaemoglobin (oxy-Hb) and deoxyhaemoglobin (deoxy-Hb) concentrations were measured by multichannel near infrared spectroscopy. Increased deoxy-Hb is assumed to reflect impaired oxygenation, whereas decreased deoxy-Hb signifies cortical activation.Exercise decreased cortical deoxy-Hb in control and nonhypoxaemic patients. Deoxy-Hb was increased in hypoxaemic patients and oxygen supplementation improved cortical oxygenation. Decreased deoxy-Hb in the pre-motor cortex (PMA) was significantly correlated with exertional dyspnoea in control participants and patients with COPD without hypoxaemia. In contrast, increased cortical deoxy-Hb concentration was correlated with dyspnoea in patients with COPD and hypoxaemia. With the administration of oxygen supplementation, exertional dyspnoea was correlated with decreased deoxy-Hb in the PMA of COPD patients with hypoxaemia.During exercise, cortical oxygenation was impaired in patients with COPD and hypoxaemia compared with control and nonhypoxaemic patients; this difference was ameliorated with oxygen supplementation. Exertional dyspnoea was related to activation of the pre motor cortex in COPD patients. PMID- 26493793 TI - CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab. AB - The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg.kg(-1), 5 mg.kg(-1), or 15 mg.kg(-1)) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo -0.582%, 1 mg.kg(-1) -0.533%, 5 mg.kg(-1) 0.799% and 15 mg.kg(-1) -0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg.kg(-1) -290 mL, 5 mg.kg(-1) -370 mL and 15 mg.kg(-1) -320 mL) compared with placebo (-130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg.kg(-1) group (53.1%) compared with 1 mg.kg(-1) (15.2%), 15 mg.kg(-1) (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted.Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients. PMID- 26493794 TI - Differential release and deposition of S100A8/A9 proteins in inflamed upper airway tissue. AB - Intracellular Ca(2+)-binding S100A8/A9 proteins gain novel functions when released during inflammation. The exact outcome of their extracellular function depends on the local tissue environment in which they are released; both anti inflammatory and pro-inflammatory responses are described, modulating the immune system by binding Toll-like receptor (TLR)-4 or the receptor for advanced glycation end-products (RAGE). However, the contribution of the proteins in the pathophysiology of chronic rhinosinusitis (CRS) remains unclear.Homomeric S100A8 and S100A9, and heteromeric S100A8/A9 proteins were evaluated in CRS with/without nasal polyps (CRSw/sNP) and controls. Functional responses were assessed in polyp tissue stimulated with S100 proteins in the presence of TLR-4 and RAGE blocking antibodies.S100A8, S100A9 and S100A8/A9 protein levels were significantly higher in CRSwNP patients, showing increased deposition on extracellular matrix (ECM) structures of CRSwNP tissue in contrast to CRSsNP and controls. In the presence of Staphylococcus aureus, S100A8/A9 is released from neutrophils and from the ECM. Extracellular S100A8 and S100A9 proteins induced increased levels of diverse inflammatory mediators via TLR-4 engagement.The inflammatory/remodelling characteristics of CRSwNP specifically allow increased retention of S100A8, S100A9 and S100A8/A9 proteins in the ECM of CRSwNP tissue. Upon release, homodimeric proteins act as a local danger signal inducing inflammatory mediators, predominantly via TLR-4 activation. PMID- 26493792 TI - Pilot randomised trial of a healthy eating behavioural intervention in uncontrolled asthma. AB - Rigorous research on the benefit of healthy eating patterns for asthma control is lacking.We randomised 90 adults with objectively confirmed uncontrolled asthma and a low-quality diet (Dietary Approaches to Stop Hypertension (DASH) scores <6 out of 9) to a 6-month DASH behavioural intervention (n=46) or usual-care control (n=44). Intention-to-treat analyses used repeated-measures mixed models.Participants were middle-aged, 67% female and multiethnic. Compared with controls, intervention participants improved on DASH scores (mean change (95% CI) 0.6 (0, 1.1) versus -0.3 (-0.8, 0.2); difference 0.8 (0.2, 1.5)) and the primary outcome, Asthma Control Questionnaire scores (-0.2 (-0.5, 0) versus 0 (-0.3, 0.3); difference -0.2 (-0.5, 0.1)) at 6 months. The mean group differences in changes in Mini Asthma Quality of Life Questionnaire overall and subdomain scores consistently favoured the intervention over the control group: overall 0.4 (95% CI 0, 0.8), symptoms 0.5 (0, 0.9), environment 0.4 (-0.1, 1.0), emotions 0.4 ( 0.2, 0.9) and activities 0.3 (0, 0.7). These differences were modest, but potentially clinical significant.The DASH behavioural intervention improved diet quality with promising clinical benefits for better asthma control and functional status among adults with uncontrolled asthma. A full-scale efficacy trial is warranted. PMID- 26493795 TI - Longitudinal assessment of airway responsiveness from 1 month to 18 years in the PIAF birth cohort. AB - The Perth Infant Asthma Follow-up (PIAF) study involves a birth cohort of unselected subjects who have undergone longitudinal assessments of airway responsiveness at 1, 6 and 12 months and 6, 11 and 18 years of age. The aim of this study was to determine the relationship between increased airway responsiveness throughout childhood and asthma in early adult life.Airway responsiveness to histamine, assessed as a dose-response slope (DRS), and a respiratory questionnaire were completed at 1, 6 and 12 months and 6, 11 and 18 years of age.253 children were initially recruited and studied. Airway responsiveness was assessed in 203, 174, 147, 103, 176 and 137 children at the above-mentioned time points, respectively (39 participants being assessed on all test occasions). Asthma at 18 years was associated with increased airway responsiveness at 6, 12 and 18 years, but not during infancy (slope 0.24, 95% CI 0.06-0.42; p=0.01; slope 0.25, 95% CI 0.08-0.49; p=0.006; and slope 0.56, 95% CI 0.29-0.83; p<0.001, respectively).Increased airway responsiveness and its association with asthma at age 18 years is established between infancy and 6 years. We propose that airway responsiveness in early life reflects the initial airway geometry and airway responsiveness later in childhood increasingly reflects immunological responses to environmental influences. PMID- 26493796 TI - Cost-effectiveness of incorporating bedaquiline into a treatment regimen for MDR/XDR-TB in Germany. PMID- 26493797 TI - The minimal important difference for the St George's Respiratory Questionnaire in patients with severe COPD. AB - The St George's Respiratory Questionnaire (SGRQ) is a validated, commonly used questionnaire for measuring quality of life in patients with chronic obstructive pulmonary disease (COPD). The current established minimal important difference (MID) for SGRQ scores in an average COPD population is -4 units. However, for patients with severe COPD, the MID has not been thoroughly validated. We re determined the SGRQ MID for this patient group.115 severe COPD patients (forced expiratory volume in 1 s (FEV1) 26+/-9% of predicted, SGRQ score 62+/-11 units; mean+/-sd,) who participated in seven different bronchoscopic lung volume reduction clinical trials were included in the analysis. Anchor- and distribution based methods were used to define the MID for SGRQ scores. FEV1, 6-min walk distance and residual volume were used as anchors.Combining both anchor- and distribution-based methods, we identified a SGRQ MID of -8.3 units at 1 month and -7.1 units at 6 months.This study proposes an alternative SGRQ MID for patients with severe COPD of -8.3 units at 1 month and -7.1 units at 6 months follow-up after intervention. Our new MID estimates could be applied for both interpreting SGRQ outcomes as well as sample size determination in future clinical trials investigating interventions in severe COPD patients. PMID- 26493798 TI - Lung inhomogeneities, inflation and [18F]2-fluoro-2-deoxy-D-glucose uptake rate in acute respiratory distress syndrome. AB - The aim of the study was to determine the size and location of homogeneous inflamed/noninflamed and inhomogeneous inflamed/noninflamed lung compartments and their association with acute respiratory distress syndrome (ARDS) severity.In total, 20 ARDS patients underwent 5 and 45 cmH2O computed tomography (CT) scans to measure lung recruitability. [(18)F]2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) uptake and lung inhomogeneities were quantified with a positron emission tomography-CT scan at 10 cmH2O. We defined four compartments with normal/abnormal [(18)F]FDG uptake and lung homogeneity.The homogeneous compartment with normal [(18)F]FDG uptake was primarily composed of well-inflated tissue (80+/-16%), double-sized in nondependent lung (32+/-27% versus 16+/-17%, p<0.0001) and decreased in size from mild, moderate to severe ARDS (33+/-14%, 26+/-20% and 5+/ 9% of the total lung volume, respectively, p=0.05). The homogeneous compartment with high [(18)F]FDG uptake was similarly distributed between the dependent and nondependent lung. The inhomogeneous compartment with normal [(18)F]FDG uptake represented 4% of the lung volume. The inhomogeneous compartment with high [(18)F]FDG uptake was preferentially located in the dependent lung (21+/-10% versus 12+/-10%, p<0.0001), mostly at the open/closed interfaces and related to recruitability (r(2)=0.53, p<0.001).The homogeneous lung compartment with normal inflation and [(18)F]FDG uptake decreases with ARDS severity, while the inhomogeneous poorly/not inflated compartment increases. Most of the lung inhomogeneities are inflamed. A minor fraction of healthy tissue remains in severe ARDS. PMID- 26493799 TI - Spontaneous pneumothorax can be associated with TGFBR2 mutation. PMID- 26493800 TI - Risk stratification of normotensive pulmonary embolism: prognostic impact of copeptin. AB - The prognostic value of copeptin, the C-terminal fragment of the precursor protein of vasopressin which is released upon stress, and hypotension in pulmonary embolism is unknown, especially if combined with biomarkers reflecting different pathophysiological axes such as myocardial injury (high-sensitivity troponin T (hsTnT)) and stretch (N-terminal pro-brain natriuretic peptide (NT proBNP)).We prospectively studied 268 normotensive pulmonary embolism patients included in a single-centre cohort study.Patients with an adverse 30-day outcome (5.6%) had higher copeptin levels than patients with a favourable course (median (interquartile range) 51.8 (21.6-90.8) versus 13.2 (5.9-39.3) pmol.L(-1); p=0.020). Patients with copeptin levels above the calculated optimal cut-off value of 24 pmol.L(-1) had a 5.4-fold increased risk for an adverse outcome (95% CI 1.68-17.58; p=0.005). We developed a strategy for risk stratification based on biomarkers. None of 141 patients (52.6%) with hsTnT <14 pg.mL(-1) or NT-proBNP <600 pg.mL(-1) had an adverse outcome (low risk). Copeptin >=24 pmol.L(-1) stratified patients with elevated hsTnT and NT-proBNP as intermediate-low and intermediate-high risk (5.6% and 20.0% adverse outcome, respectively). Compared to the algorithm proposed by the 2014 European Society of Cardiology guideline, more patients were classified as low risk (52.8% versus 17.5%, p<0.001) and more patients in the intermediate-high risk group had an adverse outcome (20.0% versus 11.6%).Copeptin might be helpful for risk stratification of normotensive patients with pulmonary embolism, especially if integrated into a biomarker-based algorithm. PMID- 26493801 TI - Lung function in children in relation to ethnicity, physique and socioeconomic factors. AB - Can ethnic differences in spirometry be attributed to differences in physique and socioeconomic factors?Assessments were undertaken in 2171 London primary schoolchildren on two occasions 1 year apart, whenever possible, as part of the Size and Lung function In Children (SLIC) study. Measurements included spirometry, detailed anthropometry, three-dimensional photonic scanning for regional body shape, body composition, information on ethnic ancestry, birth and respiratory history, socioeconomic circumstances, and tobacco smoke exposure.Technically acceptable spirometry was obtained from 1901 children (mean (range) age 8.3 (5.2-11.8) years, 46% boys, 35% White, 29% Black-African origin, 24% South-Asian, 12% Other/mixed) on 2767 test occasions. After adjusting for sex, age and height, forced expiratory volume in 1 s was 1.32, 0.89 and 0.51 z score units lower in Black-African origin, South-Asian and Other/mixed ethnicity children, respectively, when compared with White children, with similar decrements for forced vital capacity (p<0.001 for all). Although further adjustment for sitting height and chest width reduced differences attributable to ethnicity by up to 16%, significant differences persisted after adjusting for all potential determinants, including socioeconomic circumstances.Ethnic differences in spirometric lung function persist despite adjusting for a wide range of potential determinants, including body physique and socioeconomic circumstances, emphasising the need to use ethnic-specific equations when interpreting results. PMID- 26493802 TI - No added value of interferon-gamma release to a prediction model for childhood tuberculosis. AB - The predictive value of a combination of clinical and radiological features with interferon-gamma release assay (IGRA) for diagnosis of active tuberculosis (TB) disease among TB-exposed children is unknown.150 symptomatic HIV-negative children (aged 3 months to 14 years), prospectively recruited through active contact tracing, were included. Backward stepwise logistic regression and bootstrapping techniques were used for the development and internal validation of a clinical prediction model for active TB disease. Model discrimination and incremental value of a positive IGRA test were assessed by area under the receiver operating characteristic curve (AUC).35 (23%) children were diagnosed with active TB disease and started on treatment and 115 (77%) had other respiratory tract infections. A final parsimonious clinical model, comprising age <5 years (adjusted (a)OR 4.8, 95% CI 2.0-11.5) and lymphadenopathy on clinical examination (aOR 4.9, 95% CI 1.8-13.0) discriminated active TB disease from other disease with an AUC of 0.70 (95% CI 0.61-0.80). A positive IGRA result did not improve the discriminatory ability of the clinical model (c-statistic 0.72 versus 0.70; p=0.644).A clinical algorithm, including age <5 years and lymphadenopathy classified 70% of active TB disease among symptomatic TB-exposed children. IGRA does not add any discriminatory value to this prediction model. PMID- 26493803 TI - Tuberculosis in Germany: a declining trend coming to an end? PMID- 26493804 TI - Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction. AB - Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is an essential response of the pulmonary vasculature to acute and sustained alveolar hypoxia. During local alveolar hypoxia, HPV matches perfusion to ventilation to maintain optimal arterial oxygenation. In contrast, during global alveolar hypoxia, HPV leads to pulmonary hypertension. The oxygen sensing and signal transduction machinery is located in the pulmonary arterial smooth muscle cells (PASMCs) of the pre-capillary vessels, albeit the physiological response may be modulated in vivo by the endothelium. While factors such as nitric oxide modulate HPV, reactive oxygen species (ROS) have been suggested to act as essential mediators in HPV. ROS may originate from mitochondria and/or NADPH oxidases but the exact oxygen sensing mechanisms, as well as the question of whether increased or decreased ROS cause HPV, are under debate. ROS may induce intracellular calcium increase and subsequent contraction of PASMCs via direct or indirect interactions with protein kinases, phospholipases, sarcoplasmic calcium channels, transient receptor potential channels, voltage-dependent potassium channels and L-type calcium channels, whose relevance may vary under different experimental conditions. Successful identification of factors regulating HPV may allow development of novel therapeutic approaches for conditions of disturbed HPV. PMID- 26493805 TI - Change in the manifestations of asthma and asthma-related traits in childhood: a latent transition analysis. AB - It is known that asthma is a heterogeneous entity whose manifestations vary with age. Our objective was to examine changes in the manifestation of asthma and asthma-related traits in childhood by defining empirically derived childhood asthma phenotypes and examining their transitions over time.To define the phenotypes we used data on respiratory symptoms, healthcare utilisation, medications, spirometry, airway hyperresponsiveness (AHR), exhaled nitric oxide concentration and atopy from a birth cohort recruited on the basis of having a first-degree relative with asthma. Data were acquired at ages 1.5-11.5 years and analysed using latent transition analysis.In a study population of 370 participants, we classified subjects into four phenotypes: 1) nonatopic, few symptoms (prevalence range from 1.5 to 5 years: 52-60%), 2) atopic, few symptoms (3-21%), 3) nonatopic, asthma and rhinitis symptoms (13-35%), and 4) atopic, asthma and rhinitis symptoms (2-14%) in early childhood; and 1) nonatopic, no respiratory disease (prevalence range from 8 to 11.5 years: 41-46%), 2) atopic, no respiratory disease (23-33%), 3) nonatopic, asthma symptoms, no AHR or airway inflammation (8-12%) and 4) atopic asthma (19%) in mid-childhood. Transitioning between phenotypes was common in early childhood, but less common in later childhood.This analysis represents the first attempt to incorporate longitudinal patterns of several manifestations of asthma into a single model to simultaneously define phenotypes and examine their transitions over time. It provides quantitative support for the view that asthma is a heterogeneous entity, and that some children with wheeze and other respiratory symptoms in early life progress to asthma in mid-childhood, while others become asymptomatic. PMID- 26493806 TI - Risk of death and readmission of hospital-admitted COPD exacerbations: European COPD Audit. AB - Studies report high in-hospital and post-discharge mortality of chronic obstructive pulmonary disease (COPD) exacerbations varying depending upon patient characteristics, hospital resources and treatment standards. This study aimed to investigate the patient, resource and organisational factors associated with in hospital and 90-day post-discharge mortality and readmission of COPD exacerbations within the European COPD Audit. The audit collected data of COPD exacerbation admissions from 13 European countries.On admission, only 49.7% of COPD patients had spirometry results available and only 81.6% had blood gases taken. Using logistic regression analysis, the risk associated with in-hospital and post-discharge mortality was higher age, presence of acidotic respiratory failure, subsequent need for ventilatory support and presence of comorbidity. In addition, the 90-day risk of COPD readmission was associated with previous admissions. Only the number of respiratory specialists per 1000 beds, a variable related to hospital resources, decreased the risk of post-discharge mortality.The European COPD Audit identifies risk factors associated with in-hospital and post discharge mortality and COPD readmission. Addressing the deficiencies in acute COPD care such as making spirometry available and measuring blood gases and providing noninvasive ventilation more regularly would provide opportunities to improve COPD outcomes. PMID- 26493807 TI - Chronic pulmonary disease with Mycobacterium abscessus complex is a biofilm infection. PMID- 26493808 TI - Efficiency of mechanical activation of inspiratory muscles in COPD using sample entropy. PMID- 26493809 TI - Intramural esophageal dissection diagnosed on transabdominal ultrasonography. AB - Intramural esophageal dissection (IED) is an uncommon yet important clinical entity characterized by a rupture or fissure in the esophageal submucosal layer. IED could occur spontaneously or secondary to direct extrinsic injury to the esophageal mucosa. Traditionally, IED has been diagnosed on the swallowing study using water-soluble contrast agents or barium. For alternative diagnostic modalities, upper gastrointestinal endoscopy and chest computed tomography have been frequently performed. However, to the best of our knowledge, the transabdominal ultrasonography (USG) appearance of IED has not been reported in the literature yet. We report an interesting case of IED, which was initially diagnosed on the transabdominal USG. PMID- 26493810 TI - Management of vascular lake phenomenon on angiography during chemoembolization with superabsorbent polymer microspheres. AB - PURPOSE: Contrast material pooling on angiography within a tumor bed during embolization for hepatocellular carcinoma (HCC) presents as the vascular lake (VL) phenomenon. This retrospective study aimed to evaluate the frequency and management of VLs during chemoembolization with drug-eluting beads (DEBs) and the relationship between the VL and local response. MATERIALS AND METHODS: A total of 123 HCC patients without vascular invasion or intrahepatic metastases who underwent chemoembolization with DEBs (50-100 um superabsorbent polymer microspheres loaded with epirubicin) were enrolled. Gelatin sponge particles (GS) were injected for additional embolization in limited patients with steadily increasing size of VLs during DEB injection. Overall, 338 nodules were divided into three groups: lesions without a VL (non-VL; n = 250); lesions with a VL but without additional GS embolization [VL-GS (-), n = 58]; and lesions with both VL and additional GS embolization [VL-GS (+); n = 30]. The local responses were statistically compared by Fisher's exact test with the Bonferroni correction. RESULTS: The frequency of VLs was 26.0% (88/338). The response rate in the non-VL group (54.0%) was significantly lower than those in the VL-GS (-) (91.4%; P < 0.0001) and VL-GS (+) (96.7%; P < 0.0001) groups. CONCLUSIONS: VL is a common angiographic finding and might be associated with the local response. PMID- 26493811 TI - Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015. AB - Osteonecrosis of the jaw (ONJ) has been associated with the use of aminobisphosphonates and denosumab. The vast majority (>90%) of cases occur in the oncology patient population receiving high doses of intravenous bisphosphonates or subcutaneous denosumab. The incidence of ONJ in the osteoporosis patient population is very low and is estimated at 1-90 per 100,000 patient-years of exposure. In the oncology patient population the incidence appears to be related to dose and duration of exposure, and prevalence has been estimated to be as high as 18.6%. A number of risk factors in addition to antiresorptive therapy have been identified. These include the presence of periodontal disease, oral surgical procedures with extractions or implants, radiation therapy, chemotherapy, diabetes, glucocorticoid use, and smoking. Antiangiogenic agents appear to contribute to the risk of ONJ, however, data at this time are limited and further evidence is required prior to confirming a causal relationship. ONJ may be prevented with optimization of oral hygiene, the use of oral antimicrobial mouth rinses, as well as systemic antibiotic therapy. Individuals not responding to conservative management or in the advanced stages of ONJ may be considered for surgery, as data over the past several years have demonstrated surgical success in this patient population. Case reports have indicated that teriparatide may enhance healing. A number of experimental therapies are being evaluated and include the use of bone marrow stem cell intralesional transplantation, local application of platelet-derived growth factor, hyperbaric oxygen, tissue grafting, and low-level laser therapy. This paper summarizes the current research as well as the international consensus on the diagnosis and management of ONJ. PMID- 26493813 TI - Both falling and bone fragility should be targeted to prevent hip fracture in older adults. PMID- 26493812 TI - Acute and 3-month effects of calcium carbonate on the calcification propensity of serum and regulators of vascular calcification: secondary analysis of a randomized controlled trial. AB - SUMMARY: Calcium supplements have been associated with increased cardiovascular risk, but the mechanism is unknown. We investigated the effects of calcium supplements on the propensity of serum to calcify, based on the transition time of primary to secondary calciprotein particles (T50). Changes in serum calcium were related to changes in T50. INTRODUCTION: Calcium supplements have been associated with increased cardiovascular risk; however, it is unknown whether this is related to an increase in vascular calcification. METHODS: We investigated the acute and 3-month effects of calcium supplements on the propensity of serum to calcify, based on the transition time of primary to secondary calciprotein particles (T50), and on three possible regulators of calcification: fetuin-A, pyrophosphate and fibroblast growth factor-23 (FGF23). We randomized 41 postmenopausal women to 1 g/day of calcium as carbonate, or to a placebo containing no calcium. Measurements were performed at baseline and then 4 and 8 h after their first dose, and after 3 months of supplementation. Fetuin-A, pyrophosphate and FGF23 were measured in the first 10 participants allocated to calcium carbonate and placebo who completed the study. RESULTS: T50 declined in both groups, the changes tending to be greater in the calcium group. Pyrophosphate declined from baseline in the placebo group at 4 h and was different from the calcium group at this time point (p = 0.04). There were no other significant between-groups differences. The changes in serum total calcium from baseline were significantly related to changes in T50 at 4 h (r = -0.32, p = 0.05) and 8 h (r = -0.39, p = 0.01), to fetuin-A at 3 months (r = 0.57, p = 0.01) and to pyrophosphate at 4 h (r = 0.61, p = 0.02). CONCLUSIONS: These correlative findings suggest that serum calcium concentrations modulate the propensity of serum to calcify (T50), and possibly produce counter-regulatory changes in pyrophosphate and fetuin-A. This provides a possible mechanism by which calcium supplements might influence vascular calcification. PMID- 26493814 TI - Activated T cells enhance interferon-alpha production by plasmacytoid dendritic cells stimulated with RNA-containing immune complexes. AB - OBJECTIVES: Patients with systemic lupus erythematosus (SLE) have an ongoing interferon-alpha (IFN-alpha) production by plasmacytoid dendritic cells (pDCs). We investigated whether T cells can promote IFN-alpha production by pDCs. METHODS: Human pDCs were stimulated with immune complexes (ICs) containing U1 small nuclear ribonucleic proteins particles and SLE-IgG (RNA-IC) in the presence of T cells or T cell supernatants. T cells were activated by anti-CD3/CD28 antibodies or in a mixed leucocyte reaction. IFN-alpha and other cytokines were determined in culture supernatants or patient sera with immunoassays. The effect of interleukin (IL) 3 and granulocyte-macrophage-colony-stimulating factor (GM CSF) on pDCs was examined by the use of antibodies, and the expression of CD80/CD86 was determined using flow cytometry. RESULTS: Activated T cells and supernatants from activated T cells increased IFN-alpha production by >20-fold. The stimulatory effect of T cell supernatants was reduced after depletion of GM CSF (81%) or by blocking the GM-CSF receptor (55%-81%). Supernatant from activated T cells, furthermore, increased the frequency of CD80 and CD86 expressing pDCs stimulated with RNA-IC from 6% to 35% (p<0.05) and from 10% to 26% (p<0.01), respectively. Activated SLE T cells enhanced IFN-alpha production to the same extent as T cells from healthy individuals and a subset of patients with SLE had increased serum levels of GM-CSF. CONCLUSIONS: Activated T cells enhance IFN-alpha production by RNA-IC stimulated pDCs via GM-CSF and induce pDC maturation. Given the increased serum levels of GM-CSF in a subset of patients with SLE, these findings suggest that activated T cells may upregulate type I IFN production in SLE. PMID- 26493815 TI - Defining remission and treatment success using the DAPSA score: response to letter by Helliwell and Coates. PMID- 26493817 TI - Incidence and predictors for cardiovascular events in patients with psoriatic arthritis. AB - OBJECTIVE: To assess the incidence and risk factors of cardiovascular events in patients with psoriatic arthritis (PsA). METHODS: A cohort analysis was conducted involving patients recruited and followed over the period from 1978 to 2013 in a large PsA clinic. The participants were assessed at 6 to 12-month intervals according to a standard protocol. The collected information included demographics, lifestyle habits, medical history, medications use and PsA-related outcomes. The primary outcome was a composite major cardiovascular end point comprising myocardial infarction, ischaemic stroke, revascularisation or cardiovascular death. The association between the features of disease activity and the occurrence of cardiovascular events was assessed using Cox proportional hazard models. RESULTS: A total of 1091 patients with PsA were analysed. During the follow-up period, 104 cardiovascular events occurred. A considerable proportion of patients developed a cardiovascular event (19.8% of the patients by the age of 70 years and 30.1% of patient by the age of 80 years). No trend in the risk of developing cardiovascular events was observed over the decades from 1978 to 2013 (p=0.73). In multivariate analysis, the following variables were independent predictors of major cardiovascular events: hypertension (relative risk (RR) 1.81, p=0.015), diabetes (RR 2.72, p<0.001) and the number of dactylitic digits (RR 1.20, p<0.001). Sedimentation rate was a significant predictor only among women (RR 1.83, p=0.02). CONCLUSION: A significant proportion of patients with PsA develop cardiovascular events during the course of their disease. Increased cardiovascular risk is associated with a combination of traditional cardiovascular risk factors and disease activity. PMID- 26493816 TI - Gene copy-number variations (CNVs) of complement C4 and C4A deficiency in genetic risk and pathogenesis of juvenile dermatomyositis. AB - OBJECTIVE: Complement-mediated vasculopathy of muscle and skin are clinical features of juvenile dermatomyositis (JDM). We assess gene copy-number variations (CNVs) for complement C4 and its isotypes, C4A and C4B, in genetic risks and pathogenesis of JDM. METHODS: The study population included 105 patients with JDM and 500 healthy European Americans. Gene copy-numbers (GCNs) for total C4, C4A, C4B and HLA-DRB1 genotypes were determined by Southern blots and qPCRs. Processed activation product C4d bound to erythrocytes (E-C4d) was measured by flow cytometry. Global gene-expression microarrays were performed in 19 patients with JDM and seven controls using PAXgene-blood RNA. Differential expression levels for selected genes were validated by qPCR. RESULTS: Significantly lower GCNs and differences in distribution of GCN groups for total C4 and C4A were observed in JDM versus controls. Lower GCN of C4A in JDM remained among HLA DR3-positive subjects (p=0.015). Homozygous or heterozygous C4A-deficiency was present in 40.0% of patients with JDM compared with 18.2% of controls (OR=3.00 (1.87 to 4.79), p=8.2*10(-6)). Patients with JDM had higher levels of E-C4d than controls (p=0.004). In JDM, C4A-deficient subjects had higher levels of E-C4d (p=0.0003) and higher frequency of elevated levels of multiple serum muscle enzymes at diagnosis (p=0.0025). Microarray profiling of blood RNA revealed upregulation of type I interferon-stimulated genes and lower abundance of transcripts for T-cell and chemokine function genes in JDM, but this was less prominent among C4A deficient or DR3-positive patients. CONCLUSIONS: Complement C4A deficiency appears to be an important factor for the genetic risk and pathogenesis of JDM, particularly in patients with a DR3-positive background. PMID- 26493818 TI - Patient-physician discordance in global assessment in early spondyloarthritis and its change over time: the DESIR cohort. AB - OBJECTIVE: To assess patient-physician discordance in global assessment of disease activity in early axial spondyloarthritis (axSpA) over time and determinants of discordance. METHODS: DESIR (Devenir des Spondyloarthropathies Indifferenciees Recentes) is a French, multicentre, longitudinal cohort of patients with early inflammatory back pain suggestive of axSpA. Patient global assessment (PGA) and physician global assessment (PhGA) were rated with a 0-10 numerical rating scale, every 6 months during 2 years then at 3 years. Discordance was defined by the absolute difference |PGA-PhGA|>=3 (range 0-10) and was analysed at each visit. Determinants of (PGA-PhGA) were assessed at the visit level by a generalised linear mixed model. RESULTS: A total of 702 patients were analysed at baseline (401 with complete data over 3 years): mean age 33.8+/-8.6 years, 379 (54.0%) female, mean symptom duration 18.1+/-10.5 months. Mean PGA values were always higher than mean PhGA values with a mean absolute difference of 1.8 points. At baseline, 202 (28.8%) patients had discordance mainly by PGA>PhGA; over 3 years the frequency of discordance was stable (range 25.5 28.8%). Discordance was not stable at the patient level, 118 (29.4%) patients were discordant once and 88 (22.0%) twice, and only 92 (22.9%) more than twice. Determinants of (PGA-PhGA) were spine pain (beta=0.24, p<0.001) and fatigue (beta=0.13, p<0.001). CONCLUSIONS: Discordance concerned a quarter of patients with early axSpA. Over 3 years of follow-up, discordance did not decrease (no 'reference shift'). Discordance was not a stable trait, indicating discordance is not a patient characteristic. PMID- 26493819 TI - Endovascular Aneurysm Repair and Sealing (EVARS): A Useful Adjunct in Treating Challenging Morphology. AB - An 81-year-old male with previous open abdominal aortic aneurysm repair presented with asymptomatic large pseudoaneurysms at both ends of an open surgical tube graft. Endovascular aneurysm sealing (EVAS) in combination with the iliac limbs of a standard endovascular aneurysm repair (EVAR) successfully excluded both pseudoaneurysms from circulation. We describe the combination of elements of EVAS and EVAR and have termed this endovascular aneurysm repair and sealing (EVARS). EVARS has the advantage of harnessing the benefits of endobag sealing in aortic necks unsuitable for standard EVAR whilst providing the security of accurate stent placement within short common iliac arteries. In conclusion, EVAS may be combined with standard endovascular iliac limbs and is a possible treatment option for pseudoaneurysm following open aneurysm repair. PMID- 26493820 TI - Patient Evaluation and Preparation in Vascular and Interventional Radiology: What Every Interventional Radiologist Should Know (Part 1: Patient Assessment and Laboratory Tests). AB - Performing an interventional procedure imposes a commitment on interventional radiologists to conduct the initial patient assessment, determine the best course of therapy, and provide long-term care after the procedure is completed. After patient referral, contact with the referring physician and multidisciplinary team approach is vital. In addition, clinical history, physical examination, as well as full understanding of the pre-procedural laboratory results and imaging findings can guide the interventional radiologist to implement the most appropriate management plan, avoid unnecessary procedures, and prevent complications to achieve a successful outcome. We provide a comprehensive, methodical review of pre-procedural care and management in patients undergoing vascular and interventional radiology procedures. PMID- 26493821 TI - The Effect of Stent Cell Geometry on Carotid Stenting Outcomes. AB - PURPOSE: The aim of this study was to investigate the effect of stent cell geometry on midterm results of carotid artery stenting (CAS). MATERIALS AND METHOD: One hundred fifty-five patients underwent CAS between February 2010 and December 2012. Ninety-one open- and 84 closed-cell stents were used in this non randomized, retrospective study. Periprocedural complications were defined as the ones happened during the procedure or within 30 days afterwards. Starting from the 6th month after the procedure, in-stent restenosis was detected with multidetector computed tomography angiography and classified into four groups from focal restenosis to occlusion. RESULTS: Eleven complications were encountered in the periprocedural period (four on the open- and seven on the closed-cell group). Total complication rate was 6.3% (11/175). No significant difference was detected in terms of periprocedural complications between two groups (p = 0.643). There was statistically significant difference between stent design groups in regard to radiological findings (p = 0.002). Sixteen of open cell stents and three of closed-cell stents had focal restenosis. One closed-cell stent had diffuse proliferative restenosis and one open-cell stent had total occlusion. CONCLUSION: In-stent restenosis was more common in open-cell stent group, which have larger free cell area than closed-cell stents. Although our radiologic findings promote us to use closed-cell design if 'possible', no difference was detected in terms of clinical outcomes. PMID- 26493822 TI - Radiation Dose Reduction in CT Fluoroscopy-Guided Cervical Transforaminal Epidural Steroid Injection by Modifying Scout and Planning Steps. AB - BACKGROUND AND PURPOSE: In CT fluoroscopy (CTF)-guided cervical transforaminal epidural steroid injection (TFESI), the majority of radiation dose is contributed by the planning CT scan rather than the CTF procedure itself. We replaced the planning helical CT with a spot CTF and accordingly changed the patient posture during scout and planning scans. The aim of this study was to test whether radiation dose reduction would be achieved by this protocol modification while still maintaining technical performance. METHODS: Overall, 338 consecutive procedures before (control group: n = 163) and after (study group: n = 175) instituting the above-mentioned protocol modification were analyzed retrospectively, comparing patient characteristics (age, sex, neck diameter, and level injected) and technical performance [technical success rate, dose-length product (DLP), inadvertent contrast flow incidence, number of CTF acquisitions, and procedural time] between the two groups. RESULTS: All injections were technically successful at every level from C3-C4 to C7-T1 without serious complications in both groups. The median DLP of the study group (7.92 mGy.cm) was significantly reduced compared to that of the control group (39.05 mGy.cm, P < 0.001). There were no significant differences between the two groups regarding the incidence of inadvertent contrast flow (20.6 vs. 17.2%, P = 0.426), number of CTF acquisitions (median 5 vs. 4, P = 0.123), and the procedural time (median 6.62 vs. 6.90 min, P = 0.100). CONCLUSIONS: When conducting CTF-guided cervical TFESIs, a significant radiation dose reduction (median 79.7% in DLP) can be achieved by modifying scout and planning steps, without compromising the technical performance. PMID- 26493823 TI - Diaphragmatic Hernia After Lung Percutaneous Radiofrequency Ablation: Incidence and Risk Factors-Reply. PMID- 26493824 TI - Comparing Effective Doses During Image-Guided Core Needle Biopsies with Computed Tomography Versus C-Arm Cone Beam CT Using Adult and Pediatric Phantoms. AB - PURPOSE: To compare the effective doses of needle biopsies based on dose measurements and simulations using adult and pediatric phantoms, between cone beam c-arm CT (CBCT) and CT. METHOD: Effective doses were calculated and compared based on measurements and Monte Carlo simulations of CT- and CBCT-guided biopsy procedures of the lungs, liver, and kidney using pediatric and adult phantoms. RESULTS: The effective doses for pediatric and adult phantoms, using our standard protocols for upper, middle and lower lungs, liver, and kidney biopsies, were significantly lower under CBCT guidance than CT. The average effective dose for a 5-year old for these five biopsies was 0.36 +/- 0.05 mSv with the standard CBCT exposure protocols and 2.13 +/- 0.26 mSv with CT. The adult average effective dose for the five biopsies was 1.63 +/- 0.22 mSv with the standard CBCT protocols and 8.22 +/- 1.02 mSv using CT. The CT effective dose was higher than CBCT protocols for child and adult phantoms by 803 and 590% for upper lung, 639 and 525% for mid-lung, and 461 and 251% for lower lung, respectively. Similarly, the effective dose was higher by 691 and 762% for liver and 513 and 608% for kidney biopsies. CONCLUSIONS: Based on measurements and simulations with pediatric and adult phantoms, radiation effective doses during image-guided needle biopsies of the lung, liver, and kidney are significantly lower with CBCT than with CT. PMID- 26493825 TI - Osteomyelitis and Discitis Following Translumbar Repair of a Type II Endoleak. AB - Here we present the case of an 80-year-old man who developed a type II endoleak following endovascular abdominal aortic aneurysm repair. Initial attempts at treating the endoleak via a transarterial approach were unsuccessful; therefore the patient underwent percutaneous translumbar endoleak embolization. Approximately 1 month following the translumbar procedure, he developed back pain, with subsequent workup revealing osteomyelitis and discitis as a complication following repair via the translumbar approach. PMID- 26493828 TI - Inflation of Molecular Clock Rates and Dates: Molecular Phylogenetics, Biogeography, and Diversification of a Global Cicada Radiation from Australasia (Hemiptera: Cicadidae: Cicadettini). AB - Dated phylogenetic trees are important for studying mechanisms of diversification, and molecular clocks are important tools for studies of organisms lacking good fossil records. However, studies have begun to identify problems in molecular clock dates caused by uncertainty of the modeled molecular substitution process. Here we explore Bayesian relaxed-clock molecular dating while studying the biogeography of ca. 200 species from the global cicada tribe Cicadettini. Because the available fossils are few and uninformative, we calibrate our trees in part with a cytochrome oxidase I (COI) clock prior encompassing a range of literature estimates for arthropods. We show that tribe level analyses calibrated solely with the COI clock recover extremely old dates that conflict with published estimates for two well-studied New Zealand subclades within Cicadettini. Additional subclade analyses suggest that COI relaxed-clock rates and maximum-likelihood branch lengths become inflated relative to EF 1[Formula: see text] intron and exon rates and branch lengths as clade age increases. We present corrected estimates derived from: (i) an extrapolated EF 1[Formula: see text] exon clock derived from COI-calibrated analysis within the largest New Zealand subclade; (ii) post hoc scaling of the tribe-level chronogram using results from subclade analyses; and (iii) exploitation of a geological calibration point associated with New Caledonia. We caution that considerable uncertainty is generated due to dependence of substitution estimates on both the taxon sample and the choice of model, including gamma category number and the choice of empirical versus estimated base frequencies. Our results suggest that diversification of the tribe Cicadettini commenced in the early- to mid-Cenozoic and continued with the development of open, arid habitats in Australia and worldwide. We find that Cicadettini is a rare example of a global terrestrial animal group with an Australasian origin, with all non-Australasian genera belonging to two distal clades. Within Australia, we show that Cicadettini is more widely distributed than any other cicada tribe, diverse in temperate, arid and monsoonal habitats, and nearly absent from rainforests. We comment on the taxonomic implications of our findings for thirteen cicada genera. PMID- 26493827 TI - Total-Evidence Dating under the Fossilized Birth-Death Process. AB - Bayesian total-evidence dating involves the simultaneous analysis of morphological data from the fossil record and morphological and sequence data from recent organisms, and it accommodates the uncertainty in the placement of fossils while dating the phylogenetic tree. Due to the flexibility of the Bayesian approach, total-evidence dating can also incorporate additional sources of information. Here, we take advantage of this and expand the analysis to include information about fossilization and sampling processes. Our work is based on the recently described fossilized birth-death (FBD) process, which has been used to model speciation, extinction, and fossilization rates that can vary over time in a piecewise manner. So far, sampling of extant and fossil taxa has been assumed to be either complete or uniformly at random, an assumption which is only valid for a minority of data sets. We therefore extend the FBD process to accommodate diversified sampling of extant taxa, which is standard practice in studies of higher-level taxa. We verify the implementation using simulations and apply it to the early radiation of Hymenoptera (wasps, ants, and bees). Previous total-evidence dating analyses of this data set were based on a simple uniform tree prior and dated the initial radiation of extant Hymenoptera to the late Carboniferous (309 Ma). The analyses using the FBD prior under diversified sampling, however, date the radiation to the Triassic and Permian (252 Ma), slightly older than the age of the oldest hymenopteran fossils. By exploring a variety of FBD model assumptions, we show that it is mainly the accommodation of diversified sampling that causes the push toward more recent divergence times. Accounting for diversified sampling thus has the potential to close the long discussed gap between rocks and clocks. We conclude that the explicit modeling of fossilization and sampling processes can improve divergence time estimates, but only if all important model aspects, including sampling biases, are adequately addressed. PMID- 26493829 TI - Recruitment Processes in Academia: Does the Emperor Have Any Clothes? AB - The final outcome of promotion and recruitment processes in universities should be conventional and plausible by the members of the relevant scientific community, to affirm that the processes have been competitive and fair. The objective of this opinion letter is to make a plea for the importance of the post auditing and quantitative assessment of the selection criteria. It is shown that for an example case the outcome of the post-audit does not look reasonable from an external point of view, at least regarding the research competency. PMID- 26493831 TI - Bioaccessibility of Cd and Pb in tailings from a zinc smelting in Brazil: implications for human health. AB - Soils and wastes enriched with heavy metals may present ecological and human health risks. A considerable number of mining areas exist in Brazil, where high levels of metals have been found. However, studies of bioaccessibility of metals in soils/tailings from these areas are scarce, despite their potential informational contribution concerning exposure risks of residents near these areas. This study evaluated tailings collected from four sites of a zinc smelting area located in Brazil with aims to: (1) evaluate the presence of metals of potential concern; (2) investigate Cd and Pb bioaccessibility; and (3) determine the desorption kinetics of Cd and Pb. High concentrations of total Cd and Pb (up to 1743 mg Cd kg(-1) and 8675 mg Pb kg(-1)) and great variability were found in the tailings, indicating the importance of adequate planning for their final disposal, in order to avoid contamination in the surrounding environment. Cadmium and Pb bioaccessibility percentages in the intestinal phase were less than 47 and 4 %, respectively, which represents significant fractions not available for absorption in the intestinal tract. However, this material has to be monitored since its bioaccessibility may increase with eventual physicochemical changes, releasing Cd and Pb. Desorption kinetics experiments revealed that Pb in the samples remained in less labile fractions, whereas Cd was found in more labile fractions, which is in accordance with the bioaccessibility results. PMID- 26493830 TI - Hepatitis E virus antibody prevalence in hunters from a district in Central Germany, 2013: a cross-sectional study providing evidence for the benefit of protective gloves during disembowelling of wild boars. AB - BACKGROUND: In Germany, 17% of the general human population have antibodies to hepatitis E virus (HEV) (recomLine HEV-IgG/IgM immunoassay [Mikrogen GmbH]). Wild boars represent an animal reservoir for HEV genotype 3, which is the common genotype in Germany. We estimated the seroprevalence among hunters with contact to wild boars to identify factors that may be associated with past or present HEV infection. METHODS: In 2013, the local veterinarian authority in a district in Central Germany attended meetings of hunters who provided blood specimens and completed a questionnaire collecting information on age, sex, hunting-related activities and consumption of wild boar meat. Specimens of wild boars were taken during drive hunts in this district during the season 2012/2013. All specimens were tested for HEV RNA and anti-HEV IgM and IgG antibodies. Log-binomial regression was used to estimate prevalence ratios (PR) for the hunters. RESULTS: Of 126 hunters (median age 55; 94% male) 21% tested positive for anti-HEV IgG antibodies (95% confidence interval [CI] 13-28%) (recomWell HEV IgG assay [Mikrogen GmbH]). Anti-HEV prevalence was highest in the age group of the 70-79 year-olds (67%; 95% CI 39-95%). Wild boars showed an average anti-HEV prevalence of 41%. HEV RNA was detected in 4/22 (18%) liver specimens and in 1/22 (4.5%) muscle specimens. Most wild boars were tested positive for HEV RNA (3/10; 30%) and HEV-specific antibodies (7/15; 47%) in the southwestern part of the district. Hunters preferring this hunting ground had a lower anti-HEV prevalence when gloves were frequently used during disembowelling of wild boars compared to hunters using gloves never or infrequently (age-adjusted PR 0.12; 95% CI 0.02 0.86). CONCLUSIONS: Hunters may benefit from wearing gloves when in contact with blood or body fluids of HEV animal reservoirs. Anti-HEV prevalence among the hunters of this study did not significantly differ from that of the general population suggesting that other factors play a major role in the epidemiology of HEV in Germany. PMID- 26493832 TI - Inhibition of pyrite oxidation by surface coating: a long-term field study. AB - Pyrite and other iron sulfides are readily oxidized by dissolved oxygen in aqueous phase, producing acidity and Fe(2+), which causes significant environmental problems. Applications of surface coating agents (Na2SiO3 and KH2PO4) were conducted at Boeun (Chungbuk, South Korea) outcrop site, and their efficiencies to inhibit the oxidation of sulfide minerals were monitored for a long-term period (449 days). The rock sample showed positive Net Acid Production Potential (NAPP = 20.23) and low Net Acid Generation pH (NAGpH = 2.42) values, suggesting that the rock sample was categorized in the potential acid-forming group. For the monitored time period (449 days), field study results showed that the application of Na2SiO3 effectively inhibited the pyrite oxidation as compared to KH2PO4. Na2SiO3 as a surface coating agent maintained pH 5-6 and reduced oxidation of pyrite surface up to 99.95 and 97.70 % indicated by Fe(2+) and SO4 (2-) release, respectively. The scanning electron microscope and energy dispersive X-ray spectrometer analysis indicated that the morphology of rock surface was completely changed attributable to formation of iron silicate coating. The experimental results suggested that the treatment with Na2SiO3 was highly effective and it might be applicable on field for inhibition of iron sulfide oxidation. PMID- 26493833 TI - Efficacy and feasibility of autologous stem cell transplantation in patients with diffuse large B-cell lymphoma with secondary central nervous system involvement. AB - Secondary central nervous system (CNS) involvement is a fatal complication of diffuse large B-cell lymphoma (DLBCL). We evaluated the efficacy and feasibility of high-dose chemotherapy containing busulfan and thiotepa followed by autologous stem cell transplantation (HDC-ASCT) in DLBCL with secondary CNS involvement. Thirty-one patients with secondary CNS involvement including CNS involvement at diagnosis (n = 9), isolated CNS relapse (n = 14), and CNS involvement with systemic disease progression or relapse (n = 8) were selected and analyzed from our prospective cohorts. Of these, 12 patients, including seven with isolated CNS relapse, successfully completed HDC-ASCT without engraftment failure or transplantation-related mortality. After ASCT, six patients were alive; however, three patients experienced post-transplantation relapse. With a median follow-up of 29 months after secondary CNS involvement, the median overall survival of 31 patients was 9 months (95% CI 5-12 months). The survival outcomes of patients who had undergone HDC-ASCT were significantly better than those of patients who did not (p < 0.01). Accordingly, patients with isolated CNS relapse tended to have a longer survival outcome than other cases. Our results suggest that HDC-ASCT may provide survival benefits in DLBCL patients with secondary CNS involvement, especially in case of isolated CNS relapse. PMID- 26493834 TI - Transition to motherhood in women with eating disorders: A qualitative study. AB - OBJECTIVES: The aim of this study was to examine in depth the individual experience of transition from pregnancy to motherhood, among women with current eating disorders (EDs), focusing on differences between the first and subsequent pregnancies. DESIGN AND METHODS: We analysed the narratives of 12 women with severe ED during pregnancy using interpretative phenomenological analysis. We employed a sequential structure, and the emerging themes were ordered according to consecutive pregnancy stages. RESULTS: Our results indicate that experiences of pregnancy vary across pregnancy stages and in the first pregnancy compared to subsequent pregnancies. In particular, during their first pregnancy women with an ED seem to experience an inner conflict and questioned the continuity of their ED identity leading them to be more open to change. CONCLUSIONS: The first pregnancy, during its early stages, should be considered a potentially unique window for intervention for women with current ED. PRACTITIONER POINTS: Eating disorders (EDs) are known to seriously affect fertility, pregnancy, and pregnancy outcomes. Our research sheds a light on experiences of pregnancy in women with ED and ultimately helps to define a window for intervention. Our findings have important implications in understanding mechanisms of relapse in the post-partum period and consequently could help in tailoring an adequate intervention for women with ED and in preventing ED relapse. PMID- 26493835 TI - PDB-Explorer: a web-based interactive map of the protein data bank in shape space. AB - BACKGROUND: The RCSB Protein Data Bank (PDB) provides public access to experimentally determined 3D-structures of biological macromolecules (proteins, peptides and nucleic acids). While various tools are available to explore the PDB, options to access the global structural diversity of the entire PDB and to perceive relationships between PDB structures remain very limited. METHODS: A 136 dimensional atom pair 3D-fingerprint for proteins (3DP) counting categorized atom pairs at increasing through-space distances was designed to represent the molecular shape of PDB-entries. Nearest neighbor searches examples were reported exemplifying the ability of 3DP-similarity to identify closely related biomolecules from small peptides to enzyme and large multiprotein complexes such as virus particles. The principle component analysis was used to obtain the visualization of PDB in 3DP-space. RESULTS: The 3DP property space groups proteins and protein assemblies according to their 3D-shape similarity, yet shows exquisite ability to distinguish between closely related structures. An interactive website called PDB-Explorer is presented featuring a color-coded interactive map of PDB in 3DP-space. Each pixel of the map contains one or more PDB-entries which are directly visualized as ribbon diagrams when the pixel is selected. The PDB-Explorer website allows performing 3DP-nearest neighbor searches of any PDB-entry or of any structure uploaded as protein-type PDB file. All functionalities on the website are implemented in JavaScript in a platform independent manner and draw data from a server that is updated daily with the latest PDB additions, ensuring complete and up-to-date coverage. The essentially instantaneous 3DP-similarity search with the PDB-Explorer provides results comparable to those of much slower 3D-alignment algorithms, and automatically clusters proteins from the same superfamilies in tight groups. CONCLUSION: A chemical space classification of PDB based on molecular shape was obtained using a new atom-pair 3D-fingerprint for proteins and implemented in a web-based database exploration tool comprising an interactive color-coded map of the PDB chemical space and a nearest neighbor search tool. The PDB-Explorer website is freely available at www.cheminfo.org/pdbexplorer and represents an unprecedented opportunity to interactively visualize and explore the structural diversity of the PDB. ? PMID- 26493836 TI - A practical guide for performing arthrography under fluoroscopic or ultrasound guidance. AB - We propose a practical approach for performing arthrography with fluoroscopic or ultrasound guidance. Different approaches to the principal joints of the upper limb (shoulder, elbow, wrist and fingers), lower limb (hip, knee, ankle and foot) as well as the facet joints of the spine are discussed and illustrated with numerous drawings. Whenever possible, we emphasise the concept of targeting articular recesses, which offers many advantages over traditional techniques aiming at the joint space. TEACHING POINTS: * Arthrography remains a foremost technique in musculoskeletal radiology * Most joints can be successfully accessed by targeting the articular recess * Targeting the recess offers several advantages over traditional approaches * Ultrasound-guidance is now favoured over fluoroscopy and targeting the recess is equally applicable. PMID- 26493837 TI - Biceps tenodesis (long head): arthroscopic keyhole technique versus arthroscopic interference screw: a prospective comparative clinical and radiographic marker study. AB - PURPOSE: The long head biceps tenodesis (LHBT) is an alternative to tenotomy in order to prevent Popeye sign.Biomechanical studies showed that interference screw(IFS) was the strongest fixation but there might be complications and cost. What's more, the analyses of tenodesis failures are undervalued because they only take visible deformations of the arm into account. The purpose of this study was to compare a modified arthroscopic "keyhole" LHBT (modified @KH) with an arthroscopic IFS LHBT(@IFS) using an objective method. We hypothesized that modified @KH gave similar clinical outcomes as @IFS without its hassles or drawbacks. METHODS: We present a 12-month prospective comparative study (modified @KH versus @IFS) performed by two experienced orthopedic surgeons. Modified @KH was performed on one hundred and nine patients versus @IFS that was performed on one hundred and two. A radiopaque marker was placed into the tendon. The review was conducted in the sixth month with clinical examination and plain standard X ray to objectify the potential migration of the marker. RESULTS: Modified @KH showed 2.4 % visible deformity without any Popeye sign but 3.4 % radiographic metallic marker migrations. No complications were noted. @IFS showed 5.8 % visible deformity with 2.9 % Popeye sign and with 10.3 % radiographic metallic marker migrations;pain at tenodesis location was noted in 2 %. P value (0.13) indicates that there were no statistically significant differences. CONCLUSION: We confirm the hypothesis that the modified@KH gives clinical and radiographic outcomes at least similar to @IFS without any complications and cost. The establishment of the radiopaque marker allows us to know the exact number of failures.Level of evidence Consecutive prospective comparative clinical, Level II 1 studies. PMID- 26493838 TI - Impact of traditional culture on Camellia reticulata in Yunnan, China. AB - BACKGROUND: Cha-hua (Camellia reticulata) is one of China's traditional ornamental flowers developed by the local people of Yunnan Province. Today, more than 500 cultivars and hybrids are recognized. Many ancient camellia trees still survive and are managed by local peopl. A few records on cha-hua culture exist, but no studies expound the interaction between C. reticulata and traditional culture of ethnic groups. The contribution of traditional culture of different nationalities and regions to the diversity of Camellia reticulate is discussed. METHODS: Ethnobotanical surveys were conducted throughout Central and Western Yunnan to investigate and document the traditional culture related to Camellia reticulata. Five sites were selected to carry out the field investigation. Information was collected using participatory observation, semi-structured interviews, key informant interviews, focus group discussions, and participatory rural appraisal (PRA). RESULTS: Most of the ancient camellia trees were preserved or saved in the courtyards of old buildings and cultural or religious sites. Religion-associated culture plays an important role in C. reticulata protection. In every site we investigated, we found extensive traditional culture on C. reticulata and its management. These traditional cultures have not only protected the germplasm resources of C. reticulata, but also improved the diversity of Camellia cultivars. CONCLUSIONS: There are abundant and diverse genetic resources of cha-hua, Camellia reticulata in Yunnan. Cha-hua is not only an ornamental flower but also has been endowed with rich spiritual connotation. The influence of traditional culture had improved the introduction and domestication of wild plants, breeding and selection of different varieties, and the propagation and dissemination of the tree in Yunnan. However, either some ancient cha-hua trees or their associated traditional culture are facing various threats. The old cha hua trees and the ethnic camellia culture should be respected and protected since they have made great contributions in the history, and will make more contributions in the future. PMID- 26493839 TI - Sequence conservation analysis and in silico human leukocyte antigen-peptide binding predictions for the Mtb72F and M72 tuberculosis candidate vaccine antigens. AB - BACKGROUND: Requisites for an efficacious tuberculosis (TB) vaccine are a minimal genomic diversity among infectious Mycobacterium tuberculosis strains for the selected antigen, and the capability to induce robust T-cell responses in the majority of human populations. A tool in the identification of putative T-cell epitopes is in silico prediction of major histocompatibility complex (MHC) peptide binding. Candidate TB vaccine antigen Mtb72F and its successor M72 are recombinant fusion proteins derived from Mtb32A and Mtb39A (encoded by Rv0125 and Rv1196, respectively). Adjuvanted Mtb72F and M72 candidate vaccines were shown to induce CD4(+) T-cell responses in European, US, African and Asian populations. METHODS: Sequence conservation of Mtb32A, Mtb39A, Mtb72F and M72 among 46 strains (prevalent Mycobacterium strains causing human TB disease, and H37Ra) was assessed by multiple alignments using ClustalX. For Mtb32A, Mtb39A and Mtb72F, 15 mer human leukocyte antigen (HLA)-class II-binding peptides were predicted for 158 DRB1 alleles prevailing in populations with high TB burden, 6 DRB3/4/5, 8 DQ and 6 DP alleles, using NetMHCII-pan-3.0. Results for 3 DRB1 alleles were compared with previously published allele-matched in vitro binding data. Additional analyses were done for M72. Nonameric MHC class I-binding peptides in Mtb72F were predicted for three alleles representative of class I supertypes A02, A03 and B07, using seven prediction algorithms. RESULTS: Sequence identity among strains was >=98 % for each protein. Residue changes in Mtb39A comprised primarily single residue or nucleotide insertions and/or deletions in repeat regions, and were observed in 67 % of strains. For Mtb72F, 156 DRB1, 6 DRB3/4/5, 7 DQ and 5 DP alleles were predicted to contain at least one MHC class II-binding peptide, and class I-binding peptides were predicted for each HLA-A/B allele. Comparison of predicted MHC-II-binding peptides with experimental data indicated that the algorithm's sensitivity and specificity were variable among alleles. CONCLUSIONS: The sequences from which Mtb72F and M72 are derived are highly conserved among representative Mycobacterium strains. Predicted putative T-cell epitopes in M72 and/or Mtb72F covered a wide array of HLA alleles. In silico binding predictions for class I- and II-binding putative epitopes can be complemented with biochemical verification of HLA binding capacity, processing and immunogenicity of the predicted peptides. PMID- 26493840 TI - High-volume bilateral chylothorax presenting with hypoxemia and shock in a pediatric patient following tracheostomy revision: a case report. AB - INTRODUCTION: Chylothorax is a rare complication of surgical neck dissection. This is the first reported pediatric case of bilateral chylothorax following cervical surgery and the first to occur after tracheoplasty. Chylothorax can lead to significant complications, including hypoxemia and shock, and requires timely treatment. This case report discusses the clinical presentation, diagnosis, and treatment of our patient and reviews possible pathophysiologic mechanisms to explain the development of postoperative bilateral chylous effusions. CASE PRESENTATION: An 18-month-old white baby girl with a complex past medical history including choanal atresia, atrioventricular septal defect, failure to thrive, developmental delay, and tracheostomy dependence developed significant hypoxemia and shock following a routine tracehostomy revision. She was subsequently found to have developed massive bilateral chylothorax, requiring escalation of mechanical ventilation, thoracostomy tube drainage, vasoactive support, and eventual surgical ligation of her thoracic duct. CONCLUSIONS: Massive bilateral chylothorax is a rare but potentially life-threatening complication following tracheoplasty. Clinicians caring for this patient population postoperatively should be aware of this potential complication and its management. PMID- 26493842 TI - Refugee crisis and re-emergence of forgotten infections in Europe. PMID- 26493841 TI - Social support and dairy products intake among adolescents: a study from Iran. AB - BACKGROUND: Adequate daily milk and dairy products intake seems to an important for adolescents' health. This study aimed to identify the high-risk group adolescents who did not meet the recommended daily serving milk and dairy products and indeed to find out associated factors relating to their nutrition behaviors. METHODS: This cross sectional study was carried out on 7th grade students, in Tabriz, East Azerbaijan province, Iran. An anonymous self administrated questionnaire including items on perceived social support, physical activity, and sedentary behaviors was administered. In addition a valid food frequency questionnaire (FFQ) measuring daily milk products serving intake as a main outcome measure was completed for each respondent. Logistic regression analysis was applied to examine the association between milk and dairy products consumption and independents variables. RESULTS: In all 402 students (51.5 % female) participated in the study. The mean age of students was 12.9 (SD = 0.49) years. The average daily intake of milk and dairy products was 1.64 (SD = 0.78) servings per day. Overall 14.2 % of adolescents (18.8 % of girls, and 9.2 % of boys, p = 0.006) reported consumption of the recommended daily milk and dairy products serving per day. The results indicated that gender boys (OR for boys = 2.41, 95 % CI = 1.25-4.67), mother age (OR for age group 40-55 years = 2.52, 95 % CI = 1.18-5.38), poor perceived emotional family support, (OR = 1.10, 95 % CI = 1.05-3.61), and poor perceived practical family support (OR = 2.04, 95 % CI = 1.18-4.17) were the most significant contributing factors to low level milk and dairy products intake in adolescents. CONCLUSION: The findings indicated that adolescents did not take the recommended daily amount of milk and dairy products and this appeared to be strongly related to low perceived family support. To achieve the recommended daily milk and dairy products serving consumption, family involvements in any programs that specifically address emotional and practical support for promoting daily milk and dairy products intake among adolescents are suggested. PMID- 26493844 TI - Emerging bacterial pathogens: the past and beyond. AB - Since the 1950s, medical communities have been facing with emerging and reemerging infectious diseases, and emerging pathogens are now considered to be a major microbiologic public health threat. In this review, we focus on bacterial emerging diseases and explore factors involved in their emergence as well as future challenges. We identified 26 major emerging and reemerging infectious diseases of bacterial origin; most of them originated either from an animal and are considered to be zoonoses or from water sources. Major contributing factors in the emergence of these bacterial infections are: (1) development of new diagnostic tools, such as improvements in culture methods, development of molecular techniques and implementation of mass spectrometry in microbiology; (2) increase in human exposure to bacterial pathogens as a result of sociodemographic and environmental changes; and (3) emergence of more virulent bacterial strains and opportunistic infections, especially affecting immunocompromised populations. A precise definition of their implications in human disease is challenging and requires the comprehensive integration of microbiological, clinical and epidemiologic aspects as well as the use of experimental models. It is now urgent to allocate financial resources to gather international data to provide a better understanding of the clinical relevance of these waterborne and zoonotic emerging diseases. PMID- 26493843 TI - Increased risk of infections and infection-related mortality in children undergoing haematopoietic stem cell transplantation compared to conventional anticancer therapy: a multicentre nationwide study. AB - This nationwide multicentre study analysed the epidemiology of bacterial, viral and fungal infections in paediatric haematopoietic stem cell transplantation (HSCT) and paediatric haematology and oncology (PHO) patients over a period of 24 consecutive months, including incidence, hazard risk and outcome of infections as well as occurrence of multidrug-resistant bacteria. During this period, 308 HSCTs were performed and 1768 children were newly diagnosed for malignancy. Compared to PHO, the risk in HSCT patients was significantly higher for all infections (hazard ratio (HR) 2.7), bacterial (HR 1.4), fungal (HR 3.5) and viral (HR 15.7) infections. The risk was higher in allo- than auto-HSCT for bacterial (HR 1.4), fungal (HR 3.2) and viral (HR 17.7) infections. The incidence of resistant bacteria was higher in HSCT than in PHO patients for both G-negative (72.5% vs. 59.2%) and G-positive (41.4% vs. 20.5%) strains. Cumulative incidence of bacterial, fungal and viral infections in HSCT patients was 33.9, 22.8 and 38.3%, respectively. Cumulative incidence of viral infections in allo-HSCT was 28.0% for cytomegalovirus, 18.5% for BK virus, 15.5% for Epstein-Barr virus, 9.5% for adenovirus, 2.6% for varicella zoster virus, 0.9% for influenza, 0.9% for human herpesvirus 6 and 0.3% for hepatitis B virus. Survival rates from infections were lower in HSCT than in PHO patients in bacterial (96.0 vs. 98.2%), fungal (75.5 vs. 94.6%) and most viral infections. In conclusion, the risk of any infections and the occurrence of resistant bacterial strains in allo-HSCT patients were higher than in auto-HSCT and PHO patients, while the outcome of infections was better in the PHO setting. PMID- 26493845 TI - How do physicians cope with controversial topics in existing guidelines for the management of infective endocarditis? Results of an international survey. AB - International guidelines are available to help physicians prescribe appropriate antibiotic regimens to patients with infective endocarditis (IE). However some topics of these guidelines are controversial. We conducted an international survey to assess physicians' adherence to these guidelines, focusing on these controversial items. An invitation to participate to a 15-question online survey was sent in 2012-2013 to European Society of Clinical Microbiology and Infectious Diseases (ESCMID) members, scientific societies and corresponding authors of publications on IE mentioned in PubMed from 1990 to 2012, inclusive. Eight hundred thirty-seven physicians participated in the survey, and 625 (74.7%) completed it over the first question. The results showed great heterogeneity of practices. Claiming to follow guidelines was marginally associated with more guideline-based strategies. Gentamicin use depended on causative pathogens (p <0.001) and physician specialty (p 0.02). Eighty-six per cent of the physicians favoured vancomycin alone or in combination with gentamicin or rifampicin as a first-line treatment for left-sided native valve methicillin-resistant Staphylococcus aureus IE, 31% considered switching to oral therapy as a therapeutic option and 33% used the ampicillin and ceftriaxone combination for enterococcal IE as a first-line therapy. Physician specialty significantly affected the choice of a therapeutic strategy, while practicing in a university hospital or the number of years of practice had virtually no impact. Our survey, the largest on IE treatment, underscores important heterogeneity in practices for treatment of IE. Nonetheless, physicians who do not follow guidelines can have rational strategies that are based on the literature. These results could inform the revision of future guidelines and identify unmet needs for future studies. PMID- 26493846 TI - Poultry and human infections. PMID- 26493847 TI - Increased intrahepatic quasispecies heterogeneity correlates with off-treatment sustained response to nucleos(t)ide analogues in e antigen-positive chronic hepatitis B patients. AB - Finite treatment with nucleos(t)ide analogues (NAs) remains a great challenge for chronic hepatitis B in the clinic. This study aimed to investigate the relationship between intrahepatic quasispecies heterogeneity and the NAs off treatment outcomes in a prospective cohort. Eighteen HBeAg-positive patients with chronic hepatitis B who achieved the cessation criteria underwent liver biopsy, and stopped treatment thereafter. Patients were followed up prospectively for 1 year. The reverse transcriptase (RT) gene of intrahepatic hepatitis B virus (HBV) was cloned and sequenced. Intrahepatic quasispecies heterogeneity and specific gene mutations were analysed using bioinformatic methods. Ten patients achieved sustained response, and eight patients developed viral relapse. The intrahepatic quasispecies Shannon entropy and nucleotide diversity within either RT or the surface (S) region of patients with sustained response were significantly higher (p < 0.05) than those of patients who had a viral relapse. Intrahepatic quasispecies Shannon entropy at the nucleotide level predicted the sustained off treatment response (area under receiver operating characteristics curve 0.925; 95% CI 0.807-1.000; p 0.003). More positive selection sites and N-glycosylation mutations within the S region were found in patients with sustained response than in the patients with viral relapse (p < 0.01). Most of the positive selection sites in patients with sustained response were located in reported HLA-I restricted or HLA-II-restricted epitopes. Intrahepatic quasispecies heterogeneity at the end of treatment was correlated with off-treatment outcomes in HBeAg positive patients with chronic hepatitis B. More immune escape mutations were found within the S region in patients with sustained response. The higher intrahepatic quasispecies heterogeneity indicated a more robust immune control over HBV, which in turn maintained a sustained response after withdrawal of NAs. PMID- 26493848 TI - Microbiota studies in the bile duct strongly suggest a role for Helicobacter pylori in extrahepatic cholangiocarcinoma. AB - Biliary tract cancer or extrahepatic cholangiocarcinoma (ECCA) represents the sixth commonest cause of cancer in the gastrointestinal tract in western countries. We aimed to characterize the microbiota and its predicted associated functions in the biliary tract of ECCA and benign biliary pathology (BBP). Samples were taken from 100 patients with ECCA and 100 patients with BBP by endoscopic cholangio-pancreatography for DNA extraction. Ten patients with ECCA and ten with BBP were selected for microbiota studies using the V4-16S rRNA gene and sequenced in Illumina platform. Microbiota analyses included sample-to-sample distance metrics, ordination/clustering and prediction of functions. Presence of Nesterenkonia sp. and Helicobacter pylori cagA and vacA genes were tested in the 100 ECCA and 100 BBP samples. Phylum Proteobacteria dominated all samples (60.4% average). Ordination multicomponent analyses showed significant microbiota separation between ECCA and BBP (p 0.010). Analyses of 4002 operational taxonomic units with presence variation in at least one category probed a separation of ECCA from BBP. Among these, Nesterenkonia decreased, whereas Methylophilaceae, Fusobacterium, Prevotella, Actinomyces, Novosphingobium and H. pylori increased in ECCA. Predicted associated functions showed increased abundance of H. pylori virulence genes in ECCA. cagA and vacA genes were confirmed by PCR in ECCA and BBP samples. This is the first microbiota report in ECCA and BBP to show significant changes in microbial composition. Bacterial species unusual for human flora were found: Methylophilaceae and Nesterenkonia are reported in hypersaline soils, and Mesorhizobium is a nitrogen-fixing bacterium. Enrichment of virulence genes confirms previous studies suggesting that H. pylori might be associated with ECCA. PMID- 26493849 TI - Clostridium butyricum: from beneficial to a new emerging pathogen. AB - Clostridium butyricum, a strictly anaerobic spore-forming bacillus, is a common human and animal gut commensal bacterium, and is also frequently found in the environment. Whereas non-toxigenic strains are currently used as probiotics in Asia, other strains have been implicated in pathological conditions, such as botulism in infants or necrotizing enterocolitis in preterm neonates. In terms of the latter, within the same species, different strains have antagonist effects on the intestinal mucosa. In particular, short-chain fatty acids, which are products of carbohydrate fermentation, have a dose-dependent paradoxical effect. Moreover, toxin genes have been identified by genome sequencing in pathological strains. Asymptomatic carriage of these strains has also been reported. Herein, we provide an overview of the implications of C. butyricum for human health, from the beneficial to the pathogenic. We focus on pathogenic strains associated with the occurrence of necrotizing enterocolitis. We also discuss the need to use complementary microbiological methods, including culture, in order to better assess gut bacterial diversity and identify new emergent enteropathogens at the strain level. PMID- 26493850 TI - Development of global rating instruments for pediatric patients with ataxia telangiectasia. AB - INTRODUCTION: Ataxia telangiectasia (AT) is a neurodegenerative disorder with cerebellar and extrapyramidal features. Interventional and epidemiological studies in AT should rely on specific scales which encompass the specific neurological features, as well the early progressive course and the subsequent plateau. The aim of this study was to build a scale of the CGI type (Clinical Global Impression) which is disease specific, as well as to check the feasibility of the ICARS scale for ataxia in this population. METHODS: We recruited 63 patients with ataxia, aged 10.76 +/- 3.2 years, followed at 6 international AT centers, 49 of them (77.8%) with classical AT. All patients were evaluated for ataxia with ICARS scale. In patients with AT, two CGI scales were scored, unstructured as structured for which separate anchors were provided. RESULTS: Mean ICARS score was 44.7 +/- 20.52, and it's severity positively correlated with age (Spearman correlation, r = 0.46, p < 0.01). Mean CGI score was 2 (moderately involved). There was a high correlation between the structured and unstructured CGIs (Spearman correlation, r = 0.87, p < 0.01). Both CGI scales showed positive correlation between severity and increasing age (Spearman correlation r = 0.59, p < 0.01 for structured CGI and r = 0.61, p < 0.01 for unstructured). DISCUSSION: We succeeded to build two CGI scales: structured and unstructured, which are disease specific for AT. The unstructured scale showed better connection to disease course; the sensitivity of the unstructured scale could be improved by adding anchors related to extrapyramidal features. In addition we showed that ataxia can be reliably measured in children with AT by using ICARS. PMID- 26493851 TI - Is major depression associated with serum levels of tumor necrosis factor-alpha in patients with rheumatoid arthritis? AB - OBJECTIVE: This study presents the serum tumor necrosis factor-alpha (TNF-alpha) levels in rheumatoid arthritis (RA) patients with major depression and without any psychiatric disorder. METHODS: The study sample included 61 patients with a diagnosis of RA. Major depression and other psychiatric disorders were screened with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Blood sample for the determination of serum TNF-alpha level was obtained before the psychiatric interview. RESULTS: The prevalence rates of any depressive disorder and any anxiety disorder were 40.3% (n=25) and 22.6% (n=14), respectively. Fifteen (24.2%) patients had major depression alone, whereas 27 (43.5%) patients were not diagnosed with any psychiatric disorder. We could not determine any significant differences between the patients with major depression alone and patients without any psychiatric diagnosis with regard to the serum levels of TNF-alpha. CONCLUSIONS: The existence of major depression in RA patients does not seem to be associated with serum levels of TNF-alpha. PMID- 26493852 TI - Diagnosis of 21-hydroxylase deficiency by urinary metabolite ratios using gas chromatography-mass spectrometry analysis: Reference values for neonates and infants. AB - One major issue of newborn screening programs for 21-hydroxylase deficiency (21OHD) is the high rate of false-positive results, especially in preterm neonates. Urinary steroid metabolite analysis using gas chromatography-mass spectrometry (GC-MS) is suitable as a confirmatory diagnostic tool. The objective of this study was to analyze retrospectively diagnostic metabolite ratios in neonates and infants with and without 21OHD using GC-MS with emphasis on glucocorticoid metabolism, and to develop reference values for the steroid metabolite ratios for the diagnosis of 21OHD. We retrospectively analyzed urinary steroid hormone metabolites determined by GC-MS of 95 untreated neonates and infants with 21OHD (1-148 days), and 261 neonates and infants (100 preterms) without 21OHD (0-217 days). Metabolites of 17alpha-hydroxyprogesterone showed specificities below 98%, whereas the 21-deoxycortisol metabolite pregnanetriolone clearly separated 21OHD from non-21OHD subjects. The best diagnostic ratio for 21OHD was pregnanetriolone to 6alpha-hydroxy-tetrahydrocortisone. The lowest value of this ratio in the 21OHD group (0.47) was at least eight times higher than the highest values in the non-21OHD group (0.055). We have given appropriate reference values for steroid metabolite ratios in the largest 21OHD cohort so far described. Consideration of glucocorticoid metabolism, especially the use of typical neonatal 6alpha-hydroxylates metabolites, leads to improvement of diagnostic metabolite ratios. PMID- 26493853 TI - Prevention and treatment of nutritional rickets. AB - Nutritional rickets continues to be a significant health problem for children worldwide with recent evidence of increasing incidence in many developed countries. It is due to vitamin D deficiency and/or inadequate dietary calcium intake with variation in the relative contributions of each of these dependant on environmental factors such a dietary intake and sunlight exposure. Key to the prevention of rickets is ensuring that pregnant women and their infants receive vitamin D supplementation with good evidence from randomised controlled trials that infants who receive 400iu daily can achieve levels of 25 hydroxyvitamin D of >50nmol/l. However, public health implementation of daily supplementation is more challenging with a need to revisit food fortification strategies to ensure optimal vitamin D status of the population. Treatment of nutritional rickets has traditionally been with vitamin D2 or D3, often given as a daily oral dose for several weeks until biochemical and radiological evidence of healing. However, other treatment regimes with single or intermittent high doses have also proved to be effective. It is now recognised that oral calcium either as dietary intake or supplements should be routinely used in conjunction with vitamin D for treatment. PMID- 26493854 TI - Acute Responses of Functional Electrical Stimulation Cycling on the Ventilation to-CO2 Production Ratio and Substrate Utilization After Spinal Cord Injury. AB - BACKGROUND: Ventilation-to-carbon dioxide ratio is comparable with peak oxygen uptake in the prognosis of cardiovascular disorders. Currently, there are no established indices to determine the submaximal effects of functional electrical stimulation on cardiovascular performance in persons with spinal cord injury. OBJECTIVE: To determine the effects of an acute bout of functional electrical stimulation-lower extremity cycling on ventilation, carbon dioxide production, ventilation-to-carbon dioxide ratio, and substrate utilization in people with motor complete spinal cord injury. DESIGN: Observational cross-sectional design. SETTING: Clinical laboratory setting. PARTICIPANTS: Ten individuals with motor complete spinal cord injury. METHODS: Participants were allowed to cycle until fatigue. The effects of functional electrical stimulation on ventilation, carbon dioxide production, ventilation-to-carbon dioxide ratio, and substrate utilization were measured with a portable metabolic cart (COSMED K4b2). Body composition was determined with bioelectrical impedance. RESULTS: Resting and warm-up ventilation were 8.15 +/- 3.5 L/min and 8.15 +/- 2.8 L/min, respectively. Functional electrical stimulation increased ventilation significantly (14.5 +/- 6.4 L/min), which remained significantly elevated (13.3 +/- 4.3 L/min) during the recovery period. During resting and warm-up phases, the ventilation-to-carbon dioxide ratios were 41 +/- 4.8 and 38 +/- 5.4, respectively. Functional electrical stimulation decreased the ventilation-to-carbon dioxide ratio significantly to 31.5 +/- 4, which remained significantly reduced during the recovery period (34.4 +/- 3). Functional electrical stimulation relied primarily on carbohydrate utilization (188 +/- 160 g/day to 574 +/- 324 g/day; P = .001) with no changes in fat utilization (77.5 +/- 28 g/day to 93.5 +/- 133.6 g/day; P = .7) from resting to exercise periods. Significant relationships were noted between carbohydrate utilization during functional electrical stimulation and carbon dioxide (r = 0.98; P = .00010) production. The percentage whole body fat free mass was negatively related to the exercise ventilation-to-carbon ratio (r = -0.66; P = .045). CONCLUSIONS: An acute bout of functional electrical stimulation resulted in a significant drop in the ventilation-to-carbon ratio, accompanied with a reliance on carbohydrate utilization and a diminished capacity to utilize fat as a substrate. Fat-free mass may be associated with a decrease in ventilation to carbon dioxide ratio and an increase in carbohydrate utilization in persons with spinal cord injury. PMID- 26493855 TI - Ultrasound-Guided Intercostobrachial Nerve Block for Intercostobrachial Neuralgia in Breast Cancer Patients: A Case Series. AB - This case series describes 3 cases in which ultrasound-guided intercostobrachial perineural injection was used for intercostobrachial neuralgia, a common cause of postmastectomy pain syndrome. All cases had undergone modified radical mastectomy with axillary lymph node dissection for breast cancer. Two cases developed axillary and unilateral chest wall pain. The third case initially presented with axillary pain and lateral shoulder pain 1 year out from radical mastectomy. After a cervical epidural steroid injection, her lateral shoulder pain resolved, but she continued to have residual chest wall paresthesia. It was at this time, we decided to treat with an intercostobrachial nerve perineural injection. Injury to the intercostobrachial nerve is thought to be a common cause of postmastectomy pain. In our case series, all patients had pain relief after the intercostobrachial perineural injection. There is a relative dearth of published information on the treatment of postmastectomy pain and more specifically intercostobrachial neuralgia. We review the anatomy of the intercostobrachial nerve and its variants, etiologies of intercostobrachial neuralgia, and current indications and methods of an intercostobrachial perineural injection. PMID- 26493856 TI - Translation of a Motor Learning Walking Rehabilitation Program Into a Group-Based Exercise Program for Community-Dwelling Older Adults. AB - BACKGROUND: Traditional exercise programs for older adults, which focus on aerobic and strength training, have had only modest effects on walking. Recently, a motor learning exercise program was shown to have greater effects on walking compared with a traditional exercise program. Translating this novel motor learning exercise program into a group exercise program would allow it to be offered as an evidence-based, community-based program for older adults. OBJECTIVE: To translate a walking rehabilitation program based on motor learning theory from one-on-one to group delivery (On the Move) and evaluate multiple aspects of implementation in older adults with impaired mobility. DESIGN: The translation process involved multiple iterations, including meetings of experts in the field (Phase I), focus groups (Phase II), and implementation of the newly developed program (Phase III). Phase III was based on a one-group model of intervention development for feasibility, safety, potential effects, and acceptability. SETTING: Community sites, including 2 independent living facilities, an apartment building, and a community center. PARTICIPANTS: Adults 65 years of age or older who could ambulate independently and who were medically stable. Thirty-one adults, mean age 82.3 +/- 5.6 years, were eligible to participate. METHODS: The group exercise program was held twice a week for 12 weeks. MAIN OUTCOME MEASUREMENTS: Acceptability of the program was determined by retention and adherence rates and a satisfaction survey. Risk was measured by adverse events and questions on perceived challenge and safety. Mobility was assessed pre- and postintervention by gait speed, Figure of 8 Walk Test, and 6 minute walk test. RESULTS: Modifications to the program included adjustments to format/length, music, education, and group interaction. The 12-week program was completed by 24 of 31 entrants (77%). Adherence was high, with participants attending on average 83% of the classes. Safety was excellent, with only 1 subject experiencing a controlled, noninjurious fall. There was preliminary evidence for improved mobility after the intervention: gait speed improved from 0.76 +/- 0.21 to 0.81 +/- 0.22 m/s, P = .06; Figure of 8 Walk Test from 13.0 +/- 3.9 to 12.0 +/- 3.9 seconds, P = .07; and 6-minute walk test from 246 +/- 75 to 281 +/- 67 m, P = .02. CONCLUSIONS: The group-based program was safe and acceptable to older adults with impaired mobility and resulted in potentially clinically meaningful improvements in mobility. PMID- 26493857 TI - Optically Triggered Stepwise Double-Proton Transfer in an Intramolecular Proton Relay: A Case Study of 1,8-Dihydroxy-2-naphthaldehyde. AB - 1,8-Dihydroxy-2-naphthaldehyde (DHNA), having doubly intramolecular hydrogen bonds, was strategically designed and synthesized in an aim to probe a long standing fundamental issue regarding synchronous versus asynchronous double proton transfer in the excited state. In cyclohexane, DHNA shows the lowest lying S0 ->S1 (pi-pi*) absorption at ~400 nm. Upon excitation, two large Stokes shifted emission bands maximized at 520 and 650 nm are resolved, which are ascribed to the tautomer emission resulting from the first and second proton-transfer products, denoted by TA* and TB*, respectively. The first proton transfer (DHNA* > TA*) is ultrafast (< system response of 150 fs), whereas the second proton transfer is reversible, for which the rates of forward (TA* -> TB*) and backward (TA* <- TB*) proton transfer were determined to be (1.7 ps)(-1) and (3.6 ps)(-1), respectively. The fast equilibrium leads to identical population lifetimes of ~54 ps for both TA* and TB* tautomers. Similar excited-state double-proton transfer takes place for DHNA in a single crystal, resulting in TA* (560 nm) and TB* (650 nm) dual-tautomer emission. A comprehensive 2D plot of reaction potential energy surface further proves that the sequential two-step proton motion is along the minimum energetic pathway firmly supporting the experimental results. Using DHNA as a paradigm, we thus demonstrate unambiguously a stepwise, proton-relay type of intramolecular double-proton transfer reaction in the excited state, which should gain fundamental understanding of the multiple proton transfer reactions. PMID- 26493858 TI - Rehabilitation and plasticity following stroke: Insights from rodent models. AB - Ischemic injuries within the motor cortex result in functional deficits that may profoundly impact activities of daily living in patients. Current rehabilitation protocols achieve only limited recovery of motor abilities. The brain reorganizes spontaneously after injury, and it is believed that appropriately boosting these neuroplastic processes may restore function via recruitment of spared areas and pathways. Here I review studies on circuit reorganization, neuronal and glial plasticity and axonal sprouting following ischemic damage to the forelimb motor cortex, with a particular focus on rodent models. I discuss evidence pointing to compensatory take-over of lost functions by adjacent peri-lesional areas and the role of the contralesional hemisphere in recovery. One key issue is the need to distinguish "true" recovery (i.e. re-establishment of original movement patterns) from compensation in the assessment of post-stroke functional gains. I also consider the effects of physical rehabilitation, including robot-assisted therapy, and the potential mechanisms by which motor training induces recovery. Finally, I describe experimental approaches in which training is coupled with delivery of plasticizing drugs that render the remaining, undamaged pathways more sensitive to experience-dependent modifications. These combinatorial strategies hold promise for the definition of more effective rehabilitation paradigms that can be translated into clinical practice. PMID- 26493859 TI - Assessment of factors impacting cervical cancer screening among low-income women living with HIV-AIDS. AB - Very little is currently known about factors impacting the prevalence of cervical cancer screening among women living with HIV-AIDS (WLHA). To better understand this issue, we surveyed low-income, medically underserved women receiving subsidized gynecologic care through an integrated HIV clinic. A self-administered questionnaire was completed by 209 women who self-identified as HIV positive. A total of 179 subjects (85.7%) reported having had a Pap test in the last three years. The majority of WLHA (95%) knew that the Pap test screens for cervical cancer. However, overall knowledge of cervical cancer risk factors, such as multiple sexual partners or sex with a man with multiple partners, was low (43% and 35%, respectively). Unscreened women were younger and more likely to be single with multiple current sexual partners. In multivariable analyses, the only factors associated with Pap testing were a woman's perception that her partner wants her to receive regular screening (aOR 4.64; 95% CI: 1.15-23.76; p = .04), number of clinic visits during the past year (aOR 1.36, 95% CI: 1.05-1.94; p = .04) and knowledge that the need for a Pap test does not depend on whether or not a woman is experiencing vaginal bleeding (aOR 6.52, 95% CI: 1.04-49.71; p = .05). We conclude that support from male partners in addition to effective contact with the health system and knowledge of cervical cancer risk factors influence Pap utilization among low-income WLHA. Future measures to improve the care for this population should increase knowledge of cervical cancer risk factors and encourage social support for cervical cancer screening among WLHA. PMID- 26493860 TI - Towards an effective cross-task mental workload recognition model using electroencephalography based on feature selection and support vector machine regression. AB - Electroencephalographic (EEG) has been believed to be a potential psychophysiological measure of mental workload. There however remain a number of challenges in building a generalized mental workload recognition model, one of which includes the inability of an EEG-based workload classifier trained on a specific task to handle other tasks. The primary goal of the present study was to examine the possibility of addressing this challenge using feature selection and regression model. Support vector machine classifier and regression models were examined under within-task conditions (trained and tested on the same task) and cross-task conditions (trained on one task and tested on another task) for well trained verbal and spatial n-back tasks. A specifically designed cross-task recursive feature elimination (RFE) based feature selection was used to handle the possible causes responsible for the deterioration of the performance of cross task regression model. The within-task classification and regression performed fairly well. Cross-task classification and regression performance, however, deteriorated to unacceptable levels (around chance level). Trained and tested with the most robust feature subset selected by cross-task RFE, the performance of cross-task regression was significantly improved, and there were no significant changes in the performance of within-task regression. It can be inferred that workload-related features can be picked out from those which have been contaminated using RFE, and regression models rather than classifiers may be a wiser choice for cross-task conditions. These encouraging results suggest that the cross-task workload recognition model built in this study is much more generalizable across task when compared to the model built in traditional way. PMID- 26493861 TI - Atrial fibrillation, CHA2DS2-VASc score, antithrombotics and risk of non-traffic , non-cancer-related bone fractures: A population-based cohort study. AB - BACKGROUND: Accidental bone fractures are a major cause of premature disabilities and death. Whether atrial fibrillation (AF) treated with or without antithrombotics correlates with occurrence of such events remains under investigated. METHODS: Patients >=18 years with newly diagnosed AF between 2005 and 2009 without previous cancers or traffic injury were identified from the "Longitudinal Health Insurance Database 2005" (1 million beneficiaries) of Taiwan's National Health Research Institutes and served as the AF group. A fourfold number of age-, gender-, and comorbidity-matched patients but without AF served as the non-AF controls. Patients were followed, and cumulative incidence of hospitalization-requiring bone fractures was compared between groups. Predictors of accidental bone fractures were determined by Cox regression analysis. RESULTS: Within a mean follow-up of 3.6 years, bone fractures, especially those involving neck/trunk and lower limbs, were significantly more frequent in patients with AF (N=6925) than in those without (N=27,700) (7.0 vs. 3.8 per 1000 person-years, log-rank p=0.001, adjusted HR=1.85, 95% CI=1.50-2.30, p<0.001). Cox models identified female gender, previous stroke, and CHA2DS2-VASc score?1 as risk factors for bone fractures in AF patients, whereas oral anticoagulants (HR=0.62, 95% CI=0.35-0.91, p=0.034), especially when used in patients with CHA2DS2-VASc score?1 but not antiplatelet therapy (p=0.39) as negative predictors. CONCLUSION: Patients with AF are more vulnerable to non traffic-, non-cancer-related bone fractures especially when with specified characteristics. For those with higher CHA2DS2-VASc scores, the use of anticoagulant but not antiplatelet agents could be associated with lower risk of such events. PMID- 26493862 TI - Predicting Sizes of Hexagonal and Gyroid Metal Nanostructures from Liquid Crystal Templating. AB - We describe a method to predict and control the lattice parameters of hexagonal and gyroid mesoporous materials formed by liquid crystal templating. In the first part, we describe a geometric model with which the lattice parameters of different liquid crystal mesophases can be predicted as a function of their water/surfactant/oil volume fractions, based on certain geometric parameters relating to the constituent surfactant molecules. We demonstrate the application of this model to the lamellar (Lalpha), hexagonal (H1), and gyroid bicontinuous cubic (V1) mesophases formed by the binary Brij-56 (C16EO10)/water system and the ternary Brij-56/hexadecane/water system. In this way, we demonstrate predictable and independent control over the size of the cylinders (with hexadecane) and their spacing (with water). In the second part, we produce mesoporous platinum using as templates hexagonal and gyroid phases with different compositions and show that in each case the symmetry and lattice parameter of the metal nanostructure faithfully replicate those of the liquid crystal template, which is itself in agreement with the model. This demonstrates a rational control over the geometry, size, and spacing of pores in a mesoporous metal. PMID- 26493864 TI - Experimental infection of rock pigeons (Columba livia) with three West Nile virus lineage 1 strains isolated in Italy between 2009 and 2012. AB - West Nile virus (WNV) circulation dynamics in the context of the urban environment is not yet elucidated. In this perspective, three groups of eight rock pigeons (Columbia livia) were inoculated with three WNV lineage 1 strains isolated in Italy between 2009 and 2012. The pigeons did not develop any clinical signs consistent with WNV acute infection. All animals seroconverted and shed virus up to 15 days post-infection by the oral or cloacal routes. In all infected groups viraemia lasted for 4 days post-infection. No WNV-specific gross or histological lesions were found in infected birds compared to control birds and immunohistochemistry remained constantly negative from all tissues. The reservoir competence index was also assessed and it ranged between 0.11 and 0.14. This study demonstrates that pigeons are competent reservoir hosts for Italian WNV lineage 1 circulating strains thus potentially posing a risk to the public health system. PMID- 26493865 TI - Air quality impacts of a CicLAvia event in Downtown Los Angeles, CA. AB - CicLAvia in Los Angeles, CA is the open streets program that closes streets to motorized vehicles and invites people to walk, run, play or ride their bicycles on these streets, allowing them to experience the city in a new way and get exercise at the same time. Since the events reduce the motorized traffic flow, which is a significant source of air pollution, on the streets, it is reasonable to hypothesize that the CicLAvia events can reduce the concentrations of traffic emitted air pollutants during the road closure. This study is the first experiment to test this hypothesis. The on-road and community-wide ultrafine particle (UFP) and PM2.5 were measured on the Event-Sunday (October 5th, 2014) and the Pre- and Post- Sundays (September 28(th) and October 12(th), 2014). Data analysis results showed the on-road UFP and PM2.5 reduction was 21% and 49%, respectively, and the community-wide PM2.5 reduction was 12%. PMID- 26493863 TI - The green shoots of a novel training programme: progress and identified key actions to providing services to MSM at Kenyan health facilities. AB - INTRODUCTION: Although men who have sex with men (MSM) in sub-Saharan Africa are at high risk for HIV acquisition, access to and quality of health and HIV services within this population are negatively affected by stigma and capacity within the health sector. A recently developed online MSM training programme (www.marps-africa.org) was shown to contribute to reductions in MSM prejudice among healthcare providers (HCPs) in coastal Kenya. In this study, we used qualitative methods to explore the provision of MSM healthcare services two years post-training in coastal Kenya. METHODS: From February to July 2014, we held 10 focus group discussions (FGD) with 63 participants, including HCP from 25 facilities, county AIDS coordinators and MSM from local support groups. Participants discussed availability, acceptability and accessibility of HIV healthcare for MSM. HCP also discussed changes in their health service practices after completing the training. FGD were recorded, transcribed verbatim and analyzed using Ritchie and Spencer's "framework approach" for qualitative data. RESULTS: HCPs described continued improvements in their ability to provide service in a non-stigmatizing way to MSM patients since completing the training programme and expressed comfort engaging MSM patients in care. Four additional recommendations for improving MSM healthcare services were identified: 1) expanding the reach of MSM sensitivity training across the medical education continuum; 2) establishing guidelines to manage sexually transmitted anal infections; 3) promoting legal and policy reforms to support integration of MSM appropriate services into healthcare; and 4) including MSM information in national reporting tools for HIV services. CONCLUSIONS: Positive impacts of this sensitivity and skills training programme were reflected in HCP attitudes two years post-intervention. Scaling-up of efforts will rely on continued policies to include MSM in healthcare programmes to reduce stigma in health settings and guidelines for MSM STI service delivery. PMID- 26493866 TI - Monosodium glutamate-induced oxidative kidney damage and possible mechanisms: a mini-review. AB - Animal studies suggest that chronic monosodium glutamate (MSG) intake induces kidney damage by oxidative stress. However, the underlying mechanisms are still unclear, despite the growing evidence and consensus that alpha-ketoglutarate dehydrogenase, glutamate receptors and cystine-glutamate antiporter play an important role in up-regulation of oxidative stress in MSG-induced renal toxicity. This review summaries evidence from studies into MSG-induced renal oxidative damage, possible mechanisms and their importance from a toxicological viewpoint. PMID- 26493867 TI - Scalable fabrication of a hybrid field-effect and acousto-electric device by direct growth of monolayer MoS2/LiNbO3. AB - Lithium niobate is the archetypical ferroelectric material and the substrate of choice for numerous applications including surface acoustic wave radio frequencies devices and integrated optics. It offers a unique combination of substantial piezoelectric and birefringent properties, yet its lack of optical activity and semiconducting transport hamper application in optoelectronics. Here we fabricate and characterize a hybrid MoS2/LiNbO3 acousto-electric device via a scalable route that uses millimetre-scale direct chemical vapour deposition of MoS2 followed by lithographic definition of a field-effect transistor structure on top. The prototypical device exhibits electrical characteristics competitive with MoS2 devices on silicon. Surface acoustic waves excited on the substrate can manipulate and probe the electrical transport in the monolayer device in a contact-free manner. We realize both a sound-driven battery and an acoustic photodetector. Our findings open directions to non-invasive investigation of electrical properties of monolayer films. PMID- 26493869 TI - Primary care commissioners need five year budgets to transform care, says report. PMID- 26493868 TI - Microarray Analyses Reveal Marked Differences in Growth Factor and Receptor Expression Between 8-Cell Human Embryos and Pluripotent Stem Cells. AB - Previous microarray analyses of RNAs from 8-cell (8C) human embryos revealed a lack of cell cycle checkpoints and overexpression of core circadian oscillators and cell cycle drivers relative to pluripotent human stem cells [human embryonic stem cells/induced pluripotent stem (hES/iPS)] and fibroblasts, suggesting growth factor independence during early cleavage stages. To explore this possibility, we queried our combined microarray database for expression of 487 growth factors and receptors. Fifty-one gene elements were overdetected on the 8C arrays relative to hES/iPS cells, including 14 detected at least 80-fold higher, which annotated to multiple pathways: six cytokine family (CSF1R, IL2RG, IL3RA, IL4, IL17B, IL23R), four transforming growth factor beta (TGFB) family (BMP6, BMP15, GDF9, ENG), one fibroblast growth factor (FGF) family [FGF14(FH4)], one epidermal growth factor member (GAB1), plus CD36, and CLEC10A. 8C-specific gene elements were enriched (73%) for reported circadian-controlled genes in mouse tissues. High-level detection of CSF1R, ENG, IL23R, and IL3RA specifically on the 8C arrays suggests the embryo plays an active role in blocking immune rejection and is poised for trophectoderm development; robust detection of NRG1, GAB1, -2, GRB7, and FGF14(FHF4) indicates novel roles in early development in addition to their known roles in later development. Forty-four gene elements were underdetected on the 8C arrays, including 11 at least 80-fold under the pluripotent cells: two cytokines (IFITM1, TNFRSF8), five TGFBs (BMP7, LEFTY1, LEFTY2, TDGF1, TDGF3), two FGFs (FGF2, FGF receptor 1), plus ING5, and WNT6. The microarray detection patterns suggest that hES/iPS cells exhibit suppressed circadian competence, underexpression of early differentiation markers, and more robust expression of generic pluripotency genes, in keeping with an artificial state of continual uncommitted cell division. In contrast, gene expression patterns of the 8C embryo suggest that it is an independent circadian rhythm-competent equivalence group poised to signal its environment, defend against maternal immune rejection, and begin the rapid commitment events of early embryogenesis. PMID- 26493870 TI - Adaptation of a Cancer Clinical Trials Education Program for African American and Latina/o Community Members. AB - The pilot study reported in this article culturally and linguistically adapted an educational intervention to promote cancer clinical trials (CCTs) participation among Latinas/os and African Americans. The single-session slide presentation with embedded videos, originally developed through a campus-community partnership in Southern California, was chosen for adaptation because it was perceived to fit the CORRECT model of innovation (credible, observable, relevant, relatively advantageous, easy to understand, compatible, and testable) and because of the potential to customize any components not identified as core, allowing them to be revised for cultural and linguistic alignment in New York City. Most of the 143 community participants (76.2%) were female; most (54.6%) were older than 59 years. More than half (78.3%) preferred to speak English or were bilingual in English and Spanish. A large proportion (41.3%) had not completed high school. Knowledge and perceived benefits and barriers regarding CCT showed small, though statistically significant, increases. There were no statistically significant group differences for changes in mean knowledge, perceived benefits, or perceived barriers when examined by ethnicity, education level, language, or other included sociodemographic variables. However, a small, but statistically significant difference in perceived barriers was observed when examined by country of origin, with the foreign born score worsening 0.08 points (SD = 0.47, p = .007) on the 5 point Likert-type scale administered posteducation compared to preeducation. Participants' open-ended comments demonstrated the acceptability of the topic and intervention. This adaptation resulted in an intervention with the potential to educate African American and Latina/o general community members in a new geographic region about the purpose, methods, and benefits of CCTs. PMID- 26493871 TI - Impact of a pharmacist-led oral chemotherapy-monitoring program in patients with metastatic castrate-resistant prostate cancer. AB - BACKGROUND: With the introduction of oral chemotherapy, the paradigm for cancer treatment is shifting. Use of oral chemotherapy agents offers a non-invasive option for patients with metastatic castrate-resistant prostate cancer. However, these medications are not without challenges including strict adherence for optimal effects, novel toxicity profiles, frequent lab parameter monitoring, high cost, and proper handling and disposal methods. Pharmacists are positioned to play a key role in providing patients with the education required to assure an optimal treatment course is carried out. METHODS: Two cohorts of patients receiving abiraterone, bicalutamide, or enzalutamide for metastatic castrate resistant prostate cancer seen in our outpatient cancer center 21 months before and 24 months after the implementation of a pharmacist-led oral chemotherapy monitoring program in December of 2012 were retrospectively compared. Patients were evaluated for number of interventions, adherence to lab parameter monitoring, and overall time on each therapy. RESULTS: Of the 64 patients identified, 31 patients fulfilled inclusion criteria. A significant increase in the average number of interventions per patient (6.9 vs. 2.6; P = 0.004) and adherence to lab parameter monitoring (10 vs. 3; P = 0.04) in the post-program implementation cohort was found. However, no significant difference in overall time on therapy (10.3 vs. 8.1; P = 0.341) between the two groups was observed. CONCLUSION: These results suggest a potential opportunity exists to maximize oral chemotherapy treatment outcomes with the addition of a formalized monitoring program directed by an oncology pharmacist. PMID- 26493873 TI - Corrigendum: Multiple Multidentate Halogen Bonding in Solution, in the Solid State, and in the (Calculated) Gas Phase. PMID- 26493872 TI - Olfactory Dysfunctions and Decreased Nitric Oxide Production in the Brain of Human P301L Tau Transgenic Mice. AB - Different patterns of olfactory dysfunction have been found in both patients and mouse models of Alzheimer's Disease. However, the underlying mechanism of the dysfunction remained unknown. Deficits of nitric oxide production in brain can cause olfactory dysfunction by preventing the formation of olfactory memory. The aim of this study was to investigate the behavioral changes in olfaction and alterations in metabolites of nitric oxide, nitrate/nitrite concentration, in the brain of human P301L tau transgenic mice. The tau mice showed impairments in olfaction and increased abnormal phosphorylation of Tau protein at AT8 in different brain areas, especially in olfactory bulb. We now report that these olfactory deficits and Tau pathological changes were accompanied by decreased nitrate/nitrite concentration in the brain, especially in the olfactory bulb, and reduced expression of nNOS in the brain of tau mice. These findings provided evidence of olfactory dysfunctions correlated with decreased nitric oxide production in the brain of tau mice. PMID- 26493875 TI - A Boron Dipyrromethene (BODIPY)-Based Cu(II) -Bipyridine Complex for Highly Selective NO Detection. AB - A BODIPY-containing Cu(II) -bipyridine complex for the simple selective fluorogenic detection of NO in air and in live cells is reported. The detection mechanism is based on NO-promoted Cu(II) to Cu(I) reduction, followed by demetallation of the complex, which results in the clearly enhanced emission of the boron dipyrromethene (BODIPY) unit. PMID- 26493876 TI - Caspase 3 Targeted Cargo Delivery in Apoptotic Cells Using Capped Mesoporous Silica Nanoparticles. AB - Excessive apoptotic cell death is at the origin of several pathologies, such as degenerative disorders, stroke or ischemia-reperfusion damage. In this context, strategies to improve inhibition of apoptosis and other types of cell death are of interest and may represent a pharmacological opportunity for the treatment of cell-death-related disorders. In this scenario new peptide-containing delivery systems (solids S1 -P1 and S1 -P2 ) are described based on mesoporous silica nanoparticles (MSNs) loaded with a dye and capped with the KKGDEVDKKARDEVDK (P1 ) peptide that contains two repeats of the DEVD target sequence that are selectively hydrolyzed by caspase 3 (C3). This enzyme plays a central role in the execution-phase of apoptosis. HeLa cells electroporated with S1 -P1 are able to deliver the cargo in the presence of staurosporin (STS), which induces apoptosis with the consequent activation of the cytoplasmic C3 enzyme. Moreover, the nanoparticles S1 -P2 , containing both a cell-penetrating TAT peptide and P1 also entered in HeLa cells and delivered the cargo preferentially in cells treated with the apoptosis inducer cisplatin. PMID- 26493877 TI - Access to Highly Functionalized Sulfonated Cyclopentanes by Acid-Promoted Rauhut Currier Reaction with Sulfinamides. AB - An unexpected acid-mediated cascade reaction induced by conjugate addition of sulfinamides to dienediones has been developed. This highly efficient Rauhut Currier reaction enables the rapid, high-yielding construction of sulfonated cyclopentanes with three contiguous stereogenic centers in a single operation starting from simple sulfinamides. This process constitutes the first example of sulfinamide-promoted cycloisomerization. PMID- 26493878 TI - Iodine-Catalyzed Decarboxylative Amidation of beta,gamma-Unsaturated Carboxylic Acids with Chloramine Salts Leading to Allylic Amides. AB - The iodine-catalyzed decarboxylative amidation of beta,gamma-unsaturated carboxylic acids with chloramine salts is described. This method enables the regioselective synthesis of allylic amides from various types of beta,gamma unsaturated carboxylic acids containing substituents at the alpha- and beta positions. In the reaction, N-iodo-N-chloroamides, generated by the reaction of a chloramine salt with I2 , function as a key active species. The reaction provides an attractive alternative to existing methods for the synthesis of useful secondary allylic amine derivatives. PMID- 26493879 TI - Unusual Transformation from a Solvent-Stabilized 1D Coordination Polymer to a Metal-Organic Framework (MOF)-Like Cross-Linked 3D Coordination Polymer. AB - An unusual 1D-to-3D transformation of a coordination polymer based on organic linkers containing highly polar push-pull pi-conjugated side chains is reported. The coordination polymers are synthesized from zinc nitrate and an organic linker, namely, 2,5-bis{4-[1-(4-nitrophenyl)pyrrolidin-2-yl]butoxy}terephthalic acid, which possesses highly polar (4-nitrophenyl)pyrrolidine groups, with high dipole moments of about 7 D. The coordination polymers exhibit an unusual transformation from a soluble, solvent-stabilized 1D coordination polymer into an insoluble, metal-organic framework (MOF)-like 3D coordination polymer. The coordination polymer exhibits good film-forming ability, and the MOF-like films are insoluble in conventional organic solvents. PMID- 26493880 TI - Coordination Chemistry of Homoleptic Actinide(IV)-Thiocyanate Complexes. AB - The synthesis, X-ray crystal structure, vibrational and optical spectroscopy for the eight-coordinate thiocyanate compounds, [Et4 N]4 [Pu(IV) (NCS)8 ], [Et4 N]4 [Th(IV) (NCS)8 ], and [Et4 N]4 [Ce(III) (NCS)7 (H2 O)] are reported. Thiocyanate was found to rapidly reduce plutonium to Pu(III) in acidic solutions (pH<1) in the presence of NCS(-) . The optical spectrum of [Et4 N][SCN] containing Pu(III) solution was indistinguishable from that of aquated Pu(III) suggesting that inner sphere complexation with [Et4 N][SCN] does not occur in water. However, upon concentration, the homoleptic thiocyanate complex [Et4 N]4 [Pu(IV) (NCS)8 ] was crystallized when a large excess of [Et4 N][NCS] was present. This compound, along with its U(IV) analogue, maintains inner-sphere thiocyanate coordination in acetonitrile based on the observation of intense ligand-to-metal charge-transfer bands. Spectroscopic and crystallographic data do not support the interaction of the metal orbitals with the ligand pi system, but support an enhanced An(IV) -NCS interaction, as the Lewis acidity of the metal ion increases from Th to Pu. PMID- 26493881 TI - The Influence of the Amide Linkage in the Fe(III) -Binding Properties of Catechol Modified Rosamine Derivatives. AB - The two new fluorescent ligands RosCat1 and RosCat2 contain catechol receptors connected to rosamine platforms through an amide linkage and were synthesized by using microwave-assisted coupling reactions of carboxyl- or amine-substituted rosamines with the corresponding catechol units and subsequent deprotection. RosCat1 possesses a reverse amide, whereas RosCat2 has the usual oriented amide bond (HNCO vs. CONH, respectively). The ligands were characterized by means of NMR spectroscopy, mass-spectrometry, and DFT calculations and X-ray crystallography studies for RosCat1. The influence of the amide linkage on the photophysical properties of the fluorescent ligands was assessed in different solvents and showed a higher fluorescence quantum yield for RosCat1. The coordination chemistry of these ligands with a Fe(III) center has been rationalized by mass-spectrometric analysis and semiempirical calculations. Octahedral Fe(III) complexes were obtained by the chelation of three RosCat1 or RosCat2 ligands. Interestingly, the unconventional amide connectivity in RosCat1 imposes the formation of an eight-membered ring on the chelate complex through a "salicylate-type" mode of coordination. PMID- 26493882 TI - Selective Sensing of Fe(3+) and Al(3+) Ions and Detection of 2,4,6-Trinitrophenol by a Water-Stable Terbium-Based Metal-Organic Framework. AB - A water-stable luminescent terbium-based metal-organic framework (MOF), {[Tb(L1 )1.5 (H2 O)]?3 H2 O}n (Tb-MOF), with rod-shaped secondary building units (SBUs) and honeycomb-type tubular channels has been synthesized and structurally characterized by single-crystal X-ray diffraction. The high green emission intensity and the microporous nature of the Tb-MOF indicate that it can potentially be used as a luminescent sensor. In this work, we show that Tb-MOF can selectively sense Fe(3+) and Al(3+) ions from mixed metal ions in water through different detection mechanisms. In addition, it also exhibits high sensitivity for 2,4,6-trinitrophenol (TNP) in the presence of other nitro aromatic compounds in aqueous solution by luminescence quenching experiments. PMID- 26493883 TI - Heterolysis of H2 Across a Classical Lewis Pair, 2,6-Lutidine?BCl3 : Synthesis, Characterization, and Mechanism. AB - We report that 2,6-lutidine?trichloroborane (Lut?BCl3 ) reacts with H2 in toluene, bromobenzene, dichloromethane, and Lut solvents producing the neutral hydride, Lut?BHCl2 . The mechanism was modeled with density functional theory, and energies of stationary states were calculated at the G3(MP2)B3 level of theory. Lut?BCl3 was calculated to react with H2 and form the ion pair, [LutH(+) ][HBCl3 (-) ], with a barrier of DeltaH(?) =24.7 kcal mol(-1) (DeltaG(?) =29.8 kcal mol(-1) ). Metathesis with a second molecule of Lut?BCl3 produced Lut?BHCl2 and [LutH(+) ][BCl4 (-) ]. The overall reaction is exothermic by 6.0 kcal mol(-1) (Deltar G degrees =-1.1). Alternate pathways were explored involving the borenium cation (LutBCl2 (+) ) and the four-membered boracycle [(CH2 {NC5 H3 Me})BCl2 ]. Barriers for addition of H2 across the Lut/LutBCl2 (+) pair and the boracycle B?C bond are substantially higher (DeltaG(?) =42.1 and 49.4 kcal mol(-1) , respectively), such that these pathways are excluded. The barrier for addition of H2 to the boracycle B?N bond is comparable (DeltaH(?) =28.5 and DeltaG(?) =32 kcal mol(-1) ). Conversion of the intermediate 2-(BHCl2 CH2 )-6-Me(C5 H3 NH) to Lut?BHCl2 may occur by intermolecular steps involving proton/hydride transfers to Lut/BCl3 . Intramolecular protodeboronation, which could form Lut?BHCl2 directly, is prohibited by a high barrier (DeltaH(?) =52, DeltaG(?) =51 kcal mol(-1) ). PMID- 26493884 TI - A Monolithic Hybrid Cellulose-2.5-Acetate/Polymer Bioreactor for Biocatalysis under Continuous Liquid-Liquid Conditions Using a Supported Ionic Liquid Phase. AB - Mesoporous monolithic hybrid cellulose-2.5-acetate (CA)/polymer supports were prepared under solvent-induced phase separation conditions using cellulose-2.5 acetate microbeads 8-14 MUm in diameter, 1,1,1-tris(hydroxymethyl)propane and 4,4'-methylenebis(phenylisocyanate) as monomers as well as THF and n-heptane as porogenic solvents. 4-(Dimethylamino)pyridine and dibutyltin dilaurate (DBTDL), respectively, were used as catalysts. Monolithic hybrid supports were used in transesterification reactions of vinyl butyrate with 1-butanol under continuous, supported ionic liquid-liquid conditions with Candida antarctica lipase B (CALB) and octylmethylimidazolium tetrafluoroborate ([OMIM(+) ][BF4 (-) ]) immobilized within the CA beads inside the polymeric monolithic framework and methyl tert butyl ether (MTBE) as the continuous phase. The new hybrid bioreactors were successfully used in dimensions up to 2*30 cm (V=94 mL). Under continuous biphasic liquid-liquid conditions a constant conversion up to 96 % was achieved over a period of 18 days, resulting in a productivity of 58 MUmol mg(-1) (CALB) min(-1) . This translates into an unprecedented turnover number (TON) of 3.9*10(7) within two weeks, which is much higher than the one obtained under standard biphasic conditions using [OMIM(+) ][BF4 (-) ]/MTBE (TON=2.7*10(6) ). The continuous liquid-liquid setup based on a hybrid reactor presented here is strongly believed to be applicable to many other enzyme-catalyzed reactions. PMID- 26493885 TI - Coordination Complexes of a Neutral 1,2,4-Benzotriazinyl Radical Ligand: Synthesis, Molecular and Electronic Structures, and Magnetic Properties. AB - A series of d-block metal complexes of the recently reported coordinating neutral radical ligand 1-phenyl-3-(pyrid-2-yl)-1,4-dihydro-1,2,4-benzotriazin-4-yl (1) was synthesized. The investigated systems contain the benzotriazinyl radical 1 coordinated to a divalent metal cation, Mn(II) , Fe(II) , Co(II) , or Ni(II) , with 1,1,1,5,5,5-hexafluoroacetylacetonato (hfac) as the auxiliary ligand of choice. The synthesized complexes were fully characterized by single-crystal X ray diffraction, magnetic susceptibility measurements, and electronic structure calculations. The complexes [Mn(1)(hfac)2 ] and [Fe(1)(hfac)2 ] displayed antiferromagnetic coupling between the unpaired electrons of the ligand and the metal cation, whereas the interaction was found to be ferromagnetic in the analogous Ni(II) complex [Ni(1)(hfac)2 ]. The magnetic properties of the complex [Co(1)(hfac)2 ] were difficult to interpret owing to significant spin-orbit coupling inherent to octahedral high-spin Co(II) metal ion. As a whole, the reported data clearly demonstrated the favorable coordinating properties of the radical 1, which, together with its stability and structural tunability, make it an excellent new building block for establishing more complex metal-radical architectures with interesting magnetic properties. PMID- 26493886 TI - Real-Time Detection of Traces of Benzaldehyde in Benzyl Alcohol as a Solvent by a Flexible Lanthanide Microporous Metal-Organic Framework. AB - Luminescent 3D lanthanide metal-organic framework (Ln-MOF) {[Tb2 (TATAB)2 ]?4 H2 O?6 DMF}n (1) was synthesized under solvothermal conditions by using flexible ligand 4,4',4''-s-triazine-1,3,5-triyltri-p-aminobenzoate (TATAB). A phase transition was observed between low temperature and room temperature. The luminescence of 1 could be enhanced by formaldehyde and quenched efficiently by trace amounts of benzaldehyde in solvents such as benzyl alcohol (0.01-2.0 vol %) and ethanol (0.01-2.5 vol %). This is the first use of a Ln-MOF as chemical sensor for both formaldehyde and benzaldehyde. The high sensitivity and selectivity of the luminescence response of 1 to benzaldehyde allows it to be used as an excellent sensor for identifying benzaldehyde and provides a simple and convenient method for detecting traces of benzaldehyde in benzyl alcohol based injections. This work establishes a new strategy for detection of benzaldehyde in benzyl alcohol by luminescent MOFs. PMID- 26493889 TI - The impact of revised CLSI cefazolin breakpoints on the clinical outcomes of Escherichia coli bacteremia. AB - BACKGROUND/PURPOSE: The susceptibility breakpoints of cephalosporins for Enterobacteriaceae were revised by the Clinical and Laboratory Standards Institute (CLSI) in 2010 and 2011. The clinical outcome and susceptibility data were analyzed to evaluate the impact of revised CLSI cefazolin breakpoints on the treatment of Escherichia coli bacteremia. METHODS: Forty-three bacteremic Escherichia coli isolates from Taichung Veterans General Hospital, Taichung, Taiwan, during the period from January 2013 to December 2013, were selected to analyze the minimum inhibitory concentration (MIC) distributions of cefazolin and the correlated clinical responses to cefazolin therapy. RESULTS: The modal cefazolin MIC among the 43 isolates was 1 MUg/mL and accounted for 18 (42%) isolates. The cumulative percentage for MICs <= 2 MUg/mL was 79%. The conventional dosing regimens achieved clinical cure in 33 (97%) of 34 patients with bacteremia due to E. coli with a cefazolin MIC <= 2 MUg/mL, in all of the six patients with a cefazolin MIC of 4 MUg/mL, and all of the three patients with a cefazolin MIC of 8 MUg/mL. CONCLUSION: The microbiological data support the revised CLSI breakpoints of cefazolin. The conventional cefazolin dosing regimens can still achieve satisfactory clinical cure rates for bacteremia of E. coli with a cefazolin MIC <= 2 MUg/mL in patients without severe septic shock. Before the approval of the efficacy of cefazolin for the treatment of E. coli isolates with a cefazolin MIC of 4 MUg/mL, it is prudent to use cefazolin only when a high drug level can be achieved in the infection site, such as the urinary tract. PMID- 26493890 TI - Communication: Surface stability and topological surface states of cleaved Bi2Se3: First-principles studies. AB - Through systematic first principles calculations within the nonlocal van der Waals functional, we investigated the structure stability and topological surface state properties of various surface cleaves in the topological insulator Bi2Se3 Our results reveal that under Bi-rich conditions, the Bi bilayer-covered surface and the Se-terminated surface with a Bi bilayer under the first quintuple layer are even more stable than the generic Bi2Se3. The surface state bands are changed by different surface terminations, causing the formation of new Dirac states. We may distinguish various surfaces by using scanning tunneling microscopy experimentally. PMID- 26493891 TI - Gaussian process model for extrapolation of scattering observables for complex molecules: From benzene to benzonitrile. AB - We consider a problem of extrapolating the collision properties of a large polyatomic molecule A-H to make predictions of the dynamical properties for another molecule related to A-H by the substitution of the H atom with a small molecular group X, without explicitly computing the potential energy surface for A-X. We assume that the effect of the -H ->-X substitution is embodied in a multidimensional function with unknown parameters characterizing the change of the potential energy surface. We propose to apply the Gaussian Process model to determine the dependence of the dynamical observables on the unknown parameters. This can be used to produce an interval of the observable values which corresponds to physical variations of the potential parameters. We show that the Gaussian Process model combined with classical trajectory calculations can be used to obtain the dependence of the cross sections for collisions of C6H5CN with He on the unknown parameters describing the interaction of the He atom with the CN fragment of the molecule. The unknown parameters are then varied within physically reasonable ranges to produce a prediction uncertainty of the cross sections. The results are normalized to the cross sections for He - C6H6 collisions obtained from quantum scattering calculations in order to provide a prediction interval of the thermally averaged cross sections for collisions of C6H5CN with He. PMID- 26493892 TI - Resummation of divergent perturbation series: Application to the vibrational states of H2CO molecule. AB - Large-order Rayleigh-Schrodinger perturbation theory (RSPT) is applied to the calculation of anharmonic vibrational energy levels of H2CO molecule. We use the model of harmonic oscillators perturbed by anharmonic terms of potential energy. Since the perturbation series typically diverge due to strong couplings, we apply the algebraic approximation technique because of its effectiveness shown earlier by Goodson and Sergeev [J. Chem. Phys. 110, 8205 (1999); ibid. 124, 094111 (2006)] and in our previous articles [A. D. Bykov et al. Opt. Spectrosc. 114, 396 (2013); ibid. 116, 598 (2014)]. To facilitate the resummation of terms contributing to perturbed states, when resonance mixing between states is especially strong and perturbation series diverge very quick, we used repartition of the Hamiltonian by shifting the normal mode frequencies. Energy levels obtained by algebraic approximants were compared with the results of variational calculation. It was found that for low energy states (up to ~5000 cm(-1)), algebraic approximants gave accurate values of energy levels, which were in excellent agreement with the variational method. For highly excited states, strong and multiple resonances complicate series resummation, but a suitable change of normal mode frequencies allows one to reduce the resonance mixing and to get accurate energy levels. The theoretical background of the problem of RSPT series divergence is discussed along with its numerical analysis. For these purposes, the vibrational energy is considered as a function of a complex perturbation parameter. Layout and classification of its singularities allow us to model the asymptotic behavior of the perturbation series and prove the robustness of the algorithm. PMID- 26493893 TI - Revisiting the definition of the electronic chemical potential, chemical hardness, and softness at finite temperatures. AB - We extend the definition of the electronic chemical potential (MUe) and chemical hardness (etae) to finite temperatures by considering a reactive chemical species as a true open system to the exchange of electrons, working exclusively within the framework of the grand canonical ensemble. As in the zero temperature derivation of these descriptors, the response of a chemical reagent to electron transfer is determined by the response of the (average) electronic energy of the system, and not by intrinsic thermodynamic properties like the chemical potential of the electron-reservoir which is, in general, different from the electronic chemical potential, MUe. Although the dependence of the electronic energy on electron number qualitatively resembles the piecewise-continuous straight-line profile for low electronic temperatures (up to ca. 5000 K), the introduction of the temperature as a free variable smoothens this profile, so that derivatives (of all orders) of the average electronic energy with respect to the average electron number exist and can be evaluated analytically. Assuming a three-state ensemble, well-known results for the electronic chemical potential at negative ( I), positive (-A), and zero values of the fractional charge (-(I + A)/2) are recovered. Similarly, in the zero temperature limit, the chemical hardness is formally expressed as a Dirac delta function in the particle number and satisfies the well-known reciprocity relation with the global softness. PMID- 26493894 TI - Transport coefficients of helium-argon mixture based on ab initio potential. AB - The viscosity, thermal conductivity, diffusion coefficient, and thermal diffusion factor of helium-argon mixtures are calculated for a wide range of temperature and for various mole fractions up to the 12th order of the Sonine polynomial expansion with an ab initio intermolecular potential. The calculated values for these transport coefficients are compared with other data available in the open literature. The comparison shows that the obtained transport coefficients of helium-argon mixture have the best accuracy for the moment. PMID- 26493895 TI - Resonance Raman spectra of organic molecules absorbed on inorganic semiconducting surfaces: Contribution from both localized intramolecular excitation and intermolecular charge transfer excitation. AB - The time-dependent correlation function approach for the calculations of absorption and resonance Raman spectra (RRS) of organic molecules absorbed on semiconductor surfaces [Y. Zhao and W. Z. Liang, J. Chem. Phys. 135, 044108 (2011)] is extended to include the contribution of the intermolecular charge transfer (CT) excitation from the absorbers to the semiconducting nanoparticles. The results demonstrate that the bidirectionally interfacial CT significantly modifies the spectral line shapes. Although the intermolecular CT excitation makes the absorption spectra red shift slightly, it essentially changes the relative intensities of mode-specific RRS and causes the oscillation behavior of surface enhanced Raman spectra with respect to interfacial electronic couplings. Furthermore, the constructive and destructive interferences of RRS from the localized molecular excitation and CT excitation are observed with respect to the electronic coupling and the bottom position of conductor band. The interferences are determined by both excitation pathways and bidirectionally interfacial CT. PMID- 26493896 TI - Exchange splitting of the interaction energy and the multipole expansion of the wave function. AB - The exchange splitting J of the interaction energy of the hydrogen atom with a proton is calculated using the conventional surface-integral formula Jsurf[Phi], the volume-integral formula of the symmetry-adapted perturbation theory JSAPT[Phi], and a variational volume-integral formula Jvar[Phi]. The calculations are based on the multipole expansion of the wave function Phi, which is divergent for any internuclear distance R. Nevertheless, the resulting approximations to the leading coefficient j0 in the large-R asymptotic series J(R) = 2e(-R-1)R(j0 + j1R(-1) + j2R(-2) + ?) converge with the rate corresponding to the convergence radii equal to 4, 2, and 1 when the Jvar[Phi], Jsurf[Phi], and JSAPT[Phi] formulas are used, respectively. Additionally, we observe that also the higher jk coefficients are predicted correctly when the multipole expansion is used in the Jvar[Phi] and Jsurf[Phi] formulas. The symmetry adapted perturbation theory formula JSAPT[Phi] predicts correctly only the first two coefficients, j0 and j1, gives a wrong value of j2, and diverges for higher jn. Since the variational volume-integral formula can be easily generalized to many-electron systems and evaluated with standard basis-set techniques of quantum chemistry, it provides an alternative for the determination of the exchange splitting and the exchange contribution of the interaction potential in general. PMID- 26493897 TI - An atomic orbital-based formulation of analytical gradients and nonadiabatic coupling vector elements for the state-averaged complete active space self consistent field method on graphical processing units. AB - We recently presented an algorithm for state-averaged complete active space self consistent field (SA-CASSCF) orbital optimization that capitalizes on sparsity in the atomic orbital basis set to reduce the scaling of computational effort with respect to molecular size. Here, we extend those algorithms to calculate the analytic gradient and nonadiabatic coupling vectors for SA-CASSCF. Combining the low computational scaling with acceleration from graphical processing units allows us to perform SA-CASSCF geometry optimizations for molecules with more than 1000 atoms. The new approach will make minimal energy conical intersection searches and nonadiabatic dynamics routine for molecular systems with O(10(2)) atoms. PMID- 26493898 TI - Nested sampling of isobaric phase space for the direct evaluation of the isothermal-isobaric partition function of atomic systems. AB - Nested Sampling (NS) is a powerful athermal statistical mechanical sampling technique that directly calculates the partition function, and hence gives access to all thermodynamic quantities in absolute terms, including absolute free energies and absolute entropies. NS has been used predominately to compute the canonical (NVT) partition function. Although NS has recently been used to obtain the isothermal-isobaric (NPT) partition function of the hard sphere model, a general approach to the computation of the NPT partition function has yet to be developed. Here, we describe an isobaric NS (IBNS) method which allows for the computation of the NPT partition function of any atomic system. We demonstrate IBNS on two finite Lennard-Jones systems and confirm the results through comparison to parallel tempering Monte Carlo. Temperature-entropy plots are constructed as well as a simple pressure-temperature phase diagram for each system. We further demonstrate IBNS by computing part of the pressure-temperature phase diagram of a Lennard-Jones system under periodic boundary conditions. PMID- 26493900 TI - Two-dimensional vibrational-electronic spectroscopy. AB - Two-dimensional vibrational-electronic (2D VE) spectroscopy is a femtosecond Fourier transform (FT) third-order nonlinear technique that creates a link between existing 2D FT spectroscopies in the vibrational and electronic regions of the spectrum. 2D VE spectroscopy enables a direct measurement of infrared (IR) and electronic dipole moment cross terms by utilizing mid-IR pump and optical probe fields that are resonant with vibrational and electronic transitions, respectively, in a sample of interest. We detail this newly developed 2D VE spectroscopy experiment and outline the information contained in a 2D VE spectrum. We then use this technique and its single-pump counterpart (1D VE) to probe the vibrational-electronic couplings between high frequency cyanide stretching vibrations (nuCN) and either a ligand-to-metal charge transfer transition ([Fe(III)(CN)6](3-) dissolved in formamide) or a metal-to-metal charge transfer (MMCT) transition ([(CN)5Fe(II)CNRu(III)(NH3)5](-) dissolved in formamide). The 2D VE spectra of both molecules reveal peaks resulting from coupled high- and low-frequency vibrational modes to the charge transfer transition. The time-evolving amplitudes and positions of the peaks in the 2D VE spectra report on coherent and incoherent vibrational energy transfer dynamics among the coupled vibrational modes and the charge transfer transition. The selectivity of 2D VE spectroscopy to vibronic processes is evidenced from the selective coupling of specific nuCN modes to the MMCT transition in the mixed valence complex. The lineshapes in 2D VE spectra report on the correlation of the frequency fluctuations between the coupled vibrational and electronic frequencies in the mixed valence complex which has a time scale of 1 ps. The details and results of this study confirm the versatility of 2D VE spectroscopy and its applicability to probe how vibrations modulate charge and energy transfer in a wide range of complex molecular, material, and biological systems. PMID- 26493899 TI - Driven diffusion against electrostatic or effective energy barrier across alpha hemolysin. AB - We analyze the translocation of a charged particle across an alpha-Hemolysin (alphaHL) pore in the framework of a driven diffusion over an extended energy barrier generated by the electrical charges of the alphaHL. A one-dimensional electrostatic potential is extracted from the full 3D solution of the Poisson's equation. We characterize the particle transport under the action of a constant forcing by studying the statistics of the translocation time. We derive an analytical expression of translocation time average that compares well with the results from Brownian dynamic simulations of driven particles over the electrostatic potential. Moreover, we show that the translocation time distributions can be perfectly described by a simple theory which replaces the true barrier by an equivalent structureless square barrier. Remarkably, our approach maintains its accuracy also for low-applied voltage regimes where the usual inverse-Gaussian approximation fails. Finally, we discuss how the comparison between the simulated time distributions and their theoretical prediction results to be greatly simplified when using the notion of the empirical Laplace transform technique. PMID- 26493901 TI - Peculiarities of high-overtone transition probabilities in carbon monoxide revealed by high-precision calculation. AB - In the recent work devoted to the calculation of the rovibrational line list of the CO molecule [G. Li et al., Astrophys. J., Suppl. Ser. 216, 15 (2015)], rigorous validation of the calculated parameters including intensities was carried out. In particular, the Normal Intensity Distribution Law (NIDL) [E. S. Medvedev, J. Chem. Phys. 137, 174307 (2012)] was employed for the validation purposes, and it was found that, in the original CO line list calculated for large changes of the vibrational quantum number up to Deltan = 41, intensities with Deltan > 11 were unphysical. Therefore, very high overtone transitions were removed from the published list in Li et al. Here, we show how this type of validation is carried out and prove that the quadruple precision is indispensably required to predict the reliable intensities using the conventional 32-bit computers. Based on these calculations, the NIDL is shown to hold up for the 0 -> n transitions till the dissociation limit around n = 83, covering 45 orders of magnitude in the intensity. The low-intensity 0 -> n transition predicted in the work of Medvedev [Determination of a new molecular constant for diatomic systems. Normal intensity distribution law for overtone spectra of diatomic and polyatomic molecules and anomalies in overtone absorption spectra of diatomic molecules, Institute of Chemical Physics, Russian Academy of Sciences, Chernogolovka, 1984] at n = 5 is confirmed, and two additional "abnormal" intensities are found at n = 14 and 23. Criteria for the appearance of such "anomalies" are formulated. The results could be useful to revise the high-overtone molecular transition probabilities provided in spectroscopic databases. PMID- 26493902 TI - Symmetry of extremely floppy molecules: Molecular states beyond rotation vibration separation. AB - Traditionally, molecules are theoretically described as near-static structures rotating in space. Vibrational motion causing small structural deformations induces a perturbative treatment of the rotation-vibration interaction, which fails in highly fluxional molecules, where all vibrational motions have amplitudes comparable in size to the linear dimensions of the molecule. An example is protonated methane (CH5(+)) [P. Kumar and D. Marx, Phys. Chem. Chem. Phys. 8, 573 (2006); Z. Jin et al., J. Phys. Chem. A 110, 1569 (2006); and A. S. Petit et al., J. Phys. Chem. A 118, 7206 (2014)]. For these molecules, customary theory fails to simulate reliably even the low-energy spectrum [T. Oka, Science 347, 1313-1314 (2015) and O. Asvany et al., Science 347, 1346-1349 (2015)]. Within the traditional view of rotation and vibration being near-separable, rotational and vibrational wavefunctions can be symmetry classified separately in the molecular symmetry (MS) group [P. Bunker and P. Jensen, Molecular Symmetry and Spectroscopy, NRC Monograph Publishing Program (NRC Research Press, 2006)]. In this article, we discuss a fundamental group theoretical approach to the problem of determining the symmetries of molecular rotation-vibration states. We will show that all MS groups discussed so far are isomorphic to subgroups of the special orthogonal group in three dimensions SO(3). This leads to a group theoretical foundation of the technique of equivalent rotations [H. Longuet Higgins, Mol. Phys. 6, 445 (1963)]. The group G240 (the MS group of protonated methane) represents, to the best of our knowledge, the first example of a MS group which is not isomorphic to a subgroup of SO(3) (nor of O(3) or of SU(2)). Because of this, a separate symmetry classification of vibrational and rotational wavefunctions becomes impossible in this MS group, consistent with the fact that a decoupling of vibrational and rotational motion is impossible. We discuss here the consequences of this. In conclusion, we show that the prototypical, extremely floppy molecule CH5(+) represents a new class of molecules, where customary group theoretical methods for determining selection rules and spectral assignments fail so that new methods have to be developed. PMID- 26493903 TI - Rotational study of the CH4-CO complex: Millimeter-wave measurements and ab initio calculations. AB - The rotational spectrum of the van der Waals complex CH4-CO has been measured with the intracavity OROTRON jet spectrometer in the frequency range of 110-145 GHz. Newly observed and assigned transitions belong to the K = 2-1 subband correlating with the rotationless jCH4 = 0 ground state and the K = 2-1 and K = 0 1 subbands correlating with the jCH4 = 2 excited state of free methane. The (approximate) quantum number K is the projection of the total angular momentum J on the intermolecular axis. The new data were analyzed together with the known millimeter-wave and microwave transitions in order to determine the molecular parameters of the CH4-CO complex. Accompanying ab initio calculations of the intermolecular potential energy surface (PES) of CH4-CO have been carried out at the explicitly correlated coupled cluster level of theory with single, double, and perturbative triple excitations [CCSD(T)-F12a] and an augmented correlation consistent triple zeta (aVTZ) basis set. The global minimum of the five dimensional PES corresponds to an approximately T-shaped structure with the CH4 face closest to the CO subunit and binding energy De = 177.82 cm(-1). The bound rovibrational levels of the CH4-CO complex were calculated for total angular momentum J = 0-6 on this intermolecular potential surface and compared with the experimental results. The calculated dissociation energies D0 are 91.32, 94.46, and 104.21 cm(-1) for A (jCH4 = 0), F (jCH4 = 1), and E (jCH4 = 2) nuclear spin modifications of CH4-CO, respectively. PMID- 26493904 TI - Theoretical studies for the N2-N2O van der Waals complex: The potential energy surface, intermolecular vibrations, and rotational transition frequencies. AB - Theoretical studies of the potential energy surface (PES) and bound states are performed for the N2-N2O van der Waals (vdW) complex. A four-dimensional intermolecular PES is constructed at the level of single and double excitation coupled-cluster method with a non-iterative perturbation treatment of triple excitations [CCSD(T)] with aug-cc-pVTZ basis set supplemented with bond functions. Two equivalent T-shaped global minima are located, in which the O atom of N2O monomer is near the N2 monomer. The intermolecular fundamental vibrational states are assigned by inspecting the orientation of the nodal surface of the wavefunctions. The calculated frequency for intermolecular disrotation mode is 23.086 cm(-1), which is in good agreement with the available experimental data of 22.334 cm(-1). A negligible tunneling splitting with the value of 4.2 MHz is determined for the ground vibrational state and the tunneling splitting increases as the increment of the vibrational frequencies. Rotational levels and transition frequencies are calculated for both isotopomers (14)N2-N2O and (15)N2-N2O. The accuracy of the PES is validated by the good agreement between theoretical and experimental results for the transition frequencies and spectroscopic parameters. PMID- 26493905 TI - Ionization and photofragmentation of Ru3(CO)12 and Os3(CO)12. AB - In this paper, we use a combination of photoelectron spectroscopy, mass spectrometry, and density functional theory calculations to get a detailed understanding of valence single and double ionization and the subsequent dissociation processes. This is exemplified on benchmark systems, trimetallo dodecacarbonyls M3(CO)12 with M = Ru, Os, where the energy remaining in the molecule after photoionization can be retrieved by measuring the degree of fragmentation of the molecular ion. The intensity of different mass peaks can thus be directly related to ionization cross sections obtained by photoelectron spectroscopy. We find that the M-CO dissociation energy rises as the number of CO ligands decreases due to dissociation. Moreover, ionization of the CO ligands has a higher cross section than that of the metal center for both single and double ionization. After advanced fragmentation, a CO bond can break and the carbon atom remains bonded to the metal core. In addition, we found that the valence ionization cross sections of M3(CO)12 are maximal at about 40 eV photon energy thus showing a more pronounced shape resonance than Ru and Os-complexes with a single metal atom center. Finally, an np -> nd giant resonance absorption causes a significant increase of the ionization cross section above 50 eV for Ru3(CO)12. PMID- 26493906 TI - Far-infrared VRT spectroscopy of the water dimer: Characterization of the 20 MUm out-of-plane librational vibration. AB - We report the first high-resolution spectra for the out-of-plane librational vibration in the water dimer. Three vibrational subbands comprising a total of 188 transitions have been measured by diode laser spectroscopy near 500 cm(-1) and assigned to (H2O)2 libration-rotation-tunneling eigenstates. The band origin for the Ka = 1 subband is ~524 cm(-1). Librational excitation increases the interchange and bifurcation hydrogen bond rearrangement tunneling splittings by factors of 3-5 and 4-40, respectively. Analysis of the rotational constants obtained from a nonlinear least squares fit indicates that additional external perturbations to the energy levels are likely. PMID- 26493907 TI - Mode specific dynamics of the H2 + CH3 -> H + CH4 reaction studied using quasi classical trajectory and eight-dimensional quantum dynamics methods. AB - An eight-dimensional quantum dynamical model is proposed and applied to the title reaction. The reaction probabilities and integral cross sections have been determined for both the ground and excited vibrational states of the two reactants. The results indicate that the H2 stretching and CH3 umbrella modes, along with the translational energy, strongly promote the reactivity, while the CH3 symmetric stretching mode has a negligible effect. The observed mode specificity is confirmed by full-dimensional quasi-classical trajectory calculations. The mode specificity can be interpreted by the recently proposed sudden vector projection model, which attributes the enhancement effects of the reactant modes to their strong couplings with the reaction coordinate at the transition state. PMID- 26493908 TI - Characteristic footprints of an exceptional point in the dynamics of Li dimer under a laser field. AB - Non-hermitian quantum mechanics is a formalism that excels in describing time dependent states such as resonances. As one, it opens up a window to explore new and undiscovered phenomena. Under this formalism coalescence of two eigenstates and a deficient spectrum are a possible situation. These situations are unique and can occur solely in specific conditions known as Exceptional Points (EPs). An EP holds unique characteristics. One of which is a switch-like behavior: upon adiabatically changing the conditions in a closed loop around the EP, the population of one resonance can be transferred completely to another resonance. The phenomenon was not experimentally observed in an atomic or molecular system so far, although experiments involving nonlinear PT symmetry optics and microwave cavities have already indicated its existence. In this work, we demonstrate and confirm that the switch-like behavior exists in the spectrum of a lithium dimer taking into account both the rotations and the vibrations of the system. Moreover, a footprint of the EP is also shown to exist in the photo-association process of the lithium dimer. In this process, the EP's resonances serve as the mean to associate two free lithium atoms into a dimer. Based on this, we suggest a corresponding experiment to demonstrate for the first time the EP phenomenon in a molecular system. PMID- 26493909 TI - A simple transferable adaptive potential to study phase separation in large-scale xMgO-(1-x)SiO2 binary glasses. AB - A simple transferable adaptive model is developed and it allows for the first time to simulate by molecular dynamics the separation of large phases in the MgO SiO2 binary system, as experimentally observed and as predicted by the phase diagram, meaning that separated phases have various compositions. This is a real improvement over fixed-charge models, which are often limited to an interpretation involving the formation of pure clusters, or involving the modified random network model. Our adaptive model, efficient to reproduce known crystalline and glassy structures, allows us to track the formation of large amorphous Mg-rich Si-poor nanoparticles in an Mg-poor Si-rich matrix from a 0.1MgO-0.9SiO2 melt. PMID- 26493911 TI - Fluctuations of local electric field and dipole moments in water between metal walls. AB - We examine the thermal fluctuations of the local electric field Ek (loc) and the dipole moment MUk in liquid water at T = 298 K between metal walls in electric field applied in the perpendicular direction. We use analytic theory and molecular dynamics simulation. In this situation, there is a global electrostatic coupling between the surface charges on the walls and the polarization in the bulk. Then, the correlation function of the polarization density pz(r) along the applied field contains a homogeneous part inversely proportional to the cell volume V. Accounting for the long-range dipolar interaction, we derive the Kirkwood-Frohlich formula for the polarization fluctuations when the specimen volume v is much smaller than V. However, for not small v/V, the homogeneous part comes into play in dielectric relations. We also calculate the distribution of Ek (loc) in applied field. As a unique feature of water, its magnitude |Ek (loc)| obeys a Gaussian distribution with a large mean value E0 ? 17 V/nm, which arises mainly from the surrounding hydrogen-bonded molecules. Since |MUk|E0 ~ 30kBT, MUk becomes mostly parallel to Ek (loc). As a result, the orientation distributions of these two vectors nearly coincide, assuming the classical exponential form. In dynamics, the component of MUk(t) parallel to Ek (loc)(t) changes on the time scale of the hydrogen bonds ~5 ps, while its smaller perpendicular component undergoes librational motions on time scales of 0.01 ps. PMID- 26493910 TI - On the nature of the molecular ordering of water in aqueous DMSO mixtures. AB - Computer simulation studies of aqueous dimethyl sulfoxyde (DMSO) mixtures show micro-heterogeneous structures, just like aqueous alcohol mixtures. However, there is a marked difference in the aggregate structure of water between the two types of systems. While water molecules form multiconnected globular clusters in alcohols, we report herein that the typical water aggregates in aqueous DMSO mixtures are linear, favouring a 2 hydrogen bond structure per water molecule, and for all DMSO mole fractions ranging from 0.1 to 0.9. This linear-aggregate structure produces a particular signature in the water site-site structure factors, in the form of a pre-peak at k ~ 0.2-0.8 A(-1), depending on DMSO concentration. This pre-peak is either absent in other aqueous mixtures, such as aqueous methanol mixtures, or very difficult to see through computer simulations, such as in aqueous-t-butanol mixtures. This difference in the topology of the aggregates explains why the Kirkwood-Buff integrals of aqueous-DMSO mixture look nearly ideal, in contrast with those of aqueous alcohol mixtures, suggesting a connection between the shape of the water aggregates, its fluctuations, and the concentration fluctuations. In order to further study this discrepancy between aqueous DMSO and aqueous alcohol mixture, two models of pseudo-DMSO are introduced, where the size of the sulfur atom is increased by a factor 1.6 and 1.7, respectively, hence increasing the hydrophobicity of the molecule. The study shows that these mixtures become closer to the emulsion type seen in aqueous alcohol mixtures, with more globular clustering of the water molecules, long range domain oscillations in the water-water correlations and increased water water Kirkwood-Buff integrals. It demonstrates that the local ordering of the water molecules is influenced by the nature of the solute molecules, with very different consequences for structural properties and related thermodynamic quantities. This study illustrates the unique plasticity of water in presence of different types of solutes. PMID- 26493912 TI - Hydrogen-bond vibrational and energetic dynamical properties in sI and sII clathrate hydrates and in ice Ih: Molecular dynamics insights. AB - Equilibrium molecular dynamics (MD) simulations have been performed on cubic (sI and sII) polymorphs of methane hydrate, and hexagonal ice (ice Ih), to study the dynamical properties of hydrogen-bond vibrations and hydrogen-bond self-energy. It was found that hydrogen-bond energies are greatest in magnitude in sI hydrates, followed by sII, and their energies are least in magnitude in ice Ih. This is consistent with recent MD-based findings on thermal conductivities for these various materials [N. J. English and J. S. Tse, Phys. Rev. Lett. 103, 015901 (2009)], in which the lower thermal conductivity of sI methane hydrate was rationalised in terms of more strained hydrogen-bond arrangements. Further, modes for vibration and energy-transfer via hydrogen bonds in sI hydrate were found to occur at higher frequencies vis-a-vis ice Ih and sII hydrate in both the water librational and OH?H regions because of the more strained nature of hydrogen bonds therein. PMID- 26493913 TI - Metal-organic frameworks as host materials of confined supercooled liquids. AB - In this work, we examine the use of metal-organic framework (MOF) systems as host materials for the investigation of glassy dynamics in confined geometry. We investigate the confinement of the molecular glass former glycerol in three MFU type MOFs with different pore sizes (MFU stands for "Metal-Organic Framework Ulm University") and study the dynamics of the confined liquid via dielectric spectroscopy. In accord with previous reports on confined glass formers, we find different degrees of deviations from bulk behavior depending on pore size, demonstrating that MOFs are well-suited host systems for confinement investigations. PMID- 26493914 TI - Dynamics of asymmetric non-polymeric binary glass formers-A nuclear magnetic resonance and dielectric spectroscopy study. AB - We study a dynamically asymmetric binary glass former with the low-Tg component m tri-cresyl phosphate (m-TCP: Tg = 206 K) and a spirobichroman derivative as a non polymeric high-Tg component (Tg = 382 K) by means of (1)H nuclear magnetic resonance (NMR), (31)P NMR, and dielectric spectroscopy which allow component selectively probing the dynamics. The entire concentration range is covered, and two main relaxation processes with two Tg are identified, Tg 1 and Tg 2. The slower one is attributed to the high-Tg component (alpha1-process), and the faster one is related to the m-TCP molecules (alpha2-process). Yet, there are indications that a small fraction of m-TCP is associated also with the alpha1 process. While the alpha1-relaxation only weakly broadens upon adding m-TCP, the alpha2-relaxation becomes extremely stretched leading to quasi-logarithmic correlation functions at low m-TCP concentrations-as probed by (31)P NMR stimulated echo experiments. Frequency-temperature superposition does not apply for the alpha2-process and it reflects an isotropic, liquid-like motion which is observed even below Tg 1, i.e., in the matrix of the arrested high-Tg molecules. As proven by 2D (31)P NMR, the corresponding dynamic heterogeneities are of transient nature, i.e., exchange occurs within the distribution G(lntaualpha 2). At Tg 1 a crossover is found for the temperature dependence of (mean) taualpha 2(T) from non-Arrhenius above to Arrhenius below Tg 1 which is attributed to intrinsic confinement effects. This "fragile-to-strong" transition also leads to a re-decrease of Tg 2(cm - TCP) at low concentration cm - TCP, i.e., a maximum is observed in Tg 2(cm - TCP) while Tg 1(cm - TCP) displays the well-known plasticizer effect. Although only non-polymeric components are involved, we re discover essentially all features previously reported for polymer-plasticizer systems. PMID- 26493915 TI - Computational phase diagrams of noble gas hydrates under pressure. AB - We present results from a first-principles study on the stability of noble gas water compounds in the pressure range 0-100 kbar. Filled-ice structures based on the host water networks ice-Ih, ice-Ic, ice-II, and C0 interacting with guest species He, Ne, and Ar are investigated, using density functional theory (DFT) with four different exchange-correlation functionals that include dispersion effects to various degrees: the non-local density-based optPBE-van der Waals (vdW) and rPW86-vdW2 functionals, the semi-empirical D2 atom pair correction, and the semi-local PBE functional. In the He-water system, the sequence of stable phases closely matches that seen in the hydrogen hydrates, a guest species of comparable size. In the Ne-water system, we predict a novel hydrate structure based on the C0 water network to be stable or at least competitive at relatively low pressure. In the Ar-water system, as expected, no filled-ice phases are stable; however, a partially occupied Ar-C0 hydrate structure is metastable with respect to the constituents. The ability of the different DFT functionals to describe the weak host-guest interactions is analysed and compared to coupled cluster results on gas phase systems. PMID- 26493916 TI - Numerical simulations of bijel morphology in thin films with complete surface wetting. AB - Bijels are a relatively new class of soft materials that have many potential energy and environmental applications. In this work, simulation results of bijel evolution confined within thin films with preferential surface wetting are presented. The computational approach used is a hybrid Cahn-Hilliard/Brownian dynamics method. In the absence of suspended particles, we demonstrate that the model accurately captures the rich kinetics associated with diffusion-based surface-directed spinodal decomposition, as evidenced by comparison with previous theoretical and simulation-based studies. When chemically neutral particles are included in the films, the simulations capture surface-modified bijel formation, with stabilized domain structures comparable with the experimental observations of Composto and coworkers. Namely, two basic morphologies - bicontinuous or discrete - are seen to emerge, with direct dependence on the film thickness, particle volume fraction, and particle radius. PMID- 26493917 TI - Correlation between length and tilt of lipid tails. AB - It is becoming recognized from simulations, and to a lesser extent from experiment, that the classical Helfrich-Canham membrane continuum mechanics model can be fruitfully enriched by the inclusion of molecular tilt, even in the fluid, chain disordered, biologically relevant phase of lipid bilayers. Enriched continuum theories then add a tilt modulus kappatheta to accompany the well recognized bending modulus kappa. Different enrichment theories largely agree for many properties, but it has been noticed that there is considerable disagreement in one prediction; one theory postulates that the average length of the hydrocarbon chain tails increases strongly with increasing tilt and another predicts no increase. Our analysis of an all-atom simulation favors the latter theory, but it also shows that the overall tail length decreases slightly with increasing tilt. We show that this deviation from continuum theory can be reconciled by consideration of the average shape of the tails, which is a descriptor not obviously includable in continuum theory. PMID- 26493918 TI - Thermal conductivity of penta-graphene from molecular dynamics study. AB - Using classical equilibrium molecular dynamics simulations and applying the original Tersoff interatomic potential, we study the thermal transport property of the latest two dimensional carbon allotrope, penta-graphene. It is predicted that its room-temperature thermal conductivity is about 167 W/mK, which is much lower than that of graphene. With normal mode decomposition, the accumulated thermal conductivity with respect to phonon frequency and mean free path is analyzed. It is found that the acoustic phonons make a contribution of about 90% to the thermal conductivity, and phonons with mean free paths larger than 100 nm make a contribution over 50%. We demonstrate that the remarkably lower thermal conductivity of penta-graphene compared with graphene results from the lower phonon group velocities and fewer collective phonon excitations. Our study highlights the importance of structure-property relationship and provides better understanding of thermal transport property and valuable insight into thermal management of penta-graphene. PMID- 26493919 TI - Hydrophilic behavior of graphene and graphene-based materials. AB - Graphene and the graphene-based materials like graphite, carbon nanotubes, and fullerenes are not only usually regarded as hydrophobic but also have been widely employed as paradigms for the investigation of the behavior of water under nonpolar confinement, a question of major concern for fields ranging from biology to materials design. However, some experimental and theoretical insights seem to contradict, at least partially, such a picture. In this work, we will provide firm evidence for a neat hydrophilic nature of graphene surfaces. Our molecular dynamics studies will demonstrate that parallel graphene sheets present a strong tendency to remain fully hydrated for moderately long times (even when the equilibrium state is indeed the collapse of the plates), and thus, they are less prone to self-assembly than model hydrophobic surfaces we shall employ as control which readily undergo a hydrophobic collapse. Potential of mean force calculations will indeed make evident that the solvent exerts a repulsive contribution on the self-assembly of graphene surfaces. Moreover, we shall also quantify graphene hydrophilicity by means of the calculation of water density at two pressures and water density fluctuations. This latter study has never been performed on graphene and represents a means both to confirm and to quantify its neat hydrophilic behavior. We shall also make evident the relevance of the mildly attractive water-carbon interactions, since their artificial weakening will be shown to revert from typically hydrophilic to typically hydrophobic behavior. PMID- 26493920 TI - Dynamics of homogeneous nucleation. AB - The classical nucleation theory for homogeneous nucleation is formulated as a theory for a density fluctuation in a supersaturated gas at a given temperature. But molecular dynamics simulations reveal that it is small cold clusters which initiates the nucleation. The temperature in the nucleating clusters fluctuates, but the mean temperature remains below the temperature in the supersaturated gas until they reach the critical nucleation size. The critical nuclei have, however, a temperature equal to the supersaturated gas. The kinetics of homogeneous nucleation is not only caused by a grow or shrink by accretion or evaporation of monomers only but also by an exponentially declining change in cluster size per time step equal to the cluster distribution in the supersaturated gas. PMID- 26493921 TI - Opening the way to molecular cycloaddition of large molecules on supported silicene. AB - Within density functional theory, the adsorption of the H2Pc molecule on the (3 * 3) silicene/(4 * 4) Ag(111) surface has been investigated. We observe an electronic redistribution in the central macrocycle of the H2Pc molecule and the formation of two Si - N covalent bonds between the molecule and the silicene, in agreement with a cycloaddition reaction. However, while on SiC(0001)(3 * 3) or Si(111)(?3*?3)R30 degrees -boron, the H2Pc molecule remains planar, and the H2Pc molecule takes a butterfly conformation on the silicene/Ag substrate due to an electrostatic or a polarization repulsion between the molecule and the silicene. Our study opens a way to the experimental adsorption of large organic molecules on supported silicene. PMID- 26493922 TI - The polarized interface between quadrupolar insulators: Maxwell stress tensor, surface tension, and potential. AB - The quadrupolar Maxwell electrostatic equations predict several qualitatively different results compared to Poisson's classical equation in their description of the properties of a dielectric interface. All interfaces between dielectrics possess surface dipole moment which results in a measurable surface potential jump. The surface dipole moment is conjugated to the bulk quadrupole moment density (the quadrupolarization) similarly to Gauss's relation between surface charge and bulk polarization. However, the classical macroscopic Maxwell equations completely neglect the quadrupolarization of the medium. Therefore, the electrostatic potential distribution near an interface of intrinsic dipole moment can be correctly described only within the quadrupolar macroscopic equations of electrostatics. They predict that near the polarized interface a diffuse dipole layer exists, which bears many similarities to the diffuse charge layer near a charged surface, in agreement with existing molecular dynamics simulation data. It turns out that when the quadrupole terms are kept in the multipole expansion of the laws of electrostatics, the solutions for the potential and the electric field are continuous functions at the surface. A well-defined surface electric field exists, interacting with the adsorbed dipoles. This allows for a macroscopic description of the surface dipole-surface dipole and the surface dipole-bulk quadrupole interactions. They are shown to have considerable contribution to the interfacial tension-of the order of tens of mN/m! To evaluate it, the Maxwell stress tensor in quadrupolar medium is deduced, including the electric field gradient action on the quadrupoles, as well as quadrupolar image force and quadrupolar electrostriction. The dependence of the interfacial tension on the external normal electric field (the dielectrocapillary curve) is predicted and the dielectric susceptibility of the dipolar double layer is related to the quadrupolarizabilities of the bulk phases and the intrinsic polarization of the interface. The coefficient of the dielectro-Marangoni effect (surface flow due to gradient of the normal electric field) is found. A model of the Langevin type for the surface dipole moment and the intrinsic surface polarizability is presented. PMID- 26493923 TI - Impact of potassium doping on the electronic structure of tetracene and pentacene: An electron energy-loss study. AB - We report the doping induced changes of the electronic structure of tetracene and pentacene probed by electron energy-loss spectroscopy in transmission. A comparison between the dynamic response of undoped and potassium-intercalated tetracene and pentacene emphasizes the appearance of a new excitation feature in the former gap upon potassium addition. Interestingly, the momentum dependency of this new excitation shows a negative dispersion. Moreover, the analysis of the C 1s and K 2p core-level excitation results in a significantly lower doping level compared to potassium doped picene, a recently discovered superconductor. Therefore, the present electronic structure investigations open a new pathway to better understand the exceptional differences between acenes and phenacene and their divergent behavior upon alkali doping. PMID- 26493924 TI - Ferrogels cross-linked by magnetic particles: Field-driven deformation and elasticity studied using computer simulations. AB - Ferrogels, i.e., swollen polymer networks into which magnetic particles are immersed, can be considered as "smart materials" since their shape and elasticity can be controlled by an external magnetic field. Using molecular dynamics simulations on the coarse-grained level, we study a ferrogel in which the magnetic particles act as the cross-linkers of the polymer network. In a homogeneous external magnetic field, the direct coupling between the orientation of the magnetic moments and the polymers by means of covalent bonds gives rise to a deformation of the gel, independent of the interparticle dipole-dipole interaction. In this paper, we quantify this deformation, and, in particular, we investigate the gel's elastic moduli and its magnetic response for two different connectivities of the network nodes. Our results demonstrate that these properties depend significantly on the topology of the polymer network. PMID- 26493925 TI - Picosecond dissociation of amyloid fibrils with infrared laser: A nonequilibrium simulation study. AB - Recently, mid-infrared free-electron laser technology has been developed to dissociate amyloid fibrils. Here, we present a theoretical framework for this type of experiment based on laser-induced nonequilibrium all-atom molecular dynamics simulations. We show that the fibril is destroyed due to the strong resonance between its amide I vibrational modes and the laser field. The effects of laser irradiation are determined by a balance between fibril formation and dissociation. While the overall rearrangements of the fibril finish over short time scales, the interaction between the peptides and the solvent continues over much longer times indicating that the waters play an important role in the dissociation process. Our results thus provide new insights into amyloid fibril dissociation by laser techniques and open up new venues to investigate the complex phenomena associated with amyloidogenesis. PMID- 26493926 TI - Enhancing light-harvesting power with coherent vibrational interactions: A quantum heat engine picture. AB - Recent evidence suggests that quantum effects may have functional importance in biological light-harvesting systems. Along with delocalized electronic excitations, it is now suspected that quantum coherent interactions with certain near-resonant vibrations may contribute to light-harvesting performance. However, the actual quantum advantage offered by such coherent vibrational interactions has not yet been established. We investigate a quantum design principle, whereby coherent exchange of single energy quanta between electronic and vibrational degrees of freedom can enhance a light-harvesting system's power above what is possible by thermal mechanisms alone. We present a prototype quantum heat engine which cleanly illustrates this quantum design principle and quantifies its quantum advantage using thermodynamic measures of performance. We also demonstrate the principle's relevance in parameter regimes connected to natural light-harvesting structures. PMID- 26493928 TI - Erratum: "Accurate transport properties for H-CO and H-CO2" [J. Chem. Phys. 143, 054303 (2015)]. PMID- 26493927 TI - Erratum: "Average local ionization energy generalized to correlated wavefunctions" [J. Chem. Phys. 141, 084107 (2014)]. PMID- 26493929 TI - Erratum: "Phase diagram of mixtures of colloids and polymers in the thermal crossover from good to theta solvent" [J. Chem. Phys. 141, 024902 (2014)]. PMID- 26493930 TI - Exposure to bisphenol A in young adult mice does not alter ovulation but does alter the fertilization ability of oocytes. AB - Follicle growth culminates in ovulation, which allows for the expulsion of fertilizable oocytes and the formation of corpora lutea. Bisphenol A (BPA) is present in many consumer products, and it has been suggested that BPA impairs ovulation; however, the underlying mechanisms are unknown. Therefore, this study first evaluated whether BPA alters ovulation by affecting folliculogenesis, the number of corpora lutea or eggs shed to the oviduct, ovarian gonadotropin responsiveness, hormone levels, and estrous cyclicity. Because it has been suggested (but not directly confirmed) that BPA exerts toxic effects on the fertilization ability of oocytes, a second aim was to evaluate whether BPA impacts the oocyte fertilization rate using an in vitro fertilization assay and mating. The possible effects on early zygote development were also examined. Young adult female C57BL/6J mice (39 days old) were orally dosed with corn oil (vehicle) or 50 MUg/kgbw/day BPA for a period encompassing the first three reproductive cycles (12-15 days). BPA exposure did not alter any parameters related to ovulation. Moreover, BPA exposure reduced the percentage of fertilized oocytes after either in vitro fertilization or mating, but it did not alter the zygotic stages. The data indicate that exposure to the reference dose of BPA does not impact ovulation but that it does influence the oocyte quality in terms of its fertilization ability. PMID- 26493932 TI - Sum over Histories Representation for Kinetic Sensitivity Analysis: How Chemical Pathways Change When Reaction Rate Coefficients Are Varied. AB - The sensitivity of kinetic observables is analyzed using a newly developed sum over histories representation of chemical kinetics. In the sum over histories representation, the concentrations of the chemical species are decomposed into the sum of probabilities for chemical pathways that follow molecules from reactants to products or intermediates. Unlike static flux methods for reaction path analysis, the sum over histories approach includes the explicit time dependence of the pathway probabilities. Using the sum over histories representation, the sensitivity of an observable with respect to a kinetic parameter such as a rate coefficient is then analyzed in terms of how that parameter affects the chemical pathway probabilities. The method is illustrated for species concentration target functions in H2 combustion where the rate coefficients are allowed to vary over their associated uncertainty ranges. It is found that large sensitivities are often associated with rate limiting steps along important chemical pathways or by reactions that control the branching of reactive flux. PMID- 26493931 TI - Effects of sexually dimorphic growth hormone secretory patterns on arachidonic acid metabolizing enzymes in rodent heart. AB - The arachidonic acid (AA) metabolizing enzymes are the potential therapeutic targets of cardiovascular diseases (CVDs). As sex differences have been shown in the risk and outcome of CVDs, we investigated the regulation of heart AA metabolizing enzymes (COXs, LOXs, and CYPs) by sex-dependent growth hormone (GH) secretory patterns. The pulsatile (masculine) GH secretion at a physiological concentration decreased CYP1A1 and CYP2J3 mRNA levels more efficiently in the H9c2 cells compared with the constant (feminine) GH secretion; however, CYP1B1 mRNA levels were higher following the pulsatile GH secretion. Sex differences in CYP1A1, CYP1B1, and CYP2J11 mRNA levels were observed in both the wild-type and GHR deficient mice. No sex differences in the mRNA levels of COXs, LOXs, or CYP2E1 were observed in the wild-type mice. The constant GH infusion induced heart CYP1A1 and CYP2J11, and decreased CYP1B1 in the male C57/B6 mice constantly infused with GH (0.4 MUg/h, 7 days). The activity of rat Cyp2j3 promoter was inhibited by the STAT5B protein, but was activated by C/EBPalpha (CEBPA). Compared with the constant GH administration, the levels of the nuclear phosphorylated STAT5B protein and its binding to the rat Cyp2j3 promoter were higher following the pulsatile GH administration. The constant GH infusion decreased the binding of the nuclear phosphorylated STAT5B protein to the mouse Cyp2j11 promoter. The data suggest the sexually dimorphic transcription of heart AA metabolizing enzymes, which might alter the risk and outcome of CVDs. GHR STAT5B signal transduction pathway may be involved in the sex difference in heart CYP2J levels. PMID- 26493933 TI - A posterior anal sling for fecal incontinence: results of a 152-patient prospective multicenter study. AB - BACKGROUND: The transobturator posterior anal sling (TOPAS) system is a posterior anal sling that is a minimally invasive, self-fixating polypropylene mesh intended to treat fecal incontinence (FI) in women who have failed conservative therapy. OBJECTIVE: We are reporting 1-year outcome in a prospective, multicenter study under investigational device exemption, evaluating this new treatment modality. STUDY DESIGN: A total of 152 women were implanted with the TOPAS system at 14 centers in the United States. FI was assessed preoperatively and at the 12 month follow up with a 14-day bowel diary, Cleveland Clinic Incontinence Scores, and FI Quality of Life questionnaires. Treatment success was defined as reduction in number of FI episodes of >=50% compared to baseline. Missing bowel diary data were considered treatment failures. The Wilcoxon signed rank test was used to compare changes observed at 12 months vs baseline. RESULTS: Mean age was 59.6 years old (SD 9.7). The mean duration of FI was 110 mo (range 8-712) months. Mean length of the implant procedure was 33.4 (SD 11.6) minutes. Mean EBL was 12.9 (SD 10.5) mL. Average follow-up was 24.9 months. At 12 months, 69.1% of patients met the criteria for treatment success, and 19% of subjects reported complete continence. FI episodes/wk decreased from a median of 9.0 (range 2-40) at baseline to 2.5 (range 0-40) (P < .001). FI days decreased from a median of 5.0 (range 1.5-7) at baseline to 2.0 (range 0-7) (P < .001) over a 7-day period. FI associated with urgency decreased from a median at baseline of 2.0 (range 0-26) to 0 (range 0-14.5) (P < .001). The mean Cleveland Clinic Incontinence Scores decreased from 13.9 at baseline to 9.6 at 12 months (P < .001). FI Quality of Life scores for all 4 domains improved significantly from baseline to 12 months (P < .001). A total of 66 subjects experienced 104 procedure- and/or device related adverse events (AEs). Most AEs were short in duration and 97% were managed without therapy or with nonsurgical interventions. No treatment-related deaths, erosions, extrusions, or device revisions were reported. The most common AE categories were pelvic pain (n = 47) and infection (n = 26). Those subjects experiencing pelvic pain had a mean pain score (0-10 scale, 0 = no pain) during the 12-month follow-up of 1.2 (SD 2.4). CONCLUSION: The TOPAS system provides significant improvements in FI symptoms and quality of life with an acceptable AE profile and may therefore be a viable minimally invasive treatment option for FI in women. PMID- 26493935 TI - Prevalence and predictors of anaemia in Romanian infants 6-23 months old. AB - BACKGROUND: Anaemia is a public health problem that can lead to a variety of detrimental effects on physical and neurodevelopment in young children. The present study explored the epidemiology of anaemia among infants in Romania, identified risk factors and created a model for predicting it. METHODS: Data from 1532 infants aged 6-24 months were selected from a larger nationally representative cross-sectional survey. Demographic predictor variables and haemoglobin concentration were extant variables in the data set. Multiple logistic regression was used to determine the best predictors of anaemia. RESULTS: Overall, 46% of 6-24 month olds in the sample had anaemia (Hb < 11.0 g/dl). A variety of risk factors were associated with significantly greater odds of anaemia, but a five-factor model best predicted it (67.9% accuracy). These predictors included being male, living in a rural area, being third born or later, being a Hungarian and living in the South, South-West or West region of Romania. CONCLUSIONS: While data indicate a modest decrease in anaemia from earlier Romanian studies, it remains a significant problem. Models like this one have the potential to improve identification and treatment of anaemia in young children. PMID- 26493936 TI - Differential role of endogenous cathepsin and microorganism in texture softening of ice-stored grass carp (Ctenopharyngodon idella) fillets. AB - BACKGROUND: Texture deterioration often negatively affects sensory attributes and commercial values of ice-stored fish fillets. The mechanism of softening of fish fillets during chilling storage is not fully resolved. Grass carp is a predominant freshwater fish species in China. The objective of the present study was to investigate the differential role of endogenous cathepsin and microorganisms in texture softening of ice-stored grass carp fillets. RESULTS: The fillets were immersed in either NaN3 solution to reduce microbial activity or in iodoacetic acid solution to exclude cathepsin activity before ice storage. Treatment with NaN3 reduced microbial load of fillets below 2 log CFU g(-1) muscle during the entire storage period, and had no significant influence on the cathepsin activity and proteolysis. But the shear force of fillets treated with NaN3 decreased by 66% after 21 days of storage. Meanwhile, treatment with iodoacetic acid inactivated cathepsin B and B + L but did not significantly affect the microbial growth of fillets. Compared to NaN3 treatment, iodoacetic acid effectively alleviated softening and inhibited the increase in TCA-soluble peptides during storage. CONCLUSION: This study demonstrated that proteolysis induced by endogenous cathepsins, rather than microorganisms, plays an important role in texture softening of ice-stored grass carp fillets. (c) 2015 Society of Chemical Industry. PMID- 26493937 TI - Blood or sputum eosinophils to guide asthma therapy? PMID- 26493934 TI - Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. AB - Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25-32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called "toxic wounds" by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses. PMID- 26493938 TI - Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. AB - BACKGROUND: Elevated sputum eosinophil counts predict asthma exacerbations and responsiveness to inhaled corticosteroids but are impractical to measure in primary care. We investigated the relation between blood eosinophil count and prospective annual asthma outcomes for a large UK cohort. METHODS: This historical cohort study used anonymised medical record data to identify primary care patients with asthma aged 12-80 years with 2 years of continuous records, including 1 year before (baseline) and 1 year after (outcome) their most recent eosinophil count. Negative binomial regression was used to compare outcome exacerbation rates and logistic regression to compare odds of asthma control for patients with blood eosinophil counts of 400 cells per MUL or less versus greater than 400 cells per MUL, adjusting for age, sex, body-mass index, smoking status, and Charlson comorbidity index. The study is registered at ClinicalTrials.gov, number NCT02140541. FINDINGS: Overall, 20 929 (16%) of 130 248 patients had blood eosinophil counts greater than 400 cells per MUL. During the outcome year, these patients experienced significantly more severe exacerbations (adjusted rate ratio [RR] 1.42, 95% CI 1.36-1.47) and acute respiratory events (RR 1.28, 1.24-1.33) than those with counts of 400 cells per MUL or less. They also had significantly lower odds of achieving overall asthma control (OR 0.74, 95% CI 0.72-0.77), defined as limited reliever use and no asthma-related hospital attendance or admission, acute course of oral corticosteroids, or prescription for antibiotics. Exacerbation rates increased progressively with nine ascending categories of blood eosinophil count as compared with a reference category of 200 cells per MUL or less. INTERPRETATION: Patients with asthma and blood eosinophil counts greater than 400 cells per MUL experience more severe exacerbations and have poorer asthma control. Furthermore, a count-response relation exists between blood eosinophil counts and asthma-related outcomes. Blood eosinophil counts could add predictive value to Global Initiative for Asthma control-based risk assessment. FUNDING: Teva Pharmaceuticals. PMID- 26493939 TI - The role of EpCAM in physiology and pathology of the epithelium. AB - Epithelial Cell Adhesion Molecule (EpCAM) has been discovered as one of the first tumor-specific antigens overexpressed in epithelial cancer. The present review focuses on the role of EpCAM in physiology and homeostasis of epithelia. Recent research pointed to a close interaction of EpCAM with other cell-cell contact molecules like E-cadherin and claudins and an intimate crosstalk with Wnt and TGF beta signaling in the regulation of cell growth. Moreover, EpCAM has been shown to modulate trans-epithelial migration processes of white blood cells. Mutations of the EpCAM gene lead to disturbances of epithelial homeostasis and cellular differentiation from the stem cell compartment. In the intestinal tract EpCAM mutations contribute to congenital tufting enteropathy. Regarding tumorigenesis EpCAM can act as an oncogene still depending on additional driver mutations and epithelial phenotype of tumor cells. Tumor cells display increased EpCAM expression that often correlates with the loss of strict basolateral localization. Many tumors show enhanced regulated intramembrane proteolysis (RIP) of EpCAM and loose EpCAM expression under conditions of epithelial to mesenchymal transition. The resulting extracellular EpEX and intracellular EpICD fragments mediate proliferative signals to the cell. Resulting fragments can be validated either by sensitive enzyme-linked immune-sandwich assays (EpEX) or by immunohistochemistry (EpICD). The present review gives an overview on the detection of EpCAM fragments as predictive markers for disease progression and survival of cancer patients. PMID- 26493940 TI - Size does matter: crocodile mothers react more to the voice of smaller offspring. AB - Parental care is widespread in Archosaurs (birds, crocodilians, dinosaurs and pterosaurs), and this group provides a useful model for the evolution of parent offspring interactions. While offspring signalling has been well-studied in birds, the modulation of parental care in crocodilians remains an open question. Here we show that acoustic communication has a key role in the dynamics of crocodilian' mother-offspring relationships. We found embedded information about the emitter's size in juvenile calls of several species, and experimentally demonstrated that Nile crocodile mothers breeding in the wild are less receptive to the calls of larger juveniles. Using synthetized sounds, we further showed that female' reaction depends on call pitch, an important cue bearing size information. Changes in acoustic interactions may thus go with the break of maternal care as well as dispersal of juvenile crocodilians. This process could have characterized other archosaurs displaying rapid early growth such as dinosaurs and pterosaurs. PMID- 26493941 TI - Cell death: Pathways for cross-priming. PMID- 26493942 TI - Shelley procedure in axillary hyperhidrosis. PMID- 26493943 TI - Low Shear Stress Inhibited Endothelial Cell Autophagy Through TET2 Downregulation. AB - Low shear stress plays a crucial role in the initiation and progression of atherosclerotic lesions. However, the detailed mechanisms of these processes remain unclear. In this study, the effect of low shear stress on endothelial cell autophagy and its potential mechanism were investigated. Results showed autophagy dysfunction and ten-eleven translocation 2 (TET2) protein downregulation during atherosclerotic lesion progression. Autophagic markers BECLIN 1 and LC3II/LC3I under low shear stress (5 dyne/cm(2)) obviously decreased compared with those under physiological shear stress (15 dyne/cm(2)), whereas autophagic substrate p62 increased. TET2 expression was also downregulated under low shear stress. Endothelial cell autophagy was improved with TET2 overexpression but was impaired by TET2 siRNA treatment. Moreover, TET2 overexpression upregulated the expression of endothelial cell nitric oxide synthase (eNOS) and downregulated the expression of endothelin-1 (ET-1). TET2 siRNA further attenuated eNOS expression and stimulated ET-1 expression. Overall, the results showed that low shear stress downregulated endothelial cell autophagy by impaired TET2 expression, which might contribute to the atherogenic process. PMID- 26493944 TI - A Phosphole Oxide Based Fluorescent Dye with Exceptional Resistance to Photobleaching: A Practical Tool for Continuous Imaging in STED Microscopy. AB - The development of stimulated emission depletion (STED) microscopy represented a major breakthrough in cellular and molecular biology. However, the intense laser beams required for both excitation and STED usually provoke rapid photobleaching of fluorescent molecular probes, which significantly limits the performance and practical utility of STED microscopy. We herein developed a photoresistant fluorescent dye C-Naphox as a practical tool for STED imaging. With excitation using either a lambda=405 or 488 nm laser in protic solvents, C-Naphox exhibited an intense red/orange fluorescence (quantum yield PhiF >0.7) with a large Stokes shift (circa 5900 cm(-1) ). Even after irradiation with a Xe lamp (300 W, lambdaex =460 nm, full width at half maximum (FWHM)=11 nm) for 12 hours, 99.5 % of C-Naphox remained intact. The high photoresistance of C-Naphox allowed repeated STED imaging of HeLa cells. Even after recording 50 STED images, 83 % of the initial fluorescence intensity persisted. PMID- 26493945 TI - Stainless-Steel Ball-Milling Method for Hydro-/Deutero-genation using H2O/D2O as a Hydrogen/Deuterium Source. AB - A one-pot continuous-flow method for hydrogen (deuterium) generation and subsequent hydrogenation (deuterogenation) was developed using a stainless-steel (SUS304)-mediated ball-milling approach. SUS304, especially zero-valent Cr and Ni as constituents of the SUS304, and mechanochemical processing played crucial roles in the development of the reactions. PMID- 26493946 TI - FIELD CORRECTION FACTORS FOR PERSONAL NEUTRON DOSEMETERS. AB - A field-dependent correction factor can be obtained by comparing the readings of two albedo neutron dosemeters fixed in opposite directions on a polyethylene sphere to the H*(10) reading as determined with a thermal neutron detector in the centre of the same sphere. The work shows that the field calibration technique as used for albedo neutron dosemeters can be generalised for all kind of dosemeters, since H*(10) is a conservative estimate of the sum of the personal dose equivalents Hp(10) in two opposite directions. This result is drawn from reference values as determined by spectrometers within the EVIDOS project at workplace of nuclear installations in Europe. More accurate field-dependent correction factors can be achieved by the analysis of several personal dosimeters on a phantom, but reliable angular responses of these dosemeters need to be taken into account. PMID- 26493947 TI - ASSESSING THE USEFULNESS OF THE QUASI-IDEAL OBSERVER FOR QUALITY CONTROL IN FLUOROSCOPY. AB - The aim of this work was to evaluate the reliability of the square of the signal to-noise ratio rate, [Formula: see text], as a precise measurement for quality control test in a digital fluoroscopy system. The quasi-ideal model observer was used to measure [Formula: see text] The dose rate, pulse rate and field of view were varied, and their effect on dose efficiency, defined as [Formula: see text], was evaluated (where [Formula: see text] is the air kerma-area product rate). Measurements were repeated to assess reproducibility. The relative standard deviation in [Formula: see text] over seven consecutive measurements was 5 %. No significant variation in [Formula: see text] was observed across different pulse rates (10-30 pulses s(-1)). The low-dose-rate setting had a superior dose efficiency compared with the medium- and high-dose-rate settings. A smaller field of view resulted in higher dose efficiency.The results show that [Formula: see text] measurements offer the high precision required in quality control constancy tests. PMID- 26493948 TI - Oppositional defiant disorder dimensions and subtypes among detained male adolescent offenders. AB - BACKGROUND: In adolescent offenders, oppositional defiant disorder (ODD) and its dimensions/subtypes have been frequently ignored due to the stronger focus on criminal behaviours. The revised criteria of the DSM-5 now allow diagnosing ODD in older youths independent of conduct disorder (CD). This study aimed at analysing ODD dimensions/subtypes and their relation to suicidality, comorbid psychiatric disorders, and criminal behaviours after release from detention in a sample of detained male adolescents. METHODS: Suicidality and psychiatric disorders (including ODD symptoms) were assessed in a consecutive sample of 158 male adolescents (Mage = 16.89 years) from the Zurich Juvenile Detention Centre. Based on previous research findings, an irritable ODD dimension and a defiant/vindictive ODD dimension based on ODD symptoms were defined. Latent Class Analysis (LCA) was used to identify distinct subtypes of adolescent offenders according to their ODD symptom profiles. Logistic regression and Cox regression were used to analyse the relations of ODD dimensions/ODD subtypes to comorbid psychopathology and criminal reoffenses from official data. RESULTS: The ODD irritable dimension, but not the ODD defiant/vindictive dimension predicted comorbid anxiety, suicidality and violent reoffending. LCA identified four subtypes, namely, a no-ODD subtype, a severe ODD subtype and two moderate ODD subtypes with either defiant or irritable symptoms. The irritable ODD subtype and the severe ODD subtype were related to suicidality and comorbid affective/anxiety disorders. The irritable ODD subtype was the strongest predictor of criminal (violent) reoffending even when controlling for CD. CONCLUSIONS: The present findings confirm the presence of ODD dimensions/subtypes in a highly disturbed adolescent offender sample. Irritable youths were at risk of suicide and persistent criminal behaviours. Due to the severe consequences of irritability, a standardized assessment approach and a specific treatment is needed in prison to prevent suicide among the detainees and further harm to the society. As defined in the DSM-5, the present findings confirm the validity of ODD and ODD dimensions/subtypes as a diagnostic category among older youths. PMID- 26493949 TI - Single Canonical Model of Reflexive Memory and Spatial Attention. AB - Many neurons in the dorsal and ventral visual stream have the property that after a brief visual stimulus presentation in their receptive field, the spiking activity in these neurons persists above their baseline levels for several seconds. This maintained activity is not always correlated with the monkey's task and its origin is unknown. We have previously proposed a simple neural network model, based on shape selective neurons in monkey lateral intraparietal cortex, which predicts the valence and time course of reflexive (bottom-up) spatial attention. In the same simple model, we demonstrate here that passive maintained activity or short-term memory of specific visual events can result without need for an external or top-down modulatory signal. Mutual inhibition and neuronal adaptation play distinct roles in reflexive attention and memory. This modest 4 cell model provides the first simple and unified physiologically plausible mechanism of reflexive spatial attention and passive short-term memory processes. PMID- 26493950 TI - A Time and Place for Everything: Developmental Differences in the Building Blocks of Episodic Memory. AB - This research investigated whether episodic memory development can be explained by improvements in relational binding processes, involved in forming novel associations between events and the context in which they occurred. Memory for item-space, item-time, and item-item relations was assessed in an ethnically diverse sample of 151 children aged 7-11 years and 28 young adults. Item-space memory reached adult performance by 91/2 years, whereas item-time and item-item memory improved into adulthood. In path analysis, item-space, but not item-time best explained item-item memory. Across age groups, relational binding related to source memory and performance on standardized memory assessments. In conclusion, relational binding development depends on relation type, but relational binding overall supports episodic memory development. PMID- 26493951 TI - DNA methylation signatures of long intergenic noncoding RNAs in porcine adipose and muscle tissues. AB - Long intergenic noncoding RNAs (lincRNAs) are one of the major unexplored components of genomes. Here we re-analyzed a published methylated DNA immunoprecipitation sequencing (MeDIP-seq) dataset to characterize the DNA methylation pattern of pig lincRNA genes in adipose and muscle tissues. Our study showed that the methylation level of lincRNA genes was higher than that of mRNA genes, with similar trends observed in comparisons of the promoter, exon or intron regions. Different methylation pattern were observed across the transcription start sites (TSS) of lincRNA and protein-coding genes. Furthermore, an overlap was observed between many lincRNA genes and differentially methylated regions (DMRs) identified among different breeds of pigs, which show different fat contents, sexes and anatomic locations of tissues. We identify a lincRNA gene, linc-sscg3623, that displayed differential methylation levels in backfat between Min and Large White pigs at 60 and 120 days of age. We found that a demethylation process occurred between days 150 and 180 in the Min and Large White pigs, which was followed by remethylation between days 180 and 210. These results contribute to our understanding of the domestication of domestic animals and identify lincRNA genes involved in adipogenesis and muscle development. PMID- 26493953 TI - Maternal high-fat diet-induced programing of gut taste receptor and inflammatory gene expression in rat offspring is ameliorated by CLA supplementation. AB - Consumption of a high-fat (HF) diet during pregnancy and lactation influences later life predisposition to obesity and cardiometabolic disease in offspring. The mechanisms underlying this phenomenon remain poorly defined, but one potential target that has received scant attention and is likely pivotal to disease progression is that of the gut. The present study examined the effects of maternal supplementation with the anti-inflammatory lipid, conjugated linoleic acid (CLA), on offspring metabolic profile and gut expression of taste receptors and inflammatory markers. We speculate that preventing high-fat diet-induced metainflammation improved maternal metabolic parameters conferring beneficial effects on adult offspring. Sprague Dawley rats were randomly assigned to a purified control diet (CD; 10% kcal from fat), CD with CLA (CLA; 10% kcal from fat, 1% CLA), HF (45% kcal from fat) or HF with CLA (HFCLA; 45% kcal from fat, 1% CLA) throughout gestation and lactation. Plasma/tissues were taken at day 24 and RT-PCR was carried out on gut sections. Offspring from HF mothers were significantly heavier at weaning with impaired insulin sensitivity compared to controls. This was associated with increased plasma IL-1beta and TNFalpha concentrations. Gut Tas1R1, IL-1beta, TNFalpha, and NLRP3 expression was increased and Tas1R3 expression was decreased in male offspring from HF mothers and was normalized by maternal CLA supplementation. Tas1R1 expression was increased while PYY and IL-10 decreased in female offspring of HF mothers. These results suggest that maternal consumption of a HF diet during critical developmental windows influences offspring predisposition to obesity and metabolic dysregulation. This may be associated with dysregulation of taste receptor, incretin, and inflammatory gene expression in the gut. PMID- 26493952 TI - Smaller Dentate Gyrus and CA2 and CA3 Volumes Are Associated with Kynurenine Metabolites in Collegiate Football Athletes. AB - An imbalance in kynurenine pathway metabolism is hypothesized to be associated with dysregulated glutamatergic neurotransmission, which has been proposed as a mechanism underlying the hippocampal volume loss observed in a variety of neurological disorders. Pre-clinical models suggest that the CA2-3 and dentate gyrus hippocampal subfields are particularly susceptible to excitotoxicity after experimental traumatic brain injury. We tested the hypothesis that smaller hippocampal volumes in collegiate football athletes with (n = 25) and without (n = 24) a concussion history would be most evident in the dentate gyrus and CA2-3 subfields relative to nonfootball healthy controls (n = 27). Further, we investigated whether the concentration of peripheral levels of kynurenine metabolites are altered in football athletes. Football athletes with and without a self-reported concussion history had smaller dentate gyrus (p < 0.05, p < 0.10) and CA2-3 volumes (p's < 0.05) relative to healthy controls. Football athletes with and without a concussion history had a trend toward lower (p < 0.10) and significantly lower (p < 0.05) kynurenine levels compared with healthy controls, while athletes with a concussion history had greater levels of quinolinic acid compared with athletes without a concussion history (p < 0.05). Finally, plasma levels of 3-hydroxykynurenine inversely correlated with bilateral hippocampal volumes in football athletes with a concussion history (p < 0.01), and left hippocampal volume was correlated with the ratio of kynurenic acid to quinolinic acid in football athletes without a concussion history (p < 0.05). Our results raise the possibility that abnormalities of the kynurenine metabolic pathway constitute a mechanism for hippocampal volume differences in the context of sports-related brain injury. PMID- 26493954 TI - Ventilation heterogeneity is increased in patients with chronic heart failure. AB - In the healthy lung, ventilation is distributed heterogeneously due to factors such as anatomical asymmetry and gravity. This ventilation heterogeneity increases pathologically in conditions such as asthma, chronic obstructive lung disease, and cystic fibrosis. In chronic heart failure, lung biopsy demonstrates evidence of peripheral lung fibrosis and small airways narrowing and distortion. We hypothesized that this would lead to increased ventilation heterogeneity. Furthermore, we proposed that rostral fluid shifts when seated patients lie supine would further increase ventilation heterogeneity. We recruited 30 ambulatory chronic heart failure patients (57 +/- 10 years, 83% male, left ventricular ejection fraction 31 +/- 12%) as well as 10 healthy controls (51 +/- 13 years, 90% male). Heart failure patients were clinically euvolemic. Subjects underwent measurement of ventilation heterogeneity using the multiple-breath nitrogen washout technique in the seated position, followed by repeat measurements after 5 and 45 min in the supine position. Ventilation heterogeneity was calculated using the lung clearance index (LCI), Sacin and Scond which represent overall, acinar, and small conducting airway function, respectively. Lung clearance index (9.6 +/- 1.2 vs. 8.6 +/- 1.4 lung turnovers, P = 0.034) and Scond (0.029 +/- 0.014 vs. 0.006 +/- 0.016/L, P = 0.007) were higher in the heart failure patients. There was no difference in Sacin (0.197 +/- 0.171 vs. 0.125 +/- 0.081/L, P = 0.214). Measures of ventilation heterogeneity did not change in the supine position. This study confirms the presence of peripheral airway pathology in patients with chronic heart failure. This leads to subtle but detectable functional abnormalities which do not change after 45 min in the supine position. PMID- 26493955 TI - Substituting CF2 for O4' in Components of Nucleic Acids: Towards Systems with Reduced Propensity to Form Abasic Lesions. AB - Intrinsic structural features and energetics of nucleotides containing variously fluorinated sugars as potential building blocks of DNA duplexes and quadruplexes are explored systematically using the modern methods of density functional theory (DFT) and quantum chemical topology (QCT). Our results suggest that fluorination at the 2'-beta or 2'-alpha,beta positions somewhat stabilizes in vacuo the AI relative to the BI conformations. In contrast, substitution of the CF2 group for the O4' atom (O4'-CF2 modification) leads to a preference of the BI relative to AI DNA-like conformers. All the studied modifications result in a noticeable increase in the stability of the glycosidic bond [estimated by the relaxed force constants (RFC) approach], with particularly encouraging results for the O4'-CF2 derivative. Consequently, the O4'-CF2 modified systems are suggested and explored as promising scaffolds for the development of duplex and quadruplex structures with reduced propensity to form abasic lesions and to undergo DNA damage. PMID- 26493956 TI - An Adaptive Association Test for Multiple Phenotypes with GWAS Summary Statistics. AB - We study the problem of testing for single marker-multiple phenotype associations based on genome-wide association study (GWAS) summary statistics without access to individual-level genotype and phenotype data. For most published GWASs, because obtaining summary data is substantially easier than accessing individual level phenotype and genotype data, while often multiple correlated traits have been collected, the problem studied here has become increasingly important. We propose a powerful adaptive test and compare its performance with some existing tests. We illustrate its applications to analyses of a meta-analyzed GWAS dataset with three blood lipid traits and another with sex-stratified anthropometric traits, and further demonstrate its potential power gain over some existing methods through realistic simulation studies. We start from the situation with only one set of (possibly meta-analyzed) genome-wide summary statistics, then extend the method to meta-analysis of multiple sets of genome-wide summary statistics, each from one GWAS. We expect the proposed test to be useful in practice as more powerful than or complementary to existing methods. PMID- 26493957 TI - Dysembryoplastic Neuroepithelial Tumors. AB - Dysembryoplastic neuroepithelial tumor (DNT) is a benign glioneuronal neoplasm that most commonly occurs in children and young adults and may present with medically intractable, chronic seizures. Radiologically, this tumor is characterized by a cortical topography and lack of mass effect or perilesional edema. Partial complex seizures are the most common presentation. Three histologic subtypes of DNTs have been described. Histologically, the recognition of a unique, specific glioneuronal element in brain tumor samples from patients with medically intractable, chronic epilepsy serves as a diagnostic feature for complex or simple DNT types. However, nonspecific DNT has diagnostic difficulty because its histology is indistinguishable from conventional gliomas and because a specific glioneuronal element and/or multinodularity are absent. This review will focus on the clinical, radiographic, histopathological, and immunohistochemical features as well as the molecular genetics of all three variants of DNTs. The histological and cytological differential diagnoses for this lesion, especially the nonspecific variant, will be discussed. PMID- 26493958 TI - Illuminating Cancer Resistance in Elephants. AB - A new study shows that elephants have at least 20 copies of the tumor suppressor gene TP53; their cells also favor apoptosis over DNA repair when subjected to DNA damaging agents. These findings may help explain elephants' longevity and low cancer risk, and shed further light on natural cancer suppression mechanisms. PMID- 26493959 TI - ADC Shows Effectiveness in SCLC. AB - Results from a phase I trial presented during the 2015 European Cancer Congress suggest that an experimental antibody-drug conjugate, rovalpituzumab tesirine, may be effective against recurrent small cell lung cancer, for which there are few treatment options. PMID- 26493960 TI - Advancing the Precision Medicine Initiative. AB - The NIH has approved the framework to build a national research cohort of 1 million Americans, a key part of President Obama's Precision Medicine Initiative. PMID- 26493967 TI - Novel reversible and switchable electrolytes based on magneto-rheology. AB - Replacing organic liquid electrolytes with solid electrolytes has led to a new perspective on batteries, enabling high-energy battery chemistry with intrinsically safe cell designs. However, most solid/gel electrolytes are easily deformed; under extreme deformation, leakage and/or short-circuiting can occur. Here, we report a novel magneto-rheological electrolyte (MR electrolyte) that responds to changes in an external magnetic field; the electrolyte exhibits low viscosity in the absence of a magnetic field and increased viscosity or a solid like phase in the presence of a magnetic field. This change from a liquid to solid does not significantly change the conductivity of the MR electrolyte. This work introduces a new class of magnetically sensitive solid electrolytes that can enhance impact resistance and prevent leakage from electronic devices through reversible active switching of their mechanical properties. PMID- 26493961 TI - Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells. AB - Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas, whereas this function was lost in Batf3(-/-) mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects. SIGNIFICANCE: Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3 dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory mAbs. PMID- 26493968 TI - Prevalence of metabolic syndrome in patients with pulmonary hypertension. AB - BACKGROUND AND AIMS: To determine the prevalence of metabolic syndrome (MetS) - a potential phenotypical risk for pulmonary hypertension (PH) - in patients with PH and by PH diagnostic group including group 1 pulmonary arterial hypertension (PAH); group 1.1 idiopathic PAH, groups 1.2 heritable PAH, 1.3 drug and toxin induced, 1.4 associated PAH, group 2 PH with left heart disease, group 3 PH associated with lung disease and/or hypoxemia, group 4 PH owing to chronic thrombotic and/or embolic disease, and group 5 PH from multifactorial mechanisms. METHODS: We conducted a retrospective chart review of patients referred to Mayo Clinic in Florida from January 1990 to October 2013 (N = 1287). Only patients whom PH was confirmed by right heart catheterization were included (N = 640). MetS was defined with at least three of the following: systemic hypertension, diabetes mellitus, hyperlipidemia and body mass index > 30. RESULTS: MetS was prevalent in 247 of 640 (39%) with PH: 13% in group 1.1 PAH, 12% in groups 1.2 1.4 PAH, 54% in group 2, 55% in group 3, 23% in group 4 and 24% in group 5. After adjusting for age, sex and race, diagnostic subgroup analysis revealed a higher prevalence of MetS in WHO Group 2 PH patients [adjusted odd ratios (OR): 2.58, P < 0.0001] and WHO group 3 PH (adjusted OR: 2.77, P < 0.0001) when compared to group 1 PH. CONCLUSION: The prevalence of MetS was observed in 39% of patients with PH; however, among PH patients, the prevalence was higher in group 2 and 3 PH. PMID- 26493969 TI - Establishing Realistic Patient Expectations Following Total Knee Arthroplasty. AB - Nearly 20% of patients are dissatisfied following well-performed total knee arthroplasty with good functional outcomes. Surgeons must understand the drivers of dissatisfaction to minimize the number of unhappy patients following surgery. Several studies have shown that unfulfilled expectations are a principal source of patient dissatisfaction. Patients contemplating total knee arthroplasty expect pain relief, improved walking ability, return to sports, and improvement in psychological well-being and social interactions. However, patients are typically overly optimistic with regard to expected outcomes following surgery. Patient expectations and satisfaction can be influenced by age, socioeconomic factors, sex, and race. The interplay of these factors can be complex and specific to each person. Published data on clinical and functional outcomes show that persistence of symptoms, such as pain, stiffness, and failure to return to preoperative levels of function, are common and normal. Therefore, the surgeon needs to help the patient to establish realistic expectations. PMID- 26493970 TI - Acute Management of Traumatic Knee Dislocations for the Generalist. AB - Acute knee dislocations are an uncommon injury that can result in profound consequences if not recognized and managed appropriately on presentation. Patients presenting with knee pain in the setting of high- or low-energy trauma may have sustained a knee dislocation that spontaneously reduced. Prompt reduction of the dislocated knee and serial neurovascular examinations are paramount. Damage to the popliteal artery is a common associated injury that can be diagnosed on physical examination using ankle brachial indices (ABIs), CT angiography, or standard angiography. After reduction, patients with a normal pulse examination and an ABI >=0.9 may be observed, with serial examination performed to document vascular status and monitor for compartment syndrome. Patients with asymmetric pulses or an ABI <0.9 in the presence of pulses may be treated urgently depending on the results of additional vascular imaging, and patients with absent pulses and clear signs of vascular compromise should be treated emergently. Some knee dislocations are not reducible and should be taken emergently to the operating room for an open reduction. Persistent joint subluxation or severe soft-tissue injuries after reduction require temporary external fixation before definitive repair or reconstruction of ligaments is performed. PMID- 26493971 TI - Tranexamic Acid in Hip and Knee Arthroplasty. AB - Perioperative blood loss is a significant concern for patients undergoing total joint arthroplasty. A growing body of evidence has shown tranexamic acid (TXA) to be effective in decreasing perioperative blood loss and transfusion requirements in both primary and revision hip and knee arthroplasty. TXA is a synthetic drug that limits blood loss through inhibition of fibrinolysis and clot degradation. Both topical and intravenous administration of TXA, in a variety of dosing regimens, has proven effective. Further investigation is required to determine the optimal dose and dosing regimens; however, evidence exists to recommend an initial intravenous dose be given before beginning the procedure, with at least one additional intravenous dose administered postoperatively. Additionally, topical TXA doses >2 g appear to be more efficacious than lower doses. Finally, relatively few adverse reactions have been reported in arthroplasty patients, and no study to date has demonstrated an increased risk of symptomatic venous thromboembolic events in this patient population. PMID- 26493972 TI - Metal-on-Metal Total Hip Arthroplasty: Patient Evaluation and Treatment. AB - Metal-on-metal (MoM) hip articulations were thought to represent a biologic and biomechanically favorable alternative to conventional metal-on-polyethylene total hip arthroplasty implants. However, concerns emerged when registry data reported significantly higher failure rates associated with MoM implants compared with other contemporary hip implants. These high implant failure rates have been attributed to the release of metal particles into the periprosthetic space, creating macroscopic necrosis; corrosive osteolysis; large, sterile hip effusions; and periprosthetic solid and cystic masses (ie, pseudotumors)-a spectrum of findings termed adverse reaction to metal debris. A thorough clinical history and physical examination, along with laboratory data and imaging surveillance of these patients, is critical for appropriate diagnosis and treatment. The decision to perform revision hip arthroplasty of a metal-on-metal implant is multifactorial and should be based on documented, objective clinical indications. A systematic and objective approach to this evaluation and treatment is essential to optimize the care of patients who undergo total hip arthroplasty with MoM implants. PMID- 26493973 TI - The ventral hippocampus, but not the dorsal hippocampus is critical for learned approach-avoidance decision making. AB - The resolution of an approach-avoidance conflict induced by ambivalent information involves the appraisal of the incentive value of the outcomes and associated stimuli to orchestrate an appropriate behavioral response. Much research has been directed at delineating the neural circuitry underlying approach motivation and avoidance motivation separately. Very little research, however, has examined the neural substrates engaged at the point of decision making when opposing incentive motivations are experienced simultaneously. We hereby examine the role of the dorsal and ventral hippocampus (HPC) in a novel approach-avoidance decision making paradigm, revisiting a once popular theory of HPC function, which posited the HPC to be the driving force of a behavioral inhibition system that is activated in situations of imminent threat. Rats received pre-training excitotoxic lesions of the dorsal or ventral HPC, and were trained to associate different non-spatial cues with appetitive, aversive and neutral outcomes in three separate arms of the radial maze. On the final day of testing, a state of approach-avoidance conflict was induced by simultaneously presenting two cues of opposite valences, and comparing the time the rats spent interacting with the superimposed 'conflict' cue, and the neutral cue. The ventral HPC-lesioned group showed significant preference for the conflict cue over the neutral cue, compared to the dorsal HPC-lesioned, and control groups. Thus, we provide evidence that the ventral, but not dorsal HPC, is a crucial component of the neural circuitry concerned with exerting inhibitory control over approach tendencies under circumstances in which motivational conflict is experienced. PMID- 26493974 TI - A Graded Evaluation of Outcomes Following Pancreaticoduodenectomy with Major Vascular Resection in Pancreatic Cancer. AB - Previous studies examining short- and long-term outcomes of pancreaticoduodenectomy with vascular resection for pancreatic adenocarcinoma have not graded perioperative complication severity. These studies may provide incomplete assessments of the efficacy of vascular resection. In the current study, we evaluated 36 patients who had pancreaticoduodenectomy with major vascular resection. These were matched 1:3 by tumor stage and age to patients who had pancreaticoduodenectomy without vascular resection. Charts were reviewed to identify all complications and 90-day readmissions. Complications were graded as either severe or minor adverse postoperative outcomes, taking into account the total length of stay. There were no statistical differences in patient demographics, comorbidities, or symptoms between the groups. Patients who had vascular resection had significantly increased rates of severe adverse postoperative outcomes, readmissions, lengths of hospital stay, as well as higher hospital costs. Hypoalbuminemia and major vascular resection were independent predictors of severe adverse postoperative outcomes. On multivariate Cox regression survival analysis, patients who had vascular resection had decreased recurrence-free (12 vs. 17 months) and overall (17 vs. 29 months) survival. Major vascular resection was a predictor of mortality, may be an independent prognostic factor for survival, and may warrant incorporation into future staging systems. PMID- 26493975 TI - Both Pre-Transplant and Early Post-Transplant Antireflux Surgery Prevent Development of Early Allograft Injury After Lung Transplantation. AB - BACKGROUND: Antireflux surgery (ARS) has been associated with improved lung transplant outcomes. Pre-transplant ARS has been shown in small studies to improve pulmonary function among transplant candidates with gastroesophageal reflux disease (GERD). Although early post-transplant ARS has been shown to be effective in reducing chronic rejection, the optimal timing of ARS in transplant recipients remains unclear. The aim of this study is to evaluate the time to early allograft injury among lung transplant recipients by timing of ARS. METHODS: This was a retrospective cohort study of lung transplant recipients undergoing ARS before or after transplantation at a tertiary care center since 2007, with at least 1-year follow-up. Early allograft injury was defined clinically and histologically as acute rejection or lymphocytic bronchiolitis, occurring within the first year after transplantation. In accordance with prior studies, the cutoff between early and late post-transplant ARS was set at 6 months. Time-to-event analysis using the Cox proportional hazards model was applied to assess the relationship between timing of surgery and early allograft injury. Subjects not meeting this outcome were censored at 1 year in the time-to event analysis. Fisher's exact test for binary variables and Student's t test for continuous variables were performed to assess for differences among the three groups: ARS pre-transplant, ARS early post-transplant, and ARS late post transplant. RESULTS: Forty-eight subjects (60% men, mean age 55) met the inclusion criteria for the study. Patient demographics, pre-transplant cardiopulmonary function, BMI, CMV status, and PPI exposure were similar between groups. Kaplan-Meier analysis demonstrated significantly increased early allograft injury in late post-transplant ARS patients compared with both pre transplant (log-rank p = 0.007) and early post-transplant (log-rank p = 0.05) patients, as well as a significant trend across groups (log-rank p = 0.005). No significant difference between pre- and early post-transplant groups was noted. Three ARS failures were noted in the pre- and late post-transplant groups. Complications included one death due to aspiration pneumonia in a late post transplant ARS recipient. No early post-transplant ARS patients experienced ARS failure or complications. CONCLUSION: Late post-lung transplant ARS resulted in increased risk of early allograft injury compared to pre-transplant and early post-transplant ARS. Both pre- and early post-transplant ARS appear equally safe and effective in improving lung transplant outcomes. These findings support consideration of aggressive reflux testing and application of antireflux measures before or soon after transplantation to minimize the impact of reflux on allograft injury. PMID- 26493976 TI - After Pancreatectomy, the "90 Days from Surgery" Definition Is Superior to the "30 Days from Discharge" Definition for Capture of Clinically Relevant Readmissions. AB - BACKGROUND: Previous studies by different authors have reported their readmission rates after pancreatectomy as either "30 days from discharge" or "90 days from surgery." The objective of this study was to determine which of these definitions captures the most surgery-related complications. METHODS: A prospectively maintained database at a high volume center was queried to identify all individuals who underwent pancreatectomy between 2000 and 2012 for any diagnosis. The data was analyzed at 30 days after discharge and 90 days after operation. The optimal timing for complication reporting was defined as the time point that maximized the capture of surgery-related readmissions and direct major surgical complications while minimizing the capture of disease (cancer)-related readmissions. RESULTS: There were 1123 patients included during the study time period. The median age was 63 years old, and 55.6% were male. Operations included 833 (74.2%) pancreaticoduodenectomies, 257 (22.9%) distal pancreatectomies, 18 (1.6%) total pancreatectomies, and 15 (1.3%) central pancreatectomies. Surgery related readmissions occurred in 248 (22%) individuals, while readmission related to malignant disease progression occurred in 25 (2%) individuals. The 30 days from discharge definition captured 184 surgery-related readmissions and 1 disease related readmission (sensitivity 0.74, specificity 0.96). The 90 days from surgery definition captured 215 surgery-related readmissions and 1 disease related readmission (sensitivity 0.87, specificity 0.96). Major surgical complication was the only independent factor associated with readmission not captured by the 30 days from discharge definition (p = 0.002, HR 3.94, 95% CI 1.44-12.22). CONCLUSION: The 90 days from surgery definition was superior to the 30 days from discharge definition, especially with regards to readmission related to major surgical complications. PMID- 26493977 TI - FTIR spectroscopy characterization of fatty-acyl-chain conjugates. AB - FTIR spectroscopy is used to identify poly-L-lysin fatty-acyl-chain (PLL-FAC) conjugates based on structural differences found between FAC species. Twenty-one PLL-FAC models were used, from C8 to C24, and with up to 5 unsaturation levels (C20:5). Curve fitting of the 3050-2800 cm(-1) spectral interval permitted extraction of IR bands belonging to the stretching vibration modes of methyl, methylene, and alkene groups. Based on molecular structure models in 3D, the number and position of methyl bands could be set according to chain length and unsaturation level. Band positions for nu-(C = C < H), nu(as)(CH3), and nu(as)(CH2) groups did not follow the maximum intensity shift of spectrum curve; it is the underlying band's intensity that is modifying maximum intensity of spectrum curve with respect to chain length and unsaturation level. We thus propose to use FTIR spectroscopy for the production monitoring and the quality control of PLL-FAC conjugates used as nutritional complements, and this should be extended to analysis of fatty acid compounds in general. PMID- 26493979 TI - E-Health--a topic for analytical chemists? PMID- 26493978 TI - Ion source-dependent performance of 4-vinylpyridine, iodoacetamide, and N-maleoyl derivatives for the detection of cysteine-containing peptides in complex proteomics. AB - Cysteine is unique among the proteinogenic amino acids due to its ability to form disulfide bonds. While this property is of vital importance for protein structures and biological processes, it causes difficulties for the mass spectrometric identification of cysteine-containing peptides. A common approach to overcome these problems in bottom-up proteomics is the reduction and covalent modification of sulfhydryl groups prior to enzymatic digestion. In this study, established alkylating agents and N-maleoyl amino acids with variable hydrophobicity were characterized with respect to a variety of relevant parameters and subsequently evaluated in a large-scale analysis using different ion sources. Depending on the compound, the ion source had a profound impact on the relative and absolute identification of cysteine-containing peptides. The best results were obtained by derivatization of the cysteine residues with 4 vinylpyridine and subsequent matrix-assisted laser desorption ionization (MALDI). Modification with 4-vinylpyridine increased the number of cysteine-containing peptides identified with any other compound using LC-MALDI/MS at least by a factor of 2. This experimental observation is mirrored by differences in the gas phase basicities, which were computed for methyl thiolate derivatives of the compounds using density functional theory. With electrospray ionization (ESI), complementary use of reagents from three different compound classes, e.g., iodoacetamide, 4-vinylpyridine, and N-maleoyl beta-alanine, was beneficial compared to the application of a single reagent. PMID- 26493980 TI - Functionalized electrospun poly(vinyl alcohol) nanofibers for on-chip concentration of E. coli cells. AB - Positively and negatively charged electrospun poly(vinyl alcohol) (PVA) nanofibers were incorporated into poly(methyl methacrylate) (PMMA) microchannels in order to facilitate on-chip concentration of Escherichia coli K12 cells. The effects of fiber distribution and fiber mat height on analyte retention were investigated. The 3D morphology of the mats was optimized to prevent size-related retention of the E. coli cells while also providing a large enough surface area for analyte concentration. Positively charged nanofibers produced an 87% retention and over 80-fold concentration of the bacterial cells by mere electrostatic interaction, while negatively charged nanofibers reduced nonspecific analyte retention when compared to an empty microfluidic channel. In order to take advantage of this reduction in nonspecific retention, these negatively charged nanofibers were then modified with anti-E. coli antibodies. These proof-of-principle experiments showed that antibody-functionalized negatively charged nanofiber mats were capable of the specific capture of 72% of the E. coli cells while also significantly reducing nonspecific analyte retention within the channel as expected. The ease of fabrication and immense surface area of the functionalized electrospun nanofibers make them a promising alternative for on-chip concentration of analytes. The pore size and fiber mat morphology, as well as surface functionality of the fibers, can be tailored to allow for specific capture and concentration of a wide range of analytes. PMID- 26493981 TI - Measurement of volatile plant compounds in field ambient air by thermal desorption-gas chromatography-mass spectrometry. AB - Determination of volatile plant compounds in field ambient air is important to understand chemical communication between plants and insects and will aid the development of semiochemicals from plants for pest control. In this study, a thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS) method was developed to measure ultra-trace levels of volatile plant compounds in field ambient air. The desorption parameters of TD, including sorbent tube material, tube desorption temperature, desorption time, and cold trap temperature, were selected and optimized. In GC-MS analysis, the selected ion monitoring mode was used for enhanced sensitivity and selectivity. This method was sufficiently sensitive to detect part-per-trillion levels of volatile plant compounds in field ambient air. Laboratory and field evaluation revealed that the method presented high precision and accuracy. Field studies indicated that the background odor of tea plantations contained some common volatile plant compounds, such as (Z)-3 hexenol, methyl salicylate, and (E)-ocimene, at concentrations ranging from 1 to 3400 ng m(-3). In addition, the background odor in summer was more abundant in quality and quantity than in autumn. Relative to previous methods, the TD-GC-MS method is more sensitive, permitting accurate qualitative and quantitative measurements of volatile plant compounds in field ambient air. PMID- 26493982 TI - Sex-dependent alterations of Ca2+ cycling in human cardiac hypertrophy and heart failure. AB - AIMS: Clinical studies have shown differences in the propensity for malignant ventricular arrhythmias between women and men suffering from cardiomyopathies and heart failure (HF). This is clinically relevant as it impacts therapies like prophylactic implantable cardioverter-defibrillator implantation but the pathomechanisms are unknown. As an increased sarcoplasmic reticulum (SR) Ca(2+) leak is arrhythmogenic, it could represent a cellular basis for this paradox. METHODS/RESULTS: We evaluated the SR Ca(2+) leak with respect to sex differences in (i) afterload-induced cardiac hypertrophy (Hy) with preserved left ventricular (LV) function and (ii) end-stage HF. Cardiac function did not differ between sexes in both cardiac pathologies. Human cardiomyocytes isolated from female patients with Hy showed a significantly lower Ca(2+) spark frequency (CaSpF, confocal microscopy, Fluo3-AM) compared with men (P < 0.05). As Ca(2+) spark width and duration were similar in women and men, this difference in CaSpF did not yet translate into a significant difference of the calculated SR Ca(2+) leak between both sexes at this stage of disease (P = 0.14). Epifluorescence measurements (Fura2-AM) revealed comparable Ca(2+) cycling properties (diastolic Ca(2+) levels, amplitude of systolic Ca(2+) transients, SR Ca(2+) load) in patients of both sexes suffering from Hy. Additionally, the increased diastolic CaSpF in male patients with Hy did not yet translate into an elevated ratio of cells showing arrhythmic events (Ca(2+) waves, spontaneous Ca(2+) transients) (P = 0.77). In the transition to HF, both sexes showed an increase of the CaSpF (P < 0.05) and the sex dependence was even more pronounced. Female patients had a 69 +/- 10% lower SR Ca(2+) leak (P < 0.05), which now even translated into a lower ratio of arrhythmic cells in female HF patients compared with men (P < 0.001). CONCLUSION: These data show that the SR Ca(2+) leak is lower in women than in men with comparable cardiac impairment. Since the SR Ca(2+) leak triggers delayed afterdepolarizations, our findings may explain why women are less prone to ventricular arrhythmias and confirm the rationale of therapeutic measures reducing the SR Ca(2+) leak. PMID- 26493983 TI - Exploring the link between maternal attachment-related anxiety and avoidance and mindful parenting: The mediating role of self-compassion. AB - OBJECTIVE: Mindful parenting has been described as a set of parental practices or skills that seek to enhance moment-to-moment awareness in the parent-child relationship. Although it has been suggested that adopting a mindful approach in parenting may foster positive parent-child relationships and promote the psychological functioning of children and parents, little is known about the factors that may be associated with this parental skill. In this study, we aimed to examine whether attachment-related anxiety and avoidance were associated with mindful parenting through self-compassion. DESIGN AND METHODS: The sample included 290 mothers of school-aged children and adolescents recruited in school settings, who completed self-reported measures of adult attachment (Experiences in Close Relationships - Relationships Structures), self-compassion (Self compassion Scale), and mindful parenting (Interpersonal Mindfulness in Parenting Scale). RESULTS: Structural equation modelling was used to test the proposed mediation model and to ascertain direct and indirect effects among study variables. Whereas attachment avoidance had a direct effect on mindful parenting, attachment anxiety was indirectly associated with mindful parenting through self compassion. Specifically, higher levels of anxiety were associated with lower self-compassion, which, in turn, was associated with lower levels of mindful parenting. Higher levels of avoidance were directly associated with lower levels of mindful parenting. CONCLUSIONS: These results demonstrate that mothers' attachment dimensions play an important role in their levels of mindful parenting, although through different pathways. Interventions aimed at promoting mindful parenting skills should attempt to promote parents' self-compassion and consider parents' levels of attachment insecurity. PRACTITIONER POINTS: The results underline the important role of mothers' attachment on levels of mindful parenting and evidence different pathways through which attachment anxiety and attachment avoidance are associated with this parental skill. Higher levels of attachment avoidance were directly associated with lower levels of mindful parenting, whereas higher levels of anxiety were indirectly associated with lower levels of mindful parenting through lower levels of self-compassion. Mothers who are more self-compassionate are more able to adopt a mindful stance in the parent child relationship. Parenting interventions aimed at promoting mindfulness skills in the parenting context can benefit from including self-compassionate exercises and are particularly important for insecurely attached parents. PMID- 26493984 TI - Indolent cytotoxic T cell lymphoproliferation associated with nodular regenerative hyperplasia: a common liver lesion in the context of common variable immunodeficiency disorder. AB - Patients with common variable immunodeficiency disorder (CVID) are subject to lymphoproliferative disorders and predisposed to lymphoma. Some patients may also develop liver lesions. The purpose of this study was to define clinical and histopathological features of patients with CVID presenting with liver lesions suspicious of lymphoma. Four CVID cases corresponding to these criteria were retrieved from our files. Liver biopsy specimens were subjected to morphologic, immunophenotypic and molecular analysis. All patients presented with hepatosplenomegaly and two furthermore with lymphadenopathy. The clinical working diagnosis in the four cases was lymphoma. All liver biopsies revealed nodular regenerative hyperplasia (NRH), associated with mild to marked sinusoid lymphocytic infiltrate consisting of "activated" cytotoxic T cells (CD8+, Tia1+, granzyme B+, TCRbetaF1+, CD56-). EBER was negative in all cases. T cell clonality was found in one of the two interpretable cases. All patients had an indolent course and clinical symptoms regressed with immunoglobulin replacement. This study suggests that indolent proliferation in the liver sinusoid of cytotoxic T cell associated with NRH is a specific liver lesion in the context of CVID. In CVID patients clinically suspected of lymphoma, pathologists should avoid a misdiagnosis of aggressive T cell lymphoma with a risk of over treatment. PMID- 26493985 TI - Free digital image analysis software helps to resolve equivocal scores in HER2 immunohistochemistry. AB - Evaluation of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) is subject to interobserver variation and lack of reproducibility. Digital image analysis (DIA) has been shown to improve the consistency and accuracy of the evaluation and its use is encouraged in current testing guidelines. We studied whether digital image analysis using a free software application (ImmunoMembrane) can assist in interpreting HER2 IHC in equivocal 2+ cases. We also compared digital photomicrographs with whole-slide images (WSI) as material for ImmunoMembrane DIA. We stained 750 surgical resection specimens of invasive breast cancers immunohistochemically for HER2 and analysed staining with ImmunoMembrane. The ImmunoMembrane DIA scores were compared with the originally responsible pathologists' visual scores, a researcher's visual scores and in situ hybridisation (ISH) results. The originally responsible pathologists reported 9.1 % positive 3+ IHC scores, for the researcher this was 8.4 % and for ImmunoMembrane 9.5 %. Equivocal 2+ scores were 34 % for the pathologists, 43.7 % for the researcher and 10.1 % for ImmunoMembrane. Negative 0/1+ scores were 57.6 % for the pathologists, 46.8 % for the researcher and 80.8 % for ImmunoMembrane. There were six false positive cases, which were classified as 3+ by ImmunoMembrane and negative by ISH. Six cases were false negative defined as 0/1+ by IHC and positive by ISH. ImmunoMembrane DIA using digital photomicrographs and WSI showed almost perfect agreement. In conclusion, digital image analysis by ImmunoMembrane can help to resolve a majority of equivocal 2+ cases in HER2 IHC, which reduces the need for ISH testing. PMID- 26493986 TI - A radial artery originating from the thoracoacromial artery. AB - PURPOSE: The purpose of this case report is to report a rare vascular variation in the upper limbs because of its clinical importance and embryological implication. METHODS: During the educational dissection of a 73-year-old Korean male cadaver's right upper limb, we found a variant branch which is originated from the thoracoacromial artery. RESULTS: The variant branch from the thoracoacromial artery ran to the distal forearm in the deep fascia. Because it finally coursed like the radial artery in the forearm and the palm, we defined the variant artery as superficial brachioradial artery (SBRA). In the cubital region a little below the intercondylar line, the brachial artery gave off a small communicating branch to SBRA, and continued as the ulnar artery. CONCLUSIONS: We reported this unique variation and discussed its clinical and embryological implication. PMID- 26493987 TI - Weaker Functional Pinch Strength Is Associated With Early Thumb Carpometacarpal Osteoarthritis. AB - BACKGROUND: The thumb carpometacarpal (CMC) joint orchestrates pinch in its various positions, and thumb CMC osteoarthritis (OA) is a major source of orthopaedic morbidity. Self-reported pain, weakness, and physical examination may not correspond to radiographic findings when diagnosing early thumb CMC OA. Weakness is a prominent feature of the disease, but little evidence exists to quantify self-reported loss of strength with time, or to compare weakness with that of a nonarthritic population during early disease. QUESTIONS/PURPOSES: We asked: (1) Is pinch strength in subjects with early thumb CMC OA less than that in asymptomatic control subjects; and (2) weakness in which pinch position (key, tripod, or tip pinch) has the strongest association with early OA diagnosis? METHODS: For this case-control study, we recruited 23 subjects who were asymptomatic and 91 with early OA for comprehensive history, physical examination, strength measurements, pain surveys, and radiographic evaluation. We used multivariate logistic regression to quantify the association between declining pinch strength and early OA diagnosis after controlling for age, sex, and BMI. This analysis was performed for three different pinch positions (key, tripod, and tip pinch) to evaluate which measurement was most closely associated with diagnosis. RESULTS: Pinch strength was less in patients with early thumb CMC OA. Key pinch had the most robust association with OA diagnosis, in which a 20% decrease in key pinch strength from the control subjects' baseline was associated with a 10% increase in the OA diagnosis (95% CI, 3%-16%; p = 0.004). This had a stronger association with OA diagnosis than tip pinch, in which a 20% decrease in strength was associated with a 6% increase in early CMC OA (95% CI, 1.0%-11%; p = 0.031). Tripod pinch also was associated to a lesser extent; a 20% reduction in tripod pinch led to a 5% increase in OA (95% CI, 1.3%-9%; p = 0.048). CONCLUSIONS: Decreasing pinch strength, especially key pinch, is associated with early CMC arthritis before the development of extensive radiographic disease. CLINICAL RELEVANCE: Weakness in pinch strength, especially key pinch, is an important feature in the pathogenesis of early CMC OA and may appear before radiographic disease is present or advanced. These findings suggest a role for intervention in early disease for promoting nonoperative joint protection and strengthening, and designing surgical procedures aimed to delay or prevent clinical and radiographic progression. PMID- 26493988 TI - CORR Insights((r)): A Randomized Trial Among Compression Plus Nonsteroidal Antiinflammatory Drugs, Aspiration, and Aspiration With Steroid Injection for Nonseptic Olecranon Bursitis. PMID- 26493990 TI - Inflammasomes in COPD and neutrophilic asthma. PMID- 26493991 TI - Dissipation, terminal residues and risk assessment of fluopicolide and its metabolite in cucumber under field conditions. AB - In this study, the dissipation, terminal residue levels, and risk assessment of fluopicolide and its metabolite (2,6-dichlorobenzamide) in cucumber and soil under field conditions were investigated. An analytical method for the simultaneous quantification of fluopicolide and its metabolite in cucumber and soil using gas chromatography coupled with electron capture detection (GC-ECD) was developed. Recoveries were between 78 and 111%, with relative standard deviations (RSDs) from 1.6 to 10.2% at different spiked levels (0.01, 0.025, 0.5, and 2 mg kg(-1)). The limit of quantification (LOQ) was 0.01 mg kg(-1). Fluopicolide exhibited half-lives ranging from 2.0 to 3.3 days and 35 to 63 days, in cucumber and soil under field ecosystem, respectively. The results suggested that the degradation of fluopicolide to 2,6-dichlorobenzamide was quite limited. During harvest, the terminal residues of fluopicolide and its metabolite were both below 0.13 mg kg(-1), which were lower than the established temporary maximum residue limits (MRLs), 0.5 mg kg(-1). The risk quotients (RQs) ranged from 0.0033 to 0.0078, which showed low risk for different groups of people in China. The present study may provide guidance on reasonable use of this pesticide and serve as a reference for establishment official MRLs in China. PMID- 26493989 TI - Effect of isoniazid preventive therapy on immune responses to mycobacterium tuberculosis: an open label randomised, controlled, exploratory study. AB - BACKGROUND: With the renewed emphasis to implement isoniazid preventive therapy (IPT) in Sub-Saharan Africa, we investigated the effect of IPT on immunological profiles among household contacts with latent tuberculosis. METHODS: Household contacts of confirmed tuberculosis patients were tested for latent tuberculosis using the QuantiFERON(r)-TB Gold In-Tube (QFN) assay and tuberculin skin test (TST). HIV negative contacts aged above 5 years, positive to both QFN and TST, were randomly assigned to IPT and monthly visits or monthly visits only. QFN culture supernatants from enrolment and six months' follow-up were analysed for M.tb-specific Th1, Th2, Th17, and regulatory cytokines by Luminex assay, and for M.tb-specific IgG antibody concentrations by ELISA. Effects of IPT were assessed as the net cytokine and antibody production at the end of six months. RESULTS: Sixteen percent of contacts investigated (47/291) were randomised to IPT (n = 24) or no IPT (n = 23). After adjusting for baseline cytokine or antibody responses, and for presence of a BCG scar, IPT (compared to no IPT) resulted in a relative decline in M.tb-specific production of IFN gamma (adjusted mean difference at the end of six months (bootstrap 95% confidence interval (CI), p-value) -1488.6 pg/ml ((-2682.5, -294.8), p = 0.01), and IL- 2 (-213.1 pg/ml (-419.2, -7.0), p = 0.04). A similar decline was found in anti-CFP-10 antibody levels (adjusted geometric mean ratio (bootstrap 95% CI), p-value) 0.58 ((0.35, 0.98), p = 0.04). We found no effect on M.tb-specific Th2 or regulatory or Th17 cytokine responses, or on antibody concentrations to PPD and ESAT-6. CONCLUSIONS: IPT led to a decrease in Th1 cytokine production, and also in the anti CFP-10 antibody concentration. This could be secondary to a reduction in mycobacterial burden or as a possible direct effect of isoniazid induced T cell apoptosis, and may have implications for protective immunity following IPT in tuberculosis-endemic countries. TRIAL REGISTRATION: ISRCTN registry, ISRCTN15705625. Registered on 30(th) September 2015. PMID- 26493992 TI - Accuracy of dose calculation algorithms for virtual heterogeneous phantoms and intensity-modulated radiation therapy in the head and neck. AB - This study verified the dose calculation accuracy of the analytical anisotropic algorithm (AAA), Acuros XB version 10 (AXB10), and version 11 (AXB11) installed in an Eclipse treatment planning system, by comparing with Monte Carlo (MC) simulations. First, the algorithms were compared in terms of dose distributions using four types of virtual heterogeneous multi-layer phantom for 6 and 15 MV photons. Next, the clinical head and neck intensity-modulated radiation therapy (IMRT) dose distributions for 6 MV photons were evaluated using dose volume histograms (DVHs) and three-dimensional gamma analysis. In percentage depth doses (PDDs) for virtual heterogeneous phantoms, AAA overestimated absorbed doses in the air cavity, bone, and aluminum in comparison with MC, AXB10, and AXB11. The PDDs of AXB10 almost agreed with those of MC and AXB11, except for the air cavity. The dose in the air cavity was higher for AXB10 than for AXB11, because their electron cutoff energies are set at 500 and 200 keV, respectively. For head and neck IMRT dose distributions, the D95 in the clinical target volume (CTV) for AAA was almost the same as that for AXB10 and was approximately 7 % larger than that for MC. Comparing each approach with MC using a criterion of 3 %/3 mm, the pass rates for AXB10, AXB11, and AAA were 92.4, 94.7, and 90.4 % in the CTV, respectively. In conclusion, AAA produces dose errors in heterogeneous regions, while AXB11 provides calculation accuracy comparable to MC. AXB10 overestimates the dose in regions that include an air cavity. PMID- 26493994 TI - PKM2 promotes stemness of breast cancer cell by through Wnt/beta-catenin pathway. AB - Metastasis is one of the main causes of breast cancer (BCa)-related deaths in female. It has been reported that cancer stem cell played an important role in metastasis. Here we first revealed a specific role of pyruvate kinase isozymes M2 (PKM2) in the stemness of breast cancer cells. Breast cancer tissue analysis confirmed the upregulation of PKM2 in breast cancer, and high PKM2 levels were associated with poor prognosis of breast cancer patients. Holoclone assay and colony formation assay significantly elucidated the role of PKM2 in the self renewal of breast cancer cells. Moreover, PKM2 elevated the proportion of stem cell and the ability of sphere formation in breast cancer cells. PKM2 played its functional role in stemness by regulating beta-catenin. Collectively, we identified critical roles of PKM2 in the stemness of breast cancer cells which may elevate the therapeutic effect on breast cancer patients. PMID- 26493993 TI - A genetic framework for H2O2 induced cell death in Arabidopsis thaliana. AB - BACKGROUND: To survive in a changing environment plants constantly monitor their surroundings. In response to several stresses and during photorespiration plants use reactive oxygen species as signaling molecules. The Arabidopsis thaliana catalase2 (cat2) mutant lacks a peroxisomal catalase and under photorespiratory conditions accumulates H2O2, which leads to activation of cell death. METHODS: A cat2 double mutant collection was generated through crossing and scored for cell death in different assays. Selected double mutants were further analyzed for photosynthetic performance and H2O2 accumulation. RESULTS: We used a targeted mutant analysis with more than 50 cat2 double mutants to investigate the role of stress hormones and other defense regulators in H2O2-mediated cell death. Several transcription factors (AS1, MYB30, MYC2, WRKY70), cell death regulators (RCD1, DND1) and hormone regulators (AXR1, ERA1, SID2, EDS1, SGT1b) were essential for execution of cell death in cat2. Genetic loci required for cell death in cat2 was compared with regulators of cell death in spontaneous lesion mimic mutants and led to the identification of a core set of plant cell death regulators. Analysis of gene expression data from cat2 and plants undergoing cell death revealed similar gene expression profiles, further supporting the existence of a common program for regulation of plant cell death. CONCLUSIONS: Our results provide a genetic framework for further study on the role of H2O2 in regulation of cell death. The hormones salicylic acid, jasmonic acid and auxin, as well as their interaction, are crucial determinants of cell death regulation. PMID- 26493995 TI - The role of astrocytes in the progression of brain cancer: complicating the picture of the tumor microenvironment. AB - Gliomas and brain-metastatic tumors contribute to hundreds of thousands of deaths every year. Typical survival times for brain cancer patients, even with surgical, chemotherapy, and radiation treatment, remain very low despite advances in treatment. In brain cancers, astrocytes, which comprise approximately 50 % of the cells in the brain, become activated, resulting in a layer of reactive astrocytes surrounding the tumor. This process of reactive gliosis, which involves the secretion of growth factors and cytokines, helps repair injury in the brain, but also plays a role in disease progression. In this review, we survey the mechanisms by which astrocytes modulate the local tumor microenvironment, enhancing proliferation, invasion, chemoprotection, and immunoprotection of tumor cells. Consideration of the effect of astrocytes and reactive gliosis in in vitro and in vivo assays may allow us to obtain a more complete picture of the interactions occurring at the tumor microenvironment, which will provide additional insight into potential pathways that can be targeted by brain cancer therapeutics. PMID- 26493997 TI - Upregulation of MALAT-1 and its association with survival rate and the effect on cell cycle and migration in patients with esophageal squamous cell carcinoma. AB - The aim of this study is to investigate whether metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) can be used as a potential therapy target for human esophageal squamous cell carcinoma. MALAT-1 expression levels were detected in 137 paired EC samples and adjacent nonneoplastic tissues. Human esophageal carcinoma cell lines EC9706 and KYSE150 were transfected with MALAT-1 small interference RNA. Cell proliferation, migration/invasion ability, cell cycle, and apoptosis were assessed. MALAT-1 expressed higher levels in esophageal cancer tissues when compared with paired adjacent normal tissues. This high expression was associated with a decreased survival rate. MALAT-1 knockdown induced a decrease in proliferation-enhanced apoptosis, inhibited migration/invasion, and reduced colony formation and led to cell cycle arrest at the G2/M phase. These data indicates that MALAT-1 could be exploited for therapeutic benefit. PMID- 26493996 TI - Glucose-regulated protein 94 mediates cancer progression via AKT and eNOS in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a crucial health issue worldwide. High glucose regulated protein 94 (GRP94) expression has been observed in different types of cancer, suggesting a link between tumor progression and GRP94 expression. However, the mechanisms underlying the role of GRP94 in HCC progression remain unclear. We used specific small hairpin RNA (shRNA) to manipulate GRP94 expression in HCC cells. Tissue arrays, MTT assays, xCELLigence assays, and in vivo xenograft model were performed to identify clinicopathological correlations and to analyze cell growth. We found that high GRP94 expression reflected a poor response and a lower survival rate. In vitro and in vivo studies showed that silencing GRP94 suppressed cancer progression. Mechanistically, GRP94 knockdown reduced AKT, phospho-AKT, and eNOS levels but did not influence the AMPK pathway. Our results demonstrated that GRP94 is a key molecule in HCC progression that modulates the AKT pathway and eNOS levels. Our findings suggest that GRP94 may be a new prognostic and therapeutic target for HCC. PMID- 26493998 TI - FGF2-mediated reciprocal tumor cell-endothelial cell interplay contributes to the growth of chemoresistant cells: a potential mechanism for superficial bladder cancer recurrence. AB - Patients with superficial bladder cancer can be definitively cured by one single transurethral resection (TUR) with additional intravesical chemotherapy; however, up to 75 % of cases display frequent and multiple recurrences. One of the major causes of recurrence is that chemotherapeutic drugs used in intravesical regimens may induce chemoresistance. However, the mechanisms by which these chemoresistant cells develop into recurrent tumors remain unclear. Recent clinical evidence revealed that the expression of pro-angiogenic factor FGF2 was associated with early local relapse in patients with superficial bladder cancer. In this study, we conducted a preliminary investigation of the mechanisms of chemoresistant cells mediated bladder cancer recurrence, focusing on FGF2-initiated tumor cell endothelial cell interaction on chemoresistant cancer cell growth. We found that the expression of FGF2 was increased in chemoresistant bladder cell lines and in bladder tissues after intravesical chemotherapy. Although chemoresistant bladder cells grow slower than parental cells, chemoresistant bladder cancer cells had stronger ability than parental cells to stimulate endothelial cell migration, growth, and tube formation by producing FGF2. Inversely, endothelial cells significantly promoted chemoresistant bladder cancer growth in vitro and in vivo. Thus, targeting chemotherapy-induced FGF2 upregulation may provide a promising approach to manage the recurrence of superficial bladder cancer. PMID- 26493999 TI - SAHA, an HDAC inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by modulating E-cadherin. AB - Pancreatic cancer is one of the most lethal cancers and remains a major unsolved health problem. Less than 20 % of patients are surgical candidates, and the median survival for non-resected patients is approximately 3 to 4 months. Despite the existence of many conventional cancer therapies, few targeted therapies have been developed for pancreatic cancer. Combination therapy using erlotinib and gemcitabine is an approved standard chemotherapy for advanced pancreatic cancer, but it has marginal therapeutic benefit. To try to improve the therapeutic outlook, we studied the efficacy of another combination treatment and the relevance to E-cadherin in human pancreatic cancer cells. We treated two human pancreatic cancer cell lines with the histone deacetylase inhibitor (HDACi) SAHA. Interestingly, in these Panc-1 and Capan1 cells, we observed that the expression levels of E-cadherin and phosphorylated EGFR were gradually upregulated after treatment with SAHA. Furthermore, these cells underwent induced cell death after exposure to the combination treatment of SAHA and erlotinib. In Panc-1 cells, overexpression of E-cadherin activated the phosphorylation of EGFR and increased the cell sensitivity to erlotinib. In Capan1 cells, knocking down E-cadherin decreased the expression of phosphorylated EGFR, and these cells did not respond to erlotinib. Therefore, we demonstrated the efficacy of the combined treatment with SAHA and erlotinib in human pancreatic cancer cells, and we determined that the increased efficacy was due, at least in part, to the effects of SAHA on the expression of E-cadherin. Our studies suggest that E-cadherin may be a potent biomarker for pancreatic cancer. PMID- 26494001 TI - Molecular behavior of human Mrt4 protein, MRTO4, in stress conditions is regulated by its C-terminal region. AB - Protein Mrt4 is one of trans-acting factors involved in ribosome biogenesis, which in higher eukaryotic cells contains a C-terminal extension similar to the C terminal part of ribosomal P proteins. We show that human Mrt4 (hMrt4/MRTO4) undergoes phosphorylation in vivo and that serines S229, S233, and S235, placed within its acidic C-termini, have been phosphorylated by CK2 kinase in vitro. Such modification does not alter the subcellular distribution of hMrt4 in standard conditions but affects its molecular behavior during ActD induced nucleolar stress. Thus, we propose a new regulatory element important for the stress response pathway connecting ribosome biogenesis with cellular metabolism. PMID- 26494000 TI - miR-186 downregulates protein phosphatase PPM1B in bladder cancer and mediates G1 S phase transition. AB - Nuclear factor-kappaB (NF-kappaB) is a core regulator in multiple tumorigenic pathways. Its activation is mediated by IkappaB kinase beta (IKKbeta). Protein phosphatase PPM1B is reported to dephosphorylate IKKbeta, thereby terminating IKKbeta-mediated NF-kappaB activation. However, the role of PPM1B in bladder cancer is unclear. The aim of this study was to determine the expression patterns and molecular mechanisms of PPM1B in bladder cancer. Comparative analyses were conducted in six bladder cancer cell lines, a normal urinary epithelial cell line, and adjacent non-tumorous bladder epithelia. Searches were conducted through publicly available algorithms and The Cancer Genome Atlas. HT-1376 and RT4 cells were transduced to stably overexpress PPM1B and its predicted regulator miR-186. Subsequent in vitro studies included 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2H-tetrazolium bromide (MTT), colony formation, anchorage-independent growth ability, luciferase reporter assays, and flow cytometric cell cycle analyses. A xenograft model was established in nude mice to evaluate the effect of PPM1B in bladder tumors in vivo. The results revealed that PPM1B was frequently downregulated in bladder cancer cells at both protein and messenger RNA (mRNA) levels, whereas miR-186 was upregulated. Further analyses showed that miR-186 promoted G1-S transition by targeting PPM1B at its 3'-untranslated region (3'UTR). Conversely, ectopic expression of PPM1B significantly suppressed proliferation and tumorigenicity in bladder cancer cells in vitro and in vivo, thereby neutralizing the oncogenic effect of miR-186. This study has identified PPM1B and miR-186 as potential diagnostic markers in bladder cancer. Promotion of PPM1B and suppression of miR-186 may offer effective therapeutic strategies in the treatment of bladder cancer. PMID- 26494002 TI - Apelin induces vascular smooth muscle cells migration via a PI3K/Akt/FoxO3a/MMP-2 pathway. AB - Apelin is an adipokine that has a critical role in the development of atherosclerosis, which may offer potential for therapy. Because migration of vascular smooth muscle cells (VSMCs) is a key event in the development of atherosclerosis, understanding its effect on the atherosclerotic vasculature is needed. Here we investigated the effect of apelin on VSMC migration and the possible signaling mechanism. In cultured rat VSMCs, apelin dose- and time dependently promoted VSMC migration. Apelin increased the phosphorylation of Akt, whereas LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), and an Akt1/2 kinase inhibitor blocked the apelin-induced VSMC migration. Apelin dose dependently induced phosphorylation of Forkhead box O3a (FoxO3a) and promoted its translocation from the nucleus to cytoplasm, which were blocked by LY294002 and Akt1/2 kinase inhibitor. Furthermore, apelin increased matrix metalloproteinase 2 (MMP-2) expression and gelatinolytic activity. Overexpression of a constitutively active, phosphorylation-resistant mutant, TM-FoxO3a, in VSMCs abrogated the effect of apelin on MMP-2 expression and VSMC migration. ARP101, an inhibitor of MMP-2, suppressed apelin-induced VSMC migration. Moreover, the levels of apelin, phosphorylated Akt, FoxO3a, and MMP-2 were higher in human carotid-artery atherosclerotic plaque than in adjacent normal vessels. We demonstrate that PI3K/Akt/FoxO3a signaling may be involved in apelin inducing VSMC migration. Phosphorylation of FoxO3a plays a central role in mediating the apelin-induced MMP-2 activation and VSMC migration. PMID- 26494003 TI - Epigenetic-based therapy: From single- to multi-target approaches. AB - The treatment of cancer has traditionally been based on the identification of a single molecule and/or enzymatic function (target) responsible for a particular phenotype, and therefore on the ability to stimulate, attenuate or inhibit its activity through the use of selective compounds. However, cancer is no longer considered a disease caused by a single factor, but is now recognized as a multi factorial disorder. Genetic, epigenetic and metabolic factors all contribute to neoplasia, causing significant changes in molecular networks that govern cell growth, development, death and specialization. Consequently, many antitumor therapies are no longer directed against a single target but the biological system as a whole, in which functions determining the onset and maintenance of a physio-pathological state are modulated. The field of epi-drug discovery is currently in a transitional phase where the search for putative anticancer drugs is shifting from single-target-oriented molecules to network-active compounds and to epi-drugs used in combination with other epi-agents and with traditional chemotherapeutics. This review illustrates the pros and cons of each therapeutic option, providing examples in support of single-target and multi (network)-target epi-drug approaches. PMID- 26494004 TI - Strong cytoplasmic expression of NF-kappaB/p65 correlates with a good prognosis in patients with triple-negative breast cancer. AB - PURPOSE: Recent studies have indicated that constitutive NF-kappaB activity could be involved in the proliferation of triple-negative breast cancer. METHODS: The NF-kappaB/p65 expression and the effects of a NF-kappaB inhibitor, (-)-DHMEQ, were examined in triple-negative MDA-MB-231 breast cancer cells. Women with triple-negative breast cancer treated with neoadjuvant chemotherapy between 2002 and 2012 were retrospectively analyzed for their expression of NF-kappaB/p65, Bcl2 and Ki67 by immunohistochemistry in pre- and post-treatment specimens. The factors predicting the response to neoadjuvant chemotherapy and the prognosis were analyzed. RESULTS: NF-kappaB/p65 was predominantly expressed in the cytoplasm of MDA-MB-231 cells. Of 34 triple-negative breast cancer patients, positive staining for NF-kappaB/p65 expression was detected in the nuclei of a few cells in seven tumors before neoadjuvant chemotherapy, while the expression of NF-kappaB/p65 in the cytoplasm was detected in almost all tumor cells of 33 tumors. The expression levels of NF-kappaB/p65 were not associated with the response to neoadjuvant chemotherapy, although the cytoplasmic NF-kappaB/p65 staining intensity was significantly decreased in the post-treatment tumor samples compared with the pretreatment samples. All patients whose tumors showed strong cytoplasmic NF-kappaB/p65 expression before neoadjuvant chemotherapy are currently disease free. CONCLUSION: Our results suggest that strong cytoplasmic NF-kappaB/p65 expression could be a prognostic marker for patients with triple negative breast cancer. PMID- 26494005 TI - The feasibility of laparoscopic extended pelvic surgery for rectal cancer. AB - PURPOSE: The present study aimed to assess the safety and feasibility of laparoscopic extended pelvic surgery for primary or recurrent rectal cancer. METHODS: The data on 77 patients, who underwent extended pelvic surgery between February 2008 and June 2014, were retrospectively analyzed. The patients were divided, based on their treatment history, into an open surgery (OS) group (n = 41) and a laparoscopic surgery (LS) group (n = 36). RESULTS: The operative time in the LS group was significantly longer than that in the OS group (766 vs. 561 min; p < 0.001). In contrast, the LS group was associated with a significantly lower volume of intraoperative blood loss (195 vs. 923 ml; p < 0.001), fluid balance (5.38 vs. 8.23 ml/kg/h; p < 0.001) and rate of complications (40.0 vs. 68.3 %; p = 0.035), and a significantly shorter postoperative hospital stay. The postoperative levels of colloid osmotic pressure and albumin were significantly higher in the LS group. CONCLUSION: The operative time of the LS group was longer than that of the OS group; however, the LS group experienced less blood loss and fewer complications. Moreover, LS was associated with a reduction in intraoperative infusions and a reduced fluid balance, which maintained homeostasis. PMID- 26494006 TI - Mortality-related resource utilization in the inpatient care of hypoplastic left heart syndrome. AB - BACKGROUND: Quantifying resource utilization in the inpatient care of congenital heart diease is clinically relevant. Our purpose is to measure the investment of inpatient care resources to achieve survival in hypoplastic left heart syndrome (HLHS), and to determine how much of that investment occurs in hospitalizations that have a fatal outcome, the mortality-related resource utilization fraction (MRRUF). METHODS: A collaborative administrative database, the Pediatric Health Information System (PHIS) containing data for 43 children's hospitals, was queried by primary diagnosis for HLHS admissions of patients <=21 years old during 2004-2013. Institution, patient age, inpatient deaths, billed charges (BC) and length of stay (LOS) were recorded. RESULTS: In all, 11,122 HLHS admissions were identified which account for total LOS of 277,027 inpatient-days and $3,928,794,660 in BC. There were 1145 inpatient deaths (10.3%). LOS was greater among inpatient deaths than among patients discharged alive (median 17 vs. 12, p < 0.0001). BC were greater among inpatient deaths than among patients discharged alive (median 4.09 * 10(5) vs. 1.63 * 10(5), p < 0.0001). 16% of all LOS and 21% of all BC were accrued by patients who did not survive their hospitalization. These proportions showed no significant change year-by-year. The highest volume institutions had lower mortality rates, but there was no relation between institutional volume and the MRRUF. CONCLUSIONS: These data should alert providers and consumers that current practices often result in major resource expenditure for inpatient care of HLHS that does not result in survival to hospital dismissal. They highlight the need for data-driven critical review of standard practices to identify patterns of care associated with success, and to modify approaches objectively. PMID- 26494008 TI - Message From the Chairperson: Focus on Professional Involvement. PMID- 26494007 TI - Molecular study on the carAB operon reveals that carB gene is required for swimming and biofilm formation in Xanthomonas citri subsp. citri. AB - BACKGROUND: The carA and carB genes code the small and large subunits of carbamoyl-phosphate synthase (CPS) that responsible for arginine and pyrimidine production. The purpose of this work was to study the gene organization and expression pattern of carAB operon, and the biological functions of carA and carB genes in Xanthomonas citri subsp. citri. METHODS: RT-PCR method was employed to identify the full length of carAB operon transcript in X. citri subsp. citri. The promoter of carAB operon was predicted and analyzed its activity by fusing a GUS reporter gene. The swimming motility was tested on 0.25% agar NY plates with 1% glucose. Biofilm was measured by cell adhesion to polyvinyl chloride 96-well plate. RESULTS: The results indicated that carAB operon was composed of five gene members carA-orf-carB-greA-rpfE. A single promoter was predicted from the nucleotide sequence upstream of carAB operon, and its sensitivity to glutamic acid, uracil and arginine was confirmed by fusing a GUS reporter gene. Deletion mutagenesis of carB gene resulted in reduced abilities in swimming on soft solid media and in forming biofilm on polystyrene microtiter plates. CONCLUSIONS: From these results, we concluded that carAB operon was involved in multiple biological processes in X. citri subsp. citri. PMID- 26494009 TI - Advance Care Planning: The Dietitian's Role (Part 2). PMID- 26494010 TI - Applying systematic review search methods to the grey literature: a case study examining guidelines for school-based breakfast programs in Canada. AB - BACKGROUND: Grey literature is an important source of information for large-scale review syntheses. However, there are many characteristics of grey literature that make it difficult to search systematically. Further, there is no 'gold standard' for rigorous systematic grey literature search methods and few resources on how to conduct this type of search. This paper describes systematic review search methods that were developed and applied to complete a case study systematic review of grey literature that examined guidelines for school-based breakfast programs in Canada. METHODS: A grey literature search plan was developed to incorporate four different searching strategies: (1) grey literature databases, (2) customized Google search engines, (3) targeted websites, and (4) consultation with contact experts. These complementary strategies were used to minimize the risk of omitting relevant sources. Since abstracts are often unavailable in grey literature documents, items' abstracts, executive summaries, or table of contents (whichever was available) were screened. Screening of publications' full-text followed. Data were extracted on the organization, year published, who they were developed by, intended audience, goal/objectives of document, sources of evidence/resources cited, meals mentioned in the guidelines, and recommendations for program delivery. RESULTS: The search strategies for identifying and screening publications for inclusion in the case study review was found to be manageable, comprehensive, and intuitive when applied in practice. The four search strategies of the grey literature search plan yielded 302 potentially relevant items for screening. Following the screening process, 15 publications that met all eligibility criteria remained and were included in the case study systematic review. The high-level findings of the case study systematic review are briefly described. CONCLUSIONS: This article demonstrated a feasible and seemingly robust method for applying systematic search strategies to identify web based resources in the grey literature. The search strategy we developed and tested is amenable to adaptation to identify other types of grey literature from other disciplines and answering a wide range of research questions. This method should be further adapted and tested in future research syntheses. PMID- 26494011 TI - Photodynamic therapy of human lung cancer xenografts in mice. AB - BACKGROUND: There is a need to develop novel therapies for non-small cell lung cancer (NSCLC). Photodynamic therapy has been used successfully for endobronchial palliation of NSCLC, and its role in early stages of disease is being explored. We hypothesized that a novel photosensitizer, PS1, would be more effective than the standard agent, porfimer sodium (Photofrin or PFII), in treating human lung cancer xenografts in mice. MATERIALS AND METHODS: Patient-derived NSCLC xenografts were established subcutaneously in severe combined immune deficiency mice. Two groups of five mice were injected with PS1 (3-[1'-m-iodobenzyloxy]ethyl 3-devinylpyropheophorbide-a), a chlorophyll-a derivative, or PFII (a purified version of hematoporphyrin derivative) and then treated with nonthermal laser light. Four mice were treated with laser light without photosensitizer and six mice received no treatment at all. All mice were then observed for tumor growth. The tumor growth end point, time-to-1000 mm(3), was evaluated using standard Kaplan-Meier methods and the log-rank test. Tumor hematoxylin and eosin and caspase 3 staining was done to evaluate necrosis and apoptosis. RESULTS: The median time-to-1000 mm(3) was 12, 12, 26, and 52 d for the control, light only, PFII, and PS1 groups. There was a significant association between the tumor growth end point and treatment (P < 0.05). Hematoxylin and eosin staining revealed <1%, 0%, 67%, and 80% necrosis, and caspase 3 positivity was 2%, <1%, 17%, and 39%, respectively, in the same four groups. CONCLUSIONS: The mice treated with PS1 exhibited a longer time for tumor regrowth and showed more tumor necrosis and apoptosis compared with the other treatment groups. Thus, the novel photosensitizer, PS1, was demonstrated to be more effective than porfimer sodium in this preclinical pilot study. PMID- 26494012 TI - Timing of death after traumatic injury--a contemporary assessment of the temporal distribution of death. AB - BACKGROUND: The trimodal distribution of traumatic death was first described by Trunkey in 1983, which demonstrated that most deaths occur in the first 24 h. We postulate that since 1983, the time-to-death histogram described has shifted. METHODS: A retrospective analysis identifying timing of death was conducted on the National Trauma Data Bank (version 7.2) from 2002 to 2006. Early death was defined as death within 24 h of admission. International Classification of Diseases ninth edition codes with greater than 20% early deaths were called "high risk codes". Bivariate analyses were conducted to assess the association between demographics, injury factors, and death. Pearson's chi(2) test was used to compare timing of death by region of injury. Multivariate logistic regression was conducted to show the effect of region of injury on death while controlling for demographic factors and injury type. RESULTS: The cohort includes 898,982 patients. The study population was predominantly male (66%) and Caucasian (62%). Mean age and injury severity score were 45 +/- 20.3 and 11 +/- 10, respectively. Overall mortality rate was 5% with 56% dying early. Head/neck, thorax, and abdomen/pelvis injuries were more prevalent in overall deaths (35%, 22%, and 11%, respectively). Thorax and abdomen/pelvis injuries predicted early death (odds ratio 2.03 and 1.39, respectively). CONCLUSIONS: The prevalence of early death has decreased since 1983, but the majority of deaths still occur within 24 h of injury. Ample opportunity remains to impact mortality in the first 24 h after injury. PMID- 26494013 TI - A single nucleotide change in a core promoter is involved in the progressive overexpression of the duplicated CYP9M10 haplotype lineage in Culex quinquefasciatus. AB - Although the importance of cis-acting mutations on detoxification enzyme genes for insecticide resistance is widely accepted, only a few of them have been determined as concrete mutations present in genomic DNA till date. The overexpression of a cytochrome P450 gene, CYP9M10, is associated with pyrethroid resistance in the southern house mosquito Culex quinquefasciatus. The haplotypes of CYP9M10 exhibiting overexpression (resistant haplotypes) belong to one specific phylogenetic lineage that shares high nucleotide sequence homology and the same insertion of a transposable element. Among the resistant haplotypes, allelic progression involving an additional cis-acting mutation and gene duplication evolved a CYP9M10 haplotype associated with extremely high transcription and strong pyrethroid resistance. Here we show that a single nucleotide substitution G-27A, which is located near the transcription start site of CYP9M10, is involved in the progression of the duplicated haplotype lineage. The deletion of a 7-bp AT-rich sequence that includes nucleotide -27 inhibited the initiation of transcription from the original transcriptional initiation site. The mutation was suspected to reside within a core promoter, TATA-box, of CYP9M10. PMID- 26494014 TI - Odorant receptor-based discovery of natural repellents of human lice. AB - The body louse, Pediculus humanus humanus, is an obligate blood-feeding ectoparasite and an important insect vector that mediates the transmission of diseases to humans. The analysis of the body louse genome revealed a drastic reduction of the chemosensory gene repertoires when compared to other insects, suggesting specific olfactory adaptations to host specialization and permanent parasitic lifestyle. Here, we present for the first time functional evidence for the role of odorant receptors (ORs) in this insect, with the objective to gain insight into the chemical ecology of this vector. We identified seven putative full-length ORs, in addition to the odorant receptor co-receptor (Orco), and expressed four of them in the Xenopus laevis oocytes system. When screened with a panel of ecologically-relevant odorants, PhumOR2 responded to a narrow set of compounds. At the behavior level, both head and body lice were repelled by the physiologically-active chemicals. This study presents the first evidence of the OR pathway being functional in lice and identifies PhumOR2 as a sensitive receptor of natural repellents that could be used to develop novel efficient molecules to control these insects. PMID- 26494015 TI - An evaluation of China's new rural cooperative medical system: achievements and inadequacies from policy goals. AB - BACKGROUND: Although much public scrutiny and academic attention has focused on the evaluations of system implementation since the beginning of New Rural Cooperative Medical System (NRCMS) in China, few studies have systematically evaluated the achievements of the stated policy goals. The purpose of this study is to examine to what extent the policy goals of NRCMS have been achieved. METHODS: Using multistage sampling processes, two rounds of cross-sectional household surveys including 9787 and 7921 rural households were conducted in Eastern China in year 2000 and year 2008, respectively. A pre- and post implementation comparison was used to evaluate the achievement of policy goals in three measures: impoverishment from major health hazards, household financial risk from medical expenses, and rural income inequity. Intention surveys were also applied to find out potential obstacles in the implementation of NRCMS. RESULTS: The rate of re-impoverishment from health hazard was reduced from 2.69 % ex ante to 2.12 % ex post, a decrease of 21.13 %. The severity of impoverishment fell from a previous 4.66 % to 3.02 %, a decline of 35.18 %. Economic risk of medical treatment population relative to the whole population fell from 2.62 ex ante to 2.03 ex post, a 22.52 % reduction. As indication of effect on improving income equity, the Gini coefficient fell from 0.4629 to 0.4541. The effects of NRCMS were significantly better than those of RCMS. Despite the preliminary achievements, our intention survey of key respondents identified that technical difficulties in actuarial funding and more sustainable reimbursement schedules has become the most challenging barriers in achieving the goals of NRCMS, while raising the insurance premium on NRCMS was no longer as big a barrier. CONCLUSIONS: With NRCMS, China has established a medical security system to reduce the financial burden of healthcare on rural residents. NRCMS has achieved some positive though limited effects; but technical difficulties in the implementation of NRCMS have become barriers to achieve the pre-set policy goals. Efforts should be made to improve the capacity building in the design of the reimbursement schemes for the implementers of NRCMS, such as identifying medical impoverishment, calculating actuarial funding levels for the risk pooling. PMID- 26494016 TI - Recommendations for accreditation of laboratories in molecular biology of hematologic malignancies. AB - Over recent years, the development of molecular biology techniques has improved the hematological diseases diagnostic and follow-up. Consequently, these techniques are largely used in the biological screening of these diseases; therefore the Hemato-oncology molecular diagnostics laboratories must be actively involved in the accreditation process according the ISO 15189 standard. The French group of molecular biologists (GBMHM) provides requirements for the implementation of quality assurance for the medical molecular laboratories. This guideline states the recommendations for the pre-analytical, analytical (methods validation procedures, quality controls, reagents), and post-analytical conditions. In addition, herein we state a strategy for the internal quality control management. These recommendations will be regularly updated. PMID- 26494017 TI - New Antibiotic Candidates against Helicobacter pylori. AB - Helicobacter pylori is a Gram-negative bacterium that colonizes the gut of over 50% of the world's population. It is responsible for most peptic ulcers and is an important risk factor for gastric cancer. Antibiotic treatment for H. pylori infections is challenging as drug resistance has developed to antibiotics with traditional mechanisms of action. H. pylori uses an unusual pathway for menaquinone biosynthesis with 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzing an essential step. We validated MTAN as a target with a transition-state analogue of the enzyme [Wang, S.; Haapalainen, A. M.; Yan, F.; et al. Biochemistry 2012, 51, 6892-6894]. MTAN inhibitors will only be useful drug candidates if they can both include tight binding to the MTAN target and have the ability to penetrate the complex cell membrane found in Gram negative H. pylori. Here we explore structural scaffolds for MTAN inhibition and for growth inhibition of cultured H. pylori. Sixteen analogues reported here are transition-state analogues of H. pylori MTAN with dissociation constants of 50 pM or below. Ten of these prevent growth of the H. pylori with IC90 values below 0.01 MUg/mL. These remarkable compounds meet the criteria for potent inhibition and cell penetration. As a consequence, 10 new H. pylori antibiotic candidates are identified, all of which prevent H. pylori growth at concentrations 16-2000 fold lower than the five antibiotics, amoxicillin, metronidazole, levofloxacin, tetracyclin, and clarithromycin, commonly used to treat H. pylori infections. X ray crystal structures of MTAN cocrystallized with several inhibitors show them to bind in the active site making interactions consistent with transition-state analogues. PMID- 26494019 TI - Impact of mobile apps to combat obesity in children and adolescents: A systematic literature review. AB - PURPOSE: This review examines the impact of mobile app technology on obesity related anthropometric, psychosocial, and behavioral outcomes in children and adolescents. CONCLUSIONS: Nine research articles retrieved from a systematic review of the literature met criteria. Evidence is limited and mixed, but argues for an impact of mobile app use on motivation and goal-setting behavior, and supports further study of the impact on childhood obesity-related outcomes such as attitudes, perceptions, physical activity, and dietary habits. PRACTICE IMPLICATIONS: Nurses can use this evidence to discuss potential benefits of health promotion mobile apps with parents, children, and adolescents to combat childhood obesity. PMID- 26494018 TI - Early avoidance of a heroin-paired taste-cue and subsequent addiction-like behavior in rats. AB - The ability to predict individual vulnerability to substance abuse would allow for a better understanding of the progression of the disease and development of better methods for prevention and/or early intervention. Here we use drug-induced devaluation of a saccharin cue in an effort to predict later addiction-like behavior in a model akin to that used by Deroche-Gamonet et al. (2004) and seek to link such vulnerability to changes in expression of various mu opioid receptor and D2 receptor-interacting proteins in brain. The results show that the greatest heroin-induced suppression of intake of a saccharin cue is associated with the greatest vulnerability to later addiction-like behavior and to differences in the expression of WLS, beta-catenin, and NCS-1 in brain compared to rats that exhibited the least suppression of intake of the heroin-paired cue and/or saline controls. Finally, because the self-administration model employed produced no significant differences in drug intake between groups, overall, the resultant changes in protein expression can be more closely linked to individual differences in motivation for drug. PMID- 26494020 TI - High predictive ability of glycated hemoglobin on comparison with oxidative stress markers in assessment of chronic vascular complications in type 2 diabetes mellitus. AB - OBJECTIVE: To validate the diagnostic utility of oxidative stress markers along with glycated hemoglobin (HbA1c ) in the assessment of chronic vascular complications in type 2 diabetes mellitus (DM). METHODS: Ischemia modified albumin (IMA), advanced oxidation protein products (AOPP) and malondialdehyde (MDA) were measured in 100 type 2 DM (without complications n = 50, with complications n = 50) and healthy controls (n = 50). Diagnostic potential was evaluated by receiver operating characteristic analysis and their relationships to risk variables were analyzed. RESULTS: MDA, IMA and AOPP were significantly increased in diabetics, both with and without complications. Oxidative stress parameters correlated with fasting blood glucose and HbA1c (independent predictors). Duration of diabetes was an independent predictor for AOPP and MDA. The association of IMA with diabetes duration was lost on multiple regression analysis. Area under the curve, sensitivity and specificity for MDA were 0.795, 84%, 66%; for AOPP, they were 0.762, 82%, 56%; for IMA, they were 0.611, 60%, 52%; and for HbA1c, they were 0.848, 90%, 70%, respectively. CONCLUSION: MDA and AOPP could be considered better than IMA in the evaluation of diabetes progression, but MDA is more useful as a diagnostic indicator to detect vascular complications. HbA1c measurement is of greater value than the oxidative stress markers in the prediction of vascular complications. PMID- 26494021 TI - What is the effect of mandatory pasteurisation on the biogas transformation of solid slaughterhouse wastes? AB - The effect of mandatory pasteurisation on Category 3 offals, according to the Animal By-Products Regulation (ABPR 1069/2009/EC), was determined using Biochemical Methane Potential (BMP) assays as well as kinetic and statistical analysis. Pasteurised and unpasteurised offals sampled from cattle, pig and chicken slaughterhouses were characterised and their specific methane yields (SMYs) and their bioavailability was assessed. The resultant SMYs were high (465 650mLCH4gVS(-1)) with no statistically significant increase in methane production identified due to pasteurisation. However, the kinetics of the biogas transformation processes highlighted increased bioavailability of the organics due to pasteurisation. This was brought to light by the change in maximum daily SMY from day 22 to day 1 for the cattle offal (p=0.001), day 17 to day 1 for chicken offal (p=0.025) and an increase of 18.8% in the maximum daily SMY of the pig offal on day 1 (p=0.003). The increased bioavailability of the offals manifested itself in two ways with the determining factor being identified as the physical characteristics of the fats i.e. particle size. Firstly reducing the hydrolytic lag phase for the cattle offal, lambda=7.46-1.52days (p=0.013). Secondly, causing increased accumulation of Long Chain Fatty Acids to acute inhibitory levels in the chicken and pig offal indicated by increased lag phases lambda=5.05-21.91days (p=0.012), lambda=15.54-23.04days (p=0.007) respectively. PMID- 26494022 TI - Recovering Paleo-Records from Antarctic Ice-Cores by Coupling a Continuous Melting Device and Fast Ion Chromatography. AB - Recently, the increasing interest in the understanding of global climatic changes and on natural processes related to climate yielded the development and improvement of new analytical methods for the analysis of environmental samples. The determination of trace chemical species is a useful tool in paleoclimatology, and the techniques for the analysis of ice cores have evolved during the past few years from laborious measurements on discrete samples to continuous techniques allowing higher temporal resolution, higher sensitivity and, above all, higher throughput. Two fast ion chromatographic (FIC) methods are presented. The first method was able to measure Cl(-), NO3(-) and SO4(2-) in a melter-based continuous flow system separating the three analytes in just 1 min. The second method (called Ultra-FIC) was able to perform a single chromatographic analysis in just 30 s and the resulting sampling resolution was 1.0 cm with a typical melting rate of 4.0 cm min(-1). Both methods combine the accuracy, precision, and low detection limits of ion chromatography with the enhanced speed and high depth resolution of continuous melting systems. Both methods have been tested and validated with the analysis of several hundred meters of different ice cores. In particular, the Ultra-FIC method was used to reconstruct the high-resolution SO4(2-) profile of the last 10,000 years for the EDML ice core, allowing the counting of the annual layers, which represents a key point in dating these kind of natural archives. PMID- 26494024 TI - Murine models provide insight to the development of non-alcoholic fatty liver disease. AB - Associated with the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) has become the leading liver disease in North America. Approximately 30 % of patients with NAFLD may develop non-alcoholic steatohepatitis (NASH) that can lead to cirrhosis and hepatocellular carcinoma (HCC). Frequently animal models are used to help identify underlying factors contributing to NAFLD including insulin resistance, dysregulated lipid metabolism and mitochondrial stress. However, studying the inflammatory, progressive nature of NASH in the context of obesity has proven to be a challenge in mice. Although the development of effective treatment strategies for NAFLD and NASH is gaining momentum, the field is hindered by a lack of a concise animal model that reflects the development of liver disease during obesity and the metabolic syndrome. Therefore, selecting an animal model to study NAFLD or NASH must be done carefully to ensure the optimal application. The most widely used animal models have been reviewed highlighting their advantages and disadvantages to studying NAFLD and NASH specifically in the context of obesity. PMID- 26494023 TI - MIP-1alpha level in nasopharyngeal aspirates at the first wheezing episode predicts recurrent wheezing. AB - BACKGROUND: Respiratory virus-induced wheezing, such as that induced by respiratory syncytial virus (RSV) and human rhinovirus, is an important risk factor for recurrent wheezing and childhood asthma. However, no biomarkers for predicting recurrent wheezing have been identified. OBJECTIVE: We searched for predictors of recurrent wheezing using nasopharyngeal aspirates obtained from patients during the first wheezing episode who were hospitalized with an acute lower respiratory tract illness. METHODS: We enrolled 82 infants during the first wheezing episode (median age, 5.0 months) who were hospitalized for acute lower respiratory tract illness between August 2009 and June 2012 and followed these patients for 2.5 years. Nasopharyngeal aspirates and blood samples were obtained on the first day of hospitalization. Viral genomes were identified by using RT PCR and sequencing. Levels of 33 cytokines, tryptase, IgE, anti-RSV IgE, and anti RSV IgG were measured by using ELISAs or the Bio-Plex multiplex assay. Predictors of recurrent wheezing were examined by using a stepwise logistic regression model with backward elimination. RESULTS: Sixty percent of the patients experienced recurrent wheezing episodes. One or more viruses were detected in the nasopharynxes of 93% of the patients during the first wheezing episode. IFN gamma, IL-2, IL-9, MIP-1alpha, and MIP-1beta levels were significantly higher among patients with recurrent wheezing than among those without recurrent wheezing (P < .05 or .01). The stepwise model demonstrated that the MIP-1alpha level (odds ratio, 7.72; 95% CI, 1.50-39.77; P = .015) was the strongest independent predictor of the occurrence of recurrent wheezing. CONCLUSION: An increased MIP-1alpha level in nasopharyngeal aspirates from patients with acute respiratory symptoms during the first wheezing episode caused by viral infections might predict recurrent wheezing. PMID- 26494025 TI - Oatmeal consumption is associated with better diet quality and lower body mass index in adults: the National Health and Nutrition Examination Survey (NHANES), 2001-2010. AB - Data from the 2001-2010 National Health and Nutrition Examination Survey were analyzed to assess the relationship between oatmeal consumption and nutrient intake, diet quality, and physiological measures in adults 19 years and older (n = 22,823). We hypothesized that oatmeal consumption is associated with a more favorable nutrient intake profile, better diet quality, and healthier physiological end points. Oatmeal consumers (n = 1429) were defined as those who had consumed any amount of cooked oatmeal cereal during a 24-hour recall period. Multiple regression analysis, after transforming variables to normality and using appropriate sample weights to ensure national representation, was used to assess differences between oatmeal consumers and nonconsumers in terms of demographics, and covariate-adjusted analysis of variance was used to assess differences between consumers and nonconsumers in nutrient intakes, diet quality (calculated using the Healthy Eating Index-2010), and physiological measures. Our results show that oatmeal consumers were older than nonconsumers and more likely to be female; they also were less likely to smoke and consumed less alcohol. Consumers had higher intakes of protein, dietary fiber, vitamin A, thiamin, calcium, phosphorus, magnesium, iron, copper, selenium, and potassium and lower intakes of total, monounsaturated, and saturated fats; cholesterol; and vitamin B12. Oatmeal consumers had higher Healthy Eating Index-2010 scores and lower body weights, waist circumferences, and body mass indices. To conclude, our results suggest that consuming oatmeal is consistent with better nutrient intakes and a higher diet quality. PMID- 26494026 TI - Oxygenated amorphous carbon for resistive memory applications. AB - Carbon-based electronics is a promising alternative to traditional silicon-based electronics as it could enable faster, smaller and cheaper transistors, interconnects and memory devices. However, the development of carbon-based memory devices has been hampered either by the complex fabrication methods of crystalline carbon allotropes or by poor performance. Here we present an oxygenated amorphous carbon (a-COx) produced by physical vapour deposition that has several properties in common with graphite oxide. Moreover, its simple fabrication method ensures excellent reproducibility and tuning of its properties. Memory devices based on a-COx exhibit outstanding non-volatile resistive memory performance, such as switching times on the order of 10 ns and cycling endurance in excess of 10(4) times. A detailed investigation of the pristine, SET and RESET states indicates a switching mechanism based on the electrochemical redox reaction of carbon. These results suggest that a-COx could play a key role in non-volatile memory technology and carbon-based electronics. PMID- 26494027 TI - Increased Proportion of Hematopoietic Stem and Progenitor Cell Population in Cord Blood of Neonates Born to Mothers with Gestational Diabetes Mellitus. AB - We assessed the hematopoietic stem and progenitor cell (HSPC) population in the cord blood of neonates born to mothers with gestational diabetes mellitus (GDM) in a hypothesis generating pilot study, due to that, neonatal polycythemia may be the consequence of GDM pregnancy. Forty-five pregnant women with GDM (last trimester mean HbA1C = 33.9 mmol/mol) and 42 (nondiabetic) control pregnant women were enrolled after their routine 75 g oral glucose tolerance test (OGTT) between the 24th and 28th gestational week (with expected differences in their mean routine clinical characteristics: plasma glucose at OGTT: 0' = 5.07 vs. 4.62 mM, 120' = 8.9 vs. 5.76 mM, age = 35.07 vs. 31.66 years, prepregnancy body mass index = 27.9 vs. 23.9 kg/m(2), GDM vs. control, respectively) on a voluntary basis after signing the informed consent. EDTA-treated cord blood samples were analyzed by flow cytometry and the software Kaluza1.2 using CD45 and CD34-specific fluorescent antibodies to identify the HSPC population (CD34(+) cells within the CD45(dim) blast gate). The proportion of CD34(+)CD45(dim) HSPCs among the nucleated cells was significantly (P < 0.05, statistical power = 60.8%) higher in the cord blood samples of neonates born to mothers with GDM (median 0.38%) compared to neonates born to nondiabetic mothers (median 0.32%) and according to treatment types (P < 0.05) median: control 0.32%, GDM-diet only 0.37%, GDM-on insulin 0.45%; control versus GDM on insulin (P < 0.05). The increased proportion of circulating CD34(+)CD45(dim) cells in the cord blood may possibly be related to altered fetal stem cell mobilization in GDM pregnancy, yet these results should be interpreted only as preliminary due to the small sample sizes. PMID- 26494029 TI - Corrigendum: Twisted Baskets. PMID- 26494028 TI - Soluble epoxide hydrolase inhibitor enhances synaptic neurotransmission and plasticity in mouse prefrontal cortex. AB - BACKGROUND: The soluble epoxide hydrolase (sEH) is an important enzyme chiefly involved in the metabolism of fatty acid signaling molecules termed epoxyeicosatrienoic acids (EETs). sEH inhibition (sEHI) has proven to be protective against experimental cerebral ischemia, and it is emerging as a therapeutic target for prevention and treatment of ischemic stroke. However, the role of sEH on synaptic function in the central nervous system is still largely unknown. This study aimed to test whether sEH C-terminal epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) affects basal synaptic transmission and synaptic plasticity in the prefrontal cortex area (PFC). Whole cell and extracellular recording examined the miniature excitatory postsynaptic currents (mEPSCs) and field excitatory postsynaptic potentials (fEPSPs); Western Blotting determined the protein levels of glutamate receptors and ERK phosphorylation in acute medial PFC slices. RESULTS: Application of the sEH C-terminal epoxide hydrolase inhibitor, AUDA significantly increased the amplitude of mEPSCs and fEPSPs in prefrontal cortex neurons, while additionally enhancing long term potentiation (LTP). Western Blotting demonstrated that AUDA treatment increased the expression of the N-methyl-D-aspartate receptor (NMDA) subunits NR1, NR2A, NR2B; the alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR1, GluR2, and ERK phosphorylation. CONCLUSIONS: Inhibition of sEH induced an enhancement of PFC neuronal synaptic neurotransmission. This enhancement of synaptic neurotransmission is associated with an enhanced postsynaptic glutamatergic receptor and postsynaptic glutamatergic receptor mediated synaptic LTP. LTP is enhanced via ERK phosphorylation resulting from the delivery of glutamate receptors into the PFC by post-synapse by treatment with AUDA. These findings provide a possible link between synaptic function and memory processes. PMID- 26494031 TI - Near-Infrared Light and pH-Responsive Polypyrrole@Polyacrylic acid/Fluorescent Mesoporous Silica Nanoparticles for Imaging and Chemo-Photothermal Cancer Therapy. AB - We have rationally designed a new theranostic agent by coating near-infrared (NIR) light-absorbing polypyrrole (PPY) with poly(acrylic acid) (PAA), in which PAA acts as a nanoreactor and template, followed by growing small fluorescent silica nanoparticles (fSiO2 NPs) inside the PAA networks, resulting in the formation of polypyrrole@polyacrylic acid/fluorescent mesoporous silica (PPY@PAA/fmSiO2 ) core-shell NPs. Meanwhile, DOX-loaded PPY@PAA/fmSiO2 NPs as pH and NIR dual-sensitive drug delivery vehicles were employed for fluorescence imaging and chemo-photothermal synergetic therapy in vitro and in vivo. The results demonstrate that the PPY@PAA/fmSiO2 NPs show high in vivo tumor uptake by the enhanced permeability and retention (EPR) effect after intravenous injection as revealed by in vivo fluorescence imaging, which is very helpful for visualizing the location of the tumor. Moreover, the obtained NPs inhibit tumor growth (95.6 % of tumors were eliminated) because of the combination of chemo photothermal therapy, which offers a synergistically improved therapeutic outcome compared with the use of either therapy alone. Therefore, the present study provides new insights into developing NIR and pH-stimuli responsive PPY-based multifunctional platform for cancer theranostics. PMID- 26494034 TI - Finding Food Deserts: A Comparison of Methods Measuring Spatial Access to Food Stores. AB - Public health research has increasingly focused on how access to resources affects health behaviors. Mapping environmental factors, such as distance to a supermarket, can identify intervention points toward improving food access in low income and minority communities. However, the existing literature provides little guidance on choosing the most appropriate measures of spatial access. This study compared the results of different measures of spatial access to large food stores and the locations of high and low access identified by each. The data set included U.S. Census population data and the locations of large food stores in the six-county area around Chicago, Illinois. Six measures of spatial access were calculated at the census block group level and the results compared. The analysis found that there was little agreement in the identified locations of high or low access between measures. This study illustrates the importance of considering the access measure used when conducting research, interpreting results, or comparing studies. Future research should explore the correlation of different measures with health behaviors and health outcomes. PMID- 26494035 TI - Acute Achilles tendon rupture. PMID- 26494036 TI - On-line solid-phase extraction coupled to liquid chromatography tandem mass spectrometry for the analysis of cyanotoxins in algal blooms. AB - An analytical method based on on-line SPE-LC-HESI-MS/MS has been developed for the detection and quantification of eight selected cyanotoxins in algal bloom waters that include mycrocystins, anatoxin-a and cylindrospermopsin. The injection volume was 2 mL according to the expected concentration of cyanotoxins in matrix. The method provides an analysis time of 7 min per sample, acceptable recovery values (91-101%), good precision (RSD < 13%) and method limits of detection at the sub-microgram per liter levels (0.01-0.02 MUg L(-1)). A detailed discussion on optimization parameters that have an impact on the overall performance of the method are presented. In particular, method optimization permitted the chromatographic separation of anatoxin-a and phenylalanine, an isobaric interference with a similar chromatographic characteristics. All optimization and validation experiments for the on-line SPE method and chromatographic separation were performed in environmentally relevant algal bloom water matrices. The applicability of the method was tested on several algal bloom water samples from monitored lakes across the province of Quebec (Quebec, Canada) known to produce cyanotoxins. All of the targeted cyanotoxins were detected with the exception of cylindrospermopsin. In addition, it was found that total microcystin concentrations in several surface water samples exceeded the proposed guidelines established by the province of Quebec in Canada of 1.5 MUg L(-1) as well as the World Health Organization of 1 MUg L(-1) for both free and cell-bound microcystin-LR equivalent. PMID- 26494037 TI - IRE1 inhibition affects the expression of insulin-like growth factor binding protein genes and modifies its sensitivity to glucose deprivation in U87 glioma cells. AB - OBJECTIVE: The aim of the present study was to investigate the effect of inhibition of endoplasmic reticulum stress signaling mediated by IRE1/ERN1 (inositol-requiring enzyme 1/endoplasmic reticulum to nucleus signaling 1) on the expression of genes encoding different groups of insulin-like growth binding proteins (IGFBP6 and IGFBP7) and CCN family (IGFBP8/CTGF/CCN2, IGFBP9/NOV/CCN3, IGFBP10/CYR61/CCN1, WISP1/CCN4, and WISP2/CCN5) and its sensitivity to glucose deprivation in U87 glioma cells. METHODS: The expression of IGFBP6, IGFBP7, IGFBP8, IGFBP9, IGFBP10, WISP1, and WISP2 genes was studied by qPCR in control U87 glioma cells (wild-type) and its subline with IRE1 signaling enzyme loss of function upon glucose deprivation. RESULTS: The expression of IGFBP8, IGFBP9, and WISP2 genes was up-regulated in control glioma cells upon glucose deprivation with most significant changes for IGFBP9 gene. At the same time, the expression of IGFBP6, IGFBP10, and WISP1 genes was resistant to glucose deprivation in these glioma cells, but the IGFBP7 gene expression was down-regulated. The inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in glioma cells modified the sensitivity of most studied gene expressions to glucose deprivation condition: introduced sensitivity of IGFBP10 and WISP1 genes to glucose deprivation, enhanced the effect of this deprivation on IGFBP7 and IGFBP9 gene expressions, and reduced this effect on WISP2 gene and induced suppressive effect of glucose deprivation on the expression of IGFBP8 gene. Furthermore, the inhibition of IRE1 strongly affected the expression of all studied genes in glioma cells upon regular growing condition in gene specific manner: up-regulated the expression levels of IGFBP7, IGFBP8, IGFBP10, WISP1, and WISP2 genes and down regulated the IGFBP6 and IGFBP9 genes. CONCLUSIONS: The data of this investigation demonstrate that the expression of IGFBP7, IGFBP8, IGFBP9, and WISP2 genes are sensitive to glucose deprivation in U87 glioma cells and that inhibition of IRE1 signaling enzyme function may significantly affect the expression of all studied genes in the presence of glucose as well as modify the effect of glucose deprivation on the expression of most studied genes. These data also show that proteins encoded by these genes may participate in the regulation of metabolic and proliferative processes via IGF/INS receptors and possibly other signaling pathways as well, via IRE1 signaling, which is a central mediator of the unfolded protein response and an important component of the tumor growth and metabolic diseases. PMID- 26494038 TI - The protective role of the opioid antagonist LY255582 in the management of high fat diet-induced obesity in adult male albino rats. AB - OBJECTIVES: The involvement of the opioid system in energy balance has been known for several decades but many questions remain unanswered. Therefore, this study was designed to investigate the effect of the non-selective opioid receptor antagonist (LY255582) on high fat diet (HFD)-induced obesity. METHODS: Twenty four adult male albino rats were divided into 4 groups: Control, HFD non-treated, HFD+LY255582 treated during the first 4 weeks and Obese-LY255582- treated groups during the following 4 weeks after the induction of obesity. LY255582 (0.31 mg/kg, s.c.) was administrated daily with HFD feeding. Blood samples were collected for measurement of lipid profile, glucose, insulin, and leptin. Body weight, body mass index (BMI), and food intake were also measured. RESULTS: Consumption of HFD resulted in a significant increase in body weight, body mass index (BMI), glucose, insulin, leptin levels, and induced a state of dyslipideamia. Opioid antagonist LY255582 administration with HFD decreased food intake, body weight and BMI, in addition to the improvement of HFD related metabolic abnormalities (dyslipidemia and insulin resistance) during the dynamic phase of obesity development than in animals with already developed dietary obesity. CONCLUSION: The use of opioid antagonist may be a promising approach in treatment of HFD-induced obesity. PMID- 26494039 TI - Effect of unilateral adrenalectomy on acute immobilization stress response in rats. AB - OBJECTIVES: The aim of the present study was to investigate the differential effect of unilateral adrenalectomy, right vs. left, in response to acute immobilization stress (IS) in rats. METHODS: Adult male rats were subjected to unilateral right or left adrenalectomy or sham operation (control). Two weeks later, the rats were sacrificed either immediately or 3 hours after IS exposure. Plasma samples were used for determination of catecholamines (CAs), adrenocorticotrophic hormone (ACTH), corticosterone (CORT), sodium, potassium, and glucose levels. After terminating the experiment, both or remaining adrenals were removed, weighed, and used for estimation of CAs and nitric oxide (NO) levels. RESULTS: Under basal conditions, either right or left adrenal kept all the tested parameters near to the control levels, except the adrenal weight and CAs content. These were significantly higher in the remaining right than left adrenal. However, the remaining right adrenal responded better to IS exposure than the remaining left one in the term of compensatory adrenal growth and plasma parameters which were all kept insignificantly different from those of IS intact group. CONCLUSION: Our data indicate that the adrenal glands may substitute each other under basal conditions. However, the right adrenal seems to be dominant during exposure to acute immobilization stress. PMID- 26494040 TI - Biological variations in adrenal gland response to immobilization and glucoprivation stressors in rats. AB - OBJECTIVES: The aim of the present study was to investigate the potential variation in adrenal gland response to two different types of acute stressors, immobilization and glucoprivation. METHODS: Twenty-four adult male albino rats were randomly divided into three main groups (8 rats/group): a) control, i.e. non stressed group, b) immobilized group (IS), and c) glucoprivated (GS) group. Plasma catecholamines (CAs), including epinephrine (E), norepinephrine (NE), dopamine (DA), adrenocorticotrophic hormone (ACTH), corticosterone (CORT), sodium, potassium, and glucose were measured. Adrenals weight, CAs levels, and nitric oxide (NO) content were also determined. RESULTS: Immobilized group of rats showed significantly higher plasma NE and DA levels along with a significantly lower adrenal NE content than GS group. On the other hand, GS group was associated with significantly higher plasma E, ACTH, CORT, glucose, and Na+ levels as well as higher adrenal DA and NO levels along with significantly lower plasma K+ levels and adrenal E content in comparison with IS group. CONCLUSION: Stress response is unique according to the nature of the stressor. Adrenal glands play a key role in this stress-induced differentiated response probably via modulation of its adreno-medullary and/or adrenocortical hormone levels in order to assign the body cope with different types of stress challenges during the life. PMID- 26494041 TI - Incidental pheochromocytoma in a patient with nasopharyngeal carcinoma. AB - Because the adrenal glands are common locations for metastases, pheochromocytoma is frequently misdiagnosed as adrenal metastasis in patients with a history of cancer. An incidental adrenal mass was detected during an abdominal computed tomography (CT) scan performed to stage the nasopharyngeal carcinoma in a 35-year old male patient. The features of an adrenal mass on the CT, magnetic resonance imaging (MRI), and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) were thought to show adrenal metastasis. However, the patient did not complain about flushing, palpitation, headache or excessive sweating. His blood pressure was 132/74 mmHg, and his pulse rate was 82 bpm. A pheochromocytoma was found during a biochemical diagnosis that evaluated the catecholamine in urine collected over a 24-hour period. The urine had elevated urinary adrenaline, metanephrine, and vanillylmandelic. An I123 MIBG scan showed avid tracer uptake in the right adrenal mass with no evidence of abnormal uptake elsewhere. A right adrenalectomy operation was performed and a diagnosis of pheochromocytoma was confirmed histopathologically. Incidental adrenal masses detected in the presence history of cancer should always be subjected to hormonal evaluation. Although patients may be asymptomatic, the probability of incidental pheochromocytoma should not be ignored. PMID- 26494042 TI - Spaceflight osteoporosis: current state and future perspective. AB - Osteoporosis is one of the established major consequences of long-duration spaceflights in astronauts seriously undermining their health after their returning on Earth. Indeed, astronauts typically lose more bone mass during one month than postmenopausal women on Earth lose in one year. To date, countermeasures mainly consist in exercise and supplementation while pharmacological treatment as those used in postmenopausal women are not routine. However, it is evident that exercise and supplementation alone are not enough to maintain bone homeostasis. In this paper we describe the current countermeasures for bone loss during long-term spaceflight, review the modern treatment which are successfully employed to prevent osteoporosis on Earth and that could be quickly used also for astronauts and finally focus on the recent cellular and molecular understanding of bone homeostasis which might provide the basis for the development of future targeted therapies. PMID- 26494043 TI - Retinal nerve fiber layer changes after transsphenoidal and transcranial pituitary adenoma resection. AB - PURPOSE: Retinal nerve fiber layer (RNFL) will show retrograde degeneration following damage to the optic nerve or the optic tract in patients with pituitary adenoma. RNFL changes after surgery have not been studied thoroughly in patients with the transsphenoidal surgery and patients with the transcranial surgery. METHODS: Thirty-seven patients with pituitary adenoma were recruited from Huashan hospital between September 2010 and July 2014. Patients were divided into two groups: the transsphenoidal group and the transcranial group. Before surgery, 3 and 9 months after surgery, follow-up optic coherence tomography were conducted. RESULTS: Twenty-one patients underwent transsphenoidal surgery and 16 patients underwent transcranial surgery. No obvious difference were observed between these two groups before surgery. The mean RNFL thickness did not change significantly in patients who underwent transsphenoidal surgery: 91.1 before surgery, 92.7 at 3 months after surgery (p = 0.392) and 92.8 at 9 months after surgery( p = 0.395). The mean RNFL thickness decreased inpatients who underwent transcranial surgery: 93.6 before surgery, 86.1 at 3 months after surgery (p = 0.000) and 88.1 at 9 months after surgery (p = 0.005). CONCLUSIONS: In the short time follow-up, there was no change of RNFL thickness in pituitary adenoma patients underwent transsphenoidal surgery, but a decrease inpatients underwent transcranial surgery. PMID- 26494044 TI - Electrostatics effects on Ca(2+) binding and conformational changes in EF-hand domains: Functional implications for EF-hand proteins. AB - Mutations of Gln41 and Lys75 with nonpolar residues in the N-terminal domain of calmodulin (N-Cam) revealed the importance of solvation energetics in conformational change of Ca(2+) sensor EF-hand domains. While in general these domains have polar residues at these corresponding positions yet the extent of their conformational response to Ca(2+) binding and their Ca(2+) binding affinity can be different from N-Cam. Consequently, here we address the charge state of the polar residues at these positions. The results show that the charge state of these polar residues can affect substantially the conformational change and the Ca(2+) binding affinity of our N-Cam variants. Since all the variants kept their conformational activity in the presence of Ca(2+) suggests that the differences observed among them mainly originate from the difference in their molecular dynamics. Hence we propose that the molecular dynamics of Ca(2+) sensor EF-hand domains is a key factor in the multifunctional aspect of EF-hand proteins. PMID- 26494045 TI - Metabolome analyses in exposome studies: Profiling methods for a vast chemical space. AB - Metabolic profiling (metabonomics/metabolomics) is now used routinely as a tool to provide information-rich datasets for biomarker discovery, prompting and augmenting detailed mechanistic studies. The experimental design and focus of any individual study will be reflected in the types of biomarkers that can be detected; toxicological studies will likely focus on markers of response to insult, whereas clinical case-control studies may yield diagnostic markers of disease. Population studies can make use of omics analyses, including metabonomics, to provide mechanistically-relevant markers that link environmental exposures to chronic disease endpoints. In this article, examples of how metabolic profiling has played a key role in molecular epidemiological analyses of chronic disease are presented, and how these reflect different aspects of the causal pathway. A commentary on the nature of metabolome analysis as a complex mixture problem as opposed to a coded, sequence or template problem is provided, alongside an overview of current and future analytical platforms that are being applied to meet this analytical challenge. Epidemiological studies are an important nexus for integrating various measures of the human exposome, and the ubiquity, diversity and functions of small molecule metabolites, represent an important way to link individual exposures, genetics and phenotype. PMID- 26494047 TI - Production of the angiotensin I converting enzyme inhibitory peptides and isolation of four novel peptides from jellyfish (Rhopilema esculentum) protein hydrolysate. AB - BACKGROUND: Angiotensin I converting enzyme (ACE) plays an important role in regulating blood pressure in the human body. ACE inhibitory peptides derived from food proteins could exert antihypertensive effects without side effects. Jellyfish (Rhopilema esculentum) is an important fishery resource suitable for production of ACE inhibitory peptides. The objective of this study was to optimize the hydrolysis conditions for production of protein hydrolysate from R. esculentum (RPH) with ACE inhibitory activity, and to isolate and identify the ACE inhibitory peptides from RPH. RESULTS: Rhopilema esculentum protein was hydrolyzed with Compound proteinase AQ to produce protein hydrolysate with ACE inhibitory activity, and the hydrolysis conditions were optimized using response surface methodology. The optimum parameters for producing peptides with the highest ACE inhibitory activity were as follows: hydrolysis time 3.90 h, hydrolysis temperature 58 degrees C, enzyme:substrate ratio 2.8% and pH 7.60. Under these conditions, the ACE inhibitory rate reached 32.21%. In addition, four novel ACE inhibitory peptides were isolated, and their amino acids sequences were identified as Val-Gly-Pro-Tyr, Phe-Thr-Tyr-Val-Pro-Gly, Phe-Thr-Tyr-Val-Pro-Gly Ala and Phe-Gln-Ala-Val-Trp-Ala-Gly, respectively. The IC50 value of the purified peptides for ACE inhibitory activity was 8.40, 23.42, 21.15 and 19.11 umol L(-1) . CONCLUSION: These results indicate that the protein hydrolysate prepared from R. esculentum might be a commercial competitive source of ACE inhibitory ingredients to be used in functional foods. (c) 2015 Society of Chemical Industry. PMID- 26494048 TI - Phagocytosis: Mitochondria and phagosomes: better together. PMID- 26494049 TI - Mucosal immunology: Battle scars. PMID- 26494046 TI - Antibodies as Mediators of Brain Pathology. AB - The brain is normally sequestered from antibody exposure by the blood brain barrier. However, antibodies can access the brain during fetal development before the barrier achieves full integrity, and in disease states when barrier integrity is compromised. Recent studies suggest that antibodies contribute to brain pathology associated with autoimmune diseases such as systemic lupus erythematosus and neuromyelitis optica, and can lead to transient or permanent behavioral or cognitive abnormalities. We review these findings here and examine the circumstances associated with antibody entry into the brain, the routes of access and the mechanisms that then effect pathology. Understanding these processes and the nature and specificity of neuronal autoantibodies may reveal therapeutic strategies toward alleviating or preventing the neurological pathologies and behavioral abnormalities associated with autoimmune disease. PMID- 26494051 TI - Water and nitrogen availability co-control ecosystem CO2 exchange in a semiarid temperate steppe. AB - Both water and nitrogen (N) availability have significant effects on ecosystem CO2 exchange (ECE), which includes net ecosystem productivity (NEP), ecosystem respiration (ER) and gross ecosystem photosynthesis (GEP). How water and N availability influence ECE in arid and semiarid grasslands is still uncertain. A manipulative experiment with additions of rainfall, snow and N was conducted to test their effects on ECE in a semiarid temperate steppe of northern China for three consecutive years with contrasting natural precipitation. ECE increased with annual precipitation but approached peak values at different precipitation amount. Water addition, especially summer water addition, had significantly positive effects on ECE in years when the natural precipitation was normal or below normal, but showed trivial effect on GEP when the natural precipitation was above normal as effects on ER and NEP offset one another. Nitrogen addition exerted non-significant or negative effects on ECE when precipitation was low but switched to a positive effect when precipitation was high, indicating N effect triggered by water availability. Our results indicate that both water and N availability control ECE and the effects of future precipitation changes and increasing N deposition will depend on how they can change collaboratively in this semiarid steppe ecosystem. PMID- 26494052 TI - You are not alone: selecting your group members and leading an outstanding research team. PMID- 26494053 TI - Surgical Visual Reference for Auditory Brainstem Implantation in Children with Cochlear Nerve Deficiency. PMID- 26494050 TI - Resistance and tolerance to foreign elements by prokaryotic immune systems - curating the genome. AB - To engage in adaptive symbioses or genetic exchange, organisms must interact with foreign, non-self elements despite the risks of predation and parasitism. By surveying the interface between self and non-self, immune systems can help ensure the benevolence of these interactions without isolating their hosts altogether. In this Essay, we examine prokaryotic restriction-modification and CRISPR-Cas (clustered, regularly interspaced palindromic repeat-CRISPR-associated proteins) activities and discuss their analogy to mammalian immune pathways. We further explain how their capacities for resistance and tolerance are optimized to reduce parasitism and immunopathology during encounters with non-self. PMID- 26494054 TI - Complications of Pediatric Otitis Media. AB - OBJECTIVE: Otitis media (OM) is a common diagnosis in the pediatric population that is usually managed on an outpatient basis. A small proportion of children are admitted due to a complex disease course. The aim of this study was to investigate the demographics of those patients and the resources utilized during their admissions. STUDY DESIGN: Retrospective review based on the 2009 Kids' Inpatient Database. SETTING: Nationwide administrative database. SUBJECTS AND METHODS: A review based on the 2009 Kids' Inpatient Database was conducted. Inclusion criteria were clinical modification codes for OM (ICD-9 code 382). Data recorded included patient demographics, concurrent discharge diagnosis codes, length of stay, total charges, and frequency of procedures performed. RESULTS: There were 61,783 (92,548 nationally weighted) admissions with OM, which were analyzed. The average age (SD) for the patients was 2.18 (3.49) years, and the average length of stay was 2.88 days. The majority (80.75%) of patients did not have to undergo a procedure during admission, whereas a small proportion (5.4%) underwent a major operating room procedure. There were 21 deaths recorded (0.03%). A diagnosis of mastoiditis, meningitis, venous sinus thrombosis, or intracranial abscess was associated with significantly increased length of stay, incidence of procedures, and total cost of admission. CONCLUSIONS: Complicated pediatric OM remains of concern requiring prompt and thorough management. Major complications include mastoiditis and meningitis, and unfortunately, fatalities still occur in patients with OM. An understanding of resource utilization and socioeconomic implications can identify and drive opportunities for targeted quality improvement. PMID- 26494056 TI - Predicting and influencing training success: spatial abilities and instructional design. PMID- 26494057 TI - Accessory cystic artery as instructed object. PMID- 26494058 TI - Are influential teachers born or can they be taught? PMID- 26494059 TI - Academic integrity of health care educators: requisite for nurturing professionalism. PMID- 26494060 TI - When I say... patient-centredness. PMID- 26494061 TI - Spatial abilities and technical skills performance in health care: a systematic review. AB - OBJECTIVES: The aim of this study was to conduct a systematic review and meta analysis of the relationship between spatial abilities and technical skills performance in health care in beginners and to compare this relationship with those in intermediate and autonomous learners. METHODS: Search criteria included 'spatial abilities' and 'technical skills'. Keywords related to these criteria were defined. A literature search was conducted to 20 December, 2013 in Scopus (including MEDLINE) and in several databases on EBSCOhost platforms (CINAHL Plus with Full Text, ERIC, Education Source and PsycINFO). Citations were obtained and reviewed by two independent reviewers. Articles related to retained citations were reviewed and a final list of eligible articles was determined. Articles were assessed for quality using the Scottish Intercollegiate Guidelines Network-50 assessment instrument. Data were extracted from articles in a systematic way. Correlations between spatial abilities test scores and technical skills performance were identified. RESULTS: A series of 8289 citations was obtained. Eighty articles were retained and fully reviewed, yielding 36 eligible articles. The systematic review found a tendency for spatial abilities to be negatively correlated with the duration of technical skills and positively correlated with the quality of technical skills performance in beginners and intermediate learners. Pooled correlations of studies were -0.46 (p = 0.03) and -0.38 (95% confidence interval [CI] -0.53 to -0.21) for duration and 0.33 (95% CI 0.20-0.44) and 0.41 (95% CI 0.26-0.54) for quality of technical skills performance in beginners and intermediate learners, respectively. However, correlations between spatial abilities test scores and technical skills performance were not statistically significant in autonomous learners. CONCLUSIONS: Spatial abilities are an important factor to consider in selecting and training individuals in technical skills in health care. PMID- 26494062 TI - Implementation of competency-based medical education: are we addressing the concerns and challenges? AB - CONTEXT: Competency-based medical education (CBME) has emerged as a core strategy to educate and assess the next generation of physicians. Advantages of CBME include: a focus on outcomes and learner achievement; requirements for multifaceted assessment that embraces formative and summative approaches; support of a flexible, time-independent trajectory through the curriculum; and increased accountability to stakeholders with a shared set of expectations and a common language for education, assessment and regulation. OBJECTIVES: Despite the advantages of CBME, numerous concerns and challenges to the implementation of CBME frameworks have been described, including: increased administrative requirements; the need for faculty development; the lack of models for flexible curricula, and inconsistencies in terms and definitions. Additionally, there are concerns about reductionist approaches to assessment in CBME, lack of good assessments for some competencies, and whether CBME frameworks include domains of current importance. This study will outline these issues and discuss the responses of the medical education community. METHODS: The concerns and challenges expressed are primarily categorised as: (i) those related to practical, administrative and logistical challenges in implementing CBME frameworks, and (ii) those with more conceptual or theoretical bases. The responses of the education community to these issues are then summarised. CONCLUSIONS: The education community has begun to address the challenges involved in implementing CBME. Models and guidance exist to inform implementation strategies across the continuum of education, and focus on the more efficient use of resources and technology, and the use of milestones and entrustable professional activities-based frameworks. Inconsistencies in CBME definitions and frameworks remain a significant obstacle. Evolution in assessment approaches from in vitro task-based methods to in vivo integrated approaches is responsive to many of the theoretical and conceptual concerns about CBME, but much work remains to be done to bring rigour and quality to work-based assessment. PMID- 26494063 TI - 'You see?' Teaching and learning how to interpret visual cues during surgery. AB - CONTEXT: The ability to interpret visual cues is important in many medical specialties, including surgery, in which poor outcomes are largely attributable to errors of perception rather than poor motor skills. However, we know little about how trainee surgeons learn to make judgements in the visual domain. OBJECTIVES: We explored how trainees learn visual cue interpretation in the operating room. METHODS: A multiple case study design was used. Participants were postgraduate surgical trainees and their trainers. Data included observer field notes, and integrated video- and audio-recordings from 12 cases representing more than 11 hours of observation. A constant comparative methodology was used to identify dominant themes. RESULTS: Visual cue interpretation was a recurrent feature of trainer-trainee interactions and was achieved largely through the pedagogic mechanism of co-construction. Co-construction was a dialogic sequence between trainer and trainee in which they explored what they were looking at together to identify and name structures or pathology. Co-construction took two forms: 'guided co-construction', in which the trainer steered the trainee to see what the trainer was seeing, and 'authentic co-construction', in which neither trainer nor trainee appeared certain of what they were seeing and pieced together the information collaboratively. Whether the co-construction activity was guided or authentic appeared to be influenced by case difficulty and trainee seniority. Co-construction was shown to occur verbally, through discussion, and also through non-verbal exchanges in which gestures made with laparoscopic instruments contributed to the co-construction discourse. CONCLUSIONS: In the training setting, learning visual cue interpretation occurs in part through co construction. Co-construction is a pedagogic phenomenon that is well recognised in the context of learning to interpret verbal information. In articulating the features of co-construction in the visual domain, this work enables the development of explicit pedagogic strategies for maximising trainees' learning of visual cue interpretation. This is relevant to multiple medical specialties in which judgements must be based on visual information. PMID- 26494064 TI - The highly influential teacher: recognising our unsung heroes. AB - OBJECTIVES: This study was designed to investigate the roles, characteristics and contributions to the educational process of highly influential teachers described retrospectively by faculty members who were former medical students and trainees. METHODS: The authors collected 20 appreciative inquiry narratives from a convenience sample of 22 faculty members (91% collection rate) at three medical schools that had volunteered to participate in a year-long programme of faculty development in humanism in medicine. The faculty members wrote narratives in response to the prompt: 'Write about your most influential teacher.' The four authors performed qualitative analysis of the 20 narratives using the constant comparison method to identify the characteristics of influential teachers. RESULTS: Particular relational features with their learners explain the profound influences of these teachers on the professional development of their learners. All influential teachers shared qualities of excellence in teaching and nearly all were described as caring, generous and selfless in their relationships with learners. CONCLUSIONS: Highly influential teachers have no official roles, yet appear to profoundly influence the professional development of many learners at various stages of the educational process. PMID- 26494065 TI - 'It was serendipity': a qualitative study of academic careers in medical education. AB - CONTEXT: Despite a demand for educational expertise in medical universities, little is known of the roles of medical educators and the sustainability of academic careers in medical education. We examined the experiences and career paths of medical educators from diverse professional backgrounds seeking to establish, maintain and strengthen their careers in medical schools. METHODS: Semi-structured interviews were conducted with 44 lead and early-career medical educators from all 21 Australian and New Zealand medical schools. Questions explored career beginnings, rewards and challenges. Transcripts underwent systematic coding and independent thematic analysis. Final themes were confirmed by iterative review and member checking. Analysis was informed by Bourdieu's concepts of field (a social space for hierarchical interactions), habitus (individual dispositions which influence social interactions) and capital (economic, symbolic, social and cultural forms of power). RESULTS: Participants provided diverse accounts of what constitutes the practice of medical education. Serendipitous career entry and little commonality of professional backgrounds and responsibilities suggest an ambiguous habitus with ill-defined career pathways. Within the field of medicine as enacted in medical schools, educators have invisible yet essential roles, experiencing tension between service expectations, a lesser form of capital, and demands for more highly valued forms of scholarship. Participants reported increasing expectations to produce research and obtain postgraduate qualifications to enter and maintain their careers. Unable to draw upon cultural capital accrued from clinical work, non-clinician educators faced additional challenges. To strengthen their position, educators consciously built social capital through essential service relationships, capitalising on times when education takes precedence, such as curriculum renewal and accreditation. CONCLUSIONS: Bourdieu's theory provides insight into medical educator career paths and the positioning of medical education within medical schools. Medical educators have an indistinct practice, and limited cultural capital in the form of research outputs. In order to maintain and strengthen their careers, educators must create alternative sources of capital, through fostering collaborative alliances. PMID- 26494067 TI - A model for medical school application courses: widening access to student preparation. PMID- 26494068 TI - Order of curricular interventions in recognition of haematopathological images. PMID- 26494069 TI - Verisimilitude game to teach infectious disease epidemiology to medical students. PMID- 26494070 TI - Using comics for pre-class preparation. PMID- 26494071 TI - Flipped classroom on humanities: medicine, narrative and art. PMID- 26494072 TI - Lessons learned with a flipped classroom. PMID- 26494073 TI - Breakfast club: a simple, reproducible, student education initiative. PMID- 26494074 TI - Toward full student engagement in pre-clerkship training. PMID- 26494075 TI - Medical students as nutritional mentors for underserved patients. PMID- 26494076 TI - Video voiceover feedback: economised surgical skills training. PMID- 26494077 TI - Body language in workshop evaluation. PMID- 26494078 TI - Facilitated simulated patient sessions in mental-state examination teaching. PMID- 26494079 TI - Improved trainee experience with a structured subspecialty rotation. PMID- 26494080 TI - A customised board game enhances learning about obesity. PMID- 26494081 TI - CanMEDS in context: a transition to residency innovation. PMID- 26494082 TI - Using real-time Delphi to develop a consensus on competencies. PMID- 26494083 TI - CPIRD: a successful programme to foster clinical competency for rural doctors. PMID- 26494084 TI - Teaching and developing referral skills for new doctors. PMID- 26494085 TI - The Bristol Clinical Data Exam. PMID- 26494086 TI - Teamwork attitude: not just a student issue. PMID- 26494087 TI - Developing film resources for interprofessional education: effective partnerships. PMID- 26494088 TI - Team-based learning during clerkships: a cohort study. PMID- 26494089 TI - Interprofessional projects promote and strengthen interdisciplinary collaboration. PMID- 26494090 TI - Implementing patient safety interprofessional practice in developing regions. PMID- 26494091 TI - A blended-learning format to support peer tutors. PMID- 26494092 TI - Innovative intervention to improve fellows' research training. PMID- 26494093 TI - Simulation and feedback debriefing as motivational teaching tools. PMID- 26494094 TI - A faculty development blog: curated and convenient. PMID- 26494095 TI - Clicker system improvement with a web technology system. PMID- 26494096 TI - Using smartphones to learn exercise physiology. PMID- 26494097 TI - A headset communication system for interventional radiology training. PMID- 26494098 TI - Using a mobile application to facilitate post-simulation debriefing. PMID- 26494099 TI - Open access video resource for paediatric exam revision. PMID- 26494100 TI - Patient-perspective video feedback for trauma training. PMID- 26494101 TI - Practical histology in tune with the times. PMID- 26494102 TI - Feedback just in time: group-ePortfolios for PBL. PMID- 26494104 TI - Feedback and evaluation in an undergraduate teaching skills course. PMID- 26494105 TI - Regioselective Synthesis and Characterization of Multinuclear Convex-Bound Ruthenium-[n]Cycloparaphenylene (n = 5 and 6) Complexes. AB - Mono- and multinuclear complexes of ruthenium and [n]cycloparaphenylene (CPP, n = 5 and 6) were synthesized in excellent yields through ligand exchange of the cationic complex [(Cp)Ru(CH3CN)3](PF6) with CPP. In the multinuclear complexes, ruthenium selectively coordinated to alternate paraphenylene units to give bis- and tris-coordinated Ru complexes for [5] and [6]CPPs, respectively. Single crystal X-ray analysis revealed the Ru was coordinated with eta(6)-hapticity on the convex surface of CPP. PMID- 26494106 TI - Efficient Epimerization of Aldoses Using Layered Niobium Molybdates. AB - Both non-acidic LiNbMoO6 and strongly acidic HNbMoO6 efficiently catalyze the epimerization of sugars including glucose, mannose, xylose, and arabinose in water. The reactions over these oxides reached almost equilibrium within a few hours where yields of corresponding epimers from glucose, xylose, and arabinose were 24-29%. The layered mixed oxides functioned as heterogeneous catalysts and could be reused without loss of activity, whereas bulk molybdenum oxide MoO3 was completely dissolved during the reaction. A (13)C substitution experiment showed that the reaction proceeds through a 1,2-rearrangement mechanism. The surface Mo octahedra were responsible for the activity. The layered HNbMoO6 could also afford mannose from cellobiose through hydrolysis and successive epimerization. PMID- 26494107 TI - Divergent biophysical controls of aquatic CO2 and CH4 in the World's two largest rivers. AB - Carbon emissions to the atmosphere from inland waters are globally significant and mainly occur at tropical latitudes. However, processes controlling the intensity of CO2 and CH4 emissions from tropical inland waters remain poorly understood. Here, we report a data-set of concurrent measurements of the partial pressure of CO2 (pCO2) and dissolved CH4 concentrations in the Amazon (n = 136) and the Congo (n = 280) Rivers. The pCO2 values in the Amazon mainstem were significantly higher than in the Congo, contrasting with CH4 concentrations that were higher in the Congo than in the Amazon. Large-scale patterns in pCO2 across different lowland tropical basins can be apprehended with a relatively simple statistical model related to the extent of wetlands within the basin, showing that, in addition to non-flooded vegetation, wetlands also contribute to CO2 in river channels. On the other hand, dynamics of dissolved CH4 in river channels are less straightforward to predict, and are related to the way hydrology modulates the connectivity between wetlands and river channels. PMID- 26494108 TI - Helping Head Start Parents Promote Their Children's Kindergarten Adjustment: The Research-Based Developmentally Informed Parent Program. AB - Head Start enhances school readiness during preschool, but effects diminish after children transition into kindergarten. Designed to promote sustained gains, the Research-based Developmentally Informed (REDI) Parent program (REDI-P) provided home visits before and after the kindergarten transition, giving parents evidence based learning games, interactive stories, and guided pretend play to use with their children. To evaluate impact, two hundred 4-year-old children in Head Start REDI classrooms were randomly assigned to REDI-P or a comparison condition (mail home math games). Beyond the effects of the classroom program, REDI-P promoted significant improvements in child literacy skills, academic performance, self directed learning, and social competence, demonstrating the utility of the approach in promoting gains in cognitive and social-emotional skills evident after the transition into kindergarten. PMID- 26494109 TI - Genetic and functional characterization of HIV-1 Vif on APOBEC3G degradation: First report of emergence of B/C recombinants from North India. AB - HIV-1 is characterized by high genetic heterogeneity which is a challenge for developing therapeutics. Therefore, it is necessary to understand the extent of genetic variations that HIV is undergoing in North India. The objective of this study was to determine the role of genetic and functional role of Vif on APOBEC3G degradation. Vif is an accessory protein involved in counteracting APOBEC3/F proteins. Genetic analysis of Vif variants revealed that Vif C variants were closely related to South African Vif C whereas Vif B variants and Vif B/C showed distinct geographic locations. This is the first report to show the emergence of Vif B/C in our population. The functional domains, motifs and phosphorylation sites were well conserved. Vif C variants differed in APOBEC3G degradation from Vif B variants. Vif B/C revealed similar levels of APOBEC3G degradation to Vif C confirming the presence of genetic determinants in C-terminal region. High genetic diversity was observed in Vif variants which may cause the emergence of more complex and divergent strains. These results reveal the genetic determinants of Vif in mediating APOBEC3G degradation and highlight the genetic information for the development of anti-viral drugs against HIV. IMPORTANCE: Vif is an accessory HIV-1 protein which plays significant role in the degradation of human DNA-editing factor APOBEC3G, thereby impeding the antiretroviral activity of APOBEC3G. It is known that certain natural polymorphisms in Vif could degrade APOBEC3G relatively higher rate, suggesting its role in HIV-1 pathogenesis. This is the first report from North India showcasing genetic variations and novel polymorphisms in Vif gene. Subtype C is prevalent in India, but for the first time we observed putative B/C recombinants with a little high ability to degrade APOBEC3G indicating adaptation and evolving nature of virus in our population. Indian Vif C variants were able to degrade APOBEC3G well in comparison to Vif B variants. These genetic changes were most likely selected during adaptation of HIV to our population. These results elucidate that the genetic determinants of Vif and highlights the potential targets for therapeutics. PMID- 26494110 TI - Exploring Coping and Social Support with Gender and Education Among People Living with HIV in China. AB - Social support promotes positive coping strategies among people living with HIV (PLH); however, little is known about the various aspects of social support and their distinct effects on coping. The present study investigates the specific links between coping and perceived social support with respect to gender and education among PLH. A total of 522 PLH in Anhui, China, participated in an assessment that collected data on demographics, perceived tangible and emotional support, and cognitive and behavioral coping. The assessment was conducted using the computer-assisted personal interviewing method. The data were analyzed using linear mixed models. Emotional support was significantly associated with both cognitive and behavioral coping. Tangible support was significantly associated with behavioral coping but not with emotional coping. Women reported significantly lower levels of emotional support, cognitive coping, and behavioral coping than men did. Significant associations between tangible support and coping were found only among illiterate males. Women living with HIV are in greater need of social support and coping strategies. Future interventions should be gender specific, with targeted support for women with lower education levels to enhance their coping strategies. PMID- 26494111 TI - Quantitative assessment of faecal shedding of beta-lactam-resistant Escherichia coli and enterococci in dogs. AB - Quantitative data on faecal shedding of antimicrobial resistant bacteria are crucial to assess the risk of transmission from dogs to other animals as well as humans. In this study we investigated prevalence and concentrations of beta lactam-resistant Escherichia coli and enterococci in the faeces of 108 dogs presenting at a veterinary hospital in Denmark. The dogs had not been treated with antimicrobials for 4 weeks prior to the study. Total E. coli and enterococci were quantified by counts on MacConkey and Slanetz-Bartley, respectively. Resistant E. coli and enterococci were counted on the same media containing relevant antibiotic concentrations, followed by species identification using MALDI-TOF. Ampicillin- and cefotaxime-resistant E. coli were detected in 40% and 8% of the dogs, respectively, whereas approximately 15% carried ampicillin resistant enterococci, mainly Enterococcus faecium. In the faeces of the carriers, the proportion of resistant strains in the total bacterial species population was on average 15% for both ampicillin-resistant E. coli (median faecal load 3.2*10(4)cfu/g) and E. faecium (5.8*10(2) cfu/g), and 4.6% for cefotaxime-resistant E. coli (8.6*10(3) cfu/g). Cefotaxime resistance was associated with the presence of blaCTX-M-1 (n=4), blaCMY-2 (n=4) or multiple mutations in the promoter and coding region of chromosomal ampC (n=1). Altogether the results indicate that the risks of zoonotic transmission of beta-lactam resistant bacteria via human exposure to canine faeces greatly vary amongst individual dogs and are influenced by unidentified factors other than recent antimicrobial use. PMID- 26494112 TI - Bos taurus papillomavirus (BPV) E6 protein: Sequence analysis and molecular evolution. PMID- 26494113 TI - Prevalence and genetic diversity of extended-spectrum beta-lactamase (ESBL) producing Escherichia coli in nursing homes in Bavaria, Germany. AB - Main goal of this study was to determine the prevalence and molecular epidemiology of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae among 156 nursing home residents in Bavaria and to compare the results with healthy individuals from the Bavarian community. Intestinal colonisation by ESBL-producing Escherichia coli was detected in 23 nursing home residents (14.7%) using MacConkey agar supplemented with cefotaxime (1mg/L) for screening and the combined disc method for ESBL confirmation. Antimicrobial susceptibility testing revealed co-resistance to ciprofloxacin in 86.9% of the ESBL-producers. All isolates harboured CTX-M-ESBL with CTX-M-15 (65.2%) and CTX-M 27 (21.7%) as the most common types. Moreover, 16 isolates (69.6%) could be assigned by PCR-typing to the epidemic clonal lineage E. coli O25b-ST131. Further typing by rep-PCR and XbaI-macrorestriction with subsequent pulsed-field gel electrophoresis, respectively, revealed that two or more residents shared the same ESBL-producing E. coli clone in four nursing homes. In conclusion, we could show a high prevalence of ESBL-producing E. coli in Bavarian nursing homes (14.7%) compared to the healthy population (6.3%). Although the prevalence of ESBL-type CTX-M-15 in E. coli was similar in nursing home residents (65.2%) and healthy individuals (46%) the presence of E. coli O25b-ST131 clones differed substantially (69.6% and 14.2%, respectively). Furthermore, this study demonstrates that a person-to-person transmission or a common source of infection for ESBL-producing microorganisms may occur in these facilities. Therefore, basic hygiene measures should be assiduously implemented to prevent the further spread of these multidrug-resistant bacteria. PMID- 26494114 TI - Do Patients with Complete Spinal Cord Injury Benefit from Early Surgical Decompression? Analysis of Neurological Improvement in a Prospective Cohort Study. AB - The prognosis for patients with a complete traumatic spinal cord injury (SCI) is generally poor. It is unclear whether some subgroups of patients with a complete traumatic SCI could benefit from early surgical decompression of the spinal cord. The objectives of this study were: (1) to compare the effect of early and late surgical decompression on neurological recovery in complete traumatic SCI and (2) to assess whether the impact of surgical timing is different in patients with cervical or thoracolumbar SCI. A prospective cohort study was followed in a single Level 1 Trauma Center specializing in SCI care. All consecutive patients who sustained a traumatic SCI and were referred between 2010 and 2013 were screened for eligibility. Neurological status was assessed systematically using the American Spinal Injury Association impairment scale (AIS) at arrival to the trauma center and at rehabilitation discharge. Patients operated within 24 h of the trauma were compared with patients operated later than 24 h after the trauma. Potential confounders such as age, Injury Severity Score (ISS), smoking history, body mass index (BMI), Glasgow Coma Scale (GCS) score, and duration of follow-up were recorded. Fifty-three patients with complete SCI were included in the study: 33 thoracolumbar and 20 cervical SCIs. The 38 patients operated <24 h were generally younger than the 15 patients operated >= 24 h (p = 0.049). Overall, 28% (15/53) of complete SCI had improvement in AIS: 34% (13/38) who were operated <24 h and 13% (2/15) who were operated >= 24 h (p = 0.182). Sixty-four percent (9/14) of cervical complete SCI operated <24 h had improvement in AIS as opposed to none in the subgroup of six complete cervical SCI operated >= 24 h (p = 0.008). Surgical decompression within 24 h in complete SCI may optimize neurological recovery, especially in patients with cervical SCI. PMID- 26494115 TI - Stereotactic body radiotherapy for lung metastases as oligo-recurrence: a single institutional study. AB - The purpose of this study was to investigate clinical outcomes following stereotactic body radiotherapy (SBRT) for lung metastases as oligo-recurrence. From May 2003 to June 2014, records for 66 patients with 76 oligo-recurrences in the lungs treated with SBRT were retrospectively reviewed. Oligo-recurrence primary sites and patient numbers were as follows: lungs, 31; colorectal, 13; head and neck, 10; esophagus, 3; uterus, 3; and others, 6. The median SBRT dose was 50 Gy (range, 45-60 Gy) administered in a median of 5 (range, 5-9) fractions. All patients received SBRT, with no acute toxicity. Surviving patients had a median follow-up time of 36.5 months. The 3-year rates of local control, overall survival and disease-free survival were 90.6%, 76.0% and 53.7%, respectively. Longer disease-free interval from initial treatment to SBRT, and non-colorectal cancer were both associated with favorable outcomes. Disease progression after SBRT occurred in 31 patients, most with distant metastases (n = 24) [among whom, 87.5% (n = 21) had new lung metastases]. Among these 21 patients, 12 were judged as having a second oligo-recurrence. Additional SBRT was performed for these 12 patients, and all 12 tumors were controlled without disease progression. Three patients (4.5%) developed Grade 2 radiation pneumonitis. No other late adverse events of Grade >=2 were identified. Thus, SBRT for oligo-recurrence achieved acceptable tumor control, with additional SBRT also effective for selected patients with a second oligo-recurrence after primary SBRT. PMID- 26494117 TI - Insight into the Mechanism of the Initial Reaction of an OH Radical with DNA/RNA Nucleobases: A Computational Investigation of Radiation Damage. AB - Earlier theoretical investigations of the mechanism of radiation damage to DNA/RNA nucleobases have claimed OH radical addition as the dominating pathway based solely on energetics. In this study we supplement calculations of energies with the kinetics of all possible reactions with the OH radical through hydrogen abstraction and OH radical addition onto carbon sites, using DFT at the omegaB97X D/6-311++G(2df,2pd) level with the Eckart tunneling correction. The overall rate constants for the reaction with adenine, guanine, thymine, and uracil are found to be 2.17*10(-12) , 5.64*10(-11) , 2.01*10(-11) , and 5.03*10(-12) cm(3) molecules(-1) s(-1) , respectively, which agree exceptionally well with experimental values. We conclude that abstraction of the amine group hydrogen atoms competes with addition onto C8 as the most important reaction pathway for the purine nucleobases, while for the pyrimidine nucleobases addition onto C5 and C6 competes with the abstraction of H1 . Thymine shows favourability against abstraction of methyl hydrogens as the dominating pathway based on rate constants. These mechanistic conclusions are partly explained by an analysis of the electrostatic potential together with HOMO and LUMO orbitals of the nucleobases. PMID- 26494116 TI - Multi-institutional retrospective analysis of learning curves on dosimetry and operation time before and after introduction of intraoperatively built custom linked seeds in prostate brachytherapy. AB - This multi-institutional retrospective analysis examined learning curves for dosimetric parameters and operation time after introduction of intraoperatively built custom-linked (IBCL) seeds. Data from consecutive patients treated with seed implantation before and after introduction of IBCL seeds (loose seed, n = 428; IBCL seed, n = 426) were collected from 13 centers. Dose-volume histogram parameters, operation times, and seed migration rates were compared before and after introduction of IBCL seeds. At the 1-month CT analysis, no significant differences were seen in dose to 90% of prostate volume between before and after IBCL seed introduction. No learning curve for dosimetry was seen. Prostate and rectal volume receiving at least 150% of prescription dose (V150 and RV150) were higher in the loose-seed group than in the IBCL-seed group. Operation time was extended by up to 10 min when IBCL seeds were used, although there was a short learning curve of about five patients. The percentage of patients with seed migration in the IBCL-seed group was one-tenth that in the loose-seed group. Our study revealed no dosimetric demerits, no learning curve for dosimetry, and a slightly extended operation time for IBCL seeds. A significant reduction in the rate of seed migration was identified in the IBCL-seed group. PMID- 26494118 TI - Left Ventricular Thrombus in the Setting of Normal Left Ventricular Function in Patients with Crohn's Disease. AB - Crohn's disease results in a hypercoagulable state increasing the risk of venous or arterial thromboembolism. Cardiac involvement has not been routinely identified. Two cases are presented to illustrate that patients with Crohn's disease may represent an exception to the rule that left ventricular apical thrombus should be associated with an underlying wall motion abnormality and reduction in left ventricular ejection fraction. PMID- 26494119 TI - Information, connection and giving back: peer support outcomes for families following acquired brain injury in South Australia. AB - This study aimed to identify the experiences and outcomes of participation in Families4Families Inc., a peer support network for families following acquired brain injury (ABI) in South Australia. Prior to the programme's launch in January 2013, new members of the network were invited to participate in pre- and post programme phone interviews to identify benefits and limitations of the programme, and identify outcomes of participation. Fifty-five members (20 people with ABI; 35 caregivers) participated in pre-programme interviews, with 34 repeating the final interview at the end of the 18-month pilot programme in June 2014. Interview transcripts were imported into Nvivo 10, where comments were analysed using inductive data-driven thematic analysis. Responses to rating questions were analysed using SPSS 20. Attendance records indicate that 39 of 55 participants were involved in the programme (12 active, 27 occasional) and 16 participants did not attend. Active attenders reported that they provided and received higher levels of support and information than those who attended only occasionally, including the significantly higher development of new friendships and contacts (P < 0.001). Statistically significant improvements in knowledge of services by both active and occasional attenders were reported (P = 0.014 and 0.026 respectively) with non-significant improvements for non-attenders. Qualitative analysis of interview transcripts revealed three major thematic benefits of involvement. These include the opportunity to access information, receive emotional support and give back to others in the network. Reasons for no longer participating in the network are explored. Peer support programmes can enable families to share experiences, knowledge, positive coping strategies, understanding of systems and develop new social networks that last beyond the programme. The continuing need for extended regional access is highlighted, with follow-up and referral to counselling and other services also critical to ensure members are appropriately supported through difficult personal experiences. PMID- 26494120 TI - Chronic Total Uterine Inversion in a Young Adult Patient. AB - BACKGROUND: Chronic uterine inversion is a very rare and life-threatening disease. It requires emergent treatment. CASE REPORT: We present the case of a 17 year-old patient with chronic uterine inversion. A fragile, bleeding, and soft mass, which filled the entire vagina, was seen during vaginal inspection. There was also a hard and tight cervical ring palpated behind the mass. She was operated on with Haultain technique. She was treated in the first postpartum year. She had normal menstrual bleeding and normal sexual intercourse after 1 month of outpatient control. CONCLUSIONS: Immediate diagnosis and treatment of isolated chronic inversion decreases maternal morbidity and mortality. PMID- 26494121 TI - BnaC9.SMG7b Functions as a Positive Regulator of the Number of Seeds per Silique in Brassica napus by Regulating the Formation of Functional Female Gametophytes. AB - Number of seeds per silique (NSS) is an important determinant of seed yield potential in Brassicaceae crops, and it is controlled by naturally occurring quantitative trait loci. We previously mapped a major quantitative trait locus, qSS.C9, on the C9 chromosome that controls NSS in Brassica napus. To gain a better understanding of how qSS.C9 controls NSS in B. napus, we isolated this locus through a map-based cloning strategy. qSS.C9 encodes a predicted small protein with 119 amino acids, designated as BnaC9.SMG7b, that shows homology with the Ever ShorterTelomere1 tertratricopeptide repeats and Ever Shorter Telomere central domains of Arabidopsis (Arabidopsis thaliana) SUPPRESSOR WITH MORPHOGENETIC EFFECTS ON GENITALIA7 (SMG7). BnaC9.SMG7b plays a role in regulating the formation of functional female gametophyte, thus determining the formation of functional megaspores and then mature ovules. Natural loss or artificial knockdown of BnaC9.SMG7b significantly reduces the number of functional ovules per silique and thus, results in decreased seed number, indicating that qSS.C9 is a positive regulator of NSS in B. napus. Sequence and function analyses show that BnaC9.SMG7b experiences a subfunctionalization process that causes loss of function in nonsense-mediated mRNA decay, such as in Arabidopsis SMG7. Haplotype analysis in 84 accessions showed that the favorable BnaC9.SMG7b alleles are prevalent in modern B. napus germplasms, suggesting that this locus has been a major selection target of B. napus improvement. Our results represent the first step toward unraveling the molecular mechanism that controls the natural variation of NSS in B. napus. PMID- 26494123 TI - Graphene-supported Pd catalyst for highly selective hydrogenation of resorcinol to 1, 3-cyclohexanedione through giant pi-conjugate interactions. AB - The selective hydrogenation of resorcinol (RES) to 1, 3-cyclohexanedione (1,3 CHD) without the addition of alkali is a big challenge. In this article, a novel reduced graphene oxide (rGO) supported Pd catalyst was prepared through co reduction method, over which we obtained 99.9% of resorcinol conversion and 94.2% of the ever-reported highest 1,3-cyclohexanedione selectivity at 25 degrees C in only CH2Cl2 solvent. The excellent selectivity was contributed to the strong pi pi and p-pi interactions between the graphene nanosheet and the benzene ring as well as hydroxyl in RES molecule. The followed adsorption experiment and Raman analysis also showed the existence of aromatic graphite structures in rGO, which exhibited stronger adsorption towards RES than towards 1,3-CHD. PMID- 26494122 TI - Bortezomib Improves Adoptive T-cell Therapy by Sensitizing Cancer Cells to FasL Cytotoxicity. AB - Cancer immunotherapy shows great promise but many patients fail to show objective responses, including in cancers that can respond well, such as melanoma and renal adenocarcinoma. The proteasome inhibitor bortezomib sensitizes solid tumors to apoptosis in response to TNF-family death ligands. Because T cells provide multiple death ligands at the tumor site, we investigated the effects of bortezomib on T-cell responses in immunotherapy models involving low-avidity antigens. Bortezomib did not affect lymphocyte or tissue-resident CD11c(+)CD8(+) dendritic cell counts in tumor-bearing mice, did not inhibit dendritic cell expression of costimulatory molecules, and did not decrease MHC class I/II associated antigen presentation to cognate T cells. Rather, bortezomib activated NF-kappaB p65 in CD8(+) T cells, stabilizing expression of T-cell receptor CD3zeta and IL2 receptor-alpha, while maintaining IFNgamma secretion to improve FasL-mediated tumor lysis. Notably, bortezomib increased tumor cell surface expression of Fas in mice as well as human melanoma tissue from a responsive patient. In renal tumor-bearing immunodeficient Rag2(-/-) mice, bortezomib treatment after adoptive T-cell immunotherapy reduced lung metastases and enhanced host survival. Our findings highlight the potential of proteasome inhibitors to enhance antitumor T-cell function in the context of cancer immunotherapy. PMID- 26494124 TI - Diffusion weighted imaging for the differentiation of breast tumors: From apparent diffusion coefficient to high order diffusion tensor imaging. AB - BACKGROUND: To compare "standard" diffusion weighted imaging, and diffusion tensor imaging (DTI) of 2(nd) and 4(th) -order for the differentiation of malignant and benign breast lesions. METHODS: Seventy-one patients were imaged at 3 Tesla with a 16-channel breast coil. A diffusion weighted MRI sequence including b = 0 and b = 700 in 30 directions was obtained for all patients. The image data were fitted to three different diffusion models: isotropic model - apparent diffusion coefficient (ADC), 2(nd) -order tensor model (the standard model used for DTI) and a 4(th) -order tensor model, with increased degrees of freedom to describe anisotropy. The ability of the fitted parameters in the different models to differentiate between malignant and benign tumors was analyzed. RESULTS: Seventy-two breast lesions were analyzed, out of which 38 corresponded to malignant and 34 to benign tumors. ADC (using any model) presented the highest discriminative ability of malignant from benign tumors with a receiver operating characteristic area under the curve (AUC) of 0.968, and sensitivity and specificity of 94.1% and 94.7% respectively for a 1.33 * 10(-3) mm(2) /s cutoff. Anisotropy measurements presented high statistical significance between malignant and benign tumors (P < 0.001), but with lower discriminative ability of malignant from benign tumors than ADC (AUC of 0.896 and 0.897 for fractional anisotropy and generalized anisotropy respectively). Statistical significant difference was found between generalized anisotropy and fractional anisotropy for cancers (P < 0.001) but not for benign lesions (P = 0.87). CONCLUSION: While anisotropy parameters have the potential to provide additional value for breast applications as demonstrated in this study, ADC exhibited the highest differentiation power between malignant and benign breast tumors. PMID- 26494125 TI - The 5alpha-reductase inhibitor finasteride is not associated with alterations in sleep spindles in men referred for polysomnography. AB - OBJECTIVE: Endogenous neurosteroids that potentiate the gamma-aminobutyric acid type A (GABAA ) receptor are thought to enhance the generation of sleep spindles. This study tested the hypothesis that the 5alpha-reductase inhibitor finasteride, an agent associated with reductions in neurosteroids, would be associated with reduced sleep spindles in men referred for polysomnography. METHODS: Spectral analysis and spindle waveform detection were performed on electroencephalographic (EEG) sleep data in the 11-16 Hz sigma band, as well as several subranges, from 27 men taking finasteride and 27 matched comparison patients (ages 18 to 81 years). RESULTS: No significant differences between groups were observed for spectral power or sleep spindle morphology measures, including spindle density, amplitude, duration, and integrated spindle activity. CONCLUSIONS: Contrary to our hypothesis, these findings demonstrate that finasteride is not associated with alterations in sleep spindle range activity or spindle morphology parameters. PMID- 26494126 TI - Cooperative Cluster Metalation and Ligand Migration in Zirconium Metal-Organic Frameworks. AB - Cooperative cluster metalation and ligand migration were performed on a Zr-MOF, leading to the isolation of unique bimetallic MOFs based on decanuclear Zr6M4 (M = Ni, Co) clusters. The M(2+) reacts with the MU3-OH and terminal H2O ligands on an 8-connected [Zr6O4(OH)8(H2O)4] cluster to form a bimetallic [Zr6M4O8(OH)8(H2O)8] cluster. Along with the metalation of Zr6 cluster, ligand migration is observed in which a Zr-carboxylate bond dissociates to form a M carboxylate bond. Single-crystal to single-crystal transformation is realized so that snapshots for cooperative cluster metalation and ligand migration processes are captured by successive single-crystal X-ray structures. In(3+) was metalated into the same Zr-MOF which showed excellent catalytic activity in the acetaldehyde cyclotrimerization reaction. This work not only provides a powerful tool to functionalize Zr-MOFs with other metals, but also structurally elucidates the formation mechanism of the resulting heterometallic MOFs. PMID- 26494127 TI - Morphological Bases of Neuronal Hyperexcitability in Neurodegeneration. PMID- 26494129 TI - Adoption of a national antimicrobial guide (SWAB-ID) in the Netherlands. PMID- 26494128 TI - TLR3 ligand Poly IC Attenuates Reactive Astrogliosis and Improves Recovery of Rats after Focal Cerebral Ischemia. AB - AIMS: Brain ischemia activates astrocytes in a process known as astrogliosis. Although this process has beneficial effects, excessive astrogliosis can impair neuronal recovery. Polyinosinic-polycytidylic acid (Poly IC) has shown neuroprotection against cerebral ischemia-reperfusion injury, but whether it regulates reactive astrogliosis and glial scar formation is not clear. METHODS: We exposed cultured astrocytes to oxygen-glucose deprivation/reoxygenation (OGD/R) and used a rat middle cerebral artery occlusion (MCAO)/reperfusion model to investigate the effects of Poly IC. Astrocyte proliferation and proliferation related molecules were evaluated by immunostaining and Western blotting. Neurological deficit scores, infarct volumes and neuroplasticity were evaluated in rats after transient MCAO. RESULTS: In vitro, Poly IC inhibited astrocyte proliferation, upregulated Toll-like receptor 3 (TLR3) expression, upregulated interferon-beta, and downregulated interleukin-6 production. These changes were blocked by a neutralizing antibody against TLR3, suggesting that Poly IC function is TLR3-dependent. Moreover, in the MCAO model, Poly IC attenuated reactive astrogliosis, reduced brain infarction volume, and improved neurological function. In addition, Poly IC prevented MCAO-induced reductions in soma size, dendrite length, and number of dendritic bifurcations in cortical neurons of the infarct penumbra. CONCLUSIONS: By ameliorating astrogliosis-related damage, Poly IC is a potential therapeutic agent for attenuating neuronal damage and promoting recovery after brain ischemia. PMID- 26494130 TI - Panobinostat PK/PD profile in combination with bortezomib and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma. AB - PURPOSE: Panobinostat, a potent pan-deacetylase inhibitor, improved progression free survival (PFS) in patients with relapsed and refractory multiple myeloma when combined with bortezomib and dexamethasone in a phase 3 trial, PANORAMA-1. This study aims to explore exposure-response relationship for panobinostat in this combination in a phase 1 trial, B2207 and contrast with data from historical single-agent studies. METHODS: Panobinostat plasma concentration-time profiles were obtained in patients from PANORAMA-1 (n = 12) and B2207 (n = 12) trials. Overall response rates (ORR) and major adverse events (AE) by panobinostat exposure were investigated in the B2207 trial. Panobinostat PK data from combination trials were contrasted with data from single-agent studies. RESULTS: At maximum tolerated dose (MTD), the geometric mean of panobinostat area under curve from 0 to 24 h (AUC0-24) was 47.5 ng h/mL (77 % CV), and maximum plasma concentration (Cmax) was 8.1 ng/mL (90 % CV). These values were comparable with exposure data obtained in PANORAMA-1, but were 20 % lower than those without dexamethasone, and ~ 50 % lower from single-agent trials, likely due to enzyme induction by dexamethasone. Higher levels of panobinostat exposure were associated with higher response rates and higher incidences of diarrhea and thrombocytopenia. CONCLUSIONS: Apparent panobinostat exposure-AE and exposure-ORR relationships were observed when combined with bortezomib and dexamethasone in the treatment of patients with relapsed and refractory multiple myeloma. The addition of dexamethasone facilitated best response even though plasma exposure of panobinostat was reduced. Combination with a strong enzyme inducer should be avoided in future trials to prevent further reduction of panobinostat exposure. PMID- 26494131 TI - Reassessment of osteoporosis-related femoral fractures and economic burden in Saudi Arabia. AB - The current study reassesses the prevalence of fragility fractures and lifetime costs in the Eastern Province of Saudi Arabia. Forty-two percent (391) of the fractures were at the neck of the femur, and 38.6 % (354) were inter-trochanteric fractures. The overall incidence was assessed to be 7528 (1,300,336 population 55 years or older) with the direct cost of SR564.75 million ($150.60 million). A National Fracture Registry and osteoporosis awareness programs are recommended. PURPOSE: Proximal femur fragility fractures are reported to be increasing worldwide due to increased life expectancy. The current study is carried out to assess the incidence of such fractures in the Eastern Province of Saudi Arabia and to assess the costs incurred in managing them annually. Finally, by extrapolating the data, the study can calculate the overall economic burden in Saudi Arabia. METHODS: The data of fragility proximal femur fractures was collected from 24 of 28 hospitals in the Eastern Province. The data included age, sex, mode of injury, type of fracture, prescribed drug (and its cost), and length of hospital stay. Population statistics were obtained from the Department of Statistics of the Saudi Arabian government Web site. RESULTS: Twenty-four hospitals (85 %) participated in the study. A total of 780 fractures were sustained by 681 patients. Length of stay in the hospital averaged 23.28 +/- 13.08 days. The projected fracture rate from all the hospitals would be 917 (an incidence of 5.81/1000), with a total cost of SR68.77 million. Further extrapolation showed that the overall incidence could be 7528 (1,300,336 population 55 years or older) with the direct cost of SR564.75 million ($150.60 million). CONCLUSIONS: Osteoporosis-related femoral fractures in Saudi Arabia are significant causes of morbidity besides incurring economic burden. We believe that a National Fracture Registry needs to be established, and osteoporosis awareness programs should be instituted in every part of Saudi Arabia so that these patients can be diagnosed early and treated appropriately to reduce both the number of fractures and the economic burden of the fractures. PMID- 26494132 TI - Change in incidence of hip fracture in Gwangju City and Jeonnam Province, Korea, over 20 years. AB - This study determined the incidence of hip fractures in Gwangju city and Jeonnam province of Korea in 2011 and compared it with the rates in the same area in 1991 and 2001. INTRODUCTION: This study determined the incidence of hip fracture in Gwangju city and Jeonnam province in Korea in 2011 and compared it with the rates in the same area in 1991 and 2001, with the aim of identifying any changes in 2011. METHODS: Korea Health Insurance Review Agency patient data from Gwangju city and Jeonnam province for the period 2011 January 1 to December 31 was analyzed. All claims and records of patients >= 50 years of age with a diagnosis of fracture of the neck of the femur, pertrochanteric fracture, and hip fracture related surgeries including open reduction and internal fixation, closed reduction and osteosynthesis, total hip replacement, or bipolar hemiarthroplasty were analyzed. Population figures were obtained from the Korea National Statistical Office. Age- and sex-specific annual incidences were calculated. The 2011 data was compared with published data from 1991 to 2001. RESULTS: There were 1590 hip fractures in 2011, representing a crude incidence of 14.0/10,000. The incidence was 9.7/10,000 in males and 17.5/10,000 in females. The number of hip fractures and fracture incidence was 247 and 3.3/10,000 in 1991 and 1152 and 13.3/10,000 in 2001, respectively. There was a fourfold increase of fracture incidence between 1991 and 2001. Thereafter, the number of fractures increased only by 5.2 %. However, the number of arthroplasties done increased significantly. CONCLUSIONS: The incidence of fractures increased considerably between 1991 and 2001, with less increase in the ensuing 10 years. PMID- 26494133 TI - Attitudes of parents of Klinefelter boys and pediatricians towards neonatal screening and fertility preservation techniques in Klinefelter syndrome. AB - To evaluate the attitude of parents of Klinefelter syndrome (KS) boys and pediatricians with regard to early detection of KS and fertility preservation, a specific questionnaire investigating the acceptability towards neonatal screening for KS and the use of testicular biopsy and sperm collection was designed. The responses of 49 pediatricians and 18 parents were evaluated. All parents and 67% of the pediatricians consider neonatal screening for KS to be a good option. A total of 83.3% of the parents agree on performing a testicular biopsy in their pubertal KS boy, 72.2% are in favor of banking spermatozoa after masturbation while 77.7% agree on spermatozoa banking after penile vibro-stimulation or rectal electro-stimulation under general anesthesia. Sixty-nine percent of pediatricians would counsel parents and KS adolescents in favor of early detection and cryopreservation of spermatozoa after masturbation, and 71.2% agrees on testicular biopsy to detect spermatozoa or eventually spermatogonial stem cells (SSCs) for cryopreservation in minor KS patients. CONCLUSION: The majority of KS parents and pediatricians, completing a specific designed questionnaire on fertility preservation modalities, were in favor of neonatal screening of KS. Both sperm collection and SSC collection are highly appreciated by parents and pediatricians, despite the currently experimental character of these fertility preservation strategies. PMID- 26494134 TI - Seasonal variation of diseases in children: a 6-year prospective cohort study in a general hospital. AB - Seasonal variation in pediatrics has been well described in some infectious diseases, asthma, and diabetes, but data on seasonality for other diseases in children are sparse. To explore the extent of seasonal variation of the entire pediatric field, we analyzed diagnostic codes of all newly referred patients (n = 51,054) to our pediatric department of a large teaching hospital in the Netherlands over a 6-year period (2008-2013). Seasonality was analyzed using simple moving averages, the standard error of the mean (SEM) and the percentage monthly variation. We defined seasonal variation as a visually recognizable periodic pattern in every year in combination with a standard error of the mean > 0.20. Four diseases fulfilled our definition of seasonality: respiratory tract infections (peak in January, +107.0 %), gastroenteritis (peak in February-March, +95.8 % and +112.9 %, respectively), functional complaints (peak in March, +34.0 %, and November, +13.4 %), and asthma (peak in March, +27.8 %, and October, +17.5 %). Together, these four categories comprised 21.2 % of all newly referred patients. CONCLUSION: Seasonal variation occurs in more than one fifth of all patients with pediatric disease. We demonstrated not only seasonal variation for respiratory tract infections, gastroenteritis, and asthma, but also for functional complaints. WHAT IS KNOWN: * Seasonal variation has been described for pediatric diseases such as bronchiolitis, gastroenteritis, asthma, and diabetes. * Information on seasonality in other pediatric fields is sparse but may be helpful in understanding pathophysiology and workforce planning. What is new: * This study confirmed seasonal variation in respiratory infection diseases gastroenteritis and asthma. * Moreover, it showed seasonal variation for functional complaints for example (abdominal pain and headache), which has not been described previously. PMID- 26494135 TI - Cloning, Expression, and Characterization of budC Gene Encoding meso-2,3 Butanediol Dehydrogenase from Bacillus licheniformis. AB - The budC gene encoding a meso-2,3-butanediol dehydrogenase (BlBDH) from Bacillus licheniformis was cloned and overexpressed in Escherichia coli BL21(DE3). Sequence analysis reveals that this BlBDH belongs to short-chain dehydrogenase/reductase (SDR) superfamily. In the presence of NADH, BlBDH catalyzes the reduction of diacetyl to (3S)-acetoin (97.3% ee), and further to (2S,3S)-2,3-butanediol (97.3% ee and 96.5% de). Similar to other meso-2,3-BDHs, it shows oxidative activity to racemic 2,3-butanediol whereas no activity toward racemic acetoin in the presence of NAD(+). For diacetyl reduction and 2,3 butanediol oxidation, the pH optimum of BlBDH is 5.0 and 10.0, respectively. Unusually, it shows relatively high activity over a wide pH range from 5.0 to 8.0 for racemic acetoin reduction. BlBDH shows lower K m and higher catalytic efficiency toward racemic acetoin (K m = 0.47 mM, k cat /K m = 432 s(-1).mM(-1)) when compared with 2,3-butanediol (K m = 7.25 mM, k cat /K m = 81.5 s(-1).mM( 1)), indicating its physiological role in favor of reducing racemic acetoin into 2,3-butanediol. The enzymatic characterization of BlBDH provides evidence for the directed engineering of B. licheniformis for producing enantiopure 2,3 butanediol. PMID- 26494136 TI - Cloning, Overexpression, and Characterization of Halostable, Solvent-Tolerant Novel beta-Endoglucanase from a Marine Bacterium Photobacterium panuliri LBS5(T) (DSM 27646(T)). AB - A 1329 nucleotide long endoglucanase gene was amplified from marine bacterium Photobacterium panuliri strain LBS5(T).The enzyme sequence was novel as protein based similarity search revealed that it shared maximum similarity of 99% with hypothetical protein of P. aquae and 40% with endoglucanase of P. marinum AK15. The gene was cloned, overexpressed in Escherichia coli BL21 (DE3), and purified up to homogeneity using Ni-NTA affinity chromatography. The purified enzyme, designated as Cel8, was monomeric and has a molecular mass of 53 kDa. The enzyme was halostable and exhibited optimal carboxymethyl cellulase (CMCase) activity and stability at 2 M NaCl. Optimal activity was obtained at 40 degrees C and at pH 4. The enzyme exhibited remarkable stability in different organic solvents (50%, v/v), and activity increased nearly 1.5-fold in presence of butanol, isopropanol, petroleum ether, benzene, acetone, and n-hexane. It was active in Ca(2+), Ba(2+), and Ni(2+) and inhibited by Co(2+), Cd(2+), Zn(2+), Cu(2+), and Hg(2+). Under normal physiological conditions, the enzyme has 25% helix, 30% sheets, and 56% irregularities, whereas salt leads to helix to sheet transition in enzyme. Three-dimensional reconstruction analysis revealed that the enzyme has (alpha/beta)8 structure and a TIM barrel fold-like structure at the central groove of enzyme. This is the first evidenced report on halostable, organic solvent tolerant cellulase in the marine bacterial genus Photobacterium. PMID- 26494137 TI - Dilute oxalic acid pretreatment for high total sugar recovery in pretreatment and subsequent enzymatic hydrolysis. AB - Oxalic acid was evaluated as an alternative reagent to mineral inorganic acid in pretreatment of corncob to achieve high xylose yield in addition to highly digestible solid residue. A quadratic polynomial model of xylose formation was developed for optimization of pretreatment process by the response surface methodology based on the impact factors of pretreatment temperature, reaction time, acid concentration, and solid-to-liquid ratio. The highest xylose yield was 94.3 % that was obtained under the pretreatment condition of 140 degrees C for 40 min with 0.5 wt% oxalic acid at a solid loading of 7.5 %. Under these conditions, the xylose yield results of verification experiments were very close to the model prediction, which indicated that the model was applicable. The solid residue generated under this condition also demonstrated a satisfactory enzymatic digestibility and fermentability. PMID- 26494138 TI - The Effect of Light Stress and Other Culture Conditions on Photoinhibition and Growth of Dunaliella tertiolecta. AB - This work aimed to examine the effects of high light stress as well as other culture conditions including HCO3 - concentration, temperature, salinity, and pre acclimation on photoinhibition and growth of halotolerant alga Dunaliella tertiolecta. Significant photoinhibition of D. tertiolecta was observed during a short period of exposure (6 hours) to high intensity of lights (1000, 1500, and 2000 MUmol photons m-2 s-1); however, after 2 days of continuous light exposure, the alga adapted to high light stress and reached similar growth rates as low light exposure. The increase in HCO3 - concentration in the culture medium did not reduce photoinhibition, but the growth rate and chlorophyll contents increased with increasing HCO3 - concentrations. Temperature had significant effects on photoinhibition. Combined high temperature and high light intensity led to more serious photoinhibition and reduced cell growth rates, so did combined low salinity and high light intensity. Pre-acclimation by 50, 200, or 500 MUmol photons m-2 s-1 each for 1, 3, or 6 hours (a total of nine treatments) did not significantly influence photoinhibition or cell growth of D. tertiolecta, probably because the acclimation periods were not long enough. PMID- 26494139 TI - Lignocellulosic Wheat Straw-Derived Ion-Exchange Adsorbent for Heavy Metals Removal. AB - The aim of this work is to develop partially delignified Ca(2+)-and-Mg(2+)-ion exchanged product from lignocellulosic wheat straw for the removal of eight different heavy metals Pb(2+), Cd(2+), Hg(2+), Co(2+), Ni(2+), Mn(2+), Zn(2+), and Cu(2+) and for detoxification of Cr(VI). Maximum fixation capacity, pH, and initial metal concentration dependence were determined to confirm strong affinity of Pb(2+), Cd(2+), Cu(2+), Zn(2+), and Hg(2+) ions onto the product, whereas Co(2+), Ni(2+), and Mn(2+) were the least fixed. Morphology of the product characterized by scanning electron microscope showed its physical integrity. Different experimental approaches were applied to determine the role of cations such as Ca(2+), Mg(2+), and Na(+) and several functional groups present in the product in an ion exchange for the fixation of metal ions. Potentiometric titration and Scatchard and Dahlquist interpretation were employed for determination of binding site heterogeneity. Results showed strong and weak binding sites in the product. This product has advantages over other conventional processes by virtue of abundance, easy operational process, and cost reduction in waste disposal of its raw material. PMID- 26494140 TI - Plasmodium falciparum parasitaemia and malaria among pregnant women at first clinic visit in the mount Cameroon Area. AB - BACKGROUND: Pregnant women in malaria endemic areas are at high risk of P. falciparum infection and its complications. This study investigated the prevalence and risk factors for P. falciparum infection and malaria among pregnant women reporting for first antenatal care (ANC) clinic visit in the mount Cameroon area. METHODS: Venous blood samples from consented pregnant women were screened for malaria parasitaemia by light microscopy. Haemoglobin levels, white blood cell (WBC) counts, lymphocyte counts and percentage were determined using an automated haematology analyser. Socio-demographic/economic data, environmental factors and use of malaria control measures were documented. Univariate and multivariate statistical analyses were used. RESULTS: Sixty-eight (22.4%; N = 303) of the women enrolled were positive for P. falciparum parasitaemia. Malaria parasitaemia was significantly (P < 0.001) associated with febrile illness. The overall prevalence of malaria and asymptomatic infection was 16.0% (95% CI = 11 20%) and 10.5% (95% CI = 7.3-15%) respectively. A greater proportion of the malaria cases (61%) reported at the clinic during unscheduled days meanwhile women with asymptomatic parasitaemia mostly (92.8%) seek for ANC during scheduled clinic days. Lower lymphocyte percentage was significantly associated with increase parasite density (r = - 0.34; P = 0.011) and febrile status (MU = 2.46; P = 0.014). While age and gravidity were significant factors associated with P. falciparum infection and/or malaria, the presence of bush and/or standing water around human residence was an independent risk factor of P. falciparum parasitaemia (OR = 3.3: 95% CI = 1.6-7.0; P = 0.002) and malaria (OR = 5.2: 95% CI = 2.0-14; P = 0.001). Being unmarried was significantly associated with increase risk (OR = 2.6:95% CI = 1.1-6.0; P = 0.032) of P. falciparum parasitaemia. Similarly, single women (938) had a significantly higher (t = 2.70; P = 0.009) geometric mean parasite density (GMPD) compared with married women (338). CONCLUSION: Marital status and human residence in areas with bushes and/or standing water modify risk of P. falciparum infection and malaria. Education on early ANC attendance and environmental sanitation are important public health targets for malaria control in pregnancy in this setting. PMID- 26494142 TI - Next-generation sequencing and empowering personalised cancer medicine. AB - The announcement earlier this year of the US$1000 genome by Illumina has excited a debate as to when and how genomes will at last transition from the research laboratory to the clinic. Although it is still unclear what the benefit will be to patients, there is sufficient evidence supporting the importance of the genome in driving cancer development, treatment response and drug resistance. Therefore it is reasonable to assume that large-scale stratification of patients using next generation sequencing technologies will improve patient outcome in at least some common cancer types. PMID- 26494141 TI - Genetic polymorphisms and DNA methylation in exon 1 CpG-rich regions of PACAP gene and its effect on mRNA expression and growth traits in half smooth tongue sole (Cynoglossus semilaevis). AB - The pituitary adenylate cyclase activating polypeptide (PACAP) is a new type of hypophysiotropic hormone and plays an important role in regulating the synthesis and secretion of growth hormone and gonadotropin. The research on the relationship between PACAP and different growth traits would contribute to explain its function during the process of growth. Moreover, epigenetic modifications, especially DNA methylation at the CpG sites of the SNPs, play important roles in regulating gene expression. The results suggest that a SNP mutation (c.C151G) in the PACAP gene of male half smooth tongue sole (Cynoglossus semilaevis) is significantly associated with growth traits and serum physiological and biochemical parameters such as inorganic phosphorus (P < 0.05). The SNP is located in a CpG-rich region of exon 1. Intriguingly, the transition (C->G) added a new methylation site of PACAP gene. This SNP was also significantly related to the expression and methylation level of PACAP (P < 0.05). Individuals with GG genotype had faster growth rates than those of CG and CC genotypes. Moreover, GG genotype had significantly higher PACAP expression level and lower methylation level than CG and CC genotypes. In the serum indexes, only inorganic phosphorus content within GG genotypes was significantly higher than CC genotypes. This implied that the mutation and methylation status of PACAP gene could influence growth traits and this locus could be considered as a candidate genetic or epigenetic marker for Cynoglossus semilaevis molecular breeding. PMID- 26494143 TI - Clonotyping for precision oncology. AB - Advances in identifying subpopulations of cancer cells and reconstructing the clonal evolution of tumors greatly enhance our understanding of the molecular events within a patient and their context relative to one another. In the rapidly unfolding era of personalized medicine, the ability to monitor clonal dynamics throughout patient care has significant clinical implications for the appropriate development or application of targeted therapies as well as understanding the potential mechanisms driving resistance. In this review, we discuss advances in biotechnology and bioinformatics that improve precision treatment by dissecting clonal evolution, focusing first on the initial discoveries in lymphomas and leukemias followed by the more recent applications to advance our understanding of prostate cancer (PCa). PMID- 26494144 TI - Cancer 2015: a longitudinal whole-of-system study of genomic cancer medicine. AB - Genomic cancer medicine promises revolutionary change in oncology. The impacts of 'personalized medicine', based upon a molecular classification of cancer and linked to targeted therapies, will extend from individual patient outcomes to the health economy at large. To address the 'whole-of-system' impact of genomic cancer medicine, we have established a prospective cohort of patients with newly diagnosed cancer in the state of Victoria, Australia, about whom we have collected a broad range of clinical, demographic, molecular, and patient-reported data, as well as data on health resource utilization. Our goal is to create a model for investigating public investment in genomic medicine that maximizes the cost:benefit ratio for the Australian community at large. PMID- 26494145 TI - Characterization and fine mapping of a novel barley Stage Green-Revertible Albino Gene (HvSGRA) by Bulked Segregant Analysis based on SSR assay and Specific Length Amplified Fragment Sequencing. AB - BACKGROUND: Leaf color variations are common in plants. Herein we describe a natural mutant of barley cultivar Edamai No.6, whs18, whose leaf color showed stable and inheritable stage-green-revertible-albino under field condition. METHODS: Bulked Segregant Analysis (BSA) based on SSR assay and Specific Length Amplified Fragment Sequencing (SLAF-seq) was used to map the candidate gene for this trait. RESULTS: We found that leaf color of whs18 was green at seedling stage, while the seventh or eighth leaf began to show etiolation, and albino leaves emerged after a short period. The newly emerged leaves began to show stripe white before jointing stage, and normal green leaves emerged gradually. The duration of whs18 with abnormal leaf color lasted for about 3 months, which had some negative impacts on yield-related-traits. Further investigations showed that the variation was associated with changes in chlorophyII content and chloroplast development. Genetic analysis revealed that the trait was controlled by a single recessive nuclear gene, and was designed as HvSGRA in this study. Based on the F2 population derived from Edamai No.9706 and whs18, we initially mapped the HvSGRA gene on the short arm of chromosome 2H using SSR and BSA. GBMS247 on 2HS showed co-segregation with HvSGRA. The genetic distance between the other marker GBM1187 and HvSGRA was 1.2 cM. Further analysis using BSA with SLAF-seq also identified this region as candidate region. Finally, HvSGRA interval was narrowed to 0.4 cM between morex_contig_160447 and morex_contig_92239, which were anchored to two adjacent FP contigs, contig_34437 and contig_46434, respectively. Furthermore, six putative genes with high confidence in this interval were identified by POPSEQ. Further analysis showed that the substitution from C to A in the third exon of fructokinase-1-like gene generated a premature stop codon in whs18, which may lead to loss function of this gene. CONCLUSIONS: Using SSR and SLAF-seq in conjunction with BSA, we mapped HvSGRA within two adjacent FP contigs of barley. The mutation of fructokinase-1 like gene in whs18 may cause the stage green-revertible albino of barley. The current study lays foundation for hierarchical map-based cloning of HvSGRA and utilizing the gene/trait as a visualized maker in molecular breeding in future. PMID- 26494146 TI - Association between academic achievement and physical status including physical activity, aerobic and muscular fitness tests in adolescent boys. AB - OBJECTIVE: The study aimed to explore the association between academic achievement and physical status including physical activity, aerobic and muscular fitness tests in a sample of adolescents. METHODS: Five hundred and eighty 15-17 years old adolescent boys underwent standard anthropometry and various physical fitness tests (e.g., one-mile run/walk, grip strength, run speed, agility, push ups and sit and reach tests). PA was obtained by questionnaire. Academic achievement of the boys was extracted from the cumulative grade point averages (CGPA) from school records. Possible covariates/confounders such as adiposity, pubertal maturation status and socioeconomic status were obtained. RESULTS: After controlling for potential confounders PA was not significantly correlated to CGPA (P > 0.05). Among the physical fitness tests, just time in one-mile run/walk test added significant effect on prediction of CGPA (P < 0.01). None of the other fitness tests were significantly correlated to CGPA (P > 0.05). CONCLUSIONS: Aerobic fitness (but not PA and muscular fitness) was significantly correlated to better academic achievement in the adolescent boys. PMID- 26494148 TI - Comment on: Evaluation of the RAPIDEC(r) CARBA NP, the Rapid CARB Screen(r) and the Carba NP test for biochemical detection of carbapenemase-producing Enterobacteriaceae. PMID- 26494147 TI - Human oligopeptide transporter 2 (PEPT2) mediates cellular uptake of polymyxins. AB - OBJECTIVES: Polymyxins are a last-line therapy to treat MDR Gram-negative bacterial infections. Nephrotoxicity is the dose-limiting factor for polymyxins and recent studies demonstrated significant accumulation of polymyxins in renal tubular cells. However, little is known about the mechanism of polymyxin uptake into these cells. Oligopeptide transporter 2 (PEPT2) is a solute carrier transporter (SLC) expressed at the apical membrane of renal proximal tubular cells and facilitates drug reabsorption in the kidney. In this study, we examined the role of PEPT2 in polymyxin uptake into renal tubular cells. METHODS: We investigated the inhibitory effects of colistin and polymyxin B on the substrate uptake mediated through 15 essential SLCs in overexpressing HEK293 cells. The inhibitory potency of both polymyxins on PEPT2-mediated substrate uptake was measured. Fluorescence imaging was employed to investigate PEPT2-mediated uptake of the polymyxin fluorescent probe MIPS-9541 and a transport assay was conducted with MIPS-9541 and [(3)H]polymyxin B1. RESULTS: Colistin and polymyxin B potently inhibited PEPT2-mediated [(3)H]glycyl-sarcosine uptake (IC50 11.4 +/- 3.1 and 18.3 +/- 4.2 MUM, respectively). In contrast, they had no or only mild inhibitory effects on the transport activity of the other 14 SLCs evaluated. MIPS-9541 potently inhibited PEPT2-mediated [(3)H]glycyl-sarcosine uptake (IC50 15.9 MUM) and is also a substrate of PEPT2 (Km 74.9 MUM). [(3)H]polymyxin B1 was also significantly taken up by PEPT2-expressing cells (Km 87.3 MUM). CONCLUSIONS: Our study provides the first evidence of PEPT2-mediated uptake of polymyxins and contributes to a better understanding of the accumulation of polymyxins in renal tubular cells. PMID- 26494149 TI - National Variations in Comorbidities, Glycosylated Hemoglobin Reduction, and Insulin Dosage in Asian Patients with Type 2 Diabetes: The FINE-Asia Registry. AB - INTRODUCTION: The First Basal Insulin Evaluation (FINE) Asia study was a prospective, observational registry evaluating basal insulin initiation in Asian patients with type 2 diabetes mellitus inadequately controlled by oral antihyperglycemic agents. METHODS: The objective of this post hoc analysis was to observe and report the findings from individual participating countries. The primary endpoint was change in glycosylated hemoglobin (HbA1c) from baseline to month 6 after basal insulin initiation. Secondary endpoints included change in fasting blood glucose (FBG), percent of patients achieving target HbA1c and FBG levels, average insulin doses, and hypoglycemic events. RESULTS: The study included 2921 patients from 11 Asian countries at baseline, 2679 (92%) of whom had evaluable data. Following initiation of basal insulin (neutral protamine Hagedorn insulin, glargine, or detemir), there was a significant (P < 0.001) difference in HbA1c reduction and proportions of patients meeting HbA1c and FBG targets (<7% and <110 mg/dL, respectively) across all country cohorts by month 6. Glycemic control also varied greatly, with 7.4% (Taiwan) to 71.5% (China) of patients reaching target HbA1c <7% levels. Mean (+/-standard deviation) insulin dose increases over the 6-month period ranged from 0.5 +/- 3.1 U (Pakistan) to 6.0 +/- 8.6 U (Thailand). Hypoglycemia rates also varied, with 7.1% (India) to 27.3% (China) of patients experiencing one or more events. CONCLUSIONS: Data from the FINE-Asia registry study show widely varying degrees of baseline comorbidities and glycemic control in patients among the country cohorts observed. Countries with >9 years of diabetes prior to insulin initiation had the lowest reductions in HbA1c and proportions of patients achieving HbA1c and FBG targets, suggesting that earlier basal insulin initiation may afford better glycemic control in these patients. FUNDING: This study was funded by Sanofi. PMID- 26494151 TI - The sexual phase of the diatom Pseudo-nitzschia multistriata: cytological and time-lapse cinematography characterization. AB - Pseudo-nitzschia is a thoroughly studied pennate diatom genus for ecological and biological reasons. Many species in this genus, including Pseudo-nitzschia multistriata, can produce domoic acid, a toxin responsible for amnesic shellfish poisoning. Physiological, phylogenetic and biological features of P. multistriata were studied extensively in the past. Life cycle stages, including the sexual phase, fundamental in diatoms to restore the maximum cell size and avoid miniaturization to death, have been well described for this species. P. multistriata is heterothallic; sexual reproduction is induced when strains of opposite mating type are mixed, and proceeds with cells producing two functionally anisogamous gametes each; however, detailed cytological information for this process is missing. By means of confocal laser scanning microscopy and nuclear staining, we followed the nuclear fate during meiosis, and using time lapse cinematography, we timed every step of the sexual reproduction process from mate pairing to initial cell hatching. The present paper depicts cytological aspects during gametogenesis in P. multistriata, shedding light on the chloroplast behaviour during sexual reproduction, finely describing the timing of the sexual phases and providing reference data for further studies on the molecular control of this fundamental process. PMID- 26494150 TI - Inhibitors of plant hormone transport. AB - Here we present an overview of what is known about endogenous plant compounds that act as inhibitors of hormonal transport processes in plants, about their identity and mechanism of action. We have also summarized commonly and less commonly used compounds of non-plant origin and synthetic drugs that show at least partial 'specificity' to transport or transporters of particular phytohormones. Our main attention is focused on the inhibitors of auxin transport. The urgent need to understand precisely the molecular mechanism of action of these inhibitors is highlighted. PMID- 26494152 TI - Pre-apoptotic activity of aqueous extracts of Cynanchum sarcomedium Meve & Liede on cells of Allium cepa and human erythrocytes. AB - Cynanchum sarcomedium Meve & Liede is a member of Apocynaceae, seen in dry and rocky areas. The present study highlights the cytotoxic potential of C. sarcomedium mediated by apoptosis on cells of Allium cepa and human red blood cells (RBCs). Cytogenetic changes in A. cepa and in situ visualization of cell death were revealed through acetocarmine and Evans blue staining techniques. Quantitative estimation of cell death was carried out at 600 nm in a spectrophotometer. Membrane characteristics of RBC in response to the treatment were evaluated by May-Grunwald-Giemsa staining and scanning electron microscopy (SEM). Cell membrane damage is a major factor for assessing apoptosis which is observed in the present study (90.91 %). Cell shrinkage, cytoplasmic fragmentation, condensed chromatin and presence of apoptotic bodies were the common cytological changes in A. cepa associated with apoptosis. Blebs in RBC evidenced by SEM revealed the membrane damage potential of the plant. Results obtained hereby suggest that the plant is an effective source to be used in toxicological studies and anti-cancer therapy. PMID- 26494153 TI - Fluid balance and mortality in critically ill patients with acute kidney injury: a multicenter prospective epidemiological study. AB - INTRODUCTION: Early and aggressive volume resuscitation is fundamental in the treatment of hemodynamic instability in critically ill patients and improves patient survival. However, one important consequence of fluid administration is the risk of developing fluid overload (FO), which is associated with increased mortality in patients with acute kidney injury (AKI). We evaluated the impact of fluid balance on mortality in intensive care unit (ICU) patients with AKI. METHODS: The data were extracted from the Beijing Acute Kidney Injury Trial. This trial was a prospective, observational, multicenter study conducted in 30 ICUs among 28 tertiary hospitals in Beijing, China, from 1 March to 31 August 2012. In total, 3107 patients were admitted consecutively, and 2526 patients were included in this study. The data from the first 3 sequential days were analyzed. The AKI severity was classified according to the Kidney Disease: Improving Global Outcomes guidelines. The daily fluid balance was recorded, and the cumulative fluid balance was registered at 24, 48, and 72 h. A multivariate analysis was performed with Cox regression to determine the impact of fluid balance on mortality in patients with AKI. RESULTS: Among the 2526 patients included, 1172 developed AKI during the first 3 days. The mortality was 25.7 % in the AKI group and 10.1 % in the non-AKI group (P < 0.001). The daily fluid balance was higher, and the cumulative fluid balance was significantly greater, in the AKI group than in the non-AKI group. FO was an independent risk factor for the incidence of AKI (odds ratio 4.508, 95 % confidence interval 2.900 to 7.008, P < 0.001) and increased the severity of AKI. Non-surviving patients with AKI had higher cumulative fluid balance during the first 3 days (2.77 [0.86-5.01] L versus 0.93 [-0.80 to 2.93] L, P < 0.001) than survivors did. Multivariate analysis revealed that the cumulative fluid balance during the first 3 days was an independent risk factor for 28-day mortality. CONCLUSIONS: In this multicenter ICU study, the fluid balance was greater in patients with AKI than in patients without AKI. FO was an independent risk factor for the incidence of AKI and increased the severity of AKI. A higher cumulative fluid balance was an important factor associated with 28-day mortality following AKI. PMID- 26494154 TI - Proteomic and metabolomic profiles demonstrate variation among free-living and symbiotic vibrio fischeri biofilms. AB - BACKGROUND: A number of bacterial species are capable of growing in various life history modes that enable their survival and persistence in both planktonic free living stages as well as in biofilm communities. Mechanisms contributing to either planktonic cell or biofilm persistence and survival can be carefully delineated using multiple differential techniques (e.g., genomics and transcriptomics). In this study, we present both proteomic and metabolomic analyses of Vibrio fischeri biofilms, demonstrating the potential for combined differential studies for elucidating life-history switches important for establishing the mutualism through biofilm formation and host colonization. METHODS: The study used a metabolomics/proteomics or "meta-proteomics" approach, referring to the combined protein and metabolic data analysis that bridges the gap between phenotypic changes (planktonic cell to biofilm formation) with genotypic changes (reflected in protein/metabolic profiles). Our methods used protein shotgun construction, followed by liquid chromatography coupled with mass spectrometry (LC-MS) detection and quantification for both free-living and biofilm forming V. fischeri. RESULTS: We present a time-resolved picture of approximately 100 proteins (2D-PAGE and shotgun proteomics) and 200 metabolites that are present during the transition from planktonic growth to community biofilm formation. Proteins involved in stress response, DNA repair damage, and transport appeared to be highly expressed during the biofilm state. In addition, metabolites detected in biofilms correspond to components of the exopolysaccharide (EPS) matrix (sugars and glycerol-derived). Alterations in metabolic enzymes were paralleled by more pronounced changes in concentration of intermediates from the glycolysis pathway as well as several amino acids. CONCLUSIONS: This combined analysis of both types of information (proteins, metabolites) has provided a more complete picture of the biochemical processes of biofilm formation and what determines the switch between the two life history strategies. The reported findings have broad implications for Vibrio biofilm ecology, and mechanisms for successful survival in the host and environment. PMID- 26494155 TI - 3D reconstruction based on compressed-sensing (CS)-based framework by using a dental panoramic detector. AB - In this work, we propose a practical method that can combine the two functionalities of dental panoramic and cone-beam CT (CBCT) features in one by using a single panoramic detector. We implemented a CS-based reconstruction algorithm for the proposed method and performed a systematic simulation to demonstrate its viability for 3D dental X-ray imaging. We successfully reconstructed volumetric images of considerably high accuracy by using a panoramic detector having an active area of 198.4 mm * 6.4 mm and evaluated the reconstruction quality as a function of the pitch (p) and the angle step (Deltatheta). Our simulation results indicate that the CS-based reconstruction almost completely recovered the phantom structures, as in CBCT, for p<=2.0 and theta<=6 degrees , indicating that it seems very promising for accurate image reconstruction even for large-pitch and few-view data. We expect the proposed method to be applicable to developing a cost-effective, volumetric dental X-ray imaging system. PMID- 26494156 TI - Effect of inorganic salts and glucose additives on dose-response, melting point and mass density of genipin gel dosimeters. AB - Genipin gel dosimeters are hydrogels infused with a radiation-sensitive material which yield dosimetric information in three dimensions (3D). The effect of inorganic salts and glucose on the visible absorption dose-response, melting points and mass density of genipin gel dosimeters has been experimentally evaluated using 6-MV LINAC photons. As a result, the addition of glucose with optimum concentration of 10% (w/w) was found to improve the thermal stability of the genipin gel and increase its melting point (Tm) by 6 degrees C accompanied by a slight decrease of dose-response. Furthermore, glucose helps to adjust the gel mass density to obtain the desired tissue-equivalent properties. A drop of Tm was observed when salts were used as additives. As the salt concentration increased, gel Tm decreased. The mass density and melting point of the genipin gel could be adjusted using different amounts of glucose that improved the genipin gel suitability for 3D dose measurements without introducing additional toxicity to the final gel. PMID- 26494157 TI - The prognostic significance of glomerular infiltrating leukocytes during acute renal allograft rejection. AB - Transplant glomerulitis, observed in T cell-mediated and antibody-mediated rejection, is histologically characterized by intracapillary mononuclear cell infiltration. However, the prognostic value of counting various glomerular inflammatory cells during rejection has not been elucidated, which is a key step for the introduction of novel biomarkers in the clinics. We immunophenotyped glomerulitis during episodes of acute rejection in order to investigate their predictive value for transplant outcomes. To do so, we included 57 transplant biopsies of 57 renal transplant recipients with biopsy-proven acute rejection with a median follow-up of 4.2 years. We determined average glomerular cell counts for T cells, B cells, Tregs, IL-17(+) cells, neutrophils and macrophages. Logistic and Cox regression models were used to investigate the association of glomerular inflammatory cells with response to therapy and graft failure on a population level. We used novel time-dependent ROC curve analyses to investigate the value of glomerular inflammatory cell infiltrates for the prediction of transplant outcomes, applicable to the individual patient. We identified three cell types that were responsible for glomerulitis during rejection: macrophages, T cells and neutrophils. By quantification of glomerular macrophages, an emerging cell type associated with antibody-mediated rejection, we were able to predict the progression towards death-censored graft failure within the first 500 days after the initial episode of rejection. With the use of novel time-dependent ROC analyses, we propose dynamic sensitivities, specificities, and positive and negative predictive values with their corresponding cut-off values for the average amount of glomerular macrophages, depending on what time after rejection death-censored graft failure needs prediction. PMID- 26494158 TI - Nontargeted Analysis Using Ultraperformance Liquid Chromatography-Quadrupole Time of-Flight Mass Spectrometry Uncovers the Effects of Harvest Season on the Metabolites and Taste Quality of Tea (Camellia sinensis L.). AB - The chemical composition and taste quality of tea fluctuate seasonally. However, the compounds responsible for the seasonal variation of metabolic pattern and taste quality are far from clear. This study compared the metabolite profiles of green teas of nine varieties that were plucked in spring, summer, and autumn by using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) on a reversed phase column. A multivariate analysis indicated distinct differences among the metabolite phenotypes of teas harvested in different seasons. Heat-map analysis and metabolic pathway analysis demonstrated that flavan-3-ols, theasinensins, procyanidins, quercetin-O glycosides, apigenin-C-glycosides, and amino acids exhibited sharp seasonal fluctuations. An equivalent quantification of tea tastes showed that in summer and autumn teas, the bitterness and astringency were significantly elevated, whereas umami declined. Metabolite content comparisons and partial least-squares analysis suggested that several flavonoids and amino acids are mainly responsible for the seasonal variations in taste quality. PMID- 26494159 TI - Using WhatsApp and Facebook Online Social Groups for Smoking Relapse Prevention for Recent Quitters: A Pilot Pragmatic Cluster Randomized Controlled Trial. AB - BACKGROUND: Quit attempters often have episodes of smoking relapse before they eventually quit. Interactive text messaging through mobile phones has been shown to increase abstinence. This service can be potentially applied on the platform of a social networking service to help quitters maintain abstinence. OBJECTIVE: Our aim was to determine if the group discussion and reminders via the WhatsApp or Facebook social group were effective to prevent smoking relapse in quitters who had stopped smoking recently. METHODS: This was a single-blinded, parallel, 3 arm pilot cluster randomized controlled trial allocating recent quitters, who had completed an 8-week treatment and reported abstinence for at least 7 days, to WhatsApp (n=42), Facebook (n=40), and a control group (n=54). The 2 intervention groups participated in a 2-month online group discussion with either WhatsApp or Facebook moderated by a trained smoking cessation counselor and received a self help booklet on smoking cessation. The control group only received the booklet. The primary outcome was the 2- and 6-month relapse rates, defined as the proportion of participants who smoked at least 5 cigarettes in 3 consecutive days. RESULTS: Fewer participants in the WhatsApp group (17%, 7/42) reported relapse than the control group (42.6%, 23/54) at 2-month (OR 0.27, 95% CI 0.10 0.71) and 6-month (40.5%, 17/42 vs 61.1%, 33/54; OR 0.43, 95% CI 0.19-0.99) follow-ups. The Facebook group (30.0%, 12/40) had an insignificantly lower relapse rate than the control group (42.6%, 23/54) at 2-month (OR 0.58, 95% CI 0.24-1.37) and 6-month (52.5%, 13/40 vs 61.1%, 33/54; OR 0.70, 95% CI 0.31-1.61) follow-ups. The WhatsApp social groups had more moderators' posts (median 60, IQR 25 vs median 32, IQR 7; P=.05) and participants' posts (median 35, IQR 50 vs median 6, IQR 9; P=.07) than their Facebook counterparts, but the difference was insignificant. CONCLUSIONS: The intervention via the WhatsApp social group was effective in reducing relapse probably because of enhanced discussion and social support. Inactive discussion in the Facebook social group might have attributed to the lower effectiveness. CLINICALTRIAL: Clinicaltrials.gov NCT02007369; https://clinicaltrials.gov/show/NCT02007369 (Archived by WebCite(r) at http://www.webcitation.org/6c3RbltQG). PMID- 26494160 TI - Population genetic structure of Indian oil sardine, Sardinella longiceps along Indian coast. AB - Genetic stock structure and historical demography of Indian oil sardine, a commercially and ecologically important small pelagic fish, was studied using mitochondrial control region and Cytochrome C Oxidase I (COI) sequences. A 758 bp portion of the control region in 287 individuals and a 576 bp portion of the COI gene in 291 individuals from 10 locations along the distribution range were amplified resulting in 236 and 84 haplotypes, respectively. The high haplotype and low nucleotide diversity values (0.99 and 0.19 for control region and 0.85 and 0.004 for COI, respectively) are characteristic of populations having undergone a demographic expansion. Genetic differentiation, PhiST, was low and insignificant between populations using both control region and COI gene markers. Mismatch analysis showed a recent demographic and spatial expansion coinciding with the late Pleistocene epoch. Mantel tests revealed the lack of isolation by distance which is attributable either to high levels of migration overriding the effect of genetic drift or to insufficient time for accomplishing a balance between migration and drift after a recent range expansion. PMID- 26494161 TI - De novo assembly and characterization of the transcriptome of the pancreatic fluke Eurytrema pancreaticum (trematoda: Dicrocoeliidae) using Illumina paired end sequencing. AB - Eurytrema pancreaticum is one of the most common trematodes living in the pancreatic and bile ducts of ruminants and also occasionally infects humans, causing eurytremiasis. In spite of its economic and medical importance, very little is known about the genomic resources of this parasite. Herein, we performed de novo sequencing, assembly and characterization of the transcriptome of adult E. pancreaticum. Approximately 36.4 million high-quality clean reads were obtained, and the length of the transcript contigs ranged from 66 to 19,968 nt with mean length of 479 nt and N50 length of 1094 nt, and then 23,573 unigenes were assembled. Of these unigenes, 15,353 (65.1%) were annotated by blast searches against the NCBI non-redundant protein database. Among these, 15,267 (64.8%), 2732 (11.6%) and 10,354 (43.9%) of the unigenes had significant similarity with proteins in the NR, NT and Swiss-Prot databases, respectively. 5510 (23.4%) and 4567 (19.4%) unigenes were assigned to GO and COG, respectively. 8886 (37.7%) unigenes were identified and mapped onto 254 pathways in the KEGG Pathway database. Furthermore, we found that 105 (1.18%) unigenes were related to pancreatic secretion and 61 (0.7%) to pancreatic cancer. The present study represents the first transcriptome of any members of the family Dicrocoeliidae, which has little genomic information available in the public databases. The novel transcriptome of E. pancreaticum should provide a useful resource for designing new strategies against pancreatic flukes and other trematodes of human and animal health significance. PMID- 26494162 TI - Prenatal findings in cardio-facio-cutaneous syndrome. AB - Our study was designed to analyze prenatal manifestations in patients affected with cardio-facio-cutaneous syndrome (CFCS), in order to define indications of DNA testing in utero. Prenatal features were extracted from a national database and additional data were collected from 16 families contacted through the French association of CFC-Costello syndrome. We collected results of ultrasound scan (USS) biometrics, presence of congenital birth defects, and polyhydramnios. From the database, increased nuchal translucency was present in 13% of pregnancies, polyhydramnios in 52%, macrosomia and/or macrocephaly in 16%. Of the 16 pregnancies, 81% were complicated by abnormal USS findings. Polyhydramnios was reported in 67%. Head circumference, biparietal diameter, and abdominal circumference were above the 90th centile in 72%, 83% and, 81% of fetuses, respectively. Contrasting with macrosomia, femur length was below the 10th centile in 38%. Urinary tract abnormalities were found in 47% of fetuses. Most CFCS fetuses showed a combination of macrocephaly, macrosomia, and polyhydramnios, contrasting with relatively short femora. This growth pattern is also seen in Costello syndrome. We suggest that screening for CFCS and Costello gene mutations could be proposed in pregnancies showing this unusual pattern of growth parameters. PMID- 26494163 TI - Renal effects of canagliflozin in type 2 diabetes mellitus. AB - BACKGROUND: Chronic kidney disease is commonly associated with type 2 diabetes mellitus (T2DM) and may impact the efficacy and safety of glucose-lowering therapies. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces blood glucose levels in patients with T2DM by lowering the renal threshold for glucose, thereby promoting urinary glucose excretion. This review describes the pharmacology, efficacy and safety of canagliflozin according to kidney function in participants with T2DM. METHODS: Published articles that reported efficacy, safety and pharmacokinetics/pharmacodynamics data for canagliflozin in patients with T2DM and impaired renal function, and renal safety data with canagliflozin in various populations of patients with T2DM through May 2015 were included. RESULTS: Early transient reductions in estimated glomerular filtration rate were observed with canagliflozin; these changes generally stabilized or attenuated over time and reversed after discontinuation, suggesting no renal (glomerular or tubular) damage with canagliflozin treatment. Urinary albumin-to-creatinine ratios were reduced with canagliflozin. Canagliflozin was generally well tolerated in patients with normal or mild to moderately impaired renal function, with a modestly higher incidence of renal-related adverse events and volume depletion-related adverse events in patients with moderate renal impairment. Adverse events related to potassium elevations were infrequent with canagliflozin 100 mg regardless of kidney function status; however, patients with moderately impaired kidney function experienced hyperkalemia more frequently with canagliflozin 300 mg compared with patients treated with either canagliflozin 100 mg or placebo. Canagliflozin was not associated with increased cardiovascular risk across studies; however, relatively few events among patients with impaired renal function meant that the analysis was not adequately powered to examine this outcome, and results from separate trials are awaited. CONCLUSIONS: Overall, canagliflozin is associated with small, transient changes in kidney function, and is well tolerated in patients with T2DM with varying kidney function status. PMID- 26494165 TI - Molecular detection and Smoothing spline clustering of the IBV strains detected in China during 2011-2012. AB - Infectious bronchitis virus (IBV) is a highly variable virus with a large number of genotypes. During 2011-2012, nineteen wild IBV strains were isolated in China. Sequence analysis showed that these isolates were divided into five sub-clusters: A2-like, CKCHLDL08I-like, SAIBK-like, KM91-like and TW97/4-like. Phylogenetic analysis based on the 1118 sequences available on line suggested that all IBVs were classified into six clusters. The prevalent strains including all the isolates were in cluster VI with a 0.194-0.259 genetic distance to Mass type vaccines. In addition, we introduced the smoothing spline clustering (SSC) method to estimate the highly variable sites for some sub-clusters. The results showed that highly variable sites range from sub-clusters, the N-terminal sequences of 4/91-like, TW97/4-like and Arkansas-like are more variable than other sub clusters. This is the first time that the SSC method has been used for the evolution study of IBV. PMID- 26494164 TI - The value of liver resection for focal nodular hyperplasia: resection yes or no? AB - BACKGROUND: Focal nodular hyperplasia (FNH) are benign lesions in the liver. Although liver resection is generally not indicated in these patients, rare indications for surgical approaches indeed exist. We here report on our single center experience with patients undergoing liver resection for FNH, focussing on preoperative diagnostic algorithms and quality of life (QoL) after surgery. METHODS: Medical records of 100 consecutive patients undergoing liver resection for FNH between 1992 and 2012 were retrospectively analyzed with regard to diagnostic pathways and indications for surgery. Quality of life (QoL) before and after surgery was evaluated using validated assessment tools. Student's t test, one-way ANOVA, chi (2), and binary logistic regression analyses such as Wilcoxon Mann-Whitney test were used, as indicated. RESULTS: A combination of at least two preoperative diagnostic imaging approaches was applied in 99 cases, of which 70 patients were subjected to further imaging or tumor biopsy. In most patients, there was more than one indication for liver resection, including tumor associated symptoms with abdominal discomfort (n = 46, 40.7 %), balance of risk for malignancy/history of cancer (n = 54, 47.8 %/n = 18; 33.3 %), tumor enlargement/jaundice of vascular and biliary structures (n = 13, 11.5 %), such as incidental findings during elective operation (n = 1, 0.9 %). Postoperative morbidity was 19 %, with serious complications (>grade 2, Clavien-Dindo classification) being evident in 8 %. Perioperative mortality was 0 %. Liver resection was associated with a significant overall improvement in general health (very good-excellent: preoperatively 47.4 % vs. postoperatively 68.1 %; p = 0.015). CONCLUSIONS: Liver resection remains a valuable therapeutic option in the treatment of either symptomatic FNH or if malignancy cannot finally be ruled out. If clinically indicated, liver resection for FNH represents a safe approach and may lead to significant improvements of QoL especially in symptomatic patients. PMID- 26494166 TI - HIV-1 resistance to neutralizing antibodies: Determination of antibody concentrations leading to escape mutant evolution. AB - Broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV 1) are considered vital components of novel therapeutics and blueprints for vaccine research. Yet escape to even the most potent of these antibodies is imminent in natural infection. Measures to define antibody efficacy and prevent mutant selection are thus urgently needed. Here, we derive a mathematical framework to predict the concentration ranges for which antibody escape variants can outcompete their viral ancestors, referred to as mutant selection window (MSW). When determining the MSW, we focus on the differential efficacy of neutralizing antibodies against HIV-1 in two canonical infection routes, free virus infection and cell-cell transmission. The latter has proven highly effective in vitro suggesting its importance for both in vivo spread as well as for escaping targeted intervention strategies. We observed a range of MSW patterns that highlight the potential of mutants to arise in both transmission pathways and over wide concentration ranges. Most importantly, we found that only when the arising mutant has both, residual sensitivity to the neutralizing antibody and reduced infectivity compared to the parental virus, antibody dosing outside of the MSW to restrict mutant selection is possible. Emergence of mutants that provide complete escape and have no considerable fitness loss cannot be prevented by adjusting antibody doses. The latter may in part explain the ubiquitous resistance to neutralizing antibodies observed in natural infection and antibody treatment. Based on our findings, combinations of antibodies targeting different epitopes should be favored for antibody-based interventions as this may render complete resistance less likely to occur and also increase chances that multiple escapes result in severe fitness loss of the virus making longer-term antibody treatment more feasible. PMID- 26494167 TI - Aquatic viruses induce host cell death pathways and its application. AB - Virus infections of mammalian and animal cells consist of a series of events. As intracellular parasites, viruses rely on the use of host cellular machinery. Through the use of cell culture and molecular approaches over the past decade, our knowledge of the biology of aquatic viruses has grown exponentially. The increase in aquaculture operations worldwide has provided new approaches for the transmission of aquatic viruses that include RNA and DNA viruses. Therefore, the struggle between the virus and the host for control of the cell's death machinery is crucial for survival. Viruses are obligatory intracellular parasites and, as such, must modulate apoptotic pathways to control the lifespan of their host to complete their replication cycle. This paper updates the discussion on the detailed mechanisms of action that various aquatic viruses use to induce cell death pathways in the host, such as Bad-mediated, mitochondria-mediated, ROS mediated and Fas-mediated cell death circuits. Understanding how viruses exploit the apoptotic pathways of their hosts may provide great opportunities for the development of future potential therapeutic strategies and pathogenic insights into different aquatic viral diseases. PMID- 26494168 TI - A novel betapartitivirus RnPV6 from Rosellinia necatrix tolerates host RNA silencing but is interfered by its defective RNAs. AB - The family Partitiviridae comprises of five genera with bi-segmented dsRNA genomes that accommodate members infecting plants, fungi or protists. All partitiviruses with only a few exceptions cause asymptomatic infections. We report the characterization of a novel betapartitivirus termed Rosellinia necatrix partitivirus 6 (RnPV6) from a field isolate of a plant pathogenic fungus, white root rot fungus. RnPV6 has typical partitivirus features: dsRNA1 and dsRNA2 are 2462 and 2499bps in length encoding RNA-dependent RNA polymerase and capsid protein. Purified particles are spherical with a diameter of 30nm. Taking advantage of infectivity as virions, RnPV6 was introduced into a model filamentous fungal host, chestnut blight fungus to investigate virus/host interactions. Unlike other partitiviruses tested previously, RnPV6 induced profound phenotypic alterations with symptoms characterized by a reduced growth rate and enhanced pigmentation and was tolerant to host RNA silencing. In addition, a variety of defective RNAs derived from dsRNA1 appear after virion transfection. These sub-viral RNAs were shown to interfere with RnPV6 replication, at least for that of cognate segment dsRNA1. Presence of these sub viral elements resulted in reduced symptom expression by RnPV6, suggesting their nature as defective-interfering RNAs. The features of RnPV6 are similar to but distinct from those of a previously reported alphapartitivirus, Rosellinia necatrix partitivirus 2 that is susceptible to RNA silencing. PMID- 26494169 TI - Murine norovirus (MNV-1) exposure in vitro to the purine nucleoside analog Ribavirin increases quasispecies diversity. AB - Ribavirin is a pharmaceutical antiviral used for the treatment of RNA virus infections including norovirus, hepatitis C virus, hepatitis E virus, Lassa virus, respiratory syncytial virus, and rhinovirus. Despite the drug's history and documented efficacy, the antiviral mechanism of Ribavirin remains unclear. Mechanisms proposed include depletion of the intracellular GTP pool, immunomodulatory effects, induction of error catastrophe, inhibition of viral polymerase activity, and/or inhibition of viral capping. In the present study, we leveraged deep sequencing data to demonstrate that Ribavirin increases murine norovirus (MNV-1) viral diversity. By serial passaging MNV-1 in RAW 264.7 cells for twenty generations in the presence of Ribavirin, we demonstrated statistically significant increases in both the number of unique haplotypes and the average pairwise difference (APD). Based on statistically significant differences in the probability of nucleotide mutations based on Roche 454 sequencing, we also demonstrated that single nucleotide substitutions are increased in the presence of Ribavirin. Finally, we demonstrated Ribavirin's impact on statistically significantly reducing the relative proportion of the dominant sequence within the quasispecies. PMID- 26494170 TI - Development and promotion of a national website to improve dissemination of information related to the prevention of mother-to-child HIV transmission (PMTCT) in Tanzania. AB - BACKGROUND: Websites that address national public health issues provide an important mechanism to improve health education and services in resource limited countries. This article describes the development, promotion and initial evaluation of a national website to increase access to information and resources about prevention of mother-to-child transmission of HIV (PMTCT) among healthcare workers and PMTCT stakeholders in Tanzania. METHODS: A participatory approach, involving the Tanzania Ministry of Health and Social Welfare (MOHSW) and key PMTCT stakeholders, was used to develop and manage the online PMTCT National Resource Center (NRC), http://pmtct.or.tz/ . The website was created with a content management system software system that does not require advanced computer skills and facilitates content updates and site management. The PMTCT NRC hosts related regularly updated PMTCT-related news, resources and publications. Website implementation, access and performance were evaluated over two years using Google Analytics data about visits, page views, downloads, bounce rates and location of visitors, supplemented by anecdotal feedback. RESULTS: Following its launch in July 2013, the PMTCT NRC website received a total of 28,400 visits, with 66,463 page views, over 2 years; 30 % of visits were from returning visitors. During year 1, visits increased by 80 % from the first to second 6 month period and then declined slightly (9-11 %) but remained stable in Year 2. Monthly visits spiked by about 70 % during October 2013 and January 2014 in response to the release and promotion of revised national PMTCT guidelines and training manuals. The majority of visitors came from primarily urban areas in Tanzania (50 %) and from other African countries (16 %). By year 2, over one-third of visitors used mobile devices to access the site. CONCLUSIONS: The successfully implemented PMTCT NRC website provides centralized, easily accessed information designed to address the needs of clinicians, educators and program partners in Tanzania. Ongoing involvement of the MOHSW and key stakeholders are essential ensure the website's growth, effectiveness and sustainability. Additional efforts are needed to expand use of the PMTCT NRC throughout the country. Future evaluations should examine the role of the website in supporting implementation of national PMTCT guidelines and services in Tanzania. PMID- 26494171 TI - MicroRNA-encoded behavior in Drosophila. AB - The relationship between microRNA (miRNA) regulation and the specification of behavior is only beginning to be explored. We found that mutation of a single miRNA locus (miR-iab4/iab8) in Drosophila larvae affects the animal's capacity to correct its orientation if turned upside down (self-righting). One of the miRNA targets involved in this behavior is the Hox gene Ultrabithorax, whose derepression in two metameric neurons leads to self-righting defects. In vivo neural activity analysis reveals that these neurons, the self-righting node (SRN), have different activity patterns in wild type and miRNA mutants, whereas thermogenetic manipulation of SRN activity results in changes in self-righting behavior. Our work thus reveals a miRNA-encoded behavior and suggests that other miRNAs might also be involved in behavioral control in Drosophila and other species. PMID- 26494172 TI - Nlrp6 regulates intestinal antiviral innate immunity. AB - The nucleotide-binding oligomerization domain-like receptor (Nlrp) 6 maintains gut microbiota homeostasis and regulates antibacterial immunity. We now report a role for Nlrp6 in the control of enteric virus infection. Nlrp6(-/-) and control mice systemically challenged with encephalomyocarditis virus had similar mortality; however, the gastrointestinal tract of Nlrp6(-/-) mice exhibited increased viral loads. Nlrp6(-/-) mice orally infected with encephalomyocarditis virus had increased mortality and viremia compared with controls. Similar results were observed with murine norovirus 1. Nlrp6 bound viral RNA via the RNA helicase Dhx15 and interacted with mitochondrial antiviral signaling protein to induce type I/III interferons (IFNs) and IFN-stimulated genes (ISGs). These data demonstrate that Nlrp6 functions with Dhx15 as a viral RNA sensor to induce ISGs, and this effect is especially important in the intestinal tract. PMID- 26494173 TI - Cells of a common developmental origin regulate REM/non-REM sleep and wakefulness in mice. AB - Mammalian sleep comprises rapid eye movement (REM) sleep and non-REM (NREM) sleep. To functionally isolate from the complex mixture of neurons populating the brainstem pons those involved in switching between REM and NREM sleep, we chemogenetically manipulated neurons of a specific embryonic cell lineage in mice. We identified excitatory glutamatergic neurons that inhibit REM sleep and promote NREM sleep. These neurons shared a common developmental origin with neurons promoting wakefulness; both derived from a pool of proneural hindbrain cells expressing Atoh1 at embryonic day 10.5. We also identified inhibitory gamma aminobutyric acid-releasing neurons that act downstream to inhibit REM sleep. Artificial reduction or prolongation of REM sleep in turn affected slow-wave activity during subsequent NREM sleep, implicating REM sleep in the regulation of NREM sleep. PMID- 26494175 TI - Measurement and laser control of attosecond charge migration in ionized iodoacetylene. AB - The ultrafast motion of electrons and holes after light-matter interaction is fundamental to a broad range of chemical and biophysical processes. We advanced high-harmonic spectroscopy to resolve spatially and temporally the migration of an electron hole immediately after ionization of iodoacetylene while simultaneously demonstrating extensive control over the process. A multidimensional approach, based on the measurement and accurate theoretical description of both even and odd harmonic orders, enabled us to reconstruct both quantum amplitudes and phases of the electronic states with a resolution of ~100 attoseconds. We separately reconstructed quasi-field-free and laser-controlled charge migration as a function of the spatial orientation of the molecule and determined the shape of the hole created by ionization. Our technique opens the prospect of laser control over electronic primary processes. PMID- 26494174 TI - Patrolling monocytes control tumor metastasis to the lung. AB - The immune system plays an important role in regulating tumor growth and metastasis. Classical monocytes promote tumorigenesis and cancer metastasis, but how nonclassical "patrolling" monocytes (PMo) interact with tumors is unknown. Here we show that PMo are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1 deficient mice, which specifically lack PMo, showed increased lung metastasis in vivo. Transfer of Nr4a1-proficient PMo into Nr4a1-deficient mice prevented tumor invasion in the lung. PMo established early interactions with metastasizing tumor cells, scavenged tumor material from the lung vasculature, and promoted natural killer cell recruitment and activation. Thus, PMo contribute to cancer immunosurveillance and may be targets for cancer immunotherapy. PMID- 26494176 TI - Lanosterol influences cytoplasmic maturation of pig oocytes in vitro and improves preimplantation development of cloned embryos. AB - Lanosterol is a precursor of meiosis-activating sterols in the cholesterol biosynthetic pathway and induces a physiological signal that instructs the oocyte to reinitiate meiosis. In this study, we examined the effect of lanosterol on IVM of porcine oocytes, specifically on nuclear maturation, cytoplasmic maturation by investigating intracellular glutathione (GSH) levels and lipid content, embryonic development after parthenogenetic activation and somatic cell nuclear transfer (SCNT), and on gene expression in cumulus cells, oocytes, and SCNT-derived blastocysts. There was no significant difference in nuclear maturation rates between the control and treatment groups (10, 50, and 100 MUM of lanosterol added to IVM culture medium). Supplementation with 50-MUM lanosterol significantly increased lipid content and GSH levels and decreased reactive oxygen species levels compared with the control. In addition, oocytes treated with 50 MUM of lanosterol exhibited significantly increased blastocyst formation rates and total cell numbers after parthenogenetic activation (30.3% and 63.9 vs. 21.6% and 36.5, respectively) and SCNT (18.2% and 53.7 vs. 12.6% and 37.5, respectively), when compared with the control group. Cumulus cells treated with 50 MUM of lanosterol showed significantly increased 14alpha-demethylase, Delta14-reductase, and Delta7 reductase mRNA transcript levels. Significantly increased PPARgamma, SREBF1, GPX1, and Bcl-2 and decreased Bax transcript levels were observed in mature oocytes treated with 50 MUM of lanosterol compared with the control. SCNT blastocysts derived from 50-MUM lanosterol-treated oocytes had significantly higher POU5F1, FGFR2, and Bcl-2 transcript levels than control SCNT-derived blastocysts. In conclusion, supplementation with 50 MUM of lanosterol during IVM improves preimplantation development of SCNT embryos by elevating lipid content of oocytes, increasing GSH levels, decreasing reactive oxygen species levels, and regulating genes related to the cholesterol biosynthetic pathway in cumulus cells, to lipid metabolism and apoptosis in oocytes, and their developmental potential and apoptosis in blastocysts. PMID- 26494177 TI - Highly Efficient Photothermal Semiconductor Nanocomposites for Photothermal Imaging of Latent Fingerprints. AB - Optical imaging of latent fingerprints (LFPs) has been widely used in forensic science and for antiterrorist applications, but it suffers from interference from autofluorescence and the substrates background color. Cu7S4 nanoparticles (NPs), with excellent photothermal properties, were synthesized using a new strategy and then fabricated into amphiphilic nanocomposites (NCs) via polymerization of allyl mercaptan coated on Cu7S4 NPs to offer good affinities toward LFPs. Here, we develop a facile and versatile photothermal LFP imaging method based on the high photothermal conversion efficiency (52.92%, 808 nm) of Cu7S4 NCs, indicating its effectiveness for imaging LFPs left on different substrates (with various background colors), which will be extremely useful for crime scene investigations. Furthermore, by fabricating Cu7S4-CdSe@ZnS NCs, a fluorescent photothermal dual-mode imaging strategy was used to detect trinitrotoluene (TNT) in LFPs while still maintaining a complete photothermal image of LFP. PMID- 26494178 TI - Effects of nutrient profiling and price changes based on NuVal(r) scores on food purchasing in an online experimental supermarket. AB - OBJECTIVE: The goal of the present study was to apply experimental economic methods in an online supermarket to examine the effects of nutrient profiling, and differential pricing based on the nutrient profile, on the overall diet quality, energy and macronutrients of the foods purchased, and diet cost. DESIGN: Participants were provided nutrient profiling scores or price adjustments based on nutrient profile scores while completing a hypothetical grocery shopping task. Prices of foods in the top 20 % of nutrient profiling scores were reduced (subsidized) by 25 % while those in the bottom 20 % of scores were increased (taxed) by 25 %. We evaluated the independent and interactive effects of nutrient profiling or price adjustments on overall diet quality of foods purchased as assessed by the NuVal(r) score, energy and macronutrients purchased and diet cost in a 2*2 factorial design. SETTING: A large (>10 000 food items) online experimental supermarket in the USA. SUBJECTS: Seven hundred and eighty-one women. RESULTS: Providing nutrient profiling scores improved overall diet quality of foods purchased. Price changes were associated with an increase in protein purchased, an increase in energy cost, and reduced carbohydrate and protein costs. Price changes and nutrient profiling combined were associated with no unique benefits beyond price changes or nutrient profiling alone. CONCLUSIONS: Providing nutrient profile score increased overall NuVal(r) score without a reduction in energy purchased. Combining nutrient profiling and price changes did not show an overall benefit to diet quality and may be less useful than nutrient profiling alone to consumers who want to increase overall diet quality of foods purchased. PMID- 26494179 TI - Remote cognitive-behavior therapy for obsessive-compulsive symptoms: A meta analysis. AB - Obsessive-compulsive disorder (OCD) is a chronic mental health condition that results in a significant societal burden. Remote treatments do not require the patient to attend traditional face-to-face treatment services and can be used as a way to overcome barriers to accessing face-to-face treatment. The aim of the current study was to synthesize the current literature on remote treatment for OCD using a meta-analytic approach. Relevant articles were identified through an electronic database search and the references of previously completed reviews on the topic of remote treatment for OCD were also reviewed. Eighteen studies (n=823; mean age=31.20 (SD=10.36); 56.2% female) were included in the meta analysis. Within-group findings indicate that remote treatment for OCD produces a decrease in symptoms of a large magnitude (g=1.17; 95% CI: 0.91-1.43). Between group findings indicate that remote treatment for OCD is more effective than control (g=1.06; 95% CI: 0.68-1.45) and outcomes are not meaningfully different from face-to-face treatment (g=-0.21; 95% CI: -0.43-0.02). Those methodologies that are low intensity produce a decrease in symptoms of a large magnitude (g=1.36, 95% CI: 1.00-1.72), as do higher intensity treatments (g=1.64, 95% CI: 1.33-1.95). These findings have important implications for the development of stepped-care treatments, which may be able to be delivered in a purely remote fashion. PMID- 26494180 TI - Influence of Voice Focus on Oral-Nasal Balance in Speech. AB - OBJECTIVES: The concept of voice focus describes the relationship of the vocal tract length on the perceived brightness or darkness of the speaker's voice. The present study explored the impact of adjustments of the voice focus on oral-nasal balance. The vocal tract settings in question were backward focus (retracted tongue, wide pharynx, and lowered larynx) and forward focus (fronted tongue, constricted pharynx, and raised larynx). The backward focus condition was expected to decrease nasalance scores and the forward focus condition was expected to increase nasalance scores. STUDY DESIGN: Experimental repeated measures study. METHODS: Sixteen females aged 23.78 (standard deviation 1.99) produced oral and nasal test sentences with a backward focus and a forward focus. Audio recordings and nasometry measurements were made. Nine of the participants completed the task successfully. RESULTS: In a repeated-measures analysis of variance, the nasalance scores were compared across stimuli, speaking condition, and repetition. There was a main effect for stimuli (F = 109.37, P < 0.0001). In a follow-up analysis of variance we found a condition effect for the nasal stimulus (F = 17.91, P < 0.0001). For the nasal stimulus, the nasalance scores of the backward focus were lower, and the nasalance scores of the forward focus were higher than in the normal condition. CONCLUSIONS: Changing the voice focus influenced oral-nasal balance more when the velopharyngeal port was open. Future studies should explore the possible treatment potential of voice focus for patients with hypernasality. PMID- 26494182 TI - Very Small Embryonic-Like Stem Cells: A Potential Developmental Link Between Germinal Lineage and Hematopoiesis in Humans. AB - It has been suggested that hematopoietic stem/progenitor cells (HSPCs) could become specified from a population of migrating primordial germ cells (PGCs), precursors of gametes, during embryogenesis. Some recent experimental data demonstrated that the cell population that is usually considered to be PGCs, moving toward the gonadal ridges of an embryo, contains a subset of cells coexpressing several germ cell and hematopoietic markers and possessing hematopoietic activity. Experimental data showed that bone morphogenetic protein 4 (BMP4) generates PGCs from mouse bone marrow-derived pluripotent stem cells. Interestingly, functional reproductive hormone receptors have been identified in HSPCs, thus indicating their potential role in reproductive function. Several reports have demonstrated fertility restoration and germ cell generation after bone marrow transplantation in both animal models and humans. A potential link between HSPCs and germinal lineage might be represented by very small embryonic like stem cells (VSELs), which have been found in adult human bone marrow, peripheral blood, and umbilical cord blood, express a specific pattern of pluripotency, germinal lineage, and hematopoiesis, and are proposed to persist in adult tissues and organs from the embryonic period of life. Stem cell populations, similar to VSELs, expressing several genes related to pluripotency and germinal lineage, especially to PGCs, have been discovered in adult human reproductive organs, ovaries and testicles, and were related to primitive germ cell-like cell development in vitro, thus supporting the idea of VSELs as a potential link between germinal lineage and hematopoiesis. PMID- 26494181 TI - Structurally driven one-dimensional electron confinement in sub-5-nm graphene nanowrinkles. AB - Graphene-based carbon materials such as fullerenes, carbon nanotubes, and graphenes have distinct and unique electronic properties that depend on their dimensionality and geometric structures. Graphene wrinkles with pseudo one dimensional structures have been observed in a graphene sheet. However, their one dimensional electronic properties have never been observed because of their large widths. Here we report the unique electronic structure of graphene nanowrinkles in a graphene sheet grown on Ni(111), the width of which was small enough to cause one-dimensional electron confinement. Use of spatially resolved, scanning tunnelling spectroscopy revealed bandgap opening and a one-dimensional van Hove singularity in the graphene nanowrinkles, as well as the chemical potential distribution across the graphene nanowrinkles. This observation allows us to realize a metallic-semiconducting-metallic junction in a single graphene sheet. Our demonstration of one-dimensional electron confinement in graphene provides the novel possibility of controlling its electronic properties not by chemical modification but by 'mechanical structuring'. PMID- 26494183 TI - High diabetes mellitus prevalence with increasing trend among newly-diagnosed tuberculosis patients in an Asian population: A nationwide population-based study. AB - AIMS: Our aims were to investigate the prevalence of diabetes mellitus (DM) among patients with newly-diagnosed tuberculosis (TB) and to determine its associated factors in an Asian population. METHODS: The data were obtained from the National Health Insurance Research Database and included 9831 newly-diagnosed TB individuals in the period of 2000-2010. The data were divided into a DM group and a non-DM group. We measured the prevalence and the associated comorbidities of DM. RESULTS: During 2000-2010, the prevalence of DM progressively increased, with an average prevalence rate of 27.9%. The patients with ages of 55-64 years had the highest association of DM (OR=3.53) compared with those under 45 years. TB patients with heart failure, ischemic heart disease, cerebral vascular disease, hypertension, dyslipidemia, chronic kidney disease, and liver disease were more likely to associate with DM (ORs=1.27, 1.23, 1.30, 2.32, 3.26, 1.6, and 1.68, respectively) compared to those without the variables. CONCLUSIONS: The prevalence of DM among TB patients in Taiwan was high and tended to increase in the past decade. Clinically, inquiring about DM history and screening routinely for those without DM history among TB patients should be carried out in Taiwan. PMID- 26494184 TI - Transition Metal Nitrides for Electrocatalytic Energy Conversion: Opportunities and Challenges. AB - Electrocatalytic energy conversion has been considered as one of the most efficient and promising pathways for realizing energy storage and energy utilization in modern society. To improve electrocatalytic reactions, specific catalysts are needed to lower the overpotential. In the search for efficient alternatives to noble metal catalysts, transition metal nitrides have attracted considerable interest due to their high catalytic activity and unique electronic structure. Over the past few decades, numerous nitride-based catalysts have been explored with respect to their ability to drive various electrocatalytic reactions, such as the hydrogen evolution reaction and the oxygen evolution reaction to achieve water splitting and the oxygen reduction reaction coupled with the methanol oxidation reaction to construct fuel cells or rechargeable Li O2 batteries. This Minireview provides a brief overview of recent progress on electrocatalysts based on transition metal nitrides, and outlines the current challenges and future opportunities. PMID- 26494185 TI - Binge Drinking and Risk Taking Behavior Among Adolescent Females in Israel. AB - PURPOSE: This prospective study examined binge drinking and alcohol-related problem behavior among Israeli adolescent females attending public school or a residential facility for substance abuse treatment. PROBLEM: Scant information is known about adolescent females, especially those with high-risk (e.g., school dropout and immigrant origin) characteristics. METHODS: The authors hypothesized that school, residential treatment, and mothers' country of origin status are associated with binge drinking and problem behavior. FINDINGS: Females in residential treatment reported higher levels of binge drinking and problem behavior as expected. However, country of origin was not a significant factor differentiating the female adolescents in school or a residential facility. Logistic regression points to current cigarette smoking, ease of purchasing alcohol, unsupervised night activity, low religiosity, and being physically threatened as predictors of binge drinking and problem behavior. CONCLUSION: The lack of differences based on country of origin status points to acculturation as a possible reason for the homogeneity. Further research is needed to study the impact of acculturation as well as monitor the alcohol use patterns and problems of adolescents over time and across locations to address prevailing needs. PMID- 26494186 TI - Unconserved C terminal of human cytomegalovirus tegument protein pUL76 elicits nuclear aggresome formation and induces DNA damage in transfected cells. AB - BACKGROUND: The HCMV UL76 gene is a member of UL24 family in herpes virus and encodes a highly conserved herpes virus protein. Inherited from common ancestor, members of Herpes_UL24 family encode proteins with a conserved N terminal and varied in C terminal region. To define which region (conserved N terminal or unconserved C terminal) of UL76 was responsible for its ability to induce DNA damage and aggresome formation, the wild-type UL76 gene and two deletion mutants were transfected to cells and analyzed by immunofluorescent staining, Western blotting and comet assay. RESULTS: We report that the EGFP-fusion proteins present as globular aggresomes and colocalize with gamma-H2AX in cells transfected with either pEGFP-UL76 or pEGFP-UL76C. The relative expression level of gamma-H2AX and percentage of cells with comet tails were elevated in pEGFP UL76 or pEGFP-UL76C transfection groups compared to the control. CONCLUSION: Our findings suggest that the unconserved C terminal (not the conserved N terminal) of pUL76 was sufficient to induce DNA damage and aggresome formation in transfected cells. PMID- 26494187 TI - Directionality of individual cone photoreceptors in the parafoveal region. AB - The pointing direction of cone photoreceptors can be inferred from the Stiles Crawford Effect of the First Kind (SCE-I) measurement. Healthy retinas have tightly packed cones with a SCE-I function peak either centered in the pupil or with a slight nasal bias. Various retinal pathologies can change the profile of the SCE-I function implying that the arrangement or the light capturing properties of the cone photoreceptors are affected. Measuring the SCE-I may reveal early signs of photoreceptor change before actual cell apoptosis occurs. In vivo retinal imaging with adaptive optics (AO) was used to measure the pointing direction of individual cones at eight retinal locations in four control human subjects. Retinal images were acquired by translating an aperture in the light delivery arm through 19 different locations across a subject's entrance pupil. Angular tuning properties of individual cones were calculated by fitting a Gaussian to the reflected intensity profile of each cone projected onto the pupil. Results were compared to those from an accepted psychophysical SCE-I measurement technique. The maximal difference in cone directionality of an ensemble of cones, rho-, between the major and minor axes of the Gaussian fit was 0.05 versus 0.29mm(-2) in one subject. All four subjects were found to have a mean nasal bias of 0.81mm with a standard deviation of +/-0.30mm in the peak position at all retinal locations with mean rho- value decreasing by 23% with increasing retinal eccentricity. Results show that cones in the parafoveal region converge towards the center of the pupillary aperture, confirming the anterior pointing alignment hypothesis. PMID- 26494188 TI - The impact of the C-terminal domain on the gating properties of MscCG from Corynebacterium glutamicum. AB - The mechanosensitive (MS) channel MscCG from the soil bacterium Corynebacterium glutamicum functions as a major glutamate exporter. MscCG belongs to a subfamily of the bacterial MscS-like channels, which play an important role in osmoregulation. To understand the structural and functional features of MscCG, we investigated the role of the carboxyl-terminal domain, whose relevance for the channel gating has been unknown. The chimeric channel MscS-(C-MscCG), which is a fusion protein between the carboxyl terminal domain of MscCG and the MscS channel, was examined by the patch clamp technique. We found that the chimeric channel exhibited MS channel activity in Escherichia coli spheroplasts characterized by a lower activation threshold and slow closing compared to MscS. The chimeric channel MscS-(C-MscCG) was successfully reconstituted into azolectin liposomes and exhibited gating hysteresis in a voltage-dependent manner, especially at high pipette voltages. Moreover, the channel remained open after releasing pipette pressure at membrane potentials physiologically relevant for C. glutamicum. This contribution to the gating hysteresis of the C-terminal domain of MscCG confers to the channel gating properties highly suitable for release of intracellular solutes. PMID- 26494189 TI - Pathways to Firesetting for Mentally Disordered Offenders: A Preliminary Examination. AB - The current study aimed to investigate the specific pathways in the offence process for mentally disordered firesetters. In a previous study, an offence chain model was constructed (i.e., the Firesetting Offence Chain for Mentally Disordered Offenders, FOC-MD) using offence descriptions obtained from 23 mentally disordered firesetters, detailing the sequence of contextual, behavioural, affective, and cognitive factors that precipitate an incidence of firesetting for this population. The current study examines the prevalence of the specific pathways to firesetting for the original 23 mentally disordered firesetters and a further sample of 13 mentally disordered firesetters. Three distinct pathways to firesetting are identified within the FOC-MD: fire interest childhood mental health, no fire interest-adult mental health, fire interest adult mental health. In this article, we describe these three pathways in detail using illustrative case studies. The practice implications of these identified pathways are also discussed. PMID- 26494190 TI - Can Nucleoli Be Markers of Developmental Potential in Human Zygotes? AB - In 1999, Tesarik and Greco reported that they could predict the developmental potential of human zygotes from a single static evaluation of their pronuclei. This was based on the distribution and number of specific nuclear organelles - the nucleoli. Recent studies in mice show that nucleoli play a key role in parental genome restructuring after fertilization, and that interfering with this process may lead to developmental failure. These studies thus support the Tesarik Greco evaluation as a potentially useful method for selecting high-quality embryos in human assisted reproductive technologies. In this opinion article we discuss recent evidence linking nucleoli to parental genome reprogramming, and ask whether nucleoli can mirror or be used as representative markers of embryonic parameters such as chromosome content or DNA fragmentation. PMID- 26494191 TI - Thermodynamic Properties of Carbosilane Dendrimers of the Sixth Generation with Ethylene Oxide Terminal Groups. AB - The temperature dependences of heat capacities of carbosilane dendrimers of the sixth generation with ethyleneoxide terminal groups, denoted as G6[(OCH2CH2)1OCH3]256 and G6[(OCH2CH2)3OCH3]256, were measured in the temperature range from T = (6 to 520) K by precision adiabatic calorimetry and differential scanning calorimetry (DSC). In the above temperature range the physical transformations, such as glass transition and high-temperature relaxation transition, were detected. The standard thermodynamic characteristics of the revealed transformations were determined and analyzed. The standard thermodynamic functions, namely, heat capacity Cp degrees (T), enthalpy H degrees (T) - H degrees (0), entropy S degrees (T) - S degrees (0), and Gibbs energy G degrees (T) - H degrees (0) for the range from T -> 0 to 520 K, and the standard entropies of formation DeltafS degrees of the investigated dendrimers in the devitrified state at T = 298.15 K, were calculated per corresponding moles of the notional structural units. The standard thermodynamic properties of dendrimers under study were discussed and compared with literature data for carbosilane dendrimers with different functional terminal groups. PMID- 26494193 TI - Medicine's social movement: #JuniorContract. PMID- 26494192 TI - Expression and diversification analysis reveals transposable elements play important roles in the origin of Lycopersicon-specific lncRNAs in tomato. AB - Long noncoding RNAs (lncRNAs) regulate gene expression and biological processes. With the development of high-throughput RNA sequencing technology, lncRNAs have been extensively studied in recent years. Nevertheless, the expression and evolution of lncRNAs in plants remain poorly understood. Here, we identified 413 and 709 multi-exon noncoding transcripts from 353 and 595 loci of the cultivar tomato Heinz1706 and its wild relative LA1589, respectively. Systematic comparison of the sequence and expression of lncRNAs showed that they are poorly conserved in Solanaceae, with only < 0.4% lncRNAs present in all sequenced genomes of tomato and potato. Sequence analysis of Lycopersicon-specific lncRNA loci in Solanum lycopersicum and S. pennellii showed that the origins of these molecules are associated with transposable elements (TEs). LncRNA-314, a fruit specific lncRNA expressed in S. lycopersicum and S. pimpinellifolium, but not in S. pennellii, originated through two evolutionary events: speciation of S. pennellii resulted in insertion of a long terminal repeat (LTR) retrotransposon into chromosome 10 and contributed to most of the transcribed region of lncRNA 314; and a large deletion in Lycopersicon generated the promoter region and part of the transcribed region of lncRNA-314. These results provide novel insights into the evolution of lncRNAs in plants. PMID- 26494194 TI - Lack of coordination during Ebola outbreak was a "lost opportunity" to test therapies. PMID- 26494195 TI - Celebrating our first 10 years. PMID- 26494197 TI - Significant Performance Enhancement in Asymmetric Supercapacitors based on Metal Oxides, Carbon nanotubes and Neutral Aqueous Electrolyte. AB - Amongst the materials being investigated for supercapacitor electrodes, carbon based materials are most investigated. However, pure carbon materials suffer from inherent physical processes which limit the maximum specific energy and power that can be achieved in an energy storage device. Therefore, use of carbon-based composites with suitable nano-materials is attaining prominence. The synergistic effect between the pseudocapacitive nanomaterials (high specific energy) and carbon (high specific power) is expected to deliver the desired improvements. We report the fabrication of high capacitance asymmetric supercapacitor based on electrodes of composites of SnO2 and V2O5 with multiwall carbon nanotubes and neutral 0.5 M Li2SO4 aqueous electrolyte. The advantages of the fabricated asymmetric supercapacitors are compared with the results published in the literature. The widened operating voltage window is due to the higher over potential of electrolyte decomposition and a large difference in the work functions of the used metal oxides. The charge balanced device returns the specific capacitance of ~198 F g(-1) with corresponding specific energy of ~89 Wh kg(-1) at 1 A g(-1). The proposed composite systems have shown great potential in fabricating high performance supercapacitors. PMID- 26494198 TI - Moody booze: Introducing the special section on affect regulation and substance use. PMID- 26494196 TI - Self-assembly and structural-functional flexibility of oxygenic photosynthetic machineries: personal perspectives. AB - This short review, with a bit of historical aspect and a strong personal bias and emphases on open questions, is focusing on the (macro-)organization and structural-functional flexibilities of the photosynthetic apparatus of oxygenic photosynthetic organisms at different levels of the structural complexity selected problems that have attracted most my attention in the past years and decades. These include (i) the anisotropic organization of the pigment-protein complexes and photosynthetic membranes-a basic organizing principle of living matter, which can, and probably should be adopted to intelligent materials; (ii) the organization of protein complexes into chiral macrodomains, large self assembling highly organized but structurally flexible entities with unique spectroscopic fingerprints-structures, where, important, high-level regulatory functions appear to 'reside'; (iii) a novel, dissipation-assisted mechanism of structural changes, based on a thermo-optic effect: ultrafast thermal transients in the close vicinity of dissipation of unused excitation energy, which is capable of inducing elementary structural changes; it makes plants capable of responding to excess excitation with reaction rates proportional to the overexcitation above the light-saturation of photosynthesis; (iv) the 3D ultrastructure of the granum-stroma thylakoid membrane assembly and other multilamellar membrane systems, and their remodelings-associated with regulatory mechanisms; (v) the molecular organization and structural-functional plasticity of the main light-harvesting complex of plants, in relation to their crystal structure and different in vivo and in vitro states; and (vi) the enigmatic role of non-bilayer lipids and lipid phases in the bilayer thylakoid membrane warranting its high protein content and contributing to its structural flexibility. PMID- 26494199 TI - Assessing safety culture in NICU: psychometric properties of the Italian version of Safety Attitude Questionnaire and result implications. AB - RATIONALE, AIMS AND OBJECTIVE: Neonatal intensive care units (NICUs) are a high risk setting. The Safety Attitude Questionnaire (SAQ) is a widely used tool to measure safety culture. The aims of the study are to verify the psychometric properties of the Italian version of SAQ, to evaluate safety culture in the NICUs and to identify improvement interventions. METHOD: A cross-sectional study was conducted in 6 level III NICUs. The SAQ was translated into Italian and adapted to the context, a confirmatory factor analysis (CFA) was performed to validate the questionnaire. RESULTS: 193 questionnaires were collected. The mean response rate was 59.7% (range 44.5%-95.7%). The answers were analysed according to six factors: f1 - teamwork climate, f2 - safety climate, f3 - job satisfaction, f4 - stress recognition, f5 - perception of management, f6 - working conditions. The CFA indexes were adequate (McDonald's omega indexes varied from 0.74 to 0.94, the SRMR index was equal to 0.79 and the RMSEA index was 0.070, 95% CI = 0.063 0.078). The mean composite score was 57.6 (SD 17.9), ranging between 42.3 and 69.7 on a standardized 100-point scale. We highlighted significant differences among units and professions (P < 0.05). CONCLUSIONS: The Italian version of the SAQ proved to be an effective tool to evaluate and compare the safety culture in the NICUs. The obtained scores significantly varied both within and among the NICUs. The organizational and structural characteristics of the involved hospitals probably affect the safety culture perception by the staff. PMID- 26494201 TI - Realtime (31)P NMR Investigation on the Catalytic Behavior of the Enzyme Adenylate kinase in the Matrix of a Switchable Ionic Liquid. AB - The integration of highly efficient enzymatic catalysis with the solvation properties of ionic liquids for an environmentally friendly and efficient use of raw materials such as wood requires fundamental knowledge about the influence of relevant ionic liquids on enzymes. Switchable ionic liquids (SIL) are promising candidates for implementation of enzymatic treatments of raw materials. One industrially interesting SIL is constituted by monoethanol amine (MEA) and 1,8 diazabicyclo-[5.4.0]-undec-7-ene (DBU) formed with sulfur dioxide (SO2) as the coupling media (DBU-SO2-MEASIL). It has the ability to solubilize the matrix of lignocellulosic biomass while leaving the cellulose backbone intact. Using a novel (31)P NMR-based real-time assay we show that this SIL is compatible with enzymatic catalysis because a model enzyme, adenylate kinase, retains its activity in up to at least 25 wt % of DBU-SO2-MEASIL. Thus this SIL appears suitable for, for example, enzymatic degradation of hemicellulose. PMID- 26494200 TI - Crystal Structure of the Isopropylzinc Alkoxide of Pyrimidyl Alkanol: Mechanistic Insights for Asymmetric Autocatalysis with Amplification of Enantiomeric Excess. AB - Asymmetric amplification during self-replication is a key feature that is used to explain the origin of homochirality. Asymmetric autocatalysis of pyrimidyl alkanol in the asymmetric addition of diisopropylzinc to pyrimidine-5 carbaldehyde is a unique example of this phenomenon. Crystallization of zinc alkoxides of this 5-pyrimidyl alkanol and single-crystal X-ray diffraction analysis of the alkoxide crystals reveal the existence of tetramer or higher oligomer structures in this asymmetric autocatalytic system. PMID- 26494202 TI - Great influence of geographic isolation on the genetic differentiation of Myriophyllum spicatum under a steep environmental gradient. AB - Understanding how natural processes affect population genetic structures is an important issue in evolutionary biology. One effective method is to assess the relative importance of environmental and geographical factors in the genetic structure of populations. In this study, we examined the spatial genetic variation of thirteen Myriophyllum spicatum populations from the Qinghai-Tibetan Plateau (QTP) and adjacent highlands (Yunnan-Guizhou Plateau, YGP) by using microsatellite loci and environmental and geographical factors. Bioclim layers, hydrological properties and elevation were considered as environmental variables and reduced by principal component analysis. The genetic isolation by geographic distance (IBD) was tested by Mantel tests and the relative importance of environmental variables on population genetic differentiation was determined by a partial Mantel test and multiple matrix regression with randomization (MMRR). Two genetic clusters corresponding to the QTP and YGP were identified. Both tests and MMRR revealed a significant and strong correlation between genetic divergence and geographic isolation under the influence of environmental heterogeneity at the overall and finer spatial scales. Our findings suggested the dominant role of geography on the evolution of M. spicatum under a steep environmental gradient in the alpine landscape as a result of dispersal limitation and genetic drift. PMID- 26494203 TI - Highly sensitive and selective sugar detection by terahertz nano-antennas. AB - Molecular recognition and discrimination of carbohydrates are important because carbohydrates perform essential roles in most living organisms for energy metabolism and cell-to-cell communication. Nevertheless, it is difficult to identify or distinguish various carbohydrate molecules owing to the lack of a significant distinction in the physical or chemical characteristics. Although there has been considerable effort to develop a sensing platform for individual carbohydrates selectively using chemical receptors or an ensemble array, their detection and discrimination limits have been as high in the millimolar concentration range. Here we show a highly sensitive and selective detection method for the discrimination of carbohydrate molecules using nano-slot-antenna array-based sensing chips which operate in the terahertz (THz) frequency range (0.5-2.5 THz). This THz metamaterial sensing tool recognizes various types of carbohydrate molecules over a wide range of molecular concentrations. Strongly localized and enhanced terahertz transmission by nano-antennas can effectively increase the molecular absorption cross sections, thereby enabling the detection of these molecules even at low concentrations. We verified the performance of nano-antenna sensing chip by both THz spectra and images of transmittance. Screening and identification of various carbohydrates can be applied to test even real market beverages with a high sensitivity and selectivity. PMID- 26494204 TI - Criterion Validity of the WAIS-IV Cognitive Proficiency Index (CPI). AB - OBJECTIVE: The current study sought to validate the Cognitive Proficiency Index (CPI) against similar, well-established measures of attention and processing speed. Additionally, the sensitivity of the CPI and Attention Index of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and their ability to differentiate among clinical groups were compared. METHOD: The first objective was accomplished by calculating correlation coefficients between the CPI and similar attention and processing speed measures. The second objective was accomplished using a clinical group of 25 individuals with Mini-Mental State Exam (MMSE) scores of less than or equal to 23 matched to a non-clinical group of 43 participants with MMSE scores of 30, all derived from the original sample. RESULTS: The CPI correlated in expected ways with other measures of attention and processing speed (magnitude of r = .19-.77). ANCOVA, receiver operating characteristic, and discriminant function analyses suggested that the CPI is superior to the RBANS Attention Index in differentiating between clinical and non clinical groups. CONCLUSIONS: These findings provide support for convergent validity and criterion-related concurrent validity for the CPI. PMID- 26494206 TI - Secondary hemochromatosis and mechanical circulatory support with a total artificial heart. PMID- 26494205 TI - LIS1-associated classic lissencephaly: A retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs. AB - BACKGROUND: Patients with LIS1-associated classic lissencephaly typically present with severe psychomotor retardation and drug-resistant epilepsy within the first year. AIM: To analyze the epileptogenic phenotype and response to antiepileptic therapy in LIS1-associated classic lissencephaly. METHOD: Retrospective evaluation of 22 patients (8 months-24 years) with genetically and radiologically confirmed LIS1-associated classic lissencephaly in 16 study centers. RESULTS: All patients in our cohort developed drug-resistant epilepsy. In 82% onset of seizures was noted within the first six months of life, most frequently with infantile spasms. Later in infancy the epileptogentic phenotype became more variable and included different forms of focal seizures as well generalized as tonic-clonic seizures, with generalized tonic-clonic seizures being the predominant type. Lamotrigine and valproate were rated most successful with good or partial response rates in 88-100% of the patients. Both were evaluated significantly better than levetiracetam (p<0.05) and sulthiame (p<0.01) in the neuropediatric assessment and better than levetiracetam, sulthiame (p<0.05) and topiramate (p<0.01) in the family survey. Phenobarbital and vigabatrin achieved good or partial response in 62-83% of the patients. CONCLUSION: Our findings suggest that patients with LIS1-associated lissencephaly might benefit most from lamotrigine, valproate, vigabatrin or phenobarbital. PMID- 26494207 TI - Chiral Lithiated Allylic alpha-Sulfonyl Carbanions: Experimental and Computational Study of Their Structure, Configurational Stability, and Enantioselective Synthesis. AB - X-ray crystal structure analysis of the lithiated allylic alpha-sulfonyl carbanions [CH2 ?CHC(Me)SO2 Ph]Li?diglyme, [cC6 H8 SO2 tBu]Li?PMDETA and [cC7 H10 SO2 tBu]Li?PMDETA showed dimeric and monomeric CIPs, having nearly planar anionic C atoms, only O?Li bonds, almost planar allylic units with strong C?C bond length alternation and the s-trans conformation around C1?C2. They adopt a C1?S conformation, which is similar to the one generally found for alkyl and aryl substituted alpha-sulfonyl carbanions. Cryoscopy of [EtCH?CHC(Et)SO2 tBu]Li in THF at 164 K revealed an equilibrium between monomers and dimers in a ratio of 83:17, which is similar to the one found by low temperature NMR spectroscopy. According to NMR spectroscopy the lone-pair orbital at C1 strongly interacts with the C?C double bond. Low temperature (6) Li,(1) H NOE experiments of [EtCH?CHC(Et)SO2 tBu]Li in THF point to an equilibrium between monomeric CIPs having only O?Li bonds and CIPs having both O?Li and C1?Li bonds. Ab initio calculation of [MeCH?CHC(Me)SO2 Me]Li?(Me2 O)2 gave three isomeric CIPs having the s-trans conformation and three isomeric CIPs having the s-cis conformation around the C1?C2 bond. All s-trans isomers are more stable than the s-cis isomers. At all levels of theory the s-trans isomer having O?Li and C1?Li bonds is the most stable one followed by the isomer which has two O?Li bonds. The allylic unit of the C,O,Li isomer shows strong bond length alternation and the C1 atom is in contrast to the O,Li isomer significantly pyramidalized. According to NBO analysis of the s-trans and s-cis isomers, the interaction of the lone pair at C1 with the pi* orbital of the CC double bond is energetically much more favorable than that with the "empty" orbitals at the Li atom. The C1?S and C1?C2 conformations are determined by the stereoelectronic effects nC -sigmaSR * interaction and allylic conjugation. (1) H DNMR spectroscopy of racemic [EtCH?CHC(Et)SO2 tBu]Li, [iPrCH?CHC(iPr)SO2 tBu]Li and [EtCH?C(Me)C(Et)SO2 tBu]Li in [D8 ]THF gave estimated barriers of enantiomerization of DeltaG(?) =13.2 kcal mol(-1) (270 K), 14.2 kcal mol(-1) (291 K) and 14.2 kcal mol(-1) (295 K), respectively. Deprotonation of sulfone (R)-EtCH?CHCH(Et)SO2 tBu (94 % ee) with nBuLi in THF at -105 degrees C occurred with a calculated enantioselectivity of 93 % ee and gave carbanion (M)-[EtCH?CHC(Et)SO2 tBu]Li, the deuteration and alkylation of which with CF3 CO2 D and MeOCH2 I, respectively, proceeded with high enantioselectivities. Time-dependent deuteration of the enantioenriched carbanion (M)-[EtCH?CHC(Et)SO2 tBu]Li in THF gave a racemization barrier of DeltaG(?) =12.5 kcal mol(-1) (168 K), which translates to a calculated half-time of racemization of t1/2 =12 min at -105 degrees C. PMID- 26494208 TI - Phylogenomic analysis of the genus Ralstonia based on 686 single-copy genes. AB - The genus Ralstonia contains species that are devastating plant pathogens, opportunistic human pathogens, and/or important degraders of xenobiotic and recalcitrant compounds. However, significant nomenclature problems exist, especially for the Ralstonia solanacearum species complex which consists of four phylotypes. Phylogenomics of the Ralstonia genus was investigated via a comprehensive analysis of 39 Ralstonia genomes as well as four genomes of Cupriavidus necator (more commonly known by its previous name Ralstonia eutropha). These data revealed 686 single-copy orthologs that could be extracted from the Ralstonia core-genome and used to reconstruct the phylogeny of the genus Ralstonia. The generated tree has strong bootstrap support for almost all branches. We also estimated the in silico DNA-DNA hybridization (isDDH) and the average nucleotide identity (ANI) values between each genome. Our data confirmed that whole genome sequence data provides a powerful tool to resolve the complex taxonomic questions of the genus Ralstonia, e.g. strains of Ralstonia solanacearum phylotype IIA and IIB may represent two subspecies of R. solanacearum, and strains of R. solanacearum phylotype I and III may be classified into two subspecies of Ralstonia pseudosolanacearum. Recently, strains of R. solanacearum phylotype IV were proposed to be reclassified into different subspecies of Ralstonia syzygii; our study, however, showed that phylotype IV strains had high isDDH values (83.8-96.1 %), indicating it may be not appropriate to classify these closely related strains into different subspecies. We also evaluated the performance of six chromosomal housekeeping genes (gdhA, mutS, adk, leuS, rplB and gyrB) used in Ralstonia phylogenetic inference. The multilocus sequence analysis of these six marker genes was able to reliably infer the phylogenetic relationships of the genus Ralstonia. PMID- 26494209 TI - Trimeric autotransporter adhesins contribute to Actinobacillus pleuropneumoniae pathogenicity in mice and regulate bacterial gene expression during interactions between bacteria and porcine primary alveolar macrophages. AB - Actinobacillus pleuropneumoniae is an important pathogen that causes respiratory disease in pigs. Trimeric autotransporter adhesin (TAA) is a recently discovered bacterial virulence factor that mediates bacterial adhesion and colonization. Two TAA coding genes have been found in the genome of A. pleuropneumoniae strain 5b L20, but whether they contribute to bacterial pathogenicity is unclear. In this study, we used homologous recombination to construct a double-gene deletion mutant, DeltaTAA, in which both TAA coding genes were deleted and used it in in vivo and in vitro studies to confirm that TAAs participate in bacterial auto aggregation, biofilm formation, cell adhesion and virulence in mice. A microarray analysis was used to determine whether TAAs can regulate other A. pleuropneumoniae genes during interactions with porcine primary alveolar macrophages. The results showed that deletion of both TAA coding genes up regulated 36 genes, including ene1514, hofB and tbpB2, and simultaneously down regulated 36 genes, including lgt, murF and ftsY. These data illustrate that TAAs help to maintain full bacterial virulence both directly, through their bioactivity, and indirectly by regulating the bacterial type II and IV secretion systems and regulating the synthesis or secretion of virulence factors. This study not only enhances our understanding of the role of TAAs but also has significance for those studying A. pleuropneumoniae pathogenesis. PMID- 26494210 TI - Intramuscular Lipoma as an Unusual Cause of Right Ventricular Outflow Tract Obstruction. PMID- 26494211 TI - Understanding carers' lived experience of stigma: the voice of families with a child on the autism spectrum. AB - Existing research suggests that there are several unique challenges associated with caring for a child on the autism spectrum. Despite a growing evidence base regarding autism spectrum disorders and their increasing prevalence, children on the autism spectrum and their families continue to perceive stigmatisation from various sources throughout the community. These perceptions of stigma can profoundly impact the quality of life of these children and their carers alike. This exploratory study sought to investigate carers' perceptions of stigma in caring for a child with high functioning autism. Fifteen carers from Sydney and the South Coast regions of New South Wales, Australia, participated in semi structured interviews regarding their caring experiences and any perceived encounters with stigma. Four domains of stigmatising experiences were identified: (i) lack of knowledge, (ii) judgement, (iii) rejection and (iv) lack of support. These domains were each reported to exist in four main contexts: (i) school, (ii) public, (iii) family and (iv) friends. These domains and contexts established a framework which provided a detailed account of how and where carers felt stigmatised, including the suggestion of a stigmatising pathway through the four domains. The main contexts in which stigma was perceived also appeared to be related, with those carers who experienced stigma in one context being more likely to report similar experiences in other contexts. Any attempts to empower carers in the face of stigmatisation should therefore consider each of these domains, the pathway that connects them and the relationship between different social contexts. Through identifying this pathway, supportive services can be acutely aware of how carers may perceive potentially stigmatising experiences and therefore provide appropriate interventions or support for the relevant stage of the pathway. PMID- 26494212 TI - Expression of P53 and HSP70 in Chronic Hepatitis, Liver Cirrhosis, and Early and Advanced Hepatocellular Carcinoma Tissues and Their Diagnostic Value in Hepatocellular Carcinoma: An Immunohistochemical Study. AB - BACKGROUND: Tumor protein (P53) and heat shock protein 70 (HSP70) play key roles in chronic liver diseases. This study aimed to characterize P53 and HSP70 expression in chronic hepatitis (CH), liver cirrhosis (LC), early and advanced HCC, and to analyze their diagnostic value in hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Immunohistochemical staining was conducted to evaluate the expression of P53 and HSP70 in 200 human liver tissue specimens, with advanced HCC (n=80), early HCC (n=30), CH (n=30), LC (n=30), and Controls (n=30). RESULTS: P53 expression levels were lower in LC than those of HCC, but remained on par with those of CH and Controls. HSP70 expression levels were higher in HCC than those of LC, CH, and Controls. The sensitivity and specificity for HCC diagnosis were: 50.9% and 98.9% for P53, and 78.2 and 77.8% for HSP70, respectively. The sensitivity and specificity of different combinations were: 95.5% and 85.5% with either P53 or HSP70 being positive, and 33.6% and 98.9% if both were positive. Among the differentiation stages marked low, intermediate, and high in HCC, the P53 positive rate was higher in the low than in the intermediate, which was higher than that in the high. HSP70 positive rate was higher in the low and the intermediate than in the high, but no obvious changes were found between the low and the intermediate. CONCLUSIONS: P53 and HSP70 could be potential biomarkers for HCC diagnosis, and proper combinations of these 2 markers could improve diagnostic accuracy. PMID- 26494213 TI - Optically secured information retrieval using two authenticated phase-only masks. AB - We propose an algorithm for jointly designing two phase-only masks (POMs) that allow for the encryption and noise-free retrieval of triple images. The images required for optical retrieval are first stored in quick-response (QR) codes for noise-free retrieval and flexible readout. Two sparse POMs are respectively calculated from two different images used as references for authentication based on modified Gerchberg-Saxton algorithm (GSA) and pixel extraction, and are then used as support constraints in a modified double-phase retrieval algorithm (MPRA), together with the above-mentioned QR codes. No visible information about the target images or the reference images can be obtained from each of these authenticated POMs. This approach allows users to authenticate the two POMs used for image reconstruction without visual observation of the reference images. It also allows user to friendly access and readout with mobile devices. PMID- 26494216 TI - Caveolin-1 in Cardiovascular Disease: A Double-Edged Sword. PMID- 26494217 TI - Human Growth Hormone in Transgenesis: A Growing Problem? PMID- 26494215 TI - beta-Cell MicroRNAs: Small but Powerful. AB - Noncoding RNA and especially microRNAs (miRs) have emerged as important regulators of key processes in cell biology, including development, differentiation, and survival. Currently, over 2,500 mature miRs have been reported in humans, and considering that each miR has multiple targets, the number of genes and pathways potentially affected is huge. Not surprisingly, many miRs have also been implicated in diabetes, and more recently, some have been discovered to play important roles in the pancreatic islet, including beta-cell function, proliferation, and survival. The goal of this Perspective is to offer an overview of this rapidly evolving field and the miRs involved, reveal novel networks of beta-cell miR signaling, and provide an outlook of the opportunities and challenges ahead. PMID- 26494218 TI - Sweet and Low on Leptin: Hormonal Regulation of Sweet Taste Buds. PMID- 26494219 TI - A Key Role of Insulin Receptors in Memory. PMID- 26494220 TI - Enhancing the Metabolic Benefits of Bariatric Surgery: Tipping the Scales With Exercise. PMID- 26494222 TI - Reply to Letter: Complexity of venous symptoms. PMID- 26494223 TI - Sclerotherapy complications of peripheral venous malformations. AB - Background Sclerotherapy is often the primary treatment for peripheral venous malformations. It is mostly sufficient alone, but can be combined with other endovascular techniques. Despite its mini-invasiveness, it is not without potentially severe complications. Here, we systematically report sclerotherapy complications in trunk and extremity venous malformations. Methods We retrospectively assessed the complications of 127 consecutive patients who had received sclerotherapy for peripheral venous malformation in our tertiary care unit (January 2007-August 2013). We applied the Clavien-Dindo classification to grade the severity of complications. We mostly used detergent sclerosants (85.7%), and less often ethanol (5.7%) or bleomycin (4.2%). In 4.2% of the procedures, we combined glue, coils, endovascular laser or particles to sclerotherapy. Results The overall complication rate per procedure was 12.5%. Most complications (83.3%) were local and managed conservatively. We encountered four severe complications, all related to blood coagulopathy. Subcutaneous lesion location and use of ethanol significantly increased the risk of local complications. Conclusion Sclerotherapy alone or combined with other endovascular techniques is a safe method for local venous malformations with moderate risk for conservatively manageable complications. Blood coagulopathy constitutes a risk for, otherwise rare, severe complications. PMID- 26494225 TI - A Triphasic Sorting System: Coordination Cages in Ionic Liquids. AB - Host-guest chemistry is usually carried out in either water or organic solvents. To investigate the utility of alternative solvents, three different coordination cages were dissolved in neat ionic liquids. By using (19) F NMR spectroscopy to monitor the presence of free and bound guest molecules, all three cages were demonstrated to be stable and capable of encapsulating guests in ionic solution. Different cages were found to preferentially dissolve in different phases, allowing for the design of a triphasic sorting system. Within this system, three coordination cages, namely Fe4 L6 2, Fe8 L12 3, and Fe4 L4 4, each segregated into a distinct layer. Upon the addition of a mixture of three different guests, each cage (in each separate layer) selectively bound its preferred guest. PMID- 26494224 TI - Automated liver elasticity calculation for MR elastography. AB - PURPOSE: MR elastography (MRE) is a phase-contrast MRI technique that is used to quantitatively assess liver stiffness for staging hepatic fibrosis. The current approach requires manual selection of a region of interest (ROI) with good wave quality from which to measure stiffness. The purpose of this work was to develop and evaluate a fully automated approach for measuring hepatic stiffness from MRE images to further reduce measurement variability. MATERIALS AND METHODS: An automated liver elasticity calculation (ALEC) algorithm was developed to address reader stiffness measurement variability. ALEC has three stages: initial tissue estimation, segmentation, and ROI cleanup. Stiffnesses measured by the algorithm were compared with technicians and an expert radiologist in a set of 121 clinical cases acquired at 1.5 Tesla. Intra-class correlation (ICC), Bland-Altman analysis, and a noninferiority test were performed to evaluate whether the algorithm can be used in place of manual analysis by technicians. RESULTS: The stiffness measurement difference with the expert was 1.42% +/- 11.17% (mean +/- standard deviation) for the algorithm and 1.82% +/- 13.65% for the technicians. The ICCs were 0.981 and 0.984, respectively. Both the algorithm and technicians were equivalent to the expert within a 5% significance margin (P < 0.01). The algorithm had no failures in the 119 cases that were considered analyzable by the human readers. CONCLUSION: The results of this study show that the newly developed automated algorithm is able to measure stiffness in clinical liver MRE exams with an accuracy that is equivalent to that of an expert radiologist. ALEC may be useful for analysis of archived data and suitable for performing multi center studies. PMID- 26494226 TI - Prp40 and early events in splice site definition. AB - The alternative splicing (AS) of precursor messenger RNA (pre-mRNA) is a tightly regulated process through which introns are removed to leave the resulting exons in the mRNA appropriately aligned and ligated. The AS of pre-mRNA is a key mechanism for increasing the complexity of proteins encoded in the genome. In humans, more than 90% of genes undergo AS, underscoring the importance of this process in RNA biogenesis. As such, AS misregulation underlies multiple human diseases. The splicing reaction is catalyzed by the spliceosome, a highly dynamic complex that assembles at or near the intron/exon boundaries and undergoes sequential conformational and compositional changes during splicing. The initial recognition of splice sites defines the exons that are going to be removed, which is a critical step in the highly regulated splicing process. Although the available lines of evidence are increasing, the molecular mechanisms governing AS, including the initial interactions occurring at intron/exon boundaries, and the factors that modulate these critical connections by functioning as a scaffold for active-site RNAs or proteins, remain poorly understood. In this review, we summarize the major hallmarks of the initial steps in the splicing process and the role of auxiliary factors that contribute to the assembly of the spliceosomal complex. We also discuss the role of the essential yeast Prp40 protein and its mammalian homologs in the specificity of this pre-mRNA processing event. In addition, we provide the first exhaustive phylogenetic analysis of the molecular evolution of Prp40 family members. WIREs RNA 2016, 7:17-32. doi: 10.1002/wrna.1312 For further resources related to this article, please visit the WIREs website. PMID- 26494227 TI - Connexin 32 and luteolin play protective roles in non-alcoholic steatohepatitis development and its related hepatocarcinogenesis in rats. AB - Non-alcoholic steatohepatitis (NASH) has the potential to lead to the development of cirrhosis and hepatocellular carcinoma (HCC). Connexin (Cx) 32, a hepatocyte gap-junction protein, plays a preventive role in hepatocarcinogenesis. However, the precise contribution of Cx32 in the development of NASH has not been established. In this study, we aimed to clarify the role of Cx32 and the chemopreventive effect of luteolin, an antioxidant flavonoid, on the progression of NASH and NASH-related hepatocarcinogenesis. Cx32 dominant negative transgenic (Cx32DeltaTg) and wild-type (Wt) rats at 10 weeks of age were given diethylnitrosamine and fed methionine-choline-deficient diet (MCDD) or MCDD with luteolin for 12 weeks. MCDD induced steatohepatitis and fibrosis along with increased inflammatory cytokine expression and reactive oxygen species in the liver. These effects were more severe in Cx32DeltaTg rats as compared with Wt rats, and significantly suppressed by luteolin in both genotypes. Concerning NASH related hepatocarcinogenesis, the number of glutathione S-transferase placental form (GST-P)-positive foci was greater in Cx32DeltaTg versus Wt rats, and significantly reduced by luteolin in Cx32DeltaTg rats. Microarray analysis identified brain expressed, X-linked 1 (Bex1) as an upregulated gene in Cx32DeltaTg rat liver. Quantitative RT-PCR and in situ hybridization revealed that increased Bex1 mRNA was localized in GST-P-positive foci in Cx32DeltaTg rats, and the expression level was significantly decreased by luteolin. Moreover, Bex1 knockdown resulted in significant growth inhibition of the rat HCC cell lines. These results show that Cx32 and luteolin have suppressive roles in inflammation, fibrosis and hepatocarcinogenesis during NASH progression, suggesting a potential therapeutic application for NASH. PMID- 26494228 TI - PCSK9 Induces CD36 Degradation and Affects Long-Chain Fatty Acid Uptake and Triglyceride Metabolism in Adipocytes and in Mouse Liver. AB - OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor thereby elevating plasma low density lipoprotein cholesterol levels and the risk of coronary heart disease. Thus, the use of PCSK9 inhibitors holds great promise to prevent heart disease. Previous work found that PCSK9 is involved in triglyceride metabolism, independently of its action on low-density lipoprotein receptor, and that other yet unidentified receptors could mediate this effect. Therefore, we assessed whether PCSK9 enhances the degradation of CD36, a major receptor involved in transport of long-chain fatty acids and triglyceride storage. APPROACH AND RESULTS: Overexpressed or recombinant PCSK9 induced CD36 degradation in cell lines and primary adipocytes and reduced the uptake of the palmitate analog Bodipy FL C16 and oxidized low-density lipoprotein in 3T3-L1 adipocytes and hepatic HepG2 cells, respectively. Surface plasmon resonance, coimmunoprecipitation, confocal immunofluorescence microscopy, and protein degradation pathway inhibitors revealed that PCSK9 directly interacts with CD36 and targets the receptor to lysosomes through a mechanism involving the proteasome. Importantly, the level of CD36 protein was increased by >3-fold upon small interfering RNA knockdown of endogenous PCSK9 in hepatic cells and similarly increased in the liver and visceral adipose tissue of Pcsk9(-/-) mice. In Pcsk9(-/-) mice, increased hepatic CD36 was correlated with an amplified uptake of fatty acid and accumulation of triglycerides and lipid droplets. CONCLUSIONS: Our results demonstrate an important role of PCSK9 in modulating the function of CD36 and triglyceride metabolism. PCSK9-mediated CD36 degradation may serve to limit fatty acid uptake and triglyceride accumulation in tissues, such as the liver. PMID- 26494229 TI - Expansion of CD25+ Innate Lymphoid Cells Reduces Atherosclerosis. AB - OBJECTIVE: Innate lymphoid cells (ILCs) are a newly discovered subset of immune cells that promote tissue homeostasis and protect against pathogens. ILCs produce cytokines also produced by T lymphocytes that have been shown to affect atherosclerosis, but the influence of ILCs on atherosclerosis has not been explored. APPROACH AND RESULTS: We demonstrate that CD25(+) ILCs that produce type 2 cytokines (ILC2s) are present in the aorta of atherosclerotic immunodeficient ldlr(-/-)rag1(-/-) mice. To investigate the role of ILCs in atherosclerosis, ldlr(-/-)rag1(-/-) mice were concurrently fed an atherogenic diet and treated with either ILC-depleting anti-CD90.2 antibodies or IL-2/anti-IL 2 complexes that expand CD25(+) ILCs. Lesion development was not affected by anti CD90.2 treatment, but was reduced in IL-2/anti-IL-2-treated mice. These IL-2 treated mice had reduced very low-density lipoprotein cholesterol and increased triglycerides compared with controls and reduced apolipoprotein B100 gene expression in the liver. IL-2/anti-IL-2 treatment caused expansion of ILC2s in aorta and other tissues, elevated levels of IL-5, systemic eosinophila, and hepatic eosinophilic inflammation. Blockade of IL-5 reversed the IL-2 complex induced eosinophilia but did not change lesion size. CONCLUSIONS: This study demonstrates that expansion of CD25-expressing ILCs by IL-2/anti-IL-2 complexes leads to a reduction in very low-density lipoprotein cholesterol and atherosclerosis. Global depletion of ILCs by anti-CD90.2 did not significantly affect lesion size indicating that different ILC subsets may have divergent effects on atherosclerosis. PMID- 26494230 TI - Implications of alphavbeta3 Integrin Signaling in the Regulation of Ca2+ Waves and Myogenic Tone in Cerebral Arteries. AB - OBJECTIVE: The myogenic response is central to blood flow regulation in the brain. Its induction is tied to elevated cytosolic [Ca(2+)], a response primarily driven by voltage-gated Ca(2+) channels and secondarily by Ca(2+) wave production. Although the signaling events leading to the former are well studied, those driving Ca(2+) waves remain uncertain. APPROACH AND RESULTS: We postulated that alphavbeta3 integrin signaling is integral to the generation of pressure induced Ca(2+) waves and cerebral arterial tone. This hypothesis was tested in rat cerebral arteries using the synergistic strengths of pressure myography, rapid Ca(2+) imaging, and Western blot analysis. GRGDSP, a peptide that preferentially blocks alphavbeta3 integrin, attenuated myogenic tone, indicating the modest role for sarcoplasmic reticulum Ca(2+) release in myogenic tone generation. The RGD peptide was subsequently shown to impair Ca(2+) wave generation and myosin light chain 20 (MLC20) phosphorylation, the latter of which was attributed to the modulation of MLC kinase and MLC phosphatase via MYPT1-T855 phosphorylation. Subsequent experiments revealed that elevated pressure enhanced phospholipase Cgamma1 phosphorylation in an RGD-dependent manner and that phospholipase C inhibition attenuated Ca(2+) wave generation. Direct inhibition of inositol 1, 4, 5-triphosphate receptors also impaired Ca(2+) wave generation, myogenic tone, and MLC20 phosphorylation, partly through the T-855 phosphorylation site of MYPT1. CONCLUSIONS: Our investigation reveals a hitherto unknown role for alphavbeta3 integrin as a cerebral arterial pressure sensor. The membrane receptor facilitates Ca(2+) wave generation through a signaling cascade, involving phospholipase Cgamma1, inositol 1,3,4 triphosphate production, and inositol 1, 4, 5-triphosphate receptor activation. These discrete asynchronous Ca(2+) events facilitate MLC20 phosphorylation and, in part, myogenic tone by influencing both MLC kinase and MLC phosphatase activity. PMID- 26494231 TI - Association of Plasma gamma' Fibrinogen With Incident Cardiovascular Disease: The Atherosclerosis Risk in Communities (ARIC) Study. AB - OBJECTIVES: To prospectively examine the association of plasma gamma' fibrinogen with the incidence of multiple cardiovascular disease (CVD) end points, independent of established CVD risk factors, total fibrinogen, and other inflammatory markers. APPROACH AND RESULTS: The Atherosclerosis Risk in Communities (ARIC) study measured gamma' fibrinogen by enzyme-linked immunosorbent assay in stored plasma samples from 1993 to 1995 and related levels in 10 601 adults to incident CVD end points (coronary heart disease [n=1603], ischemic stroke [n=548], peripheral artery disease [n=599], heart failure [n=1411], and CVD mortality [n=705]) through 2012 (median follow-up, 18 years). In Cox models accounting for established CVD risk factors and total fibrinogen levels, gamma' fibrinogen was associated positively with peripheral artery disease (hazard ratio [HR] per 1-SD [8.80 mg/dL] increment, 1.14 [1.04-1.24]), heart failure (HR, 1.06 [1.01-1.13]), and CVD deaths (HR, 1.12 [1.04-1.21]) but not with incident coronary heart disease (HR, 1.01 [0.96-1.07]) or ischemic stroke (HR, 0.98 [0.89-1.07]). Additional adjustment for C-reactive protein, however, eliminated the associations with peripheral artery disease and heart failure. CONCLUSIONS: These findings do not lend support to the hypothesis that gamma' fibrinogen influences CVD events through its prothrombotic properties. Rather, gamma' fibrinogen concentrations seem to reflect general inflammation that accompanies and may contribute to atherosclerotic CVD, instead of gamma' fibrinogen being a causal risk factor. PMID- 26494232 TI - Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis. AB - OBJECTIVES: Sepsis is characterized by systemic activation of inflammation and coagulation in response to infection. In sepsis, activated neutrophils extrude neutrophil extracellular traps composed of cell-free DNA (CFDNA) that not only trap pathogens but also provide a stimulus for clot formation. Although the effect of CFDNA on coagulation has been extensively studied, much less is known about the impact of CFDNA on fibrinolysis. To address this, we (1) investigated the relationship between CFDNA levels and fibrinolytic activity in sepsis and (2) determined the mechanisms by which CFDNA modulates fibrinolysis. APPROACH AND RESULTS: Plasma was collected from healthy and septic individuals, and CFDNA was quantified. Clot lysis assays were performed in plasma and purified systems, and lysis times were determined by monitoring absorbance. Clot morphology was assessed using scanning electron microscopy. Clots formed in plasma from septic patients containing >5 ug/mL CFDNA were dense in structure and resistant to fibrinolysis, a phenomenon overcome by deoxyribonuclease addition. These effects were recapitulated in control plasma supplemented with CFDNA. In a purified system, CFDNA delayed fibrinolysis but did not alter tissue-type plasminogen activator-induced plasmin generation. Using surface plasmon resonance, CFDNA bound plasmin with a Kd value of 4.2+/-0.3 umol/L, and increasing concentrations of CFDNA impaired plasmin-mediated degradation of fibrin clots via the formation of a nonproductive ternary complex between plasmin, CFDNA, and fibrin. CONCLUSIONS: Our studies suggest that the increased levels of CFDNA in sepsis impair fibrinolysis by inhibiting plasmin-mediated fibrin degradation, thereby identifying CFDNA as a potential therapeutic target for sepsis treatment. PMID- 26494233 TI - Postnatal Deletion of the Type II Transforming Growth Factor-beta Receptor in Smooth Muscle Cells Causes Severe Aortopathy in Mice. AB - OBJECTIVE: Prenatal deletion of the type II transforming growth factor-beta (TGF beta) receptor (TBRII) prevents normal vascular morphogenesis and smooth muscle cell (SMC) differentiation, causing embryonic death. The role of TBRII in adult SMC is less well studied. Clarification of this role has important clinical implications because TBRII deletion should ablate TGF-beta signaling, and blockade of TGF-beta signaling is envisioned as a treatment for human aortopathies. We hypothesized that postnatal loss of SMC TBRII would cause aortopathy. APPROACH AND RESULTS: We generated mice with either of 2 tamoxifen inducible SMC-specific Cre (SMC-CreER(T2)) alleles and homozygous floxed Tgfbr2 alleles. Mice were injected with tamoxifen, and their aortas examined 4 and 14 weeks later. Both SMC-CreER(T2) alleles efficiently and specifically rearranged a floxed reporter gene and efficiently rearranged a floxed Tgfbr2 allele, resulting in loss of aortic medial TBRII protein. Loss of SMC TBRII caused severe aortopathy, including hemorrhage, ulceration, dissection, dilation, accumulation of macrophage markers, elastolysis, abnormal proteoglycan accumulation, and aberrant SMC gene expression. All areas of the aorta were affected, with the most severe pathology in the ascending aorta. Cre-mediated loss of SMC TBRII in vitro ablated both canonical and noncanonical TGF-beta signaling and reproduced some of the gene expression abnormalities detected in vivo. CONCLUSIONS: SMC TBRII plays a critical role in maintaining postnatal aortic homeostasis. Loss of SMC TBRII disrupts TGF-beta signaling, acutely alters SMC gene expression, and rapidly results in severe and durable aortopathy. These results suggest that pharmacological blockade of TGF-beta signaling in humans could cause aortic disease rather than prevent it. PMID- 26494234 TI - Prostate cancer patients' report on communication about endocrine therapy and its association with adherence. AB - BACKGROUND: Endocrine therapy is a mainstay of prostate cancer therapy. Given that few data exist on patient physician communication with regard to this field of therapy and adherence, we conducted a survey of patient members of a German support organization. PATIENTS AND METHODS: We developed a structured questionnaire that was tested in a pilot version and then programmed as an online questionnaire. RESULTS: The questionnaire was completed by 694 patients. While 58 % of participants rated the information they received as comprehensive, 42 % did not. Fifty-one percentage stated that they were informed of side effects in detail, and 35 % received information on supportive treatments available in the event of side effects. Patients with higher education more often reported receiving information on side effects (p = 0.036) as well as alternatives for treatment (p = 0.001). Only 13 % stated that their questions were answered in detail, with 43 % receiving no answers or only non-detailed answers. Additional information was sought by 82 %, mostly from the Internet (67 %) and patient support groups (66 %). Seventy-six percentage experienced side effects that imposed limitations on their daily activities. Of those patients with side effects, 60 % reported that their physicians did not react to their complaints. There is a significant association between side effects in general and depression in particular and non-adherence (p < 0.01 and p = 0.002, respectively). In contrast, better information on side effects is associated with better adherence (p < 0001). CONCLUSION: In order to improve adherence, detailed information on side effects and comprehensive supportive care is most important. Physicians should not rely on written information but should rather mainly engage in direct communication. PMID- 26494236 TI - Synthesis of Si-Sb-ZnO Composites as High-Performance Anodes for Lithium-ion Batteries. AB - The Si-Sb-ZnO composites were prepared by a chemical reduction-mechanical alloying method and were employed as anode materials for lithium-ion batteries. The electrochemical performance of the Si-Sb alloy was significantly improved by the addition of ZnO nanoparticles. Especially, the initial specific charge and discharge capacities for Si-Sb-(ZnO)0.3 composite were 845.1 and 1301.5 mAh/g, respectively, while the initial coulombic efficiency was 64.9 %. The capacity remained at 690 mAh/g after 200 cycles, and the capacity retention ratio was 81.6 %, which demonstrated excellent cycling stability and rate capability of the composite materials. PMID- 26494235 TI - Allogeneic hematopoietic cell transplantation without fluconazole and fluoroquinolone prophylaxis. AB - Fluoroquinolone (FQ) and fluconazole prophylaxis is recommended for patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). However, due to an uncertain scientific basis and the increasing emergence of resistant germs, this policy should be questioned. Therefore, FQ and fluconazole prophylaxis was omitted in alloHCT at our center. In this retrospective analysis, all consecutive patients (n = 63) who underwent first alloHCT at our institution from September 2010 to September 2013 were included. Patients neither received FQ nor fluconazole prophylaxis. Day 100 mortality, incidence of febrile neutropenia, bacterial infections, and invasive fungal diseases (IFD) were assessed. Sixteen patients who started conditioning under antimicrobial treatment/prophylaxis due to pre-existing neutropenia (3/16), IFD (12/16), or aortic valve replacement (1/16) were excluded from the analysis. Finally, 47 patients were transplanted without prophylaxis as intended. Day 100 mortality was 9 %. Febrile neutropenia occurred in 62 % (29/47); 17/47 patients (36 %) experienced a blood stream infection (BSI) with detection of Gram-positive bacteria in 14 patients, Gram negative bacteria in five patients, and candida in one patient, respectively. Coagulase-negative staphylococci were the most frequently isolated Gram-positive bacteria; 12/21 isolated Gram-positive and 3/6 Gram-negative bacteria were FQ resistant. In 21 % (10/47) of the patients, IFD (1x proven, 1x probable, and 8x possible) were diagnosed. To conclude, all three criteria, day 100 mortality, the incidence of IFD, and BSI, are in the range of published data for patients transplanted with FQ and fluconazole prophylaxis. These data demonstrate that alloHCT is feasible without FQ and fluconazole prophylaxis. PMID- 26494237 TI - Visible Light-Driven Photocatalytic Activity of Oleic Acid-Coated TiO2 Nanoparticles Synthesized from Absolute Ethanol Solution. AB - The one-step synthesis of oleic acid-coated TiO2 nanoparticles with visible light driven photocatalytic activity was reported by this manuscript, using oleic acid ethanol as crucial starting materials. The photocatalytic degradation of nitrogen monoxide (deNOx) in the gas phase was investigated in a continuous reactor using a series of TiO2 semiconductors, prepared from oleic acid- or acetic acid-ethanol solution. The surface modification on TiO2 by organic fatty acid, oleic acid, could reinvest TiO2 photocatalyst with the excellent visible light response. The deNOx ability is almost as high as 30 % destruction in the visible light region (lambda > 510 nm) which is similar to the nitrogen-doped TiO2. Meanwhile, acetic acid, a monobasic acid, has a weaker ability on visible light modification of TiO2. PMID- 26494238 TI - Erratum to: Trace Element Levels in Congenital Hypogonadotrophic Hypogonadism. PMID- 26494239 TI - Genetics, realized heritability and preliminary mechanism of spinosad resistance in Phenacoccus solenopsis Tinsley (Homoptera: Pseudococcidae): an invasive pest from Pakistan. AB - The cotton mealybug, Phenacoccus solenopsis Tinsley (Homoptera: Pseudococcidae) has gained recognition as a key pest due to its invasive nature throughout the world. The P. solenopsis has a wide range of host plants and damages the cotton crop in various parts of the world. In view of the economic importance of this pest, a study on selection, inheritance and mechanism of spinosad resistance was conducted on P. solenopsis. Selection of field collected P. solenopsis for seven generations with spinosad resulted in a high resistance ratio of 282.45-fold. Genetic studies of spinosad resistance in P. solenopsis indicated that maternal effects are not involved in spinosad resistance; and resistance development is an autosomal and incompletely dominant trait. The number of genes involved in spinosad resistance was determined to be more than one, suggesting that resistance is controlled by multiple loci. The realized heritability (h (2)) value for spinosad resistance was 0.94. Synergism bioassays of spinosad with piperonyl butoxide and S,S,S-tributyl phosphorotrithioate showed that spinosad resistance in P. solenopsis could be due to esterase only. The study provides the basic information for implementation of effective resistance management strategies to control P. solenopsis. PMID- 26494240 TI - Bovine vaginal strain Kocuria kristinae and its characterization. AB - Kocuria spp. are widely distributed in nature. They are Gram-positive, coagulase negative, coccoid bacteria belonging to the family Micrococcaceae, suborder Micrococcineae, order Actinomycetales, class Actinobacteria. In general, limited knowledge exists concerning the properties associated with the representants of the genus Kocuria, Kocuria kristinae as well. Following our previous results, K. kristinae Kk2014 Biocenol(TM) (CCM 8628) was isolated from vagina of a healthy cow. Its taxonomical allottation was confirmed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) identification system and phenotypic characteristics. Kk2014 strain showed strong adherence capability to the vaginal mucus, produced organic acids which can play a role in prevention of unsuitable contamination, and showed in vitro antagonistic/antimicrobial activity against strains Arcanobacterium pyogenes CCM 5753, Fusobacterium necrophorum CCM 5982, Streptococcus equi subsp. zooepidemicus CCM 7316, and Gardnerella vaginalis CCM 6221. Antimicrobial activity ranged from 100 to 200 AU/mL, up to 32 mm in size, respectively. PMID- 26494241 TI - The rumen microbial metagenome associated with high methane production in cattle. AB - BACKGROUND: Methane represents 16 % of total anthropogenic greenhouse gas emissions. It has been estimated that ruminant livestock produce ca. 29 % of this methane. As individual animals produce consistently different quantities of methane, understanding the basis for these differences may lead to new opportunities for mitigating ruminal methane emissions. Metagenomics is a powerful new tool for understanding the composition and function of complex microbial communities. Here we have applied metagenomics to the rumen microbial community to identify differences in the microbiota and metagenome that lead to high- and low-methane-emitting cattle phenotypes. METHODS: Four pairs of beef cattle were selected for extreme high and low methane emissions from 72 animals, matched for breed (Aberdeen-Angus or Limousin cross) and diet (high or medium concentrate). Community analysis was carried out by qPCR of 16S and 18S rRNA genes and by alignment of Illumina HiSeq reads to the GREENGENES database. Total genomic reads were aligned to the KEGG genes databasefor functional analysis. RESULTS: Deep sequencing produced on average 11.3 Gb per sample. 16S rRNA gene abundances indicated that archaea, predominantly Methanobrevibacter, were 2.5* more numerous (P = 0.026) in high emitters, whereas among bacteria Proteobacteria, predominantly Succinivibrionaceae, were 4-fold less abundant (2.7 vs. 11.2 %; P = 0.002). KEGG analysis revealed that archaeal genes leading directly or indirectly to methane production were 2.7-fold more abundant in high emitters. Genes less abundant in high emitters included acetate kinase, electron transport complex proteins RnfC and RnfD and glucose-6-phosphate isomerase. Sequence data were assembled de novo and over 1.5 million proteins were annotated on the subsequent metagenome scaffolds. Less than half of the predicted genes matched matched a domain within Pfam. Amongst 2774 identified proteins of the 20 KEGG orthologues that correlated with methane emissions, only 16 showed 100 % identity with a publicly available protein sequence. CONCLUSIONS: The abundance of archaeal genes in ruminal digesta correlated strongly with differing methane emissions from individual animals, a finding useful for genetic screening purposes. Lower emissions were accompanied by higher Succinovibrionaceae abundance and changes in acetate and hydrogen production leading to less methanogenesis, as similarly postulated for Australian macropods. Large numbers of predicted protein sequences differed between high- and low-methane-emitting cattle. Ninety-nine percent were unknown, indicating a fertile area for future exploitation. PMID- 26494243 TI - Erratum to: Comparison of pulpal anesthesia and cardiovascular parameters with lidocaine with epinephrine and lidocaine with clonidine after maxillary infiltration in type 2 diabetic volunteers. PMID- 26494244 TI - Gestational dietary betaine supplementation suppresses hepatic expression of lipogenic genes in neonatal piglets through epigenetic and glucocorticoid receptor-dependent mechanisms. AB - Methyl donors play critical roles in nutritional programming through epigenetic regulation of gene expression. Here we fed gestational sows with control or betaine-supplemented diets (3g/kg) throughout the pregnancy to explore the effects of maternal methyl-donor nutrient on neonatal expression of hepatic lipogenic genes. Betaine-exposed piglets demonstrated significantly lower liver triglyceride content associated with down-regulated hepatic expression of lipogenic genes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl CoA desaturase (SCD) and sterol regulatory element-binding protein-1c. Moreover, s-adenosyl methionine to s-adenosyl homocysteine ratio was elevated in the liver of betaine-exposed piglets, which was accompanied by DNA hypermethylation on FAS and SCD gene promoters and more enriched repression histone mark H3K27me3 on SCD gene promoter. Furthermore, glucocorticoid receptor (GR) binding to SCD gene promoter was diminished along with reduced serum cortisol and liver GR protein content in betaine-exposed piglets. GR-mediated SCD gene regulation was confirmed in HepG2 cells in vitro. Dexamethasone (Dex) drastically increased the luciferase activity of porcine SCD promoter, while the deletion of GR response element on SCD promoter significantly attenuated Dex-mediated SCD transactivation. In addition, miR-let-7e, miR-1285 and miR-124a, which respectively target porcine SCD, ACC and GR, were significantly up-regulated in the liver of betaine-exposed piglets, being in accordance with decreased protein content of these three genes. Taken together, our results suggest that maternal dietary betaine supplementation during gestation attenuates hepatic lipogenesis in neonatal piglets via epigenetic and GR-mediated mechanisms. PMID- 26494242 TI - Immunotherapeutic Approaches Targeting Amyloid-beta, alpha-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. AB - Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-beta, alpha-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-beta in Alzheimer's disease, alpha-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia. PMID- 26494245 TI - Ventilator-derived carbon dioxide production to assess energy expenditure in critically ill patients: proof of concept. AB - INTRODUCTION: Measurement of energy expenditure (EE) is recommended to guide nutrition in critically ill patients. Availability of a gold standard indirect calorimetry is limited, and continuous measurement is unfeasible. Equations used to predict EE are inaccurate. The purpose of this study was to provide proof of concept that EE can be accurately assessed on the basis of ventilator-derived carbon dioxide production (VCO2) and to determine whether this method is more accurate than frequently used predictive equations. METHODS: In 84 mechanically ventilated critically ill patients, we performed 24-h indirect calorimetry to obtain a gold standard EE. Simultaneously, we collected 24-h ventilator-derived VCO2, extracted the respiratory quotient of the administered nutrition, and calculated EE with a rewritten Weir formula. Bias, precision, and accuracy and inaccuracy rates were determined and compared with four predictive equations: the Harris-Benedict, Faisy, and Penn State University equations and the European Society for Clinical Nutrition and Metabolism (ESPEN) guideline equation of 25 kcal/kg/day. RESULTS: Mean 24-h indirect calorimetry EE was 1823 +/- 408 kcal. EE from ventilator-derived VCO2 was accurate (bias +141 +/- 153 kcal/24 h; 7.7 % of gold standard) and more precise than the predictive equations (limits of agreement -166 to +447 kcal/24 h). The 10 % and 15 % accuracy rates were 61 % and 76 %, respectively, which were significantly higher than those of the Harris Benedict, Faisy, and ESPEN guideline equations. Large errors of more than 30 % inaccuracy did not occur with EE derived from ventilator-derived VCO2. This 30 % inaccuracy rate was significantly lower than that of the predictive equations. CONCLUSIONS: In critically ill mechanically ventilated patients, assessment of EE based on ventilator-derived VCO2 is accurate and more precise than frequently used predictive equations. It allows for continuous monitoring and is the best alternative to indirect calorimetry. PMID- 26494246 TI - [Metabolic therapy with iodine 131 in patients with chronic renal failure. Clinical case]. AB - CASE REPORT: 62 year-old male with CKD stage 5 in dialysis program since 2012 who underwent surgery for papillary thyroid carcinoma with lymph node metastasis. Subsequently, the patient was admitted to the Unit of Metabolic Therapy at his reference hospital, where he is administered 80 millicuries of iodine-131 as a treatment associated with the surgery, unable to have his conventional dialysis, nursing interventions required in various stages of implementation of the continuous extrarenal clearance techniques (TCDE) were performed. CARE PLAN: The following care values were addressed targeted to patients undergoing treatment with I(131): specific equipment, personal protective measures and major diagnoses and nursing interventions. PROGRESS: TCDE, despite being attributed to very critical patients, they can be extrapolated to other patients in a given time. TCDE allowed these patients to undergo dialysis in a safe environment for staff, ensuring proper disposal of contaminated liquids. CONCLUSIONS: TCDE were an effective treatment for the removal of I131, a single ssesion being necessary to normalize the levels of radioactivity. Coordination between services allewed ensure proper and effective treatment for the patient. PMID- 26494247 TI - Effect of rhamnolipid biosurfactant on solubilization of polycyclic aromatic hydrocarbons. AB - Rhamnolipid biosurfactant-producing bacteria, Bacillus Lz-2, was isolated from oil polluted water collected from Dongying Shengli oilfield, China. The factors that influence PAH solubilization such as biosurfactant concentration, pH, ionic strength and temperature were discussed. The results showed that the solubilities of naphthalene, phenanthrene and pyrene increased linearly with the rise of rhamnolipid biosurfactant dose above the biosurfactant critical micelle concentration (CMC). Furthermore, the molar solubilization ratio (MSR) values decreased in the following order: naphthalene>phenanthrene>pyrene. However, the solubility percentage increased and followed the opposite order: pyrene>phenanthrene>naphthalene. The solubilities of PAHs in rhamnolipid biosurfactant solution increased with the rise of pH and ionic strength, and reached the maximum values under the conditions of pH11 and NaCl concentration 8 g . L(-1). The solubility of phenanthrene and pyrene increased with the rise of temperature. PMID- 26494248 TI - Variations in the abundance and structural diversity of microbes forming biofilms in a thermally stressed coral reef system. AB - Little information is known about biofilm formation in the thermally stressed coral reef systems north of the Arabian Gulf. The current study investigates the abundance and diversity of marine microbes involved in biofilm formation and their succession over a period of 14 weeks (May-August 2007) at temperatures exceeding 32 degrees C. The results showed variations in microbial numbers and the development of more stable biofilm communities as the biofilms aged. The culture-dependent technique and microscopic examination of the developed biofilms showed the dominance of key species known for their role in precipitating CaCO3 such as Vibrio and in facilitating coral larvae settlement and metamorphosis such as Pseudoalteromonas, Bacillariophyceae and Rhodophyceae. The results revealed biofilm formations with microbial diversities that have the potential to support the larval settlement and metamorphism of marine organisms and to consolidate and stabilize biofilms via the process of calcification in the thermally stressed coral reef system considered herein. PMID- 26494249 TI - Biotransformation of petroleum hydrocarbons and microbial communities in seawater with oil dispersions and copepod feces. AB - To determine biotransformation of components in crude oil dispersions in the presence of feces from marine copepods, dispersed oil was incubated alone, with the addition of clean or oil-containing feces. We hypothesized that the feces would contribute with nutrients to bacteria, and higher concentrations of oil degrading bacteria, respectively. Presence of clean feces resulted in higher degradation of aromatic oil compounds, but lower degradation of n-alkanes. Presence of oil-containing feces resulted in higher degradation of n-alkanes. The effect of clean feces on aromatic compounds are suggested to be due to higher concentrations of nutrients in the seawater where aromatic degradation takes place, while the lower degradation of n-alkanes are suggested to be due to a preference by bacteria for feces over these compounds. Large aggregates were observed in oil dispersions with clean feces, which may cause sedimentation of un weathered lipophilic oil compounds towards the seafloor if formed during oil spills. PMID- 26494250 TI - Antibiotic resistance monitoring in Vibrio spp. isolated from rearing environment and intestines of abalone Haliotis diversicolor. AB - 546 Vibrio isolates from rearing seawater (292 strains) and intestines of abalone (254 strains) were tested to ten antibiotics using Kirby-Bauer diffusion method. Resistant rates of abalone-derived Vibrio isolates to chloramphenicol (C), enrofloxacin (ENX) and norfloxacin (NOR) were <28%, whereas those from seawater showed large fluctuations in resistance to each of the tested antibiotics. Many strains showed higher resistant rates (>40%) to kanamycin (KNA), furazolidone (F), tetracycline (TE), gentamicin (GM) and rifampin (RA). 332 isolates from seawater (n=258) and abalone (n=74) were resistant to more than three antibiotics. Peaked resistant rates of seawater-derived isolates to multiple antibiotics were overlapped in May and August. Statistical analysis showed that pH had an important effect on resistant rates of abalone-derived Vibrio isolates to RA, NOR, and ENX. Salinity and dissolved oxygen were negatively correlated with resistant rates of seawater-derived Vibrio isolates to KNA, RA, and PG. PMID- 26494251 TI - Detection of the HA-33 protein in botulinum neurotoxin type G complex by mass spectrometry. AB - BACKGROUND: The disease botulism is caused by intoxication with botulinum neurotoxins (BoNTs), extremely toxic proteins which cause paralysis. This neurotoxin is produced by some members of the Clostridium botulinum and closely related species, and is produced as a protein complex consisting of the neurotoxin and neurotoxin-associated proteins (NAPs). There are seven known serotypes of BoNT, A-G, and the composition of the NAPs can differ between these serotypes. It was previously published that the BoNT/G complex consisted of BoNT/G, nontoxic-nonhemagglutinin (NTNH), Hemagglutinin 70 (HA-70), and HA-17, but that HA-33, a component of the protein complex of other serotypes of BoNT, was not found. METHODS: Components of the BoNT/G complex were first separated by SDS-PAGE, and bands corresponding to components of the complex were digested and analyzed by LC-MS/MS. RESULTS: Gel bands were identified with sequence coverages of 91% for BoNT/G, 91% for NTNH, 89% for HA-70, and 88% for HA-17. Notably, one gel band was also clearly identified as HA-33 with 93% sequence coverage. CONCLUSIONS: The BoNT/G complex consists of BoNT/G, NTNH, HA-70, HA-17, and HA 33. These proteins form the progenitor form of BoNT/G, similar to all other HA positive progenitor toxin complexes. PMID- 26494252 TI - Erk-Creb pathway suppresses glutathione-S-transferase pi expression under basal and oxidative stress conditions in zebrafish embryos. AB - Transcriptional activation of phase II enzymes including glutathione-S transferase pi class (Gst Pi) is important for redox regulation and defense from xenobiotics. The role of extracellular signal-regulated kinase (Erk) and protein kinase B (Akt) in regulation of Gst Pi expression has been described using adult mammalian cells. Whether these signaling pathways contribute to Gst Pi expression during embryogenesis is unknown. Using zebrafish embryo model, we provide novel evidence that Erk signaling acts as a specific suppressor of gstp1-2 mRNA during early embryogenesis. Addition of Erk inhibitor U0126 enhanced gstp1-2 mRNA expression during transition from blastula to the segmentation stage and from pharyngula until the hatching stage. Basal Erk activity did not affect gstp1-2 expression in tert-butylhydroquinone-exposed embryos. Addition of phorbol 12 myristate 13-acetate increased Erk activity leading to suppression of gstp1-2 mRNA. Activation of cAMP/Creb pathway by forskolin prevented gstp1-2 expression, whereas U0126 suppressed Creb phosphorylation, thus setting up Creb as a proximal transmitter of Erk inhibitory effect. Collectively, these findings suggest that Erk-Creb pathway exerts suppressive effect on gstp1-2 mRNA in a narrow developmental window. This study also provides a novel link between Erk and gstp1 2 expression, setting apart a possible differential regulation of gstp1-2 in adult and embryonic cells. PMID- 26494253 TI - A novel fluorogenic probe for the investigation of free thiols: Application to kinetic measurements of acetylcholinesterase activity. AB - A novel coumarin-derived thiol probe, based on the thiol-promoted cleavage of a quenching 2,4-dinitrobenzenesulfonyl group is described. The probe shows a sensitive fluorescence turn-on and sufficient solubility in aqueous environments. As a proof of concept, a new assay for AChE activity was developed as a useful addition to the established Ellman method. The observed reaction kinetics followed an asymmetric sigmoidal pattern and were successfully evaluated applying a three parameter Gompertz equation. Providing a linear relationship between the detected fluorescence formation curves and corresponding enzyme activities, this probe appears as a valuable tool for AChE activity measurements. PMID- 26494254 TI - Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. AB - Mitochondria are dynamic organelles that continually move, fuse and divide. The dynamic balance of fusion and fission of mitochondria determines their morphology and allows their immediate adaptation to energetic needs, keeps mitochondria in good health by restoring or removing damaged organelles or precipitates cells in apoptosis in cases of severe defects. Mitochondrial fusion and fission are essential in mammals and their disturbances are associated with several diseases. However, while mitochondrial fusion/fission dynamics, and the proteins that control these processes, are ubiquitous, associated diseases are primarily neurological disorders. Accordingly, inactivation of the main actors of mitochondrial fusion/fission dynamics is associated with defects in neuronal development, plasticity and functioning, both ex vivo and in vivo. Here, we present the central actors of mitochondrial fusion and fission and review the role of mitochondrial dynamics in neuronal physiology and pathophysiology. Particular emphasis is placed on the three main actors of these processes i.e. DRP1,MFN1-2, and OPA1 as well as on GDAP1, a protein of the mitochondrial outer membrane preferentially expressed in neurons. This article is part of a Special Issue entitled: Mitochondria & Brain. PMID- 26494255 TI - Production of Ginsenoside F2 by Using Lactococcus lactis with Enhanced Expression of beta-Glucosidase Gene from Paenibacillus mucilaginosus. AB - This study aimed to produce a pharmacologically active minor ginsenoside F2 from the major ginsenosides Rb1 and Rd by using a recombinant Lactococcus lactis strain expressing a heterologous beta-glucosidase gene. The nucleotide sequence of the gene (BglPm) was derived from Paenibacillus mucilaginosus and synthesized after codon optimization, and the two genes (unoptimized and optimized) were expressed in L. lactis NZ9000. Codon optimization resulted in reduction of unfavorable codons by 50% and a considerable increase in the expression levels (total activities) of beta-glucosidases (0.002 unit/mL, unoptimized; 0.022 unit/mL, optimized). The molecular weight of the enzyme was 52 kDa, and the purified forms of the enzymes could successfully convert Rb1 and Rd into F2. The permeabilized L. lactis expressing BglPm resulted in a high conversion yield (74%) of F2 from the ginseng extract. Utilization of this microbial cell to produce F2 may provide an alternative method to increase the health benefits of Panax ginseng. PMID- 26494256 TI - Effectiveness of a Mobile Phone App for Adults That Uses Physical Activity as a Tool to Manage Cigarette Craving After Smoking Cessation: A Study Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Results from studies on the effects of exercise on smoking-related variables have provided strong evidence that physical activity acutely reduces cigarette cravings. Mobile technology may provide some valuable tools to move from explanatory randomized controlled trials to pragmatic randomized controlled trials by testing the acute effectiveness of exercise on quitters under real-life conditions. An mHealth app was developed to be used as a support tool for quitters to manage their cigarette cravings. OBJECTIVE: The primary aim of this paper is to present the protocol of a study examining the effectiveness of the Physical over smoking app (Ph.o.S) by comparing the point prevalence abstinence rate of a group of users to a comparator group during a 6-month follow-up period. METHODS: After initial Web-based screening, eligible participants are recruited to attend a smoking cessation program for 3 weeks to set a quit smoking date. Fifty participants who succeed in quitting will be randomly allocated to the comparator and experimental groups. Both groups will separately have 1 more counseling session on how to manage cravings. In this fourth session, the only difference in treatment between the groups is that the experimental group will have an extra 10-15 minutes of guidance on how to use the fully automated Ph.o.S app to manage cravings during the follow-up period. Data will be collected at baseline, as well as before and after the quit day, and follow-up Web-based measures will be collected for a period of 6 months. The primary efficacy outcome is the 7-day point prevalence abstinence rate, and secondary efficacy outcomes are number of relapses and cravings, self-efficacy of being aware of craving experience, self-efficacy in managing cravings, and power of control in managing cravings. RESULTS: Recruitment for this project commenced in December 2014, and proceeded until May 2015. Follow-up data collection has commenced and will be completed by the end of December 2015. CONCLUSIONS: If the Ph.o.S app is shown to be effective, the study will provide evidence for the use of the app as a support tool for people who are trying to manage cravings during smoking cessation programs. It is anticipated that the results of the study will provide knowledge of how physical activity affects cigarette craving in real-life situations and inform the development and delivery of relapse prevention in smoking cessation treatment. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): ISRCTN55259451; http://www.controlled-trials.com/ISRCTN55259451 (Archived by WebCite at http://www.webcitation.org/6cKF2mzEI). PMID- 26494257 TI - BRAT1-related disease--identification of a patient without early lethality. AB - We present a patient with neonatal onset of hypertonia and seizures identified through whole exome sequencing to have compound heterozygous variants, c.294dupA (p.Leu99fs) and c.1925C>A (p.Ala642Glu), in the BRCA1-associated protein required for ATM activation-1 (BRAT1) gene. Variants in BRAT1 have been identified to cause lethal neonatal rigidity and multifocal seizure syndrome (OMIM# 614498), which consistently manifests a severe neurological phenotype that includes neonatal presentation of rigidity and hypertonia, microcephaly and arrested head growth, intractable seizures, absence of developmental progress, apneic episodes, and death usually by 6 months of age. Our patient initially had a similarly severe neurological picture but remains alive at 6 years of age, expanding the phenotype to include longer term survival and providing further insights into genotype-phenotype correlations and the natural history of this disease. PMID- 26494258 TI - Multivalent nanoparticles bind the retinal and choroidal vasculature. AB - The angiotensin II receptor type 1 (AT1R), which is expressed in blood vessels of the posterior eye, is of paramount significance in the pathogenesis of severe ocular diseases such as diabetic retinopathy and age-related macular degeneration. However, small molecule angiotensin receptor blockers (ARBs) have not proven to be a significant therapeutic success. We report here on a nanoparticle system consisting of ARB molecules presented in a multivalent fashion on the surface of quantum dots (Qdots). As a result of the multivalent receptor binding, nanoparticles targeted cells with high AT1R expression and inhibited their angiotensin receptor signaling with an IC50 of 3.8 nM while showing only minor association to cells with low AT1R expression. After intravenous injection into the tail vein of mice, multivalent nanoparticles accumulated in retinal and choroidal blood vessels of the posterior eye. At the same time, multivalent ligand display doubled the Qdot concentration in the blood vessels compared to non-targeted Qdots. Remarkably, ARB-targeted Qdots showed no pronounced accumulation in AT1R-expressing off-target tissues such as the kidney. Following systemic application, this multivalent targeting approach has the potential to amplify AT1R blockade in the eye and concomitantly deliver a therapeutic payload into ocular lesions. PMID- 26494259 TI - EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. AB - OBJECTIVES: To assess the ability of different technology platforms to detect epidermal growth factor receptor (EGFR) mutations, including T790M, from circulating tumor DNA (ctDNA) in advanced non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: A comparison of multiple platforms for detecting EGFR mutations in plasma ctDNA was undertaken. Plasma samples were collected from patients entering the ongoing AURA trial (NCT01802632), investigating the safety, tolerability, and efficacy of AZD9291 in patients with EGFR-sensitizing mutation positive NSCLC. Plasma was collected prior to AZD9291 dosing but following clinical progression on a previous EGFR-tyrosine kinase inhibitor (TKI). Extracted ctDNA was analyzed using two non-digital platforms (cobas((r)) EGFR Mutation Test and therascreenTM EGFR amplification refractory mutation system assay) and two digital platforms (Droplet DigitalTM PCR and BEAMing digital PCR [dPCR]). RESULTS: Preliminary assessment (38 samples) was conducted using all four platforms. For EGFR-TKI-sensitizing mutations, high sensitivity (78-100%) and specificity (93-100%) were observed using tissue as a non-reference standard. For the T790M mutation, the digital platforms outperformed the non-digital platforms. Subsequent assessment using 72 additional baseline plasma samples was conducted using the cobas((r)) EGFR Mutation Test and BEAMing dPCR. The two platforms demonstrated high sensitivity (82-87%) and specificity (97%) for EGFR sensitizing mutations. For the T790M mutation, the sensitivity and specificity were 73% and 67%, respectively, with the cobas((r)) EGFR Mutation Test, and 81% and 58%, respectively, with BEAMing dPCR. Concordance between the platforms was >90%, showing that multiple platforms are capable of sensitive and specific detection of EGFR-TKI-sensitizing mutations from NSCLC patient plasma. CONCLUSION: The cobas((r)) EGFR Mutation Test and BEAMing dPCR demonstrate a high sensitivity for T790M mutation detection. Genomic heterogeneity of T790M-mediated resistance may explain the reduced specificity observed with plasma-based detection of T790M mutations versus tissue. These data support the use of both platforms in the AZD9291 clinical development program. PMID- 26494260 TI - Muscarinic acetylcholine receptor binding affinities of pethidine analogs. AB - A series of pethidine analogs were synthesized and their affinities for the [(3)H]N-methyl-scopolamine (NMS) binding site on muscarinic acetylcholine receptors (mAChRs) were determined using M1, M3 or M5 human mAChRs expressed by Chinese hamster ovary (CHO) cell membranes. Compound 6b showed the highest binding affinities at M1, M3 and M5 mAChRs (Ki=0.67, 0.37, and 0.38 MUM, respectively). PMID- 26494261 TI - Esters of some non-steroidal anti-inflammatory drugs with cinnamyl alcohol are potent lipoxygenase inhibitors with enhanced anti-inflammatory activity. AB - Novel esters of non steroidal anti-inflammatory drugs, alpha-lipoic acid and indol-3-acetic acid with cinnamyl alcohol were synthesised by a straightforward method and at high yields (60-98%). They reduced acute inflammation more than the parent acids and are potent inhibitors of soybean lipoxygenase. Selected structures decreased plasma lipidemic indices in Triton-induced hyperlipidemia to rats. Therefore, the synthesised compounds may add to the current knowledge about agents acting against various inflammatory disorders. PMID- 26494262 TI - Individual oral symptoms in burning mouth syndrome may be associated differentially with depression and anxiety. AB - BACKGROUND: Burning mouth syndrome (BMS) is an idiopathic disease characterized by the feeling of burning in the oral cavity. Ten per cent of patients presenting to oral medicine clinics have BMS. Anxiety and depression are common co morbidities in BMS, but it is not known if they are associated with specific BMS symptoms. OBJECTIVE: In an exploratory analysis, this study examined the association of generalized anxiety and depression with individual BMS symptoms. METHODS: Forty-one patients were recruited from a dental outpatient clinic (30 with BMS and 11 with other oral conditions), evaluating specific BMS symptoms and their intensity. Anxiety and depression symptoms were assessed using a standardized measure (Clinical Interview Schedule-Revised). RESULTS: Taste change (p = 0.007), fear of serious illness (p = 0.011), metallic taste (p = 0.018) and sensation of a film on the gums (p = 0.047) were associated with an excess of psychiatric symptoms. More specifically, metallic taste (coefficient = 0.497, 95% CI = 0.149-0.845; p = 0.006) and sensation of film on gums (coefficient = 0.625, 95% CI = 0.148-1.103; p = 0.012) were associated significantly with higher scores for depressive symptoms; taste change (coefficient = 0.269, 95% CI = 0.077-0.461; p = 0.007), bad breath (coefficient = 0.273, 95% CI = 0.065-0.482; p = 0.012) and fear of serious illness (coefficient = 0.242, 95% CI = 0.036-0.448; p = 0.023) were associated with higher anxiety scores. CONCLUSION: Specific BMS symptoms are associated differentially with generalized anxiety and depression. Dental practitioners should ascertain which BMS symptoms are predominant and be mindful of the association of certain symptoms with anxiety or depression and, where necessary, consider medical consultation. PMID- 26494263 TI - Relationship between some indicators of reproductive history, body fatness and the menopausal transition in Hungarian women. AB - BACKGROUND: This paper analyzed the relationship between some indicators of reproductive history and body fatness in relation to the timing of the menopause transition in Hungarian women using survival analysis after controlling for birth cohort. METHODS: Data on menstruation and reproductive history were collected during the personal interviews in a sample of 1932 women (aged 35+ years). Menarcheal age, the length of menstrual cycles and menstrual bleedings, regularity of menstrual cycles, number of gestations, lactation, the ever use of contraceptives, menopausal status and age at menopause were used as indicators of reproductive history. The body fat fraction was estimated by bioelectrical impedance analysis. Body fatness was also estimated by dividing women into obese and non-obese categories (considering body mass index and waist-to-hip ratio). Survival analyses were used to analyze the relationship between the indicators of reproductive history and body fatness during the menopausal transition. RESULTS: Only the menarcheal age among the investigated reproductive life characteristics showed secular changes in the studied decades in Hungary; the mean age at menarche decreased by approximately 2.5 months per decade from the 1920s until the 1970s. Ever use of hormonal contraceptives, a relatively long cycle length in the perimenopausal transition and higher parity were all related with lower risk of early menopause. Later menarcheal age, normal length of menstrual cycle or bleeding in the climacterium, irregular bleeding pattern and postmenopausal status were associated with a higher amount of body fatness, while never use of contraceptives, regular menstruation, postmenopausal status and relatively early menopause were associated with a higher risk of abdominal obesity. CONCLUSION: This report confirms that age of menarche is not significantly predictive of age at menopause but prior use of oral contraceptives, longer mean cycle length and smaller number of gestations all are. In addition, age of menarche, irregular bleeding pattern before the climacterium, length of menstrual cycles and bleedings during the climacterium and postmenopausal status were associated with obesity during the climacterium. PMID- 26494264 TI - Photolithographic Synthesis of High-Density DNA and RNA Arrays on Flexible, Transparent, and Easily Subdivided Plastic Substrates. AB - The photolithographic fabrication of high-density DNA and RNA arrays on flexible and transparent plastic substrates is reported. The substrates are thin sheets of poly(ethylene terephthalate) (PET) coated with cross-linked polymer multilayers that present hydroxyl groups suitable for conventional phosphoramidite-based nucleic acid synthesis. We demonstrate that by modifying array synthesis procedures to accommodate the physical and chemical properties of these materials, it is possible to synthesize plastic-backed oligonucleotide arrays with feature sizes as small as 14 MUm * 14 MUm and feature densities in excess of 125 000/cm(2), similar to specifications attainable using rigid substrates such as glass or glassy carbon. These plastic-backed arrays are tolerant to a wide range of hybridization temperatures, and improved synthetic procedures are described that enable the fabrication of arrays with sequences up to 50 nucleotides in length. These arrays hybridize with S/N ratios comparable to those fabricated on otherwise identical arrays prepared on glass or glassy carbon. This platform supports the enzymatic synthesis of RNA arrays and proof-of-concept experiments are presented showing that the arrays can be readily subdivided into smaller arrays (or "millichips") using common laboratory-scale laser cutting tools. These results expand the utility of oligonucleotide arrays fabricated on plastic substrates and open the door to new applications for these important bioanalytical tools. PMID- 26494265 TI - Choice of comparator in restorative trials: A network analysis. AB - OBJECTIVES: The choice of trial comparators might impact on the validity of the available evidence. We aimed at evaluating dental restorative trial networks and the underlying comparisons made, hypothesizing that certain comparators are disproportionally preferred or avoided. METHODS: A systematic review was performed via Medline, CENTRAL and EMBASE. Randomized controlled trials on dental restoration or adhesive materials published 2005-2015 were included. Social network analysis techniques were used to assess trial networks. RESULTS: 114 studies on 15321 restorations placed in 5232 patients were included. 57 and 53 trials investigated restoration of cervical and load-bearing cavities, respectively. Four trials on non-cervical, non-load-bearing cavities did not form a network and were not evaluated. The most frequently assessed material combination was hybrid composites placed using 2-step etch-and-rinse adhesives. In cervical cavities, the majority of trials compared adhesives, not restorative materials. In load-bearing cavities, testing other restorative materials (ormocers, compomers) was common, too. In both networks, comparisons within material classes were frequent. There was significant homophily (p<0.001), i.e. certain material classes were preferred as comparators, while this preference seemed to change with time. Only very few comparisons yielded significant differences between materials. SIGNIFICANCE: The disproportional use of certain material classes as comparator might be due to their perceived role as gold standard. Compared with other scientific disciplines, dental restorative trial networks seem less prone for bias by comparator choice. Factors underlying the network geometry should be assessed to understand drivers of the research agenda. PMID- 26494266 TI - Impact of gastric acidic challenge on surface topography and optical properties of monolithic zirconia. AB - OBJECTIVE: To evaluate the surface topography and optical properties of monolithic zirconia after immersion in simulated gastric acid. MATERIALS AND METHODS: Four partially stabilized (PSZ) and one fully stabilized (FSZ) zirconia materials were selected for the study: Prettau (PRT, Zirkonzahn), Zenostar (ZEN, Ivoclar), Bruxzir (BRX, Glidewell), Katana (KAT, Noritake) and FSZ Prettau Anterior (PRTA, Zirkonzahn). IPS e.max (Ivoclar) was used as a control. The specimens (10*10*1.2mm, n=5 per material) were cut, sintered, polished and cleaned before immersed in 5ml of simulated gastric acid solution (Hydrochloric acid (HCl) 0.06M, 0.113% solution in deionized distal water, pH 1.2) for 96h in a 37 degrees C incubator. Specimens were weighed and examined for morphological changes under scanning electron microscope (SEM) coupled with energy dispersive X ray spectroscopy (EDX). Surface roughness was evaluated by a confocal microscope. Surface gloss and translucency parameter (TP) values were determined by a reflection spectrophotometer before and after acid immersion. The data was analyzed by one-way ANOVA followed by Tukey's HSD post hoc test (p<0.05). RESULTS: PRTA displayed the most weight loss (1.40%) among the zirconia specimens. IPS e.max showed about three times more weight loss (3.05%) than zirconia specimens as an average. SEM examination indicated areas of degradation, bead-like shapes and smoothening of the polishing scratches after acid immersion. EDX displayed ion interactions and possible ion leaching from all specimens. Sa and Sq values for PRTA, ZEN and IPS e.max were significantly lower (p<0.05) after acid immersion. TP values increased significantly for PRT, ZEN and IPS e.max (p<0.05), while the surface gloss of ZEN, PRTA and IPS e.max increased (p<0.05). SIGNIFICANCE: Monolithic zirconia materials show some surface alterations in an acidic environment with minimum effect on their optical properties. Whether a smoother surface is in fact a sign of true corrosion resistance or is purely the result of an evenly progressive corrosive process is yet to be confirmed by further research. PMID- 26494268 TI - 3D printing with polymers: Challenges among expanding options and opportunities. AB - OBJECTIVES: Additive manufacturing, which is more colloquially referred to as 3D printing, is quickly approaching mainstream adoption as a highly flexible processing technique that can be applied to plastic, metal, ceramic, concrete and other building materials. However, taking advantage of the tremendous versatility associated with in situ photopolymerization as well as the ability to select from a variety of preformed processible polymers, 3D printing predominantly targets the production of polymeric parts and models. The goal of this review is to connect the various additive manufacturing techniques with the monomeric and polymeric materials they use while highlighting emerging material-based developments. METHODS: Modern additive manufacturing technology was introduced approximately three decades ago but this review compiles recent peer-reviewed literature reports to demonstrate the evolution underway with respect to the various building techniques that differ significantly in approach as well as the new variations in polymer-based materials being employed. RESULTS: Recent growth of 3D printing has been dramatic and the ability of the various platform technologies to expand from rapid production prototypic models to the greater volume of readily customizable production of working parts is critical for continued high growth rates. This transition to working part production is highly dependent on adapting materials that deliver not only the requisite design accuracy but also the physical and mechanical properties necessary for the application. SIGNIFICANCE: With the weighty distinction of being called the next industrial revolution, 3D printing technologies is already altering many industrial and academic operations including changing models for future healthcare delivery in medicine and dentistry. PMID- 26494269 TI - Cost of inaction on sugar-sweetened beverage consumption: implications for obesity in South Africa. AB - OBJECTIVE: To estimate the effect of increased sugar-sweetened beverage (SSB) consumption on future adult obesity prevalence in South Africa in the absence of preventive measures. DESIGN: A model was constructed to simulate the effect of a 2.4 % annual increase in SSB consumption on obesity prevalence. The model computed the change in energy intake assuming a compounding increase in SSB consumption. The population distribution of BMI by age and sex was modelled by fitting measured data from the 2012 South African National Income Dynamics Survey to the log-normal distribution and shifting the mean values. SETTING: Over the past decade the prevalence of obesity and related non-communicable diseases has increased in South Africa, as have the sales and availability of SSB. Soft drink sales in South Africa are projected to grow between 2012 and 2017 at an annual compounded growth rate of 2.4 % in the absence of preventive measures to curb consumption. RESULTS: A 2.4 % annual growth in SSB sales alongside population growth and ageing will result in an additional 1 287 000 obese adults in South Africa by 2017, 22 % of which will be due to increased SSB consumption. CONCLUSIONS: In order to meet the South African target of reducing the number of people who are obese and/or overweight by 10 % by 2020, the country cannot afford to delay implementing effective population-wide interventions. In the face of plans to increase growth of SSB, the country will soon face even greater challenges in overcoming obesity and related non-communicable diseases. PMID- 26494267 TI - Cytotoxicity and osteogenic potential of silicate calcium cements as potential protective materials for pulpal revascularization. AB - OBJECTIVES: In pulpal revascularization, a protective material is placed coronal to the blood clot to prevent recontamination and to facilitate osteogenic differentiation of mesenchymal stem cells to produce new dental tissues. Although mineral trioxide aggregate (MTA) has been the material of choice for clot protection, it is easily displaced into the clot during condensation. The present study evaluated the effects of recently introduced calcium silicate cements (Biodentine and TheraCal LC) on the viability and osteogenic differentiation of human dental pulp stem cells (hDPSCs) by comparing with MTA Angelus. METHODS: Cell viability was assessed using XTT assay and flow cytometry. The osteogenic potential of hDPSCs exposed to calcium silicate cements was examined using qRT PCR for osteogenic gene expressions, alkaline phosphatase enzyme activity, Alizarin red S staining and transmission electron microscopy of extracellular calcium deposits. Parametric statistical methods were employed for analyses of significant difference among groups, with alpha=0.05. RESULTS: The cytotoxic effects of Biodentine and TheraCal LC on hDPSCs were time- and concentration dependent. Osteogenic differentiation of hDPSCs was enhanced after exposure to Biodentine that was depleted of its cytotoxic components. This effect was less readily observed in hDPSCs exposed to TheraCal LC, although both cements supported extracellular mineralization better than the positive control (zinc oxide-eugenol-based cement). SIGNIFICANCE: A favorable tissue response is anticipated to occur with the use of Biodentine as a blood clot-protecting material for pulpal revascularization. Further investigations with the use of in vivo animal models are required to validate the potential adverse biological effects of TheraCal LC on hDPSCs. PMID- 26494270 TI - Current therapeutic strategies of heterotopic ossification--a survey amongst orthopaedic and trauma departments in Germany. AB - BACKGROUND: Heterotopic ossification (HO) is a complication after tissue trauma, fracture and surgery (i.e. total hip arthroplasty). Prophylaxis is the most effective therapy. If HO formations become symptomatic and limit patients' quality of life, revision surgery is indicated and is usually combined with a perioperative oral prophylaxis (NSAIDs) and/or irradiation. However, a long-term use of NSAIDs can induce gastro-intestinal or cardiac side-effects and possible bony non-unions during fracture healing. Subject of this study was to assess the current status of HO prophylaxis after injuries or fractures and to evaluate current indications and strategies for excision of symptomatic HO. METHODS: Between 2013 and 2014, a questionnaire was sent to 119 orthopaedic and trauma surgery departments in Germany. Participation was voluntary and all acquired data was given anonymously. RESULTS: The cumulative feedback rate was 71 %. Trauma and orthopaedic surgery departments in Germany recommend oral HO prophylaxis after acetabulum and femoral neck fractures, elbow dislocation, and fracture or dislocation of the radial head. Pain upon movement and an increasing loss of range of motion in the affected joint are considered to be clear indications for HO surgery. A partial removal of ROM-limiting HO formations was also considered important. The vast majority of all departments include perioperative oral HO prophylaxis and/or irradiation if surgical HO removal is planned. The choice and duration of NSAIDs is highly variable. CONCLUSION: HO is of clinical significance in current traumatology and orthopaedics. Certain fractures and injuries are prone to HO, and prophylactic measures should be taken. The respondents in this survey assessed current therapeutic strategies for HO formations similarly. These concepts are in line with the literature. However, the duration of perioperative oral HO prophylaxis varied greatly among the specialist centres. This is significant as a long-term use of NSAIDs fosters a potential risk for the patients' safety and could influence the clinical outcome. National and international guidelines need to be developed to further reduce HO rates and improve patients' safety in trauma and orthopaedic surgery. PMID- 26494271 TI - Re-evaluation of the Blood-Brain Barrier in the Presence of Alzheimer's Disease Pathology. AB - Blood-brain barrier disruption is believed to occur in Alzheimer's disease, which could influence the bioavailability of drugs within the brain. However, in this issue of Neuron, Bien-Ly et al. (2015) report no evidence of widespread blood brain barrier dysfunction. PMID- 26494272 TI - A Direct Path to Action Initiation. AB - In this issue of Neuron, Sippy et al. (2015) provide the clearest evidence to date that information is differentially encoded in the direct and indirect pathways of the striatum. The results support the classical notion that the direct pathway plays a critical role in initiating actions. PMID- 26494273 TI - Default Distance Coding Properties in the Hippocampus. AB - Whereas hippocampal activity is thought to be driven by precise conjunctions of sensory input, a recent study by Villette and Malvache et al. (Villette et al., 2015, in this issue of Neuron) reveals that neurons imaged in a static sensory environment organize into sequences endowed with intrinsic spatiotemporal properties. PMID- 26494274 TI - Processing Timescales as an Organizing Principle for Primate Cortex. AB - An emerging view posits a timescale-based cortical topography, with integration windows increasing from sensory to association areas. In this issue, Chaudhuri et al. (2015) present a cortical model wherein a hierarchy of timescales arises from local and inter-regional circuit dynamics. PMID- 26494276 TI - Disinhibition, a Circuit Mechanism for Associative Learning and Memory. AB - Although a wealth of data have elucidated the structure and physiology of neuronal circuits, we still only have a very limited understanding of how behavioral learning is implemented at the network level. An emerging crucial player in this implementation is disinhibition--a transient break in the balance of excitation and inhibition. In contrast to the widely held view that the excitation/inhibition balance is highly stereotyped in cortical circuits, recent findings from behaving animals demonstrate that salient events often elicit disinhibition of projection neurons that favors excitation and thereby enhances their activity. Behavioral functions ranging from auditory fear learning, for which most data are available to date, to spatial navigation are causally linked to disinhibition in different compartments of projection neurons, in diverse cortical areas and at timescales ranging from milliseconds to days, suggesting that disinhibition is a conserved circuit mechanism contributing to learning and memory expression. PMID- 26494275 TI - Dopamine Prediction Errors in Reward Learning and Addiction: From Theory to Neural Circuitry. AB - Midbrain dopamine (DA) neurons are proposed to signal reward prediction error (RPE), a fundamental parameter in associative learning models. This RPE hypothesis provides a compelling theoretical framework for understanding DA function in reward learning and addiction. New studies support a causal role for DA-mediated RPE activity in promoting learning about natural reward; however, this question has not been explicitly tested in the context of drug addiction. In this review, we integrate theoretical models with experimental findings on the activity of DA systems, and on the causal role of specific neuronal projections and cell types, to provide a circuit-based framework for probing DA-RPE function in addiction. By examining error-encoding DA neurons in the neural network in which they are embedded, hypotheses regarding circuit-level adaptations that possibly contribute to pathological error signaling and addiction can be formulated and tested. PMID- 26494277 TI - Time-Resolved Imaging Reveals Heterogeneous Landscapes of Nanomolar Ca(2+) in Neurons and Astroglia. AB - Maintaining low intracellular calcium is essential to the functioning of brain cells, yet the phenomenology and mechanisms involved remain an enigma. We have advanced a two-photon excitation time-resolved imaging technique, which exploits high sensitivity of the OGB-1 fluorescence lifetime to nanomolar Ca(2+) concentration ([Ca(2+)]) and enables a high data acquisition rate in situ. The [Ca(2+)] readout is not affected by dye concentration, light scattering, photobleaching, micro-viscosity, temperature, or the main known concomitants of cellular activity. In quiescent tissue, standard whole-cell configuration has little effect on resting [Ca(2+)] inside neuronal dendrites or inside astroglia dye-filled via gap junctions. Mapping basal [Ca(2+)] in neurons and astrocytes with submicron resolution unveils heterogeneous concentration landscapes that depend on age and preceding activity. The rich information content represented by such landscapes in acute slices and in vivo promises to unveil the hitherto unexplored, potentially fundamental aspects of brain cell physiology. PMID- 26494278 TI - Lack of Widespread BBB Disruption in Alzheimer's Disease Models: Focus on Therapeutic Antibodies. AB - The blood-brain barrier (BBB) limits brain uptake of therapeutic antibodies. It is believed that the BBB is disrupted in Alzheimer's disease (AD), potentially increasing drug permeability de facto. Here we compared active versus passive brain uptake of systemically dosed antibodies (anti-transferrin receptor [TfR] bispecific versus control antibody) in mouse models of AD. We first confirmed BBB disruption in a mouse model of multiple sclerosis as a positive control. Importantly, we found that BBB permeability was vastly spared in mouse models of AD, including PS2-APP, Tau transgenics, and APOE4 knockin mice. Brain levels of TfR in mouse models or in human cases of AD resembled controls, suggesting target engagement of TfR bispecific is not limited. Furthermore, infarcts from human AD brain showed similar occurrences compared to age-matched controls. These results question the widely held view that the BBB is largely disrupted in AD, raising concern about assumptions of drug permeability in disease. PMID- 26494279 TI - Input- and Output-Specific Regulation of Serial Order Performance by Corticostriatal Circuits. AB - The serial ordering of individual movements into sequential patterns is thought to require synaptic plasticity within corticostriatal circuits that route information through the basal ganglia. We used genetically and anatomically targeted manipulations of specific circuit elements in mice to isolate the source and target of a corticostriatal synapse that regulates the performance of a serial order task. This excitatory synapse originates in secondary motor cortex, terminates on direct pathway medium spiny neurons in the dorsolateral striatum, and is strengthened by serial order learning. This experience-dependent and synapse-specific form of plasticity may sculpt the balance of activity in basal ganglia circuits during sequential movements, driving a disparity in striatal output that favors the direct pathway. This disparity is necessary for execution of responses in serial order, even though both direct and indirect pathways are active during movement initiation, suggesting dynamic modulation of corticostriatal circuitry contributes to the choreography of behavioral routines. PMID- 26494281 TI - A GPU-accelerated cortical neural network model for visually guided robot navigation. AB - Humans and other terrestrial animals use vision to traverse novel cluttered environments with apparent ease. On one hand, although much is known about the behavioral dynamics of steering in humans, it remains unclear how relevant perceptual variables might be represented in the brain. On the other hand, although a wealth of data exists about the neural circuitry that is concerned with the perception of self-motion variables such as the current direction of travel, little research has been devoted to investigating how this neural circuitry may relate to active steering control. Here we present a cortical neural network model for visually guided navigation that has been embodied on a physical robot exploring a real-world environment. The model includes a rate based motion energy model for area V1, and a spiking neural network model for cortical area MT. The model generates a cortical representation of optic flow, determines the position of objects based on motion discontinuities, and combines these signals with the representation of a goal location to produce motor commands that successfully steer the robot around obstacles toward the goal. The model produces robot trajectories that closely match human behavioral data. This study demonstrates how neural signals in a model of cortical area MT might provide sufficient motion information to steer a physical robot on human-like paths around obstacles in a real-world environment, and exemplifies the importance of embodiment, as behavior is deeply coupled not only with the underlying model of brain function, but also with the anatomical constraints of the physical body it controls. PMID- 26494280 TI - Internally Recurring Hippocampal Sequences as a Population Template of Spatiotemporal Information. AB - The hippocampus is essential for spatiotemporal cognition. Sequences of neuronal activation provide a substrate for this fundamental function. At the behavioral timescale, these sequences have been shown to occur either in the presence of successive external landmarks or through internal mechanisms within an episodic memory task. In both cases, activity is externally constrained by the organization of the task and by the size of the environment explored. Therefore, it remains unknown whether hippocampal activity can self-organize into a default mode in the absence of any external memory demand or spatiotemporal boundary. Here we show that, in the presence of self-motion cues, a population code integrating distance naturally emerges in the hippocampus in the form of recurring sequences. These internal dynamics clamp spontaneous travel since run distance distributes into integer multiples of the span of these sequences. These sequences may thus guide navigation when external landmarks are reduced. PMID- 26494282 TI - Designing bioinspired composite reinforcement architectures via 3D magnetic printing. AB - Discontinuous fibre composites represent a class of materials that are strong, lightweight and have remarkable fracture toughness. These advantages partially explain the abundance and variety of discontinuous fibre composites that have evolved in the natural world. Many natural structures out-perform the conventional synthetic counterparts due, in part, to the more elaborate reinforcement architectures that occur in natural composites. Here we present an additive manufacturing approach that combines real-time colloidal assembly with existing additive manufacturing technologies to create highly programmable discontinuous fibre composites. This technology, termed as '3D magnetic printing', has enabled us to recreate complex bioinspired reinforcement architectures that deliver enhanced material performance compared with monolithic structures. Further, we demonstrate that we can now design and evolve elaborate reinforcement architectures that are not found in nature, demonstrating a high level of possible customization in discontinuous fibre composites with arbitrary geometries. PMID- 26494283 TI - Preparation of reminiscent aroma mixture of Japanese soy sauce. AB - To prepare an aroma mixture of Japanese soy sauce by fewest components, the aroma concentrate of good sensory attributes was prepared by polyethylene membrane extraction, which could extract only the volatiles with diethyl ether. GC-MS Olfactometry was done with the aroma concentrate, and 28 odor-active compounds were detected. Application of aroma extract dilution analysis to the separated fraction revealed high flavor dilution factors with respect to acetic acid, 4 hydroxy-2(or5)-ethyl-5(or2)-methyl-3(2H)-furanone (HEMF), 3-methyl-1-butanol (isoamyl alcohol), and 3-(methylsulfanyl)propanal (methional). A model aroma mixture containing above four odorants showed a good similarity with the aroma of the soy sauce itself. Consequently, the reminiscent aroma mixture of soy sauce was prepared in water. The ratio of acetic acid, HEMF, isoamyl alcohol, and methional was 2500:300:100:1. PMID- 26494284 TI - The sRNA NsiR4 is involved in nitrogen assimilation control in cyanobacteria by targeting glutamine synthetase inactivating factor IF7. AB - Glutamine synthetase (GS), a key enzyme in biological nitrogen assimilation, is regulated in multiple ways in response to varying nitrogen sources and levels. Here we show a small regulatory RNA, NsiR4 (nitrogen stress-induced RNA 4), which plays an important role in the regulation of GS in cyanobacteria. NsiR4 expression in the unicellular Synechocystis sp. PCC 6803 and in the filamentous, nitrogen-fixing Anabaena sp. PCC 7120 is stimulated through nitrogen limitation via NtcA, the global transcriptional regulator of genes involved in nitrogen metabolism. NsiR4 is widely conserved throughout the cyanobacterial phylum, suggesting a conserved function. In silico target prediction, transcriptome profiling on pulse overexpression, and site-directed mutagenesis experiments using a heterologous reporter system showed that NsiR4 interacts with the 5'UTR of gifA mRNA, which encodes glutamine synthetase inactivating factor (IF)7. In Synechocystis, we observed an inverse relationship between the levels of NsiR4 and the accumulation of IF7 in vivo. This NsiR4-dependent modulation of gifA (IF7) mRNA accumulation influenced the glutamine pool and thus [Formula: see text] assimilation via GS. As a second target, we identified ssr1528, a hitherto uncharacterized nitrogen-regulated gene. Competition experiments between WT and an DeltansiR4 KO mutant showed that the lack of NsiR4 led to decreased acclimation capabilities of Synechocystis toward oscillating nitrogen levels. These results suggest a role for NsiR4 in the regulation of nitrogen metabolism in cyanobacteria, especially for the adaptation to rapid changes in available nitrogen sources and concentrations. NsiR4 is, to our knowledge, the first identified bacterial sRNA regulating the primary assimilation of a macronutrient. PMID- 26494285 TI - A dual control mechanism synchronizes riboflavin and sulphur metabolism in Bacillus subtilis. AB - Flavin mononucleotide (FMN) riboswitches are genetic elements, which in many bacteria control genes responsible for biosynthesis and/or transport of riboflavin (rib genes). Cytoplasmic riboflavin is rapidly and almost completely converted to FMN by flavokinases. When cytoplasmic levels of FMN are sufficient ("high levels"), FMN binding to FMN riboswitches leads to a reduction of rib gene expression. We report here that the protein RibR counteracts the FMN-induced "turn-off" activities of both FMN riboswitches in Bacillus subtilis, allowing rib gene expression even in the presence of high levels of FMN. The reason for this secondary metabolic control by RibR is to couple sulfur metabolism with riboflavin metabolism. PMID- 26494288 TI - Mesomeric Effects of Graphene Modified with Diazonium Salts: Substituent Type and Position Influence its Properties. AB - In the last decade, graphene and graphene derivatives have become some of the most intensively studied materials. Tuning of the electronic and electrochemical properties of graphene is of paramount importance. In this study, six diazonium modified graphenes containing different functional groups according to the diazonium salt precursor were investigated. These diazonium moieties have a strong mesomeric (resonance) effect and act as either electron-donating or withdrawing species. Different graphene precursors, such as thermally and chemically reduced graphenes were studied. All the products were characterized in detail by elemental combustion analysis, FTIR spectroscopy, Raman spectroscopy, high-resolution X-ray photoelectron spectroscopy (XPS), and cyclic voltammetry. Resistivity and zeta potential measurements were consistent with theoretical (DFT) calculations. The results show that chemical modification of graphene by diazotation strongly influences its properties, creating a huge application potential in microelectronics, energy storage and conversion devices, and electrocatalysis. PMID- 26494286 TI - Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture. AB - Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that alpha cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of beta cells by CB1 cannabinoid receptor (CB1R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and alpha/beta cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB1Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB1R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in omega-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB1R(-/-) islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis. PMID- 26494287 TI - Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome. AB - Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFbeta signaling. TGFbeta is secreted from cells as a latent complex consisting of TGFbeta, the TGFbeta propeptide, and a molecule of latent TGFbeta binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFbeta levels, and has been hypothesized as an explanation for enhanced TGFbeta signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFbeta signaling in MFS might be due to defective interaction of latent TGFbeta complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFbeta complexes composed of LTBP-3 and TGFbeta contributes to aortic disease progression. PMID- 26494289 TI - Oscillations of Skin Microvascular Blood Flow in Patients with Asthma. AB - OBJECTIVE: This research is aimed at studying the features of skin blood flow oscillations in patients with severe persistent atopic BA during a period of fine control over symptoms. METHODS: The study of microcirculation was carried out by LDF at rest and in response to a transient ischemia in 20 patients. The time amplitude adaptive wavelet analysis of the blood flow oscillations was conducted to elucidate the peculiarities of microcirculatory regulation system functioning. RESULTS: No significant changes were revealed for SBP and the oscillation amplitudes in the cardiac (0.6-2 Hz) and respiratory (0.145-0.6 Hz) intervals, both at rest and in response to transient ischemia, in patients compared to the control group. A consistent twofold decrease in the oscillation amplitudes was found in the neurogenic (0.021-0.052 Hz) interval at rest, as well as in the myogenic (0.052-0.145 Hz) and NO-dependent endothelial (0.0095-0.021 Hz) intervals both at rest and during the postocclusive reactive hyperemia in patients with lung obstruction (FEV1 < 80%) in comparison with a control group. CONCLUSIONS: The amplitudes of skin blood flow oscillations in the myogenic, neurogenic and NO-dependent endothelial intervals in patients with obstruction are different from those in patients without obstruction. PMID- 26494290 TI - Functional Recovery From Extended Warm Ischemia Associated With Partial Nephrectomy. AB - OBJECTIVE: To evaluate the impact of extended warm ischemia on incidence of acute kidney injury (AKI) and ultimate functional recovery after partial nephrectomy (PN), incorporating rigorous control for loss of parenchymal mass, and embedded within comparison to cohorts of patients managed with hypothermia or limited warm ischemia. MATERIALS AND METHODS: From 2007 to 2014, 277 patients managed with PN had appropriate studies to evaluate changes in function/mass specifically within the operated kidney. Recovery from ischemia was defined as %function saved/%parenchymal mass saved. AKI was based on global renal function and defined as a >=1.5-fold increase in serum creatinine above the preoperative level. RESULTS: Hypothermia was utilized in 112 patients (median = 27 minutes) and warm ischemia in 165 (median = 21 minutes). AKI strongly correlated with solitary kidney (P < .001) and duration (P < .001) but not type (P = .49) of ischemia. Median recovery from ischemia in the operated kidney was 100% (interquartile range [IQR] = 88%-109%) for cold ischemia, with 6 (5%) noted to have <80% recovery from ischemia. For the warm ischemia group, median recovery from ischemia was 91% (IQR = 82%-101%, P < .001 compared with hypothermia), and 34 (21%) had recovery from ischemia <80% (P < .001). For warm ischemia subgrouped by duration <25 minutes (n = 114), 25-35 minutes (n = 35), and >35 minutes (n = 16), median recovery from ischemia was 92% (IQR = 86%-100%), 90% (IQR = 78%-104%), and 91% (IQR = 80%-96%), respectively (P = .77). CONCLUSION: Our results suggest that AKI after PN correlates with duration but not with type of ischemia. However, subsequent recovery, which ultimately defines the new baseline glomerular filtration rate, is most reliable with hypothermia. However, most patients undergoing PN with warm ischemia still recover relatively strongly from ischemia, even if extended to 35-45 minutes. PMID- 26494291 TI - Comparison of Single-docking Robotic-assisted and Traditional Laparoscopy for Retroperitoneal Lymph Node Dissection During Nephroureterectomy With Bladder Cuff Excision for Upper-tract Urothelial Carcinoma. AB - OBJECTIVE: To compare the results of traditional laparoscopy and a simple, single docking robotic approach for retroperitoneal lymph node dissection (RPLND), nephroureterectomy, and bladder cuff excision. MATERIALS AND METHODS: We evaluated 63 and 37 consecutive patients who underwent laparoscopic and robotic nephrouretectomy with RPLND, respectively, for upper-tract urothelial carcinoma (UTUC). RESULTS: Our robotic approach was associated with improved lymph node procurement (21.0 nodes [interquartile range 16.0-30.0]) when compared with laparoscopy (11.0 nodes [interquartile range 5.5-21.0]) (P < .0001). Major blood loss as defined by requiring a blood transfusion was less for the robotic group than for the laparoscopic cohort (8% vs 30%) (P = .012). In contrast, the robotic group had longer operative times (5.1 vs 3.9 hours) (P = .0001) and longer hospital stays (5.0 vs 4.0 days) (P = .0002). CONCLUSION: Our single-docking robotic technique for concomitant RPLND during nephrouretectomy is associated with improved lymph node yield. PMID- 26494292 TI - An Analysis of Case Logs From American Urologists in the Treatment of Peyronie's Disease. AB - OBJECTIVE: To review recent trends in the treatment of Peyronie's disease (PD), we assess surgical practice patterns of urologists in the United States with emphasis on specialty training, demographics, and temporal changes. METHODS: Six month case log data of American urologists between 2004 and 2013 were obtained from the American Board of Urology. Current Procedural Terminology (CPT) codes were used to identify surgical procedures, including plaque injection. RESULTS: A total of 6564 urologists were included in the surgical cohort, logging 8195 surgical procedures for PD. Only 15.4% of urologists (1012/6564) reported a surgical case for PD. Andrologists (urologist subspecialty designation) accounted for 5.3% of these urologists (54/1012) and performed 18.5% of PD procedures (P = .0001). The frequency of plaque injections increased from 499 in 2004 to 797 in 2013, a 59% increase, whereas surgical correction remained stable. Urologists performed four times as many injections as surgical procedures for PD (P = .001) with andrologists more likely to attempt injection than surgical correction (P = .045). Among surgeries performed, 73.2% were corrections of angulation without plaque excision, 20.5% were excisions of plaque (with possible grafting) up to 5 cm, and 6.2% were excisions of plaque (with possible grafting) >5 cm. There was a 313% increase in the ratio of plication to plaque manipulation (0.92 in 2004 to 2.91 in 2013). CONCLUSION: PD is treated by a minority of urologists and disproportionately by subspecialist in andrology. When compared with surgical interventions, excluding prosthesis implantation, most surgeons favor conservative treatment. The majority of surgical corrections were corrections of angulation without plaque manipulation. PMID- 26494293 TI - Prostatic Urethral Lift Vs Prostate Arterial Embolization: Novel Nonablative Strategies in the Management of Lower Urinary Tract Symptoms Secondary to Benign Prostate Hyperplasia. AB - Prostate urethral lift and prostate arterial embolization represent two evolving techniques with contrasting mechanisms of action (mechanical decompression vs angiographic embolization). Both yield relief of lower urinary tract symptoms over a period of several weeks. They display similar safety profiles with self limiting pelvic discomfort characterizing the commonest minor adverse event. Both procedures have the potential to be carried out under local anesthesia and in the outpatient setting with suitability for patients with cardiovascular comorbidities. Neither has been found to cause degradation of sexual function. Further randomized studies are needed to delineate the formal position of these techniques in the surgical management of benign prostate hyperplasia. PMID- 26494294 TI - Idiopathic Calcium Nephrolithiasis and Hypovitaminosis D: A Case-control Study. AB - OBJECTIVE: To investigate the association between vitamin D deficiency (25 hydroxyvitamin D <20 ng/mL) and idiopathic calcium nephrolithiasis (ICN). METHODS: A total of 884 patients with ICN (363 males, mean age of 51 +/- 14) and 967 controls (162 males, mean age of 59 +/- 15) from an area with no food fortification policy were considered following a case-control study design. Patients were enrolled at a third-level outpatient stone clinic. Controls were selected from a laboratory database after exclusion of those with nephrolithiasis, bone, endocrine, liver, and kidney diseases. Serum 25 hydroxyvitamin-D (25-OH-D), date of test, presence/history of diabetes, and cardiovascular disease including hypertension were recorded for all subjects. Serum parathormone, calcium, phosphorus, and urinary factors of lithogenic risk were available in stone formers (SF). After univariate statistical analysis, propensity score matching with conditional logistic regression was used to control for the possible effects of covariates. RESULTS: The prevalence of 25-OH D <20 ng/mL was 56% in SF and 44% in controls (P <.001), with median levels of 18 ng/mL [interquartile range (IQR) of 12-24)] versus 23 ng/mL (IQR of 14-30) (age and sex adjusted P <.001). After a fully adjusted conditional logistic regression analysis, performed on propensity-matched cohorts (442 SF, 442 controls), there was a statistically significant association between vitamin D deficiency and odds of nephrolithiasis (estimated odds ratio of 2.29, confidence interval 95% 1.74 3.02, P <.001). 25-OH-D levels were not different in hypercalciuric and normocalciuric SF (median and IQR of 18 ng/mL and 13-23 vs 19 ng/mL and 13-26, respectively, P = .2). CONCLUSIONS: SF have lower serum 25-OH-D levels than controls. The role of hypovitaminosis D in the onset of ICN should be better reconsidered. PMID- 26494295 TI - Trends in Urology Residents' Exposure to Operative Urotrauma: A Survey of Residency Program Directors. AB - OBJECTIVE: To determine longitudinal trends in resident exposure to urotrauma and to assess whether presence of Genitourinary Reconstructive Surgeon (GURS) faculty has impacted exposure and career choice. METHODS: An identical, 31-question multiple-choice survey was sent to program directors of Accreditation Council for Graduate Medical Education (ACGME)-accredited urology residency programs in 2006 and 2013. The areas of focus included program demographics, extent of urotrauma exposure, program director perceptions regarding educational value of urotrauma, and impact of GURS fellowship trained faculty. Responses were de-identified, compiled, and compared for differences. RESULTS: Response rates were 57% (64/112) and 43% (53/123) for the 2006 and 2013 survey, respectively (P = .03). Trauma Level 1 designation (56/64 [89%] vs 44/53 [88%], P = .84) and presence of GURS faculty (22/64 [34%] vs 22/53 [43%], P = .43) were similar between survey periods. Although survey respondents felt urotrauma volume had remained constant (34/64 [53%] vs 30/53 [56%], P = .71), more recent respondents reported that conservative management strategies negatively impacted resident exposure (14/64 [22%] vs 23/53 [43%], P = .01). Residencies with GURS faculty in 2013 (22/53, 42%) were positively associated with residents publishing urotrauma literature (9/22 [41%] vs 4/31 [13%], P = .02), the presence of multidisciplinary trauma and urology conferences (3/22 [14%] vs 0/31 [0%], P = .03), and residents matriculating to GURS fellowships (15/22 [68%] vs 10/31 [32%], P = .009). CONCLUSION: Many contemporary urology residencies report poor resident exposure to urotrauma during training. Although presence of GURS faculty may influence resident career choice, additional strategies may be warranted to expose residents to urotrauma during training. PMID- 26494296 TI - Isolated Renal Sinus Lymphangiectasia-Close Mimic of Pelviureteric Junction Obstruction and Hydronephrosis. AB - Renal lymphangiectasia is a rare disorder which may present as perirenal or peripelvic collection. Isolated renal sinus lymphangiectasia is a close differential diagnosis for pelviureteric junction obstruction on ultrasound, but can be resolved without ambiguity using computed tomography and magnetic resonance imaging. Here we describe such a case where imaging helped avoid unnecessary confusion. PMID- 26494297 TI - Identification of the neural crest-specific enhancer of Seraf gene in avian peripheral nervous system development. AB - In vertebrate embryos, trunk neural crest cells give rise to Schwann cells, along with other derivatives. In this study, to elucidate the molecular mechanisms for the Schwann cell specification, we aimed to identify enhancer elements responsible for the expression of the Seraf gene, the earliest marker for the Schwann cell precursors in the avian embryos. We first compared the genomic structure around the Seraf locus in various vertebrates, and found that, while mammals do not have a Seraf homolog, teleost fish species have it. However, the intergenic sequences around the Seraf locus are not conserved between zebrafish and chicken, consistent with the fact that fish Seraf expression is not Schwann cell precursor-specific. We thus compared the intergenic sequences around the Seraf locus among avian species, and identified a potential enhancer containing a cluster of Sox10-binding sites. Accordingly, the identified enhancer is activated in a neural crest-specific manner in transfected quail embryos. We also found that Sox10 activated the enhancer in cultured cells. Thus, our results revealed a new role of Sox10 in the earliest phase of the Schwann cell fate specification. PMID- 26494298 TI - Notch increased vitronection adhesion protects myeloma cells from drug induced apoptosis. AB - Notch signaling activation was found in many human cancers including multiple myeloma. It was previously reported that notch contributes to drug resistant of myeloma cells upon chemotherapy treatment, inhibition of notch by inhibitors helped to overcome drug resistance. However, the mechanism of notch developed drug resistance is remained to be fully illustrated. In the current study, we reported that Notch signaling activation up-regulated expression of integrin alphavbeta5 in myeloma cells companied with enhanced cells adhesion on vitronectin. Silencing Notch-1 receptor with siRNA or blocking cells with integrin alphavbeta5 antibody reduced myeloma cells adhesion on vitronectin, importantly, vitronectin mediated adhesion confers protection of myeloma cells from drug induced apoptosis. Thus, we revealed a novel mechanism of myeloma cells resistance to drug induced apoptosis. This study first connected Notch signaling, VTN adhesion and drug resistance together. Therefore, blocking alphavbeta5 receptor with antibody or knock down approach would be a novel promising strategy to treat MM. PMID- 26494299 TI - microRNA-26a and -584 inhibit the colorectal cancer progression through inhibition of the binding of hnRNP A1-CDK6 mRNA. AB - While the progress of chemotherapy and molecular targeted therapy has improved the outcome of colorectal cancer patients, the mortality of colon cancer remains high, indicating the need to develop novel therapeutic targets for improving the outcome of colon cancer. Heterogeneous ribonucleoprotein A1 (hnRNP A1) is highly expressed in colorectal cancer and its expression correlates with malignant transformation. In this study, we performed a microarray analysis with the RNA immunoprecipitation (RNA-IP) method and identified hnRNP A1-interacting miRs, including miR-26a and -584, in a colorectal cancer cell line, SW620. A SRB assay revealed the tumor suppressive effect of miR-26a and -584, and the tumor suppressive effect of these miRs was diminished by the downregulation of hnRNP A1. The combined method of a transcriptome analysis and RNA-IP revealed hnRNP A1 interacting mRNAs, including cyclin dependent kinase 6 (CDK6). A Western blot analysis revealed the downregulation of CDK6 in miR-26a and -584 overexpression cells, as well as hnRNP A1 knockdown cells. The binding assay indicated that the binding of hnRNP A1-CDK6 mRNA was reduced by transfection of miR-26a and -584. The expression of cleaved caspase-3 was induced in miR-26a and -584 overexpression cells. These data indicate that miR-26a and -584 inhibit the binding of hnRNP A1-CDK6 mRNA and induce colorectal cancer cell apoptosis. PMID- 26494300 TI - Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells. AB - Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. PMID- 26494301 TI - Epigallocatechin-3-gallate attenuates the AIM2-induced secretion of IL-1beta in human epidermal keratinocytes. AB - The pro-inflammatory cytokine interleukin-1beta (IL-1beta) plays a central role in the pathogenesis of psoriasis. Keratinocytes are a major source of IL-1beta and express absent in melanoma 2 (AIM2). AIM2 recognizes a double-stranded DNA and initiates the IL-1beta-processing of inflammasome. The AIM2 inflammasome is a cytosolic multiprotein complex composed of AIM2, an apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), and pro-caspase-1. Epigallocatechin-3-Gallate (EGCG), a major polyphenolic component of green tea, has anti-inflammatory properties. In the current study, we investigated the issue of whether or how EGCG suppresses AIM2 inflammasome in human epidermal keratinocytes, neonatal (HEKn). Treatment with EGCG, before or after IFN-gamma priming, attenuated poly(dA:dT)-induced IL-1beta secretion in HEKn cells. Pre treatment with EGCG reduced the level of IFN-gamma-induced priming signal via the down-regulation of pro-IL-1beta and pro-capspase-1 in HEKn cells. Furthermore, treatment with EGCG attenuated poly(dA:dT)-induced ASC oligomerization and caspase-1 activation in IFN-gamma-primed HEKn cells. These results suggest that EGCG attenuates AIM2-induced IL-1beta secretion by suppressing both IFN-gamma mediated priming and poly(dA:dT)-induced ASC oligomerization of inflammasomes in human epidermal keratinocytes. PMID- 26494302 TI - A descriptive study of baccalaureate nursing students' responses to suicide prevention education. AB - Internationally, little is known regarding the amount of educational content on suicide in undergraduate nursing curriculum. The literature conducted found few published research studies on implementation of suicide prevention instruction in baccalaureate nursing curriculum, even though various international healthcare and nursing initiatives address suicide prevention. The aim was to describe senior baccalaureate students' responses to an evidence-based suicide prevention gatekeeper training program entitled Question-Persuade-Refer implemented in a required course. This is a multi-method descriptive study. Data were collected utilizing a pre-post-survey questionnaire administered to 150 students in four classes of a psychiatric nursing course over a two-year period. The quantitative data were statistically significant (p < 0.000) indicating an overall positive rating of the training. From the qualitative data, the main theme was 'becoming capable intervening with persons at risk for suicide'. Students responded very positively to the evidence based suicide prevention gatekeeper training program. The instruction addresses various national initiatives and strategies filling a void in nursing curriculum, as well as empowering students to engage in suicide prevention interventions. PMID- 26494303 TI - New ways of seeing: Nursing students' experiences of a pilot service learning program in Australia. AB - The objective of this paper was to evaluate pre-registration nursing students' experiences of a pilot program that placed them in community based non-government organisations for clinical placement as part of a core mental health subject. Clinical placements that adopt a Service Learning model in primary health care environments are valuable to nursing students but are not commonly available in Australia. In order to enhance student exposure to primary health care models and support experiential learning about the social determinants of health, a pilot Service Learning program was designed to provide clinical placements in non government organisations. Qualitative data were collected through one focus group with program participants. The focus group was audio-recorded and transcribed verbatim. Thematic analysis of transcribed data was undertaken. The overarching theme identified was 'new ways of seeing'. Three sub-themes - 'learning outside the box', 'confronting the real world' and 'transformative experiences' - were also identified. The authors have concluded that nursing students in community organisations for clinical practicum facilitated valuable learning and generated professional and personal insight leading to increased understanding of the social determinants of health and increased awareness of mental health nursing in the community. PMID- 26494304 TI - Surveying the experiences and perceptions of undergraduate nursing students of a flipped classroom approach to increase understanding of drug science and its application to clinical practice. AB - Patient harm from medication error is a significant issue. Individual failures by health professionals including knowledge deficits and poor communication have been identified as increasing the likelihood of medication administration errors. In Australia, the National Strategy for Quality Use of Medicines in 2002 compels health professionals to have the knowledge and skills to use medicines safely and effectively. This paper examines nursing students' perceptions of the effectiveness of a flipped classroom approach to increase understanding of pharmacology principles and the application of this knowledge to medication practice. An internet-based self-completion questionnaire was used in 2013 (n = 26) after the flipped classroom approach was implemented, and pre- (n = 6) and post-flipping (n = 25) in 2014. Students who engaged with digitally recorded lectures (eLectures) prior to face-to-face workshops stated that they had greater understanding of the subject and enhanced critical thinking skills. The replay function of the eLecture was perceived by some students as most beneficial to independent learning. However, for some students, time constraints meant that they relied on eLectures alone, while others preferred traditional teaching methods. Although limited by sample size and potential participant bias, the results provide insights about the flipped classroom experience from a student perspective. PMID- 26494306 TI - Update on the diagnosis and treatment of pulmonary tuberculosis. AB - Tuberculosis (TB) remains the most important human infectious disease. Currently, the TB diagnosis is still based on the clinical presentation, radiographic findings and microbiological results; all of which have sensitivity or specificity issues. For that reason, the immediate future involves rapid molecular microbiological techniques, in particular GeneXpert (which is more sensitive than bacilloscopy and is able to detect rifampicin resistance) and GenoType. The current six-month treatment for TB has remained unchanged for decades. Attempts to shorten this treatment have failed. In recent years, new drugs have been reported that could contribute to TB treatment in the near future, and are already being used in multi-drug-resistance TB. PMID- 26494305 TI - TNFalpha-blockade stabilizes local airway hyperresponsiveness during TLR-induced exacerbations in murine model of asthma. AB - Viral infections are a common cause of asthma exacerbation. These maladies are sometimes complicated by bacterial infections. Toll-like receptors (TLRs) are in the forefront of our microbial defence, with TLR3 responding to viral and TLR4 to bacterial stimulation. The present study was designed to evaluate the effect of concomitant TLR3 and TLR4 stimulation in a murine model of allergic asthma.BALB/c mice were stimulated intranasally with a combination of poly(I:C) and LPS activating TLR3 and TLR4, respectively. This resulted in the development of airway hyperresponsiveness (AHR) in the proximal part of the lung, along with signs of neutrophilic inflammation. Analysis of the bronchioalveolar lavage fluid (BALF) revealed a marked increase in TNFalpha. In contrast, the allergic airway inflammation induced by ovalbumin administration to sensitized mice caused AHR in the whole lung along with an increase in eosinophils and lymphocytes in the BALF and lung.When poly(I:C) + LPS were given to mice with an ongoing allergic airway inflammation induced by ovalbumin, the AHR was further increased in the peripheral lung and neutrophils appeared together with eosinophils and lymphocytes in the BALF and lung. Treatment with the TNFalpha-blocking antibody infliximab blunted the AHR increase, without affecting the cells influx in BALF.To conclude; a combined TLR3- and TLR4-stimulation, representing a concomitant viral and bacterial infection, causes an AHR that is further exaggerated during an ongoing allergic inflammation. The airway stabilizing effect of infliximab indicates the possible future use of TNFalpha blockade in treatment of microbial induced exacerbations of allergic asthma. PMID- 26494307 TI - Developing, Implementing, and Evaluating the Educational Module Students Active Learning via Internet Observations (SALIO) in Undergraduate Nursing Education. AB - PURPOSE: This study aimed not only to describe the development and implementation of the module but also to evaluate the nursing students' perceptions. DESIGN AND METHODS: A cross-sectional design including 101 students who were asked to participate and answer a survey. We describe the development of the pedagogic module Students Active Learning via Internet Observations based on situated learning. FINDINGS: The findings show that learning about service users' own lived experiences via web-based platforms was instructive according to the students: 81% agreed to a high or very high degree. Another important finding was that 96% of students responded that the module had clinical relevance for nursing work. PRACTICE IMPLICATIONS: We argue that learning that engages students with data that are contextually and culturally situated is important for developing competence in caregiving. PMID- 26494308 TI - Early and severe haemolysis after treatment with artesunate for severe malaria. PMID- 26494309 TI - Erratum: Reward feedback stimuli elicit high-beta EEG oscillations in human dorsolateral prefrontal cortex. PMID- 26494311 TI - Relationships between problematic alcohol consumption and delinquent behaviour from adolescence to young adulthood. AB - BACKGROUND: Heavy episodic drinking (HED) has been associated with increased risk for short- and long-term injury and harms, such as violence and delinquent behaviour; however, the temporal relationship between the two remains unclear, particularly on transition to young adulthood. This study investigates transactional pathways between HED and delinquent behaviour from adolescence to emerging adulthood. METHODS: Data were drawn from the Australian Temperament Project; a population-based longitudinal study that has followed the health and development of participants (and parents) across 30 years from birth in 1982. The analytic sample was 1650 participants and included five measurement waves spanning adolescence (3 waves: 13-18 years) and young adulthood (2 waves; 19-24 years). RESULTS: There was strong continuity across waves of both HED and delinquency, as well as across-time associations between them. Delinquent behaviour in adolescence was associated with up to twofold increases in the odds of HED at each subsequent adolescent wave. HED in the late teens was associated with over fourfold increases in the odds of persistent (two waves) HED in young adulthood. HED in the late teens was associated with increases in the odds of delinquent behaviour in young adulthood (over twofold for male and one and a half fold for female participants). CONCLUSIONS: While delinquent behaviour predicts both future HED and future delinquent behaviour in adolescence, once young people reach the legal drinking age of 18 years, HED becomes a predictor of current and future delinquent behaviour and future HED, suggesting that increased access to alcohol increases the likelihood of young people engaging in delinquent behaviour. [Miller PG, Butler E, Richardson B, Staiger PK, Youssef GJ, Macdonald JA, Sanson A, Edwards B, Olsson CA. Relationships between problematic alcohol consumption and delinquent behaviour from adolescence to young adulthood. Drug Alcohol Rev 2016;35:317-325]. PMID- 26494312 TI - Cuprous Oxide Catalyzed Oxidative C-C Bond Cleavage for C-N Bond Formation: Synthesis of Cyclic Imides from Ketones and Amines. AB - Selective oxidative cleavage of a C-C bond offers a straightforward method to functionalize organic skeletons. Reported herein is the oxidative C-C bond cleavage of ketone for C-N bond formation over a cuprous oxide catalyst with molecular oxygen as the oxidant. A wide range of ketones and amines are converted into cyclic imides with moderate to excellent yields. In-depth studies show that both alpha-C-H and beta-C-H bonds adjacent to the carbonyl groups are indispensable for the C-C bond cleavage. DFT calculations indicate the reaction is initiated with the oxidation of the alpha-C-H bond. Amines lower the activation energy of the C-C bond cleavage, and thus promote the reaction. New insight into the C-C bond cleavage mechanism is presented. PMID- 26494310 TI - Lactate dehydrogenase-A inhibition induces human glioblastoma multiforme stem cell differentiation and death. AB - Therapies that target the signal transduction and metabolic pathways of cancer stem cells (CSCs) are innovative strategies to effectively reduce the recurrence and significantly improve the outcome of glioblastoma multiforme (GBM). CSCs exhibit an increased rate of glycolysis, thus rendering them intrinsically more sensitive to prospective therapeutic strategies based on the inhibition of the glycolytic pathway. The enzyme lactate dehydrogenase-A (LDH-A), which catalyses the interconversion of pyruvate and lactate, is up-regulated in human cancers, including GBM. Although several papers have explored the benefits of targeting cancer metabolism in GBM, the effects of direct LDH-A inhibition in glial tumours have not yet been investigated, particularly in the stem cell subpopulation. Here, two representative LDH-A inhibitors (NHI-1 and NHI-2) were studied in GBM derived CSCs and compared to differentiated tumour cells. LDH-A inhibition was particularly effective in CSCs isolated from different GBM cell lines, where the two compounds blocked CSC formation and elicited long-lasting effects by triggering both apoptosis and cellular differentiation. These data demonstrate that GBM, particularly the stem cell subpopulation, is sensitive to glycolytic inhibition and shed light on the therapeutic potential of LDH-A inhibitors in this tumour type. PMID- 26494313 TI - Sixty seconds on: flu vaccination. PMID- 26494314 TI - The Effects of the Moms and Teens for Safe Dates Program on Dating Abuse: a Conditional Process Analysis. AB - Moms and Teens for Safe Dates (MTSD) is a dating abuse (DA) prevention program for teens exposed to domestic violence. In a randomized controlled trial (RCT), MTSD prevented certain types of DA victimization (psychological and physical) and perpetration (psychological and cyber) among teens with higher, but not lower, exposure to domestic violence. We built on these findings by using moderated mediation analysis to examine whether level of teen exposure to domestic violence conditioned the indirect effects of MTSD on these types of DA through targeted mediators. MTSD consisted of six mailed activity booklets. Mothers who had been former victims of domestic violence delivered the program to their teens. Mother and teen pairs were recruited into the RCT through community advertising and completed baseline and 6-month follow-up interviews (N = 277 pairs). As expected, MTSD had significant favorable effects for teens with higher but not lower exposure to domestic violence on several mediators that guided program content, including teen conflict management skills and mother-perceived severity of DA, self-efficacy for enacting DA prevention efforts, and comfort in communicating with her teen. MTSD had significant main effects on other mediators including teen feeling of family closeness and cohesion and mother-perceived susceptibility of her teen to DA. As expected, all significant indirect effects of MTSD on DA outcomes through mediators were for teens with higher exposure to domestic violence. Findings have implications for developing DA victimization and perpetration prevention programs for teens with high exposure to domestic violence. PMID- 26494315 TI - Toxicological and biochemical analyses demonstrate no toxic effect of Cry1C and Cry2A to Folsomia candida. AB - Collembolans are common soil arthropods that may be exposed to insecticidal proteins produced in genetically engineered (GE) plants by ingestion of crop residues or root exudates. In the present study, a dietary exposure assay was validated and used to assess the lethal and sublethal effects of two Bacillus thuringiensis (Bt) insecticidal proteins, Cry1C and Cry2A, on Folsomia candida. Using the insecticidal compounds potassium arsenate (PA), protease inhibitor (E 64), and Galanthus nivalis agglutinin (GNA) mixed into Baker's yeast, we show that the assay used can detect adverse effects on F. candida. Survival and development were significantly reduced when F. candida was fed a diet containing PA, E-64, and GNA at 9, 75, and 100 MUg/g diet, respectively, but not when fed a diet containing 300 MUg/g Cry1C or 600 MUg/g Cry2A. The activities of test antioxidant-, detoxification-, and digestion-related enzymes in F. candida were unaltered by a diet containing 300 MUg/g Cry1C or 600 MUg/g Cry2A, but were significantly increased by a diet containing 75 MUg/g E-64. The results confirm that Cry1C and Cry2A are not toxic to F. candida at concentrations that are much higher than those encountered under field conditions. PMID- 26494316 TI - Comparative analysis of antibodies to xCT (Slc7a11): Forewarned is forearmed. AB - The cystine/glutamate antiporter or system Xc- exchanges cystine for glutamate, thereby supporting intracellular glutathione synthesis and nonvesicular glutamate release. The role of system Xc- in neurological disorders can be dual and remains a matter of debate. One important reason for the contradictory findings that have been reported to date is the use of nonspecific anti-xCT (the specific subunit of system Xc-) antibodies. Often studies rely on the predicted molecular weight of 55.5 kDa to identify xCT on Western blots. However, using brain extracts from xCT knockout (xCT(-/-)) mice as negative controls, we show that xCT migrates as a 35 kDa protein. Misinterpretation of immunoblots leads to incorrect assessment of antibody specificity and thereby to erroneous data interpretation. Here we have verified the specificity of most commonly used commercial and some in-house developed anti-xCT antibodies by comparing their immunoreactivity in brain tissue of xCT(+/+) and xCT(-/-) mice by Western blotting and immunohistochemistry. The Western blot screening results demonstrate that antibody specificity not only differs between batches produced by immunizing different rabbits with the same antigen but also between bleedings of the same rabbit. Moreover, distinct immunohistochemical protocols have been tested for all the anti-xCT antibodies that were specific on Western blots in order to obtain a specific immunolabeling. Only one of our in-house-developed antibodies could reveal specific xCT labeling and exclusively on acetone-postfixed cryosections. Using this approach, we observed xCT protein expression throughout the mouse forebrain, including cortex, striatum, hippocampus, midbrain, thalamus, and amygdala, with greatest expression in regions facing the cerebrospinal fluid and meninges. PMID- 26494318 TI - Limited generalisation of changes in attentional bias following attentional bias modification with the visual probe task. AB - Although attentional bias modification (ABM) can change anxiety, recent studies failed to replicate such effects, possibly because the visual probe ABM failed to induce changes in attentional bias (AB). We investigated whether visual probe ABM generalised to different measures of AB besides the visual probe task (VPT), and thus whether ABM genuinely changes attentional processing. We trained participants (N = 60) to either attend towards or away from angry facial expressions, and we examined training effects on the dot probe task, the exogenous cueing task, and the visual search task. We found a small change in AB in the VPT, but this effect did not transfer to the exogenous cueing task or the visual search task. Our study shows that ABM does not necessarily lead to generalised effects on AB. This finding can be explained by the poor psychometric properties of the AB measures. PMID- 26494317 TI - Overshoot during phenotypic switching of cancer cell populations. AB - The dynamics of tumor cell populations is hotly debated: do populations derive hierarchically from a subpopulation of cancer stem cells (CSCs), or are stochastic transitions that mutate differentiated cancer cells to CSCs important? Here we argue that regulation must also be important. We sort human melanoma cells using three distinct cancer stem cell (CSC) markers - CXCR6, CD271 and ABCG2 - and observe that the fraction of non-CSC-marked cells first overshoots to a higher level and then returns to the level of unsorted cells. This clearly indicates that the CSC population is homeostatically regulated. Combining experimental measurements with theoretical modeling and numerical simulations, we show that the population dynamics of cancer cells is associated with a complex miRNA network regulating the Wnt and PI3K pathways. Hence phenotypic switching is not stochastic, but is tightly regulated by the balance between positive and negative cells in the population. Reducing the fraction of CSCs below a threshold triggers massive phenotypic switching, suggesting that a therapeutic strategy based on CSC eradication is unlikely to succeed. PMID- 26494319 TI - Design of a national and regional survey among French general practitioners and method of the first wave of survey dedicated to vaccination. AB - OBJECTIVES: France is currently facing a vaccine-hesitancy crisis. We conducted a questionnaire-based telephone interview with a large sample of general practitioners (GPs) as they play a crucial role in the vaccination process. Our main objectives were to study the GPs' vaccination behaviors when it comes to their own vaccination and that of their relatives, and the vaccine recommendations made to their patients. We also aimed to understand their opinion related to the severity of vaccine-preventable diseases and to assess their trust in various sources of information. Finally, we enquired about their opinion in terms of vaccination-related tools that could help them in their daily practice. The article aimed to present the design of this panel and survey. PATIENTS AND METHODS: Four samples of GPs (one national and three regional) were selected among all the French GPs (metropolitan France) using random sampling. Five cross sectional surveys should be conducted with that panel. The mean targeted sample size is 2350 GPs for each survey. The survey dedicated to vaccination was conducted by telephone or on the Internet. RESULTS: GPs were included in the survey between December 2013 and February 2014. The national sample included 1582 GPs (response rate: 46%) and the three regional samples included 1297 GPs (response rate: 44%). The survey dedicated to vaccination was conducted between April and July 2014; the national sample response rate was 92% (1582/1712). CONCLUSION: The results of the first wave of surveys, conducted on a large sample of French GPs, provide important information to guide the French vaccination policy. PMID- 26494321 TI - Abnormal Connection of the Ductus Venosus to a Dilated Coronary Sinus Imaged by Prenatal Echocardiography: Case Report. AB - We describe a case of a fetus with an ectopic connection of the ductus venosus to a dilated coronary sinus that was diagnosed at ShengJing Hospital of China Medical University. A dilated coronary sinus was initially detected with prenatal echocardiography. Neither a persistent left superior vena cava nor an anomalous pulmonary venous connection was present. After comprehensive examination, we discovered that the ductus venosus had an abnormal course draining into the coronary sinus. The postnatal outcome of this fetus was good. Once a dilated coronary sinus is confirmed, further ultrasound evaluation should be performed to search for a potential cause. PMID- 26494320 TI - Six, Seven or Eight Coordinate Fe(II) , Co(II) or Ni(II) Complexes of Amide Appended Tetraazamacrocycles for ParaCEST Thermometry. AB - Fe(II) , Co(II) and Ni(II) complexes of two tetraazamacrocycles (1,4,8,11 tetrakis(carbamoylmethyl)-1,4,8,11-tetraazacyclotetradecane (L1) and 1,4,7,10 tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (L2) show promise as paraCEST agents for registration of temperature (paraCEST=paramagnetic chemical exchange saturation transfer). The Fe(II) , Co(II) and Ni(II) complexes of L1 show up to four CEST peaks shifted <=112 ppm, whereas analogous complexes of L2 show only a single CEST peak at <=69 ppm. Comparison of the temperature coefficients (CT ) of the CEST peaks of [Co(L2)](2+) , [Fe(L2)](2+) , [Ni(L1)](2+) and [Co(L1)](2+) showed that a CEST peak of [Co(L1)](2+) gave the largest CT (-0.66 ppm (o) C(-1) at 4.7 T). NMR spectral and CEST properties of these complexes correspond to coordination complex symmetry as shown by structural data. The [Ni(L1)](2+) and [Co(L1)](2+) complexes have a six coordinate metal ion bound to the 1-, 4-amide oxygen atoms and four nitrogen atoms of the tetraazamacrocycle. The [Fe(L2)](2+) complex has an unusual eight coordinate Fe(II) bound to four amide oxygen atoms and four macrocyclic nitrogen atoms. For [Co(L2)](2+) , one structure has seven-coordinate Co(II) with three bound amide pendents and a second structure has a six-coordinate Co(II) with two bound amide pendents. PMID- 26494322 TI - Early constraints in sexual dimorphism: survival benefits of feminized phenotypes. AB - Sexual dimorphism (SD) has evolved in response to selection pressures that differ between sexes. Since such pressures change across an individual's life, SD may vary within age classes. Yet, little is known about how selection on early phenotypes may drive the final SD observed in adults. In many dimorphic species, juveniles resemble adult females rather than adult males, meaning that out of the selective pressures established by sexual selection feminized phenotypes may be adaptive. If true, fitness benefits of early female-like phenotypes may constrain the expression of male phenotypes in adulthood. Using the common kestrel Falco tinnunculus as a study model, we evaluated the fitness advantages of expressing more feminized phenotypes at youth. Although more similar to adult females than to adult males, common kestrel fledglings are still sexually dimorphic in size and coloration. Integrating morphological and chromatic variables, we analysed the phenotypic divergence between sexes as a measure of how much each individual looks like the sex to which it belongs (phenotypic sexual resemblance, PSR). We then tested the fitness benefits associated with PSR by means of the probability of recruitment in the population. We found a significant interaction between PSR and sex, showing that in both sexes more feminized phenotypes recruited more into the population than less feminized phenotypes. Moreover, males showed lower PSR than females and a higher proportion of incorrect sex classifications. These findings suggest that the mechanisms in males devoted to resembling female phenotypes in youth, due to a trend to increase fitness through more feminized phenotypes, may provide a mechanism to constrain the SD in adulthood. PMID- 26494323 TI - Is lipstick oral health? PMID- 26494324 TI - Patient confidentiality: A pertinent point. PMID- 26494325 TI - Incision and drainage can still be attempted for a superficial ranula. PMID- 26494326 TI - In practice: Glove wearing: new circumstances and many unknowns. PMID- 26494327 TI - Discrepancy in guidelines in periodontal examination. PMID- 26494328 TI - Right of reply: Stereopsis. PMID- 26494330 TI - Cochlear implant update. PMID- 26494329 TI - Communication: Naming names. PMID- 26494332 TI - Bringing smiles across Nepal. PMID- 26494337 TI - Nothing has changed. PMID- 26494341 TI - From the archive: The mysterious case of 'exploding teeth'. PMID- 26494342 TI - You can catch a killer. PMID- 26494343 TI - Are we human, or are we dentists? AB - There are often moments in life when you can pinpoint exactly where you were, what you were doing and how you felt. From the ecstasy of your wedding to the moment you found out about a family bereavement, those feelings stay with you for the rest of your life. As dental professionals, it is understandable that, given the pressures exerted by UDAs and the way the contracts are, many patients will be treated and forgotten about by the time the next person is in the chair. PMID- 26494344 TI - Effective anaesthesia of the acutely inflamed pulp: part 1. The acutely inflamed pulp. AB - Achieving profound pulpal anaesthesia in a mandibular molar diagnosed with irreversible pulpitis can be argued to be the most testing of dental anaesthetic challenges. This can be attributed to the technical complexities of conventional techniques and the presence of pulp pathosis. Reasons for why the latter influences the ability to attain pulpal anaesthesia is not yet fully understood, but its frequent occurrence is well documented. In light of overcoming this it has become common practice to prescribe antibiotics, refer onto secondary care or to even commence treatment without appropriately anaesthetising the tooth. Therefore, this two part series aims to help practitioners attain clinically acceptable pulpal anaesthesia in the most testing of scenarios; the acutely inflamed mandibular molar. They should then be able to apply these same principles to other teeth presenting with similar symptoms. This section outlines the clinical presentation and pathophysiology associated with an acutely inflamed pulp, defines what it is to attain pulpal anaesthesia and critically analyses theories as to why these teeth are up to eight times more difficult to anaesthetise than their healthy counterparts. PMID- 26494348 TI - The Hall Technique; retrospective case-note follow-up of 5-year RCT. AB - BACKGROUND AND AIM: Few paediatric dental restorative trials present outcomes for more than two years, leaving clinicians uncertain of long-term implications for their patients. This study aimed to establish the Hall Technique's success over the lifetime of primary teeth compared to conventional restorations (CR), by following up participants in the Tayside (Scotland), UK trial. DESIGN: Following the Phase 1 prospective, split-mouth randomised control trial with 132 children (264 teeth) in 17 general practices in Scotland, 142/264 (54%) teeth had reached an endpoint of exfoliation or extraction. Through practices, Phase 2 follow-up data were collected retrospectively from case-notes, using original trial outcomes. Phase 1/ 2 outcome data were combined. RESULTS: Data were obtained up until exfoliation/extraction for 184 teeth (73%) in matched pairs. Major failures: 16 CR; 4 HT (P = 0.0015); ARR = 0.13 (95%CI: 0.04;0.22), numbers needed to treat (NNT) 8 (95%CI: 4;25) favouring HT. Minor failures: 37 CR; 5 HT (P <0.0001); ARR = 0.35 (95%CI: 0.23;0.45) and NNT = 3 (95%CI: 2;4). Repeat failures occurred mostly in the conventional restoration arm for both major and minor failures. CONCLUSIONS: The HT continued to outperform GDP's standard restorations in primary molar teeth with significant caries involvement over the lifetime of the teeth. PMID- 26494349 TI - Understanding emotionally relevant situations in primary care dental practice: 1. Clinical situations and emotional responses. AB - BACKGROUND AND AIMS: The stressful nature of dental practice is well established. Much less information is available on the coping strategies used by dentists and the emotions which underlie the stressful experience. Previous research has been almost exclusively questionnaire-based, limiting the range of emotions explored. This study used qualitative methods to explore the full extent of emotions and coping strategies associated with stressful events in primary dental practice. METHOD: Semi-structured interviews were conducted with 20 dentists in Lincoln and the surrounding area. Verbatim transcriptions were analysed using thematic analysis. RESULTS: Participants reported a wide variety of stressful situations, consistent with the existing literature, which were associated with a diverse range of negative emotional responses including anxiety, anger and sadness. Dentists tended to have more difficulty identifying positive events and emotions. The designation of a situation as stressful or otherwise was dependent on the dentist's personal interpretation of the event. Data relating to the effects of stressors and the coping strategies used by dentists will be presented in subsequent papers. CONCLUSION: The situations which dentists find difficult are accompanied by a diverse set of emotions, rather than omnipresent 'stress.' This has implications for stress management programmes for those in dental practice. PMID- 26494359 TI - Unconscious Desire: The Affective and Motivational Aspects of Subliminal Sexual Priming. AB - Sexual arousal is thought to be the result of the processing of sexual cues at two levels: conscious and unconscious. Whereas numerous studies have examined the affective and motivational responses to supraliminal (consciously processed) sexual cues, much less is known regarding the responses to subliminal (processed outside of one's awareness) sexual cues. Five studies examined responses to subliminal sexual cues. Studies 1-3 demonstrated increases in adults' positive affect following exposure to subliminal sexual cues compared to control cues. Study 4 demonstrated that the positive affect resulting from exposure to subliminal sexual cues increased motivation to further engage in a neutral task. Study 5 provided evidence suggesting that the affect and motivation found in Studies 1-4 were associated with motivation to engage in sex specifically, rather than a general approach motivation. The implications of these findings for the processing of subliminal sexual cues and for human sexuality are discussed. PMID- 26494358 TI - Testicular expression of the Lin28/let-7 system: Hormonal regulation and changes during postnatal maturation and after manipulations of puberty. AB - The Lin28/let-7 system, which includes the RNA-binding proteins, Lin28a/Lin28b, and let-7 miRNAs, has emerged as putative regulator of puberty and male gametogenesis; yet, its expression pattern and regulation in postnatal testis remain ill defined. We report herein expression profiles of Lin28 and let-7 members, and related mir-145 and mir-132, in rat testis during postnatal maturation and in models of altered puberty and hormonal deregulation. Neonatal expression of Lin28a and Lin28b was low and rose markedly during the infantile period; yet, expression patterns diverged thereafter, with persistently elevated levels only for Lin28b, which peaked at puberty. Let-7a, let-7b, mir-132 and mir 145 showed profiles opposite to Lin28b. In fact, let-7b and mir-145 were abundant in pachytene spermatocytes, but absent in elongating spermatids, where high expression of Lin28b was previously reported. Perturbation of puberty by neonatal estrogenization reverted the Lin28/let-7 expression ratio; expression changes were also detected in other models of delayed puberty, due to early photoperiod or nutritional manipulations. In addition, hypophysectomy or growth hormone (GH) deficiency revealed regulation of this system by gonadotropins and GH. Our data document the expression profiles of the Lin28/let-7 system in rat testis along postnatal/pubertal maturation, and their perturbation in models of pubertal and hormonal manipulation. PMID- 26494360 TI - Diffusion Tensor Imaging of Pedophilia. AB - Pedophilia is a principal motivator of child molestation, incurring great emotional and financial burdens on victims and society. Even among pedophiles who never commit any offense,the condition requires lifelong suppression and control. Previous comparison using voxel-based morphometry (VBM)of MR images from a large sample of pedophiles and controls revealed group differences in white matter. The present study therefore sought to verify and characterize white matter involvement using diffusion tensor imaging (DTI), which better captures the microstructure of white matter than does VBM. Pedophilics ex offenders (n=24) were compared with healthy, age-matched controls with no criminal record and no indication of pedophilia (n=32). White matter microstructure was analyzed with Tract-Based Spatial Statistics, and the trajectories of implicated fiber bundles were identified by probabilistic tractography. Groups showed significant, highly focused differences in DTI parameters which related to participants' genital responses to sexual depictions of children, but not to measures of psychopathy or to childhood histories of physical abuse, sexual abuse, or neglect. Some previously reported gray matter differences were suggested under highly liberal statistical conditions (p(uncorrected)<.005), but did not survive ordinary statistical correction (whole brain per voxel false discovery rate of 5%). These results confirm that pedophilia is characterized by neuroanatomical differences in white matter microstructure, over and above any neural characteristics attributable to psychopathy and childhood adversity, which show neuroanatomic footprints of their own. Although some gray matter structures were implicated previously, only few have emerged reliably. PMID- 26494361 TI - Initiation patterns of statin therapy among adult patients undergoing intermediate to high-risk non-cardiac surgery. AB - BACKGROUND: A growing body of literature has been produced on the potential role of statins in reducing perioperative cardiac events in patients undergoing non cardiac surgery. However, evidence remains inconsistent, and little is known about the patterns of perioperative statin use in routine care. OBJECTIVES: The objective of this study was to examine patterns of perioperative statin initiation among adults undergoing non-cardiac elective surgery in the USA. METHODS: Using data from a large US healthcare insurer, we identified patients aged >=18 years who underwent moderate-risk to high-risk non-cardiac elective surgery between 2003 and 2012 and initiated statins within 30 days before surgery. We evaluated temporal trends of statin initiation and patient characteristics. In a matched analysis, we assessed the effect of temporal proximity to surgery on the likelihood of statin initiation. RESULTS: Of 460,154 patients undergoing surgery, 5628 (12 per 1000 patients) initiated a statin within 30 days before surgery. Statin initiation increased from 8 per 1000 patients in 2003 to 15 in 2012 (p = 0.0022). The increase was more pronounced among patients undergoing vascular surgery (149 initiators per 1000 patients by the end of 2012) and with Revised Cardiac Risk Index (RCRI) score >=2 (72 per 1000 patients). Proximity to surgery, in particular vascular surgery, was predictive of statin initiation. CONCLUSIONS: Despite the lack of robust evidence, perioperative statin initiation progressively increased from 2003 to 2012, particularly among patients undergoing major vascular surgery and with higher RCRI score. These trends were largely attributable to the initiation of statins in anticipation of non-cardiac surgery rather than routine dyslipidemia treatment. PMID- 26494362 TI - Are People Living in Walkable Areas Healthier and More Satisfied with Life? AB - Are people who live in more walkable areas healthier and more satisfied with life? This study investigates that question by using the 2005 Behavioral Risk Factors Surveillance System (BRFSS) survey, the largest telephone survey on health in the US (302,841 respondents from 989 metropolitan and micropolitan statistical areas [MSA]; 177,524 respondents from 703 MSAs had complete data). Using multilevel random coefficient modeling, we found that people living in walkable areas reported being generally healthier than people living in less walkable areas. In addition, aside from higher self-reported health, people living in walkable areas also had a lower body mass index (BMI). However, contrary to our prediction, people in more walkable areas were less satisfied with their lives than people in less walkable areas after controlling for various individual-level variables (age, gender, race, education, marital status, income, and unemployment). People who live in walkable areas are healthier but not happier than those living in less walkable areas. PMID- 26494364 TI - Upregulated Tim-3/galectin-9 expressions in acute lung injury in a murine malarial model. AB - Malaria is the most relevant parasitic disease worldwide, and severe malaria is characterized by cerebral edema, acute lung injury (ALI), and multiple organ dysfunctions; however, the mechanisms of lung damage need to be better clarified. In this study, we used Kunming outbred mice infected with Plasmodium berghei ANKA (PbANKA) to elucidate the profiles of T cell immunoglobulin and mucin domain-3 (Tim-3) and its ligand galecin-9 (Gal-9) in the development of ALI. Mice were injected intraperitoneally with 10(6) PbANKA-infected red blood cells. The lungs and mediastinal lymph nodes (MLNs) were harvested at days 5, 10, 15, and 20 post infections (p.i.). The grade of lung injury was histopathologically evaluated. Tim-3- and Gal-9-positive cells in the lungs and MLNs were stained by immunohistochemistry, and the messenger RNA (mRNA) expressions of Tim-3, Gal-9, and related cytokines were assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Bronchoalveolar lavage fluid (BALF) analyses were performed from days 18 to 20 p.i. The results showed that the pathological severities in the lungs were increased with times and the total protein level in the BALFs was significantly elevated in PbANKA-infected mice. The numbers of Gal-9(+) and Tim 3(+) cells in the lungs were significantly increased, and the mRNA levels of both Gal-9 and Tim-3 in the lungs and MLNs were over-expressed in PbANKA-infected mice. In conclusion, our data suggested that Tim-3/Gal-9 may play a role in PbANKA-induced ALI. PMID- 26494365 TI - Antibiotic Susceptibility of Commensal Bacteria from Human Milk. AB - Recent studies have focused on foodborne or commensal bacteria as vehicles of antibiotic resistance. However, the antibiotic resistance of milk bacteria from healthy donors is still vague in Taiwan. For this purpose, human milk samples were obtained from randomly recruited 19 healthy women between 3 and 360 days post-partum. Antibiotic susceptibility profile of bacteria from milk samples was determined. About 20 bacterial species were isolated from milk samples including Staphylococcus (6 species), Streptococcus (4 species), Enterococcus (2 species), Lactobacillus (1 species), and bacteria belonging to other genera (7 species). Some opportunistic or potentially pathogenic bacteria including Kluyvera ascorbata, Klebsiella oxytoca, Klebsiella pneumoniae, Acinetobacter baumannii, Actinomyces bovis, and Staphylococcus aureus were also isolated. Intriguingly, Staphylococcus isolates (22 strains) were resistant to 2-8 of 8 antibiotics, while Streptococcus isolates (3 strains) were resistant to 3-7 of 9 antibiotics, and members of the genus Enterococcus (5 strains) were resistant to 3-8 of 9 antibiotics. Notably, Staphylococcus lugdunensis, S. aureus, Streptococcus parasanguinis, Streptococcus pneumonia, and Enterococcus faecalis were resistant to vancomycin, which is considered as the last-resort antibiotic. Therefore, this study shows that most bacterial strains in human milk demonstrate mild to strong antibiotic resistance. Whether commensal bacteria in milk could serve as vehicles of antibiotic resistance should be further investigated. PMID- 26494363 TI - Interpreting functional effects of coding variants: challenges in proteome-scale prediction, annotation and assessment. AB - Accurate assessment of genetic variation in human DNA sequencing studies remains a nontrivial challenge in clinical genomics and genome informatics. Ascribing functional roles and/or clinical significances to single nucleotide variants identified from a next-generation sequencing study is an important step in genome interpretation. Experimental characterization of all the observed functional variants is yet impractical; thus, the prediction of functional and/or regulatory impacts of the various mutations using in silico approaches is an important step toward the identification of functionally significant or clinically actionable variants. The relationships between genotypes and the expressed phenotypes are multilayered and biologically complex; such relationships present numerous challenges and at the same time offer various opportunities for the design of in silico variant assessment strategies. Over the past decade, many bioinformatics algorithms have been developed to predict functional consequences of single nucleotide variants in the protein coding regions. In this review, we provide an overview of the bioinformatics resources for the prediction, annotation and visualization of coding single nucleotide variants. We discuss the currently available approaches and major challenges from the perspective of protein sequence, structure, function and interactions that require consideration when interpreting the impact of putatively functional variants. We also discuss the relevance of incorporating integrated workflows for predicting the biomedical impact of the functionally important variations encoded in a genome, exome or transcriptome. Finally, we propose a framework to classify variant assessment approaches and strategies for incorporation of variant assessment within electronic health records. PMID- 26494367 TI - Bringing the economic cost of informal caregiving into focus. PMID- 26494366 TI - Metanil yellow impairs the estrous cycle physiology and ovarian folliculogenesis in female rats. AB - Metanil yellow (MY) is a most frequently used food color in West Bengal, India. The toxic effects of MY on the male reproductive system have been reported discriminately in animal models. The probable toxic effects of MY on female reproductive functions have not been reported till date. Therefore, this study was designed to examine the effect of MY on estrous cycle rhythmicity and ovarian folliculogenesis in female rats. Rats have been exposed to MY at three doses of 250, 500, 750 mg kgBW-1 day-1 for two exposure durations, 20 and 30 days. We observed significant changes in the number and duration of estrous cycle along with prominent cytoarchitectural changes in the cellular characteristics of vaginal smear of component phases of estrous cycle in a dose and duration dependent manner in MY-treated rats compared to control rats. We also observed a significant decrease in serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol levels in MY-treated rats. Further, the activities of some antioxidants enzymes in brain tissues of MY-treated rats were significantly decreased and the level of malondialdehyde (MDA), a marker of lipid peroxidation, in brain tissues of MY-treated rats was also significantly increased. The ovarian folliculogenesis in this study was also significantly impaired in MY-treated rats. In conclusion, MY impairs the estrous cycle and ovarian folliculogenesis in female rats by inhibiting the secretion of FSH and estradiol from the ovary, and inducing the oxidative stress in hypothalamic-pituitary-gonadal axis. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 2057-2067, 2016. PMID- 26494368 TI - The importance of the feasibility study: Lessons from a study of the hand-held fan used to relieve dyspnea in people who are breathless at rest. AB - BACKGROUND: The dyspnea accompanying advanced cardiorespiratory disease is often refractory to palliation. It is disabling, distressing and associated with the diseases most common everywhere in the world. The hand-held fan, used to generate a draught across the face, is a simple, cost-effective, safe, and universally applicable palliative breathlessness intervention, consistently described as valuable in qualitative research. A previous crossover trial confirmed its benefit in patients breathless at rest, but the washout period was uncertain. AIM: To determine the washout period after use of the hand-held fan to inform accurate randomized controlled trial design. DESIGN: An observational methodological study. Breathlessness intensity was measured using 100 mm visual analog scale and numerical rating scale, and "relief of breathlessness" was measured on a 5-point scale. Those benefitting from the fan provided visual analog scale/numerical rating scale scores until (1) scores returned to baseline values or (2) until response had plateaued. The primary outcome measure was the time (in minutes) to reach either component of the primary study endpoint. SETTINGS/PARTICIPANTS: Four in-/out-patient hospice/hospital units; participants had chronic refractory breathlessness using the fan. RESULTS: Overall, 31 patients participated (mean age: 74.8 years; range: 49-98 years, standard deviation = 11.5 years); 64% were males. Approximately, half of the sample experienced benefit of moderate effect size. The relative reduction in breathlessness relative to the mean baseline score for the sample was 27% for the visual analog scale and 19% for the numerical rating scale. CONCLUSION: Feasibility work is essential, even for simple widely employed interventions. PMID- 26494369 TI - Quality of Life Outcomes of Bariatric Surgery: A Systematic Review. AB - Bariatric surgery is often pursued to improve quality of life (QOL). This paper systematically reviews the literature examining QOL following bariatric surgery. Fifteen controlled trials examined changes in QOL in obese (BMI > 30) adults (18 65 years) following bariatric surgery; seven compared bariatric surgery to non surgical interventions and six compared different types of bariatric surgery. Bariatric surgery resulted in greater improvements in QOL than other obesity treatments. Significant differences in QOL improvements were found between different types of bariatric surgery. QOL improvements were more likely to occur within the first 2 years following surgery, with greater improvements in physical QOL than mental QOL. Bariatric surgery improves QOL. Future research is needed to investigate changes in QOL in different domains in the short- and long-term following bariatric surgery. PMID- 26494372 TI - A case of acute compression fracture in block vertebra. PMID- 26494370 TI - Angiotensin converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis--a randomized cross-over study. AB - BACKGROUND: Endothelial dysfunction occurs in patients with end-stage renal disease (ESRD) and is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) contributes to endothelial dysfunction in ESRD. In the general population, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease ADMA levels, but no study has compared the effect of these drugs in patients with ESRD on maintenance hemodialysis (MHD). METHODS: We evaluated the effect of 1-week treatment with ramipril (5 mg/d), valsartan (160 mg/d), and placebo on ADMA levels in 15 patients on MHD in a double-blind, placebo-controlled, three x three cross-over study. RESULTS: We found that ADMA levels were increased at baseline and throughout the dialysis session during ramipril treatment (p < 0.001 compared to both, placebo and valsartan). Ramipril did not increase ADMA levels in a study of patients without ESRD, suggesting that factors related to ESRD or hemodialysis contribute to the ACE inhibitor-induced increase in ADMA. We have previously shown that ACE inhibition increases bradykinin (BK) levels during hemodialysis. We therefore evaluated the effect of bradykinin on ADMA production in A549 cells; a cell line that expresses BK receptors. Incubation with BK increased intracellular ADMA concentration through BK B2-receptor stimulation. CONCLUSION: These data indicate that short-term ACE inhibition increases ADMA in patients on MHD whereas ARBs do not. In vitro studies further suggest that this may occur through BK-mediated increase in ADMA production during ACE inhibition. TRIAL REGISTRATION: Clinicaltrials.gov NCT00732069 August 6 2008 and NCT00607672 February 4 2008. PMID- 26494371 TI - Changes in glycosylation of human blood plasma chitotriosidase in patients with type 2 diabetes. AB - Human blood plasma chitotriosidase (CHIT1) is a glycoprotein with chitinolytic activity with not fully elucidated biological function. Its increased level is observed in type 2 diabetes mellitus (T2DM) and is associated with development of diabetic complications. The CHIT1 glycosylation profile and degree is still poorly studied and never investigated in T2DM. Therefore the aim of the present study was to examine the association between glycosylation profile and degree and diabetes with accompanying nephropathy. In blood plasma of 28 patients with T2DM and 11 healthy subjects the CHIT1 concentration and specific activity were examined. The profile and degree of CHIT1 glycosylation were determined by lectin ELISA using lectins specific to O-glycans (Jacalin, MPL, VVL) and sialo-specific SNA and MAA. We revealed that both concentration and specific activity of CHIT1 significantly increased in T2DM, especially in nephropathy with elevated albuminuria. The relative reactivities with lectins, except Jacalin, decreased progressively with T2DM occurrence and albuminuria progression. The most significant differences were observed between control vs. albuminuric group (Micro and Macro). It is also possible that the observed differences in immunoblotting pattern in molecular masses of CHIT1 bands between T2DM patients and healthy subjects may be caused by the differences in degree of CHIT1 glycosylation. The analysis of CHIT1 glycosylation status and the determination of CHIT1 concentration together with its enzymatic activity in blood plasma might constitute additional valuable diagnosis tools for the evaluation the T2DM patients with accompanying nephropathy. Extension of the lectin panel specific to O-glycans occurs useful for the further research using microarray formats, which are expected to accelerate "lectin-based glycan profiling" of glycoproteins. PMID- 26494373 TI - The Team Physician: Ethical and Legal Issues. PMID- 26494374 TI - Cooled Versus Conventional Thermal Radiofrequency Neurotomy for the Treatment of Lumbar Facet-Mediated Pain. PMID- 26494375 TI - [Evaluation of midwives transfusion knowledge in Brittany public and private maternities, 2014]. AB - OBJECTIVES: This regional study aims to evaluate the transfusion knowledge of midwives in 22 Brittany maternity hospitals. MATERIALS AND METHODS: A multicentre, descriptive and comparative study used a questionnaire consisting in 16 theoretical questions about transfusion and questions being carried out. The analysis used the rate of correct answers and a pondered coefficient has been assigned to the different questions to evaluate the level of midwife knowledge. RESULTS: Twenty-two maternity hospitals participated in the study and 238 returned questionnaires could be analysed, a return rate of 36%. The rate of correct answers was between 5 and 98% depending on the questions; for example, the rate of correct answers of the ultimate control's reading varied between 64 and 98% and revealed that 5 to 7% of midwives would validate an incompatible transfusion. The average score was 31/50 with a minimum of 7/50 and a maximum of 44/50. Three statically significant links have been found according to the last year of training specific to blood transfusion, the graduation year and the level of maternity. CONCLUSION: This study revealed an insufficient knowledge of the transfusion among midwives and raised prospects, which could lead to an improvement of training courses offered to midwives. PMID- 26494376 TI - Hygiene monitoring in a hospital immunohaematological laboratory. AB - PURPOSE OF THE STUDY: Not only in blood donation services, but also in the immunohaematological laboratory of a hospital including the depository for blood products a hygiene plan must be drawn up and its realization has to be documented. MATERIAL AND METHODS: From 2011 to 2014, some equipment in the depository and in the immunohematological laboratory was microbiologically monitored once a year. The examinations were done by direct contact cultures taken from several places of each device. RESULTS: Most of the devices showed inconspicuous numbers of environmental microorganisms. Sometimes the refrigerators for fresh frozen plasma and a transport container for blood products revealed moderately, the incubator in the laboratory and a transport container for patient blood samples inadequately increased bacterial contamination. CONCLUSION: Microbiological examinations can detect critical points in the immunohaematological laboratory of a hospital. By communicating these results, the staff can be motivated to observe the regulations of the hygiene plan. PMID- 26494377 TI - In silico hybridization enables transcriptomic illumination of the nature and evolution of Myxozoa. AB - BACKGROUND: The Myxozoa, a group of oligocellular, obligate endoparasites, has long been poorly understood in an evolutionary context. Recent genome-level sequencing techniques such as RNA-seq have generated large amounts of myxozoan sequence data, providing valuable insight into their evolutionary history. However, sequences from host tissue contamination are present in next-generation sequencing reactions of myxozoan tissue, and differentiating between the two has been inadequately addressed. In order to shed light on the genetic underpinnings of myxozoan biology, assembled contigs generated from these studies that derived from the myxozoan must be decoupled from transcripts derived from host tissue and other contamination. This study describes a pipeline for categorization of transcripts asmyxozoan based on similarity searching with known host and parasite sequences, explores the extent to which host contamination is present in previously existing myxozoan datasets, and implements this pipeline on a newly sequenced transcriptome of Myxobolus pendula, a parasite of the common creek chub gill arch. METHODS: The insilico hybridization pipeline uses iterative BLAST searching and database-driven e-value comparison to categorize transcripts as deriving from host, parasite, or other contamination. Functional genetic analysis of M. pendula was conducted using further BLAST searching, Hidden Markov Modeling, and sequence alignment and phylogenetic reconstruction. RESULTS: Three RNA libraries of encysted M. pendula plasmodia were sequenced and subjected to the method. Nearly half of the final set of contiguous assembly sequences (47.3 %) was identified as putative myxozoan transcripts. Putative contamination was also identified in at least 1/3(rd) of previously published myxozoan transcripts. The set of M. pendula transcripts was mined for a range of biologically insightful genes, including taxonomically restricted nematocyst structural proteins and nematocyst proteins identified through mass tandem spectrometry of other cnidarians. Several novel findings emerged, including a fourth myxozoan minicollagen gene, putative myxozoan toxin proteins,and extracellular matrix glycoproteins. CONCLUSIONS: This study serves as a model for the handling of next generation myxozoan sequence. The need for careful categorization was demonstrated in both previous and new sets of myxozoan sequences. The final set of confidently assigned myxozoan transcripts can be mined for any biologically relevant gene or gene family without spurious misidentification of host contamination as a myxozoan homolog. As exemplified by M. pendula, the repertoire of myxozoan polar capsules may be more complex than previously thought, with an additional minicollagen homolog and putative expression of toxin proteins. PMID- 26494379 TI - Different effects of executive and visuospatial working memory on visual consciousness. AB - Consciousness and working memory are two widely studied cognitive phenomena. Although they have been closely tied on a theoretical and neural level, empirical work that investigates their relation is largely lacking. In this study, the relationship between visual consciousness and different working memory components is investigated by using a dual-task paradigm. More specifically, while participants were performing a visual detection task to measure their visual awareness threshold, they had to concurrently perform either an executive or visuospatial working memory task. We hypothesized that visual consciousness would be hindered depending on the type and the size of the load in working memory. Results showed that maintaining visuospatial content in working memory hinders visual awareness, irrespective of the amount of information maintained. By contrast, the detection threshold was progressively affected under increasing executive load. Interestingly, increasing executive load had a generic effect on detection speed, calling into question whether its obstructing effect is specific to the visual awareness threshold. Together, these results indicate that visual consciousness depends differently on executive and visuospatial working memory. PMID- 26494378 TI - Troponin T as a Predictor of End-Stage Renal Disease and All-Cause Death in African Americans and Whites From Hypertensive Families. AB - OBJECTIVE: To evaluate cardiac troponin T (cTnT) as a predictor of end-stage renal disease (ESRD) and death in a cohort of African American and white community-dwelling adults with hypertensive families. PATIENTS AND METHODS: A total of 3050 participants (whites from Rochester, Minnesota; African Americans from Jackson, Mississippi) of the Genetic Epidemiology Network of Arteriopathy study were followed from baseline examination (June 1, 1996, through August 31, 2000) through January 22, 2010. Cox proportional hazards regression models were used to examine the association of cTnT with ESRD and death after adjusting for traditional risk factors. RESULTS: Cohort demographic characteristics and measurements included 1395 whites (45.7%), 2174 hypertensive (71.3%), 992 estimated glomerular filtration rate of less than 60 mL/min per 1.73 m(2) (32.5%), 1574 high-sensitivity C-reactive protein level of greater than 3 mg/L (51.6%), and 66 abnormal cTnT level of 0.01 ng/mL or higher (2.2%). The estimated cumulative incidence of ESRD at 10 years was 27.4% among those with abnormal cTnT levels compared with 1.3% for those with normal levels. Similarly, the estimated cumulative incidence of death at 10 years was 47% among those with abnormal cTnT compared with 7.3% among those with normal cTnT. Abnormal cTnT levels were strongly associated with ESRD and death. This effect was attenuated but was still highly significant after adjustment for demographic characteristics, estimated glomerular filtration rate, and traditional risk factors for ESRD (unadjusted hazard ratio [HR], 23.91; 95% CI, 12.9-44.2; adjusted HR, 2.81; 95% CI, 1.3-5.9) and death (unadjusted HR, 8.43; 95% CI, 6.0-11.9; adjusted HR, 3.46; 95% CI, 2.3 5.1). CONCLUSION: Cardiac troponin T makes an independent contribution to the prediction of ESRD and all-cause death in community-dwelling individuals beyond traditional risk markers. Further studies may be needed to determine whether cTnT screening in individuals with hypertension or in a subset of hypertensive individuals would help identify those at risk of ESRD and all-cause death. PMID- 26494380 TI - Value-driven attentional capture in the auditory domain. AB - It is now well established that the visual attention system is shaped by reward learning. When visual features are associated with a reward outcome, they acquire high priority and can automatically capture visual attention. To date, evidence for value-driven attentional capture has been limited entirely to the visual system. In the present study, I demonstrate that previously reward-associated sounds also capture attention, interfering more strongly with the performance of a visual task. This finding suggests that value-driven attention reflects a broad principle of information processing that can be extended to other sensory modalities and that value-driven attention can bias cross-modal stimulus competition. PMID- 26494381 TI - Using multidimensional scaling to quantify similarity in visual search and beyond. AB - Visual search is one of the most widely studied topics in vision science, both as an independent topic of interest, and as a tool for studying attention and visual cognition. A wide literature exists that seeks to understand how people find things under varying conditions of difficulty and complexity, and in situations ranging from the mundane (e.g., looking for one's keys) to those with significant societal importance (e.g., baggage or medical screening). A primary determinant of the ease and probability of success during search are the similarity relationships that exist in the search environment, such as the similarity between the background and the target, or the likeness of the non-targets to one another. A sense of similarity is often intuitive, but it is seldom quantified directly. This presents a problem in that similarity relationships are imprecisely specified, limiting the capacity of the researcher to examine adequately their influence. In this article, we present a novel approach to overcoming this problem that combines multi-dimensional scaling (MDS) analyses with behavioral and eye-tracking measurements. We propose a method whereby MDS can be repurposed to successfully quantify the similarity of experimental stimuli, thereby opening up theoretical questions in visual search and attention that cannot currently be addressed. These quantifications, in conjunction with behavioral and oculomotor measures, allow for critical observations about how similarity affects performance, information selection, and information processing. We provide a demonstration and tutorial of the approach, identify documented examples of its use, discuss how complementary computer vision methods could also be adopted, and close with a discussion of potential avenues for future application of this technique. PMID- 26494383 TI - Histopathology of C Cells and Medullary Thyroid Carcinoma. AB - The human thyroid gland contains less than 0.01-0.1% calcitonin producing and secreting C cells, which in men are almost exclusively situated in an intrafollicular location; the vast majority of C cells are embryologically derived of remnants of the ultimobranchial body and ultimately of the neural crest, a small subset, however, is presumed to originate from endodermal stem cells. Thyroid tumours with C cell differentiation have been named medullary thyroid carcinoma (MTC); calcitonin is also produced and secreted by MTC which makes this peptide hormone a very useful serum marker both for early detection and clinical follow-up of patients with MTC. About 70-80% of MTC are sporadic tumours, whereas 20-30% are familial MTC which are autosomal-dominant inherited and caused by germline mutations of the RET proto-oncogene located on chromosome 10. This article summarizes the histological, immunhistochemical and molecular genetic features of C cells, C-cell hyperplasia (CCH) and MTC, emphasizing the role of diagnostic pathology. PMID- 26494384 TI - Epidemiology and Clinical Presentation of Medullary Thyroid Carcinoma. AB - Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the thyroid C cells producing mainly calcitonin (CTN) used as tumor marker. MTC occurs either sporadic (75%) or in a hereditary form (multiple endocrine neoplasia type 2, MEN2), due to germline mutations in the RET proto-oncogene. The discovery of an MTC in a patient has several diagnostic implications involving a specific strategy: preoperative evaluation of the tumor marker CTN and the extent of the disease, classification of MTC as sporadic or hereditary by DNA testing, and screening for associated endocrinopathies in hereditary MTC. Elevated CTN is a highly sensitive and specific tumor marker for diagnosis and follow-up of MTC. CTN is directly related to the tumor mass. In patients with nodular thyroid disease, diagnosis of MTC could be made by CTN determination as an indicator of tumor burden in conjunction with fine-needle aspiration. Patients with confirmed sporadic or hereditary MTC should have a total thyroidectomy and depending on the preoperative CTN value and the extent of disease additional dissection of the lymph nodes in the central and lateral neck compartment. In MEN 2 patients diagnosed by screening, the time of prophylactic thyroidectomy depends on RET mutation and CTN level. PMID- 26494385 TI - Medullary Thyroid Carcinoma: Imaging. AB - Imaging plays an important role in early detection and staging of medullary thyroid carcinoma (MTC) as well as in follow-up to localize early recurrence. MTC is a rare, calcitonin-secreting thyroid malignancy often diagnosed by ultrasound and calcitonin screening as part of the routine workup for any thyroid nodule. If calcitonin is elevated, imaging studies are needed for preoperative staging, which dictates surgical management. This can be done by ultrasound of the neck and abdomen. Computed tomography (CT) or magnetic resonance imaging (MRI) studies for more distant disease are done preoperatively if calcitonin levels are higher than 500 pg/ml. Neither FDG-PET/CT nor F-DOPA-PET/CT are used routinely for preoperative staging but may contribute in doubtful individual cases. Postoperative elevated calcitonin is related to persistence or recurrence of MTC. Imaging studies to localize tumor tissue during postoperative follow-up include ultrasound, CT, MRI as well as PET studies. They should be used wisely, however, since treatment consequences are often limited, and even patients with persistent disease may survive long enough to accumulate significant radiation doses. Imaging studies are also useful for diagnosis of associated components of the hereditary MTC such as pheochromocytoma and primary hyperparathyroidism (pHPT). PMID- 26494386 TI - Calcitonin as Biomarker for the Medullary Thyroid Carcinoma. AB - Calcitonin (CTN) is a polypeptide hormone consisting of 32 amino acids with a disulfide bridge between position 1 and 7 that is mainly produced by the C-cells of thyroid gland. The measurement of CTN concentrations in blood reflects C-cell activity and is performed in general by immunoassay methods. However, there are analytical, physiological, pharmacological, and pathological factors that can influence results of serum CTN values. Due to the influence of these factors, there is a high variability in assay-dependent cutoffs used to discriminate between MTC, C-cell hyperplasia (CCH), and the absence of the pathological impairment of C-cells. There is a lot of evidence that the measurement of serum CTN concentrations in patients with thyroid nodules can lead to an earlier diagnosis of MTC or CCH than the exclusive use of imaging procedures and/or fine needle aspiration cytology. Basal CTN concentrations higher than 60-100 pg/mL are highly indicative for the diagnosis MTC. In the range between cutoff and 60 pg/mL CTN, both MTC and HCC may be a relevant diagnosis. PCT and CTN appear to have a comparable diagnostic capability to diagnose MTCs. However, "positive" PCT values of more than 50 pg/mL may be reached also in subclinical infections and will lead, therefore, to an overdiagnosis of the tumor. Pentagastrin- or calcium stimulated serum CTN concentrations higher than cutoff values might improve diagnostics of MTC, but the non-availability of the first and the lacking of relevant cutoff values for the second tool favors the use of only basal values currently. PMID- 26494387 TI - Hereditary Medullary Thyroid Cancer Genotype-Phenotype Correlation. AB - During the last two decades, there has been a marked expansion of our knowledge of both the basic and clinical aspects of multiple endocrine neoplasia type 2 (MEN2). There are two clinically distinct types of MEN2 syndrome, termed MEN2A and MEN2B. Within MEN2A, there are four variants: (i) classical MEN2A, represented by the uniform presence of MTC and the less frequent occurrence of pheochromocytoma, or primary hyperparathyroidism, or both; (ii) MEN2A with cutaneous lichen amyloidosis; (iii) MEN2A with Hirschsprung's disease; and (iv) familial medullary thyroid carcinoma (FMTC), i.e., families or individuals with only MTC. MEN2B is associated with MTC, pheochromocytoma, and mucosal neuromas. Hereditary MTC is caused by autosomal dominant gain of function mutations in the RET proto-oncogene. Specific RET mutations may suggest a predilection toward a particular phenotype and clinical course with a strong genotype-phenotype correlation. Based upon these genotype-phenotype correlations, RET mutations are now stratified into three risk levels, i.e., highest, high, and moderate risk, based on the penetrance and aggressiveness of the MTC. Children in the highest risk category should undergo thyroidectomy in their first year of life, and perhaps even in their first months of life. Children in the high-risk category should have ultrasound of the neck and calcitonin (CTN) measurement performed prior to thyroidectomy. Thyroidectomy should typically be performed at the age of 5 or earlier, depending on the presence of elevated serum CTN levels. However, heterogeneity in disease expression and progression within these groups varies considerably. To personalize disease management, the decision regarding the age of prophylactic thyroidectomy is no longer based upon genotype alone but is currently driven by additional clinical data, the most important being serum CTN levels; specifically, the decision to perform thyroidectomy should err on the safe side if the CTN level is elevated but below 30 pg/ml, especially in the moderate risk group. Personalized management also includes decisions about the best age to begin biochemical screening for pheochromocytoma and primary hyperparathyroidism. PMID- 26494382 TI - Thyroid C-Cell Biology and Oncogenic Transformation. AB - The thyroid parafollicular cell, or commonly named "C-cell," functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that multiple endocrine neoplasia type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma (MTC). Thyroid C-cells are known to express RET at high levels relative to most cell types; therefore, aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET, the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations have uncovered mutation of RAS family members and inactivation of Rb1 regulatory pathway as potential mediators of C-cell transformation. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation, will help in the development of novel molecular-targeted therapies. PMID- 26494388 TI - Pheochromocytomas in Multiple Endocrine Neoplasia Type 2. AB - Pheochromocytoma (PC) is a neuroendocrine tumor that originates from chromaffin cells of the adrenal medulla. The production of catecholamines, including epinephrine, norepinephrine and dopamine, may lead to haemodynamic instability. Over 30% of PCs are associated with germline mutations, including re-arranged in transfection (RET) mutations seen in multiple endocrine neoplasia type 2 (MEN2) syndromes. Around 40% of individuals with MEN2 develop PC, though it is rarely the presenting feature. Compared to sporadic PC, MEN2-associated PC is more likely to be epinephine secreting and demonstrate bilateral adrenal involvement, and is less likely to be malignant. The diagnosis of PC requires clinical suspicion and biochemical testing, followed by imaging studies. Novel nuclear medicine modalities, including FDG positron emission tomography (PET) and 68Ga DOTATATE PET have added to the conventional techniques of 123I metaiodobenzylguanindine (MIBG) scintigraphy, computer tomography and magnetic resonance imaging. Treatment of PC is surgical and requires peri-operative alpha and, frequently, beta blockade. Novel surgical techniques, such as adrenal sparing surgery and a laparoscopic approach, have decreased peri-operative morbidity. Surveillance for PC is life long, due to the risk of metastatic disease. PMID- 26494389 TI - Primary Hyperparathyroidism in MEN2 Syndromes. AB - One of the components of trethe classical form of MEN2 syndromes is primary hyperparathyroidism (PHP). It occurs in 20-30% of the typical MEN2A syndrome. The prevalence is more rare in gene carriers as these frequently have familial MTC only. PHP is diagnosed more frequently in association with the exon 11, codon 634 mutation of the ret gene-so there is phenotype/genotype correlation. The clinical manifestations of PHP in MEN2 are usually mild and the peak age of diagnosis after the 3rd decade. The treatment is surgical excision of the enlarged gland(s). Although there can be multigland disease in the parathyroids, it is frequently the case that both hyperplasia and adenoma may coexist, or even a single adenoma may be found during the investigation and finally during the operation. Patients with MEN2 syndromes should be screened for PHP with serum calcium measurements. The intensity of the screening should be higher in those carrying the ret mutations most frequently associated with this manifestation. PMID- 26494390 TI - Surgical Treatment of Medullary Thyroid Cancer. AB - Medullary thyroid cancer (MTC) can vary in tumor biology and progression. The most important indicator of distant metastases, determining clinical outcome, is lymph node metastasis to the neck and mediastinum. Surgical cure is within reach in node-negative tumors or node-positive tumors with fewer than 10 lymph node metastases. From a surgical point of view, compartment-oriented lymph node dissection, clearing gross, and occult metastases are important for locoregional tumor control. The discovery of missense germline mutations in the RET proto oncogene and the close genotype-phenotype correlation in hereditary MTC promoted the worldwide breakthrough of prophylactic thyroidectomy. The best approach to hereditary MTC affords the DNA-based/biochemical concept, which is geared at limiting prophylactic surgery to total thyroidectomy at minimal surgical morbidity before the tumor can spread beyond the thyroid capsule. To improve outcome, routine calcitonin screening in nodular thyroid disease and DNA-based screening of the offspring in RET families are effective interventions. PMID- 26494391 TI - Long-Term Follow-up in Medullary Thyroid Carcinoma. AB - After surgery, patients with medullary thyroid carcinoma (MTC) should be assessed regarding the presence of residual disease, the localization of metastases, and the identification of progressive disease. Postoperatively, patients with MTC are staged to separate those at low risk from those at high risk of recurrence. The TNM staging system is based on tumor size, extra-thyroidal invasion, nodal metastasis, and distant spread of cancer. In addition, the number of lymph-node metastases, the number of compartments involved, and the postoperative calcitonin (CTN) and carcinoembryonic antigen (CEA) levels should be documented. The postoperative normalization of the serum CTN level is associated with a favorable outcome. When patients have basal serum CTN levels less than 150 pg/ml after a thyroidectomy, any persistent or recurrent disease is nearly always confined to lymph nodes in the neck. When the postoperative serum CTN level exceeds 150 pg/ml, patients should be evaluated with imaging procedures, including computed tomography (CT) of the neck and chest, contrast-enhanced magnetic resonance imaging (MRI) and ultrasound (US) of the liver, bone scintigraphy, MRI of the bone, and positron emission tomography (PET)/CT. One can estimate the growth rate of MTC metastases by quantifying increases in tumor size over time from sequential imaging studies analyzed with response evaluation criteria in solid tumors (RECIST), and by determining the tumor marker doubling time from sequential measures of serum CTN or CEA levels over multiple time points. One of the main challenges remains to find effective adjuvant and palliative options for patients with metastatic disease. Patients with persistent or recurrent MTC localized to the neck following thyroidectomy are candidates for neck operations, depending on the tumor extension. Once metastases appear, the clinician must decide which patients require therapy. This requires a balance between the (often) slow rate of tumor progression, which is associated with a good quality of life, and the limited efficacy and potential toxicities of local and systemic therapies. Considering that metastatic MTC is incurable, the management goals are to provide loco-regional disease control, palliate symptoms of hormonal excess, such as diarrhea, palliate symptomatic metastases, like pain or bone fracture, and control metastases that threaten life, such as bronchial obstruction or spinal cord compression. This can be achieved with palliative surgery, external beam radiation therapy (EBRT), or systemic therapy with tyrosine kinase inhibitor (TKI). PMID- 26494392 TI - Use of Tyrosine Kinase Inhibitors for Treatment of Medullary Thyroid Carcinoma. AB - Two independent events--the identification of activating mutations of the RET proto-oncogene, a receptor tyrosine kinase, in medullary thyroid carcinoma, and the recognition that small organic molecules could bind to and inhibit phosphorylation of signaling molecules, thereby inactivating the pathway-led to the recognition that kinase inhibitors could be used to treat medullary thyroid carcinoma (MTC). The introduction of these compounds into clinical practice has transformed the treatment of metastatic MTC and provided insight into the mechanisms by which RET causes C-cell transformation. This chapter will review the progress in this field over the past 7 years. PMID- 26494393 TI - Introductory letter from the Guest Editors. PMID- 26494394 TI - Introduction of omega-3 Desaturase Obviously Changed the Fatty Acid Profile and Sterol Content of Schizochytrium sp. AB - omega-3 fatty acids play significant roles in brain development and cardiovascular disease prevention and have been widely used in food additives and the pharmaceutical industry. The aim of this study was to assess the feasibility of omega-3 desaturase for regulating fatty acid composition and sterol content in Schizochytrium sp. The exogenous omega-3 desaturase gene driven by ubiqutin promoter was introduced by 18S homologous sequence to the genome of Schizochytrium sp. Genetically modified strains had greater size and lower polar lipids than wild type strains. In addition, the introduction of omega-3 desaturase improved the omega-3/omega-6 ratio from 2.1 to 2.58 and converted 3% docosapentaenoic acid (DPA) to docosahexaenoic acid (DHA). Furthermore, squalene and sterol contents in lipid of the genetically modified strain reduced by 37.19 and 22.31%, respectively. The present study provided an advantageous genetically engineered Schizochytrium sp. for DHA production and effective metabolic engineering strategy for fatty acid producing microbes. PMID- 26494396 TI - The categories of cutaneous mosaicism: A proposed classification. AB - Mosaic disorders can most easily be studied in the skin. This article presents a comprehensive overview of the different forms of cutaneous mosaicism. Major categories are genomic versus epigenetic mosaicism and nonsegmental versus segmental mosaicism. The class of nonsegmental mosaics includes single point mosaicism as exemplified by solitary benign or malignant skin tumors; disseminated mosaicism as noted in autosomal dominant tumor syndromes such as neurofibromatosis 1; and patchy mosaicism without midline separation as found in giant melanocytic nevus. The class of segmental mosaics includes segmental manifestation of lethal genes surviving by mosaicism as noted in Proteus syndrome; type 1 segmental mosaicism of autosomal dominant skin disorders reflecting heterozygosity for a postzygotic new mutation; type 2 segmental mosaicism of autosomal dominant skin disorders reflecting loss of heterozygosity that occurred at an early developmental stage in a heterozygous embryo; and isolated or superimposed segmental mosaicism of common polygenic skin disorders such as psoriasis or atopic dermatitis. A particular form of genomic mosaicism is didymosis (twin spotting). Revertant mosaicism is recognizable as one or more areas of healthy skin in patients with epidermolysis bullosa or other serious genodermatoses. The category of epigenetic mosaicism includes several X-linked, male lethal disorders such as incontinentia pigmenti, and the patterns of lyonization as noted in X-linked non-lethal disorders such as hypohidrotic ectodermal dysplasia of the Christ-Siemens-Touraine type. An interesting field of future research will be the concept of epigenetic autosomal mosaicism that may explain some unusual cases of autosomal transmission of linear hypo- or hypermelanosis. PMID- 26494395 TI - Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome. AB - Sepsis is a common condition that is associated with significant morbidity, mortality and health-care cost. Pulmonary and non-pulmonary sepsis are common causes of the acute respiratory distress syndrome (ARDS). The mortality from ARDS remains high despite protective lung ventilation, and currently there are no specific pharmacotherapies to treat sepsis or ARDS. Sepsis and ARDS are characterised by activation of the inflammatory cascade. Although there is much focus on the study of the dysregulated inflammation and its suppression, the associated activation of the haemostatic system has been largely ignored until recently. There has been extensive interest in the role that platelet activation can have in the inflammatory response through induction, aggregation and activation of leucocytes and other platelets. Aspirin can modulate multiple pathogenic mechanisms implicated in the development of multiple organ dysfunction in sepsis and ARDS. This review will discuss the role of the platelet, the mechanisms of action of aspirin in sepsis and ARDS, and aspirin as a potential therapy in treating sepsis and ARDS. PMID- 26494397 TI - Apoptosis modulation by activin A and follistatin in human endometrial stromal cells. AB - Activin A is a growth factor that stimulates decidualization and is abundantly expressed in endometrial proliferative disorders. Nevertheless, whether it directly affects endometrial cell survival is still unknown. This study investigated the effects of activin A on total death and apoptosis rates and on tumor necrosis factor (TNF) release by human endometrial stromal cells (HESC). We performed a controlled prospective in vitro study using primary HESC cultures obtained from healthy reproductive age women (n = 11). Cells were treated with medium alone (control) or activin A (25 ng/mL) or activin A (25 ng/mL) and its antagonist follistatin (250 ng/mL). Apoptosis and total cell death were measured by flow cytometry, while TNF concentrations in culture media were quantified by ELISA. Activin A decreased the percentage of apoptotic/dead cells from 31% to 22% (p < 0.05, paired t-test) and reduced TNF levels in culture medium by 14%, but there was no linear correlation between TNF release and apoptotic rates. Both effects of activin A were reversed by follistatin. These findings indicate that activin A promotes HESC survival, possibly by a TNF-independent pathway. This mechanism may be critical to the actions of activin A upon stromal cell growth and differentiation in physiology and disease. PMID- 26494398 TI - Targeting cancer epigenetics: Linking basic biology to clinical medicine. AB - Recent studies provide compelling evidence that epigenetic dysregulation is involved in almost every step of tumor development and progression. Differences in tumor behavior, which ultimately reflects clinical outcome, can be explained by variations in gene expression patterns generated by epigenetic mechanisms, such as DNA methylation. Therefore, epigenetic abnormalities are considered potential biomarkers and therapeutic targets. DNA methylation is stable at certain specific loci in cancer cells and predominantly reflects the characteristic clinicopathological features. Thus, it is an ideal biomarker for cancer screening, classification and prognostic purposes. Epigenetic treatment for cancers is based on the pharmacologic targeting of various core transcriptional programs that sustains cancer cell identity. Therefore, targeting aberrant epigenetic modifiers may be effective for multiple processes compared with using a selective inhibitor of aberrant single signaling pathway. This review provides an overview of the epigenetic alterations in human cancers and discusses about novel therapeutic strategies targeting epigenetic alterations. PMID- 26494399 TI - Technological development of structural DNA/RNA-based RNAi systems and their applications. AB - RNA interference (RNAi)-based gene therapy has drawn tremendous attention due to its highly specific gene regulation by selective degradation of any target mRNA. There have been multiple reports regarding the development of various cationic materials for efficient siRNA delivery, however, many studies still suffer from the conventional delivery problems such as suboptimal transfection performance, a lack of tissue specificity, and potential cytotoxicity. Despite the huge therapeutic potential of siRNAs, conventional gene carriers have failed to guarantee successful gene silencing in vivo, thus not warranting clinical trials. The relatively short double-stranded structure of siRNAs has resulted in uncompromising delivery formulations, as well as low transfection efficiency, compared with the conventional nucleic acid drugs such as plasmid DNAs. Recent developments in structural siRNA and RNAi nanotechnology have enabled more refined and reliable in vivo gene silencing with multiple advantages over naked siRNAs. This review focuses on recent progress in the development of structural DNA/RNA-based RNAi systems and their potential therapeutic applications. In addition, an extensive list of prior reports on various RNAi systems is provided and categorized by their distinctive molecular characters. PMID- 26494400 TI - Comparative analysis of the growth and biological activity of a respiratory and atheroma isolate of Chlamydia pneumoniae reveals strain-dependent differences in inflammatory activity and innate immune evasion. AB - BACKGROUND: Chlamydia pneumoniae is a common human pathogen that is associated with upper and lower respiratory tract infections. It has also been suggested that C. pneumoniae infection can trigger or promote a number of chronic inflammatory conditions, including asthma and atherosclerosis. Several strains of C. pneumoniae have been isolated from humans and animals, and sequence data demonstrates marked genetic conservation, leaving unanswered the question as to why chronic inflammatory conditions may occur following some respiratory-acquired infections. METHODS: C. pneumoniae strains AR39 and AO3 were used in vitro to infect murine bone marrow derived macrophages and L929 fibroblasts, or in vivo to infect C57BL/6 mice via the intranasal route. RESULTS: We undertook a comparative study of a respiratory isolate, AR39, and an atheroma isolate, AO3, to determine if bacterial growth and host responses to infection varied between these two strains. We observed differential growth depending on the host cell type and the growth temperature; however both strains were capable of forming plaques in vitro. The host response to the respiratory isolate was found to be more inflammatory both in vitro, in terms of inflammatory cytokine induction, and in vivo, as measured by clinical response and lung inflammatory markers using a mouse model of respiratory infection. CONCLUSIONS: Our data demonstrates that a subset of C. pneumoniae strains is capable of evading host innate immune defenses during the acute respiratory infection. Further studies on the genetic basis for these differences on both the host and pathogen side could enhance our understanding how C. pneumoniae contributes to the development chronic inflammation at local and distant sites. PMID- 26494401 TI - A combinatorial alphabeta T cell receptor expressed by macrophages in the tumor microenvironment. AB - Recent evidence indicates the presence of macrophage subpopulations that express the TCRalphabeta in two major inflammatory diseases, tuberculosis and atherosclerosis. Inflammation is also a well-established attribute of cancer progression and macrophages are one of the major immune cells that infiltrate tumors. Here, we demonstrate that the macrophage-TCRalphabeta is expressed in the tumor microenvironment of human and murine malignancies. We identify TCRalphabeta+ macrophages in each case of four randomly selected distinct human tumor entities. In human tumor tissues, the TCRalphabeta expressed by macrophages in the tumor microenvironment is a combinatorial and individual-specific immune receptor. Furthermore, we routinely find TCRalphabeta+ macrophage subpopulations in experimental tumors (TS/A, mammary adenocarcinoma) which we induced both in normal mice and mice deficient in the macrophage receptor stabilin-1. Expression of the combinatorial murine tumor macrophage TCRalphabeta is individual-specific and independent of stabilin-1. These results demonstrate that TCRalphabeta expression is a characteristic feature of macrophages in the tumor microenvironment and identify an as yet unrecognized flexible element in the macrophage-based host response to tumors. PMID- 26494402 TI - Stenting for acute cerebral venous sinus thrombosis in the superior sagittal sinus. AB - Endovascular treatment for superior sagittal sinus (SSS) thrombosis is not always successful because of difficult access and long thrombus lesions. We report the first two cases of patients with acute cerebral venous sinus thrombosis at the SSS that was not recanalized by anticoagulation, mechanical thrombectomy, or thrombolysis, but was successfully treated by stent placement. Case 1 was a 37 year-old woman with bilateral subdural hematomas. Digital subtraction angiography showed obstruction of the sinus from the SSS to the right transverse sinus. Recanalization was achieved by selective thrombolysis using urokinase followed by balloon angioplasty, but re-occlusion occurred on the next day of treatment. Repeated endovascular treatment including balloon angioplasty, thrombus aspiration and thrombolysis using recombinant tissue plasminogen activator failed to achieve recanalization. We thus placed intracranial stents in the SSS, which did achieve recanalization. Case 2 was a 69-year-old woman with a small infarction in the left parietal lobe. Digital subtraction angiography showed sinus obliteration from the SSS to the bilateral transverse sinuses. Recanalization was not achieved by balloon angioplasty, thrombus aspiration and selective thrombolysis. We thus placed intracranial stents in the SSS, which did achieve recanalization. Postoperative course was uneventful in both cases and venous sinus patency was confirmed by venography >1.5 years after treatment. When conventional endovascular strategies have been unsuccessful, placement of intracranial stents, which can easily gain access to the distal part of the SSS as compared with carotid stents, may be a useful treatment option for the acute sinus thrombosis in this region. PMID- 26494403 TI - Dual flow diversion stents for aneurysm treatment in a partial unfused basilar artery. AB - Unfused basilar arteries, frequently but erroneously referred to as 'fenestrations', are not uncommonly associated with aneurysms. The difficulty in treating these aneurysms lie in the fact that they are often wide necked and frequently incorporate both channels of the unfused segment, with varying calibres of the channels, necessitating technically challenging treatment strategies. It is important to preserve both channels because of the potential presence of perforating arteries originating from these segments. There are numerous case reports of such aneurysms being treated by coils alone, coiling with balloon assistance and stent-assisted coiling in configurations such as 'X', 'double barrel' or waffle cone. We present an exemplary case, in which an aneurysm on a partial unfused basilar segment was treated with parallel flow diverters with an excellent result on follow-up imaging. PMID- 26494404 TI - Anchor technique: Use of stent retrievers as an anchor to advance thrombectomy catheters in internal carotid artery occlusions. AB - In three recent cases of acute complete internal artery occlusions, we used stent retriever deployed through the mechanical aspiration/distal access catheters to achieve recanalization. In all cases the stent retriever was used as an anchor and supplemented mechanical thrombectomy. This report describes the technical details of the procedure and presents an alternative plan of action in difficult cases when standard thrombectomy techniques do not work. PMID- 26494405 TI - Manual aspiration thrombectomy using the Penumbra catheter in patients with acute M1 occlusion: A single-center study. AB - PURPOSE: The efficacy and safety of aspiration thrombectomy using Penumbra in acute occlusion of intracranial artery have been proved in many previous studies. Our study aimed to retrospectively assess the efficacy and safety of a manual aspiration thrombectomy using Penumbra in patients with M1 occlusion. MATERIALS AND METHODS: We conducted a retrospective review of 70 patients who underwent manual aspiration thrombectomy using Penumbra catheters for treatment of M1 occlusion between January 2012 and December 2014. We evaluated immediate angiographic results and clinical outcomes through review of patient electronic medical records. RESULTS: Male was the dominant sex in this study (M:F = 38:32) and median age was 72 (age range, 36-91). The rate of successful recanalization (TICI grade >=2 b) was 91.4% (64/70). The successful recanalization rate by single Penumbra was 82.9% (58/70). Six patients were treated in combination with Solitaire stent. Median NIHSS score was 11 (range, 4-20) at admission and was 3 (range 0-23) at discharge. Favorable clinical outcomes (mRS score at three months <=2) were seen in 42 patients (60%). Two patients were observed to have subarachnoid hemorrhage after the procedure. Another two patients died related to massive symptomatic hemorrhage, brain edema and herniation in the hospital. CONCLUSION: Manual aspiration thrombectomy appears to be safe and is capable of achieving a high rate of successful recanalization and favorable clinical outcomes in patients with M1 occlusion. PMID- 26494406 TI - Endovascular management of a carotid aneurysm into the sphenoid sinus presenting with epistaxis. AB - Non-traumatic cavernous internal carotid artery (ICA) aneurysms are rare, and favour the occurrence of massive recurrent epistaxis, which is associated with a high mortality rate. We report the case of a 67-year-old woman presenting a ruptured ICA aneurysm extending into the sphenoid sinus, revealed by epistaxis. Selective coil embolization of the aneurysm was performed. Flow-diverter stents were deployed in order to utterly exclude the aneurysm and prevent revascularization. Anti-platelet treatment was provided to lower the risk of in stent thrombosis. A left frontal hematoma associated with a subarachnoid haemorrhage occurred at day 2. Outcome was favourable with no neurological sequelae, and no clinical recurrence of epistaxis occurred. A 4 months follow-up digital subtraction angiography showed a complete exclusion of the aneurysm. In addition, a magnetic resonance cerebral angiography at 16 months showed stable results. Thus, this two-stage endovascular procedure has proven its effectiveness in preventing epistaxis recurrence while preserving the ICA patency. PMID- 26494407 TI - Normal pio-dural arterial connections. AB - The arterial blood supply to the dura mater is rich, complex and is derived from both the internal and external carotid systems. Endovascular management of a variety of intracranial diseases necessitates a thorough understanding of the dural arterial network. In this article we review the normal contributions of the pial arteries to the blood supply of the dura mater and discuss some aspects of its role in the supply of dural arteriovenous shunts (DAVS). PMID- 26494408 TI - Divalent cation-responsive myotonia and muscle paralysis in skeletal muscle sodium channelopathy. AB - We report a patient with paramyotonia congenita/hyperkalemic periodic paralysis due to Nav1.4 I693T mutation who had worsening of myotonia and muscle weakness in the setting of hypomagnesemia and hypocalcemia with marked recovery after magnesium administration. Computer simulations of the effects of the I693T mutation were introduced in the muscle fiber model by both hyperpolarizing shifts in the Nav1.4 channel activation and a faster recovery from slow channel inactivation. A further shift in the Nav1.4 channel activation in the hyperpolarizing direction as expected with low divalent cations resulted in myotonia that progressed to membrane inexcitability. Shifting the channel activation in the depolarizing direction as would be anticipated from magnesium supplementation abolished the myotonia. These observations provide clinical and biophysical evidence that the muscle symptoms in sodium channelopathy are sensitive to divalent cations. Exploration of the role of magnesium administration in therapy or prophylaxis is warranted with a randomized clinical trial. PMID- 26494409 TI - Dropped-head in recessive oculopharyngeal muscular dystrophy. AB - A 69-year-old woman presented a dropped head, caused by severe neck extensor weakness that had started two years before. She had also developed a mild degree of dysphagia, rhinolalia, eyelid ptosis and proximal limb weakness during the last months. EMG revealed myopathic changes. Muscle MRI detected fatty infiltration in the posterior neck muscles and tongue. Muscle biopsy revealed fiber size variations, sporadic rimmed vacuoles, small scattered angulated fibers and a patchy myofibrillar network. Genetic analysis revealed homozygous (GCN)11 expansions in the PABPN1 gene that were consistent with recessive oculopharyngeal muscular dystrophy (OPMD). There are a few reports of the recessive form, which has a later disease onset with milder symptoms and higher clinical variability than the typical dominantly inherited form. This patient, who is the first Italian and the eighth worldwide reported case of recessive OPMD, is also the first case of OPMD with dropped-head syndrome, which thus expands the clinical phenotype of recessive OPMD. PMID- 26494410 TI - Positive effects of bisphosphonates on bone and muscle in a mouse model of Duchenne muscular dystrophy. AB - Patients with Duchenne muscular dystrophy are at increased risk of decreased bone mineral density and bone fracture as a result of inactivity. To determine if antiresorptive bisphosphonates could improve bone quality and their effects on muscle we studied the Mdx mouse, treated with pamidronate during peak bone growth at 5 and 6 weeks of age, and examined the outcome at 13 weeks of age. Pamidronate increased cortical bone architecture and strength in femurs with increased resistance to fracture. While overall long bone growth was not affected by pamidronate, there was significant inhibition of remodeling in metaphyseal trabecular bone with evidence of residual calcified cartilage. Pamidronate treatment had positive effects on skeletal muscle in the Mdx mice with decreased serum and muscle creatine kinase and evidence of improved muscle histology and grip strength. PMID- 26494411 TI - Randomized phase II trial comparing twice daily hyperfractionated with once daily hypofractionated thoracic radiotherapy in limited disease small cell lung cancer. AB - BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy (TRT) is recommended for limited disease small cell lung cancer (LD SCLC). Twice daily TRT is well documented, but not universally implemented - probably mainly due to inconvenience and concerns about toxicity. A schedule of three-week hypofractionated TRT is a commonly used alternative. This is the first randomized trial comparing twice daily and hypofractionated TRT in LD SCLC. MATERIAL AND METHODS: Patients received four courses of cisplatin/etoposide (PE) and were randomized to TRT of 42 Gy in 15 fractions (once daily, OD) or 45 Gy in 30 fractions (twice daily, BID) between the second and third PE course. Good responders received prophylactic cranial irradiation of 30 Gy in 15 fractions. RESULTS: 157 patients were enrolled between May 2005 and January 2011 (OD: n = 84, BID: n = 73). Median age was 63 years, 52% were men, 84% had performance status 0-1, 72% had stage III disease and 11% non-malignant pleural effusion. The treatment arms were well balanced. The response rates were similar (OD: 92%, BID: 88%; p = 0.41), but more BID patients achieved a complete response (OD: 13%, BID: 33%; p = 0.003). There was no difference in one-year progression-free survival (PFS) (OD: 45%, BID: 49%; p = 0.61) or median PFS (OD: 10.2 months, BID: 11.4 months; p = 0.93). The median overall survival in the BID arm was 6.3 months longer (OD: 18.8 months, BID: 25.1 months; p = 0.61). There were no differences in grade 3-4 esophagitis (OD: 31%, BID: 33%, p = 0.80) or pneumonitis (OD: 2%, BID: 3%, p = 1.0). Patients on the BID arm reported slightly more dysphagia at the end of the TRT. CONCLUSION: There was no difference in severe toxicity between the two TRT schedules. The twice daily schedule resulted in significantly more complete responses and a numerically longer median overall survival, but no firm conclusions about efficacy could be drawn from this phase II trial. PMID- 26494412 TI - Patterned Plasmonic Nanoparticle Arrays for Microfluidic and Multiplexed Biological Assays. AB - For applications ranging from medical diagnostics and drug screening to chemical and biological warfare detection, inexpensive, rapid-readout, portable devices are required. Localized surface plasmon resonance (LSPR) technologies show substantial promise toward meeting these goals, but the generation of portable, multiplexed and/or microfluidic devices incorporating sensitive nanoparticle arrays is only in its infancy. Herein, we have combined photolithography with Hole Mask Colloidal lithography to pattern uniform nanoparticle arrays for both microfluidic and multiplexed devices. The first proof-of-concept study is carried out with 5- and 7-channel microfluidic devices to acquire one-shot binding curves and protein binding kinetic data. The second proof-of-concept study involved the fabrication of a 96-spot plate that can be inserted into a standard plate reader for the multiplexed detection of protein binding. This versatile fabrication technique should prove useful in next generation chips for bioassays and genetic screening. PMID- 26494414 TI - Accelerated partial breast irradiation: the new standard? PMID- 26494413 TI - Targeting truncated RXRalpha for cancer therapy. AB - Retinoid X receptor-alpha (RXRalpha), a unique member of the nuclear receptor superfamily, is a well-established drug target, representing one of the most important targets for pharmacologic interventions and therapeutic applications for cancer. However, how RXRalpha regulates cancer cell growth and how RXRalpha modulators suppress tumorigenesis are poorly understood. Altered expression and aberrant function of RXRalpha are implicated in the development of cancer. Previously, several studies had demonstrated the presence of N-terminally truncated RXRalpha (tRXRalpha) proteins resulted from limited proteolysis of RXRalpha in tumor cells. Recently, we discovered that overexpression of tRXRalpha can promote tumor growth by interacting with tumor necrosis factor-alpha-induced phosphoinositide 3-kinase and NF-kappaB signal transduction pathways. We also identified nonsteroidal anti-inflammatory drug Sulindac and analogs as effective inhibitors of tRXRalpha activities via a unique binding mechanism. This review discusses the emerging roles of tRXRalpha and modulators in the regulation of cancer cell survival and death as well as inflammation and our recent understanding of tRXRalpha regulation by targeting the alternate binding sites on its surface. PMID- 26494415 TI - 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. AB - BACKGROUND: In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. METHODS: We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1.44% (95% CI 0.51-2.38) with APBI and 0.92% (0.12-1.73) with whole-breast irradiation (difference 0.52%, 95% CI -0.72 to 1.75; p=0.42). No grade 4 late side-effects were reported. The 5-year risk of grade 2-3 late side-effects to the skin was 3.2% with APBI versus 5.7% with whole-breast irradiation (p=0.08), and 5-year risk of grade 2-3 subcutaneous tissue late side-effects was 7.6% versus 6.3% (p=0.53). The risk of severe (grade 3) fibrosis at 5 years was 0.2% with whole breast irradiation and 0% with APBI (p=0.46). INTERPRETATION: The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease free survival, and overall survival. FUNDING: German Cancer Aid. PMID- 26494417 TI - Exploring the association between women's access to economic resources and intimate partner violence in Dar es Salaam and Mbeya, Tanzania. AB - The relationship between women's access to economic resources, e.g. employment or access to micro-credit, and experience of intimate partner violence is complex. Empirical evidence documents that in some settings women's employment is associated with higher risk of partner violence but in other settings with lower risk. Evidence also shows that these conflicting associations exist not only between countries but also within different country settings. Using two population-based data sets gathered in 2002 in contrasting Tanzania settings-Dar es Salaam and Mbeya-, we used multivariate logistic regression to examine the relationship between women's access to economic resources and partner violence. Two indicators of economic resources were examined: whether women earned money and whether women owned a business either with someone or exclusively. In Dar es Salaam we found evidence of a higher risk association among women who earned money and who owned a business exclusively by themselves and a lower risk association among women who owned a business with someone. We found no relationship between either indicator of economic resources and partner violence in Mbeya. Other factors were similarly associated with partner violence in both settings and the strongest associations found were related to the respondents' partners: refusal to give money; alcohol use and relationships with other women. The findings support the assertion that women's access to economic resources operate differently in different country settings, thus highlighting the need for targeted prevention efforts that are relevant for the context. PMID- 26494416 TI - High protein and cholesterol intakes associated with emergence of glucose intolerance in a low-risk Canadian Inuit population. AB - OBJECTIVE: The rate of type 2 diabetes mellitus among Inuit is 12.2 % in individuals over 50 years of age, similar to the Canadian prevalence. Given marked dietary transitions in the Arctic, we evaluated the dietary and other correlates of not previously diagnosed glucose intolerance, defined as type 2 diabetes mellitus, impaired fasting glucose or impaired glucose tolerance. DESIGN: Cross-sectional analyses were limited to adults with a completed 2 h oral glucose tolerance test and without pre-existing diabetes. Anthropometric assessments, health and medication usage questionnaires and a 24 h dietary recall were administered. SETTING: Canadian International Polar Year Inuit Health Survey (2007-2008). SUBJECTS: Inuit adults (n 777). RESULTS: Glucose intolerance was associated with older age and adiposity. Percentage of energy from protein above the Acceptable Macronutrient Distribution Range of 35 %, compared with intake within the range, was associated with increased odds of glucose intolerance (OR=1.98; 95 % CI 1.09, 3.61) in multivariable analyses. Further, cholesterol intake in the highest three quartiles combined (median exposures of 207, 416 and 778 mg/d, respectively) compared with the lowest quartile (median intake of 81 mg/d) was associated with glucose intolerance (OR=2.15; 95 % CI 1.23, 3.78) in multivariable analyses. Past-day traditional food consumption was borderline protective of glucose intolerance (P=0.054) and high fibre intake was not significantly protective (P=0.08). CONCLUSIONS: The results contribute to the existing literature on high protein and cholesterol intakes as they may relate to diabetes risk. PMID- 26494418 TI - Intracardiac Doppler Echocardiography for Monitoring of Pulmonary Artery Pressures in High-Risk Patients Undergoing Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Uncontrolled pulmonary hypertension may cause worse outcomes after transcatheter aortic valve replacement (TAVR), while hemodynamic monitoring is desirable for risk control. Pulmonary artery pressure (PAP) readings obtained by intracardiac Doppler echocardiography were evaluated. METHODS: In 114 patients with symptomatic aortic stenosis and median Society of Thoracic Surgeons scores of 10.5% (interquartile range, 7.7%-15.0%), transfemoral and transapical TAVR was guided by intracardiac Doppler echocardiography. The continuous-wave Doppler beam interrogated the jet of tricuspid regurgitation from the "home view" position. Systolic PAP (PAPs) was estimated as the sum of the pressure gradient derived from the maximum transtricuspid regurgitation jet velocity and the central venous pressure. Mean PAP (PAPm) was calculated by the mean gradient method (1) and the Chemla formula (2). Measurements were obtained immediately before and after TAVR. RESULTS: Pre- and postinterventional readings showed marginal pressure underestimation in comparison with measurements derived from right-heart catheterization: PAPs, -2.7 (95% CI, -3.3 to 2.1) and -1.4 (95% CI, -1.9 to 0.9); PAPm by the mean gradient method, -1.9 (95% CI, -2.2 to -1.6) and -0.1 (95% CI, -0.4 to 0.2). Agreement (95% limits) for PAPs was -8.6 to 3.2 and -6.8 to 4.0; agreement for PAPm by the mean gradient method was -5.4 to 1.6 and -3.4 to 3.2. The repeatability coefficient (95% limits of agreement) for PAPs was excellent: 3.4 (-4.2 to 2.5) and 5.5 (-5.3 to 5.8); repeatability for PAPm was higher by the mean gradient method than by the Chemla method. In >= 85% of patients with pulmonary hypertension, PAPm improved after valve deployment. CONCLUSIONS: Intracardiac Doppler echocardiography-derived monitoring of PAP by the mean gradient method is accurate and well applicable to high-risk TAVR candidates for intraprocedural risk control. PMID- 26494420 TI - Virtual screening, docking, and dynamics of potential new inhibitors of dihydrofolate reductase from Yersinia pestis. AB - In the present work, we propose to design drugs that target the enzyme dihydrofolate redutase (DHFR) as a means of a novel drug therapy against plague. Potential inhibitors of DHFR from Yersinia pestis (YpDHFR) were selected by virtual screening and subjected to docking, molecular dynamics (MD) simulations, and Poisson-Boltzmann surface area method, in order to evaluate their interactions in the active sites of YpDHFR and human DHFR (HssDHFR). The results suggested selectivity for three compounds that were further used to propose the structures of six new potential selective inhibitors for YpDHFR. PMID- 26494419 TI - MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. AB - The presentation of protein antigens on the cell surface by major histocompatibility complex (MHC) molecules coordinates vertebrate adaptive immune responses, thereby mediating susceptibility to a variety of autoimmune and infectious diseases. The composition of symbiotic microbial communities (the microbiota) is influenced by host immunity and can have a profound impact on host physiology. Here we use an MHC congenic mouse model to test the hypothesis that genetic variation at MHC genes among individuals mediates susceptibility to disease by controlling microbiota composition. We find that MHC genotype significantly influences antibody responses against commensals in the gut, and that these responses are correlated with the establishment of unique microbial communities. Transplantation experiments in germfree mice indicate that MHC mediated differences in microbiota composition are sufficient to explain susceptibility to enteric infection. Our findings indicate that MHC polymorphisms contribute to defining an individual's unique microbial fingerprint that influences health. PMID- 26494421 TI - Development and feasibility of a personalized, interactive risk calculator for knee osteoarthritis. AB - BACKGROUND: The incidence of knee osteoarthritis (OA) is rising. While several risk factors have been associated with the development of knee OA, this information is not readily accessible to those at risk for osteoarthritis. Risk calculators have been developed for several prevalent chronic conditions but not for OA. Using published evidence on established risk factors, we developed an interactive, personalized knee OA risk calculator (OA Risk C) and conducted a pilot study to evaluate its acceptability and feasibility. METHODS: We used the Osteoarthritis Policy (OAPol) Model, a validated, state-transition simulation of the natural history and management of OA, to generate data for OA Risk C. Risk estimates for calculator users were based on a set of demographic and clinical factors (age, sex, race/ethnicity, obesity) and select risk factors (family history of knee OA, occupational exposure, and history of knee injury). OA Risk C presents personalized risk of knee OA in several ways to maximize understanding among a wide range of users. We conducted a study of 45 subjects in a primary care setting to establish the feasibility and acceptability of the OA risk calculator. Pilot study participants were asked several questions regarding ease of use, clarity of presentation, and clarity of the graphical representation of their risk. These questions used a five-level agreement scale ranging from strongly disagree to strongly agree. RESULTS: OA Risk C depicts information about users' risk of symptomatic knee OA in 5 year intervals. Study participants estimated their lifetime risk at 38 %, while their actual lifetime risk, as estimated by OA Risk C, was 25 %. Eighty-four percent of pilot study participants reported that OA Risk C was easy to understand, and 89 % agreed that the graphs depicting their risk were clear and comprehensible. CONCLUSIONS: We have developed a personalized, computer-based OA risk calculator that is easy to use. OA Risk C may be utilized to estimate individuals' knee OA risk and to deliver educational and behavioral interventions focused on osteoarthritis risk reduction. PMID- 26494423 TI - Global burden of COPD. AB - It is estimated that the world population will reach a record 7.3 billion in 2015, and the high burden of chronic conditions associated with ageing and smoking will increase further. Respiratory diseases in general receive little attention and funding in comparison with other major causes of global morbidity and mortality. In particular, chronic obstructive pulmonary disease (COPD) has been a major public health problem and will remain a challenge for clinicians within the 21st century. Worldwide, COPD is in the spotlight, since its high prevalence, morbidity and mortality create formidable challenges for health-care systems. This review emphasizes the magnitude of the COPD problem from a clinician's standpoint by drawing extensively from the new findings of the Global Burden of Disease study. Updated, distilled information on the population distribution of COPD is useful for the clinician to help provide an appreciation of the relative impact of COPD in daily practice compared with other chronic conditions, and to allocate minimum resources in anticipation of future needs in care. Despite recent trends in reduction of COPD standardized mortality rates and some recent successes in anti-smoking efforts in a number of Western countries, the overarching demographic impact of ageing in an ever-expanding world population, joined with other factors such as high rates of smoking and air pollution in Asia, will ensure that COPD will continue to pose an ever-increasing problem well into the 21st century. PMID- 26494422 TI - Evaluation of a Postoperative Pain-Like State on Motivated Behavior in Rats: Effects of Plantar Incision on Progressive-Ratio Food-Maintained Responding. AB - There has been recent interest in characterizing the effects of pain-like states on motivated behaviors in order to quantify how pain modulates goal-directed behavior and the persistence of that behavior. The current set of experiments assessed the effects of an incisional postoperative pain manipulation on food maintained responding under a progressive-ratio (PR) operant schedule. Independent variables included injury state (plantar incision or anesthesia control) and reinforcer type (grain pellet or sugar pellet); dependent variables were tactile sensory thresholds and response breakpoint. Once responding stabilized on the PR schedule, separate groups of rats received a single ventral hind paw incision or anesthesia (control condition). Incision significantly reduced breakpoints in rats responding for grain, but not sugar. In rats responding for sugar, tactile hypersensitivity recovered within 24 hr, indicating a faster recovery of incision-induced tactile hypersensitivity compared to rats responding for grain, which demonstrated recovery at PD2. The NSAID analgesic, diclofenac (5.6 mg/kg) completely restored incision-depressed PR operant responding and tactile sensitivity at 3 hr following incision. The PR schedule differentiated between sucrose and grain, suggesting that relative reinforcing efficacy may be an important determinant in detecting pain-induced changes in motivated behavior. PMID- 26494424 TI - Prognostic factors of regression and relapse of complex atypical hyperplasia and well-differentiated endometrioid carcinoma with conservative treatment. AB - OBJECTIVE: To evaluate possible prognostic factors regarding regression and relapse of complex atypical hyperplasia (CAH) and well-differentiated endometrioid adenocarcinoma (WDC) treated with conservative treatment. METHODS: The retrospective study reviewed clinicopathologic, treatment, regression and relapse data from patients diagnosed with CAH or WDC who were treated with conservative treatment at 4 institutions. Potential factor evaluation was performed. SPSS 16 was used for statistical analyses. RESULTS: Eighty-eight patients were included (51 had WDC, and 37 had CAH). Regression was evaluated in 88 patients, with a median follow-up of 61 (range 15-95) months. Seventy-seven (87.5%) patients regressed, and 11 (12.5%) had persistent or progressive disease. Univariate and multivariate analyses showed no factors associated with regression. Relapse was evaluated in 71 patients, with median follow-up of 54 (range 8-86) months. Twenty-five/71 (35.2%) patients experienced relapse. On univariate analysis, body mass index (BMI) 30 or higher (p=0.001), WCD at initial biopsy (p=0.017) and positive expression of post-treatment ki67 (p=0.033) were associated to a higher relapse probability. However, only BMI 30 or higher was significant on multivariate analysis (p=0.012). The Kaplan-Meier analysis revealed a higher relapse probability in the patients with BMI 30 or higher (p=0.001). CONCLUSION: Obesity seems to be a risk factor for relapse of CAH or WDC with conservative treatment. PMID- 26494426 TI - The scenario approach for countries considering the addition of oral cholera vaccination in cholera preparedness and control plans. AB - Oral cholera vaccination could be deployed in a diverse range of situations from cholera-endemic areas and locations of humanitarian crises, but no clear consensus exists. The supply of licensed, WHO-prequalified cholera vaccines is not sufficient to meet endemic and epidemic needs worldwide and so prioritisation is needed. We have developed a scenario approach to systematically classify situations in which oral cholera vaccination might be useful. Our scenario approach distinguishes between five types of cholera epidemiology based on experiences from around the world and provides evidence that we hope will spur the development of detailed guidelines on how and where oral cholera vaccines could, and should, be most rationally deployed. PMID- 26494425 TI - In vitro and in vivo metabolism of N-adamantyl substituted urea-based soluble epoxide hydrolase inhibitors. AB - N,N'-disubstituted urea-based soluble epoxide hydrolase (sEH) inhibitors are promising therapeutics for hypertension, inflammation, and pain in multiple animal models. The drug absorption and pharmacological efficacy of these inhibitors have been reported extensively. However, the drug metabolism of these inhibitors is not well described. Here we reported the metabolic profile and associated biochemical studies of an N-adamantyl urea-based sEH inhibitor 1 adamantan-1-yl-3-(5-(2-(2-ethoxyethoxy)ethoxy)pentyl)urea (AEPU) in vitro and in vivo. The metabolites of AEPU were identified by interpretation of liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and/or NMR. In vitro, AEPU had three major positions for phase I metabolism including oxidations on the adamantyl moiety, urea nitrogen atoms, and cleavage of the polyethylene glycol chain. In a rodent model, the metabolites from the hydroxylation on the adamantyl group and nitrogen atom were existed in blood while the metabolites from cleavage of polyethylene glycol chain were not found in urine. The major metabolite found in rodent urine was 3-(3 adamantyl-ureido)-propanoic acid, a presumably from cleavage and oxidation of the polyethylene glycol moiety. All the metabolites found were active but less potent than AEPU at inhibiting human sEH. Furthermore, cytochrome P450 (CYP) 3A4 was found to be a major enzyme mediating AEPU metabolism. In conclusion, the metabolism of AEPU resulted from oxidation by CYP could be shared with other N adamantyl-urea-based compounds. These findings suggest possible therapeutic roles for AEPU and new strategies for drug design in this series of possible drugs. PMID- 26494427 TI - Budd-Chiari syndrome: investigation, treatment and outcomes. AB - Budd-Chiari syndrome is a rare disorder characterised by hepatic venous outflow obstruction. It affects 1.4 per million people, and presentation depends upon the extent and rapidity of hepatic vein occlusion. An underlying myeloproliferative neoplasm is present in 50% of cases with other causes including infection and malignancy. Common symptoms are abdominal pain, hepatomegaly and ascites; however, up to 20% of cases are asymptomatic, indicating a chronic onset of hepatic venous obstruction and the formation of large hepatic vein collaterals. Doppler ultrasonography usually confirms diagnosis with cross-sectional imaging used for complex cases and to allow temporal comparison. Myeloproliferative neoplasms should be tested for even if a clear causative factor has been identified. Management focuses on anticoagulation with low-molecular-weight heparin and warfarin, with the new oral anticoagulants offering an exciting prospect for the future, but their current effectiveness in Budd-Chiari syndrome is unknown. A third of patients require further intervention in addition to anticoagulation, commonly due to deteriorating liver function or patients identified as having a poorer prognosis. Prognostic scoring systems help guide treatment, but management is complex and patients should be referred to a specialist liver centre. Recent studies have shown comparable procedure-related complications and long-term survival in patients who undergo transjugular intrahepatic portosystemic shunting and liver transplantation in Budd-Chiari syndrome compared with other liver disease aetiologies. Also, the optimal timing of these interventions and which patients benefit from liver transplantation instead of portosystemic shunting remains to be answered. PMID- 26494428 TI - Amino Acid-Porphyrin Conjugates: Synthesis and Study of their Photophysical and Metal Ion Recognition Properties. AB - Synthesis, photophysical and metal ion recognition properties of a series of amino acid-linked free-base and Zn-porphyrin derivatives (5-9) are reported. These porphyrin derivatives showed favorable photophysical properties including high molar extinction coefficients (>1 * 10(5) m(-1) cm(-1) for the Soret band), quantum yields of triplet excited states (63-94%) and singlet oxygen generation efficiencies (59-91%). Particularly, the Zn-porphyrin derivatives, 6 and 9 showed higher molar extinction coefficients, decreased fluorescence quantum yields, and higher triplet and singlet oxygen quantum yields compared to the corresponding free-base porphyrin derivatives. Further, the study of their interactions with various metal ions indicated that the proline-conjugated Zn-porphyrins (6 and 9) showed high selectivity toward Cu(2+) ions and signaled the recognition through changes in fluorescence intensity. Our results provide insights on the role of nature of amino acid and metallation in the design of the porphyrin systems for application as probes and sensitizers. PMID- 26494429 TI - Diversity and distribution of fungal communities in the marine sediments of Kongsfjorden, Svalbard (High Arctic). AB - This study assessed the diversity and distribution of fungal communities in eight marine sediments of Kongsfjorden (Svalbard, High Arctic) using 454 pyrosequencing with fungal-specific primers targeting the internal transcribed spacer (ITS) region of the ribosomal rRNA gene. Sedimentary fungal communities showed high diversity with 42,219 reads belonging to 113 operational taxonomic units (OTUs). Of these OTUs, 62 belonged to the Ascomycota, 26 to Basidiomycota, 2 to Chytridiomycota, 1 to Zygomycota, 1 to Glomeromycota, and 21 to unknown fungi. The major known orders included Hypocreales and Saccharomycetales. The common fungal genera were Pichia, Fusarium, Alternaria, and Malassezia. Interestingly, most fungi occurring in these Arctic sediments may originate from the terrestrial habitats and different basins in Kongsfjorden (i.e., inner basin, central basin, and outer basin) harbor different sedimentary fungal communities. These results suggest the existence of diverse fungal communities in the Arctic marine sediments, which may serve as a useful community model for further ecological and evolutionary study of fungi in the Arctic. PMID- 26494430 TI - Chronic Activation of the Renin-Angiotensin System Induces Lung Fibrosis. AB - Pulmonary fibrosis is a serious lung disorder that can lead to respiratory failure. Here we show that transgenic mice expressing active renin from the liver (RenTgMK) developed progressive pulmonary fibrosis leading to impaired pulmonary function. Histological analyses revealed a marked increase in extracellular matrix (ECM) deposition and decrease in alveolar size in the lungs of RenTgMK mice compared to wild-type (WT) littermates, accompanied with increased expression of ECM proteins and fibrogenic factors. The increase in lung fibrosis led to a substantial decrease in respiratory system compliance. Two-week treatment with aliskiren (renin inhibitor) or losartan (AT1 antagonist) ameliorated pulmonary ECM deposition, blocked the induction of ECM proteins and fibrogenic factors and improved respiratory compliance in RenTgMK mice, confirming a critical role of the renin-Ang II-AT1 cascade in promoting pulmonary fibrogenesis. However, when RenTgMK mice were treated with hydralazine (a smooth muscle relaxant), the blood pressure was normalized but the lung fibrotic abnormalities, fibrogenic gene induction and pulmonary elasticity were not corrected. Moreover, intratracheal instillation of lipopolysaccharide induced more severe lung injury in RenTgMK mice compared to WT littermates. These observations demonstrate that the renin-angiotensin system is a key mediator of lung fibrosis, and its pro-fibrotic effect is independent of blood pressure. PMID- 26494431 TI - Trajectories of alcohol use and association with symptoms of depression from early to late adolescence: The Norwegian Longitudinal Health Behaviour Study. AB - INTRODUCTION AND AIMS: Adolescence is a period in which many have an onset of alcohol use, but there is much heterogeneity in the individual development of alcohol use. Further, there is a general increase in depressive symptoms from early to late adolescence, but less is known about how different alcohol habit trajectories are associated with symptoms of depression. The aims of the present study were: to identify trajectories of alcohol consumption and drinking to intoxication during adolescence (age 13-18 years); and examine to what extent the different trajectories of alcohol use were associated with symptoms of depression over the same age span, from early to late adolescence. METHODS: Data from the Norwegian Longitudinal Health Behaviour Study were employed. Latent class growth analyses were employed to identify different trajectories of both alcohol consumption and drinking to intoxication. The resulting trajectories for each participant were used to estimate the gender-adjusted association between different development of alcohol use and symptoms of depression. RESULTS: Four trajectories of both alcohol consumption and drinking to intoxication were identified. The trajectories with an early onset of alcohol consumption or drinking to intoxication were associated with higher levels of depressive symptoms compared with late onset or stable low use trajectories. CONCLUSIONS: The findings from the present study suggest that early onset developmental trajectories of alcohol use are associated with depression. Therefore, broad assessment and interventions targeting both alcohol and depression may be indicated among early onset alcohol users, especially if they report increasing levels of consumption. [Skogen JC, Knudsen AK, Hysing M, Wold B, Sivertsen B. Trajectories of alcohol use and association with symptoms of depression from early to late adolescence: The Norwegian Longitudinal Health Behaviour Study. Drug Alcohol Rev 2016;35:307-316]. PMID- 26494432 TI - Italian legumes: effect of sourdough fermentation on lunasin-like polypeptides. AB - BACKGROUND: There is an increasing interest toward the use of legumes in food industry, mainly due to the quality of their protein fraction. Many legumes are cultivated and consumed around the world, but few data is available regarding the chemical or technological characteristics, and especially on their suitability to be fermented. Nevertheless, sourdough fermentation with selected lactic acid bacteria has been recognized as the most efficient tool to improve some nutritional and functional properties. This study investigated the presence of lunasin-like polypeptides in nineteen traditional Italian legumes, exploiting the potential of the fermentation with selected lactic acid bacteria to increase the native concentration. An integrated approach based on chemical, immunological and ex vivo (human adenocarcinoma Caco-2 cell cultures) analyses was used to show the physiological potential of the lunasin-like polypeptides. RESULTS: Italian legume varieties, belonging to Phaseulus vulgaris, Cicer arietinum, Lathyrus sativus, Lens culinaris and Pisum sativum species, were milled and flours were chemically characterized and subjected to sourdough fermentation with selected Lactobacillus plantarum C48 and Lactobacillus brevis AM7, expressing different peptidase activities. Extracts from legume doughs (unfermented) and sourdoughs were subjected to western blot analysis, using an anti-lunasin primary antibody. Despite the absence of lunasin, different immunoreactive polypeptide bands were found. The number and the intensity of lunasin-like polypeptides increased during sourdough fermentation, as the consequence of the proteolysis of the native proteins carried out by the selected lactic acid bacteria. A marked inhibitory effect on the proliferation of human adenocarcinoma Caco-2 cells was observed using extracts from legume sourdoughs. In particular, sourdoughs from Fagiolo di Lamon, Cece dell'Alta Valle di Misa, and Pisello riccio di Sannicola flours were the most active, showing a decrease of Caco-2 cells viability up to 70 %. The over-expression of Caco-2 filaggrin and involucrin genes was also induced. Nine lunasin-like polypeptides, having similarity to lunasin, were identified. CONCLUSIONS: The features of the sourdough fermented legume flours suggested the use for the manufacture of novel functional foods and/or pharmaceuticals preparations. PMID- 26494434 TI - Fabrication of Two-Dimensional Lateral Heterostructures of WS2 /WO3 ?H2 O Through Selective Oxidation of Monolayer WS2. AB - Two-dimensional (2D) lateral heterostructures have emerged as a hot topic in the fast evolving field of advanced functional materials , but their fabrication is challenging. The layer-structured WS2 was theoretically demonstrated to be inert to oxidation except for the monolayer, which can be selectively oxidized owing to the simultaneous interaction of oxygen with both sides. Combined with the theoretical calculations, a new method was developed for the successful construction of 2D lateral heterostructures of WS2 /WO3 ?H2 O in an ambient environment, based on a simple liquid-phase solution exfoliation. These lateral heterostructures of WS2 /WO3 ?H2 O have interesting properties, as indicated by enhanced photocatalytic activity toward the degradation of methyl orange (MO). PMID- 26494433 TI - Understanding the relationship between breastfeeding and postnatal depression: the role of pain and physical difficulties. AB - AIMS: To examine the relationship between specific reasons for stopping breastfeeding and depressive symptoms in the postnatal period. BACKGROUND: Difficulty breastfeeding has been connected to postnatal depression although it is unclear whether difficulty breastfeeding precedes or succeeds a diagnosis. However, the concept of 'breastfeeding difficulty' is wide and includes biological, psychological and social factors. DESIGN: A cross-sectional self report survey. METHODS: Data were collected between December 2012 and February 2013. 217 women with an infant aged 0-6 months who had started breastfeeding at birth but had stopped before 6 months old completed a questionnaire examining breastfeeding duration and reasons for stopping breastfeeding. They further completed a copy of the Edinburgh Postnatal Depression Scale. RESULTS: A short breastfeeding duration and multiple reasons for stopping breastfeeding were associated with higher depression score. However, in a regression analysis only the specific reasons of stopping breastfeeding for physical difficulty and pain remained predictive of depression score. CONCLUSIONS: Understanding women's specific reasons for stopping breastfeeding rather than breastfeeding duration is critical in understanding women's breastfeeding experience and providing women with emotional support. Issues with pain and physical breastfeeding were most indicative of postnatal depression in comparison to psychosocial reasons highlighting the importance of spending time with new mothers to help them with issues such as latch. PMID- 26494435 TI - Anaerobic ammonium oxidation and its contribution to nitrogen removal in China's coastal wetlands. AB - Over the past several decades, human activities have caused substantial enrichment of reactive nitrogen in China's coastal wetlands. Although anaerobic ammonium oxidation (anammox), the process of oxidizing ammonium into dinitrogen gas through the reduction of nitrite, is identified as an important process for removing reactive nitrogen, little is known about the dynamics of anammox and its contribution to nitrogen removal in nitrogen-enriched environments. Here, we examine potential rates of anammox and associate them with bacterial diversity and abundance across the coastal wetlands of China using molecular and isotope tracing techniques. High anammox bacterial diversity was detected in China's coastal wetlands and included Candidatus Scalindua, Kuenenia, Brocadia, and Jettenia. Potential anammox rates were more closely associated with the abundance of anammox bacteria than to their diversity. Among all measured environmental variables, temperature was a key environmental factor, causing a latitudinal distribution of the anammox bacterial community composition, biodiversity and activity along the coastal wetlands of China. Based on nitrogen isotope tracing experiments, anammox was estimated to account for approximately 3.8-10.7% of the total reactive nitrogen removal in the study area. Combined with denitrification, anammox can remove 20.7% of the total external terrigenous inorganic nitrogen annually transported into China's coastal wetland ecosystems. PMID- 26494436 TI - Sudden unexpected death in epilepsy: Identifying risk and preventing mortality. AB - Premature death among individuals with epilepsy is higher than in the general population, and sudden unexpected death is the most common cause of this mortality. A new multisite collaborative research consortium, the Center for sudden unexpected death in epilepsy (SUDEP) Research (CSR), has received major funding from the National Institutes of Health (NIH) to examine the possible biologic mechanisms underlying this potentially preventable comorbidity and develop predictive biomarkers for interventions that could lower SUDEP incidence. This inaugural report describes the structure of the CSR, its priorities for human and experimental research, and the strategic collaborations and advanced tools under development to reduce this catastrophic outcome of epilepsy. The CSR Partners Program will work closely with committed volunteer agencies, industry, and academic institutions to accelerate and communicate these advances to the professional and lay community. PMID- 26494437 TI - In vivo optical modulation of neural signals using monolithically integrated two dimensional neural probe arrays. AB - Integration of stimulation modalities (e.g. electrical, optical, and chemical) on a large array of neural probes can enable an investigation of important underlying mechanisms of brain disorders that is not possible through neural recordings alone. Furthermore, it is important to achieve this integration of multiple functionalities in a compact structure to utilize a large number of the mouse models. Here we present a successful optical modulation of in vivo neural signals of a transgenic mouse through our compact 2D MEMS neural array (optrodes). Using a novel fabrication method that embeds a lower cladding layer in a silicon substrate, we achieved a thin silicon 2D optrode array that is capable of delivering light to multiple sites using SU-8 as a waveguide core. Without additional modification to the microelectrodes, the measured impedance of the multiple microelectrodes was below 1 MOmega at 1 kHz. In addition, with a low background noise level (+/- 25 MUV), neural spikes from different individual neurons were recorded on each microelectrode. Lastly, we successfully used our optrodes to modulate the neural activity of a transgenic mouse through optical stimulation. These results demonstrate the functionality of the 2D optrode array and its potential as a next-generation tool for optogenetic applications. PMID- 26494439 TI - Redox-Robust Pentamethylferrocene Polymers and Supramolecular Polymers, and Controlled Self-Assembly of Pentamethylferricenium Polymer-Embedded Ag, AgI, and Au Nanoparticles. AB - We report the first pentamethylferrocene (PMF) polymers and the redox chemistry of their robust polycationic pentamethylferricenium (PMFium) analogues. The PMF polymers were synthesized by ring-opening metathesis polymerization (ROMP) of a PMF-containing norbornene derivative by using the third-generation Grubbs ruthenium metathesis catalyst. Cyclic voltammetry studies allowed us to determine confidently the number of monomer units in the polymers through the Bard-Anson method. Stoichiometric oxidation by using ferricenium hexafluorophosphate quantitatively and instantaneously provided fully stable (even in aerobic solutions) blue d(5) Fe(III) metallopolymers. Alternatively, oxidation of the PMF containing polymers was conducted by reactions with Ag(I) or Au(III) , to give PMFium polymer-embedded Ag and Au nanoparticles (NPs). In the presence of I2 , oxidation by using Ag(I) gave polymer-embedded Ag/AgI NPs and AgNPs at the surface of AgI NPs. Oxidation by using Au(III) also produced an Au(I) intermediate that was trapped and characterized. Engineered single-electron transfer reactions of these redox-robust nanomaterial precursors appear to be a new way to control their formation, size, and environment in a supramolecular way. PMID- 26494440 TI - Five minutes with Mark Britnell: Does a perfect health system exist? PMID- 26494441 TI - Cerebral spinal fluid dynamics: effect of hypoxia and implications for high altitude illness. AB - The pathophysiology of acute mountain sickness and high-altitude cerebral edema, the cerebral forms of high-altitude illness, remain uncertain and controversial. Persistently elevated or pathological fluctuations in intracranial pressure are thought to cause symptoms similar to those reported by individuals suffering cerebral forms of high-altitude illness. This review first focuses on the basic physiology of the craniospinal system, including a detailed discussion of the long-term and dynamic regulation of intracranial pressure. Thereafter, we critically examine the available literature, based primarily on invasive pressure monitoring, that suggests intracranial pressure is acutely elevated at altitude due to brain swelling and/or elevated sagittal sinus pressure, but normalizes over time. We hypothesize that fluctuations in intracranial pressure occur around a slightly elevated or normal mean intracranial pressure, in conjunction with oscillations in arterial Po2 and arterial blood pressure. Then these modest fluctuations in intracranial pressure, in concert with direct vascular stretch due to dilatation and/or increased blood pressure transmission, activate the trigeminal vascular system and cause symptoms of acute mountain sickness. Elevated brain water (vasogenic edema) may be due to breakdown of the blood-brain barrier. However, new information suggests cerebral spinal fluid flux into the brain may be an important factor. Regardless of the source (or mechanisms responsible) for the excess brain water, brain swelling occurs, and a "tight fit" brain would be a major risk factor to produce symptoms; activities that produce large changes in brain volume and cause fluctuations in blood pressure are likely contributing factors. PMID- 26494442 TI - Is the metabolic cost of walking higher in people with diabetes? AB - People with diabetes walk slower and display biomechanical gait alterations compared with controls, but it remains unknown whether the metabolic cost of walking (CoW) is elevated. The aim of this study was to investigate the CoW and the lower limb concentric joint work as a major determinant of the CoW, in patients with diabetes and diabetic peripheral neuropathy (DPN). Thirty-one nondiabetic controls (Ctrl), 22 diabetic patients without peripheral neuropathy (DM), and 14 patients with moderate/severe DPN underwent gait analysis using a motion analysis system and force plates and treadmill walking using a gas analyzer to measure oxygen uptake. The CoW was significantly higher particularly in the DPN group compared with controls and also in the DM group (at selected speeds only) compared with controls, across a range of matched walking speeds. Despite the higher CoW in patients with diabetes, concentric lower limb joint work was significantly lower in DM and DPN groups compared with controls. The higher CoW is likely due to energetic inefficiencies associated with diabetes and DPN reflecting physiological and biomechanical characteristics. The lower concentric joint work in patients with diabetes might be a consequence of kinematic gait alterations and may represent a natural strategy aimed at minimizing the CoW. PMID- 26494444 TI - Caffeine improves performance in double poling during acute exposure to 2,000-m altitude. AB - There is limited research on the physiological effects of caffeine (CAF) ingestion on exercise performance during acute hypoxia. The aim of the present study was therefore to test the effect of placebo (PLA) and CAF (4.5 mg/kg) on double poling (DP) performance during acute hypoxia. Thirteen male subelite cross country skiers (Vo2max 72.6 +/- 5.68 ml.kg(-1).min(-1)) were included. Performance was assessed as 1) an 8-km cross-country DP time-trial (C-PT), and 2) time until task failure at a set workload equal to ~90% of DP Vo2max. Testing was carried out in a hypobaric chamber, at 800 mbar (Pio2: ~125 mmHg) corresponding to ~2,000 m above sea level in a randomized double-blinded, placebo-controlled, cross-over design. CAF improved time to task failure from 6.10 +/- 1.40 to 7.22 +/- 1.30 min (P < 0.05) and velocity the first 4 km (P < 0.05) but not overall time usage for the 8-km C-PT. During submaximal exercise subjects reported lower pain in arms and rate of perceived exertion (RPE) following CAF ingestion. Throughout C-PTs similar RPE and pain was shown between treatments. However, higher heart rate was observed during the CAF 8 km (187 +/- 7 vs. 185 +/- 7; P < 0.05) and 90% C-PT (185 +/- 7 vs. 181 +/- 9) associated with increased ventilation, blood lactate, glucose, adrenaline, decreased pH, and bicarbonate. The present study demonstrates for the first time that CAF ingestion improves DP time to task failure although not consistently time trial performance during acute exposure to altitude. Mechanisms underpinning improvements seem related to reduced pain RPE and increased heart rate during CAF C-PTs. PMID- 26494443 TI - Eccentric contraction-induced myofiber growth in tumor-bearing mice. AB - Cancer cachexia is characterized by the progressive loss of skeletal muscle mass. While mouse skeletal muscle's response to an acute bout of stimulated low frequency concentric muscle contractions is disrupted by cachexia, gaps remain in our understanding of cachexia's effects on eccentric contraction-induced muscle growth. The purpose of this study was to determine whether repeated bouts of stimulated high-frequency eccentric muscle contractions [high-frequency electrical muscle stimulation (HFES)] could stimulate myofiber growth during cancer cachexia progression, and whether this training disrupted muscle signaling associated with wasting. Male Apc(Min/+) mice initiating cachexia (N = 9) performed seven bouts of HFES-induced eccentric contractions of the left tibialis anterior muscle over 2 wk. The right tibialis anterior served as the control, and mice were killed 48 h after the last stimulation. Age-matched C57BL/6 mice (N = 9) served as wild-type controls. Apc(Min/+) mice lost body weight, muscle mass, and type IIA, IIX, and IIB myofiber cross-sectional area. HFES increased myofiber cross-sectional area of all fiber types, regardless of cachexia. Cachexia increased muscle noncontractile tissue, which was attenuated by HFES. Cachexia decreased the percentage of high succinate dehydrogenase activity myofibers, which was increased by HFES, regardless of cachexia. While cachexia activated AMP kinase, STAT3, and ERK1/2 signaling, HFES decreased AMP kinase phosphorylation, independent of the suppression of STAT3. These results demonstrate that cachectic skeletal muscle can initiate a growth response to repeated eccentric muscle contractions, despite the presence of a systemic cachectic environment. PMID- 26494445 TI - Triceps surae muscle-tendon properties in older endurance- and sprint-trained athletes. AB - Previous studies have shown that aging is associated with alterations in muscle architecture and tendon properties (Morse CI, Thom JM, Birch KM, Narici MV. Acta Physiol Scand 183: 291-298, 2005; Narici MV, Maganaris CN, Reeves ND, Capodaglio P. J Appl Physiol 95: 2229-2234, 2003; Stenroth L, Peltonen J, Cronin NJ, Sipila S, Finni T. J Appl Physiol 113: 1537-1544, 2012). However, the possible influence of different types of regular exercise loading on muscle architecture and tendon properties in older adults is poorly understood. To address this, triceps surae muscle-tendon properties were examined in older male endurance (OE, n = 10, age = 74.0 +/- 2.8 yr) and sprint runners (OS, n = 10, age = 74.4 +/- 2.8 yr), with an average of 42 yr of regular training experience, and compared with age-matched [older control (OC), n = 33, age = 74.8 +/- 3.6 yr] and young untrained controls (YC, n = 18, age = 23.7 +/- 2.0 yr). Compared with YC, Achilles tendon cross sectional area (CSA) was 22% (P = 0.022), 45% (P = 0.001), and 71% (P < 0.001) larger in OC, OE, and OS, respectively. Among older groups, OS had significantly larger tendon CSA compared with OC (P = 0.033). No significant between-group differences were observed in Achilles tendon stiffness. In older groups, Young's modulus was 31-44%, and maximal tendon stress 44-55% lower, than in YC (P <= 0.001). OE showed shorter soleus fascicle length than both OC (P < 0.05) and YC (P < 0.05). These data suggest that long-term running does not counteract the previously reported age-related increase in tendon CSA, but, instead, may have an additive effect. The greatest Achilles tendon CSA was observed in OS followed by OE and OC, suggesting that adaptation to running exercise is loading intensity dependent. Achilles tendon stiffness was maintained in older groups, even though all older groups displayed larger tendon CSA and lower tendon Young's modulus. Shorter soleus muscle fascicles in OE runners may be an adaptation to life-long endurance running. PMID- 26494446 TI - The role of morphology in mathematical models of placental gas exchange. AB - The performance of the placenta as a gas exchanger has a direct impact on the future health of the newborn. To provide accurate estimates of respiratory gas exchange rates, placenta models need to account for both the physiology of exchange and the organ morphology. While the former has been extensively studied, accounting for the latter is still a challenge. The geometrical complexity of placental structure requires use of carefully crafted approximations. We present here the state of the art of respiratory gas exchange placenta modeling and demonstrate the influence of the morphology description on model predictions. Advantages and shortcomings of various classes of models are discussed, and experimental techniques that may be used for model validation are summarized. Several directions for future development are suggested. PMID- 26494447 TI - Fluoxetine stimulates anti-inflammatory IL-10 cytokine production and attenuates sensory deficits in a rat model of decompression sickness. AB - Despite "gold standard" hyperbaric oxygen treatment, 30% of patients suffering from neurological decompression sickness still exhibit incomplete recovery, including sensory impairments. Fluoxetine, a well-known antidepressant, is recognized as having anti-inflammatory effects in the setting of cerebral ischemia. In this study, we focused on the assessment of sensory neurological deficits and measurement of circulating cytokines after decompression in rats treated or not with fluoxetine. Seventy-eight rats were divided into a clinical (n = 38) and a cytokine (n = 40) group. In both groups, the rats were treated with fluoxetine (30 mg/kg po, 6 h beforehand) or with a saccharine solution. All of the rats were exposed to 90 m seawater for 45 min before staged decompression. In the clinical group, paw withdrawal force after mechanical stimulation and paw withdrawal latency after thermal stimulation were evaluated before and 1 and 48 h after surfacing. At 48 h, a dynamic weight-bearing device was used to assess postural stability, depending on the time spent on three or four paws. For cytokine analysis, blood samples were collected from the vena cava 1 h after surfacing. Paw withdrawal force and latency were increased after surfacing in the controls, but not in the fluoxetine group. Dynamic weight-bearing assessment highlighted a better stability on three paws for the fluoxetine group. IL-10 levels were significantly decreased after decompression in the controls, but maintained at baseline level with fluoxetine. This study suggests that fluoxetine has a beneficial effect on sensory neurological recovery. We hypothesize that the observed effect is mediated through maintained anti-inflammatory cytokine IL-10 production. PMID- 26494449 TI - Sulforaphane mitigates muscle fibrosis in mdx mice via Nrf2-mediated inhibition of TGF-beta/Smad signaling. AB - Sulforaphane (SFN), an activator of NF-E2-related factor 2 (Nrf2), has been found to have an antifibrotic effect on liver and lung. However, its effects on dystrophic muscle fibrosis remain unknown. This work was undertaken to evaluate the effects of SFN-mediated activation of Nrf2 on dystrophic muscle fibrosis. Male mdx mice (age 3 mo) were treated with SFN by gavage (2 mg/kg body wt per day) for 3 mo. Experimental results demonstrated that SFN remarkably attenuated skeletal and cardiac muscle fibrosis as indicated by reduced Sirius Red staining and immunostaining of the extracellular matrix. Moreover, SFN significantly inhibited the transforming growth factor-beta (TGF-beta)/Smad signaling pathway and suppressed profibrogenic gene and protein expressions such as those of alpha smooth muscle actin (alpha-SMA), fibronectin, collagen I, plasminogen activator inhibitor-1 (PAI-1), and tissue inhibitor metalloproteinase-1 (TIMP-1) in an Nrf2 dependent manner. Furthermore, SFN significantly decreased the expression of inflammatory cytokines CD45, TNF-alpha, and IL-6 in mdx mice. In conclusion, these results show that SFN can attenuate dystrophic muscle fibrosis by Nrf2 mediated inhibition of the TGF-beta/Smad signaling pathway, which indicates that Nrf2 may represent a new target for dystrophic muscle fibrosis. PMID- 26494448 TI - Left ventricular remodeling during and after 60 days of sedentary head-down bed rest. AB - Short periods of weightlessness are associated with reduced stroke volume and left ventricular (LV) mass that appear rapidly and are thought to be largely dependent on plasma volume. The magnitude of these cardiac adaptations are even greater after prolonged periods of simulated weightlessness, but the time course during and the recovery from bed rest has not been previously described. We collected serial measures of plasma volume (PV, carbon monoxide rebreathing) and LV structure and function [tissue Doppler imaging, three-dimensional (3-D) and 2 D echocardiography] before, during, and up to 2 wk after 60 days of 6 degrees head down tilt bed rest (HDTBR) in seven healthy subjects (four men, three women). By 60 days of HDTBR, PV was markedly reduced (2.7 +/- 0.3 vs. 2.3 +/- 0.3 liters,P< 0.001). Resting measures of LV volume and mass were ~15% (P< 0.001) and ~14% lower (P< 0.001), respectively, compared with pre-HDTBR values. After 3 days of reambulation, both PV and LV volumes were not different than pre-HDTBR values. However, LV mass did not recover with normalization of PV and remained 12 +/- 4% lower than pre-bed rest values (P< 0.001). As previously reported, decreased PV and LV volume precede and likely contribute to cardiac atrophy during prolonged LV unloading. Although PV and LV volume recover rapidly after HDTBR, there is no concomitant normalization of LV mass. These results demonstrate that reduced LV mass in response to prolonged simulated weightlessness is not a simple effect of tissue dehydration, but rather true LV muscle atrophy that persists well into recovery. PMID- 26494451 TI - Reappraisal of the acute, moderate intensity exercise-catecholamines interaction effect on speed of cognition: role of the vagal/NTS afferent pathway. PMID- 26494450 TI - Impairments in central cardiovascular function contribute to attenuated reflex vasodilation in aged skin. AB - During supine passive heating, increases in skin blood flow (SkBF) and cardiac output (Qc) are both blunted in older adults. The aim here was to determine the effect of acutely correcting the peripheral vasodilatory capacity of aged skin on the integrated cardiovascular responses to passive heating. A secondary aim was to examine the SkBF-Qc relation during hyperthermia in the presence (upright posture) and absence (dynamic exercise) of challenges to central venous pressure. We hypothesized that greater increases in SkBF would be accompanied by greater increases in Qc. Eleven healthy older adults (69 +/- 3 yr) underwent supine passive heating (0.8 degrees C rise in core temperature; water-perfused suit) after ingesting sapropterin (BH4, a nitric oxide synthase cofactor; 10 mg/kg) or placebo (randomized double-blind crossover design). Twelve young (24 +/- 1 yr) subjects served as a comparison group. SkBF (laser-Doppler flowmetry) and Qc (open-circuit acetylene wash-in) were measured during supine heating, heating + upright posture, and heating + dynamic exercise. Throughout supine and upright heating, sapropterin fully restored the SkBF response of older adults to that of young adults but Qc remained blunted. During heat + upright posture, SkBF failed to decrease in untreated older subjects. There were no age- or treatment-related differences in SkBF-Qc during dynamic exercise. The principal finding of this study was that the blunted Qc response to passive heat stress is directly related to age as opposed to the blunted peripheral vasodilatory capacity of aged skin. Furthermore, peripheral impairments to SkBF in the aged may contribute to inapposite responses during challenges to central venous pressure during hyperthermia. PMID- 26494452 TI - Cardioprotective adaptation of rats to intermittent hypobaric hypoxia is accompanied by the increased association of hexokinase with mitochondria. AB - Chronic hypoxia increases the myocardial resistance to acute ischemia-reperfusion injury by affecting the mitochondrial redox balance. Hexokinase (HK) bears a high potential to suppress the excessive formation of reactive oxygen species because of its increased association with mitochondria, thereby inhibiting the membrane permeability transition pore opening and preventing cell death. The purpose of this study was to determine the effect of severe intermittent hypobaric hypoxia (7,000 m, 8 h/day, 5 wk) on the function and colocalization of HK isoforms with mitochondria in the left (LV) and right ventricles of rat myocardium. The real time RT-PCR, Western blot, enzyme coupled assay, and quantitative immunofluorescence techniques were used. Our results showed significantly elevated expression of HK isoforms (HK1 and HK2) in the hypoxic LV. In addition, intermittent hypoxia increased the total HK activity and the association of HK isoforms with mitochondria in both ventricles. These findings suggest that HK may contribute to the cardioprotective phenotype induced by adaptation to severe intermittent hypobaric hypoxia. PMID- 26494454 TI - Understanding Aspects of Aluminum Exposure in Alzheimer's Disease Development. AB - Aluminum is a ubiquitously abundant nonessential element. Aluminum has been associated with neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, and dialysis encephalopathy. Many continue to regard aluminum as controversial although increasing evidence supports the implications of aluminum in the pathogenesis of AD. Aluminum causes the accumulation of tau protein and Abeta protein in the brain of experimental animals. Aluminum induces neuronal apoptosis in vivo and in vitro, either by endoplasmic stress from the unfolded protein response, by mitochondrial dysfunction, or a combination of them. Some, people who are exposed chronically to aluminum, either from through water and/or food, have not shown any AD pathology, apparently because their gastrointestinal barrier is more effective. This article is written keeping in mind mechanisms of action of aluminum neurotoxicity with respect to AD. PMID- 26494455 TI - Tobacco exceptionalism in airports: time to address gaps. PMID- 26494453 TI - Onset of alveolar recirculation in the developing lungs and its consequence on nanoparticle deposition in the pulmonary acinus. AB - The structure of the gas exchange region of the human lung (the pulmonary acinus) undergoes profound change in the first few years of life. In this paper, we investigate numerically how the change in alveolar shape with time affects the rate of nanoparticle deposition deep in the lung during postnatal development. As human infant data is unavailable, we use a rat model of lung development. The process of postnatal lung development in the rat is remarkably similar to that of the human, and the structure of the rat acinus is indistinguishable from that of the human acinus. The current numerical predictions support our group's recent in vivo findings, which were also obtained by using growing rat lung models, that nanoparticle deposition in infants is strongly affected by the change in the structure of the pulmonary acinus. In humans, this major structural change occurs over the first 2 yr of life. Our current predictions would suggest that human infants at the age of ~ 2 yr might be most at risk to the harmful effects of air pollution. Our results also suggest that dose estimates for inhalation therapies using nanoparticles, based on fully developed adult lungs with simple body weight scaling, are likely to overestimate deposition by up to 55% for newborns and underestimate deposition by up to 17% for 2-yr-old infants. PMID- 26494458 TI - An Unusual Localization of a Cardiac Pseudoaneurysm Complicated by Paravalvular Leak in a Patient with Prosthetic Heart Valves. PMID- 26494459 TI - Maternal Smoking During Pregnancy and Offspring Birth Weight: A Genetically Informed Approach Comparing Multiple Raters. AB - Maternal smoking during pregnancy (SDP) is a significant public health concern with adverse consequences to the health and well-being of the fetus. There is considerable debate about the best method of assessing SDP, including birth/medical records, timeline follow-back approaches, multiple reporters, and biological verification (e.g., cotinine). This is particularly salient for genetically-informed approaches where it is not always possible or practical to do a prospective study starting during the prenatal period when concurrent biological specimen samples can be collected with ease. In a sample of families (N = 173) specifically selected for sibling pairs discordant for prenatal smoking exposure, we: (1) compare rates of agreement across different types of report maternal report of SDP, paternal report of maternal SDP, and SDP contained on birth records from the Department of Vital Statistics; (2) examine whether SDP is predictive of birth weight outcomes using our best SDP report as identified via step (1); and (3) use a sibling-comparison approach that controls for genetic and familial influences that siblings share in order to assess the effects of SDP on birth weight. Results show high agreement between reporters and support the utility of retrospective report of SDP. Further, we replicate a causal association between SDP and birth weight, wherein SDP results in reduced birth weight even when accounting for genetic and familial confounding factors via a sibling comparison approach. PMID- 26494460 TI - A Swedish Population-Based Multivariate Twin Study of Externalizing Disorders. AB - In epidemiological and twin populations, prior interview studies have identified an externalizing spectrum of disorders. Could this be detected utilizing objective registry data? In 20,603 twin pairs from the Swedish Twin Registry, we obtained information from national medical, criminal and pharmacy records on drug abuse (DA), criminal behavior (CB) and alcohol use disorders (AUD). Multivariate twin modeling was performed with the OpenMx package. A common pathway model with quantitative but not qualitative sex effects fit best with twin resemblance for the latent liability to externalizing syndromes due to both genetic and shared environmental factors. Heritability of the liability was higher in females (76 vs. 62%) while shared environmental influences were considerably stronger in males (23 vs. 3%). In both sexes, this latent liability was most strongly indexed by DA and least by CB. All three syndromes had specific genetic influences (especially CB and AUD in males, and CB in females) and specific shared environmental effects (especially DA and CB in males, and AUD in females). For DA, CB and AUD in men, and DA and AUD in women, at least 75% of the genetic risk arose through the common factor. The best fit model assumed that genetic and environmental influences on these externalizing syndromes in males and females were the same. We identified, in registry data, a highly heritable externalizing spectrum. DA, CB and AUD share substantial genetic and modest to moderate shared environmental influences. The nature of the externalizing spectrum differed meaningfully between the sexes. PMID- 26494461 TI - Neonatal brain MRI: how reliable is the radiologist's eye? AB - INTRODUCTION: White matter (WM) analysis in neonatal brain magnetic resonance imaging (MRI) is challenging, as demonstrated by the issue of diffuse excessive high signal intensity (DEHSI). We evaluated the reliability of the radiologist's eye in this context. METHODS: Three experienced observers graded the WM signal intensity on axial T2-weighted 1.5T images from 60 different premature newborns on 2 occasions 4 weeks apart with a semi-quantitative classification under identical viewing conditions. RESULTS: The intra- and inter-observer correlation coefficients were fair to moderate (Fleiss' kappa between 0.21 and 0.60). CONCLUSION: This is a serious limitation of which we need to be aware, as it can lead to contradictory conclusions in the challenging context of term-equivalent age brain MRI in premature infants. These results highlight the need for a semiautomatic tool to help in objectively analyzing MRI signal intensity in the neonatal brain. PMID- 26494462 TI - Observer variability of absolute and relative thrombus density measurements in patients with acute ischemic stroke. AB - INTRODUCTION: Thrombus density may be a predictor for acute ischemic stroke treatment success. However, only limited data on observer variability for thrombus density measurements exist. This study assesses the variability and bias of four common thrombus density measurement methods by expert and non-expert observers. METHODS: For 132 consecutive patients with acute ischemic stroke, three experts and two trained observers determined thrombus density by placing three standardized regions of interest (ROIs) in the thrombus and corresponding contralateral arterial segment. Subsequently, absolute and relative thrombus densities were determined using either one or three ROIs. Intraclass correlation coefficient (ICC) was determined, and Bland-Altman analysis was performed to evaluate interobserver and intermethod agreement. Accuracy of the trained observer was evaluated with a reference expert observer using the same statistical analysis. RESULTS: The highest interobserver agreement was obtained for absolute thrombus measurements using three ROIs (ICCs ranging from 0.54 to 0.91). In general, interobserver agreement was lower for relative measurements, and for using one instead of three ROIs. Interobserver agreement of trained non experts and experts was similar. Accuracy of the trained observer measurements was comparable to the expert interobserver agreement and was better for absolute measurements and with three ROIs. The agreement between the one ROI and three ROI methods was good. CONCLUSION: Absolute thrombus density measurement has superior interobserver agreement compared to relative density measurement. Interobserver variation is smaller when multiple ROIs are used. Trained non-expert observers can accurately and reproducibly assess absolute thrombus densities using three ROIs. PMID- 26494463 TI - Non-Gaussian diffusion MR imaging of glioma: comparisons of multiple diffusion parameters and correlation with histologic grade and MIB-1 (Ki-67 labeling) index. AB - INTRODUCTION: This study was conducted to compare the association of Gaussian and non-Gaussian magnetic resonance imaging (MRI)-derived parameters with histologic grade and MIB-1 (Ki-67 labeling) index (MI) in brain glioma. METHODS: Sixty-five patients with pathologically confirmed glioma, who underwent diffusion-weighted MRI with 2 b values (0, 1000 s/mm(2)) and 22 b values (<=5000 s/mm(2)), respectively, were divided into three groups of grade II (n = 35), grade III (n = 8), and grade IV (n = 22). Comparisons by two groups were made for apparent diffusion coefficient (ADC), slow diffusion coefficient (Dslow), distributed diffusion coefficient (DDC), and heterogeneity index alpha. Analyses of receiver operating characteristic (ROC) curve were performed to maximize the area under the curve (AUC) for differentiating grade III + IV (high-grade glioma, HGG) from grade II (low-grade glioma, LGG) and grade IV (glioblastoma multiforme, GBM) from grade II + III (other grade glioma, OGG). Correlations with MI were analyzed for the MRI parameters. RESULTS: On tumor regions, the values of ADC, Dslow, DDC, and alpha were significantly higher in grade II [(1.37 +/- 0.29, 0.70 +/- 0.11, 1.39 +/- 0.34) (*10(-3) mm(2)/s) and 0.88 +/- 0.05, respectively] than in grade III [(0.99 +/- 0.13, 0.55 +/- 0.07, 1.04 +/- 0.20) (*10(-3) mm(2)/s) and 0.80 +/- 0.03, respectively] and grade IV [(1.03 +/- 0.14, 0.50 +/- 0.05, 1.02 +/- 0.16) (*10(-3) mm(2)/s) and 0.76 +/- 0.04, respectively] (all P < 0.001). The parameter alpha showed the highest AUCs of 0.950 and 0.922 in discriminating HGG from LGG and GBM from OGG, respectively. Significant correlations with histologic grade and MI were observed for the MRI parameters. CONCLUSION: The non-Gaussian MRI derived parameters alpha and Dslow are superior to ADC in glioma grading, which are comparable with ADC as reliable biomarkers in noninvasively predicting the proliferation level of glioma malignancy. PMID- 26494464 TI - Intravenous tissue plasminogen activator before endovascular treatment increases symptomatic intracranial hemorrhage in patients with occlusion of the middle cerebral artery second division: subanalysis of the RESCUE-Japan Registry. AB - INTRODUCTION: No previous study has investigated the relationship between intravenous tissue plasminogen activator (IV t-PA) and intracranial hemorrhage (ICH) according to the location of vessel occlusion. The aim of the present study was to investigate the relationship between preprocedural IV t-PA and endovascular treatment (EVT) and ICH according to the location of occlusion using data from the nationwide prospective registry of acute cerebral large vessel occlusion (LVO), the RESCUE-Japan Registry. METHODS: Among 1442 patients with acute LVO enrolled in the registry, we examined 410 patients who received EVT. Patients were divided into the following four groups according to the location of occlusion: the internal carotid artery (ICA), middle cerebral artery first division (M1), middle cerebral artery second division (M2), and vertebral artery (VA)/basilar artery (BA) groups. RESULTS: A total of 399 patients in whom the occlusion was located in these vessels were finally included. Any ICH (aICH) was identified in 127 (30.9%) patients, and symptomatic ICH (sICH) was identified in 20 (4.9%). Preprocedural IV t-PA did not increase the incidence of aICH in any group and tended to increase the incidence of sICH in only the M2 group. In multivariate analysis of the M2 group, IV t-PA was an independent risk factor for sICH. CONCLUSION: Preprocedural IV t-PA did not increase the incidence of ICH in total, but could increase the incidence of sICH in those with M2 occlusion. IV t PA before EVT may be an independent risk factor for sICH in patients with M2 occlusion. PMID- 26494465 TI - Rapid Hepatobiliary Excretion of Micelle-Encapsulated/Radiolabeled Upconverting Nanoparticles as an Integrated Form. AB - In the field of nanomedicine, long term accumulation of nanoparticles (NPs) in the mononuclear phagocyte system (MPS) such as liver is the major hurdle in clinical translation. On the other hand, NPs could be excreted via hepatobiliary excretion pathway without overt tissue toxicity. Therefore, it is critical to develop NPs that show favorable excretion property. Herein, we demonstrated that micelle encapsulated (64)Cu-labeled upconverting nanoparticles (micelle encapsulated (64)Cu-NOTA-UCNPs) showed substantial hepatobiliary excretion by in vivo positron emission tomography (PET) and also upconversion luminescence imaging (ULI). Ex vivo biodistribution study reinforced the imaging results by showing clearance of 84% of initial hepatic uptake in 72 hours. Hepatobiliary excretion of the UCNPs was also verified by transmission electron microscopy (TEM) examination. Micelle encapsulated (64)Cu-NOTA-UCNPs could be an optimal bimodal imaging agent owing to quantifiability of (64)Cu, ability of in vivo/ex vivo ULI and good hepatobiliary excretion property. PMID- 26494466 TI - Unexpected requirement for a binding partner of the syntaxin family in phagocytosis by murine testicular Sertoli cells. AB - Testicular phagocytosis by Sertoli cells (SCs) plays an essential role in the efficient clearance of apoptotic spermatogenic cells under both physiological and pathological conditions. However, the molecular mechanism underlying this unique process is poorly understood. Herein, we report for the first time that alpha taxilin protein (TXLNA), a binding partner of the syntaxin family that functions as a central player in the intracellular vesicle traffic, was dominantly expressed in SCs. Induction of apoptosis in murine meiotic spermatocytes and haploid spermatids by busulfan treatment stimulated a significant increase of TXLNA in SCs at day (d) 14 and d 24 after busulfan treatment, respectively. Consistently, TXLNA expression was steadily upregulated when SCs were co-cultured with apoptotic germ cells (GCs). Moreover, using siRNA treatment, we found that ablation of endogenous TXLNA significantly impaired the phagocytotic capacity of SCs and thereby resulted in defective spermiogenesis and reduced fertility during the late recovery after testicular heat stress. Mechanistically, upregulation of TXLNA expression by apoptotic GCs was associated with the stabilization of ATP binding cassette transporter 1 (ABCA1), a transporter-mediated lipid efflux from SCs and influencing male fertility. TXLNA acted as an upstream suppressor of ABCA1 ubiquitination and thus promoted ABCA1 stability and accumulation following GC apoptosis. We further provide in vitro evidence that epidermal growth factor receptor (EGFR)-mediated phosphorylation regulated ABCA1 ubiquitination and was enhanced by TXLNA deficiency during testicular phagocytosis. Taken together, the TXLNA/ABCA1 cascade may serve as an important feedback mechanism to modulate the magnitude of subsequent phagocytotic process of SCs in response to testicular injury. PMID- 26494467 TI - Molecular architecture of the DED chains at the DISC: regulation of procaspase-8 activation by short DED proteins c-FLIP and procaspase-8 prodomain. AB - The CD95/Fas/APO-1 death-inducing signaling complex (DISC), comprising CD95, FADD, procaspase-8, procaspase-10, and c-FLIP, has a key role in apoptosis induction. Recently, it was demonstrated that procaspase-8 activation is driven by death effector domain (DED) chains at the DISC. Here, we analyzed the molecular architecture of the chains and the role of the short DED proteins in regulating procaspase-8 activation in the chain model. We demonstrate that the DED chains are largely composed of procaspase-8 cleavage products and, in particular, of its prodomain. The DED chain also comprises c-FLIP and procaspase 10 that are present in 10 times lower amounts compared with procaspase-8. We show that short c-FLIP isoforms can inhibit CD95-induced cell death upon overexpression, likely by forming inactive heterodimers with procaspase-8. Furthermore, we have addressed mechanisms of the termination of chain elongation using experimental and mathematical modeling approaches. We show that neither c FLIP nor procaspase-8 prodomain terminates the DED chain, but rather the dissociation/association rates of procaspase-8 define the stability of the chain and thereby its length. In addition, we provide evidence that procaspase-8 prodomain generated at the DISC constitutes a negative feedback loop in procaspase-8 activation. Overall, these findings provide new insights into caspase-8 activation in DED chains and apoptosis initiation. PMID- 26494469 TI - Ring-enhancing brain lesions: Listeria monocytogenes abscesses. PMID- 26494468 TI - DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53. AB - Mutation in the TP53 gene positively correlates with increased incidence of chemoresistance in different cancers. In this study, we investigated the mechanism of chemoresistance and epithelial-to-mesenchymal transition (EMT) in colorectal cancer involving the gain-of-function (GOF) mutant p53/ephrin-B2 signaling axis. Bioinformatic analysis of the NCI-60 data set and subsequent hub prediction identified EFNB2 as a possible GOF mutant p53 target gene, responsible for chemoresistance. We show that the mutant p53-NF-Y complex transcriptionally upregulates EFNB2 expression in response to DNA damage. Moreover, the acetylated form of mutant p53 protein is recruited on the EFNB2 promoter and positively regulates its expression in conjunction with coactivator p300. In vitro cell line and in vivo nude mice data show that EFNB2 silencing restores chemosensitivity in mutant p53-harboring tumors. In addition, we observed high expression of EFNB2 in patients having neoadjuvant non-responder colorectal carcinoma compared with those having responder version of the disease. In the course of deciphering the drug resistance mechanism, we also show that ephrin-B2 reverse signaling induces ABCG2 expression after drug treatment that involves JNK-c-Jun signaling in mutant p53 cells. Moreover, 5-fluorouracil-induced ephrin-B2 reverse signaling promotes tumorigenesis through the Src-ERK pathway, and drives EMT via the Src-FAK pathway. We thus conclude that targeting ephrin-B2 might enhance the therapeutic potential of DNA-damaging chemotherapeutic agents in mutant p53-bearing human tumors. PMID- 26494470 TI - Severe digital necrosis as the clinical onset of antiphospholipid syndrome. PMID- 26494471 TI - Lung ultrasound in systemic sclerosis: correlation with high-resolution computed tomography, pulmonary function tests and clinical variables of disease. AB - Interstitial lung disease (ILD) is a hallmark of systemic sclerosis (SSc). Although high-resolution computed tomography (HRCT) is the gold standard to diagnose ILD, recently lung ultrasound (LUS) has emerged in SSc patients as a new promising technique for the ILD evaluation, noninvasive and radiation-free. The aim of this study was to evaluate if there is a correlation between LUS, chest HRCT, pulmonary function tests findings and clinical variables of the disease. Thirty-nine patients (33 women and 6 men; mean age 51 +/- 15.2 years) underwent clinical examination, HRCT, pulmonary function tests and LUS for detection of B lines. A positive correlation exists between the number of B-lines and the HRCT score (r = 0.81, p < 0.0001), conversely a negative correlation exists between the number of B-lines and diffusing capacity of the lung for carbon monoxide (DLCO) (r = -0.63, p < 0.0001). The number of B-lines increases along with the progression of the capillaroscopic damage. A statistically significant difference in the number of B-lines was found between patients with and without digital ulcers [42 (3-84) vs 16 (4-55)]. We found that the number of B-lines increased with the progression of both HRCT score and digital vascular damage. LUS may therefore, be a useful tool to determine the best timing for HRCT execution, thus, preventing for many patients a continuous and useless exposure to ionizing radiation. PMID- 26494473 TI - [Erratum to: Cytology in uropathological diagnostics]. PMID- 26494472 TI - Chronic kidney disease in the Top End of the Northern Territory of Australia, 2002-2011: a retrospective cohort study using existing laboratory data. AB - BACKGROUND: The Northern Territory of Australia has a very high incidence of treated end-stage kidney disease (ESKD), largely confined to Indigenous Australians living in remote, under-resourced areas. Surveillance of chronic kidney disease (CKD) is still in its infancy in Australia. We estimate the prevalence and rate of progression of measured CKD across a region using inexpensive readily available laboratory information. METHODS: Using a retrospective de-identified extraction of all records with a serum creatinine or urinary albumin-to-creatinine ratio from the single largest ambulatory pathology provider to the Top End of the Northern Territory of Australia between 1st February 2002 and 31st December 2011, the yearly total and age-specific prevalence of measured microalbuminuria, overt albuminuria and estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2), and the prevalence of progressive CKD, were calculated. RESULTS: There was a steady increase in the proportion tested across all health districts in the region, more prominent in non-urban districts. In 2009, the regional adult prevalence of measured microalbuminuria and overt albuminuria was as high as 8.1 %, overt albuminuria alone up to 3.0 % and eGFR < 60 up to 2.3 %. Rates of progressive disease were extremely high, particularly for those with albuminuria (53.1-100 % for those with urinary albumin-creatinine ratio > 300 mg/mmol). CONCLUSIONS: The rates of testing, particularly in districts of high measured prevalence of markers of CKD, are encouraging. However, extremely high rates of progressive CKD are troubling. Further describing the outcomes of CKD in this population would require analysis of linked datasets. PMID- 26494474 TI - Dithiothreitol enhanced arsenic-trioxide-induced cell apoptosis in cultured oral cancer cells via mitochondrial dysfunction and endoplasmic reticulum stress. AB - Arsenic is naturally occurring toxic metalloid and drinking As2 O3 containing water are recognized to be related to increased risk of neurotoxicity, liver injury, blackfoot disease, hypertension, and cancer. On the contrary, As2 O3 has been an ancient drug used in traditional Chinese medicine with substantial anticancer activities, especially in the treatment of acute promyelocytic leukemia as well as chronic wound healing. However, the cytotoxicity and detail mechanisms of As2 O3 action in solid cancer cells, such as oral cancer cells, are largely unknown. In this study, we have primarily cultured four pairs of tumor and nontumor cells from the oral cancer patients and treated the cells with As2 O3 alone or combined with dithiothreitol (DTT). The results showed that 0.5 MUM As2 O3 plus 20 MUM DTT caused a significant cell death of oral cancer cells but not the nontumor cells. Also As2 O3 plus DTT upregulated Bax and Bak, downregulated Bcl-2 and p53, caused a loss of mitochondria membrane potential in oral cancer cells. On the other way, As2 O3 also triggered endoplasmic reticulum stress and increased the levels of glucose-regulated protein 78, calpain 1 and 2. Our results suggest that DTT could synergistically enhance the effects of As2 O3 on killing oral cancer cells while nontoxic to the nontumor cells. The combination is promising for clinical practice in oral cancer therapy and worth further investigations. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 17 27, 2017. PMID- 26494475 TI - Role of ultrasound biomicroscopy in the planning for secondary implantation of intra ocular lens in aphakia. AB - Purpose This is a prospective investigational study that was performed at Tanta University Eye Hospital, Tanta, Egypt to evaluate the role of ultrasound biomicroscopy (UBM) in planning secondary implantation of intra ocular lens (IOL) in aphakia. Methods Preoperative UBM was performed for the assessment of anterior segment of 30 aphakic eyes admitted for secondary IOL implantation with special attention to central corneal thickness (CCT), anterior chamber depth (ACD), ciliary sulcus (CS), anatomical changes, and posterior capsular (PC) integrity which had been assessed by measuring the remnants of PC with special attention to the 12, 3, 5, 6, 7, and 9 o'clock meridians. Results This study involved 30 eyes in 27 patients; 16 males and 11 females. The mean age was 8.39 +/- 2.36 years. The causes of aphakia were: congenital cataract extraction in14 eyes (46.7 %); trauma in 14 eyes (46.7 %); and after extracapsular cataract extraction in 2 eyes (6.6 %). The mean CCT was 0.61 + 0.35 mm and the mean ACD was 3.03 + 0.41 mm. The ciliary sulcus was patent in 28 eyes (93.4 %). Posterior synechia was observed in 8 eyes (26.7 %), lens remnants in 11 eyes (36.7 %), corneal scars in 11 eyes (36.7 %), and vitreous in anterior chamber in 1 eye (3.3 %). The integrity of PC was illustrated with a diagram. Conclusions UBM is a useful device to evaluate aphakic eyes before secondary IOL implantation through good evaluation of the anterior segment with special attention to the posterior capsular integrity, ciliary sulcus, anterior chamber depth, corneal thickness, and detection of any structural changes in the anterior segment resulting from the remote cause of aphakia. PMID- 26494476 TI - A review of unilateral acute idiopatic maculopathy related to hand-foot-mouth disease with a representative case. AB - The purpose of this study was to review unilateral acute maculopathy associated with hand-foot-mouth disease with a representative case. Clinical course of a 24 year-old male case with unilateral acute idiopatic maculopathy documented by multimodal imaging is presented, and a review of similar cases is given. On initial examination, best-corrected visual acuity was 20/200 in the left eye. Fundoscopy revealed grayish-yellowish subretinal exudate, and fluorescein angiography demonstrated irregular mottled hyperfluorescence at the central macula. Spectral domain optical coherence tomography demonstrated disruption of ellipsoid layer, which partially resolved on follow-up examinations. Best corrected visual acuity increased to 20/20 at 3 months, with persistent retinal changes, and mild disruption of ellipsoid layer and persistent mild metamorphopsia. Although hand-foot-mouth disease is usually benign and self limited in childhood, it may be rarely associated with unilateral vision loss due to maculopathy, especially at early adulthood in both sexes. Vision loss associated with this eruption is acute and reversible in most cases, despite some residual pigmentary and scarring changes in all cases and persistent mild visual loss in some cases. Exact pathophysiology, the causes of variability of clinical features, adulthood onset, unilateral involvement, and role of multimodal imaging are issues which need to be clarified with further research. PMID- 26494477 TI - Risk factors for intra-operative complications during phacoemulsification performed by residents. AB - The purpose of this study was to determine the risk factors for occurrence of intra-operative complications during phacoemulsification performed by residents. One hundred fifty patients with cataract who underwent phacoemulsification by residents, with an experience of five or more phacoemulsification surgery, at a tertiary care centre were included in this study. The pre-operative data of these patients were collected from the hospital records. Surgeons were interviewed immediately after the surgery regarding the surgeon experience, phacoemulsification technique, machine factors, and intra-operative complications. Statistical analysis was done to determine pre-operative and intra operative risk factors. The overall surgical complication rate in resident performed phacoemulsification was 37 % of which major and minor complications were 21 and 16 %, respectively. Success in terms of placement of intraocular lens in capsular bag was 84 %. The most common major and minor complications found were posterior capsular tear and irregular capsulorhexis, respectively. Systemic and ocular features of patients as well as type of machine (longitudinal versus torsional longitudinal) had no significant association in terms of complication rate. Increase in success rate was seen with increase in semester and number of surgeries performed. Patient factors including general physical condition, systemic diseases, and anatomical factors do not influence success in resident performed phacoemulsification. With increase in semester of residents, there is a significant decrease in intra-operative complications. Minor complications in the beginning of case lead to increase in major complications later on during the case and decrease in success rate by junior-semester residents. PMID- 26494478 TI - Introduction of temperature-sensitive helper and donor plasmids into Bac-to-Bac baculovirus expression systems. AB - In the baculovirus shuttle vector (bacmid) system, a helper plasmid and a donor plasmid are employed to insert heterologous genes into a cloned baculovirus genome via Tn7 transposition in Escherichia coli. The helper and donor plasmids are usually cotransfected with constructed bacmids into insect cells, which will lead to integration of these plasmids into the viral genome, and hence to the production of defective virions. In this study, to facilitate the preparation of plasmid-free recombinant bacmids, we modified a set of helper and donor plasmids by replacing their replication origins with that of a temperature-sensitive (ts) plasmid, pSIM6. Using the resulting ts helper plasmid pMON7124(ts) and the ts donor plasmid pFB1(ts)-PH-GFP, a recombinant bacmid, bAcWT-PG(-), was constructed, and the transposition efficiency was found to be 33.1%. The plasmids were then removed by culturing at 37 degrees C. For bAcWT-PG(-), the infectious progeny virus titer and the protein expression level under the control of the polyhedrin promoter were similar to those of a bacmid constructed with unmodified helper and donor plasmids. These ts plasmids will be useful for obtaining plasmid free bacmids for both heterologous protein production and fundamental studies of baculovirus biology. PMID- 26494480 TI - Human enteric viruses--potential indicators for enhanced monitoring of recreational water quality. AB - Recreational waters contaminated with human fecal pollution are a public health concern, and ensuring the safety of recreational waters for public use is a priority of both the Environmental Protection Agency (EPA) and the Centers for Disease Control and Prevention (CDC). Current recreational water standards rely on fecal indicator bacteria (FIB) levels as indicators of human disease risk. However present evidence indicates that levels of FIB do not always correspond to the presence of other potentially harmful organisms, such as viruses. Thus, enteric viruses are currently tested as water quality indicators, but have yet to be successfully implemented in routine monitoring of water quality. This study utilized enteric viruses as possible alternative indicators of water quality to examine 18 different fresh and offshore recreational waters on O'ahu, Hawai'i, by using newly established laboratory techniques including highly optimized PCR, real time PCR, and viral infectivity assays. All sample sites were detected positive for human enteric viruses by PCR including enterovirus, norovirus genogroups I and II, and male specific FRNA coliphage. A six time-point seasonal study of enteric virus presence indicated significant variation in virus detection between the rainy and dry seasons. Quantitative PCR detected the presence of norovirus genogroup II at levels at which disease risk may occur, and there was no correlation found between enteric virus presence and FIB counts. Under the present laboratory conditions, no infectious viruses were detected from the samples PCR-positive for enteric viruses. These data emphasize both the need for additional indicators for improved monitoring of water quality, and the feasibility of using enteric viruses as these indicators. PMID- 26494479 TI - Dengue epidemiology and pathogenesis: images of the future viewed through a mirror of the past. AB - Every year, millions of individuals throughout the world are seriously affected by dengue virus. The unavailability of a vaccine and of anti-viral drugs has made this mosquito-borne disease a serious health concern. Not only does dengue cause fatalities but it also has a profoundly negative economic impact. In recent decades, extensive research has been performed on epidemiology, vector biology, life cycle, pathogenesis, vaccine development and prevention. Although dengue research is still not at a stage to suggest definite hopes of a cure, encouraging significant advances have provided remarkable progress in the fight against infection. Recent developments indicate that both anti-viral drug and vaccine research should be pursued, in parallel with vector control programs. PMID- 26494481 TI - Ocular Involvement in Systemic Autoimmune Diseases. AB - Eye involvement represents a common finding in patients with systemic autoimmune diseases, particularly rheumatoid arthritis, Sjogren syndrome, seronegative spondyloarthropathy, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. The eye is a privileged immune site but commensal bacteria are found on the ocular surface. The eye injury may be inflammatory, vascular or infectious, as well as iatrogenic, as in the case of hydroxychloroquine, chloroquine, corticosteroids, and bisphosphonates. Manifestations may affect different components of the eye, with episcleritis involving the episclera, a thin layer of tissue covering the sclera; scleritis being an inflammation of the sclera potentially leading to blindness; keratitis, referring to corneal inflammation frequently associated with scleritis; and uveitis as the inflammation of the uvea, including the iris, ciliary body, and choroid, subdivided into anterior, posterior, or panuveitis. As blindness may result from the eye involvement, clinicians should be aware of the possible manifestations and their management also independent of the ophthalmologist opinion as the therapeutic approach generally points to the underlying diseases. In some cases, the eye involvement may have a diagnostic implication, as for episcleritis in rheumatoid arthritis, or acute anterior uveitis in seronegative spondyloarthritis. Nonetheless, some conditions lack specificity, as in the case of dry eye which affects nearly 30 % of the general population. The aim of this review is to elucidate to non-ophthalmologists the major ocular complications of rheumatic diseases and their specific management and treatment options. PMID- 26494482 TI - Targeted association mapping demonstrating the complex molecular genetics of fatty acid formation in soybean. AB - BACKGROUND: The relative abundance of five dominant fatty acids (FAs) (palmitic, stearic, oleic, linoleic and linolenic acids) is a major factor determining seed quality in soybean. METHODS: To clarify the currently poorly understood genetic architecture of FAs in soybean, targeted association analysis was conducted in 421 diverse accessions phenotyped in three environments and genotyped using 1536 pre-selected SNPs. RESULTS: The population of 421 soybean accessions displayed significant genetic variation for each FA. Analysis of the molecular data revealed three subpopulations, which reflected a trend depending on latitude of cultivation. A total of 37 significant (p < 0.01) associations with FAs were identified by association mapping analysis. These associations were represented by 33 SNPs (occurring in 32 annotated genes); another four SNPs had a significant association with two different FAs due to pleiotropic interactions. The most significant associations were cross-verified by known genes/QTL or consistency across cultivation year and subpopulations. CONCLUSION: The detected marker-trait associations represent a first important step towards the implementation of molecular-marker-based selection of FA composition with the potential to substantially improve the seed quality of soybean with benefits for human health and for food processing. PMID- 26494483 TI - The neural circuitry supporting goal maintenance during cognitive control: a comparison of expectancy AX-CPT and dot probe expectancy paradigms. AB - Goal maintenance is an aspect of cognitive control that has been identified as critical for understanding psychopathology according to criteria of the NIMH sponsored CNTRICS (Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia) and Research Domain Criteria (RDoC) initiatives. CNTRICS proposed the expectancy AX-CPT, and its visual-spatial parallel the dot probe expectancy (DPX), as valid measures of the cognitive and neural processes thought to be relevant for goal maintenance. The goal of this study was to specifically examine the functional neural correlates and connectivity patterns of both goal maintenance tasks in the same subset of subjects to further validate their neural construct validity and clarify our understanding of the nature and function of the neural circuitry engaged by the tasks. Twenty-six healthy control subjects performed both the letter (AX) and dot pattern (DPX) variants of the CPT during fMRI. Behavioral performance was similar between tasks. The 2 tasks engaged the same brain networks including dorsolateral prefrontal cortex (DLPFC) and dorsal parietal regions, supporting their validity as complementary measures of the goal maintenance construct. Interestingly there was greater engagement of the frontal opercular insula region during the expectancy AX-CPT (letter) and greater functional connectivity between the PFC and medial temporal lobe in the DPX (dot pattern). These differences are consistent with differential recruitment of phonological and visual-spatial processes by the two tasks and suggest that additional long-term memory systems may be engaged by the dot probe version. PMID- 26494484 TI - Possible Involvement of Serum and Synovial Fluid Resistin in Knee Osteoarthritis: Cartilage Damage, Clinical, and Radiological Links. AB - BACKGROUND: Resistin is an adipocytokine associated with inflammation and insulin resistance. Recent studies have shown that resistin plays an important role in the pathogenesis and progression in osteoarthritis (OA) patients. The current study was aimed at investigating the relationship between resistin in serum and synovial fluid (SF) and disease severity in patients with knee osteoarthritis. METHOD: Seventy-four patients diagnosed with knee OA and 79 healthy controls receiving regular body check in our hospital were recruited in the study. The Noyes score method was used to assess articular cartilage damage arthroscopically. The symptomatic severity was evaluated according to the Western Ontario McMaster University Osteoarthritis (WOMAC) scores. The radiographic disease severity of OA was assessed by the Kellgren-Lawrence (K-L) grading system. The resistin levels in serum and SF were determined by enzyme-linked immunosorbent assay. Cartilage degradation marker CTX-II in SF was also examined. RESULTS: SF but not serum resistin levels are positively associated with Noyes scores, K-L grading scores WOMAC pain scores, physical functional scores and WOMAC total scores. In addition, SF resistin correlated positively with CTX-II. CONCLUSION: Resistin in SF might serve as a potential biomarker for reflecting the disease severity and cartilage degenerative extent of knee OA. PMID- 26494485 TI - Additional postoperative cell salvage of shed mediastinal blood in cardiac surgery does not reduce allogeneic blood transfusions: a cohort study. AB - OBJECTIVES: Does additional postoperative collection and processing of mediastinal shed blood with a cell salvage device reduce the number of allogeneic blood transfusions compared to intraoperative cell salvage alone? METHODS: A single-centre cohort study in which adult patients with coronary artery bypass grafting or aortic valve replacement were allocated to either a C.A.T.S((r)) group with intraoperative blood processing only or a CardioPat((r)) group with both intra- and postoperative blood processing. The primary endpoint was the number of allogeneic blood transfusions during hospital admission. RESULTS: The study included 99 patients; 50 in the C.A.T.S((r)) and 49 in the CardioPat((r)) group.There was no difference in the number of red blood cells (RBC) (C.A.T.S((r)) group 43 units versus CardioPat((r)) 50 units, p=0.74), fresh frozen plasma (C.A.T.S((r)) 8 units versus CardioPat((r)) 8 units, p=1.00) or platelets (C.A.T.S((r)) 5 units versus CardioPat((r)) 4 units, p=1.00) transfused during the hospital stay.Cardiac creatinine kinase (CK-MB) and troponin levels did not differ between the groups although a significant time effect (p<0.001) was present. Creatinine kinase (CK) levels were not different between the groups three hours after arrival in the intensive care unit (ICU) (CardioPat((r)) group versus C.A.T.S((r)) group, p=0.17). But, compared to the C.A.T.S((r)) group on the first (350 [232-469] IU/L) and second postoperative days (325 [201-480] IU/L), the increase in CK levels was more in the CardioPat((r)) group on the first (431 [286-642] IU/L, p=0.02) and second postoperative days (406 [239-760] IU/L, p=0.05), resulting in a difference between the groups (p=0.04) CONCLUSIONS: Postoperative cell salvage does not reduce transfusion requirements compared to intraoperative cell salvage alone, but results in elevated total CK levels that suggest haemolysis. PMID- 26494486 TI - Cardiovascular causes of emergency neurology presenting to an ICU. AB - Stroke or transient ischemic attacks (TIA) represent an urgent clinical entity that is not limited only to elderly patients. The underlying causes of stroke and TIA are diverse, with those of cardiovascular origin being among the most prominent. This review seeks to elucidate some of the most important aspects of the disease in the context of emergency and critical care practice. PMID- 26494487 TI - Asymmetric synthesis of aromatic beta-amino acids using omega-transaminase: Optimizing the lipase concentration to obtain thermodynamically unstable beta keto acids. AB - Synthesized aromatic beta-amino acids have recently attracted considerable attention for their application as precursors in many pharmacologically relevant compounds. Previous studies on asymmetric synthesis of aromatic beta-amino acids using omega-transaminases could not be done efficiently due to the instability of beta-keto acids. In this study, a strategy to circumvent the instability problem of beta-keto acids was utilized to generate beta-amino acids efficiently via asymmetric synthesis. In this work, thermodynamically stable beta-ketoesters were initially converted to beta-keto acids using lipase, and the beta-keto acids were subsequently aminated using omega-transaminase. By optimizing the lipase concentration, we successfully overcame the instability problem of beta-keto acids and enhanced the production of beta-amino acids. This strategy can be used as a general approach to efficiently generate beta-amino acids from beta ketoesters. PMID- 26494488 TI - In-hospital resource utilization in surgical and transcatheter aortic valve replacement. AB - BACKGROUND: Little is known about preoperative predictors of resource utilization in the treatment of high-risk patients with severe symptomatic aortic valve stenosis. We report results from the prospective, medical-economic "TAVI Calculation of Costs Trial". METHODS: In-hospital resource utilization was evaluated in 110 elderly patients (age >= 75 years) treated either with transfemoral (TF) or transapical (TA) transcatheter aortic valve implantation (TAVI, N = 83), or surgical aortic valve replacement (AVR, N = 27). Overall, 22 patient-specific baseline parameters were tested for within-group prediction of resource use. RESULTS: Baseline characteristics differed between groups and reflected the non-randomized, real-world allocation of treatment options. Overall procedural times were shortest for TAVI, intensive care unit (ICU) length of stay (LoS) was lowest for AVR. Length of total hospitalization since procedure (THsP) was lowest for TF-TAVI; 13.4 +/- 11.4 days as compared to 15.7 +/- 10.5 and 21.2 +/- 15.4 days for AVR and TA-TAVI, respectively. For TAVI and AVR, EuroScore I remained the main predictor for prolonged THsP (p <0.01). Within the TAVI group, multivariate regression analyses showed that TA-TAVI was associated with a substantial increase in THsP (55 to 61 %, p <0.01). Additionally, preoperative aortic valve area (AVA) was identified as an independent predictor of prolonged THsP in TAVI patients, irrespective of risk scores (p <0.05). CONCLUSIONS: Our results demonstrate significant heterogeneity in patients baseline characteristics dependent on treatment and corresponding differences in resource utilization. Prolonged ThsP is not only predicted by risk scores but also by baseline AVA, which might be useful in stratifying TAVI patients. TRIAL REGISTRATION: German Clinical Trial Register Nr. DRKS00000797. PMID- 26494489 TI - Medication use for chronic health conditions among adults in Saudi Arabia: findings from a national household survey. AB - PURPOSE: Chronic diseases and their risk factors are believed to be common in the Kingdom of Saudi Arabia (KSA). Most of them require long-term management through medications. We examined patterns of medication use for chronic health conditions (CHC) in KSA based on a national survey. METHODS: The Saudi Health Interview Survey was a cross-sectional nationally representative household survey of 10,735 individuals aged 15 years or older in 2013. The survey consisted of a detailed health questionnaire. Current medications for CHC were assessed and classified based on the Anatomical Therapeutic Chemical classification. RESULTS: Among the respondents, 11.8% (standard error = 0.4) reported taking at least one medication for CHC with a mean number of 2.05 (standard error = 0.05) medication items. In addition to older age (odds ratio = 1.94 per each decade, 95%CI: 1.83-2.05) and male gender (odds ratio = 1.22, 95%CI: 1.06-1.41), those with higher income were more likely to take medication. The most common medicines were drugs used for diabetes (A10 Anatomical Therapeutic Chemical code). The top 20 drugs accounted for about 80% of all medications. Only 32.7% of medications were reported to be used exactly as prescribed. CONCLUSIONS: Compared with the prevalence of CHC in KSA, our study indicates a potential underuse of medications as well as non adherence to the directions for use. Interventions such as improved clinical guidelines for healthcare providers to increase utilization of necessary medication and educational programs to improve patients' adherence are needed. PMID- 26494490 TI - Isoflavones in Chickpeas Inhibit Adipocyte Differentiation and Prevent Insulin Resistance in 3T3-L1 Cells. AB - Diabetes mellitus is a metabolic disease characterized by hyperglycemia arising from defects in insulin secretion. This study investigated the effects of isoflavones in chickpea sprouts germinated in light (IGL) and isoflavones in chickpea seeds (ICS) on insulin resistance through their role in suppression of 3T3-L1 adipocyte differentiation. Results showed that IGL and ICS inhibit the differentiation of 3T3-L1 pre-adipocytes induced by differentiation medium in a dose-dependent manner, and the suppressive effect of IGL was stronger (p < 0.05) than that of ICS, evidenced by a decrease of Oil Red O staining and intracellular triacylglycerol content in the mature adipocytes. IGL and ICS also stimulated glucose uptake significantly (p < 0.05). Besides, IGL and ICS treatment caused a significant decrease in mRNA and protein expression levels of adipogenesis related transcription factors peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT-enhancer-binding protein alpha (C/EBPalpha). Furthermore, the mRNA and protein expression levels of adipocyte fatty acid-binding protein (ap2), lipoprotein lipase (LPL), uncoupling protein-2 (UCP-2), and glucose transporter 4 (Glut4) in 3T3-L1 cells were also markedly down-regulated (p < 0.05). PMID- 26494491 TI - [Magnetic resonance imaging of the prostate: usefulness of diffusion sequences in detecting postembolization ischemia in patients with benign prostatic hyperplasia]. AB - OBJECTIVE: To analyze the usefulness of diffusion magnetic resonance (MR) sequences before and after prostatic artery embolization (PAE) in patients with benign prostatic hyperplasia (BPH). MATERIAL AND METHODS: We analyzed MR studies done before (7-10 days) and after (30 days) PAE in 19 patients with BPH treated with PAE between June 2012 and December 2013. We used 1.5 Tesla scanners with body surface coils. In pre-PAE MR studies, we recorded mean b40 values and minimum (min) and maximum (max) apparent diffusion coefficient (ADC) values. In post-PAE MR studies, we recorded b40, b400, and b1000 values and min, mean, and max ADC values. We compared diffusion behavior/ADC before and after PAE and areas without ischemia. We correlated these with decreased prostatic volume (PV). RESULTS: We identified ischemia with contrast in 8 (42.1%) patients. No significant difference was found in mean b40 (p= 0.1650) or in the b40 ratio (p= 0.8868) between patients with ischemia and those without before PAE. Min b40, b40 ratio, and min ADC values differed significantly between ischemic areas and nonischemic areas within patients [p= 0.048 (b40min and ratio) and p= 0.002 (min ADC)]. No significant correlation was found between the percentage decrease in PV and mean b40 (p= 0.8490) or b40 ratio (p=0.8573). CONCLUSION: Post-PAE ischemia generates objective changes in diffusion and ADC values that enable ischemic sectors to be differentiated from nonischemic sectors. Future studies should analyze whether it is possible to subjectively differentiate between these areas through the visualization of nonischemic sectors and the feasibility of replacing them with contrast to detect ischemia. PMID- 26494492 TI - [The use of metal radiotracers in PET: the new reality]. PMID- 26494493 TI - [Response to the letter: "Neither a scientist nor a moralist: only a radiologist"]. PMID- 26494494 TI - [Neither a scientist nor a moralist: only a radiologist]. PMID- 26494495 TI - [Evaluation of the new Canon HS-100 SD-OCT: Reproducibility of macular ganglion cell complex (GCC) thickness measurement in normal, hypertensive and glaucomatous eyes]. AB - PURPOSE: To evaluate intra- and interobserver reproducibility of macular GCC thickness measurement by automated segmentation on the Canon HS-100 SD-OCT (Tokyo, Japan) in normal (N), hypertensive (OHT) and glaucomatous eyes. METHODS: A total of 179 eyes of 93 patients were included: 90 N, 28 OHT and 36 early glaucoma and 25 advanced glaucoma. All patients underwent a complete ophthalmologic exam, central corneal thickness and 24-2 standard automated perimetry (HFA SITA standard). Each of two observers performed three macular acquisitions with the Canon OCT HS-100. Acquisitions were analyzed with the Glaucoma 3D mode, which estimated the macular GCC thickness in global, superior and inferior hemisectors, and in eight separate macular areas. Reproducibility was assessed by intraclass correlation coefficient (ICC), coefficient of variation (CV) and test-retest variability (TRTV) calculated as 1.96 times the standard deviation. RESULTS: Mean GCC thickness was respectively 92.4 MUm, 89.0 MUm, 80.7 MUm and 71.2 MUm in N, OHT, early and advanced glaucomatous eyes. In all groups, intra- and interobserver reproducibility ranged respectively for ICC from 89.8 to 99.8% and from 90.2 to 99.4%, for CV from 0.43 to 1.95% and from 0.58 to 2.16% and for TRTV from 0.8 to 3.22 MUm and from 1.04 to 3.53 MUm. GCC thickness measurements using the new HS-100 SD-OCT were highly reproducible. However, in the advanced glaucoma group, while the reproducibility of GCC thickness measurement is good in the average, superior and inferior hemisectors of the macula, it was slightly less for the paracentral sectors, especially inferior. These sectors correspond generally to the areas most affected by glaucoma. CONCLUSION: The reproducibility of GCC thickness measurements using the new Canon HS-100 SD-OCT is high for normal, OHT, and glaucomatous eyes. It is thus a reliable and reproducible ancillary test available to the clinician for the examination of glaucomatous optic neuropathies. PMID- 26494496 TI - [Physician information sheet: Treatment of diabetic macular edema]. PMID- 26494497 TI - Introduction. PMID- 26494498 TI - Corneal Emergencies. AB - Corneal emergencies can be due to a number of different causes and may be vision threatening if left untreated. In an attempt to stabilize the cornea, it is of benefit to place an Elizabethan collar on the patient to prevent further corneal damage. This article discusses the diagnosis, prognosis, and management of corneal emergencies in dogs and cats. PMID- 26494499 TI - Lens-Related Emergencies: Not Always So Clear. AB - Emergencies involving the crystalline lens are not common; however, their clinical signs must be recognized quickly to begin treatment or referred immediately to improve the chances of retaining sight. The lens is a unique structure because of its immunologically privileged status and its imperative clarity for vision. Any insult to the lens capsule's integrity, its position within the globe, or to its clarity may result in undesirable sequelae. PMID- 26494500 TI - Glaucomas. AB - Canine and feline glaucomas are commonly presented as ocular emergencies. Glaucoma is a common cause of vision loss and a frustrating disorder in terms of medical and surgical treatment. Increased intraocular pressure (IOP) is a significant risk factor in the disease, leading to damage of the retina and optic nerve head. IOP measurement and gonioscopic and fundic examinations provide the instruments for diagnosis of glaucoma. The primary goal in glaucoma therapy is aimed at vision preservation. Medical treatment provides temporary relief, but alone it fails to control IOP in the long term, and surgical intervention is recommended. Surgical patient selection depends on several factors, from type and stage of glaucoma to the presence of or potential for vision. Available surgical procedures to decrease IOP consist of cyclodestructive techniques to decrease aqueous humor production and filtering techniques to increase its drainage. Even with recent surgical and medical advances, pain and blindness are still common occurrences in the disease: end-stage procedures such as enucleation, evisceration with intrascleral prosthesis, and pharmacologic ablation of ciliary bodies are then recommended to address chronic discomfort for buphthalmic and blind globes. PMID- 26494501 TI - Hyphema: Considerations in the Small Animal Patient. AB - Classification, diagnosis, and treatment of hemorrhage into the anterior chamber of the eye, or hyphema, can be a challenging and frustrating process for many practitioners, especially in emergency situations. This review outlines an inclusive list of causes, diagnostics, and treatments for traumatic and nontraumatic hyphema in both canine and feline patients. The review is tailored to small animal practitioners, especially in emergency practice, and is designed to provide concise but thorough descriptions on investigating underlying causes of hyphema and treating accordingly. PMID- 26494502 TI - Management of Orbital Diseases. AB - Orbital diseases are common in dogs and cats and can present on emergency due to the acute onset of many of these issues. The difficulty with diagnosis and therapy of orbital disease is that the location of the problem is not readily visible. The focus of this article is on recognizing classical clinical presentations of orbital disease, which are typically exophthalmos, strabismus, enophthalmos, proptosis, or intraconal swelling. After the orbital disease is confirmed, certain characteristics such as pain on opening the mouth, acute vs. chronic swelling, and involvement of nearby structures can be helpful in determining the underlying cause. Abscesses, cellulitis, sialoceles, neoplasia (primary or secondary), foreign bodies, and immune-mediated diseases can all lead to exophthalmos, but it can be difficult to determine the cause of disease without advanced diagnostic imaging, such as ultrasound, magnetic resonance imaging, or computed tomography scan. Fine-needle aspirates and biopsies of the retrobulbar space can also be performed. PMID- 26494503 TI - Acute Blindness. AB - Sudden loss of vision is an ophthalmic emergency with numerous possible causes. Abnormalities may occur at any point within the complex vision pathway, from retina to optic nerve to the visual center in the occipital lobe. This article reviews specific prechiasm (retina and optic nerve) and cerebral cortical diseases that lead to acute blindness. Information regarding specific etiologies, pathophysiology, diagnosis, treatment, and prognosis for vision is discussed. PMID- 26494504 TI - Cardiovascular Safety of Concomitant Use of Atypical Antipsychotics and Long Acting Stimulants in Children and Adolescents With ADHD. AB - OBJECTIVE: This study examined cardiovascular safety of concomitant use of long acting stimulants (LAS) and atypical antipsychotics (AAP) in children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD). METHOD: The study used 2004-2007 IMS LifeLinkTM claims data involving 6- to 16-year-old children with ADHD and at least one LAS prescription from July 2004 to December 2006. Time-dependent Cox regression analysis was performed to evaluate the risk of cardiovascular disease (CVD) events due to concomitant use of LAS and AAP. RESULTS: The analytical cohort consisted of 37,903 children: 538 (1.9%) used LAS and AAP concurrently and the rest used LAS monotherapy. Time-dependent Cox regression analysis revealed no difference in CVD risk among concomitant users of LAS and AAP (hazard ratio = 1.19; 95% confidence interval = [0.60, 2.53]) when compared with users of LAS monotherapy. CONCLUSION: Concomitant use of LAS and AAP was not associated with risk of CVD events in ADHD patients when compared with LAS monotherapy. PMID- 26494505 TI - Working Memory and Increased Activity Level (Hyperactivity) in ADHD: Experimental Evidence for a Functional Relation. AB - OBJECTIVE: Converging evidence indicates large magnitude deficits in the "working" component of working memory for children with ADHD. However, our understanding of the relation between these central executive deficits and ADHD behavioral symptoms remains limited due to problems with several commonly used working memory tests. METHOD: Children with ADHD (n = 25) completed a counterbalanced series of working memory tasks that differed only in memory set predictability. RESULTS: Results indicated that central executive demands increased when memory set was unpredictable, as evidenced by moderate performance decreases (d = 0.22-0.56) and large changes in performance variability (d = 0.93 3.16) and response times (d = 1.74-4.16). Activity level remained relatively stable when memory set was unpredictable but decreased significantly over time when memory set was predictable. CONCLUSION: Results suggest that altering memory set predictability is a feasible method for increasing/maintaining central executive demands over time, and suggest a positive association between working memory demands and gross motor activity for children with ADHD. PMID- 26494506 TI - Effects of bisphenol A on lipid metabolism in rare minnow Gobiocypris rarus. AB - As one of the most abundant endocrine disrupting compounds (EDCs), bisphenol A (BPA) exists ubiquitously in an aquatic environment. Many studies on fish have focused on the reproductive toxicity effects of BPA. However, few has involved the effects of BPA on lipid metabolism. To evaluate the effects of BPA on lipid metabolism, we determine the hepato-somatic index, triglyceride contents in the liver and serum, the activities of acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), carnitine palmitoyltransferase (CPT1), and glycerol-3-phosphate acyltransferase (GPAT) enzymes and the mRNA expression of acaca, acacb, fasn, gpat1 and cpt1alpha in Gobiocypris rarus after exposure to BPA for 28days. BPA induced increasing tendency of triglyceride contents in male fish, possibly due to up-regulated lipid synthesis. Although in this process, fatty acid beta oxidation was up-regulated, it might be compensated by increasing lipogenesis. Our result also revealed that the GPAT enzyme might play a key role in lipid metabolism disturbance by BPA in females. Besides, the effect of BPA on the fatty acid beta-oxidation pathway might be gender-dependent in G. rarus. Further studies are needed to investigate BPA's effects on the signaling pathway of lipid metabolism. PMID- 26494507 TI - Berberine and Coptidis Rhizoma as potential anticancer agents: Recent updates and future perspectives. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The antineoplastic property of Coptidis Rhizoma and berberine was correlated with its traditional use of clearing internal fire, removing damp-heat and counteracting toxic pathogens. AIM OF THE STUDY: The anti tumor effect of Coptidis Rhizoma and berberine was extensively studied since our last comprehensive review in 2009. This study aims to summarize the recent updates and give rise to perspectives of Coptidis Rhizoma and berberine as potential novel antineoplastic agents. METHODS: Quality studies in recent 5 years were retrieved from PubMed, Medline and CNKI with keywords including Coptis, Coptidis Rhizoma, huanglian, berberine, tumor and cancer. Studies were focused on the pharmacological actions of Coptidis Rhizoma and berberine in cancer progression. RESULTS: It was shown that Coptidis Rhizoma extract and berberine may repress tumor progression by regressing abnormal cell proliferation, arresting cell cycle and inducing cell death. Studies also highlighted the actions of Coptidis Rhizoma extract and berberine in inhibiting tumor cell invasion and angiogenesis, which in turn abolish cancer metastasis. Some studies have also been conducted to reveal the potential effect of Coptidis Rhizoma extract and berberine in regulating tumor stromal microenvironment, as well as in preventing carcinogenesis. Most of the results have been demonstrated with in vivo models, but results of high-quality clinical trials are not yet available. Unspecified cancer type and staging, fluctuated dose information and variants of targets across studies of berberine/ Coptidis Rhizoma impede their clinical use for cancer treatment. CONCLUSION: Recent advances highlighted by this review may shed light on future direction of studies featuring Coptidis Rhizoma and berberine as novel antineoplastic agents, which should be repeatedly proven in future animal and clinical studies. Although more evidences on its specificity and clinical efficacy are necessary to support its clinical use, Coptidis Rhizoma and berberine are highly expected to be effective, safe and affordable treatments for cancer patients. PMID- 26494508 TI - Protective effects of sea buckthorn polysaccharide extracts against LPS/d-GalN induced acute liver failure in mice via suppressing TLR4-NF-kappaB signaling. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides L.) berries have been traditionally used to treat gastric disorders, cardiovascular problems, and liver injuries in oriental medicinal system. This study aimed to explore the protective effects and mechanisms of the polysaccharide extracts of Sea buckthorn (HRP) berries against lipopolysaccharide (LPS) and d-galactosamine hydrochloride (d-GalN)-induced acute liver failure in mice. MATERIALS AND METHODS: HRP was isolated by hot-water extraction and characterized by HPLC and infrared spectrum analysis. The total carbohydrate, uronic acid and protein contents of HRP were measured by a spectrophotometric method. Mice were orally administrated with HRP (50, 100, 200mg/kg) once daily for 14 consecutive days prior to the challenge with LPS (50 MUg/kg) and d-GalN (300 mg/kg). Animals of positive control group were intraperitoneally injected with dexamethasone (10mg/kg). Mice were sacrificed at 8h after LPS/d-GalN injection. RESULTS: Pretreatment with HRP significantly inhibited LPS/d-GalN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, which were accompanied by alleviated liver injuries and reduced production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). HRP was also found to reduce malondialdehyde (MDA) content and to restore superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities. Furthermore, HRP supplementation dose-dependently inhibited the expression of Toll-like receptor 4 (TLR4), phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated c Jun N-terminal kinase (p-JNK), and phosphorylated mitogen activated protein kinase 38 (p-p38 MAPK) in the liver of LPS/d-GalN challenged mice. Pretreatment with HRP also inhibited LPS/d-GalN-induced activation and translocation of nuclear factor-kappaB (NF-kappaB). CONCLUSIONS: This study indicates that pretreatment with HRP protects against LPS/d-GalN-induced liver injury in mice via suppressing the TLR4-NF-kappaB signaling pathway. Sea buckthorn may be a hopeful drug for prevention of acute live injury. PMID- 26494509 TI - Contribution to the traditional uses of medicinal plants of Turgutlu (Manisa- Turkey). AB - ETHNOBOTANICAL RELEVANCE: The aim of this study is to document and describe important ethnobotanical features of 14 villages of Turgutlu (Manisa - Turkey). MATERIALS AND METHODS: The regular ethnobotanical surveys were carried out during different seasons in the years 2009 and 2010 in 14 villages of Turgutlu. The data was collected from 91 village inhabitants using semi-structured interviews. Use value (UV) was used to calculate the relative importance of species known by the inhabitants. Informant Consensus Factor (FIC) was used to calculate the level of homogeneity of diseases. RESULTS: Twenty-nine plant families and 54 plant species were found in this ethnobotanical survey. Among them, 22 (40.7%) species were wild and 32 (59.3%) species were cultivated plants. Rosaceae (14.8%), Asteraceae (9.3%), Lamiaceae (9.3%), Apiaceae (5.6%) and Brassicaceae (5.6%) were the most common plant families. According to results of the use value (UV) calculations, Agropyron repens (L.) P.Beauv., Lactuca sativa L., Beta vulgaris L. var. crassa (Alef.) Helm, Spinacia oleracea L., Brassica nigra (L.) Koch, Capsella bursa pastoris L. and Eugenia caryophyllata Thunb. yielded the highest use value. Consensus Informants Factor (FIC) ranges were between 0.87 and 0.95. Blood disorders, wounds, dermatological diseases and chest infections were 0.95, 0.93, 0.92, 0.90 while both gastrointestinal and skeletomuscular ailments were 0.87 informant consensus values, respectively. CONCLUSIONS: The usage of medicinal plants for traditional healers is still popular among the inhabitants of the village. This study documents valuable information for traditional remedies and contributes to the usage of medicinal plants in the research area. PMID- 26494510 TI - Partial mastectomy using manual blunt dissection (MBD) in early breast cancer. AB - BACKGROUND: Breast-preserving surgery (Bp) and sentinel lymph node biopsy (SNB) are established as standard treatment for axillary lymph node-negative early breast cancer. METHODS: A surgical technique using manual blunt dissection (MBD), in which use of electrocautery, an ultrasonically activated scalpel, and ligation is minimized, is described. This involves an approach from small incisions in the axilla or areola to avoid injury to skin flaps, and with adequate mobilization of the breast, so that regardless of the tumor site, surgical wounds are not noticeable. The usefulness and tolerability of this surgical technique were examined. RESULTS: This surgical technique was evaluated in 233 patients. Surgery could be performed rapidly, with a mean operative time of 67 +/- 21 min and a low mean blood loss of only 35 +/- 28 ml. There was little need for postoperative analgesia, and surgery was well tolerated without postoperative bleeding or wound infection. CONCLUSION: Our proposed technique for partial mastectomy using MBD provides good curative and cosmetic results. PMID- 26494511 TI - DBD atmospheric plasma-modified, electrospun, layer-by-layer polymeric scaffolds for L929 fibroblast cell cultivation. AB - This paper reported a study related to atmospheric pressure dielectric barrier discharge (DBD) Ar + O2 and Ar + N2 plasma modifications to alter surface properties of 3D PCL/Chitosan/PCL layer-by-layer hybrid scaffolds and to improve mouse fibroblast (L929 ATCC CCL-1) cell attachment, proliferation, and growth. The scaffolds were fabricated using electrospinning technique and each layer was electrospun sequentially on top of the other. The surface modifications were performed with an atmospheric pressure DBD plasma under different gas flow rates (50, 60, 70, 80, 90, and 100 sccm) and for different modification times (0.5-7 min), and then the chemical and topographical characterizations of the modified samples were done by contact angle (CA) measurements, scanning electron microscopy (SEM), atomic force microscopy, and X-ray photoelectron spectroscopy. The samples modified with Ar + O2 plasma for 1 min under 70 cm(3)/min O2 flow rate (71.077 degrees +/- 3.578) showed a 18.83% decrease compare to unmodified samples' CA value (84.463 degrees +/- 3.864). Comparing with unmodified samples, the average fiber diameter values for plasma-modified samples by Ar + O2 (1 min 70 sccm) and Ar + N2 (40 s 70 sccm) increased 40.756 and 54.295%, respectively. Additionally, the average inter-fiber pore size values exhibited decrease of 37.699 and 48.463% for the same Ar + O2 and Ar + N2 plasma-modified samples, respectively, compare to unmodified samples. Biocompatibility performance was determined with MTT assay, fluorescence, Giemsa, and confocal imaging as well as SEM. The results showed that Ar + O2-based plasma modification increased the hydrophilicity and oxygen functionality of the surface, thus affecting the cell viability and proliferation on/within scaffolds. PMID- 26494512 TI - Danish retinoblastoma patients 1943-2013 - genetic testing and clinical implications. AB - BACKGROUND: In heritable retinoblastoma there is a 50% risk of transmitting the RB1 mutation, and offspring carriers have more than 90% risk of developing retinoblastoma. Today, all newly diagnosed retinoblastoma patients in Denmark are screened for mutations in RB1, as opposed to only a minority of patients diagnosed before DNA testing was offered. Knowledge of heredity increases the chance of early diagnosis in offspring, leading to improved prognosis. We present data from the Danish retinoblastoma patients that emphasize the need for genetic counseling and RB1 screening in all untested retinoblastoma survivors. MATERIAL AND METHODS: Data are extracted from The Danish Ocular Oncology Group Database, a national population database containing data on all Danish retinoblastoma patients since 1943. RESULTS: In total 323 retinoblastoma patients have been diagnosed between 1943 and 2013. Since 1963, the rate has been stable around 1 per 14 000 live births with 95% of the patients surviving their retinoblastoma. Stratifying data on the time of diagnosis and status of genetic testing, the number of screened patients gradually increased from 5% in the beginning of the period to 96% in the last five-year period. A cohort of 181 retinoblastoma survivors with sporadic disease (15% heritable) did not receive genetic testing. Since the introduction of routine testing, one of 14 sporadic unilateral patients tested (7%) has been identified with a germline mutation. Before routine testing, five additional sporadic unilateral patients have been identified as heritable. CONCLUSION: Only a minority of Danish retinoblastoma patients diagnosed before routine genetic testing was offered have been RB1 screened. To counsel the remaining untested patients and their families sufficiently regarding the risk to offspring and elevated risk of second primary cancers, we recommend information and access to genetic counseling and RB1 screening. This has ethical, psychological and possible economic consequences, and should be handled with caution. PMID- 26494513 TI - Functional interaction between OX2 and CB1 receptors in the ventral tegmental area and the nucleus accumbens in response to place preference induced by chemical stimulation of the lateral hypothalamus. AB - Orexinergic projections derived from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) and the nucleus accumbens (NAc), play a key role in the acquisition of conditioned place preference (CPP) induced by LH stimulation. On the other hand, there are several studies which support the idea of the existence of a cross-talk between the orexinergic and cannabinoid systems. Nevertheless, the function and how both systems interact in the reward circuit remain unknown. In this study, the authors tried to clarify the role of orexin-2 receptor (OX2r) within the VTA and NAc in the development of reward-related behaviors after chemical stimulation of the LH and also find out the involvement of CB1 cannabinoid receptors in this phenomenon. Animals were implanted by two separate cannulae into the LH and VTA or NAc, unilaterally. The CPP paradigm was done; and conditioning scores were recorded. The results showed that administration of TCS OX2 29 as a selective OX2r antagonist (1, 3 and 10 nM/rat) into the VTA or NAc just 5 min before microinjection of carbachol (250 nM/0.5 MUl saline), a cholinergic agonist, into the LH during the 3-day conditioning phase, could dose dependently inhibit the development of LH stimulation-induced CPP. Furthermore, concurrent injection of ineffective doses of TCS OX2 29 and AM251, as a CB1 receptor antagonist, into the NAc could reduce conditioning scores. The findings of this study showed that the OX2 receptor has a critical role in modulating reward circuit in the VTA and NAc, when the LH was stimulated by carbachol. Moreover, we suggest the existence of an interaction between orexinergic and cannabinoid systems within the VTA and NAc in place preference induced by LH stimulation. PMID- 26494514 TI - Effects of phenol on metabolic activities and transcription profiles of cytochrome P450 enzymes in Chironomus kiinensis larvae. AB - Phenol, also known as carbolic acid or phenic acid, is a priority pollutant in aquatic ecosystems. The present study has investigated metabolic activities and transcription profiles of cytochrome P450 enzymes in Chironomus kiinensis under phenol stress. Exposure of C. kiinensis larvae to three sublethal doses of phenol (1, 10 and 100 uM) inhibited cytochrome P450 enzyme activity during the 96 h exposure period. The P450 activity measured after the 24 h exposure to phenol stress could be used to assess the level (low or high) of phenol contamination in the environment. To investigate the potential of cytochrome P450 genes as molecular biomarkers to monitor phenol contamination, the cDNA of ten CYP6 genes from the transcriptome of C. kiinensis were identified and sequenced. The open reading frames of the CYP6 genes ranged from 1266 to 1587 bp, encoding deduced polypeptides composed of between 421 and 528 amino acids, with predicted molecular masses from 49.01 to 61.94 kDa and isoelectric points (PI) from 6.01 to 8.89. Among the CYP6 genes, the mRNA expression levels of the CYP6EW3, CYP6EV9, CYP6FV1 and CYP6FV2 genes significantly altered in response to phenol exposure; therefore, these genes could potentially serve as biomarkers in the environment. This study shows that P450 activity combined with one or multiple CYP6 genes could be used to monitor phenol pollution. PMID- 26494515 TI - The neurobiological basis of human aggression: A review on genetic and epigenetic mechanisms. AB - Aggression is an evolutionary conserved behavior present in most species including humans. Inadequate aggression can lead to long-term detrimental personal and societal effects. Here, we differentiate between proactive and reactive forms of aggression and review the genetic determinants of it. Heritability estimates of aggression in general vary between studies due to differing assessment instruments for aggressive behavior (AB) as well as age and gender of study participants. In addition, especially non-shared environmental factors shape AB. Current hypotheses suggest that environmental effects such as early life stress or chronic psychosocial risk factors (e.g., maltreatment) and variation in genes related to neuroendocrine, dopaminergic as well as serotonergic systems increase the risk to develop AB. In this review, we summarize the current knowledge of the genetics of human aggression based on twin studies, genetic association studies, animal models, and epigenetic analyses with the aim to differentiate between mechanisms associated with proactive or reactive aggression. We hypothesize that from a genetic perspective, the aminergic systems are likely to regulate both reactive and proactive aggression, whereas the endocrine pathways seem to be more involved in regulation of reactive aggression through modulation of impulsivity. Epigenetic studies on aggression have associated non-genetic risk factors with modifications of the stress response and the immune system. Finally, we point to the urgent need for further genome-wide analyses and the integration of genetic and epigenetic information to understand individual differences in reactive and proactive AB. (c) 2015 Wiley Periodicals, Inc. PMID- 26494517 TI - REFLECTIONS. PMID- 26494516 TI - Effects of Long-Term Aging in Arsenical Copper Alloys. AB - Archaeological materials present unique records on natural processes allowing the study of long-term material behaviors such as structural modifications and degradation mechanisms. The present work is focused on the chemical and microstructural characterization of four prehistoric arsenical copper artifacts. These artifacts were characterized by micro-energy dispersive X-ray fluorescence spectrometry, optical microscopy, scanning electron microscopy with X-ray microanalysis, micro-X-ray diffraction and synchrotron radiation micro-X-ray diffraction. Cu3As is the expected intermetallic arsenide in arsenical copper alloys, reported in the literature as exhibiting a hexagonal crystallographic structure. However, a cubic Cu3As phase was identified by X-ray diffraction in all of our analyzed archaeological artifacts, while the hexagonal Cu3As phase was clearly identified only in the artifact with higher arsenic content. Occurrence of the cubic arsenide in these particular objects, suggests that it was precipitated due to long-term aging at room temperature, which points to the need of a redefinition of the Cu-As equilibrium phase constitution. These results highlight the importance of understanding the impact of structural aging for the assessment of original properties of archaeological arsenical copper artifacts, such as hardness or color. PMID- 26494518 TI - Health trends in a geriatric and special needs clinic patient population. AB - PURPOSE: To quantify differences and recent changes in health status among patients attending the Geriatric and Special Needs Dentistry (GSND) and Family Dentistry (FAMD) clinics at the University of Iowa College of Dentistry. METHODS: A total of 388 randomly selected records from patients attending the GSND or FAMD clinics from 1996-2000 or from 2006-2010 were reviewed. Univariate and bivariate analyses were conducted, followed by multivariable logistic regression analyses to compare characteristics of patients across clinics. RESULTS: Between the two GSND cohorts, the mean number of medications reported increased from 4.0 to 6.5 (p < 0.001). Within both cohorts, mental health conditions were significantly more prevalent among patients attending the GSND than FAMD clinic (p < 0.001). CONCLUSIONS: Within cohorts, patients seen in the GSND clinic tended to have more medical problems than patients attending the FAMD clinic, particularly mental health conditions; and medication use was more common in the recent cohort in both GSND and FAMD clinics. PMID- 26494520 TI - Public Access Defibrillation Programs: Improving Outcomes Worldwide. PMID- 26494521 TI - Attitudes toward beef and vegetarians in Argentina, Brazil, France, and the USA. AB - Meat is both the most favored and most tabooed food in the world. In the developed world, there is a tension between its high nutritional density, preferred taste, and high status on the one hand, and concerns about weight, degenerative diseases, the ethics of killing animals, and the environmental cost of meat production on the other hand. The present study investigated attitudes toward beef, and toward vegetarians, among college students in Argentina, Brazil, France, and the USA. Across countries, men were more pro-beef, in free associations, liking, craving, and frequency of consumption. By country, Brazil and Argentina were generally the most positive, followed by France and then the United States. Ambivalence to beef was higher in women, and highest in Brazil. Only Brazilian and American women reported frequent negative associations to beef (e.g. "disgusting", "fatty"). Overall, most students had positive attitudes to beef, and the attitude to vegetarians was generally neutral. America and Brazilian women showed some admiration for vegetarians, while only French men and women had negative attitudes to vegetarians. In spite of frequent negative ethical, health, and weight concerns, in the majority of the sample, liking for and consumption of beef was maintained at a high level. PMID- 26494519 TI - Metformin and Myocardial Injury in Patients With Diabetes and ST-Segment Elevation Myocardial Infarction: A Propensity Score Matched Analysis. AB - BACKGROUND: Although animal studies have documented metformin's cardioprotective effects, the impact in humans remains elusive. The study objective was to explore the association between metformin and myocardial infarct size in patients with diabetes presenting with ST-segment elevation myocardial infarction. METHODS AND RESULTS: Data extraction used the National Cardiovascular Data CathPCI Registry in all patients with diabetes aged >18 years presenting with ST-segment elevation myocardial infarction at 2 academic medical centers from January 2010 to December 2013. The exposure of interest was ongoing metformin use before the event. Propensity score matching was used for the metformin and nonmetformin groups on key prognostic variables. All matched pairs had acceptable D scores of <10%, confirming an efficient matching procedure. The primary outcome was myocardial infarct size, reflected by peak serum creatine kinase-myocardial band, troponin T, and hospital discharge left ventricular ejection fraction. Of all 1726 ST segment elevation myocardial infarction cases reviewed, 493 patients had diabetes (28.5%), with 208 metformin users (42.1%) and 285 nonusers. Matched pairs analysis yielded 137 cases per group. The difference between metformin and nonmetformin groups was -18.1 ng/mL (95% CI -55.0 to 18.8; P=0.56) for total peak serum creatine kinase-myocardial band and -1.1 ng/mL (95% CI -2.8 to 0.5; P=0.41) for troponin T. Median discharge left ventricular ejection fraction in both groups was 45, and the difference between metformin and nonmetformin users was 0.7% (95% CI -2.2 to 3.6; P=0.99). CONCLUSIONS: No statistically significant association of cardioprotection was found between metformin and myocardial infarct size in patients with diabetes and acute ST-segment elevation myocardial infarction. PMID- 26494522 TI - Eating behavior associated with gray matter volume alternations: A voxel based morphometry study. AB - Little is known about whether eating behavior is associated with alterations of brain structure or whether the possible alterations are related to body weight status. The current study employed structural imaging from an open MRI data set (http://fcon_1000. PROJECTS: nitrc.org/indi/pro/nki.html) to examine the relationship between eating behavior traits and brain structural changes. The eating behavior traits were measured by the Three Factor Eating Questionnaire Scale. The brain structural alterations were analyzed using the Voxel Based Morphometry (VBM) method, and a multiple linear regression model was constructed to identify significant brain structural changes that related to eating behavior factors. We found that cognitive restraint of eating was positively correlated with the gray matter volume (GMV) in the dorsolateral prefrontal cortex (DLPFC) and negatively correlated with the GMV in the putamen; disinhibition scores were negatively associated with the GMV in the left middle frontal gyrus; hunger scores showed a positive correlation with the GMV in the hypothalamus and the visual memory areas and a negative association with the GMV in the inferior temporal gyrus and the bilateral middle frontal gyrus. These results indicated a close connection between the eating behavior traits and structural changes in particular brain regions. Conjunction analysis was also performed to further explore the brain structural alterations that were commonly associated with eating behavior and weight status. The findings add to our understanding of the neural basis underlying eating behaviors, and the connection between these behaviors and body weight status. PMID- 26494523 TI - Non-destructive mapping of grain orientations in 3D by laboratory X-ray microscopy. AB - The ability to characterise crystallographic microstructure, non-destructively and in three-dimensions, is a powerful tool for understanding many aspects related to damage and deformation mechanisms in polycrystalline materials. To this end, the technique of X-ray diffraction contrast tomography (DCT) using monochromatic synchrotron and polychromatic laboratory X-ray sources has been shown to be capable of mapping crystal grains and their orientations non destructively in 3D. Here we describe a novel laboratory-based X-ray DCT modality (LabDCT), enabling the wider accessibility of the DCT technique for routine use and in-depth studies of, for example, temporal changes in crystallographic grain structure non-destructively over time through '4D' in situ time-lapse studies. The capability of the technique is demonstrated by studying a titanium alloy (Ti beta21S) sample. In the current implementation the smallest grains that can be reliably detected are around 40 MUm. The individual grain locations and orientations are reconstructed using the LabDCT method and the results are validated against independent measurements from phase contrast tomography and electron backscatter diffraction respectively. Application of the technique promises to provide important insights related to the roles of recrystallization and grain growth on materials properties as well as supporting 3D polycrystalline modelling of materials performance. PMID- 26494525 TI - Targeting pain in Parkinson's disease. PMID- 26494526 TI - Impact of weak social ties and networks on poor sleep quality: A case study of Iranian employees. AB - The poor sleep quality is one of the major risk factors of somatic, psychiatric and social disorders and conditions as well as the major predictors of quality of employees' performance. The previous studies in Iran had neglected the impacts of social factors including social networks and ties on adults sleep quality. Thus, the aim of the current research was to determine the relationship between social networks and adult employees' sleep quality. This study was conducted with a correlational and descriptive design. Data were collected from 360 participants (183 males and 177 females) who were employed in Yazd public organizations in June and July of 2014. These samples were selected based on random sampling method. In addition, the measuring tools were the Pittsburgh Sleep Quality Index (PSQI) and Social Relations Inventory (SRI). Based on the results, the prevalence rate of sleep disorder among Iranian adult employees was 63.1% (total PSQI>5). And, after controlling for socio-demographic variables, there was significant difference between individuals with strong and poor social network and ties in terms of overall sleep quality (p<.01), subjective sleep quality (p<.01), habitual sleep efficiency (p<.05), and daytime dysfunction (p<.01). The results also revealed that the employees with strong social network and ties had better overall sleep quality, had the most habitual sleep efficiency, and less daytime dysfunction than employees with poor social network and ties. It can be implied that the weak social network and ties serve as a risk factor for sleep disorders or poor sleep quality for adult employees. Therefore, the social and behavioral interventions seem essential to improve the adult's quality sleep. PMID- 26494524 TI - Prolonged-release oxycodone-naloxone for treatment of severe pain in patients with Parkinson's disease (PANDA): a double-blind, randomised, placebo-controlled trial. AB - BACKGROUND: Pain is a common non-motor symptom of Parkinson's disease. We investigated the analgesic efficacy of prolonged-release oxycodone-naloxone (OXN PR) in patients with Parkinson's disease and chronic, severe pain. METHODS: We did this phase 2 study in 47 secondary care centres in the Czech Republic, Germany, Hungary, Poland, Romania, Spain, and the UK. We enrolled patients with Hoehn and Yahr Stage II-IV Parkinson's disease, at least one type of severe pain, and an average 24-h pain score of at least 6 (assessed on an 11-point rating scale from 0=no pain to 10=pain as bad as you can imagine). Participants were randomly assigned (1:1) with a validated automated system (block size four) to either oral OXN PR or placebo for 16 weeks (starting dose oxycodone 5 mg, naloxone 2.5 mg, twice daily). Patients and investigators were masked to treatment assignment. The primary endpoint was average 24-h pain score at 16 weeks in the full analysis population. This study is registered with EudraCT (2011-002901-31) and ClinicalTrials.gov (NCT01439100). FINDINGS: We enrolled 202 patients; 93 were assigned to OXN PR and 109 to placebo; the full analysis population consisted of 88 patients versus 106 patients. Least squares mean average 24-h pain score at 16 weeks in the full analysis population was 5.0 (95% CI 4.5 to 5.5) in the OXN PR group versus 5.6 (5.1 to 6.0) in the placebo group (difference -0.6, 95% CI -1.3 to 0.0; p=0.058). Similar proportions of patients in each group had adverse events (60/92 [65%] vs 76/109 [70%]), treatment-related adverse events (52/92 [57%] vs 62/109 [57%]), and serious adverse events (5/92 [5%] vs 7/109 [6%]). Treatment-related nausea was more common in the OXN PR group than in the placebo group (16/92 [17%] vs 10/109 [9%]), as was treatment-related constipation (16/92 [17%] vs 6/109 [6%]). INTERPRETATION: The primary endpoint, based on the full analysis population at week 16, was not significant. Nonetheless, the results of this study highlight the potential efficacy of OXN PR for patients with Parkinson's disease-related pain and might warrant further research on OXN PR in this setting. FUNDING: Mundipharma Research. PMID- 26494527 TI - Polymicrobial community-acquired pneumonia: An emerging entity. AB - Polymicrobial aetiology in community-acquired pneumonia (CAP) is more common than previously recognized. This growing new entity can influence inflammation, host immunity and disease outcomes in CAP patients. However, the true incidence is complicated to determine and probably underestimated due mainly to many cases going undetected, particularly in the outpatient setting, as the diagnostic yield is restricted by the sensitivity of currently available microbiologic tests and the ability to get certain types of clinical specimens. The observed rate of polymicrobial cases may also lead to new antibiotic therapy considerations. In this review, we discuss the pathogenesis, microbial interactions in pneumonia, epidemiology, biomarkers and antibiotic therapy for polymicrobial CAP. PMID- 26494528 TI - Multimaterial magnetically assisted 3D printing of composite materials. AB - 3D printing has become commonplace for the manufacturing of objects with unusual geometries. Recent developments that enabled printing of multiple materials indicate that the technology can potentially offer a much wider design space beyond unusual shaping. Here we show that a new dimension in this design space can be exploited through the control of the orientation of anisotropic particles used as building blocks during a direct ink-writing process. Particle orientation control is demonstrated by applying low magnetic fields on deposited inks pre loaded with magnetized stiff platelets. Multimaterial dispensers and a two component mixing unit provide additional control over the local composition of the printed material. The five-dimensional design space covered by the proposed multimaterial magnetically assisted 3D printing platform (MM-3D printing) opens the way towards the manufacturing of functional heterogeneous materials with exquisite microstructural features thus far only accessible by biological materials grown in nature. PMID- 26494529 TI - Use of Ventricular Assist Device in Univentricular Physiology: The Role of Lumped Parameter Models. AB - Failing single-ventricle (SV) patients might benefit from ventricular assist devices (VADs) as a bridge to heart transplantation. Considering the complex physiopathology of SV patients and the lack of established experience, the aim of this work was to realize and test a lumped parameter model of the cardiovascular system, able to simulate SV hemodynamics and VAD implantation effects. Data of 30 SV patients (10 Norwood, 10 Glenn, and 10 Fontan) were retrospectively collected and used to simulate patients' baseline. Then, the effects of VAD implantation were simulated. Additionally, both the effects of ventricular assistance and cavopulmonary assistance were simulated in different pathologic conditions on Fontan patients, including systolic dysfunction, diastolic dysfunction, and pulmonary vascular resistance increment. The model can reproduce patients' baseline well. Simulation results suggest that the implantation of VAD: (i) increases the cardiac output (CO) in all the three palliation conditions (Norwood 77.2%, Glenn 38.6%, and Fontan 17.2%); (ii) decreases the SV external work (SVEW) (Norwood 55%, Glenn 35.6%, and Fontan 41%); (iii) increases the mean pulmonary arterial pressure (Pap) (Norwood 39.7%, Glenn 12.1%, and Fontan 3%). In Fontan circulation, with systolic dysfunction, the left VAD (LVAD) increases CO (35%), while the right VAD (RVAD) determines a decrement of inferior vena cava pressure (Pvci) (39%) with 34% increment of CO. With diastolic dysfunction, the LVAD increases CO (42%) and the RVAD decreases the Pvci. With pulmonary vascular resistance increment, the RVAD allows the highest CO (50%) increment with the highest decrement of Pvci (53%). The single ventricular external work (SVEW) increases (decreases) increasing the VAD speed in cavopulmonary (ventricular) assistance. Numeric models could be helpful in this challenging and innovative field to support patients and VAD selection to optimize the clinical outcome and personalize the therapy. PMID- 26494530 TI - Converting the bis-FeIV state of the diheme enzyme MauG to Compound I decreases the reorganization energy for electron transfer. AB - The electron transfer (ET) properties of two types of high-valent hemes were studied within the same protein matrix; the bis-Fe(IV) state of MauG and the Compound I state of Y294H MauG. The latter is formed as a consequence of mutation of the tyrosine which forms the distal axial ligand of the six-coordinate heme that allows it to stabilize Fe(IV) in the absence of an external ligand. The rates of the ET reaction of each high-valent species with the type I copper protein, amicyanin, were determined at different temperatures and analysed by ET theory. The reaction with bis-Fe(IV) wild-type (WT) MauG exhibited a reorganization energy (lambda) that was 0.39 eV greater than that for the reaction of Compound I Y295H MauG. It is concluded that the delocalization of charge over the two hemes in the bis-Fe(IV) state is responsible for the larger lambda, relative to the Compound I state in which the Fe(V) equivalent is isolated on one heme. Although the increase in lambda decreases the rate of ET, the delocalization of charge decreases the ET distance to its natural substrate protein, thus increasing the ET rate. This describes how proteins can balance different ET properties of complex redox cofactors to optimize each system for its particular ET or catalytic reaction. PMID- 26494532 TI - In silico studies on the role of mutant Y337A to reactivate tabun inhibited mAChE with K048. AB - Organophosphorus compound (OP) tabun is resistant to reactivate by many oxime drugs after the formation of OP-conjugate with AChE. The reactivation of tabun inhibited mAChE and site-directed mutants by bispyridinium oxime, K048 (N-[4-(4 hydroxyiminomethylpyridinio)butyl]-4-carbamoylpyridinium dibromide) showed that the mutations significantly poor the overall reactivation efficacy of K048. We have unravelled the lowered efficacy of K048 with the tabun-mutant mAChE(Y337A) using docking and steered molecular dynamics (SMD) simulations. The computed results showed some interesting features for the interaction of drug molecule K048 with tabun-mAChE(wild-type) and tabun-mutant mAChE(Y337A). The SMD simulations showed that the active pyridinium ring of K048 is directed towards the phosphorus atom conjugated to the active serine (SUN203) of tabun-mAChE(wild type). The cradle shaped residues Tyr337-Phe338 present in the choline binding site stabilize the active pyridinium ring of K048 with pi-pi interaction and the residue Trp86 involved in T-shaped cation-pi interaction. However, in the case of tabun-mutant mAChE(Y337A).K048 conjugate, the replacement of aromatic Tyr337 with the aliphatic alanine unit in the choline binding site, however, loses one of the pi-pi interaction between the active pyridinium ring of K048 and the Tyr337. The placement of aliphatic alanine unit resulted in the displacement of the side chain of Phe338 towards the His447. Such displacement is causing the inaccessibility of the drug towards the phosphorus atom conjugated to the active serine (SUN203) of tabun-mutant mAChE(Y337A). Furthermore, the unbinding of the K048 with SMD studies showed that the active pyridinium ring of the drug undergoes a complete turn along the gorge axis and is directed away from the phosphorus atom conjugated to the active serine of the tabun-mutant mAChE(Y337A). Such effects inside the gorge of tabun-mutant mAChE(Y337A) would lower the efficacy of the drug molecule (K048) for the reactivation process. The binding free energy computed for the tabun-mAChE(wild-type) and tabun-mutant mAChE(Y337A) with K048 showed that the drug molecule prefers to bind strongly with the former enzyme (~30 kJ/mol) than the later one. PMID- 26494531 TI - Lactobacillus plantarum displaying CCL3 chemokine in fusion with HIV-1 Gag derived antigen causes increased recruitment of T cells. AB - BACKGROUND: Chemokines are attractive candidates for vaccine adjuvants due to their ability to recruit the immune cells. Lactic acid bacteria (LAB)-based delivery vehicles have potential to be used as a cheap and safe option for vaccination. Chemokine produced on the surface of LAB may potentially enhance the immune response to an antigen and this approach can be considered in development of future mucosal vaccines. RESULTS: We have constructed strains of Lactobacillus plantarum displaying a chemokine on their surface. L. plantarum was genetically engineered to express and anchor to the surface a protein called CCL3Gag. CCL3Gag is a fusion protein comprising of truncated HIV-1 Gag antigen and the murine chemokine CCL3, also known as MIP-1alpha. Various surface anchoring strategies were explored: (1) a lipobox-based covalent membrane anchor, (2) sortase-mediated covalent cell wall anchoring, (3) LysM-based non-covalent cell wall anchoring, and (4) an N-terminal signal peptide-based transmembrane anchor. Protein production and correct localization were confirmed using Western blotting, flow cytometry and immunofluorescence microscopy. Using a chemotaxis assay, we demonstrated that CCL3Gag-producing L. plantarum strains are able to recruit immune cells in vitro. CONCLUSIONS: The results show the ability of engineered L. plantarum to produce a functional chemotactic protein immobilized on the bacterial surface. We observed that the activity of surface-displayed CCL3Gag differed depending on the type of anchor used. The chemokine which is a part of the bacteria-based vaccine may increase the recruitment of immune cells and, thereby, enhance the reaction of the immune system to the vaccine. PMID- 26494533 TI - Normalisation theory: Does it accurately describe temporal changes in adolescent drunkenness and smoking? AB - INTRODUCTION AND AIMS: The multiple risk model postulates that accumulating risk factors increase adolescent drunkenness and smoking. The normalisation theory adds to this by arguing that the relation between accumulative risk and drunkenness and smoking is dependent on the distribution of these behaviours in the larger population. More concretely, normalisation theory predicts that: (i) when population level use increases, low risk adolescents will be more likely to use alcohol and cigarettes; and (ii) adolescents facing multiple risk factors will be equally likely to use alcohol and cigarettes, regardless of trends in population level use. The current study empirically tests these assumptions on five waves of nationally representative samples of Israeli Jewish youth. DESIGN AND METHODS: Five cross-sectional waves of data from the Israeli Health Behaviour in School-aged Children survey for Jewish 10th graders were used. Logistic regression models measured the impact of changes in population level use across waves on drunkenness and smoking, and their association with differing levels of risk factors. RESULTS: Between zero and two risk factors, the risk of drunkenness and smoking increases for each additional risk factor. When reaching two risk factors, added risk does not significantly increase the likelihood of smoking and drunkenness. Changes in population level drunkenness and smoking did not systematically relate to changes in the individual level relationship between risk factors and smoking and drunkenness. DISCUSSION AND CONCLUSIONS: The pattern of results in this study provides strong evidence for the multiple risk factor model and inconsistent evidence for the normalisation theory. [Sznitman SR, Zlotnick C, Harel-Fisch Y. Normalisation theory: Does it accurately describe temporal changes in adolescent drunkenness and smoking? Drug Alcohol Rev 2016;35:424-432]. PMID- 26494534 TI - Flexible modelling of vaccine effect in self-controlled case series models. AB - The self-controlled case series (SCCS) method, commonly used to investigate the safety of vaccines, requires information on cases only and automatically controls all age-independent multiplicative confounders, while allowing for an age dependent baseline incidence. Currently, the SCCS method represents the time varying exposures using step functions with pre-determined cut points. A less prescriptive approach may be beneficial when the shape of the relative risk function associated with exposure is not known a priori, especially when exposure effects can be long-lasting. We therefore propose to model exposure effects using flexible smooth functions. Specifically, we used a linear combination of cubic M splines which, in addition to giving plausible shapes, avoids the integral in the log-likelihood function of the SCCS model. The methods, though developed specifically for vaccines, are applicable more widely. Simulations showed that the new approach generally performs better than the step function method. We applied the new method to two data sets, on febrile convulsion and exposure to MMR vaccine, and on fractures and thiazolidinedione use. PMID- 26494535 TI - Subdiffraction localization of a nanostructured photosensitizer in bacterial cells. AB - Antibacterial treatments based on photosensitized production of reactive oxygen species is a promising approach to address local microbial infections. Given the small size of bacterial cells, identification of the sites of binding of the photosensitizing molecules is a difficult issue to address with conventional microscopy. We show that the excited state properties of the naturally occurring photosensitizer hypericin can be exploited to perform STED microscopy on bacteria incubated with the complex between hypericin and apomyoglobin, a self-assembled nanostructure that confers very good bioavailability to the photosensitizer. Hypericin fluorescence is mostly localized at the bacterial wall, and accumulates at the polar regions of the cell and at sites of cell wall growth. While these features are shared by Gram-negative and Gram-positive bacteria, only the latter are effectively photoinactivated by light exposure. PMID- 26494536 TI - Sclerostin Antibody Treatment Increases Bone Formation, Bone Mass, and Bone Strength of Intact Bones in Adult Male Rats. AB - We investigated the systemic effect of sclerostin monoclonal antibody (Scl-Ab) treatment on intact non-operated bones in an open osteotomy male Sprague Dawley (SD) rat model. Six-month-old male SD rats were subjected to transverse osteotomy at the right femur mid-shaft. Rats were injected subcutaneously with vehicle or Scl-Ab (25 mg/kg, 2 times per week) treatment for 9 weeks. Compared with vehicle control, Scl-Ab treatment significantly improved trabecular and cortical bone mass and microarchitecture at L5 vertebrae and left femora by micro-CT at week 6 and 9. Mechanical testing showed that Scl-Ab treatment resulted in significantly higher stiffness, energy to failure and ultimate load at the femora at week 9. Mineral apposition rate, mineralizing surface and bone formation rate on the trabecular bone in the distal femora was significantly increased in Scl-Ab group at week 6 and 9. The administered Scl-Ab was localized in the osteocytes and beta catenin was strongly expressed in osteoblasts. Scl-Ab treatment significantly increased serum P1NP level and there was no between-group difference in serum level of CTX-1. In conclusion, Scl-Ab treatment could induce rapid and sustained increase in bone formation, bone mass and bone strength in non-operated bones. Sclerostin inhibition might be advantageous to prevent secondary fracture(s). PMID- 26494537 TI - Three-dimensional optical transfer function in differential confocal microscopy. AB - To reveal the fundamental characteristics of differential confocal microscopy (DCM), its imaging properties were analysed by studying the 3D optical transfer function (OTF). The zero transfer at zero frequency along the axial direction in DCM, which has not been well understood and is considerably different from the transfer behaviour in conventional confocal microscopy (CM), was elucidated. The integral expressions of the OTFs for CM and DCM and the subsequent simulation results showed that DCMs have higher transfer capability than CM in the axial direction at medium and high frequencies. Conventionally, the relative optimal defocusing amount in DCMs are determined through calculations of the gradient of the point spread functions in the spatial domain. In contrast, in this study, the OTF performances were compared and the optimal defocusing amount was found to be between 5 and 7. PMID- 26494539 TI - Splitting a Substrate into Three Parts: Gold-Catalyzed Nitrogenation of Alkynes by C-C and C=C Bond Cleavage. AB - A gold-catalyzed nitrogenation of alkynes for the synthesis of carbamides and amino tetrazoles through C-C and C=C bond cleavages is described. A diverse set of functionalized carbamide and amino tetrazole derivatives were selectively constructed under mild conditions. The chemoselectivity can be easily switched by the selection of the acid additives. The reaction is characterized by its broad substrate scope, direct construction of high value products, easy operation under air, and mild conditions at room temperature. This chemistry provides a way to transform alkynes by splitting the substrate into three parts. PMID- 26494538 TI - Neural tube opening and abnormal extraembryonic membrane development in SEC23A deficient mice. AB - COPII (coat protein complex-II) vesicles transport proteins from the endoplasmic reticulum (ER) to the Golgi. Higher eukaryotes have two or more paralogs of most COPII components. Here we characterize mice deficient for SEC23A and studied interactions of Sec23a null allele with the previously reported Sec23b null allele. SEC23A deficiency leads to mid-embryonic lethality associated with defective development of extraembryonic membranes and neural tube opening in midbrain. Secretion defects of multiple collagen types are observed in different connective tissues, suggesting that collagens are primarily transported in SEC23A containing vesicles in these cells. Other extracellular matrix proteins, such as fibronectin, are not affected by SEC23A deficiency. Intracellular accumulation of unsecreted proteins leads to strong induction of the unfolded protein response in collagen-producing cells. No collagen secretion defects are observed in SEC23B deficient embryos. We report that E-cadherin is a cargo that accumulates in acini of SEC23B deficient pancreas and salivary glands. Compensatory increase of one paralog is observed in the absence of the second paralog. Haploinsufficiency of the remaining Sec23 paralog on top of homozygous inactivation of the first paralog leads to earlier lethality of embryos. Our results suggest that mammalian SEC23A and SEC23B transport overlapping yet distinct spectra of cargo in vivo. PMID- 26494540 TI - Overgeneral autobiographical memory predicts higher prospective levels of depressive symptoms and intrusions in borderline patients. AB - Overgeneral memory (OGM), the tendency to retrieve categories of events from autobiographical memory instead of single events, is found to be a reliable predictor for future mood disturbances and post-traumatic symptom severity. Patients with borderline personality disorder (BPD) often report co-morbid episodes of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Therefore, we investigated whether OGM would predict depression severity and (post-traumatic) stress symptoms in BPD patients. At admission (N = 54) and at six-month follow-up (N >= 31), BPD patients completed the Structured Clinical Interview for DSM-IV Disorders, the Assessment of DSM-IV Personality Disorders, the Autobiographical Memory Test, the Beck Depression Inventory-2nd edition (BDI II), and the Impact of Event Scale. OGM at baseline predicted (a) higher levels of depressive symptoms at follow-up and (b) more intrusions related to a stressful event over and above baseline levels of borderline symptoms, depressive symptoms, and intrusions, respectively. No association was found between memory specificity and event-related avoidance at follow-up. Despite previous findings suggesting that OGM in BPD is less robust than in MDD and PTSD, our results suggest that memory specificity in BPD patients may have some relevance for the course of depressive and stress symptomatology in BPD. PMID- 26494541 TI - Advances and challenges in paracoccidioidomycosis serology caused by Paracoccidioides species complex: an update. AB - Understanding the possible methodologies for the rapid and inexpensive identification of fungal infections is essential for disease diagnosis, but there are some limitations. To help with this problem, serological methods that detect antigens or antibodies are widely used and are useful for the diagnosis of paracoccidioidomycosis (PCM) through the detection of gp43, which is the main antigen employed for the immunodiagnosis of this disease caused by Paracoccidioides brasiliensis. However, the use of gp43 has become restricted because it was recently found that this marker is not identified in the infections caused by Paracoccidioides lutzii. Therefore, it is necessary to identify new antigens in both species or antigens specific for P. lutzii to decrease the morbidity and/or mortality associated with PCM. This review provides a discussion of new diagnostic challenges after the recent discoveries regarding the taxonomy of the Paracoccidioides genus. PMID- 26494542 TI - Intramolecular OH???Fluorine Hydrogen Bonding in Saturated, Acyclic Fluorohydrins: The gamma-Fluoropropanol Motif. AB - Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH???F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time-and in contrast to earlier reports-the occurrence of OH???F IMHBs in acyclic saturated gamma-fluorohydrins, even for the parent 3 fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding (h1) JOH???F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9 Hz). The magnitude of OH???F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the "rule of shielding" applies to OH???F IMHB energies. Surprisingly, the predicted OH???F IMHB energies are only moderately weaker than these of the corresponding OH???OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design. PMID- 26494543 TI - Large Esophageal Hematoma Following Transesophageal Echocardiography-Guided Device Closure of Atrial Septal Defect. AB - A 47-year-old woman with a large ostium secundum atrial septal defect (ASD) and severe pulmonary artery hypertension underwent device closure of ASD under transesophageal echocardiography guidance. She developed a massive esophageal hematoma which was diagnosed 4 days after the procedure. The use of dual antiplatelets after the device closure further aggravated the hematoma. As the patient remained stable and the site of leak could not be identified by contrast studies, she was managed conservatively with nil per mouth, broad-spectrum antibiotics, and continuous nasogastric aspiration. We were faced with the risk of thromboembolism after stopping antiplatelets versus the risk of increasing peri-esophageal hematoma if they were continued. With careful monitoring for thrombus formation on the device, the antiplatelets were stopped and the hematoma resolved. The hematoma resolved by 10 days, and the antiplatelets were restarted gradually. Iatrogenic esophageal injury is an important cause of esophageal perforation, which is a condition with high mortality and morbidity. Esophageal perforation following device closure of ASD is particularly challenging as the scenario is worsened by the use of antiplatelets and they have to be discontinued with the attendant risk of thromboembolism. PMID- 26494544 TI - Effects of dietary restriction followed by high dietary energy or protein on compensatory growth of Ashanti Black * Large White crossbred weaner pigs. AB - The study determined the effect of re-alimenting dietary protein or energy on compensatory growth. Eighteen Ashanti Black * Large White crossbred weaner pigs (7.5 +/- 0.30 kg) were randomly assigned to one of three dietary treatments in a completely randomized design resulting in three replicate pens per treatment (n = 3) and two pigs per pen. In the first treatment, pigs were fed ad libitum a diet containing 12.0 MJ/kg of metabolizable energy (ME) and 14.4% crude protein (CP) (maintenance diet) for 56 days. In the second and third dietary treatments, pigs were fed the maintenance diet for the initial 28 days and then switched to a high protein (17.4% dry matter (DM) CP; protein) or high (14.0 MJ/kg DM; energy) diet for the rest of the 28-day period. Dry matter intake and growth performance were similar (P >= 0.52) among treatments during the first 28 days of restrictive feeding, but pigs re-alimented with the protein diet achieved superior (P = 0.004) DM intake, average daily gain (ADG), and feed efficiency than those fed the maintenance diet or re-alimented with the energy diet in the re-alimentation period. At the end of the entire 56-day period, pigs re-alimented with the protein diet had higher (P >= 0.01) live weight gains and ADG compared with those fed the maintenance diet or re-alimented with the energy diet, but DM intake was similar (P = 0.66) among treatments. It was concluded that re-alimentation with protein rather than energy can improve compensatory growth of Ashanti Black * Large White crossbred weaner pigs. PMID- 26494545 TI - Alleviation of chronic heat stress in broilers by dietary supplementation of betaine and turmeric rhizome powder: dynamics of performance, leukocyte profile, humoral immunity, and antioxidant status. AB - Heat stress (HS), one of the most serious climate problems of tropical and subtropical countries, negatively affects the production performance of broilers. Keeping this in view, the current study was aimed at elucidating the effects of supplementing betaine (Bet) and dried turmeric rhizome powder (TRP), either singly or in combination, on growth performance, leukocyte profile, humoral immunity, and antioxidant status in broilers kept under chronic HS. A total of 625 one-day-old Ross male chicks were randomly assigned to five treatment groups (5 replicates of 25 birds per replicate pen). From day 1, the birds were either kept at the thermoneutral zone (TN) or exposed to HS (33 +/- 1 degrees C) to the conclusion of study, day 42. THeat stress (HS), one of the most serious climate problems of tropical and subtropical countries, negatively affects the production performance of broilers. Keeping this in view, the current study was aimed at elucidating the effects of supplementing betaine (Bet) and dried turmeric rhizome powder (TRP), either singly or in combination, on growth performance, leukocyte profile, humoral immunity, and antioxidant status in broilers kept under chronic HS. A total of 625 one-day-old Ross male chicks were randomly assigned to five treatment groups (5 replicates of 25 birds per replicate pen). From day 1, the birds were either kept at the thermoneutral zone (TN) or exposed to HS (33 +/- 1 degrees C) to the conclusion of study, day 42. The treatment groups were as follows: thermoneutral control (TN-CON), HS-CON, HS-Bet, HS-TRP, and HS-BT (fed Bet and TRP). The results showed that decreases in body weight gain, feed intake, and increases in feed-to-gain ratio and mortality induced by HS were partially restored by dietary supplementation of Bet and TRP. The heterophil/lymphocyte ratio, total, and IgG antibody titers against sheep red blood cell for secondary responses in the HS-TRP and HS-BT groups were also similar to those of the broilers in the TN-CON group but better (P < 0.05) than for HS-CON group. An increase (P < 0.05) in serum concentration of malondialdehyde induced by HS was significantly decreased by dietary supplementations. The serum glutathione peroxidase and superoxide dismutase activities were also higher (P < 0.05) in the supplemented groups compared to both TN and HS-CON groups. In conclusion, dietary supplementation of either Bet or TRP alone or in combination can partially ameliorate some of the detrimental effects of HS in broilers. Results also suggest that TRP might be better than Bet for improving stress tolerance and immune response in heat-stressed broilers.he treatment groups were as follows: thermoneutral control (TN-CON), HS-CON, HS-Bet, HS-TRP, and HS-BT (fed Bet and TRP). The results showed that decreases in body weight gain, feed intake, and increases in feed-to-gain ratio and mortality induced by HS were partially restored by dietary supplementation of Bet and TRP. The heterophil/lymphocyte ratio, total, and IgG antibody titers against sheep red blood cell for secondary responses in the HS-TRP and HS-BT groups were also similar to those of the broilers in the TN-CON group but better (P < 0.05) than for HS-CON group. An increase (P < 0.05) in serum concentration of malondialdehyde induced by HS was significantly decreased by dietary supplementations. The serum glutathione peroxidase and superoxide dismutase activities were also higher (P < 0.05) in the supplemented groups compared to both TN and HS-CON groups. In conclusion, dietary supplementation of either Bet or TRP alone or in combination can partially ameliorate some of the detrimental effects of HS in broilers. Results also suggest that TRP might be better than Bet for improving stress tolerance and immune response in heat-stressed broilers. PMID- 26494546 TI - The bioefficacy of crude extracts of Azadirachta indica (Meliaceae) on the survival and development of myiasis-causing larvae of Chrysomya bezziana (Diptera: Calliphoridae). AB - Myiasis is a type of parasitosis originating from the invasion of tissues of live humans and other vertebrates by dipteran larvae. The Old World screwworm fly Chrysomya bezziana-is known worldwide in the tropical regions for causing myiasis among man and domestic animals, thereby leading to health hazards and severe economic losses to the dairy farmers. Management techniques for controlling populations of the fly are needed to minimize these losses. Plant-derived materials have been increasingly evaluated these days in controlling the insects of medical and veterinary importance. This study evaluated the efficacy of crude extracts of the plant neem, Azadirachta indica, against C. bezziana. The dried leaves of the plant were extracted successively with four different solvents viz. petroleum ether, chloroform, ethyl acetate and methanol and were evaluated against the third instar larvae of C. bezziana using dipping method and thin film application technique. In the dipping method, larvae were dipped in four different concentrations of plant extracts for 30 s, whereas in the thin film application, they were exposed to a thin film of plant extracts. The results showed that all the extracts had toxic effect on the larvae in both the techniques. In the dipping method, the highest mortalities were recorded in methanol extract followed by chloroform, petroleum ether and ethyl acetate extracts with LC50 values 1.07 g/100 ml, 1.7 g/100 ml, 3.39 g/100 ml and 4.9 g/100 ml, respectively. In the thin film application method, methanol extract showed the highest mortalities followed by chloroform, ethyl acetate and petroleum ether with LC50 values 0.4 mg/cm2, 0.6 mg/cm2, 2.1 mg/cm2 and 2.5 mg/cm2. It is concluded that the crude extracts of A. indica can be used in controlling the larvae of C. bezziana by using the dipping as well as thin film application technique. PMID- 26494547 TI - Partial substitution of soybean meal by Gliricidia sepium or Guazuma ulmifolia leaves in the rations of growing lambs. AB - The partial substitution of soybean meal by Gliricidia sepium or Guazuma ulmifolia leaves in the rations of growing lambs was evaluated at an experimental station in the dry tropics of Mexico. Sixteen weaned crossbred male Pelibuey * Blackbelly lambs (initial weight 19 +/- 1.66 kg), distributed in a completely randomized design, were assigned to the following protein sources: (a) 100% soybean meal, (b) 50% soybean meal + 50% G. sepium, (c) 50 % soybean meal + 25% G. ulmifolia + 25% G. sepium, and (d) 50% soybean meal + 50% G. ulmifolia in isoproteic rations. The lambs were housed in individual pens and fed ad libitum. Substitution of protein from soybean meal with G. ulmifolia did not affect gain, intake, or feed conversion; however, the inclusion of G. sepium reduced (linear effect, P < 0.01) gain and intake and impaired feed conversion (linear effect, P < 0.01). Partial substitution up to 50% of soybean meal with 50% G. ulmifolia leaves resulted in similar growth and lamb performance, but inclusion of G. sepium leaves adversely affected lamb growth, presumably due to other factors not related to the protein content. PMID- 26494548 TI - Dispersion of Polymers in Metallic Gallium. AB - This work examines the concept of dispersing polymers in metals. Herein, this was mainly studied with molten gallium, in which 5-18 wt % of various short-chain polymers were incorporated and mixed. The nature of the solidified products was examined by using X-ray diffraction, electron microscopy, UV/Vis, differential scanning calorimetry, and thermal gravimetric analyses. It was found that some polymers can be dispersed as small domains within molten metals to form a heterogeneous solid. The ability to dope Ga with large polymers opens a new avenue to electronic materials. PMID- 26494549 TI - More complaints should be resolved locally, says health ombudsman. PMID- 26494550 TI - Olfactory Transcriptional Analysis of Salmon Exposed to Mixtures of Chlorpyrifos and Malathion Reveal Novel Molecular Pathways of Neurobehavioral Injury. AB - Pacific salmon exposed to sublethal concentrations of organophosphate pesticides (OP) have impaired olfactory function that can lead to loss of behaviors that are essential for survival. These exposures often involve mixtures and can occur at levels below those which inhibit acetylcholinesterase (AChE). In this study, juvenile Coho salmon were exposed for 24 h to either 0.1, 0.5, or 2.5 ppb chlorpyrifos (CPF), 2, 10, or 50 ppb malathion (MAL), or binary mixtures of 0.1 CPF:2 ppb MAL, 0.5 CPF:10 ppb MAL, or 2.5 CPF:10 ppb MAL to mimic single and binary environmental exposures. Microarray analysis of olfactory rosettes from pesticide-exposed salmon revealed differentially expressed genes involved in nervous system function and signaling, aryl hydrocarbon receptor signaling, xenobiotic metabolism, and mitochondrial dysfunction. Coho exposed to OP mixtures exhibited a more pronounced loss in detection of a predatory olfactory cue relative to those exposed to single compounds, whereas respirometry experiments demonstrated that exposure to OPs, individually and in mixtures, reduced maximum respiratory capacity of olfactory rosette mitochondria. The observed molecular, biochemical, and behavioral effects occurred largely in the absence of effects on brain AChE. In summary, our results provide new insights associated with the sublethal neurotoxic effects of OP mixtures relevant to environmental exposures involving molecular and cellular pathways of injury to the salmon olfactory system that underlie neurobehavioral injury. PMID- 26494551 TI - Association study of BCL9 gene polymorphism rs583583 with schizophrenia and negative symptoms in Japanese population. AB - B-cell CLL/lymphoma 9 (BCL9) is located within the schizophrenia (SCZ) suspected locus chr1q21.1. A recent study reported that a single nucleotide polyphormism (SNP) within BCL9 (rs583583) is associated with negative symptoms of Schizophrenia, as measured by the Positive and Negative Syndrome Scale (PANSS), in the Caucasian population. We therefore investigated genetic association of rs583583, and its effect on negative symptoms in the Japanese patients. For association analysis, we used a Japanese sample set comprising 1089 SCZ and 950 controls (CON). Analysis of the effect of rs586586 on negative symptoms as examined by PANSS was investigated using 280 SCZ. Furthermore, for analysis of cognitive performance, we investigated 90 SCZ and 51 CON using the Continuous Performance Test (CPT-IP) and the Wisconsin Card Sorting Test (WCST) Keio version. We did not detect association between rs583583 and SCZ. Furthermore, rs583583 was not associated with PANSS negative scores or with CPT-IT or WCST cognitive tests. Considering the results of our previous study, combined with the results of the current study of rs583583, we argue that BCL9 most likely does not harbor a common genetic variant that can increase the risk for SCZ in the Japanese population. PMID- 26494552 TI - The Interaction of Water with Free Mn4 O4 (+) Clusters: Deprotonation and Adsorption-Induced Structural Transformations. AB - As the biological activation and oxidation of water takes place at an inorganic cluster of the stoichiometry CaMn4 O5 , manganese oxide is one of the materials of choice in the quest for versatile, earth-abundant water splitting catalysts. To probe basic concepts and aid the design of artificial water-splitting molecular catalysts, a hierarchical modeling strategy was employed that explores clusters of increasing complexity, starting from the tetramanganese oxide cluster Mn4 O4 (+) as a molecular model system for catalyzed water activation. First principles calculations in conjunction with IR spectroscopy provide fundamental insight into the interaction of water with Mn4 O4 (+) , one water molecule at a time. All of the investigated complexes Mn4 O4 (H2 O)n (+) (n=1-7) contain deprotonated water with a maximum of four dissociatively bound water molecules, and they exhibit structural fluxionality upon water adsorption, inducing dimensional and structural transformations of the cluster core. PMID- 26494553 TI - Laparoscopy assisted percutaneous stone surgery can be performed in multiple ways for pelvic ectopic kidneys. AB - Pelvic kidney stones remain a unique challenge to the endourologists. Treatment options include open surgery, extracorporeal shockwave lithotripsy, percutaneous nephrolithotomy (PNL), retrograde intrarenal surgery, and laparoscopy assisted PNL (LA-PNL). As a minimal invasive option, LA-PNL can decrease the risk for bowel and major vessel injury. Here, we describe our experience using the LA-PNL procedures with different combinations, to treat kidney stones in multiple patients with a pelvic ectopic kidney (PEK). Eight patients, with PEK, kidney stones, and no other treatment choice, but open surgery, were included in the study. Two different laparoscopic techniques such as mesocolon dissection and transmesocolic, and four different percutaneous procedures such as standard-PNL, mini-PNL, micro-PNL, and a PNL through the renal pelvis were used for stone extraction in these patients. The mean age of patients was 25.6 +/- 12.9 years and mean stone size was 524.1 +/- 430.3 mm(2). Mean operation time was 150.5 +/- 40.0 (77-210) min which was composed of retrograde catheterization (14.8 +/- 2.9 min), laparoscopic procedure (48.7 +/- 20.6 min) and PNL procedure (86.8 +/- 31.1 min). Residual stones were seen in two patients (no additional treatment was need), while a 'stone-free' procedure was achieved in six patients (75.0 %). On the post-operative first month visit, a stone was observed on radiological examinations in only one patient (87.5 % stone-free). Mean hospitalization time was 2.8 +/- 0.9 days. No perioperative or post-operative complication was observed in all patients. LA-PNL surgery is a safe and effective option for treatment of PEK stones, and has several alternative approaches. PMID- 26494554 TI - CRISPR/Cas9: molecular tool for gene therapy to target genome and epigenome in the treatment of lung cancer. AB - Although varied drugs and therapies have been developed for lung cancer treatment, in the past 5 years overall survival rates have not improved much. It has also been reported that lung cancer is diagnosed in most of the patients when it is already in the advanced stages with heterogeneous tumors where single therapy is mostly ineffective. A combination of therapies are being administered and specific genes in specific tissues are targeted while protecting normal cell, but most of the therapies face drawbacks for the development of resistance against them and tumor progression. Therefore, therapeutic implications for various therapies need to be complemented by divergent strategies. This review frames utilization of CRISPR/Cas9 for molecular targeted gene therapy leading to long-term repression and activation or inhibition of molecular targets linked to lung cancer, avoiding the cycles of therapy. PMID- 26494555 TI - HuR-targeted nanotherapy in combination with AMD3100 suppresses CXCR4 expression, cell growth, migration and invasion in lung cancer. AB - The CXCR4 chemokine receptor has an important role in cancer cell metastasis. The CXCR4 antagonist, AMD3100, has limited efficacy in controlling metastasis. HuR, an RNA-binding protein, regulates CXCR4 in cancer cells. We therefore investigated whether targeting HuR using a siRNA-based nanoparticle plus AMD3100 would suppress CXCR4 and inhibit lung cancer metastasis. We treated human H1299 lung cancer cells with HuR-specific siRNA contained in a folate-targeted lipid nanoparticle (HuR-FNP) plus AMD3100, and compared this with AMD3100 alone, HuR FNP alone and no treatment. HuR-FNP plus AMD3100 treatment produced a G1 phase cell cycle arrest and reduced cell viability above and beyond the effects of AMD3100 alone. HuR and CXCR4 mRNA and protein expression levels were markedly reduced in all treatment groups. Phosphorylated (p) AKT(S473) protein was also reduced. P27 protein expression increased with HuR-FNP and combination treatment. Promoter-based reporter studies showed that the combination inhibited CXCR4 promoter activity more than did either treatment alone. Cell migration and invasion was significantly reduced with all treatments; the combination provided the most inhibition. Reduced matrix metalloprotease (MMP)-2 and -9 expression was associated with reduced invasion in all treatment groups. Thus, we found that combined HuR and CXCR4 targeting effectively controlled lung cancer metastasis. PMID- 26494556 TI - Tumor suppressor microRNA-31 inhibits gastric carcinogenesis by targeting Smad4 and SGPP2. AB - To investigate the function of microRNA-31 (miR-31) in the pathogenesis of gastric cancer (GC) and to explore the possible mechanisms involved in it. A quantitative real-time reverse transcription-PCR (RT-PCR) analysis was performed to evaluate miR-31 expression in GC cell lines. After transfecting GC cells with miR-31 precursors, Alamar blue and apoptosis assays were used to measure the respective proliferation and apoptosis rates. SGPP2 and Smad4 expression were determined by real-time RT-PCR and western blot assays after miR-31 transfection. Animal assay was used to further investigate miR-31 in the pathogenesis of GC. miR-31 was significantly reduced in GC tissues and GC cell lines, and that the reduced miR-31 was associated with distant metastasis and GC clinical pathological stages, miR-31 was lower at stages III/IV than that at stage II. SGPP2 and Smad4 were proven to be the direct target of miR-31. SGPP2 and Smad4 at mRNA and protein levels were negatively correlated with miR-31 in human GC tissues and cancer cell lines. Increased miR-31 significantly repressed SGPP2 and Smad4 at transcriptional and translational levels. Functional studies showed that increasing miR-31 inhibited GC cell proliferation, promoted apoptosis and attenuated cell migration, which were also linked to downregulation of STAT3. In vivo, miR-31 inhibited GC cell growth in tumor-bearing mice. This study has revealed miR-31 as a tumor suppressor and has identified SGPP2 and Smad4 as novel targets of miR-31, linking to STAT3 for regulating cancer cell proliferation, apoptosis and migration in GC. Therefore, miR-31 could be a useful biomarker for monitoring GC development and progression, and also could have a therapeutic potential by targeting SGPP2, Smad4 and STAT3 for GC therapy. PMID- 26494557 TI - Conditioned media from human ovarian cancer endothelial progenitor cells induces ovarian cancer cell migration by activating epithelial-to-mesenchymal transition. AB - Bone marrow-derived endothelial progenitor cells (EPCs) migrate to and engraft at ovarian cancer sites. Understanding the interactions between ovarian cancer cells and EPCs is fundamental for determining whether to harness EPC-tumor interactions for delivery of therapeutic agents or target them for intervention. Ovarian cancer cell lines (SKOV-3 and OVCAR-3) were cultured alone or in EPC-conditioned media (EPC-CM). Migration of ovarian cancer cells was detected by transwell chamber. N-cadherin and E-cadherin expression were analyzed by real-time reverse transcription PCR and western blot. EPC-CM can increase transforming growth factor-beta (TGF-beta) secretion in SKOV-3 and OVCAR-3 cells. EPC-CM induced loss of ovarian cancer cell-cell junctions, downregulation of E-cadherin, upregulation of N-cadherin and acquisition of a fibroblastic phenotype, consistent with an epithelial-to-mesenchymal transition (EMT). The specific TGF-beta inhibitor SB431542 abolished the SKOV-3 and OVCAR-3 ovarian cancer cell migration induced by EPC-CM. In SKOV-3 and OVCAR-3 cells, EPC-CM downregulated E-cadherin and concurrently upregulated N-cadherin. EPC-CM upregulated the expression of transcriptional repressors of E-cadherin, Snail and Twist. Treatment with SB431542 abolished the effects of EPC-CM on the relative expression levels of cadherin, Snail and Twist. This study demonstrates that TGF-beta has a role in EPC-CM-induced ovarian cancer migration by activating EMT. PMID- 26494558 TI - Functional studies of miR-130a on the inhibitory pathways of apoptosis in patients with chronic myeloid leukemia. AB - The p53 mutation in chronic myeloid leukemia (CML) led to decreased overall survival and therapy resistance which was also closely correlated with the downstream proto-oncogenes BCL-2, TCL-1 and MCL-1. We in this study aimed to investigate the function of miR130a in p53 tumor suppressor signaling pathway. We performed microRNA (miRNA) expression profile analysis in CML cancer stem cells of 38 cases and extracted total RNA from peripheral blood of 143 cases. Standard curves of U6 and miRNA were made from 10-fold serial dilutions of the cDNA, which were quantified using real-time quantitative PCR with SYBR Green by ABI 7300. The p53 mutations and BCR/ABL mutation status analysis in CML patients were detected by PCR and direct sequencing. Candidate targets of miR130a of putative relevance in CML pathogenesis were analyzed by bioinformatics approach. We then used dual luciferase activity assay to verify the target genes of miR130a and used western blot analysis to elucidate the mechanism of miR130a on modulating drug resistance. The levels of miR-130a expression in CML were significantly lower in poor prognostic subgroups, defined by prognostic factors including mutated BCR/ABL status, p53 and ATM deletions and p53 mutations. Furthermore, underexpression of miR-130a was significantly associated with shorter overall survival and treatment-free survival in CML patients. We demonstrated that miR130a function as tumor suppressors by inhibiting multiple anti-apoptosis proteins, including BCL-2, MCL-1 and XIAP. This was a direct effect because miR130a negatively regulated expression of a BCL-2/MCL-1/XIAP 3'untranslated region-based reporter construct. Transfection of miR130a mimics into CML cells from 30 patients without p53 aberrations led to significant increases in apoptosis compared with transfection with the miRNA control. Besides, enforced expression of miR130a had no significant drug-sensitization effect in CML cells from p53-attenuated patients. MiR-130a may have an important role in the pathogenesis of CML and may be useful for assessing prognosis in patients with CML. Moreover, miR130a may provide a possible therapeutic avenue and a sensitive indicator of the activity of the p53 in CML. PMID- 26494559 TI - Fusion expression of cecropin B-like antibacterial peptide in Pichia GS115 and its antibacterial mechanism. AB - OBJECTIVES: To establish an efficient expression system for a fusion protein of glutathione S-transferase and cecropin B (GST-CB) and to clarify the antibacterial mechanism of CB. RESULTS: The optimal incubation time and methanol concentration for induced expression of CB were 36 h and 1 % w/v, respectively. The yield of GST-CB was 2.2 g/l. The minimum inhibitory concentrations of GST-CB towards Staphylococcus aureus subsp. saprophyticus (ATCC 15305) and Escherichia coli strain CFT073 were 250 and 125 MUg/ml, respectively. Notably, mutations of proline 24 (P24) in CB produced a polypeptide without antimicrobial activity. CONCLUSION: The fusion protein GST-CB, which has a broad spectrum antimicrobial activity, can be abundantly expressed in Pichia pastoris GS115, and P24 may be an important amino acid for the antimicrobial activity of GST-CB. PMID- 26494561 TI - Associations of arsenic metabolites, methylation capacity, and skin lesions caused by chronic exposure to high arsenic in tube well water. AB - To investigate the interaction between skin lesion status and arsenic methylation profiles, the concentrations and proportions of arsenic metabolites in urine and arsenic methylation capacities of study subjects were determined. The results showed that the mean urinary concentrations of iAs (inorganic arsenic), MMA (monomethylarsonic acid), DMA (dimethylarsinic acid), and TAs (total arsenic) were 75.65, 68.78, 265.81, and 410.24 MUg/L, respectively, in the skin lesions subjects. The highest values were observed in the multiple skin lesions subjects. Higher %iAs and %MMA, and lower %DMA, PMI (primary methylation index), and SMI (secondary methylation index) were found in skin lesions subjects. The multiple skin lesions subjects had highest %iAs and %MMA, and lowest %DMA, PMI, and SMI. The prevalence of skin lesions strongly, positively correlated with arsenic levels in drinking water. The elder persons also had higher frequency of skin lesions compared with younger persons. It can be concluded that arsenic levels in drinking water significantly affected the prevalence of skin lesions. Male subjects usually had higher proportions of skin lesions when compared with female subjects. Moreover, it may be concluded that MMA was significantly related to single skin lesion, whereas DMA and iAs were associated with multiple skin lesions. It seemed that MMA had greater toxicity to hyperkeratosis, whereas DMA and iAs had higher toxicity to depigmentation or pigmentation. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 28-36, 2017. PMID- 26494560 TI - 3-Deoxyschweinfurthin B Lowers Cholesterol Levels by Decreasing Synthesis and Increasing Export in Cultured Cancer Cell Lines. AB - The schweinfurthins have potent antiproliferative activity in multiple glioblastoma multiforme (GBM) cell lines; however, the mechanism by which growth is impeded is not fully understood. Previously, we demonstrated that the schweinfurthins reduce the level of key isoprenoid intermediates in the cholesterol biosynthetic pathway. Herein, we describe the effects of the schweinfurthins on cholesterol homeostasis. Intracellular cholesterol levels are greatly reduced in cells incubated with 3-deoxyschweinfurthin B (3dSB), an analog of the natural product schweinfurthin B. Decreased cholesterol levels are due to decreased cholesterol synthesis and increased cholesterol efflux; both of these cellular actions can be influenced by liver X-receptor (LXR) activation. The effects of 3dSB on ATP-binding cassette transporter 1 levels and other LXR targets are similar to that of 25-hydroxycholesterol, an LXR agonist. Unlike 25 hydroxycholesterol, 3dSB does not act as a direct agonist for LXR alpha or beta. These data suggest that cholesterol homeostasis plays a significant role in the growth inhibitory activity of the schweinfurthins and may elucidate a mechanism that can be targeted in human cancers such as GBM. PMID- 26494562 TI - The Kidney Awareness Registry and Education (KARE) study: protocol of a randomized controlled trial to enhance provider and patient engagement with chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is common and is associated with excess mortality and morbidity. Better management could slow progression of disease, prevent metabolic complications, and reduce cardiovascular outcomes. Low patient awareness of CKD and ineffective patient-provider communication can impede such efforts. We developed provider and patient-directed interventions that harness health information technology to enhance provider recognition of CKD and delivery of guideline concordant care and augment patient understanding and engagement in CKD care. METHODS/DESIGN: We report the design and protocol of the Kidney Awareness Registry and Education (KARE) Study, a 2x2 factorial randomized controlled trial that examines the impact of a multi-level intervention on health outcomes among low-income English, Spanish and Cantonese-speaking patients with CKD in a safety net system. The intervention includes: (1) implementation of a primary care electronic CKD registry that notifies practice teams of patients' CKD status and employs a patient profile and quarterly feedback to encourage provision of guideline-concordant care at point-of-care and via outreach; and (2) a language-concordant, culturally-sensitive self-management support program that consists of automated telephone modules, provision of low-literacy written patient-educational materials and telephone health coaching. The primary outcomes of the trial are changes in systolic blood pressure (BP) and the proportion of patients with BP control (<= 140/90 mmHg) after one year. Secondary outcomes include patient understanding of CKD, participation in healthy behaviors, and practice team delivery of guideline-concordant CKD care. DISCUSSION: Results from the KARE study will provide data on the feasibility, effectiveness, and acceptability of technology-based interventions that support primary care efforts at improving health outcomes among vulnerable patients with CKD. TRIAL REGISTRATION: ClinicalTrials.gov, number: NCT01530958. PMID- 26494563 TI - Which plant trait explains the variations in relative growth rate and its response to elevated carbon dioxide concentration among Arabidopsis thaliana ecotypes derived from a variety of habitats? AB - Elevated atmospheric carbon dioxide (CO2) concentration ([CO2]) enhances plant growth, but this enhancement varies considerably. It is still uncertain which plant traits are quantitatively related to the variation in plant growth. To identify the traits responsible, we developed a growth analysis model that included primary parameters associated with morphology, nitrogen (N) use, and leaf and root activities. We analysed the vegetative growth of 44 ecotypes of Arabidopsis thaliana L. grown at ambient and elevated [CO2] (800 MUmol mol(-1)). The 44 ecotypes were selected such that they were derived from various altitudes and latitudes. Relative growth rate (RGR; growth rate per unit plant mass) and its response to [CO2] varied by 1.5- and 1.7-fold among ecotypes, respectively. The variation in RGR at both [CO2]s was mainly explained by the variation in leaf N productivity (LNP; growth rate per leaf N),which was strongly related to photosynthetic N use efficiency (PNUE). The variation in the response of RGR to [CO2] was also explained by the variation in the response of LNP to [CO2]. Genomic analyses indicated that there was no phylogenetic constraint on inter ecotype variation in the CO2 response of RGR or LNP. We conclude that the significant variation in plant growth and its response to [CO2] among ecotypes reflects the variation in N use for photosynthesis among ecotypes, and that the response of PNUE to CO2 is an important target for predicting and/or breeding plants that have high growth rates at elevated [CO2]. PMID- 26494564 TI - The Rate of Inducible MLSB Resistance in the Methicillin-Resistant Staphylococci Isolated From Clinical Samples. AB - BACKGROUND: Staphylococci are one of the most common pathogens in nasocomial and community-acquired infections. Methicillin-resistant staphylococci are known to be resistant against all beta-lactam antibiotics. Therefore, non-beta-lactam antibiotics such as macrolide and lincosamides can be used. Resistance to those antibiotics may lead to therapeutic failure. The purpose of the present study was to determine the prevalence of macrolide-lincosamide-streptogramin B (MLSB ) resistance by using D-test in staphylococcal isolates from various clinical samples. METHODS: Seventy-one methicillin-resistant Staphylococcus isolates (six S. aureus, 65 coagulase negative staphylococci) were included in this study. Staphylococci were identified with conventional methods. According to Clinical Laboratory Standards Institute (CLSI) criteria, susceptibility testing was performed by Kirby-Bauer disk diffusion method. RESULTS: One of six (16.6%) methicillin-resistant S. aureus isolates and 19 of 65 (29.2%) methicillin resistant coagulase-negative staphylococci (MR-CNS) were detected as D-test positive. Twenty of 71 (28.1%) staphylococcal isolates detected as D-test positive. Inducible clindamycin resistance was found at a higher rate in MR-CNS. CONCLUSION: Since the resistant community and hospital acquired staphylococcal infections have become a therapeutic problem, it is very important to detect MLSB resistance routinely in microbiology laboratories. D-test is a cheap and reliable diagnostic method that can be performed in every laboratory. PMID- 26494565 TI - Phosphonium alkyl PEG sulfate ionic liquids as coating materials for activation of Burkholderia cepacia lipase. AB - Lipases are among the most widely used enzymes applicable for various substrates; however, the slow reactions or poor enantioselective reactions are sometimes obtained. To develop ionic liquid type activating agents for lipase, four types of phosphonium cetyl(PEG)10 sulfate ionic liquids have been synthesized and used as coating materials of Burkholderia cepacia lipase (Lipase PS) through the lyophilization process. Tributyl ([2-methoxy]ethoxymethyl)phosphonium cetyl(PEG)10 sulfate ([P444MEM ][C16 (PEG)10 SO4 ]) (PL1) worked best among them, and PL1-coated lipase PS displayed high reactivity in transesterification of broad types of secondary alcohols using vinyl acetate as an acylating reagent with perfect enantioselectivity (E > 200). The substrate preference of PL1-PS differs from that of commercial lipase PS or [bdmim] [C16 (PEG)10 SO4 ]-coated lipase (IL1-PS); PL1-PS displayed excellent enantioselectivity in the reaction of 2-chloro-1-phenylethanol with E > 200, though insufficient E values were recorded for lipase PS (E = 12) and IL1-PS (E = 123) for this alcohol. PL1-PS also showed perfect enantioselectivity (E > 200) for the reaction of 1-(pyridin-2-yl)ethanol, while IL1-PS showed E = 130 for this compound. We further succeeded in demonstrating the recyclable use of PL1-PS five times in tributyl(3 methoxypropyl)phosphonium bis(trifluoromethylsulfonyl)amide ([P444PM ][Tf2 N]) as a solvent. Since PL1-PS is easily applicable to 10-20 gram-scaled reactions, it is expected that the IL-coated enzyme might be useful for practical preparation of a wide variety of chiral secondary alcohols. PMID- 26494566 TI - Association study of copy number variants in FCGR3A and FCGR3B gene with risk of ankylosing spondylitis in a Chinese population. AB - Ankylosing spondylitis (AS) is a common inherited autoimmune disease. Copy number variation (CNV) of DNA segments has been found to be an important part of genetic variation, and the FCGR3A and FCGR3B gene CNVs have been associated with various autoimmune disorders. The aim of the study was to determine whether CNVs of FCGR3A and FCGR3B were also associated with the susceptibility of AS. A total of 801 individuals including 402 AS patients and 399 healthy controls were enrolled in this study. The copy numbers of FCGR3 gene (two fragments, included FCGR3A and FCGR3B) were measured by AccuCopyTM methods. Chi-square test and logistic regression model were used to evaluate association between FCGR3 gene CNVs and AS susceptibility. P values, odds ratio, and 95% confidence intervals (CIs) were used to estimate the effects of risk. Significantly, difference in the frequencies of FCGR3A and FCGR3B gene CNVs was founded between the patients with AS and controls. For the FCGR3A gene, a low (<=3) copy number was significantly associated with AS [for <=3 copies versus 4 copies, (OR 2.17, 95% CI (1.41, 3.34), P < 0.001, adjusted OR 2.22, 95% CI (1.44, 3.43), P < 0.001)]. A low FCGR3B copy number was also significantly associated with increasing risk of AS [for <=3 copies versus 4 copies, (OR 1.87, 95% CI (1.25, 2.79), P = 0.002, adjusted OR 1.94, 95% CI (1.29, 2.91), P = 0.001)]; however, both the high FCGR3A and FCGR3B copy numbers (>=5) were not significantly associated with the risk of AS (>=5 copies versus 4 copies). The lower copy numbers (<=3) of FCGR3A and FCGR3B genes confer a risk factor for AS susceptibility. PMID- 26494567 TI - Real-world cost-effectiveness of infliximab, etanercept and adalimumab in rheumatoid arthritis patients: results of the CREATE registry. AB - Biological drugs have proven efficacy and effectiveness in treatment of rheumatoid arthritis (RA), although none has been shown to be superior. Few studies have evaluated the cost-effectiveness of biological drugs in real-life clinical conditions. The objective of this study was to compare the cost effectiveness of infliximab, etanercept and adalimumab in achieving clinical remission (DAS28 < 2.6) when used as initial biological therapy. Patients were diagnosed with RA who began treatment with infliximab, etanercept or adalimumab in the Reina Sofia Hospital (Cordoba, Spain) between January 1, 2007, and December 31, 2012. Effectiveness was measured as the percentage of patients who achieved clinical remission after 2 years. The cost analysis considered the use of direct health resources (perspective of the healthcare system). Cost effectiveness was calculated by dividing the total mean cost of each treatment by the percentage of patients who achieved remission. One hundred and thirty patients were included: 55 with infliximab, 44 with adalimumab and 31 with etanercept. After 2 years, 45.2 % of patients with adalimumab achieved clinical remission, versus 29.1 % with infliximab (p = 0.133) and 22.7 % with etanercept (p = 0.040), with no differences between etanercept and infliximab (p = 0.475). The average total cost at 2 years was ?29,858, ?25,329 and ?23,309 for adalimumab, infliximab and etanercept, respectively, while the mean cost (95 %CI) to achieve remission was ?66,057 (48,038-84,076), ?87,040 (78,496-95,584) and ?102,683 (94,559-110,807), respectively. Adalimumab was more efficient than etanercept (p < 0.001) and infliximab (p = 0.026), with no differences between etanercept and infliximab (p = 0.086). Adalimumab was the most cost-effective treatment in achieving clinical remission in real-life clinical conditions in RA patients during the study period. PMID- 26494568 TI - The relative importance of cancer-related and general health worries and distress among older adult, long-term cancer survivors. AB - OBJECTIVE: This research examines the relative importance that cancer-related and non-cancer illness factors play in generating general health worries and/or cancer-related worries. The analysis also examines how these in turn impact anxiety and depression among older adult, long-term cancer survivors. METHODS: Data from a longitudinal study of 245 older-adult (age 60+ years), long-term survivors (5 or more years after diagnosis) of breast, prostate, and colorectal cancer are examined to identify the measurement properties and structure of general health and cancer-related health worries. Based on that measurement analysis, structural equation models (SEM) are used to estimate the relative importance of cancer-related and other illness predictors on cancer-related worry and general health worry and how these two forms of worry affect both anxiety (POMS) and depression (CES-D). RESULTS: The results from the exploratory and confirmatory factor analysis of health worries identify two relatively independent measures of health worry, one of general health worry and a second of cancer-related worries that includes fears of recurrence, new cancers, and follow up testing. SEM analyses identified the importance of current cancer-related symptoms and comorbidities on cancer-related worry. It also documents the primacy of non-cancer symptoms and general health worry as predictors of anxiety and depression among older survivors. CONCLUSIONS: The fact that cancer-related symptoms continue to be associated with cancer-related worries years after diagnosis speaks to the significance of these continuing sequelae. While the findings suggest the relative independence of cancer-related worries and general health worries, both are correlated with anxiety and depression. This may be particularly problematic as survivors age and symptoms related to new health problems increase, while cancer-related symptoms persist. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26494569 TI - Lucid dreams, an atypical sleep disturbance in anterior and mediodorsal thalamic strokes. AB - BACKGROUND: Cognitive, affective, and behavioural disturbances are commonly reported following thalamic strokes. Conversely, sleep disorders are rarely reported in this context. OBSERVATIONS: Herein, we report the cases of two young patients admitted for an ischemic stroke located in the territories of the left pre-mammillary and paramedian arteries. Together with aphasia, memory complaint, impaired attention and executive functions, they reported lucid dreams with catastrophic content or conflicting situations. CONCLUSION: Lucid dreams are an atypical presentation in thalamic strokes. These cases enlarge the clinical spectrum of sleep-wake disturbances potentially observed after an acute cerebrovascular event. PMID- 26494570 TI - Cognitive screening in Parkinson's disease: Comparison of the Parkinson Neuropsychometric Dementia Assessment (PANDA) with 3 other short scales. AB - BACKGROUND: Cognitive screening is crucial in Parkinson's disease (PD). However, there is still a lack of short tools in French. In this study, we aimed to compare the Parkinson Neuropsychometric Dementia Assessment (PANDA) with the Mini Mental Parkinson (MMP), the Mini Mental State Examination (MMSE) and the Clock Test in French-speaking patients. We also aimed to propose cut-off scores for cognitive impairment and dementia for the French language version of the PANDA. METHOD: Fifty-one patients with PD took the PANDA, the MMSE, the MMP, and the Clock Test. They also underwent extensive neuropsychological testing by a neuropsychologist who was blinded to the above-mentioned screening test results. Patients were classified as either having normal cognition (n=15), mild cognitive impairment (n=20) or dementia (n=16). RESULTS: When compared with the three other screening tools, the PANDA exhibited the highest area under the curve (AUC) for both cognitive disorders and dementia. Using the cut-off scores proposed for the German version, the PANDA had 94% specificity and 100% sensitivity for dementia and 100% and 72%, respectively for cognitive disorders. CONCLUSIONS: In our study, the PANDA exhibited a higher discriminative power than the three other tests in detecting cognitive disorders and dementia. In PD patients, the PANDA should thus be considered for the detection of cognitive impairment in routine clinical practice. PMID- 26494571 TI - [Anticoagulation in acute phase of tandem vertebral dissection after thrombectomy of basilar artery occlusion: MRI contribution]. PMID- 26494572 TI - Massive subcutaneous emphysema and septic shock revealed by a stroke-mimic episode. PMID- 26494573 TI - [Fortuitous discovery of Fahr's syndrome after seizures]. PMID- 26494574 TI - Influence of the C5a-C5a receptor system on breast cancer progression and patient prognosis. AB - BACKGROUND: Emerging evidence has shown activation of the complement system in cancer tissues and anaphylatoxin C5a release from C5 by cancer cells, suggesting C5a as a component in the cancer microenvironment. We revealed aberrant expression of C5a receptor (C5aR) in various human cancers and C5a-elicited enhancement of C5aR-expressing cancer cell invasion. METHODS: To explore an influence of the C5a-C5aR system in breast cancer (BC), we investigated BC C5aR expression in relation to clinicopathological parameters of the patients and an effect of C5a on BC cell proliferation. RESULTS: BC cell C5aR expression was observed immunohistochemically in 22 of 171 patients (13 %) and related to larger tumor size, higher nuclear grade and Ki-67 labeling index, presence of lymph node metastasis and advanced clinical stages. Interestingly, BC cells were C5aR negative in all patients with BC in situ and C5aR-positive rate was high (38 %) in patients with hormone receptor-negative, namely triple-negative BC. For BC cells in metastasized lymph nodes, 12 of 22 patients (55 %) were C5aR-positive and included 7 patients with C5aR-negative BC in the primary site. Survival rate of patients with C5aR-positive BC was lower than that of patients with C5aR negative BC. C5a enhanced proliferation of C5aR-expressing triple-negative BC cells in a C5aR-dependent manner. CONCLUSION: Relation of BC C5aR expression to tumor development and poor prognosis of the patients and proliferation enhancing effect of C5a on C5aR-expressing BC cells suggest that the C5a-C5aR system is closely associated with BC progression. This system may be a new target to treat BC patients, particularly with triple-negative BC. PMID- 26494575 TI - Immunohistochemical analyses of CD44 variant isoforms in invasive micropapillary carcinoma of the breast: comparison with a concurrent conventional invasive carcinoma of no special type component. AB - BACKGROUND: Invasive micropapillary carcinoma (IMPC) is a distinct histopathological variant of breast carcinoma and frequently develops lymph node metastases. CD44 is a family of transmembrane glycoprotein receptors with multiple variant isoforms (CD44v), which have tissue-specific expression. Previous studies have demonstrated a loss or gain of CD44v and CD44 standard form (CD44s) expression in breast carcinomas. In this study, we analyzed the immunoprofiles of CD44s, CD44v6, and CD44v9 in IMPC and compared them with those in a concurrent invasive carcinoma of no special type (ICNST) component, thus clarifying the significance of CD44 expression in IMPC. METHODS: Twenty-one consecutive cases of mixed IMPC were included in this study. The expression statuses of CD44s, CD44v6, and CD44v9 in both the IMPC and ICNST components were analyzed semiquantitatively by immunohistochemistry. RESULTS: The immunohistochemical scores of CD44s, CD44v6, and CD44v9 were significantly decreased in the IMPC component compared to the ICNST component (p = 0.00335 for CD44s, p = 0.000982 for CD44v6, and p = 0.00271 for CD44v9). Moreover, the immunohistochemical scores of CD44v6 in the IMPC component and CD44v9 in the ICNST component of lymph node metastasis cases were significantly lower compared to cases without lymph node metastasis (p < 0.01). CONCLUSIONS: Decreased CD44 expression may play an important role in promoting lymph node metastasis in IMPC through an inability or decreased capacity to bind with the surrounding stroma. Moreover, high CD44s+ expression levels in the concurrent ICNST component may be related to the development of IMPC. PMID- 26494576 TI - Parents as a Team: Mother, Father, a Child with Autism Spectrum Disorder, and a Spinning Toy. AB - This paper is a single case study involving a visit to a diagnostic clinic for autism spectrum disorder. A young boy finds a toy that he can hold with one hand and spin with another. In order to retrieve the toy and leave it in the clinic, the parents engage in a team effort. We describe this achievement in terms of two styles of practice or interactional routines with differing participation frameworks.We examine not only how the parents work as a team using these styles, but also how they improvise to extract the spinning toy from their son's grasp with minimal protest on his part. PMID- 26494577 TI - Respite Care for Single Mothers of Children with Autism Spectrum Disorders. AB - Single mothers of children with autism spectrum disorders are rarely studied, yet they may experience unique stressors. Researchers asked 122 single mothers to complete questionnaires concerning respite care, daily hassles/uplifts, depression, and caregiver burden. More than half (59.8%) accessed respite care, which was provided for 1 h per day, often by multiple sources (41%), such as grandparents and community agencies; most were satisfied with this care. Most mothers (77%) were at risk for clinical depression. While uplifts were negatively correlated with depression, hassles and caregiver burden were positively correlated with depression. Respite care was positively related to daily uplifts, and uplifts mediated the relationship between respite care and depression. Recommendations for researchers, policymakers, and school personnel are offered. PMID- 26494578 TI - "Zeroing" in on mathematics in the monkey brain. AB - A new study documented that monkeys showed selective neuronal responding to the concept of zero during a numerical task, and that there were two distinct classes of neurons that coded the absence of stimuli either through a discrete activation pattern (zero or not zero) or a continuous one for which zero was integrated with other numerosities in the relative rate of activity. These data indicate that monkeys, like humans, have a concept of zero that is part of their analog number line but that also may have unique properties compared to other numerosities. PMID- 26494579 TI - The role of patient education in the prevention and management of type 2 diabetes: an overview. AB - The management of type 2 diabetes mellitus includes ability and empowerment of the patient to change lifestyle, maintain an adequate diet and physical activity, manage the disease, and follow a specific program of periodic medical checks and education sessions. In addition, the patient should be able to correctly identify and adequately solve problems related to the disease and actively collaborate with the healthcare system. To obtain these goals, therapeutic patient education (TPE) is now considered a crucial element not only in the treatment but also in the prevention of type 2 diabetes. Several trials showed that TPE is able to improve clinical, lifestyle, and psycho-social outcomes. Nevertheless, studies have not clarified the ideal characteristics of a comprehensive patient education program in clinical practice. Other work is needed to answer open questions regarding the type of PTE (individual or group education), themes, frequency and number of education sessions, contact time between educator and patient, background of educators, use of new technologies, and barriers to self management. The present review discusses these points on the basis of the most recent data of the literature. PMID- 26494580 TI - Identification of sensory hair-cell transcripts by thiouracil-tagging in zebrafish. AB - BACKGROUND: Sensory hair cells are exquisitely sensitive to mechanical stimuli and as such, are prone to damage and apoptosis during dissections or in vitro manipulations. Thiouracil (TU)-tagging is a noninvasive method to label cell type specific transcripts in an intact organism, thereby meeting the challenge of how to analyze gene expression in hair cells without the need to sort cells. We adapted TU-tagging to zebrafish to identify novel transcripts expressed in the sensory hair cells of the developing acoustico-lateralis organs. METHODS: We created a transgenic line of zebrafish expressing the T.gondii uracil phospho ribosyltransferase (UPRT) enzyme specifically in the hair cells of the inner ear and lateral line organ. RNA was labeled by exposing 3 days post-fertilization (dpf) UPRT transgenic larvae to 2.5 mM 4-thiouracil (4TU) for 15 hours. Following total RNA isolation, poly(A) mRNA enrichment, and purification of TU-tagged RNA, deep sequencing was performed on the input and TU-tagged RNA samples. RESULTS: Analysis of the RNA sequencing data revealed the expression of 28 transcripts that were significantly enriched (adjusted p-value < 0.05) in the UPRT TU-tagged RNA relative to the input sample. Of the 25 TU-tagged transcripts with mammalian homologs, the expression of 18 had not been previously demonstrated in zebrafish hair cells. The hair cell-restricted expression for 17 of these transcripts was confirmed by whole mount mRNA in situ hybridization in 3 dpf larvae. CONCLUSIONS: The hair cell-restricted pattern of expression of these genes offers insight into the biology of this receptor cell type and may serve as useful markers to study the development and function of sensory hair cells. In addition, our study demonstrates the utility of TU-tagging to study nascent transcripts in specific cell types that are relatively rare in the context of the whole zebrafish larvae. PMID- 26494581 TI - Teaser: Individualized benchmarking and optimization of read mapping results for NGS data. AB - Mapping reads to a genome remains challenging, especially for non-model organisms with lower quality assemblies, or for organisms with higher mutation rates. While most research has focused on speeding up the mapping process, little attention has been paid to optimize the choice of mapper and parameters for a user's dataset. Here, we present Teaser, a software that assists in these choices through rapid automated benchmarking of different mappers and parameter settings for individualized data. Within minutes, Teaser completes a quantitative evaluation of an ensemble of mapping algorithms and parameters. We use Teaser to demonstrate how Bowtie2 can be optimized for different data. PMID- 26494582 TI - Androstane derivatives induce apoptotic death in MDA-MB-231 breast cancer cells. AB - Biological investigation was conducted to study in vitro antiproliferative and pro-apoptotic potential of selected 17alpha-picolyl and 17(E)-picolinylidene androstane derivatives. The antiproliferative impact was examined on six human tumor cell lines, including two types of breast (MCF-7 and MDA-MB-231), prostate (PC3), cervical (HeLa), colon (HT 29) and lung cancer (A549), as well as one normal fetal lung fibroblasts cell line (MRC-5). All derivatives selectively decreased proliferation of estrogen receptor negative MDA-MB-231 breast cancer cells after 48 h and 72 h treatment and compounds showed time-dependent activity. We used this cell line to investigate cell cycle modulation and apoptotic cell death induction by flow cytometry, expression of apoptotic proteins by Western blot and apoptotic morphology by visual observation. Tested androstane derivatives affected the cell cycle distribution and induced apoptosis and necrosis. Compounds had different and specific mode of action, depending on derivative type and exposure time. Some compounds induced significant apoptosis measured by Annexin V test compared to reference compound formestane. Higher expression of pro-apoptotic BAX, downregulation of anti-apoptotic Bcl-2 and cleavage of PARP protein were confirmed in almost all treated samples, but the lack of caspase-3 activation suggested the induction of apoptosis in caspase independent manner. More cells with apoptotic morphology were observed in samples after prolonged treatment. Structure-activity relationship analysis was performed to find correlations between the structure variations of investigated derivatives and observed biological effects. Results of this study showed that some of the investigated androstane derivatives have good biomedical potential and could be candidates for anticancer drug development. PMID- 26494583 TI - Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain penetrant phosphodiesterase 10A inhibitor. AB - Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3 yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl) 4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3 dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice. PMID- 26494584 TI - Comment to: Retrospective observational study on the incidence of incisional hernias after reversal of a temporary diverting ileostomy following rectal carcinoma resection with follow-up CT scans. De Keersmaecker G, Beckers R, Heindryckx E, Kyle-Leinhase I, Pletinckx P, Claeys D, Vanderstraeten E, Monsaert E, Muysoms F. Hernia 2015 (Epub ahead of print). PMID- 26494585 TI - Increasing incidence of infantile hemangiomas (IH) over the past 35 years: Correlation with decreasing gestational age at birth and birth weight. AB - BACKGROUND: Infantile hemangiomas (IH) are the most common soft-tissue tumors of infancy, but little is known regarding their true incidence. OBJECTIVES: We sought to determine the current incidence of IH and examine trends in incidence, demographics, and lesion characteristics over 3 decades. METHODS: The Rochester Epidemiology Project was used to identify infants residing in Olmsted County, Minnesota, who were given a diagnosis of IH between January 1, 1976, and December 31, 2010. RESULTS: In all, 999 infants were given a diagnosis of IH. Incidence increased over the 3-decade study period from 0.97 to 1.97 per 100 person-years (P < .001). Average gestational age at birth and birth weight for infants with IH decreased over the study period (39.2-38.3 weeks, P < .001 and 3383-3185 g, P = .003, respectively). The overall age- and sex-adjusted incidence of IH was 1.64 per 100 person-years (95% confidence interval 1.54-1.75). LIMITATIONS: The population of Olmsted County, Minnesota, is predominantly non-Hispanic white, limiting our ability to report racial differences in incidence. This was a retrospective study. CONCLUSIONS: This study provides a longitudinal, population based incidence of IH. Incidence has increased steadily over the past 3 decades, correlating significantly with decreasing gestational age at birth and birth weight in affected infants. PMID- 26494586 TI - Primary cutaneous nodular amyloidosis in association with Sjogren's syndrome. PMID- 26494587 TI - Rituximab as induction therapy in relapsing eosinophilic granulomatosis with polyangiitis: A report of 6 cases. AB - OBJECTIVE: Recently few reports have suggested a potential benefit of rituximab in patients with eosinophilic granulomatosis with polyangiitis (EGPA). However, the current evidence is limited. We describe the efficacy and safety of rituximab in six patients with relapsing EGPA. METHODS: Candidates for rituximab therapy were selected from a cohort of 118 patients with EGPA. The main indication for B cells depletion was moderately severe or severe relapsing disease that was refractory to conventional immunosuppression. A primary end-point was a complete or partial remission within 3 to 6 months after rituximab administration. RESULTS: All six patients (four ANCA-positive and two ANCA-negative) had active EGPA manifesting by severe lung disease and/or deteriorating peripheral neuropathy. The median duration of follow-up after the first rituximab dose administration was 10 months. All patients rapidly responded to rituximab treatment, e.g. disappearance of lung infiltrates, improvement of asthmatic symptoms, at least partial recovery of motor and sensory function. Within 3 to 6 months, complete (4/6) or partial (2/6) remission was achieved in all patients. After switching to rituximab all patients except one discontinued cyclophosphamide or other immunomodulators. Four patients continued maintenance treatment with rituximab. One patient developed severe bronchospasm during infusion and two patients presented with moderately severe purulent bronchitis that was successfully treated with intravenous antibiotics. CONCLUSION: Our retrospective case series suggest that rituximab may be effective for induction of remission in selected EGPA patients. These data warrant further studies to evaluate safety and efficacy of rituximab in EGPA. PMID- 26494588 TI - Severe apoptotic enteropathy caused by methotrexate treatment for rheumatoid arthritis. AB - The folic acid antagonist methotrexate is a cornerstone treatment of rheumatoid arthritis. Its use is limited chiefly by gastrointestinal toxicity, which is among the main reasons for methotrexate discontinuation. Here, we report the case of a 40-year-old man on chronic methotrexate therapy in whom life-threatening apoptotic enteropathy with watery diarrhea and hypovolemic shock developed after he was switched from the oral to the intramuscular route, with no change in dosage. Colonic biopsies suggested drug-induced colitis, showing a nonspecific, mildly inflammatory infiltrate of lymphocytes and plasma cells, dilated damaged crypts, and a marked increase in basal crypt apoptosis (>20 apoptotic bodies/100 crypts). Clinicians should be aware that methotrexate can cause life-threatening apoptotic enteropathy. Increased basal crypt apoptosis in colonic biopsies with more than 5 apoptotic bodies/100 crypts should routinely suggest drug-induced enteropathy. PMID- 26494589 TI - Systemic lupus erythematosus flare triggered by a spider bite. AB - Systemic lupus erythematosus is a chronic autoimmune disease with a relapsing and remitting course characterized by disease flares. Flares are a major cause of hospitalization, morbidity and mortality in patients with systemic lupus erythematosus. Some triggers for these exacerbations have been identified, including infections, vaccines, pregnancy, environmental factors such as weather, stress and drugs. We report a patient who presented with a lupus flare with predominantly mucocutaneous, serosal and cardiac involvement after being bitten by a spider and we present the possible mechanisms by which the venom elicited such a reaction. To the best of our knowledge, this is the first such case reported in the literature. PMID- 26494590 TI - Sacroiliac joint edema by MRI: Far more often mechanical than inflammatory? PMID- 26494591 TI - Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis. AB - BACKGROUND: Calcific uremic arteriolopathy (CUA) or calciphylaxis is a severe complication of advanced chronic kidney disease (CKD) and dialysis. Few effective treatments are available and the mortality rate is high. We report 4 cases in which sodium thiosulfate therapy was rapidly effective. CASES: Sodium thiosulfate therapy was given to 4 Caucasian patients (3 females and 1 male aged 49 to 91 years) with CUA. The causes of end-stage CKD were nephroangiosclerosis (n=2) and diabetic nephropathy (n=2). The lesions developed 1 to 6.5 years after the initiation of hemodialysis and involved the lower limbs in 2 patients, the fingers in 1 patient, and a breast in the remaining patient. They were responsible for pain and skin necrosis in all 4 patients. Local superinfection occurred in 3 patients. Intravenous sodium thiosulfate was given in a dosage of 12.5 to 25g after each hemodialysis session, for 12 to 24 weeks. The pain and trophic disorders resolved fully in all 4 patients. The side effects consisted of nausea and vomiting (n=2) and a moderate blood pressure decrease (n=1). No recurrences were noted during the follow-up of 5 to 17 months after treatment discontinuation. CONCLUSION: The findings from this small case-series suggest that sodium thiosulfate may hold promise for the treatment of CUA. PMID- 26494592 TI - Rheumatoid neutrophilic dermatitis. PMID- 26494593 TI - Presence of HLA-B27 is associated with changes of serum levels of mediators of the Wnt and hedgehog pathway. AB - BACKGROUND: HLA-B27 is present in 5% of the Caucasian population and is strongly associated with the development of spondyloarthritis (SpA), a disease characterized by inflammation and substantial bone changes. We hypothesized that the presence of HLA-B27 in itself is associated with alterations of key regulatory of bone homeostasis. METHODS: Sera of 241 individuals were assessed for the serum levels of Wnt pathway regulators, sclerostin and dickkopf (Dkk)-1 as well as Indian hedgehog (IHH) and collagen type I cleavage products (CTX1). Of the 151 HLA-B27+ subjects, 31 had SpA, 30 had anterior uveitis, 30 were healthy individuals and 60 healthy siblings of patients with SpA. RESULTS: Sclerostin levels were significantly (P<0.001) lower in HLA-B27+ subjects (314+/-21pg/mL) compared to HLA-B27 negative controls (mean+/-SEM: 492+/-30pg/mL), no matter if subjects were either healthy, or affected by SpA or uveitis. Similar results were found for Dkk-1. No differences between the groups with respect to the bone resorption marker CTX1 were found. In contrast, IHH levels were significantly (P<0.001) higher in the carriers of HLA-B27 than in the negative controls. CONCLUSIONS: Changes in key regulators of the Wnt pathway as well as IHH, a molecule regulating endochondral ossification, are found in HLA-B27 carriers, independent if they were healthy or affected by uveitis or SpA. PMID- 26494594 TI - The prevalence of rheumatoid arthritis in Split-Dalmatia County in southern Croatia is 0.24. PMID- 26494595 TI - Prevention of iatrogenic infections in interventional rheumatology: Optimal measures but adapted to each risk. PMID- 26494596 TI - Sterno-clavicular involvement in polymyalgia rheumatica. PMID- 26494597 TI - Interventions to improve adherence to cardiovascular disease guidelines: a systematic review. AB - BACKGROUND: Successful management of cardiovascular disease (CVD) is impaired by poor adherence to clinical practice guidelines. The objective of our review was to synthesize evidence about the effectiveness of interventions that target healthcare providers to improve adherence to CVD guidelines and patient outcomes. METHODS: We searched PubMed, EMBASE, Cochrane Library, PsycINFO, Web of Science and CINAHL databases from inception to June 2014, using search terms related to adherence and clinical practice guidelines. Studies were limited to randomized controlled trials testing an intervention to improve adherence to guidelines that measured both a patient and adherence outcome. Descriptive summary tables were created from data extractions. Meta-analyses were conducted on clinically homogeneous comparisons, and sensitivity analyses and subgroup analyses were carried out where possible. GRADE summary of findings tables were created for each comparison and outcome. RESULTS AND DISCUSSION: We included 38 RCTs in our review. Interventions included guideline dissemination, education, audit and feedback, and academic detailing. Meta-analyses were conducted for several outcomes by intervention type. Many comparisons favoured the intervention, though only the adherence outcome for the education intervention showed statistically significant improvement compared to usual care (standardized mean difference = 0.58 [95 % confidence interval 0.35 to 0.8]). CONCLUSIONS: Many interventions show promise to improve practitioner adherence to CVD guidelines. The quality of evidence and number of trials limited our ability to draw conclusions. PMID- 26494599 TI - Peripherally inserted central catheters (PICCs): Looking to the future with a critical eye. PMID- 26494598 TI - On Teaching Old Dogs New Tricks. AB - Although older adults rarely outperform young adults on learning tasks, in the study reported here they surpassed their younger counterparts not only by answering more semantic-memory general-information questions correctly, but also by better correcting their mistakes. While both young and older adults exhibited a hypercorrection effect, correcting their high-confidence errors more than their low-confidence errors, the effect was larger for young adults. Whereas older adults corrected high-confidence errors to the same extent as did young adults, they outdid the young in also correcting their low-confidence errors. Their event related potentials point to an attentional explanation: Both groups showed a strong attention-related P3a in conjunction with high-confidence-error feedback, but the older adults also showed strong P3as to low-confidence-error feedback. Indeed, the older adults were able to rally their attentional resources to learn the true answers regardless of their original confidence in the errors and regardless of their familiarity with the answers. PMID- 26494600 TI - Donor's age and replicative senescence favour the in-vitro mineralization potential of human fibroblasts. AB - Aberrant mineralization of soft connective tissues (ectopic calcification) may occur as a frequent age-related complication. Still, it remains unclear the role of mesenchymal cell donor's age and of replicative senescence on ectopic calcification. Therefore, the ability of cells to deposit in-vitro hydroxyapatite crystals and the expression of progressive ankylosis protein homolog (ANKH), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), tissue non specific alkaline phosphatase (TNAP) and osteopontin (OPN) have been evaluated in human dermal fibroblasts derived from neonatal (nHDF) and adult (aHDF) donors (ex-vivo ageing model) or at low and high cumulative population doublings (CPD) up to replicative senescence (in-vitro ageing model). This study demonstrates that: 1) replicative senescence favours hydroxyapatite formation in cultured fibroblasts; 2) donor's age acts as a major modulator of the mineralizing potential of HDF, since nHDF are less prone than aHDF to induce calcification; 3) donor's age and replicative senescence play in concert synergistically increasing the calcification process; 4) the ANKH+ENPP1/TNAP ratio, being crucial for pyrophosphate/inorganic phosphate balance, is greatly influenced by donor's age, as well as by replicative senescence, and regulates mineral deposition; 5) OPN is only modulated by replicative senescence. PMID- 26494601 TI - A method to avoid errors associated with the analysis of hypermutated viral sequences by alignment-based methods. AB - The human genome encodes for a family of editing enzymes known as APOBEC3 (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like3). They induce context dependent G-to-A changes, referred to as "hypermutation", in the genome of viruses such as HIV, SIV, HBV and endogenous retroviruses. Hypermutation is characterized by aligning affected sequences to a reference sequence. We show that indels (insertions/deletions) in the sequences lead to an incorrect assignment of APOBEC3 targeted and non-target sites. This can result in an incorrect identification of hypermutated sequences and erroneous biological inferences made based on hypermutation analysis. PMID- 26494602 TI - Application of preparative disk gel electrophoresis for antigen purification from inclusion bodies. AB - Specific antibodies are a reliable tool to examine protein expression patterns and to determine the protein localizations within cells. Generally, recombinant proteins are used as antigens for specific antibody production. However, recombinant proteins from mammals and plants are often overexpressed as insoluble inclusion bodies in Escherichia coli. Solubilization of these inclusion bodies is desirable because soluble antigens are more suitable for injection into animals to be immunized. Furthermore, highly purified proteins are also required for specific antibody production. Plastidic acetyl-CoA carboxylase (ACCase: EC 6.4.1.2) from Arabidopsis thaliana, which catalyzes the formation of malonyl-CoA from acetyl-CoA in chloroplasts, formed inclusion bodies when the recombinant protein was overexpressed in E. coli. To obtain the purified protein to use as an antigen, we applied preparative disk gel electrophoresis for protein purification from inclusion bodies. This method is suitable for antigen preparation from inclusion bodies because the purified protein is recovered as a soluble fraction in electrode running buffer containing 0.1% sodium dodecyl sulfate that can be directly injected into immune animals, and it can be used for large-scale antigen preparation (several tens of milligrams). PMID- 26494603 TI - Expression and purification of recombinant proteins in Escherichia coli tagged with a small metal-binding protein from Nitrosomonas europaea. AB - Escherichia coli is still the preferred organism for large-scale production of recombinant proteins. The use of fusion proteins has helped considerably in enhancing the solubility of heterologous proteins and their purification with affinity chromatography. Here, the use of a small metal-binding protein (SmbP) from Nitrosomonas europaea is described as a new fusion protein for protein expression and purification in E. coli. Fluorescent proteins tagged at the N terminal with SmbP showed high levels of solubility, compared with those of maltose-binding protein and glutathione S-transferase, and low formation of inclusion bodies. Using commercially available IMAC resins charged with Ni(II), highly pure recombinant proteins were obtained after just one chromatography step. Proteins may be purified from the periplasm of E. coli if SmbP contains the signal sequence at the N-terminal. After removal of the SmbP tag from the protein of interest, high-yields are obtained since SmbP is a protein of just 9.9 kDa. The results here obtained suggest that SmbP is a good alternative as a fusion protein/affinity tag for the production of soluble recombinant proteins in E. coli. PMID- 26494604 TI - Muslim and gay: seeking identity coherence in New Zealand. AB - The process of accepting oneself as gay and of 'coming out' to family and friends is well documented. For Muslim men, this is complicated by the tension between their emerging sexual identity and their religious and cultural birth identity, which labels homosexuality as sinful. This paper explores this process in a sample of five gay Muslim men living in New Zealand, a liberal secular society where homosexuality is widely accepted and gay rights are endorsed in legislation. Identity Process Theory drives the analysis, which identifies five themes encapsulating the process of striving for psychological coherence: resistance, acceptance, tension, renegotiation and pretence. Initial phases of denial and anger at their emerging sexuality are strongly linked to the conflict with their religious identity. Later, acceptance of their sexuality as natural and even God-given protects them from blame for their 'sins'. In contrast to earlier work in the UK, for most men, renegotiation of their Muslim identity is adopted as the key strategy for achieving intrapsychic coherence. However, at an interpersonal level, families remain a source of conflict, temporarily resolved through pretence. Renegotiating religious identity leaves men having to pretend not just to be straight, but also to be strongly religious. PMID- 26494605 TI - Adherent basal plate myometrial fibers in the delivered placenta as a risk factor for development of subsequent placenta accreta. AB - BACKGROUND: Placenta accreta is implantation of chorionic tissue directly upon the myometrium without normal intervening decidua. The clinical significance of myometrial fibers attached to the basal plate (BPMYO) has yet to be fully elucidated. OBJECTIVE: To determine the importance of depth and quantity of BPMYO in predicting subsequent accreta in the next pregnancy. METHOD: Women with placentas from two successive pregnancies submitted for pathologic evaluation were included. 50 cases had clinical and/or pathologic diagnosis of accreta in an index pregnancy. 100 controls had no evidence of accreta in an index pregnancy. H&E slides were re-reviewed and stage of accreta/BPMYO was determined. The stages were defined as: Stage 0-no BPMYO; Stage 1-BPMYO with intervening decidua; Stage 2 < 2 decidual cells separating myometrium from chorionic tissue; Stage 3 accreta; Stage 4-increta; Stage 5-percreta. The amount of BPMYO for each placenta was quantified. RESULTS: Prior placentas of cases were twice as likely to have BPMYO compared to controls (84%vs42%, P < 0.001). The frequency of stage 1 BPMYO was not significantly different between the two groups (46%v40%, P = 0.489), but cases were more likely to have higher stages of BPMYO (stage 2-3) in a prior placenta (38%vs2%, P < 0.001). A significantly higher number of BPMYO foci and a larger proportion of BPMYO on the basal plate (6.2%vs0.7%, P < 0.001) in cases compared to controls. CONCLUSIONS: Small amounts and low stage BPMYO (stage 1) may be common; however, higher stages of BPMYO (stage 2-3) and greater quantities of BPMYO in a delivered placenta are significantly associated with the subsequent development of accreta. PMID- 26494606 TI - Does 2D-Histologic identification of villous types of human placentas at birth enable sensitive and reliable interpretation of 3D structure? AB - INTRODUCTION: The villous tree of human placentas is a complex three-dimensional (3D) structure which enables fetomaternal exchange. Current concepts of microscopic analyses are based on the analysis of two-dimensional (2D) histologic sections. For this approach, the assessment of the stromal core of sectioned villi is of key importance. The classification of stromal properties of sectioned villi allows allocation of villous sections to villous types which are named by their expected position in villous trees (terminal, intermediate, and stem villi). METHOD: The present study takes these current concepts of placental histology as hypothesis and validates them against predetermined 3D positions of branches of villous trees. The 3D positions were determined prior to histologic sectioning using a recently introduced 3D-microscopic approach. Individual histologic sections of villi were classified by their stromal structures and inter rater variability of these histologic assessments were determined. RESULTS/DISSCUSSION: Inter rater variability was high and indicates substantial observer influence on the outcome of histologic assessments. Cross-match of villous types with the predetermined positions of villous branches of villous trees revealed substantial mismatch between the outcome of stromal classification and 3D-position of the sectioned villi in the placental villous trees. PMID- 26494607 TI - Prognostic factors in second-line targeted therapy for metastatic clear-cell renal cell carcinoma after progression on an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor. AB - BACKGROUND: About 40% of metastatic clear-cell renal cell carcinoma (m-ccRCC) patients receive a second-line targeted therapy after failure of anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGFR-TKI). Efficacy of second-line therapy is usually limited and prognostic and predictive factors at the start of second-line therapy are lacking. To identify the subgroup of patients that will benefit from such treatment remains a challenge. METHODS: We performed a multi-institutional, retrospective study of patients who received a second-line therapy after progression on an anti-VEGFR-TKI. Univariate and multivariate analyses were performed in order to identify prognostic factors for progressive disease (PD) as best response, progression-free survival (PFS) and overall survival (OS) on second-line therapy. RESULTS: For the whole cohort of 108 patients, mOS from the start of second-line therapy was 8.9 months while mPFS on second-line therapy was 2.8 months. A total of 49/105 (47%) patients had PD, 50/105 (48%) stable disease (SD) and 6/105 (6%) a partial response (PR). On multivariate analysis, the following markers were associated with improved outcome on second-line therapy: a PFS on first-line therapy >=12 months (HR for PFS: 1.961; p = 0.008) (HR for OS: 1.724; p = 0.037) and Fuhrman grade 1-2 tumors (HR for OS: 2.198; p = 0.007). Markers associated with poorer outcome on second line therapy were: elevated serum lactate dehydrogenase (LDH) levels (HR for PFS: 0.511; p = 0.04) (HR for OS: 0.392; p = 0.017), low albumin (HR for OS: 0.392; p = 0.01) and elevated corrected calcium levels (HR for OS: 0.416; p = 0.01). The impact on OS of the Memorial Sloan Kettering Cancer Centre (MSKCC) and International Renal Cell Carcinoma Database Consortium (IMDC) prognostic scores as calculated at start of second-line therapy was validated in our patient series. CONCLUSIONS: Duration of first-line PFS, Fuhrman grade, serum LDH levels, albumin levels, corrected calcium levels and the MSKCC and IMDC scores calculated at start of second-line therapy are prognostic factors for m-ccRCC patients treated with second-line targeted therapy. PMID- 26494608 TI - Self-assessed health, perceived stress and non-participation in breast cancer screening: A Danish cohort study. AB - OBJECTIVE: Population-based cancer screening is offered in many countries to detect early stages of cancer and reduce mortality. Screening efficiency and equality is susceptible due to a group of non-participants. We investigated associations between self-assessed health, perceived stress and subsequent non participation in breast cancer screening. METHODS: This population-based cohort study included 4512 women who had participated in a Health Survey in 2006 and who were also the target group (aged 50-69 years) for the first organised breast cancer screening programme -3 years later in the Central Denmark Region in 2008 2009. RESULTS: A U-shaped association was observed for physical health assessment as women with the highest (PR=1.28, 95% CI: 1.06-1.55), and the lowest (PR=1.41, 95% CI: 1.18-1.68) physical health scores were less likely to participate in the programme than women with physical health scores in the middle range. Women with low mental health assessment were more likely not to participate than women with mental health scores in the middle range (PR=1.44, 95% CI: 1.22-1.69). Higher non participation propensity was also observed for women with the highest perceived stress scores (PR=1.27, 95% CI: 1.07-1.51) compared with women scoring in the middle range. CONCLUSIONS: Women with highest and lowest self-assessed physical health, with lowest mental health or highest perceived stress were significantly more likely not to participate in breast cancer screening 2-3 years later than women who reported average health. Interventions targeting these groups may promote equal participation in future breast cancer screening programmes. PMID- 26494609 TI - Prospective effects of pedometer use and class competitions on physical activity in youth: A cluster-randomized controlled trial. AB - OBJECTIVE: To evaluate the immediate effects of a school-based multi-component program to foster a physically active lifestyle in adolescence. DESIGN/PARTICIPANTS: In a cluster-randomized controlled trial with pre- and post assessment in 2014, 29 schools with 1162 8th grade students (48% girls) from Germany were included. Age ranged from 12 to 17 years (M=13.74; SD=0.67). INTERVENTION: While the control group attended education as usual, students in the intervention group received pedometers and took part in a class competition over a time period of 12 weeks. Classes with the most steps and best creative ideas to promote physical activity in everyday life were awarded. MAIN OUTCOME MEASURES: Primary outcomes included out-of-school sports activities (h/week), moderate to vigorous physical activity (days/week with a minimum of 60 min), active commuting (min/day), doing chores (min/day), and sedentary behavior (h/day) assessed through self-administered questionnaires as well as cardiorespiratory fitness measured using the 20-m shuttle-run test (completed laps). RESULTS: Significant interaction terms between group and wave of assessment were found on out-of-school sports activities (b=-1.09 [-1.89; -0.29], p=0.008), moderate to vigorous physical activity (b=-0.29 [-0.47; -0.10], p=0.002), and active commuting (b=-20.41 [-32.32; -8.49], p=0.001): students in the intervention group showed a higher increase of physical activity levels than students in the control group. The intervention effect on cardiorespiratory fitness missed significance marginally (b=-1.52 [-3.14; 0.98], p=0.065), There was no effect on students' sedentary behavior (b=0.06 [-0.72; 0.84], p=0.881). CONCLUSIONS: An easy to administer school-based physical activity program (12 weeks) may enhance students' leisure-time physical activity. TRIAL REGISTRATION NUMBER: ISRCTN49482118. PMID- 26494610 TI - Dual congenital transmission of Toxoplasma gondii and Sarcocystis neurona in a late-term aborted pup from a chronically infected southern sea otter (Enhydra lutris nereis). AB - Toxoplasma gondii and Sarcocystis neurona are protozoan parasites with terrestrial definitive hosts, and both pathogens can cause fatal disease in a wide range of marine animals. Close monitoring of threatened southern sea otters (Enhydra lutris nereis) in California allowed for the diagnosis of dual transplacental transmission of T. gondii and S. neurona in a wild female otter that was chronically infected with both parasites. Congenital infection resulted in late-term abortion due to disseminated toxoplasmosis. Toxoplasma gondii and S. neurona DNA was amplified from placental tissue culture, as well as from fetal lung tissue. Molecular characterization of T. gondii revealed a Type X genotype in isolates derived from placenta and fetal brain, as well as in all tested fetal organs (brain, lung, spleen, liver and thymus). This report provides the first evidence for transplacental transmission of T. gondii in a chronically infected wild sea otter, and the first molecular and immunohistochemical confirmation of concurrent transplacental transmission of T. gondii and S. neurona in any species. Repeated fetal and/or neonatal losses in the sea otter dam also suggested that T. gondii has the potential to reduce fecundity in chronically infected marine mammals through parasite recrudescence and repeated fetal infection. PMID- 26494611 TI - Translational challenges for the development of a novel nucleus pulposus substitute: Experimental results from biomechanical and in vivo studies. AB - Nucleus pulposus replacement therapy could offer a less invasive alternative to restore the function of moderately degenerated intervertebral discs than current potentially destructive surgical procedures. Numerous nucleus pulposus substitutes have already been investigated, to assess their applicability for intradiscal use. Still, the current choice of testing methods often does not lead to efficient translation into clinical application. In this paper, we present the evaluation of a novel nucleus pulposus substitute, consisting of a hydromed core and an electrospun envelope. We performed three mechanical evaluations and an in vivo pilot experiment. Initially, the swelling pressure of the implant was assessed in confined compression. Next, we incorporated the implant into mechanically damaged caprine lumbar intervertebral discs to determine biomechanical segment behaviour in bending and torsion. Subsequently, segments were serially tested in native, damaged and repaired conditions under dynamic axial compressive loading regimes in a loaded disc culture system. Finally, nucleus pulposus substitutes were implanted in a live goat spine using a transpedicular approach. In confined compression, nucleus pulposus samples as well as implants showed some load-bearing capacity, but the implant exhibited a much lower absolute pressure. In bending and torsion, we found that the nucleus pulposus substitute could partly restore the mechanical response of the disc. During dynamic axial compression in the loaded disc culture system, on the other hand, the implant was not able to recover axial compressive behaviour towards the healthy situation. Moreover, the nucleus pulposus substitutes did not remain in place in the in vivo situation but migrated out of the disc area. From these results, we conclude that implants may mimic native disc behaviour in simple mechanical tests, yet fail in other, more realistic set-ups. Therefore, we recommend that biomaterials for nucleus pulposus replacement be tested in testing modalities of increasing complexity and in their relevant anatomical surroundings, for a more reliable prediction of clinical potential. PMID- 26494612 TI - Physical preparation of alginate/chitosan polyelectrolyte complexes for biomedical applications. AB - Polyelectrolyte complexes represent a special class of polymeric compounds consisting of stoichiometric equivalents of oppositely charged polyions interacting together spontaneously to yield a complex in different forms. The present study aimed at preparing coacervates of alginate and chitosan polymers ready for casting as wound dressing films. This was based on controlling the pH of solutions and the reactions speed through controlling the rate of mixing of the polymers solutions together without using any water-miscible solvents. Alginate was modified with radiation and oxidation, and the interactions of the resulting chains and chitosan chains were tested with FTIR spectroscopy and scanning of the resulting films with SEM. This work showed the ability to prepare a complex of highly connected polymeric chains for further biomedical applications. This complex in the form of hydrogel could enhance the proliferation of cells in vitro and the healing efficiency with accelerating the wound closure rate as evidenced through the histological observations. PMID- 26494613 TI - Regarding "Segmentation of heterogeneous or small FDG PET positive tissue based on a 3D-locally adaptive random walk algorithm" By DP. Onoma et al. PMID- 26494614 TI - Molecular cloning, expression analysis and cellular localization of an LFRFamide gene in the cuttlefish Sepiella japonica. AB - Neuropeptides are important regulators of physiological processes in metazoans, such as feeding, reproduction, and heart activities. In this study, an LFRFamide gene was identified from the cuttlefish Sepiella japonica (designated as SjLFRFamide). The full-length sequence of SjLFRFamide cDNA has 841bp, and the open reading frame contains 567bp encoding 188 amino acids, which shared high similarity with precursor SOFaRP2 from Sepia officinalis. The deduced SjLFRFamdie precursor protein contains a signal peptide and four different FLPs (FMRFamide like peptides): one pentapeptide (TIFRFamide), two hexapeptides (NSLFRFamide and GNLFRFamide) and one heptapeptide (PHTPFRFamide). Multiple sequence alignment showed that SjLFRFamide contains rather conserved mature peptides, which all ended in FRF. The phylogenetic analysis suggests that SjLFRFamide belongs to the LFRFamide subfamily. The tissue distribution analysis through quantitative real time PCR method showed that SjLFRFamide mRNA is significantly expressed in the brain, and slight trace are detected in female nidamental gland and accessory nidamental gland. In situ hybridization assay of the brain indicated that SjLFRFamide is transcribed in several different functional lobes, suggesting SjLFRFamide might associate with multiple physiological regulations, such as feeding, chromatophore regulation and reproduction. This is the first study describing LFRFamide in S. japonica, which might have great importance for cuttlefish artificial breeding. PMID- 26494615 TI - Response to the letter by O. Barbier, D. Mainard. PMID- 26494616 TI - Comments on: "Is rotator cuff repair appropriate in patients older than 60 years of age? Prospective, randomized trial in 103 patients with a mean four-year follow up" by A. Jacquot, C. Dezaly, T. Goetzmann, O. Roche, F. Sirveaux, D. Mole and the French Society of Shoulder and Elbow Surgery in Orthop Surg Res 2014;100(6 Suppl.):S333-8. PMID- 26494617 TI - Initial disc structural preservation in type A1 and A3 thoracolumbar fractures. AB - PURPOSE: Despite a sizable amount of literature, the optimal management of thoracolumbar fractures remains controversial and many authors assume the existence of disc lesions in Magerl type A fractures. The purpose of the study was to assess the intervertebral discs in these fractures at the time of trauma. The hypothesis was that there was no change in shape and signal intensity of the discs initially. METHODS: Fifty-one patients diagnosed with 87 types A1 and A3 thoracolumbar fractures were enrolled in a prospective study. MRI analysis involved evaluation of disc signal, height and morphological modifications according to Oner's classification. RESULTS: No signal intensity modification was identified on MRI. Disc morphology was either normal or altered with creeping of discal tissue in the vertebral endplate depression. Overall, 98% of the discs were either type 1 or type 3. Mean disc height on MRI was 1.03 +/- 0.36 initially. CONCLUSIONS: In this study, MRI showed that no loss of height occurred in discs adjacent to fractured vertebra and that there was no major alteration of the disc in terms of signal intensity and morphology. Therefore, the intervertebral disc should not be removed in Magerl type A fractures. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26494618 TI - Do outcomes of outpatient ACL reconstruction vary with graft type? AB - BACKGROUND: Studies establishing the feasibility of anterior cruciate ligament (ACL) reconstruction as an outpatient procedure in France were usually conducted with hamstring tendon grafts. The objective of this study was to evaluate the outcomes of outpatient ACL reconstruction according to whether the graft was harvested from the hamstring tendons or patellar tendon. HYPOTHESIS: Outpatient ACL reconstruction can be performed using any type of graft. METHODS: A single centre retrospective study was conducted in consecutive patients older than 16 years who had primary ACL reconstruction using patellar tendon or hamstring tendons, with or without lateral tenodesis. Patients who underwent other procedures on bones or peripheral ligaments and those with a previous history of ACL reconstruction were excluded. The primary evaluation criterion was the occurrence of complications within 45 days after surgery. Secondary evaluation criteria were the visual analogue scale (VAS) for pain during the first 3 postoperative days, patient satisfaction on day 3, and the IKDC and Lysholm clinical scores on day 45. RESULTS: The analysis included 104 knees (one knee per patient). Hamstring tendons were used in 77 (74%) knees and patellar tendon in 27 (26%) knees. In the hamstring group, 2 (2.6%) patients spent the first postoperative night in the hospital and 2 others were re-admitted. No hospitalisations were recorded in the patellar-tendon group. None of the patients required revision surgery within 45 days of the reconstruction procedure. None of the postoperative criteria studied showed statistically significant differences between the two groups. DISCUSSION: ACL reconstruction can be performed on an outpatient basis using any type of graft. The main determinants of successful outpatient ACL reconstruction are a standardised clinical management strategy and an appropriate anaesthesia protocol. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 26494619 TI - Conservative versus surgical treatment for type II odontoid fractures in the elderly: Grading the evidence through a meta-analysis. AB - BACKGROUND: Odontoid fractures are common C-spine fractures in the elderly. However, the optimal treatment of odontoid fractures in the elderly is, still subject to controversy. HYPOTHESIS: Surgical treatment has several advantages on conservative treatment, such as reduced mortality and lower incidence of non union. This meta-analysis was performed to identify the efficacy of conservative treatment compared with surgical treatment and provides recommendations for using these procedures to treat type II odontoid fractures in the elderly. MATERIALS AND METHODS: A systematic search of all studies published was conducted using the PubMed, EMBASE, OVID, ScienceDirect and Cochrane CENTRAL databases. The randomized controlled trials (RCTs) and non-randomized controlled trials (non RCTs) that compared conservative treatment with surgical treatment and provided data on clinical effects were identified. The included trials were screened out strictly based on the criterion of inclusion and exclusion. The quality of included trials was evaluated. RevMan 5.1 was used for data analysis. RESULTS: Twelve studies involving 730 patients met the inclusion criteria. There were 441 patients with conservative treatment and 289 with surgical treatment. The results of meta-analysis indicated that no difference with regard to the mortality was noted (P > 0.05) between the two procedures. However, there was statistically significant difference with respect to the non-union numbers (P < 0.05) between the two procedures. DISCUSSION: Conservative treatment and surgical treatment are both effective procedures for treating type II odontoid fractures in the elderly. Compared with surgical treatment, there is no significant difference in mortality; With respect to non-union numbers, conservative treatment numbers are higher than surgical treatment. Due to the poor quality of the evidence currently available, high quality RCTs are required. Level of evidence Level II: low powered prospective randomized trial meta-analysis. PMID- 26494620 TI - Enhancing Autophagy with Drugs or Lung-directed Gene Therapy Reverses the Pathological Effects of Respiratory Epithelial Cell Proteinopathy. AB - Recent studies have shown that autophagy mitigates the pathological effects of proteinopathies in the liver, heart, and skeletal muscle but this has not been investigated for proteinopathies that affect the lung. This may be due at least in part to the lack of an animal model robust enough for spontaneous pathological effects from proteinopathies even though several rare proteinopathies, surfactant protein A and C deficiencies, cause severe pulmonary fibrosis. In this report we show that the PiZ mouse, transgenic for the common misfolded variant alpha1 antitrypsin Z, is a model of respiratory epithelial cell proteinopathy with spontaneous pulmonary fibrosis. Intracellular accumulation of misfolded alpha1 antitrypsin Z in respiratory epithelial cells of the PiZ model resulted in activation of autophagy, leukocyte infiltration, and spontaneous pulmonary fibrosis severe enough to elicit functional restrictive deficits. Treatment with autophagy enhancer drugs or lung-directed gene transfer of TFEB, a master transcriptional activator of the autophagolysosomal system, reversed these proteotoxic consequences. We conclude that this mouse is an excellent model of respiratory epithelial proteinopathy with spontaneous pulmonary fibrosis and that autophagy is an important endogenous proteostasis mechanism and an attractive target for therapy. PMID- 26494621 TI - The Protein Interaction of RNA Helicase B (RhlB) and Polynucleotide Phosphorylase (PNPase) Contributes to the Homeostatic Control of Cysteine in Escherichia coli. AB - PNPase, one of the major enzymes with 3' to 5' single-stranded RNA degradation and processing activities, can interact with the RNA helicase RhlB independently of RNA degradosome formation in Escherichia coli. Here, we report that loss of interaction between RhlB and PNPase impacts cysteine homeostasis in E. coli. By random mutagenesis, we identified a mutant RhlB(P238L) that loses 75% of its ability to interact with PNPase but retains normal interaction with RNase E and RNA, in addition to exhibiting normal helicase activity. Applying microarray analyses to an E. coli strain with impaired RNA degradosome formation, we investigated the biological consequences of a weakened interaction between RhlB and PNPase. We found significant increases in 11 of 14 genes involved in cysteine biosynthesis. Subsequent Northern blot analyses showed that the up-regulated transcripts were the result of stabilization of the cysB transcript encoding a transcriptional activator for the cys operons. Furthermore, Northern blots of PNPase or RhlB mutants showed that RhlB-PNPase plays both a catalytic and structural role in regulating cysB degradation. Cells expressing the RhlB(P238L) mutant exhibited an increase in intracellular cysteine and an enhanced anti oxidative response. Collectively, this study suggests a mechanism by which bacteria use the PNPase-RhlB exosome-like complex to combat oxidative stress by modulating cysB mRNA degradation. PMID- 26494622 TI - Store-operated Ca2+ Entry Mediated by Orai1 and TRPC1 Participates to Insulin Secretion in Rat beta-Cells. AB - Store-operated Ca(2+) channels (SOCs) are voltage-independent Ca(2+) channels activated upon depletion of the endoplasmic reticulum Ca(2+) stores. Early studies suggest the contribution of such channels to Ca(2+) homeostasis in insulin-secreting pancreatic beta-cells. However, their composition and contribution to glucose-stimulated insulin secretion (GSIS) remains unclear. In this study, endoplasmic reticulum Ca(2+) depletion triggered by acetylcholine (ACh) or thapsigargin stimulated the formation of a ternary complex composed of Orai1, TRPC1, and STIM1, the key proteins involved in the formation of SOCs. Ca(2+) imaging further revealed that Orai1 and TRPC1 are required to form functional SOCs and that these channels are activated by STIM1 in response to thapsigargin or ACh. Pharmacological SOCs inhibition or dominant negative blockade of Orai1 or TRPC1 using the specific pore mutants Orai1-E106D and TRPC1 F562A impaired GSIS in rat beta-cells and fully blocked the potentiating effect of ACh on secretion. In contrast, pharmacological or dominant negative blockade of TRPC3 had no effect on extracellular Ca(2+) entry and GSIS. Finally, we observed that prolonged exposure to supraphysiological glucose concentration impaired SOCs function without altering the expression levels of STIM1, Orai1, and TRPC1. We conclude that Orai1 and TRPC1, which form SOCs regulated by STIM1, play a key role in the effect of ACh on GSIS, a process that may be impaired in type 2 diabetes. PMID- 26494623 TI - Lecithin:Cholesterol Acyltransferase (LCAT) Deficiency Promotes Differentiation of Satellite Cells to Brown Adipocytes in a Cholesterol-dependent Manner. AB - Our laboratory previously reported that lecithin:cholesterol acyltransferase (LCAT) and LDL receptor double knock-out mice (Ldlr(-/-)xLcat(-/-) or DKO) spontaneously develop functioning ectopic brown adipose tissue (BAT) in skeletal muscle, putatively contributing to protection from the diet-induced obesity phenotype. Here we further investigated their developmental origin and the mechanistic role of LCAT deficiency. Gene profiling of skeletal muscle in DKO newborns and adults revealed a classical lineage. Primary quiescent satellite cells (SC) from chow-fed DKO mice, not in Ldlr(-/-)xLcat(+/+) single-knock-out (SKO) or C57BL/6 wild type, were found to (i) express exclusively classical BAT selective genes, (ii) be primed to express key functional BAT genes, and (iii) exhibit markedly increased ex vivo adipogenic differentiation into brown adipocytes. This gene priming effect was abrogated upon feeding the mice a 2% high cholesterol diet in association with accumulation of excess intracellular cholesterol. Ex vivo cholesterol loading of chow-fed DKO SC recapitulated the effect, indicating that cellular cholesterol is a key regulator of SC-to-BAT differentiation. Comparing adipogenicity of Ldlr(+/+)xLcat(-/-) (LCAT-KO) SC with DKO SC identified a role for LCAT deficiency in priming SC to express BAT genes. Additionally, we found that reduced cellular cholesterol is important for adipogenic differentiation, evidenced by increased induction of adipogenesis in cholesterol-depleted SC from both LCAT-KO and SKO mice. Taken together, we conclude that ectopic BAT in DKO mice is classical in origin, and its development begins in utero. We further showed complementary roles of LCAT deficiency and cellular cholesterol reduction in the SC-to-BAT adipogenesis. PMID- 26494624 TI - The beta5-Loop and Lid Domain Contribute to the Substrate Specificity of Pancreatic Lipase-related Protein 2 (PNLIPRP2). AB - Pancreatic triglyceride lipase (PNLIP) is essential for dietary fat digestion in children and adults, whereas a homolog, pancreatic lipase-related protein 2 (PNLIPRP2), is critical in newborns. The two lipases are structurally similar, yet they have different substrate specificities. PNLIP only cleaves neutral fats. PNLIPRP2 cleaves neutral and polar fats. To test the hypothesis that the differences in activity between PNLIP and PNLIPRP2 are governed by surface loops around the active site, we created multiple chimeras of both lipases by exchanging the surface loops singly or in combination. The chimeras were expressed, purified, and tested for activity against various substrates. The structural determinants of PNLIPRP2 galactolipase activity were contained in the N-terminal domain. Of the surface loops tested, the lid domain and the beta5-loop influenced activity against triglycerides and galactolipids. Any chimera on PNLIP with the PNLIPRP2 lid domain or beta5-loop had decreased triglyceride lipase activity similar to that of PNLIPRP2. The corresponding chimeras of PNLIPRP2 did not increase activity against neutral lipids. Galactolipase activity was abolished by the PNLIP beta5-loop and decreased by the PNLIP lid domain. The source of the beta9-loop had minimal effect on activity. We conclude that the lid domain and beta5-loop contribute to substrate specificity but do not completely account for the differing activities of PNLIP and PNLIPRP2. Other regions in the N-terminal domain must contribute to the galactolipase activity of PNLIPRP2 through direct interactions with the substrate or by altering the conformation of the residues surrounding the hydrophilic cavity in PNLIPRP2. PMID- 26494625 TI - Structural and Functional Highlights of Vacuolar Soluble Protein 1 from Pathogen Trypanosoma brucei brucei. AB - Trypanosoma brucei (T. brucei) is responsible for the fatal human disease called African trypanosomiasis, or sleeping sickness. The causative parasite, Trypanosoma, encodes soluble versions of inorganic pyrophosphatases (PPase), also called vacuolar soluble proteins (VSPs), which are localized to its acidocalcisomes. The latter are acidic membrane-enclosed organelles rich in polyphosphate chains and divalent cations whose significance in these parasites remains unclear. We here report the crystal structure of T. brucei brucei acidocalcisomal PPases in a ternary complex with Mg(2+) and imidodiphosphate. The crystal structure reveals a novel structural architecture distinct from known class I PPases in its tetrameric oligomeric state in which a fused EF hand domain arranges around the catalytic PPase domain. This unprecedented assembly evident from TbbVSP1 crystal structure is further confirmed by SAXS and TEM data. SAXS data suggest structural flexibility in EF hand domains indicative of conformational plasticity within TbbVSP1. PMID- 26494626 TI - Peptide-specific T helper cells identified by MHC class II tetramers differentiate into several subtypes upon immunization with CAF01 adjuvanted H56 tuberculosis vaccine formulation. AB - CD4(+) T-cell priming is an essential step in vaccination due to the key role of T helper cells in driving both effector and memory immune responses. Here we have characterized in C57BL/6 mice the T helper subtype differentiation among tetramer specific CD4(+) T cells primed by subcutaneous immunization with the tuberculosis vaccine antigen H56 plus the adjuvant CAF01. Peptide-specific population identified by the MHC class II tetramers differentiated into several T helper subtypes upon antigen encounter, and the frequency of subpopulations differed according to their localization. Th1 (CXCR3(+)T-bet(+)), Tfh (CXCR5(+)PD-1(+)Bcl 6(+)) and RORgammat(+) cells were induced in the lymph nodes draining the immunization site (dLN), while Th1 cells were the predominant subtype in the spleen. In addition, CD4(+) T cells co-expressing multiple T-cell lineage specifying transcription factors were also detected. In the lungs, most of the tetramer-binding T cells were RORgammat(+), while Tfh and Th1 cells were absent. After boosting, a higher frequency of tetramer-binding cells co-expressing the markers CD44 and CD127 was detected compared to primed cells, and cells showed a prevalent Th1 phenotype in both dLN and spleens, while Tfh cells were significantly reduced. In conclusion, these data demonstrate that parenteral immunization with H56 and CAF01 elicits a distribution of antigen-specific CD4(+) T cells in both lymphoid tissues and lungs, and gives rise to multiple T helper subtypes, that differ depending on localization and following reactivation. PMID- 26494627 TI - Risk factors for severe outcomes among members of the United States military hospitalized with pneumonia and influenza, 2000-2012. AB - BACKGROUND: The progression from hospitalization for a respiratory infection to requiring substantial supportive therapy is a key stage of the influenza severity pyramid. Respiratory infections are responsible for 300,000-400,000 medical encounters each year among US military personnel, some of which progress to severe acute respiratory infections. METHODS: We obtained data on 11,086 hospitalizations for pneumonia and influenza (P&I) among non-recruit US military service members during the period of 1 January 2000 through 31 December 2012. From these, we identified 512 P&I hospitalizations that progressed to severe episodes using standard case definitions. We evaluated the effect of demographic and occupational characteristics, co-morbid conditions, and history of influenza vaccination on the risk of a hospitalized P&I case becoming a severe case. We also evaluated the risk of a severe outcome and the length of time since influenza vaccination (within 180, 60, and 30 days). RESULTS: The median age of subjects at the time of the P&I episode was 32 years (range, 28-40) and subjects were predominantly male (89.5%). In a univariate analysis, demographic risk factors for a severe episode included service in the US Air Force (RR=1.6 relative to US Army, 95%CI 1.3-2.1), US Coast Guard (RR=2.1, 1.2-3.7) or US Navy (RR=1.4, 1.1-1.8). Being born in the US and recent influenza vaccination (within 180 days of episode) were protective against developing severe disease. Among co morbid conditions, univariate risk factors for severe disease included chronic renal or liver disease (RR=4.98, 95%CI 4.1-6.1), diseases of the circulatory system (RR=3.1, 95%CI 2.6-3.7), diabetes mellitus (RR=2.3, 95%CI 1.5-3.6), obesity (RR=1.6, 95%CI 1.2-2.1), cancer (RR=1.6, 95%CI 1.3-2.0), and chronic obstructive pulmonary disease (RR=1.4, 95%CI 1.1-1.7). Although many of the risk factors found to be significant in univariate analysis were no longer significant under a multivariate analysis, receipt of any influenza vaccine within 180 days of episode remained protective (RR=0.81, 95%CI 0.67-0.99), while serving in the US Coast Guard (RR=1.9, 95%CI 1.1-3.4) or US Air Force (RR=1. 5, 95%CI 1.2-2.0), presence of renal or liver disease (RR=3.6, 95%CI 2.9-4.6), and diseases of the circulatory system (RR=2.2, 95%CI 1.8-2.8), remained significantly associated with a higher risk of developing severe disease. CONCLUSIONS: In a large cohort, after adjusting for many possible risk factors, influenza vaccination was protective against severe episodes among P&I hospitalizations. The service specific (US Coast Guard or US Air Force) increased risk may represent some differences in data (e.g., coding or reporting practices) as opposed to genuine differences in physiological outcome. Our findings suggest that renal and liver disease as well as diseases of the circulatory system may contribute to influenza severity in this population independently of age and other potential comorbidities. These findings provide additional evidence for the prioritization of specific risk groups within the US military for influenza vaccination. PMID- 26494628 TI - Identifying the role of cytochrome c in post-resuscitation pathophysiology. AB - Cytochrome c, an electron carrier that normally resides in the mitochondrial intermembrane space, may translocate to the cytosol under ischemic and hypoxic conditions and contribute to mitochondrial permeability transition pore opening. In addition, reperfusion of brain tissue following ischemia initiates a cell death cascade that includes cytochrome c-mediated induction of apoptosis. Further studies are needed to determine the contribution of cytochrome c in the regulation of cell death, as well as its value as an in vivo prognostic marker after cardiac arrest and resuscitation. PMID- 26494629 TI - Simulated endotracheal intubation of a patient with cervical spine immobilization during resuscitation: a randomized comparison of the Pentax AWS, the Airtraq, and the McCoy Laryngoscopes. AB - BACKGROUND: Tracheal intubation during cardiopulmonary resuscitation is a high risk procedure. The aim of this study was to compare efficacy of intubation with the Pentax AWS, Airtraq, and McCoy laryngoscopes in patients with cervical spine immobilization during resuscitation in a randomized, controlled simulation trial. METHODS: We compared times to intubation, success rate, Cormack and Lehane grading, and ease of intubation when using Pentax AWS, Airtraq, and McCoy in randomized order. RESULTS: Sixty-seven paramedics were trained in the use of the Pentax AWS, Airtraq, and McCoy laryngoscopes with a METIman Prehospital manikin. Participants performed tracheal intubation in patients with cervical spine immobilization during resuscitation scenario. We measured success rates, times for tracheal intubation, the glottic view, and ease of intubation. RESULTS: The primary study end point, overall success rate, was highest when using Pentax AWS (94.0%) and was lower in Airtraq (86.6%; P = .017) and in McCoy (85.1%; P = .019). Time to first effective ventilation was achieved significantly shorter when using Pentax AWS (25.4 +/- 6.7 seconds) than Airtraq (35.6 +/- 5.1 seconds; P < .001) or McCoy (38.5 +/- 10.3 seconds; P < .001). The quality of glottic view and ease of use were best with Pentax AWS. CONCLUSIONS: The Pentax AWS videolaryngoscope provided a better view of the vocal cords, less insertion time, and higher success rate of the endotracheal intubation compared with the Airtraq or McCoy laryngoscopes in adults with simulated cervical spine immobilization during resuscitation. PMID- 26494630 TI - Zebrafish models of cardiovascular diseases and their applications in herbal medicine research. AB - The zebrafish (Danio rerio) has recently become a powerful animal model for cardiovascular research and drug discovery due to its ease of maintenance, genetic manipulability and ability for high-throughput screening. Recent advances in imaging techniques and generation of transgenic zebrafish have greatly facilitated in vivo analysis of cellular events of cardiovascular development and pathogenesis. More importantly, recent studies have demonstrated the functional similarity of drug metabolism systems between zebrafish and humans, highlighting the clinical relevance of employing zebrafish in identifying lead compounds in Chinese herbal medicine with potential beneficial cardiovascular effects. This paper seeks to summarise the scope of zebrafish models employed in cardiovascular studies and the application of these research models in Chinese herbal medicine to date. PMID- 26494631 TI - Secoisolariciresinol diglycoside, a flaxseed lignan, exerts analgesic effects in a mouse model of type 1 diabetes: Engagement of antioxidant mechanism. AB - Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Secoisolariciresinol diglycoside (SDG), a predominant lignan in flaxseed, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential analgesic efficacy of SDG against diabetic neuropathic pain in a mouse model of type 1 diabetes. We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200 mg/kg), and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic instead of acute SDG treatment (3, 10 or 30 mg/kg, p.o., twice per day for three weeks) ameliorated thermal hyperalgesia and mechanical allodynia in diabetic mice, and these analgesic actions persisted about three days when SDG treatment was terminated. Although chronic treatment of SDG to diabetic mice did not impact on the symptom of hyperglycemia, it greatly attenuated excessive oxidative stress in sciatic nerve and spinal cord tissues, and partially counteracted the condition of weight decrease. Furthermore, the analgesic actions of SDG were abolished by co-treatment with the reactive oxygen species donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the reactive oxygen species scavenger phenyl-N-tert-butylnitrone (PBN). These findings indicate that chronic SDG treatment can correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the analgesic actions of SDG in diabetic mice may be associated with its antioxidant activity. PMID- 26494634 TI - Seven in 10 junior doctors will leave NHS if new contract is imposed, survey finds. PMID- 26494632 TI - Assessment of the relationship between selected cardiovascular risk factors and the indices of intima-media thickness and coronary artery calcium score in various stages of chronic kidney disease. AB - Renal diseases pose a growing epidemiological and health problem worldwide. Cardiovascular diseases are the leading cause of deaths among patients with chronic kidney disease. Increased risk of atherosclerosis in these patients results from the occurrence of traditional and non-traditional risk factors. The aim of this study was to assess the relationship between selected risk factors for cardiovascular diseases (age, sex, dyslipidemia, hypertension, etc.), intima media thickness and coronary artery calcium score in patients with chronic kidney disease stages 2, 3 and 4. This study included 60 patients with chronic kidney disease divided into 3 groups on the basis of disease stage and control group consisting of 20 individuals without diagnosed chronic kidney disease and cardiovascular diseases. Blood analysis and blood pressure measurements were taken. All patients underwent carotid artery ultrasound with the assessment of the intima-media thickness, and heart CT scan in order to assess the index of coronary artery calcification. Logistic regression analysis revealed statistically significant correlation between blood vessels calcification and age -the increase in age by 1 year was associated with the increase in the risk of coronary artery calcification by 6.7 %. The increase in IMT by about 0.1 mm raises the risk of calcification by about 2 %. Second logistic regression model revealed that one-year increase in age was associated with an increase in the risk of intima-media thickening by 6.5 %. Occurrence of hypertension was associated with a ninefold increase in intima-media thickening risk in comparison with patients with normal blood pressure. To sum up, age and hypertension were associated with the growth of IMT in CKD patients, while age and exposure to tobacco smoke were associated with the increase in coronary artery calcium score. The relationship between thickening of IMT and the increase in calcification index in patients was also observed in study group. PMID- 26494633 TI - Low magnesium levels an important new prognostic parameter can be overlooked in patients with Fournier's gangrene: a multicentric study. AB - INTRODUCTION: We evaluated low magnesium levels and three different scoring systems including the Fournier's Gangrene Severity Index (FGSI), the Uludag Fournier's Gangrene Severity Index (UFGSI), and the Charlson Comorbidity Index (CCI) for predicting mortality in a multicentric, large patient population with FG. METHODS: The medical records of 99 FG patients who were treated and followed up in different clinics were reviewed. The biochemical, hematological, and bacteriological results from the admission evaluation were recorded. The CCI, FGSI, and UFGSI were evaluated and stratified by survival. RESULTS: The results were evaluated for the following patients: the survivors (n = 82) and the nonsurvivors (n = 17). The magnesium level for the survivors and nonsurvivors was 2.09 +/- 0.28 and 1.68 +/- 0.23, respectively (p 0.004). The admission FGSI, UFGSI, and CCI scores were significantly higher in nonsurvivors (p 0.001, p 0.001, p < 0.001, respectively). The receiver operating characteristics analysis revealed that the UFGSI was more powerful than the FGSI. The hypomagnesemia, low hemoglobin and hematocrit, low albumin and HCO3 levels; high alkaline phosphatase; and the high heart and respiratory rates, an FGSI >9, rectal involvement, and a high CCI were associated with a worse prognosis. CONCLUSION: Low magnesium levels might be an important parameter for a worse FG prognosis. Monitoring the serum magnesium levels might have prognostic and therapeutic implications in patients with FG. High CCI, FGSI, and UFGSI scores might be associated with a worse prognosis in patients with FG. The UFGSI might be more powerful scoring system than the FGSI. PMID- 26494635 TI - Nationwide survey of radiation exposure during pediatric computed tomography examinations and proposal of age-based diagnostic reference levels for Japan. AB - BACKGROUND: Diagnostic reference levels (DRLs) have not been established in Japan. OBJECTIVE: To propose DRLs for CT of the head, chest and abdomen for three pediatric age groups. MATERIALS AND METHODS: We sent a nationwide questionnaire by post to 339 facilities. Questions focused on pediatric CT technology, exposure parameters, CT protocols, and radiation doses for age groups <1 year, 1-5 years, and 6-10 years. RESULTS: For the three age groups in the 196 facilities that responded, the 75th percentile values of volume CT dose index based on a 16-cm phantom (CTDIvol 16 [mGy]) for head, chest and abdominal CT were for infants 39.1, 11.1 and 12.0, respectively; for 1-to 5-year-olds 46.9, 14.3 and 16.7, respectively; and for 6-to 10-year-olds 67.7, 15.0 and 17.0, respectively. The corresponding dose-length products (DLP 16 [mGy?cm]) for head, chest and abdominal CT were for infants 526.1, 209.1 and 261.5, respectively; for 1-to 5 year-olds 665.5, 296.0 and 430.8, respectively; and for 6-to 10-year-olds 847.9, 413.0 and 532.2, respectively. CONCLUSION: The majority of CTDIvol 16 and DLP 16 values for the head were higher than DRLs reported from other countries. For risk reduction, it is necessary to establish DRLs for pediatric CT in Japan. PMID- 26494636 TI - Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease. AB - In Crohn's disease, one of the two major forms of inflammatory bowel diseases in human beings, persistent and chronic inflammation promotes fibrotic processes thereby facilitating formation of strictures, the most common indication for surgical intervention in this disorder. The pathogenesis of Crohn's disease associated fibrosis is not fully understood, but variants of genes involved in the recognition of microbial components/products [e.g. CARD15 (caspase-activating recruitment domain 15) and ATG16L1 (autophagy-related 16-like 1)] are associated with this phenotype, and experimental evidence suggests that intestinal fibrosis results from an altered balance between deposition of ECM (extracellular matrix) and degradation of ECM by proteases. Studies have also contributed to identify the main phenotypic and functional alterations of cells involved in the fibrogenic process, as well as molecules that stimulate such cells to produce elevated amounts of collagen and other ECM-related proteins. In the present review, we assess the current knowledge about cellular and molecular mediators of intestinal fibrosis and describe results of recent studies aimed at testing the preventive/therapeutic effect of compounds in experimental models of intestinal fibrosis. PMID- 26494637 TI - Handcrafted multilayer PDMS microchannel scaffolds for peripheral nerve regeneration. AB - Injuries that result in the loss of limb functionality may be caused by the severing of the peripheral nerves within the affected limb. Several bioengineered peripheral nerve scaffolds have been developed in order to provide the physical support and topographical guidance necessary for the naturally disorganized axon outgrowth to reattach to distal nerve stumps as an alternative to other procedures, like nerve grafting. PDMS has been chosen for the base material of the scaffolds due to its biocompatibility, flexibility, transparency, and well developed fabrication techniques. The process of observing the axon outgrowth across the nerve gaps with PDMS scaffolds has been challenging due to the limited number and fineness of longitudinal sections that can be extracted from harvested nerve tissue samples after implantation. To address this, multilayer microchannel scaffolds were developed with the object of providing more refined longitudinal observation of axon outgrowth by longitudinally 'sectioning' the device during fabrication, removing the need for much of the sample preparation process. This device was then implanted into the sciatic nerves of Lewis rats, and then harvested after two and four weeks to analyze the difference in nerve regeneration between two different time periods. The present layer by layer structure, which is separable after nerve regeneration and is treated as an individual layer during the histology process, provides the details of biological events during axonal regeneration. Confocal microscopic imaging showed the details of peripheral nerve regeneration including nerve branches and growth cones observable from within the microchannels of the multilayer PDMS microchannel scaffolds. PMID- 26494638 TI - Implicit learning of non-linguistic and linguistic regularities in children with dyslexia. AB - One of the hallmarks of dyslexia is the failure to automatise written patterns despite repeated exposure to print. Although many explanations have been proposed to explain this problem, researchers have recently begun to explore the possibility that an underlying implicit learning deficit may play a role in dyslexia. This hypothesis has been investigated through non-linguistic tasks exploring implicit learning in a general domain. In this study, we examined the abilities of children with dyslexia to implicitly acquire positional regularities embedded in both non-linguistic and linguistic stimuli. In experiment 1, 42 children (21 with dyslexia and 21 typically developing) were exposed to rule governed shape sequences; whereas in experiment 2, a new group of 42 children were exposed to rule-governed letter strings. Implicit learning was assessed in both experiments via a forced-choice task. Experiments 1 and 2 showed a similar pattern of results. ANOVA analyses revealed no significant differences between the dyslexic and the typically developing group, indicating that children with dyslexia are not impaired in the acquisition of simple positional regularities, regardless of the nature of the stimuli. However, within group t-tests suggested that children from the dyslexic group could not transfer the underlying positional rules to novel instances as efficiently as typically developing children. PMID- 26494639 TI - Bioinspired enzymatic synthesis of silica nanocrystals provided by recombinant silicatein from the marine sponge Latrunculia oparinae. AB - The process of silica formation in marine sponges is thought to be mediated by a family of catalytically active structure-directing enzymes called silicateins. It has been demonstrated in biomimicking syntheses that silicateins facilitated the formation of amorphous SiO2. Here, we present evidence that the silicatein LoSiLA1 from the marine sponge Latrunculia oparinae catalyzes the in vitro synthesis of hexa-tetrahedral SiO2 crystals of 200-300 nm. This was possible in the presence of the silica precursor tetrakis-(2-hydroxyethyl)-orthosilicate that is completely soluble in water and biocompatible, experiences hydrolysis condensation at neutral pH and ambient conditions. PMID- 26494640 TI - Second-Opinion Interpretations of Gynecologic Oncologic MRI Examinations by Sub Specialized Radiologists Influence Patient Care. AB - PURPOSE: To determine if second-opinion review of gynaecologic oncologic (GynOnc) magnetic resonance imaging (MRI) by sub-specialized radiologists impacts patient care. METHODS: 469 second-opinion MRI interpretations rendered by GynOnc radiologists were retrospectively compared to the initial outside reports. Two gynaecologic surgeons, blinded to the reports' origins, reviewed all cases with discrepancies between initial and second-opinion MRI reports and recorded whether these discrepancies would have led to a change in patient management defined as a change in treatment approach, counselling, or referral. Histopathology or minimum 6-month imaging follow-up were used to establish the diagnosis. RESULTS: Second opinion review of GynOnc MRIs would theoretically have affected management in 94/469 (20 %) and 101/469 (21.5 %) patients for surgeons 1 and 2, respectively. Specifically, second-opinion review would have theoretically altered treatment approach in 71/469 (15.1 %) and 60/469 (12.8 %) patients for surgeons 1 and 2, respectively. According to surgeons 1 and 2, these treatment changes would have prevented unnecessary surgery in 35 (7.5 %) and 31 (6.6 %) patients, respectively, and changed surgical procedure type/extent in 19 (4.1 %) and 12 (2.5 %) patients, respectively. Second-opinion interpretations were correct in 103 (83 %) of 124 cases with clinically relevant discrepancies between initial and second-opinion reports. CONCLUSIONS: Expert second-opinion review of GynOnc MRI influences patient care. KEY POINTS: * Outside gynaecologic oncologic MRI examinations are often submitted for a second-opinion review. * One-fifth of MRIs had important discrepancies between initial and second-opinion interpretations. * Second-opinion review of gynaecologic oncologic MRI is a valuable clinical service. PMID- 26494641 TI - Changes and variability of proton density and T1 relaxation times in early multiple sclerosis: MRI markers of neuronal damage in the cerebral cortex. AB - OBJECTIVES: Proton density (PD) and T1 relaxation time are promising quantitative MRI (qMRI) markers of neuronal damage in multiple sclerosis (MS). However, it is unknown whether cortical differences of these parameters between patients and controls exist in the early stages of disease. This study investigates cortical T1 and PD in early MS stages, hypothesizing that these are altered and display a high spatial variability. METHODS: Quantitative T1 and PD mapping was performed on 11 patients with clinically isolated syndrome (CIS)/early MS in remission and 11 healthy controls. The normal appearing cortical gray matter was extracted, lobar regions were identified, and mean values and standard deviations of both parameters were calculated within each region. RESULTS: Increased PD was detected in MS/CIS patients in the cerebral cortex as a whole and all subregions, indicating an increase of water content. Increase of PD variability reached significance in the whole cortex and in the frontal and parietal regions. Longer T1 relaxation times and increased variability were found in the cerebral cortex in all regions studied, indicating a change of microstructural tissue composition that is spatially heterogeneous. CONCLUSIONS: The data show spatially heterogeneous cortical involvement in early MS is reflected in T1 and PD qMRI. KEY POINTS: * Cortical involvement in early MS is reflected in T1/PD quantitative MRI. * The changes are spatially heterogeneous. * Cortical damage goes beyond increased water content. PMID- 26494642 TI - Potential of MR histogram analyses for prediction of response to chemotherapy in patients with colorectal hepatic metastases. AB - PURPOSE: To determine if magnetic resonance imaging (MRI) histogram analyses can help predict response to chemotherapy in patients with colorectal hepatic metastases by using response evaluation criteria in solid tumours (RECIST1.1) as the reference standard. MATERIALS AND METHODS: Standard MRI including diffusion weighted imaging (b=0, 500 s/mm(2)) was performed before chemotherapy in 53 patients with colorectal hepatic metastases. Histograms were performed for apparent diffusion coefficient (ADC) maps, arterial, and portal venous phase images; thereafter, mean, percentiles (1st, 10th, 50th, 90th, 99th), skewness, kurtosis, and variance were generated. Quantitative histogram parameters were compared between responders (partial and complete response, n=15) and non responders (progressive and stable disease, n=38). Receiver operator characteristics (ROC) analyses were further analyzed for the significant parameters. RESULTS: The mean, 1st percentile, 10th percentile, 50th percentile, 90th percentile, 99th percentile of the ADC maps were significantly lower in responding group than that in non-responding group (p=0.000-0.002) with area under the ROC curve (AUCs) of 0.76-0.82. The histogram parameters of arterial and portal venous phase showed no significant difference (p>0.05) between the two groups. CONCLUSION: Histogram-derived parameters for ADC maps seem to be a promising tool for predicting response to chemotherapy in patients with colorectal hepatic metastases. KEY POINTS: * ADC histogram analyses can potentially predict chemotherapy response in colorectal liver metastases. * Lower histogram-derived parameters (mean, percentiles) for ADC tend to have good response. * MR enhancement histogram analyses are not reliable to predict response. PMID- 26494643 TI - Penetrating aerodigestive injuries in the neck: a proposed CT-aided modified selective management algorithm. AB - OBJECTIVES: To determine the specific CT findings of penetrating neck wound profile predicting aerodigestive injuries, diagnostic performance of CTA and to propose a modified selective management algorithm to reduce nontherapeutic invasive procedures. METHODS: We retrospectively evaluated CTAs of 102 patients to determine the presence of various CT signs. "Trajectory"-based signs included trajectory of the wound extending into the aerodigestive tract and trajectory violating the deep neck spaces. "Conventional" signs included transcervical injury; wall defect; air or blood in the deep neck spaces; irregular or thickened aerodigestive tract; and active mucosal bleeding. RESULTS: Trajectory of the wound extending into the aerodigestive tract (sensitivity 76 %, specificity 97 %) and trajectory of the wound violating the suprahyoid deep neck spaces or the infrahyoid visceral space (sensitivity 97 %, specificity 55 %) were the best predictors of injury on regression analysis. The most specific "conventional" CT signs were "wall defect" and "active mucosal bleed", but had very low sensitivity. The sensitivity of CTA for detecting an injury ranged from 89.5 % to 92 %, specificity ranged from 62.5 % to 89 %. CONCLUSION: CTA can be a useful technique in detecting aerodigestive injury. Our proposed management algorithm can exclude an injury with high degree of confidence (sensitivity 97 %). KEY POINTS: * Trajectory-based CT signs predict aerodigestive injury after penetrating neck trauma. * Surgery should be considered when trajectory extends into the infra-arytenoid aerodigestive tract. * Endoscopy or exploration should be considered when trajectory violates deep neck spaces. * This modified approach can decrease negative explorations and invasive diagnostic procedures. PMID- 26494644 TI - Dual adrenal venous phase contrast-enhanced MDCT for visualization of right adrenal veins in patients with primary aldosteronism. AB - PURPOSE: To evaluate the frequency of visualization of the right adrenal vein (RAV) on dual adrenal venous phase multi-detector computed tomography (MDCT) in patients with primary aldosteronism. MATERIALS AND METHODS: Images of contrast enhanced dual adrenal venous phase MDCT (45- and 55-second delays) in 90 patients with primary aldosteronism who underwent adrenal venous sampling were retrospectively evaluated. The degree of RAV visualization on each phase image was evaluated by two radiologists using a five-point scale and RAV visualization rates were estimated. RESULTS: The RAV visualization rates on the first- and second-phase images were 89 % and 91 % by radiologist A, and 93 % and 90 % by radiologist B, respectively. No significant differences in the score of RAV visualization were observed between the first- and second-phase images by the two readers (P = 0.164 and P = 0.06). The kappa values for inter-observer agreement of RAV visualization on the first- and second-phase images were 0.57 and 0.46, respectively. The consensual RAV visualization rates on the first- and second phase images were 91 % and 92 %, respectively. The overall RAV visualization rate by using both phase images was 98 %. CONCLUSION: Dual adrenal venous phase MDCT can visualize the RAV in almost all patients with primary aldosteronism. KEY POINTS: * Dual adrenal venous phase MDCT images can visualize the right adrenal veins. * The adrenal venous phase lies between the arterial and portal phases. * Anatomical information will contribute to the technical success of adrenal venous sampling. PMID- 26494645 TI - Conduction abnormalities during dipyridamole stress testing. AB - Pharmacological stress tests using dipyridamole are considered to be safe. However, cases of atrioventricular (AV) block have been reported. We retrospectively analyzed ECG at baseline and during dipyridamole stress tests of 2010 consecutive patients (patients with second or third degree AV block were excluded). At baseline, 350 (17.4%) patients had conduction abnormalities. Following dipyridamole infusion 16 patients (0.8%) developed a transient change in AV conduction (15 patients) and or sinus arrest (1 patient). Compared to patients without baseline conduction abnormalities, patients with any conduction abnormalities at baseline were at a higher risk for the development of AV block after dipyridamole infusion [0.3% vs 3.14%, respectively; P < .0001]. PMID- 26494646 TI - A helping hand for regadenoson tests. PMID- 26494647 TI - Vasodilator stress and left ventricular asynchrony. PMID- 26494648 TI - Quantifying FDG uptake to diagnose cardiac device infections: When and how should we do it? PMID- 26494650 TI - Subjective age-of-acquisition norms for 4,640 verbs in Spanish. AB - Many studies have shown that how words are processed in a variety of language related tasks is affected by their age of acquisition (AoA). Most AoA norms have been collected for nouns, a fact that limits the extent to which verb stimuli can be adequately manipulated and controlled in empirical studies. With the aim of increasing the number of verbs with AoA values in Spanish, 900 college students were recruited to provide subjective estimates for a total of 4,640 infinitive and reflexive forms. An AoA score for each verb was obtained by averaging the responses of the participants, and these norms were included, together with additional quantitative information (standard deviations, ranges, and z scores), in a database that can be downloaded with this article as supplemental materials. PMID- 26494651 TI - Adapting cultural mixture modeling for continuous measures of knowledge and memory fluency. AB - Previous research (e.g., cultural consensus theory (Romney, Weller, & Batchelder, American Anthropologist, 88, 313-338, 1986); cultural mixture modeling (Mueller & Veinott, 2008)) has used overt response patterns (i.e., responses to questionnaires and surveys) to identify whether a group shares a single coherent attitude or belief set. Yet many domains in social science have focused on implicit attitudes that are not apparent in overt responses but still may be detected via response time patterns. We propose a method for modeling response times as a mixture of Gaussians, adapting the strong-consensus model of cultural mixture modeling to model this implicit measure of knowledge strength. We report the results of two behavioral experiments and one simulation experiment that establish the usefulness of the approach, as well as some of the boundary conditions under which distinct groups of shared agreement might be recovered, even when the group identity is not known. The results reveal that the ability to recover and identify shared-belief groups depends on (1) the level of noise in the measurement, (2) the differential signals for strong versus weak attitudes, and (3) the similarity between group attitudes. Consequently, the method shows promise for identifying latent groups among a population whose overt attitudes do not differ, but whose implicit or covert attitudes or knowledge may differ. PMID- 26494649 TI - Proton detection for signal enhancement in solid-state NMR experiments on mobile species in membrane proteins. AB - Direct proton detection is becoming an increasingly popular method for enhancing sensitivity in solid-state nuclear magnetic resonance spectroscopy. Generally, these experiments require extensive deuteration of the protein, fast magic angle spinning (MAS), or a combination of both. Here, we implement direct proton detection to selectively observe the mobile entities in fully-protonated membrane proteins at moderate MAS frequencies. We demonstrate this method on two proteins that exhibit different motional regimes. Myelin basic protein is an intrinsically disordered, peripherally membrane-associated protein that is highly flexible, whereas Anabaena sensory rhodopsin is composed of seven rigid transmembrane alpha helices connected by mobile loop regions. In both cases, we observe narrow proton linewidths and, on average, a 10* increase in sensitivity in 2D insensitive nuclear enhancement of polarization transfer-based HSQC experiments when proton detection is compared to carbon detection. We further show that our proton detected experiments can be easily extended to three dimensions and used to build complete amino acid systems, including sidechain protons, and obtain inter residue correlations. Additionally, we detect signals which do not correspond to amino acids, but rather to lipids and/or carbohydrates which interact strongly with membrane proteins. PMID- 26494652 TI - Schistosomiasis in the mummified viscera of Saint-Louis (1270 AD). PMID- 26494653 TI - Effects of nanoparticles on the mechanical functioning of the lung. AB - Nanotechnology is a rapidly expanding field that has very promising applications that will improve industry, medicine, and consumer products. However, despite the growing widespread use of engineered nanoparticles in these areas, very little has been done to assess the potential health risks they may pose to high-risk areas of the body, particularly the lungs. In this review we first briefly discuss the structure of the lungs and establish that the pulmonary surfactant (PS), given its vulnerability and huge contribution to healthy lung function, is a mechanism of great concern when evaluating potential nanoparticle interactions within the lung. To warrant that these interactions can occur, studies on the transport of nanoaerols are reviewed to highlight that a plethora of factors contribute to a nanoparticle's ability to travel to the deep regions of the lung where PS resides. The focus of this review is to determine the extent that physicochemical characteristics of nanoparticles such as size, hydrophobicity, and surface charge effect PS function. Numerous nanoparticle types are taken into consideration in order to effectively evaluate observed consistencies across numerous nanoparticle types and develop general trends that exist among the physicochemical characteristics of interest. Biological responses from other mechanisms/components of the lung are briefly discussed to provide further insights on how the toxicology of different nanoparticles is determined. We conclude by discussing general trends that summarize consistencies observed among the studies in regard to physicochemical properties and their effects on monolayer function, addressing current gaps in our understanding, and discussing the future outlook of this field of research. PMID- 26494656 TI - Scottish NHS needs fundamental change, report warns. PMID- 26494654 TI - Enhanced brain release of erythropoietin, cytokines and NO during carotid clamping. AB - Although effective and safe, carotid endarterectomy (CEA) implies a reduced blood flow to the brain and likely an ischemia/reperfusion event. The high rate of uneventful outcomes associated with CEA suggests the activation of brain endogenous protection mechanisms aimed at limiting the possible ischemia/reperfusion damage. This study aims at assessing whether CEA triggers protective mechanisms such as brain release of erythropoietin and nitric oxide. CEA was performed in 12 patients; blood samples were withdrawn simultaneously from the surgically exposed ipsilateral jugular and leg veins before, during (2 and 40 min) and after clamp removal (2 min). Plasma antioxidant capacity, carbonylated proteins, erythropoietin, nitrates and nitrites (NOx) were determined. No changes in intraoperative EEG, peripheral and transcranial blood oxygen saturation were detectable, and no patients showed any neurologic sign after the intervention. Antioxidant capacity and protein carbonylation in plasma were unaffected. Differently, erythropoietin, VEGF, TNF-alpha and NOx increased during clamping in the jugular blood (2 and 40 min), while no changes were observed in the peripheral circulation. These results show that blood erythropoietin, VEGF, TNF-alpha, and NOx increased in the brain during uncomplicated CEA. This may represent an endogenous self-activated neuroprotective mechanism aimed at the prevention of ischemia/reperfusion damage. PMID- 26494655 TI - Purified Human Dental Pulp Stem Cells Promote Osteogenic Regeneration. AB - Human dental pulp stem/progenitor cells (hDPSCs) are attractive candidates for regenerative therapy because they can be easily expanded to generate colony forming unit-fibroblasts (CFU-Fs) on plastic and the large cell numbers required for transplantation. However, isolation based on adherence to plastic inevitably changes the surface marker expression and biological properties of the cells. Consequently, little is currently known about the original phenotypes of tissue precursor cells that give rise to plastic-adherent CFU-Fs. To better understand the in vivo functions and translational therapeutic potential of hDPSCs and other stem cells, selective cell markers must be identified in the progenitor cells. Here, we identified a dental pulp tissue-specific cell population based on the expression profiles of 2 cell-surface markers LNGFR (CD271) and THY-1 (CD90). Prospectively isolated, dental pulp-derived LNGFR(Low+)THY-1(High+) cells represent a highly enriched population of clonogenic cells--notably, the isolated cells exhibited long-term proliferation and multilineage differentiation potential in vitro. The cells also expressed known mesenchymal cell markers and promoted new bone formation to heal critical-size calvarial defects in vivo. These findings suggest that LNGFR(Low+)THY-1(High+) dental pulp-derived cells provide an excellent source of material for bone regenerative strategies. PMID- 26494657 TI - Genome Sequence of Paenibacillus sp. Strain FJAT-28004 for the Genome Sequencing Project for Genomic Taxonomy and Phylogenomics of Bacillus-Like Bacteria. AB - Paenibacillus sp. strain FJAT-28004 is a spore forming and strictly aerobic bacterium. Here, we report the draft 7,479,858-bp genome sequence of Paenibacillus sp. FJAT-28004, which will provide useful information for genomic taxonomy and phylogenomics of the genus Paenibacillus, as well as for the functional gene mining and application of Paenibacillus sp. FJAT-28004. PMID- 26494658 TI - Genome Sequences of Five Additional Brevibacillus laterosporus Bacteriophages. AB - Brevibacillus laterosporus has been isolated from many different environments, including beehives, and produces compounds that are toxic to many organisms. Five B. laterosporus phages have been isolated previously. Here, we announce five additional phages that infect this bacterium, including the first B. laterosporus siphoviruses to be discovered. PMID- 26494659 TI - Genome Sequence of "Candidatus Thioglobus singularis" Strain PS1, a Mixotroph from the SUP05 Clade of Marine Gammaproteobacteria. AB - Mixotrophic marine bacteria from the SUP05 clade are ubiquitous in the ocean. Here, we announce the complete genome sequence of "Candidatus Thioglobus singularis" strain PS1, the first cultured mixotrophic representative from the SUP05 clade. PMID- 26494660 TI - Genome Sequence of "Candidatus Thioglobus autotrophica" Strain EF1, a Chemoautotroph from the SUP05 Clade of Marine Gammaproteobacteria. AB - Chemoautotrophic marine bacteria from the SUP05 clade of marine gammaproteobacteria often dominate low-oxygen waters in upwelling regions, fjords, and hydrothermal systems. Here, we announce the complete genome sequence of "Candidatus Thioglobus autotrophica" strain EF1, the first cultured chemoautotrophic representative from the SUP05 clade. PMID- 26494661 TI - Draft Genome Sequence of Thiostrepton-Producing Streptomyces azureus ATCC 14921. AB - Streptomyces azureus ATCC 14921 belongs to the Streptomyces cyaneus cluster and is known to be a thiostrepton producer. Here, we report a draft genome sequence for this strain, consisting of 350 contigs containing a total of 8,790,525 bp, 8,164 predicted coding sequences, and a G+C content of 70.9%. PMID- 26494662 TI - Complete Genome Sequence of Streptococcus agalactiae Serotype III, Multilocus Sequence Type 283 Strain SG-M1. AB - Streptococcus agalactiae (group B Streptococcus) is a common commensal strain in the human gastrointestinal tract that can also cause invasive disease in humans and other animals. We report here the complete genome sequence of S. agalactiae SG-M1, a serotype III, multilocus sequence type 283 strain, isolated from a Singaporean patient suffering from meningitis. PMID- 26494663 TI - Whole-Genome Sequence of Staphylococcus aureus S54F9 Isolated from a Chronic Disseminated Porcine Lung Abscess and Used in Human Infection Models. AB - We obtained a draft genome sequence of Staphylococcus aureus strain S54F9, which was isolated from a chronic disseminated porcine lung abscess and used in porcine infection models. Genes coding for a number of toxins, including enterotoxins and superantigen, were demonstrated in this strain. PMID- 26494664 TI - Draft Genome Sequence of the Polychlorinated Biphenyl-Degrading Bacterium Pseudomonas stutzeri KF716 (NBRC 110668). AB - Pseudomonas stutzeri KF716 (NBRC 110668) utilizes biphenyl as a sole source of carbon and energy and degrades polychlorinated biphenyls. Here, we report the first draft genome sequence of a biphenyl-degrading strain of the species P. stutzeri. PMID- 26494665 TI - Complete Genome Sequence of Spiroplasma kunkelii Strain CR2-3x, Causal Agent of Corn Stunt Disease in Zea mays L. AB - Spiroplasma kunkelii causes corn stunt disease of Zea mays L. in the Americas. Here, we report the nucleotide sequence of the 1,463,926-bp circular chromosome and four plasmids of strain CR2-3x. This information will facilitate studies of Spiroplasma pathogenicity and evolutionary adaptations to transkingdom parasitism in plants and insect vectors. PMID- 26494666 TI - Draft Genome Sequence of Bradyrhizobium japonicum Is-1, Which Is Incompatible with Rj2 Genotype Soybeans. AB - We report the draft genome sequence of Bradyrhizobium japonicum Is-1, which is incompatible with Rj2 genotype soybeans. The estimated genome size of this strain is 8.9 Mb. Genome sequence information of this strain will help to identify a causal gene for this incompatibility. PMID- 26494667 TI - First Draft Genome Sequence of Salmonella enterica Serovar Gallinarum Strain VTCCBAA614, Isolated from Chicken in India. AB - Salmonella enterica subsp. enterica serovar Gallinarum biovar Gallinarum causes fowl typhoid (FT), which results in huge economic losses to poultry farmers in India. We report the draft genome sequence of Salmonella biovar Gallinarum strain VTCCBAA614, isolated from a chicken in an FT affected broiler flock. PMID- 26494668 TI - Genome Sequence of Flavobacterium akiainvivens IK-1T, Isolated from Decaying Wikstroemia oahuensis, an Endemic Hawaiian Shrub. AB - Flavobacterium spp. have been cultivated from diverse aquatic and terrestrial habitats. F. akiainvivens IK-1(T) was cultivated from decaying wood of Wikstroemia oahuensis, an endemic Hawaiian shrub. The strain's genome sequence may provide insights into niche adaptation and evolution of the genus in a mid ocean archipelago. PMID- 26494669 TI - Draft Genome Sequence of the Enteropathogenic Bacterium Campylobacter jejuni Strain cj255. AB - The enteropathogen Campylobacter jejuni is a global health disaster, being one of the leading causes of bacterial gastroenteritis. Here, we present the draft genome sequence of C. jejuni strain cj255, isolated from a chicken source in Islamabad, Pakistan. The draft genome sequence will aid in epidemiological studies and quarantine of this broad-host-range pathogen. PMID- 26494670 TI - Draft Genome Sequence of Yellow Pigmented Jeotgalibacillus alimentarius JY-13T, the First Halophile Strain of the Genus Jeotgalibacillus. AB - Jeotgalibacillus alimentarius JY-13(T) (=KCCM 80002(T) = JCM 10872(T)) is a moderate halophile. In 2001, this was the first strain of the newly proposed Jeotgalibacillus genus. The draft genome of J. alimentarius was found to consist of 32 contigs (N50, 315,125 bp) with a total size of 3,364,745 bp. This genome information will be helpful for studies on pigmentation as well as applications for this bacterium. PMID- 26494671 TI - Complete Genome Sequence of Southern tomato virus Identified in China Using Next Generation Sequencing. AB - The complete genome sequence of Southern tomato virus (STV), a double-stranded RNA virus that affects tomato in China, was determined using small RNA deep sequencing. This Chinese isolate shares 99% sequence identity to other isolates from Mexico, France, Spain, and the United States. This is the first report of STV infecting tomatoes in Asia. PMID- 26494672 TI - Genome Sequences of Multidrug-Resistant Salmonella enterica Serovar Paratyphi B (dT+) and Heidelberg Strains from the Colombian Poultry Chain. AB - Salmonella enterica is a pathogen of significant public health importance that is frequently associated with foodborne illness. We report the whole-genome sequences of four multidrug-resistant Salmonella enterica serovar Paratyphi B and Heidelberg strains, isolated from the Colombian poultry chain. The isolates contain a variety of antimicrobial resistance genes for aminoglycosides, beta lactams, fluoroquinolones, sulfonamides, tetracycline, and trimethoprim. PMID- 26494673 TI - Erratum for Chen et al., Complete Genome Sequence of Bifidobacterium actinocoloniiforme Type Strain DSM 22766T, Isolated from Bumblebee Digestive Tracts. PMID- 26494674 TI - High-Quality Draft Genome Sequence of Aneurinibacillus migulanus ATCC 9999T (DSM 2895), a Gramicidin S-Producing Bacterium Isolated from Garden Soil. AB - Aneurinibacillus migulanus ATCC 9999(T) (DSM 2895) is a Gram-positive, round spore-forming, and gramicidin S-producing bacterium. Here, we report the 6.35-Mb high-quality draft genome sequence of A. migulanus ATCC 9999(T), which will provide useful information for the genomic taxonomy and phylogenomics of Bacillus like bacteria. PMID- 26494675 TI - Genome Sequence of Bacillus butanolivorans K9T (DSM 18926), an n-Butanol Consuming Bacterium Isolated from Soil. AB - Bacillus butanolivorans K9(T) (DSM 18926) is a Gram-positive, spore-forming, strictly aerobic, and n-butanol-consuming bacterium. Here, we report the 5.68-Mb genome sequence of B. butanolivorans K9(T), which is the first genomic information of this species that will provide useful information for the genomic taxonomy and phylogenomics of Bacillus-like bacteria. PMID- 26494676 TI - Draft Genome Sequence of Bacillus murimartini LMG 21005T, an Alkalitolerant Bacterium Isolated from a Church Wall Mural in Germany. AB - Bacillus murimartini LMG 21005(T) is a Gram-positive, spore-forming, and alkalitolerant bacterium isolated from a church wall mural. Here, we report the 4.17-Mb genome sequence of B. murimartini LMG 21005(T), which will accelerate the application of this alkalitolerant bacterium and provide useful information for genomic taxonomy and phylogenomics of Bacillus-like bacteria. PMID- 26494677 TI - Draft Genome Sequence of Sporosarcina globispora W 25T (DSM 4), a Psychrophilic Bacterium Isolated from Soil and River Water. AB - Sporosarcina globispora W 25(T) (DSM 4) is a Gram-positive, round-spore-forming, and psychrophilic bacterium. Here, we report the 5.66-Mb genome sequence of S. globispora W 25(T), which will accelerate the application of this psychrophile and provide useful information for genomic taxonomy and phylogenomics of Bacillus like bacteria. PMID- 26494678 TI - Draft Genome Sequence of Komagataeibacter europaeus CECT 8546, a Cellulose Producing Strain of Vinegar Elaborated by the Traditional Method. AB - The present article reports the draft genome sequence of the strain Komagataeibacter europaeus CECT 8546, an acetic acid bacterium characterized by its ability to overproduce cellulose. This species is highly resistant to acetic acid and commonly found during vinegar elaboration. PMID- 26494679 TI - Draft Genome Sequence of Cellulolytic and Xylanolytic Paenibacillus sp. A59, Isolated from Decaying Forest Soil from Patagonia, Argentina. AB - Paenibacillus sp. A59 was isolated from decaying forest soil in Argentina and characterized as a xylanolytic strain. We report the draft genome sequence of this isolate, with an estimated genome size of 7 Mb which harbor 6,424 coding sequences. Genes coding for hydrolytic enzymes involved in lignocellulose deconstruction were predicted. PMID- 26494680 TI - Draft Genome Sequence of Burkholderia cordobensis Type Strain LMG 27620, Isolated from Agricultural Soils in Argentina. AB - Bacteria of the genus Burkholderia are commonly found in diverse ecological niches in nature. We report here the draft genome sequence of Burkholderia cordobensis type strain LMG 27620, isolated from agricultural soil in Cordoba, Argentina. This strain harbors several genes involved in chitin utilization and phenol degradation, which make it an interesting candidate for biocontrol purposes and xenobiotic degradation in polluted environments. PMID- 26494681 TI - Draft Whole-Genome Sequence of Xenorhabdus sp. Strain GDc328, Isolated from the Indigenous South African Nematode Host Steinernema khoisanae. AB - Here, we describe the draft genome sequence of Xenorhabdus sp. GDc328, an endosymbiont of the native South African entomopathogenic nematode host, Steinernema khoisanae. The total genome size of the bacteria is 4.09 Mb. The genome comprises a total of 3,608 genes with a molecular G+C content of 44.64%. PMID- 26494682 TI - Draft Genome Sequence of Aeromonas caviae Strain 429865 INP, Isolated from a Mexican Patient. AB - Aeromonas caviae is an emerging human pathogen. Here, we report the draft genome sequence of Aeromonas caviae strain 429865 INP which shows the presence of various putative virulence-related genes. PMID- 26494683 TI - Draft Genome Sequence of Chlamydia trachomatis Strain 54, Isolated from the Urogenital Tract of a Male in Japan. AB - We report the draft genome sequence of Chlamydia trachomatis strain 54, isolated from the urogenital tract of a male in Japan, with unique polymorphic membrane proteins. Detailed genomic analysis will aid our understanding of the selective pressures that lead to sexual differentiation in chlamydial adaptive evolution. PMID- 26494684 TI - Genome Sequence of Type Strain Bacillus decisifrondis E5HC-32T (DSM 11725T), Isolated from Soil Underlying the Decaying Leaf Litter of a Slash Pine Forest. AB - Bacillus decisifrondis E5HC-32(T) (DSM 11725(T)) is a Gram-positive, subterminal spherical spore-forming, strictly aerobic bacterium. Here, we report the 5,613,728-bp genome sequence of B. decisifrondis E5HC-32(T), which is the first genome information of this species and will provide useful information for genomic taxonomy and phylogenomics of Bacillus-like bacteria. PMID- 26494685 TI - Draft Genome Sequence of Streptomyces fradiae olg1-1, a Strain Resistant to Nitrone-Oligomycin. AB - We report a draft genome sequence of Streptomyces fradiae olg1-1, a mutant strain derived from the model object S. fradiae ATCC 19609, which is resistant to nitrone-oligomycin and has a mutation in the DNA-binding domain of a transcriptional regulator PadR. PMID- 26494686 TI - Complete Genome Sequence of Spiroplasma cantharicola CC-1T (DSM 21588), a Bacterium Isolated from Soldier Beetle (Cantharis carolinus). AB - Spiroplasma cantharicola CC-1(T) (DSM 21588) was isolated from the gut of a soldier beetle (Cantharis carolinus) collected in Maryland, USA. Here, we report the complete genome sequence of this bacterium to facilitate the investigation of its biology. PMID- 26494687 TI - Draft Genome Sequence of Pasteurella multocida Isolate P1062, Isolated from Bovine Respiratory Disease. AB - Here, we report the draft genome of Pasteurella multocida isolate P1062 recovered from pneumonic bovine lung in the United States in 1959. PMID- 26494688 TI - Draft Genome Sequence of Achromobacter sp. Strain DMS1, Capable of Degrading Polyaromatic Hydrocarbons Isolated from the Industrially Perturbed Environment of Amlakhadi Canal, India. AB - Here, we report the draft genome sequence of Achromobacter sp. strain DMS1, which is 4.9 Mbp and has 3,727 coding sequences (CDSs), and is capable of degrading xenobiotic compounds and harboring genes for aromatic hydrocarbon metabolism. Its genome will unravel the basic mechanism involved in bioremediation of anthropogens. PMID- 26494689 TI - Crystal structure of thermophilic dextranase from Thermoanaerobacter pseudethanolicus. AB - The crystal structures of the wild type and catalytic mutant Asp-312->Gly in complex with isomaltohexaose of endo-1,6-dextranase from the thermophilic bacterium Thermoanaerobacter pseudethanolicus (TpDex), belonging to the glycoside hydrolase family 66, were determined. TpDex consists of three structural domains, a catalytic domain comprising an (beta/alpha)8-barrel and two beta-domains located at both N- and C-terminal ends. The isomaltohexaose-complex structure demonstrated that the isomaltohexaose molecule was bound across the catalytic site, showing that TpDex had six subsites (-4 to +2) in the catalytic cleft. Marked movement of the Trp-376 side-chain along with loop 6, which was the side wall component of the cleft at subsite +1, was observed to occupy subsite +1, indicating that it might expel the cleaved aglycone subsite after the hydrolysis reaction. Structural comparison with other mesophilic enzymes indicated that several structural features of TpDex, loop deletion, salt bridge and surface exposed charged residue, may contribute to thermostability. PMID- 26494690 TI - Osseous Pseudoprogression in Vertebral Bodies Treated with Stereotactic Radiosurgery: A Secondary Analysis of Prospective Phase I/II Clinical Trials. AB - BACKGROUND AND PURPOSE: Osseous pseudoprogression on MR imaging can mimic true progression in lesions treated with spine stereotactic radiosurgery. Our aim was to describe the prevalence and time course of osseous pseudoprogression to assist radiologists in the assessment of patients after spine stereotactic radiosurgery. MATERIALS AND METHODS: A secondary analysis of 2 prospective trials was performed. MRIs before and after spine stereotactic radiosurgery were assessed for response. "Osseous pseudoprogression" was defined as transient growth in signal abnormality centered at the lesion with a sustained decline on follow-up MR imaging that was not attributable to chemotherapy. RESULTS: From the initial set of 223 patients, 37 lesions in 36 patients met the inclusion criteria and were selected for secondary analysis. Five of the 37 lesions (14%) demonstrated osseous pseudoprogression, and 9 demonstrated progressive disease. There was a significant association between single-fraction therapy and the development of osseous pseudoprogression (P = .01), and there was a significant difference in osseous pseudoprogression-free survival between single- and multifraction regimens (P = .005). In lesions demonstrating osseous pseudoprogression, time-to peak size occurred between 9.7 and 24.4 weeks after spine stereotactic radiosurgery (mean, 13.9 weeks; 95% CI, 8.6-19.1 weeks). The peak lesion size was between 4 and 10 mm larger than baseline. Most lesions returned to baseline size between 23 and 52.4 weeks following spine stereotactic radiosurgery. CONCLUSIONS: Progression on MR imaging performed between 3 and 6 months following spine stereotactic radiosurgery should be treated with caution because osseous pseudoprogression may be seen in more than one-third of these lesions. Single fraction spine stereotactic radiosurgery may be associated with osseous pseudoprogression. The possibility of osseous pseudoprogression should be incorporated into the prospective criteria for assessment of local control following spine stereotactic radiosurgery. PMID- 26494691 TI - Improved Brain Tumor Classification by Sodium MR Imaging: Prediction of IDH Mutation Status and Tumor Progression. AB - BACKGROUND AND PURPOSE: MR imaging in neuro-oncology is challenging due to inherent ambiguities in proton signal behavior. Sodium-MR imaging may substantially contribute to the characterization of tumors because it reflects the functional status of the sodium-potassium pump and sodium channels. MATERIALS AND METHODS: Sodium-MR imaging data of patients with treatment-naive glioma WHO grades I-IV (n = 34; mean age, 51.29 +/- 17.77 years) were acquired by using a 7T MR system. For acquisition of sodium-MR images, we applied density-adapted 3D radial projection reconstruction pulse sequences. Proton-MR imaging data were acquired by using a 3T whole-body system. RESULTS: We demonstrated that the initial sodium signal of a treatment-naive brain tumor is a significant predictor of isocitrate dehydrogenase (IDH) mutation status (P < .001). Moreover, independent of this correlation, the Cox proportional hazards model confirmed the sodium signal of treatment-naive brain tumors as a predictor of progression (P = .003). Compared with the molecular signature of IDH mutation status, information criteria of model comparison revealed that the sodium signal is even superior to IDH in progression prediction. In addition, sodium-MR imaging provides a new approach to noninvasive tumor classification. The sodium signal of contrast enhancing tumor portions facilitates differentiation among most glioma types (P < .001). CONCLUSIONS: The information of sodium-MR imaging may help to classify neoplasias at an early stage, to reduce invasive tissue characterization such as stereotactic biopsy specimens, and overall to promote improved and individualized patient management in neuro-oncology by novel imaging signatures of brain tumors. PMID- 26494692 TI - Low-Dose Volume-of-Interest C-Arm CT Imaging of Intracranial Stents and Flow Diverters. AB - BACKGROUND AND PURPOSE: Volume-of-interest C-arm CT is a novel technique for imaging of intracranial high-contrast objects. We performed this study to evaluate the potential diagnostic value and radiation dose reduction of this technique for imaging of intracranial stents and flow diverters. MATERIALS AND METHODS: Twenty-seven patients were imaged with a VOI C-arm CT scan following treatment with a flow diverter or stent-assisted coiling. The radiation dose-area product was recorded for VOI scans. For comparison, the dose-area product from 30 previously acquired consecutive full-view DynaCTs was used. Thermoluminescence dosimetry by using 35 evenly distributed thermoluminescence dosimeters in an anthropomorphic head phantom was also performed by using both conventional full field and VOI acquisitions. Three observers were presented with VOI images for assessment of the potential diagnostic value. RESULTS: The dose-area product measurements showed an exposure reduction of 85% compared with the full field acquisitions used for comparison. The thermoluminescence dosimetry evaluations also showed a considerable dose reduction of 79.8% throughout the volume. For most of the evaluated cases, the observers thought that diagnostically useful information was provided by the VOI images (alpha = .810). Visualization of device details, such as the extent of opening, positioning, wall apposition, and aneurysm coverage, was judged of good diagnostic quality for most cases (88.9% 92.6%). CONCLUSIONS: In this study, VOI C-arm CT provided high-quality diagnostic images of intracranial stents and flow diverters at a dramatic reduction of radiation exposure. Image content was thought to add useful information. It is a promising method to assess device status during procedures and at follow-up. PMID- 26494693 TI - Evolution of T1 Relaxation, ADC, and Fractional Anisotropy during Early Brain Maturation: A Serial Imaging Study on Preterm Infants. AB - BACKGROUND AND PURPOSE: The alteration of brain maturation in preterm infants contributes to neurodevelopmental disabilities during childhood. Serial imaging allows understanding of the mechanisms leading to dysmaturation in the preterm brain. The purpose of the present study was to provide reference quantitative MR imaging measures across time in preterm infants, by using ADC, fractional anisotropy, and T1 maps obtained by using the magnetization-prepared dual rapid acquisition of gradient echo technique. MATERIALS AND METHODS: We included preterm neonates born at <30 weeks of gestational age without major brain lesions on early cranial sonography and performed 3 MRIs (3T) from birth to term equivalent age. Multiple measurements (ADC, fractional anisotropy, and T1 relaxation) were performed on each examination in 12 defined white and gray matter ROIs. RESULTS: We acquired 107 MRIs (35 early, 33 intermediary, and 39 at term-equivalent age) in 39 cerebral low-risk preterm infants. Measures of T1 relaxation time showed a gradual and significant decrease with time in a region- and hemispheric-specific manner. ADC values showed a similar decline with time, but with more variability than T1 relaxation. An increase of fractional anisotropy values was observed in WM regions and inversely a decrease in the cortex. CONCLUSIONS: The gradual change with time reflects the progressive maturation of the cerebral microstructure in white and gray matter. Our study provides reference trajectories from 25 to 40 weeks of gestation of T1 relaxation, ADC, and fractional anisotropy values in low-risk preterm infants. We speculate that deviation thereof might reflect disturbed cerebral maturation; the correlation of this disturbed maturation with neurodevelopmental outcome remains to be addressed. PMID- 26494694 TI - A Potential Biomarker in Amyotrophic Lateral Sclerosis: Can Assessment of Brain Iron Deposition with SWI and Corticospinal Tract Degeneration with DTI Help? AB - BACKGROUND AND PURPOSE: Iron-mediated oxidative stress plays a pivotal role in the pathogenesis of amyotrophic lateral sclerosis. This study aimed to assess iron deposition qualitatively and quantitatively by using SWI and microstructural changes in the corticospinal tract by using DTI in patients with amyotrophic lateral sclerosis. MATERIALS AND METHODS: Seventeen patients with amyotrophic lateral sclerosis and 15 age- and sex-matched controls underwent brain MR imaging with SWI and DTI. SWI was analyzed for both signal-intensity scoring and quantitative estimation of iron deposition in the anterior and posterior banks of the motor and sensory cortices and deep gray nuclei. The diffusion measurements along the corticospinal tract at the level of pons and medulla were obtained by ROI analysis. RESULTS: Patients with amyotrophic lateral sclerosis showed reduced signal-intensity grades in the posterior bank of the motor cortex bilaterally. Quantitative analysis confirmed significantly higher iron content in the posterior bank of the motor cortex in patients with amyotrophic lateral sclerosis. In contrast, no significant differences were noted for the anterior bank of the motor cortex, anterior and posterior banks of the sensory cortex, and deep nuclei. Receiver operating characteristic comparison showed a cutoff of 35MUg Fe/g of tissue with an area under the curve of 0.78 (P = .008) for the posterior bank of the motor cortex in discriminating patients with amyotrophic lateral sclerosis from controls. Fractional anisotropy was lower in the pyramidal tracts of patients with amyotrophic lateral sclerosis at the pons and medulla on either side, along with higher directionally averaged mean diffusivity values. The combination of SWI and DTI revealed an area under the curve of 0.784 for differentiating patients with amyotrophic lateral sclerosis from controls. CONCLUSIONS: Measurements of motor cortex iron deposition and diffusion tensor parameters of the corticospinal tract may be useful biomarkers for the diagnosis of clinically suspected amyotrophic lateral sclerosis. PMID- 26494695 TI - Preclinical Testing of a Novel Thin Film Nitinol Flow-Diversion Stent in a Rabbit Elastase Aneurysm Model. AB - BACKGROUND AND PURPOSE: Thin film nitinol can be processed to produce a thin microporous sheet with a low percentage of metal coverage (<20%) and high pore attenuation (~70 pores/mm(2)) for flow diversion. We present in vivo results from the treatment of experimental rabbit aneurysms by using a thin film nitinol-based flow-diversion device. MATERIALS AND METHODS: Nineteen aneurysms in the rabbit elastase aneurysm model were treated with a single thin film nitinol flow diverter. Devices were also placed over 17 lumbar arteries to model perianeurysmal branch arteries of the intracranial circulation. Angiography was performed at 2 weeks (n = 7), 1 month (n = 8), and 3 months (n = 4) immediately before sacrifice. Aneurysm occlusion was graded on a 3-point scale (grade I, complete occlusion; grade II, near-complete occlusion; grade III, incomplete occlusion). Toluidine blue staining was used for histologic evaluation. En face CD31 immunofluorescent staining was performed to quantify neck endothelialization. RESULTS: Markedly reduced intra-aneurysmal flow was observed on angiography immediately after device placement in all aneurysms. Grade I or II occlusion was noted in 4 (57%) aneurysms at 2-week, in 6 (75%) aneurysms at 4 week, and in 3 (75%) aneurysms at 12-week follow-up. All 17 lumbar arteries were patent. CD31 staining showed that 75% +/- 16% of the aneurysm neck region was endothelialized. Histopathology demonstrated incorporation of the thin film nitinol flow diverter into the vessel wall and no evidence of excessive neointimal hyperplasia. CONCLUSIONS: In this rabbit model, the thin film nitinol flow diverter achieved high rates of aneurysm occlusion and promoted tissue in growth and aneurysm neck healing, even early after implantation. PMID- 26494696 TI - REPLY. PMID- 26494697 TI - Recent Advances in Understanding Gadolinium Retention in the Brain. PMID- 26494698 TI - The Effect of Body Mass Index on Pelvic Floor Support 1 Year Postpartum. AB - Elevated body mass index (BMI) is associated with the incidence, prevalence, and progression of pelvic organ prolapse (POP). This study investigated the effect of peripartum BMI on pelvic floor support 1 year postpartum (PP1y). One hundred eight nulliparous women had their BMI recorded and underwent POP assessments using the Pelvic Organ Prolapse Quantification System at baseline, third trimester (36th to 38th week of pregnancy [G36-38w]), and PP1y. Pelvic organ prolapse was defined as >=stage II. Women gained on average 1.9 kg between baseline and PP1y. After adjustment, increasing BMI PP1y was associated with increasing anterior wall descent (P < .0001) and higher odds of having POP PP1y (odds ratio: 1.41, 95% confidence interval: 1.01-1.97, P = .045). Trial of labor compared to unlabored cesarean delivery, POP G36-38w, and decreased fetal weight were independently associated with anterior vaginal wall laxity PP1y. Our finding suggests that postpartum BMI influences pelvic floor laxity 1 year after delivery. Postpartum weight reduction may serve as a strategy for POP prevention in some women. PMID- 26494699 TI - Cysteine Prevents Menopausal Syndromes in Ovariectomized Mouse. AB - Cysteine (Cys) is well known to be involved in oxidation-reduction reactions, serving as a source of sulfides in the body. Amino acids are known to improve menopausal symptoms and significantly reduce morbidity. This study aims to find an unrevealed effect of Cys with estrogenic and osteogenic actions. Ovariectomized (OVX) mice were treated with Cys daily for 8 weeks. Estrogen related and osteoporosis-related factors were analyzed in the vagina, serum, and tibia. Cys was treated in estrogen receptor (ER)-positive human osteoblast-like MG-63 cells and ER-positive human breast cancer Michigan Cancer Foundation-7 (MCF 7) cells. Cysteine administration ameliorated overweightness of the body and vaginal atrophy in the OVX mice. Cysteine increased the levels of alkaline phosphatase (ALP) and 17beta-estradiol in the serum of the OVX mice and improved the bone mineral density in the OVX mice. In MG-63 cells, Cys increased the proliferation, ERbeta messenger RNA (mRNA) expression, and estrogen response element (ERE) activity. Cysteine increased the ALP activity and the phosphorylation of extracellular signal-regulated kinase. In MCF-7 cells, Cys also increased the proliferation, ERbeta mRNA expression, and ERE activity. Taken together, these results demonstrated that Cys has estrogenic and osteogenic activities in OVX mice, MG-63 cells, and MCF-7 cells. The novel insights gained here strongly imply the potential use of Cys as a new agent for postmenopausal women. PMID- 26494700 TI - Swine Granulosa Cells Show Typical Endothelial Cell Characteristics. AB - Granulosa cells, which belong to the somatic compartment of the ovarian follicle, are actively involved as endocrine cells in follicle growth. Recently, it has been proposed that these cells are not terminally differentiated and possess multipotency. Therefore, we cultured swine granulosa cells in specific endothelial cell culture medium (EBM-2), and phenotypic and functional characteristics of endothelial cells were assessed. The collected data suggest that these endocrine cells can also behave as endothelial cells, therefore potentially contributing to follicular angiogenesis, a crucial process in follicle growth and selection. PMID- 26494701 TI - The Impact of Multiparity on Uterine Gene Expression and Decidualization in Mice. AB - It has been well established that a previous pregnancy exhibits a beneficial effect on the subsequent pregnancy. However, the underlying mechanisms have not been defined. We hypothesized that multiparity may affect decidualization process during early pregnancy. To test this hypothesis, we analyzed global gene changes associated with multiparity in the mouse uterus using RNA-sequencing (RNA-seq). We identified a total of 131 differentially expressed genes (fold change > 2 and false discovery rate < 0.05), of which 58 were downregulated and 73 genes were upregulated in the second pregnancy (SP) compared to the first pregnancy. Functional clustering analysis showed that genes involved in stress response were significantly enriched. Most importantly, a significant portion of differentially expressed genes, 14 genes or 10.7%, overlapped with the gene list associated with decidualization. Quantitative reverse transcription (RT) polymerase chain reaction (qRT-PCR) analysis confirmed a decreased expression of 4 genes (Klk1, kallikrein 1; H2-Eb1, histocompatibility 2 class II antigen E beta; Mmp7, matrix metallopeptidase 7; Pdpn, podoplanin) and an increase in expression of 2 genes (Thy1, thymus cell antigen 1; Ptgs2, prostaglandin-endoperoxide synthase 2) in SP. Beyond protein-coding genes, we also identified a differentially expressed long noncoding RNA AI506816. Our data provide new insights into the molecular mechanisms underlying the beneficial effect of multiparity. PMID- 26494703 TI - Endoscopic Treatment for Persistent Hematospermia: A Novel Technique Using a Holmium Laser. AB - PURPOSE: We present our endoscopic technique for treating ejaculatory duct and seminal vesicle diseases with a holmium laser. MATERIALS AND METHODS: Fifteen patients with persistent hematospermia were enrolled in this study from June 2007 to April 2014. All patients had failed medical treatments. All patients were evaluated with transrectal ultrasound and pelvic computed tomography or magnetic resonance imaging. We performed endoscopic treatment with a semi-rigid ureteroscope after dilation using a guidewire and ureteral serial dilator. A holmium laser was used to incise the obstructed ejaculatory duct, coagulate hemorrhagic mucosa, and fragment stones in the ejaculatory duct or seminal vesicles. Stones were removed using a basket and forceps. RESULTS: The mean duration of hematospermia was 30.6 months. Mean patient age was 45.3 years. The mean serum levels of prostate-specific antigen and testosterone were 1.36 and 4.95 ng/mL, respectively. No operative complications were encountered. Mean operative time was 35.4 min. Seven patients had ejaculatory duct or seminal vesicle stones, which were subsequently determined to be carbonate apatite, mucin, struvite, and calcium oxalate dehydrate stones. Mean duration of follow-up was 32.1 months. Although two patients showed recurrent hematospermia 11 and 12 months after the operation, hematospermia resolved in 13 patients (86.7%). The infertile patient showed an improved semen finding and had a successful pregnancy. CONCLUSION: Endoscopic treatment using a holmium laser is minimally invasive and was effective for treating ejaculatory duct and seminal vesicle diseases, which are the main cause of hematospermia. PMID- 26494702 TI - Evolutionary and Phylogenetic Analysis of the Hepaciviruses and Pegiviruses. AB - The known genetic diversity of the hepaciviruses and pegiviruses has increased greatly in recent years through the discovery of viruses related to hepatitis C virus and human pegivirus in bats, bovines, equines, primates, and rodents. Analysis of these new species is important for research into animal models of hepatitis C virus infection and into the zoonotic origins of human viruses. Here, we provide the first systematic phylogenetic and evolutionary analysis of these two genera at the whole-genome level. Phylogenies confirmed that hepatitis C virus is most closely related to viruses from horses whereas human pegiviruses clustered with viruses from African primates. Within each genus, several well supported lineages were identified and viral diversity was structured by both host species and location of sampling. Recombination analyses provided evidence of interspecific recombination in hepaciviruses, but none in the pegiviruses. Putative mosaic genome structures were identified in NS5B gene region and were supported by multiple tests. The identification of interspecific recombination in the hepaciviruses represents an important evolutionary event that could be clarified by future sampling of novel viruses. We also identified parallel amino acid changes shared by distantly related lineages that infect similar types of host. Notable parallel changes were clustered in the NS3 and NS4B genes and provide a useful starting point for experimental studies of the evolution of Hepacivirus host-virus interactions. PMID- 26494704 TI - Modelling and estimation of HIV prevalence and number of people living with HIV in India, 2010-2011. AB - This paper provides HIV estimation methodology used in India and key HIV estimates for 2010-2011. We used a modified version of the Spectrum tool that included an Estimation and Projection Package as part of its AIDS Impact Module. Inputs related to population size, age-specific pattern of fertility, gender ratio at birth, age and gender-specific pattern of mortality, and volume and age gender distribution of net migration were derived from census records, the Sample Registration System and large-scale demographic health surveys. Epidemiological and programmatic data were derived from HIV sentinel surveillance, large-scale epidemiological surveys and the programme management information system. Estimated adult HIV prevalence retained a declining trend in India, following its peak in 2002 at a level of 0.41% (within bounds 0.35-0.47%). By 2010 and 2011, it levelled at estimates of 0.28% (0.24-0.34%) and 0.27% (0.22-0.33%), respectively. The estimated number of people living with HIV (PLHIV) reduced by 8% between 2007 and 2011. While children accounted for approximately 6.3% of total HIV infections in 2007, this proportion increased to about 7% in 2011. With changing priorities and epidemic patterns, the programme has to customise its strategies to effectively address the emerging vulnerabilities and adapt them to suit the requirements of different geographical regions. PMID- 26494705 TI - Intestinal spirochaetosis causing chronic diarrhoea in a patient with HIV infection. AB - A 36-year-old Caucasian homosexual man was found to have HIV infection on routine screening. He had an eight-year history of chronic diarrhoea, which pre-dated the HIV diagnosis and did not improve after the introduction of combination antiretroviral therapy. After referral to the Gastroenterology department, he underwent fibreoptic colonoscopy. Colonic biopsies revealed the presence of intestinal spirochaetosis. He received a two-week course of metronidazole, which led to complete resolution of his diarrhoea. Intestinal spirochaetosis should be considered in the differential diagnosis of patients with HIV infection and chronic diarrhoea without other apparent cause. PMID- 26494706 TI - Laboratory Evaluations of Durability of Southern Pine Pressure Treated With Extractives From Durable Wood Species. AB - Extracts from sawdust of four naturally durable wood species [Alaskan yellow cedar, AYC, Cupressus nootkanansis D. Don 1824; eastern red cedar, ERC, Juniperus virginiana L.; honey mesquite, HM, Prosopis glandulosa Torr.; and black locust, BL, Robinia pseudoacacia L.] were used to treat southern pine, Pt, Pinus taeda L. sapwood blocks. Extractive treated blocks were evaluated for decay resistance in standard soil bottle fungal assays challenged with brown and white rot decay fungi. Results showed that extractives did impart some improvement to decay resistance of Pt blocks. BL- and HM-treated Pt blocks were also used in choice and no-choice assays to determine feeding preference and damage by eastern subterranean termites (Reticulitermes flavipes) Kollar. Minimal feeding on treated blocks was seen in both choice and no-choice assays. In choice assays, there was similar mortality between HM and BL arenas; however, in no-choice assays, complete mortality was recorded for HM-treated Pt and high mortality was seen with BL-treated Pt. Subsequent dose mortality termite assays showed HM to be effective in killing R. flavipes at low concentrations. Both HM and BL show promise as deterrents or termiticidal protectants and will be further evaluated in field studies. PMID- 26494707 TI - Heat Tolerance of the Brown Recluse Spider (Araneae: Sicariidae): Potential for Pest Control. AB - The brown recluse spider, Loxosceles reclusa Gertsch & Mulaik, is a well-known venomous spider common in the south-central United States where infestations can reach thousands of individuals in a single structure. Bites from this spider pose a risk of dermonecrotic lesions (loxoscelism) or, rarely, more serious systemic effects. The heat tolerance of this spider is understudied but may offer an alternative pest control solution to pesticides or fumigation, both of which have their disadvantages. We subjected brown recluse spiders to increasing temperatures to establish the upper lethal temperature (LT). Using probit analysis to generate probability of mortality at increasing temperatures, we then exposed adult spiders to the observed LT50 to simulate whole-room heat treatment. Laboratory results predict exposure to 48 degrees C for 130 min will achieve 100% mortality of adult spiders. Field tests need to be conducted to determine the efficacy of heat treatment in a variety of real-world situations. PMID- 26494708 TI - Effect of Aggregation and Cage Setting on Some Life-History Parameters of Aleurodicus Rugioperculatus (Hemiptera: Aleyrodidae). AB - Fecundity is defined as the number of progeny produced by an organism. In our study, we used three different experimental settings to measure the fecundity of rugose spiraling whitefly (Aleurodicus rugioperculatus Martin), a recent invasive insect in Florida, on Strelitzia nicolai host plants. The adult longevity was significantly different among treatments, with females surviving significantly longer in groups in whole-plant cages and individual females in clip cages compared with individual females in whole-plant cages. Females laid 34.5 +/- 8.4, 156.4 +/- 18.3, and 225.2 +/- 18 eggs, on average, when kept individually in whole-plant cages, in a group in whole-plant cages, and individually in clip cages, respectively. In all treatments, there was a significant correlation between the longevity and fecundity of females. Males emerged earlier than females in all treatments. Virgin females produced only males in the F1, while mated females produced both males and females, which suggests an arrhenotokous parthenogenesis. The egg-to-adult survival of the whitefly was 29 +/- 4%, and the highest mortality occurred at the crawler stage when reared on S. nicolai. The results showed a significant effect of aggregation and cage setting on longevity and fecundity of this whitefly. To conclude, the experimental setting of the group fecundity treatment is more similar to what occurs in the landscape. Such a significant effect of cage setting and aggregation on the life-history parameters should be always taken into account when designing experiments or interpreting results. PMID- 26494709 TI - Posttreatment Feeding Affects Mortality of Bed Bugs (Hemiptera: Cimicidae) Exposed to Insecticides. AB - Insecticide sprays and dusts are used for controlling bed bugs, Cimex lectularius L. In natural environments, bed bugs have daily access to hosts after they are exposed to insecticides. The established laboratory insecticide bioassay protocols do not provide feeding after insecticide treatments, which can result in inflated mortality compared with what would be encountered in the field. We evaluated the effect of posttreatment feeding on mortality of bed bugs treated with different insecticides. None of the insecticides tested had a significant effect on the amount of blood consumed and percent feeding. The effect of posttreatment feeding on bed bug mortality varied among different insecticides. Feeding significantly reduced mortality in bed bugs exposed to deltamethrin spray, an essential oil mixture (Bed Bug Fix) spray, and diatomaceous earth dust. Feeding increased the mean survival time for bed bugs treated with chlorfenapyr spray and a spray containing an essential oil mixture (Ecoraider), but did not affect the final mortality. First instars hatched from eggs treated with chlorfenapyr liquid spray had reduced feeding compared with nymphs hatched from nontreated eggs. Those nymphs hatched from eggs treated with chlorfenapyr liquid spray and successfully fed had reduced mortality and a higher mean survival time than those without feeding. We conclude that the availability of a bloodmeal after insecticide exposure has a significant effect on bed bug mortality. Protocols for insecticide efficacy testing should consider offering a bloodmeal to the treated bed bugs within 1 to 3 d after treatment. PMID- 26494710 TI - Case report: facial nerve palsy, necrotising otitis externa and leishmaniasis. PMID- 26494711 TI - Silencio/CG9754 connects the Piwi-piRNA complex to the cellular heterochromatin machinery. AB - The repression of transposable elements in eukaryotes often involves their transcriptional silencing via targeted chromatin modifications. In animal gonads, nuclear Argonaute proteins of the PIWI clade complexed with small guide RNAs (piRNAs) serve as sequence specificity determinants in this process. How binding of nuclear PIWI-piRNA complexes to nascent transcripts orchestrates heterochromatin formation and transcriptional silencing is unknown. Here, we characterize CG9754/Silencio as an essential piRNA pathway factor that is required for Piwi-mediated transcriptional silencing in Drosophila. Ectopic targeting of Silencio to RNA or DNA is sufficient to elicit silencing independently of Piwi and known piRNA pathway factors. Instead, Silencio requires the H3K9 methyltransferase Eggless/SetDB1 for its silencing ability. In agreement with this, SetDB1, but not Su(var)3-9, is required for Piwi-mediated transcriptional silencing genome-wide. Due to its interaction with the target engaged Piwi-piRNA complex, we suggest that Silencio acts as linker between the sequence specificity factor Piwi and the cellular heterochromatin machinery. PMID- 26494713 TI - Recurrent episodes of unexplained hypoelectrolytaemia of a rare cause in a young Saudi girl. AB - We report a case of a 36-month-old Saudi girl who presented with recurrent episodes of unexplained hypoelectrolytaemia. Her cystic fibrosis CFTR (Cystic Fibrosis Transmembrane conductance Regulator) full gene sequence confirmed that she was homozygous for D579G mutation. PMID- 26494712 TI - A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence. AB - Polycomb-like proteins 1-3 (PCL1-3) are substoichiometric components of the Polycomb-repressive complex 2 (PRC2) that are essential for association of the complex with chromatin. However, it remains unclear why three proteins with such apparent functional redundancy exist in mammals. Here we characterize their divergent roles in both positively and negatively regulating cellular proliferation. We show that while PCL2 and PCL3 are E2F-regulated genes expressed in proliferating cells, PCL1 is a p53 target gene predominantly expressed in quiescent cells. Ectopic expression of any PCL protein recruits PRC2 to repress the INK4A gene; however, only PCL2 and PCL3 confer an INK4A-dependent proliferative advantage. Remarkably, PCL1 has evolved a PRC2- and chromatin independent function to negatively regulate proliferation. We show that PCL1 binds to and stabilizes p53 to induce cellular quiescence. Moreover, depletion of PCL1 phenocopies the defects in maintaining cellular quiescence associated with p53 loss. This newly evolved function is achieved by the binding of the PCL1 N terminal PHD domain to the C-terminal domain of p53 through two unique serine residues, which were acquired during recent vertebrate evolution. This study illustrates the functional bifurcation of PCL proteins, which act in both a chromatin-dependent and a chromatin-independent manner to regulate the INK4A and p53 pathways. PMID- 26494714 TI - Disseminated cryptococcosis in an apparently immunocompetent patient presenting with primary intraventricular haemorrhage. AB - Disseminated cryptococcosis is uncommon and almost always occurs in HIV-infected patients. However, cryptococcosis can also be found in patients of organ transplantation, in those on disease modifying agents for rheumatological conditions and in patients with underlying immunodeficiency. Cryptococcal infection may occur in an immunocompetent patient, but the pathogenic strain is usually Cryptococcus gattii, and not C. neoformans. However, disseminated disease, especially cerebral involvement in the form of primary intraventricular haemorrhage, is exceedingly rare. We report a case of disseminated cryptococcosis with cutaneous, cerebral and bone marrow involvement in an HIV-negative, apparently immunocompetent patient. Although the patient did not have the usual immunocompromising diseases, there were clinical signs possibly indicating a weakened immune system. This report highlights the need for awareness of disseminated cryptococcosis among patients with no apparent immunocompromising conditions. PMID- 26494715 TI - Central and peripheral nervous system involvement in neuromelioidosis. AB - We report a case of a 33-year-old Sri Lankan man who presented with flaccid quadriparesis with brainstem signs and acute motor axonal polyneuropathy. MRI of the brain showed multiple abscesses with ring enhancement seen predominantly in the brainstem and upper cervical cord. The patient was initially treated with intravenous immunoglobulin, considering this to be a form of Guillain-Barre syndrome. Cerebrospinal fluid, however, showed lymphocytic pleocytosis with raised protein. Tests for Brucella, tuberculosis, toxoplasmosis, syphilis and HIV were negative. Chest X-ray revealed a cavity in the left lung, which, on bronchoscopy, showed a collection of purulent secretions. Culture of these secretions grew Burkholderia pseudomallei. The patient was treated with two courses of intravenous antibiotics, with resultant radiological improvement; however, with significant morbidity. PMID- 26494716 TI - Group C streptococcal septic arthritis of a prosthetic hip joint following dental treatment. AB - We report a case of a prosthetic joint infection occurring secondary to group C Streptococcus following dental treatment in a 66-year-old woman. This patient presented 11 years following a right hip resurfacing procedure with increasing pain and difficulty mobilising the right hip. An ultrasound and MRI scan identified a collection in the right hip joint, which was subsequently aspirated. Cultures revealed a group C Streptococcus. Extensive washout and surgical debridement of the hip joint was undertaken and the patient was treated with a protracted course of antibiotics. At 1 year follow-up, the patient demonstrated no evidence of recurrent infection. We discuss the evidence underlying prophylactic antibiotic usage regarding dental procedures in the prevention of septic arthritis in patients with prosthetic joints. We also review the spectrum of diseases caused by this organism. PMID- 26494718 TI - A shattered kidney: a pitfall in imaging of renal trauma. PMID- 26494719 TI - Prolapse of inverted ileal loops through a patent vitellointestinal duct. AB - We report a case of a prolapsed patent vitellointestinal duct (PVID) in a 2-month old girl child who presented with sudden increase in size of a polypoidal lesion into a large, 'Y'-shaped reddish, prolapsing lesion, discharging gaseous and faecal matter at her umbilicus. The lesion was diagnosed as a prolapse of inverted ileal loops through the PVID. The child had no associated congenital anomalies. A transumbilical exploration was performed, followed by wedge resection and anastomosis. The child tolerated the procedure well and the postoperative course was uneventful. If the omphalomesenteric duct fails to obliterate a range of congenital defects related to the umbilicus, it can become clinically apparent. Meckel's diverticulum is the commonest of these defects but is most often asymptomatic. PVID is the most common symptomatic anomaly of the patent omphalomesenteric duct and requires prompt surgical correction to avoid complications. PMID- 26494717 TI - A STAT1-gain-of-function mutation causing Th17 deficiency with chronic mucocutaneous candidiasis, psoriasiform hyperkeratosis and dermatophytosis. AB - During recent years, inborn errors of human IL-17 immunity have been demonstrated to underlie primary immunodeficiencies with chronic mucocutaneous candidiasis (CMC). Various defects in receptors responsible for sensing of Candida albicans or downstream signalling to IL-17 may lead to susceptibility to Candida infection. While CMC is common in patients with profound T cell immunodeficiencies, CMC is also recognised as part of other immunodeficiencies in syndromic CMC, or as relatively isolated CMC disease. We describe a 40-year-old woman with a clinical picture involving cutaneous bacterial abscesses, chronic oral candidiasis and extensive dermatophytic infection of the feet. By whole exome sequencing, we identified a STAT1-gain-of-function mutation. Moreover, the patient's peripheral blood mononuclear cells displayed severely impaired Th17 responses. The patient was treated with antifungals and prophylactic antibiotics, which led to resolution of the infection. We discuss the current knowledge within the field of Th17 deficiency and the pathogenesis and treatment of CMC. PMID- 26494720 TI - Pseudomyxoma peritonei diagnosed 19 years after appendicectomy. AB - Pseudomyxoma peritonei (PMP) is an uncommon clinical finding describing the intraperitoneal accumulation of abundant mucinous, jelly-like material. This entity may represent a spectrum of diseases ranging from mucinous ascites, commonly associated with ruptured epithelial tumours of the appendix, to frank mucinous carcinomatosis. In cases of appendiceal origin, the patient may present with signs and symptoms of acute appendicitis, and thus careful diagnosis must be made in order to correctly and appropriately guide management. This may include a combination of surgical debulking with or without intraperitoneal or systemic chemotherapy. We present a 52-year-old woman with a 4-month history of abdominal pain and distension with a previous appendicectomy 19 years earlier. Radiological and pathological investigations diagnosed a probable PMP secondary to ruptured appendicitis many years ago. We describe her unique case, with emphasis on length of time to diagnosis and clinical management by surgical cytoreduction alone. PMID- 26494721 TI - HbM methaemoglobinaemia as a rare case of early neonatal benign cyanosis. AB - Early neonatal central cyanosis that is unrelated to cardiopulmonary causes, alerts clinicians to possibility of methaemoglobinaemia. Congenital methaemoglobinaemia due to haemoglobin M is an autosomal dominant disorder characterised by lifelong cyanosis. We report a case presentation and review of diagnostic pitfalls of a newborn who presented with central cyanosis; investigations revealed a low methaemoglobin reductase (2.2 IU/g Hb), with normal maternal levels (9.1 IU/g Hb). Therefore, haemoglobinopathy investigations were completed on the mother and her baby, which showed an alpha-globin variant in both. The maternal alpha2 globin gene sequencing showed heterozygosity for haemoglobin M Boston (alpha58 His -> Tyr). PMID- 26494722 TI - Freeman-Sheldon syndrome in a 29-year-old woman presenting with rare and previously undescribed features. AB - Described are previously unreported features presenting in a case of Freeman Sheldon syndrome (FSS); these apparently unreported features may substantively inform current therapy and further research. While considered to be primarily a craniofacial syndrome, FSS is officially described as a myopathic distal arthrogryposis. Clinical diagnosis requires microstomia, whistling-face appearance (pursed lips), H-shaped chin dimpling, nasolabial folds, and two or more contractures of hands and feet. Spinal deformities, metabolic and gastroenterological problems, other dysmorphic craniofacial characteristics, and visual and auditory impairments are frequent findings. Differential diagnoses include: distal arthrogryposis type 1, 2B (Sheldon-Hall syndrome) and 3; arthrogryposis multiplex congenita and isolated non-syndromic deformities. Expression is frequently from new allelic variation. Important implications exist for geneticists, neonatologists, paediatricians, plastic surgeons and others to facilitate patients' legitimate opportunity to meaningfully overcome functional limitations and become well. Despite complexities and complications, early craniofacial surgery and aggressive physiotherapy for limb contractures can achieve excellent outcomes for patients. PMID- 26494723 TI - Intraosseous cavernous haemangioma of the inferior turbinate. AB - Intraosseous cavernous haemangiomas usually occur in the vertebral and calvarial bones, and account for <1% of primary bone tumours. Nasal cavity intraosseous cavernous haemangiomas are extremely rare. We present a case of a 47-year-old woman with an incidental left inferior turbinate mass noted on CT scan for an unrelated pathology. She had no rhinological symptoms other than a 2-year history of left-sided nasal obstruction. Preoperative imaging failed to determine the aetiology of the mass. The lesion, contiguous with the left inferior turbinate, was successfully resected via an endoscopic approach. Histopathological examination of the resected specimen demonstrated a left inferior turbinate intraosseous cavernous haemangioma. PMID- 26494724 TI - Pemphigus vulgaris: a rare cause of dysphagia. AB - Pemphigus vulgaris is a rare autoimmune blistering disease of the skin and mucous membranes. The case reported presented unusually with dyspepsia that was not responsive to protein pump inhibitor (PPI) therapy. This progressed to severe dysphagia and odynophagia. An esophagogastroduodenoscopy showed extensive ulceration of the esophagus, and direct immunofluorescence of an esophageal biopsy showed bright intercellular staining with C3 and IgG, confirming the diagnosis of pemphigus vulgaris. Immunological remission was achieved after a number of courses of pulsed intravenous methylprednisolone and cyclophosphamide. The patient has remained in remission for 5 years, but has required regular dilation of esophageal strictures for symptom relief. During this period, a chronic lymphocytosis was incidentally noted on routine blood tests, and chronic lymphocytic leukaemia was diagnosed. It is essential to investigate PPI-resistant symptoms, dysphagia and odynophagia, as they may indicate a serious underlying cause. PMID- 26494725 TI - Severe post-influenza (H1N1) encephalitis involving pulvinar nuclei in an adult patient. AB - Neurological complications of H1N1 infections are mostly found in children, but rare cases of acute encephalopathy and post-infectious encephalitis such as acute disseminated encephalomyelitis (ADEM) have been described in adults. We report a case of an adult presenting with a progressive and severe encephalopathy that developed after H1N1 respiratory infection resolution. Cerebrospinal fluid (CSF) analysis was normal, including negative PCR for herpes simplex virus, H1N1, influenza B and JC virus, and absent oligoclonal IgG bands in CSF and serum. Initial CT scan was normal, but later MRI showed posterior multifocal leucoencephalopathy with pulvinar sign. The delayed neurological findings together with the ancillary investigation, namely the MRI pattern with both grey and white matter involvement, raised the possibility of a post-infectious process, rather than an acute encephalitis. Despite aggressive immunotherapy, the patient experienced severe neurological sequelae. Early recognition of ADEM manifestations by those dealing with H1N1 infection is important as early immunotherapy may improve the prognosis. PMID- 26494726 TI - Genomic characterisation of two cancers of unknown primary cases supports a kidney cancer origin. AB - Cancer of unknown primary (CUP) comprises of 3-5% of new cancer diagnoses in the USA. Diagnostic work up typically includes CT of the chest, abdomen and pelvis, and histopathological review of tissue specimens. These measures are neither sensitive nor specific in determining tissue of origin (ToO) of primary tumours and, therefore, are unable to guide therapy. We present two cases of CUP for which we utilised ultra-deep genomic sequencing to identify the candidate ToO and to propose treatment. Patient 1 presented with metastases involving the lung, lymph nodes and bone. Patient 2 presented with an acute pathological fracture of the T7 vertebral body and metastases involving the bone, lymph nodes and soft tissue. No primary renal mass was found. Sequencing revealed SETD2 and NF2 mutations, and heterozygous loss of the short arm of chromosome 3 (3p). Mutations in conjunction with clinicopathological features strongly support a diagnosis of renal cell carcinoma. Both patients initially responded to mTORC1 inhibition therapy. PMID- 26494727 TI - Active Tuberculosis in HIV-Exposed Tanzanian Children up to 2 years of Age: Early Life Nutrition, Multivitamin Supplementation and Other Potential Risk Factors. AB - BACKGROUND: Over half a million children worldwide develop active tuberculosis (TB) each year. Early-life nutritional exposures have rarely been examined in relation to pediatric TB among HIV-exposed children. We therefore investigated independent associations of early-life nutritional exposures with active TB among HIV-exposed children up to 2 years of age. METHODS: Participants were children from a randomized controlled multivitamin supplementation trial conducted in Dar es Salaam, Tanzania, from August 2004 to May 2008, who received daily multivitamin supplements or placebo for 24 months. RESULTS: Lower mean corpuscular volumes [relative risks (RR): 0.48, 95% confidence interval (CI): 0.27, 0.87] and higher birth weights (RR: 0.61, 95% CI: 0.37, 0.99) were protective against active TB, whereas multivitamin supplementation was not associated with TB risk (RR: 0.87, 95% CI: 0.65, 1.16). CONCLUSIONS: Knowledge of nutrition-related risk and protective factors for TB in HIV-exposed children could enhance preventive and case-finding activities in this population, contributing to efforts to reduce the global TB burden. PMID- 26494728 TI - The Role of 16S rRNA Gene Sequencing in Confirmation of Suspected Neonatal Sepsis. AB - Different molecular assays for the detection of bacterial DNA in the peripheral blood represented a diagnostic tool for neonatal sepsis. We targeted to evaluate the role of 16S rRNA gene sequencing to screen for bacteremia to confirm suspected neonatal sepsis (NS) and compare with risk factors and septic screen testing. Sixty-two neonates with suspected NS were enrolled. White blood cells count, I/T ratio, C-reactive protein, blood culture and 16S rRNA sequencing were performed. Blood culture was positive in 26% of cases, and PCR was positive in 26% of cases. Evaluation of PCR for the diagnosis of NS showed sensitivity 62.5%, specificity 86.9%, PPV 62.5%, NPV 86.9% and accuracy of 79.7%. 16S rRNA PCR increased the sensitivity of detecting bacterial DNA in newborns with signs of sepsis from 26 to 35.4%, and its use can be limited to cases with the most significant risk factors and positive septic screen. PMID- 26494729 TI - A tillering inhibition gene influences root-shoot carbon partitioning and pattern of water use to improve wheat productivity in rainfed environments. AB - Genetic modification of shoot and root morphology has potential to improve water and nutrient uptake of wheat crops in rainfed environments. Near-isogenic lines (NILs) varying for a tillering inhibition (tin) gene and representing multiple genetic backgrounds were phenotyped in contrasting, controlled environments for shoot and root growth. Leaf area, shoot and root biomass were similar until tillering, whereupon reduced tillering in tin-containing NILs produced reductions of up to 60% in total leaf area and biomass, and increases in total root length of up to 120% and root biomass to 145%. Together, the root-to-shoot ratio increased two-fold with the tin gene. The influence of tin on shoot and root growth was greatest in the cv. Banks genetic background, particularly in the biculm-selected NIL, and was typically strongest in cooler environments. A separate de-tillering study confirmed greater root-to-shoot ratios with regular tiller removal in non-tin-containing genotypes. In validating these observations in a rainfed field study, the tin allele had a negligible effect on seedling growth but was associated with significantly (P<0.05) reduced tiller number ( 37%), leaf area index (-26%), and spike number (-35%) to reduce plant biomass ( 19%) at anthesis. Root biomass, root-to-shoot ratio at early stem elongation, and root depth at maturity were all increased in tin-containing NILs. Soil water use was slowed in tin-containing NILs, resulting in greater water availability, greater stomatal conductance, cooler canopy temperatures, and maintenance of green leaf area during grain-filling. Together these effects contributed to increases in harvest index and grain yield. In both the controlled and field environments, the tin gene was commonly associated with increased root length and biomass, but the significant influence of genetic background and environment suggests careful assessment of tin-containing progeny in selection for genotypic increases in root growth. PMID- 26494732 TI - AtFH1 formin mutation affects actin filament and microtubule dynamics in Arabidopsis thaliana. PMID- 26494730 TI - Overexpression of mitochondrial uncoupling protein 1 (UCP1) induces a hypoxic response in Nicotiana tabacum leaves. AB - Mitochondrial uncoupling protein 1 (UCP1) decreases reactive oxygen species production under stress conditions by uncoupling the electrochemical gradient from ATP synthesis. This study combined transcriptome profiling with experimentally induced hypoxia to mechanistically dissect the impact of Arabidopsis thaliana UCP1 (AtUCP1) overexpression in tobacco. Transcriptomic analysis of AtUCP1-overexpressing (P07) and wild-type (WT) plants was carried out using RNA sequencing. Metabolite and carbohydrate profiling of hypoxia-treated plants was performed using (1)H-nuclear magnetic resonance spectroscopy and high performance anion-exchange chromatography with pulsed amperometric detection. The transcriptome of P07 plants revealed a broad induction of stress-responsive genes that were not strictly related to the mitochondrial antioxidant machinery, suggesting that overexpression of AtUCP1 imposes a strong stress response within the cell. In addition, transcripts that mapped into carbon fixation and energy expenditure pathways were broadly altered. It was found that metabolite markers of hypoxic adaptation, such as alanine and tricarboxylic acid intermediates, accumulated in P07 plants under control conditions at similar rates to WT plants under hypoxia. These findings indicate that constitutive overexpression of AtUCP1 induces a hypoxic response. The metabolites that accumulated in P07 plants are believed to be important in signalling for an improvement in carbon assimilation and induction of a hypoxic response. Under these conditions, mitochondrial ATP production is less necessary and fermentative glycolysis becomes critical to meet cell energy demands. In this scenario, the more flexible energy metabolism along with an intrinsically activated hypoxic response make these plants better adapted to face several biotic and abiotic stresses. PMID- 26494733 TI - Smart villages. PMID- 26494731 TI - Stability of small ubiquitin-like modifier (SUMO) proteases OVERLY TOLERANT TO SALT1 and -2 modulates salicylic acid signalling and SUMO1/2 conjugation in Arabidopsis thaliana. AB - Small ubiquitin-like modifier proteases 1 and 2 (SUMO1/2) have been linked to the regulation of salicylic acid (SA)-mediated defence signalling in Arabidopsis thaliana. In order to define the role of the SUMO proteases OVERLY TOLERANT TO SALT1 and -2 (OTS1/2) in defence and to provide insight into SUMO1/2-mediated regulation of SA signalling, we examined the status of SA-mediated defences in ots1/2 mutants. The ots1 ots2 double mutant displayed enhanced resistance to virulent Pseudomonas syringae and higher levels of SA compared with wild-type (WT) plants. Furthermore, ots1 ots2 mutants exhibited upregulated expression of the SA biosynthesis gene ICS1 in addition to enhanced SA-responsive ICS1 expression beyond that of WT. SA stimulated OTS1/2 degradation and promoted accumulation of SUMO1/2 conjugates. These results indicate that OTS1 and -2 act in a feedback loop in SA signalling and that de novo OTS1/2 synthesis works antagonistically to SA-promoted degradation, adjusting the abundance of OTS1/2 to moderate SA signalling. Accumulation of SUMO1/2 conjugates coincides with SA promoted OTS degradation and may play a positive role in SA-mediated signalling in addition to its repressive roles reported elsewhere. PMID- 26494735 TI - NUCLEAR PHYSICS. U.S. targets matter-antimatter frontier. PMID- 26494736 TI - Q&A. Shining a light on sexual harassment in astronomy. PMID- 26494737 TI - NEUROSCIENCE. Second bid for brain observatory. PMID- 26494738 TI - CELL BIOLOGY. Protein 'drops' may seed brain disease. PMID- 26494739 TI - REGULATORY SCIENCE. Europe's food watchdog embraces transparency. PMID- 26494740 TI - Twisted logic. PMID- 26494741 TI - Out of the darkness. PMID- 26494742 TI - STRUCTURAL BIOLOGY. Assembling the wheel of death. PMID- 26494743 TI - PHYSICS. Chiral anomaly without relativity. PMID- 26494744 TI - NEUROSCIENCE. The unknowns of cognitive enhancement. PMID- 26494745 TI - STRUCTURAL BIOLOGY. Snapshots of a protein quake. PMID- 26494746 TI - MICROBIOLOGY. Beyond known methanogens. PMID- 26494747 TI - DEVELOPMENTAL BIOLOGY. Toward a rapid and reversible male pill. PMID- 26494748 TI - SYSTEMS BIOLOGY. Systems biology (un)certainties. PMID- 26494749 TI - NANOSAFETY. How safe are nanomaterials? PMID- 26494750 TI - Iran's environment under siege. PMID- 26494751 TI - Iran's education and research potential. PMID- 26494752 TI - With moralizing gods, exclusion reigns. PMID- 26494753 TI - Electron paramagnetic resonance of individual atoms on a surface. AB - We combined the high-energy resolution of conventional spin resonance (here ~10 nano-electron volts) with scanning tunneling microscopy to measure electron paramagnetic resonance of individual iron (Fe) atoms placed on a magnesium oxide film. We drove the spin resonance with an oscillating electric field (20 to 30 gigahertz) between tip and sample. The readout of the Fe atom's quantum state was performed by spin-polarized detection of the atomic-scale tunneling magnetoresistance. We determine an energy relaxation time of T1 ~ 100 microseconds and a phase-coherence time of T2 ~ 210 nanoseconds. The spin resonance signals of different Fe atoms differ by much more than their resonance linewidth; in a traditional ensemble measurement, this difference would appear as inhomogeneous broadening. PMID- 26494754 TI - Asteroseismology can reveal strong internal magnetic fields in red giant stars. AB - Internal stellar magnetic fields are inaccessible to direct observations, and little is known about their amplitude, geometry, and evolution. We demonstrate that strong magnetic fields in the cores of red giant stars can be identified with asteroseismology. The fields can manifest themselves via depressed dipole stellar oscillation modes, arising from a magnetic greenhouse effect that scatters and traps oscillation-mode energy within the core of the star. The Kepler satellite has observed a few dozen red giants with depressed dipole modes, which we interpret as stars with strongly magnetized cores. We find that field strengths larger than ~10(5) gauss may produce the observed depression, and in one case we infer a minimum core field strength of ~10(7) gauss. PMID- 26494755 TI - Transcriptional control of tissue formation throughout root development. AB - Tissue patterns are dynamically maintained. Continuous formation of plant tissues during postembryonic growth requires asymmetric divisions and the specification of cell lineages. We show that the BIRDs and SCARECROW regulate lineage identity, positional signals, patterning, and formative divisions throughout Arabidopsis root growth. These transcription factors are postembryonic determinants of the ground tissue stem cells and their lineage. Upon further activation by the positional signal SHORT-ROOT (a mobile transcription factor), they direct asymmetric cell divisions and patterning of cell types. The BIRDs and SCARECROW with SHORT-ROOT organize tissue patterns at all formative steps during growth, ensuring developmental plasticity. PMID- 26494756 TI - Reduced grid-cell-like representations in adults at genetic risk for Alzheimer's disease. AB - Alzheimer's disease (AD) manifests with memory loss and spatial disorientation. AD pathology starts in the entorhinal cortex, making it likely that local neural correlates of spatial navigation, particularly grid cells, are impaired. Grid cell-like representations in humans can be measured using functional magnetic resonance imaging. We found that young adults at genetic risk for AD (APOE epsilon4 carriers) exhibit reduced grid-cell-like representations and altered navigational behavior in a virtual arena. Both changes were associated with impaired spatial memory performance. Reduced grid-cell-like representations were also related to increased hippocampal activity, potentially reflecting compensatory mechanisms that prevent overt spatial memory impairment in APOE epsilon4 carriers. Our results provide evidence of behaviorally relevant entorhinal dysfunction in humans at genetic risk for AD, decades before potential disease onset. PMID- 26494757 TI - Methane metabolism in the archaeal phylum Bathyarchaeota revealed by genome centric metagenomics. AB - Methanogenic and methanotrophic archaea play important roles in the global flux of methane. Culture-independent approaches are providing deeper insight into the diversity and evolution of methane-metabolizing microorganisms, but, until now, no compelling evidence has existed for methane metabolism in archaea outside the phylum Euryarchaeota. We performed metagenomic sequencing of a deep aquifer, recovering two near-complete genomes belonging to the archaeal phylum Bathyarchaeota (formerly known as the Miscellaneous Crenarchaeotal Group). These genomes contain divergent homologs of the genes necessary for methane metabolism, including those that encode the methyl-coenzyme M reductase (MCR) complex. Additional non-euryarchaeotal MCR-encoding genes identified in a range of environments suggest that unrecognized archaeal lineages may also contribute to global methane cycling. These findings indicate that methane metabolism arose before the last common ancestor of the Euryarchaeota and Bathyarchaeota. PMID- 26494758 TI - Mechanosensitive channel MSL8 regulates osmotic forces during pollen hydration and germination. AB - Pollen grains undergo dramatic changes in cellular water potential as they deliver the male germ line to female gametes, and it has been proposed that mechanosensitive ion channels may sense the resulting mechanical stress. Here, we identify and characterize MscS-like 8 (MSL8), a pollen-specific, membrane tension gated ion channel required for pollen to survive the hypoosmotic shock of rehydration and for full male fertility. MSL8 negatively regulates pollen germination but is required for cellular integrity during germination and tube growth. MSL8 thus senses and responds to changes in membrane tension associated with pollen hydration and germination. These data further suggest that homologs of bacterial MscS have been repurposed in eukaryotes to function as mechanosensors in multiple developmental and environmental contexts. PMID- 26494760 TI - The power of mentoring. PMID- 26494759 TI - Ubiquitin facilitates a quality-control pathway that removes damaged chloroplasts. AB - Energy production by chloroplasts and mitochondria causes constant oxidative damage. A functioning photosynthetic cell requires quality-control mechanisms to turn over and degrade chloroplasts damaged by reactive oxygen species (ROS). Here, we generated a conditionally lethal Arabidopsis mutant that accumulated excess protoporphyrin IX in the chloroplast and produced singlet oxygen. Damaged chloroplasts were subsequently ubiquitinated and selectively degraded. A genetic screen identified the plant U-box 4 (PUB4) E3 ubiquitin ligase as being necessary for this process. pub4-6 mutants had defects in stress adaptation and longevity. Thus, we have identified a signal that leads to the targeted removal of ROS overproducing chloroplasts. PMID- 26494762 TI - Erratum for the Research Article "The protein LEM promotes CD8+ T cell immunity through effects on mitochondrial respiration" by I. Okoye, L. Wang, K. Pallmer, K. Richter, T. Ichimura, R. Haas, J. Crouse, O. Choi, D. Heathcote, E. Lovo, C. Mauro, R. Abdi, A. Oxenius, S. Rutschmann, P. G. Ashton-Rickardt. PMID- 26494761 TI - HIV-1 Nef hijacks clathrin coats by stabilizing AP-1:Arf1 polygons. AB - The lentiviruses HIV and simian immunodeficiency virus (SIV) subvert intracellular membrane traffic as part of their replication cycle. The lentiviral Nef protein helps viruses evade innate and adaptive immune defenses by hijacking the adaptor protein 1 (AP-1) and AP-2 clathrin adaptors. We found that HIV-1 Nef and the guanosine triphosphatase Arf1 induced trimerization and activation of AP 1. Here we report the cryo-electron microscopy structures of the Nef- and Arf1 bound AP-1 trimer in the active and inactive states. A central nucleus of three Arf1 molecules organizes the trimers. We combined the open trimer with a known dimer structure and thus predicted a hexagonal assembly with inner and outer faces that bind the membranes and clathrin, respectively. Hexagons were directly visualized and the model validated by reconstituting clathrin cage assembly. Arf1 and Nef thus play interconnected roles in allosteric activation, cargo recruitment, and coat assembly, revealing an unexpectedly intricate organization of the inner AP-1 layer of the clathrin coat. PMID- 26494763 TI - Obesity and the Incidence of Upper Gastrointestinal Cancers: An Ecological Approach to Examine Differences across Age and Sex. AB - BACKGROUND: Esophageal and gastric cancers differ in their epidemiology but have several risk factors in common. The aim of this study was to assess age and sex differences in the burden of esophageal and gastric cancers in the context of the global obesity epidemic. METHODS: Data from 50 countries were obtained from Cancer Incidence in Five Continents Volume X and GLOBOCAN 2012. Age-specific and age-standardized incidence rates of esophageal adenocarcinoma and squamous cell carcinoma (ESCC), as well as cardia (CGC) and noncardia (NCGC) gastric cancer, were estimated. Countries were grouped and analyzed according to their obesity prevalence. RESULTS: A gradient across quartiles of obesity prevalence was found for esophageal adenocarcinoma, with the highest incidence rates in high prevalence countries (ASR 3.0 vs. 0.8 per 100,000 in highest vs. lowest obesity quartiles, males). In contrast, for ESCC as well as for CGC and NCGC the reverse was true, with the highest rates observed in countries with the lowest obesity prevalence (ESCC, 2.2 vs. 11.5; CGC, 2.8 vs. 7.8; NCGC, 3.9 vs. 17.4 in highest vs. lowest obesity quartiles, males). Although for esophageal adenocarcinoma, sex and age differences in incidence were most pronounced in countries with a high prevalence of obesity, these differences were much smaller for the other cancer sites assessed. CONCLUSIONS: Variation in obesity prevalence may partly explain age and sex differences in the incidence of esophageal adenocarcinomas. IMPACT: Ecologic studies can help assess relationships between risk factors and cancer, and generate new hypotheses that may be pursued through more directed research. PMID- 26494766 TI - Alan Magill, ASTMH Immediate Past President, 1953-2015. PMID- 26494764 TI - Quality of physician communication about human papillomavirus vaccine: findings from a national survey. AB - BACKGROUND: Improving the quality of physicians' recommendations for human papillomavirus (HPV) vaccination is critical to addressing low coverage. Thus, we sought to describe HPV vaccine communication practices among primary care physicians. METHODS: Pediatricians and family physicians (n = 776) completed our national online survey in 2014. We assessed the quality of their HPV vaccine recommendations on strength of endorsement (i.e., saying the vaccine is important), timeliness (recommending it by ages 11-12), consistency (recommending it routinely vs. using a risk-based approach), and urgency (recommending same-day vaccination). RESULTS: A sizeable minority of physicians reported that they do not strongly endorse HPV vaccine (27%) or deliver timely recommendations for girls (26%) or boys (39%). Many physicians (59%) used a risk-based approach to recommending HPV vaccine, and only half (51%) usually recommended same-day vaccination. Overall recommendation quality was lower among physicians who were uncomfortable talking about HPV vaccine or who believed parents did not value it. Quality was higher among physicians who began discussions by saying the child was due for HPV vaccine versus giving information or eliciting questions. CONCLUSION: Many physicians in our national sample reported recommending HPV vaccine inconsistently, behind schedule, or without urgency. These practices likely contribute to under-immunization among adolescents, and may convey ambivalence to parents. IMPACT: As one of the first studies to assess multiple aspects of recommendation quality, these findings can inform the many state and national initiatives that aim to improve communication about HPV vaccine so as to address the persistent underuse of a powerful tool for cancer prevention. PMID- 26494767 TI - Remembering Alan Magill. PMID- 26494765 TI - "A day late and a dollar short": physicians and HPV vaccination. PMID- 26494768 TI - Identifying Patients With Chronic Low Back Pain Who Respond Best to Mechanical Diagnosis and Therapy: Secondary Analysis of a Randomized Controlled Trial. AB - BACKGROUND: "Mechanical Diagnosis and Therapy" (MDT) (also known as the McKenzie method), like other interventions for low back pain (LBP), has been found to have small effects for people with LBP. It is possible that a group of patients respond best to MDT and have larger effects. Identification of patients who respond best to MDT compared with other interventions would be an important finding. OBJECTIVE: The purpose of the study was to investigate whether baseline characteristics of patients with chronic LBP, already classified as derangement syndrome, can identify those who respond better to MDT compared with Back School. METHODS: This study was a secondary analysis of data from a previous trial comparing MDT with Back School in 148 patients with chronic LBP. Only patients classified at baseline assessment as being in the directional preference group (n=140) were included. The effect modifiers tested were: clear centralization versus directional preference only, baseline pain location, baseline pain intensity, and age. The primary outcome measures for this study were pain intensity and disability at the end of treatment (1 month). Treatment effect modification was evaluated by assessing the group versus predictor interaction terms from linear regression models. Interactions >=1.0 for pain and >=3 for disability were considered clinically important. RESULTS: Being older met our criteria for being a potentially important effect modifier; however, the effect occurred in the opposite direction to our hypothesis. Older people had 1.27 points more benefit in pain reduction from MDT (compared with Back School) than younger participants after 1 month of treatment. LIMITATIONS: The sample (n=140) was powered to detect the main effects of treatment but not to detect the interactions of the potential treatment effect modifiers. CONCLUSIONS: The results of the study suggest older age may be an important factor that can be considered as a treatment effect modifier for patients with chronic LBP receiving MDT. As the main trial was not powered for the investigation of subgroups, the results of this secondary analysis have to be interpreted cautiously, and replication is needed. PMID- 26494769 TI - 10-m Shuttle Ride Test in Youth With Osteogenesis Imperfecta Who Use Wheelchairs: Feasibility, Reproducibility, and Physiological Responses. AB - BACKGROUND: Physical fitness levels in youth with osteogenesis imperfecta (OI) who use wheelchairs are unknown. The 10-m Shuttle Ride Test (SRiT) has recently been introduced as a field test to determine cardiorespiratory fitness in children with cerebral palsy who self-propel a wheelchair. OBJECTIVE: The purpose of this study was to investigate the feasibility and reproducibility of the SRiT, as well as the physiological responses to the SRiT, in youth with moderate-to severe OI between 8 and 25 years of age who self-propel a wheelchair at least for long distances. DESIGN: A test-retest design was used. METHODS: Thirteen patients with OI (8 boys, 5 girls; mean+/-SD values for age=15.5+/-6.4 years) using a manual wheelchair performed 2 SRiTs within 2 weeks. Adverse events, reached stage, peak heart rate (HRpeak), peak respiratory exchange ratio (RERpeak), peak oxygen uptake (Vo2peak), and peak minute ventilation (Vepeak) were the main outcome parameters. RESULTS AND DISCUSSION: All participants performed a maximal effort at both SRiTs (mean+/-SD values for HRpeak of 195+/-9 beats per minute [bpm], RERpeak of 1.32+/-0.16, Vo2peak of 25.4+/-5.6 mL.kg(-1).min(-1), and Vepeak of 47.9+/-18.6 L.min(-1)), without adverse events. The intraclass correlation coefficient of the reached stage showed excellent reliability (.95). Limits of agreement (LoA) analysis revealed acceptable LoA for reached stage (mean bias=-0.58, range=-2.50 to +1.35). There was a low correlation between reached stage and Vo2peak (r=.61 and r=.45 for the first and second SRiTs, respectively). LIMITATIONS: The influence of wheelchair properties and individually adjusted wheelchair designs was not examined. CONCLUSIONS: The SRiT appears to be a feasible, safe, and reproducible maximal field test in youth with OI using wheelchairs at least for long distances. This field test might be useful to provide an indication of physical fitness and to assess the efficacy of interventions on physical fitness in these patients. PMID- 26494770 TI - Farming on the edge: farmer attitudes to bovine tuberculosis in newly endemic areas. AB - Defra's recent strategy to eradicate bovine tuberculosis (bTB) establishes three spatial zones: high-risk areas (HRAs) and low-risk areas, and an area referred to as 'the edge', which marks the areas where infection is spreading outwards from the HRA. Little is known about farmers in the edge area, their attitudes towards bTB and their farming practices. This paper examines farmers' practices and attitudes towards bTB in standardised epidemiologically defined areas. A survey was developed to collect data on farmer attitudes, behaviours, practices and environmental conditions as part of an interdisciplinary analysis of bTB risk factors. Survey items were developed from a literature review and focus groups with vets and farmers in different locations within the edge area. A case-control sampling framework was adopted with farms sampled from areas identified as recently endemic for bTB. 347 farmers participated in the survey including 117 with bTB, representing a 70per cent response rate. Results show that farmers believe they are unable to do anything about bTB but are keen for the government intervention to help control the spread of bTB. PMID- 26494771 TI - Errors in veterinary practice: preliminary lessons for building better veterinary teams. AB - Case studies in two typical UK veterinary practices were undertaken to explore teamwork, including interprofessional working. Each study involved one week of whole team observation based on practice locations (reception, operating theatre), one week of shadowing six focus individuals (veterinary surgeons, veterinary nurses and administrators) and a final week consisting of semistructured interviews regarding teamwork. Errors emerged as a finding of the study. The definition of errors was inclusive, pertaining to inputs or omitted actions with potential adverse outcomes for patients, clients or the practice. The 40 identified instances could be grouped into clinical errors (dosing/drugs, surgical preparation, lack of follow-up), lost item errors, and most frequently, communication errors (records, procedures, missing face-to-face communication, mistakes within face-to-face communication). The qualitative nature of the study allowed the underlying cause of the errors to be explored. In addition to some individual mistakes, system faults were identified as a major cause of errors. Observed examples and interviews demonstrated several challenges to interprofessional teamworking which may cause errors, including: lack of time, part-time staff leading to frequent handovers, branch differences and individual veterinary surgeon work preferences. Lessons are drawn for building better veterinary teams and implications for Disciplinary Proceedings considered. PMID- 26494772 TI - Elevated Levels of Microbial Translocation Markers and CCL2 Among Older HIV-1 Infected Men. AB - The aging of the human immunodeficiency virus type 1 (HIV-1)-infected population obligates a focus on the interaction between aging, comorbid conditions, and HIV 1. We recruited a cohort of HIV-1-infected men aged <= 35 years or >= 50 years who were receiving fully suppressive antiretroviral therapy (ART). We analyzed plasma markers of inflammation; T-cell activation, exhaustion, proliferation; and innate cellular subsets and functional capacity. Levels of lipopolysaccharide and the plasma marker of chemokine (C-C motif) ligand 2 were significantly elevated in older HIV-infected men despite comparable cellular phenotypes. Compared with similarly age-stratified uninfected subjects, older HIV-1-infected adults were also more frequently in the upper quartile of soluble CD14 expression. PMID- 26494773 TI - Pulmonary but Not Subcutaneous Delivery of BCG Vaccine Confers Protection to Tuberculosis-Susceptible Mice by an Interleukin 17-Dependent Mechanism. AB - Some of the most promising novel tuberculosis vaccine strategies currently under development are based on respiratory vaccination, mimicking the natural route of infection. In this work, we have compared pulmonary and subcutaneous delivery of BCG vaccine in the tuberculosis-susceptible DBA/2 mouse strain, a model in which parenterally administered BCG vaccine does not protect against tuberculosis. Our data show that intranasally but not subcutaneously administered BCG confers robust protection against pulmonary tuberculosis challenge. In addition, our results indicate that pulmonary vaccination triggers a Mycobacterium tuberculosis specific mucosal immune response orchestrated by interleukin 17A (IL-17A). Thus, IL-17A neutralization in vivo reduces protection and abrogates M. tuberculosis specific immunoglobulin A (IgA) secretion to respiratory airways and lung expression of polymeric immunoglobulin receptor induced following intranasal vaccination. Together, our results demonstrate that pulmonary delivery of BCG can overcome the lack of protection observed when BCG is given parenterally, suggesting that respiratory tuberculosis vaccines could have an advantage in tuberculosis-endemic countries, where intradermally administered BCG has inefficient effectiveness against pulmonary tuberculosis. PMID- 26494774 TI - HlyF Produced by Extraintestinal Pathogenic Escherichia coli Is a Virulence Factor That Regulates Outer Membrane Vesicle Biogenesis. AB - Escherichia coli can cause extraintestinal infections in humans and animals. The hlyF gene is epidemiologically associated with virulent strains of avian pathogenic E. coli and human neonatal meningitis-associated E. coli. We demonstrated that culture supernatants of E. coli expressing HlyF induced autophagy in eukaryotic cells. This phenotype coincided with an enhanced production of outer membrane vesicles (OMVs) by bacteria expressing HlyF. The HlyF protein displays a predicted catalytic domain of the short-chain dehydrogenase/reductase superfamily. This conserved domain was involved the ability of HlyF to promote the production of OMVs. The increased production of OMVs was associated with the release of toxins. hlyF was shown to be expressed during extraintestinal infection and to play a role in the virulence of extraintestinal pathogenic E. coli in a chicken model of colibacillosis. This is the first evidence that pathogenic bacteria produce a virulence factor directly involved in the production of OMVs. PMID- 26494775 TI - Sequestration and Red Cell Deformability as Determinants of Hyperlactatemia in Falciparum Malaria. AB - BACKGROUND: Hyperlactatemia is a strong predictor of mortality in severe falciparum malaria. Sequestered parasitized erythrocytes and reduced uninfected red blood cell deformability (RCD) compromise microcirculatory flow, leading to anaerobic glycolysis. METHODS: In a cohort of patients with falciparum malaria hospitalized in Chittagong, Bangladesh, bulk RCD was measured using a laser diffraction technique, and parasite biomass was estimated from plasma concentrations of Plasmodium falciparum histidine-rich protein 2 (PfHRP2). A multiple linear regression model was constructed to examine their associations with plasma lactate concentrations. RESULTS: A total of 286 patients with falciparum malaria were studied, of whom 224 had severe malaria, and 70 died. Hyperlactatemia (lactate level, >= 4 mmol/L) was present in 111 cases. RCD at shear stresses of 1.7 Pa and 30 Pa was reduced significantly in patients who died, compared with survivors, individuals with uncomplicated malaria, or healthy individuals (P < .05, for all comparisons). Multiple linear regression analysis showed that the plasma PfHRP2 level, parasitemia level, total bilirubin level, and RCD at a shear stress of 1.7 Pa were each independently correlated with plasma lactate concentrations (n = 278; R(2) = 0.35). CONCLUSIONS: Sequestration of parasitized red blood cells and reduced RCD both contribute to decreased microcirculatory flow in severe disease. PMID- 26494776 TI - The development of adultoid reproductives and brachypterous neotenic reproductives from the last instar nymphs in Reticulitermes labralis (Isoptera: Rhinotermitidae): a comparative study. AB - Secondary reproductives develop primarily from nymphs. However, they have been rarely studied; in particular, the development of adultoid reproductives (AR) with floppy wings is still unclear. In this study, the change in juvenile hormone (JH) levels, vitellogenin gene expression, and oogenesis during the development of AR and brachypterous neotenic reproductives (BN) from the last instar nymphs of Reticulitermes labralis are investigated and compared. The results showed that the AR derived from the last instar nymphs by molting, and they were more similar to neotenic reproductives in morphology. In addition, the paired AR were not able to survive in the absence of workers. In R. labralis, the process of the last instar nymphs developing into AR and BN took an increase in JH level as a starting point. The JH level of the last instar nymphs molting into BN was approximately 1.5-fold higher than that of the AR. Additionally, The JHIII level of BN peaked on day 5, and that of AR peaked on day 10, which induced the onset of vitellogenesis in BN and AR, respectively. After molting, the vitellogenin gene expression levels of both BN and AR initially increased and then declined, and the expression levels in the BN were significantly higher than those in the AR. In addition, the oocytes of BN matured earlier than those of the AR, and the number of eggs laid by the BN was higher than the number laid by the AR. Our results demonstrate that, in R. labralis, the last instar nymphs can develop into AR, which are significantly different from BN in their development. PMID- 26494777 TI - Projecting distribution of the overwintering population of Sogatella furcifera (Hemiptera: Delphacidae), in Yunnan, China with analysis on key influencing climatic factors. AB - Sogatella furcifera (Horvath) is the most threatening migratory rice pest in Yunnan, China. S. furcifera overwinters in low- altitude basins and valleys in southern Yunnan and migrates northward in spring and summer of the following year, causing serious damage during migration. The overwintering distribution, areas, and spatial pattern of S. furcifera are relevant to the migration and outbreak of this pest. Based on a 4-yr field survey (2010-2013), this study projected areas suitable for S. furcifera to overwinter using a species distribution model, and analyzed the key influencing climatic factors using principal component analysis (PCA) and ecological niche factor analysis (ENFA). Our field survey showed that the northern latitudinal- and upper elevation limits of overwintering S. furcifera was 25.4 degrees N and 1,608 m in western Yunnan and 24.2 degrees N and 1,563 m in eastern Yunnan. The species distribution model produced a fragmented distribution pattern, with most of which in western Yunnan and only a few in eastern Yunnan. The PCA and ENFA analyses showed that the mean temperature of the driest quarter and the precipitation of the coldest quarter significantly influenced the distribution of S. furcifera in winter. The results suggested that the complex topography, spatial differences in winter temperatures, and host availability altogether determined the distribution of overwintering S. furcifera. Compared with previous surveys, the northern latitudinal- and upper elevation limits of overwintering S. furcifera were higher, while the population became rarer in some suitable areas due to change of farmland utilization in winter and possibly climate change. PMID- 26494778 TI - Bone Morphogenetic Protein-2 Induces Donor-Dependent Osteogenic and Adipogenic Differentiation in Human Adipose Stem Cells. AB - Bone morphogenetic protein-2 (BMP-2) is a growth factor used to stimulate bone regeneration in clinical applications. However, there are contradicting reports on the functionality of BMP-2 in human adipose stem cells (hASCs), which are frequently used in tissue engineering. In this study, we analyzed the effects of BMP-2 on SMAD1/5 signaling, proliferation, and differentiation in hASCs. Our results indicated that BMP-2 induced dose-dependent (25-100 ng/ml) activation of SMAD signaling. Furthermore, the cell proliferation analysis revealed that BMP-2 (100 ng/ml) consistently decreased the proliferation in all the cell lines studied. However, the analysis of the differentiation potential revealed that BMP 2 (100 ng/ml) exhibited a donor-dependent dual role, inducing both osteogenic and adipogenic differentiation in hASCs. The quantitative alkaline phosphatase (qALP) activity and mineralization levels were clearly enhanced in particular donor cell lines by BMP-2 stimulus. On the contrary, in other cell lines, qALP and mineralization levels were diminished and the lipid formation was enhanced. The current study also suggests that hASCs have accelerated biochemical responsiveness to BMP-2 stimulus in human serum-supplemented culture medium compared with fetal bovine serum. The production origin of the BMP-2 growth factor is also important for its response: BMP-2 produced in mammalian cells enhanced signaling and differentiation responses compared with BMP-2 produced in Escherichia coli. These results explain the existing contradiction in the reported BMP-2 studies and indicate the variability in the functional end mechanism of BMP-2-stimulated hASCs. SIGNIFICANCE: This study examined how bone morphogenetic protein-2 (BMP-2) modulates the SMAD signaling mechanism and the proliferation and differentiation outcome of human adipose stem cells (hASCs) derived from several donors. The results indicate that BMP-2 triggers molecular SMAD signaling mechanisms in hASCs and regulates differentiation processes in human serum-culture conditions. Importantly, BMP-2 has dual activity, inducing osteogenic and adipogenic differentiation, subject to hASC donor line studied. These findings explain contradictory previous results and highlight the importance of further studies to understand how signaling pathways guide mesenchymal stem cell functions at the molecular level. PMID- 26494779 TI - Mesenchymal Stromal Cells in Animal Bleomycin Pulmonary Fibrosis Models: A Systematic Review. AB - Idiopathic pulmonary fibrosis is an inexorably progressive lung disease with few available treatments. New therapeutic options are needed. Stem cells have generated much enthusiasm for the treatment of several conditions, including lung diseases. Human trials of mesenchymal stromal cell (MSC) therapy for pulmonary fibrosis are under way. To shed light on the potential usefulness of MSCs for human disease, we aimed to systematically review the preclinical literature to determine if MSCs are beneficial in animal bleomycin pulmonary fibrosis models. The MEDLINE and Embase databases were searched for original studies of stem cell therapy in animal bleomycin models of pulmonary fibrosis. Studies using embryonic stem cells or induced pluripotent stem cells were excluded. Seventeen studies were selected, all of which used MSCs in rodents. MSC therapy led to an improvement in bleomycin-induced lung collagen deposition in animal lungs and in the pulmonary fibrosis Ashcroft score in most studies. MSC therapy improved histopathology in almost all studies in which it was evaluated qualitatively. Furthermore, MSC therapy was found to improve 14-day survival in animals with bleomycin-induced pulmonary fibrosis. Bronchoalveolar lavage total and neutrophil counts, as well as transforming growth factor-beta levels, were also reduced by MSCs. MSCs are beneficial in rodent bleomycin pulmonary fibrosis models. Since most studies examined the initial inflammatory phase rather than the chronic fibrotic phase, preclinical data offer better support for human trials of MSCs in acute exacerbations of pulmonary fibrosis rather than the chronic phase of the disease. SIGNIFICANCE: There has been increased interest in mesenchymal stromal cell therapy for lung diseases. A few small clinical trials are under way in idiopathic pulmonary fibrosis. Preclinical evidence was assessed in a systematic review, as is often done for clinical studies. The existing studies offer better support for efficacy in the initial inflammatory phase rather than the fibrotic phase that human trials are targeting. PMID- 26494780 TI - Vascular Smooth Muscle Cells From Hypertensive Patient-Derived Induced Pluripotent Stem Cells to Advance Hypertension Pharmacogenomics. AB - Studies in hypertension (HTN) pharmacogenomics seek to identify genetic sources of variable antihypertensive drug response. Genetic association studies have detected single-nucleotide polymorphisms (SNPs) that link to drug responses; however, to understand mechanisms underlying how genetic traits alter drug responses, a biological interface is needed. Patient-derived induced pluripotent stem cells (iPSCs) provide a potential source for studying otherwise inaccessible tissues that may be important to antihypertensive drug response. The present study established multiple iPSC lines from an HTN pharmacogenomics cohort. We demonstrated that established HTN iPSCs can robustly and reproducibly differentiate into functional vascular smooth muscle cells (VSMCs), a cell type most relevant to vasculature tone control. Moreover, a sensitive traction force microscopy assay demonstrated that iPSC-derived VSMCs show a quantitative contractile response on physiological stimulus of endothelin-1. Furthermore, the inflammatory chemokine tumor necrosis factor alpha induced a typical VSMC response in iPSC-derived VSMCs. These studies pave the way for a large research initiative to decode biological significance of identified SNPs in hypertension pharmacogenomics. SIGNIFICANCE: Treatment of hypertension remains suboptimal, and a pharmacogenomics approach seeks to identify genetic biomarkers that could be used to guide treatment decisions; however, it is important to understand the biological underpinnings of genetic associations. Mouse models do not accurately recapitulate individual patient responses based on their genetics, and hypertension-relevant cells are difficult to obtain from patients. Induced pluripotent stem cell (iPSC) technology provides a great interface to bring patient cells with their genomic data into the laboratory and to study hypertensive responses. As an initial step, the present study established an iPSC bank from patients with primary hypertension and demonstrated an effective and reproducible method of generating functional vascular smooth muscle cells. PMID- 26494781 TI - Therapeutic Potential of Human Adipose-Derived Stem/Stromal Cell Microspheroids Prepared by Three-Dimensional Culture in Non-Cross-Linked Hyaluronic Acid Gel. AB - Three-dimensional culture of mesenchymal stem/stromal cells for spheroid formation is known to enhance their therapeutic potential for regenerative medicine. Spheroids were prepared by culturing human adipose-derived stem/stromal cells (hASCs) in a non-cross-linked hyaluronic acid (HA) gel and compared with dissociated hASCs and hASC spheroids prepared using a nonadherent dish. Preliminary experiments indicated that a 4% HA gel was the most appropriate for forming hASC spheroids with a relatively consistent size (20-50 um) within 48 hours. Prepared spheroids were positive for pluripotency markers (NANOG, OCT3/4, and SOX-2), and 40% of the cells were SSEA-3-positive, a marker of the multilineage differentiating stress enduring or Muse cell. In contrast with dissociated ASCs, increased secretion of cytokines such as hepatocyte growth factor was detected in ASC spheroids cultured under hypoxia. On microarray ASC spheroids showed upregulation of some pluripotency markers and downregulation of genes related to the mitotic cell cycle. After ischemia-reperfusion injury to the fat pad in SCID mice, local injection of hASC spheroids promoted tissue repair and reduced the final atrophy (1.6%) compared with that of dissociated hASCs (14.3%) or phosphate-buffered saline (20.3%). Part of the administered hASCs differentiated into vascular endothelial cells. ASC spheroids prepared in a HA gel contain undifferentiated cells with therapeutic potential to promote angiogenesis and tissue regeneration after damage. SIGNIFICANCE: This study shows the therapeutic value of human adipose-derived stem cell spheroids prepared in hyarulonic acid gel. The spheroids have various benefits as an injectable cellular product and show therapeutic potential to the stem cell-depleted conditions such as diabetic chronic skin ulcer. PMID- 26494782 TI - Concise Review: Understanding the Renal Progenitor Cell Niche In Vivo to Recapitulate Nephrogenesis In Vitro. AB - Chronic kidney disease (CKD), defined as progressive kidney damage and a reduction of the glomerular filtration rate, can progress to end-stage renal failure (CKD5), in which kidney function is completely lost. CKD5 requires dialysis or kidney transplantation, which is limited by the shortage of donor organs. The incidence of CKD5 is increasing annually in the Western world, stimulating an urgent need for new therapies to repair injured kidneys. Many efforts are directed toward regenerative medicine, in particular using stem cells to replace nephrons lost during progression to CKD5. In the present review, we provide an overview of the native nephrogenic niche, describing the complex signals that allow survival and maintenance of undifferentiated renal stem/progenitor cells and the stimuli that promote differentiation. Recapitulating in vitro what normally happens in vivo will be beneficial to guide amplification and direct differentiation of stem cells toward functional renal cells for nephron regeneration. SIGNIFICANCE: Kidneys perform a plethora of functions essential for life. When their main effector, the nephron, is irreversibly compromised, the only therapeutic choices available are artificial replacement (dialysis) or renal transplantation. Research focusing on alternative treatments includes the use of stem cells. These are immature cells with the potential to mature into renal cells, which could be used to regenerate the kidney. To achieve this aim, many problems must be overcome, such as where to take these cells from, how to obtain enough cells to deliver to patients, and, finally, how to mature stem cells into the cell types normally present in the kidney. In the present report, these questions are discussed. By knowing the factors directing the proliferation and differentiation of renal stem cells normally present in developing kidney, this knowledge can applied to other types of stem cells in the laboratory and use them in the clinic as therapy for the kidney. PMID- 26494784 TI - Concise Review: The U.S. Food and Drug Administration and Regenerative Medicine. AB - Regenerative medicine (RM) is a popular term for a field of scientific and medical research. There is not one universally accepted definition of RM, but it is generally taken to mean the translation of multidisciplinary biology and engineering science into therapeutic approaches to regenerate, replace, or repair tissues and organs. RM products have the potential to provide treatments for a number of unmet needs but have substantial scientific and regulatory challenges that need to be addressed for this potential to be fully realized. FDA has established formal regulatory definitions for biologics, medical devices, and combination products, as well as human cells and tissues. Regenerative medicine products regulated by FDA are classified on the basis of these definitions, and the classification forms the basis for determining the regulatory requirements to each specific product. FDA regulations are generally written to allow the agency flexibility to accommodate new scientific questions raised by novel and evolving technologies. FDA efforts to facilitate product development in this novel and promising area include working with individual sponsors, interacting with the scientific and industry communities, participating in standards development, and developing policy and guidance. SIGNIFICANCE: Regenerative medicine is generally taken to mean the translation of multidisciplinary biology and engineering science into therapeutic approaches to regenerate, replace, or repair tissues and organs. This article provides an overview of the efforts of the U.S. Food and Drug Administration (FDA) to facilitate product development in the field commonly known was regenerative medicine. It provides an introduction to the processes by which FDA works with individual sponsors, interacts with the scientific and industry communities, participates in standards development, and develops formal FDA policy and guidance. PMID- 26494783 TI - Solution-Phase Crosstalk and Regulatory Interactions Between Multipotent Adult Progenitor Cells and Peripheral Blood Mononuclear Cells. AB - Multipotent adult progenitor cells (MAPCs) are adult adherent stromal stem cells currently being assessed in clinical trials for acute graft versus host disease with demonstrated immunomodulatory capabilities and the potential to ameliorate detrimental autoimmune and inflammation-related processes. Anti-CD3/anti-CD28 (3/28) activation of T cells within the peripheral blood mononuclear cell (PBMC) compartment was performed in the presence or absence of MAPCs. Liquid chromatography-coupled tandem mass spectrometry was used to characterize the differential secretion of proteins, and transcriptional profiling was used to monitor mRNA expression changes in both cell populations. Overall, 239 secreted and/or ectodomain-shed proteins were detected in the secretomes of PBMCs and MAPCs. In addition, 3/28 activation of PBMCs induced differential expression of 2,925 genes, and 22% of these transcripts were differentially expressed on exposure to MAPCs in Transwell. MAPCs exposed to 3/28-activated PBMCs showed differential expression of 1,247 MAPC genes. Crosstalk was demonstrated by reciprocal transcriptional regulation. Secretome proteins and transcriptional signatures were used to predict molecular activities by which MAPCs could dampen local and systemic inflammatory responses. These data support the hypothesis that MAPCs block PBMC proliferation via cell cycle arrest coupled to metabolic stress in the form of tryptophan depletion, resulting in GCN2 kinase activation, downstream signaling, and inhibition of cyclin D1 translation. These data also provide a plausible explanation for the immune privilege reported with administration of donor MAPCs. Although most components of the major histocompatibility complex class II antigen presentation pathway were markedly transcriptionally upregulated, cell surface expression of human leukocyte antigen DR is minimal on MAPCs exposed to 3/28-activated PBMCs. SIGNIFICANCE: This study documents experiments quantifying solution-phase crosstalk between multipotent adult progenitor cells (MAPCs) and peripheral blood mononuclear cells. The secretome and transcriptional changes quantified suggest mechanisms by which MAPCs are hypothesized to provide both local and systemic immunoregulation of inflammation. The potential impact of these studies includes development of a robust experimental framework to be used for preclinical evaluation of the specific mechanisms by which beneficial effects are obtained after treatment of patients with MAPCs. PMID- 26494785 TI - FoxP1 orchestration of ASD-relevant signaling pathways in the striatum. AB - Mutations in the transcription factor Forkhead box p1 (FOXP1) are causative for neurodevelopmental disorders such as autism. However, the function of FOXP1 within the brain remains largely uncharacterized. Here, we identify the gene expression program regulated by FoxP1 in both human neural cells and patient relevant heterozygous Foxp1 mouse brains. We demonstrate a role for FoxP1 in the transcriptional regulation of autism-related pathways as well as genes involved in neuronal activity. We show that Foxp1 regulates the excitability of striatal medium spiny neurons and that reduction of Foxp1 correlates with defects in ultrasonic vocalizations. Finally, we demonstrate that FoxP1 has an evolutionarily conserved role in regulating pathways involved in striatal neuron identity through gene expression studies in human neural progenitors with altered FOXP1 levels. These data support an integral role for FoxP1 in regulating signaling pathways vulnerable in autism and the specific regulation of striatal pathways important for vocal communication. PMID- 26494786 TI - A cellular, molecular, and pharmacological basis for appendage regeneration in mice. AB - Regenerative medicine aims to restore normal tissue architecture and function. However, the basis of tissue regeneration in mammalian solid organs remains undefined. Remarkably, mice lacking p21 fully regenerate injured ears without discernable scarring. Here we show that, in wild-type mice following tissue injury, stromal-derived factor-1 (Sdf1) is up-regulated in the wound epidermis and recruits Cxcr4-expressing leukocytes to the injury site. In p21-deficient mice, Sdf1 up-regulation and the subsequent recruitment of Cxcr4-expressing leukocytes are significantly diminished, thereby permitting scarless appendage regeneration. Lineage tracing demonstrates that this regeneration derives from fate-restricted progenitor cells. Pharmacological or genetic disruption of Sdf1 Cxcr4 signaling enhances tissue repair, including full reconstitution of tissue architecture and all cell types. Our findings identify signaling and cellular mechanisms underlying appendage regeneration in mice and suggest new therapeutic approaches for regenerative medicine. PMID- 26494787 TI - Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development. AB - Gene regulatory networks controlling functional activities of spatially and temporally distinct endodermal cell populations in the early mouse embryo remain ill defined. The T-box transcription factor Eomes, acting downstream from Nodal/Smad signals, directly activates the LIM domain homeobox transcription factor Lhx1 in the visceral endoderm. Here we demonstrate Smad4/Eomes-dependent Lhx1 expression in the epiblast marks the entire definitive endoderm lineage, the anterior mesendoderm, and midline progenitors. Conditional inactivation of Lhx1 disrupts anterior definitive endoderm development and impedes node and midline morphogenesis in part due to severe disturbances in visceral endoderm displacement. Transcriptional profiling and ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) experiments identified Lhx1 target genes, including numerous anterior definitive endoderm markers and components of the Wnt signaling pathway. Interestingly, Lhx1-binding sites were enriched at enhancers, including the Nodal-proximal epiblast enhancer element and enhancer regions controlling Otx2 and Foxa2 expression. Moreover, in proteomic experiments, we characterized a complex comprised of Lhx1, Otx2, and Foxa2 as well as the chromatin-looping protein Ldb1. These partnerships cooperatively regulate development of the anterior mesendoderm, node, and midline cell populations responsible for establishment of the left-right body axis and head formation. PMID- 26494789 TI - Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells. AB - Mitochondrial outer membrane permeabilization (MOMP), a key step in the intrinsic apoptotic pathway, is incompletely understood. Current models emphasize the role of BH3-only BCL2 family members in BAX and BAK activation. Here we demonstrate concentration-dependent BAK autoactivation under cell-free conditions and provide evidence that this autoactivation plays a key role in regulating the intrinsic apoptotic pathway in intact cells. In particular, we show that up to 80% of BAK (but not BAX) in lymphohematopoietic cell lines is oligomerized and bound to anti apoptotic BCL2 family members in the absence of exogenous death stimuli. The extent of this constitutive BAK oligomerization is diminished by BAK knockdown and unaffected by BIM or PUMA down-regulation. Further analysis indicates that sensitivity of cells to BH3 mimetics reflects the identity of the anti-apoptotic proteins to which BAK is constitutively bound, with extensive BCLXL*BAK complexes predicting navitoclax sensitivity, and extensive MCL1*BAK complexes predicting A1210477 sensitivity. Moreover, high BAK expression correlates with sensitivity of clinical acute myelogenous leukemia to chemotherapy, whereas low BAK levels correlate with resistance and relapse. Collectively, these results inform current understanding of MOMP and provide new insight into the ability of BH3 mimetics to induce apoptosis without directly activating BAX or BAK. PMID- 26494788 TI - JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors. AB - RUNX1-RUNX1T1 (formerly AML1-ETO), a transcription factor generated by the t(8;21) translocation in acute myeloid leukemia (AML), dictates a leukemic program by increasing self-renewal and inhibiting differentiation. Here we demonstrate that the histone demethylase JMJD1C functions as a coactivator for RUNX1-RUNX1T1 and is required for its transcriptional program. JMJD1C is directly recruited by RUNX1-RUNX1T1 to its target genes and regulates their expression by maintaining low H3K9 dimethyl (H3K9me2) levels. Analyses in JMJD1C knockout mice also establish a JMJD1C requirement for RUNX1-RUNX1T1's ability to increase proliferation. We also show a critical role for JMJD1C in the survival of multiple human AML cell lines, suggesting that it is required for leukemic programs in different AML cell types through its association with key transcription factors. PMID- 26494793 TI - Corrigendum: Dynamic enhancer-gene body contacts during transcription elongation. PMID- 26494794 TI - Craniofacial Stem Cells in Health and Disease. PMID- 26494797 TI - The Effects of the X Chromosome on Intrinsic Functional Connectivity in the Human Brain: Evidence from Turner Syndrome Patients. AB - Turner syndrome (TS), a disorder caused by the congenital absence of one of the 2 X chromosomes in female humans, provides a valuable human "knockout model" for studying the functions of the X chromosome. At present, it remains unknown whether and how the loss of the X chromosome influences intrinsic functional connectivity (FC), a fundamental phenotype of the human brain. To address this, we performed resting-state functional magnetic resonance imaging and specific cognitive assessments on 22 TS patients and 17 age-matched control girls. A novel data-driven approach was applied to identify the disrupted patterns of intrinsic FC in TS. The TS girls exhibited significantly reduced whole-brain FC strength within the bilateral postcentral gyrus/intraparietal sulcus, angular gyrus, and cuneus and the right cerebellum. Furthermore, a specific functional subnetwork was identified in which the intrinsic FC between nodes was mostly reduced in TS patients. Particularly, this subnetwork is composed of 3 functional modules, and the disruption of intrinsic FC within one of these modules was associated with the deficits of TS patients in math-related cognition. Taken together, these findings provide novel insight into how the X chromosome affects the human brain and cognition, and emphasize an important role of X-linked genes in intrinsic neural coupling. PMID- 26494799 TI - Dopaminergic Modulation of the Functional Ventrodorsal Architecture of the Human Striatum. AB - Interactions between motivational, cognitive, and motor regions of the striatum are crucial for implementing behavioral control. Work with experimental animals indicates that such interactions are sensitive to modulation by dopamine. Using systematic pharmacological manipulation of dopamine D2-receptors and resting state functional imaging, we defined the functional architecture of the human striatum and quantified the effects of dopaminergic drugs on intrinsic effective connectivity between striatal subregions. We found that dopamine modulates interactions between motivational and cognitive regions, as well cognitive and motor regions of the striatum. Stimulation and blockade of the dopamine D2 receptor had opposite (increasing and decreasing) effects on the efficacy of those interactions. Furthermore, trait impulsivity was specifically associated with dopaminergic modulation of ventral-to-dorsal striatal connectivity. Individuals with high trait impulsivity exhibited greater drug-induced increases (after stimulation) and decreases (after blockade) of ventral-to-dorsal striatal connectivity than those with low trait impulsivity. These observations establish a key link between dopamine, intrinsic effective connectivity between striatal subregions, and trait impulsivity. PMID- 26494800 TI - Selective Modulation of Axonal Sodium Channel Subtypes by 5-HT1A Receptor in Cortical Pyramidal Neuron. AB - Serotonergic innervation of the prefrontal cortex (PFC) modulates neuronal activity and PFC functions. However, the cellular mechanism for serotonergic modulation of neuronal excitability remains unclear. We performed patch-clamp recording at the axon of layer-5 pyramidal neurons in rodent PFC slices. We found surprisingly that the activation of 5-HT1A receptors selectively inhibits Na+ currents obtained at the axon initial segment (AIS) but not those at the axon trunk. In addition, Na+ channel subtype NaV1.2 but not NaV1.6 at the AIS is selectively modulated by 5-HT1A receptors. Further experiments revealed that the inhibitory effect is attributable to a depolarizing shift of the activation curve and a facilitation of slow inactivation of AIS Na+ currents. Consistently, dual somatic and axonal recording and simulation results demonstrate that the activation of 5-HT1A receptors could decrease the success rate of action potential (AP) backpropagation toward the somatodendritic compartments, enhancing the segregation of axonal and dendritic activities. Together, our results reveal a selective modulation of NaV1.2 distributed at the proximal AIS region and AP backpropagation by 5-HT1A receptors, suggesting a potential mechanism for serotonergic regulation of functional polarization in the dendro-axonal axis, synaptic plasticity and PFC functions. PMID- 26494801 TI - Mechanisms of Nicotinic Modulation of Glutamatergic Neuroplasticity in Humans. AB - The impact of nicotine (NIC) on plasticity is thought to be primarily determined via calcium channel properties of nicotinic receptor subtypes, and glutamatergic plasticity is likewise calcium-dependent. Therefore glutamatergic plasticity is likely modulated by the impact of nicotinic receptor-dependent neuronal calcium influx. We tested this hypothesis for transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity, which is abolished by NIC in nonsmokers. To reduce calcium influx under NIC, we blocked N-methyl-d aspartate (NMDA) receptors. We applied anodal tDCS combined with 15 mg NIC patches and the NMDA-receptor antagonist dextromethorphan (DMO) in 3 different doses (50, 100, and 150 mg) or placebo medication. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor-evoked potential amplitudes after plasticity induction. NIC abolished anodal tDCS induced motor cortex excitability enhancement, which was restituted under medium dosage of DMO. Low-dosage DMO did not affect the impact of NIC on tDCS-induced plasticity and high-dosage DMO abolished plasticity. For DMO alone, the low dosage had no effect, but medium and high dosages abolished tDCS-induced plasticity. These results enhance our knowledge about the proposed calcium dependent impact of NIC on plasticity in humans and might be relevant for the development of novel nicotinic treatments for cognitive dysfunction. PMID- 26494791 TI - DNA methylation epigenetically silences crossover hot spots and controls chromosomal domains of meiotic recombination in Arabidopsis. AB - During meiosis, homologous chromosomes undergo crossover recombination, which is typically concentrated in narrow hot spots that are controlled by genetic and epigenetic information. Arabidopsis chromosomes are highly DNA methylated in the repetitive centromeres, which are also crossover-suppressed. Here we demonstrate that RNA-directed DNA methylation is sufficient to locally silence Arabidopsis euchromatic crossover hot spots and is associated with increased nucleosome density and H3K9me2. However, loss of CG DNA methylation maintenance in met1 triggers epigenetic crossover remodeling at the chromosome scale, with pericentromeric decreases and euchromatic increases in recombination. We used recombination mutants that alter interfering and noninterfering crossover repair pathways (fancm and zip4) to demonstrate that remodeling primarily involves redistribution of interfering crossovers. Using whole-genome bisulfite sequencing, we show that crossover remodeling is driven by loss of CG methylation within the centromeric regions. Using cytogenetics, we profiled meiotic DNA double-strand break (DSB) foci in met1 and found them unchanged relative to wild type. We propose that met1 chromosome structure is altered, causing centromere proximal DSBs to be inhibited from maturation into interfering crossovers. These data demonstrate that DNA methylation is sufficient to silence crossover hot spots and plays a key role in establishing domains of meiotic recombination along chromosomes. PMID- 26494790 TI - Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERalpha positive breast tumorigenesis. AB - The human RNA polymerase II (RNAPII)-associated factor complex (hPAFc) and its individual subunits have been implicated in human diseases, including cancer. However, its involvement in breast cancer awaits investigation. Using data mining and human breast cancer tissue microarrays, we found that Ctr9, the key scaffold subunit in hPAFc, is highly expressed in estrogen receptor alpha-positive (ERalpha(+)) luminal breast cancer, and the high expression of Ctr9 correlates with poor prognosis. Knockdown of Ctr9 in ERalpha(+) breast cancer cells almost completely erased estrogen-regulated transcriptional response. At the molecular level, Ctr9 enhances ERalpha protein stability, promotes recruitment of ERalpha and RNAPII, and stimulates transcription elongation and transcription-coupled histone modifications. Knockdown of Ctr9, but not other hPAFc subunits, alters the morphology, proliferative capacity, and tamoxifen sensitivity of ERalpha(+) breast cancer cells. Together, our study reveals that Ctr9, a key subunit of hPAFc, is a central regulator of estrogen signaling that drives ERalpha(+) breast tumorigenesis, rendering it a potential target for the treatment of ERalpha(+) breast cancer. PMID- 26494792 TI - Feedback control of growth, differentiation, and morphogenesis of pancreatic endocrine progenitors in an epithelial plexus niche. AB - In the mammalian pancreas, endocrine cells undergo lineage allocation upon emergence from a bipotent duct/endocrine progenitor pool, which resides in the "trunk epithelium." Major questions remain regarding how niche environments are organized within this epithelium to coordinate endocrine differentiation with programs of epithelial growth, maturation, and morphogenesis. We used EdU pulse chase and tissue-reconstruction approaches to analyze how endocrine progenitors and their differentiating progeny are assembled within the trunk as it undergoes remodeling from an irregular plexus of tubules to form the eventual mature, branched ductal arbor. The bulk of endocrine progenitors is maintained in an epithelial "plexus state," which is a transient intermediate during epithelial maturation within which endocrine cell differentiation is continually robust and surprisingly long-lived. Within the plexus, local feedback effects derived from the differentiating and delaminating endocrine cells nonautonomously regulate the flux of endocrine cell birth as well as proliferative growth of the bipotent cell population using Notch-dependent and Notch-independent influences, respectively. These feedback effects in turn maintain the plexus state to ensure prolonged allocation of endocrine cells late into gestation. These findings begin to define a niche-like environment guiding the genesis of the endocrine pancreas and advance current models for how differentiation is coordinated with the growth and morphogenesis of the developing pancreatic epithelium. PMID- 26494798 TI - Human Subthalamic Nucleus Theta and Beta Oscillations Entrain Neuronal Firing During Sensorimotor Conflict. AB - Recent evidence has suggested that prefrontal cortical structures may inhibit impulsive actions during conflict through activation of the subthalamic nucleus (STN). Consistent with this hypothesis, deep brain stimulation to the STN has been associated with altered prefrontal cortical activity and impaired response inhibition. The interactions between oscillatory activity in the STN and its presumably antikinetic neuronal spiking, however, remain poorly understood. Here, we simultaneously recorded intraoperative local field potential and spiking activity from the human STN as participants performed a sensorimotor action selection task involving conflict. We identified several STN neuronal response types that exhibited different temporal dynamics during the task. Some neurons showed early, cue-related firing rate increases that remained elevated longer during high conflict trials, whereas other neurons showed late, movement-related firing rate increases. Notably, the high conflict trials were associated with an entrainment of individual neurons by theta- and beta-band oscillations, both of which have been observed in cortical structures involved in response inhibition. Our data suggest that frequency-specific activity in the beta and theta bands influence STN firing to inhibit impulsivity during conflict. PMID- 26494796 TI - Alterations in Anatomical Covariance in the Prematurely Born. AB - Preterm (PT) birth results in long-term alterations in functional and structural connectivity, but the related changes in anatomical covariance are just beginning to be explored. To test the hypothesis that PT birth alters patterns of anatomical covariance, we investigated brain volumes of 25 PTs and 22 terms at young adulthood using magnetic resonance imaging. Using regional volumetrics, seed-based analyses, and whole brain graphs, we show that PT birth is associated with reduced volume in bilateral temporal and inferior frontal lobes, left caudate, left fusiform, and posterior cingulate for prematurely born subjects at young adulthood. Seed-based analyses demonstrate altered patterns of anatomical covariance for PTs compared with terms. PTs exhibit reduced covariance with R Brodmann area (BA) 47, Broca's area, and L BA 21, Wernicke's area, and white matter volume in the left prefrontal lobe, but increased covariance with R BA 47 and left cerebellum. Graph theory analyses demonstrate that measures of network complexity are significantly less robust in PTs compared with term controls. Volumes in regions showing group differences are significantly correlated with phonological awareness, the fundamental basis for reading acquisition, for the PTs. These data suggest both long-lasting and clinically significant alterations in the covariance in the PTs at young adulthood. PMID- 26494802 TI - Multimodal Encoding of Goal-Directed Actions in Monkey Ventral Premotor Grasping Neurons. AB - Visuo-motor neurons of the ventral premotor area F5 encode "pragmatic" representations of object in terms of the potential motor acts (e.g., precision grip) afforded by it. Likewise, objects with identical pragmatic features (e.g., small spheres) but different behavioral value (e.g., edible or inedible) convey different "semantic" information and thus afford different goal-directed behaviors (e.g., grasp-to-eat or grasp-to-place). However, whether F5 neurons can extract distinct behavioral affordances from objects with similar pragmatic features is unknown. We recorded 134 F5 visuo-motor neurons in 2 macaques during a contextually cued go/no-go task in which the monkey grasped, or refrained from grasping, a previously presented edible or inedible target to eat it or placing it, respectively. Sixty-nine visuo-motor neurons showed motor selectivity for the target (35 food and 34 object), and about half of them (N = 35) exhibited congruent visual preference. Interestingly, when the monkey grasped in complete darkness and could identify the target only based on haptic feedback, visuo-motor neurons lost their precontact selectivity, but most of them (80%) showed it again 60 ms after hand-target contact. These findings suggest that F5 neurons possess a multimodal access to semantic information on objects, which are transformed into motor representations of the potential goal-directed actions afforded by them. PMID- 26494803 TI - Knee MRI patterns of bone marrow reconversion and relationship to anemia. AB - BACKGROUND: Bone marrow changes are commonly encountered on knee magnetic resonance imaging (MRI). The clinical relevance of these changes, especially as they relate to anemia, has not been studied in a large patient series. PURPOSE: To determine if the extent of bone marrow reconversion (BMR) can assist the radiologist in making recommendations for further evaluation for underlying anemia. MATERIAL AND METHODS: This study included 457 patients who had knee MRI over a 2-year period. Bone marrow patterns in the distal femur, proximal tibia, and fibula were graded as follows: 1, homogeneous fatty marrow; 2, patchy red marrow in the distal femur; 3, patchy red marrow in the distal femur and tibia and/or fibula; and 4, complete BMR in the femoral, tibial, and/or fibular metaphyses. RESULTS: There was a statistically significant difference (P < 0.001) between the hemoglobin concentration and BMR grades. In women, anemia (Hb <=12.0 g/dL) was found in 31 of 127 (24%) patients with grade 1, 31 of 83 (37%) with grade 2, 24 of 64 (37%) with grade 3, and 12 of 24 (50%) with grade 4. In men, anemia (Hb <=13.0 g/dL) was found in 33 of 125 (26%) patients with grade 1, 12 of 19 (63%) with grade 2, five of 14 (36%) with grade 3, but not in the one patient with grade 4. CONCLUSION: Women demonstrating marrow changes of a grade 4 BMR pattern should get a laboratory assessment for anemia. PMID- 26494806 TI - Diabetes and Obesity--Time Bombs to Be Defused. PMID- 26494804 TI - Characterization of a family 43 beta-xylosidase from the xylooligosaccharide utilizing putative probiotic Weissella sp. strain 92. AB - In this work, we present the first XOS degrading glycoside hydrolase from Weissella, WXyn43, a two-domain enzyme from GH43. The gene was amplified from genomic DNA of the XOS utilizing Weissella strain 92, classified under the species-pair Weissella cibaria/W.confusa, and expressed in Escherichia coli. The enzyme is lacking a putative signal peptide and is, from a homology model, shown to be composed of an N-terminal 5-fold beta-propeller catalytic domain and a C terminal beta-sandwich domain of unknown function. WXyn43 hydrolyzed short (1-4) beta-D-xylooligosaccharides, with similar kcat/KM for xylobiose (X2) and xylotriose (X3) and clearly lower efficiency in xylotetraose (X4) conversion. WXyn43 displays the highest reported kcat for conversion of X3 (900 s(-1) at 37 degrees C) and X4 (770 s(-1)), and kcat for hydrolysis of X2 (907 s(-1)) is comparable with or greater than the highest previously reported. The purified enzyme adopted a homotetrameric state in solution, while a truncated form with isolated N-terminal catalytic domain adopted a mixture of oligomeric states and lacked detectable activity. The homology model shows that residues from both domains are involved in monomer-monomer hydrogen bonds, while the bonds creating dimer-dimer interactions only involved residues from the N-terminal domain. Docking of X2 and X3 in the active site shows interactions corresponding to subsites -1 and +1, while presence of a third subsite is unclear, but interactions between a loop and the reducing-end xylose of X3 may be present. PMID- 26494807 TI - Socioeconomic Disparities in Weight and Behavioral Outcomes Among American Indian and Alaska Native Participants of a Translational Lifestyle Intervention Project. AB - OBJECTIVE: To investigate possible socioeconomic disparities in weight and behavioral outcomes among American Indian and Alaska Native (AI/AN) participants in a translational diabetes prevention project. RESEARCH DESIGN AND METHODS: We analyzed data from the Special Diabetes Program for Indians Diabetes Prevention (SDPI-DP) Program, an evidence-based lifestyle intervention to prevent diabetes in 36 AI/AN grantee sites. A total of 2,553 participants started the 16-session Lifestyle Balance Curriculum between 1 January 2006 and 31 July 2008. Linear mixed models were used to evaluate the relationships of participant and staff socioeconomic characteristics with weight and behavioral outcomes at the end of the curriculum. RESULTS: A strong, graded association existed between lower household income and less BMI reduction, which remained significant after adjusting for other socioeconomic characteristics. Compared with others, participants with annual income <$15,000 also had less improvement in physical activity and unhealthy food consumption in bivariate models, but the relationships were only marginally significant in multivariate regressions. Furthermore, grantee sites with fewer professionally prepared staff were less successful at improving participant BMI and healthy food consumption than the other sites. The strong association between income and BMI reduction was reduced by 20-30% in the models with changes in diet variables but was unrelated to changes in physical activity. CONCLUSIONS: Significant socioeconomic disparities exist in weight outcomes of lifestyle intervention at both participant and site staff levels. Helping low-income participants choose more affordable healthy foods and increasing the proportion of professionally trained staff might be practical ways to maximize the effectiveness of lifestyle interventions implemented in "real-world" settings. PMID- 26494808 TI - Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes. AB - OBJECTIVE: The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. RESEARCH DESIGN AND METHODS: The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing beta cells were revised according to their possible influence on the development of type 2 diabetes (T2D). RESULTS: The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet induced alterations in iron absorption, modulation of gluconeogenesis, heme mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate beta-cells and insulin secretion, although this has been scarcely studied. CONCLUSIONS: Iron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted. PMID- 26494810 TI - Erratum. Glycemic Variability Is Associated With Reduced Cardiac Autonomic Modulation in Women With Type 2 Diabetes. Diabetes Care 2015;38:682-688. PMID- 26494809 TI - Definitions of Metabolic Health and Risk of Future Type 2 Diabetes in BMI Categories: A Systematic Review and Network Meta-analysis. AB - OBJECTIVE: Various definitions of metabolic health have been proposed to explain differences in the risk of type 2 diabetes within BMI categories. The goal of this study was to assess their predictive relevance. RESEARCH DESIGN AND METHODS: We performed systematic searches of MEDLINE records for prospective cohort studies of type 2 diabetes risk in categories of BMI and metabolic health. In a two-stage meta-analysis, relative risks (RRs) specific to each BMI category were derived by network meta-analysis and the resulting RRs of each study were pooled using random-effects models. Hierarchical summary receiver operating characteristic curves were used to assess predictive performance. RESULTS: In a meta-analysis of 140,845 participants and 5,963 incident cases of type 2 diabetes from 14 cohort studies, classification as metabolically unhealthy was associated with higher RR of diabetes in all BMI categories (lean RR compared with healthy individuals 4.0 [95% CI 3.0-5.1], overweight 3.4 [2.8-4.3], and obese 2.5 [2.1 3.0]). Metabolically healthy obese individuals had a high absolute risk of type 2 diabetes (10-year cumulative incidence 3.1% [95% CI 2.6-3.5]). Current binary definitions of metabolic health had high specificity (pooled estimate 0.88 [95% CI 0.84-0.91]) but low sensitivity (0.40 [0.31-0.49]) in lean individuals and satisfactory sensitivity (0.81 [0.76-0.86]) but low specificity (0.42 [0.35 0.49]) in obese individuals. However, positive (<3.3 in all BMI categories) and negative (>0.4) likelihood ratios were consistent with insignificant to small improvements in prediction. CONCLUSIONS: Although individuals classified as metabolically unhealthy have a higher RR of type 2 diabetes compared with individuals classified as healthy in all BMI categories, current binary definitions of metabolic health have limited relevance to the prediction of future type 2 diabetes. PMID- 26494812 TI - Comment on Castellaneta et al. High Rate of Spontaneous Normalization of Celiac Serology in a Cohort of 446 Children With Type 1 Diabetes: A Prospective Study. Diabetes Care 2015;38:760-766. PMID- 26494813 TI - Response to Comment on Castellaneta et al. High Rate of Spontaneous Normalization of Celiac Serology in a Cohort of 446 Children With Type 1 Diabetes: A Prospective Study. Diabetes Care 2015;38:760-766. PMID- 26494814 TI - Comment on Krul-Poel et al. Effect of Vitamin D Supplementation on Glycemic Control in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo Controlled Trial. Diabetes Care 2015;38:1420-1426. PMID- 26494815 TI - Response to Comment on Krul-Poel et al. Effect of Vitamin D Supplementation on Glycemic Control in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo-Controlled Trial. Diabetes Care 2015;38:1420-1426. PMID- 26494816 TI - Comment on Juraschek et al. Cardiorespiratory Fitness and Incident Diabetes: The FIT (Henry Ford ExercIse Testing) Project. Diabetes Care 2015;38:1075-1081. PMID- 26494817 TI - Response to Comment on Juraschek et al. Cardiorespiratory Fitness and Incident Diabetes: The FIT (Henry Ford ExercIse Testing) Project. Diabetes Care 2015;38:1075-1081. PMID- 26494818 TI - Comment on Shukla et al. Food Order Has a Significant Impact on Postprandial Glucose and Insulin Levels. Diabetes Care 2015;38:e98-e99. PMID- 26494819 TI - Response to Comment on Shukla et al. Food Order Has a Significant Impact on Postprandial Glucose and Insulin Levels. Diabetes Care 2015;38:e98-e99. PMID- 26494820 TI - Comment on Erondu et al. Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program. Diabetes Care 2015;38:1680-1686. PMID- 26494821 TI - Vector-Borne Diseases in Stray Dogs in Peninsular Malaysia and Molecular Detection of Anaplasma and Ehrlichia spp. from Rhipicephalus sanguineus (Acari: Ixodidae) Ticks. AB - Little data are available on the prevalence and transmission of vector-borne diseases in stray dogs in Peninsular Malaysia. This study was designed to determine the occurrence of vector-borne pathogens in Malaysian stray dogs using serological and molecular approaches. In total, 48 dog blood samples were subjected to serological analysis using SNAP 4Dx kit (IDEXX Laboratories, Westbrook, ME). The presence of Ehrlichia and Anaplasma DNA in the dog blood samples and Rhipicephalus sanguineus (Latreille) ticks was detected using nested polymerase chain reaction assays. Positive serological findings against Ehrlichia canis and Anaplasma phagocytophilum were obtained in 17 (39.5%) and four (9.3%) of 43 dog samples, respectively. None of the dog blood samples were positive for Borrelia burgdorferi and Dirofilaria immitis. DNA of E. canis and A. phagocytophilum was detected in 12 (25.5%) and two (4.3%) of 47 dog blood samples, and 17 (51.5%) and one (3.0%) of 33 R. sanguineus ticks, respectively. Additionally, DNA of Ehrlichia spp. closely related to Ehrlichia chaffeensis was detected in two (6.1%) R. sanguineus ticks. This study highlights the prevalence of anaplasmosis and ehrlichiosis in dogs in Malaysia. Due to the zoonotic potential of Ehrlichia and Anaplasma spp., appropriate measures should be instituted for prevention and control of vector-borne diseases in dogs. PMID- 26494822 TI - Effect of Rickettsia rickettsii (Rickettsiales: Rickettsiaceae) Infection on the Biological Parameters and Survival of Its Tick Vector-Dermacentor variabilis (Acari: Ixodidae). AB - Rocky Mountain spotted fever, caused by Rickettsia rickettsii, is a potentially fatal tick-borne disease spread from North America to Argentina. The major vectors of R. rickettsii in the United States are Dermacentor andersoni Stiles and Dermacentor variabilis (Say). It is generally believed that vector ticks serve as major reservoirs of R. rickettsii in nature; however, the ability of ticks to support the indefinite perpetuation of R. rickettsii has been challenged by reports of deleterious effects of rickettsial infection on D. andersoni. To better elucidate the relationship of the pathogen with D. variabilis, we assessed the effects of R. rickettsii on the survival, fertility, and fecundity of D. variabilis. We used an isolate of R. rickettsii (Di-6), originally acquired from an opossum caught in Virginia, and ticks from a laboratory colony established from adult D. variabilis also collected in Virginia. Overall, infection with R. rickettsii protracted the feeding periods of all life stages of ticks. Infected nymphal and adult ticks experienced a slight decrease in feeding success compared with the uninfected colony, but neither larval nor nymphal molting success was affected. Infected females reached smaller engorgement weights, were less efficient in conversion of bloodmeal into eggs, and produced smaller egg clutches with a lower proportion of eggs hatching. However, no sudden die-off was observed among infected ticks, and longevity was not decreased due to R. rickettsii infection in any stage. Although infection with the studied isolate of R. rickettsii caused slight decrease in fecundity in sympatric vector ticks, no obvious deleterious effects were observed. PMID- 26494824 TI - Reply to Deguchi et al. PMID- 26494823 TI - Neural Stem Cells (NSCs) and Proteomics. AB - Neural stem cells (NSCs) can self-renew and give rise to the major cell types of the CNS. Studies of NSCs include the investigation of primary, CNS-derived cells as well as animal and human embryonic stem cell (ESC)-derived and induced pluripotent stem cell (iPSC)-derived sources. NSCs provide a means with which to study normal neural development, neurodegeneration, and neurological disease and are clinically relevant sources for cellular repair to the damaged and diseased CNS. Proteomics studies of NSCs have the potential to delineate molecules and pathways critical for NSC biology and the means by which NSCs can participate in neural repair. In this review, we provide a background to NSC biology, including the means to obtain them and the caveats to these processes. We then focus on advances in the proteomic interrogation of NSCs. This includes the analysis of posttranslational modifications (PTMs); approaches to analyzing different proteomic compartments, such the secretome; as well as approaches to analyzing temporal differences in the proteome to elucidate mechanisms of differentiation. We also discuss some of the methods that will undoubtedly be useful in the investigation of NSCs but which have not yet been applied to the field. While many proteomics studies of NSCs have largely catalogued the proteome or posttranslational modifications of specific cellular states, without delving into specific functions, some have led to understandings of functional processes or identified markers that could not have been identified via other means. Many challenges remain in the field, including the precise identification and standardization of NSCs used for proteomic analyses, as well as how to translate fundamental proteomics studies to functional biology. The next level of investigation will require interdisciplinary approaches, combining the skills of those interested in the biochemistry of proteomics with those interested in modulating NSC function. PMID- 26494825 TI - Multidrug-Resistant Mycoplasma genitalium Is Increasing. PMID- 26494826 TI - Applying social theory to understand health-related behaviours. AB - Health-related behaviours are a concern for contemporary health policy and practice given their association with a range of illness outcomes. Many of the policies and interventions aimed at changing health-related behaviours assume that people are more or less free to choose their behaviour and how they experience health. Within sociology and anthropology, these behaviours are viewed not as acts of choice but as actions and practices situated within a larger sociocultural context. In this paper, we outline three theoretical perspectives useful in understanding behaviours that may influence one's health in this wider context: theories of social practice, social networks and interactionism. We argue that by better understanding how health-related behaviours are performed in people's everyday lives, more suitable interventions and clinical management can be developed. PMID- 26494827 TI - Correction. PMID- 26494828 TI - In My Best Interest. AB - BACKGROUND: Advance directives (ADs) have traditionally been viewed as clear instructions for implementing patient wishes at times of compromised decision making capacity (DMC). However, whether individuals prefer ADs to be strictly followed or to serve as general guidelines has not been studied. The Veterans Administration's Advance Directive Durable Power of Attorney for Health Care and Living Will (VA AD) provides patients the opportunity to indicate specific treatment preferences and to indicate how strictly the directive is to be followed. OBJECTIVE: To describe preferences for life-sustaining treatments (LSTs) in various illness conditions as well as instructions for the use of VA ADs. DESIGN/SETTING: A descriptive study was performed collecting data from all ADs entered into the medical record at 1 VA Medical Center between January and June 2014. MEASUREMENTS: Responses to VA AD with emphasis on health care agents (HCAs) and LW responses. RESULTS: Veterans were more likely to reject LST when death was imminent (74.6%), when in a coma (71.1%), if they had brain damage (70.6%), or were ventilator dependent (70.4%). A majority (67.4%) of veterans preferred the document to be followed generally rather than strictly. Veterans were more likely to want VA ADs to serve as a general guide when a spouse was named HCA. CONCLUSION: Most of the sampled veterans rejected LST except under conditions of permanent disability. A majority intend VA ADs to serve as general guidelines rather than strict, binding instructions. These findings have significant implications for surrogate decision making and the use of ADs more generally. PMID- 26494829 TI - Barriers to the Collaboration Between Hematologists and Palliative Care Teams on Relapse or Refractory Leukemia and Malignant Lymphoma Patients' Care: A Qualitative Study. AB - BACKGROUND: Palliative care service (PCS) has been shown to be utilized less in patients with leukemia and malignant lymphoma than in those with solid tumors. Previous studies have suggested hematologists' limited awareness of PCS as one of the reason for low PCS referral in hematology. However, little is known about such an awareness and potential barriers to collaboration between hematologists and PCS. AIM: The present study aimed to assess ematologists and palliative care specialists' perception about the roles of the hospital-based palliative care team (HPCT) and the barriers to collaboration between hematologists and palliative care teams on relapse or refractory leukemia and malignant lymphoma patients' care MATERIALS AND METHODS: A qualitative study was conducted using semistructured interviews with hematologists and palliative care specialists recruited from a hospital that provides hematology and palliative care by the HPCT. Data were evaluated via content analysis. RESULTS: The study included 11 hematologists and 10 palliative care specialists. Our results revealed that they shared many common perceptions about the roles and expectations of the HPCT. Additionally, 7 categories of barriers to collaboration were identified, including not feeling the need to refer, the difficulty in referral timing, the lack of aggressive approach, the negative image of the HPCT, the need for hematologic malignancy-oriented management, the lack of communication, and others. CONCLUSION: We have identified hematologists' and palliative care specialists' perceptions of the HPCT's roles and the barriers to their collaboration. A better understanding of such barriers may lead to effective collaboration between hematologists and the HPCT. PMID- 26494830 TI - Advance Directives and Care Received by Older Nursing Home Residents. AB - BACKGROUND: Research shows variable success as to whether care provided aligns with individual patient preferences as reflected in their advance directives (AD). OBJECTIVE: We aimed to study AD status and subsequent care received in older nursing home (NH) residents deemed at risk for infections and care transitions: those with a urinary catheter (UC), feeding tube (FT), or both. Design/participants/measurements: A subgroup analysis of a prospective cohort of 90 residents with a UC and/or FT from 15 NHs in southeast Michigan. Outcomes assessed at enrollment and at 30-day intervals were hospitalizations and antibiotic use. The ADs were divided as follows: (1) comfort oriented: comfort measures only, no hospital transfer; (2) palliative oriented: comfort focused, allowing hospital transfer (except intensive care unit), antibiotic use, but no cardiopulmonary resuscitation; (3) usual care: full code, no limitations to care. We calculated incidences for these outcomes. RESULTS: Seventy-eight (87%) residents had ADs: 18 (23%) comfort oriented, 32 (41%) palliative oriented, and 28 (36%) usual care. The groups did not differ regarding demographics, comorbidity, function, device presence, or time in study. Using the usual care group as comparison, the comfort-oriented group was hospitalized at a similar rate (Incidence rate [IR] = 15.6/1000 follow-up days vs IR = 8.8/1000 follow-up days, Incident rate ratio [IRR] 0.6 [95% confidence interval, CI, 0.3 -1.1], P value .09) but received fewer antibiotics (IR = 18.9/1000 follow-up days vs IR = 7.5/1000 follow-up days, IRR 0.4 [95% CI, 0.2-0.8], P value .005). CONCLUSION: Nursing home residents with comfort-oriented ADs were hospitalized at a rate similar to those with usual-care ADs but received fewer antibiotics, although the small sample size of this analysis suggests these findings deserve further study. PMID- 26494831 TI - Four-Week Studies of Oral Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia. AB - Hypoxia-inducible factor prolyl hydroxylase inhibitors stabilize levels of hypoxia-inducible factor that upregulate transcription of multiple genes associated with the response to hypoxia, including production of erythropoietin. We conducted two phase 2a studies to explore the relationship between the dose of the hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 and hemoglobin response in patients with anemia of CKD (baseline hemoglobin 8.5-11.0 g/dl) not undergoing dialysis and not receiving recombinant human erythropoietin (nondialysis study) and in patients with anemia of CKD (baseline hemoglobin 9.5 12.0 g/dl) on hemodialysis and being treated with stable doses of recombinant human erythropoietin (hemodialysis study). Participants were randomized 1:1:1:1 to a once-daily oral dose of GSK1278863 (0.5 mg, 2 mg, or 5 mg) or control (placebo for the nondialysis study; continuing on recombinant human erythropoietin for the hemodialysis study) for 4 weeks, with a 2-week follow-up. In the nondialysis study, GSK1278863 produced dose-dependent effects on hemoglobin, with the highest dose resulting in a mean increase of 1 g/dl at week 4. In the hemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained mean hemoglobin concentrations after the switch from recombinant human erythropoietin, whereas mean hemoglobin decreased in the lower-dose arms. In both studies, the effects on hemoglobin occurred with elevations in endogenous erythropoietin within the range usually observed in the respective populations and markedly lower than those in the recombinant human erythropoietin control arm in the hemodialysis study, and without clinically significant elevations in plasma vascular endothelial growth factor concentrations. GSK1278863 was generally safe and well tolerated at the doses and duration studied. GSK1278863 may prove an effective alternative for managing anemia of CKD. PMID- 26494832 TI - The Dawning of a New Day in CKD Anemia Care? PMID- 26494834 TI - AnABlast: a new in silico strategy for the genome-wide search of novel genes and fossil regions. AB - Genome annotation, assisted by computer programs, is one of the great advances in modern biology. Nevertheless, the in silico identification of small and complex coding sequences is still challenging. We observed that amino acid sequences inferred from coding-but rarely from non-coding-DNA sequences accumulated alignments in low-stringency BLAST searches, suggesting that this alignments accumulation could be used to highlight coding regions in sequenced DNA. To investigate this possibility, we developed a computer program (AnABlast) that generates profiles of accumulated alignments in query amino acid sequences using a low-stringency BLAST strategy. To validate this approach, all six-frame translations of DNA sequences between every two annotated exons of the fission yeast genome were analysed with AnABlast. AnABlast-generated profiles identified three new copies of known genes, and four new genes supported by experimental evidence. New pseudogenes, ancestral carboxyl- and amino-terminal subtractions, complex gene rearrangements, and ancient fragments of mitDNA and of bacterial origin, were also inferred. Thus, this novel in silico approach provides a powerful tool to uncover new genes, as well as fossil-coding sequences, thus providing insight into the evolutionary history of annotated genomes. PMID- 26494833 TI - Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients. AB - Safety concerns with erythropoietin analogues and intravenous (IV) iron for treatment of anemia in CKD necessitate development of safer therapies. Roxadustat (FG-4592) is an orally bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF mediated transcription. We performed an open-label, randomized hemoglobin (Hb) correction study in anemic (Hb<=10.0 g/dl) patients incident to hemodialysis (HD) or peritoneal dialysis (PD). Sixty patients received no iron, oral iron, or IV iron while treated with roxadustat for 12 weeks. Mean+/-SD baseline Hb was 8.3+/ 1.0 g/dl in enrolled patients. Roxadustat at titrated doses increased mean Hb by >=2.0 g/dl within 7 weeks regardless of baseline iron repletion status, C reactive protein level, iron regimen, or dialysis modality. Mean+/-SEM maximal change in Hb from baseline (DeltaHb(max)), the primary endpoint, was 3.1+/-0.2 g/dl over 12 weeks in efficacy-evaluable patients (n=55). In groups receiving oral or IV iron, DeltaHb(max) was similar and larger than in the no-iron group. Hb response (increase in Hb of >=1.0 g/dl from baseline) was achieved in 96% of efficacy-evaluable patients. Mean serum hepcidin decreased significantly 4 weeks into study: by 80% in HD patients receiving no iron (n=22), 52% in HD and PD patients receiving oral iron (n=21), and 41% in HD patients receiving IV iron (n=9). In summary, roxadustat was well tolerated and corrected anemia in incident HD and PD patients, regardless of baseline iron repletion status or C-reactive protein level and with oral or IV iron supplementation; it also reduced serum hepcidin levels. PMID- 26494836 TI - ICRP Publication 130: Occupational Intakes of Radionuclides: Part 1. AB - Abstract -: This report is the first in a series of reports replacing Publications 30 and 68 to provide revised dose coefficients for occupational intakes of radionuclides by inhalation and ingestion. The revised dose coefficients have been calculated using the Human Alimentary Tract Model (Publication 100) and a revision of the Human Respiratory Tract Model (Publication 66) that takes account of more recent data. In addition, information is provided on absorption into blood following inhalation and ingestion of different chemical forms of elements and their radioisotopes. In selected cases, it is judged that the data are sufficient to make material-specific recommendations. Revisions have been made to many of the models that describe the systemic biokinetics of radionuclides absorbed into blood, making them more physiologically realistic representations of uptake and retention in organs and tissues, and excretion.The reports in this series provide data for the interpretation of bioassay measurements as well as dose coefficients, replacing Publications 54 and 78. In assessing bioassay data such as measurements of whole body or organ content, or urinary excretion, assumptions have to be made about the exposure scenario, including the pattern and mode of radionuclide intake, physical and chemical characteristics of the material involved, and the elapsed time between the exposure(s) and measurement. This report provides some guidance on monitoring programmes and data interpretation. PMID- 26494835 TI - Comparison of the terrestrial cyanobacterium Leptolyngbya sp. NIES-2104 and the freshwater Leptolyngbya boryana PCC 6306 genomes. AB - The cyanobacterial genus Leptolyngbya is widely distributed throughout terrestrial environments and freshwater. Because environmental factors, such as oxygen level, available water content, and light intensity, vary between soil surface and water bodies, terrestrial Leptolyngbya should have genomic differences with freshwater species to adapt to a land habitat. To study the genomic features of Leptolyngbya species, we determined the complete genome sequence of the terrestrial strain Leptolyngbya sp. NIES-2104 and compared it with that of the near-complete sequence of the freshwater Leptolyngbya boryana PCC 6306. The greatest differences between these two strains were the presence or absence of a nitrogen fixation gene cluster for anaerobic nitrogen fixation and several genes for tetrapyrrole synthesis, which can operate under micro-oxic conditions. These differences might reflect differences in oxygen levels where these strains live. Both strains have the genes for trehalose biosynthesis, but only Leptolyngbya sp. NIES-2104 has genetic capacity to produce a mycosporine like amino acid, mycosporine-glycine. Mycosporine-glycine has an antioxidant action, which may contribute to adaptation to terrestrial conditions. These features of the genomes yielded additional insights into the classification and physiological characteristics of these strains. PMID- 26494837 TI - PAX5-ESRRB is a recurrent fusion gene in B-cell precursor pediatric acute lymphoblastic leukemia. PMID- 26494838 TI - Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome. AB - Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were included in the study. There were no statistically significant differences in outcome between the up front protocols or between the relapse protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing in the period 2002-2011 was 57.5+/-3.4%, but 44.7+/-3.2% (P<0.001) if relapse occurred in the period 1992-2001. Factors independently predicting mortality after relapse included short duration of first remission, bone marrow involvement, age ten years or over, unfavorable cytogenetics, and Down syndrome. T-cell immunophenotype was not an independent prognostic factor unless in combination with hyperleukocytosis at diagnosis. The outcome for early combined pre-B relapses was unexpectedly poor (5-year overall survival 38.0+/-10.6%), which supports the notion that these patients need further risk adjustment. Although survival outcomes have improved over time, the development of novel approaches is urgently needed to increase survival in relapsed childhood acute lymphoblastic leukemia. PMID- 26494840 TI - Relevant role of von Willebrand factor in neutrophil recruitment in a mouse sepsis model involving cecal ligation and puncture. PMID- 26494839 TI - Clinical, instrumental, serological and histological findings suggest that hemophilia B may be less severe than hemophilia A. AB - Recent evidence suggests that patients with severe hemophilia B may have a less severe disease compared to severe hemophilia A. To investigate clinical, radiological, laboratory and histological differences in the arthropathy of severe hemophilia A and hemophilia B, 70 patients with hemophilia A and 35 with hemophilia B with at least one joint bleeding were consecutively enrolled. Joint bleedings (<10, 10-50, >50), regimen of treatment (prophylaxis/on demand), World Federation of Hemophilia, Pettersson and ultrasound scores, serum soluble RANK ligand and osteoprotegerin were assessed in all patients. RANK, RANK ligand and osteoprotegerin expression was evaluated in synovial tissue from 18 hemophilia A and 4 hemophilia B patients. The percentage of patients with either 10-50 or more than 50 hemarthrosis was greater in hemophilia A than in hemophilia B (P<0.001 and P=0.03, respectively), while that with less than 10 hemarthrosis was higher in hemophilia B (P<0.0001). World Federation of Hemophilia (36.6 vs. 20.2; P<0.0001) and ultrasound (10.9 vs. 4.3; P<0.0001) score mean values were significantly higher in hemophilia A patients. Serum osteoprotegerin and soluble RANK ligand were decreased in hemophilia A versus hemophilia B (P<0.0001 and P=0.006, respectively). Osteoprotegerin expression was markedly reduced in synovial tissue from hemophilia A patients. In conclusion, the reduced number of hemarthrosis, the lower World Federation of Hemophilia and ultrasound scores, and higher osteoprotegerin expression in serum and synovial tissue in hemophilia B suggest that hemophilia B is a less severe disease than hemophilia A. Osteoprotegerin reduction seems to play a pivotal role in the progression of arthropathy in hemophilia A. PMID- 26494841 TI - Presensitization to HY antigens in female donors prior to transplant is not associated with male recipient post-transplant HY antibody development nor with clinical outcomes. PMID- 26494842 TI - Strong Constraint on Human Genes Escaping X-Inactivation Is Modulated by their Expression Level and Breadth in Both Sexes. AB - In eutherian mammals, X-linked gene expression is normalized between XX females and XY males through the process of X chromosome inactivation (XCI). XCI results in silencing of transcription from one ChrX homolog per female cell. However, approximately 25% of human ChrX genes escape XCI to some extent and exhibit biallelic expression in females. The evolutionary basis of this phenomenon is not entirely clear, but high sequence conservation of XCI escapers suggests that purifying selection may directly or indirectly drive XCI escape at these loci. One hypothesis is that this signal results from contributions to developmental and physiological sex differences, but presently there is limited evidence supporting this model in humans. Another potential driver of this signal is selection for high and/or broad gene expression in both sexes, which are strong predictors of reduced nucleotide substitution rates in mammalian genes. Here, we compared purifying selection and gene expression patterns of human XCI escapers with those of X-inactivated genes in both sexes. When we accounted for the functional status of each ChrX gene's Y-linked homolog (or "gametolog"), we observed that XCI escapers exhibit greater degrees of purifying selection in the human lineage than X-inactivated genes, as well as higher and broader gene expression than X-inactivated genes across tissues in both sexes. These results highlight a significant role for gene expression in both sexes in driving purifying selection on XCI escapers, and emphasize these genes' potential importance in human disease. PMID- 26494844 TI - Ancient Male Recombination Shaped Genetic Diversity of Neo-Y Chromosome in Drosophila albomicans. AB - Researchers studying Y chromosome evolution have drawn attention to neo-Y chromosomes in Drosophila species due to their resembling the initial stage of Y chromosome evolution. In the studies of neo-Y chromosome of Drosophila miranda, the extremely low genetic diversity observed suggested various modes of natural selection acting on the nonrecombining genome. However, alternative possibility may come from its peculiar origin from a single chromosomal fusion event with male achiasmy, which potentially caused and maintained the low genetic diversity of the neo-Y chromosome. Here, we report a real case where a neo-Y chromosome is in transition from an autosome to a typical Y chromosome. The neo-Y chromosome of Drosophila albomicans harbored a rich genetic diversity comparable to its gametologous neo-X chromosome and an autosome in the same genome. Analyzing sequence variations in 53 genes and measuring recombination rates between pairs of loci by cross experiments, we elucidated the evolutionary scenario of the neo Y chromosome of D. albomicans having high genetic diversity without assuming selective force, i.e., it originated from a single chromosomal fusion event, experienced meiotic recombination during the initial stage of evolution and diverged from neo-X chromosome by the suppression of recombination tens or a few hundreds of thousand years ago. Consequently, the observed high genetic diversity on the neo-Y chromosome suggested a strong effect of meiotic recombination to introduce genetic variations into the newly arisen sex chromosome. PMID- 26494843 TI - Adaptive Evolution Is Substantially Impeded by Hill-Robertson Interference in Drosophila. AB - Hill-Robertson interference (HRi) is expected to reduce the efficiency of natural selection when two or more linked selected sites do not segregate freely, but no attempt has been done so far to quantify the overall impact of HRi on the rate of adaptive evolution for any given genome. In this work, we estimate how much HRi impedes the rate of adaptive evolution in the coding genome of Drosophila melanogaster. We compiled a data set of 6,141 autosomal protein-coding genes from Drosophila, from which polymorphism levels in D. melanogaster and divergence out to D. yakuba were estimated. The rate of adaptive evolution was calculated using a derivative of the McDonald-Kreitman test that controls for slightly deleterious mutations. We find that the rate of adaptive amino acid substitution at a given position of the genome is positively correlated to both the rate of recombination and the mutation rate, and negatively correlated to the gene density of the region. These correlations are robust to controlling for each other, for synonymous codon bias and for gene functions related to immune response and testes. We show that HRi diminishes the rate of adaptive evolution by approximately 27%. Interestingly, genes with low mutation rates embedded in gene poor regions lose approximately 17% of their adaptive substitutions whereas genes with high mutation rates embedded in gene rich regions lose approximately 60%. We conclude that HRi hampers the rate of adaptive evolution in Drosophila and that the variation in recombination, mutation, and gene density along the genome affects the HRi effect. PMID- 26494845 TI - Structured diet and physical activity programmes provide strong evidence of effectiveness for type 2 diabetes prevention and improvement of cardiometabolic health. PMID- 26494846 TI - No differences between operative and non-operative treatments of proximal humerus fractures. PMID- 26494847 TI - Universal Health Coverage's evolving location in the post-2015 development agenda: Key informant perspectives within multilateral and related agencies during the first phase of post-2015 negotiations. AB - In 2001, technocrats from four multilateral organizations selected the Millennium Development Goals mainly from the previous decade of United Nations (UN) summits and conferences. Few accounts are available of that significant yet cloistered synthesis process: none contemporaneous. In contrast, this study examines health's evolving location in the first-phase of the next iteration of global development goal negotiation for the post-2015 era, through the synchronous perspectives of representatives of key multilateral and related organizations. As part of the Go4Health Project, in-depth interviews were conducted in mid-2013 with 57 professionals working on health and the post-2015 agenda within multilaterals and related agencies. Using discourse analysis, this article reports the results and analysis of a Universal Health Coverage (UHC) theme: contextualizing UHC's positioning within the post-2015 agenda-setting process immediately after the Global Thematic Consultation on Health and High-Level Panel of Eminent Persons on the Post-2015 Development Agenda (High-Level Panel) released their post-2015 health and development goal aspirations in April and May 2013, respectively. After the findings from the interview data analysis are presented, the Results will be discussed drawing on Shiffman and Smith (Generation of political priority for global health initiatives: a framework and case study of maternal mortality.The Lancet2007; 370: : 1370-79) agenda-setting analytical framework (examining ideas, issues, actors and political context), modified by Benzianet al.(2011). Although more participants support the High Level Panel's May 2013 report's proposal-'Ensure Healthy Lives'-as the next umbrella health goal, they nevertheless still emphasize the need for UHC to achieve this and thus be incorporated as part of its trajectory. Despite UHC's conceptual ambiguity and cursory mention in the High-Level Panel report, its proponents suggest its re-emergence will occur in forthcoming State led post-2015 negotiations. However, the final post-2015 SDG framework for UN General Assembly endorsement in September 2015 confirms UHC's continued distillation in negotiations, as UHC ultimately became one of a litany of targets within the proposed global health goal. PMID- 26494848 TI - Recovery is about a focus on resilience and wellness, not a fixation with risk and illness. PMID- 26494849 TI - You say you want a revolution: Recovery, biomedicine and muddling through. PMID- 26494850 TI - Cognitive neuropsychological functioning in New Zealand Maori diagnosed with schizophrenia. AB - OBJECTIVE: Previous research suggests that New Zealand Maori may have an elevated rate of schizophrenia. However, there is limited evidence on important clinical features of the illness in this population. This study examined cognitive neuropsychological functioning in 54 adult Maori diagnosed with schizophrenia and 56 Maori controls. This study also examined associations between cognition, medication and symptoms of psychosis in the schizophrenia group. METHOD: The groups were matched on socio-demographic variables, handedness and premorbid cognitive ability. Participants were assessed on neuropsychological tests of attention, executive ability, motor, premorbid ability, verbal/non-verbal memory and verbal fluency (English/Maori versions). The Positive and Negative Syndrome Scale was used to assess psychotic symptoms. Information on cultural identity, duration of illness, duration of untreated psychosis, medication and substance abuse was collected. RESULTS: The performance of the schizophrenia group was significantly lower than the control group on all the neuropsychological tests, except the test of attention. The effect sizes were moderate to large: 0.78 for motor function; 1.3 for executive ability, verbal fluency and visual memory; 1.6 for verbal learning and 1.8 for verbal memory. These differences remained after adjustment for multiple comparisons and covariates. A higher dose of antipsychotic medication and a higher anticholinergic load were associated with greater verbal memory impairment (r = -0.38 and r = -0.38, respectively). A longer duration of illness was associated with greater impairment of verbal memory (rho = -0.48), verbal learning (rho = -0.41) and visual memory (rho = 0.44). CONCLUSION: The findings for the schizophrenia group show a profile of generalised cognitive impairment with greater impairment of verbal memory. The cognitive impairment in this group was independent of psychotic symptoms, but was associated with a higher antipsychotic dose, higher anticholinergic load and longer duration of illness. These findings have implications for clinical prescribing practices and rehabilitation for New Zealand Maori diagnosed with schizophrenia. PMID- 26494851 TI - Simulation versus lecture? Measuring educational impact: considerations for best practice. PMID- 26494852 TI - Familiarity and understanding of patients' religiosity and faith influence the level of comfort nurses and care workers feel when providing care. PMID- 26494853 TI - Lower Muscle Strength and Increased Visceral Fat Associated With No-reflow and High Gensini Score in STEMI. AB - BACKGROUND: The impact of fat distribution, muscle mass, and muscle strength on no-reflow and severity of coronary artery disease in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear. OBJECTIVE: To investigate association between muscle strength and fat and muscle mass and severity of coronary atherosclerosis. METHODS: We included 218 patients with STEMI who had undergone primary percutaneous coronary intervention. We evaluated the no-reflow phenomenon in infarct-related artery and calculated Gensini scores from initial angiograms as indicative of coronary atherosclerosis severity. The patients were divided into 2 groups as patients with no-reflow and with thrombolysis in myocardial infarction grade 3 flow and patients with low (<55) Gensini and with high (>=55) Gensini. Patients' total fat, muscle mass, visceral fat mass, and muscle strength were measured via body composition analyzer and handgrip dynamometer. RESULTS: High Gensini patients had a greater body mass index (BMI) and lower handgrip strength and more visceral fat ( P = .05, P = .017, and P < .001, respectively). The patients with no-reflow had significantly lower handgrip strength and more visceral fat (both, P < .001). In multivariate regression analysis, visceral fat and handgrip strength were associated with high no-reflow rate and high Gensini scores in patients with STEMI ( P = .001, P = .014, P = .022, and P = .010; respectively). CONCLUSION: Increased visceral fat and lower handgrip strength may be related to increased no-reflow rate and coronary plaque burden in STEMI. Visceral fat and muscle strength may be better prognostic markers than weight, BMI, total fat, and muscle mass in coronary artery disease. PMID- 26494854 TI - Seed Predators, not Herbivores, Exert Natural Selection on Solidago spp. in an Urban Archipelago. AB - The effects of urbanization on biodiversity are well established, as a growing city will reduce the size and diversity of patches of native plants. Recolonization of old patches and discovery of new ones by arthropod herbivores should occur as predicted by island biogeography theory. Although colonization represents an increase in biodiversity, such arrivals may exert new forms of natural selection on plants through herbivory and seed predation. Using a single species of old-field aster (Solidago altissima L.), we found that the level of natural selection by seed predators and herbivores follows patterns of island biogeography, with lower amounts of damage on smaller islands, where there are fewer species, and hypothetically smaller populations of arthropods. We also found that in an urban system, levels of herbivory are far below the tolerance levels of Solidago, and that seed predators are likely to be the only arthropod to cause reduced fitness. The pattern seen also implies that as a patch of Solidago grows through clonal expansion, it will come under higher selective pressure. PMID- 26494855 TI - Dissociating the neural mechanisms of pain consistency and pain intensity in the trigemino-nociceptive system. AB - BACKGROUND: Individual differences in pain perception to a standardized nociceptive input are a well-known phenomenon within pain research. Brain structures known to play a crucial role in pain modulatory processes are the rostral/subgenual anterior cingulate cortex (sACC) as well as the periaqueductal gray (PAG), which belong to the endogenous antinociceptive system. However, the exact mechanisms possibly leading to this high level of variance in pain perception are still a matter of debate. METHODS: Pain perception within the trigemino-vascular system was investigated in 37 healthy volunteers using functional magnetic resonance imaging. RESULTS: Behavioral results show high levels of variance being inversely correlated to mean pain ratings as well as to an increase in BOLD signal intensity within the sACC. In addition, higher sACC activation was coupled with activation in the PAG the lower the level of intra individual variance. CONCLUSION: This study gives first indications that coupled BOLD response within brain structures of the antinociceptive system seems to rather not code pain intensity within the trigemino-nociceptive system but the stability of volunteers' pain ratings. Intrinsic mechanisms may modulate the pain perception in the trigemino-vascular system, which is highly involved in headache disorders. PMID- 26494856 TI - High-Dose FOLFIRI plus Bevacizumab in the Treatment of Metastatic Colorectal Cancer Patients with Two Different UGT1A1 Genotypes: FFCD 0504 Study. AB - High-dose FOLFIRI has an acceptable safety profile and promising efficacy. UDP glucuronosyltransferase: (UGT1A1) polymorphism may be predictive of toxicity and efficacy of irinotecan. This phase II study aimed to evaluate the combination of high-dose FOLFIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer (MCRC) based on their UGT1A1 genotype. Patients with the UGT1A1 *1/*1 (group 1) or *1/*28 (group 2) genotype received bevacizumab plus high-dose FOLFIRI every 2 weeks. Using the Bryant and Day design with objective response rate and toxicity as the primary endpoints, 54 patients in each group were required with a planned interim analysis after inclusion of 17 patients per group. We planned to stop the trial at the interim analysis if <= 7 patients exhibited an objective response (OR) and/or >= 3 patients exhibited severe toxicity. At the interim analysis, ORs were higher than the number expected: 52.9% (group 1) and 58.8% (group 2). More than three toxic events occurred in both groups and, according to the interim analysis rule, the trial was closed due to unacceptable toxicity. Recruitment was stopped when 86 patients were included and an analysis on overall population was done for overall survival (OS) and progression-free survival (PFS). The median PFS was 10.7 months (group 1) and 10.4 months (group 2). The median OS was 25.5 months (group 1) and 23.9 months (group 2). This trial does not support the use of the intensive treatment with HD FOLFIRI plus bevacizumab combination for MCRC in patients with the UGTA1*1/UGT1A1*1 or UGT1A1*1/UGT1A1*28 genotype. PMID- 26494857 TI - Bevacizumab-Induced Inhibition of Angiogenesis Promotes a More Homogeneous Intratumoral Distribution of Paclitaxel, Improving the Antitumor Response. AB - The antitumor activity of angiogenesis inhibitors is reinforced in combination with chemotherapy. It is debated whether this potentiation is related to a better drug delivery to the tumor due to the antiangiogenic effects on tumor vessel phenotype and functionality. We addressed this question by combining bevacizumab with paclitaxel on A2780-1A9 ovarian carcinoma and HT-29 colon carcinoma transplanted ectopically in the subcutis of nude mice and on A2780-1A9 and IGROV1 ovarian carcinoma transplanted orthotopically in the bursa of the mouse ovary. Paclitaxel concentrations together with its distribution by MALDI mass spectrometry imaging (MALDI MSI) were measured to determine the drug in different areas of the tumor, which was immunostained to depict vessel morphology and tumor proliferation. Bevacizumab modified the vessel bed, assessed by CD31 staining and dynamic contrast enhanced MRI (DCE-MRI), and potentiated the antitumor activity of paclitaxel in all the models. Although tumor paclitaxel concentrations were lower after bevacizumab, the drug distributed more homogeneously, particularly in vascularized, non-necrotic areas, and was cleared more slowly than controls. This happened specifically in tumor tissue, as there was no change in paclitaxel pharmacokinetics or drug distribution in normal tissues. In addition, the drug concentration and distribution were not influenced by the site of tumor growth, as A2780-1A9 and IGROV1 growing in the ovary gave results similar to the tumor growing subcutaneously. We suggest that the changes in the tumor microenvironment architecture induced by bevacizumab, together with the better distribution of paclitaxel, may explain the significant antitumor potentiation by the combination. PMID- 26494858 TI - The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo. AB - Despite recent advances in the development of novel therapies against castration resistant prostate cancer, the advanced form of the disease remains a major treatment challenge. Aberrant sphingolipid signaling through sphingosine kinases and their product, sphingosine-1-phosphate, can promote proliferation, drug resistance, angiogenesis, and inflammation. The sphingosine kinase 2 inhibitor ABC294640 is undergoing clinical testing in cancer patients, and in this study we investigated the effects this first-in-class inhibitor in castration-resistant prostate cancer. In vitro, ABC294640 decreased prostate cancer cell viability as well as the expression of c-Myc and the androgen receptor, while lysosomal acidification increased. ABC294640 also induced a greater than 3-fold increase in dihydroceramides that inversely correlated with inhibition of dihydroceramide desaturase (DEGS) activity. Expression of sphingosine kinase 2 was dispensable for the ABC294640-mediated increase in dihydroceramides. In vivo, ABC294640 diminished the growth rate of TRAMP-C2 xenografts in syngeneic hosts and elevated dihydroceramides within tumors as visualized by MALDI imaging mass spectroscopy. The plasma of ABC294640-treated mice contained significantly higher levels of C16 and C24:1-ceramides (but not dihydro-C16-ceramide) compared with vehicle-treated mice. In summary, our results suggest that ABC294640 may reduce the proliferative capacity of castration-resistant prostate cancer cells through inhibition of both sphingosine kinase 2 and dihydroceramide desaturase, thereby providing a foundation for future exploration of this small-molecule inhibitor for the treatment of advanced disease. PMID- 26494860 TI - Lifestyle Methods for Prevention of Alzheimer's Disease From the Perspective of Traditional Persian Medicine. AB - Alzheimer's disease is considered as a major problem for society health since it affects interpersonal and social relationships. With regard to the global attention toward complementary medicine, search for preventive, diagnostic, and treatment strategies in complementary medicine schools such as the old dynamic doctrine of traditional Persian medicine seems to be necessary. In this type of medicine, description and analysis of the disease and preventive and treatment methods have great importance. The present study provides a useful classification of recommendations for prevention and control of Alzheimer's disease. Prevention is prior to the treatment and is easier and less costly. Recommendations mentioned in traditional Persian medicine texts for prevention of Alzheimer's disease provide fields of clinical and complementary studies for researches. PMID- 26494861 TI - Bitopic Sphingosine 1-Phosphate Receptor 3 (S1P3) Antagonist Rescue from Complete Heart Block: Pharmacological and Genetic Evidence for Direct S1P3 Regulation of Mouse Cardiac Conduction. AB - The molecular pharmacology of the G protein-coupled receptors for sphingosine 1 phosphate (S1P) provides important insight into established and new therapeutic targets. A new, potent bitopic S1P3 antagonist, SPM-354, with in vivo activity, has been used, together with S1P3-knockin and S1P3-knockout mice to define the spatial and functional properties of S1P3 in regulating cardiac conduction. We show that S1P3 is a key direct regulator of cardiac rhythm both in vivo and in isolated perfused hearts. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in vivo and S1P in isolated hearts induced a spectrum of cardiac effects, ranging from sinus bradycardia to complete heart block, as measured by a surface electrocardiogram in anesthetized mice and in volume-conducted Langendorff preparations. The agonist effects on complete heart block are absent in S1P3 knockout mice and are reversed in wild-type mice with SPM-354, as characterized and described here. Homologous knockin of S1P3-mCherry is fully functional pharmacologically and is strongly expressed by immunohistochemistry confocal microscopy in Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4)-positive atrioventricular node and His-Purkinje fibers, with relative less expression in the HCN4-positive sinoatrial node. In Langendorff studies, at constant pressure, SPM-354 restored sinus rhythm in S1P-induced complete heart block and fully reversed S1P-mediated bradycardia. S1P3 distribution and function in the mouse ventricular cardiac conduction system suggest a direct mechanism for heart block risk that should be further studied in humans. A richer understanding of receptor and ligand usage in the pacemaker cells of the cardiac system is likely to be useful in understanding ventricular conduction in health, disease, and pharmacology. PMID- 26494862 TI - Genomically Incorporated 5-Fluorouracil that Escapes UNG-Initiated Base Excision Repair Blocks DNA Replication and Activates Homologous Recombination. AB - 5-Fluorouracil (5-FU) and its metabolite 5-fluorodeoxyuridine (FdUrd, floxuridine) are chemotherapy agents that are converted to 5-fluorodeoxyuridine monophosphate (FdUMP) and 5-fluorodeoxyuridine triphosphate (FdUTP). FdUMP inhibits thymidylate synthase and causes the accumulation of uracil in the genome, whereas FdUTP is incorporated by DNA polymerases as 5-FU in the genome; however, it remains unclear how either genomically incorporated U or 5-FU contributes to killing. We show that depletion of the uracil DNA glycosylase (UNG) sensitizes tumor cells to FdUrd. Furthermore, we show that UNG depletion does not sensitize cells to the thymidylate synthase inhibitor (raltitrexed), which induces uracil but not 5-FU accumulation, thus indicating that genomically incorporated 5-FU plays a major role in the antineoplastic effects of FdUrd. We also show that 5-FU metabolites do not block the first round of DNA synthesis but instead arrest cells at the G1/S border when cells again attempt replication and activate homologous recombination (HR). This arrest is not due to 5-FU lesions blocking DNA polymerase delta but instead depends, in part, on the thymine DNA glycosylase. Consistent with the activation of HR repair, disruption of HR sensitized cells to FdUrd, especially when UNG was disabled. These results show that 5-FU lesions that escape UNG repair activate HR, which promotes cell survival. PMID- 26494859 TI - Potentiation of Carboplatin-Mediated DNA Damage by the Mdm2 Modulator Nutlin-3a in a Humanized Orthotopic Breast-to-Lung Metastatic Model. AB - Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73alpha and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73alpha. Following combination treatment, gammaH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC. PMID- 26494863 TI - An unusual complication of coronary angiography via the radial approach. PMID- 26494864 TI - An unusual cause of left ventricular hypertrophy. PMID- 26494865 TI - Ischaemic perforation of the free left ventricular wall covered by pericardial adhesion as an incidental finding in a patient presenting with acute cerebral ischaemia. PMID- 26494866 TI - Recent advances in natural orifice transluminal endoscopic surgery?. AB - Natural orifice transluminal endoscopic surgery (NOTES) has emerged as one of the most exciting areas in the field of minimally invasive surgery during the last decade. NOTES comprises a wide spectrum of procedures from various natural accesses such as transgastric or transvaginal routes, and different direct-target or distant-target organs. Since polypectomy was first performed in 1955, major advances in technology and refinement of endoscopic technique have allowed endoscopic surgeons to perform complex endoscopic interventions such as endoscopic submucosal dissection. Recognizing the safety and feasibility of submucosal tunnelling and mucosal closure, endoscopic resection beyond the level of mucosa has been increasingly reported. One of these procedures, peroral endoscopic myotomy for achalasia, has gained much popularity and excellent results have been published comparable with that of traditional Heller's cardiomyotomy. Submucosal tunnelling endoscopic resection has also been reported for tumours situated in the muscular layer of the gastrointestinal tract. To overcome the difficulty of intestinal closure after NOTES, researchers have collaborated with the industry in developing different endoscopic suturing devices such as the Eagle Claw (Olympus Medical Systems, Tokyo, Japan) and OverstitchTM (Apollo Endosurgery, Austin TX, USA). These devices allow precise and secure suture application with the ordinary flexible endoscope, achieving tissue approximation similar to open surgical suturing. To further expand the potential of NOTES, investigators had also developed multitasking platforms enabling the performance of surgical procedures of even higher complexity. Recently, a novel endoscopic robotic system 'Master and Slave Transluminal Endoscopic Robot' (MASTER) has been developed. Early results of endoscopic resection utilizing this system have been encouraging, allowing both experts and novices in endoscopy to perform difficult endoscopic resection with a high degree of flexibility. PMID- 26494867 TI - Decellularization of aortic valves: only time will tell. PMID- 26494868 TI - Acute intermittent porphyria: comorbidity and shared familial risks with schizophrenia and bipolar disorder in Sweden. AB - Acute intermittent porphyria (AIP) has been associated with schizophrenia in some studies, but prior research is limited by the absence of comparison populations. Here, we linked Swedish registers to examine the risk of schizophrenia and bipolar disorder in 717 individuals diagnosed with AIP and their first-degree relatives, compared with matched individuals without AIP and their first-degree relatives. Individuals with AIP had a fourfold increased risk of schizophrenia or bipolar disorder. Similarly, relatives of individuals with AIP had double the risk of schizophrenia or bipolar disorder, suggesting that these associations may be as a result of common genetic influences. PMID- 26494869 TI - Differential effects of ethnic density on the risk of postnatal depression and personality dysfunction. AB - BACKGROUND: The relationship between ethnic density and psychiatric disorder in postnatal women in the UK is unclear. AIMS: To examine the effect of own and overall ethnic density on postnatal depression (PND) and personality dysfunction. METHOD: Multilevel analysis of ethnically mixed community-level data gathered from a sample of 2262 mothers screened at 6 weeks postpartum for PND and personality dysfunction. RESULTS: Living in areas of higher own ethnic density was protective against screening positive for PND in White women (z = -3.18, P = 0.001), even after adjusting for area level deprivation, maternal age, relationship status, screening positive for personality dysfunction, parity and geographical clustering (odds ratio (OR) 0.98 (95% CI 0.96-0.99); P = 0.002), whereas the effect on personality dysfunction (z = -2.42, P = 0.016) was no longer present once the effect of PND was taken into account (OR = 0.99 (95% CI 0.90-1.0); P = 0.13). No overall ethnic density effect was found for women screening positive for PND or personality dysfunction. CONCLUSIONS: In White women, living in areas of higher own ethnic density was protective against developing PND. PMID- 26494870 TI - Aetiological overlap between obsessive-compulsive related and anxiety disorder symptoms: multivariate twin study. AB - BACKGROUND: The aetiological boundary between obsessive-compulsive related disorders (OCRDs) including obsessive-compulsive disorder (OCD) and anxiety disorders is unclear and continues to generate debate. AIMS: To determine the genetic overlap and the pattern of causal relationships among OCRDs and anxiety disorders. METHOD: Multivariate twin modelling methods and a new regression analysis to infer causation were used, involving 2495 male and female twins. RESULTS: The amount of common genetic liability observed for OCD symptoms was higher when considering anxiety disorders and OCRDs in the model v. modelling OCRD symptoms alone. OCD symptoms emerged as risk factors for the presence of generalised anxiety, panic and hoarding symptoms, whereas social phobia appeared as a risk factor for OCD symptoms. CONCLUSIONS: OCD represents a complex phenotype that includes important shared features with anxiety disorders and OCRDs. The novel patterns of risk identified between OCD and anxiety disorder may help to explain their frequent co-occurrence. PMID- 26494871 TI - Postnatal paternal depressive symptoms associated with fathers' subsequent parenting: findings from the Millennium Cohort Study. AB - Impaired parenting may lie on the causal pathway between paternal depression and children's outcomes. We use the first four surveys of the Millennium Cohort Study to investigate the association between paternal depressive symptoms and fathers' parenting (negative, positive and involvement). Findings suggest that postnatal paternal depressive symptoms are associated with fathers' negative parenting. This has implications for the design of intervention programmes for parents with depression and young children. PMID- 26494872 TI - Amygdala response to self-critical stimuli and symptom improvement in psychotherapy for depression. AB - BACKGROUND: Cognitive-behavioural therapy is efficacious in the treatment of major depressive disorder but response rates are still far from satisfactory. AIMS: To better understand brain responses to individualised emotional stimuli and their association with outcome, to enhance treatment. METHOD: Functional magnetic resonance imaging data were collected prior to individual psychotherapy. Differences in brain activity during passive viewing of individualised self critical material in 23 unmedicated out-patients with depression and 28 healthy controls were assessed. The associations between brain activity, cognitive and emotional change, and outcome were analysed in 21 patients. RESULTS: Patients showed enhanced activity in the amygdala and ventral striatum compared with the control group. Non-response to therapy was associated with enhanced activity in the right amygdala compared with those who responded, and activity in this region was negatively associated with outcome. Emotional but not cognitive changes mediated this association. CONCLUSIONS: Amygdala hyperactivity may lessen symptom improvement in psychotherapy for depression through attenuating emotional skill acquisition. PMID- 26494873 TI - Effects of the MAOA gene and levels of exposure to violence on antisocial outcomes. AB - BACKGROUND: The monoamine oxidase A (MAOA) gene has been shown to moderate the impact of maltreatment on antisocial behaviour. Replication efforts have, however, yielded inconsistent results. AIMS: To investigate whether the interaction between the MAOA gene and violence is present across the full distribution of violence or emerges at higher levels of exposure. METHOD: Participants were 327 male members of the Quebec Longitudinal Study of Kindergarten Children. Exposure to violence comprised retrospective reports of mother's and father's maltreatment, sexual and physical abuse. Conduct disorder and antisocial personality symptoms were assessed in semi-structured interviews and partner violence, property-violent crimes and arrest were self-reported. RESULTS: Non-linear interactions between the MAOA gene and violence were detected, suggesting that the genetic moderation may come about once a certain level of violence is experienced. CONCLUSIONS: Future studies should investigate the mechanisms translating substantial violence exposure, which could, subsequently, trigger the expression of genetically based differences in antisocial behaviour. PMID- 26494874 TI - Suicides during pregnancy and 1 year postpartum in Sweden, 1980-2007. AB - BACKGROUND: Although the incidence of suicide among women who have given birth during the past 12 months is lower than that of women who have not given birth, suicide remains one of the most common causes of death during the year following delivery in high-income countries, such as Sweden. AIMS: To characterise women who died by suicide during pregnancy and postpartum from a maternal care perspective. METHOD: We traced deaths (n = 103) through linkage of the Swedish Cause of Death Register with the Medical Birth and National Patient Registers. We analysed register data and obstetric medical records. RESULTS: The maternal suicide ratio was 3.7 per 100 000 live births for the period 1980-2007, with small magnitude variation over time. The suicide ratio was higher in women born in low-income countries (odds ratio 3.1 (95% CI 1.3-7.7)). Violent suicide methods were common, especially during the first 6 months postpartum. In all, 77 women had received psychiatric care at some point, but 26 women had no documented psychiatric care. Antenatal documentation of psychiatric history was inconsistent. At postpartum discharge, only 20 women had a plan for psychiatric follow-up. CONCLUSIONS: Suicide prevention calls for increased clinical awareness and cross-disciplinary maternal care approaches to identify and support women at risk. PMID- 26494875 TI - The Healthy Activity Program lay counsellor delivered treatment for severe depression in India: systematic development and randomised evaluation. AB - BACKGROUND: Reducing the global treatment gap for mental disorders requires treatments that are economical, effective and culturally appropriate. AIMS: To describe a systematic approach to the development of a brief psychological treatment for patients with severe depression delivered by lay counsellors in primary healthcare. METHOD: The treatment was developed in three stages using a variety of methods: (a) identifying potential strategies; (b) developing a theoretical framework; and (c) evaluating the acceptability, feasibility and effectiveness of the psychological treatment. RESULTS: The Healthy Activity Program (HAP) is delivered over 6-8 sessions and consists of behavioral activation as the core psychological framework with added emphasis on strategies such as problem-solving and activation of social networks. Key elements to improve acceptability and feasibility are also included. In an intention-to-treat analysis of a pilot randomised controlled trial (55 participants), the prevalence of depression (Beck Depression Inventory II ?19) after 2 months was lower in the HAP than the control arm (adjusted risk ratio = 0.55, 95% CI 0.32-0.94,P= 0.01). CONCLUSIONS: Our systematic approach to the development of psychological treatments could be extended to other mental disorders. HAP is an acceptable and effective brief psychological treatment for severe depression delivered by lay counsellors in primary care. PMID- 26494876 TI - Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure. AB - OBJECTIVE: Many patients with primary adrenal insufficiency (Addison's disease) take extra doses of glucocorticoids during stressful events, but a benefit has not been demonstrated in controlled trials. Here, we investigated the effects of a pre-exercise hydrocortisone dose on cardiorespiratory, hormonal and metabolic parameters in response to short-term strenuous physical activity. DESIGN: This was a randomized placebo-controlled, two-week cross-over clinical trial. PARTICIPANTS: Ten women with Addison's disease and 10 age-matched healthy females participated in the study. MEASUREMENTS: All women in the study underwent maximal incremental exercise testing. A stress dose of 10 mg hydrocortisone or placebo was given 1 h prior to exercise on two occasions. Blood samples were drawn before, and 0, 15 and 30 min post exercise. Oxygen uptake, maximal aerobic capacity, endocrine and metabolic responses to physical activity, as well as health status by questionnaires were evaluated. RESULTS: Maximal aerobic capacity and duration of exercise were significantly lower in patients than in healthy subjects and did not improve with the treatment. After an extra hydrocortisone dose serum cortisol was significantly higher than in the healthy subjects (P<0.001). Post-exercise glucose and adrenaline levels were significantly lower and free fatty acids insignificantly higher in patients irrespective of stress dose. Stress dosing did not alter other metabolic or hormonal parameters or quality of life after the exercise. CONCLUSIONS: The patients did not benefit from an extra dose of hydrocortisone in short strenuous exercise. Stress dosing may not be justified in this setting. Whether stress dosing is beneficial in other types of physical activity will have to be examined further. PMID- 26494878 TI - 'Encouraging trends' in use of antibiotics. PMID- 26494877 TI - Multi-centre validation of an automatic algorithm for fast 4D myocardial segmentation in cine CMR datasets. AB - AIMS: Quantitative analysis of cine cardiac magnetic resonance (CMR) images for the assessment of global left ventricular morphology and function remains a routine task in clinical cardiology practice. To date, this process requires user interaction and therefore prolongs the examination (i.e. cost) and introduces observer variability. In this study, we sought to validate the feasibility, accuracy, and time efficiency of a novel framework for automatic quantification of left ventricular global function in a clinical setting. METHODS AND RESULTS: Analyses of 318 CMR studies, acquired at the enrolment of patients in a multi centre imaging trial (DOPPLER-CIP), were performed automatically, as well as manually. For comparative purposes, intra- and inter-observer variability was also assessed in a subset of patients. The extracted morphological and functional parameters were compared between both analyses, and time efficiency was evaluated. The automatic analysis was feasible in 95% of the cases (302/318) and showed a good agreement with manually derived reference measurements, with small biases and narrow limits of agreement particularly for end-diastolic volume ( 4.08 +/- 8.98 mL), end-systolic volume (1.18 +/- 9.74 mL), and ejection fraction (-1.53 +/- 4.93%). These results were comparable with the agreement between two independent observers. A complete automatic analysis took 5.61 +/- 1.22 s, which is nearly 150 times faster than manual contouring (14 +/- 2 min, P < 0.05). CONCLUSION: The proposed automatic framework provides a fast, robust, and accurate quantification of relevant left ventricular clinical indices in 'real world' cine CMR images. PMID- 26494879 TI - US government to build an AI vaccine stockpile. PMID- 26494880 TI - Wildfowl implicated in Lancashire AI outbreak. PMID- 26494881 TI - Defra revises notifiable avian disease strategy. PMID- 26494882 TI - Royal opening for Surrey veterinary school. PMID- 26494883 TI - Case studies show how UK research contributes to global development. PMID- 26494884 TI - 150 years of the state veterinary service. PMID- 26494885 TI - 'Great year' for zoo masters course. PMID- 26494886 TI - Corporate group invests in veterinary specialist services. PMID- 26494887 TI - Blue plaque commemorates pioneering veterinary scientist. PMID- 26494888 TI - Jack Russell terrier to join pedigree list. PMID- 26494889 TI - Dog friendly business award. PMID- 26494890 TI - AVTRW conference aims to please early career researchers. PMID- 26494891 TI - Promoting evidence-based veterinary medicine. PMID- 26494892 TI - Sheep scab remains a problem. PMID- 26494893 TI - Determining the impact of badger culling on the incidence of TB in cattle. PMID- 26494895 TI - Shortage of experienced vets. PMID- 26494894 TI - Tail biting in calves. PMID- 26494896 TI - Claw trimming of dairy cattle. PMID- 26494897 TI - Licence variations regarding tiludronate disodium. PMID- 26494898 TI - Methods of rabbit identification. PMID- 26494899 TI - Dairy vet with global experience. PMID- 26494900 TI - Excess mortality for operated geriatric hip fracture in Hong Kong. AB - INTRODUCTION: Geriatric hip fracture places an increasing burden to health care systems around the world. We studied the latest epidemiology trend of geriatric hip fracture in Hong Kong, as well as the excess mortality for patients who had undergone surgery for hip fracture. METHODS: This descriptive epidemiology study was conducted in the public hospitals in Hong Kong. All patients who underwent surgery for geriatric hip fracture in public hospitals from January 2000 to December 2011 were studied. They were retrieved from the Clinical Management System of the Hospital Authority of Hong Kong. Relevant data were collected using the Clinical Data Analysis and Reporting System of the Hospital Authority. The actual and projected population size, and the age- and sex-specific mortality rates were obtained from the Census and Statistics Department of Hong Kong. The 30-day, 1-year and 5-year mortality, and excess mortality following surgery for geriatric hip fracture were calculated. RESULTS: There was a steady increase in the incidence of geriatric hip fracture in Hong Kong. The annual risk of geriatric hip fracture was decreasing in both sexes. Female patients aged 65 to 69 years had the lowest 1-year and 5-year mortality of 6.91% and 23.80%, respectively. Advancing age and male sex were associated with an increase in mortality and a higher excess mortality rate following surgery. CONCLUSION: The incidence of geriatric hip fracture is expected to increase in the future. The exact reason for a higher excess mortality rate in male patients remains unclear and should be the direction for future studies. PMID- 26494901 TI - Genome-wide genetic homogeneity between sexes and populations for human height and body mass index. AB - Sex-specific genetic effects have been proposed to be an important source of variation for human complex traits. Here we use two distinct genome-wide methods to estimate the autosomal genetic correlation (rg) between men and women for human height and body mass index (BMI), using individual-level (n = ~44 000) and summary-level (n = ~133 000) data from genome-wide association studies. Results are consistent and show that the between-sex genetic correlation is not significantly different from unity for both traits. In contrast, we find evidence of genetic heterogeneity between sexes for waist-hip ratio (rg = ~0.7) and between populations for BMI (rg = ~0.9 between Europe and the USA) but not for height. The lack of evidence for substantial genetic heterogeneity for body size is consistent with empirical findings across traits and species. PMID- 26494903 TI - Differential effects on beta-cell mass by disruption of Bardet-Biedl syndrome or Alstrom syndrome genes. AB - Rare genetic syndromes characterized by early-onset type 2 diabetes have revealed the importance of pancreatic beta-cells in genetic susceptibility to diabetes. However, the role of genetic regulation of beta-cells in disorders that are also characterized by highly penetrant obesity, a major additional risk factor, is unclear. In this study, we investigated the contribution of genes associated with two obesity ciliopathies, Bardet-Biedl Syndrome and Alstrom Syndrome, to the production and maintenance of pancreatic beta-cells. Using zebrafish models of these syndromes, we identified opposing effects on production of beta-cells. Loss of the Alstrom gene, alms1, resulted in a significant decrease in beta-cell production whereas loss of BBS genes, bbs1 or bbs4, resulted in a significant increase. Examination of the regulatory program underlying beta-cell production suggested that these effects were specific to beta-cells. In addition to the initial production of beta-cells, we observed significant differences in their continued maintenance. Under prolonged exposure to high glucose conditions, alms1 deficient beta-cells were unable to continually expand as a result of decreased proliferation and increased cell death. Although bbs1-deficient beta-cells were similarly susceptible to apoptosis, the overall maintenance of beta-cell number in those animals was sustained likely due to increased proliferation. Taken together, these findings implicate discrepant production and maintenance of beta cells in the differential susceptibility to diabetes found between these two genetic syndromes. PMID- 26494904 TI - Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes. AB - Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kinase inhibitors (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) for their activity against FGFR signaling in chondrocytes. All five TKIs strongly inhibited FGFR activation in cultured chondrocytes and limb rudiment cultures, completely relieving FGFR-mediated inhibition of chondrocyte proliferation and maturation. In contrast, TKI treatment of newborn mice did not improve skeletal growth and had lethal toxic effects on the liver, lungs and kidneys. In cell-free kinase assays as well as in vitro and in vivo cell assays, none of the tested TKIs demonstrated selectivity for FGFR3 over three other FGFR tyrosine kinases. In addition, the TKIs exhibited significant off-target activity when screened against a panel of 14 unrelated tyrosine kinases. This was most extensive in SU5402 and AZD1480, which inhibited DDR2, IGF1R, FLT3, TRKA, FLT4, ABL and JAK3 with efficiencies similar to or greater than those for FGFR. Low target specificity and toxicity of FGFR TKIs thus compromise their use for treatment of ACH. Conceptually, different avenues of therapeutic FGFR3 targeting should be investigated. PMID- 26494902 TI - Combinatorial therapeutic activation with heparin and AICAR stimulates additive effects on utrophin A expression in dystrophic muscles. AB - Upregulation of utrophin A is an attractive therapeutic strategy for treating Duchenne muscular dystrophy (DMD). Over the years, several studies revealed that utrophin A is regulated by multiple transcriptional and post-transcriptional mechanisms, and that pharmacological modulation of these pathways stimulates utrophin A expression in dystrophic muscle. In particular, we recently showed that activation of p38 signaling causes an increase in the levels of utrophin A mRNAs and protein by decreasing the functional availability of the destabilizing RNA-binding protein called K-homology splicing regulatory protein, thereby resulting in increases in the stability of existing mRNAs. Here, we treated 6 week-old mdx mice for 4 weeks with the clinically used anticoagulant drug heparin known to activate p38 mitogen-activated protein kinase, and determined the impact of this pharmacological intervention on the dystrophic phenotype. Our results show that heparin treatment of mdx mice caused a significant ~1.5- to 3-fold increase in utrophin A expression in diaphragm, extensor digitorum longus and tibialis anterior (TA) muscles. In agreement with these findings, heparin-treated diaphragm and TA muscle fibers showed an accumulation of utrophin A and beta dystroglycan along their sarcolemma and displayed improved morphology and structural integrity. Moreover, combinatorial drug treatment using both heparin and 5-amino-4-imidazolecarboxamide riboside (AICAR), the latter targeting 5' adenosine monophosphate-activated protein kinase and the transcriptional activation of utrophin A, caused an additive effect on utrophin A expression in dystrophic muscle. These findings establish that heparin is a relevant therapeutic agent for treating DMD, and illustrate that combinatorial treatment of heparin with AICAR may serve as an effective strategy to further increase utrophin A expression in dystrophic muscle via activation of distinct signaling pathways. PMID- 26494906 TI - Specialist support for hand surgery research. PMID- 26494905 TI - Hypomorphic mutations in TRNT1 cause retinitis pigmentosa with erythrocytic microcytosis. AB - Retinitis pigmentosa (RP) is a highly heterogeneous group of disorders characterized by degeneration of the retinal photoreceptor cells and progressive loss of vision. While hundreds of mutations in more than 100 genes have been reported to cause RP, discovering the causative mutations in many patients remains a significant challenge. Exome sequencing in an individual affected with non-syndromic RP revealed two plausibly disease-causing variants in TRNT1, a gene encoding a nucleotidyltransferase critical for tRNA processing. A total of 727 additional unrelated individuals with molecularly uncharacterized RP were completely screened for TRNT1 coding sequence variants, and a second family was identified with two members who exhibited a phenotype that was remarkably similar to the index patient. Inactivating mutations in TRNT1 have been previously shown to cause a severe congenital syndrome of sideroblastic anemia, B-cell immunodeficiency, recurrent fevers and developmental delay (SIFD). Complete blood counts of all three of our patients revealed red blood cell microcytosis and anisocytosis with only mild anemia. Characterization of TRNT1 in patient-derived cell lines revealed reduced but detectable TRNT1 protein, consistent with partial function. Suppression of trnt1 expression in zebrafish recapitulated several features of the human SIFD syndrome, including anemia and sensory organ defects. When levels of trnt1 were titrated, visual dysfunction was found in the absence of other phenotypes. The visual defects in the trnt1-knockdown zebrafish were ameliorated by the addition of exogenous human TRNT1 RNA. Our findings indicate that hypomorphic TRNT1 mutations can cause a recessive disease that is almost entirely limited to the retina. PMID- 26494907 TI - Commentary on Minimal important changes and differences in elective hand surgery. J. N. Rodrigues, N. T. Mabvuure, D. Nikkhah, Z. Shariff and T. R. C. Davis. J Hand Surg Eur. 2015, 40: 900-12. PMID- 26494908 TI - Commentary on The health technology assessment of the compulsory accident insurance scheme of hand transplantation in Switzerland. Brugger et al. J Hand Surg Eur. 2015, 40: 914-23. PMID- 26494909 TI - Commentary on Scaffolds for hand tissue engineering: the importance of surface topography. E. Kloczko, D. Nikkhah and L. Yildirimer. J Hand Surg Eur. 2015, 40: 973-85. PMID- 26494910 TI - Re: Goutos I, Cogswell LK, Giele H. Extravasation injuries: a review. J Hand Surg Eur. 2014, 39: 808-18. PMID- 26494913 TI - PHOTO QUIZ. An Infant With Purpuric Rash and Edema. PMID- 26494915 TI - So you know how to treat iron deficiency anemia. AB - In this issue of Blood, Moretti et al provide data that challenge the entrenched oral treatment of iron deficiency anemia. The paper shows how the newer understanding of hepcidin and iron metabolism in general can lead to very practical improvements in the management of iron deficiency anemia, a disorder that may affect as many as 1 billion people. PMID- 26494916 TI - Hypoxia-recruited angiogenic neutrophils. AB - In this issue of Blood, Massena et al identify a novel CD49d+CXCR4highVEGFR1high population of neutrophils that specifically migrate to sites of hypoxia and enhance angiogenesis. PMID- 26494917 TI - Paris-Trousseau: evidence keeps pointing to FLI1. AB - In this issue of Blood, Stevenson et al describe a family with a homozygous missense mutation in FLI1 that is associated with a platelet phenotype identical to the one observed in Paris-Trousseau syndrome, supporting existing evidence that FLI1 is directly involved in the mechanism of thrombocytopenia observed in this disease. PMID- 26494918 TI - Erythroferrone: the missing link in beta-thalassemia? AB - In this issue of Blood, Kautz et al show that the ablation of the erythroid derived factor erythroferrone (ERFE), which has been shown to be highly expressed in beta-thalassemic mice, restores hepcidin levels and corrects iron overload. However, correction of hepcidin levels in those mice does not improve anemia of beta-thalassemia. PMID- 26494919 TI - rVWF: treatment finally reaches the modern age. AB - In this issue of Blood, Gill et al describe the results of the first phase 3 clinical trial evaluating recombinant von Willebrand factor (rVWF) for the treatment of hemorrhagic events in all patients with von Willebrand disease (VWD). PMID- 26494920 TI - Not fibrin(ogen), but fibrinogen or fibrin. AB - In this issue of Blood, Prasad et al describe a mouse model with a mutation in the Aalpha chain of fibrinogen such that no fibrin polymer is formed in vivo, allowing for the first time the differentiation of the role of fibrinogen vs fibrin oligomer or polymer in antimicrobial host defense and in hemostasis/thrombosis. PMID- 26494921 TI - No CLL transmission through blood transfusion. AB - In this issue of Blood, Hjalgrim et al used the Scandinavian Donations and Transfusions (SCANDAT2) database, which includes comprehensive information on donors and recipients of >20 million blood products handled by the Danish and Swedish blood banks between 1968 and 2010, to address the clinically relevant question of whether chronic lymphocytic leukemia (CLL) is transmitted through blood transfusions. PMID- 26494922 TI - SNOs Differ: Methodological and Biological Implications. PMID- 26494923 TI - The Good and the Bad: Immune Cells and Hypertension. PMID- 26494925 TI - Corrigendum to Serum milk fat globule epidermal growth factor 8 elevation may subdivide systemic lupus erythematosus into two pathophysiologically distinct subsets. AB - This article was published in Lupus 2014; 23: 386-394, DOI: 10.1177/0961203314523870, by N Yamamoto et al. PMID- 26494924 TI - Hippo and Cardiac Hypertrophy: A Complex Interaction. PMID- 26494926 TI - Estimation of Dynamic Discrete Choice Models by Maximum Likelihood and the Simulated Method of Moments. AB - We compare the performance of maximum likelihood (ML) and simulated method of moments (SMM) estimation for dynamic discrete choice models. We construct and estimate a simplified dynamic structural model of education that captures some basic features of educational choices in the United States in the 1980s and early 1990s. We use estimates from our model to simulate a synthetic dataset and assess the ability of ML and SMM to recover the model parameters on this sample. We investigate the performance of alternative tuning parameters for SMM. PMID- 26494927 TI - Applying mathematical concepts with hands-on, food-based science curriculum. AB - This article addresses the current state of the mathematics education system in the United States and provides a possible solution to the contributing issues. As a result of lower performance in primary mathematics, American students are not acquiring the necessary quantitative literacy skills to become successful adults. This study analyzed the impact of the FoodMASTER Intermediate curriculum on fourth-grade student's mathematics knowledge. The curriculum is a part of the FoodMASTER Initiative, which is a compilation of programs utilizing food, a familiar and necessary part of everyday life, as a tool to teach mathematics and science. Students exposed to the curriculum completed a 20-item researcher developed mathematics knowledge exam (Intervention n=288; Control n=194). Overall, the results showed a significant increase in mathematics knowledge from pre- to post-test. These findings suggest that students engaged in food-based science activities provided them with the context in which to apply mathematical concepts to an everyday experience. Therefore, the FoodMASTER approach was successful at improving students' mathematics knowledge while building a foundation for becoming quantitatively literate adults. PMID- 26494928 TI - Structures, semisyntheses, and absolute configurations of the antiplasmodial alpha-substituted beta-lactam monamphilectines B and C from the sponge Svenzea flava. AB - Bioassay-guided fractionation of the Caribbean sponge Svenzea flava collected near Mona Island, off the west coast of Puerto Rico, led to the isolation of two isocyanide amphilectane-type diterpenes named monamphilectines B and C (2 and 3). Attached to the backbone of each of these compounds is the first alpha substituted monocyclic beta-lactam ring to be isolated from a marine organism. The molecular structures of 2 and 3 were established by spectroscopic methods and then confirmed unequivocally by chemical correlation and comparison of physical and chemical data with the natural products. The new beta-lactams were successfully synthesized in one step, starting from the known diisocyanide 4, via parallel Ugi four-center three-component reactions (U-4C-3CR) that also established their absolute stereostructures. Interestingly, compounds 2 and 3 exhibited activities in the low nanomolar range against the human malaria parasite Plasmodium falciparum. PMID- 26494929 TI - H-D exchange in deuterated trifluoroacetic acid via ligand-directed NHC-palladium catalysis: a powerful method for deuteration of aromatic ketones, amides, and amino acids. AB - A method has been developed for one-step ortho-selective ligand-directed H-D exchange, accompanied in some cases by concurrent acid-catalyzed electrophilic deuteration. This method is effective for deuteration of aromatic substrates ranging from ketones to amides and amino acids, including compounds of biological and pharmaceutical interest such as acetaminophen and edaravone. Use of a palladium catalyst featuring an NHC ligand is critical for the observed reactivity. Experimental evidence strongly suggests that palladium facilitates C H activation of the aromatic substrates, a mechanism seldom observed under strongly acidic conditions. 2015 Elsevier Ltd. All rights reserved. PMID- 26494930 TI - Investigations Into the Interactions of a MALDI Matrix with Organic Thin Films Using C60+ SIMS Depth Profiling. AB - Molecular depth profiling of multilayer organic films is now an established protocol for cluster secondary ion mass spectrometry (SIMS). This unique capability is exploited here to study the ionization mechanism associated with matrix-enhanced SIMS and possibly matrix assisted laser desorption/ionization (MALDI). Successful depth profiling experiments were performed on model bi-layer systems using 2,5-dihydroxybenzoic acid (DHB) as the matrix with dipalmitoylphosphatidylcholine (DPPC) or phenylalanine (PHE). The interaction between the matrix and organic analyte is monitored at the interface of the films. Tri-layer films with D2O as a thin-film sandwiched between the matrix and organic layers are also investigated to determine what role, if any, water plays during ionization. The results show successful depth profiles when taken at 90K. Mixing is observed at the interfaces of the films due to primary ion bombardment, but this mixing does not recreate the conditions necessary for ionization enhancement. PMID- 26494931 TI - Mapping eastern equine encephalitis virus risk for white-tailed deer in Michigan. AB - Eastern equine encephalitis (EEE) is a mosquito-borne viral disease that is often fatal to humans and horses. Some species including white-tailed deer and passerine birds can survive infection with the EEE virus (EEEV) and develop antibodies that can be detected using laboratory techniques. In this way, collected serum samples from free ranging white-tailed deer can be used to monitor the presence of the virus in ecosystems. This study developed and tested a risk index model designed to predict EEEV activity in white-tailed deer in a three-county area of Michigan. The model evaluates EEEV risk on a continuous scale from 0.0 (no measurable risk) to 1.0 (highest possible risk). High risk habitats are identified as those preferred by white-tailed deer that are also located in close proximity to an abundance of wetlands and lowland forests, which support disease vectors and hosts. The model was developed based on relevant literature and was tested with known locations of infected deer that showed neurological symptoms. The risk index model accurately predicted the known locations, with the mean value for those sites equal to the 94th percentile of values in the study area. The risk map produced by the model could be used refine future EEEV monitoring efforts that use serum samples from free-ranging white tailed deer to monitor viral activity. Alternatively, it could be used focus educational efforts targeted toward deer hunters that may have elevated risks of infection. PMID- 26494932 TI - Effects of an emotional literacy intervention for students identified with bullying behaviour. AB - The effectiveness of a 12-week, small group emotional literacy (EL) intervention in reducing bullying behaviour in school was evaluated. Participants were 50 primary school pupils identified through peer nomination as engaging in bullying behaviours. The intervention was implemented in schools already engaged with a universal social and emotional learning initiative, including an anti-bullying component. Within schools, participants were randomly assigned to an intervention or a wait-list comparison group. Response to the intervention was found to be dependent on baseline levels of EL. Only children whose baseline level was low showed a significant reduction in peer-rated bullying behaviour. No effect of the intervention was detected on victimisation or adjustment scores, although positive changes in adjustment were associated with increased EL. PMID- 26494933 TI - Taking working memory training from the laboratory into schools. AB - Working memory skills have been shown to be enhanced by adaptive training in several randomised controlled trials. Here, two field trials were conducted in which teachers administered working memory training to their own pupils in school. Twenty-two children aged 8-9 years participated in Trial 1. In Trial 2, 50 children aged 9-11 years with the lowest academic performance completed training. They were matched with a group of 50 children who were not trained. Following training, children in Trial 1 improved significantly in both trained and untrained working memory tasks, with effect sizes comparable to those reported in research studies. Improvements on the trained tasks in Trial 2 were comparable, and training was associated with significantly greater progress at school across the academic year in maths and English. These findings indicate that teacher-administered training leads to generalised and robust gains in working memory and educationally significant gains in academic performance. PMID- 26494934 TI - Association of social isolation and health across different racial and ethnic groups of older Americans. AB - Social isolation is a social and public health problem that affects people of all ages, especially elders. Previous studies have found that social isolation across numerous industrialised countries is associated with negative health outcomes. However, it is unknown whether and how this association differs by race/ethnicity and age. To begin to address this gap, this study examines the association of social isolation and physical and mental health among Black, White and Hispanic elders in the United States of America. Building on Cornwell and Waite's perceived isolation and social disconnectedness dimension model of social isolation, the author used multi-stage survey data from a nationally representative sample of 3,005 community-residing adults aged 57-85 from the National Social Life, Health, and Aging Project. Tests for association were conducted on health by age, gender, marital status, education and race/ethnicity separately. Multivariate logistic regressions were used to test the association of social isolation and health exclusively and separately among these three groups. Results showed that social isolation is strongly associated with physical and mental health. Both perceived isolation and social disconnectedness had a significant negative association with physical and mental health among White elders. For Blacks, social disconnectedness is negatively associated with their physical health while perceived isolation had a negative association with mental health. Among Hispanic elders, there seemed to be no association between social isolation and physical health, but a significant negative association was found with their mental health. Despite various associated patterns, however, social isolation overall was associated with health outcomes that were similar across three elder groups. By identifying factors influencing social isolation and health among minority older Americans, this study has relevance to the development of culturally sensitive health-care practice and services, which may be applicable to minority elders in different countries. PMID- 26494935 TI - Combining Parallel and Exploratory Factor Analysis in Identifying Relationship Scales in Secondary Data. AB - Common methods used in the literature to identify factors within exploratory factor analysis has been shown to be potentially problematic. This brief report illustrates a state of the art approach in identifying factor structure by adding parallel analysis prior to exploratory factor analysis. Parallel analysis enables researchers to have a high degree of confidence of the number of factors to extract prior to exploratory factor analysis. The procedure is illustrated by using items from the National Survey of Families and Households (NSFH) that were used to identify relationship scales. PMID- 26494936 TI - Helicobacter pylori Antibody Titer and Gastric Cancer Screening. AB - The "ABC method" is a serum gastric cancer screening method, and the subjects were divided based on H. pylori serology and atrophic gastritis as detected by serum pepsinogen (PG): Group A [H. pylori (-) PG (-)], Group B [H. pylori (+) PG (-)], Group C [H. pylori (+) PG (+)], and Group D [H. pylori (-) PG (+)]. The risk of gastric cancer is highest in Group D, followed by Groups C, B, and A. Groups B, C, and D are advised to undergo endoscopy, and the recommended surveillance is every three years, every two years, and annually, respectively. In this report, the reported results with respect to further risk stratification by anti-H. pylori antibody titer in each subgroup are reviewed: (1) high-negative antibody titer subjects in Group A, representing posteradicated individuals with high risk for intestinal-type cancer; (2) high-positive antibody titer subjects in Group B, representing active inflammation with high risk for diffuse-type cancer; and (3) low-positive antibody titer subjects in Group C, representing advanced atrophy with increased risk for intestinal-type cancer. In these subjects, careful follow-up with intervals of surveillance of every three years in (1), every two years in (2), and annually in (3) should be considered. PMID- 26494937 TI - HER2 Status in Premalignant, Early, and Advanced Neoplastic Lesions of the Stomach. AB - OBJECTIVES: HER2 expression in gastric cancer (GC) has received attention as a potential target for therapy with Trastuzumab. We reviewed the current knowledge on HER2 status in premalignant gastric lesions and in early (EGC) and advanced (AGC) GC to discuss the possible pathogenetic and prognostic roles of HER2 overexpression in GC. RESULTS: HER2 overexpression was documented in gastric low grade (LG) and high-grade intraepithelial neoplasia (HG-IEN), with higher frequency in gastric type dysplasia. HER2 overexpression was significantly associated with disease recurrence and poor prognosis in EGC representing an independent risk factor for lymph node metastases. HER2 overexpression was more frequent in AGC characterized by high grade, advanced stage, and high Ki-67 labeling index. The discordance in HER2 status was evidenced between primitive GC and synchronous or metachronous metastases. CONCLUSIONS: HER2 overexpression in premalignant gastric lesions suggests its potential involvement in the early steps of gastric carcinogenesis. The assessment of HER2 status in EGC may be helpful for the identification of patients who are at low risk for developing nodal metastases. Finally, the possible discordance in HER2 status between primary GC and its synchronous metastases support routine assessment of HER2 both in the primary GC and in its metastatic lesions. PMID- 26494938 TI - Oxidative Stress Parameters in Saliva and Its Association with Periodontal Disease and Types of Bacteria. AB - OBJECTIVE: To determine the association between oxidative stress parameters with periodontal disease, bleeding, and the presence of different periodontal bacteria. METHODS: A cross-sectional study in a sample of eighty-six patients, divided into three groups depending on their periodontal status. Thirty-three with chronic periodontitis, sixteen with gingivitis, and thirty-seven with periodontal healthy as control. Oxidative stress biomarkers (8-OHdG and MDA), total antioxidant capacity (TAOC), and the activity of two antioxidant enzymes (GPx and SOD) were determined in saliva. Subgingival plaque samples were obtained from the deepest periodontal pocket and PCR was used to determine the presence of the 6 fimA genotypes of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia, and Treponema denticola. RESULTS: Periodontal disease was found to be associated with increased oxidative stress parameter levels. These levels rose according to the number and type of different periodontal bacteria found in the periodontal pockets. The presence of different types of periodontal bacteria is predictive independent variables in linear regresion models of oxidative stress parameters as dependent variable, above all 8-OHdG. CONCLUSIONS: Oxidative stress parameter levels are correlated with the presence of different types of bacteria. Determination of these levels and periodontal bacteria could be a potent tool for controlling periodontal disease development. PMID- 26494940 TI - The development of counselling psychology in Ireland. AB - This paper discusses the distinctive nature of the specialism of counselling psychology and outlines the development of the discipline in Ireland in the context of international developments and its recognition as a professional branch of applied psychology. Today, counselling psychologists are employed in varied clinical and non-clinical settings including health and mental health services (statutory, private and voluntary sector) along with education, forensic, justice, industry and private practices. Counselling psychologist is the primary professional identity of many practising psychologists in Ireland and the Psychological Society of Ireland's Division of Counselling Psychology is the main affiliation of at least 179 members. With its focus on facilitating personal and interpersonal functioning across the life span and its emphasis on the therapeutic process, the specialism continues to bridge the disciplines of psychology, counselling and psychotherapy. In this article, some of the challenges still faced by counselling psychology are explored as it navigates its way through the changing landscape of further development and evolution. PMID- 26494939 TI - Bone Marrow Stromal Antigen 2 Is a Novel Plasma Biomarker and Prognosticator for Colorectal Carcinoma: A Secretome-Based Verification Study. AB - BACKGROUND: The cancer cell secretome has been recognized as a valuable reservoir for identifying novel serum/plasma biomarkers for different cancers, including colorectal cancer (CRC). This study aimed to verify four CRC cell-secreted proteins (tumor-associated calcium signal transducer 2/trophoblast cell surface antigen 2 (TACSTD2/TROP2), tetraspanin-6 (TSPAN6), bone marrow stromal antigen 2 (BST2), and tumor necrosis factor receptor superfamily member 16 (NGFR)) as potential plasma CRC biomarkers. METHODS: The study population comprises 152 CRC patients and 152 controls. Target protein levels in plasma and tissue samples were assessed by ELISA and immunohistochemistry, respectively. RESULTS: Among the four candidate proteins examined by ELISA in a small sample set, only BST2 showed significantly elevated plasma levels in CRC patients versus controls. Immunohistochemical analysis revealed the overexpression of BST2 in CRC tissues, and higher BST2 expression levels correlated with poorer 5-year survival (46.47% versus 65.57%; p = 0.044). Further verification confirmed the elevated plasma BST2 levels in CRC patients (2.35 +/- 0.13 ng/mL) versus controls (1.04 +/- 0.03 ng/mL) (p < 0.01), with an area under the ROC curve (AUC) being 0.858 comparable to that of CEA (0.867). CONCLUSION: BST2, a membrane protein selectively detected in CRC cell secretome, may be a novel plasma biomarker and prognosticator for CRC. PMID- 26494941 TI - Joint Raman spectroscopic and quantum chemical analysis of the vibrational features of Cs2RuO4. AB - The Raman spectroscopic characterization of the orthorhombic phase of Cs2RuO4 was carried out by means of group theory and quantum chemical analysis. Multiple models based on ruthenate (VI+) tetrahedra were tested, and characterization of all the active Raman modes was achieved. A comparison of Raman spectra of Cs2RuO4, Cs2MoO4, and Cs2WO4 was also performed. Raman laser heating induced a phase transition from an ordered to a disordered structure. The temperature-phase transition was calculated from the anti-Stokes/Stokes ratio and compared with the ones measured at macroscopic scale. The phase transition is connected with tilting and/or rotations of RuO4 tetrahedra, which lead to a disorder at the RuO4 sites. (c) 2015 The Authors. Journal of Raman Spectroscopy published by John Wiley & Sons Ltd. PMID- 26494942 TI - The Impact of Intimate Partner Violence (IPV) on Parenting by Mothers Within an Ethnically Diverse Population in the Netherlands. AB - Intimate partner violence (IPV) profoundly affects multiple life domains for the people involved. We report on the experiences of Dutch mothers of various ethnic backgrounds regarding their parenting during and after IPV, their perceptions of the influence of IPV on their parenting, as well as their need for and experiences with support services. We conducted qualitative interviews with 100 mothers in the Netherlands who had experienced IPV. Most reported negative experiences with parenting (both during and after the IPV), a strong effect of the IPV on their parenting, as well as circumstances that aggravated this effect. The mothers had used multiple sources of formal and informal support. Although most evaluated the support that they had received positively, some also mentioned mixed or negative experiences. Many were still in need of support. Relationships with ethnic background and the severity of IPV are discussed. PMID- 26494943 TI - A Voxel-Based Morphometry Study of the Brain of University Students Majoring in Music and Nonmusic Disciplines. AB - The brain changes flexibly due to various experiences during the developmental stages of life. Previous voxel-based morphometry (VBM) studies have shown volumetric differences between musicians and nonmusicians in several brain regions including the superior temporal gyrus, sensorimotor areas, and superior parietal cortex. However, the reported brain regions depend on the study and are not necessarily consistent. By VBM, we investigated the effect of musical training on the brain structure by comparing university students majoring in music with those majoring in nonmusic disciplines. All participants were right handed healthy Japanese females. We divided the nonmusic students into two groups and therefore examined three groups: music expert (ME), music hobby (MH), and nonmusic (NM) group. VBM showed that the ME group had the largest gray matter volumes in the right inferior frontal gyrus (IFG; BA 44), left middle occipital gyrus (BA 18), and bilateral lingual gyrus. These differences are considered to be caused by neuroplasticity during long and continuous musical training periods because the MH group showed intermediate volumes in these regions. PMID- 26494944 TI - Melodic Contour Training and Its Effect on Speech in Noise, Consonant Discrimination, and Prosody Perception for Cochlear Implant Recipients. AB - Cochlear implant (CI) recipients generally have good perception of speech in quiet environments but difficulty perceiving speech in noisy conditions, reduced sensitivity to speech prosody, and difficulty appreciating music. Auditory training has been proposed as a method of improving speech perception for CI recipients, and recent efforts have focussed on the potential benefits of music based training. This study evaluated two melodic contour training programs and their relative efficacy as measured on a number of speech perception tasks. These melodic contours were simple 5-note sequences formed into 9 contour patterns, such as "rising" or "rising-falling." One training program controlled difficulty by manipulating interval sizes, the other by note durations. Sixteen adult CI recipients (aged 26-86 years) and twelve normal hearing (NH) adult listeners (aged 21-42 years) were tested on a speech perception battery at baseline and then after 6 weeks of melodic contour training. Results indicated that there were some benefits for speech perception tasks for CI recipients after melodic contour training. Specifically, consonant perception in quiet and question/statement prosody was improved. In comparison, NH listeners performed at ceiling for these tasks. There was no significant difference between the posttraining results for either training program, suggesting that both conferred benefits for training CI recipients to better perceive speech. PMID- 26494945 TI - Exploring Vocational Evaluation Practices following Traumatic Brain Injury. AB - BACKGROUND: Individuals with traumatic brain injury (TBI) face many challenges when attempting to return to work (RTW). Vocational evaluation (VE) is a systematic process that involves assessment and appraisal of an individual's current work-related characteristics and abilities. OBJECTIVE: The aims of this study are to (1) examine demographic and employment characteristics of vocational rehabilitation providers (VRPs), (2) identify the specific evaluation methods that are used in the VE of individuals with TBI, and (3) examine the differences in assessment method practices based upon evaluator assessment preferences. METHODS: This exploratory case study used a forty-six-item online survey which was distributed to VRPs. RESULTS: One hundred and nine VRPs accessed the survey. Of these, 74 completed the survey. A majority of respondents were female (79.7%), Caucasian (71.6%), and holding a master's degree (74.3%), and more than half (56.8%) were employed as state vocational rehabilitation counselors (VRCs). In addition, over two-thirds (67.6%) were certified rehabilitation counselors (CRCs). Respondents reported using several specific tools and assessments during the VE process. CONCLUSIONS: Study findings reveal differences in use of and rationales for specific assessments amongst VRPs. Understanding VRP assessment practices and use of an evidence-based framework for VE following TBI may inform and improve VE practice. PMID- 26494946 TI - Virological Mechanisms in the Coinfection between HIV and HCV. AB - Due to shared transmission routes, coinfection with Hepatitis C Virus (HCV) is common in patients infected by Human Immunodeficiency Virus (HIV). The immune pathogenesis of liver disease in HIV/HCV coinfected patients is a multifactorial process. Several studies demonstrated that HIV worsens the course of HCV infection, increasing the risk of cirrhosis and hepatocellular carcinoma. Also, HCV might increase immunological defects due to HIV and risk of comorbidities. A specific cross-talk among HIV and HCV proteins in coinfected patients modulates the natural history, the immune responses, and the life cycle of both viruses. These effects are mediated by immune mechanisms and by a cross-talk between the two viruses which could interfere with host defense mechanisms. In this review, we focus on some virological/immunological mechanisms of the pathogenetic interactions between HIV and HCV in the human host. PMID- 26494947 TI - CXCR6 Expression Is Important for Retention and Circulation of ILC Precursors. AB - Innate lymphoid cells are present at mucosal sites and represent the first immune barrier against infections, but what contributes to their circulation and homing is still unclear. Using Rag2(-/-) Cxcr6(Gfp/+) reporter mice, we assessed the expression and role of CXCR6 in the circulation of ILC precursors and their progeny. We identify CXCR6 expressing ILC precursors in the bone marrow and characterize their significant increase in CXCR6-deficient mice at steady state, indicating their partial retention in the bone marrow after CXCR6 ablation. Circulation was also impaired during embryonic life as fetal liver from CXCR6 deficient embryos displayed decreased numbers of ILC3 precursors. When injected, fetal CXCR6-deficient ILC3 precursors also fail to home and reconstitute ILC compartments in vivo. We show that adult intestinal ILC subsets have heterogeneous expression pattern of CXCR6, integrin alpha 4 beta 7, CD62L, CD69, and CD44, with ILC1 and ILC3 being more likely tissue resident lymphocytes. Intestinal ILC subsets were unchanged in percentages and numbers in both mice. We demonstrate that the ILC frequency is maintained due to a significant increase of ILC peripheral proliferation, as well as an increased proliferation of the in situ ILC precursors to compensate their retention in the bone marrow. PMID- 26494948 TI - Semiannual Imaging Surveillance Is Associated with Better Survival in Patients with Non-B, Non-C Hepatocellular Carcinoma. AB - Since it remains elusive whether and how the imaging surveillance affects the survival in patients with non-B, non-C hepatocellular carcinoma (NBNC-HCC), we conducted this retrospective study which investigated the association between the semiannual surveillance prior to HCC diagnosis and the survival in patients with the initial diagnosis of HCC induced by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections (N = 141) and non-B, non-C etiology (N = 30). It was demonstrated that surveillance was less frequently performed in the NBNC-HCC patients compared to that in HCC patients with HBV and/or HCV infections (B/C-HCC patients), and the survival was unfavorable in NBNC-HCC patients. On the other hand, the survival of NBNC-HCC patients with semiannual surveillance was significantly favorable than those patients without semiannual surveillance, and the survival was similar between B/C-HCCs and NBNC-HCCs with semiannual surveillance. In conclusion, though NBNC-HCC patients compared to B/C-HCC patients had poorer prognosis overall, these NBNC-HCC patients with semiannual surveillance had a better survival almost equivalent to the survival of B/C-HCC patients with semiannual surveillance, demonstrating the clinical utility of the semiannual imaging surveillance program for NBNC-HCCs. PMID- 26494950 TI - New Light on the Mind's Eye: The Pupillary Light Response as Active Vision. AB - The eye's pupils constrict (shrink) in brightness and dilate (expand) in darkness. The pupillary light response was historically considered a low-level reflex without any cognitive component. Here, we review recent studies that have dramatically changed this view: The light response depends not only on a stimulus's brightness but also on whether you are aware of the stimulus, whether you are paying attention to it, and even whether you are thinking about it. We highlight the link between the pupillary light response and eye-movement preparation: When you intend to look at a bright stimulus, a pupillary constriction is prepared along with the eye movement before the eyes set in motion. This preparation allows the pupil to rapidly change its size as your eyes move from bright to dark objects and back again. We discuss the implications of these recent advances for our understanding of the subtle yet important role that pupillary responses play in vision. PMID- 26494949 TI - Liver Cirrhosis: Evaluation, Nutritional Status, and Prognosis. AB - The liver is the major organ for the metabolism of three major nutrients: protein, fat, and carbohydrate. Chronic hepatitis C virus infection is the major cause of chronic liver disease. Liver cirrhosis (LC) results from different mechanisms of liver injury that lead to necroinflammation and fibrosis. LC has been seen to be not a single disease entity but one that can be graded into distinct clinical stages related to clinical outcome. Several noninvasive methods have been developed for assessing liver fibrosis and these methods have been used for predicting prognosis in patients with LC. On the other hand, subjects with LC often have protein-energy malnutrition (PEM) and poor physical activity. These conditions often result in sarcopenia, which is the loss of skeletal muscle volume and increased muscle weakness. Recent studies have demonstrated that PEM and sarcopenia are predictive factors for poorer survival in patients with LC. Based on these backgrounds, several methods for evaluating nutritional status in patients with chronic liver disease have been developed and they have been preferably used in the clinical field practice. In this review, we will summarize the current knowledge in the field of LC from the viewpoints of diagnostic method, nutritional status, and clinical outcomes. PMID- 26494951 TI - Anticancer effect of adenosine on gastric cancer via diverse signaling pathways. AB - Extracellular adenosine induces apoptosis in a variety of cancer cells via intrinsic and extrinsic pathways. In the former pathway, adenosine uptake into cells triggers apoptosis, and in the latter pathway, adenosine receptors mediate apoptosis. Extracellular adenosine also induces apoptosis of gastric cancer cells. Extracellular adenosine is transported into cells through an adenosine transporter and converted to AMP by adenosine kinase. In turn, AMP activates AMP activated protein kinase (AMPK). AMPK is the factor responsible for caspase independent apoptosis of GT3-TKB gastric cancer cells. Extracellular adenosine, on the other hand, induces caspase-dependent apoptosis of MKN28 and MKN45 gastric cancer cells by two mechanisms. Firstly, AMP, converted from intracellularly transported adenosine, initiates apoptosis, regardless of AMPK. Secondly, the A3 adenosine receptor, linked to Gi/Gq proteins, mediates apoptosis by activating the Gq protein effector, phospholipase Cgamma, to produce inositol 1,4,5 trisphosphate and diacylglycerol, which activate protein kinase C. Consequently, the mechanisms underlying adenosine-induced apoptosis vary, depending upon gastric cancer cell types. Understand the contribution of each downstream target molecule of adenosine to apoptosis induction may aid the establishment of tailor made chemotherapy for gastric cancer. PMID- 26494952 TI - Evaluation and treatment of malignant ascites secondary to gastric cancer. AB - Malignant ascites affects approximately 10% of patients with gastric cancer (GC), and poses significant difficulties for both patients and clinicians. In addition to the dismal general condition of affected patients and the diversity of associated complications such as jaundice and ileus, problems in assessing scattered tumors have hampered the expansion of clinical trials for this condition. However, the accumulation of reported studies is starting to indicate that the weak response to treatment in GC patients with malignant ascites is more relevant to their poor prognosis rather than to the ascites volume at diagnosis. Therefore, precise assessment of initial state of ascites, repetitive evaluation of treatment efficacy, selection of suitable treatment, and swift transition to other treatment options as needed are paramount to maximizing patient benefit. Accurately determining ascites volume is the crucial first step in clinically treating a patient with malignant ascites. Ultrasonography is commonly used to identify the existence of ascites, and several methods have been proposed to estimate ascites volume. Reportedly, the sum of the depth of ascites at five points (named "five-point method") on three panels of computed tomography images is well correlated to the actual ascites volume and/or abdominal girth. This method is already suited to repetitive assessment due to its convenience compared to the conventional volume rendering method. Meanwhile, a new concept, "Clinical Benefit Response in GC (CBR-GC)", was recently introduced to measure the efficacy of chemotherapy for malignant ascites of GC. CBR-GC is a simple and reliable patient-oriented evaluation system based on changes in performance status and ascites, and is expected to become an important clinical endpoint in future clinical trials. The principal of treatment for GC patients with ascites is palliation and prevention of ascites-related symptoms. The treatment options are various, including a standard treatment based on the available guidelines, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), laparoscopic HIPEC alone, intravenous chemotherapy, intraperitoneal chemotherapy, and molecular targeting therapy. Although each treatment option is valid, further research is imperative to establish the optimal choice for each patient. PMID- 26494953 TI - Companion diagnostics for the targeted therapy of gastric cancer. AB - Gastric cancer is the fourth most common type of cancer and represents a major cause of cancer-related deaths worldwide. With recent biomedical advances in our understanding of the molecular characteristics of gastric cancer, many genetic alterations have been identified as potential targets for its treatment. Multiple novel agents are currently under development as the demand for active agents that improve the survival of gastric cancer patients constantly increases. Based on lessons from previous trials of targeted agents, it is now widely accepted that the establishment of an optimal diagnostic test to select molecularly defined patients is of equal importance to the development of active agents against targetable genetic alterations. Herein, we highlight the current status and future perspectives of companion diagnostics in the treatment of gastric cancer. PMID- 26494955 TI - Sarcopenia and liver transplant: The relevance of too little muscle mass. AB - Loss of muscle mass and function is a common occurrence in both patients with decompensated cirrhosis and those undergoing liver transplantation. Sarcopenia is associated with morbidity and mortality before and after liver transplantation. The ability of skeletal muscle mass to recover after transplant is questionable, and long term adverse events associated with persistent sarcopenia have not been well studied. Limited data is available examining mechanisms by which decreased muscle mass might develop. It is not clear which interventions might reduce the prevalence of sarcopenia and associated health burdens. However, measures to either decrease portal hypertension or improve nutrition appear to have benefit. Research on sarcopenia in the liver transplant setting is hampered by differing methodology to quantify muscle mass and varied thresholds determining the presence of sarcopenia. One area highlighted in this review is the heterogeneity used when defining sarcopenia. The health consequences, clinical course and potential pathophysiologic mechanisms of sarcopenia in the setting of cirrhosis and liver transplantation are further discussed. PMID- 26494956 TI - Liver transplantation for alcoholic liver disease: Lessons learned and unresolved issues. AB - The use of liver transplantation (LT) as a treatment for alcoholic liver disease (ALD) has been highly controversial since the beginning. The ever increasing shortage of organs has accentuated the low priority given to patients suffering from ALD, which is considered a "self-inflicted" condition. However, by improving the long-term survival rates, making them similar to those from other indications, and recognizing that alcoholism is a primary disease, ALD has become one of the most common indications for LT in Europe and North America, a situation thought unfathomable thirty years ago. Unfortunately, there are still many issues with the use of this procedure for ALD. There are significant relapse rates, and the consequences of excessive drinking after LT range from asymptomatic biochemical and histological abnormalities to graft failure and death. A minimum three-month period of sobriety is required for an improvement in liver function, thus making LT unnecessary, and to demonstrate the patient's commitment to the project, even though a longer abstinence period does not guarantee lower relapse rates after LT. Recent data have shown that LT is also effective for severe alcoholic hepatitis when the patient is unresponsive to corticosteroids therapy, with low relapse rates in highly selected patients, although these results must be confirmed before LT becomes a standard procedure in this setting. Finally, LT for ALD is accompanied by an increased risk of de novo solid organ cancer, skin cancer, and lymphoproliferative disorders, which has a large impact on the survival rates. PMID- 26494957 TI - Current status and perspectives in split liver transplantation. AB - Growing experience with the liver splitting technique and favorable results equivalent to those of whole liver transplant have led to wider application of split liver transplantation (SLT) for adult and pediatric recipients in the last decade. Conversely, SLT for two adult recipients remains a challenging surgical procedure and outcomes have yet to improve. Differences in organ shortages together with religious and ethical issues related to cadaveric organ donation have had an impact on the worldwide distribution of SLT. Despite technical refinements and a better understanding of the complex liver anatomy, SLT remains a technically and logistically demanding surgical procedure. This article reviews the surgical and clinical advances in this field of liver transplantation focusing on the role of SLT and the issues that may lead a further expansion of this complex surgical procedure. PMID- 26494954 TI - Dysregulation of non-coding RNAs in gastric cancer. AB - Gastric cancer (GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs (ncRNAs), primarily microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of non-coding RNAs, especially miRNAs and lncRNAs, in GC. We summarize instances of aberrant expression of the ncRNAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how ncRNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncRNAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncRNAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncRNAs have been identified as targets for the treatment of GC. PMID- 26494958 TI - Clinical significance of donor-specific human leukocyte antigen antibodies in liver transplantation. AB - Antibody-mediated rejection (AMR) caused by donor-specific anti-human leukocyte antigen antibodies (DSA) is widely accepted to be a risk factor for decreased graft survival after kidney transplantation. This entity also plays a pathogenic role in other solid organ transplants as it appears to be an increasingly common cause of heart graft dysfunction and an emerging issue in lung transplantation. In contrast, the liver appears relatively resistant to DSA-mediated injury. This "immune-tolerance" liver property has been sustained by a low rate of liver graft loss in patients with preformed DSA and by the intrinsic liver characteristics that favor the absorption and elimination of DSA; however, alloantibody-mediated adverse consequences are increasingly being recognized, and several cases of acute AMR after ABO-compatible liver transplant (LT) have been reported. Furthermore, the availability of new solid-phase assays, allowing the detection of low titers of DSA and the refinement of objective diagnostic criteria for AMR in solid organ transplants and particularly in LT, have improved the recognition and management of this entity. A cost-effective strategy of DSA monitoring, avoidance of class II human leukocyte antigen mismatching, judicious immunosuppression attached to a higher level of clinical suspicion of AMR, particularly in cases unresponsive to conventional anti-rejection therapy, can allow a rational approach to this threat. PMID- 26494959 TI - Candidates for liver transplantation with alcoholic liver disease: Psychosocial aspects. AB - In Europe, 30% to 50% of liver transplantations are currently due to alcoholic liver disease (ALD). In the United States, this percentage is 17.2%. Post transplant survival and other predictors of clinical course do not differ significantly from those in other types of transplanted patients, as long as there is no relapse of drinking. However, 20%-25% of these patients lapse or relapse to heavy drinking post-operatively, which has been associated with an increased risk of liver damage and mortality. It is therefore crucial to design specific selection and follow-up strategies aimed at this particular type of patient. Several good and poor prognosis factors that could help to predict a relapse have been suggested, among them the duration of abstinence, social support, a family history of alcoholism, abuse diagnosis versus alcohol dependence, non-acceptance of diagnosis related to alcohol use, presence of severe mental illness, non-adherence in a broad sense, number of years of alcoholism, and daily quantity of alcohol consumption. In this article, we discuss these and other, more controversial factors in selecting ALD patients for liver transplantation. Abstinence should be the main goal after transplantation in an ALD patient. In this article, we review the several definitions of post transplant relapse, its monitoring and the psychopharmacological and psychotherapeutic treatment. PMID- 26494960 TI - Posttransplant lymphoproliferative disorders following liver transplantation: Where are we now? AB - Liver transplantation has emerged as a life-saving treatment for several patients with acute liver failure, end stage liver disease and primary hepatic malignancies. However, long term immunosuppressive therapy aiming to reduce the risk of transplant rejection increases the incidence of several complications including malignancies. This is illustrated by the observation of a high ratio between observed and expected cases of lymphoproliferative disorders following liver transplantation. Despite a huge heterogeneity in morphological appearance of these disorders ranging from reactive-like lesions to real lymphomas, they are collectively termed posttransplant lymphoproliferative disorders. In this review we will provide an overview of this rare but challenging disorder as a complication of liver transplantation. PMID- 26494961 TI - Non-invasive assessment of liver fibrosis in patients with alcoholic liver disease. AB - Alcoholic liver disease (ALD) consists of a broad spectrum of disorders, ranging from simple steatosis to alcoholic steatohepatitis and cirrhosis. Fatty liver develops in more than 90% of heavy drinkers, however only 30%-35% of them develop more advanced forms of ALD. Therefore, even if the current "gold standard" for the assessment of the stage of alcohol-related liver injury is histology, liver biopsy is not reasonable in all patients who present with ALD. Currently, although several non-invasive fibrosis markers have been suggested as alternatives to liver biopsy in patients with ALD, none has been sufficiently validated. As described in other liver disease, the diagnostic accuracy of such tests in ALD is acceptable for the diagnosis of significant fibrosis or cirrhosis but not for lesser fibrosis stages. Existing data suggest that the use of non invasive tests could be tailored to first tier screening of patients at risk, in order to diagnose early patients with progressive liver disease and offer targeted interventions for the prevention of decompensation. We review these tests and critically appraise the existing evidence. PMID- 26494963 TI - Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis (stage F3) and cirrhosis (stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers (e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques (transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD. PMID- 26494965 TI - Active vaccination to prevent de novo hepatitis B virus infection in liver transplantation. AB - The shortage of organ donors mandates the use of liver allograft from anti-HBc(+) donors, especially in areas highly endemic for hepatitis B virus (HBV) infection. The incidence of de novo hepatitis B infection (DNH) is over 30%-70% among recipients of hepatitis B core antibody (HBcAb) (+) grafts without any prophylaxis after liver transplantation (LT). Systematic reviews showed that prophylactic therapy [lamivudine and/or hepatitits B immunoglobulin (HBIG)] dramatically reduces the probability of DNH. However, there are limited studies regarding the effects of active immunization to prevent DNH, and the role of active vaccination is not well-defined. This review focuses on the feasibility and efficacy of pre- and post-LT HBV vaccination to prevent DNH in HBsAg(-) recipient using HBcAb(+) grafts. The presence of HBsAb in combination with lamivudine or HBIG results in lower incidence of DNH and may reduce the requirement of HBIG. There was a trend towards decreasing incidence of DNH with higher titers of HBsAb. High titers of HBsAb (> 1000 IU/L) achieved after repeated vaccination could eliminate the necessity for additional antiviral prophylaxis in pediatric recipients. In summary, active vaccination with adequate HBsAb titer is a feasible, cost-effective strategy to prevent DNH in recipients of HBcAb(+) grafts. HBV vaccination is advised for candidates on waiting list and for recipients after withdrawal of steroids and onset of low dose immunosuppression after transplantation. PMID- 26494966 TI - Hepatic differentiation of rat induced pluripotent stem cells in vitro. AB - AIM: To show the efficient generation of hepatocyte-like cells (HLCs) differentiated from the induced pluripotent stem cells (iPSCs) of rats. METHODS: Hepatic differentiation was achieved using a three-step protocol with several growth factors. First, rat iPSCs were differentiated into definitive endoderm cells using Activin A and Wnt3a treatment. Then fibroblast growth factor 4 and bone morphogenetic protein 2 were added to the culture medium and used to induce hepatic differentiation. Finally, hepatocyte growth factor, Oncostatin M and dexamethasone were used for hepatic maturation. The liver-related markers and functions of HLCs were assessed at the gene and protein levels. RESULTS: After endodermal induction, the differentiated cells expressed endodermal markers forkhead box protein A2 and SRY-box containing gene 17 at the mRNA and protein levels. After 20 d of culture, the iPSCs were differentiated into HLCs. These differentiated cells expressed hepatic markers including alpha-fetoprotein, albumin CK8, CK18, CK19, and transcription factor HNF-4alpha. In addition, the cells expressed functional proteins such as alpha1-antitrypsin, cytochrome P450 1A2 and CYP 3A4. They acted like healthy hepatic cells, storing glycogen and taking up indocyanine green and low-density lipoproteins. Also, the rates of urea synthesis (20 d 1.202 +/- 0.080 mg/dL vs 0 d 0.317 +/- 0.021 mg/dL, P < 0.01) and albumin secretion (20 d 1.601 +/- 0.102 mg/dL vs 0 d 0.313 +/- 0.015 mg/dL, P < 0.01) increased significantly as differentiation progressed. CONCLUSION: Rat iPSCs can differentiate into HLCs rapidly and efficiently. These differentiated cells may be an attractive resource for treatment of end-stage liver disease. PMID- 26494964 TI - Genetic background in nonalcoholic fatty liver disease: A comprehensive review. AB - In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID- 26494967 TI - Effect of fibulin-5 on adhesion, migration and invasion of hepatocellular carcinoma cells via an integrin-dependent mechanism. AB - AIM: To elucidate the role of fibulin-5 (FBLN-5) as a suppressor of hepatocellular carcinoma (HCC) cell metastasis via integrin. METHODS: The expression of FBLN-5 was determined by immunohistochemistry in 140 HCC samples and matched normal tissues, and was further confirmed by RT-PCR and Western blot analyses in various cell lines. Recombinant FBLN-5 was expressed in Escherichia coli BL21(DE3), purified and used in cell attachment assays. Expression of a specific plasmid or a specific siRNA in HCC cells resulted in the overexpression or knockdown of FBLN-5, respectively. Further, the migration and invasion of HCC cells were investigated using the Boyden chamber and transwell assays. The concentration of secreted matrix metalloproteinase 7 (MMP-7) was determined using ELISA. RESULTS: FBLN-5 expression was found to be downregulated in HCC. Its expression was significantly correlated with advanced tumor metastasis; this was indicative of poor 5-year overall survival. Recombinant full-length human FBLN-5 promoted the attachment of HCC cells via integrins: it inhibited HCC cell adhesion and migration to fibronectin in a concentration-dependent manner. It also inhibited HCC cell migration and invasion through an integrin-binding arginine-glycine-aspartic acid (RGD) motif by downregulating MMP-7. CONCLUSION: These results suggest that lower FBLN-5 expression is an important indicator of poor survival and that FBLN-5 inhibits HCC motility via an integrin-dependent mechanism. RGD-dependent suppression of MMP-7 by FBLN-5 might contribute to the development of new therapeutic strategies for HCC. PMID- 26494962 TI - Endocrine causes of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed. PMID- 26494968 TI - Low-density lipoprotein receptor genetic polymorphism in chronic hepatitis C virus Egyptian patients affects treatment response. AB - AIM: To correlate a genetic polymorphism of the low-density lipoprotein (LDL) receptor with antiviral responses in Egyptian chronic hepatitis C virus (HCV) patients. METHODS: Our study included 657 HCV-infected patients with genotype 4 who received interferon-based combination therapy. Patients were divided into two groups based on their response to therapy: 356 were responders, and 301 were non responders. Patients were compared to 160 healthy controls. All patients and controls underwent a thorough physical examination, measurement of body mass index (BMI) and the following laboratory tests: serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total bilirubin, direct bilirubin, prothrombin time, prothrombin concentration, INR, complete blood count, serum creatinine, fasting blood sugar, HCV antibody, and hepatitis B surface antigen. All HCV patients were further subjected to the following laboratory tests: HCV-RNA using quantitative polymerase chain reaction (PCR), antinuclear antibodies, thyroid-stimulating hormone, an LDL receptor (LDLR) genotype study of LDLR exon8c.1171G>A and exon10c.1413G>A using real-time PCR based assays, abdominal ultrasonography, ultrasonographic-guided liver biopsy, and histopathological examination of liver biopsies. Correlations of LDL receptor polymorphisms with HAI, METAVIR score, presence of steatosis, and BMI were performed in all cases. RESULTS: There were no statistically significant differences in response rates between the different types of interferon used or LDLR exon10c.1413G>A. However, there was a significant difference in the frequency of the LDL receptor exon8c.1171G>A genotype between cases (AA: 25.9%, GA: 22.2%, GG: 51.9%) and controls (AA: 3.8%, GA: 53.1% and GG: 43.1%) (P < 0.001). There was a statistically significant difference in the frequency of the LDLR exon 8C:1171 G>A polymorphism between responders (AA: 3.6%, GA: 15.2%, GG: 81.2%) and non-responders (AA: 52.2%, GA: 30.6%, GG: 17.2%) (P < 0.001). The G allele of LDL receptor exon8c.1171G>A predominated in cases and controls over the A allele, and a statistically significant association with response to interferon was observed. The frequency of the LDLR exon8c.1171G>A allele in non-responders was: A: 67.4% and G: 32.6 vs A: 11.2% and G: 88.8% in responders (P < 0.001). Therefore, carriers of the A allele exhibited a 16.4 times greater risk for non response. There was a significant association between LDL receptors exon8 c.1171G>A and HAI (P < 0.011). There was a significant association between LDL receptors exon8c.1171G>A and BMI. The mean BMI level was highest in patients carrying the AA genotype (28.7 +/- 4.7 kg/m(2)) followed by the GA genotype (28.1 +/- 4.8 kg/m(2)). The lowest BMI was the GG genotype (26.6 +/- 4.3 kg/m(2)) (P < 0.001). The only significant associations were found between LDL receptors exon8 c.1171G>A and METAVIR score or steatosis (P < 0.001). CONCLUSION: LDL receptor gene polymorphisms play a role in the treatment response of HCV and the modulation of disease progression in Egyptians infected with chronic HCV. PMID- 26494969 TI - Serum vitamin D3 does not correlate with liver fibrosis in chronic hepatitis C. AB - AIM: To investigate the relationship between serum vitamin D3 levels and liver fibrosis or inflammation in treatment-naive Chinese patients with chronic hepatitis C (CHC). METHODS: From July 2010 to June 2011, we enrolled 122 CHC patients and 11 healthy controls from Dingxi city, Gansu Province, China. The patients were infected with Hepatitis C virus (HCV) during blood cell re transfusion following plasma donation in 1992-1995, and had never received antiviral treatment. At present, all the patients except two underwent liver biopsy with ultrasound guidance. The Scheuer Scoring System was used to evaluate hepatic inflammation and the Metavir Scoring System was used to evaluate hepatic fibrosis. Twelve-hour overnight fasting blood samples were collected in the morning of the day of biopsy. Serum levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, cholinesterase, prothrombin activity, albumin, gamma-glutamyl transpeptidase, hemoglobin, calcium and phosphorus were determined. Serum HCV RNA levels were measured by real-time PCR. Serum levels of 25-hydroxyvitamin D3 [25(OH)D3] and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] were measured by high-performance liquid chromatography tandem mass spectrometry. RESULTS: Serum levels of 25(OH)D3 but not 24,25(OH)2D3 were significantly lower in CHC patients than in control subjects. Serum 25(OH)D3 levels did not correlate with liver fibrosis, inflammation, patient age, or levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, prothrombin activity, cholinesterase or HCV RNA. However, serum 25(OH)D3 levels did correlate with serum 24,25(OH)2D3 levels. Serum 25(OH)D3 and 24,25(OH)2D3 levels, and the 25(OH)D3/24,25(OH)2D3 ratio, have no difference among the fibrosis stages or inflammation grades. CONCLUSION: We found that serum levels of 25(OH)D3 and its degradation metabolite 24,25(OH)2D3 did not correlate with liver fibrosis in treatment-naive Chinese patient with CHC. PMID- 26494970 TI - Prediction of the indication criteria for endoscopic resection of early gastric cancer. AB - AIM: To find risk factors of lymph node metastasis (LNM) in early gastric cancer (EGC) and to find proper endoscopic therapy indication in EGC. METHODS: We retrospectively reviewed the 2270 patients who underwent curative operation for EGC from January 2001 to December 2008. EGC was defined as malignant lesions that do not invade beyond the submucosal layer of the stomach wall irrespective of presence of lymph node metastasis. RESULTS: Among 2270 enrolled patients, LNM was observed in 217 (9%) patients. LNM in intramucosal (M) cancer and submucosal (SM) cancer was detected in 38 (2.8%, 38/1340) patients and 179 (19%, 179/930) patients, respectively. In univariate analysis, the risk factors for LNM in EGC were size of tumor, Lauren classification, ulcer, lymphatic invasion, vascular invasion, and depth of invasion. However, in multivariate analysis, size of tumor, lymphatic invasion, vascular invasion, and depth of invasion were risk factors for LNM in EGC. Size of tumor, lymphatic invasion, vascular invasion, and depth of invasion were risk factors for LNM in cases of intramucosal cancer and submucosal cancer. In particular, there was no lymph node metastasis in cases of well differentiated early gastric cancer below 1 cm in size without ulcer regardless of lymphovascular invasion. CONCLUSION: Tumor size, perilymphatic vascular invasion, and depth of invasion were risk factors for LNM in EGC. There was no LNM in EGC below 1 cm regardless risk factors. PMID- 26494971 TI - Prognostic significance of plasma interleukin-6/-8 in pancreatic cancer patients receiving chemoimmunotherapy. AB - AIM: To investigate the association of plasma levels of interleukin (IL)-6 and -8 with Wilms' tumor 1 (WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDA) treated with dendritic cells (DCs) pulsed with three types of major histocompatibility complex class I and II restricted WT1 peptides combined with chemotherapy. METHODS: During the entire treatment period, plasma levels of IL-6 and -8 were analyzed by ELISA. The induction of WT1-specific immune responses was assessed using the WT1 peptide specific delayed-type hypersensitivity (DTH) test. RESULTS: Three of 7 patients displayed strong WT1-DTH reactions throughout long-term vaccination with significantly decreased levels of IL-6/-8 after vaccinations compared with the levels prior to treatment. Moreover, overall survival (OS) was significantly longer in PDA patients with low plasma IL-6 levels (< 2 pg/mL) after 5 vaccinations than in patients with high plasma IL-6 levels (>= 2 pg/mL) (P = 0.025). After disease progression, WT1-DTH reactions decreased severely and were ultimately negative at the terminal stage of cancer. The decreased levels of IL 6/-8 observed throughout long-term vaccination were associated with WT1-specific DTH reactions and long-term OS. CONCLUSION: Prolonged low levels of plasma IL-6/ 8 in PDA patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy. PMID- 26494972 TI - Effects of daily telephone-based re-education before taking medicine on Helicobacter pylori eradication: A prospective single-center study from China. AB - AIM: To investigate the effects of daily telephone-based re-education (TRE) before taking medicine for the eradication of Helicobacter pylori (H. pylori) on the compliance and the eradication rate in a Chinese patient population. METHODS: A prospective, physician-blinded, randomized, controlled clinical study was conducted. The patients were randomly assigned to receive TRE every day before taking medicine (TRE group) or no TRE (control group). The patients in the TRE group received regular instructions before taking medicine for the eradication of H. pylori during the entire course of treatment through telephone calls. The patients in the control group received detailed instructions at the time of seeing a doctor for the guidance. The primary outcome was the H. pylori eradication rate after treatment. The secondary outcomes included the clinical remissions after treatment, adverse events, compliance, and patients' satisfaction. RESULTS: A total of 140 patients were randomized, 70 to the TRE group and 70 to the control group. As the primary outcome, the H. pylori eradication rates in the TRE and control groups were 62.7% and 71.2% in per protocol analysis (P = 0.230), and 52.9% and 52.9% in intention-to-treat analysis (P = 0.567), respectively. As the secondary outcomes, there were no significant differences in the patients' satisfaction between the two groups (good, 79.7% vs 76.9%; fair, 13.6% vs 19.2%; poor, 6.7% vs 3.9%, for the TRE group and control group, respectively; P > 0.05 for all); the rates of adverse effects were 15.2% and 63.5% in the TRE and control groups, respectively (P < 0.001); the compliance rates in the TRE and control groups were 85.7% and 74.3%, respectively (P = 0.069). CONCLUSION: Daily TRE before taking medicine had no significant impact on the patients' compliance, satisfaction, or H. pylori eradication, but reduced the rate of adverse events. PMID- 26494974 TI - Case report of primary splenic angiosarcoma with hepatic metastases. AB - Primary splenic angiosarcoma (PSA) is the most unusual type of malignancy with early multifocal metastasis through hematogenous spread. PSA is generally believed to originate from splenic sinusoidal vascular endothelium with a high rate of metastasis and to have a poor prognosis. Its etiology and pathogenetic mechanisms have not yet been clearly described. Thus far, only approximately 200 cases have been reported. PSA has variable symptomatology with the potential to present with life-threatening complications. The diagnosis of PSA is challenging; and often late. PSA should be considered in the differential diagnosis of patients with splenomegaly and anemia of unknown etiology. Surgical treatment with splenectomy is considered the only curative intervention for potential long term disease-free survival. Early diagnosis and treatment are very important. It is important that clinical doctors improve the understanding of PSA. Herein, we report one rare case of PSA with hepatic metastases, along with a review of the current literature. PMID- 26494973 TI - Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review. AB - AIM: To investigate the efficacy (survival) and safety of treatments for recurrent hepatocellular carcinoma (HCC) in liver transplantation (LT) patients. METHODS: Literature search was performed on available online databases without a time limit until January 2015. Clinical studies describing survival after HCC recurrence in LT patients were retrieved for a full-text evaluation. A total of 61 studies were selected: 13 case reports, 41 retrospective case series, and 7 retrospective comparative studies. RESULTS: Based on all included studies, the mean HCC recurrence rate was 16% of all LTs for HCC. A total of 1021 LT patients experienced HCC recurrence. The median time from LT to HCC recurrence was 13 mo (range 2-132 mo). The majority of patients (67%) presented with HCC extra-hepatic recurrences, involving lung, bone, adrenal gland, peritoneal lymph nodes, and rarely the brain. Overall survival after HCC recurrence was 12.97 mo. Surgical resection of localized HCC recurrence and Sorafenib for controlling systemic spread of HCC recurrence were associated with the higher survival rates (42 and 18 mo, respectively). However, Sorafenib, especially when combined with mTOR, was frequently associated with severe side effects that required dose reduction or discontinuation CONCLUSION: Management of recurrent HCC in LT patients is challenging and associated with poor prognosis independently of the type of treatment. PMID- 26494975 TI - A Retrospective Audit of Clinically Significant Maternal Bacteraemia in a Specialist Maternity Hospital from 2001 to 2014. AB - Maternal sepsis is a significant problem in obstetrics, with almost one in four maternal deaths related to severe sepsis. We carried out a retrospective review of clinically significant bacteraemia in obstetric patients attending Rotunda Hospital over 14 years. From 2001 to 2014, there were 252 clinically significant positive blood culture episodes in obstetric patients. There were 112,361 live births>500 g during the study period giving an overall rate of 2.24 clinically significant positive maternal blood culture episodes per 1000 live births>500 g. The median rate over the 14 years was 2.12 episodes per 1000 live births>500 g, with an interquartile range of 1.74-2.43 per 1000 live births>500 g. There was no discernable increasing or decreasing trend over the 14 years. E. coli was the most commonly isolated organism (n=92/252, 37%), followed by group B Streptococcus (n=64/252, 25%), Staphylococcus aureus (n=28/252, 11%), and anaerobes (n=11/252, 4%). These top four organisms represented three-quarters of all positive blood culture episodes (n=195/252, 77.3%). Of note, there were only five cases of listeriosis, representing a rate of 4.4 cases per 100,000 live births>500 g. The rate of invasive group A streptococcal infection was also very low at 5.3 cases per 100,000 live births>500 g. PMID- 26494976 TI - FXYD5 is a Marker for Poor Prognosis and a Potential Driver for Metastasis in Ovarian Carcinomas. AB - Ovarian cancer (OC) is a leading cause of cancer mortality, but aside from a few well-studied mutations, very little is known about its underlying causes. As such, we performed survival analysis on ovarian copy number amplifications and gene expression datasets presented by The Cancer Genome Atlas in order to identify potential drivers and markers of aggressive OC. Additionally, two independent datasets from the Gene Expression Omnibus web platform were used to validate the identified markers. Based on our analysis, we identified FXYD5, a glycoprotein known to reduce cell adhesion, as a potential driver of metastasis and a significant predictor of mortality in OC. As a marker of poor outcome, the protein has effective antibodies against it for use in tissue arrays. FXYD5 bridges together a wide variety of cancers, including ovarian, breast cancer stage II, thyroid, colorectal, pancreatic, and head and neck cancers for metastasis studies. PMID- 26494977 TI - Corrigenda: A revision of infrageneric classification in Astelia Banks & Sol. ex R.Br. (Asteliaceae). AB - [This corrects the article DOI: 10.3897/phytokeys.52.4768.]. PMID- 26494978 TI - Towards a common framework for assessing the activity and associations of groups who sexually abuse children. AB - Extensive social psychological research emphasises the importance of groups in shaping individuals' thoughts and actions. Within the child sexual abuse (CSA) literature criminal organisation has been largely overlooked, with some key exceptions. This research was a novel collaboration between academia and the UK's Child Exploitation and Online Protection Centre (CEOP). Starting from the premise that the group is, in itself, a form of social situation affecting abuse, it offers the first systematic situational analysis of CSA groups. In-depth behavioural data from a small sample of convicted CSA group-offenders (n = 3) were analysed qualitatively to identify factors and processes underpinning CSA groups' activities and associations: group formation, evolution, identity and resources. The results emphasise CSA groups' variability, fluidity and dynamism. The foundations of a general framework are proposed for researching and assessing CSA groups and designing effective interventions. It is hoped that this work will stimulate discussion and development in this long-neglected area of CSA, helping to build a coherent knowledge-base. PMID- 26494979 TI - Coenzyme A-free activity, crystal structure, and rational engineering of a promiscuous beta-ketoacyl thiolase from Ralstonia eutropha. AB - Thiolases catalyze the formation of carbon-carbon bonds in diverse biosynthetic pathways. The promiscuous beta-ketoacyl thiolase B of Ralstonia eutropha (ReBktB) has been utilized in the in vivo conversion of Coenzyme A (CoA)-linked precursors such as acetyl-CoA and glycolyl-CoA into beta-hydroxy acids, including the pharmaceutically-important 3,4-dihydroxybutyric acid. Such thiolases could serve as powerful carbon-carbon bond-forming biocatalysts in vitro if handles less costly than CoA were employable. Here, thiolase activity is demonstrated toward substrates linked to the readily-available CoA mimic, N-acetylcysteamine (NAC). ReBktB was observed to catalyze the retro-Claisen condensation of several beta ketoacyl-S-NAC substrates, with a preference for 3-oxopentanoyl-S-NAC over 3 oxobutanoyl-, 3-oxohexanoyl-, and 3-oxoheptanoyl-S-NAC. A 2.0 A-resolution crystal structure, in which the asymmetric unit consists of four ReBktB tetramers, provides insight into acyl group specificity and how it may be engineered. By replacing an active site methionine with an alanine, a mutant possessing significant activity towards alpha-methyl substituted, NAC-linked substrates was engineered. The ability of ReBktB and its engineered mutants to utilize NAC-linked substrates will facilitate the in vitro biocatalytic synthesis of diketide chiral building blocks from feedstock molecules such as acetate and propionate. PMID- 26494980 TI - An automated shotgun lipidomics platform for high throughput, comprehensive, and quantitative analysis of blood plasma intact lipids. AB - Blood plasma has gained protagonism in lipidomics studies due to its availability, uncomplicated collection and preparation, and informative readout of physiological status. At the same time, it is also technically challenging to analyze due to its complex lipid composition affected by many factors, which can hamper the throughput and/or lipidomics coverage. To tackle these issues, we developed a comprehensive, high throughput, and quantitative mass spectrometry based shotgun lipidomics platform for blood plasma lipid analyses. The main hallmarks of this technology are (i) it is comprehensive, covering 22 quantifiable different lipid classes encompassing more than 200 lipid species; (ii) it is amenable to high-throughput, with less than 5 min acquisition time allowing the complete analysis of 200 plasma samples per day; (iii) it achieves absolute quantification, by inclusion of internal standards for every lipid class measured; (iv) it is highly reproducible, achieving an average coefficient of variation of <10% (intra-day), approx. 10% (inter-day), and approx. 15% (inter site) for most lipid species; (v) it is easily transferable allowing the direct comparison of data acquired in different sites. Moreover, we thoroughly assessed the influence of blood stabilization with different anticoagulants and freeze thaw cycles to exclude artifacts generated by sample preparation. Practical applications: This shotgun lipidomics platform can be implemented in different laboratories without compromising reproducibility, allowing multi-site studies and inter-laboratory comparisons. This possibility combined with the high throughput, broad lipidomic coverage and absolute quantification are important aspects for clinical applications and biomarker research. PMID- 26494981 TI - Archaeal Enzymes and Applications in Industrial Biocatalysts. AB - Archaeal enzymes are playing an important role in industrial biotechnology. Many representatives of organisms living in "extreme" conditions, the so-called Extremophiles, belong to the archaeal kingdom of life. This paper will review studies carried by the Exeter group and others regarding archaeal enzymes that have important applications in commercial biocatalysis. Some of these biocatalysts are already being used in large scale industrial processes for the production of optically pure drug intermediates and amino acids and their analogues. Other enzymes have been characterised at laboratory scale regarding their substrate specificity and properties for potential industrial application. The increasing availability of DNA sequences from new archaeal species and metagenomes will provide a continuing resource to identify new enzymes of commercial interest using both bioinformatics and screening approaches. PMID- 26494982 TI - Archaeal Nucleic Acid Ligases and Their Potential in Biotechnology. AB - With their ability to catalyse the formation of phosphodiester linkages, DNA ligases and RNA ligases are essential tools for many protocols in molecular biology and biotechnology. Currently, the nucleic acid ligases from bacteriophage T4 are used extensively in these protocols. In this review, we argue that the nucleic acid ligases from Archaea represent a largely untapped pool of enzymes with diverse and potentially favourable properties for new and emerging biotechnological applications. We summarise the current state of knowledge on archaeal DNA and RNA ligases, which makes apparent the relative scarcity of information on in vitro activities that are of most relevance to biotechnologists (such as the ability to join blunt- or cohesive-ended, double-stranded DNA fragments). We highlight the existing biotechnological applications of archaeal DNA ligases and RNA ligases. Finally, we draw attention to recent experiments in which protein engineering was used to modify the activities of the DNA ligase from Pyrococcus furiosus and the RNA ligase from Methanothermobacter thermautotrophicus, thus demonstrating the potential for further work in this area. PMID- 26494983 TI - Phase Transformation in Radially Merged Wurtzite GaAs Nanowires. AB - III-V Nanowires (NWs) grown with metal-organic chemical vapor deposition commonly show a polytypic crystal structure, allowing growth of structures not found in the bulk counterpart. In this paper we studied the radial overgrowth of pure wurtzite (WZ) GaAs nanowires and characterized the samples with high resolution X ray diffraction (XRD) to reveal the crystal structure of the grown material. In particular, we investigated what happens when adjacent WZ NWs radially merge with each other by analyzing the evolution of XRD peaks for different amounts of radial overgrowth and merging. By preparing cross-sectional lamella samples we also analyzed the local crystal structure of partly merged NWs by transmission electron microscopy. Once individual NWs start to merge, the crystal structure of the merged segments is transformed progressively from initial pure WZ to a mixed WZ/ZB structure. The merging process is then modeled using a simple combinatorial approach, which predicts that merging of two or more WZ NWs will result in a mixed crystal structure containing WZ, ZB, and 4H. The existence large and relaxed segments of 4H structure within the merged NWs was confirmed by XRD, allowing us to accurately determine the lattice parameters of GaAs 4H. We compare the measured WZ and 4H unit cells with an ideal tetrahedron and find that both the polytypes are elongated in the c-axis and compressed in the a-axis compared to the geometrically converted cubic ZB unit cell. PMID- 26494984 TI - Role of upstream stimulatory factor 2 in diabetic nephropathy. AB - Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD). About 20%-30% of people with type 1 and type 2 diabetes develop DN. DN is characterized by both glomerulosclerosis with thickening of the glomerular basement membrane and mesangial matrix expansion, and tubulointerstitial fibrosis. Hyperglycemia and the activation of the intra-renal renin-angiotensin system (RAS) in diabetes have been suggested to play a critical role in the pathogenesis of DN. However, the mechanisms are not well known. Studies from our laboratory demonstrated that the transcription factor-upstream stimulatory factor 2 (USF2) is an important regulator of DN. Moreover, the renin gene is a downstream target of USF2. Importantly, USF2 transgenic (Tg) mice demonstrate a specific increase in renal renin expression and angiotensin II (AngII) levels in kidney and exhibit increased urinary albumin excretion and extracellular matrix deposition in glomeruli, supporting a role for USF2 in the development of diabetic nephropathy. In this review, we summarize our findings of the mechanisms by which diabetes regulates USF2 in kidney cells and its role in regulation of renal renin-angiotensin system and the development of diabetic nephropathy. PMID- 26494985 TI - Thyroid dysfunction and pregnancy outcomes. AB - BACKGROUND: Pregnancy has a huge impact on the thyroid function in both healthy women and those that have thyroid dysfunction. The prevalence of thyroid dysfunction in pregnant women is relatively high. OBJECTIVE: The objective of this review was to increase awareness and to provide a review on adverse effect of thyroid dysfunction including hyperthyroidism, hypothyroidism and thyroid autoimmune positivity on pregnancy outcomes. MATERIALS AND METHODS: In this review, Medline, Embase and the Cochrane Library were searched with appropriate keywords for relevant English manuscript. We used a variety of studies, including randomized clinical trials, cohort (prospective and retrospective), case-control and case reports. Those studies on thyroid disorders among non-pregnant women and articles without adequate quality were excluded. RESULTS: Overt hyperthyroidism and hypothyroidism has several adverse effects on pregnancy outcomes. Overt hyperthyroidism was associated with miscarriage, stillbirth, preterm delivery, intrauterine growth retardation, low birth weight, preeclampsia and fetal thyroid dysfunction. Overt hypothyroidism was associated with abortion, anemia, pregnancy induced hypertension, preeclampsia, placental abruption, postpartum hemorrhage, premature birth, low birth weight, intrauterine fetal death, increased neonatal respiratory distress and infant neuro developmental dysfunction. However the adverse effect of subclinical hypothyroidism, and thyroid antibody positivity on pregnancy outcomes was not clear. While some studies demonstrated higher chance of placental abruption, preterm birth, miscarriage, gestational hypertension, fetal distress, severe preeclampsia and neonatal distress and diabetes in pregnant women with subclinical hypothyroidism or thyroid autoimmunity; the other ones have not reported these adverse effects. CONCLUSION: While the impacts of overt thyroid dysfunction on feto-maternal morbidities have been clearly identified and its long term impact on childhood development is well known, data on the early and late complications of subclinical thyroid dysfunction during pregnancy or thyroid autoimmunity are controversial. Further studies on maternal and neonatal outcomes of subclinical thyroid dysfunction maternal are needed. PMID- 26494986 TI - Relationship between progesterone level on the day of human chorionic gonadotropin administration with outcomes of intra-cytoplasmic sperm injection in infertile couples. AB - BACKGROUND: Gonadotropin-releasing hormone agonists or antagonists are used in assisted reproductive technique cycles as premature luteinizing hormone secretion inhibition. Studies have been reported different and contradictory results on the serum progesterone effect on intra-cytoplasmic sperm injection. OBJECTIVE: The purpose of this study was to evaluate the effect of serum progesterone level on the day of Human chorionic gonadotropin (HCG) administration on the intra cytoplasmic sperm injection (ICSI) outcome in infertile women. MATERIALS AND METHODS: 249 infertile couples candidated for ICSI were enrolled in the study. Their serum progesterone level on the day of HCG administration was measured and according to serum level, patients were divided into four groups of less than 0.9, 0.9-1.4, 1.5-1.9, and >=2 ng/mL. The four groups were compared with each other regarding fertility outcomes. RESULTS: Pregnancy rate was not significantly different among the four groups (p>0.05). Also, there was no significant difference among the groups regarding frequency of abortion and ectopic pregnancy. CONCLUSION: Serum progesterone level on the day of HCG administration does not have any significant effect on pregnancy outcomes, including abortion, ectopic pregnancy, and pregnancy rate in patients undergoing ICSI treatment. PMID- 26494987 TI - The existing therapeutic interventions for orgasmic disorders: recommendations for culturally competent services, narrative review. AB - BACKGROUND: In recent years, a growing number of interventions for treatment of female orgasmic problems (FODs) have emerged. Whereas orgasm is a extra biologically and learnable experience, there is a need for practitioners that to be able to select which therapy is the most appropriate to their context. OBJECTIVE: In this critical literature review, we aimed to assess areas of controversy in the existing therapeutic interventions in FOD with taking into accounted the Iranian cultural models. MATERIALS AND METHODS: For the present study, we conducted an extensive search of electronic databases using a comprehensive search strategy from 1970 till 2014. This strategy was using Google Scholar search, "pearl-growing" techniques and by hand-searching key guidelines, to identify distinct interventions to women's orgasmic problem therapy. We utilized various key combinations of words such as:" orgasm" OR "orgasmic "," female orgasmic dysfunction" OR Female anorgasmia OR Female Orgasmic Disorder ", orgasmic dysfunction AND treatment, "orgasm AND intervention". Selection criteria in order to be included in this review, studies were required to: 1 employ clinical-based interventions, 2 focus on FOD. RESULTS: The majority of interventions (90%) related to non-pharmacological and other were about pharmacological interventions. Self-direct masturbation is suggested as the most privilege treatment in FOD. Reviewing all therapies indicates couple therapy, sexual skill training and sex therapy seem to be more appropriate to be applied in Iranian clinical settings. CONCLUSION: Since many therapeutic interventions are introduced to inform sexually-related practices, it is important to select an intervention that will be culturally appropriate and sensitive to norms and values. Professionals working in the fields of health and sexuality need to be sensitive and apply culturally appropriate therapies for Iranian population. We further suggest community well defined protocols to screen, assessment and management of women' sexual problems such as FOD in the Iranian settings. PMID- 26494988 TI - Characterization of apoptosis and autophagy through Bcl-2 and Beclin-1 immunoexpression in gestational trophoblastic disease. AB - BACKGROUND: The pathogenesis of Gestational Trophoblastic Disease (GTD) is not clearly known. OBJECTIVE: In this study, immunoexpression of proteins Bcl-2 and Beclin-1 in trophoblastic lesions and normal trophoblastic tissue was conducted to study the mechanism of apoptotic and autophagic cell death that is expected to complete the study of GTD pathogenesis. MATERIALS AND METHODS: Bcl-2 and Beclin-1 immunoexpression were studied on complete hydatidiform mole, partial hydatidiform mole, invasive mole, choriocarcinoma and normal placenta slides. RESULTS: The average total scores of Bcl-2 immunoexpression had a decreasing value, starting from partial hydatidiform mole (3.09), complete hydatidiform mole (2.36), invasive mole (1.18) to choriocarcinoma (0) when compared to normal placenta (6). The results showed no significant difference in Beclin-1 immunoexpression total score between complete hydatidiform mole, partial hydatidiform mole and invasive mole, namely that the value of the average total score of Beclin-1 was low (2.27, 2.45 and 2.36), but on the contrary choriocarcinoma showed an increasing strong Beclin-1 expression with the average total score of 4.57. CONCLUSION: Bcl-2 expression decreases in line with the excessive proliferation of trophoblast cells in hydatidiform mole and leads to malignancy in invasive mole and choriocarcinoma. The decreased expression of Beclin-1 that leads to autophagy defects in complete hydatidiform mole, partial hydatidiform mole and invasive mole shows the role of autophagy as tumor suppressor, whereas strong Beclin-1 expression shows the survival role of autophagy in choriocarcinoma. The change of Bcl-2 activity as antiapoptosis and Beclin-1 as proautophagy plays a role in pathogenesis of GTD. PMID- 26494989 TI - Increased serum oxidized low-density lipoprotein levels in pregnancies complicated by gestational diabetes mellitus. AB - BACKGROUND: Elevated serum levels of oxidized Low-density Lipoprotein (oxLDL) have been found in type 2 and in poorly controlled diabetic patients. Gestational diabetes mellitus (GDM) has common features with type 2 diabetes. OBJECTIVE: The aim of our study was to evaluate the serum levels of oxLDL in women with GDM compared to normal pregnant women. MATERIALS AND METHODS: In this cross-sectional study, ninety-two subjects were randomly allocated to either GDM (n=46) or control (n=46) groups matched for age, body mass index and parity from March 2013 to March 2014. GDM was diagnosed according to the American Diabetes Association criteria at 24-26 weeks of gestation. OxLDL was measured using enzyme-linked immunosorbent assay. T-test and Pearson correlation coefficients were applied for analyzing the data by using SPSS version 17. RESULTS: Compared to the controls, significantly higher oxLDL levels were found in the GDM group (17.16 +/- 3.71 U/L vs. 8.77 +/- 1.84 U/L, respectively, p < 0.001). No significant correlations were found between oxLDL and age and BMI of the patients in the groups. CONCLUSION: Our study found significant increase of oxLDL in GDM emphasizing the role of short-term hyperglycemia in the formation of oxLDL during GDM. The importance of aptly diagnosis of GDM in maternal health may also be concluded. PMID- 26494990 TI - Large nuclear vacuoles in spermatozoa negatively affect pregnancy rate in IVF cycles. AB - BACKGROUND: Recently, motile sperm organelle morphology examination (MSOME) criteria as a new real time tool for evaluation of spermatozoa in intracytoplasmic sperm injection (ICSI) cycles has been considered. OBJECTIVE: The aim was to investigate the predictive value of MSOME in in vitro fertilization (IVF) in comparison to ICSI cycles and evaluation of the association between MSOME parameters and traditional sperm parameters in both groups. MATERIALS AND METHODS: This is a cross sectional prospective analysis of MSOME parameters in IVF (n=31) and ICSI cycles (n=35). MSOME parameters were also evaluated as the presence of vacuole (none, small, medium, large or mix); head size (normal, small or large); cytoplasmic droplet; head shape and acrosome normality. In sub-analysis, MSOME parameters were compared between two groups with successful or failed clinical pregnancy in each group. RESULTS: In IVF group, the rate of large nuclear vacuole showed significant increase in failed as compared to successful pregnancies (13.81+/-9.7vs7.38+/-4.4, respectively, p=0.045) while MSOME parameters were the same between successful and failed pregnancies in ICSI group. Moreover, a negative correlation was noticed between LNV and sperm shape normalcy. In ICSI group, a negative correlation was established between cytoplasmic droplet and sperm shape normalcy. In addition, there was a positive correlation between sperm shape normalcy and non-vacuolated spermatozoa. CONCLUSION: The high rate of large nuclear vacuoles in sperm used in IVF cycles with failed pregnancies confirms that MSOME, is a helpful tool for fine sperm morphology assessment, and its application may enhance the assisted reproduction technology success rates. PMID- 26494991 TI - Comparison of oral dydrogesterone with vaginal progesteronefor luteal support in IUI cycles: a randomized clinical trial. AB - BACKGROUND: The aim of this study, we have compared the advantages of oral dydrogestrone with vaginal progesterone (cyclogest) for luteal support in intrauterine insemination (IUI) cycles. Progesterone supplementation is the first line treatment when luteal phase deficiency (LPD) can reasonably be assumed. OBJECTIVE: This study was conduct to compare the effect of oral dydrogestrone with vaginal Cyclogest on luteal phase support in the IUI cycles. MATERIALS AND METHODS: This prospective, randomized, double blind study was performed in a local infertility center from May 2013 to May 2014. It consisted of 150 infertile women younger than35years old undergoing ovarian stimulation for IUI cycles. They underwent ovarian stimulation with oral dydrogesterone (20 mg) as group A and vaginal cyclogest (400 mg) as group B in preparation for the IUI cycles. Clinical pregnancy and abortion rates, mid luteal progesterone (7daysafter IUI) and patient satisfaction were compared between two groups. RESULTS: The mean serum progesterone levels was significantly higher in group A in comparison with group B (p=0.001). Pregnancy rates in group A was not statistically different in comparison with group B (p =0.58). Abortion rate in two groups was not statistically different (p =0.056) although rate of abortion was higher in group B in comparison with A group. Satisfaction rates were significantly higher in group A compared to group B (p<0.001). CONCLUSION: We concluded that oral dydrogestrone is effective as vaginal progesterone for luteal-phase support in woman undergoing IUI cycles. Moreover, the mean serum progesterone levels and satisfaction rates in dydrogestrone group were higher than cyclogest group. PMID- 26494992 TI - Evaluation of the melatonin and oxidative stress markers level in serum of fertile and infertile women. AB - BACKGROUND: Infertility is defined as the inability to achieve the pregnancy within a year of unprotected intercourse. Infertility is a complex issue and different factors such as stress oxidative can be involved in this problem. So, any attempt to neutralize oxidative stress would be helpful in the treatment of infertility. Melatonin is a known scavenger of free radicals. OBJECTIVE: The aim of our study was to evaluate the level of melatonin and its correlation with oxidative biomarkers in fertile and infertile women. MATERIALS AND METHODS: The participants including fertile and infertile women were divided into two groups of 30 people. Blood sampling was performed and sera were collected. The level of Malondialdehyde (MDA), total antioxidant capacity (TAC) and melatonin were detected. Data were analyzed using T-test and their correlation was assessed using Spearman test. RESULTS: Serum melatonin from fertile women was higher than infertile women but the difference was not significant (p= 0.46). MDA level in fertile women was significantly lower than infertile women (p<0.001) and the level of TAC in fertile women was significantly higher than infertile women (p<0.001). Spearman test revealed a significant and direct correlation between melatonin and TAC in fertile and infertile women and a significant but reverse correlation between melatonin and MDA in infertile and fertile women. CONCLUSION: Differences in the level of oxidative stress biomarkers in fertile and infertile individuals have been reported. This study revealed a significant correlation between melatonin and oxidative stress biomarkers, concluding that melatonin level could be involved in infertility. PMID- 26494993 TI - Successful local and systemic medical treatment of cesarean scar pregnancy and a subsequent term pregnancy after treatment: a case series. AB - BACKGROUND: Treatment of cesarean scar pregnancy (CSP) is controversial. The objective of this study was to report our successful experience in the medical treatment of CSP with potassium chloride (KCl) and methotrexate. CASE: This is a case series of six patients between 6-12 gestational weeks with the diagnosis of CSP. In five cases the fetus was alive and in one case, despite being at a gestational age of 12 weeks based on CRL, there was no fetal heart activity. In four of these cases, an ultrasound- guided KCl injection in the heart was performed on four living fetuses and then systemic methotrexate was administered. In two other cases, methotrexate was injected into the gestational sac and subsequently the systemic methotrexate was administered. During follow-up, the patients were stable and no complications occurred. Additionally, serum beta human chorionic gonadotropin (beta-hCG) was negative between five to 11 weeks later. One of the patients became pregnant one year later. Her pregnancy continued without any complication and she was delivered by cesarean section at the gestational age of 38 weeks. During caesarean section, it was noticed that the appearance of previous cesarean scar was normal and there was no scar. CONCLUSION: Based on our experience, the combination of systemic Methotrexate with local Methotrexate or KCl is feasible and can be performed as an outpatient procedure and is successful in the treatment of CSP. PMID- 26494994 TI - Treatment of Urethral Strictures from Irradiation and Other Nonsurgical Forms of Pelvic Cancer Treatment. AB - Radiation therapy (RT), external beam radiation therapy (EBRT), brachytherapy (BT), photon beam therapy (PBT), high intensity focused ultrasound (HIFU), and cryotherapy are noninvasive treatment options for pelvic malignancies and prostate cancer. Though effective in treating cancer, urethral stricture disease is an underrecognized and poorly reported sequela of these treatment modalities. Studies estimate the incidence of stricture from BT to be 1.8%, EBRT 1.7%, combined EBRT and BT 5.2%, and cryotherapy 2.5%. Radiation effects on the genitourinary system can manifest early or months to years after treatment with the onus being on the clinician to investigate and rule-out stricture disease as an underlying etiology for lower urinary tract symptoms. Obliterative endarteritis resulting in ischemia and fibrosis of the irradiated tissue complicates treatment strategies, which include urethral dilation, direct-vision internal urethrotomy (DVIU), urethral stents, and urethroplasty. Failure rates for dilation and DVIU are exceedingly high with several studies indicating that urethroplasty is the most definitive and durable treatment modality for patients with radiation-induced stricture disease. However, a detailed discussion should be offered regarding development or worsening of incontinence after treatment with urethroplasty. Further studies are required to assess the nature and treatment of cryotherapy and HIFU-induced strictures. PMID- 26494995 TI - Visual Internal Urethrotomy for Adult Male Urethral Stricture Has Poor Long-Term Results. AB - Objective. To determine the long-term stricture-free rate after visual internal urethrotomy following initial and follow-up urethrotomies. Methods. The records of all male patients who underwent direct visual internal urethrotomy for urethral stricture disease in our hospital between July 2004 and May 2012 were reviewed. The Kaplan-Meier method was used to analyze stricture-free probability after the first, second, third, fourth, and fifth urethrotomies. Results. A total of 301 patients were included. The overall stricture-free rate at the 36-month follow-up was 8.3% with a median time to recurrence of 10 months (95% CI of 9.5 to 10.5, range: 2-36). The stricture-free rate after one urethrotomy was 12.1% with a median time to recurrence of eight months (95% CI of 7.1-8.9). After the second urethrotomy, the stricture-free rate was 7.9% with a median time to recurrence of 10 months (95% CI of 9.3 to 10.6). After the third to fifth procedures, the stricture-free rate was 0%. There was no significant difference in the stricture-free rate between single and multiple procedures. Conclusion. The long-term stricture-free rate of visual internal urethrotomy is modest even after a single procedure. PMID- 26494996 TI - Impact of Short-Stay Urethroplasty on Health-Related Quality of Life and Patient's Perception of Timing of Discharge. AB - Objective. To evaluate health-related quality of life in patients after a short stay or outpatient urethroplasty. Methods. Over a 2-year period a validated health-related quality-of-life questionnaire, EuroQol (EQ-5D), was administered to all patients after urethroplasty. Postoperatively patients were offered to be sent home immediately or to stay overnight. Within 24 hours after discharge they were assessed for mobility, self-care, usual activities, pain or discomfort, and anxiety and depression. An additional question assessing timing of discharge was added to the survey. Clinical and operative characteristics were examined. Results. Forty-eight patients after anterior urethroplasty completed the survey. Mean age and mean stricture length were 51.6 years (21-78) and 60 mm (5-200 mm), respectively. Most etiologies were idiopathic (50% n = 24), trauma (19%, n = 9), and iatrogenic (19%, n = 9). Forty-one patients (85%) stayed overnight, while 7 patients (15%) chose to be discharged the same day. Overall, ninety-six percent were discharged within 23 hours of surgery. In the short-stay and the outpatient cohorts, 90% and 86%, respectively, felt they were discharged on time. No patient reported a severe problem with postoperative pain or mobility. Conclusions. The majority of patients discharged soon after their procedure felt that discharge timing was appropriate and their health-related quality of life was only minimally affected. PMID- 26494997 TI - Anastomotic Repair versus Free Graft Urethroplasty for Bulbar Strictures: A Focus on the Impact on Sexual Function. AB - Objectives. To evaluate alterations in sexual function and genital sensitivity after anastomotic repair (AR) and free graft urethroplasty (FGU) for bulbar urethral strictures. Methods. Patients treated with AR (n = 31) or FGU (n = 16) were prospectively evaluated before, 6 weeks and 6 months after urethroplasty. Evaluation included International Prostate Symptom Score (IPSS), 5-Item International Index of Erectile Function (IIEF-5), Ejaculation/Orgasm Score (EOS), and 3 questions on genital sensitivity. Results. At 6 weeks, there was a significant decline of IIEF-5 for AR (-4.8; p = 0.005), whereas there was no significant change for FGU (+0.9; p = 0.115). After 6 months, differences with baseline were not significant overall and among subgroups. At 6 weeks, there was a significant decline in EOS for AR (-1.4; p = 0.022). In the FGU group there was no significant change (+0.6; p = 0.12). Overall and among subgroups, EOS normalized at 6 months. After 6 weeks and 6 months, respectively, 62.2 and 52% of patients reported alterations in penile sensitivity with no significant differences among subgroups. Conclusions. AR is associated with a transient decline in erectile and ejaculatory function. This was not observed with FGU. Bulbar AR and FGU are likely to alter genital sensitivity. PMID- 26494998 TI - Glycemic Control in Kenyan Children and Adolescents with Type 1 Diabetes Mellitus. AB - Background. Type 1 diabetes mellitus (T1DM) is the most common endocrine disorder in children and adolescents worldwide. While data about prevalence, treatment, and complications are recorded in many countries, few data exist for Sub-Saharan Africa. The aim of this study was to determine the degree of control in patients with T1DM aged 1-19 years over a 6-month period in 3 outpatient Kenyan clinics. It also sought to determine how control was influenced by parameters of patient and treatment. Methods. Eighty-two children and adolescents with T1DM were included in the study. Clinical history regarding duration of illness, type and dose of insulin, and recent symptoms of hypoglycemia/hyperglycemia were recorded. Glycaemia, HbA1c, and ketonuria were tested. HbA1c of 8.0% and below was defined as the cut-off for acceptable control. Results. The median HbA1c for the study population was 11.1% (range: 6.3-18.8). Overall, only 28% of patients had reasonable glycemic control as defined in this study. 72% therefore had poor control. It was also found that age above 12 years was significantly associated with poor control. Conclusions. African children and with T1DM are poorly controlled particularly in adolescents. Our data strongly support the necessity of Kenya children to receive more aggressive management and follow-up. PMID- 26494999 TI - Reported Diabetes Mellitus Prevalence Rates in the Colombia Healthcare System from 2009 to 2012: Analysis by Regions Using Data of the Official Information Sources. AB - The objective of this study was to describe the reported diabetes mellitus (DM) prevalence rates of the 20-79-year-old population in Colombia from 2009 to 2012 reported by the healthcare system. Information on number of patients treated for DM was obtained by the Integral Information System of Social Protection (SISPRO), the registry of the Ministry of Health and Social Protection, and the High Cost Account (CAC), an organization to trace high expenditure diseases. From both sources age-standardized reported DM prevalence rates per 100.000 inhabitants from 2009 to 2012 were calculated. Whereas the reported DM prevalence rates of SISPRO revealed an increase from 964/100.000 inhabitants (2009) to 1398/100.000 inhabitants in 2012 (mean annual increase 141/100.000; p value: 0.001), the respective rates in the CAC register were 1082/100.000 (2009) and 1593/100.000 in 2012 (mean annual increase 165/100.000; p value: 0.026). The number of provinces reporting not less than 19% of the highest national reported DM prevalence rates (1593/100.000) increased from two in 2009 to ten in 2012. Apparently, the registries and the information retrieving system have been improved during 2009 and 2012, resulting in a greater capacity to identify and report DM cases by the healthcare system. PMID- 26495000 TI - Nanomodified Peek Dental Implants: Bioactive Composites and Surface Modification A Review. AB - Purpose. The aim of this review is to summarize and evaluate the relevant literature regarding the different ways how polyetheretherketone (PEEK) can be modified to overcome its limited bioactivity, and thereby making it suitable as a dental implant material. Study Selection. An electronic literature search was conducted via the PubMed and Google Scholar databases using the keywords "PEEK dental implants," "nano," "osseointegration," "surface treatment," and "modification." A total of 16 in vivo and in vitro studies were found suitable to be included in this review. Results. There are many viable methods to increase the bioactivity of PEEK. Most methods focus on increasing the surface roughness, increasing the hydrophilicity and coating osseoconductive materials. Conclusion. There are many ways in which PEEK can be modified at a nanometer level to overcome its limited bioactivity. Melt-blending with bioactive nanoparticles can be used to produce bioactive nanocomposites, while spin-coating, gas plasma etching, electron beam, and plasma-ion immersion implantation can be used to modify the surface of PEEK implants in order to make them more bioactive. However, more animal studies are needed before these implants can be deemed suitable to be used as dental implants. PMID- 26495001 TI - Characterization of Staphylococcus aureus Isolates That Colonize Medical Students in a Hospital of the City of Cali, Colombia. AB - Introduction. Nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) represents a risk for the spread of bacteria. This study characterized the S. aureus isolated from medical students, who were in their clinical rotation at a hospital in the city of Cali. Materials and Methods. 216 students participated in the study and 63 isolates of S. aureus were evaluated for susceptibility and PCR amplification of agr and mecA genes. The origin of MRSA isolates was established by analyzing agr polymorphisms. Results. A total of 29.2% of students were colonized by S. aureus and nasal carriage rate was 23.6% and 14.3% MRSA. Three agr groups (agr II, and agr III) were identified; the agr I group was the most common, with a 35% prevalence; this group is from community origin. Conclusion. The present study demonstrates that medical students carry S. aureus strains, with the threat of spreading them both to community and hospital environments. PMID- 26495002 TI - Efficacy of Epley's Maneuver in Treating BPPV Patients: A Prospective Observational Study. AB - Vertigo and balance disorders are among the most common symptoms encountered in patients who visit ENT outpatient department. This is associated with risk of falling and is compounded in elderly persons with other neurologic deficits and chronic medical problems. BPPV is the most common cause of peripheral vertigo. BPPV is a common vestibular disorder leading to significant morbidity, psychosocial impact, and medical costs. The objective of Epley's maneuver, which is noninvasive, inexpensive, and easily administered, is to move the canaliths out of the canal to the utricle where they no longer affect the canal dynamics. Our study aims to analyze the response to Epley's maneuver in a series of patients with posterior canal BPPV and compares the results with those treated exclusively by medical management alone. Even though many studies have been conducted to prove the efficacy of this maneuver, this study reinforces the validity of Epley's maneuver by comparison with the medical management. PMID- 26495003 TI - Unusual Paraneoplastic Presentation of Cholangiocarcinoma. AB - Introduction. Cutaneous paraneoplastic syndromes are a heterogeneous group of skin manifestations that occur in relation to many known malignancies. Paraneoplastic occurrence of SCLE has been noted but is not commonly reported. SCLE association with cholangiocarcinoma is rare. Case Presentation. A 72-year old man with a history of extrahepatic stage IV cholangiocarcinoma presented with a pruritic rash. Cholangiocarcinoma had been diagnosed three years earlier and was treated. Five months after interruption of his chemotherapy due to a semiurgent surgery, he presented with explosive onset of a new pruritic rash, arthralgias, and lower extremity edema. Physical exam revealed a scaly erythematous rash on his arms, hands, face, neck, legs, and trunk. It was thick and scaly on sun exposed areas. Skin biopsy revealed vacuolar interface dermatitis. Immunofluorescence revealed IgM positive cytoid bodies scattered along the epidermal basement membrane zone. PET-CT scanning revealed metabolically active recurrent disease in peripancreatic and periportal region with hypermetabolic lymph nodes. Oral steroids and new regimen of chemotherapy were started. Rash improved and steroids were tapered off. Discussion. Paraneoplastic syndromes demonstrate the complex interaction between the immune system and cancer. Treatment resistant SCLE should raise a suspicion for paraneoplastic etiology. PMID- 26495004 TI - A Retrospective Analysis of Patients' Conditions Using Acupuncture in a Traditional Korean Medicine Hospital. AB - Objective. The aim of this study was to identify the patient demographics, health issues, and type of acupuncture treatments who visited a traditional Korean medical hospital for acupuncture treatment. Methods. We retrospectively analysed the data using the electronic medical records (EMRs) of patients treated with at least one treatment of acupuncture from 1 January 2010 to December 2012 in the Chung-Ju Korean hospital at Semyung University. Results. The total number of identified patients was 1189 inpatients and 10138 outpatients. The 50-59 age group received acupuncture treatment in the hospital the most, followed by the 40 49 age group. Among the patients undergoing acupuncture treatment because of a diagnosis of pain, 82.74% were outpatients and 72.85% were inpatients. Additionally, all patients with a spine condition received acupuncture treatment. The most common musculoskeletal conditions of patients at the traditional Korean medicine (TKM) hospital were associated with spine conditions, such as low back pain and neck pain. Various treatments have been performed at the hospital in conjunction with acupuncture. The study results show a high prevalence of acupuncture treatment for diagnosed diseases. Conclusion. Our study suggests the need to investigate additional TKM hospitals to analyse characteristics of patients who received specific treatments. Analysis of the characteristics of patients treated with Korean acupuncture at the TKM hospital in this study will help future researchers who want to implement strong clinical evidence. However, we cannot completely discount all symptoms because of the retrospective nature of this study, and only one hospital was used, which limits the generalisation of our findings. PMID- 26495005 TI - Extra Virgin Olive Oil Polyphenols Promote Cholesterol Efflux and Improve HDL Functionality. AB - Results of the present work give evidence from the beneficial role of extra virgin olive of oil (EVOO) consumption towards oxidative stress and cardiovascular diseases. Polyphenols contained in EVOO are responsible for inhibiting lipoproteins oxidative damages and promoting reverse cholesterol transport process via ABCA1 pathway. PMID- 26495006 TI - Active Compounds of Rhubarb Root and Rhizome in Animal Model Experiments of Focal Cerebral Ischemia. AB - Rhubarb root and rhizome (RRR) has been clinically used for stroke at least 2000 years and is still used in modern times in both China and elsewhere worldwide. The objective of present study was to evaluate the efficacy of active compounds of RRR (ACRRR) for experimental ischemic stroke. Studies of ACRRR in animal models of ischemic stroke were identified from 5 databases until April 2014. Study quality for each included article was evaluated according to the CAMARADES 10-item checklist. Outcome measures were neurological deficit score and infarct size. All the data were analyzed using RevMan 5.1 software. As a result, 20 studies were identified describing procedures involving 577 animals. The quality score of studies ranges from 2 to 6, and the median was 3.4. Six studies showed significant effects of ACRRR for improving infarct size compared with model group (P < 0.01). Six studies indicated significant effects of ACRRR for improving the neurological deficit scores according to Zea longa criterion or eight-point criterion (P < 0.01). In conclusion, these findings demonstrated a possible efficacy of ACRRR that have potential neuroprotective effect for experimental ischemic stroke. However, these apparently positive findings should be interpreted with caution because of the methodological flaws. PMID- 26495007 TI - Sibjotang Increases Atrial Natriuretic Peptide Secretion in Beating Rabbit Atria. AB - Sibjotang (Shizaotang), traditional herbal medicine formula, which was first documented in the Shanghanlun, has long been prescribed for the treatment of impairment of the body fluid homeostasis. The purpose of the present study was to identify the effects of Sibjotang on the secretion of a cardiac hormone, atrial natriuretic peptide (ANP), one of the main hormones involved in the regulation of the body fluid and blood pressure homeostasis. Water extract of Sibjotang increased ANP secretion concomitantly with an increase in atrial dynamics in a concentration-dependent manner. Sibjotang-induced increase in ANP secretion and positive inotropic effect were attenuated by GO6976 and LY333531, selective inhibitors of conventional protein kinase C, but not Rottlerin, an inhibitor of novel PKC delta . Similarly to the effect of Sibjotang, extracts of components of Sibjotang, Euphorbia kansui, and Daphne genkwa, but not Euphorbia pekinensis and Ziziphus jujuba, increased ANP secretion and atrial dynamics. Ingredients of Sibjotang, apigenin, rosmarinic acid, and salvianolic acid B decreased ANP secretion and atrial dynamics. These findings suggest that Sibjotang increases ANP secretion and atrial dynamics via activation of conventional protein kinase C signaling. This finding provides experimental evidence for the rationale in the use of Sibjotang in the treatment of impairment of the regulation of body fluid and blood pressure homeostasis. PMID- 26495008 TI - The Effects of Chinese Medicine on Activation of Wnt/beta-Catenin Signal Pathway under High Glucose Condition. AB - Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia and a series of complications. The Wnt/beta-catenin signaling pathway is a complex protein interaction network, which is also a key regulator of cell proliferation and differentiation. Many scholars have found that high glucose can activate the Wnt signaling pathway. However, the effects of activation of this pathway in the presence of high glucose levels during the progression of diabetes still remained unclear. Here, we provide a review of the study on the effects of high glucose state on the Wnt/beta-catenin signal pathway and the influence of Chinese medicine on it. PMID- 26495009 TI - Prophylactic Treatment with Adlay Bran Extract Reduces the Risk of Severe Acute Radiation Dermatitis: A Prospective, Randomized, Double-Blind Study. AB - Acute radiation dermatitis is a frequent adverse effect in patients with breast cancer undergoing radiotherapy, but there are only a small number of studies providing evidence-based interventions for this clinical condition. Adlay is a cereal crop that has been previously shown to have anti-inflammatory and antioxidant properties. In this study, we seek to evaluate the effectiveness of oral prophylactic treatment with adlay bran extract in reducing the risk of severe acute radiation dermatitis. A total of 110 patients with breast cancer undergoing radiotherapy were analyzed. Using a prospective, randomized, double blind design, 73 patients received oral treatment with adlay bran extract and 37 patients received olive oil (placebo). Treatment was started at the beginning of radiation therapy and continued until the termination of radiation treatment. Our results showed that the occurrence of severe acute radiation dermatitis (RTOG grade 2 or higher) was significantly lower in patients treated with oral adlay bran extract compared to placebo (45.2% versus 75.7%, adjusted odds ratio 0.24). No serious adverse effects from adlay bran treatment were noted. In conclusion, prophylactic oral treatment with adlay bran extract reduces the risk of severe acute radiation dermatitis and may have potential use in patients with breast cancer undergoing radiotherapy. PMID- 26495011 TI - Pain-Induced Pulsograph Changes in Patients with Primary Dysmenorrhea: A Pilot Study. AB - Objectives. To investigate changes in pulsograph caused by pain in primary dysmenorrhea (PD) patients. Methods. Pulsograph and pain level of PD patients were detected using electropulsograph and Visual-Analogue Scale (VAS), respectively, at four time points, 7-10 days before menstruation (T0), maximal pain during menstruation (T1), immediately after acupuncture analgesia (T2), and 30 mins after acupuncture analgesia (T3). Parameters (t, h, w) and normalized time parameters (t') of pulsograph were analyzed. Results. VAS pain scores decreased from 6.40 +/- 1.13 at T1 to 0.70 +/- 0.75 at T2 to 0.11 +/- 0.32 at T3 (P < 0.001 and 0.001). At T1, compared with those at T0, w1, h3, and h4 significantly increased (P < 0.01), and t2, t2', t3', and h(d) significantly decreased (P < 0.01, 0.001, 0.05, and 0.001). At T2, compared with those at T1, t1, w1, w2, h2, h3, t1', and t4' significantly decreased (P < 0.05, 0.01, 0.01, 0.001, 0.01, 0.001, and 0.05), and h(d) significantly increased (P < 0.001). There was no difference between T2 and T3. Conclusions. There are almost opposite changing trends in pulsographic parameters when pain occurs and when it is relieved in PD patients. PMID- 26495010 TI - Luteolin Ameliorates Hypertensive Vascular Remodeling through Inhibiting the Proliferation and Migration of Vascular Smooth Muscle Cells. AB - Objectives. Preliminary researches showed that luteolin was used to treat hypertension. However, it is still unclear whether luteolin has effect on the hypertensive complication such as vascular remodeling. The present study was designed to investigate the effect of luteolin on the hypertensive vascular remodeling and its molecular mechanism. Method and Results. We evaluated the effect of luteolin on aorta thickening of hypertension in spontaneous hypertensive rats (SHRs) and found that luteolin could significantly decrease the blood pressure and media thickness of aorta in vivo. Luteolin could inhibit angiotensin II- (Ang II-) induced proliferation and migration of vascular smooth muscle cells (VSMCs). Dichlorofluorescein diacetate (DCFH-DA) staining result showed that luteolin reduced Ang II-stimulated ROS production in VSMCs. Furthermore, western blot and gelatin zymography results showed that luteolin treatment leaded to a decrease in ERK1/2, p-ERK1/2, p-p38, MMP2, and proliferating cell nuclear antigen (PCNA) protein level. Conclusion. These data support that luteolin can ameliorate hypertensive vascular remodeling by inhibiting the proliferation and migration of Ang II-induced VSMCs. Its mechanism is mediated by the regulation of MAPK signaling pathway and the production of ROS. PMID- 26495012 TI - Role of Auriculotherapy in the Treatment of Temporomandibular Disorders with Anxiety in University Students. AB - Introduction. The aim of this study was to evaluate the role of auriculotherapy with mustard seeds in the treatment of temporomandibular disorders (TMDs), anxiety, and electromyographic (EMG) activity in university students. Methodology. The State Trait Anxiety Inventory (STAI), Research Diagnostic Criteria (RDC) for TMDs (RDC/TMDs), and electromyography were used in this study of 44 college students with high levels of anxiety and TMDs. The subjects were divided into two groups: an auriculotherapy (AA) group (n = 31) and an AA sham group (n = 13). The mustard seeds were applied to the shenmen, rim, sympathetic, brain stem, and temporomandibular joint (TMJ) points in the AA group and to sham points in the external ear and wrist in the AA sham group. The treatment protocol was 10 sessions (two treatments per week). Results. Anxiety (p < 0.01) was significantly reduced in the AA group. This group also showed a decrease in tender points in the mandibular posterior region (p = 0.04) and in the right side of the submandibular region (p = 0.02). Complaints of bilateral pain were reduced in the temporal tendon (p <= 0.01) and in the left side of the ATM (p < 0.01). In addition, electromyographic (EMG) activity was reduced during temporal muscle contraction (p = 0.03). Conclusion. Auriculotherapy was effective in the treatment of students with anxiety and TMDs. PMID- 26495013 TI - Suppression of Propionibacterium acnes-Induced Dermatitis by a Traditional Japanese Medicine, Jumihaidokuto, Modifying Macrophage Functions. AB - Purpose. Macrophages serve as sweepers of microbes and inflammation-derived wastes and regulators of inflammation. Some traditional Japanese medicines are reported to have adjuvant effects by modifying macrophages. Our aim was to characterize the actions of jumihaidokuto (JHT) for treatment of skin inflammations including acne vulgaris, in which Propionibacterium acnes has pathogenic roles. Methods. Dermatitis was induced in rat ears by intradermal injection of P. acnes. JHT or prednisolone (PDN) was given orally, and ear thickness and histology were evaluated. The effects of constituents and metabolites of JHT on monocytes were tested by cell-based assays using the human monocytic THP-1 cell. Results. JHT and PDN suppressed the ear thickness induced by P. acnes injection. Histological examinations revealed that JHT, but not PDN, promoted macrophage accumulation at 24 h after the injection. PDN suppressed the macrophage chemokine MCP-1 in the inflamed ears, while JHT did not affect it. The JHT constituents liquiritigenin and isoliquiritin increased expression of CD86 (type-1 macrophage marker) and CD192 (MCP-1 receptor) and enhanced phagocytosis by THP-1. Conclusions. JHT suppressed dermatitis, probably by enhancing type-1 macrophage functions, with an action different from PDN. JHT may be a beneficial drug in treatment of skin inflammation induced by P. acnes. PMID- 26495014 TI - "Ninjinto" (Ginseng Decoction), a Traditional Japanese Herbal Medicine, Improves Gastrointestinal Symptoms and Immune Competence in Patients with Chronic Intestinal Failure. AB - Background. Treating functional gastrointestinal disorders is extremely difficult. We herein report the effect of the oral administration of Ninjinto (NJT, ginseng decoction), a traditional Japanese Kampo medicine, on chronic intestinal failure. Patients and Methods. Seven patients with chronic intestinal failure treated with NJT were evaluated in this study. The primary diseases included chronic intestinal pseudoobstruction (CIPO: n = 4), short bowel syndrome (SBS: n = 2), and intestinal atresia (n = 1). All patients orally received NJT extract granules at a dose of 0.3 g/kg BW per day. The treatment outcomes were then assessed according to the patients' symptoms and consecutive abdominal X-ray findings. Results. The targeted symptoms were abdominal distension in four patients, diarrhea in three patients, and frequent hospitalization due to infections in two patients. An improvement in the symptoms was observed in six of the seven patients, whereas one patient with SBS did not show any improvement. An improvement in an abdominal roentgenogram was observed in the four patients with remarkably dilated bowel loops due to CIPO. Conclusions. NJT may be effective in controlling functional gastrointestinal disorders associated with chronic intestinal failure. The use of Kampo medicine in the field of pediatric surgery may help to improve the quality of life in children suffering from such conditions. PMID- 26495015 TI - Antitumor Activity of Tenacissoside H on Esophageal Cancer through Arresting Cell Cycle and Regulating PI3K/Akt-NF-kappaB Transduction Cascade. AB - Objective. The purpose of the study was to elucidate the molecular mechanism of tenacissoside H (TDH) inhibiting esophageal carcinoma infiltration and proliferation. Methods. In vitro, EC9706 cells were treated with TDH. Cells proliferation and cell cycle were assayed. PI3K and NF-kappaB mRNAs expression were determined by real time PCR. In vivo, model of nude mice with tumor was established. Mice were treated with TDH. Inhibition ratio of tumor volume was calculated. PCNA expression was examined. Protein expression in PI3K/Akt-NF kappaB signaling pathway was determined. Results. In vitro, TDH significantly inhibited cells proliferation in a time-and-dose-dependent manner. TDH arrested the cell cycle in S phase and significantly inhibited PI3K and NF-kappaB mRNA expression, compared with blank controlled group (P < 0.05). In vivo, TDH strongly inhibits tumor growth and volume. PCNA expression was significantly decreased after treatment of TDH. TDH downregulated proteins expression in PI3K/Akt-NF-kappaB transduction cascade (P < 0.05). Conclusion. TDH inhibited esophageal carcinoma infiltration and proliferation both in vitro and in vivo. The anticancer activity has relation to arresting the cell cycle at the S phase, inhibited the PCNA expression of transplanted tumors in nude mice, and regulated the protein expression in the PI3K/Akt-NF-kappaB transduction cascade. PMID- 26495016 TI - The Effect of Xuefuzhuyu Oral Liquid on Aspirin Resistance and Its Association with rs5911, rs5787, and rs3842788 Gene Polymorphisms. AB - Aspirin should be continued indefinitely in patients after interventional therapy, but 10% to 40% of patients experience recurrent vascular events despite adequate aspirin therapy, a condition known as aspirin resistance (AR). Xuefuzhuyu oral liquid, derived from the classic recipe Xuefuzhuyu decoction, has been well documented to inhibit platelet aggregation and to improve hemorheology. The aims of this study were to investigate the effects of Xuefuzhuyu oral liquid on AR in patients with chronic stable angina after percutaneous coronary intervention (PCI) and the possible genetic markers related to the drug response. 43 patients diagnosed as having aspirin resistance or semi-resistance were randomly divided into control and treatment groups after screening 207 stable CHD patients. Platelet aggregation rate was determined using turbidimetry. Three single nucleotide polymorphisms in COX-1 (rs5787, rs3842788) and GP IIb (rs5911) were genotyped in whole blood samples using ABI PRISM 7900 HT Fast Real-Time instrument and ABI PRISM 3730 DNA Sequencer. The results showed that Xuefuzhuyu oral liquid could effectively improve blood stasis syndrome and AR by inhibiting ADP-induced platelet aggregation and that patients with the rs5911 genetic variant exhibited better drug response upon treatment with Xuefuzhuyu oral liquid, which suggests Xuefuzhuyu oral liquid as a new possible drug for the prevention of AR. PMID- 26495017 TI - Effect of Auricular Acupressure on Uremic Pruritus in Patients Receiving Hemodialysis Treatment: A Randomized Controlled Trial. AB - Background. Uremic pruritus (UP) is a common symptom in patients undergoing maintenance hemodialysis for end-stage renal disease (ESRD). Objective. To determine the clinical efficacy of auricular acupressure therapy on pruritus in hemodialysis patients and to explore possible underlying mechanisms. Methods. Patients receiving maintenance hemodialysis at a referral medical center were recruited and assigned to intervention (n = 32) and control (n = 30) groups. The intervention group underwent auricular acupressure treatment three times a week for six weeks. Auricular acupressure was not applied to patients in the control group. However, tape without Vaccaria seeds was applied to the same six auricular acupoints as the intervention group. Pruritus scores were assessed using VAS scores, and enzyme-linked immunosorbent assays (ELISA) were used to measure levels of other possible contributory biochemical factors. Results. There was a significant difference in mean VAS scores between the postintervention and control groups during follow-up (3.844 +/- 1.687 versus 5.567 +/- 2.285, F = 22.32, P < 0.0001). Compared to the control group, serum histamine levels in the postintervention group at the six-week follow-up had decreased significantly (F = 5.01, P = 0.0290). Conclusion. Our findings suggest that auricular acupressure may be a useful treatment in the multidisciplinary management of UP in ESRD patients. PMID- 26495018 TI - Shenqi Fuzheng Injection Combined with Chemotherapy for Breast Cancer: A Meta Analysis of Randomized Controlled Trials. AB - Purpose. To evaluate the therapeutic effectiveness and safety of shenqi fuzheng injection (SFI) in the associated chemotherapy of breast cancer. Methods. 1247 subjects were included in this study for meta-analysis with RevMan 5.3. Results. The clinical curative effective rate (OR = 2.03, 95% Cl [1.44, 2.86], P < 0.0001), grades of KPS (OR = 4.11, 95% Cl [2.74, 6.16], P < 0.00001), CD3(+) cells (MD = 7.05, 95% Cl [0.45, 13.64], P = 0.04) and CD4(+) cells (MD = 8.60, 95% Cl [2.67, 14.54], P = 0.004) and CD4/CD8(+) cells (MD = 0.35, 95% Cl [0.14, 0.56], P = 0.001), WBC (OR = 0.30, 95% Cl [0.20, 0.46], P <= 0.0001), PLT (OR = 0.36, 95% Cl [0.20, 0.67], P = 0.001), gastrointestinal reaction (OR = 0.21, 95% Cl [0.14, 0.32], P < 0.00001), and ECG (OR = 0.26, 95% Cl [0.13, 0.51], P < 0.0001) in the experimental group were superior to the control group. While there were no differences between two groups in CD8(+) (MD = 0.21, 95% Cl [-2.81, 3.23], P = 0.89), NK(+) (MD = 1.06, 95% Cl [-9.40, 11.53], P = 0.84), RBC (OR = 0.49, 95% Cl [0.14, 1.74], P = 0.27), liver function (OR = 0.59, 95% Cl [0.28, 1.24], P = 0.16), renal function (OR = 0.56, 95% Cl [0.13, 2.45], P = 0.44), and bone marrow suppression (OR = 0.50, 95% Cl [0.25, 1.01], P = 0.05). Conclusion. SFI combined with chemotherapy, to some extent, can improve the effectiveness and the security in the treatment of breast cancer; the mechanism may be related to the elevated immunity. PMID- 26495019 TI - Chinese Herbal Medicines Might Improve the Long-Term Clinical Outcomes in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: Results of a Decision-Analytic Markov Model. AB - Aims. The priority of Chinese herbal medicines (CHMs) plus conventional treatment over conventional treatment alone for acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) was documented in the 5C trial (chictr.org number: ChiCTR-TRC-07000021). The study was designed to evaluate the 10-year effectiveness of CHMs plus conventional treatment versus conventional treatment alone with decision-analytic model for ACS after PCI. Methods and Results. We constructed a decision-analytic Markov model to compare additional CHMs for 6 months plus conventional treatment versus conventional treatment alone for ACS patients after PCI. Sources of data came from 5C trial and published reports. Outcomes were expressed in terms of quality-adjusted life years (QALYs). Sensitivity analyses were performed to test the robustness of the model. The model predicted that over the 10-year horizon the survival probability was 77.49% in patients with CHMs plus conventional treatment versus 77.29% in patients with conventional treatment alone. In combination with conventional treatment, 6-month CHMs might be associated with a gained 0.20% survival probability and 0.111 accumulated QALYs, respectively. Conclusions. The model suggested that treatment with CHMs, as an adjunctive therapy, in combination with conventional treatment for 6 months might improve the long-term clinical outcome in ACS patients after PCI. PMID- 26495020 TI - Ethnomedicinal Plants Used by Traditional Healers to Treat Oral Health Problems in Cameroon. AB - Objectives. The objective of the study was to determine the therapeutic methods used by traditional healers to treat oral diseases in Cameroon. Methods. A total of 200 traditional healers with a mean age of 50.4 +/- 14.2 years from all the provinces of Cameroon were studied using questionnaires. Information elicited was the local names of the medicinal plants used for the management of oral problems, their routes of administration, and methods of usage. Identification of live or dried plants or photographs of sample of the plants was done by a taxonomist. Results. The majority of the participants were males urban dwellers aged 41-50 years, 112 (56.0%) practice as herbalists and 56 (28.0%) were trained on medications preservation, 77(56.6%) treat diseases inside or outside the mouth, and 9.0% reported being specialist in oral diseases treatment. Of the 52 plants identified, 48 are used in the management of toothache, sore throat, mouth sores, abscess, broken tooth and jaw, tooth sensitivity, mouth thrush, dental caries, gingivitis, sinusitis, tonsillitis, xerostomia, oral syphilis, oral cancer, TMJ pain, halitosis, and tooth bleaching and 4 plants are used for dental extraction. Roots, leaves, and bark were the parts of plants used and some minerals as adjuncts. Conclusion. The study provides comprehensive information on therapeutic methods employed by traditional healers for the treatment of oral diseases. PMID- 26495021 TI - Ferulic Acid Induces Th1 Responses by Modulating the Function of Dendritic Cells and Ameliorates Th2-Mediated Allergic Airway Inflammation in Mice. AB - This study investigated the immunomodulatory effects of ferulic acid (FA) on antigen-presenting dendritic cells (DCs) in vitro and its antiallergic effects against ovalbumin- (OVA-) induced Th2-mediated allergic asthma in mice. The activation of FA-treated bone marrow-derived DCs by lipopolysaccharide (LPS) stimulation induced a high level of interleukin- (IL-) 12 but reduced the expression levels of the proinflammatory cytokines IL-1beta, IL-6, and tumor necrosis factor- (TNF-) alpha. Compared to control-treated DCs, FA significantly enhanced the expressions of Notch ligand Delta-like 4 (Dll4), MHC class II, and CD40 molecules by these DCs. Furthermore, these FA-treated DCs enhanced T-cell proliferation and Th1 cell polarization. In animal experiments, oral administration of FA reduced the levels of OVA-specific immunoglobulin E (IgE) and IgG1 and enhanced IgG2a antibody production in serum. It also ameliorated airway hyperresponsiveness and attenuated eosinophilic pulmonary infiltration in dose-dependent manners. In addition, FA treatment inhibited the production of eotaxin, Th2 cytokines (IL-4, IL-5, and IL-13), and proinflammatory cytokines but promoted the Th1 cytokine interferon- (IFN-) gamma production in bronchoalveolar lavage fluid (BALF) and the culture supernatant of spleen cells. These findings suggest that FA exhibits an antiallergic effect via restoring Th1/Th2 imbalance by modulating DCs function in an asthmatic mouse model. PMID- 26495022 TI - Influence of Biomedical Factors on the Five Viscera Score (FVS) on Middle-Aged and Elderly Individuals: Application of Structural Equation Modeling. AB - The five viscera score (FVS) is a diagnostic scale for traditional Chinese medicine (TCM). The purposes of current study are to elucidate the characteristics of FVS obtained from middle-aged to elderly individuals and to investigate the validity of FVS using biological medical data of middle-aged and elderly individuals. Structural equation modeling (SEM) was used to conduct assessments between FVS and medical data. Eighty men and 99 women participated in this study, whose mean ages (SD) were 58 +/- 7 years in both genders showing no significant difference. FVS of women was significantly higher than that of men in the spleen of the 50s (P = 0.019) and liver of the 60s age group (P = 0.030). By SEM, the following biomedical factors were found to influence viscera: gender, diastolic blood pressure, and HDL-C for the liver; GLU, GOT, and gamma-GTP for the spleen; age, BMI, and HCRP for the lungs; and HbA1c and creatinine clearance for the kidneys. These results provide objective evidence that FVS can be used for TCM diagnosis in middle-aged and elderly individuals. PMID- 26495023 TI - Warm Needling Therapy and Acupuncture at Meridian-Sinew Sites Based on the Meridian-Sinew Theory: Hemiplegic Shoulder Pain. AB - This study was performed to evaluate the effectiveness and safety of warm needling acupuncture at meridian-sinew sites based on the meridian-sinew theory in the treatment of hemiplegic shoulder pain (HSP) after stroke. In total, 124 subjects were randomized into a treatment group and control group. In the treatment group, warm needling therapy and acupuncture at meridian-sinew sites based on the meridian-sinew theory were performed. In the control group, usual care therapy was applied. The visual analog scale (VAS) score, range of motion (ROM), and Barthel index (BI) were used to evaluate treatment effectiveness. At 2 weeks of treatment, the VAS score, ROM, and BI had obviously changed from baseline in the two groups (P < 0.01). The changes in the VAS score and ROM in the treatment group were significantly greater than those in the control group (P < 0.01). At the 3-month follow-up after treatment, the changes in the treatment group were significantly greater than those in the control group (P < 0.01). This study indicates that warm needling therapy with acupuncture at meridian-sinew sites based on the meridian-sinew theory is effective for HSP. PMID- 26495024 TI - Effects of Kamishoyosan, a Traditional Japanese Kampo Medicine, on Pain Conditions in Patients with Intractable Persistent Dentoalveolar Pain Disorder. AB - There are patients who suffer from persistent dentoalveolar pain disorder (PDAP) which is a pain of the teeth, either dentoalveolar pain or nonodontogenic toothache, and its cause has not yet been identified. An effective intervention for PDAP has not yet been established. Interventions for patients with PDAP are generally pharmacological treatments such as antidepressants, anticonvulsants, and pregabalin. However, these medicines are not always effective for patients. The pain disorder in the orofacial region including temporomandibular disorder (TMD) and PDAP was effectively treated with our original exercise therapy. However, we did observe some intractable cases of PDAP even when our original exercise therapy was used. This paper presents our findings in which Kamishoyosan improved the pain intensity in 14 out of 15 PDAP patients refractory to our original exercise therapy. PMID- 26495025 TI - Effect of Japanese Herbal Kampo Medicine Goreisan on Reoperation Rates after Burr Hole Surgery for Chronic Subdural Hematoma: Analysis of a National Inpatient Database. AB - Goreisan is a herbal Kampo medicine used for treating chronic subdural hematoma (CSDH) in Japan. Experimental studies have suggested that Goreisan exerts a hydrogogue effect, but clinical evidence for the effectiveness of Goreisan in CSDH is currently lacking. Using a national Japanese inpatient database, we examined the association between Goreisan use and reoperation rates after burr hole surgery for CSDH. We identified 36,020 patients, including 3,889 Goreisan users and 32,131 nonusers. Propensity scores of receiving Goreisan were calculated based on hospital characteristics and patient backgrounds (age, sex, body mass index, activities of daily living, consciousness level, comorbidities, antithrombotic agent use, mannitol infusion, and corticosteroid infusion). One-to one propensity-score matching created 3,879 pairs of Goreisan users and nonusers. Propensity-matched analysis revealed that Goreisan use was significantly associated with a lower reoperation rate (4.8%) compared with nonuse (6.2%) (risk difference, -1.4%; 95% confidence interval (CI), -2.4% to -0.38%). The number needed to prevent one reoperation was 72 (95% CI, 41-265). Instrumental-variable analysis showed similar results to the propensity-matched analysis. These results suggest that Goreisan use reduced the need for reoperation after burr-hole surgery for CSDH. PMID- 26495026 TI - Hepatic S1P deficiency lowers plasma cholesterol levels in apoB-containing lipoproteins when LDLR function is compromised. AB - BACKGROUND: Site-1 protease (S1P) is the key enzyme required for activation of the sterol regulatory element binding proteins (SREBPs) that govern lipid synthesis. While S1P has been speculated to influence plasma apoB-containing lipoprotein (Blp) metabolism, there has been little investigative work. LDL receptor (LDLR) is the major receptor for clearing plasma LDL cholesterol (LDL c). Proprotein convertase subtilisin kexin type 9 (PCSK9) modulates LDL-c through post-translational degradation of the LDLR. METHODS: A hepatic-specific knockdown (KD) of S1P was achieved using floxed S1P mouse models (S1P(f/f) and LDLR(-/ )S1P(f/f)) and hepatic expression of Cre recombinase. Lipids were measured in total plasma and size fractionated plasma using colorimetric assays. Realtime polymerase chain reaction, western blotting and ELISA were used to determine hepatic expression of key genes/protein. Plasmid mediated overexpression and siRNA mediated knockdown of genes were performed in mouse primary hepatocytes to determine the mechanistic basis of PCSK9 gene regulation. RESULTS: A hepatic specific KD of S1P resulted in a 45 % and 38 % reduction in plasma total cholesterol and triglyceride levels, respectively. Hepatic S1P KD had a minimal effect on plasma Blp cholesterol (Blp-c) in S1P(f/f) mice, despite significantly reducing VLDL secretion. Notably, hepatic S1P KD decreased the LDL receptor (LDLR) mRNA expression by 50 %. However, the reduction in LDLR protein levels was less than that of mRNA expression, especially under fed conditions. Further assessment of hepatic S1P deficiency revealed that it increased LDLR protein stability in vivo. Mechanistically, hepatic S1P KD was shown to decrease the liver and plasma levels of the protein proprotein convertase subtilisin/kexin type 9 (PCSK9), which degrades LDLR protein. This effect was more prominent in the fed condition and sufficient to account for the discordance in LDLR mRNA and protein levels. Furthermore, hepatic S1P was shown to regulate PCSK9 expression through activation of the SREBPs. In the LDLR(-/-) background, hepatic S1P KD significantly reduced Blp-c levels. CONCLUSION: Hepatic S1P is a physiological modulator of plasma Blp metabolism through its regulation of LDLR and PCSK9. Hepatic S1P is a valid target for lowering plasma Blp-c levels in the situation where LDLR function is compromised. PMID- 26495027 TI - Nonsynonymous Single-Nucleotide Variations on Some Posttranslational Modifications of Human Proteins and the Association with Diseases. AB - Protein posttranslational modifications (PTMs) play key roles in a variety of protein activities and cellular processes. Different PTMs show distinct impacts on protein functions, and normal protein activities are consequences of all kinds of PTMs working together. With the development of high throughput technologies such as tandem mass spectrometry (MS/MS) and next generation sequencing, more and more nonsynonymous single-nucleotide variations (nsSNVs) that cause variation of amino acids have been identified, some of which result in the damage of PTMs. The damaged PTMs could be the reason of the development of some human diseases. In this study, we elucidated the proteome wide relationship of eight damaged PTMs to human inherited diseases and cancers. Some human inherited diseases or cancers may be the consequences of the interactions of damaged PTMs, rather than the result of single damaged PTM site. PMID- 26495028 TI - KIR Genes and Patterns Given by the A Priori Algorithm: Immunity for Haematological Malignancies. AB - Killer-cell immunoglobulin-like receptors (KIRs) are membrane proteins expressed by cells of innate and adaptive immunity. The KIR system consists of 17 genes and 614 alleles arranged into different haplotypes. KIR genes modulate susceptibility to haematological malignancies, viral infections, and autoimmune diseases. Molecular epidemiology studies rely on traditional statistical methods to identify associations between KIR genes and disease. We have previously described our results by applying support vector machines to identify associations between KIR genes and disease. However, rules specifying which haplotypes are associated with greater susceptibility to malignancies are lacking. Here we present the results of our investigation into the rules governing haematological malignancy susceptibility. We have studied the different haplotypic combinations of 17 KIR genes in 300 healthy individuals and 43 patients with haematological malignancies (25 with leukaemia and 18 with lymphomas). We compare two machine learning algorithms against traditional statistical analysis and show that the "a priori" algorithm is capable of discovering patterns unrevealed by previous algorithms and statistical approaches. PMID- 26495029 TI - Brain Injury Differences in Frontal Impact Crash Using Different Simulation Strategies. AB - In the real world crashes, brain injury is one of the leading causes of deaths. Using isolated human head finite element (FE) model to study the brain injury patterns and metrics has been a simplified methodology widely adopted, since it costs significantly lower computation resources than a whole human body model does. However, the degree of precision of this simplification remains questionable. This study compared these two kinds of methods: (1) using a whole human body model carried on the sled model and (2) using an isolated head model with prescribed head motions, to study the brain injury. The distribution of the von Mises stress (VMS), maximum principal strain (MPS), and cumulative strain damage measure (CSDM) was used to compare the two methods. The results showed that the VMS of brain mainly concentrated at the lower cerebrum and occipitotemporal region close to the cerebellum. The isolated head modelling strategy predicted higher levels of MPS and CSDM 5%, while the difference is small in CSDM 10% comparison. It suggests that isolated head model may not equivalently reflect the strain levels below the 10% compared to the whole human body model. PMID- 26495030 TI - Biomechanical Analysis of the Fixation System for T-Shaped Acetabular Fracture. AB - This study aims to evaluate the biomechanical mechanism of fixation systems in the most frequent T-shaped acetabular fracture using finite element method. The treatment of acetabular fractures was based on extensive clinical experience. Three commonly accepted rigid fixation methods (double column reconstruction plates (P * 2), anterior column plate combined with posterior column screws (P + PS), and anterior column plate combined with quadrilateral area screws (P + QS)) were chosen for evaluation. On the basis of the finite element model, the biomechanics of these fixation systems were assessed through effective stiffness levels, stress distributions, force transfers, and displacements along the fracture lines. All three fixation systems can be used to obtain effective functional outcomes. The third fixation system (P + QS) was the optimal method for T-shaped acetabular fracture. This fixation system may reduce many of the risks and limitations associated with other fixation systems. PMID- 26495031 TI - Effects of the Variation in Brain Tissue Mechanical Properties on the Intracranial Response of a 6-Year-Old Child. AB - Brain tissue mechanical properties are of importance to investigate child head injury using finite element (FE) method. However, these properties used in child head FE model normally vary in a large range in published literatures because of the insufficient child cadaver experiments. In this work, a head FE model with detailed anatomical structures is developed from the computed tomography (CT) data of a 6-year-old healthy child head. The effects of brain tissue mechanical properties on traumatic brain response are also analyzed by reconstruction of a head impact on engine hood according to Euro-NCAP testing regulation using FE method. The result showed that the variations of brain tissue mechanical parameters in linear viscoelastic constitutive model had different influences on the intracranial response. Furthermore, the opposite trend was obtained in the predicted shear stress and shear strain of brain tissues caused by the variations of mentioned parameters. PMID- 26495032 TI - Tibia Fracture Healing Prediction Using First-Order Mathematical Model. AB - The prediction of healing period of a tibia fracture in humans across limb using first-order mathematical model is demonstrated. At present, fracture healing is diagnosed using X-rays. Recent studies have demonstrated electric stimulation as a diagnostic tool in fracture healing. A DC electric voltage of 0.7 V was applied across the fracture and stabilized with Teflon coated carbon rings and the data was recorded at different time intervals until the fracture heals. The experimental data fitted a first-order plus dead time zero model (FOPDTZ) that coincided with the mathematical model of electrical simulated tibia fracture limb. Fracture healing diagnosis was proposed using model parameter process gain. Current stabilization in terms of process gain parameter becoming constant indicates that the healing of fracture is a new finding in the work. An error analysis was performed and it was observed that the measured data correlated to the FOPDTZ model with an error of less than 2 percent. Prediction of fracture healing period was done by one of the identified model parameters, namely, process gain. Moreover, mathematically, it is justified that once the fracture is completely united there is no capacitance present across the fracture site, which is a novelty of the work. PMID- 26495033 TI - The Influence of Pelvic Ramus Fracture on the Stability of Fixed Pelvic Complex Fracture. AB - This study aims to evaluate the biomechanical mechanism of pelvic ring injury for the stability of pelvis using the finite element (FE) method. Complex pelvic fracture (i.e., anterior column with posterior hemitransverse lesion) combined with pelvic ramus fracture was used to evaluate the biomechanics stability of the pelvis. Three FE fracture models (i.e., Dynamic Anterior Plate-Screw System for Quadrilateral Area (DAPSQ) for complex pelvic fracture with intact pubic ramus, DAPSQ for complex pelvic fracture with pubic ramus fracture, and DAPSQ for complex pelvic fracture with fixed pubic ramus fracture) were established to explore the biomechanics stability of the pelvis. The pubic ramus fracture leads to an unsymmetrical situation and an unstable situation of the pelvis. The fixed pubic ramus fracture did well in reducing the stress levels of the pelvic bone and fixation system, as well as displacement difference in the pubic symphysis, and it could change the unstable situation back to a certain extent. The pelvic ring integrity was the prerequisite of the pelvic stability and should be in a stable condition when the complex fracture is treated. PMID- 26495034 TI - A Finite Element Study of the Dynamic Response of Brain Based on Two Parasagittal Slice Models. AB - The objective of this study is to investigate the influence of gyri and sulci on the response of human head under transient loading. To this end, two detailed parasagittal slice models with and without gyri and sulci have been developed. The models comprised not only cerebrum and skull but also cerebellum, brain stem, CSF, and corpus callosum. In addition, white and gray matters were separated. The material properties were adopted from the literature and assigned to different parts of the models. Nahum's and Trosseille's experiments reported in relevant literature were simulated and the simulation results were compared with the test data. The results show that there is no evident difference in terms of intracranial pressure between the models with and without gyri and sulci under simulated conditions. The equivalent stress below gyri and sulci in the model with gyri and sulci is slightly higher than that in the counterpart model without gyri and sulci. The maximum principle strain in brain tissue is lower in the model with gyri and sulci. The stress and strain distributions are changed due to the existence of gyri and sulci. These findings highlight the necessity to include gyri and sulci in the finite element head modeling. PMID- 26495035 TI - Dynamic Response of the Skull with Sinuses under Blunt Frontal Impact: A Three Dimensional Computational Study. AB - The objective of this study is to analyze the biomechanical effects of sinuses in the skull on the facial impact response. Two models were built, where one had sinuses and the other had none. The models were verified using cadaver test data, including impacts to frontal bone, zygomatic bone, and maxillae. In the maxilla and zygoma impact, sinuses were found to have no significant effect on the global distribution of stress or stiffness of facial bones, and the influence was limited in local area. In forehead impact, the sinuses significantly affected the distribution of stress and strain in the skull due to its location in facial bones. The result shows that if the sinus is far away from the location of impact, its effect on the overall response of skull could be ignored. In addition, the distance between the region of interest and sinuses is another important parameter when studying the local effect of sinuses. PMID- 26495036 TI - Relevance of Blood Vessel Networks in Blast-Induced Traumatic Brain Injury. AB - Cerebral vasculature is a complex network that circulates blood through the brain. However, the role of this networking effect in brain dynamics has seldom been inspected. This work is to study the effects of blood vessel networks on dynamic responses of the brain under blast loading. Voronoi tessellations were implemented to represent the network of blood vessels in the brain. The brain dynamics in terms of maximum principal strain (MPS), shear strain (SS), and intracranial pressure (ICP) were monitored and compared. Results show that blood vessel networks significantly affected brain responses. The increased MPS and SS were observed within the brain embedded with vessel networks, which did not exist in the case without blood vessel networks. It is interesting to observe that the alternation of the ICP response was minimal. Moreover, the vessel diameter and density also affected brain dynamics in both MPS and SS measures. This work sheds light on the role of cerebral vasculature in blast-induced traumatic brain injury. PMID- 26495037 TI - Winter Season Mortality: Will Climate Warming Bring Benefits? AB - Extreme heat events are associated with spikes in mortality, yet death rates are on average highest during the coldest months of the year. Under the assumption that most winter excess mortality is due to cold temperature, many previous studies have concluded that winter mortality will substantially decline in a warming climate. We analyzed whether and to what extent cold temperatures are associated with excess winter mortality across multiple cities and over multiple years within individual cities, using daily temperature and mortality data from 36 US cities (1985-2006) and 3 French cities (1971-2007). Comparing across cities, we found that excess winter mortality did not depend on seasonal temperature range, and was no lower in warmer vs. colder cities, suggesting that temperature is not a key driver of winter excess mortality. Using regression models within monthly strata, we found that variability in daily mortality within cities was not strongly influenced by winter temperature. Finally we found that inadequate control for seasonality in analyses of the effects of cold temperatures led to spuriously large assumed cold effects, and erroneous attribution of winter mortality to cold temperatures. Our findings suggest that reductions in cold-related mortality under warming climate may be much smaller than some have assumed. This should be of interest to researchers and policy makers concerned with projecting future health effects of climate change and developing relevant adaptation strategies. PMID- 26495038 TI - Fitness trade-offs in pest management and intercropping with colour: an evolutionary framework and potential application. AB - An important modern goal of plant science research is to develop tools for agriculturalists effective at curbing yield losses to insect herbivores, but resistance evolution continuously threatens the efficacy of pest management strategies. The high-dose/refuge strategy has been employed with some success to curb pest adaptation, and has been shown to be most effective when fitness costs (fitness trade-offs) of resistance are high. Here, I use eco-evolutionary reasoning to demonstrate the general importance of fitness trade-offs for pest control, showing that strong fitness trade-offs mitigate the threat of pest adaptation, even if adaptation were to occur. I argue that novel pest management strategies evoking strong fitness trade-offs are the most likely to persist in the face of unbridled pest adaptation, and offer the manipulation of crop colours as a worked example of one potentially effective strategy against insect herbivores. PMID- 26495039 TI - Do stressful conditions make adaptation difficult? Guppies in the oil-polluted environments of southern Trinidad. AB - The ability of populations to rapidly adapt to new environments will determine their future in an increasingly human-modified world. Although meta-analyses do frequently uncover signatures of local adaptation, they also reveal many exceptions. We suggest that particular constraints on local adaptation might arise when organisms are exposed to novel stressors, such as anthropogenic pollution. To inform this possibility, we studied the extent to which guppies (Poecilia reticulata) show local adaptation to oil pollution in southern Trinidad. Neutral genetic markers revealed that paired populations in oil polluted versus not-polluted habitats diverged independently in two different watersheds. Morphometrics revealed some divergence (particularly in head shape) between these environments, some of which was parallel between rivers. Reciprocal transplant experiments in nature, however, found little evidence of local adaptation based on survival and growth. Moreover, subsequent laboratory experiments showed that the two populations from oil-polluted sites showed only weak local adaptation even when compared to guppies from oil-free northern Trinidad. We conclude that guppies show little local adaptation to oil pollution, which might result from the challenges associated with adaptation to particularly stressful environments. It might also reflect genetic drift owing to small population sizes and/or high gene flow between environments. PMID- 26495040 TI - The Trojan Female Technique for pest control: a candidate mitochondrial mutation confers low male fertility across diverse nuclear backgrounds in Drosophila melanogaster. AB - Pest species represent a major ongoing threat to global biodiversity. Effective management approaches are required that regulate pest numbers, while minimizing collateral damage to nontarget species. The Trojan Female Technique (TFT) was recently proposed as a prospective approach to biological pest control. The TFT draws on the evolutionary hypothesis that maternally inherited mitochondrial genomes are prone to the accumulation of male, but not female, harming mutations. These mutations could be harnessed to provide trans-generational fertility-based control of pest species. A candidate TFT mutation was recently described in the fruit fly, Drosophila melanogaster, which confers male-only sterility in the specific isogenic nuclear background in which it is maintained. However, applicability of the TFT relies on mitochondrial mutations whose male-sterilizing effects are general across nuclear genomic contexts. We test this assumption, expressing the candidate TFT-mutation bearing haplotype alongside a range of nuclear backgrounds and comparing its fertility in males, relative to that of control haplotypes. We document consistently lower fertility for males harbouring the TFT mutation, in both competitive and noncompetitive mating contexts, across all nuclear backgrounds screened. This indicates that TFT mutations conferring reduced male fertility can segregate within populations and could be harnessed to facilitate this novel form of pest control. PMID- 26495041 TI - The signature of fine scale local adaptation in Atlantic salmon revealed from common garden experiments in nature. AB - Understanding the extent, scale and genetic basis of local adaptation (LA) is important for conservation and management. Its relevance in salmonids at microgeographic scales, where dispersal (and hence potential gene flow) can be substantial, has however been questioned. Here, we compare the fitness of communally reared offspring of local and foreign Atlantic salmon Salmo salar from adjacent Irish rivers and reciprocal F1 hybrid crosses between them, in the wild 'home' environment of the local population. Experimental groups did not differ in wild smolt output but a catastrophic flood event may have limited our ability to detect freshwater performance differences, which were evident in a previous study. Foreign parr exhibited higher, and hybrids intermediate, emigration rates from the natal stream relative to local parr, consistent with genetically based behavioural differences. Adult return rates were lower for the foreign compared to the local group. Overall lifetime success of foreigners and hybrids relative to locals was estimated at 31% and 40% (mean of both hybrid groups), respectively. The results imply a genetic basis to fitness differences among populations separated by only 50 km, driven largely by variation in smolt to adult return rates. Hence even if supplementary stocking programs obtain broodstock from neighbouring rivers, the risk of extrinsic outbreeding depression may be high. PMID- 26495043 TI - Smooth Muscle Stiffness Sensitivity is Driven by Soluble and Insoluble ECM Chemistry. AB - Smooth muscle cell (SMC) invasion into plaques and subsequent proliferation is a major factor in the progression of atherosclerosis. During disease progression, SMCs experience major changes in their microenvironment, such as what integrin binding sites are exposed, the portfolio of soluble factors available, and the elasticity and modulus of the surrounding vessel wall. We have developed a hydrogel biomaterial platform to examine the combined effect of these changes on SMC phenotype. We were particularly interested in how the chemical microenvironment affected the ability of SMCs to sense and respond to modulus. To our surprise, we observed that integrin binding and soluble factors are major drivers of several critical SMC behaviors, such as motility, proliferation, invasion, and differentiation marker expression, and these factors modulated the effect of stiffness on proliferation and migration. Overall, modulus only modestly affected behaviors other than proliferation, relative to integrin binding and soluble factors. Surprisingly, pathological behaviors (proliferation, motility) are not inversely related to SMC marker expression, in direct conflict with previous studies on substrates coupled with single extracellular matrix (ECM) proteins. A high-throughput bead-based ELISA approach and inhibitor studies revealed that differentiation marker expression is mediated chiefly via focal adhesion kinase (FAK) signaling, and we propose that integrin binding and FAK drive the transition from a migratory to a proliferative phenotype. We emphasize the importance of increasing the complexity of in vitro testing platforms to capture these subtleties in cell phenotypes and signaling, in order to better recapitulate important features of in vivo disease and elucidate potential context-dependent therapeutic targets. PMID- 26495042 TI - Contrasting genetic structure between mitochondrial and nuclear markers in the dengue fever mosquito from Rio de Janeiro: implications for vector control. AB - Dengue is the most prevalent global arboviral disease that affects over 300 million people every year. Brazil has the highest number of dengue cases in the world, with the most severe epidemics in the city of Rio de Janeiro (Rio). The effective control of dengue is critically dependent on the knowledge of population genetic structuring in the primary dengue vector, the mosquito Aedes aegypti. We analyzed mitochondrial and nuclear genomewide single nucleotide polymorphism markers generated via Restriction-site Associated DNA sequencing, as well as traditional microsatellite markers in Ae. aegypti from Rio. We found four divergent mitochondrial lineages and a strong spatial structuring of mitochondrial variation, in contrast to the overall nuclear homogeneity across Rio. Despite a low overall differentiation in the nuclear genome, we detected strong spatial structure for variation in over 20 genes that have a significantly altered expression in response to insecticides, xenobiotics, and pathogens, including the novel biocontrol agent Wolbachia. Our results indicate that high genetic diversity, spatially unconstrained admixing likely mediated by male dispersal, along with locally heterogeneous genetic variation that could affect insecticide resistance and mosquito vectorial capacity, set limits to the effectiveness of measures to control dengue fever in Rio. PMID- 26495044 TI - Self-assembled glycopeptide nanofibers as modulators of galectin-1 bioactivity. AB - Galectins are carbohydrate-binding proteins that act as extracellular signaling molecules in various normal and pathological processes. Galectin bioactivity is mediated by specific non-covalent interactions with cell-surface and extracellular matrix (ECM) glycoproteins, which can enhance or inhibit signaling events that influence various cellular behaviors, including adhesion, proliferation, differentiation, and apoptosis. Here, we developed a materials approach to modulate galectin bioactivity by mimicking natural galectin glycoprotein interactions. Specifically, we created a variant of a peptide that self-assembles into beta-sheet nanofibers under aqueous conditions, QQKFQFQFEQQ (Q11), which has an asparagine residue modified with the monosaccharide N acetylglucosamine (GlcNAc) at its N-terminus (GlcNAc-Q11). GlcNAc-Q11 self assembled into beta-sheet nanofibers under similar conditions as Q11. Nanofibrillar GlcNAc moieties were efficiently converted to the galectin-binding disaccharide N-acetyllactosamine (LacNAc) via the enzyme beta-1,4 galactosyltransferase and the sugar donor UDP-galactose, while retaining beta sheet structure and nanofiber morphology. LacNAc-Q11 nanofibers bound galectin-1 and -3 in a LacNAc concentration-dependent manner, although nanofibers bound galectin-1 with higher affinity than galectin-3. In contrast, galectin-1 bound weakly to GlcNAc-Q11 nanofibers, while no galectin-3 binding to these nanofibers was observed. Galectin-1 binding to LacNAc-Q11 nanofibers was specific because it could be inhibited by excess soluble beta-lactose, a galectin-binding carbohydrate. LacNAc-Q11 nanofibers inhibited galectin-1-mediated apoptosis of Jurkat T cells in a LacNAc concentration-dependent manner, but were unable to inhibit galectin-3 activity, consistent with galectin-binding affinity of the nanofibers. We envision that glycopeptide nanofibers capable of modulating galectin-1 bioactivity will be broadly useful as biomaterials for various medical applications, including cancer therapeutics, immunotherapy, tissue regeneration, and viral prophylaxis. PMID- 26495046 TI - Fall Issue, 2015. PMID- 26495045 TI - Investigating Dynamic Interdomain Allostery in Pin1. AB - Signaling proteins often sequester complementary functional sites in separate domains. How do the different domains communicate with one another? An attractive system to address this question is the mitotic regulator, human Pin1 (Lu et al. 1996). Pin-1 consists of two tethered domains: a WW domain for substrate binding, and a catalytic domain for peptidyl-prolyl isomerase (PPIase) activity. Pin1 accelerates the cis-trans isomerization of phospho-Ser/Thr-Pro (pS/T-P) motifs within proteins regulating the cell cycle and neuronal development. The early x ray (Ranganathan et al. 1997; Verdecia et al. 2000) and solution NMR studies (Bayer et al. 2003; Jacobs et al. 2003) of Pin1 indicated inter- and intradomain motion. We became interested in exploring how such motions might affect interdomain communication, using NMR. Our accumulated results indicate substrate binding to Pin1 WW domain changes the intra/inter domain mobility, thereby altering substrate activity in the distal PPIase domain catalytic site. Thus, Pin1 shows evidence of dynamic allostery, in the sense of Cooper and Dryden (Cooper and Dryden 1984). We highlight our results supporting this conclusion, and summarize them via a simple speculative model of conformational selection. PMID- 26495047 TI - Improving Oral Hygiene in Institutionalised Elderly by Educating Their Caretakers in Bangalore City, India: a Randomised Control Trial. AB - BACKGROUND: The population of older people, as well as the number of dependent older people, is steadily increasing; those unable to live independently at home are being cared for in a range of settings. Practical training for nurses and auxiliary care staff has frequently been recommended as a way of improving oral health care for functionally dependent elderly. The aim was improve oral hygiene in institutionalized elderly in Bangalore city by educating their caregivers. METHODS: The study is a cluster randomized intervention trial with an elderly home as unit of randomization in which 7 out of 65 elderly homes were selected. Oral health knowledge of caregivers was assessed using a pre-tested pro forma and later oral-health education was provided to the caregivers of the study group. Oral hygiene status of elderly residents was assessed by levels of debris, plaque of dentate and denture plaque, and denture stomatitis of denture wearing residents, respectively. Oral-health education to the caregivers of control group was given at the end of six months. RESULTS: There was significant improvement in oral-health knowledge of caregivers from the baseline and also a significant reduction of plaque score from baseline score of 3.17 +/- 0.40 to 1.57 +/- 0.35 post-intervention (p < .001), debris score 2.87 +/- 0.22 to 1.49 +/- 0.34 (p < .001), denture plaque score 3.15 +/- 0.47 to 1.21 +/- 0.27 (p < .001), and denture stomatitis score 1.43 +/- 0.68 to 0.29 +/- 0.53 (p < .001). CONCLUSIONS: The result of the present study showed that there was a significant improvement in the oral-health knowledge among the caregivers and oral-hygiene status of the elderly residents. PMID- 26495048 TI - Cognitive Test Performance in Relation to Health and Function in 12 European Countries: The SHARE Study. AB - BACKGROUND: Even subtle impairments on cognitive test scores can be associated with future cognitive decline and dementia. We assayed the relationships between test score impairment and adverse outcomes. METHODS: Secondary analyses were performed on data from non-institutionalized participants, 50+ years of age (N = 30,038), from 12 countries taking part in the Survey of Health, Ageing and Retirement in Europe (SHARE) longitudinal study on aging. At baseline, participants' cognition was tested using verbal fluency, immediate recall, and delayed recall tasks. RESULTS: Greater levels of cognitive impairment at baseline were strongly associated with future poor health outcomes and functional impairment. Controlling for age, sex and education, those with 1 (OR = 1.58, 95% CI = 1.34-1.87) or >= 2 (OR = 2.59, 95% CI = 2.17-3.09) impaired tests at baseline were more likely to die after an average of 40 months compared to individuals with no impairments. After selecting for participants who reported the absence of dementia initially, those with >= 2 cognitive impairments at baseline (OR = 3.34, 95% CI = 2.27-4.92) were more likely to report dementia at follow-up compared to those with no impairment. CONCLUSIONS: People with impaired cognitive test scores at baseline are at greater risk to die or develop dementia within four years than their less impaired or unimpaired counterparts. PMID- 26495049 TI - Implications of Risk Factors for Alzheimer's Disease in Canada's Indigenous Population. AB - BACKGROUND: Indigenous peoples in Canada have higher prevalence of modifiable risk factors for Alzheimer's disease (AD). The relative importance of these risk factors on AD risk management is poorly understood. METHODS: Relative risks from literature and prevalence of risk factors from Statistics Canada or the First Nations Regional Health Survey were used to determine projected population attributable risk (PAR) associated with modifiable risk factors for AD (low education and vascular risk factors) among on- and off-reserve Indigenous and non Indigenous people in Canada using the Levin formula. RESULTS: Physical inactivity had the highest PAR for AD among Indigenous and non-Indigenous peoples in Canada (32.5% [10.1%-51.1%] and 30.5% [9.2%-48.8%] respectively). The PAR for most modifiable risk factors was higher among Indigenous peoples in Canada, particularly among on-reserve groups. The greatest differences in PAR were for low educational attainment and smoking, which were approximately 10% higher among Indigenous peoples in Canada. The combined PAR for AD for all six modifiable risk factors was 79.6% among on-reserve Indigenous, 74.9% among off-reserve Indigenous, and 67.1% among non-Indigenous peoples in Canada. (All differences significant to p < .001.). CONCLUSIONS: Modifiable risk factors are responsible for the most AD cases among Indigenous peoples in Canada. Further research is necessary to determine the prevalence of AD and the impact of risk factor modification among Indigenous peoples in Canada. PMID- 26495050 TI - Mobility and Cognition in Seniors. Report from the 2008 Institute of Aging (CIHR) Mobility and Cognition Workshop. AB - BACKGROUND: The annual Scientific Meeting of the Canadian Association on Gerontology was held on October 24 and 25, 2008 in London, Ontario. Prior to the annual meeting, mobility and cognition experts met on October 23, 2008 to engage in a pre-conference workshop. METHODS: Discussions during the workshop addressed novel areas of research and knowledge and research gaps pertaining to the interaction between mobility and cognition in seniors. RESULTS: Workshop presenters moved from the neuromuscular, biomechanics, and neurology of gait impairments, and falls through the role of cognition and mood on mobility regulation to the whole person in the environment. Research gaps were identified. CONCLUSIONS: Despite a consensus that mobility and cognition are increasingly correlated as people age, several gaps in our understanding of mechanisms and how to assess the interaction were recognized. The gaps originally identified in 2008 are still pertinent today. Common and standardized assessments for "mobility and cognition" are still not in place in current practice. Interventions that target mobility and cognitive decline as a single entity are still lacking. PMID- 26495051 TI - Escape from omnishambles in statistics: back to the basics. PMID- 26495052 TI - Neonatal anesthesia: how we manage our most vulnerable patients. AB - Neonates undergoing surgery are at higher risk than older children for anesthesia related adverse events. During the perioperative period, the maintenance of optimal hemodynamics in these patients is challenging and requires a thorough understanding of neonatal physiology and pharmacology. Data from animals and human cohort studies have shown relation of the currently used anesthetics may associate with neurotoxic brain injury that lead to later neurodevelopmental impairment in the developing brain. In this review, the unique neonatal physiologic and pharmacologic features and anesthesia-related neurotoxicity will be discussed. PMID- 26495053 TI - The effect of dexmedetomidine sedation on patient and surgeon satisfaction during retinal surgery under sub-tenon's anesthesia: a randomized controlled trial. AB - BACKGROUND: The purpose of this study was to evaluate the effect of intraoperative dexmedetomidine sedation on patient's and surgeon's satisfaction during retinal surgery under sub-tenon's anesthesia. METHODS: Forty-four patients scheduled for elective retinal surgery under sub-tenon's anesthesia were enrolled in this randomized controlled trial. The patients were divided into Dexmedetomidine (n = 22) and Control (n = 22) groups. Intravenous dexmedetomidine or 0.9% saline via infusion pump were administered continuously to the dexmedetomidine or control group, respectively. Ramsay sedation scale with a target level of 3-4 was used to assess adequacy of sedation. Perioperative pain, hemodynamic and respiratory data were collected, while satisfaction from patients and surgeon were assessed post-surgery using a 5-point satisfaction scale. RESULTS: Patient and surgeon satisfaction was higher in the dexmedetomidine group (P < 0.001, P = 0.002, respectively). The pain associated with sub-tenon's anesthesia and peripheral vitrectomy was lesser in the dexmedetomidine group than in the control group (P = 0.020). There was significant reduction of heart rate in the dexmedetomidine group (P = 0.001), but only one patient needed treatment with atropine. There was no respiratory effect on both groups. CONCLUSIONS: Dexmedetomidine sedation during retinal surgery improved satisfaction from both patient and surgeon without respiratory complication. It is a safe and preferable choice of sedation for retinal surgery. PMID- 26495054 TI - Efficacy of intraoperative dexmedetomidine infusion on visualization of the surgical field in endoscopic sinus surgery. AB - BACKGROUND: In endoscopic sinus surgery, visualization of the surgical field is a major concern, as surgical bleeding is the cause of many complications. The purpose of this study was to compare the effects of dexmedetomidine and remifentanil on the visualization of the surgical field in endoscopic sinus surgery. METHODS: Forty-three patients were prospectively enrolled and randomly allocated to the dexmedetomidine or remifentanil group and general anesthesia was induced and maintained using a propofol target-controlled infusion. In the dexmedetomidine group, dexmedetomidine was loaded for 5 min and a continuous infusion was administered. In the remifentanil group, a remifentanil target controlled infusion was used. After completion of the operation, the satisfaction with the visualization of the surgical field was assessed on a numeric rating scale, from 0 (= worst) to 10 (= best). The mean blood pressure, heart rate, recovery profiles, and postoperative pain score were recorded. RESULTS: Satisfaction score for visualization by numeric rating scale was not significantly different between the two groups (P = 0.95). There were no differences in the mean blood pressure and heart rate. The extubation time was significantly shorter in the dexmedetomidine group (8.4 +/- 1.8 min) than in the remifentanil group (11.9 +/- 5.4 min) (P = 0.04). Except for the extubation time, the recovery profiles of the two groups were comparable. CONCLUSIONS: Continuous infusions of dexmedetomidine provide a similar visualization of the surgical field and hemodynamic stability as remifentanil target-controlled infusions in patients undergoing endoscopic sinus surgery. PMID- 26495055 TI - Comparison of i-gel(r) and LMA Supreme(r) during laparoscopic cholecystectomy. AB - BACKGROUND: In laparoscopic surgical procedures, many clinicians recommend supraglottic airway devices as good alternatives to intubation. We compared the i gel(r) (i-gel) and LMA Supreme(r) (Supreme Laryngeal Mask Airway, SLMA) airway devices during laparoscopic cholecystectomy regarding sealing pressure and respiratory parameters before, during, and after pneumoperitoneum. METHODS: Following Institutional Review Board approval and written informed consent, 93 patients were randomly allocated into the i-gel (n = 47) or SLMA group (n = 46). Insertion time, number of insertion attempts, and fiberoptic view of glottis were recorded. Oropharyngeal leak pressure (OLP), the use of airway manipulation, peak inspiratory pressure, lung compliance, and hemodynamic parameters were measured before, during, and after pneumoperitoneum. RESULTS: There were no significant differences between the two groups regarding demographic data, insertion time, fiberoptic view of glottis, and the use of airway manipulation. The gastric tube insertion time was longer in the i-gel group (20.4 +/- 3.9 s) than in the SLMA group (16.7 +/- 1.6 s) (P < 0.001). All devices were inserted on the first attempt, excluding one case in each group. Peak inspiratory pressure, lung compliance, and OLP changed following carbon dioxide pneumoperitoneum in each group, but there were no significant differences between the groups. CONCLUSIONS: Both the i-gel and SLMA airway devices can be comparably used in patients who undergo laparoscopic cholecystectomy, and they offer similar performance including OLP. PMID- 26495056 TI - Clinical evaluation of a newly designed fluid warming kit on fluid warming and hypothermia during spinal surgery. AB - BACKGROUND: The Mega Acer Kit(r) (MAK) is a newly designed heated and humidified breathing circuit that warms fluid passing through the circuit lumen. In this study, we investigated the system's efficacy for the perioperative prevention of hypothermia and fluid warming. METHODS: Ninety patients undergoing spinal surgery were enrolled in this study and randomly assigned to 3 groups based on the fluid warming device used: no fluid warming system (Group C, n = 30), via a Standard Ranger (Group R, n = 30), or via the MAK (Group M, n = 30). Distal esophageal temperatures (Teso) and infusion fluid temperature (TF) were recorded at 15 min intervals for duration of 180 min during surgery. If Teso was < 35.0C, a forced air convective warming device was used. RESULTS: Final Teso values were 34.8 +/- 0.3C, 35.1 +/- 0.1C, and 35.8 +/- 0.3C in groups C, R, and M, respectively (P < 0.01). Teso was significantly higher in group M when compared with that in groups C and R throughout the study period (P < 0.05). The number of patients requiring a forced-air convective warming device was significantly lower in group M (n = 0) when compared with that in groups R (n = 17) and C (n = 30) (P < 0.05). The final infusion fluid temperature was higher in group M when compared with that in groups C and R throughout the study period (35.4 +/- 1.0 vs. 23.0 +/- 0.3 and 32.8 +/- 0.6C; P < 0.01). CONCLUSIONS: The MAK is more effective for preventing hypothermia and for warming fluid than the Standard Ranger. PMID- 26495057 TI - Spinal versus general anesthesia for Cesarean section in patients with sickle cell anemia. AB - BACKGROUND: Sickle cell anemia (SCA) increases the rate of maternal and fetal complications. This pilot study was designed to compare the maternal and fetal outcomes of spinal versus general anesthesia (GA) for parturients with SCA undergoing cesarean delivery. METHODS: Forty parturients with known SCA scheduled for elective Cesarean delivery were randomized into spinal anesthesia (n = 20) and GA groups (n = 20). Perioperative hemodynamic parameters were recorded. Postpartum complications were followed up. Opioid consumption was calculated. Blood loss during surgery and the number of patients who received intraoperative or postpartum blood transfusion were recorded. Patient satisfaction with the type of anesthesia was assessed. The Apgar score at 1 and 5 min, neonatal admission to the intensive care unit, and mortality were also recorded. RESULTS: Blood loss was significantly higher in the GA than spinal group (P = 0.01). However, the number of patients who received an intraoperative or postpartum blood transfusion was statistically insignificant. Significantly more patients developed intraoperative hypotension and bradycardia in the spinal than GA group. Opioid use during the first 24 h was significantly higher in the GA than spinal group (P < 0.0001). More patients had vaso-occlusive crisis in the GA than spinal group without statistical significance (P = 0.4). There was one case of acute chest syndrome in the GA group. No significant differences were observed in postoperative nausea and/or vomiting, patient satisfaction, or hospital length of stay. Neonatal Apgar scores were significantly better in the spinal than GA group at 1 and 5 min (P = 0.006 and P = 0.009, respectively). Neonatal intensive care admission was not significantly different between the two groups, and there was no neonatal mortality. CONCLUSIONS: Spinal anesthesia may have advantages over GA in parturients with SCA undergoing Cesarean delivery. PMID- 26495058 TI - Effect of intraoperative infusion of ketamine on remifentanil-induced hyperalgesia. AB - BACKGROUND: Opioid induced hyperalgesia (OIH) is related with high opioid dosage, a long duration of opioid administration, and abrupt discontinuation of infused opioids in anesthetic settings. Ketamine is known to attenuate OIH efficiently, but methods of administration and methods to quantify and assess a decrease in OIH vary. We demonstrated the existence of remifentanil-induced hyperalgesia and investigated the ability of ketamine to attenuate OIH. METHODS: Seventy-five patients undergoing laparoscopic gynecologic surgery under remifentanil-based anesthesia were assigned to one of the following groups: (1) group RL (remifentanil 0.05 ug/kg/min), (2) group RH (remifentanil 0.3 ug/kg/min), or (3) group KRH (remifentanil 0.3 ug/kg/min + ketamine 0.5 mg/kg bolus with 5 ug/kg/min infusion intraoperatively). Desflurane was administered for maintenance of anesthesia to target bispectral index scores (40-60) and hemodynamic parameters (heart rate and blood pressure < +/- 20% of baseline values). All parameters related to OIH and its attenuation induced by ketamine were investigated. RESULTS: There was no significant difference among the three groups related to demographic and anesthetic parameters except the end-tidal concentration of desflurane. Additional analgesic consumption, numerical rating scale scores at 6 and 24 h, and cumulative fentanyl dose were significantly higher in group RH than in the other two groups. The value difference of the Touch-Test sensory evaluation was significantly higher negative in group RH than in the other two groups. CONCLUSIONS: Remifentanil-induced hyperalgesia is significantly attenuated by intraoperative bolus and infusion of ketamine. Ketamine also decreased tactile sensitization, as measured by Touch-Test sensory evaluation. PMID- 26495059 TI - Does spinal stenosis correlate with MRI findings and pain, psychologic factor and quality of life? AB - BACKGROUND: To investigate and analyze MRI findings in relation to visual analogue scale (VAS), Oswestry Disability Index (ODI), psychological-factor, sleep-quality, and Short-Form Health Survey (SF-36) scores among patients with central lumbar spinal stenosis (LSS) for the purpose of elucidating a correlation. METHODS: From July 2013 to May 2014, 117 consecutive patients with central LSS were included in this study. All of the MRIs were evaluated by one of the authors, and the evaluated items were the dural sac cross-sectional area (DSCSA), the number of stenotic levels, and the presence and levels of spondylolisthesis. The ODI, VAS, 36-item SF-36, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Pittsburgh Sleep Quality Index (PSQI) questionnaires were used to evaluate the participants. RESULTS: There are no correlations between the ODI, VAS, BDI, BAI, PSQI, and SF-36 scores and the minimum DSCSA; however, a significant correlation was found between the ODI scores and multilevel LSS. The BDI, BAI, and PSQI scores are higher for multilevel LSS compared with single-level LSS, but the difference of this mean value is not statistically significant. CONCLUSIONS: A significant correlation was shown between those patients with multilevel LSS and the ODI scores; however, significant correlations were not found between the MRI findings and the psychological factors pertaining to sleep and life qualities. PMID- 26495061 TI - Anaphylaxis following atropine administration during general anesthesia: a case report. AB - Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast-cell- and basophile-derived mediators into the circulation. Common manifestations of anaphylactic reactions include urticaria, angioedema, nausea, vomiting, hypotension and cardiovascular collapse. Cardiovascular collapse is the first detected manifestation in up to 50% of cases in perioperative anaphylaxis, because patients are anesthetized and unable to report symptoms. A 25-year-old male presented with severe hypotension and erythema after intravenous atropine administration during general anesthesia. Postoperative laboratory findings demonstrated elevated serum tryptase and total immunoglobulin E. An intradermal test showed atropine sensitivity. Although atropine is used widely as a perioperative anticholinergic agent, it is a potential risk factor for a severe anaphylactic reaction. Therefore, prompt recognition and adequate therapeutic measures are necessary to avoid fatal consequences. PMID- 26495060 TI - Propofol attenuates hydrogenperoxide-induced apoptosis in human umbilical vein endothelial cells via multiple signaling pathways. AB - BACKGROUND: Propofol has been reported to protect vascular endothelial cells against oxidative stress. In this study we investigated its effect on hydrogen peroxide (H2O2)-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and examined the possible signaling pathways. METHODS: HUVECs were pretreated with propofol (1, 5, 25, and 50 uM) for 30 min and then co-incubated with 0.4 mM H2O2 for 4 h. Cell viability was assessed using a Cell Counting Kit 8. Cell apoptosis was analyzed using flow cytometry with annexin V/propidium iodide staining, and evaluated by quantifying caspase-3, Bax, and Bcl-2 expression levels. The expression levels of p38 mitogen activated protein kinase (MAPK), phosphorylated (p)-p38 MAPK, cJun-N-terminal kinases (JNK), phosphorylated (p)-JNK, Akt and phosphorylated Akt [(p)-Akt] (Ser473) were measured by western blotting. RESULTS: H2O2 treatment induced the activation of caspase-3, downregulated Bcl-2 expression, and up-regulated Bax expression, all of which were dose-dependently attenuated by propofol pretreatment. Furthermore, propofol significantly ameliorated H2O2-induced phosphorylation of p38 MAPK, JNK, and Akt in HUVECs. CONCLUSIONS: Propofol can protect HUVECs against H2O2-induced apoptosis via a mechanism that may involve p38 MAPK, JNK, and Akt signaling pathways. PMID- 26495062 TI - Endotracheal intubation using i-gel(r) and lightwand in a patient with difficult airway: a case report. AB - This case report involves tracheal intubation using i-gel(r) in combination with a lightwand in a patient with a difficult airway, classified as Cormack-Lehane grade 3. I-gel(r) was used during anesthesia induction to properly maintain ventilation. The authors have previously reported successful tracheal intubation on a patient with a difficult airway through the use of i-gel(r) and a fiberoptic bronchoscope. However, if the use of a fiberoptic bronchoscope is not immediately available in a patient with a difficult airway, tracheal intubation may be performed by using i-gel(r) and a lightwand in a patient with difficult airway, allowing the safe induction of anesthesia. PMID- 26495063 TI - Intraoperative three-dimensional transesophageal echocardiography for evaluating an unusual structure in the left ventricular outflow tract: a case report. AB - Intraoperative three-dimensional (3D) transesophageal echocardiography (TEE) facilitates an understanding of the complex cardiac pathology that is not fully delineated in a two-dimensional (2D) echocardiographic evaluation, and it suggests earlier and more precise surgical planning and intraoperative decision making. In the present case, the intraoperative 2D-TEE midesophageal long-axis view indicated a significant narrowing of the left ventricular outflow tract (LVOT) area by a band-like structure that vertically traversed the middle of the LVOT and connected to the anterior mitral leaflet base and the interventricular septum. However, additional 3D-TEE images of the LVOT and their cropped and rendered 2D images showed that web-like tissue, which presumably had grown around the patch closure from a previous atrioventricular septal defect, was obstructing the LVOT partially. PMID- 26495064 TI - Postdural puncture subdural hematoma or postdural puncture headache?: two cases report. AB - Spinal anesthesia is widely used for many obstetric, gynecological, orthopedic, and urological operations. Subdural hematomas may occur after trauma and are associated with high morbidity and mortality rates. Postdural puncture headache (PDPH) is a benign condition and the most frequent complication of spinal anesthesia. The high rate of headache after spinal anesthesia may mask or delay the diagnosis of subdural hematoma. The true incidence of postdural puncture subdural hematoma (PDPSH) is unknown because most affected patients are probably managed without investigation. Therefore, the true incidence of PDPSH may be greater than suggested by previous reports. The differentiation of headache associated with subdural hematoma from PDPH is crucial. We herein report two cases of bilateral subdural hematoma after epidural anesthesia and emphasize the importance of suspicion for PDPSH and careful evaluation of patients with headache after spinal anesthesia. PMID- 26495065 TI - Ultrasound-guided femoral and popliteal sciatic nerve blocks for below knee surgery in patients with severe cardiac disease. PMID- 26495066 TI - Future directions in overactive bladder treatment: Personalized medicine can be applied? PMID- 26495067 TI - Drug therapy of overactive bladder--what is coming next? AB - After the approval and introduction of mirabegron, tadalafil, and botulinum toxin A for treatment of lower urinary tract symptoms/overactive bladder, focus of interest has been on their place in therapy versus the previous gold standard, antimuscarinics. However, since these agents also have limitations there has been increasing interest in what is coming next - what is in the pipeline? Despite progress in our knowledge of different factors involved in both peripheral and central modulation of lower urinary tract dysfunction, there are few innovations in the pipe-line. Most developments concern modifications of existing principles (antimuscarinics, beta3-receptor agonists, botulinum toxin A). However, there are several new and old targets/drugs of potential interest for further development, such as the purinergic and cannabinoid systems and the different members of the transient receptor potential channel family. However, even if there seems to be good rationale for further development of these principles, further exploration of their involvement in lower urinary tract function/dysfunction is necessary. PMID- 26495068 TI - Current status of flexible ureteroscopy in urology. AB - Retrograde intrarenal surgery (RIRS) is being performed for the surgical management of upper urinary tract pathology. With the development of surgical instruments with improved deflection mechanisms, visuality, and durability, the role of RIRS has expanded to the treatment of urinary calculi located in the upper urinary tract, which compensates for the shortcomings of shock wave lithotripsy and percutaneous nephrolithotomy. RIRS can be considered a conservative treatment of upper urinary tract urothelial cancer (UTUC) or for postoperative surveillance after radical treatment of UTUC under an intensive surveillance program. RIRS has a steep learning curve and various surgical techniques can be used. The choice of instruments during RIRS should be based on increased surgical efficiency, decreased complications, and improved cost-benefit ratio. PMID- 26495069 TI - The effect of continuous androgen deprivation treatment on prostate cancer patients as compared with intermittent androgen deprivation treatment. AB - PURPOSE: To investigate the efficacy of androgen deprivation treatment (ADT) between continuous and intermittent ADT. MATERIALS AND METHODS: Between January 2006 and May 2015, 603 patients were selected and divided into continuous ADT (CADT) (n=175) and intermittent ADT (IADT) (n=428) groups. The median follow-up in this study was 48.19 (1.0-114.0) months. The primary end point was time to castration resistant prostate cancer (CRPC). The types of ADT were monotherapy and maximal androgen blockade (i.e., luteinizing hormone-releasing hormone agonist and antiandrogen). RESULTS: The characteristics of patients showed no significant differences between the CADT and IADT groups, except for the Gleason score (p<0.001). The median time to CRPC of all enrolled patients with ADT was 20.60+/-1.60 months. The median time to CRPC was 11.20+/-1.31 months in the CADT group as compared with 22.60+/-2.08 months in the IADT group. In multivariate analysis, percentage of positive core (p=0.047; hazard ratio [HR], 0.976; 95% confidence interval [CI], 0.953-1.000), Gleason score (p=0.007; HR, 1.977; 95% CI, 1.206-3.240), lymph node metastasis (p=0.030; HR, 0.498; 95% CI, 0.265 0.936), bone metastasis (p=0.028; HR, 1.921; 95% CI, 1.072-3.445), and CADT vs. IADT (p=0.003; HR, 0.254; 95% CI. 0.102-0.633) were correlated with the duration of progression to CRPC. The IADT group presented a significantly longer median time to CRPC compared with the CADT group. Additionally, patients in the IADT group showed a longer duration in median time to CRPC in subgroup analysis according to the Gleason score. CONCLUSIONS: This study found that IADT produces a longer duration in median time to CRPC than does CADT. PMID- 26495070 TI - Comparison of computed tomography findings between renal oncocytomas and chromophobe renal cell carcinomas. AB - PURPOSE: To investigate and distinguish the computed tomography (CT) characteristics of chromophobe renal cell carcinoma (chRCC) and renal oncocytoma. MATERIALS AND METHODS: Fifty-one patients with renal oncocytoma and 120 patients with chRCC, diagnosed by surgery between November 2005 and June 2015, were studied retrospectively. Two observers, who were urologists and unaware of the pathological results, reviewed the preoperative CT images. The tumors were evaluated for size, laterality, tumor type (ball or bean pattern), central stellate scar, segmental enhancement inversion, and angular interface pattern and tumor complexity. To accurately analyze the mass-enhancing pattern of renal mass, we measured Hounsfield units (HUs) in each phase and analyzed the mean, maximum, and minimum HU values and standard deviations. RESULTS: There were 51 renal oncocytomas and 120 chRCCs in the study cohort. No differences in clinical and demographic characteristics were observed between the two groups. A central stellate scar and segmental enhancement inversion were more likely in oncocytomas. However, there were no differences in ball-/bean-type categorization, enhancement pattern, and the shape of the interface between the groups. Higher HU values tended to be present in the corticomedullary and nephrogenic phases in oncocytomas than in chRCC. Receiver-operating characteristic curve analysis showed that the presence of a central stellate scar and higher mean HU values in the nephrogenic phase were highly predictive of renal oncocytoma (area under the curve=0.817, p<0.001). CONCLUSIONS: The appearance of a central stellate scar and higher mean HU values in the nephrogenic phase could be useful to distinguish renal oncocytomas from chRCCs. PMID- 26495071 TI - Comparison of biochemical recurrence in prostate cancer patients treated with radical prostatectomy or radiotherapy. AB - PURPOSE: We evaluated the biochemical recurrence (BCR) of prostate cancer patients treated by radical prostatectomy (RP) or radiotherapy (RT). MATERIALS AND METHODS: Patients who underwent RP or RT as primary definitive treatment from 2007 were enrolled for this study. They were divided into two groups; the low intermediate risk group and the high risk group according to the National Comprehensive Cancer Network guidelines. We compared differences such as age, prostate specific antigen, Gleason score, follow-up duration, clinical T staging, and BCR. Their BCR-free survival rates were analyzed. RESULTS: A total of 165 patients were enrolled. There were 115 patients in the low-intermediate risk. Among them, 88 received RP and 27 underwent RT. BCR occurred in 9 of the RP patients (10.2%) and 3 of the RT patients (11.1%). For the high risk group, 50 patients were included. RP was performed in 25 patients and RT in 25 patients. BCR was observed in 4 of the RP patients (16%) and 12 of the RT patients (48%). There were no differences in BCR-free survival for the low-intermediate group (p=0.765). For the high risk group, the RP group had a higher BCR free survival rate (p=0.032). CONCLUSIONS: No difference of BCR and BCR-free survival was seen in the low-intermediate risk group but lower BCR and better BCR-free survival were observed for patients that received RP in the high risk group. RP should be a more strongly considered option when deciding the treatment method for selected high risk patients. PMID- 26495072 TI - Discordance between location of positive cores in biopsy and location of positive surgical margin following radical prostatectomy. AB - PURPOSE: We compared location of positive cores in biopsy and location of positive surgical margin (PSM) following radical prostatectomy. MATERIALS AND METHODS: This retrospective analysis included patients who were diagnosed as prostate cancer by standard 12-core transrectal ultrasonography guided prostate biopsy, and who have PSM after radical prostatectomy. After exclusion of number of biopsy cores <12, and lack of biopsy location data, 46 patients with PSM were identified. Locations of PSM in pathologic specimen were reported as 6 difference sites (apex, base and lateral in both sides). Discordance of biopsy result and PSM was defined when no positive cores in biopsy was identified at the location of PSM. RESULTS: Most common location of PSM were right apex (n=21) and left apex (n=15). Multiple PSM was reported in 21 specimens (45.7%). In 32 specimens (69.6%) with PSM, one or more concordant positive biopsy cores were identified, but 14 specimens (28%) had no concordant biopsy cores at PSM location. When discordant rate was separated by locations of PSM, right apex PSM had highest rate of discordant (38%). The discordant group had significantly lower prostate volume and lower number of positive cores in biopsy than concordant group. CONCLUSIONS: This study showed that one fourth of PSM occurred at location where tumor was not detected at biopsy and that apex PSM had highest rate of discordant. Careful dissection to avoid PSM should be performed in every location, including where tumor was not identified in biopsy. PMID- 26495073 TI - Distribution of ureteral stones and factors affecting their location and expulsion in patients with renal colic. AB - PURPOSE: To evaluate the distribution of ureteral stones and to determine their characteristics and expulsion rate based on their location. MATERIALS AND METHODS: We retrospectively reviewed computed tomography (CT) findings of 246 patients who visited our Emergency Department (ED) for renal colic caused by unilateral ureteral stones between January 2013 and April 2014. Histograms were constructed to plot the distribution of stones based on initial CT findings. Data from 144 of the 246 patients who underwent medical expulsive therapy (MET) for 2 weeks were analyzed to evaluate the factors responsible for the stone distribution and expulsion. RESULTS: The upper ureter and ureterovesical junction (UVJ) were 2 peak locations at which stones initially lodged. Stones lodged at the upper ureter and ureteropelvic junction (group A) had a larger longitudinal diameter (4.21 mm vs. 3.56 mm, p=0.004) compared to those lodged at the lower ureter and UVJ (group B). The expulsion rate was 75.6% and 94.9% in groups A and B, respectively. There was no significant difference in the time interval from initiation of renal colic to arrival at the ED between groups A and B (p=0.422). Stone diameter was a significant predictor of MET failure (odds ratio [OR], 1.795; p=0.005) but the initial stone location was not (OR, 0.299; p=0.082). CONCLUSIONS: The upper ureter and UVJ are 2 peak sites at which stones lodge. For stone size 10 mm or less, initial stone lodge site is not a significant predictor of MET failure in patients who have no previous history of active stone treatment in the ureter. PMID- 26495074 TI - The role of noninvasive penile cuff test in patients with bladder outlet obstruction. AB - PURPOSE: The aim of this study was to compare the penile cuff test (PCT) and standard pressure-flow study (PFS) in patients with bladder outlet obstruction. MATERIALS AND METHODS: A total of 58 male patients with moderate to severe lower urinary tract symptoms (LUTS) were selected. Seven patients were excluded; thus, 51 patients were finally enrolled. Each of the patients underwent a PCT and a subsequent PFS. The sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and likelihood ratio were calculated. Chi square and Fisher exact test were used to evaluate relationships between PCT results and maximal urine flow (Qmax); a p<0.05 was considered statistically significant. RESULTS: The mean (+/-standard deviation) age of the study group was 65.5+/-10.4 years. Overall, by use of the PCT, 24 patients were diagnosed as being obstructed and 27 patients as unobstructed. At the subsequent PFS, 16 of the 24 patients diagnosed as obstructed by the PCT were confirmed to be obstructed, 4 were diagnosed as unobstructed, and the remaining 4 patients appeared equivocal. Of the 27 patients shown to be unobstructed by the PCT, 25 were confirmed to not be obstructed by PFS, with 13 equivocal and 12 unobstructed. Two patients were diagnosed as being obstructed. For detecting obstruction, the PCT showed an SE of 88.9% and an SP of 75.7%. The PPV was 66.7% and the NPV was 93%. CONCLUSIONS: The PCT is a beneficial test for evaluating patients with LUTS. In particular, this instrument has an acceptable ability to reject obstruction caused by benign prostatic hyperplasia. PMID- 26495075 TI - Robot-assisted heminephrectomy for chromophobe renal cell carcinoma in L-shaped fused crossed ectopia: Surgical challenge. AB - Renal cell carcinoma associated with fused ectopic kidneys has rarely been reported in the literature. Here we report the first case of robot-assisted heminephrectomy for chromophobe renal cell carcinoma in an L-shaped fused ectopic kidney. The present case report highlights the importance of three-dimensional vision and enhanced maneuverability with the EndoWrist technology of the robotic surgical system for precise dissection. This report also highlights the importance of preoperative contrast-enhanced computed tomography with three dimensional arterial reconstruction for surgical planning. PMID- 26495076 TI - Autophagy: Can It be a New Experimental Research Method of Neuropathic Pain? PMID- 26495077 TI - Spinal Gap Junction Channels in Neuropathic Pain. AB - Damage to peripheral nerves or the spinal cord is often accompanied by neuropathic pain, which is a complex, chronic pain state. Increasing evidence indicates that alterations in the expression and activity of gap junction channels in the spinal cord are involved in the development of neuropathic pain. Thus, this review briefly summarizes evidence that regulation of the expression, coupling, and activity of spinal gap junction channels modulates pain signals in neuropathic pain states induced by peripheral nerve or spinal cord injury. We particularly focus on connexin 43 and pannexin 1 because their regulation vastly attenuates symptoms of neuropathic pain. We hope that the study of gap junction channels eventually leads to the development of a suitable treatment tool for patients with neuropathic pain. PMID- 26495078 TI - A New Rat Model of Cisplatin-induced Neuropathic Pain. AB - BACKGROUND: Chemotherapy-induced peripheral neuropathy is a major side effect of anti-cancer drugs, and our knowledge of its mechanisms is lacking. Several models for chemotherapy-induced neuropathy have been introduced. However, the outcomes of these models differ significantly among laboratories. Our object was to create a model of chemotherapy-induced neuropathy in rats with cancer. METHODS: Female Sprague-Dawley rats were used. Mammary rat metastasis tumor (MRMT-1) cells were implanted subcutaneously in rats. Chemotherapy-induced peripheral neuropathy was induced by injection of cisplatin once a day for four days. The responses to mechanical and thermal stimuli were examined using von Frey filaments, acetone, and radiant heat. RESULTS: Cisplatin (2 mg/kg/day) produced mechanical allodynia, while it did not induce cold allodynia or thermal hyperalgesia. This dose of cisplatin could work successfully against cancer. Body weight loss was not observed in cisplatin-treated rats, nor were other abnormal behaviors noted in the same rats. CONCLUSIONS: Repeated injection of intraperitoneal cisplatin induced peripheral neuropathic pain in rats. Thus, this type of rat model has broad applicability in studies related to searching for the mechanism of cisplatin-induced mechanical allodynia and agents for the treatment of neuropathic pain. PMID- 26495079 TI - Predictive Factors of Postoperative Pain and Postoperative Anxiety in Children Undergoing Elective Circumcision: A Prospective Cohort Study. AB - BACKGROUND: Although circumcision for phimosis in children is a minor surgical procedure, it is followed by pain and carries the risk of increased postoperative anxiety. This study examined predictive factors of postoperative pain and anxiety in children undergoing circumcision. METHODS: We conducted a prospective cohort study of children scheduled for elective circumcision. Circumcision was performed applying one of the following surgical techniques: sutureless prepuceplasty (SP), preputial plasty technique (PP), and conventional circumcision (CC). Demographics and base-line clinical characteristics were collected, and assessment of the level of preoperative anxiety was performed. Subsequently, a statistical model was designed in order to examine predictive factors of postoperative pain and postoperative anxiety. Assessment of postoperative pain was performed using the Faces Pain Scale (FPS). The Post Hospitalization Behavior Questionnaire study was used to assess negative behavioral manifestations. RESULTS: A total of 301 children with a mean age of 7.56 +/- 2.61 years were included in the study. Predictive factors of postoperative pain measured with the FPS included a) the type of surgical technique, b) the absence of siblings, and c) the presence of postoperative complications. Predictive factors of postoperative anxiety included a) the type of surgical technique, b) the level of education of mothers, c) the presence of preoperative anxiety, and d) a history of previous surgery. CONCLUSIONS: Although our study was not without its limitations, it expands current knowledge by adding new predictive factors of postoperative pain and postoperative anxiety. Clearly, further randomized controlled studies are needed to confirm its results. PMID- 26495080 TI - Review of Medical Dispute Cases in the Pain Management in Korea: A Medical Malpractice Liability Insurance Database Study. AB - BACKGROUND: Pain medicine often requires medico-legal involvement, even though diagnosis and treatments have improved considerably. Multiple guidelines for pain physicians contain many recommendations regarding interventional treatment. Unfortunately, no definite treatment guidelines exist because there is no complete consensus among individual guidelines. Pain intervention procedures are widely practiced and highly associated with adverse events and complications. However, a comprehensive, systemic review of medical-dispute cases (MDCs) in Korea has not yet been reported. The purpose of this article is to analyze the frequency and type of medical dispute activity undertaken by pain specialists in Korea. METHODS: Data on medical disputes cases were collected through the Korea Medical Association mutual aid and through a private medical malpractice liability insurance company. Data regarding the frequency and type of MDCs, along with brief case descriptions, were obtained. RESULTS: Pain in the lumbar region made up a major proportion of MDCs and compensation costs. Infection, nerve injury, and diagnosis related cases were the most major contents of MDCs. Only a small proportion of cases involved patient death or unconsciousness, but compensation costs were the highest. CONCLUSIONS: More systemic guidelines and recommendations on interventional pain management are needed, especially those focused on medico-legal cases. Complications arising from pain management procedures and treatments may be avoided by physicians who have the required knowledge and expertise regarding anatomy and pain intervention procedures and know how to recognize procedural aberrations as soon as they occur. PMID- 26495081 TI - The Impact of Educational Status on the Postoperative Perception of Pain. AB - BACKGROUND: Postoperative (PO) pain interferes with the recovery and mobilization of the surgical patients. The impact of the educational status has not been studied adequately up to now. METHODS: This prospective study involved 400 consecutive general surgery patients. Various factors known to be associated with the perception of pain including the educational status were recorded as was the preoperative and postoperative pain and the analgesia requirements for the 1(st) PO week. Based on the educational status, we classified the patients in 3 groups and we compared these groups for the main outcomes: i.e. PO pain and PO analgesia. RESULTS: There were 145 patients of lower education (junior school), 150 patients of high education (high school) and 101 of higher education (university). Patients of lower education were found to experience more pain than patients of higher education in all postoperative days (from the 2(nd) to the 6(th)). No difference was identified in the type and quantity of the analgesia used. The subgroup analysis showed that patients with depression and young patients (< 40 years) had the maximum effect. CONCLUSIONS: The educational status may be a significant predictor of postoperative pain due to various reasons, including the poor understanding of the preoperative information, the level of anxiety and depression caused by that and the suboptimal request and use of analgesia. Younger patients (< 40), and patients with subclinical depression are mostly affected while there is no impact on patients over 60 years old. PMID- 26495082 TI - Epiduroscopic Removal of a Lumbar Facet Joint Cyst. AB - Facet joint synovial cysts are usually associated with osteoarthritis of the adjacent facet joint and/or spondylolisthesis. In between the conservative and operative ends of the treatment spectrum lie minimally invasive techniques such as cyst rupture using epiduroscopy. In this report, we describe an 82-year-old male patient presenting with low back pain radiating to his lower left extremity and associated paresthesia. Magnetic resonance imaging of the lumbar spine revealed a synovial cyst at left L4/5 facet joint. Using epiduroscopy, the cyst was mechanically ruptured by popping it with the tip of the scope. The patient remained symptom-free at his successive visits until 12 months after the procedure, and was opened for desired follow up. PMID- 26495083 TI - Anaphylactic Shock Following Nonionic Contrast Medium during Caudal Epidural Injection. AB - Caudal epidural injection is a common intervention in patients with low back pain and sciatica. Even though the complications of fluoroscopically directed epidural injections are less frequent than in blind epidural injections, complications due to contrast media can occur. We report a case of anaphylactic shock immediately after injection of an intravenous nonionic contrast medium (iohexol) during the caudal epidural injection for low back pain and sciatica in a patient without a previous allergic history to ionic contrast media (ioxitalamate). Five minutes after the dye was injected, the patient began to experience dizziness, and the systolic blood pressure dropped to 60 mmHg. Subsequently, the patient exhibited a mild drowsy mental state. About 30 minutes after the subcutaneous injection of 0.2 mg epinephrine, the systolic blood pressure increased to 90 mmHg. The patient recovered without any sequela. Life-threatening complications after injection of intravenous contrast medium require immediate treatment. PMID- 26495084 TI - Ultrasound Guided Transversus Abdominis Plane Block for Anterior Cutaneous Nerve Entrapment Syndrome. AB - Anterior cutaneous nerve entrapment syndrome (ACNES) is one the most common cause of chronic abdominal wall pain. The syndrome is mostly misdiagnosed, treated wrongly and inadequately. If diagnosed correctly by history, examination and a positive carnett test, the suffering of the patient can be relieved by addressing the cause i.e. local anaesthetic with steroid injection at the entrapment site. Conventionally, the injection is done by landmark technique. In this report, we have described 2 patients who were diagnosed with ACNES who were offered ultrasound guided transverses abdominis plane (TAP) injection who got significant pain relief for a long duration of time. PMID- 26495085 TI - Ultrasound-guided Continuous Axillary Brachial Plexus Block Using a Nerve Stimulating Catheter: EpiStim(r) Catheter. AB - Brachial plexus block (BPB) under ultrasound guidance has come to be widely used. However, nerve injury has been reported following ultrasound-guided BPB. We hypothesized that BPB under ultrasound guidance in conjunction with real-time electrical nerve stimulation would help us prevent nerve injury and do more successful procedure. Here, we report the successful induction and maintenance of ultrasound-guided BPB and the achievement of good peri- and postoperative pain control using a conductive catheter, the EpiStim(r). PMID- 26495086 TI - Ultrasound Guided Technique for the Caudal Epidural Injection. PMID- 26495087 TI - Attention Deficit Hyperactivity Disorder in a Patient With Congenital Mirror Movement Disorder and Colpocephaly. AB - INTRODUCTION: Congenital mirror movement disorder designates involuntary movements on one side of the body that occur as mirror of the intentional movements on the contralateral side. Colpocephaly is described as persistence of fetal configuration of lateral ventricles. CASE PRESENTATION: A two-month old male infant was brought to the hospital due to bilateral identical movements of the hands. Except for bilateral involuntary synkinetic imitative movements in hands, neurological and physical examination was normal. Cranial MRI showed corpus callosum dysgenesis, hypogenesis and dilation of bilateral lateral ventricular posterior horns (colpocephaly). At the age of 7 years, he was started to use metylphenydate to mitigate attention deficit and hyperactivity disorder. The mirror movements were decreasing in amplitude by years and were not so serious to affect normal life activities. CONCLUSIONS: Mirror movements, diagnosed usually during childhood, may be congenital or secondary to neurological diseases. Although they generally do not affect normal life activities, in some cases severity of mirror movements causes a real debilitating disease. In our case the patient was diagnosed at the age of 2 months and on follow-up no debilitating problems were observed. This is the first case to describe the association of colpocephaly and mirror movements. The exact mechanism of this association is not known. Although it is known that mirror movements may be in relation with some pychiatric pathologies, this is the first report of attention deficit and hyperactivity disorder in conjunction with mirror movements and/or colpocephaly. Managing comorbidities, either physical or psyhchological, will help the patient to live in good health without trying to cope with other pathological diseases. PMID- 26495088 TI - Our Study is Just an Introduction, Reply to: Noncompaction in Healthy Subjects, Dilated and Hypertrophic Cardiomyopathy, and Neuromuscular Disorders Is the Same Entity. PMID- 26495089 TI - The Early Intestinal Microbiota of Healthy Korean Newborns. AB - BACKGROUND: The microflora hypothesis may be the underlying explanation for the growth of inflammatory disease. In addition to many known affecting factors, knowing the gut microbiota of healthy newborns can help to understand the gut immunity and modulate it. OBJECTIVES: This study examined the microbiota of healthy newborns from urban regions. PATIENTS AND METHODS: We enrolled 128 full term newborns, born at Seoul St. Mary and St. Paul hospital from January 2009 to February 2010. All 143 samples of feces were cultivated in six culture plates to determine the amounts of total bacteria, anaerobes, gram-positive bacteria, coliforms, lactobacilli, and bifidobacteria. The samples were evaluated with a bivariate correlation between coliforms and lactobacilli. Terminal restriction fragment length polymorphism (T-RFLP) analysis with HhaI and MspI and a clustering analysis were performed for determination of diversity. RESULTS: Bacteria were cultured in 61.5% of feces in the following order: anaerobes, gram positive bacteria, lactobacilli, coliform, and bifidobacteria. The growth of total bacteria and lactobacilli increased in feces defecated after 24 hours of birth (P < 0.001, P = 0.008) and anaerobes decreased (P = 0.003). A negative correlation between the growth of lactobacilli and coliforms was found (r = -463, P < 0.001). CONCLUSIONS: This study confirms that bacterial colonization of healthy newborns born in cities is non-sterile, but has early diversification and inter-individuality. PMID- 26495090 TI - Persistent Truncus Arteriosus With Intact Ventricular Septum: Clinical, Hemodynamic and Short-term Surgical Outcome. AB - INTRODUCTION: Truncus arteriosus with intact ventricular septum is a rare and unique variant of persistent truncus arteriosus (PTA) which usually presents with central cyanosis and congestive heart failure in neonate and early infancy. Associated cardiac and non-cardiac anomalies may affect morbidity and mortality of these patients. CASE PRESENTATION: We describe clinical presentation, echocardiography and angiographic features of a 7-month old boy with PTA and intact ventricular septum who underwent surgical repair of the anomaly at our institution. Operative findings, surgical procedure and short-term outcome are reported. CONCLUSIONS: While our patient had systemic pulmonary arterial pressure at the time of complete surgical repair, it was improved after surgery. PMID- 26495091 TI - Evaluation of Educational Environment for Medical Students of a Tertiary Pediatric Hospital in Tehran, Using DREEM Questionnaire. AB - BACKGROUND: Tertiary pediatric hospitals usually provide excellent clinical services, but such centers have a lot to do for educational perfection. OBJECTIVES: This study was performed to address under-graduate educational deficits and find feasible solutions. PATIENTS AND METHODS: This cross-sectional study was done in a target population of 77 sixth year undergraduate medical students (response rate = 78%) who spent their 3-month pediatric rotation in the Children's Medical Center, the Pediatrics Center of Excellence in Tehran, Iran. The Dundee ready educational environment measure (DREEM) instrument was used for assessing educational environment of this subspecialized pediatric hospital. RESULTS: Among 60 students who answered the questionnaires, 24 were male (40%). Participants' age ranged from 23 to 24 years. The mean total score was 95.8 (48%). Comparison of scores based on students' knowledge showed no significant difference. Problematic areas were learning, academic self-perception, and social self-perception. CONCLUSIONS: Having an accurate schedule to train general practitioner, using new teaching methods, and providing a non-stressful atmosphere were suggested solutions. PMID- 26495092 TI - Introduction of Sharp Objects in to Brain With Infanticidal Intention. PMID- 26495093 TI - Atopic Manifestations: Dermatitis, Allergic Rhinitis and Asthma in Patients With Hypogammaglobulinemia. AB - BACKGROUND: Most of the hypogammaglobulinemic patients have a clinical history in favor of allergic respiratory disease. Nevertheless, in these patients the importance and prevalence of atopic disorders have not been completely explained. OBJECTIVES: This study was aimed to evaluate atopic manifestations (dermatitis, allergic rhinitis and asthma) and pulmonary function in patients with hypogammaglobulinemia. PATIENTS AND METHODS: We used the international study of asthma and allergies in childhood (ISAAC) questionnaire in forty-five patients diagnosed with hypogammaglobulinemia and spirometry was done in 41 patients older than 5 years. RESULTS: Spirometry results were normal in 21 (51%), and showed obstructive in 15 (37%) and restrictive pattern in 5 (12%) of the 41 patients who were evaluated. By the end of the study, asthma was diagnosed in nine (20%) patients and other atopies (rhinitis and dermatitis) identified in 10 (22%), and four (9%), respectively. CONCLUSIONS: Atopic conditions should be investigated in the hypogammaglobulinemic patients and the prevalence in these patients may be higher than in normal population. Also, it is recommended to perform a pulmonary function test as a routine procedure in patients with hypogammaglobulinemia and atopy should be assessed in these patients. PMID- 26495094 TI - Outcome of Multi-Cystic Dysplastic Kidneys in Children. AB - BACKGROUND: Renal cystic diseases are important causes of chronic kidney disease (CKD). OBJECTIVES: We report the pattern of renal cystic disease in children and evaluate the outcome of children with multicystic dysplastic kidney (MCDK). PATIENTS AND METHODS: Retrospective study of all children with cystic kidney diseases at King Abdulaziz University hospital from 2006 to 2014. RESULTS: Total of 55 children (30 males); 25 MCDK, 22 polycystic kidney diseases (PKD), 4 nephronophthises and 4 renal cysts. Consanguinity was positive in 96.2%. MCDK and simple renal cyst patients had good renal function while PKD and nephronophthisis developed renal impairment. Most MCKD were diagnosed ante-natally, 16 of them were followed up for 3.4 (1.97) year. Their last creatinine was 33.9 (13.5) umol/L. MCDK was spontaneously involuted at mean age of 2.6 (1.3) years in 56%. CONCLUSIONS: MCDK is the commonest cystic renal disease and diagnosed ante natally in the majority of cases. It has a good prognosis. PMID- 26495095 TI - Evaluation of the Effect of Passive Smoking on Lactoferrin and AST on 12 - 15 Years Old Children and Adolescents. AB - BACKGROUND: Passive smokers are involuntarily exposed to cigarette or tobacco smoke and as known, inhalation of environmental tobacco smoke is a serious threat. There is little information about the effect of passive smoking on salivary markers and periodontal indices. OBJECTIVES: This study investigated the effect of passive smoking on lactoferrin and AST in 12 - 15 years old children and adolescents. PATIENTS AND METHODS: This case-control analytic correlation type study with no-convenience random sampling method was performed on 160 children aged 12 - 15 who had smokers in their families. The eligible children were divided into two equal groups; 80 cot(+) children as case group and 80 cot( ) children as control group, matched according to age, sex and plaque index. Plaque index was obtained from all subjects. 2 cc unstimulated salivary samples were collected by spitting method. The collected specimens were tested by lactoferrin and AST kits in biochemistry were measured on the day of sampling laboratory. Gingival index Loe and Silness (GI) and Probing Pocket Depth (PPD). RESULTS: Mean and Standard Deviation of PPD and GI was 2.01 +/- 0.077 and 1.53 +/ 0.055 in experimental group and 1.93 +/- 0.073 and 1.49 +/- 0.046 in control group respectively (P < 0.001). The Mean and Standard Deviation parameters of lactoferrin and AST, in the experimental group was 38.66 +/- 25.15 and 13.45 +/- 6.33 and in the control group 10.18 +/- 6.82 and 6.53 +/- 2.65 group, respectively (P < 0.001). CONCLUSIONS: Passive smoking can be effective on inflammatory process of periodontal and salivary biomarkers related to inflammation. Lactoferrin was 11 - 104 in case group and 0.5 - 38 in control group. Aspartat aminotransferase in case group was 2.64 - 30.43 and in control group it was 2.16 - 12.02. PMID- 26495096 TI - Analysis of Outcome of Intraplueral Streptokinase in Pediatric Empyema Thoracis even in Advanced Stages: A Prospective Study. AB - BACKGROUND: Empyema thoracis in children causes significant morbidity. Standard treatment of Empyema thoracis includes tube drainage and antibiotics. But the tube drainage often fails. Intrapleural Streptokinase has been used in empyema thoracis with good success rate. OBJECTIVES: We evaluated the efficacy of intra pleural Streptokinase in management of empyema thoracis even in advanced stages. PATIENTS AND METHODS: A total of 28 patients with empyema thoracis requiring intercostal tube drainage aged zero to twelve years were included in the study who were admitted in Pediatric intensive care unit. 15,000 units/kg of Streptokinase was instilled into the pleural cavity. Response was assessed by clinical outcome, after unclamping and subsequent chest radiography and serial chest ultrasounds. RESULTS: Streptokinase enhanced drainage in all patients with complete resolution of empyema thoracis in 26 patients. Two patients were referred for surgery. Only 7.2% required surgery. Streptokinase was equally effective if started before or after seven days. CONCLUSIONS: Intrapleural Streptokinase is the preferred treatment for treating pediatric empyema thoracis even in advanced stages and can avoid surgery. PMID- 26495097 TI - Association of Celiac Disease With Idiopathic Pulmonary Hemosiderosis; Lane Hamilton Syndrome. AB - INTRODUCTION: Idiopathic Pulmonary Hemosiderosis (IPH) is a rare cause of alveolar hemorrhage, which is seen primarily in childhood. Celiac disease is defined as a chronic, immune-mediated enteropathy of the small intestine, caused by exposure to dietary gluten in genetically pre-disposed individuals. Association of IPH and celiac disease is known as Lane Hamilton syndrome. There are limited number of case reports of this syndrome in literature. CASE PRESENTATION: Although there were no growth and developmental delay and gastrointestinal symptoms like chronic diarrhea, chronic constipation, vomiting, abdominal bloating and pain in the two patients with IPH, they were diagnosed with Lane Hamilton Syndrome. After initiation of gluten-free diet, their IPH symptoms disappeared and hemoglobin levels were observed to return to normal. CONCLUSIONS: Even if there were no gastrointestinal symptoms in a patient with IPH, celiac disease should be investigated. These patients may benefit from gluten free diet and IPH symptoms may disappear. PMID- 26495098 TI - Side Effects of Leukotriene Receptor Antagonists in Asthmatic Children. AB - BACKGROUND: Leukotriene receptor antagonists (LTRAs) are drugs which have been widely used more than ten years. As the use of LTRAs increases, our knowledge with respect to their side effects increases as well. OBJECTIVES: The objective of our study was to evaluat the observed side effects of LTRAs used in patients with astma. PATIENTS AND METHODS: 1024 patients treated only with LTRAs owing to asthma or early wheezing were included in the study for a five-year period. The observed side effects of LTRAs in these patients were retrospectively investigated. The side effects were divided into two parts as psychiatric and non psychiatric. RESULTS: Among the 1024 cases included in the study, 67.5% of the patients out of 41 with side effects were male, 32.5% were female and the average age was 6.5 years. The rate of patients with asthma was 63.41% and 36.58% of the patients had early wheezing. It was determined that sex, age and diagnosis (early wheezing or asthma) of the patients were ineffective in the emergence of side effects. The average period for the emergence of side effects was the first month. It was observed that hyperactivity was the most frequently observed psychiatric side effect and that abdominal pain was the non-psychiatric side effect. CONCLUSIONS: The side effects of LTRAs were common in children. Therefore, patients must be informed at the beginning of the treatment and they must be evaluated at certain intervals. PMID- 26495099 TI - Experience of a Single Center in NTBC Use in Management of Hereditary Tyrosinemia Type I in Libya. AB - BACKGROUND: Hereditary Tyrosinemia type I (HTI) is a metabolic disease caused by deficiency of fumarylacetoacetate hydrolase enzyme. OBJECTIVES: This study reports beside its clinical and biochemical presentation, the outcome of NTBC [2- (2-nitro-4-trifloro-methylbenzoyl)-1, 3-cyclohexanedion] treatment of the disease and evaluates its biochemical markers in 16 pediatric Libyan patients. PATIENTS AND METHODS: The diagnosis was based on presence of high tyrosine levels in blood and succinylacetone in urine. RESULTS: The consanguinity rate was 81.2%, the median age at onset, at diagnosis and at starting treatment were 4.5, 8, and 9.5 months respectively. At presentation hepatomegaly, jaundice, rickets and high gamma glutamyl transferase (GGT) were observed in 87.5% of patients. All patients had extremely high alpha fetoprotein (AFP) and high alkaline phosphatase (ALP) levels. Fifteen patients were treated with NTBC, normalization of PT (Prothrombine time) was achieved in average in 14 days. The other biochemical parameters of liver function (transaminases, GGT, ALP, bilirubin and albumin) took longer to improve and several months to be normalized. Survival rate with NTBC was 86.6%. Patients who started treatment in a median of 3 months post onset observed a fast drop of AFP in 90.6% of patients (P = 0.003). Abnormal liver function and rickets were the common presentations, GGT was an early cholestatic sensitive test. ALP was constantly high even in asymptomatic patients. CONCLUSIONS: In HT1 a faster dropping of AFP is a marker of good prognosis. PMID- 26495100 TI - Hospital Care for Newborn Babies: Quality Assessment, A Systematic Review. AB - CONTEXT: Neonatal mortality rate is declining globally. The aim of the present study is to identify relevant indicators for assessing newborn care in hospitals by a systematic review. EVIDENCE ACQUISITION: A search on electronic data base and manual searches of personal files for studies on quality indicators of newborn care were carried out. Searching 9 bibliographic databases, we found 85 articles of which 22 exactly related ones were selected and studied. Hand search yielded 1 record were also searched and 2 records were included. RESULTS: A list of 87 structure, process and outcome indicators was formulated from the articles. Also 26 excess measures were identified in gray literature. After removing duplicates, and categorizing in 3 domains, 18 measures were input, 41 process and 34 outcome measures. CONCLUSIONS: These 93 indicators provide a framework for assessing how well the hospitals are providing neonatal care. These measures should be discussed in each context expert panels to address nationally applicable indices of neonatal care and may be adapted for local health settings. PMID- 26495101 TI - Expression and Role of CD166 in the Chronic Kidney Disease. AB - BACKGROUND: CD166, an adhesion molecule of the immunoglobulin superfamily, is one of the crucial effectors that traffic lymphocytes into tissues. Till now, the expression and role of CD166 in the chronic kidney disease remains unknown. OBJECTIVES: In the present study, we are to examine the expression of CD166 in the chronic kidney disease, and to explore its function with CD4+ T cells. MATERIALS AND METHODS: CD166 expression was tested by Flow Cytometry (FACS) in the primary macrophages stimulated with LPS. In vivo, the expression of CD166 and CD4 were examined in the kidney tissues of adriamycin-induced nephropathy (AN) mice by immnohistochemistry. Macrophages and lymphocytes were co-cultured, the interaction between CD166 and CD4 was tested by immunofluorescent staining. Furthermore, the effects of CD166 on the activation and proliferation of T cells were explored. RESULTS: In this study, CD166 expression was found to be upregulated on activated macrophages and glomerular endothelia in the adriamycin induced nephropathy (AN) mice and CD4+ T cells were increased with CD166 expression in the AN mice. The interaction between macrophages and CD4+ T cells indicated that CD166 played a key role in the recruitment of lymphocytes in the chronic kidney disease, and neither proliferation nor activation of T cells was affected by CD166. CONCLUSIONS: CD166 expressed on macrophages and endothelia in AN kidney, and the function was related to the recruitment of CD4+ T cells into inflamed kidney, indicating that CD166 may be a potential target for reducing the inflammatory infiltrates in the chronic kidney disease. PMID- 26495102 TI - Cord Blood Alkaline Phosphatase as an Indicator of Neonatal Jaundice. AB - BACKGROUND: Management of hyperbilirubinemia remains a challenge for neonatal medicine because of the risk of neurological complications related to the toxicity of severe hyperbilirubinemia. OBJECTIVES: The purpose of this study was to examine the validity of cord blood alkaline phosphatase level for predicting neonatal hyperbilirubinemia. PATIENTS AND METHODS: Between October and December 2013 a total of 102 healthy term infants born to healthy mothers were studied. Cord blood samples were collected for measurement of alkaline Phosphatase levels immediately after birth. Neonates were followed-up for the emergence of jaundice. Newborns with clinical jaundice were recalled and serum bilirubin levels measured. Appropriate treatment based on serum bilirubin level was performed. Alkaline phosphatase levels between the non-jaundiced and jaundiced treated neonates were compared. RESULTS: The incidence of severe jaundice that required treatment among followed-up neonates was 9.8%. The mean alkaline phosphatase level was 309.09 +/- 82.51 IU/L in the non-jaundiced group and 367.80 +/- 73.82 IU/L in the severely jaundiced group (P = 0.040). The cutoff value of 314 IU/L was associated with sensitivity 80% and specificity 63% for predicting neonatal hyperbilirubinemia requiring treatment. CONCLUSIONS: The cord blood alkaline phosphatase level can be used as a predictor of severe neonatal jaundice. PMID- 26495103 TI - Biodegradation of Para Amino Acetanilide by Halomonas sp. TBZ3. AB - BACKGROUND: Aromatic compounds are known as a group of highly persistent environmental pollutants. Halomonas sp. TBZ3 was isolated from the highly salty Urmia Lake of Iran. In this study, characterization of a new Halomonas isolate called Halomonas sp. TBZ3 and its employment for biodegradation of para-amino acetanilide (PAA), as an aromatic environmental pollutant, is described. OBJECTIVES: This study aimed to characterize the TBZ3 isolate and to elucidate its ability as a biodegradative agent that decomposes PAA. MATERIALS AND METHODS: Primarily, DNA-DNA hybridization between TBZ3, Halomonas denitrificans DSM18045T and Halomonas saccharevitans LMG 23976T was carried out. Para-amino acetanilide biodegradation was assessed using spectrophotometry and confirmed by gas chromatography-mass spectroscopy (GC-MS). Parameters effective on biodegradation of PAA were optimized by the Response Surface Methodology (RSM). RESULTS: The DNA DNA hybridization experiments between isolate TBZ3, H. denitrificans and H. saccharevitans revealed relatedness levels of 57% and 65%, respectively. According to GC-MS results, TBZ3 degrades PAA to benzene, hexyl butanoate, 3 methyl-1-heptanol and hexyl hexanoate. Temperature 32.92 degrees C, pH 6.76, and salinity 14% are the optimum conditions for biodegradation with a confidence level of 95% (at level alpha = 0.05). CONCLUSIONS: According to our results, Halomonas sp. TBZ3 could be considered as a biological agent for bioremediation of PAA and possibly other similar aromatic compounds. PMID- 26495104 TI - In Silico Investigation for Evaluation of the Potential of the SclA Protein in Streptococcus pyogenes. AB - BACKGROUND: Streptococcus pyogenes is an important pathogen that is associated with a range of infections in humans, and causes common and severe invasive diseases. Currently, antimicrobial therapy is the first choice for the treatment of S. pyogenes; however, the emergence of antimicrobial resistance and side effects of antibacterial drugs is increasing. Consequently, there is an increased demand for novel drug targets and vaccine design. OBJECTIVES: To develop an effective vaccine against Streptococcus pyogenes (group A streptococcus) , we described a novel collagen-like surface protein of S. pyogenes which is important virulence factors. MATERIALS AND METHODS: In this study, we focused on the SclA protein of S. pyogenes and characterized it using bioinformatic tools to introduce it as a candidate novel drug as a candidate for use in vaccine design. The secondary structure was determined and the 3D structure was modeled using SWISS-MODEL workspace. The immune epitope database analysis (IEDB) resource was used to predict regions of SclA that are likely to be recognized as epitopes. RESULTS: The SclA protein is present on the cell surface of the cell and has interact with a common ligand by its hypervariable NH2-terminal regions. The IEDB showed that the maximum peptide length that is likely to be predicted as an epitope is of 6 amino acids, from amino acid 26 to 31, with a score of 4.791. This epitope can be considered for use in Antibody and drug design. CONCLUSIONS: Data from this study about SclA were not sufficient and further studies are needed; however, the information here suggests that SclA could be a candidate for further research on the design of drugs and vaccines against S. pyogenes infections. PMID- 26495105 TI - Rapid Detection of Methicillin-Resistant Staphylococcus aureus Isolates by Turanose Fermentation Method. AB - BACKGROUND: Methicillin-Resistant Staphylococcus aureus (MRSA) is a major pathogen in the hospital and community settings. Rapid methods to diagnose S. aureus infections are sought by many researchers worldwide. The current study aimed to utilize a phenotypic method of turanose fermentation to identify methicillin-susceptible and resistant S. aureus. OBJECTIVES: The current study aimed to assay the turanose metabolism at different dilutions as a rapid phenotypic method to identify MRSA isolates. MATERIALS AND METHODS: A total of 150 Staphylococcus isolates were collected from Tehran health centers. Staphylococcus aureus isolates were identified based on cultural characteristics, biochemical reactions and positive tube coagulase test. Methicillin resistance was determined by the disk diffusion method. The Polymerase Chain Reaction amplification was used to detect the mecA gene in MRSA isolates. All the methicillin-resistant and susceptible isolates were evaluated for turanose metabolism with 1%, 0.7% and 0.5% dilutions using the microplate method. RESULTS: Out of the 150 staphylococcal isolates, 80 were identified as S. aureus. Among which 40 (50%) of the isolates were MRSA. The mecA gene was present in all S. aureus isolates resistant to methicillin. A considerable difference was also observed between susceptible and resistant isolates of S. aureus at a 0.7% dilution of turanose. CONCLUSIONS: Since it is highly important to rapidly detect MRSA isolates, especially in nosocomial infections, phenotypic methods may certainly be useful for this purpose. Resistance to methicillin in S. aureus shows a substantially increased ability in turanose metabolism. It is concluded that fermentation of turanose at 0.7% dilution could be a rapid detection method for primary screening of MRSA isolates. PMID- 26495106 TI - Structural Characterization and Antimicrobial Activity of a Biosurfactant Obtained From Bacillus pumilus DSVP18 Grown on Potato Peels. AB - BACKGROUND: Biosurfactants constitute a structurally diverse group of surface active compounds derived from microorganisms. They are widely used industrially in various industrial applications such as pharmaceutical and environmental sectors. Major limiting factor in biosurfactant production is their production cost. OBJECTIVES: The aim of this study was to investigate biosurfactant production under laboratory conditions with potato peels as the sole source of carbon source. MATERIALS AND METHODS: A biosurfactant-producing bacterial strain (Bacillus pumilus DSVP18, NCBI GenBank accession no. GQ865643) was isolated from motor oil contaminated soil samples. Biochemical characteristics of the purified biosurfactant were determined and its chemical structure was analyzed. Stability studies were performed and biological activity of the biosurfactant was also evaluated. RESULTS: The strain, when grown on modified minimal salt media supplemented with 2% potato peels as the sole carbon source, showed the ability to reduce Surface Tension (ST) value of the medium from 72 to 28.7 mN/m. The isolated biosurfactant (3.2 +/- 0.32 g/L) was stable over a wide range of temperatures (20 - 120 oC), pH (2-12) and salt concentrations (2 - 12%). When characterized using high-performance liquid chromatography (HPLC) and Fourier transform infrared spectroscopy, it was found to be a lipopeptide in nature, which was further confirmed by Matrix-assisted laser desorption/ionization time of-flight mass spectrometry (mass peak 1044.60) and nuclear magnetic resonance (NMR) studies. Data showed that the isolated biosurfactant at the concentration range of 30 - 35 ug/ml had strong antimicrobial activity when tested against standard strains of Bacillus cereus, Escherichia coli, Salmonella enteritidis, Staphylococcus aureus and Paenibacillus larvae. CONCLUSIONS: Potato peels were proved to be potentially useful substrates for biosurfactant production by B. pumilus DSVP18. The strain possessed a unique property to reduce surface tension of the media from 72 to 28.7 mN/m. In addition, it showed a stable surface activity over a wide range of temperatures, pH, and saline conditions and had strong antimicrobial activity. This potential of the identified biosurfactant can be exploited by pharmaceutical industries for its commercial usage. PMID- 26495107 TI - Fluconazole Resistance Candida albicans in Females With Recurrent Vaginitis and Pir1 Overexpression. AB - BACKGROUND: Some genes may be associated with Candida albicans resistance to azoles. Pir1 gene is described as responsible to induce resistance in C. albicans. OBJECTIVES: The current study aimed to find the relationship between fluconazole resistance and Pir1 protein (Pir1p) overexpression in the females with recurrent C. albicans vaginitis requiring longer fluconazole therapy. PATIENTS AND METHODS: A total of 52l vaginal samples were obtained from the females with C. albicans vaginitis. The azole susceptibility phenotype was determined according to the Clinical Laboratory for Standards Institute (CLSI) protocol for disk diffusion method and inhibition zone for fluconazole. Expression of pir1 gene and fluconazole -resistance were evaluated using polymerase chain reaction (PCR) in C. albicans. RESULTS: In the 52 isolates, 49 (94%) were resistant to fluconazole. Overexpression of Pir1 gene was detected in 47 (96%) fluconazole-resistant C. albicans isolates. CONCLUSIONS: The findings show fluconazole -resistance in C. albicans isolates with overexpression of Pir1p. PMID- 26495108 TI - Etiologic Agents of Otomycosis in the North-Western Area of Iran. AB - BACKGROUND: Otomycosis is a superficial fungal infection often involves the pinna and external auditory canal. It is a pathologic condition, with Candida and Aspergillus, the most common fungal species. It is common worldwide but more prevalent in tropical and subtropical countries. OBJECTIVES: The aim of this study was to determine the etiologic agents and local epidemiologic pattern of otomycosis in northwest Iran. PATIENTS AND METHODS: A series of 140 patients with clinically symptomatic otomycosis were studied in 21 cities, towns, and villages throughout northwest Iran between 2009 and 2011. Clinical samples were collected by swabs and then assessed by mycological investigation. RESULTS: Otomycosis was diagnosed in 129 cases (92%, 76 male, 53 female) with the highest prevalence of cases occurring in males between 21 - 40 years of age. From an etiological point of view, 116 patients (90%, 21 - 40 years old) were infected by saprophytic mold and 9 patients (7%) were infected by yeast. Three cases (2%) involved dermatophytes, and in one case (1%) the subject was infected with Eurotium (the perfect stage of Aspergillus fumigatus). Aspergillus niger was the most common mold that was isolated, followed by A. flavus, A. fumigatus, Penicillium spp., Fusarium spp., and Rhizopus spp. A total of 2 yeasts belonging to genus Candida, C. albicans and C. tropicalis, were isolated. CONCLUSIONS: Our study showed a high prevalence of otomycosis in the northwestern area of Iran. As such, proper diagnosis and treatment by aseptic techniques for this disease is urgently needed. PMID- 26495109 TI - RPB5-Mediating Protein Suppresses Hepatitis B Virus (HBV) Transcription and Replication by Counteracting the Transcriptional Activation of Hepatitis B virus X Protein in HBV Replication Mouse Model. AB - BACKGROUND: RPB5-Mediating protein (RMP) is associated with the RNA polymerase II subunit RPB5. This protein functionally counteracts the transcriptional activation of Hepatitis B Virus X protein (HBx) by competitively binding to the RPB5; however, the effects of RMP on Hepatitis B virus (HBV) transcription and replication remain unknown. OBJECTIVES: The purpose of this study was to investigate the effect of RMP on viral transcription and replication in vivo by using the hydrodynamic-based HBV replication mouse model. MATERIALS AND METHODS: Male balb/c mice were transfected with wild type (1.2 wt) or the HBx minus HBV plasmids (1.2x (-)) with or without HBx and RMP, to establish an HBV replication mouse model by hydrodynamic injection through the tail vein. The HBV RNA and HBV DNA replication intermediates (RI) were analyzed in the liver. RESULTS: RPB5 Mediating protein could inhibit HBV transcription and replication in groups transfected with the 1.2 wt and HBx. The inhibitory effect disappeared in the 1.2x (-) groups, yet it reappeared in the groups co-transfected with 1.2x (-) and HBx. An inhibitory effect was indicated at a low dose of RMP (0.3 ug, 0.5 ug and 0.7 ug) compared to the control group and groups that had received high doses of RMP. CONCLUSIONS: Our study demonstrated that a low dose of RMP could inhibit HBV transcription and replication, which is dependent on the appearance of HBx in vivo. PMID- 26495110 TI - Detection and Genetic Characterization of Metallo-beta-Lactamase IMP-1 and VIM-2 in Pseudomonas aeruginosa Strains From Different Hospitals in Kermanshah, Iran. AB - BACKGROUND: Pseudomonas aeruginosais a frequent nosocomial pathogen that causes severe diseases in many settings. Carbapenems, including meropenem and imipenem, are effective antibiotics against this organism. However, the use of carbapenems has been hampered by the emergence of strains resistant to carbapenemsvia different mechanisms such as the production of metallo-beta-lactamases (MBLs), which hydrolyze all carbapenems. Several kinds of MBLs have been reported, among them VIM and IMP types being the most clinically significant carbapenemases. OBJECTIVES: We aimed to determine the distribution of bla VIM-2 and bla IMP-1 transferable genes encoding MBLs in P. aeruginosa isolated from three academic hospitals in Kermanshah. PATIENTS AND METHODS: From 22nd June to 22nd September 2012, 225 isolates of P. aeruginosa were collected. These isolates were tested for antibiotic susceptibility with the Kirby-Bauer disk-diffusion method, and the MBLs were assessed using the imipenem-EDTA double-disk synergy test. The isolates were investigated for bla VIM - 2 and bla IMP-1 genes using polymerase chain reaction. RESULTS: Among the 225 isolates, 33.7% (76/225) and 18.1% (41/225) were resistant to imipenem and meropenem, respectively. Of the 76 imipenem-resistant P. aeruginosa strains, 45 (59.2%) were positive for MBLs, 34 (75%) strains carried the bla IMP-1 gene, and 1 (2.2%) strain carried the bla VIM - 2 gene. CONCLUSIONS: Our results showed that there was a high frequency of IMP-1 positive P. aeruginosa in the different wards of the hospitals. PMID- 26495111 TI - Antifungal Activity of Selenium Nanoparticles Synthesized by Bacillus species Msh 1 Against Aspergillus fumigatus and Candida albicans. AB - BACKGROUND: Fungal infections affect various parts of the body and can be difficult to treat. Aspergillus infection causes a spectrum of diverse diseases particularly in lung according to host immunity. The two major entities are invasive pulmonary aspergillosis and chronic pulmonary aspergillosis. Candida infections can be superficial or invasive. Superficial infections often affect the skin or mucous membranes. However, invasive fungal infections are often life threatening. Advances in nanotechnology have opened new horizons in nanomedicine, allowing the synthesis of nanoparticles that can be assembled into complex architectures. Novel studies and technologies are devoted to understanding the mechanisms of disease for the design of new drugs. OBJECTIVES: In the present study, the antifungal activity of biogenic selenium nanoparticles (Se NPs) against Aspergillus fumigatus and Candida albicans was investigated. MATERIALS AND METHODS: Se-reducing bacteria previously identified as Bacillus sp. MSh-1 were used for the intracellular biosynthesis of elemental Se NPs. The shape, size, and purity of the extracted NPs were determined with various instrumental techniques. The nanoparticles antifungal characterization mainly derives from the following pathways: (i) to generate sustained flux of nano-ions from the compounds that deposited on special substrates or imbedded in colloidal or semisolid matrices. (ii) To transport active those ions to sensitive targets on plasma membrane of fungi. RESULTS: The results of energy-dispersive X-ray demonstrated that the purified NPs consisted of only Se. In addition, transmission electron micrographs showed that 120- to 140-nm spherical Se NPs were the most common. An antifungal assay was performed with a standard Clinical and Laboratory Standards Institute broth microdilution method. Minimum inhibitory concentration (MIC) measurements of the antifungal activity of the Se NPs against C. albicans (70 MUg/mL) and A. fumigatus (100 MUg/mL) showed that yeast cells were more sensitive than mold cells. CONCLUSIONS: The MICs against A. fumigatus (100 MUg/mL) and C. albicans (70 MUg/mL) showed that biogenic Se NPs are useful antifungal agents. PMID- 26495112 TI - Correlation of Oxacillinase Gene Carriage With the Genetic Fingerprints of Imipenem-Resistant Clinical Isolates of Acinetobacter baumannii. AB - BACKGROUND: Emergence of multidrug-resistant Acinetobacter baumannii has resulted in the treatment failure of related infections and an increase in patient mortality. The presence of class D beta-lactamases (oxacillinases) in this organism is an important mechanism underlying resistance to beta-lactam antibiotics. OBJECTIVES: The aim of this work was to investigate the correlation between oxacillinase gene carriage and genetic fingerprints in imipenem-resistant burn and non-burn isolates of A. baumannii. MATERIALS AND METHODS: Fifty-eight A. baumannii isolates were collected from October 2011 to April 2012, which included 28 burn isolates from Shahid Motahari Hospital and 30 non-burn isolates from Imam Hossein Hospital. The minimum inhibitory and minimum bactericidal concentrations (MIC and MBC) of imipenem were measured by the broth microdilution method. The presence of oxacillinase genes (OXA-23-, OXA-24-, OXA-51-, and OXA-58-like genes) was shown using type-specific primers and PCR. Genetic profiles were generated by RAPD-PCR fingerprinting. RESULTS: OXA-23 was observed in 81% of the isolates and its distribution was similar within the two groups. The presence of OXA-51 was shown in 58.6% of the isolates, of which most were burn isolates (67.6%). OXA-24 was present in 20.7% of the isolates, all belonging to the burn group; OXA-58 was not observed in any of the isolates. RAPD-PCR fingerprints revealed two clusters at a similarity level of 70% (A, B). At a similarity level of 85%, nine different groups were observed for burn and non-bun isolates. CONCLUSIONS: Our results showed that bla OXA-23 was the most prevalent gene, followed by bla OXA-51 , among the burn and non-burn clinical isolates of A. baumannii. Bla OXA-24 -like genes were detected at a lower level and were only found among the burn isolates, which also showed higher heterogeneity compared to the non-burn group. PMID- 26495113 TI - Detection of Staphylococcus Enterotoxin B (SEB) Using an Immunochromatographic Test Strip. AB - BACKGROUND: Staphylococcus aureus is one of the most important microorganisms that causes various human diseases by secreting virulence factors known as staphylococcal super antigens (SAgs). Staphylococcal Enterotoxin B (SEB) is a bacterial antigen that is responsible for food poisoning in humans. Among SEB detection methods, a lateral flow device (LFD) is ideal for rapid immunochromatographic tests because it is easy to use, requires minimal time to produce results, and does not require personnel training. OBJECTIVES: In our laboratory, the production of an immunochromatographic test strip, for the detection of SEB using a sandwich assay and a competitive method, was described; the test can detect SEB with high sensitivity. MATERIALS AND METHODS: The strip assays were compared with PCR, a valid method for detection. For PCR, a specific sequence for SEB production was detected using primers designed according to GenBank sequences. RESULTS: In total, 80 food samples suspected of SEB contamination were assessed using the two methods. Fifty-four samples were contaminated based on the PCR technique and twenty-six of those were confirmed using the strip assay. CONCLUSIONS: The sensitivity of the sandwich method was approximately 10 ng/mL and that of the competitive method was approximately 250 ng/mL. In the LFD, a highly specific monoclonal antibody used for both the sandwich and competitive methods resulted in an increased sensitivity and accuracy for the detection of a minimal SEB concentration. PMID- 26495114 TI - Analysis of Bacillus thuringiensis Population Dynamics and Its Interaction With Pseudomonas fluorescens in Soil. AB - BACKGROUND: Bacillus thuringiensis is the most successful biological control agent, however, studies so far have shown that B. thuringiensis is very sensitive to environmental factors such as soil moisture and pH. Ultraviolet light from the sun had been considered as the main limiting factor for its persistence in soil and it has recently been shown that the antagonism exerted by other native soil organisms, such as Pseudomonas fluorescens, is a determining factor in the persistence of this bacterium under in vitro culture conditions. OBJECTIVES: The aim of the present investigation was to analyze the population dynamics of B. thuringiensis and its interaction with P. fluorescens using microbiological and molecular methods in soil, under different conditions, and to determinate the effect of nutrients and moisture on its interaction. MATERIALS AND METHODS: The monitoring was performed by microbiological methods, such as viable count of bacteria, and molecular methods such as Polymerase Chain Reaction (PCR) and hybridization, using the direct extraction of DNA from populations of inoculated soil. RESULTS: The analysis of the interaction between B. thuringiensis and P. fluorescens in soil indicated that the disappearance of B. thuringiensis IPS82 is not dependent on the moisture but the composition of nutrients that may be affecting the secretion of toxic compounds in the environment of P. fluorescens. The results showed that the recovered cells were mostly spores and not vegetative cells in all proved treatments. The molecular methods were effective for monitoring bacterial population inoculated in soil. CONCLUSIONS: Bacillus thuringiensis is very sensitive to the interaction of P. fluorescens, however is capable to survive in soil due to its capacity of sporulate. Some of the cells in the form of spores germinated and folded slightly and remained in a constant cycle of sporulation and germination. This confirms that B. thuringiensis IPS82 can germinate, grow and sporulate in soil. PMID- 26495115 TI - In Vitro Susceptibilities of Candida albicans Isolates to Antifungal Agents in Tokat, Turkey. AB - BACKGROUND: Candida albicans is the pathogenic species most commonly isolated from fungal infections. Management of these infections depends on the immune status of the host, severity of disease, and the choice of antifungal drug. In spite of the development of new antifungal drugs, epidemiological studies have shown that resistance to antifungal drugs in C. albicans strains is becoming a serious problem. OBJECTIVES: The aim of this study was to evaluate the in vitro susceptibility of C. albicans isolates to ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, amphotericin B, caspofungin, and anidulafungin. MATERIALS AND METHODS: A total of 201 C. albicans isolates were collected from clinical specimens. Antifungal susceptibility tests were performed using the Etest. RESULTS: All the tested C. albicans isolates were found to be susceptible to amphotericin B and anidulafungin. Although none of the isolates showed resistance to caspofungin, 15% of the isolates were classified as showing intermediate resistance. The resistance rates of C. albicans isolates to ketoconazole, fluconazole, itraconazole, voriconazole and posaconazole were 32%, 34%, 21%, 14% and 14%, respectively. CONCLUSIONS: Our findings indicate that resistance of C. albicans strains to azoles is more common in Tokat, Turkey. Therefore, a strategy to control the inappropriate and widespread use of antifungal drugs is urgently needed. Fungal culturing and antifungal susceptibility testing will be useful in patient management as well as resistance surveillance. PMID- 26495116 TI - Metabolism, health and fillet nutritional quality in Atlantic salmon (Salmo salar) fed diets containing n-3-rich microalgae. AB - Microalgae, as primary producers of EPA and DHA, are among the most prominent alternative sources to fish oil for n-3 long-chain PUFA in animal and human nutrition. The present study aimed to assess technical, nutritional and fish health aspects of producing n-3-rich Atlantic salmon (Salmo salar) fish fillets by dietary supplementation of increasing levels of a DHA-producing Schizochytrium sp. and reduced or without use of supplemental fish oil. Atlantic salmon smolt were fed diets with graded levels of microalgae for 12 weeks, during which all fish showed high feed intake rates with postprandial plasma leptin levels inversely correlating with final mean fish body weights. Fish performance was optimal in all experimental treatments (thermal growth coefficient about 4.0 and feed conversion ratio 0.8-0.9), protein digestibility was equal in all diets, whereas dietary lipid digestibility inversely correlated with the dietary levels of the SFA 16 : 0. Fillet quality was good and similar to the control in all treatments in terms of n-3 long-chain PUFA content, gaping, texture and liquid losses during thawing. Histological fluorescence staining and immunofluorescence analysis of salmon intestines (midgut: base of intestine and villi) revealed significant effects on slime, goblet cell production and inducible nitric oxide synthase (iNOS) activity with increasing levels of dietary Schizochytrium sp. supplementation. Microarray analysis did not reveal any signs of toxicity, stress, inflammation or any other negative effects from Schizochytrium sp. supplementation in diets for Atlantic salmon. PMID- 26495117 TI - Relative validation of the dietary intake of fatty acids among adults in the Swedish National Dietary Survey using plasma phospholipid fatty acid composition. AB - The aims of a national dietary study are several-fold. One purpose is to monitor the intake of foods and nutrients in the population and to compare intakes with dietary recommendations. It is, however, difficult to measure dietary fat intake and plasma biomarker fatty acid (FA) composition may be used as an objective measure of dietary fat intake. Thus, the relative ability of a diet record to capture habitual fat intake was validated against biomarker FA. Dietary fat intake was measured in a novel self-assisted web-based 4-d food record - the 'Riksmaten' method. Spearman rank correlations between dietary FA, certain food groups (fish-shellfish, dairy products, meat and sausages, and spreads) and the fat content of these food groups and biomarker FA were explored. Participants were 150 women and 129 men, aged 18-80 years, who took part in the Swedish National Dietary Survey, Riksmaten adults 2010-11. Blood samples were collected on average 20 d after the diet record and FA composition was measured in plasma phospholipids by GLC. Total n-3 FA (r 0.31), EPA (r 0.34) and DHA (r 0.42) were correlated between plasma and diet (all P <= 0.001). Adjustment for covariates attenuated the relationships. Linoleic acid was only marginally correlated (r 0.15; P = 0.06) in women. Plasma pentadecaenoic acid and heptadecaenoic acid were correlated with dairy product intake as previously reported. In conclusion, the Riksmaten method appears valid for the purpose of collecting data on dietary fat composition, at least in a healthy adult population. PMID- 26495118 TI - Effects of school meals with weekly fish servings on vitamin D status in Danish children: secondary outcomes from the OPUS (Optimal well-being, development and health for Danish children through a healthy New Nordic Diet) School Meal Study. AB - Children's vitamin D intake and status can be optimised to meet recommendations. We investigated if nutritionally balanced school meals with weekly fish servings affected serum 25-hydroxyvitamin D (25(OH)D) and markers related to bone in 8- to 11-year-old Danish children. We conducted an explorative secondary outcome analysis on data from 784 children from the OPUS School Meal Study, a cluster randomised cross-over trial where children received school meals for 3 months and habitual lunch for 3 months. At baseline, and at the end of each dietary period, 25(OH)D, parathyroid hormone (PTH), osteocalcin (OC), insulin-like growth factor 1 (IGF-1), bone mineral content (BMC), bone area (BA), bone mineral density (BMD), dietary intake and physical activity were assessed. School meals increased vitamin D intake by 0.9 (95 % CI 0.7, 1.1) MUg/d. No consistent effects were found on 25(OH)D, BMC, BA, BMD, IGF-1 or OC. However, season-modified effects were observed with 25(OH)D, i.e. children completing the school meal period in January/February had higher 25(OH)D status (5.5 (95 % CI 1.8, 9.2) nmol/l; P = 0.004) than children completing the control period in these months. A similar tendency was indicated in November/December (4.1 (95 % CI -0.12, 8.3) nmol/l; P = 0.057). However, the effect was opposite in March/April (-4.0 (95 % CI -7.0, 0.9) nmol/l; P = 0.010), and no difference was found in May/June (P = 0.214). Unexpectedly, the school meals slightly increased PTH (0.18 (95 % CI 0.07, 0.29) pmol/l) compared with habitual lunch. Small increases in dietary vitamin D might hold potential to mitigate the winter nadir in Danish children's 25(OH)D status while higher increases appear necessary to affect status throughout the year. More trials on effects of vitamin D intake from natural foods are needed. PMID- 26495119 TI - Maternal supplementation of seaweed-derived polysaccharides improves intestinal health and immune status of suckling piglets. AB - The experiment investigated the effect of maternal dietary supplementation of seaweed-derived polysaccharides (SDP) (-SDP v. +SDP, n 20) from day 83 of gestation until weaning (day 28) on selected sow faeces and piglet digesta microbiota populations, piglet small-intestinal morphology, and intestinal nutrient transporter and inflammatory cytokine gene expression at birth, 48 h after birth and weaning. The effect of maternal dietary treatment on the piglet gene expression profile of inflammatory cytokines in the colon following a lipopolysaccharide (LPS) challenge was also investigated. Dietary SDP reduced sow faecal Enterobacteriaceae gene numbers at parturition. Small-intestinal morphology, nutrient transporter and cytokine gene expression in newborn piglets did not differ between maternal dietary treatments (P > 0.10). At 48 h after birth, sodium-glucose-linked transporter 1 gene expression was down-regulated in the ileum of piglets suckling the SDP-supplemented sows compared with those suckling the basal sows (P = 0.050). There was a SDP * LPS challenge interaction on IL-1 and IL-6 gene expression in the colon of piglets (P < 0.05). The gene expression of IL-1 and IL-6 was down-regulated in the LPS-challenged colon of piglets suckling the SDP sows compared with those suckling the basal sows (P < 0.05). However, there was no difference in IL-1 and IL-6 gene expression in the unchallenged colon between treatment groups. At weaning, piglets suckling the SDP supplemented sows had increased villus height in the jejunum and ileum compared with those suckling the basal-fed sows (P < 0.05). In conclusion, maternal dietary SDP supplementation enhanced the immune response of suckling piglets and improved gut morphology, making them more immune competent to deal with post weaning adversities. PMID- 26495121 TI - What do Danish children eat, and does the diet meet the recommendations? Baseline data from the OPUS School Meal Study. AB - A child's diet is an important determinant for later health, growth and development. In Denmark, most children in primary school bring their own packed lunch from home and attend an after-school care institution. The aim of the present study was to evaluate the food, energy and nutrient intake of Danish school children in relation to dietary guidelines and nutrient recommendations, and to assess the food intake during and outside school hours. In total, 834 children from nine public schools located in the eastern part of Denmark were included in this cross-sectional study and 798 children (95.7 %) completed the dietary assessment sufficiently (August-November 2011). The whole diet was recorded during seven consecutive days using the Web-based Dietary Assessment Software for Children (WebDASC). Compared with the food-based dietary guidelines and nutrient recommendations, 85 % of the children consumed excess amounts of red meat, 89 % consumed too much saturated fat, and 56 % consumed too much added sugar. Additionally 35 or 91 % of the children (depending on age group) consumed insufficient amounts of fruits and vegetables, 85 % consumed insufficient amounts of fish, 86 % consumed insufficient amounts of dietary fibre, 60 or 84 % had an insufficient Fe intake (depending on age group), and 96 % had an insufficient vitamin D intake. The study also showed that there is a higher intake of fruits and bread during school hours than outside school hours; this is not the case with, for example, fish and vegetables, and future studies should investigate strategies to increase fish and vegetable intake during school hours. PMID- 26495120 TI - A comparison of the nutrient intake of a community-dwelling first-episode psychosis cohort, aged 19-64 years, with data from the UK population. AB - Psychosis increases the risk of CVD, obesity and type 2 diabetes and reduces life expectancy. There are limited data comparing the dietary habits of community dwelling first-episode psychosis sufferers - with autonomy over diet - and the general population. The data represent the retrospective evaluation of nutritional data collected between 2007 and 2013 from 143 individuals from the UK population receiving treatment for first-episode psychosis. Differences in mean nutrient intakes between the study cohort and the national sample were tested for statistical significance using independent t tests, incorporating Satterthwaite's correction where required. Mean total energy intake was lower for males (P = 0.049) and higher for females (P = 0.016) in the cohort than in the corresponding subgroups of the national sample. Females in the study cohort consumed 12.9 (95 % CI 4.3, 21.5) g more total fat per d, whilst males consumed 7.7 (95 % CI 0.5, 14.9) g less protein per d than the national sample. Males in the study also showed significantly lower mean intakes than nationally of folate, Fe, Se, vitamin D and Zn, but not vitamin C. The proportion of individuals not meeting the lower reference nutrient intakes, particularly for Se (males 54.0 % and females 57.1 %) and for Fe amongst females (29.6 %), is cause for concern regarding potentially severe deficiencies. Further exploration of dietary habits within first-episode psychosis is warranted to assess whether individuals make beneficial dietary changes for their physical and mental health and wellbeing following dietary change intervention. It would also be pertinent to assess any correlation between diet and mental health symptomology. PMID- 26495122 TI - Oral supplementations of betaine, choline, creatine and vitamin B6 and their influence on the development of homocysteinaemia in neonatal piglets. AB - Homocysteine (Hcy) is an intermediary sulphur amino acid recognised for pro oxidative properties in several species which may weaken immune competence in piglets. In this species, there is an acute 10-fold increase of concentrations of plasma Hcy (pHcy) during the first 2 weeks of life. The present experiment aimed to determine if pHcy in piglets can be regulated by oral supplementations of betaine as a methyl group supplier, creatine for reducing the demand for methyl groups, choline with both previous functions and vitamin B6 as enzymic co-factor for Hcy catabolism. A total of seventeen sows (second parity) were fed gestation and lactation diets supplemented with folic acid (10 mg/kg) and vitamin B12 (150 ug/kg). Eight piglets in each litter received daily one of the eight following oral treatments (mg/kg body weight): (1) control (saline); (2) betaine (50); (3) choline (70); (4) creatine (300); (5) pyridoxine (0.2); (6) treatments 2 and 5; (7) treatments 3 and 4; and (8) treatments 2, 3, 4 and 5. According to age, pHcy increased sharply from 2.48 um at birth to 17.96 um at 21 d of age (P < 0.01). Concentrations of pHcy tended to be lower (P = 0.09) in treated than in control piglets but the highest and sole pairwise significant decrease (23 %) was observed between treatments 1 and 8 (P = 0.03). Growth from birth to 21 d of age was not influenced by treatments (P > 0.70). Therefore, it appears possible to reduce pHcy concentrations in suckling piglets but a combination of all chosen nutrients is required. PMID- 26495123 TI - The oral [(13)C]bicarbonate technique for measurement of short-term energy expenditure of sled dogs and their physiological response to diets with different fat:carbohydrate ratios. AB - The oral [(13)C]bicarbonate technique (o(13)CBT) was assessed for the determination of short-term energy expenditure (EE) under field conditions. A total of eight Alaskan huskies were fed two experimental diets in a cross-over experiment including two periods of 3 weeks. Effects of diets on EE, apparent total tract digestibility (ATTD) and on plasma hormones, blood lactate and glucose were furthermore investigated. The percentages of metabolisable energy derived from protein (P), fat (F) and carbohydrates (C) were 26:58:16 in the PFC diet and 24:75:1 in the PF diet. Measurements of EE were performed in the post absorptive state during rest. Blood samples were collected during rest and exercise and ATTD was determined after days with rest and with exercise. EE was higher (P < 0.01) in period 2 than in period 1 (68 v. 48 kJ/kg body weight(0.75) per h). The ATTD of organic matter, crude protein and crude fat was higher (P < 0.01) in the PF diet compared with the PFC diet, and lower (P < 0.01) for total carbohydrates. Exercise did not affect ATTD. Higher (P < 0.01) insulin-like growth factor 1 and leptin concentrations were measured when fed the PF diet compared with the PFC diet. Concentrations of insulin decreased (P < 0.01), whereas cortisol and ghrelin increased (P < 0.05), after exercise. There was no effect of diet on blood lactate and glucose, but higher (P < 0.001) lactate concentrations were measured in period 1 than in period 2. The results suggest that the o(13)CBT can be used in the field to estimate short-term EE in dogs during resting conditions. Higher ATTD and energy density of the PF diet may be beneficial when energy requirements are high. PMID- 26495124 TI - The effect of enteral nutrition on adipokines in patients with acute pancreatitis. AB - The mechanism behind the beneficial effects of enteral nutrition (EN) for patients with acute pancreatitis (AP) is largely unknown. Adipokines, as mediators of metabolism and inflammation, may be a possible mechanism. The study aimed to investigate the effect of EN on adipokines early in the course of AP. Patients with AP were randomised to EN or nil-by-mouth (NBM). Blood samples were taken on the first 4 d of admission and adipokine concentrations for adiponectin, leptin, omentin, resistin and visfatin were determined by ELISA assays. A linear mixed model analysis was run to determine differences in adipokine concentrations between the two study groups. A total of thirty-two patients were included in the study. Omentin concentrations were significantly higher in patients who received EN compared with NBM across the first 4 d of admission (mean difference: 11.6 (95 % CI 1.0, 22.3) ng/ml; P = 0.033). Leptin concentrations were significantly higher in patients who received EN compared with NBM after adjusting for age, sex and BMI (mean difference: 2.3 (95 % CI 0.1, 4.5) ng/ml; P = 0.037). No significant difference in adiponectin, resistin or visfatin concentrations were observed between the two study groups. EN significantly increases omentin and leptin concentrations in AP. Future research should be directed towards understanding whether these adipokines are responsible for the therapeutic benefits of EN. PMID- 26495125 TI - Postprandial glycaemic and insulinaemic responses in adults after consumption of dairy desserts and pound cakes containing short-chain fructo-oligosaccharides used to replace sugars. AB - The present studies aimed to evaluate the glycaemic and insulinaemic responses, in healthy adults, to short-chain fructo-oligosaccharides (scFOS) from sucrose used to replace sugars in foods. Two study populations aged 18-50 years were recruited and they consumed dairy desserts or pound cakes containing either standard sugar content or scFOS to replace 30 % of the sugar content. For each study, the two products were tested once under a double-blind and cross-over design with at least 7 d between the two tests. Glucose and insulin were measured using standard methods in blood samples collected with a venous catheter for 120 min during a kinetic test. For the dairy desserts, replacing 30 % of the sugars with scFOS significantly reduced postprandial glycaemic (AUC0-120 min; P = 0.020) and insulinaemic (AUC0-120 min; P = 0.003) responses. For the pound cakes, the glycaemic response was not altered (AUC0-120 min; P = 0.322) while the insulinaemic response tended to be lower (AUC0-120 min; P = 0.067). This study showed that scFOS can be used to replace sugars with the benefit of lowering the postprandial glycaemic response without increasing the insulinaemic response. The effect might be modulated by other parameters (e.g. fat content) of the food matrices. PMID- 26495126 TI - Yogurt drink fortified with menaquinone-7 improves vitamin K status in a healthy population. AB - Population-based studies have shown an inverse association between dietary menaquinones (MK-n, vitamin K2) intake, coronary calcification and CHD risk, suggesting a potential role of vitamin K in vascular health. To date, the effects of increased menaquinone intake on (markers of) vascular health have been investigated using predominantly food supplements. Dairy products contain many essential nutrients and can serve as a good matrix for food fortification in order to support health. We were therefore interested to study the effects of a menaquinone-fortified yogurt drink (menaquinone as menaquinone-7 (MK-7); 28 ug MK 7/yogurt drink) on vitamin K status and markers of vascular health. The yogurt drink was also fortified with n-3 PUFA, vitamin D, vitamin C, Ca and Mg to support vascular and/or general health. Healthy men (n 32) and postmenopausal women (n 28) with a mean age of 56 (sd 5) years received either basic or fortified yogurt drink twice per d for 12 weeks. MK-7 was efficiently absorbed from the fortified yogurt drink. Levels of circulating MK-7 were significantly increased from 0.28 to 1.94 ng/ml. In accordance, intake of the fortified yogurt drink improved vitamin K status, as measured by significant decreases in uncarboxylated osteocalcin and desphospho-uncarboxylated matrix Gla-protein. No effects were, however, seen on markers of inflammation, endothelial dysfunction and lipid metabolism. In summary, consumption of a yogurt drink fortified with low doses of among others MK-7 for 3 months significantly improved vitamin K status in a healthy population. PMID- 26495127 TI - MLVA typing of Mycoplasma hyopneumoniae bacterins and field strains. AB - Because of the lack of information about both the genetic characteristics of Mycoplasma hyopneumoniae commercial vaccines and their relationship with field strains, the authors attempted to identify genetic subtypes of some M hyopneumoniae bacterins, and to compare them with M. hyopneumoniae field strains. Six commercial M hyopneumoniae bacterins and 28 bronchoalveolar lavages from pigs at slaughter from three herds were analysed by Multiple-Locus Variable number tandem repeat Analysis (MLVA) on p146R1, p146R3, H4, H5 and p95 loci. The results obtained showed the presence of more than one M hyopneumoniae genotype in some pigs and also in one of the bacterins analysed. It is also worth noting that MLVA typing allowed the distinction among circulating field strains and also when comparing them with vaccine strains, which, knowing the relatedness among them, could be useful in the research of the efficacy of the vaccines. PMID- 26495128 TI - Milk Modulates Campylobacter Invasion into Caco-2 Intestinal Epithelial Cells. AB - Raw milk is a recognized source of Campylobacter outbreaks, but pasteurization is an effective way to eliminate the causative agent of Campylobacteriosis. Whereas breastfeeding is protective against infectious diseases, consumption of formula milk is thought to be not. However, in relation to Campylobacter, such data is currently unavailable. Although both pasteurized and formula milk are pathogen free and prepared in a quality controlled manner, the effect they have on the virulence of Campylobacter species is unknown. Here, we studied the effect of cow, goat, horse, and formula milk on Campylobacter invasion into intestinal epithelial Caco-2 cells, a pathogenic feature of this bacterial species, using a gentamicin exclusion invasion assay. We found that all milk products modulated the invasion of Campylobacter species into the Caco-2 cells in a dose-dependent manner. Control experiments showed that the milks were not toxic for the Caco-2 cells and that the effect on invasion is caused by heat labile (e.g., milk proteins) or heat stable (e.g., sugar/lipids) components depending on the Campylobacter species studied. This in vitro study shows for the first time that pasteurized and formula milk affect the invasion of Campylobacter. We recommend a prospective study to examine whether pasteurized and formula milk affect Campylobacteriosis. PMID- 26495129 TI - Matrix Metalloproteinase-2 Mediates Intestinal Immunopathogenesis in Campylobacter Jejuni-Infected Infant Mice. AB - Increased levels of the matrix metalloproteinases (MMPs)-2 and -9 (also referred to gelatinase-A and -B, respectively) can be detected in the inflamed gut. We have recently shown that synthetic gelatinase blockage reduces colonic apoptosis and pro-inflammatory immune responses following murine Campylobacter (C.) jejuni infection. In order to dissect whether MMP-2 and/or MMP-9 is involved in mediating C. jejuni-induced immune responses, infant MMP-2(-/-), MMP-9(-/-), and wildtype (WT) mice were perorally infected with the C. jejuni strain B2 immediately after weaning. Whereas, at day 2 postinfection (p.i.), fecal C. jejuni B2 loads were comparable in mice of either genotype, mice expelled the pathogen from the intestinal tract until day 4 p.i. Six days p.i., colonic MMP-2 but not MMP-9 mRNA was upregulated in WT mice. Remarkably, infected MMP-2(-/-) mice exhibited less frequent abundance of blood in feces, less distinct colonic histopathology and apoptosis, lower numbers of effector as well as innate and adaptive immune cells within the colonic mucosa, and higher colonic IL-22 mRNA levels as compared to infected WT mice. In conclusion, these results point towards an important role of MMP-2 in mediating C. jejuni-induced intestinal immunopathogenesis. PMID- 26495130 TI - Evaluation of Bloodstream Infections During Chemotherapy-Induced Febrile Neutropenia in Patients with Malignant Hematological Diseases: Single Center Experience. AB - From year to year, it is important to get an overview of the occurrence of causative agents in febrile neutropenic patients to determine the empiric treatment. Thus our aims were to evaluate a four-year period regarding the prevalence of bloodstream infections and the most important causative agents. During this period, 1,361 patients were treated in our hematology ward because of various hematological disorders. 812 febrile episodes were recorded in 469 patients. At that time, 3,714 blood culture (BC) bottles were sent for microbiological investigations, 759 of them gave positive signal. From the majority of positive blood culture bottles (67.1%), Gram-positive bacteria, mainly coagulase-negative staphylococci (CNS), were grown. Gram-negative bacteria were isolated from 32.9% of the positive blood culture bottles, in these cases the leading pathogen was Escherichia coli. The high prevalence of CNS was attributed to mainly contamination, while lower positivity rate for Gram-negative bacteria was associated with the use of broad-spectrum empiric antibiotic treatment. PMID- 26495131 TI - ABO/Rh Blood Groups and Risk of HIV Infection and Hepatitis B Among Blood Donors of Abidjan, Cote D'ivoire. AB - Hepatitis B and HIV infection are two viral infections that represent real global public health problems. In order to improve their management, some hypotheses suggest that genetic predispositions like ABO and Rh blood groups would influence the occurrence of these diseases. The aim of the present study was to examine the association between ABO and Rhesus blood groups and the susceptibility to HIV infection and hepatitis B. We conducted a cross-sectional and analytical study in a population of voluntary blood donors in the Blood Transfusion Center of Abidjan. All blood donors who donated blood between January and June 2014 were tested for HBs antigen and anti-HIV antibodies (ELISA tests) and were ABO typed. The total number of examined blood donors during this period was 45,538, of which 0.32% and 8.07% were respectively infected with HIV and hepatitis B virus. O group donors were more infected than non-O donors. Our study is an outline concerning the search for a link between ABO and Rh blood groups and hepatitis B and HIV infection. Further studies should be conducted to confirm the interaction between these two infections and contribute to the search for new therapeutic approaches. PMID- 26495132 TI - Anti-Inflammatory Properties of NAP in Acute Toxoplasma Gondii-Induced Ileitis in Mice. AB - The octapeptide NAP has been shown to exert neuroprotective properties. Here, we investigated potential anti-inflammatory effects of NAP in an acute ileitis model. To address this, C57BL/6j mice were perorally infected with Toxoplasma gondii (day 0). Within 1 week postinfection (p.i.), placebo (PLC)-treated mice developed acute ileitis due to Th1-type immune responses. Mice that were subjected to intraperitoneal NAP treatment from day 1 until day 6 p.i., however, developed less distinct macroscopic and microscopic disease as indicated by less body weight loss, less distinct histopathological ileal changes, and lower ileal apoptotic, but higher proliferating cell numbers, less abundance of neutrophils, macrophages, monocytes, and T lymphocytes, but higher numbers of regulatory T cells in the ileal mucosa and lamina propria, and lower concentrations of pro inflammatory mediators in the ilea as compared to PLC controls at day 7 p.i. Remarkably, NAP-mediated anti-inflammatory effects could also be observed in extra-intestinal compartments including liver and spleen. Strikingly, lower MCP 1, TNF, and IL-12p70 serum concentrations in NAP as compared to PLC-treated mice at day 7 p.i. indicate a pronounced systemic anti-inflammatory effect of NAP in acute ileitis. These findings provide first evidence for NAP as a potential novel treatment option in intestinal inflammation. PMID- 26495134 TI - Safety and Efficacy of Adding Fixed-Combination Brinzolamide/Timolol Maleate to Prostaglandin Therapy for Treatment of Ocular Hypertension or Glaucoma. AB - Purpose. To evaluate the safety and efficacy of adding brinzolamide 1%/timolol maleate 0.5% fixed combination (BTFC) to a prostaglandin analog (PGA). Methods. This was a 12-week, open-label, single-arm study of patients with open-angle glaucoma or ocular hypertension with intraocular pressure (IOP) not sufficiently controlled after >=4 weeks of PGA monotherapy. The primary outcome was mean IOP change from baseline at week 12. Other outcomes included IOP change from baseline at week 4, percentage of patients achieving IOP <=18 mmHg at week 12, and patient experience survey responses at week 12. Results. Forty-seven patients were enrolled and received treatment. The most commonly used PGAs were latanoprost (47%) and travoprost (32%). Mean +/- SD IOP was decreased at week 12 (17.2 +/- 4.1 mmHg) compared with baseline (23.1 +/- 3.0 mmHg; P < 0.001, paired t-test); IOP at week 4 was 17.2 +/- 3.3 mmHg. At week 12, 70% of patients achieved IOP <=18 mmHg. Patient-reported symptoms (e.g., pain and redness) were mostly unchanged from baseline. Twenty-eight adverse events (AEs) were reported; the most frequently reported AE was headache (3 events in 2 patients). Conclusion. Adjunctive BTFC + PGA therapy was effective and well tolerated. IOP decreased by 6 mmHg at weeks 4 and 12. PMID- 26495133 TI - TFF Peptides Play a Role in the Immune Response Following Oral Infection of Mice with Toxoplasma Gondii. AB - The peptide trefoil factor family 3 (TFF3) is a major constituent of the intestinal mucus, playing an important role in the repair of epithelial surfaces. To further understand the role of TFF3 in the protection of intestinal epithelium, we tested the influence of TFF3 in a murine Toxoplasma gondii-induced ileitis model. Surprisingly, TFF3(KO) mice showed a reduced immune response in the ileum when compared to wild-type animals. Interleukin-12 and interferon-gamma expression levels as well as the number of CD4(+) lymphocytes were reduced in the infected TFF3(KO) mice. These effects were in line with the trend of elevated parasite levels in the ileum. Moreover, TFF1 expression was upregulated in the spleen of infected mice. These initial results indicate that TFF3 is involved in the immune pathology of T. gondii infection-induced intestinal inflammation. Thus far, the mechanisms of how TFF3 influences the immune response are not fully understood. Further studies should identify if TFF3 affects mucus sensing of dendritic cells and how TFF3 is involved in regulating the immune response as an intrinsic secretory peptide of immune cells. PMID- 26495135 TI - Canaloplasty: A Minimally Invasive and Maximally Effective Glaucoma Treatment. AB - Canaloplasty is a highly effective, minimally invasive, surgical technique indicated for the treatment of open-angle glaucoma that works by restoring the function of the eye's natural outflow system. The procedure's excellent safety profile and long-term efficacy make it a viable option for the majority of glaucoma patient types. It can be used in conjunction with existing drug based glaucoma treatments, after laser or other types of incisional surgery, and does not preclude or affect the outcome of future surgery. Numerous scientific studies have shown Canaloplasty to be safe and effective in lowering IOP whilst reducing medication dependence. A recent refinement of Canaloplasty, known as ab-interno Canaloplasty (ABiC), maintains the IOP-lowering and safety benefits of traditional (ab-externo) Canaloplasty using a more efficient, simplified surgical approach. This paper presents a review of Canaloplasty indications, clinical data, and complications, as well as comparisons with traditional incisional glaucoma techniques. It also addresses the early clinical evidence for ABiC. PMID- 26495136 TI - Blood Pressure and Heart Rate Variability to Detect Vascular Dysregulation in Glaucoma. AB - Purpose. To investigate blood pressure and heart rate variability in patients with primary open-angle glaucoma (POAG) to detect disturbed blood pressure regulation. Methods. Thirty-one patients with POAG (mean age 68 +/- 10 years) and 48 control subjects (mean age 66 +/- 10 years) were included in a prospective study. Continuous blood pressure and heart rate were simultaneously and noninvasively recorded over 30 min (Glaucoscreen, aviant GmbH, Jena, Germany). Data were analyzed calculating univariate linear (time domain and frequency domain), nonlinear (Symbolic Dynamics, SD) and bivariate (Joint Symbolic Dynamics, JSD) indices. Results. Using nonlinear methods, glaucoma patients were separated with more parameters compared to linear methods. In POAG, nonlinear univariate indices (pW113 and pW120_Sys) were increased while the indices pTH10_Sys and pTH11_Sys reflect a reduction of dominant patterns. Bivariate indices (JSDdia29, JSDdia50, and JSDdia52; coupling between heart rate and diastolic blood pressure) were increased in POAG. The optimum set consisting of six parameters (JSDdia29, JSDdia58, pTH9_Sys, pW231, pW110_Sys and pW120_Sys) revealed a sensitivity of 83.3% and specificity of 80.6%. Conclusions. Nonlinear uni- and bivariate indices of continuous recordings of blood pressure and heart rate are altered in glaucoma. Abnormal blood pressure variability suggests disturbed autonomic regulation in patients with glaucoma. PMID- 26495137 TI - Outcomes of Late-Onset Bleb-Related Endophthalmitis Treated with Pars Plana Vitrectomy. AB - Purpose. To investigate clinical results on bleb-related endophthalmitis (BRE) after trabeculectomy treated with pars plana vitrectomy (PPV) and to evaluate influence factors for visual prognosis. Methods. Investigating medical records retrospectively, BRE was defined as an endophthalmitis induced by bleb infection. A total of 2018 eyes of 1225 patients who had trabeculectomy between December 2000 and July 2013 were included in this study. Eleven eyes of 11 patients with BRE were performed with PPV. Results. The mean age was 56.6 years. The mean period between trabeculectomy and BRE onset was 7.4 years. The mean period from starting symptom to initiation of treatment for endophthalmitis (PSITE) was 2.3 days. Bleb leakages were observed in 7 eyes (64%). On culture examinations, highly pathogenic bacteria (HPB) were identified in 6 cases (55%). HPB infection was influence factors on visual disturbance (P = .0337). Number of HPB infections is significantly higher in poor visual outcome than without poor visual outcome (P = .0310). Conclusion. Visual prognosis of BRE treated by PPV is significantly better when the pathogenic bacteria are not HPB. Severe visual loss occurred with HPB infection even though patients had appropriate treatments. Physicians need to have careful consideration to prevent bleb infection after trabeculectomy with MMC. PMID- 26495138 TI - Micro and Macro Element Composition of Kalanchoe integra Leaves: An Adjuvant Treatment for Hypertension in Ghana. AB - Two samples, water extract and blended whole leaves, of fresh Kalanchoe integra leaves (Crassulaceae), a traditional antihypertensive medicine used in Ghana, were analyzed with Energy Dispersive X-Ray Fluorescence spectroscopy (EDXRF). Analysis revealed 12 macro and 26 micro elements in both extracts. Further quantitative assessment of the results for amounts of elements that are pharmacologically significant revealed that the amounts of calcium, potassium, and magnesium present in the extracts could be correlated to its traditional usage in managing hypertension and arrhythmias. However, heavy metals (lead and inorganic arsenic) detected in the extracts may pose a threat at doses normally used traditionally for the treatment of hypertension. PMID- 26495139 TI - Sleep Deficiency and Deprivation Leading to Cardiovascular Disease. AB - Sleep plays a vital role in an individual's mental, emotional, and physiological well-being. Not only does sleep deficiency lead to neurological and psychological disorders, but also the literature has explored the adverse effects of sleep deficiency on the cardiovascular system. Decreased quantity and quality of sleep have been linked to cardiovascular disease (CVD) risk factors, such as hypertension, obesity, diabetes, and dyslipidemia. We explore the literature correlating primary sleep deficiency and deprivation as a cause for cardiovascular disease and cite endothelial dysfunction as a common underlying mechanism. PMID- 26495140 TI - Associations of Short Sleep and Shift Work Status with Hypertension among Black and White Americans. AB - Objective. The purpose of this study was to investigate whether short sleepers (<6 hrs) who worked the non-day-shift were at greater likelihood of reporting hypertension and if these associations varied by individuals' ethnicity. Methods. Analysis was based on the 2010 National Health Interview Survey (NHIS). A total of 59,199 American adults provided valid data for the present analyses (mean age = 46.2 +/- 17.7 years; 51.5% were female). Respondents provided work schedule and estimated habitual sleep durations as well as self-report of chronic conditions. Results. Of the sample, 30.8% reported a diagnosis of hypertension, 79.1% reported daytime shift work, 11.0% reported rotating shift work, and 4.0% reported night shift work. Logistic regression analysis showed that shift work was significantly associated with hypertension among Blacks [OR = 1.35, CI: 1.06 1.72. P < 0.05], but not among Whites [OR = 1.01, CI: 0.85-1.20, NS]. Black shift workers sleeping less than 6 hours had significantly increased odds of reporting hypertension [OR = 1.81, CI: 1.29-2.54, P < 0.01], while their White counterparts did not [OR = 1.17, CI: 0.90-1.52, NS]. Conclusions. Findings suggest that Black Americans working the non-day-shift especially with short sleep duration have increased odds of reporting hypertension. PMID- 26495141 TI - Genetic Variants of C-5312T REN Increased Renin Levels and Diastolic Blood Pressure Response to Angiotensin Receptor Blockers. AB - Renin catalyzes the cleavage of angiotensinogen into angiotensin I. Genetic variant C-5312T of renin enhancer has been reported to increase in vitro renin gene transcription. However, no obvious in vivo study was performed to see the renin level in C-5312T when treated with angiotensin receptor blockers (ARB). Therefore, this study aimed to investigate the serum renin level and blood pressure response in ARB treated hypertensive patients. Single nucleotide polymorphism (SNP) of C-5312T was identified in 55 hypertensive patients by using multiplex PCR and renin serum level was assayed by ELISA. The data showed that the increase of serum renin levels after 5 months of ARB treatment was significantly higher in patients with CT/TT genotype (10 pg/mL) than those with CC genotype (4.08 pg/mL) (P = 0.025). Hypertensive patients with CT/TT genotypes also showed less diastolic pressure reduction than CC genotypes in hypertensive patients with valsartan treatment (P = 0.04) or telmisartan treatment (P = 0.03). Finally, these findings suggested that SNP of C-5312T REN enhancer might contribute to higher increased renin serum levels and less diastolic blood pressure response to ARB treatment. PMID- 26495142 TI - Epidemiology of Hypertension Stages in Two Countries in Sub-Sahara Africa: Factors Associated with Hypertension Stages. AB - Studies using the revised hypertension classification are needed to better understand epidemiology of hypertension across full distribution. The sociodemographic, biological, and health behavior characteristics associated with different stages of hypertension in Ghana and South Africa (SA) were studied using global ageing and adult health (SAGE), WAVE 1 dataset. Blood pressure was assessed for a total of 7545 respondents, 2980 from SA and 4565 from Ghana. Hypertension was defined using JNC7 blood pressure classification considering previous diagnosis and treatment. Multivariate multinomial logistic regression analysis using Stata version 12 statistical software was done to identify independent predictors. The weighted prevalence of prehypertension and hypertension in Ghana was 30.7% and 42.4%, respectively, and that of SA was 29.4% and 46%, respectively, showing high burden. After adjusting for the independent variables, only age (OR = 1.32, 95% CI: 1.14-1.53), income (OR = 1.9, 95% CI: 1.04-3.47), and BMI (OR = 1.16, 95% CI: 1.1-1.22) remained independent predictors for stage 1 hypertension in Ghana, while, for SA, age (OR = 2.27, 95% CI: 1.53 3.36), sex (OR = 0.28, 95% CI: 0.08-1), and BMI (OR = 1.15, 95% CI: 1.07-1.25) were found to be independent predictors of stage 1 hypertension. Healthy lifestyle changes and policy measures are needed to promptly address these predictors. PMID- 26495143 TI - GPs' Perceptions of Cardiovascular Risk and Views on Patient Compliance: A Qualitative Interview Study. AB - Objective. General practitioners' (GPs') perception of risk is a cornerstone of preventive care. The aims of this interview study were to explore GPs' professional and personal attitudes and experiences regarding treatment with lipid-lowering drugs and their views on patient compliance. Methods. The material was drawn from semistructured qualitative interviews. We sampled GPs purposively from ten selected practices, ensuring diversity of demographic, professional, and personal characteristics. The GPs were encouraged to describe examples from their own practices and reflect on them and were informed that the focus was their personal attitudes and experiences. Systematic text condensation was applied for analysis in order to uncover the concepts and themes. Results. The analysis revealed the following 3 main themes: (1) use of cardiovascular guidelines and risk assessment tools, (2) strategies for managing patient compliance, and (3) GPs' own risk management. There were substantial differences in the attitudes concerning all three themes. Conclusions. The substantial differences in the GPs' personal and professional risk perceptions may be a key to understanding why GPs do not always follow cardiovascular guidelines. The impact on daily clinical practice, personal consultation style, and patient behaviour with regard to prevention is worth studying further. PMID- 26495144 TI - Effect of Nitrite and Nitrate Concentrations on the Performance of AFB-MFC Enriched with High-Strength Synthetic Wastewater. AB - In order to study the effect of nitrite and nitrate on the performance of microbial fuel cell, a system combining an anaerobic fluidized bed (AFB) and a microbial fuel cell (MFC) was employed for high-strength nitrogen-containing synthetic wastewater treatment. Before this study, the AFB-MFC had been used to treat high-strength organic wastewater for about one year in a continuous flow mode. The results showed that when the concentrations of nitrite nitrogen and nitrate nitrogen were increased from 1700 mg/L to 4045 mg/L and 545 mg/L to 1427 mg/L, respectively, the nitrite nitrogen and nitrate nitrogen removal efficiencies were both above 99%; the COD removal efficiency went up from 60.00% to 88.95%; the voltage was about 375 +/- 15 mV while the power density was at 70 +/- 5 mW/m(2). However, when the concentrations of nitrite nitrogen and nitrate nitrogen were above 4045 mg/L and 1427 mg/L, respectively, the removal of nitrite nitrogen, nitrate nitrogen, COD, voltage, and power density were decreased to be 86%, 88%, 77%, 180 mV, and 17 mW/m(2) when nitrite nitrogen and nitrate nitrogen were increased to 4265 mg/L and 1661 mg/L. In addition, the composition of biogas generated in the anode chamber was analyzed by a gas chromatograph. Nitrogen gas, methane, and carbon dioxide were obtained. The results indicated that denitrification happened in anode chamber. PMID- 26495145 TI - Acute Hemoperitoneum after Administration of Prostaglandin E2 for Induction of Labour. AB - Prostaglandin E2 is widely used in obstetrics and is thought to be relatively safe for cervical ripening and induction of labour. Here we present a case in which acute hemoperitoneum was observed after administration of prostaglandin E2 in a pregnant woman. The patient had a history of endometriosis, and a severe pelvic adhesion (ASRM stage IV) was found during her last laparoscopic surgery 3 years previously. In cases with endometriosis, use of prostaglandin E2 for induction of labour in pregnant women must be done cautiously. PMID- 26495146 TI - Retained Placenta Accreta Mimicking Choriocarcinoma. AB - This case demonstrates a rare event of retained invasive placenta masquerading as choriocarcinoma. The patient presented with heavy vaginal bleeding following vaginal delivery complicated by retained products of conception. Ultrasound and computed tomography demonstrated a vascular endometrial mass, invading the uterine wall and raising suspicion for choriocarcinoma. Hysterectomy revealed retained invasive placenta. PMID- 26495147 TI - Anal Papilloma: An Exceptional Presentation of Fibrocystic Disease in Anogenital Mammary-Like Glands. AB - Previously ectopic breast tissue was thought to be derived from the caudal remnants of the primitive embryonic milk ridges; anogenital mammary-like glands are presently considered as normal constituents of the anogenital region. We report a case of young female, who presented with an anal papilloma. Histopathological examination revealed extensive fibrocystic changes in anogenital mammary-like glands. To date, a lot of benign changes and a wide range of benign and malignant neoplasms have been reported in these glands. However, extensive fibrocystic change of these glands in anal region is very rare. In addition, fibrocystic disease of anal mammary glands, masquerading clinically as an anal papilloma, has not been reported in literature. Hence, it is essential for clinicians and the pathologists to be aware of such a rare presentation. The features of fibrocystic disease in perianal region are also discussed. PMID- 26495148 TI - Catatonia in Older Adult Individuals with Intellectual Disabilities. AB - Catatonia has been described in children with intellectual disabilities (IDs). These are the first three published cases of catatonia in adults older than 50 years of age with IDs. They were followed using the KANNER scale and, in one case, creatinine phosphokinase (CPK) monitoring. Case 1 is a 67-year-old Caucasian who probably had been having intermittent episodes of undiagnosed catatonia withdrawal for many years. His episodes of agitation and withdrawal behavior responded to lorazepam up to 8 mg/day. Case 2 is a 63-year-old Caucasian male who had probably had undiagnosed catatonic episodes since age 25. An agitation episode that rated 88 on Part 2 of the KANNER scale ended within minutes after he received 1 mg of intramuscular lorazepam. He had no symptom relapses for 4 years after getting stable oral lorazepam doses (3-8.5 mg/day). Case 3 is a 55-year-old African-American male with severe ID and bradycardia (with a pacemaker). He had been "institutionalized" since age 22 and his undiagnosed catatonic episodes appeared to have been intermittently present for at least the last ten years. As he became tolerant and experienced symptom relapse, oral lorazepam was slowly increased (1.5-18 mg/day). Electroconvulsive therapy was ruled out due to his pacemaker. PMID- 26495149 TI - Anti-AMPA-Receptor Encephalitis Presenting as a Rapid-Cycling Bipolar Disorder in a Young Woman with Turner Syndrome. AB - Background. Autoimmune encephalitis is a disorder characterised by the subacute onset of seizures, short-term memory loss, and psychiatric and behavioural symptoms. Initially, it was recognised as a paraneoplastic disorder, but recently a subgroup of patients without systemic cancer was identified. Case Description. We describe a 20-year-old woman with Turner syndrome presenting with a treatment resistant rapid cycling bipolar disorder with cognitive impairment. She was diagnosed with anti-AMPA-receptor encephalitis. She showed marked improvement after starting memantine and valproic acid. Conclusion. This case description emphasises the importance of timely recognition of autoimmune limbic encephalitis in patients with psychiatric manifestations and a possible predisposition to autoimmune conditions, in order to rule out malignancy and to quickly initiate treatment. PMID- 26495150 TI - Action Observation and Motor Imagery: Innovative Cognitive Tools in the Rehabilitation of Parkinson's Disease. AB - Parkinson's disease (PD) is characterized by a progressive impairment of motor skills with deterioration of autonomy in daily living activities. Physiotherapy is regarded as an adjuvant to pharmacological and neurosurgical treatment and may provide small and short-lasting clinical benefits in PD patients. However, the development of innovative rehabilitation approaches with greater long-term efficacy is a major unmet need. Motor imagery (MI) and action observation (AO) have been recently proposed as a promising rehabilitation tool. MI is the ability to imagine a movement without actual performance (or muscle activation). The same cortical-subcortical network active during motor execution is engaged in MI. The physiological basis of AO is represented by the activation of the "mirror neuron system." Both MI and AO are involved in motor learning and can induce improvements of motor performance, possibly mediated by the development of plastic changes in the motor cortex. The review of available evidences indicated that MI ability and AO feasibility are substantially preserved in PD subjects. A few preliminary studies suggested the possibility of using MI and AO as parts of rehabilitation protocols for PD patients. PMID- 26495151 TI - Living with Parkinson's and the Emerging Role of Occupational Therapy. AB - Parkinson's disease is a chronic and increasingly complex condition, demanding multidisciplinary management. Over the last twenty years or so, alongside the growth of specialist services and healthcare teams specifically developed for people with Parkinson's, occupational therapy has grown in recognition as a treatment option, especially since evidence of its efficacy is now slowly emerging. The purpose of this work is to outline the role of occupational therapy clinical practice in the management of people living with Parkinson's disease and its emergent evidence base, combined with details of current occupational therapy philosophy and process, as applicable to occupational therapy practice for people with Parkinson's. The Canadian Practice Process Framework is used to structure this overview and was selected because it is a well-recognized, evidence-based tool used by occupational therapists and encompasses the core concepts of human occupation and person-centred practice. The framework employed allows the flexibility to reflect the pragmatic occupational therapy intervention process and so enables the illustration of the individually tailored approach required to accommodate to the complex pathology and personal, domestic, and social impacts, affecting the functioning of Parkinson's disease patients on a daily basis. PMID- 26495152 TI - The Parkinsonian Gait Spatiotemporal Parameters Quantified by a Single Inertial Sensor before and after Automated Mechanical Peripheral Stimulation Treatment. AB - This study aims to evaluate the change in gait spatiotemporal parameters in subjects with Parkinson's disease (PD) before and after Automated Mechanical Peripheral Stimulation (AMPS) treatment. Thirty-five subjects with PD and 35 healthy age-matched subjects took part in this study. A dedicated medical device (Gondola) was used to administer the AMPS. All patients with PD were treated in off levodopa phase and their gait performances were evaluated by an inertial measurement system before and after the intervention. The one-way ANOVA for repeated measures was performed to assess the differences between pre- and post AMPS and the one-way ANOVA to assess the differences between PD patients and the control group. Spearman's correlations assessed the associations between patients with PD clinical status (H&Y) and the percentage of improvement of the gait variables after AMPS (alpha < 0.05 for all tests). The PD group had an improvement of 14.85% in the stride length; 14.77% in the gait velocity; and 29.91% in the gait propulsion. The correlation results showed that the higher the H&Y classification, the higher the stride length percentage of improvement. The treatment based on AMPS intervention seems to induce a better performance in the gait pattern of PD patients, mainly in intermediate and advanced stages of the condition. PMID- 26495153 TI - Determination of Polyphenols, Capsaicinoids, and Vitamin C in New Hybrids of Chili Peppers. AB - Six hybrids were subjected to chromatographic analyses by HPLC for the determination of phytochemicals such as capsaicinoid, polyphenol, and vitamin C. The dynamics of ripening of 4 of the hybrids were also characterised. Seven capsaicinoids could be separated and determined; the major compounds were nordihydrocapsaicin, capsaicin, and dihydrocapsaicin, while homocapsaicin and homodihydrocapsaicin derivatives were detected as minor constituents. Capsaicin content ranged between 95.5 +/- 4.15 and 1610.2 +/- 91.46 MUg/g FW, and the highest value was found in Bandai (C. frutescens) at the green ripening stage. The major capsaicinoids had a decreasing tendency in Bandai and Chili 3735 hybrids, while no change was observed in Beibeihong and Lolo during ripening. Nine polyphenol compounds were detected including 8 flavonoids and a nonflavonoid compound in the pods of all hybrids. The major components were naringenin diglucoside, catechin, and vanillic acid-derivative and luteolin-glucoside. Naringenin-diglucoside ranged from 93.5 +/- 4.26 to 368.8 +/- 30.77 MUg/g FW. Except vanillic acid-derivative, dominant polyphenols increased or remained unchanged during ripening. As for vitamin C, its content tended to increase with the advance in ripening in all hybrids included in this study. The highest value of 3689.4 +/- 39.50 MUg/g FW was recorded in Fire Flame hybrid. PMID- 26495154 TI - (1)H HR-MAS NMR Spectroscopy and the Metabolite Determination of Typical Foods in Mediterranean Diet. AB - NMR spectroscopy has become an experimental technique widely used in food science. The experimental procedures that allow precise and quantitative analysis on different foods are relatively simple. For a better sensitivity and resolution, NMR spectroscopy is usually applied to liquid sample by means of extraction procedures that can be addressed to the observation of particular compounds. For the study of semisolid systems such as intact tissues, High Resolution Magic Angle Spinning (HR-MAS) has received great attention within the biomedical area and beyond. Metabolic profiling and metabolism changes can be investigated both in animal organs and in foods. In this work we present a proton HR-MAS NMR study on the typical vegetable foods of Mediterranean diet such as the Protected Geographical Indication (PGI) cherry tomato of Pachino, the PGI Interdonato lemon of Messina, several Protected Designation of Origin (PDO) extra virgin olive oils from Sicily, and the Traditional Italian Food Product (PAT) red garlic of Nubia. We were able to identify and quantify the main metabolites within the studied systems that can be used for their characterization and authentication. PMID- 26495155 TI - Chemical Analysis of Suspected Unrecorded Alcoholic Beverages from the States of Sao Paulo and Minas Gerais, Brazil. AB - Our study analyzed 152 samples of alcoholic beverages collected from the states of Sao Paulo and Minas Gerais, Brazil, using gas chromatography with flame ionization detection (GC-FID) and mass spectrometry (GC-MS), Fourier transform infrared spectroscopy (FT-IR), and inductively coupled plasma atomic emission spectrometry (ICP-AES). The methanol content varied from 20 to 180 ppm in 28 samples, and the limit of the accepted level of 200 ppm was exceeded in only one sample. High content of cyanide derivatives and ethyl carbamate, above the accepted level of 150 ppb, was observed in 109 samples. Carbonyl compounds were also observed in 111 samples, showing hydroxy 2-propanone, 4-methyl-4-hepten-3 one, furfural, and 2-hydroxyethylcarbamate as main constituents. Copper was found at concentrations above 5 ppm in 26 samples; the maximum value observed was 28 ppm. This work evaluated the human health risk associated with the poor quality of suspected unrecorded alcohols beverages. PMID- 26495158 TI - Use of Biphasic Continuous Positive Airway Pressure in Premature Infant with Cleft Lip-Cleft Palate. AB - Preterm infants (PIs) often require respiratory support due to surfactant deficiency. Early weaning from mechanical ventilation to noninvasive respiratory support decreases ventilation-associated irreversible lung damage. This wean is particularly challenging in PIs with cleft lip and cleft palate due to anatomical difficulties encountered in maintaining an adequate seal for positive pressure ventilation. PI with a cleft lip and palate often fail noninvasive respiratory support and require continued intubation and mechanical ventilation. We are presenting the first case report of a PI with cleft lip and palate who was managed by biphasic nasal continuous positive airway pressure. PMID- 26495156 TI - Sesquiterpene Lactones from Artemisia Genus: Biological Activities and Methods of Analysis. AB - Sesquiterpene lactones are a large group of natural compounds, found primarily in plants of Asteraceae family, with over 5000 structures reported to date. Within this family, genus Artemisia is very well represented, having approximately 500 species characterized by the presence of eudesmanolides and guaianolides, especially highly oxygenated ones, and rarely of germacranolides. Sesquiterpene lactones exhibit a wide range of biological activities, such as antitumor, anti inflammatory, analgesic, antiulcer, antibacterial, antifungal, antiviral, antiparasitic, and insect deterrent. Many of the biological activities are attributed to the alpha-methylene-gamma-lactone group in their molecule which reacts through a Michael-addition with free sulfhydryl or amino groups in proteins and alkylates them. Due to the fact that most sesquiterpene lactones are thermolabile, less volatile compounds, they present no specific chromophores in the molecule and are sensitive to acidic and basic mediums, and their identification and quantification represent a difficult task for the analyst. Another problematic aspect is represented by the complexity of vegetal samples, which may contain compounds that can interfere with the analysis. Therefore, this paper proposes an overview of the methods used for the identification and quantification of sesquiterpene lactones found in Artemisia genus, as well as the optimal conditions for their extraction and separation. PMID- 26495157 TI - Molecular mechanisms controlling asymmetric and symmetric self-renewal of cancer stem cells. AB - Cancer stem cells (CSCs), or alternatively called tumor initiating cells (TICs), are a subpopulation of tumor cells, which possesses the ability to self-renew and differentiate into bulk tumor mass. An accumulating body of evidence suggests that CSCs contribute to the growth and recurrence of tumors and the resistance to chemo- and radiotherapy. CSCs achieve self-renewal through asymmetric division, in which one daughter cell retains the self-renewal ability, and the other is destined to differentiation. Recent studies revealed the mechanisms of asymmetric division in normal stem cells (NSCs) and, to a limited degree, CSCs as well. Asymmetric division initiates when a set of polarity-determining proteins mark the apical side of mother stem cells, which arranges the unequal alignment of mitotic spindle and centrosomes along the apical-basal polarity axis. This subsequently guides the recruitment of fate-determining proteins to the basal side of mother cells. Following cytokinesis, two daughter cells unequally inherit centrosomes, differentiation-promoting fate determinants, and other proteins involved in the maintenance of stemness. Modulation of asymmetric and symmetric division of CSCs may provide new strategies for dual targeting of CSCs and the bulk tumor mass. In this review, we discuss the current understanding of the mechanisms by which NSCs and CSCs achieve asymmetric division, including the functions of polarity- and fate-determining factors. PMID- 26495159 TI - Intrauterine Growth Restriction Associated with Hematologic Abnormalities: Probable Manifestations of Placental Mesenchymal Dysplasia. AB - Introduction Placental mesenchymal dysplasia is a rare vascular disease associated with intrauterine growth restriction, fetal demise as well as Beckwith Wiedemann syndrome. Some neonates present hematologic abnormalities possibly related to consumptive coagulopathy and hemolytic anemia in the placental circulation. Case report We present a case of placental mesenchymal dysplasia in a fetus with intrauterine growth restriction and cerebellar hemorrhagic injury diagnosed in the 20th week of pregnancy. During 26th week, our patient had an intrauterine fetal demise in the context of gestational hypertension. We have detailed the ultrasound findings that made us suspect the presence of hematologic disorders during 20th week. Discussion We believe that the cerebellar hematoma could be the consequence of thrombocytopenia accompanied by anemia. If hemorrhagic damage during fetal life is found, above all associates with an anomalous placental appearance and with intrauterine growth restriction, PMD should be suspected along other etiologies. PMID- 26495160 TI - Successful Treatment of Corticosteroid with Antiviral Therapy for a Neonatal Liver Failure with Disseminated Herpes Simplex Virus Infection. AB - Background Herpes simplex virus (HSV) infection carries one of the poorest outcomes of neonatal liver failure (NLF). Neonates with disseminated HSV infection can develop hemophagocytic lymphohistiocytosis (HLH), and occasionally need orthotopic liver transplantation. Early interventions may be critical for the cure of NLF. Case Report We describe herewith a 6-day-old neonate with fulminant hepatic failure due to disseminated HSV-1 infection, who successfully responded to high-dose corticosteroid therapy 72 hours after the onset of disease. Preceding acyclovir, gamma globulin, and exchange blood transfusion therapies failed to control the disease. Methylprednisolone pulse therapy led to a drastic improvement of liver function and cytokine storms, and prevented the disease progression to HLH. Sustained levels of plasma and cerebrospinal fluid HSV DNA declined after prolonged acyclovir therapy. Bilateral lesions of the periventricular white matter areas, assessed by magnetic resonance imaging, disappeared at 3 months of age. The infant showed normal growth and development at 4 years of age. Conclusion Early anti-hypercytokinemia therapy using corticosteroid, and prolonged antiviral therapy might only provide the transplantation-free cure of NLF with HSV dissemination. PMID- 26495161 TI - Acute Myocardial Infarction Due to Coronary Artery Dissection in the Postpartum Period. AB - Background Though rare, myocardial infarction secondary to coronary artery dissection is a life-threatening event. In reproductive age women, it commonly occurs during pregnancy or the postpartum period. Case We present a case of pregnancy-related acute myocardial infarction due to spontaneous coronary artery dissection in a 37-year-old woman who presented to the emergency room with shortness of breath and sudden onset of retrosternal chest pain 8 days after delivery of premature twins. Coronary artery catheterization showed 75 to 90% stenosis in the left main coronary artery (LMCA), extending into the proximal and mid left anterior descending (LAD) branch. The LMCA appearance in the heart catheterization was consistent with vasospasm, but it was not responsive to medical management. Subsequently, she underwent a second coronary artery catheterization and was found to have dissection requiring emergent coronary artery bypass graft * 3 in the LMCA, circumflex, and LAD that was followed by an uneventful recovery. Conclusion Early diagnosis and management of myocardial infarction due to coronary artery dissection in the peripartum period is crucial. This condition should be suspected in young reproductive age women, even in the setting of minimal risk factors. Angiography is required for diagnosis. Management should be individualized as it may include both invasive and noninvasive measures. PMID- 26495162 TI - Anatomical Closure of Left-to-Right Shunts in Premature Infants with Bronchopulmonary Dysplasia and Pulmonary Hypertension: A Cautionary Tale. AB - Closure of a systemic to pulmonary shunt in premature infants with bronchopulmonary dysplasia may be beneficial, but in the presence of pulmonary hypertension is controversial. Here, we discuss two premature infants with pulmonary hypertension who developed acute pulmonary hypertensive crisis after closure of these shunts and hence advise caution. PMID- 26495165 TI - Semilobar Holoprosencephaly with Congenital Oropharyngeal Stenosis in a Term Neonate. AB - Background Holoprosencephaly (HPE) is often accompanied by a deficit in midline facial development; however, congenital oropharyngeal stenosis in neonates with HPE has not been reported before. We describe a case of a neonate with prenatally diagnosed semilobar HPE accompanied by congenital oropharyngeal stenosis. Case Report The patient was born at 39 weeks of gestation and developed dyspnea shortly after. Laryngoscopic test revealed oropharyngeal stenosis. Nasal continuous positive airway pressure, high-flow nasal cannula, and nasopharyngeal airway did not resolve her dyspnea; tracheostomy was required. Conclusion Neonates with HPE might be at higher risk of pharyngeal stenosis because of the functional and/or anatomical abnormalities. In the case of dyspnea in neonates with HPE, laryngoscopic evaluation should be considered. PMID- 26495163 TI - Association of Fetal Abdominal-Head Circumference Size Difference With Shoulder Dystocia: A Multicenter Study. AB - Objective This study aims to determine if shoulder dystocia is associated with a difference in the fetal abdominal (AC) to head circumference (HC) of 50 mm or more noted on antenatal ultrasound. Study Design A multicenter matched case control study was performed comparing women who had shoulder dystocia to controls who did not. Women with vaginal births of live born nonanomalous singletons >= 36 weeks of gestation with an antenatal ultrasound within 4 weeks of delivery were included. Controls were matched for gestational age, route of delivery, and diabetes status. Results We identified 181 matched pairs. Only 5% of the fetuses had an AC to HC of >= 50 mm. The proportion of AC to HC difference of >= 50 mm was significantly higher in shoulder dystocia cases (8%) than controls (1%, p = 0.002). With multivariate regression, the three significant factors associated with shoulder dystocia were AC to HC >= 50 mm (odds ratio [OR], 7.3; confidence interval [CI], 1.6-33.3; p = 0.010), femur length (OR, 1.1; CI, 1.0-1.2; p = 0.002), and induced labor (OR, 1.8; CI, 1.1-3.1; p = 0.027). Conclusion A prenatal ultrasound finding of a difference in AC to HC of >= 50 mm while uncommon is associated with shoulder dystocia. PMID- 26495164 TI - First Pregnancy, Somatic and Psychological Status of a 4-Year-Old Child Born following Annexin V TESA Sperm Separation. AB - Introduction Sperm DNA integrity is a crucial paternal factor affecting fertilization and pregnancy rates, as well as embryo development. Case The present case report describes the successful pregnancy after testicular sperm aspiration (TESA) combined with intracytoplasmic sperm injection (ICSI) (TESA ICSI) in a couple where the male presented high sperm DNA fragmentation. In order to sort damaged sperm presenting DNA fragmentation, magnetic activated cell sorting (MACS) with annexin V microbeads (MACS Miltenyi Biotec, Teterow, Germany) was used. Conclusion The authors present the first description of a successful medical case using TESA-ICSI annexin V sperm sorting. Additionally, a follow-up of the child at the age of 4 years old was done. PMID- 26495166 TI - Frontofacionasal Dysplasia in a Newborn with a De Novo Duplication of 7p15.2 p15.1. AB - We report a new case of frontofacionasal dysplasia or dysostosis (FFND) with a 1.5 Mb duplication in the region of 7p15.2-p15.1, and provide a review of the literature to understand the underlying pathogenesis better. PMID- 26495167 TI - Prenatal Diagnosis of Walker-Warburg Syndrome Using Single Nucleotide Polymorphism Array: A Clinical Experience from Three Related Palestinian Families with Congenital Hydrocephalus. AB - Background Congenital hydrocephalus is a common and often disabling disorder. Various syndromic forms of hydrocephalus have been reported in the Palestinian population including Walker-Warburg syndrome (WWS), Carpenter syndrome, and Meckel syndrome. Aim In this report we discuss the antenatal diagnosis of congenital hydrocephalus in three related Palestinian families. Method Single nucleotide polymorphism (SNP) array was performed prenatally for the third affected fetus. Results A diagnosis of WWS was found and molecular testing revealed a known pathogenic mutation in the POMT2 gene. An affected fetus from the other family was diagnosed and tested postnatally in light of this finding. Testing of another affected stillborn offspring was performed and revealed the same mutation. Conclusions Here, we show that the use of prenatal SNP array testing can be helpful in elucidating the etiology of congenital hydrocephalus and in guiding appropriate perinatal care. Also, testing for this specific POMT2 mutation should be considered in cases of prenatally detected hydrocephalus in Palestinian families. PMID- 26495168 TI - Sustained Neuromuscular Blockade after Vecuronium Use in a Premature Infant. AB - Background Prolonged use of neuromuscular blocking agents (NMBAs) is very common in critically ill children both in pediatric and neonatal intensive care units. There are no guidelines available for use of NMBAs in children or neonates in the US, and the data for their safety in this age group is limited. Case Description Our case describes prolonged neuromuscular blockade following concurrent use of a NMBA along with aminoglycosides and steroids in the setting of renal failure in a premature infant. Conclusion Prolonged use of NMBAs in preterm infants should be avoided if possible or should be restricted to the shortest possible duration and the smallest possible physiologically effective dose. Concurrent use of NMBAs with aminoglycoside and steroids should be avoided, especially in the setting of renal failure. PMID- 26495169 TI - Minimally Conjoined Omphalopagus Twins with a Body Stalk Anomaly. AB - Introduction This report will discuss a case of minimally conjoined omphalopagus twins (MCOTs) with a body stalk anomaly (BSA). Case Report We experienced monochorionic diamniotic (MD) twins born at 31 weeks. One infant was suspicious of BSA before birth, and another infant was normal. But normal infant had anal atresia with small intestine which was inserted behind the umbilicus. Twins had very short common umbilicus and infant with BSA had intestinal conjunction, two appendixes at the site of the colon, and a blind-ending colon. We diagnosed MCOTs. Discussion On the basis of the Spencer hypothesis, the etiology of MCOTs was that MD twins shared a yolk sac. However, this could not explain the presence of a BSA. It is necessary to consider the possible reasons for a singleton BSA. In addition, intestinal fusion occurred unequally in this case, although two appendixes were found in the same place, which might have occurred because of the balanced fusion. PMID- 26495170 TI - Peripartum Primary Prophylaxis Inferior Vena Cava Filter Placement in a Patient with Stage IV B-Cell Lymphoma Presenting with a Pathologic Femur Fracture. AB - Background Pulmonary embolus (PE) remains a leading etiology of maternal mortality in the developed world. Increasing utilization of retrievable inferior vena cava (IVC) filter placement currently includes pregnant patients. Case A 22 year-old woman at 27 weeks' gestation was diagnosed with Stage IV high-grade malignant B cell lymphoma following pathologic femur fracture. Significant risk factors for PE led to placement of primary prophylaxis IVC filter before cesarean delivery, open reduction and internal fixation of the fractured femur, and chemotherapy. Conclusion This case supports that primary prophylaxis placement of IVC filters in highly selected pregnant patients may assist in decreasing PE associated maternal mortality. PMID- 26495171 TI - Amniotic Sac Herniation Through a Prior Cornual Scar in The Third Trimester. AB - Introduction Uterine rupture occurs in less than 0.1% of pregnancies. This complication can be detrimental to mother and fetus if not detected and managed in a timely manner. We report an unusual presentation of uterine scar rupture that was diagnosed on ultrasound in a completely stable patient with reassuring fetal status. Case Report A 24-year-old Gravida 5, Para 3 with history of cornual resection for ectopic pregnancy and two previous uterine ruptures presented at 30 weeks' gestation with worsening abdominal pain. Ultrasound identified herniation of the amniotic sac with fetal parts. The patient underwent cesarean delivery and cornual defect repair. Conclusion Close observation and early delivery remain vital to the patient's management. PMID- 26495172 TI - Irreversible Respiratory Failure in a Full-Term Infant with Features of Pulmonary Interstitial Glycogenosis as Well as Bronchopulmonary Dysplasia. AB - Pulmonary interstitial glycogenosis (PIG) is a rare interstitial lung disease in the newborns. We report on the clinical presentation and pathological findings of a full-term male infant with pulmonary hypertension requiring extracorporeal membrane oxygenation (ECMO). An open lung biopsy demonstrated interstitial changes resembling pulmonary interstitial glycogenosis as well as bronchopulmonary dysplasia (BPD), without convincing evidence of maturational arrest, infection, alveolar proteinosis, or alveolar capillary dysplasia. The boy was treated with glucocorticoids and, after a few days, was weaned from ECMO. A few hours later, the patient died due to acute severe pulmonary hypertension with acute right ventricular failure. The etiology and underlying pathogenic mechanisms of PIG are unknown. The clinical outcomes are quite varied. Deaths have been reported when PIG exists with abnormal lung development and pulmonary vascular growth and congenital heart disease. No mortality has been reported in PIG together with BPD in full-term infants. In this article, we reported on a full-term infant with interstitial changes resembling PIG and BPD who expired despite no convincing evidence of an anatomical maturational arrest or congenital heart disease. PMID- 26495174 TI - Eosinophilic Endomyocarditis: A Rare Case of Neonatal Mortality. AB - Background Eosinophilic endomyocarditis (EEM) is a rare diagnosis that is extremely uncommon in newborns. This case report aimed to present a case of neonatal mortality from acute cardiac failure due to EEM. Case Our report presents a term male neonate with minor complications in the immediate postnatal course, who was discharged at 48 hours of life, but who developed unexpected respiratory distress, followed by cardiac arrest and death at 3 days of life. One day after discharge, the infant developed respiratory distress and cool skin, and then developed cardiac arrest at the pediatrician's office, undergoing resuscitation with intravenous fluid, cardiopulmonary resuscitation, epinephrine, atropine, and failed intubation. Autopsy revealed EEM, an inflammatory infiltrative process involving the endomyocardium. Pathology Pathogenesis involves three stages: (1) myocarditis with an acute eosinophilic inflammatory infiltrate followed by (2) myocyte necrosis and eventually (3) fibrosis in the final stage of the disease. Discussion The cause of death was acute cardiac failure due to intense eosinophilic infiltration and degranulation with early subendocardial myocyte necrosis but before development of extensive myocyte necrosis. This case appears to be the youngest patient reported with EEM. PMID- 26495173 TI - Predictive Factors for Delivery within 7 Days after Successful 48-Hour Treatment of Threatened Preterm Labor. AB - Objective The aim of this study was to assess which characteristics and results of vaginal examination are predictive for delivery within 7 days, in women with threatened preterm labor after initial treatment. Study Design A secondary analysis of a randomized controlled trial on maintenance nifedipine includes women who remained undelivered after threatened preterm labor for 48 hours. We developed one model for women with premature prelabor rupture of membranes (PPROM) and one without PPROM. The predictors were identified by backward selection. We assessed calibration and discrimination and used bootstrapping techniques to correct for potential overfitting. Results For women with PPROM (model 1), nulliparity, history of preterm birth, and vaginal bleeding were included in the multivariable analysis. For women without PPROM (model 2), maternal age, vaginal bleeding, cervical length, and fetal fibronectin (fFN) status were in the multivariable analysis. Discriminative capability was moderate to good (c-statistic 0.68; 95% confidence interval [CI] 0.60-0.77 for model 1 and 0.89; 95% CI, 0.84-0.93 for model 2). Conclusion PPROM and vaginal bleeding in the current pregnancy are relevant predictive factors in all women, as are maternal age, cervical length, and fFN in women without PPROM and nulliparity, history of preterm birth in women with PPROM. PMID- 26495175 TI - Fetofetal Transfusion Syndrome in Monochorionic-Triamniotic Triplets Treated with Fetoscopic Laser Ablation: Report of Two Cases and A Systematic Review. AB - Objective This study aims to determine the clinical outcomes of monochorionic triamniotic (MT) pregnancies complicated by severe fetofetal transfusion undergoing laser photocoagulation. Study Design We report two cases of MT triplets complicated by fetofetal transfusion syndrome (FFTS) and a systematic review classifying cases into different subtypes: MT with two donors and one recipient, MT with one donor and two recipients, MT with one donor, one recipient, and one unaffected triplet. The number of neonatal survivors was analyzed based on this classification as well as Quintero staging. Results A total of 26 cases of MT triples complicated by FFTS were analyzed. In 56% of the cases, the FFTS involved all three triplets, 50% of whom had an additional donor and 50% an additional recipient. Among the 24 cases that survived beyond 1 week after the procedure, the average gestational age of delivery was 29.6 weeks, and the average interval from procedure to delivery was 10.1 weeks. The overall neonatal survival rate was 71.7%, with demises occurring equally between donor and recipient triplets. Overall neonatal survival including survival of at least two fetuses occurred with equal frequency between the different groups. Conclusion Significant neonatal survival can be achieved in most cases of MT triplets with FFTS. PMID- 26495176 TI - Multimodality Renal Failure in a Patient with OEIS Complex. AB - Omphalocele-exstrophy of the bladder-imperforate anus-spinal defect (OEIS) complex is a rare constellation of clinical abnormalities with wide phenotypic presentation. We describe a case of a preterm neonate with OEIS complex with acute renal failure, and the challenges in diagnosis and management of this patient as renal failure can be a multifactorial process when encountered with this rare complex. PMID- 26495177 TI - Pregnancy in Desmin-Related Cardiomyopathy. AB - The course of desmin-related restrictive cardiomyopathy (DRCM) during pregnancy has not been described previously because of the rarity of the condition. Following an episode of heart failure antecedent to conception, a 28-year-old primigravida with DRCM presented to establish prenatal care during the first trimester. Prenatal management consisted of beta-blocker and diuretic therapy, with serial echocardiography to monitor cardiac function. Spontaneous labor ensued at 39 weeks' gestation, and vacuum-assisted delivery was performed for fetal indication. Postpartum blood transfusion was required for symptomatic anemia because of uterine atony, and subsequent maternal and neonatal courses were uncomplicated. Cardiac evaluation postpartum demonstrated stable maternal status. Pregnancy in women with controlled DRCM is not contraindicated, however, it requires careful planning and monitoring during the antenatal, intrapartum, and postpartum periods. On the basis of this report, pregnancy does not appear to exert a permanent deleterious effect on cardiac function in women with DRCM. PMID- 26495178 TI - Bile Acid Determination after Standardized Glucose Load in Pregnant Women. AB - Objective Intrahepatic cholestasis of pregnancy (ICP) is a rare liver disorder, usually manifesting in the third trimester and associated with increased perinatal morbidity and mortality. The hallmark laboratory abnormality in ICP is elevated fasting serum bile acids; however, there are limited data on whether a nonfasting state affects a pregnant woman's total bile acids. This study assesses fasting and nonfasting bile acid levels in 10 healthy pregnant women after a standardized glucose load to provide insight into the effects of a glucose load on bile acid profiles. Study Design Pilot prospective cohort analysis of serum bile acids in pregnant women. A total of 10 healthy pregnant women from 28 to 32 weeks' gestation were recruited for the study before undergoing a glucose tolerance test. Total serum bile acids were collected for each subject in the overnight fasting state, and 1 and 3 hours after the 100-g glucose load. Results There was a statistically significant difference between fasting versus 3-hour values. There was no statistically significant difference between fasting versus 1-hour and 1-hour versus 3-hour values. Conclusion There is a difference between fasting and nonfasting total serum bile acids after a 100-g glucose load in healthy pregnant women. PMID- 26495179 TI - Healthy Baby Born to a Robertsonian Translocation Carrier following Next Generation Sequencing-Based Preimplantation Genetic Diagnosis: A Case Report. AB - Preimplantation genetic diagnosis (PGD) is well established method for treatment of genetic problems associated with infertility. Moreover, PGD with next generation sequencing (NGS) provide new possibilities for diagnosis and new parameters for evaluation in, for example, aneuploidy screening. The aim of the study was to report the successful pregnancy outcome following PGD with NGS as the method for 24 chromosome aneuploidy screening in the case of Robertsonian translocation. Day 3 embryos screening for chromosomal aneuploidy was performed in two consecutive in vitro fertilization (IVF) cycles, first with fluorescent in situ hybridization (FISH), and then with NGS-based protocol. In each IVF attempt, three embryos were biopsied. Short duration of procedures enabled fresh embryo transfer without the need for vitrification. First IVF cycle with the embryo selected using PGD analysis with the FISH method ended with pregnancy loss in week 8. The second attempt with NGS-based aneuploidy screening led to exclusion of the following two embryos: one embryo with 22 monosomy and one with multiple aneuploidies. The transfer of the only euploid blastocyst resulted in the successful pregnancy outcome. The identification of the euploid embryo based on the NGS application was the first successful clinical application of NGS-based PGD in the case of the Robertsonian translocation carrier couple. PMID- 26495180 TI - Assessment of Cardiac Rate and Rhythm in Fetuses with Arrhythmia via Maternal Abdominal Fetal Electrocardiography. AB - Objective This study aims to report our experience using the Monica AN24 (Monica Healthcare Ltd., Nottingham, United Kingdom), a maternal transabdominal fetal electrocardiographic monitor, in a case series of fetuses with arrhythmias. Study Design We recorded fetal electrocardiograms (fECGs) on subjects with fetal arrhythmias diagnosed by fetal echocardiogram. Fetal heart rate and rhythm were determined via manual fECG analysis. Results Overall, 20 fECGs were recorded from a pool of 13 subjects. Fetal heart rate acquisition was determined to be high, medium, and poor quality in 10, 3, and 7 tracings, respectively. High-quality tracings were obtained in 9 of 11 subjects with gestational age < 26 or > 34 weeks. P waves were detectable in five tracings. Conclusion In subjects < 26 or > 34 weeks' gestational age, there was reasonable success in fetal heart rate acquisition. Further study is warranted to determine the potential role of this device in the monitoring of subjects with fetal arrhythmias. PMID- 26495181 TI - Exstrophy-Epispadias Complex in a Newborn: Case Report and Review of the Literature. AB - Aim The aim of this report is to present a brief review of the current literature on the management of EEC. Case Report A term male neonate presented at birth with classic bladder exstrophy, a variant of the exstrophy-epispadias complex (EEC). The defect was covered with sterile silicon gauzes and waterproof dressing; at 72 hours of life, primary closure without osteotomy of bladder, pelvis, and abdominal wall was successfully performed. Discussion EEC incidence is approximately 2.15 per 1,00,000 live births; several urological, musculocutaneous, spinal, orthopedic, gastrointestinal, and gynecological anomalies may be associated to EEC. Initial medical management includes use of occlusive dressings to prevent air contact and dehydration of the open bladder template. Umbilical catheters should not be positioned. Surgical repair stages include initial closure of the bladder and abdominal wall with or without osteotomy, followed by epispadias repair at 6 to 12 months, and bladder neck repair around 5 years of life. Those who fail to attain continence eventually undergo bladder augmentation and placement of a catheterizable conduit. Conclusion Modern-staged repair of EEC guarantees socially acceptable urinary continence in up to 80% of cases; sexual function can be an issue in the long term, but overall quality of life can be good. PMID- 26495182 TI - Case Report of Haemophilus parainfluenzae Sepsis in a Newborn Infant Following Water Birth and a Review of Literature. AB - Water birth has grown in popularity over the recent years. Although beneficial for mothers, there are concerns for the infants. There are previous reports of infection following water birth. The information regarding infection with Haemophilus parainfluenzae is limited. We report a case of a neonate with H. parainfluenzae bacteremia following water birth. The child was successfully treated with both antibiotic and supportive care. Previous reports of neonatal H. parainfluenzae infection are reviewed. PMID- 26495183 TI - Early Vitamin K Deficiency Bleeding in a Neonate Associated with Maternal Acute Fatty Liver of Pregnancy. AB - Introduction Acute fatty liver of pregnancy (AFLP) is a rare but potentially fatal condition occurring in the third trimester or early postpartum period. It is characterized by microvesicular fatty infiltration of the liver. Clinically, the three most prominent derangements in women with AFLP are hepatic dysfunction, renal insufficiency, and impaired coagulation. AFLP is associated with an increased incidence of morbidity and mortality in neonates, though the exact cause for this remains unclear. Deficiency of vitamin K in patients with liver disease has been widely reported. Case Description We present a unique case of severe intracranial bleeding because of the early vitamin K deficiency in a neonate whose mother had AFLP along with accompanying renal insufficiency. Conclusion We suggest that monitoring infants born to mothers with AFLP, for vitamin K deficiency bleeding will help reduce morbidity and mortality in these infants. PMID- 26495184 TI - Prenatal Therapy of Large Placental Chorioangiomas: Case Report and Review of the Literature. AB - Objective To review techniques and outcomes of different prenatal treatments for large placental chorioangiomas. Study Design Presentation of a case of laparoscopic-assisted laser coagulation and a systematic review of the literature for articles related to intervention for placental chorioangioma. Results A total of 37 cases of definitive (n = 23) and supportive therapy (n = 14) were evaluated, including one case treated in our center. Approximately 35% of the patients had a spontaneous preterm delivery in definitive treatment group versus 36% in the supportive group. The infant survival rates were 65 and 71% in the two groups, respectively. We further compared the two types of laser ablation (fetoscopic [n = 10] and interstitial [n = 4]). Approximately 30% of the patients in the fetoscopic and 25% in interstitial group, had a spontaneous preterm delivery. Survival rates were 60 and 100% in fetoscopic and interstitial groups, respectively. Conclusion Laser ablation and embolization of chorioangiomas via minimally invasive approach may prevent or reverse fetal hydrops due to high cardiac states. However, further studies are needed to refine the appropriate selection criteria that will justify the risk of this invasive in utero therapy for chorioangiomas. PMID- 26495185 TI - Spontaneous Subcapsular Hematoma of the Fetal Liver: A Case Report and Review of Literature. AB - We report a case of a cystic abdominal mass on ultrasound which presented a diagnostic dilemma at 32 weeks gestation. A presumptive antenatal diagnosis of a subcapsular liver hematoma (SCH) was made based on the location and ultrasound appearance similar to SCH seen in pediatric and adult patients. Sequential evaluation of the mass showed an evolving ultrasound appearance which reinforced our initial impression of a subcapsular hematoma of the fetal liver. Postnatal ultrasound confirmed the resolving SCH as well as a previously undetected echo bright lesion characteristic of an infantile focal hemangioma directly adjacent to the resolving SCH. A review of the literature is provided. PMID- 26495186 TI - Neonatal Presentation of an Air-Filled Neck Mass that Enlarges with Valsalva: A Case Report. AB - Branchial cleft cysts are common causes of congenital neck masses in the pediatric population. However, neonatal presentation of branchial cleft cysts is uncommon, but recognizable secondary to acute respiratory distress from airway compression or complications secondary to infection. We report a 1-day-old infant presenting with an air-filled neck mass that enlarged with Valsalva and was not associated with respiratory distress. The infant was found to have a third branchial cleft cyst with an internal opening into the pyriform sinus. The cyst was conservatively managed with endoscopic surgical decompression and cauterization of the tract and opening. We review the embryology of branchial cleft cysts and current management. PMID- 26495187 TI - First Trimester Hemolysis, Elevated Liver Enzymes, Low Platelets Syndrome in a Surrogate Pregnancy. AB - Background The occurrence of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome before 20 weeks of gestation is rare. HELLP is a possible but rare syndrome in gestational surrogate pregnancies for surrogates with risk factors for development of preeclampsia. Case A 32-year-old patient with chronic hypertension and positive antinuclear antibody presented for prenatal care at 13 weeks and 1 day. She was a surrogate for the embryo of a 43-year-old couple. By 15 weeks she developed uncontrolled hypertension requiring hospitalization. She was expectantly managed until her condition deteriorated. At 16 weeks and 1 day she developed hemolysis, elevated liver enzymes, thrombocytopenia, and fetal demise. Conclusions HELLP syndrome is rare and carries a significant morbidity and mortality for the mother and fetus. Clinicians should encourage the surrogate to share her medical history with the embryo donor for appropriate counseling on pregnancy risks. PMID- 26495188 TI - Piezosurgical Suturectomy and Sutural Distraction Osteogenesis for the Treatment of Unilateral Coronal Synostosis. AB - Different surgical procedures are used for the treatment of synostosis. Among them, suturectomy and sutural distraction osteogenesis (SDO) are suitable for young infant patients. In this report, we present the case of a young infant patient with a clear synostosis of the left coronal suture, which was treated by piezoelectric suturectomy combined with SDO and 2 internal distractors. One-year follow-up showed good results. Thirty-six months after surgery, normal skull growth and shape were observed by 3D computed tomographic examination. No infection, bleeding, fistula, and other complications were observed. The results suggested that the treatment of unilateral coronal synostosis in young infant patient by piezosurgical suturectomy and SDO is to be preferred because of its simplicity and relatively minimal invasiveness. PMID- 26495189 TI - Technique for Minimizing Donor-site Morbidity after Pedicled TRAM-Flap Breast Reconstruction: Outcomes by a Single Surgeon's Experience. AB - BACKGROUND: Breast reconstruction with pedicled transverse rectus abdominis myocutaneous (TRAM) flap can result in significant abdominal wall donor-site morbidity. We present our technique of transversely dividing the anterior fascia and rectus abdominis combined with reinforcement above the arcuate line for closure of the anterior abdominal wall defect to prevent contour deformities performed by a single senior surgeon and compare these results with those of our prior series. METHODS: We described our new technique of closure of the abdominal wall defect and retrospectively performed the comparison between the results of pedicled TRAM flaps using the new closure technique and those of 420 pedicled TRAM flaps from our 2003 publication in terms of abdominal bulging and hernia. RESULTS: Sixty-seven pedicled TRAM flaps in 65 patients were compared with 420 pedicled TRAM flaps of the 2003 series. The new technique was associated with 5 partial TRAM flap necroses (8%). There was no total flap loss with the new technique. The median follow-up period was 13 months (range, 4-36 months). There were no instances of abdominal hernia and bulge during follow-up in the new series. Compared with the previous 2003 series, the new technique was superior in terms of occurrence of abdominal wall hernia or bulging. CONCLUSIONS: We are still performing pedicled TRAM flap for autologous breast reconstruction. Using the technique of transversely dividing the anterior fascia and rectus abdominis combined with reinforcement above the arcuate line can reduce the occurrence of abdominal bulging and hernia. PMID- 26495190 TI - Full-thickness Scalp Injury Due to Hair Braiding and Weave. AB - Full-thickness scalp necrosis secondary to hair weave placement is a rare but serious complication of a common hairstyle. The defects can be large and may necessitate complex reconstruction with hair-bearing tissue. We report on the case of a young woman with extensive scalp loss following tight spiral braiding. The case description illustrates this relatively unknown complication, its treatment, and possible preventative measures. PMID- 26495191 TI - An Unusual Case of Swan Neck Deformity in a Child. AB - Supplemental Digital Content is available in the text. PMID- 26495192 TI - Haptics-assisted Virtual Planning of Bone, Soft Tissue, and Vessels in Fibula Osteocutaneous Free Flaps. AB - Virtual surgery planning has proven useful for reconstructing head and neck defects by fibula osteocutaneous free flaps (FOFF). Benefits include improved healing, function, and aesthetics, as well as cost savings. But available virtual surgery planning systems incorporating fibula in craniomaxillofacial reconstruction simulate only bone reconstruction without considering vessels and soft tissue. METHODS: The Haptics-Assisted Surgery Planning (HASP) system incorporates bone, vessels, and soft tissue of the FOFF in craniomaxillofacial defect reconstruction. Two surgeons tested HASP on 4 cases they had previously operated on: 3 with composite mandibular defects and 1 with a composite cervical spine defect. With the HASP stereographics and haptic feedback, using patient specific computed tomography angiogram data, the surgeons planned the 4 cases, including bone resection, fibula design, recipient vessels selection, pedicle and perforator location selection, and skin paddle configuration. RESULTS: Some problems encountered during the actual surgery could have been avoided as they became evident with HASP. In one case, the fibula reconstruction was incomplete because the fibula had to be reversed and thus did not reach the temporal fossa. In another case, the fibula had to be rotated 180 degrees to correct the plate and screw placement in relation to the perforator. In the spinal case, difficulty in finding the optimal fibula shape and position required extra ischemia time. CONCLUSIONS: The surgeons found HASP to be an efficient planning tool for FOFF reconstructions. The testing of alternative reconstructions to arrive at an optimal FOFF solution preoperatively potentially improves patient function and aesthetics and reduces operating room time. PMID- 26495193 TI - Distal Row Carpectomy-A Possible Salvage Procedure of Severe Carpal Trauma. AB - Complex fracture dislocations of the wrist often result in posttraumatic arthrosis. In trying to avoid total arthrodesis, alternative treatment strategies have been investigated. For this purpose, we present the case of a 56-year-old male patient who sustained a direct trauma during a circular saw accident, resulting in the destruction of the distal carpal row among other things. However, the proximal carpal row was found completely intact. We indicated an emergency distal row carpectomy. Eighteen months postoperatively, the patient showed very good range of movement with no pain, and radiologically, the proximal carpal row was still intact, with no signs of an incipient radiocarpal arthrosis. This case demonstrates the successful removal of the distal carpal row in terms of a distal row carpectomy. PMID- 26495194 TI - Lateral Abdominal Wall Defects: The Importance of Anatomy and Technique for a Successful Repair. AB - Flank and lateral abdominal wall defects can be an extremely challenging phenomenon for surgeons to undertake. Their rarity and specific idiosyncrasies in regard to embryologic and anatomical characteristics must be taken into consideration when formulating an operative plan. We will discuss these cardinal points including technical recommendations by notable experts in the field to gain a better understanding in the diagnosis and treatment of this infrequent but morbid occurrence. PMID- 26495196 TI - The Cranial Base Fracture after the Caldwell-Luc Operation. AB - Supplemental Digital Content is available in the text. PMID- 26495195 TI - Satisfaction following Unilateral Breast Reconstruction: A Comparison of Pedicled TRAM and Free Abdominal Flaps. AB - BACKGROUND: The purpose of this study was to compare patient satisfaction following unilateral pedicled transverse rectus abdominis myocutaneous (TRAM) and free abdominal flap reconstruction. METHODS: Patients who underwent unilateral breast reconstruction using pedicled TRAM or free abdominal flaps (muscle-sparing TRAM or deep inferior epigastric perforator flap) and completed the BREAST-Q were identified from 2 prospectively maintained databases. BREAST-Q scores were assessed and compared for Satisfaction with Breasts, Outcome, and Physical Well being Chest/Abdomen. RESULTS: Of the 138 patients who completed the BREAST-Q, 84 underwent pedicled TRAM flap reconstruction and 54 underwent free abdominal flap reconstruction. Overall, pedicled TRAM flap patients scored higher than free abdominal flap patients on all 4 BREAST-Q scales. This difference reached statistical significance in Satisfaction with Breasts (+7.74; P = 0.02). Similar results were found among patients who completed the BREAST-Q at <3 years postoperation. However, among patients at >=3 years postoperation, there were no statistically significant differences between the 2 groups, with the pedicled flap cohort scoring higher in Satisfaction with Breasts and Physical Well-being Chest and the free abdominal flap cohort scoring higher in Satisfaction with Outcome and Physical Well-being Abdomen scores. CONCLUSIONS: Patients who underwent unilateral pedicled TRAM flap reconstruction experienced greater initial breast satisfaction than patients who underwent unilateral free abdominal flap reconstruction, but satisfaction equalized between the two over time, suggesting that long-term satisfaction may be equivalent between the 2 methods of reconstruction. PMID- 26495197 TI - Evaluation of Face Lift Skin Perfusion and Epinephrine Effect Using Laser Fluorescence Imaging. AB - Face lift dissections are believed to compromise skin flap circulation, possibly leading to wound healing complications. To reduce blood loss, plastic surgeons commonly inject a solution of local anesthetic that contains epinephrine. However, the effect of surgery on skin perfusion and the degree of vasoconstriction caused by the epinephrine have not been quantitated. Little information is available to guide the selection of epinephrine concentration. METHODS: Nine consecutive patients undergoing a deep-plane face lift were asked to participate in this prospective study. All patients consented (inclusion rate, 100%). The SPY Elite Intraoperative Perfusion System was used to quantitate perfusion. Measurements were made at 5 sites on both sides of the face and the neck. A nondissected temple site served as a reference. Three patients received no epinephrine in their local anesthetic solution, 3 patients received 1:800,000 epinephrine, and 3 patients were injected with 1:300,000 epinephrine. RESULTS: All 9 patients were female nonsmokers. There was no reduction in skin perfusion measurements after surgery. In patients treated with 1:800,000 and 1:300,000 epinephrine, 4 sites showed significantly (P < 0.05) decreased perfusion compared with the no-epinephrine group. Combined perfusion data were almost 50% reduced, but the difference was nonsignificant, likely because of the small sample sizes. One patient developed a hematoma. Two of the 3 patients who received no epinephrine developed extensive bruising. CONCLUSIONS: A deep-plane face lift dissection does not impair skin flap perfusion. Both 1:300,000 epinephrine and 1:800,000 epinephrine concentrations are effective in producing intraoperative vasoconstriction. PMID- 26495198 TI - Posterior Pharyngeal Airway in Clockwise Rotation of Maxillomandibular Complex Using Surgery-first Orthognathic Approach. AB - BACKGROUND: Because obstructive sleep apnea is known to be an important preexisting factor causing chronic disease, many investigations have been done recently. There have been few reports regarding the posterior pharyngeal airway after clockwise rotation of maxillomandibular complex. Because the 2-jaw surgery in class III patients could cause obstructive sleep apnea or snoring, we investigated the posterior pharyngeal airway change of the clockwise maxillomandibular complex in the surgery-first orthognathic approach for the correction of class III dentofacial deformities. METHODS: A cephalometric evaluation of 35 patients with skeletal class III deformity was performed preoperatively and postoperatively. Three measurements of the posterior pharyngeal airway space (nasopharynx, oropharynx, and hypopharynx) and hyoid bone positions (the distance from palatal plane to hyoid bone and the distance from mandibular plane to the hyoid bone) were evaluated and correlated with the skeletal movement of the jaws using imaging software (V-Ceph, Osstem, Seoul, Korea). RESULTS: The preoperative airway space turned out to be enlarged in class III dentofacial deformities compared with those of normal persons. The preoperative P1, P2, and P3 in our cohort were increased and posterior nasal spine to hyoid bone and mandibular plane to hyoid bone were decreased compared with those of normal person's data because the cohort consists of prognathic patients where the mandible is located in forward position. After 6 months, most values were nearly normal. CONCLUSION: Orthognathic surgery based on clockwise rotation of maxillomandibular complex did not cause severe posterior airway space changes at 6 months postoperation. PMID- 26495199 TI - Treatment of Folliculitis on the Expanded Postauricular Skin Flap by Topical Iodine Tincture. PMID- 26495200 TI - Profunda Femoris Artery Perforator Propeller Flap: A Valid Method to Cover Complicated Ischiatic Pressure Sores. AB - We report the case of a 50-year-old paraplegic man with a complicated grade III/IV ischiatic pressure sore treated with a propeller flap based on the first perforator of the profunda femoris artery. Our aim was to surgically reconstruct an ischiatic pressure sore in a patient with ankylosis using a fasciocutaneous perforator propeller flap obtained from the posterior region of the thigh. Our decision to perform a profunda femoris artery perforator propeller flap reconstruction was mainly due to the anatomical contiguity of the flap with the site of the lesion and the good quality of the skin harvested from the posterior region of the thigh. The use of the perforator fasciocutaneous flap represents a muscle-sparing technique, providing a better long-term result in surgical reconstruction. The choice of the 180-degree propeller flap was due to its ability to provide a good repair of the pressure ulcer and to pass over the ischiatic prominence in the patient in the forced decubitus position. The operatory course did not present any kind of complication. Using this reconstructive treatment, we have obtained complete coverage of the ischiatic pressure sore. PMID- 26495201 TI - Digital Reconstruction with a Nonfrozen Osteotendinous Allograft, Nerve Allografts, and Autogenous Radial Free Flap. AB - A 21-year-old man underwent amputation of his second to fifth fingers at the proximal phalanx level on the right hand. The third and fourth fingers were reconstructed with 2 toe-to-hand free transfers. The fifth digit was reconstructed with a nonfrozen osteotendinous allograft, nerve allografts, and autogenous radial free flap without immunosuppression. The patient was lost to follow-up for 19 years. He received no rehabilitation. He reported that he had experienced no adverse reactions to the materials or the graft, or infection, or fractures. No additional surgical procedures were performed. Today, the digit is functional and has acceptable aesthetic appearance. This outcome is similar to those obtained in digits reconstructed with frozen osteotendinous allografts and autologous cutaneous covers and opens the possibility for future research. PMID- 26495202 TI - Natrelle Silicone Breast Implant Follow-up Study: Demographics, Lifestyle, and Surgical Characteristics of More Than 5000 Reconstruction Subjects. AB - BACKGROUND: A large, multicenter, 10-year observational study is comparing the long-term safety and effectiveness of Natrelle silicone breast implants versus saline implants or national norms. METHODS: Women who underwent primary augmentation, revision-augmentation, primary reconstruction, or revision reconstruction were invited to participate. Enrolled subjects had completed surgery and received one implant or matching implants. Baseline demographics, health, lifestyle, and surgical characteristics are presented here for adult subjects who underwent primary reconstruction or revision-reconstruction. RESULTS: Of 5637 subjects who underwent reconstruction surgery (86.7% primary reconstruction; 13.3% revision-reconstruction), 5407 received silicone implants and 230 received saline implants; 72.9% received bilateral implants. Silicone implants were used in 96.2% who underwent primary reconstruction and in 94.1% who underwent revision-reconstruction. Median age was about 3 years lower in those who underwent primary reconstruction versus revision-reconstruction. Most subjects were white nonsmokers and had attended college. Hispanic subjects were more likely to receive saline implants for primary reconstruction. Across groups, the most common characteristics by implant type or procedure included smooth surface implants (90.8%), mastectomy scar site (69.7%), and partial (59.2%) or complete (33.9%) submuscular placement. Implant size was larger for revision reconstruction versus primary reconstruction, and incision size was larger for silicone versus saline implants in subjects undergoing primary reconstruction. CONCLUSIONS: This study provides an unprecedented look at a large subject sample. The data offer surgeons an opportunity to make informed decisions regarding the most appropriate implant attributes and surgical approaches for women who desire breast implants for primary or revisionary breast reconstruction. PMID- 26495203 TI - Temporary Areolar Demarcation for Nipple-areola Complex Reconstruction. AB - We have described a surgical method that enhances the visual aesthetic outcome of the areola periphery in nipple-areola complex reconstruction. This technique is performed immediately following closure of the nipple flap. The created areolar outline can aid the tattoo artist and may result in a more natural-appearing areola periphery than tattooing methods alone. PMID- 26495204 TI - Bioceramic Implant Induces Bone Healing of Cranial Defects. AB - Autologous bone or inert alloplastic materials used in cranial reconstructions are techniques that are associated with resorption, infection, and implant exposure. As an alternative, a calcium phosphate-based implant was developed and previously shown to potentially stimulate bone growth. We here uncover evidence of induced bone formation in 2 patients. Histological examination 9 months postoperatively showed multinuclear cells in the central defect zone and bone ingrowth in the bone-implant border zone. An increased expression of bone associated markers was detected. The other patient was investigated 50 months postoperatively. Histological examination revealed ceramic materials covered by vascularized compact bone. The bone regenerative effect induced by the implant may potentially improve long-term clinical outcome compared with conventional techniques, which needs to be verified in a clinical study. PMID- 26495205 TI - The Vascularized Medial Femoral Corticoperiosteal Flap for Thumb Reconstruction. AB - We present an interesting method of shaping a vascularized medial femoral condyle (MFC) flap into a "neophalanx" for phalangeal reconstruction. Our patient presented with limited strength and function secondary to fracture nonunion of the proximal phalanx of the dominant thumb. Following excision of the pseudarthrosis, an MFC corticoperiosteal flap was harvested, sculpted into a prism shape and inset. The superomedial genicular pedicle was anastomosed to the princeps pollicis artery and a cephalic tributary. On follow-up, new bone growth was seen on radiographs and the patient had substantially improved function, with full metacarpophalangeal extension, a Kapandji score of 9, and a markedly reduced Disabilities of the Arm, Shoulder and Hand score of 2.68. The MFC flap is useful for reconstruction of bony defects, with minimal donor morbidity. This versatile vascularized flap can be crafted to requisite shapes and is useful for small defects in the hand, including phalangeal reconstruction. PMID- 26495206 TI - Bipedicled "Superthin" Free Perforator Flaps for Facial Burn Scar Reconstruction: Expanded Scope of Superthin Flaps: A Case Series. AB - BACKGROUND: "Superthin flap" is a distinctively thin flap that is thinned primarily to the point that the subdermal vascular network can be seen through a minimal fat layer. Reconstruction of severely disfigured neck and face can be performed using the occipito-cervico-dorsal superthin flap that is harvested from the dorsal region and supercharged by the circumflex scapular vessels. We used bipedicled superthin free perforator flaps to reconstruct scar contractures on half of the face, whole face, or the whole chin-neck area in 17 postburn patients. METHODS: This case series report includes all 17 cases. Flaps in the dorsal area were designed. In all cases, one pedicle consisted of the circumflex scapular vessels. In 11, 5, and 1 flaps, the second pedicle consisted of contralateral posterior intercostal perforators (type 1), ipsilateral posterior intercostal perforators (type 2), and ipsilateral circumflex scapular vessels (type 3), respectively. Four patients underwent whole-face reconstruction after acid burn with type 1 or type 3 perforator. The recipient vessels were the superficial temporal vessels and contralateral or ipsilateral facial vessels. Intraoperatively, all adipose tissue in the flap, including between the 2 pedicles, was thinned by scissors before the pedicles were detached from the donor sites. Maximum flap size was 35 * 15 cm. Donor sites were covered by a split full-thickness skin graft. Flap survival and functional and cosmetic results were assessed retrospectively. RESULTS: Fifteen of the 17 flaps survived completely. Two developed partial necrosis due to perforator thrombosis. Some patients developed hypertrophic scars around the flap, but these improved naturally over time. All patients were satisfied with both the cosmetic and functional outcomes of the reconstruction. CONCLUSION: Bipedicled superthin free perforator flaps may be an excellent choice for reconstruction of severe neck scar contracture. This report expands the scope of previously used "superthin flaps." PMID- 26495207 TI - AdVEGF-All6A+ Preconditioning of Murine Ischemic Skin Flaps Is Comparable to Surgical Delay. AB - BACKGROUND: Surgical flap delay is commonly used in preconditioning reconstructive flaps to prevent necrosis. However, staged procedures are not ideal. Pharmacologic up-regulation of angiogenic and arteriogenic factors before flap elevation poses a nonsurgical approach to improve flap survival. METHODS: Male Sprague Dawley rats were divided into control (n = 16), surgical delay (Delay), AdNull, AdEgr-1, and AdVEGF (n >= 9/group) groups. Delay rats had a 9 cm * 3 cm cranial based pedicle skin flap incised 10 days prior to elevation. Adenoviral groups received 28 intradermal injections (10(9) pu/animal total) throughout the distal two thirds of the flap 1 week prior to elevation. At postoperative day (POD) 0 flaps were elevated and silicone sheeting was placed between flap and wound bed. Perfusion analysis in arbitrary perfusion units of the ischemic middle third of the flap using laser Doppler imaging was conducted preoperatively and on POD 0, 3, and 7. Clinical and histopathologic assessments of the skin flaps were performed on POD 7. RESULTS: AdVEGF (50.8 +/- 10.9 APU) and AdEgr-1 (39.3 +/- 10.6 APU) perfusion levels were significantly higher than controls (16.5 +/- 4.2 APU) on POD 7. Delay models were equivalent to controls (25.9 +/- 6.8 APU). AdVEGF and Delay animals showed significantly more viable surface area on POD 7 (14.4 +/- 1.3 cm(2), P < 0.01 and 12.4 +/- 1.2 cm(2), P < 0.05, respectively) compared with Controls (8.7 +/- 0.7 cm(2)). CONCLUSIONS: AdVEGF preconditioning resulted in flap survival comparable to surgical delay. Adenoviral preconditioning maintained perfusion levels postoperatively while surgical delay did not. PMID- 26495208 TI - Evaluation of AirXpanders for Breast Reconstruction: Early Experience from Sydney. AB - AIM: Two-staged prosthetic breast reconstruction has become a popular option involving a series of saline injections to expanders to create a pocket large enough for a permanent implant. This, however, requires frequent visits to the surgeon and numerous needle pricks with potential infection risk. A new form of tissue expander, the AirXpanders, has recently been trialed in Perth and the United States. It uses a remote-controlled release of compressed CO2 where needle punctures are avoided. METHODOLOGY: Prospective data were collected on the first 10 patients to have the AirXpanders implant inserted for breast reconstruction at Western Sydney. The implants were inserted subpectorally as the saline expanders, and patients were instructed how to use the remote 4 weeks postoperation. RESULTS: Ten patients (4 immediate and 6 delayed) aged between 30 and 65 (mean, 48.3 years) underwent 14 AirXpanders insertions. One patient passed away due to metastatic malignancy. With the remaining patients, the average period of active expansion was 15.8 days (r, 6-21). The average size of final implant used was 451 g (r, 195-685). The only complications were 2 seromas. CONCLUSION: Our early results are consistent with the Perth trial. The new AirXpanders is safe to use and able to achieve satisfactory tissue expansion faster than saline expander. It also has the advantage of patient self-controlled without the need for multiple medical reviews and needle punctures. PMID- 26495209 TI - Effect of Washes and Centrifugation on the Efficacy of Lipofilling With or Without Local Anesthetic. AB - BACKGROUND: Among the different parameters that influence fat graft survival and lipofilling success, the use of local anesthetic and the way to process the fat before injection have often been pointed out. Likewise, we evaluated different techniques for processing adipose tissue before its injection and analyzed the quality of the grafts. METHODS: Adipose tissue from the same patient was gently harvested from one side of the abdomen after infiltration of a tumescent solution without lidocaine and from the other side of the abdomen using a tumescent solution containing lidocaine 2%. Harvested tissue was prepared with different protocols, from simple decantation to advanced protocols including single or multiple washes and centrifugations. Each type of processed adipose tissue was then injected subcutaneously into immunodeficient mice. Adipose grafts were collected after 1 month and analyzed by histology with a detailed scoring method. RESULTS: After lidocaine use, decantation protocol led to adipose grafts of poor quality with high resorption rate and oil vacuole formation. Larger grafts were obtained after centrifugation, but centrifugation alone resulted in increased fibrosis and necrosis, with or without the use of lidocaine. Finally, multiple washes and centrifugations greatly improved the quality of the lipografts. CONCLUSIONS: Centrifugation alone is not sufficient and must be associated with multiple washes to improve graft quality. This article aims to provide further evidence of lidocaine and washing/centrifugation effects in fat grafting to provide easy tips aimed at ensuring graft efficiency with a long-term clinical outcome. PMID- 26495210 TI - Prelamination of the Anterolateral Thigh Flap With a Fibula Graft to Successfully Reconstruct a Mandibular Defect. AB - Flap prelamination is the process whereby a complex 3- dimensional construct is fashioned in a staged manner. We present a case whereby the tissues of the anterolateral thigh, nourished by perforators of the descending branch of the lateral circumflex femoral artery, were prelaminated with a fibula in the setting of salvage head and neck reconstruction. With a paucity of recipient vessels in the neck and a previous failed free fibula transfer secondary to osteoradionecrosis, a fibula was implanted into a suprafascial pocket created in the anterolateral thigh. This was allowed to pick up a blood supply from this rich vascular bed and mature over a period of 3 weeks before being transferred with the anterolateral thigh tissues as a prelaminated osteocutaneous composite free flap. A bone scan performed both before and after transfer confirmed uptake of radionucleotide by the fibula suggesting neovascularization. The composite mandibular defect was successfully reconstructed using this technique, and we believe this could represent a new strategy in the setting of salvage head and neck surgery. PMID- 26495211 TI - Start Your Engines. PMID- 26495212 TI - A Pentagram Suture Technique for Closing Tumor Resection Sites in the Face. AB - BACKGROUND: Resection of facial skin tumors aims to remove the tumors completely and make the surgical scar unnoticeable as much as possible. By improving the purse string suture method, we developed a new pentagram suture technique that enables simple and safe suturing of small to large defects with early satisfactory esthetic outcomes. The surgical outcomes of a case series were examined in this report. METHODS: As in drawing a unicursal star, 5 suture sites were marked at specific intervals around the defect area. A needle with 5-0 polydioxanone suture was passed from the subcutaneous tissue to the superficial dermal layer at one site and then from the superficial dermal layer to the subcutaneous layer at the next site, and the process was repeated until the pentagram was complete. When apposition was not tight enough, a couple of external stitches were added using 6-0 nylon suture. RESULTS: In 13 patients (16 benign or malignant tumors; mean age, 51.1 years) with a mean tumor size of 10.1 +/- 5.2 mm and postoperative skin defect diameter of 12.1 +/- 8.2 mm, closure did not result in high tension on the suture, and there was reduced mechanical stress at the wound margin. Surgical outcomes were good esthetically at 6 months after surgery without keloid formation or scar contracture. None of the patients had postoperative pain, infection, or tumor recurrence. CONCLUSIONS: This simple alternative method for the closure of facial skin defects after skin tumor excision could be performed easily and provided satisfactory surgical outcomes. PMID- 26495213 TI - Fat Grafting to the Forehead/Glabella/Radix Complex and Pyriform Aperture: Aesthetic and Anti-Aging Implications. AB - BACKGROUND: Optimal aesthetic outcomes from rhinoplasty are heavily influenced by structures adjacent to the nose. Although the importance of the chin has been emphasized since the inception of rhinoplasty, little attention has been given to the forehead. The forehead/glabella/radix complex represents a vital triad in rhinoplasty, from which the nasofrontal angle is derived. In the present study, the authors sought to determine whether fat grafting to the forehead/glabella/radix complex and pyriform aperture can favorably impact the nasofrontal and nasolabial angles, respectively. METHODS: The authors reviewed pre- and postoperative images (obtained by an independent professional photographer) of patients who underwent autologous fat grafting to the forehead/glabella/radix region and the pyriform aperture, with or without concurrent rhinoplasty. Nasofrontal and nasolabial angles were measured on lateral images. Mean pre- and postoperative values were calculated and compared. A Wilcoxon rank-sum test was used for statistical analysis. RESULTS: Twenty-six patients underwent fat grafting alone (FG group; mean follow-up, 3.3 years), and 19 had fat grafting plus rhinoplasty (FG + R group; mean follow-up, 5.2 years). The mean nasofrontal angle in the FG group decreased by 2.0 degrees (P = 0.005), and the mean nasolabial angle increased by 2.3 degrees (P = 0.006). The mean nasofrontal angle in the FG + R group decreased by 2.0 degrees (P = 0.011), and the mean nasolabial angle increased by 6.0 degrees (P = 0.026). CONCLUSIONS: Autologous fat grafting to the forehead/glabella/radix complex and pyriform aperture is a reliable method to favorably influence the nasofrontal and nasolabial angles, respectively. Such treatment optimizes the interplay between the nose and the adjacent facial features, enhancing overall aesthetics. PMID- 26495214 TI - Pseudoangiomatous Stromal Hyperplasia: A Rare Cause of Idiopathic Gigantomastia. AB - Gigantomastia remains a rare clinical diagnosis with significant physical and psychological impacts on patients. We present the case of a 40-year-old woman with idiopathic breast enlargement. Further histological analysis of the breast tissue revealed pseudoangiomatous stromal hyperplasia. This is the first reported case of diffuse breast enlargement resulting from pseudoangiomatous stromal hyperplasia. PMID- 26495215 TI - St. Macrina, the Patron Saint of Modern Oncoplastic Surgery? PMID- 26495216 TI - Extended Component Separation for Repair of High Ventral Hernia in Pediatric Omphalocele. AB - Abdominal wall reconstruction ideally involves maintenance of domain by restoration of competent fascia and innervated muscle. Component separation allows closure of ventral hernias, but the technique is limited for high abdominal defects in the epigastric region. We describe an extended component separation that facilitated mobilization of the rectus abdominis muscle along its costal insertion to close an upper midline defect in a child with giant omphalocele, who had already undergone previous traditional component separation. PMID- 26495217 TI - Preventable Sternocleidomastoid Muscular Atrophy after Neck Dissection. AB - BACKGROUND: Modified radical neck dissection (mRND) [preserving the sternocleidomastoid muscle (SCM) and the spinal accessory nerve] and supraomohyoid neck dissection have become common surgical procedures for treating head and neck cancer. Postoperative severe asymmetry of the neck and severe atrophy of the SCM, however, have been demonstrated. METHODS: Using computed tomographic images, cross-sectional areas of the SCMs were measured in 99 patients with carcinoma of the oral cavity who underwent unilateral mRND or supraomohyoid neck dissection. An asymmetry index was used. RESULTS: Innervation to the SCM was preserved in 91 patients. The spinal accessory nerve and the innervation were sacrificed in 3 patients; the innervation was repaired in 5 patients. Sacrifice of innervation to the SCM resulted in extremely severe asymmetry. Repair of the innervation prevented severe asymmetry in 40%. Preservation of the innervation prevented severe asymmetry in 75% at the middle portion of the neck and in 56% at the lower portion after mRND. CONCLUSION: Preserving innervation to the SCM and gentle handling of the nerve during neck dissection could prevent severe asymmetry after neck dissection. PMID- 26495218 TI - Breast Reconstruction Using Contour Fenestrated AlloDerm: Does Improvement in Design Translate to Improved Outcomes? AB - BACKGROUND: Acellular dermal matrices are used in implant-based breast reconstruction. The introduction of contour fenestrated AlloDerm (Life-Cell, Branchburg, N.J.) offers sterile processing, a crescent shape, and prefabricated fenestrations. However, any evidence comparing reconstructive outcomes between this newer generation acellular dermal matrices and earlier versions is lacking. METHODS: Patients undergoing implant-based breast reconstruction from 2010 to 2014 were identified. Reconstructive outcomes were stratified by 4 types of implant coverage: aseptic AlloDerm, sterile "ready-to-use" AlloDerm, contour fenestrated AlloDerm, or total submuscular coverage. Outcomes were compared with significance set at P < 0.05. RESULTS: A total of 620 patients (1019 reconstructions) underwent immediate, implant-based breast reconstruction; patients with contour fenestrated AlloDerm were more likely to have nipple sparing mastectomy (P = 0.0001, 0.0004, and 0.0001) and immediate permanent implant reconstructions (P = 0.0001). Those with contour fenestrated AlloDerm coverage had lower infection rates requiring oral (P = 0.0016) and intravenous antibiotics (P = 0.0012) compared with aseptic AlloDerm coverage. Compared with sterile "ready-to-use" AlloDerm coverage, those with contour fenestrated AlloDerm had similar infection outcomes but significantly more minor mastectomy flap necrosis (P = 0.0023). Compared with total submuscular coverage, those with contour fenestrated AlloDerm coverage had similar infection outcomes but significantly more explantations (P = 0.0001), major (P = 0.0130) and minor mastectomy flap necrosis (P = 0.0001). Significant independent risk factors for increased infection were also identified. CONCLUSIONS: Contour fenestrated AlloDerm reduces infections compared with aseptic AlloDerm, but infection rates are similar to those of sterile, ready-to-use AlloDerm and total submuscular coverage. PMID- 26495219 TI - Gigantic LCFA-SCIP Mosaic Flap for Upper Extremity Reconstruction. PMID- 26495220 TI - Trends in Immediate Postmastectomy Breast Reconstruction in the United Kingdom. AB - BACKGROUND: The study aimed to evaluate local and national trends in immediate breast reconstruction (IBR) using the national English administrative records, Hospital Episode Statistics. Our prediction was an increase in implant-only and free flap procedures and a decline in latissimus flap reconstructions. METHODS: Data from an oncoplastic center were interrogated to derive numbers of implant only, autologous latissimus dorsi (LD), LD-assisted, and autologous pedicled or free flap IBR procedures performed between 2004 and 2013. Similarly, Hospital Episode Statistics data were used to quantify national trends in these procedures from 1996 to 2012 using a curve fitting analysis. RESULTS: National data suggest an increase in LD procedures between 1996 (n = 250) and 2002 (n = 958), a gradual rise until 2008 (n = 1398) followed by a decline until 2012 (n = 1090). As a percentage of total IBR, trends in LD flap reconstruction better fit a quadratic (R(2) = 0.97) than a linear function (R(2) = 0.63), confirming a proportional recent decline in LD flap procedures. Conversely, autologous (non-LD) flap reconstructions have increased (1996 = 0.44%; 2012 = 2.76%), whereas implant-only reconstructions have declined (1996 = 95.42%; 2012 = 84.92%). Locally, 70 implant assisted LD procedures were performed in 2003 -2004, but only 2 were performed in 2012 to 2013. CONCLUSIONS: Implants are the most common IBR technique; autologous free flap procedures have increased, and pedicled LD flap procedures are in decline. PMID- 26495221 TI - Recurrent Myoepithelioma Treated by Palatal and Piriform Apertural Approaches. AB - Myoepithelioma is a rare, benign salivary neoplasm, most frequently located in the salivary gland; extrasalivary cases most commonly occur in the palate. This tumor is prone to recurrence. We present a case of recurrent myoepithelioma in the nasal cavity with a palatal fistula treated both by a palatal approach and a piriform apertural approach. The combination of these approaches widens the surgical space, allowing removal of the mass. It is important not only to excise the mass but also to allow for reconstruction. PMID- 26495222 TI - Forequarter Replantation and the Lessons Learnt. AB - The literature on major upper limb replantation, especially those proximal to the elbow, is inadequate. An 18-year-old man presented to us with a left forequarter amputation. A replantation was attempted with a view to salvaging function and avoiding prosthesis. The procedure was technically challenging with a number of issues not highlighted in previous reports, particularly bony stabilization. The procedure was initially successful, with good perfusion. However, with time, the limb showed sepsis and had to be abandoned. We report this case to add to the literature on replantation at the shoulder level in the hope that this procedure may be reported successfully in the future. PMID- 26495223 TI - Development of Standardized Clinical Assessment and Management Plans (SCAMPs) in Plastic and Reconstructive Surgery. AB - BACKGROUND: With rising cost of healthcare, there is an urgent need for developing effective and economical streamlined care. In clinical situations with limited data or conflicting evidence-based data, there is significant institutional and individual practice variation. Quality improvement with the use of Standardized Clinical Assessment and Management Plans (SCAMPs) might be beneficial in such scenarios. The SCAMPs method has never before been reported to be utilized in plastic surgery. METHODS: The topic of immediate breast reconstruction was identified as a possible SCAMPs project. The initial stages of SCAMPs development, including planning and implementation, were entered. The SCAMP Champion, along with the SCAMPs support team, developed targeted data statements. The SCAMP was then written and a decision-tree algorithm was built. Buy-in was obtained from the Division of Plastic Surgery and a SCAMPs data form was generated to collect data. RESULTS: Decisions pertaining to "immediate implant-based breast reconstruction" were approved as an acceptable topic for SCAMPs development. Nine targeted data statements were made based on the clinical decision points within the SCAMP. The SCAMP algorithm, and the SDF, required multiple revisions. Ultimately, the SCAMP was effectively implemented with multiple iterations in data collection. CONCLUSIONS: Full execution of the SCAMP may allow better-defined selection criteria for this complex patient population. Deviations from the SCAMP may allow for improvement of the SCAMP and facilitate consensus within the Division. Iterative and adaptive quality improvement utilizing SCAMPs creates an opportunity to reduce cost by improving knowledge about best practice. PMID- 26495224 TI - Saved by De-epithelialization: DIEP Flap Dermal Skin Regeneration Salvage after Mastectomy Skin Flap Loss. AB - BACKGROUND: Wound re-epithelialization has been traditionally described to occur from the dermal appendages of the wound edges. As such, the role of the dermal wound bed in re-epithelialization has been questioned. In a patient undergoing breast reconstruction with free tissue transfer, the buried portions of the free flap skin paddle could be either de-epithelialized or deskinned. In case of mastectomy skin flap loss, the role of de-epithelialized skin in wound healing has not been described before. METHODS: We report a patient with bilateral mastectomies and bilateral deep inferior epigastric perforator flaps whose postoperative course was complicated by bilateral full-thickness mastectomy skin flap loss. Multiple debridements of nonviable skin resulted in exposure of previously buried de-epithelialized skin paddle of the deep inferior epigastric perforator flap. RESULTS: Our study demonstrates self re-epithelialization of the dermal wound bed from the dermal appendages. We noticed multiple noncontiguous neoepidermal islands in the dermal wound bed, which did not communicate with the wound edges. CONCLUSIONS: In case of full-thickness mastectomy skin flap loss, deep vascular plexus present in the dermal bed of the underlying de epithelialized skin paddle of the free flap converts an otherwise full-thickness wound to a partial-thickness wound. Our study demonstrates the self epithelialization potential of the de-epithelialized dermal wound bed from the dermal appendages when exposed to air and in the presence of wound healing elements. PMID- 26495225 TI - Metastatic Invasive Sweat Gland Adenocarcinoma of the Hand with Upper Limb Amputation/Shoulder Reconstruction. AB - A rare case of metastatic invasive sweat gland adenocarcinoma of hand in a 78 year-old woman is presented. From this analysis of the available literature, it seems that these rare primary tumors of the hand are aggressive tumors with little known about their biological behavior. Fluoropyrimidines, taxanes, and cisplatin have been reported to be active agents for metastatic sweat gland carcinomas. Further, these tumors have historically been considered radioresistant, but responses to radiation have been documented in the setting of recurrent disease, and the use of adjuvant radiotherapy has been advocated for tumors at high risk of local recurrence. We advocate an aggressive approach of high amputation and axillary lymph node dissection with adjuvant treatment using chemotherapy as the mainstay with close follow-up for metastases. PMID- 26495226 TI - Simultaneous Bilateral Submental Lymph Node Flaps for Lower Limb Lymphedema Post Leg Charles Procedure. AB - We summarize the case of a 59-year-old woman with left lower limb lymphedema for 4 years post hysterectomy, pelvic lymph node dissection, radiation therapy, and chemotherapy for endometrial cancer. She underwent the Charles procedure on her left leg 2 years before being referred to our hospital and developed several cellulitis episodes and progressive lymphedema affecting her left toes and thigh. Bilateral vascularized submental lymph node flaps were transferred to her left ankle and thigh, respectively. After a 5-month follow-up, the leg became softer and lighter without relapsing cellulites, and the circumferential reduction rates at 15 cm above knee, 15 cm below knee, and 10 cm above ankle were 23.3%, 50%, and 22.2%, respectively. The patient was satisfied with the functional recovery and discontinued use of compression garment postoperatively. PMID- 26495227 TI - Salvage of Exposed Groin Vascular Grafts with Early Intervention Using Local Muscle Flaps. AB - BACKGROUND: Peripheral vascular surgery may be complicated by wound infection and potential graft exposure in the groin area. Muscle flap coverage of the graft has been promoted to address these wound complications. The authors present their findings regarding graft salvage rates and patient outcomes using local muscle flaps to address vascular graft complications of the groin. METHODS: Data were obtained by retrospective cohort study of patients who underwent a local muscle flap procedure by a single surgeon following vascular graft complication in the groin. RESULTS: Seventeen patients undergoing local muscle flap coverage of a vascular graft were reviewed. Six men and 9 women, 51-80 years old, were included in the study. Wound complications in the groin occurred anywhere from 3 days to 3.5 years following graft placement. Graft exposure was the most common presenting complication (14 of 17 patients). Muscle flap coverage occurred within 15 days of complication presentation in all patients (average, 6.4 days). Seven of the 15 patients experienced postoperative complications within 6 months of the procedure, most commonly wound dehiscence. However, analysis demonstrated that vascular grafts were successfully salvaged in 10 of the 17 patients (59%) over the course of follow-up (range, 104-1748 days). Average time to muscle flap coverage was 4.2 days in patients who retained the graft and 9.6 days in patients who ultimately lost their vascular graft. CONCLUSION: The authors demonstrate improved vascular graft salvage rate when local muscle flap procedure is performed early after initial wound complication presentation. PMID- 26495228 TI - Applying a Dermal Regenerative Template in Management of Congenital Melanocytic Nevi of the Hand. AB - Congenital melanocytic nevus of the hand in the pediatric population is an uncommon diagnosis. These lesions have malignant potential and can cause psychosocial effects from cosmetic deformity. Early surgical intervention is recommended in these cases. The literature suggests that full-thickness skin grafting is to be performed in the hand to maintain functionality and avoid contracture and scarring. This creates a large donor-site defect and increased risk of graft loss due to slow revascularization from graft thickness. In addition, for large defects, the full-thickness skin graft donor site would require a split-thickness graft. However, split-thickness skin grafting is avoided in the hand due to increased scarring and contracture and decreased range of motion despite decreased donor-site morbidity and better revascularization. We describe a novel reconstructive technique that uses a dermal regenerative template (Integra) with split-thickness grafting. Having performed in 2 pediatric patients, we demonstrate that aesthetic and functional outcomes are equivalent to full-thickness grafting while creating a superficial donor site and allowing for improved revascularization from decreased graft thickness. PMID- 26495229 TI - Multidetector-row Computed Tomographic Angiography in the Planning of the Local Perforator Flaps. AB - The perforator vessels are highly variable in number, localization types, hemodynamic specifications, and the anatomical interactions with other structures. For these reasons, the identification of the best perforator before the operation is very important for the choice of the main feed vessel and the design of the perforator flap. METHODS: The authors retrospectively analyzed all cases in which multiple detector computed tomography (MDCT) with 3-dimensional (3D) image reconstruction was used in the preoperative planning in preparation for the reconstruction with local perforator flaps, which took place between July 2012 and December 2014 in the hospital. RESULTS: A total of 24 people were examined and underwent operations with 26 reconstructions using local perforator flaps. All perforators, which were identified during the MDCT with 3D reconstruction examination, were located intraoperationally without any errors. CONCLUSIONS: The preoperative MDCT with 3D reconstruction investigations of the topographic anatomical specifics of the perforator vessel on which the formation of the flap feed pedicle is planned allow for the fast and precise identification of the perforation at the preoperative stage while minimizing the amount of injury caused to the perforator during the operation and decrease the operation time. PMID- 26495230 TI - Lateral Calcaneal Artery Flaps in Atherosclerosis: Cadaveric Study, Vascular Assessment and Clinical Applications. AB - BACKGROUND: Soft tissue defects of the lateral malleolus (LM) and Achilles tendon pose difficult reconstructive problems due to the bony prominence and limited local tissue available. The objectives were to study the anatomical landmarks of the lateral calcaneal artery (LCA) and patency of LCA in atherosclerotic patients. METHODS: Part I: Thirty-four cadaveric feet were dissected to identify the LCA. The distance between the LCA and the most prominent point of the LM was measured horizontally (LCAa-LM), obliquely (LCAb-LM), and vertically (LCAc-LM). Part II: Thirty-two patients were divided in 2 groups as nonatherosclerotic and atherosclerotic groups. The LCA was assessed by both Doppler ultrasonography and computed tomographic angiography (CTA). Part III: Clinical applications were demonstrated. RESULTS: Part I: Mean distances of LCAa-LM, LCAb-LM, and LCAc-LM were 24.76, 33.68, and 35.03 mm, respectively. The LCA originated 94.12% from the peroneal artery. Part II: Doppler ultrasonography detected the LCA at 90.62% and 87.50% in nonatherosclerotic and atherosclerotic groups, respectively, whereas 100.00% and 93.75%, respectively, were detected by CTA. No statistically significant difference was found in the patency of the LCA between nonatherosclerotic and atherosclerotic patients. Part III: Clinical applications were performed in atherosclerotic patients. CONCLUSIONS: The LM is a reliable point to identify the LCA, and the LCA flap can be raised safely in atherosclerotic patients. Preoperative CTA should be performed in severely atherosclerotic patients or cases of major lower extremity vascular injuries. PMID- 26495231 TI - Ultrasound Shear-Wave Elastography for Follow-Up Fat Induration after Breast Reconstruction with an Autologous Flap. AB - Fat induration is associated with necrosis and remains a common complication in breast reconstructions with autologous flaps after mastectomy. Fat induration can cause deep tissue infection, pain, distress, and anxiety. However, the diagnosis for this problem has not been objectively defined. In the current article, We will share our experience of using ultrasound shear-wave elastography with 14 patients who had clinical fat induration after breast reconstruction with a deep inferior epigastric perforator (DIEP) flap. The experience suggested that shear wave elastography may be a noninvasive tool to assess alterations of tissue stiffness in a reproducible fashion after breast reconstruction with DIEP flaps. Complications, such as fat necrosis and fatty induration, may occur as a result of unstable blood flow to the flap. Thereby, objective assessments of stiffness might make a major contribution to the understanding of hemodynamics of the DIEP flap after transplantation. PMID- 26495232 TI - The Reverse Superficial Sural Artery Flap Revisited for Complex Lower Extremity and Foot Reconstruction. AB - BACKGROUND: Soft-tissue defects of the distal lower extremity and foot present significant challenges to the reconstructive surgeon. The reverse superficial sural artery flap (RSSAF) is a popular option for many of these difficult wounds. Our initial experience with this flap at multiple institutions resulted in a 50% failure rate, mostly because of critical venous congestion. To overcome this, we have modified our operative technique, which has produced a more reliable flap. METHODS: All patients reconstructed with an RSSAF between May 2002 and September 2013 were retrospectively reviewed. In response to a high rate of venous congestion in an early group of patients, we adopted a uniform change in operative technique for a late group of patients. A key modification was an increase in pedicle width to at least 4 cm. Outcomes of interest included postoperative complications and limb salvage rate. RESULTS: Twenty-seven patients were reconstructed with an RSSAF (n = 12 for early group, n = 15 for late group). Salvage rate in the early group was 50% compared with 93% in the late group (P = 0.02). Postoperative complications (75% vs. 67%, P = 0.70) were similar between groups. Venous congestion that required leech therapy was 42% in the early group (n = 5) and 0% in the late group (P = 0.01). CONCLUSIONS: Venous congestion greatly impairs the survival of the RSSAF. A pedicle width of at least 4 cm is recommended to maintain venous drainage and preserve flap viability. PMID- 26495233 TI - Tissue Inhibitor of Metalloproteinase-2 Suppresses Collagen Synthesis in Cultured Keloid Fibroblasts. AB - BACKGROUND: Keloids are defined as a kind of dermal fibroproliferative disorder resulting from the accumulation of collagen. In the remodeling of extracellular matrix, the balance between matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) is as critical as the proper production of extracellular matrix. We investigate the role of TIMPs and MMPs in the pathogenesis of keloids and examine the therapeutic potential of TIMP-2. METHODS: The expression of TIMPs and MMPs in most inflamed parts of cultured keloid fibroblasts (KFs) and peripheral normal skin fibroblasts (PNFs) in the same individuals and the reactivity of KFs to cyclic mechanical stretch were analyzed by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay (n = 7). To evaluate the effect of treating KFs with TIMP-2, collagen synthesis was investigated by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, and microscopic analysis was used to examine the treatment effects of TIMP-2 on ex vivo cultures of keloid tissue (n = 6). RESULTS: TIMP-2 was downregulated in cultured KFs compared with PNFs in the same individuals, and the reduction in TIMP-2 was exacerbated by cyclic mechanical stretch. Administration of TIMP-2 (200 or 300 ng/mL) significantly suppressed expression of Col1A2 and Col3A1 mRNA and collagen type I protein in KFs. TIMP-2 also significantly reduced the skin dermal and collagen bundle thickness in ex vivo cultures of keloid tissue. CONCLUSION: These results indicated that downregulation of TIMP-2 in KFs is a crucial event in the pathogenesis of keloids, and the TIMP-2 would be a promising candidate for the treatment of keloids. PMID- 26495234 TI - Combination of Mandibular Constriction and Intraoral Vertical Ramus Osteotomies for a Transverse Jaw Discrepancy. AB - BACKGROUND: The aim of the present study was to evaluate the treatment of patients developing a transverse jaw width discrepancy who exhibited class III malocclusion and/or facial asymmetry by a combination of mandibular constriction (MC) and intraoral vertical ramus osteotomies (IVROs). SUBJECTS AND METHODS: In a retrospective study, functional results, postoperative complications, and skeletal stability were analyzed for all the patients who had undergone MC and IVRO, with more than 2 years of follow-up. A mandibular midline osteotomy for constriction with lag screw technique and IVROs was used for MC and setback. RESULTS: Sixteen patients were included in the present study. The average degree of MC was 6.34 mm. Both the occlusal relationship and facial appearance in all patients were significantly improved by the surgical orthodontic treatment, with no harmful clinical symptoms. In addition, our original MC using lag screw technique provided the most reliable results in terms of skeletal stability. CONCLUSIONS: This study showed that MC using lag screw technique gives a very stable mandibular width constriction, and the combination of MC and IVROs offers a promising treatment alternative for patients with mandibular prognathism developing a transverse jaw width discrepancy. PMID- 26495235 TI - High Aggressive Herpetiform Squamous Cell Carcinoma. AB - We describe a highly aggressive squamous cell carcinoma that presents in a dermatome pattern shortly following shingles and review the literature on herpetiform lesions. PMID- 26495236 TI - A Novel Treatment of Denuded Areas in Newborns: A Report of 2 Successful Cases. AB - Covering denuded areas in the extremes of life is challenging for the plastic surgeon. In newborns, this becomes a greater challenge because of the immaturity of all of their systems, making any injury a potential risk for death. We present in this case report a successful treatment of 2 cases covered with cultured autologous keratinocytes. In this procedure, a small skin biopsy is taken from the retroauricular area and the keratinocytes are cultured. After 5 days, a membrane with the cells cultured is applied covering the denuded area. We find the autologous keratinocyte method a suitable option for the treatment of denuded areas in newborns, without causing any additional morbidity and in a very short period of time. PMID- 26495237 TI - Ganglion and Synovial Cyst of the Temporomandibular Joint: A Case Report and Literature Review. AB - Ganglion and synovial cysts of the temporomandibular joint (TMJ) are rare. Although histopathological findings differ, clinical presentation is comparable. This study adds a case report of a ganglion of the TMJ to existing literature and a review of all available case reports on ganglion and synovial cysts of the TMJ. Including our own case report, we reviewed 49 cases of ganglion and synovial cysts of the TMJ. They occurred in a female:male ratio of 3:1, at an median age of 46 years (range, 11-64 years). Patients mainly presented with preauricular swelling and pain. After imaging, the ganglion or synovial cyst was most commonly excised under general anesthesia. No recurrences were described. PMID- 26495238 TI - Usefulness of Simple-Designed Bilobed Flap for Reconstruction of Ischial Decubitus Ulcer. AB - The pressure ulcer of the ischial region is often accompanied by complete paraplegia in patients with spinal cord injury and is attributable to the compression and breakdown of tissue arising from constant sitting. Characteristically, a pressure ulcer of this region is circular and deep. We recently reconstructed ischial decubitus ulcer of 8 patients using simple designed bilobed flap. In all cases, the flap survived completely without any complication. Moreover, none of the patients in this group experienced any pressure ulcer relapse during the postoperative follow-up from 1 year 1 month to 9 years. In the vicinity of the ischial region, the buttock contains the most abundant amount of fatty tissue. Therefore, for our technique, we create the first flap in the buttock neighboring the defect and the second flap on the posterior thigh. Using this approach, it is possible to cover the skin or soft tissue defect of the ischial region with the flap from the buttock having a thickness large enough to bear the patient's weight during sitting. The first flap is arranged parallel to the gluteal sulcus, and the second flap from the thigh is moved to the first-flap donation site. This technique allows closure of the wound without producing tension along the suture line. The bilobed flap, which does not require the artery to be included in the flap, is applicable for patients with relapsing pressure ulcer having a history of surgery. Our flap operative procedure is particularly useful in the reconstruction of ischial decubitus ulcer. PMID- 26495239 TI - Refined Method of Lipofilling following DIEP Breast Reconstruction: 3D Analysis of Graft Survival. AB - BACKGROUND: The deep inferior epigastric perforator (DIEP) flap technique gives good clinical results, but aesthetic surgical adjustments are often necessary. Lipofilling represents a good complementary method, but fat resorption within the few months after surgery limits its use. Recently, a new protocol was introduced and successfully evaluated on murine models. This study aims to evaluate this protocol following a DIEP procedure by three-dimensional analysis. METHODS: Within a period of 4 months, every patient having undergone breast reconstruction with DIEP and who required a lipofilling adjustment was invited to take part in this study. All surgeries were performed using the Adip'sculpt disposable medical device MACROFILL (Laboratoires SEBBIN, Boissy-l'Aillerie, France). Fat resorption was analyzed using a three-dimensional photography system. RESULTS: Twenty-three patients were included, with a total of 25 breasts operated on. Injections were carried out on irradiated breasts in 73% of cases, and average injection volume was 124 mL (SD = 39 mL), whereas average operating time was 68 minutes (44-96 minutes). At an average follow-up of 5 months (4-8 months), 70.9% of projection gain afforded by the lipofilling was still present. CONCLUSIONS: It is now clear that particular rules should be respected for an efficient lipofilling, particularly regarding aspiration cannula characteristics, vacuum used, and the necessity of washes and soft centrifugations. We demonstrate here that by following a specific protocol that addresses these precautions, while using material that is specifically adapted, a 70.9% fat survival rate can be achieved, even in the very unfavorable case of postirradiation DIEP breast reconstruction. PMID- 26495240 TI - Obesity-Related Genetic Variants and their Associations with Physical Activity. AB - BACKGROUND: Meta-analysis of genome-wide association studies identified obesity related genetic variants. Due to the pleiotropic effects of related phenotypes, we tested six of these obesity-related genetic variants for their association with physical activity: fat mass and obesity-associated (FTO)(rs9939609)T>A, potassium channel tetramerization domain containing (KCTD15) (rs11084753)G>A, melanocortin receptor4 (MC4R)(rs17782313)T>C, neuronal growth regulator 1 (NEGR1)(rs2815752)A>G, SH2B adapter protein 1 (SH2B1)(rs7498665)A>G, and transmembrane protein18 (TMEM18)(rs6548238)C>T. METHOD: European-American women (n = 263) and men (n = 229) (23.5 +/- 0.3 years, 24.6 +/- 0.2 kg/m2) were genotyped and completed the Paffenbarger physical activity Questionnaire. Physical activity volume in metabolic energy equivalents [MET]-hour/week was derived from the summed time spent (hour/week) times the given MET value for vigorous, moderate, and light intensity physical activity, and sitting and sleeping, respectively. Multivariable adjusted [(age, sex, and body mass index (BMI)] linear regression tested associations among genotype (dominant/recessive model) and the log of physical activity volume. RESULT: MC4R (rs17782313)T>C explained 1.1 % (p = 0.02), TMEM18(rs6548238)C>T 1.2 % (p = 0.01), and SH2B1 (rs7498665)A>G 0.6 % (p = 0.08) of the variability in physical activity volume. Subjects with the MC4R C allele spent 3.5 % less MET-hour/week than those with the TT genotype (p = 0.02). Subjects with the TMEM18 T allele spent 4.1 % less MET-hour/week than those with the CC genotype (p = 0.01). Finally, subjects with the SH2B1 GG genotype spent 3.6 % less MET-hour/week than A allele carriers (p = 0.08). CONCLUSION: Our findings suggest a shared genetic influence among some obesity-related gene loci and physical activity phenotypes that should be explored further. Physical activity volume differences by genotype have public health importance equating to 11-13 lb weight difference annually. PMID- 26495241 TI - MECHANICAL VENTILATION FOR THE LUNG TRANSPLANT RECIPIENT. AB - Mechanical ventilation (MV) is an important aspect in the intraoperative and early postoperative management of lung transplant (LTx)-recipients. There are no randomized-controlled trials of LTx-recipient MV strategies; however there are LTx center experiences and international survey studies reported. The main early complication of LTx is primary graft dysfunction (PGD), which is similar to the adult respiratory distress syndrome (ARDS). We aim to summarize information pertinent to LTx-MV, as well as PGD, ARDS, and intraoperative MV and to synthesize these available data into recommendations. Based on the available evidence, we recommend lung-protective MV with low-tidal-volumes (<=6 mL/kg predicted body weight [PBW]) and positive end-expiratory pressure for the LTx recipient. In our opinion, the MV strategy should be based on donor characteristics (donor PBW as a parameter of actual allograft size), rather than based on recipient characteristics; however this donor-characteristics-based protective MV is based on indirect evidence and requires validation in prospective clinical studies. PMID- 26495242 TI - Recent advances and future directions in the management of knee osteoarthritis: Can biological joint reconstruction replace joint arthroplasty and when? AB - In this article, a concise description of the recent advances in the field of osteoarthritis management is presented. The main focus is to highlight the most promising techniques that emerge in both biological joint replacement and artificial joint arthroplasty. A critical view of high quality evidence regarding outcome and safety profile of these techniques is presented. The potential role of kinematically aligned total knee replacement, navigation, and robotic-assisted surgery is outlined. A critical description of both primary and stem cell-based therapies, the cell homing theory, the use of biologic factors and recent advancements in tissue engineering and regenerative medicine is provided. Based on the current evidence, some thoughts on a realistic approach towards answering these questions are attempted. PMID- 26495243 TI - Superior labral anterior posterior lesions of the shoulder: Current diagnostic and therapeutic standards. AB - Surgical treatment of superior labral anterior posterior (SLAP) lesion becomes more and more frequent which is the consequence of evolving progress in both, imaging and surgical technique as well as implants. The first classification of SLAP lesions was described in 1990, a subdivision in four types existed. The rising comprehension of pathology and pathophysiology in SLAP lesions contributed to increase the types in SLAP classification to ten. Concerning the causative mechanism of SLAP lesions, acute trauma has to be differed from chronic degeneration. Overhead athletes tend to develop a glenohumeral internal rotation deficit which forms the basis for two controversial discussed potential mechanisms of pathophysiology in SLAP lesions: Internal impingement and peel-back mechanism. Clinical examination often remains unspecific whereas soft tissue imaging such as direct or indirect magnetic resonance arthrography has technically improved and is regarded to be indispensable in detection of SLAP lesions. Concomitant pathologies as Bankart lesions, rotator cuff tears or perilabral cysts should be taken into consideration when planning a personalized therapeutic strategy. In addition, normal variants such as sublabral recess, sublabral hole, Buford complex and other less common variants have to be distinguished. The most frequent SLAP type II needs a sophisticated approach when surgical teatment comes into consideration. While SLAP repair is considered to be the standard operative option, overhead athletes benefit from a biceps tenodesis because improved patient-reported satisfaction and higher rate of return to pre injury level of sports has been reported. PMID- 26495244 TI - Osteitis pubis in elite athletes: Diagnostic and therapeutic approach. AB - Osteitis pubis (OP) is a debilitating overuse syndrome characterizing by pelvic pain and local tenderness over the pubic symphysis commonly encountered in athletes often involved in kicking, twisting and cutting activities in sports such as soccer and rugby and to a lesser degree distance running. It is a common source of groin pain in elite athletes attributable to pubis sympysis instability as the result of microtrauma caused by repetitive muscle strains on pubic bones. Diagnosis is based mainly on detailed sports history and a meticulous clinical examination, although occasionally is difficult to distinguish this nosological entity from other pathologies affecting the involved area which may occur concomitantly in the same patient. Radiologic examinations such as plain radiographs, magnetic resonance imaging and 3 phase bone isotope scanning may be helpful to differentiate from other clinical entities with similar clinical presentation. Most cases respond well to conservative treatment which includes several physical modalities and especially a progressive rehabilitation programmed individualized to each one of patients diagnosed with OP. Local injection therapies have been also been proposed as a non-operative therapeutic option for the efficient management of these patients. In refractory cases, surgical therapeutic strategies are warranted. These include several open or minimally invasive surgical interventions such as arthroscopic or open symphysis curettage, wedge or total resection of pubic sympysis, polypropylene mesh placement and pubic fusion. In this review a critical analysis of OP in elite athletes is performed with special focus on current concepts of diagnosis and management of this source of athletic groin pain. PMID- 26495245 TI - Vertebral fracture assessment: Current research status and application in patients with kyphoplasty. AB - Imaging of the spine is of paramount importance for the recognition of osteoporotic vertebral fractures (VFs), and standard radiography (SR) of the spine is the suggested diagnostic method but is not routinely used because of the cost and radiation exposure considerations. VF assessment (VFA) is an efficient, low radiation method for identifying VFs at the time of bone mineral density (BMD) measurement. Prediction models used to indicate the need for VFA may have little predictive power in subspecialty referral populations such as rheumatologic patients or patients who underwent kyphoplasty. Rheumatologic patients are frequently at increased risk for VFs, and VFA should be performed on an individual basis, also taking in account the guidelines for the general population. Kyphoplasty is a new minimal invasive procedure for the treatment of VFs and is being performed with increasing frequency. Following kyphoplasty, there may be a risk of new VFs in adjacent vertebrae. The assessment and follow up of patients who underwent kyphoplasty requires repetitive X-ray imaging with the known limitations of SR. Thus, VFA may facilitate the evaluation of VFs in these patients because most of the kyphoplasty patients would fulfill the criteria. In a pilot study, we measured the BMD and performed VFA in 28 patients treated with kyphoplasty. Ratios of anterior to posterior (A/P) and middle to posterior (M/P) height were measured, and Genant's method was used to classify vertebrae accordingly. Intraobserver and interobserver reliability for A/P, M/P and the Genant's method were determined. Only 1 patient did not meet the criteria for VFA. Of the 364 available vertebrae, 295 could be analyzed. Most missing data (concerning 69 vertebrae) occurred in the upper thoracic region. Three of the 69 non-eligible vertebrae were lumbar vertebrae with cement leakage from the kyphoplasty procedure. In our hands, VFA was highly reproducible, demonstrating very good agreement in terms of intraobserver and interobserver reliability. Agreement was very good on the vertebral level, "vertebrae with kyphoplasty" level and "2 above and 1 below the kyphoplasty vertebrae" level. The application of Genant's method to these patients also resulted in perfect agreement. We believe that the potential value of VFA in patients treated with kyphoplasty requires further evaluation, particularly comparing VFA with SR and performing a longitudinal follow-up. More research will help to adopt care processes that determine which patients require VFA and how often VFA should be performed, while also considering the impact of this technique on the cost of healthcare organizations. PMID- 26495247 TI - Comminuted olecranon fracture fixation with pre-contoured plate: Comparison of composite and cadaver bones. AB - AIM: To determine whether use of a precontoured olecranon plate provides adequate fixation to withstand supraphysiologic force in a comminuted olecranon fracture model. METHODS: Five samples of fourth generation composite bones and five samples of fresh frozen human cadaveric left ulnae were utilized for this study. The cadaveric specimens underwent dual-energy X-ray absorptiometry (DEXA) scanning to quantify the bone quality. The composite and cadaveric bones were prepared by creating a comminuted olecranon fracture and fixed with a pre contoured olecranon plate with locking screws. Construct stiffness and failure load were measured by subjecting specimens to cantilever bending moments until failure. Fracture site motion was measured with differential variable resistance transducer spanning the fracture. Statistical analysis was performed with two tailed Mann-Whitney-U test with Monte Carlo Exact test. RESULTS: There was a significant difference in fixation stiffness and strength between the composite bones and human cadaver bones. Failure modes differed in cadaveric and composite specimens. The load to failure for the composite bones (n = 5) and human cadaver bones (n = 5) specimens were 10.67 nm (range 9.40-11.91 nm) and 13.05 nm (range 12.59-15.38 nm) respectively. This difference was statistically significant (P ? 0.007, 97% power). Median stiffness for composite bones and human cadaver bones specimens were 5.69 nm/mm (range 4.69-6.80 nm/mm) and 7.55 nm/mm (range 6.31-7.72 nm/mm). There was a significant difference for stiffness (P ? 0.033, 79% power) between composite bones and cadaveric bones. No correlation was found between the DEXA results and stiffness. All cadaveric specimens withstood the physiologic load anticipated postoperatively. Catastrophic failure occurred in all composite specimens. All failures resulted from composite bone failure at the distal screw site and not hardware failure. There were no catastrophic fracture failures in the cadaveric specimens. Failure of 4/5 cadaveric specimens was defined when a fracture gap of 2 mm was observed, but 1/5 cadaveric specimens failed due to a failure of the triceps mechanism. All failures occurred at forces greater than that expected in postoperative period prior to healing. CONCLUSION: The pre contoured olecranon plate provides adequate fixation to withstand physiologic force in a composite bone and cadaveric comminuted olecranon fracture model. PMID- 26495248 TI - Is two-stage reimplantation effective for virulent pathogenic infection in a periprosthetic hip? A retrospective analysis. AB - AIM: To investigate the effectiveness of two-stage reimplantation using antibiotic-loaded bone cement (ALBC) and the risk factors associated with failure to control periprosthetic joint infection (PJI). METHODS: We retrospectively reviewed 38 consecutive hips managed using two-stage reimplantation with ALBC. The mean follow-up period was 5.4 years (range: 2.5-9 years). RESULTS: The causative pathogens were isolated from 29 patients (76%), 26 of whom were infected with highly virulent organisms. Sixteen patients (42%) underwent at least two first-stage debridements. An increased debridement frequency correlated significantly with high comorbidity (P < 0.001), a lower preoperative Harris hip score (HHS; P < 0.001), antimicrobial resistance, and gram-negative and polymicrobial infection (P = 0.002). Of the 35 patients who underwent two-stage reimplantation, 34 showed no signs of recurrence of infection. The mean HHS improved from 46 +/- 12.64 to 78 +/- 10.55 points, with 7 (20%), 12 (34%), 11 (32%) and 5 (14%) patients receiving excellent, good, fair and poor ratings, respectively. CONCLUSION: The current study demonstrated that two-stage reimplantation could successfully treat PJI after hip arthroplasty. However, the ability of ALBC to eradicate infection was limited because frequent debridement was required in high-risk patients (i.e., patients who are either in poor general health due to associated comorbidities or harbor infections due to highly virulent, difficult-to-treat organisms). LEVEL OF EVIDENCE: Level IV. PMID- 26495249 TI - Acute effects of static stretching on peak and end-range hamstring-to-quadriceps functional ratios. AB - AIM: To evaluate if static stretching influences peak and end-range functional hamstring-to-quadriceps (H/Q) strength ratios in elite women athletes. METHODS: Eleven healthy female athletes in an elite competitive level participated to the study. All the participants fulfilled the static stretching or non-stretching (control) intervention protocol in a randomized design on different days. Two static unassisted stretching exercises, one in standing and one in sitting position, were used to stretch both the hamstring and quadriceps muscles during these protocols. The total time for the static stretching was 6 +/- 1 min. The isokinetic peak torque measurements for the hamstring and quadriceps muscles in eccentric and concentric modes and the calculations for the functional H/Q strength ratios at angular velocities of 60 degrees /s and 180 degrees /s were made before (pre) and after (post) the control or stretching intervention. The strength measurements and functional strength ratio calculations were based during the entire- and end-range of knee extension. RESULTS: The pre-test scores for quadriceps and hamstring peak torque and end range values were not significantly different between the groups (P > 0.05). Subsequently, although the control group did not exhibit significant changes in quadriceps and hamstring muscle strength (P > 0.05), static stretching decreased eccentric and concentric quadriceps muscle strength at both the 60 degrees /s and 180 degrees /s test speeds (P < 0.01). Similarly, static stretching also decreased eccentric and concentric hamstring muscle strength at both the 60 degrees /s and 180 degrees /s test speeds (P < 0.01). On the other hand, when the functional H/Q strength ratios were taken into consideration, the pre-intervention values were not significant different between the groups both during the entire and end range of knee extension (P > 0.05). Furthermore, the functional H/Q strength ratios exhibited no significant alterations during the entire and end ranges of knee extension both in the static stretching or the control intervention (P > 0.05). CONCLUSION: According to our results, static stretching routine does not influence functional H/Q ratio. Athletes can confidently perform static stretching during their warm-up routines. PMID- 26495250 TI - Volume and fat infiltration of spino-pelvic musculature in adults with spinal deformity. AB - AIM: To investigate fat infiltration and volume of spino-pelvic muscles in adults spinal deformity (ASD) with magnetic resonance imaging (MRI) and 3D reconstructions. METHODS: Nineteen female ASD patients (mean age 60 +/- 13) were included prospectively and consecutively and had T1-weighted Turbo Spin Echo sequence MRIs with Dixon method from the proximal tibia up to T12 vertebra. The Dixon method permitted to evaluate the proportion of fat inside each muscle (fat water ratio). In order to investigate the accuracy of the Dixon method for estimating fat vs water, the same MRI acquisition was performed on phantoms of four vials composed of different proportion of fat vs water. With Muscl'X software, 3D reconstructions of 17 muscles or group of muscles were obtained identifying the muscle's contour on a limited number of axial images [Deformation of parametric specific objects (DPSO) Method]. Musclar volume (Vmuscle), infiltrated fat volume (Vfat) and percentage of fat infiltration [Pfat, calculated as follow: Pfat = 100 * (Vfat/Vmuscle)] were characterized by extensor or flexor function respectively for the spine, hip and knee and theirs relationship with demographic data were investigated. RESULTS: Phantom acquisition demonstrated a non linear relation between Dixon fat-water ratio and the real fat-water ratio. In order to correct the Dixon fat-water ratio, the non linear relation was approximated with a polynomial function of degree three using the phantom acquisition. On average, Pfat was 13.3% +/- 5.3%. Muscles from the spinal extensor group had a Pfat significantly greater than the other muscles groups, and the largest variability (Pfat = 31.9% +/- 13.8%, P < 0.001). Muscles from the hip extensor group ranked 2(nd) in terms of Pfat (14% +/- 8%), and were significantly greater than those of the knee extensor (P = 0.030). Muscles from the knee extensor group demonstrated the least Pfat (12% +/- 8%). They were also the only group with a significant correlation between Vmuscle and Pfat (r = 0.741, P < 0.001), however this correlation was lacking in the other groups. No correlation was found between the Vmuscle total and age or body mass index. Except for the spine flexors, Pfat was correlated with age. Vmuscle and Vfat distributions demonstrated that muscular degeneration impacted the spinal extensors most. CONCLUSION: Mechanisms of fat infiltration are not similar among the muscle groups. Degeneration impacted the spinal and hip extensors most, key muscles of the sagittal alignment. PMID- 26495251 TI - Subtrochanteric fractures after retrograde femoral nailing. AB - Secondary fractures around femoral nails placed for the management of hip fractures are well known. We report, two cases of a fracture of the femur at the interlocking screw site in the subtrochanteric area after retrograde femoral nailing of a femoral shaft fracture. Only a few reports in the existing literature have described these fractures. Two young men after sustaining a fall presented to us with pain, swelling and deformity in the upper thigh region. On enquiring, examining and radiographing them, peri-implant fractures of subtrochanteric nature through the distal interlocking screws were revealed in both patients who also had histories of previous falls for which retrograde intramedullary nailing was performed for their respective femora. Both patients were managed with similar surgical routines including removal of the existing hardware, open reduction and ace cephallomedullary antegrade nailing. The second case did show evidence of delayed healing and was additionally stabilized with cerclage wires. Both patients had uneventful postoperative outcomes and union was evident at the end of 6 mo postoperatively with a good range of motion at the hip and knee. Our report suggests that though seldom reported, peri-implant fractures around the subtrochanteric region can occur and pose a challenge to the treating orthopaedic surgeon. We suggest these be managed, after initial stabilization and resuscitation, by implant removal, open reduction and interlocking intramedullary antegrade nailing. Good results and progression to union can be expected in these patients by adhering to basic principles of osteosynthesis. PMID- 26495246 TI - Cystic lesion around the hip joint. AB - This article presents a narrative review of cystic lesions around the hip and primarily consists of 5 sections: Radiological examination, prevalence, pathogenesis, symptoms, and treatment. Cystic lesions around the hip are usually asymptomatic but may be observed incidentally on imaging examinations, such as computed tomography and magnetic resonance imaging. Some cysts may enlarge because of various pathological factors, such as trauma, osteoarthritis, rheumatoid arthritis, or total hip arthroplasty (THA), and may become symptomatic because of compression of surrounding structures, including the femoral, obturator, or sciatic nerves, external iliac or common femoral artery, femoral or external iliac vein, sigmoid colon, cecum, small bowel, ureters, and bladder. Treatment for symptomatic cystic lesions around the hip joint includes rest, nonsteroidal anti-inflammatory drug administration, needle aspiration, and surgical excision. Furthermore, when these cysts are associated with osteoarthritis, rheumatoid arthritis, and THA, primary or revision THA surgery will be necessary concurrent with cyst excision. Knowledge of the characteristic clinical appearance of cystic masses around the hip will be useful for determining specific diagnoses and treatments. PMID- 26495252 TI - Ewings sarcoma of patella: A rare entity treated with a novel technique of extensor mechanism reconstruction using tendoachilles auto graft. AB - We report a case of Ewings sarcoma (ES) involving the patella in a young female. ES of patella is a rare entity. The patient was presented with anterior knee pain and swelling arising from the patella. She was treated with neoadjuvant chemotherapy followed by wide excision of the patella and reconstruction of the extensor mechanism using split tendoachilles auto graft. The patella is an uncommon site for primary or metastatic tumors of the bone. ES, though rare, should be included in the differential diagnosis of swellings arising from the patella. Auto graft from the tendoachilles is a good alternative for reconstructing the extensor mechanism of the knee. PMID- 26495253 TI - Psychometric Properties of the Persian Language Version of Yang Internet Addiction Questionnaire: An Explanatory Factor Analysis. AB - BACKGROUND: Reliability and validity are the key concepts in measurement processes. Young internet addiction test (YIAT) is regarded as a valid and reliable questionnaire in English speaking countries for diagnosis of Internet related behavior disorders. OBJECTIVES: This study aimed at validating the Persian version of YIAT in the Iranian society. PATIENTS AND METHODS: A pilot and a cross-sectional study were conducted on 28 and 254 students of Qom University of Medical Sciences, respectively, in order to validate the Persian version of YIAT. Forward and backward translations were conducted to develop a Persian version of the scale. Reliability was measured by test-retest, Cronbach's alpha and interclass correlation coefficient (ICC). Face, content and construct validity were approved by the importance score index, content validity ratio (CVR), content validity index (CVI), correlation matrix and factor analysis. The SPSS software was used for data analysis. RESULTS: The Cronbach's alpha was 0.917 (CI 95%; 0.901 - 0.931). The average of scale-level CVI was calculated to be 0.74; the CVI index for each item was higher than 0.83 and the average of CVI index was equal to 0.89. Factor analysis extracted three factors including personal activities disorder (PAD), emotional and mood disorder (EMD) and social activities disorder (SAD), with more than 55.8% of total variances. The ICC for different factors of Persian version of Young Questionnaire including PAD, EMD and for SAD was r = 0.884; CI 95%; 0.861 - 0.904, r = 0.766; CI 95%; 0.718 - 0.808 and r = 0.745; CI 95%; 0.686 - 0.795, respectively. CONCLUSIONS: Our study showed that the Persian version of YIAT is good and usable on Iranian people. The reliability of the instrument was very good. Moreover, the validity of the Persian translated version of the scale was sufficient. In addition, the reliability and validity of the three extracted factors of YIAT were evaluated and were acceptable. PMID- 26495254 TI - Multiple Prescription Drug Abuse and Salt Craving in a Psychotic Patient: A Case Report From a Teaching Hospital in Jordan. AB - INTRODUCTION: Diuretics and laxative abuse as a means of purging is common in patients with bulimia nervosa and there may be an underestimation of the true prevalence of diuretic abuse, as some are also available without prescription. CASE PRESENTATION: A 28-year-old woman presented with tetany due to hypocalcemia, hypokalemia and hypomagnesemia. She had a history of laxative and diuretic abuse, and salt craving. Psychiatric evaluation revealed a disturbed social history with masked depression that necessitated treatment. CONCLUSIONS: Multiple prescription drug abuse and salt/salty food addiction usually reflects a personality of addiction, which leads to harmful use and dependence. PMID- 26495255 TI - The Mortality Rate of Myocardial Infraction Patients With and Without Opium Dependen. AB - BACKGROUND: Myocardial infarction (MI) is a heart condition caused by the suspension of blood circulation in a part of the myocardium. There are different risk factors contributing to a heart attack. Some believe that endorphins and endogenous opioids play an important role in causing MIs. OBJECTIVES: This study intended to determine the relationship between opium dependency and mortality rate among patients with MI. PATIENTS AND METHODS: This retrospective study investigated patients who had MI for the first time and were hospitalized in the coronary care unit (CCU) of Khatamolanbia hospital in Zahedan, Iran, from 2007 to 2010. These patients were either opium dependent or not. Four hundred patients were selected. The patients' possibilities of death and re-hospitalization after the first MI were confirmed over the phone. Data was analyzed through t-test and chi-squared test. RESULTS: Of all the patients, 19.5% were opium-dependent. The mortality rate in the non-opium-dependent group was 5.9%, while in the dependent group this rate was 11.5% (P = 0.072). The number of re-hospitalizations due to heart problems was higher in the opium-dependent patients (P < 0.001). CONCLUSIONS: There was no meaningful relationship between the mortality rate of patients with MI who were either opium-dependent or non-opium-dependent. The number of re-hospitalizations due to heart problems was meaningfully higher in the opium-dependent patients; hence, educating people and training them on the destructive effects of opium, specifically in patients with heart conditions is highly recommended. PMID- 26495256 TI - Survival Analysis of Drug Abuse Relapse in Addiction Treatment Centers. AB - BACKGROUND: Drug abuse is a chronic and enduring phenomenon, which is among the important challenging public health problems. One of the main aspects in drug abuse is the relapse. OBJECTIVES: The aims of this study were to estimate the time to relapse (survival rate) and to evaluate some of its associated variables by survival analysis. PATIENTS AND METHODS: This research was conducted in four addiction treatment centers on 140 self-referred addicts in Ilam city, Iran, in 2012. Cluster sampling method was used for selecting the samples and data were collected by interview and referring to the subjects' records. The gathered data were analyzed through the life table, Kaplan-Meier analysis, log rank test, and Cox regression. RESULTS: The relapse rate was 30.42%, mean and median of the time to relapse (survival time) were 27.40 +/- 1.63 months (CI 95%: 24.19 - 30.60) and 25 +/- 2.25 months (CI 95%: 22.5 - 27.5), respectively. In the first six months, the cumulative survival rate was 83%, while in the 24th month it was 46% and the following time was consistent. Job status (OR = 2.64), marital status (OR = 1.55), family size (OR = 1.20) and age (OR = 0.23) were statistically significant in Cox regression model. CONCLUSIONS: In the initial treatment, it seems necessary to supervise and monitor the treatment process through staff in addiction treatment centers together with the company of the addicts' families to reduce relapse rate. PMID- 26495257 TI - Cigarette Smoking and Skin Prick Test in Patients With Allergic Rhinitis. AB - BACKGROUND: Allergic Rhinitis (AR) is the most common allergic disease, affecting 30% of population around the world. The disease is predominantly associated with exposure to some aeroallergens like cigarette smoking. Skin Prick Test (SPT) is a method of detecting immediate allergic reactions and is applied for controlling disease and therapeutic modality. OBJECTIVES: This study was designed to investigate the effect of cigarette smoking on SPT results among male and female individuals with AR disease. PATIENTS AND METHODS: A total of 478 patients with AR admitted to the 2 main hospitals of Zahedan City from 2005 to 2012, were recruited in this analytic-descriptive study. Categories of smokers and never smokers were used based on patient's statements and their history of smoking. SPT was performed with panel of some allergens and results were recorded and analyzed statistically. Odds ratio and confidence interval method were calculated using univariate logistic regression. RESULTS: The results of this study indicated that 41.4% of patients with allergic rhinitis was smoker with ages ranged from 15 to 70 years. The result of this study also showed that smoking has no effect on SPT results of pollen and weeds aeroallergens conducted on male and female AR patients. However, male were significantly more sensitive than female in terms of sensitivity to the aspergillus, cladosporium, house dust mite, grasses, wheat, cockroach, and feather allergens. CONCLUSIONS: Our findings did not support the effect of cigarette smoking on SPT reactivity to pollen and weeds aeroallergens. However, male were significantly more sensitive than female in terms of sensitivity to some allergens. PMID- 26495258 TI - Effect of Abstinence on Depression, Anxiety, and Quality of Life in Chronic Methamphetamine Users in a Therapeutic Community. AB - BACKGROUND: During withdrawal, patients experience different symptoms. These symptoms are associated with relapse. Understanding different outcomes of methamphetamine abstinence is useful for finding better treatments for dependence. OBJECTIVES: This study aimed to show the effects of abstinence on depression, anxiety, and quality of life in methamphetamine users. PATIENTS AND METHODS: A prospective quasi-experimental (before and after study) method was used to show the effect of 3 weeks abstinence on depression, anxiety, and quality of life. A convenient sample of addicted people entered into the study and 34 people completed the study. Beck Depression Scale, Cattell Anxiety Inventory and Short Form Health Survey (SF-36) (for assessing quality of life), were used for outcome assessments. RESULTS: The mean depression score after abstinence decreased significantly (P < 0.001). Both hidden and obvious anxiety and total anxiety had a high level at admission and after 3 weeks of abstinence, the mean level of anxiety did not change significantly (P < 0.096). However, the quality of life increased after 3 weeks of abstinence (P < 0.001). CONCLUSIONS: Depression and anxiety are prevalent in methamphetamine users. Short-term abstinence improves depression and quality of life but does not improve anxiety in methamphetamine abusers. During follow up of these patients, addressing depression and anxiety is important to achieve better results. PMID- 26495259 TI - Chronic Administration of High Doses of Nandrolone Decanoate on the Pituitary Gonadal Axis in Male Rats. AB - BACKGROUND: Anabolic-androgenic steroids (AAS) are abused by athletes. OBJECTIVES: The present study was designed to evaluate chronic administration of high doses of nandrolone decanoate (ND) on the pituitary-gonadal axis and hematological parameters in normal male rats. MATERIALS AND METHODS: Thirty Wistar-Albino male rats were divided assigned to control (C), placebo (P) and test (T) groups (n = 10). Group T received 15 mg/kg intramuscular (IM) ND for eight weeks. Group P received the same volume of peanut oil, but group C did not receive any agent during the trial period. At the end, animals were anesthetized, killed and blood samples collected from cervical vessels. Serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were determined by sensitive rat gonadotropins kit, using ELISA methods. Serum testosterone and hematological parameters were measured by ordinary laboratory methods. Obtained data was analyzed using SPSS 17 by ANOVA and Tukey statistical tests. Results were expressed as Mean +/- SD. Statistical difference considered significantly by P < 0.05. RESULTS: Serum testosterone, LH, FSH, weight gain, food and water intake in group T were significantly decreased compared to other groups (P < 0.05). In addition erythrocyte, leucocytes, hemoglobin and hematocrit in group T were significantly increased compared to those of other groups (P < 0.05). CONCLUSIONS: Chronic administration of high doses of ND can alter serum FSH, LH and testosterone and hematological parameters in male rats. PMID- 26495260 TI - Metacognitive and Meta-Emotional Styles in Patients With Alcohol and the Other Substance Dependence. AB - BACKGROUND: Both alcohol and other substances are utilized for emotional and cognitive regulation. OBJECTIVES: The purpose of the present study was to compare metacognitive styles and distress intolerance in patients with alcohol and other substance dependence. PATIENTS AND METHODS: According to DSM-IV TR criteria, 45 patients with alcohol dependence (AD), 44 patients with substance dependence (SD), and 43 volunteers without AD or SD (control group) were enrolled. Socio demographic information form, Distress Tolerance Scale (DTS), and metacognitive questionaire-30 (MCQ-30) were used to evaluate the participants. RESULTS: Patients with AD had significantly lower "tolerance" subscale and total DTS scores than those with SD and control group (P = 0.008 for SD sample and P = 0.004 for control group). Patients with SD had significantly higher scores in "appraisal" subscale DTS than control group (P = 0.005). Patients of both AD and SD groups had significantly higher scores in "positive beliefs" subscale of MCQ 30 than control group (P = 0.012 for AD group and P = 0. 001 for SD group). There was no significant difference between AD and SD groups in any MCQ-30 subscale and total scores (P = 0.440). CONCLUSIONS: Metacognitive regulation strategies are more considerable prediction than emotional regulation strategies in SD group than in AD group. Individuals with AD use alcohol as a means of both cognitive and emotional regulation strategy. PMID- 26495261 TI - An Extended Theory of Planned Behavior (TPB) Used to Predict Smoking Behavior Among a Sample of Iranian Medical Students. AB - BACKGROUND: Smoking among the youth is an important public health concern. Although several studies have investigated the correlates of smoking behavior, no theory-based study has particularly assessed this problem among medical students. OBJECTIVES: This study aimed to evaluate the efficacy of the extended theory of planned behavior (TPB) to predict smoking behavior among a sample of Iranian medical students. PATIENTS AND METHODS: This is a cross-sectional study carried out in Ahvaz, Iran, 2014. The data were collected through a self-administered questionnaire, which included items on demographics, smoking behavior, and components of the TPB model (attitude, subjective norms, perceived behavior control, and intention), and an added construct on smoking refusal skill. Data were analyzed using descriptive correlation, and linear regression statistics by SPSS, version 16. RESULTS: One hundred and seventy medical students with a mean age of 21.25 (SD = 2.9) years were enrolled in the study. Of them, 24 (13.5%) students were smokers. All components of the TPB model and smoking refusal skill were statistically significant as to intention to smoke (P < 0.001). The TPB constructs with and without smoking refusal skill accounted for 77% (adjusted R2) and 78% of the variance observed for intention to smoke, respectively. The results also revealed the highest weight for perceived behavior control (beta= 0.40). CONCLUSIONS: The findings of this study indicated that all TPB variables are useful tools for prediction of the smoking behaviors among students. Particularly, students' perceived behavioral control and attitudes towards smoking were found to be important determinants of smoking intentions. Thus, the findings could be used for planning effective tobacco control programs targeting University students. PMID- 26495263 TI - Heart, Lung and Vessels... but brain and hands too! The case for a novel journal in the cardiovascular scholarly arena. PMID- 26495262 TI - Metacognition and Body Image in Predicting Alexithymia in Substance Abusers. AB - BACKGROUND: Substance dependency is one of the biggest problems and worries of the world. It stunts the growth of society and causes various problems such as reduction in public health, increase in mortality, rise in social and domestic traumas, loss of educational and occupational opportunities, involvement with the judicial system, and development of the substance-abuse cycle. OBJECTIVES: The aim of this study was to determine the role of metacognition and body image in predicting alexithymia in substance abusers. PATIENTS AND METHODS: The research sample included addicts (males and females aged 10 to 70 years) who referred to the addiction treatment and counseling centers of three Iranian cities of Zahedan, Sari, and Neyriz. Participants were selected by random sampling. The metacognitive strategy questionnaire (MCQ-30), physical self-description questionnaire (PSDQ), and Toronto alexithymia scale (TAS-20) were used for data collection. The hypotheses were tested using the Pearson's correlation method and regression analysis. RESULTS: According to the results of the current study, the highest correlation was between alexithymia and the cognitive awareness subscale (r = 0.305; P < 0.01).There was no significant correlation between alexithymia and body image. Based on the multiple regression analysis, the three predictors explained 11% of the variance (R(2) = 0. 11, F = 3.981; P < 0.01). Cognitive awareness significantly predicted 9% of the variance (beta = 0.305; P < 0.01), and the other subscales predicted about 2%. CONCLUSIONS: These findings demonstrated that metacognition had an important role in predicting alexithymia in the substance abusers, which underscores the necessity of precautionary measures. PMID- 26495264 TI - Oral direct thrombin inhibition: a double-edged sword? AB - New oral anticoagulants have been shown to be not inferior to vitamin K antagonists in reducing thrombo-embolic events in patients with non-valvular atrial fibrillation and venous thrombo-embolism. However, those among them whichdirectly inhibit thrombin have been associated with greater risk of myocardial infarction. In this article we review the pleiotropic physiological effects of thrombin and their potential link with the observed greater incidence of myocardial infarction during therapy with oral direct thrombin inhibitors. On this basis, we believe that further studies are necessary to clear out doubts on the use of these drugs in the general population and, more specifically, in patients with coronary artery disease. For these reasons, in our opinion at present it may be prudent to especially caution high risk patients initiating therapy with a direct thrombin inhibitor (or those who are already taking it) about this possible risk. For patients with established coronary artery disease an alternative oral anticoagulant may be at present a better choice. PMID- 26495265 TI - Novel therapeutic and diagnostic management of heart transplant patients. AB - Heart transplantation was performed for the first time 40 years ago and it is now universally considered the "gold standard" treatment for individuals suffering from end-stage heart failure. The increased understanding of the molecular mechanisms and of the role of the immune system in allograft rejection led to an overall improvement of graft survival, which is now around 10 years. The introduction of novel immunosuppressive drugs reduced the rate of acute allograft rejection but did not improve significantly the long-term graft survival. In addition, adverse effects (e.g. infections, cancer and renal failure) associated with immunosuppressive drugs are increasing over time and may affect post transplantation outcomes. An immunosuppression-free protocol based on tolerance induction is the Holy Grail for heart transplant recipients, but it is still far beyond our reach. In this review, we discuss the landscape of immunological challenges that heart transplanted individuals face and we critically review the novel immunological approaches available to overcome these remaining issues. Some of the novel approaches, successfully tested in preclinical and clinical models, may lead to a prolongation of patient's and heart allograft survival. PMID- 26495266 TI - Clinical utility of semi-automated estimation of ejection fraction at the point of-care. AB - INTRODUCTION: To compare estimation of ejection fraction at the bedside by AutoEF compared with conventional methods and to assess feasibility and time consumption. METHODS: A total of 102 relatively hemodynanically stable mixed medical and surgical patients were included. All patients underwent ultrasonography of the heart at the bedside performed by a novice examiner. Three assessments of ejection fraction were made: 1) Expert eyeballing by a single specialist in cardiology and expert in echocardiography; 2) Manual planimetry by an experienced examiner; 3) AutoEF by a novice examiner with limited experience in echocardiography. RESULTS: Expert eyeballing of ejection fraction was performed in 100% of cases. Manual planimetry was possible in 89% of cases and AutoEF was possible in 83% of cases. The correlation between expert eyeballing and AutoEF was r=0.82, p < 0.001, for manual planimetry and for AutoEF it was r=0.82, p < 0.001; for expert eyeballing and manual planimetry it was r=0.80, p < 0.001. The mean time consumption for manual planimetry was 98 ( 90-106 ) seconds; correspondingly the mean time spent for AutoEF was 41 ( 36-46 ) seconds, which was significantly less (p < 0.001). CONCLUSIONS: AutoEF seems to be a valid supplement to the clinical assessment of ejection fraction in the hands of less experienced examiners, yielding result similar to manual planimetry with less time consumption and less intra-observer variability. However, manual editing may be required and training is thus recommended before AutoEF is applicable for use by novices. PMID- 26495267 TI - Paravertebral analgesia in transapical transcatheter aortic valve replacement. AB - INTRODUCTION: Transapical transcatheter aortic valve replacement is an option for patients who are not candidates for traditional aortic valve surgery but have severe aortic stenosis and unfavorable ileo-femoral anatomy. Epidural analgesia in these cases has been associated with improved morbidity and mortality. The following manuscript presents the findings of an initial clinical experience employing paravertebral analgesia for patients undergoing transapical transcatheter aortic valve replacement. METHODS: A retrospective review was performed of 61 transapical transcatheter aortic valve replacement cases over a two-year period from November 2012 through July 2014. Paravertebral analgesia was provided as left sided single injections covering 1-3 dermatome levels using 0.2% ropivicaine with supplemental clonidine to 48 patients. The following outcome metrics were collected: 1) peri-operative opiate administration, 2) rate of extubation in the operating room, 3) new atrial fibrillation, 4) duration of intensive care stay, 5) 30-day mortality. RESULTS: The mean opiate administration was less in patients with paravertebral analgesia (128.65mcg vs. 163.46mcg fentanyl, p value 0.05) and these patients were more frequently extubated in the operating room (83.3% vs. 46.2%, p-value 0.0107). Incidence of atrial fibrillation was less in patients who received paravertebral analgesia (18.8% vs. 75.0%, p-value 0.0048). There was a non-significant trend towards decreased intensive care stay in patients who received paravertebral analgesia (58.3 hrs vs 75.8 hrs, p value 0.35). There was no difference in 30-day mortality. No complications resulted from paravertebral analgesia. CONCLUSIONS: This is the first reported case series of paravertebral blockade in transapical transcatheter aortic valve replacement patients. The findings suggest that paravertebral single shot blocks are both safe and practical for use in this patient population. A formal prospective investigation of paravertebral analgesia in these patients is warranted. PMID- 26495268 TI - Nursing procedures during continuous renal replacement therapies: a national survey. AB - INTRODUCTION: The current role of nurses in the management of critically ill patients needing continuous renal replacement therapies is clearly fundamental. The care of these complex patients is typically shared by critical care and dialysis nurses: their precise duties may vary from country to country. METHODS: To clarify this issue we conducted a national-level survey at a recent Italian course on nursing practices during continuous renal replacement therapies. RESULTS: A total of 119 questionnaires were analysed. The participants, who were equally divided between critical care and dialysis nurses, came from 44 different hospitals and 35 Italian cities. Overall, 23% of participants answered that "the dialysis staff" were responsible for continuous renal replacement therapies in the Intensive Care Unit, while 39% answered "the critical care nurse", and 38% "a shared organization". Interestingly, less than the half of participants claimed specific continuous renal replacement therapies training was provided to employees before handling an acute dialysis machine. Finally, about 60% of participants had experience of extra-corporeal membrane oxygenation machines used in conjunction with continuous renal replacement therapies. CONCLUSIONS: Workload coordination and management of critically ill patients undergoing continuous renal replacement therapies in Italy is not standardized. At present, the duties of critical care and dialysis nurses vary significantly across the country. They frequently overlap or leave gaps in the assistance received by patients. The role of nurses involved in the care of continuous renal replacement therapies patients in Italy currently requires better organization, possibly starting with intensive standardized training and educational programs. PMID- 26495269 TI - Effects of hydrogen sulfide (H2S) on mesenteric perfusion in experimental induced intestinal ischemia in a porcine model. AB - INTRODUCTION: Insufficient mesenteric perfusion is a dramatic complication in critically ill patients. Hydrogen sulfide, a newly recognized endogenous gaseous mediator, acts as an intestinal vasoactive agent and seems to protect against mesenteric ischemic damage. We investigated whether sodium hydrogen sulfide, a hydrogen sulfide donor, can improve mesenteric perfusion in an experimental model of pigs, both in physiological and ischemic conditions. METHODS: The study was conducted at Careggi University Hospital (Florence, IT). Fourteen male domestic pigs (~10 Kg) were anesthetized and mechanically ventilated. Animals were randomized in control and ischemia groups. Mesenteric ischemia was induced with a positive end-expiratory pressure of 15 cmH2O. After mini-laparotomy, each animal received incremental doses of sodium hydrogen sulfide every 20 minutes. Perfusion of both the jejunal mucosa and sternal skin were measured by laser Doppler flowmeter, and systemic hemodynamic parameters were monitored. RESULTS: In the control group, sodium hydrogen sulfide was able to significantly improve the mesenteric perfusion, showing a 50% increase from the baseline blood flow. In the ischemia group, NaHS-induced a two-fold increase of the mesenteric post-ischemic perfusion with a recovery up to 70% of pre- positive end-expiratory pressure mesenteric blood flow. Sodium hydrogen sulfide did not directly or indirectly (by blood flow redistribution) affect the sternal skin microcirculation, heart rates, or mean arterial pressure, suggesting a tissue-specific micro-vascular action. CONCLUSIONS: In a porcine model, we observed a mesenteric perfusion recovery mediated by administration of hydrogen sulfide donor without affecting general hemodynamic. PMID- 26495270 TI - Impact of different dosage of protamine on heparin reversal during off-pump coronary artery bypass: a clinical study. AB - INTRODUCTION: Currently, a dose of protamine equal to 1 mg for each 100 units of heparin given is used to reverse the residual heparin activity following off-pump coronary artery bypass. We hypothesized that a 1:1 ratio (ratio of protamine to heparin) could be higher than necessary inducing post-operative disturbance of hemostasis. METHODS: Between January and March 2014 in 9 patients undergoing off pump coronary artery bypass, we evaluated the effect of a dose of protamine equal to 1 mg per 100 units of heparin (Total Calculated Dose) on hemostasis as evaluated by means of thromboelastomery. Two data analyses were performed: the first after the administration of 2/3 of the Total Calculated Dose of protamine and the second after the administration of the Total Calculated Dose of protamine. RESULTS: We found that the administration of 2/3 of Total Calculated Dose of protamine was always able to reverse the anticoagulant effect of heparin and that a significant clotting time elongation was induced by the infusion of the second part of the Total Calculated Dose of protamine. No modification in clot firmness was observed. CONCLUSIONS: The present study seems to suggest that the commonly applied ratio equal to 1:1 (ratio of protamine to heparin) could be higher than needed with potential and hazardous impacts on the efficacy of the coagulation system. PMID- 26495271 TI - Innovative cold storage of donor organs using the Paragonix Sherpa Pak TM devices. AB - INTRODUCTION: Currently, the gold standard for donor organ preservation in clinical organ transplantation consists of 3 plastic bags and an ice box. The first plastic bag includes the organ itself immersed in preservation solution (e.g. Celsior). This bag is put in a second bag filled with saline, and then these two are put in a third bag filled with saline which is then put in the ice box. The disadvantage of this method is that the organ usually gets too cold. It has been shown that the theoretical perfect temperature for organ preservation is 4 degrees C - 8 degrees C. While higher temperatures lead to hypoxic injury of the organ because the metabolism is not decreased efficiently, lower temperatures than 4 degrees C increase the risk of cold injury with protein denaturation. In the current study, we investigated a device that keeps the organ temperature consistently in the desired range of 4 degrees C - 8 degrees C and can potentially decrease cold injury to donor organs. METHODS: Three different ex vivo studies were performed with the Paragonix Sherpa PakTM devices: 1) the temperature of the fluid-filled device was measured for up to 30 hours at an outside temperature set at 22 degrees C, 2) the temperature of the fluid-filled device was measured for up to 30 hours at extreme outside temperatures set at -8 degrees C and 31 degrees C, 3) the temperature of a pig heart attached to the device was measured up to 12 hours. RESULTS: All studies showed that the Paragonix Sherpa PakTM can keep the temperature of the heart consistently between 4 degrees and 8 degrees C. CONCLUSIONS: The Paragonix Sherpa PakTM device may decrease cold injury of donor organs by maintaining the temperature consistently between 4 degrees C and 8 degrees C and therefore may decrease primary graft failure after organ transplantation. PMID- 26495272 TI - Subcutaneous immunoglobulin replacement therapy in a heart transplant recipient with severe recurrent infections. AB - Intravenous immunoglobulin has been shown to decrease the risk of post-transplant infections in heart recipients with IgG hypogammaglobulinemia, however the use of subcutaneous immunoglobulin has not been reported. We report on immune reconstitution, clinical efficacy and tolerability of subcutaneous immunoglobulin replacement therapy in a heart transplant recipient with secondary antibody deficiency. Maintenance of IgG levels, specific antibodies and control of infections were observed after change from intravenous immunoglobulin to subcutaneous immunoglobulin due to poor intravenous access. Recurrences of severe infections were observed when subcutaneous immunoglobulin infusions were stopped. Our observations suggest that subcutaneous immunoglobulin replacement therapy might be effective and well tolerated in selected heart recipients. PMID- 26495273 TI - Aortic to right atrial fistula secondary to chronic ruptured sinus of Valsalva aneurysm. PMID- 26495274 TI - Life-threatening shock due to inferior vena cava filter thrombosis. PMID- 26495275 TI - Intraoperative aortic dissection in a Turner syndrome patient. PMID- 26495276 TI - Risk assessment for a high-altitude alpinist with coronary artery disease. PMID- 26495277 TI - Water Properties Influencing the Abundance and Diversity of Denitrifiers on Eichhornia crassipes Roots: A Comparative Study from Different Effluents around Dianchi Lake, China. AB - To evaluate effects of environmental conditions on the abundance and communities of three denitrifying genes coding for nitrite (nirK, nirS) reductase and nitrous oxide (nosZ) reductase on the roots of Eichhornia crassipes from 11 rivers flowing into the northern part of Dianchi Lake. The results showed that the abundance and community composition of denitrifying genes on E. crassipes root varied with different rivers. The nirK gene copies abundance was always greater than that of nirS gene on the roots of E. crassipes, suggesting that the surface of E. crassipes roots growth in Dianchi Lake was more suitable for the growth of nirK-type denitrifying bacteria. The DGGE results showed significant differences in diversity of denitrifying genes on the roots of E. crassipes among the 11 rivers. Using redundancy analysis (RDA), the correlations of denitrifying microbial community compositions with environmental factors revealed that water temperature (T), dissolved oxygen (DO), and pH were relatively important environmental factors to modifying the community structure of the denitrifying genes attached to the root of E. crassipes. The results indicated that the specific environmental conditions related to different source of rivers would have a stronger impact on the development of denitrifier communities on E. crassipes roots. PMID- 26495278 TI - Changes in the Physiological Parameters of SbPIP1-Transformed Wheat Plants under Salt Stress. AB - The SbPIP1 gene is a new member of the plasma membrane major intrinsic gene family cloned from the euhalophyte Salicornia bigelovii Torr. In order to understand the physiological responses in plants that are mediated by the SbPIP1 gene, SbPIP1-overexpressing wheat lines and WT plants of the wheat cv. Ningmai 13 were treated with salt stress. Several physiological parameters, such as the proline content, the malondialdehyde (MDA) content, and the content of soluble sugars and proteins, were compared between SbPIP1-transformed lines and WT plants under normal growth or salt stress conditions. The results indicate that overexpression of the SbPIP1 gene can increase the accumulation of the osmolyte proline, decrease the MDA content, and enhance the soluble sugar biosynthesis in the early period but has no influence on the regulation of soluble protein biosynthesis in wheat. The results suggest that SbPIP1 contributes to salt tolerance by facilitating the accumulation of the osmolyte proline, increasing the antioxidant response, and increasing the biosynthesis of soluble sugar in the early period. These results indicate SbPIP1 plays an important role in the salt stress response. Overexpression of SbPIP1 might be used to improve the salt tolerance of important crop plants. PMID- 26495279 TI - The Calcium Sensor CBL-CIPK Is Involved in Plant's Response to Abiotic Stresses. AB - Abiotic stress halts the physiological and developmental process of plant. During stress condition, CBL-CIPK complex is identified as a primary element of calcium sensor to perceive environmental signals. Recent studies established that this complex regulates downstream targets like ion channels and transporters in adverse stages conditions. Crosstalks between the CBL-CIPK complex and different abiotic stresses can extend our research area, which can improve and increase the production of genetically modified crops in response to abiotic stresses. How this complex links with environmental signals and creates adjustable circumstances under unfavorable conditions is now one of the burning issues. Diverse studies are already underway to delineate this signalling mechanism underlying different interactions. Therefore, up to date experimental results should be concisely published, thus paving the way for further research. The present review will concisely recapitulate the recent and ongoing research progress of positive ions (Mg(2+), Na(+), and K(+)), negative ions (NO3 (-), PO4 (-)), and hormonal signalling, which are evolving from accumulating results of analyses of CBL and CIPK loss- or gain-of-function experiments in different species along with some progress and perspectives of our works. In a word, this review will give one step forward direction for more functional studies in this area. PMID- 26495280 TI - New developments in peritoneal fibroblast biology: implications for inflammation and fibrosis in peritoneal dialysis. AB - Uraemia and long-term peritoneal dialysis (PD) can lead to fibrotic thickening of the peritoneal membrane, which may limit its dialytic function. Peritoneal fibrosis is associated with the appearance of myofibroblasts and expansion of extracellular matrix. The extent of contribution of resident peritoneal fibroblasts to these changes is a matter of debate. Recent studies point to a significant heterogeneity and complexity of the peritoneal fibroblast population. Here, we review recent developments in peritoneal fibroblast biology and summarize the current knowledge on the involvement of peritoneal fibroblasts in peritoneal inflammation and fibrosis. PMID- 26495281 TI - Development and mining of a volatile organic compound database. AB - Volatile organic compounds (VOCs) are small molecules that exhibit high vapor pressure under ambient conditions and have low boiling points. Although VOCs contribute only a small proportion of the total metabolites produced by living organisms, they play an important role in chemical ecology specifically in the biological interactions between organisms and ecosystems. VOCs are also important in the health care field as they are presently used as a biomarker to detect various human diseases. Information on VOCs is scattered in the literature until now; however, there is still no available database describing VOCs and their biological activities. To attain this purpose, we have developed KNApSAcK Metabolite Ecology Database, which contains the information on the relationships between VOCs and their emitting organisms. The KNApSAcK Metabolite Ecology is also linked with the KNApSAcK Core and KNApSAcK Metabolite Activity Database to provide further information on the metabolites and their biological activities. The VOC database can be accessed online. PMID- 26495282 TI - Discovering distinct functional modules of specific cancer types using protein protein interaction networks. AB - BACKGROUND: The molecular profiles exhibited in different cancer types are very different; hence, discovering distinct functional modules associated with specific cancer types is very important to understand the distinct functions associated with them. Protein-protein interaction networks carry vital information about molecular interactions in cellular systems, and identification of functional modules (subgraphs) in these networks is one of the most important applications of biological network analysis. RESULTS: In this study, we developed a new graph theory based method to identify distinct functional modules from nine different cancer protein-protein interaction networks. The method is composed of three major steps: (i) extracting modules from protein-protein interaction networks using network clustering algorithms; (ii) identifying distinct subgraphs from the derived modules; and (iii) identifying distinct subgraph patterns from distinct subgraphs. The subgraph patterns were evaluated using experimentally determined cancer-specific protein-protein interaction data from the Ingenuity knowledgebase, to identify distinct functional modules that are specific to each cancer type. CONCLUSION: We identified cancer-type specific subgraph patterns that may represent the functional modules involved in the molecular pathogenesis of different cancer types. Our method can serve as an effective tool to discover cancer-type specific functional modules from large protein-protein interaction networks. PMID- 26495283 TI - Structure and antioxidant activity of soy protein isolate-dextran conjugates obtained by TiO2 photocatalysis. AB - The aim of this study was to investigate the structural characteristics and antioxidant activities of soy protein isolate- (SPI-) dextran conjugates obtained by TiO2 photocatalysis treatment. Results revealed that the UV-vis absorption and the fluorescence intensity increased as the photocatalytic power increased (P < 0.05). Higher photocatalytic power could promote the extent of glycation and the formation of high molecular weight SPI-dextran conjugates, which were evidenced by free amino group content and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The Fourier transform infrared (FT-IR) spectra suggested that the amide I, II, and III bands of SPI were altered by the glycation induced by TiO2 photocatalysis. Moreover, significant changes of secondary structure occurred in SPI-dextran conjugates. The alpha-helix, beta sheet, beta-turns, and random coil were changed from approximately 10.6%, 37.9%, 12.9%, and 38.6% to 3.8%, 10.4%, 17.7%, and 68.8%, respectively, after treatment at photocatalytic power of 1000 W. In addition, SPI-dextran conjugates obtained by TiO2 photocatalysis treatment exhibited high hydroxyl radical scavenging activity and possessed increased reducing power. All data indicated that TiO2 photocatalysis was an efficient method for promoting protein-polysaccharide copolymerisation. PMID- 26495284 TI - The potential of GMP-compliant platelet lysate to induce a permissive state for cardiovascular transdifferentiation in human mediastinal adipose tissue-derived mesenchymal stem cells. AB - Human adipose tissue-derived mesenchymal stem cells (ADMSCs) are considered eligible candidates for cardiovascular stem cell therapy applications due to their cardiac transdifferentiation potential and immunotolerance. Over the years, the in vitro culture of ADMSCs by platelet lysate (PL), a hemoderivate containing numerous growth factors and cytokines derived from platelet pools, has allowed achieving a safe and reproducible methodology to obtain high cell yield prior to clinical administration. Nevertheless, the biological properties of PL are still to be fully elucidated. In this brief report we show the potential ability of PL to induce a permissive state of cardiac-like transdifferentiation and to cause epigenetic modifications. RTPCR results indicate an upregulation of Cx43, SMA, c kit, and Thy-1 confirmed by immunofluorescence staining, compared to standard cultures with foetal bovine serum. Moreover, PL-cultured ADMSCs exhibit a remarkable increase of both acetylated histones 3 and 4, with a patient-dependent time trend, and methylation at lysine 9 on histone 3 preceding the acetylation. Expression levels of p300 and SIRT-1, two major regulators of histone 3, are also upregulated after treatment with PL. In conclusion, PL could unravel novel biological properties beyond its routine employment in noncardiac applications, providing new insights into the plasticity of human ADMSCs. PMID- 26495285 TI - Does defensive medicine change the behaviors of vascular surgeons? A qualitative review. AB - Although in literature few successful claims have been shown in comparison with other medical specialties such as gynaecology and orthopaedics, vascular surgery is included among high-risk specialties. The high-risk of receiving medical claims may lead vascular surgeons to practice defensive medicine, as is normal in several other areas of clinical practice. No studies are available to our knowledge of the incidence of defensive medicine in the field of vascular surgery. Taking into consideration the scarce amount of information, the authors provide a critical discussion regarding the application of defensive medicine behaviour among vascular surgeons. PMID- 26495286 TI - Hemodynamic and biologic determinates of arteriovenous fistula outcomes in renal failure patients. AB - The outcome of patients with end-stage renal disease on hemodialysis depends on a functioning vascular access. Although a variety of access options are available, the arteriovenous fistula remains the best vascular access. Unfortunately the success rate of mature fistula use remains poor. The creation of an arteriovenous fistula is followed by altered hemodynamic and biological changes that may result in neointimal hyperplasia and eventual venous stenosis. This review provides an overview of these changes and the needed research to provide a long lasting vascular access and hence improve outcomes for patients with end-stage renal disease. PMID- 26495288 TI - Using multicriteria decision analysis to support research priority setting in biomedical translational research projects. AB - Translational research is conducted to achieve a predefined set of economic or societal goals. As a result, investment decisions on where available resources have the highest potential in achieving these goals have to be made. In this paper, we first describe how multicriteria decision analysis can assist in defining the decision context and in ensuring that all relevant aspects of the decision problem are incorporated in the decision making process. We then present the results of a case study to support priority setting in a translational research consortium aimed at reducing the burden of disease of type 2 diabetes. During problem structuring, we identified four research alternatives (primary, secondary, tertiary microvascular, and tertiary macrovascular prevention) and a set of six decision criteria. Scoring of these alternatives against the criteria was done using a combination of expert judgement and previously published data. Lastly, decision analysis was performed using stochastic multicriteria acceptability analysis, which allows for the combined use of numerical and ordinal data. We found that the development of novel techniques applied in secondary prevention would be a poor investment of research funds. The ranking of the remaining alternatives was however strongly dependent on the decision maker's preferences for certain criteria. PMID- 26495287 TI - Dissemination of health-related research among scientists in three countries: access to resources and current practices. AB - OBJECTIVES: In public health and clinical settings insufficient dissemination of evidence-based practices limits the reach of new discoveries to broad populations. This study aimed to describe characteristics of the dissemination process by researchers across three countries (Brazil, United Kingdom, and United States), explore how designing for dissemination practices has been used, and analyze factors associated with dissemination. METHODS: A similar online survey was used to query researchers across the three countries; data were pooled to draw cross-country conclusions. FINDINGS: This study identified similarities and differences between countries. Importance of dissemination to nonresearcher audiences was widely recognized as important; however, traditional academic venues were the main dissemination method. Several factors were associated with self-rated dissemination effort in the pooled sample, but these predictive factors (e.g., support and resources for dissemination) had low prevalence. Less than one-third of researchers rated their level of effort for dissemination as excellent. Respondents reported limited support and resources to make it easier for researchers who might want to disseminate their findings. CONCLUSION: Though intentions show the importance of dissemination, researchers across countries lack supports to increase dissemination efforts. Additional resources and training in designing for dissemination along with improved partnerships could help bridge the research-practice gap. PMID- 26495289 TI - Comparison of five 2nd-generation supraglottic airway devices for airway management performed by novice military operators. AB - OBJECTIVES: Five different second-generation supraglottic airway devices, ProSeal LMA, Supreme LMA, i-gel, SLIPA, and Laryngeal Tube Suction-D, were studied. Operators were inexperienced users with a military background, combat lifesavers, nurses, and physicians. METHODS: This was a prospective, randomized, single blinded study. Devices were inserted in the operating room in low light conditions after induction of general anesthesia. Primary outcome was successful insertion on the first attempt while secondary aims were insertion time, number of attempts, oropharyngeal seal pressure, ease of insertion, fibre optic position of device, efficacy of ventilation, and intraoperative trauma or regurgitation of gastric contents. RESULTS: In total, 505 patients were studied. First-attempt insertion success rate was higher in the Supreme LMA (96%), i-gel (87.9%), and ProSeal LMA (85.9%) groups than in the Laryngeal Tube Suction-D (80.6%) and SLIPA (69.4%) groups. Insertion time was shortest in the Supreme LMA (70.4 +/- 32.5 s) and i-gel (74.4 +/- 41.1 s) groups (p < 0.001). Oropharyngeal seal pressures were higher in the Laryngeal Tube Suction-D and ProSeal LMA groups than in other three devices. CONCLUSIONS: Most study parameters for the Supreme LMA and i-gel were found to be superior to the other three tested supraglottic airway devices when inserted by novice military operators. PMID- 26495290 TI - Vulnerability assessment and application of bacterial technology on urban rivers for pollution eradication. AB - To protect against the environmental pollution, the present research was undertaken to enumerate the Bacterial Technologies (BTs) on the restoration of polluted urban rivers, that is, Fenghu-Song Yang River (FSR) and Xuxi River (XXR). Experimental research accounted for the physiochemical parameters (pH; temperature; dissolved oxygen (DO); chemical oxygen demand (COD); total phosphorus (TP); total nitrogen (TN); and ammonia nitrogen (NH3N)) before and after the BT operation. The results declared that the BT is efficient to restore the polluted rivers up to reliable condition. These results were analyzed by using multivariate statistical techniques (principal component analysis (PCA) and cluster analysis (CA)). These techniques interpreted the complex data sets and expressed the point source information about the water quality of these rivers at SA5, SA6, and SB3 under highly polluted regions. For better understanding, water quality index (WQI) was applied to compute the single numeric value. WQI results are evidence of the above results which prove the water quality of both rivers faced under outrageous condition (below 50 WQI scores) before the BT treatment, but, after the treatment, the rivers were restored from fair to good level (above 50 WQI scores) and overall output of these scores was quite similar to detect the point source of pollution. These results described an abrupt recovery of the urban rivers up to reliable condition for aquatic organism and clear effluents from the rivers. PMID- 26495291 TI - METSP: a maximum-entropy classifier based text mining tool for transporter substrate identification with semistructured text. AB - The substrates of a transporter are not only useful for inferring function of the transporter, but also important to discover compound-compound interaction and to reconstruct metabolic pathway. Though plenty of data has been accumulated with the developing of new technologies such as in vitro transporter assays, the search for substrates of transporters is far from complete. In this article, we introduce METSP, a maximum-entropy classifier devoted to retrieve transporter substrate pairs (TSPs) from semistructured text. Based on the high quality annotation from UniProt, METSP achieves high precision and recall in cross validation experiments. When METSP is applied to 182,829 human transporter annotation sentences in UniProt, it identifies 3942 sentences with transporter and compound information. Finally, 1547 confidential human TSPs are identified for further manual curation, among which 58.37% pairs with novel substrates not annotated in public transporter databases. METSP is the first efficient tool to extract TSPs from semistructured annotation text in UniProt. This tool can help to determine the precise substrates and drugs of transporters, thus facilitating drug-target prediction, metabolic network reconstruction, and literature classification. PMID- 26495292 TI - Cellular metabolic network analysis: discovering important reactions in Treponema pallidum. AB - T. pallidum, the syphilis-causing pathogen, performs very differently in metabolism compared with other bacterial pathogens. The desire for safe and effective vaccine of syphilis requests identification of important steps in T. pallidum's metabolism. Here, we apply Flux Balance Analysis to represent the reactions quantitatively. Thus, it is possible to cluster all reactions in T. pallidum. By calculating minimal cut sets and analyzing topological structure for the metabolic network of T. pallidum, critical reactions are identified. As a comparison, we also apply the analytical approaches to the metabolic network of H. pylori to find coregulated drug targets and unique drug targets for different microorganisms. Based on the clustering results, all reactions are further classified into various roles. Therefore, the general picture of their metabolic network is obtained and two types of reactions, both of which are involved in nucleic acid metabolism, are found to be essential for T. pallidum. It is also discovered that both hubs of reactions and the isolated reactions in purine and pyrimidine metabolisms play important roles in T. pallidum. These reactions could be potential drug targets for treating syphilis. PMID- 26495293 TI - Heart rate variability in shift workers: responses to orthostatism and relationships with anthropometry, body composition, and blood pressure. AB - In order to investigate the response of heart rate variability (HRV) components to postural change and their association with cardiovascular risk factors in shift workers, a cross-sectional study with 438 Brazilian males rotating shift workers was done. Anthropometric, body composition, and clinical measures were collected. Electrocardiogram was recorded for 3 minutes, in the supine and orthostatic position, and HRV components were extracted. Descriptive analyses showed that mean values of body mass index, waist circumference (WC), waist-to height ratio, visceral fat area (VFA), and blood pressure (BP) were higher than the reference values. In the regression model, age, WC, VFA, and systolic BP showed negative association with HRV components. These findings suggest the need for determining effective strategies for the evaluation and promotion of health among shift workers focused on the altered variables. PMID- 26495294 TI - Breast cancer by age at diagnosis in the Gharbiah, Egypt, population-based registry compared to the United States Surveillance, Epidemiology, and End Results Program, 2004-2008. AB - OBJECTIVE: Although breast cancers (BCs) in young women often display more aggressive features, younger women are generally not screened for early detection. It is important to understand the characteristics of young onset breast cancer to increase awareness in this population. This analysis includes all ages, with emphasis placed on younger onset BC in Egypt as compared to the United States. METHODS: BC cases in the Gharbiah cancer registry (GCR), Egypt, were compared to those in the Surveillance, Epidemiology, and End Results (SEER) database. This analysis included 3,819 cases from the GCR and 273,019 from SEER diagnosed 2004-2008. RESULTS: GCR cases were diagnosed at later stages, with <5% diagnosed at Stage I and 12% diagnosed at Stage IV. 48% of all SEER cases were diagnosed at Stage I, dropping to 30% among those <=40. Significant differences in age, tumor grade, hormone receptor status, histology, and stage exist between GCR and SEER BCs. After adjustment, GCR cases were nearly 45 times more likely to be diagnosed at stage III and 16 times more likely to be diagnosed at stage IV than SEER cases. CONCLUSIONS: Future research should examine ways to increase literacy about early detection and prompt therapy in young cases. PMID- 26495295 TI - Guided tissue regeneration in heart valve replacement: from preclinical research to first-in-human trials. AB - Heart valve tissue-guided regeneration aims to offer a functional and viable alternative to current prosthetic replacements. Not requiring previous cell seeding and conditioning in bioreactors, such exceptional tissue engineering approach is a very fascinating translational regenerative strategy. After in vivo implantation, decellularized heart valve scaffolds drive their same repopulation by recipient's cells for a prospective autologous-like tissue reconstruction, remodeling, and adaptation to the somatic growth of the patient. With such a viability, tissue-guided regenerated conduits can be delivered as off-the-shelf biodevices and possess all the potentialities for a long-lasting resolution of the dramatic inconvenience of heart valve diseases, both in children and in the elderly. A review on preclinical and clinical investigations of this therapeutic concept is provided with evaluation of the issues still to be well deliberated for an effective and safe in-human application. PMID- 26495296 TI - Full GMP-compliant validation of bone marrow-derived human CD133(+) cells as advanced therapy medicinal product for refractory ischemic cardiomyopathy. AB - According to the European Medicine Agency (EMA) regulatory frameworks, Advanced Therapy Medicinal Products (ATMP) represent a new category of drugs in which the active ingredient consists of cells, genes, or tissues. ATMP-CD133 has been widely investigated in controlled clinical trials for cardiovascular diseases, making CD133(+) cells one of the most well characterized cell-derived drugs in this field. To ensure high quality and safety standards for clinical use, the manufacturing process must be accomplished in certified facilities following standard operative procedures (SOPs). In the present work, we report the fully compliant GMP-grade production of ATMP-CD133 which aims to address the treatment of chronic refractory ischemic heart failure. Starting from bone marrow (BM), ATMP-CD133 manufacturing output yielded a median of 6.66 * 10(6) of CD133(+) cells (range 2.85 * 10(6)-30.84 * 10(6)), with a viability ranged between 96,03% and 99,97% (median 99,87%) and a median purity of CD133(+) cells of 90,60% (range 81,40%-96,20%). Based on these results we defined our final release criteria for ATMP-CD133: purity >= 70%, viability >= 80%, cellularity between 1 and 12 * 10(6) cells, sterile, and endotoxin-free. The abovementioned criteria are currently applied in our Phase I clinical trial (RECARDIO Trial). PMID- 26495297 TI - Development of self-compressing BLSOM for comprehensive analysis of big sequence data. AB - With the remarkable increase in genomic sequence data from various organisms, novel tools are needed for comprehensive analyses of available big sequence data. We previously developed a Batch-Learning Self-Organizing Map (BLSOM), which can cluster genomic fragment sequences according to phylotype solely dependent on oligonucleotide composition and applied to genome and metagenomic studies. BLSOM is suitable for high-performance parallel-computing and can analyze big data simultaneously, but a large-scale BLSOM needs a large computational resource. We have developed Self-Compressing BLSOM (SC-BLSOM) for reduction of computation time, which allows us to carry out comprehensive analysis of big sequence data without the use of high-performance supercomputers. The strategy of SC-BLSOM is to hierarchically construct BLSOMs according to data class, such as phylotype. The first-layer BLSOM was constructed with each of the divided input data pieces that represents the data subclass, such as phylotype division, resulting in compression of the number of data pieces. The second BLSOM was constructed with a total of weight vectors obtained in the first-layer BLSOMs. We compared SC-BLSOM with the conventional BLSOM by analyzing bacterial genome sequences. SC-BLSOM could be constructed faster than BLSOM and cluster the sequences according to phylotype with high accuracy, showing the method's suitability for efficient knowledge discovery from big sequence data. PMID- 26495298 TI - Pain following craniotomy: reassessment of the available options. AB - Pain following craniotomy has frequently been neglected because of the notion that postcraniotomy patients do not experience severe pain. However a gradual change in this outlook is observed because of increased sensitivity of neuroanaesthesiologists and neurosurgeons toward acute postcraniotomy pain. Multiple modalities exist for treating this variety of pain each with its own share of advantages and disadvantages. However, individually none of these modalities has been proclaimed as the best and applicable universally. A considerable amount of dispute remains to ascertain the appropriate therapeutic regimen for treating postcraniotomy pain in spite of numerous trials using different drugs and their combinations. This review aims to highlight the genesis, characteristics, and different strategies that are undertaken for management of acute postcraniotomy pain. Chronic postcraniotomy pain which can be debilitating sequelae is also discussed concisely. PMID- 26495299 TI - Comparison between procalcitonin, brain natriuretic peptide, and uric acid in children with cardiomyopathy and controls. AB - OBJECTIVE: This study was performed to determine the level of procalcitonin, Brain Natriuretic Peptide (BNP), and uric acid in children with cardiomyopathy in comparison with controls and the association with echocardiographic findings. METHODS: The levels of BNP, procalcitonin, and serum uric acid were measured and the amounts of biomarkers compared with echocardiographic findings. RESULTS: In this study mean age of participants was the same (p=0.321). The majority of echocardiographic indices in left and right heart have different means in case and controls (p<0.05). Means of BNP, procalcitonin, and uric acid were 213.814 +/ 309.601, 9.326 +/- 3.881, and 6.846 +/- 1.814 for case group and 2.76 +/- 1.013, 1.851 +/- 1.466, and 3.317 +/- 0.924 for control (p<0.001), respectively. In the patients group there was relationship of Ross classification with BNP (chi (2) = 15.845, p<0.05) and with age (chi (2) = 8.946, p<0.05). For uric acid and procalcitonin no significant relationships were observed. CONCLUSIONS: Procalcitonin, uric acid, and BNP had significant relationship with many echocardiographic findings in participants. For patients, procalcitonin did not show correlation. The severity of illness based on the Ross classification showed significant correlation with BNP level and age in patients. PMID- 26495300 TI - EMRlog method for computer security for electronic medical records with logic and data mining. AB - The proper functioning of a hospital computer system is an arduous work for managers and staff. However, inconsistent policies are frequent and can produce enormous problems, such as stolen information, frequent failures, and loss of the entire or part of the hospital data. This paper presents a new method named EMRlog for computer security systems in hospitals. EMRlog is focused on two kinds of security policies: directive and implemented policies. Security policies are applied to computer systems that handle huge amounts of information such as databases, applications, and medical records. Firstly, a syntactic verification step is applied by using predicate logic. Then data mining techniques are used to detect which security policies have really been implemented by the computer systems staff. Subsequently, consistency is verified in both kinds of policies; in addition these subsets are contrasted and validated. This is performed by an automatic theorem prover. Thus, many kinds of vulnerabilities can be removed for achieving a safer computer system. PMID- 26495301 TI - Glutamine: an obligatory parenteral nutrition substrate in critical care therapy. AB - Critical illness is characterized by glutamine depletion owing to increased metabolic demand. Glutamine is essential to maintain intestinal integrity and function, sustain immunologic response, and maintain antioxidative balance. Insufficient endogenous availability of glutamine may impair outcome in critically ill patients. Consequently, glutamine has been considered to be a conditionally essential amino acid and a necessary component to complete any parenteral nutrition regimen. Recently, this scientifically sound recommendation has been questioned, primarily based on controversial findings from a large multicentre study published in 2013 that evoked considerable uncertainty among clinicians. The present review was conceived to clarify the most important questions surrounding glutamine supplementation in critical care. This was achieved by addressing the role of glutamine in the pathophysiology of critical illness, summarizing recent clinical studies in patients receiving parenteral nutrition with intravenous glutamine, and describing practical concepts for providing parenteral glutamine in critical care. PMID- 26495302 TI - The potential role of NFAT5 and osmolarity in peritoneal injury. AB - A rise in osmotic concentration (osmolarity) activates the transcription factor Nuclear Factor of Activated T Cells 5 (NFAT5, also known as Tonicity-responsive Enhancer Binding Protein, TonEBP). This is part of a regulatory mechanism of cells adjusting to environments of high osmolarity. Under physiological conditions these are particularly important in the kidney. Activation of NFAT5 results in the modulation of various genes including some which promote inflammation. The osmolarity increases in patients with renal failure. Additionally, in peritoneal dialysis the cells of the peritoneal cavity are repeatedly exposed to a rise and fall in osmotic concentrations. Here we review the current information about NFAT5 activation in uremic patients and patients on peritoneal dialysis. We suggest that high osmolarity promotes injury in the "uremic" milieu, which results in inflammation locally in the peritoneal membrane, but most likely also in the systemic circulation. PMID- 26495303 TI - True unipolar ECG machine for Wilson Central Terminal measurements. AB - Since its invention (more than 80 years ago), modern electrocardiography has employed a supposedly stable voltage reference (with little variation during the cardiac cycle) for half of the signals. This reference, known by the name of "Wilson Central Terminal" in honor of its inventor, is obtained by averaging the three active limb electrode voltages measured with respect to the return ground electrode. However, concerns have been raised by researchers about problems (biasing and misdiagnosis) associated with the ambiguous value and behavior of this reference voltage, which requires perfect and balanced contact of at least four electrodes to work properly. The Wilson Central Terminal has received scant research attention in the last few decades even though consideration of recent widespread medical practice (limb electrodes are repositioned closer to the torso for resting electrocardiography) has also sparkled concerns about the validity and diagnostic fitness of leads not referred to the Wilson Central Terminal. Using a true unipolar electrocardiography device capable of precisely measuring the Wilson Central Terminal, we show its unpredictable variability during the cardiac cycle and confirm that the integrity of cardinal leads is compromised as well as the Wilson Central Terminal when limb electrodes are placed close to the torso. PMID- 26495305 TI - An update on renal artery denervation and its clinical impact on hypertensive disease. AB - Hypertension is a globally prevalent condition, with a heavy clinical and economic burden. It is the predominant risk factor for premature cardiovascular and cerebrovascular disease, and is associated with a variety of clinical disorders including stroke, congestive cardiac failure, ischaemic heart disease, chronic renal failure, and peripheral arterial disease. A significant subset of hypertensive patients have resistant hypertensive disease. In this group of patients, catheter-based renal artery denervation has emerged as a potential therapy, with favourable clinical efficacy and safety in early trials. Additional benefits of this therapy are also being identified and include effects on left ventricular remodeling, cardiac performance, and symptom status in congestive cardiac failure. Utility of renal denervation for the management of resistant hypertension, however, has become controversial since the release of the Symplicity HTN-3 trial, the first large-scale blinded randomised study investigating the efficacy and safety of renal artery denervation. The aim of this paper is to evaluate the history, utility, and clinical efficacy of renal artery denervation technology, including an in-depth appraisal of the current literature and principal trials. PMID- 26495304 TI - Vitamin D can ameliorate chlorhexidine gluconate-induced peritoneal fibrosis and functional deterioration through the inhibition of epithelial-to-mesenchymal transition of mesothelial cells. AB - BACKGROUND: Peritoneal dialysis (PD) can induce fibrosis and functional alterations in PD patients' peritoneal membranes, due to long-term unphysiological dialysate exposure, partially occurring via triggering of epithelial-to-mesenchymal transition (EMT) in peritoneal mesothelial cells (MCs). Vitamin D can ameliorate these negative effects; however, the mechanism remains unexplored. Therefore, we investigated its possible links to MCs EMT inhibition. METHODS: Peritoneal fibrosis was established in Sprague-Dawley rats by chlorhexidine gluconate (CG) intraperitoneal injection for 21 days, with and without 1alpha,25(OH)2D3 treatment. Morphological and functional evaluation and western blot analysis of EMT marker were performed upon peritoneum tissue. In vitro study was also performed in a primary human peritoneal MC culture system; MCs were incubated with transforming growth factor-beta1 (TGF-beta1) in the absence or presence of 1alpha,25(OH)2D3. EMT marker expression, migration activities, and cytoskeleton redistribution of MCs were determined. RESULTS: 1alpha,25(OH)2D3 ameliorated CG-induced morphological and functional deterioration in animal model, along with CG-induced upregulation of alpha-SMA and downregulation of E-cadherin expression. Meanwhile, 1alpha,25(OH)2D3 also ameliorated TGF-beta1-induced decrease in E-cadherin expression, increase in Snai1 and alpha-SMA expression, intracellular F-actin redistribution, and migration activity in vitro. CONCLUSION: 1alpha,25(OH)2D3 can ameliorate CG induced peritoneal fibrosis and attenuate functional deterioration through inhibiting MC EMT. PMID- 26495306 TI - Utility of a gum-elastic bougie for difficult airway management in infants: a simulation-based crossover analysis. AB - BACKGROUND: Direct laryngoscopy with the Miller laryngoscope (Mil) for infant tracheal intubation is often difficult to use even for skilled professionals. We performed a simulation trial evaluating the utility of a tracheal tube introducer (gum-elastic bougie (GEB)) in a simulated, difficult infant airway model. METHODS: Fifteen anesthesiologists performed tracheal intubation on an infant manikin at three different degrees of difficulty (normal [Cormack-Lehane grades (Cormack) 1-2], cervical stabilization [Cormack 2-3], and anteflexion [Cormack 3 4]) with or without a GEB, intubation success rate, and intubation time. RESULTS: In the normal and cervical stabilization trials, all intubation attempts were successful regardless of whether or not the GEB was used. In contrast, only one participant succeeded in tracheal intubation without the GEB in the anteflexion trial; the success rate significantly improved with the GEB (P = 0.005). Intubation time did not significantly change under the normal trial with or without the GEB (without, 12.7 +/- 3.8 seconds; with, 13.4 +/- 3.6 seconds) but was significantly shorter in the cervical stabilization and anteflexion trials with the GEB. CONCLUSION: GEB use shortened the intubation time and improved the success rate of difficult infant tracheal intubation by anesthesiologists in simulations. PMID- 26495307 TI - Cross-omics comparison of stress responses in mesothelial cells exposed to heat- versus filter-sterilized peritoneal dialysis fluids. AB - Recent research suggests that cytoprotective responses, such as expression of heat-shock proteins, might be inadequately induced in mesothelial cells by heat sterilized peritoneal dialysis (PD) fluids. This study compares transcriptome data and multiple protein expression profiles for providing new insight into regulatory mechanisms. Two-dimensional difference gel electrophoresis (2D-DIGE) based proteomics and topic defined gene expression microarray-based transcriptomics techniques were used to evaluate stress responses in human omental peritoneal mesothelial cells in response to heat- or filter-sterilized PD fluids. Data from selected heat-shock proteins were validated by 2D western-blot analysis. Comparison of proteomics and transcriptomics data discriminated differentially regulated protein abundance into groups depending on correlating or noncorrelating transcripts. Inadequate abundance of several heat-shock proteins following exposure to heat-sterilized PD fluids is not reflected on the mRNA level indicating interference beyond transcriptional regulation. For the first time, this study describes evidence for posttranscriptional inadequacy of heat-shock protein expression by heat-sterilized PD fluids as a novel cytotoxic property. Cross-omics technologies introduce a novel way of understanding PDF bioincompatibility and searching for new interventions to reestablish adequate cytoprotective responses. PMID- 26495308 TI - Respiratory strategies and airway management in patients with pulmonary alveolar proteinosis: a review. AB - BACKGROUND: Pulmonary alveolar proteinosis is a rare disorder characterized by a large accumulation of lipoproteinaceous material within the alveoli. This causes respiratory failure due to a restriction of gas exchange and changes in the ventilation/perfusion ratio. Treatment methods include noninvasive pharmacological approaches and invasive procedures, such as whole-lung lavage under general anesthesia. METHODS: Based on the literature search using free-term key words, we have analyzed published articles concerning the perioperative management of adult and pediatric patients with pulmonary alveolar proteinosis. RESULTS AND DISCUSSION: In total, 184 publications were analyzed. Only a few manuscripts were related to anesthetic, respiratory, and airway management in patients suffering from pulmonary alveolar proteinosis. Airway should be strictly separated using a double-lumen tube. Respiratory strategies involve the use of manual clapping, continuous positive airway pressure, high-frequency jet ventilation of the affected lung, and employment of venovenous extracorporeal membrane oxygenation in the most serious of cases. CONCLUSION: The goal of this review is to summarize the current published information about an anesthetic management strategy with a focus on airway management, ventilation, and oxygenation techniques in PAP patients. PMID- 26495309 TI - Can acute pain treatment reduce postsurgical comorbidity after breast cancer surgery? A literature review. AB - Regional analgesia, opioids, and several oral analgesics are commonly used for the treatment of acute pain after breast cancer surgery. While all of these treatments can suppress the acute postsurgical pain, there is growing evidence that suggests that the postsurgical comorbidity will differ in accordance with the type of analgesic used during the surgery. Our current study reviewed the effect of analgesics used for acute pain treatments on the major comorbidities that occur after breast cancer surgery. A considerable number of clinical studies have been performed to investigate the relationship between the acute analgesic regimen and common comorbidities, including inadequate quality of recovery after the surgery, persistent postsurgical pain, and cancer recurrence. Previous studies have shown that the choice of the analgesic modality does affect the postsurgical comorbidity. In general, the use of regional analgesics has a beneficial effect on the occurrence of comorbidity. In order to determine the best analgesic choice after breast cancer surgery, prospective studies that are based on a clear definition of the comorbidity state will need to be undertaken in the future. PMID- 26495310 TI - Systematic analysis of the associations between adverse drug reactions and pathways. AB - Adverse drug reactions (ADRs) are responsible for drug candidate failure during clinical trials. It is crucial to investigate biological pathways contributing to ADRs. Here, we applied a large-scale analysis to identify overrepresented ADR pathway combinations through merging clinical phenotypic data, biological pathway data, and drug-target relations. Evaluation was performed by scientific literature review and defining a pathway-based ADR-ADR similarity measure. The results showed that our method is efficient for finding the associations between ADRs and pathways. To more systematically understand the mechanisms of ADRs, we constructed an ADR-pathway network and an ADR-ADR network. Through network analysis on biology and pharmacology, it was found that frequent ADRs were associated with more pathways than infrequent and rare ADRs. Moreover, environmental information processing pathways contributed most to the observed ADRs. Integrating the system organ class of ADRs, we found that most classes tended to interact with other classes instead of themselves. ADR classes were distributed promiscuously in all the ADR cliques. These results reflected that drug perturbation to a certain pathway can cause changes in multiple organs, rather than in one specific organ. Our work not only provides a global view of the associations between ADRs and pathways, but also is helpful to understand the mechanisms of ADRs. PMID- 26495311 TI - Analysis of chemical properties of edible and medicinal ginger by metabolomics approach. AB - In traditional herbal medicine, comprehensive understanding of bioactive constituent is important in order to analyze its true medicinal function. We investigated the chemical properties of medicinal and edible ginger cultivars using a liquid-chromatography mass spectrometry (LC-MS) approach. Our PCA results indicate the importance of acetylated derivatives of gingerol, not gingerol or shogaol, as the medicinal indicator. A newly developed ginger cultivar, Z. officinale cv. Ogawa Umare or "Ogawa Umare" (OG), contains more active ingredients, showing properties as a new resource for the production of herbal medicines derived from ginger in terms of its chemical constituents and rhizome yield. PMID- 26495312 TI - Role of ketamine in acute postoperative pain management: a narrative review. AB - OBJECTIVES: The objective of this narrative review was to examine the usage of ketamine as a postoperative analgesic agent across a wide variety of surgeries. DESIGN: A literature search was performed using the phrases "ketamine" and "postoperative pain." The authors analyzed the studies that involved testing ketamine's effectiveness at controlling postoperative pain. Effectiveness was assessed through various outcomes such as the amount of opiate consumption, visual analog scale (VAS) pain scores, and persistent postoperative pain at long term follow-up. RESULTS: While many different administration protocols were evaluated, delivering ketamine both as a pre- or perioperative bolus and postoperative infusion for up to 48 hours appeared to be the most effective. These effects are dose-dependent. However, a number of studies analyzed showed no benefit in using ketamine versus placebo for controlling postoperative pain. While ketamine is a safe and well-tolerated drug, it does have adverse effects, and there are concerns for possible neurotoxicity and effects on memory. CONCLUSIONS: In a number of limited situations, ketamine has shown some efficacy in controlling postoperative pain and decreasing opioid consumption. More randomized controlled trials are necessary to determine the surgical procedures and administrations (i.e., intravenous, epidural) that ketamine is best suited for. PMID- 26495313 TI - Evaluation of natural materials as exogenous carbon sources for biological treatment of low carbon-to-nitrogen wastewater. AB - In the bacterial processes involved in the mitigation of nitrogen pollution, an adequately high carbon-to-nitrogen (C : N) ratio is key to sustain denitrification. We evaluated three natural materials (woodchips, barley grains, and peanut shells) as carbon sources for low C : N wastewater. The amount of organic matter released from these materials to aqueous media was evaluated, as well as their pollution swapping potential by measuring the release of total Kjeldahl nitrogen, N-NH4 (+), NO2 (-), and NO3 (-), and total phosphorous. Barley grains yielded the highest amount of organic matter, which also showed to be the most easily biodegradable. Woodchips and peanut shells released carbon rather steadily and so they would not require frequent replenishment from biological reactors. These materials produced eluates with lower concentrations of nutrients than the leachates from barley grains. However, as woodchips yielded lower amounts of suspended solids, they constitute an adequate exogenous source for the biological treatment of carbon-deficient effluents. PMID- 26495314 TI - The regulation by phenolic compounds of soil organic matter dynamics under a changing environment. AB - Phenolics are the most abundant plant metabolites and are believed to decompose slowly in soils compared to other soil organic matter (SOM). Thus, they have often been considered as a slow carbon (C) pool in soil dynamics models. Here, however, we review changes in our concept about the turnover rate of phenolics and quantification of different types of phenolics in soils. Also, we synthesize current research on the degradation of phenolics and their regulatory effects on decomposition. Environmental changes, such as elevated CO2, warming, nitrogen (N) deposition, and drought, could influence the production and form of phenolics, leading to a change in SOM dynamics, and thus we also review the fate of phenolics under environmental disturbances. Finally, we propose the use of phenolics as a tool to control rates of SOM decomposition to stabilize organic carbon in ecosystems. Further studies to clarify the role of phenolics in SOM dynamics should include improving quantification methods, elucidating the relationship between phenolics and soil microorganisms, and determining the interactive effects of combinations of environmental changes on the phenolics production and degradation and subsequent impact on SOM processing. PMID- 26495315 TI - Effect of chitosan coating with cinnamon oil on the quality and physiological attributes of China jujube fruits. AB - Effects of chitosan coating with cinnamon oil on the physiological attributes and preservation quality of China jujube fruits during storage at 4 degrees C for 60 days were investigated. Results indicated that weight loss and decay of jujube fruits were significantly reduced by chitosan-oil coating during the period of 60 day storage, which also exhibited a quite beneficial effect on maintaining the sensory quality for jujube fruits. Meanwhile, the contents of vitamin C and titratable acid decreased to 3.08 mg.g(-1) and 0.342% for the fruits treated by chitosan-oil coating (1.0% + 0.10%), respectively. Polyphenol oxidase, superoxide dismutase, and peroxidase activities were 13.40 U.g(-1), 14.53 U.g(-1), and 63.6 U.g(-1) at the end of storage, respectively. The contents of total soluble phenolics and MDA were 34.51 mg.g(-1) and 19.43 MUmol.g(-1) for the combined coating treated samples and control fruits, respectively. These results suggested that the chitosan-oil coating might be recognized as one efficiency technology on the preservation quality of jujube fruits during the storage time. PMID- 26495316 TI - microRNA regulation of peritoneal cavity homeostasis in peritoneal dialysis. AB - Preservation of peritoneal cavity homeostasis and peritoneal membrane function is critical for long-term peritoneal dialysis (PD) treatment. Several microRNAs (miRNAs) have been implicated in the regulation of key molecular pathways driving peritoneal membrane alterations leading to PD failure. miRNAs regulate the expression of the majority of protein coding genes in the human genome, thereby affecting most biochemical pathways implicated in cellular homeostasis. In this review, we report published findings on miRNAs and PD therapy, with emphasis on evidence for changes in peritoneal miRNA expression during long-term PD treatment. Recent work indicates that PD effluent- (PDE-) derived cells change their miRNA expression throughout the course of PD therapy, contributing to the loss of peritoneal cavity homeostasis and peritoneal membrane function. Changes in miRNA expression profiles will alter regulation of key molecular pathways, with the potential to cause profound effects on peritoneal cavity homeostasis during PD treatment. However, research to date has mainly adopted a literature based miRNA-candidate methodology drawing conclusions from modest numbers of patient-derived samples. Therefore, the study of miRNA expression during PD therapy remains a promising field of research to understand the mechanisms involved in basic peritoneal cell homeostasis and PD failure. PMID- 26495317 TI - Near-infrared spectroscopy for the evaluation of anesthetic depth. AB - The standard-of-care guidelines published by the American Society of Anesthesiologists (ASA) recommend monitoring of pulse oximetry, blood pressure, heart rate, and end tidal CO2 during the use of anesthesia and sedation. This information can help to identify adverse events that may occur during procedures. However, these parameters are not specific to the effects of anesthetics or sedatives, and therefore they offer little, to no, real time information regarding the effects of those agents and do not give the clinician the lead-time necessary to prevent patient "awareness." Since no "gold-standard" method is available to continuously, reliably, and effectively monitor the effects of sedatives and anesthetics, such a method is greatly needed. Investigation of the use of functional near-infrared spectroscopy (fNIRS) as a method for anesthesia or sedation monitoring and for the assessment of the effects of various anesthetic drugs on cerebral oxygenation has started to be conducted. The objective of this paper is to provide a thorough review of the currently available published scientific studies regarding the use of fNIRS in the fields of anesthesia and sedation monitoring, comment on their findings, and discuss the future work required for the translation of this technology to the clinical setting. PMID- 26495318 TI - A novel reference plasmid for the qualitative detection of genetically modified rice in food and feed. AB - Rice is one of the most important food crops in the world. Genetically modified (GM) technology has been used in rice to confer herbicide tolerance and pathogen or insect resistance. China invests heavily in research on GM rice. By the end of 2014, at least 250 transgenic rice lines had been developed in China. To monitor the presence of GM rice in food and feed, we collected information on foreign elements from 250 transgenic rice lines and found 5 elements, including the Agrobacterium tumefaciens nopaline synthase terminator (T-NOS), the cauliflower mosaic virus 35S promoter (CaMV35S), the ubiquitin gene (Ubi), the bar gene, and the hygromycin phosphotransferase gene (Hpt), that are commonly present in GM rice. Therefore, we constructed a novel plasmid (pBJGMM001) that contains fragments of these elements and two endogenous reference genes (the sucrose phosphate synthase gene, SPS, and the phosphoenolpyruvate carboxylase gene, PEPC). pBJGMM001 can serve as a standard for detecting 96% of GM rice lines in China. The primers, amplicons, reaction mixture, and PCR program were developed based on Chinese National Standards. The protocol was validated and determined to be suitable for practical use in monitoring and identifying GM rice. PMID- 26495319 TI - Propofol requirement for induction of unconsciousness is reduced in patients with Parkinson's disease: a case control study. AB - Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, but whether the neurodegenerative process influences the pharmacodynamics of propofol remains unclear. We aimed to evaluate the effect of PD on pharmacodynamics of propofol. A total of 31 PD patients undergoing surgical treatment (PD group) and 31 pair-controlled non-PD patients undergoing intracranial surgery (NPD group) were recruited to investigate the propofol requirement for unconsciousness induction. Unconsciousness was induced in all patients with target-controlled infusion of propofol. The propofol concentration at which unconsciousness was induced was compared between the two groups. EC50 and EC95 were calculated as well. Demographic data, bispectral index, and hemodynamic values were comparable between PD and NPD groups. The mean target concentration of propofol when unconsciousness was achieved was 2.32 +/- 0.38 MUg/mL in PD group, which was significantly lower than that in NPD group (2.90 +/ 0.35 MUg/mL). The EC50 was 2.05 MUg/mL (95% CI: 1.85-2.19 MUg/mL) in PD group, much lower than the 2.72 MUg/mL (95% CI: 2.53-2.88 MUg/mL) in NPD group. In conclusion, the effective propofol concentration needed for induction of unconsciousness in 50% of patients is reduced in PD patients. (This trial is registered with NCT01998204.). PMID- 26495320 TI - Shaped 3D singular spectrum analysis for quantifying gene expression, with application to the early zebrafish embryo. AB - Recent progress in microscopy technologies, biological markers, and automated processing methods is making possible the development of gene expression atlases at cellular-level resolution over whole embryos. Raw data on gene expression is usually very noisy. This noise comes from both experimental (technical/methodological) and true biological sources (from stochastic biochemical processes). In addition, the cells or nuclei being imaged are irregularly arranged in 3D space. This makes the processing, extraction, and study of expression signals and intrinsic biological noise a serious challenge for 3D data, requiring new computational approaches. Here, we present a new approach for studying gene expression in nuclei located in a thick layer around a spherical surface. The method includes depth equalization on the sphere, flattening, interpolation to a regular grid, pattern extraction by Shaped 3D singular spectrum analysis (SSA), and interpolation back to original nuclear positions. The approach is demonstrated on several examples of gene expression in the zebrafish egg (a model system in vertebrate development). The method is tested on several different data geometries (e.g., nuclear positions) and different forms of gene expression patterns. Fully 3D datasets for developmental gene expression are becoming increasingly available; we discuss the prospects of applying 3D-SSA to data processing and analysis in this growing field. PMID- 26495321 TI - Potential Use of Interleukin-10 Blockade as a Therapeutic Strategy in Human Cutaneous Leishmaniasis. AB - Interleukin-10 overproduction has been associated with worse prognosis in human cutaneous leishmaniasis, while IFN-gamma-dependent responses are associated with parasite killing and host protection. Innovative strategies are needed to overcome therapeutic failure observed in endemic areas. The use of monoclonal antibody-based immunotherapy targeting IL-10 cytokine was evaluated here. Partial IL-10 blockade in Leishmania braziliensis whole soluble antigen-stimulated cells from endemic area CL patients with active or healed lesions and asymptomatic controls was evaluated. Overall decrease in IL-10, IL-4, and TNF-alpha production was observed in all groups of subjects. Only patients with active lesions still produced some levels of TNF-alpha after anti-IL-10 stimulation in association with Leishmania antigens. Moreover, this strategy showed limited modulatory effects on IFN-gamma-dependent chemokine CXCL10 production. Results suggest the potential immunotherapeutic use of partial IL-10 blockade in localized cutaneous leishmaniasis. PMID- 26495322 TI - Comparative Immune Response in Children and Adults with H. pylori Infection. AB - Helicobacter pylori (H. pylori) infection is generally acquired during early childhood; therefore, the immune response which usually takes place at this age may influence or even determine susceptibility to the infection contributing to the clinical outcomes in adulthood. Several cytokines including IL-6, IL-10, and TGF-beta1 as well as Foxp3(+) cell numbers have been shown to be higher; however, some other cytokines consisting of IL-1beta, IL-17A, and IL-23 are lower in infected children than in infected adults. Immune response to H. pylori infection in children is predominant Treg instead of Th17 cell response. These results indicate that immune system responses probably play a role in persistent H. pylori infection. Childhood H. pylori infection is also associated with significantly lower levels of inflammation and ulceration compared with adults. This review, therefore, aimed to provide critical findings of the available literature about comparative immune system in children and adults with H. pylori infection. PMID- 26495324 TI - Recurrent Aeromonas Bacteremia Due to Contaminated Well Water. AB - Although they are ubiquitous to aquatic environments, Aeromonas species have traditionally been considered nonvirulent; however, in the past 30 years, they have emerged as important human pathogens that can cause a wide spectrum of disease. In this study, we describe a case of recurrent Aeromonas bacteremia in an immunocompetent patient, and this exposure was linked to the patient's home well water supply. PMID- 26495326 TI - Teach It, Don't Preach It: The Differential Effects of Directly-communicated and Self-generated Utility Value Information. AB - Social-psychological interventions in education have used a variety of "self persuasion" or "saying-is-believing" techniques to encourage students to articulate key intervention messages. These techniques are used in combination with more overt strategies, such as the direct communication of messages in order to promote attitude change. However, these different strategies have rarely been systematically compared, particularly in controlled laboratory settings. We focus on one intervention based in expectancy-value theory designed to promote perceptions of utility value in the classroom and test different intervention techniques to promote interest and performance. Across three laboratory studies, we used a mental math learning paradigm in which we varied whether students wrote about utility value for themselves or received different forms of directly communicated information about the utility value of a novel mental math technique. In Study 1, we examined the difference between directly-communicated and self-generated utility-value information and found that directly-communicated utility-value information undermined performance and interest for individuals who lacked confidence, but that self-generated utility had positive effects. However, Study 2 suggests that these negative effects of directly-communicated utility value can be ameliorated when participants are also given the chance to generate their own examples of utility value, revealing a synergistic effect of directly communicated and self-generated utility value. In Study 3, we found that individuals who lacked confidence benefited more when everyday examples of utility value were communicated, rather than career and school examples. PMID- 26495325 TI - Knowledge of Federal Regulations for Mental Health Research Involving Prisoners. AB - BACKGROUND: Given their vulnerability to coercion and exploitation, prisoners who participate in research are protected by Office for Human Research Protections (OHRP) regulations designed to ensure their safety and wellbeing. Knowledge of these regulations is essential for researchers who conduct and institutional review boards (IRBs) that oversee mental health research in correctional settings. METHODS: We explored depth of knowledge of OHRP regulations by surveying a nationwide sample of: (1) mental health researchers who have conducted research in correctional settings; (2) mental health researchers who have conducted research in non-correctional settings; (3) IRB members who have overseen mental health research in correctional settings; (4) IRB members who have overseen mental health research in in non-correctional settings; and (5) IRB prisoner representatives. Participants responded to a 10-item knowledge questionnaire based on OHRP regulations. RESULTS: 1,256 participants provided usable data (44.9% response rate). Results revealed limited knowledge of OHRP regulations, with a mean across groups of 44.1% correct answers. IRB Prisoner representatives, IRB members, and researchers with correctional experience demonstrated the highest levels of knowledge; however, even these participants were able to correctly answer only approximately 50% of the items. CONCLUSIONS: Although awareness that prisoners are a protected population and that different regulatory procedures apply to research with them is likely to be universal among researchers and IRB members, our findings reveal limited mastery of the specific OHRP regulations that are essential knowledge for researchers who conduct and IRB members who oversee mental health research in correctional settings. Given well documented health and healthcare disparities, prisoners could potentially benefit greatly from mental health research; increasing knowledge of the OHRP regulations among researchers and IRB members is a crucial step toward meeting this important public health goal. PMID- 26495327 TI - Utilization of Failure Mode and Effects Analysis (FMEA) Method in Increasing the Revenue of Emergency Department; a Prospective Cohort Study. AB - INTRODUCTION: The balance between revenue and cost of an organization/system is essential to maintain its survival and quality of services. Emergency departments (ED) are one of the most important parts of health care delivery system. Financial discipline of EDs, by increasing the efficiency and profitability, can directly affect the quality of care and subsequently patient satisfaction. Accordingly, the present study attempts to investigate failure mode and effects analysis (FMEA) method in identifying the problems leading to the loss of ED revenue and offer solutions to help fix these problems. METHODS: This prospective cohort study investigated the financial records of ED patients and evaluated the effective errors in reducing the revenue in ED of Imam Hossein hospital, Tehran, Iran, from October 2007 to November 2009. The whole department was divided into one main system and six subsystems, based on FMEA. The study was divided into two phases. In the first phase, the problems leading to the loss of revenue in each subsystem were identified and weighted into four groups using risk priority number (RPN), and the solutions for fixing them were planned. Then, in the second phase, discovered defects in the first phase were fixed according to their priority. Finally, the impact of each solution was compared before and after intervention using the repeated measure ANOVA test. RESULTS: 100 financial records of ED patients were evaluated during the first phase of the study. The average of ED revenue in the six months of the first phase was 73.1+/-3.65 thousand US dollars/month. 12 types of errors were detected in the predefined subsystems. ED revenue rose from 73.1 to 153.1, 207.06, 240, and 320 thousand US dollars/month after solving first, second, third, and fourth priority problems, respectively (337.75% increase in two years) (p<0.001). 111.0% increase in the ED revenue after solving of first priority problems revealed that they were extremely indispensable in decreasing the revenue (p<0.0001). CONCLUSION: The findings of the present study revealed that FMEA could be considered as an efficient model for increasing the revenue of emergency department. According to this model, not recording the services by the nursing unit, and lack of specific identifying code for the patients moving from ED to any other department, were the two first priority problems in decreasing our ED revenue. PMID- 26495328 TI - Accuracy of Ultrasonography in Confirmation of Adequate Reduction of Distal Radius Fractures. AB - INTRODUCTION: Restoration of normal anatomic alignment is a key component of the treatment of distal radius fractures (DRF). This study aimed to evaluate the accuracy of ultrasonography (US) in determining the adequacy of closed reduction in these fractures. METHODS: DRF patients admitted to the emergency department of Al-Zahra Hospital, Isfahan, Iran from September 2011 to 2012, were enrolled. After closed reduction, the adequacy was investigated through both US and control plain radiography. Then, sensitivity, specificity, positive and negative predicative values of US in confirmation of closed reduction was evaluated. In addition, inter-rater agreement between the two diagnostic tools was analyzed by calculating Cohen's kappa coefficient. RESULTS: Finally, 154 patients were evaluated (females: 53.9%) with mean age of 40.03+/-14.7 (range: 22-73). US had sensitivity, specificity, positive and negative predictive value of 99.3% (95%CI: 96.2-99.9), 100.0% (95%CI: 62.9-100.0), 100.0% (95%CI: 97.5-100.0), and 88.9% (95%CI: 51.7-98.1) in confirmation of the adequate reduction, respectively. In addition, inter-rater reliability was 0.94 (95%CI: 0.89-0.99; p<0.0001). CONCLUSION: It seems that US could be considered as a highly sensitive, accurate, easy to use, noninvasive and safe tool for guidance and confirmation of closed reduction in DRF. PMID- 26495323 TI - Complexity and Controversies over the Cytokine Profiles of T Helper Cell Subpopulations in Tuberculosis. AB - Tuberculosis (TB) is a contagious infectious disease caused by the TB-causing bacillus Mycobacterium tuberculosis and is considered a public health problem with enormous social impact. Disease progression is determined mainly by the balance between the microorganism and the host defense systems. Although the immune system controls the infection, this control does not necessarily lead to sterilization. Over recent decades, the patterns of CD4+ T cell responses have been studied with a goal of complete understanding of the immunological mechanisms involved in the maintenance of latent or active tuberculosis infection and of the clinical cure after treatment. Conflicting results have been suggested over the years, particularly in studies comparing experimental models and human disease. In recent years, in addition to Th1, Th2, and Th17 profiles, new standards of cellular immune responses, such as Th9, Th22, and IFN-gamma-IL-10 double-producing Th cells, discussed here, have also been described. Additionally, many new roles and cellular sources have been described for IL-10, demonstrating a critical role for this cytokine as regulatory, rather than merely pathogenic cytokine, involved in the establishment of chronic latent infection, in the clinical cure after treatment and in keeping antibacillary effector mechanisms active to prevent immune-mediated damage. PMID- 26495329 TI - Nerve Stimulator Guided Axillary Block in Painless Reduction of Distal Radius Fractures; a Randomized Clinical Trial. AB - INTRODUCTION: Given the high prevalence of upper extremity fractures and increasing need to perform painless reduction in the emergency departments, the use of analgesic methods with fewer complications and more satisfaction appears to be essential. The aim of this study is comparison the nerve stimulator guided axillary block (NSAB) with intravenous sedation in induction of analgesia for painless reduction of distal radius fractures. METHODS: In the present randomized clinical trial, 60 patients (18-70 years of age) suffered from distal radius fractures, were divided into two equal groups. One group received axillary nerve block by nerve stimulator guidance and the other procedural sedation and analgesia (PSA) using midazolam/fentanyl. Onset of analgesia, duration of analgesic effect, total procedure time and pain scores were recorded using visual analogue scale (VAS) and the outcomes were compared. Chi-squared and student t test were performed to evaluate differences between two groups. RESULTS: Sixty patients were randomly divided into two groups (83.3% male). The mean age of patients was 31 +/-0.7 years. While the onset of analgesia was significantly longer in the NSAB group, the mean total time of procedure was shorter than PSA (p<0.001). The NSAB group needed a shorter post-operative observation time (P<0.001). Both groups experienced equal pain relief before, during and after procedure (p>0.05). CONCLUSION: It seems that shorter post-operative monitoring time and consequently lesser total time of procedure, make nerve stimulator guided axillary block as an appropriate alternative for procedural sedation and analgesia in painless reduction of distal radius fractures in emergency department. PMID- 26495330 TI - Sonographic Optic Nerve Sheath Diameter as a Screening Tool for Detection of Elevated Intracranial Pressure. AB - INTRODUCTION: Timely diagnosis and treatment of post-traumatic elevated intracranial pressure (EICP) could be reduced morbidity and mortality, and improved patients' outcome. This study is trying to evaluate the diagnostic accuracy of sonographic optic nerve sheath diameter (ONSD) in detection of EICP. METHODS: Sonographic ONSD of patients with head trauma or cerebrovascular accident suspicious for EICP were evaluated by a trained chief resident of emergency medicine, who was blind to the clinical and brain computed tomography scan (BCT) findings of patients. Immediately after ultrasonography, BCT was performed and reported by an expert radiologist without awareness from other results of the patients. Finally, ultrasonographic and BCT findings regarding EICP were compared. To evaluate the ability of sonographic ONSD in predicting the BCT findings and obtain best cut-off level, receiver operating characteristic (ROC) curve were used. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) of sonographic ONSD in determining of EICP was calculated. P < 0.05 was considered as statistically significant. RESULTS: There were 222 patients (65.3% male), with mean age of 42.2+/-19.5 years (range: 16-90 years). BCT showed signs of EICP, in 28 cases (12.6%). The means of the ONSD in the patients with EICP and normal ICP were 5.5 +/- 0.56 and 3.93 +/- 0.53 mm, respectively (P<0.0001). ROC curve demonstrated that the best cut off was 4.85 mm. Sensitivity, specificity, PPV, NPV, PLR, and NLR of ONSD for prediction of EICP were 96.4%, 95.3%, 72.2%, 98.9%, 20.6, and 0.04, respectively. CONCLUSION: Sonographic diameter of optic nerve sheath could be considered as an available, accurate, and noninvasive screening tool in determining the elevated intracranial pressure in cases with head trauma or cerebrovascular accident. PMID- 26495331 TI - Emergency Department Performance Indexes Before and After Establishment of Emergency Medicine. AB - INTRODUCTION: Emergency department performance index (EPI) greatly influences the function of other hospital's units and patient satisfaction. Recently, the Iranian Ministry of Health has defined specific national EPI containing five indexes. In the present study the performance indexes of emergency department (ED) in one educational hospital has been assessed before and after establishment of emergency medicine. METHODS: In the present cross-sectional study the ED of Shohadaye Tajrish Hospital, Tehran, Iran was assessed during one-year period from March 2012 to February 2013. The study was divided into two six-month periods of before and after establishment of emergency medicine. Five performance indexes including: the percentage of patients were disposed during 6-hour, leaved the ED in a 12-hour, had unsuccessful cardiopulmonary resuscitations (CPR), discharged against medical advice, and the mean time of triage were calculated using data of department of medical records on daily patients' files. Then, Mann-Whitney U test was used to make comparisons at P<0.05. RESULTS: The average triage time decreased from 6.04 minutes in the first six months to 1.5 minutes in the second six months (P=0.06). The percentage of patients leaving the ED in a 12-hour decreased from 97.3% to 90.4% (P=0.004). However, the percentage of disposed patients during 6-hour (P=0.2), unsuccessful CPR (P=0.34) and discharged against medical advice (P=0.42) did not differ between the two periods. CONCLUSION: It seems that establishment of emergency medicine could be able to improve ED performances indexes such as time to triage and leave in a 12-hour period. PMID- 26495332 TI - Report of 267 Cases of Scorpion Bite Referring to an Emergency Department during One Year. AB - Scorpion bite is a common health problem in many parts of the world, including the Iran's tropics. There are thousands of cases and a number of deaths due to scorpion bite every year in the country. The present study aims to provide further data regarding the details, complications and outcomes of scorpion bite cases referring to Razi Hospital, Ahwaz, from March 2011 to April 2012. 267 patients (56.3% females) with a mean age of 35.2+/-15.8 years were included in the study. The most common genus of scorpion involved was Hemiscorpius (69.3%) and the most frequent body part involved was the lower limb (38.9%). The frequency of hemolysis-induced renal insufficiency and death after scorpion bite were 1.9% and 1.1%, respectively. Of all the factors evaluated in this series only the old age was associated with higher possibility of renal insufficiency (P<0.001). PMID- 26495333 TI - A 33-year-old woman with severe postpartum headache. PMID- 26495334 TI - The Risk of Venous Thromboembolism with Different Generation of Oral Contraceptives; a Systematic Review and Meta-Analysis. AB - INTRODUCTION: Oral contraceptives (OCs) are considered as one of the most common risk factor of venous thromboembolism (VTE) in childbearing age. Some of the recent researches indicate that the odds of VTE may be even higher with newer generations of OCs. The present meta-analysis was designed to evaluate the effect of different generation of OCs on the occurrence of VTE. METHODS: Two researchers independently ran a thorough search in Pubmed, ISI Web of Science, EMBASE, CINAHL and Scopus databases regarding study keywords including thromboembolic event, thromboembolism, embolism, thromboembolic, thrombotic and thrombosis, combined with oral contraceptive. The outcomes were the incidence of diagnosed thromboembolism, such as deep vein thrombosis, pulmonary embolism and cerebral venous thrombosis. Based on the heterogeneity of the studies, random effect model was used and pooled odds ratio was reported. RESULTS: Three cohort and 17 case control studies with 13,265,228 subjects were entered into meta-analysis. Analysis showed that the odds of VTE in women taking OCs are more than three-fold (OR=3.13; 95% CI: 2.61-3.65). The risk of VTE in women taking first-, second- and third-generation OCs are 3.5 fold (OR=3.48; 95% CI: 2.01-4.94), 3 fold (OR=3.08; 95% CI: 2.43-3.74) and 4.3 fold (OR=4.35; CI: 3.69-5.01), respectively. CONCLUSION: It seems that the risk of VTE is not same between different generations of OCs, so that third-generation has highest risk. Taking second and third-generation OCs increases the risk of VTE up to 3 and 4.3 fold, respectively. The researchers of the present study suggest that more trials be designed in relation to the effect of newer generations of OCs in different communities. PMID- 26495335 TI - A cause of Sudden Cardiac Deaths on Autopsy Findings; a Four-Year Report. AB - INTRODUCTION: Incidence of sudden cardiac death (SCD) has been steadily increasing all over the world. While knowing the cause of SCD is one of the favorites of the physicians involved with these cases, it is very difficult and challenging task for the forensic physician. The present report is a prospective study regarding cause of SCDs on autopsy examination in four-year period, Bangalore, India. METHODS: The present prospective study is based on autopsy observations, carried out for four-year period from 2008 to 2011, and analyzed for cause of SCDs. The cases were chosen as per the definition of sudden death and autopsied. The material was divided into natural and unnatural groups. Finally, on histopathology, gross examination, hospital details, circumstantial, and police reports the cause of death was inferred. RESULTS: A total of 2449 autopsy was conducted of which 204 cases were due to SCD. The highest SCDs were reported in 50-60 years age group (62.24%; n-127), followed closely by the age group 60-69 (28.43%; n-58). Male to female ratio was around 10:1. The maximum number of deaths (n=78) was within few hours (6 hours) after the onset of signs and symptoms. In 24 (11.8%) cases major narrowing was noted in both the main coronaries, in 87 (42.6%) cases in the left anterior descending coronary artery (LAD), and in 18 (51.5%) cases in the right coronary artery (RCA). The major cardiac pathology resulting in sudden death was coronary artery disease (n-116; 56.86%) and myocardial infarction (n-104; 50.9%). most of the SCDs occurred in the place of residence (n-80; 39.2%) followed closely by death in hospital (n-49; 24.01%). CONCLUSION: Coronary occlusion was the major contributory cause of sudden death with cardiac origin and the highest number of deaths were reported in the age 50-59 years with male to female ratio of 10:1. PMID- 26495336 TI - Short-Term Outcome of Discharged Low-Risk Chest Pain without Provoke Ischemia Study. AB - INTRODUCTION: Chest pain is a common problem in patients referring to emergency units. The present study was undertaken to evaluate the short-term outcome of patients presenting with a low risk chest pain and discharging without provoke ischemia study during emergency department admission. METHODS: In the present prospective cohort study, patients with low-risk chest pain, referring to the emergency department of Imam Hossein Hospital, Tehran, during the first half of 2012, were evaluated. All the patients underwent electrocardiogram (ECG) and cardiac enzyme tests, including cardiac isoenzymes creatine kinase MB and troponin I. One week after referring to the emergency department, the patients underwent an exercise test and were followed for a month. Data were analyzed with chi-squared test at a significant level of P<0.05. RESULTS: A total of 252 patients were included. The mean and standard deviation of patient ages was 56+/ 7.7 years (47.5% male). The results of exercise tests for 47 (26.3%) subjects were positive [32 (28.8%) patients in the 41-60 year age group and 15 (22.7%) over 60 years of age].The angiography examination results of 5 patients (2.8%) were abnormal. There were no significant relationships between the age and gender and the results of exercise test and angiography (P>0.05). During the one-month follow-up no cases of mortality, cardiac problems, or referring again to the hospital were recorded. CONCLUSION: Based on the results of the present study, prevalence of cardiac etiology in patients with low risk chest pain was 2.8% and one-month follow-up did not reveal any complications or serious problems in such cases. PMID- 26495337 TI - QT Interval in Pregnant and Non-pregnant Women. AB - INTRODUCTION: Prolongation of QT interval might result in dangerous cardiac arrhythmias, including Torsades de Pointes (TdP), consequently leading to syncope or death. A limited number of studies carried out in this respect to date have shown that QT interval might increase during pregnancy. On the other hand, it has been shown that each pregnancy might result in an increase in the risk of cardiac accidents in patients with long QT interval. Therefore, the present study was undertaken to compare QT intervals in pregnant and non-pregnant women. METHODS: Pregnant women group consisted of 40 women in the second and third trimesters of pregnancy and the non-pregnant control group consisted of healthy women 18-35 years of age. All the patients underwent standard 12-lead electrocardiogram (ECG). The QT interval was measured for each patient at lead II. The mean corrected QT interval (QTc) and QT dispersions (QTd) were compared between the two groups. RESULTS: Mean heart rates in the pregnant and non-pregnant groups were 98.55+/-14.09 and 72.53+/-13.17 beats/minutes (P<0.001). QTd and QTc means were in the normal range in both groups; however, these variables were 49.50+/ 12.80 and 43.03+/-18.47 milliseconds in the pregnant group and 39.5+/-9.59 and 40.38+/-17.20 milliseconds in the control group, respectively (P<0.001). CONCLUSION: The QT interval was longer in pregnant women compared to non-pregnant women; however, it was in the normal range in both groups. Therefore, it is important to monitor and manage risk factors involved in prolongation of QT interval and prevent concurrence of these factors with pregnancy. PMID- 26495338 TI - Synergistic Effects of Citalopram and Morphine in the Renal Colic Pain Relief; a Randomized Clinical Trial. AB - INTRODUCTION: Although the synergistic effects of opioids and other analgesic drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) have been established in relieving acute pain due to renal calculi, no studies today have evaluated the concomitant administration of opiates and other drugs with analgesic effects, such as serotonin re-uptake inhibitors. Considering the high prevalence of renal colic, the present study was carried out to compare the effect of concomitant prescription of morphine and a placebo with that of morphine and citalopram on the management of acute pain due to renal calculi. METHODS: The present double-blind randomized clinical trial was carried out from October 2012 to March 2013 in the Al-Zahra educational Hospital in Isfahan, Iran. 90 patients with acute renal colic pain were randomly divided into two groups of 45 subjects. The subjects in one group received morphine/ placebo and another one morphine/citalopram. The patients' pain severity was determined by visual analogue scale (VAS) before and 20 minutes after administration of medications. In case of persistent pain, the second or even third dose was administered and the pain severity was once again determined. Data were analyzed with STATA 11.0 using chi-squared, two-way ANOVA, Bonferroni post hoc test, and log rank test. RESULTS: The decrease in pain severity in the morphine/citalopram group was significantly compared to the morphine/placebo group and the time before administration of the medications (p<0.001). In contrast, administration of morphine/placebo did not have a significant effect on pain severity at this interval (p=0.32). Kaplan-Meier curve showed that the first injection was successful in relieving pain in 15 (33.3%) and 26 (57.8%) subjects in the morphine/placebo and morphine/citalopram groups, respectively. The second injection of these medications resulted in therapeutic success in 35 (87.8%) and 42 (95.6%) subjects in the above groups, respectively. Log rank test showed a significant difference in the treatment success between the two groups (p=0.001). CONCLUSION: It seems that the combination of citalopram and morphine sulfate causes increased efficacy and higher success rate in pain control of patients presented to the emergency department with a complaint of renal colic. PMID- 26495339 TI - Cause of Emergency Department Mortality; a Case-control Study. AB - INTRODUCTION: Based on previous studies, cardiovascular diseases, traffic accidents, traumas and cancers are the most important etiology of mortalities in emergency departments (ED). However, contradictory findings have been reported in relation to mortality in emergency departments. Therefore, the present study was undertaken to evaluate the role of clinical factors in mortality among patients referring to an emergency department in a third-level hospital in Tehran, Iran. METHODS: In the present case-control study, all the patients over 18 years of age were evaluated, referring to the ED of Imam Hossein Hospital, Tehran, Iran, from the beginning of 2009 to the end of 2010. The patients died in the ED were placed in the case group and those discharged or hospitalized in other hospital wards in the control group. Demographic data, background diseases, and the final diagnoses were recorded. Chi-squared test, multivariate logistic regression, and Pearson's correlation coefficient were used to evaluate the relationship between the variables mentioned above and patient mortality. RESULTS: 2907 patients (969 (59.9% male) in the case and 1938 (62.2% male) in the control groups) were evaluated. Cardiovascular diseases (39.2%), severe traumas (18.5%), and cerebrovascular accidents (17.7%) were the most frequent etiology of patient mortality in ED. Multivariate regression analysis showed that presentation with cardiovascular complaints (OR=7.3; 95% CI: 3.5-16.1; p<0.001), a history of hypertension (OR=5.4; 95% CI: 1.2-12.3; p<0.001), severe trauma (OR=4.6; 95% CI: 2.0-13.2; p<0.001), age over 60 (OR=3.8; 95% CI: 1.8-7.8; p<0.01) and a final diagnosis of renal disease (OR=3.4; 95% CI: 2.1-6.4; p<0.001) were factors that increased the odds of mortality in patients referring to the ED. Multivariate regression analysis in patients over 60 years showed that sepsis was an independent factor increasing the risk of death (OR=2.9; 95% CI: 1.3-5.9; p=0.009). A patient's risk of death increases with an increase in the number of risk factors in that patient (r(2)=0.96; p=0.02). CONCLUSION: It appears the odds of mortality in patients referring to ED with cardiovascular complaints, a history of hypertensive, severe trauma, age over 60 and a final diagnosis of renal disease are higher versus other patients. In addition, the patients' odds of death increase with an increase in the number of risk factors. Such an increase is more noticeable at age over 60. PMID- 26495340 TI - The Effect of Intravenous Ketamine in Suicidal Ideation of Emergency Department Patients. AB - INTRODUCTION: Suicidal ideation is an emergent problem in the Emergency Department (ED) that often complicates patient disposition and discharge. It has been shown that ketamine possesses fast acting antidepressant and anti-suicidal effects. This study was conducted to examine the effects of a single intravenous bolus of ketamine on patients with suicidal ideations in ED. METHODS: Forty-nine subjects with suicidal ideations with or without an unsuccessful suicide attempt, received 0.2 mg/kg of ketamine. Scale for suicidal ideation (SSI) and Montgomery Abserg depression-rating scale (MADRS) were evaluated before and 40, 80 and 120 minutes after drug intervention. The results were compared using the paired t test and patients were followed up 10 days after ED admission for remnant suicide ideation. RESULTS: SSI (df: 3, 46; F=80.7; p<0.001) and MADRS (df: 3, 46; F=87.2; p<0.001) scores significantly dropped after ketamine injection; the SSI score before and after 20, 40, and 80 minutes of ketamine injection were 23.0+/-6.7, 16.2+/-5.2, 14.3+/-4.3, and 13.6+/-4.0 respectively. The MADRS scores were 38.2+/ 9.3, 25.6+/-7.1, 22.7+/-6.3, and 22.1+/-5.95 at the same time intervals. 25.5% of patients were hospitalized, 63.3% received medications and 12.2% discharged. 6.2% of patients had suicidal ideations ten days after ED disposition. CONCLUSION: It seems that Ketamine could not be a good choice for fast reduction of suicidal ideations in ED patients. Further studies are needed to determine the optimal dose of ketamine for different patients. PMID- 26495341 TI - Treatment Costs of Traffic Accident Casualties in a Third-level Hospital in Iran; a Preliminary Study. AB - INTRODUCTION: The costs of traffic accidents in low- and middle-income countries are estimated to add up to $65 billion annually, which is a little higher than the amount they receive as a final aid for development. The present retrospective study aims to evaluate the treatment costs of the hospitalized injured individuals in traffic accidents. METHODS: The present study was carried out in Imam Hossein Hospital, Tehran, Iran. The study population consisted of all the individuals injured in traffic accidents, admitted to the hospital wards. Data were collected by a trained emergency physician. Demographic data, injury mechanism, the type of vehicle, the admission ward of the patient, and treatment costs were collected. RESULTS: 200 patient files were evaluated (males: 89%). The results showed that 54% of the patients were in the 18-40-year age group and collisions between cars and motorcycles were the most frequent accidents (47%). The mean hospitalization cost for each patient was estimated to be $1622.1. Statistical analyses showed that treatment costs in the neurosurgery ward was significantly higher than orthopedic and general surgery (df: 3; F=9.5, P=0.008). CONCLUSION: The results of the present study showed that the mean cost of each traffic accident victim in Tehran is approximately $1622.1 and these patients sustain significantly higher costs in neurosurgery ward. PMID- 26495342 TI - A Young Man with Myocardial Infarction due to Trenbolone Acetate; a Case Report. AB - Over the four decades, a significant decrease has been observed in age-related mortality caused by cardiovascular disease. People in developing countries suffer from CAD at a relatively younger age and about half of MI occurs under the age of fifty years. Abuse of anabolic steroids is one of the less common causes of atherosclerosis. In this report, a 23-year-old body builder male referred to emergency department (ED) with myocardial infarction (MI) following chronic Trenbolone acetate consumption. It seems that a comprehensive history of steroid consumption in young patients referred to ED with the chief complaint of chest pain or its equivalents is necessary in adjunct to other cardiac risk factors. PMID- 26495343 TI - Atypical Presentation of Massive Pulmonary Embolism, a Case Report. AB - The lack of pathognomonic signs and symptoms makes the diagnosis of pulmonary embolism (PE) difficult. Here, we report a case of a 42-year-old man presented to the emergency department with worsening epigastric pain, hypotension, frank bradycardia, and final diagnosis of PE. Although previous studies have indicated that abdominal pain was observed in 6.7% of patients with PE, the exact reason for abdominal pain in PE still remains unknown. Tension on the sensory nerve endings, hepatic congestion, and distention of Gilson's capsule are some of the possible mechanisms of abdominal pain in PE. We conclude that emergency physicians should pay more attention to PE, which is an important differential diagnosis of shock state. In this context, rapid ultrasound in shock (RUSH) should be considered as a vital sign that needs to be evaluated when recording the history of patients presented to the emergency department with signs and symptoms of shock. PMID- 26495344 TI - Epidural Hematoma Following Hemodialysis in a Methanol Poisoned Patient; a Case Report. AB - Brain injury associated with methanol toxicity can be ischemic, necrotic or hemorrhagic in nature. It most commonly affects the putamen area bilaterally; however, it can be seen in other locations. This report describes a 22-year-old intoxicated patient who developed an epidural hematoma following hemodialysis. Heparinization during hemodialysis may contribute to cerebral hemorrhagic complications in methanol poisoning. In addition, a history of head trauma may raise the incidence of post-hemodialysis hemorrhagic brain insults. Heparin-free dialysis or peritoneal dialysis can be a good option in these cases. PMID- 26495345 TI - A 16-Year-Old Girl with Acute Onset Respiratory Distress. PMID- 26495346 TI - The Risk of Venous Thromboembolism Associated with Oral Contraceptive; the Search Is Still On. PMID- 26495347 TI - Poisonous Spiders: Bites, Symptoms, and Treatment; an Educational Review. AB - More than 40,000 species of spiders have been identified in the world. Spider bites is a common problem among people, however few of them are harmful but delay in treatment can cause death. Since the spider bites are risk full to human, they should be taken seriously, especially in endemic areas. Our objective in this review was to study about poisonous spiders and find out treatments of them. Therefore, we collected related articles from PubMed database and Google Scholar. Three important syndromes caused by spider bites are loxoscelism, latrodectism and funnel web spider syndrome. Many treatments are used but much more studies should have done to decrease the mortality. In this review, we describes different venomous spiders according to their appearance, symptoms after their bites and available treatments. PMID- 26495348 TI - Development of an Easy-to-Use Tool for the Assessment of Emergency Department Physical Design. AB - Physical design of the emergency department (ED) has an important effect on its role and function. To date, no guidelines have been introduced to set the standards for the construction of EDs in Iran. In this study, we aim to devise an easy-to-use tool based on the available literature and expert opinion for the quick and effective assessment of EDs in regards to their physical design. For this purpose, based on current literature on emergency design, a comprehensive checklist was developed. Then, this checklist was analyzed by a panel consisting of heads of three major EDs and contradicting items were decided. 178 crude items were derived from available literature. The Items were categorized in to three major domains of Physical space, Equipment, and Accessibility. The final checklist approved by the panel consisted of 163 items categorized into six domains. Each item was phrased as a "Yes or No" question for ease of analysis, meaning that the criterion is either met or not. PMID- 26495349 TI - Report of 121 Cases of Bell's Palsy Referred to the Emergency Department. AB - INTRODUCTION: According to the high incidence of Bell's palsy (IFP) and lack of clinical data regarding different aspects of disease, the present study investigated 121 Iranian patients with peripheral facial paralysis referred to the emergency department. METHODS: In this retrospective study, all patients with peripheral facial paralysis, referred to the emergency department of Poursina hospital, Rasht, Iran, from August 2012 to August 2013, were enrolled. For all patients with diagnosis of Bell's palsy variables such as age, sex, occupation, clinical symptoms, comorbid disease, grade of paralysis, and the severity of the facial palsy were reviewed and analyzed using STATA version 11.0. RESULTS: 121 patients with peripheral facial paralysis were assessed with a mean age of 47.14+/-18.45 years (52.9% male). The majority of patients were observed in the summer (37.2%) and autumn (33.1%) and the recurrence rate was 22.3%. The most common grades of nerve damage were IV and V based on House-Brackman grading scale (47.1%). Also, the most frequent signs and symptoms were ear pain (43.8%), taste disturbance (38.8%), hyperacusis (15.7%) and increased tearing (11.6%). There were not significant correlations between the severity of palsy with age (p= 0.08), recurrence rate (p=0.18), season (p=0.9), and comorbid disease including hypertension (p=0.18), diabetes (p=0.29), and hyperlipidemia (p=0.94). The patients with any of following symptoms such as ear pain (p<0.001), taste disturbance (p<0.001), increased tearing (p=0.03), and Hyperacusis (p<0.001) have more severe palsy. CONCLUSION: There was equal gender and occupational distribution, higher incidence in fourth decade of life, higher incidence in summer and autumn, higher grade of nerve damage (grade V and VI), and higher incidence of ear pain and taste disturbance in patients suffered from IFP. In addition, there was significant association between severity of nerve damage and presence of any simultaneous symptoms. PMID- 26495350 TI - Knowledge of Emergency Medicine Residents in Relation to Prevention of Tetanus. AB - INTRODUCTION: Knowledge of emergency medicine residents about the management of patients suspected of having tetanus-favoring wounds is very important due to their responsibility for the treatment of such patients. The aim of the present study was to evaluate this knowledge and making sure of the adequacy of instructions they have received in relation to prevention of tetanus. METHODS: A reliable and reproducible questionnaire was used to evaluate knowledge of all the emergency medicine residents in Imam Hussein Hospital in Tehran, Iran, about conditions favoring tetanus (9 questions) and proper interventions in such conditions (12 questions). The questionnaires were completed and scored as poor and good. The Mann-Whitney U test was used to analyze data. Statistical significance was set at P<0.05. RESULTS: In the present study, 73 emergency medicine residents were evaluated (45.2% male). Knowledge of 31 (42.5%) residents in relation to conditions favoring tetanus and 41 (56.2%) residents in correct therapeutic interventions was in good level. The most frequent incorrect answer was related to diabetic ulcers and wounds in patients with sepsis. There was an increase in scores of conditions favoring tetanus (P<0.001) and correct therapeutic interventions (P=0.001) with an increase in educational years. However, age (P=0.64), gender (P=0.31), job experience (P=0.38) and participation in educational courses (P=0.67) had no effect on the knowledge level of emergency medicine residents. CONCLUSION: According to the findings of the present study, the knowledge of emergency medicine residents about correct management of patients suspected of tetanus was low, which emphasizes the necessity of providing further instructions on prevention of tetanus in wound management. PMID- 26495351 TI - Comparison of Intravenous Ketamine with Morphine in Pain Relief of Long Bones Fractures: a Double Blind Randomized Clinical Trial. AB - INTRODUCTION: The selective medication for pain control in many clinical situations is morphine but its complications prevent its widespread use. Ketamine has been introduced as an alternative for morphine in some studies. However, the efficacy of its solitary use has not yet been evaluated. Therefore, the present study was undertaken to evaluate the effect of ketamine alone in relieving pain in trauma patients referring to an emergency unit. METHODS: In this double-blind clinical trial, patients with long bone fractures were randomly divided into two groups of treatment with intravenous (IV) morphine at a dose of 0.1 mg/kg and treatment with IV ketamine at a dose of 0.5 mg/kg. Pain severity of the patients was recorded before and 10 minutes after injection based on numeric rating scale. The means in the two groups were compared using independent t-test. Then the Kaplan-Meier curve and log rank analysis were used to evaluate the success of treatment. RESULTS: 126 patients were included in this study. The mean ages of the patients in the morphine and ketamine groups were 33.6+/-14.3 and 35.1+/-13.5 years, respectively (P=0.54). After therapeutic intervention, the pain severity significantly decreased in ketamine (2.7+/-1.8; P<0.0001) and morphine (2.4+/ 1.5; P<0.0001) groups, with a similar effect of both medications on alleviating pain (P=0.28). The success rate of the treatment at 10-minute interval in groups receiving ketamine and morphine were 59 (93.65%) and 61 (96.8%) patients, respectively (P=0.62). CONCLUSION: The results of the present study showed that administration of ketamine at a low dose (0.5 mg/kg) results in a significant decrease in the severity of acute pain in patients with fractures of long bones. This palliative effect is very similar to that of morphine. PMID- 26495352 TI - Diagnostic Accuracy of Ultrasonography in the Initial Evaluation of Patients with Penetrating Chest Trauma. AB - INTRODUCTION: Traumatic chest injuries (TCI) are one of the most common causes of referring to the emergency departments, with high mortality and disability. This study was designed to evaluate the diagnostic accuracy of ultrasonography versus chest X ray (CXR) in detection of hemo-pneumothorax for patients suffering penetrating TCI. METHODS: The present cross-sectional study was performed to evaluate the diagnostic accuracy of ultrasonography in penetrating TCI victims referred to the emergency department of Shahid Kashani and Alzahra Hospitals of Isfahan, Iran, from July 2012 to June 2013. Bedside ultrasonography and plain CXR was done on arrival and three hours after admission. The results of ultrasonography and radiography were separately evaluated by an emergency medicine specialist and a radiologist, who were blind to the aims of the study. Then, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa coefficient was considered to evaluate the accuracy of ultrasonography. RESULTS: In this research, 64 patients with penetrating chest trauma were assessed (98.4% male). The mean age of them was 25.6+/-8.5 years (rang: 13-65). The plain radiography revealed the eight (12.5%) cases of pneumothorax and one (1.6%) hemothorax. The findings of primary ultrasonography also showed the same number of hemo-pneumothorax. Sensitivity and specificity of primary ultrasound in diagnosis of pneumothorax were 100% (95% Cl: 60.7- 100) and 100.0% (95% Cl, 92.0% to 100.0%) and in detection of hemothorax were 100% (95% Cl: 50.5-100) and 100% (95% Cl: 92.8-100), respectively. Sensitivity and specificity of ultrasound in the third hour were 100% (95% Cl: 31.3-100) and 100% (95% Cl: 91.4-100), respectively. CONCLUSION: Findings of the present study have shown that ultrasonography has an acceptable diagnostic accuracy in the initial assessment of patients with penetrating chest trauma. However, because of its dependency on operator proficiency and other limitations more studies are needed in this area. PMID- 26495353 TI - Oral Chloral Hydrate Compare with Rectal Thiopental in Pediatric Procedural Sedation and Analgesia; a Randomized Clinical Trial. AB - INTRODUCTION: The increasing use of diagnostic imaging in pediatric medicine has resulted in growing need for procedural sedation and analgesia (PSA) to minimize motion artifacts during procedures. The drug of choice in pediatric PSA was not introduced until now. The aim of the present study was comparison of oral chloral hydrate (OCH) and rectal sodium thiopental (RST) in pediatric PSA. METHODS: In the present randomized clinical trial, 2-6 years old pediatrics who referred for performing brain computed tomography scan was enrolled and were randomly divided in to two groups. OCH (50mg/kg) and RST (25mg/kg) were prescribed and a trained nurse recorded the time from drug prescription to receiving the conscious sedation (onset of action), the total period which the patient has the Ramsay score>=4 (duration of action), and adverse effect of agents. Mann-Whitney U test and chi-squared test, and Non-parametric analysis of covariance (ANCOVA) were used for comparisons. RESULTS: One hundred and forty children were entered to two groups of OCH and RST, randomly. The patients of two groups had similar age, sex, weight, and baseline vital signs except for diastolic blood pressure (p<0.001). The onset of action in OCH and RST groups were 24.5+/-6.1and 28.7+/-5.2 minutes, respectively (p<0.001). Duration of action in OCH and RST groups were 12.9+/-2.8 minutes and 13.7+/-2.6 minutes, respectively (p=0.085). Non-parametric ANCOVA revealed that only diastolic blood pressure was affected by drug prescription (p=0.001). In 11(15.7%) patients in RST group, diarrhea was observed during 24 hours (p=0.001). Oxygen desaturation was observed only in two patients, both in OCH group. CONCLUSION: Each of the sedative has advantages and disadvantages that should be considered when selecting one for inducing short-term sedation. It seems that rectal sodium thiopental and oral chloral hydrate are equally effective in pediatric PSA and based on patient's condition we can administrate one of these agents. PMID- 26495354 TI - Effects of Intravenous Fluid Therapy on Clinical and Biochemical Parameters of Trauma Patients. AB - INTRODUCTION: The administration of crystalloid fluids is considered as the first line treatment in management of trauma patients. Infusion of intravenous fluids leads to various changes in hemodynamic, metabolic and coagulation profiles of these patients. The present study attempted to survey some of these changes in patients with mild severity trauma following normal saline infusion. METHODS: This study comprised 84 trauma patients with injury of mild severity in Shahid Rajaei Hospital, Shiraz, Iran, during 2010-2011. The coagulation and metabolic values of each patient were measured before and one and six hours after infusion of one liter normal saline. Then, the values of mentioned parameters on one and six hours after infusion were compared with baseline measures using repeated measures analysis of variance. RESULTS: Eighty four patients included in the present study (76% male). Hemoglobin (Hb) (df: 2; F=32.7; p<0.001), hematocrit (Hct) (df: 2; F=30.7; p<0.001), white blood cells (WBC) (df: 2; F=10.6; p<0.001), and platelet count (df: 2; F=4.5; p=0.01) showed the decreasing pattern following infusion of one liter of normal saline. Coagulation markers were not affected during the time of study (p>0.05). The values of blood urea nitrogen (BUN) showed statistically significant decreasing pattern (df: 2; F=5.6; p=0.007). Pressure of carbon dioxide (PCO2) (df: 2; F=6.4; p=0.002), bicarbonate (HCO3) (df: 2; F=7.0; p=0.001), and base excess (BE) (df: 2; F=3.3; p=0.04) values showed a significant deteriorating changes following hydration therapy. CONCLUSION: It seems that, the infusion of one liter normal saline during one hour will cause a statistically significant decrease in Hb, Hct, WBC, platelet, BUN, BE, HCO3, and PCO2 in trauma patients with mild severity of injury and stable condition. The changes in, coagulation profiles, pH, PvO2, and electrolytes were not statistically remarkable. PMID- 26495355 TI - A 55-Year Old Man with Acute Painful Flank Mass, a Case Report. AB - Lumbar hernias (LH) accounts for less than 1.5% of total hernia incidence. It can occur in two separate triangular areas of the flank. About 300 cases have been reported in the literature. Here, we report a 55-year old man with acute painful left side flank mass and final diagnosis of LH. The mass was appeared about three hours before admission and his pain was slight at first but became more severe gradually. He had stable vital sign and the only positive finding on his physical examination was the sphere shape, firm, mobile, and mild tender mass at his left flank. PMID- 26495356 TI - Thoracic Pneumorrhachis in Patient with Lumbar Fractures; a Case Report. AB - Pneumorrhachis as a relatively rare condition may be an indication of substantial intra-spinal column injury. Here we report a 39-year-old man was admitted because of low back pain and dyspenea after locating between motor vehicle and wall three days before admission. On arrival, physical exams and vital signs were normal. Computed tomography (CT) scan showed bilateral pleural effusion, fracture of ribs number 8, 9 and 10 in lower left side of thorax, fracture of vertebra in L2-L4, and air bubbles in upper thoracic spinal canal. PMID- 26495357 TI - Transient Unexplained Shock in 30-year-old Trauma Patient. AB - Shock as an inadequate tissue perfusion is one of the frequent causes of death in trauma patients. In this context, there are various reasons for hemodynamic instability and shock including hypovolemic (hemorrhagic), obstructive (cardiac tamponade, tension pneumothorax), cardiogenic, neurogenic, and rarely septic. In the present report, a 30-year-old trauma patient with full clinical signs and symptoms of shock referred while had unknown origin; it was finally recognized as anaphylactic shock. PMID- 26495358 TI - Confusing Hypoxia in a 21-Year-Old Intubated Multiple Trauma Patient. PMID- 26495359 TI - Peritoneal Dialysis as an Alternative Choice for Renal Replacement Therapy in Emergency Department. PMID- 26495360 TI - The Effects of Air Pollution on Cardiovascular and Respiratory Causes of Emergency Admission. AB - INTRODUCTION: Today, air pollution is one of the critical problems in metropolitans and necessary preparations are needed for confronting this crisis. The present study was based on the goal of determining the relationship of air pollutant levels with the rate of emergency admissions for respiratory and cardiovascular patients. METHODS: In the present retrospective cross-sectional study, all respiratory and cardiovascular patients, referred to emergency department during 2012, were assessed. The meteorological and air pollution data were collected. Information regarding the numbers and dates (month, day) of admission for respiratory and cardiovascular diseases was achieved from the hospital's electronic registration system. The relation of air pollution and respiratory and cardiovascular admissions were analyzed by generalize additive model (GAM). RESULTS: 5922 patients were assessed which included 4048 (68.36%) cardiovascular and 1874 (31.64%) respiratory. Carbon monoxide (CO) level was an independent risk factor of cardiovascular disease on the same day (RR=1.49; 95% CI: 1.25- 1.77; P<0.001), the day before (RR=1.22; 95% CI: 1.02- 1.45; P=0.03), and the last two days (RR=1.3; 95% CI: 1.09- 1.54; P<0.001). The same process was repeated for ozone (O3). In addition, the O3 level on the same day (RR=1.49; 95% CI: 1.25- 1.77; P<0.001), the day before (RR=1.22; 95% CI: 1.02- 1.45; P=0.03), the last two days (RR=1.3; 95% CI: 1.09- 1.54; P<0.001), and the last week (RR=1.004; 95% CI: 1.0007-1.008; P=0.02) were independent risk factors of respiratory admissions. The increased level of particulate matter less than 2.5 micrometers in diameter (PM2.5) like O3 led to growth in the admissions to emergency department. CONCLUSION: The findings of the present study suggested that rising levels of CO and O3 during two days leads to a significant increase in cardiovascular admission on the third day. Furthermore, increase in O3, PM2.5, nitrogen dioxide (NO2), and CO levels causes a rise in respiratory admissions to emergency department. PMID- 26495361 TI - A Retrospective Analysis of the Burn Injury Patients Records in the Emergency Department, an Epidemiologic Study. AB - INTRODUCTION: Burns can be very destructive, and severely endanger the health and lives of humans. It maybe cause disability and even psychological trauma in individuals. . Such an event can also lead to economic burden on victim's families and society. The aim of our study is to evaluate epidemiology and outcome of burn patients referring to emergency department. METHODS: This is a cross-sectional study was conducted by evaluation of patients' files and forensic reports of burned patients' referred to the emergency department (ED) of Akdeniz hospital, Turkey, 2008. Demographic data, the season, place, reason, anatomical sites, total body surface area, degrees, proceeding treatment, and admission time were recorded. Multinomial logistic regression was used to compare frequencies' differences among single categorized variables. Stepwise logistic regression was applied to develop a predictive model for hospitalization. P<0.05 was defined as a significant level. RESULTS: Two hundred thirty patients were enrolled (53.9% female). The mean of patients' ages was 25.3 +/- 22.3 years. The most prevalence of burn were in the 0-6 age group and most of which was hot liquid scalding (71.3%). The most affected parts of the body were the left and right upper extremities. With increasing the severity of triage level (OR=2.2; 95% CI: 1.02 4.66; p=0.046), intentional burn (OR=4.7; 95% CI: 1.03-21.8; p=0.047), referring from other hospitals or clinics (OR=3.4; 95% CI: 1.7-6.6; p=0.001), and percentage of burn (OR=18.1; 95% CI: 5.42-62.6; p<0.001) were independent predictive factor for hospitalization. In addition, odds of hospitalization was lower in patients older than 15 years (OR=0.7; 95% CI: 0.5-0.91; p=0.035). CONCLUSION: This study revealed the most frequent burns are encountered in the age group of 0-6 years, percentage of <10%, second degree, upper extremities, indoor, and scalding from hot liquids. Increasing ESI severity, intentional burn, referring from other hospitals or clinics, and the percentage of burn were independent predictive factors for hospitalization. PMID- 26495362 TI - Diagnostic Accuracy of Ultrasound in Detection of Traumatic Lens Dislocation. AB - INTRODUCTION: Traumatic eye injuries (TEI) involved about 3% of cases referred to the emergency departments of developing countries. Lens dislocation is one of the critical cases of ophthalmic emergencies. The present study was aimed to evaluate the diagnostic accuracy of ultrasonography in detection of traumatic lens dislocation. METHODS: In this cross-sectional study the findings of ultrasonography and orbital computed tomography (OCT) of head and face trauma patients, referred to Imam Reza hospital, Tabriz, Iran, from July 2013 to June 2014, have been compared. The sensitivity, specificity, positive and negative likelihood ratio, positive and negative predictive value, and accuracy of ultrasonography were calculated. Cohen's kappa coefficient was presented to assess the agreement of ultrasonography with OCT findings. RESULTS: One hundred thirty patients with the mean age of 35.4+/-18.0 were evaluated (75.4% male). Sensitivity and specificity of ultrasonography were 84.6% (95% Cl: 53.7-97.3) and 98.3% (95% Cl: 93.3- 99.7), respectively. In addition, positive and negative likelihood ratio were calculated 49.5 (95% Cl: 12.3-199.4) and 0.15 (95% Cl: 0.04 0.56), respectively. Cohen's kappa coefficient of 0.83 (95% Cl: 0.66-1.0; p<0.0001) was representative of excellent agreement of these two tests. CONCLUSION: The finding of this project was representative of 84.6% sensitivity, 98.3% specificity, and 96.9% accuracy of ultrasonography in detection of traumatic lens dislocation. It seems that in cases, which OCT is not possible, ultrasonography, could be an acceptable option to assess traumatic eye injuries. PMID- 26495363 TI - Outcome of Patients Underwent Emergency Department Thoracotomy and Its Predictive Factors. AB - INTRODUCTION: Emergency department thoracotomy (EDT) may serve as the last survival chance for patients who arrive at hospital in extremis. It is considered as an effective tool for improvement of traumatic patients' outcome. The present study was done with the goal of assessing the outcome of patients who underwent EDT and its predictive factors. METHODS: In the present study, medical charts of 50 retrospective and 8 prospective cases underwent emergency department thoracotomy (EDT) were reviewed during November 2011 to June 2013. Comparisons between survived and died patients were performed by Mann-Whitney U test and the predictive factors of EDT outcome were measured using multivariate logistic regression analysis. P < 0.05 considered statistically significant. RESULTS: Fifty-eight cases of EDT were enrolled (86.2% male). The mean age of patients was 43.27+/-19.85 years with the range of 18-85. The mean time duration of CPR was recorded as 37.12+/-12.49 minutes. Eleven cases (19%) were alive to be transported to OR (defined as ED survived). The mean time of survival in ED survived patients was 223.5+/-450.8 hours. More than 24 hours survival rate (late survived) was 6.9% (4 cases). Only one case (1.7%) survived to discharge from hospital (mortality rate=98.3%). There were only a significant relation between ED survival and SBP, GCS, CPR duration, and chest trauma (p=0.04). The results demonstrated that initial SBP lower than 80 mmHg (OR=1.03, 95% CI: 1.001-1.05, p=0.04) and presence of chest trauma (OR=2.6, 95% CI: 1.75-3.16, p=0.02) were independent predictive factors of EDT mortality. CONCLUSION: The findings of the present study showed that the survival rate of trauma patients underwent EDT was 1.7%. In addition, it was defined that falling systolic blood pressure below 80 mmHg and blunt trauma of chest are independent factors that along with poor outcome. PMID- 26495364 TI - An Audit of Emergency Department Accreditation Based on Joint Commission International Standards (JCI). AB - INTRODUCTION: Despite thousands of years from creation of medical knowledge, it not much passes from founding the health care systems. Accreditation is an effective mechanism for performance evaluation, quality enhancement, and the safety of health care systems. This study was conducted to assess the results of emergency department (ED) accreditation in Shohadaye Tajrish Hospital, Tehran, Iran, 2013 in terms of domesticated standards of joint commission international (JCI) standards. METHODS: This cohort study with a four-month follow up was conducted in the ED of Shohadaye Tajrish Hospital in 2013. The standard evaluation checklist of Iran hospitals (based on JCI standards) included 24 heading and 337 subheading was used for this purpose. The effective possible causes of weak spots were found and their solutions considered. After correction, assessment of accreditation were repeated again. Finally, the achieved results of two periods were analyzed using SPSS version 20. RESULTS: Quality improvement, admission in department and patient assessment, competency and capability test for staffs, collection and analysis of data, training of patients, and facilities had the score of below 50%. The mean of total score for accreditation in ED in the first period was 60.4+/-30.15 percent and in the second period 68.9+/-22.9 (p=0.005). Strategic plans, head of department, head nurse, resident physician, responsible nurse for the shift, and personnel file achieved the score of 100%. Of total headings below 50% in the first period just in two cases, collection and analysis of data with growth of 40% as well as competency and capability test for staffs with growth of 17%, were reached to more than 50%. CONCLUSION: Based on findings of the present study, the ED of Shohadaye Tajrish hospital reached the score of below 50% in six heading of quality improvement, admission in department and patient assessment, competency and capability test for staffs, collection and analysis of data, training of patients, and facilities. While, the given score in strategic plans, head of department, head nurse, resident physician, responsible nurse for the shifts, and personnel file was 100%. PMID- 26495365 TI - Quality of Life in Emergency Medicine Specialists of Teaching Hospitals. AB - INTRODUCTION: Quality of life (QOL) of emergency medicine specialists can be effective in providing services to patients. The aim of the present study was evaluating the lifestyle of emergency medicine practitioners, understanding their problems, and addressing the solutions to enhance and improve their lifestyles, in teaching hospitals in Iran. METHOD: This descriptive cross-sectional study was conducted on emergency medicine physicians in 10 teaching hospitals of Iran in 2011. Emergency physicians with at least three years of experience, who interested in the study, were enrolled in the project. All participants filled out the consent form and QOL questionnaires, and then underwent physical examinations and some medical laboratory tests. Categorical variables were reported as percentages, while continuous variables expressed as means and standard deviations. p <0.05 was considered statistically significant. RESULTS: Totally, 100 subjects participated in the study, of whom 48 were male. The mean and standard deviation of the physicians' age were 38.7+/-5.1 years. 43% of physicians had an average QOL, while 37% good. 96% of studied physicians had a good condition regarding habitual history, while 93% of them had a poor condition in performing screening tests. Exercise program and personal health in individuals with normal BMI were correlated with higher levels of QOL. BMI was higher in 40-50 years old subjects than youth. Hypertension was present in five cases (5%), hypercholesterolemia in six (6%), hypertriglyceridemia in six (6%), increased LDL in four (4%), low HDL in four (4%), and impaired FBS in 4 (4%). CONCLUSION: The findings showed that 63% of studied emergency physicians had an average level of QOL and other ones good. The majority of physicians had undesirable situation regarding the performance of screening tests. PMID- 26495366 TI - Diagnostic Accuracy of Ascites Fluid Gross Appearance in Detection of Spontaneous Bacterial Peritonitis. AB - INTRODUCTION: Spontaneous bacterial peritonitis (SBP) as a monomicrobial infection of ascites fluid is one of the most important causes of morbidity and mortality in cirrhotic patients. This study was aimed to determine the diagnostic accuracy of ascites fluid color in detection of SBP in cirrhotic cases referred to the emergency department. METHODS: Cirrhotic patients referred to the ED for the paracentesis of ascites fluid were enrolled. For all studied patients, the results of laboratory analysis and gross appearance of ascites fluid registered and reviewed by two emergency medicine specialists. The sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ration of the ascites fluid gross appearance in detection of SBP were measured with 95% confidence interval. RESULTS: The present project was performed in 80 cirrhotic patients with ascites (52.5 female). The mean of the subjects' age was 56.25+/-12.21 years (35-81). Laboratory findings revealed SBP in 23 (29%) cases. Fifty nine (73%) cases had transparent ascites fluid appearance of whom 17 (29%) ones suffered from SBP. From 21 (26%) cases with opaque ascites appearance, 15 (71%) had SBP. The sensitivity and specificity of the ascites fluid appearance in detection of SBP were 46.88% (Cl: 30.87-63.55) and 87.50% (95% Cl: 75.3-94.14), respectively. CONCLUSION: It seems that the gross appearance of ascites fluid had poor diagnostic accuracy in detection of SBP and considering its low sensitivity, it could not be used as a good screening tool for this propose. PMID- 26495367 TI - Gastric Perforation and Phlegmon Formation by Foreign BodyIngestion. AB - This is a case report of foreign body ingestion in a suicide attempt resulting in gastric perforation and phlegmon formation during a subsequent 6 month period that eventually required surgical intervention. The patient had a prolonged course because she did not report a history of foreign body ingestion and the initial evaluating physicians had no suspicion about possible foreign body ingestion and may have missed important findings on physical examination. Gastric perforation by a foreign object may have a slow course rather than presenting acute abdomen. The realization of a proper physical examination in the emergency department is key to an accurate diagnosis. PMID- 26495368 TI - Hashimoto Encephalopathy in Case of Progressive Cognitive Impairment; a Case Report. AB - Hashimoto's encephalopathy (HE) is a rare condition characterized by atypical psychiatric and heterogeneous neurological manifestations such as acute cerebral ischemia, seizure, tremors, myoclonus, psychosis, depression, cognitive disorders, and fluctuating loss of consciousness. Here, a case of 28 year-old man was reported who referred to the emergency department (ED) with different acute neurologic disorders and final diagnose of HE. PMID- 26495369 TI - Worsened Dysrhythmia after Chemical Cardioversion with Digoxin; a Case of Malpractice. PMID- 26495370 TI - Door to Electrocardiography (ECG) and Needle Times in Patients with Myocardial Infarction. PMID- 26495371 TI - The Effect of Intrathecal Administration of Muscimol on Modulation of Neuropathic Pain Symptoms Resulting from Spinal Cord Injury; an Experimental Study. AB - INTRODUCTION: Neuropathic pain can be very difficult to treat and it is one of the important medical challenging about pain treatments. Muscimol as a new agonist of gamma-Aminobutyric acid receptor type A (GABAA) have been introduced for pain management. Thus, the present study was performed to evaluate the pain alleviating effect of intrathecal injection of different doses of muscimol as GABAA receptor agonist in spinal cord injury (SCI) model of neuropathic pain. METHODS: In the present experimental study, male Wistar rats were treated by muscimol 0.01, 0.1 or 1 ug/10ul, intrathecally (i.t.) three weeks after induction of spinal cord injury using compression injury model. Neuropathic pain symptoms were assessed at before treatment, 15 minutes, one hour and three hours after muscimol administration. The time of peak effect and optimum dosage was assessed by repeated measures analysis of variance and analysis of covariance, respectively. RESULTS: Muscimol with the dose of 0.01 ug in 15 minutes caused to improve the thermal hyperalgesia (df: 24, 5; F= 6.6; p<0.001), mechanical hyperalgesia (df: 24, 5; F= 7.8; p<0.001), cold allodynia (df: 24, 5; F= 6.96; p<0.001), and mechanical allodynia (df: 24, 5; F= 15.7; p<0.001). The effect of doses of 0.1 ug and 1 ug were also significant. In addition, the efficacy of different doses of muscimol did not have difference on thermal hyperalgesia (df: 24, 5; F= 1.52; p= 0.24), mechanical hyperalgesia (df: 24, 5; F= 0.3; p= -0.75), cold allodynia (df: 24, 5; F= 0.8; p= -0.56), and mechanical allodynia (df: 24, 5; F= 1.75; p= 0.86). CONCLUSION: The finding of the present study revealed that using muscimol with doses of 0.01ug, 0.1ug, and 1 ug reduces the symptoms of neuropathic pain. In addition, the effect of GABAA agonist is short term and its effectiveness gradually decreases by time. PMID- 26495372 TI - Inter-Rater Agreement of Emergency Nurses and Physicians in Emergency Severity Index (ESI) Triage. AB - INTRODUCTION: Triage is one of the most important systems in patients prioritizing at the time of arrival to hospital. Based on the severity of the injury and the need for treatment, this system manages patients in the least time, which could lead to rotation of patients with high reliability and safety. Currently, the most accepted method for triage is emergency severity index (ESI) system, considered as five-level triage method, too. This method were implemented in Al Zahra Hospital of Isfahan by trained nurses since March to May 2010. This study was aimed to evaluate the accuracy of emergency nursing triage using ESI. METHODS: This prospective cross sectional study was carried out on 601 patients referred to Al-Zahra hospital of Isfahan through May 2010. The patients' triage level were determined by physicians and nurses separately and the results compared. To define the level of agreement between two groups (inter-rater agreement), the kappa index was evaluated. To specify the association between the time interval of initial triage and patient final status, Chi-Square test was applied using SPSS 18 statistical software. RESULTS: There was no significant difference between results of nurses and physicians triage (P<0/0001). The agreement level (kappa index) between two groups was 94% (95% CI: 0.931-0.957). Of 601 patients, 44.1% ones were hospitalized at the emergency department, 52.6% discharged and 3.3% died. The average of time interval between nursing triage and physician visit was 9.55 minutes at the level one triage, 21.64 minutes at level two, 26.03 minutes at level three, 26.93 minutes at level four, and 11.70 minutes at level five. CONCLUSION: It seems that there is an acceptable inter-rater agreement between emergency nurses and physicians regarding patients' triage in terms of ESI system. PMID- 26495373 TI - A Survey of Patients' Satisfaction in Emergency Department of Rasht Poursina Hospital. AB - INTRODUCTION: Patients' satisfaction (PS) is one of the important indicators of emergency care quality and outcomes of health care services. Some researchers believe that improve the work processes and hospital quality are not possible without caring to comments, requirements, expectations, and satisfaction of patients. The percent study was aimed to assess the emergency department (ED) PS of Poursina hospital, Rasht, Iran. METHODS: In this descriptive cross sectional study, the samples was selected from 378 patients admitted to ED of Poursina Hospital, Rasht, Iran, 2013. For each patient a check list and a questionnaire, including 37 questions about PS, were filled that had categories like physical comfort and residential aspects, physicians care, nurse care, behavioral aspect, and waiting time for service presentation. Data were analyzed by SPSS version 16. RESULTS: Entirely, 378 patients were entered to the study with mean age of 38.44+/-17.8 (60.8% male). The mean score of total satisfaction of ED patients was 106.94+/-13.62 (range: 72-144). The mean score of physical comfort was 33.25+/-4.76 out of the highest obtainable score of 55, nurse care 25.33+/-5.13 out of 40, physician care 24.34+/-3.38 out of 40, waiting time for services 13.42+/-5.48 out of 30, and behavioral aspects 10.58+/-2.66 out of 20. There were significant relation among PS, sex (P=0.0001), and the shift of admission (P=0.023). CONCLUSION: The findings of percent study showed that giving services to emergency clients in various fields such as physical comfort and residential aspects, physicians care, nurse care, and the total ED satisfaction is relatively agreeable. The periodic and continuous assessment as well as comparison of satisfaction and dissatisfaction parameters during the time, before and after performing the changes, could be effectual. PMID- 26495374 TI - Predictive Factors of Suicide Attempt and Non-Suicidal Self-Harm in Emergency Department. AB - INTRODUCTION: Suicide is the third cause of mortality in America, second leading cause of death in developed countries, and one of the major health problems. Self harm is self-inflicted damage to one's self with or without suicidal intent. In the present study, the predictive factors of suicide attempt and non-suicidal self-harm were evaluated in patients referred to emergency department (ED) with these problem. METHODS: The total number of 45 patients with suicide attempt or self-harm admitted to ED were included. Clinical symptoms, thoughts and behaviors of suicidal, and non-suicidal self-harm in these patients were evaluated at baseline. Suicidality, suicidal intent and ideation, non-suicidal self-injury, social withdrawal, disruptive behavior, and poor family functions were evaluated at admission time. Brief clinical visits were scheduled for the twelfth weeks. In the twelfth week, patients returned for their final visit to determine their maintenance treatment. Finally, data were analyzed using chi-squared and multiple logistic regression. RESULTS: Forty-five patients were included in the study (56.1% female). The mean age of patients was 23.3+/-10.2 years (range: 15-75; 33.3% married). Significant association of suicide and self-injury was presented at the baseline and in the month before attempting (p=0.001). The most important predictive factors of suicide and self-harm based on univariate analysis were depression (suicidal and non-suicidal items of Hamilton depression rating scale), anxiety, hopelessness, younger age, history of non-suicidal self-harm and female gender (p<0.05). The participants' quality of life analysis showed a significant higher quality in physical component summary (p=0.002), mental component summary (p=0.001), and general health (p=0.001) at follow up period. CONCLUSION: At the time of admission in ED, suicide attempt and non-suicidal self-harm are subsequent clinical markers for the patient attempting suicide again. The most independent predictive factors of suicide attempt and self-harm were poor family function, hopelessness, non-suicidality items of Hamilton depression rating scale, history of non-suicidal self-harm, and anxiety disorders. PMID- 26495375 TI - Potential Risk Factors of Death in Multiple Trauma Patients. AB - INTRODUCTION: rauma has been recognized as one of the leading causes of death in many countries for decades. Reduction in mortality and morbidity rate of trauma cases is one of the most important attitudes in this field. Evaluation of different risk factors have been considered as the main goal of some studies. The purpose of this study was determining potential risk factors of death in trauma patients. METHOD: In a retrograde study, data of 740 patients admitted during three years (2009-2011) were studied. Demographic data (sex and age), clinical factors (blood pressure, pulse rate, respiratory rate, Glasgow coma scale (GCS)), trauma characteristics (location, type of injury, etc.), as well as outcome of patients were evaluated. Data analyses was done using SPSS 18.0. Stepwise multivariate regression analysis was used for recognition of independent predictive factors of death in multiple trauma patients. RESULTS: Of those admitted, majority of patients were male (81.4%), 68% between 18 to 60 years, and 11.2% of them died during the course of treatment. Age; type of trauma; abnormal respiration rate, pulse rate, blood pressure; total GCS <=8; abnormal pupil size; and head and neck; vertebral, and extremities fractures were obtained as significant predictive factor of death. GCS<=8, head and neck fracture, and abnormal pulse rate were independent death predictors. CONCLUSION: We identified GCS<=8, head and neck fracture, and abnormal pulse rate as predictive factors of mortality after trauma, which remained independent in the presence of all other factors and potentially treatable. PMID- 26495376 TI - Clinical Presentation and Microbial Analyses of Contact Lens Keratitis; an Epidemiologic Study. AB - INTRODUCTION: Microbial keratitis is an infective process of the cornea with a potentially and serious visual impairments. Contact lenses are a major cause of microbial keratitis in the developed countries especially among young people. Therefore, the purpose of the present study was to evaluate the frequency and microbiological characteristic of CLK in patients referred to the emergency department (ED) of teaching hospitals, Babol, Iran. METHODS: This is a cross sectional study of all patients with contact lens induced corneal ulcers admitted to the teaching hospitals of Babol, Iran, from 2011- 2013. An ophthalmologist examined patients with the slit-lamp and clinical features of them were noted (including pain, redness, foreign body sensation, chemosis, epiphora, blurred vision, discomfort, photophobia, discharge, ocular redness and swelling). All suspected infectious corneal ulcers were scraped for microbial culture and two slides were prepared. Data were analyzed using SPSS software, version 18.0. RESULTS: A total of 14 patients (17 eyes) were recruited into the study (100% female). The patients' age ranged from 16-37 years old (mean age 21.58+/-7.23 years). The most prevalent observed clinical signs were pain and redness. Three samples reported as sterile. The most common isolated causative organism was pseudomonas aeroginosa (78.6%), Staphylococcus aureus 14.3%, and enterobacter 7.1%, respectively. Treatment outcome was excellent in 23.5%, good in 47.1%, and poor in 29.4% of cases. CONCLUSION: Improper lens wear and care as well as the lack of awareness about the importance of aftercare visits have been identified as potential risk factors for the corneal ulcer among contact lens wearers. Training and increasing the awareness of adequate lens care and disinfection practices, consulting with an ophthalmologist, and frequent replacement of contact lens storage cases would greatly help reducing the risk of microbial keratitis. PMID- 26495377 TI - Essential Thrombocytosis Following Multiple Psychic Traumas. AB - The associations between exposure to traumatic events and psychiatric disorders such as posttraumatic stress disorder (PTSD), depression, and anxiety have been established. It is important that clinicians notice to this phenomenon and avoid from inappropriate interpretations and additional laboratory tests. Here, a case of 45-year-old man with Essential thrombocytosis developed after multiple psychic traumas was introduced. PMID- 26495378 TI - Pneumatic Rupture of Rectosigmoid; a Case Report. AB - Pneumatic rectosigmoid rapture is usually occurred following the inappropriate fun by direct entering a high volume of the air through the pneumatic device to the anus. Such an event was reported for the first time in 1904 by Stone. Diagnosis and treatment of such injuries are often delayed because of some social limitations and preventing the patient form explaining the event. Colon sigmoid rupture and pneumoperitoneum is one of the most dangerous and life treating complications of entering a high volume of the air to the rectum in a short time. There are only a few reports regarding the similar cases. Here, a case of pneumatic rectosigmoid rapture was reported in a 53 year-old male following an inappropriate fun. PMID- 26495379 TI - Spontaneous Spinal Epidural Hematoma; a Case Report. AB - Spontaneous spinal epidural hematoma (SSHE) is a rare entity can have several reasons. Its prevalence in population is 0.1 per 100,000 with the male to female ratio of 1/4:1. For the first time Jackson in 1869 reported a case of SSHE and after that, it was declared as several hundred cases in literatures. Here, a case of SSHE was reported in a 52-year-old male referred to emergency department following severe low back pain. PMID- 26495380 TI - Part 1: Simple Definition and Calculation of Accuracy, Sensitivity and Specificity. PMID- 26495381 TI - Erythrocyte Sedimentation Rate Measurement Using as a Rapid Alternative to the Westergren Method. AB - INTRODUCTION: Erythrocyte sedimentation rate (ESR) remains as one of the most reliable tests in clinical practices. Yet its use is time consuming and requires a large blood sample. The aim of this study was assessing a faster and reliable method of ESR estimation. METHODS: An ESR estimation method was described and performed on 108 patients using capillary tube (micro ESR) and capillary peripheral blood. Micro ESR results at different intervals were measured and compared with Westergren ESR (conventional ESR) estimation by Pearson and Spearman's coefficients. A regression equation was derived to predict conventional ESR values based on micro ESR results. The agreement of two measurements was demonstrated using the Bland-Altman plot. RESULTS: Micro ESR results at 20 minutes showed the earliest close correlation with conventional ESR results at one hour (r = 0.987). The presented regression equation was able to closely predict ESR values (r(2) = 0.974) and the Bland-Altman plot showed an acceptable agreement between converted and conventional ESR measurements. CONCLUSION: Using capillary tube and capillary blood sample (micro ESR) appears to be a faster, cheaper, more reliable, and precise tool for ESR measurement in the ED. The results have acceptable correlation with conventional ESR, especially at 20 minutes of measurement. PMID- 26495382 TI - Diagnostic Accuracy of Optic Nerve Ultrasonography and Ophthalmoscopy in Prediction of Elevated Intracranial Pressure. AB - INTRODUCTION: Elevated intracranial pressure (ICP) is a major and potentially lethal disorder in patients admitted to the emergency department (ED). Several methods are being used to investigate for elevated ICP. Here we assessed and compared the diagnostic accuracy of two existing tools of ophthalmoscopy and optic nerve ultrasonography in detection of elevated ICP. METHODS: 131 participants with probable elevation of ICP referred to the emergency department of Al-Zahra Hospital, Isfahan, Iran, from 2012 to 2014, were enrolled. Brain computed tomography (CT) scan, ultrasonography of optic nerve sheath, and ophthalmoscopy were performed for them. The optic nerves sheath with diameter more than 5 millimeters was considered as elevated ICP. Widening of optic nerve, ocular venous engorgement, blurring, hemorrhage over optic disk, elevation of optic disk, and retinal venous tortuosity were recorded as evidences of ICP rising in ophthalmoscopy. Diagnostic accuracy of the two tools in prediction of ICP rising were compared with the results of brain CT scan as a gold standard. RESULTS: The mean age of participants was 46.29 +/- 10 years (77% male). The number of diagnosed elevated ICPs with ophthalmoscopy and ultrasound were 98 (74.8%) and 102 (77.9%) cases, respectively. The calculated sensitivity and specificity of ophthalmoscopy and ultrasonography in detection of ICP rising were 100.0% (95% CI: 88.6-100.0) and 35.4% (95% CI: 26.0-46.2), 100.0% (95% CI: 84.0 100.0) and 31.9% (95% CI: 23.0-41.7), respectively. CONCLUSION: The present study revealed that bedside ultrasonography of optic nerve sheath and ophthalmoscopy have enough accuracy for the screening of patients with probable elevation of ICP. Of course, it should be considered that despite the high sensitivity of both tools, their specificity is low. PMID- 26495383 TI - A Randomized Clinical Trial of Intravenous and Intramuscular Ketamine for Pediatric Procedural Sedation and Analgesia. AB - INTRODUCTION: Ketamine is an agent broadly used for pediatric procedural sedation and analgesia in emergency departments. It has been found to be safe and with a low risk of complications. Choosing between intravenous (IV) and intramuscular (IM) injections is a matter of concern, so we did a comparison between the two methods in terms of their efficacy and rate of complications. METHODS: This single-blind clinical trial recruited 240 children (age: three months to 15 years, weight > 5 kg), who underwent short and painful procedures at the emergency departments. They were randomly allocated to two groups of 120 patients to receive either IV or IM ketamine with of 1.5 and 4 mg/kg doses, respectively. Indications for use, dose, side effects, and efficacy of the medications as well as duration of the procedure and time to recovery were compared between the two groups. RESULTS: The mean age of the IV and IM groups were 6.5 +/- 3.6 and 3.05 +/- 2.6 years, respectively (p < 0.001). The onset of action of ketamine was 1.7 +/- 1.1 minutes in the IV group and 8.6 +/- 3.1 in the IM ones (p < 0.001). Patients of the IV and IM groups remained in optimal sedation for 20.6+/-12.0 and 37.2+/-11.8 minutes, respectively (P < 0.001). Time until emergency department discharge was 65.3 +/- 36.9 minutes in the IV group and 72.2 +/- 14.5 in the IM group (P = 0.40). Ketamine had excellent and moderate efficacy in 66.7% and 32.5% of the IV group and 70.0% and 25.0% in the IM group, respectively (p = 0.02). Totally, 60.0% of IV group patients and 40.0% of IM group experienced drug side effects (p = 0.21). Need for rescue dose was significantly higher in IV group (26.7% vs. 10.0%; p < 0.001). Finally, recovery was tranquil and comfortable in 88 patients (73.3%) of the IV group and 108 patients (90.0%) of the IM group (p = 0.06). CONCLUSION: We found that although the sedative and analgesic effects of IM and IV ketamine are not significantly different, duration of effect and onset of action are more desirable in the IV group for suturing, fracture reduction, and foreign body removal. Meanwhile, the IM method can lead to lesser need of rescue doses. PMID- 26495384 TI - Oral Midazolam-Ketamine versus Midazolam alone for Procedural Sedation of Children Undergoing Computed Tomography; a Randomized Clinical Trial. AB - INTRODUCTION: Motion artifacts are a common problem in pediatric radiographic studies and are a common indication for pediatric procedural sedation. This study aimed to compare the combination of oral midazolam and ketamine (OMK) with oral midazolam alone (OM) as procedural sedatives among children undergoing computed tomography (CT) imaging. METHODS: The study population was comprised of six-month to six-year old patients with medium-risk minor head trauma, who were scheduled to undergo brain CT imaging. Patients were randomly allocated to two groups: one group received 0.5 mg/kg midazolam (OM group; n = 33) orally and the other one received 0.2 mg/kg midazolam and 5 mg/kg ketamine orally (OMK group; n=33). The vital signs were monitored and recorded at regular intervals. The primary outcome measure was the success rate of each drug in achieving adequate sedation. Secondary outcome measures were the time to achieve adequate sedation, time to discharge from radiology department, and the incidence of adverse events. RESULTS: Adequate sedation was achieved in five patients (15.2%) in OM group and 15 patients (45.5%) in OMK group, which showed a statistically significant difference between the groups (p = 0.015). No significant difference was noted between OM and OMK groups with respect to the time of achieving adequate sedation (33.80 +/- 7.56 and 32.87 +/- 10.18 minutes, respectively; p = 0.854) and the time of discharging from radiology department (89.60 +/- 30.22 and 105.27 +/- 21.98 minutes, respectively; p=0.223). The complications were minor and similar among patients of both groups. CONCLUSION: This study demonstrated that in comparison with OM, OMK was more effective in producing a satisfactory level of sedation in children undergoing CT examinations without additional complications; however, none of these two regimens fulfilled clinical needs for procedural sedation. PMID- 26495385 TI - Comparison of Intravenous Metoclopramide and Acetaminophen in Primary Headaches: a Randomized Controlled Trial. AB - INTRODUCTION: Headache is the most common neurologic symptom among referees to the emergency department (ED), while the best treatment has not yet been found. Therefore, in the present study pain relief effects of metoclopramide and acetaminophen were compared in patients suffered acute primary headache. METHODS: This study was a double-blind randomized clinical trial performed in Imam Khomeini Hospital, Urmia, Iran, through July to October 2014. All adult patients, with acute primary (migraine, tension type and cluster) headache referred to the ED were included in this study. Pain severity was measured with 10 centimeters numeric rating scales. The patients were randomized into two groups of intravenous (IV) metoclopramide (10 milligrams) and acetaminophen (1 gram). Pain score, success rate, and drug complications were compared between the 2 groups at 0, 15, 30, 60, and 120 minutes after injection. RESULTS: 100 patients were equally categorized into two groups (mean age of 32 +/- 13.2 years; 51.2% male). Initial pain score in metoclopramide and acetaminophen groups were 9.1 and 9.4, respectively (p = 0.46). IV metoclopramide did not have any analgesic effect at 15 minutes, but had good effect at 30 minutes. While, the analgesic effect of acetaminophen initiated after 15 minutes. After 2 hours, both drugs had good therapeutic effect on primary headaches (p < 0.001). CONCLUSION: The present study demonstrated that efficacy of metoclopramide for pain relief in primary headaches is lower than acetaminophen. In this regard, success rate of acetaminophen was 42.0% versus 0% for metoclopramide within 15 minutes. The efficacy of acetaminophen continued until 60 minutes. PMID- 26495386 TI - Brachial Artery Aneurysm as a Limb Threatening Condition: a Case Report. AB - Brachial artery aneurysms are rare but potentially limb threatening condition. The presented case here is a 52-year old male referred to the emergency department complaining a sudden onset and progressive pain with coldness of his right upper extremity during brushing. The right upper extremity was pulseless and three-dimensional computed tomography showed an aneurysm of the proximal right brachial artery associated with arterial occlusion in its distal branch. Embolectomy was done, the aneurysm resected, and the artery successfully re vascularised by interposing a saphenous vein graft. PMID- 26495387 TI - Periampullary Diverticulum Perforation Following Endoscopic Retrograde Cholangiopancreatography (ERCP); a Case Report. AB - Endoscopic Retrograde Cholangiopancreatography (ERCP) is widely used for the diagnosis and treatment of biliary and pancreatic tract disease. Perforation is a rare complication of it, but it is associated with high rate of mortality, an overall mortality rate of 1.0-1.5%. Here, a case of massive subcutaneous emphysema following ERCP was reported without an obvious retroperitoneal or peritoneal perforation. PMID- 26495388 TI - Battered Child Syndrome; a Case Study. AB - One of the important and usual missed causes of pediatric traumas is child abuse. This ominous phenomenon, which can be presented physically, psychologically, sexually, and emotionally has grown significantly in recent years. Many children are not diagnosed in the early stages of evaluation. Battered Child Syndrome is used to describe the clinical condition of the child serious physical abuse by parents or caregivers. Medical staff should always keep the syndrome in their mind for those brought to the emergency department with trauma. In this report, we described a patient complained of dysphagia following a falling from a height and multiple epidural hematomas and final diagnosis of battered child syndrome. PMID- 26495389 TI - Medical Journalism and Emergency Medicine. PMID- 26495390 TI - Evidence Based Emergency Medicine Part 2: Positive and negative predictive values of diagnostic tests. PMID- 26495391 TI - The Value of Serum NR2 Antibody in Prediction of Post-Cardiopulmonary Resuscitation Survival. AB - INTRODUCTION: N-methyl-D-aspartate receptor subunits antibody (NR2-ab) is a sensitive marker of ischemic brain damage in clinical circumstances, such as cerebrovascular accidents. We aimed to assess the value of serum NR2-ab in predicting the post-cardiopulmonary resuscitation (CPR) survival. METHODS: In this cohort study, we examined serum NR2-ab levels 1 hour after the return of spontaneous circulation (ROSC) in 49 successfully resuscitated patients. Patients with traumatic or asphyxic arrests, prior neurological insults, or major medical illnesses were excluded. Participants were followed until death or hospital discharge. Demographic data, coronary artery disease risk factors, time before initiation of CPR, and CPR duration were documented. In addition, Glasgow coma scale (GCS), blood pressure, and survival status of patients were recorded at 1, 6, 24, and 72 hour(s) after ROSC. Descriptive analyses were performed, and the Cox proportional hazard model was applied to assess if NR2-ab level is an independent predictive factor of survival. RESULTS: 49 successfully resuscitated patients were evaluated; 27 (55%) survived to hospital discharge, 4 (8.1%) were in vegetative state, 10 (20.4%) were physically disabled, and 13 (26.5%) were physically functional. Within 72 hours of ROSC all of the 12 NR2-ab positive patients died. In contrast, 31 (84%) of the NR2-ab negative patients survived. Sensitivity, specificity, positive and negative likelihood ratios of NR2-ab in prediction of survival were 54.5% (95%CI=32.7%-74.9%), 100% (95%CI=84.5%-100%), infinite, and 45.5% (95%CI=28.8%-71.8%), respectively. Subsequent analysis showed that both NR2-ab status and GCS were independent risk factors of death. CONCLUSIONS: A positive NR2-ab serum test 1 hour after ROSC correlated with lower 72-hour survival. Further studies are required to validate this finding and demonstrate the value of a quantitative NR2-ab assay and its optimal time of measurement. PMID- 26495392 TI - Diagnostic Accuracy of Cincinnati Pre-Hospital Stroke Scale. AB - INTRODUCTION: Stroke is recognized as the third cause of mortality after cardiovascular and cancer diseases, so that lead to death of about 5 million people, annually. There are several scales to early prediction of at risk patients and decreasing the rate of mortality by transferring them to the stroke center. In the present study, the accuracy of Cincinnati pre-hospital stroke scale was assessed. METHODS: This was a retrospective cross-sectional study done to assess accuracy of Cincinnati scale in prediction of stroke probability in patients referred to the emergency department of Poursina Hospital, Rasht, Iran, 2013 with neurologic symptoms. Three criteria of Cincinnati scale including facial droop, dysarthria, and upper extremity weakness as well as the final diagnosis of patients were gathered. Sensitivity, specificity, predictive values, and likelihood ratios of Cincinnati scale were calculated using SPSS version 20. RESULTS: 448 patients were assessed. The agreement rate of Cincinnati scale and final diagnosis was 0.483 +/- 0.055 (p<0.0001). The sensitivity of 93.19% (95% Cl: 90.11-95.54), specificity of 51.85% (95% Cl: 40.47-63.10), positive predictive value of 89.76% (95% Cl: 86.27-92.62), negative predictive value of 62.69% (95% Cl: 55.52-72.45), positive likelihood ratio of 1.94% (95% Cl: 1.54 2.43), and negative likelihood ratio of 0.13% (95% Cl: 0.09-0.20) were calculated. CONCLUSION: It seems that pre-hospital Cincinnati scale can be an appropriate screening tool in prediction of stroke in patients with acute neurologic syndromes. PMID- 26495393 TI - Comparison of the Analgesic Effect of Intravenous Acetaminophen and Morphine Sulfate in Rib Fracture; a Randomized Double-Blind Clinical Trial. AB - INTRODUCTION: Rib fracture is one of the common causes of trauma disabilities in many events and the outcome of these patients are very extensive from temporary pain management to long-term significant disability. Control and management of the pain in such patients is one of the most important challenges in emergency departments. Thus, the aim of the present study was assessing the efficacy of IV acetaminophen in pain control of patients with rib fracture. METHODS: In this double-blind clinical trial, 54 patients over 18 years of age, referred to two educational hospitals with rib fracture, were entered. Patients were randomly categorized in two groups of morphine sulfate (0.1 milligram per kilogram of body weight) and IV acetaminophen (1gram), as single-dose infused in 100 cc normal saline. The pain severity was measured by numeric rating scale (NRS) on arrival and 30 minutes after drug administration. At least three scores reduction was reported as therapeutic success. RESULTS: The mean and standard deviation of patients' age was 41.2 +/- 14.1 years. There is no difference in gender (p=0.24) and age frequency (p=0.77) between groups. 30 minutes after drug administration the mean of pain severity were 5.5 +/- 2.3 and 4.9 +/- 1.7 in morphine and acetaminophen groups, respectively (p=0.23). Success rate in morphine and acetaminophen groups were 58.6% (95% Cl: 39.6-77.7) and 80% (95% Cl: 63.2-96.7), respectively, (p=0.09). Only 3 (5.6%) patients had dizziness (p=0.44) and other effects were not seen in any of patients. CONCLUSION: The findings of the present study shows that intravenous acetaminophen and morphine have the same therapeutic value in relieving the pain of rib fracture. The success rate after 30 minutes drug administration were 80% and 58.6% in acetaminophen and morphine groups, respectively. Presentation of side effects was similar in both groups. PMID- 26495394 TI - Brief Emergency Department Patient Satisfaction Scale (BEPSS); Development of a New Practical Instrument. AB - INTRODUCTION: Methodologically correct assessment of patient satisfaction (PS) plays a crucial role for quality-improvement purposes. Evaluation of Iranian literature on emergency department's PS resulted in an emerging need for developing a new instrument with satisfactory psychometric properties. The present study, aimed to develop and initially validate a scale to measure PS in emergency departments. METHODS: A sample of 301 patients was selected in 2014 from two hospitals in Tehran. A pool of 24 items was prepared for administering. An item analysis was conducted to evaluate the quality of each item. Validity and reliability of the scale were evaluated. The data were analyzed using SPSS. RESULTS: Item analysis and exploratory factor analysis yielded in a 20-item scale in five domains named emergency department staff, emergency department environment, physician care satisfaction, general patient satisfaction, and patient's family's satisfaction. Validity and factor structure of the scale were reported satisfactory. Reliability coefficients of the domains ranged between 0.75 and 0.88. CONCLUSION: The findings of the present study provided evidence for psychometric properties of a newly developed scale for PS assessment in emergency departments. Five underlying components of PS were found in the item pool. In sum, this scale may be used in research and emergency departments to measure PS. PMID- 26495395 TI - Comparison of Oral Midazolam and Promethazine with Oral Midazolam alone for Sedating Children during Computed Tomography. AB - INTRODUCTION: Both midazolam and promethazine are recommended to be used as sedatives in many studies but each have some side effects that limits their use. Combination therapy as an alternative method, may decreases these limitations. Therefore, this study aimed to compare midazolam with midazolam-promethazine regarding induction, maintenance, and recovery characteristics following pediatric procedural sedation and analgesia. METHODS: Children under 7 years old who needed sedation for being CT scanned were included in this double-blind randomized clinical trial. The patients were randomly divided into 2 groups: one only received midazolam (0.5 mg/kg), while the other group received a combination of midazolam (0.5 mg/kg) and promethazine (1.25 mg/kg). University of Michigan Sedation Scale (UMSS) was used to assess sedation induction. In addition to demographic data, the child's vital signs were evaluated before prescribing the drugs and after inducing sedation (reaching UMSS level 2). The primary outcomes in the present study were onset of action after administration and duration of the drugs' effect. RESULTS: 107 patients were included in the study. Mean onset of action was 55.4+/-20.3 minutes for midazolam and 32.5+/-11.1 minutes for midazolam-promethazine combination (p<0.001). But duration of effect was not different between the 2 groups (p=0.36). 8 (7.5%) patients were unresponsive to the medication, all 8 of which were in the midazolam treated group (p=0.006). Also in 18 (16.8%) cases a rescue dose was prescribed, 14 (25.9%) were in the midazolam group and 4 (7.5%) were in the midazolam-promethazine group (p=0.02). Comparing systolic (p=0.20) and diastolic (p=0.34) blood pressure, heart rate (p=0.16), respiratory rate (p=0.17) and arterial oxygen saturation level (p=0.91) showed no significant difference between the 2 groups after intervention. CONCLUSION: Based on the findings of this study, it seems that using a combination of midazolam and promethazine not only speeds up the sedation induction, but also decreases unresponsiveness to the treatment and the need for a rescue dose. PMID- 26495396 TI - Diagnostic Accuracy of Chest x-Ray and Ultrasonography in Detection of Community Acquired Pneumonia; a Brief Report. AB - INTRODUCTION: Chest x-ray (CXR) is the simplest diagnostic tool of Community Acquired Pneumonia (CAP), but it has some limitation. Therefore, the aim of this study is comparing the diagnostic accuracy of CXR and chest ultrasonography (CUS) in detection of CAP. METHODS: In the present study, a consecutive sample of suspected patients with CAP was underwent CUS, CXR, and chest computed tomography (CT) scan. Diagnostic accuracy of CUS and CXR was assessed by calculating the sensitivity, specificity, predictive values, and likelihood ratios using SPSS 20 statistical software. RESULTS: 30 patients with CAP were enrolled (93.3% male with mean age of 63.8 +/- 18.3 years). Sensitivity of CUS and CXR in detection of CAP were 100.0% (95% Cl: 85.4-100.0) and 93.1% (95% Cl: 75.8-98.8), respectively. Specificity of CXR was 0.0 (95% Cl: 0.0-94.5), while the CUS specificity was not calculable. CONCLUSION: Findings of the present study demonstrated on the higher diagnostic accuracy of CUS versus CXR in detection of pneumonia. PMID- 26495397 TI - Pharyngeal Aspiration of Complete Upper Denture in 90-Year-Old Man; a Case Report. AB - Foreign body aspiration is unusual in adults, except those who are debilitated or have neuropsychiatric disorders. It can be a life-threatening situation and it often requires a high index of suspicion, because the diagnosis can be obscure. Prompt diagnosis and intervention through foreign body retrieval are critical to prevent significant morbidity and mortality. We present a case of denture aspiration by a debilitated 90 years old man. He had aspirated his complete upper denture to pharynx causing incomplete obstruction with pleasure whistling respiratory sound, dyspnea, dysphagia and dysphonia. He underwent successful retrieval of the dental plate manually by fingers with complete resolution of symptoms. PMID- 26495398 TI - Periumbilical Pain with Radiation to Both Legs Following Tarantula Bite; a Case Report. AB - Tarantulas have recently become as pets in most parts of the world that increased the probability of encountering emergency physicians with patients hurt with these spiders. Their attacks usually do not cause general manifestation, however there are some case reports in this regard. Here, a 40-year-old man was reported who was referred to the emergency department with severe periumbilical pain that radiated to both legs and diagnosed as a victim of tarantula bite. Such symptoms usually are belonging to other spiders like Black Widow spider, but it seems that tarantula can mimic them in some cases, too. PMID- 26495399 TI - Odontogenic Pain as the Principal Presentation of Vertebral Artery Pseudoaneurysm; a Case Report. AB - Dissection of the vertebral artery is an important but rare cause of cerebrovascular accidents. Here we report a 48-year-old man with toothache since 4 days before who presented to the emergency department with neck pain and final diagnosis of dissecting right vertebral artery pseudoaneurysm. To our knowledge, this maybe the first report of odontogenic pain as the first manifestation of vertebral artery pseudoaneurysm in the literatures. PMID- 26495400 TI - An 88-Year-Old Man with Sudden Onset Abdominal Pain. PMID- 26495401 TI - Diagnostic Accuracy of Ultrasonography and Radiography in Detection of Pulmonary Contusion; a Systematic Review and Meta-Analysis. AB - INTRODUCTION: Ultrasonography is currently being used as one of the diagnostic modalities in various medical emergencies for screening of trauma patients. The diagnostic value of this modality in detection of traumatic chest injuries has been evaluated by several studies but its diagnostic accuracy in diagnosis of pulmonary contusion is a matter of discussion. Therefore, the present study aimed to determine the diagnostic accuracy of ultrasonography and radiography in detection of pulmonary contusion through a systematic review and meta-analysis. METHODS: An extended systematic search was performed by two reviewers in databases of Medline, EMBASE, ISI Web of Knowledge, Scopus, Cochrane Library, and ProQuest. They extracted the data and assessed the quality of the studies. After summarization of data into true positive, false positive, true negative, and false negative meta-analysis was carried out via a mixed-effects binary regression model. Further subgroup analysis was performed due to a significant heterogeneity between the studies. RESULTS: 12 studies were included in this meta analysis (1681 chest trauma patients, 76% male). Pooled sensitivity of ultrasonography in detection of pulmonary contusion was 0.92 (95% CI: 0.81-0.96; I2= 95.81, p<0.001) and its pooled specificity was calculated to be 0.89 (95% CI: 0.85-0.93; I2 = 67.29, p<0.001) while these figures for chest radiography were 0.44 (95% CI: 0.32-0.58; I2= 87.52, p<0.001) and 0.98 (95% CI: 0.88-1.0; I2= 95.22, p<0.001), respectively. Subgroup analysis showed that the sources of heterogeneity between the studies were sampling method, operator, frequency of the transducer, and sample size. CONCLUSION: Ultrasonography was found to be a better screening tool in detection of pulmonary contusion. Moreover, an ultrasonography performed by a radiologist / intensivist with 1-5MHz probe has a higher diagnostic value in identifying pulmonary contusions. PMID- 26495402 TI - Comparing the Antiemetic Effects of Ondansetron and Metoclopramide in Patients with Minor Head Trauma. AB - INTRODUCTION: Nausea and vomiting are the most common complications after minor head trauma that increases the risk of intracranial pressure rising. Therefore, the present study was aimed to compare the antiemetic effects of metoclopramide and ondansetron in the treatment of post-traumatic nausea and vomiting. METHODS: The study was a controlled, randomized, double blind clinical trial, which was conducted in the first 6 months of 2014 in emergency department Al-Zahra and Kashani Hospitals in Isfahan, Iran. The patients with minor head trauma associated with nausea and vomiting were randomly divided into 2 groups: treatment with metoclopramide (10mg/2ml, slow injection) and treatment with ondansetron (4mg/2ml, slow injection). The comparison between the 2 groups was done regarding antiemetic efficacy and side effects using SPSS 21 statistical software. RESULTS: 120 patients with minor head trauma were distributed and studied into two groups of 60 patients (mean age 35.6+/-14.1 years; 50.0% male). Administration of both ondansetron and metoclopramide significantly reduced the severity of nausea (P<0.001). Changes in the severity of nausea in both groups before and after the treatment revealed that nausea had been decreased significantly in both groups (P < 0.001). The incidence of fatigue (p=0.44), headache (p=0.58) and dystonia (p=0.06) had no significant difference in the two groups but the incidence of drowsiness and anxiety in the metoclopramide group was significantly higher (P < 0.001). CONCLUSION: The present study indicated that the treatment effectiveness of ondansetron and metoclopramide are similar. However, incidence of drowsiness and anxiety in the metoclopramide was considerably higher. Since these complications can have adverse effects on the treatment of patients with brain injury, it is suggested that it may be better to use ondansetron in these patients. PMID- 26495403 TI - An Epidemiologic Study of Traumatic Brain Injuries in Emergency Department. AB - INTRODUCTION: Traumatic brain injuries (TBI) are one of the most important causes of death in patients under the age of 25 years and is responsible for one third of total deaths caused by trauma. Therefore, knowing its epidemiologic pattern in different populations seems vital. Therefore, this study aims to examine the epidemiologic pattern of TBI in emergency department. METHODS: In this cross sectional study, the profiles of 1000 patients affected by TBI were selected using simple random sampling. The examined variables in this study included demographic, season, mechanism of injury, accompanying injuries, level of consciousness, hospitalization duration, computed tomography (CT) scan results, needing surgery, admission to intensive care unit, and outcome of the patient. In the end, independent risk factors for the death of patients were determined. RESULTS: 1000 patients suffering from were studied (81.8% male; mean age 38.5+/ 21.7 years). The frequency of their referral to hospital in spring (31.4%) was more (p<0.01). 45.9% of the patients had a level of consciousness less than 9 based on the Glasgow Coma Scale (GCS). Subdural (45.9%) and epidural bleeding (23.7%) were the most common findings in CT scans in this study (p<0.001). Finally, 233 (23.3%) of the patients were dead. Over 60 years of age, falling and motorcycle accidents, intracranial hemorrhage accompanied by brain contusion, subdural bleeding, a GCS of less than 9, and the need to be admitted to intensive care unit were independent risk factors of death in TBI. CONCLUSION: Age Over 60 years, falling and motorcycle accidents, intracranial hemorrhage accompanied by brain contusion, subdural bleeding, a GCS of less than 9, and need to be admitted to intensive care unit were independent risk factors for the death in TBI patients. PMID- 26495404 TI - The Effect of Emergency Department Overcrowding on Efficiency of Emergency Medicine Residents' Education. AB - INTRODUCTION: Creating a calm and stress-free environment affects education significantly. The effects of the emergency department overcrowding (EDO) on the training of emergency medicine residents (EMR) is a highly debated subject. Therefore, this study aimed to evaluate the effect of EDO on efficiency of EMR's education. METHODS: In this cross-sectional study, the effects of overcrowding on EMR's education in the resuscitation room and acute care unit. Data collection was done using a questionnaire, which was filled out by the second year EMRs. The crowding level was calculated based on the national emergency department overcrowding scale (NEDOCS). The relationship between the two studied variables was evaluated using independent sample t-test and SPSS 21 statistical software. RESULTS: 130 questionnaires were filled out during 61 shifts. 47 (77.05%) shifts were overcrowded. The attend's ability to teach was not affected by overcrowding in the resuscitation room (p=0.008). The similar results were seen regarding the attend's training ability in the acute care unit. CONCLUSION: It seems that the emergency department overcrowding has no effect on the quality of education to the EMRs. PMID- 26495405 TI - The Effect of Blood Loss in the Presence and Absence of Severe Soft Tissue Injury on Hemodynamic and Metabolic Parameters; an Experimental study. AB - INTRODUCTION: The effect of severe soft tissue injury on the severity of hemorrhagic shock is still unknown. Therefore, the present study was aimed to determine hemodynamic and metabolic changes in traumatic/hemorrhagic shock in an animal model. METHODS: Forty male rats were randomly divided into 4 equal groups including sham, hemorrhagic shock, soft tissue injury, and hemorrhagic shock + soft tissue injury groups. The changes in blood pressure, central venous pressure (CVP) level, acidity (pH), and base excess were dynamically monitored and comparedsented. RESULTS: Mean arterial blood pressure decreased significantly in hemorrhagic shock (df: 12; F=10.9; p<0.001) and severe soft tissue injury + hemorrhagic shock (df: 12; F=11.7; p<0.001) groups 15 minutes and 5 minutes after injury, respectively. A similar trend was observed in CVP in severe soft tissue injury + hemorrhagic shock group (df: 12; F=8.9; p<0.001). After 40 minutes, pH was significantly lower in hemorrhagic shock (df: 12; F=6.8; p=0.009) and severe soft tissue injury + hemorrhagic shock (df: 12; F=7.9; p=0.003) groups. Base excess changes during follow ups have a similar trend. (df: 12; F=11.3; p<0.001). CONCLUSION: The results of this study have shown that the effect of hemorrhage on the decrease of mean arterial blood pressure, CVP, pH, and base excess is the same in the presence or absence of soft tissue injury. PMID- 26495406 TI - Non-Judicial Hanging in Guilan Province, Iran between 2011 and 2013. AB - INTRODUCTION: Hanging is one of the most commonly used way to commit suicide in many countries. This method used in suicide is considered a problem in Iran too, but no clear data exists regarding hanging in different regions or the country as a whole. Because of the epidemiologic differences in non-judicial hanging in different regions, this study aimed to assess it in Gilan province, Iran between 2011 and 2013. METHODS: In this cross-sectional study, profiles of hanging cases registered in Poorsina hospital in Gilan, Iran between 2011 and 2013 were evaluated. Age, sex, marital status, place of residency, level of education, occupation, history of suicide, history of clinical illness, season of suicide and hanging outcome were evaluated. RESULTS: 59 cases of hanging (mean age 31.4 +/- 13.1 years and 83.0% male) were evaluated. 12 (20.34%) suffered from psychological disorders, and 9 (15.2%) confessed to substance abuse. 7 (11.9%) had a history of suicide attempts by hanging. Hanging was significantly higher in men (p<0.001), people with an education level of less than high school diploma (p=0.02) and the unemployed (p<0.05) patients. In the end, 20 (33.9%) of these attempts resulted in death. CONCLUSION: The results of this study showed that in 2 years, 59 cases committed suicide by hanging themselves, 33.9% of which finally died. Committing suicide by hanging was significantly more prevalent in men, people with an education level of less than high school diploma and the unemployed. PMID- 26495407 TI - Prevalence of Tramadol Consumption in First Seizure Patients; a One-Year Cross sectional Study. AB - INTRODUCTION: Previous studies have shown that there is a probability of seizure even with therapeutic doses of tramadol. Yet, no accurate data exist regarding this problem in Iran. Therefore, the present study aimed to evaluate the prevalence of tramadol consumption in patients with first seizure referred to the emergency department (ED). METHODS: In the present retrospective one-year cross sectional study, all patients who were referred to the ED of Poursina Hospital, Rasht, Iran, with the complaint of first seizure were evaluated. Demographic data and data regarding history of tramadol consumption, duration, total dose, last dose, and time passed from the last dose of consumption were recorded and analyzed regarding the study questions using SPSS 20. RESULTS: 383 (68.9%) out of the 556 patients referred to the ED, were experiencing their first seizure (mean age 26.43 +/- 6.48 years; 70.5% male). 84 (21.9%) patients had recently used tramadol. History of seizure in the family of tramadol consumers was significantly lower (3.6% compared to 11%; p = 0.036). Mean total tramadol consumption dose in the last 24 hours was 140.17 +/- 73.53 mg (range: 50-300 mg). Duration of tramadol consumption was less than 10 days in 84.5% (df: 2; chi(2) = 96.1; p < 0.001). In addition, 62 (73.8%) patients had seizure within 6 hours of consumption (df: 3; chi(2) = 29.5; p < 0.001). CONCLUSION: Results of the present study showed that 21.9% of the patients with first seizure had a history of tramadol consumption. Seizure following tramadol consumption is more prevalent in the initial 10 days and within 6 hours of consumption. In addition, it seems that lower doses of tramadol may also induce seizure. PMID- 26495408 TI - Third Ventricle Colloid Cyst as a Cause of Sudden Drop Attacks of a 13-Year-Old Boy. AB - Colloid cysts are mucous-filled masses with an outer fibrous layer. These cysts are rare developmental malformation and not a true neoplasm. They usually found incidentally and are asymptomatic; but in some cases may associate with rapid neurologic deterioration, herniation, and sudden death. Recognition of this rare but important diagnosis may result in decreasing mortality. In this report, we presented a 13-year-old boy with complaint of two times drop attack and final diagnosis of colloid cyst in the third brain ventricle. PMID- 26495409 TI - An Immediate Death by Seat Belt Compression; a Forensic Medicine Report. AB - Although death is a gradual process, sometimes sudden death occurs in a fraction of a minute or seconds. Here we report a 49-year-old man without any underlying disease, which has instantly died in an accident scene due to compression of neck critical elements by a three-point seat belt. The examination of the body and the results of the autopsy, toxicology and pathology tests are described from the viewpoint of forensic medicine. PMID- 26495410 TI - A 78-Year-Old Woman with Fecaloid Vaginal Discharge. PMID- 26495411 TI - Evidence Based Emergency Medicine Part 3: Positive and Negative Likelihood Ratios of Diagnostic Tests. PMID- 26495413 TI - Scalable Clustering of High-Dimensional Data Technique Using SPCM with Ant Colony Optimization Intelligence. AB - Clusters of high-dimensional data techniques are emerging, according to data noisy and poor quality challenges. This paper has been developed to cluster data using high-dimensional similarity based PCM (SPCM), with ant colony optimization intelligence which is effective in clustering nonspatial data without getting knowledge about cluster number from the user. The PCM becomes similarity based by using mountain method with it. Though this is efficient clustering, it is checked for optimization using ant colony algorithm with swarm intelligence. Thus the scalable clustering technique is obtained and the evaluation results are checked with synthetic datasets. PMID- 26495412 TI - Diminished expression of CRHR2 in human colon cancer promotes tumor growth and EMT via persistent IL-6/Stat3 signaling. AB - BACKGROUND & AIMS: Chronic inflammation promotes development and progression of colorectal cancer (CRC). We explored the distribution of Corticotropin-Releasing Hormone (CRH)-family of receptors and ligands in CRC and their contribution in tumor growth and oncogenic EMT. METHODS: mRNA expression of CRH-family members was analyzed in CRC (N=56) and control (N=46) samples, 7 CRC cell lines and normal NCM460 cells. Immunohistochemical detection of CRHR2 was performed in 20 CRC and 5 normal tissues. Cell proliferation, migration and invasion were compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing (CRHR2+) cells in absence or presence of IL-6. CRHR2/Ucn2-targeted effects on tumor growth and EMT were validated in SW620-xenograft mouse models. RESULTS: CRC tissues and cell lines showed decreased mRNA and protein CRHR2 expression compared to controls and NCM460, respectively. The opposite trend was shown for Ucn2. CRHR2/Ucn2 signaling inhibited cell proliferation, migration, invasion and colony formation in CRC-CRHR2+ cells. In vivo, SW620-CRHR2+ xenografts showed decreased growth, reduced expression of EMT-inducers and elevated levels of EMT suppressors. IL-1b, IL-6 and IL-6R mRNAs where diminished in CRC-CRHR2+ cells, while CRHR2/Ucn2 signaling inhibited IL-6-mediated Stat3 activation, invasion, migration and expression of downstream targets acting as cell cycle- and EMT inducers. Expression of cell cycle- and EMT-suppressors was augmented in IL 6/Ucn2-stimulated CRHR2+ cells. In patients, CRHR2 mRNA expression was inversely correlated with IL-6R and vimentin levels and metastasis occurrence, while positively associated with E-cadherin expression and overall survival. CONCLUSIONS: CRHR2 downregulation in CRC supports tumor expansion and spread through maintaining persistent inflammation and constitutive Stat3 activation. CRHR2low CRC phenotypes are associated with higher risk for distant metastases and poor clinical outcomes. PMID- 26495414 TI - Syndrome Differentiation Analysis on Mars500 Data of Traditional Chinese Medicine. AB - Mars500 study was a psychological and physiological isolation experiment conducted by Russia, the European Space Agency, and China, in preparation for an unspecified future manned spaceflight to the planet Mars. Its intention was to yield valuable psychological and medical data on the effects of the planned long term deep space mission. In this paper, we present data mining methods to mine medical data collected from the crew consisting of six spaceman volunteers. The synthesis of the four diagnostic methods of TCM, inspection, listening, inquiry, and palpation, is used in our syndrome differentiation. We adopt statistics method to describe the syndrome factor regular pattern of spaceman volunteers. Hybrid optimization based multilabel (HOML) is used as feature selection method and multilabel k-nearest neighbors (ML-KNN) is applied. According to the syndrome factor statistical result, we find that qi deficiency is a base syndrome pattern throughout the entire experiment process and, at the same time, there are different associated syndromes such as liver depression, spleen deficiency, dampness stagnancy, and yin deficiency, due to differences of individual situation. With feature selection, we screen out ten key factors which are essential to syndrome differentiation in TCM. The average precision of multilabel classification model reaches 80%. PMID- 26495415 TI - Patterns Exploration on Patterns of Empirical Herbal Formula of Chinese Medicine by Association Rules. AB - BACKGROUND: In this study, we use association rules to explore the latent rules and patterns of prescribing and adjusting the ingredients of herbal decoctions based on empirical herbal formula of Chinese Medicine (CM). MATERIALS AND METHODS: The consideration and development of CM prescriptions based on the knowledge of CM doctors are analyzed. The study contained three stages. The first stage is to identify the chief symptoms to a specific empirical herbal formula, which can serve as the key indication for herb addition and cancellation. The second stage is to conduct a case study on the empirical CM herbal formula for insomnia. Doctors will add extra ingredients or cancel some of them by CM syndrome diagnosis. The last stage of the study is to divide the observed cases into the effective group and ineffective group based on the assessed clinical effect by doctors. The patterns during the diagnosis and treatment are selected by the applied algorithm and the relations between clinical symptoms or indications and herb choosing principles will be selected by the association rules algorithm. RESULTS: Totally 40 patients were observed in this study: 28 patients were considered effective after treatment and the remaining 12 were ineffective. 206 patterns related to clinical indications of Chinese Medicine were checked and screened with each observed case. In the analysis of the effective group, we used the algorithm of association rules to select combinations between 28 herbal adjustment strategies of the empirical herbal formula and the 190 patterns of individual clinical manifestations. During this stage, 11 common patterns were eliminated and 5 major symptoms for insomnia remained. 12 association rules were identified which included 5 herbal adjustment strategies. CONCLUSION: The association rules method is an effective algorithm to explore the latent relations between clinical indications and herbal adjustment strategies for the study on empirical herbal formulas. PMID- 26495417 TI - Energy Efficient Cluster Based Scheduling Scheme for Wireless Sensor Networks. AB - The energy utilization of sensor nodes in large scale wireless sensor network points out the crucial need for scalable and energy efficient clustering protocols. Since sensor nodes usually operate on batteries, the maximum utility of network is greatly dependent on ideal usage of energy leftover in these sensor nodes. In this paper, we propose an Energy Efficient Cluster Based Scheduling Scheme for wireless sensor networks that balances the sensor network lifetime and energy efficiency. In the first phase of our proposed scheme, cluster topology is discovered and cluster head is chosen based on remaining energy level. The cluster head monitors the network energy threshold value to identify the energy drain rate of all its cluster members. In the second phase, scheduling algorithm is presented to allocate time slots to cluster member data packets. Here congestion occurrence is totally avoided. In the third phase, energy consumption model is proposed to maintain maximum residual energy level across the network. Moreover, we also propose a new packet format which is given to all cluster member nodes. The simulation results prove that the proposed scheme greatly contributes to maximum network lifetime, high energy, reduced overhead, and maximum delivery ratio. PMID- 26495416 TI - Acupuncture for Vascular Dementia: A Pragmatic Randomized Clinical Trial. AB - In this trial, patients who agreed to random assignment were allocated to a randomized acupuncture group (R-acupuncture group) or control group. Those who declined randomization were assigned to a nonrandomized acupuncture group (NR acupuncture group). Patients in the R-acupuncture group and NR-acupuncture group received up to 21 acupuncture sessions during a period of 6 weeks plus routine care, while the control group received routine care alone. Cognitive function, activities of daily living, and quality of life were assessed by mini-mental state examination (MMSE), Activities of Daily Living Scale (ADL), and dementia quality of life questionnaire (DEMQOL), respectively. All the data were collected at baseline, after 6-week treatment, and after 4-week follow-up. No significant differences of MMSE scores were observed among the three groups but pooled acupuncture group had significant higher score than control group. Compared to control group, ADL score significantly decreased in NR-acupuncture group and pooled-acupuncture group. For DEMQOL scores, no significant differences were observed among the three groups, as well as between pooled-acupuncture group and control group. Additional acupuncture to routine care may have beneficial effects on the improvements of cognitive status and activities of daily living but have limited efficacy on health-related quality of life in VaD patients. PMID- 26495418 TI - Researches on Mathematical Relationship of Five Elements of Containing Notes and Fibonacci Sequence Modulo 5. AB - Considering the five periods and six qi's theory in TCM almost shares a common basis of stem-branch system with the five elements of containing notes, studying the principle or mathematical structure behind the five elements of containing notes can surely bring a novel view for the five periods and six qi's researches. By analyzing typical mathematical rules included in He tu, Luo shu, and stem branch theory in TCM as well as the Fibonacci sequence especially widely existent in the biological world, novel researches are performed on mathematical relationship between the five elements of containing notes and the Fibonacci sequence modulo 5. Enlightened by elementary Yin or Yang number grouping principle of He tu, Luo shu, the 12534 and 31542 key number series of Fibonacci sequence modulo 5 are obtained. And three new arrangements about the five elements of containing notes are then introduced, which have shown close relationship with the two obtained key subsequences of the Fibonacci sequence modulo 5. The novel discovery is quite helpful to recover the scientific secret of the five periods and six qi's theory in TCM as well as that of whole traditional Chinese culture system, but more data is needed to elucidate the TCM theory further. PMID- 26495419 TI - An Improved Differential Evolution Solution for Software Project Scheduling Problem. AB - This paper proposes a differential evolution (DE) method for the software project scheduling problem (SPSP). The interest on finding a more efficient solution technique for SPSP is always a topic of interest due to the fact of ever growing challenges faced by the software industry. The curse of dimensionality is introduced in the scheduling problem by ever increasing software assignments and the number of staff who handles it. Thus the SPSP is a class of NP-hard problem, which requires a rigorous solution procedure which guarantees a reasonably better solution. Differential evolution is a direct search stochastic optimization technique that is fairly fast and reasonably robust. It is also capable of handling nondifferentiable, nonlinear, and multimodal objective functions like SPSP. This paper proposes a refined DE where a new mutation mechanism is introduced. The superiority of the proposed method is experimented and demonstrated by solving the SPSP on 50 random instances and the results are compared with some of the techniques in the literature. PMID- 26495420 TI - Improved TV-CS Approaches for Inverse Scattering Problem. AB - Total Variation and Compressive Sensing (TV-CS) techniques represent a very attractive approach to inverse scattering problems. In fact, if the unknown is piecewise constant and so has a sparse gradient, TV-CS approaches allow us to achieve optimal reconstructions, reducing considerably the number of measurements and enforcing the sparsity on the gradient of the sought unknowns. In this paper, we introduce two different techniques based on TV-CS that exploit in a different manner the concept of gradient in order to improve the solution of the inverse scattering problems obtained by TV-CS approach. Numerical examples are addressed to show the effectiveness of the method. PMID- 26495421 TI - Using Bioinformatics Approach to Explore the Pharmacological Mechanisms of Multiple Ingredients in Shuang-Huang-Lian. AB - Due to the proved clinical efficacy, Shuang-Huang-Lian (SHL) has developed a variety of dosage forms. However, the in-depth research on targets and pharmacological mechanisms of SHL preparations was scarce. In the presented study, the bioinformatics approaches were adopted to integrate relevant data and biological information. As a result, a PPI network was built and the common topological parameters were characterized. The results suggested that the PPI network of SHL exhibited a scale-free property and modular architecture. The drug target network of SHL was structured with 21 functional modules. According to certain modules and pharmacological effects distribution, an antitumor effect and potential drug targets were predicted. A biological network which contained 26 subnetworks was constructed to elucidate the antipneumonia mechanism of SHL. We also extracted the subnetwork to explicitly display the pathway where one effective component acts on the pneumonia related targets. In conclusions, a bioinformatics approach was established for exploring the drug targets, pharmacological activity distribution, effective components of SHL, and its mechanism of antipneumonia. Above all, we identified the effective components and disclosed the mechanism of SHL from the view of system. PMID- 26495422 TI - Subspace Compressive GLRT Detector for MIMO Radar in the Presence of Clutter. AB - The problem of optimising the target detection performance of MIMO radar in the presence of clutter is considered. The increased false alarm rate which is a consequence of the presence of clutter returns is known to seriously degrade the target detection performance of the radar target detector, especially under low SNR conditions. In this paper, a mathematical model is proposed to optimise the target detection performance of a MIMO radar detector in the presence of clutter. The number of samples that are required to be processed by a radar target detector regulates the amount of processing burden while achieving a given detection reliability. While Subspace Compressive GLRT (SSC-GLRT) detector is known to give optimised radar target detection performance with reduced computational complexity, it however suffers a significant deterioration in target detection performance in the presence of clutter. In this paper we provide evidence that the proposed mathematical model for SSC-GLRT detector outperforms the existing detectors in the presence of clutter. The performance analysis of the existing detectors and the proposed SSC-GLRT detector for MIMO radar in the presence of clutter are provided in this paper. PMID- 26495423 TI - Tomato Seed Coat Permeability to Selected Carbon Nanomaterials and Enhancement of Germination and Seedling Growth. AB - Seed coat permeability was examined using a model that tested the effects of soaking tomato (Solanum lycopersicon) seeds in combination with carbon-based nanomaterials (CBNMs) and ultrasonic irradiation (US). Penetration of seed coats to the embryo by CBNMs, as well as CBNMs effects on seed germination and seedling growth, was examined. Two CBNMs, C60(OH)20 (fullerol) and multiwalled nanotubes (MWNTs), were applied at 50 mg/L, and treatment exposure ranged from 0 to 60 minutes. Bright field, fluorescence, and electron microscopy and micro-Raman spectroscopy provided corroborating evidence that neither CBNM was able to penetrate the seed coat. The restriction of nanomaterial (NM) uptake was attributed to the semipermeable layer located at the innermost layer of the seed coat adjacent to the endosperm. Seed treatments using US at 30 or 60 minutes in the presence of MWNTs physically disrupted the seed coat; however, the integrity of the semipermeable layer was not impaired. The germination percentage and seedling length and weight were enhanced in the presence of MWNTs but were not altered by C60(OH)20. The combined exposure of seeds to NMs and US provided insight into the nanoparticle-seed interaction and may serve as a delivery system for enhancing seed germination and early seedling growth. PMID- 26495424 TI - Distilling Big Data: Refining Quality Information in the Era of Yottabytes. AB - Big Data is the buzzword of the modern century. With the invasion of pervasive computing, we live in a data centric environment, where we always leave a track of data related to our day to day activities. Be it a visit to a shopping mall or hospital or surfing Internet, we create voluminous data related to credit card transactions, user details, location information, and so on. These trails of data simply define an individual and form the backbone for user-profiling. With the mobile phones and their easy access to online social networks on the go, sensor data such as geo-taggings and events and sentiments around them contribute to the already overwhelming data containers. With reductions in the cost of storage and computational devices and with increasing proliferation of Cloud, we never felt any constraints in storing or processing such data. Eventually we end up having several exabytes of data and analysing them for their usefulness has introduced new frontiers of research. Effective distillation of these data is the need of the hour to improve the veracity of the Big Data. This research targets the utilization of the Fuzzy Bayesian process model to improve the quality of information in Big Data. PMID- 26495425 TI - ISMAC: An Intelligent System for Customized Clinical Case Management and Analysis. AB - Clinical cases are primary and vital evidence for Traditional Chinese Medicine (TCM) clinical research. A great deal of medical knowledge is hidden in the clinical cases of the highly experienced TCM practitioner. With a deep Chinese culture background and years of clinical experience, an experienced TCM specialist usually has his or her unique clinical pattern and diagnosis idea. Preserving huge clinical cases of experienced TCM practitioners as well as exploring the inherent knowledge is then an important but arduous task. The novel system ISMAC (Intelligent System for Management and Analysis of Clinical Cases in TCM) is designed and implemented for customized management and intelligent analysis of TCM clinical data. Customized templates with standard and expert standard symptoms, diseases, syndromes, and Chinese Medince Formula (CMF) are constructed in ISMAC, according to the clinical diagnosis and treatment characteristic of each TCM specialist. With these templates, clinical cases are archived in order to maintain their original characteristics. Varying data analysis and mining methods, grouped as Basic Analysis, Association Rule, Feature Reduction, Cluster, Pattern Classification, and Pattern Prediction, are implemented in the system. With a flexible dataset retrieval mechanism, ISMAC is a powerful and convenient system for clinical case analysis and clinical knowledge discovery. PMID- 26495426 TI - Modeling and Simulation of a Novel Relay Node Based Secure Routing Protocol Using Multiple Mobile Sink for Wireless Sensor Networks. AB - Data gathering and optimal path selection for wireless sensor networks (WSN) using existing protocols result in collision. Increase in collision further increases the possibility of packet drop. Thus there is a necessity to eliminate collision during data aggregation. Increasing the efficiency is the need of the hour with maximum security. This paper is an effort to come up with a reliable and energy efficient WSN routing and secure protocol with minimum delay. This technique is named as relay node based secure routing protocol for multiple mobile sink (RSRPMS). This protocol finds the rendezvous point for optimal transmission of data using a "splitting tree" technique in tree-shaped network topology and then to determine all the subsequent positions of a sink the "Biased Random Walk" model is used. In case of an event, the sink gathers the data from all sources, when they are in the sensing range of rendezvous point. Otherwise relay node is selected from its neighbor to transfer packets from rendezvous point to sink. A symmetric key cryptography is used for secure transmission. The proposed relay node based secure routing protocol for multiple mobile sink (RSRPMS) is experimented and simulation results are compared with Intelligent Agent-Based Routing (IAR) protocol to prove that there is increase in the network lifetime compared with other routing protocols. PMID- 26495427 TI - Predicting Defects Using Information Intelligence Process Models in the Software Technology Project. AB - A key differentiator in a competitive market place is customer satisfaction. As per Gartner 2012 report, only 75%-80% of IT projects are successful. Customer satisfaction should be considered as a part of business strategy. The associated project parameters should be proactively managed and the project outcome needs to be predicted by a technical manager. There is lot of focus on the end state and on minimizing defect leakage as much as possible. Focus should be on proactively managing and shifting left in the software life cycle engineering model. Identify the problem upfront in the project cycle and do not wait for lessons to be learnt and take reactive steps. This paper gives the practical applicability of using predictive models and illustrates use of these models in a project to predict system testing defects thus helping to reduce residual defects. PMID- 26495429 TI - Quality of Service Routing in Manet Using a Hybrid Intelligent Algorithm Inspired by Cuckoo Search. AB - A hybrid computational intelligent algorithm is proposed by integrating the salient features of two different heuristic techniques to solve a multiconstrained Quality of Service Routing (QoSR) problem in Mobile Ad Hoc Networks (MANETs) is presented. The QoSR is always a tricky problem to determine an optimum route that satisfies variety of necessary constraints in a MANET. The problem is also declared as NP-hard due to the nature of constant topology variation of the MANETs. Thus a solution technique that embarks upon the challenges of the QoSR problem is needed to be underpinned. This paper proposes a hybrid algorithm by modifying the Cuckoo Search Algorithm (CSA) with the new position updating mechanism. This updating mechanism is derived from the differential evolution (DE) algorithm, where the candidates learn from diversified search regions. Thus the CSA will act as the main search procedure guided by the updating mechanism derived from DE, called tuned CSA (TCSA). Numerical simulations on MANETs are performed to demonstrate the effectiveness of the proposed TCSA method by determining an optimum route that satisfies various Quality of Service (QoS) constraints. The results are compared with some of the existing techniques in the literature; therefore the superiority of the proposed method is established. PMID- 26495428 TI - Florivory Modulates the Seed Number-Seed Weight Relationship in Halenia elliptica (Gentianaceae). AB - Generally, plant reproductive success might be affected negatively by florivory, and the effects may vary depending on the timing and intensity of florivory. To clarify the impacts of florivory by the sawfly larvae (Tenthredinidae) on seed production of Halenia elliptica D. Don, we simulated florivory by removing different proportion of flowers at three reproductive stages in this alpine herb and then examined the seed number per fruit, the seed weight, and the seed mass per fruit of the remaining flowers. Seed number per fruit reduced significantly when flowers were removed at flowering and fruiting stages or when 15% and 60% of flowers were removed. However, seed weight increased significantly after flowers were removed, independent of treatments of reproductive stage and proportion. There was a similar seed mass per fruit between the plants subjected to simulation of florivory and control. The results indicated that florivory modulated the seed number-seed weight relationship in this alpine species. Our study suggested that selective seed abortion and resource reallocation within fruits may ensure fewer but larger seeds, which were expected to be adaptive in the harsh environments. PMID- 26495430 TI - Proactive Alleviation Procedure to Handle Black Hole Attack and Its Version. AB - The world is moving towards a new realm of computing such as Internet of Things. The Internet of Things, however, envisions connecting almost all objects within the world to the Internet by recognizing them as smart objects. In doing so, the existing networks which include wired, wireless, and ad hoc networks should be utilized. Moreover, apart from other networks, the ad hoc network is full of security challenges. For instance, the MANET (mobile ad hoc network) is susceptible to various attacks in which the black hole attacks and its versions do serious damage to the entire MANET infrastructure. The severity of this attack increases, when the compromised MANET nodes work in cooperation with each other to make a cooperative black hole attack. Therefore this paper proposes an alleviation procedure which consists of timely mandate procedure, hole detection algorithm, and sensitive guard procedure to detect the maliciously behaving nodes. It has been observed that the proposed procedure is cost-effective and ensures QoS guarantee by assuring resource availability thus making the MANET appropriate for Internet of Things. PMID- 26495431 TI - Synchronous Firefly Algorithm for Cluster Head Selection in WSN. AB - Wireless Sensor Network (WSN) consists of small low-cost, low-power multifunctional nodes interconnected to efficiently aggregate and transmit data to sink. Cluster-based approaches use some nodes as Cluster Heads (CHs) and organize WSNs efficiently for aggregation of data and energy saving. A CH conveys information gathered by cluster nodes and aggregates/compresses data before transmitting it to a sink. However, this additional responsibility of the node results in a higher energy drain leading to uneven network degradation. Low Energy Adaptive Clustering Hierarchy (LEACH) offsets this by probabilistically rotating cluster heads role among nodes with energy above a set threshold. CH selection in WSN is NP-Hard as optimal data aggregation with efficient energy savings cannot be solved in polynomial time. In this work, a modified firefly heuristic, synchronous firefly algorithm, is proposed to improve the network performance. Extensive simulation shows the proposed technique to perform well compared to LEACH and energy-efficient hierarchical clustering. Simulations show the effectiveness of the proposed method in decreasing the packet loss ratio by an average of 9.63% and improving the energy efficiency of the network when compared to LEACH and EEHC. PMID- 26495432 TI - Standardization of Syndrome Differentiation Defined by Traditional Chinese Medicine in Operative Breast Cancer: A Modified Delphi Study. AB - OBJECTIVE: The aim of this study was to establish the standardization of syndrome differentiation of operative breast cancer treated with Traditional Chinese Medicine (TCM) by the modified Delphi method. METHOD: A literature search for standardization of syndrome differentiation of operative breast cancer was conducted and eligible articles were identified in indexed databases from 1982 to 2013. We carried out two rounds of investigation between March and October 2013 and organized 20 experts who focused on TCM or integrative medicine in breast cancer research. Experts' judgments were collected via posted questionnaires or e mail. A final evaluation was carried out after the end of both rounds. RESULT: The response ratio of the 1st round investigation reached 100%, and two experts were excluded due to the uncompleted questionnaire. The 2nd round investigation was completed by 18 experts in the 1st round panel board. In both rounds, the experts agreed that the stage of breast cancer defined by TCM could be divided into the perioperation period, the perichemotherapy period, the periradiotherapy period, and the consolidation period. CONCLUSION: We identified the feasibility and reasonability to establish the standardization of syndrome differentiation of operative breast cancer. According to the suggestions from experts in our Delphi study, we preliminarily established the TCM standard of syndrome differentiation based on different treatment stages of operative breast cancer. PMID- 26495433 TI - Detecting Disease in Radiographs with Intuitive Confidence. AB - This paper argues in favor of a specific type of confidence for use in computer aided diagnosis and disease classification, namely, sine/cosine values of angles represented by points on the unit circle. The paper shows how this confidence is motivated by Chinese medicine and how sine/cosine values are directly related with the two forces Yin and Yang. The angle for which sine and cosine are equal (45 degrees ) represents the state of equilibrium between Yin and Yang, which is a state of nonduality that indicates neither normality nor abnormality in terms of disease classification. The paper claims that the proposed confidence is intuitive and can be readily understood by physicians. The paper underpins this thesis with theoretical results in neural signal processing, stating that a sine/cosine relationship between the actual input signal and the perceived (learned) input is key to neural learning processes. As a practical example, the paper shows how to use the proposed confidence values to highlight manifestations of tuberculosis in frontal chest X-rays. PMID- 26495434 TI - Support Detection for SAR Tomographic Reconstructions from Compressive Measurements. AB - The problem of detecting and locating multiple scatterers in multibaseline Synthetic Aperture Radar (SAR) tomography, starting from compressive measurements and applying support detection techniques, is addressed. Different approaches based on the detection of the support set of the unknown sparse vector, that is, of the position of the nonzero elements in the unknown sparse vector, are analyzed. Support detection techniques have already proved to allow a reduction in the number of measurements required for obtaining a reliable solution. In this paper, a support detection method, based on a Generalized Likelihood Ratio Test (Sup-GLRT), is proposed and compared with the SequOMP method, in terms of probability of detection achievable with a given probability of false alarm and for different numbers of measurements. PMID- 26495435 TI - Framing a Knowledge Base for a Legal Expert System Dealing with Indeterminate Concepts. AB - Despite decades of development of formal tools for modelling legal knowledge and reasoning, the creation of a fully fledged legal decision support system remains challenging. Among those challenges, such system requires an enormous amount of commonsense knowledge to derive legal expertise. This paper describes the development of a negotiation decision support system (the Parenting Plan Support System or PPSS) to support parents in drafting an agreement (the parenting plan) for the exercise of parental custody of minor children after a divorce is granted. The main objective here is to discuss problems of framing an intuitively appealing and computationally efficient knowledge base that can adequately represent the indeterminate legal concept of the well-being of the child in the context of continental legal culture and of Polish law in particular. In addition to commonsense reasoning, interpretation of such a concept demands both legal expertise and significant professional knowledge from other domains. PMID- 26495436 TI - Competitive inhibition can linearize dose-response and generate a linear rectifier. AB - Many biological responses require a dynamic range that is larger than standard bi molecular interactions allow, yet the also ability to remain off at low input. Here we mathematically show that an enzyme reaction system involving a combination of competitive inhibition, conservation of the total level of substrate and inhibitor, and positive feedback can behave like a linear rectifier that is, a network motif with an input-output relationship that is linearly sensitive to substrate above a threshold but unresponsive below the threshold. We propose that the evolutionarily conserved yeast SAGA histone acetylation complex may possess the proper physiological response characteristics and molecular interactions needed to perform as a linear rectifier, and we suggest potential experiments to test this hypothesis. One implication of this work is that linear responses and linear rectifiers might be easier to evolve or synthetically construct than is currently appreciated. PMID- 26495437 TI - The Role of Macrophage in the Pathogenesis of Brain Arteriovenous Malformation. AB - Brain arteriovenous malformation (BAVM) is an important risk factor for intracranial hemorrhage, especially in children and young adults. Inflammation has been implicated in BAVM lesion progression. Among various inflammatory components, macrophage is one of the major inflammatory cells present in human ruptured and unruptured BAVM and in the BAVM lesions of animal models. The role of macrophage in BAVM pathogenesis is not fully understood. In this review, we summarize recent studies on macrophages and introduce a non-invasive imaging protocol as a potential tool for detecting macrophage in BAVM and predicting the risk of BAVM rupture. PMID- 26495438 TI - Protein thermal stabilization in aqueous solutions of osmolytes. AB - Proteins' thermal stabilization is a significant problem in various biomedical, biotechnological, and technological applications. We investigated thermal stability of hen egg white lysozyme in aqueous solutions of the following stabilizing osmolytes: Glycine (GLY), N-methylglycine (NMG), N,N-dimethylglycine (DMG), N,N,N-trimethylglycine (TMG), and trimethyl-N-oxide (TMAO). Results of CD UV spectroscopic investigation were compared with FTIR hydration studies' results. Selected osmolytes increased lysozyme's thermal stability in the following order: Gly>NMG>TMAO~DMG>TMG. Theoretical calculations (DFT) showed clearly that osmolytes' amino group protons and water molecules interacting with them played a distinctive role in protein thermal stabilization. The results brought us a step closer to the exact mechanism of protein stabilization by osmolytes. PMID- 26495439 TI - The roles of purinergic signaling in psychiatric disorders. AB - Ecto-purines and ecto-pyrimidines are present in the extracellular space of the central nervous system (CNS). Together with P1 and P2 receptors and nucleotides metabolizing ecto-enzymes, they make signaling system involved in neurotransmission, the modulation of sensory signals, including pain stimuli conduction, and the induction of apoptosis and necrosis of the cells. Purines and pyrimidines have a dual effect: positive (neuroprotective) of nucleosides, and negative (pro-inflammatory and pro-apoptotic) of nucleotides. Adenosine-5' triphosphate (ATP) in the CNS triggers the pro-inflammatory reactions, predominantly by activation of the P2X7 receptor, which results in production and release of pro-inflammatory cytokines. In contrast to ATP, adenosine acts generally as an anti-inflammatory agent and plays an important role in neuroprotection. Currently, it is believed that the initiation of CNS diseases, including mental disorders, is caused by any imbalance between the concentration of ATP and adenosine in the extracellular space. Genetic tests provide also the evidence for the participation of purinergic signaling in psychiatric disorders. It is believed that any action leading to the effective increase of adenosine concentration: activation of nucleotide metabolizing ecto-enzymes (mainly NTPDases - nucleoside triphosphate diphosphohydrolases), inhibition of adenosine deaminase and/or adenosine kinase activity as well as therapies using P1 receptor agonists (adenosine or its analogues) might be beneficial in therapy of psychiatric disorders. PMID- 26495441 TI - Characterization of a novel laccase purified from the fungus Hohenbuehelia serotina and its decolourisation of dyes. AB - A novel laccase was purified from the white rot fungus, Hohenbuehelia serotina, to investigate the applications of this laccase in the decoloration of various dyes. SDS-PAGE revealed a single band of this laccase corresponding to a molecular weight of approximately 57.8 kDa. The enzyme showed activity towards several substrates, the most sensitive of which was 2,2'-Azinobis-(3 ethylbenzthiazoline-6-sulphonate) (ABTS). The highest enzymatic activity using ABTS as a substrate was observed at pH 6.8 and 30 degrees C. The enzyme activity was found to be significantly enhanced in the presence of Zn(2+) ions and inhibited by Fe(2+) ions. Moreover, SDS and beta-mercaptoethanol were inhibitory, and inhibition by L-cysteine was observed while EDTA and DMSO had almost no inhibitory effect. The laccase could effectively decolorize seven different dyes within 30 minutes at 40 degrees C. PMID- 26495440 TI - Intra-strains diversity of expression of polymorphic PKS4 gene in comparison in zearalenone production by Fusarium graminearum during in vitro cultivation. AB - Filamentous fungi belonging to the Fusarium genus are responsible for large economic losses due to their high pathogenicity and toxigenicity. Fusarium sp. may produce variety of mycotoxins, one of them is zearalenone (ZEA). The presence of the PKS4 gene shows the possibility of zearalenone biosynthesis by Fusarium sp. In this study, in four Fusarium graminearum and one Fusarium poae strains the presence of PKS4 genes and ZEA concentrations were determined. The presence of the PKS4 gene was confirmed by classical polymerase chain reaction (PCR) in three of four strains of F. graminearum. One strain with no PKS4 gene detected was found while still producing ZEA. In the present study, a real-time PCR assay has been successfully performed for the relative expression of Fusarium strains based on new designed primers targeting the PKS4 gene involved in ZEA biosynthesis. Result shows that P56/4 strain of F. graminearum has the highest mRNA level, in the range of 12, what correlates to the high production of this mycotoxin. In this study, a real-time PCR assay has been successfully developed for the prediction of the production of ZEA by F. graminearum strains by PCR real-time techniques based on primers targeting the gene, PKS4, involved in ZEA biosynthesis. The special significance was pointed to occurring genes polymorphism. PMID- 26495442 TI - Fluorescence of N-acylated dansylamide with a long hydrophobic tail: sensitive response to premicellar aggregation of sodium deoxycholate. AB - The present work describes the synthesis and photophysical studies of two fluorescent dansylamide derivatives, in which the amine group is acylated by a long hydrophobic chain (a part of a biologically relevant palmitic acid) and by a short hydrophobic tail (a part of acetic acid). The long chain tethered dansyl analogue is successfully utilized in estimating critical micellar concentration (CMC) of bile salts (NaDC, NaC) as well as anionic and cationic surfactants (SDS, CTAB) with the help of enhanced fluorescence intensity facilitated by better solubilization of the molecule in microheterogeneous media. The long chain tethered dansylamide derivative shows significant fluorescence solvatochromism with a red shift (ca. 4000 cm(-1)) from hexane to water. In contrast, the solvatochromism exhibited by the parent/short acyl chain analogue is much less (ca. 2230 cm(-1) from hexane to water) and the fluorescence is not sensitive to micellization. Interestingly, the long chain tethered fluorescent probe shows high sensitivity towards premicellar aggregation of sodium deoxycholate (NaDC) bile salt, through a clear blue shift of emission maxima and concomitant enhancement of fluorescent intensity. Such an observation of fluorescence sensing of premicellar aggregation is unusual. PMID- 26495443 TI - Solid oxide electrolysis--a key enabling technology for sustainable energy scenarios. AB - Production of fuels and chemicals from steam and/or CO2 with solid oxide electrolysis cells (SOEC) and electricity have attracted considerable interest recently. This paper is an extended version of the introductory lecture presented at the first Faraday Discussions meeting on the subject. The focus is on the state of the art of cells, stacks and systems. Thermodynamics, performance and degradation are addressed. Remaining challenges and potential application of the technology are discussed from an industrial perspective. PMID- 26495444 TI - Towards ultra-high peak capacities and peak-production rates using spatial three dimensional liquid chromatography. AB - In order to successfully tackle the truly complex separation problems arising from areas such as proteomics research, the development of ultra-efficient and fast separation technology is required. In spatial three-dimensional chromatography, components are separated in the space domain with each peak being characterized by its coordinates in a three-dimensional separation body. Spatial three-dimensional (3D-)LC has the potential to offer unprecedented resolving power when orthogonal retention mechanisms are applied, since the total peak capacity is the product of the three individual peak capacities. Due to parallel developments during the second- and third-dimension separations, the analysis time is greatly reduced compared to a coupled-column multi-dimensional LC approach. This communication discusses the different design aspects to create a microfluidic chip for spatial 3D-LC. The use of physical barriers to confine the flow between the individual developments, and flow control by the use of (2)D and (3)D flow distributors is discussed. Furthermore, the in situ synthesis of monolithic stationary phases is demonstrated. Finally, the potential performance of a spatial 3D-LC systems is compared with the performance obtained with state of-the-art 1D-LC and (coupled-column) 2D-LC approaches via a Pareto-optimization approach. The proposed microfluidic device for 3D-LC featuring 16 (2)D channels and 256 (3)D channels can potentially yield a peak capacity of 8000 in a total analysis time of 10 minutes. PMID- 26495445 TI - The SPL7013 dendrimer destabilizes the HIV-1 gp120-CD4 complex. AB - The poly (l-lysine)-based SPL7013 dendrimer with naphthalene disulphonate surface groups blocks the entry of HIV-1 into target cells and is in clinical trials for development as a topical microbicide. Its mechanism of action against R5 HIV-1, the HIV-1 variant implicated in transmission across individuals, remains poorly understood. Using docking and fully atomistic MD simulations, we find that SPL7013 binds tightly to R5 gp120 in the gp120-CD4 complex but weakly to gp120 alone. Further, the binding, although to multiple regions of gp120, does not occlude the CD4 binding site on gp120, suggesting that SPL7013 does not prevent the binding of R5 gp120 to CD4. Using MD simulations to compute binding energies of several docked structures, we find that SPL7013 binding to gp120 significantly weakens the gp120-CD4 complex. Finally, we use steered molecular dynamics (SMD) to study the kinetics of the dissociation of the gp120-CD4 complex in the absence of the dendrimer and with the dendrimer bound in each of the several stable configurations to gp120. We find that SPL7013 significantly lowers the force required to rupture the gp120-CD4 complex and accelerates its dissociation. Taken together, our findings suggest that SPL7013 compromises the stability of the R5 gp120-CD4 complex, potentially preventing the accrual of the requisite number of gp120-CD4 complexes across the virus-cell interface, thereby blocking virus entry. PMID- 26495447 TI - [Management of more frequent complications of laparoscopic surgery. Minimally invasive or always open surgery?]. AB - BACKGROUND: Two decades after the far-reaching establishment of elective laparoscopic surgery, the questions arise whether and when the benefits of this technology can be sufficiently and safely implemented even in cases of complications. MATERIAL AND METHODS: The currently available literature was analyzed in the context of recommendations for the management of complications in laparoscopic surgery. RESULTS: Intraoperative and postoperative complications of minimally invasive surgery necessitating treatment are extremely rare and can be expected in only 0.1-5 % of interventions, depending on the complexity of the intervention. In addition to adhesion-related and anatomical limitations, they are responsible for the necessity to convert to open surgery in approximately 40 60 % of the cases. DISCUSSION: Due to the relative rarity and great variety of potential complications, there is no scientific evidence at the study level that can give reliable recommendations for a management strategy in every situation. It still has to be decided on an individual basis and depending on the particular clinical situation if a successful laparoscopic management can be sufficiently and safely carried out. It has been found that a number of complications can be well controlled by minimally invasive procedures; however, in addition to a high level of personal experience in laparoscopy, optimal technical, institutional and instrumental conditions must be available. If these factors are not present in total, a conventional open approach should still be given preference. PMID- 26495448 TI - [Management of complications after bariatric surgery]. AB - The frequency of bariatric surgical interventions is increasing throughout Europe. Minimally invasive techniques have led to decreased morbidity and mortality as well as shorter hospitalization; therefore, non-bariatric surgeons are more likely to be confronted with bariatric emergency situations. Knowledge of the specific clinical behavior of morbidly obese patients is important. This article describes the most frequent early and late complications following the most popular bariatric operations in German speaking parts of Europe (e.g. gastric bypass, sleeve gastrectomy and gastric banding). PMID- 26495449 TI - [Enanthema and painful ulceration of the tongue in a young woman]. PMID- 26495450 TI - [Rhinosinusitis in cystic fibrosis]. AB - In cystic fibrosis (CF) mucociliary clearance of the entire respiratory system is impaired. This allows pathogens, such as Pseudomonas aeruginosa to persist and proliferate, which by progressive pulmonary destruction causes 90 % of premature deaths due to this inherited disease. The dramatic improvement in life expectation of patients due to intensive therapy has resulted in the inevitable but variably expressed sinonasal involvement coming into the clinical and scientific focus. Thereby, almost all CF patients reveal sinonasal pathology and many suffer from chronic rhinosinusitis. Recently, the sinonasal niche has been recognized as a site of initial and persistent colonization by pathogens. This article presents the pathophysiological background of this multiorgan disease as well as general diagnostic and therapeutic standards. The focus of this article is on sinonasal involvement and conservative and surgical options for treatment. Prevention of pathogen acquisition is an essential issue in the otorhinolaryngological treatment of CF patients. PMID- 26495451 TI - [History of the German Spine Society]. AB - The objective of this article is to summarize the history of the German Spine Society (DWG). This society resulted in the year 2006 after several attempts from the fusion of two established German societies, which were dealing with topics around the spine, der "German Society for Spine Research" founded in the year 1958 and the "German Society for Spine Surgery" founded in the year 1987. This fusion was the beginning of a success story, as from this time on the annual membership increased so much that the DWG became the largest spine society in Europe and one of all spine societies worldwide. PMID- 26495446 TI - Adhesion receptors involved in HSC and early-B cell interactions with bone marrow microenvironment. AB - Hematopoiesis takes place in the bone marrow of adult mammals and is the process by which blood cells are replenished every day throughout life. Differentiation of hematopoietic cells occurs in a stepwise manner through intermediates of differentiation that could be phenotypically identified. This has allowed establishing hematopoietic cell classification with hematopoietic stem cells (HSCs) at the top of the hierarchy. HSCs are mostly quiescent and serve as a reservoir for maintenance of lifelong hematopoiesis. Over recent years, it has become increasingly clear that HSC quiescence is not only due to intrinsic properties, but is also mediated by cognate interactions between HSCs and surrounding cells within micro-anatomical sites called "niches". This hematopoietic/stromal crosstalk model also applies to more mature progenitors such as B cell progenitors, which are thought to reside in distinct "niches". This prompted many research teams to search for specific molecular mechanisms supporting leuko-stromal crosstalk in the bone marrow and acting at specific stage of differentiation to regulate hematopoietic homeostasis. Here, we review recent data on adhesion mechanisms involved in HSCs and B cell progenitors interactions with surrounding bone marrow stromal cells. PMID- 26495452 TI - [Seasonal distribution of clinical case codes (DOC study)]. AB - OBJECTIVES: The German diagnosis-related groups remuneration system (G-DRG) was implemented in 2004 and patient-related diagnoses and procedures lead to allocation to specific DRGs. This system includes several codes, such as case mix (CM), case mix index (CMI) and number of cases. Seasonal distribution of these codes as well as distribution of diagnoses and DRGs may lead to logistical consequences for clinical management. METHODS: From 2004 to 2013 all the main diagnoses and DRGs for inpatients were recorded. Monthly and seasonal distributions were analyzed using ANOVA. RESULTS: The average monthly number of cases was 265 +/- 25 cases, the average CM was 388.50 +/- 51.75 and the average CMI was 1.46 +/- 0.15 with no significant seasonal differences (p > 0.1). Concussion was the most frequently occurring main diagnosis (3739 cases) followed by fractures of the humeral head (699). Significant distribution differences could be shown for humeral head fractures in monthly (p = 0.018) and seasonal comparisons (p = 0.006) with a maximum in winter. Radius (p = 0.01) and ankle fractures (p <= 0.001) also occurred most frequently in winter. Non-bony lesions of the shoulder were significantly less in spring (p = 0.04). The DRGs showed no evidence of a monthly or seasonal clustering (p > 0.1). CONCLUSION: The significant clustering of injuries in specific months and seasons should lead to logistic consequences (e.g. operating room slots, availability of nursing and anesthesia staff). For a needs assessment the analysis of main diagnoses is more appropriate than DRGs. PMID- 26495453 TI - Reply to Function and Structure of the RWD Domain. PMID- 26495454 TI - Whips in racing: is it time to take a stronger stand? PMID- 26495455 TI - Graduate survey: Uncertain futures. PMID- 26495456 TI - Guido Tarone, Ph.D. (1951-2015). PMID- 26495457 TI - [Examination fanaticism]. PMID- 26495458 TI - [Straightforward and clear premises]. PMID- 26495459 TI - [HPV vaccination for girls is effective and safe]. PMID- 26495460 TI - [Unethical to continue to promote the HPV vaccine]. PMID- 26495461 TI - [Physicians' role in prioritization should be limited]. PMID- 26495463 TI - [Caught in the registry jungle]. PMID- 26495464 TI - [KRIS and RADS enhances the quality of medication use]. PMID- 26495465 TI - [Adverse events and side effects--can it also be patient injuries?]. PMID- 26495466 TI - [Like a developing country when it comes to medicine and prioritization]. PMID- 26495467 TI - [OECD views on general practice in Denmark]. PMID- 26495468 TI - [Half of the new cancer treatments are better than the old treatments!]. PMID- 26495469 TI - [Reply: Rosthoj misunderstands averages]. PMID- 26495470 TI - [Lack of clarity about asthma and allergies in children]. PMID- 26495471 TI - [Reply: Allergy is not always the cause of asthma]. PMID- 26495472 TI - [It is over with the general practice we know and love]. PMID- 26495473 TI - [Troubling increase in consumption of the sleeping drug melatonin for children]. PMID- 26495474 TI - [I am confused and frustrated]. PMID- 26495475 TI - [Outpatient induction of Labour--not who or how, but where]. PMID- 26495476 TI - [Not Available]. PMID- 26495478 TI - [Not Available]. PMID- 26495477 TI - [Reply: Guidelines are not based on individual cases]. PMID- 26495480 TI - [Not Available]. PMID- 26495479 TI - [Not Available]. PMID- 26495481 TI - [Who knows the number of side effects?]. PMID- 26495483 TI - [Reply: We have balanced benefits against disadvantages]. PMID- 26495482 TI - [Not solid evidence for induction of labour with misoprostol]. PMID- 26495484 TI - [Reply: All side effects must be reported]. PMID- 26495485 TI - [Region uses medication reviews despite weak evidence]. PMID- 26495486 TI - [Better technique for lumbar puncture]. PMID- 26495487 TI - [Implementation of LEAN Healthcare in an emergency department]. PMID- 26495488 TI - [Too positive and uncritical dissemination of Glycopyrronium]. PMID- 26495489 TI - [The simple, the difficult and the obvious--about the opportunities and pitfalls of the diagnostic warranty]. PMID- 26495490 TI - [Reply: Good with options]. PMID- 26495491 TI - [Conscientious hesitation]. PMID- 26495493 TI - [Why is it so difficult to diagnose schizophrenia?]. PMID- 26495494 TI - [The world's psychiatry plan--and Denmark's]. PMID- 26495495 TI - [Open letter to the authors of the chronicle "Faith in the future of general practice?"]. PMID- 26495496 TI - [Human rights, the new religion?]. PMID- 26495497 TI - [It can be dangerous to operate--but it can also be dangerous to leave it be...]. PMID- 26495498 TI - [Our research on the pharmaceutical industry is well documented]. PMID- 26495499 TI - [Thrombosis in the brain]. PMID- 26495500 TI - [Municipalities actions for people with back issues is risky]. PMID- 26495501 TI - [Medical school and the real World]. PMID- 26495502 TI - [Choosing function measurements]. PMID- 26495503 TI - [The debate on The Danish Committees on Scientific Dishonesty and Gotzsche, the persecuted innocence or...]. PMID- 26495504 TI - [Real physicians do not cry?]. PMID- 26495506 TI - [Good prognosis for heart transplant patients in Denmark]. PMID- 26495505 TI - [Anniversary--Bispebjerg hospital 19. September 1913-2013]. PMID- 26495507 TI - [We're sorry that the message has not come through clearly enough]. PMID- 26495508 TI - [The future of psychiatry]. PMID- 26495509 TI - Diabetics at increased risk of advanced breast cancer. PMID- 26495510 TI - [Should we reduce the number of hospital beds now?]. PMID- 26495512 TI - A Tribute to RHM Founding Editor, Marge Berer. PMID- 26495511 TI - [Treatment of cerebral ischemia using mesenchymal stem cell-clinical trial phase III]. PMID- 26495514 TI - Extension of the Expiration Date for State Disability Examiner Authority To Make Fully Favorable Quick Disability Determinations and Compassionate Allowance Determinations. Final rule. AB - We are extending the expiration date of our rule that authorizes State agency disability examiners to make fully favorable determinations without the approval of a State agency medical or psychological consultant in claims that we consider under our quick disability determination (QDD) and compassionate allowance (CAL) processes. The current rule will expire on November 13, 2015. In this final rule, we are changing the November 13, 2015 expiration or ''sunset'' date to November 11, 2016, extending the authority for 1 year. We are making no other substantive changes. PMID- 26495513 TI - Medical Bill Sticker Shock. Five years after the Affordable Care Act become law, more of us than ever now have health insurance--but we're also paying more out of pocket. Just in time for open enrollment, we identify 7 costly traps to avoid. PMID- 26495515 TI - Medical Devices; Cardiovascular Devices; Classification of the Coronary Vascular Physiologic Simulation Software Device. Final order. AB - The Food and Drug Administration (FDA) is classifying the coronary vascular physiologic simulation software device into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the coronary vascular physiologic simulation software device's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26495516 TI - Progress toward eliminating onchocerciasis in the WHO Region of the Americas: verification of elimination of transmission in Mexico. PMID- 26495517 TI - Progress towards poliomyelitis eradication: Afghanistan, January 2014-August 2015. PMID- 26495518 TI - Pain and punishment for persons with mental disabilities behind bars in the USA. PMID- 26495519 TI - Asserting control: a cautionary tale. PMID- 26495520 TI - [NODULAR POLYARTERITIS ASSOCIATED WITH HEPATITIS B VIRUS (A CASE STUDY)]. AB - This study is focused on a case of nodular polyarteritis associated with hepatitis B virus successfully treated by immunosuppressive and antiviral agents. PMID- 26495521 TI - [MAJOR MOLECULAR AND CELLULAR MANIFESTATIONS OF ATHEROSCLEROSIS]. AB - The authors consider machanisms and peculiarities of development of atherosclerosis at the tissue level and the main characteristics of atherogenesis, viz. lipoidosis, fibrosis, enhanced intimacyte proliferation, local intima-media thickening. Results of counting subendothelial cells, assessment of their proliferative and synthetic activities in affected and intact arterial segments are presented Variants of lipid metabolism disorders are described. PMID- 26495522 TI - [CURRENT VIEWS OF DIAGNOSTICS AND STRATEGY OF THE TREATMENT OF STABLE ISCHEMIC HEART DISEASE]. AB - Ischemic heart disease (IHD) is a leading cause of mortality worldwide and stable IHD is one of its most important clinical forms. Recent decades brought new data on algorithms of diagnostics, pharmacotherapy and myocardium revascularization in patients with stable IHD. They were summarised in American (2012) and European (2013) recommendations on the management of this condition. The present paper is designed to discuss these algorithms with reference to the currently available evidence, results of the last studies and international guidelines. PMID- 26495523 TI - [INTRAHEPATIC CHOLESTASIS OF PREGNANCY: STATE-OF-THE-ART]. AB - Intrahepatic cholestasis of pregnancy (ICP) is a relatively benign cholestatic pathology of the liver developing in II or III trimester of pregnancy and characterized by itchy skin and enhanced serum bile acid levels. The cause of ICP is unknown; it may have a multifactor nature involving genetic (ABCB4, EXR, ABCC2 genes), hormonal (estrogens, progesterone), and environmental factors. As a rule, ICP first manifests itself on weeks 28-30 of pregnancy in the form of pruritus especially pronounced at night time. Almost half of the patients develop jaundice, usually within 1-4 weeks after appearance of pruritus. The enhanced serum bile acid level is sometimes the first or the sole laboratory sign of the disease. Ursodeoxycholic acid is currently the drug of choice for the treatment of ICP due to its confirmed effectiveness and safety. PMID- 26495524 TI - [PIECETIME BURNS. SOURCES OF DANGER]. AB - We analysed 54 foreign publications concerning sources of danger of thermal injuries inflicted in pieacetime. The negative effect of alcohol consumption is emphasised. Special attention is given to the necessity of safety measures when makingfire by people engaging in leisure activities and to the cases of chemical burns resulting from aggressive attacks of third persons. Certain authors report marked cicatrical deformities developing after skin restoration. A variety of sources of danger necessitates the development and introduction of effective of socio-legislative normatives designed to reduce the occurrence of thermal injuries. PMID- 26495525 TI - [LEFT VENTRICULAR MYOCARDIAL REMODELING IN PATIENTS WITH ARTERIAL HYPERTENSION ASSOCIATED WITH ACID-DEPENDENT DISEASES]. AB - Comorbid pathologies remain a serious challenge for researchers and practitioners. According to different authors, from 11.6 to 50% therapeutic patients suffer arterial hypertension (AH) concomitant with acid-dependent diseases (ADD). Peculiarities of such combination are poorly known. The aim of this work was to evaluate the structural and functional status of left ventricular (LV) myocardium in patients with AH and ADD. It included 127 patients of mean age 42.44:2.78 years. Control group consisted of 25 age-matched patients with isolated AH. The ultrasound study of structural and functional parameters of LV myocardium was followed by the analysis of various types of its remodeling. It was shown that patients with isolated AH are characterized by significantly higher structural and functional parameters of LV myocardium remodeling compared with the patients having AH and concomitant ADD. It suggests a specific type of remodeling in the former group that can be used as a predictor of higher cardiovascular risk in these patients. PMID- 26495526 TI - [CARDIOVASCULAR DISEASES AS A RISK FACTOR OF CHRONIC GLOMERULONEPHRITIS PROGRESS]. AB - The study was aimed at studying progression of chronic glomerulonephritis (CGN) associated with cardiovascular diseases (CVD). MATERIALS AND METHODS: The clinical course of CGN with and without concomitant CVD was followed up in 75 men and 44 women aged 17-66 (mean 37.6 +/- 12.9) years. Duration of the disease varied from 1 to 17 years. The appearance of persistent proteinuria and/or hematuria was regarded as the onset of the disease. The following laboratory parameters were recorded: hemoglobin level, packed cell volume, erythrocyte number daily proteinuria, glomerular filtration rate. CVD were diagnosed using electro- and echocardiography, veloergometry, and 24 hr Holter monitoring. RESULTS: Patients with CGN and CVD showed a significantly increased serum creatinine level] 110 (180-181) vs 87 (64-134) mcmol/l, p = 0.01], reduced glomerular filtration rate [79.1 (41.1-104.5) vs 103.1 (67.2-146.8) ml/min, p = 0.0I] compared to the patients with CGN without CVD. Combination of CGN and CVD significantly decreased the 5 and 7 year survival rate. CONCLUSION: Combination of CGN and SVD at the pre-dialysis stage deteriorates nitrogen excretion by the liver and reduces the liver survival rate. PMID- 26495527 TI - [BRONCHIAL ASTHMA AND METABOLIC SYNDROME]. AB - Bronchial asthma (BA) and metabolic syndrome (MS) are important socio-medical problems with complicated pathogenetic relations between them that account for the development of mutually aggravating conditions making it dificult to control BA and deteriorating quality of life. AIM: To study the clinical picture of BA in patients with MS and analyse the influence of MS components on BA control. MATERIALS AND METHODS: The study included 95 patients with partly controlled BA divided into 2 groups. Group 1 comprised 35 patients with BA without MS, group 2 consisted of 60 patients with BA and MS. Their comprehensive clinical and instrumental examination included evaluation of clinical symptoms and BA control, quality of life, anthropometric and spirometric data, arterial pressure, carbohydrate metabolism, blood lipid spectrum. RESULTS AND DISCUSSION: Patients with BA and MS suffered more pronounced changes of bronchial patency (forced expiratory volume during the first second) and the spread of daily peak exhalation rates than patients without MC. Also, they showed a tendency toward a decrease of vital lung capacity and Tiffeneau index. The assessment of the quality of life based on the Short Form-36 questionnaire revealed marked negative effect of BA +MS combination. Results of the first stage of the study were confirmed by correlation analysis of MS components, BA picture and control, spirometric data and quality of life characteristics. Among MS components, abdominal obesity and BMI showed the best correlation with the parameters characterizing the clinical picture of BA, such as apnea, BA control, results of spirometry (forced expiratory volume during the first second), and the spread of daily peak exhalation rates. CONCLUSION: The presence of MS components (obesity, arterial hypertension, disordered lipid and carbohydrate metabolism) increases severity of BA and accounts for the deterioration of the patients' quality of life. PMID- 26495528 TI - [PROGNOSTIC SIGNIFICANCE OF THE ENDOTHELIN-I LEVEL IN PATIENTS WITH ARTERIAL HYPERTENSION DIFFERING IN VITAMIN D LEVEL]. AB - The aim of the study was to measure blood vitamin D (25(OH)D) and endothelin-1 levels by enzyme immunoassay and estimate their relation to results of 24-hr arterial pressure monitoring (APM) in patients with arterial hypertension differing in vitamin D level. The study included 144 patients with grade II AH (114 women of mean aged 50.8 +/- 6 yr and 30 men of mean age 46 +/- 6 yr). They were divided into 3 groups depending on the total 25(OH)D level. Group I was comprised of patients with 25(OH)D deficiency (below 20 ng/ml), group 2 included patients with 25(OH) D insufficiency (20-30 ng/ml), group 3 consisted of patients with optimal 25(OH)D level (over 39 ng/ml). Mean total 25(OH)D and endothelin-1 levels were 24.87 [17.03;34.07] ng/ml and 0.54 [0.38;0.63]pg/ml respectively The patients of groups 1 and 2, but not group 3 showed positive correlations between the following APM characteristics: mean systolic/diastolic arterial pressure (SAP/DAP) and SAP/DAP time index during 24 hours, day- and night-time; SAP/DAP variability at night-time and endothelin-1 level. The endothelin-1 level 10.51 pg/ml or higher measured with a sensitivity of 8% allows to predict, regardless of the 25(OH)D level, the superthreshold values of the following APM parameters: mean daily SAP/DAP during 24 hours, day- and night-time, SAP/DAP time index during 24 hours and daytime, enhanced SAP/DAP variability at night-time, DAP at daytime. PMID- 26495529 TI - [SEVERE HCV-ASSOCIATED CRYOGLOBULINEMIC VASCULITIS]. AB - A case of severe recurrent cryoglobulinemic vasculitis with hepatic lesions and diffuse skin necrosis is described. The relevant literature data and approaches to the treatment of different forms of the disease are discussed. PMID- 26495530 TI - [THE USE OF PROTON MAGNETIC RESONANCE SPECTROSCOPY IN THE PATIENTS WITH FATTY INFILTRATION OF THE LIVER]. AB - The number of patients with metabolic syndrome, type 2 diabetes mellitus, and obesity increases all over the world; the prevalence of these conditions in developed countries amounts to 20-30 per 1,000 adult population. Most studies demonstrate their direct relation to non-alcoholic fatty infiltration of the liver. MRI is the only non-invasive method allowing to quantitatively determine the degree of fatty infiltration of the liver with high sensitivity and specificity comparable with those attainable by morphological studies. Proton magnetic resonance spectroscopy is an effective non-invasive diagnostic method for dynamic and quantitative evaluation of fat content in the liver undergoing non-alcoholic fatty infiltration. Specifically, its application to estimate the efficacy of a lipid-reducing diet and therapy revealed normalization of lipid metabolism in 57% of the patients within 6 months after the onset of the treatment (the lipid level decreased two-fold in 28% of the patients). PMID- 26495531 TI - [THE PHARMACOTHERAPEUTIC EFFICIENCY OF CYTOFLAVIN IN PATIENTS WITH DIABETIC FOOT SYNDROME: IMMEDIATE AND LONG-TERM RESULTS]. AB - Immediate and long-term results of parenteral and oral administration of cytoflavin to patients with diabetic foot complicated by grade I and II trophic ulcers (Wagner classification) are considered with special reference to the assessment of reparative processes, normalization of the serum pro oxidant antioxidant system, and improvement of clinical and instrumental bloodflow characteristics. PMID- 26495532 TI - [CAUSES OF DEATH IN PATIENTS WITH ACUTE MYOCARDIAL INFECTION IN NON-SPECIALIZED SETTINGS]. AB - The aim of the study was to analyse the causes of death in patients with acute myocardial infection (AMI) treated in non-specialized settings of the city of Tomsk based on the WHO registry of AIM. A total of 156 deaths from AIM that occurred in 2013 were studied. The diagnoses were verified using results of autopsies. The study group included 42.3% of men and 57.7% of women. 91.7% of the deceased patients aged above 50 years including 30.4% of those above 80 years. All patients were referred to the clinics by the emergency aid services. Most of them presented with the atypical onset and clinical picture of AIM, had an aggravated medical history, and died soon after hospitalization. Results of primary medical examination suggested AIM only in 58.3% of the cases. The remaining patients showed ECG signs of possible AIM. Positive results of serum enzyme tests (creatine phosphokinase, its MB fraction, troponin) were obtained in 72.4% of the cases. It is concluded that the above death cases were very complicated diagnostically, clinically, and prognostically. To prevent lethal outcomes, all patients with unstable angina should be hospitalized only in specialized clinics providing regular ECG monitoring and control of biochemical markers of myocardial necrosis for diagnostics of suspected AIM. PMID- 26495533 TI - [HISTORY OF THE NAVAL MEDICAL ACADEMY]. AB - The article presents information on the history of the Naval Medical Academy (NMA), the preconditions of its creation, the composition of the faculty of Naval Department of the 1st Leningrad Medical Institute, of the 3rd Leningrad medical Institute andfirst teachers of NMA. PMID- 26495534 TI - [The myopia epidemic]. PMID- 26495535 TI - [Vaccine preventative interventions of clinic infections - dream or reality in progressive antibiotic resistance]. PMID- 26495536 TI - [BeKD 2015 Annual Congress: health and pediatric nurses in the school]. PMID- 26495537 TI - [Compartment syndrome and Volkmann contracture]. PMID- 26495539 TI - [Family health as research focus]. PMID- 26495538 TI - [New nursing career regulation: only with GKiKP prioritization]. PMID- 26495540 TI - [The first 1000 days: survey of pregnant women and mothers. Proper nutrition for a healthy future]. PMID- 26495541 TI - [Rheinland-Pfalzer beware: the countdown is in progress!]. PMID- 26495542 TI - In today's complex and changing healthcare environment, engaged and effective board governance is critical. PMID- 26495543 TI - Board Governance: Transformational Approaches Under Healthcare Reform. AB - Previous successes of healthcare organizations and effective governance practices in the pre-reform environment are not predictive of future success. Healthcare has been through numerous phases of growth and development using tried-and-true strategies. The challenge is that our toolbox does not contain what is needed to build the future healthcare delivery systems required in the post-reform world. Healthcare has had a parochial focus at the local level, with some broadening of horizons at the state and national levels. But healthcare delivery is now a global issue that requires a totally different perspective, and many countries are confronting similar issues. US healthcare reform initiatives have far reaching implications. Compounding the reform dynamics are the simultaneously occurring, gamechanging accelerants such as enabling information technologies and mobile health, new providers of healthcare, increased consumer demands, and limited healthcare dollars, to name a few. Operating in this turbulent environment requires transformational board, executive, and physician leadership because traditional ways of planning for incremental change and attempting to time those adjustments can prove disastrous. Creating the legacy healthcare system for tomorrow requires governing boards and executive leadership to act today as they would in the desired future system. Boards need to create a culture that fosters.innovation with a tolerance for risk and some failure. To provide effective governance, boards must essentially develop new skills, expertise, and ways of thinking. The rapid rate of change requires board members to possess certain capabilities, including the ability to deal with ambiguity and uncertainty while demonstrating flexibility and adaptability, all with a driving commitment to metrics and results. This requires development plans for both individual members and the overall board. In short, the board needs to function differently, particularly regarding the types of discussions at and the focus of board meetings. PMID- 26495544 TI - Governance Resilience: The Presbyterian Journey. AB - Presbyterian Healthcare Services, based in Albuquerque, New Mexico, is the state's only private, not-for-profit integrated healthcare system. It was founded in 1908 as a sanitorium for tuberculosis patients who came to the arid Southwest in search of a cure. Today, Presbyterian is thriving as a twenty-first-century integrated healthcare system, serving one in three New Mexicans in its statewide hospital system; it also includes a 440,000-member health plan and a 700-plus provider medical group. Presbyterian remains dedicated to its singular purpose of improving the health of the patients, members, and communities it serves. Just as Presbyterian has progressed and grown during its 106-year history, its governance system has evolved over time. Presbyterian has always believed that the New Mexico communities it serves deserve not just good governance but great governance and relies on strong structure and processes to lead it to superior outcomes. The ebb and flow of change, our ability to learn from trial and error, and our commitment to success in spite of obstacles make up the story of Presbyterian's strong governance system. PMID- 26495545 TI - Rafting the Rapids of Reform with the Governing Directors on Board. PMID- 26495546 TI - Building a Better Board. PMID- 26495547 TI - Board Governance: Reform-Driven Transformation and Reexamination of Fundamentals. PMID- 26495548 TI - Response from a Feature Author. PMID- 26495549 TI - HEALTHCARE HAS FAILED. PMID- 26495550 TI - Retail and Real Estate: The Changing Landscape of Care Delivery. AB - By its nature, retail medicine is founded in real estate. That retail medicine has expanded so dramatically in a relatively short period of time has taken people by surprise. This rapid growth of integrating healthcare services into retail real estate begs the question of whether real estate will eventually take on the importance in healthcare delivery that it has in retail. This article advances the view that it will. In the end, what retail and healthcare have in common is that they both reflect the attributes of demanding consumers as part of an experience-based economy, where products and services are sought based on how they fit with their lifestyles and how they make them feel (Pine and Gilmore 1998). Changing the selection process for healthcare services to be more like retail is already expanding how and where healthcare services are delivered. PMID- 26495551 TI - Geisinger's Retail Innovation Journey. AB - In 2003, Geisinger Health System formed a new group, Geisinger Ventures (GV), to accelerate the growth of new lines of business that were extensions of the core mission of the organization. Careworks, the convenient care clinic line of business, began in early 2006 as one of the early components of the GV portfolio. Over the past nine years, Geisinger has tested several retail and walk-in models, including in-store clinics, separate retail sites, and models colocated with primary care practices and emergency departments. Each site and model presents different benefits and challenges with respect to patient care, marketing, staffing, and clinical integration. With the implementation of healthcare reform and a decision to participate in Medicaid'managed care, Geisinger's strategic need for convenient care options has intensified, and new models, including e visits and telemedicine specialty consultations, are being actively explored. Geisinger's view is that healthcare is rapidly changing, being affected by demographic shifts, diagnostic and treatment options, payment changes, and communication technologies. Healthcare delivery must flex to adjust to these and other trends, and retail clinics are part of that response. Careful examination of the critical elements necessary for optimal care (including wellness, prevention, and management of chronic disease and severe multimorbid disease) and then matching those elements to the optimal mode and site of care will lead to a streamlined healthcare system. The historical--and still most prevalent- methodology of traditional office, emergency department, and inpatient care options are not ideal for all patients' care needs in the twenty-first century. A thoughtful, deliberate extension of those options will be necessary. Rather than simply adding a static retail or virtual offering, medical professionals should develop a process to continually assess patients, technology, payment, and disease changes so that they are constantly adding exciting new options to the clinical delivery model. The ability to assess and respond to the changes that these varied inputs drive will be the most important element of success for the future. PMID- 26495552 TI - Virtua and CVS Health: Partnering Within a Population Health Delivery Model. PMID- 26495553 TI - Retail Clinics: The Bellin Experience. PMID- 26495554 TI - The Challenge and Promise of Retail Medicine. PMID- 26495555 TI - Hospital design Innovation on show at Queensland facility. AB - In a follow-up to an article on the hospital that first appeared in the autumn 2010 issue of The Australian Hospital Engineer, and was then republished with the help of the magazine. The Institute of Hospital Engineering Australia, and the IFHE in the November 2011 edition of HEJ, principals at architectural firm, Hassell, Kieren Morgan and Megan Reading, explain how the new Gold Coast University Hospital (GCUH) in Southport, Queensland, 'demonstrates how good design can improve delivery of care, as well as staff retention and attraction'. PMID- 26495556 TI - Serious impact of poor planning shown. AB - This article analyses the design, project management, and construction work entailed in of the renovation of the emergency department and surgical suite of an old, highly complex healthcare facility in Caracas which has a School of Medicine, and encounters high patient throughput due to its location in the centre of the metropolitan area of Caracas. The project, involving an area of 3,000 m, had to overcome obstacles including security, the site's location, and its immediate environs. The article describes the remodeling project, and some of the lessons learned, in some detail. PMID- 26495557 TI - Considerable challenges in ensuring patient safety. AB - John Prendergast, a decontamination engineer working within the specialist team at NHS Wales Shared Services Partnership / Specialist Estates Services dedicated to decontamination and reprocessing of medical devices, considers 'the array of standards that are in place to provide rules, guidance, or characteristics, for various decontamination activities'. He also sets out some of the key steps to take to ensure that instrument decontamination is undertaken to the high standards needed to ensure patient safety. PMID- 26495559 TI - Addressing disconnects, broadening training. PMID- 26495558 TI - HBN guidance sets out key principles. AB - With an ageing population in many countries, health and social care providers are under growing pressure to improve the quality and safety of care environments for older people, and ensure they are fit-for-purpose for caring for those with age related conditions, including dementia. Health Building Note 08-02: Dementia friendly health and social care environments, recently published, is the first HBN to offer specific guidance on the subject. Here Loughborough University research associates, Efthimia Pantzartzis and Federica Pascale, and Andrew Price, who is Professor of Project Management at the University, explain the background to the new HBN, and offer insights into its structure and content. June's HEJ reported on 115 Department of Health-funded pilot projects undertaken throughout England in 2013-2014 aimed at creating more 'dementia-friendly' environments in health and social care settings implemented under the DH Capital Programme, Improving the environment of care for people with dementia. The results and findings helped shape the new HBN guidance. PMID- 26495560 TI - Distance learning course proving its worth. PMID- 26495561 TI - Better informed for a better choice. PMID- 26495562 TI - Healthcare facilities looking to 'future-proof'. PMID- 26495563 TI - Back to School. PMID- 26495564 TI - Using Technology to Map Out a Population Health Strategy. PMID- 26495565 TI - 4 Case Studes: Leading IT Innovation in Care. PMID- 26495566 TI - IT'S TIME TO TAKE A NEW LOOK AT INCLUSION IN HEALTHCARE ORGANIZATIONS. PMID- 26495567 TI - The Urgent Need for Fatigue Management Policies. PMID- 26495568 TI - A Model for Change. PMID- 26495569 TI - Improving the Health of Patient-Care Staff. PMID- 26495570 TI - What's Next for Healthcare Reform? PMID- 26495571 TI - Coaching Emerging Healthcare Leaders. PMID- 26495572 TI - Governance Principles for Physician Organizations. PMID- 26495573 TI - Assessing Community Health Needs. PMID- 26495574 TI - Physician Employment Alternatives. PMID- 26495575 TI - 350 YEARS OF SCIENTIFIC PERIODICALS. PMID- 26495576 TI - FIT FOR PRINT: DEVELOPING AN INSTITUTIONAL MODEL OF SCIENTIFIC PERIODICAL PUBLISHING IN ENGLAND, 1665-CA. 1714. AB - This paper explores the contested afterlife of Philosophical Transactions following the death of its founder, Henry Oldenburg. It investigates the complex interrelation between the institution and the periodical at a time when the latter was supposedly independent, and outlines the competing proposals for institutional publishing in science contemplated in the Royal Society, linking some publications that were actually attempted to those proposals and to the Society's attempts to revitalize its experimental programme between 1677 and 1687. It argues that the Society was concerned to produce experimental natural knowledge over which it could claim ownership, and intended this work for publication in other venues than Transactions, whereas the periodical was seen as a more suitable site for work reported to the Society than for research that the institution had primarily produced. It was only from the early 1690s, after the collapse of the Society's experimental programme, that Transactions gradually became a more straightforward reflection of the mainstream of Royal Society activity, paving the way for its formal reinvention as the official publication of the Society in 1752. PMID- 26495577 TI - THE PROFITS AND PERILS OF PUBLICITY: ALLGEMEINE LITERATUR- ZEITUNG, THE THURN UND TAXIS POST, AND THE PERIODICAL TRADE AT THE END OF THE EIGHTEENTH CENTURY. AB - Recent historiography on the growth of periodical publishing has emphasized newspapers and journals as constituents of an emergent communications system in early modern Europe. This system comprised the newspapers, journals and other publications that contributed its content, and also the postal systems that were the principal method of distributing that content. This article describes how the growth of this system in central Europe was supported in large measure by financial incentives that it offered to both constituents. First, in contrast with postal systems in France and the UK, the Thurn und Taxis Reichspost inserted itself as a middleman in the sale of periodicals, which gave the Reichspost an incentive to promote the trade. Second, the financial conditions for periodical publication made their costs depend more heavily on costs that were scalable to circulation than is true today, which resulted in the viability of publications with a lower circulation. The same cost structure also made it possible for certain prominent periodicals of the era to earn considerable profits for their publishers, as illustrated in this article by Allgemeine Literatur-Zeitung, which was published in Jena from 1785. PMID- 26495578 TI - JOURNALS, LEARNED SOCIETIES AND MONEY: PHILOSOPHICAL TRANSACTIONS, CA. 1750-1900. AB - This paper investigates the finances of the Royal Society and its Philosophical Transactions, showing that in the late eighteenth and nineteenth centuries journal publishing was a drain on funds rather than a source of income. Even without any expectation of profit, the costs of producing Transactions nevertheless had to be covered, and the way in which this was done reflected the changing financial situation of the Society. An examination of the Society's financial accounts and minute books reveals the tensions between the Society's desire to promote the widespread communication of natural knowledge, and the ever increasing cost of doing so, particularly by the late nineteenth century. PMID- 26495579 TI - PUBLISHING SOUTH AFRICAN SCHOLARSHIP IN THE GLOBAL ACADEMIC COMMUNITY. AB - South Africa's academic publishing history has been profoundly influenced by its colonial heritage. This is reflected in the publication of Transactions of the South African Philosophical Society (later, the Royal Society of South Africa) from 1878. Although the Society and journal sought to promote original research about South Africa, it was modelled after the Royal Society in London and formed part of an imperial scientific community. As the local higher education institutions grew more independent and research-focused, local scholarly publishing developed as well, with university presses playing an increasingly important role. The University of South Africa (Unisa) Press started publishing departmental journals in the 1950s, with a focus on journals that 'speak to the student', and it is today the only South African university press with an active journals publishing programme. As external funding declined and the country became intellectually isolated in the high apartheid period, the Press managed to attract journals that could no longer be subsidized by learned societies and other universities. More recently, new co-publishing arrangements have brought South African journals back into an international intellectual community. Although some argue that this constitutes a re-colonization of South African knowledge production, it is also an innovative strategy for positioning local research in a global context. PMID- 26495580 TI - CONSERVATIVE ATTITUDES TO OLD-ESTABLISHED ORGANS: OLIVER LODGE AND PHILOSOPHICAL MAGAZINE. AB - In 1921 Oliver Lodge defended Philosophical Magazine against charges of mismanagement from the National Union of Scientific Workers. They alleged that its editors performed little editorial work, the bulk being done by the publishers, Taylor & Francis. Lodge reassured Nature's readers that the journal did consult its editors, and suggested 'a conservative attitude towards old established organs is wise; and that it is possible to over-organise things into lifelessness.' The paper explores Lodge's response by considering the editorial arrangements at Philosophical Magazine. Founded in 1798, it remained remarkably unchanged and so appeared old-fashioned when compared with its closest rivals, Proceedings of the Royal Society and Proceedings of the Physical Society. We argue that for Lodge the management of Philosophical Magazine gave it the flexibility and independence required to sustain the kind of physics, also open to accusations of obsolescence, in which he believed. PMID- 26495581 TI - CREDIBILITY, PEER REVIEW, AND NATURE, 1945-1990. AB - This paper examines the refereeing procedures at the scientific weekly Nature during and after World War II. In 1939 former editorial assistants L. J. F. Brimble and A. J. V. Gale assumed a joint editorship of Nature. The Brimble-Gale era is now most famous for the editors' unsystematic approach to external refereeing. Although Brimble and Gale did sometimes consult external referees, papers submitted or recommended by scientists whom the pair trusted were often not sent out for further review. Their successor, John Maddox, would also print papers he admired without external refereeing. It was not until 1973 that editor David Davies made external peer review a requirement for publication in Nature. Nature's example shows that as late as the 1960s a journal could be considered scientifically respectable even if its editors were known to eschew systematic external peer review. PMID- 26495582 TI - Iconography on Scientific Instruments. Introduction. PMID- 26495583 TI - "Perhaps Irrelevant". The Iconography of Tycho Brahe's Small Gilt Brass Quadrant. AB - When Tycho Brahe published a description of his astronomical instruments in 1598 as part of a strategy to procure royal patronage, it was not with one of his grander, precision measurement tools that he opened his account, but rather a small brass quadrant with limited observational utility. The defining feature of this instrument was seemingly a small emblematic image inscribed within the arc of the quadrant. Through this symbolic motif Tycho conveyed a moralising message about the relative worth of astronomy. Considering a range of visual productions that may have influenced his iconography, the present paper situates the quadrant within the broader context of Renaissance visual culture and examines the significance of the quadrant in Tycho's wider instrument collection. PMID- 26495584 TI - Perfect in Every Sense. Scientific Iconography on an Equation Clock by Jost Burgi and the Self-Understanding of the Astronomers at the Kassel Court in the Late 1580s. AB - At the center of this article is an iconographic analysis of the eight silver reliefs on the sides of a table clock made in 1591 by Jost Burgi, the court clockmaker of Landgrave Wilhelm iv of Hessen-Kassel. The reliefs present an astronomical ancestral picture gallery, running from the Patriarchs of the Old Testament to Copernicus. The author argues that the "storyboard" for this sequence of images must have been conceived down to its smallest details by the Kassel court astronomer Christoph Rothmann; indeed, many of the scenes shown, along with many particular details depicted within them, are literally described in Rothmann's never-published manuscript Observationes stellarum fixarum of 1589. The final section of the essay compares these reliefs to the images created for Tycho Brahe at his Uraniborg and Stjerneborg observatories. The author concludes that the sequence of the reliefs in Kassel, culminating in the representation of Copernicus and his world view, is a reflection of the acrimonious debate extending over many years between the heliocentrist Rothmann and the geo heliocentrist Brahe regarding the veracity of the heliocentric world view. PMID- 26495585 TI - Heavenly Networks. Celestial Maps and Globes in Circulation between Artisans, Mathematicians, and Noblemen in Renaissance Europe. AB - The aim of this paper is to examine the iconography on a set of star charts by Albrecht Durer (1515), and celestial globes by Caspar Vopel (1536) and Christoph Schissler (1575). The iconography on these instruments is conditioned by strong traditions which include not only the imagery on globes and planispheres (star charts), but also ancient literature about the constellations. Where this iconography departs from those traditions, the change had to do with humanism in the sixteenth century. This "humanistic" dimension is interwoven with other concerns that involve both "social" and "technical" motivations. The interplay of these three dimensions illustrates how the iconography on celestial charts and globes expresses some features of the shared knowledge and shared culture between artisans, mathematicians, and nobles in Renaissance Europe. PMID- 26495586 TI - Moving Shadows, Moving Sun. Early Modem Sundials Restaging Miracles. AB - Irrespective of geo- or heliocentric presuppositions, the functioning of sundials is based on the observation of moving shadows or light spots. Even though the cast shadow was often simply used to indicate the time, it could also remind the users of the ephemerality of earthly things or function as an index of planetary movements. This article examines the various ways in which early modem sundials visually interpret the moving shadow or light spot. The instruments address the shadow in inscriptions, integrate it into their design (e.g., in cruciform dials) or even manipulate its course (as in the so-called Horologium Ahaz). Both the crucifix and the Ahaz dials not only refer to astronomical miracles but actually restage them. Even though by means of the horologium it was not possible to explain the Old Testament miracle of the shadow moving backward, adepts were able to recreate it on a terrestrial scale. PMID- 26495587 TI - Metrics of Justice. A Sundial's Nomological Figuration. AB - This paper examines a polyhedral dial from the British Museum made by the instrument maker Ulrich Schniep, and discusses the status of multifunctional scientific instruments. It discerns a multifaceted iconic meaning considering different dimensions such as scientific functionality (astronomy), the complex allegorical figure of Justice (iconography), and the representation of the sovereign (politics), the court and the Kunstkammer of Albrecht v of Bavaria. As a numen mixtum the figure of "Justicia" touches different fields that go far beyond pure astronomical measurement and represents the power of the ruler as well as the rules of economic justice. PMID- 26495588 TI - Les Observatoires astronomiques en Italie. An 1863 Report by Otto Wilhelm Struve. AB - In the autumn of 1863 Otto Wilhelm Struve, director of the Pulkovo Astronomical Observatory in Russia, visited most of the observatories in Italy. The report that he wrote on this occasion provides an overview on the conditions of astronomical research in Italyjust after the unification of the country. Later Struve sent a French translation of his report to the Italian astronomer Giovan Battista Donati, who used it to promote the construction of the Arcetri Observatory in Florence, which was inaugurated in 1872. We present here a transcription of the French translation of Struve's report and the transcription of a letter written by him in support of Donati's project PMID- 26495589 TI - The Palermo Merz Equatorial Telescope. An Instrument, a Manuscript, Some Drawings. AB - A manuscript by Georg and Sigmund Merz dated 1862 and containing instructions for assembling the equatorial telescope acquired by the Palermo Observatory is conserved in the archives of the Museo Astronomico e Copernicano in Rome. It is a rare document that reveals "tricks of the trade" and technical knowledge not usually included in textbooks or treatises. It was sent to the Palermo Observatory as an aid to the installation of the telescope, which made a signal contribution to the development of solar physics in Italy in the 19th century. Based on the study of unpublished sources (consisting of texts and drawings), the history of the instrument has been retraced. This paper presents a detailed description of the Merz manuscript (including a complete transcript) and some technical drawings recently discovered in the archives of the Palermo Observatory. PMID- 26495590 TI - Automated blood culture testing: A retrospective study indicates that a three-day incubation period is sufficient. PMID- 26495591 TI - FDA regulation of LDTs--an update. PMID- 26495592 TI - Clinical application of thromboelastometry in cardiovascular and thoracic surgery. AB - VET with ROTEM and TEG have become more integrated into the practice guidelines of multiple medical associations with increasing levels of evidence and recommendation for their use to manage perioperative bleeding. VET, in conjunction with SLT, provides a clearer picture of why a patient bleeds and how to best resolve it. In the clinical setting of CVTS, ROTEM has been shown to reduce transfusion rates and reduce costs associated with transfusion products and transfusion-related adverse events while improving patient outcomes. Incorporating VET into a hospital-wide transfusion restrictive strategy has been proven to be cost-effective and clinically beneficial but requires a multi-level commitment for planning, education and implementation. PMID- 26495593 TI - The changing landscape of point-of-care diagnostics for influenza virus infections. PMID- 26495594 TI - The TB elimination challenge gets a global call: the expanding role of clinical labs. PMID- 26495595 TI - The evolving influenza test: new options for the management of RIDT. PMID- 26495596 TI - Image is everything! Quality issues remain as digital pathology enters the clinical lab. PMID- 26495597 TI - Whole slide imaging: it's time to take another look. PMID- 26495598 TI - Freeze-thaw cycles and nucleic acid stability: what's safe for your samples? PMID- 26495599 TI - Laboratory-developed tests are not the practice of medicine. PMID- 26495602 TI - A NEW HOME. Parkland Hospital's successful move. PMID- 26495601 TI - MEANINGFUL USE? Taking analytics to the next level. PMID- 26495603 TI - NOTHING'S OFF LIMITS. Using'culture councils' to transform the patient experience. PMID- 26495604 TI - MOST WIRED. Health IT proves useful in reducing unnecessary utilization. PMID- 26495605 TI - BED TO BED. Using technology to improve ED performance. PMID- 26495606 TI - STROKE CARE. Three questions with: Iman Andrabi, M.D. PMID- 26495607 TI - HIP FACTOR. Health system wetlness effort goes to waist. PMID- 26495608 TI - Pedaling hard for cancer research. PMID- 26495609 TI - DISRUPT YOUR BUSINESS. CONTROL YOUR FUTURE. PMID- 26495610 TI - Lessons from the Barrio and Beyond. PMID- 26495611 TI - THE 2016 ENVIRONMENTAL SCAN. AB - Every year, the American Hospital Association compiles the Environmental Scan to provide hospital leaders with insight and information about market forces that are likely to affect the health care field. One common theme this year is the pace of change. PMID- 26495612 TI - What the EVOLUTION of one medical home can teach us all. PMID- 26495613 TI - POPULATION HEALTH AND THE RISE OF CONSUMERISM. AB - Earlier this summer, we convened a panel of health care executives and industry experts to consider how hospitals can balance the demands of high-value, more efficient care with the emergence of the savvy health care consumer. Their insights and words of advice are eye-opening. PMID- 26495615 TI - Absorbing the Lessons of WHO's Ebola Response. PMID- 26495614 TI - Reaping the Benefits of Supplier Diversity. PMID- 26495616 TI - The Trouble with Tablets. AB - The biggest recommendation is to get your tablet screen up. This can be done by using a case or a tablet stand. Avoid using the tablet on your lap because posture follows vision. If you must use it on your lap, try placing it on a pillow to raise its height and reduce dangerous neck flexion. Whenever possible, set the tablet on a table rather than holding it with your hands because hands and forearms fatigue quickly. Consider finding an external keyboard that can be separated from the tablet screen. This way, you can set the tablet on a higher surface to elevate the screen and have a lower keyboard to eliminate some of the wrist extension when keying. PMID- 26495617 TI - Preventing Manual Handling Injuries. PMID- 26495618 TI - DOT and OSHA Training. PMID- 26495619 TI - Keeping Communities and Workers Safe From Benzene. PMID- 26495620 TI - First-Class Protection. PMID- 26495621 TI - Optimizing Worker Safety: It's in the Lights. PMID- 26495622 TI - Innovative Approach to Duct Sealing Turns IAQ Problems Inside Out. PMID- 26495623 TI - The Wellness Imperative. PMID- 26495624 TI - Wellness and Safety Programs Expand to Embrace Employee Well-being. PMID- 26495625 TI - Why Incentives Are a Key to Surviving Tight Safety Budget Challenges. PMID- 26495626 TI - Emphasize Calling 911 When an Emergency Occurs. PMID- 26495627 TI - IOM Looks to Improve Cardiac Arrest Survival. PMID- 26495628 TI - The Prescription Drug Misuse Epidemic: Are We Making Progress? PMID- 26495629 TI - What to Look for in a C/TPA or Program Manager. PMID- 26495630 TI - Safety, Without Compromising Comfort. PMID- 26495631 TI - Odors, Smells & Other Strange 'Stuff'. PMID- 26495632 TI - Arc Flash Hearing Protection. PMID- 26495633 TI - Hearing Protectors On the Job Site. PMID- 26495634 TI - Combat Workplace Noise Pollution to Help Prevent Hearing Loss. PMID- 26495635 TI - What It Takes to Make Behavior-Based Safety Work. PMID- 26495636 TI - Blueprints for Successful Cultural Leadership. PMID- 26495637 TI - [Effects of Lime on Seedling Growth,Yield and Volatile Constituents of Atractylodes lancea]. AB - OBJECTIVE: To investigate the effects of different amounts of lime on yield and quality of Atractylodes lancea, and to provide reference for the herb growing site soil improvement and self-poisoning ease. METHODS: Add different gradients of lime, and then measure their growth targets, yield and four kinds of volatile constituents content(hinesol, atractylone, beta-eudesmol and atractylodin). Volatile constituents yield per plant was calculated. RESULTS: Adding 160 g/m2 lime had a significant role in promoting the growth and yield of herb; Adding 80 g/m2 lime was conducive to the volatile constituents production, and adding lime decreased the atractylone and atractylodin content, while increased the hinesol and beta-eudesmol content; Adding 160 g/m2 lime promoted the volatile constituents yield per plant. CONCLUSION: Adding lime plays a role of neutralize soil pH, antibacteria and prevention incognita, and has a certain degree of ease autotoxicity and obstacle,and then promotes the yield and volatile constituents production of Atractylodes lancea. PMID- 26495638 TI - [Effects of Different Shading Treatment and Planting Patterns on Several Main Characters and Yield of Elephantopus scaber]. AB - OBJECTIVE: To study the growth and yield of Elephantopus scaber under different light conditions. METHODS: Several main characters and yield performances were studied under six shading treatment as well as two planting patterns. RESULTS: The plant height, leaf number, root length and root-shoot ratio were increased under moderate shading. With the increase of shading ratio, the process of Elephantopus scaber vegetative growth to reproductive growth were shortened, seed yield, dry biomass and root yield decreased as well. Among different shading treatments, dry seed-yield showed 8. 46 ~31. 10 kg/667 m2 dry biomass showed 327. 28 ~ 800. 95 kg/ 667 m2 and dry root yield showed 30. 65 ~ 70. 72 kg/667 m2. CONCLUSION: Elephantopus scaber is a light-demanding but shade-tolerant plant. The patterns of hole seeding were suggested in planting, and not more than 60% shade density may be good under plantations. PMID- 26495639 TI - [Influences of Base Fertilizer Dosage and Root Size on Quality and Yield of Gentiana crassicaulis Root]. AB - OBJECTIVE: In order to optimize the base fertilizer dosage and root size of Gentiana crassicaulis in Ludian,Yulong, Yunnan,the differences in yield and quality of Gentiana crassicaulis caused by different base fertilizer dosage and root size were investigated. METHODS: The variation in fresh weight, dry weight, drying rate, length, diameter, branches as well as the contents of gentiopicroside, loganin acid, alcohol-soluble extract and total ash were determined. The ideal distance grey relational degree comprehensive evaluation method was applied to make a comprehensive evaluation on the quality and yield of Gentiana crassicaulis. RESULTS: There were big differences in yield and quality of Gentiana crassicaulis among different base fertilizer dosage and root size. 2 000 kg/667 m2 of manure, 20 kg/667 m2 of superphosphate, 100 kg/667 m2 of plant ash and mix size of transplanting roots showed the best comprehensive quality and the highest yield. CONCLUSION: 2 000 kg/667 m2 of manure, 20 kg/667 m2 of superphosphate,100 kg/667 m2 of plant ash, high quality transplanting roots and stagger certain depth to transplant are highly recommended to produce high quality and high yield of Gentiana crassicaulis in Ludian, Yulong, Yunnan. PMID- 26495640 TI - [Identification of Pathogens Causing Root Rot Disease on Ligusticum chuanxiong in Sichuan]. AB - OBJECTIVE: To identify the pathogens causing root rot disease on Ligusticum chuanxiong from the main producing areas in Sichuan, and to provide gist of management of this disease in the future. METHODS: The diseased rhizomes of Ligusticurn chuanxiong with root rot symptom were sampled in two main producing areas in Sichuan. According to Koch's postulate, the pathogenicity on Ligusticum chuanxiong rhizomes of the isolates was confirmed. The representative isolates were identified based on their morphological characteristics and ribosomal DNA internal transcribed spacer(rDNA-ITS) sequences. RESULTS: The isolates(f2-16, 3 2, f4-19 and f5-7)which caused root rot disease held high homology reached 99%, 99%, 100% and 100% respectively, when compared with GenBank sequences GQ229075, JQ796755, JN232136 and FJ481024. CONCLUSION: The causing agents of root rot disease on Ligusticum chuanxiong belong to Fusarium solani, Fusarium oxysporum, Plectosphaerella cucumerina and Phoma glomerata. Pathogens from different regions are varied. PMID- 26495641 TI - [Population Status of Centropus sinensis in Guangxi Province]. AB - OBJECTIVE: T0 understand the population distribution, species abundance and habitats requirement of a medicinal animal, Centropus sinensis, in Guangxi Province. METHODS: Line transect methods were used to census population number and habitat types in 18 counties or cities of Guangxi. RESULTS: Centropus sinensis distributed in all study area, with a higher population density in the south than in the north. Among seven habitat types, the species preferred living in forest-farmland ecotone, while seldom in broad-leaves forest or plantations. CONCLUSION: The results of habitat preference show an advantage to the population recovering for forest-farmland ecotone commonly existing in Guangxi Province. But the speed of population recovering is slowly under illegal hunting pressure. More attention should be paid to protect this species. PMID- 26495642 TI - [Spatial Distribution and Global Potential Suitability Regions of Artemisia annua]. AB - OBJECTIVE: To study the spatial distribution and potential climatic suitability regions of Artemisia annua around the world. METHODS: The spatial distribution and climatic characteristics were researched by factor analysis based on Global Biodiversity Information Facility Database and World Climate Database. The global potential suitability regions of Artemisia annua were analyzed by ArcGIS. RESULTS: Artemisia annua distributed in three longitude zones, including 90. 55 degrees W - 77. 14 degrees W, 2. 03 degrees E - 11. 75 degrees E and 98. 27 degrees E - 111. 05 degrees E,which were respectively in North America, Europe and Asia. The latitude range was mainly 29. 15 degrees N - 51. 36 degrees N. 80% of Artemisia annua were in the regions which elevation range was 22. 00 - 491. 00 m, annual precipitation was 492. 30 ~ 1 366. 70 mm, annual average temperature was from 8. 10 to 17. 27 degrees C. The potential suitability regions of Artemisia annua with 95% ~ 100% climate similarity were mainly in 30 degrees S and 30 degrees N regions, centered around the equator axis. Conclusion: Latitude is closely related to the distribution of Artemisia annua, the key affecting climatic factors are annual precipitation, the wettest season precipitation, the warmest season precipitation and the highest temperature in the warmest month, the average temperature of the warmest season, as well as the average temperature of the wettest season. The potential suitability regions of Artemnisia annua are in eastern North America, western Europe and eastern Asia. PMID- 26495643 TI - [Suitable Habitats Prediction of Original Plants of Rhei Radix et Rhizoma Under Climate Change]. AB - OBJECTIVE: To predict the distribution patterns of the original plants of Rhei Radix et Rhizoma current and in future in China under climate change. METHODS: A maximum entropy modeling and variety of climate change scenarios were employed to predict its current and future distribution ranges in China. RESULTS: The resultant models exhibited excellent predictive power. The current suitable habitats for original plants of Rhei Radix et Rhizoma totaled 84. 20 x 10(4) km2 accounting for 8. 77% of the total area of China; 57. 05% of its current suitable habitats(i. e. low impact areas) would be relatively lowly impacted by the climate change. Compared with its current distribution pattern,its distribution ranges during 2020s, 2030s, 2040s, 2050, 2060s, 2070s and 2080s would be shrunk to some extent. However, the moderately suitable area would be expanded to a certain degree. CONCLUSION: Climate change has a negative impact on the total area and the habitat suitability for the original plants of Rhei Radix et Rhizoma. PMID- 26495644 TI - [Simultaneous Determination of Five Active Components in Puerariae Lobatae Radix from Different Habitats by UHPLC]. AB - OBJECTIVE: To develop a UHPLC method for determination of 3'-hydroxy puerarin,puerarin, 3'-methoxy puerarin, daid- zin, and daidzein in Puerariae Lobatae Radix from different habitats. METHODS: The analysis was carried out on an Agela Venusil MP C18 (100 mm x 2. 1 mm, 3 um) column. The mobile phase was composed of 0. 1% formic acid and methanol with gradient elution. The de- tection wavelength was set at 250 nm. RESULTS: The standard curves of five components showed a good linearity in 12. 41 ~ 248. 24 ng(r =0. 9999), 58. 82 ~ 1 176. 47 ng(r =0. 9997), 12. 65 ~252. 94 ng(r=0. 9999), 12.14 ~ 242.82 ng(r=0. 9998), and 1. 82 ~ 36.30 ng(r =0. 9997), respectively. The average recoveries were 99. 03% ~ 100. 32%, and RSD values were 0. 26% ~ 1. 37%. CONCLUSION: This method is simple, quick,reproducible and can be used to control the quality of Puerariae Lobatae Radix. PMID- 26495645 TI - [Diversity of Endogeny Eumycetes in Gynostemma pentaphyllum and Its Correlation with Gypenoside XLIX]. AB - OBJECTIVE: To study the correlation between active components and endogeny eumycetes in Gynostemma pentaphyllum of different types from different habitats. METHODS: Endogeny eumycetes from different parts of Gynostemma pentaphyllum were isolated by general isolation methods. Insert method and point planting method were used for identification. The content of gypenoside XLIX were determined by HPLC. RESULTS: 125 endogeny eumycetes inhabiting in Gynostemma pentaphyllum were isolated from roots, rhizomes and leaves. By colony morphology and microscopic characteristics, 22 genera from 10 families, 7 orders, 2 classes were identified. Fusarium was the most abundant endogeny eumycetes in Gynostemma pentaphyllum with the account of 22. 4%. Penicillium and Leptosphaeria was 12. 8% and 9. 6% respectively. The correlation between Gypenoside XLIX and endogeny eumycetes in Gynostemma pentaphyllum was revealed. CONCLUSION: Endogeny eumycetes are diverse in species and quantity. The endogeny eumycetes species is related to the quality of Gynostemma pentaphyllum. PMID- 26495646 TI - [Determination of Flavonoids in Cycas revoluta Leaves by Chemiluminescence-Flow Injection Analysis Method]. AB - OBJECTIVE: To detect flavonoids from Cycas revoluta leaves by means of Chemiluminescence-Flow Injection Analysis (CL-FIA). METHODS: Under alkaline condition, a CL-FIA method was established to determine flavonoids from leaves of Cycas revoluta on the basis of inhibiting effect of flavonoids to the Luminol H2O2-Cu2+ chemiluminescence system and the reversed flow injection technique. RESULTS: In the range of 2. 0 x 10(-6) ~ 1. 0 x 10(-3) mg/mL, the decrease of CL intensity was correlated with flavonoids concentration while the detection limit was 0. 0265 ug/mL. Under the optimized conditions, the flavonoids of Cycas revoluta leaves were detected with its average rate reaching 1. 61% and RSD 1. 32%. CONCLUSION: Through the interference test and compared with the data of CL FIA and UV, it is concluded that CL-FIA can be used in the analysis and detection of flavonoids from Cycas revoluta leaves. PMID- 26495647 TI - [Isolation and Identification of Bacteria and Mycete from Preservation of Morinda officinalis]. AB - OBJECTIVE: In order to select antistaling agent which had obvious antibacterial effect on Morinda officinalis, the colony counts of microorganism from the surface of Morinda officinalis and the species of bacteria and mycete were analyzed. METHODS: Bacteria and moulds classification identification method were carried out. RESULTS: After using 10 g burdock oligosaccharide, 20 g chitosan and 0. 5 g potassium sorbate treated for 60 d, the total bacteria on the surface of Morinda officinalis was 3. 0 x 10(4) cfu/g, mycete total of 1. 5 x 10(4) cfu/g, preservation effect was better than the other treatments. CONCLUSION: The common advantage microorganisms group of Morinda officinalis on the surface are from Leuconostoc ,Aerococcus and Penicillium genera. PMID- 26495648 TI - [HPLC Fingerprint and Analysis of Component Difference of Crude and Wine Processed Products for Dipsacus asper Root]. AB - OBJECTIVE: To study the HPLC fingerprint of Dipsacus asper root before and after wine processed, and to compare the changes of fingerprint and chemical composition. METHODS: The HPLC analysis was performed on an Agilent C18 (250 mm x 4. 6 mm, 5 jim) column with gradient elution of acetonitrile-0. 05% phosphoric acid at a flow rate of 1. 0 mL/min, and the column temperature was set at 25 degrees C. RESULTS: The content of chemical composition changed in different degree after processed, the asperosaponin VI content increased significantly, and two new chromatographic peaks were found in the fingerprint. CONCLUSION: This method can be used to reflect the difference of chemical composition of Dipsacus asper root and its wine processed products. It would he an efficient way for qualitative control of Dipsacus asper root. PMID- 26495649 TI - [HPLC Characteristic Fingerprint of "Boju" Chrysanthemum morifolium]. AB - OBJECTIVE: To provide a scientific basis for quality control of "Boju" Chrysanthemum morifolium by establishing a HPLC characteristic fingerprint. METHODS: The HPLC analysis was performed on a Spursil C18 chromatographic column (250 mm x 4. 6 mm, 5 um), and the mobile phase was acetonitrile-0. 1% phosphoric acid in a gradient mode with the flow rate of 1. 0 mL/min. The detection wavelength was 325 nm and the temperature of column was 30 degrees C. RESULTS: The common pattern of HPLC characteristic chromatographic profile was established. There were 16 common peaks, five of which were identified in the pattern. The similarities of 10 batches of "Boju" Chrysanthemum monrfolium were evaluated, and all of them were greater than 0. 900. CONCLUSION: This analysis method of HPLC characteristic chromatographic fingerprint is simple and reproducible, and it can provide a scientific basis for identification and quality evaluation of "Boju" Chrysanthemum monfolium. PMID- 26495650 TI - [Chemical Constituents from Melissa officinalis Leaves]. AB - OBJECTIVE: To investigate the chemical constituents of Melissa officinalis leaves. METHODS: The chemical constituents were separated by silica gel column chromatography and their structures were determined by spectroscopic experiments. RESULTS: 13 compounds were isolated and identified as protocatechuyl aldehyde(1), serratagenic acid(2), vanillin(3), 2alpha,3beta-dihydroxy-urs-12-en-28-oic acid(4), ursolic acid(5), oleanolic acid(6), daucosterol(7),2alpha,3beta,23,29 tetrahydroxyolean-12-en-28-oic acid-29-O-beta-D-gluco- pyranoside(8), luteolin(9) rosmarinic acid(10), luteolin-7-O-beta-D-glucoside (11), beta-stitosterol(12) and palmitic acid(13). CONCLUSION: Compounds 1 ~ 8 are separated from this plant for the first time and compounds 1-4 and 8 are isolated from this genus for the first time. PMID- 26495651 TI - [Chemical Constituents of Euphorbia lunulata]. AB - OBJECTIVE: To investigate the chemical constituents in the ethanol extract from the whole plant of Euphorbia lunulata. METHODS: The whole plant of Euphorbia lunulata was extracted by 95% ethanol, then partitioned by system solvents with different polarity. The ethyl acetate and n-butyl alcohol extracts were separated on silica gel, Sephadex LH-20,and MCI columns. The isolated compounds were determined by detailed analysis of their spectral data. RESULTS: Twelve compounds were isolated and identified from the ethyl acetate and n-butyl alcohol extracts of Euphorbia lunulata and the structures were identified as 7beta-methoxy stigmast-5-ene-3beta-ol (1), 7beta-methoxy-stigmast-5-ene-3beta,22beta-diol(2), asperglaucide(3), moscatin (4), p-hydroxybenzoic acid (5),3-methoxy-4-hydroxy benzoic acid(6), erigeside C(7),5,7,4'-trihydroxy flavanone(8), kaempferol(9), quercetin(10), corosolic acid(11) and acacetin (12). CONCLUSION: All compounds except for 9 and 10 are reported from this plant for the first time. PMID- 26495652 TI - [Chemical Constituents of Petroleum Ether Fraction of Lonicera macranthoides Roots]. AB - OBJECTIVE: To study chemical constituents of petroleum ether fraction of the roots of Lonicera macranthoides. METHODS: The chemical constituents were isolated and purified by several separation and purification techniques and their structures were elucidated by physicochemical properties and spectroscopic methods. RESULTS: Six compounds were isolated from petroleum ether fraction of the roots of Lonicera macranthoides as 3alpha, 16beta-dihydroxyaphidicolane (1), (22E,24R)-ergosta-6,9,22-trien-3beta,5alpha,8alpha-triol (2), (22E)-5alpha,8alpha epidioxyergosta-6,22-dien-3beta-ol (3), (24S)-stigmast-4-en-3-one (4), beta amyrin (5) and beta-amyrin acetate (6). CONCLUSION: Compounds 1 ~ 3 and 6 are isolated from this genus for the first time. All the compounds are isolated from this plant for the first time. Compound 1 is a new natural product. PMID- 26495653 TI - [n-Butyl Alcohol-soluble Chemical Constituents of Psidium guajava Leaves]. AB - OBJECTIVE: To study the chemical constituents of the leaves of Psidium guajava. METHODS: The chemical constituents were isolated by column chromatography on silica gel, Sephadex LH-20 and MPLC. Their chemical structures were elucidated on the basis of special analysis. RESULTS: Seven compounds were isolated from n butyl alcohol fraction, whose structures were elucidated as morin-3-O-alpha-L arabopyranoside (1), morin-3-O-alpha-L-iyxopyranoside (2), 2,6-dihydroxy-4-O-beta D-glucopyranosyl-benzophenone (3), casuarictin (4),2,6-dihydroxy-3,5-dimethyl-4-O (6"-O-galloyl-beta-D-glucopyranosyl)-benzophenone(5), globulusin A(6), and kaempferol-3-O-beta-D-(6"-galloyl) galactopyranoside (7). CONCLUSION: Compounds 3 and 5 ~ 7 are isolated from this plant for the first time. PMID- 26495654 TI - [Chemical Constituents of Paulownia tomentosa Fruits]. AB - OBJECTIVE: To investigate the chemical constituents from the fruits of Paulownia tomentosa. METHODS: The compounds were isolated and purified by column chromatography and their structures were identified on the basis of physicochemical properties and spectral analyses. RESULTS: Seven compounds were isolated and their structures were identified as ursolic acid (1), sesamin(2),2alpha,3alpha, 19a-trihydroxyurs-12-en-28-oic acid(3), luteolin(4), tricin-7-O-beta-D-glucoside(5),3',4',5,7-tetrahydroxy-6-[7-hydroxy-3,7-dimethyl 2(E)-octenyl] flavanone(6) and stigmasterol(7). CONCLUSION: Compounds 3, 5 and 7 are isolated from Paulownia genus for the first time. Compound 2 is isolated from Paulownia tomentosa for the first time. PMID- 26495655 TI - [Chemical Constituents from Leaves of Acanthus ilicifolius and Their Anti influenza Virus Activities]. AB - OBJECTIVE: To study the chemical constituents from the leaves of Acanthus ilicifolius. METHODS: The compounds were isolated by silica and gel column chromatographic methods and identified by spectoscopic analysis. The anti influenza virus activities of these compounds were obtained by measuring the neuraminidase activity of influenza virus. RESULTS: Five compounds were isolated and their structures were identified as blepharin(1), acteoside(2), isoverbascoside(3), daucosterol(4), and 3-O-beta-D-glucopyranosyl stigmasterol(5). CONCLUSION: All the compounds are isolated from the leaves of Acanthus ilicifolius for the first time, and compounds 1 ~ 3 exhibit the anti influenza virus activities. PMID- 26495656 TI - [Determination of Six Ingredients in Gardenia jaminoides Fruits with Quantitative Analysis of Muti-components by Single Marker]. AB - OBJECTIVE: To establish a method of quantitative analysis of multi-components, by single marker(QAMS)for simultaneously determining six ingredients in Gardenia jasminoides fruits. METHODS: A multi-wavelength segmentation detection method was used. A methodological mode was found to analysis six ingredients in Gardenia jasminoides fruits by quantitative analysis of QAMS. Taken geniposide as reference to create RCF with gardenia acid, chlorogenic acid, crocin I, crocin II and crocin III. RESULTS: The good reproducibility and acceptable durability of method was validated between two HPLC systems and three columns. 20 batches of Gardenia jaminoides fruits was analysis, and the results showed good linear correlation compared to external standard method (r > 0. 999). CONCLUSION: QAMS can be used as quality evaluation method of multi-component Gardenia jaminoides fruits. PMID- 26495657 TI - [Fingerprint and Simultaneous Determination of Multi-components in Water-soluble Components of Salvia miltiorrhiza in Miao Autonomous County of Songtao, Guizhou]. AB - OBJECTIVE: To establish the HPLC fingerprint of water-soluble components of Salvia miltiorrhiza in Songtao, Guizhou, and to perform simultaneous determination of six components in it, so as to provide analytical method for its quality control. METHODS: The analyses were performed on a Phenomenex Luna C18 (2) (250 mm x 4. 6 mm, 5um) column eluted with 0. 4% formic acid(A) - acetonitrile(B) in a gradient mode. The flow rate was 1. 0 mL/min, column temperature was set at 30 degrees C. RESULTS: Eleven common peaks were identified form the HPLC fingerprint of Salvia miltiorrhiza from 10 batches, the HPLC fingerprint similarities of 10 batches were not less than 0. 999. The linear ranges of danshensu, protocatechuic aldehyde, caffeic acid, rosmarinic acid, lithospermic acid and salvianolic acid B were 0. 0680 ~ 1. 3583 mg/mL, 0. 0008 ~ 0. 3967 mg/mL, 0. 0005 ~ 0. 2660 mg/mL, 0. 0020 ~ 0. 3992 mg/mL, 0. 0063 ~ 0. 6311 mg/mL and 0. 0097 ~ 1. 9306 mg/mL with r >= 0. 9999, respectively. The recovery rates were 100. 84%,102. 44%, 100. 53% ,100. 63%, 100. 83% and 100. 35% with RSD <2. 3%, respectively. CONCLUSION: The established method is simple, accurate and can provide reference for quality control of Salvia miltiorrhiza. PMID- 26495658 TI - [Therapeutic Effect of Paconol on Alcoholic Fatty Liver in Rats]. AB - OBJECTIVE: To make clear the therapeutic effect of paconol on alcoholic fatty liver disease (AFLD). METHODS: Model rats of AFLD were established with alcohol intragastric administration. Paconol was applied to treat the model rats for four weeks(75, 150 and 300 mg/kg), with silybin as control administration. The content of TC and TG in serum and liver were determined with 4-Aminoantipyrine (4-AAP) method, ALT and AST levels were determined with Reitman-Frankel method, serum HDL content with direct method, serum LDL content with precipitation method, serum TNF-alpha content with enzyme linked immunosorbent assay sandwich technique, FFA content in serum and liver with enzymic colorimetric method, MDA content with thiobarbituric acid reactive substance assay method, liver CYP2E1 expression with SABC method, and the pathological changes of liver were observed directly or with optical microscope. RESULTS: Paconol lowered TC, TG, HDL, LDL, ALT, AST, TNF alpha, FFA and MDA levels in serum, as well as TC, TG and FFA levels in liver, inhibited the expression of protein CYP2E1, and improved the pathological changes of model rats. CONCLUSION: There is a certain therapeutic effect of paconol on AFLD in rats. PMID- 26495659 TI - [Intestinal Absorption Characteristics and Mechanism of Polygala tenuifolia Hydrolysate in Rats]. AB - OBJECTIVE: To evaluate the absorption feature and mechanism of tenuifolin(TF) and polygalaxanthone III (PT) in different intestinal parts of rats and the impact of MRP2 and P-glycoprotein (P-gp) on it. METHODS: In situ unidirectional perfusion was used to detect the concentration of TF and PT through HPLC-DAD with gravimetric method. Furthermore, impact of different parts, cosolvents and inhibitors to TF and PT was also explored with data of Ka and Papp. RESULTS: Tween as cosolvent, Ka and Papp of TF was significantly higher in colon than in other intestinal parts(P <0. 05 or P <0. 01). Whereas, Ka of PT was in sequence of colon, duodenum, jejunum, ileum,but with no significant difference among them(P >0. 05). SDS as cosolvent, Papp of TF was higher in colon than in duodenum(P <0. 05). K. of TF was significantly higher compared with control when added with VH, an inhibitor of P-gp(P <0. 05). In addition, Papp of PT in different concentration of VH increased(P <0. 05, P <0. 01). Papp of TF significantly increased with IT at the concentration of 0. 02 and 0. 04 mmol/L, an inhibitor of MRP2(P <0. 05, P <0. 01). Meanwhile, Ka of PT,with IT at the concentration of 0. 04 and 0. 08 mmol/L, was significantly higher(P <0. 05, P <0. 01). CONCLUSION: TF is mainly absorbed in colon, whereas PT is in duodenum. P-gp but not MRP2 influences the intestinal absorption of TF, indicating TF as substrate of P-gp. However, both of P-gp and MRP2 impact the absorption of PT, illustrating PT as substrate of P-gp and MRP2. It also indicates that inhibitors of P-gp and/or MRP2 in combined application may improve the absorption of PT and TF. PMID- 26495660 TI - [Intervention of Qi-activating and Spleen-strengthening Herbs on Ca2+/CaMK II Signaling Pathways Key Factors in Skeletal Muscle Tissue of Rats with Spleen-qi Deficiency]. AB - OBJECTIVE: To observe changes of [Ca2+]i concentration and CaM, CaMK II and p CaMK II of Ca2+/CaMK II signaling pathways in skeletal muscle tissue of rats with spleen-qi deficiency and intervention of Sijunzi decoction and extract of Hedysarum polybotrys. METHODS: Rats were randomized into four groups: normal control group, spleen-qi deficient model group, extract from Hedysarum polybotrys group and Sijunzi decoction group, ten rats in each group. After the spleen-qi deficient models were built by comprehensive application of rhubarb, exhaustive and hungry methods, and treatment groups were treated with extract from Hedysarum polybotrys at 6 g/(kg . d) or Sijunzi decoction at 20 g/(kg . d) for 21 d. Then, general existence,gastrointestinal hormones GAS and MOT levels, and activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase of skeletal muscle were evaluated. Also, confocal laser technology was used to test cellular[Ca2+]i concentrations in skeletal muscle and Western blotting technique was used to test CaM, CaMK II and p-CaMK 11 expression in intestinal tissue of spleen-qi deficient model rats. RESULTS: Compared with normal group, general condition was poor, levels of GAS and MOT decreased (P <0. 01), activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase, [Ca2+]i concentration as well as expression of CaM, CaMK II and p-CaMK II in skeletal muscle decreased significantly (P < 0. 01) in spleen-qi deficienct model rats. Compared with model group, general condition improved significantly, as well as level of MOT in intestinal increased (P <0. 05) in the rats of extract from Hedysarum polybotrys group and Sijunzi decoction group,while level of GAS increased in intestinal(P <0. 05) in the rats of Sijunzi decoction group; Moreover, activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase as well as [Ca2+]i concentration and expression of CaM and CaMK II in skeletal muscle tissue increased (P < 0. 05) in the rats of extract from Hedysarum polybotrys group and Sijunzi decoction group, while p-CaMK II in skeletal muscle tissue increased in the rats of Sijunzi decoction group (P < 0. 05). CONCLUSION: Sijunzi decoction and extract of Hedysarum polybotrys can be applied to treat spleen-qi deficiency syndrome through the mechanism of regulating GAS and MOT secretion and raising expression of Ca2+ /CaM signaling pathways key factors in skeletal muscle tissue. Sijunzi decoction has the better effect PMID- 26495661 TI - [Pharmacodynamics Study on Gualou Xiebai Dropping Pills and Its Medicinal Ingredients in Prescription]. AB - OBJECTIVE: To study the pharmacodynamics of Gualou Xiebai Dropping Pills and its medicinal ingredients in prescription on anti-myocardial ischemia. METHODS: SPF Rats were divided randomly into eleven groups with ten rats in each group and half male and half female, the rats were respectively given the physiological saline(blank group and model group), Gualou, Xiebai, Gualou Xiebai Baijiutang (all equivalent to the crude herb of 22. 5 g/kg), Gualou Xiebai. Dropping Pills in the doses of 3. 75,11. 25,22. 5,33. 75 and 45 g/kg and Compound Danshen Drop Pills of 0. 085 g/kg by gavage one time a day for seven days. Except blank group, other rats were given by intraperitoneal injection of isoproterenol to establish myocardial ischemia models, changes of ST segments in ECG were observed in all groups, and the levels of SOD, NO, HDL-C, MDA, CAT, LDH and CK in blood plasma were detected, and the pathological changes of myocardial tissues were observed under light microscope by HE staining. RESULTS: Compared with model group, ST segments in ECG dropped markedly at different time point which included 10,11 and 12 (P <0. 05) in Gualou Xiebai Drop Pills groups of 22. 5, 33. 75 and 45 g/kg, time points were more than those of other groups. Gualou Xiebai Dropping Pills groups of 22. 5 and 33. 75 g/kg improved the levels of SOD, MDA, CAT, NO, HDL-C, LDH and CK in blood plasma in model rats significantly (P <0. 01 or P <0. 05). Gualou Xeibai Dropping Pills improved the pathological changes of myocardial tissues at all dosages. CONCLUSION: Gualou Xiebai Drop Pills can effectively restrain the acute myocardial ischemia induced by isoproterenol in rats, compared with Gualou, Xiebai or Gualou Xiebai Baijiutang, Gualou Xiebai Drop Pills obtains a favourable effect. PMID- 26495662 TI - [Pharmacokinetics Study on Curcumin Hydroxypropyl-beta-Cyclodextrin Phospholipid Complex in Rats]. AB - OBJECTIVE: To compare the in vivo pharmacokinetics of curcumin hydroxypropyl-beta cyclodextrin phospholipid complex, curcumin hydroxypropyl-beta-cyclodextrin and curcumin phospholipid complex, and to discuss the advantage of hydroxypropyl-beta cyclodextrin phospholipid complex as carrier. METHODS: Drawing blood after SD rats were oral administered with the above preparations and free drug at 50 mg/kg( corresponding to curcumin) , and the blood concentration were determined by HPLC. RESULTS: The AUC0-infinity of curcumin hydroxypropyl-beta-cyclodextrin phospholipid complex was(1 126. 20 +/- 323. 24) g/(L . h), which was 5. 89, 1. 49 and 1. 17 times as curcumin (191. 08 +/- 43. 27) ug/( L . h), curcumin phospholipid complex(754. 93 +/- 55. 33) ug/(L . h), curcumin hydroxypropyl-beta- cyclodextrin(961. 21 +/- 253. 65) ug/(L . h). CONCLUSION: The curcumin hydroxypropyl-beta-cyclodextrin phospholipid complex has a better absorption property than curcumin phospholipid complex and curcumin hydroxypropyl-beta cyclodextrin, which is more beneficial to improve the bioavailability. PMID- 26495663 TI - [Study on HPLC Fingerprint of Kanggongyan Series]. AB - OBJECTIVE: To establish analysis methods for fingerprint of Kanggongyan series by HPLC. METHODS: A Shiseido CAP-CELL PAK C18(250 mm x 4. 6 mm, 3 um) column was used with acetonitrile-0. 5% phosphoric acid as the mobile phase by gradient elution. The flow rate was 0. 8 mL/min, the column temperature was 30 degrees C, and the detection wavelength was set at 280 nm during 0 ~ 44 min and at 332 nm during 44 ~ 115 min. RESULTS: Ten common peaks were selected as characteristic peaks in the chromatogram of Kanggongyan particles, eleven common peaks were selected as characteristic peaks in the chromatogram of Kanggongyan tablets and capsules ,the similarities were greater than 0. 9 among all batches. CONCLUSION: The method is simple, steady and repeatable. It provides a basis for the quality control of Kanggongyan series. PMID- 26495664 TI - [Study on Ultrasonic-Surfactant Extraction of Total Flavonoids from Albizia julibrissin Flower by Response Surface Methodology]. AB - OBJECTIVE: To optimize the extraction technology of total flavonoids from Albizia julibrissin flower by combining surfactant with ultrasonic technology. METHODS: Using Box-Behnken central composition design and response surface methodology, the effects of surfactant concentration, liquid-solid ratio and ultrasound time on the yield of total flavonoids were studied based on the extraction rate to determine the optimum extraction conditions of total flavonoids. RESULTS: Optimum conditions for extraction of Albizia julibrissin flower were as follows: mass percentage of 2. 5% SDS,15 times of 60% ethanol,ultrasonic time of 31 min. Under these conditions,the extraction rate of total flavonoids from Albizia julibrissin flower was 0. 853%. Using this technology, the extraction yield increased by 93. 0% as compared with that using ultrasonic technology alone. CONCLUSION: The optimum extraction technology can be used for extraction of total flavonoids from Albizia julibrissin flower for its simplicity and responsibility. PMID- 26495665 TI - [Optimization of SFE-CO2 Extraction for Ursolic Acid from Punica granatum Peel by Plackett-Burman and Central Composite Design]. AB - OBJECTIVE: The optimum extraction of ursolic acid from Punica granatum peel by SFE-CO2 was investigated. METHODS: Based on the design of Plackett-Burman(PB), significant factors influencing the yield of ursolic acid in the operation process were filtered, with the extraction rate of ursolic acid as the index. The results obtained by steepest ascent method approximated the maximum area of ursolic acid yield. Then the Central Composite Design(CCD) design was used to carry on the response surface optimization of significant factors, getting a two order mathematical model affecting the ursolic acid yield, as well as the optimum process conditions. RESULTS: The best technological conditions of the extraction of ursolic acid from Punica granatum peel by SFE-CO2 were that the extraction temperature was 46. 29 degrees C, extraction time was 91. 6 min and the extraction pressure was 34. 49 MPa. Under the optimal conditions, verification test of ursolic acid yield was 12. 508 mg/g, approximating to the predicted value of 12. 645 mg/g. CONCLUSION: The PB test and CCD test design are combined to optimize the extraction process of ursolic acid from Punica granatum peel by SFE CO2. The screening results are statistically significant and the process operation is feasible. PMID- 26495666 TI - [Simultaneous Determination of Index Components in Wuwei Shaji Oral Liquid by HPLC]. AB - OBJECTIVE: To establish an HPLC method of detecting geniposide, mono-ammonium glycyrrhizinate, liquiritin, costunolide and dehydrocostus lactone in the Wuwei Shaji oral liquid simutaneously. METHODS: Diamonsil C18 (2) column(250 mm x 4. 6 mm, 5 um) was used to analyze above components with mobile phase of acetonitrile(A)-0. 2 phosphoric acid(B) in gradient elution mode at the flow rate of 1. 0 mL/min under wavelength of 220 nm. RESULTS: There was a good linear relationship of the five components, the RSD of the accuracy, repeatability, stability were all bellow 3% and the average recovery were 99. 95%, 95. 00%,100. 26%, 99. 82%, 101. 33%. CONCLUSION: This method is convenience, accuracy and specific,which can be a further supplement for the quality control of Wuwei Shaji oral liquid. PMID- 26495667 TI - President's Message. PMID- 26495668 TI - Patient Records. PMID- 26495669 TI - What if a Practitioner Passes Away? PMID- 26495670 TI - Medicaid Dental Care at 50. PMID- 26495671 TI - Oral Pathology Quiz #88. Case number 1. Granular cell tumor. PMID- 26495672 TI - Oral Pathology Quiz #88. Case Number 2. Epithelial dysplasia. PMID- 26495673 TI - Oral Pathology Quiz #88. Case Number 3. Melanotic macule. PMID- 26495675 TI - Colleague Connection. PMID- 26495674 TI - Oral pathology quiz #88. Case Number 4. Peripheral ossifying fibroma. PMID- 26495676 TI - Root Supported Overdentures - Case Report. PMID- 26495677 TI - Five Things to Consider When Performing Maxillary Sinus Augmentation for Dental Implant Placement. PMID- 26495678 TI - Case Report: Mandibular Gingival Lesions as a First Sign of Multiple Myeloma. PMID- 26495679 TI - Our New Strategic Plan. PMID- 26495680 TI - ACHIEVING PHYSICIAN-LED CLINICAL INTEGRATION. PMID- 26495681 TI - Physician Executive Competencies: Collaboration, Teaming Serve as the Foundation for Success. PMID- 26495682 TI - The Journey to Value-Based Care for Population Health. PMID- 26495683 TI - Humility and Leadership. PMID- 26495684 TI - Palliative Medicine and Patient Satisfaction. PMID- 26495685 TI - Engaging Residents. PMID- 26495686 TI - Mental Health and Substance Abuse. PMID- 26495687 TI - Enhance Candidacy Odds by Analyzing Job Requirements. PMID- 26495688 TI - Physicians Key in Value-Driven Environment. PMID- 26495689 TI - Patient-Reported Measures. PMID- 26495690 TI - Changing of the Guard. PMID- 26495691 TI - Relationship between of short-course preoperative radiotherapy and serum albumin level and postoperative complications in rectal cancer surgery. AB - BACKGROUND/AIM: The identification of risk factors could play a role in improving early postoperative outcome for rectal cancer surgery patients. The air of this s5udy was to determine the relationship between short-course preoperative radiotherapy (RT), serum albumin level and the development of postoperative complications in patients after anterior rectal resection due to rectal cancer without creation of diverting stoma. METHODS: This retrospective study included patients with histopathologically confirmed adenocarcinoma of the rectum with the clinical stage of T2-T4 operated on between 2007 and 2012. All the patients underwent open anterior rectal resection without diverting stoma creation. Preoperative serum albumin was measured in each patient. Tumor location was noted intraoperatively as the distance between the inferior tumor margin and anal verge. Tumor size was measured and noted by the pathologist who assessed specimens. Some of the patients received short-course preoperative RT, and some did not. The patients were divided into two groups (group 1 with short-course preoperative RT, group 2 without short-course preoperative RT). Postoperative complications included clinically apparent anastomotic leakage, wound infection, diffuse peritonitis and pneumonia. They were compared between the groups, in relation to preoperative serum albumin level, patient age, tumor size and location. RESULTS: The study included 107 patients (51 in the group 1 and 56 in the group 2). There were no significant difference in age (p = 0.95), gender (p = 0.12) and tumor distance from anal verge (p = 0.53). The size of rectal carcinoma was significantly higher in the group 1 than in the group 2 (51.37 +/- 12.04 mm vs. 45.57 +/- 9.81 mm, respectively; p = 0.007). The preoperative serum albumin level was significantly lower in the group 1 than in the group 2 (34.80 +/- 2.85 g/L vs. 37.55 +/- 2.74 g/L, respectively; p < 0.001). A significant correlation between the tumor size and the serum albumin level was found (p = 0.042). Overall, postoperative complications were observed in 13 (25.5%) patients in the group 1 and in 10 (17.8%) patients in the group 2 without significant difference between the groups (p = 0.18). A significantly lower level of serum albumin was found in patients with postoperative complications and in those who died. A significant difference in anastomotic leakage occurrence between groups was found (p = 0.039). Male gender and the lower level of serum albumin were significant predictors for anastomotic leakage occurrence (p = 0.05 and p = 0.002, respectively), but preoperative RT had no significant impact on it. CONCLUSIONS: A lower serum albumin level, but not short-course of preoperative RT, was significantly associated with postoperative complications development after rectal resection with' out diverting stoma. PMID- 26495692 TI - A novel microscopic method for analyzing Gram-stained vaginal smears in the diagnosis of disorders of vaginal microflora. AB - BACKGROUND/AIM: The Nugent's score is still the gold standard in the great majority of studies dealing with the assessment of vaginal flora and the diagnosis of bacterial vaginosis (BV). The aim of this study was to show that the analysis of Gram-stained vaginal samples under microscope at the magnification of x200 (a novel microscopic method--NMM), as a fast and simple tool, easily applicable in everyday practice, better reflects complexity of vaginal microflora than the Nugent's methodology (x1000). METHODS: Gram-stained vaginal smears from 394 asymptomatic pregnant women (24-28 week of pregnancy) were classified according to the Nugent's microscopic criteria (immersion, magnification x1000). The smears were then reexamined under immersion but at magnification x200. All samples were classified into 6 groups according to semiquanititative assessment of numbers (cellularity) and the ratio of rod (length < 1.5 microm) and small bacterial (< 1.5 microm) forms: hypercellular (normal full--NF), moderately cellular (normal mid-NM), hypocellular (normal empty--NE), bacterial vaginosis full (BVF), bacterial vaginosis mid (BVM), and bacterial vaginosis empty (BVE). Also yeasts, coccae, bifido and lepto bacterial forms as well polymorphonuclear (PMN) leukocytes were identified. RESULTS: According to the Nugent's scoring, BV was found in 78, intermediate findings in 63, and yeasts in 48 patients. By our criteria BV was confirmed in 88 patients (37 BVF, 24 BVM, and 27 BVN). Generally, both tools proved to be highly concordant for the diagnosis of BV (Lin's concordance correlation coefficient = 0.9852). In 40% of the women mixed flora was found: yeasts in 126 (32%), coccae in 145 (37%), bifido forms in 32 (8%) and lepto forms in 20 (5%). Almost a half of BV patients had also yeasts (39/88). Elevated PMN numbers were found in 102 (33%) patients with normal and in 36 (41%) women with BV. CONCLUSION: The newly described methodology is simpler to apply and much better reflects diversity of vaginal microflora. In this way it may be more valuable to molecular biologists and their attempts based on quantitative polymerase chain reaction (PCR) to define formulas for molecular diagnosis of bacterial vaginosis. PMID- 26495693 TI - Changing body structure components and motor skills in Military High School students within one year. AB - BACKGROUND/AIM. Proper growth and development ofadolescents in the morphological, functional and psychosocial aspects is the imperative of the educational process. The aim of this study was to determine the status and changes in the indicators of morphological characteristics, motor skills and lifestyle habits among the students of the Military High School in Belgrade. METHODS: The study included 217 students aged 15 to 18 years (from the first to the fourth grade). The two measurements performed at the intervals of one year were used to determine: the body structure by means of 10 variables and motor skills by 4 variables, while life habits were determined by 25 variables. RESULTS: The differences in the indicators of morphological characteristics were recorded in all the groups, being the highest in the first year of schooling. During the period of growing up, a reduction of fatty component in percentage values was found, as well as an increase of muscle mass. The progressive growth of motor skills in the first, second and the third grade was recorded in the manifestation of power, and endurance improved only in the first year. In terms of dietary habits, there was no difference among the groups. CONCLUSION: The obtained results indicate proper morphological and motor development and the formation of lifestyle habits. The data obtained will serve as a basis for health and functional prevention and upgrading in terms of improvement of the process of military education. PMID- 26495694 TI - Efficacy of nanocrystalline bone substitute biphasic calcium phosphate/poly-DL lactide-co-glycolide for periodontal intrabony defects filling. AB - BACKGROUND/AIM: Different bone substitutes have been used for filling and reparation of intrabony defects. The aim of this study was to compare nanocrystalline material, biphasic calcium phosphate poly-DL-lactide-co-glycolide (BCP/PLGA) with deproteinised bovine bone (DPBB) and beta-tricalcium phosphate (P TCP) in the treatment of periodontal intrabony defects. METHODS: The study included 24 patients with bilateral, intrabony defects in the region of the upper first and second premolar, and the upper first molar. On one side of the mouth, DPBB (BioOss) was used to fill defects in upper premolars while P-TCP (RTR) was used for the upper first molar. BCP/PLGA was applied into periodontal defects of the upper premolars and upper first molar of the opposite side. RESULTS: The comparison of the BCP/PLGA and the P-TCP group, 6 months following filling of defects, showed a statistically significant reduction of periodontal pocket depth (PPD) and the position of the cement-enamel junction (CEJ) in the group with BCP/PLGA, when compared to the beta-TCP group. The reduction of PPD and CEJ was similar in the groups treated with BCP/PLGA and DPBB. CONCLUSION: Significant reductions of PPD and CEJ were registered in the group with BCP/PLGA when compared to the beta-TCP group. PMID- 26495695 TI - Outdoor and indoor ozone level--A potential impact on human health. AB - BACKGROUND/AIM: Air pollution outside and inside is still one of the most sensitive issues. The aim of this study was to assess the ozone level in ambient air and working premises in terms of its possible influence on human health. METHODS: The study was based on the results obtained in Lithuanian conditions. Continuous ozone measurement data from the rural monitoring station in Preila over the period 1995-2011 were analyzed. More than 180,000 hourly values were examined according to the requirements in the Directive 2008/50/EC. The World Health Organization (WHO) and European Union indicators the Sum of Ozone Means Over 35 ppb (SOMO 35), the maximum daily 8-hour mean concentration of ozone higher than 100 and 120 microg/m3 were estimated. Indoor ozone concentrations in copying and welding rooms were evaluated. The ozone concentration was measured with the ozone analyzer 0341M. RESULTS: The frequency distribution of ozone hourly concentrations at the Preila station showed that less than 1% of the data were higher than 120 microg/m3 and 6% of them higher than 100 microg/m3, that could have the adverse effect on human health, during 1995-2011. The investigations made in working premises showed that near a copying machine the ozone concentration can reach 330 +/- microg/m3, however in the room, i.e., 0.5 m from the machine, the average ozone concentration during automatic copying was 165 microg/m3 and during manual copying it was 50 microg/m3. Measurements in a welding room showed that the ozone concentration was in the range of 380-1850 microg/m3 at the distance of 25 cm from the electrode and at the distance of 1 m from the source the ozone concentration decreased 2.5 times. Conclusion. The danger of the ambient ozone level to human health practically was not observed in Lithuanian conditions. However, almost 6% of the data exceed the new WHO guideline of 100 microg/m3 during the measurement time. Indoor ozone during welding reached a higher level than during, copying that can cause human health problems. PMID- 26495696 TI - Impact of the combined presence of left ventricular systolic and renal dysfunction on the 5-year outcome after ST-elevation myocardial infarction. AB - BACKGROUND/AIM: The coincidence of left ventricular systolic dysfunction (LVSD) and renal dysfunction (RD) is a strong independent predictor of adverse events in the short-term and mid-term follow-ups of patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). The aim of this study was primarily to assess the prognostic impact of the LVSD-RD combination on the 5-year all-cause mortality in patients with STEMI treated with pPCI, as well as to assess the prognostic impact of the LVSD-RD combination on the occurrence of major adverse cardiovascular events (MACEs: cardiovascular death, reinfarction, stroke and target vessel revas- cularization) in these patients. METHODS: We analyzed 951 patients divided into 4 groups according to the presence of LVSD (ejection fraction < 40%) and/or baseline RD (creatinine clearance < 60 mL/min): group I (no LVSD, no RD); group II (LVSD, no RD); group III (RD, no LVSD); group IV (LVSD+RD). RESULTS: The 5-year mortality rates were 2.3%, 17.6%, 11.7% and 38.3%, while the 5-year MACE rates were 8.8%, 28.4%, 18.3% and 44.4% in the groups I, II, III and IV, respectively (p < 0.001). The highest percentage of lethal outcomes and MACE was registered in the first year of follow-up in all the groups. The 1-year landmark analysis confirmed that the patients with LVSD-RD combination had the highest percentage of lethal outcomes in the period of 1 to 5 years (p = 0.028). There was a strong trend toward the significance in the occurrence of MACE among the analyzed groups in the period of 1 to 5 years (p = 0.085). In the Cox regression model the LVSD-RD combination was a strong independent predictor of 5-year mortality and the occurrence of MACE: mortality hazard ratio (HR) 4.5 (95%CI 1.9-10.8); MACE HR 2.5 (95% CI 1.4-4.5). CONCLUSION: The strong negative independent prognostic impact of the LVSD-RD combination persisted in the long-term follow-up of the patients with STEMI treated with pPCI. PMID- 26495697 TI - Migraine with aura and TCD bubble-test: The significance of positive result. AB - BACKGROUND/AIM: The association between the right-to-left shunt (RLS) and migraine with aura (MA) has been proven so far. The aim of this study was to determine if the presence of RLS detected as a result of transcranial doppler (TCD) bubble-test, makes any difference in clinical presentation, aura and headache in patients with MA. METHODS: A single-group descriptive study was conducted on 153 patients diagnosed with MA. TCD bubble-test was performed on 135 of them. The recorded demographic and clinical features of patients were analyzed and compared with the results of the TCD bubble test. RESULTS: In the group of 135 patients, 88 (65.2%) had positive TCD bubble-test. The difference in the investigated clinical features of patients of the patients and aura between the patients with and without RLS, was not found. CONCLUSION: The results of our study confirm a high prevalence of right-to-left shunt in patients with MA, but the clinical relevance of this association was not shown. PMID- 26495698 TI - Motivation and job satisfaction of health workers in a specialized health institution in Serbia. AB - BACKGROUND/AIM: Health care system is specific for each country, and therefore involves different motivation and job satisfaction factors. The aim of this study was to confirm the validity and applicability of the General Nordic Questionnaire translated into Serbian for analyzing motivation and job satisfaction, as well as to analyze the motivation factors and job satisfaction of health workers at the Institute for Treatment and Rehabilitation "Niska Banja". METHODS: The General Nordic Questionnaire was translated into Serbian. It included 73 questions (5 answers by the Likert scale), which formed 24 scales. In May, 2012, 196 (82.3%) health workers filled in the questionnaire. RESULTS: A correlation of Ceronbach's alpha values between the Scandinavian study results and the results of Serbian study was statistically significant (r = 0.424; p < 0.05). The lowest Cronbach' alfa coefficient was for the scale "learning demand in job demands" (alpha 0.28). The other scale with no satisfactory reliability was "control of work pacing" (alpha 0.46). Intrinsic motivation positively correlated with all the scales of organizational module, apart from inequality. Within this module, the degree of extrinsic motivation correlated with the support from the superior and coworkers, with fair leadership and human resources primacy. A negative correlation appeared with inequality. CONCLUSION: The general Nordic Questionnaire can be applied to a great extent to the conditions in our country. Our study shows a low consistency of the scales learning job demands, control of decision, control of work pacing, so the questions in them should be adjusted to the conditions in our country. Extrinsic motivation resulted in higher values than the values of intrinsic motivation in our workers, which is opposite to the results of the original questionnaire. PMID- 26495699 TI - Treatment of recurrent aphthous stomatitis by laser therapy: A systematic review of the literature. AB - BACKGROUND/AIM: Recurrent aphthous stomatitis (RAS) is defined as multifactor immunologic inflammatory lesions in the oral cavity, characterized by painful, recurrent single/multiple, shallow, round or ovoid ulcerations of mucosal tissues. To date, a considerable number of RAS treatment protocols have been suggested, but since the etiology of RAS is idiopathic, these treatment options have symptomatic rather than curative or preventive effect. Recently, it has been suggested that laser therapy could be successfully used as an efficient treatment approach in therapy of RAS. Therefore, the aim of this review was to estimate the effects of laser therapy in treatment of RAS analyzing results of clinical studies published in peer reviewed journals. METHODS: The studies published until 31 December 2013 were obtained from the Medline/PubMed, Science Direct and Cochrane Library of the Cochrane Collaboration (CENTRAL) online databases, using following search terms and key words: "laser" AND "recurrent aphthous stomatitis", "laser" AND "aphthous", and "laser" AND "aphthae". In total 4 original research articles met the all required inclusion/exclusion criteria, and were used for this review. The main outcome measures assessed were: a reduction of pain associated with RAS and a reduction in episode duration (faster RAS healing). RESULTS: The assessed literature demonstrates the benefits of laser therapy mainly due to immediate analgesia and ability to speed up a RAS healing process. CONCLUSION: Even thoughthe assessed literature suggests beneficial outcomes of laser therapy in treatment of RAS, these results should be interpreted with caution. The issues related to the study designs and different sets of laser irradiation parameters of a limited number of available studies with the same treatment outcomes prevent us from making definite conclusions. PMID- 26495700 TI - [Medical expertise in criminal and civil proceedings]. PMID- 26495701 TI - Posterior reversible encephalopathy syndrome--A case report. AB - INTRODUCTION: Posterior reversible encephalopathy syndrome (PRES) is characterized by the following symptoms: seizures, impaired consciousness and/or vision, vomiting, nausea, and focal neurological signs. Diagnostic imaging includes examination by magnetic resonance (MR) and computed tomography (CT), where brain edema is visualized bilaterally and symmetrically, predominantly posteriorly, parietally, and occipitally. CASE REPORT: We presented a 73-year-old patient with the years-long medical history of hypertension and renal insufficiency, who developed PRES with the symptomatology of the rear cranium. CT and MR verified changes in the white matter involving all lobes on both sides of the brain. After a two-week treatment (antihypertensive, hypolipemic and rehydration therapy) clinical improvement with no complications occurred, with complete resolution of changes in the white matter observed on CT and MR. CONCLUSION: PRES is a reversible syndrome in which the symptoms withdraw after several days to several weeks if early diagnosis is made and appropriate treatment started without delay. PMID- 26495702 TI - Lymphoproliferative neoplasms and renal cell carcinoma of clear cell type--Where is the link? AB - INTRODUCTION: The etiology of higher than expected occurrence of lymphoproliferative neoplasms (LPN) and renal cell carcinoma (RCC) in the same patient has not yet been clarified. Several explanations for this co-occurrence have been postulated: prior cytotoxic treatment, viral infections, immunomodulatory effects of tumor itself and shared genetic and/or environmental factors. CASE REPORT: Medical records of 680 consecutive patients with LPN and 570 consecutive patients with RCC diagnosed between January 1997 and December 2011 in two centers were retrospectively analyzed. Co-occurrence of both diseases was registered in five of the patients (3 males, 2 females) and their demographic, clinical and pathological characteristics were presented. CONCLUSION: Synchronous occurrence of LPN neoplasms and RCC or a short latent period between the diagnoses of these two malignancies in the same patient, as well as the lack of cytotoxic treatment for firstly occurring neoplasm implies a possible common pathobiology of both diseases. PMID- 26495703 TI - Severe form of streptococcal necrotizing fasciitis of the upper limb--diagnostic and therapeutic challenge: A case report. AB - INTRODUCTION: Since delay in recognition and effective treatment of necrotizing fasciitis (NF) caused by invasive group A streptococcus increases the mortality and disability, the early diagnosis and management of this disease are essential for a better outcome. We presented a patient with a severe form of streptococcal NF of the left upper limb in whom amputation was performed as a life saving procedure. CASE REPORT: A 65-year-old man, previously healthy, suffered an injury to his left hand by sting on a fish bone. Two days after that the patient got fever, redness, swelling and pain in his left hand. Clinical examination of the patient after admission indicated NF that spread quickly to the entire left upper limb, left armpit, and the left side of the chest and abdomen. Despite the use of aggressive antibiotic and surgical therapy severe destruction of the skin and subcutaneous tissues developed with the development of gangrene of the left upper limb. In this situation, the team of specialists decided that the patient must be operated on submitted to amputation of the left arm, at the shoulder. After amputation and aggressive debridement of soft tissue on the left side of the trunk, the patient completely recovered. beta-hemolytic streptococcus group A was isolated from the skin and tissue obtained during the surgery. CONCLUSION: In the most severe forms of streptococcal NF of the extremities, adequate multidisciplinary treatment, including limb amputation, can save the life of a patient. PMID- 26495704 TI - Diagnostic approach to localised organising pneumonia--A case report. AB - INTRODUCTION: Localised organising pneumonia, radiologically presented with oval or round shadows mimicing lung cancer or metastases, is a major issue in differential diagnosis. CASE REPORT: A female patient was hospitalized to clarified the etiology of multiple nodular lung lesions. The chest X-ray and the chest computed tomography (CT) revealed bilateral patchy and nodular shadows, and round lung lesions, respectively. Neither sputum analyses, nor histology of bronchoscopy samples clarified the etiology of these lung lesions. As secondary deposits in the lungs were suspected, video-assisted thoracoscopy and anterolateral right minithoracotomy with atypical upper and lower lobe resection were performed. The frozen-section analysis suggested the benign nature of the lesion, and the definite histopathological finding of localised organising pneumonia was established. Due to bilateral lung lesions, corticosteroids were applied. Seven weeks later, the chest CT finding revealed a total regression of the lesions. CONCLUSION: A surgical resection was necessary to diagnose the localised organising pneumonia which mimiced secondary malignant lesions, thus establishing the definite etiology of lung lesions. Bronchoscopic cryobiopsy, recently introduced in order to obtain peripheral lung biopsy samples, has provided new possibilities in the diagnosis and treatment of neoplastic and non neoplastic lung diseases. PMID- 26495705 TI - [THE MODEL OF NUCLEOSOME STRUCTURE BASED ON THE LOCAL ROTATION OF THE NUCLEOHISTONE CHAIN, WHICH INDUCES ITS FOLDING]. AB - An alternative model to the "double turn of DNA on the histone core" approach is forwarded based on the biochemical, cytological, and crystallographic data on the structural organization of the chromatin units--nucleosomes. The model assumes that the initial structure is a linear nucleohistone cord with a repeating symmetrical histone sequence. The compact (core) particle (a minimal nucleosome) is forming upon a stepwise rotation of DNA (kinks) at the centre and at two symmetrical sites into each repeating fragment stemming from the electrostatic binding of the lysine epsilon-NH2-groups with the followed one by one phosphates of the sugar-phosphate chain. As a result, we have a rhomboid structure composed of two counter-symmetrical DNA folds stabilized by histone-histone interactions. Based on disposable data, the histone sequence along nucleosome DNA is deduced. The following characteristics of the sequence are considered: continuity, non overlapping, versatility, and dyadic symmetry in dispose of two every kind histone molecules and the sequence on the whole. The model is in agreement with a topology of nucleosome DNA, as well as the pattern of DNA-histone and histone histone interactions in chromatin. PMID- 26495706 TI - [NEW ACHIEVEMENTS IN THE STUDY OF THE MECHANISMS AND TARGETS OF ACTION OF PROINSULIN C-PEPTIDE]. AB - The C-peptide, product of proinsulin proteolysis, is a chaperone for insulin during its storage in the transport vesicles of pancreatic beta-cells and further after its secretion into the bloodstream. Along with this, C-peptide functions as endogenous regulator of a number of the intracellular effector proteins, including phospholipase Cbeta, phosphatidylinositol 3-kinase, mitogen-activated protein kinases, non-receptor tyrosine kinases, and controls cAMP- and cGMP dependent cascades. Recently, the specific receptor GPR146 for C-peptide, which belongs to the superfamily of G protein-coupled receptors, has been identified. The decrease in the C-peptide level and the activity of its signaling cascades in diabetes mellitus lead to a wide range of complications of this disease including diabetic nephropathy, cardiomyopathy, angiopathy, and neuropathy. The changes in C-peptide functions has been found in non-diabetic patients with cardiovascular system disorders and renal failure. This review is devoted to the most significant events in the exploration of structural and functional organization of the C-peptide molecule, the identification of its receptor, the study of the molecular mechanisms of its action on cells that have taken place over the last few years. This review focuses on the most significant events recent years in the study of structural-functional organization of C-peptide and the molecular mechanisms of its action on the cell. PMID- 26495707 TI - [AGGLUTINATION OF MESOPHYLL PLASTIDS AND OBLITERATION OF PHLOEM SIEVE TUBES ARE THE TOTAL RESULT OF SEASONAL PAUSES IN PHOTOSYNTHATE EXPORT]. AB - Chloroplast agglutination and sieve tube obliteration are related to the different plant tissues: the agglutination--to the leaf mesophyll, and the obliteration--to the axis phloem. Being equally produced by photosynthate export dynamics, both phenomena are synchronous and can be used for diagnostics of seasonal flashes and pauses of photosynthetic activity with equal success. The nature of the mobility of chloroplast and their shuttle displacements from the nuclear envelope to the cell periphery connected with export dynamics have been established. It is assumed that nuclear envelope is the base structure of the endoplasmic reticulum (ER) inside which the chloroplasts are localized. Activation of photosynthesis and sugar accumulation inside the ER induces its expansion followed by centrifugal diffusion of chloroplasts. Come back effect--ER collapse, its return to the source--can be induced by the blockade of photosynthesis. Centripetal collapse is accompanied by plastid concentration around the nuclear envelope. Displacements of ER and the chloroplasts dislocating inside it are reversible. It depends on seasonal fluctuations of photosynthesis and export intensities. Changes in the volume of sieve tubes, which are due to the same reason, are irreversible. Each seasonal wave of photosynthesis and sugar export forms new series of sieve tubes, replacing obliterated ones. PMID- 26495708 TI - [INCREASE IN CELL RADIOSENSITIVITY AFTER INHIBITION OF CELL ABILITY TO RECOVER FROM POTENTIALLY LETHAL RADIATION DAMAGE]. AB - The paper presents new experimental results demonstrating the recovery of irradiated cells on a nutrient medium, which usually occurs at a delay of cell division. Using the previously proposed method, the contribution of such a recovery in radiation sensitivity of diploid yeast cells of different strains after exposure to ionizing and ultraviolet radiation has been estimated. It is shown that the actual increase in cell radiosensitivity significantly exceeds the expected one in the case of inhibition of the recovery from potentially lethal damage. These data indicate that inhibition of cell ability to recover from potentially lethal radiation damage by exposing the irradiated cells in non nutritive medium in many cases serve as an indicator of suppression of the overall ability of cells to repair. Experimental data indicating that it is not a universal rule are presented. PMID- 26495709 TI - [EFFECT OF STROMAL CELLS AND OXYGEN CONCENTRATION ON THE MAINTENANCE OF CORD BLOOD HEMATOPOIETIC PRECURSORS]. AB - The paper analyses the morphological and functional features of cord blood cells (CBCs) in the co-culture with multipotent mesenchymal stromal cells (MMSCs) from human adipose tissue under tissue-related oxygen. We have established that MMSCs effectively maintained viability of CBCs at different oxygen concentrations (1, 5 and 20%). According to the data obtained, the oxygen concentration affected the number of colony-forming units (CFUs) formed by CBCs in selective medium. In particular, not co-cultured CBCs the 1 and 5% O2 than at 20% O2. After co-culture with MMSCs, the CFUs numbers were similar at 1 and 20% O2 and increased by 30 at 5% O2. Tissue related O2 concentrations had an impact on the proportion of lineage-resctricted CFCs among CBCs: the number of more committed progenitors- CFU-G and CFU-M, increased, and multi and bipotent--CFU-GEMM and CFU-GM, decreased at low oxygen concentrations. This effect was more pronounced after co culture compared to that of initial CBCs. Thus, the presence of stromal cells and tissue-related oxygen jointly and severally influenced CBCs in vitro. PMID- 26495710 TI - [DYNAMICS OF NITROGEN OXIDE METABOLITES IN THE PLASMA AND ASCITES DURING ZAJDEL HEPATOMA GROWTH IN VIVO]. AB - The dynamics of extracellular nitrogen oxide metabolites localized in the plasma and ascites during Zajdel ascites hepatoma growth in the abdominal cavity has been investigated. An increase in peroxynitrite concentration was found by the levels of nitrotyrosine (up to 10-11 nM) in blood plasma at the initial stage of tumor cell development. In the course of further tumor development, an oxidative stress developed, which might cause oxidation of protein components including tyrosine. All these processes may cause a decrease in the accessible amount of tyrosine for nitration and lead to a fall in nitrotyrosine level (to 3-6 nM) at the final stages of tumor growth. Nitrotyrosine dynamics in the region of tumor growth is essentially analogous to that in the plasma because proteins during tumor growth cames from the blood plasma of tumor bearer. In studying the dynamics of nitrosylation of sulfur-bearing protein groups, an increase in the concentration of S-nitrosothyols was found to occur in the blood plasma for up to 6 days of the experiment, subsequently their concentration decreased. In the ascites, where protein R-SNO arrives, the mean concentration of nitrosothyols upon tumor growth is lower compared to that of the plasma. In studying the dynamics of final stable nitrogen oxide decay products--nitrites/nitrates, it has been found that during tumor development the concentration of these metabolites in the plasma varies only moderately within some range and sharply increases at the final stage of the experiment. In the area of tumor growth, an analogous trend in the behavior of nitrites/nitriaes has been registered (noted, marked), but with a higher background level, which might be due to both the functioning of immunocompetent cells, microphages in particular, and a decreased rate of utilization of substances from the ascites. Based on the aforesaid, it has been concluded that the nitrosylating stress in the organism of the bearer of a tumor is being developed along with the oxidative stress. PMID- 26495711 TI - [PECULIAR PROPERTIES OF SOME COMPONENTS OF MORPHOLOGICAL STRUCTURE IN A PLANT CELL VACUOLE REVEALED BY CONFOCAL MICROSCOPY]. AB - Results of investigations of peculiar properties related to the structure of plant cell vacuolar membranes are discussed. The study was carried out using confocal microscopy, which allowed us in the process of scanning to identify membrane tubes and vesicules in the preparations of isolated vacuoles. Such membrane tubes were found both inside and outside the vacuoles, and, in the case of scanning intermittently at equal time intervals, transition of vesicles with the membrane tube was observed. Furthermore, scanning of isolated vacuoles was conducted at various distances from the glass substrate. Each time, in the upper area of the isolated vacuole lying on the substrate, we observed a large segment of vacuolar membrane and registered the effect of highly intensive fluorescing of some of membrane segments. The distributions of laurdan fluorescence generalized polarization (GP) values for the vacuolar membrane on the whole and for the intensively fluorescing membrane segments have been obtained. We have found that the microviscosity of the intensively fluorescing membrane segments essentially differs from that of the rest part of the membrane. PMID- 26495712 TI - [THE EFFECT OF PLANT EXTRACTS ON THE CYCLOPHOSPHAMIDE INDUCTION OF MICRONUCLEUS IN RED BLOOD CELLS OF OUTBRED WHITE MICE]. AB - Antimutagenic properties flavonoids extracts of the three plants Gratiola officinalis L., Helichrysum arenarium L., anthocyanin forms Zea mays L. were investigated. Analysis was performed by counting the micronucleus in peripheral blood erythrocytes outbred white mice; the mutagen was cyclophosphamide. Selected extracts reduce the number of micronucleus. Gratiola officinalis L. extract reduces the mutagenic action of cyclo- phosphamide at a dose of 200 mg/kg, Helichrysum arenarium L. extract--at doses of 100 and 200 mg/kg (maximum protective effect was observed at a dose of 200 mg/kg), anthocyanin forms Zea mays L. extract at doses of 50, 100 and 200 mg/kg (a dose of 50 mg/kg--maximum antimutagenic effect). PMID- 26495713 TI - [CYTOGENETIC RESPONSE OF SCOTS PINE (PINUS SYLVESTRIS L.) TO CADMIUM AND NICKEL]. AB - We studied cytogenetic polymorphism of the seeds of Pinus sylvestris L. in response to heavy metals exposure in laboratory settings over 2 years' time. We compared results obtained from the seedlings of different years: 2012 and 2013. With an increase in Ni2+ and Cd2+ concentration we observed a decrease in mitotic activity with concurrent rise in the percentage of cells in the prophase. This fact demonstrates the heavy metals act similar to both fixatives and substances that block cleavage spindle formation. In terms of pathological mitosis and the frequency of micronuclei cells, Cd2+ shows higher mutagenity compared to Ni2+. In addition, in the experimental samples, we have distinguished abnormalities such as fragmentations and agglutinations of chromosomes and especially C mitosis occurrence, which are not observed in the control. PMID- 26495714 TI - [Efficacy of Statin Therapy in the Prevention of Atrial Fibrillation in Early Postoperative Period after Coronary Artery Bypass Grafting]. AB - BACKGROUND: The incidence of the postoperative atrialfibrillation (POAF) after open heart surgery is up to 65%. Statin therapy has shown conflicting data in the prevention of the POAF. OBJECTIVE: Our aim was eo evaluate the role of statin therapy in the primary prevention of AF after CABG. METHODS: Group 1 (n = 82) included those patients who received no statin therapy and the Group 2 (n = 124) included those patients who did receive statin therapy for at least three days prior to the operation and for all days in the postoperative period. WBC count in different periods after surgery and rate of AF were evaluated. The risk of occurrence of postoperative AF was evaluated using the Cox-regression model and odds ratio. RESULTS: A retrospective analysis of 206 medical records of the patients without pre-existing AF after CABG was performed. The rate of AF was 26% in Group 1 and 6.5 % in Group 2 (p = 0.0001). On Day 4 after surgery, WBC count was 11 (9;13) in the first group and 9 (7.6;10.2) x 10(9) e/L in the second group (p = 0.000001). "Statin use" and "number of grafts" and were found to be statistically meaningful: p = 0.002 and p = 0.0125 respectively (chi2 = 28.3; p < 0.001). In accordance with the Cox model of regression, the risk of AF was 0.201 for "statin use"; and 2.099 for "number of grafts". Odds ratio was 0.2 (95% CI 0.08-0.5). CONCLUSION: Statin therapy prior to and after GABG wasfound to be an effective method of primary prevention of AF in the early postoperative period. PMID- 26495715 TI - [One-Stage Application of Mitral Valve Correction, Surgical Radiofrequency Ablation and Left Atrial Atrioplasty]. AB - OBJECTIVE: Our aim was to evaluate sinus rhythm restoration and its failure predictors after one-stage application of surgical radiofrequency ablation, left atrial reduction and mitral valve correction. METHODS: This is a prospective longitudinal cohort study with historical controls. Patients were divided into 2 groups according to the performed type of operation--the main group included patients undergone one-stage mitral valve correction, surgical radiofrequency ablation and left atrial atrioplasty (n = 47); and the control group consisted of patients undergone only mitral valve correction (n = 76). Surgical radiofrequency ablation was performed under the scheme Maze-IV. Left atrial atrioplasty procedure was performed according to echocardiography data: if in women LA antero posterior dimensions were more than 4.7 cm and in men more than 5.2 cm. RESULTS: The study included 123 patients. In the main group (age of the patients 61.0 +/- 9.1 years, 55% male) sinus rhythm restoration was observed in 32 (68%) patients during the early postoperative period, but at the time of discharge it reduced to 19 (40%), but in 6 months it increased up to 37 (78%), and in 36 months sinus rhythm already was detected in 40 (85%) patients. At the same time, during the early postoperative period in the control group (patients aged 59.0 +/- 11.0 years, 61% male) only 31 (40%) of patients had sinus rhythm, in 6 months it was detected in 11 (14%) cases, and in 36 months sinus rhythm--only in 28 (37%) patients. Predictors of atrial fibrillation recurrence were revealed: valve disease continuance < 4 years (p = 0.017) and atrial fibrillation history < 3 years (p =0.029). CONCLUSION: One-stage peforming of mitral valve correction, surgical radiofrequency ablation and left atrial atrioplasty restores and maintains more regular sinus rhythm, even in presence of atrial fibrillation recurrence predictors. PMID- 26495716 TI - [Cardiovascular Diseases in the Context of Russia's Long-Term Socio-Economic Development Priorities]. AB - The paper presents results of a comprehensive analysis of the cardiovascular diseases (CVD) situation, both in the global and Russian contexts. It introduces original data illustrating the declining mortality rate from CVD, and the diminishing contribution of these diseases to overall mortality rate--globally and, to a larger extent, in developed countries. The paper also analyses the reasons for continuing CVD epidemic in Russia. Based on factual evidence, it argues that those include insufficient expenditures on treating CVD patients, and critically inadequate funding of prevention programmes. Unsatisfactory use of these funds to subsidise Russian regions (without taking into account their actual needs determined by the CVD mortality rate) only makes the problem worse. Through modelling, "average" efficiency of the Russian health care system in reducing CVD mortality was revealed. The paper describes various scenarios for future development of the Russian CVD situation. In the context of innovation based scenario, the advantages of technologicalforesight are analysed; specifically, the authors summarise major S & T development trends in the health sector (using data of the Russian S & T Foresight 2030), which could significantly contribute to stopping the CVD epidemic in Russia. PMID- 26495717 TI - [Results of Percutaneous Coronary Intervention in Elderly Diabetic Patients]. AB - OBJECTIVE: Our aim was to compare results of the percutaneous coronary intervention (PCI) with drug elutingstent (DES) and bare metal stent (BMS) in older patients with coronary heart disease (CHD) and diabetes mellitus (DM) type 2. METHODS: Patients (> 65 years) with DM type 2 were divided into two groups: the 1st group--58 patients after PCI with DES, the 2nd group--62 patients after PCI with BMS. The average follow-up period was 32.6 +/- 8.0 months. The end points of the study were death, non-fatal myocardial infarction and restenosis of the target stenosis. RESULTS: Endovascular treatment of patients older than 65 years with DM is highly effective and safe despite the complexity of coronary lesions. There are no significant differences in the rate of early (hospital) complications in two groups. Also, we did notfind differences in three-year mortality between the groups. But the incidence of myocardial infarction in the groups with DES and BMS was 9% and 18% respectively (p = 0.039). Major adverse cardiovascular events (death, myocardial infarction and restenosis of the target stenosis) frequency was also lower in the group with DES compared to BMS (36% and 61% respectively, p = 0.001). CONCLUSION: Endovascular treatment of patients older than 65 years with DM type 2 is a highly effective and safe method despite the complexity of coronary lesions. PCI with DES compared to BMS in older patients with DM is associated with improvement of medium-term results and decreases the number of cardiovascular events. PMID- 26495718 TI - [Medical and Social Problems of Assisted Reproductive Technologies from the Perspective of Pediatrics]. AB - The article presents a literature review over the last few years devoted to the health status and development peculiarities of children born using assisted reproductive technologies (ART) procedures. The statistics shows an explosive increase in the frequency of ART application as a fertility treatment method. The presented data analysis reflects the perinatal outcomes after ART in children, the frequency of congenital malformations and genetic diseases in this population, possible long-term malconditions and pathologies in children born using ART. The overwhelming majority of investigators consider the adverse effect of ART on a child's body to be the result of prematurity and multiple pregnancy (transfer multiple embryos followed by partial reduction). It is stated that the widespread introduction of ART may contribute to the vertical transmission of parental infertility factors in the population. The application of ARTprocedures in some cases is associated with controversial ethical and legal issues (surrogacy, oocyte donation). Further improvements in ART procedures (preimplantation training, medical and genetic diagnosis, reducing the frequency of multiple pregnancy) cannot be stated as an alternative to the general medical and social prevention of reproductive disorders in adolescents and youth. PMID- 26495719 TI - [Child and Adolescent Interepydemic Immunity to Influenza Viruses]. AB - OBJECTIVE: Our aim was to evaluate the child and adolescent population immunity to influenza A viruses (IAV) and influenza B virus (IBV). METHODS: The concentration and specificity of antiviral antibodies was evaluated by hemagglutination inhibition assay (HAI) that was performed using commercial HAI diagnostic kits. RESULTS: The serum samples of 254 clinically healthy children and adolescents were examined in this study. 245 participants had the antibodies to IAV, 199--to IAV and IBV and only 4 children aged between 1 and 4 years and a 12-year-old boy had no immunity to IAVor IBV. The number of children with specific immunity increased in elder groups by 43% (from 81 to 116) for N0N1, and H3N2 subtypes and by 110% (from 38 to 80) for H1N1 subtype of IAV. In children younger than 4 years the titer of specific antibodies against the H1N1pdm09 was 1:210 and against the H3N2--1:270, whereas in adolescents of 10-14 years these figures were by 1.6 and 2.4 times lower (1:130 and 1:120) respectively. Antibodies to the subtypes H2N2 and H5N1 were not detected. CONCLUSION: The results indicate that 98.4% of child and adolescent population in interepidemic influenza season are immune to the various IAV (H3N2, H1N1, H0N1) as well as to the IBV. More than half of children and adolescents (57.4%) are immune to H1N1pdm09 subtype of IAV. The strength of immune response to the recent pathogens (H3N2 u H1N1pdm09) is higher in infants than in teenagers. PMID- 26495720 TI - [Parathyreoidectomy in Rats Using Microsurgery and Medical Adhesive Sulfacrylate]. AB - BACKGROUND: One of the main difficulties in assessing the effectiveness of etiologic treatment of hypoparathyroidism is absence of its standardized model. OBJECTIVE: The aim of the study was to develop a method of hypoparathyroidism modeling. METHODS: Controlled nonrandomized study was performed on female Wistar rats aged 10 month. Group 1 (n =14) was performed with destruction of parathyroid glands with electrocoagulation; group 2 (n =12)--parathyroidectomy by the developed method. In 3 and 14 days after the surgery the levels of ionized calcium, parathyroid hormone, number of white blood cells, blood leukocyte formula, indicators of immunological tests, histological examination of organs in the area of operations were performed. Statistical analysis was performed using the nonparametric Mann-Whitney-Wilcoxon test. RESULTS: Selection of animals by sex and age criteria, angular skin incision, use of the operating microscope, microsurgical techniques, extirpation of parathyroid glands via resection of thyroid gland with the closure of the wound defect glue appeared to be the distinctive features of the developed method. In 14 days the group 2 showed decrease in ionized calcium (p = 0.016), PTH (p = 0.094), leucocytes (p = 0.004), PI (p = 0.003), spontaneous NBT test (p = 0.004), induced NBT test (p = 0.003) compared with group 1. Histological examination in the group 2 revealed no changes in thyroid gland, thin connective tissue capsule, cavity with a small amount of glue, however, there were determined foci of necrosis with perifocal inflammation in the group 1. CONCLUSION: Combination of several techniques allowed to simulate metabolic disorders with persistent hypocalcemia as well as lack of mortality in early postoperative period. PMID- 26495721 TI - [Interaction of the Humoral Agonist During the Platelets Activation in Patients with Chronic Cerebral Ischemia]. AB - OBJECTIVE: The aim of the study was to determine the effect of the standard drug therapy of 95 patients with chronic cerebral ischemia (CCI) on the functional status of platelets as possible participants of microcirculation of the brain. METHODS: Platelets were isolated from peripheral blood by centrifugation and examined at 24 hours after initiation of standard medical therapy including aspirin (100 mg). The cells were stimulated in vitro using adenosine diphosphate (ADP), epinephrine, platelet activating factor (PAF) and serotonin in an effective concentration (EC50) inducing in healthy individuals platelet aggregation in the range of 50 +/- 5%. A study of platelet aggregation was carried out on aggregometer Chrono-Log (USA). RESULTS: Research included 95 patients with CCI 1-2 Stage--82 patients taking antiplatelet and antihypertensive drugs before hospitalization (main group), 13--did not receive these drugs during 7 days prior to hospitalization (comparison group). After start conservative treatment, only ADP induced platelet aggregation, which was similar (p > 0.05) with values in healthy individuals. The pharmacological inhibition of the functional activity of platelets other investigated agonists reproduced hyporesponsiveness of platelets. Against this background, in 34 (41.5%) patients at 24 hours after initiation of therapy occurred potentiation effects of PAF and epinephrine in the test in vitro; whereas the summation of the effects of serotonin and epinephrine on platelets was detected in 12 (14.6%) patients. The basis of this phenomenon may be strengthening effect of ADP secreted from dense granules, additional stimulation by Gi-protein signaling system by epinephrine and Gq-protein by the action of PAF and serotonin. CONCLUSION: Response to the combined action of platelet agonists may be predictor of the risk of thrombogenesis at CCI. PMID- 26495722 TI - [Reparative Osteogenesis and Angiogenesis in Low Intensity Electromagnetic Radiation of Ultra-High Frequency]. AB - BACKGROUND: Non-drug correction of reparative bone tissue regeneration in different pathological states - one of the most actual problems of modern medicine. OBJECTIVE: Our aim was to conduct morphological analysis of the influence of electromagnetic radiation of ultra-high frequency and low intensity on reparative osteogenesis and angiogenesis in fracture treatment under transosseous osteosynthesis. METHODS: A controlled nonrandomized study was carried out. In the experiment conducted on rats we modeled tibial fracture with reposition and fixation of the bone fragments both in control and experimental groups. In the animals of the experimental group the fracture zone was exposed to low intensity electromagnetic radiation of ultra-high frequency. Exposure simulation was performed in the control group. The operated bones were examined using radiography, light and electronic microscopy, X-ray electronic probe microanalysis. RESULTS: It has been established that electromagnetic radiation of ultra-high frequency sessions in fracture treatment stimulate secretory activity and degranulation of mast cells, produce microcirculatory bed vascular permeability increase, endotheliocyte migration phenotype expression, provide endovascular endothelial outgrowth formation, activate reparative osteogenesis and angiogenesis while fracture reparation becomes the one of the primary type. The full periosteal, intermediary and intraosteal bone union was defined in 28 days. CONCLUSION: Among the therapeutic benefits of electromagnetic radiation of ultra-high frequency in fracture treatment we can detect mast cell secretorv activity stimulation and endovascular anziozenesis activation. PMID- 26495723 TI - [Diagnostics of Regional Healthcare Management System in Russia Basing on Modeling and Forecasting of Health and Demographic Indicators]. AB - BACKGROUND: Justification of the study direction of public health improving is quite general. But the identification of the most effective indicators of the healthcare system improvement remains unexplored. OBJECTIVE: Our aim was to determine the interaction between the basic demographic indicators of the region (Smolensk region) and efficacy endpoints of the Healthcare management identified in the study. METHODS: The study reviewed the demographic changes of the Smolensk region at present and the forecast for 2015, 2016, 2017. The forecast of demographic and health indicators was based on exponential smoothing models and autoregressive model. RESULTS: The study identified the most appropriate medical and demographic indicators. 1) The ratio of physicians (per 10,000 people in population, the rate maximum was 62 in 2004, in 2015 this figure has fallen to 52, and it is supposed to decrease to 49 by 2017). 2) The overall mortality rate (per 1000 people in population). Reduction of the resident population of the Smolensk region is 8.2 thousand people in annual average. This fact shows a stable depopulation of the region. 3) The average load on the ambulance. It has been found that the increase and decrease of these parameters directly affect the population rate. CONCLUSION: The study revealed a stable downtrend of average resident population number which confirms the long regional depopulation. It is associated in particular with the lack of stimulation of the health and demographic indicators' increase including but not limited to inefficient healthcare management arrangements. PMID- 26495724 TI - [Demographic Ageing in Russia at the Present Stage]. AB - In the article data ofthe article describes thefindings of modern demographic indicators in Russia andforeign countriesfor the period 2010-2013. As a result of monitoring was defined Russia's status by demographics such as: proportion of population aged 60 years and older; total (men and women) life expectancy at birth; the rate of natural increase of population; mortality; fertility rate; the coefficient of migration growth and the dependency ratio. This article was presented analogy age-sex structure disclosed negative and positive aspects of the ageing of the population in Russia and foreign countries. PMID- 26495725 TI - [Peculiarities of Platelet Activation Changes in Patients with Chronic Schizophrenia, Depending on the Severity of Positive and Negative Symptoms during the Remission Formation]. AB - OBJECTIVE: The aim of our study was to compare the changes in the severity of positive, negative and psychopathological PANSS symptoms which occur at an outcome of an attack in schizophrenic patients along with remission formation and the degree of platelet activation in these patients. METHODS: Psychometric scale of the Positive and Negative Syndrome Scale (PA NSS) and the method of estimation of platelet activation based on the calculation of cells number after elution from the column with sepharose CL-2B were used. RESULTS: The changes in the severity of the disease were estimated using the PANSS scale of chronic schizophrenic patients in remission formation. An increase in platelet activation was determined on the basis of the above described quantitative parameter. Comparison of changes in platelet activation parameter with changes in the disease severity rating detected similar statistically indistinguishable (p > 0.05) changes in the severity of positive symptoms and quantitative variable of platelet activation between the 1st and the 3rd visits in the period of remission formation. Platelet number after elution from the column during the 3rd visit was approximately two times less than during the 1st visit (p < 0.002). PANSS positive subscale shows a decrease of the severity of the syndrome by 1.6 times (p < 0.0002). In addition the difference between the platelet activation parameter and severity of the negative syndrome was fixed during the 3rd visit (p < 0.034). CONCLUSION: Similar changes in the severity of positive syndrome and platelet activation parameter were presented from 1st to 3rd visit in the remission formation. A distinction between the platelet activation parameter and severity of the negative syndrome was fixed during the 3rd visit. PMID- 26495726 TI - [New Radiopharmaceuticals Based on Prostate-Specific Inhibitors of Membrane Antigen for Diagnostics and Therapy of Metastatic Prostate Cancer]. AB - About 10.7% cases of prostate cancer were registered in Russia in 2011 (40,000 patients). More than half of cancer cases were revealed in advanced (III-IV) stages when metastases inevitably developed quickly. Clinical problem of early diagnostics and treatment of metastatic prostate cancer is still not solved. Anatomical imaging techniques have low sensitivity and specificity for the detection of this disease. Metabolic visualization methods which use prostate specific antigen (PSA) as a marker are also ineffective. This article describes prostate-specific membrane antigens (PSMA) that are proposed as a marker for diagnostics and therapy of prostate cancer. The most promising PSMA-based radiopharmaceutical agent for diagnostics has been developed and clinically tested in the European countries. These pharmaceuticals are based on small peptide molecules modified with urea, and have the highest affinity to PSMA. Favorable phannacokinetics, rapid accumulation in the tumor and rapid excretion from the body are beneficial features of these pharmaceuticals. PMID- 26495727 TI - [Biodistribution of Rifabutin Polymeric Transport Form]. AB - BACKGROUND: One way to increase drug efficacy is to provide a drug delivery transport system to the target organ. A widely used method is to incorporate the drug in a biodegradable polymer composition with forming nanosized drug's transport forms. Objective: Our aim was to investigate the tissue biodistribution of antibiotic rifabutin transport system based on lactic and glycolic acids copolymer, and to compare it with the pure substance of rifabutin. METHODS: These substances were administered to two groups of rats intragastrically in the doses of 10 mg/kg. After a certain period of time, the animals were sacrificed by cervical dislocation. Samples preparation for analysis was carried out of the liquid-liquid extraction. Active substance's concentrations were measured by high performance liquid chromatography method. RESULTS: The study included 8-week-aged Wistar rats of both sexes weighing 0.22 +/- 0.02 kg. Animals were divided into 2 groups. The study group received polymer form of antibiotic, and the comparison group received substance of rifabutin. In intervals of 10 min, 30 min, 1 h, 2 h, 4 h, 7h, 15 h, 24 h after drug administration liver, lung, spleen, kidney, intestines, stomach, heart and brain were resected respectively. Organs were measured by their weight. The drug was not detected in the brain. Rifabutin was determined in other examined tissues within 10 minutes and the maximum drug concentration in organs was fixed in 1.5-3.5 hours after administration. The rifabutin concentrations defined in the lungs were significantly higher in polymerform (p < 0.05). The polymer form's distribution coefficient was higher in the liver and lungs (15.83 and 10.14 ug/g respectively) in comparison with the substance one. The minimum amount of the active ingredient was observed in the heart (0.02 ug/g). CONCLUSION: It is shown that the inclusion of the drug in a polymeric form substantially alters its localization in organs and tissues. Extensive biodistribution nanorifabutin in lung tissue, liver and spleen is established. PMID- 26495728 TI - [Transpalpebral Tetrapolar Reoophtalmography in the Assessment of Parameters of the Eye Blood Circulatory System]. AB - BACKGROUND: Quantitative assessment of hemodynamic parameters is an important element of ophthalmic diagnostics especially in early detection of myopia, glaucoma, diabetic retinopathy. The assessment of hemodynamic changes is essential in evaluating of the efficiency of treatment. Objective: Our aim was to determine the adequate of eye hemodynamics assessment using reoophtalmography in patients with various clinical refractions. METHODS: A controlled study was carried out. All tests were performed using transpalpebral tetrapolar method. Signal registration lasted for 20 seconds in the supine position, and then the diagnostic parameters were calculated. RESULTS: We present the results of examination of 76 patients aged 5 to 22 years (average age 13.0 +/- 1.1). 32 patients had low myopia (62 reoophtalmography records), 23 patients had moderate myopia (42 records) and 5 patients had high myopia (12 records). The control group was composed of 16 patients. The main differences were found in the rheographic index, which is equal to 58.1 +/- 4.1 mOhm in the control group. It is significantly reducing with refraction increase, from 47.8 +/- 3.2 mOhm in low myopia to 34.0 +/- 2.5 mOhm in high myopia (p = 0.050). This is an evidence of blood supply deficiency in the myopic eyes. CONCLUSION: Rheographic index was shown to differ in different breathing phases, which agrees with the known physiological regularities. The proposed method is highly informative and sufficiently accurate what allows assessing the eye blood supply state objectively. It is easy to apply and requires no contact with the eye surface, which is especially important in pediatric practice. PMID- 26495729 TI - [Clinical and Laboratory Predictors for Forecasting the Outcomes of Ixodes Tick Borne Borreliosis]. AB - OBJECTIVE: Our aim was to identify the most informative clinical and laboratory predictors of chronicity of Ixodes tick-borne borreliosis in the acute phase of the disease based on the "optimal cut-off values" (COV) and the predicted probability of the outcomes. METHODS: A retrospective cohort controlled study was carried out. We used the technique of ROC-analysis to estimate the information content of the clinical and laboratory indicators in patients with Ixodes tick borne borreliosis in the acute phase of the disease with erythemal (n =16), non erythemal (n = 77) forms of Ixodes tick-borne borreliosis and co-infection with the tick-borne encephalitis (n = 68) for the prediction of the outcomes: recovery or chronization. RESULTS: A retrospective analysis of clinical and laboratory parameters recorded in the acute phase of the disease in 161 patients with chronic Ixodes tick-borne borreliosis. The calculations were performed for the informative clinical and laboratory prognostic predictors of the outcomes for the intervals above and below the COVvalues are defined probabilities of recovery or chronization of Ixodes tick-borne borreliosis. A general predictor of outcomes for all clinicalforms of the disease--the interleukin 8--was established: the probability of chronization after erythemal form is 100.0% at the level of its production over 107.89 pg/ml (AUC = 1.0), after non-erythemal form is 54.63 +/- 0.23% at serum concentrations above 94.64 pg/ml (AUC = 0.770), after co-infection with the tick-borne encephalitis is 52.69 +/- 0.27% at the level of interleukin 8 above 84.96 pg/ml (AUC = 0.780). CONCLUSION: The results of the study suggest the possibility of predicting the outcomes of infection in the acute phase, which allows to optimize the etiopathogenic therapy of the disease in a timely manner. PMID- 26495730 TI - [NOS UNCOUPLING IS ACCOMPANIED WITH INDUCTION OF THE OXIDATIVE STRESS AND THE CARDIOHEMODYNAMICS DISTURBANCES IN HYPERTENSION]. AB - We compared the performance of cardiaohemodynamics and indicators of oxidative and nitrosative stress in the heart and aorta in normotensive Wistar rats (WKR) and spontaneously hypertensive rats (SHR). On the basis of experimentally determined parameters to calculate cNOS uncoupling index and biochemical index of function (BIF) in these organs of the cardiovascular system. In the heart, and especially in the aorta of SHR develop a combined oxidative and nitrosative stress that leads to cNOS uncoupling, BIF lowering that correlate with lowering of systolic and diastolic functions, inhibition of the efficiency Frank-Starling mechanism, oxygen consumption of the heart and increasing arterial stiffness. We made the assumption of the existence of the vicious circle of enhancing oxidative stress in organs of the cardiovascular system due to additional superoxide generation by uncoupling cNOS. PMID- 26495731 TI - [ENDOTHELIAL MONOCYTEACTIVATING FACTOR II CANCELS OXIDATIVE STRESS, CONSTITUTIVE NOS UNCOUPLING AND INDUCED VIOLATIONS OF CARDIAC HEMODYNAMICS IN HYPERTENSION (PART II)]. AB - The purpose of this study was to investigate the effect of EMAP II on free radical state of the heart and blood vessels, to restore cNOS coupling and cardiac hemodynamics in spontaneously hypertensive rats. It was found that, due to the combined inhibition of oxidative and nitrosative stress, EMAP I quickly restores impaired in hypertension constitutive de novo synthesis of NO by restoring cNOS coupling. Restoration by EMAP II of constitutive de novo synthesis NO abolished cardiac and endothelial dysfunction in spontaneously hypertensive rats. In hypertension, the introduction of EMAP II helped to improve the performance of the pumping function of the heart (stroke volume increased by 18.2 %, cardiac output -22 %), an arterial stiffness decreased by 23.2 %, process of relaxation of the left ventricle improved, due to decreased in 4,7 times myocardial end-diastolic stiffness. PMID- 26495732 TI - [USING THE SERIAL RAMP RECORDINGS FOR RAPID TESTING OF THE GENERATING ABILITY OF IMPULSE ACTIVITY OF ISOLATED HIPPOCAMPAL NEURONS]. AB - In this study we investigated changes of impulse activity of hippocampal neurons of the hippocampus by using ramp recordings. We have described the usage of serial ramp recordings of neuronal electrical activity for rapid testing of the generating ability of isolated hippocampal neurons. An analysis of the data has shown that the proposed protocol of serial ramp recordings allows to define additional characteristics of the neuronal impulse activity: (i) the thresholds for initiation of generation and suppression of the generation, (ii) the shape and amplitude of relationship between the interpulse intervals and neuronal depolarizations. The suggested stimulation protocols and related analysis are tools that can be effectively used to justify influence of chemicals or other experimental factors on the impulse activity of neurons. PMID- 26495733 TI - [THE ROLE OF HYDROGEN SULFIDE IN REGULATION OF CIRCULATION BLOOD LIVER]. AB - It was shown in acute experiments on laboratory rats that intraportalinjectionof hydrogen sulfide's precursor L-cysteine (15 mg/kg)caused dilatation of the intrahepatic vessels. As a result, systemic blood pressure (SBP) and blood pressure in the portal vein (PVP) significantly decreased on 17,6 and 24,5%, respectively, and the rate of local blood flow in the liver (LF) and its blood filling (BF) increased on 28,2 and 24,4% respectively. Application of hydrogen sulfide donor NaHS (7 mg/kg) resulted in similarly directed changes: SBP and PVP decreased on 20,8% i 26,2% respectively,LF and BF increased on 16,4% and 30,9% respectively. Application of L-cysteine in the conditions of tsystationin-gamma lyase blockade by LD-proparhilhlitsyn led to an increase in SBP on 20,4 % and PVP on 26,6% and a decrease of BF on 21,5% and LF in the liver on 11,7% comparing with baseline values of these parameters. So, blockade of tsystationin-gamma lyase not only completely removed the effects of L-cysteine, but also inhibited synthesis of H2S from its endogenous predecessors,which led to vasoconstriction of liver's blood vessels and, consequently, to an increase of blood pressure and a decrease of liver blood flow rat's and volume of blood deposited in liver. PMID- 26495734 TI - [THE INFLUENCE OF THE NORMOBARIC HYPOXIA FOR THE BREATHIHG INDEXES OF THE CHILDREN LIVED IN RADIOACTIVE CONTAMINATED TERRITORIES]. AB - There was conducted a research of the influence the sanogenic level of intermittent normobaric hypoxia (INH) for children lived in radioactively contaminated territories. The research involved 106 children in the age from 6 to 17 with symptoms ofbronchospasm: 55 persons of the main group and 51 persons of the screening group. It was confirmed that after the course of sessions INH (12 % oxygen in nitrogen) the respiratory system has changed. It is known statistically that in the main group the indexes of ventilation lung capacity have increased : vital capacity of the lungs, bronchial obstruction proximal bronchi of large and medium diameter, and distal bronchi small diameter. The bronchospasm has removed completely or partially. It was confirmed significantly that the breath-holding time becomes longer (test Stange) and heart rat reduced in companson with the screening group. PMID- 26495735 TI - [THE INFLUENCE OF NANODISPERSE CERIUM DIOXIDE ON ONTOGENETIC CHANGES OF ANTIOXIDANT SYSTEM IN THE MUCOSA OF THE STOMACH AND COLON IN RATS]. AB - It was established that with age the content of lipid peroxidation products increased in the mucosa of the stomach: Diene conjugates by 30%, products which react to thiobarbituric acid by 285% and Schif bases by 181%. Nanodisperse cerium dioxide (NCD) reduced the content of lipid peroxidation in the gastric mucosa in old rats: Diene conjugates by 43 %, products which react to thiobarbituric acid by 51% and Schif bases by 44% relative to the control group of rats given age. Similarly, it was established that the content of Diene conjugates increased by 40%, products which react to thiobarbituric acid by 114% and Schif bases by 132% in the mucosa of the colon of old rats. NDC significant reduced the content of products which react to thiobarbituric acid by 69% and Schyf basics by 132%. In the stomach superoxide dismutase (by 43%) and catalase activity (by 24%) decreases with age, while in the colon superoxide dismutase activity increases (by 43%). In the colon NCD significant decreased superoxide dismutase (by 34%) and catalase activity (by 21%) relative to controls. Thus, the NDC restores lipid peroxidation in the gastric mucosa and colon, in which develops oxidative stress with age. PMID- 26495736 TI - [FEATURES OF EATING BEHAVIOR IN PERSONS WITH NORMAL AND INCREASED BODY WEIGHT]. AB - Using the Dutch Eating Behavior Questionnaire (DEBQ) and Three-factor Eating Questionnaire-R18 (TFEQ-RI8), we defined the peculiarities of eating behavior and their impact on quality of life in young people aged 18-25 years. All participants were divided into two groups according to body mass index (BMI). The control group included 41 persons with normal body weight (BMI 18.5-24.9 kg/m2). The group of young adults with increased body weight (BMI over 25 kg/M2) consisted of 27 persons. We found eating behavior disorders in 85,19 % of overweight people and in 41,46 % of persons with normal weight. The restrictive eating behaviors as well as a significant percentage of violations by external type had predominated in overweight individuals by the structure of disorders. The external and restrictive types of eating behavior disorders were predominated in persons with normal weight. Investigation of quality of life using the SF-36 questionnaire showed a significantly decline in the physical role functioning and pain. Index of general physical health component, being not high enough in both groups, was significantly lower in overweight people with 52.70 points against 56.11. We concluded that the eating behavior disorders in persons with normal weight and in overweight people required an individual approach to forming healthy lifestyle and fixing broken food stereotype. It will counteract the further increase of body weight and contribute to improving the quality of life. PMID- 26495737 TI - [THE CONTENT OF LIPIDS AND PRODUCTS OF THEIR PEROXIDATION OF RAT THYMOCYTES IN EXPERIMENTAL ULCEROGENESIS]. AB - The work is dedicated to the research of the content of lipids and products of their peroxidation in rats thymocytes in experimental ulceration. It was found significant increase of the content of lipid peroxidation products diene conjugates (DC), malondialdehyde (MDA), schiff base (SB) in experimental models of gastric ulcers (ethanol and stress). It was established that under ethanol gastric the contents of DC increases by 1.8 times, MDA by 2.1 and SB by 1.3 times relative to control values. Under stress model it was observed an increase in the number of DC by 2 times, MDA by 1.9 and SB by 1.3 times relative to control. When ethanol and stress ulcers cholesterol increased by 1.7 and 1.5 times, triacylglycerol by 2 and 2.3 times and fatty acids by 2.2 and 1.9 times, respectively, relative to controls. Phosphatidylethanolamine content decreases by 1.5 and 1.3 times compared to control. Also, the stress model, it was observed reduction of phosphatidylinositol by 1.3 times and increased lizofosfatydylholinu by 1.7 times compared to control. Therefore, our studies indicate quantitative changes of lipid content (neutral- and phospholipids) in rats' thymocytes under experimental (ethanol and stress) ulceration. The reason of this changes may be activation of lipid peroxidation, as shown by the increase of lipid peroxidation products' (DK, MDA, SB) content. PMID- 26495738 TI - [THE EFFECT OF EXOGENOUS MELATONIN ON BONE REMODELING]. AB - It was investigated in spring 28-day experiment the administration of pharmacological doses (5 mg/kg) of melatonin to 3-month male rats with high and low levels of energy metabolismat remodeling of bone tissue. It was shown the decrease in activity of osteoblast and increase of osteoclast activity regardless of energy metabolism intensity, increase in concentration of glycosaminoglycans and free amino acids. This indicates the inhibition of physiological bone remodeling and helps to maintain the integrity of the organic matrix and the inorganic component of the fixation of the connective tissue - hydroxyapatite crystals. PMID- 26495739 TI - [ROLE OF THROMBOXANE AND LEUKOTRIENES IN MECHANISMS OF CONTRACTILE REACTIONS OF PORTAL VEIN, INDUCED BY ACETYLCHLINE AND PHENYLEPHRINE]. AB - Effects of picotamide and zileuton on tonic contractile activity of the rat portal vein preparations, induced by acetylcholine (2.10(-5) mol/1) and phenylephrine (5.10(-7) mol/1) were investigated. Conversion of arachidonic acid products (prostaglandins, leukotrienes) synthesized by endothelial cells, plays an important role in the local regulation of vascular tone. The compounds formed in a cascade of enzymatic transformations can modulate the effect of other vasoactive factors. Picotamide (6,5.10(-5) mol/1) - thromboxane receptor and thromboxane -synthase blocker - depress acetylcholine-induction tonic contraction of isolated segments of portal vein with intact endothelium by 29% and norepinephrine-induction reduction of 45% relative to the control values. The obtained results indicate a participation of thromboxane and/or endoperoxide H2 in this reaction. Partial inhibition of the contractions by 5-lipoxygenase blocker zileuton(4,2.10(-5) mol/1) at 23% relative to control values suggests, that products of lipoxigenase pathways of arachidonic acid conversion are involved in mechanisms of specified reactions. These data indicate complex mechanisms of regulation of vascular tone of the portal vein, which play an important role eicosanoids. Further study of these mechanisms is necessary for the formation of basic knowledge, as well as to elucidate the mechanisms of occurrence and development of pathological conditions of vessels and the development of methods of their correction. PMID- 26495740 TI - [COMPARATIVE STUDY OF MECHANICAL STRESS EFFECT ON HUMAN AND ANIMAL ERYTHROCYTES]. AB - Sensitivity of human and animal (bovine, rat, rabbit, equine) erythrocytes to the effect of mechanical stress has been studied. Mechanical stress effect was demonstrated to result in a time-dependent (5-60 min) release of potassium cations out of mammalian erythrocytes and a partial hemolytic cell damage. Herewith the release levels of potassium ions and hemolysis did not coincide for erythrocytes of all the mammals except rabbit ones. The most sensitive to mechanical stress (60 min) by the parameters of hemolytic damage and potassium ion release were rat (32%) and bovine (66%) erythrocytes respectively, the lowest sensitive by both parameters were rabbit ones (about 20%). Implemented correlation analysis has demonstrated a statistically significant negative relation between the values of mechanical hemolysis of mammalian erythrocytes and surface-volumetric ratio of cells (rs = -0.900, P = 0.037). A feasible relationship between the content of phosphatidylethanolamine in mammalian erythrocyte membranes and the level of potassium cation loss under mechanical stress effect is under discussion. PMID- 26495741 TI - [CHANGING OF ISCHEMIC M. SOLEUS TETANIC CONTRACTION PARAMETERS IN RATS WITH CHRONIC ALCOHOL INTOXICATION]. AB - This article deals with the changes of isolated ischemic m. soleus tetanus parameters in rats with chronic alcohol intoxication. The experiments were carried out on 15 male Wistar rats that were divided into three groups for 5 animals in each: group I (control) and two groups in which was induced hind limbs acute muscles ischemia: group II - rats without alcoholic intoxication, group III - rats with chronic alcoholic intoxication. Strain measurement muscle mechanical activity were conducted in isometric mode under conditions of direct electrical muscular preparation stimulation. It is proved that ischemic m. soleus tetanic force in rats with chronic alcoholic intoxication in comparison with rats without alcoholic intoxication does not significant changes. But signifycantly increases the reaching tetanus peak time. It is shown that in rats without alcoholic intoxication and with chronic alcoholic intoxication in comparison with intact animals, significantly decreases the duration of ischemic m. soleus stabile force level. It is shoved significant changes of individual muscles contraction time course of ischemic m. soleus tetanus in this rats group in comparison to intact animal. It is shown that these changes influence on successive muscular contraction efficiency of frequency summation in ischemic m. soleus tetanus and their speed-power characteristics. PMID- 26495742 TI - [NONLINEAR ELECTROENCEPHALOGRAPHIC CORRELATES OF AUDITORY-MOTOR INTEGRATION IN BOYS WITH OBTAINED VISUAL DYSFUNCTION]. AB - This research aims to study the nonlinear dynamics of the brain electrical activity in the performance of complex auditory-motor choice reaction. The boys with obtained visual dysfunction (n = 27, vis. OS 0,70 +/- 0,04, vis. OD 0,56 +/- 0,05 with correction) and normal sighted (n = 27) boys aged from 8 to 12 years were examined. Nonlinear parameters such as embedding dimension, correlation dimension, Lyapunov maximum exponent and Kolmogorov-Sinai entropy were determined. The auditory-motor integration are induced the activation of the right occipital area and the deactivation of the left occipital area in boys with obtained visual dysfunction. This is not typical for the sighted boys. The results are discussed in the context of cross-modal plasticity and supramodal brain organization. PMID- 26495743 TI - Remote ischemic preconditioning versus intermittent hypoxia training: a comparative analysis for cardioprotection. AB - Ischemic preconditioning (IPC) is an adaptive phenomenon that occurs after one or more short periods of ischemia/reperfusion, and consists in increasing the tolerance of an organ or tissue to the damaging effect of a long period of ischemia/reperfusion. Although IPC was shown to have a protective effect in animal models or during operative interventions, the obvious difficulties involved in subjecting the heart to direct IPC restrict its potential clinical applications. In this perspective, the phenomenon of remote ischemic preconditioning (RIPC: ischemia/reperfusion cycles in the arm or leg) appears extremely encouraging. Intermittent hypoxic training (IHI, periodic exposure of an organism to hypoxic gas mixtures, or stay in the chamber or altitudes) also has powerful adaptogenic effect increasing the resistance to subsequent episodes of severe hypoxia/ischemia. This review discusses main mechanisms and clinical applications of RIPC in cardiology versus IHT technologies. Benefits and disadvantages of both methods are under consideration. Positive and negative effects of hypercapnia during the RIPC technology are also examined. We wish to stimulate a comprehensive understanding of such a complex physiological phenomenon as intermittent hypoxia and ischemic preconditioning in order to prevent or reduce their harmful consequences, while maximize their potential utility as an effective therapeutic tools. PMID- 26495744 TI - "A More Rounded Full Care Model": Interprofessional Team Members' Perceptions of Home-Based Primary Care in Ontario, Canada. AB - This study explores interprofessional team members' perspectives and experiences providing home-based primary care (HBPC) in Ontario, Canada. Employing an inductive qualitative methodology using procedures informed by grounded theory, themes emerged in the data in relation to the benefits of the HBPC model, and the barriers associated with its provision, as well as the key components that enable or hinder interprofessional collaboration in the HBPC environment. This research deepens our understanding of the key features and processes of interprofessional teams providing high-quality care in the home. PMID- 26495746 TI - Advances in small-molecule drug discovery for triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a subtype of poor prognosis, highly invasive and difficult-to-treat breast cancers accounting for approximately 15% of clinical cases. Given the poor outlook and lack of sustained response to conventional therapies, TNBC has been the subject of intense studies on new therapeutic approaches in recent years. The development of targeted cancer therapies, often in combination with established chemotherapy, has been applied to a number of new clinical studies in this setting in recent years. This review will highlight recent therapeutic advances in TNBC, focusing on small-molecule drugs and their associated biological mechanisms of action, and offering the possibility of improved prospects for this patient group in the near future. PMID- 26495745 TI - Association of intimate partner violence and health-care provider-identified obesity. AB - The association of physical and nonphysical intimate partner violence (IPV) with obesity was examined. Women (N = 1,179) were surveyed regarding demographics, obesity, and IPV exposure using humiliate-afraid-rape-kick (HARK), an IPV screening tool. A three-level lifetime IPV exposure variable measured physical, nonphysical or no IPV. Health-care provider-identified obesity was defined if participants were told by a medical provider within the past 5 years that they were obese. Bivariate analyses examined obesity by IPV and demographics. Multivariable logistic regression assessed odds of obesity by IPV type, adjusting for age, race/ethnicity, education, and marital status. Among participants, 44% reported lifetime IPV (25% physical, 19% nonphysical), and 24% reported health care provider-identified obesity. In unadjusted analyses, obesity was more prevalent among women exposed to physical IPV (30%) and nonphysical IPV (27%), compared to women without IPV (20%, p = .002). In multivariable models, women reporting physical IPV had 1.67 times greater odds of obesity (95% confidence interval [CI] 1.20, 2.33), and women reporting nonphysical IPV had 1.46 times greater odds of obesity (95% CI 1.01, 2.10), compared to women reporting no exposure. This study extends prior data by showing, not only an association between physical IPV and obesity, but also an association between obesity and nonphysical IPV. PMID- 26495747 TI - Development of Biochar-Based Functional Materials: Toward a Sustainable Platform Carbon Material. PMID- 26495748 TI - Quantitative Detection Method of Hydroxyapatite Nanoparticles Based on Eu(3+) Fluorescent Labeling in Vitro and in Vivo. AB - One major challenge for application of hydroxyapatite nanoparticles (nHAP) in nanomedicine is the quantitative detection method. Herein, we exploited one quantitative detection method for nHAP based on the Eu(3+) fluorescent labeling via a simple chemical coprecipitation method. The trace amount of nHAP in cells and tissues can be quantitatively detected on the basis of the fluorescent quantitative determination of Eu(3+) ions in nHAP crystal lattice. The lowest concentration of Eu(3+) ions that can be quantitatively detected is 0.5 nM using DELFIA enhancement solution. This methodology can be broadly applicable for studying the tissue distribution and metabolization of nHAP in vivo. PMID- 26495749 TI - Antioxidant impregnated ultra-high molecular weight polyethylene wear debris particles display increased bone remodeling and a superior osteogenic:osteolytic profile vs. conventional UHMWPE particles in a murine calvaria model. AB - Periprosthetic osteolysis remains a major limitation of long-term successful total hip replacements with ultra-high molecular weight polyethylene (UHMWPE) bearings. As intra and extracellular reactive oxygen species are know to contribute to wear debris-induced osteoclastic bone resorption and decreased osteoblastic bone formation, antioxidant doped UHMWPE has emerged as an approach to reduce the osteolytic potential of wear debris and maintain coupled bone remodeling. To test this hypothesis in vivo, we evaluated the effects of crosslinked UHMWPE wear debris particles (AltrX(TM) ), versus similar wear particles made from COVERNOX(TM) containing UHMWPE (AOX(TM) ), in an established murine calvaria model. Eight-week-old female C57B/6 mice (n = 10/Group) received a pre-op micro-CT scan prior to surgical implantation of the UHMWPE particles (2mg), or surgery without particles (sham). Dynamic labeling was performed by intraperitoneal injection of calcein on day 7 and alizarin on day 9, and the calvaria were harvested for micro-CT and histology on day 10. Surprisingly, we found that AOX particles induced significantly more bone resorption (1.72-fold) and osteoclast numbers (1.99-fold) vs. AltrX (p < 0.001). However, AOX also significantly induced 1.64-fold more new bone formation vs. AltrX (p < 0.01). Moreover, while the osteolytic:osteogenic ratio of both particles was very close to 1.0, which is indicative of coupled remodeling, AOX was more osteogenic (Slope = 1.13 +/- 0.10 vs. 0.97 +/- 0.10). Histomorphometry of the metabolically labeled undecalcified calvaria revealed a consistent trend of greater MAR in AOX vs. AltrX. Collectively, these results demonstrate that anti-oxidant impregnated UHMWPE particles have decreased osteolytic potential due to their increased osteogenic properties that support coupled bone remodeling. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:845-851, 2016. PMID- 26495750 TI - Interactions Between Diet and Exposure to Secondhand Smoke on Metabolic Syndrome Among Children: NHANES 2007-2010. AB - CONTEXT: Metabolic syndrome is likely influenced by a complex interaction between exposure to secondhand smoke (SHS) and diet, but no studies have evaluated this relationship. OBJECTIVE: This study aimed to investigate the interaction between diet and exposure to SHS on metabolic syndrome among 12-19 year olds. DESIGN AND PARTICIPANTS: We used weighted logistic regression, adjusting for potential confounders, to examine interaction of these risk factors on the prevalence of metabolic syndrome among 12-19 year olds participating in the National Health and Nutrition Examination Survey (2007-2010). Interaction was assessed by introducing product terms between SHS (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, cotinine, and self-report) and the individual nutrients (dietary fiber, eicosapentaenoic acid, docosahexaenoic acid, vitamin C, and vitamin E) and nutrient patterns in separate models; the relative excess risk due to interaction was used to evaluate interaction on the additive scale. RESULTS: The joint effect between high exposure to SHS and low levels of certain nutrients (vitamin E and omega-3 polyunsaturated fatty acids) on metabolic syndrome risk was greater than would be expected from the effects of the individual exposures alone (for example, relative excess risk due to interaction for SHS and vitamin E = 7.5; 95% confidence interval, 2.5-17.8). CONCLUSIONS: Prevention strategies for metabolic syndrome aimed at reducing SHS exposures and improving diet quality may exceed the expected benefits based on targeting these risk factors separately. PMID- 26495752 TI - Treatment With Diet and Exercise for Women With Gestational Diabetes Mellitus Diagnosed Using IADPSG Criteria. AB - CONTEXT: Prevalence of gestational diabetes mellitus (GDM) and obesity continue to increase. OBJECTIVE: This study aimed to ascertain whether diet and exercise is a successful intervention for women with GDM and whether a subset of these women have comparable outcomes to those with normal glucose tolerance (NGT). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of five antenatal centers along the Irish Atlantic seaboard of 567 women diagnosed with GDM and 2499 women with NGT during pregnancy. INTERVENTION: Diet and exercise therapy on diagnosis of GDM were prescribed and multiple maternal and neonatal outcomes were examined. RESULTS: Infants of women with GDM were more likely to be hypoglycemic (adjusted odds ratio [aOR], 7.25; 95% confidence interval [CI], 2.94 17.9) at birth. They were more likely to be admitted to the neonatal intensive care unit (aOR, 2.16; 95% CI, 1.60-2.91). Macrosomia and large-for-gestational age rates were lower in the GDM group (aOR, 0.48; 95% CI, 0.37-0.64 and aOR, 0.61; 95% CI, 0.46-0.82, respectively). There was no increase in small for gestational age among offspring of women with GDM (aOR, 0.81; 95% CI, 0.49-1.34). Women with diet-treated GDM and body mass index (BMI) < 25 kg/m(2) had similar outcomes to those with NGT of the same BMI group. Obesity increased risk for poor pregnancy outcomes regardless of diabetes status. CONCLUSION: Medical nutritional therapy and exercise for women with GDM may be successful in lowering rates of large for gestational age and macrosomia without increasing small-for-gestational age rates. Women with GDM and a BMI less than 25 kg/m(2) had outcomes similar to those with NGT suggesting that these women could potentially be treated in a less resource intensive setting. PMID- 26495753 TI - Internal migration, international migration, and physical growth of left-behind children: A study of two settings. AB - Parental out-migration has become a common experience of childhood worldwide and tends to have important ramifications for child development. There has been much debate on whether overall children benefit or suffer from parental out-migration. The present study examines how the relationship between parental out-migration and children's growth differs by the type of migration (internal vs. international). This comparison is conducted in two diverse settings, Mexico and Indonesia. Data are from two national longitudinal surveys: the Mexican Family Life Survey and the Indonesian Family Life Survey. Results from fixed-effect regressions show that international migration tends to have a less beneficial, sometimes even more detrimental, impact on the growth of children left behind than internal migration. Results also reveal contextual differences in the role of parental out-migration. Possible explanations are discussed. PMID- 26495751 TI - Subclinical Thyroid Dysfunction and Frailty Among Older Men. AB - CONTEXT: Both subclinical thyroid dysfunction and frailty are common among older individuals, but data on the relationship between these 2 conditions are conflicting. OBJECTIVE: The purpose of this study was to assess the cross sectional and prospective associations between subclinical thyroid dysfunction and frailty and the 5 frailty subdomains (sarcopenia, weakness, slowness, exhaustion, and low activity). SETTING AND DESIGN: The Osteoporotic Fractures in Men Study is a prospective cohort study. PARTICIPANTS: Men older than 65 years (n = 1455) were classified into 3 groups of thyroid status: subclinical hyperthyroidism (n = 26, 1.8%), subclinical hypothyroidism (n = 102, 7.0%), and euthyroidism (n = 1327, 91.2%). MAIN OUTCOME MEASURES: Frailty was defined using a slightly modified Cardiovascular Health Study Index: men with 3 or more criteria were considered frail, men with 1 to 2 criteria were considered intermediately frail, and men with no criteria were considered robust. We assessed the cross-sectional relationship between baseline thyroid function and the 3 categories of frailty status (robust/intermediate/frail) as well as the prospective association between baseline thyroid function and subsequent frailty status and mortality after a 5-year follow-up. RESULTS: At baseline, compared with euthyroid participants, men with subclinical hyperthyroidism had an increased likelihood of greater frailty status (adjusted odds ratio, 2.48; 95% confidence interval, 1.15-5.34), particularly among men aged <74 years at baseline (odds ratio for frailty, 3.63; 95% confidence interval, 1.21-10.88). After 5 years of follow-up, baseline subclinical hypothyroidism and hyperthyroidism were not consistently associated with overall frailty status or frailty components. CONCLUSION: Among community-dwelling older men, subclinical hyperthyroidism, but not subclinical hypothyroidism, is associated with increased odds of prevalent but not incident frailty. PMID- 26495754 TI - Exploring cultural differences in women's body weight perception: The impact of self-construal on perceived overweight and engagement in health activities. AB - We examined the cultural influence on perceived body weight and the level of health practices at a national and individual level. At a national level, we found that Japanese women (n = 80) overestimate body weight more than Korean (n = 82) and American (n = 63) women. At an individual level, individuals with interdependent self-construal were more prone to overestimate weight than those with independent self-construal (N = 182; American women). Based on the data, we identify that the relationship is mediated by self-criticism, and, importantly, it is self-criticism rather than perceived overweight that predicts the level of health activities. Health practitioners and campaign designers across cultures are recommended to concentrate on promoting positive body esteem instead of encouraging engagement in corrective health behaviors for weight loss. PMID- 26495756 TI - Letter From the Editor. PMID- 26495755 TI - Restoring Light Sensitivity in Blind Retinae Using a Photochromic AMPA Receptor Agonist. AB - Retinal degenerative diseases can have many possible causes and are currently difficult to treat. As an alternative to therapies that require genetic manipulation or the implantation of electronic devices, photopharmacology has emerged as a viable approach to restore visual responses. Here, we present a new photopharmacological strategy that relies on a photoswitchable excitatory amino acid, ATA. This freely diffusible molecule selectively activates AMPA receptors in a light-dependent fashion. It primarily acts on amacrine and retinal ganglion cells, although a minor effect on bipolar cells has been observed. As such, it complements previous pharmacological approaches based on photochromic channel blockers and increases the potential of photopharmacology in vision restoration. PMID- 26495757 TI - Delivery of Constitutively Active Mutant MKK6(E) With TAT-OSBP Induces Apoptosis in Human Ovarian Carcinoma HO8910 Cells. AB - Biologically active peptides and proteins are novel agents that show promise in the development of anticancer drugs. Their relatively low cell permeability and poor tumor selectivity, however, impede their widespread applicability. In this study, we evaluated the tumor selectivity, cellular internalization, and biological activity of a cell-permeable ovarian cancer cell-specific therapeutic protein consisting of TAT-OSBP and constitutively active MKK6(E), an upstream kinase of the p38 signaling pathway that mediates cellular apoptosis. OSBP, a 7 amino-acid peptide with high affinity for human ovarian cancer HO8910 cells, was conjugated to the cell-penetrating peptide (TAT) to form a tumor-selective peptide (TAT-OSBP), which was further conjugated with EGFP or MKK6(E). Flow cytometry and fluorescent microscopy were performed to evaluate the tumor targeted penetration of TAT-OSBP-EGFP. The inhibitory effects of TAT-OSBP-MKK6(E) were determined by cell proliferation and apoptosis assays. The internalization efficiency of TAT-OSBP-EGFP was significantly higher than that of TAT-EGFP. TAT OSBP-EGFP selectively penetrated HO8910 cells. TAT-OSBP-MKK6(E) fusion protein inhibited cancer cell growth to varying degrees, with the highest level of inhibition in HO8910 cells. Moreover, TAT-OSBP-MKK6(E) significantly induced apoptosis of HO8910 cells. However, there was no significant difference in apoptosis in the normal ovarian epithelial cells treated with either TAT-OSBP MKK6(E) or TAT-MKK6(E). Our results demonstrate that TAT-OSBP-MKK6(E) is a novel artificially designed molecule, which induces apoptosis and selectively targets human ovarian carcinoma HO8910 cells. Our study provides novel insights that may aid in the development of a new generation of anticancer drugs. PMID- 26495759 TI - Long-Term Outcome of Aromatase Inhibitor Therapy With Letrozole in Patients With Advanced Low-Grade Endometrial Stromal Sarcoma. AB - BACKGROUND: There has been no consensus on the indications for the treatment of advanced low-grade endometrial stromal sarcoma (LGESS), and the possible effects of hormonal treatment including progestins and aromatase inhibitors have been reported. The aim of this study was to investigate the efficacy of aromatase inhibitor therapy with letrozole for patients with residual or recurrent LGESS. METHODS: We retrospectively reviewed the clinical response of patients with advanced LGESS who had been treated with letrozole. We also analyzed the adverse effects after the administration of letrozole. The expression levels of estrogen receptor and aromatase in the tumors were immunohistochemically examined. RESULTS: In 5 patients who had been treated for unresectable LGESS lesions after initial or repeat surgical procedures, residual lesions in 3 patients and recurrence lesions in 2 patients were the indications for hormonal therapy with letrozole. The median duration of letrozole exposure at retrospective analysis was 53 (10-96) months. The clinical outcomes were classified as complete response in 2 patients, partial response in 1 patient, and stable disease in 2 patients. Myalgias, hot flashes, and arthralgias were not observed during the follow-up period in any patients. The median serum levels of estradiol were <5.0 (cutoff value, <0.5-11.8) pg/mL. The median age-matched bone mineral densities were 92% (79%-123%). The LGESS tissues in all 5 patients were positive for estrogen receptor and aromatase expression. CONCLUSIONS: Letrozole as well as progestins could be the first choice of treatment for patients with recurrent or residual LGESS, which is difficult to resect surgically because of its efficacy and minimal adverse effects. PMID- 26495758 TI - Cytokeratin 5-Positive Cells Represent a Therapy Resistant subpopulation in Epithelial Ovarian Cancer. AB - OBJECTIVE: Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)(+) breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5(+) cell populations to cisplatin therapy. MATERIALS AND METHODS: Cytokeratin 5 expression was evaluated in 2 ovarian tissue microarrays, representing 137 neoplasms, and 6 ovarian cancer cell lines. Cell lines were treated with IC(50) (half-maximal inhibitory concentration) cisplatin, and the prevalence of CK5(+) cells pretreatment and posttreatment was determined. Proliferation of CK5(+) versus CK5(-) cell populations was determined using 5 bromo-2'-deoxyuridine incorporation. Chemotherapy-induced apoptosis in CK5(+) versus CK5(-) cells was measured using immunohistochemical staining for cleaved caspase-3. RESULTS: Cytokeratin 5 was expressed in 39.3% (42 of 107) of epithelial ovarian cancers with a range of 1% to 80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5(+) specimens. Cytokeratin 5 expression correlated with ER positivity (38 of 42 CK5(+) tumors were also ER(+)). Cytokeratin 5 was expressed in 5 of 6 overall and 4 of 4 ER(+) epithelial ovarian cancer cell lines ranging from 2.4% to 52.7% positive cells. Cytokeratin 5(+) compared with CK5(-) cells were slower proliferating. The prevalence of CK5(+) cells increased after 48-hour cisplatin treatment in 4 of 5 cell lines tested. Cytokeratin 5(+) ovarian cancer cells compared with CK5(-) ovarian cancer cells were more resistant to cisplatin-induced apoptosis. CONCLUSIONS: Cytokeratin 5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating chemoresistant subpopulation that may warrant cotargeting in combination therapy. PMID- 26495760 TI - Clinicopathologic Factors of Cervical Adenocarcinoma Stages IB to IIB. AB - OBJECTIVE: The aim of this study was to clarify the clinicopathologic factors of stages IB to IIB cervical adenocarcinoma. METHODS: Several clinicopathologic factors were compared between 35 patients who underwent radical hysterectomy and pelvic lymphadenectomy due to cervical adenocarcinoma stages IB to IIB and 77 patients with squamous cell carcinoma (SCC). RESULTS: In patients with adenocarcinoma, univariate analysis demonstrated that International Federation of Gynecology and Obstetrics stage, tumor size, and lymphovascular space invasion were significantly associated with progression-free survival (PFS), whereas FIGO stage, lymphovascular space invasion, and lymph node metastasis were significantly associated with overall survival (OS). However, multivariate analysis revealed that FIGO stage was the only significant factor for PFS in patients with adenocarcinoma. In patients with SCC, univariate analysis demonstrated that FIGO stage and lymph node metastasis were significantly associated with PFS, whereas FIGO stage, lymphovascular space invasion, and lymph node metastasis were significantly associated with OS. Multivariate analysis revealed that lymph node metastasis was the only significant factor for PFS and OS in patients with SCC. In 26 patients who were positive for high-risk human papillomavirus (HPV), including both adenocarcinoma and SCC patients, univariate and multivariate analyses revealed that HPV18 was significantly associated with poorer PFS compared with non-HPV18. There was a significant difference in distribution of HPV genotype between adenocarcinoma and SCC. CONCLUSIONS: Careful treatment may be necessary for the patients with lymphovascular space invasion in early-stage cervical adenocarcinoma. The presence of HPV18 may have an influence on the prognosis of early-stage cervical carcinoma. PMID- 26495761 TI - Changing Trends in Vulvar Cancer Incidence and Mortality Rates in Australia Since 1982. AB - BACKGROUND: The objective of this study was to assess trends in vulvar cancer incidence and mortality in Australia. METHODS: Case numbers for invasive carcinoma of the vulva (1982-2009) and vulvar cancer deaths (1982-2011) were obtained from the National Cancer Statistics database. Standardized rate ratios (SRRs) were used to assess changes in age-standardized incidence and mortality rates, for all ages and for younger than 60 years and 60+ years. RESULTS: Age standardized incidence rates in women across all ages did not significantly change from 1982-1984 to 2007-2009 (from 2.1 to 2.5 per 100,000 women; SRR from the later to the earlier period, 1.13 [95% CI, 1.00-1.27]). However, there was a significant 84% increase in incidence in women younger than 60 years (SRR, 1.84 [95% CI, 1.49-2.26]), with no change for women 60+ years (SRR, 0.90 [95% CI, 0.79 1.04]). Age-standardized mortality in women across all ages significantly decreased by 22% from 1982-1986 to 2007-2011 (from 0.7 to 0.5 per 100,000 women; SRR, 0.78 [95% CI, 0.66-0.93]). However, this was driven by declines in older women, with stable rates in women younger than 60 years (SRR, 1.05 [95% CI, 0.62 1.79]); rates in 60+ years decreased by 24% (SRR, 0.76 [95% CI, 0.63-0.91]). CONCLUSION: Since the early 1980s, vulvar cancer incidence has increased by more than 80% in women younger than 60 years in Australia, but there has been no increased incidence in older women. These findings are consistent with the possibility of increased exposure to the human papillomavirus in cohorts born after 1950. By contrast, age-standardized vulvar cancer mortality rates have been stable in younger women, but have declined in older women. PMID- 26495762 TI - Robot-Assisted Radical Hysterectomy in Cervical Carcinoma: The Belgian Experience. AB - OBJECTIVE: The purpose of this study was to report the experience and oncological outcome of robot-assisted radical hysterectomies (RRHs) for cervical cancer performed in Belgium. METHODS: Patients undergoing RRH for cervical cancer (n = 109) were prospectively collected between July 2007 and April 2014 in the 5 Belgian centers performing RRH for cervical cancer. RESULTS: The median age of the patients was 46 years (range, 31-80 years). Histological types included squamous cell carcinoma in 61 patients, adenocarcinoma in 22 patients, adenosquamous in 8 patients, endometrioid carcinoma in 2 patients, and other types (n = 16). The International Federation of Gynecology and Obstetrics stage distribution was IA (n = 9), stage IB1 (n = 71), stage IB2 (n = 4), stage II (n = 24), and unknown (n = 1). Twenty-four patients received adjuvant therapy, 17 patients underwent radiochemotherapy, and 7 underwent adjuvant radiation. Eighteen patients relapsed, and 5 died of disease. The median follow-up was 27.5 months (range, 3-82 months). The 2- and 5-year overall survivals were 96% and 89%, respectively. The 2- and 5-year disease-free survivals (DFSs) were 88% and 72%, respectively. The 2-year DFS per stage was 100% for IA, 88% for IB1, 100% for IB2, and 83% for II. The 5-year DFS per stage was 100% for stage IA and 75% for IB1. The complications were as expected for radical hysterectomy. CONCLUSIONS: This series confirms the feasibility and safety of RRH not only in cervical cancer stage IA to IB1, but also after neoadjuvant chemotherapy in stage IB2 to IIB. PMID- 26495763 TI - Interaction of organic carbon, reduced sulphur and nitrate in anaerobic baffled reactor for fresh leachate treatment. AB - Interaction of organic carbon, reduced sulphur and nitrate was examined using anaerobic baffled reactor for fresh leachate treatment by supplementing nitrate and/or sulphide to compartment 3. Nitrate was removed completely throughout the study mostly via denitrification (>80%) without nitrite accumulation. Besides carbon source, various reduced sulphur (e.g. sulphide, elemental sulphur and organic sulphur) could be involved in the nitrate reduction process via sulphur based autotrophic denitrification when dissolved organic carbon/nitrate ratio decreased below 1.6. High sulphide concentration not only stimulated autotrophic denitrification, but it also inhibited heterotrophic denitrification, resulting in a shift (11-20%) from heterotrophic denitrification to dissimilatory nitrate reduction to ammonia. High-throughput 16S rRNA gene sequencing analysis further confirmed that sulphur-oxidizing nitrate-reducing bacteria were stimulated with increase in the proportion of bacterial population from 18.6% to 27.2% by high sulphide concentration, meanwhile, heterotrophic nitrate-reducing bacteria and fermentative bacteria were inhibited with 25.5% and 66.6% decrease in the bacterial population. PMID- 26495764 TI - Highly Stable Bimetallic AuIr/TiO2 Catalyst: Physical Origins of the Intrinsic High Stability against Sintering. AB - It has been a long-lived research topic in the field of heterogeneous catalysts to find a way of stabilizing supported gold catalyst against sintering. Herein, we report highly stable AuIr bimetallic nanoparticles on TiO2 synthesized by sequential deposition-precipitation. To reveal the physical origin of the high stability of AuIr/TiO2, we used aberration-corrected scanning transmission electron microscopy (STEM), STEM-tomography, and density functional theory (DFT) calculations. Three-dimensional structures of AuIr/TiO2 obtained by STEM tomography indicate that AuIr nanoparticles on TiO2 have intrinsically lower free energy and less driving force for sintering than Au nanoparticles. DFT calculations on segregation behavior of AuIr slabs on TiO2 showed that the presence of Ir near the TiO2 surface increases the adhesion energy of the bimetallic slabs to the TiO2 and the attractive interactions between Ir and TiO2 lead to higher stability of AuIr nanoparticles as compared to Au nanoparticles. PMID- 26495765 TI - Genes, Genetics, and Environment in Type 2 Diabetes: Implication in Personalized Medicine. AB - Type 2 diabetes (T2D) is a multifactorial anomaly involving 57 genes located on 16 different chromosomes and 136 single nucleotide polymorphisms (SNPs). Ten genes are located on chromosome 1, followed by seven genes on chromosome 11 and six genes on chromosomes 3. Remaining chromosomes harbor two to five genes. Significantly, chromosomes 13, 14, 16, 18, 21, 22, X, and Y do not have any associated diabetogenic gene. Genetic components have their own pathways encompassing insulin secretion, resistance, signaling, and beta-cell dysfunction. Environmental factors include epigenetic changes, nutrition, intrauterine surroundings, and obesity. In addition, ethnicity plays a role in conferring susceptibility to T2D. This scenario poses a challenge toward the development of biomarker for quick disease diagnosis or for generating a consensus to delineate different categories of T2D patients. We believe, before prescribing a generic drug, detailed genotypic information with the background of ethnicity and environmental factors may be taken into consideration. This nonconventional approach is envisaged to be more robust in the context of personalized medicine and perhaps would cause lot less burden on the patient ensuring better management of T2D. PMID- 26495766 TI - The role of auxin signaling in early embryo pattern formation. AB - Pattern formation of the early Arabidopsis embryo generates precursors to all major cell types, and is profoundly controlled by the signaling molecule auxin. Here we discuss recent milestones in our understanding of auxin-dependent embryo patterning. Auxin biosynthesis, transport and response mechanisms interact to generate local auxin accumulation in the early embryo. New auxin-dependent reporters help identifying these sites, while atomic structures of transcriptional response mediators help explain the diverse outputs of auxin signaling. Key auxin outputs are control of cell identity and cell division orientation, and progress has been made towards understanding the cellular basis of each. Importantly, a number of studies have combined computational modeling and experiments to analyze the developmental role, genetic circuitry and molecular mechanisms of auxin-dependent cell division control. PMID- 26495767 TI - Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires In Vivo Expansion of Regulatory T Cells. AB - Recently, the immune-regulating potential of invariant natural killer T (iNKT) cells has attracted considerable attention. We previously reported that a combination treatment with a liposomal ligand for iNKT cells and an anti-CD154 antibody in a sublethally irradiated murine bone marrow transplant (BMT) model resulted in the establishment of mixed hematopoietic chimerism through in vivo expansion of regulatory T cells (Tregs). Herein, we show the lack of alloreactivity of CD8(+) T cells in chimeras and an early expansion of donor derived dendritic cells (DCs) in the recipient thymi accompanied by a sequential reduction in the donor-reactive Vbeta-T cell receptor repertoire, suggesting a contribution of clonal deletion in this model. Since thymic expansion of donor DCs and the reduction in the donor-reactive T cell repertoire were precluded with Treg depletion, we presumed that Tregs should preform before the establishment of clonal deletion. In contrast, the mice thymectomized before BMT failed to increase the number of Tregs and to establish CD8(+) T cell tolerance, suggesting the presence of mutual dependence between the thymic donor-DCs and Tregs. These results provide new insights into the regulatory mechanisms that actively promote clonal deletion. PMID- 26495768 TI - Quantum Chemical Study on .Cl-Initiated Atmospheric Degradation of Monoethanolamine. AB - Recent findings on the formation of .Cl in continental urban areas necessitate the consideration of .Cl initiated degradation when assessing the fate of volatile organic pollutants. Monoethanolamine (MEA) is considered as a potential atmospheric pollutant since it is a benchmark and widely utilized solvent in a leading CO2 capture technology. Especially, .Cl may have specific interactions with the N atom of MEA, which could make the MEA + .Cl reaction have different pathways and products from those of the MEA + .OH reaction. Hence, .Cl initiated reactions with MEA were investigated by a quantum chemical method [CCSD(T)/aug-cc pVTZ//MP2/6-31+G(3df,2p)] and kinetics modeling. Results show that the overall rate constant for .Cl initiated H-abstraction of MEA is 5 times faster than that initiated by .OH, and the tropospheric lifetimes of MEA will be overestimated by 6-46% when assuming that [.Cl]/[.OH] = 1-10% if the role of .Cl is ignored. The MEA + .Cl reaction exclusively produces MEA-N that finally transforms into several products including mutagenic nitramine and carcinogenic nitrosamine via further reactions with O2/NOx, and the contribution of .Cl to their formation is about 25-250% of that of .OH. Thus, it is necessary to consider .Cl initiated tropospheric degradation of MEA for its risk assessment. PMID- 26495769 TI - Mechanically activated, catalyst-free polyhydroxyurethane vitrimers. AB - Vitrimers are polymer networks whose cross-links undergo associative exchange processes at elevated temperature, usually in the presence of an embedded catalyst. This design feature enables the reshaping of materials with mechanical properties similar to thermoset resins. Here we report a new class of vitrimers consisting of polyhydroxyurethanes (PHUs) derived from six-membered cyclic carbonates and amines. PHU networks relax stress and may be reprocessed at elevated temperature and pressure in the absence of an external catalyst. The as synthesized networks exhibit tensile properties comparable to those of leading thermosets and recover ca. 75% of their as-synthesized values following reprocessing. Stress relaxation occurs through an associative process involving nucleophilic addition of free hydroxyl groups to the carbamate linkages and exhibits an Arrhenius activation energy of 111 +/- 10 kJ/mol, which is lower than that observed for molecular model compounds (148 +/- 7 kJ/mol). These findings suggest that transcarbamoylation is activated by mechanical stress, which we attribute, on the basis of DFT calculations, to the twisting of N lone pairs out of conjugation with the carbonyl pi orbitals. PHU vitrimers are a promising new class of repairable networks because of their outstanding mechanical properties, avoidance of toxic isocyanate monomers, and catalyst-free repair processes. PMID- 26495771 TI - Quality improvement in diabetes--successful in achieving better care with hopes for prevention. AB - Diabetes affects 29 million Americans and is associated with billions of dollars in health expenditures and lost productivity. Robust evidence has shown that lifestyle interventions in people at high risk for diabetes and comprehensive management of cardiometabolic risk factors like glucose, blood pressure, and lipids can delay the onset of diabetes and its complications, respectively. However, realizing the "triple aim" of better health, better care, and lower cost in diabetes has been hampered by low adoption of lifestyle interventions to prevent diabetes and poor achievement of care goals for those with diabetes. To achieve better care, a number of quality improvement (QI) strategies targeting the health system, healthcare providers, and/or patients have been evaluated in both controlled trials and real-world programs, and have shown some successes, though barriers still impede wider adoption, effectiveness, real-world feasibility, and scalability. Here, we summarize the effectiveness and cost effectiveness data regarding QI strategies in diabetes care and discuss the potential role of quality monitoring and QI in trying to implement primary prevention of diabetes more widely and effectively. Over time, achieving better care and better health will likely help bend the ever-growing cost curve. PMID- 26495770 TI - Side-effects of SSRIs disrupt multimodal treatment for pediatric OCD in a randomized-controlled trial. AB - OBJECTIVE: Activation Syndrome (AS) is a side-effect of antidepressants consisting of irritability, mania, self-harm, akathisia, and disinhibition. The current study was conducted to analyze how AS may hinder treatment outcome for multimodal treatment for children and adolescents with Obsessive-Compulsive Disorder. METHODS: Fifty-six children or adolescents were recruited at two treatment sites in a double-blind randomized-controlled trial where participants received Cognitive-Behavioral Therapy and were randomized to slow titration of sertraline, regular titration of sertraline or placebo. RESULTS: Using a recently developed measure of AS, results suggested that higher average levels of irritability, akathisia, and disinhibition significantly interfered with treatment response and explained 18% of the variance in obsessive-compulsive symptoms during treatment. Interestingly, only session-to-session increases in irritability resulted in a session-to-session increase in obsessive-compulsive symptoms. The observed results were unchanged with the addition of SSRI dosage as a covariate. CONCLUSIONS: Results provide empirical support for the proposed hypothesis that AS may hinder multimodal treatment outcome for pediatric OCD. These findings suggest that dosage changes due to AS do not explain why those with higher AS had worse multimodal outcome. Other possible mechanisms explaining this observed disruption are proposed, including how AS may interfere with Cognitive-Behavioral Therapy. PMID- 26495772 TI - Loss of signal transducer and activator of transcription 1 is associated with prostate cancer recurrence. AB - STAT1 loss has previously been implicated in cell line studies to modify prostate cancer cell growth and survival, however the clinical significance of this has not previously been established. This study investigated if STAT1 loss was associated with patient outcome measures and the phenotypic consequence of STAT1 silencing. STAT1 expression was assessed in two patient cohorts with localised (n = 78) and advanced prostate cancer at initial diagnosis (n = 39) by immunohistochemistry (IHC). Impact of STAT1 silencing on prostate cancer cells lines was assessed using Cell Death detection ELISA, TLDA gene signature apoptosis arrays, WST-1 assay, xCELLigence system, clonogenic assay, and wound healing assay. In the localised patient cohort, low expression of STAT1 was associated with shorter time to disease recurrence (3.8 vs 7.3 years, P = 0.02) and disease specific survival (6.6 vs 9.3 years, P = 0.05). In the advanced patient cohort, low expression was associated with shorter time to disease recurrence (2.0 vs 3.9 years, P = 0.001). When STAT1 was silenced in PC3 cells (AR negative) and LNCaP cells (AR positive) silencing did not influence levels of apoptosis in either cell line and had little effect on cell viability in the LNCaP cells. In contrast, STAT1 silencing in the PC3 cells resulted in a pronounced increase in cell viability (WST-1 assay: mock silenced vs STAT1 silenced, P < 0.001), clonagenicity (clonogenic assay: mock silenced vs STAT1 silenced, P < 0.001), and migration (wound healing: mock silenced vs STAT1 silenced, P < 0.001). In conclusion, loss of STAT1 may promote prostate cancer recurrence in AR negative patients via increasing cell viability. (c) 2015 Wiley Periodicals, Inc. PMID- 26495774 TI - Low Probability of Lymphatic Drainage to Cloquet's Node Is of Limited Value as Indicator for Pelvic Lymph Node Dissection in Patients with Lower Limb Melanoma. AB - BACKGROUND AND OBJECTIVES: For patients with melanoma, the choice between an inguinal lymph node dissection (ILND) alone and both an ILND and a pelvic lymph node dissection (PLND) is controversial. Although Cloquet's node (CN) is considered the sentinel pelvic node, evaluation of this factor to predict pelvic node status has produced varied results. We investigated inguinal and pelvic lymphatic drainage patterns and focused on CN to clarify whether CN status could be an indicator of PLND. METHODS: Patients with primary cutaneous lower limb melanoma who underwent lymphatic mapping and sentinel lymph node biopsy (SLNB) using dynamic lymphoscintigraphy and SPECT/CT were retrospectively reviewed. RESULTS: Thirty-two patients underwent lymphatic mapping and SLNB. Each patient's CN was identified by SPECT/CT. A radioactive CN was detected in only 37.5% (12/32) of patients, and no lymphatic drainage to CN occurred in 62.5% (20/32). In 37.5% (12/32) of patients, the lymph drained directly from the inguinal to the pelvic nodes bypassing CN. CONCLUSION: In melanoma patients, lymphatic drainage from the lower extremity does not always pass from the inguinal node to the pelvic nodes via CN. Tumor-negative status of CN alone is of limited value as an indicator for avoiding PLND. PMID- 26495775 TI - Evaluation of Modified Glasgow Prognostic Score for Pancreatic Cancer: A Retrospective Cohort Study. AB - OBJECTIVES: The modified Glasgow prognostic score (mGPS) is known to be useful in determining the prognosis of cancers. However, the utility of mGPS for pancreatic cancer (PC) has been examined based primarily on a surgical series of early-stage cancers. The purpose of this study was to examine the utility of mGPS for PC of all stages using a retrospective cohort design. METHODS: We conducted a retrospective cohort study using data from a computerized database. A total of 807 patients with pathologically confirmed PC were analyzed (mGPS-0, n = 620; mGPS-1, n = 153; mGPS-2, n = 34). RESULTS: Median overall survival (OS) was significantly worse for the mGPS-1 group than for the mGPS-0 group (5.8 vs 15.8 months, respectively) but was comparable between the mGPS-2 and mGPS-1 groups (4.8 vs 5.8 months, respectively). After adjustment, both mGPS-1 and mGPS-2 were independent predictive factors of OS (mGPS-1: hazard ratio, 1.772; 95% confidence interval, 1.417-2.215; mGPS-2: hazard ratio, 2.033; 95% confidence interval, 1.284-3.219). Subgroup analysis showed that OS was significantly worse in the mGPS-1 and mGPS-2 groups than in the mGPS-0 group for all except the following 2 subgroups: localized disease and curative resection. CONCLUSIONS: The present results show that the mGPS is an independent prognostic factor in patients with PC, especially for advanced-stage disease. PMID- 26495776 TI - Clinical Characteristics and Risk Factors for the Development of Postoperative Hepatic Steatosis After Total Pancreatectomy. AB - OBJECTIVES: The occurrence of hepatic steatosis after pancreatectomy is known to be associated with the remnant pancreatic function. However, other risk factors for hepatic steatosis after pancreatectomy remain unknown. The aims of this study were to identify other risk factors in addition to the remnant pancreatic function and elucidate the relationship between postoperative hepatic steatosis and pancreatic exocrine insufficiency in totally pancreatomized patients. METHODS: Forty-three patients who underwent total pancreatectomy were analyzed. Hepatic steatosis was defined as the attenuation of unenhanced computed tomography values. Clinical findings and laboratory data were compared between patients with and without hepatic steatosis. RESULTS: Sixteen (37.2%) patients developed hepatic steatosis after total pancreatectomy, with marked declines in the Controlling Nutritional Status score and body mass index. Multiple linear regression analysis revealed that the attenuation of computed tomography values was correlated with female sex (P = 0.002), early postoperative serum albumin levels (P = 0.003), and pancreatic enzyme replacement therapy with high-dose pancrelipase (P = 0.032). CONCLUSIONS: Postoperative hepatic steatosis after pancreatectomy is associated with sex, malnutrition, and pancreatic exocrine insufficiency. High-dose pancreatic enzyme replacement therapy may have preventive effects on hepatic steatosis occurring after pancreatectomy. PMID- 26495777 TI - Pancreatic Exocrine Insufficiency in Patients With Pancreatic or Periampullary Cancer: A Systematic Review. AB - OBJECTIVES: The aim of this study was to determine the prevalence of pancreatic exocrine insufficiency in patients with pancreatic or periampullary cancer, both before and after resection. METHODS: Systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines). We included studies reporting on pancreatic exocrine insufficiency in patients with pancreatic or periampullary cancer. Data on patient demographics, type of pancreatic resection, diagnostic test, and occurrence of pancreatic exocrine insufficiency were extracted. Prevalence of pancreatic exocrine insufficiency was calculated before and after pancreatic resections and in patients with locally advanced pancreatic cancer. RESULTS: Nine observational cohort studies with 693 patients were included. Median preoperative prevalence of pancreatic exocrine insufficiency was 44% (range, 42%-47%) before pancreatoduodenectomy, 20% (range, 16%-67%) before distal pancreatectomy, 63% before total pancreatectomy, and 25% to 50% in patients with locally advanced pancreatic cancer. The median prevalence of pancreatic exocrine insufficiency at least 6 months after pancreatoduodenectomy was 74% (range, 36%-100%) and 67% to 80% after distal pancreatectomy. CONCLUSION: Pancreatic exocrine insufficiency is diagnosed in approximately half of all patients scheduled to undergo resection for pancreatic or periampullary cancer. The prevalence increases markedly after resection. These data highlight the need of pancreatic enzyme suppletion in these patients. PMID- 26495778 TI - Relationships Between Fasting Serum Amylase and Ghrelin or Peptide YY3-36 Levels in Healthy Men. AB - OBJECTIVES: Appetite and carbohydrate metabolism are important contributors to the development of obesity. Recently, low serum amylase was shown to be associated with obesity and metabolic disorder. We investigated the relationship between amylase and ghrelin or peptide YY (PYY) levels in healthy men. METHODS: Twenty-one men were enrolled in this cross-sectional study; all subjects were asymptomatic with no medical history. Fasting serum amylase, ghrelin, PYY3-36, anthropometry, and nutritional intake were measured. Linear regression analyses were performed to examine associations between amylase and ghrelin or PYY3-36. RESULTS: The mean (SD) age and waist circumference of the subjects were 51.5 (10.9) years and 87.0 (4.4) cm, respectively. Amylase was found to be correlated with waist circumference (r = -0.438, P = 0.054), ghrelin (r = 0.533, P = 0.015), and PYY3-36 (r = -0.511, P = 0.021). Multivariate linear regression analysis revealed a negative association between amylase and PYY3-36 (beta = -0.428, P = 0.045) but a nonsignificantly positive association between amylase and ghrelin (beta = 0.260, P = 0.146). CONCLUSIONS: Amylase levels were found to be associated with ghrelin and PYY3-36 in healthy men. Amylase, ghrelin, and PYY3-36 may play a role in obesity; further research is required to identify the underlying mechanism. PMID- 26495781 TI - Low Stromal Area and High Stromal Microvessel Density Predict Poor Prognosis in Pancreatic Cancer. AB - OBJECTIVES: Excessive stroma is a unique property of cancer tissue of the pancreas. The aim of this study was to analyze the relationship of cancer stromal area (SA) and tumor microvessel density (MVD) with prognostic and clinicopathological findings. METHODS: Pancreatic adenocarcinoma tissues obtained from 104 patients were subjected to cytokeratin 19 and CD31 double immunostaining to identify cancer cells and endothelial cells simultaneously. Stromal area and MVD were assessed in the same sections. Patients were divided into 2 groups for each analysis by the median value of the respective measure. RESULTS: Stromal area negatively correlated with MVD. The low SA group harbored more poorly differentiated carcinoma than the high SA group. Patients of the low SA group showed a higher incidence of hematogenous recurrence. As a consequence, patients in the low SA and the high MVD groups had poorer prognosis in terms of both disease-free survival and overall survival than their respective groups. Multivariate analysis showed that a low SA was an independent prognostic factor for disease-free and overall survival. CONCLUSIONS: Our data indicate that the stroma of pancreatic cancer may play an auxiliary role as a barrier to cancer cell invasion. The depletion of tumor stroma alone does not suppress pancreatic cancer progression. PMID- 26495779 TI - Robust Early Inflammation of the Peripancreatic Visceral Adipose Tissue During Diet-Induced Obesity in the KrasG12D Model of Pancreatic Cancer. AB - OBJECTIVES: Obesity increases the incidence of multiple types of cancer. Our previous work has shown that a high-fat, high-calorie diet (HFCD) leads to visceral obesity, pancreatic inflammation, and accelerated pancreatic neoplasia in KrasG12D (KC) mice. In this study, we aimed to investigate the effects of an HFCD on visceral adipose inflammation with emphasis on potential differences between distinct visceral adipose depots. METHODS: We examined the weight and visceral obesity in both wild-type and KC mice on either control diet (CD) or HFCD. After 3 months, mice were killed for histological examination. Multiplex assays were also performed to obtain cytokine profiles between different adipose depots. RESULTS: Both wild-type and KC mice on an HFCD exhibited significantly increased inflammation in the visceral adipose tissue, particularly in the peripancreatic fat (PPF), compared with animals on a CD. This was associated with significantly increased inflammation in the pancreas. Cytokine profiles were different between visceral adipose depots and between mice on the HFCD and CD. CONCLUSIONS: Our results clearly demonstrate that an HFCD leads to obesity and inflammation in the visceral adipose tissue, particularly the PPF. These data suggest that obesity-associated inflammation in PPF may accelerate pancreatic neoplasia in KC mice. PMID- 26495780 TI - Nab-Paclitaxel Plus S-1 Shows Increased Antitumor Activity in Patient-Derived Pancreatic Cancer Xenograft Mouse Models. AB - OBJECTIVES: To investigate the antitumor activity of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus S-1 in patient-derived pancreatic cancer xenograft mouse models and to explore biomarkers that could predict drug efficacy. METHODS: Ten patient-derived xenograft models were established. The third-generation tumor-bearing mice were randomized into 4 treatment groups: (1) control; (2) S-1; (3) nab-paclitaxel; (4) S-1 plus nab-paclitaxel. Resected tumors were tested by immunohistochemistry for the expression of thymidylate synthase, orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase (DPD), secreted protein that is acidic and rich in cysteine, human epidermal growth factor receptor 2 (HER2), collagen-1, and CD31. RESULTS: Tumor growth inhibition of the S-1 group, nab-paclitaxel group, and combination group was 69.52%, 86.63%, 103.56%, respectively (P < 0.05). The efficacy of S-1 is better in thymidylate synthase-negative, OPRT-positive, and DPD-negative tumors. The efficacy of nab-paclitaxel is better in HER2-positive tumors. Collagen-1 was decreased and CD31 was increased in tumors treated with nab-paclitaxel and S-1 plus nab-paclitaxel compared with control or S-1. CONCLUSIONS: This preclinical study showed that S-1 plus nab-paclitaxel exerted significantly better antitumor activity than S-1 or nab-paclitaxel alone. Thymidylate synthase, OPRT, and DPD were possibly biomarkers of S-1 and HER2 of nab-paclitaxel. PMID- 26495782 TI - Progression of Incidental Intraductal Papillary Mucinous Neoplasms of the Pancreas in Liver Transplant Recipients. AB - OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are premalignant pancreatic cysts commonly found incidentally. Immunosuppression accelerates carcinogenesis.Thus, we aimed to compare IPMN progression in liver transplant (LT) recipients on chronic immunosuppression to progression among an immunocompetent population. METHODS: We retrospectively assessed adult LT recipients between 2008 and 2014 for imaging evidence of IPMN. Diagnosis of IPMN was based on history, imaging, and cyst fluid analysis. The immunocompetent control group consisted of nontransplant patients from our pancreatic cyst surveillance program with IPMN under surveillance for greater than 12 months between 1997 and 2013. Four hundred fifty-four patients underwent LT in the study period and had cross-sectional imaging. RESULTS: The prevalence of suspected IPMN was 6.6% (30 of 454). Compared with 131 controls, the transplant cohort was younger, with increased prevalence of diabetes and smoking. The prevalence of other risk factors for IPMN progression (history of pancreatitis, family history of pancreatic cancer) was similar. After an average follow-up of 31 months, most cysts increased in diameter, with a similar increase of dominant cyst (0.4 cm vs 0.5 cm; P = 0.6). Type of immunosuppression was not associated with the increased rate of cyst growth. CONCLUSIONS: Our findings suggest that LT recipients with incidental IPMN can be managed under similar guidelines as immunocompetent patients. PMID- 26495783 TI - Combination of Telmisartan and Linagliptin Preserves Pancreatic Islet Cell Function and Morphology in db/db Mice. AB - OBJECTIVES: The present study aimed to investigate the synergistic action of telmisartan and linagliptin in ameliorating pancreatic islet functions and morphology in type 2 diabetes mellitus and to delineate the molecular signaling pathway involved. METHODS: db/db mice were given telmisartan (3 mg/kg) or linagliptin (3 mg/kg) alone or in combination, daily for 8 weeks, and were studied in vivo by fasting and random blood glucose tests, oral glucose tolerance tests, and intraperitoneal insulin tolerance tests, as well as ex vivo by glucose stimulated insulin secretion and morphology of pancreatic islets. The underlying signaling pathways were examined by Western blot, real-time quantitative polymerase chain reaction, and dihydroethidium staining analyses using mouse pancreatic islets and rat beta-insulinoma cells. RESULTS: Telmisartan/linagliptin combination induced significantly better glucose homeostasis than the monotherapies. Posttreatment reactive oxygen species level was suppressed most significantly after the telmisartan/linagliptin combined therapy, whereas no significant change in peroxisome proliferator-activated receptor gamma expressions was observed after treatments. CONCLUSIONS: The telmisartan/linagliptin combination preserved pancreatic islet cell functions and morphology via reduction of oxidative stress but independent of the peroxisome proliferator-activated receptor gamma pathway. Our data shed light on the therapeutic potential of using the telmisartan/linagliptin combination in the treatment of human type 2 diabetes mellitus and its related complications. PMID- 26495784 TI - Efficacy and Safety of Pancrelipase/Pancreatin in Patients With Exocrine Pancreatic Insufficiency and a Medical History of Diabetes Mellitus. AB - OBJECTIVES: The aim of this study was to perform exploratory analyses of the efficacy and safety of pancrelipase delayed-release capsules (Creon) in patients with exocrine pancreatic insufficiency (EPI) with (n = 36) and without (n = 18) concurrent diabetes mellitus (DM). METHODS: This was a retrospective, post hoc, subgroup (+/-DM) analysis of a double-blind, randomized, placebo-controlled trial of pancrelipase in patients with EPI due to chronic pancreatitis or pancreatectomy (total or partial). After a 5-day placebo run-in period (baseline), patients were randomized to pancrelipase (72,000 lipase units/meal, 36,000/snack) or placebo for 7 days. Outcomes included changes in coefficients of fat absorption (CFA) and nitrogen absorption (CNA) from baseline to the end of the double-blind period. RESULTS: Mean changes in nutrient absorption were greater with pancrelipase versus placebo in patients with DM (CFA, 36.0% vs 7.5%, P < 0.0001; CNA, 33.4% vs 3.7%, P = 0.0002) and without DM (CFA, 25.2% vs 12.3%, P = 0.0326; CNA, 39.1% vs 17.6%, P = 0.1187). Diabetes mellitus was not significantly associated with outcomes for CFA (P = 0.0802) and CNA (P = 0.2934). Incidences of adverse events, including hypoglycemia and hyperglycemia, were similar in the pancrelipase and placebo arms. CONCLUSIONS: Pancrelipase improved fat and protein absorption in patients with EPI due to chronic pancreatitis or pancreatectomy, with or without DM, and matched the safety profile previously reported. PMID- 26495785 TI - IL-8-Positive Tumor-Infiltrating Inflammatory Cells Are a Novel Prognostic Marker in Pancreatic Ductal Adenocarcinoma Patients. AB - OBJECTIVES: Tumor-infiltrating inflammatory cells (TIICs) in pancreatic ductal adenocarcinoma (PDAC) are reported to initiate and exacerbate invasion and metastasis. Interleukin-8 (IL-8), a proinflammatory cytokine, is expressed in both neoplastic cells and TIICs in PDAC tissues and increased in patient serum. The aim of this study is to evaluate the values of IL-8 expression profiles in tumor tissues and predict the source of serum IL-8 in PDAC patients. METHODS: We used 2 independent groups of PDAC patient samples that included 240 cases. Tissue expression profiles of cytokines were evaluated with immunohistochemistry and serum levels with human IL-8 assay. The prognostic values of the variables were assessed by Kaplan-Meier or Cox regression analysis. RESULTS: Higher levels of IL 8-positive TIICs but not tumor cells in PDAC patients correlated with worse prognosis (P = 0.009) and higher blood serum IL-8 levels (P = 0.002). Controlling other independent factors, the relative hazard ratio for PDAC with higher IL-8 positive TIIC levels compared with those with lower TIIC levels was 1.588 (95% confidence interval, 1.04-2.42). CONCLUSIONS: Higher IL-8-positive TIIC levels in PDAC tumors indicate poorer prognosis and positively correlate with serum IL-8 concentrations and vice versa. These data suggested that IL-8 might have a potential target for PDAC therapies. PMID- 26495786 TI - Glucagon-Like Peptide-1 Receptor Expression in Normal and Neoplastic Human Pancreatic Tissues. AB - OBJECTIVES: Studies have proposed pro-oncogenic effects of glucagon-like peptide 1 receptor (GLP-1R) agonists in the pancreas by promoting GLP-1R overactivation in pancreatic cells. However, the expression of GLP-1R in normal and neoplastic pancreatic cells remains poorly defined, and reliable methods for detecting GLP 1R in tissue specimens are needed. METHODS: We used RNA in situ hybridization to quantify glp-1r RNA in surgically resected human pancreatic specimens, including pancreatic ductal adenocarcinoma (PDAC), preinvasive intraepithelial lesions (pancreatic intraepithelial neoplasia), and non-neoplastic ductal, acinar, and endocrine cells. A mixed-effect linear regression model was used to investigate the relationship between glp-1r signals and all cells, ordered by increasing grade of dysplasia. RESULTS: All cell types had evidence of glp-1r transcripts, with the highest expression in endocrine cells and lowest in ductal cells. The slope of the fitted line was not significantly different from zero (0.07; 95% confidence interval, -0.0094 to 0.244; P = 0.39), suggesting that progression from normal cells to PDAC is not associated with a parallel increase in glp-1r RNA. A series of pairwise comparisons between all cell types with respect to their glp-1r expression showed no significant difference in glp-1r in cancer, pancreatic intraepithelial neoplasia, and acinar and ductal cells. CONCLUSIONS: Our study supports the lack of evidence for GLP-1R overexpression in PDAC. PMID- 26495787 TI - Microscopic Residual Tumor After Pancreaticoduodenectomy: Is Standardization of Pathological Examination Worthwhile? AB - OBJECTIVES: R1 resection rate after pancreaticoduodenectomy (PD) for cancer is highly variable. The aim of this study was to verify if a standardized histopathological work-up of the specimen affects the rate of R1 resection after PD for cancer. METHODS: Two groups of specimens were managed with (standardized method [SM] group) or without (non-standardized method [NSM] group) a SM of histopathological work-up. Each group included 50 cases of PD for periampullary cancer. Differences in terms of R1 resection rate between the 2 groups were evaluated. Correlation between R1 status and local recurrence was also evaluated. RESULTS: The cohort of 100 patients consisted of 66 pancreatic ductal adenocarcinoma, 15 cholangiocarcinoma, and 19 ampullary cancer. The R1 resection rate resulted statistically higher in the SM group (66% vs 10%). Local recurrence was more frequently related to R1 resection in the SM group (34.3% of cases) than in NSM group (20% of cases). CONCLUSIONS: The use of the SM of pathological evaluation of the specimen after PD for cancer determines a significant increase of R1 resection. This remarkable difference seems to be due to the different definition of minimum clearance. The SM seems to better discriminate patients in terms of risk of local recurrence. PMID- 26495788 TI - FAM111B Mutation Is Associated With Inherited Exocrine Pancreatic Dysfunction. AB - OBJECTIVES: Few genetic causes of exocrine pancreatic dysfunction have been described to date. We identified a family with multiple affected members manifesting exocrine pancreatic dysfunction. Additional associated features included facial rash, sparse hair, hypohidrosis, and swelling of the extremities. The transmission pattern of these clinical features was consistent with an autosomal dominant mode of inheritance. The 2 proband siblings also had transient elevated liver transaminases with hepatic steatosis early in life. This study identifies the genetic cause of exocrine pancreatic dysfunction in this family. METHODS: Whole exome sequencing was performed to identify the genetic cause of exocrine pancreatic dysfunction. RESULTS: A heterozygous germline in-frame deletion in the gene FAM111B (c.1261_1263delAAG, p.Lys421del) cosegregated with the phenotype: the variant was present in all affected relatives genotyped and absent in all unaffected relatives genotyped. The variant is also absent from public control sequence databases. CONCLUSIONS: Our findings implicate FAM111B in autosomal dominantly inheritable exocrine pancreatic dysfunction. PMID- 26495789 TI - Variability in Pancreatitis Care in Pediatrics: A Single Institution's Survey Report. AB - OBJECTIVE: The incidence of acute pancreatitis (AP) in childhood has increased in the last 2 decades, yet management has been largely extrapolated from adult studies. We sought to determine whether there is a consensus for treatment of AP among different pediatric subspecialists. METHODS: Providers from subspecialties seeing most patients admitted for AP were surveyed on their practice patterns in managing a first attack of uncomplicated AP. RESULTS: From November 2009 to August 2013, there were 284 admissions for patients with AP to our center. Patients were primarily admitted to the gastroenterology or hospitalist service (39% and 26%, respectively). Survey results found practice patterns for diagnostic evaluation, fluid resuscitation, pain management, and introduction of nutrition were variable between practitioners belonging to different subspecialties as well as within the same subspecialty group. CONCLUSIONS: There is a lack of consensus on management of acute uncomplicated pancreatitis among pediatric providers, which may be improved through development of evidence-based pediatric guidelines. PMID- 26495790 TI - Interplay Between Gemcitabine and Erlotinib Over Pancreatic Adenocarcinoma Cells. AB - OBJECTIVES: Pancreatic ductal adenocarcinoma remains as a chemoresistant disease with the poorest prognosis. Gemcitabine has been the standard treatment during the last decade. Erlotinib, a tyrosine kinase inhibitor, in combination with gemcitabine produces a small increase in survival. However, these results remain insufficient. The aim of this study was to investigate the molecular interplay in vitro between them regarding their effects over cytotoxicity, proliferation, apoptosis, and invasion. METHODS: Using the human pancreatic cancer cell lines Panc-1 and BxPC-3 in vitro, the effects of gemcitabine and erlotinib therapy on growth, proliferation, and invasion were tested by cytotoxicity, cell cycle, and Annexin V-Fluorescein Isothiocyanate analysis, reverse transcription polymerase chain reaction, protein expression, and Chip assays. RESULTS: Therapy decreased cell proliferation causing G0/G1 phase cell cycle arrest with induction of apoptosis in the Panc-1 cell line. This blockade was associated with increased p27 expression. Besides, treatments enhanced the nuclear factor-kappaB (NF kappaB) pathway and the binding of NF-kappaB to the promoters of genes related to the proliferation and the evasion of apoptosis. CONCLUSIONS: Our data suggest that, although gemcitabine and erlotinib exert antiproliferative effects over pancreatic cancer cell lines, the gemcitabine-induced activation of NF-kappaB expression and its DNA-binding activities are important drawbacks of this treatment against pancreatic cancer. PMID- 26495791 TI - Apoptotic Mechanisms of Peroxisome Proliferator-Activated Receptor-gamma Activation in Acinar Cells During Acute Pancreatitis. AB - OBJECTIVE: The objective of this study was to determine the mechanism by which activation of peroxisome proliferator-activated receptor-gamma promotes apoptosis of acinar cells in pancreatitis. METHODS: AR42j cells pretreated with the peroxisome proliferator-activated receptor-gamma agonist pioglitazone were activated by cerulein as an in vitro model of acute pancreatitis. Inflammatory cytokines and amylase were detected by enzyme-linked immunosorbent assay. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis was measured by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Activity of caspases was determined. Bax and Bcl-2 levels were assayed by Western blot. RESULTS: Cytokines, amylase, and cellular proliferation decreased in pioglitazone pretreated cells. Pioglitazone increased the activity of caspases 3, 8, and 9 in cerulein-activated AR42j cells as well as in the pancreas of rats 3 hours after induction of severe acute pancreatitis. Acinar cell apoptosis was induced by reducing the mitochondrial membrane potential in the pioglitazone group. Pioglitazone increased expression of proapoptotic Bax proteins and decreased antiapoptotic Bcl-2 in cerulein-induced AR42j cells and decreased Bcl-2 levels in pancreatic tissue of severe acute pancreatitis rats 1 and 3 hours after induction. CONCLUSION: Pioglitazone may promote apoptosis of acinar cells through both intrinsic and extrinsic apoptotic pathways in acute pancreatitis. PMID- 26495792 TI - Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model. AB - OBJECTIVES: Progranulin (PGRN) promotes cell growth and cell cycle progression in several cell types and contributes to tumorigenesis in diverse cancers. We have recently reported PGRN expression in islets and tumors developed in an MEN1 transgenic mouse. Here we sought to investigate PGRN expression and regulation after exposure to hypoxia as well as its effects on pancreatic islet cells and neuroendocrine tumors (NETs) in MEN1(+/-) mice. METHODS: Gene and protein expression were analyzed by quantitative polymerase chain reaction, immunohistochemistry, and Western blot. We also investigated PGRN expression in samples from patients carrying pancreatic NETs associated or not with the multiple endocrine neoplasia 1 syndrome, using enzyme-linked immunosorbent assay and immunohistochemistry analysis. RESULTS: Progranulin is upregulated in tumors and islets of the MEN1 mouse as well as in the serum of patients with pancreatic NETs associated with glucagonoma syndrome. In normal mice islets and pancreatic tumors, PGRN expression was strongly potentiated by hypoxia. Progranulin promotes cell proliferation in islet cells and betaTC-6 cells, a process paralleled by activation of the mitogen-activated protein kinase signaling cascade. CONCLUSIONS: Our findings identify PGRN as an effective inducer of pancreatic islet cell proliferation and a possible important factor for pancreatic endocrine tumor development. PMID- 26495793 TI - Synthetic Triterpenoid RTA dh404 (CDDO-dhTFEA) Ameliorates Acute Pancreatitis. AB - OBJECTIVES: Nuclear factor-erythroid-2-related factor (Nrf2) is a ubiquitous transcriptional factor that regulates expression of cellular antioxidant and detoxifying molecules. This study was undertaken to test the hypothesis that administration of the Nrf2 activator (dh404) may attenuate acute pancreatitis. METHODS: Rats were treated with dh404 (1 mg/kg) 24 hours before induction of pancreatitis and for 3 days thereafter. Pancreatitis was induced with L-arginine (600 mg/100 g) or cerulein (40 MUg/kg). Pancreases were processed for histology and malondialdehyde, whereas serum was analyzed for amylase. Islet extracted human pancreatic tissue from organ donors were used for in vitro studies. The tissues were incubated with dh404 at 0, 250, and 500 nM for 30 minutes, 60 minutes, 12 hours, and 24 hours. Nuclear factor-erythroid-2-related factor nuclear translocation and expression of Nrf2's target genes and inflammatory mediators were determined. RESULTS: The dh404-treated rat pancreases demonstrated significantly less infiltration of inflammatory cells, destruction of acinar architecture, perilobar edema, and necrosis. Serum amylase and pancreatic malondialdehyde in the dh404-treated rats were significantly lower. dh404-treated human pancreatic tissue showed a significantly higher expression of antioxidant enzymes, lower expression of inflammatory mediators, and greater viability against oxidative stress. CONCLUSION: Administration of dh404 attenuates acute pancreatitis by lowering oxidative stress and reducing proinflammatory mediators. PMID- 26495795 TI - Symptoms of Pancreatic Cancer in Primary Care: A Systematic Review. AB - OBJECTIVES: The aim of this study was to quantify the risk of pancreatic cancer in patients presenting in primary care with symptoms that may indicate pancreatic cancer. METHODS: We searched MEDLINE, PreMEDLINE, EMBASE, the Cochrane Library, Web of Science, and ISI Proceedings (1980 to August 2014) and PsychINFO (1980 to May 2013) for diagnostic studies of symptomatic adult patients in primary care. Study quality was assessed using QUADAS-II, and data were extracted to calculate the positive predictive values (PPVs) of symptoms, singly or in combination, for pancreatic cancer. RESULTS: Eight studies with 3,438,363 patients were included. The PPV of jaundice was more than 4.1% in patients 40 years or older and increased with age, although only 30% of patients reported jaundice. The PPVs of other single symptoms were low, with the highest PPV being 1% for repeated attendance with abdominal pain in patients 60 years or older. Excluding jaundice, symptom combinations with high PPVs were those including weight loss, ranging from 1.5% to 2.7% in patients 60 years or older, apart from when weight loss was combined with malaise (PPV, 0.9%). CONCLUSION: The only high-risk feature of pancreatic cancer in primary care was jaundice, and this clearly warrants investigation. Weight loss accompanied by a second symptom may warrant investigation, although this would probably require abdominal computed tomography. PMID- 26495794 TI - Parathyroid Hormone-Related Protein Interacts With the Transforming Growth Factor beta/Bone Morphogenetic Protein-2/Gremlin Signaling Pathway to Regulate Proinflammatory and Profibrotic Mediators in Pancreatic Acinar and Stellate Cells. AB - OBJECTIVES: Transforming growth factor beta (TGF-beta) regulates immune and fibrotic responses of chronic pancreatitis. The bone morphogenetic protein 2 (BMP 2) antagonist gremlin is regulated by TGF-beta. Parathyroid hormone-related protein (PTHrP) levels are elevated in chronic pancreatitis. Here, we investigated the cross-talk between TGF-beta/BMP-2/gremlin and PTHrP signaling. METHODS: Reverse transcription/real-time polymerase chain reaction, chromatin immunoprecipitation, Western blotting, and transient transfection were used to investigate PTHrP regulation by TGF-beta and BMP-2 and gremlin regulation by PTHrP. The PTHrP antagonist PTHrP (7-34) and acinar cells with conditional Pthrp gene deletion (PTHrP) were used to assess PTHrP's role in the proinflammatory and profibrotic effects of TGF-beta and gremlin. RESULTS: Transforming growth factor beta increased PTHrP levels in acinar cells and pancreatic stellate cells (PSCs) through a Smad3-dependent pathway. Transforming growth factor beta's effects on levels of IL-6 and intercellular adhesion molecule 1 (ICAM-1) (acinar cells) and procollagen I and fibronectin (PSCs) were inhibited by PTHrP (7-34). PTHrP suppressed TGF-beta's effects on IL-6 and ICAM-1. Parathyroid hormone-related hormone increased gremlin in acinar cells, and inhibiting gremlin action suppressed TGF-beta's and PTHrP's effects on IL-6 and ICAM-1. Transforming growth factor beta-mediated gremlin up-regulation was suppressed in PTHrP cells. Bone morphogenetic protein 2 suppressed PTHrP levels in PSCs. CONCLUSIONS: Parathyroid hormone-related hormone functions as a novel mediator of the proinflammatory and profibrotic effects of TGF-beta. Transforming growth factor beta and BMP-2 regulate PTHrP expression, and PTHrP regulates gremlin levels. PMID- 26495796 TI - Optical Imaging of Drug-Induced Metabolism Changes in Murine and Human Pancreatic Cancer Organoids Reveals Heterogeneous Drug Response. AB - OBJECTIVES: Three-dimensional organoids derived from primary pancreatic ductal adenocarcinomas are an attractive platform for testing potential anticancer drugs on patient-specific tissue. Optical metabolic imaging (OMI) is a novel tool used to assess drug-induced changes in cellular metabolism, and its quantitative end point, the OMI index, is evaluated as a biomarker of drug response in pancreatic cancer organoids. METHODS: Optical metabolic imaging is used to assess both malignant cell and fibroblast drug response within primary murine and human pancreatic cancer organoids. RESULTS: Anticancer drugs induce significant reductions in the OMI index of murine and human pancreatic cancer organoids. Subpopulation analysis of OMI data revealed heterogeneous drug response and elucidated responding and nonresponding cell populations for a 7-day time course. Optical metabolic imaging index significantly correlates with immunofluorescence detection of cell proliferation and cell death. CONCLUSIONS: Optical metabolic imaging of primary pancreatic ductal adenocarcinoma organoids is highly sensitive to drug-induced metabolic changes, provides a nondestructive method for monitoring dynamic drug response, and presents a novel platform for patient specific drug testing and drug development. PMID- 26495797 TI - The 10 Pillars of Lung Cancer Screening: Rationale and Logistics of a Lung Cancer Screening Program. AB - On the basis of the National Lung Screening Trial data released in 2011, the U.S. Preventive Services Task Force made lung cancer screening (LCS) with low-dose computed tomography (CT) a public health recommendation in 2013. The Centers for Medicare and Medicaid Services (CMS) currently reimburse LCS for asymptomatic individuals aged 55-77 years who have a tobacco smoking history of at least 30 pack-years and who are either currently smoking or had quit less than 15 years earlier. Commercial insurers reimburse the cost of LCS for individuals aged 55-80 years with the same smoking history. Effective care for the millions of Americans who qualify for LCS requires an organized step-wise approach. The 10-pillar model reflects the elements required to support a successful LCS program: eligibility, education, examination ordering, image acquisition, image review, communication, referral network, quality improvement, reimbursement, and research frontiers. Examination ordering can be coupled with decision support to ensure that only eligible individuals undergo LCS. Communication of results revolves around the Lung Imaging Reporting and Data System (Lung-RADS) from the American College of Radiology. Lung-RADS is a structured decision-oriented reporting system designed to minimize the rate of false-positive screening examination results. With nodule size and morphology as discriminators, Lung-RADS links nodule management pathways to the variety of nodules present on LCS CT studies. Tracking of patient outcomes is facilitated by a CMS-approved national registry maintained by the American College of Radiology. Online supplemental material is available for this article. PMID- 26495798 TI - Imaging Acute Airway Obstruction in Infants and Children. AB - Acute airway obstruction is much more common in infants and children than in adults because of their unique anatomic and physiologic features. Even in young patients with partial airway occlusion, symptoms can be severe and potentially life-threatening. Factors that predispose children to airway compromise include the orientation of their larynx, the narrow caliber of their trachea, and their weak intercostal muscles. Because the clinical manifestations of acute airway obstruction are often nonspecific, clinicians often rely on the findings at imaging to establish a diagnosis. Several key anatomic features of the pediatric airway make it particularly susceptible to respiratory distress, and the imaging recommendations for children suspected of having acute airway obstruction are presented. Although cross-sectional imaging may be helpful, the diagnosis can often be established by using radiographs alone. Radiographs of the chest and upper airway should be routinely acquired; however, for the child who is in severe distress, a single lateral radiographic view may be all that is necessary. The purpose of this article is to provide an imaging approach to acquired causes of acute airway obstruction in children, including (a) abnormalities affecting the upper portion of the airway, such as croup, acute epiglottitis, retropharyngeal infection, and foreign bodies, and (b) abnormalities affecting the lower portion of the airway, such as asthma, bronchiolitis, and foreign bodies. It is essential that the radiologist recognize key imaging findings and understand the pathophysiologic features of acute airway obstruction because in most cases, when the cause is identified, the condition responds well to prompt management. PMID- 26495799 TI - Meta-Analysis of Efficacy and Safety of Apixaban in Patients Undergoing Catheter Ablation for Atrial Fibrillation. AB - BACKGROUND: The efficacy and safety of apixaban in patients undergoing catheter ablation (CA) for atrial fibrillation (AF) are little investigated. METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE were searched up to September 2015. Four literatures comparing apixaban with vitamin K antagonists (VKAs) were included. Data were pooled in Review Manager Software, using Mantel-Haenszel methods with a fixed-effects model. The funnel plots and Egger's test were used to examine publication bias. Heterogeneity was assessed using the I(2) test. Risk ratios (RR) and 95% confidence intervals (CI) of each study were calculated and pooled. RESULTS: No significant differences were observed in rates of total bleeding (RR = 0.91, 95% CI [0.57, 1.46], I(2) = 0.0%), thromboembolic complications (RR = 0.75, 95% CI [0.03, 18.22], I(2) = 0.0%), or total events (RR = 0.90, 95% CI [0.56, 1.44], I(2) = 0.0%) between apixaban and VKAs group. The frequency of major bleeding was similar between apixaban and VKAs group (RR = 1.34, 95% CI [0.34, 5.30], I(2) = 0.0%). CONCLUSION: Apixaban was as effective and safe as VKAs in the periprocedural period of CA. PMID- 26495800 TI - Prevalence, awareness, and burden of major depressive disorder in urban China. AB - OBJECTIVES: This cross-sectional study examined the prevalence and burden of major depressive disorder (MDD) among adults in urban China. METHODS: Data were included from the 2012 China National Health and Wellness Survey. Respondents self-reporting physician diagnosis of depression and screening positive for MDD (Patient Health Questionnaire-9), plus those screening positive for MDD, but undiagnosed and not experiencing depression, were compared with non-depressed controls. Outcomes included health-related quality of life (HRQoL), productivity loss, and resource utilization. Multivariable models assessed outcomes as a function of MDD, controlling for covariates. RESULTS: MDD prevalence was 6.0%; only 8.3% of these respondents were diagnosed, among whom 51.5% currently used prescription medication for depression. Adults with MDD (diagnosed or undiagnosed) reported significantly poorer HRQoL and greater productivity loss and resource utilization than controls. CONCLUSIONS: MDD in urban China may be under-diagnosed and undertreated. Awareness and better access to treatments may help alleviate the burden of MDD. PMID- 26495801 TI - Perspectives on cytokine-directed therapies in multiple sclerosis. AB - Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). Over the past 10 years there has been a heated debate as to whether MS pathogenesis commences in the CNS or whether it is actually primarily a disease of the immune system. The combined clinical data, therapy responses, pathology, animal models and genetic studies now provide overwhelming support for the concept that MS is a disease of the immune system and that the CNS is only the unfortunate target of a misguided immune attack. Immune cells communicate through the use of cytokines and these proteins can orchestrate the most complex behaviour in immune cells. We propose that MS is a disease where immune communication is derailed, which makes MS very amenable to immunotherapy and in particular makes cytokines an attractive target to repair this miscommunication disorder. PMID- 26495802 TI - Statin protects endothelial cell against ischemia reperfusion injury through HMGB1/TLR4 pathway. PMID- 26495803 TI - A confluence of circumstances: A case of IVF, extreme exercise and spontaneous coronary artery dissection. PMID- 26495805 TI - Synergistic Amination of Graphene: Molecular Dynamics and Thermodynamics. AB - Functionalization of graphene using organic moieties constitutes an affordable way to modulate its physical and chemical properties. Finding an exact structural formula of functionalized graphene using experimental approaches is challenging. We studied in detail the thermal stability and thermodynamics of amino- and ethylamino-graphene and found a surprising synergistic effect: more amino groups stabilize functionalized graphene favoring further amination, whereas a small concentration of amino groups is unstable in many cases. The functional groups can be attached either on the same side or simultaneously on different sides of the graphene sheet. Deformation of functionalized graphene is proportional to the number of amino groups. Complete amination leading to formation of the ultimate product, Cx(NH2)x, is hindered sterically. Our study assists in the determination of the structure of chemically modified graphene and makes specific predictions that can be tested and validated experimentally. PMID- 26495804 TI - Coronary CT angiography in calcified coronary plaques: Comparison of diagnostic accuracy between bifurcation angle measurement and coronary lumen assessment for diagnosing significant coronary stenosis. AB - BACKGROUND: To investigate the diagnostic value of coronary CT angiography (CCTA) by bifurcation angle measurement in the assessment of calcified plaques compared to conventional coronary lumen analysis. METHODS: Fifty-three patients with calcified plaques identified on CCTA in the left coronary artery were included in the study. Minimal lumen diameter (MLD) and bifurcation angle between the left anterior descending (LAD) and left circumflex (LCx) arteries were measured and compared between CCTA and invasive coronary angiography (ICA), while the areas under the curves (AUCs) by receiver-operating characteristic curve analysis (ROC) were compared between CCTA and ICA with regard to the diagnostic value of using bifurcation angle as a criterion. RESULTS: On a per-vessel assessment, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) and 95% confidence interval (CI) with the use of bifurcation angle for determining coronary stenosis were 100% (86%, 100%), 79% (59%, 92%), 81% (62%, 92%), and 100% (85%, 100%) for CCTA, and 100% (86%, 100%), 82% (63%, 94%), 83% (65%, 94%), and 100% (85%, 100%) for ICA, respectively. While the sensitivity and NPV remained unchanged, the specificity and PPV of CCTA by MLD were 33% (21%, 47%) and 43% (31%, 56%). The AUCs by ROC curve analysis for CCTA and ICA bifurcation angle measurements demonstrated no significant difference (p>0.05, 0.79 vs 0.86, and 0.70 vs 0.68 at the LAD and LCx assessment, respectively). CONCLUSION: Coronary CT angiography by bifurcation angle measurement shows significant improvement in the diagnosis of calcified plaques with diagnostic value comparable to invasive coronary angiography. PMID- 26495806 TI - Monitoring and evaluating the quality of cancer care in Japan using administrative claims data. AB - The importance of measuring the quality of cancer care has been well recognized in many developed countries, but has never been successfully implemented on a national level in Japan. We sought to establish a wide-scale quality monitoring and evaluation program for cancer by measuring 13 process-of-care quality indicators (QI) using a registry-linked claims database. We measured two QI on pre-treatment testing, nine on adherence to clinical guidelines on therapeutic treatments, and two on supportive care, for breast, prostate, colorectal, stomach, lung, liver and cervical cancer patients who were diagnosed in 2011 from 178 hospitals. We further assessed the reasons for non-adherence for patients who did not receive the indicated care in 26 hospitals. QI for pretreatment testing were high in most hospitals (above 80%), but scores on adjuvant radiation and chemoradiation therapies were low (20-37%), except for breast cancer (74%). QI for adjuvant chemotherapy and supportive care were more widely distributed across hospitals (45-68%). Further analysis in 26 hospitals showed that most of the patients who did not receive adjuvant chemotherapy had clinically valid reasons for not receiving the specified care (above 70%), but the majority of the patients did not have sufficient reasons for not receiving adjuvant radiotherapy (52-69%) and supportive care (above 80%). We present here the first wide-scale quality measurement initiative of cancer patients in Japan. Patients without clinically valid reasons for non-adherence should be examined further in future to improve care. PMID- 26495807 TI - Quantitative profiling of tissue drug distribution by MS imaging. AB - This article highlights recent advancements in the quantitative measurement of drug distribution by MS imaging (MSI). Quantitation by MSI was recently considering the primary disadvantage of MSI approaches particularly when compared with widely used autoradiography techniques. These approaches show significant progress in the area of quantitative MSI and have been used in numerous drug and metabolite distribution measurements. As quantitative limitations are overcome, the use of MSI in drug development should increase significantly providing key insights into both tissue-target validation as well as identifying off tissue target issues with drug delivery. PMID- 26495808 TI - Development of an ellipse fitting method with which to analyse selected area electron diffraction patterns. AB - A software method has been developed which uses ellipse fitting to analyse electron diffraction patterns from polycrystalline materials. The method, which requires minimal user input, can determine the pattern centre and the diameter of diffraction rings with sub-pixel precision. This enables accurate crystallographic information to be obtained in a rapid and consistent manner. Since the method fits ellipses, it can detect, quantify and correct any elliptical distortion introduced by the imaging system. Distortion information derived from polycrystalline patterns as a function of camera length can be subsequently recalled and applied to single crystal patterns, resulting in improved precision and accuracy. The method has been implemented as a plugin for the DigitalMicrograph software by Gatan, and is a freely available via the internet. PMID- 26495809 TI - Determination of Apparent Amylose Content in Rice by Using Paper-Based Microfluidic Chips. AB - Determination of apparent amylose content in rice is a key function for rice research and the rice industry. In this paper, a novel approach with paper-based microfluidic chip is reported to determine apparent amylose content in rice. The conventional color reaction between amylose and iodine was employed. Blue color of amylose-iodine complex generated on-chip was converted to gray and measured with Photoshop after the colored chip was scanned. The method for preparation of the paper chip is described. In situ generation of iodine for on-chip color reaction was designed, and factors influencing color reaction were investigated in detail. Elimination of yellow color interference of excess iodine by exploiting color removal function of Photoshop was presented. Under the optimized conditions, apparent amylose content in rice ranging from 1.5 to 26.4% can be determined, and precision was 6.3%. The analytical results obtained with the developed approach were in good agreement with those with the continuous flow analyzer method. PMID- 26495810 TI - Transverse Myelitis and Syrinx Formation Caused by Varicella-Zoster Infection. PMID- 26495811 TI - Re: "Kinesio Taping Improves Pain, Range of Motion, and Proprioception in Older Patients with Knee Osteoarthritis: A Randomized Controlled Trial". PMID- 26495813 TI - Recovery of an Injured Cingulum via the Lateral Cholinergic Pathway in a Patient with Traumatic Brain Injury. AB - We report on a patient with traumatic brain injury who showed recovery of an injured cingulum via the lateral cholinergic pathway, using diffusion tensor tractography (DTT). A 63-year-old man underwent craniotomy for subarachnoid hemorrhage and subdural hemorrhage in both frontotemporal lobes, which occurred by hitting his head against a floor after falling from approximately 2 m. The Wechsler Intelligence Scale and the Seoul neuropsychological screening battery were used for evaluation of cognitive function. At 4 weeks after onset, the patient exhibited mild cognitive impairment (total IQ, 85; verbal immediate recall, 26.76 percentile; visual immediate recall, 29.81 percentile; verbal delayed recall, 24.51 percentile; visual delayed recall, 11.70 percentile). By contrast, at the 9-month evaluation, the cognitive impairment had improved as much as total IQ, 96; verbal immediate recall, 56.75 percentile; visual immediate recall, 89.49 percentile; verbal delayed recall, 78.23 percentile; and visual delayed recall, 89.07 percentile. On 4-week DTT, discontinuations were observed superior to the genu of the corpus callosum in both cingula. However, on 9-month DTT, the discontinued anterior part of the right cingulum was elongated inferoposteriorly through an unusual neural tract, which ran through the external capsule and the white matter of the temporo-occipital lobes. The results of this study seem to suggest a mechanism for recovery of an injured cingulum after brain injury. PMID- 26495812 TI - Intervertebral Disc Cells Produce Interleukins Found in Patients with Back Pain. AB - OBJECTIVE: To examine the link between cytokines in intervertebral disc (IVD) tissues and axial back pain. DESIGN: In vitro study with human IVD cells cultured from cadaveric donors and annulus fibrosus (AF) tissues from patients. RESULTS: Cultured nucleus pulposus (NP) and AF cells were stimulated with interleukin (IL) 1beta. IL-8 and IL-7 gene expression was analyzed using real-time polymerase chain reaction. IL-8 protein was quantified by enzyme-linked immunosorbent assay. After IL-1beta stimulation, IL-8 gene expression increased 26,541 fold in NP cells and 22,429 fold in AF cells, whereas protein released by the NP and AF cells increased 2,389- and 1,784-fold, respectively. IL-7 gene expression increased 3.3-fold in NP cells (P < 0.05).Cytokine profiles in AF tissues collected from patients undergoing surgery for back pain (painful group) or scoliosis (controls) were compared by cytokine array. IL-8 protein in the AF tissues from patients with back pain was 1.81-fold of that in controls. IL-7 and IL-10 in AF tissues from the painful group were 6.87 and 4.63 times greater than the corresponding values in controls, respectively (P < 0.05). CONCLUSION: Inflammatory mediators found in AF tissues from patients with discogenic back pain are likely produced by IVD cells and may play a key role in back pain. PMID- 26495814 TI - Pelvic and Spinal Motion During Walking in Persons With Transfemoral Amputation With and Without Low Back Pain. AB - OBJECTIVE: Low back pain (LBP) is prevalent in people with transfemoral amputation (TFA), imposing significant disability. Yet, limited data exist describing spine kinematics in people with and without LBP despite the suggestion that gait adaptations required to walk with a prosthesis may be associated or causative of LBP. Hence, the purpose of this study was to determine if there were any differences in pelvic and spinal kinematics in persons with TFA with and without LBP. DESIGN: With the use of a lower body model combined with a regional spine model, pelvic, lumbar, and thoracic kinematics were recorded while walking and compared for participants with TFA with (n = 12) and without (n = 11) self reported LBP. RESULTS: Opposite patterns of motion were observed between groups in sagittal and transverse lumbar kinematics but inferential analysis using the chi test was unable to confirm that these differing patterns were independently related to LBP. CONCLUSIONS: For community ambulators with TFA who report low levels of LBP, differences in lumbar and thoracic motion do not seem to be independently related to LBP. Results may not generalize to those with higher levels of LBP and associated disability. PMID- 26495815 TI - What Should Be the Role of Physiatrists in Early Acute Care Rehabilitation?: Current Literature, Models of Care, and Thoughts for the Future. PMID- 26495816 TI - Effects of Yoga on Symptoms, Physical Function, and Psychosocial Outcomes in Adults with Osteoarthritis: A Focused Review. AB - Osteoarthritis (OA) is a highly prevalent and disabling chronic condition. Because physical activity is a key component in OA management, effective exercise interventions are needed. Yoga is an increasingly popular multimodal mind-body exercise that aims to promote flexibility, strength, endurance, and balance. Its gentle approach is potentially a safe and effective exercise option for managing OA. The purpose of this focused review is to examine the effects of yoga on OA symptoms and physical and psychosocial outcomes. A comprehensive search was conducted using seven electronic databases. Twelve reports met inclusion criteria involving a total of 589 participants with OA-related symptoms. A variety of types, frequencies, and durations of yoga interventions were reported; Hatha and Iyengar yoga were the most commonly used types. Frequency of intervention ranged from once a week to 6 days a week. Duration of the interventions ranged from 45 to 90 mins per session for 6 to 12 wks. Yoga intervention resulted in reductions in pain, stiffness, and swelling, but results on physical function and psychosocial well-being were inconclusive because of a variety of outcome measures being used. PMID- 26495817 TI - Progressive Paraplegia from Spinal Cord Stimulator Lead Fibrotic Encapsulation: A Case Report. AB - Ten years after placement of a spinal cord stimulator (SCS) and resolution of pain, this patient presented with progressive paraplegia, worsening thoracic radicular pain at the same dermatome level of the electrodes, and bowel and bladder incontinence. Computed tomographic myelogram confirmed thoracic spinal cord central canal stenosis at the level of electrodes. After removal of the fibrotic tissue and electrodes, the patient had resolution of his thoracic radicular pain and a return of his pre-SCS pain and minimal neurologic and functional return. To the authors' knowledge, no studies have been identified with thoracic SCS lead fibrosis in the United States causing permanent paraplegia. Only one other case has been reported in Madrid, Spain. Patients with SCS presenting with loss of pain relief, new-onset radicular or neuropathic pain in same dermatome(s) as SCS electrodes, worsening neuromuscular examination, or new bladder or bowel incontinence need to be evaluated for complications regarding SCS implantation causing spinal stenosis and subsequent cord compression to avoid permanent neurologic deficits. PMID- 26495818 TI - Ultrasound-Guided Injection of Carpal Tunnel: Do You Mind the Retinaculum? PMID- 26495819 TI - Spinothalamic Tract Injury Due to Primary Brainstem Injury: A Case Report. PMID- 26495821 TI - Observational prospective study comparing mucoactive and antibiotic treament in the management of acute cough from upper respiratory tract infections. AB - AIM: Since the efficacy of antibiotics in the management of cough from upper respiratory tract infections (URTI) is unclear, we conducted an observational study to evaluate the efficacy of antibiotic compared to symptomatic treatment in adults with productive cough from URTI in a real life setting. METHODS: One hundred and 50 subjects presenting to five general practice ambulatories with productive cough due to URTI were included in the study. According to the physician judgment, patients were treated with either oral antibiotics (group A, 50 patients), a mucoactive syrup (sobrerol: group S, 50 patients) as symptomatic treatment, or both sobrerol and oral antibiotics (group SA, 50 patients). Cough severity was assessed daily with a diary, by means of a validated verbal category descriptive (VCD) Scale. RESULTS: In every treatment group cough severity decreased over time (P<0.001); however, during the first week of treatment patients in groups S and SA experienced significantly lower VCD score values in comparison to Group A (P=0.045 and P=0.010, respectively). On the other hand, the VCD score was never significantly different between the two groups that received symptomatic treatment at any of the 4 weeks of the study, suggesting that the effect observed was due to the action of the mucoactive syrup. CONCLUSION: Our data confirm the lack of efficacy of antibiotics in the management of productive cough in URTI and suggest that symptomatic treatment should be preferred to antibiotics in acute cough from URTI. PMID- 26495822 TI - An update on atrial fibrillation: focus on stroke risk reduction strategies. AB - Atrial fibrillation (AF) currently affects approximately 2% of the general adult population, and the number of patients suffering from AF constantly increases. Although the occurrence of AF rarely poses an immediate threat to patient's survival, the arrhythmia is associated with significant cardiovascular morbidity and mortality mostly resulting from ischemic stroke or systemic thromboembolism, or heart failure. Overall, patients with AF have a 5-fold greater risk of stroke compared to individuals in sinus rhythm, but individual stroke risk depends on the presence of various stroke risk factors, and optimal stroke prevention is essential for AF patients. Several major advances in AF-related stroke prevention have been achieved recently, including the refinements in stroke and bleeding risk assessment with an essential shift in the recognition of AF patients who should be offered oral anticoagulant (OAC) therapy, the advent of non-vitamin K antagonist oral anticoagulants (NOACs) which are increasingly used in the "real world" setting, as well as the development of non-pharmacological means of thromboprophylaxis in AF patients (e.g., left atrial appendage [LAA] occluding devices). In this review article, we summarize these recent developments in stroke risk reduction strategies and discuss the main principles of decision making regarding OAC therapy in AF patients. PMID- 26495820 TI - Effects of Developmental Activation of the Aryl Hydrocarbon Receptor by 2,3,7,8 Tetrachlorodibenzo-p-dioxin on Long-term Self-renewal of Murine Hematopoietic Stem Cells. AB - BACKGROUND: Human epidemiological and animal studies suggest that developmental exposure to contaminants that activate the aryl hydrocarbon receptor (AHR) lead to suppression of immune system function throughout life. The persistence of immune deficiency throughout life suggests that the cellular target of AHR activation is a fetal hematopoietic progenitor or stem cell. OBJECTIVES: The aim of this study was to identify the effects of transplacental exposure to an AHR agonist on long-term self-renewal of fetal hematopoietic stem cells. METHODS: Pregnant C57BL/6 or AHR+/- mice were exposed to the AHR agonist, 2,3,7,8-tetra chlorodibenzo-p-dioxin (TCDD). On day 14 of gestation, hematopoietic progenitors from wild-type or AHR-deficient fetuses were placed into in vitro T-lymphocyte differentiation cultures to identify the effects of transplacental TCDD on AHR activation in the fetus. We next analyzed the fetal hematopoietic progenitor cells for changes in reactive oxygen species (ROS). Finally, hematopoietic progenitors from fetuses exposed transplacentally to TCDD were mixed 1:1 with cells from congenic controls and used to reconstitute lethally irradiated recipients for analysis of long-term self-renewal potential. RESULTS: Our findings suggested that the effects of TCDD on the developing hematopoietic system were mediated by direct AHR activation in the fetus. Furthermore, developmental AHR activation by TCDD increased ROS in the fetal hematopoietic stem cells, and the elevated ROS was associated with a reduced capacity of the TCDD-exposed fetal cells to compete with control cells in a mixed competitive irradiation/reconstitution assay. CONCLUSIONS: Our findings indicate that AHR activation by TCDD in the fetus during pregnancy leads to impairment of long-term self-renewal of hematopoietic stem cells. CITATION: Laiosa MD, Tate ER, Ahrenhoerster LS, Chen Y, Wang D. 2016. Effects of developmental activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin on long-term self-renewal of murine hematopoietic stem cells. Environ Health Perspect 124:957 965; http://dx.doi.org/10.1289/ehp.1509820. PMID- 26495823 TI - New roles of factors from perivascular tissue in regulation of vascular tone. PMID- 26495824 TI - Effect of Product Dimensions and Surface Browning Method on Salmonella Contamination in Frozen, Surface-Browned, Breaded Chicken Products Treated with Antimicrobials. AB - Not-ready-to-eat breaded chicken products formulated with antimicrobial ingredients were tested for the effect of sample dimensions, surface browning method and final internal sample temperature on inoculated Salmonella populations. Fresh chicken breast meat portions (5 * 5 * 5 cm), inoculated with Salmonella (7-strain mixture; 5 log CFU/g), were mixed with (5% v/w total moisture enhancement) (i) distilled water (control), (ii) caprylic acid (CAA; 0.0625%) and carvacrol (CAR; 0.075%), (iii) CAA (0.25%) and epsilon-polylysine (POL; 0.5%), (iv) CAR (0.15%) and POL (0.5%), or (v) CAA (0.0625%), CAR (0.075%) and POL (0.5%). Sodium chloride (1.2%) and sodium tripolyphosphate (0.3%) were added to all treatments. The mixtures were then ground and formed into 9 * 5 * 3 cm (150 g) or 9 * 2.5 * 2 cm (50 g) portions. The products were breaded, browned in (i) an oven (208 degrees C, 15 min) or (ii) deep fryer (190 degrees C, 15 s), packaged, and stored at -20 degrees C (8 d). Overall, maximum internal temperatures of 62.4 +/- 4.0 degrees C (9 * 2.5 * 2 cm) and 46.0 +/- 3.0 degrees C (9 * 5 * 3 cm) were reached in oven-browned samples, and 35.0 +/- 1.1 degrees C (9 * 2.5 * 2 cm) and 31.7 +/- 2.6 degrees C (9 * 5 * 3 cm) in fryer browned samples. Irrespective of formulation treatment, total (after frozen storage) reductions of Salmonella were greater (P < 0.05) for 9 * 2.5 * 2 cm oven browned samples (3.8 to at least 4.6 log CFU/g) than for 9 * 5 * 3 cm oven browned samples (0.7 to 2.5 log CFU/g). Product dimensions did not (P >= 0.05) affect Salmonella reductions (0.6 to 2.8 log CFU/g) in fryer-browned samples. All antimicrobial treatments reduced Salmonella to undetectable levels (<0.3 log CFU/g) in oven-browned 9 * 2.5 * 2 cm samples. Overall, the data may be useful for the selection of antimicrobials, product dimensions, and surface browning methods for reducing Salmonella contamination. PMID- 26495825 TI - Dioxins and cytogenetic status of villagers after 40 years of agent Orange application in Vietnam. AB - We have examined cytogenetic status of the rural population living on dioxin contaminated territories (DCT, TCDD in soil 2.6 ng/kg) compared to the villagers of the control area (TCDD in soil 0.18 ng kg(-1)). The examination took place almost 40 years after the war. The consequences of some confounding factors (years of residence in the region, farming, and aging) has been examined. Karyological analysis of buccal and nasal epitheliocytes among healthy adult males living on DCT and control area (26 and 35 persons) was conducted. A wide range of cytogenetic (micronuclei, nuclear protrusions), proliferative (binucleated cells and cells with doubled nucleus) and endpoints of cell death (cells with perinuclear vacuoles, with damaged nucleus membrane, condensed chromatin, pyknosis, karyorrhexis, karyolysis) had been analyzed. The frequent amount of cells with nuclear protrusions in both epithelia was slightly decreased in the DST group. Biomarkers of early and late stages of nuclear destruction in buccal epithelium (cells with damaged nuclear membrane, karyolysis) were elevated significantly in DCT. Higher level of the same parameters was also identified in nasal epithelium. The cytogenetic status of healthy adult males on DCT had got "normalization" by present moment in comparison with our early data. Nevertheless, in exposed group some alteration of the cytogenetic status was being registered (mostly biomarkers of apoptosis). Years of residence (and exposure to dioxins) affected the cytogenetic status of DCT inhabitants, whereas no influence of farming factors (pesticides, fertilizers, etc.) had been discovered. Some biomarkers of proliferation and cell death were affected by aging. PMID- 26495826 TI - Bioaccessibility of barium from barite contaminated soils based on gastric phase in vitro data and plant uptake. AB - Barite contamination of soil commonly occurs from either barite mining or explorative drilling operations. This work reported in vitro data for barite contaminated soils using the physiologically based extraction test (PBET) methodology. The existence of barite in plant tissue and the possibility of 'biomineralised' zones was also investigated using Scanning Electron Microscopy. Soils with low barium (Ba) concentrations showed a higher proportion of Ba extractability than barite rich samples. Barium uptake to spinach from soil was different between short term spiking studies and field weathered soils. Furthermore, Ba crystals were not evident in spinach tissue or acid digest solutions grown in barium nitrate spiked soils despite high accumulation. Barite was found in the plant digest solutions from barite contaminated soils only. Results indicate that under the conservative assumptions made, a child would need to consume extreme quantities of soil over an extended period to cause chronic health problems. PMID- 26495827 TI - Bioavailability assessments following biochar and activated carbon amendment in DDT-contaminated soil. AB - The effects of 2.8% w/w granulated activated carbon (GAC) and two types of biochar (Burt's and BlueLeaf) on DDT bioavailability in soil (39 MUg/g) were investigated using invertebrates (Eisenia fetida), plants (Cucurbita pepo spp. pepo) and a polyoxymethylene (POM) passive sampler method. Biochar significantly reduced DDT accumulation in E. fetida (49%) and showed no detrimental effects to invertebrate health. In contrast, addition of GAC caused significant toxic effects (invertebrate avoidance and decreased weight) and did not significantly reduce the accumulation of DDT into invertebrate tissue. None of the carbon amendments reduced plant uptake of DDT. Bioaccumulation of 4,4'DDT and 4,4'-DDE in plants (C. pepo spp. pepo) and invertebrates (E. fetida) was assessed using bioaccumulation factors (BAFs) and compared to predicted bioavailability using the freely-dissolved porewater obtained from a polyoxymethylene (POM) equilibrium biomimetic method. The bioavailable fraction predicted by the POM samplers correlated well with measured invertebrate uptake (<50% variability), but was different from plant root uptake by 134%. A literature review of C. pepo BAFs across DDT soil contamination levels and the inclusion of field data from a 2.5 MUg/g DDT-contaminated site found that these plants exhibit a concentration threshold effect at [DDT](soil) > 10 MUg/g. The results of these studies illustrate the importance of including plants in bioavailability studies as the use of carbon materials for in situ contaminant sorption moves from predominantly sediment to soil remediation technologies. PMID- 26495828 TI - Causes of endocrine disrupting potencies in surface water in East China. AB - Surface water is essential for human health and ecological diversity, but some endocrine disrupting chemicals are detectable. Both thyroid receptor (TR) and androgen receptor (AR) agonistic/antagonistic potencies in grade II surface water in East China were investigated using reporter gene assays. While none of the water exhibited agonistic potency, significant AR and TR antagonistic potencies were detectable. TR antagonistic equivalents (TR-AntEQ) and AR antagonistic equivalents (AR-AntEQ) ranged from 3.6 to 76.1 MUg dibutyl phthalate/L and from 2.3 to 242.6 MUg flutamide/L, respectively. The TR and AR antagonistic potencies in the Yangtze River watershed were highlighted, with equivalents greater than the lowest observable effect concentration (LOEC) of dibutyl phthalate and flutamide, respectively. Phthalate esters (PAEs) being the most abundant explained most of the TR antagonistic potency, contributing more than 65% of the TR-AntEQ and diisobutyl phthalate (DiBP) was the major contributor. In most surface waters studied, PAEs contributed little of the AR-AntEQ, but the frequently detected octylphenol, nonylphenol and benzo[a]pyrene might be responsible. PMID- 26495829 TI - Identification and application of Phyto-Fenton reactions. AB - The formation of hydroxyl radicals (*OHs) by aquatic plants was investigated using electron-spin-resonance (ESR) spectroscopy and fluorescence microscopy. ESR observations, using 5- (diethoxyphosphoryl)-5-methyl-pyrroline N-oxide as a trapping agent, indicated that the signals produced by aquatic plants ground with ferrous iron ions are almost identical to those produced by Fenton's reagent. In addition, fluorescence was observed in the oxidized form of aminophenyl fluorescein in the presence of ferrous ions as well as any particles of colloidal ferrihydrite, magnetite, and ferric-ion-exchanged zeolite, while no fluorescence appeared in the absence of these iron compounds. Moreover, fluorescence microscopy observations demonstrated that fluorescence mainly occurs on the surface of aquatic plants at neutral pH in the presence of the latter three solid iron compounds, implying the occurrence of heterogeneous phyto-Fenton reactions utilizing endogenous hydrogen peroxide (H2O2) in the aquatic plants. Furthermore, batch treatments of the pollutant 17alpha-ethinylestradiol (EE2), using colloidal ferrihydrite iron, indicated the feasible removal of EE2 with enhanced performance, lower-or apparently no-consumption of endogenous H2O2, and no significant stress to the aquatic plants. We concluded that the treatment of environmental pollutants through *OH formations via heterogeneous phyto-Fenton reactions should be a feasible alternative to conventional wastewater and water treatment processes. PMID- 26495830 TI - A practical approach to estimate emission rates of indoor air pollutants due to the use of personal combustible products based on small-chamber studies. AB - As emission rates of airborne pollutants are commonly measured from combusting substances placed inside small chambers, those values need to be re-evaluated for the possible significance under practical conditions. Here, a simple numerical procedure is investigated to extrapolate the chamber-based emission rates of formaldehyde that can be released from various combustible sources including e cigarettes, conventional cigarettes, or scented candles to their concentration levels in a small room with relatively poor ventilation. This simple procedure relies on a mass balance approach by considering the masses of pollutants emitted from source and lost through ventilation under the assumption that mixing occurs instantaneously in the room without chemical reactions or surface sorption. The results of our study provide valuable insights into re-evaluation procedure of chamber data to allow comparison between extrapolated and recommended values to judge the safe use of various combustible products in confined spaces. If two scented candles with a formaldehyde emission rate of 310 ug h(-1) each were lit for 4 h in a small 20 m(3) room with an air change rate of 0.5 h(-1), then the 4 h (candle lit) and 8-h (up to 8 h after candle lighting) TWA [FA] were determined to be 28.5 and 23.5 ppb, respectively. This is clearly above the 8-h NIOSH recommended exposure limit (REL) time weighted average of 16 ppb. PMID- 26495831 TI - Massive airborne Endosulfan inputs related to intensive agriculture in Argentina's Pampa. AB - In order to evaluate the impact of intensive agriculture on air quality in the most productive and populated Argentina's Pampas, a comprehensive assessment of airborne Endosulfan (?Endo) was performed using polyurethane passive samplers deployed from 2010 to 2013 covering the critical period of Endosulfan restrictions at twenty nine sites in the Rural Pampa and Great Buenos Aires Metropolitan Area (GBA: Horticultural and Urban subareas). ?Endo concentrations were very high and variable (0.01-63 ng m(-3)), exceeding worldwide reported maxima at Horticultural GBA and Rural Pampa with lowest values at Urban GBA (geometric means: 3.1, 1.1 and 0.53 ng m(-3), respectively). The composition was relatively fresh with strong predominance of Endo I (72 +/- 18%) over Endo II (23 +/- 15%) and Endo SO4 (5 +/- 10%). Airborne ?Endo was significantly correlated to annual soybean crop in Rural Pampa. ?Endo concentrations showed a temporal pattern defined by consistent peaks enriched in Endo I during summer application periods, cold temperature minima with higher proportions of Endo SO4 and a general exponentially declining trend over time related to incipient control policies. PMID- 26495832 TI - Biochemical responses in freshwater fish after exposure to water-soluble fraction of gasoline. AB - The water-soluble fraction of gasoline (WSFG) is a complex mixture of mono polycyclic aromatic hydrocarbons. The study aimed to evaluate the effects of WSFG diluted 1.5% on freshwater fish. Astyanax altiparanae were exposed to the WSFG for 96 h, under a semi-static system, with renewal of 25% of the gasoline test solution every 24 h. In addition, a decay of the contamination (DC) was carried out. During DC, the fish was exposed to the WSFG for 8 d, followed by another 7 d with renewal of 25% of volume aquaria with clean water every 24 h. For depuration, fish were transferred to aquaria with clean water, and in addition, 25% of the water was replaced every 24 h. The liver and kidney biotransformation, antioxidant defenses and lipid peroxidation (LPO) levels were evaluated. In the liver, the WSFG 1.5% caused reduction of glutathione S-transferase (GST) after 96 h and DC. In the kidney, only in depuration an increased GST activity was observed, and after DC a higher LPO levels. An increase of the superoxide dismutase (SOD) activity occurred at 96 h in both tissues; however, in the liver was also observed during the depuration. In WSFG 96 h, the glutathione peroxidase (GPx) activity in the kidney increased. As biomarkers of neurotoxicity, the brain and muscle acetylcholinesterase activities were measured, but the WSFG 1.5% did not change them. Therefore, this study brought forth more data about WSFG effects on freshwater fish after lower concentrations exposure and a DC, simulating an environmental contamination. PMID- 26495833 TI - Hydroxylated and methoxylated polybrominated diphenyl ethers in long-tailed ducks (Clangula hyemalis) and their main food, Baltic blue mussels (Mytilus trossulus * Mytilus edulis). AB - Long-tailed ducks (Clangula hyemalis) that breed in northern Europe and western Siberia and commonly winter in the Baltic Sea, are threatened by a significant population decrease. The ducks are, by primarily feeding on Baltic blue mussels (Mytilus trossulus * Mytilus edulis) while wintering in the Baltic Sea, potentially subjected to high levels of toxic hydroxylated polybrominated diphenyl ethers (OH-PBDEs). To assess long-tailed ducks exposure to polybrominated phenols (PBPs), polybrominated anisoles (PBAs), hydroxylated polybrominated diphenyl ethers (OH-PBDEs), their methylated counterparts (MeO PBDEs) and polybrominated diphenyl ethers (PBDEs), livers of ten long-tailed ducks wintering in the Baltic Sea were analysed. Pattern and levels of analytes in long-tailed ducks (liver) and blue mussels sampled in March and May at nine sites in the Baltic Sea were compared. The geometric mean concentration (ng/g l.w.) in livers of long-tailed ducks and Baltic blue mussels were: Sigma(2)PBPs: 0.57 and 48; Sigma(2)PBAs: 0.83 and 11; Sigma(7)OH-PBDEs: 6.1 and 45; Sigma(7)MeO PBDEs: 3.8 and 69; Sigma(7)PBDEs: 8.0 and 7.2, respectively. Based on an estimated daily intake of 450 g fresh blue mussel meat, long-tailed ducks daily dietary intake of brominated substances while foraging in the Baltic Sea in March May was estimated to; 390 ng Sigma(2)PBPs, 90 ng Sigma(2)PBAs, 370 ng Sigma(7)OH PBDEs, 590 ng Sigma(7)MeO-PBDEs and 59 ng Sigma(7)PBDEs. The low levels of PBPs, PBAs, OH-PBDEs and MeO-PBDEs in the long-tailed duck livers compared to blue mussel, despite a continuous daily intake, suggest that these compounds are poorly retained in long-tailed ducks. PMID- 26495834 TI - Concise Synthesis of Annulated Pyrido[3,4-b]indoles via Rh(I)-Catalyzed Cyclization. AB - The synthesis of pyridines bearing multiple ring fusions poses a considerable challenge for organic chemists. To address this problem, we describe the synthesis of a small library of pyrido[3,4-b]indoles via an efficient, five-step sequence. The key transformation is a Rh(I)-catalyzed [2 + 2 + 2] cyclization that forms three rings in one reaction flask. Our method is high yielding, accommodates a variety of functional groups, and suffers no entropic costs as ring size increases. PMID- 26495835 TI - Skin tight: macrophage-specific COX-2 induction links salt handling in kidney and skin. AB - The relationship between dietary salt intake and the associated risk of hypertension and cardiovascular disease is an important public health concern. In this issue of the JCI, a study by Zhang and associates shows that consumption of a high-sodium diet induces expression of cyclooxygenase-2 (COX-2) in macrophages, resulting in enhanced levels of prostaglandin E2 (PGE2), autocrine activation of the macrophage E-prostanoid 4 (EP4) receptor, and subsequent triggering of parallel pathways in the kidney and in skin that help dispose of excess sodium. The authors found that blockade or genetic elimination of the COX-2/PGE2/EP4 receptor pathway in hematopoietic cells causes salt-sensitive hypertension in mice. These studies illuminate an unexpected central role for the macrophage in coordinating homeostatic responses to dietary salt intake and suggest a complex pathophysiology for hypertension associated with NSAID use. PMID- 26495836 TI - Inhibition of HIV-1 Viral Infection by an Engineered CRISPR Csy4 RNA Endoribonuclease. AB - The bacterial defense system CRISPR (clustered regularly interspaced short palindromic repeats) has been explored as a powerful tool to edit genomic elements. In this study, we test the potential of CRISPR Csy4 RNA endoribonuclease for targeting HIV-1. We fused human codon-optimized Csy4 endoribonuclease with VPR, a HIV-1 viral preintegration complex protein. An HIV-1 cell model was modified to allow quantitative detection of active virus production. We found that the trans-expressing VPR-Csy4 almost completely blocked viral infection in two target cell lines (SupT1, Ghost). In the MAGI cell assay, where the HIV-1 LTR beta-galactosidase is expressed under the control of the tat gene from an integrated provirus, VPR-Csy4 significantly blocked the activity of the provirus-activated HIV-1 reporter. This proof-of-concept study demonstrates that Csy4 endoribonuclease is a promising tool that could be tailored further to target HIV-1. PMID- 26495837 TI - Steroid Receptor Isoform Expression in Drosophila Nociceptor Neurons Is Required for Normal Dendritic Arbor and Sensitivity. AB - Steroid hormones organize many aspects of development, including that of the nervous system. Steroids also play neuromodulatory and other activational roles, including regulation of sensitivity to painful stimuli in mammals. In Drosophila, ecdysteroids are the only steroid hormones, and therefore the fly represents a simplified model system in which to explore mechanisms of steroid neuromodulation of nociception. In this report, we present evidence that ecdysteroids, acting through two isoforms of their nuclear ecdysone receptor (EcR), modulate sensitivity to noxious thermal and mechanical stimuli in the fly larva. We show that EcRA and EcRB1 are expressed by third instar larvae in the primary nociceptor neurons, known as the class IV multidendritic neurons. Suppression of EcRA by RNA interference in these cells leads to hyposensitivity to noxious stimulation. Suppression of EcRB1 leads to reduction of dendritic branching and length of nociceptor neurons. We show that specific isoforms of the ecdysone receptor play critical cell autonomous roles in modulating the sensitivity of nociceptor neurons and may indicate human orthologs that represent targets for novel analgesic drugs. PMID- 26495838 TI - An Exploration of the Universe of Polyglutamine Structures. AB - Deposits of misfolded proteins in the human brain are associated with the development of many neurodegenerative diseases. Recent studies show that these proteins have common traits even at the monomer level. Among them, a polyglutamine region that is present in huntingtin is known to exhibit a correlation between the length of the chain and the severity as well as the earliness of the onset of Huntington disease. Here, we apply bias exchange molecular dynamics to generate structures of polyglutamine expansions of several lengths and characterize the resulting independent conformations. We compare the properties of these conformations to those of the standard proteins, as well as to other homopolymeric tracts. We find that, similar to the previously studied polyvaline chains, the set of possible transient folds is much broader than the set of known-to-date folds, although the conformations have different structures. We show that the mechanical stability is not related to any simple geometrical characteristics of the structures. We demonstrate that long polyglutamine expansions result in higher mechanical stability than the shorter ones. They also have a longer life span and are substantially more prone to form knotted structures. The knotted region has an average length of 35 residues, similar to the typical threshold for most polyglutamine-related diseases. Similarly, changes in shape and mechanical stability appear once the total length of the peptide exceeds this threshold of 35 glutamine residues. We suggest that knotted conformers may also harm the cellular machinery and thus lead to disease. PMID- 26495839 TI - A Convex Formulation for Magnetic Particle Imaging X-Space Reconstruction. AB - Magnetic Particle Imaging (mpi) is an emerging imaging modality with exceptional promise for clinical applications in rapid angiography, cell therapy tracking, cancer imaging, and inflammation imaging. Recent publications have demonstrated quantitative mpi across rat sized fields of view with x-space reconstruction methods. Critical to any medical imaging technology is the reliability and accuracy of image reconstruction. Because the average value of the mpi signal is lost during direct-feedthrough signal filtering, mpi reconstruction algorithms must recover this zero-frequency value. Prior x-space mpi recovery techniques were limited to 1d approaches which could introduce artifacts when reconstructing a 3d image. In this paper, we formulate x-space reconstruction as a 3d convex optimization problem and apply robust a priori knowledge of image smoothness and non-negativity to reduce non-physical banding and haze artifacts. We conclude with a discussion of the powerful extensibility of the presented formulation for future applications. PMID- 26495840 TI - Apolipoprotein E e4 and Cognitive Function: A Modifiable Association Results from Two Independent Cohort Studies. AB - BACKGROUND: The apolipoprotein E (APOE) e4 genetic polymorphism is a major risk factor for Alzheimer' s disease, hence the possible prevention of its detrimental effects on cognition is of high relevance. METHODS: We used linear regression models to assess associations of APOE e4 with cognitive performance in a population-based cohort study (n = 1,434) and in a cohort of patients with coronary heart disease (n = 366), and restricted cubic splines to explore dose response relationships between serum cholesterol levels and cognition depending on APOE polymorphism. RESULTS: The association of APOE e4 with cognitive function was strongly amplified in the presence of hypercholesterolemia and cardiovascular disease in both independent cohorts; hypercholesterolemia was associated with cognitive function only among APOE e4 carriers in the presence of cardiovascular disease. The interaction effect between APOE genotype and hypercholesterolemia was statistically significant in both cohorts. CONCLUSIONS: The detrimental effects of APOE e4 polymorphism on cognition may strongly depend on modifiable risk factors. PMID- 26495841 TI - Physical Constraint Finite Element Model for Medical Image Registration. AB - Due to being derived from linear assumption, most elastic body based non-rigid image registration algorithms are facing challenges for soft tissues with complex nonlinear behavior and with large deformations. To take into account the geometric nonlinearity of soft tissues, we propose a registration algorithm on the basis of Newtonian differential equation. The material behavior of soft tissues is modeled as St. Venant-Kirchhoff elasticity, and the nonlinearity of the continuum represents the quadratic term of the deformation gradient under the Green- St.Venant strain. In our algorithm, the elastic force is formulated as the derivative of the deformation energy with respect to the nodal displacement vectors of the finite element; the external force is determined by the registration similarity gradient flow which drives the floating image deforming to the equilibrium condition. We compared our approach to three other models: 1) the conventional linear elastic finite element model (FEM); 2) the dynamic elastic FEM; 3) the robust block matching (RBM) method. The registration accuracy was measured using three similarities: MSD (Mean Square Difference), NC (Normalized Correlation) and NMI (Normalized Mutual Information), and was also measured using the mean and max distance between the ground seeds and corresponding ones after registration. We validated our method on 60 image pairs including 30 medical image pairs with artificial deformation and 30 clinical image pairs for both the chest chemotherapy treatment in different periods and brain MRI normalization. Our method achieved a distance error of 0.320+/-0.138 mm in x direction and 0.326+/-0.111 mm in y direction, MSD of 41.96+/-13.74, NC of 0.9958+/-0.0019, NMI of 1.2962+/-0.0114 for images with large artificial deformations; and average NC of 0.9622+/-0.008 and NMI of 1.2764+/-0.0089 for the real clinical cases. Student's t-test demonstrated that our model statistically outperformed the other methods in comparison (p-values <0.05). PMID- 26495842 TI - Worse Health Status and Higher Incidence of Health Disorders in Rhesus Negative Subjects. AB - Rhesus-positive and Rhesus-negative persons differ in the presence-absence of highly immunogenic RhD protein on the erythrocyte membrane. The biological function of the RhD molecule is unknown. Its structure suggests that the molecular complex with RhD protein transports NH3 or CO2 molecules across the erythrocyte cell membrane. Some data indicate that RhD positive and RhD negative subjects differ in their tolerance to certain biological factors, including, Toxoplasma infection, aging and fatique. Present cross sectional study performed on 3,130 subjects) showed that Rhesus negative subjects differed in many indices of their health status, including incidences of many disorders. Rhesus negative subjects reported to have more frequent allergic, digestive, heart, hematological, immunity, mental health, and neurological problems. On the population level, a Rhesus-negativity-associated burden could be compensated for, for example, by the heterozygote advantage, but for Rhesus negative subjects this burden represents a serious problem. PMID- 26495843 TI - Understanding Heroin Overdose: A Study of the Acute Respiratory Depressant Effects of Injected Pharmaceutical Heroin. AB - Opioids are respiratory depressants and heroin/opioid overdose is a major contributor to the excess mortality of heroin addicts. The individual and situational variability of respiratory depression caused by intravenous heroin is poorly understood. This study used advanced respiratory monitoring to follow the time course and severity of acute opioid-induced respiratory depression. 10 patients (9/10 with chronic airflow obstruction) undergoing supervised injectable opioid treatment for heroin addiction received their usual prescribed dose of injectable opioid (diamorphine or methadone) (IOT), and their usual prescribed dose of oral opioid (methadone or sustained release oral morphine) after 30 minutes. The main outcome measures were pulse oximetry (SpO2%), end-tidal CO2% (ETCO2%) and neural respiratory drive (NRD) (quantified using parasternal intercostal muscle electromyography). Significant respiratory depression was defined as absence of inspiratory airflow >10s, SpO2% < 90% for >10s and ETCO2% per breath >6.5%. Increases in ETCO2% indicated significant respiratory depression following IOT in 8/10 patients at 30 minutes. In contrast, SpO2% indicated significant respiratory depression in only 4/10 patients, with small absolute changes in SpO2% at 30 minutes. A decline in NRD from baseline to 30 minutes post IOT was also observed, but was not statistically significant. Baseline NRD and opioid-induced drop in SpO2% were inversely related. We conclude that significant acute respiratory depression is commonly induced by opioid drugs prescribed to treat opioid addiction. Hypoventilation is reliably detected by capnography, but not by SpO2% alone. Chronic suppression of NRD in the presence of underlying lung disease may be a risk factor for acute opioid-induced respiratory depression. PMID- 26495844 TI - Membrane Cholesterol Modulates LOX-1 Shedding in Endothelial Cells. AB - The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor responsible for ox-LDL recognition, binding and internalization, which is up-regulated during atherogenesis. Its activation triggers endothelium dysfunction and induces inflammation. A soluble form of LOX 1 has been identified in the human blood and its presence considered a biomarker of cardiovascular diseases. We recently showed that cholesterol-lowering drugs inhibit ox-LDL binding and internalization, rescuing the ox-LDL induced apoptotic phenotype in primary endothelial cells. Here we have investigated the molecular bases of human LOX-1 shedding by metalloproteinases and the role of cell membrane cholesterol on the regulation of this event by modulating its level with MbetaCD and statins. We report that membrane cholesterol affects the release of different forms of LOX-1 in cells transiently and stably expressing human LOX-1 and in a human endothelial cell line (EA.hy926). In particular, our data show that i) cholesterol depletion triggers the release of LOX-1 in exosomes as a full-length transmembrane isoform and as a truncated ectodomain soluble fragment (sLOX-1); ii) endothelial cells secrete a soluble metalloproteinase which induces LOX-1 ectodomain shedding and iii) long term statins treatment enhances sLOX-1 proteolytic shedding. PMID- 26495845 TI - Adenomatous Polyposis Coli Mutation Leads to Myopia Development in Mice. AB - Myopia incidence in China is rapidly becoming a very serious sight compromising problem in a large segment of the general population. Therefore, delineating the underlying mechanisms leading to myopia will markedly lessen the likelihood of other sight compromising complications. In this regard, there is some evidence that patients afflicted with familial adenomatous polyposis (FAP), havean adenomatous polyposis coli (APC) mutation and a higher incidence of myopia. To clarify this possible association, we determined whether the changes in pertinent biometric and biochemical parameters underlying postnatal refractive error development in APCMin mice are relevant for gaining insight into the pathogenesis of this disease in humans. The refraction and biometrics in APCMin mice and age matched wild-type (WT) littermates between postnatal days P28 and P84 were examined with eccentric infrared photorefraction (EIR) and customized optical coherence tomography (OCT). Compared with WT littermates, the APCMin mutated mice developed myopia (average -4.64 D) on P84 which was associated with increased vitreous chamber depth (VCD). Furthermore, retinal and scleral changes appear in these mice along with: 1) axial length shortening; 2) increased retinal cell proliferation; 3) and decreased tyrosine hydroxylase (TH) expression, the rate limiting enzyme of DA synthesis. Scleral collagen fibril diameters became heterogeneous and irregularly organized in the APCMin mice. Western blot analysis showed that scleral alpha-1 type I collagen (col1alpha1) expression also decreased whereas MMP2 and MMP9 mRNA expression was invariant. These results indicate that defective APC gene function promotes refractive error development. By characterizing in APCMin mice ocular developmental changes, this approach provides novel insight into underlying pathophysiological mechanisms contributing to human myopia development. PMID- 26495846 TI - Corneal Sensitivity and Dry Eye Symptoms in Patients with Keratoconus. AB - PURPOSE: To investigate corneal sensitivity to selective mechanical, chemical, and thermal stimulation and to evaluate their relation to dry eye symptoms in patients with keratoconus. METHODS: Corneal sensitivity to mechanical, chemical, and thermal thresholds were determined using a gas esthesiometer in 19 patients with keratoconus (KC group) and in 20 age-matched healthy subjects (control group). Tear film dynamics was assessed by Schirmer I test and by the non invasive tear film breakup time (NI-BUT). All eyes were examined with a rotating Scheimpflug camera to assess keratoconus severity. RESULTS: KC patients had significatly decreased tear secretion and significantly higher ocular surface disease index (OSDI) scores compared to controls (5.3+/-2.2 vs. 13.2+/-2.0 mm and 26.8+/-15.8 vs. 8.1+/-2.3; p<0.001). There was no significant difference in NI BUT between the two groups (KC: 9.8+/-4.8 vs. control: 10.7+/-3.8; p>0.05). The mean threshold for selective mechanical (KC: 139.2+/-25.8 vs. control: 109.1+/ 24.0 ml/min), chemical (KC: 39.4+/-3.9 vs. control: 35.2+/-1.9%CO2), heat (KC: 0.91+/-0.32 vs. control: 0.54+/-0.26 Delta degrees C) and cold (KC: 1.28+/-0.27 vs. control: 0.98+/-0.25 Delta degrees C) stimulation in the KC patients were significantly higher than in the control subjects (p<0.001, for all parameters). No correlation was found between age and mechanical, chemical, heat or cold thresholds in the patients with KC (p>0.05), whereas in the control subjects both mechanical (r = 0.52, p = 0.02), chemical (r = 0.47, p = 0.04), heat (r = 0.26, p = 0.04) and cold threshold (r = 0.40, p = 0.03) increased with age. In the KC group, neither corneal thickness nor tear flow, NI-BUT or OSDI correlated significantly with mechanical, chemical, heat or cold thresholds (p>0.05 for all variables). CONCLUSIONS: Corneal sensitivity to different types of stimuli is decreased in patients with keratoconus independently of age and disease severity. The reduction of the sensory input from corneal nerves may contribute to the onset of unpleasant sensations in these patients and might lead to the impaired tear film dynamics. PMID- 26495847 TI - Does the Wage Gap between Private and Public Sectors Encourage Political Corruption? AB - We present a dynamic network model of corrupt and noncorrupt employees representing two states in the public and private sector. Corrupt employees are more connected to one another and are less willing to change their attitudes regarding corruption than noncorrupt employees. This behavior enables them to prevail and become the majority in the workforce through a first-order phase transition even though they initially represented a minority. In the model, democracy-understood as the principle of majority rule-does not create corruption, but it serves as a mechanism that preserves corruption in the long run. The motivation for our network model is a paradox that exists on the labor market. Although economic theory indicates that higher risk investments should lead to larger rewards, in many developed and developing countries workers in lower-risk public sector jobs are paid more than workers in higher-risk private sector jobs. To determine the long-run sustainability of this economic paradox, we study data from 28 EU countries and find that the public sector wage premium increases with the level of corruption. PMID- 26495848 TI - Virus Satellites Drive Viral Evolution and Ecology. AB - Virus satellites are widespread subcellular entities, present both in eukaryotic and in prokaryotic cells. Their modus vivendi involves parasitism of the life cycle of their inducing helper viruses, which assures their transmission to a new host. However, the evolutionary and ecological implications of satellites on helper viruses remain unclear. Here, using staphylococcal pathogenicity islands (SaPIs) as a model of virus satellites, we experimentally show that helper viruses rapidly evolve resistance to their virus satellites, preventing SaPI proliferation, and SaPIs in turn can readily evolve to overcome phage resistance. Genomic analyses of both these experimentally evolved strains as well as naturally occurring bacteriophages suggest that the SaPIs drive the coexistence of multiple alleles of the phage-coded SaPI inducing genes, as well as sometimes selecting for the absence of the SaPI depressing genes. We report similar (accidental) evolution of resistance to SaPIs in laboratory phages used for Staphylococcus aureus typing and also obtain the same qualitative results in both experimental evolution and phylogenetic studies of Enterococcus faecalis phages and their satellites viruses. In summary, our results suggest that helper and satellite viruses undergo rapid coevolution, which is likely to play a key role in the evolution and ecology of the viruses as well as their prokaryotic hosts. PMID- 26495850 TI - Correction: Impacts of the Glucuronidase Genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on Tamoxifen Metabolism in Breast Cancer Patients. PMID- 26495849 TI - Culture at a Higher Temperature Mildly Inhibits Cancer Cell Growth but Enhances Chemotherapeutic Effects by Inhibiting Cell-Cell Collaboration. AB - Acute febrile infections have historically been used to treat cancer. To explore the underlying mechanism, we studied chronic effects of fever on cancer cell growth and chemotherapeutic efficacy in cell culture. We found that culturing cancer cells at 39 degrees C mildly inhibited cell growth by arresting the cells at the G1 phase of the cell cycle. When cells were seeded in culture dishes at a lower density, e.g. about 1000-2000 cells per 35-mm dish, the growth inhibition was much greater, manifested as many fewer cell colonies in the 39 degrees C dishes, compared with the results at a higher density seeding, e.g. 20,000 cells per dish, suggesting that cell-cell collaboration as the Allee effect in cell culture is inhibited at 39 degrees C. Withdrawal of cells from serum enhanced the G1 arrest at 39 degrees C and, for some cell lines such as A549 lung cancer cells, serum replenishment failed to quickly drive the cells from the G1 into the S and G2-M phases. Therapeutic effects of several chemotherapeutic agents, including clove bud extracts, on several cancer cell lines were more potent at 39 degrees C than at 37 degrees C, especially when the cells were seeded at a low density. For some cell lines and some agents, this enhancement is long-lasting, i.e. continuing after the cessation of the treatment. Collectively these results suggest that hyperthermia may inhibit cancer cell growth by G1 arrest and by inhibition of cell-cell collaboration, and may enhance the efficacy of several chemotherapeutic agents, an effect which may persist beyond the termination of chemotherapy. PMID- 26495851 TI - Insulin Like Growth Factor 2 Expression in the Rat Brain Both in Basal Condition and following Learning Predominantly Derives from the Maternal Allele. AB - Insulin like growth factor 2 (Igf2) is known as a maternally imprinted gene involved in growth and development. Recently, Igf2 was found to also be regulated and required in the adult rat hippocampus for long-term memory formation, raising the question of its allelic regulation in adult brain regions following experience and in cognitive processes. We show that, in adult rats, Igf2 is abundantly expressed in brain regions involved in cognitive functions, like hippocampus and prefrontal cortex, compared to the peripheral tissues. In contrast to its maternal imprinting in peripheral tissues, Igf2 is mainly expressed from the maternal allele in these brain regions. The training-dependent increase in Igf2 expression derives proportionally from both parental alleles, and, hence, is mostly maternal. Thus, Igf2 parental expression in the adult rat brain does not follow the imprinting rules found in peripheral tissues, suggesting differential expression regulation and functions of imprinted genes in the brain. PMID- 26495852 TI - T-Cell Responses Are Associated with Survival in Acute Melioidosis Patients. AB - BACKGROUND: Melioidosis is an increasingly recognised cause of sepsis and death across South East Asia and Northern Australia, caused by the bacterium Burkholderia pseudomallei. Risk factors include diabetes, alcoholism and renal disease, and a vaccine targeting at-risk populations is urgently required. A better understanding of the protective immune response in naturally infected patients is essential for vaccine design. METHODS: We conducted a longitudinal clinical and immunological study of 200 patients with melioidosis on admission, 12 weeks (n = 113) and 52 weeks (n = 65) later. Responses to whole killed B. pseudomallei were measured in peripheral blood mononuclear cells (PBMC) by interferon-gamma (IFN-gamma) ELIspot assay and flow cytometry and compared to those of control subjects in the region with diabetes (n = 45) and without diabetes (n = 43). RESULTS: We demonstrated strong CD4+ and CD8+ responses to B. pseudomallei during acute disease, 12 weeks and 52 weeks later. 28-day mortality was 26% for melioidosis patients, and B. pseudomallei-specific cellular responses in fatal cases (mean 98 IFN-gamma cells per million PBMC) were significantly lower than those in the survivors (mean 142 IFN-gamma cells per million PBMC) in a multivariable logistic regression model (P = 0.01). A J-shaped curve association between circulating neutrophil count and mortality was seen with an optimal count of 4000 to 8000 neutrophils/MUl. Melioidosis patients with known diabetes had poor diabetic control (median glycated haemoglobin HbA1c 10.2%, interquartile range 9.2-13.1) and showed a stunted B. pseudomallei-specific cellular response during acute illness compared to those without diabetes. CONCLUSIONS: The results demonstrate the role of both CD4+ and CD8+ T-cells in protection against melioidosis, and an interaction between diabetes and cellular responses. This supports development of vaccine strategies that induce strong T cell responses for the control of intracellular pathogens such as B. pseudomallei. PMID- 26495853 TI - Intervention Associated Acute Kidney Injury and Long-Term Cardiovascular Outcomes. AB - BACKGROUND: Acute kidney injury (AKI) has been associated with all-cause short- and long-term mortality. However, its association with cardiovascular (CV) events remains unclear. We sought to investigate this in patients undergoing open (OAR) or endovascular (EVAR) abdominal aortic aneurysm repair, as they are likely to develop both AKI and CV morbidity. A meta-analysis was subsequently performed to confirm this in other CV-interventions. METHODS: AKI-incidence was assessed in a multicentre-cohort of 1,068 patients undergoing EVAR (947 individuals) or OAR electively using the 'Acute Kidney Injury Network' criteria. A composite-endpoint was used, consisting of non-fatal myocardial infarction (MI), stroke, vascular event, hospitalisation due to heart failure and CV death. A systematic literature review identified studies reporting AKI-incidence and CV events. Risk ratios (RRs) at 1 and 5 years were combined using meta-analysis. RESULTS: During a median follow-up of 62 months (range 11-121), AKI was associated with CV events on adjusted (for CV risk-factors) analyses (Incidence 36% of EVAR, 32% of OAR patients; hazard ratio 1.73, 95% CI 1.06-3.39, p=0.03) for the overall population. In the meta-analysis, 7 studies reported incidence of MI on 23,936 patients 1-year after coronary intervention (PCI) with a pooled RR of 1.76 (95% CI 1.45-2.83, p<0.001); at 2 years, 3 studies reported MI incidence on 17,773 patients after PCI with a pooled RR of 1.34 (95% CI 1.10-1.63, p=0.003). MI incidence was reported 5 years after cardiac surgery by 3 studies (33,701 patients) with a pooled RR of 1.60 (95% CI 1.43-1.81). CONCLUSION: AKI is associated with long-term CV events after surgery or endovascular intervention. PMID- 26495856 TI - Beat-to-Beat Heart Rate and Blood Pressure Variability and Hypertensive Disease in Pregnancy (Podcast). PMID- 26495854 TI - Yersinia pestis Requires Host Rab1b for Survival in Macrophages. AB - Yersinia pestis is a facultative intracellular pathogen that causes the disease known as plague. During infection of macrophages Y. pestis actively evades the normal phagosomal maturation pathway to establish a replicative niche within the cell. However, the mechanisms used by Y. pestis to subvert killing by the macrophage are unknown. Host Rab GTPases are central mediators of vesicular trafficking and are commonly targeted by bacterial pathogens to alter phagosome maturation and killing by macrophages. Here we demonstrate for the first time that host Rab1b is required for Y. pestis to effectively evade killing by macrophages. We also show that Rab1b is specifically recruited to the Yersinia containing vacuole (YCV) and that Y. pestis is unable to subvert YCV acidification when Rab1b expression is knocked down in macrophages. Furthermore, Rab1b knockdown also altered the frequency of association between the YCV with the lysosomal marker Lamp1, suggesting that Rab1b recruitment to the YCV directly inhibits phagosome maturation. Finally, we show that Rab1b knockdown also impacts the pH of the Legionella pneumophila containing vacuole, another pathogen that recruits Rab1b to its vacuole. Together these data identify a novel role for Rab1b in the subversion of phagosome maturation by intracellular pathogens and suggest that recruitment of Rab1b to the pathogen containing vacuole may be a conserved mechanism to control vacuole pH. PMID- 26495855 TI - Distributed flow sensing for closed-loop speed control of a flexible fish robot. AB - Flexibility plays an important role in fish behavior by enabling high maneuverability for predator avoidance and swimming in turbulent flow. This paper presents a novel flexible fish robot equipped with distributed pressure sensors for flow sensing. The body of the robot is molded from soft, hyperelastic material, which provides flexibility. Its Joukowski-foil shape is conducive to modeling the fluid analytically. A quasi-steady potential-flow model is adopted for real-time flow estimation, whereas a discrete-time vortex-shedding flow model is used for higher-fidelity simulation. The dynamics for the flexible fish robot yield a reduced model for one-dimensional swimming. A recursive Bayesian filter assimilates pressure measurements to estimate flow speed, angle of attack, and foil camber. The closed-loop speed-control strategy combines an inverse-mapping feedforward controller based on an average model derived for periodic actuation of angle-of-attack and a proportional-integral feedback controller utilizing the estimated flow information. Simulation and experimental results are presented to show the effectiveness of the estimation and control strategy. The paper provides a systematic approach to distributed flow sensing for closed-loop speed control of a flexible fish robot by regulating the flapping amplitude. PMID- 26495857 TI - Perfluoroalkyl Acids in Maternal Serum and Indices of Fetal Growth: The Aarhus Birth Cohort. AB - BACKGROUND: Previous studies indicated an association between intrauterine exposure to perfluorooctane sulfonate (PFOS) or perfluorooctanoate (PFOA) and lower birth weight. However, these perfluoroalkyl acids (PFAAs) have to some extent been substituted by other compounds on which little is known. OBJECTIVES: We investigated the association between specific PFAAs and birth weight, birth length, and head circumference at birth. METHODS: We studied 1,507 mothers and their children from the Aarhus Birth Cohort (2008-2013). Nulliparous women were included during pregnancy, and serum levels of 16 PFAAs were measured between 9 and 20 completed gestational weeks (96% within 13 weeks). For compounds with quantifiable values in > 50% of samples (7 compounds), we report the associations with birth weight, birth length, and head circumference at birth determined by multivariable linear regression. RESULTS: Estimated mean birth weights were lower among women with serum perfluorohexane sulfonate, perfluoroheptane sulfonate, and PFOS concentrations above the lowest exposure quartile, but we found no consistent monotonic dose-response patterns. These associations were stronger when the population was restricted to term births (n = 1,426). For PFOS, the birth weight estimates for the highest versus lowest quartile were -50 g (95% CI: -123, 23 g) in all births and -62 g (95% CI: -126, 3 g) in term births. For the other PFAAs, the direction of the associations was inconsistent, and no overall association with birth weight was apparent. No PFAAs were associated with birth length or head circumference at birth. CONCLUSIONS: Overall, we did not find strong or consistent associations between PFAAs and birth weight or other indices of fetal growth, though estimated mean birth weights were lower among those with exposures above the lowest quartile for some compounds. CITATION: Bach CC, Bech BH, Nohr EA, Olsen J, Matthiesen NB, Bonefeld-Jorgensen EC, Bossi R, Henriksen TB. 2016. Perfluoroalkyl acids in maternal serum and indices of fetal growth: the Aarhus Birth Cohort. Environ Health Perspect 124:848-854; http://dx.doi.org/10.1289/ehp.1510046. PMID- 26495858 TI - Identifying Challenges Associated With the Care Transition Workflow From Hospital to Skilled Home Health Care: Perspectives of Home Health Care Agency Providers. AB - Older adults discharged from the hospital to skilled home health care (SHHC) are at high risk for experiencing suboptimal transitions. Using the human factors approach of shadowing and contextual inquiry, we studied the workflow for transitioning older adults from the hospital to SHHC. We created a representative diagram of the hospital to SHHC transition workflow, we examined potential workflow variations, we categorized workflow challenges, and we identified artifacts developed to manage variations and challenges. We identified three overarching challenges to optimal care transitions-information access, coordination, and communication/teamwork. Future investigations could test whether redesigning the transition from hospital to SHHC, based on our findings, improves workflow and care quality. PMID- 26495859 TI - Prolonged lymphocytopenia after bendamustine therapy in patients with relapsed or refractory indolent B-cell and mantle cell lymphoma. PMID- 26495860 TI - Characteristics of exceptional responders to lenalidomide-based therapy in multiple myeloma. AB - We studied all patients at our institution with a diagnosis of multiple myeloma (MM), from 1 January 2004 to 1 July 2009, who received lenalidomide-dexamethasone (Rd) as initial therapy and had a time to progression of 72 months or longer. Of 240 patients, we identified 33 exceptional responders. Twenty-five patients received primary therapy with Rd and eight patients received Rd induction followed by early stem cell transplantation (SCT). Seven of the eight patients who received SCT did not receive maintenance therapy; one patient received 9 months of lenalidomide post transplant. Fifteen (45%) patients had known clonal plasma cell disorder before the diagnosis of MM. The dominant mode of clinical presentation was with lytic lesions in 28 patients. Of those with informative cytogenetics (n=24), trisomies were present in 19 (79%), including one patient with concurrent trisomies and t(11;14). Overall, 21 of 24 patients (88%) had either trisomies or t(11;14). None of these exceptional responders had high-risk cytogenetic features at baseline. Twenty-five patients (76%) had a complete response (CR), whereas eight patients (24%) achieved the exceptional response state without ever achieving a CR. We identify a cohort of exceptional responders to Rd-based therapy, representing ~10-15% newly diagnosed MM patients with normal renal function. PMID- 26495861 TI - Positron emission tomography-computed tomography in the diagnostic evaluation of smoldering multiple myeloma: identification of patients needing therapy. AB - We studied 188 patients with a suspected smoldering multiple myeloma (MM) who had undergone a positron emission tomography-computed tomography (PET-CT) scan as part of their clinical evaluation. PET-CT was positive (clinical radiologist interpretation of increased bone uptake and/or evidence of lytic bone destruction) in 74 patients and negative in 114 patients. Of these, 25 patients with a positive PET-CT and 97 patients with a negative PET-CT were observed without therapy and formed the study cohort (n=122). The probability of progression to MM within 2 years was 75% in patients with a positive PET-CT observed without therapy compared with 30% in patients with a negative PET-CT; median time to progression was 21 months versus 60 months, respectively, P=0.0008. Of 25 patients with a positive PET-CT, the probability of progression was 87% at 2 years in those with evidence of underlying osteolysis (n=16) and 61% in patients with abnormal PET-CT uptake but no evidence of osteolysis (n=9). Patients with positive PET-CT and evidence of underlying osteolysis have a high risk of progression to MM within 2 years when observed without therapy. These observations support recent changes to imaging requirements in the International Myeloma Working Group updated diagnostic criteria for MM. PMID- 26495862 TI - Peripubertal Caffeine Exposure Impairs Longitudinal Bone Growth in Immature Male Rats in a Dose- and Time-Dependent Manner. AB - This study investigated the dose- and time-dependent effects of caffeine consumption throughout puberty in peripubertal rats. A total of 85 male SD rats were randomly divided into four groups: control and caffeine-fed groups with 20, 60, or 120 mg/kg/day through oral gavage for 10, 20, 30, or 40 days. Caffeine decreased body weight gain and food consumption in a dose- and time-dependent manner, accompanied by a reduction in muscle and body fat. In addition, it caused a shortening and lightening of leg bones and spinal column. The total height of the growth plate decreased sharply at 40 days in the controls, but not in the caffeine-fed groups, and the height of hypertrophic zone in the caffeine-fed groups was lower than in the control. Caffeine increased the height of the secondary spongiosa, whereas parameters related to bone formation, such as bone area ratio, thickness and number of trabeculae, and bone perimeter, were significantly reduced. Furthermore, serum levels of IGF-1, estradiol, and testosterone were also reduced by the dose of caffeine exposure. Our results demonstrate that caffeine consumption can dose- and time-dependently inhibit longitudinal bone growth in immature male rats, possibly by blocking the physiologic changes in body composition and hormones relevant to bone growth. PMID- 26495863 TI - Clonal Clustering Using 10-Gene Multilocus Sequence Typing Reveals an Association Between Genotype and Listeria monocytogenes Maximum Growth Rate in Defined Medium. AB - We used a 10-gene (10G) multilocus sequence typing scheme to investigate the diversity and phylogenetic distribution of 124 Listeria monocytogenes strains across major lineages, major serotypes, and seven epidemic clones that have been previously associated with outbreaks. The 124 isolates proved to be diverse, with a total of 81 sequence types (10G-STs) belonging to 13 clonal complexes (CCs), where all STs of the same CC differ from one another in up to 3 of the 10 alleles (named as 10G-triple-locus-variant-clonal-complexes [10G-TLV-CCs]). Phenotypic characterization for 105 of the 124 strains showed that L. monocytogenes had variable maximum growth rate (MU(max)) in a defined medium at 16 degrees C, and classification by lineage or serotype was not able to reflect the genetic basis for the difference of this phenotype. Among the six major 10G-TLV-CCs, 10G-TLV CC4 that included lineage I strains had significantly lower MU(max) (Tukey honestly significant difference adjusted [adj.] p < 0.05) compared to 10G-TLV-CC1 and 10G-TLV-CC3 that both comprised lineage II strains, indicating a distinct difference in growth of these L. monocytogenes isolates under nutrient-limited conditions among some of the CCs. However, the other three (10G-TLV-CC2, 6, and 10) of the six major 10G-TLV-CCs containing either lineage I or lineage II strains did not show significantly different MU(max) compared to the others (adj. p < 0.05). Our findings highlighted the importance of using molecular typing methods that can be used in evolutionary analyses as a framework for further understanding the phenotypic characteristics of subgroups of L. monocytogenes. PMID- 26495865 TI - The spatial distribution of smoking violations on a no-smoking campus: Implications for prevention. AB - OBJECTIVE: The present study extends research on campus smoking bans by examining where smokers are violating the policy at a large university in the southeastern region of the United States. PARTICIPANTS: The data collection was conducted by one graduate student from the university in August of 2014. METHODS: A global positioning system device was used to collect the geo-coordinates of littered cigarette butts as a proxy measure for smoking violations. RESULTS: A hot spot analysis found a number of spatial concentrations on campus, largely around classroom and administrative buildings along with parking lots and garages. CONCLUSIONS: The implications of such findings can direct enforcement to target these areas in order to reduce offenses and fulfill the initial goals of policy makers and university administrators who support smoke-free campuses. PMID- 26495864 TI - Parental intention regarding the administration of the HPV vaccine for adolescent daughters in Taiwan. AB - This study aimed to investigate parental intention regarding the human papilloma virus (HPV) vaccination for adolescent daughters. Parents or guardians of adolescent girls, aged 12-14 years, from junior high schools in Taiwan participated and completed a HPV vaccination intention survey based on the Theory of Planned Behavior. The survey was conducted from October to November, 2009. Most, 78%, of the respondents reported a high intention to vaccinate daughters against HPV. A high intention of vaccination was associated with a family history of gynecological tumors (adjusted odds ratio [OR]: 2.22, 95% confidence interval [CI]: 1.10-4.51) and HPV awareness (adjusted OR: 2.33, 95% CI: 1.45-3.76). Higher parental intention was reported by respondents with a positive attitude toward the HPV vaccine (adjusted OR: 6.83, 95% CI: 4.16-11.22), perceived greater influence of subjective norms (adjusted OR: 121.23, 95% CI: 42.69-344.21), greater perceived behavioral control (adjusted OR: 67.69, 95% CI: 16.40-279.41), and perceived that the vaccine had limited influence on adolescent sexual behavior (adjusted OR: 2.24, 95% CI: 1.41-3.78). Health-care professionals must be knowledgeable about the HPV and actively promote vaccination among adolescent girls. Improvements in vaccination can be achieved through recommendations by physicians and nurses. PMID- 26495867 TI - Gypsum blocks produced from TiO2 production by-products. AB - Calcined titanium gypsum was investigated by the ways of XRD (powder X-ray diffraction), XRF (X-ray fluorescence) and TG-DTA (thermogravimetric-differential thermal analyses). It was employed as raw material for making lightweight materials. The influence of cement, amount of water/solid (W/S) ratio, water reducing agent, citric acid content and the hydration age on the gypsum blocks was investigated. The results showed that the optimum W/S ratio, cement content and water-reducing agent are 0.9, 10% and 2 wt% for the calcined gypsum from titanium gypsum, respectively. The 5.96 MPa was attained after 7 days of ageing. It was also found that the citric acid is inappropriate to be used in the production of gypsum blocks from TiO2 production by-products. PMID- 26495868 TI - SSBP3 Interacts With Islet-1 and Ldb1 to Impact Pancreatic beta-Cell Target Genes. AB - Islet-1 (Isl1) is a Lin11, Isl1, Mec3 (LIM)-homeodomain transcription factor important for pancreatic islet cell development, maturation, and function, which largely requires interaction with the LIM domain-binding protein 1 (Ldb1) coregulator. In other tissues, Ldb1 and Isl1 interact with additional factors to mediate target gene transcription, yet few protein partners are known in beta cells. Therefore, we hypothesize that Ldb1 and Isl1 participate in larger regulatory complexes to impact beta-cell gene expression. To test this, we used cross-linked immunoprecipitation and mass spectrometry to identify interacting proteins from mouse beta-cells. Proteomic datasets revealed numerous interacting candidates, including a member of the single-stranded DNA-binding protein (SSBP) coregulator family, SSBP3. SSBPs potentiate LIM transcription factor complex activity and stability in other tissues. However, nothing was known of SSBP3 interaction, expression, or activity in beta-cells. Our analyses confirmed that SSBP3 interacts with Ldb1 and Isl1 in beta-cell lines and in mouse and human islets and demonstrated SSBP3 coexpression with Ldb1 and Isl1 pancreas tissue. Furthermore, beta-cell line SSBP3 knockdown imparted mRNA deficiencies similar to those observed upon Ldb1 reduction in vitro or in vivo. This appears to be (at least) due to SSBP3 occupancy of known Ldb1-Isl1 target promoters, including MafA and Glp1r. This study collectively demonstrates that SSBP3 is a critical component of Ldb1-Isl1 regulatory complexes, required for expression of critical beta-cell target genes. PMID- 26495869 TI - Absence of TGF-beta Receptor Activation by Highly Purified hCG Preparations. AB - Recently, several LH/human chorionic gonadotropin (hCG) receptor-independent activities for hCG have been described, including activation of the TGF-beta receptor (TGFbetaR) by hyperglycosylated hCG and stimulation of trophoblast invasion. Because the hCG concentrations used in these studies have been rather high, reflecting physiological hCG levels in pregnancy, even a minor contamination with growth factors, which act at very low concentrations, may be significant. Several commercial hCG preparations have been found to contain significant amounts of epidermal growth factor (EGF), which we also confirmed here. Furthermore, we found that some hCG preparations also contain significant amounts of TGF-beta1. These hCG preparations were able to activate ERK1/2 in JEG 3 choriocarcinoma cells or TGFbetaR in mink lung epithelial cells transfected with a reporter gene for TGFbetaR activation. No such activation was found with highly purified hCG or its free beta-subunit (hCGbeta), irrespective of whether they were hyperglycosylated or not. Taken together, our results suggest that the growth factor contaminations in the hCG preparations can cause activation of TGFbetaR and, at least in JEG-3 cells, MAPK signaling. This highlights the importance to carefully control for potential contaminations and that highly purified hCG preparations have to be used for biological studies. PMID- 26495871 TI - Low-Dose Gamma Radiation Does Not Induce an Adaptive Response for Micronucleus Induction in Mouse Splenocytes. AB - Low-dose ionizing radiation is known to induce radioadaptive responses in cells in vitro as well as in mice in vivo. Low-dose radiation decreases the incidence and increases latency for spontaneous and radiation-induced tumors in mice, potentially as a result of enhanced cellular DNA repair efficiency or a reduction in genomic instability. In this study, the cytokinesis-block micronucleus (CBMN) assay was used to examine dose response and potential radioadaptive response for cytogenetic damage and cell survival in C57BL/6 and BALB/c spleen cells exposed in vitro or in vivo to low-dose 60Co gamma radiation. The effects of genetic background, radiation dose and dose rate, sampling time and cell cycle were investigated with respect to dose response and radioadaptive response. In C57BL/6 mice, a linear-quadratic dose-response relationship for the induction of micronuclei (MN) was observed for doses between 100 mGy and 2 Gy. BALB/c mice exhibited increased radiosensitivity for MN induction compared to C57BL/6 mice. A 20 mGy dose had no effect on MN frequencies in splenocytes of either mouse strain, however, increased spleen weight and a reduced number of dead cells were noted in the C57BL/6 strain only. Multiple experimental parameters were investigated in radioadaptive response studies, including dose and dose rate of the priming dose (20 mGy at 0.5 mGy/min and 100 mGy at 10 mGy/min), time interval (4 and 24 h) between priming and challenge doses, cell cycle stage (resting or proliferating) at exposure and kinetics after the challenge dose. Radioadaptive responses were not observed for MN induction for either mouse strain under any of the experimental conditions investigated. In contrast, a synergistic response for radiation-induced micronuclei in C57BL/6 spleen was detected after in vivo 20 mGy irradiation. This increase in the percentage of cells with cytogenetic damage was associated with a reduction in the number of nonviable spleen cells, suggesting that low-dose irradiation led to a reduction in the turnover of damaged cells within the spleen of C57BL/6 mice. Overall, these results indicate that long-term protective effects against tumor latency and other beneficial health outcomes observed after low-dose irradiation are not mediated by a reduction of the proportion of cells harboring radiation-induced cytogenetic damage. PMID- 26495870 TI - Total Body Irradiation in the "Hematopoietic" Dose Range Induces Substantial Intestinal Injury in Non-Human Primates. AB - The non-human primate has been a useful model for studies of human acute radiation syndrome (ARS). However, to date structural changes in various parts of the intestine after total body irradiation (TBI) have not been systematically studied in this model. Here we report on our current study of TBI-induced intestinal structural injury in the non-human primate after doses typically associated with hematopoietic ARS. Twenty-four non-human primates were divided into three groups: sham-irradiated control group; and total body cobalt-60 (60Co) 6.7 Gy gamma-irradiated group; and total body 60Co 7.4 Gy gamma-irradiated group. After animals were euthanized at day 4, 7 and 12 postirradiation, sections of small intestine (duodenum, proximal jejunum, distal jejunum and ileum) were collected and fixed in 10% formalin. The intestinal mucosal surface length, villus height and crypt depths were assessed by computer-assisted image analysis. Plasma citrulline levels were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total bone marrow cells were counted and hematopoietic stem/progenitor cells in bone marrow were analyzed by flow cytometer. Histopathologically, all segments exhibited conspicuous disappearance of plicae circulares and prominent atrophy of crypts and villi. Intestinal mucosal surface length was significantly decreased in all intestinal segments on day 4, 7 and 12 after irradiation (P < 0.02-P < 0.001). Villus height was significantly reduced in all segments on day 4 and 7 (P = 0.02-0.005), whereas it had recovered by day 12 (P > 0.05). Crypt depth was also significantly reduced in all segments on day 4, 7 and 12 after irradiation (P < 0.04-P < 0.001). Plasma citrulline levels were dramatically reduced after irradiation, consistent with intestinal mucosal injury. Both 6.7 and 7.4 Gy TBI reduced total number of bone marrow cells. And further analysis showed that the number and function of CD45(+)CD34(+) hematopoietic stem/progenitors in bone marrow decreased significantly. In summary, TBI in the hematopoietic ARS dose range induces substantial intestinal injury in all segments of the small bowel. These findings underscore the importance of maintaining the mucosal barrier that separates the gut microbiome from the body's interior after TBI. PMID- 26495872 TI - Design and pharmacokinetical aspects for the use of inorganic nanoparticles in radiomedicine. AB - The potential use of nanoparticles (NPs) in medicine is determined by the pharmacokinetical and biodistribution aspects that govern NP behaviour. In this context, diagnosis (low irradiation dose) and therapy (high irradiation dose) is about the same for the NP, as much as to deliver toxic doses of radiation or toxic doses of a chemotherapeutic agent. The NP effects also have to be correlated with how they interact, evolve and are transformed during their exposure to the human body, during their administration, distribution, metabolization and expulsion. Indeed, owing to interactions between NPs and components from the biological medium, NPs are known to suffer different types of alterations, such as loss of colloidal stability (aggregation and sedimentation), protein adsorption (and consequent exposure to or escape from the immune system) and chemical transformation (oxidation, corrosion and dissolution). Their original performance and these alterations have a major impact on NP behaviour and have to be taken into account for any intended use of them in medicine, also including their use for enhanced radiodiagnosis, radiotherapy and radiochemotherapy. PMID- 26495873 TI - The effect of chemotherapy on the mammographic appearance of breast cancer and correlation with histopathology. AB - OBJECTIVE: To document the mammographic changes after neoadjuvant chemotherapy with histopathological correlation, to calculate the accuracy of mammography (MG) in predicting residual tumour size and to measure the interobserver agreement in reading mammograms. METHODS: In 446 consecutive cases, the pre- and post chemotherapy mammograms were retrospectively evaluated by two blinded observers, and consensus findings were compared with reference standard of surgical specimen. The accuracy of MG in predicting residual tumour size was calculated. Kappa statistics were calculated for measuring the interobserver agreement for reading mammograms. The sensitivity, specificity, positive-predictive value and negative-predictive value for the prediction of residual disease were calculated. RESULTS: The most common primary abnormalities were mass lesions without and with microcalcifications. After chemotherapy, there was decrease in size of most (95.1%) of the measurable masses, with decrease in the mean tumour size from 4.1 to 2.5 cm. The density of the tumour decreased in 66.6% (241/362) cases with residual disease. There was almost perfect interobserver agreement for describing the primary abnormality in the pre- as well as post-chemotherapy mammograms (k = 0.87 and 0.81, respectively) with substantial agreement for measurement of the mass lesions before and after chemotherapy (k = 0.69 and 0.68, respectively). MG showed accuracy of 60.0%, sensitivity of 94.4%, specificity of 50.0%, positive predictive value of 91.3% and negative-predictive value of 61.8%. CONCLUSION: MG remains a highly sensitive and reproducible investigation for the assessment of residual disease after chemotherapy. ADVANCES IN KNOWLEDGE: There is substantial interobserver agreement in characterizing and measuring breast tumours on mammograms. PMID- 26495874 TI - Prevalence, awareness, characteristics, and health outcomes associated with COPD at-risk status among adults in Japan. AB - OBJECTIVES: We examined the prevalence of chronic obstructive pulmonary disease (COPD) diagnosed and at-risk status, and public awareness of COPD among adults in Japan, as well as respondent characteristics and health outcomes compared with controls. METHODS: Regression models used 2012 National Health and Wellness Survey in Japan data to compare COPD-diagnosed, at-risk, and healthy adults (aged >=18) on demographics, health behaviors, health-related quality of life (HRQoL), productivity and healthcare resource use. RESULTS: Among n = 29,978 respondents, diagnosed COPD prevalence was 0.9%; 26.9% were at-risk. Relative to controls, those at-risk and diagnosed with COPD had significantly greater healthcare resource use, with lower productivity and HRQoL. Fewer than 20% of respondents were aware of COPD. CONCLUSIONS: Over 25% of adult Japanese respondents were at risk for COPD and had health outcomes impairments relative to controls. Efforts to increase awareness among the general public are needed. PMID- 26495875 TI - Heat Dissipation Interfaces Based on Vertically Aligned Diamond/Graphite Nanoplatelets. AB - Crystalline carbon-based materials are intrinsically chemically inert and good heat conductors, allowing their applications in a great variety of devices. A technological step forward in heat dissipators production can be given by tailoring the carbon phase microstructure, tuning the CVD synthesis conditions. In this work, a rapid bottom-up synthesis of vertically aligned hybrid material comprising diamond thin platelets covered by a crystalline graphite layer was developed. A single run was designed in order to produce a high aspect ratio nanostructured carbon material favoring the thermal dissipation under convection governed conditions. The produced material was characterized by multiwavelength Raman spectroscopy and electron microscopy (scanning and transmission), and the macroscopic heat flux was evaluated. The results obtained confirm the enhancement of heat dissipation rate in the developed hybrid structures, when compared to smooth nanocrystalline diamond films. PMID- 26495877 TI - Absorption Spectroscopy of Single Optically Trapped Gold Nanorods. AB - Extinction spectra of single gold nanorods optically trapped in water were measured by spatial modulation spectroscopy. Comparison of the extinction cross sections and resonance frequencies to finite element calculations allows us to determine the dimensions of the nanorod and estimate the contribution of radiation damping to the LSPR line width. Subtracting the radiation damping and bulk contributions from the measured line widths yields the electron-surface scattering contribution. The results show that the surfactant coating for the nanorods causes large electron-surface scattering effects with significant particle-to-particle variations. These effects are more pronounced than those seen for substrate-supported particles in previous single particle studies. Indeed, the measured line widths are only slightly narrower than that of the ensemble spectrum. These results show the importance of removing surfactant for sensing applications of these materials. PMID- 26495876 TI - Natural Diels-Alderases: Elusive and Irresistable. AB - Eight examples of biosynthetic pathways wherein a natural enzyme has been identified and claimed to function as a catalyst for the [4 + 2] cycloaddition reaction, namely, Diels-Alderases, are briefly reviewed. These are discussed in the context of the mechanistic challenges associated with the technical difficulty of proving that the net formal [4 + 2] cycloaddition under study indeed proceeds through a synchronous mechanism and that the putative biosynthetic enzyme deploys the pericyclic transition state required for a Diels Alder cycloaddition reaction. PMID- 26495878 TI - Mechanism of the Ti(III)-Catalyzed Acyloin-Type Umpolung: A Catalyst-Controlled Radical Reaction. AB - The titanium(III)-catalyzed cross-coupling between ketones and nitriles provides an efficient stereoselective synthesis of alpha-hydroxyketones. A detailed mechanistic investigation of this reaction is presented, which involves a combination of several methods such as EPR, ESI-MS, X-ray, in situ IR kinetics, and DFT calculations. Our findings reveal that C-C bond formation is turnover limiting and occurs by a catalyst-controlled radical combination involving two titanium(III) species. The resting state is identified as a cationic titanocene nitrile complex and the beneficial effect of added Et3N.HCl on yield and enantioselectivity is elucidated: chloride coordination initiates the radical coupling. The results are fundamental for the understanding of titanium(III) catalysis and of relevance for other metal-catalyzed radical reactions. Our conclusions might apply to a number of reductive coupling reactions for which conventional mechanisms were proposed before. PMID- 26495879 TI - Effects of Fuel Aromatic Content on Nonvolatile Particulate Emissions of an In Production Aircraft Gas Turbine. AB - Aircraft engines emit particulate matter (PM) that affects the air quality in the vicinity of airports and contributes to climate change. Nonvolatile PM (nvPM) emissions from aircraft turbine engines depend on fuel aromatic content, which varies globally by several percent. It is uncertain how this variability will affect future nvPM emission regulations and emission inventories. Here, we present black carbon (BC) mass and nvPM number emission indices (EIs) as a function of fuel aromatic content and thrust for an in-production aircraft gas turbine engine. The aromatics content was varied from 17.8% (v/v) in the neat fuel (Jet A-1) to up to 23.6% (v/v) by injecting two aromatic solvents into the engine fuel supply line. Fuel normalized BC mass and nvPM number EIs increased by up to 60% with increasing fuel aromatics content and decreasing engine thrust. The EIs also increased when fuel naphthalenes were changed from 0.78% (v/v) to 1.18% (v/v) while keeping the total aromatics constant. The EIs correlated best with fuel hydrogen mass content, leading to a simple model that could be used for correcting fuel effects in emission inventories and in future aircraft engine nvPM emission standards. PMID- 26495880 TI - Exploiting Dispersion-Driven Aggregators as a Route to New One-Dimensional Organic Nanowires. AB - The efficiency of charge carrier mobility in organic semiconductors is heavily dependent upon the long-range organization (i.e., morphology) and the local relative arrangement of the transporting molecules. Here, we exploit London dispersion forces as a design principle to construct compact one-dimensional (1 D) assemblies of quaterthiophene cores. We demonstrate that the substitution of quaterthiophene with dispersion-driven aggregators (e.g., [7]ladderanes, hydrogenated pyrenes, etc.) leads to the formation of highly stable and tightly packed 1-D supramolecular assemblies with electronic compactness superior to that of quaterthiophene crystals. Tunability and even tighter stacking arrangements can be achieved by inserting molecular linkers between the quaterthiophene fragments and the dispersion-driven components. The proposed 1-D nanowires represent an original route toward the rational design of efficient organic semiconductors. PMID- 26495881 TI - A Non-Inferiority Study: Modified Dual Therapy Consisting Higher Doses of Rabeprazole Is as Successful as Standard Quadruple Therapy in Eradication of Helicobacter pylori. AB - The aim is to compare high-dose rabeprazole and amoxicillin containing modified dual therapy (MDT) with bismuth subcitrate containing standard quadruple therapy (SQT) as the first-line Helicobacter pylori eradication treatment in terms of efficacy, safety, and adherence to treatment. A total of 200 consecutive patients diagnosed endoscopically with nonulcer dyspepsia with H. pylori infection were randomly assigned into 2 groups, 1 treated with amoxicillin 750 mg thrice daily plus rabeprazole 20 mg thrice daily (MDT group) or rabeprazole 20 mg b.i.d., bismuth subcitrate 120 mg q.i.d., tetracycline 500 mg q.i.d., metronidazole 500 mg t.i.d. (SQT group). Overall, 196 patients (98 in the MDT group and 98 in the SQT group) completed the study. H. pylori eradication was achieved in 84.7% of patients in the MDT group by intention to treat analysis and 84.9% by per protocol analysis, which were comparable with SQT group (87.8% and 88.8%, respectively). Adverse events including nausea (P = 0.03), dysgeusia (P < 0.001), diarrhea (P = 0.001), black colored stool (P < 0.001), headache (P = 0.01), and abdominal pain (P = 0.05) were significantly higher in SQT group. The MDT is an efficient and safe treatment choice that could be recommended in the first-line eradication treatment of H. pylori. PMID- 26495882 TI - Clinical Outcomes of a Pharmacy-Led Blood Factor Stewardship Program. AB - To report the results of a pharmacist-directed blood factor stewardship program targeting off-label utilization designed to limit use to established organizational guidelines in high-risk populations. Prospective evaluation of recombinant factor VIIa and prothrombin complex concentrate orders beginning June 2013 through May 2014 and a matched retrospective cohort from June 2012 to May 2013. Matched cohorts were evaluated for 28-day mortality, change in international normalized ratio (INR), adverse events, concurrent blood product use, and cost savings. Forty-two orders for blood factor were ordered between June 2013 and May 2014, 70 orders in the year before (N = 112). Twenty eight-day mortality was not different between the cohorts: 53.9% versus 50% (P = 0.77). Blood factor use with underlying liver failure and active bleeding was strongly associated with 28-day mortality: odds ratio (95% confidence interval), 2.9 (1.5 7.14) and 2.91 (0.01-2.91), respectively. Blood products dispensed increased over the year with plasma products the most significant (1 vs. 4 P = 0.004). All other clinical outcomes were nonsignificant. An annual cost savings of $375,539 was achieved, primarily through a significant reduction in recombinant factor VIIa and avoidance in high-risk patients. Use of off-label blood factors can be controlled through a pharmacist-led stewardship program. Twenty eight-day mortality was not different between the 2 cohorts; however, identification of risk factors for death associated with blood factor use allows for restriction in high-risk populations, creates a discussion of futile care, and yields cost savings. PMID- 26495883 TI - HIV-Infected Ugandan Women on Antiretroviral Therapy Maintain HIV-1 RNA Suppression Across Periconception, Pregnancy, and Postpartum Periods. AB - BACKGROUND: HIV-infected women risk sexual and perinatal HIV transmission during conception, pregnancy, childbirth, and breastfeeding. We compared HIV-1 RNA suppression and medication adherence across periconception, pregnancy, and postpartum periods, among women on antiretroviral therapy (ART) in Uganda. METHODS: We analyzed data from women in a prospective cohort study, aged 18-49 years, enrolled at ART initiation and with >=1 pregnancy between 2005 and 2011. Participants were seen quarterly. The primary exposure of interest was pregnancy period, including periconception (3 quarters before pregnancy), pregnancy, postpartum (6 months after pregnancy outcome), or nonpregnancy related. Regression models using generalized estimating equations compared the likelihood of HIV-1 RNA <=400 copies per milliliter, <80% average adherence based on electronic pill caps (medication event monitoring system), and likelihood of 72 hour medication gaps across each period. RESULTS: One hundred eleven women contributed 486 person-years of follow-up. Viral suppression was present at 89% of nonpregnancy, 97% of periconception, 93% of pregnancy, and 89% of postpartum visits, and was more likely during periconception (adjusted odds ratio, 2.15) compared with nonpregnant periods. Average ART adherence was 90% [interquartile range (IQR), 70%-98%], 93% (IQR, 82%-98%), 92% (IQR, 72%-98%), and 88% (IQR, 63% 97%) during nonpregnant, periconception, pregnant, and postpartum periods, respectively. Average adherence <80% was less likely during periconception (adjusted odds ratio, 0.68), and 72-hour gaps per 90 days were less frequent during periconception (adjusted relative risk, 0.72) and more frequent during postpartum (adjusted relative risk, 1.40). CONCLUSIONS: Women with pregnancy were virologically suppressed at most visits, with an increased likelihood of suppression and high adherence during periconception follow-up. Increased frequency of 72-hour gaps suggests a need for increased adherence support during postpartum periods. PMID- 26495884 TI - An Evaluation of Various Ventilator-Associated Infection Criteria in a PICU. AB - OBJECTIVE: To describe characteristics and overlap associated with various ventilator-associated infection criteria in the PICU. DESIGN: Retrospective observational study. SETTING: A quaternary care children's hospital PICU. PATIENTS: Children ventilated more than 48 hours, excluding patients with tracheostomy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ventilator associated infection, including pneumonia, infection-related ventilator associated condition, tracheobronchitis, and lower respiratory tract infection were defined according to criteria from the Centers for Disease Control and Prevention or medical literature. Clinical data were abstracted to assign diagnoses of each ventilator-associated infection. In 300 episodes of mechanical ventilation, there were 30 individual episodes of ventilator-associated infection. Nine episodes met more than one definition. Rates per 1,000 ventilator days were 2.60 for ventilator-associated pneumonia, 2.16 for infection-related ventilator-associated condition, 5.19 for ventilator-associated tracheobronchitis, and 6.92 for lower respiratory tract infection. The rate of any ventilator-associated infection was 12.98 per 1,000 ventilator days. Individual criteria had similar risk factors and outcomes. Risk factors for development of any ventilator-associated infection included older age (p = 0.003) and trauma (p = 0.007), while less cardiac surgery patients developed ventilator associated infection (p = 0.015). On multivariate analysis, trauma was the only independent risk factor (adjusted odds ratio, 3.10; 95% CI, 1.15-8.38). Developing any ventilator-associated infection was associated with longer duration of mechanical ventilation (p < 0.001) and longer PICU length of stay (p < 0.001) but not PICU mortality (p = 0.523). CONCLUSIONS: There is little overlap in diagnosis of various ventilator-associated infection. However, the risk factors and outcomes associated with individual criteria are similar, indicating that they may have validity in identifying true pathology. Ventilator-associated infection in general is likely a larger problem than indicated by low hospital reported rates of ventilator-associated pneumonia. There is clinical confusion due to the presence of several diagnostic criteria for ventilator-associated infection. Developing a more inclusive and clinically relevant criterion for diagnosing ventilator-associated infection is warranted to accurately assess their impact and improve guidance for clinicians in evaluating and treating ventilator-associated infection. PMID- 26495885 TI - Association between ADAMTS-4 gene polymorphism and lumbar disc degeneration in Chinese Han population. AB - Low back pain (LBP) is a common health problem and many LBP are caused by lumbar disc degeneration (LDD). ADAMTS-4 (a disintegrin and metalloprotease with thrombospondin motifs-4), also known as aggrecanse-1, plays a core role in degeneration of extracellular matrix in LDD. To investigate the association between ADAMTS-4 genetic polymorphism and LDD, we genotyped SNPs in and around ADAMTS-4. We recruited 482 sporadic cases of LDD and 496 healthy controls from Chinese Han population. Five SNPs were selected and phenotyped by the Sequenom MassARRAY system. Allelic, genotypic, and haplotypic association was performed. Rs4233367 (c.1877 C>T), which located in exon of ADAMTS-4 showed significant association with LDD. The T allele conferred a lower risk of LDD with an OR of 0.69 and TT genotype is at nearly one-fifth of the risk compared to CC genotype. Other tested SNPs didn't show significant difference between the case and control groups. The SNP rs4233367 in the exon of ADAMTS-4 gene may be associated with lumbar disc degeneration. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:860-864, 2016. PMID- 26495886 TI - Application of mercapto-silica polymerized high internal phase emulsions for the solid-phase extraction and preconcentration of trace lead(II). AB - A new class of solid-phase extraction column prepared with grafted mercapto silica polymerized high internal phase emulsion particles was used for the preconcentration of trace lead. First, mercapto-silica polymerized high internal phase emulsion particles were synthesized by using high internal phase emulsion polymerization and carefully assembled in a polyethylene syringe column. The influences of various parameters including adsorption pH value, adsorption and desorption solvents, flow rate of the adsorption and desorption procedure were optimized, respectively, and the suitable uploading sample volumes, adsorption capacity, and reusability of solid phase extraction column were also investigated. Under the optimum conditions, Pb(2+) could be preconcentrated quantitatively over a wide pH range (2.0-5.0). In the presence of foreign ions, such as Na(+) , K(+) , Ca(2+) , Zn(2+) , Mg(2+) , Cu(2+) , Fe(2+) , Cd(2+) , Cl( ) and NO3 (-) , Pb(2+) could be recovered successfully. The prepared solid-phase extraction column performed with high stability and desirable durability, which allowed more than 100 replicate extractions without measurable changes of performance. The feasibility of the developed method was further validated by the extraction of Pb(2+) in rice samples. At three spiked levels of 40.0, 200 and 800 MUg/kg, the average recoveries for Pb(2+) in rice samples ranged from 87.3 to 105.2%. PMID- 26495888 TI - How cockroaches exploit tactile boundaries to find new shelters. AB - Animals such as cockroaches depend on exploration of unknown environments, and their strategies may inspire robotic approaches. We have previously shown that cockroach behavior, with respect to shelters and the walls of an otherwise empty arena, can be captured with a stochastic state-based algorithm. We call this algorithm RAMBLER, randomized algorithm mimicking biased lone exploration in roaches. In this work, we verified and extended this model by adding a barrier in the previously used arena and conducted more cockroach experiments. In two arena configurations, our simulated model's path length distribution was similar to the experimental distribution (mean experimental path length 3.4 and 3.2 m, mean simulated path length 3.9 and 3.3 m). By analyzing cockroach behavior before, along, and at the end of the barrier, we have generalized RAMBLER to address arbitrarily complex 2D mazes. For biology, this is an abstract behavioral model of a decision-making process in the cockroach brain. For robotics, this is a strategy that may improve exploration for goals, especially in unpredictable environments with non-convex obstacles. Generally, cockroach behavior seems to recommend variability in the absence of planning, and following paths defined by walls. PMID- 26495889 TI - An overview of the use of SNaPshot for predicting blood group antigens. AB - The use of SNaPshot (Applied Biosystems, Foster City, CA) for predicting blood group antigens has emerged as an alternative to hemagglutination testing and also to the current low- and highthroughput blood group genotyping methods. Several groups have developed multiplex-polymerase chain reaction SNaPshot assays to determine single nucleotide polymorphisms (SNPs) in blood group genes with the purpose of identifying clinically relevant antigens and rare alleles. The selection of SNPs is based on the population or laboratory reality and the purpose of the genatyping. Unlike high-throughput genotyping strategies that are provided as commercial platforms, the SNPs can be chosen to best meet the needs of the user, and the interpretation of the results do not depend on the manufacturer. PMID- 26495890 TI - Multiplex ligation-dependent probe amplification (MLPA) assay for blood group genotyping, copy number quantification, and analysis of RH variants. AB - The blood group multiplex ligation-dependent probe amplification (MLPA) is a comprehensive assay, developed for genotyping the majority of clinically relevant blood group antigens in both patients and donors. The MLPA is an easy method to apply and only requires a thermal cycler and capillary electrophoresis equipment. Because the molecular basis of blood group antigens can be a single nucleotide polymorphism, an insertion/deletion polymorphism, or genetic recombination, a single assay such as the MLPA to facilitate these different types of genetic variation is a prerequisite in blood group typing. An MLPA assay allows the simultaneous detection of up to 50 polymorphisms in a single tube. The blood group MLPA currently consists of three separate probe pools targeting 104 different blood group alleles of 18 blood group systems. The assay is performed in a 96-well plate; therefore, a maximum of 32 genomic DNA samples can be processed simultaneously. Results are available within 24 hours,and software for analysis of the MLPA results is available free of charge. In addition to the analysis of genetic variation in blood group genes, a major advantage of the test is the ability to detect aberrations in gene copy numbers, which is especially useful for the determination of homo- or hemizygous status of RHD or other blood group genes and for detection of blood chimerism. A relatively large number of RH wild-type and mutation-specific probes are included in the assay, allowing an extensive analysis of RHD variants. In our reference lab in the Netherlands, the MLPA was validated to detect RH variants in patients, donors, and pregnant women. Furthermore, we have used the MLPA to provide comprehensive typing after blood transfusion of 52 blood group antigens simultaneously, in patients with red cell autoantibodies or patients with rare phenotypes. PMID- 26495887 TI - Mechanisms of drug resistance: daptomycin resistance. AB - Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction into clinical practice in 2003, DAP has become an important key frontline antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP resistance (DAP-R) has been extensively documented in clinically important organisms such as Staphylococcus aureus, Enterococcus spp., and Streptococcus spp. Studies on the mechanisms of DAP-R in Bacillus subtilis and other Gram-positive bacteria indicate that the genetic pathways of DAP-R are diverse and complex. However, a common phenomenon emerging from these mechanistic studies is that DAP-R is associated with important adaptive changes in cell wall and cell membrane homeostasis with critical changes in cell physiology. Findings related to these adaptive changes have provided novel insights into the genetics and molecular mechanisms of bacterial cell envelope stress response and the manner in which Gram-positive bacteria cope with the antimicrobial peptide attack and protect vital structures of the cell envelope, such as the cell membrane. In this review, we will examine the most recent findings related to the molecular mechanisms of resistance to DAP in relevant Gram-positive pathogens and discuss the clinical implications for therapy against these important bacteria. PMID- 26495891 TI - An overview of the Progenika ID CORE XT: an automated genotyping platform based on a fluidic microarray system. AB - Automated testing platforms facilitate the introduction of red cell genotyping of patients and blood donors. Fluidic microarray systems, such as Luminex XMAP (Austin, TX), are used in many clinical applications, including HLA and HPA typing. The Progenika ID CORE XT (Progenika Biopharma-Grifols, Bizkaia, Spain) uses this platform to analyze 29 polymorphisms determining 37 antigens in 10 blood group systems. Once DNA has been extracted, processing time is approximately 4 hours. The system is highly automated and includes integrated analysis software that produces a file and a report with genotype and predicted phenotype results. PMID- 26495892 TI - Mass-scale donor red cell genotyping using real-time array technology. AB - Blood centers are in the unique position to evaluate large numbers of blood donations for antigen-negative blood types. The limitations with the use of hemagglutination, however, can be circumvented with red cell genotyping. The reagents used for genotyping are synthesized and can be designed for any of the known blood group antigen single nucleotide polymorphisms that are associated with blood group antigen expression. There is interest in the application of mass scale red cell genotyping of blood donors to find rare phenotypes and rare combinations of antigens. When performed on donors who are predicted to donate again after testing, integrating the genotype information with existing donor data and demographics provides the blood center with real-time information to identify the common clinically relevant blood group antigens demanded by hospital transfusion services. This review outlines a red cell genotype methodology using TaqMan chemistry and existing algorithms and data handling to gain the full value of mass-scale red cell genotyping of blood donors. PMID- 26495893 TI - Blood group genotyping: the power and limitations of the Hemo ID Panel and MassARRAY platform. AB - Matrix-assisted laser desorption/ionization, time-of-flight mass spectrometry (MALDI-TOF MS), is a sensitive analytical method capable of resolving DNA fragments varying in mass by a single nucleotide. MALDI-TOF MS is applicable to blood group genotyping, as the majority of blood group antigens are encoded by single nucleotide polymorphisms. Blood group genotyping by MALDI-TOF MS can be performed using a panel (Hemo ID Blood Group Genotyping Panel, Agena Bioscience Inc., San Diego, CA) that is a set of genotyping assays that predict the phenotype for 101 antigens from 16 blood group systems. These assays involve three fundamental stages: multiplex target-specific polymerase chain reaction amplification, allele-specific single base primer extension, and MALDI-TOFMS analysis using the MassARRAY system. MALDI-TOF MS-based genotyping has many advantages over alternative methods including high throughput, high multiplex capability, flexibility and adaptability, and the high level of accuracy based on the direct detection method. Currently available platforms for MALDI-TOF MS-based genotyping are not without limitations, including high upfront instrumentation costs and the number of non-automated steps. The Hemo ID Blood Group Genotyping Panel, developed and optimized in a collaboration between the vendor and the Blood Transfusion Service of the Swiss Red Cross in Zurich, Switzerland, is not yet widely utilized, although several laboratories are currently evaluating the MassARRAY system for blood group genotyping. Based on the accuracy and other advantages offered by MALDITOF MS analysis, in the future, this method is likely to become widely adopted for blood group genotyping, in particular, for population screening. PMID- 26495894 TI - HEA BeadChipTM technology in immunohematology. AB - Classic methods to determine human red blood cell (RBC) antigens are based on serologic testing. Thanks to increased knowledge of the molecular basis associated with many blood group antigens, it is currently possible to predict their presence or absence on the red cell membrane. Several molecular techniques have been developed to detect the most important allelic variations attributable to single nucleotide polymorphisms. The human erythrocyte antigen (HEA) BeadChipTM system manufactured by BioArray Solutions (Immucor, Warren, NJ) is one of the commercial DNA array platforms currently available to predict HEAs by DNA analysis. This technology provides a useful tool to increase the inventory of antigen-negative RBC units and prevent immunization of patients who require chronic transfusion by providing compatible RBC units based on matching by DNA testing. PMID- 26495896 TI - sTREM-1 in patients with chronic kidney disease on hemodialysis. AB - The triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. TREM-1 has been implicated as an amplifier of inflammation. Soluble TREM-1 (sTREM-1) was investigated in different clinical conditions, but not in hemodialysis (HD) patients. We aimed to investigate sTREM 1 as a marker of inflammation in HD patients. We investigated 40 CKD patients undergoing chronic HD treatment and 15 controls. Routine laboratory investigations in addition to CRP measured by immunoturbidimetry, TNF- alpha, and sTREM-1 measured by ELISA were assayed in post-hemodialysis patients' blood samples and in controls' blood samples. CRP, TNF-alpha, and sTREM-1 levels were significantly higher in HD patients than in controls (p < 0.001 for all). sTREM-1 was positively correlated with CRP and TNF-alpha (r = +0.50, p < 0.001 and r = +0.53, p < 0.001 respectively). It was negatively correlated with hemoglobin concentration (r = -0.69, p < 0.001). Hemoglobin concentration was the significant predictor of sTREM-1 level (p < 0.001). In conclusion, sTREM-1 level is significantly increased in HD patients as are other pro-inflammatory markers. PMID- 26495895 TI - Crataegus azarolus Leaves Induce Antiproliferative Activity, Cell Cycle Arrest, and Apoptosis in Human HT-29 and HCT-116 Colorectal Cancer Cells. AB - Limited success has been achieved in extending the survival of patients with metastatic colorectal cancer (CRC). There is a strong need for novel agents in the treatment and prevention of CRC. Therefore, in the present study we evaluated the antiproliferative and pro-apoptotic potential of Crataegus azarolus ethyl acetate extract in HCT-116 and HT-29 human colorectal cancer cell lines. Moreover, we attempted to investigate the signaling pathways that should be involved in its cytotoxic effect. The Crataegus azarolus ethyl acetate extract induced growth inhibitory effect was associated with DNA fragmentation, sub-G1 peak, loss of mitochondrial potential, and poly (ADP-ribose) polymerase (PARP) cleavage. In addition, ethyl acetate extract of Crataegus azarolus induced the cleavage of caspase-8. It has no effect on steady-state levels of total Bcl-2 protein. Whereas Bax levels decreased significantly in a dose-dependent manner in both tested cell lines. Taken together, these findings confirm the involvement of the extrinsic pathway of apoptosis. The apoptotic cell death induced by ethyl acetate extract of Crataegus azarolus was accompanied by an enhancement of the p21 expression but not through p53 activation in human colorectal cancer cells. The above-mentioned data provide insight into the molecular mechanisms of Crataegus azarolus ethyl acetate extract-induced apoptosis in CRC. Therefore, this compound should be a potential anticancer agent for the treatment of CRC. PMID- 26495897 TI - Systemic Epstein-Barr virus-negative mature natural killer-cell lymphoma with cutaneous and visceral involvement. PMID- 26495898 TI - Absence of osmotic nephrosis in renal tissue removed during laparoscopic nephrectomy after infusion of 6% Hydroxyethyl starch 130/0.4. PMID- 26495899 TI - Selective digestive decontamination and Enterococcus faecalis overgrowth and infection: a robust relation is yet unproven. PMID- 26495900 TI - Pretreatment With Inactivated Bacillus Calmette-Guerin Increases CD4+CD25+ Regulatory T Cell Function and Decreases Functional and Structural Effects of Asthma Induction in a Rat Asthma Model. AB - Bacillus Calmette-Guerin (BCG) has been shown to have therapeutic effects on asthma through CD4+CD25+ regulatory T cells (Tregs). We sought to assess pretreatment with inactivated BCG on CD4+CD25+ Tregs and its functional and structural effects in rat asthma model. The rat asthma model was established using ovalbumin (OVA) sensitization and challenge. Ten rats were pretreated with BCG prior to OVA and received continued BCG injections during OVA challenge (BCG+OVA group), 10 rats were treated with OVA alone (OVA group), and 10 rats were treated with saline (control group). After 9 weeks, histamine dihydrochloride effect on airway resistance was measured. Number of CD4+CD25+ Tregs was measured by flow cytometry, expression of Foxp3 and CTLA-4 mRNA was measured, and serum TGF-beta levels were determined. Differential cell count in bronchoalveolar lavage fluid (BALF) was determined, and lung tissue was processed and stained with hematoxylin and eosin, Masson's trichrome, and alcine blue and periodic acid Schiff's reaction to evaluate inflammatory cell infiltration, collagen deposition, and presence of goblet cells, respectively. BCG treatment led to an increase in CD4+CD25+ Tregs, as well as an increase in Foxp3 and CTLA-4 expression and serum TGF-beta levels. In addition, we observed a decrease in histamine dihydrochloride-induced airway resistance, a decrease in inflammatory leukocytes in BALF, and a decrease in airway remodeling indicators in BCG+OVA treated rats compared with OVA-treated rats. Intradermally injected inactivated BCG has the potential to improve airway inflammation, airway resistance, and airway remodeling through a mechanism that may involve CD4+CD25+ Tregs. PMID- 26495901 TI - Bauhinia purprea agglutinin-modified liposomes for human prostate cancer treatment. AB - Bauhinia purprea agglutinin (BPA) is a well-known lectin that recognizes galactosyl glycoproteins and glycolipids. In the present study, we firstly found that BPA bound to human prostate cancer specimens but not to normal prostate ones. Therefore, we sought to develop BPA-PEG-modified liposomes (BPA-PEG-LP) encapsulating anticancer drugs for the treatment of prostate cancer. We examined the tumor targetability of BPA-PEG-LP with human prostate cancer DU145 cells, and observed that fluorescently labeled BPA-PEG-LP dominantly associated with the cells via the interaction between liposome-surface BPA and cell-surface galactosyl molecules. We also observed that BPA-PEG-LP accumulated in the prostate cancer tissue after the i.v. injection to DU145 solid cancer-bearing mice, and strongly bound to the cancer cells. In a therapeutic study, DU145 solid cancer-bearing mice were i.v. injected thrice with BPA-PEG-LP encapsulating doxorubicin (BPA-PEG-LPDOX, 2 mg/kg/day as the DOX dosage) or PEG-modified liposomes encapsulating DOX (PEG-LPDOX). As a result, BPA-PEG-LPDOX significantly suppressed the growth of the DU145 cancer cells, whereas PEG-LPDOX at the same dosage as DOX showed little anti-cancer effect. The present study suggested that BPA-PEG-LP could be a useful drug carrier for the treatment of human prostate cancers. PMID- 26495903 TI - High-resolution analysis of the murine MHC class II immunopeptidome. AB - The reliable identification of peptides bound to major histocompatibility complex (MHC) class II is fundamental for the study of the host immune response against pathogens and the pathogenesis of autoimmune conditions. Here, we describe an improved methodology combining immuno-affinity enrichment of MHC class II complexes, optimized elution conditions and quadrupole Orbitrap mass spectrometry based characterization of the immunopeptidome. The methodology allowed the identification of over 1000 peptides with 1% false discovery rate from 10(8) murine A20 lymphoma cells. The study revealed the I-A(d) -specific motif in high resolution after multisequence alignment. The methodology was generally applied to the purification of MHC class II from cell lines and murine spleens. We identified 2963 peptides from BALB/c and 2712 from C57BL/6 mouse spleens. The identification of peptides bound to MHC class II in vitro and in vivo will facilitate the characterization of T-cell specificities, as well as the development of biotherapeutics and vaccines. PMID- 26495902 TI - Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats. AB - AIM: Blocking of lysophosphatidic acid (LPA) receptor (LPAR) 1 may be a novel therapeutic option for bronchopulmonary dysplasia (BPD) by preventing the LPAR1 mediated adverse effects of its ligand (LPA), consisting of lung inflammation, pulmonary arterial hypertension (PAH) and fibrosis. METHODS: In Wistar rats with experimental BPD, induced by continuous exposure to 100% oxygen for 10 days, we determined the beneficial effects of LPAR1 deficiency in neonatal rats with a missense mutation in cytoplasmic helix 8 of LPAR1 and of LPAR1 and -3 blocking with Ki16425. Parameters investigated included survival, lung and heart histopathology, fibrin and collagen deposition, vascular leakage and differential mRNA expression in the lungs of key genes involved in LPA signalling and BPD pathogenesis. RESULTS: LPAR1-mutant rats were protected against experimental BPD and mortality with reduced alveolar septal thickness, lung inflammation (reduced influx of macrophages and neutrophils, and CINC1 expression) and collagen III deposition. However, LPAR1-mutant rats were not protected against alveolar enlargement, increased medial wall thickness of small arterioles, fibrin deposition and vascular alveolar leakage. Treatment of experimental BPD with Ki16425 confirmed the data observed in LPAR1-mutant rats, but did not reduce the pulmonary influx of neutrophils, CINC1 expression and mortality in rats with experimental BPD. In addition, Ki16425 treatment protected against PAH and right ventricular hypertrophy. CONCLUSION: LPAR1 deficiency attenuates pulmonary injury by reducing pulmonary inflammation and fibrosis, thereby reducing mortality, but does not affect alveolar and vascular development and, unlike Ki16425 treatment, does not prevent PAH in neonatal rats with experimental BPD. PMID- 26495904 TI - Chromohalobacter is a Causing Agent for the Production of Organic Acids and Putrescine during Fermentation of Ganjang, a Korean Traditional Soy Sauce. AB - Ganjang, a Korean traditional fermented soy sauce, is prepared by soaking doenjang-meju (fermented soybeans) in approximately 20% (w/v) solar salt solution. The metabolites and bacterial communities during ganjang fermentation were simultaneously investigated to gain a better understanding of the roles of the microbial population. The bacterial community analysis based on denaturing gradient gel electrophoresis of 16S rRNA gene sequences showed that initially, the genus Cobetia was predominant (0 to 10 d), followed by Bacillus (5 to 74 d), and eventually, Chromohalobacter became predominant until the end of the fermentation process (74 to 374 d). Metabolite analysis using (1)H-NMR showed that carbon compounds, such as fructose, galactose, glucose, and glycerol, probably released from doenjang-meju, increased rapidly during the early fermentation period (0 to 42 d). After removal of doenjang-meju from the ganjang solution (42 d), the initial carbon compounds remained nearly constant without the increase of fermentation products. At this point, Bacillus species, which probably originated from doenjang-meju, were predominant, suggesting that Bacillus is not mainly responsible for ganjang fermentation. Fermentation products including acetate, lactate, alpha-aminobutyrate, gamma-aminobutyrate, and putrescine increased quickly with the rapid decrease of the initial carbon compounds, while Chromohalobacter, probably derived from the solar salts, was predominant. Multivariate redundancy analysis indicated that the Chromohalobacter population was closely correlated with the production of the organic acids and putrescine during the ganjang fermentation. These results may suggest that Chromohalobacter is a causing agent responsible for the production of organic acids and putrescine during ganjang fermentation and that the solar salts, not doenjang-meju, is an important microbial source for ganjang fermentation. PMID- 26495905 TI - Identification of mineral compositions in some renal calculi by FT Raman and IR spectral analysis. AB - We present in this paper accurate and reliable Raman and IR spectral identification of mineral constituents in nine samples of renal calculi (kidney stones) removed from patients suffering from nephrolithiasis. The identified mineral components include Calcium Oxalate Monohydrate (COM, whewellite), Calcium Oxalate Dihydrate (COD, weddellite), Magnesium Ammonium Phosphate Hexahydrate (MAPH, struvite), Calcium Hydrogen Phosphate Dihydrate (CHPD, brushite), Pentacalcium Hydroxy Triphosphate (PCHT, hydroxyapatite) and Uric Acid (UA). The identification is based on a satisfactory assignment of all the observed IR and Raman bands (3500-400c m(-1)) to chemical functional groups of mineral components in the samples, aided by spectral analysis of pure materials of COM, MAPH, CHPD and UA. It is found that the eight samples are composed of COM as the common component, the other mineral species as common components are: MAPH in five samples, PCHT in three samples, COD in three samples, UA in three samples and CHPD in two samples. One sample is wholly composed of UA as a single component; this inference is supported by the good agreement between ab initio density functional theoretical spectra and experimental spectral measurements of both sample and pure material. A combined application of Raman and IR techniques has shown that, where the IR is ambiguous, the Raman analysis can differentiate COD from COM and PCHT from MAPH. PMID- 26495906 TI - Direct and indirect effects of alcohol expectancies through drinking motives on alcohol outcomes among students in Vietnam. AB - OBJECTIVE: To investigate whether the links between alcohol expectancies (tension reduction; global positive change; improved cognitive and motor abilities; and change in social behavior) and alcohol outcomes (drinking volume, 6+ drinks, alcohol problems, and symptoms of alcohol dependence) are mediated by drinking motives (social, enhancement, conformity, and coping). METHOD: A multi-stage sampling strategy was used in four Vietnamese provinces, resulting in a final sample of 4756 students (43.2% females) with mean age 20.6 (SD 1.8) years. Structural equation models, including indirect effects, were estimated for women and men separately. RESULTS: Overall, there were many cases of full mediation (indirect effects range from -0.006 to 0.083 and p-values from <0.05 to <0.001) and little indication of partial mediation (indirect effects range from -0.009 to 0.025 and p-values from <0.05 to <0.001). In both men and women, coping motives most frequently mediated the influence of expectancies on alcohol outcomes. Among men, enhancement motives and, to a lesser extent, social motives also played a role in mediating the effects of expectancies on alcohol outcomes. Among women, full mediation was found far less often and less consistently. CONCLUSION: By confirming that, in Vietnam, motives mediate the link between expectancies and drinking behavior, this study supports the cultural robustness of a key assumption of the motivational model (i.e. that drinking motives are more closely associated with alcohol use than expectancies). Enhancement, coping and social motives are most frequently found as mediators among male students whereas coping motive only is most frequently found as a mediator among female students. As most of the effects of expectancies were mediated by motives, drinking motives appear to be a promising factor for interventions. PMID- 26495907 TI - Fish consumption and depressive symptoms in undergraduate students: A cross sectional analysis. AB - BACKGROUND: Emerging evidence suggests that fish consumption may have beneficial effects on mood disorders. However, no study has been reported on this issue in young adults to date. The aim of this study was to investigate the relationship between fish consumption and depressive symptoms in Japanese undergraduate students. METHODS: The 20-item Center for Epidemiologic Studies Depression Scale was used to measure depressive symptoms with a cut-off score of 16. A total of 4190 completed questionnaires (from 2124 men and 2066 women) were received for analysis. RESULTS: Multivariate logistic analysis showed that fish intake was inversely associated with risk of depressive symptoms in undergraduate students. After adjustment for possible confounders, the odds-ratios (95% confidence intervals) for fish intake 1-2 times/month, 1-2 times/week, 3-4 times/week, and almost every day (compared with "almost never") were 0.78 (0.62-0.99), 0.70 (0.56 0.87), 0.67 (0.53-0.85) and 0.65 (0.46-0.92), respectively. This association tended to be stronger in women than in men. CONCLUSIONS: Frequent fish consumption in undergraduate students seems to moderate depressive symptoms. Further research is warranted to clarify the causality. PMID- 26495908 TI - APL: An angle probability list to improve knowledge-based metaheuristics for the three-dimensional protein structure prediction. AB - Tertiary protein structure prediction is one of the most challenging problems in structural bioinformatics. Despite the advances in algorithm development and computational strategies, predicting the folded structure of a protein only from its amino acid sequence remains as an unsolved problem. We present a new computational approach to predict the native-like three-dimensional structure of proteins. Conformational preferences of amino acid residues and secondary structure information were obtained from protein templates stored in the Protein Data Bank and represented as an Angle Probability List. Two knowledge-based prediction methods based on Genetic Algorithms and Particle Swarm Optimization were developed using this information. The proposed method has been tested with twenty-six case studies selected to validate our approach with different classes of proteins and folding patterns. Stereochemical and structural analysis were performed for each predicted three-dimensional structure. Results achieved suggest that the Angle Probability List can improve the effectiveness of metaheuristics used to predicted the three-dimensional structure of protein molecules by reducing its conformational search space. PMID- 26495910 TI - Radiofrequency denervation for chronic low back pain. AB - BACKGROUND: Radiofrequency (RF) denervation, an invasive treatment for chronic low back pain (CLBP), is used most often for pain suspected to arise from facet joints, sacroiliac (SI) joints or discs. Many (uncontrolled) studies have shown substantial variation in its use between countries and continued uncertainty regarding its effectiveness. OBJECTIVES: The objective of this review is to assess the effectiveness of RF denervation procedures for the treatment of patients with CLBP. The current review is an update of the review conducted in 2003. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, three other databases, two clinical trials registries and the reference lists of included studies from inception to May 2014 for randomised controlled trials (RCTs) fulfilling the inclusion criteria. We updated this search in June 2015, but we have not yet incorporated these results. SELECTION CRITERIA: We included RCTs of RF denervation for patients with CLBP who had a positive response to a diagnostic block or discography. We applied no language or date restrictions. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently selected RCTs, extracted data and assessed risk of bias (RoB) and clinical relevance using standardised forms. We performed meta-analyses with clinically homogeneous studies and assessed the quality of evidence for each outcome using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: In total, we included 23 RCTs (N = 1309), 13 of which (56%) had low RoB. We included both men and women with a mean age of 50.6 years. We assessed the overall quality of the evidence as very low to moderate. Twelve studies examined suspected facet joint pain, five studies disc pain, two studies SI joint pain, two studies radicular CLBP, one study suspected radiating low back pain and one study CLBP with or without suspected radiation. Overall, moderate evidence suggests that facet joint RF denervation has a greater effect on pain compared with placebo over the short term (mean difference (MD) 1.47, 95% confidence interval (CI) -2.28 to -0.67). Low-quality evidence indicates that facet joint RF denervation is more effective than placebo for function over the short term (MD -5.53, 95% CI -8.66 to -2.40) and over the long term (MD -3.70, 95% CI -6.94 to -0.47). Evidence of very low to low quality shows that facet joint RF denervation is more effective for pain than steroid injections over the short (MD -2.23, 95% CI -2.38 to -2.08), intermediate (MD 2.13, 95% CI -3.45 to -0.81), and long term (MD -2.65, 95% CI -3.43 to -1.88). RF denervation used for disc pain produces conflicting results, with no effects for RF denervation compared with placebo over the short and intermediate term, and small effects for RF denervation over the long term for pain relief (MD -1.63, 95% CI -2.58 to -0.68) and improved function (MD -6.75, 95% CI -13.42 to -0.09). Lack of evidence of short-term effectiveness undermines the clinical plausibility of intermediate-term or long-term effectiveness. When RF denervation is used for SI joint pain, low-quality evidence reveals no differences from placebo in effects on pain (MD -2.12, 95% CI -5.45 to 1.21) and function (MD -14.06, 95% CI 30.42 to 2.30) over the short term, and one study shows a small effect on both pain and function over the intermediate term. RF denervation is an invasive procedure that can cause a variety of complications. The quality and size of original studies were inadequate to permit assessment of how often complications occur. AUTHORS' CONCLUSIONS: The review authors found no high-quality evidence suggesting that RF denervation provides pain relief for patients with CLBP. Similarly, we identified no convincing evidence to show that this treatment improves function. Overall, the current evidence for RF denervation for CLBP is very low to moderate in quality; high-quality evidence is lacking. High-quality RCTs with larger patient samples are needed, as are data on long-term effects. PMID- 26495909 TI - Patterns of psychological distress in mothers of preterm infants. AB - Mothers of preterm infants experience significant psychological distress, with elevated levels of inter-correlated depressive, stress, anxiety and post traumatic stress symptoms. In a sample of racially and ethnically diverse mothers of preterm infants, we identified differing patterns of psychological distress during infant hospitalization and examined the effect of these psychological distress patterns on longitudinal trajectories of each psychological distress measure and on maternal perceptions of the child over the first year of the infant's life. Mothers of preterm infants (N=232) completed five questionnaires assessing depressive symptoms, anxiety, post-traumatic stress symptoms, stress due to infant appearance, and stress due to parental role alteration during enrollment during the neonatal hospitalization, discharge, and at 2, 6, and 12 months of age adjusted for prematurity. Latent class analysis on the enrollment psychological distress variables allowed us to identify five sub-groups of mothers exhibiting similar patterns of psychological distress, differing primarily in degree and type: low distress, moderate distress, high NICU-related distress, high depressive and anxiety symptoms, and extreme distress. These classes continued to show different longitudinal trajectories for the psychological distress measures through 12 months corrected age. Mothers in the extreme distress class and, to a lesser degree, mothers in the high depressive and anxiety symptom class remained at risk of significant psychological distress one year after discharge and had less positive perceptions of their child (greater worry and higher perceptions of child vulnerability). In conclusion, distinctive sub-groups of mothers during hospitalization had different patterns of psychological distress throughout the 12-month period and may require different interventions in the NICU. PMID- 26495911 TI - Temperature-Dependent Abnormal and Tunable p-n Response of Tungsten Oxide--Tin Oxide Based Gas Sensors. AB - We observed the sensing response of temperature-dependent abnormal p-n transitions in WO3-SnO2 hybrid hollow sphere based gas sensors for the first time. The sensors presented a normal n-type response to ethanol at elevated temperatures but abnormal p-type responses in a wide range of operation temperatures (room temperature to about 95 degrees C). By measuring various reducing gases and applying complex impedance plotting techniques, we demonstrated the abnormal p-type sensing behavior to be a pseudo-response resulting from the reaction between target gas and adsorbed water on the material surface. The temperature-controlled n-p switch is ascribed to the competition of intrinsic and extrinsic sensing behaviors, which resulted from the reaction of target gas with adsorbed oxygen ions and protons from adsorbed water, respectively. The former can modulate the intrinsic conductivity of the sensor by changing the electron concentration of the sensing materials, while the latter can regulate the conduction of the water layer, which contributes to the total conductivity as an external part. The hollow and hybrid nanostructures facilitated the observation of extrinsic sensing behaviors due to its large-area active sites and abundant oxygen vacancies, which could enhance the adsorption of water. This work might give new insight into gas sensing mechanisms and opens up a promising way to develop practical temperature and humidity controllable gas sensors with little power consumption based on the extrinsic properties. PMID- 26495912 TI - Combination Therapy Of Tadalafil And Pentoxifylline In Severe Erectile Dysfunction; A Prospective Randomized Trial. AB - The aim of the study was to assess efficacy of Tadalafil alone versus Tadalafil plus Pentoxifylline in the treatment of erectile dysfunction by using self administered IIEF-5 questionnaire. MATERIAL AND METHODS: Two hundred and thirty seven patients presenting with ED at andrology OPD were evaluated for ED by a self administered IIEF (International Index of Erectile Function) questionnaire. Patients were systematically randomized by computer generated random table into two groups groups namely, group A: Tadalafil only group, group B: combination of Tadalafil + Pentoxifyl-line. All the patients were re-assessed by IIEF-5 questionnaire after 8 weeks of medical therapy. Statistical analysis was performed using student's unpaired t-test, paired t-test, chi square test. p value < 0.05 was considered statistically significant. RESULTS: Two hundred and thirty seven patients were included in the present study, in group A: 92 patients (78.6%) showed improvement in their IIEF score after 8 weeks of tadalafil treatment. While in group B, overall 104 patients(86.6%) showed improvement after combination of Tadalafil and Pentoxifylline. There was a statistically significant difference of percentage change in IIEF score was seen in group B (group A 90.7+/-15.2%, group B 95.6+/-13.4%; p value - 0.014). We found this difference even more statistically significant in patients with severe ED (group A 72.7+/-47.2%, group B 132.3+/-54.3%; p value - 0.000). There was no significant difference in between the two groups with regards to occur-rence of side effects. CONCLUSIONS: Both tadalafil and combination of Tadalafil + Pentoxifylline improve erectile function in patients of ED. Patients with severe ED showed much significant improvement in erectile function with combination therapy. PMID- 26495913 TI - The Use Of Anterolateral Thigh Flap (ALTF) For Functional Tongue Reconstruction With Postoperative Quality Of Live Evaluation. AB - The use of microsurgery for oral reconstruction of cancer patients, has become standard treatment in restoring oral function. The free anterolateral thigh flap is one of the most preferred options in reconstruction after total, subtotal or hemiresection of the tonque due to squamous cell cancer. The aim of the study was to present the reconstructive method using anterolateral thigh free flap with evaluation of quality of live. MATERIAL AND METHODS: Clinical material includes 46 consecutive patients with tongue cancer, who underwent complex surgical treatment between 2009 and 2011. There were 36 males and 10 females and the M: F ratio was 3.6: 1. All of them were reconstructed using the anterolateral thigh free flap. The quality of life was evaluated 6 months after completing the treatment, based on postoperative functional and aesthetic status. RESULTS: The overall flap survival rate was 96%. Surgical complications were observed in 8 patients (17%). Donor site was closed primarly in 42 cases and in remaining 4 skin graft was required. In all 46 cases understandable speech and return to unrestricted diet mastication and swallowing were achieved. The mean follow-up period after treatment was 32 months. Analysis of aesthetic effects evaluated in 23 cases and shows generally very good results. According to average transformed scores the QOL can be characterized as excellent for >90, very good for 76-90, good for 51-75, moderate for 25-50 and bad for <25 points. CONCLUSIONS: Anterolateral thigh flap, with its versatility in design, long pedicle with a suitable vessel diameter, low donor site morbidity, and very good aesthetic effects, could be the ideal flap for functional tongue reconstruction. PMID- 26495914 TI - Rare Facial Clefts. AB - In 1976 Dr. Paul Tessier described numeric classification for rare craniofacial clefts. He first emphasized that a fissure of the soft tissue corresponds, as a general rule, to a cleft of the bony structure. The classification, easy to understand, became widely accepted because the recording of the malformations was simple and facilitated communication between observers. The aim of this study was to present our own experience with treatment of patients with rare facial clefts. MATERIAL AND METHODS: Our Department has 11 patients with rare craniofacial clefts under its care. This group includes 8 boys and 3 girls. The patients aged from 2 months to 18 years at the time of the first consultation. RESULTS: In two patients the cleft was median, in seven patients it was one-sided and in two- bilateral. The most common type of cleft was number 6, and the rarest were 2, 3, and 7. All patients underwent surgical treatment. CONCLUSIONS: Atypical facial clefts are rare congenital anomalies, however because of functional and aesthetic disturbances they constitute a serious medical and therapeutic problem. Facial clefts are characterized by variable clinical presentation and require individualized treatment plan. PMID- 26495915 TI - How Do Patients Assess Outcomes Of Treatment Of Prognathism? AB - The aim of the study was to analyze the results of patients' subjective self assessment of surgical treatment of prognathism. MATERIALS AND METHODS: The study included 35 patients who underwent extraoral vertical ramus osteotomy. Each patient responded to 12 questions contained in the questionnaire created by the authors. RESULTS: All respondents positively assessed their appearance after surgery. In most cases they pointed out the positive impact of treatment on their self-confidence (82.9% of responses). The vast majority of respondents felt improvement in biting off food (91.4%). CONCLUSIONS: Patients positively evaluate the outcome of surgical treatment with extraoral vertical ramus osteotomy. The subjective improvement of the facial appearance, as well as chewing and articulation functions took place after the treatment. PMID- 26495916 TI - Randomized Clinical Trial To Compare The Effects Of Preoperative Oral Carbohydrate Loading Versus Placebo On Insulin Resistance And Cortisol Level After Laparoscopic Cholecystectomy. AB - Postoperative insulin resistance, used as a marker of stress response, is clearly an adverse event. It may induce postoperative hyperglycemia, which according to some authors can increase the risk of postoperative complications. One of the elements of modern perioperative care is preoperative administration of oral carbohydrate loading (CHO-loading), which shortens preoperative fasting and reduces insulin resistance. The aim of the study is to establish the influence of CHO-loading on the level of insulin resistance and cortisol in patients undergoing elective laparoscopic cholecystectomy. MATERIAL AND METHODS: Patients were randomly allocated to one of 2 groups. The intervention group included 20 patients who received CHO-loading (400 ml Nutricia pre-op(r)) 2 hours prior surgery. The control group received a placebo (clear water). In every patient blood samples were taken 2 hours prior to surgery, immediately after surgery, and on the 1st postoperative day. Levels and changes in glucose, cortisol and insulin resistance were analyzed in both groups. RESULTS: Although there were differences in the levels of cortisol, insulin, and insulin resistance, no statistically significant differences were observed between groups in every measurement. The length of stay and postoperative complications were comparable in both groups. CONCLUSIONS: We believe that CHO-loading is not clinically justified in case of laparoscopic cholecystectomy. No effect on the levels of glucose, insulin resistance and cortisol was observed. Even though such procedure is safe, in our opinion there is no clinical benefit from CHO-loading prior to laparoscopic cholecystectomy. PMID- 26495917 TI - Description Of Minimally Invasive Methods Of Treatment Of Walled-Off Pancreatic Necrosis (WOPN)--The Use Of "Step-Up Approach" In Patient With Pancreatic Necrosis. AB - The study presents description of treatment of patients with walled-off pancreatic necrosis (WOPN). The strategy of treatment was to extend access to necrotic areas ("step-up approach"). Applied endoscopic transmural access (transgastric) and percutaneous access (transperitoneal). The endoscopic necrosectomy under fluoroscopic guidance was repeated four times during active transluminal drainage. Endoscopic treatment with percutaneous drainage gave very beneficial clinical effects. PMID- 26495918 TI - Parietal Strangulation Of Small Intestine In Femoral Hernia Site With Symptoms Of Intestinal Obstruction In Patient With Incidentally Found Small Intestine Tumor- A Case Report. AB - Richter's hernia (partial enterocele) is the strangulation/entrapment of only part of the circumference of the intestinal wall. It is relatively rare, and presents without mechanical obstruction - giving vague, non-specific symptoms and signs, and a threat of intestinal necrosis, gangrene, followed by perforation. A report of a case of entrapment of the jejunum in the femoral ring, which did not cause the gangrene, but symptoms of mechanical obstruction, is presented. Further inspection of the small bowel in this case revealed an extra-luminal tumour, which appeared to be a GIST. The entrapped part of the jejunum has been released and the tumour has been resected. PMID- 26495919 TI - Colorectal Cancer In The Elderly Patient. AB - Colorectal neoplasms present a serious diagnostic and therapeutic problem. Continuously increasing morbidity affects the elderly people in particular and considering the aging of the society and enhanced impact of the factors with a proved role in carcinogenesis, this tendency is predicted to remain unchanged in the near future. Therefore, it seems justified to thoroughly analyze the specificity of this patient group accordingly adjust the diagnostic and therapeutic procedures. The elderly patients require an interdisciplinary care both in the preparation and postoperative period. A multispecialty senior staff case meeting seems thus essential to determine the most beneficial treatment approach. Development of additional algorithms for the elderly patient with colorectal cancer is warranted. PMID- 26495920 TI - Porcine Model In The Laparoscopic Liver Surgery Training. AB - The aim of the study was to evaluate the possibility to use live anesthetized pigs as a model for laparoscopic liver resection. During two days laparoscopy course two trainees were operating on two live animals performing exposure of the liver, Pringle manoeuver, division of liver ligaments, dissecting of the structures inside the hepatoduodenal ligament, dissection of the hepatic veins and left lateral liver sectionectomy. Exposure of the liver and Pringle manoeuver were performed correctly within 50 and 35 minutes. Left lateral sectionectomy has been performed correctly within 2 hours. The full dissection of the hepatoduodenal ligament and exposure of the hepatic veins were judged as insufficient by experienced laparoscopic tutors. There was one injury to the suprahepatic vena cava that was managed laparoscopically. The porcine model can be used as an advanced training for laparoscopic liver surgery. PMID- 26495921 TI - A guide on how to build a novel home-made part task training simulator for cervical cerclage training. AB - Cervical cerclage is a experience demanding procedure and which is difficult for most of the residents and maternal fetal medicine fellows to have the first experience on real patients. In this study we presented an in-expensive and easy to build model for cervical cerclage training. PMID- 26495922 TI - Reference values for the single deepest vertical pocket to assess the amniotic fluid volume in the second and third trimesters of pregnancy. AB - AIM: To establish reference values for the single deepest vertical pocket to assess the amniotic fluid volume in the second and third trimesters of pregnancy. METHODS: We performed a retrospective cross-sectional study with 3554 consecutive singleton low-risk pregnant women between 14 and 41 weeks of gestation. To perform the largest deepest vertical pocket measurement, the transabdominal convex probe was positioned vertical to the uterine contour of abdomen and parallel to the maternal sagittal plane. In order to obtain reference values for the largest deepest vertical pocket measurement and gestational age (GA), we have used a polynomial regression model. RESULTS: The mean+/-standard deviation for the largest deepest vertical pocket measurement (cm) ranged from 3.1+/-1.1 (1.5 4.9) at 14-14+6 to 3.7+/-1.6 (0-6.7) at 41-41+6 weeks, respectively. A best-fit was a second-degree polynomial regression: largest deepest pocket=-1.478+0.197*GA 0.0030*GA2 (R2=0.014). CONCLUSION: Reference values for the single deepest vertical pocket to assess the amniotic fluid volume in the second and third trimesters of pregnancy in a large heterogeneous population were established. PMID- 26495923 TI - Rare and curable renin-mediated hypertension: a series of six cases and a literature review. AB - BACKGROUND: Reninoma is an extremely rare renal tumor characterized by excessive renin secretion causing secondary hypertension and hypokalemia. Reninoma is a benign and highly manageable lesion if it is discovered early and removed surgically. METHODS: We report six cases of reninoma and provide a literature review on this rare disease, highlighting the diagnostic evaluation and follow-up of each patient. RESULTS AND CONCLUSIONS: Reninoma should be considered in young adults with elevated renin activity and refractory hypertension. Imaging studies and selective venous catheterization are often helpful in identifying the lesion. In most cases of reninoma presenting with renin-mediated hypertension, conservative surgical treatment should be considered to remove the small, superficial lesion. PMID- 26495924 TI - Analysis of the PAX8 gene in 32 children with thyroid dysgenesis and functional characterization of a promoter variant. AB - BACKGROUND: The molecular basis underlying the development of thyroid dysgenesis remains largely unknown. The objective of this study was to analyze the PAX8 gene in 32 children with congenital hypothyroidism due to thyroid dysgenesis for mutations, and to characterize the functional consequences of the mutations. METHODS: The 5'-untranslated region and the entire coding region of the PAX8 gene were analyzed in 32 children. Functional analyses with a reporter gene assay were performed in transfected PCCL3 and TSA cells. RESULTS: Thirty children did not have any sequence alterations. Two individuals had a previously identified monoallelic cytosine to thymine transition at position -983 in the promoter ( 983C>T; mutant P. A of the ATG of the initiator codon is designated as +1), and a novel guanine to cytosine transversion in the non-coding exon 1 (-465G>C; mutant E). Functional analysis revealed that the basal transcriptional activity of the mutants is decreased compared to the wild type. Gel mobility shift assays indicated that mutant P does not interact with a transacting factor whose nature remains to be elucidated. The DNA binding property of mutant E were similar compared to the wild type. CONCLUSIONS: These results suggest that mutations in PAX8 are most likely a very rare cause of thyroid dysgenesis. The observed sequence alterations result in diminished transcriptional activity and, in conjunction with other genetic and non-genetic modifiers, they may contribute to the pathogenesis of thyroid hypoplasia and hypothyroidism. PMID- 26495925 TI - Schoolchildren born VLBW or VLGA show height-related changes in body composition and muscle function but no evidence of metabolic syndrome risk factors. Results from the NEOLONG study. AB - BACKGROUND: Children born small for gestational age (SGA) are at risk for the metabolic syndrome (MetS) as adults. We examined whether indicators of MetS could be identified in pre-pubertal children born very preterm. METHODS: Parameters associated with MetS were studied in 141 pre-pubertal schoolchildren with either very low birth weight (VLBW) or GA <32 weeks (SGA: n=43). RESULTS: At 8.3+/-0.8 years, 36 children (SGA: n=15) were classified short. There were no differences between the SGA and appropriate for age (AGA) groups; nor were dissimilarities observed between short children and those with normal height for parameters such as body mass index (BMI), serum levels of hormones, HDL cholesterol, triglycerides, glucose, insulin, HOMA-IR, body composition, resting energy expenditure, grip strength and jump force. CONCLUSIONS: Neither SGA at birth nor short stature at follow-up (irrespective of size at birth), could be associated with parameters that indicate an increased risk for the MetS during childhood. PMID- 26495926 TI - A cross-sectional study of biomarkers of exposure and effect in smokers and moist snuff consumers. AB - BACKGROUND: Cigarette smoking is a major risk factor for several chronic diseases. Epidemiological data indicate the use of smokeless tobacco (ST) is associated with significantly lower risk for smoking-related diseases compared to cigarettes. Several biomarkers of exposure (BioExp) and effect (BioEff) associated with smoking and use of moist snuff (ST) were evaluated. METHODS: A single site, cross-sectional clinical study enrolled three groups of generally healthy male smokers (SMK), moist snuff consumers (MSC), and non-tobacco consumers (NTC), and several BioExp and BioEff were evaluated. RESULTS: Blood and urinary BioExp, including total nicotine equivalents and tobacco-specific nitrosamines, were higher in MSC compared to SMK. Biomarkers of combustion related toxicants and cadmium were elevated in SMK. Elevated levels of some BioEff associated with oxidative stress (urinary isoprostanes and leukotriene E4), inflammation (white blood cell count), platelet activation (thromboxane metabolites), and lipid metabolism (apolipoprotein B100 and oxidized low-density lipoprotein) were observed in SMK relative to NTC and MSC (all p<0.05). The non smoking groups (MSC and NTC) showed similar levels of combustion-related BioExp and BioEff. CONCLUSIONS: Higher levels of exposure to nicotine and some N' nitrosamines may be observed in MSC, and SMK are exposed to higher levels of combustion-related toxicants. Changes in BioEff consistent with some aspects of inflammation, oxidative stress, and altered lipid metabolism were detected in SMK compared to the non-smoking groups. The biomarker data further improve our understanding of pathophysiological changes and the risk continuum associated with various tobacco products, and could be useful components of future assessments of tobacco products. PMID- 26495927 TI - Hemoglobin A2-Leuven (alpha2delta2 143(H21) His>Asp): a novel delta-chain variant potentially interfering in hemoglobin A1c measurement using cation exchange HPLC. PMID- 26495928 TI - Assessing the commutability of reference material formats for the harmonization of amyloid-beta measurements. AB - BACKGROUND: The cerebrospinal fluid (CSF) amyloid-beta (Abeta42) peptide is an important biomarker for Alzheimer's disease (AD). Variability in measured Abeta42 concentrations at different laboratories may be overcome by standardization and establishing traceability to a reference system. Candidate certified reference materials (CRMs) are validated herein for this purpose. METHODS: Commutability of 16 candidate CRM formats was assessed across five CSF Abeta42 immunoassays and one mass spectrometry (MS) method in a set of 48 individual clinical CSF samples. Promising candidate CRM formats (neat CSF and CSF spiked with Abeta42) were identified and subjected to validation across eight (Elecsys, EUROIMMUN, IBL, INNO-BIA AlzBio3, INNOTEST, MSD, Simoa, and Saladax) immunoassays and the MS method in 32 individual CSF samples. Commutability was evaluated by Passing Bablok regression and the candidate CRM termed commutable when found within the prediction interval (PI). The relative distance to the regression line was assessed. RESULTS: The neat CSF candidate CRM format was commutable for almost all method comparisons, except for the Simoa/MSD, Simoa/MS and MS/IBL where it was found just outside the 95% PI. However, the neat CSF was found within 5% relative distance to the regression line for MS/IBL, between 5% and 10% for Simoa/MS and between 10% and 15% for Simoa/MSD comparisons. CONCLUSIONS: The neat CSF candidate CRM format was commutable for 33 of 36 method comparisons, only one comparison more than expected given the 95% PI acceptance limit. We conclude that the neat CSF candidate CRM can be used for value assignment of the kit calibrators for the different Abeta42 methods. PMID- 26495929 TI - Underestimation of hepcidin concentration by time of flight mass spectrometry and competitive ELISA in hepcidin p.Gly71Asp heterozygotes. PMID- 26495930 TI - Biological variation of high sensitivity cardiac troponin-T in stable dialysis patients: implications for clinical practice. PMID- 26495931 TI - Steroid hormone secretion in inflammatory breast cancer cell lines. AB - Inflammatory breast carcinoma (IBC) is a special type of breast cancer with a poor survival rate. Though several IBC cell lines have been established, recently a first IMC cell line was established. The aims of this study were: (1) to validate a highly sensitive, reliable, accurate and direct amplified enzyme immunoassay (EIA) to measure several cell-secreted steroid hormones: progesterone (P4), androstenedione (A4), testosterone (T), 17beta-estradiol (E2) and estrone sulfate (SO4E1) in the culture medium. (2) To assess whether hormone production profile by IPC-366 cells validates the IMC model for human IBC. We validated a non-competitive amplified EIA for inflammatory breast cancer cell lines based on the results of accuracy, precision, sensitivity and parallelism. The low detection limits of the technique were: P4=13.2 pg/well, A4=2.3 pg/well, T=11.4 pg/well, E2=1.9 pg/well and SO4E1=4.5 pg/well. Intra- and inter-assay coefficient of variation percentages were <10%. The mean recovery rate of hormone added to the culture medium was >90%. In all hormones studied SUM149 have higher levels (1.4 times, but not significant) than IPC-366, and the correlation index between SUM149 and IPC-366 concentrations were >97%. We can coclude that cells of both cell lines, IPC-366 and SUM149, are capable to produce steroid hormone in culture media. The presented EIA methodology is very valuable for the detection of steroid production in culture media and could be used in hormone regulation studies and therapeutic agents in cell lines of inflammatory and non-inflammatory mammary carcinoma or other cancer cell lines in preclinical studies. PMID- 26495932 TI - Effects of environmental factors on microalgal biomass production in wastewater using cyanobacteria Aphanothece clathrata and Microcystis wesenbergii. AB - Effects of temperature, light, coexistent microbes, and dissolved matter on the growth of cyanobacteria Aphanothece clathrata and Microcystis wesenbergii were discussed using a batch incubation system in this research for microbial biomass production in wastewater. As a result, water temperature in the effluents from the municipal wastewater treatment plants in Tokyo was suitable for the growth of these cyanobacteria, though preheating of wastewater may be required for M. wesenbergii in winter. The dissolved matter in the treated wastewater did not affect the growth of A. clathrata and enhanced the growth of M. wesenbergii. However, the microbes in the treated wastewater attacked the cyanobacteria and inhibited their growth. Therefore, pretreatment of microbes might be required for biomass production in the treated wastewater. The maximum methane production potentials of A. clathrata and M. wesenbergii in the treated wastewater were estimated to be 13.5 and 2.12 L-CH4*m-2*day-1, respectively, when the depth of the bioreactor was set at 4.8 m for A. clathrata and 0.7 m for M. wesenbergii. The potential of A. clathrata was higher than that of grasses. Consequently, cyanobacteria, especially A. clathrata, may become a good biomass for bioenergy production. PMID- 26495933 TI - Correlated 3D Nanoscale Mapping and Simulation of Coupled Plasmonic Nanoparticles. AB - Electron tomography in combination with electron energy-loss spectroscopy (EELS) experiments and simulations was used to unravel the interplay between structure and plasmonic properties of a silver nanocuboid dimer. The precise 3D geometry of the particles fabricated by means of electron beam lithography was reconstructed through electron tomography, and the full three-dimensional information was used as an input for simulations of energy-loss spectra and plasmon resonance maps. Excellent agreement between experiment and theory was found throughout, bringing the comparison between EELS imaging and simulations to a quantitative and correlative level. In addition, interface mode patterns, normally masked by the projection nature of a transmission microscopy investigation, could be unambiguously identified through tomographic reconstruction. This work overcomes the need for geometrical assumptions or symmetry restrictions of the sample in simulations and paves the way for detailed investigations of realistic and complex plasmonic nanostructures. PMID- 26495934 TI - The influence of celebrity exemplars on college students' smoking. AB - OBJECTIVE: This study examined the effect of celebrity smoking exemplars in health news on college students' perceptions of smoking-related health risks and smoking intentions. PARTICIPANTS AND METHODS: The data were collected using a Web based survey of 219 undergraduate students at a large midwestern university in March 2011. Separate analyses of covariance were conducted. RESULTS: The influence of negative exemplars of celebrity smoking on perceptions of smoking related health risks and smoking intentions varied according to smoking status. Ever-smokers who read smoking news with negative exemplars of celebrity smoking were more likely than ever-smokers who read the same news absent any exemplar to report higher levels of perceptions of smoking-related health risks and lower levels of smoking intentions. However, these patterns were not found in never smokers. CONCLUSIONS: Exemplification theory enhanced by the celebrity element may be effectively applied as a strategy to change health behavior in college students. PMID- 26495935 TI - Effects of organic matter on crystallization of struvite in biologically treated swine wastewater. AB - A sustainable way to recover phosphorus (P) in swine wastewater involves a preliminary step of P dissolution followed by the separation of particulate organic matter (OM). The next two steps are firstly the precipitation of struvite crystals done by adding a crystallization reagent (magnesia) and secondly the filtration of the crystals. To develop the process successfully at an industrial scale, the control of the mechanisms of precipitation is the key point in order to obtain high value-added products, that is, big struvite crystals easy to harvest and handle. Experiments with process parameters optimized previously in a synthetic swine wastewater were performed on real swine wastewater to assess the role of the OM on struvite crystallization. After 24 h, with a pH increase to 6.8 only, 90% of the initial P was precipitated and 60% was precipitated as struvite. 80% of the solid recovered was in the fraction > 100 um. The other forms recovered were brushite, amorphous calcium phosphate, NaCl, KCl and OM. The influence of OM on struvite precipitation in acidified swine wastewater was negative on the reaction kinetics but positive on the size of the struvite crystals. The presence of colloidal particles increased the size of the struvite crystals but slowed down the kinetics due to the viscosity induced by the repulsive force of the colloids. The maximum size of single struvite crystals (200 um) was observed with the presence of particulate OM. PMID- 26495936 TI - There is a need once again for a multifactorial assessment and intervention for fall prevention among the elderly. PMID- 26495937 TI - Bidirectional Direct Sequencing of Noncanonical RNA by Two-Dimensional Analysis of Mass Chromatograms. AB - Mass spectrometry (MS) is a powerful technique for characterizing noncanonical nucleobases and other chemical modifications in small RNAs, yielding rich chemical information that is complementary to high-throughput indirect sequencing. However, mass spectra are often prohibitively complex when fragment ions are analyzed following either solution phase hydrolysis or gas phase fragmentation. For all but the simplest cases, ions arising from multiple fragmentation events, alternative fragmentation pathways, and diverse salt adducts frequently obscure desired single-cut fragment ions. Here we show that it is possible to take advantage of predictable regularities in liquid chromatographic (LC) separation of optimized RNA digests to greatly simplify the interpretation of complex MS data. A two-dimensional analysis of extracted compound chromatograms permits straightforward and robust de novo sequencing, using a novel Monte Carlo algorithm that automatically generates bidirectional paired-end reads, pinpointing the position of modified nucleotides in a sequence. We demonstrate that these advances permit routine LC-MS sequencing of RNAs containing noncanonical nucleotides, and we furthermore examine the applicability of this approach to the study of oligonucleotides containing artificial modifications as well as those commonly observed in post-transcriptionally modified RNAs. PMID- 26495938 TI - "My hair or my health:" Overcoming barriers to physical activity in African American women with a focus on hairstyle-related factors. AB - Physical activity disparities among African American (AA) women may be related to sociocultural barriers, including difficulties with restyling hair after exercise. We sought to identify physical activity barriers and facilitators in AA women with a focus on sociocultural factors related to hairstyle maintenance. Participants (n = 51) were AA women aged 19-73 years who completed valid surveys and participated in structured focus groups, stratified by age and physical activity levels, from November 2012 to February 2013. The Constant Comparison method was used to develop qualitative themes for barriers and facilitators. The most frequently reported general physical activity barrier among exercisers was "lack of money" (27%) and among non-exercisers was "lack of self-discipline" (57%). A hairstyle-related barrier of "sweating out my hairstyle" was reported by 7% of exercisers and 29% of non-exercisers. This hairstyle-related barrier included the need for extra time and money to restyle hair due to perspiration. Hairstyle-related facilitators included: prioritizing health over hairstyle and high self-efficacy to restyle hair after perspiration. Participants were interested in resources to simplify hairstyle maintenance. AA women whose hairstyle is affected by perspiration may avoid physical activity due to time and financial burdens. Increasing self-efficacy to restyle hair after perspiration may help to overcome this barrier. PMID- 26495939 TI - Intraparenchymal ultrasound application and improved distribution of infusate with convection-enhanced delivery in rodent and nonhuman primate brain. AB - OBJECT Convection-enhanced delivery (CED) is an effective drug delivery method that delivers high concentrations of drugs directly into the targeted lesion beyond the blood-brain barrier. However, the drug distribution attained using CED has not satisfactorily covered the entire targeted lesion in tumors such as glioma. Recently, the efficacy of ultrasound assistance was reported for various drug delivery applications. The authors developed a new ultrasound-facilitated drug delivery (UFD) system that enables the application of ultrasound at the infusion site. The purpose of this study was to demonstrate the efficacy of the UFD system and to examine effective ultrasound profiles. METHODS The authors fabricated a steel bar-based device that generates ultrasound and enables infusion of the aqueous drug from one end of the bar. The volume of distribution (Vd) after infusion of 10 ml of 2% Evans blue dye (EBD) into rodent brain was tested with different frequencies and applied voltages: 252 kHz/30 V; 252 kHz/60 V; 524 kHz/13 V; 524 kHz/30 V; and 524 kHz/60 V. In addition, infusion of 5 mM gadopentetate dimeglumine (Gd-DTPA) was tested with 260 kHz/60 V, the distribution of which was evaluated using a 7-T MRI unit. In a nonhuman primate (Macaca fascicularis) study, 300 MUl of 1 mM Gd-DTPA/EBD was infused. The final distribution was evaluated using MRI. Two-sample comparisons were made by Student t-test, and 1-way ANOVA was used for multiple comparisons. Significance was set at p < 0.05. RESULTS After infusion of 10 MUl of EBD into the rat brain using the UFD system, the Vds of EBD in the UFD groups were significantly larger than those of the control group. When a frequency of 252 kHz was applied, the Vd of the group in which 60 V was applied was significantly larger than that of the group in which 30 V was used. When a frequency of 524 kHz was applied, the Vd tended to increase with application of a higher voltage; however, the differences were not significant (1-way ANOVA). The Vd of Gd-DTPA was also significantly larger in the UFD group than in the control group (p < 0.05, Student t-test). The volume of Gd DTPA in the nonhuman primate used in this study was 1209.8 +/- 193.6 mm(3). This volume was much larger than that achieved by conventional CED (568.6 +/- 141.0 mm(3)). CONCLUSIONS The UFD system facilitated the distribution of EBD and Gd DTPA more effectively than conventional CED. Lower frequency and higher applied voltage using resonance frequencies might be more effective to enlarge the Vd. The UFD system may provide a new treatment approach for CNS disorders. PMID- 26495940 TI - Obituary: John Anthony Jane Sr., MD, PhD, 1931-2015. PMID- 26495941 TI - The influence of maximum safe resection of glioblastoma on survival in 1229 patients: Can we do better than gross-total resection? AB - OBJECTIVE: Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor. The value of extent of resection (EOR) in improving survival in patients with GBM has been repeatedly confirmed, with more extensive resections providing added advantages. The authors reviewed the survival of patients with significant EORs and assessed the relative benefit/risk of resecting 100% of the MRI region showing contrast-enhancement with or without additional resection of the surrounding FLAIR abnormality region, and they assessed the relative benefit/risk of performing this additional resection. METHODS: The study cohort included 1229 patients with histologically verified GBM in whom >= 78% resection was achieved at The University of Texas MD Anderson Cancer Center between June 1993 and December 2012. Patients with > 1 tumor and those 80 years old or older were excluded. The survival of patients having 100% removal of the contrast enhancing tumor, with or without additional resection of the surrounding FLAIR abnormality region, was compared with that of patients undergoing 78% to < 100% EOR of the enhancing mass. Within the first subgroup, the survival durations of patients with and without resection of the surrounding FLAIR abnormality were subsequently compared. The data on patients and their tumor characteristics were collected prospectively. The incidence of 30-day postoperative complications (overall and neurological) was noted. RESULTS: Complete resection of the T1 contrast-enhancing tumor volume was achieved in 876 patients (71%). The median survival time for these patients (15.2 months) was significantly longer than that for patients undergoing less than complete resection (9.8 months; p < 0.001). This survival advantage was achieved without an increase in the risk of overall or neurological postoperative deficits and after correcting for established prognostic factors including age, Karnofsky Performance Scale score, preoperative contrast-enhancing tumor volume, presence of cyst, and prior treatment status (HR 1.53, 95% CI 1.33-1.77, p < 0.001). The effect remained essentially unchanged when data from previously treated and previously untreated groups of patients were analyzed separately. Additional analyses showed that the resection of >= 53.21% of the surrounding FLAIR abnormality beyond the 100% contrast-enhancing resection was associated with a significant prolongation of survival compared with that following less extensive resections (median survival times 20.7 and 15.5 months, respectively; p < 0.001). In the multivariate analysis, the previously treated group with < 53.21% resection had significantly shorter survival than the 3 other groups (that is, previously treated patients who underwent FLAIR resection >= 53.21%, previously untreated patients who underwent FLAIR resection < 53.21%, and previously untreated patients who underwent FLAIR resection >= 53.21%); the previously untreated group with >= 53.21% resection had the longest survival. CONCLUSIONS: What is believed to be the largest single center series of GBM patients with extensive tumor resections, this study supports the established association between EOR and survival and presents additional data that pushing the boundary of a conventional 100% resection by the additional removal of a significant portion of the FLAIR abnormality region, when safely feasible, may result in the prolongation of survival without significant increases in overall or neurological postoperative morbidity. Additional supportive evidence is warranted. PMID- 26495942 TI - Vasospasm on transcranial Doppler is predictive of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. AB - OBJECT The impact of transcranial Doppler (TCD) ultrasonography evidence of vasospasm on patient-centered clinical outcomes following aneurysmal subarachnoid hemorrhage (aSAH) is unknown. Vasospasm is known to lead to delayed cerebral ischemia (DCI) and poor outcomes. This systematic review and meta-analysis evaluates the predictive value of vasospasm on DCI, as diagnosed on TCD. METHODS MEDLINE, Scopus, the Cochrane trial register, and clinicaltrials.gov were searched through September 2014 using key words and the terms "subarachnoid hemorrhage," "aneurysm," "aneurysmal," "cerebral vasospasm," "vasospasm," "transcranial Doppler," and "TCD." Sensitivities, specificities, and positive and negative predictive values were pooled by a DerSimonian and Laird random-effects model. RESULTS Seventeen studies (n = 2870 patients) met inclusion criteria. The amount of variance attributable to heterogeneity was significant (I(2) > 50%) for all syntheses. No studies reported the impact of TCD evidence of vasospasm on functional outcome or mortality. TCD evidence of vasospasm was found to be highly predictive of DCI. Pooled estimates for TCD diagnosis of vasospasm (for DCI) were sensitivity 90% (95% confidence interval [CI] 77%-96%), specificity 71% (95% CI 51%-84%), positive predictive value 57% (95% CI 38%-71%), and negative predictive value 92% (95% CI 83%-96%). CONCLUSIONS TCD evidence of vasospasm is predictive of DCI with high accuracy. Although high sensitivity and negative predictive value make TCD an ideal monitoring device, it is not a mandated standard of care in aSAH due to the paucity of evidence on clinically relevant outcomes, despite recommendation by national guidelines. High-quality randomized trials evaluating the impact of TCD monitoring on patient-centered and physician-relevant outcomes are needed. PMID- 26495943 TI - Editorial: Excellence, mentorship, and the final transition. PMID- 26495944 TI - Hemispheric surgery for refractory epilepsy: a systematic review and meta analysis with emphasis on seizure predictors and outcomes. AB - OBJECTIVE: Conflicting conclusions have been reported regarding several factors that may predict seizure outcomes after hemispheric surgery for refractory epilepsy. The goal of this study was to identify the possible predictors of seizure outcome by pooling the rates of postoperative seizure freedom found in the published literature. METHODS: A comprehensive literature search of PubMed, Embase, and the Cochrane Library identified English-language articles published since 1970 that describe seizure outcomes in patients who underwent hemispheric surgery for refractory epilepsy. Two reviewers independently assessed article eligibility and extracted the data. The authors pooled rates of seizure freedom from papers included in the study. Eight potential prognostic variables were identified and dichotomized for analyses. The authors also compared continuous variables within seizure-free and seizure-recurrent groups. Random- or fixed effects models were used in the analyses depending on the presence or absence of heterogeneity. RESULTS: The pooled seizure-free rate among the 1528 patients (from 56 studies) who underwent hemispheric surgery was 73%. Patients with an epilepsy etiology of developmental disorders, generalized seizures, nonlateralization on electroencephalography, and contralateral MRI abnormalities had reduced odds of being seizure-free after surgery. CONCLUSIONS: Hemispheric surgery is an effective therapeutic modality for medically intractable epilepsy. This meta-analysis provides useful evidence-based information for the selection of candidates for hemispheric surgery, presurgical counseling, and explanation of seizure outcomes. PMID- 26495945 TI - Initial experience with dual-lumen balloon catheter injection for preoperative Onyx embolization of skull base paragangliomas. AB - OBJECT Paragangliomas are highly vascular head and neck tumors for which preoperative embolization is often considered to facilitate resection. The authors evaluated their initial experience using a dual-lumen balloon to facilitate preoperative embolization in 5 consecutive patients who underwent preoperative transarterial Onyx embolization assisted by the Scepter dual-lumen balloon catheter between 2012 and 2014. OBJECT The authors reviewed the demographic and clinical records of 5 patients who underwent Scepter-assisted Onyx embolization of a paraganglioma followed by resection between 2012 and 2014. Descriptive statistics of clinical outcomes were assessed. RESULTS Five patients (4 with a jugular and 1 with a vagal paraganglioma) were identified. Three paragangliomas were embolized in a single session, and each of the other 2 were completed in 3 staged sessions. The mean volume of Onyx used was 14.3 ml (range 6 30 ml). Twenty-seven vessels were selectively catheterized for embolization. All patients required selective embolization via multiple vessels. Two patients required sacrifice of parent vessels (1 petrocavernous internal carotid artery and 1 vertebral artery) after successful balloon test occlusion. One patient underwent embolization with Onyx-18 alone, 2 with Onyx-34 alone, and 1 with Onyx 18 and -34. In each case, migration of Onyx was achieved within the tumor parenchyma. The mean time between embolization and resection was 3.8 days (range 1-8 days). Gross-total resection was achieved in 3 (60%) patients, and the other 2 patients had minimal residual tumor. The mean estimated blood loss during the resections was 556 ml (range 200-850 ml). The mean postoperative hematocrit level change was -17.3%. Two patients required blood transfusions. One patient, who underwent extensive tumor penetration with Onyx, developed a temporary partial cranial nerve VII palsy that resolved to House-Brackmann Grade I (out of VI) at the 6-month follow-up. One patient experienced improvement in existing facial nerve weakness after embolization. CONCLUSIONS Scepter catheter-based Onyx embolization seems to be safe and effective. It was associated with excellent distal tumor vasculature penetration and holds promise as an adjunct to conventional transarterial Onyx embolization of paragangliomas. However, the ease of tumor penetration should encourage caution in practitioners who may be able to effect comparable improvement in blood loss with more conservative proximal Onyx penetration. PMID- 26495946 TI - Letter to the Editor: Cranioplasty complications and the timing of surgery. PMID- 26495948 TI - Letter to the Editor: Utility of dual-energy CT in differentiating contrast extravasation from intracranial hematoma. PMID- 26495947 TI - Clinical outcomes using ClearPoint interventional MRI for deep brain stimulation lead placement in Parkinson's disease. AB - OBJECTIVE: The ClearPoint real-time interventional MRI-guided methodology for deep brain stimulation (DBS) lead placement may offer advantages to frame-based approaches and allow accurate implantation under general anesthesia. In this study, the authors assessed the safety and efficacy of DBS in Parkinson's disease (PD) using this surgical method. METHODS: This was a prospective single-center study of bilateral DBS therapy in patients with advanced PD and motor fluctuations. Symptom severity was evaluated at baseline and 12 months postimplantation using the change in Unified Parkinson's Disease Rating Scale (UPDRS) Part III "off" medication score as the primary outcome variable. RESULTS: Twenty-six PD patients (15 men and 11 women) were enrolled from 2010 to 2013. Twenty patients were followed for 12 months (16 with a subthalamic nucleus target and 4 with an internal globus pallidus target). The mean UPDRS Part III "off" medication score improved from 40.75 +/- 10.9 to 24.35 +/- 8.8 (p = 0.001). "On" medication time without troublesome dyskinesia increased 5.2 +/- 2.6 hours per day (p = 0.0002). UPDRS Parts II and IV, total UPDRS score, and dyskinesia rating scale "on" medication scores also significantly improved (p < 0.01). The mean levodopa equivalent daily dose decreased from 1072.5 +/- 392 mg to 828.25 +/- 492 mg (p = 0.046). No significant cognitive or mood declines were observed. A single brain penetration was used for placement of all leads, and the mean targeting error was 0.6 +/- 0.3 mm. There were 3 serious adverse events (1 DBS hardware related infection, 1 lead fracture, and 1 unrelated death). CONCLUSIONS: DBS leads placed using the ClearPoint interventional real-time MRI-guided method resulted in highly accurate lead placement and outcomes comparable to those seen with frame-based approaches. PMID- 26495950 TI - Alcohol and mortality after moderate to severe traumatic brain injury: a meta analysis of observational studies. AB - OBJECT Experimental studies have shown numerous neuroprotective properties of alcohol ("ethanol") after TBI, but clinical studies have provided conflicting results. The authors aimed to assess the relationship between positive blood alcohol concentration (BAC) on hospital admission and mortality after moderate to severe traumatic brain injury (TBI). METHODS The authors searched 8 databases for observational studies reported between January 1, 1990, and October 7, 2013, and investigated the effect of BAC on mortality after moderate to severe TBI. Reviews of each study were conducted, and data were extracted according to the MOOSE and PRISMA guidelines. Study quality was assessed using the Newcastle-Ottawa scale. The Mantel-Haenszel fixed effect methodology was used to generate pooled estimates. Heterogeneity was dealt with by multiple sensitivity analyses. RESULTS Eleven studies with a total of 95,941 patients (42% BAC positive and 58% BAC negative) were identified for the primary analysis (overall mortality 12%). Primary analysis showed a significantly lower risk of death for BAC-positive patients compared with BAC-negative patients (crude mortality 11.0% vs 12.3%, pooled OR 0.84 [95% CI 0.81-0.88]), although flawed by heterogeneity (I(2) = 68%). Multiple sensitivity analyses, including 55,949 and 51,772 patients, yielded similar results to the primary analysis (crude mortality 12.2% vs 14.0%, pooled OR 0.87 [95% CI 0.83-0.92] and crude mortality 8.7% vs 10.7%, pooled OR 0.78 [95% CI 0.74-0.83]) but with good study homogeneity (I(2) = 36% and 14%). CONCLUSIONS Positive BAC was significantly associated with lower mortality rates in moderate to severe TBI. Whether this observation is due to selection bias or neuroprotective effects of alcohol remains unknown. Future prospective studies adjusting for TBI heterogeneity is advocated to establish the potential favorable effects of alcohol on outcome after TBI. PMID- 26495949 TI - Sequential changes in Rotterdam CT scores related to outcomes for patients with traumatic brain injury who undergo decompressive craniectomy. AB - OBJECT Rotterdam CT scoring is a CT classification system for grouping patients with traumatic brain injury (TBI) based on multiple CT characteristics. This retrospective study aimed to determine the relationship between initial or preoperative Rotterdam CT scores and TBI prognosis after decompressive craniectomy (DC). METHODS The authors retrospectively reviewed the medical records of all consecutive patients who underwent DC for nonpenetrating TBI in 2 hospitals from January 2006 through December 2013. Univariate and multivariate logistic regression and receiver operating characteristic (ROC) curve analyses were used to determine the relationship between initial or preoperative Rotterdam CT scores and mortality at 30 days or Glasgow Outcome Scale (GOS) scores at least 3 months after the time of injury. Unfavorable outcomes were GOS Scores 1-3 and favorable outcomes were GOS Scores 4 and 5. RESULTS A total of 48 cases involving patients who underwent DC for TBI were included in this study. Univariate analyses showed that initial Rotterdam CT scores were significantly associated with mortality and both initial and preoperative Rotterdam CT scores were significantly associated with unfavorable outcomes. Multivariable logistic regression analysis adjusted for established predictors of TBI outcomes showed that initial Rotterdam CT scores were significantly associated with mortality (OR 4.98, 95% CI 1.40-17.78, p = 0.01) and unfavorable outcomes (OR 3.66, 95% CI 1.29 10.39, p = 0.02) and preoperative Rotterdam CT scores were significantly associated with unfavorable outcomes (OR 15.29, 95% CI 2.50-93.53, p = 0.003). ROC curve analyses showed cutoff values for the initial Rotterdam CT score of 5.5 (area under the curve [AUC] 0.74, 95% CI 0.59-0.90, p = 0.009, sensitivity 50.0%, and specificity 88.2%) for mortality and 4.5 (AUC 0.71, 95% CI 0.56-0.86, p = 0.02, sensitivity 62.5%, and specificity 75.0%) for an unfavorable outcome and a cutoff value for the preoperative Rotterdam CT score of 4.5 (AUC 0.81, 95% CI 0.69-0.94, p < 0.001, sensitivity 90.6%, and specificity 56.2%) for an unfavorable outcome. CONCLUSIONS Assessment of changes in Rotterdam CT scores over time may serve as a prognostic indicator in TBI and can help determine which patients require DC. PMID- 26495951 TI - Real-time magnetic resonance imaging-guided frameless stereotactic brain biopsy: technical note. AB - OBJECTIVE: The object of this study was to assess the feasibility, accuracy, and safety of real-time MRI-compatible frameless stereotactic brain biopsy. METHODS: Clinical, imaging, and histological data in consecutive patients who underwent stereotactic brain biopsy using a frameless real-time MRI system were analyzed. RESULTS: Five consecutive patients (4 males, 1 female) were included in this study. The mean age at biopsy was 45.8 years (range 29-60 years). Real-time MRI permitted concurrent display of the biopsy cannula trajectory and tip during placement at the target. The mean target depth of biopsied lesions was 71.3 mm (range 60.4-80.4 mm). Targeting accuracy analysis revealed a mean radial error of 1.3 +/- 1.1 mm (mean +/- standard deviation), mean depth error of 0.7 +/- 0.3 mm, and a mean absolute tip error of 1.5 +/- 1.1 mm. There was no correlation between target depth and absolute tip error (Pearson product-moment correlation coefficient, r = 0.22). All biopsy cannulae were placed at the target with a single penetration and resulted in a diagnostic specimen in all cases. Histopathological evaluation of biopsy samples revealed dysembryoplastic neuroepithelial tumor (1 case), breast carcinoma (1 case), and glioblastoma multiforme (3 cases). CONCLUSIONS: The ability to place a biopsy cannula under real-time imaging guidance permits on-the-fly alterations in the cannula trajectory and/or tip placement. Real-time imaging during MRI-guided brain biopsy provides precise safe targeting of brain lesions. PMID- 26495952 TI - Neuroimaging characteristics of ruptured aneurysm as predictors of outcome after aneurysmal subarachnoid hemorrhage: pooled analyses of the SAHIT cohort. AB - OBJECT Neuroimaging characteristics of ruptured aneurysms are important to guide treatment selection, and they have been studied for their value as outcome predictors following aneurysmal subarachnoid hemorrhage (SAH). Despite multiple studies, the prognostic value of aneurysm diameter, location, and extravasated SAH clot on computed tomography scan remains debatable. The authors aimed to more precisely ascertain the relation of these factors to outcome. METHODS The data sets of studies included in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository were analyzed including data on ruptured aneurysm location and diameter (7 studies, n = 9125) and on subarachnoid clot graded on the Fisher scale (8 studies; n = 9452) for the relation to outcome on the Glasgow Outcome Scale (GOS) at 3 months. Prognostic strength was quantified by fitting proportional odds logistic regression models. Univariable odds ratios (ORs) were pooled across studies using random effects models. Multivariable analyses were adjusted for fixed effect of study, age, neurological status on admission, other neuroimaging factors, and treatment modality. The neuroimaging predictors were assessed for their added incremental predictive value measured as partial R(2). RESULTS Spline plots indicated outcomes were worse at extremes of aneurysm size, i.e., less than 4 or greater than 9 mm. In between, aneurysm size had no effect on outcome (OR 1.03, 95% CI 0.98-1.09 for 9 mm vs 4 mm, i.e., 75th vs 25th percentile), except in those who were treated conservatively (OR 1.17, 95% CI 1.02-1.35). Compared with anterior cerebral artery aneurysms, posterior circulation aneurysms tended to result in slightly poorer outcome in patients who underwent endovascular coil embolization (OR 1.13, 95% CI 0.82-1.57) or surgical clipping (OR 1.32, 95% CI 1.10-1.57); the relation was statistically significant only in the latter. Fisher CT subarachnoid clot burden was related to outcome in a gradient manner. Each of the studied predictors accounted for less than 1% of the explained variance in outcome. CONCLUSIONS This study, which is based on the largest cohort of patients so far analyzed, has more precisely determined the prognostic value of the studied neuroimaging factors. Treatment choice has strong influence on the prognostic effect of aneurysm size and location. These findings should guide the development of reliable prognostic models and inform the design and analysis of future prospective studies, including clinical trials. PMID- 26495953 TI - Arteriovenous malformation of the filum terminale: an exceptional case. AB - Arteriovenous malformations (AVMs) of the spine display a variety of different locations, angioarchitectures, and clinical presentations. The authors describe an exceptional case of a filum terminale AVM that is not described in any classification and discuss the origin and management of this malformation. A 59 year-old woman was admitted in June 2012 for cauda equina syndrome. Magnetic resonance imaging and spinal angiography revealed an AVM of the filum terminale, located below the conus medullaris, fed by the anterior spinal artery. After an unsuccessful attempt to reach the nidus with a microcatheter, the AVM was resected. At 20 months after surgery, the patient was fully independent and radiological images confirmed the exclusion of the malformation. AVMs that originate from the filum terminale are exceptional. According to updated classifications, AVMs of the filum terminale should be categorized as a separate entity. PMID- 26495954 TI - Quantitative evaluation of headache severity before and after endoscopic transsphenoidal surgery for pituitary adenoma. AB - OBJECT The relationship between headaches, pituitary adenomas, and surgical treatment of pituitary adenomas remains unclear. The authors assessed the severity and predictors of self-reported headaches in patients referred for surgery of pituitary adenomas and evaluated the impact of endoscopic transsphenoidal surgery on headache severity and quality of life (QOL). METHODS In this prospective study, 79 patients with pituitary adenomas underwent endoscopic transsphenoidal resection and completed the Headache Impact Test (HIT 6) and the 36-Item Short Form Health Survey (SF-36) QOL questionnaire preoperatively and at 6 weeks and 6 months postoperatively. RESULTS Preoperatively, 49.4% of patients had mild headache severity, 13.9% had moderate severity, 13.9% had substantial severity, and 22.8% had intense severity. Younger age and hormone-producing tumors predisposed greater headache severity, while tumor volume, suprasellar extension, chiasmal compression, and cavernous sinus invasion of the pituitary tumors did not. Preoperative headache severity was found to be significantly associated with reduced scores across all SF-36 QOL dimensions and most significantly associated with mental health. By 6 months postoperatively, headache severity was reduced in a significant proportion of patients. Of the 40 patients with headaches causing an impact on daily living (moderate, substantial, or intense headache), 70% had improvement of at least 1 category on HIT-6 by 6 months postoperatively, while headache worsened in 7.6% of patients. The best predictors of headache response to surgery included younger age, poor preoperative SF-36 mental health score, and hormone-producing microadenoma. CONCLUSIONS The results of this study confirm that surgery can significantly improve headaches in patients with pituitary adenomas by 6 months postoperatively, particularly in younger patients whose preoperative QOL is impacted. A larger multicenter study is underway to evaluate the long-term effect of surgery on headaches in this patient group. PMID- 26495955 TI - Gold-Catalyzed Ammonium Acetate Assisted Cascade Cyclization of 2 Alkynylarylketones. AB - An ammonium acetate assisted gold-catalyzed cascade cyclization reaction of 2 alkynylarylketones is described. Under the reported conditions, a gold-catalyzed intramolecular cyclization of 2-alkynylarylketones takes place through two competing reaction mechanisms-a 5-exo-dig or a 6-endo-dig cyclization-leading to two regioisomeric intermediates: isobenzofuranium or isobenzopyrylium. In the presence of ammonium acetate, the two intermediate compounds undergo further rearrangement to 2,3-disubstituted indenones and 1,3-disubstituted isoquinolines, respectively. While both reaction pathways proceed via a cyclization rearrangement cascade, the gold-mediated 5-exo-dig process is especially notable, as it provides a novel cyclization protocol of 2-alkynylarylketones. PMID- 26495956 TI - Intussusceptive-like angiogenesis in human fetal lung xenografts: Link with bronchopulmonary dysplasia-associated microvascular dysangiogenesis? AB - BACKGROUND: Human fetal lung xenografts display an unusual pattern of non sprouting, plexus-forming angiogenesis that is reminiscent of the dysmorphic angioarchitecture described in bronchopulmonary dysplasia (BPD). The aim of this study was to determine the clinicopathological correlates, growth characteristics and molecular regulation of this aberrant form of graft angiogenesis. METHODS: Fetal lung xenografts, derived from 12 previable fetuses (15 to 22 weeks' gestation) and engrafted in the renal subcapsular space of SCID-beige mice, were analyzed 4 weeks posttransplantation for morphology, vascularization, proliferative activity and gene expression. RESULTS: Focal plexus-forming angiogenesis (PFA) was observed in 60/230 (26%) of xenografts. PFA was characterized by a complex network of tortuous nonsprouting vascular structures with low endothelial proliferative activity, suggestive of intussusceptive-type angiogenesis. There was no correlation between the occurrence of PFA and gestational age or time interval between delivery and engraftment. PFA was preferentially localized in the relatively hypoxic central subcapsular area. Microarray analysis suggested altered expression of 15 genes in graft regions with PFA, of which 7 are known angiogenic/lymphangiogenic regulators and 5 are known hypoxia-inducible genes. qRT-PCR analysis confirmed significant upregulation of SULF2, IGF2, and HMOX1 in graft regions with PFA. CONCLUSION: These observations in human fetal lungs ex vivo suggest that postcanalicular lungs can switch from sprouting angiogenesis to an aberrant intussusceptive-type of angiogenesis that is highly reminiscent of BPD-associated dysangiogenesis. While circumstantial evidence suggests hypoxia may be implicated, the exact triggering mechanisms, molecular regulation and clinical implications of this angiogenic switch in preterm lungs in vivo remain to be determined. PMID- 26495957 TI - Intraindividual comparison of image quality using retrospective and prospective respiratory gating for the acquisition of thin sliced four dimensional multidetector CT of the thorax in a porcine model. AB - PURPOSE: To intraindividually compare image quality and anatomical depiction of the lung and mediastinum using retrospective and prospective respiratory gating techniques for the acquisition of 4D-multidetector computed tomography (MDCT) of the chest in a porcine model. MATERIALS AND METHODS: Twelve trachealy intubated domestic pigs underwent 64-row MDCT of the thorax. For retrospective and prospective gating the automated respiratory frequency was adjusted to 10, 14, 18, and 22 respiratory cycles per minute. Further, free breathing MDCT scans of the lung were performed at the same respiratory settings. A breathhold scan was acquired which served as the reference standard. Three reviewers independently analyzed the MDCT data applying a 4-point-grading scale regarding the degree of artifacts observed and anatomical depiction (1, excellent, no artifacts; 4, nondiagnostic due to severe artifacts). For statistical analysis the Wilcoxon matched pairs and Chi-square test were used. RESULTS: Breathhold imaging allowed for the highest image quality (mean value: trachea, 1.00; bronchi, 1.10; lung parenchyma, 1.08; diaphragm, 1.00; pericardium, 1.80). Retrospective gating proved to be of superior image quality compared to prospective gating for all respiratory frequencies. With the respiratory frequency set to 14/min retrospective gating even enabled an identical image quality score as at breathhold. Performing image acquisition during continuous breathing lead to a severe decrease in image quality. CONCLUSIONS: High image quality can be acquired using respiratory gating techniques for 4D-MDCT of the thorax. Retrospective is superior to prospective gating and can be of an equivalent image quality as standard breathhold imaging, but at the cost of a significantly higher radiation dose. PMID- 26495959 TI - Absinthin attenuates LPS-induced ALI through MIP-1alpha-mediated inflammatory cell infiltration. AB - Acute lung injury (ALI) is characterized by severe lung inflammation, and anti inflammatory treatment is proposed to be a pertinent therapeutic strategy for the disease. Absinthin is a triterpene, extracted from a Chinese herb, with anti inflammatory properties. The aim of this study was to evaluate whether absinthin can attenuate ALI in a mouse model of lung injury. Mice were treated with various concentrations (20 mg/kg, 40 mg/kg, and 80mg/kg) of absinthin, and lipopolysaccharide (LPS) to induce ALI. We found that the administration of absinthin relieved LPS-induced acute lung injury, as suggested by reduced histological scores, wet-to-dry ratio, myeloperoxidase activity, and accumulation of inflammatory cells in lung bronchoalveolar lavage fluid. Moreover, we demonstrated that absinthin significantly enhanced the expression of matrix metalloproteinase-8 (MMP-8); this effect could inhibit the accumulation of inflammatory cells in lung tissues through a mechanism dependent on MMP-8 mediated inactivation of macrophage inflammatory protein-1alpha. Therefore, we propose that absinthin is a promising novel therapeutic candidate for the treatment of ALI. PMID- 26495958 TI - Heparin and LPS-induced COX-2 expression in airway cells: a link between its anti inflammatory effects and GAG sulfation. AB - PURPOSE/AIM: Previous studies have indicated that the sulfated polysaccharide heparin has anti-inflammatory effects. However, the mechanistic basis for these effects has not been fully elucidated. MATERIALS AND METHODS: NCI-H292 (mucoepidermoid) and HBE-1 (normal) human bronchial epithelial cells were treated with LPS alone or in the presence of high-molecular-weight (HMW) fully sulfated heparin or desulfated HMW heparin. Cells were harvested to examine the phosphorylation levels of ERK1/2, p38, and NF-kB p65 and COX-2 protein expression by Western blot and gene expression of both COX-2 and CXCL-8 by TaqMan qRT-PCR. RESULTS: Heparin is known to exert an influence on receptor-mediated signaling through its ability to both potentiate and inhibit the receptor-ligand interaction, depending upon its concentration. In H292 cells, fully-sulfated HMW heparin significantly reduced LPS-induced gene expression of both COX-2 and CXCL 8 for up to 48 hours, while desulfated heparin had little to no significant suppressive effect on signaling or on COX-2 gene or protein expression. Desulfated heparin, initially ineffective at preventing LPS-induced CXCL8 up regulation, reduced CXCL8 transcription at 24 hours. In contrast, in normal HBE-1 cells, fully sulfated heparin significantly suppressed only ERK signaling, COX-2 gene expression at 12 hours, and CXCL-8 gene expression at 6 and 12 hours, while desulfated heparin had no significant effects on LPS-stimulated signaling or on gene or protein expression. Sulfation determines heparin's influence and may reflect the moderating role of GAG sulfation in lung injury and health. CONCLUSIONS: Heparin's anti-inflammatory effects result from its nonspecific suppression of signaling and gene expression and are determined by its sulfation. PMID- 26495960 TI - Letter to the Editor Regarding the Article by Natsch et al., 2015. PMID- 26495961 TI - Trial-based cost-effectiveness of abatacept for rheumatoid arthritis patients in Italy. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic, inflammatory disorder leading to disability and reduced quality of life. Effective treatment is a significant economic burden on the Italian healthcare system. Economic models in RA are commonly based on indirect treatment comparisons. METHODS: This study assessed the cost-effectiveness of abatacept relative to adalimumab for RA in Italy based on a head-to-head trial by means of a cost-consequence analysis. RESULTS: Health benefits based on the most stringent efficacy criteria were in favor of abatacept compared to adalimumab. Rates for more costly adverse events were higher for adalimumab compared to abatacept, which was reflected in the lower costs for abatacept (-?237,246 or -?237per patient). CONCLUSION: The health economic value of abatacept compared with adalimumab from the perspective of the Italian NHS depends on the choice of health outcome. Health gains with abatacept were generally based on more stringent criteria and lower total costs. PMID- 26495962 TI - Tungsten Sulfide Quantum Dots as Multifunctional Nanotheranostics for In Vivo Dual-Modal Image-Guided Photothermal/Radiotherapy Synergistic Therapy. AB - Designing a multifunctional nanomedicine for integration of precise diagnosis and effective treatment of tumors is desirable but remains a great challenge. Here, we report a multifunctional nanomedicine based on WS2 quantum dots (QDs), which was prepared by a facile and "green" method through physical grinding and ultrasonication. The as-obtained WS2 QDs with small size (3 nm) possess not only significant X-ray computed tomography (CT)/photoaccoustic (PA) imaging signal enhancement but also remarkable photothermal therapy (PTT)/radiotherapy (RT) synergistic effect for tumor treatment. With CT/PA imaging and the synergistic effect between PTT and RT, the tumor could be accurately positioned and thoroughly eradicated in vivo after intravenous injection of WS2 QDs. Moreover, hematoxylin and eosin staining, blood hematology, and biochemistry analysis revealed no noticeable toxicity of WS2 QDs in vitro and in vivo, which confirmed that WS2 QDs possess good biocompatibility. This multifunctional nanoparticle could play an important role in facilitating simultaneously multimodal imaging and synergistic therapy between PTT and RT to achieve better therapeutic efficacy. PMID- 26495963 TI - Declining Acidic Deposition Begins Reversal of Forest-Soil Acidification in the Northeastern U.S. and Eastern Canada. AB - Decreasing trends in acidic deposition levels over the past several decades have led to partial chemical recovery of surface waters. However, depletion of soil Ca from acidic deposition has slowed surface water recovery and led to the impairment of both aquatic and terrestrial ecosystems. Nevertheless, documentation of acidic deposition effects on soils has been limited, and little is known regarding soil responses to ongoing acidic deposition decreases. In this study, resampling of soils in eastern Canada and the northeastern U.S. was done at 27 sites exposed to reductions in wet SO4(2-) deposition of 5.7-76%, over intervals of 8-24 y. Decreases of exchangeable Al in the O horizon and increases in pH in the O and B horizons were seen at most sites. Among all sites, reductions in SO4(2-) deposition were positively correlated with ratios (final sampling/initial sampling) of base saturation (P < 0.01) and negatively correlated with exchangeable Al ratios (P < 0.05) in the O horizon. However, base saturation in the B horizon decreased at one-third of the sites, with no increases. These results are unique in showing that the effects of acidic deposition on North American soils have begun to reverse. PMID- 26495964 TI - Time-Dependent Wave Packet Study of the H2 + CH3 -> H + CH4 Reaction. AB - The initial state selected time-dependent wave packet method has been developed to study the H2 + CH3 -> H + CH4 reaction, by employing the seven- and eight dimensional models proposed by Palma and Clary in which the nonreacting CH3 moiety is restricted in C3v symmetry. Total reaction probabilities and integral cross sections were calculated for the ground and a number of vibrationally excited initial states to investigate the effects of vibrational excitations of both reagents on the reaction. The eight-dimensional calculations showed that the CH stretching excitation does not have any important effect on the reaction and the seven-dimensional model with the CH bond length fixed works very well for the reaction. The excitation of H2 vibrations could enhance the reaction but is less effective than the translation in the low energy region. In contrast, the first umbrella excitation is very effective on reducing the reaction threshold. The calculated rate constants are found to be in good agreement with available experimental measurements and other theoretical results. PMID- 26495965 TI - Distribution Pattern and Climate Preferences of the Representatives of the Cosmopolitan Genus Sirthenea Spinola, 1840 (Heteroptera: Reduviidae: Peiratinae). AB - The main goal of this study was to predict, through the use of GIS tool as ecological niche modelling, potentially suitable ecological niche and defining the conditions of such niche for the representatives of the cosmopolitan genus Sirthenea. Among all known genera of the subfamily Peiratinae, only Sirthenea occurs on almost all continents and zoogeographical regions. Our research was based on 521 unique occurrence localities and a set of environmental variables covering the whole world. Based on occurrence localities, as well as climatic variables, digital elevation model, terrestrial ecoregions and biomes, information about the ecological preferences is given. Potentially useful ecological niches were modelled using Maxent software, which allowed for the creation of a map of the potential distribution and for determining climatic preferences. An analysis of climatic preferences suggested that the representatives of the genus were linked mainly to the tropical and temperate climates. An analysis of ecoregions also showed that they preferred areas with tree vegetation like tropical and subtropical moist broadleaf forests biomes as well as temperate broadleaf and mixed forest biomes. Therefore, on the basis of the museum data on the species occurrence and ecological niche modelling method, we provided new and valuable information on the potentially suitable habitat and the possible range of distribution of the genus Sirthenea along with its climatic preferences. PMID- 26495966 TI - Comparison of Two Different Ultrasound Systems for the Evaluation of Tissue Doppler Velocities in Fetuses. AB - INTRODUCTION: Recent studies have reported variations of up to 30% between different ultrasound machines for tissue Doppler imaging (TDI), a problem that can significantly impact clinical diagnosis, patient management and research studies. The objective of this study was to assess repeatability and agreement between fetal myocardial peak velocities evaluated by TDI with two different ultrasound systems. MATERIALS AND METHODS: Systolic (S'), early (E') and late (A') diastolic myocardial peak velocities at mitral and tricuspid annuli as well as at the basal septum were evaluated by spectral TDI in 150 fetuses using two different ultrasound systems: Siemens Antares (Siemens Medical Systems, Malvern, Pa., USA) and Vivid Q (General Electric Healthcare, Horten, Norway). A method comparison study was performed, calculating intraclass correlation coefficients (ICC), and agreement was assessed by Bland-Altman plots. RESULTS: Annular peak velocities showed lower values when measured by Vivid Q compared to values measured by Siemens Antares. ICC ranged from 0.07 (septal S') to 0.33 (right A'), showing very poor repeatability for clinical application. Agreement between the two systems was also poor, with high coefficients of variation for all measurements. CONCLUSIONS: Fetal annular peak velocities obtained with different ultrasound systems are not directly comparable. This is consistent with previous data in adults and warrants the need of system-specific reference values, suggesting that the same ultrasound machine should be used for longitudinal follow-up. PMID- 26495967 TI - Can Sibling Sex Ratios Be Used as a Valid Test for the Prenatal Androgen Hypothesis of Autism Spectrum Disorders? AB - BACKGROUND: Sibling sex ratios have been applied as an indirect test of a hypothesized association between prenatal testosterone levels and risk for autism, a developmental disorder disproportionately affecting males. Differences in sibling sex ratios between those with and without autism would provide evidence of a shared risk factor for autism and offspring sex. Conclusions related to prenatal testosterone, however, require additional assumptions. Here, we used directed acyclic graphs (DAGs) to clarify the elements required for a valid test of the hypothesis that sibling sex ratios differ between children with and without autism. We then conducted such a test using a large, population-based sample of children. METHODS: Over 1.1 million subjects, born in California from 1992-2007, and identified through birth records, were included. The association between autism diagnosis, determined using the administrative database of the California Department of Developmental Services, and the sex of the subsequent sibling was examined using generalized estimating equations. Sources of potential bias identified using DAGs were addressed. RESULTS: Among male children with autism, 52.2% of next-born siblings were brothers, versus 51.0% for unaffected males. For females with autism, 50.2% of following siblings were brothers versus 51.2% among control females. The relative risk of a subsequent male sibling associated with autism diagnosis was 1.02 (95% confidence interval: 0.99, 1.04). CONCLUSIONS: In a large, population-based sample we failed to find evidence suggesting an excess of brothers among children with autism while controlling for several threats to validity. This test cannot rule out a role of any given exposure, including prenatal testosterone, in either risk of autism or offspring sex ratio, but suggests against a common cause of both. PMID- 26495968 TI - The Role of Linkers in the Excited-State Dynamic Planarization Processes of Macrocyclic Oligothiophene 12-Mers. AB - Linkers adjoining chromophores play an important role in modulating the structure of conjugated systems, which is bound up with their photophysical properties. However, to date, the focus of works dealing with linker effects was limited only to linear pi-conjugated materials, and there have been no detailed studies on cyclic counterparts. Herein we report the linker effects on the dynamic planarization processes of pi-conjugated macrocyclic oligothiophene 12-mers, where the different ratio between ethynylene and vinylene linkers was chosen to control the backbone rigidity. By analyzing transient fluorescence spectra, we demonstrate that the connecting linkers play a crucial role in the excited-state dynamics of cyclic conjugated systems. Faster dynamic planarization, longer exciton delocalization length, and higher degree of planarity were observed in vinylene inserted cyclic oligothiophenes. Molecular dynamics simulations and density functional theory calculations also stress the importance of the role of linkers in modulating the structure of cyclic oligothiophenes. PMID- 26495969 TI - Correction: Human Cardiac Progenitor Spheroids Exhibit Enhanced Engraftment Potential. PMID- 26495970 TI - Renal Effects and Underlying Molecular Mechanisms of Long-Term Salt Content Diets in Spontaneously Hypertensive Rats. AB - Several evidences have shown that salt excess is an important determinant of cardiovascular and renal derangement in hypertension. The present study aimed to investigate the renal effects of chronic high or low salt intake in the context of hypertension and to elucidate the molecular mechanisms underlying such effects. To this end, newly weaned male SHR were fed with diets only differing in NaCl content: normal salt (NS: 0.3%), low salt (LS: 0.03%), and high salt diet (HS: 3%) until 7 months of age. Analysis of renal function, morphology, and evaluation of the expression of the main molecular components involved in the renal handling of albumin, including podocyte slit-diaphragm proteins and proximal tubule endocytic receptors were performed. The relationship between diets and the balance of the renal angiotensin-converting enzyme (ACE) and ACE2 enzymes was also examined. HS produced glomerular hypertrophy and decreased ACE2 and nephrin expressions, loss of morphological integrity of the podocyte processes, and increased proteinuria, characterized by loss of albumin and high molecular weight proteins. Conversely, severe hypertension was attenuated and renal dysfunction was prevented by LS since proteinuria was much lower than in the NS SHRs. This was associated with a decrease in kidney ACE/ACE2 protein and activity ratio and increased cubilin renal expression. Taken together, these results suggest that LS attenuates hypertension progression in SHRs and preserves renal function. The mechanisms partially explaining these findings include modulation of the intrarenal ACE/ACE2 balance and the increased cubilin expression. Importantly, HS worsens hypertensive kidney injury and decreases the expression nephrin, a key component of the slit diaphragm. PMID- 26495971 TI - Residual Upper Arm Motor Function Primes Innervation of Paretic Forearm Muscles in Chronic Stroke after Brain-Machine Interface (BMI) Training. AB - BACKGROUND: Abnormal upper arm-forearm muscle synergies after stroke are poorly understood. We investigated whether upper arm function primes paralyzed forearm muscles in chronic stroke patients after Brain-Machine Interface (BMI)-based rehabilitation. Shaping upper arm-forearm muscle synergies may support individualized motor rehabilitation strategies. METHODS: Thirty-two chronic stroke patients with no active finger extensions were randomly assigned to experimental or sham groups and underwent daily BMI training followed by physiotherapy during four weeks. BMI sessions included desynchronization of ipsilesional brain activity and a robotic orthosis to move the paretic limb (experimental group, n = 16). In the sham group (n = 16) orthosis movements were random. Motor function was evaluated with electromyography (EMG) of forearm extensors, and upper arm and hand Fugl-Meyer assessment (FMA) scores. Patients performed distinct upper arm (e.g., shoulder flexion) and hand movements (finger extensions). Forearm EMG activity significantly higher during upper arm movements as compared to finger extensions was considered facilitation of forearm EMG activity. Intraclass correlation coefficient (ICC) was used to test inter-session reliability of facilitation of forearm EMG activity. RESULTS: Facilitation of forearm EMG activity ICC ranges from 0.52 to 0.83, indicating fair to high reliability before intervention in both limbs. Facilitation of forearm muscles is higher in the paretic as compared to the healthy limb (p<0.001). Upper arm FMA scores predict facilitation of forearm muscles after intervention in both groups (significant correlations ranged from R = 0.752, p = 0.002 to R = 0.779, p = 0.001), but only in the experimental group upper arm FMA scores predict changes in facilitation of forearm muscles after intervention (R = 0.709, p = 0.002; R = 0.827, p<0.001). CONCLUSIONS: Residual upper arm motor function primes recruitment of paralyzed forearm muscles in chronic stroke patients and predicts changes in their recruitment after BMI training. This study suggests that changes in upper arm-forearm synergies contribute to stroke motor recovery, and provides candidacy guidelines for similar BMI-based clinical practice. PMID- 26495972 TI - Immunologic Control of Mus musculus Papillomavirus Type 1. AB - Persistent papillomas developed in ~10% of out-bred immune-competent SKH-1 mice following MusPV1 challenge of their tail, and in a similar fraction the papillomas were transient, suggesting potential as a model. However, papillomas only occurred in BALB/c or C57BL/6 mice depleted of T cells with anti-CD3 antibody, and they completely regressed within 8 weeks after depletion was stopped. Neither CD4+ nor CD8+ T cell depletion alone in BALB/c or C57BL/6 mice was sufficient to permit visible papilloma formation. However, low levels of MusPV1 were sporadically detected by either genomic DNA-specific PCR analysis of local skin swabs or in situ hybridization of the challenge site with an E6/E7 probe. After switching to CD3+ T cell depletion, papillomas appeared upon 14/15 of mice that had been CD4+ T cell depleted throughout the challenge phase, 1/15 of CD8+ T cell depleted mice, and none in mice without any prior T cell depletion. Both control animals and those depleted with CD8-specific antibody generated MusPV1 L1 capsid-specific antibodies, but not those depleted with CD4 specific antibody prior to T cell depletion with CD3 antibody. Thus, normal BALB/c or C57BL/6 mice eliminate the challenge dose, whereas infection is suppressed but not completely cleared if their CD4 or CD8 T cells are depleted, and recrudescence of MusPV1 is much greater in the former following treatment with CD3 antibody, possibly reflecting their failure to generate capsid antibody. Systemic vaccination of C57BL/6 mice with DNA vectors expressing MusPV1 E6 or E7 fused to calreticulin elicits potent CD8 T cell responses and these immunodominant CD8 T cell epitopes were mapped. Adoptive transfer of a MusPV1 E6 specific CD8+ T cell line controlled established MusPV1 infection and papilloma in RAG1-knockout mice. These findings suggest the potential of immunotherapy for HPV-related disease and the importance of host immunogenetics in the outcome of infection. PMID- 26495973 TI - Abdominal Adipose Tissue was Associated with Glomerular Hyperfiltration among Non Diabetic and Normotensive Adults with a Normal Body Mass Index. AB - Glomerular hyperfiltration is recognized as an early marker of progressive kidney dysfunction in the obese population. This study aimed to identify the relationship between glomerular hyperfiltration and body fat distribution measured by computed tomography (CT) in healthy Korean adults. The study population included individuals aged 20-64 years who went a routine health check up including an abdominal CT scan. We selected 4,378 individuals without diabetes and hypertension. Glomerular filtration rate was estimated using the CKD-EPI equation, and glomerular hyperfiltration was defined as the highest quintile of glomerular filtration rate. Abdominal adipose tissue areas were measured at the level of the umbilicus using a 16-detector CT scanner, and the cross-sectional area was calculated using Rapidia 2.8 CT software. The prevalence of glomerular hyperfiltration increased significantly according to the subcutaneous adipose tissue area in men (OR = 1.74 (1.16-2.61), P for trend 0.016, for the comparisons of lowest vs. highest quartile) and visceral adipose tissue area in women (OR = 2.34 (1.46-3.75), P for trend < 0.001) in multivariate analysis. After stratification by body mass index (normal < 23 kg/m2, overweight >= 23 kg/m2), male subjects with greater subcutaneous adipose tissue, even those in the normal BMI group, had a higher prevalence of glomerular hyperfiltration (OR = 2.11 (1.17 3.80), P for trend = 0.009). Among women, the significance of visceral adipose tissue area on glomerular hyperfiltration resulted from the normal BMI group (OR = 2.14 (1.31-3.49), P for trend = 0.002). After menopause, the odds ratio of the association of glomerular hyperfiltration with subcutaneous abdominal adipose tissue increased (OR = 2.96 (1.21-7.25), P for trend = 0.013). Subcutaneous adipose tissue areas and visceral adipose tissue areas are positively associated with glomerular hyperfiltration in healthy Korean adult men and women, respectively. In post-menopausal women, visceral adipose tissue area shows significant positive association with glomerular hyperfiltration as in men. PMID- 26495975 TI - An Efficient Augmented Lagrangian Method for Statistical X-Ray CT Image Reconstruction. AB - Statistical iterative reconstruction (SIR) for X-ray computed tomography (CT) under the penalized weighted least-squares criteria can yield significant gains over conventional analytical reconstruction from the noisy measurement. However, due to the nonlinear expression of the objective function, most exiting algorithms related to the SIR unavoidably suffer from heavy computation load and slow convergence rate, especially when an edge-preserving or sparsity-based penalty or regularization is incorporated. In this work, to address abovementioned issues of the general algorithms related to the SIR, we propose an adaptive nonmonotone alternating direction algorithm in the framework of augmented Lagrangian multiplier method, which is termed as "ALM-ANAD". The algorithm effectively combines an alternating direction technique with an adaptive nonmonotone line search to minimize the augmented Lagrangian function at each iteration. To evaluate the present ALM-ANAD algorithm, both qualitative and quantitative studies were conducted by using digital and physical phantoms. Experimental results show that the present ALM-ANAD algorithm can achieve noticeable gains over the classical nonlinear conjugate gradient algorithm and state-of-the-art split Bregman algorithm in terms of noise reduction, contrast-to noise ratio, convergence rate, and universal quality index metrics. PMID- 26495974 TI - Identification of O-Linked Glycoproteins Binding to the Lectin Helix pomatia Agglutinin as Markers of Metastatic Colorectal Cancer. AB - BACKGROUND: Protein glycosylation is an important post-translational modification shown to be altered in all tumour types studied to date. Mucin glycoproteins have been established as important carriers of O-linked glycans but other glycoproteins exhibiting altered glycosylation repertoires have yet to be identified but offer potential as biomarkers for metastatic cancer. METHODOLOGY: In this study a glycoproteomic approach was used to identify glycoproteins exhibiting alterations in glycosylation in colorectal cancer and to evaluate the changes in O-linked glycosylation in the context of the p53 and KRAS (codon 12/13) mutation status. Affinity purification with the carbohydrate binding protein from Helix pomatia agglutinin (HPA) was coupled to 2-dimensional gel electrophoresis with mass spectrometry to enable the identification of low abundance O-linked glycoproteins from human colorectal cancer specimens. RESULTS: Aberrant O-linked glycosylation was observed to be an early event that occurred irrespective of the p53 and KRAS status and correlating with metastatic colorectal cancer. Affinity purification using the lectin HPA followed by proteomic analysis revealed annexin 4, annexin 5 and CLCA1 to be increased in the metastatic colorectal cancer specimens. The results were validated using a further independent set of specimens and this showed a significant association between the staining score for annexin 4 and HPA and the time to metastasis; independently (annexin A4: Chi square 11.45, P = 0.0007; HPA: Chi square 9.065, P = 0.0026) and in combination (annexin 4 and HPA combined: Chi square 13.47; P = 0.0002). CONCLUSION: Glycoproteins showing changes in O-linked glycosylation in metastatic colorectal cancer have been identified. The glycosylation changes were independent of p53 and KRAS status. These proteins offer potential for further exploration as biomarkers and potential targets for metastatic colorectal cancer. PMID- 26495976 TI - Relationship between Humoral Immune Responses against HPV16, HPV18, HPV31 and HPV45 in 12-15 Year Old Girls Receiving Cervarix(r) or Gardasil(r) Vaccine. AB - BACKGROUND: Human papillomavirus (HPV) vaccines confer protection against the oncogenic genotypes HPV16 and HPV18 through the generation of type-specific neutralizing antibodies raised against virus-like particles (VLP) representing these genotypes. The vaccines also confer a degree of cross-protection against HPV31 and HPV45, which are genetically-related to the vaccine types HPV16 and HPV18, respectively, although the mechanism is less certain. There are a number of humoral immune measures that have been examined in relation to the HPV vaccines, including VLP binding, pseudovirus neutralization and the enumeration of memory B cells. While the specificity of responses generated against the vaccine genotypes are fairly well studied, the relationship between these measures in relation to non-vaccine genotypes is less certain. METHODS: We carried out a comparative study of these immune measures against vaccine and non vaccine genotypes using samples collected from 12-15 year old girls following immunization with three doses of either Cervarix(r) or Gardasil(r) HPV vaccine. RESULTS: The relationship between neutralizing and binding antibody titers and HPV-specific memory B cell levels for the vaccine genotypes, HPV16 and HPV18, were very good. The proportion of responders approached 100% for both vaccines while the magnitude of these responses induced by Cervarix(r) were generally higher than those following Gardasil(r) immunization. A similar pattern was found for the non-vaccine genotype HPV31, albeit at a lower magnitude compared to its genetically-related vaccine genotype, HPV16. However, both the enumeration of memory B cells and VLP binding responses against HPV45 were poorly related to its neutralizing antibody responses. Purified IgG derived from memory B cells demonstrated specificities similar to those found in the serum, including the capacity to neutralize HPV pseudoviruses. CONCLUSIONS: These data suggest that pseudovirus neutralization should be used as the preferred humoral immune measure for studying HPV vaccine responses, particularly for non-vaccine genotypes. PMID- 26495977 TI - Multifrequency Oscillatory Ventilation in the Premature Lung: Effects on Gas Exchange, Mechanics, and Ventilation Distribution. AB - BACKGROUND: Despite the theoretical benefits of high-frequency oscillatory ventilation (HFOV) in preterm infants, systematic reviews of randomized clinical trials do not confirm improved outcomes. The authors hypothesized that oscillating a premature lung with multiple frequencies simultaneously would improve gas exchange compared with traditional single-frequency oscillatory ventilation (SFOV). The goal of this study was to develop a novel method for HFOV, termed "multifrequency oscillatory ventilation" (MFOV), which relies on a broadband flow waveform more suitable for the heterogeneous mechanics of the immature lung. METHODS: Thirteen intubated preterm lambs were randomly assigned to either SFOV or MFOV for 1 h, followed by crossover to the alternative regimen for 1 h. The SFOV waveform consisted of a pure sinusoidal flow at 5 Hz, whereas the customized MFOV waveform consisted of a 5-Hz fundamental with additional energy at 10 and 15 Hz. Per standardized protocol, mean pressure at airway opening ((Equation is included in full-text article.)) and inspired oxygen fraction were adjusted as needed, and root mean square of the delivered oscillatory volume waveform (Vrms) was adjusted at 15-min intervals. A ventilatory cost function for SFOV and MFOV was defined as (Equation is included in full-text article.), where Wt denotes body weight. RESULTS: Averaged over all time points, MFOV resulted in significantly lower VC (246.9 +/- 6.0 vs. 363.5 +/- 15.9 ml mmHg kg) and (Equation is included in full-text article.)(12.8 +/- 0.3 vs. 14.1 +/- 0.5 cm H2O) compared with SFOV, suggesting more efficient gas exchange and enhanced lung recruitment at lower mean airway pressures. CONCLUSION: Oscillation with simultaneous multiple frequencies may be a more efficient ventilator modality in premature lungs compared with traditional single frequency HFOV. PMID- 26495978 TI - Repeated Time-to-event Analysis of Consecutive Analgesic Events in Postoperative Pain. AB - BACKGROUND: Reduction in consumption of opioid rescue medication is often used as an endpoint when investigating analgesic efficacy of drugs by adjunct treatment, but appropriate methods are needed to analyze analgesic consumption in time. Repeated time-to-event (RTTE) modeling is proposed as a way to describe analgesic consumption by analyzing the timing of consecutive analgesic events. METHODS: Retrospective data were obtained from 63 patients receiving standard analgesic treatment including morphine on request after surgery following hip fracture. Times of analgesic events up to 96 h after surgery were extracted from hospital medical records. Parametric RTTE analysis was performed with exponential, Weibull, or Gompertz distribution of analgesic events using NONMEM, version 7.2 (ICON Development Solutions, USA). The potential influences of night versus day, sex, and age were investigated on the probability. RESULTS: A Gompertz distribution RTTE model described the data well. The probability of having one or more analgesic events within 24 h was 80% for the first event, 55% for the second event, 31% for the third event, and 18% for fourth or more events for a typical woman of age 80 yr. The probability of analgesic events decreased in time, was reduced to 50% after 3.3 days after surgery, and was significantly lower (32%) during night compared with day. CONCLUSIONS: RTTE modeling described analgesic consumption data well and could account for time-dependent changes in probability of analgesic events. Thus, RTTE modeling of analgesic events is proposed as a valuable tool when investigating new approaches to pain management such as opioid sparing analgesia. PMID- 26495979 TI - An Innovative Analysis of Analgesic Consumption in the Postoperative Period. PMID- 26495980 TI - A Conceptual Framework for Appropriateness in Surgical Care: Reviewing Past Approaches and Looking Ahead to Patient-centered Shared Decision Making. PMID- 26495982 TI - T-Cell Surface Antigens and sCD30 as Biomarkers of the Risk of Rejection in Solid Organ Transplantation. AB - T-cell activation is a characteristic of organ rejection. T cells, located in the draining lymph nodes of the transplant recipient, are faced with non-self molecules presented by antigen presenting cells and become activated. Activated T cells are characterized by up-regulated surface antigens, such as costimulatory molecules, adhesion molecules, chemokine receptors, and major histocompatibility complex class II molecules. Surface antigen expression can be followed by flow cytometry using monoclonal antibodies in either cell function assays using donor specific or nonspecific stimulation of isolated cells or whole blood and without stimulation on circulating lymphocytes. Molecules such as CD30 can be proteolytically cleaved off the surface of activated cells in vivo, and the determination of the soluble protein (sCD30) in serum or plasma is performed by immunoassays. As promising biomarkers for rejection and long-term transplant outcome, CD28 (costimulatory receptor for CD80 and CD86), CD154 (CD40 ligand), and sCD30 (tumor necrosis factor receptor superfamily, member 8) have been identified. Whereas cell function assays are time-consuming laboratory-developed tests which are difficult to standardize, commercial assays are frequently available for soluble proteins. Therefore, more data from clinical trials have been published for sCD30 compared with the surface antigens on activated T cells. This short review summarizes the association between selected surface antigens and immunosuppression, and rejection in solid organ transplantation. PMID- 26495981 TI - Secondary Structure across the Bacterial Transcriptome Reveals Versatile Roles in mRNA Regulation and Function. AB - Messenger RNA acts as an informational molecule between DNA and translating ribosomes. Emerging evidence places mRNA in central cellular processes beyond its major function as informational entity. Although individual examples show that specific structural features of mRNA regulate translation and transcript stability, their role and function throughout the bacterial transcriptome remains unknown. Combining three sequencing approaches to provide a high resolution view of global mRNA secondary structure, translation efficiency and mRNA abundance, we unraveled structural features in E. coli mRNA with implications in translation and mRNA degradation. A poorly structured site upstream of the coding sequence serves as an additional unspecific binding site of the ribosomes and the degree of its secondary structure propensity negatively correlates with gene expression. Secondary structures within coding sequences are highly dynamic and influence translation only within a very small subset of positions. A secondary structure upstream of the stop codon is enriched in genes terminated by UAA codon with likely implications in translation termination. The global analysis further substantiates a common recognition signature of RNase E to initiate endonucleolytic cleavage. This work determines for the first time the E. coli RNA structurome, highlighting the contribution of mRNA secondary structure as a direct effector of a variety of processes, including translation and mRNA degradation. PMID- 26495983 TI - Evaluation of an Inexpensive Growth Medium for Direct Detection of Escherichia coli in Temperate and Sub-Tropical Waters. AB - The cost and complexity of traditional methods for the detection of faecal indicator bacteria, including E. coli, hinder widespread monitoring of drinking water quality, especially in low-income countries and outside controlled laboratory settings. In these settings the problem is exacerbated by the lack of inexpensive media for the detection of E. coli in drinking water. We developed a new low-cost growth medium, aquatest (AT), and validated its use for the direct detection of E. coli in temperate and sub-tropical drinking waters using IDEXX Quanti-Tray(r). AT was compared with IDEXX Colilert-18(r) and either EC-MUG or MLSB for detecting low levels of E. coli from water samples from temperate (n = 140; Bristol, UK) and subtropical regions (n = 50, Pretoria/Tshwane, South Africa). Confirmatory testing (n = 418 and 588, respectively) and the comparison of quantitative results were used to assess performance. Sensitivity of AT was higher than Colilert-18(r) for water samples in the UK [98.0% vs. 86.9%; p<0.0001] and South Africa [99.5% vs. 93.2%; p = 0.0030]. There was no significant difference in specificity, which was high for both media (>95% in both settings). Quantitative results were comparable and within expected limits. AT is reliable and accurate for the detection of E. coli in temperate and subtropical drinking water. The composition of the new medium is reported herein and can be used freely. PMID- 26495984 TI - Modeling the Evolution of Beliefs Using an Attentional Focus Mechanism. AB - For making decisions in everyday life we often have first to infer the set of environmental features that are relevant for the current task. Here we investigated the computational mechanisms underlying the evolution of beliefs about the relevance of environmental features in a dynamical and noisy environment. For this purpose we designed a probabilistic Wisconsin card sorting task (WCST) with belief solicitation, in which subjects were presented with stimuli composed of multiple visual features. At each moment in time a particular feature was relevant for obtaining reward, and participants had to infer which feature was relevant and report their beliefs accordingly. To test the hypothesis that attentional focus modulates the belief update process, we derived and fitted several probabilistic and non-probabilistic behavioral models, which either incorporate a dynamical model of attentional focus, in the form of a hierarchical winner-take-all neuronal network, or a diffusive model, without attention-like features. We used Bayesian model selection to identify the most likely generative model of subjects' behavior and found that attention-like features in the behavioral model are essential for explaining subjects' responses. Furthermore, we demonstrate a method for integrating both connectionist and Bayesian models of decision making within a single framework that allowed us to infer hidden belief processes of human subjects. PMID- 26495985 TI - Impact of Water Chemistry, Pipe Material and Stagnation on the Building Plumbing Microbiome. AB - A unique microbiome establishes in the portion of the potable water distribution system within homes and other buildings (i.e., building plumbing). To examine its composition and the factors that shape it, standardized cold water plumbing rigs were deployed at the treatment plant and in the distribution system of five water utilities across the U.S. Three pipe materials (copper with lead solder, CPVC with brass fittings or copper/lead combined pipe) were compared, with 8 hour flush cycles of 10 minutes to simulate typical daily use patterns. High throughput Illumina sequencing of 16S rRNA gene amplicons was employed to profile and compare the resident bulk water bacteria and archaea. The utility, location of the pipe rig, pipe material and stagnation all had a significant influence on the plumbing microbiome composition, but the utility source water and treatment practices were dominant factors. Examination of 21 water chemistry parameters suggested that the total chlorine concentration, pH, P, SO42- and Mg were associated with the most of the variation in bulk water microbiome composition. Disinfectant type exerted a notably low-magnitude impact on microbiome composition. At two utilities using the same source water, slight differences in treatment approaches were associated with differences in rare taxa in samples. For genera containing opportunistic pathogens, Utility C samples (highest pH of 9 10) had the highest frequency of detection for Legionella spp. and lowest relative abundance of Mycobacterium spp. Data were examined across utilities to identify a true universal core, special core, and peripheral organisms to deepen insight into the physical and chemical factors that shape the building plumbing microbiome. PMID- 26495986 TI - Differences in Expression Level of Helios and Neuropilin-1 Do Not Distinguish Thymus-Derived from Extrathymically-Induced CD4+Foxp3+ Regulatory T Cells. AB - Helios transcription factor and semaphorin receptor Nrp-1 were originally described as constitutively expressed at high levels on CD4+Foxp3+ T regulatory cells of intrathymic origin (tTregs). On the other hand, CD4+Foxp3+ Tregs generated in the periphery (pTregs) or induced ex vivo (iTregs) were reported to express low levels of Helios and Nrp-1. Soon afterwards the reliability of Nrp-1 and Helios as markers discriminating between tTregs and pTregs was questioned and until now no consensus has been reached. Here, we used several genetically modified mouse strains that favor pTregs or tTregs formation and analyzed the TCR repertoire of these cells. We found that Tregs with variable levels of Nrp-1 and Helios were abundant in mice with compromised ability to support natural differentiation of tTregs or pTregs. We also report that TCR repertoires of Treg clones expressing high or low levels of Nrp-1 or Helios are similar and more alike repertoire of CD4+Foxp3+ than repertoire of CD4+Foxp3- thymocytes. These results show that high vs. low expression of Nrp-1 or Helios does not unequivocally identify Treg clones of thymic or peripheral origin. PMID- 26495987 TI - A Trial of Lifestyle Modification on Cardiopulmonary, Inflammatory, and Metabolic Effects among Obese with Chronic Kidney Disease. AB - BACKGROUND: The feasibility and benefits of lifestyle intervention in chronic kidney disease (CKD) patients who are obese has not been well studied. We examined the early effects of an exercise plus weight loss intervention on body composition, exercise capacity, metabolic parameters and kidney function in obese subjects with CKD. METHODS: Nine subjects (median age 57 years, body mass index (BMI) 43.9) underwent a lifestyle intervention program that included supervised aerobic exercise (i.e. ~85% maximum heart rate) and dietary counseling (500 kcal reduction in daily caloric intake). Body composition (iDXA), exercise capacity (maximal oxygen consumption), quality of life, insulin resistance (Matsuda index), inflammation (high sensitivity C-reactive protein), adipokines (leptin and total adiponectin) and kidney function (iothalamate glomerular filtration rate) were measured at baseline and after 12 weeks of the intervention. Changes in parameters were compared using the Wilcoxon signed-rank test. RESULTS: After 12 weeks of intervention, there was a significant decrease in BMI and fat mass (median -4.9 kg (25th-75th percentile -5.9 to -3.0)). There was a significant increase in exercise capacity (3.7 ml/kg/min (3.0-4.7)), along with improvements in insulin sensitivity (0.55 (0.43-1.2)), total adiponectin (780.9 MUg/ml (262.1 1,497.1)) and leptin (-5.1 ng/ml (-14.5 to -3.3)). There were improvements in biomarkers of kidney disease very quality of life measures, but kidney function remained unchanged. CONCLUSION: Lifestyle modification is feasible in obese patients with CKD and produces weight loss that is related to improvements in exercise capacity, insulin resistance and adipokines. Whether lifestyle-induced weight loss and fitness can be sustained and whether it will mediate improvements in kidney function over time merits further investigation. PMID- 26495990 TI - Multidimensional preparative liquid chromatography to isolate flavonoids from bergamot juice and evaluation of their anti-inflammatory potential. AB - Important objectives of a high-performance liquid chromatography preparative process are: purity of products isolated, yield, and throughput. The multidimensional preparative liquid chromatography method used in this work was developed mainly to increase the throughput; moreover purity and yield are increased thanks to the automated collection of the molecules based on the intensity of a signal generated from the mass spectrometer detector, in this way only a specific product can be targeted. This preparative system allowed, in few analyses both in the first and second dimensions, the isolation of eight pure compounds present at very different concentration in the original sample with high purity (>95%) and yield, which showed how the system is efficient and versatile. Pure molecules were used to validate the analytical method and to test the anti-inflammatory and antiproliferative potential of flavonoids. The contemporary presence, in bergamot juice, of all the flavonoids together increases the anti-inflammatory effect with respect to the single compound alone. PMID- 26495988 TI - The Effect of Cooled Perches on Immunological Parameters of Caged White Leghorn Hens during the Hot Summer Months. AB - The objective of this study was to determine if thermally cooled perches improve hen immunity during hot summer. White Leghorn pullets at 16 week of age were randomly assigned to 18 cages of 3 banks at 9 hens per cage. Each bank was assigned to 1 of the 3 treatments up to 32 week of age: 1) thermally cooled perches, 2) perches with ambient air, and 3) cages without perches. Hens were exposed to natural ambient temperatures from June through September 2013 in Indiana with a 4 h acute heat episode at 27.6 week of age. The packed cell volume, heterophil to lymphocyte (H/L) ratio, plasma concentrations of total IgG, and cytokines of interleukin-1beta and interleukin-6, plus lipopolysaccharide induced tumor necrosis factor-alpha factor were measured at both 27.6 and 32 week of age. The mRNA expressions of these cytokines, toll-like receptor-4, and inducible nitric oxide synthase were also examined in the spleen of 32 week-old hens. Except for H/L ratio, thermally cooled perches did not significantly improve currently measured immunological indicators. These results indicated that the ambient temperature of 2013 summer in Indiana (24 degrees C, 17.1 to 33.1 degrees C) was not high enough and the 4 h heat episode at 33.3 degrees C (32 to 34.6 degrees C) was insufficient in length to evoke severe heat stress in hens. However, cooled perch hens had a lower H/L ratio than both air perch hens and control hens at 27.6 week of age and it was still lower compared to control hens (P < 0.05, respectively) at 32 week of age. The lowered H/L ratio of cooled perch hens may suggest that they were able to cope with acute heat stress more effectively than control hens. Further studies are needed to evaluate the effectiveness of thermally cooled perches on hen health under higher ambient temperatures. PMID- 26495992 TI - Identifying and modeling motion primitives for the hydromedusae Sarsia tubulosa and Aequorea victoria. AB - The movements of organisms can be thought of as aggregations of motion primitives: motion segments containing one or more significant actions. Here, we present a means to identify and characterize motion primitives from recorded movement data. We address these problems by assuming that the motion sequences can be characterized as a series of dynamical-system-based pattern generators. By adopting a nonparametric, Bayesian formalism for learning and simplifying these pattern generators, we arrive at a purely data-driven model to automatically identify breakpoints in the movement sequences. We apply this model to swimming sequences from two hydromedusa. The first hydromedusa is the prolate Sarsia tubulosa, for which we obtain five motion primitives that correspond to bell cavity pressurization, jet formation, jetting, cavity fluid refill, and coasting. The second hydromedusa is the oblate Aequorea victoria, for which we obtain five motion primitives that correspond to bell compression, vortex separation, cavity fluid refill, vortex formation, and coasting. Our experimental results indicate that the breakpoints between primitives are correlated with transitions in the bell geometry, vortex formation and shedding, and changes in derived dynamical quantities. These dynamics quantities include terms like pressure, power, drag, and thrust. Such findings suggest that dynamics information is inherently present in the observed motions. PMID- 26495991 TI - Formalin Inactivation of Japanese Encephalitis Virus Vaccine Alters the Antigenicity and Immunogenicity of a Neutralization Epitope in Envelope Protein Domain III. AB - Formalin-inactivated Japanese encephalitis virus (JEV) vaccines are widely available, but the effects of formalin inactivation on the antigenic structure of JEV and the profile of antibodies elicited after vaccination are not well understood. We used a panel of monoclonal antibodies (MAbs) to map the antigenic structure of live JEV virus, untreated control virus (UCV), formalin-inactivated commercial vaccine (FICV), and formalin-inactivated virus (FIV). The binding activity of T16 MAb against Nakayama-derived FICV and several strains of FIV was significantly lower compared to live virus and UCV. T16 MAb, a weakly neutralizing JEV serocomplex antibody, was found to inhibit JEV infection at the post-attachment step. The T16 epitope was mapped to amino acids 329, 331, and 389 within domain III (EDIII) of the envelope (E) glycoprotein. When we explored the effect of formalin inactivation on the immunogenicity of JEV, we found that Nakayama-derived FICV, FIV, and UCV all exhibited similar immunogenicity in a mouse model, inducing anti-JEV and anti-EDII 101/106/107 epitope-specific antibodies. However, the EDIII 329/331/389 epitope-specific IgG antibody and neutralizing antibody titers were significantly lower for FICV-immunized and FIV immunized mouse serum than for UCV-immunized. Formalin inactivation seems to alter the antigenic structure of the E protein, which may reduce the potency of commercially available JEV vaccines. Virus inactivation by H2O2, but not by UV or by short-duration and higher temperature formalin treatment, is able to maintain the antigenic structure of the JEV E protein. Thus, an alternative inactivation method, such as H2O2, which is able to maintain the integrity of the E protein may be essential to improving the potency of inactivated JEV vaccines. PMID- 26495993 TI - Effects of low temperature on tropical and temperate isolates of marine Synechococcus. AB - Temperature is an important factor influencing the distribution of marine picocyanobacteria. However, molecular responses contributing to temperature preferences are poorly understood in these important primary producers. We compared the temperature acclimation of a tropical Synechococcus strain WH8102 with temperate strain BL107 at 18 degrees C relative to 22 degrees C and examined their global protein expression, growth patterns, photosynthetic efficiency and lipid composition. Global protein expression profiles demonstrate the partitioning of the proteome into major categories: photosynthesis (>40%), translation (10-15%) and membrane transport (2-8%) with distinct differences between and within strains grown at different temperatures. At low temperature, growth and photosynthesis of strain WH8102 was significantly decreased, while BL107 was largely unaffected. There was an increased abundance of proteins involved in protein biosynthesis at 18 degrees C for BL107. Each strain showed distinct differences in lipid composition with higher unsaturation in strain BL107. We hypothesize that differences in membrane fluidity, abundance of protein biosynthesis machinery and the maintenance of photosynthesis efficiency contribute to the acclimation of strain BL107 to low temperature. Additional proteins unique to BL107 may also contribute to this strain's improved fitness at low temperature. Such adaptive capacities are likely important factors favoring growth of temperate strains over tropical strains in high latitude niches. PMID- 26495994 TI - Cyanobacterial reuse of extracellular organic carbon in microbial mats. AB - Cyanobacterial organic matter excretion is crucial to carbon cycling in many microbial communities, but the nature and bioavailability of this C depend on unknown physiological functions. Cyanobacteria-dominated hypersaline laminated mats are a useful model ecosystem for the study of C flow in complex communities, as they use photosynthesis to sustain a more or less closed system. Although such mats have a large C reservoir in the extracellular polymeric substances (EPSs), the production and degradation of organic carbon is not well defined. To identify extracellular processes in cyanobacterial mats, we examined mats collected from Elkhorn Slough (ES) at Monterey Bay, California, for glycosyl and protein composition of the EPS. We found a prevalence of simple glucose polysaccharides containing either alpha or beta (1,4) linkages, indicating distinct sources of glucose with differing enzymatic accessibility. Using proteomics, we identified cyanobacterial extracellular enzymes, and also detected activities that indicate a capacity for EPS degradation. In a less complex system, we characterized the EPS of a cyanobacterial isolate from ES, ESFC-1, and found the extracellular composition of biofilms produced by this unicyanobacterial culture were similar to that of natural mats. By tracing isotopically labeled EPS into single cells of ESFC-1, we demonstrated rapid incorporation of extracellular-derived carbon. Taken together, these results indicate cyanobacteria reuse excess organic carbon, constituting a dynamic pool of extracellular resources in these mats. PMID- 26495995 TI - Microbiome shifts and the inhibition of quorum sensing by Black Band Disease cyanobacteria. AB - Disruption of the microbiome often correlates with the appearance of disease symptoms in metaorganisms such as corals. In Black Band Disease (BBD), a polymicrobial disease consortium dominated by the filamentous cyanobacterium Roseofilum reptotaenium displaces members of the epibiotic microbiome. We examined both normal surface microbiomes and BBD consortia on Caribbean corals and found that the microbiomes of healthy corals were dominated by Gammaproteobacteria, in particular Halomonas spp., and were remarkably stable across spatial and temporal scales. In contrast, the microbial community structure in black band consortia was more variable and more diverse. Nevertheless, deep sequencing revealed that members of the disease consortium were present in every sampled surface microbiome of Montastraea, Orbicella and Pseudodiploria corals, regardless of the health status. Within the BBD consortium, we identified lyngbic acid, a cyanobacterial secondary metabolite. It strongly inhibited quorum sensing (QS) in the Vibrio harveyi QS reporters. The effects of lyngbic acid on the QS reporters depended on the presence of the CAI-1 receptor CqsS. Lyngbic acid inhibited luminescence in native coral Vibrio spp. that also possess the CAI-1-mediated QS. The effects of this naturally occurring QS inhibitor on bacterial regulatory networks potentially contribute to the structuring of the interactions within BBD consortia. PMID- 26495997 TI - Acupuncture Treatment for Dyspnea due to Combined Pulmonary Fibrosis and Emphysema: A Case Report. AB - OBJECTIVE: Combined idiopathic pulmonary fibrosis with pulmonary emphysema (CPFE) is a syndrome with a characteristic presentation of upper lobe emphysema and lower lobe fibrosis. Dyspnea on exertion (DOE) is a major symptom of CPFE. We report a patient with DOE due to CPFE who was successfully treated with acupuncture. DESIGN: Case report. CASE PRESENTATION: A 72-year-old Japanese man with a 4-year history of DOE was diagnosed with CPFE 2 years previously in another hospital. He received standard Western medicine treatment, which included bronchodilators. However, his DOE did not improve. Consequently, he visited our hospital for acupuncture treatment and received acupuncture treatment once a week for 1 year. RESULTS: After 10 weeks of acupuncture treatment, the results of the 6-minute walk test (6-minute walking distance, 379 m; lowest oxygen saturation, 86%; modified Borg dyspnea scale score: 2 units) were better than those at baseline (352 m, 84%, 4 units, respectively). These values were sustained at both 30 weeks (470 m, 88%, 1 unit) and 60 weeks (473 m, 85%, 2 units). Serum interstitial biomarkers, Krebs von den Lungen and surfactant protein-D, decreased after commencement of acupuncture therapy. CONCLUSION: A patient with CPFE showed improvements in dyspnea scores, exercise tolerance, and serum biomarkers during a 1-year course of acupuncture treatment. Use of acupuncture might be an effective adjunct therapy in relieving DOE due to CPFE. A large, well-designed cohort study that includes patients with CPFE treated with acupuncture should be conducted. PMID- 26495996 TI - Non-pathogenic Rhizobium radiobacter F4 deploys plant beneficial activity independent of its host Piriformospora indica. AB - The Alphaproteobacterium Rhizobium radiobacter F4 (RrF4) was originally characterized as an endofungal bacterium in the beneficial endophytic Sebacinalean fungus Piriformospora indica. Although attempts to cure P. indica from RrF4 repeatedly failed, the bacterium can easily be grown in pure culture. Here, we report on RrF4's genome and the beneficial impact the free-living bacterium has on plants. In contrast to other endofungal bacteria, the genome size of RrF4 is not reduced. Instead, it shows a high degree of similarity to the plant pathogenic R. radiobacter (formerly: Agrobacterium tumefaciens) C58, except vibrant differences in both the tumor-inducing (pTi) and the accessor (pAt) plasmids, which can explain the loss of RrF4's pathogenicity. Similar to its fungal host, RrF4 colonizes plant roots without host preference and forms aggregates of attached cells and dense biofilms at the root surface of maturation zones. RrF4-colonized plants show increased biomass and enhanced resistance against bacterial leaf pathogens. Mutational analysis showed that, similar to P. indica, resistance mediated by RrF4 was dependent on the plant's jasmonate-based induced systemic resistance (ISR) pathway. Consistent with this, RrF4- and P. indica-induced pattern of defense gene expression were similar. In clear contrast to P. indica, but similar to plant growth-promoting rhizobacteria, RrF4 colonized not only the root outer cortex but also spread beyond the endodermis into the stele. On the basis of our findings, RrF4 is an efficient plant growth-promoting bacterium. PMID- 26495998 TI - Pomolic Acid Inhibits Invasion of Breast Cancer Cells Through the Suppression of CXC Chemokine Receptor Type 4 Expression. AB - High mortality of cancer-mediated deaths is due to metastasis. CXC chemokine receptor type 4 (CXCR4) signaling has been demonstrated to be involved in migration of breast cancer. Thus, identification of CXCR4 inhibitor has been challenged constantly as an anticancer drug. This study is aimed to investigate the CXCR4 inhibitor that could inhibit tumor metastasis from natural products. We demonstrated that pomolic acid (PA), a component of Euscaphis japonica, could downregulate CXCR4 expression in breast cancer cells. Treatment with proteasomal and lysosomal inhibitors did not show significant effects on PA's ability. When we further explored the molecular mechanism, suppression of CXCR4 occurred at transcriptional level and was correlated with inhibition of nuclear factor-kappaB (NF-kappaB) activation. Downregulation of CXCR4 by PA was accompanied by the inhibition of CXC motif chemokine 12 (CXCL12)-induced invasion of breast cancer cells. Overall, our results indicate that PA, as a novel inhibitor of CXCR4, can be a promising therapeutic agent for treatment of cancer metastasis. PMID- 26495999 TI - Pediatric investigation plans for specific immunotherapy: Questionable contributions to childhood health. AB - Allergen-specific immunotherapy (SIT) is the only disease-modifying treatment for children, adolescents, and adults with allergic diseases. The EU has a combined system of national and EU-wide marketing authorization for all medicines. Germany introduced a new therapy allergen ordinance in 2008. Allergen products manufacturers had to apply for marketing authorization application for the major allergen groups (grass group, birch group, mites group, bee/wasp venom). Due to the EU pediatric regulation, in force since 2007, manufacturers had also to submit a pediatric investigation plan (PIP) for each allergen product. We investigated the allergic rhinoconjunctivitis (ARC) standard PIP, developed jointly by the European Medicines Agency (EMA) and the German Paul Ehrlich Institut (PEI). We analyzed the 118 EMA PIP decisions, looked for SIT trials in children in www.clinicaltrials.gov, and further analyzed EMA/EU justifications. The PIPs request a 1-year dose-finding study in adults, a 5-year placebo controlled (PC) efficacy & safety (E&S) study in adults, and a 5-year PC E&S study in children. Fifty-eight PIP development programs will have to be performed until 2031. But children benefit even more from SIT for ARC than adults. There is no convincing medical/scientific justification for PC E&S studies in children in the relevant EMA documents. The PIP requirement to withhold effective treatment to thousands of children in the placebo group over a 5-year period raises profound concerns. The EMA justifications are formalistic and lack scientific foundation. A critical academic review of the ARC PIPs and the entire PIP system is urgently needed. PMID- 26496001 TI - Tetralogy of Fallot Cardiac Function Evaluation and Intelligent Diagnosis Based on Dual-Source Computed Tomography Cardiac Images. AB - Tetralogy of Fallot (TOF) is the most common complex congenital heart disease (CHD) of the cyanotic type. Studies on ventricular functions have received an increasing amount of attention as the development of diagnosis and treatment technology for CHD continues to advance. Reasonable options for imaging examination and accurate assessment of preoperative and postoperative left ventricular functions of TOF patients are important in improving the cure rate of TOF radical operation, therapeutic evaluation, and judgment prognosis. Therefore, with the aid of dual-source computed tomography (DSCT), cardiac images with high temporal resolution and high definition, we measured the left ventricular time volume curve using image data and calculating the left ventricular function parameters to conduct the preliminary evaluation on TOF patients. To comprehensively evaluate the cardiac function, the segmental ventricular wall function parameters were measured, and the measurement results were mapped to a bull's eye diagram to realize the standardization of segmental ventricular wall function evaluation. Finally, we introduced a new clustering method based on auto regression model parameters and combined this method with Euclidean distance measurements to establish an intelligent diagnosis of TOF. The results of this experiment show that the TOF evaluation and the intelligent diagnostic methods proposed in this article are feasible. PMID- 26496000 TI - Endocrine Dysfunction in Diamond-Blackfan Anemia (DBA): A Report from the DBA Registry (DBAR). AB - BACKGROUND: Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome. The mainstays of treatment involve chronic red cell transfusions, long term glucocorticoid therapy, and stem cell transplantation. Systematic data concerning endocrine function in DBA are limited. We studied patients in the DBA Registry (DBAR) of North America to assess the prevalence of various endocrinopathies. PROCEDURE: In a pilot study, retrospective data were collected for 12 patients with DBA. Subsequently, patients with DBA aged 1-39 years were recruited prospectively. Combined, 57 patients were studied; 38 chronically transfused, 12 glucocorticoid-dependent, and seven in remission. Data were collected on anthropometric measurements, systematic screening of pituitary, thyroid, parathyroid, adrenal, pancreatic, and gonadal function, and ferritin levels. Descriptive statistics were tabulated and group differences were assessed. RESULTS: Fifty-three percent of patients had >= 1 endocrine disorder, including adrenal insufficiency (32%), hypogonadism (29%), hypothyroidism (14%), growth hormone dysfunction (7%), diabetes mellitus (2%), and/or diabetes insipidus (2%). Ten of the 33 patients with available heights had height standard deviation less than -2. Low 25-hydroxy vitamin D (25(OH)D) levels were present in 50%. A small proportion also had osteopenia, osteoporosis, or hypercalciuria. Most with adrenal insufficiency were glucocorticoid dependent; other endocrinopathies were more common in chronically transfused patients. CONCLUSIONS: Endocrine dysfunction is common in DBA, as early as the teenage years. Although prevalence is highest in transfused patients, patients taking glucocorticoids or in remission also have endocrine dysfunction. Longitudinal studies are needed to better understand the etiology and true prevalence of these disorders. PMID- 26496002 TI - Knowledge and attitudes survey in bleeding disorders providers regarding pain. AB - INTRODUCTION: The National Pain Study identified respondents (39%) were not satisfied with their pain management yet over 50% seek out their Haemophilia Treatment Centre (HTC) providers for pain management. This study's purpose was to assess the knowledge and attitudes of HTC providers regarding pain assessment and treatment. METHODS: One hundred and fifty-two HTC providers responded to a Survey MonkeyTM Questionnaire. RESULTS: Knowledge deficits noted in pharmacology included (i) potentiators of opioids, (ii) time to peak effect of oral morphine, (iii) benzodiazepines usage as effective pain relievers and (iv) dose escalation/respiratory depression in an opioid tolerant patient. Areas of deficit in the substance abuse category involved (i) likelihood of a previous alcohol/drug abuse problem and (ii) signs and symptoms of discontinuation syndrome. Despite 100% confirmation from all providers that the patient is the best source of pain reporting, when presented with two identical case scenarios except for the patient's visual pain presentation; pain ratings were reported differently for patients who rated their pain similarly (8/10), yet displayed their pain symptoms differently resulting in different pain medication regimens. Responses were consistent between the provider groups but varied between case studies suggesting disparity between personal attitudes of providers when prescribing pain medication in the haemophilia population. CONCLUSIONS: Continued research in the area of haemophilia pain as well as treatment is needed. In addition, continuing pain education is recommended for HTC provider's at the local, regional and national levels so providers could remain up to date in the changes and progress of pain management theory. PMID- 26496003 TI - Evolution of Drosophila resistance against different pathogens and infection routes entails no detectable maintenance costs. AB - Pathogens exert a strong selective pressure on hosts, entailing host adaptation to infection. This adaptation often affects negatively other fitness-related traits. Such trade-offs may underlie the maintenance of genetic diversity for pathogen resistance. Trade-offs can be tested with experimental evolution of host populations adapting to parasites, using two approaches: (1) measuring changes in immunocompetence in relaxed-selection lines and (2) comparing life-history traits of evolved and control lines in pathogen-free environments. Here, we used both approaches to examine trade-offs in Drosophila melanogaster populations evolving for over 30 generations under infection with Drosophila C Virus or the bacterium Pseudomonas entomophila, the latter through different routes. We find that resistance is maintained after up to 30 generations of relaxed selection. Moreover, no differences in several classical life-history traits between control and evolved populations were found in pathogen-free environments, even under stresses such as desiccation, nutrient limitation, and high densities. Hence, we did not detect any maintenance costs associated with resistance to pathogens. We hypothesize that extremely high selection pressures commonly used lead to the disproportionate expression of costs relative to their actual occurrence in natural systems. Still, the maintenance of genetic variation for pathogen resistance calls for an explanation. PMID- 26496005 TI - The association of perceived stress, contextualized stress, and emotional eating with body mass index in college-aged Black women. AB - A growing body of literature supports the association between adverse stress experiences and health inequities, including obesity, among African American/Black women. Adverse stress experiences can contribute to poor appetite regulation, increased food intake, emotional eating, binge eating, and sedentary behavior, all of which can contribute to weight gain and obesity. Most research studies concerning the effect of psychological stress on eating behaviors have not examined the unique stress experience, body composition, and eating behaviors of African American/Black women. Even fewer studies have examined these constructs among Black female college students, who have an increased prevalence of overweight and obesity compared to their counterparts. Therefore, the aim of the current study is to examine the associations among emotional eating, perceived stress, contextualized stress, and BMI in African American female college students. All participants identified as African American or Black (N=99). The mean age of the sample was 19.4 years (SD=1.80). A statistically significant eating behavior patterns*perceived stress interaction was evident for body mass index (BMI) (beta=0.036, S.E.=.0118, p<.01). In addition, a statistically significant eating behavior patterns*contextualized stress interaction was observed for BMI (beta=0.007, S.E.=.0027, p=.015). Findings from this study demonstrate that the stress experience interacts with emotional eating to influence BMI. Based on these findings, culturally relevant interventions that target the unique stress experience and eating behavior patterns of young African American women are warranted. PMID- 26496006 TI - GhNAC12, a neutral candidate gene, leads to early aging in cotton (Gossypium hirsutum L). AB - NAC (NAM, ATAF, and CUC) is one of the largest transcription factor families in plants, and its members play various roles in plant growth, development, and the response to biotic and abiotic stresses. Currently, 77 NAC genes have been reported in cotton (Gossypium hirsutum L.). And GhNAC12 showed up-regulation during leaf senescence, but its role in this process is poorly understood. In the present study, a preliminary function analysis of GhNAC12 was performed during leaf senescence. qRT-PCR analysis indicated that GhNAC12 expression increased during the early-aging process and the aging of cotyledons. Additionally, we observed that overexpression of GhNAC12 in Arabidopsis led to early senescence (early aging). Our findings suggest that GhNAC12 is a candidate gene for early aging in upland cotton cultivars. Neutrality tests suggested that there was no selection pressure imposed on GhNAC12 during the domestication of upland cotton. PMID- 26496004 TI - The fetal brain sparing response to hypoxia: physiological mechanisms. AB - How the fetus withstands an environment of reduced oxygenation during life in the womb has been a vibrant area of research since this field was introduced by Joseph Barcroft, a century ago. Studies spanning five decades have since used the chronically instrumented fetal sheep preparation to investigate the fetal compensatory responses to hypoxia. This defence is contingent on the fetal cardiovascular system, which in late gestation adopts strategies to decrease oxygen consumption and redistribute the cardiac output away from peripheral vascular beds and towards essential circulations, such as those perfusing the brain. The introduction of simultaneous measurement of blood flow in the fetal carotid and femoral circulations by ultrasonic transducers has permitted investigation of the dynamics of the fetal brain sparing response for the first time. Now we know that major components of fetal brain sparing during acute hypoxia are triggered exclusively by a carotid chemoreflex and that they are modified by endocrine agents and the recently discovered vascular oxidant tone. The latter is determined by the interaction between nitric oxide and reactive oxygen species. The fetal brain sparing response matures as the fetus approaches term, in association with the prepartum increase in fetal plasma cortisol, and treatment of the preterm fetus with clinically relevant doses of synthetic steroids mimics this maturation. Despite intense interest into how the fetal brain sparing response may be affected by adverse intrauterine conditions, this area of research has been comparatively scant, but it is likely to take centre stage in the near future. PMID- 26496007 TI - Transcriptome characterization and expression profiles of the related defense genes in postharvest mango fruit against Colletotrichum gloeosporioides. AB - Anthracnose, caused by Colletotrichum gloeosporioides, is a major disease of the postharvest mango (Mangifera indica L.) fruit. However, a lack of transcriptomic and genomic information hinders our understanding of the molecular mechanisms underlying the mango fruit defense response. Here, we studied the host responses of the mango fruit against C. gloeosporioides using Illumina paired-end sequencing technology, and expression profiles of 35 defense-related genes were further analyzed by qRT-PCR. The results indicated that 5.9Gigabase pair clean reads were assembled into a total of 131,750 unigenes, of which 89,050 unigenes found to be homologous to genes in the NCBI GenBank database and 61,694 unigenes annonated in the Swiss-Prot database. Orthologous analyses showed that 47,770 unigenes were assigned with one or more Gene Ontology terms and 44,145 unigenes were classified into 256 Kyoto Encyclopedia of Genes and Genomes pathways. Moreover, qRT-PCR of 35 defense-related unigenes, including 17 ethylene response factors (ERFs), 6 nucleotide binding site-leucine-rich repeats (NBS-LRRs), 6 nonexpressor of pathogenesis-related genes (NPRs) and 6 pathogenesis-related protein (PRs), revealed that most of these defense-related genes were up regulated after C. gloeosporioides infection. Taken together, our study provides a platform to discover new candidate genes in mango fruit in relation to pathogen resistance. PMID- 26496008 TI - Diabetes in people with intellectual disabilities: A systematic review of the literature. AB - OBJECTIVE: To present an analysis of the evidence related to the prevalence of diabetes in people with intellectual disabilities (ID), their experiences of their condition and treatment and those of their carers. MATERIALS AND METHODS: A systematic literature review was conducted. A total of 22 studies exploring diabetes prevalence and 5 exploring views and experiences of diabetes in people with ID were identified and included. A narrative synthesis approach was utilised to amalgamate data extracted from the included studies regarding some 49,046 participants with ID and diabetes and 31 care professionals and family members across Europe, North America, New Zealand, Australia, China and Hong Kong. RESULTS: Prevalence rates of diabetes in people with ID were highly varied, ranging from 0.4% to 25%. 7 studies reported significantly higher rates of diabetes in people with ID than the general population. People with ID reported a basic understanding of diabetes and wanted to know more. Carers reported that they lack diabetes knowledge and do not routinely encourage diabetes self management skills. Several studies neglected to report vital demographic information such as participants' level of ID (13 studies) and diabetes type (16 studies) and the quality of included prevalence studies was variable. CONCLUSIONS: Further research in this field is required, notably prevalence studies which control for participant demographics and personal situations to obtain more accurate diabetes prevalence rates in this population group. People with ID and diabetes should be encouraged to participate in future research and we recommend exploring the feasibility of adapting current mainstream diabetes management programmes for these individuals. PMID- 26496009 TI - Editorial overview: Molecular and genetic bases of disease: Enter the post-GWAS era. PMID- 26496010 TI - Ian Curtis: Punk rock, epilepsy, and suicide. AB - Ian Curtis was the front man of the post-punk band Joy Division. He suffered from epilepsy and actively incorporated his experiences of the disease in his lyrics. Curtis had frequent epileptic seizures, both on and off stage. After dying from suicide in 1980, he became a legend in the post-punk milieu. The impact which the epilepsy, the epilepsy treatment, and comorbid depression had on his artistic life and premature death is not well known. PMID- 26496011 TI - Chronic methamphetamine treatment reduces the expression of synaptic plasticity genes and changes their DNA methylation status in the mouse brain. AB - Methamphetamine (METH) is a highly addictive psychostimulant that may cause long lasting synaptic dysfunction and abnormal gene expression. We aimed to explore the differential expression of synaptic plasticity genes in chronic METH-treated mouse brain. We used the RT(2) Profiler PCR Array and the real-time quantitative PCR to characterize differentially expressed synaptic plasticity genes in the frontal cortex and the hippocampus of chronic METH-treated mice compared with normal saline-treated mice. We further used pyrosequencing to assess DNA methylation changes in the CpG region of the five immediate early genes (IEGs) in chronic METH-treated mouse brain. We detected six downregulated genes in the frontal cortex and the hippocampus of chronic METH-treated mice, including five IEGs (Arc, Egr2, Fos, Klf10, and Nr4a1) and one neuronal receptor gene (Grm1), compared with normal saline-treated group, but only four genes (Arc, Egr2, Fos, and Nr4a1) were confirmed to be different. Furthermore, we found several CpG sites of the Arc and the Fos that had significant changes in DNA methylation status in the frontal cortex of chronic METH-treated mice, while the klf10 and the Nr4a1 that had significant changes in the hippocampus. Our results show that chronic administration of METH may lead to significant downregulation of the IEGs expression in both the frontal cortex and the hippocampus, which may partly account for the molecular mechanism of the action of METH. Furthermore, the changes in DNA methylation status of the IEGs in the brain indicate that an epigenetic mechanism-dependent transcriptional regulation may contribute to METH addiction, which warrants additional study. PMID- 26496012 TI - Physiological adaptations following Roux-en-Y gastric bypass and the identification of targets for bariatric mimetic pharmacotherapy. AB - The present opinion article provides an overview of the key improvements in metabolic and cardiovascular health following Roux-en-Y Gastric Bypass (RYGB). Some clinically important long-term complications of RYGB are also briefly described to contextualise the potential value of finding selective non-surgical means of replicating only the beneficial aspects of RYGB. Three biological responses linked to changes in gastrointestinal tract structure and function post RYGB, that are implicated in the clinical efficacy of RYGB and that have actual or potential applications as non-surgical mimetic based approaches are addressed. These are (1) exaggerated post-prandial gut hormone responses; (2) local increases in undiluted bile in the gut lumen and augmented circulating bile acid and FGF19 concentrations and (3) compositional changes in the gut microbiota. PMID- 26496013 TI - The synthesis of indolo[2,3-b]quinoline derivatives with a guanidine group: highly selective cytotoxic agents. AB - The synthesis of indolo[2,3-b]quinoline derivatives containing guanidine, amino acid or guanylamino acid substituents as well as their in vitro evaluation for the cytotoxic and antifungal activity are reported. The influence of the guanidine group on the selective cytotoxic and hemolytic properties of indolo[2,3 b]quinoline was investigated. Most of the compounds displayed a high cytotoxic activity in vitro and two of the most promising compounds (3 and 12) exhibited a high selectivity between normal and cancer cell-lines. The cytotoxic activity of compound 3 was about 600-fold lower against normal fibroblasts than against A549 and MCF-7 cancer cell lines. Novel entities acted as the DNA-intercalators when tested using a DNA-methyl green assay but demonstrated zero or low hemolytic activity in comparison to their unsubstituted analogs. The mechanism of action was studied for guanidine derivatives 3 and 12 and both compounds were found to be very effective inducers of apoptosis. PMID- 26496014 TI - The association between serum ferritin levels and post-stroke depression. AB - BACKGROUND: Post-stroke depression (PSD) is a common neuropsychiatric affective disorder occurring after stroke. Elevated serum ferritin levels have been reported to contribute to depression. Our aim was to determine whether there is a relationship between serum ferritin levels and PSD. METHODS: 196 ischemic stroke patients were consecutively recruited within the first 24h of stroke onset and were followed up for 2 months. Serum ferritin levels were assayed by electrochemiluminescence immunoassay at hospital admission. Clinical depression was diagnosed according to DSM-IV criteria and a HAMD -17 score of >= 7. Meanwhile, 100 normal control subjects were also recruited. RESULTS: We found that 56 stroke patients (28.6%) were diagnosed with PSD at two months. There was a significant intergroup difference in serum ferritin levels within 24h after admission (F=25.044, P<0.001). Serum ferritin levels were significantly higher at admission in PSD patients than in non-PSD patients and normal controls. There was a positive correlation between serum ferritin levels and hs-CRP at admission in PSD patients (r=0.129, P=0.042). In multivariate analyses, serum levels of ferritin >= 130.15 ug/L were independently associated with PSD at two months [odds ratio OR=5.388, 95%CI:1.725-16.829; P=0.004] after adjusting for all possible variables. LIMITATIONS: We excluded patients with severe aphasia and with serious conditions.In addition, the information for dietary intake was not recorded, which may influence body iron stores. CONCLUSION: Our findings show that elevated serum ferritin levels at admission are associated with PSD and may predict its development at 2 months post-stroke. PMID- 26496015 TI - Asenapine: Efficacy and safety of 5 and 10mg bid in a 3-week, randomized, double blind, placebo-controlled trial in adults with a manic or mixed episode associated with bipolar I disorder. AB - BACKGROUND: Asenapine is an atypical antipsychotic for acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. The recommended asenapine starting dose is 10mg bid with the option to reduce the dose to 5mg bid if needed due to adverse effects/tolerability. METHODS: Phase IIIb, international, double-blind, fixed-dose, parallel-group, 3-week placebo controlled trial of asenapine 5 and 10mg bid in adults with an acute bipolar I disorder manic or mixed episode. Primary outcome was difference in asenapine versus placebo in mean change from baseline to day 21 in the Young-Mania Rating Scale (YMRS) total score. Others included difference in asenapine versus placebo in the Clinical Global Impression Scale for Bipolar Severity (CGI-BP-S) and rate of YMRS responders. RESULTS: Both asenapine doses were statistically superior to placebo in mean change from baseline to day 21 in YMRS total score (-10.9, -14.4, and -14.9 for placebo, asenapine 5mg bid, 10mg bid, respectively). Both asenapine doses had statistically superior improvement in mean change in CGI-BP-S score at day 21. Neither asenapine dose had significantly more YMRS responders at day 21 than placebo. LIMITATIONS: Results may not be generalizable to the entire population with bipolar I disorder owing to strict inclusion criteria. CONCLUSIONS: This study evaluated, by a fixed-dose design, the efficacy and safety of asenapine versus placebo in patients with bipolar I disorder. Both asenapine 5 and 10mg bid were efficacious in treating mania associated with bipolar I disorder and were generally well tolerated. PMID- 26496017 TI - World survey of mental illness stigma. AB - OBJECTIVE: To obtain rapid and reproducible opinions that address mental illness stigma around the world. METHOD: Random global Web users were exposed to brief questions, asking whether they interacted daily with someone with mental illness, whether they believed that mental illness was associated with violence, whether it was similar to physical illness, and whether it could be overcome. RESULTS: Over a period of 1.7 years, 596,712 respondents from 229 countries completed the online survey. The response rate was 54.3%. China had the highest proportion of respondents in daily contact with a person with mental illness. In developed countries, 7% to 8% of respondents endorsed the statement that individuals with mental illness were more violent than others, in contrast to 15% or 16% in developing countries. While 45% to 51% of respondents from developed countries believed that mental illness was similar to physical illness, only 7% believed that mental illness could be overcome. To test for reproducibility, 21 repeats of the same questions were asked monthly in India for 21 months. Each time, 10.1 +/- 0.11% s.e., of respondents endorsed the statement that persons who suffer from mental illness are more violent than others, indicating strong reproducibility of response. CONCLUSION: This study shows that surveys of constructs such as stigma towards mental illness can be carried out rapidly and repeatedly across the globe, so that the impact of policy interventions can be readily measured. LIMITATIONS: The method engages English speakers only, mainly young, educated males. PMID- 26496016 TI - Establishing the cut-off score for remission and severity-ranges on the Psychotic Depression Assessment Scale (PDAS). AB - BACKGROUND: The Psychotic Depression Assessment Scale (PDAS) is a rating scale dedicated to the measurement of severity in psychotic depression (PD). The aim of this study was to establish the PDAS cut-off for remission of PD as well as PDAS score-ranges for mild, moderate, and severe PD. The secondary aim was to test how remission, as defined by the PDAS, would perform as outcome measure when applied to the data from a large randomized controlled trial (RCT) in PD. METHODS: The study was based on data from the Study of Pharmacotherapy in Psychotic Depression (STOP-PD). The cut-off for remission on the PDAS and the severity-ranges for mild, moderate, and severe PD were defined using the Clinical Global Impression - Severity scale (CGI-S) as reference by means of pair-wise receiver operating characteristic (ROC) analyses. Subsequently, it was tested whether remission on the PDAS could separate the effects of Olanzapine+Sertraline vs. Olanzapine+Placebo through an intention-to-treat, mixed-effects logistic regression of the data from STOP-PD. RESULTS: According to the ROC analyses, the ideal cut-off for remission of PD was a PDAS total score <8, while the severity ranges for mild, moderate and severe PD were 8-15, 16-23, and >23 respectively. When applying the PDAS total score <8 (remission) as outcome on the STOP-PD data, treatment with Olanzapine+Sertraline performed significantly better than Olanzapine+Placebo (p<0.001). LIMITATIONS: The STOP-PD was not designed specifically to answer the research questions of the present study. CONCLUSIONS: According to this study, a total score <8 on the PDAS corresponds to remission of PD. PMID- 26496018 TI - Decision-making in unipolar or bipolar suicide attempters. AB - OBJECTIVE: Disadvantageous decision-making (mainly measured by the Iowa Gambling Task) has been demonstrated in patients with suicidal behavior compared to controls. We, therefore, aimed at clarifying the qualitative and quantitative relationship between decision-making and the risk of suicidal behavior in unipolar and bipolar disorders respectively, as well as establishing the strength of this relationship. METHODS: (1) We conducted a cross-sectional study comparing IGT performances between 141 unipolar suicide attempters and 57 bipolar suicide attempters. (2) We conducted a systematic review and a meta-analysis of studies comparing IGT performances in patients with vs. without a history of suicidal acts in bipolar and unipolar disorder, together and separately. RESULTS: (1) Among suicide attempters, bipolar and unipolar groups performed similarly (t(195)=-0.7; p=0.48). Unipolar non-attempters performed better IGT than unipolar suicide attempters (t(221)=3.1; p=0.002), only in female gender, whereas performances were similar in bipolar patients whatever the history of suicide attempt (t(77)=-0.3; p=0.7). (2) A meta-analysis of 10 studies confirmed significantly impaired decision-making with a moderate effect-size (-0.38 (95% CI[-0.61--0.16]; z=-3.3; p=0.001) in unipolar disorder and (g=-0.4 (95% CI[-0.75 to -0.05]; z=-2.2; p<0.026) in bipolar disorder suicide attempters compared to unipolar and bipolar non-attempters, respectively. LIMITATIONS: It was not possible to analyse according to the level of lethality attempt. CONCLUSION: Overall, a strong significant association was found between decision-making and the risk of suicidal behavior in unipolar disorder and bipolar disorder. However, further neuropsychological studies need to analyse separately unipolar and bipolar disorder and to study gender differences. PMID- 26496019 TI - Inactivation of Escherichia coli in a baffled pond with attached growth: treating anaerobic effluent under the Sahelian climate. AB - This study aimed to investigate and understand the zero-level detection of Escherichia coli (E. coli) at the outlet of an improved waste stabilization pond. Wastewaters were collected from the International Institute for Water and Environmental Engineering (2iE) campus and were subjected to biological treatment. The system included two-stage Anaerobic Reactors followed by a Baffled Pond (AR-BP) with recycled plastic media as a medium for attached growth and a control pond (CP). Three vertical baffles were installed, giving four compartments in the baffled pond (BP). The research was conducted on the pilot scale from March to July 2014, by monitoring E. coli, pH, temperature, dissolved oxygen (DO) and chlorophyll-a in each compartment and at different depths. The results show that E. coli concentrations were lower in top layers of all compartments with an undetectable level in the last compartment up to 0.60 m deep. E. coli mean removal efficiencies and decay rates were achieved by significant difference in BP (4.5 log-units, 9.1 day(-1)) and CP (1.1 log-units, 1.1 day(-1)). Higher values of pH (>=9), temperature (>=32 degrees C), DO (>= 8 mg/L) and chlorophyll-a (>= 1000 ug/L) were observed at the surface of BP, whereas lower values were shown at the bottom. Sedimentation combined with the synergetic effects of the physicochemical parameters and environmental factors would be responsible for the inactivation of E. coli in BP. It was concluded that the AR-BP could be applied as an alternative low-cost wastewater treatment technology for developing countries and recommended for reuse of their effluent for restricted peri-urban irrigation. PMID- 26496020 TI - Cross-Linkable Fluorene-Diphenylamine Derivatives for Electrochromic Applications. AB - Multicolor electrochromic systems based on heat cross-linkable arylamine substituted fluorene derivatives, FD and FDOMe, are reported. These derivatives with pendant vinyl groups have been synthesized by the Buchwald-Hartwig amination reaction and were well-characterized using various analytical and spectroscopic techniques such as NMR, ESI-MS, and single-crystal X-ray diffraction analysis. FD and FDOMe exhibited thermally activated cross-linking above their melting temperatures, which was confirmed through absorption, differential scanning calorimetry (DSC), FT-IR, and wide-angle X-ray diffraction (WAXD) techniques. Cross-linked FD films (FD-X) on ITO showed two reversible redox peaks at 0.74 and 0.91 V (versus Ag/AgCl) that correspond to the formation of radical cations and dications, respectively. The corresponding redox peaks were observed at 0.6 and 0.8 V for cross-linked FDOMe films (FDOMe-X). Spectroelectrochemical studies of the electrochromic films on ITO revealed multicolor electrochromism of FD-X (colorless-yellow-dark cyan) and FDOMe-X (colorless-brick red-blue) with a color contrast of ~44% at 485 nm for FD-X and ~63% at 500 nm for FDOMe-X and good switching stability between the neutral and oxidized states (>300 cycles) with low switching voltages (<0.9 V for the first oxidation and <1.3 V for the second oxidation). Furthermore, fabrication of electrochromic devices using FD-X and FDOMe-X on FTO substrate with PMMA-based solid electrolyte was demonstrated, where the devices exhibited reasonably low switching time between the redox states (<30 s) with good optical contrast. PMID- 26496022 TI - Neuroestradiol in the Stalk Median Eminence of Female Rhesus Macaques Decreases in Association With Puberty Onset. AB - In primates, despite the fact that GnRH neurons are mature at birth, a gonadal steroid independent central inhibition restrains the initiation of puberty. The neural substrates responsible for this central inhibition, however, are unclear. In this study, we tested the hypothesis that neuroestradiol release in the hypothalamus decreases prior to the pubertal increase in GnRH release. We found that in female monkeys at the prepubertal stage, when GnRH release was low, estradiol (E2) levels in the stalk-median eminence of the hypothalamus were higher than those in older, early pubertal females in which nocturnal GnRH release begins to increase. Furthermore, estrone (E1) levels were higher in the stalk-median eminence of prepubertal and early pubertal monkeys compared with midpubertal monkeys, which have the highest GnRH release. The elevated E2 and E1 levels at the prepubertal stage are likely hypothalamic in origin because circulating E2 and E1 levels in prepubertal and early pubertal monkeys were much lower than those in midpubertal monkeys. Heightened synthesis and release of neuroestradiol during the prepubertal period and subsequent reduction at puberty onset indicate possible roles for neuroestradiol in central inhibition of GnRH release. The mechanism governing the reduction in neuroestradiol synthesis at puberty onset remains to be determined. PMID- 26496023 TI - Enantioselective Synthesis of alpha-exo-Methylene gamma-Butyrolactones via Chromium Catalysis. AB - Enantioenriched alpha-exo-methylene gamma-butyrolactones have been obtained via a two-step sequence consisting of a highly enantioselective chromium-catalyzed carbonyl 2-(alkoxycarbonyl)allylation and lactonization. A variety of functional groups are compatible under the mild reaction conditions. The synthetic utility of this methodology was demonstrated by two short derivatization transformations and the enantioselective synthesis of (+)-methylenolactocin. PMID- 26496021 TI - Bisphenol A Disrupts HNF4alpha-Regulated Gene Networks Linking to Prostate Preneoplasia and Immune Disruption in Noble Rats. AB - Exposure of humans to bisphenol A (BPA) is widespread and continuous. The effects of protracted exposure to BPA on the adult prostate have not been studied. We subjected Noble rats to 32 weeks of BPA (low or high dose) or 17beta-estradiol (E2) in conjunction with T replenishment. T treatment alone or untreated groups were used as controls. Circulating T levels were maintained within the physiological range in all treatment groups, whereas the levels of free BPA were elevated in the groups treated with T+low BPA (1.06 +/- 0.05 ng/mL, P < .05) and T+high BPA (10.37 +/- 0.43 ng/mL, P < .01) when compared with those in both controls (0.1 +/- 0.05 ng/mL). Prostatic hyperplasia, low-grade prostatic intraepithelial neoplasia (PIN), and marked infiltration of CD4+ and CD8+ T cells into the PIN epithelium (P < .05) were observed in the lateral prostates (LPs) of T+low/high BPA-treated rats. In contrast, only hyperplasia and high-grade PIN, but no aberrant immune responses, were found in the T+E2-treated LPs. Genome-wide transcriptome analysis in LPs identified differential changes between T+BPA vs T+E2 treatment. Expression of multiple genes in the regulatory network controlled by hepatocyte nuclear factor 4alpha was perturbed by the T+BPA but not by the T+E2 exposure. Collectively these findings suggest that the adult rat prostate, under a physiologically relevant T environment, is susceptible to BPA-induced transcriptomic reprogramming, immune disruption, and aberrant growth dysregulation in a manner distinct from those caused by E2. They are more relevant to our recent report of higher urinary levels BPA found in patients with prostate cancer than those with benign disease. PMID- 26496024 TI - Disentangling the microRNA regulatory milieu in multiple myeloma: integrative genomics analysis outlines mixed miRNA-TF circuits and pathway-derived networks modulated in t(4;14) patients. AB - The identification of overexpressed miRNAs in multiple myeloma (MM) has progressively added a further level of complexity to MM biology. miRNA and gene expression profiles of two large representative MM datasets, available from retrospective and prospective series and encompassing a total of 249 patients at diagnosis, were analyzed by means of in silico integrative genomics methods, based on MAGIA2 and Micrographite computational procedures. We first identified relevant miRNA/transcription factors/target gene regulation circuits in the disease and linked them to biological processes. Members of the miR-99b/let 7e/miR-125a cluster, or of its paralog, upregulated in t(4;14), were connected with the specific transcription factors PBX1 and CEBPA and several target genes. These results were validated in two additional independent plasma cell tumor datasets. Then, we reconstructed a non-redundant miRNA-gene regulatory network in MM, linking miRNAs, such as let-7g, miR-19a, mirR-20a, mir-21, miR-29 family, miR 34 family, miR-125b, miR-155, miR-221 to pathways associated with MM subtypes, in particular the ErbB, the Hippo, and the Acute myeloid leukemia associated pathways. PMID- 26496025 TI - Transient receptor potential melastatin 4 channel contributes to migration of androgen-insensitive prostate cancer cells. AB - Impaired Ca2+ signaling in prostate cancer contributes to several cancer hallmarks, such as enhanced proliferation and migration and a decreased ability to induce apoptosis. Na+ influx via transient receptor potential melastatin 4 channel (TRPM4) can reduce store-operated Ca2+ entry (SOCE) by decreasing the driving force for Ca2+. In patients with prostate cancer, gene expression of TRPM4 is elevated. Recently, TRPM4 was identified as a cancer driver gene in androgen-insensitive prostate cancer.We investigated TRPM4 protein expression in cancer tissue samples from 20 patients with prostate cancer. We found elevated TRPM4 protein levels in prostatic intraepithelial neoplasia (PIN) and prostate cancer tissue compared to healthy tissue. In primary human prostate epithelial cells (hPEC) from healthy tissue and in the androgen-insensitive prostate cancer cell lines DU145 and PC3, TRPM4 mediated large Na+ currents. We demonstrated significantly increased SOCE after siRNA targeting of TRPM4 in hPEC and DU145 cells. In addition, knockdown of TRPM4 reduced migration but not proliferation of DU145 and PC3 cells. Taken together, our data identify TRPM4 as a regulator of SOCE in hPEC and DU145 cells, demonstrate a role for TRPM4 in cancer cell migration and suggest that TRPM4 is a promising potential therapeutic target. PMID- 26496026 TI - VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer. AB - AIM: VE1 is a monoclonal antibody detecting mutant BRAFV(600E) protein by immunohistochemistry. Here we aim to determine the inter-observer agreement and concordance of VE1 with mutational status, investigate heterogeneity in colorectal cancers and metastases and determine the prognostic effect of VE1 in colorectal cancer patients. METHODS: Concordance of VE1 with mutational status and inter-observer agreement were tested on a pilot cohort of colorectal cancers (n = 34), melanomas (n = 23) and thyroid cancers (n = 8). Two prognostic cohorts were evaluated (n = 259, Cohort 1 and n = 226, Cohort 2) by multiple-punch tissue microarrays. VE1 staining on preoperative biopsies (n = 118 patients) was compared to expression in resections. Primary tumors and metastases from 13 patients were tested for VE1 heterogeneity using a tissue microarray generated from all available blocks (n = 100 blocks). RESULTS: Inter-observer agreement was 100% (kappa = 1.0). Concordance between VE1 and V600E mutation was 98.5%. Cohort 1: VE1 positivity (seen in 13.5%) was associated with older age (p = 0.0175) and MLH1 deficiency (p < 0.0001). Cohort 2: VE1 positivity (seen in 12.8%) was associated with female gender (p = 0.0016), right-sided tumor location (p < 0.0001), higher tumor grade (p < 0.0001) and mismatch repair (MMR)-deficiency (p < 0.0001). In survival analysis, MMR status and postoperative therapy were identified as possible confounding factors. Adjusting for these features, VE1 was an unfavorable prognostic factor. Preoperative biopsy staining matched resections in all cases except one. No heterogeneity was found across any primary/metastatic tumor blocks. CONCLUSION: VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens, preoperative biopsies, metastatic lesions and tissue microarrays. PMID- 26496027 TI - Regenerating islet-derived protein 1 inhibits the activation of islet stellate cells isolated from diabetic mice. AB - Emerging evidence indicates that the islet fibrosis is attributable to activation of islet stellate cells (ISCs). In the present study, we compared the differences in biological activity of ISCs isolated from diabetic db/db and non-diabetic db/m mice, and the effects of the regenerating islet-derived protein 1 (Reg1) on ISC function. We showed that ISCs isolated from db/db mice were activated more rapidly than those from db/m mice during culture. Both Reg1 and its putative receptor exostosin-like glycosyltransferase 3 (EXTL3) were highly expressed by diabetic ISCs. Treatment with Reg1 inhibited migration, viability, and synthesis and secretion of Type I Collagen(Col-I), Type III Collagen(Col-III) and Fibronectin(FN) by diabetic ISCs, and this was associated with deactivation of the PI3K/Akt, MAPK/Erk1/2 signaling pathway in an EXTL3-dependent manner. In conclusion, our observations (i) confirmed the presence of fibrogenic stellate cells within pancreatic islets, which are prone to be activated in Type 2 diabetes, and (ii) revealed a potential role for Reg1 in preventing ISC activation. PMID- 26496028 TI - Moderate exercise training attenuates aging-induced cardiac inflammation, hypertrophy and fibrosis injuries of rat hearts. AB - Aging is the most important risk factor in cardiovascular disease (CVD), which is the leading causes of death worldwide and the second major cause of death in Taiwan. The major factor in heart failure during aging is heart remodeling, including long-term stress-induced cardiac hypertrophy and fibrosis. Exercise is good for aging heart health, but the impact of exercise training on aging is not defined. This study used 3-, 12- and 18-month-old rats and randomly divided each age group into no exercise training control groups (C3, A12 and A18) and moderate gentle swimming exercise training groups (E3, AE12 and AE18). The protocol of exercise training was swimming five times weekly with gradual increases from the first week from 20 to 60 min for 12 weeks. Analyses of protein from rat heart tissues and sections revealed cardiac inflammation, hypertrophy and fibrosis pathway increases in aged rat groups (A12 and A18), which were improved in exercise training groups (AE12 and AE18). There were no heart injuries in young rat hearts in exercise group E3. These data suggest that moderate swimming exercise training attenuated aging-induced cardiac inflammation, hypertrophy and fibrosis injuries of rat hearts. PMID- 26496030 TI - Elucidating the cancer-specific genetic alteration spectrum of glioblastoma derived cell lines from whole exome and RNA sequencing. AB - Cell lines derived from tumor tissues have been used as a valuable system to study gene regulation and cancer development. Comprehensive characterization of the genetic background of cell lines could provide clues on novel genes responsible for carcinogenesis and help in choosing cell lines for particular studies. Here, we have carried out whole exome and RNA sequencing of commonly used glioblastoma (GBM) cell lines (U87, T98G, LN229, U343, U373 and LN18) to unearth single nucleotide variations (SNVs), indels, differential gene expression, gene fusions and RNA editing events. We obtained an average of 41,071 SNVs out of which 1,594 (3.88%) were potentially cancer-specific. The cell lines showed frequent SNVs and indels in some of the genes that are known to be altered in GBM- EGFR, TP53, PTEN, SPTA1 and NF1. Chromatin modifying genes- ATRX, MLL3, MLL4, SETD2 and SRCAP also showed alterations. While no cell line carried IDH1 mutations, five cell lines showed hTERT promoter activating mutations with a concomitant increase in hTERT transcript levels. Five significant gene fusions were found of which NUP93-CYB5B was validated. An average of 18,949 RNA editing events was also obtained. Thus we have generated a comprehensive catalogue of genetic alterations for six GBM cell lines. PMID- 26496031 TI - Inhibition of iNOS activity enhances the anti-tumor effects of alpha galactosylceramide in established murine cancer model. AB - Alpha-garactosylceramide (GalCer) has been shown to have anti-tumor effect in the basic research and clinical studies. However, anti-tumor effect of GalCer is limited. The administration of GalCer increases the production of IFN-gamma which is involved in the suppression of tumor growth. On the other hand, the enhancement of IFN-gamma production increases immunosuppressive factors such as nitric oxide. This suppressive action might impair the anti-tumor effect of GalCer. In the present study, we evaluated the anti-tumor effect of GalCer in the absence of inducible nitric oxide synthase (iNOS). In lung metastatic model, the number of tumor nodules in the lung of iNOS-KO mice treated with GalCer was significantly reduced compared with that of WT mice treated with GalCer. Moreover, L-NAME, which is the inhibitor for iNOS, enhanced the anti-tumor effect of GalCer in lung metastatic model. The frequency of CD8+ cells in bronchoalveolar lavage fluid increased in iNOS-KO mice treated with GalCer. The administration of GalCer increased the frequency of myeloid-derived suppressor cells (MDSCs) in the lung from tumor-bearing WT mice, but the increase of MDSCs in the lung was not induced in iNOS-KO mice. The subcutaneous tumor experiments revealed that the administration of GalCer in the absence of iNOS expression significantly enhanced the induction of tumor antigen-specific response. Finally, our results indicated that the inhibition of iNOS expression could enhance the therapeutic efficacy of GalCer via the increase of tumor antigen-specific immune response and the suppression of MDSCs. PMID- 26496032 TI - Association between serum uric acid and bone health in general population: a large and multicentre study. AB - Previous studies proposed that serum uric acid (UA), an endogenous antioxidant, could be a protective factor against bone loss. However, recently, a study with a population of US adults did not note the protective effects of serum UA. Therefore, the exact association between serum UA and bone health remains unclear. We performed a retrospective consecutive cohort study in a Chinese population to examine the association between serum UA and bone health. This cross-sectional study included 17,735 individuals who underwent lumbar spine bone mineral density (BMD) measurements as part of a health examination. In covariance analyses (multivariable-adjusted), a high serum UA level was associated with a high BMD, T-score, and Z-score. In binary logistic regression analyses (multivariable-adjusted), a high serum UA level was associated with low odds ratios (ORs) for at least osteopenia and osteoporosis in male (age >=50 years) (OR = 0.72-0.60 and OR = 0.49-0.39, respectively) and postmenopausal female participants (OR = 0.61-0.51 and OR = 0.66-0.49, respectively). In conclusion, serum UA is associated with BMD, the T-score, and the Z-score, and has a strong protective effect against at least osteopenia and osteoporosis. PMID- 26496029 TI - Multifactorial resistance to aminopeptidase inhibitor prodrug CHR2863 in myeloid leukemia cells: down-regulation of carboxylesterase 1, drug sequestration in lipid droplets and pro-survival activation ERK/Akt/mTOR. AB - Aminopeptidase inhibitors are receiving attention as combination chemotherapeutic agents for the treatment of refractory acute myeloid leukemia. However, the factors determining therapeutic efficacy remain elusive. Here we identified the molecular basis of acquired resistance to CHR2863, an orally available hydrophobic aminopeptidase inhibitor prodrug with an esterase-sensitive motif, in myeloid leukemia cells. CHR2863 enters cells by diffusion and is retained therein upon esterase activity-mediated conversion to its hydrophilic active metabolite drug CHR6768, thereby exerting amino acid depletion. Carboxylesterases (CES) serve as candidate prodrug activating enzymes given CES1 expression in acute myeloid leukemia specimens. We established two novel myeloid leukemia sublines U937/CHR2863(200) and U937/CHR2863(5uM), with low (14-fold) and high level (270 fold) CHR2863 resistance. The latter drug resistant cells displayed: (i) complete loss of CES1-mediated drug activation associated with down-regulation of CES1 mRNA and protein, (ii) marked retention/sequestration of the prodrug, (iii) a substantial increase in intracellular lipid droplets, and (iv) a dominant activation of the pro-survival Akt/mTOR pathway. Remarkably, the latter feature coincided with a gain of sensitivity to the mTOR inhibitor rapamycin. These finding delineate the molecular basis of CHR2863 resistance and offer a novel modality to overcome this drug resistance in myeloid leukemia cells. PMID- 26496033 TI - The demographic features, clinicopathologic characteristics, treatment outcome and disease-specific prognostic factors of solitary fibrous tumor: a population based analysis. AB - BACKGROUND: Solitary fibrous tumor's (SFT) demographic features, clinicopathologic characteristics, treatment outcome and disease-specific prognostic factors were unexplored comprehensively. METHODS: SEER program was used to identify patients diagnosed with SFT from 1973 to 2012. Overall collected data were analyzed by using the SPSS 18.0. RESULTS: In total, 804 cases were found including 613 cases with SFT-specific mortality and 801 patients were analyzed for overall survival (OS). The 3-year disease specific survival (DSS), 5 year DSS and 10-year DSS were 73.3%, 65.7% and 53.3%. The 3-year OS, 5-year OS and 10-year OS were 71.9%, 63.3% and 47.3%. In the multivariate survival analysis, the age > 51 years (hazard ratio [HR] = 1.851 for DSS, P = 0.024 and HR = 1.652 for OS, P = 0.033; Reference [Ref] <= 51 years for DSS and <= 53 years for OS), SEER stage metastasized tumor (HR = 4.269 for DSS, P = 0.000 and HR = 2.905 for OS, P = 0.028, Ref - localized + regional tumor), pathologic grade III + IV (HR = 2.734 for DSS, P = 0.001 and HR = 2.585 for OS, P = 0.000, Ref - grade I + II) were adversely associated with DSS and OS. In addition, surgery was favorably associated with DSS (HR = 0.217, P = 0.045, Ref - surgery + radiotherapy). CONCLUSIONS: The surgery was an independent prognostic factor for DSS. The patient's age, SEER stage and pathologic grade were SFT-specific independent prognostic indicators for DSS and OS. PMID- 26496034 TI - Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy. AB - Chimeric antigen receptor (CAR)-based T-cell adoptive immunotherapy is a distinctively promising therapy for cancer. The engineering of CARs into T cells provides T cells with tumor-targeting capabilities and intensifies their cytotoxic activity through stimulated cell expansion and enhanced cytokine production. As a novel and potent therapeutic modality, there exists some uncontrollable processes which are the potential sources of adverse events. As an extension of this impactful modality, CAR-T cell-derived exosomes may substitute CAR-T cells to act as ultimate attackers, thereby overcoming some limitations. Exosomes retain most characteristics of parent cells and play an essential role in intercellular communications via transmitting their cargo to recipient cells. The application of CAR-T cell-derived exosomes will make this cell-based therapy more clinically controllable as it also provides a cell-free platform to diversify anticancer mediators, which responds effectively to the complexity and volatility of cancer. It is believed that the appropriate application of both cellular and exosomal platforms will make this effective treatment more practicable. PMID- 26496036 TI - c-Maf regulates pluripotency genes, proliferation/self-renewal, and lineage commitment in ROS-mediated senescence of human mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are therapeutically relevant multilineage and immunomodulatory progenitors. Ex vivo expansion of these rare cells is necessary for clinical application and can result in detrimental senescent effects, with mechanisms still largely unknown. We found that vigorous ex vivo expansion of human adipose tissue-derived MSCs (hAMSCs) results in proliferative decline, cell cycle arrest, and altered differentiation capacity. This senescent phenotype was associated with reactive oxygen species (ROS) accumulation, and with increased expression of G1 cell -cycle inhibitors- p15INK4b and p16INK4a - but decreased expression of pluripotency genes-Oct-4, Sox-2, Nanog, and c-Myc-as well as c-Maf a co-factor of MSC lineage-specific transcription factor and sensitive to oxidative stress. These global changes in the transcriptional and functional programs of proliferation, differentiation, and self-renewal were all mediated by ROS-induced suppression of c-Maf, as evidenced by binding of c-Maf to promoter regions of multiple relevant genes in hAMSCs which could be reduced by exogenous ROS. Our findings implicate the strong effects of ROS on multiple stem cell functions with a central role for c-Maf in stem cell senescence. PMID- 26496035 TI - Cancer stem cell targeted therapy: progress amid controversies. AB - Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy. PMID- 26496037 TI - Mismatch repair gene defects in sporadic colorectal cancer enhance immune surveillance. AB - BACKGROUND: There is evidence that colorectal cancers (CRC) with DNA mismatch repair deficiency (MMR-D) are associated with a better prognosis than the generality of large bowel malignancies. Since an active immune surveillance process has been demonstrated to influence CRC outcome, we investigated whether MMR-D can enhance the immune response in CRC. PATIENTS AND METHODS: A group of 113 consecutive patients operated for CRC (42 stage I or II and 71 with stage III or IV) was retrospectively analyzed. The expression of MMR genes (MSH2, MLH1, MSH6 and PSM2) and co-stimulatory molecule CD80 was assessed by tissue microarray immunohistochemistry. In addition, tumor infiltrating mononuclear cells (TIMC) and T cell subpopulations (CD4, CD8, T-bet and FoxP-3) were quantified. The effect of specific siRNA (siMSH2, siMLH1, siMSH6 and siPSM2) transfection in HT29 on CD80 expression was quantified by flow cytometry. Non parametric statistics and survival analysis were used. RESULTS: Patients with MMR-D showed a higher T bet/CD4 ratio (p = 0.02), a higher rate of CD80 expression and CD8 lymphocyte infiltration compared to those with no MMR-D. Moreover, in the MMR-D group, the Treg marker FoxP-3 was not expressed (p = 0.05). MMR-D patients with stage I or II and T-bet expression had a significant better survival (p = 0.009). Silencing of MSH2, MLH1 and MSH6, but not PSM2, significantly increased the rate of CD80+ HT29 cells (p = 0.007, p = 0.023 and p = 0.015, respectively). CONCLUSIONS: CRC with MMR-D showed a higher CD80 expression, and CD8+ and Th1 T-cell infiltration. In vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate. These results suggest an enhanced immune surveillance mechanism in presence of MMR-D. PMID- 26496039 TI - Learning Spatiotemporally Encoded Pattern Transformations in Structured Spiking Neural Networks. AB - Information encoding in the nervous system is supported through the precise spike timings of neurons; however, an understanding of the underlying processes by which such representations are formed in the first place remains an open question. Here we examine how multilayered networks of spiking neurons can learn to encode for input patterns using a fully temporal coding scheme. To this end, we introduce a new supervised learning rule, MultilayerSpiker, that can train spiking networks containing hidden layer neurons to perform transformations between spatiotemporal input and output spike patterns. The performance of the proposed learning rule is demonstrated in terms of the number of pattern mappings it can learn, the complexity of network structures it can be used on, and its classification accuracy when using multispike-based encodings. In particular, the learning rule displays robustness against input noise and can generalize well on an example data set. Our approach contributes to both a systematic understanding of how computations might take place in the nervous system and a learning rule that displays strong technical capability. PMID- 26496040 TI - Positive Neural Networks in Discrete Time Implement Monotone-Regular Behaviors. AB - We study the expressive power of positive neural networks. The model uses positive connection weights and multiple input neurons. Different behaviors can be expressed by varying the connection weights. We show that in discrete time and in the absence of noise, the class of positive neural networks captures the so called monotone-regular behaviors, which are based on regular languages. A finer picture emerges if one takes into account the delay by which a monotone-regular behavior is implemented. Each monotone-regular behavior can be implemented by a positive neural network with a delay of one time unit. Some monotone-regular behaviors can be implemented with zero delay. And, interestingly, some simple monotone-regular behaviors cannot be implemented with zero delay. PMID- 26496038 TI - Anti-leukemic effects of the V-ATPase inhibitor Archazolid A. AB - Prognosis for patients suffering from T-ALL is still very poor and new strategies for T-ALL treatment are urgently needed. Our study shows potent anti-leukemic effects of the myxobacterial V-ATPase inhibitor Archazolid A. Archazolid A reduced growth and potently induced death of leukemic cell lines and human leukemic samples. By inhibiting lysosomal acidification, Archazolid A blocked activation of the Notch pathway, however, this was not the mechanism of V-ATPase inhibition relevant for cell death induction. In fact, V-ATPase inhibition by Archazolid A decreased the anti-apoptotic protein survivin. As underlying mode of action, this work is in line with recent studies from our group demonstrating that Archazolid A induced S-phase cell cycle arrest by interfering with the iron metabolism in leukemic cells. Our study provides evidence for V-ATPase inhibition as a potential new therapeutic option for T-ALL. PMID- 26496041 TI - Symbolic Computation Using Cellular Automata-Based Hyperdimensional Computing. AB - This letter introduces a novel framework of reservoir computing that is capable of both connectionist machine intelligence and symbolic computation. A cellular automaton is used as the reservoir of dynamical systems. Input is randomly projected onto the initial conditions of automaton cells, and nonlinear computation is performed on the input via application of a rule in the automaton for a period of time. The evolution of the automaton creates a space-time volume of the automaton state space, and it is used as the reservoir. The proposed framework is shown to be capable of long-term memory, and it requires orders of magnitude less computation compared to echo state networks. As the focus of the letter, we suggest that binary reservoir feature vectors can be combined using Boolean operations as in hyperdimensional computing, paving a direct way for concept building and symbolic processing. To demonstrate the capability of the proposed system, we make analogies directly on image data by asking, What is the automobile of air? PMID- 26496042 TI - Rhythmic Inhibition Allows Neural Networks to Search for Maximally Consistent States. AB - Gamma-band rhythmic inhibition is a ubiquitous phenomenon in neural circuits, yet its computational role remains elusive. We show that a model of gamma-band rhythmic inhibition allows networks of coupled cortical circuit motifs to search for network configurations that best reconcile external inputs with an internal consistency model encoded in the network connectivity. We show that Hebbian plasticity allows the networks to learn the consistency model by example. The search dynamics driven by rhythmic inhibition enable the described networks to solve difficult constraint satisfaction problems without making assumptions about the form of stochastic fluctuations in the network. We show that the search dynamics are well approximated by a stochastic sampling process. We use the described networks to reproduce perceptual multistability phenomena with switching times that are a good match to experimental data and show that they provide a general neural framework that can be used to model other perceptual inference phenomena. PMID- 26496043 TI - A Sparse Reformulation of the Green's Function Formalism Allows Efficient Simulations of Morphological Neuron Models. AB - We prove that when a class of partial differential equations, generalized from the cable equation, is defined on tree graphs and the inputs are restricted to a spatially discrete, well chosen set of points, the Green's function (GF) formalism can be rewritten to scale as O(n) with the number n of inputs locations, contrary to the previously reported O(n(2)) scaling. We show that the linear scaling can be combined with an expansion of the remaining kernels as sums of exponentials to allow efficient simulations of equations from the aforementioned class. We furthermore validate this simulation paradigm on models of nerve cells and explore its relation with more traditional finite difference approaches. Situations in which a gain in computational performance is expected are discussed. PMID- 26496044 TI - Periodic Forcing of Inhibition-Stabilized Networks: Nonlinear Resonances and Phase-Amplitude Coupling. AB - Inhibition-stabilized networks (ISNs) are neural architectures with strong positive feedback among pyramidal neurons balanced by strong negative feedback from inhibitory interneurons, a circuit element found in the hippocampus and the primary visual cortex. In their working regime, ISNs produce damped oscillations in the [Formula: see text]-range in response to inputs to the inhibitory population. In order to understand the properties of interconnected ISNs, we investigated periodic forcing of ISNs. We show that ISNs can be excited over a range of frequencies and derive properties of the resonance peaks. In particular, we studied the phase-locked solutions, the torus solutions, and the resonance peaks. Periodically forced ISNs respond with (possibly multistable) phase-locked activity, whereas networks with sustained intrinsic oscillations respond more dynamically to periodic inputs with tori. Hence, the dynamics are surprisingly rich, and phase effects alone do not adequately describe the network response. This strengthens the importance of phase-amplitude coupling as opposed to phase phase coupling in providing multiple frequencies for multiplexing and routing information. PMID- 26496045 TI - Surface electromyography as a measure of trunk muscle activity in patients with spinal cord injury: a meta-analytic review. AB - CONTEXT: Surface electromyography (SEMG) may be a sensitive marker for distinguishing the activity of trunk muscles, which are critical to functional mobility recovery in patients with spinal cord injury (SCI). OBJECTIVES: This manuscript presents a systematic review and meta-analysis of the published literature on the effect of SEMG as a measure of trunk muscle activity in patients with SCI. METHODS: A comprehensive search of the research literature included Pubmed, Medline, CNKI, WANFANG DATA, Web of Science, Elsevier, Wiley Blackwell, Karger, OVID, and a review of reference lists within found articles. Case-control, cohort, and cross-sectional studies were included in the review. RESULTS: Eleven studies were included in this meta-analysis. Trunk muscle activities for the sitting condition were greater in patients with SCI than normal subjects. SEMG activity of trunk muscles for the sitting condition and posterior transfer was greater in patients with high level (HL)-SCI compared to those with low level (LL)-SCI. In addition, across studies, the level of trunk muscle activity for various difficulty settings was different for a given SCI group. CONCLUSION: This systematic review evaluated the value of trunk muscles for patients with SCI. We recommend use of SEMG as an assessment tool for improving the comparability and interpretability of trunk muscle activity of SCI therapeutic strategies. PMID- 26496046 TI - Chloroxyanion Residues in Cantaloupe and Tomatoes after Chlorine Dioxide Gas Sanitation. AB - Chlorine dioxide gas is effective at cleansing fruits and vegetables of bacterial pathogens and(or) rot organisms, but little data are available on chemical residues remaining subsequent to chlorine gas treatment. Therefore, studies were conducted to quantify chlorate and perchlorate residues after tomato and cantaloupe treatment with chlorine dioxide gas. Treatments delivered 50 mg of chlorine dioxide gas per kg of tomato (2-h treatment) and 100 mg of gas per kg of cantaloupe (6-h treatment) in sealed, darkened containers. Chlorate residues in tomato and cantaloupe edible flesh homogenates were less than the LC-MS/MS limit of quantitation (60 and 30 ng/g respectively), but were 1319 +/- 247 ng/g in rind + edible flesh of cantaloupe. Perchlorate residues in all fractions of chlorine dioxide-treated tomatoes and cantaloupe were not different (P > 0.05) than perchlorate residues in similar fractions of untreated tomatoes and cantaloupe. Data from this study suggest that chlorine dioxide sanitation of edible vegetables and melons can be conducted without the formation of unwanted residues in edible fractions. PMID- 26496047 TI - Psychometric properties of the Greek version of the Social Constraints Scale in a sample of women with breast cancer. AB - This study evaluated the psychometric properties of the Greek version of the Social Constraints Scale, developed in English by Lepore and Ituarte (1999). The scale was culturally adapted in Greek and was then administered, along with measures of psychological distress and intrusions, to a sample of 202 women with breast cancer, recruited from July 2012 to October 2013. Although the scale has usually been treated as a unidimensional measure, exploratory factor analysis revealed three underlying factors in the Greek Social Constraints Scale: unsupportive behaviors, avoidant behaviors, and suggestions for pretense and distraction. The three-factor solution explained 55% of the total variance. Subscale reliability was satisfactory (Cronbach's alpha coefficients ranging from 0.77 to 0.88). All subscales were significantly related to intrusions and psychological distress. Thus, the Greek Social Constraints Scale is a reliable and valid multidimensional instrument. The results of the present study show that, among all kinds of social constraints, unsupportive behaviors are the most highly correlated with distress, while distraction/pretense is most correlated with intrusiveness. Findings suggested that health professionals should aim to educate both the patient to claim her right to express feelings and thoughts and her social network to adopt disclosure-facilitating behaviors to compensate for intrusiveness and distress. PMID- 26496049 TI - Cross-Conjugated Systems Based On An (E)-Hexa-3-en-1,5-diyne-3,4-diyl Skeleton: Spectroscopic and Spectroelectrochemical Investigations. AB - A series of cross-conjugated compounds based on an (E)-4,4'-(hexa-3-en-1,5-diyne 3,4-diyl)bis(N,N-bis(4-methoxyphenyl)aniline) skeleton (1-6) have been synthesized. The linear optical absorption properties can be tuned by modification of the substituents at the 1 and 5 positions of the hexa-3-en-1,5 diynyl backbone (1: Si(CH(CH3)2)3, 2: C6H4C=CSi(CH3)3, 3: C6H4COOCH3, 4: C6H4CF3, 5: C6H4C=N, 6: C6H4C=CC5H4N), although attempts to introduce electron-donating (C6H4CH3, C6H4OCH3, C6H4Si(CH3)3) substituents at these positions were hampered by the ensuing decreased stability of the compounds. Spectroelectrochemical investigations of selected examples, supported by DFT-based computational studies, have shown that one- and two-electron oxidation of the 1,2 bis(triarylamine)ethene fragment also results in electronic changes to the perpendicular pi-system in the hexa-3-en-1,5-diynyl branch of the molecule. These properties suggest that (E)-hexa-3-en-1,5-diynyl-based compounds could have applications in molecular sensing and molecular electronics. PMID- 26496050 TI - Deciding whether to refer a colleague to a physician health program. PMID- 26496048 TI - Four Principles to Consider Before Advising Women on Screening Mammography. AB - This article reviews four important screening principles applicable to screening mammography in order to facilitate informed choice. The first principle is that screening may help, hurt, or have no effect. In order to reduce mortality and mastectomy rates, screening must reduce the rate of advanced disease, which likely has not happened. Through overdiagnosis, screening produces substantial harm by increasing both lumpectomy and mastectomy rates, which offsets the often promised benefit of less invasive therapy. Next, all-cause mortality is the most reliable way to measure the efficacy of a screening intervention. Disease specific mortality is biased due to difficulties in attribution of cause of death and to increased mortality due to overdiagnosis and the resulting overtreatment with radiotherapy and chemotherapy. To enhance participation, the benefit from screening is often presented in relative instead of absolute terms. Third, some screening statistics must be interpreted with caution. Increased survival time and the percentage of early-stage tumors at detection sound plausible, but are affected by lead-time and length biases. In addition, analyses that only include women who attend screening cannot reliably correct for selection bias. The final principle is that accounting for tumor biology is important for accurate estimates of lead time, and the potential benefit from screening. Since "early detection" is actually late in a tumor's lifetime, the time window when screen detection might extend a woman's life is narrow, as many tumors that can form metastases will already have done so. Instead of encouraging screening mammography, physicians should help women make an informed decision as with any medical intervention. PMID- 26496051 TI - Conscientious refusal or discrimination against gay parents? PMID- 26496052 TI - Force-feeding prisoners is wrong. PMID- 26496053 TI - Should an undocumented immigrant receive a heart transplant? PMID- 26496054 TI - Medical education on human trafficking. PMID- 26496055 TI - Professionalism and conflicting interests: the American Psychological Association's involvement in torture. PMID- 26496056 TI - Humanitarian uses of drones and satellite imagery analysis: the promises and perils. PMID- 26496057 TI - King v. Burwell: US Supreme Court extends tax credits for health insurance coverage to all 50 states. PMID- 26496058 TI - Medical associations and accountability for physician participation in torture. PMID- 26496059 TI - Forced sterilizations of HIV-positive women: a global ethics and policy failure. PMID- 26496060 TI - Promoting health as a human right in the post-ACA United States. PMID- 26496061 TI - Dual loyalties, human rights violations, and physician complicity in apartheid South Africa. PMID- 26496062 TI - Uncompromised professional responsibility in apartheid South Africa. PMID- 26496063 TI - #BlackLivesMatter: physicians must stand for racial justice. PMID- 26496064 TI - Additional commentary on deception in statin research. AB - Response to: Ferenci T. Absolute risk reduction may depend on the duration of the follow-up. Expert Rev Clin Pharmacol. 2017;10(12):1409-1410. PMID- 26496065 TI - Response to the Letter to the Editor Regarding Our Article (Natsch et al., 2015). PMID- 26496067 TI - Real-Time Monitoring Surface Chemistry-Dependent In Vivo Behaviors of Protein Nanocages via Encapsulating an NIR-II Ag2S Quantum Dot. AB - Protein nanocages (PNCs) have been recognized as a promising platform for nanomedicine innovation. Real-time in vivo tracking of PNCs can provide critically important information for the development of PNC-based diagnostics and therapeutics. Here we demonstrate a general strategy for monitoring the behaviors of PNCs in vivo by encapsulating a Ag2S quantum dot (QD) with fluorescence in the second near-infrared window (NIR-II, 1000-1700 nm) inside the PNC, using simian virus 40 (SV40) PNC (PNCSV40) as a model. Benefiting from the high spatiotemporal resolution and deep tissue penetration of NIR-II fluorescence imaging, the dynamic distribution of the PNCSV40 in living mice was tracked in real time with high fidelity, and adopting the PEGylation strategy, surface chemistry-dependent in vivo behaviors of PNCSV40 were clearly revealed. This study represents the first evidence of real-time tracking of the intrinsic behaviors of PNCs in vivo without interference in PNC-host interactions by encapsulating nanoprobes inside. The as-described imaging strategy will facilitate the study of interactions between exogenously introduced PNCs and host body and prompt the development of future protein-based drugs, sensors, and high-efficacy targeted delivery systems. PMID- 26496066 TI - The potential clinical impact of the release of two drafts of the human proteome. AB - The authors have carried out an investigation of the two "draft maps of the human proteome" published in 2014 in Nature. The findings include an abundance of poor spectra, low-scoring peptide-spectrum matches and incorrectly identified proteins in both these studies, highlighting clear issues with the application of false discovery rates. This noise means that the claims made by the two papers - the identification of high numbers of protein coding genes, the detection of novel coding regions and the draft tissue maps themselves - should be treated with considerable caution. The authors recommend that clinicians and researchers do not use the unfiltered data from these studies. Despite this these studies will inspire further investigation into tissue-based proteomics. As long as this future work has proper quality controls, it could help produce a consensus map of the human proteome and improve our understanding of the processes that underlie health and disease. PMID- 26496068 TI - Synthesis, Photochemical, and Redox Properties of Gold(I) and Gold(III) Pincer Complexes Incorporating a 2,2':6',2"-Terpyridine Ligand Framework. AB - Reaction of [Au(C6F5)(tht)] (tht = tetrahydrothiophene) with 2,2':6',2" terpyridine (terpy) leads to complex [Au(C6F5)(eta(1)-terpy)] (1). The chemical oxidation of complex (1) with 2 equiv of [N(C6H4Br-4)3](PF6) or using electrosynthetic techniques affords the Au(III) complex [Au(C6F5)(eta(3) terpy)](PF6)2 (2). The X-ray diffraction study of complex 2 reveals that the terpyridine acts as tridentate chelate ligand, which leads to a slightly distorted square-planar geometry. Complex 1 displays fluorescence in the solid state at 77 K due to a metal (gold) to ligand (terpy) charge transfer transition, whereas complex 2 displays fluorescence in acetonitrile due to excimer or exciplex formation. Time-dependent density functional theory calculations match the experimental absorption spectra of the synthesized complexes. In order to further probe the frontier orbitals of both complexes and study their redox behavior, each compound was separately characterized using cyclic voltammetry. The bulk electrolysis of a solution of complex 1 was analyzed by spectroscopic methods confirming the electrochemical synthesis of complex 2. PMID- 26496069 TI - Effect of Initial Vibrational-State Excitation on Subfemtosecond Photodynamics of Water. AB - We discuss the effect of initial vibrational-state excitation on the subfemtosecond photodynamics of water. Photoelectron spectra of Franck-Condon ionization to the (2)B1 state of the H2O(+) (D2O(+)) from the ground and several vibrationally excited states of the neutral are reported. Also calculated are ratios of the high-order harmonic generation (HHG) signals as a function of time for each initial vibrational state of the neutral molecule as predicted from the ratios of the square of the autocorrelation functions for D2O(+) and H2O(+). They reveal maxima as a function of time for each vibrational state of the neutral molecule. In turn, the HHG signals are found to be enhanced with vibrational excitation, with the calculated expectation values of the bond lengths and bond angle revealing quasiperiodic oscillations in time for all initial vibrational states of the neutral species. Although the bond lengths show only a marginal increase, the bond angle is found to be enhanced markedly by vibrational excitation, this being therefore responsible for the observed rise in the HHG signal. PMID- 26496071 TI - Interfacial Water at Polyurethane-Sapphire Interface. AB - Infrared-visible sum frequency generation spectroscopy (SFG) was used to directly probe water between polyurethane (PU) and sapphire substrates after exposing samples to liquid water and water vapor. For liquid water, the observation of SFG peaks associated with H2O bands (3000-3400 cm(-1)) and D2O bands (2300-2600 cm( 1)) indicated water molecules diffused to the buried interface and existed in the form of a hydrogen-bonded water network. The water layer disrupted interactions between polyurethane and sapphire. When PU films were exposed to water vapor, the SFG peak intensities of PU hydrocarbon and sapphire hydroxyl groups changed significantly, which suggested water molecules had reached the interface. However, no hydrogen-bonded water bands were present; instead, the H2O peak at 3550 cm(-1) and D2O peaks (2600-2700 cm(-1)) were observed. We assigned these peaks to low-coordination water molecules or hydroxyl groups hydrogen bonded with carboxyl groups of PU at the interface. The water molecules did not form a uniform layer at the interface and as a consequence did not completely disrupt the PU/sapphire interactions. These results provide important implications for understanding interfacial adhesion, coatings, and corrosion. PMID- 26496070 TI - Discovery of a Novel, Potent Spirocyclic Series of gamma-Secretase Inhibitors. AB - In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of gamma-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent gamma-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-beta (Abeta) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of gamma-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs. PMID- 26496072 TI - Protective Effect of Platelet Rich Plasma on Experimental Ischemia/Reperfusion Injury in Rat Ovary. AB - BACKGROUND/AIMS: Ovarian torsion is a common cause of local ischemic damage, reduced follicular activity and infertility. Platelet-rich plasma (PRP) contains growth factors with demonstrated cytoprotective properties; so we evaluated PRP efficacy in a rat ischemia/reperfusion (I/R) model. METHODS: Sixty adult female Sprague-Dawley albino rats were randomly assigned to 6 groups of 8 animals each: Sham, Ischemia, I/R, Sham + PRP, I + PRP and I/R + PRP; and the remaining 12 used to prepare PRP. Ischemia groups were subjected to bilateral adnexal torsion for 3 h, while I/R and I/R + PRP groups received subsequent detorsion for 3 h. Intraperitoneal PRP was administered 30 min prior to ischemia (Ischemia + PRP) or reperfusion (I/R + PRP). RESULTS: Total oxidant status (TOS), oxidative stress index (OSI) and total ovarian histopathological scores were higher in Ischemia and I/R groups than in the Sham group (p < 0.05). PRP decreased mean TOS, OSI and histopathological scores in I + PRP and I/R + PRP groups compared to the corresponding Ischemia and I/R groups (p < 0.001). There was a strong correlation between total histopathological score and OSI (r = 0.877, p < 0.001). Peritoneal vascular endothelial growth factor was significantly higher in PRP-treated groups than corresponding untreated groups (p < 0.05). CONCLUSION: PRP is effective for the prevention of ischemia and reperfusion damage in rat ovary. PMID- 26496073 TI - HIV Prevalence Correlates with High-Risk Sexual Behavior in Ethiopia's Regions. AB - BACKGROUND: HIV prevalence varies between 0.9 and 6.5% in Ethiopia's eleven regions. Little has been published examining the reasons for this variation. METHODS: We evaluated the relationship between HIV prevalence by region and a range of risk factors in the 2005 and 2011 Ethiopian Demographic Health Surveys. Pearson's correlation was used to assess the relationship between HIV prevalence and each variable. RESULTS: There was a strong association between HIV prevalence and three markers of sexual risk: mean lifetime number of partners (men: r = 0.87; P < 0.001; women: r = 0.60; P = 0.05); reporting sex with a non-married, non-cohabiting partner (men: r = 0.92; P < 0.001, women r = 0.93; P < 0.001); and premarital sex. Condom usage and HIV testing were positively associated with HIV prevalence, while the prevalence of circumcision, polygamy, age at sexual debut and male migration were not associated with HIV prevalence. CONCLUSION: Variation in sexual behavior may contribute to the large variations in HIV prevalence by region in Ethiopia. Population-level interventions to reduce risky sexual behavior in high HIV incidence regions should be considered. PMID- 26496074 TI - Quantification of Conventional and Nonconventional Charge-Assisted Hydrogen Bonds in the Condensed and Gas Phases. AB - Charge-assisted hydrogen bonds (CAHBs) play critical roles in many systems from biology through to materials. In none of these areas has the role and function of CAHBs been explored satisfactorily because of the lack of data on the energy of CAHBs in the condensed phases. We have, for the first time, quantified three types of CAHBs in both the condensed and gas phases for 1-(2'-hydroxylethyl)-3 methylimidazolium acetate ([C2OHmim][OAc]). The energy of conventional OH...[OAc](-) CAHBs is ~10 kcal.mol(-1), whereas nonconventional C(sp2)H...[OAc]( ) and C(sp3)H...[OAc](-) CAHBs are weaker by ~5-7 kcal.mol(-1). In the gas phase, the strength of the nonconventional CAHBs is doubled, whereas the conventional CAHBs are strengthened by <20%. The influence of cooperativity effects on the ability of the [OAc](-) anion to deprotonate the imidazolium cation is evaluated. The ability to quantify CAHBs in the condensed phase on the basis of easier accessible gas-phase estimates is highlighted. PMID- 26496076 TI - Correction: Trap Configuration and Spacing Influences Parameter Estimates in Spatial Capture-Recapture Models. PMID- 26496075 TI - Genome-Wide Association Mapping of Yield and Grain Quality Traits in Winter Wheat Genotypes. AB - The main goal of this study was to investigate the genetic basis of yield and grain quality traits in winter wheat genotypes using association mapping approach, and identify linked molecular markers for marker assisted selection. A total of 120 elite facultative/winter wheat genotypes were evaluated for yield, quality and other agronomic traits under rain-fed and irrigated conditions for two years (2011-2012) at the Tel Hadya station of ICARDA, Syria. The same genotypes were genotyped using 3,051 Diversity Array Technologies (DArT) markers, of which 1,586 were of known chromosome positions. The grain yield performance of the genotypes was highly significant both in rain-fed and irrigated sites. Average yield of the genotypes ranged from 2295 to 4038 kg/ha and 4268 to 7102 kg/ha under rain-fed and irrigated conditions, respectively. Protein content and alveograph strength (W) ranged from 13.6-16.1% and 217.6-375 Jx10-4, respectively. DArT markers wPt731910 (3B), wPt4680 (4A), wPt3509 (5A), wPt8183 (6B), and wPt0298 (2D) were significantly associated with yield under rain-fed conditions. Under irrigated condition, tPt4125 on chromosome 2B was significantly associated with yield explaining about 13% of the variation. Markers wPt2607 and wPt1482 on 5B were highly associated with protein content and alveograph strength explaining 16 and 14% of the variations, respectively. The elite genotypes have been distributed to many countries using ICARDA's International system for potential direct release and/or use as parents after local adaptation trials by the NARSs of respective countries. The QTLs identified in this study are recommended to be used for marker assisted selection after through validation using bi-parental populations. PMID- 26496077 TI - Evidence of Extensive Alternative Splicing in Post Mortem Human Brain HTT Transcription by mRNA Sequencing. AB - Despite 20 years since its discovery, the gene responsible for Huntington's Disease, HTT, has still not had its function or transcriptional profile completely characterized. In response to a recent report by Ruzo et al. of several novel splice forms of HTT in human embryonic stem cell lines, we have analyzed a set of mRNA sequencing datasets from post mortem human brain from Huntington's disease, Parkinson's disease, and neurologically normal control subjects to evaluate support for previously observed and to identify novel splice patterns. A custom analysis pipeline produced supporting evidence for some of the results reported by two previous studies of alternative isoforms as well as identifying previously unreported splice patterns. All of the alternative splice patterns were of relatively low abundance compared to the canonical splice form. PMID- 26496078 TI - Proteomic and Metabolomic Analyses Reveal Contrasting Anti-Inflammatory Effects of an Extract of Mucor Racemosus Secondary Metabolites Compared to Dexamethasone. AB - Classical drug assays are often confined to single molecules and targeting single pathways. However, it is also desirable to investigate the effects of complex mixtures on complex systems such as living cells including the natural multitude of signalling pathways. Evidence based on herbal medicine has motivated us to investigate potential beneficial health effects of Mucor racemosus (M rac) extracts. Secondary metabolites of M rac were collected using a good manufacturing process (GMP) approved production line and a validated manufacturing process, in order to obtain a stable product termed SyCircue (National Drug Code USA: 10424-102). Toxicological studies confirmed that this product does not contain mycotoxins and is non-genotoxic. Potential effects on inflammatory processes were investigated by treating stimulated cells with M rac extracts and the effects were compared to the standard anti-inflammatory drug dexamethasone on the levels of the proteome and metabolome. Using 2D-PAGE, slight anti-inflammatory effects were observed in primary white blood mononuclear cells, which were more pronounced in primary human umbilical vein endothelial cells (HUVECs). Proteome profiling based on nLC-MS/MS analysis of tryptic digests revealed inhibitory effects of M rac extracts on pro-inflammatory cytoplasmic mediators and secreted cytokines and chemokines in these endothelial cells. This finding was confirmed using targeted proteomics, here treatment of stimulated cells with M rac extracts down-regulated the secretion of IL-6, IL-8, CXCL5 and GROA significantly. Finally, the modulating effects of M rac on HUVECs were also confirmed on the level of the metabolome. Several metabolites displayed significant concentration changes upon treatment of inflammatory activated HUVECs with the M rac extract, including spermine and lysophosphatidylcholine acyl C18:0 and sphingomyelin C26:1, while the bulk of measured metabolites remained unaffected. Interestingly, the effects of M rac treatment on lipids were orthogonal to the effect of dexamethasone underlining differences in the overall mode of action. PMID- 26496079 TI - Correction: The cabABC Operon Essential for Biofilm and Rugose Colony Development in Vibrio vulnificus. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005192.]. PMID- 26496080 TI - Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines. AB - Recent clinical trials investigating receptor tyrosine kinase (RTK) inhibitors showed a limited clinical response in medulloblastoma. The present study investigated the role of micro-environmental growth factors expressed in the brain, such as HGF and EGF, in relation to the effects of hepatocyte growth factor receptor (MET) and epidermal growth factor receptor family (ErbB1-4) inhibition in medulloblastoma cell lines. Medulloblastoma cell lines were treated with tyrosine kinase inhibitors crizotinib or canertinib, targeting MET and ErbB1 4, respectively. Upon treatment, cells were stimulated with VEGF-A, PDGF-AB, HGF, FGF-2 or EGF. Subsequently, we measured cell viability and expression levels of growth factors and downstream signaling proteins. Addition of HGF or EGF phosphorylated MET or EGFR, respectively, and demonstrated phosphorylation of Akt and ERK1/2 as well as increased tumor cell viability. Crizotinib and canertinib both inhibited cell viability and phosphorylation of Akt and ERK1/2. Specifically targeting MET using shRNA's resulted in decreased cell viability. Interestingly, addition of HGF to canertinib significantly enhanced cell viability as well as phosphorylation of Akt and ERK1/2. The HGF-induced bypass of canertinib was reversed by addition of crizotinib. HGF protein was hardly released by medulloblastoma cells itself. Addition of canertinib did not affect RTK cell surface or growth factor expression levels. This manuscript points to the bypassing capacity of exogenous HGF in medulloblastoma cell lines. It might be of great interest to anticipate on these results in developing novel clinical trials with a combination of MET and EGFR inhibitors in medulloblastoma. PMID- 26496081 TI - Laparoscopic Sleeve Gastrectomy in Children Younger Than 14 Years: Refuting the Concerns. AB - OBJECTIVE: To evaluate the effect of laparoscopic sleeve gastrectomy (LSG) on growth in children younger than 14 years in a matched control study. BACKGROUND: Debatable concerns result in denying young children access to bariatric surgery. METHODS: Our multidisciplinary program database was used to extract data of young nonsyndromic children (age <=14 years) who underwent LSG. Patients were age, sex, and height z-score matched with those on nonsurgical weight management, and their results were compared with those of older adolescents (age > 14 years) who underwent LSG. Generalized estimating equation analysis was done to assess growth. RESULTS: One hundred sixteen children younger than 14 years (mean +/- SD, 11.2 +/- 2.5 years) underwent LSG. Compared with the 1:1 matched group of nonsurgical weight management, these children experienced significantly higher growth, gaining 0.9 mm more per month on average. Compared with 158 adolescents (age, 17.3 +/- 2.0 years) who underwent LSG in our institution, children younger than 14 years had a significantly lower prevalence of comorbidities (P < 0.001) but similar resolution rates (P = 0.72-0.99). There was no significant difference in the rate of complications (P = 0.77), and no mortality or significant morbidity was observed in any of the groups. CONCLUSIONS: This study challenges existing concerns regarding the safety and efficacy of bariatric surgery in prepubertal children. LSG is evidently safe and effective in this age group, resulting in significant weight loss, improved growth, and resolution of comorbidities without mortality or significant morbidity. PMID- 26496082 TI - Differential Effects of Intraoperative Positive End-expiratory Pressure (PEEP) on Respiratory Outcome in Major Abdominal Surgery Versus Craniotomy. AB - OBJECTIVES: In this study, we examined whether (1) positive end-expiratory pressure (PEEP) has a protective effect on the risk of major postoperative respiratory complications in a cohort of patients undergoing major abdominal surgeries and craniotomies, and (2) the effect of PEEP is differed by surgery type. BACKGROUND: Protective mechanical ventilation with lower tidal volumes and PEEP reduces compounded postoperative complications after abdominal surgery. However, data regarding the use of intraoperative PEEP is conflicting. METHODS: In this observational study, we included 5915 major abdominal surgery patients and 5063 craniotomy patients. Analysis was performed using multivariable logistic regression. The primary outcome was a composite of major postoperative respiratory complications (respiratory failure, reintubation, pulmonary edema, and pneumonia) within 3 days of surgery. RESULTS: Within the entire study population (major abdominal surgeries and craniotomies), we found an association between application of PEEP >=5 cmH2O and a decreased risk of postoperative respiratory complications compared with PEEP <5 cmH2O. Application of PEEP >5 cmH2O was associated with a significant lower odds of respiratory complications in patients undergoing major abdominal surgery (odds ratio 0.53, 95% confidence interval 0.39 - 0.72), effects that translated to deceased hospital length of stay [median hospital length of stay : 6 days (4-9 days), incidence rate ratios for each additional day: 0.91 (0.84 - 0.98)], whereas PEEP >5 cmH2O was not significantly associated with reduced odds of respiratory complications or hospital length of stay in patients undergoing craniotomy. CONCLUSIONS: The protective effects of PEEP are procedure specific with meaningful effects observed in patients undergoing major abdominal surgery. Our data suggest that default mechanical ventilator settings should include PEEP of 5-10 cmH2O during major abdominal surgery. PMID- 26496083 TI - Bioelectricity Generation and Bioremediation of an Azo-Dye in a Microbial Fuel Cell Coupled Activated Sludge Process. AB - Simultaneous bioelectricity generation and dye degradation was achieved in the present study by using a combined anaerobic-aerobic process. The anaerobic system was a typical single chambered microbial fuel cell (SMFC) which utilizes acid navy blue r (ANB) dye along with glucose as growth substrate to generate electricity. Four different concentrations of ANB (50, 100, 200 and 400 ppm) were tested in the SMFC and the degradation products were further treated in an activated sludge post treatment process. The dye decolorization followed pseudo first order kinetics while the negative values of the thermodynamic parameter ?G (change in Gibbs free energy) shows that the reaction proceeds with a net decrease in the free energy of the system. The coulombic efficiency (CE) and power density (PD) attained peak values at 10.36% and 2,236 mW/m2 respectively for 200 ppm of ANB. A further increase in ANB concentrations results in lowering of cell potential (and PD) values owing to microbial inhibition at higher concentrations of toxic substrates. Cyclic voltammetry studies revealed a perfect redox reaction was taking place in the SMFC. The pH, temperature and conductivity remain 7.5-8.0, 27(+/-2 degrees C and 10.6-18.2 mS/cm throughout the operation. The biodegradation pathway was studied by the gas chromatography coupled with mass spectroscopy technique, suggested the preferential cleavage of the azo bond as the initial step resulting in to aromatic amines. Thus, a combined anaerobic aerobic process using SMFC coupled with activated sludge process can be a viable option for effective degradation of complex dye substrates along with energy (bioelectricity) recovery. PMID- 26496084 TI - Identification of Promising Mutants Associated with Egg Production Traits Revealed by Genome-Wide Association Study. AB - Egg number (EN), egg laying rate (LR) and age at first egg (AFE) are important production traits related to egg production in poultry industry. To better understand the knowledge of genetic architecture of dynamic EN during the whole laying cycle and provide the precise positions of associated variants for EN, LR and AFE, laying records from 21 to 72 weeks of age were collected individually for 1,534 F2 hens produced by reciprocal crosses between White Leghorn and Dongxiang Blue-shelled chicken, and their genotypes were assayed by chicken 600 K Affymetrix high density genotyping arrays. Subsequently, pedigree and SNP-based genetic parameters were estimated and a genome-wide association study (GWAS) was conducted on EN, LR and AFE. The heritability estimates were similar between pedigree and SNP-based estimates varying from 0.17 to 0.36. In the GWA analysis, we identified nine genome-wide significant loci associated with EN of the laying periods from 21 to 26 weeks, 27 to 36 weeks and 37 to 72 weeks. Analysis of GTF2A1 and CLSPN suggested that they influenced the function of ovary and uterus, and may be considered as relevant candidates. The identified SNP rs314448799 for accumulative EN from 21 to 40 weeks on chromosome 5 created phenotypic differences of 6.86 eggs between two homozygous genotypes, which could be potentially applied to the molecular breeding for EN selection. Moreover, our finding showed that LR was a moderate polygenic trait. The suggestive significant region on chromosome 16 for AFE suggested the relationship between sex maturity and immune in the current population. The present study comprehensively evaluates the role of genetic variants in the development of egg laying. The findings will be helpful to investigation of causative genes function and future marker assisted selection and genomic selection in chickens. PMID- 26496086 TI - Bronchoscopic Multimodal Management of Tracheal Neurofibroma. AB - Neurofibromas involving airways are rare and their management is usually surgical. Herein, we report the case of an endotracheal polypoid neurofibroma successfully treated by multimodal interventional bronchoscopy and cryotherapy. PMID- 26496087 TI - Hemothorax After Endobronchial Ultrasound-guided Transbronchial Needle Aspiration. AB - Endobronchial ultrasound-guided transbronchial needle aspiration is a minimally invasive method for diagnosing paratracheal and peribronchial lesions, with a low rate of complications. However, as the procedure has gained widespread acceptance, major complications have occasionally been reported. In this report, we describe a case of hemothorax after endobronchial ultrasound-guided transbronchial needle aspiration in a patient with a right upper lobe mass. PMID- 26496085 TI - A Metabolic Probe-Enabled Strategy Reveals Uptake and Protein Targets of Polyunsaturated Aldehydes in the Diatom Phaeodactylum tricornutum. AB - Diatoms are unicellular algae of crucial importance as they belong to the main primary producers in aquatic ecosystems. Several diatom species produce polyunsaturated aldehydes (PUAs) that have been made responsible for chemically mediated interactions in the plankton. PUA-effects include chemical defense by reducing the reproductive success of grazing copepods, allelochemical activity by interfering with the growth of competing phytoplankton and cell to cell signaling. We applied a PUA-derived molecular probe, based on the biologically highly active 2,4-decadienal, with the aim to reveal protein targets of PUAs and affected metabolic pathways. By using fluorescence microscopy, we observed a substantial uptake of the PUA probe into cells of the diatom Phaeodactylum tricornutum in comparison to the uptake of a structurally closely related control probe based on a saturated aldehyde. The specific uptake motivated a chemoproteomic approach to generate a qualitative inventory of proteins covalently targeted by the alpha,beta,gamma,delta-unsaturated aldehyde structure element. Activity-based protein profiling revealed selective covalent modification of target proteins by the PUA probe. Analysis of the labeled proteins gave insights into putative affected molecular functions and biological processes such as photosynthesis including ATP generation and catalytic activity in the Calvin cycle or the pentose phosphate pathway. The mechanism of action of PUAs involves covalent reactions with proteins that may result in protein dysfunction and interference of involved pathways. PMID- 26496088 TI - Follicular Lymphoma Diagnosed With Medical Thoracoscopy. AB - Non-Hodgkin lymphomas may present with a recurrent pleural effusion, usually with involvement of other thoracic or extrathoracic sites. Lymphomas typically presenting with pleural disease include primary effusion lymphoma and pyothorax associated lymphoma. We describe an unusual case of recurrent pleural effusion secondary to follicular lymphoma with no other known extrathoracic involvement at the time of diagnosis. PMID- 26496089 TI - Electromagnetic Navigation Bronchoscopy-directed Pleural Tattoo to Aid Surgical Resection of Peripheral Pulmonary Lesions. AB - BACKGROUND: Limited (wedge) resection of pulmonary lesions is frequently performed as a diagnostic/therapeutic procedure. Some lesions may be difficult to locate thoracoscopically with conversion to open thoracotomy or incomplete resection being potential limitations to this approach. Multiple methods have been described to aid video-assisted thoracoscopic surgical (VATS) wedge resection of pulmonary nodules, including hookwire localization, percutaneous tattoo, or intraoperative ultrasound. We report on our experience using electromagnetic navigation bronchoscopic dye marking of small subpleural lesions to aid VATS wedge resection. METHODS: A retrospective cohort study of consecutive patients undergoing VATS wedge resection of peripheral lesions. Preoperative bronchoscopy with electromagnetic navigation was utilized to guide a 25 G needle to within/adjacent to the target lesion with injection of 1 mL of methylene blue or indigo carmine under fluoroscopic vision. RESULTS: Six patients underwent bronchoscopic marking of peripheral pulmonary lesions, navigation deemed successful in all patients, with no procedural complications. Surgery was performed within 24 hours of bronchoscopic marking. Pleural staining by dye was visible thoracoscopically in all 6 lesions either adjacent to or overlying the lesion. All lesions were fully excised with wedge resection. Pathologic examination confirmed accuracy of dye staining. CONCLUSIONS: Electromagnetic navigation bronchoscopic dye marking of peripheral lesions is feasible, without complications commonly associated with percutaneous marking procedures. Further experience is required but early findings suggest that this method may have utility in aiding minimally invasive resection of small subpleural lesions. PMID- 26496090 TI - Unilateral Emphysema in Infancy, a Rare Presentation of Aberrant Bronchial Artery: Case Report and Review of Literature. AB - Aberrant bronchial arteries are rarely seen and may originate from various vascular structures. Hemoptysis is the most common clinical presentation of cases with anomalous bronchial artery. We report a case of a 1-month-old infant presented with respiratory distress and left lung emphysema. Radiologic investigations and bronchoscopy revealed that the cause is an aberrant left bronchial artery compressing the left main bronchus. Surgical division of the aberrant vessel was performed with gradual improvement of the emphysema and respiratory distress. Unilateral emphysema due to vascular compression was previously reported. However, to the best of our knowledge, this is the first reported case of aberrant bronchial artery presenting with external compression of a main bronchus and unilateral emphysema. Also, this is the youngest reported case with an aberrant bronchial artery. PMID- 26496091 TI - Temporary Endobronchial Stent as a Bridge to Corrective Surgery For Severe Kyphoscoliosis-associated Central-Airway Extrinsic Compression. AB - Kyphoscoliosis is known to compromise lung function, with the primary mechanism being reduced chest wall compliance with a resultant restrictive pulmonary physiology. Severe scoliosis can also cause extrinsic compression of the central airways, leading to recurrent respiratory infections, lobar atelectasis, and potentially acute respiratory failure. Definitive therapy is corrective surgery of the spine. However, patients with severe scoliosis are at a potentially high risk of perioperative pulmonary complications. To our knowledge, we report the first successful use of retrievable endobronchial stents as a bridge to corrective surgery for kyphoscoliosis-associated complete central-airway extrinsic compression in a patient who was considered as too high risk for surgical correction due to her respiratory status. After surgery, the stents were removed and our patient experienced sustained improvement in pulmonary function and the clinical respiratory status. PMID- 26496092 TI - Mediastinitis: A Serious Complication of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration. AB - Mediastinitis is a rare but a serious complication of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound guided fine needle aspiration (EUS-FNA). We present 3 cases of mediastinitis following these diagnostic procedures. In 2 of the patients oropharyngeal bacteria were found in the cultures from the mediastinal abscess. All 3 cases were treated successfully with thoracotomy and drainage of the abscess together with intravenous antibiotics. On the basis of these cases and an updated review of the literature we discuss the most likely etiology for mediastinitis in association with EBUS-TBNA and EUS-FNA procedures and propose how to reduce the risk for this serious complication. The possibility of mediastinitis should always be kept in mind when a patient complains of fever over a long period of time as well as chest pain and malaise after an EBUS-TBNA or EUS-FNA procedure. PMID- 26496093 TI - Pulmonary Parenchymal Lymphoma Diagnosed by Bronchoscopic Cryoprobe Lung Biopsy. AB - A 51-year-old man presented with progressively worsening lung infiltrates and respiratory failure. Extensive investigations including bronchoscopy with bronchoalveolar lavage and conventional transbronchial forceps biopsies failed to establish the diagnosis. After transfer to our institution, he underwent repeat bronchoscopy with transbronchial cryobiopsy, which provided large, high-quality biopsy specimens establishing the diagnosis of parenchymal diffuse large B-cell lymphoma. PMID- 26496094 TI - Diagnosing Hodgkin Lymphoma From an Endobronchial Ultrasound Core Needle Biopsy. AB - Hodgkin lymphoma (HL) commonly presents as isolated mediastinal adenopathy. Although there is evidence to support minimally invasive techniques such as endobronchial ultrasound (EBUS) fine-needle aspiration as the initial diagnostic test for suspected lymphoma involving the mediastinum, it consistently performs the poorest at definitively diagnosing HL for a variety of reasons, and therefore histology specimens are usually required. We present a case of HL presenting as isolated mediastinal adenopathy that was definitively diagnosed on EBUS using a 22 G coring needle in which cellular and histologic specimens were obtained, allowing the core biopsy to be fixed in formalin and treated as a surgical specimen. The patient started treatment soon after the procedure without requiring any further invasive tests. Although it seems intuitive that a coring EBUS needle would be advantageous in diseases such as HL, further studies are needed before definitive recommendations can be made. PMID- 26496095 TI - Risks go beyond the violence: Association between intimate partner violence, mental illness, and substance abuse among females admitted to a rural Level I trauma center. AB - BACKGROUND: Intimate partner violence (IPV) is a significant cause of intentional injury among women but remains underrecognized, and its relationship to other risk factors for all-cause injury remains poorly defined. This study aimed to assess IPV and its association with alcohol abuse, illicit substance use, selected mental illnesses, and other risk factors for injury. METHODS: This is a cross-sectional study of prospectively collected data among adult females admitted to a rural, Level I trauma center. Well-validated instruments assessed IPV, substance abuse, and mental illness. Bivariate relationships were assessed with chi, odds ratios, and t test analyses. RESULTS: Eighty-one women were enrolled; 51% reported lifetime IPV, and 31% reported past-year IPV. Both groups were significantly more likely to have a mental illness than those without a history of IPV. Those reporting lifetime IPV exposure were significantly more likely to report illicit substance use, and past-year IPV was associated with alcohol abuse (28% vs. 7.1%, p = 0.01). Participants reporting past-year IPV were significantly more likely to have a partner possessing a firearm (40% vs. 12.5%, p = 0.005). CONCLUSION: The experience of lifetime and past-year IPV among women at a Level I, rural trauma center was high, and it was significantly associated with mental illness, substance abuse, and high-risk scenarios for intentional injury including firearm ownership by a significant other. These findings inform the potential value of IPV screening and intervention and suggest that IPV, mental illness, and substance abuse should be considered associated entities in prevention and recidivism reduction efforts in the female trauma population. LEVEL OF EVIDENCE: Prognostic study, level II; therapeutic study, level III. PMID- 26496096 TI - Trauma patient readmissions: Why do they come back for more? AB - BACKGROUND: Hospital readmissions are a frequent challenge. Speculation exists that rates of readmission following traumatic injury will be publicly disclosed. The primary aim of this study was to characterize and model 1-year readmission patterns to multiple institutions among patients originally admitted to a single, urban Level I trauma center. Additional analyses within the superutilizers subgroup identified predictors of 30-day readmissions as well as patient loyalty for readmission to their index hospital. We hypothesized that hospital readmission among trauma patients would be associated with socioeconomic, demographic, and clinical features and superutilizers would be identifiable during initial hospitalization. METHODS: Data were retrospectively gathered for 2,411 unique trauma patients admitted to a Level I American College of Surgeons certified trauma center over 1 year, with readmissions identified 1 year after index admission. A regional hospital database was queried for readmissions. Outcomes of all readmission encounters were analyzed using a binary logistic regression model including demographic, diagnoses, Injury Severity Score (ISS), procedures, Elixhauser comorbidities, insurance, and disposition data. Subset analysis of superutilizers was also performed to examine patterns among superutilizers. RESULTS: A total of 434 patients (21%) were readmitted during the study period, accounting for 720 readmission encounters. Sixty-three patients accounting for 269 encounters were identified as superutilizers (3+ readmissions). A total of 136 patients (6%) were readmitted within 30 days of initial discharge. Fifty-seven percent of readmissions returned to the originating hospital. CONCLUSION: Complications including comorbid disease (diabetes and congestive heart failure), septicemia, weight loss, and trauma recidivism distinguish the superutilizer trauma patient. Having Medicaid funding increased the odds of readmission by 274%. It is imperative that interventions be developed and targeted toward those at high risk of superutilization of health care resources to curb spending. These results strongly support continuation of longitudinal readmission research in trauma patients conducted in multicenter settings. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 26496097 TI - Thrombin generation and procoagulant microparticle profiles after acute trauma: A prospective cohort study. AB - OBJECTIVE: The two sides of trauma-induced coagulopathy, the hypocoagulable and the hypercoagulable states, are poorly understood. To identify potential mechanisms for venous thromboembolism and bleeding after acute trauma, we estimated changes in circulating procoagulant microparticles (MPs) and thrombin activity during hospitalization for trauma. METHODS: Whole blood was collected by venipuncture into 3.2% trisodium citrate at 0, 6, 12, 24, and 72 hours after injury and discharge. Platelet-poor plasma was harvested and stored at -80 degrees C until analysis. Thrombin generation was determined using the calibrated automated thrombogram (CAT), reported as lag time (minutes), peak height (nM thrombin), and time to reach peak height (ttPeak, minutes). The concentration of total procoagulant MPs (number/MUL) was measured by flow cytometry. Data are presented as median (interquartile range [IQR]). RESULTS: Among 443 trauma patients (1,734 samples; Injury Severity Score [ISS], 13.0 [IQR, 6.0-22.0]; hospital length of stay, 4.0 days [IQR, 2.0-10.0]; age, 48 years [IQR, 28-65]; 70.7% male; 95% with blunt mechanism; mortality, 3.2%), no discernable patterns in thrombin generation or MP concentration were observed over time. The peak height and MPs were significantly different from healthy volunteers and were 337 nM (IQR, 285-395) and 400/MUL plasma (IQR, 211-772), respectively. Extreme (defined as highest or lowest 5%) values reflecting a possible "hypercoagulable state" (lag time <= 1.98, peak height >= 486.2, ttPeak <= 3.61, and total procoagulant MP >= 2,278) were reached within 12 hours after acute trauma, while extreme values representing a possible "hypocoagulable state" (lag time >= 18.6, peak height <= 17.8, and ttPeak >= 29.45) were not reached until 1 day to 3 days. CONCLUSION: Although there was no predictable pattern of coagulopathy observed in each patient after trauma, those who reached extreme values did so relatively early after injury. These findings should be taken into account when designing risk model tools involving coagulation laboratory parameters. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 26496098 TI - Impact of common crystalloid solutions on resuscitation markers following Class I hemorrhage: A randomized control trial. AB - BACKGROUND: Resuscitation after hemorrhage with crystalloid solutions can lead to marked acidosis and iatrogenically worsen the lethal triad. The effect of differing solutions on base deficit and lactate has been sparsely prospectively studied in humans. We sought to quantify the effect of normal saline (NS) and lactated Ringer's (LR) resuscitation in voluntary blood donors as a model for Class I hemorrhage. METHODS: A prospective randomized control trial was conducted in conjunction with blood drives. Donors were randomized to receive no intravenous fluid (noIVF), 2-L NS, or 2-L LR after blood donation of 500 mL. Lactate and base deficit were measured before and after fluid administration using an iSTAT. The mean laboratory values were compared between groups first using a global test followed by pairwise testing between groups using the Wilcoxon rank-sum and Kruskal-Wallis tests. The Bonferroni correction was used and a statistical significance of p < 0.0167 was set. RESULTS: A total of 157 patients completed the study. The mean (SD) age was 39.2 (12.7), and 65.0% were female. Patients in each group lost equivalent amounts of total blood volume, and a similar amount was replaced in the crystalloid group (p > 0.0167). Donors had comparable increases in lactate and base deficit after donation regardless of the group (p > 0.0167). After resuscitation with 2-L crystalloid, the lactate level increased higher in the LR group than in the noIVF or the NS group (1.36 mmol/L vs. 1.00 mmol/L vs. 1.54 mmol/L, p < 0.0001). In addition, the resuscitation base deficit increased in the NS group more than in the noIVF or LR group (-0.65 vs. 3.06 vs. -0.34, p < 0.0001). CONCLUSION: This study is one of the first human studies to prospectively demonstrate quantifiable differences in base deficit and lactate by type of crystalloid resuscitation. LR resuscitation elevated lactate levels, and NS negatively affected the base deficit. These findings are critical to the interpretation of trauma patient resuscitation with crystalloid solutions. LEVEL OF EVIDENCE: Therapeutic study, level II. PMID- 26496099 TI - An evidence-based method for targeting an abusive head trauma prevention media campaign and its evaluation. AB - BACKGROUND: A triple-dose abusive head trauma (AHT) prevention program (Period of PURPLE Crying) was implemented. The third dose consisted of an education media campaign. The study objectives were to describe the qualitative and spatial methods developed to target AHT prevention and to evaluate this campaign. METHODS: A questionnaire on the level of importance of factors, rated on a 7 point Likert scale, was distributed to a panel of experts to determine the best advertising locations. Ranked factors were used to create weights for statistical modeling and mapping within a Geographic Information Systems to determine optimal ad locations. The media campaign was evaluated via a telephone survey of randomly selected households. RESULTS: The survey found locations of new families, high population density, and high percentage of lone parents to be the most important factors for selecting billboard sites. Spatial analysis revealed six areas that ranked highest in our factors. Five billboards, four media posters, and six transit shelters were selected for our advertisements. A population-based telephone survey revealed that 23% of respondents knew the campaign. Nearly half (42%) heard the radio public service announcements, and 9% saw billboards. CONCLUSION: Extending primary prevention efforts to the public helps to create a cultural change in the way inconsolable crying, the trigger for AHT, is viewed. With the use of ranked factors and Geographic Information Systems, geographic locations with high visibility and specific risk factors for AHT were identified for targeting the campaign, facilitating the likelihood that our message was reaching the population in greatest need. PMID- 26496100 TI - Epigenetic regulatory pathways involving microRNAs may modulate the host immune response following major trauma. AB - BACKGROUND: Posttraumatic nosocomial pneumonia is a common complication resulting in significant morbidity. Trauma-induced immunocompromise is associated with an enhanced susceptibility to pneumonia. In this study, we explore the hypothesis that posttranscriptional epigenetic regulation of gene expression may be an important factor in determining this immune phenotype. We describe the pattern of production of microRNAss (miRs) and their association with nosocomial pneumonia following severe trauma. METHODS: A convenience sample of 30 ventilated polytrauma patients ( UKCRN ID: 5637) and 16 healthy controls were recruited. Messenger RNA and protein levels of key cytokines were quantified within 2 hours of the injury and at 24 hours. Three miRs per cytokine were then selected based on miRBase target prediction scores and quantified using polymerase chain reaction. Nosocomial pneumonia was defined using the Centers for Disease Control and Prevention definitions. RESULTS: Median Injury Severity Score (ISS) was 29, and 47% of the patients developed nosocomial pneumonia. miR-125a and miR-202 decreased by 34% and 77%, respectively, immediately following injury, whereas their target, IL-10, increased messenger RNA levels 3-fold and protein levels 180 fold. Tumor necrosis factor alpha (TNF-alpha) and IL-12 gene expression decreased by 68% and 43%, respectively, following injury, and this was mirrored by a 10 fold increase in miR-181, an miR predicted to target TNF-alpha transcripts. Lower levels of miR-125a and miR-374b were associated with the later acquisition of hospital-acquired pneumonia. CONCLUSION: Alteration in the expression of miRs with highly predicted complementarity to IL-10 and TNF-alpha may be an important mechanism regulating the posttraumatic immunosuppressive phenotype in intensive care unit patients. LEVEL OF EVIDENCE: Retrospective observational study, level III. PMID- 26496101 TI - An FcgammaRIIa polymorphism with decreased C-reactive protein binding is associated with sepsis and decreased monocyte HLA-DR expression in trauma patients. AB - BACKGROUND: A dysregulated immune response leading to sepsis is the most frequent cause of late posttraumatic deaths. We have found a novel anti-inflammatory pathway that is initiated by the acute phase protein, C-reactive protein (CRP), interacting with Fcgamma receptor (FcgammaR) on monocytes. This pathway is protective in animal models of endotoxin shock. We hypothesized that genetic polymorphisms in the FcgammaR might contribute to monocyte responses and susceptibility to infectious complications after severe trauma. METHODS: We conducted an observational study on a prospectively identified cohort of adult patients with convenience enrollment admitted after severe trauma. We enrolled 66 patients and collected blood samples at enrollment and again at 48 hours and 72 hours. Patients were followed through their hospital stay, and any septic events before 14 days were recorded. Cytokine and CRP levels were determined in the plasma from all three blood draws. In addition, DNA was extracted from blood and analyzed for the 131 H/R FcgammaRIIa polymorphism that strongly affects the binding of IgG and CRP to this receptor. RESULTS: Elevated levels of interleukin 8 (IL-8), IL-6, IL-10, monocyte chemotactic protein 1, and CRP were associated with reduced time to posttraumatic sepsis in Cox regression analysis. Expression of monocyte human leukocyte antigen DR less than 45% on patient monocytes was also associated with sepsis (hazard ratio, 3.15; 95% confidence interval, 1.45 6.93). Genetic analysis found that individuals with the polymorphism of the FcgammaRIIa receptor that binds CRP poorly were also more likely to have decreased monocyte human leukocyte antigen DR and posttraumatic sepsis. In vitro studies showed that CRP could attenuate monocyte deactivation in volunteers with the polymorphism of the FcgammaRIIa receptor that binds CRP. CONCLUSION: Our findings suggest that a common genetic variation in the FcgammaRIIa receptor may contribute to infectious susceptibility in trauma patients. In vitro experiments suggest that this association is related to the inability of CRP to bind to this FcgammaRIIa receptor variant. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 26496102 TI - Novel role of group VIB Ca2+-independent phospholipase A2gamma in leukocyte endothelial cell interactions: An intravital microscopic study in rat mesentery. AB - BACKGROUND: Phospholipase A2 (PLA2) is associated with a variety of inflammatory processes related to polymorphonuclear neutrophil (PMN)-endothelial cell interactions. However, the cellular and molecular mechanisms underlying the interactions and the causative isoform(s) of PLA2 remain elusive. In addition, we recently showed that calcium-independent PLA2gamma (iPLA2gamma), but not cytosolic PLA2 (cPLA2), is responsible for the cytotoxic functions of human PMN including respiratory bursts, degranulation, and chemotaxis. We therefore hypothesized that iPLA2gamma is a prerequisite for the PMN recruitment cascade into the site of inflammation. The aim of this study was to elucidate the roles of the three major phospholipases A2, iPLA2, cPLA2 and secretory PLA2, in leukocyte rolling and adherence and in the surface expression of beta2-integrins in vivo and in vitro in response to well-defined stimuli. METHODS: Male Wistar rats were pretreated with PLA2 inhibitors selective for iPLA2beta, iPLA2gamma, cPLA2, or secretory PLA2. Leukocyte rolling/adherence in the mesenteric venules superfused with platelet-activating factor (PAF) were quantified by intravital microscopy. Furthermore, isolated human PMNs or whole blood were incubated with each PLA2 inhibitor and then activated with formyl-methionyl-leucyl-phenylalanine (fMLP) or PAF. PMN adherence was assessed by counting cells bound to purified fibrinogen, and the surface expression of lymphocyte function-associated antigen 1 and macrophage antigen 1 (Mac-1) was measured by flow cytometry. RESULTS: The iPLA2gamma-specific inhibitor almost completely inhibited the fMLP/PAF-induced leukocyte adherence in vivo and in vitro and also decreased the fMLP/PAF stimulated surface expression of Mac-1 by 60% and 95%, respectively. In contrast, the other inhibitors did not affect these cellular functions. CONCLUSION: iPLA2gamma seems to be involved in leukocyte/PMN adherence in vivo and in vitro as well as in the up-regulation of Mac-1 in vitro in response to PAF/fMLP. This enzyme is therefore likely to be a major regulator in the PMN recruitment cascade. PMID- 26496103 TI - The safety of early fresh, whole blood transfusion among severely battle injured at US Marine Corps forward surgical care facilities in Afghanistan. AB - BACKGROUND: In Afghanistan, care of the acutely injured trauma patient commonly occurred in facilities with limited blood banking capabilities. Apheresis platelets were often not available. Component therapy consisted of 1:1 packed red blood cells and fresh frozen plasma. Fresh, whole blood transfusion often augmented therapy in the severely injured patient. This study analyzed the safety of fresh, whole blood use in a resource-limited setting. METHODS: A retrospective analysis was performed on a prospectively collected data set of US battle injuries presenting to three US Marine Corps (USMC) expeditionary surgical care facilities in Helmand Province, Afghanistan, between January 2010 and July 2012. Included in the review were patients with Injury Severity Scores (ISSs) of 15 or higher receiving blood transfusions. Univariate analyses were performed, followed by multivariable logistic regression to describe the relationship between the treatment group and posttreatment complications such as trauma-induced coagulopathy, infection, mortality, venous thromboembolism, and transfusion reaction. Propensity scores were calculated and included in multivariable models to adjust for potential bias in treatment selection. RESULTS: A total of 61 patients were identified; all were male marines with a mean (SD) age of 23.5 (3.6) years. The group receiving fresh, whole blood was noted to have higher ISSs and lower blood pressure, pH, and base deficits on arrival. Traumatic coagulopathy was significantly less common in the group receiving fresh, whole blood (odds ratio, 0.01; 95% confidence interval, 0.00-0.18). Multivariable models found no other significant differences between the treatment groups. CONCLUSION: The early use of fresh, whole blood in a resource-limited setting seems to confer a benefit in reducing traumatic coagulopathy. This study's small sample size precludes further statement on the overall safety of fresh, whole blood use. LEVEL OF EVIDENCE: Therapy study, level IV. PMID- 26496104 TI - Platelet function in reconstituted whole blood variants: An observational study over 5 days of storage time. AB - BACKGROUND: Platelet concentrates (PCs) are usually stored at room temperature under constant gentle agitation. Risk of bacterial contamination limits maximum storage time to 5 days. The objective of the study was to investigate platelet function with regard to storage time in different reconstituted whole blood (RWB) variants. METHODS: Donated apheresis PCs were stored at 22 degrees C over 5 days. To obtain RWB, apheresis PCs were mixed with plasma-free packed red blood cells (RBCs) and either prethawed fresh frozen plasma (PT) or solvent-detergent plasma (SD) [1:1:1 ratio], or with leukocyte- and platelet-depleted whole blood (LD-WB) as control. Platelet function in RWB variants was assessed by impedance aggregometry (Multiplate) on Days 0, 1, 3, and 5 following platelet donation. RESULTS: Platelet aggregometry did not reach the lower limits determined from healthy volunteers in any of the RWB variants. Platelet aggregability measured by ASPI test, ADP test, and COL test declined over storage time in all RWB variants. No differences were observed in the TRAP test. At most measurement time points, LD-RWB provided significantly higher platelet aggregability compared with SD-RWB and PT-RWB (p < 0.01). SD-RWB demonstrated higher platelet aggregability on Day 0 in the ASPI test, ADP test, and TRAP test compared with PT-RWB. CONCLUSION: Apheresis PCs stored for 5 days at 22 degrees C demonstrated reduced platelet aggregability, as measured by multiple electrode aggregometry when mixed with RBCs and plasma. As platelet aggregation in LD-RWB was superior compared with SD RWB and PT-RWB variants, it might be possible that additives in RBCs or plasma are responsible for the observed depressed platelet function. Critical evaluation of current massive transfusion recommendations proposing early platelet transfusion is indicated. PMID- 26496105 TI - Deep organ space infection after emergency bowel resection and anastomosis: The anatomic site does not matter. AB - BACKGROUND: Deep organ space infection (DOSI) is a serious complication after emergency bowel resection and anastomosis. The aim of this study was to identify the incidence and risk factors for the development of DOSI. METHODS: National Surgical Quality Improvement Program database study including patients who underwent large bowel or small bowel resection and primary anastomosis. The incidence, outcomes, and risk factors for DOSI were evaluated using univariate and multivariate analyses. RESULTS: A total of 87,562 patients underwent small bowel, large bowel, or rectal resection and anastomosis. Of these, 14,942 (17.1%) underwent emergency operations and formed the study population. The overall mortality rate in emergency operations was 12.5%, and the rate of DOSI was 5.6%. A total of 18.0% required ventilatory support in more than 48 hours, and 16.0% required reoperation. Predictors of DOSI included age, steroid use, sepsis or septic shock on admission, severe wound contamination, and advanced American Society of Anesthesiologists classification. The anatomic location of resection and anastomosis was not significantly associated with DOSI. CONCLUSION: Patients undergoing emergency bowel resection and anastomosis have a high mortality, risk of DOSI, and systemic complications. Independent predictors of DOSI include wound and American Society of Anesthesiologists classification, sepsis or septic shock on admission, and steroid use. The anatomic location of resection and anastomosis was not significantly associated with DOSI. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III. PMID- 26496106 TI - Gangrenous cholecystitis: Deceiving ultrasounds, significant delay in surgical consult, and increased postoperative morbidity! AB - BACKGROUND: Gangrenous cholecystitis (GC) is difficult to diagnose preoperatively in the patient with suspected acute cholecystitis. We sought to characterize preoperative risk factors and post-operative complications. METHODS: Pathology reports of all patients undergoing cholecystectomy for suspected acute cholecystitis from June 2010 to January 2014 and admitted through the emergency department were examined. Patients with GC were compared with those with acute/chronic cholecystitis (AC/CC). Data collected included demographics, preoperative signs and symptoms, radiologic studies, operative details, and clinical outcomes. RESULTS: Thirty-eight cases of GC were identified and compared with 171 cases of AC/CC. Compared with AC/CC, GC patients were more likely to be older (57 years vs. 41 years, p < 0.001), of male sex (63% vs. 31%, p < 0.001), hypertensive (47% vs. 22%, p = 0.002), hyperlipidemic (29% vs. 14%, p = 0.026), and diabetic (24% vs. 8%, p = 0.006). GC patients were more likely to have a fever (29% vs. 12%, p = 0.007) and less likely to have nausea/vomiting (61% vs. 80%, p = 0.019) or an impacted gallstone on ultrasound (US) (8% vs. 26%, p = 0.017). Otherwise, there was no significant difference in clinical or US findings. Among GC patients, US findings were absent (8%, n = 3) or minimal (42%, n = 16). Median time from emergency department registration to US (3.3 hours vs. 2.8 hours, p = 0.28) was similar, but US to operation was longer (41.2 hours vs. 18.4 hours, p < 0.001), conversion to open cholecystectomy was more common (37% vs. 10%, p < 0.001), and hospital stay was longer (median, 4 days vs. 2 days, p < 0.0001). Delay in surgical consultation occurred in 16% of GC patients compared with 1% of AC patients (p < 0.001). CONCLUSION: Demographic features may be predictive of GC. Absent or minimal US signs occur in 50%, and delay in surgical consultation is common. Postoperative morbidity is greater for patients with GC compared with those with AC/CC. LEVEL OF EVIDENCE: Epidemiologic study, level III; therapeutic study, level IV. PMID- 26496107 TI - Intravascular ultrasound enhanced aortic sizing for endovascular treatment of blunt aortic injury. AB - BACKGROUND: Blunt aortic injury (BAI) in young patients with a compliant aorta and evolving hyperdynamic physiology may result in significant variation in aortic diameter during the cardiac cycle. Intravascular ultrasound (IVUS) may be useful to detect real-time variations in aortic diameters for more reliable sizing in patients undergoing thoracic endovascular aortic repair (TEVAR) of BAI. METHODS: This is a single-institution retrospective study of patients who underwent TEVAR for BAI in a Level 1 trauma center from January 2004 to January 2014. Patients underwent either trauma survey computed tomography (CT) alone (CT group) or IVUS and CT (IVUS group). We compared predeployment aortic measurements, implanted device size, landing zones, and repair outcomes between the groups. RESULTS: Forty-one patients underwent TEVAR for BAI: 28 were in the CT group and 13 in the IVUS group. Left subclavian artery (LSCA) coverage was performed in 50% (CT group) and 38% (IVUS group) of patients. CT-based median aortic diameter was similar in both groups (20.5 mm in the CT group vs. 19.0 mm in the IVUS group, p = 0.374). The median proximal diameter of the proximal device implanted was 26 mm in the CT group and 24 mm in the IVUS group (p = 0.329), which resulted in oversizing of 25.7% and 13.7% (p < 0.001), respectively. The implanted device was changed in 6 of 13 patients and in 4 of 5 patients in which the LSCA was covered because of IVUS measured-diameters. Graft extension proximal to the LSCA resulted in greater differences between the CT and IVUS measurements of the proximal aorta than if the graft was isolated to the descending aorta (18.8% vs. 5.57%, p = 0.005). Technical success of repair for both groups was 100%; no secondary interventions were required in either group. CONCLUSION: In combination with CT, IVUS provides important separate sizing information at the point of implantation for more accurate device selection, eliminating need for a repeat CT. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 26496108 TI - Outcomes of pediatric patients with persistent midline cervical spine tenderness and negative imaging result after trauma. AB - BACKGROUND: There is little evidence to guide management of pediatric patients with persistent cervical spine tenderness after trauma but with negative initial imaging study findings. Our objective was to determine the prevalence of clinically significant cervical spine injury among pediatric blunt trauma patients discharged from the emergency department with negative imaging study findings but persistent midline cervical spine tenderness. METHODS: We performed a single-center, retrospective study of subjects 1 year to 15 years of age discharged in a rigid cervical spine collar after blunt trauma over a 5-year period. We included patients with negative imaging results who were maintained in a collar because of persistent midline cervical spine tenderness. Primary outcome was clinically significant cervical spine injury. Secondary outcome was continued use of the collar after follow-up. Outcomes were ascertained from the medical record or self-report via telephone call. RESULTS: A total of 307 subjects met inclusion criteria, of whom 289 (94.1%) had follow-up information available (89.6% in chart, 10.4% via telephone call). Of those with follow-up information, 189 (65.4%) had subspecialty follow-up in the spine clinic. Of those with spine clinic follow-up, 84.6% had the hard collar discontinued at the first visit (median time to visit, 10 days). Of subjects with spine clinic follow-up, 10.1% were left in the collar for persistent tenderness without findings on imaging and 2.1% had imaging findings related to their injury; none required surgical intervention. CONCLUSION: A very small percentage of subjects with persistent midline cervical spine tenderness and normal radiographic study findings have a clinically significant cervical spine injury identified at follow-up. Referral for subspecialty evaluation may only be necessary in a small number of patients with persistent tenderness or concerning signs/symptoms. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 26496109 TI - Which pediatric blunt trauma patients do not require pelvic imaging? AB - BACKGROUND: This study aimed to develop a tool in identifying traumatized children at low risk of pelvic fracture and to determine the sensitivity of this low-risk model for pelvic fractures. We hypothesized that the proportion of children without predictors with pelvic fracture is less than 1%. METHODS: This is a retrospective trauma registry analysis of previously healthy children 1 year to 17 years old presenting to the pediatric emergency department with blunt trauma. Postulated predictors of pelvic fracture on radiograph or computed tomography included pain/abnormal examination result of the pelvis/hip, femur deformity, hematuria, abdominal pain/tenderness, Glasgow Coma Scale (GCS) score of 13 or lower, and hemodynamic instability. We used multivariable logistic regression to identify independent predictors of fracture. RESULTS: Of 1,121 eligible patients (mean [SD] age, 8.5 [4.6] years), 87 (7.8%) had pelvic fracture. Independent predictors included pain/abnormal examination result of the pelvis/hip (odds ratio [OR], 16.7; 95% confidence interval [CI], 9.6-29.1), hematuria (OR, 6.6; 95% CI, 3.0-14.6), femoral deformity (OR, 5.9; 95% CI, 3.1 11.3), GCS score of 13 or lower (OR, 2.4; 95% CI, 1.3-4.3), and hemodynamic instability (OR, 3.4; 95% CI, 1.7-6.9). One of 590 children (0.2%; 95% CI, 0 0.5%) without predictors had pelvic fractures versus 86 (16.2%) of 531 in those with one or more predictors (OR, 119; 95% CI, 16.6-833). One of 87 children with pelvic fractures had no predictors (1.1%; 95% CI, 0-3%). When assuming a 100% radiography rate, this tool saves 53% pelvic radiographs. CONCLUSION: Children with multiple blunt trauma without pain/abnormal examination result of the pelvis/hip, femur deformity, hematuria, abdominal pain/tenderness, GCS score of 13 or lower, or hemodynamic instability constitute a low-risk population for pelvic fracture, with less than 0.5% risk rate. This population does not require routine pelvic imaging. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 26496110 TI - Contact isolation is a risk factor for venous thromboembolism in trauma patients. AB - BACKGROUND: Contact isolation (CI) is a series of precautions used to prevent the transmission of medically significant infectious pathogens in the health care setting. Our institution's implementation of CI includes limiting patient movement to the assigned room. Our objective was to define the association between CI and venous thromboembolism (VTE) at our Level I trauma center. METHODS: Our institution's prospective trauma database was retrospectively queried for all patients admitted to the trauma service between January 1, 2011, and December 31, 2012. Data including demographics, Injury Severity Score (ISS), preexisting medical conditions, injury type, and VTE development were collected. CI status data were obtained from our institution's infection control database. chi2 was used to examine the unadjusted relationship between CI status and VTE. As the groups were not equivalent, logistic regression was then used to examine the relationship between CI and VTE while adjusting for relevant covariates including sex, age, ISS, and comorbidities. RESULTS: Of the 4,423 trauma patients admitted during the study period, 4,318 (97.6%) had complete records and were included in subsequent analyses. A total of 249 (5.8%) of the patients were on CI. VTE occurred in 44 patients (17.7%) on CI versus 141 patients (3.5%) who were not isolated (p < 0.0001; odds ratio, 6.0; 95% confidence interval, 4.1-8.6). With the use of lasso [least absolute shrinkage and selection operator] regression to adjust for patient risk factors, this relationship remained highly significant (p < 0.0001; odds ratio, 2.61; 95% confidence interval, 1.7-4.0). CONCLUSION: CI, ISS, hospital length of stay, and cardiac comorbidity were associated with VTE. After adjustment for other risk factors, CI remained most strongly associated with VTE. Although any medical intervention may come with unintended consequences, the risks and benefits of CI in this population need to be reevaluated. Further study is planned to identify opportunities to mitigate this increased VTE risk. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III; therapeutic study, level IV. PMID- 26496111 TI - Association of transfusion red blood cell storage age and blood oxygenation, long term neurologic outcome, and mortality in traumatic brain injury. AB - BACKGROUND: The effect of red blood cell (RBC) storage on oxygenation in critically ill patients is still unknown. The objective of this study was to determine the association of RBC storage with oxygenation, long-term neurologic recovery, and death after traumatic brain injury. METHODS: We used data from a 2 * 2 factorial randomized controlled trial of administration of erythropoietin or placebo and of assignment to transfusion threshold of less than 7g/dL or less than 10 g/dL in neurosurgical intensive care units in two US Level 1 trauma centers. Patients had severe traumatic brain injury with closed head injury, were unable to follow commands, and were enrolled within 6 hours of injury. Blood oxygenation 1 hour after the transfusion as measured by jugular venous oxygen saturation (n = 59) was the primary outcome. Secondary outcomes were brain tissue oxygenation (n = 77), 6-month Glasgow Outcome Scale (GOS) score (n = 122) collected using a structured interview and dichotomized into favorable (good recovery or moderate disability) or unfavorable outcome (severe disability, vegetative state, or dead), and mortality (n = 125). RBC age was defined as the maximum age of RBCs over all units in one transfusion per patient. For long-term outcomes, RBC age was defined as the mean age over all units given. RESULTS: We failed to detect an association of RBC age with jugular venous oxygen saturation (linear regression beta = 1.59; 95% confidence interval [CI], -2.99 to 6.18; p = 0.49), brain tissue oxygenation (linear regression beta = 0.20; 95% CI, -0.23 to 0.63; p = 0.36), GOS score (odds ratio, 1.37; 95% CI, 0.53-3.57; p = 0.52), and mortality (hazard ratio, 1.35; 95% CI, 0.61-2.98; p = 0.46). CONCLUSION: Limitations of this study include the fact that the RBC ages were not randomized, although this was a prospective study. We conclude that older blood does not seem to have adverse effects in severe traumatic brain injury. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 26496112 TI - Redefining "dead on arrival": Identifying the unsalvageable patient for the purpose of performance improvement. AB - BACKGROUND: Significant variation exists across registries in the criteria used to identify patients with no chance of survival, with potential for profound impact on trauma center mortality. The purpose of this study was to identify the optimal case definition for the unsalvageable patient, for the purpose of exclusion from performance improvement (PI) endeavors. METHODS: Data were derived from the American College of Surgeons' Trauma Quality Improvement Program for 2012 to 2013. We proposed three potential case definitions for the unsalvageable patient: (1) no signs of life as determined by local providers (NSOL), (2) prehospital cardiac arrest (PHCA), and (3) a proxy definition (PROXY) based on presenting vital signs, defined as emergency department (ED) heart rate = 0, ED systolic blood pressure = 0, and Glasgow Coma Scale score motor component = 1. Case definitions were compared using standard predictive tests to determine specificity and positive predictive value (PPV) for in-hospital mortality. After the optimal definition was identified, hierarchical logistic regression was used to assess the impact of including unsalvageable patients on trauma center risk adjusted mortality. The impact on trauma center performance was determined as change in outlier status and performance decile after exclusion of patients who met the optimal case definition. RESULTS: During the study period, 223,643 patients met inclusion criteria across 192 trauma centers. Overall in-hospital mortality was 7.2%. The PROXY definition had excellent PPV for death, with less than 1% of patients meeting the PROXY criterion surviving. By contrast, NSOL and PHCA had PPVs low enough such that many of these patients went on to live (33% and 10%, respectively). After exclusion of patients who met the PROXY definition, 7% of trauma centers changed performance decile. This change was greatest for patients with penetrating injury and shock, with change in performance decile at 23% and 33% of centers, respectively. CONCLUSION: The PROXY case definition has excellent predictive utility to identify patients who, based on presenting vital signs, will go on to die. PROXY should be used to exclude unsalvageable patients from PI endeavors. PMID- 26496113 TI - Inadequately marketing our brand: Medical student awareness of acute care surgery. AB - BACKGROUND: Despite focused national efforts to promote acute care surgery (ACS), little is known about medical student awareness of ACS as a career choice. The impending shortage of general surgeons emphasizes the need to increase interest in this comprehensive surgical specialty. The goal of this study was to determine whether students would be more likely to consider choosing ACS if they were aware of the specialty and its benefits. METHODS: A survey was distributed electronically to medical students at our institution, a Level I trauma center with an active ACS service. The survey asked questions regarding specialty choice and factors that were used in making that decision. Also included were questions regarding their familiarity and affinity for ACS. RESULTS: The survey was returned by 518 students. Each medical school year was proportionately represented. Twenty-one percent of the students reported surgery as their career choice; however, women were half as likely to choose surgery as men. When asked to define ACS, 23% of all students gave the correct response. Only 8.9% of the students in the preclinical years correctly defined ACS. Even in the clinical years, 54% were unaware of ACS as a specialty. Students reported that the top factors that influenced their choice were controllable lifestyle, predictable schedule, and a positive medical school role model. When asked to identify what would make ACS appealing, a 50-hour work week was deemed most influential. When given the definition of ACS with approximate pay and on-call hours, 41.5% of the students and 75% of those interested in surgery would be likely to choose ACS as a career. CONCLUSION: This study highlights that awareness of ACS as a specialty is lacking. This may reflect inadequate marketing of our "brand" both locally and nationally. Focused efforts at familiarizing students with ACS and increased role modeling may increase interest in ACS. PMID- 26496114 TI - Damage-control neurosurgery: Packing to halt relentless intracranial bleeding. AB - BACKGROUND: The objective of this study was to review the efficacy of intracranial packing as a means of tamponade for life-threatening intraoperative hemorrhage that was refractory to more common techniques for achieving hemostasis. METHODS: Neuroimaging and hospital records were reviewed for the seven adult patients who had experienced life-threateningly severe hemorrhage during intracranial surgery and in whom packing was used to control the bleeding. All packing was left in place at the time of closure and was removed when the patient's condition was considered safe for a second operation. RESULTS: Hemorrhage was successfully halted in all seven patients, and all survived their operations. Six were discharged from the hospital, but one patient with severe parenchymal injury from trauma and multiple medical comorbidities died on postoperative Day 2 after supportive care was withdrawn. Four had an improved Glasgow Outcome Scale (GOS) score at the time of last follow-up, and two of these improved from dependent to independent living. There were no postoperative intracranial or wound infections. CONCLUSION: Intracranial packing to tamponade severe intracranial hemorrhage can be a lifesaving neurosurgical maneuver. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 26496116 TI - A medical history of Governor John B. Connally and his gunshot wounds. AB - : On November 22, 1963, the Governor of Texas, John Connally, was injured during the assassination of President John F. Kennedy. Multiple authors have documented President Kennedy's injuries, the attempted resuscitation, and the controversies surrounding these events. However, the injuries sustained by Governor Connally have been overlooked by historians predominantly because of the extraordinary importance of the presidential assassination and its impact on the national consciousness. This review discusses the governor's political life, the mechanism of injury, his medical care, and the role the injuries had on his subsequent public life. PMID- 26496115 TI - Risk factors for the development of heterotopic ossification in seriously burned adults: A National Institute on Disability, Independent Living and Rehabilitation Research burn model system database analysis. AB - BACKGROUND: Heterotopic ossification (HO) is a debilitating complication of burn injury; however, incidence and risk factors are poorly understood. In this study, we use a multicenter database of adults with burn injuries to identify and analyze clinical factors that predict HO formation. METHODS: Data from six high volume burn centers, in the Burn Injury Model System Database, were analyzed. Univariate logistic regression models were used for model selection. Cluster adjusted multivariate logistic regression was then used to evaluate the relationship between clinical and demographic data and the development of HO. RESULTS: Of 2,979 patients in the database with information on HO that addressed risk factors for development of HO, 98 (3.5%) developed HO. Of these 98 patients, 97 had arm burns, and 96 had arm grafts. When controlling for age and sex in a multivariate model, patients with greater than 30% total body surface area burn had 11.5 times higher odds of developing HO (p < 0.001), and those with arm burns that required skin grafting had 96.4 times higher odds of developing HO (p = 0.04). For each additional time a patient went to the operating room, odds of HO increased by 30% (odds ratio, 1.32; p < 0.001), and each additional ventilator day increased odds by 3.5% (odds ratio, 1.035; p < 0.001). Joint contracture, inhalation injury, and bone exposure did not significantly increase odds of HO. CONCLUSION: Risk factors for HO development include greater than 30% total body surface area burn, arm burns, arm grafts, ventilator days, and number of trips to the operating room. Future studies can use these results to identify highest-risk patients to guide deployment of prophylactic and experimental treatments. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 26496117 TI - Casualty distribution in emergencies: Some critiques of load index model. PMID- 26496118 TI - Re: Casualties distribution in emergencies: Some critiques of load index model. PMID- 26496121 TI - Association of the Long Non-coding RNA Steroid Receptor RNA Activator (SRA) with TrxG and PRC2 Complexes. AB - Long non-coding RNAs (lncRNAs) have been recognized as key players in transcriptional regulation. We show that the lncRNA steroid receptor RNA activator (SRA) participates in regulation through complex formation with trithorax group (TrxG) and polycomb repressive complex 2 (PRC2) complexes. Binding of the SRA-associated RNA helicase p68 preferentially stabilizes complex formation between SRA and a TrxG complex but not PRC2. In human pluripotent stem cells NTERA2, SRA binding sites that are also occupied by p68 are significantly enriched for H3K4 trimethylation. Consistent with its ability to interact with TrxG and PRC2 complexes, some SRA binding sites in human pluripotent stem cells overlap with bivalent domains. CTCF sites associated with SRA appear also to be enriched for bivalent modifications. We identify NANOG as a transcription factor directly interacting with SRA and co-localizing with it genome-wide in NTERA2. Further, we show that SRA is important for maintaining the stem cell state and for reprogramming of human fibroblasts to achieve the pluripotent state. Our results suggest a mechanism whereby the lncRNA SRA interacts with either TrxG or PRC2. These complexes may then be recruited by various DNA binding factors to deliver either activating or silencing signals, or both, to establish bivalent domains. PMID- 26496122 TI - Signaling and Adaptation Modulate the Dynamics of the Photosensoric Complex of Natronomonas pharaonis. AB - Motile bacteria and archaea respond to chemical and physical stimuli seeking optimal conditions for survival. To this end transmembrane chemo- and photoreceptors organized in large arrays initiate signaling cascades and ultimately regulate the rotation of flagellar motors. To unravel the molecular mechanism of signaling in an archaeal phototaxis complex we performed coarse grained molecular dynamics simulations of a trimer of receptor/transducer dimers, namely NpSRII/NpHtrII from Natronomonas pharaonis. Signaling is regulated by a reversible methylation mechanism called adaptation, which also influences the level of basal receptor activation. Mimicking two extreme methylation states in our simulations we found conformational changes for the transmembrane region of NpSRII/NpHtrII which resemble experimentally observed light-induced changes. Further downstream in the cytoplasmic domain of the transducer the signal propagates via distinct changes in the dynamics of HAMP1, HAMP2, the adaptation domain and the binding region for the kinase CheA, where conformational rearrangements were found to be subtle. Overall these observations suggest a signaling mechanism based on dynamic allostery resembling models previously proposed for E. coli chemoreceptors, indicating similar properties of signal transduction for archaeal photoreceptors and bacterial chemoreceptors. PMID- 26496123 TI - Evaluating the Diagnostic Accuracy of Xpert MTB/RIF Assay in Pulmonary Tuberculosis. AB - Pulmonary tuberculosis still remains a major communicable disease worldwide. In 2013, 9 million people developed TB and 1.5 million people died from the disease. India constitutes 24% of the total TB burden. Early detection of TB cases is the key to successful treatment and reduction of disease transmission. Xpert MTB/RIF, an automated cartridge-based molecular technique detects Mycobacterium tuberculosis and rifampicin resistance within two hours has been endorsed by WHO for rapid diagnosis of TB. Our study is the first study from India with a large sample size to evaluate the performance of Xpert MTB/RIF assay in PTB samples. The test showed an overall sensitivity and specificity of 95.7% (430/449) and 99.3% (984/990) respectively. In smear negative-culture positive cases, the test had a sensitivity of 77.7%. The sensitivity and specificity for detecting rifampicin resistance was 94.5% and 97.7% respectively with respect to culture as reference standard. However, after resolving the discrepant samples with gene sequencing, the sensitivity and specificity rose to 99.0% and 99.3% respectively. Hence, while solid culture still forms the foundation of TB diagnosis, Xpert MTB/RIF proposes to be a strong first line diagnostic tool for pulmonary TB cases. PMID- 26496125 TI - Physiological Responses of a Model Marine Diatom to Fast pH Changes: Special Implications of Coastal Water Acidification. AB - Diatoms and other phytoplankton in coastal waters experience rapid pH changes in milieu due to high biological activities and/or upwelled CO2-rich waters. While CO2 concentrating mechanisms (CCMs) are employed by all diatoms tested to counter low CO2 availability in seawater, little is known how this mechanism responds to fast pH changes. In the present study, the model diatom Thalassiosira pseudonana was acclimated for 20 generations to low pH (7.81) at an elevated CO2 of 1000 MUatm (HC) or to high pH (8.18) at ambient CO2 levels of 390 MUatm (LC), then its physiological characteristics were investigated as cells were shifted from HC to LC or vice versa. The maximal electron transport rate (ETRmax) in the HC acclimated cells was immediately reduced by decreased CO2 availability, showing much lower values compared to that of the LC-acclimated cells. However, the cells showed a high capacity to regain their photochemical performance regardless of the growth CO2 levels, with their ETRmax values recovering to initial levels in about 100 min. This result indicates that this diatom might modulate its CCMs quickly to maintain a steady state supply of CO2, which is required for sustaining photosynthesis. In addition, active uptake of CO2 could play a fundamental role during the induction of CCMs under CO2 limitation, since the cells maintained high ETR even when both intracellular and periplasmic carbonic anhydrases were inhibited. It is concluded that efficient regulation of the CCM is one of the key strategies for diatoms to survive in fast changing pH environment, e.g. for the tested species, which is a dominant species in coastal waters where highly fluctuating pH is observed. PMID- 26496124 TI - Community Participation in Health Systems Research: A Systematic Review Assessing the State of Research, the Nature of Interventions Involved and the Features of Engagement with Communities. AB - BACKGROUND: Community participation is a major principle of people centered health systems, with considerable research highlighting its intrinsic value and strategic importance. Existing reviews largely focus on the effectiveness of community participation with less attention to how community participation is supported in health systems intervention research. OBJECTIVE: To explore the extent, nature and quality of community participation in health systems intervention research in low- and middle-income countries. METHODOLOGY: We searched for peer-reviewed, English language literature published between January 2000 and May 2012 through four electronic databases. Search terms combined the concepts of community, capability/participation, health systems research and low- and middle-income countries. The initial search yielded 3,092 articles, of which 260 articles with more than nominal community participation were identified and included. We further excluded 104 articles due to lower levels of community participation across the research cycle and poor description of the process of community participation. Out of the remaining 160 articles with rich community participation, we further examined 64 articles focused on service delivery and governance within health systems research. RESULTS: Most articles were led by authors in high income countries and many did not consistently list critical aspects of study quality. Articles were most likely to describe community participation in health promotion interventions (78%, 202/260), even though they were less participatory than other health systems areas. Community involvement in governance and supply chain management was less common (12%, 30/260 and 9%, 24/260 respectively), but more participatory. Articles cut across all health conditions and varied by scale and duration, with those that were implemented at national scale or over more than five years being mainstreamed by government. Most articles detailed improvements in service availability, accessibility and acceptability, with fewer efforts focused on quality, and few designs able to measure impact on health outcomes. With regards to participation, most articles supported community's in implementing interventions (95%, n = 247/260), in contrast to involving communities in identifying and defining problems (18%, n = 46/260). Many articles did not discuss who in communities participated, with just over a half of the articles disaggregating any information by sex. Articles were largely under theorized, and only five mentioned power or control. Majority of the articles (57/64) described community participation processes as being collaborative with fewer describing either community mobilization or community empowerment. Intrinsic individual motivations, community-level trust, strong external linkages, and supportive institutional processes facilitated community participation, while lack of training, interest and information, along with weak financial sustainability were challenges. Supportive contextual factors included decentralization reforms and engagement with social movements. CONCLUSION: Despite positive examples, community participation in health systems interventions was variable, with few being truly community directed. Future research should more thoroughly engage with community participation theory, recognize the power relations inherent in community participation, and be more realistic as to how much communities can participate and cognizant of who decides that. PMID- 26496126 TI - Association Analysis of the Reticulon 1 Gene in End-Stage Kidney Disease. AB - BACKGROUND: The reticulon 1 gene (RTN1) encodes reticulons, endoplasmic reticulum stress proteins recently implicated in kidney disease progression. METHODS: RTN1 single nucleotide polymorphisms (SNPs) were tested for association with type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) in African Americans (AAs) and European Americans (EAs), and AAs with non-diabetic ESKD. RTN1 SNPs that were associated with T2D-ESKD in AA cases compared to non-nephropathy controls were identified from a discovery genome-wide association study (n=1,797), then tested for replication in 1,847 additional AA T2D-ESKD cases and controls. RESULTS: Three intronic RTN1 variants were nominally associated with T2D-ESKD in both discovery and replication analyses: rs1952034, rs12431381 and rs12434215 (additive models); combined T2D-ESKD (discovery+replication) p values were 0.015-3.0*10(-4) (ORs 0.67-0.77; minor alleles protective). In addition, rs12434215 was weakly associated with T2D-ESKD in 557 EA T2D-ESKD cases contrasted with 753 EA non-nephropathy controls (p=0.019; OR 0.69, dominant model). Nominal association extended to non-diabetic causes of ESKD in 1,459 additional AA cases (rs12431381 and rs12434215 p values 0.014-0.015; OR 0.77). An all-cause ESKD association analysis contrasted the 3,594 AA ESKD cases with 1,489 AA non-nephropathy controls and detected association with rs12434215 (p=6.7*10( 4), OR 0.73) and rs12431381 (p=7.5*10(-4), OR 0.75) in dominant models. Of the 3 SNPs, only rs12434215 was weakly associated with T2D per se when contrasting T2D non-nephropathy cases with non-diabetic controls (additive model p=0.032 AAs; p=0.048 EAs). CONCLUSIONS: These results suggest evidence of genetic association between common variants in RTN1 and ESKD in AAs and EAs. PMID- 26496127 TI - Climate Change and Crop Exposure to Adverse Weather: Changes to Frost Risk and Grapevine Flowering Conditions. AB - The cultivation of grapevines in the UK and many other cool climate regions is expected to benefit from the higher growing season temperatures predicted under future climate scenarios. Yet the effects of climate change on the risk of adverse weather conditions or events at key stages of crop development are not always captured by aggregated measures of seasonal or yearly climates, or by downscaling techniques that assume climate variability will remain unchanged under future scenarios. Using fine resolution projections of future climate scenarios for south-west England and grapevine phenology models we explore how risks to cool-climate vineyard harvests vary under future climate conditions. Results indicate that the risk of adverse conditions during flowering declines under all future climate scenarios. In contrast, the risk of late spring frosts increases under many future climate projections due to advancement in the timing of budbreak. Estimates of frost risk, however, were highly sensitive to the choice of phenology model, and future frost exposure declined when budbreak was calculated using models that included a winter chill requirement for dormancy break. The lack of robust phenological models is a major source of uncertainty concerning the impacts of future climate change on the development of cool climate viticulture in historically marginal climatic regions. PMID- 26496128 TI - Hierarchical macroscopic fibrillar adhesives: in situ study of buckling and adhesion mechanisms on wavy substrates. AB - Nature uses hierarchical fibrillar structures to mediate temporary adhesion to arbitrary substrates. Such structures provide high compliance such that the flat fibril tips can be better positioned with respect to asperities of a wavy rough substrate. We investigated the buckling and adhesion of hierarchically structured adhesives in contact with flat smooth, flat rough and wavy rough substrates. A macroscopic model for the structural adhesive was fabricated by molding polydimethylsiloxane into pillars of diameter in the range of 0.3-4.8 mm, with up to three different hierarchy levels. Both flat-ended and mushroom-shaped hierarchical samples buckled at preloads one quarter that of the single level structures. We explain this behavior by a change in the buckling mode; buckling leads to a loss of contact and diminishes adhesion. Our results indicate that hierarchical structures can have a strong influence on the degree of adhesion on both flat and wavy substrates. Strategies are discussed that achieve highly compliant substrates which adhere to rough substrates. PMID- 26496130 TI - Review of in situ derivatization techniques for enhanced bioanalysis using liquid chromatography with mass spectrometry. AB - Accurate and specific analysis of target molecules in complex biological matrices remains a significant challenge, especially when ultra-trace detection limits are required. Liquid chromatography with mass spectrometry is often the method of choice for bioanalysis. Conventional sample preparation and clean-up methods prior to the analysis of biological fluids such as liquid-liquid extraction, solid-phase extraction, or protein precipitation are time-consuming, tedious, and can negatively affect target recovery and detection sensitivity. An alternative or complementary strategy is the use of an off-line or on-line in situ derivatization technique. In situ derivatization can be incorporated to directly derivatize target analytes in their native biological matrices, without any prior sample clean-up methods, to substitute or even enhance the extraction and preconcentration efficiency of these traditional sample preparation methods. Designed appropriately, it can reduce the number of sample preparation steps necessary prior to analysis. Moreover, in situ derivatization can be used to enhance the performance of the developed liquid chromatography with mass spectrometry-based bioanalysis methods regarding stability, chromatographic separation, selectivity, and ionization efficiency. This review presents an overview of the commonly used in situ derivatization techniques coupled to liquid chromatography with mass spectrometry-based bioanalysis to guide and to stimulate future research. PMID- 26496129 TI - The Effect of Hygiene-Based Lymphedema Management in Lymphatic Filariasis-Endemic Areas: A Systematic Review and Meta-analysis. AB - BACKGROUND: Lymphedema of the leg and its advanced form, known as elephantiasis, are significant causes of disability and morbidity in areas endemic for lymphatic filariasis (LF), with an estimated 14 million persons affected worldwide. The twin goals of the World Health Organization's Global Program to Eliminate Lymphatic Filariasis include interrupting transmission of the parasitic worms that cause LF and providing care to persons who suffer from its clinical manifestations, including lymphedema-so-called morbidity management and disability prevention (MMDP). Scaling up of MMDP has been slow, in part because of a lack of consensus about the effectiveness of recommended hygiene-based interventions for clinical lymphedema. METHODS AND FINDINGS: We conducted a systemic review and meta-analyses to estimate the effectiveness of hygiene-based interventions on LF-related lymphedema. We systematically searched PubMed, Embase, ISI Web of Knowledge, MedCarib, Lilacs, REPIDISCA, DESASTRES, and African Index Medicus databases through March 23, 2015 with no restriction on year of publication. Studies were eligible for inclusion if they (1) were conducted in an area endemic for LF, (2) involved hygiene-based interventions to manage lymphedema, and (3) assessed lymphedema-related morbidity. For clinical outcomes for which three or more studies assessed comparable interventions for lymphedema, we conducted random-effects meta-analyses. Twenty-two studies met the inclusion criteria and two meta-analyses were possible. To evaluate study quality, we developed a set of criteria derived from the GRADE methodology. Publication bias was assessed using funnel plots. Participation in hygiene-based lymphedema management was associated with a lower incidence of acute dermatolymphagioadenitis (ADLA), (Odds Ratio 0.32, 95% CI 0.25-0.40), as well as with a decreased percentage of patients reporting at least one episode of ADLA during follow-up (OR 0.29, 95% CI 0.12-0.47). Limitations included high heterogeneity across studies and variation in components of lymphedema management. CONCLUSIONS: Available evidence strongly supports the effectiveness of hygiene-based lymphedema management in LF-endemic areas. Despite the aforementioned limitations, these findings highlight the potential to significantly reduce LF-associated morbidity and disability as well as the need to develop standardized approaches to MMDP in LF-endemic areas. PMID- 26496132 TI - In response: challenges for statistical evaluation of ecotoxicological experiments--an industry perspective. PMID- 26496131 TI - Fish consumption as a driver of risk-management decisions and human health-based water quality criteria. AB - The use and interpretation of fish consumption surveys and interviews, the application of fish consumption rates for sediment evaluation and cleanup, and the development of human health water quality criteria (HH WQC) are complex and interrelated issues. The present article focuses on these issues using examples from the United States, although the issues may be relevant for other countries. Some key considerations include the fact that there are many types of fish consumption surveys (e.g., 24-h recall surveys, food frequency questionnaires, creel surveys), and these surveys have different advantages and limitations. Identification of target populations for protection, identification of the species and quantities of fish consumed, and determination of bioaccumulation assumptions are important factors when developing water quality and sediment screening levels and standards. Accounting for the cultural importance of fish consumption for some populations is an even more complex element. Discussions about HH WQC often focus only on the fish consumption rate and may not have broad public input. Some states are trying to change this through extensive public participation efforts and use of probabilistic approaches to derive HH WQC. Finally, there are limits to what WQC can achieve. Solutions beyond the establishment of WQC that target toxics reduction from other sources may provide the greatest improvements to water quality and reductions in human health risks in the future. PMID- 26496133 TI - The challenge: statistical challenges in ecotoxicology. PMID- 26496134 TI - In response: regression or significance tests: what other choice is there?--an academic perspective. PMID- 26496135 TI - In response: biological arguments for selecting effect sizes in ecotoxicological testing--a governmental perspective. PMID- 26496136 TI - In response: some species sensitivity distribution statistics revisited--a governmental perspective. PMID- 26496137 TI - In response: challenges when weighing evidence about environmental risks--an industry perspective. PMID- 26496138 TI - In response: benefits of the ARRIVE guidelines for improving scientific reporting in ecotoxicology--an academic perspective. PMID- 26496140 TI - Center-Based Quality Initiative Targets Youth Preparedness for Medical Independence: HEMO-Milestones Tool in a Comprehensive Hemophilia Clinic Setting. AB - BACKGROUND: Patient transition readiness self-assessment tools and investigation into patient and parent perceptions of the transition process from pediatric to adult care models have informed recognition of gaps in care, particularly for those with chronic disease. Implementation of a longitudinal transition process with patient tracking provides the opportunity for individualized education and skill building and fosters a patient-centered model. PROCEDURE: Quality improvement intervention was used to assess and improve our transition process at annual comprehensive clinic visits for patients with bleeding disorders at our tertiary care pediatric center. RESULTS: Thirty-one patients with rare bleeding disorders received an introduction to the transition process using the HEMO milestones tool in our hemophilia comprehensive clinic from September to December 2014. The percentage of patients with documented, age-specific hemophilia knowledge/skill assessment increased from 21% to 97%. The percentage of patients with documented skill building or adult care transfer plan increased from 55% to 93%. Designated postclinic team debriefings facilitated the creation of collaborative documentation summarizing each patient's transition readiness and plan for continued skill building. CONCLUSIONS: The HEMO-milestones tool promotes a standardized approach to evaluation of self-management competency. When combined with a collaborative multidisciplinary effort, it increases plans for skill building in patients with hemophilia. This tool is easily modifiable for alternate subspecialty use and does not require extensive training for implementation. PMID- 26496141 TI - Effects of Laughter Therapy on Immune Responses in Postpartum Women. AB - OBJECTIVE: To examine the effects of laughter therapy on secretory IgA (sIgA) in postpartum women. METHODS: The study used a nonequivalent control group with nonsynchronized design. The participants were 76 postpartum women who agreed to participate in this study and were selected by convenience sampling (experimental group, n = 38; control group, n = 38). The data were collected from December 15, 2009, to April 8, 2010. The experimental group participated in a postpartum laughter program from a laughter therapy expert for 60 minutes per session, twice a week for 2 weeks, for a total of four sessions. To evaluate the effects of the postpartum laughter program, sIgA levels in breast milk were measured. The data were analyzed using SPSS WIN 20.0 software. RESULTS: Immune response (sIgA) significantly differed between the experimental and control groups. CONCLUSION: A postpartum laughter program can be applied as a complementary and alternative intervention to postpartum women in a transitional mother-infant care center. PMID- 26496142 TI - Free p-Cresol Alters Neutrophil Function in Dogs. AB - To achieve a clearer understanding of the mechanisms responsible for neutrophil dysfunction recently described in dogs with chronic renal failure (CRF), the plasma concentrations of free p-cresol in healthy dogs (n = 20) and those with CRF (n = 20) were compared. The degree of correlation was determined between plasma levels of p-cresol and markers of oxidative stress and function of neutrophils in these dogs. The effect of this compound on oxidative metabolism and apoptosis was assessed in neutrophils isolated from 16 healthy dogs incubated in RPMI 1640 supplemented with p-cresol (0.405 mg/L) and compared with medium supplemented with uremic plasma (50%). To achieve this, the plasma concentration of p-cresol was quantified by liquid phase high-performance liquid chromatography. The neutrophil oxidative metabolism was determined using the probes hydroethidine and 2',7'-dichlorofluorescein diacetate and apoptosis was measured using Annexin V-PE by capillary flow cytometry. Compared with the healthy dogs, uremic dogs presented higher concentrations of free p-cresol, greater oxidative stress, and neutrophils primed for accelerated apoptosis. The free p-cresol induced in neutrophils from healthy dogs increased apoptosis and decreased reactive oxygen species production. We conclude that the health status presented during uremia concomitant with the increase in plasma free p-cresol can contribute to the presence of immunosuppression in dogs with CRF. PMID- 26496143 TI - The association of nurse practitioners' mortality risk assessments and advance care planning discussions on nursing home patients' clinical outcomes. AB - PURPOSE: To investigate the impact nurse practitioners' (NPs) documented mortality risk assessments (MRAs) and advance care planning (ACP) discussions have on clinical outcomes for newly enrolled Medicare Advantage nursing home patients. METHODS: Data collection in this mixed-method study consisted of quantitative data from a convenience sample of NPs' MRAs and medical record reviews 6 months later, and qualitative data from two NP focus groups. Quantitative analyses include descriptive statistics, bivariate ANOVA, and logistic regression. The qualitative content analysis included an iterative process of rereading transcribed notes, identifying codes, themes and significant statements. CONCLUSIONS: MRAs prioritize ACP discussions with patients/families (p = .0258). Positive clinical outcomes following ACP discussions include more patients with a comfort goal of care (86% increase), fewer patients with a full code status (26% reduction), and a reduction in hospitalizations (p = .025). NPs agreed that ACP discussions have a positive impact on patient outcomes including a "good death." IMPLICATIONS FOR PRACTICE: MRAs and ACP discussions are beneficial to achieving better outcomes and fewer hospitalizations. Opportunity exists to further develop policy changes focused on enhancing the NPs' role in MRAs and ACP discussions with nursing home patients and families. PMID- 26496145 TI - To Replay, Perchance to Consolidate. AB - After a memory is formed, it continues to be processed by the brain. These "off line" processes consolidate the memory, leading to its enhancement and to changes in memory circuits. Potentially, these memory changes are driven by off-line replay of the pattern of neuronal activity present when the memory was being formed. A new study by Dhaksin Ramanathan and colleagues, published in PLOS Biology, demonstrates that replay occurs predominately after the acquisition of a new motor skill and that it is related to changes in memory performance and to the subsequent changes in memory circuits. Together, these observations reveal the importance of neuronal replay in the consolidation of novel motor skills. PMID- 26496144 TI - Controlling the cytokine storm in severe bacterial diarrhoea with an oral Toll like receptor 4 antagonist. AB - Shigella dysenteriae causes the most severe of all infectious diarrhoeas and colitis. We infected rhesus macaques orally and also treated them orally with a small and non-absorbable polypropyletherimine dendrimer glucosamine that is a Toll-like receptor-4 (TLR4) antagonist. Antibiotics were not given for this life threatening infection. Six days later, the clinical score for diarrhoea, mucus and blood was 54% lower, colon interleukin-8 and interleukin-6 were both 77% lower, and colon neutrophil infiltration was 75% less. Strikingly, vasculitis did not occur and tissue fibrin thrombi were reduced by 67%. There was no clinical toxicity or adverse effect of dendrimer glucosamine on systemic immunity. This is the first report in non-human primates of the therapeutic efficacy of a small and orally bioavailable TLR antagonist in severe infection. Our results show that an oral TLR4 antagonist can enable controlled resolution of the infection-related inflammatory response and can also prevent neutrophil-mediated gut wall necrosis in severe infectious diarrhoeas. PMID- 26496146 TI - Left ventricular atrioventricular plane displacement is preserved with lifelong endurance training and is the main determinant of maximal cardiac output. AB - Age-related decline in cardiac function can be prevented or postponed by lifelong endurance training. However, effects of normal ageing as well as of lifelong endurance exercise on longitudinal and radial contribution to stroke volume are unknown. The aim of this study was to determine resting longitudinal and radial pumping in elderly athletes, sedentary elderly and young sedentary subjects. Furthermore, we aimed to investigate determinants of maximal cardiac output in elderly. Eight elderly athletes (63 +/- 4 years), seven elderly sedentary (66 +/- 4 years) and ten young sedentary subjects (29 +/- 4 years) underwent cardiac magnetic resonance imaging. All subjects underwent maximal exercise testing and for elderly subjects maximal cardiac output during cycling was determined using a dye dilution technique. Longitudinal and radial contribution to stroke volume did not differ between groups (longitudinal left ventricle (LV) 52-65%, P = 0.12, right ventricle (RV) 77-87%, P = 0.16, radial 7.9-8.6%, P = 1.0). Left ventricular atrioventricular plane displacement (LVAVPD) was higher in elderly athletes and young sedentary compared with elderly sedentary subjects (14 +/- 3, 15 +/- 2 and 11 +/- 1 mm, respectively, P < 0.05). There was no difference between groups for RVAVPD (P = 0.2). LVAVPD was an independent predictor of maximal cardiac output (R(2) = 0.61, P < 0.01, beta = 0.78). Longitudinal and radial contributions to stroke volume did not differ between groups. However, how longitudinal pumping was achieved differed; elderly athletes and young sedentary subjects showed similar AVPD whereas this was significantly lower in elderly sedentary subjects. Elderly sedentary subjects achieved longitudinal pumping through increased short-axis area of the ventricle. Large AVPD was a determinant of maximal cardiac output and exercise capacity. PMID- 26496147 TI - Chemokine receptor expression on monocytes from healthy individuals. AB - Chronic immune mediated inflammation is characterized by continuous chemokine mediated recruitment and activation of pro-inflammatory cells, monocytes in particular. We believe that an evaluation of the recruitment profile of monocytes during healthy condition is essential for the understanding of cellular response in disease. For this, we have established normal reference values and 95% confidence intervals for receptor expression of 20 chemokine receptors on monocyte subsets; classical (CD14+ CD16-), non-classical (CD14+ CD16+) and HLA DRhi monocytes from 20 healthy controls using flow cytometry. We demonstrate significant differences in the chemokine receptor expression profiles and high correlation between fraction of cells and level of expression. This is the first global approach to provide a platform for comparable evaluation of cell recruitment during normal and under inflammatory conditions. This will be useful when exploring chemokine-chemokine receptor interactions, inhibition of chemokine signaling and selective removal of migrating cells, which are new treatment strategies in immune mediated diseases. PMID- 26496149 TI - "Unique choline-containing phosphoglycolipids in Mycoplasma fermentans". PMID- 26496148 TI - Olfactory learning skews mushroom body output pathways to steer behavioral choice in Drosophila. AB - Learning permits animals to attach meaning and context to sensory stimuli. How this information is coded in neural networks in the brain, and appropriately retrieved and utilized to guide behavior, is poorly understood. In the fruit fly olfactory memories of particular value are represented within sparse populations of odor-activated Kenyon cells (KCs) in the mushroom body ensemble. During learning reinforcing dopaminergic neurons skew the mushroom body network by driving zonally restricted plasticity at synaptic junctions between the KCs and subsets of the overall small collection of mushroom body output neurons. Reactivation of this skewed KC-output neuron network retrieves memory of odor valence and guides appropriate approach or avoidance behavior. PMID- 26496150 TI - Reprint of: "Synthetic lipids and their role in defining macromolecular assemblies". AB - Lipids have a variety of physiological roles, ranging from structural and biophysical contributions to membrane functions to signaling contributions in normal and abnormal physiology. This review highlights some of the contributions made by Robert Bittman to our understanding of lipid assemblies through the production of synthetic lipid analogs in the sterol, sphingolipid, and glycolipid classes. His contributions have included the development of a fluorescent cholesterol analog that shows strong functional analogies to cholesterol that has allowed live imaging of cholesterol distribution in living systems, to stereospecific synthetic approaches to both sphingolipid and glycolipid analogs crucial in defining the structure-activity relationships of lipid biological targets. PMID- 26496151 TI - "Pulmonary Endothelial Cell Barrier Enhancement by Novel FTY720 Analogs: Methoxy FTY720, Fluoro-FTY720, and beta-Glucuronide-FTY720". AB - Effective therapeutic agents are lacking for the prevention and reversal of vascular leak, a frequent pathophysiologic result of inflammatory processes such as acute respiratory distress syndrome (ARDS) and sepsis. We previously demonstrated the potent barrier-enhancing effects of related compounds sphingosine 1-phosphate (S1P), the pharmaceutical agent FTY720, and its analog (S)-FTY720 phosphonate (Tys) in models of inflammatory lung injury. In this study, we characterize additional novel FTY720 analogs for their potential to reduce vascular leak as well as utilize them as tools to better understand the mechanisms by which this class of agents modulates permeability. Transendothelial resistance (TER) and labeled dextran studies demonstrate that (R)-methoxy-FTY720 ((R)-OMe-FTY), (R)/(S)-fluoro-FTY720 (FTY-F), and beta-glucuronide-FTY720 (FTY-G) compounds display in vitro barrier-enhancing properties comparable or superior to FTY720 and S1P. In contrast, the (S)-methoxy-FTY720 ((S)-OMe-FTY) analog disrupts lung endothelial cell (EC) barrier integrity in TER studies in association with actin stress fiber formation and robust intracellular calcium release, but independent of myosin light chain or ERK phosphorylation. Additional mechanistic studies with (R)-OMe-FTY, FTY-F, and FTY-G suggest that lung EC barrier enhancement is mediated through lipid raft signaling, Gi-linked receptor coupling to downstream tyrosine phosphorylation events, and S1PR1-dependent receptor ligation. These results provide important mechanistic insights into modulation of pulmonary vascular barrier function by FTY720-related compounds and highlight common signaling events that may assist the development of novel therapeutic tools in the prevention or reversal of the pulmonary vascular leak that characterizes ARDS. PMID- 26496152 TI - "Endocytic pH regulates cell surface localization of glycolipid antigen loaded CD1d complexes". AB - Invariant natural killer T (iNKT) cells recognize glycolipid antigens presented by CD1d, an antigen presenting protein structurally similar to MHC class I. Stimulation of iNKT cells by glycolipid antigens can induce strong immune responses in vivo, with rapid production of a wide variety of cytokines including those classically associated with either T helper type 1 (Th1) or type 2 (Th2) responses. Alterations in the lipid tails or other portions of CD1d-presented glycolipid ligands can bias the iNKT response towards production of predominantly Th1 or Th2 associated cytokines. However, the mechanism accounting for this structure-activity relationship remains controversial. The Th1-biasing glycolipids have been found to consistently form complexes with CD1d that preferentially localize to plasma membrane cholesterol rich microdomains (lipid rafts), whereas CD1d complexes formed with Th2-biasing ligands are excluded from these microdomains. Here we show that neutralization of endosomal pH enhanced localization of CD1d complexes containing Th2-biasing glycolipids to plasma membrane lipid rafts of antigen presenting cells (APC). Transfer of APCs presenting these "stabilized" CD1d/alphaGC complexes into mice resulted in immune responses with a more prominent Th1-like bias, characterized by increased NK cell transactivation and interferon-gamma production. These findings support a model in which low endosomal pH controls stability and lipid raft localization of CD1d glycolipid complexes to regulate the outcome of iNKT cell mediated responses. PMID- 26496153 TI - Outdoor air pollution exposures and micronuclei frequencies in lymphocytes from pregnant women and newborns in Crete, Greece (Rhea cohort). AB - BACKGROUND: Micronuclei (MN) are biomarkers of early genetic effects that have been used to investigate the association between environmental exposures and cancer. However, few studies have examined the association between environmental exposures during pregnancy and MN in mothers and newborns. OBJECTIVES: We examined MN frequency in maternal blood and in cord blood, in relation to maternal air pollution exposure, and the potential interaction with maternal vitamin C intake and maternal smoking. METHODS: We used the cytokinesis-block micronucleus assay to assess MN frequency per 1000 bi-nucleated T-lymphocytes from 181 mothers and 183 newborns born in 2007-2008 in Heraklion (Crete, Greece). The ESCAPE land-use regression methods were used to estimate annual mean exposure to outdoor air pollution [particulate matter (PM), black carbon, nitrogen dioxide (NO2) and nitrogen oxides (NOx)] at maternal home addresses. Food frequency questionnaires were used to estimate maternal dietary vitamin C intake during pregnancy. Smoking habits were self-reported using questionnaires which were checked by measuring maternal urinary cotinine levels. RESULTS: Exposure to PM2.5 was associated with increased MN frequencies in pregnant women [rate ratio [RR (95%CI)] per 5 ug/m(3)=1.53 (1.02, 2.29)]. This increase was considerably higher among women who did not fulfill the recommended vitamin C dietary allowances [RR=9.35 (2.77, 31.61); n=20]. Exposure to PM2.5-10, PM10, NO2 and NOx were also associated with a higher incidence of MN frequencies in smoker women (n=56). No associations were found for newborns. CONCLUSIONS: We found an association between air pollution, particularly PM2.5, and MN frequency in mothers but not in newborns. This association was more pronounced among women with a lower dietary intake of vitamin C during pregnancy and among women who smoked during pregnancy. While results are clear in mothers, the association between maternal carcinogenic exposures during pregnancy and biomarkers of early biologic effect in the newborn remains poorly understood. PMID- 26496154 TI - Effect of electrical stimulation and hot boning on the eating quality of Gannan yak longissimus lumborum. AB - The objective of this study was to evaluate the effects of electrical stimulation (ES) versus non-electrical stimulation (NES) and type of boning (hot versus cold) on the eating quality of Gannan yak longissimus lumborum. Eighteen Gannan yak bulls were randomly divided into two groups: ES and NES. Hot boning (HB) and cold boning (CB) were applied to the left and right side of the carcasses, respectively. All of the four treatments missed the "ideal" pH/temperature window. HB reduced the rate of pH decline, decreased meat tenderness and water holding capacity. ES increased the rate of pH decline and improved yak meat tenderness (P<0.05); however, ES explained only 1% of the variation in WBSF. HB and ES had no significant effects on cooking loss, L* or b* values of yak meat. Postmortem aging increased yak meat tenderness and improved meat color parameters. HB had negative effects on yak meat quality, while ES could not reverse these deleterious effects. PMID- 26496155 TI - The possible role of virus-specific CD8(+) memory T cells in decidual tissue. AB - The most abundant lymphocyte present in decidual tissue is the CD8(+) T cell. It has been shown that most decidual CD8(+) T cells have an effector-memory phenotype, but expressed reduced levels of perforin and granzyme B compared with the peripheral CD8(+) effector-memory T cells. The specificity of these CD8(+) memory T cells has yet to be determined. One hypothesis is that the decidual memory T cells are virus-specific T cells that should protect the fetus against incoming pathogens. As virus-specific CD8(+) memory T cells can cross-react with human leukocyte alloantigens, an alternative, but not mutually exclusive, hypothesis is that these CD8(+) T cells are fetus-specific. Using virus-specific tetramers, we found increased percentages of virus-specific CD8(+) T cells in decidual tissue compared with peripheral blood after uncomplicated pregnancy. So far, no evidence has been obtained for a cross-reactive response of these virus specific T cells to fetal human leukocyte antigens. These results suggest that the virus-specific memory T cells accumulate in the placenta to protect the fetus from a harmful infection. PMID- 26496156 TI - What is the antiviral potential of pyrrole-imidazole polyamides? PMID- 26496157 TI - Design Rules for Fluorocarbon-Free Omniphobic Solvent Barriers in Paper-Based Devices. AB - The utility of hydrophobic wax barriers in paper-based lateral flow and multiwell devices for containment of aqueous solvents was extended to organic solvents and challenging aqueous surfactant solutions by preparation of a three layer barrier, consisting of internal pullulan impregnated paper barriers surrounded by external wax barriers. When paper impregnated with pullulan solution dries, the polymer forms solvent blocking lenses in the paper structure. Lens formation was illustrated by forming pullulan lenses in glass capillaries. The lens shapes were less curved compared to the predictions of a model based upon minimizing surface area. For barriers on Whatman # 1 filter paper, the pullulan molecular weight must be greater than ~70 kDa, the mass fraction of pullulan in the barrier zone must be at least 32%, and there are restrictions on the minimum width of the pullulan impregnated zone. PMID- 26496158 TI - Intramolecular Friedel-Crafts Acylation Reaction Promoted by 1,1,1,3,3,3 Hexafluoro-2-propanol. AB - Simple dissolution of an arylalkyl acid chloride in 1,1,1,3,3,3-hexafluoro-2 propanol promotes an intramolecular Friedel-Crafts acylation without additional catalysts or reagents. This reaction is operationally trivial in both execution and product isolation (only requiring concentration followed by purification) and accommodates a broad range of substrates. Preliminary studies that bear upon potential reaction mechanisms are reported. PMID- 26496159 TI - Malachite green and chloramphenicol in aquatic products from regions around Dongting Lake in Hunan, China. AB - Aquatic products are important sources of animal proteins in human diet, especially in developing countries. As such, the safety of aquatic products is of primary concern. In this study, a standard method is used to detect malachite green (MG) and chloramphenicol (CAP) and to analyse the contents of these banned chemicals in turtle, mandarin fish and grass carp sampled from the region surrounding Dongting Lake area in Hunan, China. Results showed that 10.6% of the samples were MG-positive, most of them turtles. CAP was found in 8.3% of the samples, mostly in mandarin fish. These data indicated that these banned substances are still used in the surveyed area. Hence, adequate strategies must be implemented by the local government to control these banned substances. PMID- 26496161 TI - Editorial: Treatment of metastatic spine disease with selective intraarterial chemotherapy. PMID- 26496160 TI - Effects of a cognitive stimulation program on psychological well-being in a sample of elderly long-term care hospital inpatients. AB - OBJECTIVES: The primary objective of this work is to report the observed changes in psychological well-being in a sample of long-term medically hospitalized patients, after attending a cognitive stimulation program. The secondary aim is to determine if the observed changes were related to previous cognitive level. METHODS: Inclusion criteria for study participation were to be a long-term care hospital inpatient, to be 65 years old or older, and to be cognitively preserved or with mild cognitive impairment. A total of 176 participants were included and distributed in two groups: Cognitive Stimulation Group (N = 123) and Non Cognitive Stimulation Group (N = 53). Measures were applied just before the beginning of the program and just when it finished, two months later. Participants of the Non-Cognitive Stimulation Group were re-assessed again after two months. RESULTS: No differences were found between the two groups in the measures assessed at baseline. After treatment, participants of the Cognitive Stimulation Group improved significantly more in psychological well-being (p < .001) than the ones of the Non-Cognitive Stimulation Group. When unimpaired and mild cognitively impaired participants of the Cognitive Stimulation Group were studied separately, both groups improved their psychological well-being, but the unimpaired experienced a greater effect. CONCLUSION: Cognitive stimulation plays a role in the improvement of psychological well-being of elderly medically hospitalized patients unimpaired or with mild cognitive impairment. The improvements in psychological well-being were related to the previous cognitive status and to the number of sessions that had been attended. PMID- 26496162 TI - Spinal intraarterial chemotherapy: interim results of a Phase I clinical trial. AB - OBJECT Despite advances in therapies using radiation oncology and spinal oncological surgery, there is a subgroup of patients with spinal metastases who suffer from progressive or recurrent epidural disease and remain at risk for neurological compromise. In this paper the authors describe their initial experience with a novel therapeutic approach that consists of intraarterial (IA) infusion of chemotherapy to treat progressive spinal metastatic disease. METHODS The main inclusion criterion was the presence of progressive, metastatic epidural disease to the spine causing spinal canal compromise in patients who were not candidates for the standard treatments of radiation therapy and/or surgery. All tumor histological types were eligible for this trial. Using the transfemoral arterial approach and standard neurointerventional techniques, all patients were treated with IA infusion of melphalan in the arteries supplying the epidural tumor. The protocol allowed for up to 3 procedures repeated at 3- to 6-week intervals. Outcome measures included physiological measures: 1) periprocedural complications according to the National Cancer Institute's Common Terminology Criteria for Adverse Events; and 2) MRI to assess for tumor response. RESULTS Nine patients with progressive spinal metastatic disease and cord compression were enrolled in a Phase I clinical trial of selective IA chemotherapy. All patients had metastatic disease from solid organs and were not candidates for further radiation therapy or surgery. A total of 19 spinal intraarterial chemotherapy (SIAC) procedures were performed, and the follow-up period ranged from 1 to 7 months (median 3 months). There was 1 serious adverse event (febrile neutropenia). Local tumor control was seen in 8 of 9 patients, whereas tumor progression at the treated level was seen in 1 patient. CONCLUSIONS These preliminary results support the hypothesis that SIAC is feasible and safe. PMID- 26496163 TI - Demographically corrected normative data for the Hopkins Verbal Learning Test Revised and Brief Visuospatial Memory Test-Revised in an elderly sample. AB - Demographic variables, such as age, education, and gender, routinely affect performance on neuropsychological tests. Whereas normative data are available to correct for these variables on many tests, data are lacking on the Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT R), especially in the elderly. The current study examined the influence of age, education, and gender on HVLT-R and BVMT-R scores in 290 cognitively intact older adults. Age negatively correlated with nearly every score on the HVLT-R and BVMT R, and education positively correlated with most scores on these same 2 memory tests. There were fewer gender differences on these tests. Using stepwise multiple regression, HVLT-R and BVMT-R scores were predicted from age, education, and/or gender. When observed scores are compared to these demographically adjusted predicted scores, clinicians can make assumptions about how an individual compared to his/her age-, education-, and gender-matched peers. The current conorming of these 2 memory tests also allows for direct comparison between verbal and visual memory in older patients. PMID- 26496164 TI - Identifying States along the Hematopoietic Stem Cell Differentiation Hierarchy with Single Cell Specificity via Raman Spectroscopy. AB - A major challenge for expanding specific types of hematopoietic cells ex vivo for the treatment of blood cell pathologies is identifying the combinations of cellular and matrix cues that direct hematopoietic stem cells (HSC) to self-renew or differentiate into cell populations ex vivo. Microscale screening platforms enable minimizing the number of rare HSCs required to screen the effects of numerous cues on HSC fate decisions. These platforms create a strong demand for label-free methods that accurately identify the fate decisions of individual hematopoietic cells at specific locations on the platform. We demonstrate the capacity to identify discrete cells along the HSC differentiation hierarchy via multivariate analysis of Raman spectra. Notably, cell state identification is accurate for individual cells and independent of the biophysical properties of the functionalized polyacrylamide gels upon which these cells are cultured. We report partial least-squares discriminant analysis (PLS-DA) models of single cell Raman spectra enable identifying four dissimilar hematopoietic cell populations across the HSC lineage specification. Successful discrimination was obtained for a population enriched for long-term repopulating HSCs (LT-HSCs) versus their more differentiated progeny, including closely related short-term repopulating HSCs (ST-HSCs) and fully differentiated lymphoid (B cells) and myeloid (granulocytes) cells. The lineage-specific differentiation states of cells from these four subpopulations were accurately identified independent of the stiffness of the underlying biomaterial substrate, indicating subtle spectral variations that discriminated these populations were not masked by features from the culture substrate. This approach enables identifying the lineage-specific differentiation stages of hematopoietic cells on biomaterial substrates of differing composition and may facilitate correlating hematopoietic cell fate decisions with the extrinsic cues that elicited them. PMID- 26496165 TI - Mitotic 4E-BP1 hyperphosphorylation and cap-dependent translation. PMID- 26496166 TI - Mystery of Trbp, tale of a RBP in the miRNA pathway. PMID- 26496167 TI - Cyclin B3: an anaphase onset controller in meiosis. PMID- 26496169 TI - Corrigendum. PMID- 26496168 TI - Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression. AB - Mesenchymal stem cells (MSC) participate to tumor stroma development and several evidence suggests that they play a role in facilitating cancer progression. Because melanoma often shows extracellular pH low enough to influence host cell as tumor cell behavior, the aim of this study is to elucidate whether acidity affects cross talk between MSC and melanoma cells to disclose new liaisons promoting melanoma progression, and to offer new therapeutic opportunities. We found that MSC grown in a low pH medium (LpH-MSC) stimulate melanoma xenografts more than MSC grown in a standard pH medium. LpH-MSC express a higher level of TGFbeta that is instrumental of epithelial-to-mesenchymal transition (EMT)-like phenotype induction in melanoma cells. LpH-MSC profile also shows a switching to an oxidative phosphorylation metabolism that was accompanied by a forced glycolytic pathway of melanoma cells grown in LpH-MSC-conditioned medium. Metformin, an inhibitor of mitochondrial respiratory chain was able to reconvert oxidative metabolism and abrogate TGFbeta expression in LpH-MSC. In addition, esomeprazole, a proton pump inhibitor activated in acidosis, blocked TGFbeta expression in LpH-MSC through the downregulation of IkB. Both agents, metformin and esomeprazole, inhibited EMT profile in melanoma cells grown in LpH-MSC medium, and reduced glycolytic markers. Thus, acidosis of tumor microenvironment potentiates the pro-tumoral activity of MSC and orchestrates for a new potential symbiosis, which could be target to limit melanoma progression. PMID- 26496170 TI - Physical activity levels of economically disadvantaged women living in the Olympic city of Rio de Janeiro. AB - The objective of this study was to analyze the physical activity patterns of women living in a low-income community located in close proximity to the 2016 Rio de Janeiro Olympic Park. Data (N = 140) were collected in June and July 2012 using the International Physical Activity Questionnaire. Findings indicated that the majority (54.8%) of participants reported high levels of physical activity. The domains that contributed the most to this pattern were occupational and household physical activity. Significantly, 88.1% of participants reported low physical activity levels during their leisure-time. In the transport-related domain, participants were relatively more active, but more than half of them (57%) spent less than 600 MET-minutes/week in this domain. The results highlighted the discrepancies between different physical activity domains. In addition, the findings also suggested that low-income women in our study engaged little in physical activity during their leisure time. Therefore, the proposed commitments found in the Rio de Janeiro Candidature File to host the 2016 Olympic Games to increase sport/physical activity participation within low-income communities in Rio de Janeiro need to be implemented effectively if this physical activity behavior during self-directed time is to be changed. PMID- 26496171 TI - Photocyclization and Photoaddition Reactions of Arylphenols via Intermediate Quinone Methides. AB - A series of five benzannelated derivatives of 2-phenylphenol were prepared, and their photochemistry was investigated. Two of these (3-phenyl-2-naphthol, 10, and 1-phenyl-2-naphthol, 11) were photoinert. For 2-(1-naphthyl)phenol (12) and 1-(1 naphthyl)-2-naphthol (13), ESPT took place to either the 2'-position or the 7' position of the naphthalene ring to give quinone methides (QMs) that underwent either reverse proton transfer (RPT) or electrocyclic ring closure to give dihydrobenzoxanthenes. The intermediate QMs for 12 and 13 were detected and characterized by laser flash photolysis. For 2-(9-phenanthryl)phenol (14), ESPT took place either to the 5'-position to give a QM that underwent quantitative electrocyclic ring closure to give the corresponding benzoxanthene or to the 10' position to give a QM that underwent RPT. If the solution contained methanol, the QM produced on ESPT to the 10'-position in 14 could be trapped as the photoaddition product. The compounds studied in this work demonstrate three possible reactions of QMs produced following ESPT to aromatic carbon atoms: (1) reverse proton transfer (RPT) to regenerate starting material; (2) addition of hydroxylic solvents to give the photoaddition product; and (3) electrocyclic ring closure to give benzoxanthene derivatives. PMID- 26496172 TI - Managing patients with side effects and adverse events to immunoglobulin therapy. AB - Immunoglobulin therapy has not only served as a lifesaving approach for the prevention and treatment of infections in primary and secondary immunodeficiency diseases, but has also been used as an immunomodulatory agent for autoimmune and inflammatory disorders and to provide passive immunity for some infectious diseases. Most of the adverse effects associated with immunoglobulin therapy are mild, transient and self-limiting. However, serious side effects also occur. Therefore, to minimize the adverse events of immunoglobulin therapy, specialist review of patient clinical status and immunoglobulin products, in addition to selection of appropriate treatment strategy for the management of patients with associated side effects and adverse events, are crucial. PMID- 26496173 TI - Infrared and Raman Spectroscopy of Eugenol, Isoeugenol, and Methyl Eugenol: Conformational Analysis and Vibrational Assignments from Density Functional Theory Calculations of the Anharmonic Fundamentals. AB - IR and Raman spectra of eugenol, isoeugenol and methyl eugenol have been obtained in the liquid phase. Vibrational spectroscopic results are discussed in relation to computed structures and spectra of the low energy conformations of these molecules obtained from DFT calculations at the B3LYP/cc-pVTZ level. Although computed differences in vibrational spectra for the different conformers were generally small, close examination, in conjunction with the experimental spectra, enabled conformational analysis of all three molecules. Anharmonic contributions to computed vibrational spectra were obtained from calculations of cubic and quartic force constants at the B3LYP/DZ level. This permitted the determination of the anharmonic fundamentals for comparison with the experimental IR and Raman band positions, leading to an excellent fit between calculated and experimental spectra. Band assignments were obtained in terms of potential energy distributions (ped's). PMID- 26496174 TI - Principles of K-Ras effector organization and the role of oncogenic K-Ras in cancer initiation through G1 cell cycle deregulation. AB - Illustrated here is the critical role of oncogenic KRAS in the initiation of cancer through deregulation of the G1 cell cycle, and elements and scenarios taking place under physiological conditions and in KRAS-driven cancer. Raf, PI3K and RalGDS are major K-Ras effectors. They bind at the same Ras site. What decides the cell selection among them? This temporal and spatial decision is critical since in some cellular context the outcome of their signaling pathways may oppose each other. Key among them is the concentration of calcium/calmodulin, negative feedback loops, where a downstream member of the pathway inhibits its upstream activator and cross-inhibition, where inhibition entails blocking another pathway. These three elements, in addition to spatial restrictions by K Ras-membrane interactions, are not independent; they integrate to provide blueprints for cell decisions. Importantly, elucidation of signaling requires not only K-Ras binary interactions; but the structures and dynamics of its multiprotein complexes. PMID- 26496176 TI - The expert patient and chronic respiratory diseases. PMID- 26496175 TI - Identification of beta-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma. AB - The treatment of activated B cell-like DLBCL (ABC-DLBCL) is one of the urgent unmet medical needs because it is the most resistant DLBCL subtype to current therapies eagerly awaiting effective therapeutic strategies. Recently, the paracaspase MALT1 has emerged as a promising therapeutic target for the treatment of ABC-DLBCL. Herein, we report a new class of MALT1 inhibitors developed by high throughput screening and structure-based drug design. The original hit, 4-amino 1,2-naphthoquinone series inhibited MALT1 activity but suffered from poor cellular activity. The extensive pharmacophore search led to the discovery of structurally similar beta-lapachone that is a direct inhibitor of MALT1 and possesses favorable physicochemical properties. Molecular simulation studies suggested the possibility of the formation of a covalent bond between MALT1 and beta-lapachone, which was corroborated by experimental wash-out studies. Inspired by this, we explored the structure-activity relationships by incorporating electron-withdrawing substituents at C8 position of beta-lapachone. These MALT1 inhibitors exhibited potent antiproliferative activity to OCI-LY3 cell line and inhibited the cleavage of CYLD mediated MALT1. PMID- 26496177 TI - Deposition of Quantum Dots in a Capillary Tube. AB - The ability to assemble nanomaterials, such as quantum dots, enables the creation of functional devices that present unique optical and electronic properties. For instance, light-emitting diodes with exceptional color purity can be printed via the evaporative-driven assembly of quantum dots. Nevertheless, current studies of the colloidal deposition of quantum dots have been limited to the surfaces of a planar substrate. Here, we investigate the evaporation-driven assembly of quantum dots inside a confined cylindrical geometry. Specifically, we observe distinct deposition patterns, such as banding structures along the length of a capillary tube. Such coating behavior can be influenced by the evaporation speed as well as the concentration of quantum dots. Understanding the factors governing the coating process can provide a means to control the assembly of quantum dots inside a capillary tube, ultimately enabling the creation of novel photonic devices. PMID- 26496178 TI - Assessment of Food Waste Prevention and Recycling Strategies Using a Multilayer Systems Approach. AB - Food waste (FW) generates large upstream and downstream emissions to the environment and unnecessarily consumes natural resources, potentially affecting future food security. The ecological impacts of FW can be addressed by the upstream strategies of FW prevention or by downstream strategies of FW recycling, including energy and nutrient recovery. While FW recycling is often prioritized in practice, the ecological implications of the two strategies remain poorly understood from a quantitative systems perspective. Here, we develop a multilayer systems framework and scenarios to quantify the implications of food waste strategies on national biomass, energy, and phosphorus (P) cycles, using Norway as a case study. We found that (i) avoidable food waste in Norway accounts for 17% of sold food; (ii) 10% of the avoidable food waste occurs at the consumption stage, while industry and retailers account for only 7%; (iii) the theoretical potential for systems-wide net process energy savings is 16% for FW prevention and 8% for FW recycling; (iv) the theoretical potential for systems-wide P savings is 21% for FW prevention and 9% for FW recycling; (v) while FW recycling results in exclusively domestic nutrient and energy savings, FW prevention leads to domestic and international savings due to large food imports; (vi) most effective is a combination of prevention and recycling, however, FW prevention reduces the potential for FW recycling and therefore needs to be prioritized to avoid potential overcapacities for FW recycling. PMID- 26496179 TI - Letter to the Editor Regarding the Article by Natsch et al., 2015. PMID- 26496181 TI - Synthesis of Ultrathin Copper Nanowires Using Tris(trimethylsilyl)silane for High Performance and Low-Haze Transparent Conductors. AB - Colloidal metal nanowire based transparent conductors are excellent candidates to replace indium-tin-oxide (ITO) owing to their outstanding balance between transparency and conductivity, flexibility, and solution-processability. Copper stands out as a promising material candidate due to its high intrinsic conductivity and earth abundance. Here, we report a new synthetic approach, using tris(trimethylsilyl)silane as a mild reducing reagent, for synthesizing high quality, ultrathin, and monodispersed copper nanowires, with an average diameter of 17.5 nm and a mean length of 17 MUm. A study of the growth mechanism using high-resolution transmission electron microscopy reveals that the copper nanowires adopt a five-fold twinned structure and evolve from decahedral nanoseeds. Fabricated transparent conducting films exhibit excellent transparency and conductivity. An additional advantage of our nanowire transparent conductors is highlighted through reduced optical haze factors (forward light scattering) due to the small nanowire diameter. PMID- 26496182 TI - Changes in Vascular Tone Occur Early During Hemodialysis Treatments Independently of Volume Reduction. AB - Hypotension commonly occurs during hemodialysis (HD). Hypotension can result from an absolute reduction in plasma volume following excessive ultrafiltration or from a reduction in vascular tone. We hypothesized that changes in vascular tone could occur during dialysis. Aortic pulse wave velocity (aPWV) was measured in 197 HD patients, mean age 63.3 +/- 16.6 years, 62% male, 49% diabetic, during a single HD session. aPWV did not change (9.6 +/- 2.2 vs. 9.6 +/- 2.2 m/s) with HD. Systolic blood pressure (SBP) declined from 151 +/- 31 to 147 +/- 32 after 20 min and to 140 +/- 36 mm Hg on completion of HD (P < 0.05), with an ultrafiltration volume of 2.2 +/- 0.9 L over a 3.9 +/- 0.4 h HD session. Aortic SBP declined from 154 +/- 32 to 146 +/- 29 after 20 min and 143 +/- 35 at the end of HD, P < 0.001. Aortic augmentation index (Aortic Aix) decreased from 65% (52-79%) to 36.7% (23.3 52.9%) by 20 min and to 34.3 (15.1-49.1%) on completion of HD (P < 0.05), and brachial augmentation index (brachial Aix) from 5.7% (-25.2 to 27.5%) to -1.9% ( 2.2 to 30.1%) and -6.6% (-44 to 22.7%), respectively, P < 0.05. Diastolic reflection area (DRA) increased from 36.7 (27.9-46.3) to 40.4 (32.2-51) after 20 min and 47.1 (34.2-60.5) on completion of HD, P < 0.05. We report changes in arterial tone within 20 min of starting HD, when minimal ultrafiltration has occurred, suggesting that volume changes may not be the only predisposing cause of intradialytic hypotension. The combination of a fall in SBP and a rise in DRA would suggest a reduction in coronary blood flow in keeping with reports of "myocardial stunning" during HD. PMID- 26496183 TI - Roles of the Excitation in Harvesting Energy from Vibrations. AB - The study investigated the role of excitation in energy harvesting applications. While the energy ultimately comes from the excitation, it was shown that the excitation may not always behave as a source. When the device characteristics do not perfectly match the excitation, the excitation alternately behaves as a source and a sink. The extent to which the excitation behaves as a sink determines the energy harvesting efficiency. Such contradictory roles were shown to be dictated by a generalized phase defined as the instantaneous phase angle between the velocity of the device and the excitation. An inductive prototype device with a diamagnetically levitated seismic mass was proposed to take advantage of the well established phase changing mechanism of vibro-impact to achieve a broader device bandwidth. Results suggest that the vibro-impact can generate an instantaneous, significant phase shift in response velocity that switches the role of the excitation. If introduced properly outside the resonance zone it could dramatically increase the energy harvesting efficiency. PMID- 26496184 TI - Dispersion-Corrected Relativistic Density Functional Theory (DFT) Calculations of Structure and (119)Sn Mossbauer Parameters for M=SnR Bonding in Filippou's Stannylidyne Complexes of Molybdenum and Tungsten. AB - (119)Sn Mossbauer isomer shift (IS) and quadrupole splitting (DeltaEQ) for M=SnR bonding in metal-stannylidyne complexes trans-[Cl(PMe3)4Mo=Sn-R] (1), trans [Cl(PMe3)4W=Sn-R] (2), trans-[Cl(dppe)2Mo=Sn-R] (3), trans-[Cl(dppe)2W=Sn-R] (4), [(dppe)2Mo=Sn-R](+) (5), [(dppe)2W=Sn-R](+) (6) (R = C6H3-2,6-Mes2) have been investigated for the first time. Calculations of optimized structures and (119)Sn Mossbauer parameters were carried out at the DFT/TPSS-D3(BJ)/TZVPP/ZORA level of theory. The calculated geometry parameters of stannylidyne complexes of molybdenum and tungsten (1-6) are in good agreement with experimental values of W Sn and Sn-C bond distances. The calculated values of the isomer shift for the complexes (1-6) are almost same to the experimental values (within +/-0.1 mm/s). Experimental values (ISexptl, 2.38-2.50 mm/s) and calculated values (IScalcd, 2.37-2.49 mm/s) of isomer shifts indicate that the oxidation state of tin in the studied complexes with M=Sn-R bonding is Sn(II). The variations of ISexptl, as a function of Sn s electrons (Ns(Sn)), also exhibit a linear trend. (IS = 0.477Ns(Sn) - 1.888, R(2) = 0.9973). Calculated values of isomer shift (IScalcd) using the linear regression with the Ns(Sn) electron density are in excellent concord with the ISexptl.The calculated values of nuclear quadrupole splitting parameters (DeltaEQ(calcd)) of (119)Sn using the relation DeltaEQ(calcd) = (0.540 + 0.28) V are in agreement with the experimental values. PMID- 26496185 TI - Correction: Sandbox University: Estimating Influence of Institutional Action. PMID- 26496186 TI - Comparison of three human papillomavirus DNA detection methods: Next generation sequencing, multiplex-PCR and nested-PCR followed by Sanger based sequencing. AB - To compare the diagnostic performance for HPV infection using three laboratorial techniques. Ninty-five cervicovaginal samples were randomly selected; each was tested for HPV DNA and genotypes using 3 methods in parallel: Multiplex-PCR, the Nested PCR followed by Sanger sequencing, and the Next_Gen Sequencing (NGS) with two assays (NGS-A1, NGS-A2). The study was approved by the Brazilian National IRB (CONEP protocol 16,800). The prevalence of HPV by the NGS assays was higher than that using the Multiplex-PCR (64.2% vs. 45.2%, respectively; P = 0.001) and the Nested-PCR (64.2% vs. 49.5%, respectively; P = 0.003). NGS also showed better performance in detecting high-risk HPV (HR-HPV) and HPV16. There was a weak interobservers agreement between the results of Multiplex-PCR and Nested-PCR in relation to NGS for the diagnosis of HPV infection, and a moderate correlation for HR-HPV detection. Both NGS assays showed a strong correlation for detection of HPVs (k = 0.86), HR-HPVs (k = 0.91), HPV16 (k = 0.92) and HPV18 (k = 0.91). NGS is more sensitive than the traditional Sanger sequencing and the Multiplex PCR to genotype HPVs, with promising ability to detect multiple infections, and may have the potential to establish an alternative method for the diagnosis and genotyping of HPV. PMID- 26496180 TI - Character, Incidence, and Predictors of Knee Pain and Activity After Infrapatellar Intramedullary Nailing of an Isolated Tibia Fracture. AB - OBJECTIVE: To study the activity and incidence of knee pain after sustaining an isolated tibia fracture treated with an infrapatellar intramedullary nail at 1 year. DESIGN: Retrospective review of prospective cohort. SETTING: Multicenter Academic and Community hospitals. PATIENTS: Four hundred thirty-seven patients with an isolated tibia fracture completed a 12-month assessment on pain and self reported activity. INTERVENTION: Infrapatellar intramedullary nail. OUTCOMES: Demographic information, comorbid conditions, injury characteristics, and surgical technique were recorded. Knee pain was defined on a 1-7 scale with 1 being "no pain" and 7 being a "very great deal of pain." Knee pain >4 was considered clinically significant. Patients reported if they were "able," "able with difficulty," or "unable" to perform the following activities: kneel, run, climb stairs, and walk prolonged. Variables were tested in multilevel multivariable regression analyses. RESULTS: In knee pain, 11% of patients reported a "good deal" to a "very great deal" of pain (>4), and 52% of patients reported "no" or "very little" pain at 12 months. In activity at 12 months, 26% and 29% of patients were unable to kneel or run, respectively, and 31% and 35% of patients, respectively, stated they were able with difficulty or unable to use stairs or walk. CONCLUSIONS: Clinically significant knee pain (>4/7) was present in 11% of patients 1 year after a tibia fracture. Of note, 31%-71% of patients had difficulty performing or were unable to perform routine daily activities of kneeling, running, and stair climbing, or walking prolonged distances. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 26496187 TI - Surgical and Non-Surgical Procedures Associated with Recurrence of Periodontitis in Periodontal Maintenance Therapy: 5-Year Prospective Study. AB - BACKGROUND AND OBJECTIVE: Prospective studies that investigated the influence of surgical and nonsurgical procedures in the recurrence of periodontitis and tooth loss in periodontal maintenance therapy (PMT) programs have not been previously reported. The objective of this study was to evaluate longitudinally the recurrence of periodontitis in regular compliers (RC) and irregular compliers (IC) individuals undergoing surgical and non-surgical procedures over 5 years in a program of PMT. MATERIALS AND METHODS: A total of 212 individuals participated in this study. Full-mouth periodontal examination including bleeding on probing, probing depth, and clinical attachment level were determined at all PMT visits over 5 years. The recurrence of periodontitis was evaluated in RC and IC individuals undergoing surgical and non-surgical procedures in PMT. The influences of risk variables of interest were tested through univariate analysis and multivariate logistic regression. RESULTS: Recurrence of periodontitis was significantly lower among RC when compared to IC. Individuals with recurrence of periodontitis and undergoing surgical procedures showed higher probing depth and clinical attachment loss than those who received non-surgical procedures. Recurrence of periodontitis was higher in individual undergoing surgical procedures and irregular compliance during PMT. CONCLUSIONS: Irregular compliance and surgical procedures in individuals undergoing PMT presented higher rates of recurrence of periodontitis when compared to regular compliant patients undergoing non-surgical procedures. PMID- 26496188 TI - Extraction and preconcentration of hemin from human blood serum and breast cancer supernatant. AB - A green, facile, fast, and sensitive liquid-phase microextraction method is presented for the extraction and preconcentration of hemin in the presence of free iron ions prior to flame atomic absorption spectroscopic determination. In this technique, an anion-functionalized task-specific ionic liquid is used as the extracting solvent. The interface between the extracting solvent and the bulk aqueous phase containing hemin is enormously enlarged by dispersing the ionic liquid to the aqueous phase with the help of ultrasound radiation. Hemin is selectively extracted into the ionic liquid after interaction with the functional group of the ionic liquid. Then, the concentration of the extracted hemin is determined through the absorbance of the iron ions contained in the hemin structure using flame atomic absorption spectroscopy. Different experimental parameters affecting the extraction efficiency have been optimized. Under the optimized conditions, the proposed method has a hemin concentration linear range of 0.020-0.80 mg/L with a detection limit of 0.0080 mg/L. This method has been successfully applied to the extraction and determination of hemin in human serum and supernatant samples. PMID- 26496189 TI - Spatial Distribution Patterns in the Very Rare and Species-Rich Picea chihuahuana Tree Community (Mexico). AB - The very rare Mexican Picea chihuahuana tree community covers an area of no more than 300 ha in the Sierra Madre Occidental. This special tree community has been the subject of several studies aimed at learning more about the genetic structure and ecology of the species and the potential effects of climate change. The spatial distribution of trees is a result of many ecological processes and can affect the degree of competition between neighbouring trees, tree density, variability in size and distribution, regeneration, survival, growth, mortality, crown formation and the biological diversity within forest communities. Numerous scale-dependent measures have been established in order to describe spatial forest structure. The overall aim of most of these studies has been to obtain data to help design preservation and conservation strategies. In this study, we examined the spatial distribution pattern of trees in the P. chihuahuana tree community in 12 localities, in relation to i) tree stand density, ii) diameter distribution (vertical structure), iii) tree species diversity, iv) geographical latitude and v) tree dominance at a fine scale (in 0.25 ha plots), with the aim of obtaining a better understanding of the complex ecosystem processes and biological diversity. Because of the strongly mixed nature of this tree community, which often produces low population densities of each tree species and random tree fall gaps caused by tree death, we expect aggregated patterns in individual Picea chihuahuana trees and in the P. chihuahuana tree community, repulsive Picea patterns to other tree species and repulsive patterns of young to adult trees. Each location was represented by one plot of 50 x 50 m (0.25 ha) established in the centre of the tree community. The findings demonstrate that the hypothesis of aggregated tree pattern is not applicable to the mean pattern measured by Clark-Evans index, Uniform Angle index and Mean Directional index of the uneven-aged P. chihuahuana trees and P. chihuahuana tree community and but to specific spatial scales measured by the univariate L-function. The spatial distribution pattern of P. chihuahuana trees was found to be independent of patches of other tree species measured by the bivariate L-function. The spatial distribution was not significantly related to tree density, diameter distribution or tree species diversity. The index of Clark and Evans decreased significantly from the southern to northern plots containing all tree species. Self-thinning due to intra and inter-specific competition-induced mortality is probably the main cause of the decrease in aggregation intensity during the course of population development in this tree community. We recommend the use of larger sampling plots (> 0.25 ha) in uneven-aged and species-rich forest ecosystems to detect less obvious, but important, relationships between spatial tree pattern and functioning and diversity in these forests. PMID- 26496190 TI - Use of Chronic Kidney Disease to Enhance Prediction of Cardiovascular Risk in Those at Medium Risk. AB - Based on global cardiovascular (CV) risk assessment for example using the Framingham risk score, it is recommended that those with high risk should be treated and those with low risk should not be treated. The recommendation for those of medium risk is less clear and uncertain. We aimed to determine whether factoring in chronic kidney disease (CKD) will improve CV risk prediction in those with medium risk. This is a 10-year retrospective cohort study of 905 subjects in a primary care clinic setting. Baseline CV risk profile and serum creatinine in 1998 were captured from patients record. Framingham general cardiovascular disease risk score (FRS) for each patient was computed. All cardiovascular disease (CVD) events from 1998-2007 were captured. Overall, patients with CKD had higher FRS risk score (25.9% vs 20%, p = 0.001) and more CVD events (22.3% vs 11.9%, p = 0.002) over a 10-year period compared to patients without CKD. In patients with medium CV risk, there was no significant difference in the FRS score among those with and without CKD (14.4% vs 14.6%, p = 0.84) However, in this same medium risk group, patients with CKD had more CV events compared to those without CKD (26.7% vs 6.6%, p = 0.005). This is in contrast to patients in the low and high risk group where there was no difference in CVD events whether these patients had or did not have CKD. There were more CV events in the Framingham medium risk group when they also had CKD compared those in the same risk group without CKD. Hence factoring in CKD for those with medium risk helps to further stratify and identify those who are actually at greater risk, when treatment may be more likely to be indicated. PMID- 26496191 TI - ARK: Aggregation of Reads by K-Means for Estimation of Bacterial Community Composition. AB - MOTIVATION: Estimation of bacterial community composition from high-throughput sequenced 16S rRNA gene amplicons is a key task in microbial ecology. Since the sequence data from each sample typically consist of a large number of reads and are adversely impacted by different levels of biological and technical noise, accurate analysis of such large datasets is challenging. RESULTS: There has been a recent surge of interest in using compressed sensing inspired and convex optimization based methods to solve the estimation problem for bacterial community composition. These methods typically rely on summarizing the sequence data by frequencies of low-order k-mers and matching this information statistically with a taxonomically structured database. Here we show that the accuracy of the resulting community composition estimates can be substantially improved by aggregating the reads from a sample with an unsupervised machine learning approach prior to the estimation phase. The aggregation of reads is a pre-processing approach where we use a standard K-means clustering algorithm that partitions a large set of reads into subsets with reasonable computational cost to provide several vectors of first order statistics instead of only single statistical summarization in terms of k-mer frequencies. The output of the clustering is then processed further to obtain the final estimate for each sample. The resulting method is called Aggregation of Reads by K-means (ARK), and it is based on a statistical argument via mixture density formulation. ARK is found to improve the fidelity and robustness of several recently introduced methods, with only a modest increase in computational complexity. AVAILABILITY: An open source, platform-independent implementation of the method in the Julia programming language is freely available at https://github.com/dkoslicki/ARK. A Matlab implementation is available at http://www.ee.kth.se/ctsoftware. PMID- 26496192 TI - Modular Coils with Low Hydrogen Content Especially for MRI of Dry Solids. AB - INTRODUCTION: Recent advances have enabled fast magnetic resonance imaging (MRI) of solid materials. This development has opened up new applications for MRI, but, at the same time, uncovered new challenges. Previously, MRI-invisible materials like the housing of MRI detection coils are now readily depicted and either cause artifacts or lead to a decreased image resolution. In this contribution, we present versatile, multi-nuclear single and dual-tune MRI coils that stand out by (1) a low hydrogen content for high-resolution MRI of dry solids without artifacts; (2) a modular approach with exchangeable inductors of variable volumes to optimally enclose the given object; (3) low cost and low manufacturing effort that is associated with the modular approach; (4) accurate sample placement in the coil outside of the bore, and (5) a wide, single- or dual-tune frequency range that covers several nuclei and enables multinuclear MRI without moving the sample. MATERIALS AND METHODS: The inductors of the coils were constructed from self-supporting copper sheets to avoid all plastic materials within or around the resonator. The components that were mounted at a distance from the inductor, including the circuit board, coaxial cable and holder were manufactured from polytetrafluoroethylene. RESULTS AND CONCLUSION: Residual hydrogen signal was sufficiently well suppressed to allow 1H-MRI of dry solids with a minimum field of view that was smaller than the sensitive volume of the coil. The SNR was found to be comparable but somewhat lower with respect to commercial, proton-rich quadrature coils, and higher with respect to a linearly-polarized commercial coil. The potential of the setup presented was exemplified by 1H/23Na high resolution zero echo time (ZTE) MRI of a model solution and a dried human molar at 9.4 T. A full 3D image dataset of the tooth was obtained, rich in contrast and similar to the resolution of standard cone-beam computed tomography. PMID- 26496193 TI - Esculentoside A Attenuates Allergic Airway Inflammation via Activation of the Nrf 2 Pathway. AB - BACKGROUND: The role of airway inflammation and inflammation-induced oxidative stress in the pathogenesis and progression of chronic inflammatory airway diseases has received increasing attention in recent years. We investigated the potential anti-inflammatory and antioxidative effects of esculentoside A (EsA), a saponin isolated from the Chinese herb Phytolacca esculenta, in comparison to dexamethasone, a potent corticosteroid, in a murine model of allergic asthma. METHODS: EsA was added to cultures of A549 cells at different concentrations or for different lengths of time, and nuclear factor erythroid 2-related factor 2 (Nrf-2) translocation and heme oxygenase 1 expression were monitored. Mice treated with or without EsA and Nrf-2 siRNA were sensitized and challenged with ovalbumin (OVA) and developed airway inflammation and oxidative lung damage. The Th2-type cytokine levels and inflammatory cells in bronchoalveolar lavage fluid (BALF) and the serum immunoglobulin production and adhesion molecule expression in the lung tissues were measured. The activities of related antioxidases and glutathione were measured using assay kits. RESULTS: EsA enhanced nuclear Nrf-2 translocation in both A549 cells and the lungs of OVA-challenged mice. Airway inflammation induced by OVA was reduced. Additionally, EsA increased mRNA expression of antioxidant enzymes regulated by Nrf-2, leading to a reduction in Th2 cytokines and the expression of adhesion molecule mRNA in the BALF and lung tissues. Inhibition of Nrf-2 by siRNA abrogated the regulatory effects of EsA on inflammation and oxidant stress. CONCLUSIONS: This is the first study to illustrate that EsA acts as a novel Nrf-2 activator, which modulates the oxidative stress pathway to improve lung injury and ameliorate the development of airway inflammation. PMID- 26496194 TI - DCA1 Acts as a Transcriptional Co-activator of DST and Contributes to Drought and Salt Tolerance in Rice. AB - Natural disasters, including drought and salt stress, seriously threaten food security. In previous work we cloned a key zinc finger transcription factor gene, Drought and Salt Tolerance (DST), a negative regulator of drought and salt tolerance that controls stomatal aperture in rice. However, the exact mechanism by which DST regulates the expression of target genes remains unknown. In the present study, we demonstrated that DST Co-activator 1 (DCA1), a previously unknown CHY zinc finger protein, acts as an interacting co-activator of DST. DST was found to physically interact with itself and to form a heterologous tetramer with DCA1. This transcriptional complex appears to regulate the expression of peroxidase 24 precursor (Prx 24), a gene encoding an H2O2 scavenger that is more highly expressed in guard cells. Downregulation of DCA1 significantly enhanced drought and salt tolerance in rice, and overexpression of DCA1 increased sensitivity to stress treatment. These phenotypes were mainly influenced by DCA1 and negatively regulated stomatal closure through the direct modulation of genes associated with H2O2 homeostasis. Our findings establish a framework for plant drought and salt stress tolerance through the DCA1-DST-Prx24 pathway. Moreover, due to the evolutionary and functional conservation of DCA1 and DST in plants, engineering of this pathway has the potential to improve tolerance to abiotic stress in other important crop species. PMID- 26496196 TI - Enhanced Recyclable Magnetized Palm Shell Waste-Based Powdered Activated Carbon for the Removal of Ibuprofen: Insights for Kinetics and Mechanisms. AB - A novel preparation method of magnetized palm shell waste-based powdered activated carbon (MPPAC, avg. size 112 MUm) was developed. The prepared MPPAC was assessed by several physicochemical analyses, and batch tests were performed for ibuprofen (IBP) removal. Field emission scanning electron microscopy (FESEM) and N2 gas isotherms revealed that magnetite and maghemite were homogeneous and deposited mostly on the surface of PPAC without a significant clogging effect on the micropores. Isotherm results showed that 3.8% Fe (w/w) impregnated PPAC [MPPAC-Fe(3.8%)] had about 2.2-fold higher maximum sorption capacity (157.3 mg g 1) and a 2.5-fold higher sorption density (0.23 mg m-2) than pristine PPAC. Both Fourier-transform infrared spectroscopy (FTIR) and isotherm data indicated that the high sorption capacity and density of IBP by MPPAC was primarily attributable to donor-acceptor complexes with the C = O group and dispersive pi-pi interactions with the carbon surface. Based on kinetic and repeated adsorption tests, pore diffusion was the rate-limiting step, and MPPAC-Fe(3.8%) had about 1.9~2.8- and 9.1~15.8-fold higher rate constants than MPPAC-Fe(8.6%) and palm shell-waste granular activated carbon (PGAC, avg. size 621 MUm), respectively. MPPAC showed almost eight fold greater re-adsorption capacity than PPAC due to a thermal catalytic effect of magnetite/maghemite. PMID- 26496195 TI - Protein O-Glucosyltransferase 1 (POGLUT1) Promotes Mouse Gastrulation through Modification of the Apical Polarity Protein CRUMBS2. AB - Crumbs family proteins are apical transmembrane proteins with ancient roles in cell polarity. Mouse Crumbs2 mutants arrest at midgestation with abnormal neural plate morphology and a deficit of mesoderm caused by defects in gastrulation. We identified an ENU-induced mutation, wsnp, that phenocopies the Crumbs2 null phenotype. We show that wsnp is a null allele of Protein O-glucosyltransferase 1 (Poglut1), which encodes an enzyme previously shown to add O-glucose to EGF repeats in the extracellular domain of Drosophila and mammalian Notch, but the role of POGLUT1 in mammalian gastrulation has not been investigated. As predicted, we find that POGLUT1 is essential for Notch signaling in the early mouse embryo. However, the loss of mouse POGLUT1 causes an earlier and more dramatic phenotype than does the loss of activity of the Notch pathway, indicating that POGLUT1 has additional biologically relevant substrates. Using mass spectrometry, we show that POGLUT1 modifies EGF repeats in the extracellular domain of full-length mouse CRUMBS2. CRUMBS2 that lacks the O-glucose modification fails to be enriched on the apical plasma membrane and instead accumulates in the endoplasmic reticulum. The data demonstrate that CRUMBS2 is the target of POGLUT1 for the gastrulation epithelial-to-mesenchymal transitions (EMT) and that all activity of CRUMBS2 depends on modification by POGLUT1. Mutations in human POGLUT1 cause Dowling-Degos Disease, POGLUT1 is overexpressed in a variety of tumor cells, and mutations in the EGF repeats of human CRUMBS proteins are associated with human congenital nephrosis, retinitis pigmentosa and retinal degeneration, suggesting that O-glucosylation of CRUMBS proteins has broad roles in human health. PMID- 26496197 TI - Mantle Branch-Specific RNA Sequences of Moon Scallop Amusium pleuronectes to Identify Shell Color-Associated Genes. AB - Amusium pleuronectes (Linnaeus) that secretes red- and white-colored valves in two branches of mantle tissues is an excellent model for shell color research. High-throughput transcriptome sequencing and profiling were applied in this project to reveal the detailed molecular mechanism of this phenotype differentiation. In this study, 50,796,780 and 54,361,178 clean reads were generated from the left branch (secreting red valve, RS) and right branch (secreting white valve, WS) using the Illumina Hiseq 2000 platform. De novo assembly generated 149,375 and 176,652 unigenes with an average length of 764 bp and 698 bp in RS and WS, respectively. Kyoto encyclopedia of genes and genomes (KEGG) metabolic pathway analysis indicated that the differentially expressed genes were involved in 228 signaling pathways, and 43 genes were significantly enriched (P<0.01). Nineteen of 20 differentially expressed vitellogenin genes showed significantly high expression in RS, which suggested that they probably played a crucial role in organic pigment assembly and transportation of the shell. Moreover, 687 crystal formation-related (or biomineralization-related) genes were detected in A. pleuronectes, among which 144 genes exhibited significant difference between the two branches. Those genes could be classified into shell matrix framework participants, crystal nucleation and growth-related elements, upstream regulation factors, Ca level regulators, and other classifications. We also identified putative SNP and SSR markers from these samples which provided the markers for genetic diversity analysis, genetic linkage, QTL analysis. These results provide insight into the complexity of shell color differentiation in A. pleuronectes so as valuable resources for further research. PMID- 26496198 TI - Virtual Pharmacist: A Platform for Pharmacogenomics. AB - We present Virtual Pharmacist, a web-based platform that takes common types of high-throughput data, namely microarray SNP genotyping data, FASTQ and Variant Call Format (VCF) files as inputs, and reports potential drug responses in terms of efficacy, dosage and toxicity at one glance. Batch submission facilitates multivariate analysis or data mining of targeted groups. Individual analysis consists of a report that is readily comprehensible to patients and practioners who have basic knowledge in pharmacology, a table that summarizes variants and potential affected drug response according to the US Food and Drug Administration pharmacogenomic biomarker labeled drug list and PharmGKB, and visualization of a gene-drug-target network. Group analysis provides the distribution of the variants and potential affected drug response of a target group, a sample-gene variant count table, and a sample-drug count table. Our analysis of genomes from the 1000 Genome Project underlines the potentially differential drug responses among different human populations. Even within the same population, the findings from Watson's genome highlight the importance of personalized medicine. Virtual Pharmacist can be accessed freely at http://www.sustc-genome.org.cn/vp or installed as a local web server. The codes and documentation are available at the GitHub repository (https://github.com/VirtualPharmacist/vp). Administrators can download the source codes to customize access settings for further development. PMID- 26496199 TI - Qualitative and Quantitative Analysis of ROS-Mediated Oridonin-Induced Oesophageal Cancer KYSE-150 Cell Apoptosis by Atomic Force Microscopy. AB - High levels of intracellular reactive oxygen species (ROS) in cells is recognized as one of the major causes of cancer cell apoptosis and has been developed into a promising therapeutic strategy for cancer therapy. However, whether apoptosis associated biophysical properties of cancer cells are related to intracellular ROS functions is still unclear. Here, for the first time, we determined the changes of biophysical properties associated with the ROS-mediated oesophageal cancer KYSE-150 cell apoptosis using high resolution atomic force microscopy (AFM). Oridonin was proved to induce ROS-mediated KYSE-150 cell apoptosis in a dose dependent manner, which could be reversed by N-acetylcysteine (NAC) pretreatment. Based on AFM imaging, the morphological damage and ultrastructural changes of KYSE-150 cells were found to be closely associated with ROS-mediated oridonin-induced KYSE-150 cell apoptosis. The changes of cell stiffness determined by AFM force measurement also demonstrated ROS-dependent changes in oridonin induced KYSE-150 cell apoptosis. Our findings not only provided new insights into the anticancer effects of oridonin, but also highlighted the use of AFM as a qualitative and quantitative nanotool to detect ROS-mediated cancer cell apoptosis based on cell biophysical properties, providing novel information of the roles of ROS in cancer cell apoptosis at nanoscale. PMID- 26496200 TI - Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation. AB - T follicular helper cells (Tfh) are critical for the longevity and quality of antibody-mediated protection against infection. Yet few signaling pathways have been identified to be unique solely to Tfh development. ROQUIN is a post transcriptional repressor of T cells, acting through its ROQ domain to destabilize mRNA targets important for Th1, Th17, and Tfh biology. Here, we report that ROQUIN has a paradoxical function on Tfh differentiation mediated by its RING domain: mice with a T cell-specific deletion of the ROQUIN RING domain have unchanged Th1, Th2, Th17, and Tregs during a T-dependent response but show a profoundly defective antigen-specific Tfh compartment. ROQUIN RING signaling directly antagonized the catalytic alpha1 subunit of adenosine monophosphate activated protein kinase (AMPK), a central stress-responsive regulator of cellular metabolism and mTOR signaling, which is known to facilitate T-dependent humoral immunity. We therefore unexpectedly uncover a ROQUIN-AMPK metabolic signaling nexus essential for selectively promoting Tfh responses. PMID- 26496201 TI - Polyanhydride Nanoparticle Delivery Platform Dramatically Enhances Killing of Filarial Worms. AB - Filarial diseases represent a significant social and economic burden to over 120 million people worldwide and are caused by endoparasites that require the presence of symbiotic bacteria of the genus Wolbachia for fertility and viability of the host parasite. Targeting Wolbachia for elimination is a therapeutic approach that shows promise in the treatment of onchocerciasis and lymphatic filariasis. Here we demonstrate the use of a biodegradable polyanhydride nanoparticle-based platform for the co-delivery of the antibiotic doxycycline with the antiparasitic drug, ivermectin, to reduce microfilarial burden and rapidly kill adult worms. When doxycycline and ivermectin were co-delivered within polyanhydride nanoparticles, effective killing of adult female Brugia malayi filarial worms was achieved with approximately 4,000-fold reduction in the amount of drug used. Additionally the time to death of the macrofilaria was also significantly reduced (five-fold) when the anti-filarial drug cocktail was delivered within polyanhydride nanoparticles. We hypothesize that the mechanism behind this dramatically enhanced killing of the macrofilaria is the ability of the polyanhydride nanoparticles to behave as a Trojan horse and penetrate the cuticle, bypassing excretory pumps of B. malayi, and effectively deliver drug directly to both the worm and Wolbachia at high enough microenvironmental concentrations to cause death. These provocative findings may have significant consequences for the reduction in the amount of drug and the length of treatment required for filarial infections in terms of patient compliance and reduced cost of treatment. PMID- 26496202 TI - Deciphering the Developmental Dynamics of the Mouse Liver Transcriptome. AB - During development, liver undergoes a rapid transition from a hematopoietic organ to a major organ for drug metabolism and nutrient homeostasis. However, little is known on a transcriptome level of the genes and RNA-splicing variants that are differentially regulated with age, and which up-stream regulators orchestrate age specific biological functions in liver. We used RNA-Seq to interrogate the developmental dynamics of the liver transcriptome in mice at 12 ages from late embryonic stage (2-days before birth) to maturity (60-days after birth). Among 21,889 unique NCBI RefSeq-annotated genes, 9,641 were significantly expressed in at least one age, 7,289 were differently regulated with age, and 859 had multiple (> = 2) RNA splicing-variants. Factor analysis showed that the dynamics of hepatic genes fall into six distinct groups based on their temporal expression. The average expression of cytokines, ion channels, kinases, phosphatases, transcription regulators and translation regulators decreased with age, whereas the average expression of peptidases, enzymes and transmembrane receptors increased with age. The average expression of growth factors peak between Day-3 and Day-10, and decrease thereafter. We identified critical biological functions, upstream regulators, and putative transcription modules that seem to govern age specific gene expression. We also observed differential ontogenic expression of known splicing variants of certain genes, and 1,455 novel splicing isoform candidates. In conclusion, the hepatic ontogeny of the transcriptome ontogeny has unveiled critical networks and up-stream regulators that orchestrate age-specific biological functions in liver, and suggest that age contributes to the complexity of the alternative splicing landscape of the hepatic transcriptome. PMID- 26496204 TI - Different interaction modes for the default mode network revealed by resting state functional magnetic resonance imaging. AB - The default mode network (DMN), which, in the resting state, is in charge of both the brain's intrinsic mentation and its reflexive responses to external stimuli, is recognized as an essential network in the human brain. These two roles of mentation and reflexive response recruit the DMN nodes and other task networks differently. Existing research has revealed that the interactions inside the DMN (between nodes within the DMN) and outside the DMN (between nodes in the DMN and nodes in task networks) have different modes, in terms of both strength and timing. These findings raise interesting questions. For example, are the internal and external interactions of the DMN equally linear or nonlinear? This study examined these interaction patterns using datasets from the Human Connectome Project. A maximal information-based nonparametric exploration statistics strategy was utilized to characterize the full correlations, and the Pearson correlation was used to capture the linear component of the full correlations. We then contrasted the level of linearity/nonlinearity with respect to the internal and external interactions of the DMN. After a brain-wide exploration, we found that the interactions between the DMN and the sensorimotor-related networks (including the sensorimotor, sensory association, and integration areas) showed more nonlinearity, whereas those between the intra-DMN nodes were similarly less nonlinear. These findings may provide a clue for understanding the underlying neuronal principles of the internal and external roles of the DMN. PMID- 26496203 TI - A Novel Strategy for Detection and Enumeration of Circulating Rare Cell Populations in Metastatic Cancer Patients Using Automated Microfluidic Filtration and Multiplex Immunoassay. AB - Size selection via filtration offers an antigen-independent approach for the enrichment of rare cell populations in blood of cancer patients. We evaluated the performance of a novel approach for multiplex rare cell detection in blood samples from metastatic breast (n = 19) and lung cancer patients (n = 21), and healthy controls (n = 30) using an automated microfluidic filtration and multiplex immunoassay strategy. Captured cells were enumerated after sequential staining for specific markers to identify circulating tumor cells (CTCs), circulating mesenchymal cells (CMCs), putative circulating stem cells (CSCs), and circulating endothelial cells (CECs). Preclinical validation experiments using cancer cells spiked into healthy blood demonstrated high recovery rate (mean = 85%) and reproducibility of the assay. In clinical studies, CTCs and CMCs were detected in 35% and 58% of cancer patients, respectively, and were largely absent from healthy controls (3%, p = 0.001). Mean levels of CTCs were significantly higher in breast than in lung cancer patients (p = 0.03). Fifty-three percent (53%) of cancer patients harbored putative CSCs, while none were detectable in healthy controls (p<0.0001). In contrast, CECs were observed in both cancer and control groups. Direct comparison of CellSearch(r) vs. our microfluidic filter method revealed moderate correlation (R2 = 0.46, kappa = 0.47). Serial blood analysis in breast cancer patients demonstrated the feasibility of monitoring circulating rare cell populations over time. Simultaneous assessment of CTCs, CMCs, CSCs and CECs may provide new tools to study mechanisms of disease progression and treatment response/resistance. PMID- 26496205 TI - Single-Blinded, Randomized Preliminary Study Evaluating the Effect of Transcutaneous Electrical Nerve Stimulation on Postoperative Pain in Patients with Colles' Fracture. AB - OBJECTIVE: Transcutaneous electrical nerve stimulation (TENS) has been widely used for pain relief; however, the effect remains controversial. The authors hypothesized that TENS can relieve acute pain. Therefore, a single-blinded, randomized, controlled preliminary study was designed on postoperative pain in patients with Colles' fracture. METHODS: In total, 36 patients were assigned to a real TENS or sham TENS group (18 patients in each group). TENS (50 Hz, 15 min/day) was applied near the Quchi (LI11) and Waiguan (TE5) surfaces of the operative side continuously for 5 days after surgical treatment. RESULTS: The visual analog scale (VAS) scores did not differ significantly between the real and sham TENS groups before the TENS period, from the first to fifth day after surgical treatment (all p > 0.05), whereas the VAS scores were lower for the real TENS group than for the sham TENS group in the post-TENS period, on the first, third, fourth, and fifth days after surgical treatment (all p <= 0.01). CONCLUSION: TENS might be valuable as a treatment of postoperative pain, but clinicians and researchers should know that it is no different than a treatment with placebo. Especially, since this form of treatment and sham treatment has a great chance of working under the mechanism of the placebo effect due to its single-blindedness. PMID- 26496206 TI - Simultaneous measurement of aerodynamic forces and kinematics in flapping wings of tethered locust. AB - Aerodynamic and inertial forces and corresponding kinematics of flapping wings of locusts, Schistocerca americana, were investigated in a low-speed wind tunnel. The experimental setup included live locusts mounted on microbalance synchronized with a high-speed video system. Simultaneous measurements of wing kinematics and forces were carried out on three locusts at 7 degrees angle of attack and velocities of 0 m s(-1) and 4 m s(-1). Time variations of flapping and pitching angles exhibit similar patterns in fore- and hindwings and among the animals. Significant tip to root variations in pitching angle are found in both wings. The locusts have much larger flapping and pitching amplitudes in still air causing larger oscillations in inertial forces. Inertial forces are added to the lift and thrust on one part of the stroke, resulting in higher reaction forces and subtracted on the other part. Plots of the lift demonstrate similar trends with and without the wind. The global maxima and peak-to-peak amplitudes in lift are about the same in both tests. However, local minima are significantly lower in still air, resulting in much smaller stroke-averaged lift. Amplitudes of thrust force oscillations are much higher in still air; consequently, the stroke averaged thrust is higher compared to the non-zero freestream velocity case. PMID- 26496208 TI - Potential role of 8-oxoguanine DNA glycosylase 1 as a STAT1 coactivator in endotoxin-induced inflammatory response. AB - Human 8-oxoguanine DNA glycosylase 1 (OGG1) is the major DNA repair enzyme that plays a key role in excision of oxidative damaged DNA bases such as 8-oxoguainine (8-oxoG). Recent studies suggest another function of OGG1, namely that it may be involved in the endotoxin- or oxidative stress-induced inflammatory response. In this study, we investigated the role of OGG1 in the inflammatory response. OGG1 expression is increased in the organs of endotoxin-induced or myelin oligodendrocyte glycoprotein (MOG)-immunized mice and immune cells, resulting in induction of the expression of pro-inflammatory mediators at the transcriptional levels. Biochemical studies showed that signal transducer and activator of transcription 1 (STAT1) plays a key role in endotoxin-induced OGG1 expression and inflammatory response. STAT1 regulates the transcriptional activity of OGG1 through recruiting and binding to the gamma-interferon activation site (GAS) motif of the OGG1 promoter region, and chromatin remodeling by acetylation and dimethylation of lysine-14 and -4 residues of histone H3. In addition, OGG1 acts as a STAT1 coactivator and has transcriptional activity in the presence of endotoxin. The data presented here identifies a novel mechanism, and may provide new therapeutic strategies for the treatment of endotoxin-mediated inflammatory diseases. PMID- 26496207 TI - Anticancer therapeutic potential of Mn porphyrin/ascorbate system. AB - Ascorbate (Asc) as a single agent suppressed growth of several tumor cell lines in a mouse model. It has been tested in a Phase I Clinical Trial on pancreatic cancer patients where it exhibited no toxicity to normal tissue yet was of only marginal efficacy. The mechanism of its anticancer effect was attributed to the production of tumoricidal hydrogen peroxide (H2O2) during ascorbate oxidation catalyzed by endogenous metalloproteins. The amount of H2O2 could be maximized with exogenous catalyst that has optimized properties for such function and is localized within tumor. Herein we studied 14 Mn porphyrins (MnPs) which differ vastly with regards to their redox properties, charge, size/bulkiness and lipophilicity. Such properties affect the in vitro and in vivo ability of MnPs (i) to catalyze ascorbate oxidation resulting in the production of H2O2; (ii) to subsequently employ H2O2 in the catalysis of signaling proteins oxidations affecting cellular survival pathways; and (iii) to accumulate at site(s) of interest. The metal-centered reduction potential of MnPs studied, E1/2 of Mn(III)P/Mn(II)P redox couple, ranged from -200 to +350 mV vs NHE. Anionic and cationic, hydrophilic and lipophilic as well as short- and long-chained and bulky compounds were explored. Their ability to catalyze ascorbate oxidation, and in turn cytotoxic H2O2 production, was explored via spectrophotometric and electrochemical means. Bell-shape structure-activity relationship (SAR) was found between the initial rate for the catalysis of ascorbate oxidation, vo(Asc)ox and E1/2, identifying cationic Mn(III) N-substituted pyridylporphyrins with E1/2>0 mV vs NHE as efficient catalysts for ascorbate oxidation. The anticancer potential of MnPs/Asc system was subsequently tested in cellular (human MCF-7, MDA-MB-231 and mouse 4T1) and animal models of breast cancer. At the concentrations where ascorbate (1mM) and MnPs (1 or 5 uM) alone did not trigger any alteration in cell viability, combined treatment suppressed cell viability up to 95%. No toxicity was observed with normal human breast epithelial HBL-100 cells. Bell-shape relationship, essentially identical to vo(Asc)oxvs E1/2, was also demonstrated between MnP/Asc-controlled cytotoxicity and E1/2-controlled vo(Asc)ox. Magnetic resonance imaging studies were conducted to explore the impact of ascorbate on T1 relaxivity. The impact of MnP/Asc on intracellular thiols and on GSH/GSSG and Cys/CySS ratios in 4T1 cells was assessed and cellular reduction potentials were calculated. The data indicate a significant increase in cellular oxidative stress induced by MnP/Asc. Based on vo(Asc)oxvs E1/2 relationships and cellular toxicity, MnTE-2-PyP(5+) was identified as the best catalyst among MnPs studied. Asc and MnTE-2-PyP(5+) were thus tested in a 4T1 mammary mouse flank tumor model. The combination of ascorbate (4 g/kg) and MnTE-2-PyP(5+) (0.2mg/kg) showed significant suppression of tumor growth relative to either MnTE-2-PyP(5+) or ascorbate alone. About 7-fold higher accumulation of MnTE-2-PyP(5+) in tumor vs normal tissue was found to contribute largely to the anticancer effect. PMID- 26496210 TI - Paricalcitol, Microvascular and Endothelial Function in Non-Diabetic Chronic Kidney Disease: A Randomized Trial. AB - BACKGROUND: Vitamin D deficiency, sympathetic activation and endothelial dysfunction are associated with increased cardiovascular risk in patients with chronic kidney disease (CKD). Studies have so far failed to establish the role of vitamin D and vitamin D receptor activator (VDRA) treatment in moderate CKD. This trial was designed to assess whether VDRA treatment can ameliorate sympathetic activation and macro- and microvascular dysfunction in non-diabetic patients with moderate CKD. METHODS: We conducted a randomized controlled double-blind trial using placebo, 1 or 2 MUg of paricalcitol, a VDRA, for 3 months. We assessed muscle sympathetic nerve activity (MSNA) by microneurography, pulse wave velocity (PWV) by tonometry, flow mediated vasodilatation (FMD) by brachial ultrasound, skin microcirculation assessed by iontophoresis and capillary blood velocity (CBV) by videophotometric capillaroscopy. RESULTS: Thirty-six patients with a mean age of 65 years and mean estimated glomerular filtration rate of 40 ml/min/1.73 m2 were included. We found a significant decline in endothelial function after 3 months, except in the group receiving 2 MUg of paricalcitol. The higher dose (2 MUg) seemed to attenuate the decline in microvascular endothelial function, assessed by iontophoresis of acetylcholine (p=0.06 for all groups, p=0.65 for the 2 MUg group) and for FMD (p=0.006 for all groups, p=0.54 for the 2 MUg group). We found a borderline significance (p=0.05) for improved CBV in the treated groups. We found no significant changes between treatments in MSNA, PWV or albuminuria. CONCLUSIONS: Endothelial function declined significantly over 3 months in patients with moderate CKD, and this decline could be ameliorated by VDRA treatment (NCT01204528). PMID- 26496209 TI - The Cannabinoid Receptor CB1 Interacts with the WAVE1 Complex and Plays a Role in Actin Dynamics and Structural Plasticity in Neurons. AB - The molecular composition of the cannabinoid type 1 (CB1) receptor complex beyond the classical G-protein signaling components is not known. Using proteomics on mouse cortex in vivo, we pulled down proteins interacting with CB1 in neurons and show that the CB1 receptor assembles with multiple members of the WAVE1 complex and the RhoGTPase Rac1 and modulates their activity. Activation levels of CB1 receptor directly impacted on actin polymerization and stability via WAVE1 in growth cones of developing neurons, leading to their collapse, as well as in synaptic spines of mature neurons, leading to their retraction. In adult mice, CB1 receptor agonists attenuated activity-dependent remodeling of dendritic spines in spinal cord neurons in vivo and suppressed inflammatory pain by regulating the WAVE1 complex. This study reports novel signaling mechanisms for cannabinoidergic modulation of the nervous system and demonstrates a previously unreported role for the WAVE1 complex in therapeutic applications of cannabinoids. PMID- 26496211 TI - A multi-institutional analysis of 429 patients undergoing major hepatectomy for colorectal cancer liver metastases: The impact of concomitant bile duct resection on survival. AB - BACKGROUND: Data are lacking on long-term outcomes of patients undergoing major hepatectomy requiring bile duct resection (BDR) for the treatment of colorectal cancer liver metastases. METHODS: Patients who underwent major hepatectomy (>=3 segments) for metastatic colorectal cancer from 2000-2010 at three US academic institutions were included. The primary outcome was disease-specific survival (DSS). RESULTS: Of 429 patients, nine (2.1%) underwent BDR, which was associated with pre-operative portal vein embolization (25.0% vs. 4.3%; P = 0.049). There were no significant differences in age, ASA class, margin status, number of lesions, tumor size, cirrhosis, perineural invasion, or lymphovascular invasion. BDR was independently associated with increased postoperative major complications (OR: 6.22; 95%CI:1.44-26.97; P = 0.015). There were no differences in length of stay, reoperation, readmission, or 30-day mortality. Patients who underwent BDR had markedly decreased DSS (9.3 vs. 39.9 mo; P = 0.002). When accounting for differences between the two groups, the need for BDR was independently associated with reduced DSS (HR: 3.06; 95%CI:1.12-8.34; P = 0.029). CONCLUSION: Major hepatectomy with concomitant bile duct resection is seldom performed in patients undergoing resection of colorectal cancer liver metastases and is associated with higher major morbidity and reduced disease-specific survival compared to major hepatectomy alone. Stringent selection criteria should be applied when patients may need bile duct resection during hepatectomy for colorectal cancer liver metastases. PMID- 26496212 TI - Multidisciplinary approach of lumbo-sacral chordoma: From oncological treatment to reconstructive surgery. AB - Lumbo-sacral chordoma is a rare, slow-growing tumor, arising from embryonic nothocordal remnants. Wide en bloc excision with clear margins remains mandatory to achieve satisfactory recurrence rates and disease-free survival. No chemotherapy has been demonstrated to be effective and radiotherapy is only marginally effective. Tyrosine kinase receptor inhibitors have showed encouraging results in locally advanced and metastatic chordoma. Reconstructive surgery may become very complex. Multidisciplinary approach in tertiary hospitals is always necessary. PMID- 26496213 TI - Performance, carotenoids yield and microbial population dynamics in a photobioreactor system treating acidic wastewater: Effect of hydraulic retention time (HRT) and organic loading rate (OLR). AB - Effects of hydraulic retention time (HRT) and influent organic loading rate (OLR) were investigated in a photobioreactor containing PNSB (Rhodopseudomonas palustris)-chemoheterotrophic bacteria to treat volatile fatty acid wastewater. Pollutants removal, biomass production and carotenoids yield in different phases were investigated in together with functional microbial population dynamics. The results indicated that properly decreasing HRT and increasing OLR improved the nutrient removal performance as well as the biomass and carotenoids productions. 85.7% COD, 89.9% TN and 91.8% TP removals were achieved under the optimal HRT of 48h and OLR of 2.51g/L/d. Meanwhile, the highest biomass production and carotenoids yield were 2719.3mg/L and 3.91mg/g-biomass respectively. In addition, HRT and OLR have obvious impacts on PNSB and total bacteria dynamics. Statistical analyses indicated that the COD removal exhibited a positive relationship with OLR, biomass and carotenoids production. PNSB/total bacteria ratio had a positive correlation with the carotenoids yield. PMID- 26496214 TI - Optimization and microbial community analysis of anaerobic co-digestion of food waste and sewage sludge based on microwave pretreatment. AB - The effects of microwave pretreatment (MW) on co-digestion of food waste (FW) and sewage sludge (SS) have never been investigated. In this study, a series of mesophilic biochemical methane potential (BMP) tests were conducted to determine the optimized ratio of FW and SS based on MW, and the evolution of bacterial and archaeal community was investigated through high-throughput sequencing method. Results showed that the optimized ratio was 3:2 for co-digestion of FW and SS based on MW, and the methane production was 316.24 and 338.44mLCH4/gVSadded for MW-FW and MW-SS, respectively. The MW-SS was superior for methane production compared to MW-FW, in which accumulation of propionic acid led to the inhibition of methanogenesis. Proteiniborus and Parabacteroides were responsible for proteins and polysaccharides degradation for all, respectively, while Bacteroides only dominated in co-digestion. Methanosphaera dominated in MW-FW at the active methane production phase, while it was Methanosarcina in MW-SS and mono-SS. PMID- 26496215 TI - Effect of frequency and reaction time in focused ultrasonic pretreatment of energy cane bagasse for bioethanol production. AB - Pretreatment of lignocellulosic biomass is a critical steps in bioethanol production. Ultrasonic pretreatment significantly improves cellulose hydrolysis increasing sugar yields, but current system designs have limitations related to efficiency and scalability. This study evaluates the ultrasonic pretreatment of energy cane bagasse in a novel scalable configuration and by maximizing coupling of ultrasound energy to the material via active modulation of frequency. Pretreatment was conducted in 28% ammonia water mixture at a sample:ammonia:water ratio of 1:0.5:8. Process performance was investigated as a function of frequency (20, 20.5, 21kHz), reaction time (30, 45, 60min), temperature, and power levels for multiple combinations of ammonia, water and sample mixture. Results indicated an increased enzymatic digestibility, with maximum glucose yield of 24.29g/100g dry biomass. Theoretical ethanol yields obtained ranged from 6.47 to a maximum of 24.29g/100g dry biomass. Maximum energy attainable was 886.34kJ/100g dry biomass. PMID- 26496216 TI - Effect of alkali lignins with different molecular weights from alkali pretreated rice straw hydrolyzate on enzymatic hydrolysis. AB - This study investigated the effect of alkali lignins with different molecular weights on enzymatic hydrolysis of lignocellulose. Different alkali lignins fractions, which were obtained from cascade ultrafiltration, were added into the dilute acid pretreated (DAP) and alkali pretreated (AP) rice straws respectively during enzymatic hydrolysis. The results showed that the addition of alkali lignins enhanced the hydrolysis and the enhancement for hydrolysis increased with increasing molecular weights of alkali lignins, with maximum enhancement being 28.69% for DAP and 20.05% for AP, respectively. The enhancement was partly attributed to the improved cellulase activity, and filter paper activity increased by 18.03% when adding lignin with highest molecular weight. It was found that the enhancement of enzymatic hydrolysis was correlated with the adsorption affinity of cellulase on alkali lignins, and the difference in surface charge and hydrophobicity of alkali lignins were responsible for the difference in affinity between cellulase and lignins. PMID- 26496217 TI - Biotechnological potential of Synechocystis salina co-cultures with selected microalgae and cyanobacteria: Nutrients removal, biomass and lipid production. AB - Cultivation of microalgae and cyanobacteria has been the focus of several research studies worldwide, due to the huge biotechnological potential of these photosynthetic microorganisms. However, production of these microorganisms is still not economically viable. One possible alternative to improve the economic feasibility of the process is the use of consortia between microalgae and/or cyanobacteria. In this study, Chlorella vulgaris, Pseudokirchneriella subcapitata and Microcystis aeruginosa were co-cultivated with Synechocystis salina to evaluate how dual-species cultures can influence biomass and lipid production and nutrients removal. Results have shown that the three studied consortia achieved higher biomass productivities than the individual cultures. Additionally, nitrogen and phosphorus consumption rates by the consortia provided final concentrations below the values established by European Union legislation for these nutrients. In the case of lipid productivities, higher values were determined when S. salina was co-cultivated with P. subcapitata and M. aeruginosa. PMID- 26496218 TI - Effect of pretreatment severity in continuous steam explosion on enzymatic conversion of wheat straw: Evidence from kinetic analysis of hydrolysis time courses. AB - Focusing on continuous steam explosion, the influence of pretreatment severity due to varied acid loading on hydrolysis of wheat straw by Trichoderma reesei cellulases was investigated based on kinetic evaluation of the saccharification of each pretreated substrate. Using semi-empirical descriptors of the hydrolysis time course, key characteristics of saccharification efficiency were captured in a quantifiable fashion. Not only hydrolysis rates per se, but also the transition point of their bi-phasic decline was crucial for high saccharification degree. After 48h the highest saccharification was achieved for substrate pretreated at relatively low severity (1.2% acid). Higher severity increased enzyme binding to wheat straw, but reduced the specific hydrolysis rates. Higher affinity of the lignocellulosic material for cellulases does not necessarily result in increased saccharification, probably because of lignin modifications occurring at high pretreatment severities. At comparable severity, continuous pretreatment produced a substrate more susceptible to enzymatic hydrolysis than the batch process. PMID- 26496219 TI - Radially oriented nanostrand electrodes to boost glucose sensing in mammalian blood. AB - Architecture of nanoscale electrochemical sensors for ultra-trace detection of glucose in blood is important in real-life sampling and analysis. To broaden the application of electrochemical sensing of glucose, we fabricated, for the first time, a glucose sensor electrode based on radially oriented NiO nanostrands (NSTs) onto 3D porous Ni foam substrate for monitoring, as well as selective and sensitive sensing of glucose in mammalian blood. The simple, scalable one-pot fabrication of this NST-Ni sensor design enabled control of the pattern of radially oriented NSTs onto 3D porous Ni foam substrate. The radial orientation of NST-Ni electrode onto the interior of the 3D porous substrate with controlled crystal structure size and atomic arrangement along the axis of the strands, intrinsic surface defects, and superior surface properties, such as hydrophilicity, high surface energy, and high density led to highly exposed catalytic active sites. The hierarchical NST-Ni electrode was used to develop a sensitive and selective sensor over a wide range of glucose concentrations among actively competitive ions, chemical species and molecular agents, and multi cyclic sensing assays. The NST-Ni electrode shows significant glucose sensing performance in terms of unimpeded diffusion pathways, a wide range of concentration detection, and lower limit of detection (0.186 uM) than NiO nanosheet (NS)-Ni foam electrode pattern, indicating the effectiveness of the shape-dependent structural architecture of NST-Ni electrode. In this study, the NST-Ni electrode is fabricated to develop a simple, selective method for detecting glucose in physiological fluids (e.g., mammalian blood). PMID- 26496220 TI - Switchable fluorescence of gold nanoclusters for probing the activity of alkaline phosphatase and its application in immunoassay. AB - In this work, a novel strategy for modulating the fluorescence of gold nanoclusters (Au NCs) is developed. The fluorescence of bovine serum albumin (BSA) protected Au NCs is firstly quenched by KMnO4 and then restored by ascorbic acid (AA) due to the deterioration/restoration of the surface structure. Based on which, a novel "switch-on" fluorescent assay for probing the activity of alkaline phosphatase (ALP) is developed with a detection limit as low as 0.002 U/L. In addition, this testing protocol is also expanded to the detection of the inhibitor of ALP and mouse IgG (as a model), the detection limits are 15 ng/mL for the inhibitor of 2,4-Dichlorophenoxyacetic acid (2,4-DA) and 1.5 pg/mL for mouse IgG. The present method paves a new way to develop convenient, sensitive, and selective metal NCs-based fluorescent "turn-on" probes with promising applications in versatile biosensing. PMID- 26496221 TI - SERS assay of telomerase activity at single-cell level and colon cancer tissues via quadratic signal amplification. AB - As an important biomarker and therapeutic target, telomerase has attracted extensive attention concerning its detection and monitoring. Recently, enzyme assisted amplification approaches have provided useful platforms for the telomerase activity detection, however, further improvement in sensitivity is still hindered by the single-step signal amplification. Herein, we develop a quadratic signal amplification strategy for ultrasensitive surface-enhanced Raman scattering (SERS) detection of telomerase activity. The central idea of our design is using telomerase-induced silver nanoparticles (AgNPs) assembly and silver ions (Ag(+))-mediated cascade amplification. In our approach, each telomerase-aided DNA sequence extension could trigger the formation of a long double-stranded DNA (dsDNA), making numerous AgNPs assembling along with this long strand through specific Ag-S bond, to form a primary amplification element. For secondary amplification, each conjugated AgNP was dissolved into Ag(+), which can effectively induce the 4-aminobenzenethiol (4-ABT) modified gold nanoparticles (AuNPs@4-ABT) to undergo aggregation to form numerous "hot-spots". Through quadratic amplifications, a limit of detection down to single HeLa cell was achieved. More importantly, this method demonstrated good performance when applied to tissues from colon cancer patients, which exhibits great potential in the practical application of telomerase-based cancer diagnosis in early stages. To demonstrate the potential in screening the telomerase inhibitors and telomerase-targeted drugs, the proposed design is successfully employed to measure the inhibition of telomerase activity by 3'-azido-3'-deoxythymidine. PMID- 26496222 TI - Invertase-labeling gold-dendrimer for in situ amplified detection mercury(II) with glucometer readout and thymine-Hg(2+)-thymine coordination chemistry. AB - A simple, low-cost transducer with glucometer readout was designed for sensitive detection of mercury(II) (Hg(2+)), coupling with thymine-Hg(2+)-thymine (T-Hg(2+) T) coordination chemistry and invertase-functionalized gold-dendrimer nanospheres for the signal amplification. Initially, nanogold-encapsulated poly(amidoamine) dendrimers (Au DENs) were synthesized by in-situ reduction of gold(III). Thereafter, the as-prepared Au DENs were utilized for the labeling of invertase and T-rich signal DNA probe. In the presence of target Hg(2+), the functionalized Au DENs were conjugated to capture DNA probe-modified electrode via T-Hg(2+)-T coordination chemistry. Accompanying the Au DENs, the labeled invertase could hydrolyze sucrose into glucose, which could be quantitatively monitored by an external personal glucometer (PGM). The PGM signal increased with the increasing target Hg(2+) in the sample. Under the optimal conditions, our designed sensing platform exhibited good PGM responses toward target Hg(2+), and allowed the detection of Hg(2+) at a concentration as low as 4.2 pM. This sensing system also displayed remarkable specificity relative to target Hg(2+) against other competing ions, and could be applied for reliable monitoring of spiked Hg(2+) into the environmental water samples with satisfactory results. With the advantages of cost-effectiveness, simplicity, portability, and convenience, our strategy provides a tremendous potential to be a promising candidate for point-of use monitoring of non-glucose targets by the public. PMID- 26496223 TI - Sensitive detection of Escherichia coli O157:H7 using Pt-Au bimetal nanoparticles with peroxidase-like amplification. AB - Escherichia coli O157:H7 is one of the most notorious foodborne pathogens causing serious disease at low infectious dose. To protect consumers from deadly foodborne E. coli O157:H7 infection, it is vital to develop a simple, reliable, sensitive and rapid method which can detect low level E. coli O157:H7 in foods at real-time. We have successfully developed a novel immunochromatographic assay (ICA) with enhanced sensitivity for the visual and quantitative detection of E. coli O157:H7. Sandwich-type immunoreactions were performed on the ICA, and Pt-Au bimetal nanoparticles (NPs) were accumulated on the test zone. The signal amplification is based on Pt-Au bimetal NPs possessing high peroxidase activity toward 3,3',5,5'-tetramethylbenzidine, which can produce characteristic colored bands and thus, enable visual detection of E. coli O157:H7 without instrumentation. The innovative aspect of this approach lies in the visualization and quantification of target pathogen through the detection of color intensity. Due to the excellent peroxidase activity of Pt-Au NPs, they emit strong visible color intensity in less than 1 min for visual observation even in low concentration range of E. coli O157:H7. Quantification was performed using a commercial assay meter. The sensitivity was improved more than 1000-folds compared to the conventional test strip based on colored gold-colloids. Although the feasibility was demonstrated using E. coli O157:H7 as a model analyte, this approach could be easily developed to be a universal signal amplification technique and applied to detection of a wide variety of foodborne pathogens and protein biomarkers. PMID- 26496224 TI - Silicon nanowire biosensors for detection of cardiac troponin I (cTnI) with high sensitivity. AB - We have demonstrated highly sensitive and label-free detection of cardiac troponin I (cTnI), a biomarker for diagnosis of acute myocardial infarction, using silicon nanowire field-effect transistors. A honeycomb-like structure is utilized for nanowire configuration to offer improved electrical performance and increased sensing area. The fabricated devices show n-type behavior with a relatively high ON-OFF current ratio, small sub-threshold swing and low gate leakage current. Monoclonal antibodies for cTnI were covalently immobilized on the nanowire surface and the attachment of antibodies is clearly visualized by atomic force microscope. The sensitivity with various concentrations of buffer solution was also investigated in order to determine the optimal buffer condition. The devices exhibit highest sensitivity under buffer solutions with low ion concentration. In addition, the detection limit of the sensor is as low as ~5 pg/mL, the lowest reported in the literature to date and nearly an order of magnitude smaller than the suggested threshold limit. The fabricated devices demonstrate a good selectivity for detecting cTnI. PMID- 26496225 TI - Examining challenging behaviors of clients with borderline personality disorder. AB - Few studies have examined effects of challenging behaviors of clients with borderline personality disorder (BPD) on psychotherapy outcomes. Dialectical behavior therapy (DBT) is an evidence-based treatment designed to treat chronic suicidality, self-directed violence (SDV), and emotion dysregulation, while targeting challenging behaviors. DBT has been shown to be effective with clients with BPD. We evaluated whether therapist reported challenging behaviors, such as high volume phone contacts or violating the therapist's limits, during DBT would be associated with dropping out of DBT, severity and frequency of SDV, emotion regulation deficits, psychological symptom severity and client's and therapist's satisfaction of treatment. The current study examined challenging behaviors reported by therapists in a sample of 63 psychiatrically disabled outpatient DBT clients diagnosed with BPD (73% women, average age 37 years). More frequent phone contacts were associated with a decrease in dropout and psychological symptoms, and an increase in client and therapist satisfaction. More avoidance/disengagement behavior was associated with more than twice the risk of SDV and a decrease in therapist satisfaction. Findings suggest that the phone coaching might serve to maximize client satisfaction and reduce the likelihood of dropout. PMID- 26496226 TI - Immediate-early response 5 (IER5) interacts with protein phosphatase 2A and regulates the phosphorylation of ribosomal protein S6 kinase and heat shock factor 1. AB - Immediate-early response 5 (IER5) is a growth factor-inducible protein with homology to the N-terminus of IER2. Deletion analysis shows that a large region of IER5, including the N-terminal region, is involved in cell growth and stress resistance. The N-terminal region mediates IER5 oligomerization and binding to the B55 regulatory subunit of protein phosphatase 2A (PP2A). IER5 physically interacts with the PP2A target proteins ribosomal protein S6 kinase (S6K) and heat shock factor 1 (HSF1), and the interactions are essential for the reduced phosphorylation of S6K and HSF1. Our data indicate that oligomeric IER5 regulates PP2A activity and cell growth. PMID- 26496227 TI - An anatomy of old-age disability: Time use, affect and experienced utility. AB - Complementing the commonly used concepts of evaluative wellbeing and decision utility, emotional wellbeing and experienced utility are important welfare criteria to assess individuals' subjective wellbeing, especially for valuing health and disability. Yet, almost all empirical evidences on the link between disability and experienced wellbeing come from developed countries. This paper studies the relationship between old-age disability and experienced utility in five low- and middle-income countries. Using data on individual time use and activity-specific affective experiences from an abbreviated version of the Day Reconstruction Method, we document a strong negative association between disability and experienced utility. These differences in experienced utility by disability status are exclusively due to worse activity-specific affective experiences among persons with disabilities. By contrast, disability-related differences in time use provide small compensating effects. Interventions or technologies that facilitate daily life hold most promise to improve experienced utility among persons with disabilities in the developing world. PMID- 26496228 TI - A unified set-based test with adaptive filtering for gene-environment interaction analyses. AB - In genome-wide gene-environment interaction (GxE) studies, a common strategy to improve power is to first conduct a filtering test and retain only the SNPs that pass the filtering in the subsequent GxE analyses. Inspired by two-stage tests and gene-based tests in GxE analysis, we consider the general problem of jointly testing a set of parameters when only a few are truly from the alternative hypothesis and when filtering information is available. We propose a unified set based test that simultaneously considers filtering on individual parameters and testing on the set. We derive the exact distribution and approximate the power function of the proposed unified statistic in simplified settings, and use them to adaptively calculate the optimal filtering threshold for each set. In the context of gene-based GxE analysis, we show that although the empirical power function may be affected by many factors, the optimal filtering threshold corresponding to the peak of the power curve primarily depends on the size of the gene. We further propose a resampling algorithm to calculate P-values for each gene given the estimated optimal filtering threshold. The performance of the method is evaluated in simulation studies and illustrated via a genome-wide gene gender interaction analysis using pancreatic cancer genome-wide association data. PMID- 26496229 TI - Modulators of the human ABCC2: hope from natural sources? AB - Human ABCC2 is an ATP-binding cassette transporter involved in the export of endobiotics and xenobiotics. It is involved in cisplatin resistance in cancer cells, particularly in ovarian cancer. The few known ABCC2 modulators are poorly efficient, so it is necessary to explore new ways to select and optimize efficient compounds ABCC2. Natural products offer an original scaffold for such a strategy and brings hope for this aim. This review covers basic knowledge about ABCC2, from distribution and topology aspects to physiological and pathological functions. It summarizes the effect of natural products as ABCC2 modulators. Certain plant metabolites act on different ABCC2 regulation levels and therefore are promising candidates to block the multidrug resistance mediated by ABCC2 in cancer cells. PMID- 26496230 TI - Regioselective Ring Opening of Di-isopropylsilylenes Derived from 1,3-Diols with Alkyl Lithium Reagents. AB - The selective alkyl lithium-induced ring opening of 1,3-di-isopropylsilylenes is described. The reaction affords a differentially substituted 1,3-diol bearing a silane that resides at the oxygen in the more sterically demanding position. The reaction can be highly selective with a regiochemical preference up to >50:1 and likely proceeds via an alkoxy-silane intermediate. This intermediate can by trapped by methyl iodide to provide the corresponding silyl methyl ether, wherein the silane again resides at the oxygen in the more sterically demanding position. PMID- 26496231 TI - Reduced Graphene Oxide/Tin-Antimony Nanocomposites as Anode Materials for Advanced Sodium-Ion Batteries. AB - Reduced graphene oxides loaded with tin-antimony alloy (RGO-SnSb) nanocomposites were synthesized through a hydrothermal reaction and the subsequent thermal reduction treatments. Transmission electron microscope images confirm that SnSb nanoparticles with an average size of about 20-30 nm are uniformly dispersed on the RGO surfaces. When they were used as anodes for rechargeable sodium (Na)-ion batteries, these as-synthesized RGO-SnSb nanocomposite anodes delivered a high initial reversible capacity of 407 mAh g(-1), stable cyclic retention for more than 80 cycles and excellent cycle stability at ultra high charge/discharge rates up to 30C. The significantly improved performance of the synthesized RGO-SnSb nanocomposites as Na-ion battery anodes can be attributed to the synergetic effects of RGO-based flexible framework and the nanoscale dimension of the SnSb alloy particles (<30 nm). Nanosized intermetallic SnSb compounds can exhibit improved structural stability and conductivity during charge and discharge reactions compared to the corresponding individuals (Sn and Sb particles). In the meantime, RGO sheets can tightly anchor SnSb alloy particles on the surfaces, which can not only effectively suppress the agglomeration of SnSb particles but also maintain excellent electronic conduction. Furthermore, the mechanical flexibility of the RGO phase can accommodate the volume expansion and contraction of SnSb particles during the prolonged cycling, therefore, improve the electrode integrity mechanically and electronically. All of these contribute to the electrochemical performance improvements of the RGO-SnSb nanocomposite-based electrodes in rechargeable Na-ion batteries. PMID- 26496232 TI - Agism and burnout among nurses in long-term care facilities in Israel. AB - OBJECTIVES: The extent to which agism and professional qualifications are associated with nurses' burnout in long-term care facilities for older adults has been barely examined. This study is aimed to examine the extent to which agism, professional education, and geriatric training explain work burnout. METHOD: The study included a convenience sample of 154 nurses working in 17 long-term care facilities in the Tel Aviv area in Israel. To examine agism, Kogan's Attitudes toward Old People Scale was used, and to probe burnout, the Maslach Burnout Inventory was used. RESULTS: Overall burnout was significantly explained by agism, nurses' professional education, length of working as a nurse, and type of facility ownership. When examining each dimension of burnout, agism was a significant predictor of depersonalization and personal achievement. CONCLUSION: Agism plays a role in overall burnout. Therefore, training programs that can combat agism can reduce burnout of nurses in long-term care facilities. PMID- 26496233 TI - Permanence of a predator-prey discrete system with Holling-IV functional response and distributed delays. AB - A predator-prey discrete-time model with Holling-IV functional response and distributed delays is investigated in this paper. By using the comparison theorem of the difference equation and some analysis technique, some sufficient conditions are obtained for the permanence of the discrete predator-prey system. Two examples are given to illustrate the feasibility of the obtained result. PMID- 26496235 TI - Smart and Fast Blood Counting of Trace Volumes of Body Fluids from Various Mammalian Species Using a Compact, Custom-Built Microscope Cytometer. AB - We report an accurate method to count red blood cells, platelets, and white blood cells, as well as to determine hemoglobin in the blood of humans, horses, dogs, cats, and cows. Red and white blood cell counts can also be performed on human body fluids such as cerebrospinal fluid, synovial fluid, and peritoneal fluid. The approach consists of using a compact, custom-built microscope to record large field-of-view, bright-field, and fluorescence images of samples that are stained with a single dye and using automatic algorithms to count blood cells and detect hemoglobin. The total process takes about 15 min, including 5 min for sample preparation, and 10 min for data collection and analysis. The minimum volume of blood needed for the test is 0.5 MUL, which allows for minimally invasive sample collection such as using a finger prick rather than a venous draw. Blood counts were compared to gold-standard automated clinical instruments, with excellent agreement between the two methods as determined by a Bland-Altman analysis. Accuracy of counts on body fluids was consistent with hand counting by a trained clinical lab scientist, where our instrument demonstrated an approximately 100 fold lower limit of detection compared to current automated methods. The combination of a compact, custom-built instrument, simple sample collection and preparation, and automated analysis demonstrates that this approach could benefit global health through use in low-resource settings where central hematology laboratories are not accessible. PMID- 26496236 TI - Dementia worry and its relationship to dementia exposure, psychological factors, and subjective memory concerns. AB - With increased societal awareness of dementia, older adults show increased concern about developing dementia, leading to misidentification of aging-related cognitive glitches as signs of dementia. While some researchers have suggested self-reported cognitive concerns accurately identify older adults with early signs of dementia, there is evidence that subjective cognitive decline is not associated with objective cognitive performance and instead reflects psychological factors consistent with models of health anxiety, including dementia worry. We examined the construct of dementia worry and its relationship to subjective memory concerns in 100 older adults (Mage = 69 years) without signs of dementia, using a recently developed measure of dementia worry. Consistent with hypotheses, dementia worry was related to exposure to dementia, having a high number of depressive or general worry symptoms, and having more memory concerns. Exposure to dementia moderated the relationship of dementia worry to depression and general worry. Furthermore, dementia worry moderated the relationship of objective memory impairment to subjective memory ratings. The results provide further evidence of the role of psychological factors such as dementia worry in subjective memory report and emphasize the need for objective cognitive testing before making determinations about dementia in older adults expressing memory concerns. PMID- 26496238 TI - Radical Cyclization Followed by the Fragmentation of Carbonyl Compounds: Effect of an alpha-Benzoyl Group. AB - To study a recently developed radical cyclization reaction followed by a fragmentation process in more detail, a series of alpha-benzoyl carbonyl compounds were prepared, including precursors with aldehyde and ketone moieties. Initiated by tributyltin hydride and AIBN, radical cyclization followed by fragmentation proceeded to give the desired carbonyl translocation products in 4 benzoyl-5-pentanal, 4-benzoyl-5-pentanone, 5-benzoyl-6-hexanal, and 5-benzoyl-6 hexanone radical systems. In comparison with early reports on radical cyclization reactions of alpha-oxy carbonyl compounds, neither a geminal dialkyl effect nor a conformationally rigid system was required to give the desired carbonyl translocation products. This effect clearly proves that a benzoyl group serves as a protecting group in these radical processes, which not only enhances cyclization efficiency but also increases the rate of the fragmentation step, eventually producing the desired carbonyl translocation products. These observations provide an alternative point of view in the field of radical cyclization reactions. Since the fragmentation step could be enhanced by appropriately positioning an alpha-benzoyl group, these four radical processes could be used to convert the naturally occurring d-sugars, such as d-pentoses and d-hexoses, into rare deoxy-l-sugars. Furthermore, a cascade radical process involving radical cyclization and fragmentation followed by addition to the allyltin reagent was developed and is reported herein. PMID- 26496237 TI - Calcium-dependent antigen binding as a novel modality for antibody recycling by endosomal antigen dissociation. AB - The pH-dependent antigen binding antibody, termed a recycling antibody, has recently been reported as an attractive type of second-generation engineered therapeutic antibody. A recycling antibody can dissociate antigen in the acidic endosome, and thus bind to its antigen multiple times. As a consequence, a recycling antibody can neutralize large amounts of antigen in plasma. Because this approach relies on histidine residues to achieve pH-dependent antigen binding, which could limit the epitopes that can be targeted and affect the rate of antigen dissociation in the endosome, we explored an alternative approach for generating recycling antibodies. Since calcium ion concentration is known to be lower in endosome than in plasma, we hypothesized that an antibody with antigen binding properties that are calcium-dependent could be used as recycling antibody. Here, we report a novel anti-interleukin-6 receptor (IL-6R) antibody, identified from a phage library that binds to IL-6R only in the presence of a calcium ion. Thermal dynamics and a crystal structure study revealed that the calcium ion binds to the heavy chain CDR3 region (HCDR3), which changes and possibly stabilizes the structure of HCDR3 to make it bind to antigen calcium dependently (PDB 5AZE). In vitro and in vivo studies confirmed that this calcium dependent antigen-binding antibody can dissociate its antigen in the endosome and accelerate antigen clearance from plasma, making it a novel approach for generating recycling antibody. PMID- 26496239 TI - Novel strategies for the diagnosis and treatment of cardiac amyloidosis. AB - Systemic amyloidoses are rare, complex diseases caused by misfolding of autologous protein. The presence of heart involvement is the most important prognostic determinant. The diagnosis of amyloid cardiac involvement relies on echocardiography and magnetic resonance imaging, while scintigraphy with bone tracers is helpful in differentiating light chain amyloidosis from other types of amyloidosis involving the heart. Although these diseases are fatal, effective treatments exist that can alter their natural history, provided that they are started before irreversible cardiac damage has occurred. Refined diagnostic techniques, accurate patients' stratification based on biomarkers of cardiac dysfunction, the availability of novel, more powerful drugs, and ultimately, the unveiling of the cellular mechanisms of cardiac damage created a favorable environment for a dramatic improvement in the treatment of this disease that we expect in the next few years. PMID- 26496240 TI - Plasma hepcidin in early-stage breast cancer patients: no relationship with interleukin-6, erythropoietin and erythroferrone. AB - OBJECTIVE: Hepcidin-25 production is stimulated by systemic inflammation, and it interferes with iron utilization, leading to anemia. This study aimed to investigate the relationships between the plasma levels of hepcidin, interleukin 6 (IL-6), erythropoietin (EPO) and erythroferrone (ERFE) in patients with benign breast disease or cancer. METHODS: Plasma samples from a cohort of 131 patients (47 with benign breast disease and 84 with breast cancer) were subjected to the evaluation of hepcidin, IL-6, EPO and ERFE using SELDI-TOF-MS or immunoassays. RESULTS: An elevated hepcidin was observed in malignant breast tumors compared to benign ones. No correlation was observed between hepcidin and IL-6, EPO or ERFE. CONCLUSION: Since the study included a cohort of patients (87%) with breast cancers smaller than 2 cm, these results may support our previous evidence about the potential role of hepcidin in breast cancer disease. PMID- 26496241 TI - Prevalence and Characteristics of Duodenal Villous Atrophy in Renal Transplant Patients Presenting With Persistent Diarrhea in a Developing Country. AB - OBJECTIVES: Persistent diarrhea is a common complication after solid-organ transplant, including kidney transplant. Data on duodenal villous atrophy as a cause of persistent diarrhea in renal transplant recipients are scarce. MATERIALS AND METHODS: We conducted a prospective analysis of 207 patients who received renal transplants from 2009 to 2012 with persistent diarrhea and who underwent upper gastrointestinal endoscopy and duodenal biopsies. Duodenal biopsies were examined for duodenal villous atrophy. Age, sex, transplant duration, and drugs were compared between patients with and without duodenal villous atrophy. After exclusion of known causes of duodenal villous atrophy, a 3-month course of antibiotics was given and outcomes were analyzed. RESULTS: Of 207 renal transplant recipients, 104 patients (49.8%) displayed duodenal villous atrophy. Of these, 92 (88.5%) were male patients. The mean age of patients with duodenal villous atrophy was 34.9 +/- 10.3 years. The mean onset of persistent diarrhea in DVA-positive patients posttransplant was 2.16 +/- 0.8 years. Celiac disease serology was positive in 18 (17.3) patients. Giardiasis was demonstrated in 11 patients (10.7%), whereas immunoproliferative small intestinal disease was shown in 7 patients (6.8%). The remaining 68 patients (65.38%) received antibiotics, with 50 recipients (74.6%) showing complete response, although 13 of these patients (26%) relapsed. Among the remaining 18 patients (26.47%), 9 (50%) had other causes and 9 (50%) had no cause found. Isoniazid prophylaxis showed statistically significant negative association with duodenal villous atrophy. CONCLUSIONS: Duodenal villous atrophy is highly prevalent in renal transplant recipients irrespective of age, sex, and posttransplant duration. We found tropical sprue, giardiasis, immunoproliferative small intestinal disease, and celiac disease to be important causes of duodenal villous atrophy. Therefore, duodenal biopsy is recommended in renal transplant recipients with persistent diarrhea. PMID- 26496242 TI - Evaluation of Improved Glycogen Synthase Kinase-3alpha Inhibitors in Models of Acute Myeloid Leukemia. AB - The challenge for glycogen synthase kinase-3 (GSK-3) inhibitor design lies in achieving high selectivity for one isoform over the other. The therapy of certain diseases, such as acute myeloid leukemia (AML), may require alpha-isoform specific targeting. The scorpion shaped GSK-3 inhibitors developed by our group achieved the highest GSK-3alpha selectivity reported so far but suffered from insufficient aqueous solubility. This work presents the solubility-driven optimization of our isoform-selective inhibitors using a scorpion shaped lead. Among 15 novel compounds, compound 27 showed high activity against GSK 3alpha/beta with the highest GSK-3alpha selectivity reported to date. Compound 27 was profiled for bioavailability and toxicity in a zebrafish embryo phenotype assay. Selective GSK-3alpha targeting in AML cell lines was achieved with compound 27, resulting in a strong differentiation phenotype and colony formation impairment, confirming the potential of GSK-3alpha inhibition in AML therapy. PMID- 26496243 TI - Coupling of Ag Nanoparticle with Inverse Opal Photonic Crystals as a Novel Strategy for Upconversion Emission Enhancement of NaYF4: Yb(3+), Er(3+) Nanoparticles. AB - Rare-earth-ion-doped upconversion (UC) nanoparticles have generated considerable interest because of their potential application in solar cells, biological labeling, therapeutics, and imaging. However, the applications of UC nanoparticles were still limited because of their low emission efficiency. Photonic crystals and noble metal nanoparticles are applied extensively to enhance the UC emission of rare earth ions. In the present work, a novel substrate consisting of inverse opal photonic crystals and Ag nanoparticles was prepared by the template-assisted method, which was used to enhance the UC emission of NaYF4: Yb(3+), Er(3+) nanoparticles. The red or green UC emissions of NaYF4: Yb(3+), Er(3+) nanoparticles were selectively enhanced on the inverse opal substrates because of the Bragg reflection of the photonic band gap. Additionally, the UC emission enhancement of NaYF4: Yb(3+), Er(3+) nanoparticles induced by the coupling of metal nanoparticle plasmons and photonic crystal effects was realized on the Ag nanoparticles included in the inverse opal substrate. The present results demonstrated that coupling of Ag nanoparticle with inverse opal photonic crystals provides a useful strategy to enhance UC emission of rare-earth-ion-doped nanoparticles. PMID- 26496244 TI - Intrinsically Microporous Polymer Retains Porosity in Vacuum Thermolysis to Electroactive Heterocarbon. AB - Vacuum carbonization of organic precursors usually causes considerable structural damage and collapse of morphological features. However, for a polymer with intrinsic microporosity (PIM-EA-TB with a Brunauer-Emmet-Teller (BET) surface area of 1027 m(2)g(-1)), it is shown here that the rigidity of the molecular backbone is retained even during 500 degrees C vacuum carbonization, yielding a novel type of microporous heterocarbon (either as powder or as thin film membrane) with properties between those of a conducting polymer and those of a carbon. After carbonization, the scanning electron microscopy (SEM) morphology and the small-angle X-ray scattering (SAXS) Guinier radius remain largely unchanged as does the cumulative pore volume. However, the BET surface area is decreased to 242 m(2)g(-1), but microporosity is considerably increased. The new material is shown to exhibit noticeable electrochemical features including two pH dependent capacitance domains switching from ca. 33 Fg(-1) (when oxidized) to ca. 147 Fg(-1) (when reduced), a low electron transfer reactivity toward oxygen and hydrogen peroxide, and a four-point-probe resistivity (dry) of approximately 40 MOmega/square for a 1-2 MUm thick film. PMID- 26496245 TI - Development of A Multidimensional Scale to Assess Attitudinal Determinants of Sanitation Uptake and Use. AB - Over 1 billion people still practice open defecation. Low uptake and use of new sanitation technologies in a number of settings has underscored our current limited understanding of the complex attitudinal factors that influence a household's decision to adopt and use new sanitation technologies. Mokken scaling techniques were applied to series of population-based surveys in Odisha, India between September 2011 and October 2013 (sample sizes 120, 500, 2200). Surveys contained simple, agree/disagree statements about attitudes toward sanitation use and sanitation technologies. Analysis produced two scales-a 10-question General Scale, reflecting attitudes toward defecation and norms regarding latrine use for all respondents, and a 6-question Experiential Scale, reflecting personal experiences with and perceived convenience of sanitation technologies targeted at respondents with a latrine. Among all respondents, a one-point change in the General Scale was associated with a 5-percentage point change in the marginal probability of having access to a functioning latrine. Among respondents with a functional latrine at home, a one-point increase in the General and Experiential Scales were associated with a 4- and 8-percentage point decrease in the probability of engaging in any open defecation in the last 7 days, respectively. PMID- 26496246 TI - Effects of Sample Size and Dimensionality on the Performance of Four Algorithms for Inference of Association Networks in Metabonomics. AB - We investigated the effect of sample size and dimensionality on the performance of four algorithms (ARACNE, CLR, CORR, and PCLRC) when they are used for the inference of metabolite association networks. We report that as many as 100-400 samples may be necessary to obtain stable network estimations, depending on the algorithm and the number of measured metabolites. The CLR and PCLRC methods produce similar results, whereas network inference based on correlations provides sparse networks; we found ARACNE to be unsuitable for this application, being unable to recover the underlying metabolite association network. We recommend the PCLRC algorithm for the inference on metabolite association networks. PMID- 26496247 TI - Pediatric Patients with Vitiligo in Eastern China: Abnormalities in 145 Cases Based on Thyroid Function Tests and Immunological Findings. AB - BACKGROUND: The aim of this study was to evaluate abnormalities in thyroid function according to tests and the humoral immune systems of patients from Eastern China with pediatric vitiligo. MATERIAL AND METHODS: A total of 145 pediatric patients with vitiligo were investigated in this study, along with 59 children without autoimmune diseases as controls. Laboratory tests of thyroid function were conducted, and these tests examined free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), thyroglobulin antibody (TG-Ab), thyroid peroxidase antibody (TPO-Ab), antinuclear antibodies (ANAs), immunoglobulins (IgA, IgM, and IgG), and complements (C3 and C4). RESULTS: A total of 63 patients (43.4%), including 39 boys (44.3%) and 24 girls (42.1%), displayed abnormalities in thyroid function according to the tests. This finding indicated that patients with vitiligo differed significantly from those in the control group (P<0.001), particularly in terms of FT3 and TSH abnormalities (P<0.05). However, these groups did not deviate significantly with respect to FT4, Tg-Ab, and TPO-Ab abnormalities (P>0.05). Thirteen patients (8.9%) and 1 (1.7%) control were positive for ANA. All 12 specific antibodies were detected in 8 patients. Anti-SSA/Ro-60 and anti-SSA/Ro-52 were the most prevalent antibodies, followed by anti-dsDNA and then by anti-SmD1 and CENB-P. The serum levels of IgA and IgG decreased more significantly in the vitiligo group than in the control group (P<0.001). However, no significant difference was observed in terms of IgM levels (P>0.05). C4 serum levels also decreased more significantly in the vitiligo group than in the control group (P=0.035). CONCLUSIONS: Results suggest that the incidence of abnormalities in the thyroid functions of children and adolescents is significantly higher in those with vitiligo than that in those in the control group. In addition, immunological dysfunction is common in the vitiligo group. PMID- 26496248 TI - Matrix Effect of Human Reconstructed Epidermis on the Chemoselectivity of a Skin Sensitizing alpha-Methylene-gamma-Butyrolactone: Consequences for the Development of in Chemico Alternative Methods. AB - Adoption of new legislations and social pressure are pushing toward the development of alternative methods to the use of animals for the assessment of most toxicological end-points including skin sensitization. To that respect, much efforts have been put in the first step of the adverse outcome pathway focusing on chemical interactions taking place between sensitizing chemicals or haptens and epidermal proteins. However, these in chemico approaches have been so far only based on the use of model nucleophiles, amino acids, peptides, or proteins in water/buffer solution and focused mainly on thiol reactivity. These studies even if bringing a valuable set of information are very far from reflecting chemical interactions that may happen between a xenobiotic and nucleophiles present in a complex heterogeneous tissue such as the epidermis. Recently, we have shown that using a high-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) technique it was possible to characterize chemical interactions taking place between a skin sensitizer and nucleophilic amino acids present in a 3-D reconstructed human epidermis (RHE). We have now compared the chemical reactivity and chemoselectivity of a sensitizing alpha-methylene-gamma butyrolactone toward human serum albumin used as a model protein and RHE. Using this technique, we showed that amino acid modifications by this hapten was different according to the model used and that in RHE histidine residues seem to have an important role in the formation of adducts. Obviously, the role of histidine in the induction of skin sensitization has been so far neglected and should probably be taken into account for the refinement of in chemico approaches for the detection and potency classification of skin sensitizers. PMID- 26496249 TI - Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age-Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo. AB - Rac1 and Rac2 are thought to have important roles in osteoclasts. Therefore, mice with deletion of both Rac1 and Rac2 in mature osteoclasts (DKO) were generated by crossing Rac1(flox/flox) mice with mice expressing Cre in the cathepsin K locus and then mating these animals with Rac2(-/-) mice. DKO mice had markedly impaired tooth eruption. Bone mineral density (BMD) was increased 21% to 33% in 4- to 6 week-old DKO mice at all sites when measured by dual-energy X-ray absorptiometry (DXA) and serum cross-linked C-telopeptide (CTx) was reduced by 52%. The amount of metaphyseal trabecular bone was markedly increased in DKO mice, but the cortices were very thin. Spinal trabecular bone mass was increased. Histomorphometry revealed significant reductions in both osteoclast and osteoblast number and function in 4- to 6-week-old DKO animals. In 14- to 16-week old animals, osteoclast number was increased, although bone density was further increased. DKO osteoclasts had severely impaired actin ring formation, an impaired ability to generate acid, and reduced resorptive activity in vitro. In addition, their life span ex vivo was reduced. DKO osteoblasts expressed normal differentiation markers except for the expression of osterix, which was reduced. The DKO osteoblasts mineralized normally in vitro, indicating that the in vivo defect in osteoblast function was not cell autonomous. Confocal imaging demonstrated focal disruption of the osteocytic dendritic network in DKO cortical bone. Despite these changes, DKO animals had a normal response to treatment with once-daily parathyroid hormone (PTH). We conclude that Rac1 and Rac2 have critical roles in skeletal metabolism. PMID- 26496251 TI - Correction: Induction of TLR-2 and TLR-5 Expression by Helicobacter pylori Switches cagPAI-Dependent Signalling Leading to the Secretion of IL-8 and TNF alpha. PMID- 26496250 TI - Decreased Phototoxic Effects of TiO2 Nanoparticles in Consortium of Bacterial Isolates from Domestic Waste Water. AB - This study is aimed to explore the toxicity of TiO2 nanoparticles at low concentrations (0.25, 0.50 & 1.00 MUg/ml); on five bacterial isolates and their consortium in waste water medium both in dark and UVA conditions. To critically examine the toxic effects of nanoparticles and the response mechanism(s) offered by microbes, several aspects were monitored viz. cell viability, ROS generation, SOD activity, membrane permeability, EPS release and biofilm formation. A dose and time dependent loss in viability was observed for treated isolates and the consortium. At the highest dose, after 24h, oxidative stress was examined which conclusively showed more ROS generation & cell permeability and less SOD activity in single isolates as compared to the consortium. As a defense mechanism, EPS release was enhanced in case of the consortium against the single isolates, and was observed to be dose dependent. Similar results were noticed for biofilm formation, which substantially increased at highest dose of nanoparticle exposure. Concluding, the consortium showed more resistance against the toxic effects of the TiO2 nanoparticles compared to the individual isolates. PMID- 26496252 TI - Neoadjuvant Therapy of DOF Regimen Plus Bevacizumab Can Increase Surgical Resection Ratein Locally Advanced Gastric Cancer: A Randomized, Controlled Study. AB - Locally advanced gastric cancer (LAGC) is best treated with surgical resection. Bevacizumab in combination with chemotherapy has shown promising results in treating advanced gastric cancer. This study aimed to investigate the efficacy of neoadjuvant chemotherapy using the docetaxel/oxaliplatin/5-FU (DOF) regimen and bevacizumab in LAGC patients.Eighty LAGC patients were randomized to receive DOF alone (n = 40) or DOF plus bevacizumab (n = 40) as neoadjuvant therapy before surgery. The lesions were evaluated at baseline and during treatment. Circulating tumor cells (CTCs) were counted using the FISH test. Patients were followed up for 3 years to analyze the disease-free survival (DFS) and overall survival (OS).The total response rate was significantly higher in the DOF plus bevacizumab group than the DOF group (65% vs 42.5%, P = 0.0436). The addition of bevacizumab significantly increased the surgical resection rate and the R0 resection rate (P < 0.05). The DOF plus bevacizumab group showed significantly greater reduction in CTC counts after neoadjuvant therapy in comparison with the DOF group (P = 0.0335). Although the DOF plus bevacizumab group had significantly improved DFS than the DOF group (15.2 months vs 12.3 months, P = 0.013), the 2 groups did not differ significantly in OS (17.6 +/- 1.8 months vs 16.4 +/- 1.9 months, P = 0.776. Cox proportional model analysis showed that number of metastatic lymph nodes, CTC reduction, R0 resection, and neoadjuvant therapy are independent prognostic factors for patients with LAGC.Neoadjuvant of DOF regimen plus bevacizumab can improve the R0 resection rate and DFS in LAGC. These beneficial effects might be associated with the reduction in CTC counts. PMID- 26496253 TI - Increased Causal Connectivity Related to Anatomical Alterations as Potential Endophenotypes for Schizophrenia. AB - Anatomical and functional abnormalities in the cortico-cerebellar-thalamo cortical circuit have been observed in schizophrenia patients and their unaffected siblings. However, it remains unclear to the relationship between anatomical and functional abnormalities within this circuit in schizophrenia patients and their unaffected siblings, which may serve as potential endophenotypes for schizophrenia.Anatomical and resting-state functional magnetic resonance imaging data were acquired from 49 first-episode, drug-naive schizophrenia patients, 46 unaffected siblings, and 46 healthy controls. Data were analyzed by using voxel-based morphometry and Granger causality analysis.The patients and the siblings shared anatomical deficits in the left middle temporal gyrus (MTG) and increased left MTG-left angular gyrus (AG) connectivity. Moreover, the left MTG-left AG connectivity negatively correlates to the duration of untreated psychosis in the patients.The findings indicate that anatomical deficits in the left MTG and its increased causal connectivity with the left AG may serve as potential endophenotypes for schizophrenia with clinical implications. PMID- 26496254 TI - Anthropometric Measures of 9- to 10-Year-Old Native Tibetan Children Living at 3700 and 4300 m Above Sea Level and Han Chinese Living at 3700 m. AB - A high residential altitude impacts on the growth of children, and it has been suggested that linear growth (height) is more affected than body mass. The aim of the present study was to estimate the prevalence of obesity, overweight, underweight, and stunting in groups of native Tibetan children living at different residential altitudes (3700 vs 4300 m above sea level) and across ancestry (native Tibetan vs Han Chinese children living at the same altitude of 3700 m), as well as to examine the total effect of residential altitude and ancestry with stunting.Two cross-sectional studies of 1207 school children aged 9 to 10 years were conducted in Lhasa in 2005 and Tingri in 2007. Conventional age- and sex-specific cutoff values were used for defining underweight, normal weight, overweight, or obesity, whereas stunting was defined from sex-specific height-for age z-scores (<=-2.0).The prevalence of underweight was high at 36.7% among Tingri Tibetan girls and 31.1% in Tingri Tibetan boys. The prevalence was statistically significant lower in Lhasa Tibetan girls (20.2%) than in both Tingri Tibetan girls and Han Chinese girls (33.7%), with a similar trend seen among boys. Severe and moderate stunting were found in 14.6% and 35.7%, respectively, of Tingri children, and near null among Han Chinese and native Tibetans in Lhasa. In logistic regression analyses, socioeconomic status and diet did not substantially change the observed crude association (total effect) (odds ratio [OR] = 3.3; 95% confidence interval [CI] 1.1-10.3) between ancestry and stunting. Similarly, adjustment for diet did not alter the crude association (direct effect) (OR = 101.3; 95% CI 37.1-276.4) between residential altitude and stunting.The prevalence estimates of stunting and underweight were high, and clearly higher among native Tibetan children living at a higher residential altitude (Tingri) than the lower residential altitude (Lhasa), in addition to being higher among Han Chinese children than Tibetan children living at the same residential altitude (Lhasa). Thus, physical growth according to age, in terms of both height and weight, affected children living at an altitude of 4300 m above sea level. PMID- 26496255 TI - Proinflammatory Cytokines and Antiskin Autoantibodies in Patients With Inherited Epidermolysis Bullosa. AB - Epidermolysis bullosa (EB) is a rare disorder characterized by inherited skin adhesion defects with abnormal disruption of the epidermal-dermal junction in response to mechanical trauma. Our aim was to investigate a set of cytokine levels in serum samples from patients suffering from epidermolysis bullosa simplex (EBS), dystrophic epidermolysis bullosa (DEB), and healthy controls (HCs), exploring their potential correlations with antiskin autoantibody titers and disease activity. Forty patients afferent to the Dermatological Ward of Bari City Hospital and 9 HCs were enrolled and subdivided according to the dystrophic (DEB) and simplex forms (EBS). We found a significant increase in interleukin (IL)-1beta plasmatic levels of DEB (P = 0.0224) and EBS (P = 0.0465) patients compared to HCs; IL-6 levels were significantly higher in DEB than in EBS patients (P = 0.0004) or HCs (P = 0.0474); IL-2 levels were significantly increased in DEB compared with EBS (P = 0.0428). Plasmatic tumor necrosis factor beta and interferon-gamma were higher in DEB patients than in HCs (P = 0.0448 and 0.0229). Conversely, tumor necrosis factor-alpha was significantly decreased in DEB (P = 0.0034). IL-5 correlated with anti-BP180 (r = -0.5018, P = 0.0338), anti BP230 (r = -0.6097, P = 0.0122), and anticollagen VII (r = -0.5166, P = 0.0405) autoantibodies; interferon-gamma correlated with anti-BP180 (r = 0.9633, P < 0.0001), anti-BP230 (r = 0.9071, P < 0.0001), and anticollagen VII (r = 0.8619, P = 0.0045) autoantibodies. Score of disease severity was significantly correlated with IL-6 (r = 0.6941, P = 0.029) and IL-12 (r = 0.5503, P = 0.0272). The present study supports that EB might be considered a systemic inflammatory disease rather than a skin-limited disorder; clinical disease activity scores could be also integrated by laboratory data such as IL-6 and IL-12 dosage; biotherapies targeting specific cytokine networks probably represent a way to go in the future. PMID- 26496256 TI - Association Study between an SNP in CD147 and Its Expression With Acute Coronary Syndrome in a Jiangsu Chinese Population. AB - CD147 is an important molecule in the inflammation and proteolysis process. This molecule crucially contributes to the initial and progression of atherosclerotic lesions. A single nucleotide polymorphism in CD147 gene, the rs8259 T/A in the 3' untranslated region, is responsible for its expression in various cells. This study assessed whether the genetic variation rs8259 is associated with acute coronary syndrome (ACS) and CD147. A total of 943 ACS subjects and 439 stable angina subjects, and 851 controls were genotyped for rs8259 polymorphism by polymerase chain reaction restriction fragment length polymorphism and DNA sequencing method. Plasma soluble CD147 (sCD147) level was measured by enzyme linked immunosorbent assay. CD147 mRNA and protein expression in peripheral blood mononuclear cells were tested by real-time quantitative polymerase chain reaction and western blot, respectively. We found that TT genotype and T-allele frequency of CD147 rs8259 in ACS patients were much lower than the other patient groups. Significant difference was not observed between stable angina and controls. CD147 T allele was negatively related to ACS. ACS patients exhibited the highest CD147 expression in peripheral blood mononuclear cells and plasma sCD147 level. The plasma sCD147 levels in the culprit vessel were higher than those in the radial artery. In ACS patients, AA gene carriers had the highest CD147 levels, whereas TT gene carriers had the lowest CD147 levels. Linear regression analysis showed that genotypes and disease conditions contributed 49% to the change of the plasma CD147 level. These results suggested that the single nucleotide polymorphism of CD147 gene rs8259 T/A was associated with ACS susceptibility. Allele T gene may decrease the relative risk of suffering from ACS through downregulation of CD147 expression. PMID- 26496257 TI - Shear Wave Elastography: Is It a Valuable Additive Method to Conventional Ultrasound for the Diagnosis of Small (<=2 cm) Breast Cancer? AB - The aim of this study is to evaluate the diagnostic value of shear wave elastography (SWE) added to conventional ultrasound (US) in the diagnosis of small (<=2 cm) breast cancer.Among 410 patients who underwent SWE before US guided biopsy from June 2012 to June 2013, 171 patients (mean age: 45.17 +/- 9.37 years) with 177 small (<=2 cm) breast lesions were enrolled in this study. Diagnostic performances of each quantitative SWE parameters were calculated by receiver operating characteristic (ROC) curves. Performances of conventional US and US combined to SWE was also compared. Histologic diagnosis was used as a reference standard.Of the 177 lesions, 22 lesions (12.4%) were malignant and 155 (87.6%) were benign. With respect to conventional US, when a cutoff point between category 3 and 4a was used, the Az value was 0.915 (100% sensitivity, 36.8% specificity, 18.3% positive predictive value (PPV), and 100% negative predictive value (NPV)). All average quantitative elastography values were significantly higher in malignant lesions compared to benign lesions (P = 0.001).The Emax value with a cutoff of 87.5 kPa had the highest Az value of 0.796 (68.2% sensitivity and 87.1% specificity, 42.9% PPV, and 95.1% NPV). Az value of combined data (0.861, 95% CI: 0.801, 0.909) was significantly lower than that of conventional US alone (P = 0.02). By using an Emax value for downgrading Breast Imaging Reporting and Data System (BI-RADS) category 4a lesions to category 3, 76/94 category 4a lesions (80.9%) were downgraded. After downgrading, 5 cancers were missed and the malignancy rate of category 3 lesions increased from 0% (0/55) to 3.8% (5/133) (P = 0.01).In conclusion, combined use of SWE and conventional US increased the specificity by reducing the number of unnecessary biopsies in differential diagnosis of small breast lesions. However, we propose that the application of conservative strategy for downgrading of soft category 4a lesions would be appropriate to minimize false-negative cases. PMID- 26496258 TI - Severe Hypoglycemia Caused by Recurrent Sarcomatoid Carcinoma in the Pelvic Cavity: A Case Report. AB - Nonislet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome characterized by persistent, severe hypoglycemia in different tumor types of mesochymal or epithelial origin; however, NICTH is infrequently induced by sarcomatoid carcinoma (SC). Despite some sarcomatoid and epithelioid characteristics in few cases of malignancies from epithelium, NICTH induced by recurrent SC in pelvic cavity in this report is extremely rare.We report a case in which NICTH caused by recurrence and pulmonary metastases from SC in the pelvic cavity, and the computed tomography scan revealed multiple pelvic masses and multiple large masses in the pulmonary fields. During the treatment of intestinal obstruction, the patient presented paroxysmal loss of consciousness and sweating. Her glucose even reached 1.22 mmol/L while the serum glycosylated hemoglobin was normal and previous history of diabetes or use of oral hypoglycemic agents and insulin denied.The laboratory examination showed that the low level of insulin, C-peptide, and growth hormone levels in the course of hypoglycemic episodes suggesting to the diagnosis of hypoglycemia induced by nonislet cell tumor, and the decreased levels of insulin-like growth factor (IGF) I and IGFBP3 and the high expression of big IGF-II in the serum further confirmed the diagnosis of NICTH. Because of the widely pelvic recurrence and pulmonary metastases were unresected, the patient was discharged from the hospital after 2 weeks treatment with dexamethasone and glucose and unfortunately died 1 week later.NICTH caused by SC in the pelvic cavity is extremely rare case in clinical. The aim of this report was to present the importance to examine big IGF-II expression in patient's serum in order to reach the diagnosis of NICTH in cases of intractable cancer-associated hypoglycemia. PMID- 26496259 TI - Hearing Aid Use and Associated Factors in South Korea. AB - Despite the high prevalence of hearing impairment in the elderly, the rate of hearing aid use is still low. The objectives of this study were to report the nation-wide prevalence of hearing aid use in the Korean population and to determine the associated factors with hearing aid use utilizing a nationally representative data set.We obtained data from the 2010 to 2012 Korea National Health and Nutrition Examination Surveys, which were cross-sectional surveys of the civilian, noninstitutionalized population of the Republic of Korea at age >=40 years (N = 12,709). A field survey team performed interviews as well as physical examinations. Hearing aid use was assessed using an interviewer administered questionnaire and pure-tone audiometry was administered for all participants in a sound-attenuating booth. Prevalence of hearing aid acquisition and regular use were calculated in participants who reported perceived hearing loss and who have bilateral hearing thresholds exceeding the 40 dB hearing level. Multivariable analyses were used to examine the associated factors with hearing aid use.The prevalence of hearing aid acquisition and regular use was 17.4% and 12.6%, respectively, in South Korea. Increased hearing threshold (OR 1.05, 95% CI 1.03-1.07), severe perceived hearing loss (OR 10.73, 95% CI 4.52-25.46), annoying tinnitus (OR 3.30, 95% CI 1.61-6.74), balance problems (OR 0.39, 95% CI 0.18 0.86), and myopia (OR 0.30, 95% CI 0.12-0.76) were associated factors of regular use of hearing aids.The prevalence of hearing aid use in Korea is relatively low. Finding relevant factors of hearing aid use could provide further insight in setting up hearing-rehabilitation strategy for the elderly with significant hearing loss. PMID- 26496260 TI - Pyogenic Sacroiliitis in a 13-Month-Old Child: A Case Report and Literature Review. AB - Pyogenic sacroiliitis is exceptional in very young children. Diagnosis is difficult because clinical examination is misleading. FABER test is rarely helpful in very young children. Inflammatory syndrome is frequent. Bone scintigraphy and MRI are very sensitive for the diagnosis. Joint fluid aspiration and blood cultures are useful to identify the pathogen. Appropriate antibiotic therapy provides rapid regression of symptoms and healing. We report the case of pyogenic sacroiliitis in a 13-month-old child.Clinical, biological, and imaging data of this case were reviewed and reported retrospectively.A 13-month-old girl consulted for decreased weight bearing without fever or trauma. Clinical examination was not helpful. There was an inflammatory syndrome. Bone scintigraphy found a sacroiliitis, confirmed on MRI. Aspiration of the sacroiliac joint was performed. Empiric intravenous biantibiotic therapy was started. Patient rapidly recovered full weight bearing. On the 5th day, clinical examination and biological analysis returned to normal. Intravenous antibiotic therapy was switched for oral. One month later, clinical examination and biological analysis were normal and antibiotic therapy was stopped.Hematogenous osteoarticular infections are common in children but pyogenic sacroiliitis is rare and mainly affects older children. Diagnosis can be difficult because clinical examination is poor. Moreover, limping and decreased weight bearing are very common reasons for consultation. This may delay the diagnosis or refer misdiagnosis. Bone scintigraphy is useful to locate a bone or joint disease responsible for limping. In this observation, bone scintigraphy located the infection at the sacroiliac joint. Given the young age, MRI was performed to confirm the diagnosis. Despite the very young age of the patient, symptoms rapidly disappeared with appropriate antibiotic therapy.We report the case of pyogenic sacroiliitis in a 13-month-old child. It reminds the risk of misdiagnosing pyogenic sacroiliitis in children because it is exceptional and clinical examination is rarely helpful. It also highlights the usefulness of bone scintigraphy and MRI in osteoarticular infections in children. PMID- 26496261 TI - BDNF Val66Met Polymorphism on Functional MRI During n-Back Working Memory Tasks. AB - Val66Met polymorphism on the brain-derived neurotrophic factor (BDNF) gene is associated with hippocampal pathology and impaired episodic memory. However, the influence of this polymorphism on working memory (WM) performance and patterns of brain activation is controversial. This study investigated the effects of BDNF Val66Met polymorphism on functional magnetic resonance imaging (fMRI) during n back WM tasks in healthy middle-aged adults.A total of 110 participants without subjective or objective cognitive impairment underwent BDNF genotyping. Eleven Met allele carriers and 9 noncarriers underwent fMRI during WM tasks.The WM performance was similar between the 2 groups. Increased brain activation in response to increases in WM loads was observed in both groups. The Met allele carrier group showed consistently lower brain activation in the right superior frontal gyrus (SFG) and the middle occipital gyrus than that of the noncarrier group (P < 0.001). No brain region showed increased activation during WM tasks in the Met allele group.BDNF Val66Met polymorphism may affect the WM network. Met allele carriers have lower brain activation in the right SFG and middle occipital gyrus than do noncarriers during WM tasks. Defective development of the WM network during brain maturation or differentiation is a possible mechanism. Additional studies with a larger sample and longer follow-up period are warranted. PMID- 26496262 TI - Case Report: Human Bocavirus Associated Pneumonia as Cause of Acute Injury, Cologne, Germany. AB - Although the human bocavirus (HBoV) is known since a decade, limited information about its pathogenesis is available due to the lack of an animal model. Thus, clinical cases and studies are the major source of novel information about the course of infection and the related pathophysiology.In this context, a clinical case of an adult patient suffering from severe HBoV-pneumonia is described that was associated with loss of consciousness followed by acute rib fracture and subsequent neurological disorder.Following initial global respiratory dysfunction the clinical respiratory symptoms recovered but the neurological symptoms maintained after weaning and intensive care in the stroke unit. During the initial phase, an acute active HBoV infection was confirmed by positive polymerase chain reactions from bronchoalveolar lavage fluid and serum.The case further demonstrates that HBoV can cause severe pneumonia, induce secondary disease also in adults, and may be associated with neurological symptoms as previously assumed. PMID- 26496263 TI - Risk Factors for Autoimmune Diseases Development After Thrombotic Thrombocytopenic Purpura. AB - Autoimmune thrombotic thrombocytopenic purpura (TTP) can be associated with other autoimmune disorders, but their prevalence following autoimmune TTP remains unknown. To assess the prevalence of autoimmune disorders associated with TTP and to determine risk factors for and the time course of the development of an autoimmune disorder after a TTP episode, we performed a cross sectional study. Two-hundred sixty-one cases of autoimmune TTP were included in the French Reference Center registry between October, 2000 and May, 2009. Clinical and laboratory data available at time of TTP diagnosis were recovered. Each center was contacted to collect the more recent data and diagnosis criteria for autoimmunity. Fifty-six patients presented an autoimmune disorder in association with TTP, 9 years before TTP (median; min: 2 yr, max: 32 yr) (26 cases), at the time of TTP diagnosis (17 cases) or during follow-up (17 cases), up to 12 years after TTP diagnosis (mean, 22 mo). The most frequent autoimmune disorder reported was systemic lupus erythematosus (SLE) (26 cases) and Sjogren syndrome (8 cases). The presence of additional autoimmune disorders had no impact on outcomes of an acute TTP or the occurrence of relapse. Two factors evaluated at TTP diagnosis were significantly associated with the development of an autoimmune disorder during follow-up: the presence of antidouble stranded (ds)DNA antibodies (hazard ratio (HR): 4.98; 95% confidence interval (CI) [1.64-15.14]) and anti-SSA antibodies (HR: 9.98; 95% CI [3.59-27.76]). A follow-up across many years is necessary after an acute TTP, especially when anti-SSA or anti-dsDNA antibodies are present on TTP diagnosis, to detect autoimmune disorders early before immunologic events spread to prevent disabling complications. PMID- 26496264 TI - Association Between Consumption of Fruits and Vegetables and Risk of Colorectal Adenoma: A PRISMA-Compliant Meta-Analysis of Observational Studies. AB - There have been contradictory results about the association of fruits and vegetables intake with colorectal adenoma (CRA) risk, the precursor lesion of colorectal cancer. Herein, we have conducted a meta-analysis of the published observational studies to have a clear understanding about this association.Eligible studies up to November 30, 2014, were identified and retrieved by searching MEDLINE and EMBASE databases along with the manual review of the reference list of the retrieved studies. The quality of the included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale, and random effects model was used to calculate summary relative risk (SRR) and corresponding 95% confidence interval (CI).A total of 22 studies involving 11,696 CRA subjects were part of this meta-analysis. The SRR for the highest versus the lowest intake of vegetables alone was 0.91 (95% CI: 0.80-1.02, Pheterogeneity = 0.025), whereas for vegetables and fruits combined, it was 0.82 (95% CI: 0.75-0.91, Pheterogeneity = 0.369), and for fruits alone, it was 0.79 (95% CI: 0.71-0.88, Pheterogeneity = 0.111). In addition, linear dose-response analysis also showed similar results, for example, for per 100 g/d increment of fruits, the SRR was 0.94 (95% CI: 0.92-0.97) and for vegetables it was 0.98 (95% CI: 0.96-1.01). Nonlinear association was only observed for vegetables (Pnonlinearity = 0.024), but not for fruits (Pnonlinearity = 0.583).Thus, this meta-analysis suggested that fruits consumption have a significant protective effect on CRA risk, but not vegetables. Moreover, we recommend additional studies with prospective designs that use validated questionnaires and control for important confounders to further validate the overall results. PMID- 26496265 TI - Double-Blind Randomized Trial of Pirfenidone in Chinese Idiopathic Pulmonary Fibrosis Patients. AB - Idiopathic pulmonary fibrosis (IPF) lacks effective treatment. Pirfenidone has been used to treat IPF patients. N-acetylcysteine (NAC) exerts antioxidant and antifibrotic effects on IPF cases.This study is a double-blind, modified placebo controlled, randomized phase II trial of pirfenidone in Chinese IPF patients. We randomly assigned the enrolled Chinese IPF patients with mild to moderate impairment of pulmonary function to receive either oral pirfenidone (1800 mg per day) and NAC (1800 mg per day) or placebo and NAC (1800 mg per day) for 48 weeks. The primary endpoints were the changes in forced vital capacity (FVC) and walking distance and the lowest SPO2 during the 6-minute walk test (6MWT) at week 48. The key secondary endpoint was the progression-free survival time. This study is registered in ClinicalTrials.gov as number NCT01504334.Eighty-six patients were screened, and 76 cases were enrolled (pirfenidone + NAC: 38; placebo + NAC: 38). The effect of pirfenidone treatment was significant at the 24th week, but this effect did not persist to the 48th week. At the 24th week, the mean decline in both FVC and DeltaSPO2 (%) during the 6MWT in the pirfenidone group was lower than that in the control group (-0.08 +/- 0.20 L vs -0.22 +/- 0.29 L, P = 0.02 and -3.44% +/- 4.51% vs -6.29% +/- 6.06%, P = 0.03, respectively). However, there was no significant difference between these 2 groups at the 48th week (-0.15 +/- 0.25 L vs -0.25 +/- 0.28 L, P = 0.11 and -4.25% +/- 7.27% vs -5.31% +/- 5.49%, P = 0.51, respectively). The pirfenidone treatment group did not achieve the maximal distance difference on the 6MWT at either the 24th or the 48th week. But pirfenidone treatment prolonged the progression-free survival time in the IPF patients (hazard ratio = 1.88, 95% confidence interval: 1.092-3.242, P = 0.02). In the pirfenidone group, the adverse event (AE) rate (52.63%) was higher than that in the control group (26.3%, P = 0.03). Rash was more common in the pirfenidone group (39.5% vs 13.2%, P = 0.02).Compared with placebo combined with high-dose NAC, pirfenidone combined with high-dose NAC prolonged the progression free survival of Chinese IPF patients with mild to moderate impairment of pulmonary function. (ClinicalTrials.gov number, NCT01504334). PMID- 26496266 TI - Association Between the Body Mass Index and Prostate Cancer at Biopsy is Modified by Genetic Risk: A Cross-Sectional Analysis in China. AB - Herein, we aimed to examine whether the association of body mass index (BMI) with prostate cancer (PCa) at biopsy differs according to genetic susceptibility.In a multicenter prospective cohort including 1120 men undergoing diagnostic prostate biopsy in China, we evaluated the interaction between BMI and genetic risk score (GRS) comprising 24 PCa-associated single nucleotide polymorphisms (SNPs), as well as a GRS consisting of 7 SNPs derived from an East-Asian population. The genetic risk was defined as low, intermediate, or high when GRS fell in the first, second, and third tertiles, respectively.We observed a significant interaction between BMI and PCa GRS (Pinteraction = 0.047), suggesting that the predictive value of BMI on PCa was strongly modified by genetic susceptibility. In men with high genetic risk, BMI was an independent predictor of PCa (odds ratio [OR] = 1.167, P = 0.008) after adjusting for conventional risk factors. The relationship between BMI and PCa risk diminished (P = 0.990) in men with low genetic risk. The interaction was more pronounced with the East-Asian GRS (Pinteraction = 0.032), suggesting that the overall GRS interaction most likely occurs through genetic susceptibility in the East-Asian population.Our results suggest that the predictive effect of BMI on the PCa risk is strongly modified by individual genetic susceptibility. The association is more positive among men with high genetic risk for PCa. PMID- 26496267 TI - Relationship Between Myo-Inositol Supplementary and Gestational Diabetes Mellitus: A Meta-Analysis. AB - To determine whether myo-inositol supplement will increase the action of endogenous insulin, which is mainly measured by markers of insulin resistance such as homeostasis model assessment of insulin resistance.PubMed, Cochrane Library, Embase, and web of science were comprehensively searched using "gestational diabetes mellitus" and "myo-inositol" to identify relevant studies. Both subject headings and free texts were adopted. The methodological quality of the included studies were assessed and pooled analyzed by the methods recommended by the Cochrane collaboration.A total of 5 trials containing 513 participants were included. There was a significant reduction in aspects of gestational diabetes incidence (risk ratio [RR], 0.29; 95% confidence interval (95% CI), 0.19 0.44), birth weight (mean difference [MD], -116.98; 95% CI, -208.87 to -25.09), fasting glucose oral glucose tolerance test (OGTT) (MD, -0.36; 95% CI, -0.51 to 0.21), 1-h glucose OGTT (MD, -0.63; 95% CI, -1.01 to -0.26), 2-h glucose OGTT (MD, -0.45; 95% CI, -0.75 to -0.16), and related complications (odds ratio [OR], 0.28; 95% CI 0.14-0.58).On the basis of current evidence, myo-inositol supplementation reduces the development of gestational diabetes mellitus (GDM), although this conclusion requires further evaluation in large-scale, multicenter, blinded randomized controlled trials. PMID- 26496268 TI - Methicillin-Resistant Staphylococcus aureus Ocular Infection in Taiwan: Clinical Features, Genotying, and Antibiotic Susceptibility. AB - Methicillin-resistant Staphylococcus aureus (MRSA) infection is an important public health issue. This observational study aimed to characterize clinical features, antibiotic susceptibility, and genotypes of ocular infections caused by MRSA based on the clinical and molecular definitions of community-associated (CA) and healthcare-associated (HA) strains.Fifty-nine patients with culture-proven S aureus ocular infection were enrolled from January 1, 2010 to December 31, 2011 at Chang Gung Memorial Hospital, Taiwan. Antibiotic susceptibility was verified using disk diffusion/E test. For characterization, staphylococcal cassette chromosome mec (SCCmec), pulsed-field gel electrophoresis (PFGE), multilocus sequence type (MLST), and Panton-Valentine leukocidin (PVL) gene, were performed. MRSA isolates from the patients with HA factors were classified as clinically defined HA-MRSA, and those carrying SCCmec type I to III as molecularly defined HA-MRSA.Thirty-four patients with MRSA ocular infection were identified. The most common clone of CA-MRSA and HA-MRSA isolates was ST59/PFGE type D/SCCmec IV,VT/PVL (+) (n = 12) and CC 239/PFGE type A/SCCmec III, IIIA/PVL(-) (n = 10), respectively. All the 11 patients with molecularly defined HA-MRSA infections and 50% of the 22 patients with molecularly defined CA-MRSA infections were found to have HA factors (P = .005). CA-MRSA tended to cause lid infections, whereas HA MRSA tended to cause corneal infections. Contrary to HA-MRSA isolates, nearly all the CA-MRSA isolates were susceptible to trimethoprim/sulfamethoxazole and fluoroquinolones under either clinical or molecular classifications.In Taiwan, CA MRSA isolates exhibited considerably higher susceptibility to fluoroquinolones when compared with HA-MRSA isolates. A strong correlation was observed between the HA factors and molecularly defined HA-MRSA isolates. PMID- 26496269 TI - Dry Eye in Vernal Keratoconjunctivitis: A Cross-Sectional Comparative Study. AB - The purpose of this comparative cross-sectional study was to investigate the use of standardized clinical tests for dry eye in pediatric patients with active and quiet vernal keratoconjunctivitis (VKC) and to compare them with healthy children.We recruited 35 active VKC, 35 inactive VKC, and 70 age-matched control healthy subjects. Each child underwent a complete eye examination, including visual analog scale symptoms assessment, biomicroscopy, fluorescein break-up time (BUT), corneal fluorescein and conjunctival lissamine green staining, corneal esthesiometry, Schirmer test with anesthetic, and meibomian glands inspection and expression.Active VKC patients showed significantly increased symptoms and signs of ocular surface disease, compared with the other 2 groups. Inactive VKC patients, compared with control subjects, showed increased photophobia (P < 0.05; Mann-Whitney U test), conjunctival lissamine green staining and Schirmer test values, and reduced BUT and corneal sensitivity [P < 0.05 by analysis of variance (ANOVA) least significant difference posthoc test for BUT and Schirmer; P < 0.001 by Mann-Whitney U test for lissamine green staining and corneal sensitivity].Our results confirm the association between VKC and short-BUT dry eye. This syndrome seems to affect the ocular surface in quiescent phases too, determining abnormalities in tear film stability, epithelial cells integrity, and corneal nerves function. The very long-term consequences of this perennial mechanism of ocular surface damage have not been fully understood yet. PMID- 26496270 TI - Characteristics of Small Intestinal Diseases on Single-Balloon Enteroscopy: A Single-Center Study Conducted Over 6 Years in China. AB - The small intestine has been considered inaccessible for a long term. The development of single-balloon endoscopy has greatly improved the diagnosis and treatment possibilities for small intestinal diseases.In this study, we aimed to explore the demographic characteristics and small intestinal diseases of patients who underwent single-balloon enteroscopy between 2009 and 2014 at our endoscopy center. We determined the enteroscopic findings for each small intestinal disease and the most susceptible age groups.In total, 186 patients were included in the study. Their mean age was 45.87 +/- 15.77 years. Patients who underwent single balloon enteroscopy were found to have neoplasms (most common age group: 14-45 years, most common lesion location: jejunum), lymphoma (46-59 and 60-74 years, ileum), protuberant lesions (45-59 years, jejunum), inflammation (14-45 and 46-59 years, ileum), benign ulcers (14-45 years, jejunum), diverticulum (14-45 years, ileum), vascular malformations (60-74 years, jejunum), polyps (14-45 years, jejunum), Crohn's disease (14-45 years, jejunum), hookworm infection (14-45 years, jejunum), lipid pigmentation (14-45 and 46-59 years, jejunum), undetermined bleeding (46-59 years, ileum), or undetermined stenosis (31 years, duodenum). Each small intestinal disease had distinct enteroscopic findings. PMID- 26496271 TI - Diagnostic Potential of Zymogen Granule Glycoprotein 2 Antibodies as Serologic Biomarkers in Chinese Patients With Crohn Disease. AB - The need for reliable biomarkers for distinguishing Crohn disease (CD) from ulcerative colitis (UC) is increasing. This study aimed at evaluating the diagnostic potential of anti-GP2 antibodies as a biomarker in Chinese patients with CD. In addition, a variety of autoantibodies, including anti-saccharomyces cerevisiae antibodies (ASCA), perinuclear anti-neutrophil cytoplasmic antibodies (PANCA), anti-intestinal goblet cell autoantibodies (GAB), and anti-pancreatic autoantibodies (PAB), were evaluated.A total of 91 subjects were prospectively enrolled in this study, including 35 patients with CD, 35 patients with UC, 13 patients with non-IBD gastrointestinal diseases as disease controls (non-IBD DC), and 8 healthy controls (HC). The diagnosis of IBD was determined based on the Lennard-Jones criteria, and the clinical phenotypes of the IBD patients were determined based on the Montreal Classification.Anti-GP2 IgG antibodies were significantly elevated in patients with CD, compared with patients with UC (P = 0.0038), HC (P = 0.0055), and non-IBD DC (P = 0.0063). The prevalence of anti-GP2 IgG, anti-GP2 IgA and anti-GP2 IgA, or IgG antibodies in patients with CD was 40.0%, 37.1%, and 54.3%, respectively, which were higher than those in non-IBD DC (anti-GP2 IgG, 15.4%; anti-GP2 IgA, 7.7%; and anti-GP2 IgA or IgG, 23.1%) and those in patients with UC (anti-GP2 IgG, 11.4%; anti-GP2 IgA, 2.9%; and anti-GP2 IgA or IgG, 14.3%). For distinguishing CD from UC, the sensitivity, specificity, positive predictive value (PPV) and positive likelihood ratios (LR+) were 40%, 88.6%, 77.8%, and 3.51 for anti-GP2 IgG, 37.1%, 97.1%, 92.9%, and 13.0 for anti GP2 IgA, and 54.3%, 85.3%, 79.2%, and 3.69 for anti-GP2 IgA or IgG. For CD diagnosis, the combination of anti-GP2 antibodies with ASCA IgA increased the sensitivity to 68.6% with moderate loss of specificity to 74.3%. Spearman's rank of order revealed a significantly positive correlation of anti-GP2 IgG with ileocolonic location of disease (L3) (P = 0.043) and a negative correlation of anti-GP2 IgA with biologic therapy (P = 0.012).Our findings suggest that anti-GP2 antibodies could serve as a biomarker for distinguishing patients with CD from patients with UC, and the combination of anti-GP2 antibodies with ASCA IgA may improve the predictive power. PMID- 26496272 TI - Localized Autoimmune Pancreatitis: Report of a Case Clinically Mimicking Pancreatic Cancer and a Literature Review. AB - Autoimmune pancreatitis (AIP) is a rare disease with clinical presentations that greatly mimic pancreatic cancer (PC). It is critical for clinicians to distinguish AIP from PC because their treatments and prognoses are entirely different. Typical images show characteristic features such as diffuse pancreatic swelling and strictures of the main pancreatic duct (MPD). However, AIP may present as a localized pancreatic mass, in which case it is very difficult to differentiate from PC. Here, we report a case of a 40-year-old man with computed tomography (CT) imaging studies confirming an area of low-density neoplasm in the uncinate process of the pancreas with dilation in the common biliary duct (CBD) and MPD. Increased uptake in the uncinate mass was observed by positron emission tomography (PET)/CT scan, which strongly suggested PC. Further laboratory analyses showed a marked elevation of serum IgG4. Because there was not enough evidence to rule out a diagnosis of malignancy, a histopathological biopsy became the criterion standard. An endoscopic ultrasound (EUS)-guided needle biopsy failed. As an alternative, a pancreaticoduodenectomy was conducted for the biopsy, and pathological analysis confirmed IgG4-related sclerotic chronic pancreatitis with moderate lymphoplasmacellular infiltration.We suggest that an accurate preoperative diagnosis for localized AIP with MPD and CBD obstructions mimicking PC is of great importance. Radiological imaging findings, particularly observations of diffused enlargement of the pancreas and delayed enhancement during the venous and portal phases, are essential for diagnosing AIP. Careful consideration should be given if serum IgG4 was taken as a special indicator for a differential diagnosis between AIP and PC. A history of IgG4-related diseases involving the biliary, lacrimal, salivary, retroperitoneal, renal, or pulmonary systems should also be highlighted. Thus, the pathology of extrapancreatic organs can be utilized as diagnostic evidence when the pathology for a pancreatic mass is not available, as in the case presented here. Furthermore, cautious use of hormone therapy is indicated for patients who cannot be ruled out as having PC. The results of future studies on localized AIP are eagerly awaited. PMID- 26496273 TI - Emergency Transcatheter Arterial Embolization for Acute Renal Hemorrhage. AB - The aims of this study were to identify arteriographic manifestations of acute renal hemorrhage and to evaluate the efficacy of emergency embolization. Emergency renal artery angiography was performed on 83 patients with acute renal hemorrhage. As soon as bleeding arteries were identified, emergency embolization was performed using gelatin sponge, polyvinyl alcohol particles, and coils. The arteriographic presentation and the effect of the treatment for acute renal hemorrhage were analyzed retrospectively. Contrast extravasation was observed in 41 patients. Renal arteriovenous fistulas were found in 12 of the 41 patients. In all, 8 other patients had a renal pseudoaneurysm, 5 had pseudoaneurysm rupture complicated by a renal arteriovenous fistula, and 1 had pseudoaneurysm rupture complicated by a renal artery-calyceal fistula. Another 16 patients had tumor vasculature seen on arteriography. Before the procedure, 35 patients underwent renal artery computed tomography angiography (CTA). Following emergency embolization, complete hemostasis was achieved in 80 patients, although persistent hematuria was present in 3 renal trauma patients and 1 patient who had undergone percutaneous nephrolithotomy (justifying surgical removal of the ipsilateral kidney in this patient). Two-year follow-up revealed an overall effective rate of 95.18 % (79/83) for emergency embolization. There were no serious complications. Emergency embolization is a safe, effective, minimally invasive treatment for renal hemorrhage. Because of the diversified arteriographic presentation of acute renal hemorrhage, proper selection of the embolic agent is a key to successful hemostasis. Preoperative renal CTA plays an important role in diagnosing and localizing the bleeding artery. PMID- 26496274 TI - Nocardia Arthritis: 3 Cases and Literature Review. AB - Nocardia are Gram-positive filamentous bacteria responsible for infections ranging from opportunistic life-threatening disseminated diseases to chronic skin and soft-tissue infections.Even if virtually all organs can be infected, articular involvement is rare. Therefore, we report 3 recent cases and performed a literature review of cases of Nocardia arthritis in order to describe clinical features, therapeutic challenges, and outcome of these patients.Among 34 patients (31 in the literature plus our 3 cases), 21 (62%) were due to hematogenous dissemination, 9 (26%) were due to direct bacterial inoculation through the skin, and in 4 cases, the mechanism of infection was unknown. Four out of these 34 cases occurred on prosthetic joints.Whereas hematogenous infections mostly occurred in immunocompromised hosts (17 of 21, 81%), direct inoculation was mostly seen in immunocompetent patients.Eighty-two percent of patients (28 out of 34) received trimethoprim-sulfamethoxazole-containing regimens and median antibiotic treatment duration was 24 weeks (range, 12-120) for hematogenous infections and 12 weeks (range, 6-24) for direct inoculations. Outcome was favorable in 27 cases despite unsystematic surgical management (17 cases) without sequelae in 70% of the cases.Nocardia arthritis is rare but its management is complex and should rely on a combined approach with rheumatologist, infectious diseases expert, and surgeon. PMID- 26496275 TI - Characteristic CT Findings After Percutaneous Cryoablation Treatment of Malignant Lung Nodules. AB - Assess computed tomography (CT) imaging characteristics after percutaneous cryotherapy for lung cancer.A retrospective IRB-approved analysis of 40 patients who underwent nonsurgical treatment for primary stage 1 lung cancer performed from January 2007 to March 2011 was included in this study. All procedures were performed using general anesthesia and CT guidance. Follow-up imaging with CT of the chest was obtained at 1 month, 3 months, 6 months, and 12 months postprocedure to evaluate the ablated lung nodule. Nodule surface area, density (in Hounsfield units), and presence or absence of cavitations were recorded. In addition, the degree of nodule enhancement was also recorded. Patients who were unable to obtain the aforementioned follow-up were excluded from the study.Thirty six patients underwent percutaneous cryoablation with men to women ratio of 75% with mean age for men 74.6 and mean age for women 74.3 years of age. The average nodule surface area preablation and postcryoablation at 1-, 3-, 6-, and 12-month follow-ups were 2.99, 7.86, 3.89, 3.18 and 3.07[REPLACEMENT CHARACTER]cm, respectively. The average precontrast nodule density before cryoablation was 8.9 and average precontrast nodule density postprocedure at 1, 3, 6, and 12 months follow-ups were 8.5, -5.9, -9.4, and -3.8 HU, respectively. There is increased attenuation of lung nodules over time with an average postcontrast enhancement of 11.4, 18.5, 16.1, and 25.7 HU at the aforementioned time intervals. Cavitations occurred in the cryoablation zone in 53% (19/36) of patients. 80.6% (29/36) of the cavitations in the cryoablation zone resolved within 12 months. Four patients (11%) had recurrence of tumor at the site of cryoablation and none of the patients had satellite or distant metastasis.Our study shows that patients who underwent cryotherapy for lung nodules treatment had characteristic changes on follow-up CT including. The surface area of the nodule increases at the 1-month follow-up with subsequent gradual decrease in the surface area. Decreased nodule density (Hounsfield units) at each interval follow-up is associated with complete ablation of the lung cancer whereas increasing nodule density was suggestive of recurrence. Cavity formation within the region of the ablated nodule, most of which typically resolved within the first 3 to 6 months. Nodule enhancement is difficult to assess because of the limited data sets that are available. PMID- 26496276 TI - Tissue Factor Pathway Inhibitor-2 Gene Polymorphisms Associate With Coronary Atherosclerosis in Chinese Population. AB - Tissue factor pathway inhibitor-2 (TFPI-2) may play critical roles in the pathogenesis of atherosclerosis. In this study, we aimed to investigate the association between TFPI-2 gene polymorphisms and coronary atherosclerosis.Four hundred and seven patients with coronary atherosclerosis and 306 individuals with normal coronary artery were enrolled in the present study. Nine single-nucleotide polymorphisms (SNPs) (rs3763473, rs59805398, rs60215632, rs59999573, rs59740167, rs34489123, rs4517, rs4264, and rs4271) were detected with polymerase chain reaction-direct sequencing method. Severity of coronary atherosclerosis was assessed by Gensini score. After the baseline investigation, patients with coronary atherosclerosis were followed up for incidence of cardiovascular events (CVEs).Eight SNPs were in accordance with the Hardy-Weinberg equilibrium, and 8 haplotypes were constructed based on rs59999573, rs59740167, and rs34489123 after linkage disequilibrium and haplotype analysis. Two SNPs (rs59805398 and rs34489123) and 5 haplotypes correlated with coronary atherosclerosis even after adjustment by Gensini score. At follow-up (median 53 months, range 1-60 months), 85 patients experienced CVE. However, there was no strong association between the gene polymorphisms and the occurrence of CVE.Tissue factor pathway inhibitor-2 gene polymorphisms were associated with coronary atherosclerosis in the Chinese population, suggesting that the information about TFPI-2 gene polymorphisms was useful for assessing the risk of developing coronary atherosclerosis, but there was not enough evidence showing it could predict occurrence of CVE. PMID- 26496278 TI - Improving Emergency Department Door to Doctor Time and Process Reliability: A Successful Implementation of Lean Methodology. AB - The aim of this study is to determine the effectiveness of using lean management methods on improving emergency department door to doctor times at a tertiary care hospital.We performed a before and after study at an academic urban emergency department with 49,000 annual visits after implementing a series of lean driven interventions over a 20 month period. The primary outcome was mean door to doctor time and the secondary outcome was length of stay of both admitted and discharged patients. A convenience sample from the preintervention phase (February 2012) was compared to another from the postintervention phase (mid-October to mid-November 2013). Individual control charts were used to assess process stability.Postintervention there was a statistically significant decrease in the mean door to doctor time measure (40.0 minutes +/- 53.44 vs 25.3 minutes +/- 15.93 P < 0.001). The postintervention process was more statistically in control with a drop in the upper control limits from 148.8 to 72.9 minutes. Length of stay of both admitted and discharged patients dropped from 2.6 to 2.0 hours and 9.0 to 5.5 hours, respectively. All other variables including emergency department visit daily volumes, hospital occupancy, and left without being seen rates were comparable.Using lean change management techniques can be effective in reducing door to doctor time in the Emergency Department and improving process reliability. PMID- 26496277 TI - Meta-Analysis of Studies Comparing Single and Multi-Tablet Fixed Dose Combination HIV Treatment Regimens. AB - Availability of a single source review of once-daily fixed-dose single tablet regimen (STR) and multiple tablet fixed-dose regimen (MTR) would optimally inform healthcare providers and policy makers involved in the management of population with human immunodeficiency virus (HIV).We conducted a meta-analysis of published literature to compare patient adherence, clinical, and cost outcomes of STR to MTR.Published literature in English between 2005 and 2014 was searched using Embase, PubMed (Medline in-process), and ClinicalTrials.Gov databases. Two-level screening was undertaken by 2 independent researchers to finalize articles for evidence synthesis. Adherence, efficacy, safety, tolerability, healthcare resource use (HRU), and costs were assessed comparing STR to MTR. A random effects meta-analysis was performed and heterogeneity examined using meta regression.Thirty-five articles were identified for qualitative evidence synthesis, of which 9 had quantifiable data for meta-analysis (4 randomized controlled trials and 5 observational studies). Patients on STR were significantly more adherent when compared to patients on MTR of any frequency (odds ratio [OR]: 2.37 [95% CI: 1.68, 3.35], P < 0.001; 4 studies), twice-daily MTR (OR: 2.53 [95% CI: 1.13, 5.66], P = 0.02; 2 studies), and once-daily MTR (OR: 1.81 [95% CI: 1.15, 2.84], P = 0.01; 2 studies). The relative risk (RR) for viral load suppression at 48 weeks was higher (RR: 1.09 [95% CI: 1.04, 1.15], P = .0003; 3 studies) while RR of grade 3 to 4 laboratory abnormalities was lower among patients on STR (RR: 0.68 [95% CI: 0.49, 0.94], P = 0.02; 2 studies). Changes in CD4 count at 48 weeks, any severe adverse events (SAEs), grade 3 to 4 AEs, mortality, and tolerability were found comparable between STR and MTR. Several studies reported significant reduction in HRU and costs among STR group versus MTR.Study depicted comparable tolerability, safety (All-SAE and Grade 3-4 AE), and mortality and fewer Grade 3 to 4 lab abnormalities and better viral load suppression and adherence among patients on FDC-containing STR versus MTR; literature depicted favorable HRU and costs for STRs.These findings may help decision makers especially in resource-poor settings to plan for optimal HIV disease management when the choice of both STRs and MTRs are available. PMID- 26496279 TI - BRCA2 N372H Polymorphism and Risk of Epithelial Ovarian Cancer: An Updated Meta Analysis With 2344 Cases and 9672 Controls. AB - The BRCA2 N372H is the only common polymorphism that leads to the amino acid change based on the reports up to date. Previous studies explored the relationship between the single nucleotide polymorphism and ovarian cancer risk, but the results were inconsistent or inconclusive.To investigate the association between N372H in BRCA2 gene and ovarian cancer susceptibility, a systematic literature search was performed for related publications in the databases of PubMed, Gene, and Google Scholar.Total 2344 cases and 9672 controls in eligible studies were included in this meta-analysis. chi -based Q test and an I index were used to identify the heterogeneous records. Potential publication biases were assessed by Begg and Egger tests.In the overall analysis, the results showed a significant association between BRCA2 codon 372 polymorphism and increased risk of ovarian cancer (HH versus NN: odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.01-1.48, P = 0.037). In the Australia subgroup analysis, significant association was also detected (HH versus NN: OR = 1.40, 95% CI 1.04-1.87, P = 0.026). The subgroup analysis for serous cancer subgroup showed that the significant association could be detected under recessive model (OR = 1.38, 95% CI, 1.01-1.89, P = 0.04) and under homozygote comparison (OR = 1.46, 95% CI, 1.06 2.01, P = 0.022).Our meta-analysis suggests that the N372H polymorphism is associated with susceptibility of ovarian cancer. The allele H might increase the risk of ovarian cancer, especially, for ovarian cancers of the serous subtype. PMID- 26496280 TI - Analysis of the Fibrinogen and Neutrophil-Lymphocyte Ratio in Esophageal Squamous Cell Carcinoma: A Promising Blood Marker of Tumor Progression and Prognosis. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies in gastrointestinal tract cancers and even patients with early ESCC have a high metastatic potential. Difficulties are associated with clinically predicting tumor progression and prognosis based on conventional tumor markers determined from preoperative blood examinations. The aim of the present study was to measure plasma fibrinogen levels and the neutrophil-lymphocyte ratio (NLR) in blood and compare the clinical impacts of their combined values (fibrinogen and neutrophil-lymphocyte ratio score-F-NLR score) and the modified Glasgow Prognostic Score (mGPS) in patients with ESCC.We classified 238 patients with ESCC based on cut-off values for hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0) as F-NLR scores of 2 (both of these hematological abnormalities), 1 (one of these abnormalities), or 0 (neither abnormality). We also categorized patients based on cut-off values for high C-reactive protein (CRP) (>0.5 mg/dL) and hypoalbuminemia (<3.8 g/dL) as mGPS of 2 (elevated CRP and hypoalbuminemia), 1 (either elevated CRP or hypoalbuminemia), or 0 (neither elevated CRP nor hypoalbuminemia).The F-NLR score correlated with the depth of tumor invasion, lymph node metastasis, lymphovascular invasion, tumor size, and stage (all P < 0.05). Prognoses among the groups based on the F-NLR score and mGPS significantly differed (all P < 0.001). A multivariate analysis identified the depth of tumor invasion, lymph node metastasis, and F-NLR score as independent prognostic factors (P = 0.002, P = 0.007, and P = 0.037, respectively).The results of the present study showed that the F-NLR score is a promising blood predictor for tumor progression and outcomes in patients with ESCC. PMID- 26496281 TI - Inflammatory Myofibroblastic Tumor of Genitourinary Tract Beyond Collecting System: A Rare Case Report With Literature Review. AB - Inflammatory myofibroblastic tumor (IMT) rarely arises in genitourinary tract especially beyond collecting system, which determines the unspecific clinic symptoms and sometimes can mimic malignancy. Therefore, IMT's diagnosis may usually be a pitfall. This case report characterizes a 35-year-old woman with a history of lower quadrant lasting pain followed by fever. Furthermore, radiologic examinations revealed that there were 2 lesions located in left adrenal area and left renalis. Owing to the anatomic complexity, the surgical resection was not complete. The pathologic diagnosis of the lesions was IMT. Adjuvant nonsteroids anti-inflammatory drugs were administrated after the operation. The symptoms were controlled finally and no further growing lesion was observed during a 1-year follow-up.Inflammatory myofibroblastic tumor is rare in genitourinary tract beyond the collecting system. Diagnosis should be based on histopathology. Presently, the authors report this rare case with the aim to share the experience regarding differential diagnosis and therapy. PMID- 26496282 TI - Demographic and Socioeconomic Factors Influencing Public Attitudes Toward a Presumed Consent System for Organ Donation Without and With a Priority Allocation Scheme. AB - The influence of demographic and socioeconomic factors on the public's attitude towards a presumed consent system (PCS) of organ donation was estimated in 2 scenarios: without and with a priority allocation scheme (PAS). Self-administered questionnaires were completed by 775 respondents. Using multiple logistic regressions, respondents' objections to donating organs in both scenarios were estimated. In total, 63.9% of respondents would object to donating under a PCS, whereas 54.6% would object under a PCS with a PAS. Respondents with pretertiary education were more likely to object than were respondents with tertiary education, in both the first (adjusted odds ratio [AOR] = 1.615) and second (AOR = 1.728) scenarios. Young respondents were less likely to object than were middle aged respondents, in both the first (AOR = 0.648) and second (AOR = 0.572) scenarios. Respondents with mid-ranged personal monthly income were more likely to object than were respondents with low income, in both the first (AOR = 1.994) and second (AOR = 1.519) scenarios. It does not seem that Malaysia is ready to implement a PCS. The educational level, age, and income of the broader public should be considered if a PCS, without or with a PAS, is planned for implementation in Malaysia. PMID- 26496283 TI - Heterotopic Gastric Mucosa in the Distal Part of Esophagus in a Teenager: Case Report. AB - Heterotopic gastric mucosa (HGM) of the esophagus is a congenital anomaly consisting of ectopic gastric mucosa. It may be connected with disorders of the upper gastrointestinal tract, exacerbated by Helicobacter pylori. The diagnosis of HGM is confirmed via endoscopy with biopsy. Histopathology provides the definitive diagnosis by demonstrating gastric mucosa adjacent to normal esophageal mucosa. HGM located in the distal esophagus needs differentiation from Barrett's esophagus. Barrett's esophagus is a well-known premalignant injury for adenocarcinoma of the esophagus. Malignant progression of HGM occurs in a stepwise pattern, following the metaplasia-dysplasia-adenocarcinoma sequence.We present a rare case of a teenage girl with HGM located in the distal esophagus, associated with chronic gastritis and biliary duodenogastric reflux. Endoscopy combined with biopsies is a mandatory method in clinical evaluation of metaplastic and nonmetaplastic changes within HGM of the esophagus. PMID- 26496284 TI - Inhaled Corticosteroids Increase the Risk of Pneumonia in Patients With Chronic Obstructive Pulmonary Disease: A Nationwide Cohort Study. AB - The association of inhaled corticosteroids (ICS) and pneumonia in patients with chronic obstructive pulmonary disease (COPD) is still controversial.From the National Health Insurance Database of Taiwan, COPD cases with history of acute exacerbation (AE) were identified (COPD cohort). Time-dependent Cox regression analysis was applied to investigate the risk factors for pneumonia with COPD severity controlled by surrogate variables. Among the COPD cohort, those who continuously used ICS for more than 360 days without interruption were selected (ICS cohort). The incidence rate of pneumonia during ICS use was compared with those before ICS use and after ICS discontinuation by using pair t test.A total of 6034 and 842 cases were identified as the COPD and ICS cohorts, respectively. In the COPD cohort, recent ICS use was independently associated with pneumonia (hazard ratio: 1.06 [1.02-1.11] for per 80 mg of budesonide). Other independent risk factors included age, male, diabetes mellitus, malignancy, low income, baseline pneumonia event, and recent use of oral corticosteroids and aminophylline. In the ICS cohort, while AE rate gradually decreased, the incidence rate of pneumonia significantly increased after ICS use (from 0.10 to 0.21 event/person-year, P = 0.001).This study demonstrates the association between ICS use and pneumonia in patients with COPD and history of AE. ICS should be judiciously used in indicated COPD patients. PMID- 26496285 TI - Periodontal Treatment Elevates Carotid Wall Shear Stress in the Medium Term. AB - Periodontal disease is associated with endothelial dysfunction of the brachial artery and hemodynamic alterations of the common carotid artery. Periodontal therapy improves endothelial function. It is not known if it is able also to improve the hemodynamics of the carotid artery. The aim of the current study was to evaluate the efficacy of 2 different periodontal treatments on carotid hemodynamics: scaling and root planing (SRP) alone or together with low-level laser therapy (LLLT). Forty patients were recruited and randomly treated with SRP (n = 20) or SRP + LLLT (n = 20). Periodontal indices (plaque, gingival, and probing depth indices) were measured before and 5 months after treatment. Blood viscosity, common carotid wall shear stress, circumferential wall tension, and Peterson elastic modulus were evaluated before, soon after and 5 months after treatment. It was found that the periodontal indices improved in both groups, but significantly more so for SRP + LLLT than for SRP (decrease in gingival index 69.3% versus 45.4%, respectively, P = 0.04). In the SRP + LLLT group, after a transient reduction by 5% immediately after therapy, shear stress increased by 11% after 5 months. In SRP only group, however, shear stress variations were less marked. No significant changes were found for the other hemodynamic parameters in either of the groups. Periodontal disease treatment by SRP + LLLT can therefore be said to improve common carotid wall shear stress. This suggests a possible mechanism by which the treatment of periodontal disease has beneficial effects on the cardiovascular system. PMID- 26496286 TI - Association between Dioxin and Diabetes Mellitus in an Endemic Area of Exposure in Taiwan: A Population-Based Study. AB - Dioxin has been recognized as an environmental endocrine disruptor, but epidemiology studies of its effects on type 2 diabetes mellitus (DM) found inconsistent results, especially in men. Therefore, we conducted a study in Taiwan to evaluate the association between exposure to dioxin and DM.We recruited participants in an area where the residents were exposed to dioxin released from a factory. Using 20 and 64 pg WHO98-TEQDF/g lipid as the cut-offs, we categorized participants into 3 groups according to the level of polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs) in the serum. We defined DM as a fasting plasma glucose level more than 126 mg/dl or an existing diagnosis.Of the 2898 participants, 425 patients of DM were identified, and we observed positive associations between dioxin and DM. After adjusting for age and body mass index (BMI), we found that a high serum dioxin level was an independent risk factor for DM (adjusted odds ratio [AOR] associated with 20-63 pg WHO98-TEQDF/g lipid = 2.1, 95% confidence interval [95% CI] 1.5-2.9; AOR for >=64 pg WHO98-TEQDF/g lipid = 3.2, 95% CI 2.1-4.8). The findings are compatible with those in previous studies of PCDD/Fs. When we stratified the participants by sex, the serum dioxin level remained an independent risk factor for DM in both men and women.Exposure to dioxin is a risk factor for DM, independent of age and BMI in both men and women. Therefore, screening and intervention programs should be considered in endemic areas of exposure to dioxin. PMID- 26496287 TI - Brachium Pontis Gliosarcoma With Well-Differentiated Cartilaginous Tissue: A Case Report. AB - Gliosarcoma (GS) belongs to World Health Organization grade IV neoplasm and displaying glial and mesenchymal differentiation. Only rare cases of GS have been reported in the brachium pontis and 4th ventricle region. Here, we report a rare case of GS located on brachium pontis region and extending into the 4th ventricle with well-differentiated cartilaginous metaplasia. A 28-year-old male patient experienced intermittent headache, vomiting, and gait disorders for 3 months. Magnetic resonance imaging (MRI) showed a heterogeneous ring-enhancement lesion with weak central enhancement in left brachium pontis and 4th ventricle region. Histology revealed the GS was constituted with glial and sarcomatous elements. After immunohistochemical analysis, a diagnosis of GS with cartilaginous differentiation was then made.Symptoms of GS, including headache, aphasia, hemiparesis, cognitive decline, and seizures, mainly determined by the location. The clinical manifestation and radiologic characteristic is not significantly different from that of glioblastoma. The grade of resection is the significant factor related to prognosis of GS, and the clinical effect of adjuvant radiotherapy and chemotherapy need further study. Reporting additional cases would be of great help in better understanding of this location and pathologic type of GS. PMID- 26496288 TI - Implementation of Pharmaceutical Practice Guidelines by a Project Model Based: Clinical and Economic Impact. AB - All around the world a few studies have been found on the effect of guideline implementation on direct medications' expenditure. The goal of this study was to evaluate cost savings of guideline implementation among patients who had to receive 3 costly medications including albumin, enoxaparin, and pantoprazole in a tertiary hospital in Shiraz, Iran.An 8-month prospective study was performed in 2 groups; group 1 as an observational group (control group) in 4 months from June to September 2014 and group 2 as an interventional group from October 2014 to January 2015.For group 1 the pattern of costly medications usage was determined without any intervention. For group 2, after guideline implementation, the economic impact was evaluated by making comparisons between the data achieved from the 2 groups.A total of 12,680 patients were evaluated during this study (6470 in group 1; 6210 in group 2). The reduction in the total value of costly administered drugs was 56% after guideline implementation. Such reduction in inappropriate prescribing accounts for the saving of 85,625 United States dollars (USD) monthly and estimated 1,027,500 USD annually.Guideline implementation could improve the adherence of evidence-based drug utilization and resulted in significant cost savings in a major teaching medical center via a decrease in inappropriate prescribing of costly medications. PMID- 26496289 TI - Clinical Outcomes of Revascularization Strategies for Patients With MVD/LMCA Disease: A Systematic Review and Network Meta-Analysis. AB - Hybrid coronary revascularization (HCR), a new minimally invasive procedure for patients requiring revascularization for multivessel coronary lesions, combines coronary artery bypass grafting (CABG) for left anterior descending (LAD) lesions and percutaneous coronary intervention (PCI) for non-LAD coronary lesions. However, available data related to outcomes comparing the 3 revascularization therapies is limited to small studies.We conducted a search in MEDLINE, EMBASE, and the Cochrane Library of Controlled Trials up to December 31, 2014, without language restriction. A total of 16 randomized trials (n=4858 patients) comparing HCR versus PCI or off-pump CABG (OPCAB) were included in this meta-analysis. The primary outcomes were major adverse cardiac and cerebrovascular events (MACCE), all-cause death, myocardial infarction (MI), cerebrovascular events (CVE), and target vessel revascularization (TVR). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using random-effect and fixed-effect models. Ranking probabilities were used to calculate a summary numerical value: the surface under the cumulative ranking (SUCRA) curve.No significant differences were seen between the HCR and PCI in short term (in hospital and 30 days) with regard to MACCE (odds ratio [OR] = 0.51, 95% confidence interval [CI] 0.00-2.35), all-cause death (OR = 2.09, 95% CI 0.34-7.66), MI (OR = 1.02, 95% CI 0.19-2.95), CVE (OR = 4.45, 95% CI 0.39-19.16), and TVR (OR = 6.99, 95% CI 0.17-39.39). However, OPCAB had lower MACCE than HCR (OR = 0.19, 95% CI 0.00-0.95). In midterm (1 year and 3 year), in comparison with HCR, PCI had higher all-cause death (OR = 5.66, 95% CI 0.00-13.88) and CVE (OR = 4.40, 95% CI 0.01-5.68), and lower MI (OR = 0.51, 95% CI 0.00-2.86), TVR (OR = 0.53, 95% CI 0.05-2.26), and thus the MACCE (OR = 0.51, 95% CI 0.00-2.35). Off-pump CABG presented a better outcome than HCR with significant lower MACCE (OR = 0.17, 95% CI 0.01-0.68). Surface under the cumulative ranking probabilities showed that HCR may be the superior strategy for MVD and LMCA disease when regarded to MACCE (SUCRA = 0.84), MI (SUCRA = 0.76) in short term, and regarded to MACCE (SUCRA = 0.99), MI (SUCRA = 0.94), and CVE (SUCRA = 0.92) in midterm.Hybrid coronary revascularization seemed to be a feasible and acceptable option for treatment of LMCA disease and MVD. More powerful evidences are required to precisely evaluate risks and benefits of the 3 therapies for patients who have different clinical characteristics. PMID- 26496290 TI - Early Markers of Tubulointerstitial Fibrosis in Children With Idiopathic Nephrotic Syndrome: Preliminary Report. AB - Tubulointerstitial fibrosis and tubular atrophy play a crucial role in the pathogenesis of chronic kidney disease (CKD). They are also major determinants in chronic kidney disease development and progression in patients with primary renal diseases characterized by persistent or recurrent proteinuria. The purpose of the study was to assess urinary excretion of alpha-glutathione S-transferase (alpha GST), pi-glutathione S-transferase (pi-GST), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and serum NGAL level in children with idiopathic nephrotic syndrome (INS). PATIENTS AND METHODS: the study group comprised of 39 children with INS and the control group consisted of 20 healthy children. A total of 23 patients were affected with steroid-dependent nephrotic syndrome (SDNS) and 16 with steroid-resistant nephrotic syndrome (SRNS). In the majority of patients, a histopathologic examination revealed minimal change disease (MCD)-25 (64%). Focal segmental glomerulosclerosis (FSGS), mesangioproliferative glomerulonephritis (MesPGN), membranoproliferative glomerulonephritis (MPGN), and membranous glomerulonephritis (MGN) were diagnosed in 4 (10.3 %), 6 (15.5%), 2 (5.1%), and 2 (5.1%) children, respectively. Urinary alpha-GST, urinary pi-GST, urinary KIM-1, and urinary and serum NGAL concentrations were measured using specific enzyme-linked immunosorbent assay. The urinary results were expressed in nanograms per milligram of creatinine (ng/mg). RESULTS: The authors observed significantly higher levels of urinary alpha-GST/creatinine ratio (P = 0.03), urinary KIM-1/creatinine ratio (P < 0.02), serum NGAL level (P < 0.01), and urinary NGAL/creatinine ratio (P = 0.02) in children with INS compared with controls. The median values of urinary pi GST/creatinine ratio in children with INS and controls did not differ significantly. In children with SRNS, the median values of urinary NGAL/creatinine ratio (P = 0.02) and urinary KIM-1/creatinine ratio (P = 0.02) were significantly higher compared with children with SDNS. The authors noted significant positive correlation between KIM-1/creatinine ratio and proteinuria (r = 0.56, P < 0.05). The analysis of alpha-GST/creatinine ratio, pi GST/creatinine ratio, sNGAL, and uNGAL/creatinine ratio concerning the histopathologic examination, the duration of the disease, and number of relapses did not show any significant differences. CONCLUSIONS: 1. Both children with SDNS and those with SRNS were characterized by increased tubular injury marker levels. 2. Patients with SRNS and higher proteinuria are more susceptible to early kidney damage. PMID- 26496291 TI - The Risk Factors That Predict Chronic Hypertension After Delivery in Women With a History of Hypertensive Disorders of Pregnancy. AB - Hypertensive disorders of pregnancy (HDP) is one of the most important lethal complications in pregnant mothers. It is also associated with the subsequent development of chronic hypertension. The objective of this study was to identify the clinical risk factors of postpartum chronic hypertension in women diagnosed with HDP.Six hundred patients as HDP, who diagnosed and followed-up at least 6 month after delivery, were included in the study. We divided the included subjects in 2 groups based on the development of postpartum chronic hypertension: presenting with the chronic hypertension, "case group" (n = 41) and without chronic hypertension, "control group" (n = 559).Clinical and demographic factors were evaluated. By multiple regression analysis, early onset hypertension with end-organ dysfunction, smoking, higher prepregnancy body mass index (BMI), and comorbidities, systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APLS), were associated with progression to chronic hypertension in the postpartum period. The value of area under the curves (AUC) for the 5 models, that generated to combine the significant factors, increased from 0.645 to 0.831, which indicated improved prediction of progression to the chronic hypertension. Additional multivariate analysis revealed significant specific risk factors.This retrospective single hospital-based study demonstrated that the clinical risk factors, that is early onset hypertension with end-organ dysfunction, smoking, and higher prepregnancy BMI, were significant independent predictors of chronic hypertension in women after delivery. Identification of risk factors allowed us to narrow the subject field for monitoring and managing high blood pressure in the postpartum period. PMID- 26496292 TI - Extent of Serosal Changes Predicts Peritoneal Recurrence and Poor Prognosis After Curative Surgery for Gastric Cancer. AB - To investigate whether the width of gastric serosal lesions in advanced gastric cancer patients have a predictive value for peritoneal recurrence and the 5-year survival rate.A total of 1109 patients with advanced noncardia primary gastric adenocarcinoma, who underwent curative gastrectomy between January 1997 and December 2007, were included. Data about tumor size, longitudinal tumor location, resection type, serum albumin concentration, lymphatic/venous invasion, lymph node metastasis status, lesion size, histological and Borrmann type of tumor, as well as the recurrence rate and width of the gastric serosal lesions were collected and analyzed.The peritoneal recurrence rate in patients with gastric serosal lesions <=3 cm was lower than in patients with gastric serosal lesions >3 cm. Multivariate analyses of the 5-year survival rate variables for all patients revealed significant correlations with serum albumin concentrations (HR 1.382, P = 0.002, 95% CI 1.123-1.701), width of serosa changes (HR 1.377, P = 0.020, 95% CI 1.053-1.802), depth of invasion (HR 1.529, P < 0.001, 95% CI 1.288-1.814), and lymph node metastasis (HR 1.551, P < 0.001, 95% CI 1.420-1.694), whereas for recurrent patients only serum albumin concentrations (HR 2.000, P < 0.001, 95% CI 1.425-2.805), width of serosa changes (HR 1.867, P = 0.002, 95% CI 1.248-2.793), and lymph node metastasis (HR 1.521, P < 0.001, 95% CI 1.249-1.852) correlated with the 5-year survival rate.Gastric serosal lesions >3 cm may indicate a high risk for peritoneal recurrence and serve as additional indicators for preventive postoperative adjuvant chemotherapies in patients with advanced gastric cancer. PMID- 26496293 TI - Markers of Bone Metabolism in Patients With Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma. AB - There are no studies comparing some of the most important markers, such as vitamin D, parathormone, osteocalcin, bone alkaline phosphatase, and calcium, in patients with chronic benign and malignant pancreatic diseases. Our objective was to comparatively evaluate serum markers of bone metabolism in patients with chronic pancreatitis and in those with ductal pancreatic adenocarcinoma. Sixty three consecutive subjects were studied: 30 patients with a firm diagnosis of chronic pancreatitis and 33 having histologically confirmed pancreatic adenocarcinoma. Serum 25-hydroxyvitamin D, bone alkaline phosphatase, osteocalcin, parathormone, and calcium were determined using commercially available kits. Taking into consideration the clinical variables of all 63 patients studied, 25-hydroxyvitamin D was inversely correlated with only the body mass index (P = 0.007), whereas it was not correlated with age (P = 0.583) or fecal elastase-1 concentrations (P = 0.556). Regarding the other substances studied, parathormone was positively correlated with only the age of the patients (P = 0.015). Of the 5 substances studied, only bone alkaline phosphates were significantly different (P < 0.001) between patients with chronic pancreatitis and those with pancreatic ductal adenocarcinoma. Within the 2 groups of patients, the 23 patients with chronic pancreatitis without diabetes mellitus had serum concentrations of 25-hydroxyvitamin D significantly lower (P = 0.045) than those with chronic pancreatitis having diabetes mellitus, whereas smokers with pancreatic ductal adenocarcinoma had serum concentrations of calcium significantly higher (P < 0.001) as compared to nonsmokers. Altered bone metabolism seems to be associated with chronic diseases of the pancreas; however, the mechanism should be better elucidated. PMID- 26496294 TI - Effect of Blood Cadmium Level on Mortality in Patients Undergoing Maintenance Hemodialysis. AB - Previous studies of general populations indicated environmental exposure to low level cadmium increases mortality. However, the effect of cadmium exposure on maintenance hemodialysis (MHD) patients is unclear.A total of 937 MHD patients from 3 centers in Taiwan were enrolled in this 36-month observational study. Patients were stratified by baseline blood cadmium level (BCL) into 3 groups: high BCL (>0.521 MUg/L; n = 312), intermediate BCL (0.286-0.521 MUg/L; n = 313), and low BCL (<0.286 MUg/L; n = 312). The mortality rates and causes of death were analyzed.The analytic results demonstrated patients in the high BCL group had a significantly higher prevalence of malnutrition and inflammation than patients in the low and intermediate BCL groups. After 3 years of follow-up, 164 (17.5%) patients died and the major cause of death was cardiovascular disease. A Cox multivariate analysis indicated the high BCL group had increased hazard ratios (HRs) for all-cause mortality (HR = 1.72; 95% confidence interval [CI]: 1.14 2.63; P = 0.018), cardiovascular-related mortality (HR = 1.85; 95% CI: 1.09-3.23; P = 0.032), and infection-related mortality (HR = 2.27; 95% CI: 1.12-4.55; P = 0.035). A Cox multivariate analysis of MHD patients who never smoked (n = 767) indicated the high BCL group had increased HRs for all-cause mortality (HR = 1.67; 95% CI: 1.04-2.63; P = 0.048) and cardiovascular-related mortality (HR = 2.08; 95% CI: 1.08-4.00; P = 0.044).In conclusion, BCL is an important determinant of mortality in MHD patients. Therefore, MHD patients should avoid cadmium exposure as much as possible, such as tobacco smoking and eating cadmium containing foods. PMID- 26496295 TI - Liver Metastasis of a Triple-Negative Breast Cancer and Complete Remission for 5 Years After Treatment With Combined Bevacizumab/Paclitaxel/Carboplatin: Case Report and Review of the Literature. AB - Triple-negative breast cancer (TNBC) is aggressive, with high risk of visceral metastasis and death. A substantial proportion of patients with TNBC is associated with BRCA mutations, implying that these tumors are sensitive to DNA damaging agents. We report successful treatment of a metastatic TNBC in a woman with a BRCA2 germline mutation using combined bevacizumab/paclitaxel/carboplatin (BPC) therapy. The patient was pregnant and had liver metastases, and a complete clinical response was sustained for approximately 5 years. Mastectomy was performed during the 29th week of pregnancy, and the baby was later delivered by caesarean section. Subsequently, multiple metastases in both liver lobes were detected using computed tomography and magnetic resonance imaging and the patient was treated with a BPC regimen, which led to complete disappearance of metastatic lesions in the liver. No additional treatment was provided, and after 5 years the patient consented to direct sequencing of BRCA2 and a 6781delG mutation was identified. At the most recent (5-year) follow-up, the patient was alive with good quality of life and no evidence of metastases.This finding suggests that BPC therapy might be considered a good therapeutic option for the treatment of metastatic TNBC in a woman with a BRCA2 germline mutation. PMID- 26496296 TI - Branchial Cleft-Like Cysts Involving 3 Different Organs: Thyroid Gland, Thymus, and Parotid Gland. AB - Branchial cleft cysts (BCCs) are also named lateral cervical cysts and widely acknowledged as being derived from embryonic remnants. Lymphoepithelial cysts (LECs) generally show microscopic features that are identical to those of BCCs, and rarely occur at unusual sites or organs.A case of multiple cysts arising in both lobes of the thyroid gland, thymus, and right parotid gland in a 41-year-old man is reported. Clinically, the patient presented with Hashimoto's thyroiditis for about 20 years and had past histories of idiopathic thrombocytopenic purpura and severe respiratory infection.This case is unusual in that multiple cysts arose synchronously and/or heterochronously and grew, increasing their sizes in these different organs. Microscopic examinations revealed that all of the cysts were composed of squamous epithelium, dense lymphoid tissue with germinal centers, and a fibrous capsule. These findings corresponded to those of BCCs or LECs. It is notable that the histopathological features were nearly the same in the individual organs. A review of the literature disclosed no previous such reported cases.The etiology is unknown. However, based upon the similar histopathological features of all the excised specimens, common immune and/or hematopoietic disorders may have contributed to their occurrence and development in association with putative genetic abnormalities. PMID- 26496297 TI - Diagnostic Value of Fetal Echocardiography for Congenital Heart Disease: A Systematic Review and Meta-Analysis. AB - Prenatal diagnosis of fetal congenital heart disease (CHD) has been shown to have a significant effect on prenatal and postnatal management and outcomes. However, the factors influencing the diagnostic accuracy and which pregnant trimester is the most adaptive for fetal heart disease remain uncertain despite of extensive researches. The aim of the present study was to evaluate the accuracy of echocardiography for detecting CHD and potential influence factors.We searched Chinese Biomedical Database (CBM), Medline, ISI Web of Knowledge, the Cochrane Library, and China National Knowledge Infrastructure (CNKI) to identify relevant studies from January 1, 1990 to August 13, 2015.Overall, the pooled sensitivity, specificity, diagnostic odds ratio, positive likelihood ratio, and negative likelihood ratio were 68.5% (95% confidence interval [CI], 66.8%-70.2%), 99.8% (95% CI, 99.7%-99.8%), 3026.9 (95% CI, 1417.9-6461.8), 659.41 (95% CI, 346.38 1255.3), and 0.246 (95% CI, 0.187-0.324) respectively (AUC = 0.9924). The pooled sensitivity of basic cardiac echocardiographic examination (BCEE), extended cardiac echocardiographic examination (ECEE), BCEE plus outflow tract view (BCEE + OTV), BCEE + OTV + 3VTV (BCEE plus outflow tract view plus three vessel and trachea view) for the prenatal diagnosis of CHD were 49.0%, 75.5%, 66.1%, and 83.7% respectively. The pooled sensitivity of the prenatal echocardiographic diagnosis of CHD during the first trimester, second trimester, the second to third trimester were 60.3%, 60.9%, and 77.4%, respectively. The pooled sensitivity of BCEE and ECEE for the prenatal diagnosis of CHD during the second to third trimester was significantly higher than that during the second trimester. The pooled sensitivity of the prenatal echocardiographic diagnosis of CHD for pregnancies with low risk, high risk, low and high risk, and unselected risk were 45.4%, 85.1%, 89.1%, and 66.2%, respectively. The sensitivity analysis was robust and risk level was significant source of heterogeneity. Deek test indicated no potential significant publication bias.Prenatal ultrasound is a powerful tool for the diagnosis of CHD; however, echocardiography has individual sensitivity for different gestation period, different levels of risk, and different echo-views. PMID- 26496298 TI - Treatment of Aseptic Necrosis of the Lunate Bone (Kienbock Disease) Using a Nickel-Titanium Memory Alloy Arthrodesis Concentrator: A Series of 24 Cases. AB - Avascular necrosis of the lunate bone (Kienbock disease) is caused by loss of blood supply of the bone. This study aimed to evaluate the efficacy and safety of a novel nickel-titanium (Ni-Ti) memory alloy arthrodesis concentrator in the treatment of this disease.A consecutive 24 patients with stage IIIb aseptic lunate necrosis were treated with scapho-trapezio-trapezoeid (STT) arthrodesis using a Ni-Ti arthrodesis concentrator from August 2008 to December 2012. Wrist pain, grip strength, carpal height, and scapholunate angle were measured and compared before and after the surgery. The wrist functions were evaluated using the Mayo scale.Patients were followed up for a mean of 12 months (range, 6-24 months). Grip strength of the affected side was significantly improved after the surgery (18 +/- 4.74 kg vs. 30.21 +/- 7.14 kg, P < 0.0001). Wrist pain score was significantly decreased from 5.88 +/- 0.9 to 0.5 +/- 0.51 (P < 0.0001). Carpal height and Mayo score were also significantly increased after the surgery (P < 0.0001). Scapholunate angle was significantly decreased after the surgery (68.38 +/- 7.28 degrees vs. 49.91 +/- 4.28 degrees , P < 0.0001). No implant breakage, loose implant, wound infection, or nonunion occurred.STT arthrodesis is effective for the treatment of stage IIIb lunate necrosis. The Ni-Ti memory alloy arthrodesis concentrator is a convenient tool for STT arthrodesis with excellent and reliable results. PMID- 26496299 TI - Impact of Admission White Blood Cell Count on Short- and Long-term Mortality in Patients With Type A Acute Aortic Dissection: An Observational Study. AB - Studies have shown inflammation is involved in the development of acute aortic dissection (AAD). The hypothesis that white blood cell count (WBCc) on admission may have an impact on the short- and long-term outcomes of type A AAD was tested in a large-scale, prospective observational cohort study.From 2008 to 2010, a total of 570 consecutive patients with type A AAD in Fuwai hospital were enrolled and were followed up. Baseline characteristics and WBCc on admission were collected. The primary outcomes were 30-day and long-term all-cause mortality.During a median of 1.89 years of follow-up, the 30-day and long-term all-cause mortality were 10.7% and 6.5%, respectively. Univariate Cox regression analysis identified admission WBCc as an independent predictor of 30-day mortality when considered as a continuous variable or as a categorical variable using the cutoff of 11.0 * 10 cells/L (all P < 0.05). After adjustment for age, sex, C-reactive protein, D-dimer, and surgical intervention, elevated admission WBCc (>11.0 * 10 cells/L) remained an independent predictor of 30-day mortality of AAD (hazard ratio = 3.31, 95% confidence interval 1.38-7.93, P = 0.007). No impact of admission WBCc was observed on the long-term all-cause mortality.In conclusion, elevated admission WBCc may be valuable as a predictor of 30-day mortality, and may be useful in the risk stratification of type A AAD during hospitalization. PMID- 26496300 TI - Costs of Physician-Hospital Integration. AB - Given that the enactment of the Patient Protection and Affordable Care Act of 2010 is expected to generate forces toward physician-hospital integration, this study examined an understudied, albeit important, area of costs incurred in physician-hospital integration. Such costs were analyzed through 24 semi structured interviews with physicians and hospital administrators in a multiple case, inductive study. Two extreme types of physician-hospital arrangements were examined: an employed model (ie, integrated salary model, a group of physicians integrated by a hospital system) and a private practice (ie, a physician or group of physicians who are independent of economic or policy control). Interviews noted that integration leads to 3 evident costs, namely, monitoring, coordination, and cooperation costs. Improving our understanding of the kinds of costs that are incurred after physician-hospital integration will help hospitals and physicians to avoid common failures after integration. PMID- 26496301 TI - Tracheomegaly Secondary to Tracheotomy Tube Cuff in Amyotrophic Lateral Sclerosis: A Case Report. AB - Tracheomegaly has not been reported in amyotrophic lateral sclerosis (ALS). Herein, the authors report a case of tracheomegaly secondary to tracheotomy tube cuff in a patient with ALS. To our knowledge, this is the first report of an ALS patient with tracheomegaly and of tracheomegaly being associated with tracheotomy tube cuff and home tracheotomy mechanical ventilator.The clinician should consider the possibility of tracheomegaly in the differential diagnosis, if a patient with ALS develops repeat air leakage around the tracheotomy tube or rupture of tracheotomy tube cuff. PMID- 26496302 TI - Laparoscopic Colorectal Resection in Octogenarian Patients: Is it Safe? A Systematic Review and Meta-Analysis. AB - The population older than 80 years has been increasing. A significant proportion of colorectal diseases that require colorectal resection occur in very elderly patients. However, the benefits of laparoscopy remain controversial in octogenarians. A systematic review and meta-analysis of observational study was performed to compare clinical outcomes between laparoscopic versus open colorectal resection in octogenarians.The PubMed, EMBASE, Ovid, Web of Science, and Cochrane databases from the years 1990 to 2015 were searched for studies that compare surgical outcomes between laparoscopic and open colorectal resection in octogenarians (>=80 years old).Seven eligible studies including 528 laparoscopic and 484 open colorectal resections were identified. Laparoscopic approach was associated with lower rate of mortality (odds ratio [OR] 0.48, P = 0.03), overall complications (OR 0.54, P < 0.001), and prolonged ileus (OR 0.56, P = 0.009), quicker bowel function return (standardized mean difference [SMD] -0.50, P< 0.001), and shorter length of hospital stay (SMD -0.47, P = 0.007). No differences were found in anastomotic leak (OR 1.16, P = 0.72), respiratory complication (OR 0.60, P = 0.07), and reoperation (OR 0.85, P = 0.69).Laparoscopic colorectal resection is as safe as open approach, and the short-term outcomes appear to be more favorable in octogenarians. PMID- 26496304 TI - The Impact of Body Mass Index on the Surgical Outcomes of Patients With Gastric Cancer: A 10-Year, Single-Institution Cohort Study. AB - This study aimed to investigate the impact of body mass index (BMI) on the short term and long-term results of a large cohort of gastric cancer (GC) patients undergoing gastrectomy.Recently, the "obesity paradox" has been proposed, referring to the paradoxically "better" outcomes of overweight and obese patients compared with nonoverweight patients. The associations between BMI and surgical outcomes among patients with GC remain controversial.A single-institution cohort of 1249 GC patients undergoing gastrectomy between 2000 and 2010 were categorized to low-BMI (<18.49 kg/m), normal-BMI (18.50-24.99 kg/m), and high-BMI (>=25.00 kg/m) groups. The postoperative complications were classified according to the Clavien-Dindo system, and their severity was assessed by using the Comprehensive Complication Index (CCI). The impact of BMI on the postoperative complications and overall survival was analyzed.There were 908, 158, and 182 patients in the normal-BMI, low-BMI, and high-BMI groups, respectively. The overall morbidity in the high-BMI group (24.7%) was higher than that in either the low-BMI or the normal-BMI group (20.9% and 15.5%, respectively; P = 0.006), but the mean CCI in the low-BMI group was significantly higher (8.32 +/- 19.97) than the mean CCI in the normal-BMI and high-BMI groups (3.76 +/- 11.98 and 5.58 +/- 13.07, respectively; P < 0.001). The Kaplan-Meier curve and the log-rank test demonstrated that the low-BMI group exhibited the worst survival outcomes compared with the normal-BMI group, whereas the high-BMI group exhibited the best survival outcomes (P < 0.001). In multivariate analysis, BMI was identified as an independent prognostic factor. In the stage-specific subgroup analysis, a low BMI was associated with poorer survival in the cases of stage III-IV diseases.Low BMI was associated with more severe postoperative complications and poorer prognosis. Despite a higher risk of mild postoperative complications, the high-BMI patients exhibited paradoxically "superior" survival outcomes compared with the normal-BMI patients. These findings confirm the "obesity paradox" in GC patients undergoing gastrectomy. PMID- 26496303 TI - Gray Matter Loss and Related Functional Connectivity Alterations in A Chinese Family With Benign Adult Familial Myoclonic Epilepsy. AB - Benign adult familial myoclonic epilepsy (BAFME) is a non-progressive monogenic epilepsy syndrome. So far, the structural and functional brain reorganizations in BAFME remain uncharacterized. This study aims to investigate gray matter atrophy and related functional connectivity alterations in patients with BAFME using magnetic resonance imaging (MRI).Eleven BAFME patients from a Chinese pedigree and 15 matched healthy controls were enrolled in the study. Optimized voxel-based morphometric and resting-state functional MRI approaches were performed to measure gray matter atrophy and related functional connectivity, respectively. The Trail-Making Test-part A and part B, Digit Symbol Test (DST), and Verbal Fluency Test (VFT) were carried out to evaluate attention and executive functions.The BAFME patients exhibited significant gray matter loss in the right hippocampus, right temporal pole, left orbitofrontal cortex, and left dorsolateral prefrontal cortex. With these regions selected as seeds, the voxel wise functional connectivity analysis revealed that the right hippocampus showed significantly enhanced connectivity with the right inferior parietal lobule, bilateral middle cingulate cortex, left precuneus, and left precentral gyrus. Moreover, the BAFME patients showed significant lower scores in DST and VFT tests compared with the healthy controls. The gray matter densities of the right hippocampus, right temporal pole, and left orbitofrontal cortex were significantly positively correlated with the DST scores. In addition, the gray matter density of the right temporal pole was significantly positively correlated with the VFT scores, and the gray matter density of the right hippocampus was significantly negatively correlated with the duration of illness in the patients.The current study demonstrates gray matter loss and related functional connectivity alterations in the BAFME patients, perhaps underlying deficits in attention and executive functions in the BAFME. PMID- 26496305 TI - Serological Screening for Celiac Disease in Adult Chinese Patients With Diarrhea Predominant Irritable Bowel Syndrome. AB - Celiac disease (CD) is common in Caucasians, but thought to be rare in Asians. Our aim was to determine the prevalence of CD in Chinese patients with chronic diarrhea predominant irritable bowel syndrome (IBS-D).From July 2010 to August 2012, 395 adult patients with IBS-D and 363 age and sex-matched healthy controls were recruited in Zhongnan Hospital of Wuhan University and Xiaogan Central Hospital in Hubei province, central China. Patients with IBS-D were diagnosed according to the Rome III criteria. Serum Immunoglobulin (IgA/IgG) anti-human tissue transglutaminase (anti-htTG)-deamidated gliadin peptide (DGP) antibodies were measured in a single ELISA (QUANTA Lite h-tTG/DGP Screen). Upper endoscopy with duodenal biopsies and HLA-DQA1 and HLA-DQB1 genotyping were performed in seropositive subjects and a gluten-free diet was prescribed.Seven IBS-D patients (7/395, 1.77%) and 2 healthy controls (2/363, 0.55%), were positive for anti htTG/DGP antibodies. Of these 9 cases, 1 was lost to follow-up, 3 were suspected to have CD and 5 were eventually diagnosed as CD with intestinal histological lesions classified as Marsh Type II in 2 and Type III in 3. Of these 5 diagnosed CD patients, 4 (4/395, 1.01%) were from the IBS-D group and 1 (1/363, 0.28%) from the healthy control had asymptomatic CD. Two Type III CD patients with relatively high titers in the serologic assay were homozygous and heterozygous for haplotype HLA-DQA1*03-DQB1*03:03 (HLA-DQ9.3), respectively.In the present study, CD was present in 1.01% of patients with IBS-D and in 0.28% of the control group. We like to suggest that the haplotype HLA-DQA1*03-DQB1*03:03 (HLA-DQ9.3), which is common in Chinese, is a new susceptibility factor for CD in China. Larger screening and genetic studies are needed in the Chinese population of different regions. PMID- 26496306 TI - Early Liver Dysfunction in Patients With Intra-Abdominal Infections. AB - Liver dysfunction is commonly seen in patients with severe sepsis; however, few studies were reported in intra-abdominal infections (IAIs). This study was performed to assess the risk factors for early liver dysfunction (ELD) in patients with IAIs and to determine the effects of ELD on outcomes of these patients.From January 2011 to November 2014, a retrospective study that screened 421 patients with IAIs was performed. ELD was defined as an increase in serum total bilirubin (TB) >2 mg/dL or aminotransferases levels greater than twice the normal value within 48 hours after IAIs' onset. Patients with pre-existing liver disease or major hepatobiliary injury were excluded. Risk factors for ELD and outcomes were compared by univariate and multivariate analyses. Subgroup analysis was performed for ELD patients within 24 to 48 hours.Of 353 enrolled patients admitted with IAIs, 147 (41.6%) developed ELD. Significant independent risk factors for ELD were trauma (odds ratio [OR] 1.770, 95% confidential interval [CI] 1.126-2.783, P = 0.01) and abdominal compartment syndrome (ACS) (OR 3.199, 95% CI 1.184-8.640, P = 0.02). Successful source control <24 hours was shown to exert protection against ELD after 24 hours during IAIs (OR 0.193, 95% CI 0.091 0.409, P < 0.001). ELD was associated with significantly worse outcomes, including longer ICU length of stay and higher in-hospital mortality. Multivariate analysis also showed that development of ELD was a predisposing factor of mortality in IAIs patients (P < 0.001).ELD was a common complication in patients with IAIs associated with worse outcomes. Trauma and ACS were relevant risk factors. Early successful source control appeared to be an important method to prevent and/or reduce ELD in patients with IAIs. PMID- 26496308 TI - Correlations Between the EGFR Mutation Status and Clinicopathological Features of Clinical Stage I Lung Adenocarcinoma. AB - Advanced lung cancers with epidermal growth factor receptor (EGFR) exon 19 deletions (Ex19s) and EGFR exon 21 L858R point mutations (Ex21s) exhibit different clinical behavior. However, these differences are unclear in resectable primary lung tumors.The clinicopathological features of 88 (20.9%) Ex19, 124 (29.4%) Ex21, and 198 (46.9%) EGFR wild-type (Wt) clinical stage I primary adenocarcinomas resected between January 1, 2012 and October 31, 2014 were compared by using Chi-square tests, residual error analysis, analysis of variance, and Tukey tests.Ex21 lesions occurred more frequently in women and never-smokers and had a higher tumor disappearance rate (TDR: 59.6% vs 43.9%; P < 0.001) and lower maximum standardized uptake value (maxSUV: 2.0 vs 3.5; P < 0.01) than Wt lesions; Ex19 lesions had intermediate values (52.8% and 2.6). There was a low frequency of vascular invasion in Ex21 lesions (12.1%; P < 0.05) and a high frequency in Wt lesions (22.7%; P < 0.05). Most Ex19 lesions were intermediate grade adenocarcinoma (lepidic, acinar, and papillary predominant: 73.9%; P < 0.05). Wt and Ex21 lesions were predominately high-grade (micropapillary or solid predominant, mucinous variant) and low-grade (adenocarcinoma in situ and minimally invasive adenocarcinoma) adenocarcinoma, respectively. Wt lesions had smaller lepidic components (42.1% vs 56.3%; P < 0.001) and larger papillary and solid components (papillary: 15.5% vs 9.0%; P < 0.05; solid: 13.2% vs 3.2%; P < 0.001) than Ex21 lesions. Most Ex19 lesions had intermediate component rates.Most Ex21 lesions were low-grade adenocarcinoma with lepidic growth patterns. Wt high grade adenocarcinomas included solid and papillary components with vascular invasion. Ex19 lesions were intermediate grade between Ex21 and Wt. PMID- 26496307 TI - Cardiovascular Risk Factors Increase the Risks of Diabetic Peripheral Neuropathy in Patients With Type 2 Diabetes Mellitus: The Taiwan Diabetes Study. AB - This study aimed to examine whether poor glycemic control, measured by glycated hemoglobin A1C (HbA1c) and other cardiovascular risk factors, can predict diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus (DM).Patients aged >=30 years with type 2 DM, enrolled in the National Diabetes Care Management Program, and free of DPN (n = 37,375) in the period 2002 to 2004 were included and followed up until 2011. The related factors were analyzed using Cox proportional hazards regression models.For an average follow-up of 7.00 years, 8379 cases of DPN were identified, with a crude incidence rate of 32.04/1000 person-years. After multivariate adjustment, patients with HbA1c levels 7 to 8%, 8 to 9%, 9 to 10%, and >=10% exhibited higher risk of DPN (adjusted HR: 1.11 [1.04-1.20], 1.30 [1.21-1.40], 1.32 [1.22-1.43], and 1.62 [1.51-1.74], respectively) compared with patients with HbA1c level 6 to 7%. There was a significant linear trend in DPN incidence with increasing HbA1c (P < 0.001) and significant HRs of DPN for patients with HbA1c level >=7%, blood pressure >=130/85 mm Hg, triglycerides (TG) >=150 mg/dL, high density of lipoprotein cholesterol (HDL-C) <40 mg/dL in males and <50 mg/dL in females, low density of lipoprotein-cholesterol (LDL-C) >=100 mg/dL, and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m.Patients with type 2 DM and HbA1c >=7.0% exhibit increased risk of DPN, demonstrating a linear relationship. The incidence of DPN is also associated with poor glucose control and cardiovascular risk factors like hypertension, hyper-triglyceridemia, low HDL-C, high LDL-C, and decreased eGFR. PMID- 26496309 TI - Inflammatory Response After Laparoscopic Versus Open Resection of Colorectal Liver Metastases: Data From the Oslo-CoMet Trial. AB - Laparoscopic and open liver resection have not been compared in randomized trials. The aim of the current study was to compare the inflammatory response after laparoscopic and open resection of colorectal liver metastases (CLM) in a randomized controlled trial.This was a predefined exploratory substudy within the Oslo CoMet-study. Forty-five patients with CLM were randomized to laparoscopic (n = 23) or open (n = 22) resection. Ethylenediaminetetraacetic acid-plasma samples were collected preoperatively and at defined time points during and after surgery and snap frozen at -80 C. A total of 25 markers were examined using luminex and enzyme-linked immunosorbent assay techniques: high-mobility box group 1(HMGB-1), cell-free DNA (cfDNA), cytokines, and terminal C5b-9 complement complex complement activation.Eight inflammatory markers increased significantly from baseline: HMGB-1, cfDNA, interleukin (IL)-6, C-reactive protein, macrophage inflammatory protein -1beta, monocyte chemotactic protein -1, IL-10, and terminal C5b-9 complement complex. Peak levels were reached at the end of or shortly after surgery. Five markers, HMGB-1, cfDNA, IL-6, C-reactive protein, and macrophage inflammatory protein -1beta, showed significantly higher levels in the open surgery group compared with the laparoscopic surgery group.Laparoscopic resection of CLM reduced the inflammatory response compared with open resection. The lower level of HMGB-1 is interesting because of the known association with oncogenesis. PMID- 26496310 TI - Respiratory Syncytial Virus Coinfections With Rhinovirus and Human Bocavirus in Hospitalized Children. AB - It is not clearly established if coinfections are more severe than single viral respiratory infections.The aim of the study was to study and to compare simple infections and viral coinfections of respiratory syncytial virus (RSV) in hospitalized children.From September 2005 to August 2013, a prospective study was conducted on children younger than 14 years of age, admitted with respiratory infection to the Pediatric Department of the Severo Ochoa Hospital, in Spain. Specimens of nasopharyngeal aspirate were taken for virological study by using polymerase chain reaction, and clinical data were recorded. Simple RSV infections were selected and compared with double infections of RSV with rhinovirus (RV) or with human bocavirus (HBoV).In this study, 2993 episodes corresponding to 2525 children were analyzed. At least 1 virus was detected in 77% (2312) of the episodes. Single infections (599 RSV, 513 RV, and 81 HBoV) were compared with 120 RSV-RV and 60 RSV-HBoV double infections. The RSV-RV coinfections had fever (63% vs 43%; P < 0.001) and hypoxia (70% vs 43%; P < 0.001) more often than RV infections. Hypoxia was similar between single or dual infections (71%). Bronchiolitis was more frequent in the RSV simple group (P < 0.001). Pediatric intensive care unit admission was more common in RSV simple or RSV-RV groups than in the RV monoinfection (P = 0.042).Hospitalization was longer for both RSV simple group and RSV-HBoV coinfection, lasting about 1 day (4.7 vs 3.8 days; P < 0.001) longer than in simple HBoV infections. There were no differences in PICU admission. RSV single group was of a younger age than the other groups.Coinfections between RSV-RV and RSV-HBoV are frequent. Overall viral coinfections do not present greater severity, but have mixed clinical features. PMID- 26496311 TI - The Outcome of Patients With 2 Different Protocols of Do-Not-Resuscitate Orders: An Observational Cohort Study. AB - Lack of clarity about the exact clinical implications of do-not-resuscitate (DNR) has caused confusion that has been addressed repeatedly in the literature. To provide improved understanding about the portability of DNR and the medical care provided to DNR patients, the state of Ohio passed a Do-Not-Resuscitate Law in 1998, which clearly pointed out 2 different protocols of do-not-resuscitate: DNR comfort care (DNRCC) and DNR comfort care arrest (DNRCC-Arrest). The objective of this study was to examine the outcome of patients with the 2 different protocols of DNR orders.This is a retrospective observational study conducted in a medical intensive care unit (MICU) in a hospital located in Northeast Ohio. The medical records of the initial admissions to the MICU during data collection period were concurrently and retrospectively reviewed. The association between 2 variables was examined using Chi-squared test or Student's t-test. The outcome of DNRCC, DNRCC-Arrest, and No-DNR patients were compared using multivariate logistic regression analysis.The total of 188 DNRCC-Arrest, 88 DNRCC, and 2051 No-DNR patients were included in this study. Compared with the No-DNR patients, the DNRCC (odds ratio = 20.77, P < 0.01) and DNRCC-Arrest (odds ratio = 3.69, P < 0.01) patients were more likely to die in the MICU. Furthermore, the odds of dying during MICU stay for DNRCC patients were 7.85 times significantly higher than that for DNRCC-Arrest patients (odds ratio = 7.85, P < 0.01).Given Do-Not Resuscitate Law in Ohio, we examined the outcome of the 2 different protocols of DNR orders, and to compare with the conventional DNR orders. Similar to conventional DNR, DNDCC and DNRCC-Arrest were both associated with the increased risk of death. Patients with DNRCC were more likely to be associated with increased risk of death than those with DNRCC-Arrest. PMID- 26496312 TI - Diagnostic Accuracy of APRI, AAR, FIB-4, FI, King, Lok, Forns, and FibroIndex Scores in Predicting the Presence of Esophageal Varices in Liver Cirrhosis: A Systematic Review and Meta-Analysis. AB - Aspartate aminotransferase-to-platelet ratio (APRI), aspartate aminotransferase to-alanine aminotransferase ratio (AAR), FIB-4, FI, King, Lok, Forns, and FibroIndex scores may be simple and convenient noninvasive diagnostic tests, because they are based on the regular laboratory tests and demographic data. This study aimed to systematically evaluate their diagnostic accuracy for the prediction of varices in liver cirrhosis.All relevant papers were searched via PubMed, EMBASE, CNKI, and Wanfang databases. The area under the summary receiver operating characteristic curve (AUSROC), sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), and diagnostic odds ratio (DOR) were calculated.Overall, 12, 4, 5, 0, 0, 4, 3, and 1 paper was identified to explore the diagnostic accuracy of APRI, AAR, FIB-4, FI, King, Lok, Forns, and FibroIndex scores, respectively. The AUSROCs of APRI, AAR, FIB-4, Lok, and Forns scores for the prediction of varices were 0.6774, 0.7275, 0.7755, 0.7885, and 0.7517, respectively; and those for the prediction of large varices were 0.7278, 0.7448, 0.7095, 0.7264, and 0.6530, respectively. The diagnostic threshold effects of FIB 4 and Forns scores for the prediction of varices were statistically significant. The sensitivities/specificities/PLRs/NLRs/DORs of APRI, AAR, and Lok scores for the prediction of varices were 0.60/0.67/1.77/0.58/3.13, 0.64/0.63/1.97/0.54/4.18, and 0.74/0.68/2.34/0.40/5.76, respectively. The sensitivities/specificities/PLRs/NLRs/DORs of APRI, AAR, FIB-4, Lok, and Forns scores for the prediction of large varices were 0.65/0.66/2.15/0.47/4.97, 0.68/0.58/2.07/0.54/3.93, 0.62/0.64/2.02/0.56/3.57, 0.78/0.63/2.09/0.37/5.55, and 0.65/0.61/1.62/0.59/2.75, respectively.APRI, AAR, FIB-4, Lok, and Forns scores had low to moderate diagnostic accuracy in predicting the presence of varices in liver cirrhosis. PMID- 26496313 TI - Adult Living Donor Liver Transplantation Across ABO-Incompatibility. AB - The objective of this study was to evaluate the results of adult ABO-incompatible living donor liver transplantation (LDLT).ABO-incompatible LDLT is an aggressive treatment that crosses the blood-typing barrier for saving lives from liver diseases. Although graft and patient survival have been improved recently by various treatments, the results of adult ABO-incompatible LDLT require further evaluation.Two regimens were designed based on isoagglutinin IgG and IgM titers and the time course of immunological reactions at this institute. When isoagglutinin IgG and IgM titers were <=64, liver transplantation was directly performed and rituximab (375 mg/m) was administrated on postoperative day 1 (regimen I). When isoagglutinin titers were >64, rituximab (375 mg/m) was administered preoperatively with or without plasmapheresis and boosted on postoperative day 1 (regimen II). Immunosuppression was achieved by administration of mycophenolate mofetil, tacrolimus, and steroids.Forty-six adult ABO-incompatible and 340 ABO-compatible LDLTs were performed from 2006 to 2013. The Model for End-Stage Liver Disease scores for ABO-incompatible recipients ranged from 7 to 40, with a median of 14. The graft-to-recipient weight ratio ranged from 0.61% to 1.61% with a median of 0.91%. The 1-, 3-, and 5-year survival rates were 81.7%, 75.7%, and 71.0%, respectively, for ABO-incompatible LDLT recipients, compared to 81.0%, 75.2%, and 71.5% for ABO-C recipients (P = 0.912). The biliary complication rate was higher in ABO-incompatible LDLT recipients than in the ABO-compatible recipients (50.0% vs 29.7%, P = 0.009).In the rituximab era, the blood type barrier can be crossed to achieve adult ABO incompatible LDLT with survival rates comparable to those of ABO-compatible LDLT, but with more biliary complications. PMID- 26496314 TI - Statin-Based Palliative Therapy for Hepatocellular Carcinoma. AB - Most hepatocellular carcinoma (HCC) patients worldwide do not receive curative treatments. Alternative treatments for most HCC patients include palliative treatments, such as transarterial chemoembolization (TACE), chemotherapy, and radiotherapy. Although statins may be a chemopreventive treatment option for reducing hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related HCC risks, their therapeutic effects are unknown. This study evaluated the effects of statin on HCC patients receiving palliative treatment.Data from the National Health Insurance claims database and cancer registry databases of The Collaboration Center of Health Information Application, Taiwan, were analyzed. We included HCC patients who were treated between January 1, 2001, and December 31, 2010, and followed them from the index date to December 31, 2012. The inclusion criteria were presence of HBV carrier-related HCC, age >20 years, and having received TACE, radiotherapy, or chemotherapy as palliative treatment. The exclusion criteria were cancer diagnosis before HCC was confirmed, surgery, liver transplantation, radiofrequency ablation, or percutaneous ethanol injection as curative treatment, missing sex-related information, HCC diagnosis before HBV, and age <20 years. We enrolled 20,200 HCC patients.The median follow-up duration was 1.66 years (interquartile range, 0.81). In total, 1988 and 18,212 patients received palliative treatment with and without statin use, respectively. HCC patients who received palliative treatment with statin use had lower HCC-specific deaths in all stages than those who received palliative treatment without statin use (P = 0.0001, 0.0002, 0.0012, and 0.0002, and relative risk (RR) = 0.763, 0.775, 0.839, and 0.718, for stages I-IV, respectively). In all-cause and HCC specific deaths, decreasing trends (P for trend <0.0001) of adjusted hazard ratios (aHRs) were observed in all stages with no treatment, statin use only, palliative treatment only, and palliative treatment plus statin use. The aHRs of all-cause and HCC-specific deaths increased with the progress in cancer stage and reduced with the use of advanced therapeutic modalities (P for trend <0.0001). Differences in HBV- and non-HBV-related HCC were solely due to statin use. Statin use alone reduced HCC-specific deaths by 36% in non-HBV-related HCC in stage I and 50% in HBV-related HCC in stages II and III. With a relatively substantial reduction in mortality, the therapeutic effects of statin use were stronger in HBV-related HCC than in non-HBV-related HCC.Palliative treatments are critical for HCC patients. Multiple therapeutic methods with statin use reduced the mortality risk. Statins prolong the survival of patients with advanced HCC receiving palliative treatment, thus demonstrating its therapeutic value as an adjuvant treatment. Furthermore, statin-based palliative treatment in early stage HCC remarkably reduced the number of deaths. For patients who cannot tolerate palliative treatments, statin use only might possibly reduce mortality, particularly in HBV-related early stage HCC patients (>50% reduction in HCC deaths). PMID- 26496315 TI - Urinary Cyclophilin A as a New Marker for Diabetic Nephropathy: A Cross-Sectional Analysis of Diabetes Mellitus. AB - Type 2 diabetes mellitus (DM) is the most common single cause of end-stage renal disease. Albuminuria is the most commonly used marker to predict onset of diabetic nephropathy (DN) without enough sensitivity and specificity to detect early DN. This is the first study to identify urinary cyclophilin A (CypA) as a new biomarker for early DN.We recruited DM outpatients and healthy control subjects from January 2014 to December 2014. In this cross-sectional study, patients' urine samples were collected to determine the expression of urinary CypA. We also treated mesangial (MES-13) and tubular (HK-2) cells with glucose or free radicals to observe the expression of secreted CypA in Western blot analysis.A total of 100 DN patients and 20 healthy control subjects were enrolled. All variables were matched. In univariate analysis, the concentration of urinary CypA correlated well with the progression of renal function. A significant increase in urinary CypA was noted in stage 2 DN and persisted in later stages. We could diagnose stage 2 DN using urinary CypA with a sensitivity of 90.0% and specificity of 72.7%. The area under curve was up to 0.85, indicating a good discriminatory power. In cellular models, MES-13 and HK-2 cells can both release CypA.Urinary CypA is a good biomarker for early DN detection in humans and it can be released from either mesangial or tubular cells. The underlying molecular mechanisms still need further clarification in cellular and animal studies. PMID- 26496316 TI - New Insights in Histogenetic Pathways of Gastric Cancer. AB - The aim of this paper was to describe 3 possible histogenetic pathways for poorly cohesive (diffuse) carcinomas and 2 for intestinal-type gastric carcinomas (GCs), which might influence the behavior of GC. In the present observational study, 102 patients with early (n = 50) and advanced GCs (n = 52) were evaluated, and the histogenetic background was analyzed. All of the cases were sporadic GCs. For particular aspects, Maspin, E-cadherin, and SLUG immunostains were performed. For our final conclusions, the results were correlated with literature data. In early stages, poorly cohesive carcinomas can display 3 histogenetic pathways, with particular molecular behaviors: "carcinoma with intraepithelial pagetoid onset" (with or without a switch from E-cadherin to SLUG positivity), "carcinoma with early lymphatic invasion" (carcinoma limited to mucosa but with carcinomatosis of the lymph vessels from subjacent layers), and "microglandular-type poorly cohesive carcinoma" (the onset is similar with adenocarcinoma but abrupt dedifferentiation can be seen in the submucosa, with persistence of a dual component in the deep layers). The intestinal type carcinoma can be developed on the background of superficially located dysplasia ("classic adenocarcinoma") or in the submucosal heterotopic mucosa ("adenocarcinoma arising from the mucosal infolding in the submucosa"). Based on personal observations correlated with literature data, 5 histopathogenetic pathways are proposed with specific denominations. Each of them can partially explain the aberrant behavior of early gastric cancer. PMID- 26496317 TI - Effect of Hypovitaminosis D on Postoperative Pain Outcomes and Short-Term Health Related Quality of Life After Knee Arthroplasty: A Cohort Study. AB - Vitamin D may have an important role in pain perception. Inadequate vitamin D levels are associated with suboptimal recovery after surgery. However, the effects of hypovitaminosis D on postoperative pain-related outcomes and its impact on health-related quality of life after surgery are not well understood. The objective of this study was to determine the effects of hypovitaminosis D on postoperative pain-related outcomes and health-related quality of life at 3 months after knee arthroplasty.This was a longitudinal cohort study of 191 consecutive Hong Kong Chinese patients who were given patient-controlled morphine analgesia for up to 72 hours after 214 knee arthroplasties. Serum total 25 hydroxyvitamin D (25-OHD) concentration was assessed by liquid chromatography tandem mass spectrometry. The primary outcomes were postoperative pain intensity at rest scores (0-72 h), Western Ontario and McMaster Universities (WOMAC) osteoarthritis index (pain, stiffness and function), and moderate-to-severe persistent pain (transformed WOMAC pain score of 0-75 at 3 months after knee arthroplasty; 0, extreme pain; 100, no pain). Group differences were analyzed using generalized estimating equation models and a logistic regression model.The prevalence of preoperative hypovitaminosis D (25-OHD <50 nmol/L) was 44% (95% confidence interval [CI]: 37%-51%). There were transient higher pain intensity scores in the moderate-to-severe hypovitaminosis D (25-OHD <30 nmol/L) group compared with the sufficient vitamin D group. Vitamin D status had no effect on total WOMAC index (P = 0.22). The incidence of moderate-to-severe persistent pain was 9% (95% CI: 6%-14%). Hypovitaminosis D increased the risk of moderate-to severe persistent pain (adjusted odds ratio 2.64, 95% CI: 1.03-6.77).Preoperative hypovitaminosis D had subtle effects on pain intensity scores in the early postoperative period and is a risk factor for moderate-to-severe persistent pain after knee arthroplasty. Hypovitaminosis D was not associated with worse health related quality of life at 3 months after knee arthroplasty. PMID- 26496318 TI - Case Report: Brown Fat Accumulation of Tc-99m Macroaggregated Albumin in a Lung Perfusion Study in a Patient With Multiple Lung Arteriovenous Malformations and Right-to-Left Shunting. AB - An 18-year-old man was preoperatively assessed for a varicocele and found to be hypoxemic. A Tc-99m macroaggregated albumin lung perfusion scan showed right-to left shunting, evidenced by increased radiotracer uptake in the brain, kidneys, thyroid gland, and bilateral supraclavicular areas, a typical location for brown adipose tissue. Chest computerized tomography angiogram study showed supraclavicular fat density areas and multiple pulmonary arteriovenous malformations.The authors report a rare case of brown fat visualization on a lung perfusion scan in a patient with right-to-left shunting, likely because of increased perfusion to activated brown adipose tissue. PMID- 26496319 TI - The Hemoptysis and the Subclavian Artery Pseudoaneurysm due to a Fishbone Injury: A Case Report. AB - Ingestion of a foreign body is a common cause of esophageal injury, but hemoptysis is a rare manifestation of the esophageal penetration by a swallowed foreign body. The swallowing of a fishbone is hard to diagnose and the definite diagnosis is usually made during surgery. We describe the case of a 50-year-old man with direct injury to the lung parenchyma, the azygos vein, and the subclavian artery pseudoaneurysm due to a fishbone penetration from the upper esophagus into the lung. To our knowledge, this is the first case report that we know of in which a swallowed foreign body that penetrated from the upper esophagus into the lung caused vascular injuries and lung damage and it was solved by minimally invasive surgery and an endovascular stent.We successfully diagnosed and treated a case with the migration of the fishbone from the upper esophagus into the lung. A contrast-enhanced computed tomography (CT) scan is recommended to clarify the fact of vascular injury before surgery. Thoracoscopic operation (VATS) combined with endovascular treatment could be a safer and a more feasible treatment option in this rare condition. PMID- 26496320 TI - Efficacy and Safety of Zoledronic Acid and Pamidronate Disodium in the Treatment of Malignant Skeletal Metastasis: A Meta-Analysis. AB - Solid tumors frequently metastasize to bone. Two bisphosphonates have been investigated for bone metastases including pamidronate disodium and zoledronic acid.By searching the PubMed, Embase, Wanfang, and China National Knowledge Infrastructure (CNKI) databases, we conducted a meta-analysis to determine the efficacy and safety of zoledronic acid compared with pamidronate disodium in reducing pain in patients with bone metastases.Studies were pooled, and the relative risk (RR) and its corresponding 95 % confidence interval (CI) were calculated. Version 12.0 STATA software was used for statistical analysis. Twenty relevant articles were included for this meta-analysis study.The complete response rate in cancer patients treatment with zoledronic acid was significantly higher than that with pamidronate disodium (relative risk [RR] = 1.32 [95% confidence interval (CI), 1.00-1.75]; P = 0.987, I = 0%). However, there was no significant difference in the rate of partial response rate (RR = 1.04, 95% CI: 0.90-1.20; P = 0.942, I = 0%) and in the total effective rate (RR = 1.06, 95% CI: 1.00-1.12; P = 0.998, I = 0%). For adverse events (AE), the incidence of headache in cancer patients with zoledronic acid was significantly lower than that with pamidronate disodium (RR = 0.82, 95% CI: 0.70-0.96; P = 0.793, I = 0%). There was no significant difference in nausea or vomiting (RR = 1.00, 95% CI: 0.92-1.09; P = 0.494, I = 0%), fever (RR = 0.98, 95% CI: 0.85-1.14; P =0.633, I = 0%), fatigue (RR = 1.01, 95% CI: 0.91-1.11; P = 0.914, I = 0%) and anorexia (RR = 1.31, 95% CI: 0.91-1.87; P = 0.024, I = 64.4%).In conclusion, this meta-analysis indicates that treatment with zoledronic acid was more effective than pamidronate disodium in the complete response assessments and the incidence of headache, an AE, was significantly lower in cancer patients with zoledronic acid. PMID- 26496321 TI - Abnormal Pap Smear and Diagnosis of High-Grade Vaginal Intraepithelial Neoplasia: A Retrospective Cohort Study. AB - The aim of this study was to analyze the correlation between the first diagnosis of high-grade Vaginal Intraepithelial Neoplasia (HG-VaIN: VaIN 2-VaIN 3) and the cytological abnormalities on the referral pap smear.All the women with histological diagnosis of HG-VaIN consecutively referred to the Gynecological Oncology Unit of the Aviano National Cancer Institute (Aviano, Italy) from January 1991 to April 2014 and with a pap smear performed in the 3 months before the diagnosis were considered, and an observational cohort study was performed.A total of 87 women with diagnosis of HG-VaIN were identified. Major cytological abnormalities (HSIL and ASC-H) on the referral pap smear were significantly more frequent than lesser abnormalities (ASC-US and LSIL) in postmenopausal women (64.9% vs 36.7%, P = 0.02) and in women with a previous diagnosis of HPV-related cervical preinvasive or invasive lesions (70.5% vs 39.5%, P = 0.01). Diagnosis of VaIN 3 was preceded by major cytological abnormalities in most of the cases (72.7% vs 27.3%, P < 0.001).The diagnosis of HG-VaIN can be preceded by different abnormalities on referral pap smear. Major abnormalities are usually reported in postmenopausal women and in women with previous cervical HPV-related disease. However, ASC-US or LSIL do not exclude HG-VaIN, especially VaIN2. An accurate examination of the whole vaginal walls (or vaginal vault) must be performed in all the women who underwent colposcopy for an abnormal pap smear, and a biopsy of all suspicious areas is mandatory. PMID- 26496322 TI - Development and Validation of the Standard Chinese Version of the CARE Item Set (CARE-C) for Stroke Patients. AB - The Continuity Assessment Record and Evaluation (CARE) item set is a standardized, integrative scale for evaluation of functional status across acute and postacute care (PAC) providers. The aim of this study was to develop a Chinese version of the CARE (CARE-C) item set and to examine its reliability and validity for assessment of functional outcomes among stroke patients.The CARE-C was administered in two samples. Sample 1 included 30 stroke patients in the outpatient clinic setting for the purpose of examining interrater and test-retest reliabilities and internal consistency. Sample 2 included 138 stroke patients admitted to rehabilitation units for the purpose of investigating criterion related validity with the Barthel index, Lawton Instrumental Activities of Daily Living (IADL) scale, EuroQOL five dimensions questionnaire (EQ-5D), and Mini Mental State Examination (MMSE).The CARE-C was categorized into 11 subscales, 52 items of which were analyzed. At the subscale level, the interrater reliability and test-retest reliability expressed by intraclass correlation coefficient (ICC) ranged from 0.72 to 0.99 and 0.60 to 1.00, respectively. Six of the 11 subscales met acceptable levels of internal consistency (Cronbach alpha > 0.7). The criterion-related validity of the CARE-C showed moderate to high correlations of its subscales of cognition and basic and instrumental activities of daily living with the Barthel index, IADL scale, and MMSE.The CARE-C is a useful instrument for evaluating functional quality metrics in the Chinese stroke population. The development of the CARE-C also facilitates the assessment of the PAC program in Taiwan and future research is warranted for validating the capability of CARE-C to identify patients' functional change over time and its generalizability for nonstroke populations. PMID- 26496323 TI - Assessment of Breast Specimens With or Without Calcifications in Diagnosing Malignant and Atypia for Mammographic Breast Microcalcifications Without Mass: A STARD-Compliant Diagnostic Accuracy Article. AB - Presence of microcalcifications within the specimens frequently signifies a successful attempt of stereotactic vacuum-assisted breast biopsy (VABB) in obtaining a pathologic diagnosis of the breast microcalcifications. In this study, the authors aimed to assess and compare the accuracy and consistency of calcified or noncalcified specimens obtained from same sites of sampling on isolated microcalcifications without mass in diagnosing high-risk and malignant lesions. To the best of our knowledge, an individual case-based prospective comparison has not been reported.With the approval from institutional review board of our hospital (Chang Gung Memorial Hospital), the authors retrospectively reviewed all clinical cases of stereotactic VABBs on isolated breast microcalcifications without mass from our database. The authors included those having either surgery performed or had clinical follow-up of at least 3 years for analysis. All the obtained specimens with or without calcification were identified using specimen radiographs and separately submitted for pathologic evaluation. The concordance of diagnosis was assessed for both atypia and malignant lesions.A total of 390 stereotactic VABB procedures (1206 calcified and 1456 noncalcified specimens) were collected and reviewed. The consistent rates between calcified and noncalcified specimens were low for atypia and malignant microcalcifications (44.44% in flat epithelial atypia, 46.51% in atypical ductal hyperplasia, 55.73% in ductal carcinoma in situ, and 71.42% in invasive ductal carcinoma). The discordance in VABB diagnoses indicated that 41.33% of malignant lesions would be misdiagnosed by noncalcified specimens. Furthermore, calcified specimens showed higher diagnostic accuracy of breast cancer as compared with the noncalcified specimens (91.54 % versus 69.49%, respectively). The evaluation of both noncalcified specimens and calcified specimens did not show improvement of diagnostic accuracy as compared with evaluating calcified specimens alone (91.54% versus 91.54%, respectively).The high prevalence of diagnostic discordance between the calcified and noncalcified specimens indicated the higher value of calcified specimens in diagnosing atypia and malignant microcalcifications. Noncalcified specimens did not provide additional diagnostic benefit from this study. The separation of calcified and noncalcified specimens may facilitate more focused interpretation from pathologists among the large number of specimens. PMID- 26496324 TI - Clinical Impact of Sagittal Spinopelvic Parameters on Disc Degeneration in Young Adults. AB - The sagittal balance plays an important role in the determination of shear and compressive forces applied on the anterior (vertebral bodies and intervertebral discs) and posterior (facet joints) elements of the lumbar vertebral column. Many studies have also examined the effect of structural changes in the disc on the biomechanical characteristics of the spinal segment. Nevertheless, the relationship between sagittal balance and the degree of disc degeneration has not been extensively explored. Thus, here we investigated the relationships between various sagittal spinopelvic parameters and the degree of disc degeneration in young adults.A total of 278 young adult male patients were included in this study (age range: 18-24 years old). Multiple sagittal spinopelvic parameters, including pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), lumbar lordosis (LL), sacral inclination (SI), lumbosacral angle (LSA), and sacral table angle (STA), were measured from standing lateral lumbosacral radiographs. The degree of intervertebral disc degeneration was classified using a modified Pfirrmann scale. To assess the pain intensity of each patient, the visual analogue scale (VAS) score for low back pain (LBP) was obtained from all the patients. Finally, the relationships between these spinopelvic parameters and the degree of disc degeneration in young adults were analyzed. Also, we performed multiple logistic regression study.Out of all the spinopelvic parameters measured in this study, a low STA and a low SI were the only significant risk factors that were associated with disc degeneration in young adults. It means that patients with disc degeneration tend to have more severe sacral kyphosis and vertical sacrum.We found that patients with disc degeneration showed a lower SI and lower STA compared with patients without disc degeneration in young adults. Therefore, we suggest that the patients with disc degeneration tend to have more vertical sacrum, more sacral kyphosis, and more severe LBP, and that SI and STA measurements should be carefully considered to predict or prevent further disc degeneration and LBP. PMID- 26496325 TI - Acoustic Radiation Force Impulse Elastography: A Useful Tool for Differential Diagnosis of Thyroid Nodules and Recommending Fine-Needle Aspiration: A Diagnostic Accuracy Study. AB - To investigate the diagnostic performance of combined use of conventional ultrasound (US) and elastography, including conventional strain elastography such as elasticity imaging (EI) and acoustic radiation force impulse (ARFI) elastography, and to evaluate their usefulness in recommending fine-needle aspiration (FNA).A total of 556 pathologically proven thyroid nodules were evaluated by US, EI, and ARFI examinations in this study. Three blinded readers scored the likelihood of malignancy for 4 datasets (ie, US alone, US and EI, US and virtual touch tissue imaging [VTI], and US and virtual touch tissue quantification [VTQ]). The diagnostic performances of 4 datasets in differentiating malignant from benign thyroid nodules were evaluated. The decision-making changes for FNA recommendation in the indeterminate nodules or the probably benign nodules on conventional US were evaluated after review of elastography.The diagnostic performance in terms of area under the ROC curve did not show any change after adding EI, VTI, or VTQ for analysis; and no differences were found among different readers; however, the specificity and positive predictive value (PPV) improved significantly after adding VTI or VTQ for analysis in the senior reader. For the indeterminate nodules on US that were pathologically benign, VTQ made correct decision-making changes from FNA biopsy to follow-up in a mean of 82.6% nodules, which was significantly higher than those achieved by EI (46.8%) and VTI (54.4%) (both P < 0.05). With regard to the probably benign nodules on US that were pathologically malignant, EI made the highest correct decision-making change from follow-up to FNA biopsy in a mean of 62.6% nodules (compared with 41.5% on VTQ, P < 0.05).The results indicated that ARFI increases the specificity and PPV in diagnosing thyroid nodules. US combined VTQ might be helpful in reducing unnecessary FNA for indeterminate nodules on US whereas US combined EI is useful to detect the false negative nodules that are probably benign on conventional US. PMID- 26496326 TI - Elevation of Interleukin-18 Correlates With Cardiovascular, Cerebrovascular, and Peripheral Vascular Events: A Cohort Study of Hemodialysis Patients. AB - Cardiocerebral vascular events are the major cause of mortality among patients with end-stage renal disease (ESRD). Subclinical inflammation and atherosclerosis have been implicated in the pathophysiology of ESRD. Evidence has shown the crucial role of interleukin-18 (IL-18) in inflammation. Interleukin-18 has been markedly upregulated in ESRD patients. Nevertheless, the ability of the IL-18 level to predict cardiocerebral vascular events and the correlation between IL-18 levels and cardiocerebral vascular events have not been established in hemodialysis patients.To determine whether the serum IL-18 level predicts cardiocerebral vascular events, the authors studied 171 ESRD patients. Samples were collected and patients were followed for 24 months. Demographic data, the duration of hemodialysis, nutrition status, inflammatory parameters, dialysis adequacy, and lipid profiles were analyzed to predict the outcome by using multivariate logistic regression. Cutoff points were calculated by acquiring the highest Youden index. The Kaplan-Meier method was used to scrutinize the cumulative proportion of events.The multivariate logistic regression model revealed that serum creatinine, C-reactive protein, and IL-18 levels were independent predictors for cardiocerebral vascular events. The odds ratio of events for each increase in IL-18 (pg/mL) was 1.008 for cardiocerebral vascular events. The area under the receiver operating characteristic curve of IL-18 was 0.779 +/- 0.039, the overall correctness was 73%, and the Youden index was highest at a cutoff of 463 pg/mL. In the Kaplan-Meier model, patients with an IL 18 level higher than 463 pg/mL exhibited the highest probability of experiencing an adverse event during the entire follow-up period.Increased serum IL-18 could be considered as a predictor of cardiocerebral vascular events in dialysis patients. It is noteworthy that various comorbidities might interfere the expression of IL-18; therefore, further validation study is required to incorporate IL-18 in clinical use. PMID- 26496327 TI - Personalized Therapy of Chronic Hepatitis C and B Dually Infected Patients With Pegylated Interferon Plus Ribavirin: A Randomized Study. AB - We aimed to investigate whether response-guided therapy (RGT) with peginterferon alpha plus ribavirin by using hepatitis C virus (HCV) genotype, pretreatment HCV RNA levels, and rapid virological response (RVR, undetectable HCV RNA at treatment week 4) could be applied for active HCV/hepatitis B virus (HBV) dually infected patients, without compromised the treatment efficacy.A total of 203 patients, seropositive of HCV antibody, HCV RNA and HBV surface antigen (HBsAg), and seronegative for HBV e antigen for >6 months, were randomized to receive peginterferon-alpha/ribavirin by either genotype-guided therapy (GGT, n = 102: HCV genotype 1 [HCV-1], 48 weeks; HCV-2/3, 24 weeks) or RGT (n = 101: HCV-1, 48 or 24 weeks if patients with baseline VL <400,000 IU/mL and RVR; HCV-2/3, 24 or 16 weeks if patients with RVR). The primary endpoint was HCV-sustained virological response (SVR).The HCV SVR rate was comparable between the GGT (77.5%, 79/102) and RGT groups (70.3%, 71/101, P = 0.267), either among HCV-1/HBV (69.4% [43/62] vs 63.5% [40/63], P = 0.571) or among HCV-2/3/HBV (90.0% [36/40] vs 81.6% [31/38], P = 0.342) dually infected patients based on intention-to-treat analysis. In HCV-1/HBV dually infected patients, RVR (odds ratio [OR]: 6.05; 95% confidence intervals [CI]: 2.148-17.025, P = 0.001) and lower pretreatment blood glucose levels (OR: 0.97; CI: 0.944-0.989, P = 0.003) were independent predictors of HCV SVR. Although RVR (OR: 10.68; CI: 1.948-58.514, P = 0.006) was the only significant factor associated with HCV SVR in HCV-2/3/HBV dually infected patients. HBsAg loss at 1 year posttreatment was observed in 17 of 185 (9.2%) patients. The rates of discontinuation and adverse events were similar between the 2 groups.RGT with peginterferon-alpha/RBV may be considered for HBeAg negative HBV/HCV dually infected patients. PMID- 26496328 TI - The Ascending Reticular Activating System in a Patient With Severe Injury of the Cerebral Cortex: A Case Report. AB - We reported on the ascending reticular activating system (ARAS) finding of a patient in whom severe injury of the cerebral cortex was detected following a hypoxic-ischemic brain injury (HIBI).A 67-year-old female patient who suffered from HIBI induced by cardiac arrest after surgery for lumbar disc herniation underwent cardiopulmonary resuscitation approximately 20 to 30 minutes after cardiac arrest. The patient exhibited impaired alertness, with a Glasgow Coma Scale (GCS) score of 4 (eye opening: 2, best verbal response: 1, and best motor response: 1). Approximately 3 years after onset, she began to whimper sometimes and showed improved consciousness, with a GCS score of 10 (eye opening: 4, best verbal response: 2, and best motor response: 4) and Coma Recovery Scale-Revised score of 9 (auditory function: 1, visual function: 1, motor function: 2, verbal function: 2, communication: 1, and arousal: 2).Results of diffusion tensor tractography for the upper connectivity of the ARAS showed decreased neural connectivity to each cerebral cortex in both hemispheres. The right lower ARAS between the pontine reticular formation and the thalamic intralaminar nuclei (ILN) was thinner compared with the left side.Severe injury of the upper portion of the ARAS between the thalamic ILN and cerebral cortex was demonstrated in a patient with some level of consciousness. PMID- 26496329 TI - Association of Periodontitis With Urinary Albumin Excretion in Korean Adults With Diabetes: The 2012 Korea National Health and Nutrition Examination Survey. AB - Albuminuria and periodontitis are both commonly associated with systemic inflammation. However, the association between urinary albumin excretion (UAE) and periodontitis in patients with type 2 diabetes has not been fully investigated. This study aimed to investigate the association between UAE and periodontitis in Korean adults with type 2 diabetes.This study performed a cross sectional analysis and used hierarchical multivariable logistic regression analysis models. Data from the 2012 Korean National Health and Nutrition Examination Survey were analyzed. A total of 547 patients, with type 2 diabetes without renal impairment, were included in this study. UAE was assessed using the urinary albumin to creatinine ratio (UACR). A community periodontal index greater than or equal to code 3 was used to define periodontitis.The risk of periodontitis tended to increase as UACR increased even after adjustment for potential confounders (P for trend in the odds ratios = 0.05 in model 1; 0.02 in model 2; and 0.01 in model 3). In a subgroup analysis, the prevalence of periodontitis was significantly higher in the patients with albuminuria (UACR >30 mg/g) than in those without albuminuria among patients younger than 65 years (P = 0.03), those with newly diagnosed diabetes (P = 0.04), or those without obesity (P = .04).UAE was positively associated with the risk of periodontitis in Korean adults with type 2 diabetes. In the patients who were younger, were newly diagnosed with diabetes, or had normal body mass index, individuals with albuminuria were more likely to have a higher prevalence of periodontitis. Early identification of periodontitis may be helpful in Korean diabetic adults with increased UAE. PMID- 26496330 TI - A Congenital Peribronchial Myofibroblastic Tumor Detected in a Premature Infant at 28 Weeks but That Resolved in the Late Stage of Pregnancy: A Case Report. AB - A congenital peribronchial myofibroblastic tumor (CPMT) is a rare benign tumor arising from the lungs. Although CPMT is a benign tumor, it is characterized by rapid growth, and is easily misdiagnosed during the prenatal period when the symptoms are nonspecific. The authors present a rare case of CPMT in a premature infant, which was detected at 28 weeks on ultrasonography (US) but resolved at a later stage of pregnancy. The knowledge concerning the diagnosis and management of CPMT is reviewed. Herein, the authors report of a 30-minute-old premature newborn infant in whom a pulmonary mass was discovered 1 month before delivery. Maternal prenatal US demonstrated a 0.8 * 1 cm well-defined oval-shaped mass in the left hemithorax in the 28th week of gestational age. The pulmonary mass, however, was not apparent on repeat US examination at 32 weeks. The child was delivered by cesarean section at 34 weeks estimated gestational age. Chest radiography and computed tomography revealed a mass-like lesion in the left lower pulmonary lobe. The chest computed tomography characteristics of the tumor included large size (4 cm), an irregular margin, and surrounding ground-glass opacity, which led to misdiagnosis as a malignant tumor. The patient underwent a left inferior lung lobectomy and was pathologically diagnosed with CPMT. He is currently alive 12-month postresection with no evidence of disease recurrence.The authors report this rare case of CPMT, which was detected at 28 weeks and resolved at a later stage of pregnancy. Congenital peribronchial myofibroblastic tumor is an uncommon benign tumor. Lobectomy or pneumonectomy is often required. The prognosis after surgery is good. PMID- 26496331 TI - Oscillating Positive Expiratory Pressure on Respiratory Resistance in Chronic Obstructive Pulmonary Disease With a Small Amount of Secretion: A Randomized Clinical Trial. AB - This study aims to evaluate the acute effects of an oscillating positive expiratory pressure device (flutter) on airways resistance in patients with chronic obstructive pulmonary disease (COPD).Randomized crossover study: 15 COPD outpatients from Asthma Lab-Royal Brompton Hospital underwent spirometry, impulse oscillometry (IOS) for respiratory resistance (R) and reactance (X), and fraction exhaled nitric oxide (FeNO) measures.Thirty minutes of flutter exercises: a "flutter-sham" procedure was used as a control, and airway responses after a short-acting bronchodilator were also assessed.Respiratory system resistance (R): in COPD patients an increase in X5insp (-0.21 to -0.33 kPa/L/s) and Fres (24.95 to 26.16 Hz) occurred immediately after flutter exercises without bronchodilator. Following 20 min of rest, a decrease in the R5, DeltaR5, R20, X5, and Ax was observed, with R5, R20, and X5 values lower than baseline, with a moderate effect size; there were no changes in FeNO levels or spirometry.The use of flutter can decrease the respiratory system resistance and reactance and expiratory flow limitation in stable COPD patients with small amounts of secretions. PMID- 26496332 TI - Significant Shrinkage of Multifocal Liver Metastases and Long-Term Survival in a Patient With Rectal Cancer, After Trans-Arterial Chemoembolization (TACE): A Case Report. AB - In this paper, we present the successful therapeutic approach of unresectable liver metastases in a patient with rectal cancer.A 63-year-old male underwent endoscopic polypectomy followed by rectosigmoid resection for an adenocarcinoma of the rectum diagnosed in pT2N0 stage. The angio-computed tomography (CT) revealed four metastatic hepatic nodules ranging from 12 to 130 mm in diameter. After one cure of trans-arterial chemoembolization (TACE) with lipiodol and 5 fluorouracil, combined with FOLFOX4 + capecitabine systemic chemotherapy, the diameter of all hepatic nodules decreased to half size, at 6 months after TACE. Further curative surgical hepatic metastasectomy was done and complete pathologic response was obtained. The patient is free of recurrences and metastases after 26 months of follow-up.This representative case shows that an efficient trans disciplinary approach could lead to successful therapeutic management even in patients with advanced-staged colorectal carcinomas. PMID- 26496334 TI - Adrenal Pheochromocytoma Incidentally Discovered in a Patient With Parkinsonism. AB - To evaluate the diagnostic route of pheochromocytoma (PHEO) in a patient under dopaminergic treatment.A 70-year-old man with Parkinsonism and under treatment with levodopa and carbidopa came to our observation for evaluation of arterial hypertension and right adrenal mass discovered incidentally.To evaluate adrenal hormone levels we performed a dexamethasone suppression test, plasma aldosterone levels and 24-hr urinary metanephrine, which revealed elevated levels of catecholamines metabolities. 123-I-metaiodobenzylguanidine SPECT scintiscan revealed raised activity within the right adrenal gland concordant with the mass. The diagnosis of PHEO was posed and an elective laparoscopic adrenalectomy was performed; histopathological examination confirmed the PHEO diagnosis.Recently the coexistence of PHEO and Parkinsonism is a very rare association of diseases, with only 3 cases reported in literature. In this article, another case is reported and diagnostic procedures are discussed. PMID- 26496333 TI - Efficacy and Safety of a Traditional Chinese Herbal Formula Xuefu Zhuyu Decoction for Hypertension: A Systematic Review and Meta-Analysis. AB - The cardioprotective role of xuefu zhuyu decoction (XZD), a well-known classical herbal formula, has been documented for hypertension treatment recently. This study aims to summarize the efficacy and safety of XZD in treating hypertension.Seven databases were searched to identify randomized controlled trials evaluating the efficacy of XZD in hypertensive patients. Fifteen studies involving 1364 hypertensive patients were included. All studies compared XZD and antihypertensive drugs with antihypertensive drugs used alone.In all, 15 studies reported significant effects of XZD for lowering blood pressure compared with the control group (P < 0.05), and 7 studies reported significant effects of XZD for improving symptoms compared with the control group (P < 0.00001). Meanwhile, studies reported XZD was more efficacious than antihypertensive drugs in improving total cholesterol, triglycerides, low-density lipoprotein cholesterol, homocysteine, hemorheology, carotid intima-media thickness, and left ventricular mass index (P < 0.05). No severe adverse event was reported.This meta-analysis provides evidence that XZD is beneficial for hypertension. Although concerns regarding selective bias and methodologic flaws were raised, our findings suggests XZD as a new candidate cardioprotective drug for hypertension, which should be given priority for future preclinical and clinical studies. PMID- 26496335 TI - Cytogenetic and Clinical Features in Children Suspected With Congenital Abnormalities in 1 Medical Center of Zhejiang Province From 2011 to 2014. AB - This study aimed to investigate the detection rate of chromosome abnormalities in children suspected with congenital disorders in 1 single center, identify any differences according to different classification criteria, and try to enlighten the medical professionals what clinical features should be transferred for cytogenetic analysis.From January 1, 2011 to March 31, 2014, children who were suspected with chromosomal disorders were included. All the cytogenetic analyses were performed in the Medical Biology and Genetic Department Laboratory in Zhejiang DIAN Diagnostics. We evaluated the variants of clinical indications, and incidence and types of chromosomal abnormalities among groups.During the study period, 4129 samples were collected and analyzed. Among them, 769 children were detected with chromosome abnormalities, accounting for 18.62% of all referral cases. The ratio of sex-linked chromosomal abnormalities to autosomal ones was 1:3.2. The detection rates were 19.66% (365/1857) for boys and 17.78% (404/2272) for girls. Most of trisomy 21 were found before the age of 1 year old, while most of children with Turner syndrome were found after 6 years old. The group presenting with specific clinical stigmata had highest detection rate of 59.1%.We demonstrated the detection rates of chromosome abnormalities in children who were suspected with chromosomal disorders. Combined with previous report, we established a database of common chromosomal anomalies and the clinical features that could be useful for genetic counseling and remind the medical professionals what kind of patients should be transferred to genetic analysis. PMID- 26496337 TI - Prognostic Value of the Metastatic Lymph Node Ratio in Patients With Resectable Carcinoma of Ampulla of Vater. AB - Patients with carcinoma of the ampulla of Vater (CAV) have better outcomes among periampullary malignancies. However, little is known about the metastatic lymph node ratio (LNR) as a prognostic factor for resectable CAV. We retrospectively reviewed our CAV patients undergoing curative surgery and analyzed their prognostic factors.A total of 212 CAV patients who received radical surgery at Chang Gung Memorial Hospital, Linkou, between 2000 and 2010 were admitted in this study. The lymph node ratio was defined as the number of metastatic lymph nodes (LNs) divided by the total number of LNs removed. The patients' demographic data, comorbidities, operation type, and tumor features were analyzed retrospectively for survival prediction of patients.The median age of the patients was 62 years, and 57% of the patients were men. The surgical procedure was standard pancreaticoduodenectomy and pylorus-preserving pancreaticoduodenectomy in 53% and 47% of the patients, respectively. The median follow-up duration was 32.6 months, and 50% of the patients had died by the end of the study. The median overall survival time (OS) and disease-free survival time (DFS) were 65.8 and 33.7 months, respectively. In multivariate analysis, patients with a metastatic LNR >0.056 had a significantly poor prognosis in both OS and DFS.A metastatic LNR >0.056 predicted a poor DFS and OS in CAV patients after radical surgery. Greater awareness on the impact of metastatic LNR may help clinicians provide appropriate adjuvant treatment for high-risk CAV patients. PMID- 26496336 TI - Putative Role of Serum Amyloid-A and Proinflammatory Cytokines as Biomarkers for Behcet's Disease. AB - Behcet's disease (BD) is a multisystemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of vascular, gastrointestinal, neurological, and musculoskeletal system. Although disease pathogenesis is still unclear, both innate and adaptive immunity have shown to play a pivotal role, and multiple proinflammatory cytokines seem to be involved in different pathogenic pathways that eventually lead to tissue damage.The aims of our study were to evaluate serum cytokines levels of IL-8, IL 18, IFN-alpha2a, IL-6, IFN-gamma, CXCL10, CXCL11, CXCL9, and SAA levels in patients with BD, in comparison to healthy controls (HC), and to correlate their levels to disease activity.We included 78 serum samples obtained from 58 BD patients and analyzed a set of proinflammatory cytokines including IL-8, IL-18, IFN-alpha2a, IL-6, IFN-gamma, CXCL10, CXCL11, and CXCL9 by multiplex bead analysis as well as SAA by enzyme-linked immunosorbent assay.Compared to HC, BD patients showed elevated cytokine levels of IL-8, IL-18, IFN-alpha2a, and IL-6, and low levels of CXCL11. BD patients with SAA serum levels >20 mg/L showed higher levels of proinflammatory markers than HC or group with SAA <=20 mg/L. IL 18, IFN-alpha2a, and IL-6 were higher in BD group with SAA >20 mg/L than HC, while IL-8 and CXCL9 levels were higher than in patients with SAA <=20 mg/L and HC.Active BD patients with SAA >20 mg/L exhibited elevated levels of inflammatory mediators, suggesting that may exist a relationship between SAA and proinflammatory cytokines in the intricate scenario of BD pathogenesis. PMID- 26496338 TI - Genetic Polymorphisms of Functional Candidate Genes and Recurrent Acute Otitis Media With or Without Tympanic Membrane Perforation. AB - Evaluation of the genetic contribution to the development of recurrent acute otitis media (rAOM) remains challenging. This study aimed to evaluate the potential association between single nucleotide polymorphisms (SNPs) in selected genes and rAOM and to analyze whether genetic variations might predispose to the development of complicated recurrent cases, such as those with tympanic membrane perforation (TMP).A total of 33 candidate genes and 47 SNPs were genotyped in 200 children with rAOM (116 with a history of TMP) and in 200 healthy controls.INFgamma rs 12369470CT was significantly less common in the children with rAOM than in healthy controls (odds ratio [OR] 0.5, 95% confidence interval [CI] 0.25-1, P = 0.04). Although not significant, interleukin (IL)-1beta rs 1143627G and toll-like receptor (TLR)-4 rs2737191AG were less frequently detected in the children with rAOM than in controls. The opposite was true for IL-8 rs2227306CT, which was found more frequently in the children with rAOM than in healthy controls. The IL-10 rs1800896TC SNP and the IL-1alpha rs6746923A and AG SNPs were significantly more and less common, respectively, among children without a history of TMP than among those who suffered from this complication (OR 2.17, 95% CI 1.09-4.41, P = 0.02, and OR 0.42, 95% CI 0.21-0.84, P = 0.01).This study is the first report suggesting an association between variants in genes encoding for factors of innate or adaptive immunity and the occurrence of rAOM with or without TMP, which confirms the role of genetics in conditioning susceptibility to AOM. PMID- 26496340 TI - Broad-spectrum Antibiotic Plus Metronidazole May Not Prevent the Deterioration of Necrotizing Enterocolitis From Stage II to III in Full-term and Near-term Infants: A Propensity Score-matched Cohort Study. AB - Necrotizing enterocolitis (NEC) is the most common and frequently dangerous neonatal gastrointestinal disease. Studies have shown broad-spectrum antibiotics plus anaerobic antimicrobial therapy did not prevent the deterioration of NEC among very low birth preterm infants. However, few studies about this therapy which focused on full-term and near-term infant with NEC has been reported. The aim of this study was to evaluate the effect of broad-spectrum antibiotic plus metronidazole in preventing the deterioration of NEC from stage II to III in full term and near-term infants.A retrospective cohort study based on the propensity score (PS) 1:1 matching was performed among the full-term and near-term infants with NEC (Bell stage >=II). All infants who received broad-spectrum antibiotics were divided into 2 groups: group with metronidazole treatment (metronidazole was used >=4 days continuously, 15 mg/kg/day) and group without metronidazole treatment. The depraved rates of stage II NEC between the 2 groups were compared. Meanwhile, the risk factors associated with the deterioration of stage II NEC were analyzed by case-control study in the PS-matched cases.A total of 229 infants met the inclusion criteria. Before PS-matching, we found the deterioration of NEC rate in the group with metronidazole treatment was higher than that in the group without metronidazole treatment (18.1% [28/155] vs 8.1% [6/74]; P = 0.048). After PS-matching, 73 pairs were matched, and the depraved rate of NEC in the group with metronidazole treatment was not lower than that in the group without metronidazole treatment (15.1% vs 8.2%; P = 0.2). Binary logistic regression analysis showed that sepsis after NEC (odds ratio [OR] 3.748, 95% confidence interval [CI] 1.171-11.998, P = 0.03), the need to use transfusion of blood products after diagnosis of NEC (OR 8.003, 95% CI 2.365-27.087, P = 0.00), and the need of longer time for nasogastric suction were risk factors for stage II NEC progressing to stage III (OR 1.102, 95% CI 1.004-1.21, P = 0.04).Broad-spectrum antibiotic plus metronidazole may not prevent the deterioration of NEC in full-term and near-term infants. Those infants who had sepsis required transfusion of blood products, and needed longer time for nasogastric suction after stage II NEC was more likely to progress to stage III. PMID- 26496339 TI - Modified Glasgow Prognostic Score is Associated With Risk of Recurrence in Bladder Cancer Patients After Radical Cystectomy: A Multicenter Experience. AB - Recently, many studies explored the role of inflammation parameters in the prognosis of urinary cancers, but the results were not consistent. The modified Glasgow Prognostic Score (mGPS), a systemic inflammation marker, is a prognostic marker in various types of cancers. The aim of the present study was to investigate the usefulness of the preoperative mGPS as predictor of recurrence free (RFS), overall (OS), and cancer-specific (CSS) survivals in a large cohort of urothelial bladder cancer (UBC) patients.A total of 1037 patients with UBC were included in this study with a median follow-up of 22 months (range 3-60 months). An mGPS = 0 was observed in 646 patients (62.3%), mGPS = 1 in 297 patients (28.6 %), and mGPS = 2 in 94 patients (9.1%).In our study cohort, subjects with an mGPS equal to 2 had a significantly shorter median RFS compared with subjects with mGPS equal to 1 (16 vs 19 months, hazard ratio [HR] 1.54, 95% CI 1.31-1.81, P < 0.001) or with subjects with mGPS equal to 0 (16 vs 29 months, HR 2.38, 95% CI 1.86-3.05, P < 0.001). The association between mGPS and RFS was confirmed by weighted multivariate Cox model. Although in univariate analysis higher mGPS was associated with lower OS and CSS, this association disappeared in multivariate analysis where only the presence of lymph node-positive bladder cancer and T4 stage were predictors of worse prognosis for OS and CSS.In conclusion, the mGPS is an easily measured and inexpensive prognostic marker that was significantly associated with RFS in UBC patients. PMID- 26496341 TI - Radiochemotherapy Versus Surgery in Nonmetastatic Anorectal Neuroendocrine Carcinoma: A Multicenter Study by the Association des Gastro-Enterologues Oncologues. AB - Neuroendocrine carcinomas (NEC) of the anus or the rectum are a rare disease, accounting for less than 1% of all digestive malignancies. Most are metastatic at diagnosis and treated with a platinum-based chemotherapy. No guidelines for localized tumors exist. The purpose of this study was to describe the characteristics of anorectal localized NEC, their management and their outcomes.We retrospectively reviewed patients from 11 French centers with anorectal localized NEC. We compared 2 therapeutic managements: surgery (group A) versus chemotherapy with or without radiation (group B). Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method.A total of 24 patients were identified with a median follow-up of 25 months (3-60 months). Median age was 63 years old and 17 had a rectal tumor (71%). Mean Ki-67 was 72% (range: 20-100), and 75% of the tumors had a high proliferative index (Ki-67 > 50%). Global PFS and OS were 13.1 and 44.1 months, respectively. Thirty-seven percent of patients were in group A and 63% in group B. There was no difference between group A and group B, whether in terms of PFS (13.0 months vs. 13.2 months, P = 0.75) or OS (49.1 months vs. 39.2 months, P = 0.42).In patients with anorectal localized NEC, chemotherapy with or without radiation obtained a similar outcome as surgery and this conservative approach could be deemed a reasonable option. PMID- 26496342 TI - A Generalized Entropy Measure of Within-Host Viral Diversity for Identifying Recent HIV-1 Infections. AB - There is a need for incidence assays that accurately estimate HIV incidence based on cross-sectional specimens. Viral diversity-based assays have shown promises but are not particularly accurate. We hypothesize that certain viral genetic regions are more predictive of recent infection than others and aim to improve assay accuracy by using classification algorithms that focus on highly informative regions (HIRs).We analyzed HIV gag sequences from a cohort in Botswana. Forty-two subjects newly infected by HIV-1 Subtype C were followed through 500 days post-seroconversion. Using sliding window analysis, we screened for genetic regions within gag that best differentiate recent versus chronic infections. We used both nonparametric and parametric approaches to evaluate the discriminatory abilities of sequence regions. Segmented Shannon Entropy measures of HIRs were aggregated to develop generalized entropy measures to improve prediction of recency. Using logistic regression as the basis for our classification algorithm, we evaluated the predictive power of these novel biomarkers and compared them with recently reported viral diversity measures using area under the curve (AUC) analysis.Change of diversity over time varied across different sequence regions within gag. We identified the top 50% of the most informative regions by both nonparametric and parametric approaches. In both cases, HIRs were in more variable regions of gag and less likely in the p24 coding region. Entropy measures based on HIRs outperformed previously reported viral-diversity-based biomarkers. These methods are better suited for population level estimation of HIV recency.The patterns of diversification of certain regions within the gag gene are more predictive of recency of infection than others. We expect this result to apply in other HIV genetic regions as well. Focusing on these informative regions, our generalized entropy measure of viral diversity demonstrates the potential for improving accuracy when identifying recent HIV-1 infections. PMID- 26496343 TI - Invasive Cervical Cancer and Antidepressants: A Nationwide Population-Based Study. AB - To our knowledge, no prior population-based study has been published wherein the primary aim was to evaluate whether an association between psychotropic drug prescription and cervical cancer exists. Herein we have conducted the first study that primarily aimed to determine the association between antidepressants use and risk of invasive cervical cancer in the general population.This is a population based study utilizing Taiwan's National Health Insurance Research Database. We identified 26,262 cases with invasive cervical cancer and 129,490 controls. We adopted the conditional logistic regression model as the statistical method and adjusted for potential confounding factors.The prescription of selective serotonin reuptake inhibitors (SSRIs) (adjusted OR = 0.93, 95% CI = 0.84-1.04), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin norepinephrine reuptake inhibitors (SNRIs), mirtazapine and bupropion, adjusting for cumulative dose, was not associated with an increased, or decreased, risk for invasive cervical cancer. An association between trazodone prescription and invasive cervical cancer was observed (adjusted OR = 1.22, 95% CI = 1.03-1.43).An association between the major classes of antidepressants and invasive cervical cancer was not observed herein. Our preliminary finding regarding a possible association between trazodone and cervical cancer requires replication. PMID- 26496344 TI - Single-Site Robotic Cholecystectomy: Reverse-Port Technique. AB - This study aims to introduce an alternative technique for effective single-site robotic cholecystectomy (SSRC) using a reverse port.Proper exposure of Calot's triangle is critical for safe laparoscopic cholecystectomy. Current robotic surgical systems are useful for single-site cholecystectomy. However, in exposing Calot's triangle, the gallbladder is usually retracted in a medial and upward direction, resulting in a narrow triangle. This intraoperative view is a major obstacle to safe laparoscopic cholecystectomy.From October 2013 to October 2014, 55 consecutive patients underwent SSRC by a single surgeon at Yonsei University Severance Hospital. Initially, 5 patients underwent the original robotic single site cholecystectomy technique, and the remaining 50 patients underwent robotic single site cholecystectomy using our reverse port technique.There were no differences between the SSRC-O (original port) group and the SSRC-R (reverse port) group in terms of patient age (P = 0.244), body mass index (P = 0.503), and pathologic conditions of the gallbladder (P = 0.841). Total operation time (132.6 vs 99.12 min; P = 0.009), actual dissection time (51.6 vs 30.28 min; P = 0.001), and console time (84.4 vs 50.46 min; P = 0.001) were all significantly shorter in the SSRC-R group. Mean intraoperative blood loss was minimal in both groups (20 vs 12.4 mL, P = 0.467), and bile spillage occurred in 2 patients of the SSRC-R group. There was one case of laparoscopic conversion in the SSRC-R group.The reverse port technique described in this study successfully widened Calot's triangle and improved the safety of the current robotic surgical system for single-site robotic cholecystectomy. PMID- 26496345 TI - Clinical Characteristics and Treatment of Extremity Chronic Osteomyelitis in Southern China: A Retrospective Analysis of 394 Consecutive Patients. AB - Although extremity chronic osteomyelitis is common in China, updated data were still limited regarding its characterizations. The present study aimed to review clinical features of extremity chronic osteomyelitis in Southern China.A retrospective analysis was conducted in the patients who had sought medical attention from January 2010 to April 2015 for extremity chronic osteomyelitis in Nanfang Hospital in Southern China. Clinical data were collected and analyzed.A total of 394 patients (307 males and 87 females) were included, giving a gender ratio of 3.53. The median age at first diagnosis was 42 years for all. The most frequent type was traumatic osteomyelitis (262 cases, 66.50%), which was mainly caused by open injury (166 cases, 63.36%) and during a road accident (91 cases, 34.73%). Single-site infection accounted for 81.98% (323 cases), with tibia (126 cases), femur (79 cases), calcaneus (37 cases), and toes (37 cases) as the top sites. The positive rate of intraoperative culture was 70.63% (214/303), 78.97% (169/214) of which was monomicrobial infection. Staphylococcus aureus (59 cases) was the most frequent bacteria for monomicrobial infection, followed by Pseudomonas aeruginosa (29 cases) and Escherichia coli (11 cases). The positive ratios of preoperative serum white blood cell (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were 21.63%, 64.92%, 53.27%, 42.25%, 72.82%, and 66.67%, respectively. The most frequently used intravenous antibiotic was cephalosporins. The overall cure rate was 77.74%, with a total amputation rate of 16.75%.In this representative Chinese cohort, extremity chronic osteomyelitis was mostly caused by open injury and during a road accident, predominated in males and favored the tibia. S. aureus was the most frequent pathogenic organism. Preoperative elevated levels of serum IL-6, TNF-alpha, and ESR may be helpful diagnostic indicators of the disease. Most patients achieved a favorable clinical efficacy after appropriate treatment. PMID- 26496346 TI - Impact of Asthma on the Development of Coronary Vasospastic Angina: A Population Based Cohort Study. AB - Although asthma increases the risk of cardiovascular disease, little is known about the relation of asthma and its severity to coronary vasospastic angina (CVsA). We hypothesized that asthma contributed to the development of CVsA.Patients in this population-based cohort study were retrospectively collected from the Taiwan National Health Insurance database. Using propensity score matching, subjects were stratified at a 1 : 4 ratio into a study group comprising 3087 patients with a diagnosis of CVsA, and a control group consisting of 12,348 patients who underwent coronary intervention for obstructive coronary artery disease (CAD) during the period 2000 to 2011.Asthma significantly increased the risk of new-onset CVsA independent of other comorbidities [adjusted odds ratio (OR) = 1.85, 95% confidence interval (95% CI) = 1.47-2.32, P < 0.001]. In addition, the risk of new-onset CVsA was significantly higher in previous users of oral or inhaled corticosteroids (oral corticosteroids: OR = 1.22, 95% CI = 1.01-1.49, P = 0.04; inhaled corticosteroids: OR = 1.89, 95% CI = 1.28-2.79, P = 0.001). In addition, the prevalence of asthma was highest among patients with CVsA alone, followed by patients with CAD and CVsA and patients who underwent coronary intervention for CAD alone (P trend < 0.001).Our study suggests that asthma is independently associated with CVsA and prior steroid use increases the risk of CVsA development. PMID- 26496347 TI - Dynamic Changes of QRS Morphology of Premature Ventricular Contractions During Ablation in the Right Ventricular Outflow Tract: A Case Report. AB - Electrocardiographic characteristics can be useful in differentiating between right ventricular outflow tract (RVOT) and aortic sinus cusp (ASC) ventricular arrhythmias. Ventricular arrhythmias originating from ASC, however, show preferential conduction to RVOT that may render the algorithms of electrocardiographic characteristics less reliable. Even though there are few reports describing ventricular arrhythmias with ASC origins and endocardial breakout sites of RVOT, progressive dynamic changes in QRS morphology of the ventricular arrhythmias during ablation obtained were rare.This case report describes a patient with symptomatic premature ventricular contractions of left ASC origin presenting an electrocardiogram (ECG) characteristic of right ventricular outflow tract before ablation. Pacing at right ventricular outflow tract reproduced an excellent pace map. When radiofrequency catheter ablation was applied to the right ventricular outflow tract, the QRS morphology of premature ventricular contractions progressively changed from ECG characteristics of right ventricular outflow tract origin to ECG characteristics of left ASC origin.Successful radiofrequency catheter ablation was achieved at the site of the earliest ventricular activation in the left ASC. The distance between the successful ablation site of the left ASC and the site with an excellent pace map of the RVOT was 20 mm.The ndings could be strong evidence for a preferential conduction via the myocardial bers from the ASC origin to the breakout site in the right ventricular outflow tract. This case demonstrates that ventricular arrhythmias with a single origin and exit shift may exhibit QRS morphology changes. PMID- 26496348 TI - Arthroscopic Resection of a Tenosynovial Giant Cell Tumor in the Wrist: A Case Report. AB - The treatment for giant cell tumors of the tendon sheath is surgical therapy, but surgical recurrence rates were reported to be as high as 50% in some cases. Therefore, complete radical excision of the lesion is the treatment of choice. If the tumor originates from the joint, it is important to perform capsulotomy. Here, the authors report the first case of successful treatment of a localized intra-articular giant cell tumor in the wrist by arthroscopic resection.A 28-year old right-handed woman visited the clinic because of left wrist ulnar-side pain, which had been aggravated during the previous 15 days. Vague ulnar-side wrist pain had begun 2 years ago. When the authors examined the patient, the wrist showed mild swelling on the volo-ulnar aspect and the distal radioulnar joint, as well as volar joint line tenderness. She showed a positive result on the ulnocarpal stress test and displayed limited range of motion. Magnetic resonance imaging revealed an intra-articular mass with synovitis in the ulnocarpal joint. Wrist arthroscopy was performed using standard portals under regional anesthesia. The arthroscopic findings revealed a large, well-encapsulated, yellow lobulated soft-tissue mass that was attached to the volar side of the ulnocarpal ligament and connected to the extra-articular side. The mass was completely excised piece by piece with a grasping forceps. Histopathologic examination revealed that the lesion was an intra-articular localized form of a tenosynovial giant cell tumor.At 24-month follow-up, the patient was completely asymptomatic and had full range of motion in her left wrist, and no recurrence was found in magnetic resonance imaging follow-up evaluations.The authors suggest that the arthroscopic excision of intra-articular giant cell tumors, as in this case, may be an alternative method to open excisions, with many advantages. PMID- 26496349 TI - Integrating Ecosystem Engineering and Food Web Ecology: Testing the Effect of Biogenic Reefs on the Food Web of a Soft-Bottom Intertidal Area. AB - The potential of ecosystem engineers to modify the structure and dynamics of food webs has recently been hypothesised from a conceptual point of view. Empirical data on the integration of ecosystem engineers and food webs is however largely lacking. This paper investigates the hypothesised link based on a field sampling approach of intertidal biogenic aggregations created by the ecosystem engineer Lanice conchilega (Polychaeta, Terebellidae). The aggregations are known to have a considerable impact on the physical and biogeochemical characteristics of their environment and subsequently on the abundance and biomass of primary food sources and the macrofaunal (i.e. the macro-, hyper- and epibenthos) community. Therefore, we hypothesise that L. conchilega aggregations affect the structure, stability and isotopic niche of the consumer assemblage of a soft-bottom intertidal food web. Primary food sources and the bentho-pelagic consumer assemblage of a L. conchilega aggregation and a control area were sampled on two soft-bottom intertidal areas along the French coast and analysed for their stable isotopes. Despite the structural impacts of the ecosystem engineer on the associated macrofaunal community, the presence of L. conchilega aggregations only has a minor effect on the food web structure of soft-bottom intertidal areas. The isotopic niche width of the consumer communities of the L. conchilega aggregations and control areas are highly similar, implying that consumer taxa do not shift their diet when feeding in a L. conchilega aggregation. Besides, species packing and hence trophic redundancy were not affected, pointing to an unaltered stability of the food web in the presence of L. conchilega. PMID- 26496350 TI - Accuracy of Electronic Health Record Data for Identifying Stroke Cases in Large Scale Epidemiological Studies: A Systematic Review from the UK Biobank Stroke Outcomes Group. AB - OBJECTIVE: Long-term follow-up of population-based prospective studies is often achieved through linkages to coded regional or national health care data. Our knowledge of the accuracy of such data is incomplete. To inform methods for identifying stroke cases in UK Biobank (a prospective study of 503,000 UK adults recruited in middle-age), we systematically evaluated the accuracy of these data for stroke and its main pathological types (ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage), determining the optimum codes for case identification. METHODS: We sought studies published from 1990-November 2013, which compared coded data from death certificates, hospital admissions or primary care with a reference standard for stroke or its pathological types. We extracted information on a range of study characteristics and assessed study quality with the Quality Assessment of Diagnostic Studies tool (QUADAS-2). To assess accuracy, we extracted data on positive predictive values (PPV) and-where available-on sensitivity, specificity, and negative predictive values (NPV). RESULTS: 37 of 39 eligible studies assessed accuracy of International Classification of Diseases (ICD)-coded hospital or death certificate data. They varied widely in their settings, methods, reporting, quality, and in the choice and accuracy of codes. Although PPVs for stroke and its pathological types ranged from 6-97%, appropriately selected, stroke-specific codes (rather than broad cerebrovascular codes) consistently produced PPVs >70%, and in several studies >90%. The few studies with data on sensitivity, specificity and NPV showed higher sensitivity of hospital versus death certificate data for stroke, with specificity and NPV consistently >96%. Few studies assessed either primary care data or combinations of data sources. CONCLUSIONS: Particular stroke-specific codes can yield high PPVs (>90%) for stroke/stroke types. Inclusion of primary care data and combining data sources should improve accuracy in large epidemiological studies, but there is limited published information about these strategies. PMID- 26496351 TI - Quantifying the Role of Homophily in Human Cooperation Using Multiplex Evolutionary Game Theory. AB - Nature shows as human beings live and grow inside social structures. This assumption allows us to explain and explore how it may shape most of our behaviours and choices, and why we are not just blindly driven by instincts: our decisions are based on more complex cognitive reasons, based on our connectedness on different spaces. Thus, human cooperation emerges from this complex nature of social network. Our paper, focusing on the evolutionary dynamics, is intended to explore how and why it happens, and what kind of impact is caused by homophily among people. We investigate the evolution of human cooperation using evolutionary game theory on multiplex. Multiplexity, as an extra dimension of analysis, allows us to unveil the hidden dynamics and observe non-trivial patterns within a population across network layers. More importantly, we find a striking role of homophily, as the higher the homophily between individuals, the quicker is the convergence towards cooperation in the social dilemma. The simulation results, conducted both macroscopically and microscopically across the network layers in the multiplex, show quantitatively the role of homophily in human cooperation. PMID- 26496353 TI - Crystal Structures and Magnetic Properties of Nickel Chain Compounds PbM2Ni6Te3O18 (M = Mn, Cd). AB - The synthesis, crystal structures, and magnetic properties of the pentanary oxides PbM2Ni6Te3O18 (M = Mn and Cd) were investigated. These compounds crystallize in a hexagonal structure with space group P63/m, in which the Ni(2+) ions form a zigzag chain along the c axis. From the magnetic susceptibility and specific heat measurements, we found that the PbCd2Ni6Te3O18 behaves as a low dimensional magnet due to the intrachain antiferromagnetic interaction between Ni(2+) ions. Both compounds show a long-range antiferromagnetic ordering at 25.7 K (M = Cd) and 86.0 K (Mn). The magnetic structure of PbMn2Ni6Te3O18 determined by neutron diffraction measurements is a collinear antiferromagnetic arrangement of Mn(2+) ions in the Mn2O9 dimeric unit and Ni(2+) ions in the zigzag chain. PMID- 26496352 TI - A New Method for Noninvasive Genetic Sampling of Saliva in Ecological Research. AB - Noninvasive samples for genetic analyses have become essential to address ecological questions. Popular noninvasive samples such as faeces contain degraded DNA which may compromise genotyping success. Saliva is an excellent alternative DNA source but scarcity of suitable collection methods makes its use anecdotal in field ecological studies. We develop a noninvasive method of collection that combines baits and porous materials able to capture saliva. We report its potential in optimal conditions, using confined dogs and collecting saliva early after deposition. DNA concentration in saliva extracts was generally high (mean 14 ng MUl(-1)). We correctly identified individuals in 78% of samples conservatively using ten microsatellite loci, and 90% of samples using only eight loci. Consensus genotypes closely matched reference genotypes obtained from hair DNA (99% of identification successes and 91% of failures). Mean genotyping effort needed for identification using ten loci was 2.2 replicates. Genotyping errors occurred at a very low frequency (allelic dropout: 2.3%; false alleles: 1.5%). Individual identification success increased with duration of substrate handling inside dog's mouth and the volume of saliva collected. Low identification success was associated with baits rich in DNA-oxidant polyphenols and DNA concentrations <1 ng MUl(-1). The procedure performed at least as well as other noninvasive methods, and could advantageously allow detection of socially low-ranked individuals underrepresented in sources of DNA that are involved in marking behaviour (faeces or urine). Once adapted and refined, there is promise for this technique to allow potentially high rates of individual identification in ecological field studies requiring noninvasive sampling of wild vertebrates. PMID- 26496354 TI - Effects of SOX2 on Proliferation, Migration and Adhesion of Human Dental Pulp Stem Cells. AB - As a key factor for cell pluripotent and self-renewing phenotypes, SOX2 has attracted scientists' attention gradually in recent years. However, its exact effects in dental pulp stem cells (DPSCs) are still unclear. In this study, we mainly investigated whether SOX2 could affect some biological functions of DPSCs. DPSCs were isolated from the dental pulp of human impacted third molar. SOX2 overexpressing DPSCs (DPSCs-SOX2) were established through retroviral infection. The effect of SOX2 on cell proliferation, migration and adhesion ability was evaluated with CCK-8, trans-well system and fibronectin-induced cell attachment experiment respectively. Whole genome expression of DPSCs-SOX2 was analyzed with RNA microarray. Furthermore, a rescue experiment was performed with SOX2-siRNA in DPSC-SOX2 to confirm the effect of SOX2 overexpression in DPSCs. We found that SOX2 overexpression could result in the enhancement of cell proliferation, migration, and adhesion in DPSCs obviously. RNA microarray analysis indicated that some key genes in the signal pathways associated with cell cycle, migration and adhesion were upregulated in different degree, and the results were further confirmed with qPCR and western-blot. Finally, DPSC-SOX2 transfected with SOX2 siRNA showed a decrease of cell proliferation, migration and adhesion ability, which further confirmed the biological effect of SOX2 in human DPSCs. This study indicated that SOX2 could improve the cell proliferation, migration and adhesion ability of DPSCs through regulating gene expression about cell cycle, migration and adhesion, and provided a novel strategy to develop seed cells with strong proliferation, migration and adhesion ability for tissue engineering. PMID- 26496355 TI - Dengue Virus Serotype-2 Interferes with the Formation of Neutrophil Extracellular Traps. AB - OBJECTIVES: Neutrophils play an important role in the control of pathogens through several mechanisms, including phagocytosis and the formation of neutrophil extracellular traps (NETs). The latter consists of DNA as a backbone with embedded antimicrobial peptides, histones, and proteases, providing a matrix to entrap and in some cases to kill microbes. Some metabolic requirements for NET formation have recently been described. The virus-induced formation of NETs and the role of these traps in viral infections remain scarcely reported. Here, we analyzed whether dengue virus serotype-2 (DENV-2) induces NET formation and the DENV-2 effect on phorbol myristate acetate (PMA)-induced NETs. METHODS: Peripheral blood-derived neutrophils were exposed in vitro to DENV-2 or exposed to DENV-2 and then stimulated with PMA. NET formation was assessed by fluorescence microscopy. Cell membrane Glut-1, glucose uptake, and reactive oxygen species (ROS) production were assessed. RESULTS: DENV-2 does not induce the formation of NETs. Moreover, DENV-2 inhibits PMA-induced formation of NETs by about 80%. This effect is not related to the production of ROS. The mechanism seemingly accountable for this inhibitory effect is the DENV-2-mediated inhibition of PMA-induced glucose uptake by neutrophils. CONCLUSION: Our results suggest that DENV-2 inhibits glucose uptake as a metabolism-based way to avoid the formation of NETs. PMID- 26496358 TI - On Extrapolating Past the Range of Observed Data When Making Statistical Predictions in Ecology. AB - Ecologists are increasingly using statistical models to predict animal abundance and occurrence in unsampled locations. The reliability of such predictions depends on a number of factors, including sample size, how far prediction locations are from the observed data, and similarity of predictive covariates in locations where data are gathered to locations where predictions are desired. In this paper, we propose extending Cook's notion of an independent variable hull (IVH), developed originally for application with linear regression models, to generalized regression models as a way to help assess the potential reliability of predictions in unsampled areas. Predictions occurring inside the generalized independent variable hull (gIVH) can be regarded as interpolations, while predictions occurring outside the gIVH can be regarded as extrapolations worthy of additional investigation or skepticism. We conduct a simulation study to demonstrate the usefulness of this metric for limiting the scope of spatial inference when conducting model-based abundance estimation from survey counts. In this case, limiting inference to the gIVH substantially reduces bias, especially when survey designs are spatially imbalanced. We also demonstrate the utility of the gIVH in diagnosing problematic extrapolations when estimating the relative abundance of ribbon seals in the Bering Sea as a function of predictive covariates. We suggest that ecologists routinely use diagnostics such as the gIVH to help gauge the reliability of predictions from statistical models (such as generalized linear, generalized additive, and spatio-temporal regression models). PMID- 26496356 TI - HENMT1 and piRNA Stability Are Required for Adult Male Germ Cell Transposon Repression and to Define the Spermatogenic Program in the Mouse. AB - piRNAs are critical for transposable element (TE) repression and germ cell survival during the early phases of spermatogenesis, however, their role in adult germ cells and the relative importance of piRNA methylation is poorly defined in mammals. Using a mouse model of HEN methyltransferase 1 (HENMT1) loss-of function, RNA-Seq and a range of RNA assays we show that HENMT1 is required for the 2' O-methylation of mammalian piRNAs. HENMT1 loss leads to piRNA instability, reduced piRNA bulk and length, and ultimately male sterility characterized by a germ cell arrest at the elongating germ cell phase of spermatogenesis. HENMT1 loss-of-function, and the concomitant loss of piRNAs, resulted in TE de repression in adult meiotic and haploid germ cells, and the precocious, and selective, expression of many haploid-transcripts in meiotic cells. Precocious expression was associated with a more active chromatin state in meiotic cells, elevated levels of DNA damage and a catastrophic deregulation of the haploid germ cell gene expression. Collectively these results define a critical role for HENMT1 and piRNAs in the maintenance of TE repression in adult germ cells and setting the spermatogenic program. PMID- 26496357 TI - LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in Mice. AB - Skeletal dysplasias are a common, genetically heterogeneous cause of short stature that can result from disruptions in many cellular processes. We report the identification of the lesion responsible for skeletal dysplasia and male infertility in the spontaneous, recessive mouse mutant chagun. We determined that Poc1a, encoding protein of the centriole 1a, is disrupted by the insertion of a processed Cenpw cDNA, which is flanked by target site duplications, suggestive of a LINE-1 retrotransposon-mediated event. Mutant fibroblasts have impaired cilia formation and multipolar spindles. Male infertility is caused by defective spermatogenesis early in meiosis and progressive germ cell loss. Spermatogonial stem cell transplantation studies revealed that Poc1a is essential for normal function of both Sertoli cells and germ cells. The proliferative zone of the growth plate is small and disorganized because chondrocytes fail to re-align after cell division and undergo increased apoptosis. Poc1a and several other genes associated with centrosome function can affect the skeleton and lead to skeletal dysplasias and primordial dwarfisms. This mouse mutant reveals how centrosome dysfunction contributes to defects in skeletal growth and male infertility. PMID- 26496359 TI - A Design Pattern for Decentralised Decision Making. AB - The engineering of large-scale decentralised systems requires sound methodologies to guarantee the attainment of the desired macroscopic system-level behaviour given the microscopic individual-level implementation. While a general-purpose methodology is currently out of reach, specific solutions can be given to broad classes of problems by means of well-conceived design patterns. We propose a design pattern for collective decision making grounded on experimental/theoretical studies of the nest-site selection behaviour observed in honeybee swarms (Apis mellifera). The way in which honeybee swarms arrive at consensus is fairly well-understood at the macroscopic level. We provide formal guidelines for the microscopic implementation of collective decisions to quantitatively match the macroscopic predictions. We discuss implementation strategies based on both homogeneous and heterogeneous multiagent systems, and we provide means to deal with spatial and topological factors that have a bearing on the micro-macro link. Finally, we exploit the design pattern in two case studies that showcase the viability of the approach. Besides engineering, such a design pattern can prove useful for a deeper understanding of decision making in natural systems thanks to the inclusion of individual heterogeneities and spatial factors, which are often disregarded in theoretical modelling. PMID- 26496362 TI - Evidence of autochthonous hepatitis E in a Portuguese pediatric cohort, 1992 1995. AB - Despite the growing importance of hepatitis E virus (HEV) in industrialized countries, minimal attention has been given to autochthonous HEV infection in children. The present study screened archived sera (N = 71) from a Portuguese pediatric cohort collected in 1992-1995 for the presence of antibodies against HEV, using enzyme immunoassays and immunodot. Anti-HEV IgG was detected in two children and anti-HEV IgM in one, suggesting an acute HEV infection. This shows that HEV was circulating in the paediatric population of Portugal in the early 1990s. PMID- 26496361 TI - A Randomized Controlled Trial of the Use of Oral Glucose with or without Gentle Facilitated Tucking of Infants during Neonatal Echocardiography. AB - OBJECTIVE: To compare the effect of oral glucose given with or without facilitated tucking (FT), versus placebo (water) to facilitate image acquisition during a targeted neonatal echocardiography (TNE). DESIGN: Factorial, double blind, randomized controlled trial. SETTING: Tertiary neonatal intensive care unit (NICU). PATIENTS: Infants born between 26 and 42 weeks of gestation (GA). INTERVENTIONS: One of four treatment groups: oral water (placebo), oral glucose (25%), facilitated tucking with oral water or facilitated tucking with oral glucose, during a single, structured TNE. All infants received a soother. MAIN OUTCOME MEASURE: Change in Behavioral Indicators of Infant Pain (BIIP) scores. RESULTS: 104 preterm infants were randomized (mean +/- SD GA: 33.4 +/- 3.5 weeks). BIIP scores remained low during the echocardiography scan (median, [IQ range]: 0, [0 to 1]). There were no differences in the level of agitation of infants amongst the treatment groups, with estimated reductions in mean BIIP relative to control of 0.27 (95%CI -0.40 to 0.94) with use of oral glucose and .04 (-0.63 to 0.70) with facilitated tucking. There were also no differences between treatment groups in the quality and duration of the echocardiography scans. CONCLUSIONS: In stable infants in the NICU, a TNE can be performed with minimal disruption in a majority of cases, simply by providing a soother. The use of 25% glucose water in this context did not provide further benefit in reducing agitation and improving image acquisition. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov: NCT01253889. PMID- 26496360 TI - Downregulation of Choline Kinase-Alpha Enhances Autophagy in Tamoxifen-Resistant Breast Cancer Cells. AB - Choline kinase-alpha (Chk-alpha) and autophagy have gained much attention, as they relate to the drug-resistance of breast cancer. Here, we explored the potential connection between Chk-alpha and autophagy in the mechanisms driving to tamoxifen (TAM) resistance, in estrogen receptor positive (ER+) breast cancer cells (BCCs). Human BCC lines (MCF-7 and TAM-resistant MCF-7 (MCF-7/TAM) cells) were used. Chk-alpha expression and activity was suppressed by the transduction of shRNA (shChk-alpha) with lentivirus and treatment with CK37, a Chk-alpha inhibitor. MCF-7/TAM cells had higher Chk-alpha expression and phosphocholine levels than MCF-7 cells. A specific downregulation of Chk-alpha by the transduction of shChk-alpha exhibited a significant decrease in phosphocholine levels in MCF-7 and MCF-7/TAM cells. The autophagy-related protein, cleaved microtubule-associated protein light chain 3 (LC3) and autophagosome-like structures were significantly increased in shChk-alpha-transduced or CK37-treated MCF-7 and MCF-7/TAM cells. The downregulation of Chk-alpha attenuated the phosphorylation of AKT, ERK1/2, and mTOR in both MCF-7 and MCF-7/TAM cells. In MCF-7 cells, the downregulation of Chk-alpha resulted in an induction of autophagy, a decreased proliferation ability and an activation of caspase-3. In MCF-7/TAM cells, despite a significant decrease in proliferation ability and an increase in the percentage of cells in the G0/G1 phase of the cell cycle, the downregulation of Chk-alpha did not induced caspase-dependent cell death and further enhanced autophagy and G0/G1 phase arrest. An autophagy inhibitor, methyladenine (3-MA) induced death and attenuated the level of elevated LC3 in MCF-7/TAM cells. Elucidating the interplay between choline metabolism and autophagy will provide unique opportunities to identify new therapeutic targets and develop novel treatment strategies that preferentially target TAM-resistance. PMID- 26496363 TI - Quick and selective extraction of Z-ligustilide from Angelica sinensis using magnetic multiwalled carbon nanotubes. AB - A facile and highly efficient magnetic solid-phase extraction method has been developed for Z-ligustilide, the major therapeutic agent in Angelica sinensis. The solid-phase adsorbent material used was prepared by conjugating carbon nanotubes with magnetic Fe3 O4 nanoparticles via a hydrothermal reaction. The magnetic material showed a high affinity toward Z-ligustilide due to the pi-pi stacking interaction between the carbon nanotubes and Z-ligustilide, allowing a quick and selective exaction of Z-ligustilide from complex sample matrices. Factors influencing the magnetic solid-phase extraction such as the amount of the added adsorbent, adsorption and desorption time, and desorption solvent, were investigated. Due to its high extraction efficiency, this method was proved highly useful for sample cleanup/enrichment in quantitative high-performance liquid chromatography analysis. The proposed method had a linear calibration curve (R(2) = 0.9983) over the concentration between 4 ng/mL and 200 MUg/mL Z ligustilide. The accuracy of the method was determined by the recovery, which was from 92.07 to 104.02%, with the relative standard deviations >4.51%. PMID- 26496364 TI - Understanding How Grammatical Aspect Influences Legal Judgment. AB - Recent evidence suggests that grammatical aspect can bias how individuals perceive criminal intentionality during discourse comprehension. Given that criminal intentionality is a common criterion for legal definitions (e.g., first degree murder), the present study explored whether grammatical aspect may also impact legal judgments. In a series of four experiments participants were provided with a legal definition and a description of a crime in which the grammatical aspect of provocation and murder events were manipulated. Participants were asked to make a decision (first- vs. second-degree murder) and then indicate factors that impacted their decision. Findings suggest that legal judgments can be affected by grammatical aspect but the most robust effects were limited to temporal dynamics (i.e., imperfective aspect results in more murder actions than perfective aspect), which may in turn influence other representational systems (i.e., number of murder actions positively predicts perceived intentionality). In addition, findings demonstrate that the influence of grammatical aspect on situation model construction and evaluation is dependent upon the larger linguistic and semantic context. Together, the results suggest grammatical aspect has indirect influences on legal judgments to the extent that variability in aspect changes the features of the situation model that align with criteria for making legal judgments. PMID- 26496365 TI - Cytokine Release Assays as Tests for Exposure to Leishmania, and for Confirming Cure from Leishmaniasis, in Solid Organ Transplant Recipients. AB - Spain has one of the world's largest pools of organ donors and is a global leader in terms of the number of transplants it performs. The current outbreak of leishmaniasis in Fuenlabrada (in the southwest of the region of Madrid, Spain) has involved 600 clinical cases since late 2009 (prevalence 0.2%). It may therefore be wise to monitor the town's transplanted population for Leishmania infantum; its members are immunosuppressed and at greater risk of infection and relapse following treatment. The present work examines the use of cytokine release assays to determine the prevalence of Leishmania infection in this population, and to confirm recovery following treatment for visceral leishmaniasis (VL). The humoral and cellular immune responses to L. infantum were characterized in 63 solid organ transplant (SOT) recipients from Fuenlabrada, 57 of whom reported no previous episode of VL (NVL subjects), and six of whom had been cured of VL (CVL subjects). Seventeen subjects (12 NVL and 5 CVL) showed a patent lymphoproliferative response to soluble Leishmania antigen (SLA). Stimulation of peripheral blood mononuclear cell cultures and of whole blood with SLA led to the production of different combinations of cytokines that might serve to confirm Leishmania infection or recovery from VL and help prevent cured patients from relapsing into this serious condition. PMID- 26496366 TI - The Analgesic Efficacy of Dexmedetomidine as an Adjunct to Local Anesthetics in Supraclavicular Brachial Plexus Block: A Randomized Controlled Trial. AB - BACKGROUND: This study was designed to assess the effects of dexmedetomidine on the onset and duration of block and postoperative analgesia during supraclavicular brachial plexus block in patients undergoing upper limb surgeries. METHODS: Sixty adult patients undergoing upper limb and hand surgeries were randomly allocated into 2 groups. The control group received equal volumes of 0.75% ropivacaine and 2% lidocaine with adrenaline, whereas the dexmedetomidine (dexmed) group received 1 MUg/kg dexmedetomidine along with equal volumes of 0.75% ropivacaine and 2% lidocaine with adrenaline. A total volume of 0.5 mL/kg was administered in ultrasound-guided supraclavicular brachial plexus block in both groups. Patients were observed for hemodynamic stability, onset and duration of sensory and motor blockade, duration of analgesia, postoperative pain, and adverse effects. RESULTS: The onset time of motor blockade was shortened and the duration of sensory, as well as motor, block was significantly prolonged in the dexmed group (P < 0.0001). The duration of postoperative analgesia was also longer in the dexmed group compared with the control group (median [interquartile range], 12 [10.5-13.5] hours and 17 [10.5-19.5] hours in control and dexmed group, respectively [95% confidence interval, -5 {-5, -4}, P < 0.0001]). The requirement for rescue analgesic during the 24-hour postoperative period was less in the dexmed group (P < 0.0001). Postoperative pain scores were comparable among groups except at 8 and 10 hours, when pain scores were lower in the dexmed group. Patients receiving dexmedetomidine were more sedated for 2 hours than the control group patients (P < 0.0001). No episode of bradycardia, hypotension, respiratory depression, or dizziness was reported. CONCLUSIONS: We conclude that the addition of dexmedetomidine to ropivacaine-lidocaine prolonged the duration of supraclavicular brachial plexus block and improved postoperative analgesia without significant adverse effects in patients undergoing upper limb surgeries. PMID- 26496367 TI - The Accuracy of the CNAP(r) Device Compared with Invasive Radial Artery Measurements for Providing Continuous Noninvasive Arterial Blood Pressure Readings at a Medical Intensive Care Unit: A Method-Comparison Study. AB - BACKGROUND: In cases of intensive care unit (ICU) patients without an arterial line, noninvasive continuous blood pressure monitoring could be very beneficial. The CNAP(r) monitor (CNSystems Medizintechnik AG) provides noninvasive, beat-to beat blood pressure (BP) estimates using the volume clamp method to measure finger arterial pressure calibrated to brachial pressure values. The aim of this study was to compare noninvasive BP estimates of the CNAP monitor with invasive blood pressure (IBP) measurements obtained via a radial arterial catheter in unselected medical ICU patients under routine clinical conditions. METHODS: In 40 adult patients, IBP and noninvasive CNAP blood pressure (CBP) were measured simultaneously for 30 minutes. Bland-Altman analysis accounting for repeated measurements revealed accuracy and precision of CBP toward IBP. Percentage errors were calculated using the summary measures method and tested for interchangeability. Trending analysis was assessed using 4-quadrant plots and polar plots, whereby each reported statistical calculation used the sample size of n = 40 patients. RESULTS: A total of 7200 measurement pairs of CBP and IBP were analyzed. For mean arterial pressure, accuracy +/- precision resulted in 4.6 +/- 6.7 mm Hg (limits of agreement -8.7 to 17.8 mm Hg) with a percentage error of 6.77% (95% confidence interval [CI], 6.57%-6.97%). Trending analysis of 3-minute intervals showed a concordance rate of 94.6% (95% CI, 94.0%-95.2%; exclusion zone 10%) and a polar concordance rate of 99.50% (95% CI, 99.48%-99.52%) for changes lying within 10% limits. CONCLUSIONS: The CNAP device provided feasible estimates of BP in unselected medical ICU patients under routine clinical conditions. Mean arterial pressure met interchangeability criteria for accuracy toward radial arterial pressure, as well as for percentage error, and showed good trending capabilities according to the Critchley predefined criteria. PMID- 26496368 TI - The Effects of Single-Dose Etomidate Versus Propofol on Cortisol Levels in Pediatric Patients Undergoing Urologic Surgery: A Randomized Controlled Trial. AB - BACKGROUND: The effects of general anesthetics on the hypothalamus-pituitary adrenal axis and cortisol release in children are poorly characterized. Normal, daily fluctuation of cortisol levels complicates assessment of these effects. This study aimed to characterize the effects of etomidate compared with propofol on the normal cortisol secretory pattern in children undergoing urologic surgery by using a salivary cortisol assay. METHODS: In this prospective, randomized, double-blind, controlled study, we recruited 80 children aged 3 to 12 years assigned ASA physical status I who were scheduled for urologic surgery and 11 healthy child volunteers. Before surgery, cortisol levels of the 11 volunteers and 15 study patients were tested from 7:00 AM to 9:00 PM every hour for 1 day. The study patients were then randomly allocated into an etomidate group and a propofol group, receiving etomidate 0.3 mg/kg (n = 38) or propofol 2 mg/kg (n = 39) and midazolam 0.1 mg/kg, fentanyl 2 MUg/kg, and rocuronium 0.6 mg/kg for induction, respectively. The cortisol levels of the patients were assessed continuously for 2 days postoperatively. RESULTS: The cortisol levels of the etomidate group were continuously and significantly lower than those of the propofol group from the time of discharge from the postanesthesia care unit (approximately 2:00 PM) until 8:00 AM the next morning (all P < 0.0001) and were significantly lower than before surgery at the same time points (all P < 0.0001). Except at 11:00 AM just before the operation, no significant differences in cortisol levels were detected before and after the operation in the propofol group (P max = 0.476, P min = 0.002). Also, no significant differences in clinical outcomes were detected between the 2 groups undergoing surgery (all P > 0.070). CONCLUSIONS: Compared with propofol, a single induction dose of etomidate suppressed postoperative cortisol levels in healthy children undergoing urologic surgery. This suppression lasted approximately 24 hours and was not associated with any changes in clinical outcomes. PMID- 26496369 TI - The Effect of General Anesthesia on Aminotransferase Levels in Patients with Elevated Aminotransferase Levels: A Single-Center 5-Year Retrospective Study. AB - BACKGROUND: The effect of commonly used anesthetics on postoperative aminotransferase levels in patients with preoperatively elevated values is unclear. METHODS: The medical records of 25,567 adult patients undergoing elective general anesthesia were retrospectively reviewed. Patients were classified into normal (<= 40 IU/L), mild (41-119 IU/L), moderate (120-199 IU/L), and marked elevation (200+ IU/L) groups according to their preoperative alanine aminotransferase levels. Changes in these levels before and after general anesthesia were compared according to the anesthetics used. RESULTS: Among the patients with preoperative mild or moderate elevation, 97.8% (2589/2647) did not show a higher alanine aminotransferase level after surgery. Compared with total IV anesthesia (TIVA), sevoflurane showed adjusted odds ratios (95% confidence interval) of 1.27 (1.10-1.46) for mild, 1.33 (0.86-2.05) for moderate, and 3.35 (1.58-7.04) for marked postoperatively elevated levels of alanine aminotransferase versus normal levels. Similarly, compared with TIVA, desflurane showed adjusted odds ratios (95% confidence interval) of 1.21 (0.96-1.53) for mild, 1.44 (0.70-2.94) for moderate, and 3.18 (1.14-8.89) for marked postoperatively elevated levels of alanine aminotransferase versus normal levels (P = 0.05). CONCLUSIONS: In most cases, postoperative alanine aminotransferase levels did not worsen even in patients with preoperatively elevated levels. Sevoflurane was associated with increased odds for postoperative elevation of these levels after general surgery compared with TIVA. PMID- 26496370 TI - Spatiotemporal Context Awareness for Urban Traffic Modeling and Prediction: Sparse Representation Based Variable Selection. AB - Spatial-temporal correlations among the data play an important role in traffic flow prediction. Correspondingly, traffic modeling and prediction based on big data analytics emerges due to the city-scale interactions among traffic flows. A new methodology based on sparse representation is proposed to reveal the spatial temporal dependencies among traffic flows so as to simplify the correlations among traffic data for the prediction task at a given sensor. Three important findings are observed in the experiments: (1) Only traffic flows immediately prior to the present time affect the formation of current traffic flows, which implies the possibility to reduce the traditional high-order predictors into an 1 order model. (2) The spatial context relevant to a given prediction task is more complex than what is assumed to exist locally and can spread out to the whole city. (3) The spatial context varies with the target sensor undergoing prediction and enlarges with the increment of time lag for prediction. Because the scope of human mobility is subject to travel time, identifying the varying spatial context against time lag is crucial for prediction. Since sparse representation can capture the varying spatial context to adapt to the prediction task, it outperforms the traditional methods the inputs of which are confined as the data from a fixed number of nearby sensors. As the spatial-temporal context for any prediction task is fully detected from the traffic data in an automated manner, where no additional information regarding network topology is needed, it has good scalability to be applicable to large-scale networks. PMID- 26496371 TI - Automatic Prediction of Protein 3D Structures by Probabilistic Multi-template Homology Modeling. AB - Homology modeling predicts the 3D structure of a query protein based on the sequence alignment with one or more template proteins of known structure. Its great importance for biological research is owed to its speed, simplicity, reliability and wide applicability, covering more than half of the residues in protein sequence space. Although multiple templates have been shown to generally increase model quality over single templates, the information from multiple templates has so far been combined using empirically motivated, heuristic approaches. We present here a rigorous statistical framework for multi-template homology modeling. First, we find that the query proteins' atomic distance restraints can be accurately described by two-component Gaussian mixtures. This insight allowed us to apply the standard laws of probability theory to combine restraints from multiple templates. Second, we derive theoretically optimal weights to correct for the redundancy among related templates. Third, a heuristic template selection strategy is proposed. We improve the average GDT-ha model quality score by 11% over single template modeling and by 6.5% over a conventional multi-template approach on a set of 1000 query proteins. Robustness with respect to wrong constraints is likewise improved. We have integrated our multi-template modeling approach with the popular MODELLER homology modeling software in our free HHpred server http://toolkit.tuebingen.mpg.de/hhpred and also offer open source software for running MODELLER with the new restraints at https://bitbucket.org/soedinglab/hh-suite. PMID- 26496372 TI - Intestinal Microbiota Profiles of Healthy Pre-School and School-Age Children and Effects of Probiotic Supplementation. AB - OBJECTIVES: This study aims to establish the baseline profile of intestinal microbiota in pre-school and school-age Japanese children and to investigate the effects of a probiotic on the microbiota. METHODS: We analyzed the intestinal microbiota and investigated the effects (before, during and after the ingestion period) on intestinal microbiota and the environment of 6 months of daily ingestion of a probiotic (Lactobacillus casei strain Shirota (LcS)-fermented milk). RESULTS: We performed an open trial in 23 children (14 boys, 9 girls; age 7.7 +/- 2.4 years (mean +/- SD); BMI 19.6 +/- 4.6). The composition of intestinal microbiota of healthy pre-school and school-age children resembled that of adults. During probiotic supplementation, the population levels of Bifidobacterium and total Lactobacillus increased significantly, while those of Enterobacteriaceae, Staphylococcus and Clostridium perfringens decreased significantly. A significant increase in fecal concentrations of organic acids and also a decrease in fecal pH were observed during the ingestion period. However, the patterns of fecal microbiota and intestinal environment were found to revert to the baseline levels (i.e. before ingestion) within 6 months following the cessation of probiotic intake. CONCLUSION: Regular intake of an LcS containing probiotic product may modify the gut microbiota composition and intestinal environment in pre-school and school-age children while maintaining the homeostasis of the microbiota. PMID- 26496373 TI - Chloroplast lipid transfer processes in Chlamydomonas reinhardtii involving a TRIGALACTOSYLDIACYLGLYCEROL 2 (TGD2) orthologue. AB - In plants, lipids of the photosynthetic membrane are synthesized by parallel pathways associated with the endoplasmic reticulum (ER) and the chloroplast envelope membranes. Lipids derived from the two pathways are distinguished by their acyl-constituents. Following this plant paradigm, the prevalent acyl composition of chloroplast lipids suggests that Chlamydomonas reinhardtii (Chlamydomonas) does not use the ER pathway; however, the Chlamydomonas genome encodes presumed plant orthologues of a chloroplast lipid transporter consisting of TGD (TRIGALACTOSYLDIACYLGLYCEROL) proteins that are required for ER-to chloroplast lipid trafficking in plants. To resolve this conundrum, we identified a mutant of Chlamydomonas deleted in the TGD2 gene and characterized the respective protein, CrTGD2. Notably, the viability of the mutant was reduced, showing the importance of CrTGD2. Galactoglycerolipid metabolism was altered in the tgd2 mutant with monogalactosyldiacylglycerol (MGDG) synthase activity being strongly stimulated. We hypothesize this to be a result of phosphatidic acid accumulation in the chloroplast outer envelope membrane, the location of MGDG synthase in Chlamydomonas. Concomitantly, increased conversion of MGDG into triacylglycerol (TAG) was observed. This TAG accumulated in lipid droplets in the tgd2 mutant under normal growth conditions. Labeling kinetics indicate that Chlamydomonas can import lipid precursors from the ER, a process that is impaired in the tgd2 mutant. PMID- 26496374 TI - "A Concept Analysis of Patient-Centered Care" Response From Authors. PMID- 26496375 TI - In Response to the Article: "A Concept Analysis of Patient-Centered Care (Lusk & Fater, 2013)". PMID- 26496377 TI - Ultrafast fiber lasers based on self-similar pulse evolution: a review of current progress. AB - Self-similar fiber oscillators are a relatively new class of mode-locked lasers. In these lasers, the self-similar evolution of a chirped parabolic pulse in normally-dispersive passive, active, or dispersion-decreasing fiber (DDF) is critical. In active (gain) fiber and DDF, the novel role of local nonlinear attraction makes the oscillators fundamentally different from any mode-locked lasers considered previously. In order to reconcile the spectral and temporal expansion of a pulse in the self-similar segment with the self-consistency required by a laser cavity's periodic boundary condition, several techniques have been applied. The result is a diverse range of fiber oscillators which demonstrate the exciting new design possibilities based on the self-similar model. Here, we review recent progress on self-similar oscillators both in passive and active fiber, and extensions of self-similar evolution for surpassing the limits of rare-earth gain media. We discuss some key remaining research questions and important future directions. Self-similar oscillators are capable of exceptional performance among ultrashort pulsed fiber lasers, and may be of key interest in the development of future ultrashort pulsed fiber lasers for medical imaging applications, as well as for low-noise fiber-based frequency combs. Their uniqueness among mode-locked lasers motivates study into their properties and behaviors and raises questions about how to understand mode-locked lasers more generally. PMID- 26496378 TI - Rupture of a Subcapsular Hematoma After Kidney Transplant: Case Report. AB - Subcapsular hematoma after kidney transplant may result in kidney ischemia and graft loss. In this report, we present a patient who had a subcapsular hematoma that had no intraoperative enlargement but ruptured after surgery. A man who had chronic kidney disease secondary to hypertension had a preemptive living-donor kidney transplant from his wife. After declamping, appropriate renal perfusion and urinary output were observed. At perfusion, a subcapsular hematoma (diameter, 3 cm) was observed at the upper pole of the kidney. The hematoma did not enlarge during the surgery. Capsulotomy was not performed due to possible risks, and transplant surgery was completed with the plan for close postoperative ultrasonography and hemodynamic follow-up. Decreased urinary output was observed early after surgery. Renal Doppler ultrasonography showed decreased diastolic flow and a hematoma (width, 9 mm) that completely surrounded the transplanted kidney. The patient had emergency reoperation due to active hemorrhage from his surgical drain at 40 hours after surgery. Rupture of the capsule and hemorrhage from the surface of the kidney were observed. Extended capsulotomy and hemostasis of the kidney were performed. After surgery, urinary flow increased and renal Doppler ultrasonography findings improved. In summary, intervention for a subcapsular hematoma after kidney transplant is controversial. Capsulotomy should be considered for treatment of increased pressure to the graft, risk of permanent damage, and risk of graft loss. PMID- 26496379 TI - Re: Awada HK, Fletter PC, Zaszczurynski PJ, Cooper MA, Damaser MS. Conversion of urodynamic pressures measured simultaneously by air-charged and water-filled catheter systems. Neurourol Urodyn. 2015; 34: 507-512. PMID- 26496380 TI - Microdose flare protocol with interrupted follicle stimulating hormone and added androgen for poor responders--an observational pilot study. AB - OBJECTIVE: To investigate whether temporarily withholding FSH and adding androgen could improve follicular response during a microdose flare protocol in women with slow follicular growth or asynchronous follicular development. DESIGN: Observational pilot study. SETTING: University-affiliated private fertility center. PATIENT(S): Twenty-six women aged 34-47 years with poor response to stimulation or a previous cancelled IVF cycle and with slow or asynchronous follicular growth during a microdose flare cycle. INTERVENTION(S): For 13 women, after initiation of ovarian stimulation using the microdose flare protocol, gonadotropin administration was interrupted and transdermal testosterone gel was added for several days (4.4 +/- 1.2 d) starting after cycle day 7 (mean cycle day 10 +/- 2.6). MAIN OUTCOME MEASURE(S): FSH, E2, follicular growth, and total number of mature oocytes retrieved were determined for all of the patients. Cycle cancellation rate as well as pregnancy rate following embryo transfer were also documented when applicable. RESULT(S): FSH levels declined (25.2 +/- 6.5 to 6.8 +/- 3.2 IU/L), E2 levels increased (896 +/- 687 to 2,163 +/- 1,667 pmol/L), and follicular growth improved significantly during gonadotropin interruption and were tracked for 2 days during this time frame. The average number of oocytes retrieved was 5.3 +/- 2.6, and the ratio of mature to total oocytes was 4:5. Four of the 13 women in the interruption group conceived following frozen embryo transfer, whereas none in the control group did. CONCLUSION(S): The androgen interrupted FSH protocol may improve follicular response to gonadotropins in cycles that might otherwise be cancelled. PMID- 26496376 TI - Developments in the management of Chagas cardiomyopathy. AB - Over 100 years have elapsed since the discovery of Chagas disease and there is still much to learn regarding pathogenesis and treatment. Although there are antiparasitic drugs available, such as benznidazole and nifurtimox, they are not totally reliable and often toxic. A recently released negative clinical trial with benznidazole in patients with chronic Chagas cardiomyopathy further reinforces the concerns regarding its effectiveness. New drugs and new delivery systems, including those based on nanotechnology, are being sought. Although vaccine development is still in its infancy, the reality of a therapeutic vaccine remains a challenge. New ECG methods may help to recognize patients prone to developing malignant ventricular arrhythmias. The management of heart failure, stroke and arrhythmias also remains a challenge. Although animal experiments have suggested that stem cell based therapy may be therapeutic in the management of heart failure in Chagas cardiomyopathy, clinical trials have not been promising. PMID- 26496381 TI - Getting it right: 3D cell cultures for the assessment of photosensitizers for photodynamic therapy. PMID- 26496382 TI - Sequential release of nanoparticle payloads from ultrasonically burstable capsules. AB - In many biomedical contexts ranging from chemotherapy to tissue engineering, it is beneficial to sequentially present bioactive payloads. Explicit control over the timing and dose of these presentations is highly desirable. Here, we present a capsule-based delivery system capable of rapidly releasing multiple payloads in response to ultrasonic signals. In vitro, these alginate capsules exhibited excellent payload retention for up to 1 week when unstimulated and delivered their entire payloads when ultrasonically stimulated for 10-100 s. Shorter exposures (10 s) were required to trigger delivery from capsules embedded in hydrogels placed in a tissue model and did not result in tissue heating or death of encapsulated cells. Different types of capsules were tuned to rupture in response to different ultrasonic stimuli, thus permitting the sequential, on demand delivery of nanoparticle payloads. As a proof of concept, gold nanoparticles were decorated with bone morphogenetic protein-2 to demonstrate the potential bioactivity of nanoparticle payloads. These nanoparticles were not cytotoxic and induced an osteogenic response in mouse mesenchymal stem cells. This system may enable researchers and physicians to remotely regulate the timing, dose, and sequence of drug delivery on-demand, with a wide range of clinical applications ranging from tissue engineering to cancer treatment. PMID- 26496383 TI - Efficient bridging of 20 mm rat sciatic nerve lesions with a longitudinally micro structured collagen scaffold. AB - An increasing number of biomaterial nerve guides has been developed that await direct comparative testing with the 'gold-standard' autologous nerve graft in functional repair of peripheral nerve defects. In the present study, 20 mm rat sciatic nerve defects were bridged with either a collagen-based micro-structured nerve guide (Perimaix) or an autologous nerve graft. Axons regenerated well into the Perimaix scaffold and, the majority of these axons grew across the 20 mm defect into the distal nerve segment. In fact, both the total axon number and the number of retrogradely traced somatosensory and motor neurons extending their axons across the implant was similar between Perimaix and autologous nerve graft groups. Implantation of Schwann cell-seeded Perimaix scaffolds provided only a beneficial effect on myelination within the scaffold. Functional recovery supported by the implanted, non-seeded Perimaix scaffold was as good as that observed after the autologous nerve graft, despite the presence of thinner myelin sheaths in the Perimaix implanted nerves. These findings support the potential of the Perimaix collagen scaffold as a future off-the-shelf device for clinical applications in selected cases of traumatic peripheral nerve injury. PMID- 26496385 TI - Amyloid Fibril Solubility. AB - It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain-side-chain interactions, backbone hydrogen bonding, and temperature affect amyloid fibril solubility, which might prove to be a powerful tool to design protein fibrils with desired solubility and aggregation properties in general. PMID- 26496386 TI - Correction: Beyond Two-Stage Models for Lung Carcinogenesis in the Mayak Workers: Implications for Plutonium Risk. PMID- 26496384 TI - 3D brown adipogenesis to create "Brown-Fat-in-Microstrands". AB - The ability of brown adipocytes (fat cells) to dissipate energy as heat shows great promise for the treatment of obesity and other metabolic disorders. Employing pluripotent stem cells, with an emphasis on directed differentiation, may overcome many issues currently associated with primary fat cell cultures. In addition, three-dimensional (3D) cell culture systems are needed to better understand the role of brown adipocytes in energy balance and treating obesity. To address this need, we created 3D "Brown-Fat-in-Microstrands" by microfluidic synthesis of alginate hydrogel microstrands that encapsulated cells and directly induced cell differentiation into brown adipocytes, using mouse embryonic stem cells (ESCs) as a model of pluripotent stem cells, and brown preadipocytes as a positive control. Brown adipocyte differentiation within microstrands was confirmed by immunocytochemistry and qPCR analysis of the expression of the brown adipocyte-defining marker uncoupling protein 1 (UCP1), as well as other general adipocyte markers. Cells within microstrands were responsive to a beta-adrenergic agonist with an increase in gene expression of thermogenic UCP1, indicating that these "Brown-Fat-in-Microstrands" are functional. The ability to create "Brown Fat-in-Microstrands" from pluripotent stem cells opens up a new arena to understanding brown adipogenesis and its implications in obesity and metabolic disorders. PMID- 26496387 TI - Accuracy of a New Platelet Count System (PLT-F) Depends on the Staining Property of Its Reagents. AB - BACKGROUND: Platelet count is essential for the diagnosis and management of hemostasis abnormalities. Although existing platelet count methods installed in common hematology analyzers can correctly count platelets in normal blood samples, they tend to miscount platelets in some abnormal samples. The newly developed PLT-F channel in the XN-Series hematology analyzer (Sysmex) has been reported to be a reliable platelet count system, even in abnormal samples. However, how the PLT-F platelet counting system achieves such accuracy has not been described in scientific articles. METHODS: Isolated platelets, erythrocytes, and fragmented erythrocytes were examined using an automated hematology analyzer. The samples were labeled by combining PLT-F reagents and anti-CD62p, CD63, Grp75, Calreticulin, CD41, or CD61 antibody, and analyzed using confocal laser scanning microscopy or flow cytometry. RESULTS: The PLT-F system correctly discriminated platelets in erythrocytes. Its reagents strongly stained some intraplatelet organelles labeled with anti-Grp75, but only faintly stained the plasma membrane of both platelets and erythrocytes. Microscopic observation and flow cytometric examination revealed that all of these strongly stained cells were also labeled with platelet-specific anti-CD41 and anti-CD61 antibodies. CONCLUSIONS: This study revealed that the staining property of the PLT-F reagents, by which platelets and fragmented erythrocytes are clearly distinguished, contributes to the platelet-counting accuracy of the PLT-F system. PMID- 26496388 TI - How to Triage PAINS-Full Research. AB - Nonspecific bioactivity and assay artifacts have gained increasing attention in recent years. This focus has arisen primarily from the publication of a set of chemical substructures, termed pan assay interference compounds (PAINS), which are associated with promiscuous bioactivity and assay interference in real and virtual high-throughput screening (HTS) campaigns. Despite an increasing awareness in the HTS and medicinal chemistry communities about the liabilities of these compounds, articles featuring PAINS and PAINS-like compounds are still being published. In this perspective, we describe some of the factors we believe are driving this resource-sapping trend. We also provide what we hope are helpful insights that may lead to the earlier recognition of these generally nontranslatable compounds, thus preventing the propagation of PAINS-full costly research. PMID- 26496390 TI - Capitalizing on opportunistic data for monitoring relative abundances of species. AB - With the internet, a massive amount of information on species abundance can be collected by citizen science programs. However, these data are often difficult to use directly in statistical inference, as their collection is generally opportunistic, and the distribution of the sampling effort is often not known. In this article, we develop a general statistical framework to combine such "opportunistic data" with data collected using schemes characterized by a known sampling effort. Under some structural assumptions regarding the sampling effort and detectability, our approach makes it possible to estimate the relative abundance of several species in different sites. It can be implemented through a simple generalized linear model. We illustrate the framework with typical bird datasets from the Aquitaine region in south-western France. We show that, under some assumptions, our approach provides estimates that are more precise than the ones obtained from the dataset with a known sampling effort alone. When the opportunistic data are abundant, the gain in precision may be considerable, especially for rare species. We also show that estimates can be obtained even for species recorded only in the opportunistic scheme. Opportunistic data combined with a relatively small amount of data collected with a known effort may thus provide access to accurate and precise estimates of quantitative changes in relative abundance over space and/or time. PMID- 26496389 TI - Timescales and Frequencies of Reversible and Irreversible Adhesion Events of Single Bacterial Cells. AB - In the environment, most bacteria form surface-attached cell communities called biofilms. The attachment of single cells to surfaces involves an initial reversible stage typically mediated by surface structures such as flagella and pili, followed by a permanent adhesion stage usually mediated by polysaccharide adhesives. Here, we determine the absolute and relative timescales and frequencies of reversible and irreversible adhesion of single cells of the bacterium Caulobacter crescentus to a glass surface in a microfluidic device. We used fluorescence microscopy of C. crescentus expressing green fluorescent protein to track the swimming behavior of individual cells prior to adhesion, monitor the cell at the surface, and determine whether the cell reversibly or irreversibly adhered to the surface. A fluorescently labeled lectin that binds specifically to polar polysaccharides, termed holdfast, discriminated irreversible adhesion events from reversible adhesion events where no holdfast formed. In wild-type cells, the holdfast production time for irreversible adhesion events initiated by surface contact (23 s) was 30-times faster than the holdfast production time that occurs through developmental regulation (13 min). Irreversible adhesion events in wild-type cells (3.3 events/min) are 15-times more frequent than in pilus-minus mutant cells (0.2 events/min), indicating the pili are critical structures in the transition from reversible to irreversible surface-stimulated adhesion. In reversible adhesion events, the dwell time of cells at the surface before departing was the same for wild-type cells (12 s) and pilus-minus mutant cells (13 s), suggesting the pili do not play a significant role in reversible adhesion. Moreover, reversible adhesion events in wild-type cells (6.8 events/min) occur twice as frequently as irreversible adhesion events (3.3 events/min), demonstrating that most cells contact the surface multiple times before transitioning from reversible to irreversible adhesion. PMID- 26496391 TI - Feasibility and Safety of Video Endoscopic Inguinal Lymphadenectomy in Vulvar Cancer: A Systematic Review. AB - OBJECTIVE: To systematically review previous studies and to evaluate the feasibility and safety of video endoscopic inguinal lymphadenectomy (VEIL) in vulvar cancer. METHODS: We conducted a comprehensive review of studies published through September 2014 to retrieve all relevant articles. The PubMed, EMBASE, Web of Science, Cochrane Library, Wan Fang Data and Chinese National Knowledge Infrastructure databases were systematically searched for all relevant studies published in English or Chinese through September 2014. Data were abstracted independently by two reviewers, and any differences were resolved by consensus. RESULTS: A total of 9 studies containing 249 VEIL procedures involving 138 patients were reviewed. Of the 249 VEIL procedures, only 1 (0.4%) was converted to an open procedure for suturing because of injury to the femoral vein. The range of operative time was 62 to 110 minutes, and the range of estimated blood loss was 5.5 to 22 ml. The range of the number of harvested lymph nodes was 7.3 to 16. The length of hospital stay varied from 7 to 13.6 days across reports. The incidence of lymph node metastasis was 19.7% (27/138), and the recurrence rate was 4.3% (3/70) within 3 to 41 months of follow-up. One or more short-term complications were documented in 18 of 138 (13.0%) patients. Complications after VEIL were observed in 14 (10.13%) patients and in 15 (6.0%) of the VEIL cases, including major lymphocyst formation in 9 (3.6%), lymphorrhea in 2 (0.8%), inguinal wound infection without wound breakdown in 3 (1.2%) and lymphedema in 1 (0.4%). CONCLUSIONS: VEIL appears to be a feasible procedure in the management of vulvar cancer. There may be potential benefits that result in lower morbidity compared to traditional methods, but this has yet to be objectively proven. PMID- 26496392 TI - Development of PCR-Based Markers to Determine the Sex of Kelps. AB - Sex discriminating genetic markers are commonly used to facilitate breeding programs in economically and ecologically important animal and plant species. However, despite their considerable economic and ecological value, the development of sex markers for kelp species has been very limited. In this study, we used the recently described sequence of the sex determining region (SDR) of the brown algal model Ectocarpus to develop novel DNA-based sex-markers for three commercially relevant kelps: Laminaria digitata, Undaria pinnatifida and Macrocystis pyrifera. Markers were designed within nine protein coding genes of Ectocarpus male and female (U/V) sex chromosomes and tested on gametophytes of the three kelp species. Seven primer pairs corresponding to three loci in the Ectocarpus SDR amplified sex-specific bands in the three kelp species, yielding at least one male and one female marker for each species. Our work has generated the first male sex-specific markers for L. digitata and U. pinnatifida, as well as the first sex markers developed for the genus Macrocystis. The markers and methodology presented here will not only facilitate seaweed breeding programs but also represent useful tools for population and demography studies and provide a means to investigate the evolution of sex determination across this largely understudied eukaryotic group. PMID- 26496393 TI - Dependable and Efficient Clinical Molecular Diagnosis of Chinese RP Patient with Targeted Exon Sequencing. AB - Retinitis pigmentosa (RP) is the most common inherited retinal disease. It is a clinically and genetically heterogeneous disorder, which is why it is particularly challenging to diagnose. The aim of this study was to establish a targeted next-generation sequencing (NGS) approach for the comprehensive, rapid, and cost-effective clinical molecular diagnosis of RP. A specific hereditary eye disease enrichment panel (HEDEP) based on exome capture technology was used to collect the protein coding regions of 371 targeted hereditary eye disease genes, followed by high-throughput sequencing on the Illumina HiSeq2000 platform. From a cohort of 34 Chinese RP families, 13 families were successfully diagnosed; thus, the method achieves a diagnostic rate of approximately 40%. Of 16 pathogenic mutations identified, 11 were novel. Our study demonstrates that targeted capture sequencing offers a rapid and effective method for the molecular diagnosis of RP, which helps to provide a more accurate clinical diagnosis and paves the way for genetic counseling, family planning, and future gene-targeted treatment. PMID- 26496394 TI - Targeted Evolution of Embedded Librarian Services: Providing Mobile Reference and Instruction Services Using iPads. AB - The University at Buffalo Health Sciences Library provides reference and instructional services to support research, curricular, and clinical programs of the University at Buffalo. With funding from an NN/LM MAR Technology Improvement Award, the University at Buffalo Health Sciences Library (UBHSL) purchased iPads to develop embedded reference and educational services. Usage statistics were collected over a ten-month period to measure the frequency of iPad use for mobile services. While this experiment demonstrates that the iPad can be used to meet the library user's needs outside of the physical library space, this article will also offer advice for others who are considering implementing their own program. PMID- 26496395 TI - Creating Interactive Online Instruction: The McGoogan Library Experience. AB - Online instruction is a hot topic at academic medical centers. Seizing the opportunity to join the online movement at the University of Nebraska Medical Center (UNMC), the McGoogan Library created an open access course made up of six learning modules. The modules addressed three issues: 1) supplementing one-shot library instruction, 2) offering opportunity for instruction when a librarian is not embedded in a course, and 3) showcasing the library as an online instruction supporter. This article discusses the planning process, technology used, how the modules were received, and how this initial project increased McGoogan Library's involvement in the UNMC online movement. PMID- 26496396 TI - Asking a Great Question: A Librarian Teaches Questioning Skills to First-Year Medical Students. AB - In a single one-hour session, first-year medical students were taught a framework for differentiating between lower-order questions that lead to knowledge of facts and higher-order questions that lead to integration of concepts and deeper learning, thereby preparing them for problem-based learning (PBL). Students generated lists of questions in response to an assertion prompt and categorized them according to Bloom's Taxonomy. These data were analyzed in addition to data from the course exam, which asked them to formulate a higher-level question in response to a prompt. Categorizing questions according to Bloom's Taxonomy was a more difficult task for students than was formulating higher-order questions. Students reported that the skills that they learned were used in subsequent PBL sessions to formulate higher-order learning objectives that integrated new and previously-learned concepts. PMID- 26496397 TI - Librarians in Evidence-Based Medicine Curricula: A Qualitative Study of Librarian Roles, Training, and Desires for Future Development. AB - This study aims to describe librarians' roles in evidence-based medicine (EBM) from the librarian perspective, identify how librarians are trained to teach, and highlight preferences for professional development. A multiinstitution qualitative study was conducted. Nine medical librarians identified by their faculty as integrated into EBM training were interviewed. Participants' descriptions indicated that they were active in curriculum development, deployment (including teaching activities), and assessment to support EBM. Participants identified direct experience and workshop participation as primary methods of learning to teach. Participants desired continuing development as teachers and requested opportunities for in-person workshops, shadowing physicians, and online training. PMID- 26496398 TI - Repurposing With Purpose: Creating a Collaborative Learning Space to Support Institutional Interprofessional Initiatives. AB - When the University of Mississippi Medical Center embraced a didactic shift to patient-centered, interprofessional education of its medical, dental, nursing, pharmacy, and allied health students, the Rowland Medical Library repurposed space to support the cause and created a collaborative learning space designated for campus-wide utility. PMID- 26496399 TI - Partnership for Diversity: A Multidisciplinary Approach to Nurturing Cultural Competence at an Emerging Medical School. AB - Fostering cultural competence in higher education institutions is essential, particularly in training future health care workers to care for diverse populations. The opportunity to explore techniques to address diversity and cultural competence at a new medical school was undertaken by a multidisciplinary team of librarians, faculty, staff, and medical students. From 2011 to 2015, the team sponsored a voluntary programming series to promote cultural competence and raise awareness of health care disparities for the medical school. Thirteen events were hosted with 562 participants across all. This approach to diversity proved effective and could be adapted in any higher education setting. PMID- 26496400 TI - Natural Medicines: A Complementary and Alternative Medicines Tool Combining Natural Standard and the Natural Medicines Comprehensive Database. AB - Natural Medicines is a subscription-based database of complementary and alternative medicine information, building on the information previously available within Natural Standard and the Natural Medicines Comprehensive Database. Natural Medicines offers several special features including an Interaction Checker and Effectiveness Checker, as well as tools focused on Nutrient Depletion, Pregnancy & Lactation, and Adverse Effects. This column features a sample search of Natural Medicines, along with descriptions of the special features and how they might be used in practice by health care providers and health sciences information professionals. PMID- 26496401 TI - An Introduction to Gamification: Adding Game Elements for Engagement. AB - Gamification is defined as the use of game design elements in a nongame context. While gamification is not a new concept, new dynamics are unfolding that may cause more businesses, educators, and librarians to consider the use of game-like elements into future endeavors. In addition to more generation Y or millennials entering higher education and the workplace, there has been a significant acceptance of routinely using smartphones and playing games. This column will explain what gamification is, provide an overview of the benefits and concerns surrounding gamification, and describe how and where it is currently being used. PMID- 26496402 TI - Developing a Marketing Orientation in Hospital Library Services: A Case Report. AB - When the four Providence Health & Services libraries in Oregon regionalized services and resources, the transition, which was originally met with apprehension from some library users, turned out to be a resounding success. Despite a loss of two-thirds of the professional staff and a decreased budget, the new regionalized library experienced an increase in business and recognition. While many factors contributed to the success, a creative marketing and outreach campaign was a key component. This column describes the steps taken to promote regionalized library reference services and online resources. PMID- 26496403 TI - The Process of Becoming an Embedded Curriculum Librarian in Multiple Health Sciences Programs. AB - Higher education is moving to offer more fully online programs, and the health science fields are no different. These programs are either hybrid or completely online. It is up to the health sciences librarian to adapt services offered by the academic library to these types of courses. This column discusses the multiple ways a librarian can be an embedded librarian in a course using a learning management system (LMS). The process of creating a customized embedded librarian program, results, and lessons learned from the different embedded librarian roles are also discussed. PMID- 26496408 TI - Development of hydroxylated naphthylchalcones as polyphenol oxidase inhibitors: Synthesis, biochemistry and molecular docking studies. AB - Polyphenol oxidase (Tyrosinase) has received great attention, since it is the key enzyme in melanin biosynthesis. In this study, novel hydroxy naphthylchalcone compounds were synthesized, and their inhibitory effects on mushroom tyrosinase activity were evaluated. The structures of the compounds synthesized were confirmed by (1)H NMR, (13)C NMR, FTIR and HRMS. Two of the compounds synthesized inhibited the diphenolase activity of tyrosinase in a dose dependent manner and exhibited much higher tyrosinase inhibitory activities (IC50 values of 10.4MUM and 14.4MUM, respectively) than the positive control, kojic acid (IC50: 27.5MUM). Kinetic analysis showed that their inhibition was reversible. Both the novel compounds displayed competitive inhibition with their Ki values of 3.8MUM and 4.5MUM, respectively. Docking results confirmed that the active inhibitors strongly interacted with the mushroom tyrosinase residues. This study suggests hydroxy naphthylchalcone compounds to serve as promising candidates for use as depigmentation agents. PMID- 26496409 TI - One-Pot Catalysis Using a Chiral Iridium Complex/Bronsted Base: Catalytic Asymmetric Synthesis of Catalponol. AB - Tandem asymmetric hydrogen transfer oxidation/aldol condensation under relay catalysis of a chiral iridium complex/achiral Bronsted base binary system is described for the synthesis of alpha-benzylidene-gamma-hydroxytetralones with high ee's. A two-step synthesis of catalponol was achieved using this sequential methodology together with regio- and stereoselective hydroboration. PMID- 26496410 TI - Magnetic field on fouling control of ultrafiltration membranes applied in treatment of a synthetic textile effluent. AB - Membrane performance is decreased by fouling, reducing permeate flux and membrane lifespan. This paper assesses ultrafiltration of a model textile effluent assisted by permanent magnetic field as an alternative to improve the water permeability recovery. Ultrafiltration was performed in a tangential module and model solutions, composed of carboxymethylcellulose (CMC) and sodium sulphate (Na2SO4). The feed was permeated through 30 kDa polysulphone membrane with and without the presence of a permanent magnetic field of 0.41 T, perpendicular to the membrane surface. Magnetic induction (MI) of feed solution was also investigated by recirculation of the feed stream through the magnetic field for 3 h. The increase in feed concentration did not affect permeate flux, while the presence of salt resulted in a severe flux decline. Effective water permeability recovery was obtained when the magnetic field was applied in the ultrafiltration process, although the MI of the CMC and Na2SO4 solutions also caused some enhancement in permeability recovery. Scanning electron microscopy images showed differences between the assays done with and without the presence of magnetic field. The magnetic field application in ultrafiltration of CMC and Na2SO4 solutions has proved to be an attractive alternative for improving the permeability recovery. PMID- 26496411 TI - Reconstructive Phase Transition in Ultrashort Peptide Nanostructures and Induced Visible Photoluminescence. AB - A reconstructive phase transition has been found and studied in ultrashort di- and tripeptide nanostructures, self-assembled from biomolecules of different compositions and origin such as aromatic, aliphatic, linear, and cyclic (linear FF-diphenylalanine, linear LL-dileucine, FFF-triphenylalanine, and cyclic FF diphenylalanine). The native linear aromatic FF, FFF and aliphatic LL peptide nanoensembles of various shapes (nanotubes and nanospheres) have asymmetric elementary structure and demonstrate nonlinear optical and piezoelectric effects. At elevated temperature, 140-180 degrees C, these native supramolecular structures (except for native Cyc-FF nanofibers) undergo an irreversible thermally induced transformation via reassembling into a completely new thermodynamically stable phase having nanowire morphology similar to those of amyloid fibrils. This reconstruction process is followed by deep and similar modification at all levels: macroscopic (morphology), molecular, peptide secondary, and electronic structures. However, original Cyc-FF nanofibers preserve their native physical properties. The self-fabricated supramolecular fibrillar ensembles exhibit the FTIR and CD signatures of new antiparallel beta sheet secondary folding with intermolecular hydrogen bonds and centrosymmetric structure. In this phase, the beta-sheet nanofibers, irrespective of their native biomolecular origin, do not reveal nonlinear optical and piezoelectric effects, but do exhibit similar profound modification of optoelectronic properties followed by the appearance of visible (blue and green) photoluminescence (PL), which is not observed in the original peptides and their native nanostructures. The observed visible PL effect, ascribed to hydrogen bonds of thermally induced beta-sheet secondary structures, has the same physical origin as that of the fluorescence found recently in amyloid fibrils and can be considered to be an optical signature of beta-sheet structures in both biological and bioinspired materials. Such PL centers represent a new class of self-assembled dyes and can be used as intrinsic optical labels in biomedical microscopy as well as for a new generation of novel optoelectronic nanomaterials for emerging nanophotonic applications, such as biolasers, biocompatible markers, and integrated optics. PMID- 26496412 TI - Enhanced antimicrobial effect of organic acid washing against foodborne pathogens on broccoli by vacuum impregnation. AB - This study was undertaken to evaluate the effect of vacuum impregnation applied to the washing process for removal of Salmonella Typhimurium and Listeria monocytogenes from broccoli surfaces. Broccoli was inoculated with the two foodborne pathogens and treated with simple dipping washing or with vacuum impregnation in 2% malic acid for 5, 10, 20, or 30 min. There were two methods of vacuum impregnation: continuous and intermittent. After 30 min of 101.3 kPa (=14.7 psi, simple dipping), 61.3 kPa (=8.9 psi), and 21.3 kPa (=3.1 psi) of continuous vacuum impregnation treatment, there were 1.6, 2.0, and 2.4 log 10 CFU/g reductions of S. Typhimurium and 1.5, 1.7, and 2.3 log 10 CFU/g reductions of L. monocytogenes, respectively. After 30 min of 101.3, 61.3, and 21.3 kPa of intermittent vacuum impregnation treatment, there were 1.5, 2.3, and 3.7 log 10 CFU/g reductions of S. Typhimurium and 1.6, 2.1, and 3.2 log 10 CFU/g reductions of L. monocytogenes, respectively. Scanning electron photomicrographs showed that bacteria tend to attach to or become entrapped in protective sites after simple wash processing (dipping). However, most bacteria were washed out of protective sites after intermittent treatment. Direct treatment of cell suspensions with vacuum impregnation showed that it had no inactivation capacity in itself since there were no significant differences (P >= 0.05) between the reduction rates of non- and vacuum impregnation treatment. These results demonstrate that the increased antimicrobial effect of vacuum impregnation can be attributed to increased accessibility of sanitizer and an enhanced washing effect in protected sites on produce. Color, texture and titratable acidity values of broccoli treated with intermittent vacuum impregnation in 2% malic acid for 30 min were not significantly (P >= 0.05) different from those of untreated samples even though a storage interval was needed for titratable acidity values to be reduced to levels comparable to those of untreated controls. PMID- 26496413 TI - Mammary analog secretory carcinoma of the parotid gland: A case report and literature review. AB - BACKGROUND: Mammary analog secretory carcinoma (MASC) was first described in 2010 by Skalova et al. This entity shares morphologic and immunohistochemical features with the secretory carcinoma (SC) of the breast. MASC usually presents as an asymptomatic mass in the parotid gland and predominantly affects men. This tumor is considered a low-grade carcinoma but has the potential for high-grade transformation. We report one MASC case and a review of world literature. CASE REPORT: A 66-year-old male patient presented because he noticed a mass of approximately 3*3cm on the right pre-auricular region. Physical examination demonstrated a 3*3.5cm, firm, fixed, non-tender mass in the right pre-auricular region. An MRI of the head and neck showed an ovoid heterogeneous lesion, dependent of the right parotid gland of 27*28mm. We performed a superficial parotidectomy with identification and preservation of the facial nerve. The immunophenotype was positive for epithelial membrane antigen (EMA), CK8/18, vimentin, S-100 protein, and mammoglobin. No further surgical interventions or adjuvant therapies were needed. The patient will have a close follow up. CONCLUSION: The presence of t(12;15) (p13;q25) translocation which results in the ETV6-NTRK3 gene fusion or positive immunochemical studies for STAT5, mammoglobin and S100 protein, are necessary to confirm the diagnosis of MASC. MASC treatment should mimic the management of other low-grade malignant salivary gland neoplasms. The inhibition of ETV6-NTRK3 gene fusion could be used as treatment in the future. PMID- 26496415 TI - Nanoparticle-Drug Bioconjugate as Dual Functional Affinity Ligand for Rapid Point of-Care Detection of Endotoxin in Water and Serum. AB - Endotoxin or lipopolysaccharide (LPS) is a major constituent of the Gram-negative bacterial cell wall that causes a life-threatening disorder called septicemia resulting from the unregulated activation of the innate immune system. We demonstrate a simple and robust drug-assisted dot blot bioassay for endotoxin detection that can be used right by the critically ill patients' bedside. Target LPS molecules are trapped from serum or water on glass substrates via long-chain alkyls and tagged with reporter gold nanoparticles (NPs) preconjugated to an antibiotic drug called polymyxin B sulfate (PMB). A post-silver-enhancement step enables signal visibility to the bare eye over a wide and clinically relevant concentration range of 50 fg/mL-50 ng/mL, allowing effortless diagnosis of sepsis at various stages, from early sepsis to septic shock. PMID- 26496414 TI - The inhibitory neurotransmitter GABA evokes long-lasting Ca(2+) oscillations in cortical astrocytes. AB - Studies over the last decade provided evidence that in a dynamic interaction with neurons glial cell astrocytes contribut to fundamental phenomena in the brain. Most of the knowledge on this derives, however, from studies monitoring the astrocyte Ca(2+) response to glutamate. Whether astrocytes can similarly respond to other neurotransmitters, including the inhibitory neurotransmitter GABA, is relatively unexplored. By using confocal and two photon laser-scanning microscopy the astrocyte response to GABA in the mouse somatosensory and temporal cortex was studied. In slices from developing (P15-20) and adult (P30-60) mice, it was found that in a subpopulation of astrocytes GABA evoked somatic Ca(2+) oscillations. This response was mediated by GABAB receptors and involved both Gi/o protein and inositol 1,4,5-trisphosphate (IP3 ) signalling pathways. In vivo experiments from young adult mice, revealed that also cortical astrocytes in the living brain exibit GABAB receptor-mediated Ca(2+) elevations. At all astrocytic processes tested, local GABA or Baclofen brief applications induced long-lasting Ca(2+) oscillations, suggesting that all astrocytes have the potential to respond to GABA. Finally, in patch-clamp recordings it was found that Ca(2+) oscillations induced by Baclofen evoked astrocytic glutamate release and slow inward currents (SICs) in pyramidal cells from wild type but not IP3 R2(-/-) mice, in which astrocytic GABAB receptor-mediated Ca(2+) elevations are impaired. These data suggest that cortical astrocytes in the mouse brain can sense the activity of GABAergic interneurons and through their specific recruitment contribut to the distinct role played on the cortical network by the different subsets of GABAergic interneurons. PMID- 26496416 TI - Dysnatremia as a poor prognostic indicator in patients with acute subarachnoid hemorrhage. AB - BACKGROUND: Dysnatremias are common and carry a risk of poor prognosis in acute subarachnoid hemorrhage (SAH) patients. The aim of this study was to determine the frequency and outcome of dysnatremias in 344 SAH patients treated by a targeted sodium management regimen. METHODS: We performed a 10-year observational dysnatremia study. Hyponatremia was defined as serum sodium (SNa) below 135 mmol/L, hypernatremia SNa above 150 mmol/L. RESULTS: Dysnatremia occurred in 35.8% patients; this was more frequently hyponatremia (19.8%) with a mean SNa 132.23+/-2.09 mmol/L, (16.0% mild, 3.2% moderate, 0.6% severe). Hypernatremia occurred less commonly in 11.9%, P<0.001 with a mean SNa 154.21+/-3.72 mmol/L, (6.1% mild, 2.9% moderate, 2.9% severe). In 4.8% of patients there were episodes of both dysnatremias. The incidence of hypo-osmolar hyponatremia was 6.4%, Cerebral salt wasting (CSW) 3.5%, syndrome of inappropriate secretion of antidiuretic hormone (SIADH) 0.3% and Central diabetes insipidus 1.7%. The hypernatremic patients had a higher inpatient mortality rate (P=0.001) and a worse overall outcome (P<0.001) than those hyponatremic or normotremic patients. Multivariate logistic regression showed that hypernatremia was an independent risk factor for increased inpatient mortality and poor outcome in patients with SAH. CONCLUSIONS: Our 10-year targeted sodium management regimen in acute SAH patients showed that dysnatremias were frequent, predominantly hyponatremia of which the more usual causes were CSW and not SIADH. Hypernatremia was shown to be an independent risk factor for inpatient mortality and poor outcome. PMID- 26496417 TI - Antimicrobial susceptibility of bacteria isolated from neonatal foal samples submitted to a New Zealand veterinary pathology laboratory (2004 to 2013). AB - AIMS: To describe antimicrobial susceptibility, and identify antimicrobial resistance (AMR), in bacteria isolated from New Zealand foals. METHODS: A database search was performed of submissions to a veterinary pathology laboratory between April 2004 and December 2013 for bacterial culture of samples from foals <3 weeks of age. Culture and susceptibility results were compiled with demographic information. Susceptibility results were as defined for the Kirby Bauer disk diffusion susceptibility test based on Clinical Laboratory Standards Institute guidelines. Multi-drug resistance (MDR) was defined as non susceptibility to >=3 of a panel of antimicrobials (ceftiofur, enrofloxaxin, gentamicin, penicillin, tetracycline, trimethoprim-sulfonamide); penicillin susceptibility was not included for Gram-negative isolates. RESULTS: Submissions from 102 foals were examined, and 127 bacterial isolates were cultured from 64 (63%) foals. Of the 127 isolates, 32 (25%) were Streptococcus spp., 30 (24%) were Staphylococcus spp., 12 (10%) were Enterococcus spp. and 26 (21%) were Escherichia coli. Of 83 Gram-positive isolates, 57 (69%) were susceptible to penicillin. Over all isolates, 92/126 (73%) were susceptible to gentamicin and 117/126 (93%) to enrofloxacin; 62/82 (76%) of Gram-positive, and 22/42 (52%) of Gram-negative bacteria were susceptible to ceftiofur; 53/81 (65%) of Gram positive, and 23/44 (52%) of Gram-negative bacteria were susceptible to tetracycline; 59/82 (72%) of Gram-positive, and 23/44 (43%) of Gram-negative bacteria were susceptible to trimethoprim-sulfonamide. Of 126 isolates, 33 (26%) had MDR; >1 isolate with MDR was cultured from 24/64 (38%) foals, and >=2 isolates with MDR were recovered from 8/64 (13%) foals. CONCLUSIONS: Multi-drug resistance, including resistance to commonly used antimicrobials, was found in bacterial isolates from foals in New Zealand. CLINICAL RELEVANCE: The results of this study are of concern from a treatment perspective as they indicate a potential for antimicrobial treatment failure. For future surveillance of AMR and the creation of national guidelines, it is important to record more data on samples submitted for bacterial culture. PMID- 26496418 TI - Tear Fluid SIgA as a Noninvasive Biomarker of Mucosal Immunity and Common Cold Risk. AB - PURPOSE: Research has not convincingly demonstrated the utility of saliva secretory immunoglobulin-A (SIgA) as a biomarker of upper respiratory tract infection (URTI) risk, and disagreement exists about the influence of heavy exercise ("open-window theory") and dehydration on saliva SIgA. Prompted by the search for viable alternatives, we compared the utility of tear and saliva SIgA to predict URTI prospectively (study 1) and assessed the influence of exercise (study 2) and dehydration (study 3) using a repeated-measures crossover design. METHODS: In study 1, 40 subjects were recruited during the common-cold season. Subjects provided tear and saliva samples weekly and recorded upper respiratory symptoms (URS) daily for 3 wk. Real-time PCR confirmed common-cold pathogens in 9 of 11 subjects reporting URS (82%). Predictive utility of tear and saliva SIgA was explored by comparing healthy samples with those collected during the week before URS. In study 2, 13 subjects performed a 2-h run at 65% VO2peak. In study 3, 13 subjects performed exercise heat stress to 3% body mass loss followed by overnight fluid restriction. RESULTS: Tear SIgA concentration and secretion rate were 48% and 51% lower, respectively, during URTI and 34% and 46% lower the week before URS (P < 0.05), but saliva SIgA remained unchanged. The risk of URS the following week increased ninefold (95% confidence interval, 1.7-48) when the tear SIgA secretion rate was <5.5 MUg.min(-1) and sixfold (95% confidence interval, 1.2-29) when the tear SIgA secretion rate decreased >30%. Tear SIgA secretion rate >5.5 MUg.min(-1) or no decrease of >30% predicted subjects free of URS in >80% of cases. Tear SIgA concentration decreased after exercise (-57%, P < 0.05) in line with the "open-window theory" but was unaffected by dehydration. Saliva flow rate decreased and saliva SIgA concentration increased after exercise and during dehydration (P < 0.05). CONCLUSIONS: Tear SIgA has utility as a noninvasive biomarker of mucosal immunity and common-cold risk. PMID- 26496419 TI - Using Sit-to-Stand Workstations in Offices: Is There a Compensation Effect? AB - PURPOSE: Sit-to-stand workstations are becoming common in modern offices and are increasingly being implemented in sedentary behavior interventions. The purpose of this study was to examine whether the introduction of such a workstation among office workers leads to reductions in sitting during working hours, and whether office workers compensate for any reduction in sitting at work by increasing sedentary time and decreasing physical activity (PA) outside work. METHODS: Office workers (n = 40; 55% female) were given a WorkFit-S, sit-to-stand workstation for 3 months. Participants completed assessments at baseline (before workstation installation), 1 wk and 6 wk after the introduction of the workstation, and again at 3 months (postintervention). Posture and PA were assessed using the activPAL inclinometer and ActiGraph GT3X+ accelerometer, which participants wore for 7 d during each measurement phase. RESULTS: Compared with baseline, the proportion of time spent sitting significantly decreased (75% +/- 13% vs 52% +/- 16% to 56% +/- 13%), and time spent standing and in light activity significantly increased (standing: 19% +/- 12% vs 32% +/- 12% to 37% +/- 15%, light PA: 14% +/- 4% vs 16% +/- 5%) during working hours at all follow-up assessments. However, compared with baseline, the proportion of time spent sitting significantly increased (60% +/- 11% vs 66% +/- 12% to 68% +/- 12%) and light activity significantly decreased (21% +/- 5% vs 19% +/- 5%) during nonworking hours across the follow-up measurements. No differences were seen in moderate-to-vigorous activity during nonworking hours throughout the study. CONCLUSION: The findings suggest that introducing a sit-to-stand workstation can significantly reduce sedentary time and increase light activity levels during working hours. However, these changes were compensated for by reducing activity and increasing sitting outside of working hours. An intervention of a sit-to stand workstation should be accompanied by an intervention outside of working hours to limit behavior compensation. PMID- 26496420 TI - Peripheral and Central Fatigue Development during All-Out Repeated Cycling Sprints. AB - PURPOSE: We investigated the development and recovery of peripheral and central fatigue during repeated cycling sprints and its influence on power output. METHODS: On six separate days, 12 healthy males performed the following tests: 1, 4, 6, 8, and 10 * 10 s sprints with 30 s of passive recovery between sprints, as well as 8 * 10 s sprints with 10 s of passive recovery. Peripheral and central fatigue levels were quantified via changes in preexercise- to postexercise potentiated quadriceps twitch force, as evoked by supramaximal electrical stimulation of the femoral nerve (30 s through 6 min recovery), and quadriceps voluntary activation (VA), respectively. Root mean square of the vastus lateralis and the vastus medialis electromyogram during sprints were normalized by maximal M wave amplitude (RMS.Mmax). RESULTS: From the first to the sixth sprint, we found significant and gradual reductions in power output (-25% +/- 7%), RMS.Mmax (-7% +/- 4%), twitch force (-47% +/- 11%) and VA (-11% +/- 6%). During the subsequent sprints, no additional reduction in power output, RMS.Mmax, twitch force or VA, was found. Reduction in between-sprints recovery duration led to a significant reduction in power output and RMS.Mmax but no change in peripheral and central fatigue. CONCLUSION: These findings are consistent with the hypothesis that central motor command and power output during all-out repeated sprints are limited in order to prevent excessive locomotor muscle fatigue. They also demonstrate that both the peripheral and central fatigue contribute significantly to the decline in power output elicited via repeated sprints. PMID- 26496421 TI - Reduction of the Pentavalent Arsenical Dimethylarsinic Acid and the GSTO1 Substrate S-(4-Nitrophenacyl)glutathione by Rat Liver Cytosol: Analyzing the Role of GSTO1 in Arsenic Reduction. AB - Dimethylarsinic acid (DMAs(V)) is the major urinary metabolite of inorganic arsenic. The relatively atoxic DMAs(V) is reduced in the body to the much more toxic and thiol-reactive dimethylarsinous acid (DMAs(III)). Glutathione S transferase omega 1 (GSTO1) can catalyze this toxification step; however, its role in the reduction of DMAs(V) in vivo or by tissue extracts is unclear. Therefore, we assessed the role of GSTO1 in the reduction of DMAs(V) to DMAs(III) by rat liver cytosol. The experiments revealed that glutathione (GSH) supported the cytosolic DMAs(V) reduction specifically and that GSH analogues and GSH conjugates, such as S-alkylglutathiones and S-(4-nitrophenacyl)glutathione (4 NPG; a GSTO1 specific substrate), inhibited the formation of DMAs(III). Observations in line with the view that GSTO1 catalyzes the cytosolic reduction of DMAs(V) include (i) findings pointing to the presence of a GSH-binding site on the DMAs(V)-reducing cytosolic enzyme, (ii) identical responsiveness of the DMAs(V)- and 4-NPG-reducing activities in rat liver cytosol to the GSTO1 specific inhibitors KT53 and chloromethylfluorescein diacetate, and (iii) perfect coelution of the two activities during affinity and anion exchange chromatography of cytosolic proteins. Other observations appear ambiguous as to the role of GSTO1 in the cytosolic reduction of DMAs(V). These include the different sensitivities of the DMAs(V)-reducing and GSTO1 activities to aurothioglucose, trivalent antimony, and zinc ions, as well as the preserved GSTO1 activity in cytosols whose DMAs(V)-reducing activity was lost due to spontaneous thiol oxidation. These disparate findings may be reconciled by assuming that GSTO1 catalyzes the reduction of both DMAs(V) and 4-NPG in rat liver cytosol; however, the enzyme employs different sites and/or mechanisms when reducing these substrates. PMID- 26496422 TI - Printed Multicolor High-Contrast Electrochromic Devices. AB - In this study, electrochemical responses of inkjet-printed multicolored electrochromic devices (ECD) were studied to evaluate the feasibility of presenting multiple colors in one ECD. Metallo-supramolecular polymers (MEPE) solutions with two primary colors were inkjet-printed on flexible electrodes. By digitally controlling print dosages of each species, the colors of the printed EC thin film patterns can be adjusted directly without premixing or synthesizing new materials. The printed EC thin films were then laminated with a solid transparent thin film electrolyte and a transparent conductive thin film to form an ECD. After applying a dc voltage, the printed ECDs exhibited great contrast with a transmittance change (DeltaT) of 40.1% and a high coloration efficiency of 445 cm(2) C(-1) within a short darkening time of 2 s. The flexible ECDs also showed the same darkening time of 2 s and still had a high DeltaT of 30.1% under bending condition. This study demonstrated the feasibility to fabricate display devices with different color setups by an all-solution process and can be further extended to other types of displays. PMID- 26496423 TI - Graphene-Catalyzed Direct Friedel-Crafts Alkylation Reactions: Mechanism, Selectivity, and Synthetic Utility. AB - Transition-metal-catalyzed alkylation reactions of arenes have become a central transformation in organic synthesis. Herein, we report the first general strategy for alkylation of arenes with styrenes and alcohols catalyzed by carbon-based materials, exploiting the unique property of graphenes to produce valuable diarylalkane products in high yields and excellent regioselectivity. The protocol is characterized by a wide substrate scope and excellent functional group tolerance. Notably, this process constitutes the first general application of graphenes to promote direct C-C bond formation utilizing polar functional groups anchored on the GO surface, thus opening the door for an array of functional group alkylations using benign and readily available graphene materials. Mechanistic studies suggest that the reaction proceeds via a tandem catalysis mechanism in which both of the coupling partners are activated by interaction with the GO surface. PMID- 26496424 TI - Permissive beliefs and attitudes about older adult suicide: a suicide enabling script? AB - OBJECTIVES: In the United States, suicide rates are highest among European American older adults. This phenomenon calls attention to cultural factors, specifically, the suicide beliefs and attitudes of European Americans. Beliefs and attitudes matter in the vulnerability to suicide. As predicted by cultural scripts of suicide theory, suicide is most likely among individuals and in communities where it is expected and is most acceptable. This study examined beliefs about the precipitants of, and protectors against older adult suicide, as well as suicide attitudes, in a predominantly European American community. DESIGN AND METHODS: Two hundred and fifty-five older adults (86% European American) and 281 younger adults (81% European American) indicated what they thought were the most likely older adult suicide precipitants and protectors, and their opinion about older adult suicide, depending on precipitant. RESULTS: Health problems were the most endorsed older adult suicide precipitants. Suicide precipitated by health problems was also rated most positively (e.g., rational, courageous). Older adults, persons with more education, and persons who did not identify with a religion expressed the most favorable attitudes about older adult suicide, across suicide precipitants. Men viewed older adult suicide as more admissible, and women, with more sympathy. Perceived suicide protectors included religiosity among older adults, and supportive relationships among younger adults. CONCLUSIONS: The belief, in this study's predominantly European American community, that older adult suicide is triggered by health problems, together with favorable attitudes about older adult suicide, suggest an enabling older adult suicide script, with implications for suicide risk and prevention. PMID- 26496425 TI - A Layered Manganese(IV)-Containing Heteropolyvanadate with a 1:14 Stoichiometry. AB - A novel manganese(IV)-containing symmetrical heteropolyvanadate was prepared by the transformation of K7[MnV13O38].18H2O (K7MnV13) to K4Li2[MnV14O40].21H2O (1) at pH 4. The heteropolyanion [MnV14O40](6-) (MnV14) is composed of a MnO6 octahedron surrounded by 14 edge-sharing VO6 octahedra. The simplified representation of MnV14 has a new topology termed jba1 with a total point symbol of {3(10)}2{3(14).4(7)}4{3(18).4(10)}8{3(44).4(46).5}. In the crystal lattice of 1, MnV14 packs with potassium ions, forming a 2D layered K2[MnV14O40](4-) network (ABABAB...). Four K(+) ions cap the four square O4 faces of MnV14, apparently stabilizing the heteropolyanion. Compound 1 catalyzes the t-BuOOH-based oxidation of 2-chloroethyl ethyl sulfide (a mustard gas simulant). The magnetic and catalytic properties of 1 are discussed. PMID- 26496426 TI - Molecular Analysis of the HOXA2-Dependent Degradation of RCHY1. AB - The homeodomain transcription factor Hoxa2 interacts with the RING-finger type E3 ubiquitin ligase RCHY1 and induces its proteasomal degradation. In this work, we dissected this non-transcriptional activity of Hoxa2 at the molecular level. The Hoxa2-mediated decay of RCHY1 involves both the 19S and 20S proteasome complexes. It relies on both the Hoxa2 homeodomain and C-terminal moiety although no single deletion in the Hoxa2 sequence could disrupt the RCHY1 interaction. That the Hoxa2 homeodomain alone could mediate RCHY1 binding is consistent with the shared ability all the Hox proteins we tested to interact with RCHY1. Nonetheless, the ability to induce RCHY1 degradation although critically relying on the homeodomain is not common to all Hox proteins. This identifies the homeodomain as necessary but not sufficient for what appears to be an almost generic Hox protein activity. Finally we provide evidence that the Hoxa2-induced degradation of RCHY1 is evolutionarily conserved among vertebrates. These data therefore support the hypothesis that the molecular and functional interaction between Hox proteins and RCHY1 is an ancestral Hox property. PMID- 26496427 TI - Curare Alkaloids: Constituents of a Matis Dart Poison. AB - A phytochemical study of dart and arrow poison from the Matis tribe led to the identification of D-(-)-quinic acid, L-malic acid, ethyldimethylamine, magnoflorine, and five new bisbenzyltetrahydroisoquinoline alkaloids (BBIQAs), 1 5. D-Tubocurarine could not be identified among these products. BBIQA (3) contains a unique linkage at C-8 and C-11'. All structures were characterized by a combination of NMR and HRESIMS data. The effects of Matis poison and individual BBIQAs (1-3) on rat muscle nAChR expressed in Xenopus oocytes have been investigated using the two-electrode voltage clamp technique. PMID- 26496428 TI - Night-Time Light Data: A Good Proxy Measure for Economic Activity? AB - Much research has suggested that night-time light (NTL) can be used as a proxy for a number of variables, including urbanization, density, and economic growth. As governments around the world either collect census data infrequently or are scaling back the amount of detail collected, alternate sources of population and economic information like NTL are being considered. But, just how close is the statistical relationship between NTL and economic activity at a fine-grained geographical level? This paper uses a combination of correlation analysis and geographically weighted regressions in order to examine if light can function as a proxy for economic activities at a finer level. We use a fine-grained geo-coded residential and industrial full sample micro-data set for Sweden, and match it with both radiance and saturated light emissions. We find that the correlation between NTL and economic activity is strong enough to make it a relatively good proxy for population and establishment density, but the correlation is weaker in relation to wages. In general, we find a stronger relation between light and density values, than with light and total values. We also find a closer connection between radiance light and economic activity, than with saturated light. Further, we find the link between light and economic activity, especially estimated by wages, to be slightly overestimated in large urban areas and underestimated in rural areas. PMID- 26496429 TI - Influence of molecular size on tissue distribution of antibody fragments. AB - Biodistribution coefficients (BC) allow estimation of the tissue concentrations of proteins based on the plasma pharmacokinetics. We have previously established the BC values for monoclonal antibodies. Here, this concept is extended by development of a relationship between protein size and BC values. The relationship was built by deriving the BC values for various antibody fragments of known molecular weight from published biodistribution studies. We found that there exists a simple exponential relationship between molecular weight and BC values that allows the prediction of tissue distribution of proteins based on molecular weight alone. The relationship was validated by a priori predicting BC values of 4 antibody fragments that were not used in building the relationship. The relationship was also used to derive BC50 values for all the tissues, which is the molecular weight increase that would result in 50% reduction in tissue uptake of a protein. The BC50 values for most tissues were found to be ~35 kDa. An ability to estimate tissue distribution of antibody fragments based on the BC vs. molecular size relationship established here may allow better understanding of the biologics concentrations in tissues responsible for efficacy or toxicity. This relationship can also be applied for rational development of new biotherapeutic modalities with optimal biodistribution properties to target (or avoid) specific tissues. PMID- 26496430 TI - Global Spread of Human Chromoblastomycosis Is Driven by Recombinant Cladophialophora carrionii and Predominantly Clonal Fonsecaea Species. AB - Global distribution patterns of Cladophialophora carrionii, agent of human chromoblastomycosis in arid climates of Africa, Asia, Australia, Central-and South-America, were compared with similar data of the vicarious Fonsecaea spp., agents of the disease in tropical rain forests. Population diversities among 73 C. carrionii strains and 60 strains of three Fonsecaea species were analyzed for rDNA ITS, partial beta-tubulin, and amplified fragment-length polymorphism (AFLP) fingerprints. Populations differed significantly between continents. Lowest haplotype diversity was found in South American populations, while African strains were the most diverse. Gene flow was noted between the African population and all other continents. The general pattern of Fonsecaea agents of chromoblastomycosis differed significantly from that of C. carrionii and revealed deeper divergence among three differentiated species with smaller numbers of haplotypes, indicating a longer evolutionary history. PMID- 26496432 TI - Coping With Client Death: How Prepared Are Home Health Aides and What Characterizes Preparedness? AB - This study explored the experiences of 80 home health aides (HHAs) whose client died within the last 2 months. Data collection involved comprehensive semi structured in-person interviews to try to better understand characteristics of HHAs and their clients associated with preparedness for death. Among those, personal end-of-life (EOL) care preferences of HHAs and having knowledge of preferences and decisions regarding client's EOL care showed significant links to preparedness. Findings suggest that HHAs' preparedness for client death could be enhanced both by addressing their personal views on EOL care and by providing more information about the client's EOL care plans. PMID- 26496433 TI - Use of probiotics in pediatric infectious diseases. AB - We summarize current evidence and recommendations for the use of probiotics in childhood infectious diseases. Probiotics may be of benefit in treating acute infectious diarrhea and reducing antibiotic-associated diarrhea. Potential benefits of probiotic on prevention of traveler's diarrhea,Clostridium difficile associated diarrhea, side effects of triple therapy in Helicobacter pylori eradication, necrotizing enterocolitis, acute diarrhea, acute respiratory infections and recurrent urinary tract infections remain unclear. More studies are needed to investigate optimal strain, dosage, bioavailability of drops and tablets, duration of treatment and safety. Probiotics and recombinant probiotic strain represent a promising source of molecules for the development of novel anti-infectious therapy. PMID- 26496431 TI - A Role for the Chaperone Complex BAG3-HSPB8 in Actin Dynamics, Spindle Orientation and Proper Chromosome Segregation during Mitosis. AB - The co-chaperone BAG3, in complex with the heat shock protein HSPB8, plays a role in protein quality control during mechanical strain. It is part of a multichaperone complex that senses damaged cytoskeletal proteins and orchestrates their seclusion and/or degradation by selective autophagy. Here we describe a novel role for the BAG3-HSPB8 complex in mitosis, a process involving profound changes in cell tension homeostasis. BAG3 is hyperphosphorylated at mitotic entry and localizes to centrosomal regions. BAG3 regulates, in an HSPB8-dependent manner, the timely congression of chromosomes to the metaphase plate by influencing the three-dimensional positioning of the mitotic spindle. Depletion of BAG3 caused defects in cell rounding at metaphase and dramatic blebbing of the cortex associated with abnormal spindle rotations. Similar defects were observed upon silencing of the autophagic receptor p62/SQSTM1 that contributes to BAG3 mediated selective autophagy pathway. Mitotic cells depleted of BAG3, HSPB8 or p62/SQSTM1 exhibited disorganized actin-rich retraction fibres, which are proposed to guide spindle orientation. Proper spindle positioning was rescued in BAG3-depleted cells upon addition of the lectin concanavalin A, which restores cortex rigidity. Together, our findings suggest the existence of a so-far unrecognized quality control mechanism involving BAG3, HSPB8 and p62/SQSTM1 for accurate remodelling of actin-based mitotic structures that guide spindle orientation. PMID- 26496434 TI - Controlled Burning of Forest Detritus Altering Spectroscopic Characteristics and Chlorine Reactivity of Dissolved Organic Matter: Effects of Temperature and Oxygen Availability. AB - Forest fires occur with increasing frequency and severity in the western United States, potentially altering the chemistry and quantity of dissolved organic matter (DOM) and disinfection byproduct (DBP) precursors exported from forested watersheds. However, little is known concerning effects of the fire triangle (heat, oxygen, and fuel) on DOM alteration. Using detritus from Pinus ponderosa and Abies concolor (dominant species in forests in the western United States), we prepared DOM from unburned and burned detritus under hypoxic (pyrolysis) and oxic conditions (thermal oxidation) at 250 and 400 degrees C. DOM characteristics and chlorine reactivity were evaluated by absorption and fluorescence spectroscopy and chlorination-based DBP formation potential tests. Spectroscopic results suggest that burned-detritus extracts had lower molecular weight (reflected by increased E2:E3 and fluorescence index) and divergent aromaticity (reflected by SUVA254) depending on oxygen availability. Temperature and oxygen availability interacted to alter the chlorine reactivity of fire-affected DOM. Increasing temperature from 50 to 400 degrees C resulted in decreased reactivities for trihalomethane and chloral hydrate formation and divergent reactivities for haloacetonitrile formation (unchanged for pyrolysis and increased for oxidation) and haloketone formation (increased for pyrolysis and decreased for oxidation). We demonstrate that DBP precursors in fire-affected forest detritus are highly dependent on temperature and oxygen availability. PMID- 26496435 TI - Getting Bigger, Quicker? Gendered Socioeconomic Trajectories in Body Mass Index across the Adult Lifecourse: A Longitudinal Study of 21,403 Australians. AB - Do socioeconomic inequities in body mass index (BMI) widen across the adult lifecourse? BMI data for 29,104 male and 32,454 female person-years aged 15 years and older (21,403 persons in total) were extracted from the Household, Income and Labour Dynamics in Australia between 2006 and 2012. Multilevel linear regression was used to examine age and gender specific trajectories in BMI by quintiles of neighborhood socioeconomic circumstance. Models were adjusted for probable sources of confounding, including couple status, number of children resident, if somebody in the household had been pregnant in the last 12 months, the highest level of education achieved, the average household gross income, and the percentage of time in the last year spent unemployed. Approximately 9.6% of BMI variation was observed between neighborhoods. High neighborhood disadvantage was associated with 2.09 kg/m2 heavier BMI (95%CI 1.82, 2.36). At age 15-24y, socioeconomic inequity in BMI was already evident among men and women especially (22.6 kg/m2 among women in the most affluent areas compared with 25.4 kg/m2 among the most disadvantaged). Among women only, the socioeconomic gap widened from 2.8 kg/m2 at age 15-24y to 3.2 kg/m2 by age 35-44y. Geographical factors may contribute to more rapid weight gain among women living in disadvantaged neighborhoods. PMID- 26496437 TI - A case of misdiagnosis of mild cognitive impairment: The utility of symptom validity testing in an outpatient memory clinic. AB - Noncredible symptom reports hinder the diagnostic process. This fact is especially the case for medical conditions that rely on subjective report of symptoms instead of objective measures. Mild cognitive impairment (MCI) primarily relies on subjective report, which makes it potentially susceptible to erroneous diagnosis. In this case report, we describe a 59-year-old female patient diagnosed with MCI 10 years previously. The patient was referred to the neurology department for reexamination by her general practitioner because of cognitive complaints and persistent fatigue. This case study used information from the medical file, a new magnetic resonance imaging brain scan, and neuropsychological assessment. Current neuropsychological assessment, including symptom validity tests, clearly indicated noncredible test performance, thereby invalidating the obtained neuropsychological test data. We conclude that a blind spot for noncredible symptom reports existed in the previous diagnostic assessments. This case highlights the usefulness of formal symptom validity testing in the diagnostic assessment of MCI. PMID- 26496436 TI - Effects of the Interactions between Dust Exposure and Genetic Polymorphisms in Nalp3, Caspase-1, and IL-1beta on the Risk of Silicosis: A Case-Control Study. AB - OBJECTIVES: To evaluate the effects of the interactions between polymorphisms in Nalp3, caspase-1, and interleukin(IL)-1beta genes and occupational dust exposure on the risk of silicosis. METHODS: We conducted a population-based case-control study in a large iron mine in China. Between January 2006 and December 2009, we identified 179 patients with silicosis to evaluate as cases and 201 individuals without silicosis to evaluate as controls. We estimated cumulative dust exposure (CDE) for all subjects and we genotyped polymorphisms in Nalp3, caspase-1, and IL 1beta genes. We estimated odds ratios(ORs), 95% confidence intervals(95%CIs), and p-values using logistic regression models adjusted for selected confounders. RESULTS: After adjusting for age, smoking status, and CDE, subjects with the CT genotype of Ex4-849C>T in Nalp3 and the GA genotype of Ex2+37G>A in caspase-1 had increased risks of silicosis (adjusted ORs[95%CIs] = 2.40 [1.12-5.12] and 3.62 [1.63-8.02], respectively). Among subjects younger than 70 years old, those with the CC genotype of IVS8-7652A>C in Nalp3 had a lower risk of silicosis than those with other genotypes (adjusted OR[95%CI] = 0.24[0.06-0.88]). Among subjects aged 70 years and older, those with the CT genotype of Ex4-849C>T in Nalp3 and those with the GA genotype of Ex2+37G>A in caspase-1 had a higher risk of silicosis than those with other genotypes (adjusted ORs [95%CI] = 2.52[1.04-6.12] and 5.19[1.88-14.35], respectively). Among subjects with CDE greater than 120 mg/m3*year and among smokers, those with the GA genotype of Ex2+37G>A in caspase 1 had a higher risk of silicosis than those with other genotypes (adjusted ORs[95%CIs] = 26.37[3.35-207.39] and 3.47[1.40-8.64], respectively). CONCLUSIONS: Genetic polymorphisms in Nalp3 and caspase-1 may be associated with individual susceptibility to silicosis, especially when the polymorphisms interact with age, CDE, or smoking status. PMID- 26496438 TI - Potential Distribution Predicted for Rhynchophorus ferrugineus in China under Different Climate Warming Scenarios. AB - As the primary pest of palm trees, Rhynchophorus ferrugineus (Olivier) (Coleoptera: Curculionidae) has caused serious harm to palms since it first invaded China. The present study used CLIMEX 1.1 to predict the potential distribution of R. ferrugineus in China according to both current climate data (1981-2010) and future climate warming estimates based on simulated climate data for the 2020s (2011-2040) provided by the Tyndall Center for Climate Change Research (TYN SC 2.0). Additionally, the Ecoclimatic Index (EI) values calculated for different climatic conditions (current and future, as simulated by the B2 scenario) were compared. Areas with a suitable climate for R. ferrugineus distribution were located primarily in central China according to the current climate data, with the northern boundary of the distribution reaching to 40.1 degrees N and including Tibet, north Sichuan, central Shaanxi, south Shanxi, and east Hebei. There was little difference in the potential distribution predicted by the four emission scenarios according to future climate warming estimates. The primary prediction under future climate warming models was that, compared with the current climate model, the number of highly favorable habitats would increase significantly and expand into northern China, whereas the number of both favorable and marginally favorable habitats would decrease. Contrast analysis of EI values suggested that climate change and the density of site distribution were the main effectors of the changes in EI values. These results will help to improve control measures, prevent the spread of this pest, and revise the targeted quarantine areas. PMID- 26496439 TI - Human bocavirus in children with acute gastroenteritis in Albania. AB - Human Bocavirus (HBoV) has been recently identified in association with acute viral gastroenteritis (AGE). The objective of this work was to investigate the prevalence of HBoV in children with AGE in Albania. Stool specimens collected from 142 children were analyzed by amplification of partial NP1 and Vp1/Vp2 genes. HBoV was detected in 13 samples (9.1%), 12 HBoV-1 and one HBoV-2. All HBoV positive patients were co-infected with rotavirus and/or adenovirus, a finding which might indicate that there is no clear causal association of this agent with diarrhea. Further investigation is needed to assess the pathogenic role of HBoV in childhood diarrhea. PMID- 26496440 TI - Experience in Prehospital Endotracheal Intubation Significantly Influences Mortality of Patients with Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Patients with severe traumatic brain injury (TBI) are at high risk for airway obstruction and hypoxia at the accident scene, and routine prehospital endotracheal intubation has been widely advocated. However, the effects on outcome are unclear. We therefore aim to determine effects of prehospital intubation on mortality and hypothesize that such effects may depend on the emergency medical service providers' skill and experience in performing this intervention. METHODS AND FINDINGS: PubMed, Embase and Web of Science were searched without restrictions up to July 2015. Studies comparing effects of prehospital intubation versus non-invasive airway management on mortality in non paediatric patients with severe TBI were selected for the systematic review. Results were pooled across a subset of studies that met predefined quality criteria. Random effects meta-analysis, stratified by experience, was used to obtain pooled estimates of the effect of prehospital intubation on mortality. Meta-regression was used to formally assess differences between experience groups. Mortality was the main outcome measure, and odds ratios refer to the odds of mortality in patients undergoing prehospital intubation versus odds of mortality in patients who are not intubated in the field. The study was registered at the International Prospective Register of Systematic Reviews (PROSPERO) with number CRD42014015506. The search provided 733 studies, of which 6 studies including data from 4772 patients met inclusion and quality criteria for the meta-analysis. Prehospital intubation by providers with limited experience was associated with an approximately twofold increase in the odds of mortality (OR 2.33, 95% CI 1.61 to 3.38, p<0.001). In contrast, there was no evidence for higher mortality in patients who were intubated by providers with extended level of training (OR 0.75, 95% CI 0.52 to 1.08, p = 0.126). Meta regression confirmed that experience is a significant predictor of mortality (p = 0.009). CONCLUSIONS: Effects of prehospital endotracheal intubation depend on the experience of prehospital healthcare providers. Intubation by paramedics who are not well skilled to do so markedly increases mortality, suggesting that routine prehospital intubation of TBI patients should be abandoned in emergency medical services in which providers do not have ample training, skill and experience in performing this intervention. PMID- 26496441 TI - Heterogeneity in the Infection Biology of Campylobacter jejuni Isolates in Three Infection Models Reveals an Invasive and Virulent Phenotype in a ST21 Isolate from Poultry. AB - Although Campylobacter is the leading cause of bacterial foodborne gastroenteritis in the world and the importance of poultry as a source of infection is well understood we know relatively little about its infection biology in the broiler chicken. Much of what we know about the biology of Campylobacter jejuni is based on infection of inbred or SPF laboratory lines of chickens with a small number of isolates used in most laboratory studies. Recently we have shown that both the host response and microbial ecology of C. jejuni in the broiler chicken varies with both the host-type and significantly between C. jejuni isolates. Here we describe heterogeneity in infection within a panel of C. jejuni isolates in two broiler chicken breeds, human intestinal epithelial cells and the Galleria insect model of virulence. All C. jejuni isolates colonised the chicken caeca, though colonisation of other parts of the gastrointestinal tract varied between isolates. Extra-intestinal spread to the liver varied between isolates and bird breed but a poultry isolate 13126 (sequence type 21) showed the greatest levels of extra-intestinal spread to the liver in both broiler breeds with over 70% of birds of the fast growing breed and 50% of the slower growing breed having C. jejuni in their livers. Crucially 13126 is significantly more invasive than other isolates in human intestinal epithelial cells and gave the highest mortality in the Galleria infection model. Taken together our findings suggest that not only is there considerable heterogeneity in the infection biology of C. jejuni in avian, mammalian and alternative models, but that some isolates have an invasive and virulent phenotype. Isolates with an invasive phenotype would pose a significant risk and increased difficulty in control in chicken production and coupled with the virulent phenotype seen in 13126 could be an increased risk to public health. PMID- 26496442 TI - Monitoring of the Parasite Load in the Digestive Tract of Rhodnius prolixus by Combined qPCR Analysis and Imaging Techniques Provides New Insights into the Trypanosome Life Cycle. AB - BACKGROUND: Here we report the monitoring of the digestive tract colonization of Rhodnius prolixus by Trypanosoma cruzi using an accurate determination of the parasite load by qPCR coupled with fluorescence and bioluminescence imaging (BLI). These complementary methods revealed critical steps necessary for the parasite population to colonize the insect gut and establish vector infection. METHODOLOGY/PRINCIPAL FINDINGS: qPCR analysis of the parasite load in the insect gut showed several limitations due mainly to the presence of digestive-derived products that are thought to degrade DNA and inhibit further the PCR reaction. We developed a real-time PCR strategy targeting the T. cruzi repetitive satellite DNA sequence using as internal standard for normalization, an exogenous heterologous DNA spiked into insect samples extract, to precisely quantify the parasite load in each segment of the insect gut (anterior midgut, AM, posterior midgut, PM, and hindgut, H). Using combined fluorescence microscopy and BLI imaging as well as qPCR analysis, we showed that during their journey through the insect digestive tract, most of the parasites are lysed in the AM during the first 24 hours independently of the gut microbiota. During this short period, live parasites move through the PM to establish the onset of infection. At days 3 4 post-infection (p.i.), the parasite population begins to colonize the H to reach a climax at day 7 p.i., which is maintained during the next two weeks. Remarkably, the fluctuation of the parasite number in H remains relatively stable over the two weeks after refeeding, while the populations residing in the AM and PM increases slightly and probably constitutes the reservoirs of dividing epimastigotes. CONCLUSIONS/SIGNIFICANCE: These data show that a tuned dynamic control of the population operates in the insect gut to maintain an equilibrium between non-dividing infective trypomastigote forms and dividing epimastigote forms of the parasite, which is crucial for vector competence. PMID- 26496443 TI - A catalogue of novel bovine long noncoding RNA across 18 tissues. AB - Long non-coding RNA (lncRNA) have been implicated in diverse biological roles including gene regulation and genomic imprinting. Identifying lncRNA in bovine across many differing tissue would contribute to the current repertoire of bovine lncRNA, and help further improve our understanding of the evolutionary importance and constraints of these transcripts. Additionally, it could aid in identifying sites in the genome outside of protein coding genes where mutations could contribute to variation in complex traits. This is particularly important in bovine as genomic predictions are increasingly used in genetic improvement for milk and meat production. Our aim was to identify and annotate novel long non coding RNA transcripts in the bovine genome captured from RNA Sequencing (RNA Seq) data across 18 tissues, sampled in triplicate from a single cow. To address the main challenge in identifying lncRNA, namely distinguishing lncRNA transcripts from unannotated genes and protein coding genes, a lncRNA identification pipeline with a number of filtering steps was developed. A total of 9,778 transcripts passed the filtering pipeline. The bovine lncRNA catalogue includes MALAT1 and HOTAIR, both of which have been well described in human and mouse genomes. We attempted to validate the lncRNA in libraries from three additional cows. 726 (87.47%) liver and 1,668 (55.27%) blood class 3 lncRNA were validated with stranded liver and blood libraries respectively. Additionally, this study identified a large number of novel unknown transcripts in the bovine genome with high protein coding potential, illustrating a clear need for better annotations of protein coding genes. PMID- 26496444 TI - Using Incentives to Improve Resource Utilization: A Quasi-Experimental Evaluation of an ICU Quality Improvement Program. AB - OBJECTIVES: Healthcare systems strive to provide quality care at lower cost. Arterial blood gas testing, chest radiographs, and RBC transfusions provide an important example of opportunities to reduce excess resource utilization within the ICU. We describe the effect of a multifaceted quality improvement program designed to decrease the avoidable arterial blood gases, chest radiographs, and RBC utilization on utilization of these resources and patient outcomes. DESIGN: Prospective pre-post cohort study. SETTING: Seven ICUs in an academic healthcare system. PATIENTS: All adult ICU patients admitted to study ICUs during consecutive baseline (n = 7,357), intervention (n = 7,553), and follow-up (n = 7,657) years between September 2010 and August 2013. INTERVENTIONS: A multifaceted quality improvement program including provider education, audit and feedback, and unit-based provider financial incentives targeting arterial blood gas, chest radiograph, and RBC utilization. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the number of orders for arterial blood gases, chest radiographs, and RBCs per patient. Compared with the baseline period, unadjusted arterial blood gas, chest radiograph, and RBC utilization in the intervention period was reduced by 42%, 26%, and 17%, respectively (p < 0.01). After adjusting for potentially relevant patient factors, the intervention was associated with 128 fewer arterial blood gases, 73 fewer chest radiographs, and 16 fewer RBCs per 100 patients (p < 0.01). This effect was durable during the follow-up year. This reduction yielded an approximate net savings of $1.5 M in direct costs over the intervention and follow-up years after accounting for the direct costs of the program. Unadjusted hospital mortality decreased from 7% in the baseline period to 5.2% in the intervention period (p < 0.01). This reduction remained significant after adjusting for patient factors (odds ratio = 0.43; p < 0.01). CONCLUSIONS: Implementation of a multifaceted quality improvement program including financial incentives was associated with significant improvements in resource utilization. Our findings provide evidence supporting the safety, effectiveness, and sustainability of incentive-based quality improvement interventions. PMID- 26496445 TI - Systemic PaO2 Oscillations Cause Mild Brain Injury in a Pig Model. AB - OBJECTIVE: Systemic PaO2 oscillations occur during cyclic recruitment and derecruitment of atelectasis in acute respiratory failure and might harm brain tissue integrity. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Adult anesthetized pigs. INTERVENTIONS: Pigs were randomized to a control group (anesthesia and extracorporeal circulation for 20 hr with constant PaO2, n = 10) or an oscillation group (anesthesia and extracorporeal circulation for 20 hr with artificial PaO2 oscillations [3 cycles min-1], n = 10). Five additional animals served as native group (n = 5). MEASUREMENTS AND MAIN RESULTS: Outcome following exposure to artificial PaO2 oscillations compared with constant PaO2 levels was measured using 1) immunohistochemistry, 2) real-time polymerase chain reaction for inflammatory markers, 3) receptor autoradiography, and 4) transcriptome analysis in the hippocampus. Our study shows that PaO2 oscillations are transmitted to brain tissue as detected by novel ultrarapid oxygen sensing technology. PaO2 oscillations cause significant decrease in NISSL-stained neurons (p < 0.05) and induce inflammation (p < 0.05) in the hippocampus and a shift of the balance of hippocampal neurotransmitter receptor densities toward inhibition (p < 0.05). A pathway analysis suggests that cerebral immune and acute-phase response may play a role in mediating PaO2 oscillation-induced brain injury. CONCLUSIONS: Artificial PaO2 oscillations cause mild brain injury mediated by inflammatory pathways. Although artificial PaO2 oscillations and endogenous PaO2 oscillations in lung-diseased patients have different origins, it is likely that they share the same noxious effect on the brain. Therefore, PaO2 oscillations might represent a newly detected pathway potentially contributing to the crosstalk between acute lung and remote brain injury. PMID- 26496446 TI - Intestine-Derived Matrix Metalloproteinase-8 Is a Critical Mediator of Polymicrobial Peritonitis. AB - OBJECTIVE: Inhibition of matrix metalloproteinase-8 improves survival following cecal ligation and puncture in mice, making it a potential therapeutic target. In the current study, we expand our understanding of the role of matrix metalloproteinase-8 in sepsis by using an adoptive transfer approach and alternative sepsis models. DESIGN: We used three different sepsis models: cecal ligation and puncture, cecal slurry, and intestinal implantation. In our first model, adoptive transfer experiments were followed by cecal ligation and puncture to test the hypothesis that matrix metalloproteinase-8-containing myeloid cells are a critical factor in sepsis following cecal ligation and puncture. Our second model, cecal slurry, used intraperitoneal injections of cecal contents to induce polymicrobial peritonitis without tissue compromise in the recipient. Our third model, intestinal implantation, involved ligating and puncturing a cecum from a donor, and then removing the cecum and placing it into the recipient's peritoneal cavity. Clinically, blood samples were drawn from pediatric patients within 24 hours of meeting criteria for septic shock. SETTING: Basic science laboratory. SUBJECTS: Wild type and genetically modified mice. INTERVENTIONS: Experimental models of sepsis. MEASUREMENTS AND MAIN RESULTS: In our adoptive transfer experiments, matrix metalloproteinase-8 null mice receiving wild-type marrow had a survival advantage when compared with wild-type mice receiving matrix metalloproteinase-8 null marrow, suggesting that matrix metalloproteinase-8 containing myeloid cells are not a critical factor in sepsis following cecal ligation and puncture. In our cecal slurry model, no survival advantage was seen among matrix metalloproteinase-8 null mice. Our third model, intestinal implantation, found that mice receiving matrix metalloproteinase-8 null intestine had a survival advantage when compared with mice receiving wild-type intestine, regardless of recipient genotype. Clinically, median matrix metalloproteinase-8 serum concentrations were higher in patients with sepsis and primary intestinal pathology than in septic patients without primary intestinal pathology. CONCLUSIONS: Intestine-derived matrix metalloproteinase-8 is a critical component of septic peritonitis secondary to intestinal compromise. PMID- 26496447 TI - Changes in Therapeutic Hypothermia and Coronary Intervention Provision and In Hospital Mortality of Patients With Out-of-Hospital Cardiac Arrest: A Nationwide Database Study. AB - OBJECTIVES: To evaluate the change in provision of therapeutic hypothermia and coronary intervention (postresuscitation care) over time and to clarify the association between these provisions and in-hospital mortality in patients with out-of-hospital cardiac arrest. DESIGN: A nationwide retrospective cohort study using multiple propensity score analyses. SETTING: Japanese Diagnosis Procedure Combination inpatient database. PATIENTS: Adult patients with cardiogenic out-of hospital cardiac arrest related to ventricular fibrillation were identified from July to December in 2008-2012 (385 hospitals; n = 3,413). MEASUREMENTS AND MAIN RESULTS: We evaluated the proportion of patients receiving postresuscitation care and all-cause mortality at 30 days after out-of-hospital cardiac arrest. The proportion of postresuscitation care provision increased significantly over the study period (Mantel-Haenszel trend test, p < 0.001). The overall 30-day mortality was 52.0% (1,774/3,413), and the crude 30-day mortality decreased significantly during the study period (p = 0.006). Logistic regression analysis showed significant associations between the fiscal years 2011 and 2012 and 30-day mortality (2011: odds ratio, 0.75; 95% CI, 0.57-0.98 and 2012: odds ratio, 0.61; 95% CI, 0.47-0.81). Multiple propensity score analysis incorporating postresuscitation care showed that 30-day mortality was significantly associated with postresuscitation care, and the significant associations between 30-day mortality and the years 2011 and 2012 were no longer observed (2011: odds ratio, 1.05; 95% CI, 0.82-1.3 and 2012: odds ratio, 0.95; 95% CI, 0.74-1.2). CONCLUSIONS: The 30-day survival rate of adult patients with cardiogenic out-of hospital cardiac arrest related to ventricular fibrillation improved significantly after 2010 in Japan. This improvement may be associated with an increase in postresuscitation care provision. PMID- 26496448 TI - Duration of Antimicrobial Treatment for Bacteremia in Canadian Critically Ill Patients. AB - OBJECTIVES: The optimum duration of antimicrobial treatment for patients with bacteremia is unknown. Our objectives were to determine duration of antimicrobial treatment provided to patients who have bacteremia in ICUs, to assess pathogen/patient factors related to treatment duration, and to assess the relationship between treatment duration and survival. DESIGN: Retrospective cohort study. SETTINGS: Fourteen ICUs across Canada. PATIENTS: Patients with bacteremia and were present in the ICU at the time culture reported positive. INTERVENTIONS: Duration of antimicrobial treatment for patients who had bacteremia in ICU. MEASUREMENTS AND MAIN RESULTS: Among 1,202 ICU patients with bacteremia, the median duration of treatment was 14 days, but with wide variability (interquartile range, 9-17.5). Most patient characteristics were not associated with treatment duration. Coagulase-negative staphylococci were the only pathogens associated with shorter treatment (odds ratio, 2.82; 95% CI, 1.51 5.26). The urinary tract was the only source of infection associated with a trend toward lower likelihood of shorter treatment (odds ratio, 0.67; 95% CI, 0.42 1.08); an unknown source of infection was associated with a greater likelihood of shorter treatment (odds ratio, 2.14; 95% CI, 1.17-3.91). The association of treatment duration and survival was unstable when analyzed based on timing of death. CONCLUSIONS: Critically ill patients who have bacteremia typically receive long courses of antimicrobials. Most patient/pathogen characteristics are not associated with treatment duration; survivor bias precludes a valid assessment of the association between treatment duration and survival. A definitive randomized controlled trial is needed to compare shorter versus longer antimicrobial treatment in patients who have bacteremia. PMID- 26496449 TI - Cerebral Effect of Intratracheal Aerosolized Surfactant Versus Bolus Therapy in Preterm Lambs. AB - OBJECTIVE: Aerosolization has been proposed as a useful alternative to rapid intratracheal instillation for the delivery of exogenous surfactant in neonatal respiratory distress syndrome. However, there is a lack of information regarding the likely safety of this new therapeutic approach for the neonatal brain. We aimed to compare the cerebral effects of aerosolized versus bolus surfactant administration in premature lambs with respiratory distress syndrome. DESIGN: Prospective randomized study. SETTING: BioCruces Institute Animal Research Facility. SUBJECTS: Fourteen intensively monitored and mechanically ventilated preterm lambs. INTERVENTIONS: Preterm lambs were randomly assigned to receive intratracheal aerosolized surfactant or bolus surfactant. Brain hemodynamics (cerebral and regional cerebral blood flow) and cerebral oxygen metabolism (cerebral oxygen delivery, cerebral metabolic rate of oxygen, and oxygen extraction fraction) were measured every 30 minutes for 6 hours. We also performed cerebral biochemical and histological analysis. MEASUREMENTS AND MAIN RESULTS: In preterm lambs with respiratory distress syndrome, cerebral blood flow, regional cerebral blood flow, cerebral oxygen delivery, and cerebral metabolic rate of oxygen increased significantly in the bolus surfactant group during the first 5 minutes, without changes in cerebral oxygen extraction fraction. By 60 minutes, all parameters had decreased in both groups, cerebral blood flow and regional cerebral blood flow (in inner and cerebellum brainstem regions) remaining higher in the bolus surfactant than in the aerosolized surfactant group. Overall, the impact of aerosol surfactant was not significantly different to that of bolus surfactant in terms of cerebral necrosis, edema, inflammation, hemorrhage, infarct, apoptosis, or oxidative stress. CONCLUSIONS: In preterm lambs with severe respiratory distress syndrome, aerosol surfactant administration seems to be as safe as bolus administration, showing more stable cerebral hemodynamics and cerebral oxygen metabolism to the same dose of surfactant administered as a standard bolus. PMID- 26496450 TI - Palliative Care Utilization in Nontraumatic Intracerebral Hemorrhage in the United States. AB - OBJECTIVES: Palliative care is now recognized as an essential component of comprehensive care in serious illness that interferes with quality of life. We explored utilization of palliative care in spontaneous intracerebral hemorrhage at a population level using a large national database. DESIGN: Population based cross-sectional study. SETTING: Inpatient hospital admissions from the Nationwide Inpatient Sample. PATIENTS: A total of 311,217 patients with intracerebral hemorrhage. INTERVENTIONS: Palliative care use. MEASUREMENTS AND MAIN RESULTS: Intracerebral hemorrhage patients with and without palliative care were identified from the 2007-2011 Nationwide Inpatient Sample using International Classification of Diseases, 9th Revision, codes. Demographics, comorbidities, surgical procedures, and hospital characteristics were compared between patients receiving and not receiving palliative care (code V66.7). Resource utilization measures were inflation-adjusted cost of care and length of stay. Pearson chi square and Wilcoxon-Mann-Whitney tests were used for categorical and continuous variables respectively. Logistic regression was used to construct a predictive model of palliative care. Of the 311,217 intracerebral hemorrhage patients, 32,159 (10.3%) received palliative care. Utilization of palliative care increased from 4.3% in 2007 to 16.2% in 2011 (trend p < 0.001). Patients receiving palliative care had higher Charlson comorbidity scores (p < 0.001), higher all patient refined diagnosis-related group mortality risk (p < 0.001), and lower resource utilization measures compared with those without palliative care. Independent predictors of palliative care use were older age (odds ratio, 4.06; 95% CI, 3.87-4.23; p < 0.001), female sex (odds ratio, 1.17; 95% CI, 1.14-1.20; p < 0.001), Caucasian race (p < 0.001), Medicare insurance (p < 0.001), hospitals in the west and mid-west (p < 0.001), hospital transfer (odds ratio, 1.23; 95% CI, 1.18-1.30; p < 0.001), high intracerebral hemorrhage case volume (p < 0.001), anticoagulant use (odds ratio, 1.24; 95% CI, 1.19-1.31; p < 0.001), higher Charlson comorbidity score, ventriculostomy placement (odds ratio, 1.18; 95% CI, 1.13-1.29; p < 0.001), and mechanical ventilation (odds ratio, 1.44; 95% CI, 1.39 1.49; p < 0.001). Cerebral angiogram, craniotomy, and gastrostomy were independently associated with absence of palliative care use. CONCLUSIONS: An apparent increasing trend of palliative care utilization in intracerebral hemorrhage has occurred over the last decade. After clinical severity adjustment, gender and racial differences and hospital characteristics appear to influence palliative care use among intracerebral hemorrhage patients in the United States. PMID- 26496451 TI - A Selective V(1A) Receptor Agonist, Selepressin, Is Superior to Arginine Vasopressin and to Norepinephrine in Ovine Septic Shock. AB - OBJECTIVE: Selective vasopressin V(1A) receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V(1A) receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model. DESIGN: Randomized animal study. SETTING: University hospital animal research laboratory. SUBJECTS: Forty-six adult female sheep. INTERVENTIONS: Fecal peritonitis was induced in the anesthetized, mechanically ventilated, fluid resuscitated sheep, and they were randomized in two successive phases. Three late intervention groups (each n = 6) received IV selepressin (1 pmol/kg/min), arginine vasopressin (0.25 pmol [0.1 mU]/kg/min), or norepinephrine (3 nmol [0.5 MUg]/kg/min) when mean arterial pressure remained less than 70 mm Hg despite fluid challenge; study drugs were thereafter titrated to keep mean arterial pressure at 70-80 mm Hg. Three early-intervention groups (each n = 7) received selepressin, arginine vasopressin, or norepinephrine at the same initial infusion rates as for the late intervention, but already when mean arterial pressure had decreased by 10% from baseline; doses were then titrated as for the late intervention. A control group (n = 7) received saline. All animals were observed until death or for a maximum of 30 hours. MEASUREMENTS AND MAIN RESULTS: In addition to hemodynamic and organ function assessment, plasma interleukin-6 and nitrite/nitrate levels were measured. In the late-intervention groups, selepressin delayed the decrease in mean arterial pressure and was associated with lower lung wet/dry weight ratios than in the other two groups. In the early intervention groups, selepressin maintained mean arterial pressure and cardiac index better than arginine vasopressin or norepinephrine, slowed the increase in blood lactate levels, and was associated with less lung edema, lower cumulative fluid balance, and lower interleukin-6 and nitrite/nitrate levels. Selepressin treated animals survived longer than the other animals. CONCLUSIONS: In this clinically relevant model, selepressin, a selective V(1A) receptor agonist, was superior to arginine vasopressin and to norepinephrine in the treatment of septic shock, especially when administered early. PMID- 26496452 TI - A Severe Sepsis Mortality Prediction Model and Score for Use With Administrative Data. AB - OBJECTIVE: Administrative data are used for research, quality improvement, and health policy in severe sepsis. However, there is not a sepsis-specific tool applicable to administrative data with which to adjust for illness severity. Our objective was to develop, internally validate, and externally validate a severe sepsis mortality prediction model and associated mortality prediction score. DESIGN: Retrospective cohort study using 2012 administrative data from five U.S. states. Three cohorts of patients with severe sepsis were created: 1) International Classification of Diseases, 9th Revision, Clinical Modification codes for severe sepsis/septic shock, 2) Martin approach, and 3) Angus approach. The model was developed and internally validated in International Classification of Diseases, 9th Revision, Clinical Modification, cohort and externally validated in other cohorts. Integer point values for each predictor variable were generated to create a sepsis severity score. SETTING: Acute care, nonfederal hospitals in New York, Maryland, Florida, Michigan, and Washington. SUBJECTS: Patients in one of three severe sepsis cohorts: 1) explicitly coded (n = 108,448), 2) Martin cohort (n = 139,094), and 3) Angus cohort (n = 523,637) INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Maximum likelihood estimation logistic regression to develop a predictive model for in-hospital mortality. Model calibration and discrimination assessed via Hosmer-Lemeshow goodness-of-fit and C-statistics, respectively. Primary cohort subset into risk deciles and observed versus predicted mortality plotted. Goodness-of-fit demonstrated p value of more than 0.05 for each cohort demonstrating sound calibration. C-statistic ranged from low of 0.709 (sepsis severity score) to high of 0.838 (Angus cohort), suggesting good to excellent model discrimination. Comparison of observed versus expected mortality was robust although accuracy decreased in highest risk decile. CONCLUSIONS: Our sepsis severity model and score is a tool that provides reliable risk adjustment for administrative data. PMID- 26496453 TI - Obesity, Acute Kidney Injury, and Mortality in Critical Illness. AB - OBJECTIVES: Although obesity is associated with risk for chronic kidney disease and improved survival, less is known about the associations of obesity with risk of acute kidney injury and post acute kidney injury mortality. DESIGN: In a single-center inception cohort of almost 15,000 critically ill patients, we evaluated the association of obesity with acute kidney injury and acute kidney injury severity, as well as in-hospital and 1-year survival. Acute kidney injury was defined using the Kidney Disease Outcome Quality Initiative criteria. MEASUREMENTS AND MAIN RESULTS: The acute kidney injury prevalence rates for normal, overweight, class I, II, and III obesity were 18.6%, 20.6%, 22.5%, 24.3%, and 24.0%, respectively, and the adjusted odds ratios of acute kidney injury were 1.18 (95% CI, 1.06-1.31), 1.35 (1.19-1.53), 1.47 (1.25-1.73), and 1.59 (1.31 1.87) when compared with normal weight, respectively. Each 5-kg/m2 increase in body mass index was associated with a 10% risk (95% CI, 1.06-1.24; p < 0.001) of more severe acute kidney injury. Within-hospital and 1-year survival rates associated with the acute kidney injury episodes were similar across body mass index categories. CONCLUSION: Obesity is a risk factor for acute kidney injury, which is associated with increased short- and long-term mortality. PMID- 26496455 TI - Organ System Network Disruption in Nonsurvivors of Critically Ill Patients. AB - OBJECTIVES: As interactions of each organ system have been conceptually known to play an important role during life-threatening conditions, we quantitatively evaluated the organ system interactions in critically ill patients and examined the difference in the organ system network structure between the survivors and the nonsurvivors. DESIGN: Prospective observational study. SETTINGS: An ICU of a university hospital. PATIENTS: Two hundred and eighty-two patients who were admitted to the ICU. INTERVENTIONS: Blood samples were obtained at ICU admission. MEASUREMENTS AND MAIN RESULTS: We analyzed the associations among nine representative laboratory variables of each organ system using network analysis. We compared the network structure of the variables in the 40 nonsurvivors with that in the 40 survivors. Their baseline characteristics, including the degree of organ dysfunction, were matched using propensity score matching method. Network structure was quantitatively evaluated using edge (significant correlation among variables evaluated by the p value), weight (connective strength of edge evaluated by coefficient), and cluster (group with tight connection evaluated by edge betweenness). The number of edges among the nine variables was significantly fewer for the nonsurvivors than for the severity-matched survivors (3 vs 12; p = 0.035). The mean weight of edges was significantly smaller for the nonsurvivors (0.055 vs 0.119; p = 0.007). The nine laboratory variables for the nonsurvivors were divided into a significantly larger number of clusters (7 vs 2; p = 0.001). Statistical conclusions were preserved with Bonferroni multiple comparison procedure. These findings were consistently observed in comparison of the 40 nonsurvivors with all the survivors. CONCLUSIONS: This study, as a preliminary proof-of-concept, quantitatively demonstrated a more disrupted network structure of organ systems in the nonsurvivors compared with that in the survivors. These observations suggest the necessity of assessment for organ system interactions to evaluate critically ill patients. PMID- 26496454 TI - Remote Ischemic Preconditioning and Protection of the Kidney--A Novel Therapeutic Option. AB - OBJECTIVE: Acute kidney injury is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis, major surgery, and nephrotoxic drugs are the most common causes of acute kidney injury. There is currently no effective strategy available to prevent or treat acute kidney injury. Therefore, novel treatment regimens are required to decrease acute kidney injury prevalence and to improve clinical outcomes. Remote ischemic preconditioning, triggered by brief episodes of ischemia and reperfusion applied in distant tissues or organs before the injury of the target organ, attempts to invoke adaptive responses that protect against acute kidney injury. We sought to evaluate the clinical evidence for remote ischemic preconditioning as a potential strategy to protect the kidney and to review the underlying mechanisms in light of recent studies. DATA SOURCES: We searched PubMed for studies reporting the effect of remote ischemic preconditioning on kidney function in surgical patients (search terms: "remote ischemic preconditioning," "kidney function," and "surgery"). We also reviewed bibliographies of relevant articles to identify additional citations. STUDY SELECTION: Published studies, consisting of randomized controlled trials, are reviewed. DATA EXTRACTION: The authors used consensus to summarize the evidence behind the use of remote ischemic preconditioning. DATA SYNTHESIS: In addition, the authors suggest patient populations and clinical scenarios in which remote ischemic preconditioning might be best applied. CONCLUSIONS: Several experimental and clinical studies have shown tissue-protective effects of remote ischemic preconditioning in various target organs, including the kidneys. Remote ischemic preconditioning may offer a novel, noninvasive, and inexpensive treatment strategy for decreasing acute kidney injury prevalence in high-risk patients. Although many new studies have further advanced our knowledge in this area, the appropriate intensity of remote ischemic preconditioning, its mechanisms of action, and the role of biomarkers for patient selection and monitoring are still unknown. PMID- 26496456 TI - Polymeric scaffolds in tissue engineering: a literature review. AB - The tissue engineering scaffold acts as an extracellular matrix that interacts to the cells prior to forming new tissues. The chemical and structural characteristics of scaffolds are major concerns in fabricating of ideal three dimensional structure for tissue engineering applications. The polymer scaffolds used for tissue engineering should possess proper architecture and mechanical properties in addition to supporting cell adhesion, proliferation, and differentiation. Much research has been done on the topic of polymeric scaffold properties such as surface topographic features (roughness and hydrophilicity) and scaffold microstructures (pore size, porosity, pore interconnectivity, and pore and fiber architectures) that influence the cell-scaffold interactions. In this review, efforts were given to evaluate the effect of both chemical and structural characteristics of scaffolds on cell behaviors such as adhesion, proliferation, migration, and differentiation. This review would provide the fundamental information which would be beneficial for scaffold design in future. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 431-459, 2017. PMID- 26496458 TI - Stress-related exhaustion disorder--clinical manifestation of burnout? A review of assessment methods, sleep impairments, cognitive disturbances, and neuro biological and physiological changes in clinical burnout. AB - The aim of this paper was to provide an overview of the literature on clinically significant burnout, focusing on its assessment, associations with sleep disturbances, cognitive impairments, as well as neurobiological and physiological correlates. Fifty-nine English language articles and six book chapters were included. The results indicate that exhaustion disorder (ED), as described in the Swedish version of the International Classification of Diseases, seems to be the most valid clinical equivalent of burnout. The data supports the notion that sleep impairments are causative and maintaining factors for this condition. Patients with clinical burnout/ED suffer from cognitive impairments in the areas of memory and executive functioning. The studies on neuro-biological mechanisms have reported functional uncoupling of networks relating the limbic system to the pre-frontal cortex, and decreased volumes of structures within the basal ganglia. Although there is a growing body of literature on the physiological correlates of clinical burnout/ED, there is to date no biomarker for this condition. More studies on the role of sleep disturbances, cognitive impairments, and neurobiological and physiological correlates in clinical burnout/ED are warranted. PMID- 26496457 TI - The Invariance Hypothesis Implies Domain-Specific Regions in Visual Cortex. AB - Is visual cortex made up of general-purpose information processing machinery, or does it consist of a collection of specialized modules? If prior knowledge, acquired from learning a set of objects is only transferable to new objects that share properties with the old, then the recognition system's optimal organization must be one containing specialized modules for different object classes. Our analysis starts from a premise we call the invariance hypothesis: that the computational goal of the ventral stream is to compute an invariant-to transformations and discriminative signature for recognition. The key condition enabling approximate transfer of invariance without sacrificing discriminability turns out to be that the learned and novel objects transform similarly. This implies that the optimal recognition system must contain subsystems trained only with data from similarly-transforming objects and suggests a novel interpretation of domain-specific regions like the fusiform face area (FFA). Furthermore, we can define an index of transformation-compatibility, computable from videos, that can be combined with information about the statistics of natural vision to yield predictions for which object categories ought to have domain-specific regions in agreement with the available data. The result is a unifying account linking the large literature on view-based recognition with the wealth of experimental evidence concerning domain-specific regions. PMID- 26496459 TI - Optimizing hereditary angioedema management through tailored treatment approaches. AB - Hereditary angioedema (HAE) is a rare but serious and potentially life threatening autosomal dominant condition caused by low or dysfunctional C1 esterase inhibitor (C1-INH) or uncontrolled contact pathway activation. Symptoms are characterized by spontaneous, recurrent attacks of subcutaneous or submucosal swellings typically involving the face, tongue, larynx, extremities, genitalia or bowel. The prevalence of HAE is estimated to be 1:50,000 without known racial differences. It causes psychological stress as well as significant socioeconomic burden. Early treatment and prevention of attacks are associated with better patient outcome and lower socioeconomic burden. New treatments and a better evidence base for management are emerging which, together with a move from hospital-centered to patient-centered care, will enable individualized, tailored treatment approaches. PMID- 26496460 TI - Coordinated Dynamics of RNA Splicing Speckles in the Nucleus. AB - Despite being densely packed with chromatin, nuclear bodies and a nucleoskeletal network, the nucleus is a remarkably dynamic organelle. Chromatin loops form and relax, RNA transcripts and transcription factors move diffusively, and nuclear bodies move. We show here that RNA splicing speckled domains (splicing speckles) fluctuate in constrained nuclear volumes and remodel their shapes. Small speckles move in a directed way toward larger speckles with which they fuse. This directed movement is reduced upon decreasing cellular ATP levels or inhibiting RNA polymerase II activity. The random movement of speckles is reduced upon decreasing cellular ATP levels, moderately reduced after inhibition of SWI/SNF chromatin remodeling and modestly increased upon inhibiting RNA polymerase II activity. To define the paths through which speckles can translocate in the nucleus, we generated a pressure gradient to create flows in the nucleus. In response to the pressure gradient, speckles moved along curvilinear paths in the nucleus. Collectively, our results demonstrate a new type of ATP-dependent motion in the nucleus. We present a model where recycling splicing factors return as part of small sub-speckles from distal sites of RNA processing to larger splicing speckles by a directed ATP-driven mechanism through interchromatin spaces. PMID- 26496461 TI - Reference set for performance testing of pediatric vaccine safety signal detection methods and systems. AB - BACKGROUND: Safety signal detection in spontaneous reporting system databases and electronic healthcare records is key to detection of previously unknown adverse events following immunization. Various statistical methods for signal detection in these different datasources have been developed, however none are geared to the pediatric population and none specifically to vaccines. A reference set comprising pediatric vaccine-adverse event pairs is required for reliable performance testing of statistical methods within and across data sources. METHODS: The study was conducted within the context of the Global Research in Paediatrics (GRiP) project, as part of the seventh framework programme (FP7) of the European Commission. Criteria for the selection of vaccines considered in the reference set were routine and global use in the pediatric population. Adverse events were primarily selected based on importance. Outcome based systematic literature searches were performed for all identified vaccine-adverse event pairs and complemented by expert committee reports, evidence based decision support systems (e.g. Micromedex), and summaries of product characteristics. Classification into positive (PC) and negative control (NC) pairs was performed by two independent reviewers according to a pre-defined algorithm and discussed for consensus in case of disagreement. RESULTS: We selected 13 vaccines and 14 adverse events to be included in the reference set. From a total of 182 vaccine adverse event pairs, we classified 18 as PC, 113 as NC and 51 as unclassifiable. Most classifications (91) were based on literature review, 45 were based on expert committee reports, and for 46 vaccine-adverse event pairs, an underlying pathomechanism was not plausible classifying the association as NC. CONCLUSION: A reference set of vaccine-adverse event pairs was developed. We propose its use for comparing signal detection methods and systems in the pediatric population. PMID- 26496462 TI - Pathogenic T helper type 17 cells contribute to type 1 diabetes independently of interleukin-22. AB - We have shown that pathogenic T helper type 17 (Th17) cells differentiated from naive CD4(+) T cells of BDC2.5 T cell receptor transgenic non-obese diabetic (NOD) mice by interleukin (IL)-23 plus IL-6 produce IL-17, IL-22 and induce type 1 diabetes (T1D). Neutralizing interferon (IFN)-gamma during the polarization process leads to a significant increase in IL-22 production by these Th17 cells. We also isolated IL-22-producing Th17 cells from the pancreas of wild-type diabetic NOD mice. IL-27 also blocked IL-22 production from diabetogenic Th17 cells. To determine the functional role of IL-22 produced by pathogenic Th17 cells in T1D we neutralized IL-22 in vivo by using anti-IL-22 monoclonal antibody. We found that blocking IL-22 did not alter significantly adoptive transfer of disease by pathogenic Th17 cells. Therefore, IL-22 is not required for T1D pathogenesis. The IL-22Ralpha receptor for IL-22 however, increased in the pancreas of NOD mice during disease progression and based upon our and other studies we suggest that IL-22 may have a regenerative and protective role in the pancreatic islets. PMID- 26496463 TI - Carboplatin and Etoposide in Heavily Pretreated Patients with Progressive High Grade Glioma. AB - BACKGROUND: Treatment of recurrent anaplastic glioma and glioblastoma remains a particular challenge in neurooncology. The lack of controlled trials results in poor evidence for all therapeutic options. Upon recurrence, many patients are treated with bevacizumab or one of the frequently used nitrosoureas such as lomustine. However, patients who still present in overall good condition after failure of multiple lines of therapy may ask for additional therapy. METHODS: Here, we report our experience with the use of carboplatin in combination with etoposide as fourth- or fifth-line therapy in patients with progressive high grade glioma. RESULTS: The median Karnofsky performance status at the beginning of treatment was 80%. The median progression-free survival (PFS) was 2.5 months. PFS at 6 months was 0%. Administration of carboplatin and etoposide was associated with grade 3 or 4 hematotoxicity in 8 of 12 patients. CONCLUSION: Carboplatin in combination with etoposide has an unfavorable risk-benefit profile in heavily pretreated glioma patients. PMID- 26496464 TI - Wax Lining in an Impression Tray and Accuracy in Gypsum Cast Fabrication. AB - PURPOSE: Controversy exists as to whether lining a metal-perforated impression tray with wax will yield a distorted irreversible hydrocolloid impression. Two current textbooks have completely different recommendations, but there is no evidence to support either theory. This project evaluates distortion in gypsum casts that have been prepared from wax-lined and unlined metal impression trays. The purpose of this study was to assess the influence of wax on the border and in the palate of metal-perforated impression trays on the dimensional stability of the resulting irreversible hydrocolloid impression. MATERIALS AND METHODS: A dentaform was prepared with marks on the cusp tips of teeth 6 and 11 and distobuccal cusps of teeth 2 and 15. Using a standard maxillary rim lock impression tray, alginate impressions were made using a dentaform with no wax lining, wax lining the border of the tray, and wax lining the border and the palate (n = 10). Casts were randomized. Six measurements were taken using a stereographic measuring microscope, from tooth #6 to #11, #11 to #15, #15 to #2, #2 to #6, #6 to #15, and #2 to #11. An acrylic template was used to position the cast in a reproducible position on the microscope. RESULTS: Trays lined with wax on the border and the palate yielded casts with significantly different dimensions when compared to those poured from unlined or border-lined trays (p < 0.05). Casts produced from unlined and border-lined trays were not significantly different in dimension from the dentaform (p > 0.05). CONCLUSION: There is no difference between the metal tray with no wax, the metal tray with a wax around the border, and the dentaform. The clinician can make irreversible hydrocolloid impressions using wax on the periphery or without wax on the periphery and feel confident that the impression has not been compromised in its ability to accurately reproduce the maxillary arch when used. Caution should be exercised when adding wax to the palate of the impression tray. PMID- 26496465 TI - New melatonin-cinnamate hybrids as multi-target drugs for neurodegenerative diseases: Nrf2-induction, antioxidant effect and neuroprotection. AB - BACKGROUND: Neurodegenerative diseases share many pathological pathways, such as abnormal protein aggregation, mitochondrial dysfunction, extensive oxidative stress and neuroinflammation. Cells have an intrinsic mechanism of protection, the Nrf2 transcriptional factor, known as the master regulator of redox homeostasis. RESULTS: Based on the common features of these diseases we have designed a multi-target hybrid structure derived from melatonin and ethyl cinnamate. The obtained derivatives were Nrf2 inducers and potent-free radical scavengers. These new compounds showed a very interesting neuroprotective profile in several in vitro models of oxidative stress, Alzheimer's disease and brain ischemia. CONCLUSION: We have designed a new hybrid structure with complementary activities. We have identified compound 5h as an interesting Nrf2 inducer, very potent antioxidant and neuroprotectant. PMID- 26496466 TI - Reply: To PMID 26496468. PMID- 26496467 TI - Validation of a Serum Biomarker for Irritable Bowel Syndrome: Is an Accurate, Single Biomarker Test Possible? PMID- 26496468 TI - Getting a NOTCH-up on Macrophage Activation in Alcoholic Liver Disease. PMID- 26496469 TI - Time-Resolved Twisting Dynamics in a Porphyrin Dimer Characterized by Two Dimensional Electronic Spectroscopy. AB - Molecular conformational changes in electronic excited states play a key role in numerous light-activated processes. In the case of porphyrin oligomers intramolecular twisting influences energy and charge transport dynamics. Here we address the twisting reaction in both ground and excited states in a model porphyrin dimer, employing two-dimensional electronic spectroscopy (2D ES). By spreading the information over excitation and detection frequencies, cross-peaks reveal the twisting reaction in both the ground and excited states unambiguously and distinctly from other dynamics. A quasi-barrierless planarization reaction is observed in the excited state on a tens of picoseconds time scale. This is accompanied by a spectral narrowing, indicative of a reduction in conformational disorder. The reverse reaction is suppressed in the excited state due to a steep activation energy barrier. However, in the ground state the barrier is within the thermal energy distribution, and therefore contributions from reverse and forward reactions could be observed on the subnanosecond time scale. Crucially 2D ES enables simultaneous assessment of ground and excited state reactions through analysis of different spectral regions on the 2D spectral maps. PMID- 26496470 TI - Effect of Surface Adsorption on Temporal and Spatial Broadening in Micro Free Flow Electrophoresis. AB - Analyte adsorption onto surfaces presents a challenge for many separations, often becoming a significant source of peak broadening and asymmetry. We have shown that surface adsorption has no effect on peak position or spatial broadening in micro free flow electrophoresis (MUFFE) separations. Surface adsorption does affect the time it takes an analyte to travel through the MUFFE separation channel and therefore contributes to temporal broadening. These results were confirmed using MUFFE separations of fluorescein, rhodamine 110, and rhodamine 123 in a low ionic strength buffer to promote surface adsorption. Peak widths and asymmetries were measured in both the temporal and spatial dimensions. Under these conditions rhodamine 123 exhibited significant interactions with the separation channel surface, causing increased peak broadening and asymmetry in the temporal dimension. Broadening or asymmetry in the spatial dimension was not significantly different than that of fluorescein, which did not interact with the capillary surface. The effect of strong surface interactions was assessed using MUFFE separations of Chromeo P503 labeled myoglobin and cytochrome c. Myoglobin and cytochrome c were well resolved and gave rise to symmetrical peaks in the spatial dimension even under conditions where permanent adsorption onto the separation channel surface occurred. PMID- 26496471 TI - Subcapsular Hematoma Causing Anuria After Renal Graft Trauma. AB - A 67-year-old man presented to the emergency department 22 hours after a trauma to his kidney graft. He was asymptomatic during the first 10 hours, then he became anuric. His serum creatinine level was 2.73 mg/dL (baseline, 0.7 mg/dL), and his hemoglobin concentration was 13.1 g/dL. Computer tomography showed a 4-cm subcapsular hematoma without active bleeding. He underwent urgent decompression of the hematoma, and we did not find any active bleeding or parenchymal laceration. Urinary output had already recovered by the end of surgery without early or late complications. In conclusion, subcapsular hematoma, complicating a traumatic event on a kidney graft, can lead to a progressive parenchymal compression resulting in anuria. So, although in the absence of anemia, such events require urgent surgical decompression. Symptoms cannot be immediate, so all the graft trauma should be investigated with early ultrasound. Little is known in the case of major renal trauma but mildly symptomatic. Probably surgical exploration is better than observation to prevent possible early and late complications such as organ rejection or a Page kidney. PMID- 26496472 TI - Efficient bacteria capture and inactivation by cetyltrimethylammonium bromide modified magnetic nanoparticles. AB - Functionalized magnetic nanoparticles have shown great application potentials in water treatment processes especially for bacterial removal. Antibacterial agent, cetyltrimethylammonium bromide (CTAB), was employed to modify Fe3O4 nanoparticles to fabricate bactericidal paramagnetic nanoparticles (Fe3O4@CTAB). The as prepared Fe3O4@CTAB could effectively capture both Gram-negative Escherichia coli and Gram-positive Bacillus subtilis from water. For both cell types, more than 99% of bacteria with initial concentration of 1.5 * 10(7)CFU/mL could be inactivated by Fe3O4@CTAB (0.5 g/L) within 60 min. Fe3O4@CTAB could remove more than 99% of cells over a wide pH (from 3 to 10) and solution ionic strength range (from 0 to 1000 mM). The copresence of sulfate and nitrate did not affect the bacterial capture efficiencies, whereas, phosphate and silicate slightly decreased the bacterial removal rates. However, more than 91% and 81% of cells could be captured at 10mM of phosphate and silicate, respectively. Over 80% of cells could be removed even in the presence of 10mg/L of humic acid. Moreover, Fe3O4@CTAB exhibited good reusability, and greater than 83% of cells could be captured even in the fifth regeneration cycle. Fe3O4@CTAB prepared in this study have great application potentials for water disinfection. PMID- 26496473 TI - Functionalized polyanilines disrupt Pseudomonas aeruginosa and Staphylococcus aureus biofilms. AB - The purpose of the present study was to investigate the antimicrobial effects of functionalized polyanilines (fPANIs) against stationary phase cells and biofilms of Pseudomonas aeruginosa and Staphylococcus aureus using homopolymer of sulfanilic acid (poly-SO3H) as a model. The chemically synthesized poly-SO3H was characterized using Fourier Transform Infra-Red (FTIR) and Ultraviolet-Visible (UV-Vis) spectroscopies. The molecular weight (Mw) and elemental analysis of homopolymer poly-SO3H were also examined. We found that poly-SO3H was bactericidal against stationary phase cells of P. aeruginosa and S. aureus at a concentration of 20 mgml(-1). Surprisingly, we discovered that the same concentration (20 mgml(-1)) of poly-SO3H significantly disrupted and killed bacterial cells present in pre-established forty-eight hour static biofilms of these organisms, as shown by crystal violet and bacterial live/dead fluorescence staining assays. In support of these data, poly-SO3H extensively diminished the expression of bacterial genes related to biofilm formation in stationary phase cells of P. aeruginosa, and seemed to greatly reduce the amount of the quorum sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) able to be recovered from biofilms of this organism. Furthermore, we found that poly-SO3H was able to effectively penetrate and kill cells in biofilms formed by the P. aeruginosa (AESIII) isolate derived from the sputum of a cystic fibrosis patient. Taken together, the results of the present study emphasise the broad antimicrobial activities of fPANI, and suggest that they could be developed further and used in some novel ways to construct medical devices and/or industrial equipment that are refractory to colonization by biofilm-forming bacteria. PMID- 26496474 TI - Correction: Diffusion-Weighted Imaging in 3.0 Tesla Breast MRI: Diagnostic Performance and Tumor Characterization Using Small Subregions vs. Whole Tumor Regions of Interest. PMID- 26496475 TI - Functional Characterization of AbeD, an RND-Type Membrane Transporter in Antimicrobial Resistance in Acinetobacter baumannii. AB - BACKGROUND: Acinetobacter baumannii is becoming an increasing menace in health care settings especially in the intensive care units due to its ability to withstand adverse environmental conditions and exhibit innate resistance to different classes of antibiotics. Here we describe the biological contributions of abeD, a novel membrane transporter in bacterial stress response and antimicrobial resistance in A. baumannii. RESULTS: The abeD mutant displayed ~ 3.37 fold decreased survival and >5-fold reduced growth in hostile osmotic (0.25 M; NaCl) and oxidative (2.631 MUM-6.574 MUM; H2O2) stress conditions respectively. The abeD inactivated cells displayed increased susceptibility to ceftriaxone, gentamicin, rifampicin and tobramycin (~ 4.0 fold). The mutant displayed increased sensitivity to the hospital-based disinfectant benzalkonium chloride (~3.18-fold). In Caenorhabditis elegans model, the abeD mutant exhibited (P<0.01) lower virulence capability. Binding of SoxR on the regulatory fragments of abeD provide strong evidence for the involvement of SoxR system in regulating the expression of abeD in A. baumannii. CONCLUSION: This study demonstrates the contributions of membrane transporter AbeD in bacterial physiology, stress response and antimicrobial resistance in A. baumannii for the first time. PMID- 26496476 TI - Repetitive transcranial magnetic stimulation induced slow wave activity modification: A possible role in disorder of consciousness differential diagnosis? AB - Slow wave activity (SWA) generation depends on cortico-thalamo-cortical loops that are disrupted in patients with chronic Disorders of Consciousness (DOC), including the Unresponsive Wakefulness Syndrome (UWS) and the Minimally Conscious State (MCS). We hypothesized that the modulation of SWA by means of a repetitive transcranial magnetic stimulation (rTMS) could reveal residual patterns of connectivity, thus supporting the DOC clinical differential diagnosis. We enrolled 10 DOC individuals who underwent a 24hh polysomnography followed by a real or sham 5Hz-rTMS over left primary motor area, and a second polysomnographic recording. A preserved sleep-wake cycle, a standard temporal progression of sleep stages, and a SWA perturbation were found in all of the MCS patients and in none of the UWS individuals, only following the real-rTMS. In conclusion, our combined approach may improve the differential diagnosis between MCS patients, who show a partial preservation of cortical plasticity, and UWS individuals, who lack such properties. PMID- 26496477 TI - Dreaming and personality: Wake-dream continuity, thought suppression, and the Big Five Inventory. AB - Studies have found relationships between dream content and personality traits, but there are still many traits that have been underexplored or have had questionable conclusions drawn about them. Experimental work has found a 'rebound' effect in dreams when thoughts are suppressed prior to sleep, but the effect of trait thought suppression on dream content has not yet been researched. In the present study participants (N=106) reported their Most Recent Dream, answered questions about the content of the dream, and completed questionnaires measuring trait thought suppression and the 'Big Five' personality traits. Of these, 83 were suitably recent for analyses. A significant positive correlation was found between trait thought suppression and participants' ratings of dreaming of waking-life emotions, and high suppressors reported dreaming more of their waking-life emotions than low suppressors did. The results may lend support to the compensation theory of dreams, and/or the ironic process theory of mental control. PMID- 26496479 TI - Anxiety and rumination moderate menstrual cycle effects on mood in daily life. AB - Evidence for menstrual cycle-related mood fluctuations in the general population of women has been mixed. While most previous research has relied on retrospective self-report and did not consider possible moderators, the present study aimed to examine cycle-related mood variations in daily life and possible moderating effects of anxiety and trait rumination. Fifty-nine women with natural menstrual cycles, aged 18-44 years, were examined between January and October, 2012. Mood components of calmness, positive valence, energetic-arousal, and irritability were assessed, using smartphones, by ambulatory assessment ten times per day on eight days across the cycle. The menstrual, follicular, ovulatory, and late luteal phases were each covered by two consecutive assessment days. Moderators were assessed with questionnaires. Hierarchical linear models (HLMs) revealed higher calmness in the luteal and menstrual than in the follicular and ovulatory phase, while the menstrual cycle did not exhibit significant main effects on other mood components. Anxiety and ruminative self-reflection moderated the association between menstrual cycle and all mood variables. Specifically, highly anxious and ruminative women showed an increase in irritability, while women with lower anxiety and lower rumination were protected against mood deterioration toward the end of the cycle. Further research could examine whether reducing anxiety and rumination helps to prevent premenstrual syndrome-related syndromes. PMID- 26496478 TI - Predicting Abdominal Aortic Aneurysm Target Genes by Level-2 Protein-Protein Interaction. AB - Abdominal aortic aneurysm (AAA) is frequently lethal and has no effective pharmaceutical treatment, posing a great threat to human health. Previous bioinformatics studies of the mechanisms underlying AAA relied largely on the detection of direct protein-protein interactions (level-1 PPI) between the products of reported AAA-related genes. Thus, some proteins not suspected to be directly linked to previously reported genes of pivotal importance to AAA might have been missed. In this study, we constructed an indirect protein-protein interaction (level-2 PPI) network based on common interacting proteins encoded by known AAA-related genes and successfully predicted previously unreported AAA related genes using this network. We used four methods to test and verify the performance of this level-2 PPI network: cross validation, human AAA mRNA chip array comparison, literature mining, and verification in a mouse CaPO4 AAA model. We confirmed that the new level-2 PPI network is superior to the original level-1 PPI network and proved that the top 100 candidate genes predicted by the level-2 PPI network shared similar GO functions and KEGG pathways compared with positive genes. PMID- 26496480 TI - Concordance of Epileptic Networks Associated with Epileptic Spikes Measured by High-Density EEG and Fast fMRI. AB - OBJECTIVE: The present study aims to investigate whether a newly developed fast fMRI called MREG (magnetic resonance encephalography) measures metabolic changes related to interictal epileptic discharges (IED). For this purpose BOLD changes are correlated with the IED distribution and variability. METHODS: Patients with focal epilepsy underwent EEG-MREG using a 64 channel cap. IED voltage maps were generated using 32 and 64 channels and compared regarding their correspondence to the BOLD response. The extents of IEDs (defined as number of channels with >50% of maximum IED negativity) were correlated with the extents of positive and negative BOLD responses. Differences in inter-spike variability were investigated between interictal epileptic discharges (IED) sets with and without concordant positive or negative BOLD responses. RESULTS: 17 patients showed 32 separate IED types. In 50% of IED types the BOLD changes could be confirmed by another independent imaging method. The IED extent significantly correlated with the positive BOLD extent (p = 0.04). In 6 patients the 64-channel EEG voltage maps better reflected the positive or negative BOLD response than the 32-channel EEG; in all others no difference was seen. Inter-spike variability was significantly lower in IED sets with than without concordant positive or negative BOLD responses (with p = 0.04). SIGNIFICANCE: Higher density EEG and fast fMRI seem to improve the value of EEG-fMRI in epilepsy. The correlation of positive BOLD and IED extent could suggest that widespread BOLD responses reflect the IED network. Inter-spike variability influences the likelihood to find IED concordant positive or negative BOLD responses, which is why single IED analysis may be promising. PMID- 26496482 TI - Binding of palladium (II) 5, 10, 15, 20-tetrakis (4-sulfonatophenyl) porphyrin to a lectin for photosensitizer targeted delivery. PMID- 26496481 TI - Variable Pringle Maneuvers and Effect on Intestinal Epithelium in Rats. A Pilot Experimental Study in Rats. AB - BACKGROUND: It is observed that combined liver and colon surgery especially when this includes major liver resection with Pringle maneuver (PM) performance does not have a favorable outcome. Aim of our experimental study is to investigate the impact of portal triad occlusion on the large bowel and intra-abdominal inflammation and potent protective effects of the variants of (PM) in the combined surgical cases. MATERIALS AND METHODS: Forty-four rats were divided into four groups. In group A (control group), 1cm of the left partial colon was resected and then an end-to-end anastomosis was performed. In group B, a continuous PM for 30 minutes was performed followed by resection of 1cm of the left colon and an end-to-end anastomosis. In group C, the left colonic resection and anastomosis was performed after intermittent PM (IPM), which was 10 minutes PM followed by 5 minutes reperfusion repeated for three circles. In group D, an ischemic preconditioning for 10 minutes was initially performed followed by 5 minutes reperfusion and then continuous PM for 30 minutes. Finally the rats in group D underwent a 1cm left colonic resection and an end-to-end anastomosis. RESULTS: The percentage of colitis was higher in the B group (P = 0,19). The percentage of inflammation was not significantly higher even when we compared all "occlusion" groups (B+C+D) with the sham group. No evidence of pancreatitis was found in the sham group whereas amylase and lipase levels were higher in Groups B, C and D together (P = 0,0267). The comparison of group A to group B showed a significant difference (P = 0,0014) caused by continuous PM for 30 minutes, but there was no such result after IPM. CONCLUSIONS: Major liver resections are performed with PM in order to minimize intra-operative blood loss. In the combined cases of colon surgery and major liver resections where PM is needed our results showed that IPM presents with better outcome and could be preferred compared with the other PM variants. PMID- 26496483 TI - Esophageal Cancer Epigenomics and Integrome Analysis of Genome-Wide Methylation and Expression in High Risk Northeast Indian Population. AB - Esophageal cancer is a major global health burden with a strong host-environment interaction component and epigenomics underpinnings that remain to be elucidated further. Certain populations such as the Northeast Indians suffer at a disproportionately higher rate from this devastating disease. Promoter methylation is correlated with transcriptional silencing of various genes in esophageal cancer. Very few studies on genome-wide methylation for esophageal cancer exist and yet, no one has carried out an integromics analysis of methylation and gene expression. In the present study, genome-wide methylation was measured in samples collected from the Northeast Indian population by Infinium 450k array, and integration of the methylation data was performed. To prepare a network of genes displaying enriched pathways, together with the list of genes exhibiting promoter hypermethylation or hypomethylation with inversely correlated expression, we performed an integrome analysis. We identified 23 Integrome network enriched genes with relevance to tumor progression and associated with the processes involved in metastasis such as cell adhesion, integrin signaling, cytoskeleton, and extracellular matrix organizations. These included four genes (PTK2, RND1, RND3, and UBL3) with promoter hypermethylation and downregulation, and 19 genes (SEMG2, CD97, CTNND2, CADM3, OMD, NEFM, FBN2, CTNNB1, DLX6, UGT2B4, CCDC80, PZP, SERPINA4, TNFSF13B, NPC1, COL1A1, TAC3, BMP8A, and IL22RA2) with promoter hypomethylation and upregulation. A Methylation Efficiency Index was further calculated for these genes; the top five gene with the highest index were COL1A1, TAC3, SERPINA4, TNFSF13B, and IL22RA2. In conclusion, we recommend that the circulatory proteins IL22RA2, TNFSF13B, SERPINA4, and TAC3 in serum of patients and disease-free healthy controls can be examined in the future as putative noninvasive biomarkers. PMID- 26496485 TI - Carbenylative Amination and Alkylation of Vinyl Iodides via Palladium Alkylidene Intermediates. AB - Most palladium-catalyzed reactions involving insertion of alkylidenes with alpha hydrogens undergo beta-hydride elimination from alkylpalladium(II) intermediates to form alkenes. Vinyl iodides were shown to generate eta(3)-allylpalladium intermediates that resist beta-hydride elimination, preserving the sp(3) center adjacent to the carbene moiety. Acyclic stereocontrol (syn/anti) for carbenylative amination and alkylation reactions was low, suggesting a lack of control in the migratory insertion step. Highly hindered carbene precursors inexplicably led to formation of Z-alkenes with high levels of stereocontrol. PMID- 26496484 TI - Motorcycle helmet type and the risk of head injury and neck injury during motorcycle collisions in California. AB - The use of novelty motorcycle helmets is often prompted by beliefs that wearing a standard helmet can contribute to neck injury during traffic collisions. The goal of this analysis was to examine the association between helmet type and neck injury risk and the association between helmet type and head injury. Data were collected during the investigation of motorcycle collisions of any injury severity by the California Highway Patrol (CHP) and 83 local law enforcement agencies in California between June 2012 and July 2013. We estimated head injury and neck injury risk ratios from data on 7051 collision-involved motorcyclists using log-binomial regression. Helmet type was strongly associated with head injury occurrence but was not associated with the occurrence of neck injury. Rider age, rider alcohol use, and motorcycle speed were strong, positive predictors of both head and neck injury. Interventions to improve motorcycle helmet choice and to counteract misplaced concerns surrounding neck injury risk are likely to lead to reductions in head injury, brain injury, and death. PMID- 26496486 TI - Synergistic Interactions of Sugars/Polyols and Monovalent Salts with Phospholipids Depend upon Sugar/Polyol Complexity and Anion Identity. AB - We found that interactions of dipalmitoylphosphatidylcholine (DPPC) lipid monolayers with sugars are influenced by addition of NaCl. This work is of general importance in understanding how sugar-lipid-salt interactions impact biological systems. Using Langmuir isothermal compressions, fluorescence microscopy, atomic force microscopy, and neutron reflectometry, we examined DPPC monolayers upon addition of sugars/polyols and/or monovalent salts. Sugar-lipid interactions in the presence of NaCl increased with increasing complexity of the sugar/polyol in the order glycerol ? glucose < trehalose. When the anion was altered in the series NaF, NaCl, and NaBr, only minor differences were observed. When comparing LiCl, NaCl, and KCl, sodium chloride had the greatest influence on glucose and trehalose interactions with DPPC. We propose that heterogeneity created by cation binding allows for sugars to bind the lipid headgroups. While cation binding increases in the order K(+) < Na(+) < Li(+), lithium ions may also compete with glucose for binding sites. Thus, both cooperative and competitive factors contribute to the overall influence of salts on sugar-lipid interactions. PMID- 26496487 TI - Sugar and volatile fatty acids dynamic during anaerobic treatment of olive mill wastewater. AB - Biogas production has been the main route used to exploit olive mill wastewater (OMW), after pretreatment and/or in combination with other effluents, but more recently the production of chemicals and biopolymers by biotechnological routes has deserved increasing attention by the scientific community. The present paper aims to explore the potential of fresh OMW as a source of volatile fatty acids (VFAs) and biogas. The time profile of VFAs production and the corresponding sugar consumption was followed by high-performance liquid chromatography, in batch anaerobic assays. The experimental results have revealed the very high potential of the OMW for the production of VFAs, mainly due to the high sugar concentration in the effluent (37.8 g/L) and its complete conversion into VFAs, in a time period of 2-3 days. The most abundant VFAs were acetic (48-50%), n butanoic (12-27%), iso-pentanoic (12-14%) and propanoic (5-13%). The ratio of VFA containing even and odd carbon chains increased with the reduction in the initial chemical oxygen demand concentration of the samples used in the experiments. The conversion of the VFAs to biogas was inhibited at concentrations of 3.5 g/L of VFAs. PMID- 26496489 TI - Altered Gene Expression Associated with microRNA Binding Site Polymorphisms. AB - Allele-specific gene expression associated with genetic variation in regulatory regions can play an important role in the development of complex traits. We hypothesized that polymorphisms in microRNA (miRNA) response elements (MRE-SNPs) that either disrupt a miRNA binding site or create a new miRNA binding site can affect the allele-specific expression of target genes. By integrating public expression quantitative trait locus (eQTL) data, miRNA binding site predictions, small RNA sequencing, and Argonaute crosslinking immunoprecipitation (AGO-CLIP) datasets, we identified genetic variants that can affect gene expression by modulating miRNA binding efficiency. We also identified MRE-SNPs located in regions associated with complex traits, indicating possible causative mechanisms associated with these loci. The results of this study expand the current understanding of gene expression regulation and help to interpret the mechanisms underlying eQTL effects. PMID- 26496490 TI - A Mumps Outbreak in Vojvodina, Serbia, in 2012 Underlines the Need for Additional Vaccination Opportunities for Young Adults. AB - In 2012, mumps was introduced from Bosnia and Herzegovina to Vojvodina, causing an outbreak with 335 reported cases. The present manuscript analyses the epidemiological and laboratory characteristics of this outbreak, identifies its main causes and suggests potential future preventive measures. Sera of 133 patients were tested for mumps-specific antibodies by ELISA and 15 nose/throat swabs were investigated for mumps virus RNA by RT-PCR. IgG antibodies were found in 127 patients (95.5%). Mumps infection was laboratory-confirmed in 53 patients, including 44 IgM and 9 PCR positive cases. All other 282 cases were classified as epidemiologically-confirmed. More than half of the patients (n = 181, 54%) were 20-29 years old, followed by the 15-19 age bracket (n = 95, 28.4%). Twice as many males as females were affected (67% versus 33%). Disease complications were reported in 13 cases (3.9%), including 9 patients with orchitis and 4 with pancreatitis. According to medical records or anamnestic data, 190 patients (56.7%) were immunized with two doses and 35 (10.4%) with one dose of mumps containing vaccine. The Serbian sequences corresponded to a minor genotype G variant detected during the 2011/2012 mumps outbreak in Bosnia and Herzegovina. Vaccine failures, the initial one-dose immunization policy and a vaccine shortage between 1999 and 2002 contributed to the outbreak. Additional vaccination opportunities should be offered to young adults during transition periods in their life trajectories. PMID- 26496491 TI - Is Nebivolol Really Effective in Preventing Contrast Induced Nephropathy? AB - BACKGROUND/AIMS: Contrast induced nephropathy (CIN) has multifactorial etiopatogenesis including oxidative stress and vasoconstriction. Nebivolol is an antioxidant and has vasodilatatory effect via NO release and may prevent CIN development. We have noticed that a few number of studies that have evaluated the effectiveness of nebivolol for the prevention of CIN used serum creatinine (sCr) levels for CIN detection. However, sCr is an insensitive marker for renal damage. Therefore in this study we used serum neutrophil-gelatinase associated lipocalin (NGAL), a more sensitive marker of renal damage, to evaluate preventive role of nebivolol in CIN. METHODS: 159 patients undergoing coronary angiography (CAG) who had at least one risk factor for CIN were divided into nebivolol (+) and (-) groups. CIN was defined as a rise in sCr of 0.5mg/dl or a 25% increase from the baseline value. Serum Cr, glomerular filtration rate (eGFR) and NGAL levels were assessed before and 48 h after CAG. Mehran risk scores were calculated for both groups. RESULTS: Both groups were similar in terms of baseline characteristics, Mehran risk scores, and current medications. Clinically, CIN developed at similar rates in both groups. Serum Cr, eGFR and NGAL values were similar in both groups before and after CAG. Serum Cr and NGAL levels increased and eGFR decreased significantly compared to the levels before CAG. Patients who developed CIN were significantly older (p=0.003), and were more likely to have DM (p=0.012), a higher mean contrast agent volume (p<0.001), and a higher Mehran score (p <0.001). We did not observe any favorable effect of Nebivolol in the prevention of CIN in patients undergoing CAG. CONCLUSION: According to the results of our study Nebivolol does not seem to prevent CIN in patients undergoing CAG. However, further randomised controlled trials with more sensitive renal damage markers are obviously needed to understand the actual effect of nebivolol on CIN especially through oxidative pathways and in high risk patients. PMID- 26496492 TI - Genome-Wide Association Analysis of Adaptation Using Environmentally Predicted Traits. AB - Current methods for studying the genetic basis of adaptation evaluate genetic associations with ecologically relevant traits or single environmental variables, under the implicit assumption that natural selection imposes correlations between phenotypes, environments and genotypes. In practice, observed trait and environmental data are manifestations of unknown selective forces and are only indirectly associated with adaptive genetic variation. In theory, improved estimation of these forces could enable more powerful detection of loci under selection. Here we present an approach in which we approximate adaptive variation by modeling phenotypes as a function of the environment and using the predicted trait in multivariate and univariate genome-wide association analysis (GWAS). Based on computer simulations and published flowering time data from the model plant Arabidopsis thaliana, we find that environmentally predicted traits lead to higher recovery of functional loci in multivariate GWAS and are more strongly correlated to allele frequencies at adaptive loci than individual environmental variables. Our results provide an example of the use of environmental data to obtain independent and meaningful information on adaptive genetic variation. PMID- 26496488 TI - Reciprocal regulation of TGF-beta and reactive oxygen species: A perverse cycle for fibrosis. AB - Transforming growth factor beta (TGF-beta) is the most potent pro-fibrogenic cytokine and its expression is increased in almost all of fibrotic diseases. Although signaling through Smad pathway is believed to play a central role in TGF beta's fibrogenesis, emerging evidence indicates that reactive oxygen species (ROS) modulate TGF-beta's signaling through different pathways including Smad pathway. TGF-beta1 increases ROS production and suppresses antioxidant enzymes, leading to a redox imbalance. ROS, in turn, induce/activate TGF-beta1 and mediate many of TGF-beta's fibrogenic effects, forming a vicious cycle (see graphic flow chart on the right). Here, we review the current knowledge on the feed-forward mechanisms between TGF-beta1 and ROS in the development of fibrosis. Therapeutics targeting TGF-beta-induced and ROS-dependent cellular signaling represents a novel approach in the treatment of fibrotic disorders. PMID- 26496493 TI - Phylogeny of Symbiotic Genes and the Symbiotic Properties of Rhizobia Specific to Astragalus glycyphyllos L. AB - The phylogeny of symbiotic genes of Astragalus glycyphyllos L. (liquorice milkvetch) nodule isolates was studied by comparative sequence analysis of nodA, nodC, nodH and nifH loci. In all these genes phylograms, liquorice milkvetch rhizobia (closely related to bacteria of three species, i.e. Mesorhizobium amorphae, Mesorhizobium septentrionale and Mesorhizobium ciceri) formed one clearly separate cluster suggesting the horizontal transfer of symbiotic genes from a single ancestor to the bacteria being studied. The high sequence similarity of the symbiotic genes of A. glycyphyllos rhizobia (99-100% in the case of nodAC and nifH genes, and 98-99% in the case of nodH one) points to the relatively recent (in evolutionary scale) lateral transfer of these genes. In the nodACH and nifH phylograms, A. glycyphyllos nodule isolates were grouped together with the genus Mesorhizobium species in one monophyletic clade, close to M. ciceri, Mesorhizobium opportunistum and Mesorhizobium australicum symbiovar biserrulae bacteria, which correlates with the close relationship of these rhizobia host plants. Plant tests revealed the narrow host range of A. glycyphyllos rhizobia. They formed effective symbiotic interactions with their native host (A. glycyphyllos) and Amorpha fruticosa but not with 11 other fabacean species. The nodules induced on A. glycyphyllos roots were indeterminate with apical, persistent meristem, an age gradient of nodule tissues and cortical vascular bundles. To reflect the symbiosis-adaptive phenotype of rhizobia, specific for A. glycyphyllos, we propose for these bacteria the new symbiovar "glycyphyllae", based on nodA and nodC genes sequences. PMID- 26496494 TI - Complementing ODE-Based System Analysis Using Boolean Networks Derived from an Euler-Like Transformation. AB - In this paper, we present a systematic transition scheme for a large class of ordinary differential equations (ODEs) into Boolean networks. Our transition scheme can be applied to any system of ODEs whose right hand sides can be written as sums and products of monotone functions. It performs an Euler-like step which uses the signs of the right hand sides to obtain the Boolean update functions for every variable of the corresponding discrete model. The discrete model can, on one hand, be considered as another representation of the biological system or, alternatively, it can be used to further the analysis of the original ODE model. Since the generic transformation method does not guarantee any property conservation, a subsequent validation step is required. Depending on the purpose of the model this step can be based on experimental data or ODE simulations and characteristics. Analysis of the resulting Boolean model, both on its own and in comparison with the ODE model, then allows to investigate system properties not accessible in a purely continuous setting. The method is exemplarily applied to a previously published model of the bovine estrous cycle, which leads to new insights regarding the regulation among the components, and also indicates strongly that the system is tailored to generate stable oscillations. PMID- 26496495 TI - Configurational Statistics of Magnetic Bead Detection with Magnetoresistive Sensors. AB - Magnetic biosensors detect magnetic beads that, mediated by a target, have bound to a functionalized area. This area is often larger than the area of the sensor. Both the sign and magnitude of the average magnetic field experienced by the sensor from a magnetic bead depends on the location of the bead relative to the sensor. Consequently, the signal from multiple beads also depends on their locations. Thus, a given coverage of the functionalized area with magnetic beads does not result in a given detector response, except on the average, over many realizations of the same coverage. We present a systematic theoretical analysis of how this location-dependence affects the sensor response. The analysis is done for beads magnetized by a homogeneous in-plane magnetic field. We determine the expected value and standard deviation of the sensor response for a given coverage, as well as the accuracy and precision with which the coverage can be determined from a single sensor measurement. We show that statistical fluctuations between samples may reduce the sensitivity and dynamic range of a sensor significantly when the functionalized area is larger than the sensor area. Hence, the statistics of sampling is essential to sensor design. For illustration, we analyze three important published cases for which statistical fluctuations are dominant, significant, and insignificant, respectively. PMID- 26496496 TI - Composition of Lutein Ester Regioisomers in Marigold Flower, Dietary Supplement, and Herbal Tea. AB - Characterization of lutein and its esters in a health product is necessary for its efficacy. In the current study lutein ester regioisomers were quantified and identified in several dietary supplements and herbal teas in comparison with marigold flower, the commercial source of lutein. The products were extracted with three solvents and separated on a C30 column. The separated esters were identified/confirmed with LC-MS in APCI+ve mode with the use of synthetic lutein esters. The total content of lutein esters substantially varied among marigold flowers (167-5752 MUg/g), supplements (88,000-110,700 MUg/g), and herbal teas (12.4-91.3 MUg/g). Lutein supplement had a lutein profile similar to that of marigold flower, whereas herbal tea showed an extremely different profile. Lutein dipalmitate was the dominant compound in supplements and marigold flowers followed by lutein 3'-O-myristate-3-O-palmitate and lutein 3'-O-palmitate-3-O myristate. Lutein was the major compound in marigold herbal tea with small amounts of lutein mono- and diesters. Differences in the concentration and composition of lutein compounds among marigold products could indicate distinct product quality and lutein bioavailability. PMID- 26496497 TI - Long-Term Arthralgia after Mayaro Virus Infection Correlates with Sustained Pro inflammatory Cytokine Response. AB - Mayaro virus (MAYV), an alphavirus similar to chikungunya virus (CHIKV), causes an acute debilitating disease which results in the development of long-term arthralgia in more than 50% of infected individuals. Currently, the immune response and its role in the development of MAYV-induced persistent arthralgia remain unknown. In this study, we evaluated the immune response of individuals with confirmed MAYV infection in a one-year longitudinal study carried out in Loreto, Peru. We report that MAYV infection elicits robust immune responses that result in the development of a strong neutralizing antibody response and the secretion of pro-inflammatory immune mediators. The composition of these inflammatory mediators, in some cases, differed to those previously observed for CHIKV. Key mediators such as IL-13, IL-7 and VEGF were strongly induced following MAYV infection and were significantly increased in subjects that eventually developed persistent arthralgia. Although a strong neutralizing antibody response was observed in all subjects, it was not sufficient to prevent the long-term outcomes of MAYV infection. This study provides initial immunologic insight that may eventually contribute to prognostic tools and therapeutic treatments against this emerging pathogen. PMID- 26496498 TI - The Importance of Networking in Autism Gaze Analysis. AB - Visual scanning of faces in individuals with Autism Spectrum Disorder (ASD) has been intensively studied using eye-tracking technology. However, most of studies have relied on the same analytic approach based on the quantification of fixation time, which may have failed to reveal some important features of the scanning strategies employed by individuals with ASD. In the present study, we examined the scanning of faces in a group of 20 preschoolers with ASD and their typically developing (TD) peers, using both classical fixation time approach and a new developed approach based on transition matrices and network analysis. We found between group differences in the eye region in terms of fixation time, with increased right eye fixation time for the ASD group and increased left eye fixation time for the TD group. Our complementary network approach revealed that the left eye might play the role of an anchor in the scanning strategies of TD children but not in that of children with ASD. In ASD, fixation time on the different facial parts was almost exclusively dependent on exploratory activity. Our study highlights the importance of developing innovative measures that bear the potential of revealing new properties of the scanning strategies employed by individuals with ASD. PMID- 26496499 TI - A Common Polymorphism within the IGF2 Imprinting Control Region Is Associated with Parent of Origin Specific Effects in Infantile Hemangiomas. AB - Infantile hemangioma (IH) is the most common tumor of the pediatric age group, affecting up to 4% of newborns ranging from inconsequential blemishes, to highly aggressive tumors. Following well defined growth phases (proliferative, plateau involutional) IH usually regress into a fibro-fatty residuum. Despite the high prevalence of IH, little is known regarding the pathogenesis of disease. A reported six fold decrease in IGF2 expression (correlating with transformation of proliferative to involuted lesions) prompted us to study the IGF-2 axis further. We demonstrate that IGF2 expression in IH is strongly related to the expression of a cancer testes and suspected oncogene BORIS (paralog of CTCF), placing IH in the unique category of being the first known benign BORIS positive tumor. IGF2 expression was strongly and positively related to BORIS transcript expression. Furthermore, a stronger association was made when comparing BORIS levels against the expression of CTCF via either a percentage or difference between the two. A common C/T polymorphism at CTCF BS6 appeared to modify the correlation between CTCF/BORIS and IGF2 expression in a parent of origin specific manner. Moreover, these effects may have phenotypic consequences as tumor growth also correlates with the genotype at CTCF BS6. This may provide a framework for explaining the clinical variability seen in IH and suggests new insights regarding CTCF and BORIS related functionality in both normal and malignant states. PMID- 26496500 TI - Pulmonary Impairment in Tuberculosis Survivors: The Korean National Health and Nutrition Examination Survey 2008-2012. AB - OBJECTIVES: Pulmonary tuberculosis (TB) can affect lung function, but studies regarding long-term follow-up in patients with no sequelae on chest X-ray (CXR) have not been performed. We evaluated lung functional impairment and persistent respiratory symptoms in those with prior pulmonary TB and those with prior pulmonary TB with no residual sequelae on CXR, and determined risk factors for airflow obstruction. METHODS: We used data from adults aged >= 40 years from the annual Korean National Health and Nutrition Examination Surveys conducted between 2008 and 2012. P values for comparisons were adjusted for age, sex, and smoking status. RESULTS: In total of 14,967 adults, 822 subjects (5.5%) had diagnosed and treated pulmonary TB (mean 29.0 years ago). The FVC% (84.9 vs. 92.6), FEV1% (83.4 vs. 92.4), and FEV1/FVC% (73.4 vs. 77.9) were significantly decreased in subjects with prior pulmonary TB compared to those without (p < 0.001, each). In 12,885 subjects with no sequalae on CXR, those with prior pulmonary TB (296, 2.3%) had significantly lower FEV1% (90.9 vs. 93.4, p = 0.001) and FEV1/FVC% (76.6 vs. 78.4, p < 0.001) than those without. Subjects with prior pulmonary TB as well as subjects with no sequalae on CXR were more likely to experience cough and physical activity limitations due to pulmonary symptoms than those without prior pulmonary TB (p < 0.001, each). In total subjects, prior pulmonary TB (OR, 2.314; 95% CI, 1.922-2.785), along with age, male, asthma, and smoking mount was risk factor for airflow obstruction. In subjects with prior pulmonary tuberculosis, inactive TB lesion on chest x-ray (OR, 2.300; 95% CI, 1.606-3.294) were risk factors of airflow obstruction. CONCLUSION: In addition to subjects with inactive TB lesion on CXR, subjects with no sequelae on CXR can show impaired pulmonary function and respiratory symptoms. Prior TB is a risk factor for airflow obstruction and that the risk is more important when they have inactive lesions on chest X-ray. Hence, the patients with treated TB should need to have regular follow-up of lung function and stop smoking for early detection and prevention of the chronic airway disease. PMID- 26496501 TI - Cytological Diagnostic Approach in 3 Cases of Langerhans Cell Histiocytosis Presenting Primarily as a Thyroid Mass. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a monoclonal disease of specialised histiocytes characterised by the proliferation of neoplastic Langerhans cells (LCs) with a varying admixture of mature lymphocytes, eosinophils and plasma cells. LCH commonly occurs in the paediatric population and young adults with the involvement of bone, skin and lymph nodes. LCH has a protracted clinical course with an overall mortality rate of 3%. Primary involvement of the thyroid gland in LCH at presentation is a rare phenomenon that can result in misdiagnosis with consequent mismanagement. CASE: Ultrasound-guided fine-needle aspiration cytology (FNAC) of the thyroid was performed in 3 cases at a tertiary cancer centre, including 2 referral cases where the patient presented with the only symptom of progressive thyroid enlargement. These cases were reported initially or on review and the results were correlated with histology/ancillary techniques. A cytological diagnosis of suspicion for LCH was offered in 2 cases at our centre and 1 case was referred to our centre with a diagnosis of suspected papillary thyroid carcinoma. On review of outside smears at our centre, the diagnosis was changed to suspected LCH. The diagnosis was confirmed by immunopositivity for CD68, CD1a and S100 in 1 case and Tru-cut biopsy followed by immunohistochemistry for CD1a, S100, TTF-1 and LCA in the other 2 cases. CONCLUSION: FNAC was helpful in accurately diagnosing LCH even though the presentation was unusual. Thus, unnecessary surgery was obviated. PMID- 26496503 TI - Patients' and Family Caregivers' Goals for Care During Transitions Out of the Hospital. AB - The aims of this study were to (a) describe the nature of patients' goals upon discharge from hospital, family caregivers' goals for their loved ones, and family caregivers' goals for themselves; (b) determine the degree of concordance with respect to the three elicited goals; (c) ascertain goal attainment across the three elicited goals; and (d) examine factors predictive of goal attainment. Our findings support the position that eliciting patient and family caregiver goals and promoting goal attainment may represent an important step toward promoting greater patient and family caregiver engagement in their care. PMID- 26496504 TI - Reversible Luminescence Modulation upon Photochromic Reactions in Rare-Earth Doped Ferroelectric Oxides by in Situ Photoluminescence Spectroscopy. AB - Reversible luminescence photoswitching upon photochromic reactions with excellent reproducibility is achieved in a new inorganic luminescence material: Na(0.5)Bi(2.5)Nb2O9: Pr(3+) (NBN:Pr) ferroelectric oxides. Upon blue light (452 nm) or sunlight irradiation, the material exhibits a reversible photochromism (PC) performance between dark gray and green color by alternating visible light and thermal stimulus without inducing any structure changes and is accompanied by a red emission at 613 nm. The coloration and decoloration process can be quantitatively evaluated by in situ photoluminescence spectroscopy. Meanwhile, the luminescence emission intensity based on PC reactions is effectively tuned by changing irradiation time and excitation wavelength, and the degree of luminescence modulation has no significant degradation after several periods, showing very excellent reproducibility. On the basis of the luminescence modulation behavior, a double-exponential relaxation model is proposed, and a combined equation is adopted to well describe the luminescence response to light irradiation, being in agreement with the experimental data. PMID- 26496502 TI - Reinforcement Learning of Linking and Tracing Contours in Recurrent Neural Networks. AB - The processing of a visual stimulus can be subdivided into a number of stages. Upon stimulus presentation there is an early phase of feedforward processing where the visual information is propagated from lower to higher visual areas for the extraction of basic and complex stimulus features. This is followed by a later phase where horizontal connections within areas and feedback connections from higher areas back to lower areas come into play. In this later phase, image elements that are behaviorally relevant are grouped by Gestalt grouping rules and are labeled in the cortex with enhanced neuronal activity (object-based attention in psychology). Recent neurophysiological studies revealed that reward-based learning influences these recurrent grouping processes, but it is not well understood how rewards train recurrent circuits for perceptual organization. This paper examines the mechanisms for reward-based learning of new grouping rules. We derive a learning rule that can explain how rewards influence the information flow through feedforward, horizontal and feedback connections. We illustrate the efficiency with two tasks that have been used to study the neuronal correlates of perceptual organization in early visual cortex. The first task is called contour integration and demands the integration of collinear contour elements into an elongated curve. We show how reward-based learning causes an enhancement of the representation of the to-be-grouped elements at early levels of a recurrent neural network, just as is observed in the visual cortex of monkeys. The second task is curve-tracing where the aim is to determine the endpoint of an elongated curve composed of connected image elements. If trained with the new learning rule, neural networks learn to propagate enhanced activity over the curve, in accordance with neurophysiological data. We close the paper with a number of model predictions that can be tested in future neurophysiological and computational studies. PMID- 26496505 TI - Magnetic Ligand Fishing as a Targeting Tool for HPLC-HRMS-SPE-NMR: alpha Glucosidase Inhibitory Ligands and Alkylresorcinol Glycosides from Eugenia catharinae. AB - A bioanalytical platform combining magnetic ligand fishing for alpha-glucosidase inhibition profiling and HPLC-HRMS-SPE-NMR for structural identification of alpha glucosidase inhibitory ligands, both directly from crude plant extracts, is presented. Magnetic beads with N-terminus-coupled alpha-glucosidase were synthesized and characterized for their inherent catalytic activity. Ligand fishing with the immobilized enzyme was optimized using an artificial test mixture consisting of caffeine, ferulic acid, and luteolin before proof-of concept with the crude extract of Eugenia catharinae. The combination of ligand fishing and HPLC-HRMS-SPE-NMR identified myricetin 3-O-alpha-L-rhamnopyranoside, myricetin, quercetin, and kaempferol as alpha-glucosidase inhibitory ligands in E. catharinae. Furthermore, HPLC-HRMS-SPE-NMR analysis led to identification of six new alkylresorcinol glycosides, i.e., 5-(2-oxopentyl)resorcinol 4-O-beta-D glucopyranoside, 5-propylresorcinol 4-O-beta-D-glucopyranoside, 5 pentylresorcinol 4-O-[alpha-D-apiofuranosyl-(1->6)]-beta-D-glucopyranoside, 5 pentylresorcinol 4-O-beta-D-glucopyranoside, 4-hydroxy-3-O-methyl-5 pentylresorcinol 1-O-beta-D-glucopyranoside, and 3-O-methyl-5-pentylresorcinol 1 O-[beta-D-glucopyranosyl-(1->6)]-beta-D-glucopyranoside. PMID- 26496506 TI - Heavy and light chain pairing of bivalent quadroma and knobs-into-holes antibodies analyzed by UHR-ESI-QTOF mass spectrometry. AB - The quadroma antibody represents the first attempt to produce a bispecific heterodimeric IgG antibody by somatic fusion of 2 hybridoma cells each expressing monoclonal antibodies with distinctive specificities. However, because of random heavy and light chain pairing, the desired functional bispecific antibody represents only a small fraction of the protein produced. Subsequently, the knobs into-holes (KiH) approach was developed to enforce correct heavy chain heterodimerization. Assuming equimolar expression of 4 unmodified chains comprising 2 heavy and 2 light chains, the statistical distribution of all paired combinations can be calculated. With equimolar expression as the goal, we transfected HEK cells with 1:1:1:1 plasmid ratios and analyzed the protein A affinity-purified antibodies from the quadroma and KiH approaches qualitatively and quantitatively with regard to the estimated relative amounts of the products using electrospray quadrupole time-of-flight mass spectrometry. Our results show that all expected species are formed, and that, within the methodological limits, the species distribution in the mixtures corresponds approximately to the statistical distribution. PMID- 26496507 TI - Mapping Habitats and Developing Baselines in Offshore Marine Reserves with Little Prior Knowledge: A Critical Evaluation of a New Approach. AB - The recently declared Australian Commonwealth Marine Reserve (CMR) Network covers a total of 3.1 million km2 of continental shelf, slope, and abyssal habitat. Managing and conserving the biodiversity values within this network requires knowledge of the physical and biological assets that lie within its boundaries. Unfortunately very little is known about the habitats and biological assemblages of the continental shelf within the network, where diversity is richest and anthropogenic pressures are greatest. Effective management of the CMR estate into the future requires this knowledge gap to be filled efficiently and quantitatively. The challenge is particularly great for the shelf as multibeam echosounder (MBES) mapping, a key tool for identifying and quantifying habitat distribution, is time consuming in shallow depths, so full coverage mapping of the CMR shelf assets is unrealistic in the medium-term. Here we report on the results of a study undertaken in the Flinders Commonwealth Marine Reserve (southeast Australia) designed to test the benefits of two approaches to characterising shelf habitats: (i) MBES mapping of a continuous (~30 km2) area selected on the basis of its potential to include a range of seabed habitats that are potentially representative of the wider area, versus; (ii) a novel approach that uses targeted mapping of a greater number of smaller, but spatially balanced, locations using a Generalized Random Tessellation Stratified sample design. We present the first quantitative estimates of habitat type and sessile biological communities on the shelf of the Flinders reserve, the former based on three MBES analysis techniques. We contrast the quality of information that both survey approaches offer in combination with the three MBES analysis methods. The GRTS approach enables design based estimates of habitat types and sessile communities and also identifies potential biodiversity hotspots in the northwest corner of the reserve's IUCN zone IV, and in locations close to shelf incising canyon heads. Design based estimates of habitats, however, vary substantially depending on the MBES analysis technique, highlighting the challenging nature of the reserve's low profile reefs, and improvements that are needed when acquiring MBES data for small GRTS locations. We conclude that the two survey approaches are complementary and both have their place in a successful and flexible monitoring strategy; the emphasis on one method over the other should be considered on a case by case basis, taking into account the survey objectives and limitations imposed by the type of vessel, time available, size and location of the region where knowledge is required. PMID- 26496508 TI - Self-Assembly of a Functional Oligo(Aniline)-Based Amphiphile into Helical Conductive Nanowires. AB - A tetra(aniline)-based cationic amphiphile, TANI-NHC(O)C5H10N(CH3)3(+)Br(-) (TANI PTAB) was synthesized, and its emeraldine base (EB) state was found to self assemble into nanowires in aqueous solution. The observed self-assembly is described by an isodesmic model, as shown by temperature-dependent UV-vis investigations. Linear dichroism (LD) studies, combined with computational modeling using time-dependent density functional theory (TD-DFT), suggests that TANI-PTAB molecules are ordered in an antiparallel arrangement within nanowires, with the long axis of TANI-PTAB arranged perpendicular to the nanowire long axis. Addition of either S- or R- camphorsulfonic acid (CSA) to TANI-PTAB converted TANI to the emeraldine salt (ES), which retained the ability to form nanowires. Acid doping of TANI-PTAB had a profound effect on the nanowire morphology, as the CSA counterions' chirality translated into helical twisting of the nanowires, as observed by circular dichroism (CD). Finally, the electrical conductivity of CSA doped helical nanowire thin films processed from aqueous solution was 2.7 mS cm( 1). The conductivity, control over self-assembled 1D structure and water solubility demonstrate these materials' promise as processable and addressable functional materials for molecular electronics, redox-controlled materials and sensing. PMID- 26496509 TI - Measles in Italy: Co-circulation of B3 variants during 2014. AB - In 2013, the majority of the WHO/EUR countries reported an annual incidence of >1 case per one million population indicating that the elimination target is far from being met. Thus, there is the urgent need to uncover and analyze chains of measles virus (MV) transmission with the objective to identify vulnerable groups and avoid possible routes of introduction of MV variants in the European population. The analysis of molecular epidemiology of MV B3 strains identified in 2014 has shown that four different variants co-circulated in Italy, including the strain that caused a cruise-line ship outbreak at the beginning of the year. PMID- 26496510 TI - Carotid plaque stabilization induced by the supplement association Pycnogenol(r) and centella asiatica (Centellicum(r)). AB - BACKGROUND: Aim of this registry study was the evaluation of the stability of carotid plaques by ultrasound in asymptomatic subjects with high oxidative stress following supplementation with a combination of the extract from bark of Pinus pinaster, Pycnogenol(r), with an extract from Centella asiatica leaves, Centellicum(r). METHODS: 50 patients, mean age 61.5 years, with carotid plaques (<50% stenosis) and high oxidative stress were included in this 3 months registry study. 26 patients received the combination of Pycnogenol(r) and Centellicum(r) and standard management, a control group received standard management only. The 2 groups were comparable. RESULTS: The combination of Pycnogenol(r) and Centellicum(r) reduced significantly (p<0.05) plaque height and length as well as the number of plaques relative to controls. The plaque stability index, based on the echogenicity in the ultrasound picture of the "white" components of the plaque, increased significantly (p<0.01) in the verum group, no changes were observed in the controls. Plasma free radicals were significantly (p<0.05) decreased by the combination product, whereas the levels of plasma free radicals remained unchanged in the control group. No unwanted effects or abnormal laboratory tests were recorded. CONCLUSIONS: This registry study revealed a significant increase in stability of plaques, indicated by an enhanced density of the plaques, following supplementation with the combination of Pycnogenol(r) and Centellicum(r). As size and number of plaques was simultaneously reduced, the combination of the two plant extracts could be a safe option for prevention of cardiovascular events for patients with carotid plaques. PMID- 26496511 TI - Addition of Cladribine to Idarubicin and Cytarabine during Induction Increases the Overall Efficacy Rate in Adult Patients with Acute Myeloid Leukemia: A Matched-Pair Retrospective Comparison. AB - OBJECTIVES: The aims of this study were to evaluate a novel induction regimen composed of idarubicin (IDA), cytarabine (Ara-C) and cladribine (IAC regimen) for acute myeloid leukemia (AML) patients, and to identify the prognostic factors affecting treatment outcomes. METHODS: The clinical data of 27 untreated AML patients who received the IAC regimen as primary induction therapy in our hospital between April and November 2014 were analyzed retrospectively. The treatment outcomes of the IAC regimen were compared with two IA (IDA + Ara-C) regimens (IDA 10 mg/m2 and IDA 12 mg/m2) in a pair-matched analysis. RESULTS: The complete remission (CR) rate in the IAC arm was higher compared to the IA(L) arm (p = 0.002) as was the overall efficacy rate (p = 0.017). There was no significant difference in outcomes between the IAC and IA(H) (Ara-C with high dose IDA) arms. The IAC arm contained significantly higher CR rates than the IA(L) (Ara-C with low-dose IDA) arm in both the intermediate group (p = 0.050) and the unfavorable group (p = 0.013). Toxicity did not differ between the IAC group and the other two arms. High WBC at diagnosis (p = 0.022) and an unfavorable karyotype (p = 0.026) were related to a poorer response. The IAC regimen (p = 0.013) had greater superiority over the IAL regimen on efficacy than over the IA(H) regimen (p = 0.041). CONCLUSIONS: The IAC regimen achieved a more significant advantage over the IA(L) regimen without increasing the risk of adverse events. The efficacy of induction therapy is associated with WBC at diagnosis, karyotype and induction regimen. PMID- 26496512 TI - Contribution of N-Nitrosamines and Their Precursors to Domestic Sewage by Greywaters and Blackwaters. AB - N-nitrosamines and their precursors are significant concerns for water utilities exploiting wastewater-impacted water supplies, particularly those practicing potable reuse of wastewater. Previous efforts to identify specific precursors in municipal wastewater accounting for N-nitrosamine formation have met with limited success. As an alternative, we quantified the relative importance of greywater (i.e., shower, kitchen sink, bathroom washbasin, and laundry) and blackwater (i.e., urine and feces) streams in terms of their loadings of ambient specific and total N-nitrosamines and chloramine-reactive and ozone-reactive N-nitrosamine precursors to domestic sewage. Accounting for the volume fractions of individual greywater and blackwater streams, laundry water represented the most significant source of N-nitrosamines and their precursors, followed by shower water and urine. Laundry water was particularly important for ozone-reactive N-nitrosamine precursors, accounting for ~99% of N-nitrosodimethylamine (NDMA) precursors and ~69% of precursors for other uncharacterized N-nitrosamines. For the other greywater streams, consumer products contributed additional N-nitrosamines and precursors, but the remarkable uniformity across different products suggested the importance of common macroconstituents. The consumption of a standard dose of the antacid ranitidine substantially increased NDMA and its chloramine-reactive precursors in urine. Nevertheless, nearly 40% of the American population would need to consume ranitidine daily to match the NDMA loadings from laundry water. PMID- 26496513 TI - Partially-Screened Field Effect and Selective Carrier Injection at Organic Semiconductor/Graphene Heterointerface. AB - Due to the lack of a bandgap, applications of graphene require special device structures and engineering strategies to enable semiconducting characteristics at room temperature. To this end, graphene-based vertical field-effect transistors (VFETs) are emerging as one of the most promising candidates. Previous work attributed the current modulation primarily to gate-modulated graphene semiconductor Schottky barrier. Here, we report the first experimental evidence that the partially screened field effect and selective carrier injection through graphene dominate the electronic transport at the organic semiconductor/graphene heterointerface. The new mechanistic insight allows us to rationally design graphene VFETs. Flexible organic/graphene VFETs with bending radius <1 mm and the output current per unit layout area equivalent to that of the best oxide planar FETs can be achieved. We suggest driving organic light emitting diodes with such VFETs as a promising application. PMID- 26496514 TI - GLT1 overexpression reverses established neuropathic pain-related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury. AB - Development of neuropathic pain occurs in a major portion of traumatic spinal cord injury (SCI) patients, resulting in debilitating and often long-term physical and psychological burdens. Following SCI, chronic dysregulation of extracellular glutamate homeostasis has been shown to play a key role in persistent central hyperexcitability of superficial dorsal horn neurons that mediate pain neurotransmission, leading to various forms of neuropathic pain. Astrocytes express the major CNS glutamate transporter, GLT1, which is responsible for the vast majority of functional glutamate uptake, particularly in the spinal cord. In our unilateral cervical contusion model of mouse SCI that is associated with ipsilateral forepaw heat hypersensitivity (a form of chronic at level neuropathic pain-related behavior), we previously reported significant and long-lasting reductions in GLT1 expression and functional GLT1-mediated glutamate uptake in cervical spinal cord dorsal horn. To therapeutically address GLT1 dysfunction following cervical contusion SCI, we injected an adeno-associated virus type 8 (AAV8)-Gfa2 vector into the superficial dorsal horn to increase GLT1 expression selectively in astrocytes. Compared to both contusion-only animals and injured mice that received AAV8-eGFP control injection, AAV8-GLT1 delivery increased GLT1 protein expression in astrocytes of the injured cervical spinal cord dorsal horn, resulting in a significant and persistent reversal of already established heat hypersensitivity. Furthermore, AAV8-GLT1 injection significantly reduced expression of the transcription factor and marker of persistently increased neuronal activation, DeltaFosB, in superficial dorsal horn neurons. These results demonstrate that focal restoration of GLT1 expression in the superficial dorsal horn is a promising target for treating chronic neuropathic pain following SCI. PMID- 26496515 TI - Iminothiazoline-Sulfonamide Hybrids as Jack Bean Urease Inhibitors; Synthesis, Kinetic Mechanism and Computational Molecular Modeling. AB - The present work reports the synthesis of several 2-iminothiazoline derivatives of sulfanilamide (3a-j) as inhibitors of jack bean ureases. The title compounds were synthesized by the heterocyclization of sulfanilamide thioureas with propragyl bromide in dry ethanol in the presence of 1,8-Diazabicyclo[5.4.0]undec 7-ene as a base. All of the compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (3h) and (3i) exhibited excellent enzyme inhibitory activity with IC50 0.064 and 0.058 MUm, respectively, while IC50 of thiourea is 20.9 MUm. The kinetic mechanism analyzed by Dixon plot showed that compound (3h) is a mixed-type inhibitor while (3i) is a competitive one. Docking studies suggested that Asp633, Ala636, His492, Ala440, Lue523, Asp494 and Arg439 are the major interacting residues in the binding site of the protein and may have an instrumental role in the inhibition of enzyme's function. 2 iminothiazoline analogues (3a-j) showed good docking score (-10.6466 to -8.7215 Kcal/mol) and binding energy (London dG ranging from -14.4825 to -10.4087 Kcal/mol) which is far better than the standard thiourea (binding score in S field -4.5790 Kcal/mol London dG -4.7726 Kcal/mol). Our results inferred compound (3i) may serve as a structural model for the design of most potent urease inhibitors. PMID- 26496516 TI - The authors reply "Variation in printed handoff documents: Results and recommendations from a multicenter needs assessment". PMID- 26496517 TI - "The AYA Director": A Synthesizing Concept to Understand Psychosocial Experiences of Adolescents and Young Adults With Cancer. AB - BACKGROUND: Adolescents and young adults with cancer face distinct psychosocial challenges because of the multiple developmental tasks associated with their age. Research on psychosocial care, directed to the unique needs and demands of this population, is limited. OBJECTIVE: The aim of this study was to describe the psychosocial experiences of adolescents and young adults with cancer to further the understanding of the meanings they attribute to their experiences. INTERVENTION/METHODS: This study used a qualitative design in which individual semistructured interviews were conducted with 23 participants aged 15 to 25 years. RESULTS: Physical consequences of the disease and its treatment, loss of independence, and being alone were significant challenges. Major coping strategies of the participants were to avoid the possible threats to life and maintain a positive attitude and normal life. Participants were "directors" who took control in order to manage their illness, maintain a sense of control, and master their lives to the fullest extent possible. CONCLUSIONS: The concept of the "AYA (adolescent and young adult) director" provides insight for healthcare professionals to understand how adolescents and young adults experience cancer. IMPLICATIONS FOR PRACTICE: Throughout the cancer experience, participants wanted to be treated as individuals with specific needs and preferences. They preferred circumstances they are accustomed to; some found it difficult to accept restrictions imposed by the hospital. Adolescents and young adults with cancer want to be involved in the way healthcare professionals communicate with them and the information they are provided. PMID- 26496518 TI - Nursing Diagnosis of "Spiritual Distress" in Women With Breast Cancer: Prevalence and Major Defining Characteristics. AB - BACKGROUND: Spirituality and spiritual needs of cancer patients are frequently mentioned in the nursing literature, but the most significant defining characteristics of spiritual distress in the context of clinical reasoning and nursing diagnosis are rarely explored. Understanding of these is important for effective spiritual intervention. OBJECTIVE: The aim of this study was to identify the prevalence and the defining characteristics of the nursing diagnosis "spiritual distress," as classified according to NANDA International, among women with breast cancer. METHODS: This was a quantitative and cross-sectional study, comprising the third phase of a larger study investigating the clinical validation of spiritual distress in cancer patients undergoing chemotherapy. Fehring's clinical diagnostic validation model was used to identify the prevalence and the major defining characteristics of the diagnosis. A convenience sample was used, and data were collected by structured interview. RESULTS: A total of 70 women participated; most were married (62.9%) and had a mean age of 54 years, and 55.7% reported having at least 1 person depending on them. The average length of time since the cancer diagnosis was 30.9 months. Twenty-seven participants were experiencing spiritual distress (38.6%). Eleven defining characteristics were classified as major. CONCLUSIONS: The prevalence of spiritual distress and the major defining characteristics give clinical evidence about the nurse's role in providing spiritual care. The results are useful for the improved use of the NANDA International diagnoses within this domain. IMPLICATIONS FOR PRACTICE: The findings highlight the importance of assessing the defining characteristics of the diagnosis as an objective strategy to improve clinical reasoning related to spirituality and to facilitate more effective interventions. PMID- 26496519 TI - Implementation of a Psychoeducational Program for Cancer Survivors and Family Caregivers at a Cancer Support Community Affiliate: A Pilot Effectiveness Study. AB - BACKGROUND: Psychoeducational interventions, tested for efficacy in randomized clinical trials, are seldom implemented in clinical practice where cancer survivors and their family caregivers can benefit from them. OBJECTIVE: This study examined the effectiveness of the FOCUS Program on cancer survivors' and their family caregivers' outcomes when implemented at a Cancer Support Community (CSC) affiliate by agency social workers. Study aims were to (1) test effects of the program on survivor and caregiver outcomes as a unit and (2) determine program feasibility in terms of enrollment, retention, intervention fidelity, and satisfaction. METHODS: A preintervention and postintervention pilot effectiveness study was conducted with 34 cancer survivor-caregiver dyads (ie, pairs). The FOCUS Program, originally delivered by nurses in dyads' homes, was modified to a small-group format and delivered by CSC social workers. The primary outcome was quality of life (QOL). Intermediary outcomes were benefits of illness/caregiving, communication, support, and self-efficacy. Analyses included repeated-measures analysis of variance. RESULTS: Dyads had significant improvements in total QOL; physical, emotional, and functional QOL; benefits of illness; and self-efficacy. Effect sizes were similar to prior randomized clinical trial findings. Although dyads were difficult to recruit (enrollment, 60%), both retention (92%) and intervention fidelity (94%) were high. CONCLUSIONS: It was possible to implement the FOCUS Program at a CSC affiliate by agency staff, obtain positive intervention effects, and maintain intervention fidelity. IMPLICATIONS FOR PRACTICE: Researchers and clinicians need to collaborate to implement more evidence-based interventions in practice settings for cancer survivors and their family caregivers. PMID- 26496520 TI - Nurses' Experiences in Safe Handling of Chemotherapeutic Agents: The Taiwan Case. AB - BACKGROUND: Nurses are the least compliant with the guidelines for use of personal protective equipment (PPE) among health professionals. While the literature regarding nurses not following the guidelines focuses on nonuse of PPE, the experiences of using PPE from nurses' perspectives have not been examined. OBJECTIVE: The aim of this study was to explore the concerns of nurses regarding their decision to use or not to use PPE in the cultural context of Taiwan. METHODS: An ethnographic design was used, and ethnographic interviews of 57 nurses working with chemotherapy for more than 2 years were conducted. The participating nurses were observed in 2 accredited medical centers with oncology care teams in Taiwan. The constant comparison method was applied for data analysis, and cultural themes were generated from all transcripts. RESULTS: Wearing PPE was identified as an obstacle to professional image and performance. Nurses transformed safety into efficiency and prioritized social roles over professional roles. Experienced nurses, as insiders, believed that they have gained clinical wisdom to avoid occupational exposure to chemotherapy toxicity. CONCLUSIONS: This study explored the characteristics of clinical wisdom regarding PPE use in the context of Taiwanese chemotherapy care. Perceived professional image, efficiency on the job, PPE cost, and hospital rules influenced the use or nonuse of PPE by oncology care nurses. IMPLICATIONS FOR PRACTICE: Acceptable nurse-patient ratios and refraining from chemotherapy toxicity exposure for pregnant and breast-feeding women are advocated for policy making. The experiential expertise of nurses should be shared as credible evidence in developing guidelines. PMID- 26496522 TI - Reducing the distal profile of dual mobility liners can mitigate soft-tissue impingement and liner entrapment without affecting mechanical performance. AB - Soft-tissue impingement with dual mobility liners can cause anterior hip pain and intra-prosthetic dislocation. The hypothesis of this study was that reducing liner profile below the equator (contoured design) can mitigate soft-tissue impingement without compromising inner-head pull-out resistance and hip joint stability. The interaction of conventional and contoured liners with anterior soft tissues was evaluated in cadaver specimens via visual observation and fluoroscopic imaging. Resistance to inner-head pull-out was evaluated via finite element analyses, and hip joint stability was evaluated by rigid-body mechanics simulation of dislocation in two modes (A, B). Cadaveric experiments showed that distal portion of conventional liners impinge on anterior hip capsule and cause iliopsoas tenting at low flexion angles (<=30 degrees ). During hip extension, the rotation imparted to the liner from posterior engagement with femoral neck was impeded by anterior soft-tissue impingement. The iliopsoas tenting was significantly reduced with contoured liners (p <= 0.04). Additionally, the contoured and conventional liners had identical inner-head pull-out resistance (901 N vs. 909 N), jump distance (9.4 mm mode-A, 11.7 mm mode-B) and impingement free range of motion (47 degrees mode-A, 29 degrees mode-B). Thus, soft-tissue impingement with conventional dual mobility liners may be mitigated by reducing liner profile below the equator, without affecting mechanical performance. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:889-897, 2016. PMID- 26496521 TI - N-Methylation as a Strategy for Enhancing the Affinity and Selectivity of RNA binding Peptides: Application to the HIV-1 Frameshift-Stimulating RNA. AB - Human Immunodeficiency Virus (HIV) type 1 uses a -1 programmed ribosomal frameshift (-1 PRF) event to translate its enzymes from the same transcript used to encode the virus' structural proteins. The frequency of this event is highly regulated, and significant deviation from the normal 5-10% frequency has been demonstrated to decrease viral infectivity. Frameshifting is primarily regulated by the Frameshift Stimulatory Signal RNA (FSS-RNA), a thermodynamically stable, highly conserved stem loop that has been proposed as a therapeutic target. We describe the design, synthesis, and testing of a series of N-methyl peptides able to bind the HIV-1 FSS RNA stem loop with low nanomolar affinity and high selectivity. Surface plasmon resonance (SPR) data indicates increased affinity is a reflection of a substantially enhanced on rate. Compounds readily penetrate cell membranes and inhibit HIV infectivity in a pseudotyped virus assay. Viral infectivity inhibition correlates with compound-dependent changes in the ratios of Gag and Gag-Pol in virus particles. As the first compounds with both single digit nanomolar affinities for the FSS RNA and an ability to inhibit HIV in cells, these studies support the use of N-methylation for enhancing the affinity, selectivity, and bioactivity of RNA-binding peptides. PMID- 26496523 TI - Does adenosine deaminase activity play a role in the early diagnosis of ectopic pregnancy? AB - Early diagnosis of ectopic pregnancy (EP) is important due to life-threatening consequences in the first trimester of pregnancy. In this study we aimed to investigate the role of adenosine deaminase (ADA) activity in the prediction of EP. Forty-one patients with unruptured ectopic pregnancy comprised the case group and forty-two first trimester pregnant women with shown foetal heart beating in ultrasound comprised the control group. The mean ADA level in EP (10.9 +/- 3.0 IU/L) was higher than that in control group (9.2 +/- 3.6 IU/L) (p = 0.018). Receiver operating characteristics or ROC curve identified ADA value of 10.95 IU/L as optimal threshold for the prediction of EP with 56% sensitivity and 67% specificity. High ADA levels are valuable in the early diagnosis of EP. However more comprehensive studies are required. PMID- 26496524 TI - Does a Heavy Fe-Isotope Composition of Akilia Quartz-Amphibole-Pyroxene Rocks Necessitate a BIF Origin? AB - The age and origin of the quartz-amphibole-pyroxene (qap) gneiss from the island of Akilia, southern West Greenland, have been the subject of intense debate since the light C-isotope composition of graphite inclusions in apatite was interpreted to indicate the presence of Earth's earliest biological activity. Although this claim for biogenic relicts has been vigorously challenged, the possibility that the rocks might represent some of Earth's earliest water-lain sediments and, hence, a suitable repository for life remains an open question. While some workers have suggested that the entire sequence represents an originally mafic ultramafic igneous precursor subsequently modified by metasomatism, quartz injection, high-grade metamorphism, and extreme ductile deformation, others maintain that at least a small part of the sequence retains geochemical characteristics indicative of a chemical sedimentary origin. Fractionated Fe isotopes with delta(56)Fe values similar to those observed in Isua BIF have been reported from high-SiO2 units of qap and used to support a chemical sedimentary protolith for the qap unit. Here, we present new Fe isotope data from all lithologic variants in the qap gneiss on Akilia, including layers of undisputed ultramafic igneous origin. Since the latter require introduction of fractionated Fe into at least part of the qap unit, we argue that Fe isotopes must therefore be treated with considerable caution when used to infer BIF for part or all of the qap protolith. PMID- 26496525 TI - Ultrastructural Heterogeneity of Carbonaceous Material in Ancient Cherts: Investigating Biosignature Origin and Preservation. AB - Opaline silica deposits on Mars may be good target sites where organic biosignatures could be preserved. Potential analogues on Earth are provided by ancient cherts containing carbonaceous material (CM) permineralized by silica. In this study, we investigated the ultrastructure and chemical characteristics of CM in the Rhynie chert (c. 410 Ma, UK), Bitter Springs Formation (c. 820 Ma, Australia), and Wumishan Formation (c. 1485 Ma, China). Raman spectroscopy indicates that the CM has experienced advanced diagenesis or low-grade metamorphism at peak metamorphic temperatures of 150-350 degrees C. Raman mapping and micro-Fourier transform infrared (micro-FTIR) spectroscopy were used to document subcellular-scale variation in the CM of fossilized plants, fungi, prokaryotes, and carbonaceous stromatolites. In the Rhynie chert, ultrastructural variation in the CM was found within individual fossils, while in coccoidal and filamentous microfossils of the Bitter Springs and formless CM of the Wumishan stromatolites ultrastructural variation was found between, not within, different microfossils. This heterogeneity cannot be explained by secondary geological processes but supports diverse carbonaceous precursors that experienced differential graphitization. Micro-FTIR analysis found that CM with lower structural order contains more straight carbon chains (has a lower R3/2 branching index) and that the structural order of eukaryotic CM is more heterogeneous than prokaryotic CM. This study demonstrates how Raman spectroscopy combined with micro-FTIR can be used to investigate the origin and preservation of silica permineralized organics. This approach has good capability for furthering our understanding of CM preserved in Precambrian cherts, and potential biosignatures in siliceous deposits on Mars. PMID- 26496526 TI - Tracing Biosignature Preservation of Geothermally Silicified Microbial Textures into the Geological Record. AB - New Zealand and Argentine (Late Jurassic-Recent) siliceous hot-spring deposits (sinter) reveal preservation pathways of environmentally controlled, microbe dominated sedimentary facies over geological time scales. Texturally distinctive, laminated to thinly layered, dense and vertically oriented, microtubular "palisade" fabric is common in low-temperature (<40 degrees C) sinter-apron terraces. In modern hot springs, the dark green to brown, sheathed, photosynthetic cyanobacterium Calothrix spp. (family Rivulariaceae) constructs felted palisade mats in shallow terrace(tte) pools actively accreting opaline silica. The resulting stacked layers of silicified coarse filaments-a stromatolite-are highly porous and readily modified by postdepositional environmental perturbations, secondary silica infill, and diagenetic silica phase mineral transformations (opal-A to quartz). Fossil preservation quality is affected by relative timing of silicification, and later environmental and geological events. A systematic approach was used to characterize palisade fabric in sinters of different ages to refine tools for recognizing biosignatures in extreme environments and to track their long-term preservation pathways into the geological record. Molecular techniques, scanning electron microscopy, Raman spectrometry, X-ray powder diffraction, petrography, and lipid biomarker analyses were applied. Results indicate that microbial communities vary at the micron scale and that early and rapid silicification is paramount to long-term preservation, especially where minimal postdepositional disturbance follows fossilization. Overall, it appears that the most robust biomarkers of fossil microbial activity in hot-spring deposits are their characteristic macro- and microtextures and laser micro-Raman identified carbon. Studies of Phanerozoic geothermal deposits with mineralized microbial components are relevant analogs for Precambrian geobiology because early life is commonly preserved as microbial microfossils and biofilms in silica, some of it hydrothermal in origin. Yet the diagenetic "movie" has already been run. Hence, studying younger sinters of a range of ages provides an opportunity to "play it again" and follow the varied influences on biosignatures into the deep-time geological record. PMID- 26496527 TI - A Test of the Biogenicity Criteria Established for Microfossils and Stromatolites on Quaternary Tufa and Speleothem Materials Formed in the "Twilight Zone" at Caerwys, UK. AB - The ability to distinguish the features of a chemical sedimentary rock that can only be attributed to biology is a challenge relevant to both geobiology and astrobiology. This study aimed to test criteria for recognizing petrographically the biogenicity of microbially influenced fabrics and fossil microbes in complex Quaternary stalactitic carbonate rocks from Caerwys, UK. We found that the presence of carbonaceous microfossils, fabrics produced by the calcification of microbial filaments, and the asymmetrical development of tufa fabrics due to the more rapid growth of microbially influenced laminations could be recognized as biogenic features. Petrographic evidence also indicates that the development of "speleothem-like" laminae was related to episodes of growth interrupted by intervals of nondeposition and erosion. The lack of any biogenic characteristics in these laminae is consistent with their development as a result of variation in the physicochemical parameters that drive calcite precipitation from meteoric waters in such environmental settings. PMID- 26496528 TI - A Hierarchical System for Evaluating the Biogenicity of Metavolcanic- and Ultramafic-Hosted Microalteration Textures in the Search for Extraterrestrial Life. AB - The low-temperature alteration of submarine volcanic glasses has been argued to involve the activity of microorganisms, and analogous fluid-rock-microbial mediated alteration has also been postulated on Mars. However, establishing the extent to which microbes are involved in volcanic glass alteration has proven to be difficult, and the reliability of resulting textural biosignatures is debated, particularly in the early rock record. We therefore propose a hierarchical scheme to evaluate the biogenicity of candidate textural biosignatures found in altered terrestrial and extraterrestrial basaltic glasses and serpentinized ultramafic rocks. The hierarchical scheme is formulated to give increasing confidence of a biogenic origin and involves (i) investigation of the textural context and syngenicity of the candidate biosignature; (ii) characterization of the morphology and size range of the microtextures; (iii) mapping of the geological and physicochemical variables controlling the occurrence and preservation of the microtextures; (iv) in situ investigation of chemical signatures that are syngenetic to the microtexture; and (v) identification of growth patterns suggestive of biological behavior and redox variations in the host minerals. The scheme results in five categories of candidate biosignature as follows: Category 1 indicates preservation of very weak evidence for biogenicity, Categories 2 through 4 indicate evidence for increasing confidence of a biogenic origin, and Category 5 indicates that biogenic origin is most likely. We apply this hierarchical approach to examine the evidence for a biogenic origin of several examples, including candidate bacterial encrustations in altered pillow lavas, granular and tubular microtextures in volcanic glass from the subseafloor and a Phanerozoic ophiolite, mineralized microtextures in Archean metavolcanic glass, and alteration textures in olivines of the martian meteorite Yamato 000593. The aim of this hierarchical approach is to provide a framework for identifying robust biosignatures of microbial life in the altered oceanic crust on Earth, and in extraterrestrial altered mafic-ultramafic rocks, particularly on Mars. PMID- 26496529 TI - Eye gaze performance for children with severe physical impairments using gaze based assistive technology-A longitudinal study. AB - Gaze-based assistive technology (gaze-based AT) has the potential to provide children affected by severe physical impairments with opportunities for communication and activities. This study aimed to examine changes in eye gaze performance over time (time on task and accuracy) in children with severe physical impairments, without speaking ability, using gaze-based AT. A longitudinal study with a before and after design was conducted on 10 children (aged 1-15 years) with severe physical impairments, who were beginners to gaze based AT at baseline. Thereafter, all children used the gaze-based AT in daily activities over the course of the study. Compass computer software was used to measure time on task and accuracy with eye selection of targets on screen, and tests were performed with the children at baseline, after 5 months, 9-11 months, and after 15-20 months. Findings showed that the children improved in time on task after 5 months and became more accurate in selecting targets after 15-20 months. This study indicates that these children with severe physical impairments, who were unable to speak, could improve in eye gaze performance. However, the children needed time to practice on a long-term basis to acquire skills needed to develop fast and accurate eye gaze performance. PMID- 26496530 TI - Executive Functioning of Combat Mild Traumatic Brain Injury. AB - This study investigates neuropsychological deficits in recently deployed veterans with mild traumatic brain injury (mTBI). Veterans discharged from 2007 to 2012 were recruited from Veterans Affairs clinics. Independent groups of participants with mTBI (n = 57) and those without TBI (n = 57) were administered the Beck Depression Inventory-II, Combat Exposure Scale, Word Memory Test, and the Self Awareness of Deficits Interview. Neuropsychological instruments included the Rey Osterrieth Complex Figure Test, Letter and Category Fluency, Trail-Making Test Parts A and B, Christiansen H-abbreviated, Soper Neuropsychology Screen, Wechsler Memory Scale subtests Logical Memory I and II, and the Street Completion Test. The mTBI group performed significantly worse on all of the executive and nonexecutive measurements with the exception of Category Fluency, after controlling for age, depression effort, and combat exposure. Depression and combat exposure were greater for the mTBI group. The mTBI group scored poorer on effort, but only the Multiple Choice subtest was significant. The mTBI group had good awareness of their deficits. PMID- 26496531 TI - Efficient Molecular Imprinting Strategy for Quantitative Targeted Proteomics of Human Transferrin Receptor in Depleted Human Serum. AB - Soluble transferrin receptor (sTfR) in serum has been suggested as a marker for breast cancer diagnosis, monitoring and treatment. However, sTfR levels in some situations could be far below the limit of quantification (LOQ) of most assays. Thus, an efficient sample pretreatment strategy is required. In this study, molecularly imprinted polymers (MIPs) were developed and coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted proteomics for sTfR measurement. The key to this effort was that the same surrogate peptide of sTfR (VEYHFLSPYVSPK, VK13) was employed in both the enrichment by MIPs and the quantification by targeted proteomics. Specifically, three peptide templates with different lengths were evaluated for the synthesis of MIPs, and the imprinting conditions were optimized. The characteristics of MIPs, including the adsorption capacity, adsorption kinetics, and binding selectivity, were also investigated. As a result, a ~12-fold enhancement of sensitivity was achieved using MIPs. An LOQ of 200 ng.mL(-1) was obtained. The intra- and interday precision were <10.7 and 7.8%, respectively. The accuracy was 7.5% at the lower limit of quantification (LLOQ) and <8.4% for the other QC levels. After validation, the assay was applied to determine the sTfR levels in breast cancer patients (n = 20) and healthy volunteers (n = 20) using the standard addition method. The corresponding levels of sTfR were 1.59 +/- 0.36 MUg.mL(-1) (range: 0.96-2.34 MUg.mL(-1)) in the volunteers and 1.82 +/- 0.42 MUg.mL(-1) (range: 0.95-2.47 MUg.mL(-1)) in the patients. This study is among the first to combine MIPs and LC MS/MS targeted proteomics for protein quantification at the peptide level. PMID- 26496532 TI - Differential relationships between chronic hormone profiles in pregnancy and maternal investment in rhesus monkey mothers with hair loss in the neonatal period. AB - Hair loss is commonly used as an indicator of well being in primate facilities, yet it has been shown to also occur in otherwise healthy pregnant and postpartum females. There is significant variability in the incidence of hair loss during these important developmental periods, reasons for which remain unclear. We studied female rhesus monkeys (Macaca mulatta, n = 47) with and without hair loss in pregnancy/postpartum. We hypothesized that, similar to previously published reports, pregnancy would result in an increased likelihood of hair loss, and that hair loss would be correlated with higher hair cortisol concentrations (HCCs). We further hypothesized that hair loss among pregnant females is related to differential maternal investment. We studied a subset of monkeys (n = 26) from mid-to-late pregnancy through peak lactation, some of which exhibited hair loss in the perinatal period (n = 15), and some of which did not (n = 11). We examined fetal measurements, infant birth weight, infant growth rate, and milk yield volume (MYV) in the first 30 days as indices of investment. We found that pregnant monkeys showed a greater incidence of hair loss across the study year (chi2(2) = 6.55, P = 0.038), and that mothers with hair loss had significantly higher HCCs in pregnancy than those without (F(2,28) = 3.8, P = 0.017, etap2 = 0.21). HCCs in pregnancy were correlated with severity of hair loss in the neonatal period (r(37) = 0.42, P = 0.008). Moreover, HCCs in pregnancy were positively correlated with infant birth weight (r(12) = 0.56, P = 0.038), infant growth rate (r(12) = 0.64, P = 0.014), and MYV (r(11) = 0.85, P < 0.001) for alopecic but not non-alopecic mothers. These mothers did not differ in fetal measurements, infant birth weight/growth rate, or MYV. Our results suggest that hair loss in some monkeys, especially during the birthing season, may be a signal of greater physiological stress during pregnancy and differential investment by mothers to their offspring. Am. J. Primatol. 79:e22489, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26496533 TI - Common and Rare Genetic Variants Associated With Alzheimer's Disease. AB - Alzheimer's disease (AD) is one of the most devastating disorders. Despite the continuing increase of its incidence among aging populations, no effective cure has been developed mainly due to difficulties in early diagnosis of the disease before damaging of the brain, and the failure to explore its complex underlying molecular mechanisms. Recent technological advances in genome-wide association studies (GWAS) and high throughput next generation whole genome, and exome sequencing had deciphered many of AD-related loci, and discovered single nucleotide polymorphisms (SNPs) that are associated with altered AD molecular pathways. Highlighting altered molecular pathways linked to AD pathogenesis is crucial to identify novel diagnostic and therapeutic AD targets. PMID- 26496534 TI - HbA1c: A Useful Screening Test for Gestational Diabetes Mellitus. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is associated with adverse maternal and fetal outcomes, and the oral glucose tolerance test (OGTT) is the recommended test for its diagnosis. We evaluated the role of glycated hemoglobin (HbA1c) in screening and diagnosis of GDM and its correlation with adverse pregnancy outcomes. SUBJECTS AND METHODS: In this prospective observational study, OGTT and HbA1c were performed in 500 antenatal women between 24 and 28 weeks of gestation; the pregnant women were followed up thereafter. Repeat OGTT and HbA1c were done in women with GDM at 6 weeks postpartum. RESULTS: Among the 500 women, 45 were diagnosed with GDM, for an incidence of 9%. The mean HbA1c level in women with GDM was 6.2 +/- 0.6%, whereas it was 5.4 +/- 0.5% in those with normoglycemia. Women with GDM had a higher incidence of pregnancy-related complications compared with normoglycemic women. An HbA1c cutoff of 5.3% had a sensitivity of 95.6% and a specificity of 51.6% for the diagnosis of GDM and would have avoided OGTT in approximately half of antenatal women, while missing 5% of the women. However, those with an abnormal HbA1c will require a confirmatory OGTT, as 50% of normoglycemic women would be misclassified as having GDM by this approach. On repeat testing postpartum, two of 45 women (4.4%) had overt diabetes mellitus, whereas five (11.1%) had impaired glucose tolerance. CONCLUSIONS: Although HbA1c cannot replace OGTT in the diagnosis of GDM, it can be used as a screening test, avoiding OGTT in approximately 50% of women, if a cutoff of 5.3% is used. PMID- 26496535 TI - Primary cutaneous lymphoma in southern Brazil: a 12-year single-center experience. AB - BACKGROUND: Primary cutaneous lymphomas (PCL) are a group of extranodal non Hodgkin lymphomas presenting with no evidence of extracutaneous disease at the time of diagnosis. Few longitudinal studies of PCL have been conducted, particularly in South American populations. Our objective was to describe the behavior of PCL and evaluate patient survival in a cohort of patients from southern Brazil. METHODS: We conducted a retrospective cohort study of all patients with a histopathological diagnosis of PCL receiving care at a tertiary referral center in southern Brazil from 2000 to 2012. Clinical, laboratory, and histopathological data, treatment variables, and survival curves were analyzed. RESULTS: Eighty-nine patients with PCL were included, with a mean age at diagnosis of 58.9 years. Cutaneous T-cell and natural killer (NK) cell lymphomas (CTCL/NKCL) accounted for 78.4% of cases and cutaneous B-cell lymphomas (CBCL) for 21.6%; 57.4% of patients with CTCL/NKCL and 50% of patients with CBCL were male. Half of all cases were mycosis fungoides (MF). The 5-year survival rate was 74.8% for MF, 61% for Sezary syndrome, 87.5% for primary cutaneous CD30+ lymphoproliferative disorders, and 88.9% for primary cutaneous follicle center lymphoma. CONCLUSIONS: In this cohort of patients with PCL from southern Brazil, CTCL/NKCL was more prevalent than CBCL, and the MF subtype was predominant. Survival curves were similar to those reported in the literature, except for Sezary syndrome, which had a better prognosis in this sample. PMID- 26496536 TI - A series of ceramide analogs modified at the 1-position with potent activity against the intracellular growth of Chlamydia trachomatis. AB - BACKGROUND: Chlamydia trachomatis is an intracellular pathogen that requires different nutrients, including sphingolipids, for survival. Components for the transport and biosynthesis of sphingolipids thus may have a potential as antichlamydial targets. RESULTS: In this study, we synthesized a collection of 24 ceramide derivatives. Three derivatives show pronounced activity with submicromolar IC50. The potency of these compounds was one order of magnitude higher than that of the antibiotic chloramphenicol. We show a detailed structure activity relationship study for this novel compound class exhibiting a significant effect on the growth of C. trachomatis L2 without penetrating the bacteria itself. CONCLUSION: The structure-activity relationship presented here defines an important step toward the molecular target of this compound class, which is still elusive. PMID- 26496537 TI - Efficacy and safety of sublingual immunotherapy in children. AB - Allergen immunotherapy (AIT) is currently the only available disease-modifying and aetiological treatment of IgE-mediated diseases. Sublingual allergen immunotherapy (SLIT) constitutes the preferred route of administration of AIT for respiratory allergies in Europe. Recently it has also been approved in the US. Further applications are currently under evaluation, such as IgE-mediated food allergy and IgE-mediated atopic dermatitis. The SLIT safety profile is overall favourable, although local adverse events, usually mild, are described. Most of the meta-analyses confirmed the efficacy of SLIT in reducing symptoms and medication intake in children with allergic diseases. AIT, as an immune modulating treatment, can modify the natural history of the allergic diseases: reduction of the risk of development of asthma and bronchial hyperreactivity in patients with allergic rhinitis, and reduction of the onset of new sensitizations. A great interest is now devoted to the preventive effects of AIT and, consequently, to the optimal time of initiation. PMID- 26496538 TI - Section Editor's Notebook: Health Policy and Practice. PMID- 26496539 TI - Trend Toward an Increase in Authorship for Leading Radiology Journals. AB - OBJECTIVE: The purpose of this study was to determine authorship trends in two leading radiology journals over the past 2 decades. MATERIALS AND METHODS: All original articles (n = 5195) published in AJR and Radiology for the periods 1991 1993, 2001-2003, and 2011-2013 were reviewed. The following variables were extrapolated from each article: number of authors, radiologic subspecialty, and country of origin. The number of authors listed per article was correlated with the publication period, journal, radiologic subspecialty, and country of origin. RESULTS: The mean number of authors per article increased from 5.1 in 1991-1993 to 6.2 in 2001-2003 and to 7.1 in 2011-2013 across both journals (p < 0.0001). Both AJR and Radiology had statistically significant increases in the number of authors per article over time, but the number of authors per article in Radiology was significantly higher than that in AJR (p < 0.0001 for all study periods). The number of authors per article significantly increased for all radiologic subspecialties. The mean numbers of authors per article by country of origin are as follows: Italy, 8.3; Japan, 7.6; France, 7.5; Germany, 7.4; China, 7.3; Austria, 7.2; and South Korea, 6.8. These were significantly higher than the mean number of authors from Switzerland, which was 6.3. CONCLUSION: The number of authors significantly and consistently increased in two leading radiology journals over the past 2 decades. PMID- 26496540 TI - How Much Do Common Imaging Studies Cost? A Nationwide Survey of Radiology Trainees. AB - OBJECTIVE: The objective of this study was to gauge the knowledge of radiology trainees regarding the costs of common imaging services and to assess their perceptions of current relevant education. SUBJECTS AND METHODS: During mid-2014, an online survey of 5325 U.S. residents and fellows who were members of the American College of Radiology was conducted. Respondents were asked to provide information about year of training, relevant advanced degrees (e.g., Master of Business Administration or Master of Public Health), number of hours of formal education in health care economics provided annually by their training program, self-perception of knowledge of health care economics, and desire to learn more about the costs of imaging. Respondents were asked to estimate Medicare-allowable fees for five commonly performed imaging examinations: two-view chest radiography, contrast-enhanced CT of the abdomen and pelvis, unenhanced MRI of the lumbar spine, complete abdominal ultrasound, and unenhanced CT of the brain. Responses within +/- 25% of published allowable amounts in the Medicare fee schedule were deemed correct. RESULTS: A total of 1066 of 5325 trainees (20.0%) returned surveys that were sufficiently complete for analysis. Only 17.1% of all responses were correct; 65.3% of responses were overestimations of actual costs, and 17.6% were underestimations. Almost half of the trainees (45.1%) incorrectly estimated the cost of every examination. Overall, knowledge of costs of examinations did not improve with advancing years of training, hours of education in health care economics, or attainment of a relevant advanced degree. Only 9.3% of trainees considered their knowledge of imaging costs to be adequate. An overwhelming 89.7% of trainees desired more focused education. CONCLUSION: Radiology trainees have limited knowledge of the costs of commonly performed imaging studies. Effective training program curricula currently appear to be lacking. Targeted education and integration of cost information into clinical decision support tools are probably warranted. PMID- 26496541 TI - Time-Out: It's Radiology's Turn--Incidence of Wrong-Patient or Wrong-Study Errors. AB - OBJECTIVE: The purpose of this study was to describe the utility of a two-person verification system (Rad Check) in successfully decreasing wrong-patient or wrong study errors. MATERIALS AND METHODS: In this retrospective study performed at a tertiary-care pediatric hospital, monthly radiology incident reports from January 2009 through December 2014 were reviewed for documentation of wrong-patient or wrong-study events. The date, imaging modality, nature of the event, and number of imaging studies for this time period by year were recorded and analyzed. These data were tracked before and after implementation of the two-person verification system in July 2012. RESULTS: Over 72 months, 45 reported wrong-patient or wrong study events were confirmed. The data were analyzed before and after implementation of a two-person verification system implemented in July 2012, midway through the study period. Over the first 42 months, 36 wrong-patient or wrong-study occurrences were identified, corresponding to an average of one error every 35 days, with the number of days between events ranging from 3 to 150. After implementation of the verification process, nine events were documented over 30 months, corresponding to an average of one error every 101 days, with the maximum number of days between events exceeding 410. CONCLUSION: Wrong-patient or wrong-study events can be significantly reduced by utilizing a brief two-person verification approach. More robust documentation of these events is warranted so that individual institutions can assess the incidence of these events within their own department and develop tailored plans to prevent these errors. PMID- 26496542 TI - JOURNAL CLUB: Radiologists' Perceptions of Computerized Decision Support: A Focus Group Study From the Medicare Imaging Demonstration Project. AB - OBJECTIVE: The purpose of this study was to discern radiologists' perceptions regarding the implementation of a decision support system intervention as part of the Medicare Imaging Demonstration project and the effect of decision support on radiologists' interactions with ordering clinicians, their radiology work flow, and appropriateness of advanced imaging. SUBJECTS AND METHODS: A focus group study was conducted with a diverse sample of radiologists involved in interpreting advanced imaging studies at Medicare Imaging Demonstration project sites. A semistructured moderator guide was used, and all focus group discussions were recorded and transcribed verbatim. Qualitative data analysis software was used to code thematic content and identify representative segments of text. Participating radiologists also completed an accompanying survey designed to supplement focus group discussions. RESULTS: Twenty-six radiologists participated in four focus group discussions. The following major themes related to the radiologists' perceptions after decision support implementation were identified: no substantial change in radiologists' interactions with referring clinicians; no substantial change in radiologist work flow, including protocol-writing time; and no perceived increase in imaging appropriateness. Radiologists provided suggestions for improvements in the decision support system, including increasing the usability of clinical data captured, and expressed a desire to have greater involvement in future development and implementation efforts. CONCLUSION: Overall, radiologists from health care systems involved in the Medicare Imaging Demonstration did not perceive that decision support had a substantial effect, either positive or negative, on their professional roles and responsibilities. Radiologists expressed a desire to improve efficiencies and quality of care by having greater involvement in future efforts. PMID- 26496543 TI - After-Hours Radiology: Challenges and Strategies for the Radiologist. AB - OBJECTIVE: Because of the increase in the use of 24-hour-a-day 7-day-a-week real time radiologic interpretation, radiologists more frequently perform after-hours work. The purpose of this article was to examine the challenges arising from after-hours work and describe evidence-based strategies meant to limit the adverse physical and psychologic stresses of after-hours work. CONCLUSION: Working nontraditional hours affects a radiologist's health, social life, professional productivity, and possibly interpretive accuracy. Appropriate attention to these factors and targeted countermeasures can optimize the professional development and personal well-being of radiologists working after hours. PMID- 26496544 TI - Radiologic Characterization of Ischemic Cholangiopathy in Donation-After-Cardiac Death Liver Transplants and Correlation With Clinical Outcomes. AB - OBJECTIVE: The purpose of this study was to define the cholangiographic patterns of ischemic cholangiopathy and clinically silent nonanastomotic biliary strictures in donation-after-cardiac-death (DCD) liver grafts in a large single institution series. We also examined the correlation of the radiologic findings with laboratory data and clinical outcomes. MATERIALS AND METHODS: Data were collected for all DCD liver transplants at one institution from December 1998 to December 2011. Posttransplant cholangiograms were obtained during postoperative weeks 1 and 3 and when clinically indicated. Intrahepatic biliary strictures were classified by anatomic distribution and chronologic development. Radiologic findings were correlated with laboratory data and with 1-, 3-, and 5-year graft and patient survival rates. RESULTS: A total of 231 patients received DCD grafts. Cholangiograms were available for 184 of these patients. Postoperative cholangiographic findings were correlated with clinical data and divided into the following three groups: A, normal cholangiographic findings with normal laboratory values; B, radiologic abnormalities and cholangiopathy according to laboratory values; and C, radiologic abnormalities without laboratory abnormalities. Group B had four distinct abnormal cholangiographic patterns that were predictive of graft survival. Group C had mild nonprogressive multifocal stenoses and decreased graft and patient survival rates, although cholangiopathy was not detected in these patients according to laboratory data. CONCLUSION: Patterns and severity of nonanastomotic biliary abnormalities in DCD liver transplants can be defined radiologically and correlate with clinical outcomes. Postoperative cholangiography can depict the mild biliary abnormalities that occur in a subclinical manner yet cause a marked decrease in graft and patient survival rates in DCD liver transplants. PMID- 26496545 TI - Usefulness of Ultralow-Dose (Submillisievert) Chest CT Using Iterative Reconstruction for Initial Evaluation of Sharp Fish Bone Esophageal Foreign Body. AB - OBJECTIVE: The purpose of this article was to evaluate the usefulness of ultralow dose chest CT as an initial imaging study for evaluation of sharp fish bone esophageal foreign body (FB). MATERIALS AND METHODS: A total of 57 subjects who underwent ultralow-dose chest CT were included in this retrospective study. All subjects had a history of ingestion and symptoms of esophageal FB. All ultralow dose chest CT data were reconstructed twice, once with filtered back projection (FBP) and once with iterative reconstruction, and three observers reviewed the images independently. ROC analysis was used to evaluate diagnostic performance of ultralow-dose chest CT. Intraclass correlation coefficient (ICC) was calculated for analysis of interobserver agreement. RESULTS: Among 57 patients, 42 were confirmed as having esophageal FB. Significant objective noise reduction of mediastinum was achieved using an iterative reconstruction technique. Subjective image noise of iterative reconstruction was significantly better than that of FBP. Overall diagnostic performance of ultralow-dose chest CT for esophageal FB of iterative reconstruction (AUC = 0.999) was significantly better than that of FBP (AUC = 0.95) (p = 0.02). Interobserver agreement was greater for iterative reconstruction (ICC = 0.944) than for FBP (ICC = 0.778). CONCLUSION: Ultralow dose chest CT using iterative reconstruction provided satisfactory diagnostic image quality for identifying fish bone esophageal FB with reduced radiation dose and high observer accuracy. Therefore, ultralow-dose chest CT would be adequate as a first-line imaging modality for fish bone esophageal FB. PMID- 26496546 TI - Cystic Duct Enhancement: A Useful CT Finding in the Diagnosis of Acute Cholecystitis Without Visible Impacted Gallstones. AB - OBJECTIVE: The purpose of this study was to determine the incremental value of the presence of cystic duct enhancement for diagnosing acute cholecystitis without visible impacted gallstones. MATERIALS AND METHODS: CT scans of 63 patients with acute cholecystitis and 63 control subjects were retrospectively and independently reviewed by two radiologists to determine the presence of cystic duct enhancement or impacted stones. Two additional radiologists were then asked to independently evaluate all CT images using a 5-point scoring system for diagnosing acute cholecystitis. They conducted the evaluations both before and after being informed that cystic duct enhancement could be substituted for a CT finding of impacted gallstones. RESULTS: The prevalence of either cystic duct enhancement or stone impaction was observed to be significantly more common in the patient group (86-91%) than in the control group (6-14%) (p < 0.001) with good interobserver agreement (kappa = 0.79). Diagnostic sensitivities increased significantly from 60.3% to 85.7% for reviewer 1 (p = 0.001) and from 71.4% to 87.3% for reviewer 2 (p = 0.028) after the reviewers were informed of the presence of cystic duct enhancement. Diagnostic accuracy increased significantly for the less experienced radiologist, from 75.4% to 87.3% (p = 0.015). CONCLUSION: The accuracy and sensitivity of CT for the diagnosis of acute cholecystitis improved significantly when cystic duct enhancement was used as an alternative to impacted gallstones as a diagnostic criterion. PMID- 26496547 TI - Small (< 4 cm) Renal Mass: Differentiation of Oncocytoma From Renal Cell Carcinoma on Biphasic Contrast-Enhanced CT. AB - OBJECTIVE: The purpose of this study was to evaluate whether small (< 4 cm) oncocytomas can be differentiated from renal cell carcinomas (RCCs) on biphasic contrast-enhanced CT. MATERIALS AND METHODS: Forty-three patients with 53 oncocytomas and 123 patients with 128 RCCs (24 papillary subtype and 104 clear cell and other subtypes) who underwent biphasic contrast-enhanced CT were included in the study. Patient demographics and CT tumor characteristics were evaluated in each case. A multinomial logistic regression model was then constructed for differentiating oncocytoma from clear cell and other subtype RCCs, oncocytoma from papillary RCCs, and clear cell and other subtype RCCs from papillary RCCs. The probability of each group was calculated from the model. Diagnostic performance among three pairwise diagnoses and between oncocytoma and any RCC (clear cell and other subtypes and papillary) were assessed by AUC values. RESULTS: Patient age, tumor CT attenuation values and skewness (i.e., histogram analysis of CT values) in both the corticomedullary and nephrographic phases, and subjective tumor heterogeneity were statistically significant variables in the multinomial logistic regression analysis. The logistic regression model using the variables yielded AUCs of 0.82, 0.95, 0.91, and 0.84 for differentiating oncocytomas from clear cell and other subtype RCCs, oncocytomas from papillary RCCs, clear cell and other subtype RCCs from papillary RCCs, and oncocytomas from any RCC (clear cell and other subtypes and papillary), respectively. CONCLUSION: A combination of imaging features on biphasic CT, including tumor CT attenuation values and tumor texture (heterogeneity and skewness), can help differentiate oncocytoma from RCC. PMID- 26496548 TI - Evaluation of Posttreatment Follow-Up of Patients With Prostate Cancer Relative to the American College of Radiology's Appropriateness Criteria. AB - OBJECTIVE: The American College of Radiology (ACR) Appropriateness Criteria panel has recommended that patients with prostate cancer who have received treatment undergo imaging only after suspected cancer recurrence. We examined whether local physicians followed this recommendation and what types of imaging examinations were ordered in a cohort of patients with local prostate cancer. MATERIALS AND METHODS: The Rochester Epidemiology Project, a research consortium that collects, links, and stores medical record information of Olmsted County, Minnesota, residents, was used to capture the complete medical history of treated patients with prostate cancer from 2000 through 2011. Clinical information and imaging examinations performed were retrieved by chart review. Suspected recurrence was defined as treatment-specific prostate-specific antigen level elevations, bone pain, or abnormal digital rectal examination findings. RESULTS: Of the 670 treated patients with prostate cancer who were included in the final analysis, 129 (19%) underwent posttreatment imaging. After excluding imaging related to retreatment or another cancer, 13 patients (i.e., 2% of the entire cohort and 10% of imaged patients) underwent imaging in the absence of suspected recurrence. A total of 90 patients (70% of imaged patients) underwent imaging after suspected recurrence. Of these 90 patients, 62 (69%) underwent a bone scan as their first imaging modality either alone or in combination with other imaging modalities. Of the providers who ordered a bone scan first, 27% were urologists, 23% were radiation oncologists, and 24% were primary care physicians. CONCLUSION: Most patients in this study did not undergo imaging in the absence of suspected recurrence. Various types of imaging examinations were ordered for patients with suspected recurrence. PMID- 26496549 TI - CT Gray-Level Texture Analysis as a Quantitative Imaging Biomarker of Epidermal Growth Factor Receptor Mutation Status in Adenocarcinoma of the Lung. AB - OBJECTIVE: The purpose of this study was to investigate the radiogenomic correlation between CT gray-level texture features and epidermal growth factor receptor (EGFR) mutation status in adenocarcinoma of the lung. MATERIALS AND METHODS: This retrospective study included 25 patients with exon 19 short inframe deletion (exon 19) and 21 patients with exon 21 L858R point (exon 21) EGFR mutations among 125 patients with EGFR mutant adenocarcinoma of the lung. The randomly formed control group consisted of 20 patients selected from 126 patients with EGFR mutation-negative (wild-type) adenocarcinomas. Five gray-level texture features (contrast, correlation, inverse difference moment, angular second moment, and entropy) were analyzed. RESULTS: Contrast differentiated both exon 19 (p = 0.00027) and exon 21 (p = 0.00001) mutants from the wild type. Wild-type adenocarcinomas had high scores for contrast (mean, 1598.547) compared with EGFR mutants (mean, 679.463). Correlation differentiated both exon 19 (p = 0.017) and exon 21 (p = 0.0015) mutants from wild-type adenocarcinomas. Inverse difference moment differentiated exon 19 mutants from exon 21 mutants (p = 0.019) and both exon 19 (p = 0.044) and exon 21 (p = 0.00001) mutants from wild-type adenocarcinomas. Angular second moment and entropy were not associated with statistically significant differences between mutation statuses. CONCLUSION: Contrast, correlation, and inverse difference moment texture features correlate with EGFR mutation status in adenocarcinoma of the lung. Further investigation with larger prospective studies is needed to validate the role of CT gray-level texture analysis as a quantitative imaging biomarker. PMID- 26496551 TI - Current Concepts in Total Ankle Replacement for Radiologists: Features and Imaging Assessment. AB - OBJECTIVE: This article reviews the current concepts of total ankle replacement (TAR). The features of traditional and new prosthetic designs, materials, and surgical techniques are discussed. Normal postoperative imaging findings are illustrated. CONCLUSION: TAR is becoming a mainstream treatment of end-stage ankle arthritis. Although the results after TAR have not reached the same level as those for hip arthroplasty and knee arthroplasty, the revision rates show that this form of therapy is rational and promising. For this reason, assessment of postoperative imaging is important. The foundation of the radiologic interpretation of TAR is knowledge of the physiologic purpose, orthopedic trends, imaging findings, and complications. PMID- 26496550 TI - Radiation Dose Reduction in Pediatric Body CT Using Iterative Reconstruction and a Novel Image-Based Denoising Method. AB - OBJECTIVE: The objective of this study was to evaluate the radiation dose reduction potential of a novel image-based denoising technique in pediatric abdominopelvic and chest CT examinations and compare it with a commercial iterative reconstruction method. MATERIALS AND METHODS: Data were retrospectively collected from 50 (25 abdominopelvic and 25 chest) clinically indicated pediatric CT examinations. For each examination, a validated noise-insertion tool was used to simulate half-dose data, which were reconstructed using filtered back projection (FBP) and sinogram-affirmed iterative reconstruction (SAFIRE) methods. A newly developed denoising technique, adaptive nonlocal means (aNLM), was also applied. For each of the 50 patients, three pediatric radiologists evaluated four datasets: full dose plus FBP, half dose plus FBP, half dose plus SAFIRE, and half dose plus aNLM. For each examination, the order of preference for the four datasets was ranked. The organ-specific diagnosis and diagnostic confidence for five primary organs were recorded. RESULTS: The mean (+/- SD) volume CT dose index for the full-dose scan was 5.3 +/- 2.1 mGy for abdominopelvic examinations and 2.4 +/- 1.1 mGy for chest examinations. For abdominopelvic examinations, there was no statistically significant difference between the half dose plus aNLM dataset and the full dose plus FBP dataset (3.6 +/- 1.0 vs 3.6 +/- 0.9, respectively; p = 0.52), and aNLM performed better than SAFIRE. For chest examinations, there was no statistically significant difference between the half dose plus SAFIRE and the full dose plus FBP (4.1 +/- 0.6 vs 4.2 +/- 0.6, respectively; p = 0.67), and SAFIRE performed better than aNLM. For all organs, there was more than 85% agreement in organ-specific diagnosis among the three half-dose configurations and the full dose plus FBP configuration. CONCLUSION: Although a novel image-based denoising technique performed better than a commercial iterative reconstruction method in pediatric abdominopelvic CT examinations, it performed worse in pediatric chest CT examinations. A 50% dose reduction can be achieved while maintaining diagnostic quality. PMID- 26496552 TI - Unilateral Sacroiliitis: Differential Diagnosis Between Infectious Sacroiliitis and Spondyloarthritis Based on MRI Findings. AB - OBJECTIVE: The purpose of this study was to identify the MRI features that aid in the differentiation between infectious sacroiliitis and unilateral sacroiliitis associated with spondyloarthritis. MATERIALS AND METHODS: The MR images of 54 patients who received a diagnosis unilateral sacroiliitis between August 2001 and August 2013 were reviewed. MR images were evaluated for bone lesions (extent and distribution of bone marrow edema and presence and size of bone erosions), soft tissue lesions (capsulitis, extracapsular fluid collections, and periarticular muscle edema), and joint space enhancement. The Fisher exact test was used for comparison of categoric data, and multivariate stepwise logistic regression analysis was performed. RESULTS: Thick capsulitis, extracapsular fluid collection, and periarticular muscle edema were all more frequently observed in infectious sacroiliitis (p < 0.001). Iliac-dominant bone marrow edema and joint space enhancement were statistically significantly more common in spondyloarthritis (p < 0.001 and p = 0.014, respectively). The presence of periarticular muscle edema was the only independently differentiating variable on multivariate stepwise logistic regression analysis. When periarticular muscle edema was the sole predictor, unilateral sacroiliitis in spondyloarthritis was correctly identified in 77.3% of cases, and infectious sacroiliitis was correctly identified in 90.6% of cases. The overall accuracy was 85.2%. CONCLUSION: MRI features of the bone lesions, soft-tissue lesions, and joint space enhancement in unilateral sacroiliitis aid in the differential diagnosis between infection and spondyloarthritis. Among various findings, periarticular muscle edema was the single most important predictor of infectious sacroiliitis. PMID- 26496553 TI - Usefulness of Unenhanced MRI and MR Arthrography of the Shoulder in Detection of Unstable Labral Tears. AB - OBJECTIVE: Shoulder surgeons commonly intervene to repair unstable labral tears (tears that displace with patient movement). Surgeons can detect unstable tears at surgery. It is difficult to be certain if a tear is unstable from a static MR image. This study reports the comparative benefits of using unenhanced MRI and MR arthrography together to detect unstable labral tears. MATERIALS AND METHODS: One hundred fifty consecutive unenhanced shoulder MRI and MR arthrography examinations performed on the same patients were reviewed retrospectively by consensus reading of two musculoskeletal radiologists. Both unenhanced MRI and MR arthrography were performed on each patient on the same day. Labral tears were assessed. It was also determined if there was any difference in position of the labral tear between unenhanced MR images and MR arthrograms. A change in position of 4 mm or more between unenhanced MR images and MR arthrograms was considered indicative of an unstable tear. All patients proceeded to arthroscopy. RESULTS: Of these 150 patients, 94 had superior labral anterior-to-posterior (SLAP) tears, 53 had posterior labral tears, and 42 had anterior labral tears on MRI. All lesions described on MRI were described on arthroscopy. Twenty-three SLAP tears, 16 posterior labral tears, and 17 anterior labral tears showed a change in the position of the labral tear when comparing unenhanced MR images versus MR arthrograms of 4 mm or more. All of these labral tears were considered unstable by the surgeon, and all of these patients had surgical tacking performed. The other labral tears showed motion on unenhanced MR images and MR arthrograms of less than 4 mm. All of these tears except for three were considered stable on arthroscopic examination. There were five SLAP tears, three anterior labral tears, and four posterior labral tears seen on arthroscopy that were not seen on unenhanced MRI or MR arthrography. The tears not seen on unenhanced MRI or MR arthrography were considered stable at arthroscopy. CONCLUSION: In this study, unenhanced MRI and MR arthrography of the shoulder was useful in diagnosing unstable labral tears in 23 patients with SLAP tears, 16 patients with posterior labral tears, and 17 patients with anterior labral tears. This information was useful in surgical planning. Of 133 tears that moved less than 4 mm on unenhanced MR images and MR arthrograms, 130 were considered stable on arthroscopy. PMID- 26496554 TI - Calcaneal Avulsion Fractures: An Often Forgotten Diagnosis. AB - OBJECTIVE: The calcaneus is the primary weight bearing bone in the heel, and its many surface contours render it a relatively difficult bone to visualize in its entirety. The stabilizing ligaments that hold the calcaneus in place occupy very specific locations, and the Achilles tendon enthesis is in a relatively constant location; therefore, avulsion fractures occur in reproducible locations. CONCLUSION: The mechanisms of injuries include overuse and neuropathic conditions, although most cases are related to trauma. PMID- 26496556 TI - Performance of Apparent Diffusion Coefficient Values and Conventional MRI Features in Differentiating Tumefactive Demyelinating Lesions From Primary Brain Neoplasms. AB - OBJECTIVE: Tumefactive demyelinating lesions (TDLs) remain one of the most common brain lesions to mimic a brain tumor, particularly primary CNS lymphoma (PCNSL) and high-grade gliomas. The purpose of our study was to evaluate the ability of apparent diffusion coefficient (ADC) values and conventional MRI features to differentiate TDLs from PCNSLs and high-grade gliomas. MATERIALS AND METHODS: Seventy-five patients (24 patients with TDLs, 28 with PCNSLs, and 23 with high grade gliomas) with 168 brain lesions (70 TDLs, 68 PCNSLs, and 30 high-grade gliomas) who underwent DWI before surgery or therapy were included in the study. Minimum ADC (ADC(min)) and average ADC (ADC(avg)) values were calculated for each lesion. ANOVA and ROC analyses were performed. ROC analyses were also performed for the presence of incomplete rim enhancement and for the number of lesions. Multiple-variable logistic regression with ROC analysis was then performed to evaluate performance in multiple-variable models. RESULTS: ADC(min) was statistically significantly higher (p < 0.01) in TDLs (mean, 0.886; 95% CI, 0.802 0.931) than in PCNSLs (0.547; 95% CI, 0.496-0.598) and high-grade gliomas (0.470; 95% CI, 0.385-0.555). (All ADC values in this article are reported in units of * 10(-3) mm(2)/s.) ADC(avg) was statistically significantly higher (p < 0.01) in TDLs (mean, 1.362; 95% CI, 1.268-1.456) than in PCNSLs (0.990; 95% CI, 0.919 1.061) but not in high-grade gliomas (1.216; 95% CI, 1.074-1.356). Multiple variable models showed statistically significant individual effects and superior diagnostic performance on ROC analysis. CONCLUSION: TDLs can be diagnosed on preoperative MRI with a high degree of specificity; MRI features of incomplete rim enhancement, high ADC values, and a large number of lesions individually increase the probability and diagnostic confidence that a lesion is a TDL. PMID- 26496557 TI - MRI Findings After Surgery for Chiari Malformation Type I. AB - OBJECTIVE: Surgery plays an important role in the management of Chiari I malformation. The purpose of this article is to review expected and unexpected MRI findings after the various types of surgery performed during the treatment of Chiari I malformation and associated abnormalities. CONCLUSION: Familiarity with optimal MRI techniques and findings is important when evaluating postoperative changes after treatment of Chiari I malformation. PMID- 26496555 TI - Hippocampal Malrotation Is Associated With Prolonged Febrile Seizures: Results of the FEBSTAT Study. AB - OBJECTIVE: Hippocampal malrotation is characterized by incomplete hippocampal inversion with a rounded shape and blurred internal architecture. There is still debate about whether hippocampal malrotation has pathologic significance. We present findings from the Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study on the frequency of and risk factors for hippocampal malrotation. SUBJECTS AND METHODS: FEBSTAT is a prospective multicenter study investigating the consequences of febrile status epilepticus in childhood. MRI studies of 226 patients with febrile status epilepticus were analyzed visually by two board certified neuroradiologists blinded to clinical details and were compared with MRI studies of 96 subjects with first simple febrile seizure. Quantitative analysis of hippocampal volume was performed by two independent observers. RESULTS: Hippocampal malrotation was present in 20 of 226 (8.8%) patients with febrile status epilepticus compared with two of 96 (2.1%) control subjects (odds ratio [OR], 4.56; 95% CI, 1.05-19.92). Hippocampal malrotation was exclusively left-sided in 18 of 22 (81.8%) patients and bilateral in the remaining four patients (18.2%). There was no case of exclusively right-sided hippocampal malrotation. Hippocampal malrotation was more common in boys than in girls (OR, 6.1; 95% CI, 1.7-21.5). On quantitative volumetric MRI analysis, the left hippocampal volume was smaller in patients with hippocampal malrotation than in control subjects with simple febrile seizure (p = 0.004), and the right-to-left hippocampal volume ratio was higher in the hippocampal malrotation group than in the simple febrile seizure group (p < 0.001). CONCLUSION: Hippocampal malrotation is a developmental malformation that predominantly affects the left hippocampus in male patients and is more frequently found in children with prolonged febrile status epilepticus than in control subjects. These data provide further evidence that hippocampal malrotation represents a pathologic error in brain development rather than a normal variant. PMID- 26496558 TI - Comparison of Standardized Uptake Values in Normal Structures Between PET/CT and PET/MRI in a Tertiary Pediatric Hospital: A Prospective Study. AB - OBJECTIVE: The purpose of this study was to compare standardized uptake values (SUVs) of normal tissues using MR attenuation-corrected versus CT attenuation corrected (18)F-FDG PET in a pediatric population. SUBJECTS AND METHODS: Thirty five patients (21 boys; mean age, 13.3 years) referred for 47 PET/CT scans were recruited to undergo PET/MRI. MR attenuation correction was performed using an automated three-segment model. ROIs were drawn over nine normal structures to estimate SUV(min), SUV(mean), and SUV(max). Pearson rank correlation coefficients were calculated to compare SUVs obtained from MR and CT attenuation correction. In nine patients who underwent multiple PET/MRI studies, coefficients of variance and intraclass correlation coefficients were calculated to evaluate intrapatient SUV(max) variation. RESULTS: Mean (+/- SD) time to imaging after FDG injection was 108 +/- 17 minutes for PET/CT and 61 +/- 6 minutes for PET/MRI. PET/MRI SUVs in all tissues were lower than those for PET/CT (mean difference, -28.9% +/- 31.1%; p < 0.05). Very high or high correlation between PET/MRI and PET/CT SUV(max) was found in brain (r = 0.72), myocardium (r = 0.95), and bone marrow (r = 0.85) (p < 0.001). Moderate correlation was found in liver (r = 0.54), fat (r = 0.41), mean blood pool (r = 0.40), and psoas muscle (r = 0.38) (p < 0.01). Weak correlation was found in lung (r = 0.12) and iliacus muscle (r = 0.12). Compared with PET/CT, PET/MRI systematically undermeasured SUV. In nine patients who underwent multiple PET/MRI examinations, moderate or strong agreement was found in the SUV(max) of six of nine tissues, similar to the corresponding PET/CT examinations. CONCLUSION: Our study showed overall high correlation for SUV measurements obtained from MR attenuation correction compared with CT attenuation correction, although PET/MRI underestimated SUV compared with PET/CT. SUVs measured from PET/MRI indicated good intrapatient reliability. PMID- 26496559 TI - Intratherapy or Posttherapy FDG PET or FDG PET/CT for Patients With Head and Neck Cancer: A Systematic Review and Meta-analysis of Prognostic Studies. AB - OBJECTIVE: The objective of this study was to determine the predictive value of intra-therapy or posttherapy FDG PET or FDG PET/CT with regard to overall survival (OS) and event-free survival (EFS) outcomes for patients with head and neck cancer (HNC). MATERIALS AND METHODS: A systematic search of the MEDLINE and EMBASE databases was performed. Studies in which PET/CT was performed during or after completion of primary therapy and for which survival outcomes were reported were included. OS and EFS were considered as outcomes. The pooled estimates of hazard ratios (HRs) and Mantel-Haenszel risk ratios (RRs) were generated for summary effects. RESULTS: Twenty-six studies were eligible for inclusion. The pooled HRs for OS (nine studies, 600 patients) and EFS (eight studies, 479 patients) were 3.55 (95% CI, 2.35-5.37) and 4.73 (95% CI, 2.61-8.56), respectively. Results from the RR analyses, including all 26 studies, showed that intratherapy or posttherapy PET/CT could significantly predict the 2-year and 3- to 5-year risk of death or disease progression. A positive PET result was associated with a more-than-sixfold increase in the risk of death within 2 years (2-year RR, 6.19 [95% CI, 3.04- 12.62]), which is attenuated--but remains significant--with longer follow-up (3- to 5-year RR, 2.42 [95% CI, 1.76-3.32]). The estimated pooled RRs for 2-year mortality were 8.31 (95% CI, 3.83-18.01) for posttherapy PET/CT versus 3.99 (95% CI, 1.43-11.10) for intratherapy PET/CT. CONCLUSION: Positive results of intratherapy or posttherapy PET/CT examinations strongly predict the risk of adverse events and death, particularly within 2 years but also up to 5 years, for patients with HNC. PMID- 26496560 TI - Safety of Blood Pool Contrast Agent Administration in Children and Young Adults. AB - OBJECTIVE: The objective of our study was to determine the adverse reaction rate associated with the administration of blood pool contrast material in children and young adults. MATERIALS AND METHODS: A review of the MRI and pharmacy databases identified all patients who received gadofosveset trisodium from October 1, 2011, to June 30, 2014. Patients were classified as having been anesthetized or not anesthetized for the MRI examinations. A review of the electronic medical records identified adverse reactions recorded within 24 hours of contrast administration. The adverse reactions were graded as mild, moderate, or severe. Risk ratios were calculated between the adverse reaction rate experienced by anesthetized patients and that experience by nonanesthetized patients. RESULTS: During the study period, 626 patients (mean age, 11.7 years) received 711 doses of gadofosveset trisodium; 137 adverse reactions were recorded, which yields a 19.3% (137/711) adverse reaction rate. There were 115 adverse reactions experienced by 367 anesthetized patients (31.3%): 93.0% (107/115) were mild and 7.0% (8/115) were moderate. The remaining 22 adverse reactions were experienced by 344 (6.4%) nonanesthetized patients, and 90.9% (20/22) were mild. Three nonanesthetized patients had allergiclike reactions; of these allergiclike reactions, one was mild and two were severe for a severe allergiclike reaction rate of 0.28% (2/711). Severe allergiclike reactions were treated without any adverse outcomes. Anesthetized patients were 5.7 times more likely to experience an adverse event than nonanesthetized patients; most reactions in anesthetized patients were seen after the administration of anesthesia alone. CONCLUSION: Most reactions after gadofosveset trisodium administration in children and young adults are mild; however, severe allergiclike reactions occur, so policies must be in place to treat patients with adverse reactions when using this contrast agent. These data may be useful to centers considering administering gadofosveset trisodium to pediatric patients. PMID- 26496561 TI - Predictive Value of MRI Findings for the Identification of a Hernia Sac in Fetuses With Congenital Diaphragmatic Hernia. AB - OBJECTIVE: The purpose of this study was to identify MRI features of diaphragmatic hernia sac, as well as to assess the accuracy of diagnosing a sac prenatally. MATERIALS AND METHODS: All fetal MRI examinations performed for intrapleural congenital diaphragmatic hernia (CDH) from 2004 to 2013 were retrospectively reviewed by two pediatric radiologists blinded to the hernia sac status (defined intraoperatively or at autopsy). Reviewers noted whether a sac was present on the basis of identification of the following four MRI findings: 1, meniscus of lung posterior or apical to the hernia contents; 2, encapsulated appearance of hernia contents, exerting less than expected mass effect on the heart and mediastinum; 3, presence of pleural fluid outlining a sac from above; and 4, presence of ascites outlining a sac from below. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each finding and for various combinations. Contingency tables, chi square testing, and logistic regression were applied to calculate the probability of a sac. RESULTS: Ninety patients were included: 21 with and 69 without a sac. The first three MRI findings correlated with the presence of a sac. Logistic regression yielded high predicted probability of a sac when one finding was identified (finding 1, 94.4%; finding 2, 96.2%). Adding a second and a third finding improved the probability to 99.7% and 99.9%, respectively. Sensitivity and specificity for the presence of a sac were 0.43 and 0.97, respectively. PPV and NPV were 83.8% and 80%, respectively. CONCLUSION: On fetal MRI, presence of a hernia sac in CDH can be diagnosed with high specificity when indicative findings are present. PMID- 26496562 TI - Repeat Large-Volume Paracentesis Versus Tunneled Peritoneal Catheter Placement for Malignant Ascites: A Cost-Minimization Study. AB - OBJECTIVE: The objective of this study was to determine the point in time at which tunneled peritoneal catheter placement becomes less costly than repeat large-volume paracentesis (LVP) for patients with malignant ascites. MATERIALS AND METHODS: Procedure costs were based on 2013 Medicare reimbursement rates. Rates for specific complications were obtained from the literature and were assigned costs. A decision tree-based Markov chain Monte Carlo model was designed with 11 cycles of 10 days, to simulate 4000 subjects per trial. Patients were grouped according to initial treatment decision (LVP vs catheter placement), and the total cost at the end of each 10-day cycle was calculated. The point at which catheter placement became less costly than LVP was determined. Additional simulations were used for bivariate analyses of all cost and probability variables and for trivariate analysis of cycle length and volume of fluid drained per cycle. RESULTS: Individual input probabilities were not significantly different from corresponding simulation outcomes (p value range, 0.068-0.95). When complications were included in the model, the cost curves crossed at a mean (+/- SD) of 82.8 +/- 3.6 days (range, 75.8-89.6 days), corresponding to a time between the performance of the ninth and 10th LVP procedures. Intersection occurred earlier in simulations with a shorter cycle length and less fluid per cycle, but it was minimally affected by changing individual complication probabilities and costs. CONCLUSION: For patients with malignant ascites, LVP becomes more costly once the procedure is performed nine or 10 times or at approximately 83 days, if paracentesis is repeated every 10 days, with 5 L of fluid removed each time. Use of a tunneled peritoneal catheter improves the cost advantage for patients who receive LVP more frequently or patients who have less than 5 L of fluid drained per procedure. PMID- 26496563 TI - Radiologic Retrograde Gastrostomy Tube Insertions Without the Use of Barium: Implications for Radiation Dose in Children. AB - OBJECTIVE: Historically, percutaneous radiologic retrograde gastrostomy tube insertions in children were performed using barium to opacify the colon. The purpose of this study was to examine whether performing radiologic gastrostomy tube insertions without barium affects patient radiation dose. CONCLUSION: The method of radiologic gastrostomy tube insertion without barium significantly reduced patient dose, fluoroscopy time, dose-area product (DAP), and weight-and time-adjusted DAP. PMID- 26496564 TI - CT-Guided Lead Placement for Selective Sacral Neuromodulation to Treat Lower Urinary Tract Dysfunctions. AB - OBJECTIVE: Selective sacral neuromodulation may fail after fluoroscopically guided lead placement because of malpositioning. We implemented a new technique to attain precise lead placement. CONCLUSION: CT-guided tined lead placement was successful in eight patients after 12-month follow-up. Especially in patients with an altered anatomy in the sacral region, this new technique may prevent treatment failure. PMID- 26496565 TI - Baseline Screening Mammography: Performance of Full-Field Digital Mammography Versus Digital Breast Tomosynthesis. AB - OBJECTIVE: Baseline mammography studies have significantly higher recall rates than mammography studies with available comparison examinations. Digital breast tomosynthesis reduces recalls when compared with digital mammographic screening alone, but many sites operate in a hybrid environment. To maximize the effect of screening digital breast tomosynthesis with limited resources, choosing which patient populations will benefit most is critical. This study evaluates digital breast tomosynthesis in the baseline screening population. MATERIALS AND METHODS: Outcomes were compared for 10,728 women who underwent digital mammography screening, including 1204 (11.2%) baseline studies, and 15,571 women who underwent digital breast tomosynthesis screening, including 1859 (11.9%) baseline studies. Recall rates, cancer detection rates, and positive predictive values were calculated. Logistic regression estimated the odds ratios of recall for digital mammography versus digital breast tomosynthesis for patients undergoing baseline screening and previously screened patients, adjusted for age, race, and breast density. RESULTS: In the baseline subgroup, recall rates for digital mammography and digital breast tomosynthesis screening were 20.5% and 16.0%, respectively (p = 0.002); digital breast tomosynthesis screening in the baseline subgroup resulted in a 22% reduction in recall compared with digital mammography, or 45 fewer patients recalled per 1000 patients screened. Digital breast tomosynthesis screening in the previously screened patients resulted in recall reduction of 14.3% (p < 0.001; p for interaction = 0.21). The recall rate reduction for baseline screening was especially pronounced in women younger than 50 years (p = 0.005). DBT implementation resulted in an increase in cancer detection in the baseline subgroup of 40.5% versus an increase in the previously screened subgroup of 17.4%. DBT implementation resulted in an increase in PPV1 in the baseline subgroup of 85% versus 35.3% in the previously screened subgroup, although the p-interaction was not significant. CONCLUSION: If resources are limited, women younger than 50 years who are undergoing baseline screening or do not have prior available mammograms may benefit more from digital breast tomosynthesis than from digital mammography alone. PMID- 26496566 TI - "Off Label" Use of FDA-Approved Devices and Digital Breast Tomosynthesis. AB - OBJECTIVE: The purpose of this article is to clarify for radiologists the meaning of U.S. Food and Drug Administration (FDA) approval with respect to Digital Breast Tomosynthesis (DBT). CONCLUSION: DBT is a major improvement over 2D mammography in the detection of cancers (sensitivity) and the reduction in recalls resulting from screening (specificity). Most imaging systems that have been approved by the FDA are used "off label" for breast imaging. Although the FDA determines which claims a manufacturer can make for a device, physicians may use approved devices, such as DBT, off label to provide better patient care. PMID- 26496567 TI - Question on Nuclear Medicine Shipments. PMID- 26496568 TI - Project Management for Quality Improvement in Radiology. AB - OBJECTIVE: This article outlines a structured approach for applying project management principles to quality improvement in radiology. We highlight the framework we use for managing improvement projects in our department and review basic project management principles. CONCLUSION: Project management involves techniques for executing projects effectively and efficiently. We recognize the following phases for managing improvement projects: idea, project evaluation and selection, role assignment, planning, improvement, and sustaining improvement. PMID- 26496569 TI - MR Enterography of the Ileoanal Pouch: Descriptive Radiologic Analysis With Endoscopic and Pathologic Correlation. AB - OBJECTIVE: The purpose of this study was to describe the MR enterography (MRE) appearance of inflammation of the ileoanal pouch after ileal pouch-anal anastomosis (IPAA) surgery and to correlate it with pouch endoscopic and histopathologic findings. MATERIALS AND METHODS: All MRE studies performed between October 1, 2007, and September 30, 2013, for patients who had previously undergone IPAA (n = 54) were retrieved. After review of medical records, the patients who underwent MRE, pouch endoscopy, and biopsy within 90 days (14 men, 14 women; mean age, 42.2 years; range, 24-67 years) were selected for inclusion in the study. Two blinded MRI radiologists in consensus retrospectively evaluated MRE studies for multiple MRI features. Two MRI scores were then calculated: an active and a composite inflammation score. A gastroenterologist retrospectively reviewed the pouch endoscopic images, and a pathologist reviewed the slides; both of these investigators were blinded. Both MRI scores were correlated with the pouch endoscopic and histopathologic findings. RESULTS: The composite MRI score had strong positive correlation with the endoscopic score (r = 0.61; p = 0.0005) but weak positive correlation with the histopathologic score (r = 0.31; p = 0.10, not statistically significant). The active inflammation MRI score had moderate positive correlation with the endoscopic score (r = 0.57; p = 0.0017) and weak positive correlation with the histopathologic score (r = 0.20; p = 0.31, not statistically significant). An MRI score >= 4 indicated the best results, with sensitivity of 86%, specificity of 79%, positive predictive value of 80%, negative predictive value of 85%, and accuracy of 82% for pouch inflammation. A positive likelihood ratio of 4.00 and negative likelihood ratio of 0.18 were obtained. CONCLUSION: In patients who have undergone IPAA surgery, the MRE findings strongly correlate with the pouch endoscopic findings with high sensitivity and positive predictive value for pouch inflammation. Therefore, MRE is a useful noninvasive test performed without ionizing radiation that can be used to evaluate patients with clinical symptoms and possibly alleviate the need for endoscopy in a select patient population. PMID- 26496570 TI - Low-Dose (2-mSv) CT in Adolescents and Young Adults With Suspected Appendicitis: Advantages of Additional Review of Thin Sections Using Multiplanar Sliding-Slab Averaging Technique. AB - OBJECTIVE: The purpose of this study is to assess the advantages of additional multiplanar sliding-slab averaging review of 2-mm-thick (thin) sections over stack review of 5-mm-thick (thick) sections in difficult cases of 2-mSv CT in adolescents and young adults with suspected appendicitis. MATERIALS AND METHODS: We included 149 patients (mean age, 28.0 years; 61 male patients and 88 female patients) for whom the initial CT reports were inconclusive for the diagnosis of appendicitis. Five independent radiologists retrospectively reviewed the thick sections in the stack mode and then the thin sections using sliding-slab averaging. In each review, they rated the likelihood of appendicitis and the appendix visualization using 5- and 3-point Likert scales, respectively. Diagnostic performance and confidence were compared between the two reviews using ROC analysis, McNemar tests, and Wilcoxon signed-rank tests. RESULTS: The pooled AUCs were 0.90 and 0.93 for the stack and sliding-slab averaging reviews, respectively (90% CI for the difference, 0.002-0.06; p = 0.087). For the individual readers, the sliding-slab averaging review tended to increase the AUC (range, 0.86-0.93 for stack vs 0.87-0.97 for sliding-slab averaging review), improve the confidence in diagnosing (mean score, 3.6-4.7 vs 3.9-4.7) or ruling out (1.6-2.1 vs 1.5-1.9) appendicitis, reduce indeterminate interpretations (0 15% vs 0-11%), and enhance the normal appendix visualization (1.1-1.7 vs 1.1 1.9), although the differences were not always statistically significant. CONCLUSION: Sliding-slab averaging review of thin sections is helpful when the diagnosis of appendicitis is difficult at 2-mSv CT in adolescents and young adults. PMID- 26496571 TI - Split-Bolus Portal Venous Phase Dual-Energy CT Urography: Protocol Design, Image Quality, and Dose Reduction. AB - OBJECTIVE: The purpose of this study is to evaluate the image quality of split bolus portal venous phase urography and the potential reduction of radiation dose by using a second-generation dual-source dual-energy CT (DECT) scanner. MATERIALS AND METHODS: DECT urography was performed in 84 patients. Unenhanced CT was performed 20 minutes after drinking 800 mL of water. The split-bolus protocol consisted of a sequence of injections, as follows: 200 mL of normal saline (2.0 mL/s), 50 mL of contrast medium (2.5 mL/s) at 0 second, 70 mL of contrast medium (2.5 mL/s) at 360 seconds, and a saline flush of 25 mL. The scan was started at 420 seconds. Virtual unenhanced images were reconstructed from contrast-enhanced images. The mean CT density and signal-to-noise ratio (SNR) of the renal parenchyma, vessels, upper urinary tract, normal reference tissues, and tumors were measured for image quantitative analysis. Image quality and opacification of the collecting systems were rated by two radiologists using 3- or 4-point scales. RESULTS: The SNR of all measured sites, except the renal pelvis, showed a statistically significant correlation (p < 0.001) between the true unenhanced and virtual unenhanced images. The overall sensitivity of stone detection was 87.5% (28/32) in virtual unenhanced images. Image quality of the renal parenchyma, arteries, and veins was excellent in 59.5%, 75.0%, and 97.6% of cases, respectively. Opacification of the intrarenal collecting systems, proximal, middle, and distal ureters, and bladder was complete in 92.9%, 83.9%, 78.6%, 77.4%, and 26.2% of patients, respectively. Omitting the unenhanced scan can reduce the mean radiation dose from 15.6 to 6.7 mSv. CONCLUSION: Portal venous phase split-bolus DECT urography provides sufficient image quality with potential to reduce radiation exposure. PMID- 26496572 TI - Rotator Cuff Tear Arthropathy: Pathophysiology, Imaging Characteristics, and Treatment Options. AB - OBJECTIVE: The purpose of this article is to review the biomechanical properties of the rotator cuff and glenohumeral joint and the pathophysiology, imaging characteristics, and treatment options of rotator cuff tear arthropathy (RCTA). CONCLUSION: Although multiple pathways have been proposed as causes of RCTA, the exact cause remains unclear. Increasing knowledge about the clinical diagnosis, imaging features, and indicators of severity improves recognition and treatment of this pathologic condition. PMID- 26496573 TI - Visual Defects in Patients With Pituitary Adenomas: The Myth of Bitemporal Hemianopsia. AB - OBJECTIVE: The objective of this study was to test the hypothesis that bitemporal hemianopsia (BHA) is the most common visual field (VF) defect in patients with pituitary macroadenoma and to assess the degree of optic pathway compression necessary to produce visual defects. MATERIALS AND METHODS: We reviewed the MRI findings and medical records of 119 patients with pituitary macroadenoma who had undergone formal assessment of VFs. We then evaluated the degree of optic pathway displacement caused by the pituitary macroadenoma, as observed on MR images. The classifications of optic pathway displacement included no contact, abutment but no displacement, mild displacement (< 3 mm), and moderate displacement (>= 3 mm). Qualitative analysis classified VFs as normal or as having defects that were monocular, bitemporal, mixed (bitemporal with additional defects), homonymous, or nonspecific. RESULTS: A total of 89 of 115 patients had an abnormal VF. Only one patient had true BHA. The most common defects were bitemporal or mixed defects (in 49 of 115 patients [42.6%]), likely because more than just the chiasm is often compressed by the pituitary macroadenoma. Classification of optic pathway displacement by the pituitary macroadenoma was as follows: 23 patients had no contact, eight had abutment but no displacement, 27 had mild displacement, and 57 had moderate displacement. In 78 of the 92 patients (84.8%) with pituitary macroadenoma that had contact with the optic pathway, contact was with the optic chiasm and the prechiasmal optic nerve. Of the 49 patients with bitemporal or mixed defects, 42 had moderate displacement of the optic pathway caused by their tumors. CONCLUSION: BHA is exceedingly uncommon in patients with pituitary macroadenoma. However, although bitemporal and mixed defects are the most common abnormal VF findings, they were found in only 42.6% of patients. Such defects rarely occur if the tumor displaces the optic pathway less than 3 mm from baseline. PMID- 26496574 TI - Characteristics and Limitations of FDG PET/CT for Imaging of Squamous Cell Carcinoma of the Head and Neck: A Comprehensive Review of Anatomy, Metastatic Pathways, and Image Findings. AB - OBJECTIVE: This image-based article illustrates the anatomic regions of squamous cell carcinomas of the head and neck and describes the metastatic pathways in and TNM staging for each region. Both the role and limitations of FDG PET/CT in imaging such cancers are discussed, and cases exemplifying these issues are reported. Also included is a discussion of the use of FDG PET/CT to monitor the response of squamous cell carcinomas of the head and neck to therapy, in addition to a brief comparison of PET/CT with such traditional imaging modalities as CT, MRI, and ultrasound. CONCLUSION: Understanding the characteristics of squamous cell carcinoma of the head and neck, as imaged by FDG PET/CT, is crucial for determining treatment strategy, because it helps to avoid incorrect staging and also provides an accurate assessment of treatment response. PMID- 26496575 TI - Voiding Dysfunction: What Can Radiologists Tell Patients and Pediatric Urologists? AB - OBJECTIVE: Imaging children with dysfunctional voiding remains a challenge because 98% of these children have normal anatomy. Identifying the 1-2% of children who do have an anatomic basis for incontinence is important; this article focuses on how pediatric urologists use imaging for the evaluation of patients with this condition. CONCLUSION: Imaging a patient with dysfunctional voiding can provide findings that will allow an accurate diagnosis and lead to optimal management. The key for the pediatric urologist is using imaging studies judiciously because the diagnostic yield is low. If every patient with dysfunctional voiding who presents to the clinic undergoes imaging, there will be little gain. Understanding in which patients to try imaging sooner versus trying medical and behavioral management first is a function of experience. PMID- 26496576 TI - Meta-analysis of Air Versus Liquid Enema for Intussusception Reduction in Children. AB - OBJECTIVE: The purpose of this study was to assess the effectiveness and safety of air versus liquid enema reduction in the treatment of intussusception in children. MATERIALS AND METHODS: Literature searches of the PubMed, Embase, and Cochrane Library databases were conducted from January 1, 1966, through May 31, 2013. Articles on the use of air or liquid enema in children with a confirmed diagnosis of intussusception and reporting either a success rate for enema reduction of intussusception or a perforation rate were selected. Enema reduction success rate, perforation rate, and recurrence rate were the main outcomes and were calculated by random effects modeling. RESULTS: One hundred two articles (101 reporting success rate, 71 reporting perforation rate) were included that presented results for 32,451 children (age range, 1 day-22 years; boys, 66%; girls, 34%). In 44 studies (16,187 children), the combined estimate for success rate of air enema was 82.7% (95% CI, 79.9-85.6%; inconsistency index [I(2)] = 97%), and in 52 studies (13,081 children) of liquid enema, it was 69.6% (95% CI, 65.0-74.1%; I(2) = 98%). In 38 studies (15,752 children), the combined estimate of perforation rate for air enema was 0.39% (95% CI, 0.23- 0.55%; I(2) = 40%), and in 30 studies (9429 children) of liquid enema, it was 0.43% (95% CI, 0.24- 0.62%; I(2) = 9%). Among 10,494 children (26 studies) undergoing air enema reduction, the rate of first intussusception recurrence was 6% (95% CI, 4.5-7.5%; I(2) = 89%), similar to the 7.3% (95% CI, 5.8-8.8%; I(2) = 71%) found for 4004 children (24 studies) undergoing liquid enema reduction. CONCLUSION: Air enema was superior to liquid enema for intussusception reduction. The success rate was higher without a difference in perforation rate. Limitations included heterogeneity and publication bias. PMID- 26496577 TI - Differential Diagnosis of Chronic Total Occlusive and Subtotal Occlusive Disease of the Lower Extremity Arteries Using Reverse Attenuation Gradient Sign on CT Angiography. AB - OBJECTIVE: The purpose of this study is to evaluate the diagnostic usefulness of the reverse attenuation gradient sign in occlusive lower extremity arterial disease through CT angiography (CTA). MATERIALS AND METHODS: This study sample enrolled 45 men and eight women in the chronic total occlusion group and 30 men and seven women in the subtotal occlusion group. Luminal CT attenuation (in Hounsfield units) was measured at three points from the end of the occlusion site to the first collateral vessel's insertion point. We also used Hounsfield units to measure the CT attenuation of the opposite side artery at the same level in a similar manner. We compared each value using the Mann-Whitney U test. RESULTS: The absolute value of the mean differences in the Hounsfield units among the proximal, middle, and distal portion of chronic total occlusions were higher than those of subtotal occlusions, and this result was statistically significant (p < 0.001). The mean ratios of the Hounsfield units (Hounsfield units of the stenosed lumen divided by Hounsfield units of the opposite normal lumen) of the proximal portion of chronic total occlusions were statistically significantly lower than those of subtotal occlusions. CONCLUSION: The reverse attenuation gradient sign can be applied to the lower extremity arteries and can be helpful for differential diagnosis of chronic total occlusions from subtotal occlusions using CTA. PMID- 26496578 TI - Preoperative Pelvic MRI and Serum Cancer Antigen-125: Selecting Women With Grade 1 Endometrial Cancer for Lymphadenectomy. AB - OBJECTIVE: The objective of our study was to determine the predictive value of preoperative pelvic MRI and serum cancer antigen-125 (CA-125) evaluation in selecting women with grade 1 endometrial cancer for lymphadenectomy as part of the cancer staging operation. MATERIALS AND METHODS: A new preoperative clinical protocol including MRI and CA-125 evaluation was adopted at our institution in patients with grade 1 endometrioid adenocarcinoma. Lymphadenectomy was considered as part of the surgical staging operation if there was an elevated CA-125 value or a positive MRI finding (>= 50% myometrial invasion, cervical invasion, abnormal lymph nodes, extrauterine disease, or tumor index >= 36 cm). From January 2012 through May 2013, a retrospective analysis was performed of 100 women who underwent preoperative MRI and CA-125 evaluation; we refer to this cohort as the "preoperative study cohort." The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated using final surgical pathology and CA-125 results as the reference standard. The rate of metastatic lymph nodes in the preoperative study cohort was determined. From May 2009 through January 2011, a retrospective analysis of a cohort who did not undergo preoperative MRI and CA-125 evaluation was undertaken to compare lymphadenectomy and lymph node metastasis rates before and after implementation of the new protocol; we refer to this cohort as the "historical cohort." RESULTS: The new clinical protocol had sensitivity of 94%, specificity of 91%, PPV of 84%, and NPV of 97%. When histologic grade alone was considered, positive lymph node rates in the preoperative study cohort was 4.0% versus 4.2% in the historical cohort. In the preoperative study cohort, the lymph node metastasis rate increased to 11.1% with a positive MRI finding or elevated CA-125 value. CONCLUSION: Preoperative MRI and CA-125 evaluation identified women for lymphadenectomy with a high NPV. PMID- 26496579 TI - Medicolegal--Malpractice and Ethical Issues in Radiology. What Is Reasonable Conduct? PMID- 26496580 TI - Vascular, Gastrointestinal, and Urogenital Associations of Tuberous Sclerosis: Classic but Less Known. PMID- 26496581 TI - I. INTRODUCTION. PMID- 26496582 TI - II. GENERAL METHODOLOGY FOR ALL PHASES OF THE LONGITUDINAL STUDY. PMID- 26496583 TI - III. JUSTIFICATION FOR CORTISOL RESPONSE CATEGORIES. PMID- 26496584 TI - IV. LONGITUDINAL ANALYSES OF CORTISOL AND MATERNAL SENSITIVITY. PMID- 26496585 TI - V. CORTISOL RESPONSE PATTERNS AND DETECTION OF CHANGE IN AUDITORY AND VISUAL STIMULI. PMID- 26496586 TI - VI. MATERNAL SENSITIVITY AND DETECTION OF CHANGE IN AUDITORY AND VISUAL STIMULI. PMID- 26496587 TI - VII. GENERAL DISCUSSION. PMID- 26496590 TI - GLUCOCORTICOIDS AND LEARNING DURING INFANCY. AB - In this monograph titled "A Longitudinal Study of Infant Cortisol Response During Learning Events," Laura A. Thompson, Gin Morgan, and Kellie A. Jurado describe the results of an important study of the associations between maternal sensitivity and adrenocortical activity as they influence infant learning over the first year of life. Although the researchers argue that the work can be understood from a stress framework, I disagree. However, I argue that overall what they have done is provide us with a set of findings that are quite provocative and add nicely to the archival literature on the role of maternal behavior and activity of the hypothalamic-pituitary-adrenocortical system in early learning and memory. PMID- 26496594 TI - Treatment for hypoactive sexual desire. AB - Flibanserin acts at cortical, limbic, hypothalamic, and brainstem nuclei to inhibit serotonin release by binding to 5-HT1A autoreceptors and block postsynaptic action of serotonin at 5-HT2A receptors. This gradually disinhibits the turnover of other monoamines like dopamine and noradrenaline that are critical for sexual desire. PMID- 26496595 TI - Much ado about zero. AB - LINE retrotransposons actively shape mammalian genomes. Denli et al. reveal a new open reading frame, ORF0, on the antisense strand of human LINE-1 encoding a small regulatory protein. This finding may represent the birth of an emerging retrotransposon gene that can adopt various fates, as it can be fused to adjacent host sequences. PMID- 26496596 TI - Evolutionary reprograming of protein-protein interaction specificity. AB - Using mutation libraries and deep sequencing, Aakre et al. study the evolution of protein-protein interactions using a toxin-antitoxin model. The results indicate probable trajectories via "intermediate" proteins that are promiscuous, thus avoiding transitions via non-interactions. These results extend observations about other biological interactions and enzyme evolution, suggesting broadly general principles. PMID- 26496597 TI - Bacterial backstabbing: EF-Tu, brute? AB - Bacterial type VI secretion is an offensive and defensive weapon that utilizes a molecular warhead to inject toxins into neighboring cells. In this issue of Cell, Whitney et al. report a new class of toxin that disrupts the core metabolism of recipient cells and uncover a surprising requirement for EF-Tu. PMID- 26496598 TI - A futile approach to fighting obesity? AB - The current obesity epidemic has focused a great deal of attention on mechanisms controlling energy balance. While diet and nutrient absorption affect energy intake, on the other side of the equation, energy expenditure is determined by basal metabolism, physical activity, and adaptive thermogenesis. Given various challenges in modulating these energy balance mechanisms to combat human obesity, many efforts have concentrated on how it might be possible to achieve weight loss through increased thermogenesis. In this issue of Cell, Kazak et al. describe a previously unrecognized molecular pathway for thermogenesis in fat cells. PMID- 26496599 TI - Imaging the neural basis of locomotion. AB - To investigate the fundamental question of how nervous systems encode, organize, and sequence behaviors, Kato et al. imaged neural activity with cellular resolution across the brain of the worm Caenorhabditis elegans. Locomotion behavior seems to be continuously represented by cyclical patterns of distributed neural activity that are present even in immobilized animals. PMID- 26496600 TI - Ethylene prunes translation. AB - Ethylene regulates many aspects of plant growth and development. In the presence of ethylene, the C terminus of EIN2 (EIN2C) translocates into the nucleus and activates transcription. Li et al. and Merchante et al. show that EIN2C also regulates translation through an interaction with the 3' UTRs of transcripts. PMID- 26496601 TI - Germinal center selection and the antibody response to influenza. AB - In this Minireview, we discuss basic aspects of germinal center biology in the context of immunity to influenza infection and speculate on how the simultaneous evolutionary races of virus and antibody may impact our efforts to design a universal influenza vaccine. PMID- 26496602 TI - A relay race on the evolutionary adaptation spectrum. AB - Adaptation is the process in which organisms improve their fitness by changing their phenotype using genetic or non-genetic mechanisms. The adaptation toolbox consists of varied molecular and genetic means that we posit span an almost continuous "adaptation spectrum." Different adaptations are characterized by the time needed for organisms to attain them and by their duration. We suggest that organisms often adapt by progressing the adaptation spectrum, starting with rapidly attained physiological and epigenetic adaptations and culminating with slower long-lasting genetic ones. A tantalizing possibility is that earlier adaptations facilitate realization of later ones. PMID- 26496603 TI - Mitochondrial ROS signaling in organismal homeostasis. AB - Generation, transformation, and utilization of organic molecules in support of cellular differentiation, growth, and maintenance are basic tenets that define life. In eukaryotes, mitochondrial oxygen consumption plays a central role in these processes. During the process of oxidative phosphorylation, mitochondria utilize oxygen to generate ATP from organic fuel molecules but in the process also produce reactive oxygen species (ROS). While ROS have long been appreciated for their damage-promoting, detrimental effects, there is now a greater understanding of their roles as signaling molecules. Here, we review mitochondrial ROS-mediated signaling pathways with an emphasis on how they are involved in various basal and adaptive physiological responses that control organismal homeostasis. PMID- 26496604 TI - Early divergent strains of Yersinia pestis in Eurasia 5,000 years ago. AB - The bacteria Yersinia pestis is the etiological agent of plague and has caused human pandemics with millions of deaths in historic times. How and when it originated remains contentious. Here, we report the oldest direct evidence of Yersinia pestis identified by ancient DNA in human teeth from Asia and Europe dating from 2,800 to 5,000 years ago. By sequencing the genomes, we find that these ancient plague strains are basal to all known Yersinia pestis. We find the origins of the Yersinia pestis lineage to be at least two times older than previous estimates. We also identify a temporal sequence of genetic changes that lead to increased virulence and the emergence of the bubonic plague. Our results show that plague infection was endemic in the human populations of Eurasia at least 3,000 years before any historical recordings of pandemics. PMID- 26496605 TI - Primate-specific ORF0 contributes to retrotransposon-mediated diversity. AB - LINE-1 retrotransposons are fast-evolving mobile genetic entities that play roles in gene regulation, pathological conditions, and evolution. Here, we show that the primate LINE-1 5'UTR contains a primate-specific open reading frame (ORF) in the antisense orientation that we named ORF0. The gene product of this ORF localizes to promyelocytic leukemia-adjacent nuclear bodies. ORF0 is present in more than 3,000 loci across human and chimpanzee genomes and has a promoter and a conserved strong Kozak sequence that supports translation. By virtue of containing two splice donor sites, ORF0 can also form fusion proteins with proximal exons. ORF0 transcripts are readily detected in induced pluripotent stem (iPS) cells from both primate species. Capped and polyadenylated ORF0 mRNAs are present in the cytoplasm, and endogenous ORF0 peptides are identified upon proteomic analysis. Finally, ORF0 enhances LINE-1 mobility. Taken together, these results suggest a role for ORF0 in retrotransposon-mediated diversity. PMID- 26496606 TI - A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. AB - Thermogenic brown and beige adipose tissues dissipate chemical energy as heat, and their thermogenic activities can combat obesity and diabetes. Herein the functional adaptations to cold of brown and beige adipose depots are examined using quantitative mitochondrial proteomics. We identify arginine/creatine metabolism as a beige adipose signature and demonstrate that creatine enhances respiration in beige-fat mitochondria when ADP is limiting. In murine beige fat, cold exposure stimulates mitochondrial creatine kinase activity and induces coordinated expression of genes associated with creatine metabolism. Pharmacological reduction of creatine levels decreases whole-body energy expenditure after administration of a beta3-agonist and reduces beige and brown adipose metabolic rate. Genes of creatine metabolism are compensatorily induced when UCP1-dependent thermogenesis is ablated, and creatine reduction in Ucp1 deficient mice reduces core body temperature. These findings link a futile cycle of creatine metabolism to adipose tissue energy expenditure and thermal homeostasis. PAPERCLIP. PMID- 26496607 TI - EIN2-directed translational regulation of ethylene signaling in Arabidopsis. AB - Ethylene is a gaseous phytohormone that plays vital roles in plant growth and development. Previous studies uncovered EIN2 as an essential signal transducer linking ethylene perception on ER to transcriptional regulation in the nucleus through a "cleave and shuttle" model. In this study, we report another mechanism of EIN2-mediated ethylene signaling, whereby EIN2 imposes the translational repression of EBF1 and EBF2 mRNA. We find that the EBF1/2 3' UTRs mediate EIN2 directed translational repression and identify multiple poly-uridylates (PolyU) motifs as functional cis elements of 3' UTRs. Furthermore, we demonstrate that ethylene induces EIN2 to associate with 3' UTRs and target EBF1/2 mRNA to cytoplasmic processing-body (P-body) through interacting with multiple P-body factors, including EIN5 and PABs. Our study illustrates translational regulation as a key step in ethylene signaling and presents mRNA 3' UTR functioning as a "signal transducer" to sense and relay cellular signaling in plants. VIDEO ABSTRACT. PMID- 26496608 TI - Gene-specific translation regulation mediated by the hormone-signaling molecule EIN2. AB - The central role of translation in modulating gene activity has long been recognized, yet the systematic exploration of quantitative changes in translation at a genome-wide scale in response to a specific stimulus has only recently become technically feasible. Using the well-characterized signaling pathway of the phytohormone ethylene and plant-optimized genome-wide ribosome footprinting, we have uncovered a molecular mechanism linking this hormone's perception to the activation of a gene-specific translational control mechanism. Characterization of one of the targets of this translation regulatory machinery, the ethylene signaling component EBF2, indicates that the signaling molecule EIN2 and the nonsense-mediated decay proteins UPFs play a central role in this ethylene induced translational response. Furthermore, the 3'UTR of EBF2 is sufficient to confer translational regulation and required for the proper activation of ethylene responses. These findings represent a mechanistic paradigm of gene specific regulation of translation in response to a key growth regulator. PMID- 26496609 TI - Learning the sequence determinants of alternative splicing from millions of random sequences. AB - Most human transcripts are alternatively spliced, and many disease-causing mutations affect RNA splicing. Toward better modeling the sequence determinants of alternative splicing, we measured the splicing patterns of over two million (M) synthetic mini-genes, which include degenerate subsequences totaling over 100 M bases of variation. The massive size of these training data allowed us to improve upon current models of splicing, as well as to gain new mechanistic insights. Our results show that the vast majority of hexamer sequence motifs measurably influence splice site selection when positioned within alternative exons, with multiple motifs acting additively rather than cooperatively. Intriguingly, motifs that enhance (suppress) exon inclusion in alternative 5' splicing also enhance (suppress) exon inclusion in alternative 3' or cassette exon splicing, suggesting a universal mechanism for alternative exon recognition. Finally, our empirically trained models are highly predictive of the effects of naturally occurring variants on alternative splicing in vivo. PMID- 26496610 TI - A human interactome in three quantitative dimensions organized by stoichiometries and abundances. AB - The organization of a cell emerges from the interactions in protein networks. The interactome is critically dependent on the strengths of interactions and the cellular abundances of the connected proteins, both of which span orders of magnitude. However, these aspects have not yet been analyzed globally. Here, we have generated a library of HeLa cell lines expressing 1,125 GFP-tagged proteins under near-endogenous control, which we used as input for a next-generation interaction survey. Using quantitative proteomics, we detect specific interactions, estimate interaction stoichiometries, and measure cellular abundances of interacting proteins. These three quantitative dimensions reveal that the protein network is dominated by weak, substoichiometric interactions that play a pivotal role in defining network topology. The minority of stable complexes can be identified by their unique stoichiometry signature. This study provides a rich interaction dataset connecting thousands of proteins and introduces a framework for quantitative network analysis. PMID- 26496611 TI - Timing of CFTR pore opening and structure of its transition state. AB - In CFTR, the chloride ion channel mutated in cystic fibrosis (CF) patients, pore opening is coupled to ATP-binding-induced dimerization of two cytosolic nucleotide binding domains (NBDs) and closure to dimer disruption following ATP hydrolysis. CFTR opening rate, unusually slow because of its high-energy transition state, is further slowed by CF mutation DeltaF508. Here, we exploit equilibrium gating of hydrolysis-deficient CFTR mutant D1370N and apply rate equilibrium free-energy relationship analysis to estimate relative timing of opening movements in distinct protein regions. We find clear directionality of motion along the longitudinal protein axis and identify an opening transition state structure with the NBD dimer formed but the pore still closed. Thus, strain at the NBD/pore-domain interface, the DeltaF508 mutation locus, underlies the energetic barrier for opening. Our findings suggest a therapeutic opportunity to stabilize this transition-state structure pharmacologically in DeltaF508-CFTR to correct its opening defect, an essential step toward restoring CFTR function. PMID- 26496613 TI - SnapShot: antiviral restriction factors. AB - Restriction factors are cellular proteins that inhibit viruses at different steps of their replication cycle and represent an important first line of defense against viral pathogens. This SnapShot provides an overview of cell-intrinsic antiviral factors, describes their properties, and illustrates the striking variety of antiviral mechanisms as well the sophisticated viral countermeasures. To view this SnapShot, open or download the PDF. PMID- 26496612 TI - Engineering a therapeutic lectin by uncoupling mitogenicity from antiviral activity. AB - A key effector route of the Sugar Code involves lectins that exert crucial regulatory controls by targeting distinct cellular glycans. We demonstrate that a single amino-acid substitution in a banana lectin, replacing histidine 84 with a threonine, significantly reduces its mitogenicity, while preserving its broad spectrum antiviral potency. X-ray crystallography, NMR spectroscopy, and glycocluster assays reveal that loss of mitogenicity is strongly correlated with loss of pi-pi stacking between aromatic amino acids H84 and Y83, which removes a wall separating two carbohydrate binding sites, thus diminishing multivalent interactions. On the other hand, monovalent interactions and antiviral activity are preserved by retaining other wild-type conformational features and possibly through unique contacts involving the T84 side chain. Through such fine-tuning, target selection and downstream effects of a lectin can be modulated so as to knock down one activity, while preserving another, thus providing tools for therapeutics and for understanding the Sugar Code. PMID- 26496614 TI - Synthetic biology: Novel approaches for microbiology. AB - In the past twenty years, molecular genetics has created powerful tools for genetic manipulation of living organisms. Whole genome sequencing has provided necessary information to assess knowledge on gene function and protein networks. In addition, new tools permit to modify organisms to perform desired tasks. Gene function analysis is speed up by novel approaches that couple both high throughput data generation and mining. Synthetic biology is an emerging field that uses tools for generating novel gene networks, whole genome synthesis and engineering. New applications in biotechnological, pharmaceutical and biomedical research are envisioned for synthetic biology. In recent years these new strategies have opened up the possibilities to study gene and genome editing, creation of novel tools for functional studies in virus, parasites and pathogenic bacteria. There is also the possibility to re-design organisms to generate vaccine subunits or produce new pharmaceuticals to combat multi-drug resistant pathogens. In this review we provide our opinion on the applicability of synthetic biology strategies for functional studies of pathogenic organisms and some applications such as genome editing and gene network studies to further comprehend virulence factors and determinants in pathogenic organisms. We also discuss what we consider important ethical issues for this field of molecular biology, especially for potential misuse of the new technologies. PMID- 26496616 TI - Antagonism of entomopathogenic fungi by Bacillus spp. associated with the integument of cicadellids and delphacids. AB - Entomopathogenic fungi are potential tools to biocontrol cicadellids and delphacids, two groups of insects that cause extensive damage to agricultural crops. However, bacteria living on the host cuticle may inhibit fungal growth. In the present work, following the molecular characterization of 10 strains of Bacillus isolated from the integument of cicadellids and delphacids, we selected isolates of the fungi Beauveria bassiana and Metarhizium anisopliae that are resistant to the antimicrobials secreted by these bacterial strains. The antagonistic activity of the 10 bacterial isolates belonging to the genus Bacillus (i.e., B. amyloliquefaciens, B. pumilus, and B. subtilis) against 41 isolates of Bea. bassiana and 20 isolates of M. anisopliae was investigated in vitro on tryptic soy agar using the central disk test. With this approach, isolates of Bea. bassiana and M. anisopliae resistant to antagonistic bacteria were identified that can be further developed as biological control agents. PMID- 26496615 TI - Unexpected distribution of the fluoroquinolone-resistance gene qnrB in Escherichia coli isolates from different human and poultry origins in Ecuador. AB - Fluoroquinolone resistance can be conferred through chromosomal mutations or by the acquisition of plasmids carrying genes such as the quinolone resistance gene (qnr). In this study, 3,309 strains of commensal Escherichia coli were isolated in Ecuador from: (i) humans and chickens in a rural northern coastal area (n = 2368, 71.5%) and (ii) chickens from an industrial poultry operation (n = 827, 25%). In addition, 114 fluoroquinolone-resistant strains from patients with urinary tract infections who were treated at three urban hospitals in Quito, Ecuador were analyzed. All of the isolates were subjected to antibiotic susceptibility screening. Fluoroquinolone-resistant isolates (FRIs) were then screened for the presence of qnrB genes. A significantly higher phenotypic resistance to fluoroquinolones was determined in E. coli strains from chickens in both the rural area (22%) and the industrial operation (10%) than in strains isolated from humans in the rural communities (3%). However, the rates of qnrB genes in E. coli isolates from healthy humans in the rural communities (11 of 35 isolates, 31%) was higher than in chickens from either the industrial operations (3 of 81 isolates, 6%) or the rural communities (7 of 251 isolates, 2.8%). The occurrence of qnrB genes in human FRIs obtained from urban hospitals was low (1 of 114 isolates, 0.9%). These results suggested that the qnrB gene is more widely distributed in rural settings, where antibiotic usage is low, than in urban hospitals and industrial poultry operations. The role of qnrB in clinical resistance to fluoroquinolones is thus far unknown. PMID- 26496617 TI - IS200 and multilocus sequence typing for the identification of Salmonella enterica serovar Typhi strains from Indonesia. AB - In this work, IS200 and multi-locus sequence typing (MLST) were used to analyze 19 strains previously serotyped as Salmonella enterica serovar Typhi and isolated in Indonesia (16 strains), Mexico (2 strains), and Switzerland (1 strain). Most of the strains showed the most common Typhi sequence types, ST1 and ST2, and a new Typhi genotype (ST1856) was described. However, one isolate from Mexico and another from Indonesia were of the ST365 and ST426 sequence types, indicating that they belonged to serovars Weltevreden and Aberdeen, respectively. These results were supported by the amplification of IS200 fragments, which rapidly distinguish Typhi from other serovars. Our results demonstrate the utility of IS200 and MLST in the classification of Salmonella strains into serovars. These methods provide information on the clonal relatedness of strains isolated worldwide. PMID- 26496618 TI - Aquatic bacterial assemblage structure in Pozas Azules, Cuatro Cienegas Basin, Mexico: Deterministic vs. stochastic processes. AB - The aim of this study was to determine the contributions of stochastic vs. deterministic processes in the distribution of microbial diversity in four ponds (Pozas Azules) within a temporally stable aquatic system in the Cuatro Cienegas Basin, State of Coahuila, Mexico. A sampling strategy for sites that were geographically delimited and had low environmental variation was applied to avoid obscuring distance effects. Aquatic bacterial diversity was characterized following a culture-independent approach (16S sequencing of clone libraries). The results showed a correlation between bacterial beta diversity (1-Sorensen) and geographic distance (distance decay of similarity), which indicated the influence of stochastic processes related to dispersion in the assembly of the ponds' bacterial communities. Our findings are the first to show the influence of dispersal limitation in the prokaryotic diversity distribution of Cuatro Cienegas Basin. PMID- 26496619 TI - Characterization of a S-adenosyl-l-methionine (SAM)-accumulating strain of Scheffersomyces stipitis. AB - S-adenosyl-l-methionine (SAM) is an important molecule in the cellular metabolism of mammals. In this study, we examined several of the physiological characteristics of a SAM-accumulating strain of the yeast Scheffersomyces stipitis (M12), including SAM production, ergosterol content, and ethanol tolerance. S. stipitis M12 accumulated up to 52.48 mg SAM/g dry cell weight. Proteome analyses showed that the disruption of C-24 methylation in ergosterol biosynthesis, a step mediated by C-24 sterol methyltransferase (Erg6p), results in greater SAM accumulation by S. stipitis M12 compared to the wild-type strain. A comparative proteome-wide analysis identified 25 proteins that were differentially expressed by S. stipitis M12. These proteins are involved in ribosome biogenesis, translation, the stress response, ubiquitin-dependent catabolic processes, the cell cycle, ethanol tolerance, posttranslational modification, peroxisomal membrane stability, epigenetic regulation, the actin cytoskeleton and cell morphology, iron and copper homeostasis, cell signaling, and energy metabolism. PMID- 26496620 TI - Bioremediation of oil polluted marine sediments: A bio-engineering treatment. AB - The fate of hydrocarbon pollutants and the development of oil-degrading indigenous marine bacteria in contaminated sediments are strongly influenced by abiotic factors such as temperature, low oxygen levels, and nutrient availability. In this work, the effects of different biodegradation processes (bioremediation) on oil-polluted anoxic sediments were analyzed. In particular, as a potential bioremediation strategy for polluted sediments, we applied a prototype of the "Modular Slurry System" (MSS), allowing containment of the sediments and their physical-chemical treatment (by air insufflations, temperature regulation, and the use of a slow-release fertilizer). Untreated polluted sediments served as the blank in a non-controlled experiment. During the experimental period (30 days), bacterial density and biochemical oxygen demand were measured and functional genes were identified by screening. Quantitative measurements of pollutants and an eco-toxicological analysis (mortality of Corophium orientale) were carried out at the beginning and end of the experiments. The results demonstrated the high biodegradative capability achieved with the proposed technology and its strong reduction of pollutant concentrations and thus toxicity. PMID- 26496621 TI - Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. AB - OBJECTIVES: To determine the effects of daily oral doses of enclomiphene citrate compared with topical testosterone gel treatment on serum total testosterone (TT), luteinising hormone (LH), follicle-stimulating hormone (FSH), and sperm counts in men with secondary hypogonadism. PATIENTS AND METHODS: Two parallel randomised, double-blind, double-dummy, placebo-controlled, multicentre, phase III studies were undertaken to evaluate two doses of enclomiphene citrate vs testosterone gel (AndroGel((r)) 1.62%) on TT, LH, FSH, and sperm counts in overweight men aged 18-60 years with secondary hypogonadism. Men were screened and enrolled in the trials (ZA-304 and ZA-305). All enrolled men had early morning serum TT levels in the low or low normal range (<=300 ng/dL; <=10.4 nmol/L) and had low or normal LH (<9.4 IU/L) levels measured on two separate occasions 2-10 days apart. Serum samples were obtained over the course of the study to determine relevant hormone levels at baseline and after 16 weeks of treatment. Men provided semen samples twice to enroll at the beginning and twice at the end of the study. RESULTS: TT levels increased between baseline and after 16 weeks of treatment in all the treatment groups. FSH and LH levels increased in the enclomiphene citrate groups and decreased in the testosterone gel group at 16 weeks. Enclomiphene citrate maintained sperm concentration in the normal range over the treatment period, while there was a marked reduction in spermatogenesis in the testosterone gel group. CONCLUSIONS: Enclomiphene citrate consistently increased serum TT, LH and FSH, restoring normal levels of serum TT. Enclomiphene citrate treatment maintained sperm concentrations in the normal range. The effects on TT were also seen with testosterone replacement via testosterone gel but sperm counts were not maintained. PMID- 26496622 TI - nZVI injection into variably saturated soils: Field and modeling study. AB - Nano-scale zero valent iron (nZVI) has been used at a number of contaminated sites over the last decade. At most of these sites, significant decreases in contaminant concentrations have resulted from the application of nZVI. However, limited work has been completed investigating nZVI field-scale mobility. In this study, a field test was combined with numerical modeling to examine nZVI reactivity along with transport properties in variably saturated soils. The field test consisted of 142L of carboxymethyle cellulose (CMC) stabilized monometallic nZVI synthesized onsite and injected into a variably saturated zone. Periodic groundwater samples were collected from the injection well, as well as, from two monitoring wells to analyze for chlorinated solvents and other geochemistry indicators. This study showed that CMC stabilized monometallic nZVI was able to decrease tricholorethene (TCE) concentrations in groundwater by more than 99% from the historical TCE concentrations. A three dimensional, three phase, finite difference numerical simulator, (CompSim) was used to further investigate nZVI and polymer transport at the variably saturated site. The model was able to accurately predict the field observed head data without parameter fitting. In addition, the numerical simulator estimated the mass of nZVI delivered to the saturated and unsaturated zones and distinguished the nZVI phase (i.e. aqueous or attached). The simulation results showed that the injected slurry migrated radially outward from the injection well, and therefore nZVI transport was governed by injection velocity and viscosity of the injected solution. A suite of sensitivity analyses was performed to investigate the impact of different injection scenarios (e.g. different volume and injection rate) on nZVI migration. Simulation results showed that injection of a higher nZVI volume delivered more iron particles at a given distance; however, the travel distance was not proportional to the increase in volume. Moreover, simulation results showed that using a 1D transport equation to simulate nZVI migration in the subsurface may overestimate the travel distance. This is because the 1D transport equation assumes a constant velocity while pore water velocity radially decreases from the well during injection. This study suggests that on-site synthesized nZVI particles are mobile in the subsurface and that a numerical simulator can be a valuable tool for optimal design of nZVI field applications. PMID- 26496623 TI - Dental Age Estimation (DAE): Data management for tooth development stages including the third molar. Appropriate censoring of Stage H, the final stage of tooth development. AB - INTRODUCTION: The final stage of dental development of third molars is usually helpful to indicate whether or not a subject is aged over 18 years. A complexity is that the final stage of development is unlimited in its upper border. Investigators usually select an inappropriate upper age limit or censor point for this tooth development stage. MATERIALS AND METHODS: The literature was searched for appropriate data sets for dental age estimation and those that provided the count (n), the mean (x-), and the standard deviation (sd) for each of the tooth development stages. The Demirjian G and Demirjian H were used for this study. Upper and lower limits of the Stage G and Stage H data were calculated limiting the data to plus or minus three standard deviations from the mean. The upper border of Stage H was limited by appropriate censoring at the maximum value for Stage G. RESULTS: The maximum age at attainment from published data, for Stage H, ranged from 22.60 years to 34.50 years. These data were explored to demonstrate how censoring provides an estimate for the correct maximum age for the final stage of Stage H as 21.64 years for UK Caucasians. CONCLUSION: This study shows that confining the data array of individual tooth developments stages to +/- 3sd provides a reliable and logical way of censoring the data for tooth development stages with a Normal distribution of data. For Stage H this is inappropriate as it is unbounded in its upper limit. The use of a censored data array for Stage H using Percentile values is appropriate. This increases the reliability of using third molar Stage H alone to determine whether or not an individual is over 18 years old. For Stage H, individual ancestral groups should be censored using the same technique. PMID- 26496624 TI - In Vivo Comparison of the Masticatory Efficiency of Artificial Teeth with Two Different Cusp Heights in Complete Dentures: A Preliminary Study. AB - PURPOSE: The goal of complete denture rehabilitation is to restore facial esthetics and masticatory function to edentulous patients. Several types of artificial teeth with different occlusal anatomy are available. Theoretically, teeth with a higher cusp height provide improved masticatory efficiency. The aim of this study was to compare the masticatory efficiency of complete denture wearers using artificial teeth with two cusp heights. MATERIALS AND METHODS: Sixteen complete denture wearers were given complete dentures with Heraeus Premium teeth. Fifteen days after denture installation, a first masticatory efficiency test was performed with Optocal. A new pair of complete dentures with Dentsply Biotone teeth was then given to each participant to replace the first set. This second set was fabricated by duplicating the same models used to fabricate the first set of dentures. Fifteen days after installation of the dentures with Biotone teeth, a second masticatory efficiency test was performed with Optocal. On both tests, the comminuted material was treated and sieved through a stack of sieves under vibration. The content of each sieve was weighed, and the obtained data were tabulated. Statistical analysis was performed using the Kolmogorov-Smirnov and Wilcoxon tests. RESULTS: Mean and standard deviation of participants' masticatory efficiency, as measured by X50 particle size (mm), were 8.39 and 5.59 for dentures with Premium teeth, and 8.56 and 5.84 for dentures with Biotone teeth. CONCLUSION: According to the results, there were no differences (p < 0.05) in the masticatory efficiency of the complete denture sets using teeth with the two cusp heights. PMID- 26496626 TI - Protein-protein interactions: a supra-structural phenomenon demanding trans disciplinary biophysical approaches. AB - Responsive formation of protein:protein interaction (PPI) upon diverse stimuli is a fundament of cellular function. As a consequence, PPIs are complex, adaptive entities, and exist in structurally heterogeneous interplays defined by the energetic states of the free and complexed protomers. The biophysical and structural investigations of PPIs consequently demand hybrid approaches, implementing orthogonal methods and strategies for global data analysis. Currently, impressive developments in hardware and software within several methodologies define a new era for the biostructural community. Data can be obtained at increasing resolution, at relevant time-scales and under increasingly relevant experimental conditions, intricate data are interpreted reliably, and the questions posed and answered grow in complexity. With this review, highlights from the study of PPIs using a multitude of biophysical methods, are reported. The aim is to depict how the elucidation of the interplay of structures requires the interplay of methods. PMID- 26496625 TI - Functional coupling between writers, erasers and readers of histone and DNA methylation. AB - DNA and histone lysine methylation are dynamic chemical modifications that play a crucial role in the establishment of gene expression patterns during development. Both types of genomic methylation patterns are enzymatically regulated by the opposing activities of enzymes that introduce and remove these marks, known as methylation 'writers' and 'erasers', respectively. The appropriate localization and activity of these enzymes on chromatin is, in part, regulated by chromatin 'readers', protein modules that recognize histone and DNA modifications. Such reading modules are either encoded within the same polypeptide as the catalytic domains of writers and erasers, or present in protein partners that associate with them. Here, we review recent structural, biochemical and biological studies that demonstrate that there are multiple mechanisms by which reader domains can regulate the writers and erasers of histone and DNA methylation. PMID- 26496628 TI - Barriers and facilitators to cervical cancer screening in high incidence populations: A synthesis of qualitative evidence. AB - Despite the efficacy and availability of screening and treatment for cervical cancer, it remains the leading cause of death for women in many low resource countries. The inability or reluctance of women to use screening and treatment is the largest contributor to cervical cancer morbidity and mortality. The aim of the author in this article is to determine knowledge, attitudes, and beliefs that facilitate or hinder women's use of screening in high incidence countries through a synthesis of qualitative research. CINAHL, Medline, AnthroSource, Sociological Abstracts, Social Service Abstracts, GenderWatch, Ethnic News Watch, and ASSIA databases were queried for qualitative research published from 2008 to 2013. Ten studies meeting inclusion criteria were reviewed and analyzed using constant comparative analysis. Barriers to cervical cancer screening included fatalism, mistrust of non-traditional healthcare providers, masculine/feminine beliefs, limited knowledge, and misunderstandings of causes of cervical cancer. Facilitators included knowledge of sexual risk factors, recognition of signs and symptoms, and community/social support. Pragmatic solutions suggested by this synthesis, that may decrease barriers and enhance facilitators, involved cultural humility (a continual commitment to cultural competence), promotion of gender equality, collaboration among stakeholders, and the translation of evidence-based practices from low to high incidence populations. PMID- 26496627 TI - Modeling the Effects of Vorinostat In Vivo Reveals both Transient and Delayed HIV Transcriptional Activation and Minimal Killing of Latently Infected Cells. AB - Recent efforts to cure human immunodeficiency virus type-1 (HIV-1) infection have focused on developing latency reversing agents as a first step to eradicate the latent reservoir. The histone deacetylase inhibitor, vorinostat, has been shown to activate HIV RNA transcription in CD4+ T-cells and alter host cell gene transcription in HIV-infected individuals on antiretroviral therapy. In order to understand how latently infected cells respond dynamically to vorinostat treatment and determine the impact of vorinostat on reservoir size in vivo, we have constructed viral dynamic models of latency that incorporate vorinostat treatment. We fitted these models to data collected from a recent clinical trial in which vorinostat was administered daily for 14 days to HIV-infected individuals on suppressive ART. The results show that HIV transcription is increased transiently during the first few hours or days of treatment and that there is a delay before a sustained increase of HIV transcription, whose duration varies among study participants and may depend on the long term impact of vorinostat on host gene expression. Parameter estimation suggests that in latently infected cells, HIV transcription induced by vorinostat occurs at lower levels than in productively infected cells. Furthermore, the estimated loss rate of transcriptionally induced cells remains close to baseline in most study participants, suggesting vorinostat treatment does not induce latently infected cell killing and thus reduce the latent reservoir in vivo. PMID- 26496631 TI - Young adults with spina bifida transitioned to a medical home: a survey of medical care in Jacksonville, Florida. AB - OBJECT The transition of the young adult with spina bifida (YASB) from pediatric to adult health care is considered a priority by organized pediatrics. There is a paucity of transition programs and related studies. Jacksonville Health and Transition Services (JaxHATS) is one such transition program in Jacksonville, Florida. This study's purpose was to evaluate the health care access, utilization, and quality of life (QOL) of a group of YASBs who have transitioned from pediatric care. METHODS A survey tool addressing access to health care and quality of health and life was developed based on an established survey. Records of the Spinal Defects Clinic held at Wolfson Children's Hospital and JaxHATS Clinic were reviewed and YASBs (> 18 and < 30 years old) were identified. RESULTS Ten of the 12 invited YASBs in the Jacksonville area completed the surveys. The mean age of respondents was 25.1 years. All reported regular medical home visits, 8 with JaxHATS and 2 with other family care groups. All reported easy access to medical care and routine visits to spina bifida (SB) specialists; none reported difficulty or delays in obtaining health care. Only 2 patients required emergent care in the last year for an SB-related medical problem. Seven respondents reported very good to excellent QOL. Family, lifestyle, and environmental factors were also examined. CONCLUSIONS In this small group of YASBs with a medical home, easy access to care for medical conditions was the norm, with few individuals having recent emergency visits and almost all reporting at least a good overall QOL. Larger studies of YASBs are needed to evaluate the positive effects of medical homes on health and QOL in this population. PMID- 26496629 TI - Comparison of Extended-Spectrum beta-Lactamase (ESBL) CTX-M Genotypes in Franklin Gulls from Canada and Chile. AB - Migratory birds have been suggested to contribute to long-distance dispersal of antimicrobial resistant bacteria, but tests of this hypothesis are lacking. In this study we determined resistance profiles and genotypes of ESBL-producing bacteria in randomly selected Escherichia coli from Franklin's gulls (Leucophaeus pipixcan) at breeding sites in Canada and compared with similar data from the gulls' wintering grounds in Chile. Resistant E. coli phenotypes were common, most notably to ampicillin (30.1%) and cefadroxil (15.1%). Furthermore, 17.0% of the gulls in Canada carried ESBL producing bacteria, which is higher than reported from human datasets from the same country. However, compared to gulls sampled in Chile (30.1%) the prevalence of ESBL was much lower. The dominant ESBL variants in Canada were blaCTX-M-14 and blaCTX-M-15 and differed in proportions to the data from Chile. We hypothesize that the observed differences in ESBL variants are more likely linked to recent exposure to bacteria from anthropogenic sources, suggesting high local dissemination of resistant bacteria both at breeding and non-breeding times rather than a significant trans-hemispheric exchange through migrating birds. PMID- 26496630 TI - Evaluation of Residence Time on Nitrogen Oxides Removal in Non-Thermal Plasma Reactor. AB - Non-thermal plasma (NTP) has been introduced over the last few years as a promising after- treatment system for nitrogen oxides and particulate matter removal from diesel exhaust. NTP technology has not been commercialised as yet, due to its high rate of energy consumption. Therefore, it is important to seek out new methods to improve NTP performance. Residence time is a crucial parameter in engine exhaust emissions treatment. In this paper, different electrode shapes are analysed and the corresponding residence time and NOx removal efficiency are studied. An axisymmetric laminar model is used for obtaining residence time distribution numerically using FLUENT software. If the mean residence time in a NTP plasma reactor increases, there will be a corresponding increase in the reaction time and consequently the pollutant removal efficiency increases. Three different screw thread electrodes and a rod electrode are examined. The results show the advantage of screw thread electrodes in comparison with the rod electrode. Furthermore, between the screw thread electrodes, the electrode with the thread width of 1 mm has the highest NOx removal due to higher residence time and a greater number of micro-discharges. The results show that the residence time of the screw thread electrode with a thread width of 1 mm is 21% more than for the rod electrode. PMID- 26496632 TI - Allograft versus autograft for pediatric posterior cervical and occipito-cervical fusion: a systematic review of factors affecting fusion rates. AB - OBJECT Fusion rates are high for children undergoing posterior cervical fusion (PCF) and occipito-cervical fusion (OCF). Autologous bone has been widely used as the graft material of choice, despite the risk of donor-site morbidity associated with harvesting the bone, possibly because very low fusion rates were reported with posterior allograft cervical fusions in children several decades ago. Higher overall fusion rates using allograft in adults, associated with improvements in internal fixation techniques and the availability of osteoinductive substances such as bone morphogenetic protein (BMP), have led to heightened enthusiasm for the use of bank bone during pediatric PCF. A systematic review was performed to study factors associated with successful bone fusion, including the type of bone graft used. METHODS The authors performed a comprehensive PubMed search of English-language articles pertaining to PCF and OCF in patients less than 18 years old. Of the 561 abstracts selected, 148 articles were reviewed, resulting in 60 articles that had sufficient detail to be included in the analysis. A meta regression analysis was performed to determine if and how age, fusion technique, levels fused, fusion substrate, BMP use, postoperative bracing, and radiographic fusion criteria were related to the pooled prevalence estimates. A systematic review of the literature was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. RESULTS A total of 604 patients met the specific inclusion and exclusion criteria. The overall fusion rate was 93%, with a mean age of 9.3 years and mean follow-up of 38.7 months. A total of 539 patients had fusion with autograft (94% fusion rate) and 65 patients with allograft (80% fusion rate). Multivariate meta-regression analysis showed that higher fusion rates were associated with OCF compared with fusions that excluded the occiput (p < 0.001), with the use of autograft instead of allograft (p < 0.001), and with the use of CT to define fusion instead of plain radiography alone. The type of internal fixation, the use of BMP, patient age, and the duration of follow-up were not found to be associated with fusion rates in the multivariate analysis. CONCLUSIONS Fusion rates for PCF are high, with higher rates of fusion seen when autograft is used as the bone substrate and when the occiput is included in the fusion construct. Further study of the use of allograft as a viable alternative to autograft bone fusion is warranted because limited data are available regarding the use of allograft in combination with more rigid internal fixation techniques and osteoinductive substances, both of which may enhance fusion rates with allograft. PMID- 26496633 TI - Penetrating head injuries in children due to BB and pellet guns: a poorly recognized public health risk. AB - OBJECT Nonpowder guns, defined as spring- or gas-powered BB or pellet guns, can be dangerous weapons that are often marketed to children. In recent decades, advances in compressed-gas technology have led to a significant increase in the power and muzzle velocity of these weapons. The risk of intracranial injury in children due to nonpowder weapons is poorly documented. METHODS A retrospective review was conducted at 3 institutions studying children 16 years or younger who had intracranial injuries secondary to nonpowder guns. RESULTS The authors reviewed 14 cases of intracranial injury in children from 3 institutions. Eleven (79%) of the 14 children were injured by BB guns, while 3 (21%) were injured by pellet guns. In 10 (71%) children, the injury was accidental. There was 1 recognized assault, but there were no suicide attempts; in the remaining 3 patients, the intention was indeterminate. There were no mortalities among the patients in this series. Ten (71%) of the children required operative intervention, and 6 (43%) were left with permanent neurological injuries, including epilepsy, cognitive deficits, hydrocephalus, diplopia, visual field cut, and blindness. CONCLUSIONS Nonpowder guns are weapons with the ability to penetrate a child's skull and brain. Awareness should be raised among parents, children, and policy makers as to the risk posed by these weapons. PMID- 26496634 TI - Obstetrical brachial plexus injury: burden in a publicly funded, universal healthcare system. AB - OBJECT The aim of this study was to determine the volume and timing of referrals for obstetrical brachial plexus injury (OBPI) to multidisciplinary centers in a national demographic sample. Secondarily, we aimed to measure the incidence and risk factors for OBPI in the sample. The burden of OBPI has not been investigated in a publicly funded system, and the timing and volume of referrals to multidisciplinary centers are unknown. The incidence and risk factors for OBPI have not been established in Canada. METHODS This is a retrospective cohort study. The authors used a demographic sample of all infants born in Canada, capturing all children born in a publicly funded, universal healthcare system. OBPI diagnoses and corresponding risk factors from 2004 to 2012 were identified and correlated with referrals to Canada's 10 multidisciplinary OBPI centers. Quality indicators were approved by the Canadian OBPI Working Group's guideline consensus group. The primary outcome was the timing of initial assessment at a multidisciplinary center, "good" if assessed by the time the patient was 1 month of age, "satisfactory" if by 3 months of age, and "poor" if thereafter. Joinpoint regression analysis was used to determine the OBPI incidence over the study period. Odds ratios were calculated to determine the strength of association for risk factors. RESULTS OBPI incidence was 1.24 per 1000 live births, and was consistent from 2004 to 2012. Potential biases underestimate the level of injury identification. The factors associated with a very strong risk for OBPI were humerus fracture, shoulder dystocia, and clavicle fracture. The majority (55% 60%) of OBPI patients identified at birth were not referred. Among those who were referred, the timing of assessment was "good" in 28%, "satisfactory" in 66%, and "poor" in 34%. CONCLUSIONS Shoulder dystocia was the strongest modifiable risk factor for OBPI. Most children with OBPI were not referred to multidisciplinary care. Of those who were referred, 72% were assessed later than the target quality indicator of 1 month that was established by the national guideline consensus group. A referral gap has been identified using quality indicators at clinically relevant time points; this gap should be addressed with the use of knowledge tools (e.g., a clinical practice guideline) to target variations in referral rates and clinical practice. Interventions should guide the referral process. PMID- 26496635 TI - Detecting Hotspot Information Using Multi-Attribute Based Topic Model. AB - Microblogging as a kind of social network has become more and more important in our daily lives. Enormous amounts of information are produced and shared on a daily basis. Detecting hot topics in the mountains of information can help people get to the essential information more quickly. However, due to short and sparse features, a large number of meaningless tweets and other characteristics of microblogs, traditional topic detection methods are often ineffective in detecting hot topics. In this paper, we propose a new topic model named multi attribute latent dirichlet allocation (MA-LDA), in which the time and hashtag attributes of microblogs are incorporated into LDA model. By introducing time attribute, MA-LDA model can decide whether a word should appear in hot topics or not. Meanwhile, compared with the traditional LDA model, applying hashtag attribute in MA-LDA model gives the core words an artificially high ranking in results meaning the expressiveness of outcomes can be improved. Empirical evaluations on real data sets demonstrate that our method is able to detect hot topics more accurately and efficiently compared with several baselines. Our method provides strong evidence of the importance of the temporal factor in extracting hot topics. PMID- 26496637 TI - Directing and Boosting of Cell Migration by the Entropic Force Gradient in Polymer Solution. AB - Noncontact manipulation of nano/micromaterials presents a great challenge in fields ranging from biotechnology to nanotechnology. In this study we developed a new strategy for the manipulation of molecules and cells based on diffusiophoresis driven by a concentration gradient of a polymer solute. By using laser focusing in a microfluidic device, we created a sharp concentration gradient of poly(ethylene glycol) (PEG) in a solution of this polymer. Because diffusiophoresis essentially depends on solute gradients alone, PEG solute contrast resulted in trapping of DNA and eukaryotic cells with little material dependence. Furthermore, quantitative analysis revealed that the motility of migrating cells was enhanced with the PEG concentration, consistent with a theoretical model of boosted cell migration. Our results support that a solute contrast of polymer can exert an interfacial force gradient that physically propels objects and may have application for the manipulation of soft materials. PMID- 26496636 TI - Dynamics Govern Specificity of a Protein-Protein Interface: Substrate Recognition by Thrombin. AB - Biomolecular recognition is crucial in cellular signal transduction. Signaling is mediated through molecular interactions at protein-protein interfaces. Still, specificity and promiscuity of protein-protein interfaces cannot be explained using simplistic static binding models. Our study rationalizes specificity of the prototypic protein-protein interface between thrombin and its peptide substrates relying solely on binding site dynamics derived from molecular dynamics simulations. We find conformational selection and thus dynamic contributions to be a key player in biomolecular recognition. Arising entropic contributions complement chemical intuition primarily reflecting enthalpic interaction patterns. The paradigm "dynamics govern specificity" might provide direct guidance for the identification of specific anchor points in biomolecular recognition processes and structure-based drug design. PMID- 26496638 TI - Antagonistic Activities of Novel Peptides from Bacillus amyloliquefaciens PT14 against Fusarium solani and Fusarium oxysporum. AB - Bacillus species have recently drawn attention due to their potential use in the biological control of fungal diseases. This paper reports on the antifungal activity of novel peptides isolated from Bacillus amyloliquefaciens PT14. Reverse phase high-performance liquid chromatography revealed that B. amyloliquefaciens PT14 produces five peptides (PT14-1, -2, -3, -4a, and -4b) that exhibit antifungal activity but are inactive against bacterial strains. In particular, PT14-3 and PT14-4a showed broad-spectrum antifungal activity against Fusarium solani and Fusarium oxysporum. The PT14-4a N-terminal amino acid sequence was identified through Edman degradation, and a BLAST homology analysis showed it not to be identical to any other protein or peptide. PT14-4a displayed strong fungicidal activity with minimal inhibitory concentrations of 3.12 mg/L (F. solani) and 6.25 mg/L (F. oxysporum), inducing severe morphological deformation in the conidia and hyphae. On the other hand, PT14-4a had no detectable hemolytic activity. This suggests PT14-4a has the potential to serve as an antifungal agent in clinical therapeutic and crop-protection applications. PMID- 26496639 TI - The Influence of Data Resolution on Predicted Distribution and Estimates of Extent of Current Protection of Three 'Listed' Deep-Sea Habitats. AB - Modelling approaches have the potential to significantly contribute to the spatial management of the deep-sea ecosystem in a cost effective manner. However, we currently have little understanding of the accuracy of such models, developed using limited data, of varying resolution. The aim of this study was to investigate the performance of predictive models constructed using non-simulated (real world) data of different resolution. Predicted distribution maps for three deep-sea habitats were constructed using MaxEnt modelling methods using high resolution multibeam bathymetric data and associated terrain derived variables as predictors. Model performance was evaluated using repeated 75/25 training/test data partitions using AUC and threshold-dependent assessment methods. The overall extent and distribution of each habitat, and the percentage contained within an existing MPA network were quantified and compared to results from low resolution GEBCO models. Predicted spatial extent for scleractinian coral reef and Syringammina fragilissima aggregations decreased with an increase in model resolution, whereas Pheronema carpenteri total suitable area increased. Distinct differences in predicted habitat distribution were observed for all three habitats. Estimates of habitat extent contained within the MPA network all increased when modelled at fine scale. High resolution models performed better than low resolution models according to threshold-dependent evaluation. We recommend the use of high resolution multibeam bathymetry data over low resolution bathymetry data for use in modelling approaches. We do not recommend the use of predictive models to produce absolute values of habitat extent, but likely areas of suitable habitat. Assessments of MPA network effectiveness based on calculations of percentage area protection (policy driven conservation targets) from low resolution models are likely to be fit for purpose. PMID- 26496640 TI - The Direct Actions of GABA, 2'-Methoxy-6-Methylflavone and General Anaesthetics at beta3gamma2L GABAA Receptors: Evidence for Receptors with Different Subunit Stoichiometries. AB - 2'-Methoxy-6-methylflavone (2'MeO6MF) is an anxiolytic flavonoid which has been shown to display GABAA receptor (GABAAR) beta2/3-subunit selectivity, a pharmacological profile similar to that of the general anaesthetic etomidate. Electrophysiological studies suggest that the full agonist action of 2'MeO6MF at alpha2beta3gamma2L GABAARs may mediate the flavonoid's in vivo effects. However, we found variations in the relative efficacy of 2'MeO6MF (2'MeO6MF-elicited current responses normalised to the maximal GABA response) at alpha2beta3gamma2L GABAARs due to the presence of mixed receptor populations. To understand which receptor subpopulation(s) underlie the variations observed, we conducted a systematic investigation of 2'MeO6MF activity at all receptor combinations that could theoretically form (alpha2, beta3, gamma2L, alpha2beta3, alpha2gamma2L, beta3gamma2L and alpha2beta3gamma2L) in Xenopus oocytes using the two-electrode voltage clamp technique. We found that 2'MeO6MF activated non-alpha-containing beta3gamma2L receptors. In an attempt to establish the optimal conditions to express a uniform population of these receptors, we found that varying the relative amounts of beta3:gamma2L subunit mRNAs resulted in differences in the level of constitutive activity, the GABA concentration-response relationships, and the relative efficacy of 2'MeO6MF activation. Like 2'MeO6MF, general anaesthetics such as etomidate and propofol also showed distinct levels of relative efficacy across different injection ratios. Based on these results, we infer that beta3gamma2L receptors may form with different subunit stoichiometries, resulting in the complex pharmacology observed across different injection ratios. Moreover, the discovery that GABA and etomidate have direct actions at the alpha-lacking beta3gamma2L receptors raises questions about the structural requirements for their respective binding sites at GABAARs. PMID- 26496641 TI - Metformin-Derived Growth Inhibition in Renal Cell Carcinoma Depends on miR-21 Mediated PTEN Expression. AB - PURPOSE: Metformin (MF) acts as a tumour-suppressor in renal cell carcinoma (RCC) by inhibiting the AKT/mTOR pathway via AMPK activation. Here, we explore the influence of miR-21 and its target gene PTEN on MF effects in CAKI-1 and CAKI-2 cells. METHODS: Proliferation assays (MTS) and qRT-PCR after transient transfection with pre- and anti-miR-21 and MF treatment were conducted. AMPK dependency was assessed via transfection of siAMPK. The expression of PTEN, AKT and miR-21 after transient pre-miR-21 transfection and MF treatment was analysed. RESULTS: We demonstrate that CAKI-1 cells, which were found to be less sensitive towards MF, showed a significant higher miR-21 and lower PTEN expression than CAKI-2. This was confirmed in a primary RCC collective (n = 28): miR-21 and PTEN expression correlated negatively. MF treatment lowered miR-21 AMPK-dependently and increased PTEN expression in the cell lines. Ectopic miR-21 regulation modulated MF sensitivity. Western blot analysis showed that pre-miR-21 transfection and MF treatment regulated PTEN expression with impact on pAKT levels in the cells. CONCLUSIONS: We show that differing MF sensitivity in RCC cells is associated with and mediated through the regulation of miR-21/PTEN expression with an impact on subsequent AKT signalling. This provides imaginable clinical implications regarding MF therapy of RCC patients for the future. PMID- 26496643 TI - Correction: Epidermal Micromorphology and Mesophyll Structure of Populus euphratica Heteromorphic Leaves at Different Development Stages. PMID- 26496642 TI - ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation during Drosophila Regeneration. AB - Upon apoptotic stimuli, epithelial cells compensate the gaps left by dead cells by activating proliferation. This has led to the proposal that dying cells signal to surrounding living cells to maintain homeostasis. Although the nature of these signals is not clear, reactive oxygen species (ROS) could act as a signaling mechanism as they can trigger pro-inflammatory responses to protect epithelia from environmental insults. Whether ROS emerge from dead cells and what is the genetic response triggered by ROS is pivotal to understand regeneration of Drosophila imaginal discs. We genetically induced cell death in wing imaginal discs, monitored the production of ROS and analyzed the signals required for repair. We found that cell death generates a burst of ROS that propagate to the nearby surviving cells. Propagated ROS activate p38 and induce tolerable levels of JNK. The activation of JNK and p38 results in the expression of the cytokines Unpaired (Upd), which triggers the JAK/STAT signaling pathway required for regeneration. Our findings demonstrate that this ROS/JNK/p38/Upd stress responsive module restores tissue homeostasis. This module is not only activated after cell death induction but also after physical damage and reveals one of the earliest responses for imaginal disc regeneration. PMID- 26496644 TI - An Automated Strategy for Unbiased Morphometric Analyses and Classifications of Growth Cones In Vitro. AB - During neural circuit development, attractive or repulsive guidance cue molecules direct growth cones (GCs) to their targets by eliciting cytoskeletal remodeling, which is reflected in their morphology. The experimental power of in vitro neuronal cultures to assay this process and its molecular mechanisms is well established, however, a method to rapidly find and quantify multiple morphological aspects of GCs is lacking. To this end, we have developed a free, easy to use, and fully automated Fiji macro, Conographer, which accurately identifies and measures many morphological parameters of GCs in 2D explant culture images. These measurements are then subjected to principle component analysis and k-means clustering to mathematically classify the GCs as "collapsed" or "extended". The morphological parameters measured for each GC are found to be significantly different between collapsed and extended GCs, and are sufficient to classify GCs as such with the same level of accuracy as human observers. Application of a known collapse-inducing ligand results in significant changes in all parameters, resulting in an increase in 'collapsed' GCs determined by k-means clustering, as expected. Our strategy provides a powerful tool for exploring the relationship between GC morphology and guidance cue signaling, which in particular will greatly facilitate high-throughput studies of the effects of drugs, gene silencing or overexpression, or any other experimental manipulation in the context of an in vitro axon guidance assay. PMID- 26496645 TI - Learning What to Want: Context-Sensitive Preference Learning. AB - We have developed a method for learning relative preferences from histories of choices made, without requiring an intermediate utility computation. Our method infers preferences that are rational in a psychological sense, where agent choices result from Bayesian inference of what to do from observable inputs. We further characterize conditions on choice histories wherein it is appropriate for modelers to describe relative preferences using ordinal utilities, and illustrate the importance of the influence of choice history by explaining all major categories of context effects using them. Our proposal clarifies the relationship between economic and psychological definitions of rationality and rationalizes several behaviors heretofore judged irrational by behavioral economists. PMID- 26496646 TI - Availability and Primary Health Care Orientation of Dementia-Related Services in Rural Saskatchewan, Canada. AB - Community-based services are important for improving outcomes for individuals with dementia and their caregivers. This study examined: (a) availability of rural dementia-related services in the Canadian province of Saskatchewan, and (b) orientation of services toward six key attributes of primary health care (i.e., information/education, accessibility, population orientation, coordinated care, comprehensiveness, quality of care). Data were collected from 71 rural Home Care Assessors via cross-sectional survey. Basic health services were available in most communities (e.g., pharmacists, family physicians, palliative care, adult day programs, home care, long-term care facilities). Dementia-specific services typically were unavailable (e.g., health promotion, counseling, caregiver support groups, transportation, week-end/night respite). Mean scores on the primary health care orientation scales were low (range 12.4 to 17.5/25). Specific services to address needs of rural individuals with dementia and their caregivers are limited in availability and fit with primary health care attributes. PMID- 26496647 TI - Gains in Life Expectancy Associated with Higher Education in Men. AB - BACKGROUND: Many studies show large differences in life expectancy across the range of education, intelligence, and socio-economic status. As educational attainment, intelligence, and socio-economic status are highly interrelated, appropriate methods are required to disentangle their separate effects. The aim of this paper is to present a novel method to estimate gains in life expectancy specifically associated with increased education. Our analysis is based on a structural model in which education level, IQ at age 18 and mortality all depend on (latent) intelligence. The model allows for (selective) educational choices based on observed factors and on an unobserved factor capturing intelligence. Our estimates are based on information from health examinations of military conscripts born in 1944-1947 in The Netherlands and their vital status through age 66 (n = 39,798). RESULTS: Our empirical results show that men with higher education have lower mortality. Using structural models to account for education choice, the estimated gain in life expectancy for men moving up one educational level ranges from 0.3 to 2 years. The estimated gain in months alive over the observational period ranges from -1.2 to 5.7 months. The selection effect is positive and amounts to a gain of one to two months. Decomposition of the selection effect shows that the gain from selection on (latent) intelligence is larger than the gain from selection on observed factors and amounts to 1.0 to 1.7 additional months alive. CONCLUSION: Our findings confirm the strong selection into education based on socio-economic status and intelligence. They also show significant higher life expectancy among individuals with higher education after the selectivity of education choice has been taken into account. Based on these estimates, it is plausible therefore that increases in education could lead to increases in life expectancy. PMID- 26496648 TI - Effectiveness Study of Paromomycin IM Injection (PMIM) for the Treatment of Visceral Leishmaniasis (VL) in Bangladesh. AB - BACKGROUND: This study was conducted in Bangladeshi patients in an outpatient setting to support registration of Paromomycin Intramuscular Injection (PMIM) as a low-cost treatment option in Bangladesh. METHODOLOGY: This Phase IIIb, open label, multi-center, single-arm trial assessed the efficacy and safety of PMIM administered at 11 mg/kg (paromomycin base) intramuscularly once daily for 21 consecutive days to children and adults with VL in a rural outpatient setting in Bangladesh. Patients >=5 and <=55 years were eligible if they had signs and symptoms of VL (intermittent fever, weight loss/decreased appetite, and enlarged spleen), positive rK39 test, and were living in VL-endemic areas. Compliance was the percentage of enrolled patients who received 21 daily injections over no more than 22 days. Efficacy was evaluated by initial clinical response, defined as resolution of fever and reduction of splenomegaly at end of treatment, and final clinical response, defined as the absence of new clinical signs and symptoms of VL 6 months after end of treatment. Safety was assessed by evaluation of adverse events. PRINCIPAL FINDINGS: A total of 120 subjects (49% pediatric) were enrolled. Treatment compliance was 98.3%. Initial clinical response in the Intent to-Treat population was 98.3%, and final clinical response 6 months after end of treatment was 94.2%. Of the 119 subjects who received >=1 dose of PMIM, 28.6% reported at least one adverse event. Injection site pain was the most commonly reported adverse event. Reversible renal impairment and/or hearing loss were reported in 2 subjects. CONCLUSIONS/SIGNIFICANCE: PMIM was an effective and safe treatment for VL in Bangladesh. The short treatment duration and lower cost of PMIM compared with other treatment options may make this drug a preferred treatment to be investigated as part of a combination therapy regimen. This study supports the registration of PMIM for use in government health facilities in Bangladesh. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01328457. PMID- 26496649 TI - Synthesis of a Novel Highly Oleophilic and Highly Hydrophobic Sponge for Rapid Oil Spill Cleanup. AB - A highly hydrophobic and highly oleophilic sponge was synthesized by simple vapor phase deposition followed by polymerization of polypyrrole followed by modification with palmitic acid. The prepared sponge shows high absorption capacity in the field of separation and removal of different oil spills from water surface and was able to emulsify oil/water mixtures. The sponge can be compressed repeatedly without collapsing. Therefore, absorbed oils can be readily collected by simple mechanical squeezing of the sponge. The prepared hydrophobic sponge can collect oil from water in both static and turbulent conditions. The proposed method is simple and low cost for the manufacture of highly oleophilic and highly hydrophobic sponges, which can be successfully used for effective oil spill cleanup and water filtration. PMID- 26496650 TI - Periconceptional Heat Stress of Holstein Dams Is Associated with Differences in Daughter Milk Production and Composition during Multiple Lactations. AB - Heat stress at the time of conception affects the subsequent milk production of primiparous Holstein cows; however, it is unknown whether these effects are maintained across multiple lactations. Therefore, the objective of the current study was to examine the relationship between periconceptional heat stress and measurements of milk production and composition in cows retained within a herd for multiple lactations. National Dairy Herd Improvement Association data was obtained from Dairy Records Management Systems. Records included milk production data and milk composition data from over 75,000 and 44,000 Holstein cows, respectively, born between 2000 and 2010 in Florida, Georgia, and Texas. Conception dates were calculated by subtracting 276 d from the recorded birth date. Records for cows conceived within the months of June, July, and August were retained as heat stress conceived (HSC) cows; cows conceived within the months of December, January, and February were retained as thermoneutral conceived (TNC) contemporaries. Adjusted 305-d mature equivalent milk, protein percent and fat percent were evaluated with a mixed model ANOVA using SAS. Milk production was significantly affected by periconceptional heat stress. When a significant difference or tendency for a difference was detected between the HSC and TNC cows, the TNC produced more milk in all but one comparison. The advantage in milk production for the TNC cows over the HSC cows ranged from 82 +/- 42 to 399 +/- 61 kg per lactation. Alterations in fat and protein percentage were variable and most often detected in first lactations (first > second or third). Overall, the most striking result of this study is the consistency of the relationship between HSC and milk production. The nature of this relationship suggests that heat stress at or around the time of conception impairs cow milk yield throughout her lifetime. PMID- 26496651 TI - Application of retinoic acid improves form and function of tissue engineered corneal construct. AB - Retinoic acid has recently been shown to control the phenotype and extracellular matrix composition of corneal stromal cells cultured in vitro as monolayers. This study set out to investigate the effects of retinoic acid on human corneal keratocytes within a 3D environment. Human corneal keratocytes were encapsulated in collagen gels, which were subsequently compressed under load, and cultured in serum-free media supplemented with 10 uM retinoic acid or DMSO vehicle for 30 days. Cell proliferation was quantified on selected days, while the expression of several important keratocytes markers was evaluated at day 30 using RT-PCR and immunoblotting. The weight and size of the collagen constructs were measured before and after hydration and contraction analyses. Retinoic acid enhanced keratocyte proliferation until day 30, whereas cells in control culture conditions showed reduced numbers after day 21. Both gene and protein expressions of keratocyte-characteristic proteoglycans (keratocan, lumican and decorin), corneal crystallins and collagen type I and V were significantly increased following retinoic acid supplementation. Retinoic acid also significantly reduced the expression of matrix metalloproteases 1, 3 and 9 while not increasing alpha smooth muscle actin and fibronectin expression. Furthermore, these effects were also correlated with the ability of retinoic acid to significantly inhibit the contractility of keratocytes while allowing the build-up of corneal stromal extracellular matrix within the 3D constructs. Thus, retinoic acid supplementation represents a promising strategy to improve the phenotype of 3D cultured keratocytes, and their usefulness as a model of corneal stroma for corneal biology and regenerative medicine applications. PMID- 26496652 TI - Effect of fibroin sponge coating on in vivo performance of knitted silk small diameter vascular grafts. AB - Vascular grafts under 5 mm or less in diameter are not developed due to a problem caused by early thrombus formation, neointimal hyperplasia, etc. Bombyx mori silk fibroin (SF) which has biodegradability and tissue infiltration is focused as tube and coating material of vascular grafts. Coating is an important factor to maintain the strength of the anastomotic region of vascular grafts, and to prevent the blood leak from the vascular grafts after implantation. Therefore, in this research, we focused on the SF concentration of the coating solution, and tissue infiltration and remodeling were compared among each SF concentration. Silk poly (-ethylene) glycol diglycidyl ether (PGDE) coating with concentrations of 1.0%, 2.5%, 5.0%, and 7.5% SF were applied for the double-raschel knitted small-sized vessel with 1.5 mm diameter and 1cm in length. The grafts were implanted in the rat abdominal aorta and removed after 3 weeks or 3 months. Vascular grafts patency was monitored by ultrasound, and morphological evaluation was performed by histopathological examination. SF concentration had no significant effects on the patency rate. However, tissue infiltration was significantly higher in the sample of 2.5% SF in 3 weeks, and 1.0% and 2.5% SF in 3 months. Also, in comparison of length inside of the graft, stenosis were not found in 3 weeks, however, found with 5.0% and 7.5% in 3 months. From these results, it is clear that 2.5% SF coating is the most suitable concentration, based on the characteristics of less stenosis, early tissue infiltration, and less neointimal hyperplasia. PMID- 26496654 TI - Acute Kidney Injury: A Modifiable Risk Factor for Cardiovascular Morbidity and Mortality. PMID- 26496653 TI - Energy Landscape of Alginate-Epimerase Interactions Assessed by Optical Tweezers and Atomic Force Microscopy. AB - Mannuronan C-5 epimerases are a family of enzymes that catalyze epimerization of alginates at the polymer level. This group of enzymes thus enables the tailor making of various alginate residue sequences to attain various functional properties, e.g. viscosity, gelation and ion binding. Here, the interactions between epimerases AlgE4 and AlgE6 and alginate substrates as well as epimerization products were determined. The interactions of the various epimerase polysaccharide pairs were determined over an extended range of force loading rates by the combined use of optical tweezers and atomic force microscopy. When studying systems that in nature are not subjected to external forces the access to observations obtained at low loading rates, as provided by optical tweezers, is a great advantage since the low loading rate region for these systems reflect the properties of the rate limiting energy barrier. The AlgE epimerases have a modular structure comprising both A and R modules, and the role of each of these modules in the epimerization process were examined through studies of the A- module of AlgE6, AlgE6A. Dynamic strength spectra obtained through combination of atomic force microscopy and the optical tweezers revealed the existence of two energy barriers in the alginate-epimerase complexes, of which one was not revealed in previous AFM based studies of these complexes. Furthermore, based on these spectra estimates of the locations of energy transition states (xbeta), lifetimes in the absence of external perturbation (tau0) and free energies (DeltaG#) were determined for the different epimerase-alginate complexes. This is the first determination of DeltaG# for these complexes. The values determined were up to 8 kBT for the outer barrier, and smaller values for the inner barriers. The size of the free energies determined are consistent with the interpretation that the enzyme and substrate are thus not tightly locked at all times but are able to relocate. Together with the observed different affinities determined for AlgE4-polymannuronic acid (poly-M) and AlgE4-polyalternating alginate (poly-MG) macromolecular pairs these data give important contribution to the growing understanding of the mechanisms underlying the processive mode of these enzymes. PMID- 26496655 TI - Nanoparticle Superlattices as Efficient Bifunctional Electrocatalysts for Water Splitting. AB - The solar-driven water splitting process is highly attractive for alternative energy utilization, while developing efficient, earth-abundant, bifunctional catalysts for both oxygen evolution reaction and hydrogen evolution reaction has remained as a major challenge. Herein, we develop an ordered CoMnO@CN superlattice structure as an efficient bifunctional water-splitting electrocatalyst, in which uniform Co-Mn oxide (CoMnO) nanoparticles are coated with a thin, continuous nitrogen-doped carbon (CN) framework. The CoMnO nanoparticles enable optimized OER activity with effective electronic structure configuration, and the CN framework serves as an excellent HER catalyst. Importantly, the ordered superlattice structure is beneficial for enhanced reactive sites, efficient charge transfer, and structural stability. This bifunctional superlattice catalyst manifests optimized current densities and electrochemical stability in overall water splitting, outperforming most of the previously reported single- or bifunctional electrocatalysts. Combining with a silicon photovoltaic cell, this CoMnO@CN superlattice bifunctional catalyst enables unassisted solar water splitting continuously for ~5 days with a solar-to hydrogen conversion efficiency of ~8.0%. Our discovery suggests that these transition metal oxide-based superlattices may serve as a unique structure modality for efficient bifunctional water splitting electrocatalysts with scale up potentials. PMID- 26496657 TI - Determining the Site of Accessory Pathways in Orthodromic Reciprocating Tachycardia by Using the Response to Right Ventricular Pacing. AB - BACKGROUND: Postpacing interval (PPI) after right ventricular (RV) pacing entrainment minus tachycardia cycle length (TCL) with a correction for atrioventricular (AV) node delay (corrected PPI-TCL) was useful to differentiate atrioventricular node reentrant tachycardia (AVNRT) from orthodromic reciprocating tachycardia (ORT). However, the value of corrected PPI-TCL in determining the site of the accessory pathway (AP) in ORT has not been investigated. The purpose of this study was to assess whether the corrected PPI TCL is useful in differentiating ORT using a left-sided AP from a right-sided AP. METHODS: We studied 52 patients with ORT using a left-sided AP and 13 patients with a right-sided AP. The PPI was measured upon cessation of the RV pacing at a cycle length 10-40 ms shorter than the TCL. The corrected PPI-TCL was calculated from the subtraction of the increment in AV nodal conduction time of the first PPI from the PPI-TCL. RESULTS: The mean corrected PPI-TCL was 83 +/- 20 ms in patients with ORT using a left-sided AP and 27 +/- 19 ms in patients with a right sided AP (P <= 0.001). All patients with ORT using a left-sided AP except three patients with left septal AP and none of the patients with ORT using a right sided AP had a corrected PPI-TCL > 55 ms. CONCLUSIONS: The corrected PPI-TCL after the RV pacing entrainment is useful to guide differentiating ORT using a left-sided AP from a right-sided AP. PMID- 26496656 TI - Critical Roles of the Direct GABAergic Pallido-cortical Pathway in Controlling Absence Seizures. AB - The basal ganglia (BG), serving as an intermediate bridge between the cerebral cortex and thalamus, are believed to play crucial roles in controlling absence seizure activities generated by the pathological corticothalamic system. Inspired by recent experiments, here we systematically investigate the contribution of a novel identified GABAergic pallido-cortical pathway, projecting from the globus pallidus externa (GPe) in the BG to the cerebral cortex, to the control of absence seizures. By computational modelling, we find that both increasing the activation of GPe neurons and enhancing the coupling strength of the inhibitory pallido-cortical pathway can suppress the bilaterally synchronous 2-4 Hz spike and wave discharges (SWDs) during absence seizures. Appropriate tuning of several GPe-related pathways may also trigger the SWD suppression, through modulating the activation level of GPe neurons. Furthermore, we show that the previously discovered bidirectional control of absence seizures due to the competition between other two BG output pathways also exists in our established model. Importantly, such bidirectional control is shaped by the coupling strength of this direct GABAergic pallido-cortical pathway. Our work suggests that the novel identified pallido-cortical pathway has a functional role in controlling absence seizures and the presented results might provide testable hypotheses for future experimental studies. PMID- 26496658 TI - A retrospective evaluation of the association of celiac disease and growth hormone deficiency: more than a casual association? AB - BACKGROUND: A transient dysfunction of the endocrine growth axis has been reported in celiac disease (CD). This apparent growth hormone deficiency (GHD) generally normalizes with the institution of a gluten-free diet (GFD). However, in few cases, the dysfunction of the GH axis persists despite a good adherence to the GFD. Aims of this study were to investigate pediatric patients with concurrent CD and GHD and to compare them with patients with isolated CD. METHODS: Data regarding CD patients with and without associated GHD were retrospectively collected. Inclusion criteria were availability of anthropometric and laboratory data at baseline and regularly at the reference center up to a 2 year follow-up. In case of poor catch-up growth despite a good adherence to the GFD, endocrinological investigation was carried on. RESULTS: Fifty-three patients with CD were included. Four (7.5%) out of 53 CD patients had a concurrent GHD. In two cases, firstly diagnosed with CD, GHD was suspected because of a poor catch up growth despite a good adherence to the GFD. In two other cases, firstly diagnosed with GHD, gastrointestinal symptoms revealed the diagnosis of CD. Normalization of height velocity was achieved by GH treatment in all cases. No statistical significant difference between the two groups of patients was found as regard laboratory and histological features of CD. It is to note that 2 out of 4 patients with concomitant CD and GHD had thyroiditis compared to 6% of patients with isolated CD (P=0.004). CONCLUSIONS: A high prevalence of CD and GHD association was found. CD patients with poor catch-up growth despite a good adherence to the GFD should be carefully investigated for endocrine disorders. PMID- 26496660 TI - Rotating Ring-Disk Electrode and Quantum-Chemical Study of the Electrochemical Reduction of Monoiodoacetic Acid and Iodoform. AB - This study examined the electrochemical (EC) reduction of monoiodoacetic acid (MIAA) and iodoform (CHI3), which are typical iodine-containing disinfection byproducts (I-DBPs). Experiments carried out using the method of a rotating ring disk electrode (RRDE) with a gold working electrode showed that the reduction of CHI3 and MIAA is diffusion-controlled. The MIAA diffusion coefficient was determined to be (1.86 +/- 0.24).10(-5) cm(2) s(-1). The yield of the iodide ion formed as a result of MIAA or CHI3 reduction was affected by the presence of dissolved organic matter (DOM) and resorcinol. Increasing concentrations of DOM or resorcinol did not affect the EC reduction of the examined I-DBPs, but the formation of iodide was suppressed. This indicated that free iodine, .I, was formed as a result of the first step in the EC reduction of MIAA and CHI3. This also indicated that the pathway of the EC reduction of MIAA and CHI3 was different from that typical for the reduction of Br- and Cl-containing DBPs, in which case Br(-) or Cl(-) tend to be formed as a result of the electron transfer. Quantum-chemical (QC) calculations confirmed the thermodynamic likelihood of and possible preference to the formation of free iodine species as a result of the EC reduction of MIAA, CHI3, and other I-DBPs. PMID- 26496661 TI - Delayed Exciton Emission and Its Relation to Blinking in CdSe Quantum Dots. AB - The efficiency and stability of emission from semiconductor nanocrystal quantum dots (QDs) is negatively affected by "blinking" on the single-nanocrystal level, that is, random alternation of bright and dark periods. The time scales of these fluctuations can be as long as many seconds, orders of magnitude longer than typical lifetimes of exciton states in QDs. In this work, we investigate photoluminescence from QDs delayed over microseconds to milliseconds. Our results prove the existence of long-lived charge-separated states in QDs. We study the properties of delayed emission as a direct way to learn about charge carrier separation and recovery of the exciton state. A new microscopic model is developed to connect delayed emission to exciton recombination and blinking from which we conclude that bright periods in blinking are in fact not characterized by uninterrupted optical cycling as often assumed. PMID- 26496659 TI - Cooperative Effects of FOXL2 with the Members of TGF-beta Superfamily on FSH Receptor mRNA Expression and Granulosa Cell Proliferation from Hen Prehierarchical Follicles. AB - Forkhead box L2 (FOXL2) is a member of the forkhead nuclear factor 3 gene family and plays an essential role in ovarian growth and maturation in mammals. However, its potential effects and regulative mechanism in development of chicken ovarian prehierarchical follicles remain unexplored. In this study, the cooperative effects of FOXL2 with activin A, growth differentiation factor-9 (GDF9) and follistatin, three members of the transforming growth factor beta (TGF-beta) superfamily that were previously suggested to exert a critical role in follicle development was investigated. We demonstrated herein, using in-situ hybridization, Northern blot and immunohistochemical analyses of oocytes and granulosa cells in various sizes of prehierarchical follicles that both FOXL2 transcripts and FOXL2 proteins are predominantly expressed in a highly similar expression pattern to that of GDF9 gene. In addition, the FOXL2 transcript was found at lower levels in theca cells in the absence of GDF9. Furthermore, culture of granulosa cells (GCs) from the prehierarchical follicles (6-8 mm) in conditioned medium revealed that in the pcDNA3.0-FOXL2 transfected GCs, there was a more dramatic increase in FSHR mRNA expression after treatment with activin A (10 ng/ml) or GDF9 (100 ng/ml) for 24 h which caused a stimulatory effect on the GC proliferation. In contrast, a significant decrease of FSHR mRNA was detected after treatment with follistatin (50 ng/ml) and resulted in an inhibitory effect on the cell proliferation. The results of this suggested that FOXL2 plays a bidirectional modulating role involved in the intracellular FSHR transcription and GC proliferation via an autocrine regulatory mechanism in a positive or negative manner through cooperation with activin A and/or GDF9, and follistatin in the hen follicle development. This cooperative action may be mediated by the examined Smad signals and simultaneously implicated in modulation of the StAR, CCND2, and CYP11A1 expression. PMID- 26496664 TI - Abstracts of the UK Stroke Forum 2015 Conference, 1-3 December 2015, Liverpool, UK. PMID- 26496662 TI - Myelin-specific T cells induce interleukin-1beta expression in lesion-reactive microglial-like cells in zones of axonal degeneration. AB - Infiltration of myelin-specific T cells into the central nervous system induces the expression of proinflammatory cytokines in patients with multiple sclerosis (MS). We have previously shown that myelin-specific T cells are recruited into zones of axonal degeneration, where they stimulate lesion-reactive microglia. To gain mechanistic insight, we used RNA microarray analysis to compare the transcript profile in hippocampi from perforant pathway axonal-lesioned mice with and without adoptively transferred myelin-specific T cells 2 days postlesion, when microglia are clearly lesion reactive. Pathway analysis revealed that, among the 1,447 differently expressed transcripts, the interleukin (IL)-1 pathway including all IL-1 receptor ligands was upregulated in the presence of myelin specific T cells. Quantitative polymerase chain reaction showed increased mRNA levels of IL-1beta, IL-1alpha, and IL-1 receptor antagonist in the T-cell infiltrated hippocampi from axonal-lesioned mice. In situ hybridization and immunohistochemistry showed a T-cell-enhanced lesion-specific expression of IL 1beta mRNA and protein, respectively, and induction of the apoptosis-associated speck-like protein, ASC, in CD11b(+) cells. Double in situ hybridization showed colocalization of IL-1beta mRNA in a subset of CD11b mRNA(+) cells, of which many were part of cellular doublets or clusters, characteristic of proliferating, lesion-reactive microglia. Double-immunofluorescence showed a T-cell-enhanced colocalization of IL-1beta to CD11b(+) cells, including lesion-reactive CD11b(+) ramified microglia. These results suggest that myelin-specific T cells stimulate lesion-reactive microglial-like cells to produce IL-1beta. These findings are relevant to understand the consequences of T-cell infiltration in white and gray matter lesions in patients with MS. PMID- 26496663 TI - Bacterial Quorum Sensing Inhibition Activity of the Traditional Chinese Herbs, Ficus carica L. and Perilla frutescens. AB - BACKGROUND: Quorum sensing (QS), as the basis of bacterial cell-to-cell communication, is a promising approach to reduce the incidence of multidrug resistance. The objective of this study was to search for novel quorum sensing inhibitors from plants and control detrimental infections. METHODS: The crude extracts of Ficus carica and Perilla frutescens were examined for their anti-QS properties. Powdered plant samples were treated sequentially with organic solvents of increasing polarity. The extracts of each solvent were concentrated in vacuo to give crude extracts and tested against Chromobacterium violaceum CV026 and Pseudomonas aeruginosa PA01 especially. Anti-QS activity was measured by quantifying violacein production and swarming motility. RESULTS: All extracts of these two plants display anti-QS ability. Interestingly, the extract of F. carica with dichloromethane and of P. frutescens with MeOH exhibited the most pronounced inhibition of QS activity. CONCLUSIONS: These two plants can offer bioactive natural products with potential for attenuating pathogens. PMID- 26496665 TI - In reference to "Variation in printed handoff documents: Results and recommendations from a multicenter needs assessment". PMID- 26496666 TI - Short-Term and Working Memory Impairments in Early-Implanted, Long-Term Cochlear Implant Users Are Independent of Audibility and Speech Production. AB - OBJECTIVE: To determine whether early-implanted, long-term cochlear implant (CI) users display delays in verbal short-term and working memory capacity when processes related to audibility and speech production are eliminated. DESIGN: Twenty-three long-term CI users and 23 normal-hearing controls each completed forward and backward digit span tasks under testing conditions that differed in presentation modality (auditory or visual) and response output (spoken recall or manual pointing). RESULTS: Normal-hearing controls reproduced more lists of digits than the CI users, even when the test items were presented visually and the responses were made manually via touchscreen response. CONCLUSIONS: Short term and working memory delays observed in CI users are not due to greater demands from peripheral sensory processes such as audibility or from overt speech motor planning and response output organization. Instead, CI users are less efficient at encoding and maintaining phonological representations in verbal short-term memory using phonological and linguistic strategies during memory tasks. PMID- 26496667 TI - Nanostructured electrolytes for stable lithium electrodeposition in secondary batteries. AB - Secondary batteries based on lithium are the most important energy storage technology for contemporary portable devices. The lithium ion battery (LIB) in widespread commercial use today is a compromise technology. It compromises high energy, high power, and design flexibility for long cell operating lifetimes and safety. Materials science, transport phenomena, and electrochemistry in the electrodes and electrolyte that constitute such batteries are areas of active study worldwide because significant improvements in storage capacity and cell lifetime are required to meet new demands, including the electrification of transportation and for powering emerging autonomous aircraft and robotics technologies. By replacing the carbonaceous host material used as the anode in an LIB with metallic lithium, rechargeable lithium metal batteries (LMBs) with higher storage capacity and compatibility with low-cost, high-energy, unlithiated cathodes such as sulfur, manganese dioxide, carbon dioxide, and oxygen become possible. Large-scale, commercial deployment of LMBs are today limited by safety concerns associated with unstable electrodeposition and lithium dendrite formation during cell recharge. LMBs are also limited by low cell operating lifetimes due to parasitic chemical reactions between the electrode and electrolyte. These concerns are greater in rechargeable batteries that utilize other, more earth abundant metals such as sodium and to some extent even aluminum. Inspired by early theoretical works, various strategies have been proposed for alleviating dendrite proliferation in LMBs. A commonly held view among these early studies is that a high modulus, solid-state electrolyte that facilitates fast ion transport, is nonflammable, and presents a strong-enough physical barrier to dendrite growth is a requirement for any commercial LMB. Unfortunately, poor room-temperature ionic conductivity, challenging processing, and the high cost of ceramic electrolytes that meet the modulus and stability requirements have to date proven to be insurmountable obstacles to progress. In this Account, we first review recent advances in continuum theory for dendrite growth and proliferation during metal electrodeposition. We show that the range of options for designing electrolytes and separators that stabilize electrodeposition is now substantially broader than one might imagine from previous literature accounts. In particular, separators designed at the nanoscale to constrain ion transport on length scales below a theory-defined cutoff, and structured electrolytes in which a fraction of anions are permanently immobilized to nanoparticles, to a polymer network or ceramic membrane are considered particularly promising for their ability to stabilize electrodeposition of lithium metal without compromising ionic conductivity or room temperature battery operation. We also review recent progress in designing surface passivation films for metallic lithium that facilitate fast deposition of lithium at the electrolyte/electrode interface and at the same time protect the lithium from parasitic side reactions with liquid electrolytes. A promising finding from both theory and experiment is that simple film-forming halide salt additives in a conventional liquid electrolyte can substantially extend the lifetime and safety of LMBs. PMID- 26496668 TI - Cartilage degeneration and excessive subchondral bone formation in spontaneous osteoarthritis involves altered TGF-beta signaling. AB - Transforming growth factor-beta (TGF-beta) has been demonstrated as a potential therapeutic target in osteoarthritis. However, beneficial effects of TGF-beta supplement and inhibition have both been reported, suggesting characterization of the spatiotemporal distribution of TGF-beta during the whole time course of osteoarthritis is important. To investigate the activity of TGF-beta in osteoarthritis progression, we collected knee joints from Dunkin-Hartley (DH) guinea pigs at 3, 6, 9, and 12-month old (n = 8), which develop spontaneous osteoarthritis in a manner extraordinarily similar to humans. Via histology and micro-computed tomography (CT) analysis, we found that the joints exhibited gradual cartilage degeneration, subchondral plate sclerosis, and elevated bone remodeling during aging. The degenerating cartilage showed a progressive switch of the expression of phosphorylated Smad2/3 to Smad1/5/8, suggesting dual roles of TGF-beta/Smad signaling during chondrocyte terminal differentiation in osteoarthritis progression. In subchondral bone, we found that the locations and age-related changes of osterix(+) osteoprogenitors were in parallel with active TGF-beta, which implied the excessive osteogenesis may link to the activity of TGF-beta. Our study, therefore, suggests an association of cartilage degeneration and excessive bone remodeling with altered TGF-beta signaling in osteoarthritis progression of DH guinea pigs. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:763-770, 2016. PMID- 26496669 TI - Otopathology of Vasculitis in Granulomatosis With Polyangitis. AB - OBJECTIVE: To describe the temporal bone histopathology of vasculitis in granulomatosis with polyangitis. BACKGROUND: Granulomatosis with polyangitis is an autoimmune disease that presents as granulomatosis and vasculitis. Otologic findings, including otitis media, hearing loss, vertigo, and facial paralysis are common in this condition. MATERIAL AND METHODS: The temporal bones of four subjects with manifestations of vasculitis attributed to granulomatosis with polyangitis were studied under light microscopy. RESULTS: The four subjects had manifestations of vasculitis including hemorrhage within the cochlea and vestibule, and inflammation and occlusion of vessels in the lateral cochlear wall and the vasa nervorum of the facial nerve. CONCLUSIONS: We infer that sensorineural hearing loss, vestibulopathy, and facial nerve paresis in granulomatosis with polyangitis can be the results of vasculitis. PMID- 26496670 TI - Speech Perception of Elderly Cochlear Implant Users Under Different Noise Conditions. AB - OBJECTIVE: The primary objective of this study was the comparison of younger and older (>75 yr) CI recipients' performance for speech perception in quiet and in competing continuous and fluctuating noise. STUDY DESIGN: Prospective, comparative clinical study. SETTING: University hospital. PATIENTS: Fifty patients, 25 older and 25 younger than 75 years, with a postlingually acquired profound hearing loss who received a cochlear implant at least 1 year before study start were enrolled. INTERVENTIONS: Cochlear implantation. MAIN OUTCOME MEASURES: We measured speech perception using monosyllable (Freiburg monosyllables) and sentence materials (Gottingen sentences) in quiet. In addition, speech perception for sentences was measured under two different noise conditions: with a continuous, speech-simulating noise signal (CCITT noise) and the FASTL noise (fluctuating noise). RESULTS: We did not find a significant difference between the performance for younger and the older cohort on speech perception tasks in quiet for Freiburg monosyllables (63.4% +/- 20% and 61.7% +/- 18.1%, respectively) and for the Gottingen sentences in quiet (73.5% +/- 24.3% and 75% +/- 25%, respectively). No significant difference was observed for performance between the two age groups when listening in continuous CCITT noise (18.9% +/- 24.0% and 29.5% +/- 25.2% perception score respectively) or in FASTL noise (27.8% +/- 24.2% and 34.4% +/- 27.8% perception score, respectively). CONCLUSION: There is no supporting evidence from our evaluations of word and sentence perception in quiet and noise that elderly CI users older than 75 years of age perform more poorly than those younger than 75 years of age. PMID- 26496671 TI - Outcomes in Stapedotomy Surgery: The Learning Curve Redefined. AB - OBJECTIVE: The aim of this study is to determine if the cumulative summation test for the learning curve (LC-CUSUM) and the cumulative summation graph (CUSUM) can be used to demonstrate landmark points of competence and maintenance of proficiency in stapes surgery over a continuous time period. STUDY DESIGN: Retrospective review from January 1999 until August 2014. SETTING: Tertiary referral hospital. PATIENTS: All adult patients with confirmed otosclerosis. INTERVENTION(S): Two-hundred and four primary and revision stapedotomy. MAIN OUTCOME MEASURE(S): Learning curves were constructed using the CUSUM and LC CUSUM. Failure was defined as closure of the ABG >10 dB in less than 10% of patients to demonstrate the landmark point of competency and to highlight any fluctuations over a prolonged period. RESULTS: When the failure rate was defined as closure of the ABG >10 dB, it was not possible to create useful LC-CUSUM and CUSUM graphs, but by redefining the failure rate as > 15 dB, competency was reached at case 43 and maintained with natural fluctuations occurring between cases 137 and 149 and again at case 196. CONCLUSIONS: LC-CUSUM and CUSUM are a more robust analytical method of illustrating the learning curve and suggest that the traditional benchmark of closure of the ABG <=10 dB in more than 90% of patients may need reconsideration. It can also be used as standardized audit tools when monitoring results and used to plan future training programs as they clearly define a point when novice trainees become competent. PMID- 26496672 TI - Incidence of Retrocochlear Pathology Found on MRI in Patients With Non-Pulsatile Tinnitus. AB - OBJECTIVE: To identify the incidence of retrocochlear pathology on MRI in patients with non-pulsatile tinnitus. STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center. PATIENTS: Adults with MRIs performed between March 1, 2008 and February 1, 2014 for non-pulsatile tinnitus with or without hearing loss. INTERVENTION: MRI. MAIN OUTCOME MEASURE: Incidence of retrocochlear pathology. RESULTS: Of the 218 patients who met inclusion criteria, 198 (91.3%) had unremarkable MRIs. Six patients (2.7%) had MRI findings that accounted for their tinnitus. Of these patients, five had unilateral tinnitus with asymmetric hearing loss because of acoustic neuroma found on MRI. One patient presented with bilateral tinnitus with asymmetric hearing loss and was found to have a right acoustic neuroma. Twenty (9.2%) patients had bilateral or unilateral tinnitus without hearing loss, all with unremarkable MRIs. Fourteen patients (6.4%) had incidental findings including two acoustic neuromas that were identified contralateral to the side of presenting tinnitus. CONCLUSIONS: Imaging should be used judiciously in the evaluation of tinnitus. Patients with unilateral tinnitus and asymmetric hearing loss were most likely to have abnormal findings. The majority of MRIs performed for tinnitus were normal in our study. Given the low incidence of MRI findings in the workup of tinnitus, every effort should be made to optimize screening protocols. Noncontrasted fast spin-echo T2-weighted MRI should be used to assess patients with tinnitus when there is low suspicion for retrocochlear pathology. Patients with unilateral non-pulsatile tinnitus with symmetric hearing may be observed, but clinical judgement should determine the need for further imaging. PMID- 26496673 TI - Histopathology of the Human Inner Ear in a Patient With Sensorineural Hearing Loss Caused by a Variant in DFNA5. AB - HYPOTHESIS: Describe the histopathology of the inner ear in a patient with hearing loss caused by a pathogenic variant of the DFNA5 gene. BACKGROUND: Variants in DFNA5 have been described as causing an autosomal dominant nonsyndromic sensorineural hearing loss. To date, there has been no description of the histopathology of the inner ear in humans with hearing loss because of pathogenic variants in DFNA5. METHODS: Temporal bone histopathology by light microscopy, next-generation sequencing (NGS) of DNA obtained from blood, and Sanger sequencing of DNA obtained from formalin fixed temporal bone sections. RESULTS: Both the temporal bone donor and her daughter were shown to have the same pathogenic variant in the DFNA5 gene. The principal histopathologic correlates of the hearing loss were loss of the inner and outer hair cells and severe degeneration of the stria vascularis and spiral ligament throughout the cochlea. In addition, there was severe degeneration of spiral ganglion cells, particularly in the basal turn, and degeneration of vestibular neuroepithelium and neurons. The donor had undergone unilateral cochlear implantation during life. Histopathology demonstrated that the cochlear implant was inserted into the scala vestibuli with considerable new bone formation around the track of the implanted electrode. CONCLUSIONS: This is the first report of the histopathology of the inner ear in a patient with hearing loss caused by a pathogenic variant in the DFNA5 gene. PMID- 26496674 TI - Natural Fibers: A Missing Link to Chemical Pollution Dispersion in Aquatic Environments. PMID- 26496676 TI - "Let's Get This Party Started!": An Analysis of Health Risk Behavior on MTV Reality Television Shows. AB - Past research has examined portrayals of risk behavior in various media, including television, advertising, and film. To address an underexplored area, this study analyzed drinking, smoking, and sexual activities in MTV reality programming popular among adolescent viewers from 2004 to 2011. Cast members' demographic attributes were also examined in relation to their risk behaviors. Results demonstrated that drinking and casual sexual behaviors were pervasive among cast members. Smoking and more intense sexual behaviors were also present, but to a smaller degree. Men and young adult cast members were more likely to engage in risk behaviors than women and teenage cast members. Also, ethnic/racial minority characters were shown drinking more often than were White cast members. Interpretations of these findings are discussed based in social cognitive theory and the concept of super peers. Implications for future research are provided. PMID- 26496677 TI - Mesoporous Silica-Based Supports for the Controlled and Targeted Release of Bioactive Molecules in the Gastrointestinal Tract. AB - Mesoporous silica particles (MSPs) have attracted increasing interest as supports in the design of controlled delivery materials. Besides their excellent properties as loading supports (that is, large surface area and pore volume), the modification of their external surface with molecular/supramolecular ensembles allows the design of gated MSPs. Delivery systems based on gated MSPs show "zero delivery" until an adequate stimulus is present and triggers gate opening and the cargo is released. Encapsulation of bioactive molecules in gated MSPs may improve biological stability, facilitate component handling, mask unpleasant sensorial properties, and modulate the bioaccessibility of target molecules along the gastrointestinal tract. These properties make gated MSPs excellent candidates for encapsulating bioactive molecules and their subsequent utilization in the formulation of functional foods. This text highlights the most significant endogenous triggering stimuli that might be applied to design these site-specific delivery systems, as well as the strategies to develop them. Given the novelty of using MSPs in the food sector, the benefits and current potential limitations of employing MSPs in human food have been identified and discussed. PMID- 26496679 TI - ERRATUM. PMID- 26496678 TI - 8th Annual Symposium on Self-Monitoring of Blood Glucose (SMBG): April 16-18, 2015, Republic of Malta. AB - International experts in the fields of diabetes, diabetes technology, endocrinology, mobile health, sport science, and regulatory issues gathered for the 8(th) Annual Symposium on Self-Monitoring of Blood Glucose (SMBG) with a focus on personalized diabetes management. The aim of this meeting was to facilitate new collaborations and research projects to improve the lives of people with diabetes. The 2015 meeting comprised a comprehensive scientific program, parallel interactive workshops, and two keynote lectures. PMID- 26496680 TI - Pain control in orthodontics using a micropulse vibration device: A randomized clinical trial. AB - OBJECTIVE: To investigate the relationship between a micropulse vibration device and pain perception during orthodontic treatment. MATERIALS AND METHODS: This study was a parallel group, randomized clinical trial. A total of 58 patients meeting eligibility criteria were assigned using block allocation to one of two groups: an experimental group using the vibration device or a control group (n = 29 for each group). Patients used the device for 20 minutes daily. Patients rated pain intensity on a visual analog scale at appropriate intervals during the weeks after the separator or archwire appointment. Data were analyzed using repeated measures analysis of variance at alpha = .05. RESULTS: During the 4 month test period, significant differences between the micropulse vibration device group and the control group for overall pain (P = .002) and biting pain (P = .003) were identified. The authors observed that perceived pain was highest at the beginning of the month, following archwire adjustment. CONCLUSION: The micropulse vibration device significantly lowered the pain scores for overall pain and biting pain during the 4-month study period. PMID- 26496681 TI - Severe case of fetal hemolytic disease caused by anti-C(w) requiring serial intrauterine transfusions complicated by pancytopenia and cholestasis. AB - BACKGROUND: Anti-C(w) are rarely found as a source for severe fetal and neonatal hemolytic diseases. We report a case with serial intrauterine transfusions complicated by pancytopenia and cholestasis in the neonatal period. CASE REPORT: A 37-year-old woman revealed anti-C(w) with a titer of 512 in her fourth pregnancy. The fetus developed fetal anemia and a severe hydrops requiring three intrauterine red blood cell (RBC) transfusions. After birth at 33 + 0 weeks the newborn presented only transfused RBCs and suffered from anemia, thrombocytopenia, leukopenia, and a cholestatic liver disease. Blood counts improved after transfusion of 2 RBC units and one platelet concentrate and administration of hematopoietic growth factors. The symptoms of cholestasis improved slowly after therapy with ursodeoxycholic acid, vitamins, and medium chain triglyceride-enriched formula feeding. CONCLUSION: Anti-C(w) may lead to severe fetal anemia and consecutive complications. Surveillance of affected pregnancies with high antibody titers using sonographic evaluation of the middle cerebral artery peak systolic velocity should be warranted, especially in multiparous women. PMID- 26496682 TI - Nuclear Pore Complex: From Structural View to Chemical Tools. AB - Nuclear pore complexes (NPCs) are the macromolecular turnstiles between the cytoplasm and the nucleus that control the trafficking of proteins, RNAs and viruses. The giant NPC structures are extremely complex. Here, I highlight several recent findings on NPC architectures, and briefly discuss how chemical biologists might use this information to design synthetic devices and improve strategies for nuclear drug delivery. PMID- 26496684 TI - Characterization of the Biosynthetic Gene Cluster for Benzoxazole Antibiotics A33853 Reveals Unusual Assembly Logic. AB - A33853, which shows excellent bioactivity against Leishmania, is a benzoxazole family compound formed from two moieties of 3-hydroxyanthranilic acid and one 3 hydroxypicolinic acid. In this study, we have identified the gene cluster responsible for the biosynthesis of A33853 in Streptomyces sp. NRRL12068 through genome mining and heterologous expression. Bioinformatics analysis and functional characterization of the orfs contained in the gene cluster revealed that the biosynthesis of A33853 is directed by a group of unusual enzymes. In particular, BomK, annotated as a ketosynthase, was found to catalyze the amide bond formation between 3-hydroxypicolinic and 3-hydroxyanthranilic acid during the assembly of A33853. BomJ, a putative ATP-dependent coenzyme A ligase, and BomN, a putative amidohydrolase, were further proposed to be involved in the benzoxazole formation in A33853 according to gene deletion experiments. Finally, we have successfully utilized mutasynthesis to generate two analogs of A33853, which were reported previously to possess excellent anti-leishmanial activity. PMID- 26496683 TI - XBP1s Links the Unfolded Protein Response to the Molecular Architecture of Mature N-Glycans. AB - The molecular architecture of the mature N-glycome is dynamic, with consequences for both normal and pathologic processes. Elucidating cellular mechanisms that modulate the N-linked glycome is, therefore, crucial. The unfolded protein response (UPR) is classically responsible for maintaining proteostasis in the secretory pathway by defining levels of chaperones and quality control proteins. Here, we employ chemical biology methods for UPR regulation to show that stress independent activation of the UPR's XBP1s transcription factor also induces a panel of N-glycan maturation-related enzymes. The downstream consequence is a distinctive shift toward specific hybrid and complex N-glycans on N-glycoproteins produced from XBP1s-activated cells, which we characterize by mass spectrometry. Pulse-chase studies attribute this shift specifically to altered N-glycan processing, rather than to changes in degradation or secretion rates. Our findings implicate XBP1s in a new role for N-glycoprotein biosynthesis, unveiling an important link between intracellular stress responses and the molecular architecture of extracellular N-glycoproteins. PMID- 26496685 TI - Three Redundant Synthetases Secure Redox-Active Pigment Production in the Basidiomycete Paxillus involutus. AB - The symbiotic fungus Paxillus involutus serves a critical role in maintaining forest ecosystems, which are carbon sinks of global importance. P. involutus produces involutin and other 2,5-diarylcyclopentenone pigments that presumably assist in the oxidative degradation of lignocellulose via Fenton chemistry. Their precise biosynthetic pathways, however, remain obscure. Using a combination of biochemical, genetic, and transcriptomic analyses, in addition to stable-isotope labeling with synthetic precursors, we show that atromentin is the key intermediate. Atromentin is made by tridomain synthetases of high similarity: InvA1, InvA2, and InvA5. An inactive atromentin synthetase, InvA3, gained activity after a domain swap that replaced its native thioesterase domain with that of InvA5. The found degree of multiplex biosynthetic capacity is unprecedented with fungi, and highlights the great importance of the metabolite for the producer. PMID- 26496686 TI - Fluorinated Sterols Are Suicide Inhibitors of Ergosterol Biosynthesis and Growth in Trypanosoma brucei. AB - Trypanosoma brucei, the causal agent for sleeping sickness, depends on ergosterol for growth. Here, we describe the effects of a mechanism-based inhibitor, 26 fluorolanosterol (26FL), which converts in vivo to a fluorinated substrate of the sterol C24-methyltransferase essential for sterol methylation and function of ergosterol, and missing from the human host. 26FL showed potent inhibition of ergosterol biosynthesis and growth of procyclic and bloodstream forms while having no effect on cholesterol biosynthesis or growth of human epithelial kidney cells. During exposure of cloned TbSMT to 26-fluorocholesta-5,7,24-trienol, the enzyme is gradually killed as a consequence of the covalent binding of the intermediate C25 cation to the active site (kcat/kinact = 0.26 min(-1)/0.24 min( 1); partition ratio of 1.08), whereas 26FL is non-productively bound. These results demonstrate that poisoning of ergosterol biosynthesis by a 26-fluorinated Delta(24)-sterol is a promising strategy for developing a new treatment for trypanosomiasis. PMID- 26496687 TI - Engineered Domain Swapping as an On/Off Switch for Protein Function. AB - Domain swapping occurs when identical proteins exchange segments in reciprocal fashion. Natural swapping mechanisms remain poorly understood, and engineered swapping has the potential for creating self-assembling biomaterials that encode for emergent functions. We demonstrate that induced swapping can be used to regulate the function of a target protein. Swapping is triggered by inserting a "lever" protein (ubiquitin) into one of four loops of the ribose binding protein (RBP) target. The lever splits the target, forcing RBP to refold in trans to generate swapped oligomers. Identical RBP-ubiquitin fusions form homo-swapped complexes with the ubiquitin domain acting as the hinge. Surprisingly, some pairs of non-identical fusions swap more efficiently with each other than they do with themselves. Nuclear magnetic resonance experiments reveal that the hinge of these hetero-swapped complexes maps to a region of RBP distant from both ubiquitins. This design is expected to be applicable to other proteins to convert them into functional switches. PMID- 26496689 TI - Epigenetics of T lymphocytes in health and disease. AB - The risk of developing autoimmune diseases depends on both genetic and environmental factors, with epigenetic mechanisms of regulation potentially translating environmental cues into stable modifications in gene expression. Such stable memory of a functional state has been deciphered into a number of molecular mechanisms that collectively define the epigenetic status of a cell. In recent years, it has become increasingly clear that epigenetic modifications are highly dynamic and are able to adapt to the changing environment, with important impact on the onset and development of a number of diseases. Here, we describe some of the epigenetic mechanisms of regulation of cellular functional states in T lymphocytes, with a particular focus on DNA methylation. We will also discuss current knowledge on the role of epigenetics in autoimmunity and consider open questions in the field. PMID- 26496688 TI - Mapping Proteome-Wide Targets of Environmental Chemicals Using Reactivity-Based Chemoproteomic Platforms. AB - We are exposed to a growing number of chemicals in our environment, most of which have not been characterized in terms of their toxicological potential or mechanisms. Here, we employ a chemoproteomic platform to map the cysteine reactivity of environmental chemicals using reactivity-based probes to mine for hyper-reactive hotspots across the proteome. We show that environmental contaminants such as monomethylarsonous acid and widely used pesticides such as chlorothalonil and chloropicrin possess common reactivity with a distinct set of proteins. Many of these proteins are involved in key metabolic processes, suggesting that these targets may be particularly sensitive to environmental electrophiles. We show that the widely used fungicide chlorothalonil specifically inhibits several metabolic enzymes involved in fatty acid metabolism and energetics, leading to dysregulated lipid metabolism in mice. Our results underscore the utility of using reactivity-based chemoproteomic platforms to uncover novel mechanistic insights into the toxicity of environmental chemicals. PMID- 26496690 TI - Developmental Effects of the ToxCastTM Phase I and Phase II Chemicals in Caenorhabditis elegans and Corresponding Responses in Zebrafish, Rats, and Rabbits. AB - BACKGROUND: Modern toxicology is shifting from an observational to a mechanistic science. As part of this shift, high-throughput toxicity assays are being developed using alternative, nonmammalian species to prioritize chemicals and develop prediction models of human toxicity. METHODS: The nematode Caenorhabditis elegans (C. elegans) was used to screen the U.S. Environmental Protection Agency's (EPA's) ToxCastTM Phase I and Phase II libraries, which contain 292 and 676 chemicals, respectively, for chemicals leading to decreased larval development and growth. Chemical toxicity was evaluated using three parameters: a biologically defined effect size threshold, half-maximal activity concentration (AC50), and lowest effective concentration (LEC). RESULTS: Across both the Phase I and Phase II libraries, 62% of the chemicals were classified as active <= 200 MUM in the C. elegans assay. Chemical activities and potencies in C. elegans were compared with those from two zebrafish embryonic development toxicity studies and developmental toxicity data for rats and rabbits. Concordance of chemical activity was higher between C. elegans and one zebrafish assay across Phase I chemicals (79%) than with a second zebrafish assay (59%). Using C. elegans or zebrafish to predict rat or rabbit developmental toxicity resulted in balanced accuracies (the average value of the sensitivity and specificity for an assay) ranging from 45% to 53%, slightly lower than the concordance between rat and rabbit (58%). CONCLUSIONS: Here, we present an assay that quantitatively and reliably describes the effects of chemical toxicants on C. elegans growth and development. We found significant overlap in the activity of chemicals in the ToxCastTM libraries between C. elegans and zebrafish developmental screens. Incorporating C. elegans toxicological assays as part of a battery of in vitro and in vivo assays provides additional information for the development of models to predict a chemical's potential toxicity to humans. CITATION: Boyd WA, Smith MV, Co CA, Pirone JR, Rice JR, Shockley KR, Freedman JH. 2016. Developmental effects of the ToxCastTM Phase I and II chemicals in Caenorhabditis elegans and corresponding responses in zebrafish, rats, and rabbits. Environ Health Perspect 124:586-593; http://dx.doi.org/10.1289/ehp.1409645. PMID- 26496691 TI - Predictors of Satisfaction with Dentures in a Cohort of Individuals Wearing Old Dentures: Functional Quality or Patient-Reported Measures? AB - PURPOSE: To examine the extent to which denture satisfaction can be determined by a measure of the denture's functional quality and by patient-reported measures. MATERIALS AND METHODS: This study used data obtained from 117 edentulous individuals with a mean age of 73.7 (SD = 5.6) years in southern Brazil. The edentulous individuals rated their levels of general satisfaction with their actual dentures, using a visual analog scale. Explanatory variables included the individual's information about ability to chew, ability to speak, esthetics, and sociodemographic factors. The dentures were evaluated using the validated 9-item Functional Assessment of Dentures instrument. Bivariate statistical analyses and Poisson regression models (prevalence ratio [PR]; 95% CI; p < 0.05) were used to test the association of explanatory variables with patients' general satisfaction with their complete dentures. RESULTS: There was a statistically significant association between patients' general satisfaction and stability of maxillary (rocking movement) (adjusted PR = 1.28; 95% CI: 1.07-1.52) and mandibular dentures (occlusal displacement) (adjusted PR = 1.68; 95% CI: 1.16-2.43), masticatory ability (adjusted PR = 1.54; 95% CI: 1.08-2.19), and the age of the mandibular denture (adjusted PR = 1.47; 95% CI: 1.10-1.97). CONCLUSIONS: The results of this study indicated that measures of denture stability, masticatory ability, and age of dentures appeared to be determinants of patients' satisfaction with dentures. PMID- 26496692 TI - Gravitropism in Arabidopsis thaliana: Root-specific action of the EHB gene and violation of the resultant law. AB - Gravitropic bending of seedlings of Arabidopsis thaliana in response to centrifugal accelerations was determined in a range between 0.0025 and 4*g to revisit and validate the so-called resultant law, which claims that centrifugation causes gravitropic organs to orient parallel to the resultant stimulus vector. We show here for seedlings of A. thaliana that this empirical law holds for hypocotyls but surprisingly fails for roots. While the behavior of hypocotyls could be modeled by an arc tangent function predicted by the resultant law, roots displayed a sharp maximum at 1.8*g that substantially overshoots the predicted value and that represents a novel phenomenon, diagravitropism elicited by centrifugal acceleration. The gravitropic bending critically depended on the orientation of the seedling relative to the centrifugal acceleration. If the centrifugal vector pointed toward the cotyledons, gravitropic bending of hypocotyls and roots was substantially enhanced. The complex behavior of Arabidopsis seedlings provides strong evidence that gravitropic bending entails a cosine component (longitudinal stimulus) to which the seedlings were more sensitive than to the classical sine component. The absolute gravitropic thresholds of hypocotyls and roots were determined in a clinostat-centrifuge and found to be below 0.015*g. A tropism mutant lacking the EHB1 protein, which interacts with ARF-GAP (ARF GTPase-activating protein) and thus indirectly with a small ARF-type G protein, displayed a lower gravitropic threshold for roots and also enhanced bending, while the responses of the hypocotyls remained nearly unaffected. PMID- 26496693 TI - Coincidence summing corrections for point and volume 152Eu sources. AB - In this article, the X-ray and gamma-ray coincidence summing effect in (152)Eu is studied. Coincidence summing corrections and peak and total efficiencies of point and volume sources were determined using the direct matrices multiplication (DMM) method. The theoretically evaluated peak count rates were found to be in good agreement with the experimentally obtained values. Validation was performed by comparing the calculated efficiency curves and the corresponding correction factors with the results obtained using GESPECOR 4.2 software. PMID- 26496694 TI - Identification of a Novel Lipoprotein Regulator of Clostridium difficile Spore Germination. AB - Clostridium difficile is a Gram-positive spore-forming pathogen and a leading cause of nosocomial diarrhea. C. difficile infections are transmitted when ingested spores germinate in the gastrointestinal tract and transform into vegetative cells. Germination begins when the germinant receptor CspC detects bile salts in the gut. CspC is a subtilisin-like serine pseudoprotease that activates the related CspB serine protease through an unknown mechanism. Activated CspB cleaves the pro-SleC zymogen, which allows the activated SleC cortex hydrolase to degrade the protective cortex layer. While these regulators are essential for C. difficile spores to outgrow and form toxin-secreting vegetative cells, the mechanisms controlling their function have only been partially characterized. In this study, we identify the lipoprotein GerS as a novel regulator of C. difficile spore germination using targeted mutagenesis. A gerS mutant has a severe germination defect and fails to degrade cortex even though it processes SleC at wildtype levels. Using complementation analyses, we demonstrate that GerS secretion, but not lipidation, is necessary for GerS to activate SleC. Importantly, loss of GerS attenuates the virulence of C. difficile in a hamster model of infection. Since GerS appears to be conserved exclusively in related Peptostreptococcaeace family members, our results contribute to a growing body of work indicating that C. difficile has evolved distinct mechanisms for controlling the exit from dormancy relative to B. subtilis and other spore forming organisms. PMID- 26496695 TI - Grafting on a Non-Transgenic Tolerant Tomato Variety Confers Resistance to the Infection of a Sw5-Breaking Strain of Tomato spotted wilt virus via RNA Silencing. AB - RNA silencing controls endogenous gene expression and drives defensive reactions against invasive nucleic acids like viruses. In plants, it has been demonstrated that RNA silencing can be transmitted through grafting between scions and silenced rootstocks to attenuate virus and viroid accumulation in the scions. This has been obtained mostly using transgenic plants, which may be a drawback in current agriculture. In the present study, we examined the dynamics of infection of a resistance-breaking strain of Tomato spotted wilt virus (RB-TSWV) through the graft between an old Apulian (southern Italy) tomato variety, denoted Sl-Ma, used as a rootstock and commercial tomato varieties used as scions. In tests with non-grafted plants, Sl-Ma showed resistance to the RB-TSWV infection as viral RNA accumulated at low levels and plants recovered from disease symptoms by 21 days post inoculation. The resistance trait was transmitted to the otherwise highly susceptible tomato genotypes grafted onto Sl-Ma. The results from the analysis of small RNAs hallmark genes involved in RNA silencing and virus-induced gene silencing suggest that RNA silencing is involved in the resistance showed by Sl Ma against RB-TSWV and in scions grafted on this rootstock. The results from self grafted susceptible tomato varieties suggest also that RNA silencing is enhanced by the graft itself. We can foresee interesting practical implications of the approach described in this paper. PMID- 26496698 TI - Antibodies are not required to a protective immune response against dengue virus elicited in a mouse encephalitis model. AB - Generating neutralizing antibodies have been considered a prerequisite to control dengue virus (DENV) infection. However, T lymphocytes have also been shown to be important in a protective immune state. In order to investigate the contribution of both humoral and cellular immune responses in DENV immunity, we used an experimental model in which a non-lethal DENV2 strain (ACS46) is used to intracranially prime Balb/C mice which develop protective immunity against a lethal DENV2 strain (JHA1). Primed mice generated envelope-specific antibodies and CD8(+) T cell responses targeting mainly non-structural proteins. Immune sera from protected mice did not confer passive protection to naive mice challenged with the JHA1 strain. In contrast, depletion of CD4(+) and CD8(+) T lymphocytes significantly reduced survival of ACS46-primed mice challenged with the JHA1 strain. Collectively, results presented in this study show that a cellular immune response targeting non-structural proteins are a promising way in vaccine development against dengue. PMID- 26496696 TI - Measurement of Systemic Mitochondrial Function in Advanced Primary Open-Angle Glaucoma and Leber Hereditary Optic Neuropathy. AB - Primary Open Angle Glaucoma (POAG) is a common neurodegenerative disease characterized by the selective and gradual loss of retinal ganglion cells (RGCs). Aging and increased intraocular pressure (IOP) are glaucoma risk factors; nevertheless patients deteriorate at all levels of IOP, implying other causative factors. Recent evidence presents mitochondrial oxidative phosphorylation (OXPHOS) complex-I impairments in POAG. Leber Hereditary Optic Neuropathy (LHON) patients suffer specific and rapid loss of RGCs, predominantly in young adult males, due to complex-I mutations in the mitochondrial genome. This study directly compares the degree of OXPHOS impairment in POAG and LHON patients, testing the hypothesis that the milder clinical disease in POAG is due to a milder complex-I impairment. To assess overall mitochondrial capacity, cells can be forced to produce ATP primarily from mitochondrial OXPHOS by switching the media carbon source to galactose. Under these conditions POAG lymphoblasts grew 1.47 times slower than controls, whilst LHON lymphoblasts demonstrated a greater degree of growth impairment (2.35 times slower). Complex-I enzyme specific activity was reduced by 18% in POAG lymphoblasts and by 29% in LHON lymphoblasts. We also assessed complex-I ATP synthesis, which was 19% decreased in POAG patients and 17% decreased in LHON patients. This study demonstrates both POAG and LHON lymphoblasts have impaired complex-I, and in the majority of aspects the functional defects in POAG were milder than LHON, which could reflect the milder disease development of POAG. This new evidence places POAG in the spectrum of mitochondrial optic neuropathies and raises the possibility for new therapeutic targets aimed at improving mitochondrial function. PMID- 26496697 TI - Biochemical analysis of the multifunctional vaccinia mRNA capping enzyme encoded by a temperature sensitive virus mutant. AB - Prior biochemical analysis of the heterodimeric vaccinia virus mRNA capping enzyme suggests roles not only in mRNA capping but also in early viral gene transcription termination and intermediate viral gene transcription initiation. Prior phenotypic characterization of Dts36, a temperature sensitive virus mutant affecting the large subunit of the capping enzyme was consistent with the multifunctional roles of the capping enzyme in vivo. We report a biochemical analysis of the capping enzyme encoded by Dts36. Of the three enzymatic activities required for mRNA capping, the guanylyltransferase and methyltransferase activities are compromised while the triphosphatase activity and the D12 subunit interaction are unaffected. The mutant enzyme is also defective in stimulating early gene transcription termination and intermediate gene transcription initiation in vitro. These results confirm that the vaccinia virus mRNA capping enzyme functions not only in mRNA capping but also early gene transcription termination and intermediate gene transcription initiation in vivo. PMID- 26496699 TI - The Frequency of Cytidine Editing of Viral DNA Is Differentially Influenced by Vpx and Nucleosides during HIV-1 or SIVMAC Infection of Dendritic Cells. AB - Two cellular factors are currently known to modulate lentiviral infection specifically in myeloid cells: SAMHD1 and APOBEC3A (A3A). SAMHD1 is a deoxynucleoside triphosphohydrolase that interferes with viral infection mostly by limiting the intracellular concentrations of dNTPs, while A3A is a cytidine deaminase that has been described to edit incoming vDNA. The restrictive phenotype of myeloid cells can be alleviated through the direct degradation of SAMHD1 by the HIV-2/SIVSM Vpx protein or else, at least in the case of HIV-1, by the exogenous supplementation of nucleosides that artificially overcome the catabolic activity of SAMHD1 on dNTPs. Here, we have used Vpx and dNs to explore the relationship existing between vDNA cytidine deamination and SAMHD1 during HIV 1 or SIVMAC infection of primary dendritic cells. Our results reveal an interesting inverse correlation between conditions that promote efficient infection of DCs and the extent of vDNA editing that may reflect the different susceptibility of vDNA to cytoplasmic effectors during the infection of myeloid cells. PMID- 26496701 TI - Image segmentation and registration algorithm to collect thoracic skeleton semilandmarks for characterization of age and sex-based thoracic morphology variation. AB - Thoracic anthropometry variations with age and sex have been reported and likely relate to thoracic injury risk and outcome. The objective of this study was to collect a large volume of homologous semilandmark data from the thoracic skeleton for the purpose of quantifying thoracic morphology variations for males and females of ages 0-100 years. A semi-automated image segmentation and registration algorithm was applied to collect homologous thoracic skeleton semilandmarks from 343 normal computed tomography (CT) scans. Rigid, affine, and symmetric diffeomorphic transformations were used to register semilandmarks from an atlas to homologous locations in the subject-specific coordinate system. Homologous semilandmarks were successfully collected from 92% (7077) of the ribs and 100% (187) of the sternums included in the study. Between 2700 and 11,000 semilandmarks were collected from each rib and sternum and over 55 million total semilandmarks were collected from all subjects. The extensive landmark data collected more fully characterizes thoracic skeleton morphology across ages and sexes. Characterization of thoracic morphology with age and sex may help explain variations in thoracic injury risk and has important implications for vulnerable populations such as pediatrics and the elderly. PMID- 26496700 TI - Role of the YAP Oncoprotein in Priming Ras-Driven Rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS), a cancer characterized by features of skeletal muscle histogenesis, is the most common soft tissue sarcoma of childhood and adolescence. Survival for high-risk groups is less than 30% at 5 years. RMS also occurs during adulthood, with a lower incidence but higher mortality. Recently, mutational profiling has revealed a correlation between activating Ras mutations in the embryonal (eRMS) and pleomorphic (pRMS) histologic variants of RMS, and a poorer outcome for those patients. Independently, the YAP transcriptional coactivator, an oncoprotein kept in check by the Hippo tumor suppressor pathway, is upregulated in eRMS. Here we show that YAP promotes cell proliferation and antagonizes apoptosis and myogenic differentiation of human RMS cells bearing oncogenic Ras mutations in cell culture studies in vitro and in murine xenografts in vivo. Pharmacologic inhibition of YAP by the benzoporphyrin derivative verteporfin decreased cell proliferation and tumor growth in vivo. To interrogate the temporal contribution of YAP in eRMS tumorigenesis, we used a primary human cell-based genetic model of Ras-driven RMS. Constitutively active YAP functioned as an early genetic lesion, permitting bypass of senescence and priming myoblasts to tolerate subsequent expression of hTERT and oncogenic Ras, which were necessary and sufficient to generate murine xenograft tumors mimicking RMS in vivo. This work provides evidence for cooperation between YAP and oncogenic Ras in RMS tumorigenesis, laying the foundation for preclinical co-targeting of these pathways. PMID- 26496702 TI - Nonlinear analysis of EEGs of patients with major depression during different emotional states. AB - BACKGROUND: Although patients with major depressive disorder (MDD) have dysfunctions in cognitive behaviors and the regulation of emotions, the underlying brain dynamics of the pathophysiology are unclear. Therefore, nonlinear techniques can be used to understand the dynamic behavior of the EEG signals of MDD patients. METHODS: To investigate and clarify the dynamics of MDD patients' brains during different emotional states, EEG recordings were analyzed using nonlinear techniques. The purpose of the present study was to assess whether there are different EEG complexities that discriminate between MDD patients and healthy controls during emotional processing. Therefore, nonlinear parameters, such as Katz fractal dimension (KFD), Higuchi fractal dimension (HFD), Shannon entropy (ShEn), Lempel-Ziv complexity (LZC) and Kolmogorov complexity (KC), were computed from the EEG signals of two groups under different experimental states: noise (negative emotional content) and music (positive emotional content) periods. RESULTS: First, higher complexity values were generated by MDD patients relative to controls. Significant differences were obtained in the frontal and parietal scalp locations using KFD (p<0.001), HFD (p<0.05), and LZC (p=0.05). Second, lower complexities were observed only in the controls when they were subjected to music compared to the resting baseline state in the frontal (p<0.05) and parietal (p=0.005) regions. In contrast, the LZC and KFD values of patients increased in the music period compared to the resting state in the frontal region (p<0.05). Third, the patients' brains had higher complexities when they were exposed to noise stimulus than did the controls' brains. Moreover, MDD patients' negative emotional bias was demonstrated by their higher brain complexities during the noise period than the music stimulus. Additionally, we found that the KFD, HFD and LZC values were more sensitive in discriminating between patients and controls than the ShEn and KC measures, according to the results of ANOVA and ROC calculations. CONCLUSION: It can be concluded that the nonlinear analysis may be a useful and discriminative tool in investigating the neuro-dynamic properties of the brain in patients with MDD during emotional stimulation. PMID- 26496703 TI - Methicillin-Resistant Staphylococcus aureus-Related Henoch-Schonlein Purpura Treated Without Systemic Immunosuppressants. PMID- 26496704 TI - Characterization of Dnmt1 Binding and DNA Methylation on Nucleosomes and Nucleosomal Arrays. AB - The packaging of DNA into nucleosomes and the organisation into higher order structures of chromatin limits the access of sequence specific DNA binding factors to DNA. In cells, DNA methylation is preferentially occuring in the linker region of nucleosomes, suggesting a structural impact of chromatin on DNA methylation. These observations raise the question whether DNA methyltransferases are capable to recognize the nucleosomal substrates and to modify the packaged DNA. Here, we performed a detailed analysis of nucleosome binding and nucleosomal DNA methylation by the maintenance DNA methyltransferase Dnmt1. Our binding studies show that Dnmt1 has a DNA length sensing activity, binding cooperatively to DNA, and requiring a minimal DNA length of 20 bp. Dnmt1 needs linker DNA to bind to nucleosomes and most efficiently recognizes nucleosomes with symmetric DNA linkers. Footprinting experiments reveal that Dnmt1 binds to both DNA linkers exiting the nucleosome core. The binding pattern correlates with the efficient methylation of DNA linkers. However, the enzyme lacks the ability to methylate nucleosomal CpG sites on mononucleosomes and nucleosomal arrays, unless chromatin remodeling enzymes create a dynamic chromatin state. In addition, our results show that Dnmt1 functionally interacts with specific chromatin remodeling enzymes to enable complete methylation of hemi-methylated DNA in chromatin. PMID- 26496705 TI - Optimal Allocation of Node Capacity in Cascade-Robustness Networks. AB - The robustness of large scale critical infrastructures, which can be modeled as complex networks, is of great significance. One of the most important means to enhance robustness is to optimize the allocation of resources. Traditional allocation of resources is mainly based on the topology information, which is neither realistic nor systematic. In this paper, we try to build a framework for searching for the most favorable pattern of node capacity allocation to reduce the vulnerability to cascading failures at a low cost. A nonlinear and multi objective optimization model is proposed and tackled using a particle swarm optimization algorithm (PSO). It is found that the network becomes more robust and economical when less capacity is left on the heavily loaded nodes and the optimized network performs better resisting noise. Our work is helpful in designing a robust economical network. PMID- 26496706 TI - The RNAPII-CTD Maintains Genome Integrity through Inhibition of Retrotransposon Gene Expression and Transposition. AB - RNA polymerase II (RNAPII) contains a unique C-terminal domain that is composed of heptapeptide repeats and which plays important regulatory roles during gene expression. RNAPII is responsible for the transcription of most protein-coding genes, a subset of non-coding genes, and retrotransposons. Retrotransposon transcription is the first step in their multiplication cycle, given that the RNA intermediate is required for the synthesis of cDNA, the material that is ultimately incorporated into a new genomic location. Retrotransposition can have grave consequences to genome integrity, as integration events can change the gene expression landscape or lead to alteration or loss of genetic information. Given that RNAPII transcribes retrotransposons, we sought to investigate if the RNAPII CTD played a role in the regulation of retrotransposon gene expression. Importantly, we found that the RNAPII-CTD functioned to maintaining genome integrity through inhibition of retrotransposon gene expression, as reducing CTD length significantly increased expression and transposition rates of Ty1 elements. Mechanistically, the increased Ty1 mRNA levels in the rpb1-CTD11 mutant were partly due to Cdk8-dependent alterations to the RNAPII-CTD phosphorylation status. In addition, Cdk8 alone contributed to Ty1 gene expression regulation by altering the occupancy of the gene-specific transcription factor Ste12. Loss of STE12 and TEC1 suppressed growth phenotypes of the RNAPII-CTD truncation mutant. Collectively, our results implicate Ste12 and Tec1 as general and important contributors to the Cdk8, RNAPII-CTD regulatory circuitry as it relates to the maintenance of genome integrity. PMID- 26496707 TI - Single-Item Measurement of Suicidal Behaviors: Validity and Consequences of Misclassification. AB - Suicide is a leading cause of death worldwide. Although research has made strides in better defining suicidal behaviors, there has been less focus on accurate measurement. Currently, the widespread use of self-report, single-item questions to assess suicide ideation, plans and attempts may contribute to measurement problems and misclassification. We examined the validity of single-item measurement and the potential for statistical errors. Over 1,500 participants completed an online survey containing single-item questions regarding a history of suicidal behaviors, followed by questions with more precise language, multiple response options and narrative responses to examine the validity of single-item questions. We also conducted simulations to test whether common statistical tests are robust against the degree of misclassification produced by the use of single items. We found that 11.3% of participants that endorsed a single-item suicide attempt measure engaged in behavior that would not meet the standard definition of a suicide attempt. Similarly, 8.8% of those who endorsed a single-item measure of suicide ideation endorsed thoughts that would not meet standard definitions of suicide ideation. Statistical simulations revealed that this level of misclassification substantially decreases statistical power and increases the likelihood of false conclusions from statistical tests. Providing a wider range of response options for each item reduced the misclassification rate by approximately half. Overall, the use of single-item, self-report questions to assess the presence of suicidal behaviors leads to misclassification, increasing the likelihood of statistical decision errors. Improving the measurement of suicidal behaviors is critical to increase understanding and prevention of suicide. PMID- 26496708 TI - Improving the pH-stability of Versatile Peroxidase by Comparative Structural Analysis with a Naturally-Stable Manganese Peroxidase. AB - Versatile peroxidase (VP) from the white-rot fungus Pleurotus eryngii is a high redox potential peroxidase of biotechnological interest able to oxidize a wide range of recalcitrant substrates including lignin, phenolic and non-phenolic aromatic compounds and dyes. However, the relatively low stability towards pH of this and other fungal peroxidases is a drawback for their industrial application. A strategy based on the comparative analysis of the crystal structures of VP and the highly pH-stable manganese peroxidase (MnP4) from Pleurotus ostreatus was followed to improve the VP pH stability. Several interactions, including hydrogen bonds and salt bridges, and charged residues exposed to the solvent were identified as putatively contributing to the pH stability of MnP4. The eight amino acid residues responsible for these interactions and seven surface basic residues were introduced into VP by directed mutagenesis. Furthermore, two cysteines were also included to explore the effect of an extra disulfide bond stabilizing the distal Ca2+ region. Three of the four designed variants were crystallized and new interactions were confirmed, being correlated with the observed improvement in pH stability. The extra hydrogen bonds and salt bridges stabilized the heme pocket at acidic and neutral pH as revealed by UV-visible spectroscopy. They led to a VP variant that retained a significant percentage of the initial activity at both pH 3.5 (61% after 24 h) and pH 7 (55% after 120 h) compared with the native enzyme, which was almost completely inactivated. The introduction of extra solvent-exposed basic residues and an additional disulfide bond into the above variant further improved the stability at acidic pH (85% residual activity at pH 3.5 after 24 h when introduced separately, and 64% at pH 3 when introduced together). The analysis of the results provides a rational explanation to the pH stability improvement achieved. PMID- 26496710 TI - Effects of Forest Gaps on Soil Properties in Castanopsis kawakamii Nature Forest. AB - The aim of this study is to analyze the effects of forest gaps on the variations of soil properties in Castanopsis kawakamii natural forest. Soil physical and chemical properties in various sizes and development stages were studied in C. kawakamii natural forest gaps. The results showed that forest gaps in various sizes and development stages could improve soil pore space structure and water characteristics, which may effectively promote the water absorbing capacity for plant root growth and play an important role in forest regeneration. Soil pore space structure and water characteristics in small gaps showed more obvious improvements, followed by the medium and large gaps. Soil pore space structure and water characteristics in the later development stage of forest gaps demonstrated more obvious improvements, followed by the early and medium development stages. The contents of hydrolysable N and available K in various sizes and development stages of forest gaps were higher than those of non-gaps, whereas the contents of total N, total P, available P, organic matter, and organic carbon were lower. The contents of total N, hydrolysable N, available K, organic matter, and organic carbon in medium gaps were higher than those of large and small gaps. The disturbance of forest gaps could improve the soils' physical and chemical properties and increase the population species' richness, which would provide an ecological basis for the species coexistence in C. kawakamii natural forest. PMID- 26496709 TI - A Functional Magnetic Resonance Imaging Study to Investigate the Utility of a Picture Imagination Task in Investigating Neural Responses in Patients with Chronic Musculoskeletal Pain to Daily Physical Activity Photographs. AB - Pain-related anxiety and fear are associated with increased difficulties in attention, increased awareness of pain, impaired disengagement from pain, and can moderate the effects of attentional coping attempts. Accurately assessing the direct impact of pain-related anxiety and fear on pain behavior has proved difficult. Studies have demonstrated no or limited influence of pain-related fear and anxiety on behavior but this may be due to inherent problems with the scales used. Neuroimaging has improved the understanding of neural processes underlying the factors that influence pain perception. This study aimed to establish if a Picture and Imagination Task (PIT), largely developed from the Photographs of Daily Activity (PHODA) assessment tool, could help explore how people living with chronic pain process information about daily activities. Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to compare brain responses in patients with chronic musculoskeletal pain (CMSKP) (n = 15) and healthy controls (n = 15). Subjects were asked to imagine how they would feel mentally and physically if asked to perform daily activities illustrated in PIT. The results found that a number of regions involved in pain processing saw increased BOLD activation in patients compared with controls when undertaking the task and included the insula, anterior cingulate cortex, thalamus and inferior and superior parietal cortices. Similarly, increased BOLD responses in patients compared to controls in the frontal pole, paracingulate and the supplementary motor cortex may be suggestive of a memory component to the responses The amygdala, orbitofrontal cortex, substantia nigra/ventral tegmentum, putamen, thalamus, pallidum, inferior parietal (supramarginal and angular gyrus) and cingulate cortex were also seen to have greater differences in BOLD signal changes in patients compared with controls and many of these regions are also associated with general phobic responses. Therefore, we suggest that PIT is a useful task to explore pain- and movement-related anxiety and fear in fMRI studies. Regions in the Default Mode Network remained active or were less deactivated during the PIT task in patients with CMSKP compared to healthy controls supporting the contention that the DMN is abnormal in patients with CMSKP. PMID- 26496711 TI - M2 Polarization of Monocytes-Macrophages Is a Hallmark of Indian Post Kala-Azar Dermal Leishmaniasis. AB - The high level of functional diversity and plasticity in monocytes/macrophages has been defined within in vitro systems as M1 (classically activated), M2 (alternatively activated) and deactivated macrophages, of which the latter two subtypes are associated with suppression of cell mediated immunity, that confers susceptibility to intracellular infection. Although the Leishmania parasite modulates macrophage functions to ensure its survival, what remains an unanswered yet pertinent question is whether these macrophages are deactivated or alternatively activated. This study aimed to characterize the functional plasticity and polarization of monocytes/macrophages and delineate their importance in the immunopathogenesis of Post kala-azar dermal leishmaniasis (PKDL), a chronic dermatosis of human leishmaniasis. Monocytes from PKDL patients showed a decreased expression of TLR-2/4, along with an attenuated generation of reactive oxidative/nitrosative species. At disease presentation, an increased mRNA expression of classical M2 markers CD206, ARG1 and PPARG in monocytes and lesional macrophages indicated M2 polarization of macrophages which was corroborated by increased expression of CD206 and arginase-1. Furthermore, altered vitamin D signaling was a key feature in PKDL, as disease presentation was associated with raised plasma levels of monohydroxylated vitamin D3 and vitamin D3- associated genes, features of M2 polarization. Taken together, in PKDL, monocyte/macrophage subsets appear to be alternatively activated, a phenotype that might sustain disease chronicity. Importantly, repolarization of these monocytes to M1 by antileishmanial drugs suggests that switching from M2 to M1 phenotype might represent a therapeutic opportunity, worthy of future pharmacological consideration. PMID- 26496712 TI - Involvement of Peripheral Nerves in the Transgenic PLP-alpha-Syn Model of Multiple System Atrophy: Extending the Phenotype. AB - Multiple system atrophy (MSA) is a fatal, rapidly progressive neurodegenerative disease with (oligodendro-)glial cytoplasmic alpha-synuclein (alpha-syn) inclusions (GCIs). Peripheral neuropathies have been reported in up to 40% of MSA patients, the cause remaining unclear. In a transgenic MSA mouse model featuring GCI-like inclusion pathology based on PLP-promoter driven overexpression of human alpha-syn in oligodendroglia motor and non-motor deficits are associated with MSA like neurodegeneration. Since alpha-syn is also expressed in Schwann cells we aimed to investigate whether peripheral nerves are anatomically and functionally affected in the PLP-alpha-syn MSA mouse model. RESULTS: To this end, heat/cold as well as mechanical sensitivity tests were performed. Furthermore, in vivo and ex vivo nerve conduction and the G-ratios of the sciatic nerve were analyzed, and thermosensitive ion channel mRNA expression in dorsal root ganglia (DRG) was assessed. The presence of human alpha-syn in Schwann cells was associated with subtle behavioral impairments. The G-ratio of the sciatic nerve, the conduction velocity of myelinated and unmyelinated primary afferents and the expression of thermosensitive ion channels in the sensory neurons, however, were similar to wildtype mice. CONCLUSION: Our results suggest that the PNS appears to be affected by Schwann cell alpha-syn deposits in the PLP-alpha-syn MSA mouse model. However, there was no consistent evidence for functional PNS perturbations resulting from such alpha-syn aggregates suggesting a more central cause of the observed behavioral abnormalities. Nonetheless, our results do not exclude a causal role of alpha-syn in the pathogenesis of MSA associated peripheral neuropathy. PMID- 26496715 TI - Common Genotypes of Long QT Syndrome in China and the Role of ECG Prediction. AB - OBJECTIVES: Genetic testing, a gold standard for long QT syndrome (LQTS) diagnosis, is time-consuming and costly when all the 15 candidate genes are screened. Since genotype-specific ECG patterns are present in most LQT1-3 mutation carriers, we tested the utility of ECG-guided genotyping in a large cohort of Chinese LQTS patients. METHODS AND RESULTS: We enrolled 230 patients (26 +/- 17 years, 66% female) with a clinical diagnosis of LQTS. Genotypes were predicted as LQT1-3 based on the presence of ECG patterns typical for each genotype in 200 patients (85 LQT1, 110 LQT2 and 5 LQT3). Family-based genotype prediction was also conducted if gene-specific ECG patterns were found in other affected family members. Mutational screening identified 104 mutations (44% novel), i.e. 46 KCNQ1, 54 KCNH2 and 4 SCN5A mutations. The overall predictive accuracy of ECG-guided genotyping was 79% (157/200) and 79% (67/85), 78% (86/110) and 80% (4/5) for LQT1, LQT2 and LQT3, respectively. The predictive accuracy was 98% (42/43) when family-based ECG assessment was performed. CONCLUSIONS: From this large-scale genotyping study, we found that LQT2 is the most common genotype among the Chinese. Family-based ECG-guided genotyping is highly accurate. ECG guided genotyping is time- and cost-effective. We therefore recommend it as an optimal approach for the genetic diagnosis of LQTS. PMID- 26496713 TI - Influence of Bisphenol A on Thyroid Volume and Structure Independent of Iodine in School Children. AB - BACKGROUND: Although several studies have evaluated the relationship between bisphenol A (BPA) and thyroid functions, their results are not entirely consistent. Little is known about BPA in relation to thyroid volume and structure. METHODS: We examined the association of BPA with thyroid volume and thyroid nodules using data from 718 Chinese children living in the East Coast of China in 2012. First morning urine samples were collected for the determination of urinary BPA, creatinine, and urinary iodine concentrations (UIC). Thyroid volume (TV) and nodules were assessed by thyroid ultrasonography. RESULTS: The median of TV was 3.14ml. 459(63.9%) children took iodized salt at home and the median of UIC was 159MUg/l. BPA was detected in 99.9% of the urine samples and the medians for boys and girls were 2.64 and 2.35MUg/g creatinine, respectively. Of all participants 14.0% had thyroid nodules. Urinary BPA concentration was inversely associated with thyroid volume (beta = -0.033, 95% CI: -0.053, -0.013) and the risk for multiple nodules (OR = 0.78; 95% CI: 0.63, 0.97). The associations above were similar for children who consumed iodized salt and those consumed non-iodized salt. CONCLUSIONS: The data suggest that BPA may be one of the influencing factors for TV and thyroid nodules and its effects are independent of iodine nutrition status in children. PMID- 26496714 TI - One Step forward: Benthic Pelagic Coupling and Indicators for Environmental Status. AB - A large data set from the Eastern Mediterranean was analyzed to explore the relationship between seawater column variables and benthic community status. Our results showed a strong quantitative link between the seawater column variables (Chlorophyll a and Eutrophication Index) and various indicators describing benthic diversity and community composition. The percentage of benthic opportunistic species increased significantly in the stations with high trophic status of the seawater column and so did the strength of the coupling between values of seawater column and benthic indicators. The Eutrophication Index threshold level of 0.85, separating the "Bad and Poor" from "Moderate to High" conditions could serve as an acceptable critical value above which there is a readily observable change in benthic community composition. PMID- 26496716 TI - Prevalence of ragweed allergy in rural Geneva - a pilot study. AB - OBJECTIVE: The prevalence of ragweed allergy is increasing worldwide. Ragweed distribution and abundance is spreading in Europe in a wide area ranging from the Rhone valley in France to Hungary and Ukraine, where the rate of the prevalence can peak at as high as 12%. Low-grade ragweed colonisation was seen in Geneva and Ticino, less than two decades ago. There were fears that allergies to ragweed would increase Switzerland. The intent of this study was to assess the rate of prevalence of sensitisation and allergy to ragweed in the population living in the first rural Swiss setting where ragweed had been identified in 1996, and to evaluate indirectly the efficacy of elimination and containment strategies. MATERIAL AND METHODS: In 2009, 35 adults in a rural village in the Canton of Geneva were recruited. Data were collected by means of questionnaires and skin prick tests were done on each participant. The study was approved by the local Ethics Committee. RESULTS: Based on questionnaires, 48.6% had rhinitis (95% confidence interval [CI] 32.9-64.4; n = 17/35) and 17.1% asthma (95% CI 8.1-32.6; n = 6/35). Atopy was diagnosed in 26.4% (95% CI 12.9-44.4) of the sample (n = 9/34). Ragweed sensitisation was found in 2.9% (95% CI 0.7-19.7; n = 1/34), mugwort sensitisation in 2.9% (95% CI 0.1-14.9; n = 1/35), alder sensitisation in 17.1% (95% CI 6.6-33.6; n = 6/35), ash sensitisation in 12.5% (95% CI 3.5-29.0; n = 4/32) and grass sensitisation in 22.9% (95% CI 10.4-40.1; n = 8/35). Ragweed (95% CI 0.1-14.9; n = 1/34) and mugwort allergies (95% CI 0.1-14.9; n = 1/35) were both found in 2.9% of the population. CONCLUSION: This study showed a surprisingly low incidence of ragweed sensitisation and allergy, of 2.9% and 2.9%, respectively, 20 years after the first ragweed detection in Geneva. The feared rise in ragweed allergy seems not to have happened in Switzerland, compared with other ragweed colonised countries. These results strongly support early field strategies against ragweed. PMID- 26496717 TI - A novel histopathologic finding in the Descemet's membrane of a patient with Peters Anomaly: a case-report and literature review. AB - BACKGROUND: Peters anomaly is a rare developmental abnormality of the anterior segment of the eye and is one of the main causes of congenital corneal opacities. Typically, histopathology of Peters anomaly shows immature or absent Descemet's membrane and attenuated endothelial cells in the area of the corneal opacity, in addition to thinning or absence of Bowman's membrane and defects in the posterior stroma. In this report, we present a novel histopathological finding, which has not been previously reported, in the Descemet's membrane of a patient who is clinically diagnosed with Peters anomaly. CASE PRESENTATION: A 7-years old female child with developmentally delayed was born of a normal pregnancy, labor, and delivery. Apparent bilateral corneal opacifications were present at birth. On ophthalmologic examination, the child had a visual acuity of FC/20 cm in the right eye and that of FC/10 cm in the left one. Horizontal nystagmus and congenital cataract were found in both eyes. Slit-lamp examination revealed bilateral central corneal opacities which covered the iris and pupils. High frequency UBM and AS-OCT both showed a shallow anterior chamber with multiple areas of iridocorneal adhesions and no corneal lenticular touch in each eye. A corneal specialist performed a penetrating keratoplasty with extra-capsular cataract extraction and intraocular lens implantation. Histopathologic procedures were conducted on the host corneal button, including Hematoxylin-Eosin stain and Periodic Acid-Schiff stain. All the sections were examined by light microscopy. CONCLUSION: The "multiple-layer" structure of the Descemet's membrane described in our case has not been reported before as in association with abnormalities of the cornea tissues in Peters anomaly. Such pathological finding need to be reported to enhance further understanding of the special structure of Descemet's membrane as an abnormality during embryogenesis and neural crest cell differentiations. PMID- 26496718 TI - A disease resistance locus on potato and tomato chromosome 4 exhibits a conserved multipartite structure displaying different rates of evolution in different lineages. AB - BACKGROUND: In plant genomes, NB-LRR based resistance (R) genes tend to occur in clusters of variable size in a relatively small number of genomic regions. R-gene sequences mostly differentiate by accumulating point mutations and gene conversion events. Potato and tomato chromosome 4 harbours a syntenic R-gene locus (known as the R2 locus in potato) that has mainly been examined in central American/Mexican wild potato species on the basis of its contribution to resistance to late blight, caused by the oomycete pathogen Phytophthora infestans. Evidence to date indicates the occurrence of a fast evolutionary mode characterized by gene conversion events at the locus in these genotypes. RESULTS: A physical map of the R2 locus was developed for three Solanum tuberosum genotypes and used to identify the tomato syntenic sequence. Functional annotation of the locus revealed the presence of numerous resistance gene homologs (RGHs) belonging to the R2 gene family (R2GHs) organized into a total of 4 discrete physical clusters, three of which were conserved across S. tuberosum and tomato. Phylogenetic analysis showed clear orthology/paralogy relationships between S. tuberosum R2GHs but not in R2GHs cloned from Solanum wild species. This study confirmed that, in contrast to the wild species R2GHs, which have evolved through extensive sequence exchanges between paralogs, gene conversion was not a major force for differentiation in S. tuberosum R2GHs, and orthology/paralogy relationships have been maintained via a slow accumulation of point mutations in these genotypes. CONCLUSIONS: S. tuberosum and Solanum lycopersicum R2GHs evolved mostly through duplication and deletion events, followed by gradual accumulation of mutations. Conversely, widespread gene conversion is the major evolutionary force that has shaped the locus in Mexican wild potato species. We conclude that different selective forces shaped the evolution of the R2 locus in these lineages and that co-evolution with a pathogen steered selection on different evolutionary paths. PMID- 26496719 TI - Monitoring inflammation and airway remodeling by fluorescence molecular tomography in a chronic asthma model. AB - BACKGROUND: Asthma is a multifactorial disease for which a variety of mouse models have been developed. A major drawback of these models is represented by the transient nature of the airway pathology peaking 24-72 h after challenge and resolving in 1-2 weeks. We characterized the temporal evolution of pulmonary inflammation and tissue remodeling in a recently described mouse model of chronic asthma (8 week treatment with 3 allergens: Dust mite, Ragweed, and Aspergillus; DRA). METHODS: We studied the DRA model taking advantage of fluorescence molecular tomography (FMT) imaging using near-infrared probes to non-invasively evaluate lung inflammation and airway remodeling. At 4, 6, 8 or 11 weeks, cathepsin- and metalloproteinase-dependent fluorescence was evaluated in vivo. A subgroup of animals, after 4 weeks of DRA, was treated with Budesonide (100 ug/kg intranasally) daily for 4 weeks. RESULTS: Cathepsin-dependent fluorescence in DRA sensitized mice resulted significantly increased at 6 and 8 weeks, and was markedly inhibited by budesonide. This fluorescent signal well correlated with ex vivo analysis such as bronchoalveolar lavage eosinophils and pulmonary inflammatory cell infiltration. Metalloproteinase-dependent fluorescence was significantly increased at 8 and 11 weeks, nicely correlated with collagen deposition, as evaluated histologically by Masson's Trichrome staining, and airway epithelium hypertrophy, and was only partly inhibited by budesonide. CONCLUSIONS: FMT proved suitable for longitudinal studies to evaluate asthma progression, showing that cathepsin activity could be used to monitor inflammatory cell infiltration while metalloproteinase activity parallels airway remodeling, allowing the determination of steroid treatment efficacy in a chronic asthma model in mice. PMID- 26496720 TI - Early results of low-level laser application for masticatory muscle pain: a double-blind randomized clinical study. AB - BACKGROUND: To evaluate the effect of Low Level Laser (LLL) application at the points of greatest pain in patients with chronic masticatory muscle pain. METHODS: A total number of 30 (21 women, 9 men, with a mean age of 39.2) were selected after the diagnosis of MPDS according to the Research Diagnostic Criteria for Temporomandibular Disorder (RDC/TMD). The patients were randomly divided into three groups; laser group I (n = 10); patients received the LLL at the point of greatest pain, laser group II (n = 10); patients received LLL at pre established points in the effected muscles and placebo group (n = 10). LLL and placebo were applied three times per week, for a total of 12 sessions. Mandibular mobility was examined, masticator muscles tenderness were assessed and PPT values were obtained. Subjective pain levels were evaluated using VAS. The measurements performed before the treatment and after the completion of the therapy. Descriptive statistics (mean, standard deviation, and frequency) Student's t test, Mann-Whitney U-test and paired-sample t-tests were used for analysis. RESULTS: In both laser groups, there was a statically significant reduction in PPT values of the muscles, number of muscles without any pain on palpation increased significantly, mandibular movements' ranges were improved. Laser group I demonstrated statistically better results than the Laser group II in all of the measured values. Plasebo group did not show any statistically difference in any of the measured values. CONCLUSIONS: LLLT can be accepted as an alternative treatment modality in the management of masticatory muscle pain and direct irradiation seems to effect better. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31085 , Date of registration 28/08/20145. PMID- 26496721 TI - Prognosis of nonspecific interstitial pneumonia correlates with perivascular CD4+ T lymphocyte infiltration of the lung. AB - BACKGROUND: Nonspecific interstitial pneumonia (NSIP) is characterized by interstitial infiltration of T lymphocytes, and subpopulations of these cells may be associated with the progression of fibrosis. However, few studies evaluate the correlation of prognosis with this characteristic. Therefore, we performed morphological and quantitative analyses of T lymphocytes in patients with NSIP and evaluated the relationship between T lymphocytes and prognosis. METHODS: Immunohistochemistry was used to detect the presence of CD4+ and CD8+ T lymphocytes in 55 biopsies of patients with NSIP to determine the numbers of these T cell subpopulations in lymphoid follicles as well as in perivascular, interstitial, and peribronchial anatomical compartments. The relationship between CD4+ and CD8+ T lymphocyte populations and prognosis was analyzed. RESULTS: The mean age of 55 patients was 48.9 +/- 10.5 years, and 36 (65 %) of patients were women. All patients were followed for a mean duration of 46 +/- 25 months. Thirteen (23.6 %) patients died during follow-up. Perivascular CD4+ lymphocyte infiltration (HR, 0.939; 95 % CI, 0.883-0.999; p = 0.048) was an independent risk factor for survival. Perivascular infiltrates of CD4+ T lymphocytes correlated with survival time (r = 0.270, p = 0.046). Patients with improved forced vital capacity survived longer and had higher numbers of CD4+ T lymphocytes that infiltrated perivascular tissue. The densities of CD4+ and CD8+ T lymphocytes infiltrating other tissues were not significantly associated with survival time. CONCLUSIONS: Perivascular infiltration of CD4+ T lymphocytes in patients with NSIP correlated with prognosis. The underlying mechanisms are unknown and require further studies. PMID- 26496722 TI - An uncommon variant of cyanotic congenital heart disease in a young adult female: a rare case of right pulmonary artery to left atrial fistula (PALAF). AB - BACKGROUND: Cyanotic congenital heart disease is not a rare entity, but fistula between the right pulmonary artery and the left atrium is an uncommon vascular anomaly. Although it is a real challenge to diagnose the case, detailed clinical evaluation and selective investigations are keys for diagnosis, and surgical intervention is still considered the best treatment option. CASE PRESENTATION: A 19 years old girl from the remote village of Nepal presented with the history of exercise intolerance associated with cyanosis and clubbing of the extremities. We diagnosed her as a case of right pulmonary artery to left atrial fistula, a rare variant of pulmonary arteriovenous malformation. She underwent successful surgical correction of the anomaly under cardiopulmonary bypass surgery. CONCLUSION: Direct communication between the right pulmonary artery and the left atrium is a rare cyanotic congenital heart disease, which is diagnosed late and often associated with the atrial septal defect. The best treatment available is surgical correction. PMID- 26496723 TI - Safe Infant Sleep Interventions: What is the Evidence for Successful Behavior Change? AB - Sudden infant death syndrome (SIDS) and other sleep-related infant deaths, such as accidental suffocation and strangulation in bed and ill-defined deaths, account for >4000 deaths annually in the USA. Evidence-based recommendations for reducing the risk of sleep-related deaths have been published, but some caregivers resist adoption of these recommendations. Multiple interventions to change infant sleep-related practices of parents and professionals have been implemented. In this review, we will discuss illustrative examples of safe infant sleep interventions and evidence of their effectiveness. Facilitators of and barriers to change, as well as the limitations of the data currently available for these interventions, will be considered. PMID- 26496724 TI - A potent anti-inflammatory peptide from the salivary glands of horsefly. AB - BACKGROUND: A diverse group of physiologically active peptides/proteins are present in the salivary glands of horsefly Tabanus yao (Diptera, Tabanidae) that facilitate acquisition of blood meal. However, their roles in the regulation of local inflammation remains poorly understood. METHODS: Induction expression profiles of immune-related molecules in the salivary glands of T. yao was analyzed by quantitative PCR (qPCR) after bacterial feeding. A significantly up regulated molecule (cecropin-TY1) was selected for anti-inflammatory assay in lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages. The transcription levels of inducible NO synthase (iNOS) and pro-inflammatory cytokines were quantified by qPCR. Nitric oxide (NO) production was determined by Griess reagent. Pro-inflammatory cytokine production was determined by an enzyme linked immunosorbent assay (ELISA). The inflammatory signals were assayed by Western blotting analysis. The secondary structure of cecropin-TY1 was measured by Circular dichroism (CD) spectroscopy. Interaction of cecropin-TY1 with LPS was evaluated by the dissociation of fluorescein isothiocyanate (FITC)-conjugated LPS aggregates and neutralization of LPS determined by a quantitative Chromogenic End point Tachypleus amebocyte lysate (TAL) assay kit. Homology modeled structure analysis and mutation of key residues/structures were performed to understand its structure-activity relationship. RESULTS: Cecropin-TY1 was demonstrated to possess high anti-inflammatory activity and low cytotoxicity toward mouse macrophages. In LPS-stimulated mouse peritoneal macrophage, addition of cecropin TY1 significantly inhibited the production of nitric oxide (NO) and pro inflammatory cytokines. Further study revealed that cecropin-TY1 inhibited inflammatory cytokine production by blocking activation of mitogen-activated protein kinases (MAPKs) and transcriptional nuclear factor-kappaB (NF-kappaB) signals. Cecropin-TY1 even interacted with LPS and neutralized LPS. The secondary structure analysis revealed that cecropin-TY1 adopted unordered structures in hydrophobic environment but converted to alpha-helical confirmation in membrane mimetic environments. Homology modeled structure analysis demonstrated that cecropin-TY1 adopted two alpha-helices (Leu3-Thr24, Ile27-Leu38) linked by a hinge (Leu25-Pro26) and the structure surface was partly positively charged. Structure-activity relationship analysis indicated that several key residues/structures are crucial for its anti-inflammatory activity including alpha-helices, aromatic residue Trp2, positively charged residues Lys and Arg, hinge residue Pro26 and N-terminal amidation. CONCLUSIONS: We found a novel anti inflammatory function of horsefly-derived cecropin-TY1 peptide, laying groundwork for better understanding the ectoparasite-host interaction of horsefly with host and highlighting its potency in anti-inflammatory therapy for sepsis and endotoxin shock caused by Gram-negative bacterial infections. PMID- 26496727 TI - Brain metastasis: clinical characteristics, pathological findings and molecular subtyping for therapeutic implications. AB - Metastases are the most common brain tumors especially in adults. Although they are generally considered a single disease entity which is universally fatal in patients with advanced cancer, brain metastases are remarkably heterogeneous both clinically and pathologically. As members of the multidisciplinary clinical team for the diagnosis and management of metastatic brain tumors, pathologists must be familiar not only with clinicopathologic features of brain metastases but also with any characteristic and clinically significant molecular findings. We discuss here the epidemiology, general gross and microscopic features of brain metastases with emphasis on how to differentiate them from primary brain tumors using immunohistochemistry (e.g., for identification of the primary site and differential diagnosis), and unique pathologic patterns of brain metastases (namely, dural metastasis, leptomeningeal carcinomatosis, miliary metastasis, ''intravascular carcinomatosis'', and tumor-to-tumor metastasis) with their clinical and radiological characteristics. We specifically address metastatic breast and non-small cell lung cancers which are the two most commonly encountered in daily practice, with emphasis on the molecular alterations related to therapy and their clinicopathologic significance. PMID- 26496731 TI - Erratum to: The acrosome of eutherian mammals. PMID- 26496730 TI - Up in Smoke: Neighborhood Contexts of Marijuana Use from Adolescence Through Young Adulthood. AB - The current understanding of the neighborhood contexts wherein adolescent substance use emerges remains limited by conflicting findings regarding geographic variation in, and neighborhood effects on, both the prevalence of and risk factors for such use. Using four waves of longitudinal data from the National Longitudinal Study of Adolescent to Adult Health [n = 18,697 (51% female, 54% White, 24% Black, 16 % Hispanic, 7% Asian, 2% American Indian/Other)], latent class analysis, and growth curve modeling, this study identified distinct neighborhood types--patterned by race/ethnicity, socioeconomic class, and geography--and explored how trajectories of adolescent and young adult marijuana use differed across neighborhood types. The results demonstrated complexity in neighborhood contexts, illustrating variation in trajectories of marijuana use across neighborhood types heretofore unobserved in neighborhoods research, and largely unexplained by key individual, family, and peer risk and protective factors. This approach highlights how social structural forces intersect and anchor trajectories of youth substance-using risk behavior PMID- 26496732 TI - Novel antennal lobe substructures revealed in the small hive beetle Aethina tumida. AB - The small hive beetle, Aethina tumida, is an emerging pest of social bee colonies. A. tumida shows a specialized life style for which olfaction seems to play a crucial role. To better understand the olfactory system of the beetle, we used immunohistochemistry and 3-D reconstruction to analyze brain structures, especially the paired antennal lobes (AL), which represent the first integration centers for odor information in the insect brain. The basic neuroarchitecture of the A. tumida brain compares well to the typical beetle and insect brain. In comparison to other insects, the AL are relatively large in relationship to other brain areas, suggesting that olfaction is of major importance for the beetle. The AL of both sexes contain about 70 olfactory glomeruli with no obvious size differences of the glomeruli between sexes. Similar to all other insects including beetles, immunostaining with an antiserum against serotonin revealed a large cell that projects from one AL to the contralateral AL to densely innervate all glomeruli. Immunostaining with an antiserum against tachykinin-related peptides (TKRP) revealed hitherto unknown structures in the AL. Small TKRP immunoreactive spherical substructures are in both sexes evenly distributed within all glomeruli. The source for these immunoreactive islets is very likely a group of about 80 local AL interneurons. We offer two hypotheses on the function of such structures. PMID- 26496726 TI - Morphological changes of placental syncytium and their implications for the pathogenesis of preeclampsia. AB - Preeclampsia is a hypertensive disease that complicates many pregnancies, typically presenting with new-onset or worsening hypertension and proteinuria. It is well recognized that the placental syncytium plays a key role in the pathogenesis of preeclampsia. This review summarizes the findings pertaining to the structural alterations in the syncytium of preeclamptic placentas and analyzes their pathological implications for the development of preeclampsia. Changes in the trophoblastic lineage, including those in the proliferation of cytotrophoblasts, the formation of syncytiotrophoblast through cell fusion, cell apoptosis and syncytial deportation, are discussed in the context of preeclampsia. Extensive correlations are made between functional deficiencies and the alterations on the levels of gross anatomy, tissue histology, cellular events, ultrastructure, molecular pathways, and gene expression. Attention is given to the significance of dynamic changes in the syncytial turnover in preeclamptic placentas. Specifically, experimental evidences for the complex and obligatory role of syncytin-1 in cell fusion, cell-cycle regulation at the G1/S transition, and apoptosis through AIF-mediated pathway, are discussed in detail in the context of syncytium homeostasis. Finally, the recent observations on the aberrant fibrin deposition in the trophoblastic layer and the trophoblast immature phenotype in preeclamptic placentas and their potential pathogenic impact are also reviewed. PMID- 26496734 TI - Changes in Microbial Composition of Wastewater During Treatment in a Full-Scale Plant. AB - The monitoring of wastewater treatment plants is important for their proper functioning as well as for re-use of water and also to avoid possible circulation of human or animal pathogens in our environment. The samples in this study originated from a full-scale wastewater treatment plant where the structure of the bacterial community was monitored using 454-pyrosequencing. The composition differed in different parts of the plant. In the effluent, bacteria belonging to phyla Proteobacteria, Actinobacteria, TM7 and Bacteroidetes were most frequently detected. The presence of Mycobacterium sp., Mycobacterium avium, Norovirus, Hepatitis A and E viruses was examined using quantitative real-time PCR. Mycobacterium sp. was detected in the effluent in quantities of up to 10(4) cells/ml. Mycobacterium avium subsp. paratuberculosis and subsp. hominissuis were detected in amounts of up to 10(3) cells/ml, and Norovirus group 1 and 2 were also detected. Our findings show the importance of monitoring and controlling the occurrence of specific pathogens in effluent, mainly because of the negative impact on human health when the water is reused. PMID- 26496725 TI - Circadian mRNA expression: insights from modeling and transcriptomics. AB - Circadian clocks synchronize organisms to the 24 h rhythms of the environment. These clocks persist under constant conditions, have their origin at the cellular level, and produce an output of rhythmic mRNA expression affecting thousands of transcripts in many mammalian cell types. Here, we review the charting of circadian output rhythms in mRNA expression, focusing on mammals. We emphasize the challenges in statistics, interpretation, and quantitative descriptions that such investigations have faced and continue to face, and outline remaining outstanding questions. PMID- 26496735 TI - The impact of surgical quality on prognosis in patients undergoing rectal carcinoma surgery after preoperative chemoradiation. AB - PURPOSE: The aim of the study was to analyse the impact of surgical quality on the prognosis of rectal carcinoma patients who underwent preoperative long-term chemoradiation and TME surgery. METHODS: In a total of 314 patients, four quality indicators, including plane of surgery, pathological circumferential resection margin (pCRM), intraoperative local tumour cell dissemination and anastomotic leakage, were analysed with respect to locoregional recurrence, distant metastasis and overall survival. RESULTS: In 260 (82.8 %) of the patients, all four quality indicators were fulfilled. In 30 (9.6 %) of the patients, at least one quality indicator was not fulfilled; in 24 (7.6 %) of the patients, the data were not complete. Locoregional recurrence was significantly increased in patients who underwent surgery in the muscularis propria plane, who had a pCRM <= 1 mm or who experienced local tumour cell dissemination. In patients who had at least one quality indicator that was not fulfilled (suboptimal surgical quality), the 5-year rate of locoregional recurrence in those patients was 23.1 % compared to 4.8 % in patients who underwent optimal surgery (P = 0.001). In multivariate analysis, suboptimal surgery (hazard ratio (HR) 3.9; P = 0.020), abdominoperineal excision (HR 4.7; P = 0.003) and poor regression of primary tumours (HR 8.5; P < 0.001) were identified as independent prognostic factors for locoregional recurrence. In contrast to type of surgical treatment, ypT, ypN and regression grade, the quality of surgery did not significantly influence distant metastasis or overall survival. CONCLUSIONS: Even after preoperative chemoradiation, the surgical quality still has a strong impact on local control in patients with rectal carcinoma. PMID- 26496733 TI - Prohibitin( PHB) roles in granulosa cell physiology. AB - Ovarian granulosa cells (GC) play an important role in the growth and development of the follicle in the process known as folliculogenesis. In the present review, we focus on recent developments in prohibitin (PHB) research in relation to GC physiological functions. PHB is a member of a highly conserved eukaryotic protein family containing the repressor of estrogen activity (REA)/stomatin/PHB/flotillin/HflK/C (SPFH) domain (also known as the PHB domain) found in diverse species from prokaryotes to eukaryotes. PHB is ubiquitously expressed in a circulating free form or is present in multiple cellular compartments including mitochondria, nucleus and plasma membrane. In mitochondria, PHB is anchored to the mitochondrial inner membrane and forms complexes with the ATPases associated with proteases having diverse cellular activities. PHB continuously shuttles between the mitochondria, cytosol and nucleus. In the nucleus, PHB interacts with various transcription factors and modulates transcriptional activity directly or through interactions with chromatin remodeling proteins. Many functions have been attributed to the mitochondrial and nuclear PHB complexes such as cellular differentiation, anti proliferation, morphogenesis and maintenance of the functional integrity of the mitochondria. However, to date, the regulation of PHB expression patterns and GC physiological functions are not completely understood. PMID- 26496736 TI - Vilazodone: a review in major depressive disorder in adults. AB - Vilazodone (Viibryd((r))) exhibits the combined properties of a selective serotonin reuptake inhibitor (SSRI) and a serotonin 5-HT1A receptor partial agonist, and is approved in the US for the treatment of major depressive disorder (MDD) in adults. In four randomized, double-blind, clinical trials, oral vilazodone 20 or 40 mg once daily for 8 or 10 weeks reduced from baseline (improved) the Montgomery-Asberg Depression Rating Scale (MADRS) total score significantly more than placebo in adult patients with MDD. In these trials, significantly greater reductions in MADRS total score with vilazodone compared with placebo were seen from either week 1, week 2 (two trials) or week 6. In a noncomparative study, MADRS total scores continued to improve throughout therapy for up to 1 year. Vilazodone was generally well tolerated, with the most common treatment-emergent adverse events being mild or moderate diarrhoea, nausea and headache. Vilazodone had only limited adverse effects on sexual function or bodyweight. Therefore, vilazodone is an effective agent for treating MDD in adults. PMID- 26496737 TI - RIP1K and RIP3K provoked by shikonin induce cell cycle arrest in the triple negative breast cancer cell line, MDA-MB-468: necroptosis as a desperate programmed suicide pathway. AB - Resistance to cell death and reprogramming of metabolism are important in neoplastic cells. Increased resistance to apoptosis and recurrence of tumors are the major roadblocks to effective treatment of triple negative breast cancer. It has been thought that execution of necroptosis involves ROS generation and mitochondrial dysfunction in malignant cells. In this study, the effect of shikonin, an active substance from the dried root of Lithospermum erythrorhizon, on the induction of necroptosis or apoptosis, via RIP1K-RIP3K expressions has been examined in the triple negative breast cancer cell line. The expression levels of RIP1K and RIP3K, caspase-3 and caspase-8 activities, the levels of ROS, and mitochondrial membrane potential have been studied in the shikonin-treated MDA-MB-468 cell line. An increase in the ROS levels and a reduction in mitochondrial membrane potential have been observed in the shikonin-treated cells. Cell death has mainly occurred through necroptosis with a significant increase in the RIP1K and RIP3K expressions, and characteristic morphological changes have been observed. In the presence of Nec-1, caspase-3 mediating apoptosis has occurred in the shikonin-treated cells. The current findings have revealed that shikonin provoked mitochondrial ROS production in the triple negative breast cancer cell line, which works as a double-edged executioner's ax in the execution of necroptosis or apoptosis. The main route of cell death induced by shikonin is RIP1K-RIP3K-mediated necroptosis, but in the presence of Nec-1, apoptosis has prevailed. The present results shed a new light on the possible treatment of drug-resistant triple negative breast cancer. PMID- 26496738 TI - Depressive Symptoms and the Experience of Pleasure in Daily Life: An Exploration of Associations in Early and Late Adolescence. AB - Although loss of pleasure (i.e., anhedonia) is one of the two core symptoms of depression, very little research has examined the relation between depressive symptoms and the experience of pleasure in daily life. This exploratory study in two population-based adolescent samples aimed to examine how depressive symptoms and anhedonia specifically were related to (1) the proportion and intensity of positive events, (2) mean and variability of positive affect (PA), (3) reactivity to positive events, and (4) reactivity to PA (i.e., whether PA elicits positive events). We used Experience Sampling to measure positive events and PA several times a day during 6 to 14 days in early (N = 284) and late (N = 74) adolescents. Results showed that depressive symptoms were related to a lower proportion and intensity of positive events, lower mean PA, and higher variability in PA regardless of sex and stage of adolescence. No clear evidence was found for differential reactivity to positive events or to PA. Anhedonia was not associated with most daily life experiences of pleasure. Our findings, though preliminary, suggest that although adolescents with many depressive symptoms experience less positive events and lower PA, they are able to enjoy pleasurable events to the same extent as individuals with fewer depressive symptoms. PMID- 26496740 TI - Generalized linear stability of non-inertial rimming flow in a rotating horizontal cylinder. AB - The stability of a thin film of viscous liquid inside a horizontally rotating cylinder is studied using modal and non-modal analysis. The equation governing the film thickness is derived within lubrication approximation and up to first order in aspect ratio (average film thickness to radius of the cylinder). Effect of gravity, viscous stress and capillary pressure are considered in the model. Steady base profiles are computed in the parameter space of interest that are uniform in the axial direction. A linear stability analysis is performed on these base profiles to study their stability to axial perturbations. The destabilizing behavior of aspect ratio and surface tension is demonstrated which is attributed to capillary instability. The transient growth that gives maximum amplification of any initial disturbance and the pseudospectra of the stability operator are computed. These computations reveal weak effect of non-normality of the operator and the results of eigenvalue analysis are recovered after a brief transient period. Results from nonlinear simulations are also presented which also confirm the validity of the modal analysis for the flow considered in this study. PMID- 26496739 TI - Hyponatremia, a risk factor for osteoporosis and fractures in women. AB - SUMMARY: Hyponatremia has been linked to an increased risk of osteoporosis and fractures. We found an increased hazard ratio of major osteoporotic fractures adjusted for potential confounders, including osteoporosis and medication. A reduced BMD was not sufficiently explaining the association. Our data indicate that hyponatremia should be considered a risk factor for osteoporosis and fractures. INTRODUCTION: Hyponatremia is the most common electrolyte disorder in clinical practice and could be a risk factor for both osteoporosis and fractures. Mild hyponatremia has traditionally been regarded as a benign and asymptomatic condition; however, data from large population and animal studies have led to a reappraisal of this view. The purpose of this study was to evaluate the association of hyponatremia with osteoporosis and major osteoporotic fractures (MOF) in women. METHODS: This is a historical cohort study with fracture follow up. The study consisted of 5610 patients with available serum sodium and a bone density measurement. Information on potential risk factor was obtained through a questionnaire. Additional information on medication, comorbidities, and fractures was obtained through national registries. RESULTS: Hyponatremia was associated with significant lower T-scores at total hip and a borderline significant lower T score at femoral neck in the multivariate analysis. No association was found between hyponatremia and the lumbar spine T-score. Hyponatremia was associated with an increased hazard ratio of sustaining a MOF in the period from 6 months prior to 12 months after serum sodium measurement. Finally, data showed a relationship with increasing serum sodium and an increasing T-score estimate and a decreasing hazard ratio of MOF. CONCLUSIONS: Our data suggest that hyponatremia in women increases the risk of osteoporosis and MOF. The increased risk of MOF was independent of osteoporosis. PMID- 26496742 TI - Cut special offers on sugary foods, says delayed review. PMID- 26496741 TI - Continuing EGFR-TKI treatment in combination with super-selective arterial infusion chemotherapy beyond disease progression for patients with advanced EGFR mutant non-small cell lung cancer. AB - Regional therapy has shown promising results in patients with an oligo-metastasis after the occurrence of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). This study evaluated the efficacy and safety of continuing EGFR-TKI therapy concurrently with arterial infusion chemotherapy in 6 patients (median age 55.9 years) with advanced EGFR-mutant non-small cell lung cancer (NSCLC) who had a locally progressive, centrally located lung lesion after EGFR-TKI therapy. The patients received a super-selective arterial infusion of docetaxel (75 mg/m(2)) every 28 days concurrently with EGFR-TKI therapy until further progressive disease (PD) or unacceptable adverse effects (AEs) occurred. Treatment outcomes were assessed via progression-free survival (PFS) times (PFS 1: time to PD after EGFR-TKI therapy; PFS-2: time to further PD after arterial infusion chemotherapy with EGFR-TKI therapy), the occurrence of treatment-related AEs, and patient responses to the QLQ-LC13 quality-of-life questionnaire. Three of the 6 patients achieved partial responses, and three had stable disease. The median PFS-1 was 10.42 months, and the median PFS-2 was 4.1 months (range, 2.1 5.7 months). The median overall survival (OS) was 28.6 months (range, 24.1-32.9 months). All AEs were either grade 1 or grade 2 in severity, and no unexpected AEs were observed. One patient died of lung cancer. The patients reported significant reductions from baseline in symptoms of cough, chest pain, dyspnea, and hemoptysis (P < 0.05 for all comparisons). Thus, continuing EGFR-TKI therapy in combination with super-selective arterial infusion chemotherapy beyond PD for patients with advanced EGFR-mutant NSCLC is feasible, and this approach warrants further investigation. PMID- 26496743 TI - Transcriptional Profiling of Dibenzo[def,p]chrysene-induced Spleen Atrophy Provides Mechanistic Insights into its Immunotoxicity in MutaMouse. AB - Dibenzo[def,p]chrysene (DBC) is the most carcinogenic polycyclic aromatic hydrocarbon (PAH) examined to date. We investigated the immunotoxicity of DBC, manifested as spleen atrophy, following acute exposure of adult MutaMouse males by oral gavage. Mice were exposed to 0, 2.0, 6.2, or 20.0 mg DBC /kg-bw per day, for 3 days. Genotoxic endpoints (DBC-DNA adducts and lacZ mutant frequency in spleen and bone marrow, and red blood cell micronucleus frequency) and global gene expression changes were measured. All of the genotoxicity measures increased in a dose-dependent manner in spleen and bone marrow. Gene expression analysis showed that DBC activates p53 signaling pathways related to cellular growth and proliferation, which was evident even at the low dose. Strikingly, the expression profiles of DBC exposed mouse spleens were highly inversely correlated with the expression profiles of the only published toxicogenomics dataset of enlarged mouse spleen. This analysis suggested a central role for Bnip3l, a pro-apoptotic protein involved in negative regulation of erythroid maturation. RT-PCR confirmed expression changes in several genes related to apoptosis, iron metabolism, and aryl hydrocarbon receptor signaling that are regulated in the opposite direction during spleen atrophy versus benzo[a]pyrene-mediated splenomegaly. In addition, benchmark dose modeling of toxicogenomics data yielded toxicity estimates that are very close to traditional toxicity endpoints. This work illustrates the power of toxicogenomics to reveal rich mechanistic information for immunotoxic compounds and its ability to provide information that is quantitatively similar to that derived from standard toxicity methods in health risk assessment. PMID- 26496744 TI - The Role of MAPK Pathways in Airborne Fine Particulate Matter-Induced Upregulation of Endothelin Receptors in Rat Basilar Arteries. AB - Airborne fine particulate matter (PM(2.5)) increases the risk of cerebrovascular diseases. However, existing experimental data do not sufficiently explain how PM(2.5) affects cerebral vessels. This study sought to examine whether PM(2.5) alters endothelin (ET) receptor expression on rat cerebral arteries and the potential underlying mechanisms. Isolated rat basilar arteries were cultured with PM(2.5) aqueous suspension in the presence of mitogen-activated protein kinase (MAPK) pathway inhibitors. ET receptor-mediated vasomotor functions were recorded by a sensitive myograph. ET(A) and ET(B) receptor mRNA and protein expressions were assessed using quantitative real-time PCR, Western blotting, and immunohistochemistry, respectively. Compared with fresh and culture alone arteries, PM(2.5) significantly enhanced ET(A) and ET(B) receptor-mediated contractions and increased receptor mRNA and protein expressions in basilar arteries, indicating PM(2.5) upregulates ET(A) and ET(B) receptors. Culturing with SB386023 (MEK/ERK1/2 inhibitor), U0126 (ERK1/2 inhibitor), SP600125 [c-Jun N terminal kinase (JNK) inhibitor], or SB203580 (p38 inhibitor) attenuated PM(2.5) induced ETB receptor upregulation. PM(2.5)-induced enhancement of ET(A) receptor mediated contraction and receptor expression was notably inhibited by SB386023 or U0126. However, neither SP600125 nor SB203580 had an effect on PM(2.5)-induced ET(A) receptor upregulation. In conclusion, PM(2.5) upregulates ET(A) and ET(B) receptors in rat basilar arteries. ET(B) receptor upregulation is involved in MEK/ERK1/2, JNK, and p38 MAPK pathways, and ET(A) receptors upregulation is associated with MEK/ERK1/2 pathway. PMID- 26496745 TI - Association between praziquantel treatment and cholangiocarcinoma: a hospital based matched case-control study. AB - BACKGROUND: Infection by the liver fluke, Opisthorchis viverrini, remains an important public health problem in Thailand and has resulted in the highest prevalence of infection and incidence of subsequent cholangiocarcinoma (CCA) in the world. Praziquantel (PZQ) is the antihelminthic drug of choice for treatment. Previous studies in hamsters showed that repeated infection and PZQ treatment could increase the risk of CCA. However, the few available epidemiology studies in humans have shown unclear evidence of an increased risk of CCA with frequency of PZQ intake. The present study investigated the relationship between the number of repeated PZQ treatments and CCA. METHODS: A hospital-based matched case control study was conducted. All cases and controls were inpatients of a tertiary hospital in Northeast Thailand. During 2012-2014 a total of 210 incident cases of pathologically diagnosed CCA and 840 control subjects were selected from a hospital inpatient database (four controls per case). The four recruited controls were individually matched with CCA cases by gender, age and date of admission. Data were collected in face-to-face interviews using a standardised pre-tested questionnaire. Multivariable conditional logistic regression was used in the analysis of the data. RESULTS: The frequencies of PZQ usage among the 210 cases and 840 controls were 48.6 vs. 66.0 for never, 32.9 vs. 24.4 for once, 8.6 vs. 4.9 for twice, and 10.0% vs. 4.8% for more than twice, respectively. There was a statistically significant dose-response relationship (p < 0.001). Compared with subjects who never used PZQ, those who used the medication once, twice, and more than twice were 1.49, 1.82, and 2.30 times more likely to develop CCA (95% confidence intervals: 1.02 - 2.20, 0.92 - 3.60, and 1.20 - 4.40). These odds ratios (adjusted ORs) had already been adjusted for the effects of eating raw fish, a family history of cancer, and highest educational attainment. Additional PZQ usage increased the odds of developing CCA by 23.0% (adjusted OR = 1.23; 95% CI: 1.07 - 1.43). CONCLUSIONS: The findings show that repeated PZQ treatments are associated with an increased risk of CCA. Paradoxically, this contradicts the common belief that repeated PZQ treatments decrease the risk of CCA. The study also showed a strong association between the number of repeated PZQ treatments and the consumption of raw freshwater fish. This suggests that repeated PZQ treatments may be a surrogate marker of habit of eating raw fish. PMID- 26496746 TI - Impact of library preparation protocols and template quantity on the metagenomic reconstruction of a mock microbial community. AB - BACKGROUND: The rapid development of sequencing technologies has provided access to environments that were either once thought inhospitable to life altogether or that contain too few cells to be analyzed using genomics approaches. While 16S rRNA gene microbial community sequencing has revolutionized our understanding of community composition and diversity over time and space, it only provides a crude estimate of microbial functional and metabolic potential. Alternatively, shotgun metagenomics allows comprehensive sampling of all genetic material in an environment, without any underlying primer biases. Until recently, one of the major bottlenecks of shotgun metagenomics has been the requirement for large initial DNA template quantities during library preparation. RESULTS: Here, we investigate the effects of varying template concentrations across three low biomass library preparation protocols on their ability to accurately reconstruct a mock microbial community of known composition. We analyze the effects of input DNA quantity and library preparation method on library insert size, GC content, community composition, assembly quality and metagenomic binning. We found that library preparation method and the amount of starting material had significant impacts on the mock community metagenomes. In particular, GC content shifted towards more GC rich sequences at the lower input quantities regardless of library prep method, the number of low quality reads that could not be mapped to the reference genomes increased with decreasing input quantities, and the different library preparation methods had an impact on overall metagenomic community composition. CONCLUSIONS: This benchmark study provides recommendations for library creation of representative and minimally biased metagenome shotgun sequencing, enabling insights into functional attributes of low biomass ecosystem microbial communities. PMID- 26496748 TI - Research progress of genome editing and derivative technologies in plants. AB - Genome editing technologies using engineered nucleases have been widely used in many model organisms. Genome editing with sequence-specific nuclease (SSN) creates DNA double-strand breaks (DSBs) in the genomic target sites that are primarily repaired by the non-homologous end joining (NHEJ) or homologous recombination (HR) pathways, which can be employed to achieve targeted genome modifications such as gene mutations, insertions, replacements or chromosome rearrangements. There are three major SSNs?zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9) system. In contrast to ZFN and TALEN, which require substantial protein engineering to each DNA target, the CRISPR/Cas9 system requires only a change in the guide RNA. For this reason, the CRISPR/Cas9 system is a simple, inexpensive and versatile tool for genome engineering. Furthermore, a modified version of the CRISPR/Cas9 system has been developed to recruit heterologous domains that can regulate endogenous gene expression, such as activation, depression and epigenetic regulation. In this review, we summarize the development and applications of genome editing technologies for basic research and biotechnology, as well as highlight challenges and future directions, with particular emphasis on plants. PMID- 26496749 TI - The molecular mechanism of CRISPR/Cas9 system and its application in gene therapy of human diseases. AB - CRISPR/Cas system is an adaptive immune system that confers resistance to exogenous virus or plasmid in bacteria and archaea. In recent years, the booming CRISPR/Cas9 genome editing technology modified from type2 CRISPR/Cas adaptive immune system has been widely applied to various research fields of life science and led to revolutionary changes. In this review, we summarize the origin and development of CRISPR/Cas9 genome editing technology as well as its applications in life science research. We focus on the latest application of this system in gene therapy of human diseases and the associated side/off-target effects, which may provide references for researchers in related areas. PMID- 26496750 TI - Use of genome editing tools in human stem cell-based disease modeling and precision medicine. AB - Precision medicine emerges as a new approach that takes into account individual variability. The successful conduct of precision medicine requires the use of precise disease models. Human pluripotent stem cells (hPSCs), as well as adult stem cells, can be differentiated into a variety of human somatic cell types that can be used for research and drug screening. The development of genome editing technology over the past few years, especially the CRISPR/Cas system, has made it feasible to precisely and efficiently edit the genetic background. Therefore, disease modeling by using a combination of human stem cells and genome editing technology has offered a new platform to generate " personalized " disease models, which allow the study of the contribution of individual genetic variabilities to disease progression and the development of precise treatments. In this review, recent advances in the use of genome editing in human stem cells and the generation of stem cell models for rare diseases and cancers are discussed. PMID- 26496751 TI - DNA fragment editing of genomes by CRISPR/Cas9. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated nuclease 9 (Cas9) system from bacteria and archaea emerged recently as a new powerful technology of genome editing in virtually any organism. Due to its simplicity and cost effectiveness, a revolutionary change of genetics has occurred. Here, we summarize the recent development of DNA fragment editing methods by CRISPR/Cas9 and describe targeted DNA fragment deletions, inversions, duplications, insertions, and translocations. The efficient method of DNA fragment editing provides a powerful tool for studying gene function, regulatory elements, tissue development, and disease progression. Finally, we discuss the prospects of CRISPR/Cas9 system and the potential applications of other types of CRISPR system. PMID- 26496752 TI - Progress of application and off-target effects of CRISPR/Cas9. AB - The clustered regulatory interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) system mediates genome editing and is revolutionizing genetic researches. Scientists are able to manipulate the gene of interest from any organism with CRISPR/Cas9. Compared with zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) technologies, the CRISPR/Cas9 technology provides an easy and efficient approach to manipulate the genome. In this system, sgRNA (Single guide RNA), a short RNA matching the targeted DNA fragment, guides the CRISPR/Cas9 to interrogate the genome. Because sgRNA can tolerate certain mismatches to the DNA targets and thereby promote undesired off target mutagenesis, the key limit of this technology is off-target effects. To eliminate the off-target effects, different strategies have been adopted. In this review, we summarize the application of CRISPR/Cas9 and different strategies for addressing off-target effects. PMID- 26496753 TI - CRISPR/Cas9 genome editing technique and its application in site-directed genome modification of animals. AB - CRISPR/Cas system, which uses CRISPR RNAs (crRNAs) to guide Cas nuclease to silence invading nucleic acids, is self-defense system against exogenous virus or plasmid in bacteria and archaea. Through molecular modification, the typeIICRISPR/Cas system has become a highly efficient site-directed genome editing technique, which is simpler than zinc-finger nucleases (ZFNs) and transcription activator like effector nucleases (TALENs) and easier to be designed and applied. In this review, we summarize the evolutionary history of CRISPR/Cas9 system, the working principle and modification process of type II CRISPR/Cas and its application in animal genome modification. We also analyze the existing problems and improvement program of the CRISPR/Cas9 system as well as its application prospect combined with successful cases, which may provide innovative perspectives on improving animal traits and establishing animal models of human diseases. PMID- 26496754 TI - From gene editing to genome reconstitution: evolving techniques in yeast. AB - Homologous recombination is one of the main repair pathways in response to DNA double strand break (DSB) in eukaryotes. Based on this, a series of techniques to introduce DSB have been developed in order to edit the DNA sequence of genome. In eukaryotes, the gene editing technique was first established in S. cerevisiae by transformation of a foreign DNA fragment containing the sequence homologous to the targeted site more than thirty years ago. The core of all currently available editing methods lies in the introduction of DSB. Here, we try to convey a historic view of various editing techniques from its original version to the up to-dated genome synthesis and reconstitution. We believe that this review will help to illustrate the trend of the development of genome editing techniques, which will provide a valuable reference for developing similar techniques in mammals. PMID- 26496755 TI - Generation of site-specific mutant mice using the CRISPR/Cas9 system. AB - The CRISPR/Cas9 system is a recently developed important technology for genome editing in cellular and animal models. Here we established a CRISPR/Cas9-based system of generating site-specific mutant mice using DNA double-strand breaks (DSBs) induced homologous recombination (HR)-dependent or independent repair mechanism. Through co-microinjection of Cas9 mRNA and single-guide RNA (sgRNA) targeting genomic DNA sequence corresponding to enzyme activity of lysine (K) specific demethylase 2b (Kdm2b), both a frame-shifted Kdm2b null mutant and a Kdm2b enzyme activity disrupted mouse strain were obtained simultaneously. Moreover, sgRNA targeting flavin containing monooxygenases3 (Fmo3) gene and the corresponding single strand oligonucleotides (ssODN) donor template with point mutation were co-injected into the male pronucleus of one-cell mouse embryos stimulated HR-mediated repair mechanism. Genomic sequence analysis of F0 mice showed that frame-shifted Fmo3 knockout mouse and site-specific Fmo3 knock-in mouse with single base substitution were successfully generated, and these mutations could be stably transmitted to the next generation. Therefore, we successfully generated mouse strains containing site-specific mutations through HR-dependent and -independent DSB repair using the CRISPR/Cas9 system. PMID- 26496756 TI - Generating amphioxus Hedgehog knockout mutants and phenotype analysis. AB - The amphioxus is a promising animal model for evolutionary-developmental studies due to its key position on the animal phylogenetic tree. In the present study, we reported a genetically modified amphioxus strain on the Hedgehog (Hh) gene locus using the TALEN method. The result showed that our TALEN pair injection could bring about 34% mutations in the amphioxus Hh coding region. Further analysis on the F(0) gametic DNA revealed that the mutations had entered into gametes. So, we paired one F(0) male carrying an 8 bp deletion with a wild-type (WT) female, and carefully nursed the F(1) embryos up to adulthood. We then screened F(1) individually via analyzing their genomic DNA from a tiny tail tip, and obtained eight heterozygous mutants from the F(1) offspring. Moreover, our observation on the F(2) embryos generated by mating F(1) mutants also revealed that about 25% of early larvae developed aberrantly with head and tail curving ventrally, agenesis of the mesoblastic tissue under their anterior notochord, and no mouth opening. With the larva growth, deformities (such as twist of head and tail, mouth absent, ventrally localized endostyle and gill slits) became more severe, and eventually those malformed larvae died due to no food intake. Genetic analysis showed that all these deformed embryos were homozygous mutants and the ratio of Hh hetorozygotes vs WT agreed with Mondel's law. WT amphioxus larvae are asymmetric with the mouth on the left and gill slits on the right side. However, the homozygous mutant larvae became left-right symmetric with the gill slits on the ventral side, indicating a conserved role of Hedgehog signaling in establishing the left-right embryonic axis. PMID- 26496757 TI - Highly efficient CRISPR/Cas9-mediated targeted mutagenesis of multiple genes in Populus. AB - The typeIICRISPR/Cas9 system (Clustered regularly interspaced short palindromic repeats /CRISPR-associated 9) has been widely used in bacteria, yeast, animals and plants as a targeted genome editing technique. In previous work, we have successfully knocked out the endogenous phytoene dehydrogenase (PDS) gene in Populus tomentosa Carr. using this system. To study the effect of target design on the efficiency of CRISPR/Cas9-mediated gene knockout in Populus, we analyzed the efficiency of mutagenesis using different single-guide RNA (sgRNA) that target PDS DNA sequence. We found that mismatches between the sgRNA and the target DNA resulted in decreased efficiency of mutagenesis and even failed mutagenesis. Moreover, complementarity between the 3' end nucleotide of sgRNA and target DNA is especially crucial for efficient mutagenesis. Further sequencing analysis showed that two PDS homologs in Populus, PtPDS1 and PtPDS2, could be knocked out simultaneously using this system with 86.4% and 50% efficiency, respectively. These results indicated the possibility of introducing mutations in two or more endogenous genes efficiently and obtaining multi-mutant strains of Populus using this system. We have indeed generated several knockout mutants of transcription factors and structural genes in Populus, which establishes a foundation for future studies of gene function and genetic improvement of Populus. PMID- 26496758 TI - Development and application of dual-fluorescence reporter systems for measuring specific nuclease activity based on SSA repair mechanism. AB - Reporter vector system has become an important method for measuring activity of specific nucleases because of its fast construction, simple modification, easy operation, economic effectiveness as well as its role in enriching positive cells with genomic modification through mediating screen of specific nucleases positive cells. After introducing double strand breaks (DSBs), a reporter system based on non-homologous end joining (NHEJ)-mediated repair can only repair maximally two thirds of reporter genes after optimization, while single strand annealing (SSA) mediated repair can repair all reporter genes theoretically which has higher sensitivity and facilitates the detection of specific nuclease with low activity and provides an effective way to detect specific nuclease activity in genome modification studies. In this study, we designed and constructed three sets of dual-fluorescence reporter systems based on SSA repair mechanism and applied the mRFP-eGFP system in measuring the effective activity of three pairs of ZFNs, which was 8.9%, 9.3% and 5.0%, respectively. Our study provides an effective way to detect the activity of nucleases. PMID- 26496759 TI - Development of a graphical user interface for sgRNAcas9 and its application. AB - The CRISPR/Cas9 genome editing technique is a powerful tool for researchers. However, off-target effects of the Cas9 nuclease activity is a recurrent concern of the CRISPR system. Thus, designing sgRNA (single guide RNA) with minimal off target effects is very important. sgRNAcas9 is a software package, which can be used to design sgRNA and to evaluate potential off-target cleavage sites. In this study, a graphical user interface for sgRNAcas9 was developed using the Java programming language. In addition, off-target effect for sgRNAs was evaluated according to mismatched number and "seed sequence" specification. Moreover, sgRNAcas9 software was used to design 34 124 sgRNAs, which can target 4691 microRNA (miRNA) precursors from human, mouse, rat, pig, and chicken. In particular, the off-target effect of a sgRNA targeting to human miR-206 precursor was analyzed, and the on/off-target activity of this sgRNA was validated by T7E1 assay in vitro. Taken together, these data showed that the interface can simplify the usage of the sgRNAcas9 program, which can be used to design sgRNAs for the majority of miRNA precursors. We also found that the GC% of those sgRNAs ranged from 40% to 60%. In summary, the sgRNAcas9 software can be easily used to design sgRNA with minimal off-target effects for any species. The software can be downloaded from BiooTools website (http://www.biootools.com/). PMID- 26496761 TI - Assessing the impact of pneumococcal conjugate vaccines on invasive pneumococcal disease using polymerase chain reaction-based surveillance: an experience from South Africa. AB - BACKGROUND: The use of molecular diagnostic techniques for the evaluation of the impact of pneumococcal conjugate vaccines (PCVs) has not been documented. We aimed to evaluate the impact of PCVs on invasive pneumococcal disease (IPD) using polymerase chain reaction (PCR)-based techniques and compare with results obtained from culture-based methods. METHODS: We implemented two independent surveillance programs for IPD among individuals hospitalized at one large surveillance site in Soweto, South Africa during 2009-2012: (i) PCR-based (targeting the lytA gene) syndromic pneumonia surveillance; and (ii) culture based laboratory surveillance. Positive samples were serotyped. The molecular serotyping assay included targets for 42 serotypes including all serotypes/serogroups included in the 7-valent (PCV-7) and 13-valent (PCV-13) PCV. The Quellung reaction was used for serotyping of culture-positive cases. We calculated the change in rates of IPD (lytA- or culture-positive) among HIV uninfected children aged <2 years from the year of PCV-7 introduction (2009) to the post-vaccine years (2011 or 2012). RESULTS: During the study period there were 607 lytA-positive and 1,197 culture-positive cases that were serotyped. Samples with lytA cycle threshold (Ct)-values >=35 (30.2 %; 123/407) were significantly less likely to have a serotype/serogroup detected for serotypes included in the molecular serotyping assay than those with Ct-values <35 (78.0 %; 156/200) (p < 0.001). From 2009 to 2012 rates of PCV-7 serotypes/serogroups decreased -63.8 % (95 % CI: -79.3 % to -39.1 %) among lytA-positive cases and 91.7 % (95 % CI: -98.8 % to -73.6 %) among culture-positive cases. Rates of lytA positive non-vaccine serotypes/serogroups also significantly decreased (-71.7 %; 95 % CI: -81.1 % to -58.5 %) over the same period. Such decline was not observed among the culture-positive non-vaccine serotypes (1.2 %; 95 % CI: -96.7 % to 58.4 %). CONCLUSIONS: Significant downward trends in IPD PCV-7 serotype-associated rates were observed among patients tested by PCR or culture methods; however trends of non-vaccine serotypes/serogroups differed between the two groups. Misclassifications of serotypes/serogroups, affecting the use of non-vaccine serotypes as a control group, may have occurred due to the low performance of the serotyping assay among lytA-positive cases with high Ct-values. Until PCR methods improve further, culture methods should continue to be used to monitor the effects of PCV vaccination programs on IPD incidence. PMID- 26496762 TI - A cross-sectional survey of emergency and essential surgical care capacity among hospitals with high trauma burden in a Central African country. AB - BACKGROUND: As the overwhelming surgical burden of injury and disease steadily increases, disproportionately affecting low- and middle-income countries, adequate surgical and trauma care systems are essential. Yet, little is known about the emergency and essential surgical care (EESC) capacity of facilities in many African countries. The objective of this study was to assess the EESC capacity in different types of hospitals across Cameroon. METHODS: This cross sectional survey used the WHO Tool for Situational Analysis to Assess EESC, investigating four key areas: infrastructure, human resources, interventions, and equipment and supplies. Twelve hospitals were surveyed between August and September 2009. Facilities were conveniently sampled based on proximity to road traffic and sociodemographic composition of population served in four regions of Cameroon. To complete the survey, investigators interviewed heads of facilities, medical advisors, and nursing officers and consulted hospital records and statistics at each facility. RESULTS: Seven district hospitals, two regional hospitals, two general hospitals, and one missionary hospital completed the survey. Infrastructure for EESC was generally inadequate with the largest gaps in availability of oxygen concentrator supply, an on-site blood bank, and pain relief management guidelines. Human resources were scarce with a combined total of six qualified surgeons, seven qualified obstetrician/gynecologists, and no anesthesiologists at district, regional, and missionary hospitals. Of 35 surgical interventions, 16 were provided by all hospitals. District hospitals reported referring patients for 22 interventions. Only nine of the 67 pieces of equipment were available at all hospitals for all patients all of the time. CONCLUSIONS: Severe shortages highlighted by this survey demonstrate the significant gaps in capacity of hospitals to deliver EESC and effectively address the increasing surgical burden of disease and injury in Cameroon. This data provides a foundation for evidence-based decision-making surrounding appropriate allocation and provision of resources for adequate EESC in the country. PMID- 26496763 TI - Laboratory Animal Allergy in the Modern Era. AB - Laboratory animal workers face a high risk of developing laboratory animal allergy as a consequence of inhaling animal proteins at work; this has serious consequences for their health and future employment. Exposure to animal allergen remains to be the greatest risk factor although the relationship is complex, with attenuation at high allergen exposure. Recent evidence suggests that this may be due to a form of natural immunotolerance. Furthermore, the pattern of exposure to allergen may also be important in determining whether an allergic or a tolerant immune response is initiated. Risk associated with specific tasks in the laboratory need to be determined to provide evidence to devise a code of best practice for working within modern laboratory animal facilities. Recent evidence suggests that members of lipocalin allergens, such as Mus m 1, may act as immunomodulatory proteins, triggering innate immune receptors through toll-like receptors and promoting airway laboratory animal allergy. This highlights the need to understand the relationship between endotoxin, animal allergen and development of laboratory animal allergy to provide a safe working environment for all laboratory animal workers. PMID- 26496764 TI - Nasal Mucociliary Clearance in Adenoid Hypertrophy and Otitis Media with Effusion. AB - Mucociliary clearance (MCC), which exists in many systems, is the first defensive mechanism of the human body. Nasal MCC has an important role in transporting the secretions of the nasal cavity and paranasal sinuses along with the trapped inhaled pathogens to the nasopharynx. Physiologic or pathologic situations that effect nasal MCC, such as temperature, humidity, nasal obstruction, allergic rhinitis, chronic infections, etc., lead to impaired MCC and related local or circumjacent system disorders. With this perspective, when a unified airway with a multiple disease principle is considered, investigating the relationship between adenoid hypertrophy (AH), otitis media with effusion (OME) and nasal MCC is logical. In this review, histological and physiologic properties of nasal MCC and its possible role involving pathologic situations such as AH and OME is discussed together with recent literature findings. PMID- 26496765 TI - Midline shift in relation to thickness of traumatic acute subdural hematoma predicts mortality. AB - BACKGROUND: Traumatic acute subdural hematoma has a high mortality despite intensive treatment. Despite the existence of several prediction models, it is very hard to predict an outcome. We investigated whether a specific combination of initial head CT-scan findings is a factor in predicting outcome, especially non-survival. METHODS: We retrospectively studied admission head CT scans of all adult patients referred for a traumatic acute subdural hematoma between April 2009 and April 2013. Chart review was performed for every included patient. Midline shift and thickness of the hematoma were measured by two independent observers. The difference between midline shift and thickness of the hematoma was calculated. These differences were correlated with outcome. IRB has approved the study. RESULTS: A total of 59 patients were included, of whom 29 died. We found a strong correlation between a midline shift exceeding the thickness of the hematoma by 3 mm or more, and subsequent mortality. For each evaluation, specificity was 1.0 (95 % CI: 0.85-1 for all evaluations), positive predictive value 1.0 (95 % CI between 0.31-1 and 0.56-1), while sensitivity ranged from 0.1 to 0.23 (95 % CI between 0.08-0.39 and 0.17-0.43), and negative predictive value varied from 0.52 to 0.56 (95 % CI between 0.38-0.65 and 0.41-0.69). CONCLUSIONS: In case of a traumatic acute subdural hematoma, a difference between the midline shift and the thickness of the hematoma >= 3 mm at the initial CT predicted mortality in all cases. This is the first time that such a strong correlation was reported. Especially for the future development of prediction models, the relation between midline shift and thickness of the hematoma could be included as a separate factor. PMID- 26496766 TI - A prospective study of appetite and food craving in 30 patients with Cushing's disease. AB - CONTEXT: Glucocorticoid (GC) exposure increases food intake, but the mechanisms in humans are not known. Investigation of appetite and food craving has not been done in patients with chronic GC exposure due to Cushing's disease (CD), either before or after treatment, and could provide insight into mechanisms of food intake and obesity in these patients. PURPOSE: To examine whether surgical remission of CD changes appetite (prospective consumption, hunger, satisfaction, and fullness) and food cravings (sweet, salty, fatty, and savory); and to identify predictors of appetite and craving in CD remission. METHODS: 30 CD patients, mean age 40.0 years (range 17-70), mean BMI 32.3 +/- 6.4, were prospectively studied before and at a mean of 17.4 mo. after remission. At each visit fasting and post-test meal (50% carbohydrate, 35% protein, 15% fat) appetite and craving scores were assessed. RESULTS: Remission decreased prospective consumption, sweet and savory craving (p < 0.05), but did not change hunger, satisfaction, fullness, or fat craving, despite decreases in BMI and fat mass. In CD remission, serum cortisol predicted lower satisfaction and fullness, and masses of abdominal fat depots predicted higher hunger and consumption (p < 0.05). CONCLUSIONS: Chronic GC exposure in CD patients may stimulate the drive to eat by enhancing craving, rather than regulating the sensation of hunger. Continued alterations in appetite regulation due to abdominal fat mass and circulating cortisol could play a role in the cardiovascular and metabolic risk that has been reported in CD patients despite remission. PMID- 26496767 TI - Pegvisomant-primed glucagon stimulation test in assessing GH reserve and GH/IGF kinetics in adults suspected of GH deficiency. AB - PURPOSE: The accuracy of the glucagon stimulation test(GST) in diagnosing adult GH deficiency (GHD) has recently been questioned. Because pegvisomant (PegV)increases endogenous GH secretion, we hypothesized that priming PegV to the GST (PegV-GST) 72 h beforehand would improve the diagnostic accuracy of this test. This pilot study aimed to prospectively compare PegV-GST to two other diagnostic tests for adult GHD. METHODS: Adults suspected of GHD underwent PegVGST,GST and insulin tolerance test (ITT) in random order.Growth hormone levels (measured by a PegV insensitive assay) during PegV-GST, GST and ITT were compared,and acute effects of PegV on GH/IGF kinetics were assessed. RESULTS: Ten subjects with hypothalamic-pituitary disease and 1-4 pituitary hormone deficiencies were studied. Basal and peak GH levels with the PegV-GST were comparable to those of the GST and ITT. The five subjects that failed the GST and ITT were the same subjects that failed the PegVGST,using the peak GH cut point of<3 ng/mL for this test. After PegV priming, basal GH and GH binding protein(GHBP) increased (both P<0.01) and total IGF-I and bioactive IGF decreased (both P<0.05), whereas IGF-II and IGFBPs -1, -2 and -3 were unchanged compared to pre-PegV priming. Serum PegV levels correlated positively with basal GH, peak GH, IGFBP-1 and IGFBP-2 levels, and negatively with D bioactive IGF and DGHBP (all P<0.05). CONCLUSION: Single dose PegV administration in adults suspected of GHD increased basal GH and GHBP, with concomitant rapid fall in IGF-I levels and bioactive IGF. PegV priming did not appear to improve the diagnostic accuracy of the GST. Further studies involving larger subject numbers are needed to verify the clinical utility of PegV-GST in evaluating adult GHD. PMID- 26496768 TI - The influence of socioeconomic status on future risk for developing Type 2 diabetes in the Canadian population between 2011 and 2022: differential associations by sex. AB - BACKGROUND: Articulating future risk of diabetes at the population level can inform prevention strategies. While previous studies have characterized diabetes burden according to socioeconomic status (SES), none have studied future risk. METHODS: We quantified the influence of multiple constructs of SES on future diabetes risk using the Diabetes Population Risk Tool (DPoRT), a validated risk prediction algorithm that generates 10-year rates of new diabetes cases. We applied DPoRT to adults aged 30-64 in the 2011-2012 Canadian Community Health Survey (n = 65,372) and calculated risk for 2021-22. A multi-category outcome was created classifying risk as low (<=5%), moderate (greater than 5% and less than 20%), and high (>=20%), then assessed the impact of individual-level SES indicators, and area-level measures of marginalization on being moderate or high risk using multinomial logistic regression, stratified by sex. RESULTS: We found nuanced profiles of social determinants by sex, where women are more sensitive to social context. Women living in households where highest educational attainment was less than secondary school were at greater risk [odds ratio (OR) of high compared to low diabetes risk 3.10, 95% confidence interval (CI) 2.19-4.40, p < 0.0001). The same relationship was less pronounced for males (OR 2.17, 95% CI 1.42-3.32, p = 0.0004). Lower household income and being food insecure predicted high future diabetes risk for women (OR 1.37, 95% CI 1.01-1.86, p = 0.0418 comparing quintile 1 to quintile 5; OR 2.64, 95% CI 1.78-3.92, p < 0.0001 comparing severely food insecure to food secure), but not men (OR 1.15, 95% CI 0.84-1.57, p = 0.3818 and OR 1.22, 95% CI 0.71-2.10, p = 0.4815). At the area level, material deprivation was significantly associated with increased future risk comparing the most to the least deprived (OR females 2.39, 95% CI 1.77-3.23; OR males 1.61, 95% CI 1.22-2.14). Additionally, a strong protective effect was observed for women living in ethnically dense areas (OR 0.75, 95% CI 0.63-0.89, p = 0.0011) which was not as pronounced for men (OR 0.95, 95% CI 0.76-1.18, p = 0.6351). CONCLUSIONS: This study characterized socio-contextual predictors for future diabetes risk, showing sex-specific effects. Diabetes prevention must consider factors beyond individual-level behavioral lifestyle change and actively take steps to mitigate the adverse impacts of socio-contextual factors. PMID- 26496769 TI - The effects of diet- and RYGB-induced weight loss on insulin sensitivity in obese patients with and without type 2 diabetes. AB - AIMS: The impact of diet-induced weight loss and weight loss due to RYGB in patients with (T2DM, N = 16) and without (OB, N = 27) type 2 diabetes was studied. METHODS: At inclusion (A), after diet-induced weight loss (B), 4 months post-surgery (C) and 18 months post-surgery (D) body composition, hepatic glucose production (HGP), insulin-mediated glucose uptake (GIR), respiratory exchange ratio, hepatic insulin sensitivity and clearance were determined. GLUT4, intramuscular triglycerides (IMTG) and glycogen content were measured in skeletal muscle. RESULTS: Weight loss was 35-40 kg, and approximately one-third of the total improvement in GIR in T2DM was observed after the diet-induced weight loss of only ~6 kg (B). Insulin clearance, visceral fat and fasting plasma insulin also improved significantly after the diet (P < 0.05). Throughout the study, HGP, GLUT4 and glycogen content did not change significantly, but IMTG decreased significantly consistent with significant increases in GIR. Metabolic flexibility and hepatic insulin sensitivity improved after RYGB. CONCLUSIONS: Metabolic improvements of RYGB are present already after the diet-induced weight loss prior to surgery. GLUT4 content in skeletal muscle cannot and IMTG content can only partly explain increases in GIR after RYGB. PMID- 26496770 TI - Hepatic insulin resistance in NAFLD: relationship with markers of atherosclerosis and metabolic syndrome components. AB - AIMS: Fat accumulation in the liver and in the muscle results in hepatic and muscle insulin resistance and has been associated with increased cardiovascular risk. It is unclear whether the individual role of hepatic and muscle insulin resistance in the onset of dyslipidaemia is observed in nonalcoholic fatty liver disease (NAFLD) patients and whether this association is mediated through traditional risk factors. The aim of this study was to assess hepatic and muscle insulin resistance in NAFLD and its relationship with carotid artery intima-media thickness (IMT) and the apoB/apoAI ratio as markers of atherosclerosis. METHODS: We studied 132 patients with a non-invasive diagnosis of NAFLD stratified into two groups according to the severity of steatosis at ultrasound scan. In all subjects, we measured hepatic insulin resistance (H-IR) and muscle insulin sensitivity index (MISI) by oral glucose tolerance test as proposed by DeFronzo, IMT, apoB/apoAI and the components of the metabolic syndrome (MS) as defined by ATP III. RESULTS: H-IR was significantly higher in moderate/severe steatosis than in the mild steatosis group (p < 0.0001). By contrast, MISI did not differ between the two groups. There was a significant correlation between H-IR, MISI and all of the components of MS. H-IR was significantly correlated with carotid IMT (r = 0.35; p < 0.0001) and the apoB/apoAI ratio (r = 0.43; p < 0.0001). Otherwise, a significant correlation was observed only between MISI and apoB/apoAI ratio. Multivariate analysis revealed that H-IR is related to early markers of atherosclerosis independent of MS components. CONCLUSIONS: In our study population, NAFLD was positively associated with carotid IMT, and this association is independent of MS components, but strictly related to H-IR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio. By contrast, no significant relation was observed between MISI and carotid IMT. PMID- 26496771 TI - A modified choline-deficient, ethionine-supplemented diet reduces morbidity and retains a liver progenitor cell response in mice. AB - The choline-deficient, ethionine-supplemented (CDE) dietary model induces chronic liver damage, and stimulates liver progenitor cell (LPC)-mediated repair. Long term CDE administration leads to hepatocellular carcinoma in rodents and lineage tracing studies show that LPCs differentiate into functional hepatocytes in this model. The CDE diet was first modified for mice by our laboratory by separately administering choline-deficient chow and ethionine in the drinking water (CD+E diet). Although this CD+E diet is widely used, concerns with variability in weight loss, morbidity, mortality and LPC response have been raised by researchers who have adopted this model. We propose that these inconsistencies are due to differential consumption of chow and ethionine in the drinking water, and that incorporating ethionine in the choline-deficient chow, and altering the strength, will achieve better outcomes. Therefore, C57Bl/6 mice, 5 and 6 weeks of age, were fed an all-inclusive CDE diet of various strengths (67% to 100%) for 3 weeks. The LPC response was quantitated and cell lines were derived. We found that animal survival, LPC response and liver damage are correlated with CDE diet strength. The 67% and 75% CDE diet administered to mice older than 5 weeks and greater than 18 g provides a consistent and acceptable level of animal welfare and induces a substantial LPC response, permitting their isolation and establishment of cell lines. This study shows that an all-inclusive CDE diet for mice reproducibly induces an LPC response conducive to in vivo studies and isolation, whilst minimizing morbidity and mortality. PMID- 26496772 TI - MAP3K1 function is essential for cytoarchitecture of the mouse organ of Corti and survival of auditory hair cells. AB - MAP3K1 is a serine/threonine kinase that is activated by a diverse set of stimuli and exerts its effect through various downstream effecter molecules, including JNK, ERK1/2 and p38. In humans, mutant alleles of MAP3K1 are associated with 46,XY sex reversal. Until recently, the only phenotype observed in Map3k1(tm1Yxia) mutant mice was open eyelids at birth. Here, we report that homozygous Map3k1(tm1Yxia) mice have early-onset profound hearing loss accompanied by the progressive degeneration of cochlear outer hair cells. In the mouse inner ear, MAP3K1 has punctate localization at the apical surface of the supporting cells in close proximity to basal bodies. Although the cytoarchitecture, neuronal wiring and synaptic junctions in the organ of Corti are grossly preserved, Map3k1(tm1Yxia) mutant mice have supernumerary functional outer hair cells (OHCs) and Deiters' cells. Loss of MAP3K1 function resulted in the downregulation of Fgfr3, Fgf8, Fgf10 and Atf3 expression in the inner ear. Fgfr3, Fgf8 and Fgf10 have a role in induction of the otic placode or in otic epithelium development in mice, and their functional deficits cause defects in cochlear morphogenesis and hearing loss. Our studies suggest that MAP3K1 has an essential role in the regulation of these key cochlear morphogenesis genes. Collectively, our data highlight the crucial role of MAP3K1 in the development and function of the mouse inner ear and hearing. PMID- 26496774 TI - Computational Identification of MicroRNAs and Their Targets from Finger Millet (Eleusine coracana). AB - MicroRNAs are endogenous small RNAs regulating intrinsic normal growth and development of plant. Discovering miRNAs, their targets and further inferring their functions had become routine process to comprehend the normal biological processes of miRNAs and their roles in plant development. In this study, we used homology-based analysis with available expressed sequence tag of finger millet (Eleusine coracana) to predict conserved miRNAs. Three potent miRNAs targeting 88 genes were identified. The newly identified miRNAs were found to be homologous with miR166 and miR1310. The targets recognized were transcription factors and enzymes, and GO analysis showed these miRNAs played varied roles in gene regulation. The identification of miRNAs and their targets is anticipated to hasten the pace of key epigenetic regulators in plant development. PMID- 26496773 TI - A modern approach for epitope prediction: identification of foot-and-mouth disease virus peptides binding bovine leukocyte antigen (BoLA) class I molecules. AB - Major histocompatibility complex (MHC) class Imolecules regulate adaptive immune responses through the presentation of antigenic peptides to CD8+ T cells. Polymorphisms in the peptide binding region of class I molecules determine peptide binding affinity and stability during antigen presentation, and different antigen peptide motifs are associated with specific genetic sequences of class I molecules. Understanding bovine leukocyte antigen (BoLA), peptide-MHC class I binding specificities may facilitate development of vaccines or reagents for quantifying the adaptive immune response to intracellular pathogens, such as foot and-mouth disease virus (FMDV). Six synthetic BoLA class I (BoLA-I) molecules were produced, and the peptide binding motif was generated for five of the six molecules using a combined approach of positional scanning combinatorial peptide libraries (PSCPLs) and neural network-based predictions (NetMHCpan). The updated NetMHCpan server was used to predict BoLA-I binding peptides within the P1 structural polyprotein sequence of FMDV (strain A24 Cruzeiro) for Bo-LA-1*01901, BoLA-2*00801, BoLA-2*01201, and BoLA-4*02401. Peptide binding affinity and stability were determined for these BoLA-I molecules using the luminescent oxygen channeling immunoassay (LOCI) and scintillation proximity assay (SPA). The functional diversity of known BoLA alleles was predicted using theMHCcluster tool, and functional predictions for peptide motifs were compared to observed data from this and prior studies. The results of these analyses showed that BoLA alleles cluster into three distinct groups with the potential to define BBoLA supertypes.^ This streamlined approach identifies potential T cell epitopes from pathogens, such as FMDV, and provides insight into T cell immunity following infection or vaccination. PMID- 26496775 TI - CD147 is increased in HCC cells under starvation and reduces cell death through upregulating p-mTOR in vitro. AB - Transarterial chemoembolization (TACE) is the standard of care for treatment of intermediate hepatocellular carcinoma (HCC), however, key molecules involved in HCC cell survival and tumor metastasis post-TACE remain unclear. CD147 is a member of the immunoglobulin superfamily that is overexpressed on the surface of HCC cells and is associated with malignant potential and poor prognosis in HCC patients. In this study, using an Earle's Balanced Salt Solution medium culture model that mimics nutrient deprivation induced by TACE, we investigated the regulation of CD147 expression on HCC cells under starvation conditions and its functional effects on HCC cell death. During early stages of starvation, the expression of CD147 was considerably upregulated in SMMC7721, HepG2 and HCC9204 hepatoma cell lines at the protein levels. Downregulation of CD147 by specific small interfering RNA (siRNA) significantly promoted starvation-induced cell death. In addition, CD147 siRNA-transfected SMMC7721 cells demonstrated significantly increased levels of both apoptosis and autophagy as compared to cells transfected with control siRNA under starvation conditions, whereas no difference was observed between the two treatment groups under normal culture conditions. Furthermore, silencing of CD147 resulted in a remarkable downregulation of phosphorylated mammalian target of rapamycin (p-mTOR) in starved SMMC7721 cells. Finally, the combined treatment of starvation and anti CD147 monoclonal antibody exhibited a synergistic HCC cell killing effect. Our study suggests that upregulation of CD147 under starvation may reduce hepatoma cell death by modulating both apoptosis and autophagy through mTOR signaling, and that CD147 may be a novel potential molecular target to improve the efficacy of TACE. PMID- 26496776 TI - Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis. AB - Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2 AKT-mTOR signaling, providing a new insight into apoptotic mechanisms. PMID- 26496777 TI - Adaptive Immunity in Neurodegenerative and Neuropsychological Disorders. AB - Neurodegenerative and neuropsychological disorders are becoming a greater proportion of the global disease burden; however the pathogenic mechanisms by which these disorders originate and contribute to disease progression are not well-described. Increasing evidence supports neuroinflammation as a common underlying component associated with the neuropathological processes that effect disease progression. This collection of articles explores the role of adaptive immunity in autoimmunity, neurodegeneration, neurotrauma, and psychological disorders. The section emphasizes the interactions of T cells with innate cellular responses within the CNS and the effects on neurological functions. One recurrent theme is that modified and aggregated self-proteins upregulate innate mediated inflammation and provide a permissive environment for polarization of T cells to proinflammatory effector cells. Moreover, infiltration and reactivation of those T effector cells exacerbate neuroinflammation and oxidative stress to greater neurotoxic levels. Another recurrent theme in these disorders promotes diminished regulatory functions that reduce control over activated T effector cells and microglia, and ultimately augment proinflammatory conditions. Augmentation of regulatory control is discussed as therapeutic strategies to attenuate neuroinflammation, mitigate neurodegeneration or neuronal dysfunction, and lessen disease progression. PMID- 26496778 TI - Correlation of Bone Mineral Density Scores and Proton Pump Inhibitors Use in the Elderly. AB - OBJECTIVE: We aimed to identify any correlation between long-term proton pump inhibitor use and low bone mineral density in the elderly. MATERIALS AND METHODS: This is a retrospective cohort study looking at PPI usage and bone mineral density scores of patients age 65 and above within a period of two years. Lumbar spine, right hip, and left hip bone mineral density t-scores were reviewed in PPI users and non-users. RESULTS: A total of 1,016 patients who had bone mineral density scans within that period were identified. Non-adjusted data showed no statistically significant association between PPI users and non-users in lumbar spine (p = 0.903), right hip (p = 0.775) and left hip (p = 0.407) bone mineral density scores. After adjusting for age and gender, PPI use was still not associated with low bone mineral density at the lumbar spine (p = 0.957), right hip (p = 0.440), or left hip (p = 0.691). The logistic regression did not show a statistically significant difference in low bone mineral density scores in lumbar spine (p = 0.162), right hip (p = 0.796), and left hip (p = 0.196) when length of use was considered. CONCLUSION: Among adults 65 years and older proton pump inhibitors users; there appears to be no correlation between PPI use and low bone mineral density and/or the length of PPI use. PMID- 26496779 TI - Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics. AB - Phenobarbital is an effective and safe anticonvulsant drug introduced in clinical use in 1904. Its mechanism of action is the synaptic inhibition through an action on GABAA. The loading dose of phenobarbital is 20 mg/kg intravenously and the maintenance dose is 3 to 4 mg/kg by mouth. The serum concentration of phenobarbital is up to 40 ug/ml. Nonresponders should receive additional doses of 5 to 10 mg/kg until seizures stop. Infants with refractory seizures may have a serum concentration of phenobarbital of 100 ug/ml. Phenobarbital is metabolized in the liver by CYP2C9 with minor metabolism by CYP2C19 and CYP2E1. A quarter of the dose of phenobarbital is excreted unchanged in the urine. In adults, the half life of phenobarbital is 100 hours and in term and preterm infants is 103 and 141 hours, respectively. The half-life of phenobarbital decreases 4.6 hours per day and it is 67 hours in infants 4 week old. PMID- 26496780 TI - "Childhood Vitiligo". AB - Vitiligo in children is a distinct subset of vitiligo and differs from adult vitiligo. Characteristic features include family history of autoimmune or endocrine disease, higher incidence of segmental vitiligo , development of early or premature graying, increased incidence of autoantibodies and poor response to topical PUVA. The exact prevalence of vitiligo in children varies between 0.1-4% of the world population and seems to be higher in India than in other countries and it occurs more frequently in females. Around 12% to 35% of pediatric vitiligo patients have family members with the disease. The most common type of vitiligo in pediatric patients is vitiligo vulgaris, representing 78% of cases. The most commonly associated autoimmune disease is thyroiditis. Phototherapy and topical corticosteroids are the most commonly used treatments for adult vitiligo but are less useful in the pediatric population. PMID- 26496781 TI - The Role of Wrist Fusion and Wrist Arthroplasty in Rheumatoid Arthritis. AB - Rheumatoid arthritis is the most common form of inflammatory arthritis with a predilection for the hand and wrist. The aggressive nature of the disease can lead to severe joint destruction causing significant disability. Surgical options for pan-carpal arthritis include total wrist arthroplasty and total wrist fusion both with varying outcomes, yet both have a role in the carefully selected patients. Fusion remains a popular procedure with consistent reliable results with few complications. We present a review of current evidence, indications and guidance for both fusion and arthroplasty in rheumatoid arthritis. PMID- 26496782 TI - No Zinc Deficiency But a Putative Immunosuppressive Role for Labile Zn in Patients with Systemic Autoimmune Disease. AB - BACKGROUND: Zn (Zn) is an essential trace element with important roles in protein structure and function. Labile Zn is the fraction available for regulatory functions through it loose binding to albumin. As Zn deprivation reduces labile Zn levels and leads to an immune compromised state, we investigated labile Zn levels in the context of systemic autoimmune disease. METHODS: Cross sectional case control study in patients with Systemic Lupus Erythematosus (SLE; n= 45), primary Sjogren's Syndrome (n= 53) and healthy controls (HC; n= 27). Serum labile Zn levels were measured by an in-house assay using the UV-excitable fluorophore zinquin ethyl ester. Associations between labile Zn levels and SLE manifestations were investigated by nonparametric methods. RESULTS: None of the SLE or pSS patients was found to be Zn deficient. Labile Zn levels were significantly higher in SLE (31.7 mcg/dl) than in pSS patients (22.3 mcg/dl) and HC (19.7 mcg/dl) (p<0.001). Labile Zn levels did not associate with demographics, disease activity scores, or inflammatory cytokine levels, but correlated inversely with lymphocyte counts (Rs -0.37, p<0.01), antidsDNA, anticardiolipin (Rs -0.29, p=0.01), anti rib P antibody levels (Rs -0.24, p=0.02) and with circulating NK-cell numbers in SLE patients (Rs .27, p= 0.02). CONCLUSIONS: There is no evidence of Zn deficiency in patients with pSS or SLE. Labile Zn levels are unexpectedly high in SLE patients, independent of cytokine levels and may play a role in immune modulation through increased NK numbers and autoantibody containment. PMID- 26496783 TI - Systemic Lupus Erythematosus: Correlation Between Immunodysregulation and Clinical Manifestations. AB - Systemic Lupus Erythematosus is considered a prototype of an autoimmune disorder. The greatly compromise immune system reflects in a global loss of self-tolerance and an array of autoantibodies which are the hallmark of the disease. Diagnosis and clinical management are a challenge to physicians owing its complex clinical course. Specific correlation between immunodysregulation and the clinical manifestations have been studied and we intended in this paper to review recent studies, highlighting new discoveries in this matter. PMID- 26496784 TI - Arthritis and Periodontitis: An Association Debated for Over Two Centuries. AB - The chronic diseases, rheumatoid arthritis (RA) and periodontal disease (PD) lead to confined destruction of soft and hard tissues as a result of inflammatory processes. Their pathogenesis is dictated by a network of inflammatory cells and its mediators. They also share some etiological risk factors and therapeutic alternatives. The evolution of focal infection theory is summarized in this review, with special reference to PD and its relationship to RA. Foci of chronic infections exist in the oral cavity and may result in anatomically distant disease in certain individuals. Recent cumulative evidences document the influence of inflammatory diseases such as RA on the development of PD. Historical evidences and new theories on the interrelationship between the two diseases have the potential to identify novel mechanisms and therapy to improve patient outcomes. This review focuses on not only the association of focal infection theory and RA, but also on the reciprocal effects of RA and PD. PMID- 26496785 TI - Structural gamma-epsilon phase transition in Fe-Mn alloys from a CPA + DMFT approach. AB - We present a computational scheme for total energy calculations of disordered alloys with strong electronic correlations. It employs the coherent potential approximation combined with the dynamical mean-field theory and allows one to study the structural transformations. The material-specific Hamiltonians in the Wannier function basis are obtained by density functional theory. The proposed computational scheme is applied to study the gamma-epsilon structural transition in paramagnetic Fe-Mn alloys for Mn content from 10 to 20 at.%. The electronic correlations are found to play a crucial role in this transition. The calculated transition temperature decreases with increasing Mn content and is in good agreement with experiment. We demonstrate that in contrast to the alpha-gamma transition in pure iron, the gamma-epsilon transition in Fe-Mn alloys is driven by a combination of kinetic and Coulomb energies. The latter is found to be responsible for the decrease of the gamma-epsilon transition temperature with Mn content. PMID- 26496786 TI - Five-year experience with intraoperative extracorporeal membrane oxygenation in lung transplantation: Indications and midterm results. AB - BACKGROUND: Since April 2010, extracorporeal membrane oxygenation (ECMO) has replaced cardiopulmonary bypass for intraoperative support during lung transplantation at our institution. The aim of this study was to present our 5 year experience with this technique. METHODS: Records of patients who underwent transplantation between April 2010 and January 2015 were retrospectively reviewed. Patients who underwent transplantation without ECMO formed Group A. Patients in whom the indication for ECMO support was set a priori before the beginning of the operation formed Group B. The remaining patients in whom the indication for ECMO support was set during transplantation formed Group C. RESULTS: Among 595 patients, 425 (71%) patients (Group A) did not require intraoperative ECMO; the remaining 170 (29%) patients did. Among these patients, 95 (56%) patients formed Group B, and the remaining 75 (44%) patients comprised Group C. Pulmonary fibrosis and pre-operative dilated or hypertrophied right ventricle emerged as risk factors for the indication of non-a priori intraoperative ECMO. Patients in Groups B and C showed a higher pre-operative risk profile and higher prevalence of post-operative complications than patients in Group A. Overall survival at 1 year was 93%, 83%, and 82% and at 4 years was 73%, 68%, and 69% in Groups A, B, and C (p = 0.11). The intraoperative use of ECMO did not emerge as a risk factor for in-hospital mortality or mortality after hospital discharge. CONCLUSIONS: Intraoperative ECMO filled the gap between pre operative and post-operative ECMO in lung transplantation. Although complications and in-hospital mortality were higher in patients who received ECMO, survival was similar among patients who underwent transplantation with or without ECMO. PMID- 26496787 TI - Influence of human leukocyte antigen mismatching on bronchiolitis obliterans syndrome in lung transplantation. AB - BACKGROUND: Varying results have been reported in the investigation of human leukocyte antigen (HLA) mismatching and bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). METHODS: The UNOS database was queried for the period 1997 to 2013 to examine HLA mismatching and its association with BOS in LTx. RESULTS: Of 16,959 first-time adult LTx recipients, 16,854 were included in the univariate Cox analysis and Kaplan-Meier survival function evaluation, and 14,578 were included in multivariate Cox models. Multivariate Cox analysis showed that the number of total HLA mismatches was significantly associated with greater hazard of BOS (HR = 1.060; 95% CI 1.013 to 1.108; p = 0.011), as was the presence of 2 HLA-A mismatches, when compared with 0 or 1 mismatch at that locus (HR = 1.128; 95% CI 1.026 to 1.240; p = 0.012). These results were confirmed using competing-risks regression models that adjusted for death before BOS diagnosis. Multivariate Cox models identified no significant association with BOS hazard for HLA-B (HR = 1.014; 95% CI 0.914 to 1.126; p = 0.785) or HLA-DR (HR = 1.085; 95% CI 0.987 to 1.193; p = 0.090) mismatches. Higher body mass index was associated with increased risk for BOS, whereas older age was protective against BOS. Induction with alemtuzumab (HR = 0.343; 95% CI 0.252 to 0.467; p < 0.001) or basiliximab (HR = 0.862; 95% CI 0.758 to 0.980; p = 0.023) and longer ischemic time (HR = 0.909; 95% CI 0.877 to 0.942; p < 0.001) were associated with lower hazard of BOS. CONCLUSIONS: Total HLA mismatches are associated with increased risk for BOS, specifically at the A locus. Induction with alemtuzumab or basiliximab reduced the risk, whereas greater ischemic time appears to also be protective. PMID- 26496788 TI - An experimental investigation into the colonization of concealed cadavers by necrophagous blowflies. AB - We used seven baited boxes with different combinations of access holes and odor diffusion surfaces to study the arrival of necrophagous flies. During laboratory experiments, 30 gravid Lucilia sericata females were kept in a chamber with one of the boxes. The box with the largest odor diffusion surface (99 cm(2)) combined with the lowest accessibility (one 1 cm(2) entrance hole) was entered least (5 +/ 3.7 flies per run). In contrast, the most frequently entered box (one 9 cm(2) entrance hole with no additional odor diffusion surface) caught a mean of 24.6 +/ 3.4 flies per run. These results indicate that 1) L. sericata entered nearly inaccessible places and 2) both odor diffusion and accessibility impacted the number of flies caught. During field experiments, the seven boxes were placed together outdoors. The box with the most entrances (ten 9-cm(2) holes) caught the most flies (55.6-99.4% of the total). Only a few flies entered the other boxes. Access to the less accessible boxes (poor odor diffusion and small entrances) was also delayed. The major conclusions of the field experiments are that 1) boxes with low accessibility took longer to be accessed; 2) larger odor diffusion surfaces were more attractive to flies; and 3) flies accessed boxes more readily through larger holes than through an equivalent surface area made up of smaller holes. With these conclusions in mind, attempts to quantify the preappearance interval or to interpret the number of flies observed in indoor forensic entomology cases should be approached with caution. PMID- 26496789 TI - Genetic variation and geographic differentiation among populations of the nonmigratory agricultural pest Oedaleus infernalis (Orthoptera: Acridoidea) in China. AB - The nonmigratory grasshopper Oedaleus infernalis Saussure (Orthoptera : Acridoidea) is an agricultural pest to crops and forage grasses over a wide natural geographical distribution in China. The genetic diversity and genetic variation among 10 geographically separated populations of O. infernalis was assessed using polymerase chain reaction-based molecular markers, including the intersimple sequence repeat and mitochondrial cytochrome oxidase sequences. A high level of genetic diversity was detected among these populations from the intersimple sequence repeat (H: 0.2628, I: 0.4129, Hs: 0.2130) and cytochrome oxidase analyses (Hd: 0.653). There was no obvious geographical structure based on an unweighted pair group method analysis and median-joining network. The values of FST, theta(II), and Gst estimated in this study are low, and the gene flow is high (Nm > 4). Analysis of the molecular variance suggested that most of the genetic variation occurs within populations, whereas only a small variation takes place between populations. No significant correlation was found between the genetic distance and geographical distance. Overall, our results suggest that the geographical distance plays an unimpeded role in the gene flow among O. infernalis populations. PMID- 26496790 TI - Calpain-like: A Ca(2+) dependent cystein protease in Entamoeba histolytica cell death. AB - Entamoeba histolytica programmed cell death (PCD) induced by G418 is characterized by the release of important amounts of intracellular calcium from reservoirs. Nevertheless, no typical caspases have been detected in the parasite, the PCD phenotype is inhibited by the cysteine protease inhibitor E-64. These results strongly suggest that Ca(2+)-dependent proteases could be involved in PCD. In this study, we evaluate the expression and activity of a specific dependent Ca(2+) protease, the calpain-like protease, by real-time quantitative PCR (RTq-PCR), Western blot assays and a enzymatic method during the induction of PCD by G418. Alternatively, using cell viability and TUNEL assays, we also demonstrated that the Z-Leu-Leu-Leu-al calpain inhibitor reduced the rate of cell death. The results demonstrated 4.9-fold overexpression of calpain-like gene 1.5 h after G418 PCD induction, while calpain-like protein increased almost two-fold with respect to basal calpain-like expression after 3 h of induction, and calpain activity was found to be approximately three-fold higher 6 h after treatment compared with untreated trophozoites. Taken together, these results suggest that this Ca(2+)-dependent protease could be involved in the executory phase of PCD. PMID- 26496791 TI - Melatonin as a possible antidote to UV radiation induced cutaneous damages and immune-suppression: An overview. AB - The sun rays brings along the ultraviolet radiations (UVRs) which prove deleterious for living organisms. The UVR is a known mutagen and is the prime cause of skin carcinomas. UVR causes acute oxidative stress and this in turn deteriorates other physiological functions. Inflammatory conditions and elevation of pro-inflammatory molecules are also associated with UVR mediated cellular damages. The inflammatory conditions can secondarily trigger the generation of free radicals and this act cumulatively in further deterioration of tissue homeostasis. Photoimmunologists have also related UVR to the suppression of not only cutaneous but also systemic immunity by different mechanisms. Some researchers have proposed the use of various plant products as antioxidants against UVR induced oxidative imbalances but Melatonin is gaining rapid interest as a product that can be utilized to delineate the pathological effects of UVR since it is an established antioxidant. Besides the antioxidative nature, the capacity of melatonin to attenuate apoptosis and more importantly the efficacy of its metabolites to further aid in the detoxification of free radicals have made it a key player to be utilized against UVR mediated aggravated conditions. However, there is need for further extensive investigation to speculate melatonin as an antidote to UVR. Although too early to prescribe melatonin as a clinical remedy, the hormone can be integrated into dermal formulations or oral supplements to prevent the ever increasing incidences of skin cancers due to the prevalence of the UVR on the surface of the earth. The present review focuses and substantiates the work by different photo-biologists demonstrating the protective effects of melatonin and its metabolites against solar UVR - Melatonin as a possible antidote to UV radiation induced cutaneous damages and immune suppression: an overview. J Photochem Photobiol B. PMID- 26496792 TI - Influence of humic acid on the stability and bacterial toxicity of zinc oxide nanoparticles in water. AB - The present study investigated the stability of zinc oxide nanoparticles (ZnO NPs) by the adsorption of humic acid (HA) and the mechanism of adsorption. The effect of humic acid on NP toxicity was determined by Escherichia coli (ATCC 13534), E. coli (ATCC 25922), and Pseudomonas putida (MTCC 4910). The nanoparticles showed low zeta potential and were least stable in the absence of HA. However, the negative surface charge of the particles increased in the presence of HA (0-50mg/L) that reduced the propensity of nanoparticles to aggregate in water. A decrease in absorbance of ZnO NPs at 375 nm (plasmon peak) was noted in the presence of HA by UV-visible spectrophotometric analysis. A blue shift towards 370 nm was noted when the concentration of HA was above 20mg/L. The HA adsorbed ZnO NPs showed higher zeta potential (>-30 mV) and were highly stable. HA reduced the photocatalytic activity of ZnO and at the same time increased the photostability of ZnO. PMID- 26496793 TI - Effect of photodamage on the outermost cuticle layer of human hair. AB - The surface of the hair is the region most exposed to solar radiation and to the environment in general. Many of the well-known damaging effects of sun exposure on hair must start or even be restricted to the most external cuticle layers. As such, this work investigates morphological, ultrastructural and chemical changes in the outermost cuticle layer of dark brown hair, using atomic force microscopy (AFM), field emission scanning electron microscopy (FESEM) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The results showed that after 230 h of irradiation with a mercury lamp, small bumps with globular shape (heights lying in the 1-5 nm range) appeared on the cuticle surface and their size increased with increasing irradiation times. In addition, the enlargement of pre-existing holes was also observed (holes increase around 350% in depth) and the height of the steps formed between the edges of two cuticle scales increased around 65%, as a result of 500 h of irradiation. The damages in hair strands were accurately identified by analyzing exactly the same surface region before and after irradiation by AFM images. Finally, the results were discussed in terms of the chemical differences between the non-irradiated and the irradiated hair, for instance, the increased level of cystine oxidation as a consequence of photodegradation. PMID- 26496794 TI - Atypical presentation of Legionella pneumonia among patients with underlying cancer: A fifteen-year review. AB - BACKGROUND: Immunocompromised patients, especially those receiving treatment with corticosteroids and cytotoxic chemotherapy are at increased risk for developing Legionella pneumonia. OBJECTIVE: The aim of this study was to determine clinical and radiographic characteristics of pulmonary infection due to Legionella in persons undergoing treatment for cancer and stem cell transplant (SCT) recipients. METHODS: Retrospective review of Legionella cases at MSKCC over a fifteen-year study period from January 1999 and December 2013. Cases were identified by review of microbiology records. RESULTS: During the study period, 40 cases of Legionella infection were identified; nine among these were due to non-pneumophila species. Most cases occurred during the summer. The majority [8/9, (89%)] of patients with non-pneumophila infection had underlying hematologic malignancy, compared to 18/31 (58%) with Legionella pneumophila infections. Radiographic findings were varied-nodular infiltrates mimicking invasive fungal infection were seen only among patients with hematologic malignancy and hematopoietic stem cell transplant (SCT) recipients and were frequently associated with non-pneumophila infections (50% vs 16%; P = 0.0594). All cases of nodular Legionella pneumonia were found incidentally or had an indolent clinical course. CONCLUSIONS: Legionella should be considered in the differential diagnosis of nodular lung lesions in immunocompromised patients, especially those with hematologic malignancy and SCT recipients. Most cases of nodular disease due to Legionella are associated with non-pneumophila infections. PMID- 26496795 TI - Locus coeruleus neuronal activity determines proclivity to consume alcohol in a selectively-bred line of rats that readily consumes alcohol. AB - Sprague-Dawley rats selectively-bred for susceptibility to stress in our laboratory (Susceptible, or SUS rats) voluntarily consume large amounts of alcohol, and amounts that have, as shown here, pharmacological effects, which normal rats will not do. In this paper, we explore neural events in the brain that underlie this propensity to readily consume alcohol. Activity of locus coeruleus neurons (LC), the major noradrenergic cell body concentration in the brain, influences firing of ventral tegmentum dopaminergic cell bodies of the mesocorticolimbic system (VTA-DA neurons), which mediate rewarding aspects of alcohol. We tested the hypothesis that in SUS rats alcohol potently suppresses LC activity to markedly diminish LC-mediated inhibition of VTA-DA neurons, which permits alcohol to greatly increase VTA-DA activity and rewarding aspects of alcohol. Electrophysiological single-unit recording of LC and VTA-DA activity showed that in SUS rats alcohol decreased LC burst firing much more than in normal rats and as a result markedly increased VTA-DA activity in SUS rats while having no such effect in normal rats. Consistent with this, in a behavioral test for reward using conditioned place preference (CPP), SUS rats showed alcohol, given by intraperitoneal (i.p.) injection, to be rewarding. Next, manipulation of LC activity by microinfusion of drugs into the LC region of SUS rats showed that (a) decreasing LC activity increased alcohol intake and increasing LC activity decreased alcohol intake in accord with the formulation described above, and (b) increasing LC activity blocked both the rewarding effect of alcohol in the CPP test and the usual alcohol-induced increase in VTA-DA single-unit activity seen in SUS rats. An important ancillary finding in the CPP test was that an increase in LC activity was rewarding by itself, while a decrease in LC activity was aversive; consequently, effects of LC manipulations on alcohol-related reward in the CPP test were perhaps even larger than evident in the test. Finally, when increased LC activity was associated with (i.e., conditioned to) i.p. alcohol, subsequent alcohol consumption by SUS rats was markedly reduced, indicating that SUS rats consume large amounts of alcohol because of rewarding physiological consequences requiring increased VTA-DA activity. The findings reported here are consistent with the view that the influence of alcohol on LC activity leading to changes in VTA-DA activity strongly affects alcohol-mediated reward, and may well be the basis of the proclivity of SUS rats to avidly consume alcohol. PMID- 26496796 TI - Computed tomography assessment of peripubertal craniofacial morphology in a sheep model of binge alcohol drinking in the first trimester. AB - Identification of facial dysmorphology is essential for the diagnosis of fetal alcohol syndrome (FAS); however, most children with fetal alcohol spectrum disorders (FASD) do not meet the dysmorphology criterion. Additional objective indicators are needed to help identify the broader spectrum of children affected by prenatal alcohol exposure. Computed tomography (CT) was used in a sheep model of prenatal binge alcohol exposure to test the hypothesis that quantitative measures of craniofacial bone volumes and linear distances could identify alcohol exposed lambs. Pregnant sheep were randomly assigned to four groups: heavy binge alcohol, 2.5 g/kg/day (HBA); binge alcohol, 1.75 g/kg/day (BA); saline control (SC); and normal control (NC). Intravenous alcohol (BA; HBA) or saline (SC) infusions were given three consecutive days per week from gestation day 4-41, and a CT scan was performed on postnatal day 182. The volumes of eight skull bones, cranial circumference, and 19 linear measures of the face and skull were compared among treatment groups. Lambs from both alcohol groups showed significant reduction in seven of the eight skull bones and total skull bone volume, as well as cranial circumference. Alcohol exposure also decreased four of the 19 craniofacial measures. Discriminant analysis showed that alcohol-exposed and control lambs could be classified with high accuracy based on total skull bone volume, frontal, parietal, or mandibular bone volumes, cranial circumference, or interorbital distance. Total skull volume was significantly more sensitive than cranial circumference in identifying the alcohol-exposed lambs when alcohol exposed lambs were classified using the typical FAS diagnostic cutoff of <=10th percentile. This first demonstration of the usefulness of CT-derived craniofacial measures in a sheep model of FASD following binge-like alcohol exposure during the first trimester suggests that volumetric measurement of cranial bones may be a novel biomarker for binge alcohol exposure during the first trimester to help identify non-dysmorphic children with FASD. PMID- 26496797 TI - In-Depth N-Glycosylation Reveals Species-Specific Modifications and Functions of the Royal Jelly Protein from Western (Apis mellifera) and Eastern Honeybees (Apis cerana). AB - Royal jelly (RJ), secreted by honeybee workers, plays diverse roles as nutrients and defense agents for honeybee biology and human health. Despite being reported to be glycoproteins, the glycosylation characterization and functionality of RJ proteins in different honeybee species are largely unknown. An in-depth N glycoproteome analysis and functional assay of RJ produced by Apis mellifera lingustica (Aml) and Apis cerana cerana (Acc) were conducted. RJ produced by Aml yielded 80 nonredundant N-glycoproteins carrying 190 glycosites, of which 23 novel proteins harboring 35 glycosites were identified. For Acc, all 43 proteins glycosylated at 138 glycosites were reported for the first time. Proteins with distinct N-glycoproteomic characteristics in terms of glycoprotein species, number of N-glycosylated sites, glycosylation motif, abundance level of glycoproteins, and N-glycosites were observed in this two RJ samples. The fact that the low inhibitory efficiency of N-glycosylated major royal jelly protein 2 (MRJP2) against Paenibacillus larvae (P. larvae) and the absence of antibacterial related glycosylated apidaecin, hymenoptaecin, and peritrophic matrix in the Aml RJ compared to Acc reveal the mechanism for why the Aml larvae are susceptible to P. larvae, the causative agent of a fatal brood disease (American foulbrood, AFB). The observed antihypertension activity of N-glycosylated MRJP1 in two RJ samples and a stronger activity found in Acc than in Aml reveal that specific RJ protein and modification are potentially useful for the treatment of hypertensive disease for humans. Our data gain novel understanding that the western and eastern bees have evolved species-specific strategies of glycosylation to fine tune protein activity for optimizing molecular function as nutrients and immune agents for the good of honeybee and influence on the health promoting activity for human as well. This serves as a valuable resource for the targeted probing of the biological functions of RJ proteins for honeybee and medical communities. PMID- 26496799 TI - Icaritin acts synergistically with epirubicin to suppress bladder cancer growth through inhibition of autophagy. AB - Bladder cancer is one of the most commonly diagnosed urological malignancies. Acquired resistance to chemotherapy is a great barrier for achieving successful treatment of bladder cancer. In the present study, we investigated the effect and mechanisms of icaritin, a flavonol glycoside derived from genus Epimedium, against human bladder cancer cells. It was found that despite the low cytotoxicity in normal human HEK293 cells, icaritin significantly inhibited the proliferation and colony formation of BT5637 and T24 bladder cancer cells time- and dose-dependently compared to the DMSO vehicle control. Moreover, cell viability monitored through mitochondrial membrane potential was inhibited markedly after icaritin treatment. Further investigation indicated that icaritin may inhibit epirubicin (EPI)-induced autophagy, and acted synergistically with EPI to suppress the proliferation of BT5637 and T24 cells. These findings suggest that icaritin may prove to be a novel potent therapeutic agent for the treatment of bladder cancer. PMID- 26496798 TI - Cytoarchitecture and cortical connections of the anterior insula and adjacent frontal motor fields in the rhesus monkey. AB - The cytoarchitecture and cortical connections of the ventral motor region are investigated using Nissl, and NeuN staining methods and the fluorescent retrograde tract tracing technique in the rhesus monkey. On the basis of gradual laminar differentiation, it is shown that the ventral motor region stems from the ventral proisocortical area (anterior insula and dorsal Sylvian opercular region). The cytoarchitecture of the ventral motor region is shown to progress in three lines, as we have recently shown for the dorsal motor region. Namely, root (anterior insular and dorsal Sylvian opercular area ProM), belt (ventral premotor cortex) and core (precentral motor cortex) lines. This stepwise architectonic organization is supported by the overall patterns of corticocortical connections. Areas in each line are sequentially interconnected (intralineal connections) and all lines are interconnected (interlinear connections). Moreover, root areas, as well as some of the belt areas of the ventral and dorsal trend are interconnected. The ventral motor region is also connected with the ventral somatosensory areas in a topographic manner. The root and belt areas of ventral motor region are connected with paralimbic, multimodal and prefrontal (outer belt) areas. In contrast, the core area has a comparatively more restricted pattern of corticocortical connections. This architectonic and connectional organization is consistent in part, with the functional organization of the ventral motor region as reported in behavioral and neuroimaging studies which include the mediation of facial expression and emotion, communication, phonic articulation, and language in human. PMID- 26496800 TI - Epigenetic Modifications of Histones in Periodontal Disease. AB - Periodontitis is a chronic infectious disease driven by dysbiosis, an imbalance between commensal bacteria and the host organism. Periodontitis is a leading cause of tooth loss in adults and occurs in about 50% of the US population. In addition to the clinical challenges associated with treating periodontitis, the progression and chronic nature of this disease seriously affect human health. Emerging evidence suggests that periodontitis is associated with mechanisms beyond bacteria-induced protein and tissue degradation. Here, we hypothesize that bacteria are able to induce epigenetic modifications in oral epithelial cells mediated by histone modifications. In this study, we found that dysbiosis in vivo led to epigenetic modifications, including acetylation of histones and downregulation of DNA methyltransferase 1. In addition, in vitro exposure of oral epithelial cells to lipopolysaccharides resulted in histone modifications, activation of transcriptional coactivators, such as p300/CBP, and accumulation of nuclear factor-kappaB (NF-kappaB). Given that oral epithelial cells are the first line of defense for the periodontium against bacteria, we also evaluated whether activation of pathogen recognition receptors induced histone modifications. We found that activation of the Toll-like receptors 1, 2, and 4 and the nucleotide binding oligomerization domain protein 1 induced histone acetylation in oral epithelial cells. Our findings corroborate the emerging concept that epigenetic modifications play a role in the development of periodontitis. PMID- 26496801 TI - Biochemical Characterization of Branched Chain Amino Acids Uptake in Trypanosoma cruzi. AB - Trypanosoma cruzi is the etiological agent of Chagas disease. During its life cycle, it alternates among vertebrate and invertebrate hosts. Metabolic flexibility is a main biochemical characteristic of this parasite, which is able to obtain energy by oxidizing a variety of nutrients that can be transported from the extracellular medium. Moreover, several of these metabolites, more specifically amino acids, have a variety of functions beyond being sources of energy. Branched chain amino acids (BCAA), beyond their role in ATP production, are involved in sterol biosynthesis; for example, leucine is involved as a negative regulator of the parasite differentiation process occurring in the insect midgut. BCAA are essential metabolites in most nonphotosynthetic eukaryotes, including trypanosomes. In view of this, the metabolism of BCAA in T. cruzi depends mainly on their transport into the cell. In this work, we kinetically characterized the BCAA transport in T. cruzi epimastigotes. Our data point to BCAA as being transported by a single saturable transport system able to recognize leucine, isoleucine and valine. In view of this, we used leucine to further characterize this system. The transport increased linearly with temperature from 10 to 45 degrees C, allowing the calculation of an activation energy of 51.30 kJ/mol. Leucine uptake was an active process depending on ATP production and a H(+) gradient, but not on a Na(+) or K(+) gradient at the cytoplasmic membrane level. PMID- 26496803 TI - 3D documentation and visualization of external injury findings by integration of simple photography in CT/MRI data sets (IprojeCT). AB - This study evaluated the feasibility of documenting patterned injury using three dimensions and true colour photography without complex 3D surface documentation methods. This method is based on a generated 3D surface model using radiologic slice images (CT) while the colour information is derived from photographs taken with commercially available cameras. The external patterned injuries were documented in 16 cases using digital photography as well as highly precise photogrammetry-supported 3D structured light scanning. The internal findings of these deceased were recorded using CT and MRI. For registration of the internal with the external data, two different types of radiographic markers were used and compared. The 3D surface model generated from CT slice images was linked with the photographs, and thereby digital true-colour 3D models of the patterned injuries could be created (Image projection onto CT/IprojeCT). In addition, these external models were merged with the models of the somatic interior. We demonstrated that 3D documentation and visualization of external injury findings by integration of digital photography in CT/MRI data sets is suitable for the 3D documentation of individual patterned injuries to a body. Nevertheless, this documentation method is not a substitution for photogrammetry and surface scanning, especially when the entire bodily surface is to be recorded in three dimensions including all external findings, and when precise data is required for comparing highly detailed injury features with the injury-inflicting tool. PMID- 26496802 TI - Inhibition of DYRK1A and GSK3B induces human beta-cell proliferation. AB - Insufficient pancreatic beta-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from beta-cells in diabetic patients, no pharmacological agents have been described that increase beta-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust beta-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B. Aminopyrazine treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces beta-cell proliferation, increases beta-cell mass and insulin content, and improves glycaemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore beta-cell mass, and highlights a tractable pathway for future drug discovery efforts. PMID- 26496804 TI - A patterned abrasion caused by the impact of a cartridge case may simulate an atypical muzzle imprint mark. AB - In contact shots, the muzzle imprint is an informative finding associated with the entrance wound. It typically mirrors the constructional components being in line with the muzzle or just behind. Under special conditions, other patterned skin marks located near a gunshot entrance wound may give the impression to be part of the muzzle imprint. A potential mechanism causing a patterned pressure abrasion in close proximity to the bullet entrance site is demonstrated on the basis of a suicidal shot to the temple. The skin lesion in question appeared as a ring-shaped excoriation with a diameter corresponding to that of the cartridge case. Two hypotheses concerning the causative mechanism were investigated by test shots: - After being ejected, the cartridge case ricocheted inside a confined space (car cabin in the particular case) and secondarily hit the skin near the gunshot entrance wound. - The ejection of the cartridge case failed so that the case became stuck in the ejection port and its mouth contacted the skin when the body collapsed after being hit. PMID- 26496805 TI - Medical Nutrition Therapy for Chronic Kidney Disease in Pregnancy: A Case Report. PMID- 26496806 TI - Ultrasound-Guided Aspiration With and Without Ethanol Sclerotherapy in the Management of Simple Adnexal Cysts: A Single-Center Experience. AB - STUDY OBJECTIVES: To compare the efficacy of ultrasound-guided aspiration versus aspiration with ethanol sclerotherapy in the management of simple adnexal cysts measuring 3 to 10 cm, and to explore the risk factors for recurrence associated with each approach. DESIGN: A prospective follow-up of patients after cyst aspiration with and without ethanol sclerotherapy in simple adnexal cysts in a single-center trial (Canadian Task Force classification II-1). SETTING: Bellvitge Teaching Hospital, Barcelona, Spain. PATIENTS: Cyst aspiration and ethanol sclerotherapy were performed in 66 and 75 patients, respectively, between 2002 and 2014. Women enrolled before March 2009 underwent simple aspiration (group 1), and those enrolled after March 2009 underwent ethanol sclerotherapy (group 2). INTERVENTIONS: Ultrasound-guided fine-needle aspiration with and without ethanol sclerotherapy. MEASUREMENTS AND MAIN RESULTS: Potential risk factors for recurrence-age, menopausal status, symptoms, cyst diameter, laterality, aspirated volume, simple US-guided aspiration or alcohol sclerotherapy, and complications were analyzed by logistic regression. The recurrence rates were analyzed by the Kaplan-Meier and Mantel-Haenszel methods. The overall recurrence rates were 72.7% (48 of 66) in group 1 and 22.7% (17 of 75) in group 2 (p < .0001). Risk factors significantly associated with recurrence were simple aspiration without ethanol sclerotherapy (odds ratio [OR], 19.7; 95% confidence interval [CI], 6.756 57.714), postmenopausal status (OR, 9.3; 95% CI, 1.720-50.956), and cyst size (OR, 1.04; 95% CI, 1.005-1.093). CONCLUSION: Based on the lower recurrence rate, ethanol sclerotherapy was more efficacious than simple aspiration in the management of simple adnexal cysts measuring <10 cm. PMID- 26496807 TI - Discussion. PMID- 26496808 TI - Early and late outcomes of repaired acute DeBakey type I aortic dissection after graft replacement. AB - OBJECTIVE: The present study aimed to determine the impact of the extent of graft replacement on early and late outcomes in acute DeBakey type I aortic dissection. METHODS: Between October 1999 and July 2014, 197 consecutive patients were surgically treated for acute DeBakey type I aortic dissection. The extent of graft replacement (hemiarch, partial, or total arch replacement) was mainly determined by the location of the primary entry. Early and late results were compared in patients after total arch replacement (n = 88) and combined hemiarch and partial arch replacement: non-total arch replacement (n = 109). RESULTS: The in-hospital mortality rates of the total arch replacement and non-total arch replacement groups were 10.2% and 14.7%, respectively (P = .47). Multivariate analysis revealed preoperative cardiopulmonary resuscitation and visceral organ malperfusion as significant risk factors for in-hospital mortality, but not total arch replacement. During a mean follow-up period of 60 +/- 48 months, the 5-year survivals in the total arch replacement and non-total arch replacement groups were 88.6% +/- 4.2% and 83.8% +/- 4.4%, respectively (P = .54). Rates of distal aortic events (defined as freedom from surgery for distal aorta dilation or distal arch diameter expanding to 50 mm) at 5 years were significantly better in the total arch replacement group than in the non-total arch replacement group (94.9% +/- 3.5% vs 83.6% +/- 4.9%, P = .01). CONCLUSIONS: The operative mortality of patients with acute DeBakey type I aortic dissection treated by total arch replacement was acceptable with good long-term survival after both total arch replacement and non-total arch replacement. The frequency of distal aortic events might be reduced in patients after total arch replacement compared with non-total arch replacement. PMID- 26496809 TI - Long-term behavior of aortic intramural hematomas and penetrating ulcers. AB - OBJECTIVE: For intramural hematoma and penetrating atherosclerotic ulcer, long term behavior and treatment are controversial. This study evaluates the long-term behavior of intramural hematoma and penetrating atherosclerotic ulcer, including radiologic follow-up and survival analysis. METHODS: Between 1995 and 2014, 108 patients (mean age, 70.8 +/- 10 years; 56% female) presented with intramural hematoma or penetrating atherosclerotic ulcer to Yale-New Haven Hospital (New Haven, Conn). We reviewed the medical records, radiology, and online mortality databases. RESULTS: Ten of 55 patients (18%) with intramural hematoma and 17 of 53 patients (32%) with penetrating atherosclerotic ulcer had rupture state symptoms on admission, both greater than type A (8%) or type B dissection (4%) (P < .001). No branch vascular occlusion occurred. For patients with intramural hematoma with follow-up imaging, 8 of 14 (57%) worsened (mean follow-up, 9.4 months) and 6 (43%) underwent late surgery. For patients with penetrating atherosclerotic ulcer with follow-up imaging, 6 of 20 (30%) worsened and underwent late surgery, and 11 (55%) showed no change (mean follow-up, 34.3 months). Overall survivals were 77%, 70%, 58%, and 33% at 1, 3, 5, and 10 years, respectively. No operative deaths occurred for patients with nonrupture state. Patients with penetrating atherosclerotic ulcer with initial surgical treatment had better long-term survival than patients treated medically (P = .037). In the intramural hematoma group, no such difference was observed (P = .10). CONCLUSIONS: At presentation, the incidence of early rupture of intramural hematoma and penetrating atherosclerotic ulcer was higher than for typical dissection. For branch vessels, intramural hematoma never occludes branch arteries. On imaging follow-up, patients with intramural hematoma and penetrating atherosclerotic ulcer rarely improved, with late surgery commonly needed. Better survival was observed for the initial surgical management of patients with penetrating atherosclerotic ulcer compared with initial medical management. PMID- 26496810 TI - Pseudoaneurysm at the origin of the left subclavian artery following type A interrupted aortic arch repair in adulthood, London, United Kingdom. PMID- 26496811 TI - Childhood obesity: a (re) programming disease? AB - The aim of our article was to review the current literature on the effects of metabolic (re) programming on childhood obesity. PubMed/MEDLINE was the data source used to track the studies. Descriptors applied: children obesity, epigenetic, metabolic programming, exercise and nutrition. The focus was to analyze and discuss the international findings on the theme. The gathering of the papers was performed between June and August 2014. The search of articles with the descriptors used found 33.054 studies. In all, 5.709 studies were selected by crossing chosen keywords. Among these, after careful reading of the titles, 712 papers were considered potential as references. After applying inclusion/exclusion criteria, 50 studies were selected from 132 eligible abstracts. Most studies linked the development and treatment of obesity from epigenetically stimulated metabolic programming during the early stages of pregnancy and life. This review provides theoretical basis to the understanding that the programmed development of childhood obesity may be linked to early exposure to environmental factors, such as (nutrition and regular practice of exercise) and stimulus can epigenetically alter the modulation of the obesogenic metabolic behavior during pregnancy and the developmental stages of children and/or postpone the pathophysiologic disease stage to adulthood. PMID- 26496813 TI - Total synthesis and preliminary SAR study of (+/-)-merochlorins A and B. AB - A modular synthesis of merochlorins A and B, two naturally occurring antibiotics, has been achieved concisely from readily available building blocks in 4-6 steps. The key steps include the bio-inspired tandem phenol oxidative dearomatization/[5 + 2] and [3 + 2] cycloadditions to construct the tricyclic cores of the targets, and the intermolecular Diels-Alder reaction followed by dehydrogenative aromatization to assemble the remaining aromatic units. The antibacterial activities of merochlorins A, B and some advanced synthetic intermediates were also evaluated, which provided valuable information on the structure-activity relationship (SAR) of this class of new antibiotics. PMID- 26496814 TI - Palladium-catalyzed Heck-type reaction of oximes with allylic alcohols: synthesis of pyridines and azafluorenones. AB - We describe herein a palladium-catalyzed Heck-type reaction of O-acetyl ketoximes and allylic alcohols to synthesise pyridines. This protocol allows the robust synthesis of pyridines and azafluorenones in good to excellent yields with tolerance of various functional groups under mild conditions. The reaction is supposed to go through an oxidative addition of oximes to palladium(0) complexes, generating an alkylideneamino-palladium(II) species, which is utilized as a key intermediate to capture the nonbiased alkenes for carbon-carbon bond formation. PMID- 26496815 TI - Genetically-defined ovarian cancer mouse models. AB - Epithelial ovarian cancer (EOC), the deadliest of gynaecological cancers, is a disease that remains difficult to detect early and treat efficiently. A significant challenge for researchers in the field is that the aetiology of EOC and the molecular pathways important for its development are poorly understood. Moreover, precursor lesions have not been readily identifiable, making the mechanisms of EOC progression difficult to delineate. In order to address these issues, several genetically-defined ovarian mouse models have been generated in the past 15 years. However, because of the recent suggestion that most EOCs may not originate from the ovarian surface 'epithelium', but from other tissues of the female genital tract, some models may need to be re-evaluated within this new paradigm. In this review, we examine several genetically-defined EOC models and discuss how the new paradigm may explain some of the features of these models. A better understanding of the strengths and limitations of the current EOC mouse models will undoubtedly allow us to utilize these tools to better understand the biology of the disease and develop new approaches for EOC prevention, detection, and treatment. PMID- 26496816 TI - Effects of Wenyangbushen formula on the expression of VEGF, OPG, RANK and RANKL in rabbits with steroid-induced femoral head avascular necrosis. AB - The present study aimed to investigate the effects of Wenyangbushen formula on the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), osteoprotegerin (OPG), receptor activator of nuclear factor (NF) kappabeta ligand (RANK), and RANK ligand (RANKL) in a rabbit model of steroid induced avascular necrosis of the femoral head (SANFH). The present study also aimed to examine the potential mechanism underlying the effect of this formula on the treatment of SANFH. A total of 136 New Zealand rabbits were randomly divided into five groups: Normal group, model group, and three groups treated with the traditional Chinese medicine (TCM), Wenyangbushen decoction, at a low, moderate and high dose, respectively. The normal group and positive control group were intragastrically administered with saline. The TCM groups were treated with Wenyangbushen decoction at the indicated dosage. Following treatment for 8 weeks, the mRNA and protein expression levels of VEGF, OPG, RANK and RANKL in the femoral head tissues were determined using reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. The data revealed that Wenyangbushen decoction effectively promoted the growth of bone cells, osteoblasts and chondrocytes, and prevented cell apoptosis in the SANFH. The mRNA and protein expression levels of OPG and VEGF were increased, while the levels of RANK and RANKL were reduced in the necrotic tissue of the model group, compared with those in the normal rabbits. Wenyangbushen treatment prevented these changes, manifested by an upregulation in the expression levels of VEGF and OPG, and downregulation in the expression levels of RANK and RANKL in a dose dependent manner. It was concluded that treatment with Wenyangbushen formula alleviated necrosis of the femoral head induced by steroids. It was observed to promote bone cell, osteoblast and chondrocyte growth, as well as prevent cell apoptosis. In addition, it upregulated the expression levels of OPG and VEGF, and inhibited the expression levels of RANK and RANKL. These results suggest the potential use of Wenyangbushen formula as a possible approach for the effective treatment of SANFH. PMID- 26496818 TI - Retraction: Ultrastructural analysis between fetal and adult wound healing process of marsupial opossum skin. PMID- 26496817 TI - BAG2 expression dictates a functional intracellular switch between the p38 dependent effects of nicotine on tau phosphorylation levels via the alpha7 nicotinic receptor. AB - The histopathological hallmarks present in Alzheimer's disease (AD) brain are plaques of Abeta peptide, neurofibrillary tangles of hyperphosphorylated tau protein, and a reduction in nicotinic acetylcholine receptor (nAChR) levels. The role of nAChRs in AD is particularly controversial. Tau protein function is regulated by phosphorylation, and its hyperphosphorylated forms are significantly more abundant in AD brain. Little is known about the relationship between nAChR and phospho-tau degradation machinery. Activation of nAChRs has been reported to increase and decrease tau phosphorylation levels, and the mechanisms responsible for this discrepancy are not presently understood. The co-chaperone BAG2 is capable of regulating phospho-tau levels via protein degradation. In SH-SY5Y cell line and rat primary hippocampal cell culture low endogenous BAG2 levels constitute an intracellular environment conducive to nicotine-induced accumulation of phosphorylated tau protein. Further, nicotine treatment inhibited endogenous expression of BAG2, resulting in increased levels of phosphorylated tau indistinguishable from those induced by BAG2 knockdown. Conversely, overexpression of BAG2 is conducive to a nicotine-induced reduction in cellular levels of phosphorylated tau protein. In both cases the effect of nicotine was p38MAPK-dependent, while the alpha7 antagonist MLA was synthetic to nicotine treatment, either increasing levels of phospho-Tau in the absence of BAG2, or further decreasing the levels of phospho-Tau in the presence of BAG2. Taken together, these findings reconcile the apparently contradictory effects of nicotine on tau phosphorylation by suggesting a role for BAG2 as an important regulator of p38-dependent tau kinase activity and phospho-tau degradation in response to nicotinic receptor stimulation. Thus, we report that BAG2 expression dictates a functional intracellular switch between the p38-dependent functions of nicotine on tau phosphorylation levels via the alpha7 nicotinic receptor. PMID- 26496819 TI - Safety evaluation of traces of nickel and chrome in cosmetics: The case of Dead Sea mud. AB - BACKGROUND: Metal impurities such as nickel and chrome are present in natural ingredients-containing cosmetic products. These traces are unavoidable due to the ubiquitous nature of these elements. Dead Sea mud is a popular natural ingredient of cosmetic products in which nickel and chrome residues are likely to occur. OBJECTIVE: To analyze the potential systemic and local toxicity of Dead Sea mud taking into consideration Dead Sea muds' natural content of nickel and chrome. METHODS: The following endpoints were evaluated: (Regulation No. 1223/20, 21/12/2009) systemic and (SCCS's Notes of Guidance) local toxicity of topical application of Dead Sea mud; health reports during the last five years of commercial marketing of Dead Sea mud. RESULTS AND CONCLUSIONS: Following exposure to Dead Sea mud, MoS (margin of safety) calculations for nickel and chrome indicate no toxicological concern for systemic toxicity. Skin sensitization is also not to be expected by exposure of normal healthy skin to Dead Sea mud. Topical application, however, is not recommended for already nickel-or chrome sensitized persons. As risk assessment of impurities present in cosmetics may be a difficult exercise, the case of Dead Sea mud is taken here as an example of a natural material that may contain traces of unavoidable metals. PMID- 26496821 TI - Recreational nitrous oxide use: Prevalence and risks. AB - Nitrous oxide (N2O; laughing gas) is clinically used as a safe anesthetic (dentistry, ambulance, childbirth) and appreciated for its anti-anxiety effect. Since five years, recreational use of N2O is rapidly increasing especially in the dance and festival scene. In the UK, N2O is the second most popular recreational drug after cannabis. In most countries, nitrous oxide is a legal drug that is widely available and cheap. Last month prevalence of use among clubbers and ravers ranges between 40 and almost 80 percent. Following one inhalation, mostly from a balloon, a euphoric, pleasant, joyful, empathogenic and sometimes hallucinogenic effect is rapidly induced (within 10 s) and disappears within some minutes. Recreational N2O use is generally moderate with most users taking less than 10 balloons of N2O per episode and about 80% of the users having less than 10 episodes per year. Side effects of N2O include transient dizziness, dissociation, disorientation, loss of balance, impaired memory and cognition, and weakness in the legs. When intoxicated accidents like tripping and falling may occur. Some fatal accidents have been reported due to due to asphyxia (hypoxia). Heavy or sustained use of N2O inactivates vitamin B12, resulting in a functional vitamin B12 deficiency and initially causing numbness in fingers, which may further progress to peripheral neuropathy and megaloblastic anemia. N2O use does not seem to result in dependence. Considering the generally modest use of N2O and its relative safety, it is not necessary to take legal measures. However, (potential) users should be informed about the risk of vitamin B12-deficiency related neurological and hematological effects associated with heavy use. PMID- 26496820 TI - Drinking water toxicity study of the environmental contaminant--Bromate. AB - Bromate is a byproduct of water disinfection that is produced when waters contain bromide treated with ozone. To investigate the level of the toxicity of bromate and find the most sensitive indicators in a short time, a series of toxicological assessments were conducted including the acute toxicity, cumulative toxicity, genetic toxicity and subacute toxicity of bromate (using Potassium Bromate to represent bromate). The LD50 of orally administered Potassium Bromate was 215 mg/kg in Wistar rats and 464 mg/kg in ICR mice. The cumulative toxicity of Potassium Bromate was not obvious. The Ames test, mouse bone marrow cell micronucleus test and mouse sperm abnormality test did not indicate mutagenicity. The results of the subacute study did not exhibit significant differences in most of the parameters, except the white blood cell count, which was significantly decreased in male rats. In addition, Potassium Bromate influenced the albumin, creatinine, total cholesterol, triglycerides and glucose levels in male rats to various extents. A thorough analysis of the above tests clearly demonstrates that bromate has toxicity, not obvious cumulative toxicity and the white blood cell count can be used as an indicator to reflect the toxicity of bromate and investigate bromate's toxic mechanism. PMID- 26496822 TI - Ti implants with nanostructured and HA-coated surfaces for improved osseointegration. AB - This study was aimed at comparing the osseointegration of titanium (Ti)-based Kuntscher nails (K-nails) and plates with modified nanostructured and hydroxyapatite-coated surfaces in a rat femur model. Material surfaces were first modified via a simple anodization protocol in which the materials were treated in hydrogen fluoride (1% w/w) at 20 V. This modification resulted in tubular titanium oxide nanostructures of 40-65 nm in diameter. Then, hydroxyapatite deposited layers, formed of particles (1-5) MUm, were produced via incubation in a simulated body fluid, followed by annealing at 500 degrees C. Both surface modifications significantly improved cell proliferation and alkaline phosphatase (ALP) activity as compared to the control (non-modified Ti implants). The controls and modified nails and plates were implanted in the femur of 21 male Sprague-Dawley rats. The implants, with surrounding tissues, were removed after 10 weeks, and then mechanical tests (torque and pull-out) were performed, which showed that the modified K-nails exhibited significantly better osseointegration than the controls. Histologic examinations of the explants containing plates showed similar results, and the modified plates exhibited significantly better osseointegration than the controls. Surface nanostructuring of commercially available titanium-based implants by a very simple method - anodization - seems to be a viable method for increasing osseointegration without the use of bioactive surface coatings such as hydroxyapatite. PMID- 26496823 TI - Gas Evolution in Operating Lithium-Ion Batteries Studied In Situ by Neutron Imaging. AB - Gas generation as a result of electrolyte decomposition is one of the major issues of high-performance rechargeable batteries. Here, we report the direct observation of gassing in operating lithium-ion batteries using neutron imaging. This technique can be used to obtain qualitative as well as quantitative information by applying a new analysis approach. Special emphasis is placed on high voltage LiNi0.5Mn1.5O4/graphite pouch cells. Continuous gassing due to oxidation and reduction of electrolyte solvents is observed. To separate gas evolution reactions occurring on the anode from those associated with the cathode interface and to gain more insight into the gassing behavior of LiNi0.5Mn1.5O4/graphite cells, neutron experiments were also conducted systematically on other cathode/anode combinations, including LiFePO4/graphite, LiNi0.5Mn1.5O4/Li4Ti5O12 and LiFePO4/Li4Ti5O12. In addition, the data were supported by gas pressure measurements. The results suggest that metal dissolution in the electrolyte and decomposition products resulting from the high potentials adversely affect the gas generation, particularly in the first charge cycle (i.e., during graphite solid-electrolyte interface layer formation). PMID- 26496824 TI - Enantioselective NHC-Catalyzed Redox [2+2] Cycloadditions with Perfluoroketones: A Route to Fluorinated Oxetanes. AB - The N-heterocyclic carbene (NHC) catalyzed redox formal [2+2] cycloaddition between alpha-aroyloxyaldehydes and perfluoroketones, followed by ring-opening in situ delivers a variety of perfluorinated beta-hydroxycarbonyl compounds in good yield, and excellent diastereo- and enantioselectivity. Through a reductive work up and subsequent cyclization, this protocol offers access to highly substituted fluorinated oxetanes in two steps and in high ee. PMID- 26496825 TI - Nacre extract restores the mineralization capacity of subchondral osteoarthritis osteoblasts. AB - Osteoarthritis (OA) is the most common cause of joint chronic pain and involves the entire joints. Subchondral osteoarthritic osteoblasts present a mineralization defect and, to date, only a few molecules (Vitamin D3 and Bone Morphogenetic Protein2) could improve the mineralization potential of this cell type. In this context, we have tested for the first time the effect of nacre extract on the mineralization capacity of osteoblasts from OA patients. Nacre extract is known to contain osteogenic molecules which have demonstrated their activities notably on the MC3T3 pre-osteoblastic cell line. For this goal, molecules were extracted from nacre (ESM, Ethanol Soluble Matrix) and tested on osteoblasts of the subchondral bone from OA patients undergoing total knee replacement and on MC3T3 cells for comparison. We chose to investigate the mineralization with Alizarin Red staining and with the study of extracellular matrix (ECM) structure and composition. In a complementary way the structure of the ECM secreted during the mineralization phase was investigated using second harmonic generation (SHG). Nacre extract was able to induce the early presence (after 7 days) of precipitated calcium in cells. Raman spectroscopy and electron microscopy showed the presence of nanograins of an early crystalline form of calcium phosphate in OA osteoblasts ECM and hydroxyapatite in MC3T3 ECM. SHG collagen fibers signal was present in both cell types but lower for OA osteoblasts. In conclusion, nacre extract was able to rapidly restore the mineralization capacity of osteoarthritis osteoblasts, therefore confirming the potential of nacre as a source of osteogenic compounds. PMID- 26496826 TI - A comprehensive analysis of membrane and morphology of erythrocytes from patients with glucose-6-phosphate dehydrogenase deficiency. AB - Acute hemolytic anemia could be triggered by oxidative stress in the patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, the underlying hemolytic mechanism is unknown. To make clear the hemolytic mechanisms, a systematic study on membrane ultrastructure had been undertaken. A comprehensive method was used including atomic force microscopy, scanning electron microscopy, flow cytometer and fluorescence microscopy to analyze the membrane ultrastructure, externalized phosphatidylserine (PS), intracellular Ca(2+) concentration, morphology and the distributions of band 3 protein in G6PD deficient red blood cells (RBCs) after tert-butyl-hydroperoxide (t-BHP) oxidation. The results showed that erythrocyte shrinkage, annexin-V binding to externalized PS on the membrane of early-stage apoptotic cells, the increased membrane roughness and intracellular Ca(2+) concentration, as well as the change of distributions of band 3 protein in RBCs. Compared with the control RBCs, as the concentration of t-BHP up to 0.1mM, the membrane roughness of G6PD deficient RBCs showed significant difference (p<0.05) and as the concentration of t-BHP up to 0.3mM, externalized PS showed significant difference (p<0.05). Furthermore, the population types of RBCs showed dramatic difference between control groups and G6PD deficient groups. Oxidative stress induced more serious erythrocyte apoptosis and resulted in increased roughness of erythrocyte membrane and abnormal distributed band 3 protein in G6PD deficient RBCs. Echinocytes are the predominant abnormal erythrocyte shape occurring in the peripheral blood from patients with G6PD deficiency, which may shorten the RBCs lifespan. The results in the present study will give an increased understanding for the hemolytic mechanism of G6PD deficiency. PMID- 26496828 TI - Diabetes prevention and continuing health-care reform in China. PMID- 26496827 TI - Treatment with harmine ameliorates functional impairment and neuronal death following traumatic brain injury. AB - Traumatic brain injury (TBI) is a leading cause of mortality in young individuals, and results in motor and cognitive deficiency. Excitotoxicity is an important process during neuronal cell death, which is caused by excessive release of glutamate following TBI. Astrocytic glutamate transporters have a predominant role in maintaining extracellular glutamate concentrations below excitotoxic levels, and glutamate transporter 1 (GLT-1) may account for >90% of glutamate uptake in the brain. The beta-carboline alkaloid harmine has been demonstrated to exert neuroprotective actions in vivo, and the beneficial effects were specifically due to elevation of GLT-1. However, whether harmine provides neuroprotection following TBI remains to be elucidated. The present study performed intraperitoneal harmine injections in rats (30 mg/kg per day for up to 5 days), in order to investigate whether harmine treatment attenuates brain edema and improves functional recovery in a rat model of TBI. The neuronal survival ratio and the protein expression of apoptosis-associated caspase 3 were also assessed in the hippocampus of the rat brain. Furthermore, the expression levels of GLT-1 and inflammatory cytokines were detected, in order to determine the underlying mechanisms. The results of the present study demonstrated that administration of harmine significantly attenuated cerebral edema, and improved learning and memory ability. In addition, harmine significantly increased the protein expression of GLT-1, and markedly attenuated the expression levels of interleukin-1beta and tumor necrosis factor-alpha, thereby attenuating apoptotic neuronal death in the hippocampus. These results provided in vivo evidence that harmine may exert neuroprotective effects by synergistically reducing excitotoxicity and inflammation following TBI. PMID- 26496829 TI - Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles. AB - Over the past fifteen years, focused ultrasound coupled with intravenously administered microbubbles (FUS) has been proven an effective, non-invasive technique to open the blood-brain barrier (BBB) in vivo. Here we show that FUS can safely and effectively open the BBB at the basal ganglia and thalamus in alert non-human primates (NHP) while they perform a behavioral task. The BBB was successfully opened in 89% of cases at the targeted brain regions of alert NHP with an average volume of opening 28% larger than prior anesthetized FUS procedures. Safety (lack of edema or microhemorrhage) of FUS was also improved during alert compared to anesthetized procedures. No physiological effects (change in heart rate, motor evoked potentials) were observed during any of the procedures. Furthermore, the application of FUS did not disrupt reaching behavior, but in fact improved performance by decreasing reaction times by 23 ms, and significantly decreasing touch error by 0.76 mm on average. PMID- 26496830 TI - What is the best design for early childhood interventions? PMID- 26496831 TI - The role of EVI-1 in normal hematopoiesis and myeloid malignancies (Review). AB - Ecotropic virus integration site-1 (EVI-1) gene, locus on chromosome 3 (3q26.2) in the human genome, was first found in the AKXD strain of mice, in a model of retrovirus-induced acute myeloid leukemia (AML) established twenty years ago. Since then, EVI-1 was regarded as one of the most invasive proto-oncogenes in human leukemia. EVI-1 can encode a unique zinc-finger protein of 145 kDa that can bind with DNA, and its overexpression was closely related to human hemopoietic diseases. Furthermore, accumulating research indicates that EVI-1 is involved in the differentiation, apoptosis and proliferation of leukemia cells. The present review focuses on the biochemical properties of EVI-1 which plays a role in myeloid malignancies. PMID- 26496832 TI - Trends and outcomes in the utilization of laparoscopic appendectomies in a low income population in Taiwan from 2003 to 2011. AB - BACKGROUND: Numerous epidemiological studies have compared outcomes between laparoscopic appendectomies (LA) and open appendectomies (OA); however, few studies have assessed the efficacy of LA specifically in a low-income population (LIP). METHODS: We analyzed the trends in the utilization and outcomes of LA versus OA in an LIP in Taiwan using data from the National Health Insurance (NHI) Research Database. RESULTS: Steady temporal growth trends were observed for the patients who underwent LA in both the LIP and general population (GP); however, in each study year, the proportion of LIP patients who underwent LA was lower than the proportion of GP patients who underwent the procedure. The LIP patients were more susceptible to payment policies than the GP patients; thus, more attention should be paid to vulnerable patient populations when formulating and revising NHI payment policies. Compared with OAs, LAs were associated with a slightly higher rate of routine patient discharges and a lower rate of in hospital complications (1.48% vs. 3.76%, p < 0.05). The rate of readmission for complications was lower in patients after LA than in patients after OA (1.64% vs. 3.89%, p < 0.05). The overall case-fatality rate of LIP patients who underwent LA was lower than that of those who underwent OA. LA was correlated with a significantly shorter length of hospital stay (LOS) compared with OA (3.80 +/- 0.08 vs. 5.51 +/- 0.11, p < 0.05). The average hospital cost for LA was slightly less than that for OA (1178 +/- 13 vs. 1191 +/- 19 USD, p < 0.05). A higher percentage of patients who underwent OA required an LOS longer than 14 days compared to patients who underwent LA (7.73% vs. 1.97%, p < 0.05). Regarding hospital costs and LOS, LA showed significant advantages over OA in the subpopulations of male patients, patients 45 years old and older, patients with Charlson Comorbidity Index (CCI) scores of two or more, and patients with complicated cases of appendicitis. CONCLUSION: The LIP patients benefited more from the LA approach than the OA approach in the treatment of appendicitis, especially regarding LOS, in-hospital complications, in-hospital mortality, and routine discharge rates. PMID- 26496833 TI - Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress. AB - BACKGROUND: Although some molecularly targeted drugs for colorectal cancer are used clinically and contribute to a better prognosis, the current median survival of advanced colorectal cancer patients is not sufficient. Autophagy, a basic cell survival mechanism mediated by recycling of cellular amino acids, plays an important role in cancer. Recently, autophagy has been highlighted as a promising new molecular target. The unfolded protein response (UPR) reportedly act in complementary fashion with autophagy in intestinal homeostasis. However, the roles of UPR in colon cancer under autophagic inhibition remain to be elucidated. We aim to clarify the inhibitory effect of autophagy on colon cancer. METHODS: We crossed K19 (CreERT) and Atg5 (flox/flox) mice to generate Atg5 (flox/flox)/K19 (CreERT) mice. Atg5 (flox/flox)/K19 (CreERT) mice were first treated with azoxymethane/dextran sodium sulfate and then injected with tamoxifen to inhibit autophagy in CK19-positive epithelial cells. To examine the anti-cancer mechanisms of autophagic inhibition, we used colon cancer cell lines harboring different p53 gene statuses, as well as small interfering RNAs (siRNAs) targeting Atg5 and immunoglobulin heavy-chain binding protein (BiP), a chaperone to aid folding of unfolded proteins. RESULTS: Colon tumors in Atg5 (flox/flox)/K19 (CreERT) mice showed loss of autophagic activity and decreased tumor size (the total tumor diameter was 28.1 mm in the control and 20.7 mm in Atg5 (flox/flox)/K19 (CreERT) mice, p = 0.036). We found that p53 and UPR/endoplasmic reticulum (ER) stress-related proteins, such as cleaved caspase 3, and CAAT/enhancer-binding protein homologous protein, are up-regulated in colon tumors of Atg5 (flox/flox)/K19 (CreERT) mice. Although Atg5 and BiP silencing, respectively, increased apoptosis in p53 wild type cells, Atg5 silencing alone did not show the same effect on apoptosis in p53 mutant cells. However, co transfection of Atg5 and BiP siRNAs led to increased apoptosis in p53 mutant cells. CONCLUSIONS: Blocking autophagy has potential in the treatment of colon cancer by inducing apoptosis via p53 and ER stress, and suppressing the UPR pathway is a valid strategy to overcome resistance to autophagic inhibition. PMID- 26496835 TI - Solving the Controversy on the Wetting Transparency of Graphene. AB - Since its discovery, the wetting transparency of graphene, the transmission of the substrate wetting property over graphene coating, has gained significant attention due to its versatility for potential applications. Yet, there have been debates on the interpretation and validity of the wetting transparency. Here, we present a theory taking two previously disregarded factors into account and elucidate the origin of the partial wetting transparency. We show that the liquid bulk modulus is crucial to accurately calculate the van der Waals interactions between the liquid and the surface, and that various wetting states on rough surfaces must be considered to understand a wide range of contact angle measurements that cannot be fitted with a theory considering the flat surface. In addition, we reveal that the wetting characteristic of the substrate almost vanishes when covered by any coating as thick as graphene double layers. Our findings reveal a more complete picture of the wetting transparency of graphene as well as other atomically thin coatings, and can be applied to study various surface engineering problems requiring wettability-tuning. PMID- 26496834 TI - Nitrogen fluxes at the root-soil interface show a mismatch of nitrogen fertilizer supply and sugarcane root uptake capacity. AB - Globally only ~50% of applied nitrogen (N) fertilizer is captured by crops, and the remainder can cause pollution via runoff and gaseous emissions. Synchronizing soil N supply and crop demand will address this problem, however current soil analysis methods provide little insight into delivery and acquisition of N forms by roots. We used microdialysis, a novel technique for in situ quantification of soil nutrient fluxes, to measure N fluxes in sugarcane cropping soils receiving different fertilizer regimes, and compare these with N uptake capacities of sugarcane roots. We show that in fertilized sugarcane soils, fluxes of inorganic N exceed the uptake capacities of sugarcane roots by several orders of magnitude. Contrary, fluxes of organic N closely matched roots' uptake capacity. These results indicate root uptake capacity constrains plant acquisition of inorganic N. This mismatch between soil N supply and root N uptake capacity is a likely key driver for low N efficiency in the studied crop system. Our results also suggest that (i) the relative contribution of inorganic N for plant nutrition may be overestimated when relying on soil extracts as indicators for root-available N, and (ii) organic N may contribute more to crop N supply than is currently assumed. PMID- 26496836 TI - Erratum to: Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression. AB - The original version of this article [1] unfortunately contained a mistake. The author list contained a spelling error for the author Hannah V. McCue. The original article has been corrected for this error. The corrected author list is given below:Xi Chen, Hannah V. McCue, Shi Quan Wong, Sudhanva S. Kashyap, Brian C. Kraemer, Jeff W. Barclay, Robert D. Burgoyne and Alan Morgan PMID- 26496837 TI - Time-dependent effectiveness of the intracanal medicaments used for pulp revascularization on the dislocation resistance of MTA. AB - BACKGROUND: The aim of the present study was to evaluate the time-dependent effectiveness of the intracanal medicaments used in pulp revascularization on the dislocation resistance of mineral trioxide aggregate (MTA). METHODS: One hundred ninety-two extracted human maxillary incisor teeth were sectioned apically 12 mm below and coronally 2 mm above the cemento-enamel junction. Roots were enlarged to size 40 (Protaper F4). Next, Peeso reamers from #1 to #5 were used sequentially. Sodium hypochlorite (2.5 %), EDTA (17 %), and distilled water were used in final irrigation. The specimens were randomly divided into four groups (n = 48): Group 1, in which triple antibiotic paste (TAP) (ciprofloxacin + metronidazole + minocycline) was prepared and delivered into the canals using a lentulo spiral; Group 2, in which double antibiotic paste (DAP) (ciprofloxacin + metronidazole) was placed into the canals; Group 3, in which calcium hydroxide paste (CH) (calcium hydroxide + distilled water) was introduced into the roots; and Group 4 (control), in which no medicament was applied into the root canals. Then, the samples were kept in saline solution for 2, 4, and 12 weeks, after which time 16 roots were selected randomly from each group, representing the samples of each time point. After removal of the medicaments, MTA was placed into the coronal third of the roots, and the samples were incubated for 7 days. A push out test was used to measure the dislocation resistance (DR) of MTA. The data were analyzed using a two-way ANOVA followed by Tukey's pairwise comparisons (p = 0.05). RESULTS: The time factor displayed a significant effect on the DR of MTA (p < 0.05). All medicaments resulted in significantly smaller DR values after 12 weeks compared to after 1 week (p < 0.05). A significant unfavorable effect of TAP and DAP was observed as early as 2 weeks after the application, while 2 and 4 weeks after the application of CH there was no effect on the DR of MTA. No significant differences were found between the time points in the control group (p > 0.05). CONCLUSION: The type and the intracanal duration of medicaments used for pulp revascularization should be chosen carefully to provide maximum antimicrobial effect while creating a favorable environment both for stem cell attachment and MTA adhesion. PMID- 26496838 TI - Evaluation of hydrocyclone and post-treatment technologies for remediation of contaminated dredged sediments. AB - There are many disposal and treatment methods for contaminated dredged sediments, depending on their properties. In this study, treatment methods for the remediation of dredged sediments as well as the reduction of pore water generated from dredged sediments were optimized. The efficiency of separation using hydrocyclone as the pre-treatment increased with greater inflow velocity of hydrocyclone, deeper insertion of the vortex finder, and smaller hydrocyclone diameter. In the post-treatment of hydrocyclone overflow, the chemical coagulation and membrane filtration methods had high efficiency with regard to the removal of solid and organic compounds, but the former was less feasible, due to its excessive operation and sludge disposal costs. The membrane filtration was easily applicable in the field, based on its convenience of installation and lower cost of operation despite low removal efficiency of trace organic contaminants. PMID- 26496839 TI - Effects of elemental sulphur on heavy metal uptake by plants growing on municipal sewage sludge. AB - In this study experiment was carried out to determine the phytoextraction potential of six plant species (Conium maculatum, Brassica oleraceae var. oleraceae, Brassica juncea, Datura stramonium, Pelargonium hortorum and Conyza canadensis) grown in a sewage sludge medium amended with metal uptake promoters. The solubility of Cu, Cd and Pb was significantly increased with the application of elemental S due to decrease of pH. Faecal coliform number was markedly decreased by addition of elemental sulphur. The extraction of Cu, Cr and Pb from sewage sludge by using B. juncea plant was observed as 65%, 65% and 54% respectively that is statistically similar to EDTA as sulphur. The bioaccumulation factors were found higher (>1) in the plants tested for Cu and Pb like B. juncea. Translocation index (TI) calculated values for Cd and Pb were greater than one (>1) in both C. maculatum and B. oleraceae var. oleraceae. The results cleared that the amendment of sludge with elemental sulphur showed potential to solubilize heavy metals in phytoremediation as much as EDTA. PMID- 26496840 TI - Application of TOPSIS and VIKOR improved versions in a multi criteria decision analysis to develop an optimized municipal solid waste management model. AB - Selecting a suitable Multi Criteria Decision Making (MCDM) method is a crucial stage to establish a Solid Waste Management (SWM) system. Main objective of the current study is to demonstrate and evaluate a proposed method using Multiple Criteria Decision Making methods (MCDM). An improved version of Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) applied to obtain the best municipal solid waste management method by comparing and ranking the scenarios. Applying this method in order to rank treatment methods is introduced as one contribution of the study. Besides, Viekriterijumsko Kompromisno Rangiranje (VIKOR) compromise solution method applied for sensitivity analyses. The proposed method can assist urban decision makers in prioritizing and selecting an optimized Municipal Solid Waste (MSW) treatment system. Besides, a logical and systematic scientific method was proposed to guide an appropriate decision-making. A modified TOPSIS methodology as a superior to existing methods for first time was applied for MSW problems. Applying this method in order to rank treatment methods is introduced as one contribution of the study. Next, 11 scenarios of MSW treatment methods are defined and compared environmentally and economically based on the waste management conditions. Results show that integrating a sanitary landfill (18.1%), RDF (3.1%), composting (2%), anaerobic digestion (40.4%), and recycling (36.4%) was an optimized model of integrated waste management. An applied decision-making structure provides the opportunity for optimum decision-making. Therefore, the mix of recycling and anaerobic digestion and a sanitary landfill with Electricity Production (EP) are the preferred options for MSW management. PMID- 26496841 TI - Optimum BET surface areas for activated carbon produced from textile sewage sludges and its application as dye removal. AB - The purpose of this experimental study is to determine optimum preparation conditions for activated carbons obtained from textile sewage sludge (TSS) for removal of dyes from aqueous solutions. The textile sewage sludge activated carbon (TSSAC) was prepared by chemical activation with potassium hydroxide using Response Surface Methodology (RSM). The most influential factor on each experimental design responses was identified via ANNOVA analysis. Based on the central composite design (CCD), quadratic model was developed to correlate the preparation variables for one response which is the Brunauer-Emmelt-Teller (BET) surface area. RSM based on a three-variable CCD was used to determine the effect of pyrolyzed temperature (400-700 degrees C), carbonization time (45-180 min) and KOH: weight of TSS (wt%) impregnation ratio (0.5:1-1.5:1) on BET surface area. According to the results, pyrolyzed temperature and impregnation ratio were found as the significant factors for maximizing the BET surface area. The major effect which influences the BET surface area was found as pyrolyzed temperature. Both carbonization time and impregnation ratio of KOH had no significant effect. The optimum conditions for preparing TSSAC, based on response surface and contour plots, were found as follows: pyrolyzed temperature 700 degrees C, carbonization time of 45 min and chemical impregnation ratio of 0.5. The maximum and optimum BET surface area of TSSAC were found as 336 m(2)/g and 310.62 m(2)/g, respectively. Synozol Blue reactive (RSB) and Setapers Yellow-Brown (P2RFL) industrial textile dyes adsorption capacities were investigated. As expected the TSSAC which has the biggest BET surface area (336 m(2)/g) adsorbed dye best. The maximum (RSB) and (P2RFL) uptake capacities were found as 8.5383 mg/g and 5.4 mg/g, respectively. The results of this study indicated the applicability of TSSAC for removing industrial dyes from aqueous solution. PMID- 26496842 TI - Co-treatment of landfill leachate and municipal wastewater using the ZELIAC/zeolite constructed wetland system. AB - Constructed wetland (CW) is a low-cost alternative technology to treat wastewater. This study was conducted to co-treat landfill leachate and municipal wastewater by using a CW system. Typha domingensis was transplanted to CW, which contains two substrate layers of adsorbents, namely, ZELIAC and zeolite. Response surface methodology and central composite design have been utilized to analyze experimental data. Contact time (h) and leachate-to-wastewater mixing ratio (%; v/v) were considered as independent variables. Colour, COD, ammonia, nickel, and cadmium contents were used as dependent variables. At optimum contact time (50.2 h) and leachate-to-wastewater mixing ratio (20.0%), removal efficiencies of colour, COD, ammonia, nickel, and cadmium contents were 90.3%, 86.7%, 99.2%, 86.0%, and 87.1%, respectively. The accumulation of Ni and Cd in the roots and shoots of T. domingensis was also monitored. Translocation factor (TF) was >1 in several runs; thus, Typha is classified as a hyper-accumulator plant. PMID- 26496843 TI - Impact of soybean stover- and pine needle-derived biochars on Pb and As mobility, microbial community, and carbon stability in a contaminated agricultural soil. AB - Biochar is gaining attention as a potential soil amendment to remediate and revitalize the contaminated soils. Simultaneous effects of biochar on metals mobility, microbial abundance, bacterial diversity and carbon storage in soil are scarcely addressed. This study assessed the effect of biochars on metal mobility, microbial abundance, bacterial community, and carbon storage in an agricultural soil contaminated with heavy metals. Biochars derived from soybean stover at 300 and 700 degrees C (S-BC300 and S-BC700, respectively) and pine needles at the same temperatures (P-BC300 and P-BC700, respectively) were used. A maximum reduction of Pb mobility by 95% was observed from a soil treated with S-BC700, associated with precipitation of chloropyromorphite and hydroxylpyromorphite. In contrast, As was desorbed from soil particles because of P competition. The abundance of Gram-positive and negative bacteria, fungi, actinomycetes, and arbuscular mycorrhizal fungi increased in the soils treated with biochar produced at 300 degrees C, possibly due to the high dissolved organic and active organic carbons. Microbial abundance in the soils treated with S-BC700 and P-BC700 was constant due to the existence of fixed or non-labile carbon. Changes to bacterial communities in the biochar-treated soils depended on feedstock type and pyrolysis temperature. Actinobacteria substantially increased whereas Acidobacteria and Chloroflexi decreased in the biochar-treated soils. The non-labile carbon fraction was ~25 fold higher in the biochar-treated soil than the control soil, indicating long-term carbon storage. PMID- 26496844 TI - Soluble phosphate fertilizer production using acid effluent from metallurgical industry. AB - Preventive and effective waste management requires cleaner production strategies and technologies for recycling and reuse. Metallurgical industries produce a great amount of acid effluent that must be discarded in a responsible manner, protecting the environment. The focus of this study was to examine the use of this effluent to increase reactivity of some phosphate rocks, thus enabling soluble phosphate fertilizer production. The effluent was diluted in deionized water with the following concentrations 0; 12.5; 25; 50; 75% (v v(-1)), which were added to four natural phosphate rocks: Araxa, Patos, Bayovar and Catalao and then left to react for 1 h and 24 h. There was an increase in water (PW), neutral ammonium citrate (PNAC) and citric acid (PCA) soluble phosphorus fractions. Such increases were dependent of rock type while the reaction time had no significant effect (p < 0.05) on the chemical and mineralogical phosphate characteristics. Phosphate fertilizers with low toxic metal concentrations and a high level of micronutrients were produced compared to the original natural rocks. The minimum amount of total P2O5, PNAC and PW, required for national legislation for phosphate partially acidulated fertilizer, were met when using Catalao and the effluent at the concentration of 55% (v v(-1)). Fertilizer similar to partially acidulated phosphate was obtained when Bayovar with effluent at 37.5% (v v(-1)) was used. Even though fertilizers obtained from Araxa and Patos did not contain the minimum levels of total P2O5 required by legislation, they can be used as a nutrient source and for acid effluent recycling and reuse. PMID- 26496845 TI - Efficiencies of metal separation and recovery in ash-melting of municipal solid waste under non-oxidative atmospheres with different reducing abilities. AB - Ash-melting of municipal solid waste produces molten metal that contains Fe and Cu, and melting furnace fly ash (MFA) that contains Pb and Zn. To recover the metal from the fly ash, Pb and Zn are extracted from the ash by water or enriched in the ash by washing out salts; this separation depends on their leachability. In this study, we investigated the effects of the reducing ability of the atmosphere on the efficiencies of metal separation during melting and metal recovery in water treatment. Different feedstocks (incineration residues) were melted under N2 or CO + N2 atmospheres. In some of the feedstock materials, volatilization of metallic Cu into MFA was promoted under the atmosphere with greater reducing ability (CO + N2). This increased volatilization inhibited the metal separation in the ash-melting process. Moreover, the higher reducing ability inhibited the formation of water-soluble lead chlorides and decreased the efficiency of metal recovery from the MFA because of the water leaching of the lead compounds. The reducing ability of the atmosphere is difficult to control uniformly in actual ash-melting plants, and we investigated appropriate melting conditions under which the effect of the reducing ability was minimized to promote metal separation and recovery. This minimization was achieved by melting incineration fly ash without additives with Cl gas treatment at 1400 degrees C. PMID- 26496846 TI - Effects of extreme natural events on the provision of ecosystem services in a mountain environment: The importance of trail design in delivering system resilience and ecosystem service co-benefits. AB - A continued supply of ecosystem services (ES) from a system depends on the resilience of that system to withstand shocks and perturbations. In many parts of the world, climate change is leading to an increased frequency of extreme weather events, potentially influencing ES provision. Our study of the effects of an intense rainfall event in Gorce National Park, Poland, shows: (1) the intense rainfall event impacted heavily on the supply of ES by limiting potential recreation opportunities and reducing erosion prevention; (2) these negative impacts were not only restricted to the period of the extreme event but persisted for up to several years, depending on the pre-event trail conditions and post event management activities; (3) to restore the pre-event supply of ES, economic investments were required in the form of active repairs to trails, which, in Gorce National Park, were an order of magnitude higher than the costs of normal trail maintenance; and (4) when recreational trails were left to natural restoration, loss of biodiversity was observed, and recovery rates of ES (recreation opportunities and soil erosion prevention) were reduced in comparison to their pre-event state. We conclude that proper trail design and construction provides a good solution to avoid some of the negative impacts of extreme events on recreation, as well as offering co-benefits in terms of protecting biodiversity and enhancing the supply of regulating services such as erosion prevention. PMID- 26496847 TI - Chestnut green waste composting for sustainable forest management: Microbiota dynamics and impact on plant disease control. AB - Making compost from chestnut lignocellulosic waste is a possible sustainable management strategy for forests that employs a high-quality renewable organic resource. Characterization of the microbiota involved in composting is essential to better understand the entire process as well as the properties of the final product. Therefore, this study investigated the microbial communities involved in the composting of chestnut residues obtained from tree cleaning and pruning. The culture-independent approach taken highlighted the fact that the microbiota varied only slightly during the process, with the exception of those of the starting substrate and mature compost. The statistical analysis indicated that most of the bacterial and fungal species in the chestnut compost persisted during composting. The dominant microbial population detected during the process belonged to genera known to degrade recalcitrant lignocellulosic materials. Specifically, we identified fungal genera, such as Penicillium, Fusarium, Cladosporium, Aspergillus and Mucor, and prokaryotic species affiliated with Bacilli, Actinobacteria, Flavobacteria and gamma-Proteobacteria. The suppressive properties of compost supplements for the biocontrol of Sclerotinia minor and Rhizoctonia solani were also investigated. Compared to pure substrate, the addition of compost to the peat-based growth substrates resulted in a significant reduction of disease in tomato plants of up to 70 % or 51 % in the presence of Sclerotinia minor or Rhizoctonia solani, respectively. The obtained results were related to the presence of putative bio-control agents and plant growth-promoting rhizobacteria belonging to the genera Azotobacter, Pseudomonas, Stenotrophomonas, Bacillus, Flavobacterium, Streptomyces and Actinomyces in the chestnut compost. The composting of chestnut waste may represent a sustainable agricultural practice for disposing of lignocellulosic waste by transforming it into green waste compost that can be used to improve the fitness of agricultural plants. PMID- 26496848 TI - Timbre Brownfield Prioritization Tool to support effective brownfield regeneration. AB - In the last decade, the regeneration of derelict or underused sites, fully or partly located in urban areas (or so called "brownfields"), has become more common, since free developable land (or so called "greenfields") has more and more become a scare and, hence, more expensive resource, especially in densely populated areas. Although the regeneration of brownfield sites can offer development potentials, the complexity of these sites requires considerable efforts to successfully complete their revitalization projects and the proper selection of promising sites is a pre-requisite to efficiently allocate the limited financial resources. The identification and analysis of success factors for brownfield sites regeneration can support investors and decision makers in selecting those sites which are the most advantageous for successful regeneration. The objective of this paper is to present the Timbre Brownfield Prioritization Tool (TBPT), developed as a web-based solution to assist stakeholders responsible for wider territories or clusters of brownfield sites (portfolios) to identify which brownfield sites should be preferably considered for redevelopment or further investigation. The prioritization approach is based on a set of success factors properly identified through a systematic stakeholder engagement procedure. Within the TBPT these success factors are integrated by means of a Multi Criteria Decision Analysis (MCDA) methodology, which includes stakeholders' requalification objectives and perspectives related to the brownfield regeneration process and takes into account the three pillars of sustainability (economic, social and environmental dimensions). The tool has been applied to the South Moravia case study (Czech Republic), considering two different requalification objectives identified by local stakeholders, namely the selection of suitable locations for the development of a shopping centre and a solar power plant, respectively. The application of the TBPT to the case study showed that it is flexible and easy to adapt to different local contexts, allowing the assessors to introduce locally relevant parameters identified according to their expertise and considering the availability of local data. PMID- 26496849 TI - Nursing management, religion and spirituality: a bibliometric review, a research agenda and implications for practice. AB - AIMS: This article aims to contribute to the growing field of spirituality and nursing management by analysing bibliographic data on peer-reviewed research in the field. BACKGROUND: Articles on spirituality and nursing management often claim that these fields have grown over the past two decades. This article gathers empirical evidence to test these claims. EVALUATION: Bibliometric data on peer-reviewed research articles on nursing, nursing management, spirituality and religion in the Social Sciences Citation Index were analysed to ascertain general trends in publication and citation. KEY ISSUES: The data support claims that research activity and interest in both spirituality and religion in the field of nursing have grown steeply over recent years, and continue to accelerate. CONCLUSIONS: The research identified spirituality as a beneficial variable in management, training and/or care scenarios. Critical studies of nursing management spiritual initiatives could add considerably to the growing body of research and theory in this field. IMPLICATIONS FOR NURSING MANAGEMENT: It is essential that nurse managers be equipped to foster not only a broader understanding of the variety of faith traditions found in a multi-cultural society, but also to develop an understanding of the ways in which individuals engage in spiritual practice outside traditional religious settings. PMID- 26496851 TI - Climate change and environmental concentrations of POPs: A review. AB - In recent years, the climate change impact on the concentrations of persistent organic pollutants (POPs) has become a topic of notable concern. Changes in environmental conditions such as the increase of the average temperature, or the UV-B radiation, are likely to influence the fate and behavior of POPs, ultimately affecting human exposure. The state of the art of the impact of climate change on environmental concentrations of POPs, as well as on human health risks, is here reviewed. Research gaps are also identified, while future studies are suggested. Climate change and POPs are a hot issue, for which wide attention should be paid not only by scientists, but also and mainly by policy makers. Most studies reported in the scientific literature are focused on legacy POPs, mainly polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs) and pesticides. However, the number of investigations aimed at estimating the impact of climate change on the environmental levels of polycyclic aromatic hydrocarbons (PAHs) is scarce, despite of the fact that exposure to PAHs and photodegradation byproducts may result in adverse health effects. Furthermore, no data on emerging POPs are currently available in the scientific literature. In consequence, an intensification of studies to identify and mitigate the indirect effects of the climate change on POP fate is needed to minimize the human health impact. Furthermore, being this a global problem, interactions between climate change and POPs must be addressed from an international perspective. PMID- 26496850 TI - Socio-economic inequalities in curative health-seeking for children in Egypt: analysis of the 2008 Demographic and Health Survey. AB - BACKGROUND: The existence and magnitude of socio-economic inequalities in health seeking behaviours for child curative care in Egypt and mechanisms underlying these associations have not been comprehensively assessed. This study examined whether socio-economic position (SEP) was associated with health-seeking behaviours for diarrhoea and acute respiratory infection (ARI) in children and explored potential mechanisms underlying these associations using mediation analysis. METHODS: Children aged under-five years living with their mothers sampled by the 2008 Egypt Demographic and Health Survey were used to estimate the prevalence of diarrhoea and ARI in the two-week period preceding the survey. If either illness was reported, three dimensions of health-seeking were examined in adjusted mediation models, separately by illness: whether medical care was sought, whether such care was timely (within one day of symptom onset), and whether it was sought from private providers. Latent variables of parental socio cultural capital and household-level economic capital were the main exposures of interest. RESULTS: In the sample of 10,006 children, 8.4% had diarrhoea and 7.6% had ARI. Care was sought for 62.0% of children with diarrhoea and 78.5% with ARI; two-thirds of care-seeking for both illnesses was timely. More than 7 in 10 children who sought care were taken to private providers. Socio-cultural capital or economic capital were not independently associated with seeking care for either illness. Socio-cultural capital was positively associated with timely care seeking, and economic capital was positively associated with private provider use in adjusted analyses for both illnesses. CONCLUSIONS: SEP was not a strong determinant of care-seeking for diarrhoea or ARI, but there was a modest positive effect of SEP on timely receipt of care and private provider use. Further research is needed to explore perceptions of illness severity and the availability and quality of care from public and private providers. PMID- 26496852 TI - Comparison of the effects of extreme temperatures on daily mortality in Madrid (Spain), by age group: The need for a cold wave prevention plan. AB - A number of studies have shown that there is a time trend towards a reduction in the effects of heat on mortality. In the case of cold, however, there is practically no research of this type and so there is no clearly defined time trend of the impact of cold on mortality. Furthermore, no other specific studies have yet analysed the time trend of the impact of both thermal extremes by age group. We analysed data on daily mortality due to natural causes (ICD-10: A00 R99) in the city of Madrid across the period 2001-2009 and calculated the impact of extreme temperatures on mortality using Poisson regression models for specific age groups. The groups of age selected coinciding with the pre-existing age groups analyzed in previous papers. For heat waves the groups of age used were: <10 years, 10-17 years, 18-44 years, 45-64 years, 65-74 years and over-75 years. For cold waves the groups of age used were: <1 year; 1-5 years, 6-17 years, 18-44 years, 45-64 years, 65-74 years and over-75 years. <1, 1-17, 18-44, 45-66, 65-74 and over-75 years. We controlled for confounding variables, such as air pollution, noise, influenza, pollen, pressure and relative humidity, trend of the series, as well as seasonalities and autoregressive components of the series. The results of these models were compared to those obtained for the same city during the period 1986-1997 and published in different studies. Our results show a lightly reduction in the effects of heat, especially in the over-45-year age group. In the case of cold, the behaviour pattern was the opposite, with an increase in its effect. Heat adaptation and socio-economic and public-health prevention and action measures may be behind this amelioration in the effects of heat, whereas the absence of such actions in respect of low temperatures may account for the increase in the effects of cold on mortality. From a public health point of view, the implementation of cold wave prevention plans covering all age groups is thus called for. PMID- 26496853 TI - Traditional serrated adenoma with BRAF mutation is associated with synchronous/metachronous BRAF-mutated serrated lesions. AB - AIMS: To determine whether traditional serrated adenoma (TSA) results in an increased risk of developing subsequent serrated polyps or colorectal cancer (CRC). METHODS AND RESULTS: We recruited 111 patients with an index TSA, and analysed the pathological and molecular features of their synchronous/metachronous serrated lesions. Fifty hyperplastic polyps, 14 sessile serrated adenomas, an additional 27 TSAs and 17 CRCs were identified from 46 patients. Twenty-seven percent of TSAs showed a precursor serrated polyp in the periphery and were strongly correlated with BRAF mutation (P < 0.001). Serrated polyps occurred more commonly in patients with BRAF-mutated index TSAs than in patients with KRAS-mutated index TSAs. BRAF-mutated index TSAs were strongly associated with a right-sided location and BRAF mutation of synchronous/metachronous serrated polyps (P = 0.013 and P = 0.005, respectively). The 17 CRCs occurred more frequently in women, and were characterized by a high BRAF mutation rate (59%), a positive CpG island methylator phenotype (59%), and stable or low levels of microsatellite instability (77%). CONCLUSIONS: BRAF mutated TSA is distinct from KRAS-mutated TSA in predisposing to the acquisition of subsequent serrated neoplasia. This indicates the presence of an intestinal field defect in the tumour microenvironment that results in tumour initiation and malignant progression. PMID- 26496854 TI - Lung function in very preterm infants with patent ductus arteriosus under conservative management: an observational study. AB - BACKGROUND: Persistent patent ductus arteriosus (PDA) during hospitalization is thought to be associated with adverse pulmonary outcomes in very preterm infants. This observational study aimed to compare the lung function in very preterm infants with and without PDA at discharge. METHODS: Very preterm infants, admitted to our neonatal intensive unit, who required respiratory support soon after birth and had undergone a lung function test at discharge, were enrolled. Infants with a need for positive-pressure support (either an invasive ventilator, or nasal continuous positive airway pressure without oxygen) or supplemental oxygen at a postmenstrual age of 36 weeks were defined as having bronchopulmonary dysplasia (BPD). Echocardiography was performed weekly for each of the very preterm infants with PDA to confirm closure of the PDA. The data were collected retrospectively. RESULTS: Fifty-two very preterm infants received lung function tests before discharge during the study period, 28 of whom had PDA and received conservative management, and 20 who did not. The other 4 infants who were given active treatment for PDA were excluded. Gestational age was significantly smaller in the PDA group than in the no-PDA group (27.1 +/- 2.0 vs. 28.6 +/- 1.6 weeks, p = 0.009). Birth weight did not differ significantly in those with and those without PDA (0.98 +/- 0.26 vs. 1.12 +/- 0.26 kg, p = 0.074). Significantly more infants with PDA had BPD (p = 0.002) and required respiratory support for a longer period (p = 0.001) than those without PDA. However, functional residual capacity (ml/kg) at discharge was comparable between the two groups after adjusting for gestational age and postmenstrual age at testing (21.6 +/- 8.4 vs. 21.5 +/- 6.7 ml/kg, p = 0.894). Other lung function test parameters were also comparable. CONCLUSION: Under a definition of BPD (including infants needing CPAP but without oxygen) other than the conventional definition, the very preterm infants in our study who received conservative management for PDA had a higher percentage of BPD than the infants without PDA. The parameters of the lung function test and lung clearance index were comparable between these two groups at discharge. PMID- 26496855 TI - Rifampin resistance and diabetes mellitus in a cross-sectional study of adult patients in rural South India. AB - BACKGROUND: Despite increasing reports of the linkage between diabetes and tuberculosis (TB), there is limited information regarding diabetes and TB drug resistance. METHODS: In this cross-sectional study, sputum and blood samples were collected from 304 adult patients in rural Andhra Pradesh. Rifampin resistance was assessed by Xpert MTB/RIF (Xpert), and diabetes status was based on self report. Additionally, samples were assayed by acid-fast bacilli sputum smear microscopy (AFB) and QuantiFERON-TB Gold In-Tube (QFT-G), in order to compare relative diagnostic performances. RESULTS: Among patients with confirmed TB (n = 194), diabetes was associated with 3.0-fold higher risk of rifampin resistance (95 % CI 1.3-6.7). Considering Xpert MTB/RIF the gold standard, AFB had lower sensitivity (72.2 vs. 82.5 %) and higher specificity (96.4 vs. 37.0 %) compared to QFT-G for diagnosing TB. CONCLUSIONS: The increased risk of rifampin resistance in patients with diabetes highlights the need for integrated diabetes surveillance in TB programs, particularly in settings undergoing the epidemiological transition. PMID- 26496856 TI - Effects of chlorpyrifos on life cycle parameters, cytochrome P450S expression, and antioxidant systems in the monogonont rotifer Brachionus koreanus. AB - Chlorpyrifos is a widely used organophosphorus insecticide for controlling diverse insect pests of crops. In the monogonont rotifer Brachionus koreanus, population growth retardation with the inhibition of lifespan, fecundity, and individual body size of ovigerous females was shown over 10 d in response to chlorpyrifos exposure. At the molecular and biochemical levels, the rotifer B. koreanus defensome, composed of cytochrome P450 complements, heat shock protein 70, and antioxidant enzymatic systems (i.e., glutathione, glutathione peroxidase, glutathione reductase, and glutathione S-transferase), was significantly induced in response to different concentrations of chlorpyrifos. Thus, chlorpyrifos strongly induced a defensome system to mitigate the deleterious effects of chlorpyrifos at in vivo and in vitro levels as a trade-off in fitness costs. Environ Toxicol Chem 2016;35:1449-1457. (c) 2015 SETAC. PMID- 26496857 TI - Amplification by (-)-epigallocatechin gallate and chlorogenic acid of TNF-alpha stimulated interleukin-6 synthesis in osteoblasts. AB - Polyphenolic compounds in foods and beverages have beneficial effects on human health. (-)-Epigallocatechin gallate (EGCG) and chlorogenic acid (CGA), a major flavonoid in green tea and a major phenolic acid in coffee, respectively, have potent properties, including antioxidative effects. Our previous study demonstrated that p70 S6 kinase acts as a negative regulator in tumor necrosis factor-alpha (TNF-alpha)-stimulated interleukin-6 synthesis in osteoblast-like MC3T3-E1 cells. In the present study, the effects of EGCG and CGA on the TNF alpha-stimulated interleukin-6 synthesis were investigated in MC3T3-E1 cells. EGCG and CGA significantly enhanced TNF-alpha-stimulated interleukin-6 release. In addition, the interleukin-6 mRNA expression levels induced by TNF-alpha were supported by EGCG, as well as CGA. EGCG markedly attenuated the TNF-alpha-induced phosphorylation of p70 S6 kinase whereas CGA failed to affect the phosphorylation. These results strongly suggest that EGCG and CGA enhance the TNF alpha-stimulated interleukin-6 synthesis in osteoblasts, and that the amplifying effect of EGCG, but not CGA, is exerted via inhibiting p70 S6 kinase. PMID- 26496858 TI - Hydrogen capture by porphyrins at the TiO2(110) surface. AB - Metal-free porphyrin molecules adsorb on the rutile TiO2(110) surface with their pyrrolic nitrogen atoms atop the O-bridge rows, whereas the iminic nitrogen atoms capture two additional hydrogen atoms. Hydrogenation occurs spontaneously at room temperature, irrespective of the distance of the polypyrrolic macrocycle from the surface, as varied by changing the porphyrin functionalization. PMID- 26496859 TI - Knockout of a transgene by transcription activator-like effector nucleases (TALENs) in the sawfly, Athalia rosae (Hymenoptera) and the ladybird beetle, Harmonia axyridis (Coleoptera). AB - Transcription activator-like effector nucleases (TALENs) are efficient tools for targeted genome editing and have been utilized in a number of insects. Here, we demonstrate the gene disruption (knockout) caused by TALENs targeting a transgene, 3xP3-driven enhanced green fluorescence protein (EGFP), that is integrated in the genome of two species, the sawfly Athalia rosae (Hymenoptera) and the ladybird beetle Harmonia axyridis (Coleoptera). Messenger RNAs of TALENs targeting the sequences adjacent to the chromophore region were microinjected into the eggs/embryos of each species. In At. rosae, when microinjection was performed at the posterior end of eggs, 15% of G(0) individuals showed a somatic mosaic phenotype for eye EGFP fluorescence. Three-quarters of the somatic mosaics produced EGFP-negative G(1) progeny. When eggs were injected at the anterior end, 63% of the G(0) individuals showed somatic mosaicism, and 17% of them produced EGFP-negative G(1) progeny. In H. axyridis, 25% of posterior-injected and 8% of anterior-injected G(0) individuals produced EGFP-negative G(1) progeny. In both species, the EGFP-negative progeny retained the EGFP gene, and various deletions were detected in the target sequences, indicating that gene disruption was successfully induced. Finally, for both species, 18-21% of G(0) founders produced gene knockout progeny sufficient for establishing knockout strains. PMID- 26496860 TI - Editorial Comment from Dr Saito and Dr Shimizu to Propiverine increases urethral wall catecholamine levels and bladder leak point pressure in rats. PMID- 26496861 TI - In Situ Photo Sonosynthesis of Organic/Inorganic Nanocomposites on Wool Fabric Introducing Multifunctional Properties. AB - Here, a novel and efficient process is introduced for producing wool fabric with multifunctional features through facile in situ photosonochemical synthesis of organic/inorganic nanocomposites. The fabric was treated with titanium isopropoxide, silver nitrate and ammonia in a sonobath for 1 h at 75-80 degrees C. The crystal phase of the sono-treated samples was characterized by X-ray diffraction. The uniform distribution of the nanocomposite on the fiber surface was proved by field emission scanning electron microscope, energy dispersive X ray and mapping patterns. Further, the composition of the nanocomposites was investigated by X-ray photoelectron spectroscopy. The sono-treated wool fabrics illustrated excellent photocatalytic activities toward discoloration of Methylene Blue under sunlight and UV-A irradiation. Also the fabrics indicated reasonable antibacterial/antifungal activities against Staphylococcus aureus, Escherichia coli and Candida albicans. The tensile properties of the sono-treated fabrics enhanced comparing to the untreated and even conventional stirrer-treated fabrics. Moreover, a central composite design based on response surface methodology was used to study the influence of titanium isopropoxide and silver molar ratio on the prepared nanocomposites sonobath. Finally, the optimum molar ratio was reported for the best responses. PMID- 26496862 TI - Effects of diazoxide on Abeta1-42-induced expression of the NR2B subunit in cultured cholinergic neurons. AB - The accumulation of amyloid-beta protein (Abeta) is significant in the pathogenesis of Alzheimer's disease. Several previous studies indicate that the NR2B-containing N-methyl-D-aspartate receptors are critically involved in the Abeta mediated disruption of neuronal function. Diazoxide (DZ), a highly selective drug capable of opening mitochondrial ATP-sensitive potassium channels, has neuroprotective effects against neuronal cell death. However, the mechanism by which DZ protects cholinergic neurons against Abeta-induced cytotoxicity remains to be elucidated. The present study was designed to investigate the effects of DZ pretreatment against Abeta1-42-induced expression of NR2B in order to gain novel insights into the neuroprotective mechanisms. Following exposure to Abeta1-42 for 24 h, the expression of the NR2B subunit remained unchanged compared with the control group. However, a significant increase in the expression of the NR2B subunit was observed following treatment with Abeta1-42 for 72 h (P<0.05); and the upregulation of the expression of the NR2B subunit was reversed by pretreatment with DZ (P<0.05). These results suggested that DZ may counteract Abeta1-42-mediated cytotoxicity by alleviating the expression of NR2B. PMID- 26496863 TI - Lack of tissue accumulation of grape seed flavanols after daily long-term administration in healthy and cafeteria-diet obese rats. AB - After ingestion flavanols are metabolized by phase-II enzymes and the microbiota and are distributed throughout the body depending on several factors. Herein we aim to evaluate whether flavanols are tissue-accumulated after the long-term administration of a grape seed polyphenol extract (GSPE) in rats and to study if compounds present in tissues differ in a cafeteria-diet obesity state. For that, plasma, liver, mesenteric white adipose tissue (MWAT), brain, and aorta flavanol metabolites from standard chow-diet-fed (ST) and cafeteria-diet-fed (CAF) rats were analyzed by high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) 21 h after the last 12-week-daily GSPE (100 mg/kg) dosage. Results showed that long-term GSPE intake did not trigger a flavanol tissue accumulation, indicating a clearance of products at each daily dosage. Therefore, results suggest that polyphenol benefits in a disease state would be due to a daily pulsatile effect. Moreover, obesity induced by diet also influences the metabolism and bioavailability of flavanols in rats. PMID- 26496864 TI - Impact of early intervention on comprehensive language and academic achievement in Japanese hearing-impaired children with cochlear implants. AB - OBJECTIVES: Early hearing detection and intervention (EHDI) is critical for achievement of age-appropriate speech perception and language development in hearing-impaired children. It has been 15 years since newborn hearing screening (NHS) was introduced in Japan, and its effectiveness for language development in hearing-impaired children has been extensively studied. Moreover, after over 20 years of cochlear implantation in Japan, many of the prelingual cochlear implant (CI) users have reached school age, and the effect of CI on language development have also been assessed. To identify prognostic factors for language development, audiological/language test scores and demographic factors were compared among prelingual severe-to-profound hearing-impaired children with CI divided into subgroups according to age at first hearing aid (HA) use and whether they received NHS. METHODS: Prelingual severe-to-profound deafened children from the Research on Sensory and Communicative Disorders (RSCD) project who met the inclusion criteria were divided into groups according to the age (in months) of HA commencement (before 6 months: group A, after 7 months: group B), and the presence or absence of NHS (groups C and D). Language development and socio economic data were obtained from audiological/language tests and a questionnaire completed by caregivers, respectively. RESULTS: In total, 210 children from the RSCD project participated in this study. Group A (n=49) showed significantly higher scores on comprehensive vocabulary and academic achievement (p<0.05) than group B (n=161), with no difference in demographics except for significantly older age in group B. No differences in language scores were observed between group C (n=71) and group D (n=129), although participants of group D was significantly older and had used CIs longer (p<0.05). CONCLUSIONS: Early use of HAs until the CI operation may result in better language perception and academic achievement among CI users with prelingual deafness. A long-term follow-up is required to assess the usefulness of NHS for language development. PMID- 26496865 TI - Analysis of genetic differentiation and genomic variation to reveal potential regions of importance during maize improvement. AB - BACKGROUND: Exploring genetic differentiation and genomic variation is important for both the utilization of heterosis and the dissection of the genetic bases of complex traits. METHODS: We integrated 1857 diverse maize accessions from America, Africa, Europe and Asia to investigatetheir genetic differentiation, genomic variation using 43,252 high-quality single-nucleotide polymorphisms(SNPs),combing GWAS and linkage analysis strategy to exploring the function of relevant genetic segments. RESULTS: We uncovered many more subpopulations that recently or historically formed during the breeding process. These patterns are represented by the following lines: Mo17, GB, E28, Ye8112, HZS, Shen137, PHG39, B73, 207, A634, Oh43, Reid Yellow Dent, and the Tropical/subtropical (TS) germplasm. A total of 85 highly differentiated regions with a DEST of more than 0.2 were identified between the TS and temperate subpopulations. These regions comprised 79% of the genetic variation, and most were significantly associated with adaptive traits. For example, the region containing the SNP tag PZE.108075114 was highly differentiated, and this region was significantly associated with flowering time (FT)-related traits, as supported by a genome-wide association study (GWAS) within the interval of FT related quantitative trait loci (QTL). This region was also closely linked to zcn8 and vgt1, which were shown to be involved in maize adaptation. Most importantly, 197 highly differentiated regions between different subpopulation pairs were located within an FT- or plant architecture-related QTL. CONCLUSIONS: Here we reported that 700-1000 SNPs were necessary needed to robustly estimate the genetic differentiation of a naturally diverse panel. In addition, 13 subpopulations were observed in maize germplasm, 85 genetic regions with higher differentiation between TS and temperate maize germplasm, 197 highly differentiated regions between different subpopulation pairs, which contained some FT- related QTNs/QTLs/genes supported by GWAS and linkage analysis, and these regions were expected to play important roles in maize adaptation. PMID- 26496866 TI - Separation and simultaneous quantification of nine furanocoumarins from Radix Angelicae dahuricae using liquid chromatography with tandem mass spectrometry for bioavailability determination in rats. AB - Radix Angelicae dahuricae is a well-known medicinal herb in a number of herb preparations for medical uses. In this study, a rapid and selective method using liquid chromatography with tandem mass spectrometry was developed for the separation and simultaneous quantitation of nine furanocoumarins from Radix A. dahuricae, namely imperatorin, isoimperatorin, oxypeucedanin hydrate, bergapten, oxypeucedanin, xanthotoxol, xanthotoxin, isopimpinellin, and psoralen. Chromatographic separation was achieved on a CAPCELL PAK MG II C18 analytical column. Detection was performed using positive electrospray ion source in the multiple reaction monitoring mode. The method was fully validated for analyzing these principles in rat plasma with a lower limit of quantification from 0.5 to 5 ng/mL. The intra- and interbatch precisions were less than 10%, and the accuracies ranged from -7.5 to 8.0%. The extraction recovery of the analytes was above 70% without a significant matrix effect. The method was used to determine the oral and intravenous pharmacokinetic profiles of these furanocoumarins after dosing with Radix A. dahurica extract. The bioavailability of these furanocoumarins ranged from 10.1 to 82.8%. These data provide critical information for a better understanding of the pharmacological mechanisms and herb drug interaction potential of Radix A. dahurica. PMID- 26496867 TI - ISSR-based analysis of genetic diversity among sorghum landraces growing in some parts of Saudi Arabia and Yemen. AB - Inter simple sequence repeats (ISSR) analysis was used to determine the genetic diversity among 15 genotypes of sorghum [Sorghum bicolor (L.) Moench] growing in some parts of Saudi Arabia and Yemen. A total of 92 alleles were amplified, with an average of 13 ISSR alleles per primer. Cluster analysis divided the 15 genotypes into two main groups. Group A consisted of five genotypes with white grains from Jazan and Abha with a similarity coefficient range of 0.527 to 0.818. Group B was comprised of 10 genotypes; two genotypes from Al-Qassim were clearly delimited from the remaining eight samples with a coefficient range from 0.709 to 0.490. The eight genotypes were divided into two clusters; one was comprised of landraces with dark grains from Abha in Saudi Arabia and Ab in Yemen, with a similarity coefficient range between 0.563 and 0.781, and the other cluster was differentiated into three white-colored-grain genotypes and one colored-grain genotype; all samples from North Yemen had a similarity coefficient range from 0.454 to 0.800. The current results encourage further collection and authentication of sorghum landraces in the gene banks of Saudi Arabia. PMID- 26496869 TI - Reducing bloodstream infection with a chlorhexidine gel IV dressing. AB - The use of vascular access devices (VAD) is common in healthcare provision but there is a significant risk of acquiring an infection. Central venous catheters (CVC) are associated with the highest risk of intravenous catheter-related bloodstream infection (CRBSI). 3MTM TegadermTM CHG IV dressing is a semi permeable transparent adhesive dressing with an integrated gel pad containing chlorhexidine gluconate 2%. This product was reviewed by the National Institute for Health and Care Excellence (NICE) in 2015, recommending that Tegaderm CHG could be used for CVC and arterial line dressings in high-dependency and intensive-care settings. This article discusses issues around CRBSI, interventions to reduce the risk of CRBSI, and the use of Tegaderm CHG dressing. PMID- 26496870 TI - Complex vascular access requires making the best use of technology. PMID- 26496871 TI - Totally implanted ports: the trapezius approach in practice. AB - Implanted ports (IPs) are an essential device for many patients who require long term vascular access. IPs offer some advantages over other central venous access devices, such as lifestyle, body image benefits and lower infection rates. A typical implantation site for a port is the anterior chest wall. For some patients with breast cancer who have metastatic chest wall disease this site may lead to problems with the function of the device if disease spreads to the port site. One option for this patient group is to place the implanted port over the trapezius muscle. This article discusses six patients, all of whom had metastatic breast cancer with some degree of subcutaneous disease on the anterior chest wall. Three patients had received trapezius port placements and three had anterior chest wall placements. A retrospective review of the patients' medical records was undertaken from the time of insertion until removal or until the patient died. The anterior chest wall group of patients had their devices in for an average of 368 days vs 214 in the trapezius group. The total complications were higher in the anterior chest wall group (7 vs 2 in the trapezius group). Disease spread to two of the devices in the anterior chest wall group meaning the devices could no longer be used. The trapezius approach appears to be a safe and a reliable form of vascular access and may offer fewer complications than the traditional method of anterior chest wall placement when standard anterior chest wall approach is not suitable. PMID- 26496868 TI - Analysis of heat shock protein 70 gene polymorphisms Mexican patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown etiology. Genetic variation within different major histocompatibility complex (MHC) loci contributes to the susceptibility to IPF. The effect of 70 kDa heat shock proteins (HSP70) gene polymorphisms in the susceptibility to IPF is unknown. The aim of this study was to explore the association between HSP70 polymorphisms and IPF susceptibility in the Mexican population. METHODS: Four HSP70 single nucleotide polymorphisms (SNPs) were evaluated using real time PCR assays in 168 IPF patients and 205 controls: +2763 C>T of HSPA1L (rs2075800), +2437 of HSP HSPA1L A>G (rs2227956), +190 of HSPA1A G>C (rs1043618) and +1267 of HSPA1B G>A (rs1061581). RESULTS: The analysis of the recessive model revealed a significant decrease in the frequency of the genotype HSPA1B AA (rs1061581) in IPF patients (OR = 0.27, 95 % CI = 0.13-0.57, Pc = 0.0003) when compared to controls. Using a multivariate logistic regression analysis in a codominant model the HSPA1B (rs1061581) GA and AA genotypes were associated with a lower risk of IPF compared with GG (OR = 0.22, 95 % CI = 0.07-0.65; p = 0.006 and OR = 0.17, 95 % CI = 0.07-0.41; p = <0.001). Similarly, HSPA1L (rs2227956) AG genotype (OR = 0.34, 95 % CI = 0.12-0.99; p = 0.04) and the dominant model AG + GG genotypes were also associated with a lower risk of IPF (OR = 0.24, 95 % CI = 0.08-0.67; p = 0.007). In contrast, the HSPA1L (rs2075800) TT genotype was associated with susceptibility to IPF (OR = 2.52, 95 % CI = 1.32-4.81; p = 0.005). CONCLUSION: Our findings indicate that HSPA1B (rs1061581), HSPA1L (rs2227956) and HSPA1 (rs1043618) polymorphisms are associated with a decreased risk of IPF. PMID- 26496872 TI - Challenges of vascular access in red cell exchange in sickle cell patients. PMID- 26496873 TI - Providing an outpatient antimicrobial therapy service. PMID- 26496874 TI - Bringing intravenous antibiotics home. PMID- 26496875 TI - Infusion pump development and implications for nurses. AB - Infusion pumps are commonplace in today's healthcare settings and their design and development has kept pace with technology over the decades. In the 1970s and 1980s infusion pumps began to emerge in the UK market and were basic, mechanical devices with limited functions. Today, infusion pumps have a plethora of functions and features and a range of alarms to help alert the user and the patient that infusions are nearing completion, have ended or their range of sensors has detected that the infusion pump, or patient, requires attention. The role of the nurse in safely managing this ever-changing technology should not be underestimated. This paper reviews the progress made over the past 40 years in the UK healthcare setting and how the nurses have had to keep up to speed with the technology as it develops. It highlights the importance of fully integrating infusion pumps into intravenous (IV) therapy training and assessment. The important role the nurse plays is highlighted as well as exploring how he or she can help organisations better understand infusion pumps in the day-to-day management of patients undergoing intravenous therapy. PMID- 26496876 TI - Clinically indicated replacement of peripheral cannulas. AB - Insertion of peripheral venous cannulas is one of the most frequently performed procedures in hospitals. In the UK, one in three patients will have at least one cannula inserted while in hospital. Cannula insertion is uncomfortable and causes anxiety and distress to patients. The risks associated with this include infection, phlebitis and infiltration. In the UK, it is widely accepted that cannulas should be routinely changed every 72--96 hours in line with national guidelines ( Department of Health (DH) 2007). The updated epic3 guidelines recommend to change cannulas when clinically indicated, rather than routinely. The objective in a local NHS trust, was to look at the evidence for this, with an aim to change local policy and practice to reflect the new recommendation. The primary outcomes of the first 6 months from implementation suggest that patients have not been adversely affected. The change to practice has provided a significant reduction in financial costs to the trust, enabling a stock reduction of 25%. It is estimated that a total of 11 750 clinical hours have been saved for busy clinical staff. The most important outcome has been for patients, who have been spared the unnecessary pain and potential risks associated with repeated insertion of cannulas when there has been no clinical indication to do this. PMID- 26496877 TI - Ultrafast immunoassays by coupling dielectrophoretic biomarker enrichment in nanoslit channel with electrochemical detection on graphene. AB - Heterogeneous immunoassays usually require long incubation times to promote specific target binding and several wash steps to eliminate non-specific binding. Hence, signal saturation is rarely achieved at detection limit levels of analyte, leading to significant errors in analyte quantification due to extreme sensitivity of the signals to incubation time and methodology. The poor binding kinetics of immunoassays at detection limit levels can be alleviated through creating an enriched analyte plug in the vicinity of immobilized capture probes to enable signal saturation at higher levels and at earlier times, due to higher analyte association and its faster replenishment at the binding surface. Herein, we achieve this by coupling frequency-selective dielectrophoretic molecular dam enrichment of the target biomarker in physiological media to capture probes immobilized on graphene-modified surfaces in a nanoslit to enable ultrafast immunoassays with near-instantaneous (<2 minutes) signal saturation at dilute biomarker levels (picomolar) within ultra-low sample volumes (picoliters). This methodology is applied to the detection of Prostate Specific Antigen (PSA) diluted in serum samples, followed by validation against a standard two-step immunoassay using three de-identified patient samples. Based on the ability of dielectrophoretic molecular dam analyte enrichment methods to enable the detection of PSA at 1-5 pg mL(-1) levels within a minute, and the relative insensitivity of the signals to incubation time after the first two minutes, we envision its application for improving the sensitivity of immunoassays and their accuracy at detection limit levels. PMID- 26496878 TI - Festination in Chinese patients with Parkinson's disease. AB - OBJECTIVE: To investigate the occurrence and clinical associations of festination in Chinese patients with Parkinson's disease (PD). METHODS: A total of 480 PD patients were recruited in this cross-sectional study. Assessments scales included the Unified PD Rating Scale (UPDRS) part III, PD Questionnaire-39 (PDQ 39), Non-Motor Symptoms Scale (NMSS), Mini-Mental State Examination (MMSE), frontal assessment battery (FAB), Montreal Cognitive Assessment (MoCA), Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA). RESULTS: One hundred and forty PD patients (29.2%) reported festination. Festination occurred more frequently in patients with lower limbs as the site of onset and patients with longer disease duration or higher Hoehn and Yahr (H&Y) stage (P<0.05). The mean age, levodopa and entacapone use, incidences of motor complications, falls and freezing of gait, and the scores for the UPDRS part III, NMSS, HAMD and HAMA were higher in patients with festination than those without festination (P<0.05). There were no differences in the scores for the PDQ-39, MMSE, FAB and MoCA between the patients with and without festination. The binary logistic regression model indicated that UPDRS part III, lower limbs as the site of onset, freezing of gait and falls were associated with festination. CONCLUSIONS: Festination is a relatively common disabling symptom in Chinese PD patients. Patients with lower limbs as the site of onset and more severe disability were more likely to experience festination. Festination in PD is not related to non-motor symptoms and cognitive dysfunction. PMID- 26496880 TI - Transaortic Repair as Bailout Procedure for Left Atrial Tear in Redo Mitral Valve Surgery via Superior Transseptal Approach. AB - We encountered a tear of the left atrium with severe calcification during redo mitral surgery, and report a technique for its repair. An 82-year-old woman underwent redo mitral valve replacement. The mitral valve was performed via a superior transseptal approach. The atriotomy was closed directly. The roof of the left atrium was found to be torn after aortic de-clamping. There was no remaining intact left atrial tissue on the aortic side. Patch closure was performed using transaortic stitches passing through the subaortic curtain to fix the patch. The left atrial roof and atrial septum were closed with the same patch. PMID- 26496879 TI - DCIS in BRCA1 and BRCA2 mutation carriers: prevalence, phenotype, and expression of oncodrivers C-MET and HER3. AB - BACKGROUND: Studies report conflicting evidence regarding the existence of a DCIS associated premalignant pathway in BRCA mutation carriers. We aimed to examine the prevalence, phenotype, and expression of oncodrivers in pure DCIS (pDCIS) and invasive breast cancer with concurrent DCIS (IBC + DCIS) in mutation carriers. METHODS: A cohort of BRCA1 and BRCA2 mutation carriers >18 years old who underwent surgery for breast cancer at an academic hospital (1992-2011) and had pathology available for review were included for study. Invasive breast cancer (IBC) and DCIS were stained for ER, PR, HER1, HER2, and HER3, and C-MET. DCIS prevalence was evaluated. Correlation of IBC and DCIS phenotypes was evaluated in patients with IBC + DCIS. DCIS and IBC expression of tumor markers were examined by BRCA mutation. RESULTS: We identified 114 breast tumors. Of all BRCA1 associated tumors, 21.1 % were pDCIS and 63.4 % were IBC + DCIS. Of all BRCA2 associated tumors, 23.3 % were pDCIS and 60.5 % were IBC + DCIS. In BRCA1 and BRCA2 mutation carriers with IBC + DCIS, there was a significant correlation in ER, PR, and HER3 expression between the DCIS and IBC components. Most BRCA1 associated DCIS did not express ER, PR or HER2, while most BRCA2-associated DCIS did express ER and PR. BRCA1- as well as BRCA2-associated DCIS had expression of HER3 and C-MET. CONCLUSIONS: The majority of BRCA-associated tumors had DCIS present. Concordance of DCIS and IBC phenotypes was high, arguing for the existence of a DCIS-associated premalignant pathway. Oncodrivers HER3 and C-MET were expressed in the DCIS of mutation carriers, suggesting an opportunity for prevention strategies. PMID- 26496881 TI - Unfolded protein response is required for Aspergillus oryzae growth under conditions inducing secretory hydrolytic enzyme production. AB - Unfolded protein response (UPR) is an intracellular signaling pathway for adaptation to endoplasmic reticulum (ER) stress. In yeast UPR, Ire1 cleaves the unconventional intron of HAC1 mRNA, and the functional Hac1 protein translated from the spliced HAC1 mRNA induces the expression of ER chaperone genes and ER associated degradation genes for the refolding or degradation of unfolded proteins. In this study, we constructed an ireA (IRE1 ortholog) conditionally expressing strain of Aspergillus oryzae, a filamentous fungus producing a large amount of amylolytic enzymes, and examined the contribution of UPR to ER stress adaptation under physiological conditions. Repression of ireA completely blocked A. oryzae growth under conditions inducing the production of hydrolytic enzymes, such as amylases and proteases. This growth defect was restored by the introduction of unconventional intronless hacA (hacA-i). Furthermore, UPR was observed to be induced by amylolytic gene expression, and the disruption of the transcriptional activator for amylolytic genes resulted in partial growth restoration of the ireA-repressing strain. In addition, a homokaryotic ireA disruption mutant was successfully generated using the strain harboring hacA-i as a parental host. These results indicated that UPR is required for A. oryzae growth to alleviate ER stress induced by excessive production of hydrolytic enzymes. PMID- 26496882 TI - Development of a decision model for the techno-economic assessment of municipal solid waste utilization pathways. AB - Economic competitiveness is one of the key factors in making decisions towards the development of waste conversion facilities and devising a sustainable waste management strategy. The goal of this study is to develop a framework, as well as to develop and demonstrate a comprehensive techno-economic model to help county and municipal decision makers in establishing waste conversion facilities. The user-friendly data-intensive model, called the FUNdamental ENgineering PrinciplEs based ModeL for Estimation of Cost of Energy and Fuels from MSW (FUNNEL-Cost MSW), compares nine different waste management scenarios, including landfilling and composting, in terms of economic parameters such as gate fees and return on investment. In addition, a geographic information system (GIS) model was developed to determine suitable locations for waste conversion facilities and landfill sites based on integration of environmental, social, and economic factors. Finally, a case study on Parkland County and its surrounding counties in the province of Alberta, Canada, was conducted and a sensitivity analysis was performed to assess the influence of the key technical and economic parameters on the calculated results. PMID- 26496884 TI - Personalized and Regenerative Medicine for Liver Diseases. AB - Regeneration of diseased organ is a ubiquitous clinical need. The clinical utilities of adult stem cells and microRNA have become a promising strategy for treatment of a number disease. This review aims to highlight the current clinical evidence of personalized and regenerative therapy for diseases like liver which could revolutionize patient care in the near future at a global scale. Herein, we explain the importance of personalized and regenerative medicine for bedside (intraoperative) in situ and In vivo regeneration of damaged organ/ tissues that is now being transferred to a larger field of clinical applications in a novel translational approach. PMID- 26496885 TI - Umbilical Cord is a Rich Source of Mesenchymal Stromal Cells for Cell Therapy. AB - Recently, umbilical cord (UC) and UC-derived mesenchymal stromal cells (UC-MSCs) have attracted much attention for many reasons, including (1) abundant sources and ease of collection, storage, and transport; (2) little ethical controversy; (3) multipotency to differentiate into various cell types; and (4) low immunogenicity with significant immunosuppressive ability. In this review, we provide a brief introduction to UC and UC-MSCs in terms of characteristics, isolation, and cryopreservation, as well as emphasizing their potential clinical application in regenerative medicine and immunotherapy. PMID- 26496883 TI - Emerging Role of Stem Cells - Derived Exosomes as Valuable Tools for Cardiovascular Therapy. AB - In modern society, myocardial infarction is a major cause of mortality, morbidity and deterioration of quality of life. Although various therapeutic approaches are available, none of them lead to the regeneration of infarcted tissue. The use of mesenchymal stem cells in cell therapy for myocardial infarction showed a beneficial effect consisting in reduced infarcted area and improved cardiac function, which can be explained by paracrine mechanism. It has been shown that stem cells are able to release a very complex range of factors including growth factors, cytokines and chemokines, along with an abundant mixture of membrane vesicles. These secreted elements contribute to the beneficial effect of stem cells therapy observed both in vitro and in vivo. Recent studies have shown that exosomes, which are small membrane vesicles originating in the endocytic pathway of the cells and carry a complex cargo consisting in mRNA, microRNA and various other anti-apoptotic and pro-angiogenic factors, are the main mediators of stem cells paracrine effect. In this review, we discuss the capacity of mesenchymal stem cells to protect the ischemic myocardium, the role of exosomes as protective factors secreted by stem cells and the possibility to use these vesicles in developing a novel approach in cardiovascular therapy, involving a non-cellular use of mesenchymal stem cells paracrine activity. PMID- 26496886 TI - Phenotypic and Genetic Evaluation of the Influence of Pseudomonas aeruginosa Culture Fractions on the Human Mesenchymal Stem Cells Viability, Apoptotic Pathways and Cytokine Profile. AB - The objective of this study was to investigate the effects of P. aeruginosa PAO1 cellular and soluble culture fractions on human mesenchymal stem cells (MSCs) death signaling pathways and cytokine profile. The bone marrow isolated MSCs, incubated for different periods of time with one of the three P. aeruginosa PAO1 culture fractions, i.e. low density whole cultures, heat inactivated bacterial cultures sediments and sterile supernatants, were submitted to the following assays: i) fluorescence microscopy evaluation of cellular morphology and viability; ii) bax, caspase 9, relA and bcl-2 genes expression analysis by qRT PCR; and iii) quantification of the level of IL-1beta, IL-6, IL-8 and IL-10 cytokines released in the MSCs supernatants determined by ELISA. Results were statistically analyzed using the GraphPad In Stat software. The PAO1 whole cultures exhibited the most relevant influences, impacting on MSCs morphology and viability, interfering with apoptotic pathways and significantly stimulating the production of IL-1beta and IL-10, while decreasing the production of IL-6 and IL 8. The culture supernatants increased the production of IL-1beta and reduced the secretion of all other tested cytokines, while heat-inactivated bacterial cells significantly stimulated both IL-1beta and IL-10 production. These data could suggest that in vivo, the fate of P. aeruginosa infection depends on the proportion between different bacterial culture fractions (i.e. the number of viable bacterial cells, the number of dead cells and the amount of bacterial soluble products accumulated locally) that could be influenced by the initial infective dose, by the host defense mechanisms, and also by the administered antimicrobial treatment that may thus interfere with the evolution and magnitude of the induced lesions. PMID- 26496887 TI - Extracellular Signals for Guiding Mesenchymal Stem Cells Osteogenic Fate. AB - Understanding the spatiotemporal dynamics of stem cell fate regulation is important for both fundamental biology and for directing the generation of a specific phenotype during the fabrication of tissue engineering materials. Recent findings revealed aspects of extracellular signals transduction by mesenchymal stem cells that are further integrated to modulate their lineage specification. This review focuses on recent developments in the field of nanobiomaterials design and fabrication for use in research and therapy of bone tissue. Also, new methods of assessment of stem cell multipotency or differentiated phenotype developed for clinical quality control applications are described. Materials engineered for understanding fundamental mechanisms of stem cell interaction with substrates are highlighted as key studies to drive advances in bone implants design. The use of polymers with defined biomechanical and topographical features to mimic the extracellular matrix biochemistry or biophysical cues is discussed. Bioengineered scaffolds able to induce osteogenic fate of bone marrow-derived mesenchymal stem cells in the absence of differentiation factors are successful models for potential development of implant biomaterials with enhanced osseointegration capacity and decreased soft tissue encapsulation. PMID- 26496888 TI - Hematopoietic Stem Cells Therapies. AB - Stem cell-based therapies are recognized as a new way to treat various diseases and injuries, with a wide range of health benefits. The goal is to heal or replace diseased or destroyed organs or body parts with healthy new cells provided by stem cell transplantation. The current practical form of stem cell therapy is the hematopoietic stem cells transplant applied for the treatment of hematological disorders. There are over 2100 clinical studies in progress concerning hematopoietic stem cell therapies. All of them are using hematopoietic stem cells to treat various diseases like: cancers, leukemia, lymphoma, cardiac failure, neural disorders, auto-immune diseases, immunodeficiency, metabolic or genetic disorders. Several challenges are to be addressed prior to developing and applying large scale cell therapies: 1) to explain and control the mechanisms of differentiation and development toward a specific cell type needed to treat the disease, 2) to obtain a sufficient number of desired cell type for transplantation, 3) to overcome the immune rejection and 4) to show that transplanted cells fulfill their normal functions in vivo after transplants. PMID- 26496889 TI - Application of Mesenchymal Stem Cells in the Targeted Gene Therapy for Gastric Cancer. AB - The incidence of gastric cancer is third most prevalent among all malignant tumors in China. The conventional therapies for advanced gastric cancer are futile. Targeted gene therapy has become a promising alternative approach. Mesenchymal stem cells (MSCs) can be used as potential cellular vehicles for cancer therapy in vivo. This review will summarize the published data about the application of MSC-based targeted therapy for gastric cancer, and discuss some of the challenges associated with this method. PMID- 26496890 TI - Fermentative profile and bacterial diversity of corn silages inoculated with new tropical lactic acid bacteria. AB - AIMS: This study aimed to evaluate the effects of inoculation of strains of lactic acid bacteria (LAB) isolated from sugarcane grown in a Brazil on the quality of corn silage. METHODS AND RESULTS: Three strains of Lactobacillus buchneri (UFLA SLM11, UFLA SLM103 and UFLA SLM108), five strains of Lactobacillus plantarum (UFLA SLM08, UFLA SLM41, UFLA SLM45, UFLA SLM46 and UFLA SLM105), and one strain of Leuconostoc mesenteroides (UFLA SLM06) were evaluated at 0, 10, 30, 60 and 90 day after inoculating corn forage. The inoculation of the LAB strains did not influence the chemical composition of the silage, but pH, acetic acid and 1,2-propanediol were affected by treatment. The silages inoculated with UFLA SLM11 and SLM108 contained the lowest yeast and filamentous fungi counts during fermentation. Bacteria belonging to the Enterobacteriaceae family, Clostridium genus were detected in the silages inoculated with Lact. buchneri UFLA SLM 11, 103 and 108, as shown by DGGE analysis. Silages inoculated with Lact. buchneri UFLA SLM 11 showed higher aerobic stability. CONCLUSIONS: The Lact. buchneri UFLA SLM11 strain was considered promising as a starter culture or inoculant for corn silages. SIGNIFICANCE AND IMPACT OF THE STUDY: The selection of microbial inoculants for each crop promotes improvement of silage quality. Studies on the chemical and microbiological characteristics of silage provide useful information for improving ensiling techniques. PMID- 26496891 TI - Whole genome sequencing reveals genomic heterogeneity and antibiotic purification in Mycobacterium tuberculosis isolates. AB - BACKGROUND: Whole genome sequencing has revolutionised the interrogation of mycobacterial genomes. Recent studies have reported conflicting findings on the genomic stability of Mycobacterium tuberculosis during the evolution of drug resistance. In an age where whole genome sequencing is increasingly relied upon for defining the structure of bacterial genomes, it is important to investigate the reliability of next generation sequencing to identify clonal variants present in a minor percentage of the population. This study aimed to define a reliable cut-off for identification of low frequency sequence variants and to subsequently investigate genetic heterogeneity and the evolution of drug resistance in M. tuberculosis. METHODS: Genomic DNA was isolated from single colonies from 14 rifampicin mono-resistant M. tuberculosis isolates, as well as the primary cultures and follow up MDR cultures from two of these patients. The whole genomes of the M. tuberculosis isolates were sequenced using either the Illumina MiSeq or Illumina HiSeq platforms. Sequences were analysed with an in-house pipeline. RESULTS: Using next-generation sequencing in combination with Sanger sequencing and statistical analysis we defined a read frequency cut-off of 30% to identify low frequency M. tuberculosis variants with high confidence. Using this cut-off we demonstrated a high rate of genetic diversity between single colonies isolated from one population, showing that by using the current sequencing technology, single colonies are not a true reflection of the genetic diversity within a whole population and vice versa. We further showed that numerous heterogeneous variants emerge and then disappear during the evolution of isoniazid resistance within individual patients. Our findings allowed us to formulate a model for the selective bottleneck which occurs during the course of infection, acting as a genomic purification event. CONCLUSIONS: Our study demonstrated true levels of genetic diversity within an M. tuberculosis population and showed that genetic diversity may be re-defined when a selective pressure, such as drug exposure, is imposed on M. tuberculosis populations during the course of infection. This suggests that the genome of M. tuberculosis is more dynamic than previously thought, suggesting preparedness to respond to a changing environment. PMID- 26496892 TI - Dielectric Barrier Discharge Ionization of Perfluorinated Compounds. AB - The soft ionization ability based on plasma-jet protonation of molecules initiated by a dielectric barrier discharge ionization source (DBDI) is certainly an interesting application for analytical chemistry. Since the change of an applied sinusoidal voltage may lead to different discharge modes the applied discharge was powered by a square wave generator in order to get a homogeneous plasma. It is known that besides the protonation [M+H](+) of unpolar as well as some polar molecules the homogeneous DBDI can be used to ionize molecules directly [M](+). Here we prove that the DBDI can be applied to exchange fluorine by oxygen of perfluorinated compounds (PFC). PFC are organofluorine compounds with carbon-fluorine and carbon-carbon bonds only but no carbon-hydrogen bonds. While the position of the introduction into the plasma-jet is essential, PFC can be measured in the negative mass spectrometer (MS) mode. PMID- 26496894 TI - Agreement between transperineal ultrasound measurements and digital examinations of cervical dilatation during labor. AB - BACKGROUND: To compare 2D transperineal ultrasound assessment of cervical dilatation with vaginal examination and to investigate intra-observer variability of the ultrasound method. METHODS: A prospective observational study was performed at Skane University Hospital, Lund, Sweden between October 2013 and June 2014. Women with one fetus in cephalic presentation at term had the cervical dilatation assessed with ultrasound and digital vaginal examinations during labor. Inter-method agreement between ultrasound and digital examinations and intra-observer repeatability of ultrasound examinations were tested. RESULTS: Cervical dilatation was successfully assessed with ultrasound in 61/86 (71 %) women. The mean difference between cervical dilatation and ultrasound measurement was 0.9 cm (95 % CI 0.47-1.34). Interclass correlation coefficient (ICC) was 0.83 (95 % CI 0.72-0.90). Intra-observer repeatability was analysed in 26 women. The intra-observer ICC was 0.99 (95 % CI 0.97-0.99). The repeatability coefficient was +/- 0.68 (95 % CI 0.45-0.91). CONCLUSION: The mean ultrasound measurement of cervical dilatation was approximately 1 cm less than clinical assessment. The intra-observer repeatability of ultrasound measurements was high. PMID- 26496893 TI - Effect of gastro-intestinal nematode infection on sheep performance: a systematic review and meta-analysis. AB - BACKGROUND: Gastrointestinal nematode (GIN) infections are common in domestic sheep and impact directly and indirectly on the health of infected animals as well as on the associated economic production. In this study, we aim at summarizing the current knowledge on the influence of GIN infections on sheep production by conducting a systematic review. A subsequent meta-analysis of relevant studies was performed to provide an estimate of the effect of GIN infections on weight gain, wool production and milk yield. METHODS: A literature search was performed on the CAB, Pubmed and Web of Science database for the period 1960-2012. Inclusion criteria were: 1) Measurement of at least one production parameter. 2) Comparison between groups of sheep with different nematode burdens. 3) Same conditions regarding all aspects except parasite burden between groups. 4) Quantitative measurements of one or more production traits. RESULTS: Altogether, 88 studies describing 218 trials were included in this review. The majority of studies (86%) reported that GIN infections had a negative effect on production but this was reported to be statistically significant in only 43% of the studies. Meta-analysis indicated that performances of sheep infected with nematodes was 85, 90 and 78% of the performance in uninfected individuals for weight gain, wool production and milk yield respectively. Our results suggest a possible reporting bias or small study effect for the estimation of the impact of GIN infections on weight gain. Finally, a general linear model provided an estimate for the decrease in weight gain in relation to the increase in faecal egg count of nematodes. CONCLUSION: This study underlines the importance of GIN infections for sheep production and highlights the need to improve parasite management in sheep, in particular in face of challenges such as anthelmintic resistance. PMID- 26496895 TI - The reflection anisotropy spectroscopy of the Au(1 1 0) surface structures in liquid environments. AB - The reflection anisotropy (RAS) profiles of the Au(1 1 0)-(1 * 1), (1 * 2) and (1 * 3) surface structures in electrochemical environments are shown to arise mainly from surface dipole transitions directed along the principal axes of the Au(1 1 0) surface. There are weak contributions to the RAS profiles of the Au(1 1 0)-(1 * 1) and (1 * 3) surfaces in the region of 4.0 eV which probably arise from (1 1 1) facets that are either intrinsic to the surface structures or are associated with steps. A transition involving a surface state just above the Fermi level, E F, contributes to the RAS profiles of the (1 * 2) and (1 * 3) surfaces but not to the RAS profile of the (1 * 1) surface. A strong feature at 2.5 eV in the RAS profiles of the Au(1 1 0)-(1 * 1) and (1 * 2) surfaces is attributed to a transition in the vicinity of the L point of the Brillouin zone between the 5d band and the [Formula: see text] band at E F. It is argued that the applied potential of -0.6 V, which creates the Au(1 1 0)-(1 * 3) surface, lifts E F above the [Formula: see text] band causing it to become occupied and quenching this contribution to the RAS profile. PMID- 26496897 TI - Lauric acid can improve the sensitization of Cetuximab in KRAS/BRAF mutated colorectal cancer cells by retrievable microRNA-378 expression. AB - EGFR-inhibitor (Cetuximab) is one of the main targeted drugs used for metastatic colorectal carcinoma (CRC). The benefit from Cetuximab appears to be limited to a subtype of patients, not for the patients with tumors harboring mutated BRAF or KRAS genes; unfortunately, it accounts for ~40-50% of CRC cases. Previous studies have connected higher expression levels of miR-378 to be commonly presented in patients without BRAF or KRAS mutants than in mutated CRCs. The microRNA-378 (miR 378) is coexpressed with PGC-1beta and can be easily induced by fatty acid, for example lauric acid. Therefore, we hypothesized that elevation of miR-378 expression in mutated CRCs may stimulate the cell response to Cetuximab. Herein, seven CRC cell lines with confirmed mutation status were involved in two parallel experiments; directly in vitro transfected miR-378 mimics, and using lauric acid to indirectly induce the level of miR-378 in cells. After the increase of miR-378 in cells by either direct or indirect approaches, sensitivity to Cetuximab was restored in all BRAF mutants (p-value <0.0001-0.0003), and half of KRAS mutants CRC (p-value 0.039-0.007). Further evidence was gained by decreasing expression of MEK and ERK2 proteins after transfection with miR-378; it was similar to the indirect induction by lauric acid approach. In conclusion, the present study demonstrated that lauric acid may efficiently induce miR-378 expression in CRC mutants, and both BRAF and a subtype of KRAS mutants presented significantly improved sensitivity to Cetuximab. Notably, BRAF mutants could even be inhibited in cell proliferation after elevated concentration of miR-378 in cells without combining with targeted therapy. This new approach may shed new light on BRAF or KRAS mutation in CRC patients for clinical trial, since lauric acid may easily be obtain from natural food, and it is supposed to be harmless to the cardiovascular system. PMID- 26496896 TI - Brucella infection of the thoracic vertebral arch presenting with an epidural abscess: a case report. AB - INTRODUCTION: Although Brucella spondylitis and Brucella discitis have been frequently reported, Brucella infection of the vertebral arch is rare and has not been previously described. We present the first case of Brucella infection of the thoracic vertebral arch with epidural abscess formation and discuss the clinical key points. CASE PRESENTATION: A 57-year-old man of Han nationality with a history of contact with an isolated sheep stomach 2 months previously was admitted with an undulant fever, night sweats, back pain, and weakness. Thoracic magnetic resonance imaging showed laminar destruction of T9 and an epidural abscess at the T9 to 10 level with significant cord compression. Diagnosis of Brucella infection of his vertebral arch was confirmed by a positive blood culture with growth of Brucella melitensis. Total laminectomy, abscess cleansing, and percutaneous pedicular screw fixation was performed initially, followed by antibiotic treatment with a combination of doxycycline and rifampin for 4 months. Recovery was confirmed by clinical, magnetic resonance imaging, and blood culture findings. CONCLUSIONS: This is an unusual case of Brucella infection of the vertebral arch with epidural abscess formation. Effective antibiotic therapy of a sufficient duration and timely performance of surgical treatment are the key points in management of such cases. PMID- 26496898 TI - HER3/ErbB3, an emerging cancer therapeutic target. AB - HER3 is a member of the HER (EGFR/ErbB) receptor family consisting of four closely related type 1 transmembrane receptors (EGFR, HER2, HER3, and HER4). HER receptors are part of a complex signaling network intertwined with the Ras/Raf/MAPK, PI3K/AKT, JAK/STAT, and PKC signaling pathways. Aberrant activation of the HER receptors and downstream signaling molecules tips the balance on cellular events, leading to various types of cancers. Monoclonal antibodies (mAbs) and small molecule inhibitors targeting EGFR and HER2 tyrosine kinase activities exhibit clinical benefits in the treatment of several types of cancers, but their clinical efficacy is limited by the occurrence of drug resistance. HER3 is the preferred dimerization partner of HER2 and it is well established that HER3 plays an important role in drug resistance to EGFR- and HER2-targeting therapies. Since HER3 has limited kinase activity, mAbs are being explored to target HER3 for cancer therapy. Currently, approximately a dozen of anti-HER3 mAbs are at different stages of clinical development. However, the lack of established biomarkers has made it more challenging to stratify cancer patients to whom HER3-targeting therapies can be more effective. In this review, we focus on the validation of HER3 as a cancer drug target, the recent development in biomarker discovery for anti-HER3 therapies, and the progress made in the clinical development of HER3-targeting mAbs. PMID- 26496899 TI - Leptin signaling plays a critical role in the geniposide-induced decrease of tau phosphorylation. AB - We have previously demonstrated that geniposide attenuates the production of Abeta1-42 both in vitro and in vivo via enhancing leptin receptor signaling. But the role played by geniposide in the phosphorylation of tau and its underlying molecular mechanisms remain unclear. In this study, we investigated the effect of geniposide on the phosphorylation of tau and the role of leptin signaling in this process. Our data suggested that, accompanied by the up-regulation of leptin receptor expression, geniposide significantly decreased the phosphorylation of tau in rat primary cultured cortical neurons and in APP/PS1 transgenic mice, and this geniposide-induced decrease of tau phosphorylation could be prevented by leptin antagonist (LA). Furthermore, LA also prevented the phosphorylation of Akt at Ser-473 site and GSK-3beta at Ser-9 site induced by geniposide. All these results indicate that geniposide may regulate tau phosphorylation through leptin signaling, and geniposide may be a promising therapeutic compound for the treatment of Alzheimer's disease in the future. PMID- 26496900 TI - CXC195 induces apoptosis and endoplastic reticulum stress in human hepatocellular carcinoma cells by inhibiting the PI3K/Akt/mTOR signaling pathway. AB - CXC195 exhibits strong protective effects against neuronal apoptosis by exerting antioxidant activity. However, the pharmacological function of CXC195 in cancer remains to be elucidated. The present study demonstrated that CXC195 exhibited significant cytotoxic effects, and induced cell cycle arrest and apoptosis in HepG2 human hepatocellular carcinoma (HCC) cell lines. Following treatment of HepG2 cells with 150 uMU CXC195 for 24 , cell viability and the apoptotic rate were assessed using an MTT assay and Annexin V/propidium iodide staining followed by flow cytometric analysis. Molecular markers of the cell cycle, apoptosis, mitochondrial function and endoplasmic reticulum (ER) stress were analyzed by western blot or polymerase chain reaction analysis. Caspase activation, cytochrome c and apoptosis-inducing factor release, and analysis of the B cell lymphoma 2 (Bcl-2)-associated X protein/Bcl-2 ratio demonstrated that the anticancer effects of CXC195 in HepG2 cells were mediated by caspase and mitochondria-dependent apoptosis. CXC195 also induced the expression of ER stress associated proteins, including CCAAT-enhancer-binding protein homologous protein, and glucose-regulated proteins 94 and 78, and led to the activation of multiple branches of ER stress transducers, including inositol-requiring enzyme 1alpha apoptosis signal-regulating kinase-p38/c-Jun N-terminal kinase, and protein kinase R-like endoplasmic reticulum kinase-eukaryotic translation initiation factor 2alpha-activating transcription factor (ATF)4 and ATF6, in the HepG2 cells. In addition, CXC195 inhibited the phosphorylation of phosphoinositide 3 kinase (PI3K), Akt and mammalian target of rapamycin (mTOR) in the HepG2 cells. These effects were enhanced following treatment with selected inhibitors of PI3K (LY294002), Akt (SH-6) and mTOR (rapamycin). Furthermore, these inhibitors enhanced the pro-apoptotic effects of CXC195 in the HepG2 cells. In conclusion, the results of the present study indicated that CXC195 induced apoptosis and ER stress in HepG2 cells through the inhibition of the PI3K/Akt/mTOR signaling pathway. PMID- 26496902 TI - Molecular and genomic sciences in health: apply the established rules of evidence. PMID- 26496903 TI - Overweight and obese midlife women in Israel: cultural differences in perceived weight status. AB - OBJECTIVES: To examine cultural differences in Weight status misperception (WSMP) and identify associations between weight perception and weight control efforts among overweight/obese midlife women in Israel. METHODS: Data from the nationally representative Women's-Health-in-Midlife-National-Study were used. Participants included overweight (25 <= BMI < 30) and obese (BMI >= 30) midlife women (45-64 years) from three cultural groups: Long-Term Jewish Residents (LTJR), Immigrants from the former USSR, and Arabs. Interviews included measures of BMI, weight perception, lifestyle, and socio-demographics. RESULTS: Most overweight/obese women (88 %) perceived their weight status correctly. No significant differences were found in overall WSMP rates across cultural groups. Overweight women of Arab origin were significantly more likely (p < 0.001) to perceive their weight as "about right" relative to LTJR and Immigrants. WSMP was associated with several unhealthy eating patterns [eating red meat (OR = 2.1, 95 % CI = 1.13-3.97), white bread (OR = 2.4, 95 % CI = 1.26-4.58)] and with more perceived barriers to exercising (OR = 1.8, 95 % CI = 1.00-3.42). CONCLUSIONS: Health care providers are encouraged to pay attention to overweight/obese women who misperceive their weight status. These women are more likely to consume unhealthy foods and to be at higher risks of suffering from medical complications associated with obesity. PMID- 26496904 TI - Graduate public health training in healthcare of refugee asylum seekers and clinical human rights: evaluation of an innovative curriculum. AB - OBJECTIVES: An innovative curriculum was developed to equip public health students with appropriate attitude and skills to address healthcare of asylum seekers. METHODS: Implemented in 2005 the curriculum included: (1) didactic sessions covering epidemiology and health sequelae of torture, asylum laws, and approaches to identify survivors' healthcare needs; (2) panel discussions with survivors and advocates; and (3) participating in medico-legal process of asylum seeking. Complementary mixed methods evaluations included pre- and post curriculum questionnaires, formal curriculum evaluations, final papers and oral presentations. RESULTS: 125 students participated. Students showed improved knowledge regrading sequelae of abuse and survivors' healthcare needs (P < 0.01), improved attitudes towards working with survivors (P < 0.05) and self-efficacy in identifying at-risk populations and addressing healthcare of survivors (P < 0.05). Students reported increased desire to pursue global health and human rights careers. CONCLUSIONS: As an advocacy and cultural competency training in public health practice addressing healthcare of refugees domestically, this curriculum was well received and effective, and will also help students better serve other similar populations. Population case-based domestic opportunities to teach global health and health and human rights should be effectively utilized to develop a well-equipped global health corps. PMID- 26496905 TI - Developmental Associations Between Conduct Problems and Expressive Language in Early Childhood: A Population-Based Study. AB - Conduct problems have been associated with poor language development, however the direction of this association in early childhood remains unclear. This study examined the longitudinal directional associations between conduct problems and expressive language ability. Children enrolled in the UK Millennium Cohort Study (N = 14, 004; 50.3 % boys) were assessed at 3 and 5 years of age. Parent reports of conduct problems and standardised assessments of expressive language were analyzed using cross-lagged modeling. Conduct problems at 3 years was associated with poorer expressive language at 5 years and poorer expressive language at 3 years was associated with increased conduct problems by 5 years. The results support reciprocal associations, rather than a specific unidirectional path, which is commonly found with samples of older children. The emergence of problems in either domain can thus negatively impact upon the other over time, albeit the effects were modest. Studies examining the effects of intervention targeting conduct problems and language acquisition prior to school entry may be warranted in testing the efficacy of prevention programmes related to conduct problems and poor language ability early in childhood. PMID- 26496906 TI - Warm Parenting and Effortful Control in Toddlerhood: Independent and Interactive Predictors of School-Age Externalizing Behavior. AB - Externalizing symptoms, such as aggression, impulsivity, and inattention, represent the most common forms of childhood maladjustment (Campbell et al. Development and Psychopathology, 12, 467-488, 2000). Several dimensions of parenting behavior, including overreactive and warm parenting, have been linked to children's conduct problems. However, the majority of these studies involve biologically-related family members, thereby limiting understanding of the role of genetic and/or environmental underpinnings of parenting on child psychopathology. This study extends previous research by exploring associations between overreactive and warm parenting during toddlerhood and school-age externalizing problems, as well as the potential moderating effects of child effortful control (EC) on such associations using a longitudinal adoption design. The sample consisted of 225 adoption-linked families (adoptive parents, adopted child [124 male and 101 female] and birth parent[s]), thereby allowing for a more precise estimate of environmental influences on the association between parenting and child externalizing problems. Adoptive mothers' warm parenting at 27 months predicted lower levels of child externalizing problems at ages 6 and 7. Child EC moderated this association in relation to teacher reports of school-age externalizing problems. Findings corroborate prior research with biological families that was not designed to unpack genetic and environmental influences on associations between parenting and child externalizing problems during childhood, highlighting the important role of parental warmth as an environmental influence. PMID- 26496909 TI - A distinctive pediatric case of low-grade glioma with extensive expression of CD34. PMID- 26496907 TI - Therapeutic Approach to the Management of Pediatric Demyelinating Disease: Multiple Sclerosis and Acute Disseminated Encephalomyelitis. AB - Acquired pediatric demyelinating diseases manifest acutely with optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, or with various other acute deficits in focal or polyfocal areas of the central nervous system. Patients may experience a monophasic illness (as in the case of acute disseminated encephalomyelitis) or one that may manifest as a chronic, relapsing disease [e.g., multiple sclerosis (MS)]. The diagnosis of pediatric MS and other demyelinating disorders of childhood has been facilitated by consensus statements regarding diagnostic definitions. Treatment of pediatric MS has been modeled after data obtained from clinical trials in adult-onset MS. There are now an increasing number of new therapeutic agents for MS, and many will be formally studied for use in pediatric patients. There are important efficacy and safety concerns regarding the use of these therapies in children and young adults. This review will discuss acute management as well as chronic immunotherapies in acquired pediatric demyelination. PMID- 26496911 TI - Erratum to: Validity of a New Patient Engagement Measure: The Altarum Consumer Engagement (ACE) Measure. PMID- 26496912 TI - [Old and offline? : Findings on the use of the Internet by people aged 65 years and older in Switzerland]. AB - BACKGROUND: The supply of information and communication is becoming continuously more focused on the Internet. While the age groups up to 64 years have shown a vast increase in the use of the Internet since 1997, intensive use of the Internet by age groups above 64 years lags behind and this is not only the case in Switzerland. Against this background and an interest in finding out more about Internet (non)use of older people, two representative surveys were conducted in Switzerland, one in 2009 and another one in 2014. MATERIAL AND METHODS: The data used were acquired throughout Switzerland via a standardized telephone survey. The random sample (2014) consisted of 1037 people aged between 65 and 100 years old. RESULTS: Although the digital divide between the age groups has lessened over the past years, only 55.7 % of the elderly people interviewed were using the Internet in the autumn of 2014. Internet usage differs greatly between age groups. Resources such as education, income and health positively impact actual use of the Internet. Additionally, recommendations from a person's social environment, as well as an affinity for technology and a personal benefit assessment have a positive impact on Internet usage. In particular, security concerns and difficulties of use were mentioned as predominant reasons for the non-use of the Internet. Some of the people questioned felt excluded from society because they did not use the Internet. CONCLUSION: Internet usage among elderly people depends on individual and social resources, as well as on general attitude towards technology and personal benefit expectations. The exclusion of today's elderly "offliners" should be avoided, even if the digital divide will decrease in the future. PMID- 26496910 TI - Ectopic expression of UGT75D1, a glycosyltransferase preferring indole-3-butyric acid, modulates cotyledon development and stress tolerance in seed germination of Arabidopsis thaliana. AB - The formation of auxin glucose conjugate is proposed to be one of the molecular modifications controlling auxin homeostasis. However, the involved mechanisms and relevant physiological significances are largely unknown or poorly understood. In this study, Arabidopsis UGT75D1 was at the first time identified to be an indole 3-butyric acid (IBA) preferring glycosyltransferase. Assessment of enzyme activity and IBA conjugates in transgenic plants ectopically expressing UGT75D1 indicated that the UGT75D1 catalytic specificity was maintained in planta. It was found that the expression pattern of UGT75D1 was specific in germinating seeds. Consistently, we found that transgenic seedlings with over-produced UGT75D1 exhibited smaller cotyledons and cotyledon epidermal cells than the wild type. In addition, UGT75D1 was found to be up-regulated under mannitol, salt and ABA treatments and the over-expression lines were tolerant to osmotic and salt stresses during germination, resulting in an increased germination rate. Quantitative RT-PCR analysis revealed that the mRNA levels of ABA INSENSITIVE 3 (ABI3) and ABI5 gene in ABA signaling were substantially down-regulated in the transgenic lines under stress treatments. Interestingly, AUXIN RESPONSE FACTOR 16 (ARF16) gene of transgenic lines was also dramatically down-regulated under the same stress conditions. Since ARF16 functions as an activator of ABI3 transcription, we supposed that UGT75D1 might play a role in stress tolerance during germination through modulating ARF16-ABI3 signaling. Taken together, our work indicated that, serving as the IBA preferring glycosyltransferase but distinct from other auxin glycosyltransferases identified so far, UGT75D1 might be a very important player mediating a crosstalk between cotyledon development and stress tolerance of germination at the early stage of plant growth. PMID- 26496913 TI - [Principles of social gerontology]. AB - Social gerontology is seen as a science-based but application-oriented subdiscipline of gerontology. It focuses particularly on social relationships in old age, social participation of elderly and old people and the protection of their individual needs. Self-determination and autonomy are important value orientations. Central issues are the quality of life and life satisfaction from the perspective of personal resources and biographical influences and the conditions of individual aging in the sense of differential gerontology. Against this background, in the first part of this article Kirsten Aner discusses the social construction of aging and in part two Ines Himmelsbach describes the typical life events and developmental tasks in the process of aging. The article concludes with a theoretical basis in which Cornelia Kricheldorff outlines social aging theories and derives a brief description of approaches and interventions. PMID- 26496914 TI - A Latent Class Analysis of Heterosexual Young Men's Masculinities. AB - Parallel bodies of research have described the diverse and complex ways that men understand and construct their masculine identities (often termed "masculinities") and, separately, how adherence to traditional notions of masculinity places men at risk for negative sexual and health outcomes. The goal of this analysis was to bring together these two streams of inquiry. Using data from a national, online sample of 555 heterosexually active young men, we employed latent class analysis (LCA) to detect patterns of masculine identities based on men's endorsement of behavioral and attitudinal indicators of "dominant" masculinity, including sexual attitudes and behaviors. LCA identified four conceptually distinct masculine identity profiles. Two groups, termed the Normative and Normative/Male Activities groups, respectively, constituted 88 % of the sample and were characterized by low levels of adherence to attitudes, sexual scripts, and behaviors consistent with "dominant" masculinity, but differed in their levels of engagement in male-oriented activities (e.g., sports teams). Only eight percent of the sample comprised a masculinity profile consistent with "traditional" ideas about masculinity; this group was labeled Misogynistic because of high levels of sexual assault and violence toward female partners. The remaining four percent constituted a Sex-Focused group, characterized by high numbers of sexual partners, but relatively low endorsement of other indicators of traditional masculinity. Follow-up analyses showed a small number of differences across groups on sexual and substance use health indicators. Findings have implications for sexual and behavioral health interventions and suggest that very few young men embody or endorse rigidly traditional forms of masculinity. PMID- 26496915 TI - A case of a quadricuspid pulmonary valve in a Japanese female. AB - A supernumerary cusp of the pulmonary valve was incidentally found in an 88-year old Japanese female during a gross anatomy course. The valve was composed of three equal-sized leaflets and one smaller leaflet. The supernumerary leaflet was located between the anterior and right semilunar leaflets. This pulmonary valve consisted of four pulmonary aortic bulbs. The donated body was a female who had a past history of myocardial infarction and was diagnosed as having ischemic heart disease at the last admission. Tricuspid valve regurgitation and pulmonary hypertension were diagnosed on echocardiography. These findings were considered to have been caused by left heart failure and not by the quadricuspid pulmonary valve. This asymptomatic anatomical variation might have developed from a protrusion between the anterior and right swelling of the outflow tract during semilunar valve development. PMID- 26496916 TI - Surviving the acid barrier: responses of pathogenic Vibrio cholerae to simulated gastric fluid. AB - When bacteria are subjected to low acidic pHs of the gastric environment, they may enter the viable but nonculturable (VBNC) state of survival. In this state, bacteria cannot be cultured on solid media, still exhibit signs of metabolic activity (viability). In this study, the response of pathogenic Vibrio cholerae O1 and O139 to low pH-simulated environments of the human stomach was evaluated for their survival by culturability (plate count) and viability (flow cytometry FC) assays. Bacteria were acid challenged with simulated gastric fluid (SGF) at pH 1.5, 2.5, 3.5 and 4.5 over a period of 180 min. Exposure to SGF up to 120 min increased acid tolerance of the Vibrios up to pH 3.5 with acid challenge occurring at pH 4.5. Bacteria were culturable from pH 2.5 to 4.5 up to 60 min SGF exposure. The stationary-phase cultures of Vibrio were able to survive SGF at all pHs in an 'injured' state with FC. This could possibly mean that the bacteria have entered the VBNC stage of survival. This is a worrying public health concern due to the fact that once favourable conditions arise (intestines), these Vibrios can change back to an infectious state and cause disease. PMID- 26496917 TI - Microbial community dynamics in Baolige oilfield during MEOR treatment, revealed by Illumina MiSeq sequencing. AB - This study was carried out to understand microbial diversity and function in the microbial enhanced oil recovery (MEOR) process and to assess the impact of MEOR treatment on the microbial community in an oil reservoir. The Illumina MiSeq based method was used to investigate the structure and dynamics of the microbial community in a MEOR-treated block of the Baolige oilfield, China. The results showed that microbial diversity was high and that 23 phyla occurred in the analyzed samples. Proteobacteria, Firmicutes, Bacteroidetes, Thermotogae, and Euryarchaeota were present in relatively high abundance in all analyzed samples. Injection of bacteria and nutrients resulted in interesting changes in the composition of the microbial community. During MEOR treatment, the community was dominated by the known hydrocarbon-utilizing genera Pseudomonas and Acinetobacter. After the treatment, the two genera decreased in abundance over time while Methanobacteriaceae, as well as known syntrophic genera such as Syntrophomonas, Pelotomaculum, Desulfotomaculum, and Thermacetogenium gradually increased. The change in dominant microbial populations indicated the presence of a succession of microbial communities over time, and the hydrocarbon degradation and syntrophic oxidation of acetate and propionate to methane in the MEOR-treated oilfield. This work contributes to a better understanding of microbial processes in oil reservoirs and helps to optimize MEOR technology. PMID- 26496918 TI - A specific RAGE-binding peptide biopanning from phage display random peptide library that ameliorates symptoms in amyloid beta peptide-mediated neuronal disorder. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder in which amyloid beta (Abeta) peptide accumulates in the brain. The receptor for advanced glycation end product (RAGE) is a cellular binding site for Abeta peptide and mediates amyloid beta-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a specific high-affinity RAGE inhibitor (APDTKTQ named RP-1) from a phage display library. RP-1 bound to RAGE and inhibited Abeta peptide-induced cellular stress in human neuroblastoma SH-SYSY cells in vitro. Three amino acids in RP-1 are identical to those in the Abeta peptide. RP-1 shows high homology to the 16-23 (KLVFFAED) regions in Abeta peptide and high-affinity RAGE. Functional analyses indicated that RP-1 significantly reduced the level of reactive oxygen species (ROS) and ROS products and that it enhanced catalase and glutathione peroxidase (GPx) activity. Furthermore, it inactivated caspase3 and caspase9 and inhibited the upregulation of RAGE, nuclear factor-kappaB (NF-kappaB), and beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein expression. In addition, RP-1 activated the PI3K/AKT signaling pathway, inhibiting the interaction between Bax and Bcl-2. Our data suggest that RP-1 is a potent RAGE blocker that effectively controls the progression of Abeta peptide-mediated brain disorders and that it may have potential as a disease-modifying agent for AD. PMID- 26496919 TI - Spatiotemporal variation of bacterial and archaeal communities in a pilot-scale constructed wetland for surface water treatment. AB - Microorganisms play important roles in the reduction of organic and inorganic pollutants in constructed wetlands used for the treatment of polluted surface water. However, the diversity and structure of microbial community in surface water constructed wetland system remain poorly known. The present study was made to characterize bacterial and archaeal communities in a surface water constructed wetland using Illumina high-throughput sequencing. The diversity and structure of both bacterial and archaeal communities illustrated a remarkable spatiotemporal variation. Archaeal communities showed lower richness and diversity than bacterial communities. Bacterial diversity decreased with increasing wetland layer depth. A variety of bacterial phyla or candidate divisions were found in wetland bacterial communities, including Proteobacteria, Chloroflexi, Firmicutes, Acidobacteria, Bacteroidetes, Nitrospirae, Actinobacteria, Spirochaetae, Planctomycetes, Chlorobi, Deferribacteres, Cyanobacteria, OP8, WS3, TA06, and OP11, while Proteobacteria, Chloroflexi, and Firmicutes were the major bacterial groups. Euryarchaeota and Thaumarchaeota dominated wetland archaeal communities. PMID- 26496920 TI - Regulons of global transcription factors in Corynebacterium glutamicum. AB - Corynebacterium glutamicum, a high GC content gram-positive soil bacterium in Actinobacteria, has been used for the industrial production of amino acids and engineered to produce various compounds, including polymer building blocks and biofuels. Since its genome sequence was first published, its versatile metabolic pathways and their genetic components and regulatory mechanisms have been extensively studied. Previous studies on transcriptional factors, including two component systems and sigma factors, in the bacterium have revealed transcriptional regulatory links among the metabolic pathways and those among the stress response systems, forming a complex transcriptional regulatory network. The regulatory links are based on knowledge of the transcription factors, such as their target genes (regulons), DNA sequence motifs for recognition, and effector molecules controlling their activities, all of which are fundamental for understanding their physiological functions. Recent advances in chromatin immunoprecipitation (ChIP)-based genome-wide analyses provide an opportunity to comprehensively identify the transcription factor regulon, composed of its direct target genes, and its precise consensus binding motif. A common feature among the regulon constituents may provide clues to identify an effector molecule targeting the factor. In this mini-review, we summarize the current knowledge of the regulons of the C. glutamicum transcription factors that have been analyzed via ChIP-based technologies. The regulons consisting of direct target genes revealed new physiological roles of the transcription factors and new regulatory interactions, contributing to refinement and expansion of the transcriptional regulatory network and the development of guidelines and genetic tools for metabolic engineering of C. glutamicum. PMID- 26496921 TI - A novel interaction between ATOH8 and PPP3CB. AB - ATOH8 is a bHLH transcription factor playing roles in a variety of developmental processes such as neurogenesis, differentiation of pancreatic precursor cells, development of kidney and muscle, and differentiation of endothelial cells. PPP3CB belongs to the catalytic subunit of the serine/threonine phosphatase, calcineurin, which can dephosphorylate its substrate proteins to regulate their physiological activities. In our study, we demonstrated that ATOH8 interacts with PPP3CB in vitro with different approaches. We show that the conserved catalytic domain of PPP3CB interacts with both the N-terminus and the bHLH domain of ATOH8. Although the interaction domain of PPP3CB is conserved among all isoforms of calcineurin A, ATOH8 selectively interacts with PPP3CB instead of PPP3CA, probably due to the unique proline-rich region present in the N-terminus of PPP3CB, which controls the specificity of its interaction partners. Furthermore, we show that inhibition of the interaction with calcineurin inhibitor, cyclosporin A (CsA), leads to the retention of ATOH8 to the cytoplasm, suggesting that the interaction renders nuclear localization of ATOH8 which may be critical to control its activity as transcription factor. PMID- 26496922 TI - Galanin regulates blood glucose level in the zebrafish: a morphological and functional study. AB - The present study has demonstrated the galaninergic innervation of the endocrine pancreas including sources of the galaninergic nerve fibers, and the influence of galanin receptor agonists on blood glucose level in the zebrafish. For the first time, a very abundant galaninergic innervation of the endocrine pancreas during development is shown, from the second day post-fertilization to adulthood. The fibers originated from ganglia consisting of galanin-IR, non-adrenergic (non sensory) neurons located rostrally to the pancreatic tissue. The ganglia were found on the dorsal side of the initial part of the anterior intestinal segment, close to the intestinal branch of the vagus nerve. The galanin-IR neurons did not show immunoreactivity for applied antibodies against tyrosine hydroxylase, choline acetyltransferase, and vesicular acetylcholine transporter. Intraperitoneal injections of galanin analog NAX 5055 resulted in a statistically significant increase in the blood glucose level. Injections of another galanin receptor agonist, galnon, also caused a rise in blood glucose level; however, it was not statistically significant. The present findings suggest that, like in mammals, in the zebrafish galanin is involved in the regulation of blood glucose level. However, further studies are needed to elucidate the exact mechanism of the galanin action. PMID- 26496923 TI - Immunohistochemical study of the membrane skeletal protein, membrane protein palmitoylated 6 (MPP6), in the mouse small intestine. AB - The membrane protein palmitoylated (MPP) family belongs to the membrane associated guanylate kinase (MAGUK) family. MPP1 interacts with the protein 4.1 family member, 4.1R, as a membrane skeletal protein complex in erythrocytes. We previously described the interaction of another MPP family, MPP6, with 4.1G in the mouse peripheral nervous system. In the present study, the immunolocalization of MPP6 in the mouse small intestine was examined and compared with that of E cadherin, zonula occludens (ZO)-1, and 4.1B, which we previously investigated in intestinal epithelial cells. The immunolocalization of MPP6 was also assessed in the small intestines of 4.1B-deficient (-/-) mice. In the small intestine, Western blotting revealed that the molecular weight of MPP6 was approximately 55 kDa, and MPP6 was immunostained under the cell membranes in the basolateral portions of almost all epithelial cells from the crypts to the villi. The immunostaining pattern of MPP6 in epithelial cells was similar to that of E cadherin, but differed from that of ZO-1. In intestinal epithelial cells, the immunostained area of MPP6 was slightly different from that of 4.1B, which was restricted to the intestinal villi. The immunolocalization of MPP6 in small intestinal epithelial cells was similar between 4.1B(-/-) mice and 4.1B(+/+) mice. In the immunoprecipitation study, another MAGUK family protein, calcium/calmodulin-dependent serine protein kinase (CASK), was shown to molecularly interact with MPP6. Thus, we herein showed the immunolocalization and interaction proteins of MPP6 in the mouse small intestine, and also that 4.1B in epithelial cells was not essential for the sorting of MPP6. PMID- 26496924 TI - Aquaporin 2-labeled cells differentiate to intercalated cells in response to potassium depletion. AB - The mammalian renal collecting duct consists of principal cells (PCs) and intercalated cells (ICs). Both PCs and ICs are involved in potassium (K(+)) homeostasis, PCs through their role in K(+) secretion and ICs through their ability to facilitate K(+) resorption. We previously hypothesized that PCs may differentiate into ICs upon K(+) depletion. However, no direct evidence has yet been obtained to conclusively demonstrate that PCs differentiate into ICs in response to K(+) depletion. Here, we present direct evidence for the differentiation of PCs into ICs by cell lineage tracing using aquaporin 2 (AQP2) Cre mice and R26R-EYFP transgenic mice. In control mice, AQP2-EYFP(+) cells exhibited mainly a PC phenotype (AQP2-positive/H(+)-ATPase-negative). Interestingly, some AQP2-EYFP(+) cells exhibited an IC phenotype (H(+)-ATPase positive/AQP2-negative); these cells accounted for 1.7 %. After K(+) depletion, the proportion of AQP2-EYFP(+) cells with an IC phenotype was increased to 4.1 %. Furthermore, some AQP2-EYFP(+) cells exhibited a "null cell" phenotype (AQP2 negative/H(+)-ATPase-negative) after K(+) depletion. Collectively, our data demonstrate that AQP2-labeled cells can differentiate into ICs, as well as null cells, in response to K(+) depletion. This finding indicates that some of AQP2 labeled cells possess properties of progenitor cells and that they can differentiate into ICs in the adult mouse kidney. PMID- 26496925 TI - Safety, efficacy, and cost of surgery for patients with unruptured aneurysms deemed unsuitable for endovascular therapy. AB - BACKGROUND: Open surgery is a frequent option given to patients with unruptured intracranial aneurysms (UIAs) unsuitable for endovascular repair. Since the risk of rupture of UIAs is generally low, we determined whether the risks and costs of surgery in this patient subset are warranted. METHODS: The safety, efficacy, and costs of minimally invasive surgery by minicraniotomy were evaluated in 102 consecutive patients with anterior circulation UIAs deemed unsuitable for endovascular repair by an interdisciplinary conference of surgeons and neurointerventionalists. Data from 107 UIA patients treated by endovascular means in the same period were used as the standard. RESULTS: Surgical patients comprised a different subset of aneurysms, with more MCA and fewer paraophthalmic aneurysms (54 vs. 6, p < 0.0001 and 4 vs. 60, p < 0.0001, for minicraniotomy and endovascular, respectively). However, surgery incurred shorter anesthesia time (197.7 vs. 149.3 min, p < 0.0001), higher rates of complete aneurysm obliteration (94.57 vs. 66.67 %, p < 0.0001), and lower overall hospital costs ($8,287 CAD vs. $17,732 CAD, p < 0.0001) than the endovascular cohort. There were no treatment related surgical deaths, but one patient had an mRS of 3 after 6 months due to temporal lobe epilepsy and memory problems. This compared favorably with the endovascular cohort in which two patients died due to treatment (mRS = 6) and one suffered a severe stroke (mRS = 5 at 6 months). CONCLUSIONS: For patients counseled to undergo treatment but have UIAs unsuitable for endovascular repair, surgery is safe, effective, and cost-efficient. PMID- 26496926 TI - Upregulation of fractalkine contributes to the proliferative response of prostate cancer cells to hypoxia via promoting the G1/S phase transition. AB - Hypoxia is a common phenomenon in prostate cancer, which leads to cell proliferation and tumor growth. Fractalkine (FKN) is a membrane-bound chemokine, which is implicated in the progression of human prostate cancer and skeletal metastasis. However, the association between FKN and hypoxia-induced prostate cancer cell proliferation remains to be elucidated. The present study demonstrated that hypoxia induced the expression and secretion of FKN in the DU145 prostate cancer cell line. Furthermore, inhibiting the activity of FKN with the anti-FKN FKN-specific antibody markedly inhibited hypoxia-induced DU145 cell proliferation. Under normoxic conditions, DU145 cell proliferation markedly increased following exogenous administration of human recombinant FKN protein, and the increase was significantly alleviated by anti-FKN, indicating the importance of FKN in DU145 cell proliferation. In addition, subsequent determination of cell cycle distribution and expression levels of two core cell cycle regulators, cyclin E and cyclin-dependent kinase (CDK)2, suggested that FKN promoted the G1/S phase transition by upregulating the expression levels of cyclin E and CDK2. The results of the present study demonstrated that hypoxia led to the upregulation of the secretion and expression of FKN, which enhanced cell proliferation by promoting cell cycle progression in the prostate cancer cells. These findings provide evidence of a novel function for FKN, and suggest that FKN may serve as a potential target for treating androgen-independent prostate cancer. PMID- 26496927 TI - Establishment of an immortalized cell line derived from the prairie vole via lentivirus-mediated transduction of mutant cyclin-dependent kinase 4, cyclin D, and telomerase reverse transcriptase. AB - The prairie vole (Microtus ochrogaster) shows social behaviors such as monogamy and parenting of infants with pair bonding. These social behaviors are specific to the prairie vole and have not been observed in other types of voles, such as mountain voles. Although the prairie vole has several unique characteristics, an in vitro cell culture system has not been established for this species. Furthermore, establishment of cultured cells derived from the prairie vole may be beneficial based on the three Rs (i.e., Replacement, Reduction, and Refinement) concept. Therefore, in this study, we attempted to establish an immortalized cell line derived from the prairie vole. Our previous research has shown that transduction with mutant forms of cyclin-dependent kinase 4 (CDK4), cyclin D, and telomerase reverse transcriptase (TERT) could efficiently immortalize cells from multiple species, including humans, cattle, pigs, and monkeys. Here, we introduced these three genes into prairie vole-derived muscle fibroblasts. The expression of mutant CDK4 and cyclin D proteins was confirmed by western blotting, and telomerase activity was detected in immortalized vole muscle derived fibroblasts (VMF-K4DT cells or VMFs) by stretch PCR. Population doubling analysis showed that the introduction of mutant CDK4, cyclin D, and TERT extended the lifespan of VMFs. To the best of our knowledge, this is the first report describing the establishment of an immortalized cell line derived from the prairie vole through the expression of mutant CDK4, cyclin D, and human TERT. PMID- 26496928 TI - Adjacent segment infection after surgical treatment of spondylodiscitis. AB - BACKGROUND: This is the first case series to describe adjacent segment infection (ASI) after surgical treatment of spondylodiscitis (SD). MATERIALS AND METHODS: Patients with SD, spondylitis who were surgically treated between 1994 and 2012 were included. Out of 1187 cases, 23 (1.94 %) returned to our institution (Zentralklinik Bad Berka) with ASI: 10 males, 13 females, with a mean age of 65.1 years and a mean follow-up of 69 months. RESULTS: ASI most commonly involved L3-4 (seven patients), T12-L1 (five) and L2-3 (four). The mean interval between operations of primary infection and ASI was 36.9 months. All cases needed surgical intervention, debridement, reconstruction and fusion with longer instrumentation, with culture and sensitivity-based postoperative antimicrobial therapy. At last follow-up, six patients (26.1 %) were mobilized in a wheelchair with a varying degree of paraplegia (three had pre-existing paralysis). Three patients died within 2 months after the ASI operation (13 %). Excellent outcomes were achieved in five patients, and good in eight. CONCLUSIONS: Adjacent segment infection after surgical treatment of spondylodiscitis is a rare complication (1.94 %). It is associated with multimorbidity and shows a high mortality rate and a high neurological affection rate. Possible explanations are: haematomas of repeated micro-fractures around screw loosening, haematogenous spread, direct inoculation or a combination of these factors. ASI may also lead to proximal junctional kyphosis, as found in this series. We suggest early surgical intervention with anterior debridement, reconstruction and fusion with posterior instrumentation, followed by antimicrobial therapy for 12 weeks. LEVEL OF EVIDENCE: Level IV retrospective uncontrolled case series. PMID- 26496929 TI - Long-term clinical results and MRI changes after autologous chondrocyte implantation in the knee of young and active middle aged patients. AB - BACKGROUND: Autologous chondrocyte implantation (ACI) represents a valid surgical option for symptomatic full-thickness chondral lesions of the knee. Here we report long-term clinical and MRI results of first-generation ACI. MATERIALS AND METHODS: Fifteen patients (mean age 21.3 years) underwent first-generation ACI for symptomatic chondral defects of the knee between 1997 and 2001. The mean size of the lesions was 5.08 cm(2) (range 2-9 cm(2)). Patients were evaluated using the International Knee Documentation Committee (IKDC) Knee Examination Form, the Tegner Activity Scale, and the Knee Injury and Osteoarthritis Outcome Score (KOOS). High-resolution MRI was used to analyze the repair tissue with nine variables (the MOCART scoring system). RESULTS: The mean follow-up period was 148 months (range 125-177 months). ACI resulted in substantial improvements in all clinical outcome parameters, even as much as 12 years after implantation. A significant decrease in the MOCART score was recorded at final measurement. Reoperation was required in 2 patients; failure was caused by partial detachment of the graft in both cases. CONCLUSION: Autologous chondrocyte implantation is an effective and durable solution for the treatment of large, full-thickness cartilage and osteochondral lesions, even in young and active middle-aged patients. High-resolution MRI is a useful and noninvasive method for evaluating the repaired tissue. LEVEL OF EVIDENCE: IV. PMID- 26496930 TI - Effects of the fungicide pyrimethanil on biofilm and organic matter processing in outdoor lentic mesocosms. AB - The effect of the fungicide pyrimethanil (0.7 mg L(-1)) on biofilm development and alder leaf litter decomposition in aquatic ecosystems was assessed in outdoor lentic mesocosms immediately and 274 days after pyrimethanil application. Pyrimethanil decreased ergosterol concentrations (an indicator of fungal biomass) and the abundance and richness of the macroinvertebrate community associated with decomposing leaves. However, because neither fungi nor macroinvertebrates were main factors contributing to decomposition in this particular system, organic matter processing rates were not affected. After 274 days, pyrimethanil concentration in the water column was <=0.004 mg L(-1) but richness, biomass and composition of the invertebrate community associated with decomposing leaf-litter still showed the effect. The comparison of ergosterol (a molecule existing on both algae and fungal cell membranes), with chlorophyll (an indicator of algal biomass) associated with biofilm suggests that pyrimethanil may decrease fungal biomass and alter the relative abundance of algae and fungi on biofilm developing in control- and treated-mesocosms. PMID- 26496931 TI - All-Cause and Cause-Specific Mortality Associated with Bariatric Surgery: A Review. AB - The question of whether or not nonsurgical intentional or voluntary weight loss results in reduced mortality has been equivocal, with long-term mortality following weight loss being reported as increased, decreased, and not changed. In part, inconsistent results have been attributed to the uncertainty of whether the intentionality of weight loss is accurately reported in large population studies and also that achieving significant and sustained voluntary weight loss in large intervention trials is extremely difficult. Bariatric surgery has generally been free of these conflicts. Patients voluntarily undergo surgery and the resulting weight is typically significant and sustained. These elements, combined with possible non-weight loss-related mechanisms, have resulted in improved comorbidities, which likely contribute to a reduction in long-term mortality. This paper reviews the association between bariatric surgery and long-term mortality. From these studies, the general consensus is that bariatric surgical patients have: 1) significantly reduced long-term all-cause mortality when compared to severely obese non-bariatric surgical control groups; 2) greater mortality when compared to the general population, with the exception of one study; 3) reduced cardiovascular-, stroke-, and cancer-caused mortality when compared to severely obese non-operated controls; and 4) increased risk for externally caused death such as suicide. PMID- 26496933 TI - The Proceedings of Medical Quality 2015. PMID- 26496932 TI - Immune adjuvant effect of Juzentaihoto, a Japanese traditional herbal medicine, on tumor vaccine therapy in a mouse model. AB - Japanese traditional herbal medicine (Kampo) have been used to improve the general physical condition after surgery and to mitigate the side effects of radiation and chemotherapy in tumor patients. Juzentaihoto (JTT) consists of ten medical herbs, and is also called Shi-Quan-Da-Bu-Tang in Chinese herbal medicine. Among Kampo medicines, JTT has especially gained attention as a biological response modifier. Currently, clinical trials of various tumor vaccine therapies are being performed world-wide. However, tumor antigens that are inoculated as vaccines do not have high immunogenicity; thus, it is difficult to obtain an effective therapeutic effect. Thus, it is necessary to develop a tumor vaccine adjuvant that is more potent and very safe. In the present study, we examined the efficacy of JTT as an oral adjuvant when given together with tumor vaccines. As a result, JTT enhanced the phagocytic ability of OVA antigen and the presentation ability of OVA antigen in dendritic cells in vitro. Furthermore, tumor growth was markedly decreased, and the survival period was significantly prolonged in mice inoculated with mouse lymphoma, which is expressed with tumor model antigen. In conclusion, these findings suggest that JTT can be used with tumor vaccines as an immune adjuvant. PMID- 26496934 TI - Why the drug development pipeline is not delivering better medicines. PMID- 26496935 TI - Clinical results of definitive intensity-modulated radiation therapy for oropharyngeal cancer: retrospective analysis of treatment efficacy and safety. AB - OBJECTIVE: To evaluate the clinical outcomes of intensity-modulated radiotherapy for patients with oropharyngeal carcinoma. METHODS: Ninety-three oropharyngeal carcinoma patients histopathologically diagnosed with squamous cell carcinoma and treated with definitive intensity-modulated radiotherapy using helical tomotherapy between January 2006 and December 2013 were analyzed. Planning target volume primary and involved nodes was delivered 66-70 Gy at 2 Gy per fraction, while planning target volume prophylactic was delivered 54 Gy using the simultaneous integrated boost technique. RESULTS: The median follow-up period among the surviving patients was 40 months (range, 13-96). There were 76 males and 17 females with a median age of 60 years (range, 34-80). The disease was Stage II in 13%, Stage III in 10% and Stage IV in 77% of patients. Ninety-two patients received chemotherapy (99%); 68 patients received induction chemotherapy (73%), while 21 received concurrent chemotherapy (23%). The 3-year overall survival, progression-free survival and locoregional control rates were 80, 68 and 79%, respectively. Multivariate analysis identified an advanced T-category (T3-4), having double cancer, and smoking habit as significantly unfavorable factors for overall survival, progression-free survival and both progression-free survival and locoregional control, respectively. Only two patients who achieved disease control required percutaneous endoscopic gastrostomy tubes in the last follow-up. The rate of Grade 2 xerostomia at 2 years was 23%. CONCLUSIONS: Intensity-modulated radiotherapy using helical tomotherapy for patients with oropharyngeal carcinoma provided not only sufficient efficacy, but also preserved parotid function. PMID- 26496936 TI - Determinants of willingness to pay for the retreatment of insecticide treated mosquito nets in rural area of eastern Ethiopia. AB - OBJECTIVE: Is to determine willingness to pay(WTP)/demand for the retreatment of Insecticide treated mosquito nets for malaria control in Ethiopia. METHODS: A community based cross-sectional study was conducted in Gursum district in Eastern Ethiopia. A total of 335 households were surveyed using a pre-tested structured questionnaire. Multivariable regression analyses using the Tobit model were used to test the theoretical validity of elicited WTP. RESULTS: About 159(76.4%) of them have received a treated insecticide when they obtained. One hundred twenty five (60.4%) know that the net should be retreated. Around 110(50.7%), 80(36.9%) and 27(12.4%) of the participants feel that the current price of ITNs as negotiable/ not as such expensive, expensive and cheap. About 306(96.5%) of them reported that they support that ITNs be given freely and 257(82.9%) were mentioned that the retreatment service should be provided without charge. The WTP amounts ranged from 0 to 10.4 USD. The mean with SD of the respondents from open ended elicitation method for willingness to pay was 1 USD and 1.53 USD. The reduced tobit regression models showed that average income more than 10.4 USD per month and those household who live within a distance in 30 min to the health facility were the determinant for willingness to pay. CONCLUSION: The mean with SD of the respondents for willingness to pay was 1 USD and 1.53 USD. Average monthly income and those household who live within a distance in 30 min to the health facility were determinant for willingness to pay. Government and other development partners should seek a mechanism to make a subsidy or free of charge for the retreatment services. Differential treatment from the public to address the poor and vulnerable households and those who are living far distance from the local health facility is warranted. PMID- 26496937 TI - A randomized controlled trial comparing a prepackaged low-residue diet with a restricted diet for colonoscopy preparation: the impact on the results of colonoscopy in adenoma detection. AB - AIM: This study aimed to investigate the clinical utility of a prepackaged low residue diet (PLD) compared with a restricted diet (RD) for colonoscopic bowel preparation. METHOD: A prospective randomized controlled trial was carried out with patients undergoing colonoscopy. One hundred patients were randomly assigned to PLD and RD groups. In the RD group, the patients received an information sheet containing acceptable low-residue options and instructions from the medical staff. All patients received 10 ml sodium picosulphate the day before colonoscopy and 1 l of polyethylene glycol with ascorbic acid (PEG-A) on the day of the colonoscopy. If the bowel preparation was not adequate, an additional PEG-A solution was given. The primary outcome was the efficacy of colonic cleansing as rated by the Boston Bowel Preparation Scale (BBPS). The additional amount of PEG A solution, adenoma detection rate and patient tolerance were assessed as secondary outcomes. RESULTS: The BBPS score in the PLD group was 7.3 +/- 1.7 compared with 6.5 +/- 1.7 in the RD group. The quality of bowel preparation was significantly better in the PLD group (P < 0.05). The mean amount of additional PEG-A solution in the PLD group was smaller than in the RD group (293.8 +/- 474.8 vs 444.1 +/- 625.0 ml), but there was no statistical difference between the two groups. Adenoma detection rates and patient tolerance were similar in the two groups. CONCLUSION: Prepackaged low-residue diets PLD is superior to RD for bowel preparation for colonoscopy. PMID- 26496939 TI - The motivation for special interests in individuals with autism and controls: Development and validation of the special interest motivation scale. AB - Clinical observations and first person accounts of living with autism suggest that individuals with autism are highly motivated to engage in special interests, and that these interests remain important throughout life. Previous research assessing special interests has mainly focused on parental reports of children with autism spectrum conditions (ASC). To better understand the significance of and motivations for engaging in special interests it is essential to use self report ratings. This paper aims to systematically explore the motivations for engagement in special interests, and whether these differ in adults with ASC, first-degree relatives and general population controls. The Special Interest Motivation Scale (SIMS) was developed to assess motivation to engage in special interests. The internal structure of this scale was evaluated using factor analysis, and mean scores on the SIMS factors were subsequently compared across individuals with autism, parents and general population controls. Factor analysis indicated a 20-item SIMS containing five factors assessing Personal life values and goals; Intrinsic interest and knowledge; Prestige; Engagement and "flow" and Achievement. Individuals with autism were more motivated by Intrinsic interest and knowledge and by Engagement and flow than controls. The 20-item SIMS is a quick to administer measure that provides a reliable description of motivation to engage in special interests. This study indicates that individuals with ASC are highly motivated to engage in their special interest, and are more motivated than controls by intrinsic motivational factors, some of which are associated with positive affect. This has implications for research and clinical practice. Autism Res 2016, 9: 677-688. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26496938 TI - TrkA is amplified in malignant melanoma patients and induces an anti proliferative response in cell lines. AB - BACKGROUND: The nerve growth factor (NGF) receptor tyrosine-kinase TrkA is a well known determinant of the melanocytic lineage, through modulation of the MAPK and AKT cascades. While TrkA gene is frequently rearranged in cancers, its involvement in malignant melanoma (MM) development is still unclear. METHODS: We analyzed a dataset of primary cutaneous MM (n = 31) by array comparative genomic hybridization (aCGH), to identify genomic amplifications associated with tumor progression. The analysis was validated by genomic quantitative PCR (qPCR) on an extended set of cases (n = 64) and the results were correlated with the clinical outcome. To investigate TrkA molecular pathways and cellular function, we generated inducible activation of the NGF-TrkA signaling in human MM cell lines. RESULTS: We identified amplification of 1q23.1, where the TrkA locus resides, as a candidate hotspot implicated in the progression of MM. Across 40 amplicons detected, segmental amplification of 1q23.1 showed the strongest association with tumor thickness. By validation of the analysis, TrkA gene amplification emerged as a frequent event in primary melanomas (50 % of patients), and correlated with worse clinical outcome. However, experiments in cell lines revealed that induction of the NGF-TrkA signaling produced a phenotype of dramatic suppression of cell proliferation through inhibition of cell division and pronounced intracellular vacuolization, in a way straightly dependent on NGF activation of TrkA. These events were triggered via MAPK activity but not via AKT, and involved p21(cip1) protein increase, compatibly with a mechanism of oncogene-induced growth arrest. CONCLUSIONS: Taken together, our findings point to TrkA as a candidate oncogene in MM and support a model in which the NGF-TrkA-MAPK pathway may mediate a trade-off between neoplastic transformation and adaptive anti proliferative response. PMID- 26496940 TI - Targeting type-2 metabotropic glutamate receptors to protect vulnerable hippocampal neurons against ischemic damage. AB - BACKGROUND: To examine whether metabotropic glutamate (mGlu) receptors have any role in mechanisms that shape neuronal vulnerability to ischemic damage, we used the 4-vessel occlusion (4-VO) model of transient global ischemia in rats. 4-VO in rats causes a selective death of pyramidal neurons in the hippocampal CA1 region, leaving neurons of the CA3 region relatively spared. We wondered whether changes in the expression of individual mGlu receptor subtypes selectively occur in the vulnerable CA1 region during the development of ischemic damage, and whether post ischemic treatment with drugs targeting the selected receptor(s) affords neuroprotection. RESULTS: We found that 4-VO caused significantly reduction in the transcript of mGlu2 receptors in the CA1 region at times that preceded the anatomical evidence of neuronal death. Down-regulation of mGlu2 receptors was associated with reduced H3 histone acetylation at the Grm2 promoter. The transcripts of other mGlu receptor subtypes were unchanged in the CA1 region of 4 VO rats. Ischemia did not cause changes in mGlu2 receptor mRNA levels in the resistant CA3 region, which, interestingly, were lower than in the CA1 region. Targeting the mGlu2 receptors with selective pharmacologic ligands had profound effects on ishemic neuronal damage. Post-ischemic oral treatment with the selective mGlu2 receptor NAM (negative allosteric modulator), ADX92639 (30 mg/kg), was highly protective against ischemic neuronal death. In contrast, s.c. administration of the mGlu2 receptor enhancer, LY487379 (30 mg/kg), amplified neuronal damage in the CA1 region and extended the damage to the CA3 region. CONCLUSION: These findings suggest that the mGlu2 receptor is an important player in mechanisms regulating neuronal vulnerability to ischemic damage, and that mGlu2 receptor NAMs are potential candidates in the experimental treatments of disorders characterized by brain hypoperfusion, such as hypovolemic shock and cardiac arrest. PMID- 26496941 TI - beta-catenin signaling induces the osteoblastogenic differentiation of human pre osteoblastic and bone marrow stromal cells mainly through the upregulation of osterix expression. AB - Both beta-catenin (beta-cat) and osterix (OSX) are known to be essential for embryonic and postnatal osteoblast differentiation and bone growth. In the present study, we explored the crosstalk between beta-cat signaling and OSX, and assessed its effect on the osteoblastogenic differentiation of human pre osteoblastic cells (MG-63) and bone marrow stromal cells (HS-27A). In the HS-27A and MG-63 cells, the selective beta-cat signaling inhibitor, CCT031374, and the stable overexpression of a constitutively active beta-cat mutant respectively decreased and increased the cytoplasmic/soluble beta-cat levels, and respectively decreased and increased TOPflash reporter activity, the mRNA levels of beta-cat signaling target genes c-Myc and c-Jun, as well as the mRNA and protein expression levels of OSX. Mutational analyses and electrophoretic mobility shift assays revealed that the increased binding activity of c-Jun at a putative c-Jun binding site (-858/-852 relative to the translation start codon, which was designated as +1) in the human OSX gene promoter was required for teh beta-cat signaling-induced expression of OSX in the HS-27A and MG-63 cells. During osteoblastogenic culture, stimulating beta-cat signaling activity by the stable overexpression of the active beta-cat mutant markedly increased alkaline phosphatase (ALP) activity and calcium deposition in the HS-27A and MG-63 cells, which was abolished by knocking down OSX using shRNA. On the other hand, the inhibition of beta-cat signaling activity with CCT031374 decreased the ALP activity and calcium deposition, which was completely reversed by the overexpression of OSX. On the whole, the findings of our study suggest that beta cat signaling upregulates the expression of OSX in human pre-osteoblastic and bone marrow stromal cells by trans-activating the OSX gene promoter mainly through increased c-Jun binding at a putative c-Jun binding site; OSX largely mediates beta-cat signaling-induced osteoblastogenic differentiation. The present study provides new insight into the molecular mechanisms underlying osteoblast differentiation. PMID- 26496942 TI - Perspectives on cervical cancer screening among educated Muslim women in Dubai (the UAE): a qualitative study. AB - BACKGROUND: Cervical cancer (CC) is the seventh leading cause of death among women in the United Arab Emirates (UAE), with most deaths attributed to late detection of this cancer. The UAE lacks a national CC screening programme. Thus, cervical screening is only performed opportunistically during women's visits to health facilities. CC screening rates in the UAE are as low as 16.9 %, and little is known about the perspectives of the nation's educated Muslim women regarding screening. Consequently, the aim of this study is to explore Muslim women's perspectives towards cervical screening in Dubai to promote strategies for increasing its uptake, thereby leading to a decrease in morbidity and mortality associated with CC. METHODS: Interpretivist and social constructivist epistemological approaches were applied for this qualitative study. Data were obtained through 13 in-depth interviews. Purposive and snowballing methods were used to recruit six South Asian women and seven Emirati women living in Dubai. Thematic content analysis was concurrently applied with comparative analysis to the data. RESULTS: Four themes regarding women's perceptions of CC emerged from the data. First, CC was considered a 'silent disease' that could be detected with early screening. However, it was also associated with extramarital sexual relations, which negatively influenced screening uptake. Second, women's fear, pain and embarrassment, along with cultural influences, deterred them from undergoing screening. Third, a growing mistrust of allopathic medicine and impersonal healthcare promoted a negative view of screening. Last, women became aware of screening mainly when they were pregnant or receiving fertility treatment. CONCLUSIONS: The study highlighted a number of important factors relating to cultural, religious and sexual behaviour that shaped educated Muslim women's perspectives on CC screening. Evidently, the current opportunistic approach to screening is flawed. A national awareness programme on CC screening should be developed, tailored to the sociocultural norms of the Muslim community, to promote knowledge regarding the causes of CC and the importance of screening. PMID- 26496943 TI - Multiple comparisons. AB - Oat plants grown at an agricultural research facility produce higher yields in Field 1 than in Field 2, under well fertilised conditions and with similar weather exposure; all oat plants in both fields are healthy and show no sign of disease. In this study, the authors hypothesised that the soil microbial community might be different in each field, and these differences might explain the difference in oat plant growth. They carried out a metagenomic analysis of the 16 s ribosomal 'signature' sequences from bacteria in 50 randomly located soil samples in each field to determine the composition of the bacterial community. The study identified >1000 species, most of which were present in both fields. The authors identified two plant growth-promoting species that were significantly reduced in soil from Field 2 (Student's t-test P < 0.05), and concluded that these species might have contributed to reduced yield. PMID- 26496944 TI - Autoregulation of topoisomerase I expression by supercoiling sensitive transcription. AB - The opposing catalytic activities of topoisomerase I (TopoI/relaxase) and DNA gyrase (supercoiling enzyme) ensure homeostatic maintenance of bacterial chromosome supercoiling. Earlier studies in Escherichia coli suggested that the alteration in DNA supercoiling affects the DNA gyrase and TopoI expression. Although, the role of DNA elements around the promoters were proposed in regulation of gyrase, the molecular mechanism of supercoiling mediated control of TopoI expression is not yet understood. Here, we describe the regulation of TopoI expression from Mycobacterium tuberculosis and Mycobacterium smegmatis by a mechanism termed Supercoiling Sensitive Transcription (SST). In both the organisms, topoI promoter(s) exhibited reduced activity in response to chromosome relaxation suggesting that SST is intrinsic to topoI promoter(s). We elucidate the role of promoter architecture and high transcriptional activity of upstream genes in topoI regulation. Analysis of the promoter(s) revealed the presence of sub-optimal spacing between the -35 and -10 elements, rendering them supercoiling sensitive. Accordingly, upon chromosome relaxation, RNA polymerase occupancy was decreased on the topoI promoter region implicating the role of DNA topology in SST of topoI. We propose that negative supercoiling induced DNA twisting/writhing align the -35 and -10 elements to facilitate the optimal transcription of topoI. PMID- 26496946 TI - Colorectal cancer atlas: An integrative resource for genomic and proteomic annotations from colorectal cancer cell lines and tissues. AB - In order to advance our understanding of colorectal cancer (CRC) development and progression, biomedical researchers have generated large amounts of OMICS data from CRC patient samples and representative cell lines. However, these data are deposited in various repositories or in supplementary tables. A database which integrates data from heterogeneous resources and enables analysis of the multidimensional data sets, specifically pertaining to CRC is currently lacking. Here, we have developed Colorectal Cancer Atlas (http://www.colonatlas.org), an integrated web-based resource that catalogues the genomic and proteomic annotations identified in CRC tissues and cell lines. The data catalogued to-date include sequence variations as well as quantitative and non-quantitative protein expression data. The database enables the analysis of these data in the context of signaling pathways, protein-protein interactions, Gene Ontology terms, protein domains and post-translational modifications. Currently, Colorectal Cancer Atlas contains data for >13 711 CRC tissues, >165 CRC cell lines, 62 251 protein identifications, >8.3 million MS/MS spectra, >18 410 genes with sequence variations (404 278 entries) and 351 pathways with sequence variants. Overall, Colorectal Cancer Atlas has been designed to serve as a central resource to facilitate research in CRC. PMID- 26496945 TI - CstF-64 and 3'-UTR cis-element determine Star-PAP specificity for target mRNA selection by excluding PAPalpha. AB - Almost all eukaryotic mRNAs have a poly (A) tail at the 3'-end. Canonical PAPs (PAPalpha/gamma) polyadenylate nuclear pre-mRNAs. The recent identification of the non-canonical Star-PAP revealed specificity of nuclear PAPs for pre-mRNAs, yet the mechanism how Star-PAP selects mRNA targets is still elusive. Moreover, how Star-PAP target mRNAs having canonical AAUAAA signal are not regulated by PAPalpha is unclear. We investigate specificity mechanisms of Star-PAP that selects pre-mRNA targets for polyadenylation. Star-PAP assembles distinct 3'-end processing complex and controls pre-mRNAs independent of PAPalpha. We identified a Star-PAP recognition nucleotide motif and showed that suboptimal DSE on Star PAP target pre-mRNA 3'-UTRs inhibit CstF-64 binding, thus preventing PAPalpha recruitment onto it. Altering 3'-UTR cis-elements on a Star-PAP target pre-mRNA can switch the regulatory PAP from Star-PAP to PAPalpha. Our results suggest a mechanism of poly (A) site selection that has potential implication on the regulation of alternative polyadenylation. PMID- 26496947 TI - Transient overexpression of DNA adenine methylase enables efficient and mobile genome engineering with reduced off-target effects. AB - Homologous recombination of single-stranded oligonucleotides is a highly efficient process for introducing precise mutations into the genome of E. coli and other organisms when mismatch repair (MMR) is disabled. This can result in the rapid accumulation of off-target mutations that can mask desired phenotypes, especially when selections need to be employed following the generation of combinatorial libraries. While the use of inducible mutator phenotypes or other MMR evasion tactics have proven useful, reported methods either require non mobile genetic modifications or costly oligonucleotides that also result in reduced efficiencies of replacement. Therefore a new system was developed, Transient Mutator Multiplex Automated Genome Engineering (TM-MAGE), that solves problems encountered in other methods for oligonucleotide-mediated recombination. TM-MAGE enables nearly equivalent efficiencies of allelic replacement to the use of strains with fully disabled MMR and with an approximately 12- to 33-fold lower off-target mutation rate. Furthermore, growth temperatures are not restricted and a version of the plasmid can be readily removed by sucrose counterselection. TM MAGE was used to combinatorially reconstruct mutations found in evolved salt tolerant strains, enabling the identification of causative mutations and isolation of strains with up to 75% increases in growth rate and greatly reduced lag times in 0.6 M NaCl. PMID- 26496948 TI - Backtracking behavior in viral RNA-dependent RNA polymerase provides the basis for a second initiation site. AB - Transcription in RNA viruses is highly dynamic, with a variety of pauses interrupting nucleotide addition by RNA-dependent RNA polymerase (RdRp). For example, rare but lengthy pauses (>20 s) have been linked to backtracking for viral single-subunit RdRps. However, while such backtracking has been well characterized for multi-subunit RNA polymerases (RNAPs) from bacteria and yeast, little is known about the details of viral RdRp backtracking and its biological roles. Using high-throughput magnetic tweezers, we quantify the backtracking by RdRp from the double-stranded (ds) RNA bacteriophage Phi6, a model system for RdRps. We characterize the probability of entering long backtracks as a function of force and propose a model in which the bias toward backtracking is determined by the base paring at the dsRNA fork. We further discover that extensive backtracking provides access to a new 3'-end that allows for the de novo initiation of a second RdRp. This previously unidentified behavior provides a new mechanism for rapid RNA synthesis using coupled RdRps and hints at a possible regulatory pathway for gene expression during viral RNA transcription. PMID- 26496949 TI - KLIFS: a structural kinase-ligand interaction database. AB - Protein kinases play a crucial role in cell signaling and are important drug targets in several therapeutic areas. The KLIFS database contains detailed structural kinase-ligand interaction information derived from all (>2900) structures of catalytic domains of human and mouse protein kinases deposited in the Protein Data Bank in order to provide insights into the structural determinants of kinase-ligand binding and selectivity. The kinase structures have been processed in a consistent manner by systematically analyzing the structural features and molecular interaction fingerprints (IFPs) of a predefined set of 85 binding site residues with bound ligands. KLIFS has been completely rebuilt and extended (>65% more structures) since its first release as a data set, including: novel automated annotation methods for (i) the assessment of ligand-targeted subpockets and the analysis of (ii) DFG and (iii) alphaC-helix conformations; improved and automated protocols for (iv) the generation of sequence/structure alignments, (v) the curation of ligand atom and bond typing for accurate IFP analysis and (vi) weekly database updates. KLIFS is now accessible via a website (http://klifs.vu-compmedchem.nl) that provides a comprehensive visual presentation of different types of chemical, biological and structural chemogenomics data, and allows the user to easily access, compare, search and download the data. PMID- 26496950 TI - OpenTein: a database of digital whole-slide images of stem cell-derived teratomas. AB - Human stem cells are promising sources for regenerative therapy. To ensure safety of future therapeutic applications, the differentiation potency of stem cells has to be tested and be widely opened to the public. The potency is generally assessed by teratoma formation comprising differentiated cells from all three germ layers, and the teratomas can be inspected through high-quality digital images. The teratoma assay, however, lacks consistency in transplantation protocols and even in interpretation, which needs community-based efforts for improving the assay quality. Here, we have developed a novel database OpenTein (Open Teratoma Investigation, http://opentein.hgc.jp/) to archive and freely distribute high-resolution whole-slide images and relevant records. OpenTein has been designed as a searchable, zoomable and annotatable web-based repository system. We have deposited 468 images of teratomas derived by our transplantation of human stem cells, and users can freely access and process such digital teratoma images. Approximately, the current version of OpenTein responds within 11.2 min for processing 2.03 gigapixel teratoma images. Our system offers valuable tools and resources in the new era of stem cell biology. PMID- 26496951 TI - Competitive and Predacious Interactions Among Three Phytoseiid Species Under Experimental Conditions (Acari: Phytoseiidae). AB - The effect of competition on species that coexist with similar ecological niches is an important theme in ecology. Furthermore, species displacement by introduced or invaded species is also an important environmental problem for biological control and conservation ecology. We tested whether two species of phytoseiids could coexist in closed cages with ample quantities of the extraguild prey species Carpoglyphus lactis (L.). Three species of phytoseiid mites-Amblyseius eharai Amitai & Swirski (a species native to China), Amblyseius swirskii (Athias Henriot) and Neoseiulus cucumeris (Oudemans) (both species were introduced from outside of China)-were tested under experimental conditions (25 +/- 1 degrees C, 90 +/- 5% relative humidity, and a photoperiod of 14:10 [L:D] h). With extraguild prey, we found that the numbers of a single population of each phytoseiid species (initial density of 10 females per cage) reached a plateau between 18 and 25 d after introduction into the experimental cages, suggesting that density-dependent factors were operating. In closed environments, one of these density-dependent factors might be cannibalism by these species. With regression analyses, Lotka Volterra equations estimated the rate of population increase (r) and the carrying capacity (K) of each species with the data from observations on population dynamics. We next observed the interactions of two phytoseiid species with abundant extraguild prey. In all species combinations, one species went extinct and the other increased in population size, despite the availability of sufficient extraguild prey, suggesting some type of competition must have caused the extinctions. We suggested that intraguild predation is the most plausible hypothesis to explain the results. PMID- 26496952 TI - Structure of Phoretic Mite Assemblages Across Subcortical Beetle Species at a Regional Scale. AB - Mites associated with subcortical beetles feed and reproduce within habitats transformed by tree-killing herbivores. Mites lack the ability to independently disperse among these habitats, and thus have evolved characteristics that facilitate using insects as transport between resources. Studies on associations between mites and beetles have historically been beetle-centric, where an assemblage of mite species is characterized on a single beetle species. However, available evidence suggests there may be substantial overlap among mite species on various species of beetles utilizing similar host trees. We assessed the mite communities of multiple beetle species attracted to baited funnel traps in Pinus stands in southern Wisconsin, northern Arizona, and northern Georgia to better characterize mite dispersal and the formation of mite-beetle phoretic associations at multiple scales. We identified approximately 21 mite species totaling 10,575 individuals on 36 beetle species totaling 983 beetles. Of the mites collected, 97% were represented by eight species. Many species of mites were common across beetle species, likely owing to these beetles' common association with trees in the genus Pinus. Most mite species were found on at least three beetle species. Histiostoma spp., Iponemus confusus Lindquist, Histiogaster arborsignis Woodring and Trichouropoda australis Hirschmann were each found on at least seven species of beetles. While beetles had largely similar mite membership, the abundances of individual mite species were highly variable among beetle species within each sampling region. Phoretic mite communities also varied within beetle species between regions, notably for Ips pini (Say) and Ips grandicollis (Eichhoff). PMID- 26496953 TI - Differences upon admission and in hospital course of children hospitalized with community-acquired pneumonia with or without radiologically-confirmed pneumonia: a retrospective cohort study. AB - BACKGROUND: The use of chest radiograph (CXR) for the diagnosis of childhood community-acquired pneumonia (CAP) is controversial. We assessed if children with CAP diagnosed on clinical grounds, with or without radiologically-confirmed pneumonia on admission, evolved differently. METHODS: Children aged >= 2 months, hospitalized with CAP diagnosed on clinical grounds, treated with 200,000 IU/Kg/day of aqueous penicillin G for >= 48 h and with CXR taken upon admission, without pleural effusion, were included in this retrospective cohort. One researcher, blinded to the radiological diagnosis, collected data on demographics, clinical history and physical examination on admission, daily hospital course during the first 2 days of treatment, and outcome, all from medical charts. Radiological confirmation of pneumonia was based on presence of pulmonary infiltrate detected by a paediatric radiologist who was also blinded to clinical data. Variables were initially compared by bivariate analysis. Multi variable logistic regression analysis assessed independent association between radiologically-confirmed pneumonia and factors which significantly differed during hospital course in the bivariate analysis. The multi-variable analysis was performed in a model adjusted for age and for the same factor present upon admission. RESULTS: 109 (38.5%) children had radiologically-confirmed pneumonia, 143 (50.5%) had normal CXR and 31 (11.0%) had atelectasis or peribronchial thickening. Children without radiologically-confirmed pneumonia were younger than those with radiologically-confirmed pneumonia (median [IQR]: 14 [7-28 months versus 21 [12-44] months; P = 0.001). None died. The subgroup with radiologically confirmed pneumonia presented fever on D1 (33.7 vs. 19.1; P = 0.015) and on D2 (31.6% vs. 16.2%; P = 0.004) more frequently. The subgroup without radiologically confirmed pneumonia had chest indrawing on D1 (22.4% vs. 11.9%; P = 0.027) more often detected. By multi-variable analysis, Fever on D2 (OR [95% CI]: 2.16 [1.15 4.06]) was directly and independently associated with radiologically-confirmed pneumonia upon admission. CONCLUSION: The compared subgroups evolved differently. PMID- 26496954 TI - Factors associated with the frequency of monitoring of liver enzymes, renal function and lipid laboratory markers among individuals initiating combination antiretroviral therapy: a cohort study. AB - BACKGROUND: As the average age of the HIV-positive population increases, there is increasing need to monitor patients for the development of comorbidities as well as for drug toxicities. METHODS: We examined factors associated with the frequency of measurement of liver enzymes, renal function tests, and lipid levels among participants of the Canadian Observational Cohort (CANOC) collaboration which follows people who initiated HIV antiretroviral therapy in 2000 or later. We used zero-inflated negative binomial regression models to examine the associations of demographic and clinical characteristics with the rates of measurement during follow-up. Generalized estimating equations with a logit link were used to examine factors associated with gaps of 12 months or more between measurements. RESULTS: Electronic laboratory data were available for 3940 of 7718 CANOC participants. The median duration of electronic follow-up was 3.5 years. The median (interquartile) rates of tests per year were 2.76 (1.60, 3.73), 2.55 (1.44, 3.38) and 1.42 (0.50, 2.52) for liver, renal and lipid parameters, respectively. In multivariable zero-inflated negative binomial regression models, individuals infected through injection drug use (IDU) were significantly less likely to have any measurements. Among participants with at least one measurement, rates of measurement of liver, renal and lipid tests were significantly lower for younger individuals and Aboriginal Peoples. Hepatitis C co-infected individuals with a history of IDU had lower rates of measurement and were at greater risk of having 12 month gaps between measurements. CONCLUSIONS: Hepatitis C co-infected participants infected through IDU were at increased risk of gaps in testing, despite publicly funded health care and increased risk of comorbid conditions. This should be taken into consideration in analyses examining factors associated with outcomes based on laboratory parameters. PMID- 26496955 TI - Prediction of Rupture Sites in Abdominal Aortic Aneurysms After Finite Element Analysis. AB - PURPOSE: To associate regions of highest local rupture risk from finite element analysis (FEA) to subsequent rupture sites in abdominal aortic aneurysms (AAA). METHODS: This retrospective multicenter study analyzed computed tomography angiography (CTA) data from 13 asymptomatic AAA patients (mean age 76 years; 8 men) experiencing rupture at a later point in time between 2005 and 2011. All patients had CTA scans before and during the rupture event. FEA was performed to calculate peak wall stress (PWS), peak wall rupture risk (PWRR), rupture risk equivalent diameters (RRED), and the intraluminal thrombus volume (ILTV). PWS and PWRR locations in the prerupture state were compared with subsequent CTA rupture findings. Visible contrast extravasation was considered a definite (n=5) rupture sign, while a periaortic hematoma was an indefinite (n=8) sign. A statistical comparison was performed between the 13-patient asymptomatic AAA group before and during rupture and a 23-patient diameter-matched asymptomatic AAA control group that underwent elective surgery. RESULTS: The asymptomatic AAAs before rupture showed significantly higher PWRR and RRED values compared to the matched asymptomatic AAA control group (median values 0.74 vs 0.52 and 77 vs 59 mm, respectively; p<0.0001 for both). No statistical differences could be found for PWS and ILTV. Ruptured AAAs showed the highest maximum diameters, PWRR, and RRED values. In 7 of the ruptured AAAs (2 definite and 5 indefinite rupture signs), CTA rupture sites correlated with prerupture PWRR locations. CONCLUSION: The location of the PWRR in unruptured AAAs predicted future rupture sites in several cases. Asymptomatic AAA patients with high PWRR and RRED values have an increased rupture risk. PMID- 26496956 TI - An In Vitro Phantom Study on the Role of the Bird-Beak Configuration in Endograft Infolding in the Aortic Arch. AB - PURPOSE: To assess endograft infolding for excessive bird-beak configurations in the aortic arch in relation to hemodynamic variables by quantifying device displacement and rotation of oversized stent-grafts deployed in a phantom model. METHODS: A patient-specific, compliant, phantom pulsatile flow model was reconstructed from a patient who presented with collapse of a Gore TAG thoracic endoprosthesis. Device infolding was measured under different flow and pressure conditions for 3 protrusion extensions (13, 19, and 24 mm) of the bird-beak configuration resulting from 2 TAG endografts with oversizing of 11% and 45%, respectively. RESULTS: The bird-beak configuration with the greatest protrusion extension exhibited the maximum TAG device displacement (1.66 mm), while the lowest protrusion extension configuration led to the minimum amount of both displacement and rotation parameters (0.25 mm and 0.6 degrees , respectively). A positive relationship was found between the infolding parameters and the flow circulating in the aorta and left subclavian artery. Similarly, TAG device displacement was positively and significantly (p<0.05) correlated with the pulse pressure for all bird-beak configurations and device sizes. However, no collapse was observed under chronic perfusion testing maintained for 30 days and pulse pressure of 100 mm Hg. CONCLUSION: These findings suggest that endograft infolding depends primarily on the amount of aortic pulsatility and flow rate and that physiological flows do not necessarily engender hemodynamic loads on the proximal bird-beak segment sufficient to cause TAG collapse. Hemodynamic variables may allow for identification of patients at high risk of endograft infolding and help guide preventive intervention to avert its occurrence. PMID- 26496957 TI - Systematic Review of Off-the-Shelf or Physician-Modified Fenestrated and Branched Endografts. AB - PURPOSE: To determine the safety and efficacy of off-the-shelf fenestrated/branched grafts (OSFGs) and physician-modified stent-grafts (PMSGs) for the treatment of complex abdominal aortic aneurysms. METHODS: A systematic search of the MEDLINE database via PubMed from January 2001 through March 2015 retrieved 23 relevant articles evaluating the clinical outcomes following the management of patients with pararenal or thoracoabdominal aortic aneurysms. The 15 articles on PMSGs and 8 on OSFGs contained data on 308 patients (mean age 72.93+/-2.89 years; 213 men). The safety endpoint was major adverse events; the efficacy outcome measure was clinical treatment success (aneurysm exclusion without type I/III endoleak, permanent paralysis, long-term dialysis, or unresolved major complications). Extracted outcome data were pooled and compared between groups; data are given as the pooled proportions and 95% confidence interval (CI). Clinical data are presented as the weighted mean. RESULTS: Of the 308 patients analyzed, almost one third were operated on an emergency basis. The mean aneurysm diameters were 75.9+/-17.3 mm (range 56-115) for the PMSGs and 68.1+/-13.7 mm (range 60-100) for the OSFGs. A total of 936 renal and visceral vessels were targeted. Major adverse events (safety) occurred in 24 (12.8%) PMSG patients (95% CI 8.6% to 18.7%) and in 9 (7.4%) OSFG patients (95% CI 3.7% to 14%). Clinical treatment success (efficacy) was observed in 171/187 (91.4%) PMSG patients (95% CI 86.2% to 94.9%) and in 115/121 (95%) OSFG patients (95% CI 89.1% to 98.0%). Corresponding cumulative 30-day target vessel and branch stent perfusion rates were 97.2% (95% CI 95.1% to 98.4%) and 97.6% (95% CI 95.5% to 98.8%) for the PMSG group and 99.6% (95% CI 98.3% to 99.9%) and 98.4% (95% CI 96.5% to 99.4%) for the OSFG group. Six (3.2%) deaths occurred in the PMSG group only; 2 (1.1%) were aneurysm related. Overall branch patency was recorded in 443/458 (96.7%) and in 468/478 (97.9%) of target vessels in the PMSG and OSFG groups, respectively. CONCLUSION: Off-the-shelf and physician-modified technology seems effective and safe, in both the elective and acute settings, for the treatment of complex aortic aneurysms. Future research within a randomized trial should investigate the true limitations of these devices. PMID- 26496959 TI - Responses to mild water deficit and rewatering differ among secondary metabolites but are similar among provenances within Eucalyptus species. AB - Water deficit associated with drought can severely affect plants and influence ecological interactions involving plant secondary metabolites. We tested the effect of mild water deficit and rewatering on physiological, morphological and chemical traits of juvenile Eucalyptus globulus Labill. and Eucalyptus viminalis Labill. We also tested if responses of juvenile eucalypts to water deficit and rewatering varied within species using provenances across a rainfall gradient. Both species and all provenances were similarly affected by mild water deficit and rewatering, as only foliar abscisic acid levels differed among provenances during water deficit. Across species and provenances, water deficit decreased leaf water potential, above-ground biomass and formylated phloroglucinol compound concentrations, and increased condensed tannin concentrations. Rewatering reduced leaf carbon : nitrogen, and total phenolic and chlorogenic acid concentrations. Water deficit and rewatering had no effect on total oil or individual terpene concentrations. Levels of trait plasticity due to water deficit and rewatering were less than levels of constitutive trait variation among provenances. The overall uniformity of responses to the treatments regardless of native provenance indicates limited diversification of plastic responses when compared with the larger quantitative variation of constitutive traits within these species. These responses to mild water deficit may differ from responses to more extreme water deficit or to responses of juvenile/mature eucalypts growing at each locality. PMID- 26496958 TI - Leaf morphological and physiological adaptations of a deciduous oak (Quercus faginea Lam.) to the Mediterranean climate: a comparison with a closely related temperate species (Quercus robur L.). AB - 'White oaks'--one of the main groups of the genus Quercus L.--are represented in western Eurasia by the 'roburoid oaks', a deciduous and closely related genetic group that should have an Arcto-Tertiary origin under temperate-nemoral climates. Nowadays, roburoid oak species such as Quercus robur L. are still present in these temperate climates in Europe, but others are also present in southern Europe under Mediterranean-type climates, such as Quercus faginea Lam. We hypothesize the existence of a coordinated functional response at the whole-shoot scale in Q. faginea under Mediterranean conditions to adapt to more xeric habitats. The results reveal a clear morphological and physiological segregation between Q. robur and Q. faginea, which constitute two very contrasting functional types in response to climate dryness. The most outstanding divergence between the two species is the reduction in transpiring area in Q. faginea, which is the main trait imposed by the water deficit in Mediterranean-type climates. The reduction in leaf area ratio in Q. faginea should have a negative effect on carbon gain that is partially counteracted by a higher inherent photosynthetic ability of Q. faginea when compared with Q. robur, as a consequence of higher mesophyll conductance, higher maximum velocity of carboxylation and much higher stomatal conductance (gs). The extremely high gs of Q. faginea counteracts the expected reduction in gs imposed by the stomatal sensitivity to vapor pressure deficit, allowing this species to diminish water losses maintaining high net CO2 assimilation values along the vegetative period under nonlimiting soil water potential values. In conclusion, the present study demonstrates that Q. faginea can be regarded as an example of adaptation of a deciduous oak to Mediterranean type climates. PMID- 26496960 TI - Photosynthetic enhancement by elevated CO2 depends on seasonal temperatures for warmed and non-warmed Eucalyptus globulus trees. AB - Arguments based on the biochemistry of photosynthesis predict a positive interaction between elevated atmospheric [CO2] and temperature on photosynthesis as well as growth. In contrast, few long-term studies on trees find greater stimulation of photosynthesis in response to elevated [CO2] at warmer compared with cooler temperatures. To test for CO2 * temperature interactions on leaf photosynthesis and whole-plant growth, we planted Eucalyptus globulus Labill. in climate-controlled chambers in the field at the Hawkesbury Forest Experiment research site, and investigated how photosynthetic enhancement changed across a range of seasonal temperatures. Trees were grown in a complete two-way factorial design with two CO2 concentrations (ambient and ambient + 240 ppm) and two temperatures (ambient and ambient + 3 degrees C) for 15 months until they reached ~10 m height, after which they were harvested for biomass. There was significant enhancement of photosynthesis and growth with elevated [CO2], with the photosynthetic stimulation varying with season, but there was no significant effect of warming. Photosynthetic enhancement was higher in summer (+46% at 28 degrees C) than in winter (+14% at 20 degrees C). Photosynthetic enhancement as a function of leaf temperature was consistent with theoretical expectations, but was strongly mediated by the intercellular [CO2]/ambient [CO2] (Ci/Ca) ratio across seasons. Total tree biomass after 15 months was 66% larger in elevated CO2 (P = 0.017) with no significant warming effect detected. The fraction of biomass in coarse roots was reduced in warmed trees compared with ambient temperature controls, but there was no evidence of changed biomass allocation patterns in elevated CO2. We conclude that there are strong and consistent elevated CO2 effects on photosynthesis and biomass of E. globulus. It is crucial to consider stomatal conductance under a range of conditions to appraise the interactive effect of [CO2] and temperature on photosynthetic enhancement and subsequent implications for tree growth and forest productivity in future climates. PMID- 26496961 TI - Maternal gestational diabetes mellitus and overweight and obesity in offspring: a study in Chinese children. AB - The purpose of this study was to investigate the effects of maternal gestational diabetes mellitus (GDM) and breast feeding on childhood overweight and obesity in a mainland Chinese population. The incidence of and factors associated with overweight and obesity were compared between children of mothers with (n=1068) and without (n=1756) GDM. The independent roles of the associated factors were examined by multiple logistic regression analysis. The incidence of overweight was higher (16.6 v. 12.6%, P=0.002) in the GDM group, but that of obesity was not different (10.7 v. 12.0%, P=0.315). At age 1-2 and 2-5 years, no difference in overweight (11.0 v. 12.0%, P=0.917, and 15.7 v. 14.6%, P=0.693, respectively) was found, while obesity (8.0 v. 13.6%, P=0.019, and 8.4 v. 13.4%, P=0.014, respectively) was less frequent in the GDM offspring. At age 5-10 years, increased overweight (22.2 v. 12.1%, P<0.001) and obesity (15.9 v. 9.0%, P=0.001) were found in the GDM group, which was associated with maternal obesity, being born large-for-gestational age, male gender and formula feeding. After adjusting for confounding factors, GDM remained an independent determinant of offspring overweight and obesity (aOR 2.28, 95% CI 1.61-3.22), suggesting that the effects of GDM were independent of breast feeding, as well as of maternal obesity and birth size. PMID- 26496962 TI - Maternal hyperglycemia at different stages of gestation and its effects on male reproductive functions in rats. AB - The critical period during which maternal hyperglycemia predisposes offspring to develop reproductive disorders in adult life is not known. The relationship between maternal hyperglycemia at different stages and reproductive functions of male offspring was investigated. A single intraperitoneal injection of alloxan (90 mg/kg body weight) was administered at gestation days (GD) 1, 8 and 15. Animals were subsequently given 10% glucose solution daily as drinking water until parturition. All male pups were sacrificed on the 63rd day of postnatal life. Birth weight, anogenital distance index (AGDi), testes descent day, preputial separation day, sperm profile, serum testosterone, luteinizing hormone and follicle-stimulating hormone levels and the histology of the testis were assessed. Data significance test was based on 95% confidence interval. GD1 pups showed a significant increase in mean birth weight, whereas GD8 pups and GD15 pups had significantly reduced birth weight as compared with control. AGDi was significantly increased in GD8 and GD15 pups. Testes descent and preputial separation in all the experimental groups were significantly earlier. There was a significant reduction in sperm count and viability in GD8 offspring. Sperm motility was reduced in all test groups. Testosterone level was reduced in all test groups. Histology of the testis showed varying degrees of pathologies. It was deduced from this study that maternal hyperglycemia caused alterations in reproductive functions in male offspring of Wistar rats irrespective of the period of gestation involved, although GD8 pups were most severely affected. PMID- 26496963 TI - Body composition in male rats subjected to early weaning and treated with diet containing flour or flaxseed oil after 21 days until 60 days. AB - The aim of this study was analyzed if the flour or flaxseed oil treatment contributes to body composition in male rats subjected to early weaning. Pups were weaned for separation from mother at 14 (early weaning, EW) and 21 days (control, C). At 21 days, part of the pups was evaluated (C21 v. EW21). After 21 days, control (C60) was fed with control diet. EW was divided in control (EWC60); flaxseed flour (EWFF60); flaxseed oil (EWFO60) diets until 60 days. Body mass, length and body composition by dual-energy X-ray absorptiometry were determined. EW21 (v. C21) and EWC60 (v. C60 and EWFF60) showed lower (P<0.05) mass, length and body composition. EWFO60 (v. C60 and EWFF60) showed lower (P<0.05) body mass and length, body and trunk lean mass, bone mineral density and content and bone area. Flaxseed flour, in comparison with flaxseed oil, contributes to recovery of body composition after early weaning. PMID- 26496964 TI - Dexamethasone protects normal human liver cells from apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand by upregulating the expression of P-glycoproteins. AB - Glucocorticoids are effective for the treatment of acute-on-chronic pre-liver failure, severe chronic hepatitis B and acute liver failure; however, the mechanism underlying the effects of treatment by glucocorticoids remains to be fully elucidated. The role and detailed mechanism of how glucocorticoids prevent liver disease progression can be elucidated by investigating the apoptosis of hepatocytes following glucocorticoid treatment. P-glycoproteins (P-gps) also confer resistance to apoptosis induced by a diverse range of stimuli. Glucocorticoids, particularly dexamethasone (DEX), upregulate the expression of P gp in several tissues. In the present study, the normal human L-02 liver cell line was used, and techniques, including immunocytochemistry, western blot analysis, flow cytometry and reverse transcription-quantitative polymerase chain reaction analysis were used for determining the expression levels of P-gps, and for evaluating the effect of DEX pretreatment on the expression of P-gps. DEX (1 10 uM) was added to the cell culture media and incubated for 24-72 h. The results revealed that DEX upregulated the mRNA and protein levels of P-gp in a dose- and time-dependent manner. Subsequently, tumor necrosis factor-related apoptosis inducing ligand (TRAIL) was used for the induction of apoptosis in the cells, followed by a terminal deoxynucleotidyl transferase dUTP nick end labeling assay to assess the apoptotic stages. The results demonstrated that apoptosis in the group of cells, which were pre-treated with DEX was significantly lower than that in the control group. Treatment with tariquidar, a P-gp inhibitor, reduced the anti-apoptotic effects of DEX. These results established that DEX protects normal human liver cells from TRAIL-induced apoptosis by upregulating the expression of P-gp. These observations may be useful for elucidating the mechanism of DEX for preventing the progression of liver disease. PMID- 26496965 TI - PAMAM G4.5-chlorin e6 dendrimeric nanoparticles for enhanced photodynamic effects. AB - There is currently great interest in the development of efficient and specific carrier delivery platforms for systemic photodynamic therapy. Therefore, we aimed to develop covalent conjugates between the photosensitizer chlorin e6 (Ce6) and PAMAM G4.5 dendrimers. Singlet oxygen generation (SOG) efficiency and fluorescence emission were moderately affected by the covalent binding of the Ce6 to the dendrimer. Compared to free Ce6, PAMAM anchored Ce6 displays a much higher photodynamic effect, which is ascribable to better internalization in a tumor cell model. Intracellular fate and internalization pathway of our different compounds were investigated using specific inhibition conditions and confocal fluorescence microscopy. Free Ce6 was shown to enter the cells by a simple diffusion mechanism, while G4.5-Ce6-PEG internalization was dependent on the caveolae pathway, whereas G4.5-Ce6 was subjected to the clathrin-mediated endocytosis pathway. Subcellular localization of PAMAM anchored Ce6, PEGylated or not, was very similar suggesting that the nanoparticles behave similarly in the cells. As a conclusion, we have demonstrated that PEGylated G4.5 PAMAM-Ce6 dendrimers may offer effective biocompatible nanoparticles for improved photodynamic treatment in a preclinical tumor model. PMID- 26496966 TI - Core-Shell Ferromagnetic Nanorod Based on Amine Polymer Composite (Fe3O4@DAPF) for Fast Removal of Pb(II) from Aqueous Solutions. AB - Heavy metal ion removal from wastewater constitutes an important issue in the water treatment industry. Although a variety of nanomaterials have been developed for heavy metal removal via adsorption, the adsorption capacity, removal efficiency, and material recyclability still remain a challenge. Here, we present novel Fe3O4@DAPF core-shell ferromagnetic nanorods (CSFMNRs) for the removal of Pb(II) from aqueous solutions; they were prepared by the facile surface modification of twin-like ferromagnetic Fe3O4 nanorods using a 2,3-diaminophenol and formaldehyde (DAPF)-based polymer. The crystallinity and structure of the Fe3O4 nanorods were confirmed via X-ray diffraction (XRD). Transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) revealed the core shell morphology and composition of the materials. Pb(II) removal using the prepared Fe3O4@DAPF CSFMNRs was assessed, and comparable adsorption capacities (83.3 mg g(-1)) to the largest value were demonstrated. A thermodynamic study of the adsorption clearly indicated that the adsorption was exothermic and spontaneous. Due to the ferromagnetic properties with a high saturation magnetization value (56.1 emu g(-1)) of the nanorods, the nanorods exhibited excellent reusability with one of the fastest recovery times (25 s) among reported materials. Therefore, the Fe3O4@DAPF CSFMNRs can serve as recyclable adsorbent materials and as an alternative to commonly used sorbent materials for the rapid removal of heavy metals from aqueous solutions. PMID- 26496967 TI - Using confined bacteria as building blocks to generate fluid flow. AB - In many technological applications, materials are transported by fluid flow at micro/nanometer scales. Conventionally, macroscopic apparatuses, such as syringe pumps, are used to drive the flow. This work explores the possibility of utilizing motile bacteria as microscopic pumps. We used micro-fabricated structures to confine smooth-swimming bacteria in a prescribed configuration. The flagella of confined bacteria rotate to collectively generate flow that can transport materials along designed trajectories. Different structures are combined to realize complex functions, such as collection or dispersion of particles. Experimental findings are reproduced in numerical simulations. Our method opens new ways to generate transport flow at the micrometer scale and to drive bio-hybrid devices. PMID- 26496968 TI - Successful resumption of tocilizumab for rheumatoid arthritis after resection of a pulmonary Mycobacterium avium complex lesion: a case report. AB - BACKGROUND: Biological agents inhibiting TNF-alpha and other molecules involved in inflammatory cascade have been increasingly used to treat rheumatoid arthritis (RA). However, it remains controversial whether biological agents can be used safely in a patient with an underlying chronic infectious disease. CASE PRESENTATION: A 63-year-old woman who had been treated with tocilizumab (TCZ), anti-interleukin-6 receptor antibody, for RA presented to our outpatient clinic due to hemoptysis. She was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection, and high-resolution computed tomography (HRCT) showed a single cavitary lesion in the right upper lobe. After diagnosis of pulmonary MAC disease, TCZ was discontinued and combination chemotherapy with clarithromycin, rifampicin, ethambutol and amikacin was started for MAC pulmonary disease. Since the lesion was limited in the right upper lobe as a single cavity formation, she underwent right upper lobectomy. As her RA symptoms were deteriorated around the operation, TCZ was resumed. After resumption of TCZ, her RA symptoms improved and a recurrence of pulmonary MAC infection has not been observed for more than 1 year. CONCLUSION: This case suggested that TCZ could be safely reintroduced after the resection of a pulmonary MAC lesion. Although the use of biological agents is generally contraindicated in patients with pulmonary MAC disease, especially in those with a fibrocavitary lesion, a multimodality intervention for MAC including both medical and surgical approaches may enable introduction or resumption of biological agents. PMID- 26496969 TI - New horizons for GAG therapy in the management of urothelial damage. AB - Urothelial defects may manifest as various types of signs of symptoms such as frequency and urgency, haematuria and pain. Both prevention and treatment of urothelial damage is fundamental. Many currently adopted treatments lack robust clinical data and are associated with variability in management strategies. Glycosoaminoglycan (GAG) therapy is one of the most promising therapies in treatment of chemotherapy and radiotherapy-induced urothelium defects, and has been investigated in both animal models and clinical studies. PMID- 26496970 TI - Stable n-type doping of graphene via high-molecular-weight ethylene amines. AB - We demonstrate a stable and strong n-type doping method to tune the electrical properties of graphene via vapor phase chemical doping with various high molecular-weight ethylene amines. The resulting carrier concentration after doping with pentaethylenehexamine (PEHA) is as high as -1.01 * 10(13) cm(-2), which reduces the sheet resistance of graphene by up to ~400% compared to pristine graphene. Our study suggests that the branched structure of the dopant molecules is another important factor that determines the actual doping degree of graphene. PMID- 26496971 TI - Thermoelectric transport properties of pristine and Na-doped SnSe(1-x)Te(x) polycrystals. AB - SnSe, a "simple" and "old" binary compound composed of earth-abundant elements, has been reported to exhibit a high thermoelectric performance in single crystals, which stimulated recent interest in its polycrystalline counterparts. This work investigated the electrical and thermal transport properties of pristine and Na-doped SnSe1-xTex polycrystals prepared by mechanical alloying and spark plasma sintering. It is revealed that SnSe1-xTex solid solutions are formed when x ranges from 0 to 0.2. An energy barrier scattering mechanism is suitable for understanding the electrical conducting behaviour observed in the present SnSe polycrystalline materials, which may be associated with abundant defects at grain boundaries. The thermal conductivity was greatly reduced upon Te substitution due to alloy scattering of phonons as well explained by the Debye model. Due to the increased carrier concentration by Na-doping, thermoelectric figure of merit (ZT) was enhanced in the whole temperature range with a maximum value of 0.72 obtained at a relatively low temperature (773 K) for Sn0.99Na0.01Se0.84Te0.16. PMID- 26496972 TI - Elucidating temporal resource allocation and diurnal dynamics in phototrophic metabolism using conditional FBA. AB - The computational analysis of phototrophic growth using constraint-based optimization requires to go beyond current time-invariant implementations of flux balance analysis (FBA). Phototrophic organisms, such as cyanobacteria, rely on harvesting the sun's energy for the conversion of atmospheric CO2 into organic carbon, hence their metabolism follows a strongly diurnal lifestyle. We describe the growth of cyanobacteria in a periodic environment using a new method called conditional FBA. Our approach enables us to incorporate the temporal organization and conditional dependencies into a constraint-based description of phototrophic metabolism. Specifically, we take into account that cellular processes require resources that are themselves products of metabolism. Phototrophic growth can therefore be formulated as a time-dependent linear optimization problem, such that optimal growth requires a differential allocation of resources during different times of the day. Conditional FBA then allows us to simulate phototrophic growth of an average cell in an environment with varying light intensity, resulting in dynamic time-courses for all involved reaction fluxes, as well as changes in biomass composition over a diurnal cycle. Our results are in good agreement with several known facts about the temporal organization of phototrophic growth and have implications for further analysis of resource allocation problems in phototrophic metabolism. PMID- 26496973 TI - High-performing nonlinear visualization of terahertz radiation on a silicon charge-coupled device. AB - Photoinduced electron transitions can lead to significant changes of the macroscopic electronic properties in semiconductors. This principle is responsible for the detection of light with charge-coupled devices. Their spectral sensitivity is limited by the semiconductor bandgap which has restricted their visualization capabilities to the optical, ultraviolet, and X-ray regimes. The absence of an imaging device in the low frequency terahertz range has severely hampered the advance of terahertz imaging applications in the past. Here we introduce a high-performing imaging concept to the terahertz range. On the basis of a silicon charge-coupled device we visualize 5-13 THz radiation with photon energy under 2% of the sensor's band-gap energy. The unprecedented small pitch and large number of pixels allow the visualization of complex terahertz radiation patterns in real time and with high spatial detail. This advance will have a great impact on a wide range of terahertz imaging disciplines. PMID- 26496974 TI - A nitrogen-containing carbon film derived from vapor phase polymerized polypyrrole as a fast charging/discharging capability anode for lithium-ion batteries. AB - A nitrogen-containing carbon (N-C) film was synthesized by pyrolysis of vapor phase polymerized polypyrrole (PPy). This carbon film exhibits excellent rate capability and cyclability as a lithium-ion battery anode. The reversible capacities are 908.4, 825.7, 664.0, 531.6, 415.5 and 325.9 mA h g(-1) at 1C, 2C, 5C, 10C, 20C and 40C, respectively. PMID- 26496975 TI - Chelating effect in short polymers for the design of bidentate binders of increased affinity and selectivity. AB - The design of new strong and selective binders is a key step towards the development of new sensing devices and effective drugs. Both affinity and selectivity can be increased through chelation and here we theoretically explore the possibility of coupling two binders through a flexible linker. We prove the enhanced ability of double binders of keeping their target with a simple model where a polymer composed by hard spheres interacts with a spherical macromolecule, such as a protein, through two sticky spots. By Monte Carlo simulations and thermodynamic integration we show the chelating effect to hold for coupling polymers whose radius of gyration is comparable to size of the chelated particle. We show the binding free energy of flexible double binders to be higher than that of two single binders and to be maximized when the binding sites are at distances comparable to the mean free polymer end-to-end distance. The affinity of two coupled binders is therefore predicted to increase non linearly and in turn, by targeting two non-equivalent binding sites, this will lead to higher selectivity. PMID- 26496976 TI - First Principles Study on the Electronic Structure and Interface Stability of Hybrid Silicene/Fluorosilicene Nanoribbons. AB - The interface stability of hybrid silicene/fluorosilicene nanoribbons (SFNRs) has been investigated by using density functional theory calculations, where fluorosilicene is the fully fluorinated silicene. It is found that the diffusion of F atoms at the zigzag and armchair interfaces of SFNRs is endothermic, and the corresponding minimum energy barriers are respectively 1.66 and 1.56 eV, which are remarkably higher than the minimum diffusion energy barrier of one F atom and two F atoms on pristine silicene 1.00 and 1.29 eV, respectively. Therefore, the thermal stability of SFNRs can be significantly enhanced by increasing the F diffusion barriers through silicene/fluorosilicene interface engineering. In addition, the electronic and magnetic properties of SFNRs are also investigated. It is found that the armchair SFNRs are nonmagnetic semiconductors, and the band gap of armchair SFNRs presents oscillatory behavior when the width of silicene part changing. For the zigzag SFNRs, the antiferromagnetic semiconducting state is the most stable one. This work provides fundamental insights for the applications of SFNRs in electronic devices. PMID- 26496977 TI - Cardiovascular magnetic resonance findings in patients with PRKAG2 gene mutations. AB - BACKGROUND: Autosomal dominantly inherited PRKAG2 cardiac syndrome is due to a unique defect of the cardiac cell metabolism and has a distinctive histopathology with excess intracellular glycogen, and prognosis different from sarcomeric hypertrophic cardiomyopathy. We aimed to define the distinct characteristics of PRKAG2 using cardiovascular magnetic resonance (CMR). METHODS: CMR (1.5 T) and genetic testing were performed in two families harboring PRKAG2 mutations. On CMR, segmental analysis of left ventricular (LV) hypertrophy (LVH), function, native T1 mapping, and late gadolinium enhancement (LGE) were performed. RESULTS: Six individuals (median age 23 years, range 16-48; two females) had a PRKAG2 mutation: five with an R302Q mutation (family 1), and one with a novel H344P mutation (family 2). Three of six mutation carriers had LV mass above age and gender limits (203 g/m2, 157 g/m2 and 68 g/m2) and others (with R302Q mutation) normal LV masses. All mutation carriers had LVH in at least one segment, with the median maximal wall thickness of 13 mm (range 11-37 mm). Two R302Q mutation carriers with markedly increased LV mass (203 g/m2 and 157 g/m2) showed a diffuse pattern of hypertrophy but predominantly in the interventricular septum, while other mutation carriers exhibited a non-symmetric mid-infero-lateral pattern of hypertrophy. In family 1, the mutation negative male had a mean T1 value of 963 ms, three males with the R302Q mutation, LVH and no LGE a mean value of 918 +/- 11 ms, and the oldest male with the R302Q mutation, extensive hypertrophy and LGE a mean value of 973 ms. Of six mutations carriers, two with advanced disease had LGE with 11 and 22 % enhancement of total LV volume. CONCLUSIONS: PRKAG2 cardiac syndrome may present with eccentric distribution of LVH, involving focal mid infero-lateral pattern in the early disease stage, and more diffuse pattern but focusing on interventricular septum in advanced cases. In patients at earlier stages of disease, without LGE, T1 values may be reduced, while in the advanced disease stage T1 mapping may result in higher values caused by fibrosis. CMR is a valuable tool in detecting diffuse and focal myocardial abnormalities in PRKAG2 cardiomyopathy. PMID- 26496979 TI - Impact of KITENIN on tumor angiogenesis and lymphangiogenesis in colorectal cancer. AB - Angiogenesis and lymphangiogenesis are involved in the dissemination of tumor cells from solid tumors to regional lymph nodes and various distant sites. KAI1 COOH-terminal interacting tetraspanin (KITENIN) contributes to tumor progression and poor clinical outcomes in various cancers including colorectal cancer. The aim of the present study was to evaluate whether KITENIN affects tumor angiogenesis and lymphangiogenesis in colorectal cancer. A KITENIN small interfering RNA vector was used to silence KITENIN expression in colorectal cancer cell lines including DLD1 and SW480 cells. To evaluate the ability of KITENIN to induce angiogenesis and lymphangiogenesis in human umbilical vein endothelial cells (HUVECs) and lymphatic endothelial cells (HLECs), we performed Matrigel invasion and tube formation assays. Immunohistochemistry was used to determine the expression of KITENIN in colorectal cancer tissues. Angiogenesis and lymphangiogenesis were evaluated by immunostaining with CD34 and D2-40 antibodies. KITENIN silencing inhibited both HUVEC invasion and tube formation in the DLD1 and SW480 cells. KITENIN silencing led to decreased expression of the angiogenic inducers vascular endothelial growth factor (VEGF)-A and hypoxia inducible factor-1alpha and increased expression of the angiogenic inhibitor angiostatin. KITENIN silencing did not inhibit either HLEC invasion or tube formation in all tested cells, but it resulted in decreased expression of the lymphangiogenic inducer VEGF-C. KITENIN expression was significantly associated with tumor stage, depth of invasion, lymph node and distant metastases and poor survival. The mean microvessel density was significantly higher in the KITENIN positive tumors than that in the KITENIN-negative tumors. However, the mean lymphatic vessel density of KITENIN-positive tumors was not significantly higher than that of the KITENIN-negative tumors. These results suggest that KITENIN promotes tumor progression by enhancing angiogenesis in colorectal cancer. PMID- 26496978 TI - Integrated analysis of miRNA and mRNA paired expression profiling of prenatal skeletal muscle development in three genotype pigs. AB - MicroRNAs (miRNAs) play a vital role in muscle development by binding to messenger RNAs (mRNAs). Based on prenatal skeletal muscle at 33, 65 and 90 days post-coitus (dpc) from Landrace, Tongcheng and Wuzhishan pigs, we carried out integrated analysis of miRNA and mRNA expression profiling. We identified 33, 18 and 67 differentially expressed miRNAs and 290, 91 and 502 mRNA targets in Landrace, Tongcheng and Wuzhishan pigs, respectively. Subsequently, 12 mRNAs and 3 miRNAs differentially expressed were validated using quantitative real-time PCR (qPCR), and 5 predicted miRNA targets were confirmed via dual luciferase reporter or western blot assays. We identified a set of miRNAs and mRNA genes differentially expressed in muscle development. Gene ontology (GO) enrichment analysis suggests that the miRNA targets are primarily involved in muscle contraction, muscle development and negative regulation of cell proliferation. Our data indicated that more mRNAs are regulated by miRNAs at earlier stages than at later stages of muscle development. Landrace and Tongcheng pigs also had longer phases of myoblast proliferation than Wuzhishan pigs. This study will be helpful to further explore miRNA-mRNA interactions in myogenesis and aid to uncover the molecular mechanisms of muscle development and phenotype variance in pigs. PMID- 26496981 TI - Molecular pathogenesis and therapeutic strategies of human osteosarcoma. AB - Osteosarcoma (OS) is a devastating illness with rapid rates of dissemination and a poor overall prognosis, despite aggressive standard-of-care surgical techniques and combination chemotherapy regimens. Identifying the molecular mechanisms involved in disease pathogenesis and progression may offer insight into new therapeutic targets. Defects in mesenchymal stem cell differentiation, abnormal expression of oncogenes and tumor suppressors, and dysregulation within various important signaling pathways have all been implicated in development of various disease phenotypes. As such, a variety of basic science and translational studies have shown promise in identifying novel markers and modulators of these disease specific aberrancies. Born out of these and similar investigations, a variety of emerging therapies are now undergoing various phases of OS clinical testing. They broadly include angiogenesis inhibitors, drugs that act on the bone microenvironment, receptor tyrosine kinase inhibitors, immune system modulators, and other radio- or chemo-sensitizing agents. As new forms of drug delivery are being developed simultaneously, the possibility of targeting tumors locallywhile minimizing systemic toxicityis is seemingly more achievable now than ever. In this review, we not only summarize our current understanding of OS disease processes, but also shed light on the multitude of potential therapeutic strategies the scientific community can use to make long-term improvements in patient prognosis. PMID- 26496980 TI - Co-treatment of THP-1 cells with naringenin and curcumin induces cell cycle arrest and apoptosis via numerous pathways. AB - Acute myeloid leukemia (AML) is a hematological malignancy with a low survival rate. Curcumin, which is a multi-targeted anticancer agent, has been shown to exert anti-oxidant, anti-inflammatory, anti-mutagenic and anti-carcinogenic activities. Naringenin is extracted from citrus fruits and exerts anti-mutagenic and anti-carcinogenic activities in various types of cancer cells. However, the effects of curcumin and naringenin in combination in AML cells have yet to be studied. The present study aimed to investigate the combination effects of curcumin and naringenin on the viability, cell cycle distribution and apoptosis rate of THP-1 cells using cell viability assays, flow cytometry, and western blotting. Naringenin enhanced curcumin-induced apoptosis and cell viability inhibition. In addition, curcumin and naringenin induced cell cycle arrest at S phase and G2/M phase. Numerous pathways, including p53, c-Jun N-terminal kinases (JNK), Akt and extracellular signal-regulated kinases (ERK)1/2 pathways were markedly altered following treatment of THP-1 cells with curcumin and naringenin. These results indicated that naringenin may enhance curcumin-induced apoptosis through inhibiting the Akt and ERK pathways, and promoting the JNK and p53 pathways. PMID- 26496982 TI - Control of Risk Factors for Cardiovascular Disease among Multinational Patient Population in the Arabian Gulf. AB - We evaluated the control of cardiovascular disease (CVD) risk factors among patients with atherosclerotic cardiovascular disease (ASCVD) in the Centralized Pan-Middle East Survey on the undertreatment of hypercholesterolaemia (CEPHEUS) in the Arabian Gulf. Of the 4398 enrolled patients, overall mean age was 57 +/- 11 years, 60% were males, 13% were smokers, 76% had diabetes, 71% had metabolic syndrome and 78% had very high ASCVD risk status. The proportion of subjects with body mass index <25 kgm2, HbA1c <7% (in diabetics), low-density lipoprotein cholesterol (LDL-C) <2.6 mmol/L (100 mg/dL) and <1.8 mmol/L (70 mg/dL) for high and very high ASCVD risk cohorts, respectively and controlled blood pressure (<140/90 mmHg) was 14, 26, 31% and 60%, respectively. Only 1.4% of the participants had all of their CVD risk factors controlled with significant differences among the countries (P < .001). CVD risk goal attainment rates were significantly lower in those with very high ASCVD risk compared with those with high ASCVD risk status (P < .001). Females were also, generally, less likely to attain goals when compared with males (P < .001). PMID- 26496984 TI - Molt-dependent transcriptomic analysis of cement proteins in the barnacle Amphibalanus amphitrite. AB - BACKGROUND: A complete understanding of barnacle adhesion remains elusive as the process occurs within and beneath the confines of a rigid calcified shell. Barnacle cement is mainly proteinaceous and several individual proteins have been identified in the hardened cement at the barnacle-substrate interface. Little is known about the molt- and tissue-specific expression of cement protein genes but could offer valuable insight into the complex multi-step processes of barnacle growth and adhesion. METHODS: The main body and sub-mantle tissue of the barnacle Amphibalanus amphitrite (basionym Balanus amphitrite) were collected in pre- and post-molt stages. RNA-seq technology was used to analyze the transcriptome for differential gene expression at these two stages and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) was used to analyze the protein content of barnacle secretions. RESULTS: We report on the transcriptomic analysis of barnacle cement gland tissue in pre- and post-molt growth stages and proteomic investigation of barnacle secretions. While no significant difference was found in the expression of cement proteins genes at pre- and post-molting stages, expression levels were highly elevated in the sub-mantle tissue (where the cement glands are located) compared to the main barnacle body. We report the discovery of a novel 114kD cement protein, which is identified in material secreted onto various surfaces by adult barnacles and with the encoding gene highly expressed in the sub-mantle tissue. Further differential gene expression analysis of the sub-mantle tissue samples reveals a limited number of genes highly expressed in pre-molt samples with a range of functions including cuticular development, biominerialization, and proteolytic activity. CONCLUSIONS: The expression of cement protein genes appears to remain constant through the molt cycle and is largely confined to the sub-mantle tissue. Our results reveal a novel and potentially prominent protein to the mix of cement-related components in A. amphitrite. Despite the lack of a complete genome, sample collection allowed for extended transcriptomic analysis of pre- and post-molt barnacle samples and identified a number of highly-expressed genes. Our results highlight the complexities of this sessile marine organism as it grows via molt cycles and increases the area over which it exhibits robust adhesion to its substrate. PMID- 26496985 TI - Health related quality of life two to five years after gestational diabetes mellitus: cross-sectional comparative study in the ATLANTIC DIP cohort. AB - BACKGROUND: There is no consensus on the effect of gestational diabetes mellitus (GDM) on health-related quality of life (HRQOL) for the mother in the short or long term. In this study we examined HRQOL in a group of women who had GDM in the index pregnancy 2 to 5 years previously and compared it to a group of women with normal glucose tolerance (NGT) in the index pregnancy during the same time period. METHODS: The sample included 234 women who met International Association of Diabetes Study Groups (IADPSG) criteria for GDM in the index pregnancy and 108 who had NGT. The sample was drawn from the ATLATIC-DIP (Diabetes In Pregnancy) cohort - a network of antenatal centers along the Irish Atlantic seaboard serving a population of approximately 500,000 people. HRQOL was measured using the visual analogue component of the EQ-5D-3 L instrument in a cross-sectional survey. RESULTS: The difference in HRQOL between GDM and NGT groups was not significant when adjusted for the effects of the covariates. HRQOL was negatively affected by increased BMI and abnormal glucose tolerance post-partum in the NGT group. Moderate alcohol consumption was positively associated with HRQOL in the NGT group only. The negative association with smoking on HRQOL was substantially higher in the GDM group. CONCLUSIONS: A diagnosis of GDM does not appear to have an adverse effect on HRQOL, 2 to 5 years after the index pregnancy. On the contrary, its diagnosis might lead to the development of coping strategies, which, consequently attenuates the adverse effect of the subsequent acquisition of abnormal glucose tolerance post-partum on HRQOL. Women whose pregnancy was affected by GDM are more susceptible to the adverse effects on HRQOL of alcohol use and tobacco smoking. PMID- 26496983 TI - Modelling the distribution and transmission intensity of lymphatic filariasis in sub-Saharan Africa prior to scaling up interventions: integrated use of geostatistical and mathematical modelling. AB - BACKGROUND: Lymphatic filariasis (LF) is one of the neglected tropical diseases targeted for global elimination. The ability to interrupt transmission is, partly, influenced by the underlying intensity of transmission and its geographical variation. This information can also help guide the design of targeted surveillance activities. The present study uses a combination of geostatistical and mathematical modelling to predict the prevalence and transmission intensity of LF prior to the implementation of large-scale control in sub-Saharan Africa. METHODS: A systematic search of the literature was undertaken to identify surveys on the prevalence of Wuchereria bancrofti microfilaraemia (mf), based on blood smears, and on the prevalence of antigenaemia, based on the use of an immuno-chromatographic card test (ICT). Using a suite of environmental and demographic data, spatiotemporal multivariate models were fitted separately for mf prevalence and ICT-based prevalence within a Bayesian framework and used to make predictions for non-sampled areas. Maps of the dominant vector species of LF were also developed. The maps of predicted prevalence and vector distribution were linked to mathematical models of the transmission dynamics of LF to infer the intensity of transmission, quantified by the basic reproductive number (R0). RESULTS: The literature search identified 1267 surveys that provide suitable data on the prevalence of mf and 2817 surveys that report the prevalence of antigenaemia. Distinct spatial predictions arose from the models for mf prevalence and ICT-based prevalence, with a wider geographical distribution when using ICT-based data. The vector distribution maps demonstrated the spatial variation of LF vector species. Mathematical modelling showed that the reproduction number (R0) estimates vary from 2.7 to 30, with large variations between and within regions. CONCLUSIONS: LF transmission is highly heterogeneous, and the developed maps can help guide intervention, monitoring and surveillance strategies as countries progress towards LF elimination. PMID- 26496986 TI - Annually recurring erythema annulare centrifugum: a case report. AB - INTRODUCTION: Erythema annulare centrifugum is a rare cutaneous disease characterized by erythematous and violaceous annular plaques that usually involved the thighs and the legs. The eruption may be associated with an underlying disease and its accompanying characteristic symptoms. For these reasons, a full physical examination should be conducted to exclude underlying disorders. Annually recurring erythema annulare centrifugum is a rare and peculiar variant of erythema annulare centrifugum with the same clinical and histopathological characteristics. The lesions of annually recurring erythema annulare centrifugum tend to regress spontaneously after a variable period of days to months with yearly recurrence for many years. CASE PRESENTATION: We present the case of a 46-year-old caucasian woman affected by annually recurring erythema annulare centrifugum, which is a peculiar form of superficial erythema annulare centrifugum. The lesions have the same clinical and histopathological characteristics of the classical superficial form of erythema annulare centrifugum and tend to regress spontaneously after a variable period of days to months. In our case, no precipitating factors were identified and no underlying diseases were found. Every year for the last 12 years the lesions started to appear in the summer months and regressed spontaneously in autumn. CONCLUSIONS: Cases of annually recurring erythema annulare centrifugum are rarely reported in the literature and generally no causative agent can be detected. The main feature of annually recurring erythema annulare centrifugum is the constant annual and seasonal recurrence of the lesions for many years. PMID- 26496987 TI - Cardiac monitoring always required after electrical injuries? AB - BACKGROUND: Controversy still exists regarding inpatient monitoring of patients exposed to electrical injuries. MATERIALS AND METHODS: In a monocentric retrospective study, we evaluated the medical records of 169 patients admitted to the University Hospital of Cologne from January 2000 to January 2014 because of electrical trauma. The electrocardiogram (ECG) data of 40 patients were missing. RESULTS: Patients in our collective were predominantly young men (60 %) with an average age of 17.5 +/- 17 years (1 year to 73 years). The electrical trauma occurred occupational (20 %), domestic (65 %), and during leisure time (15 %). In the high-voltage (>= 1000 V) group (n = 7; 71 % male; 40.0 +/- 19.4 years) one death was reported, related to an open intracranial injury and cardiac arrest. Of the six surviving patients five showed normal ECGs and one a sinus tachycardia. In the low-voltage (< 1000 V) group (n = 162, 56 % male; 5.0 +/- 4.3 years) the ECG findings were as follows: 104 normal, 5 sinus tachycardia, 3 sinus arrhythmia, 6 ST segment changes, 3 premature atrial contraction, 1 premature ventricular contraction, 1 atrio-ventricular (AV)-Block and 1 delta wave. In all, one patient showed a self-limiting supraventricular tachycardia. CONCLUSION: Asymptomatic and stable patients without any risk factors and with a normal initial ECG need no inpatient cardiac monitoring after an electrical injury. PMID- 26496988 TI - Reflections of Black Women Who Choose to Breastfeed: Influences, Challenges and Supports. AB - OBJECTIVES: Black women continue to have the lowest rates of breastfeeding. Of those who choose to breastfeed up to half cease nursing within the first few days or months postpartum. This study identified factors that influence and challenge Black women who choose to breastfeed, and supportive strategies that facilitate successful breastfeeding experiences. METHODS: Four focus groups were conducted in 2013 with 16 self-identified Black women aged 21-46 (M = 31.35 years), with 11 18 (M = 14.94) years of education, and were either pregnant or had given birth to an infant within the prior 5 years (range of pregnancies 1-7; M = 2.44). A standard set of questions guided discussions. Data saturation occurred after three groups. All discussions were audiotaped and transcribed. Qualitative methods were used to identify categories and subthemes. Reviewers met periodically to resolve ambiguities and coding discrepancies. Member checking was conducted. RESULTS: Four major categories emerged: Balancing the influences: People, myths, and technology; Being in the know; Critical periods; and, Supportive Transitions. Most women experienced little help with breastfeeding from health providers or systems. More influential was the interplay of family members,myths and the internet "as my friend". Role models and personalized support were noted as important but lacking among Black women. Patient profiling, experienced by some of the women, impacted breastfeeding choices. CONCLUSIONS: Black women such as our participants are critical partners as we develop systems of care to decrease disparities and increase Black women's successes in breastfeeding. Findings underscore the importance of having diverse, readily available, user-friendly, culturally sensitive options for Black women who choose to breastfeed. PMID- 26496989 TI - Life Course Factors Associated with Initiation and Continuation of Exclusive Breastfeeding. AB - INTRODUCTION: Exclusive breastfeeding (EBF) benefits the life course health development of infants, families, and society. Professional health associations recommend EBF for 4 months, and many now recommend EBF for 6 months. Yet only 18.8 % of US infants born in 2011 were exclusively breastfed. Numerous studies on breastfeeding are published, but few describe EBF. This study describes characteristics of women who initiated EBF and examines the associations of those factors with EBF lasting >=4 months. The Life Course Health Development (LCHD)framework was used to structure the analysis and interpret results. METHODS: Data collected through the Infant Feeding Practices Study II survey (2005-2007) were used to identify a cohort of women (n = 1226) practicing EBF at the time of hospital discharge and their sociodemographic, health, work, and child care characteristics. Associations of these characteristics with EBF lasting >=4 months were studied by bivariate and logistic regression analyses. RESULTS: College education [odds ratio (OR) 2.14, 95 %confidence interval (CI) 1.58-2.89] and marriage (OR2.19, 95 % CI 1.43-3.37) were associated with greater odds of EBF lasting >=4 months, whereas the plan to return to work after birth (OR 0.57, 95 % CI 0.43-0.74), living in the south (OR 0.67, 95 % CI 0.47-0.95), and postpartum depression risk (OR 0.43, 95 % CI 0.28-0.66)were associated with lower odds of EBF lasting >= 4 months. DISCUSSION: Several factors associated with disparities in continued EBF were identified. The application of the LCHD framework furthers understanding of the multiple and interacting risks associated with early discontinuation of EBF. PMID- 26496990 TI - Quantitative trait loci with sex-specific effects for internal organs weights and hematocrit value in a broiler-layer cross. AB - Rapid growth in broilers is associated with susceptibility to metabolic disorders such as pulmonary hypertension syndrome (ascites) and sudden death. This study describes a genome search for QTL associated with relative weight of cardio respiratory and metabolically important organs (heart, lungs, liver and gizzard), and hematocrit value in a Brazilian broiler-layer cross. QTL with similar or different effects across sexes were investigated. At 42 days of age after fasted for 6 h, the F2 chickens were weighed and slaughtered. Weights and percentages of the weight relative to BW42 of gizzard, heart, lungs, liver and hematocrit were used in the QTL search. Parental, F1 and F2 individuals were genotyped with 128 genetic markers (127 microsatellites and 1 SNP) covering 22 linkage groups. QTL mapping analyses were carried out using mixed models. A total of 11 genome-wide significant QTL and five suggestive linkages were mapped. Thus, genome-wide significant QTL with similar effects across sexes were mapped to GGA2, 4 and 14 for heart weight, and to GGA2, 8 and 12 for gizzard %. Additionally, five genome wide significant QTL with different effects across sexes were mapped to GGA 8, 19 and 26 for heart weight; GGA26 for heart % and GGA3 for hematocrit value. Five QTL were detected in chromosomal regions where QTL for similar traits were previously mapped in other F2 chicken populations. Seven novel genome-wide significant QTL are reported here, and 21 positional candidate genes in QTL regions were identified. PMID- 26496992 TI - Bilateral uveal melanomas with different gene expression detected with 7 years interval. AB - PURPOSE: To report a bilateral uveal melanoma detected in a micrometastasis study. METHOD: Case report. RESULTS: At enucleation of a circumpapillary amelanotic mixed melanoma in a patient with ocular melanocytosis, a pigmented lesion in the other eye was detected, thought to be a naevus. BAP1 was positive showing nuclear staining of the tumour cells. Seven years later the naevus showed growth and development of a retinal detachment. FNAB disclosed monosomy 3 in the spindle tumour cells. CONCLUSION: A case of bilateral melanoma with long-term survival without metastatic diseases is reported. Different gene expressions in the two eyes were revealed. The case is a reminder that follow-up over years is essential in patients with a uveal melanoma, especially with ocular melanocytosis. PMID- 26496993 TI - Transgenerational effects of land use on offspring performance and growth in Trifolium repens. AB - Central European grasslands vary widely in productivity and in mowing and grazing regimes. The resulting differences in competition and heterogeneity among grasslands might have direct effects on plants, but might also affect the growth and morphology of their offspring through maternal effects or adaptive evolution. To test for such transgenerational effects, we grew plants of the clonal herb Trifolium repens from seeds collected in 58 grassland sites differing in productivity and mowing and grazing intensities in different treatments: without competition, with homogeneous competition, and with heterogeneous competition. In the competition-free treatment, T. repens from more productive, less frequently mown, and less intensively grazed sites produced more vegetative offspring, but this was not the case in the other treatments. When grown among or in close proximity to competitors, T. repens plants did not show preferential growth towards open spaces (i.e., no horizontal foraging), but did show strong vertical foraging by petiole elongation. In the homogeneous competition treatment, petiole length increased with the productivity of the parental site, but this was not the case in the heterogeneous competition treatment. Moreover, petiole length increased with mowing frequency and grazing intensity of the parental site in all but the homogeneous competition treatment. In summary, although the expression of differences between plants from sites with different productivities and land-use intensities depended on the experimental treatment, our findings imply that there are transgenerational effects of land use on the morphology and performance of T. repens. PMID- 26496991 TI - Metacognitive Awareness of Facial Affect in Higher-Functioning Children and Adolescents with Autism Spectrum Disorder. AB - Higher-functioning participants with and without autism spectrum disorder (ASD) viewed a series of face stimuli, made decisions regarding the affect of each face, and indicated their confidence in each decision. Confidence significantly predicted accuracy across all participants, but this relation was stronger for participants with typical development than participants with ASD. In the hierarchical linear modeling analysis, there were no differences in face processing accuracy between participants with and without ASD, but participants with ASD were more confident in their decisions. These results suggest that individuals with ASD have metacognitive impairments and are overconfident in face processing. Additionally, greater metacognitive awareness was predictive of better face processing accuracy, suggesting that metacognition may be a pivotal skill to teach in interventions. PMID- 26496994 TI - Cofilin phosphorylation is elevated after F-actin disassembly induced by Rac1 depletion. AB - Cytoskeletal reorganization is essential to keratinocyte function. Rac1 regulates cytoskeletal reorganization through signaling pathways such as the cofilin cascade. Cofilin severs actin filaments after activation by dephosphorylation. Rac1 was knocked out in mouse keratinocytes and it was found that actin filaments disassembled. In the epidermis of mice in which Rac1 was knocked out only in keratinocytes, cofilin phosphorylation was aberrantly elevated, corresponding to repression of the phosphatase slingshot1 (SSH1). These effects were independent of the signaling pathways for p21-activated kinase/LIM kinase (Pak/LIMK), protein kinase C, or protein kinase D or generation of reactive oxygen species. Similarly, when actin polymerization was specifically inhibited or Rac1 was knocked down, cofilin phosphorylation was enhanced and SSH1 was repressed. Repression of SSH1 partially blocked actin depolymerization induced by Rac1 depletion. Therefore, aberrant cofilin phosphorylation that induces actin polymerization might be a consequence of actin disassembly induced by the absence of Rac1. PMID- 26496995 TI - Over-expression of prothymosin-alpha antagonizes TGFbeta signalling to promote the development of emphysema. AB - Emphysema, a major consequence of chronic obstructive pulmonary disease (COPD), is characterized by the permanent airflow restriction resulting from enlargement of alveolar airspace and loss of lung elasticity. Transforming growth factor-beta (TGFbeta) signalling regulates the balance of matrix metalloproteinase (MMP)/tissue inhibitor of matrix metalloproteinase (TIMP) to control matrix homeostasis. Patients with COPD have dysregulated TGFbeta signalling and reduced histone deacetylase (HDAC) activity through epigenetic up-regulation of histone acetylation in the promoters of pro-inflammatory genes. However, the potential link between decreased HDAC activity and dysregulated TGFbeta signalling in emphysema pathogenesis remains to be determined. Prothymosin alpha (ProT), a highly conserved acidic nuclear protein, plays a role in the acetylation of histone and non-histone proteins. The aim of this study was to test the hypothesis that ProT inhibits TGFbeta-Smad signalling through Smad7, thereby contributing to emphysema pathogenesis. We show that ProT enhances Smad7 acetylation by decreasing its association with HDAC and thereby down-regulates TGFbeta-Smad signalling. ProT caused an imbalance between MMP and TIMP through acetylated Smad7 in favour of MMP expression. In addition to interfering with R Smad activation and targeting receptors for degradation in the cytoplasm, acetylated Smad7 potentiated by ProT competitively antagonized binding of the pSmad2/3-Smad4 complex to the TIMP-3 promoter, resulting in reduced TIMP-3 expression. These effects were detected in ProT-over-expressing cells, lungs of ProT transgenic mice displaying an emphysema phenotype and in emphysema patients. Importantly, increased Smad7 and reduced TIMP-3 were found in the lungs of emphysema patients and mice with cigarette smoke extract (CSE)-induced emphysema. Such effects could be abrogated by silencing endogenous ProT expression. Collectively, our results uncover acetylated Smad7 regulated by ProT as an important determinant in dysregulated TGFbeta signalling that contributes to emphysema pathogenesis. PMID- 26496996 TI - Conditioned inhibition in preweanling rats. AB - Inhibitory conditioning is a very well established phenomenon in associative learning that has been demonstrated in both humans and adult animals. But in spite of the fact that this topic has generated much empirical and theoretical work, there are no published studies assessing inhibitory learning during the early ontogeny of the rat. In this study we test the possibility of finding conditioned inhibition in infant rats (Day 10) using a conditioned taste aversion procedure. We tested whether the consumption of saccharin (A) was reduced when paired with a LiCl injection compared to the presentation of saccharin in compound with a lemon odor (AX) without any aversive consequence. After training, retardation, and summation tests were conducted in order to evaluate the inhibitory properties of the lemon odor (X). The results of this study showed that in male pups, after conditioned inhibition training, stimulus X passed both retardation and summation tests. These results indicate that conditioned inhibition can be established in the early development of the rat, suggesting that animals at this stage of ontogeny have the capacity to acquire and to express inhibitory conditioning, although this effect appears to be sex dependent. PMID- 26496997 TI - [Hepatocellular tumours in noncirrhotic liver tissue]. AB - In recent years, the spectrum of tissue-based diagnostics of hepatocellular tumours has changed due to novel molecular pathological findings. Innovative radiographics filter out small lesions and ambiguous tumours for bioptical sampling. The spectrum of these tumours includes hepatocellular carcinoma, hepatocellular adenomas, focal nodular hyperplasia and macroregenerative nodules. Primarily, morphological analysis should identify the dignity of a lesion. After exclusion of HCC and reactive liver cell nodules, hepatocellular adenomas should be further subclassified based on immunohistochemical/molecular pathological criteria according to the WHO classification of liver tumours. This procedure provides significant additional information regarding the prognosis and therapeutic implications of hepatocellular adenomas. PMID- 26496998 TI - Reply to comment to Meta-analysis and systematic review of laparoscopic versus open mesh repair for elective incisional hernia. Jensen K, Jorgensen LN. PMID- 26496999 TI - Calpain-1 is associated with adverse relapse free survival in breast cancer: a confirmatory study. AB - AIMS: Calpain-1 is a ubiquitously expressed calcium-activated intracellular cysteine protease. Altered expression of calpain system proteins has been implicated in cancer progression and response to chemotherapy. METHODS AND RESULTS: The aim of the current study was to confirm previous data that suggested that calpain-1 expression is associated with relapse-free survival in trastuzumab treated breast cancer patients (n = 93). An expanded patient cohort from Nottingham (n = 194; including 72 of the previous cohort) and an independent patient cohort from Newcastle (n = 87) were used. All patients received trastuzumab following adjuvant therapy according to local guidelines with expression of calpain-1 investigated using standard immunohistochemistry. Results show that calpain-1 expression is associated with relapse-free survival in both the Nottingham (P = 0.01) and Newcastle (P = 0.019) cohorts, with high expression associated with adverse relapse-free survival. Expression was also associated with poor relapse-free survival when patient cohorts were combined (n = 281, P = 0.01). Calpain-1 remained, from multivariate analysis, an independent marker for relapse-free survival in the Newcastle cohort [hazard ratio (HR) = 5.169; 95% confidence interval (CI) 1.468-18.200; P = 0.011]. CONCLUSIONS: Calpain-1 expression is associated with poor relapse-free survival in breast cancer patients treated with trastuzumab. Further work is warranted to standardize and develop methodology with a view to potentially introducing assessment of this important biomarker into clinical practice. PMID- 26497000 TI - The Chemical Aquatic Fate and Effects database (CAFE), a tool that supports assessments of chemical spills in aquatic environments. AB - The Chemical Aquatic Fate and Effects (CAFE) database is a centralized repository that allows for rapid and unrestricted access to data. Information in CAFE is integrated into a user-friendly tool with modules containing fate and effects data for 32 377 and 4498 chemicals, respectively. Toxicity data are summarized in the form of species sensitivity distributions (SSDs) with associated 1st and 5th percentile hazard concentrations (HCs). An assessment of data availability relative to reported chemical incidents showed that CAFE had fate and toxicity data for 32 and 20 chemicals, respectively, of 55 chemicals reported in the US National Response Center database (2000-2014), and fate and toxicity data for 86 and 103, respectively, of 205 chemicals reported by the National Oceanic and Atmospheric Administration (2003-2014). Modeled environmental concentrations of 2 hypothetical spills (acrylonitrile, 625 barrels; and denatured ethanol, 857 barrels) were used to demonstrate CAFE's practical application. Most species in the 24-h SSD could be potentially impacted by acrylonitrile and denatured ethanol during the first 35 min and 15 h post spill, respectively, with concentrations falling below their HC5s (17 mg/L and 2676 mg/L) at 45 min and 60 h post spill, respectively. Comparisons of CAFE-based versus published HC5 values for 100 chemicals showed that nearly half of values were within a 2-fold difference, with a relatively small number of comparisons exceeding a 10-fold difference. The development of CAFE facilitates access to relevant environmental information, with potential uses likely expanding beyond those related to assessment of spills in aquatic environments. Environ Toxicol Chem 2016;35:1576-1586. (c) 2015 SETAC. PMID- 26497001 TI - New member of the R2R3-MYB transcription factors family in grapevine suppresses the anthocyanin accumulation in the flowers of transgenic tobacco. AB - In grapevine, anthocyanins and proanthocyanidins are the main flavonoids in berries, which are associated to organoleptic properties in red wine such as color and astringency. Flavonoid pathway is specifically regulated at transcriptional level and several R2R3-MYB proteins have shown to act as positive regulators. However, some members of this family have shown to repress the flavonoid biosynthesis. In this work, we present the characterization of VvMYB4 like gene, which encodes a putative transcriptional factor highly expressed in the skin of berries at the pre veraison stage in grapevine. Its over-expression in tobacco resulted in the loss of pigmentation in flowers due a decrease in anthocyanin accumulation. Severity in anthocyanin suppression observed in petals could be associated with the expression level of the VvMYB4-like transgene. Expression analysis of flavonoid structural genes revealed the strong down regulation of the flavonoid-related genes anthocyanidin synthase (ANS) and dihydroflavonol reductase (DFR) genes and also the reduction of the anthocyanin related gene UDP glucose:flavonoid 3-O-glucosyl transferase (UFGT), which was dependent of the transgene expression. In addition, expression of VvMYB4-like in the model plant Arabidopsis showed similar results, with the higher down regulation observed in the AtDFR and AtLDOX genes. These results suggest that VvMYB4-like may play an important role in regulation of anthocyanin biosynthesis in grapevine acting as a transcriptional repressor of flavonoid structural genes. PMID- 26497002 TI - The Irish Cost-Effectiveness Threshold: Does it Support Rational Rationing or Might it Lead to Unintended Harm to Ireland's Health System? AB - Ireland is one of the few countries worldwide to have an explicit cost effectiveness threshold. In 2012, an agreement between government and the pharmaceutical industry that provided substantial savings on existing medications set the threshold at ?45,000/quality-adjusted life-year (QALY). This replaced a previously unofficial threshold of ?20,000/QALY. According to the agreement, drugs within the threshold will be granted reimbursement, whereas those exceeding it may still be approved following further negotiation. A number of drugs far exceeding the threshold have been approved recently. The agreement only applies to pharmaceuticals. There are four reasons for concern regarding Ireland's threshold. The absence of an explicit threshold for non-drug interventions leaves it unclear if there is parity in willingness to pay across all interventions. As the threshold resembles a price floor rather than a ceiling, in principle it only offers a weak barrier to cost-ineffective interventions. It has no empirical basis. Finally, it is probably too high given recent estimates of a threshold for the UK based on the cost effectiveness of services forgone of approximately L13,000/QALY. An excessive threshold risks causing the Irish health system unintended harm. The lack of an empirically informed threshold means the policy recommendations of cost-effectiveness analysis cannot be considered as fully evidence- based rational rationing. Policy makers should consider these issues and recent Irish legislation that defined cost effectiveness in terms of the opportunity cost of services forgone when choosing what threshold to apply once the current industry agreement expires at the end of 2015 PMID- 26497003 TI - Transforming Healthcare Delivery: Integrating Dynamic Simulation Modelling and Big Data in Health Economics and Outcomes Research. AB - In the era of the Information Age and personalized medicine, healthcare delivery systems need to be efficient and patient-centred. The health system must be responsive to individual patient choices and preferences about their care, while considering the system consequences. While dynamic simulation modelling (DSM) and big data share characteristics, they present distinct and complementary value in healthcare. Big data and DSM are synergistic-big data offer support to enhance the application of dynamic models, but DSM also can greatly enhance the value conferred by big data. Big data can inform patient-centred care with its high velocity, volume, and variety (the three Vs) over traditional data analytics; however, big data are not sufficient to extract meaningful insights to inform approaches to improve healthcare delivery. DSM can serve as a natural bridge between the wealth of evidence offered by big data and informed decision making as a means of faster, deeper, more consistent learning from that evidence. We discuss the synergies between big data and DSM, practical considerations and challenges, and how integrating big data and DSM can be useful to decision makers to address complex, systemic health economics and outcomes questions and to transform healthcare delivery. PMID- 26497004 TI - Calculating Total Health Service Utilisation and Costs from Routinely Collected Electronic Health Records Using the Example of Patients with Irritable Bowel Syndrome Before and After Their First Gastroenterology Appointment. AB - INTRODUCTION: Health economic models are increasingly important in funding decisions but most are based on data, which may therefore not represent the general population. We sought to establish the potential of real-world data available within the Clinical Practice Research Datalink (CPRD) and linked Hospital Episode Statistics (HES) to determine comprehensive healthcare utilisation and costs as input variables for economic modelling. METHODS: A cohort of patients with irritable bowel syndrome (IBS) who first saw a gastroenterologist in 2008 or 2009, and with 3 years of data before and after their appointment, was created in the CPRD. Primary care, outpatient, inpatient, prescription and colonoscopy data were extracted from the linked CPRD and HES. The appropriate cost to the NHS was attached to each event. Total and stratified annual healthcare utilisation rates and costs were calculated before and after the gastroenterology appointment with distribution parameters. Absolute differences were calculated with 95% confidence intervals. RESULTS: Total annual healthcare costs over 3 years increase by L935 (95% CI L928-941) following a gastroenterology appointment for IBS. We derived utilisation and cost data with parameter distributions stratified by demographics and time. Women, older patients, smokers and patients with greater comorbidity utilised more healthcare resources, which generated higher costs. CONCLUSIONS: These linked datasets provide comprehensive primary and secondary care data for large numbers of patients, which allows stratification of outcomes. It is possible to derive input parameters appropriate for economic models and their distributions directly from the population of interest. PMID- 26497005 TI - Long-term outcome of patients with and without super-response to CRT-D. AB - OBJECTIVE: To compare outcome between patients with and without super-response to cardiac resynchronization therapy-defibrillator (CRT-D). METHODS AND RESULTS: In this cohort study, 167 consecutive CRT-D candidates were included. Super-response to CRT-D was defined clinically [improvement of >=1 New York Heart Association (NYHA) class or >=50 m in six-minute walk distance (6MWD)] and echocardiographically [increase of left ventricular ejection fraction (LVEF) >=1 category (LVEF <30 to 30-40 % or 30-40 to 41-51 %) or reduction of left ventricular end-diastolic diameter (LVEDD) >=10 mm]. Clinical outcome (death, cardiac transplantation and appropriate shock therapy) was compared between super responders (n = 32) and non-super-responders (n = 135). During follow-up (616 patient-years; median 3.3 years), all-cause mortality was significantly lower in super-responders compared to non-super-responders (log rank p < 0.05). At least one appropriate shock was noted in 22 % of super-responders and 39 % of non-super responders (p = 0.069). Time to appropriate shock therapy was significantly longer in super-responders (log rank p < 0.05). Event-free survival from death or cardiac transplantation was comparable between the two groups. CONCLUSION: Super response to CRT-D is associated with improved survival and lower risk of appropriate shock therapy compared to non-super-responders. Further information about the mechanisms of super-response and its long-term consequences are needed to foresee favorable outcome after implantation of CRT-D. PMID- 26497006 TI - Functional organization of the local circuit in the inferior colliculus. AB - The inferior colliculus (IC) is the first integration center of the auditory system. After the transformation of sound to neural signals in the cochlea, the signals are analyzed by brainstem auditory nuclei that, in turn, transmit this information to the IC. However, the neural circuitry that underlies this integration is unclear. This review consists of two parts: one is about the cell type which is likely to integrate sound information, and the other is about a technique which is useful for studying local circuitry. Large GABAergic (LG) neurons receive dense excitatory axosomatic terminals that originate from the lower brainstem auditory nuclei as well as local IC neurons. Dozens of axons coming from both local and lower brainstem neurons converge on a single LG soma. Excitatory neurons in IC can innervate many nearby LG somata in the same fibrodendritic lamina. The combination of local and ascending inputs is well suited for auditory integration. LG neurons are one of the main sources of inhibition in the medial geniculate body (MGB). LG neurons and the tectothalamic inhibitory system are present in a wide variety of mammalian species. This suggests that the circuitry of excitatory and inhibitory tectothalamic projections may have evolved earlier than GABAergic interneurons in the MGB, which are found in fewer species. Cellular-level functional imaging provides both morphological and functional information about local circuitry. In the last part of this review, we describe an in vivo calcium imaging study that sheds light on the functional organization of the IC. PMID- 26497007 TI - Genetic diversity loss in a biodiversity hotspot: ancient DNA quantifies genetic decline and former connectivity in a critically endangered marsupial. AB - The extent of genetic diversity loss and former connectivity between fragmented populations are often unknown factors when studying endangered species. While genetic techniques are commonly applied in extant populations to assess temporal and spatial demographic changes, it is no substitute for directly measuring past diversity using ancient DNA (aDNA). We analysed both mitochondrial DNA (mtDNA) and nuclear microsatellite loci from 64 historical fossil and skin samples of the critically endangered Western Australian woylie (Bettongia penicillata ogilbyi), and compared them with 231 (n = 152 for mtDNA) modern samples. In modern woylie populations 15 mitochondrial control region (CR) haplotypes were identified. Interestingly, mtDNA CR data from only 29 historical samples demonstrated 15 previously unknown haplotypes and detected an extinct divergent clade. Through modelling, we estimated the loss of CR mtDNA diversity to be between 46% and 91% and estimated this to have occurred in the past 2000-4000 years in association with a dramatic population decline. In addition, we obtained near-complete 11 loci microsatellite profiles from 21 historical samples. In agreement with the mtDNA data, a number of 'new' microsatellite alleles was only detected in the historical populations despite extensive modern sampling, indicating a nuclear genetic diversity loss >20%. Calculations of genetic diversity (heterozygosity and allelic rarefaction) showed that these were significantly higher in the past and that there was a high degree of gene flow across the woylie's historical range. These findings have an immediate impact on how the extant populations are managed and we recommend the implementation of an assisted migration programme to prevent further loss of genetic diversity. Our study demonstrates the value of integrating aDNA data into current-day conservation strategies. PMID- 26497008 TI - Applying Multivariate Discrete Distributions to Genetically Informative Count Data. AB - We present a novel method of conducting biometric analysis of twin data when the phenotypes are integer-valued counts, which often show an L-shaped distribution. Monte Carlo simulation is used to compare five likelihood-based approaches to modeling: our multivariate discrete method, when its distributional assumptions are correct, when they are incorrect, and three other methods in common use. With data simulated from a skewed discrete distribution, recovery of twin correlations and proportions of additive genetic and common environment variance was generally poor for the Normal, Lognormal and Ordinal models, but good for the two discrete models. Sex-separate applications to substance-use data from twins in the Minnesota Twin Family Study showed superior performance of two discrete models. The new methods are implemented using R and OpenMx and are freely available. PMID- 26497009 TI - Recent developments and applications of capillary and microchip electrophoresis in proteomic and peptidomic analyses. AB - This review presents recent developments and applications of capillary and microchip electromigration methods in proteomics and peptidomics. Sample preparation methods as well as instrumental innovations in the coupling of these advanced electromigration methods with mass spectrometry detection employed in proteomic and peptidomic analyses are presented. Interesting applications of various capillary electromigration methods in bottom-up as well as top-down proteomics, including investigation of post-translational modifications of proteins are described. In addition, several examples of the use of capillary electromigration methods combined with mass spectrometry detection in clinical proteomics and peptidomics are demonstrated. PMID- 26497011 TI - Mechanisms of immune system activation in mammalians by small interfering RNA (siRNA). AB - RNA interference (RNAi) guided by small interfering RNAs (siRNA), because of its potential to target and silence the expression of specific genes is utilized as an effective tool in a variety of biological applications. RNAi guided by siRNAs is a powerful tool to attain gene silencing in mammalian cells. One of the features which make siRNA as an amazing biological tool is extremely specific knockdown of target genes by degradation of analogous mRNAs. However, various non specific effects limit the use of RNAi including the activation of innate immunity and inhibition of inadvertent target genes. One of the most common non specific effects is inducing the innate immune system including cytoplasmic and endosomal activation of innate immune system, potentially offending the single in mammals. This activation is mainly interceded by immune cells, regularly through a Toll-like receptor (TLR) pathway. The siRNA sequence association of these pathways changes with the sort and position of the TLR involved. In contrast, non immune cell activation can also arise generally siRNAs which enter into cytoplasm interacting with cytoplasmic RNA sensors such as retinoic acid-inducible gene I. Here, we explain the off-target effects of siRNAs that activate innate immune system and methods to alleviate them, to help enable impressive application of this exciting technology, Also we bold the aspect of molecular strategies permitting the design of therapeutic siRNAs with minute off-target effects. PMID- 26497010 TI - Impact of pulsed-electric field and high-voltage electrical discharges on red wine microbial stabilization and quality characteristics. AB - AIMS: In this study, pulsed-electric fields (PEF) and high-voltage electrical discharges (HVED) are proposed as new techniques for the microbial stabilization of red wines before bottling. The efficiency of the treatment was then evaluated. METHODS AND RESULTS: PEF and HVED-treatments have been applied to wine for the inactivation of Oenococcus oeni CRBO 9304, O. oeni CRBO 0608, Pediococcus parvulus CRBO 2.6 and Brettanomyces bruxellensis CB28. Different treatment times (1, 2, 4, 6, 8 and 10 ms) were used at 20 kV cm(-1) for the PEF treatments and at 40 kV for the HVED treatments, which correspond to applied energies from 80 to 800 kJ l(-1) . The effects of the treatments on the microbial inactivation rate and on various characteristics of red wines (phenolic composition, chromatic characteristics and physico-chemical parameters) were measured. CONCLUSIONS: The application of PEF or HVED treatments on red wine allowed the inactivation of alteration yeasts (B. bruxellensis CB28) and bacteria (O. oeni CRBO 9304, O. oeni CRBO 0608 and P. parvulus CRBO 2.6). The electric discharges at 40 kV were less effective than the PEF even after 10 ms of treatments. Indeed, 4 ms of PEF treatment at 20 kV cm(-1) were sufficient to inactivate all micro-organisms present in the wines. Also, the use of PEF had no negative impact on the composition of wines compared to the HVED treatments. Contrary to PEF, the phenolics compounds were degraded after the HVED treatment and the physico chemical composition of wine were modified with HVED. SIGNIFICANCE AND IMPACT OF THE STUDY: PEF technology seems to be an interesting alternative to stabilize microbiologically wines before bottling and without modifying their composition. This process offers many advantages for winemakers: no chemical inputs, low energy consumption (320 kJ l(-1) ), fast (treatment time of 4 ms) and athermal (DeltaT ~ 10 degrees C). PMID- 26497012 TI - S100A4 interacts with mutant p53 and affects gastric cancer MKN1 cell autophagy and differentiation. AB - The acquired p53 mutations are the most common genetic alterations in human cancers. Mutant p53 proteins tend to accumulate, augmenting their oncogenic potential. However, the mechanisms for mutant p53 accumulation are not known. Previous studies have shown that S100A4 interacts with wild-type p53. The present study marks the first time the effect of S100A4 on mutant p53 levels in gastric cancer MKN1 cells, which harbor mutant p53V143A, and the functional consequences have been investigated. S100A4 interacted with mutant p53V143A in the cells, and S100A4 inhibition decreased mutant p53V143A levels, indicating that S100A4 promoted mutant p53 accumulation through their interaction. We also found that S100A4 inhibition altered the expression of the mutant p53V143A target genes [c Myc and inhibitor of DNA binding 2 (Id2)]. Moreover, we demonstrated that S100A4 knockdown increased mutant p53-related autophagy and cell differentiation. In conclusion, our data suggest a novel mechanism for mutant p53V143A accumulation and add a new facet to the role of S100A4 in cancer. PMID- 26497013 TI - Intensity of swimming exercise influences tracheal reactivity in rats. AB - Studies that evaluate the mechanisms for increased airway responsiveness are very sparse, although there are reports of exercise-induced bronchospasm. Therefore, we have evaluated the tracheal reactivity and the rate of lipid peroxidation after different intensities of swimming exercise in rats. Thus, male Wistar rats (age 8 weeks; 250-300 g) underwent a forced swimming exercise for 1h whilst carrying attached loads of 3, 4, 5, 6 and 8% of their body weight (groups G3, G4, G5, G6 and G8, respectively; n=5 each). Immediately after the test, the trachea of each rat was removed and suspended in an organ bath to evaluate contractile and relaxant responses. The rate of lipid peroxidation was estimated by measuring malondialdehyde levels. According to a one-way ANOVA, all trained groups showed a significant decrease in the relaxation induced by aminophylline (10(-12)-10(-1) M) (pD2=3.1, 3.2, 3.3, 3.3 and 3.2, respectively for G3, G4, G5, G6 and G8) compared to the control group (pD2=4.6) and the Emax values of G5, G6, G8 groups were reduced by 94.2, 88.0 and 77.0%, respectively. Additionally, all trained groups showed a significant increase in contraction induced by carbachol (10(-9) 10 (-3) M) (pD2=6.0, 6.5, 6.5, 7.2 and 7.3, respectively for G3, G4, G5, G6 and G8) compared to the control group (pD2=5.7). Lipid peroxidation levels of G3, G4 and G5 were similar in both the trachea and lung, however G6 and G8 presented an increased peroxidation in the trachea. In conclusion, a single bout of swimming exercise acutely altered tracheal responsiveness in an intensity-related manner and the elevation in lipid peroxidation indicates a degree of oxidative stress involvement. PMID- 26497014 TI - Effect of the one-carbon unit cycle on overall DNA methylation in children with Down's syndrome. AB - DNA methylation is a major epigenetic mechanism regulating gene expression. In order to analyze the impact of the one-carbon unit cycle on the overall level of DNA methylation in children with Down's syndrome (DS), the levels of indicators associated with the one-carbon unit cycle, including folic acid (FA), vitamin B12 (VB12) and homocysteine (Hcy), and the overall DNA methylation level of DS and healthy controls (HCs) were determined in the present study. A total of 36 DS children and 40 age- and gender-matched HCs were included in the present study to determine the levels of FA, VB12, Hcy and overall DNA methylation. The effect of the one-carbon unit cycle on the overall level of DNA methylation within the DS group was analyzed. The results demonstrated that the level of VB12 was decreased (P=0.008), while the Hcy level was increased (P=0.000) in DS patients compared with the HCs. FA and VB12 levels decreased with increasing age in DS patients (P<0.05). DNA hypermethylation and hypomethylation were observed in DS patients with VB12 deficiency and hyperhomocysteinemia, respectively (P=0.031, P=0.021). Abnormalities in the one-carbon unit cycle tend to worsen with increasing age in DS children. Thus, one-carbon unit cycle-associated alterations in DNA methylation may be important in the neuropathological alterations observed in DS. PMID- 26497015 TI - Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity. AB - Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD. Autism Res 2016, 9: 621-631. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26497016 TI - Evodiamine, a novel inhibitor of the Wnt pathway, inhibits the self-renewal of gastric cancer stem cells. AB - Gastric cancer stem cells (GCSCs) have an important role in metastasis and recurrence of gastric cancer, and novel treatment strategies that target GCSCs are urgently required. Although evodiamine (Evo), a derivative of the traditional herbal medicine Evodia rutaecarpa, has been reported to have various biological effects, its effect on GCSCs remains unknown. In order to determine the effect of Evo on apoptosis of GCSCs, an MTS assay, flow cytometry and western blot analysis were performed. The effect of Evo on self-renewal in GCSCs was measured by alterations in the sphere formation ability, the expression of induced pluripotent stem cell factors, expression of epithelial-to-mesenchymal transition (EMT) factors and oxaliplatin resistance of gastric cancer cells (GCCs). Evo inhibited proliferation, promoted the Bax/B-cell lymphoma 2 ratio and altered active caspase-3 expression of GCSCs. In addition, Evo decreased the sphere formation ability, the expression of Sox2, KLF4, Bmi-1 and Oct4, and oxaliplatin resistance in GCCs. Evo decreased the expression of Slug, Twist, Zeb1 and vimentin, suggesting an inhibitory effect on EMT. Furthermore, the expression of beta-catenin, c-Myc and cyclin D1 was decreased in Evo-treated spheroids from GCCs. In conclusion, Evo inhibited the Wnt/beta-catenin signaling pathway to inhibit proliferation and stem cell properties of GCSCs and repressed the EMT. The present findings highlight the prospect of Evo as a CSCs-targeted therapy in gastric cancer. PMID- 26497017 TI - Biochemical characterization of a halotolerant feruloyl esterase from Actinomyces spp.: refolding and activity following thermal deactivation. AB - Ferulic acid esterases (FAE, EC. 3.1.1.73) hydrolyse the linkage between hemicellulose and lignin and thus have potential for use in mild enzymatic pretreatment of biomass as an alternative to thermochemical approaches. Here, we report the characterization of a novel FAE (ActOFaeI) obtained from the bacterium, Actinomyces sp. oral which was recombinantly expressed in Escherichia coli BL21 in two forms: with and without its putative signal peptide. The truncated form was found to have <10 % relative activity compared to the full length and was more prone to aggregation after purification. The enzyme with retained peptide demonstrated 2 to 4-fold higher activity against methyl caffeate and methyl p-coumarate, with specific activities of 477.6 and 174.4 U mg(-1) respectively, than the equivalent activities of the benchmark FAE from Aspergillus niger A and B. ActOFaeI retained activity over a broad pH range with a maximum at 9 but >90 % relative activity at pH 6.5 and an optimum reaction temperature of 30 degrees C. ActOFaeI increased activity by 15% in high salt conditions (1000 mMNaCl) and its thermal unfolding temperature improved from 41.5 degrees C in standard buffer to 74 degrees C in the presence of 2500 mM sodium malonate. ActOFaeI also released ferulic acid from destarched wheat bran when combined with a xylanase preparation. After treatment above the thermal denaturation temperature followed by cooling to room temperature, ActOFaeI demonstrated spontaneous refolding into an active state. ActOFaeI displays many useful characteristics for enzymatic pretreatment of lignocellulose and contributes to our understanding of this important family. PMID- 26497018 TI - Spore behaviors reveal a category of mating-competent infertile heterokaryons in the offspring of the medicinal fungus Agaricus subrufescens. AB - Strain breeding is much less advanced in the edible and medicinal species Agaricus subrufescens than in Agaricus bisporus, the button mushroom. Both species have a unifactorial system of sexual incompatibility, a mating type locus tightly linked to a centromere, and basidia producing both homokaryotic (n) and heterokaryotic (n + n) spores. In A. bisporus, breeding is mainly based on direct selection among the heterokaryotic offspring and on hybridization between homokaryotic offspring. The parental heterozygosity is highly maintained in the heterokaryotic offspring due to suppression of recombination and preferential pairing in the spores of nuclei, each one per second meiotic divisions; such "non sister nuclei" heterokaryons are fertile. In A. subrufescens, recent studies revealed that recombination is not suppressed and that nuclei from the same second meiotic division can also be paired in a spore that give rise to a "sister nuclei" heterokaryon in which the nuclei bear the same mating type allele. The objective of the present work was to investigate the potential function of the different categories of spores in A. subrufescens and their possible use in a genetic breeding program. Using eight co-dominant molecular markers, we found that half of the offspring of the A. subrufescens strain WC837 were heterokaryotic, one quarter of them being sister nuclei heterokaryons. These heterokaryons were infertile and behaved like homokaryons, being even able to cross between each other. In contrast, non-sister nuclei heterokaryons could fruit but inconsistently due to inbreeding depression. Potential roles of these two categories of heterokaryons in nature and consequences for strain breeding are discussed. PMID- 26497019 TI - Secondary sex ratio in regions severely exposed to methylmercury "Minamata disease". AB - PURPOSE: Secondary sex ratio (i.e., male proportion at birth) is considered to function as a sentinel health indicator. Thus, examining this ratio spatially and temporally in regions with severe environmental exposure to compounds such as methylmercury may provide insight into the evolution of exposure. METHODS: We evaluated spatial and temporal distributions of the secondary sex ratio in Minamata, Japan, and neighboring areas, where severe methylmercury poisoning occurred in the 1950s and 1960s. We selected four areas exposed to methylmercury: Minamata, Ashikita, Goshonoura, and Izumi. After obtaining the number of live births, we conducted descriptive analyses by study area. RESULTS: We observed a reduction in male births in the exposed areas. In particular, a decline in the sex ratio of the Minamata area, where the first patient was officially identified in 1956, was seen around 1955. The ratio during 1955-1959 around Minamata was 0.496 [95% confidence interval (CI) 0.481-0.511]; the 95% CI did not include the value of 0.515 (the secondary sex ratio of the entire Japanese population during the study period). Declines in this ratio were also observed in other exposed areas around 1960, when acetaldehyde production (the origin of methylmercury) reached its peak. CONCLUSIONS: These analyses demonstrate that temporal and spatial distributions of the secondary sex ratio reflect the evolution of methylmercury exposure corresponding with the known history of Minamata disease. PMID- 26497020 TI - Fate and toxic effects of environmental stressors: environmental control. AB - The potential for toxicants to harm organisms in the environment is influenced by the physicochemistry of the substances and their environmental behaviors and transformation within ecosystems. This special issue is composed of 20 papers that report on studies which have investigated the fate and toxicity of various toxicants including engineered nanoparticles, pharmaceuticals and personal care products, antibiotics, pathogens, heavy metals, and agricultural nutrients. The environmental transformations of these substances and how these processes affect their toxicity are emphasized. This paper highlights the important findings and perspectives of the selected papers in this special edition, with an aim of providing insights into full-scale evaluation on the toxicity of various contaminants that exist in ecosystems. General suggestions are provided for the future directions of toxicological research. PMID- 26497021 TI - Decreased fish diversity found near marble industry effluents in River Barandu, Pakistan. AB - In a recently published study we observed that effluents from marble industry affected physicochemical characteristics of River Barandu in District Buner, Pakistan. These changes in water quality due to marble effluents may affect fish community. The present study was therefore conducted to evaluate the impacts of marble industry effluents on fish communities in River Barandu using abundance, richness, diversity and evenness of fish species as end point criteria. The fish samples were collected by local fishermen on monthly basis from three selected sites (upstream, effluents/industrial, and downstream sites). During the study period, a total of 18 fish species were found belonging to 4 orders, 5 families and 11 genera. The Cyprinidae was observed to be the dominant family at all the three selected sites. Lower abundance and species diversity was observed at the industrial (22%) and downstream sites (33%) as compared to the upstream site (45%). Effluents of marble industry were associated with lower abundance of species in River Barandu. It is recommended that industries should be shifted away from the vicinity of river and their effluents must be treated before discharging to prevent further loss of fish abundance and diversity in the River. PMID- 26497022 TI - Profiling of methylation and demethylation pathways during brain development and ageing. AB - Numerous signal pathways are epigenetically controlled during brain development and ageing. Thereby, both 5-methylcytosine (5mC) and the newly described 5 hydroxymethylcytosine (5hmC) are highly exhibited in the brain. As there is an uneven distribution of 5hmC in the brain depending on age and region, there is the need to investigate the underlying mechanisms being responsible for 5hmC generation and decline. The aim of this study was to quantify expression levels of genes that are associated with DNA methylation/demethylation in different brain regions and at different ages. Therefore, we investigated frontal cortex and cerebellum of 40 mice (strain C57BL/6), each eight mice sacrificed at day 0, 7, 15, 30 and 120 after birth. We performed expression profiling of methylation/demethylation genes depending on age and brain region. Interestingly, we see significant expression differences of genes being responsible for methylation/demethylation with a significant reduction of expression levels during ageing. Validating selected expression data on protein level using immunohistochemistry verified the expression data. In conclusion, our findings demonstrate that the regulation of methylation/demethylation pathways is highly controlled depending on brain region and age. Thus our data will help to better understand the complexity and plasticity of the brain epigenome. PMID- 26497024 TI - Identifying the Adamkiewicz artery using 3-T time-resolved magnetic resonance angiography: its role in addition to multidetector computed tomography angiography. AB - PURPOSE: This study assessed Adamkiewicz artery (AKA) detectability using multidetector computed tomography angiography (MDCTA) and time-resolved magnetic resonance angiography (MRA) at 3 T. MATERIALS AND METHODS: This Institutional Review Board-approved retrospective study included 117 patients with thoracoabdominal aortic disease scheduled for aortic repair. A total of 111 patients underwent MDCTA for AKA identification; 43 patients whose AKA identification was not definitive on MDCTA underwent additional MRA. The remaining six patients, who were not indicated for iodine-contrast MDCTA, underwent only MRA. Two reviewers independently evaluated both MDCTA and MRA data. The 4-point confidence index was used. Grades 3-4 were considered sufficient for AKA diagnosis. RESULTS: AKA detectability was at 80.2% (89/111) using MDCTA and 89.8% (44/49) with MRA. In the 43 patients who underwent both MDTCA and MRA, the AKA detectability and consensus grades were significantly elevated using MRA vs. MDCTA (detectability: 88.4 vs. 69.8%, respectively, p = 0.043). AKA detectability was also higher in aortic aneurysm than aortic dissection patients on MDCTA (90.9 vs. 69.6%, respectively, p < 0.01), but not on MRA (92.9 vs. 88.6%, respectively, p = 0.99). CONCLUSIONS: Time-resolved MRA at 3 T increases AKA detectability and is recommended for patients without definitive AKA identification on MDCTA. PMID- 26497025 TI - Congenital anomaly of combined atlas-odontoid process fusion and bipartite atlas. AB - Congenital fusion of the atlas with the odontoid process of the axis is a very rare condition caused by a segmental defect of the first cervical somite. Only 9 such cases have been reported in the literature to date. The bipartite atlas, another well-documented rare anomaly, has been observed in only 0.1% of the general population. We describe the first case of a 70-year-old male with both of these complex congenital anomalies. PMID- 26497026 TI - The phrenic nerve with accompanying vessels: a silent cause of cardiovascular border obliteration on chest radiography. AB - PURPOSE: Our aim was to clarify the frequency of cardiovascular border obliteration on frontal chest radiography and to prove that the phrenic nerve with accompanying vessels can be considered as a cause of obliteration of cardiovascular border on an otherwise normal chest radiography. MATERIALS AND METHODS: Two radiologists reviewed chest radiographs and computed tomography (CT) images of 100 individuals. CT confirmed the absence of intrapulmonary or extrapulmonary abnormalities in all of them. We examined the frequency of cardiovascular border obliteration on frontal chest radiography and summarized the causes of obliteration as pericardial fat pad, phrenic nerve, intrafissure fat, pulmonary vessels, and others, comparing them with CT in each case. RESULTS: Cardiovascular border was obliterated on frontal chest radiography in 46 cases on the right and in 61 on the left. The phrenic nerve with accompanying vessels was found to be a cause of obliteration in 34 of 46 cases (74%) on the right and 29 of 61 (48%) cases on the left. The phrenic nerve was the most frequent cause of cardiovascular border obliteration on both sides. CONCLUSION: The phrenic nerve with accompanying vessels, forming a prominent fold of parietal pleura, can be attributed as a cause of cardiovascular border obliteration on frontal chest radiography. PMID- 26497023 TI - Brainstem control of locomotion and muscle tone with special reference to the role of the mesopontine tegmentum and medullary reticulospinal systems. AB - The lateral part of the mesopontine tegmentum contains functionally important structures involved in the control of posture and gait. Specifically, the mesencephalic locomotor region, which may consist of the cuneiform nucleus and pedunculopontine tegmental nucleus (PPN), occupies the interest with respect to the pathophysiology of posture-gait disorders. The purpose of this article is to review the mechanisms involved in the control of postural muscle tone and locomotion by the mesopontine tegmentum and the pontomedullary reticulospinal system. To make interpretation and discussion more robust, the above issue is considered largely based on our findings in the experiments using decerebrate cat preparations in addition to the results in animal experimentations and clinical investigations in other laboratories. Our investigations revealed the presence of functional topographical organizations with respect to the regulation of postural muscle tone and locomotion in both the mesopontine tegmentum and the pontomedullary reticulospinal system. These organizations were modified by neurotransmitter systems, particularly the cholinergic PPN projection to the pontine reticular formation. Because efferents from the forebrain structures as well as the cerebellum converge to the mesencephalic and pontomedullary reticular formation, changes in these organizations may be involved in the appropriate regulation of posture-gait synergy depending on the behavioral context. On the other hand, abnormal signals from the higher motor centers may produce dysfunction of the mesencephalic-reticulospinal system. Here we highlight the significance of elucidating the mechanisms of the mesencephalic-reticulospinal control of posture and locomotion so that thorough understanding of the pathophysiological mechanisms of posture-gait disorders can be made. PMID- 26497027 TI - Multiple imputation strategies for zero-inflated cost data in economic evaluations: which method works best? AB - Cost and effect data often have missing data because economic evaluations are frequently added onto clinical studies where cost data are rarely the primary outcome. The objective of this article was to investigate which multiple imputation strategy is most appropriate to use for missing cost-effectiveness data in a randomized controlled trial. Three incomplete data sets were generated from a complete reference data set with 17, 35 and 50 % missing data in effects and costs. The strategies evaluated included complete case analysis (CCA), multiple imputation with predictive mean matching (MI-PMM), MI-PMM on log transformed costs (log MI-PMM), and a two-step MI. Mean cost and effect estimates, standard errors and incremental net benefits were compared with the results of the analyses on the complete reference data set. The CCA, MI-PMM, and the two-step MI strategy diverged from the results for the reference data set when the amount of missing data increased. In contrast, the estimates of the Log MI-PMM strategy remained stable irrespective of the amount of missing data. MI provided better estimates than CCA in all scenarios. With low amounts of missing data the MI strategies appeared equivalent but we recommend using the log MI-PMM with missing data greater than 35 %. PMID- 26497029 TI - The Association of Amyloid-beta Protein Precursor With alpha- and beta-Secretases in Mouse Cerebral Cortex Synapses Is Altered in Early Alzheimer's Disease. AB - Amyloid-beta peptides (Abeta), the proposed triggers of synaptic dysfunction in early Alzheimer's disease (AD), derive from the endoproteolytic cleavage of amyloid-beta precursor protein (APP) by beta-secretases (BACE1), whereas APP cleavage by alpha-secretases (ADAM10) abrogates Abeta formation. We now mapped the synaptic localization of APP, ADAM10, and BACE1 in the mouse cerebral cortex. All three proteins were present in cortical synapses and subsynaptic fractionation revealed that APP was located mainly in the pre-synaptic active zone (53 %) and in the post-synaptic density (37 %), whereas ADAM10 was enriched in the post-synaptic density (61 %) and BACE1 was concentrated in extra-synaptic regions (72 %). Immunocytochemistry analysis further showed that APP and BACE1 were co-localized in about 30 % of both glutamatergic and GABAergic terminals, whereas few terminals were endowed with ADAM10. This distribution is modified in a mouse model of early AD based on Abeta1-42-intracerebroventricular injection, where the synaptic levels of APP and ADAM10 increased by 30 %, whereas BACE1 levels were reduced. This suggests that, in early AD, there are compensatory mechanisms to avoid Abeta overload in cortical synapses favoring the non amyloidogenic processing of APP. PMID- 26497028 TI - Protein Palmitoylation Regulates Neural Stem Cell Differentiation by Modulation of EID1 Activity. AB - The functional significance of palmitoylation in the switch between self-renewal and differentiation of neural stem cells (NSCs) is not well defined, and the underlying mechanisms of protein palmitoylation are not well understood. Here, mouse NSCs were used as a model system and cell behavior was monitored in the presence of the protein palmitoylation inhibitor 2-bromopalmitate (2BRO). Our data show that 2BRO impaired the differentiation of NSCs into both neurons and glia and impaired NSC cell cycle exit. Moreover, the results show that palmitoylation modified E1A-like inhibitor of differentiation one (EID1) and this modification regulated EID1 degradation and CREB-binding protein (CBP)/p300 histone acetyltransferase activity at the switch between self-renewal and differentiation of NSCs. Our results extended the cellular role of palmitoylation, suggesting that it acts as a regulator in the acetylation dependent gene expression network, and established the epigenetic regulatory function of palmitoylation in the switch between maintenance of multipotency and differentiation in NSCs. PMID- 26497030 TI - The Ras/Raf/Erk Pathway Mediates the Subarachnoid Hemorrhage-Induced Apoptosis of Hippocampal Neurons Through Phosphorylation of p53. AB - Apoptosis plays a crucial role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). However, the exact molecular mechanisms underlying neuronal apoptosis in EBI after SAH have not been fully elucidated. The present study showed that EBI induced significantly neuronal apoptosis activation of Ras/Raf/Erk signals in hippocampus after SAH. Intracisternal administration of PD98059, an inhibitor of Erk1/2, decreased the hippocampal neuronal apoptosis and alleviated the cognitive deficits induced by SAH. Interestingly, an increase in phosphorylation of p53 was paralleled with p-Erk, and PD98059 also blocked the level of p-p53. In primary cultures, oxyhemoglobin (OxyHb) treatment significantly increased p-Erk, p-p53, and apoptosis, which was used to mimic the pathological injury of SAH. Both p53 small interfering RNA (siRNA) and PD98059 reduced the OxyHb-induced apoptosis. Moreover, PD98059 significantly decreased the levels of p-Erk and p-p53; however, p53 siRNA had little effect on the level of p-Erk. Taken together, our study implicates that the Ras/Raf/Erk signals contribute to neuronal death through the phosphorylation of p53 in hippocampus after SAH and also suggests Erk/p53 as a potential target for clinical drug treatment of SAH. PMID- 26497031 TI - Golli Myelin Basic Proteins Modulate Voltage-Operated Ca(++) Influx and Development in Cortical and Hippocampal Neurons. AB - The golli proteins, products of the myelin basic protein gene, are widely expressed in oligodendrocyte progenitor cells and neurons during the postnatal development of the brain. While golli appears to be important for oligodendrocyte migration and differentiation, its function in neuronal development is completely unknown. We have found that golli proteins function as new and novel modulators of voltage-operated Ca(++) channels (VOCCs) in neurons. In vitro, golli knock-out (KO) neurons exhibit decreased Ca(++) influx after plasma membrane depolarization and a substantial maturational delay. Increased expression of golli proteins enhances L-type Ca(++) entry and processes outgrowth in cortical neurons, and pharmacological activation of L-type Ca(++) channels stimulates maturation and prevents cell death in golli-KO neurons. In situ, Ca(++) influx mediated by L type VOCCs was significantly decreased in cortical and hippocampal neurons of the golli-KO brain. These Ca(++) alterations affect cortical and hippocampal development and the proliferation and survival of neural progenitor cells during the postnatal development of the golli-KO brain. The CA1/3 sections and the dentate gyrus of the hippocampus were reduced in the golli-KO mice as well as the density of dendrites in the somatosensory cortex. Furthermore, the golli-KO mice display abnormal behavior including deficits in episodic memory and reduced anxiety. Because of the expression of the golli proteins within neurons in learning and memory centers of the brain, this work has profound implication in neurodegenerative diseases and neurological disorders. PMID- 26497032 TI - Peripheral Blood MicroRNA Expression Profiles in Alzheimer's Disease: Screening, Validation, Association with Clinical Phenotype and Implications for Molecular Mechanism. AB - A series of investigations have been performed regarding microRNA (miRNA, miR) of Alzheimer's disease (AD) patients. However, most of these used microarray with neither validation by PCR nor any follow-up on the biological mechanism implicated by findings. Further, there were rarely any analyses linking clinical phenotype of de novo, drug-naive patients to cellular pathogenic mechanism(s) to date. Microarray screening followed by validation via quantitative PCR (Q-PCR) assays and the relationship between miRNAs and phenotypic indices were evaluated. Additionally, the cellular mechanism of miRNAs through effects of beta-site amyloid precursor protein (APP) cleaving enzyme (BACE1) was assessed. We identified 2 specific differentially expressed (DE) miRNAs (miR-339 and miR-425) as potential diagnostic biomarkers for AD and revealed that these DE miRNAs could be involved in modulating the pathogenesis of AD via BACE1 protein inhibition. The findings presented here reveal a detailed snapshot of the profile of peripheral blood mononuclear cells (PBMC) miRNA changes in AD patients, association with clinical phenotype, and potential roles in cellular pathogenesis. PMID- 26497033 TI - Inflammation and B-cell Lymphoma-2 Associated X Protein Regulate Zinc-Induced Apoptotic Degeneration of Rat Nigrostriatal Dopaminergic Neurons. AB - Clinical evidences showing zinc (Zn) accumulation in the post-mortem brain of Parkinson's disease (PD) patients and experimental studies on rodents chronically exposed to Zn suggested its role in PD. While oxidative stress is implicated in Zn-induced neurodegeneration, roles of inflammation and apoptosis in degeneration of the nigrostriatal dopaminergic neurons have yet been elusive. The present study investigated the contribution of the nuclear factor kappa B (NF-kappaB), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and B-cell lymphoma 2 (Bcl-2) family proteins in Zn-induced Parkinsonism. Male Wistar rats were treated with/without zinc sulfate (Zn; 20 mg/kg, intraperitoneally), twice a week, for 2-12 weeks. In a few sets, animals were treated intraperitoneally with a NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC; 100 mg/kg), a TNF-alpha inhibitor, pentoxyfylline (PTX; 50 mg/kg), and an anti-inflammatory agent, dexamethasone (DEX; 5 mg/kg), prior to Zn exposure along with respective controls. Zn caused neurobehavioral impairments and reduction in dopamine and its metabolites, tyrosine hydroxylase (TH)-positive neurons, catalase activity, and expression of TH, Bcl-2, and NOXA. On the contrary, Zn augmented lipid peroxidation, activity of superoxide dismutase, expression of TNF-alpha, IL 1beta, Bcl-xl, and p53-upregulated modulator of apoptosis (PUMA), and translocation of NF-kappaB and Bax from the cytosol to the nucleus and mitochondria, respectively, with concomitant increase in the mitochondrial cytochrome c release and activation of procaspase-3 and -9. Pre-treatment with PTX, DEX, or PDTC invariably ameliorated Zn-induced changes in behavioral and neurodegenerative indexes, inflammatory mediators, and apoptosis. Results demonstrate that inflammation regulates Bax expression that subsequently contributes to the nigrostriatal dopaminergic neurodegeneration. PMID- 26497034 TI - Brain Insulin Administration Triggers Distinct Cognitive and Neurotrophic Responses in Young and Aged Rats. AB - Aging is a major risk factor for cognitive deficits and neurodegenerative disorders, and impaired brain insulin receptor (IR) signaling is mechanistically linked to these abnormalities. The main goal of this study was to investigate whether brain insulin infusions improve spatial memory in aged and young rats. Aged (24 months) and young (4 months) male Wistar rats were intracerebroventricularly injected with insulin (20 mU) or vehicle for five consecutive days. The animals were then assessed for spatial memory using a Morris water maze. Insulin increased memory performance in young rats, but not in aged rats. Thus, we searched for cellular and molecular mechanisms that might account for this distinct memory response. In contrast with our expectation, insulin treatment increased the proliferative activity in aged rats, but not in young rats, implying that neurogenesis-related effects do not explain the lack of insulin effects on memory in aged rats. Furthermore, the expression levels of the IR and downstream signaling proteins such as GSK3-beta, mTOR, and presynaptic protein synaptophysin were increased in aged rats in response to insulin. Interestingly, insulin treatment increased the expression of the brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptors in the hippocampus of young rats, but not of aged rats. Our data therefore indicate that aged rats can have normal IR downstream protein expression but failed to mount a BDNF response after challenge in a spatial memory test. In contrast, young rats showed insulin-mediated TrkB/BDNF response, which paralleled with improved memory performance. PMID- 26497035 TI - Thrombin/Matrix Metalloproteinase-9-Dependent SK-N-SH Cell Migration is Mediated Through a PLC/PKC/MAPKs/NF-kappaB Cascade. AB - Thrombin has been known to activate inflammatory genes including matrix metalloproteinases (MMPs). The elevated expression of MMP-9 has been observed in patients with neuroinflammatory diseases and may contribute to the pathology of brain diseases. However, the mechanisms underlying thrombin-induced MMP-9 expression in SK-N-SH cells remain unknown. The effects of thrombin on MMP-9 expression were examined in SK-N-SH cells by gelatin zymography, Western blot, real-time PCR, promoter activity assay, and cell migration assay. The detailed mechanisms were analyzed by using pharmacological inhibitors and small intefering RNA (siRNA) transfection. Here, we demonstrated that thrombin induced the expression of proform MMP-9 and migration of SK-N-SH cells, which were attenuated by pretreatment with the inhibitor of thrombin (PPACK), Gq (GPA2A), PC-PLC (D609), PI-PLC (ET-18-OCH3), nonselective protien kinase C (PKC, GF109203X), PKCalpha/betaII (Go6983), PKCdelta (Rottlerin), p38 mitogen-activated protein kinases (MAPK) (SB202190), JNK1/2 (SP600125), or NF-kappaB (Bay11-7082 or Helenalin) and transfection with siRNA of Gq, PKCalpha, PKCbeta, PKCdelta, p38, JNK1/2, IKKalpha, IKKbeta, or p65. Moreover, thrombin-stimulated PKCalpha/betaII, PKCdelta, p38 MAPK, JNK1/2, or p65 phosphorylation was abrogated by their respective inhibitor of PPACK, GPA2A, D609, ET-18-OCH3, Go6983, Rottlerin, SB202190, SP600125, Bay11-7082, or Helenalin. Pretreatment with these inhibitors or transfection with MMP-9 siRNA also blocked thrombin-induced SK-N-SH cell migration. Our results show that thrombin stimulates a Gq/PLC/PKCs/p38 MAPK and JNK1/2 cascade, which in turn triggers NF-kappaB activation and ultimately induces MMP-9 expression and cell migration in SK-N-SH cells. PMID- 26497036 TI - Selenoprotein T Deficiency Leads to Neurodevelopmental Abnormalities and Hyperactive Behavior in Mice. AB - Selenoprotein T (SelT) is a newly discovered thioredoxin-like protein, which is abundantly but transiently expressed in the neural lineage during brain ontogenesis. Because its physiological function in the brain remains unknown, we developed a conditional knockout mouse line (Nes-Cre/SelTfl/fl) in which SelT gene is specifically disrupted in nerve cells. At postnatal day 7 (P7), these mice exhibited reduced volume of different brain structures, including hippocampus, cerebellum, and cerebral cortex. This phenotype, which is observed early during the first postnatal week, culminated at P7 and was associated with increased loss of immature neurons but not glial cells, through apoptotic cell death. This phenomenon was accompanied by elevated levels of intracellular reactive oxygen species, which may explain the increased neuron demise and reduced brain structure volumes. At the second postnatal week, an increase in neurogenesis was observed in the cerebellum of Nes-Cre/SelTfl/fl mice, suggesting the occurrence of developmental compensatory mechanisms in the brain. In fact, the brain volume alterations observed at P7 were attenuated in adult mice. Nevertheless, SelT mutant mice exhibited a hyperactive behavior, suggesting that despite an apparent morphological compensation, SelT deficiency leads to cerebral malfunction in adulthood. Altogether, these results demonstrate that SelT exerts a neuroprotective role which is essential during brain development, and that its loss impairs mice behavior. PMID- 26497037 TI - Contra-directional Coupling of Nur77 and Nurr1 in Neurodegeneration: A Novel Mechanism for Memantine-Induced Anti-inflammation and Anti-mitochondrial Impairment. AB - Recent evidence suggests that nerve growth factor IB (Nur77) and nuclear receptor related1 (Nurr1) are differentially involved in dopaminergic neurodegeneration. Since memantine has shown clinically relevant efficacy in Parkinson's disease (PD) and displayed a potent protective effect on dopaminergic neurons in experimental PD models, we asked if it exerts its neuroprotection by regulating Nur77 and Nurr1 signaling. We adopted a well-established in vitro PD model, 6 hydroxydopamine (OHDA)-lesioned PC12 cells, to test our hypothesis. Different concentrations of memantine were incubated with 6-OHDA-lesioned PC12 cells, and Nur77/Nurr1 and their related signaling molecules were examined by Western blot and immunocytochemistry. Nur77-deficient PC12 cells were used to verify the influences of Nur77 on neurodegeneration and memantine-mediated neuroprotection. We found that memantine reversed Nur77 upregulation and restored Nurr1 downregulation in 6-OHDA-lesioned PC12 cells. 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and induced co-localization of Cyt c/HSP60/Nur77 in the cytosol. Memantine strongly reduced the sub-cellular translocations of Nur77/Cyt c/HSP60 under 6-OHDA-induced oxidative condition. Knockdown of Nur77 enhanced the viability of PC12 cells exposed to 6-OHDA, while memantine-induced neuroprotection was much less in the cells with Nur77 knockdown than in those without it. We conclude that Nur77 plays a crucial role in modulating mitochondrial impairment and contributes to neurodegeneration under the experimental PD condition. Memantine effectively suppresses such Nur77 mediated neurodegeneration and promotes survival signaling through post translational modification of Nurr1. Nur77 and Nurr1 present a contra directionally coupling interaction in memantine-mediated neuroprotection. PMID- 26497038 TI - Dehydroascorbic Acid Promotes Cell Death in Neurons Under Oxidative Stress: a Protective Role for Astrocytes. AB - Ascorbic acid (AA), the reduced form of vitamin C, is incorporated into neurons via the sodium ascorbate co-transporter SVCT2. However, this transporter is not expressed in astrocytes, which take up the oxidized form of vitamin C, dehydroascorbic acid (DHA), via the facilitative hexose transporter GLUT1. Therefore, neuron and astrocyte interactions are thought to mediate vitamin C recycling in the nervous system. Although astrocytes are essential for the antioxidant defense of neurons under oxidative stress, a condition in which a large amount of ROS is generated that may favor the extracellular oxidation of AA and the subsequent neuronal uptake of DHA via GLUT3, potentially increasing oxidative stress in neurons. This study analyzed the effects of oxidative stress and DHA uptake on neuronal cell death in vitro. Different analyses revealed the presence of the DHA transporters GLUT1 and GLUT3 in Neuro2a and HN33.11 cells and in cortical neurons. Kinetic analyses confirmed that all cells analyzed in this study possess functional GLUTs that take up 2-deoxyglucose and DHA. Thus, DHA promotes the death of stressed neuronal cells, which is reversed by incubating the cells with cytochalasin B, an inhibitor of DHA uptake by GLUT1 and GLUT3. Additionally, the presence of glial cells (U87 and astrocytes), which promote DHA recycling, reverses the observed cell death of stressed neurons. Taken together, these results indicate that DHA promotes the death of stressed neurons and that astrocytes are essential for the antioxidative defense of neurons. Thus, the astrocyte-neuron interaction may function as an essential mechanism for vitamin C recycling, participating in the antioxidative defense of the brain. PMID- 26497039 TI - Intracerebral Glycine Administration Impairs Energy and Redox Homeostasis and Induces Glial Reactivity in Cerebral Cortex of Newborn Rats. AB - Accumulation of glycine (GLY) is the biochemical hallmark of glycine encephalopathy (GE), an aminoacidopathy characterized by severe neurological dysfunction that may lead to early death. In the present study, we evaluated the effect of a single intracerebroventricular administration of GLY on bioenergetics, redox homeostasis, and histopathology in brain of neonatal rats. Our results demonstrated that GLY decreased the activities of the respiratory chain complex IV and creatine kinase, induced reactive species generation, and diminished glutathione (GSH) levels 1, 5, and 10 days after GLY injection in cerebral cortex of 1-day-old rats. GLY also increased malondialdehyde (MDA) levels 5 days after GLY infusion in this brain region. Furthermore, GLY differentially modulated the activities of superoxide dismutase, catalase, and glutathione peroxidase depending on the period tested after GLY administration. In contrast, bioenergetics and redox parameters were not altered in brain of 5 day-old rats. Regarding the histopathological analysis, GLY increased S100beta staining in cerebral cortex and striatum, and GFAP in corpus callosum of 1-day old rats 5 days after injection. Finally, we verified that melatonin prevented the decrease of complex IV and CK activities and GSH concentrations, and the increase of MDA levels and S100beta staining caused by GLY. Based on our findings, it may be presumed that impairment of redox and energy homeostasis and glial reactivity induced by GLY may contribute to the neurological dysfunction observed in GE. PMID- 26497040 TI - Impact of Gut Microbiota on Obesity, Diabetes, and Cardiovascular Disease Risk. AB - Gut microbiota has been recently established to have a contributory role in the development of cardiometabolic disorders, such as atherosclerosis, obesity, and type 2 diabetes. Growing interest has focused on the modulation of gut microbiota as a therapeutic strategy in cardiovascular diseases and metabolic disorders. In this paper, we have reviewed the impact of gut microbiota on metabolic disorders and cardiovascular disease risk, focusing on the newest findings in this field. PMID- 26497041 TI - Polypill: Progress and Challenges to Global Use--Update on the Trials and Policy Implementation. AB - Cardiovascular disease (CVD) is the leading cause of mortality globally. Most people with cardiovascular disease do not take long-term cholesterol-lowering, anti-platelet and blood pressure-lowering medications despite proven benefits. Fixed-dose combination pills ('polypills') have been shown to improve adherence to these recommended medications with corresponding improvements in risk factors such as blood pressure and low-density lipoprotein (LDL) cholesterol. Among patients not taking the full complement of recommended CVD preventive therapies, use of a polypill-based strategy (i.e. initiating treatment with single-pill combination medication then titrating further therapy as needed) has large potential benefits in reducing global morbidity and mortality. Despite this, few polypills are available on the market due to market failure in the funding of research and development for affordable non-communicable disease medicines. Additionally, defining a path to market has been problematic in that fixed-dose combinations with multiple different drug classes included are quite novel, and regulatory processes to review these types of applications are not well established. Despite these delays, progress is slowly being made. PMID- 26497042 TI - Nominations open for eighth annual BMJ Awards. PMID- 26497044 TI - Survival benefit of greater number of lymph nodes dissection for advanced node negative gastric cancer patients following radical gastrectomy. AB - OBJECTIVE: A common clinicopathological factor except for T stage that could significantly influence the clinical outcome of advanced node-negative gastric cancer patients following radical gastrectomy was unknown. This study was designed to investigate the clinicopathological characteristics of these patients, and to evaluate the outcome indicators and improve the risk stratification. METHODS: A total of 195 patients harboring advanced gastric adenocarcinoma with no lymph node and distant metastases and following radical gastrectomy were retrospectively analyzed from the prospectively collected database of Zhongshan Hospital of Fudan University between 2006 and 2010. RESULTS: The 3-year and 5-year overall survival rates of this study population were 85.0 and 69.6%. Factors influencing the overall survival were the degree of tumor differentiation, the depth of invasion and the number of lymph nodes resected (LN, cutoff = 18). Lymph node was recognized as an independent prognostic factor for overall survival of advanced node-negative gastric cancer patients, and the prognosis of the patients with greater number of lymph nodes resected (LN >= 18) was significantly better than those with lymph node < 18, and only the patients with T3/T4 stage could be significantly stratified by lymph node. Based on this condition, a new staging system named tumor-node-metastasis staging system for T3/T4 node-negative gastric cancer was constructed, which could have statistically different overall survival between subgroups. CONCLUSIONS: Lymph node was an independent prognostic factor of patients with advanced node-negative gastric cancer, and retrieval of more than 18 lymph nodes should be warranted. In addition, these patients with lesser number of lymph nodes resected might need aggressive postoperative treatment and closer follow up. PMID- 26497043 TI - Arsenic exposure is associated with pediatric pneumonia in rural Bangladesh: a case control study. AB - BACKGROUND: Pneumonia is the leading cause of death for children under 5 years of age globally, making research on modifiable risk factors for childhood pneumonia important for reducing this disease burden. Millions of children globally are exposed to elevated levels of arsenic in drinking water. However, there is limited data on the association between arsenic exposure and respiratory infections, particularly among pediatric populations. METHODS: This case control study of 153 pneumonia cases and 296 controls 28 days to 59 months of age in rural Bangladesh is the first to assess whether arsenic exposure is a risk factor for pneumonia in a pediatric population. Cases had physician diagnosed World Health Organization defined severe or very severe pneumonia. Urine collected during hospitalization (hospital admission time point) and 30 days later (convalescent time point) from cases and a single specimen from community controls was tested for urinary arsenic by graphite furnace atomic absorption. RESULTS: The odds for pneumonia was nearly double for children with urinary arsenic concentrations higher than the first quartile (>=6 MUg/L) at the hospital admission time point (Odd Ratio (OR):1.88 (95% Confidence Interval (CI): 1.01, 3.53)), after adjustment for urinary creatinine, weight for height, breastfeeding, paternal education, age, and number of people in the household. This was consistent with findings at the convalescent time point where the adjusted OR for children with urinary arsenic concentrations greater than the first quartile (>=6 MUg/L) was 2.32 (95% CI: 1.33, 4.02). CONCLUSION: We observed a nearly two times higher odds of pneumonia for children with creatinine adjusted urinary arsenic concentrations greater than the first quartile (>=6 MUg/L) at the hospital admission time point. This novel finding suggests that low to moderate arsenic exposure may be a risk factor for pneumonia in children under 5 years of age. PMID- 26497045 TI - The prognostic value of CXC-chemokine receptor 2 (CXCR2) in gastric cancer patients. AB - BACKGROUND: CXC chemokine receptor 2 (CXCR2) has been reported to play an important role in the proliferation and invasion of gastric cancer cells. The present study aims to investigate the impact of CXCR2 expression on the overall survival (OS) of gastric cancer patients after radical resection. METHODS: Intratumoral CXCR2 expression was evaluated with immunohistochemistry on tissue microarrays containing tumor samples of 357 gastric cancer patients from a single center. CXCR2 expression levels were correlated to clinicopathological variables and OS. RESULTS: CXCR2 expression was mainly located in the cytoplasm of gastric carcinoma cells. High CXCR2 expression was associated with poor tumor differentiation (p = 0.021), increased tumor depth (p < 0.001), lymph node metastasis (p < 0.001), advanced TNM stage (p < 0.001) and short OS (p = 0.001). CXCR2 expression was an independent prognostic factor for OS (p = 0.001) in multivariate analysis, and could be combined with TNM stage to generate a predictive nomogram for clinical outcome in patients with gastric cancer. CONCLUSION: Intratumoral CXCR2 expression is a novel independent predictor for survival in gastric cancer patients. CXCR2 might be a promising therapeutic target of postoperative adjuvant treatment. PMID- 26497046 TI - Identification of plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral Sclerosis. AB - BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, which leads to the loss of upper and lower motor neurons, with a currently unknown etiology. Specific biomarkers could help in early detection and diagnosis, and could also act as indicators of disease progression and therapy effectiveness. MicroRNAs (miRNAs) are small (18-25 nucleotides), single-stranded non-coding RNA molecules that play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression, and are essential for nervous system development. Many of the genes associated with genetic ALS have pathological biological pathways related to RNA metabolism, and their pathogenesis may be affecting the maturing processes of miRNA. RESULTS: We compared miRNA from the plasma of sALS patients and healthy controls using two cohorts; a discovery cohort analyzed with microarray (16 sALS patients and ten healthy controls) and a validation cohort confirmed with qPCR (48 sALS patients, 47 healthy controls and 30 disease controls). We measured the total amount of extracted RNA along with a spike-in control that ensured the quality of our quantification. A percentage of the 10-40 nt RNAs extracted from the total RNA showed a significant increase in ALS patients. There was a negative correlation between total RNA concentration and disease duration from onset to end point. Three of the miRNAs were up-regulated and six were down-regulated significantly in the discovery cohort. Since an internal control is required as a sample stability indicator of both the patients and controls in microarray analysis, we selected the miRNA showing the smallest dispersion and equivalency between the two groups' mean value, and decided to use hsa-miR-4516. We found hsa-miR-4649-5p to be up-regulated, and hsa-miR-4299 to be down-regulated, where each was not influenced by clinical characteristics. EPHA4, a target gene linked to the nervous system which has also been reported to be a disease modifier of ALS, is the common and most notable target gene of hsa-miR-4649-5p and hsa-miR-4299. CONCLUSION: We have shown the relationship circulating plasma miRNA has with both healthy controls and diseased patients. Hsa-miR-4649-5p and hsa-miR-4299 have the potential to be ALS diagnosis biomarkers. PMID- 26497047 TI - Impaired decision-making in symptomatic anorexia and bulimia nervosa patients: a meta-analysis. AB - BACKGROUND: Impaired decision-making is a potential neurocognitive phenotype of eating disorders. It is therefore important to disentangle the decision-making deficits associated with the eating disorder subtypes and determine whether this putative impairment is a state or trait marker of the disease or more related to starvation. We systematically reviewed the literature on decision-making in eating disorders and conducted a meta-analysis to explore its role in anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED). METHOD: A search of the Medline and EMBASE databases and article references was performed. A total of 23 studies (2044 participants) met the selection criteria. When the Iowa gambling task (IGT) was used in at least three of the studies, a meta analysis was run. RESULTS: IGT performance was significantly worse in patients with an eating disorder diagnosis (AN, BN or BED) compared with healthy controls, indicating that eating disorders have a negative effect on decision-making. Hedges' g effect sizes were moderate to large (-0.72 in AN, -0.62 in BN, and 1.26 in BED). Recovered AN patients had IGT scores similar to those of healthy controls. Restrictive AN patients had significantly lower IGT net scores than purging AN patients, and both AN subtypes had worse performances than healthy controls. Age and body mass index did not explain results. CONCLUSIONS: Decision making was significantly altered in patients with eating disorders. Poor decision making was more pronounced during the acute phase than in the recovered state of AN. Nutritional status during the acute phase of the disease did not seem to influence decision-making skills. PMID- 26497048 TI - The relationship of social support concept and repeat mammography among Iranian women. AB - BACKGROUND: Breast cancer ranks as the first most common cancer among the Iranian women. The regular repeat of mammography with 1-2 year intervals leads to the increased efficiency of early detection of breast cancer. The present study examined the predictors of repeat mammography. It was hypothesized that higher social support is connected with mammography repeat. METHODS: A cross-sectional study was carried out among 400 women 50 years and older in Sanandaj, Iran. Data was collected by the questionnaire including information on socio demographical variables and measuring social support level. Data was analyzed by SPSS16 software. Multiple logistic regression was used to determine the predictive power of demographic variables and dimensions of social support for repeat mammography. RESULTS: Women aged 50-55 years had three times odds of repeat mammography compared to women aged 56-60 years) OR, 3.02). Married women had greater odds of repeat mammography compared to single women (P < 0.006). The probability of repeat mammography in women with higher social support was 0.93 times greater than the women with lower social support (OR, 0.93; 95 % CI, 0.91-0.95; P < 0.0001). CONCLUSIONS: Iranian women are less likely repeat mammography than other Asian women. Identifying the associations between perceived social support and repeat mammography may offer detailed information to allow for future study and guide the development of interventions not only for Iranian women but also for similar cultural that received pay too little attention to date in the breast cancer literature. PMID- 26497049 TI - Discovery of 1,1'-Biphenyl-4-sulfonamides as a New Class of Potent and Selective Carbonic Anhydrase XIV Inhibitors. AB - New 1,1'-biphenylsulfonamides were synthesized and evaluated as inhibitors of the ubiquitous human carbonic anhydrase isoforms I, II, IX, XII, and XIV using acetazolamide (AAZ) as reference compound. The sulfonamides 1-21 inhibited all the isoforms, with Ki values in the nanomolar range of concentration, and were superior to AAZ against all of them. X-ray crystallography and molecular modeling studies on the adducts that compound 20, the most potent hCA XIV inhibitor of the series (Ki = 0.26 nM), formed with the five hCAs, provided insight into the molecular determinants responsible for the high affinity of this molecule toward the target enzymes. The results pave the way to the development of 1.1' biphenylsulfonamides as a new class of highy potent hCA XIV inhibitors. PMID- 26497051 TI - Pressure-driven occlusive flow of a confined red blood cell. AB - When red blood cells (RBCs) move through narrow capillaries in the microcirculation, they deform as they flow. In pathophysiological processes such as sickle cell disease and malaria, RBC motion and flow are severely restricted. To understand this threshold of occlusion, we use a combination of experiment and theory to study the motion of a single swollen RBC through a narrow glass capillary of varying inner diameter. By tracking the movement of the squeezed cell as it is driven by a controlled pressure drop, we measure the RBC velocity as a function of the pressure gradient as well as the local capillary diameter, and find that the effective blood viscosity in this regime increases with both decreasing RBC velocity and tube radius by following a power-law that depends upon the length of the confined cell. Our observations are consistent with a simple elasto-hydrodynamic model and highlight the role of lateral confinement in the occluded pressure-driven slow flow of soft confined objects. PMID- 26497050 TI - Chloride intracellular channel 1 regulates migration and invasion in gastric cancer by triggering the ROS-mediated p38 MAPK signaling pathway. AB - Chloride intracellular channel 1 (CLIC1) has been demonstrated to be overexpressed in gastric cancer, and elevated CLIC1 expression levels are markedly associated with the processes of tumor cell migration and invasion. However, the regulatory mechanism and signaling pathway underlying these processes have remained to be elucidated. The present study examined the impact of N-acetyl cysteine (NAC), indanyloxyacetic acid (IAA)-94 and SB203580, inhibitors of reactive oxygen species (ROS), as well as CLIC1 and p38 mitogen activated protein kinase (MAPK) on the migration and invasion of SGC-7901 gastric cancer cells in a hypoxia-reoxygenation (H-R) microenvironment. The results demonstrated that intracellular ROS and CLIC1 levels were increased under H-R conditions, and that functional inhibition of CLIC1 significantly decreased the H R-elevated ROS generation and p-p38 MAPK levels in SGC-7901 cells, as well as inhibited the migration and invasion of SGC-7901 cells. In addition, the expression levels of MMP-2 and MMP-9 were inhibited by NAC, IAA-94 and SB203580. These results indicated that CLIC1 regulates gastric cancer-cell migration and invasion via the ROS-mediated p38 MAPK signaling pathway. PMID- 26497052 TI - Adding anthropometric measures of regional adiposity to BMI improves prediction of cardiometabolic, inflammatory and adipokines profiles in youths: a cross sectional study. AB - BACKGROUND: Paediatric research analysing the relationship between the easy-to use anthropometric measures for adiposity and cardiometabolic risk factors remains highly controversial in youth. Several studies suggest that only body mass index (BMI), a measure of relative weight, constitutes an accurate predictor, whereas others highlight the potential role of waist-to-hip ratio (WHR), waist circumference (Waist C), and waist-to-height ratio (WHtR). In this study, we examined the effectiveness of adding anthropometric measures of body fat distribution (Waist C Z Score, WHR Z Score and/or WHtR) to BMI Z Score to predict cardiometabolic risk factors in overweight and obese youth. We also examined the consistency of these associations with the "total fat mass + trunk/legs fat mass" and/or the "total fat mass + trunk fat mass" combinations, as assessed by dual energy X-ray absorptiometry (DXA), the gold standard measurement of body composition. METHODS: Anthropometric and DXA measurements of total and regional adiposity, as well as a comprehensive assessment of cardiometabolic, inflammatory and adipokines profiles were performed in 203 overweight and obese 7-17 year-old youths from the Paediatrics Clinic, Centre Hospitalier de Luxembourg. RESULTS: Adding only one anthropometric surrogate of regional fat to BMI Z Score improved the prediction of insulin resistance (WHR Z Score, R(2): 45.9%. Waist C Z Score, R(2): 45.5%), HDL-cholesterol (WHR Z Score, R(2): 9.6%. Waist C Z Score, R(2): 10.8%. WHtR, R(2): 6.5%), triglycerides (WHR Z Score, R(2): 11.7%. Waist C Z Score, R(2): 12.2%), adiponectin (WHR Z Score, R(2): 14.3%. Waist C Z Score, R(2): 17.7%), CRP (WHR Z Score, R(2): 18.2%. WHtR, R(2): 23.3%), systolic (WHtR, R(2): 22.4%), diastolic blood pressure (WHtR, R(2): 20%) and fibrinogen (WHtR, R(2): 21.8%). Moreover, WHR Z Score, Waist C Z Score and/or WHtR showed an independent significant contribution according to these models. These results were in line with the DXA findings. CONCLUSIONS: Adding anthropometric measures of regional adiposity to BMI Z Score improves the prediction of cardiometabolic, inflammatory and adipokines profiles in youth. PMID- 26497053 TI - Hierarchical-Multiplex DNA Patterns Mediated by Polymer Brush Nanocone Arrays That Possess Potential Application for Specific DNA Sensing. AB - This paper provides a facile and cost-efficient method to prepare single-strand DNA (ssDNA) nanocone arrays and hierarchical DNA patterns that were mediated by poly(2-hydroxyethyl methacrylate) (PHEMA) brush. The PHEMA brush nanocone arrays with different morphology and period were fabricated via colloidal lithography. The hierarchical structure was prepared through the combination of colloidal lithography and traditional photolithography. The DNA patterns were easily achieved via grafting the amino group modified ssDNA onto the side chain of polymer brush, and the anchored DNA maintained their reactivity. The as-prepared ssDNA nanocone arrays can be applied for target DNA sensing with the detection limit reaching 1.65 nM. Besides, with the help of introducing microfluidic ideology, the hierarchical-multiplex DNA patterns on the same substrate could be easily achieved with each kind of pattern possessing one kind of ssDNA, which are promising surfaces for the preparation of rapid, visible, and multiplex DNA sensors. PMID- 26497054 TI - Change of treatment guidelines and evolution of ART initiation in rural South Africa: data of a large HIV care and treatment programme. AB - BACKGROUND: While WHO recommendations are to treat people earlier and earlier, it will considerably increase the number of HIV infected people eligible for antiretroviral therapy (ART). In South Africa, a country which carries one of the highest HIV burden worldwide, very few studies are available on the impact of the ART guidelines on time to ART initiation in both individuals with low CD4 count and those newly eligible for ART. We thus aimed to describe ART initiation percentages in a large HIV programme in rural KwaZulu-Natal, South Africa, according to the temporal changes of national ART eligibility guidelines from 2007 to 2012. METHODS: Adults who accessed the decentralized Hlabisa HIV treatment programme in 2007-2012 were included. Three periods following the temporal change of ART eligibility guidelines were defined (Period 1: until April 2010; Period 2: April 2010 - July 2011; Period 3: from August 2011). Percentages of ART initiation within three months of programme entry were estimated in men, in women of childbearing age (<40 years old) and in older women, and stratifying by CD4 count. Trend tests and logistic regression models were used to study the effects of change of guidelines on ART initiation percentages. RESULTS: In individuals with CD4 count <=200 cells/MUL (N = 5709 men, N = 6743 women <40 years old and N = 2017 older women), percentages of ART initiation did not differ over time (p trend = 0.25; 0.28; and 0.14, respectively). In individuals with CD4 count = 201-350 cells/MUL (N = 2680 men, N = 6086 women <40 years old and N = 1415 older women), percentages of ART initiation significantly increased over time (p trend <0.01 for the three groups): from 6 % in Period 1 to 20 % in Period 2 to 40 % in Period 3 in women of childbearing age, and from 7 % to 8-10 % to 42 % in men and in older women. CONCLUSIONS: As temporal changes of guidelines, percentages of ART initiation significantly increased in newly ART eligible people and did not decrease in individuals with very low CD4 counts. It will be crucial to continue verifying the evolution of these percentages of ART initiation with future recommendations reaching near-to-universal access to ART, to ensure that individuals most in need of ART receive it. PMID- 26497055 TI - Why creating standardized core outcome sets for chronic kidney disease will improve clinical practice. AB - Chronic kidney disease (CKD) is common and is associated with increased mortality, morbidity and cost. However, insufficient high-quality trial data are available to answer many relevant clinical questions in this field. In addition, a wide range of variable outcomes are used in studies, and often they are incompletely reported. Furthermore, there is a lack of patient-relevant outcomes, such as mortality, morbidity, quality of life, pain, need for dialysis or costs. Common problems with outcome reporting are as follows: choosing the wrong domains to measure; within domains, choosing the wrong measures (invalid surrogates, composite, non-patient relevant); within measures, choosing the wrong/variable metrics; and within metrics, choosing variable presentation methods. With this article, we aim to underline why standardized outcome reporting is key to achieving evidence-based guidance and improving clinical care for patients; highlight the frameworks available for achieving core outcome sets; and starting from these frameworks, we propose steps needed to develop a core outcome set in the field of CKD. We hope that standardized core outcome sets for nephrology will lead to the most important outcome of guideline production, improving outcomes for our patients. PMID- 26497056 TI - Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants. AB - BACKGROUND: Invasive fungal infection is an important cause of mortality and morbidity in very preterm and very low birth weight infants. Early diagnosis is difficult and treatment is often delayed. Systemically absorbed antifungal agents (usually azoles) are increasingly used as prophylaxis against invasive fungal infection in this population. OBJECTIVES: To assess the effect of prophylactic systemic antifungal therapy on mortality and morbidity in very preterm or very low birth weight infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 8), MEDLINE, EMBASE, and CINAHL (to May 2015), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised controlled trials or quasi randomised controlled trials that compared the effect of prophylactic systemic antifungal therapy versus placebo or no drug or another antifungal agent or dose regimen in very low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors. MAIN RESULTS: We identified 15 eligible trials enrolling a total of 1690 infants. Ten trials (1371 infants) compared systemic antifungal prophylaxis versus placebo or no drug. These trials were generally of good methodological quality. Meta-analysis found a statistically significant reduction in the incidence of invasive fungal infection (typical risk ratio (RR) 0.43, 95% confidence interval (CI) 0.31 to 0.59; risk difference (RD) -0.09, 95% CI -0.12 to -0.06). The average incidence of invasive fungal infection in the control groups of the trials (16%) was much higher than that generally reported from large cohort studies. Meta-analysis did not find a statistically significant difference in the risk of death prior to hospital discharge (typical RR 0.79, 95% CI 0.61 to 1.02; typical RD -0.04, 95% CI -0.07 to 0.00). Very limited data on long-term neurodevelopmental outcomes were available. Three trials that compared systemic versus oral or topical non-absorbed antifungal prophylaxis did not detect any statistically significant effects on invasive fungal infection or mortality. Two trials that compared different dose regimens of prophylactic intravenous fluconazole did not detect any significant differences in infection rates or mortality. AUTHORS' CONCLUSIONS: Prophylactic systemic antifungal therapy reduces the incidence of invasive fungal infection in very preterm or very low birth weight infants. This finding should be interpreted and applied cautiously since the incidence of invasive fungal infection was very high in the control groups of many of the included trials. Meta-analysis does not demonstrate a statistically significant effect on mortality. There are currently only limited data on the long-term neurodevelopmental consequences for infants exposed to this intervention. In addition, there is a need for further data on the effect of the intervention on the emergence of organisms with antifungal resistance. PMID- 26497058 TI - Seroprevalence against selected pathogens involved in porcine respiratory disease complex in free-range fattening pigs in Spain. PMID- 26497059 TI - Postoperative cognitive dysfunction after inhalational anesthesia in elderly patients undergoing major surgery: the influence of anesthetic technique, cerebral injury and systemic inflammation. AB - BACKGROUND: Elderly patients are reportedly at higher risk of postoperative cognitive dysfunction (POCD) after inhalational anesthesia with sevoflurane. We hypothesized that the incidence of POCD would be higher in elderly patients undergoing major surgery under inhalational rather than intravenous anesthesia. We also measured plasma S-100beta protein concentration as a biomarker of central nervous system injury, and plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha concentrations to judge the contribution of systemic inflammation to POCD. METHODS: Ninety patients aged 65-75 years scheduled for resection of an esophageal carcinoma were randomly assigned to one of three groups (n = 30) as follows: a group receiving sevoflurane anesthesia (Group S); a group receiving preoperative methylprednisolone before sevoflurane anesthesia (Group S + MP); and a control group maintained with intravenous propofol (Group C). The mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) were used to measure patients' cognitive function the day before surgery, and on the first, third and seventh postoperative days. The plasma concentrations of TNF-alpha, IL 6 and S-100beta protein were measured 10 min before anesthesia, and on the first, third and seventh postoperative days. RESULTS: There were no significant differences in the demographic or clinical characteristics, or perioperative hemodynamic status, of the three groups. The MMSE and MoCA scores were significantly lower in Group S than in the propofol control (Group C) and Group S + MP on the first, third and seventh postoperative days (P <0.05). Throughout the first postoperative week the plasma concentrations of TNF-alpha, IL-6, and S 100beta protein were significantly elevated in Group S compared with Group C (P <0.05), but were significantly lower in Group S + MP than Group S (P <0.05). CONCLUSIONS: The incidence of POCD was higher in elderly patients undergoing major surgery under inhalational anesthesia with sevoflurane than those maintained on intravenous propofol, and lower in elderly patients pro-treating with methylprednisolone. Furthermore, we found elevated plasma concentrations of S-100beta protein, TNF-alpha and IL-6 in those receiving sevoflurane anesthesia. TRIAL REGISTRATION: ChiCTR-IOR-15007007 (02-09-2015). PMID- 26497060 TI - Profiles of responses of immunological factors to different subtypes of Kawasaki disease. AB - BACKGROUND: The responses of immunological factors to different subtypes of Kawasaki disease (KD) remain poorly understood. METHODS: We recruited 388 patients with KD, 160 patients with infectious febrile disease and 85 normal children who served as control subjects. Both the levels and percentages of T lymphocyte subsets, natural killer cells (NK cells) and B cells were analyzed via flow cytometry. The levels of serum IgG, IgM, IgA and C3, C4 were assessed via velocity scatter turbidimetry. RESULTS: The most significant differences noted between the patients with infectious febrile disease and the normal children were the elevated levels of B cells, C3 and the ratio of CD4/CD8, and the decreased levels of CD8+ T cells and NK cells, as well as the moderate increase in the absolute value of the CD3+ cells. The decreased T cell levels and the elevated B cell levels were helpful in distinguishing typical KD from atypical KD; the elevated T cell levels, the elevated NK cell and B cell levels and the decreased B cell levels were helpful in predicting the effectiveness of IVIG; low C3 and C4 levels were linked with prodromal infections. CONCLUSIONS: Lymphocytes subsets and complement markers may be useful in differentiating among the different subtypes of KD and in helping clinicians understand the pathophysiology of KD. PMID- 26497061 TI - Influence of Ligand Shell Composition upon Interparticle Interactions in Multifunctional Nanoparticles. AB - The interactions of nanoparticles with biomolecules, surfaces, or other nanostructures are dictated by the nanoparticle's surface chemistry. Thus, far, shortcomings of syntheses of nanoparticles with defined ligand shell architectures have limited our ability to understand how changes in their surface composition influence reactivity and assembly. We report new synthetic approaches to systematically control the number (polyvalency), length, and steric interactions of omega-functionalized (targeting) ligands within an otherwise passivating (diluent) ligand shell. A mesofluidic reactor was used to prepare nanoparticles with the same core diameter for each of the designed ligand architectures. When the targeting ligands are malonamide groups, the nanoparticles assemble via cross-linking in the presence of trivalent lanthanides. We examined the influence of ligand composition on assembly by monitoring the differences in optical properties of the cross-linked and free nanoparticles. Infrared spectroscopy, electron microscopy, and solution small angle X-ray scattering provided additional insight into the assembly behavior. Lower (less than 33%) malonamide ligand densities (where the binding group extends beyond the periphery of diluent ethylene glycol ligands) produce the strongest optical responses and largest assemblies. Surprisingly, nanoparticles containing a higher surface number of targeting ligand did not produce an optical response or assemble, underscoring the importance of an informed mixed ligand strategy for highest nanoparticle performance. PMID- 26497057 TI - Iron and zinc exploitation during bacterial pathogenesis. AB - Ancient bacteria originated from metal-rich environments. Billions of years of evolution directed these tiny single cell creatures to exploit the versatile properties of metals in catalyzing chemical reactions and biological responses. The result is an entire metallome of proteins that use metal co-factors to facilitate key cellular process that range from the production of energy to the replication of DNA. Two key metals in this regard are iron and zinc, both abundant on Earth but not readily accessible in a human host. Instead, pathogenic bacteria must employ clever ways to acquire these metals. In this review we describe the many elegant ways these bacteria mine, regulate, and craft the use of two key metals (iron and zinc) to build a virulence arsenal that challenges even the most sophisticated immune response. PMID- 26497062 TI - Thermodynamics of protein denaturation at temperatures over 100 degrees C: CutA1 mutant proteins substituted with hydrophobic and charged residues. AB - Although the thermodynamics of protein denaturation at temperatures over 100 degrees C is essential for the rational design of highly stable proteins, it is not understood well because of the associated technical difficulties. We designed certain hydrophobic mutant proteins of CutA1 from Escherichia coli, which have denaturation temperatures (Td) ranging from 101 to 113 degrees C and show a reversible heat denaturation. Using a hydrophobic mutant as a template, we successfully designed a hyperthermostable mutant protein (Td = 137 degrees C) by substituting six residues with charged ones. Thermodynamic analyses of these mutant proteins indicated that the hydrophobic mutants were stabilized by the accumulation of denaturation enthalpy (DeltaH) with no entropic gain from hydrophobic solvation around 100 degrees C, and that the stabilization due to salt bridges resulted from both the increase in DeltaH from ion-ion interactions and the entropic effect of the electrostatic solvation over 113 degrees C. This is the first experimental evidence that has successfully overcome the typical technical difficulties. PMID- 26497064 TI - Inhibition mechanism of SAHA in HDAC: a revisit. AB - SAHA (vorinostat, Merck) is a famous clinical drug for zinc-containing histone deacetylase (HDAC) targets against cancer and several other human disorders, whose inhibition mechanism (namely the protonation mechanism) upon binding to HDAC has been debated for more than ten years. It is very challenging to verify experimentally and is still controversial theoretically. The popular "Class dependent" (namely "Tyr-dependent") hypothesis is that the deprotonation of SAHA is mostly regulated by the conserved Tyr308 in class I HDAC while it is replaced by the His843 in class IIa HDAC. Herein, by elaborate QM(DFT)/MM MD simulations, we exclude the prevalent "Class-dependent" mechanism and advance a novel "Metal dependent" mechanism, where the remote second metal site (K(+) in most HDAC and Ca(2+) in HDAC2) determines the protonation of SAHA. This proof-of-principle "Metal-dependent" mechanism opens up a new avenue to utilize the second metal site for isoform-selective inhibitor design. PMID- 26497063 TI - Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using (99m)Tc HMPAO. AB - Exosomes known as nano-sized extracellular vesicles attracted recent interests due to their potential usefulness in drug delivery. Amid remarkable advances in biomedical applications of exosomes, it is crucial to understand in vivo distribution and behavior of exosomes. Here, we developed a simple method for radiolabeling of macrophage-derived exosome-mimetic nanovesicles (ENVs) with (99m)Tc-HMPAO under physiologic conditions and monitored in vivo distribution of (99m)Tc-HMPAO-ENVs using SPECT/CT in living mice. ENVs were produced from the mouse RAW264.7 macrophage cell line and labeled with (99m)Tc-HMPAO for 1 hr incubation, followed by removal of free (99m)Tc-HMPAO. SPECT/CT images were serially acquired after intravenous injection to BALB/c mouse. When ENVs were labeled with (99m)Tc-HMPAO, the radiochemical purity of (99m)Tc-HMPAO-ENVs was higher than 90% and the expression of exosome specific protein (CD63) did not change in (99m)Tc-HMPAO-ENVs. (99m)Tc-HMPAO-ENVs showed high serum stability (90%) which was similar to that in phosphate buffered saline until 5 hr. SPECT/CT images of the mice injected with (99m)Tc-HMPAO-ENVs exhibited higher uptake in liver and no uptake in brain, whereas mice injected with (99m)Tc-HMPAO showed high brain uptake until 5 hr. Our noninvasive imaging of radiolabeled-ENVs promises better understanding of the in vivo behavior of exosomes for upcoming biomedical application. PMID- 26497065 TI - Quantum Hall states stabilized in semi-magnetic bilayers of topological insulators. AB - By breaking the time-reversal symmetry in three-dimensional topological insulators with the introduction of spontaneous magnetization or application of magnetic field, the surface states become gapped, leading to quantum anomalous Hall effect or quantum Hall effect, when the chemical potential locates inside the gap. Further breaking of inversion symmetry is possible by employing magnetic topological insulator heterostructures that host non-degenerate top and bottom surface states. Here we demonstrate the tailored-material approach for the realization of robust quantum Hall states in the bilayer system, in which the cooperative or cancelling combination of the anomalous and ordinary Hall responses from the respective magnetic and non-magnetic layers is exemplified. The appearance of quantum Hall states at filling factor 0 and +1 can be understood by the relationship of energy band diagrams for the two independent surface states. The designable heterostructures of magnetic topological insulator may explore a new arena for intriguing topological transport and functionality. PMID- 26497066 TI - Effect of lipopolysaccharide on angiotensin II type 1 receptor expression and function in human pulmonary microvascular endothelial cells. AB - Lipopolysaccharides (LPSs) are an important initiation factor in acute respiratory distress syndrome. The aim of the present study was to investigate the effect of LPSs on the regulation of angiotensin II (Ang II) receptors in human pulmonary microvascular endothelial cells (HPMECs). HPMECs were treated with 0, 50, 100 or 200 ng/ml LPS and incubated for 4, 8, 12 or 16 h. The expression of Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) was determined using reverse transcription-polymerase chain reaction and western blot analysis. The affinity to Ang II was measured using a radioligand binding assay. No AT2R expression was detected with or without LPS administration in HPMECs, and LPS treatment increased the expression level of AT1R. A time-dependent increase of AT1R transcription was observed in the 50 ng/ml group, while in the 100 and 200 ng/ml groups, the AT1R mRNA levels reached peak values at 4 h and remained unchanged. The protein level of AT1R increased significantly in a dose-dependent manner for each incubation time period. A time-dependent increase in the protein level was observed in the 50 and 100 ng/ml groups. As for the 200 ng/ml group, the level of AT1R reached a peak value at 8 h. Maximal binding (Bmax) significantly increased following LPS treatment and Bmax of the 50 ng/ml group exhibited a time-dependent increase. The Bmax of the 100 and 200 ng/ml groups reached peak values at 12 and 8 h, respectively, and decreased thereafter. The dissociation constant remained unchanged following LPS treatment. Thus, treatment with LPS increased AT1R expression and its Bmax to Ang II in HPMECs, however, did not alter the affinity of AT1R to Ang II. PMID- 26497067 TI - Do we represent intentional action as recursively embedded? The answer must be empirical. A comment on Vicari and Adenzato (2014). AB - The relationship between linguistic syntax and action planning is of considerable interest in cognitive science because many researchers suggest that "motor syntax" shares certain key traits with language. In a recent manuscript in this journal, Vicari and Adenzato (henceforth VA) critiqued Hauser, Chomsky and Fitch's 2002 (henceforth HCF's) hypothesis that recursion is language-specific, and that its usage in other domains is parasitic on language resources. VA's main argument is that HCF's hypothesis is falsified by the fact that recursion typifies the structure of intentional action, and recursion in the domain of action is independent of language. Here, we argue that VA's argument is incomplete, and that their formalism can be contrasted with alternative frameworks that are equally consistent with existing data. Therefore their conclusions are premature without further empirical testing and support. In particular, to accept VA's argument it would be necessary to demonstrate both that humans in fact represent self-embedding in the structure of intentional action, and that language is not used to construct these representations. PMID- 26497068 TI - Emotions and language about motion: Differentiating affective dominance with syntax from valence with semantics. AB - Motion as encoded in linguistic cues is used to differentiate affective valence and dominance. Participants were invited to rate their affective responses to different words along valence and dominance scales. The words were nouns describing static cues and verbs describing motion, connected to DOWN/UP and Avoidance/Approach cues. The results of three studies showed that valence and dominance could be differentiated through syntax and semantics of motion. On one hand, dominance feelings, compared to valence ones, are particularly influenced by motion encoded in syntactic classes (verbs vs. nouns). On the other hand, valence feelings, compared to dominance ones, are influenced by a semantics of motion through DOWN/UP and Avoidance/Approach cues, considered as polarities. A polarity correspondence effect is proposed to explain these results. PMID- 26497069 TI - Attentional control and inferences of agency: Working memory load differentially modulates goal-based and prime-based agency experiences. AB - Previous research indicates that people can infer self-agency, the experience of causing outcomes as a result of one's own actions, in situations where information about action-outcomes is pre-activated through goal-setting or priming. We argue that goal-based agency inferences rely on attentional control that processes information about matches and mismatches between intended and actual outcomes. Prime-based inferences follow an automatic cognitive accessibility process that relies on matches between primed and actual information about outcomes. We tested an improved task for a better examination of goal-based vs. primed-based agency inferences, and examined the moderating effect of working memory load on both types of inferences. Findings of four studies showed that goal-based, but not prime-based agency inferences dwindled under working memory load. These findings suggest that goal-based (vs. primed based) agency inferences indeed rely on attentional control, thus rendering goal based agency inferences especially prone to conditions that modulate goal directed control processes. PMID- 26497070 TI - Mechanistic insight into proton-coupled mixed valency. AB - Stabilisation of the mixed-valence state in [Mo2(TiPB)3(HDOP)]2(+) (HTiPB = 2,4,6 triisopropylbenzoic acid, H2DOP = 3,6-dihydroxypyridazine) by electron transfer (ET) is related to the proton coordinate of the bridging ligands. Spectroelectrochemical studies suggest that ET is slower than 10(9) s(-1). The mechanism has been probed using DFT calculations, which show that proton transfer induces a larger dipole in the molecule resulting in ET. PMID- 26497071 TI - d/Deaf and Hard of Hearing With a Disability or an Additional Disability: The Need for Theory, Research, and Practice. PMID- 26497072 TI - Need for Organizational Support for Faculty With Hearing Loss. PMID- 26497073 TI - Theory, Research, and Practice for Students Who Are Deaf and Hard of Hearing With Disabilities: Addressing the Challenges from Birth to Postsecondary Education. AB - Students who are deaf with a disability or disabilities (DWD) constitute nearly half of the population of K-12 learners who are deaf or hard of hearing. However, there is a dearth of information on theory, research, and practice related to these learners. The authors present an overview of (a) how the field of education of students who are D/deaf and hard of hearing might refer to this unique population in a way that represents the learner, not the disability; (b) the demographic data that further define these learners; (c) a theoretical framework within which to guide research and practice; (d) prevalence and frequency of the existing research; and (e) the practices and resources available to guide practitioners and the parents of students who are DWD. Questions are posed to the field on how to continue to improve the theory, research, and pedagogy used with these students. PMID- 26497074 TI - Deafness and Diversity: Early Intervention. AB - earlier identification has increased the number of infants identified with hearing loss. A significant and growing proportion of children who are D/deaf or hard of hearing have a disability (DWD). Literature related to infants and toddlers who are DWD is scarce because of the heterogeneity of the population and because many disabilities may go undiagnosed until a child is older. Service availability, professional preparation, and use of evidence-based practices must improve to best meet the needs of these children and their families. An examination of theory, research, and practice in early intervention for children who are DWD revealed a lack of qualified professionals and a need for targeted instruction in teacher preparation programs and for technological advances paired with treatment (e.g., telepractice). Increased transdisciplinary collaboration and technology utilization in teacher preparation hold promise as ways of improving service provision to young children who are DWD. PMID- 26497075 TI - Communication and Language in Learners Who Are Deaf and Hard of Hearing With Disabilities: Theories, Research, and Practice. AB - Findings are presented from communication intervention research in three areas related to deafness with disability (DWD): D/deaf and hard of hearing (DHH) with (a) intellectual disability, (b) autism spectrum disorders, (c) deafblindness. Early identification, prevalence, theoretical perspectives, and evidence-based practices are discussed. Developmental theory, behavioral theory, and social interactionism theory undergird many assessment and intervention practices in communication. The tri-focus framework and the four aspects of communication are useful frameworks. While communication research is a relative strength in the deafblindness field, a dire need exists for research in the other two DWD areas. Across all DWD areas there is a need for interventions addressing receptive language. Effective communication and language intervention can only occur when children who are DWD are identified early, placed in individually suitable classrooms with appropriately prepared professionals, and provided with services that build on their strengths and meet their needs. PMID- 26497076 TI - From the Margins to the Spotlight: Diverse Deaf and Hard of Hearing Student Populations and Standardized Assessment Accessibility. AB - Designing assessments and tests is one of the more challenging aspects of creating an accessible learning environment for students who are deaf or hard of hearing (DHH), particularly for deaf students with a disability (DWD). Standardized assessments are a key mechanism by which the educational system in the United States measures student progress, teacher effectiveness, and the impact of school reform. The diversity of student characteristics within DHH and DWD populations is only now becoming visible in the research literature relating to standardized assessments and their use in large-scale accountability reforms. The purpose of this article is to explore the theoretical frameworks surrounding assessment policy and practice, current research related to standardized assessment and students who are DHH and DWD, and potential implications for practice within both the assessment and instruction contexts. PMID- 26497077 TI - Transition Services for DHH Adolescents and Young Adults With Disabilities: Challenges and Theoretical Frameworks. AB - Deaf and hard of hearing (DHH) adolescents and young adults with disabilities (DWD) are a highly diverse group who may also demonstrate a range of functional limitations. These present unique challenges to professional efforts to provide high-quality transition services. Despite these issues, a majority of this population has cognitive abilities within the typical range, and therefore, their transition expectations should be commensurately high in comparison to those of their DHH peers. Research-based transition practices offer a range of interventions, and although none have been validated with DHH or DWD students, several provide important foundational learning opportunities. Yet their implementation will require modifications with programming and expertise beyond what is available in most school districts. Use of a multilevel, ecological framework and person-centered planning offers systematic strategies for increasing access to transition resources and supports to address these unique needs and lead to successful adulthood. PMID- 26497078 TI - Evaluating Teachers' Preparedness to Work With Students Who Are Deaf and Hard of Hearing With Disabilities. AB - A national survey was conducted to determine the needs of teachers and service providers working with students who are deaf and hard of hearing with disabilities (DWD). Quantitative and qualitative questions were asked regarding knowledge of, training with, and strategies used with students who are DWD. Responses from 264 professionals working with this population are reported. Results are reviewed and tied to previous research before and after the 2008 revalidation of the Council on Education of the Deaf standards for teachers of the deaf. Final recommendations are made for (a) virtual learning opportunities, (b) hands-on field experiences and course work in teacher preparation programs, and (c) empirically based research. By understanding the needs of professionals who are currently working with students who are DWD, researchers can help improve teacher preparation programs as well as improve the educational systems currently in place for these learners. PMID- 26497079 TI - Neural and psychological underpinnings of gambling disorder: A review. AB - Gambling disorder affects 0.4 to 1.6% of adults worldwide, and is highly comorbid with other mental health disorders. This article provides a concise primer on the neural and psychological underpinnings of gambling disorder based on a selective review of the literature. Gambling disorder is associated with dysfunction across multiple cognitive domains which can be considered in terms of impulsivity and compulsivity. Neuroimaging data suggest structural and functional abnormalities of networks involved in reward processing and top-down control. Gambling disorder shows 50-60% heritability and it is likely that various neurochemical systems are implicated in the pathophysiology (including dopaminergic, glutamatergic, serotonergic, noradrenergic, and opioidergic). Elevated rates of certain personality traits (e.g. negative urgency, disinhibition), and personality disorders, are found. More research is required to evaluate whether cognitive dysfunction and personality aspects influence the longitudinal course and treatment outcome for gambling disorder. It is hoped that improved understanding of the biological and psychological components of gambling disorder, and their interactions, may lead to improved treatment approaches and raise the profile of this neglected condition. PMID- 26497080 TI - Cell motility and spreading promoted by CEACAM6 through cyclin D1/CDK4 in human pancreatic carcinoma. AB - Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) belongs to the human carcino-embryonic antigen (CEA) family. Numerous lines of studies have indicated that altered expression of CEACAM6 may have a role in carcinogenesis and development. However, few studies have defined functional roles and mechanisms of action. In the present study, the relationship between clinical and pathological parameters was also analyzed. The relative CEACAM6 protein expression of pancreatic carcinoma was significantly higher than that in non cancerous tissue. Different clinical stages and lymph node metastasis between groups were significantly different (P<0.05). We used siRNA and forced-expression in multiple cell lines to define the role of CEACAM6 in the regulation of proliferation of pancreatic carcinoma in vitro and in vivo. Knockdown of endogenous CEACAM6 decreased proliferation of BxPC-3 and SW1990 cells. These changes significantly reduced cyclin D1 and CDK4 protein levels. Conversely, overexpression of CEACAM6 in MIA PaCa-2 cells stimulated proliferation and increased cyclin D1 and CDK4 protein levels. Our results confirm that CEACAM6 promoted cell proliferation, and these changes were mediated by cyclin D1/CDK4. These observations contribute to our understanding of the important roles of CEACAM6 in pancreatic carcinoma development and progression and could be a promising molecular target for the development of new diagnostic and therapeutic strategies of pancreatic carcinoma. PMID- 26497082 TI - Comparison of the effects of continuous positive airway pressure and mandibular advancement devices on sleepiness in patients with obstructive sleep apnoea: a network meta-analysis. AB - BACKGROUND: Excessive daytime sleepiness is the most important symptom of obstructive sleep apnoea and can affect work productivity, quality of life, and the risk of road traffic accidents. We aimed to quantify the effects of the two main treatments for obstructive sleep apnoea (continuous positive airway pressure and mandibular advancement devices) on daytime sleepiness and to establish predictors of response to continuous positive airway pressure. METHODS: We searched MEDLINE and the Cochrane Library from inception to May 31, 2015, to identify randomised controlled trials comparing the effects of continuous positive airway pressure, mandibular advancement devices or an inactive control (eg, placebo or no treatment) on the Epworth Sleepiness Scale (ESS, range 0-24 points) in patients with obstructive sleep apnoea. We did a network meta-analysis using multivariate random-effects meta-regression to assess the effect of each treatment on ESS. We used meta-regression to assess the association of the reported effects of continuous positive airway pressure versus inactive controls with the characteristics of trials and their risk of bias. FINDINGS: We included 67 studies comprising 6873 patients in the meta-analysis. Compared with an inactive control, continuous positive airway pressure was associated with a reduction in ESS score of 2.5 points (95% CI 2.0-2.9) and mandibular advancement devices of 1.7 points (1.1-2.3). We estimated that, on average, continuous positive airway pressure reduced the ESS score by a further 0.8 points compared with mandibular advancement devices (95% CI 0.1-1.4; p=0.015). However, there was a possibility of publication bias in favour of continuous positive airway pressure that might have resulted in this difference. We noted no evidence that studies reporting higher continuous positive airway pressure adherence also reported larger treatment effects (p=0.70). INTERPRETATION: Continuous positive airway pressure and mandibular advancement devices are effective treatments for reducing daytime sleepiness in patients with obstructive sleep apnoea. Continuous positive airway pressure seemed to be a more effective treatment than mandibular advancement devices, and had an increasingly larger effect in more severe or sleepier obstructive sleep apnoea patients when compared with inactive controls. However, mandibular advancement devices are an effective alternative treatment should continuous positive airway pressure not be tolerated. FUNDING: Swiss National Science Foundation and the University of Zurich Clinical Research Priority Program Sleep and Health. PMID- 26497083 TI - Transcriptional analysis of the dachsous gene uncovers novel isoforms expressed during development in Drosophila. AB - The Drosophila cadherin-related protein Dachsous (Ds) plays a prominent role in planar cell polarity (PCP) and growth. The regulation of these two processes is based on the interaction between Ds and Fat proteins, generating an intracellular response required for tissue polarization and modulation of Hippo pathway activity. Here we have performed a comprehensive molecular study of the ds gene during larval development that has shown an unexpected complexity in its transcriptional regulation and revealed the expression of hitherto unsuspected transcripts. Also, knockdown of several isoforms provides new evidence on the importance of the cytoplasmic domain in the mechanism of action of Ds during development. PMID- 26497084 TI - Structural stability of amyloid fibrils depends on the existence of the peripheral sequence near the core cross-beta region. AB - Amyloid fibrils are fibrous protein assemblies with distinctive cross-beta structures. For amyloidosis, there are disease-associated mutations outside of the cross-beta structures. Thus, it is necessary to elucidate the role of peripheral sequences outside the cross-beta structure. Amyloid fibrils are generally 10nm in width; however, the amyloid fibrils of truncated barnase M1 peptides missing the C-terminal sequence outside the cross-beta structure are 20 nm in width. In this study, we performed comparative analysis of the structural stability of amyloids formed by the respective peptides. We found that the C terminal amino acids dramatically affect the conformational instability in the presence of a denaturing reagent. PMID- 26497085 TI - Profiling metabolic remodeling in PP2Acalpha deficiency and chronic pressure overload mouse hearts. AB - Our understanding of how metabolic switches occur in the failing heart is still limited. Here, we report the emblematic pattern of metabolic alternations in two different mouse models. PP2Acalpha deficient hearts exhibited a dramatic decrease in the levels of mRNA encoding for transporters and enzymes involved in glucose utilization, which compensated by higher expression levels of genes controlling fatty acid utilization. These features were partly reproduced in cultured PP2Acalpha KD cardiomyocytes. Equivalently, a decrease in the expression of most of the transporters and enzymes controlling both glucose and fatty acid metabolism were observed in TAC model. PMID- 26497081 TI - Effectiveness of Simeprevir Plus Sofosbuvir, With or Without Ribavirin, in Real World Patients With HCV Genotype 1 Infection. AB - BACKGROUND & AIMS: The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. METHODS: We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET--a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment--a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. RESULTS: The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%-87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. CONCLUSIONS: In a large prospective observational cohort study, a 12-week regimen of simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811. PMID- 26497086 TI - A Biomechanical Comparison of Locking Versus Conventional Plate Fixation for Distal Fibula Fractures in Trimalleolar Ankle Injuries. AB - Previous biomechanical studies have advocated the use of locking plates for isolated distal fibula fractures in osteoporotic bone. Complex rotational ankle injuries involve an increased number of fractures, which can result in instability, potentially requiring the same fixed angle properties afforded by locking plates. However, the mechanical indication for locking plate technology has not been tested in this fracture model. The purpose of the present study was to compare the biomechanical properties of locking and conventional plate fixation for distal fibula fractures in trimalleolar ankle injuries. Fourteen (7 matched pairs) fresh-frozen cadaver leg specimens were used. The bone mineral density of each was obtained using dual x-ray absorptiometry scans. The fracture model simulated an OTA 44-B3.3 fracture. The syndesmosis was not disrupted. Each fracture was fixated in the same fashion, except for the distal fibula plate construct: locking (n = 7) and one-third tubular (n = 7). The specimens underwent axial and torsional cyclic loading, followed by torsional loading to failure. No statistically significant differences were found between the locking and conventional plate constructs during both fatigue and torque to failure testing (p > .05). Our specimen bone mineral density averages did not represent poor bone quality. The clinical implication of the present study is that distal fibular locking plates do not provide a mechanical advantage for trimalleolar ankle injuries in individuals with normal bone density and in the absence of fracture comminution. PMID- 26497087 TI - Dendrimer-Based Responsive MRI Contrast Agents (G1-G4) for Biosensor Imaging of Redundant Deviation in Shifts (BIRDS). AB - Biosensor imaging of redundant deviation in shifts (BIRDS) is a molecular imaging platform for magnetic resonance that utilizes unique properties of low molecular weight paramagnetic monomers by detecting hyperfine-shifted nonexchangeable protons and transforming the chemical shift information to reflect its microenvironment (e.g., via temperature, pH, etc.). To optimize translational biosensing potential of BIRDS we examined if this detection scheme observed with monomers can be extended onto dendrimers, which are versatile and biocompatible macromolecules with modifiable surface for molecular imaging and drug delivery. Here we report on feasibility of paramagnetic dendrimers for BIRDS. The results show that BIRDS is resilient with paramagnetic dendrimers up to the fourth generation (i.e., G1-G4), where the model dendrimer and chelate were based on poly(amido amine) (PAMAM) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA(4-)) complexed with thulium ion (Tm(3+)). Temperature sensitivities of two prominent signals of Gn-PAMAM-(TmDOTA(-))x (where n = 1-4, x = 6-39) were comparable to that of prominent signals in TmDOTA(-). Transverse relaxation times of the coalesced nonexchangeable protons on Gn-PAMAM-(TmDOTA(-))x were relatively short to provide signal-to-noise ratio that was comparable to or better than that of TmDOTA(-). A fluorescent dye, rhodamine, was conjugated to a G2-PAMAM (TmDOTA)12 to create a dual-modality nanosized contrast agent. BIRDS properties of the dendrimer were unaltered with rhodamine conjugation. Purposely designed paramagnetic dendrimers for BIRDS in conjunction with novel macromolecular surface modification for functional ligands/drugs could potentially be used for biologically compatible theranostic sensors. PMID- 26497089 TI - Term rules for simple metal clusters. AB - Hund's term rules are only valid for isolated atoms, but have no generalization for molecules or clusters of several atoms. We present a benchmark calculation of Al2 and Al3, for which we find the high and low-spin ground states (3)Piu and , respectively. We show that the relative stabilities of all the molecular terms of Al2 and Al3 can be described by simple rules pertaining to bonding structures and symmetries, which serve as guiding principles to determine ground state terms of arbitrary multi-atom clusters. PMID- 26497088 TI - Detection and characterization of mineralo-organic nanoparticles in human kidneys. AB - Ectopic calcification is associated with various human diseases, including atherosclerosis, cancer, chronic kidney disease, and diabetes mellitus. Although mineral nanoparticles have been detected in calcified blood vessels, the nature and role of these particles in the human body remain unclear. Here we show for the first time that human kidney tissues obtained from end-stage chronic kidney disease or renal cancer patients contain round, multilamellar mineral particles of 50 to 1,500 nm, whereas no particles are observed in healthy controls. The mineral particles are found mainly in the extracellular matrix surrounding the convoluted tubules, collecting ducts and loops of Henle as well as within the cytoplasm of tubule-delineating cells, and consist of polycrystalline calcium phosphate similar to the mineral found in bones and ectopic calcifications. The kidney mineral nanoparticles contain several serum proteins that inhibit ectopic calcification in body fluids, including albumin, fetuin-A, and apolipoprotein A1. Since the mineralo-organic nanoparticles are found not only within calcified deposits but also in areas devoid of microscopic calcifications, our observations indicate that the nanoparticles may represent precursors of calcification and renal stones in humans. PMID- 26497090 TI - Rectal cancer with synchronous liver metastases: Do we have a clear direction? AB - Rectal cancer is a common entity and often presents with synchronous liver metastases. There are discrepancies in management guidelines throughout the world regarding the treatment of advanced rectal cancer, which are further compounded when it presents with synchronous liver metastases. The following article examines the evidence regarding treatment options for patients with synchronous rectal liver metastases and suggests potential treatment algorithms. PMID- 26497091 TI - Identification and mucosal expression analysis of cathepsin B in channel catfish (Ictalurus punctatus) following bacterial challenge. AB - The mucosal surfaces of fish (skin, gill and intestine) constitute the primary line of defense against pathogen invasion. Although the importance of fish mucosal surfaces as the first barriers against pathogens cannot be overstated, the knowledge of teleost mucosal immunity are still limited. Cathepsin B, a lysosomal cysteine protease, is involved in multiple levels of physiological and biological processes, and playing crucial roles for host immune defense against pathogen infection. In this regard, we identified the cathepsin B (ctsba) of channel catfish and investigated the expression patterns of the ctsba in mucosal tissues following Edwardsiella ictaluri and Flavobacterium columnare challenge. Here, catfish ctsba gene was widely expressed in all examined tissues with the lowest expression level in muscle, and the highest expression level in trunk kidney, followed by spleen, gill, head kidney, intestine, liver and skin. In addition, the phylogenetic analysis showed the catfish ctsba had the strongest relationship to zebrafish. Moreover, the ctsba showed a general trend of up regulated in mucosal tissues following both Gram-negative bacterial challenge. Taken together, the increased expression of ctsba in mucosal surfaces indicated the protective function of ctsba against bacterial infection, and the requirement for effective clearance of invading bacteria. Further studies are needed, indeed, to expand functional characterization and examine whether ctsba may play additional physiological and biological roles in catfish mucosal tissues. PMID- 26497092 TI - The protective immunity against grass carp reovirus in grass carp induced by a DNA vaccination using single-walled carbon nanotubes as delivery vehicles. AB - To reduce the lethal hemorrhagic disease caused by grass carp reovirus (GCRV) and improve the production of grass carp, efficient and economic prophylactic measure against GCRV is the most pressing desired for the grass carp farming industry. In this work, a novel SWCNTs-pEGFP-vp5 DNA vaccine linked vp5 recombinant in the form of plasmid pEGFP-vp5 and ammonium-functionalized SWCNTs by a chemical modification method was prepared to enhance the efficacy of a vp5 DNA vaccine against GCRV in juvenile grass carp. After intramuscular injection (1, 2.5 and 5 MUg) and bath administration (1, 10, and 20 mg/L), the ability of the different immune treatments to induce transgene expression was analyzed. The results showed that higher levels of transcription and expression of vp5 gene could be detected in muscle tissues of grass carp in SWCNTs-pEGFP-vp5 treatment groups compare with naked pEGFP-vp5 treatment groups. Moreover, antibody levels, immune-related genes, and relative percentage survival were significantly enhanced in fish immunized with SWCNTs-pEGFP-vp5 vaccine. In addition, we found that a good immune protective effect was observed in bath immunization group; which at a concentration of 20 mg/L could reach the similar relative percentage survival (approximately 100%) in injection group at a dose of 5 MUg. All these results indicated that ammonium-functionalized SWCNTs could provide extensive application prospect to aquatic vaccine and might be used to vaccinate fish by intramuscular injection or bath administration method. PMID- 26497093 TI - Antimicrobial activity of a novel hypervariable immunoglobulin domain-containing receptor Dscam in Cherax quadricarinatus. AB - Down syndrome cell adhesion molecule (Dscam) mediates innate immunity against pathogens in arthropods. Here, a novel Dscam from red claw crayfish Cherax quadricarinatus (CqDscam) was isolated. The CqDscam protein contains one signal peptide, ten immunoglobulin domains, six fibronectin type III domains, one transmembrane domain and cytoplasmic tail. CqDscam phylogenetically clustered with other invertebrate Dscams. Variable regions of CqDscam in N-terminal halves of Ig2 and Ig3 domains, complete Ig7 domain and TM domain can be reshuffled after transcription to produce a deluge of >37,620 potential alternative splice forms. CqDscam was detected in all tissues tested and abundantly expressed in immune system and nerve system. Upon lipopolysaccharides (LPS) and b-1, 3-glucans (Glu) challenged, the expression of CqDscam was up-regulated, while no response in expression occurred after injection with peptidoglycans (PG). Membrane-bound and secreted types of CqDscam were separated on the protein level, and were both extensively induced post LPS challenge. Membrane-bound CqDscam protein was not detected in the serum, but localized to the hemocyte surface by immuno localization assay. In the antimicrobial assays, the recombinant LPS-induced isoform of CqDscam protein displayed bacterial binding and growth inhibitory activities, especially with Escherichia coli. These results suggested that CqDscam, as one of pattern-recognition receptors (PRRs), involved in innate immune recognition and defense mechanisms in C. quadricarinatus, possibly through alternative splicing. PMID- 26497094 TI - Effects of dietary linseed oil on innate immune system of Eurasian perch and disease resistance after exposure to Aeromonas salmonicida achromogen. AB - This study was designated to investigate the effects of dietary fish oil (FO diet) replacement by linseed oil (LO diet) on regulation of immune response and disease resistance in Eurasian perch (Perca fluviatilis). A control diet containing fish oil (FO = cod liver oil) and characterized by high levels of n-3 high LC-PUFA (6% EPA, 7.5% of total fatty acids (FAs)) was compared to linseed oil diet (LO diet) composed of low LC-PUFA contents (1% EPA, 2.3% DHA of total FAs) but high C18 fatty acids levels. The experiment was conducted in quadruplicate groups of 80 fish each. After 10 weeks of feeding, the innate immune status was evaluated in various organs (liver, spleen, and head-kidney) (feeding condition). Two days later, a bacterial challenge was performed on fish from 2 rearing conditions: fish infected with Aeromonas salmonicida (bacteria condition) and fish injected with sterile medium but maintained in the same flow system that fish challenged with bacteria (sentinel condition). Three days after injection of bacteria, a significant decrease of lymphocyte, thrombocyte and basophil populations was observed while neutrophils were not affected. In addition, plasma lysozyme activity and reactive oxygen species production in kidney significantly increased in fish challenged with A. salmonicida while the plasma alternative complement pathway activity was not affected. Increase of plasma lysozyme activity as well as reactive oxygen species production in spleen and kidney of sentinel fish suggest that these immune defenses can also be activated, but at lower bacteria concentration than infected fish. No differences in leucocyte populations, plasma lysozyme and alternative complement pathway activities were observed between dietary treatments. Similarly, expression of genes related to eicosanoid synthesis in liver were not affected by the dietary oil source but were strongly stimulated in fish challenged with A. salmonicida. These findings demonstrated that the use of linseed oil does not deplete the innate immune system of Eurasian perch juveniles. PMID- 26497095 TI - Transcriptome analysis of the unfolded protein response in hemocytes of Litopenaeus vannamei. AB - In this study, Litopenaeus vannamei was injected with double-stranded RNA (dsRNA) against L. vannamei immunoglobulin heavy chain binding protein (LvBip) to activating UPR in the hemocytes, shirmps injected dsRNA against enhanced green fluorescence protein (eGFP) as control group. And genes expression in hemocytes of then were analyzed using Illumina Hiseq 2500 (PE100). By comparing the analyzed results, 1418 unigenes were significantly upregulated, and 596 unigenes were significantly down-regulated upon UPR. Analysis of the differentially expressed genes against known databases indicated that the distribution of gene pathways between the upregulated and down-regulated genes were substantially different. A total of 208 genes of UPR system were obtained, and 69 of them were differentially expressed between the two groups. Results also showed that L. vannamei UPR was involved in various metabolic processes, such as glycometabolism, lipid metabolism, amino acid metabolism, and nucleic acid metabolism. In addition, UPR was emgaged in immune-assicoated signaling pathways, such as NF-kappaB signaling pathway, NOD-like receptor signaling pathway, Hippo signaling pathway, p38 MAPK signaling pathway and Wnt signaling pathway in L. vannamei. These results improved our current understanding of the L. vannamei UPR, and highlighted its importance in cell homeostasis upon environmental stress. PMID- 26497096 TI - Children's exposure to community and war violence and mental health in four African countries. AB - In this article we review the mental health consequences of children's exposure to community and war violence (ETV) in four African countries: South Africa, Sierra Leone, Gambia and Rwanda. A focus on Africa is particularly pressing because of children's high levels of community and war ETV in countries therein. Regions of Africa present important macro-contexts for understanding children's various types of violence exposure amidst war and economic disadvantage. Findings of the review across 20 quantitative studies from 2004 to 2015 indicate consistent associations between exposure to war and community violence and children's symptoms of Post-traumatic Stress disorder (PTSD), depression, and aggression. School climate and family support mitigate these ETV influences upon children: however, more research is needed on the buffering effects of such resources. The effects of war violence are mediated by perceived discrimination in communities post-conflict. We integrate findings across studies to synthesize knowledge on children's ETV in Africa around a model of its correlates, mediators, and moderators in relation to mental health. Emerging research points to avenues for prevention and future inquiry. PMID- 26497097 TI - Family and community driven response to intimate partner violence in post conflict settings. AB - This study explores risk factors, individual and family consequences and community-driven responses to intimate partner violence (IPV) in post-conflict eastern Democratic Republic of Congo (DRC). This qualitative study was conducted in 3 rural villages in South Kivu Province of DRC, an area that has experienced prolonged conflict. Participants included 13 female survivors and 5 male perpetrators of IPV as reported during baseline data collection for the parent study, an impact evaluation of the Congolese-led livestock microfinance program, Pigs for Peace. Participants described social and behavioral circumstances that increase risk for IPV; social, health and economic consequences on women and their families; and resources to protect women and their families. Social and behavioral factors reported by survivors and perpetrators indicate that IPV was linked to husband's alcohol consumption, household economic instability, male desire to maintain his position as head of family and perceived disrespect of husband by wife. In addition to well-known health consequences of IPV, women reported negative social consequences, such as stigma, resulting in barriers for the well-being of the family. Survivors and perpetrators described the impact of IPV on their children, specifically the lack of proper parental guidance and lack of safety and stability that could result in the child(ren) misbehaving and using violence in their relationships resulting in further stigma towards the child and family. Strategies employed by survivors to protect themselves and family, include placating male behaviors (e.g., not responding to insults, trying to meet household demands). Perpetrators that tried to reduce the impact of IPV reported a preference for social and financial control of their partner rather than physical violence, believing this to be less severe. Participants described community and family based social support systems including couple's mediation, responsible partner and fatherhood programs and economic activities that can influence behavior, maintain confidentiality, address social stigma and other multi-level outcomes. PMID- 26497098 TI - Interactions between aggression, boldness and shoaling within a brood of convict cichlids (Amatitlania nigrofasciatus). AB - A behavioral syndrome is considered present when individuals consistently express correlated behaviors across two or more axes of behavior. These axes of behavior are shy-bold, exploration-avoidance, activity, aggression, and sociability. In this study we examined aggression, boldness and sociability (shoaling) within a juvenile convict cichlid brood (Amatitlania nigrofasciatus). Because young convict cichlids are social, we used methodologies commonly used by ethologists studying social fishes. We did not detect an aggression-boldness behavioral syndrome, but we did find that the aggression, boldness, and possibly the exploration behavioral axes play significant roles in shaping the observed variation in individual convict cichlid behavior. While juvenile convict cichlids did express a shoaling preference, this social preference was likely convoluted by aggressive interactions, despite the small size and young age of the fish. There is a need for the development of behavioral assays that allow for more reliable measurement of behavioral axes in juvenile neo-tropical cichlids. PMID- 26497099 TI - PML: The Dark Side of Immunotherapy in Multiple Sclerosis. AB - Progressive multifocal leukoencephalopathy (PML) is a threat to patients with multiple sclerosis (MS) who undergo treatment with drugs that interfere with normal immune physiology. Here, we summarize PML incidence in MS, risk factors, surveillance strategies, and case definitions to inform neurologists and other clinicians treating patients with immune-mediated diseases. PMID- 26497100 TI - 3D printing of 5-drug polypill. PMID- 26497101 TI - Sensory characterisation and consumer acceptability of potassium chloride and sunflower oil addition in small-caliber non-acid fermented sausages with a reduced content of sodium chloride and fat. AB - The effect of the simultaneous reduction of fat proportion (from 20% to 10% and 7%) and added salt (from 2.5% to 1.5%) and the subsequent addition of 0.64% KCl and sunflower oil (1.5% and 3.0%) on the physicochemical, instrumental colour and texture, sensory properties and consumer acceptability of small caliber non-acid fermented sausages (fuet type) was studied. This simultaneous reduction of fat and salt increased weight loss, moisture, water activity (aw), redness, instrumental texture parameters (hardness, chewiness and cohesiveness), sensory attributes (darkness, hardness, elasticity) and the consumer acceptability. The subsequent addition of 0.64% KCl to the leanest batch decreased the aw and barely affected instrumental texture parameters and consumer acceptability. Subsequent sunflower oil addition decreased hardness, chewiness and cohesiveness and increased crumbliness and oil flavour which may decrease the consumer acceptability. The simultaneous reduction of fat and NaCl with the addition of 0.64% KCl was the preferred option by the consumers. PMID- 26497102 TI - The changes in springbok (Antidorcas marsupialis) Longissimus thoracis et lumborum and Biceps femoris muscles during the rigour period. AB - This study describes the changes taking place during rigour in springbok (Antidorcas marsupialis) Longissimus thoracis et lumborum (LTL) and Biceps femoris (BF) muscles. Samples from six male and six female springbok were snap frozen at 2, 3, 5, 8, 12, 18, 24 and 30h post-mortem (PM) and the pH, calpains I, II and calpastatin activities and cathepsins B, BL and H activities were determined. The temperature was also recorded. Significant third-order interactions were found for the pH and temperature, with the female LTL cooling more rapidly and acidifying slower than the other samples. Female muscles were at risk of developing cold-shortening and all the samples cooled more rapidly than recommended for cattle or sheep. Cathepsin BL activity increased PM, likely due to the degradation of the lysosomes. Calpains I, II and calpastatin activity declined during rigour, indicating that the calpains were activated early PM. Gender and muscle had a significant effect on calpain and cathepsin activity. PMID- 26497103 TI - Quantitative Analysis of Filament Branch Orientation in Listeria Actin Comet Tails. AB - Several bacterial and viral pathogens hijack the host actin cytoskeleton machinery to facilitate spread and infection. In particular, Listeria uses Arp2/3 mediated actin filament nucleation at the bacterial surface to generate a branched network that will help propel the bacteria. However, the mechanism of force generation remains elusive due to the lack of high-resolution three dimensional structural data on the spatial organization of the actin mother and daughter (i.e., branch) filaments within this network. Here, we have explored the three-dimensional structure of Listeria actin tails in Xenopus laevis egg extracts using cryo-electron tomography. We found that the architecture of Listeria actin tails is shared between those formed in cells and in cell extracts. Both contained nanoscopic bundles along the plane of the substrate, where the bacterium lies, and upright filaments (also called Z filaments), both oriented tangentially to the bacterial cell wall. Here, we were able to identify actin filament intersections, which likely correspond to branches, within the tails. A quantitative analysis of putative Arp2/3-mediated branches in the actin network showed that mother filaments lie on the plane of the substrate, whereas daughter filaments have random deviations out of this plane. Moreover, the analysis revealed that branches are randomly oriented with respect to the bacterial surface. Therefore, the actin filament network does not push directly toward the surface but rather accumulates, building up stress around the Listeria surface. Our results favor a mechanism of force generation for Listeria movement where the stress is released into propulsive motion. PMID- 26497104 TI - BE360, a new selective estrogen receptor modulator, produces antidepressant and antidementia effects through the enhancement of hippocampal cell proliferation in olfactory bulbectomized mice. AB - We have reported that the carborane compound BE360 is a novel selective estrogen receptor modulator and new therapy option for osteoporosis. The aim of this study was to explore the effects and underlying mechanisms of BE360 on depressive-like behavior and memory impairment in the olfactory bulbectomized (OBX) mice, an experimental animal model of depression and dementia. BE360 was administered subcutaneously to mice using a mini-osmotic pump for 2 weeks. Depressive-like behavior was measured as the reduced intake of a sweet solution in the sucrose preference test. Short-term memory was assessed using the Y-maze test. Cell proliferation was assessed by the analysis of cells expressing 5-bromo-2' deoxyuridine (BrdU) uptake. The expression of phosphorylated cyclic-AMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were measured by immunoblot. The depressive-like behavior and memory impairment in OBX mice were improved by the chronic treatment with BE360. Immunohistochemical analysis showed that the number of BrdU-positive cells in the dentate gyrus of the hippocampus significantly decreased in OBX mice whereas they increased after the chronic treatment with BE360. Immunoblotting studies revealed that pCREB and BDNF were significantly increased in the hippocampus of OBX mice treated with BE360. The present study has shown that BE360 has antidepressant and antidementia effects characterized by hippocampal cell proliferation potentially activated via CREB/BDNF signaling pathways. These results indicate that BE360 may have valuable therapeutic potential against depression and neurodegenerative diseases. PMID- 26497106 TI - Maternal separation facilitates extinction of social fear in adult male mice. AB - Early life stress, such as child abuse or neglect, is a risk factor for the development of psychopathologies characterized by abnormal social and emotional behaviors. In rodents, long-lasting changes in stress coping and emotional behavior can be induced by separating pups from their mother. We used maternal separation (MS; 3h daily on postnatal days 1-14) to test whether early life stress alters acquisition and extinction of social fear in adult male mice as studied in a specific model of social fear, i.e., in the social fear conditioning paradigm. We show that MS facilitated extinction of social fear without altering acquisition or expression of social fear. This facilitatory effect of MS on social fear extinction was not due to improved social learning and memory abilities or to increased social interest, as MS rather impaired social memory in the social discrimination test and did not alter social preference in the social preference-avoidance test. In contrast, MS did not alter acquisition and extinction of non-social, cued fear, or non-social memory as assessed in the object discrimination test and non-social anxiety as assessed in the elevated plus-maze. These results suggest that a social stress like MS in early life may improve coping with and recovery from a traumatic social experience in adulthood in mice. PMID- 26497105 TI - Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance. AB - Opioids produce antinociception by activation of G protein signaling linked to the mu-opioid receptor (MOPr). However, opioid binding to the MOPr also activates beta-arrestin signaling. Opioids such as DAMGO and fentanyl differ in their relative efficacy for activation of these signaling cascades, but the behavioral consequences of this differential signaling are not known. The purpose of this study was to evaluate the behavioral significance of G protein and internalization dependent signaling within ventrolateral periaqueductal gray (vlPAG). Antinociception induced by microinjecting DAMGO into the vlPAG was attenuated by blocking Galphai/o protein signaling with administration of pertussis toxin (PTX), preventing internalization with administration of dynamin dominant-negative inhibitory peptide (dyn-DN) or direct inhibition of ERK1/2 with administration of the MEK inhibitor, U0126. In contrast, the antinociceptive effect of microinjecting fentanyl into the vlPAG was not altered by administration of PTX or U0126, and was enhanced by administration of dyn-DN. Microinjection of DAMGO, but not fentanyl, into the vlPAG induced phosphorylation of ERK1/2, which was blocked by inhibiting receptor internalization with administration of dyn-DN, but not by inhibition of Galphai/o proteins. ERK1/2 inhibition also prevented the development and expression of tolerance to repeated DAMGO microinjections, but had no effect on fentanyl tolerance. These data reveal that ERK1/2 activation following MOPr internalization contributes to the antinociceptive effect of some (e.g., DAMGO), but not all opioids (e.g., fentanyl) despite the known similarities for these agonists to induce beta arrestin recruitment and internalization. PMID- 26497107 TI - Systemic sclerosis: New evidence re-enforces the role of B cells. AB - Systemic sclerosis (SSc) is characterized by widespread fibrosis, microangiopathy (vasospasms and stenosis), and formation of autoantibodies. T cell activation has been shown to contribute to fibrosis and microvasculopathy in SSc. However, recent evidence suggests that B cells are also likely to contribute in the pathogenesis of the disease. B cells are hyperactivated in SSc, as indicated by the overexpression of the stimulatory CD19 receptor and impairment of the inhibitory CD22 receptor. They lead to the production of many autoantibodies, some of which induce collagen production and vasoconstriction. They promote fibroblast collagen production through cell contact. Furthermore, B cells can function as antigen-presenting cells to T cells and induce dendritic cell maturation that promotes profibrotic Th2 response. Lately, interleukin (IL)-10 producing B regulatory cells, which induce generation of T regulatory cells and can ameliorate autoimmune diseases, were found to be reduced in SSc, favoring autoaggression of B cells in this disease. Finally, B cell depletion with rituximab improves or stabilizes skin fibrosis and lung function. These finding suggest that new therapeutic strategies targeting B cell function(s) can be developed for SSc. PMID- 26497108 TI - A meta-analysis of serum and cerebrospinal fluid autoantibodies in neuropsychiatric systemic lupus erythematosus. AB - Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most devastating presentations of SLE and comprises of psychiatric, central and peripheral neurological signs and symptoms. Previous studies suggest the possible associations between various autoantibodies (Abs) and NPSLE. The magnitudes of such association varied between studies. We performed a meta-analysis to pool data on serum and cerebrospinal fluid (CSF) levels and positivity of Abs in blood and cerebrospinal fluid in patients with NPSLE and SLE. A systematic literature search was conducted to identify studies that fulfilled inclusion criteria. A random-effects model was used to calculate overall combined odd ratio (OR) and mean levels with its corresponding 95% confidence interval to evaluate the relationship between individual Abs and NPSLE patients relative to SLE patients. Forty-one studies met the inclusion criteria and were used in this analysis. There was a significantly greater proportion of NPSLE patients who demonstrated positivity for serum anti-cardiolipin (aCL) Abs (OR=1.63, p=0.016), lupus anticoagulants (LA) Abs (OR=1.91 p=0.01), anti-phospholipid (APL) Abs (OR=2.08, p=0.001), anti-ribosomal P Abs (OR=2.29, p<0.001), anti-neuronal Abs (OR=9.50, p<0.001) as compared to SLE patients. In NPSLE patients, there was a significant increased prevalence of positive titres for CSF anti-neuronal Abs (OR=36.84, p=0.001) as compared to SLE patients. Among the 19 neuropsychiatric syndromes, the positivity of these serum autoantibodies were found specifically significantly associated with the manifestations of mood disorder, psychosis, cerebrovascular disease, seizure disorders, acute confusional state, cognitive dysfunction, headache, movement disorder, demyelinating syndrome and polyneuropathy, with ORs ranging from 1.84 to 4.73. Meta-regression identified proportion of women as significant moderator for the heterogeneity of aCL (p=0.004) and anti-neuronal Abs (p=0.0007); mean age for the heterogeneity of aCL (p=0.042) and LA (p=0.020) Abs, mean duration of illness for the heterogeneity of aCL Abs (p=0.035), and mean SLEDAI scores for the heterogeneity of anti-ribosomal P Abs (p=0.014). NPSLE patients are more likely to have elevated serum levels of aCL, LA, APL, anti-ribosomal P Abs and anti-neuronal Abs compared with SLE patients. Further research is required to evaluate the accuracy of using the above antibodies as an adjunct diagnostic tool in NPSLE. PMID- 26497109 TI - A comparison of the efficacy of once-daily fluticasone furoate/vilanterole with twice-daily fluticasone propionate/salmeterol in asthma-COPD overlap syndrome. AB - BACKGROUND: Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is important because patients with ACOS have significantly worse outcomes compared with those with asthma or chronic obstructive pulmonary disease (COPD) alone. Inhaled corticosteroids (ICS), together with a long-acting beta2 agonist (LABA), are recommended, but no therapeutic studies for ACOS have been conducted. Recently, fluticasone furoate/vilanterole (FF/VI) has been approved as the first once-daily ICS/LABA combination therapy for asthma and COPD. METHODS: A 12-week, randomized, open-label cross-over study was conducted in 16 patients with ACOS to compare the effectiveness of once-daily FF/VI 200/25 MUg vs. twice-daily fluticasone propionate/salmeterol (FP/SAL) 500/50 MUg. The study period included a 4-week run-in, the first 4-week treatment, and the second 4-week treatment. Respiratory functions, including forced expiratory volume in 1 s (FEV1) and respiratory impedance using the forced oscillation technique (FOT), were measured, as was fractional exhaled nitric oxide (FeNO). A COPD assessment test (CAT) scores and asthma control test (ACT) scores were recorded 0, 4, and 8 weeks after randomization. RESULTS: The mean values for the FEV1 were 1.33 (+/-0.29) L in the run-in period, 1.38 (+/-0.39) L after the FP/SAL treatment period, and 1.47 (+/-0.38) L after the FF/VI treatment period. The FEV1 value after the FF/VI treatment was significantly greater than the value after the run-in period (p < 0.01). FOT parameters, FeNO levels, CAT scores, ACT scores, and other blood tests were not significantly different during the run-in period, the FP/SAL treatment period, and the FF/VI treatment period. CONCLUSIONS: FF/VI, the first once-daily ICS/LABA, can provide substantial improvement in lung functions, indicating that FF/VI should be considered for the regular treatment of ACOS. PMID- 26497110 TI - The Eighth 2014 International London Cough Symposium. PMID- 26497111 TI - The mechanism of the keyhole lesion reassessed: An experimental approach. AB - The initial description of the keyhole defect was detailed as a peculiar gunshot entrance wound in the cranial vault due to firearm discharge in a tangential path. This injury may be described in two parts: a rounded section with inner table beveling and a triangular section with outer table beveling. We report a case of a gunshot skull wound "keyhole" shaped, appeared to have been made perpendicularly to the bone. Performing an experimental study on cranial bones with shots made perpendicularly to the skull approved this hypothesis, and bone injuries were then architecturally characterised using high-resolution micro computed tomography. The singular link between the tangential gunshot path and the keyhole pattern has been refuted several times, and some authors have hypothesised that there is an important role for concentric fractures that occur far away from the initial impact point of the bullet. Micro computed tomography analysis of the bone showed these keyhole defect features with a particular high description. Then, the whole pattern has a spider-web effect, and these concentric fractures could explain the keyhole pattern even in a perpendicular gunshot path. PMID- 26497112 TI - Efficient regulation of elemental sulfur recovery through optimizing working height of upflow anaerobic sludge blanket reactor during denitrifying sulfide removal process. AB - In this study, two lab-scale UASB reactors were established to testify S(0) recovery efficiency, and one of which (M-UASB) was improved from the previous T UASB by shortening reactor height once S(2-) over oxidation was observed. After the height was shortened from 60 to 30cm, S(0) recovery rate was improved from 7.4% to 78.8%, and while, complete removal of acetate, nitrate and S(2-) was simultaneously maintained. Meanwhile, bacterial community distribution was homogenous throughout the reactor, with denitrifying sulfide oxidization bacteria predominant, such as Thauera and Azoarcus spp., indicating the optimized condition for S(0) recovery. The effective control of working height/volume in reactors plays important roles for the efficient regulation of S(0) recovery during DSR process. PMID- 26497113 TI - Two step esterification-transesterification process of wet greasy sewage sludge for biodiesel production. AB - Sewage sludge generated in municipal wastewater treatment plants was used as a feedstock for biodiesel production via esterification/transesterification in a two-step process. In the first esterification step, greasy and secondary sludge were tested using acid and enzymatic catalysts. The results indicate that both catalysts performed the esterification of free fatty acids (FFA) simultaneously with the transesterification of triacylglycerols (TAG). Acid catalyst demonstrated better performance in FFA esterification compared to TAG transesterification, while enzymatic catalyst showed the ability to first hydrolyze TAG in FFA, which were esterified to methyl esters. In addition, FAME concentration using greasy sludge were higher (63.9% and 58.7%), compared with those of secondary sludge (11% and 16%), using acid and enzymatic catalysts, respectively. Therefore, only greasy sludge was used in the second step of alkaline transesterification. The alkaline transesterification of the previously esterified greasy sludge reached a maximum FAME concentration of 65.4% when using acid catalyst. PMID- 26497114 TI - Hierarchical multi-step organization during viral capsid assembly. AB - Formation of the HIV-1 core by the association of capsid proteins is a critical, not fully understood, step in the viral life cycle. Understanding the early stages of the mechanism may improve treatment opportunities. Here, spectroscopic analysis (opacity) is used to follow the kinetics of capsid protein assembly, which shows three stages: a lag phase, followed by a linear increase stage and terminated by a plateau. Adding pre-incubated capsid proteins at the start of the lag phase shortens it and increases the rate of assembly at the linear stage, demonstrating autoacceleration and cooperative assembly. Cryogenic transmission electron microscopy is used to probe structural evolution at these three stages. At the beginning of the lag phase, short tubular assemblies are found alongside micron long tubes. Their elongation continues all throughout the lag phase, at the end of which tubes start to assemble into bundles. Based on these results, we suggest a multi-step self-assembly process including fast nucleation and elongation followed by tubes packing into arrays. PMID- 26497115 TI - Microspheres prepared with different co-polymers of poly(lactic-glycolic acid) (PLGA) or with chitosan cause distinct effects on macrophages. AB - Microencapsulation of bioactive molecules for modulating the immune response during infectious or inflammatory events is a promising approach, since microspheres (MS) protect these labile biomolecules against fast degradation, prolong the delivery over longer periods of time and, in many situations, target their delivery to site of action, avoiding toxic side effects. Little is known, however, about the influence of different polymers used to prepare MS on macrophages. This paper aims to address this issue by evaluating in vitro cytotoxicity, phagocytosis profile and cytokines release from alveolar macrophages (J-774.1) treated with MS prepared with chitosan, and four different co-polymers of PLGA [poly (lactic-co-glycolic acid)]. The five MS prepared presented similar diameter and zeta potential each other. Chitosan-MS showed to be cytotoxic to J-774.1 cells, in contrast to PLGA-MS, which were all innocuous to this cell linage. PLGA 5000-MS was more efficiently phagocytized by macrophages compared to the other MS tested. PLGA 5000-MS and 5002-MS induced significant production of TNF-alpha, while 5000-MS, 5004-MS and 7502-MS decreased spontaneous IL-6 release. Nevertheless, only PLGA 5002-MS induced significant NFkB/SEAP activation. These findings together show that MS prepared with distinct PLGA co-polymers are differently recognized by macrophages, depending on proportion of lactic and glycolic acid in polymeric chain, and on molecular weight of the co-polymer used. Selection of the most adequate polymer to prepare a microparticulate drug delivery system to modulate immunologic system may take into account, therefore, which kind of immunomodulatory response is more adequate for the required treatment. PMID- 26497116 TI - Bombyx mori nucleopolyhedrovirus (BmNPV) Bm64 is required for BV production and per os infection. AB - BACKGROUND: Bombyx mori nucleopolyhedrovirus (BmNPV) orf64 (Bm64, a homologue of ac78) is a core baculovirus gene. Recently, Li et al. reported that Ac78 was not essential for budded viruses (BVs) production and occlusion-derived viruses (ODVs) formation (Virus Res 191:70-82, 2014). Conversely, Tao et al. demonstrated that Ac78 was localized to the BV and ODV envelopes and was required for BV production and ODV formation (J Virol 87:8441-50, 2013). In this study, the function of Bm64 was characterized to determine the role of Bm64 in the BmNPV infection cycle. METHOD: The temporal expression of Bm64 was examined using total RNA extracted from BmNPV-infected BmN cells at different time points by reverse transcription PCR (RT-PCR) and 5' RACE analysis. To determine the functions of Bm64 in viral replication and the viral phenotype throughout the viral life cycle, a deletion virus (vBm(64KO)) was generated via homologous recombination in Escherichia coli. Viral replication and BV production were determined by real time PCR. Electron microscopy was used to detect virion morphogenesis. The subcellular localization of Bm64 was determined by microscopy, and per os infectivity was used to determine its role in the baculovirus oral infection cycle. RESULTS: Viral plaque and titer assay results showed that a few infectious BVs were produced by vBm(64KO), suggesting that deletion of Bm64 affected BV production. Viral DNA replication was detected and polyhedra were observed in vBm(64KO)-transfected cells. Microscopy analysis revealed that Bm64 was predominantly localized to the ring zone of the nuclei during the infection cycle. Electron microscopy showed that Bm64 was not essential for the formation of ODVs or the subsequent occlusion of ODV into polyhedra. The per os infectivity results showed that the polyhedra of vBm(64KO) were unable to infect silkworm larvae. CONCLUSION: In conclusion, our results suggest that Bm64 plays an important role in BV production and per os infection, but is not required for viral DNA replication or ODV maturation. PMID- 26497118 TI - Fibroblast-derived tenascin-C promotes Schwann cell migration through beta1 integrin dependent pathway during peripheral nerve regeneration. AB - Peripheral nerve regeneration requires precise coordination and dynamic interaction among various types of cells in the tissue. It remains unclear, however, whether the cellular crosstalk between fibroblasts and Schwann cells (SCs) is related to phenotype modulation of SCs, a critical cellular process after peripheral nerve injury. In this study, microarray analysis revealed that a total of 6,046 genes were differentially expressed in the proximal nerve segment after sciatic nerve transection in rats, and bioinformatics analysis further identified tenascin-C (TNC), an extracellular matrix (ECM) protein, as a key gene regulator. TNC was abundantly produced by nerve fibroblasts accumulating at the lesion site, rather than by SCs as usually expected. TNC significantly promoted SC migration without effects on SC proliferation in primary culture. In co culture of fibroblasts and SCs, inhibition of TNC expression either by siRNA transfection or antibody blockade could suppress SC migration, while TNC stimulated SC migration was mediated by TNC binding to beta1-integrin receptor in SCs through activation of Rac1 effectors. The in vivo evidence showed that exogenous TNC protein enhanced SC migration and axonal regrowth. Our results highlight that TNC-mediated cellular interaction between fibroblasts and SCs may regulate SC migration through beta1-integrin-dependent pathway during peripheral nerve regeneration. PMID- 26497119 TI - Individual variation in fathers' testosterone reactivity to infant distress predicts parenting behaviors with their 1-year-old infants. AB - Positive father involvement is associated with positive child outcomes. There is great variation in fathers' involvement and fathering behaviors, and men's testosterone (T) has been proposed as a potential biological contributor to paternal involvement. Previous studies investigating testosterone changes in response to father-infant interactions or exposure to infant cues were unclear as to whether individual variation in T is predictive of fathering behavior. We show that individual variation in fathers' T reactivity to their infants during a challenging laboratory paradigm (Strange Situation) uniquely predicted fathers' positive parenting behaviors during a subsequent father-infant interaction, in addition to other psychosocial determinants of paternal involvement, such as dispositional empathy and marital quality. The findings have implications for understanding fathering behaviors and how fathers can contribute to their children's socioemotional development. PMID- 26497117 TI - UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis. AB - The cellular defence protein Nrf2 is a mediator of oncogenesis in pancreatic ductal adenocarcinoma (PDAC) and other cancers. However, the control of Nrf2 expression and activity in cancer is not fully understood. We previously reported the absence of Keap1, a pivotal regulator of Nrf2, in ~70% of PDAC cases. Here we describe a novel mechanism whereby the epigenetic regulator UHRF1 suppresses Keap1 protein levels. UHRF1 expression was observed in 20% (5 of 25) of benign pancreatic ducts compared to 86% (114 of 132) of pancreatic tumours, and an inverse relationship between UHRF1 and Keap1 levels in PDAC tumours (n = 124) was apparent (p = 0.002). We also provide evidence that UHRF1-mediated regulation of the Nrf2 pathway contributes to the aggressive behaviour of PDAC. Depletion of UHRF1 from PDAC cells decreased growth and enhanced apoptosis and cell cycle arrest. UHRF1 depletion also led to reduced levels of Nrf2-regulated downstream proteins and was accompanied by heightened oxidative stress, in the form of lower glutathione levels and increased reactive oxygen species. Concomitant depletion of Keap1 and UHRF1 restored Nrf2 levels and reversed cell cycle arrest and the increase in reactive oxygen species. Mechanistically, depletion of UHRF1 reduced global and tumour suppressor promoter methylation in pancreatic cancer cell lines, and KEAP1 gene promoter methylation was reduced in one of three cell lines examined. Thus, methylation of the KEAP1 gene promoter may contribute to the suppression of Keap1 protein levels by UHRF1, although our data suggest that additional mechanisms need to be explored. Finally, we demonstrate that K-Ras drives UHRF1 expression, establishing a novel link between this oncogene and Nrf2 mediated cellular protection. Since UHRF1 over-expression occurs in other cancers, its ability to regulate the Keap1-Nrf2 pathway may be critically important to the malignant behaviour of these cancers. PMID- 26497120 TI - Increased symptom reporting persists in 1990-1991 Gulf War veterans 20 years post deployment. AB - BACKGROUND: Following the 1990-1991 Gulf War, Gulf War veterans (veterans) reported health symptoms more commonly than non-deployed groups. This article examines symptom persistence, incidence and prevalence 20 years on. METHODS: In 2000-2003 and 2011-2012, a 63-item symptom checklist was administered to 697 veterans and 659 comparison group. Symptomatology was compared using log-binomial regression. RESULTS: Both veterans and comparison group reported significantly increased prevalence (3-52%) over time in more than half the symptoms, with a similar overall rate of increase. Half the symptoms had higher incidence (risk ratios ranged 1.43-1.50) and a quarter were more persistent (risk-ratios ranged 1.12-1.20) in veterans than the comparison group. CONCLUSIONS: Symptomatology increased in both groups over time, but persisted to a similar extent and had higher incidence among veterans than the comparison group. The gap in symptom prevalence between the two groups remained unchanged. These findings suggest enduring health consequences of Gulf War service. PMID- 26497121 TI - Clonorchis sinensis excretory/secretory products promote the secretion of TNF alpha in the mouse intrahepatic biliary epithelial cells via Toll-like receptor 4. AB - BACKGROUND: Toll-like receptor 4 (TLR4), as one of the most important pathogen pattern recognitions (PPRs) plays a central role in elicitation of innate immunity and mediation of adaptive responses against foreign antigens. However, little is known of the roles of TLR4 in the immune responses of biliary epithelial cells (BECs) induced by Clonorchis sinensis, a parasite of significance in human health. METHODS: In the present study, the primary mouse intrahepatic biliary epithelial cells (MIBECs) were pre-treated with TLR4 inhibitor peptide or control peptide and then stimulated by excretory/secretory products (ESP) of C. sinensis, respectively. The expressions of TLR4 and relative cytokines were determined using western blot and a bead-based analytic detection system, respectively. RESULTS: The results showed that ESP of C. sinensis significantly increased the expression of TLR4 which promoted the expression of MyD88 and NF-kappaB in BECs; the levels of TNF-alpha but not IL-6 from MIBECs stimulated by ESP alone were also considerably increased, compared with the group of the medium stimulated. However, the concentration of TNF-alpha was significantly decreased when MIBECs were pre-treated with TLR4 inhibitor. In addition, ESP could depress the level of IL-6 in MIBECs which was elevated by LPS. CONCLUSIONS: Our data for the first time demonstrate that ESP of C. sinensis can potently induce secretion of pro-inflammatory cytokines via TLR4 in MIBECs, which suggests that TLR4 plays an important role in host defenses against C. sinensis and the pathogenesis of clonorchiasis. PMID- 26497123 TI - Information from familiar and related conspecifics affects foraging in a solitary wolf spider. AB - As neighbours become familiar with one another, they can divert attention away from one another and focus on other activities. Since familiarity is a likely mechanism by which animals recognise relatives, both kinship and prior association with conspecifics should allow individuals to increase foraging. We attempted to determine if the interference observed among conspecific foragers could be mitigated by familiarity and/or kinship. Because Pardosa milvina wolf spiders are sensitive to chemotactile cues deposited on substrates by other spiders, we used cues to manipulate the information available to focal spiders. We first verified that animals could use these cues to differentiate relatives and familiar conspecifics. We then documented foraging in the presence of all combinations of related and familiar animal cues. Test spiders were slower foragers, less likely to capture prey, and consumed less of each prey item when on cues from unfamiliar kin, but were faster and more effective foragers on cues from familiar non-kin. Their reactions to familiar kin and unfamiliar non-kin were intermediate. High foraging intensity on familiar cues is consistent with the idea that animals pay less attention to neighbours after some prior association. Lower foraging effort in the presence of cues from relatives may be an attempt to reduce kin competition by shifting attention toward dispersal or to provide increased access to prey for hungry relatives nearby. These findings reveal that information from conspecifics mediates social interactions among individuals and affects foraging in ways that can influence their role in the food web. PMID- 26497122 TI - Infiltrating epitheliosis of the breast: characterization of histological features, immunophenotype and genomic profile. AB - AIMS: Infiltrating epitheliosis is a rare complex sclerosing lesion (CSL) of the breast, characterized by infiltrating ducts immersed in a scleroelastotic stroma and filled with cells having architectural and cytological patterns reminiscent of those of usual ductal hyperplasia. In this study we sought to define the molecular characteristics of infiltrating epitheliosis. METHODS AND RESULTS: Eight infiltrating epitheliosis, adjacent breast lesions (one usual ductal hyperplasia, one papilloma, one micropapillary ductal carcinoma in situ and one low-grade adenosquamous carcinoma), and corresponding normal breast tissue from each case were microdissected and subjected to massively parallel sequencing analysis targeting all coding regions of 254 genes mutated recurrently in breast cancer and/or related to DNA repair. Mutations in components of the PI3K pathway were found in all infiltrating epitheliosis samples, seven of which harboured PIK3CA hotspot mutations, while the remaining case displayed a PIK3R1 somatic mutation. CONCLUSIONS: Somatic mutations affecting PI3K pathway genes were found to be highly prevalent in infiltrating epitheliosis, suggesting that these lesions may be neoplastic rather than hyperplastic. The landscape of somatic genetic alterations found in infiltrating epitheliosis is similar to that of radial scars/CSLs, suggesting that infiltrating epitheliosis may represent one end of this spectrum of lesions. PMID- 26497124 TI - Belowground fungal associations and water interact to influence the compensatory response of Ipomopsis aggregata. AB - Although the concept that some plants benefit from being eaten is counterintuitive, there is now considerable evidence demonstrating enhanced fitness following herbivory. It has been assumed that plants growing in high resource conditions are the ones best able to compensate for herbivory. However, just the opposite has been found for dicotyledonous plants exhibiting patterns of overcompensation, with most occurring in resource-poor conditions. Long-term studies of the monocarpic biennial, scarlet gilia, Ipomopsis aggregata growing in resource-poor conditions have shown that ungulate herbivory by mule deer and elk can result in a threefold increase in plant fitness over uneaten controls. These observations led us to hypothesize that fungal associations would facilitate the compensatory response most commonly observed in this Arizona population of scarlet gilia; perhaps mutualistic associations with fungi, such as arbuscular mycorrhizal fungi, would explain the phenomenon of overcompensation altogether. Fungal removal experiments, using Captan(r), a commercially available fungicide, showed that a reduction in fungal abundance altered the compensatory response following ungulate herbivory, particularly in years in which water was limited, increasing fitness compensation from equal compensation to overcompensation. A multifactorial experiment revealed that the interactive effects of water and fungicide maximized fruit production following herbivory. Our results are counter to the "modification of tolerance hypothesis" in which plants associating with mycorrhizal fungi will have higher tolerance to herbivory. It is likely that arbuscular mycorrhizal fungi and dark septate endophytes compete with plants for photosynthates following herbivory, thereby limiting the magnitude of compensation. Thus, fungi appear to be parasitic on scarlet gilia following ungulate herbivory. PMID- 26497125 TI - Dietary and taxonomic controls on incorporation of microbial carbon and phosphorus by detritivorous caddisflies. AB - Heterotrophic microbes on detritus play critical roles in the nutrition of detritivorous animals, yet few studies have examined factors controlling the acquisition of microbial nutrients toward detritivore growth, which is termed "incorporation". Here, we assessed effects of detrital substrate identity (leaf type), background nutrients, and detritivore species identity on detritivore incorporation of microbial carbon (C) and phosphorus (P) in leaf litter diets. We fed oak and maple litter conditioned under two nutrient concentrations (50 or 500 ug P L(-1)) to the detritivorous caddisfly larvae Ironoquia spp., Lepidostoma spp., and Pycnopsyche lepida and used the radioisotopes 14C as glucose and 33P as phosphate to dually trace incorporation of microbial C and P by caddisflies. Incorporation efficiencies of microbial C (mean +/- SE = 12.3 +/- 1.3%) were one order of magnitude higher than gross growth efficiencies for bulk detrital C from recent studies (1.05 +/- 0.08%). Litter type did not affect incorporation of microbial nutrients; however, caddisflies incorporated microbial P 11 % less efficiently when fed litter from the higher P concentration. Two lower body C:P species (Pycnopsyche and Ironoquia) exhibited 9.9 and 7.1% greater microbial C and 19.0 and 17.7% greater microbial P incorporation efficiencies, respectively, than the higher body C:P species (Lepidostoma). Our findings support ecological stoichiometry theory on post-ingestive regulation that animals fed lower C:P diets should reduce P incorporation efficiency due to excess diet P or alleviation of P-limited growth, and that lower C:P species must incorporate dietary C and P more efficiently to support fast growth of P-rich tissues. PMID- 26497126 TI - Snow cover and late fall movement influence wood frog survival during an unusually cold winter. AB - Understanding how organisms will respond to altered winter conditions is hampered by a paucity of information on the winter ecology for many species. Amphibians are sensitive to environmental temperature and moisture conditions and may be vulnerable to changes in winter climate. We used a combination of radio telemetry and field enclosures to monitor survival of the freeze-tolerant wood frog (Lithobates sylvaticus) during the unusually cold winter of 2013-2014. We experimentally manipulated snow cover to determine the effect of snow removal on winter survival. In addition, we placed a group of untracked frogs at locations used by tracked frogs prior to long-distance late fall movement to investigate whether late fall movement entailed survival consequences. Winter survival was highest (75.3 %) among frogs at post-movement locations that received natural snow cover. The odds of surviving the winter for frogs in the snow removal treatment was only 21.6 % that of frogs in the natural snow treatment. Likewise, paired frogs placed at pre-fall movement locations had only 35.1 % the odds of surviving as tracked frogs at post-fall movement locations. A comparison of a priori models that included microhabitat conditions measured at wood frog overwintering locations revealed that the minimum temperature experienced and the depth of the frog in the substrate explained additional variation in winter survival. Our results suggest that acute exposure to lethal temperature conditions is the most likely cause of mortality during this study, rather than energy exhaustion or desiccation. They also demonstrate the importance of snow cover to the winter survival of wood frogs. PMID- 26497127 TI - Chemical Composition and Inhibitory Effects of Hypericum brasiliense and H. connatum on Prolyl Oligopeptidase and Acetylcholinesterase Activities. AB - BACKGROUND: The genus Hypericum (family Clusiaceae) comprises various species that are used in traditional medicine, such as wound healing, antidepressant, and anticancer agents. OBJECTIVE: The aim of this study was to evaluate the inhibitory capacity of extracts and fractions from two Hypericum species used in the Brazilian folk medicine (H. brasiliense and H. connatum) against the enzymes prolyl oligopeptidase (POP), dipeptidyl peptidase-IV (DPP-IV), and acetylcholinesterase (AChE), as well as to identify their main active constituents. METHODS: Dried aerial parts of H. connatum and H. brasiliense were subjected to extraction with 8:2 methanol-H2O. Each hydroalcoholic extract was fractioned resulting in ethyl acetate and aqueous fractions. The activity of POP, DPP-IV and AChE was determined in vitro in 96-well microplates. RESULTS: The main components identified in the plant extracts were chlorogenic acid (1), quercitrin (2), rutin (3), quercetin (4), and isoquercitrin (5). Hydroalcoholic extracts, ethyl acetate and aqueous fractions showed high POP inhibitory activity with IC50 values of 2.6 to 3.7 ug/mL. AChE and DPP-IV inhibitory effects were very low for all extracts and substances. CONCLUSION: Chlorogenic acid (1) and quercetin (4) were the main constituent responsible for the activity observed against POP. Parallel artificial membrane permeability assay of ethyl acetate fractions of both species showed that the metabolite that can effectively pass through the lipid membrane is 4, the aglycone form of 2, 3 and 5. PMID- 26497128 TI - Lipidomics analysis of follicular fluid by ESI-MS reveals potential biomarkers for ovarian endometriosis. AB - PURPOSE: The aim of the present study was to analyze the lipid profile of follicular fluid from patients with endometriosis and endometrioma who underwent in vitro fertilization treatment (IVF). METHODS: The control group (n = 10) was composed of women with tubal factor or minimal male factor infertility who had positive pregnancy outcomes after IVF. The endometriosis group consisted of women with endometriosis diagnosed by videolaparoscopy (n = 10), and from the same patients, the endometriomas fluids were collected, which composed the endometrioma group (n = 10). From the follicular fluid and endometriomas, lipids were extracted by the Bligh and Dyer method, and the samples were analyzed by tandem mass spectrometry. RESULTS: We observed phosphatidylglycerol phosphate, phosphatidylcholine, phosphatidylserine, and phosphatidylnositol bisphosphate in the control group. In the endometriosis group, sphingolipids and phosphatidylcholines were more abundant, while in the endometrioma group, sphingolipids and phosphatidylcholines with different m/z from the endometriosis group were found in high abundance. CONCLUSION: This analysis demonstrated that there is a differential representation of these lipids according to their respective groups. In addition, the lipids found are involved in important mechanisms related to endometriosis progress in the ovary. Thus, the metabolomic approach for the study of lipids may be helpful in potential biomarker discovery. PMID- 26497129 TI - Genetic import and phenotype specific alleles associated with hyper-invasion in Campylobacter jejuni. AB - BACKGROUND: Campylobacter jejuni is a major zoonotic pathogen, causing gastroenteritis in humans. Invasion is an important pathogenesis trait by which C. jejuni causes disease. Here we report the genomic analysis of 134 strains to identify traits unique to hyperinvasive isolates. METHODS: A total of 134 C. jejuni genomes were used to create a phylogenetic tree to position the hyperinvasive strains. Comparative genomics lead to the identification of mosaic capsule regions. A pan genome approach led to the discovery of unique loci, or loci with unique alleles, to the hyperinvasive strains. RESULTS: Phylogenetic analysis showed that the hyper-invasive phenotype is a generalist trait. Despite the fact that hyperinvasive strains are only distantly related based on the whole genome phylogeny, they all possess genes within the capsule region with high identity to capsule genes from C. jejuni subsp. doylei and C. lari. In addition there were genes unique to the hyper-invasive strains with identity to non-C. jejuni genes, as well as allelic variants of mainly pathogenesis related genes already known in the other C. jejuni. In particular, the sequence of flagella genes, flgD-E and flgL were highly conserved amongst the hyper-invasive strains and divergent from sequences in other C. jejuni. A novel cytolethal distending toxin (cdt) operon was also identified as present in all hyper-invasive strains in addition to the classic cdt operon present in other C. jejuni. CONCLUSIONS: Overall, the hyper-invasive phenotype is strongly linked to the presence of orthologous genes from other Campylobacter species in their genomes, notably within the capsule region, in addition to the observed association with unique allelic variants in flagellar genes and the secondary cdt operon which is unlikely under random sharing of accessory alleles in separate lineages. PMID- 26497130 TI - Differences in pregnancy outcomes and characteristics between insulin- and diet treated women with gestational diabetes. AB - BACKGROUND: Our aim was to evaluate the difference in pregnancy outcomes and characteristics between insulin- and diet-treated women with gestational diabetes (GDM). METHODS: Retrospective analysis of the medical files from 2010-2013 of women with GDM diagnosed with the Carpenter & Coustan criteria attending two clinics, one in a university and another in a non-university hospital. Characteristics associated with insulin use were analyzed. Multivariable logistic regression was used to adjust for confounders. For women attending the university hospital, indices of insulin sensitivity such as the reciprocal of the homeostasis model assessment of insulin resistance (1/HOMA-IR) and an index of beta-cell function, the Insulin Secretion-Sensitivity Index-2 (ISSI-2) were calculated. RESULTS: Over a 4 year period, 601 women were identified with GDM of whom 22.9% were obese at first prenatal visit. 24.2% needed insulin. Insulin did not prevent adverse outcomes, as women on insulin had higher rates of large-for gestational age infants (LGA) (28.5% vs. 13.1 %, p < 0.0001) and more cesarean sections (44.1% vs. 27.0%, p = 0.001), remaining significant after adjustment for confounders. Compared to diet-treated women, women on insulin more often had an ethnic minority background (33.3 % vs. 21.6%, p = 0.004), more often had a history of GDM (21.5% vs. 10.4%, p = 0.002), were more often multiparous (59.3% vs. 47.6%, p = 0.044) and were diagnosed with GDM earlier in pregnancy (weeks 25.3 +/- 4.9 vs. 27.1 +/- 3.7, p < 0.0001). When undergoing an oral glucose tolerance test, women treated with insulin had a higher fasting glycaemia (97.6 +/- 18.8 vs.87.7 +/- 10.3, p < 0.0001), a higher 1-hour glycaemia (197.7 +/- 30.1 vs.184.5 +/- 25.8, p < 0.0001), a higher 2-hour glycaemia (185.2 +/- 28.5 vs. 175.0 +/- 22.8, p < 0.0001), more often 3 and 4 abnormal values (58.1% vs. 37.8%, p < 0.0001 and 24.8% vs. 7.7%, p < 0.0001) and higher HbA1c levels (5.5 +/- 0.6 vs 5.2 +/- 0.5, p < 0.0001). ISSI-2 (1.3 +/- 0.5 vs. 1.7 +/- 0.5, p < 0.0001) and 1/HOMA-IR [0.01 (0.001-0.002) vs. 0.02 (0.01-0.03), p = 0.027] were lower in women on insulin. Women on insulin more often received corticoids in preparation of preterm delivery (11.0% vs. 2.4%, p < 0.0001). CONCLUSION: Compared to diet treated women with GDM, women treated with insulin have a higher risk profile, impaired beta-cell function and lower insulin sensitivity. Rates of LGA and cesarean sections were higher in insulin-treated women. PMID- 26497131 TI - 'It Was Easier Because I Had Help': Mothers' Reflections on the Long-Term Impact of Sustained Nurse Home Visiting. AB - OBJECTIVES: This qualitative descriptive study sought women's views of the Maternal Early Childhood Sustained Home-visiting (MECSH) program they received from prior to birth to child-age 2-years. MECSH is a structured nurse home visiting program for a broad range of women of all ages (both primiparous and multiparous) who experienced stressors in pregnancy that could negatively impact on maternal and child outcomes. Women were asked for their perceptions of how and why the intervention worked for them, and the impact of the intervention on their subsequent parenting to child-age 5-years. METHODS: Thirty-six women participated in a semi-structured interview when their child commenced formal schooling at age 5-years. Recorded and transcribed data were analysed using qualitative content analysis. RESULTS: Women described the importance of a positive relationship with the nurse, and nurses' availability and responsiveness as critical to positive impacts. The interventions they recalled receiving were consistent with the comprehensive MECSH program model. The intervention impacted on women's emotional well-being, confidence and help-seeking behaviour, and positively impacted on their parenting of their MECSH program child and their older and subsequent children. A small number of women reported feeling stressed and disconnected from services following program completion, however, most women continued to apply the learnings from the program. CONCLUSIONS: Overall women reported positive impacts not just for themselves and their parenting abilities during the 2-year intervention program, but also described ongoing benefit to their subsequent parenting in the preschool period. PMID- 26497132 TI - [Quality assurance concepts in intensive care medicine]. AB - Intensive care medicine (ICM) is characterized by a high degree of complexity and requires intense communication and collaboration on interdisciplinary and multiprofessional levels. In order to achieve good quality of care in this environment and to prevent errors, a proactive quality and error management as well as a structured quality assurance system are essential. Since the early 1990s, German intensive care societies have developed concepts for quality management and assurance in ICM. In 2006, intensive care networks were founded in different states to support the implementation of evidence-based knowledge into clinical routine and to improve medical outcome, efficacy, and efficiency in ICM. Current instruments and concepts of quality assurance in German ICM include core intensive care data from the data registry DIVI REVERSI, quality indicators, peer review in intensive care, IQM peer review, and various certification processes. The first version of German ICM quality indicators was published in 2010 by an interdisciplinary and interprofessional expert commission. Key figures, indicators, and national benchmarks are intended to describe the quality of structures, processes, and outcomes in intensive care. Many of the quality assurance tools have proved to be useful in clinical practice, but nationwide implementation still can be improved. PMID- 26497133 TI - Use of ultra-high molecular weight polycaprolactone scaffolds for ACL reconstruction. AB - Previously, we reported on the implantation of electrospun polycaprolactone (PCL) grafts for use in ACL tissue engineering in a small animal model. In the present study, we hypothesized that grafts fabricated from ultra-high molecular weight polycaprolactone (UHMWPCL) would have similarly favorable biologic properties but superior mechanical properties as compared to grafts fabricated from PCL. Two forms of polycaprolactone were obtained (UHMWPCL, MW = 500 kD, and PCL, MW = 80 kD) and electrospun into scaffolds that were used to perform ACL reconstruction in 7-8 week old male Lewis rats. The following groups were examined: UHMWPCL, PCL, flexor digitorum longus (FDL) allograft, native ACL, as well as sham surgery in which the ACL was transsected. At 16 weeks post-operatively, biomechanical testing, histology, and immunohistochemistry (IHC) were performed. Analysis of cellularity indicated that there was no significant difference among the UHMWPCL, PCL, and FDL allograft groups. Quantification of birefringence from picrosirius red staining demonstrated significantly more aligned collagen fibers in the allograft than the PCL group, but no difference between the UHMWPCL and allograft groups. The peak load to failure of the UHMWPCL grafts was significantly higher than PCL, and not significantly different from FDL allograft. This in vivo study establishes the superiority of the higher molecular weight version of polycaprolactone over PCL as a scaffold material for ACL reconstruction. By 16 weeks after implantation, the UHMWPCL grafts were not significantly different from the FDL allografts in terms of cellularity, peak load to failure, stiffness, and collagen fiber alignment. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:828-835, 2016. PMID- 26497134 TI - Optimization of adipose tissue-derived mesenchymal stem cells by rapamycin in a murine model of acute graft-versus-host disease. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) can protect bone marrow transplantation (BMT) recipients from the lethal acute graft-versus-host disease (aGVHD) development. However, the mechanisms underlying the anti-inflammatory properties of MSCs in aGVHD remain to be elucidated. The immunoregulatory properties of MSCs are mediated by their production of anti-inflammatory molecules, including IL-10 and TGF-beta. On the other hand, MSCs can also produce proinflammatory cytokines during their normal growth, such as IL-1beta and IL-6. These opposite actions may limit their therapeutic application in aGVHD. Therefore, optimization of the functional properties of MSCs can increase their benefits. METHODS: The expressions of mRNA and protein were analyzed by real-time PCR and western blotting, respectively. Expression of MSC markers was assessed by flow cytometry. An animal model of aGVHD was established by transplanting C57BL/6 donor bone marrow cells and spleen cells into lethally irradiated BALB/c recipient mice. The recipient mice were divided into the control group and the therapy [adipose tissue-derived human MSCs (Ad-hMSCs) or rapamycin-treated Ad hMSCs] groups. The survival, body weight and clinical score of aGVHD in transplanted mice were monitored. RESULTS: Rapamycin pre-treatment of Ad-hMSCs increased mRNA synthesis of IL-10, indoleamine 2,3-dioxygenase, and TGF-beta compared with untreated Ad-hMSCs. Rapamycin-treated Ad-hMSCs suppressed clonal expansion of interleukin-17-producing CD4(+) T (Th17) cells more effectively than untreated cells. mRNA expression of autophagy markers such as ATG5, LC3A and LC3B was significantly increased in the rapamycin-treated Ad-hMSCs compared with untreated Ad-hMSCs. Transmission electron microscopy revealed that Ad-hMSCs exposure to rapamycin resulted in the appearance of autophagic vacuoles. Interestingly, in vitro migration efficiency of rapamycin-treated Ad-hMSCs toward the CD4(+) T cells was increased significantly compared with the untreated cells. And, these effects were associated with autophagy induction capacity of rapamycin. In vivo, the inhibiting properties of MSCs on the clinical severities of aGVHD were greater in the mice receiving rapamycin-treated Ad-hMSCs compared with untreated Ad-hMSCs. The beneficial effects of rapamycin treatment in Ad hMSCs shown in vivo were associated with a reduction of Th17 cells and an increase in regulatory T cells. CONCLUSIONS: Rapamycin can optimize the immunomodulatory potential of Ad-hMSCs, suggesting a promising strategy of MSC use in aGVHD treatment. PMID- 26497135 TI - The devil is in the details: comparison between COP9 signalosome (CSN) and the LID of the 26S proteasome. AB - The COP9 signalosome (CSN) and the proteasomal LID are conserved macromolecular complexes composed of at least eight subunits with molecular weights of approximately 350 kDa. CSN and LID are part of the ubiquitin-proteasome pathway and cleave isopeptide linkages of lysine side chains on target proteins. CSN cleaves the isopeptide bond of ubiquitin-like protein Nedd8 from cullins, whereas the LID cleaves ubiquitin from target proteins sentenced for degradation. CSN and LID are structurally and functionally similar but the order of the assembly pathway seems to be different. The assembly differs in at least the last subunit joining the pre-assembled subcomplex. This review addresses the similarities and differences in structure, function and assembly of CSN and LID. PMID- 26497136 TI - A new rapid and efficient system with dominant selection developed to inactivate and conditionally express genes in Candida albicans. AB - Candida albicans is an important human fungal pathogen but its study has been hampered for being a natural diploid that lacks a complete sexual cycle. Gene knock-out and essential gene repression are used to study gene function in C. albicans. To effectively study essential genes in wild-type C. albicans, we took advantage of the compatible effects of the antibiotics hygromycin B and nourseothricin, the recyclable CaSAT1-flipper and the tetracycline-repressible (Tet-off) system. To allow deleting two alleles simultaneously, we created a cassette with a C. albicans HygB resistance gene (CaHygB) flanked with the FLP recombinase target sites that can be operated alongside the CaSAT1-flipper. Additionally, to enable conditionally switching off essential genes, we created a CaHygB-based Tet-off cassette that consisted of the CaTDH3 promoter, which is used for the constitutive expression of the tetracycline-regulated transactivator and a tetracycline response operator. To validate the new systems, all strains were constructed based on the wild-type strain and selected by the two dominant selectable markers, CaHygB and CaSAT1. The C. albicans general transcriptional activator CaGCN4 and its negative regulator CaPCL5 genes were targeted for gene deletion, and the essential cyclin-dependent kinase CaPHO85 gene was placed under the Tet-off system. Cagcn4, Capcl5, the conditional Tet-off CaPHO85 mutants, and mutants bearing two out of the three mutations were generated. By subjecting the mutants to various stress conditions, the functional relationship of the genes was revealed. This new system can efficiently delete genes and conditionally switch off essential genes in wild-type C. albicans to assess functional interaction between genes. PMID- 26497137 TI - Cardiopulmonary exercise testing responses to different external portable drivers in a patient with a CardioWest Total Artificial Heart. AB - Management of patients treated with CardioWest Total Artificial Heart (CW-TAH) as a bridge to heart transplantation (HTx) is complicated by difficulties in determining the optimal timing of transplantation. We present a case of a 53-year old man supported as an outpatient with a CW-TAH, whose condition deteriorated following exchange of the portable driver. The patient was followed-up with serial cardiopulmonary exercise testing (CPET) which demonstrated a fall of peak VO2 to below 12 ml/kg/min following driver substitution, and the patient was subsequently treated with urgent orthotopic HTx. This case highlights the potential utility of CPET as a means for monitoring and indicating timing of HTx in patients with CW-TAH, as well as the potential for clinical deterioration following portable driver substitution. PMID- 26497138 TI - Seventeen years of subcutaneous infection by Aspergillus flavus; eumycetoma confirmed by immunohistochemistry. AB - Chronic subcutaneous infections caused by Aspergillus species are considered to be extremely rare. Because these fungi are among the most common laboratory contaminants, their role as eumycetoma causative agents is difficult to ascertain. Here, we report the first case of A. flavus eumycetoma confirmed by isolation, molecular identification and immunohistochemical analysis. Patient was a 55-year-old male from Sudan suffering from eumycetoma on his left foot for a period of 17 years. He developed swelling, sinuses and white grain discharge was observed. He has been operated nine times and was treated with several regimens of ketoconazole and itraconazole without improvement. Initial diagnosis based on histology and radiology was Scedosporium eumycetoma. However, examination of the biopsy revealed A. flavus, which was identified by molecular analysis and MALDI TOF MS. Immunohistochemistry using antibody directed against Aspergillus species was positive. Because of the earlier treatment failures with ketoconazole and itraconazole, therapy with voriconazole was initiated. However, in vitro susceptibility testing yielded a lower Minimum Inhibitory Concentration (MIC) value for itraconazole (0.25 MUg ml(-1) ) than for voriconazole (1 MUg ml(-1) ). Based on the presented results, A. flavus can be considered as one of the agents of white-grain eumycetoma. PMID- 26497139 TI - Effects of ethylene on photosystem II and antioxidant enzyme activity in Bermuda grass under low temperature. AB - The phytohormone ethylene has been reported to mediate plant response to cold stress. However, it is still debated whether the effect of ethylene on plant response to cold stress is negative or positive. The objective of the present study was to explore the role of ethylene in the cold resistance of Bermuda grass (Cynodon dactylon (L).Pers.). Under control (warm) condition, there was no obvious effect of the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) or the antagonist Ag(+) of ethylene signaling on electrolyte leakage (EL) and malondialdehyde (MDA) content. Under cold stress conditions, ACC-treated plant leaves had a greater level of EL and MDA than the untreated leaves. However, the EL and MDA values were lower in the Ag(+) regime versus the untreated. In addition, after 3 days of cold treatment, ACC remarkably reduced the content of soluble protein and also altered antioxidant enzyme activity. Under control (warm) condition, there was no significant effect of ACC on the performance of photosystem II (PS II) as monitored by chlorophyll alpha fluorescence transients. However, under cold stress, ACC inhibited the performance of PS II. Under cold condition, ACC remarkably reduced the performance index for energy conservation from excitation to the reduction of intersystem electron acceptors (PI(ABS)), the maximum quantum yield of primary photochemistry (phiP0), the quantum yield of electron transport flux from Q(A) to Q(B) (phiE0), and the efficiency/probability of electron transport (PsiE0). Simultaneously, ACC increased the values of specific energy fluxes for absorption (ABS/RC) and dissipation (DI0/RC) after 3 days of cold treatment. Additionally, under cold condition, exogenous ACC altered the expressions of several related genes implicated in the induction of cold tolerance (LEA, SOD, POD-1 and CBF1, EIN3-1, and EIN3-2). The present study thus suggests that ethylene affects the cold tolerance of Bermuda grass by impacting the antioxidant system, photosystem II, as well as the CBF transcriptional regulatory cascade. PMID- 26497140 TI - Heterosis Increases Fertility, Fecundity, and Survival of Laboratory-Produced F1 Hybrid Males of the Malaria Mosquito Anopheles coluzzii. AB - The success of vector control strategies aiming to decrease disease transmission via the release of sterile or genetically-modified male mosquitoes critically depends on mating between laboratory-reared males and wild females. Unfortunately, mosquito colonization, laboratory rearing, and genetic manipulations can all negatively affect male competitiveness. Heterosis is commonly used to produce domestic animals with enhanced vigor and homogenous genetic background and could therefore potentially improve the mating performance of mass-reared male mosquitoes. Here, we produced enhanced hybrid males of the malaria mosquito Anopheles coluzzii by crossing two strains colonized >35 and 8 years ago. We compared the amount of sperm and mating plug proteins they transferred to females, as well as their insemination rate, reproductive success and longevity under various experimental conditions. Across experiments, widespread adaptations to laboratory mating were detected in the older strain. In large-group mating experiments, no overall hybrid advantage in insemination rates and the amount of sperm and accessory gland proteins transferred to females was detected. Despite higher sperm activity, hybrid males did not appear more fecund. However, individual-male mating and laboratory-swarm experiments revealed that hybrid males, while inseminating fewer females than older inbred males, were significantly more fertile, producing larger mating plugs and drastically increasing female fecundity. Heterotic males also showed increased longevity. These results validate the use of heterosis for creating hybrid males with improved fitness from long-established inbred laboratory strains. Therefore, this simple approach could facilitate disease control strategies based on male mosquito releases with important ultimate benefits to human health. PMID- 26497141 TI - Genome-Enabled Estimates of Additive and Nonadditive Genetic Variances and Prediction of Apple Phenotypes Across Environments. AB - The nonadditive genetic effects may have an important contribution to total genetic variation of phenotypes, so estimates of both the additive and nonadditive effects are desirable for breeding and selection purposes. Our main objectives were to: estimate additive, dominance and epistatic variances of apple (Malus * domestica Borkh.) phenotypes using relationship matrices constructed from genome-wide dense single nucleotide polymorphism (SNP) markers; and compare the accuracy of genomic predictions using genomic best linear unbiased prediction models with or without including nonadditive genetic effects. A set of 247 clonally replicated individuals was assessed for six fruit quality traits at two sites, and also genotyped using an Illumina 8K SNP array. Across several fruit quality traits, the additive, dominance, and epistatic effects contributed about 30%, 16%, and 19%, respectively, to the total phenotypic variance. Models ignoring nonadditive components yielded upwardly biased estimates of additive variance (heritability) for all traits in this study. The accuracy of genomic predicted genetic values (GEGV) varied from about 0.15 to 0.35 for various traits, and these were almost identical for models with or without including nonadditive effects. However, models including nonadditive genetic effects further reduced the bias of GEGV. Between-site genotypic correlations were high (>0.85) for all traits, and genotype-site interaction accounted for <10% of the phenotypic variability. The accuracy of prediction, when the validation set was present only at one site, was generally similar for both sites, and varied from about 0.50 to 0.85. The prediction accuracies were strongly influenced by trait heritability, and genetic relatedness between the training and validation families. PMID- 26497142 TI - Extreme Diversity in the Regulation of Ndt80-Like Transcription Factors in Fungi. AB - The Saccharomyces cerevisiae Ndt80 protein is the founding member of a class of p53-like transcription factors that is known as the NDT80/PhoG-like DNA-binding family. The number of NDT80-like genes in different fungi is highly variable and their roles, which have been examined in only a few species, include regulation of meiosis, sexual development, biofilm formation, drug resistance, virulence, the response to nutrient stress and programmed cell death. The protein kinase Ime2 regulates the single NDT80 gene present in S. cerevisiae. In this study we used a genetic approach to investigate whether the Aspergillus nidulans Ime2 homolog, ImeB, and/or protein kinases MpkC, PhoA and PhoB regulate the two NDT80 like genes (xprG and ndtA) in A. nidulans. Disruption of imeB, but not mpkC, phoA or phoB, led to increased extracellular protease activity and a defect in mycotoxin production similar to the xprG1 gain-of-function mutation. Quantitative RT-PCR showed that ImeB is a negative regulator of xprG expression and XprG is a negative regulator of xprG and ndtA expression. Thus, in contrast to Ime2, which is a positive regulator of NDT80 in S. cerevisiae, ImeB is a negative regulator as in Neurospora crassa. However, the ability of Ndt80 to autoregulate NDT80 is conserved in A. nidulans though the autoregulatory effect is negative rather than positive. Unlike N. crassa, a null mutation in imeB does not circumvent the requirement for XprG or NdtA. These results show that the regulatory activities of Ime2 and Ndt80-like proteins display an extraordinarily level of evolutionary flexibility. PMID- 26497143 TI - SMRT Sequencing for Parallel Analysis of Multiple Targets and Accurate SNP Phasing. AB - Single-molecule real-time (SMRT) sequencing generates much longer reads than other widely used next-generation (next-gen) sequencing methods, but its application to whole genome/exome analysis has been limited. Here, we describe the use of SMRT sequencing coupled with barcoding to simultaneously analyze one or a small number of genomic targets derived from multiple sources. In the budding yeast system, SMRT sequencing was used to analyze strand-exchange intermediates generated during mitotic recombination and to analyze genetic changes in a forward mutation assay. The general barcoding-SMRT approach was then extended to diffuse large B-cell lymphoma primary tumors and cell lines, where detected changes agreed with prior Illumina exome sequencing. A distinct advantage afforded by SMRT sequencing over other next-gen methods is that it immediately provides the linkage relationships between SNPs in the target segment sequenced. The strength of our approach for mutation/recombination studies (as well as linkage identification) derives from its inherent computational simplicity coupled with a lack of reliance on sophisticated statistical analyses. PMID- 26497144 TI - Cell-Specific mRNA Profiling of the Caenorhabditis elegans Somatic Gonadal Precursor Cells Identifies Suites of Sex-Biased and Gonad-Enriched Transcripts. AB - The Caenorhabditis elegans somatic gonad differs greatly between the two sexes in its pattern of cell divisions, migration, and differentiation. Despite decades of study, the genetic pathways directing early gonadal development and establishing sexual dimorphism in the gonad remain largely unknown. To help define the genetic networks that regulate gonadal development, we employed cell-specific RNA-seq. We identified transcripts present in the somatic gonadal precursor cells and their daughter cells of each sex at the onset of sexual differentiation. We identified several hundred gonad-enriched transcripts, including the majority of known regulators of early gonadal development, and transgenic reporter analysis confirmed the effectiveness of this approach. Before the division of the somatic gonad precursors, few sex-biased gonadal transcripts were detectable; less than 6 hr later, after their division, we identified more than 250 sex-biased transcripts, of which about a third were enriched in the somatic gonad compared to the whole animal. This indicates that a robust sex-biased developmental program, some of it gonad-specific, initiates in the somatic gonadal precursor cells around the time of their first division. About 10% of male-biased transcripts had orthologs with male-biased expression in the early mouse gonad, suggesting possible conservation of gonad sex differentiation. Cell-specific analysis also identified approximately 70 previously unannotated mRNA isoforms that are enriched in the somatic gonad. Our data illustrate the power of cell specific transcriptome analysis and suggest that early sex differentiation in the gonad is controlled by a relatively small suite of differentially expressed genes, even after dimorphism has become apparent. PMID- 26497145 TI - Turnover of Sex Chromosomes in Celebensis Group Medaka Fishes. AB - Sex chromosomes and the sex-determining (SD) gene are variable in vertebrates. In particular, medaka fishes in the genus Oryzias show an extremely large diversity in sex chromosomes and the SD gene, providing a good model to study the evolutionary process by which they turnover. Here, we investigated the sex determination system and sex chromosomes in six celebensis group species. Our sex linkage analysis demonstrated that all species had an XX-XY sex determination system, and that the Oryzias marmoratus and O. profundicola sex chromosomes were homologous to O. latipes linkage group (LG) 10, while those of the other four species, O. celebensis, O. matanensis, O. wolasi, and O. woworae, were homologous to O. latipes LG 24. The phylogenetic relationship suggested a turnover of the sex chromosomes from O. latipes LG 24 to LG 10 within this group. Six sex-linkage maps showed that the former two and the latter four species shared a common SD locus, respectively, suggesting that the LG 24 acquired the SD function in a common ancestor of the celebensis group, and that the LG 10 SD function appeared in a common ancestor of O. marmoratus and O. profundicola after the divergence of O. matanensis. Additionally, fine mapping and association analysis in the former two species revealed that Sox3 on the Y chromosome is a prime candidate for the SD gene, and that the Y-specific 430-bp insertion might be involved in its SD function. PMID- 26497146 TI - Dynamics of Wolbachia pipientis Gene Expression Across the Drosophila melanogaster Life Cycle. AB - Symbiotic interactions between microbes and their multicellular hosts have manifold biological consequences. To better understand how bacteria maintain symbiotic associations with animal hosts, we analyzed genome-wide gene expression for the endosymbiotic alpha-proteobacteria Wolbachia pipientis across the entire life cycle of Drosophila melanogaster. We found that the majority of Wolbachia genes are expressed stably across the D. melanogaster life cycle, but that 7.8% of Wolbachia genes exhibit robust stage- or sex-specific expression differences when studied in the whole-organism context. Differentially-expressed Wolbachia genes are typically up-regulated after Drosophila embryogenesis and include many bacterial membrane, secretion system, and ankyrin repeat-containing proteins. Sex biased genes are often organized as small operons of uncharacterized genes and are mainly up-regulated in adult Drosophila males in an age-dependent manner. We also systematically investigated expression levels of previously-reported candidate genes thought to be involved in host-microbe interaction, including those in the WO-A and WO-B prophages and in the Octomom region, which has been implicated in regulating bacterial titer and pathogenicity. Our work provides comprehensive insight into the developmental dynamics of gene expression for a widespread endosymbiont in its natural host context, and shows that public gene expression data harbor rich resources to probe the functional basis of the Wolbachia-Drosophila symbiosis and annotate the transcriptional outputs of the Wolbachia genome. PMID- 26497147 TI - Examination of Endogenous Rotund Expression and Function in Developing Drosophila Olfactory System Using CRISPR-Cas9-Mediated Protein Tagging. AB - The zinc-finger protein Rotund (Rn) plays a critical role in controlling the development of the fly olfactory system. However, little is known about its molecular function in vivo. Here, we added protein tags to the rn locus using CRISPR-Cas9 technology in Drosophila to investigate its subcellular localization and the genes that it regulates . We previously used a reporter construct to show that rn is expressed in a subset of olfactory receptor neuron (ORN) precursors and it is required for the diversification of ORN fates. Here, we show that tagged endogenous Rn protein is functional based on the analysis of ORN phenotypes. Using this method, we also mapped the expression pattern of the endogenous isoform-specific tags in vivo with increased precision. Comparison of the Rn expression pattern from this study with previously published results using GAL4 reporters showed that Rn is mainly present in early steps in antennal disc patterning, but not in pupal stages when ORNs are born. Finally, using chromatin immunoprecipitation, we showed a direct binding of Rotund to a previously identified regulatory element upstream of the bric-a-brac gene locus in the developing antennal disc. PMID- 26497150 TI - Chromatographic methods enabling the characterization of stationary phases and retention prediction in high-performance liquid chromatography and supercritical fluid chromatography. AB - In the scope of the present review, the current status of high-performance liquid chromatography/ultra-high performance liquid chromatography and supercritical fluid chromatography is briefly provided. These techniques and their retention mechanisms are compared. Various alternative approaches utilized for the determination and description of the retention processes in these two systems are mapped. Two frequently used concepts, linear-free energy relationships, and hydrophobic subtraction models, used for the characterization of the retention interactions, are discussed. Principles and selected applications of the both methods are also covered. Then the models applied for the prediction of retention behavior of solutes on stationary phases are outlined. The procedures utilized for the sorbent/column classification are also covered. Simple chromatographic tests frequently used for the basic characterization and mutual comparison of stationary phases are summarized and briefly commented on. The importance of a statistical evaluation of complex retention data obtained from the chromatographic measurements is outlined. Finally, computer simulations aiming at the facilitation of the quest to optimize separation conditions for a given mixture of analytes are touched upon. PMID- 26497148 TI - Parallels with the Female Athlete Triad in Male Athletes. AB - Participation in sports offers many health benefits to athletes of both sexes. However, subsets of both female and male athletes are at increased risk of impaired bone health and bone stress injuries. The Female Athlete Triad (Triad) is defined as the interrelationship of low energy availability (with or without disordered eating), menstrual dysfunction, and low bone mineral density. The Triad may result in health consequences, including bone stress injuries. Our review presents evidence that an analogous process may occur in male athletes. Our review of the available literature indicates that a subset of male athletes may experience adverse health issues that parallel those associated with the Triad, including low energy availability (with or without disordered eating), hypogonadotropic hypogonadism, and low bone mineral density. Consequently, male athletes may be predisposed to developing bone stress injuries, and these injuries can be the first presenting feature of associated Triad conditions. We discuss the evidence for impaired nutrition, hormonal dysfunction, and low bone mineral density in a subset of male athletes, and how these health issues may parallel those of the Triad. With further research into the mechanisms and outcomes of these health concerns in active and athletic men, evidence-based guidelines can be developed that result in best practice. PMID- 26497149 TI - Can Doping be a Good Thing? Using Psychoactive Drugs to Facilitate Physical Activity Behaviour. PMID- 26497151 TI - A hole in my heart: mitral abscess and fistula. PMID- 26497152 TI - Point-of-care echocardiography for aortic dissection, pulmonary embolism and acute coronary syndrome in patients with killer chest pain: EASY screening focused on the assessment of effusion, aorta, ventricular size and shape and ventricular asynergy. AB - Focus assessed transthoracic echocardiography and focused cardiac ultrasound are point-of-care echo protocols for the evaluation of cardiac disease in the emergency room; however, these protocols may not adequately assess aortic dissection, pulmonary embolism, and acute coronary syndrome in patients with killer chest pain. Here, I present an echocardiography protocol focused on screening for these critical cardiovascular diseases. This protocol (termed EASY screening) consists of the assessment of effusion in the pericardial space, aortic abnormalities, the size and shape of the ventricles and asynergy of the left ventricle. Aortic dissection is suggested by positive findings for effusion and/or abnormal aortic findings. Pulmonary embolism is suggested by a dilated right ventricle and a D-shaped left ventricle in the short-axis view. Acute coronary syndrome is suggested by asynergy of left ventricular wall motion. EASY screening may facilitate the assessment of aortic dissection, pulmonary embolism and acute coronary syndrome in patients presenting to the emergency room with killer chest pain. PMID- 26497153 TI - Resin luting materials: Tissue response in dog's teeth. AB - The aim of this study was to evaluate radiographically and histologically the pulpal and periapical response to self-adhesive (Rely XTM Unicem) and self etching and self-curing (Multilink((r))) resin-based luting materials in deep cavities in dogs' teeth. Deep class V cavities (0.5-mm-thick dentin) were prepared in 60 canine premolars and the following materials were applied on cavity floor: Groups I/V-RelyXTM Unicem; Groups II/VI-Multilink((r)); Groups III/VII-zinc phosphate cement (control) and; Groups IV/VIII-gutta-percha (control). Cavities were restored with silver amalgam. Animals were euthanized after 10 days (groups I-IV) and 90 days (groups V-VIII). Tooth/bone blocks were radiographed and processed for histopathological evaluation of pulp and periapical tissue response to the materials. All materials presented similar histopathological features and radiographic findings at both periods. The pulp tissue was intact. The apical and periapical regions and periodontal ligament thickness were normal. No inflammatory cells, resorption of mineralized tissue (dentin, cementum, and alveolar bone) or bacteria were observed. The lamina dura was intact and no areas of periapical bone rarefaction or internal/external root resorption were observed radiographically. It can be concluded that Rely XTM Unicem and Multilink((r)) caused no adverse tissue reactions and may be indicated for cementation of indirect restorations in deep dentin cavities without pulp exposure. PMID- 26497154 TI - The impact of MTHFR 677 C/T genotypes on folate status markers: a meta-analysis of folic acid intervention studies. AB - PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme with the T variant of the MTHFR gene increasing the risk of low folate status, particularly coupled with low folate intake. As genetic variability of MTHFR influences folate status, it is important to ensure an adequate intake that overrides genetic effects but minimises any adverse effects. Our aim was to assess the influence of MTHFR genotype on folate status followed by response to supplementation. METHODS: We performed a meta-analysis of ten folate intervention studies to assess the degree to which MTHFR C677T genotype influenced plasma homocysteine and serum folate levels as measures of folate status. We then examined response after supplementation at intake values up to the upper tolerable limit. RESULTS: The MTHFR 677TT genotype was associated with higher plasma homocysteine (2.7 MUmol/L, TT vs. CT/CC; 2.8 MUmol/L, TT vs. CC) and lower serum folate (2.5 nmol/L, TT vs. CT/CC; 3.6 nmol/L, TT vs. CC). In two studies, the TT groups had mean plasma Hcy >15 MUmol/L. Serum folate levels were >7 nmol/L for all genotype groups. After supplementation of 400 up to 1670 MUg DFEs of folic acid or folic acid + fortified foods and/or natural food folates for a minimum of 4 weeks, there were no significant differences in plasma homocysteine levels; however, individuals with the TT genotype had a lower serum folate response to supplementation (7.2 nmol/L, TT vs. CT/CC; 8.7 nmol/L, TT vs. CC). CONCLUSIONS: This meta-analysis confirms observations from observational and intervention studies that MTHFR TT genotype is associated with increased plasma homocysteine and lowered serum folate and less response to short-term supplementation. The results can be used for modelling and guiding personalised intake recommendations for the nutrient folate. PMID- 26497155 TI - Inactivation of Bacillus cereus spores in a tsuyu sauce using continuous ohmic heating with five sequential elbow-type electrodes. AB - AIMS: The effect of ohmic heating (OH) in a pilot plant system which had a zig zag shaped (elbow-type) ohmic heater with five sequential voltage electrodes was investigated on Bacillus cereus spores in a commercial tsuyu sauce. METHODS AND RESULTS: The electrical field was fixed at 26.7 V cm(-1) with an alternating current frequency of 25 kHz. Raw tsuyu sauce (50 l) inoculated with B. cereus spores was submitted in a 4 * 3 factorial design to the OH system and heated at 95, 105, 115, and 125 degrees C each for 30, 60, and 90 s. Survival of B. cereus spores and colour change in the commercial tsuyu sauce were both measured before and after treatment. As the treatment temperature and time increased, the number of surviving B. cereus spores decreased. The OH treatment in a bath-type process at 105 degrees C for more than 30 s resulted in the total inactivation of the inoculated B. cereus spores (average 5.4 log reductions to undetectable levels after treatment). The OH protocol of heating at 105 degrees C for 60 s which ensure complete eradication of the inoculated spores without compromising product quality was chosen and investigated for its suitability for commercial application on bulk quantities of samples (500 l). Reliable and reproducible reductions in B. cereus spore counts of 4.7-5.5 log CFU ml(-1) (mean +/- standard deviation = 5.1 +/- 0.3 CFU ml(-1) ) were achieved by the selected protocol of the continuous OH treatment (105 degrees C for 60 s). CONCLUSION: This study suggests that OH treatment with five sequential elbow-type electrodes has great potential as an industrial sterilizing method for liquid food contaminated with B. cereus spores. SIGNIFICANCE AND IMPACT OF THE STUDY: This procedure will enhance the microbiological quality of liquid foods while minimizing quality deterioration. PMID- 26497156 TI - Neurofunctional assessment at term equivalent age can predict 3-year neurodevelopmental outcomes in very low birth weight infants. AB - AIM: Preterm infants are at high risk of developing motor delay, learning difficulties and behavioural problems and the availability of valid neurodevelopmental assessments is a major clinical issue. This study evaluated the relationship between preterm infants' neurofunctional assessment at term equivalent age and neurodevelopment outcome at three years of chronological age. METHODS: Neurofunctional assessment was performed in 70 very low birth weight infants at term equivalent age and neurodevelopmental outcome was assessed at three years of chronological age with the Griffiths Mental Development Scale - Extended Revised. RESULTS: At term equivalent age, 81% of the children had normal neurofunctional scores and 82.5% of those showed normal neurodevelopmental outcome at three years. Of the 19% who had impaired development at term equivalent age, 38.5% had neurodevelopmental delay at three years. Impaired neurofunctional status was associated with an increased risk of developmental delay in the global quotient (odds ratio 12.1) and locomotor sub-quotient (odds ratio 18.35) compared with normal neurofunctional status. Infants with sepsis or necrotising enterocolitis also faced a higher risk of neurodevelopmental delay. CONCLUSION: Neurofunctional assessment performed at term equivalent age appeared to provide early identification of preterm infants at risk of neurodevelopmental delay at three years of chronological age. PMID- 26497157 TI - Reviving the Louisville Twin Study: An Introduction. AB - Researchers who are interested in breathing new life into the long dormant Louisville Twin Study (LTS) presented several papers at the 2015 meeting of the behavior genetics association. This brief introduction provides a short history of the Kentucky LTS as well as synopses of expanded analyses from the presentations on genetic change and continuity in cognitive and behavioral development and those exploring aspects of the influence of gene-environment interaction on cognition. PMID- 26497158 TI - The Scarr-Rowe Interaction in Complete Seven-Year WISC Data from the Louisville Twin Study: Preliminary Report. AB - We examine updated Wechsler IQ data in 7-year old twins from the Louisville Twin Study for evidence of an interaction between the heritability of IQ and socioeconomic status. Data records that had never been entered were recovered, allowing us to increase previously reported sample sizes by more than 20%. Twin families were assigned socioeconomic status scores using a Hollingshead index based on parental education and occupation. A structural equation model in which genetic and environmental variances were modeled as squared linear functions of SES provided ambiguous replication of earlier findings from the National Collaborative Perinatal Project: relations between SES and heritability for performance and full scale IQ were in the same direction as the previous report, but at p < 0.07. As was the case in Turkheimer et al. (Psychol Sci 14(6):623-628, 2003), no interaction was found for VIQ. These results cannot yet be taken as a definitive replication of Turkheimer et al. (Psychol Sci 14(6):623-628, 2003). Many more measurement occasions, subtests and environmental moderators remain to be analyzed. PMID- 26497159 TI - Decline in cognitive function due to diffuse axonal injury does not necessarily imply a corresponding decline in ability to perform activities. AB - PURPOSE: The study explored the direction of change (decline vs. improvement) after diffuse axonal injury (DAI) in the domains of the ICF: body structure, body function, and activity. METHODS: Thirteen patients with DAI were assessed by using diffusion tensor imaging (DTI) to measure body structure, the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS) to measure body function, and the Assessment of Motor and Process Skills (AMPS) to measure activity. The DTI, BNIS, and AMPS were applied at the acute phase (A1), and at 6 and 12 months post-injury (A2 and A3). Visual and statistical analyses were conducted to explore time-dependent changes in the ICF domains. RESULTS: Improvements were observed for most patients in all ICF domains from injury until six months. Thereafter, the results diverged, with half of the subjects showing a decline in DTI and BNIS scores between A2-A3, and all but one of the patients exhibiting identical or better A2-A3 AMPS process skill scores. CONCLUSIONS: From 6 to 12 months post-injury, some patients underwent an ongoing degenerative process, causing a decline in cognitive function. The same decline was not observed in the activity measure, which might be explained by the use of compensatory strategies. IMPLICATIONS FOR REHABILITATION: In rehabilitation it is essential to be aware that in some cases with TBI, an ongoing degenerative process in the white matter can be expected, causing an adverse late effect on cognitive function. The cognitive decline, caused by DAI, does not necessarily mean a concurrent decrease in activity performance, possibly explained by the use of compensatory strategies. This suggests that, after the post-acute phase, rehabilitation offering strategy training may be beneficial to enhance every-day functioning. Strategy use requires awareness, which imply the need to assess level of awareness in order to guide rehabilitation. PMID- 26497160 TI - Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers. AB - AIMS: Phenotypic heterogeneity and incomplete penetrance are common in patients with hypertrophic cardiomyopathy (HCM). We aim to improve the understanding in genotype-phenotype correlations in HCM, particularly the contribution of an MYL2 founder mutation and risk factors to left ventricular hypertrophic remodelling. METHODS AND RESULTS: We analysed 14 HCM families of whom 38 family members share the MYL2 c.64G > A [p.(Glu22Lys)] mutation and a common founder haplotype. In this unique cohort, we investigated factors influencing phenotypic outcome in addition to the primary mutation. The mutation alone showed benign disease manifestation with low penetrance. The co-presence of additional risk factors for hypertrophy such as hypertension, obesity, or other sarcomeric gene mutation increased disease penetrance substantially and caused HCM in 89% of MYL2 mutation carriers (P = 0.0005). The most prominent risk factor was hypertension, observed in 71% of mutation carriers with HCM and an additional risk factor. CONCLUSION: The MYL2 mutation c.64G > A on its own is incapable of triggering clinical HCM in most carriers. However, the presence of an additional risk factor for hypertrophy, particularly hypertension, adds to the development of HCM. Early diagnosis of risk factors is important for early treatment of MYL2 mutation carriers and close monitoring should be guaranteed in this case. Our findings also suggest that the presence of hypertension or another risk factor for hypertrophy should not be an exclusion criterion for genetic studies. PMID- 26497161 TI - The CAHP (Cardiac Arrest Hospital Prognosis) score: a tool for risk stratification after out-of-hospital cardiac arrest. AB - AIMS: Survival after out-of-hospital cardiac arrest (OHCA) remains disappointingly low. Among patients admitted alive, early prognostication remains challenging. This study aims to establish a stratification score for patients admitted in intensive care unit (ICU) after OHCA, according to their neurological outcome. METHODS AND RESULTS: The CAHP (Cardiac Arrest Hospital Prognosis) score was developed from the Sudden Death Expertise Center registry (Paris, France). The primary outcome was poor neurological outcome defined as Cerebral Performance Category 3, 4, or 5 at hospital discharge. Independent prognostic factors were identified using logistic regression analysis and thresholds defined to stratify low-, moderate-, and high-risk groups. The CAHP score was validated in both a prospective and an external data set (Parisian Cardiac Arrest Registry). The developmental data set included 819 patients admitted from May 2011 to December 2012. After multivariate analysis, seven variables were independently associated with poor neurological outcome and subsequently included in the CAHP score (age, non-shockable rhythm, time from collapse to basic life support, time from basic life support to return of spontaneous circulation, location of cardiac arrest, epinephrine dose, and arterial pH). Three risks groups were identified: low risk (score <=150, 39% of unfavourable outcome), medium risk (score 150-200, 81% of unfavourable outcome) and high-risk group (score >=200, 100% of unfavourable outcome). The AUC of the CAHP score were 0.93, and the discrimination value in the validation data sets was consistent (respectively, AUC 0.91 and 0.85). CONCLUSION: The CAHP score represents a simple tool for early stratification of patients admitted in ICU after OHCA. A high-risk category of patients with very poor prognosis can be easily identified. PMID- 26497162 TI - Association between pregnancy losses in women and risk of atherosclerotic disease in their relatives: a nationwide cohort study?. AB - AIMS: A common underlying mechanism with a genetic component could link pregnancy losses with vascular disease. We examined whether pregnancy losses (miscarriages and stillbirths) and atherosclerotic outcomes co-aggregated in families. METHODS AND RESULTS: Using Danish registers, we identified women with pregnancies in 1977 2008, and their parents (>1 million) and brothers (>435 000). We followed parents for incident ischaemic heart disease (IHD), myocardial infarction (MI), and cerebrovascular infarction (CVI), and brothers for a broader combined atherosclerotic endpoint. Using Cox regression, we estimated hazard ratios (HRs) for each outcome by history of pregnancy loss in daughters/sisters. Overall, parents whose daughters had 1, 2, and >=3 miscarriages had 1.01 [95% confidence interval (CI) 0.99-1.04], 1.07 (95% CI 1.02-1.11), and 1.10 (95% CI 1.02-1.19) times the rate of MI, respectively, as parents whose daughters had no miscarriages. For parents with >=3 daughters, the HRs were 1.12 (95% CI 1.02 1.24), 1.29 (95% CI 1.13-1.48), and 1.33 (95% CI 1.12-1.57). Effect magnitudes did not differ for fathers and mothers. We observed similar patterns for IHD and CVI (parents) and the atherosclerotic endpoint (brothers). Parents whose daughters had stillbirths had 1.14 (95% CI 1.05-1.24) and 1.07 (95% CI 0.96-1.18) times the rates of MI and CVI, respectively, as parents whose daughters had no stillbirths. CONCLUSION: Certain pregnancy losses and atherosclerotic diseases in both heart and brain may have a common aetiologic mechanism. Women in families with atherosclerotic disease may be predisposed to pregnancy loss; conversely, pregnancy losses in first-degree relatives may have implications for atherosclerotic disease risk. PMID- 26497163 TI - Heart failure: when form fails to follow function. AB - Cardiac performance is normally determined by architectural, cellular, and molecular structures that determine the heart's form, and by physiological and biochemical mechanisms that regulate the function of these structures. Impaired adaptation of form to function in failing hearts contributes to two syndromes initially called systolic heart failure (SHF) and diastolic heart failure (DHF). In SHF, characterized by high end-diastolic volume (EDV), the left ventricle (LV) cannot eject a normal stroke volume (SV); in DHF, with normal or low EDV, the LV cannot accept a normal venous return. These syndromes are now generally defined in terms of ejection fraction (EF): SHF became 'heart failure with reduced ejection fraction' (HFrEF) while DHF became 'heart failure with normal or preserved ejection fraction' (HFnEF or HFpEF). However, EF is a chimeric index because it is the ratio between SV--which measures function, and EDV--which measures form. In SHF the LV dilates when sarcomere addition in series increases cardiac myocyte length, whereas sarcomere addition in parallel can cause concentric hypertrophy in DHF by increasing myocyte thickness. Although dilatation in SHF allows the LV to accept a greater venous return, it increases the energy cost of ejection and initiates a vicious cycle that contributes to progressive dilatation. In contrast, concentric hypertrophy in DHF facilitates ejection but impairs filling and can cause heart muscle to deteriorate. Differences in the molecular signals that initiate dilatation and concentric hypertrophy can explain why many drugs that improve prognosis in SHF have little if any benefit in DHF. PMID- 26497164 TI - Role of the paraventricular nucleus in the reflex diuresis to pulmonary lymphatic obstruction in rabbits. AB - The changes in urine flow and renal sympathetic nerve activity (RSNA) due to pulmonary lymphatic obstruction (PLO) were examined in anesthetized, artificially ventilated New Zealand white rabbits. PLO was produced by pressurizing an isolated pouch created in the right external jugular vein at the points of entry of the right lymphatic ducts. During this maneuver, urine flow increased from 8.5 +/- 0.3 mL/10 min to 12 +/- 0.5 mL/10 min (P < 0.0001) and RSNA increased from 24.0 +/- 4 to 40.0 +/- 5 MUV.s (P < 0.0001). Bilateral lesioning of the paraventricular nucleus (PVN) of the hypothalamus or cervical vagotomy abolished these responses. PLO increased c-fos gene expression in the PVN. The increase in urine flow due to PLO was attenuated by muscimol and abolished by kynurenic acid microinjections into the PVN. The results show that (i) neurons in the PVN are an important relay site in the reflex arc, which is activated by PLO; and (ii) this activation is regulated by glutamatergic and partly by GABAergic input to the PVN. PMID- 26497165 TI - Feasibility study of the Fab fragment of a monoclonal antibody against tissue factor as a diagnostic tool. AB - Tissue factor (TF) is expressed strongly in various types of cancer, especially cancers that are often refractory to treatment, such as pancreatic cancer. In this study, we compared the differences in the biophysical and pharmacological properties of whole IgG and the Fab fragment of anti-human TF monoclonal antibody (1849 antibodies), in order to determine their suitability for application in the diagnosis and treatment of cancers. In the biophysical examination, we investigated the characteristics of 1849-whole IgG and 1849-Fab by SPR sensing and confocal fluorescence microscopy analysis using recombinant human TF antigen and TF-overexpressing human pancreatic cancer cell line, BxPC3, respectively. After conjugation with Alexa-Flour-647, in vivo imaging was conducted in mice bearing BxPC3 xenograft tumors. Furthermore, the distribution of the conjugates in tumors and major organs was evaluated by ex vivo study. The in vitro experiments showed that 1849 antibodies had high affinity against TF antigen. In addition, 1849-Fab showed a faster dissociation rate from the antigen than 1849 whole IgG. In mice, 1849-Fab-Alexa-Flour-647 showed rapid renal clearance and faster tumor accumulation, achieving a high contrast signal over nearby normal tissues in the early phase and enhanced tumor penetration after administration. On the other hand, 1849-whole IgG-Alexa-Flour-647 showed slow clearance from the blood and sustained high tumor accumulation. These results suggest that 1849-Fab may be a useful tool for pancreatic cancer diagnosis. PMID- 26497166 TI - Lower leaf gas-exchange and higher photorespiration of treated wastewater irrigated Citrus trees is modulated by soil type and climate. AB - Water quality, soil and climate can interact to limit photosynthesis and to increase photooxidative damage in sensitive plants. This research compared diffusive and non-diffusive limitations to photosynthesis as well as photorespiration of leaves of grapefruit trees in heavy clay and sandy soils having a previous history of treated wastewater (TWW) irrigation for >10 years, with different water qualities [fresh water (FW) vs TWW and sodium amended treated wastewater (TWW + Na)] in two arid climates (summer vs winter) and in orchard and lysimeter experiments. TWW irrigation increased salts (Na(+) and Cl( ) ), membrane leakage, proline and soluble sugar content, and decreased osmotic potentials in leaves of all experiments. Reduced leaf growth and higher stomatal and non-stomatal (i.e. mesophyll) limitations were found in summer and on clay soil for TWW and TWW + Na treatments in comparison to winter, sandy soil and FW irrigation, respectively. Stomatal closure, lower chlorophyll content and altered Rubisco activity are probable causes of higher limitations. On the other hand, non-photochemical quenching, an alternative energy dissipation pathway, was only influenced by water quality, independent of soil type and season. Furthermore, light and CO2 response curves were investigated for other possible causes of higher non-stomatal limitation. A higher proportion of non-cyclic electrons were directed to the O2 dependent pathway, and a higher proportion of electrons were diverted to photorespiration in summer than in winter. In conclusion, both diffusive and non-diffusive limitations contribute to the lower photosynthetic performance of leaves following TWW irrigation, and the response depends on soil type and environmental factors. PMID- 26497167 TI - Corrigendum: apixaban for the treatment of Japanese subjects with acute venous thromboembolism (AMPLIFY-J Study). PMID- 26497168 TI - Corrigendum: augmentation index does not reflect risk of coronary artery disease in elderly patients. PMID- 26497171 TI - Lysyl oxidase modulates the osteoblast differentiation of primary mouse calvaria cells. AB - Lysyl oxidase (LOX) is an extracellular amine oxidase that mediates the formation of collagen fibers. Thus far, five LOX family genes [LOX, lysyl oxidase-like (LOXL)1, LOXL2, LOXL3 and LOXL4] have been identified in humans, each encoding the characteristic C-terminal domains that are required for amine oxidase activity. During osteoblastogenesis, collagen fibers function as a three dimensional scaffold for organizing mineral deposition. In this study, to assess the functional roles of the LOX family members in osteoblastogenesis, we investigated the temporal expression of these genes as a function of phenotypic development during the osteoblast differentiation of primary cultured mouse calvaria cells. Of the LOX family members, only LOX was prominently expressed during osteoblast differentiation. LOX expression was highest on day 9 of differentiation, as shown by RT-PCR and western blot analysis. The expression pattern of collagen, type I, alpha 2 (COL1A2), which encodes the alpha2-chain of mouse collagen type I, was similar to that of LOX. The total amine oxidase activity of the differentiating calvaria cells exhibited a temporal pattern that paralleled LOX expression, reaching the highest level on day 9 of differentiation. We also noted that the inhibition of the amine oxidase activity of LOX significantly suppressed both mineral nodule formation and the expression of osteoblast marker genes during the differentiation of primary calvaria cells. Taken together, these findings suggest that the LOX-mediated organization of collagen fibers in the extracellular matrix is an important regulator of osteoblastogenesis. PMID- 26497172 TI - Bioactive poly(ethylene glycol) hydrogels to recapitulate the HSC niche and facilitate HSC expansion in culture. AB - Hematopoietic stem cells (HSCs) have been used therapeutically for decades, yet their widespread clinical use is hampered by the inability to expand HSCs successfully in vitro. In culture, HSCs rapidly differentiate and lose their ability to self-renew. We hypothesize that by mimicking aspects of the bone marrow microenvironment in vitro we can better control the expansion and differentiation of these cells. In this work, derivatives of poly(ethylene glycol) diacrylate hydrogels were used as a culture substrate for hematopoietic stem and progenitor cell (HSPC) populations. Key HSC cytokines, stem cell factor (SCF) and interferon-gamma (IFNgamma), as well as the cell adhesion ligands RGDS and connecting segment 1 were covalently immobilized onto the surface of the hydrogels. With the use of SCF and IFNgamma, we observed significant expansion of HSPCs, ~97 and ~104 fold respectively, while maintaining c-kit(+) lin(-) and c kit(+) Sca1(+) lin(-) (KSL) populations and the ability to form multilineage colonies after 14 days. HSPCs were also encapsulated within degradable poly(ethylene glycol) hydrogels for three-dimensional culture. After expansion in hydrogels, ~60% of cells were c-kit(+), demonstrating no loss in the proportion of these cells over the 14 day culture period, and ~50% of colonies formed were multilineage, indicating that the cells retained their differentiation potential. The ability to tailor and use this system to support HSC growth could have implications on the future use of HSCs and other blood cell types in a clinical setting. PMID- 26497174 TI - Exploiting the genome sequence of Streptomyces nodosus for enhanced antibiotic production. AB - The genome of the amphotericin producer Streptomyces nodosus was sequenced. A single scaffold of 7,714,110 bp was obtained. Biosynthetic genes were identified for several natural products including polyketides, peptides, siderophores and terpenes. The majority of these clusters specified known compounds. Most were silent or expressed at low levels and unlikely to compete with amphotericin production. Biosynthesis of a skyllamycin analogue was activated by introducing expression plasmids containing either a gene for a LuxR transcriptional regulator or genes for synthesis of the acyl moiety of the lipopeptide. In an attempt to boost amphotericin production, genes for acyl CoA carboxylases, a phosphopantetheinyl transferase and the AmphRIV transcriptional activator were overexpressed, and the effects on yields were investigated. This study provides the groundwork for metabolic engineering of S. nodosus strains to produce high yields of amphotericin analogues. PMID- 26497173 TI - Atorvastatin protects endothelial colony-forming cells against H2O2-induced oxidative damage by regulating the expression of annexin A2. AB - Endothelial dysfunction and injury are central events in the pathogenesis of ischemic vascular disorders. Endothelial progenitor cells (EPCs) are mobilized from the bone marrow into the peripheral circulation, where they locate to sites of injured endothelium and are involved in endothelial repair and vascular regeneration. During these processes, EPCs are exposed to oxidative stress, a crucial pathological condition, which occurs during vascular injury and limits the efficacy of EPCs in the repair of injured endothelium. Statins are effective inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, and are commonly used to manage and prevent ischemic vascular disease by reducing plasma cholesterol levels. In addition to lowering cholesterol, statins have also been reported to exert pleiotropic actions, including anti-inflammatory and anti oxidative activities. The present study aimed to investigate the ability of atorvastatin to protect endothelial colony-forming cells (ECFCs), a homogeneous subtype of EPCs, from hydrogen peroxide (H2O2)-induced oxidative damage, and to determine the mechanism underlying this protective action. MTT assay, acridine orange/ethidium bromide staining, reactive oxygen species assay, western blot analysis and tube formation assay were employed. The results demonstrated that H2O2 induced cell death and decreased the tube-forming ability of the ECFCs, in a concentration-dependent manner; however, these effects were partially attenuated following administration of atorvastatin. The reversion of the quantitative and qualitative impairment of the H2O2-treated ECFCs appeared to be mediated by the regulation of annexin A2, as the expression levels of annexin A2 were decreased following treatment with H2O2 and increased following treatment with atorvastatin. These results indicated that annexin A2 may be involved in the H2O2 induced damage of ECFCs, and in the protective activities of atorvastatin in response to oxidative stress. PMID- 26497175 TI - Complete genome sequence of a distinct calla lily chlorotic spot virus isolated in mainland China. AB - The first complete genome sequence of calla lily chlorotic spot virus (CCSV) from Lijiang in northwestern Yunnan Province was obtained using RT-PCR with designed primers. The genome of CCSV isolate LJ-1-Yunnan is tripartite. The small (S) RNA is 3182 nucleotides (nt) in length and encodes a nonstructural protein (NSs, 1383 nt) and a nuclear nucleocapsid (N, 834 nt), separated by an 836-nt intergenic region (IGR). The medium (M) RNA is 4749 nt in length and encodes a nonstructural movement protein (NSm, 930 nt) and a glycoprotein (GnGc, 3,372 nt), also separated by a 349-nt IGR. The large (L) RNA is 8912 nt in length and encodes a predicted RNA-dependent RNA polymerase (RdRp, 8652 nt). The nucleotide sequences of the three viral RNA segments are 92-94 % identical to the published CCSV genome sequence, and the amino acid sequences of the encoded proteins are 96-98 % identical. However, the IGRs of the S and M RNAs are less similar, with 86 and 72 % identity, respectively. Genome sequence comparisons and phylogenetic analysis indicate that the Lijiang CCSV isolate is a unique tospovirus isolate that differs from CCSV isolates in other geographic regions. PMID- 26497176 TI - Complete genome sequence of the first bluetongue virus serotype 7 isolate from China: evidence for entry of African-lineage strains and reassortment between the introduced and native strains. AB - Bluetongue virus (BTV) mainly infects sheep but can be transmitted to other domestic and wild ruminants, resulting in a considerable financial burden and trade restriction. Our understanding of the origin, movement, and distribution of BTV has been hindered by the fact that this virus has a segmented genome with the possibility of reassortment, the existence of 27 identified serotypes, and a lack of complete sequences of viruses isolated from different parts of the world. BTV serotype 7 is one of the prevalent BTV serotypes in Asia. Nonetheless, no complete genomic sequence of an Asian isolate of this serotype is available. In an effort to understand the molecular epidemiology of BTV infection in China, for the first time, we report here the complete genome sequence of a BTV serotype 7 strain, GDST008, which was isolated in 2014 in China. This sequence also represents the first complete genome sequence of a BTV serotype 7 from Asia and the third one in the world. Sequence analysis suggests that GDST008 consists of segments from BTV viruses of African lineage as well as those from China. Together, these results improve our understanding of the origin, emergence/re emergence, and movement of BTV and thus can be applied in the development of vaccines and diagnostics. PMID- 26497177 TI - Productive HIV-1 infection is enriched in CD4(-)CD8(-) double negative (DN) T cells at pleural sites of dual infection with HIV and Mycobacterium tuberculosis. AB - A higher human immunodeficiency virus 1 (HIV-1) viral load at pleural sites infected with Mycobacterium tuberculosis (MTB) than in peripheral blood has been documented. However, the cellular source of productive HIV infection in HIV-1/MTB coinfected pleural fluid mononuclear cells (PFMCs) remains unclear. In this study, we observed significant quantities of HIV-1 p24(+) lymphocytes in PFMCs, but not in peripheral blood mononuclear cells (PBMCs). HIV-1 p24(+) lymphocytes were mostly enriched in DN T cells. Intracellular CD4 expression was detectable in HIV-1 p24(+) DN T cells. HIV-1 p24(+) DN T cells showed lower surface expression of human leukocyte antigen (HLA)-ABC and tetherin than did HIV-1 p24(+) CD4 T cells. Upon in vitro infection of PFMC CD4 T cells from TB mono infected subjects, Nef- and/or Vpu-deleted HIV mutants showed lower generation of HIV-1 p24(+) DN T cells than the wild-type virus. These data indicate that productively HIV-1-infected DN T cells, generated through down-modulation of surface CD4, likely by HIV-1 Nef and Vpu, are the predominant source of HIV-1 at pleural sites of HIV/MTB coinfection. PMID- 26497178 TI - Hepatitis C virus genotypes in Kenya. AB - Hepatitis C virus is a great public-health concern worldwide. Phylogenetic analysis of the HCV genome has identified six different genotypes that have generally been divided into several subtypes. There is very little information on HCV seroprevalence and genotypes in Kenya. To determine the genotypes of HCV circulating in Kenya, blood donor samples were serologically tested and confirmed by polymerase chain reaction (PCR). Positive samples were cloned and sequenced, and phylogenetic analysis conducted to determine the HCV genotypes. One hundred Murex-seropositive samples were re-tested using a passive hemagglutination test, and 16 of these were identified as seropositive. Further testing of all of the samples by PCR identified only 10 of the 16 samples as positive. Thus, only 10 % (10/100) of the samples were viremic. Six were from females (60 %), and four were from males (40 %). The mean age of the positive donors was considerably low, at 25 +/- 9 years. Genotypic testing indicated the presence of genotype 1a (10 %) and genotype 2b (90 %). This study reports on HCV genotypes in a blood donor population in Kenya where little had been done to provide information on HCV genotypes. PMID- 26497179 TI - Effect of equine herpesvirus type 1 (EHV-1) infection of nasal mucosa epithelial cells on integrin alpha 6 and on different components of the basement membrane. AB - The respiratory mucosa is the common port of entry of equine herpesvirus type 1 (EHV-1) and several other alphaherpesviruses. An important prerequisite for successful host invasion of the virus is to cross the epithelial cell layer and the underlying basement membrane barrier. In the present study, an analysis was performed to see if an EHV-1 infection of nasal mucosa epithelial cells leads to damage of the underlying extracellular matrix proteins. Nasal mucosa explants were inoculated with EHV-1 and collected at 0, 24 and 48 hours post-inoculation (hpi). Then, double immunofluorescence staining was performed to detect viral antigen-positive cells on the one hand and integrin alpha 6, laminin, collagen IV and collagen VII on the other hand. The area of these extracellular matrix proteins was measured in regions of interest (ROIs) at a magnification of 200X by means of the software imaging system ImageJ. ROIs were defined beneath uninfected and infected regions. In uninfected regions, 22-28 % of the ROI was stained for integrin alpha 6, 18-37 % for laminin, 14-38 % for collagen IV and 18-26 % for collagen VII. In infected regions, the percentage positive for integrin alpha 6 was significantly decreased to 0.1-9 % and 0.1-6 % after 24 and 48 hours of inoculation, respectively. Infection did not alter the percentages for laminin and collagen IV. For collagen VII, an increase in the percentage (from 18-26 % to 28-39 %) could be observed underneath EHV-1-infected plaques at 48 hours of inoculation. In conclusion, the results revealed a substantial impact of EHV-1 infection on integrin alpha 6 and collagen VII, two important components of the extracellular matrix, which are associated with the basement membrane and may facilitate virus penetration via hijacked leukocytes to underlying tissues. PMID- 26497180 TI - Expression of a synthetic rust fungal virus cDNA in yeast. AB - Mycoviruses are viruses that infect fungi. Recently, mycovirus-like RNAs were sequenced from the fungus Phakopsora pachyrhizi, the causal agent of soybean rust. One of the RNAs appeared to represent a novel mycovirus and was designated Phakopsora pachyrhizi virus 2383 (PpV2383). The genome of PpV2383 resembles Saccharomyces cerevisiae virus L-A, a double-stranded (ds) RNA mycovirus of yeast. PpV2383 encodes two major, overlapping open reading frames with similarity to gag (capsid protein) and pol (RNA-dependent RNA polymerase), and a -1 ribosomal frameshift is necessary for the translation of a gag-pol fusion protein. Phylogenetic analysis of pol relates PpV2383 to members of the family Totiviridae, including L-A. Because the obligate biotrophic nature of P. pachyrhizi makes it genetically intractable for in vivo analysis and because PpV2383 is similar to L-A, we synthesized a DNA clone of PpV2383 and tested its infectivity in yeast cells. PpV2383 RNA was successfully expressed in yeast, and mass spectrometry confirmed the translation of gag and gag-pol fusion proteins. There was, however, no production of PpV2383 dsRNA, the evidence of viral replication. Neither the presence of endogenous L-A nor the substitution of the 5' and 3' untranslated regions with those from L-A was sufficient to rescue replication of PpV2383. Nevertheless, the proof of transcription and translation from the clone in vivo are steps toward confirming that PpV2383 is a mycovirus. Further development of a surrogate biological system for the study of rust mycoviruses is necessary, and such research may facilitate biological control of rust diseases. PMID- 26497181 TI - A novel nonsegmented double-stranded RNA mycovirus identified in the phytopathogenic fungus Nigrospora oryzae shows similarity to partitivirus-like viruses. AB - Nigrospora oryzae is a pathogen that can infect plants of various species. Here, we report the isolation of a novel mycovirus from N. oryzae infecting rice, as well as the complete genome sequence and genomic organization of this virus, which we have named "Nigrospora oryzae nonsegmented RNA virus 1" (NoNRV1). The genome of NoNRV1 contained two non-overlapping open reading frames (ORF1 and ORF2) potentially encoding a protein with an unknown function in ORF1 and a putative RNA-dependent RNA polymerase (RdRp) in ORF2. Homology and phylogenetic analysis revealed that NoNRV1 was most similar to the Ustilaginoidea virens nonsegmented virus 1 (UvNV-1) and distantly related to members of the virus family Partitiviridae. It is proposed that NoNRV1, together with UvNV-1 and other related viruses, might represent a novel virus taxon of mycoviruses belonging to a partitivirus-like lineage. PMID- 26497182 TI - Impact of IL-8-251A/T gene polymorphism on severity of disease caused by enterovirus 71 infection. AB - The study was performed in EV71-infected patients, with 97 mild cases and 80 severe cases. IL-8251A/T genotypes were determined by the polymerase chain reaction restriction fragment length polymorphism technique. Severe cases had a significantly higher frequency of the IL8-251 AT and TT genotypes than mild cases (52.5 % vs. 49.5 % and 42.5 % vs. 30.9 %, respectively; p = 0.024). The frequency of IL-8-251T alleles among the severe cases was also significantly higher than that of mild cases (68.7 % vs. 55.7 %, OR = 1.8, 95 % CI = 1.1-2.7, p = 0.012). There were significant differences in gender, age, fever days, WBC, CRP and BG concentration, and IL-8 levels among genotypes of IL-8251A/T in EV71-infected patients, but there were no significant differences in ALT, AST, CK-MB and EV71 loads. These findings suggested that the IL-8-251T allele is associated with susceptibility to severe disease in Chinese patients infected with EV71. PMID- 26497183 TI - Percutaneous recanalization for hepatic vein-type Budd-Chiari syndrome: long-term patency and survival. AB - OBJECTIVE: To determine the long-term patency and survival of percutaneous recanalization for hepatic vein (HV)-type Budd-Chiari syndrome (BCS). METHODS: From March 2009 to November 2014, consecutive symptomatic HV-type BCS patients were treated by percutaneous recanalization in our centers. These patients underwent main HV (MHV) or accessory HV (AHV) recanalization. Data on patient characteristics, technical success, clinical success, long-term patency, and survival were collected and analyzed. RESULTS: During the enrolled periods, a total of 143 symptomatic HV-type BCS patients were treated by percutaneous recanalization in our centers. Technical success was achieved in 140 of 143 patients. One hundred eleven patients underwent MHV recanalization, and 29 underwent AHV recanalization. Clinical success was achieved in 136 of 140 patients. The mean MHV/AHV pressure decreased from 33.5 +/- 4.1 mmHg before treatment to 12.5 +/- 3.1 mmHg after treatment (p = 0.000). The 136 patients were followed for 7-75 months (mean 33.9 +/- 15.3 months). Twenty-eight patients experienced re-obstruction of MHV (n = 24) or AHV (n = 4) at 3 to 36 months (mean 18.0 +/- 11.5 months) after treatment. The cumulative 1-, 3-, and 6-year primary patency rates were 91.1, 77.4, and 74.0%, respectively. The cumulative 1-, 3-, and 6-year secondary patency rates were 97.0, 92.4, and 88.8%, respectively. The cumulative 1-, 3-, and 6-year survival rates were 97.7, 92.2, and 90.0%, respectively. CONCLUSION: Percutaneous recanalization can provide good long-term patency and survival in HV-type BCS patients. PMID- 26497185 TI - Species-specific differences in the role of L-type Ca2+ channels in the regulation of coronary arterial smooth muscle contraction. AB - The L-type calcium channel (LCC) plays a regulatory role in various physical and pathological processes. In the vasculature, LCCs mediate agonist-induced vascular smooth muscle contraction. However, whether LCC-mediated vessel responses to certain vasoconstrictors vary among species remains unclear. The coronary arteries were dissected from the hearts of rats and mice. Coronary arterial ring contraction was measured using the Multi Myograph system. High K+ (60 mM)-induced coronary artery contractions were stronger in rats than in mice, whereas CaCl2 induced contraction curves did not differ significantly between the two groups. Endothelin-1, U46619 (thromboxane A2 receptor agonist), and 5-hydroxytryptamine (5-HT) induced concentration-dependent vasoconstriction of coronary arterial rings in rats and mice. The vessel rings of mice were more sensitive to ET-1 and U46619 and less sensitive to 5-HT than those of rats. The LCC blocker nifedipine significantly inhibited coronary artery contractions induced by ET-1, U46619, and 5-HT. The inhibitory effect of 1 MUM nifedipine on ET-1- and 5-HT-induced coronary artery contractions was stronger in mice than in rats, whereas its effect on U46619-induced vessel contractions was weaker in mice than in rats. The 5-HT2A receptor and LCC mRNA levels were higher in the coronary arteries of rats than in those of mice, whereas the expressions of the ETA and TXA2 receptors and Orai1 mRNA levels were comparable between the two groups. LCC plays an important role in coronary arterial contraction. Rats and mice show different responses to vasoconstrictors and LCC blockers, suggesting that the coronary arteries of rats and mice have different biological characteristics. PMID- 26497184 TI - Ferulic acid ethyl ester diminished Complete Freund's Adjuvant-induced incapacitation through antioxidant and anti-inflammatory activity. AB - Ferulic acid ethyl ester (FAEE) is a derivate from ferulic acid which reportedly has antioxidant effect; however, its role on inflammation was unknown. In this study, we investigated the orally administered FAEE anti-inflammatory activity on experimental inflammation models and Complete Freund's Adjuvant (CFA)-induced arthritis in rats. CFA-induced arthritis has been evaluated by incapacitation model and radiographic knee joint records at different observation time. FAEE (po) reduced carrageenan-induced paw edema (p < 0.001) within the 1st to 5th hours at 50 and 100 mg/kg doses. FAEE 50 and 100 mg/kg, po inhibited leukocyte migration into air pouch model (p < 0.001), and myeloperoxidase, superoxide dismutase, and catalase activities (p < 0.001) increased total thiol concentration and decreased the TNF-alpha and IL-1beta concentrations, NO, and thiobarbituric acid reactive species. In the CFA-induced arthritis, FAEE 50 and 100 mg/kg significantly reduced the edema and the elevation paw time, a joint disability parameter, since second hour after arthritis induction (p < 0.001). FAEE presented rat joint protective activity in radiographic records (p < 0.001). The data suggest that the FAEE exerts anti-inflammatory activity by inhibiting leukocyte migration, oxidative stress reduction, and pro-inflammatory cytokines. PMID- 26497186 TI - Lack of effect of Z-butylidenephthalide on presynaptic N-type Ca2+ channels in isolated guinea-pig ileum. AB - Z-Butylidenephthalide (Bdph) was reported to more potently inhibit electrically induced twitch responses than acetylcholine-induced tonic contraction in isolated guinea-pig ileum (GPI). The aim of the present study was to investigate the inhibitory effects of Z-Bdph on Ca2+ and K+ channels on GPI. In Locke-Ringer's solution, both responses were isometrically recorded on a polygraph. Incubation of omega-conotoxin MVIIC, but not Z-Bdph, in the electrically stimulated GPI prior to adding omega-conotoxin GVIA, an irreversible blocker of N-type voltage dependent Ca2+ channels (VDCCs), protected the binding sites and resulted in the twitch responses reversible by washing, suggesting that Z-Bdph did not bind to the N-type VDCCs. Interestingly, we found Z-Bdph concentration dependently delayed the onsets of K+-induced twitch responses, suggesting that Z-Bdph may be a blocker of K+ channels to interfere extracellular K+ across through the pre junctional membrane of nerve ending in K+-free medium. Z-Bdph similar to nifedipine non-competitively inhibited cumulative ACh-induced phasic contractions, suggesting that Z-Bdph may bind to L-type of inositol-1,4,5 trisphosphate (IP3)-sensitive Ca2+ channels on the endoplasmic reticulum (ER) membrane. In the presence of verapamil, a L-type Ca2+ channel blocker or Z-Bdph, the twitch inhibitions by either were effectively reversed by exogenous Ca2+, suggesting that they may freely pass through pre-junctional N-type, but not L type which was blocked at least a part by either, of VDDCs open when each electrical coaxial stimulation (ECS) into intracellular space of cholinergic nerve terminal and trigger release of transmitters. In conclusion, results confirm that Z-Bdph more potently inhibits ECS-induced twitch responses than ACh induced PCs in GPI and suggest that this effect is not mediated by interaction with presynaptic N-type VDCCs. PMID- 26497188 TI - A model for the compressible, viscoelastic behavior of human amnion addressing tissue variability through a single parameter. AB - A viscoelastic, compressible model is proposed to rationalize the recently reported response of human amnion in multiaxial relaxation and creep experiments. The theory includes two viscoelastic contributions responsible for the short- and long-term time-dependent response of the material. These two contributions can be related to physical processes: water flow through the tissue and dissipative characteristics of the collagen fibers, respectively. An accurate agreement of the model with the mean tension and kinematic response of amnion in uniaxial relaxation tests was achieved. By variation of a single linear factor that accounts for the variability among tissue samples, the model provides very sound predictions not only of the uniaxial relaxation but also of the uniaxial creep and strip-biaxial relaxation behavior of individual samples. This suggests that a wide range of viscoelastic behaviors due to patient-specific variations in tissue composition can be represented by the model without the need of recalibration and parameter identification. PMID- 26497187 TI - Possible vasculoprotective role of linagliptin against sodium arsenite-induced vascular endothelial dysfunction. AB - Vascular endothelial dysfunction (VED) interrupts the integrity and function of endothelial lining through enhanced markers of oxidative stress and decrease endothelial nitric oxide synthase (eNOS) expression. The main aim of the present study has been designed to investigate the possible vasculoprotective role of linagliptin against sodium arsenite-induced VED. Sodium arsenite (1.5 mg/kg, i.p., 2 weeks) abrogated the acetylcholine-induced, endothelium-dependent vasorelaxation by depicting the decrease in serum nitrite/nitrate concentration, reduced glutathione level, and simultaneously enhance the thiobarbituric acid reactive substances (TBARS) level, superoxide level, and tumor necrosis factor alpha. These elevated markers interrupt the integrity of endothelial lining of thoracic aorta which was assessed histologically. The study elicits dose dependent effect of linagliptin (1.5 mg/kg, i.p. and 3 mg/kg, i.p.) or atorvastatin (30 mg/kg, p.o.) treatment, improved the endothelium-dependent independent relaxation, improve the integrity of endothelium lining which was assessed histologically by enhancing the serum nitrite/nitrate level, reduced glutathione level and simultaneously decreasing the TBARS level, superoxide anion level and tumor necrosis factor-alpha (TNF-alpha) level. L-NAME (25 mg/kg, i.p.), eNOS inhibitor, abrogated the ameliorative potential of linagliptin. However, the ameliorative potential of linagliptin has been enhanced by l-arginine (200 mg/kg, i.p.) which elicits that ameliorative potential of linagliptin was through eNOS signaling cascade and it may be concluded that linagliptin 3 mg/kg, i.p. has more significantly activated the eNOS and decreased the oxidative markers than linagliptin 1.5 mg/kg, i.p. and prevented sodium arsenite-induced VED. PMID- 26497189 TI - Chinese population exposure to triclosan and triclocarban as measured via human urine and nails. AB - Triclosan (TCS) and triclocarban (TCC) exposures are highly concerned due to their suspected endocrine-disrupting effects. The present study investigated TCS and TCC exposure levels in the general Chinese population by biomonitoring human urine and nail samples. TCS (69-80 %) and TCC (99-100 %) were frequently detected, which demonstrates that the general Chinese population has extensive exposure to these chemicals. The geometric mean (GM) urinary concentrations were 0.40 MUg/g creatinine (creat), 95 % confidence interval (CI) 0.30-0.56, for TCS and 0.40 MUg/g creat, 95 % CI 0.29-0.56, for TCC. On the other hand, the GM levels of TCS and TCC were 13.57 (5.67 MUg/kg) and 84.66 MUg/kg (41.50 MUg/kg) in fingernail (toenail) samples, respectively, indicating that the levels in fingernails were approximately twice as high as those in toenails. Pearson's correlation coefficients between the urine and fingernail (toenail) samples were 0.715 (0.614) for TCS and 0.829 (0.812) for TCC. These data suggest that nail samples can be applied to the biomonitoring for TCS and TCC in the general population. We observed that the levels of both chemicals were higher in females than in males for urine and fingernail samples, but no significant differences were found between different genders for either compound in toenails. Nineteen- to 29-year-olds had the highest TCS levels in their nail samples, whereas TCC levels did not differ with regard to age. Region of residence significantly influenced TCS and TCC concentrations in the three biological matrices measured. PMID- 26497190 TI - Modified Blumgart Suturing Technique for Remnant Closure After Distal Pancreatectomy: a Propensity Score-Matched Analysis. AB - Despite recent advances in surgical techniques including staple closure and ultrasonic devices, the reported incidence of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) remains high. Therefore, we devised a new strategy in which the pancreatic stump is enveloped with the elevated jejunum (EJ) by a modified Blumgart anastomotic technique. Eighty-one patients who underwent open DP with splenectomy from January 2008 to December 2014 were enrolled. Comparisons were made between 42 patients who underwent placement of an EJ patch using the modified Blumgart method after scalpel transection and 39 patients who underwent scalpel transection alone, using unmatched and propensity score-matched analysis. After 25 patients from each group were selected by propensity score matching, the EJ patch technique was significantly associated with a lower incidence of clinically relevant POPF (P = 0.036). Multivariate analysis showed that the EJ patch was an independent predictor of a lower incidence of POPF (odds ratio, 0.16; 95 % confidence interval, 0.01-0.48; P = 0.017) as was the estimated remnant pancreatic volume. Addition of the EJ patch improves postoperative outcomes in patients who undergo open DP with splenectomy by scalpel transection and hand-sewn closure of the pancreatic remnant. PMID- 26497191 TI - Conjoined Unification Venoplasty for Double Portal Vein Branches of Right Liver Graft: 1-Year Experience at a High-Volume Living Donor Liver Transplantation Center. AB - Autologous portal Y-graft (PYG) interposition has been regarded as the standard procedure for reconstruction of double portal vein (PV) orifices of right liver grafts during living donor liver transplantation, but it has the drawback of being vulnerable to functional PV stenosis. A refined technique of conjoined unification venoplasty (CUV) was developed to secure PV reconstruction. We reviewed the surgical experience on reconstruction of graft double PVs in 28 cases during a 1-year period of 2014. Computational simulation and modeling studies led us to develop CUV, which consists of placing a unification patch between two graft PV orifices and overlying the coverage with a crotch-opened autologous PYG, the shape of which provides a wide range of tolerance for alignment mismatching in PV anastomosis. During the 1-year study period, the numbers of patients using autologous PYG interposition, circumferential PV fencing with greater saphenous vein, homograft vein interposition, and CUV were 11, 3, 1, and 0, respectively, for 6 months before implementing CUV, and 5, 1, 1, and 6, respectively, for 6 months after implementing CUV. PV complications occurred in 2 of 16 patients with autologous PYG interposition, but no complications were observed in 12 patients operated on using other techniques including CUV. The drawback of conventional autologous PYG interposition can be overcome technically by CUV, which secures PV patency through hemodynamic compliant offset of anatomical discrepancy and anastomotic alignment mismatching. We believe that CUV could be a useful and effective technical option for reconstruction of right liver grafts with two graft PVs. PMID- 26497192 TI - The findings of Damas et al. have not influenced the previously proposed time course of skeletal muscle hypertrophy. PMID- 26497193 TI - What Is Known About the Benefits of Patient-Centered Care in Patients with Heart Failure. AB - Treatment for chronic heart failure (CHF) has improved, and symptom burden has been identified as an important treatment goal. Because patient-centered care may ease the burden, we need to know its benefits for patients with CHF, hence this systematic literature review. We found that one benefit of person-centered care is an increase in quality of life in patients with CHF. Improvements were found in self-care, physical and mental status, health care costs, general uncertainty regarding illness and recovery, patient dignity, treatment, and systems of care. Improvements also were observed in symptom burden, self-efficacy, and quality of life. These findings indicate that person-centered care is a powerful approach to current and future health care. However, because an appropriate tool to measure person-centered care does not yet exist, it will be a challenge to determine whether the goal has been reached from a long-term and patient perspective. PMID- 26497194 TI - Clinical significance of STAT3 and MAPK phosphorylation, and the protein expression of cyclin D1 in skin squamous cell carcinoma tissues. AB - The present study aimed to investigate the significance of the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK), and the protein expression of cyclin D1, in skin squamous cell carcinoma (SCC) tissues. SCC specimens from the skin were collected from 30 patients, and normal skin tissues were collected from 10 individuals as a control. Immunohistochemistry was used to assess the protein expression levels of phosphorylated (p-)STAT3, p-MAPK and cyclin D1 in the SCC tissues. The levels of p-STAT3 protein were abnormally increased in SCC (P<0.05); however, no significant differences in the protein expression of p-MAPK were identified between the normal skin and the SCC specimens. The extent of the upregulation of the expression of p-STAT3 and cyclin D1 correlated with the depth of tumor invasion (P<0.05). A positive correlation existed between the expression of p STAT3 and cyclin D1 in SCC. However, no association between the expression intensity of p-MAPK and cyclin D1 was identified in SCC. It is postulated that the activation of STAT3 may induce the overexpression of cyclin D1, which results in the persistent proliferation of these tumor cells in SCC. PMID- 26497195 TI - David Oliver: Is Lord Prior right about scrapping beds? PMID- 26497196 TI - Evaluation of risedronate as an antibiofilm agent. AB - Escherichia coli cra null mutants have been reported in the literature to be impaired in biofilm formation. To develop E. coli biofilm-inhibiting agents for prevention and control of adherent behaviour, analogues of a natural Cra ligand, fructose-1,6-bisphosphate, were identified based on two-dimensional similarity to the natural ligand. Of the analogues identified, those belonging to the bisphosphonate class of drug molecules were selected for study, as these are approved for clinical use in humans and their safety has been established. Computational and in vitro studies with purified Cra protein showed that risedronate sodium interacted with residues in the fructose-1,6-bisphosphate binding site. Using a quantitative biofilm assay, risedronate sodium, at a concentration of 300-400 MUM, was found to decrease E. coli and Salmonella pullorum biofilm formation by >60 %. Risedronate drastically reduced the adherence of E. coli cells to a rubber Foley urinary catheter, demonstrating its utility in preventing the formation of biofilm communities on medical implant surfaces. The use of risedronate, either alone or in combination with other agents, to prevent the formation of biofilms on surfaces is a novel finding that can easily be translated into practical applications. PMID- 26497197 TI - Prognostic significance of macrophage invasion in hilar cholangiocarcinoma. AB - BACKGROUND: Tumor-associated macrophages (TAMs) promote tumor progression and have an effect on survival in human cancer. However, little is known regarding their influence on tumor progression and prognosis in human hilar cholangiocarcinoma. METHODS: We analyzed surgically resected tumor specimens of hilar cholangiocarcinoma (n = 47) for distribution and localization of TAMs, as defined by expression of CD68. Abundance of TAMs was correlated with clinicopathologic characteristics, tumor recurrence and patients' survival. Statistical analysis was performed using SPSS software. RESULTS: Patients with high density of TAMs in tumor invasive front (TIF) showed significantly higher local and overall tumor recurrence (both rho < 0.05). Furthermore, high density of TAMs was associated with decreased overall (one-year 83.6% vs. 75.1%; three year 61.3% vs. 42.4%; both rho < 0.05) and recurrence-free survival (one-year 93.9% vs. 57.4%; three-year 59.8% vs. 26.2%; both rho < 0.05). TAMs in TIF and tumor recurrence, were confirmed as the only independent prognostic variables in the multivariate survival analysis (all rho < 0.05). CONCLUSIONS: Overall survival and recurrence free survival of patients with hilar cholangiocarcinoma significantly improved in patients with low levels of TAMs in the area of TIF, when compared to those with a high density of TAMs. These observations suggest their utilization as valuable prognostic markers in routine histopathologic evaluation, and might indicate future therapeutic approaches by targeting TAMs. PMID- 26497199 TI - Enhanced Gas-Sensing Properties of the Hierarchical TiO2 Hollow Microspheres with Exposed High-Energy {001} Crystal Facets. AB - Anatase hierarchical TiO2 with innovative designs (hollow microspheres with exposed high-energy {001} crystal facets, hollow microspheres without {001} crystal facets, and solid microspheres without {001} crystal facets) were synthesized via a one-pot hydrothermal method and characterized. Based on these materials, gas sensors were fabricated and used for gas-sensing tests. It was found that the sensor based on hierarchical TiO2 hollow microspheres with exposed high-energy {001} crystal facets exhibited enhanced acetone sensing properties compared to the sensors based on the other two materials due to the exposing of high-energy {001} crystal facets and special hierarchical hollow structure. First principle calculations were performed to illustrate the sensing mechanism, which suggested that the adsorption process of acetone molecule on TiO2 surface was spontaneous, and the adsorption on high-energy {001} crystal facets would be more stable than that on the normally exposed {101} crystal facets. Further characterization indicated that the {001} surface was highly reactive for the adsorption of active oxygen species, which was also responsible for the enhanced sensing performance. The present studies revealed the crystal-facets-dependent gas-sensing properties of TiO2 and provided a new insight into improving the gas sensing performance by designing hierarchical hollow structure with special crystal-facets exposure. PMID- 26497198 TI - Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome. AB - BACKGROUND: This report focuses on the adaptive phase I trial design aimed to find the clinically applicable dose for decitabine maintenance treatment after allogeneic hematopoietic stem cell transplantation in patients with higher-risk myelodysplastic syndrome and secondary acute myeloid leukemia. METHODS: The first cohort (three patients) was given the same initial daily dose of decitabine (5 mg/m(2)/day, five consecutive days with 4-week intervals). In all cohorts, the doses for Cycles 2 to 4 were individualized using pharmacokinetic-pharmacodynamic modeling and simulations. The goal of dose individualization was to determine the maximum dose for each patient at which the occurrence of grade 4 (CTC-AE) toxicities for both platelet and neutrophil counts could be avoided. The initial doses for the following cohorts were also estimated with the data from the previous cohorts in the same manner. RESULTS: In all but one patient (14 out of 15), neutrophil count was the dose-limiting factor throughout the cycles. In cycles where doses were individualized, the median neutrophil nadir observed was 1100/mm(3) (grade 2) and grade 4 toxicity occurred in 5.1 % of all cycles (while it occurred in 36.8 % where doses were not individualized). The initial doses estimated for cohorts 2 to 5 were 4, 5, 5.5, and 5 mg/m(2)/day, respectively. The median maintenance dose was 7 mg/m(2)/day. CONCLUSIONS: We determined the acceptable starting dose and individualized the maintenance dose for each patient, while minimizing the toxicity using the adaptive approach. Currently, 5 mg/m(2)/day is considered to be the most appropriate starting dose for the regimen studied. TRIAL REGISTRATION: Clinicaltrials.gov NCT01277484. PMID- 26497200 TI - Emotional suppression and depressive symptoms in women newly diagnosed with early breast cancer. AB - BACKGROUND: Patients with breast cancer usually present varying levels of depressive symptoms. Emotional suppression, as a coping style, refers to an individual's ability to consciously control expression of negative emotions. Thus, emotional suppression is an important psychological factor related to depressive symptoms in patients with breast cancer. It has long been considered that compared to European and American women, Chinese women are more likely to ascribe to norms of negative emotion control for smooth social interaction. However, there is paucity of research focusing on emotional suppression among Chinese women with breast cancer. Thus the aims of the current study were (1) to investigate the incidence of depressive symptoms in women newly diagnosed with early breast cancer in Mainland China, and (2) to examine the relationships between emotional suppression and depressive symptoms in these patients. METHODS: The Center for Epidemiological Studies Depression Scale (CES-D), the Beck Anxiety Inventory (BAI) and the Chinese version of the Courtauld Emotional Control Scale (CECS) were used to assess the level of depressive symptoms, anxiety symptoms and emotional suppression respectively in 247 women with early breast cancer and 362 healthy women. Analyses of variance were conducted to investigate group differences on depressive symptoms and emotional suppression. Bivariate correlations and Hierarchical regression analyses were performed to examine the effect of emotional suppression on depressive symptoms in participants after controlling the impact of group membership and anxiety level. RESULTS: (1) The incidence rates of clinical and severe depressive symptoms in patients were 36.4 and 36.0 % respectively. (2) Patients scored significantly higher than healthy women on CECS. (3) The scores on CECS were significantly associated with the total CES-D scores in all participants; Anger suppression significantly predicted the total CES-D scores. CONCLUSIONS: The majority of women newly diagnosed with early breast cancer reported clinical or severe depressive symptoms. As well, these patients presented a controlled emotion coping style. Emotional suppression was associated with the level of depressive symptoms in women newly diagnosed with breast cancer. Anger suppression might play a unique role in the depressive symptoms among women newly diagnosed with breast cancer. PMID- 26497201 TI - Dereplication, sequencing and identification of peptidic natural products: from genome mining to peptidogenomics to spectral networks. AB - Covering: 2000 to 2015. While recent breakthroughs in the discovery of peptide antibiotics and other Peptidic Natural Products (PNPs) raise a challenge for developing new algorithms for their analyses, the computational technologies for high-throughput PNP discovery are still lacking. We discuss the computational bottlenecks in analyzing PNPs and review recent advances in genome mining, peptidogenomics, and spectral networks that are now enabling the discovery of new PNPs via mass spectrometry. We further describe the connections between these advances and the new generation of software tools for PNP dereplication, de novo sequencing, and identification. PMID- 26497202 TI - Prophylactic oral/topical non-absorbed antifungal agents to prevent invasive fungal infection in very low birth weight infants. AB - BACKGROUND: Invasive fungal infection is an important cause of mortality and morbidity in very preterm or very low birth weight infants. Uncertainty exists about the effect of prophylactic oral/topical non-absorbed antifungals to reduce mucocutaneous colonisation and so limit the risk of invasive fungal infection in this population. OBJECTIVES: To assess the effect of prophylactic oral/topical non-absorbed antifungal therapy on the incidence of invasive fungal infection, mortality and morbidity in very preterm or very low birth weight infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL: The Cochrane Library, 2015, Issue 7), MEDLINE, EMBASE, and CINAHL (to May 2015), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled trials that compared the effect of prophylactic oral/topical non-absorbed antifungal therapy versus placebo or no drug or another antifungal agent or dose regimen in very preterm or very low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by two review authors. MAIN RESULTS: Four trials, in which a total of 1800 infants participated, compared oral/topical non-absorbed antifungal prophylaxis (nystatin or miconazole) with placebo or no drug. These trials had various methodological weaknesses including quasi-randomisation, lack of allocation concealment, and lack of blinding of intervention and outcomes assessment. The incidence of invasive fungal infection was very high in the control groups of three of these trials. Meta-analysis found a statistically significant reduction in the incidence of invasive fungal infection (typical risk ratio 0.20, 95% confidence interval 0.14 to 0.27; risk difference -0.18, -0.21 to -0.15) but substantial statistical heterogeneity was present. We did not find a statistically significant effect on mortality (typical risk ratio 0.87, 0.72 to 1.05; risk difference -0.03, -0.06 to 0.01). None of the trials assessed posthospital discharge outcomes. Three trials (N = 326) assessed the effect of oral/topical non-absorbed versus systemic antifungal prophylaxis. Meta-analyses did not find any statistically significant differences in the incidences of invasive fungal infection or all-cause mortality. AUTHORS' CONCLUSIONS: The finding of a reduction in risk of invasive fungal infection in very low birth weight infants treated with oral/topical non-absorbed antifungal prophylaxis should be interpreted cautiously because of methodological weaknesses in the included trials. Further large randomised controlled trials in current neonatal practice settings are needed to resolve this uncertainty. These trials might compare oral/topical non-absorbed antifungal agents with placebo, with each other, or with systemic antifungal agents and should include an assessment of effect on long-term neurodevelopmental outcomes. PMID- 26497203 TI - Diagnosis of skin cancer by correlation and complexity analyses of damaged DNA. AB - Skin cancer is a common, low-grade cancerous (malignant) growth of the skin. It starts from cells that begin as normal skin cells and transform into those with the potential to reproduce in an out-of-control manner. Cancer develops when DNA, the molecule found in cells that encodes genetic information, becomes damaged and the body cannot repair the damage. A DNA walk of a genome represents how the frequency of each nucleotide of a pairing nucleotide couple changes locally. In this research in order to diagnose the skin cancer, first DNA walk plots of genomes of patients with skin cancer were generated. Then, the data so obtained was checked for complexity by computing the fractal dimension. Furthermore, the Hurst exponent has been employed in order to study the correlation of damaged DNA. By analysing different samples it has been found that the damaged DNA sequences are exhibiting higher degree of complexity and less correlation compared to normal DNA sequences. This investigation confirms that this method can be used for diagnosis of skin cancer. The method discussed in this research is useful not only for diagnosis of skin cancer but can be applied for diagnosis and growth analysis of different types of cancers. PMID- 26497204 TI - EBV-miR-BART10-3p facilitates epithelial-mesenchymal transition and promotes metastasis of nasopharyngeal carcinoma by targeting BTRC. AB - Epstein-Barr virus (EBV) infection is closely associated with tumorigenesis and development of nasopharyngeal carcinoma (NPC), but the underlying molecular mechanisms remain poorly understood. It has been recently reported that EBV encodes 44 mature miRNAs, some of which were found to promote tumor development by targeting virus-infected host genes or self-viral genes. However, few targets of EBV encoded-miRNAs that are related to NPC development have been identified to date. In this study, we revealed that in NPC cells, EBV-miR-BART10-3p directly targets BTRC gene that encodes betaTrCP (beta-transducin repeat containing E3 ubiquitin protein ligase). We found that EBV-miR-BART10-3p expression in clinical samples from a cohort of 106 NPC patients negatively correlated with BTRC expression levels. Over-expression of EBV-miR-BART10-3p and down-regulation of BTRC were associated with poor prognosis in NPC patients. EBV-miR-BART10-3p promoted the invasion and migration cabilities of NPC cells through the targeting of BTRC and regulation of the expression of the downstream substrates beta catenin and Snail. As a result, EBV-miR-BART10-3p facilitated epithelial mesenchymal transition of NPC. Our study presents an unreported mechanism underlying EBV infection in NPC carcinogenesis, and provides a potential novel biomarker for NPC diagnosis, treatment and prognosis. PMID- 26497205 TI - Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-beta signaling pathway. AB - Interstitial lung disease (ILD) is a serious side-effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Therefore, it is necessary to study underlying mechanisms for the development of pulmonary fibrosis induced by EGFR-TKI and potential approaches to attenuate it. Metformin is a well-established and widely prescribed oral hypoglycemic drug, and has gained attention for its potential anticancer effects. Recent reports have also demonstrated its role in inhibiting epithelial-mesenchymal transition and fibrosis. However, it is unknown whether metformin attenuates EGFR-TKI-induced pulmonary fibrosis. The effect of metformin on EGFR-TKI-induced exacerbation of pulmonary fibrosis was examined in vitro and in vivo using MTT, Ki67 incorporation assay, flow cytometry, immunostaining, Western blot analysis, and a bleomycin-induced pulmonary fibrosis rat model. We found that in lung HFL-1 fibroblast cells, TGF-beta or conditioned medium from TKI-treated lung cancer PC 9 cells or conditioned medium from TKI-resistant PC-9GR cells, induced significant fibrosis, as shown by increased expression of Collegen1a1 and alpha actin, while metformin inhibited expression of fibrosis markers. Moreover, metformin decreased activation of TGF-beta signaling as shown by decreased expression of pSMAD2 and pSMAD3. In vivo, oral administration of gefitinib exacerbated bleomycin-induced pulmonary fibrosis in rats, as demonstrated by HE staining and Masson staining. Significantly, oral co-administration of metformin suppressed exacerbation of bleomycin-induced pulmonary fibrosis by gefitinib. We have shown that metformin attenuates gefitinib-induced exacerbation of TGF-beta or bleomycin-induced pulmonary fibrosis. These observations indicate metformin may be combined with EGFR-TKI to treat NSCLC patients. PMID- 26497206 TI - A prognostic classifier for patients with colorectal cancer liver metastasis, based on AURKA, PTGS2 and MMP9. AB - BACKGROUND: Prognosis of patients with colorectal cancer liver metastasis (CRCLM) is estimated based on clinicopathological models. Stratifying patients based on tumor biology may have additional value. METHODS: Tissue micro-arrays (TMAs), containing resected CRCLM and corresponding primary tumors from a multi institutional cohort of 507 patients, were immunohistochemically stained for 18 candidate biomarkers. Cross-validated hazard rate ratios (HRRs) for overall survival (OS) and the proportion of HRRs with opposite effect (P(HRR < 1) or P(HRR > 1)) were calculated. A classifier was constructed by classification and regression tree (CART) analysis and its prognostic value determined by permutation analysis. Correlations between protein expression in primary tumor CRCLM pairs were calculated. RESULTS: Based on their putative prognostic value, EGFR (P(HRR < 1) = .02), AURKA (P(HRR < 1) = .02), VEGFA (P(HRR < 1) = .02), PTGS2 (P(HRR < 1) = .01), SLC2A1 (P(HRR > 1) < 01), HIF1alpha (P(HRR > 1) = .06), KCNQ1 (P(HRR > 1) = .09), CEA (P (HRR > 1) = .05) and MMP9 (P(HRR < 1) = .07) were included in the CART analysis (n = 201). The resulting classifier was based on AURKA, PTGS2 and MMP9 expression and was associated with OS (HRR 2.79, p < .001), also after multivariate analysis (HRR 3.57, p < .001). The prognostic value of the biomarker-based classifier was superior to the clinicopathological model (p = .001). Prognostic value was highest for colon cancer patients (HRR 5.71, p < .001) and patients not treated with systemic therapy (HRR 3.48, p < .01). Classification based on protein expression in primary tumors could be based on AURKA expression only (HRR 2.59, p = .04). CONCLUSION: A classifier was generated for patients with CRCLM with improved prognostic value compared to the standard clinicopathological prognostic parameters, which may aid selection of patients who may benefit from adjuvant systemic therapy. PMID- 26497207 TI - Liposomal doxorubicin for active targeting: surface modification of the nanocarrier evaluated in vitro and in vivo: challenges and prospects. AB - Due to the inability of classical chemotherapeutic agents to exclusively target tumor cells, these treatments are associated with severe toxicity profiles. Thus, long-circulating liposomes have been developed in the past to enhance accumulation in tumor tissue by passive targeting. Accordingly, commercially available liposomal formulations of sterically stabilized liposomal doxorubicin (Caelyx, Doxil, Lipodox) are associated with improved off-target profiles. However, these preparations are still not capable to selectively bind to target cells. Thus, in an attempt to further optimize existing treatment schemes immunoliposomes have been established to enable active targeting of tumor tissues. Recently, we have provided evidence for therapeutic efficacy of anti IGF1R-targeted, surface modified doxorubicin loaded liposomes. Our approach involved a technique, which allows specific post-modifications of the liposomal surface by primed antibody-anchor conjugates thereby facilitating personalized approaches of commercially available liposomal drugs. In the current study, post modification of sterically stabilized liposomal Dox was thoroughly investigated including the influence of different modification techniques (PIT, SPIT, SPIT60), lipid composition (SPC/Chol, HSPC/Chol), and buffers (HBS, SH). As earlier in vivo experiments did not take into account the presence of non-integrated ab anchor conjugates this was included in the present study. Our experiments provide evidence that post-modification of commercially available liposomal preparations for active targeting is possible. Moreover, lyophilisation represents an applicable method to obtain a storable precursor of surface modifying antibody anchor conjugates. Thus, these findings open up new approaches in patient individualized targeting of chemotherapeutic therapies. PMID- 26497208 TI - Dysregulated expression of cell surface glycoprotein CDCP1 in prostate cancer. AB - CUB-domain-containing protein 1 (CDCP1) is a trans-membrane protein regulator of cell adhesion with a potent pro-migratory function in tumors. Given that proteolytic cleavage of the ectodomain correlates with outside-in oncogenic signaling, we characterized glycosylation in the context of cellular processing and expression of CDCP1 in prostate cancer. We detected 135 kDa full-length and proteolytic processed 70 kDa species in a panel of PCa cell models. The relative expression of full-length CDCP1 correlated with the metastatic potential of syngeneic cell models and an increase in surface membrane expression of CDCP1 was observed in tumor compared to adjacent normal prostate tissues. We demonstrated that glycosylation of CDCP1 is a prerequisite for protein stability and plasma membrane localization, and that the expression level and extent of N glycosylation of CDCP1 correlated with metastatic status. Interestingly, complex N-linked glycans with sialic acid chains were restricted to the N-terminal half of the ectodomain and absent in the truncated species. Characterization of the extracellular expression of CDCP1 identified novel circulating forms and revealed that extracellular vesicles provide additional processing pathways. Employing immunoaffinity mass spectrometry, we detected elevated levels of circulating CDCP1 in patient urine with high-risk disease. Our results establish that differential glycosylation, cell surface presentation and extracellular expression of CDCP1 are hallmarks of PCa progression. PMID- 26497209 TI - Characterization of novel biomarkers in selecting for subtype specific medulloblastoma phenotypes. AB - Major research efforts have focused on defining cell surface marker profiles for characterization and selection of brain tumor stem/progenitor cells. Medulloblastoma is the most common primary malignant pediatric brain cancer and consists of 4 molecular subgroups: WNT, SHH, Group 3 and Group 4. Given the heterogeneity within and between medulloblastoma variants, surface marker profiles may be subtype-specific. Here, we employed a high throughput flow cytometry screen to identify differentially expressed cell surface markers in self-renewing vs. non-self-renewing SHH medulloblastoma cells. The top 25 markers were reduced to 4, CD271/p75NTR/NGFR, CD106/VCAM1, EGFR and CD171/NCAM-L1, by evaluating transcript levels in SHH tumors relative to samples representing the other variants. However, only CD271/p75NTR/NGFR and CD171/NCAM-L1 maintain differential expression between variants at the protein level. Functional characterization of CD271, a low affinity neurotrophin receptor, in cell lines and primary cultures suggested that CD271 selects for lower self-renewing progenitors or stem cells. Moreover, CD271 levels were negatively correlated with expression of SHH pathway genes. Our study reveals a novel role for CD271 in SHH medulloblastoma and suggests that targeting CD271 pathways could lead to the design of more selective therapies that lessen the broad impact of current treatments on developing nervous systems. PMID- 26497210 TI - EZH2 in normal hematopoiesis and hematological malignancies. AB - Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies. PMID- 26497212 TI - GDF15 promotes EMT and metastasis in colorectal cancer. AB - Metastasis is the major cause of cancer deaths, and the epithelial-mesenchymal transition (EMT) has been considered to be a fundamental event in cancer metastasis. However, the role of growth differentiation factor 15 (GDF15) in colorectal cancer (CRC) metastasis and EMT remains poorly understood. Here, we showed that GDF15 promoted CRC cell metastasis both in vitro and in vivo. In addition, the EMT process was enhanced by GDF15 through binding to TGF-beta receptor to activate Smad2 and Smad3 pathways. Clinical data showed GDF15 level in tumor tissues, and the serum was significantly increased, in which high GDF15 level correlated with a reduced overall survival in CRC. Thus, GDF15 may promote colorectal cancer metastasis through activating EMT. Promisingly, GDF15 could be considered as a novel prognostic marker for CRC in the clinic. PMID- 26497211 TI - Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro. AB - Clinical studies propose a causative link between the consumption of alcohol and the development and progression of liver disease in obese individuals. However, it is incompletely understood how alcohol and obesity interact and whether the combined effects are additive or synergistic. In this study, we developed an in vitro model to address this question. Lipid accumulation in primary human hepatocytes was induced by incubation with oleic acid. Subsequently, steatotic and control hepatocytes were incubated with up to 50 mM alcohol. This alcohol concentration on its own revealed only minimal effects but significantly enhanced oleate-induced lipogenesis and cellular triglyceride content compared to control cells. Similarly, lipid peroxidation, oxidative stress and pro-inflammatory gene expression as well as CYP2E1 levels and activity were synergistically induced by alcohol and steatosis. CYP2E1 inhibition blunted these synergistic pathological effects. Notably, alcohol and cellular steatosis also induced autophagy in a synergistic manner, and also this was mediated via CYP2E1. Further induction of autophagy ameliorated the joint effects of alcohol and oleic acid on hepatocellular lipid accumulation and inflammatory gene expression while inhibition of autophagy further enhanced the dual pathological effects. Further analyses revealed that the joint synergistic effect of alcohol and steatosis on autophagy was mediated via activation of the JNK-pathway. In summary, our data indicate that alcohol induces not only pathological but also protective mechanisms in steatotic hepatocytes via CYP2E1. These findings may have important implications on the prognosis and treatment of alcoholic liver disease particularly in obese individuals. PMID- 26497213 TI - Aurora B kinase is a potent and selective target in MYCN-driven neuroblastoma. AB - Despite advances in multimodal treatment, neuroblastoma (NB) is often fatal for children with high-risk disease and many survivors need to cope with long-term side effects from high-dose chemotherapy and radiation. To identify new therapeutic targets, we performed an siRNA screen of the druggable genome combined with a small molecule screen of 465 compounds targeting 39 different mechanisms of actions in four NB cell lines. We identified 58 genes as targets, including AURKB, in at least one cell line. In the drug screen, aurora kinase inhibitors (nine molecules) and in particular the AURKB-selective compound, barasertib, were the most discriminatory with regard to sensitivity for MYCN amplified cell lines. In an expanded panel of ten NB cell lines, those with MYCN amplification and wild-type TP53 were the most sensitive to low nanomolar concentrations of barasertib. Inhibition of the AURKB kinase activity resulted in decreased phosphorylation of the known target, histone H3, and upregulation of TP53 in MYCN-amplified, TP53 wild-type cells. However, both wild-type and TP53 mutant MYCN-amplified cell lines arrested in G2/M phase upon AURKB inhibition. Additionally, barasertib induced endoreduplication and apoptosis. Treatment of MYCN-amplified/TP53 wild-type neuroblastoma xenografts resulted in profound growth inhibition and tumor regression. Therefore, aurora B kinase inhibition is highly effective in aggressive neuroblastoma and warrants further investigation in clinical trials. PMID- 26497214 TI - CCN: core regulatory proteins in the microenvironment that affect the metastasis of hepatocellular carcinoma? AB - Hepatocellular carcinoma (HCC) results from an underlying chronic liver inflammatory disease, such as chronic hepatitis B or C virus infections, and the general prognosis of patients with HCC still remains extremely dismal because of the high frequency of HCC metastases. Throughout the process of tumor metastasis, tumor cells constantly communicate with the surrounding microenvironment and improve their malignant phenotype. Therefore, there is a strong rationale for targeting the tumor microenvironment as primary treatment of HCC therapies. Recently, CCN family proteins have emerged as localized multitasking signal integrators in the inflammatory microenvironment. In this review, we summarize the current knowledge of CCN family proteins in inflammation and the tumor. We also propose that the CCN family proteins may play a central role in signaling the tumor microenvironment and regulating the metastasis of HCC. PMID- 26497215 TI - Tumor-associated fibroblast-conditioned medium induces CDDP resistance in HNSCC cells. AB - OBJECTIVE: EMT (epithelial to mesenchymal transition) contributes to tumor progression and metastasis. We aimed to investigate the effects of EMT on CDDP resistance in HNSCC (head and neck squamous cell carcinoma)-cells. METHODS: EMT was induced using conditioned medium from a tumor cell/fibroblast co-culture. HNSCC cells were alternatively treated with TGF-beta1. The response to CDDP was evaluated with viability and clonogenic assays. RESULTS: Treatment of SCC-25/ Detroit 562 cells with conditioned medium increased viability of the tumor cells. Moreover, it doubled the IC50 of CDDP of SCC-25 cells from 6.2 MUM to 13.1 MUM (p < 0.001). The IC50 of CDDP of Detroit 562 cells was increased following treatment with conditioned medium from 13.1 MUM to 26.8 MUM (p < 0.01). Colony forming ability after treatment with 5 or 10 MUM CDDP was significantly higher in HNSCC cells treated with co-culture conditioned medium than in controls (p < 0.05). Treatment with TGF-beta1 had no effect on the IC50 of CDDP (p > 0.1). CONCLUSIONS: Cell free medium from a co-culture was able to induce EMT in HNSCC cells. Co-culture treated HNSCC cells revealed increased viability and were less sensitive to CDDP treatment. TGF-beta1 also induced a mesenchymal phenotype, but did not alter resistance to CDDP in HNSCC cells. PMID- 26497216 TI - HAG regimen improves survival in adult patients with hypocellular acute myeloid leukemia. AB - BACKGROUND: Hypocellular acute myeloid leukemia (Hypo-AML) is a rare disease entity. Studies investigating the biological characteristics of hypo-AML have been largely lacking. We examined the clinical and biological characteristics, as well as treatment outcomes of hypo-AML in our institutes over a seven years period. DESIGN AND METHODS: We retrospectively analyzed data on 631 adult AML patients diagnosed according to the French-American-British (FAB) classification and WHO classification of tumors of haematopoietic and lymphoid tissue, including 43 patients with hypo-AML. Biological variables, treatment outcomes and follow-up data on hypo-AML patients were analyzed. RESULTS: Out of 631 AML patients, 47 (7.4%) were diagnosed as hypo-AML, out of which 43 patients were evaluable. Compared with non-hypocellular AML, hypo-AML patients tended to be older (P = 0.05), more likely to present with leukocytopenia (P < 0.01) and anterior hematological diseases (P = 0.02). The overall complete remission (CR) rate, disease free survival (DFS), and overall survival (OS) in hypo-AML patients were comparable to those in non-hypo AML patients. Twenty-seven (62.8%) patients with hypocellular AML were treated with the standard regimen of anthracyclines and cytarabine (XA) (associated CR rate: 51.9%; median OS: 7 months; median DFS: 6.5 months). Sixteen (37.2%) patients were treated with a priming regimen containing homoharringtonine, cytarabine and G-CSF (HAG) (associated CR rate: 81.25%; median OS: 16 months; median DFS: 16 months). CONCLUSIONS: The overall prognosis of hypo AML was not inferior to that of non-hypo AML. HAG regimen might increase response rates and improve survival in hypo-AML patients. PMID- 26497217 TI - Linking estrogen receptor beta expression with inflammatory bowel disease activity. AB - Crohn disease (CD) and ulcerative colitis (UC) are chronic forms of inflammatory bowel disease (IBD) whose pathogenesis is only poorly understood. Estrogens have a complex role in inflammation and growing evidence suggests that these hormones may impact IBD pathogenesis. Here, we demonstrated a significant reduction (p < 0.05) of estrogen receptor (ER)beta expression in peripheral blood T lymphocytes from CD/UC patients with active disease (n = 27) as compared to those in remission (n = 21) and healthy controls (n = 29). Accordingly, in a subgroup of CD/UC patients undergoing to anti-TNF-alpha therapy and responsive to treatment, ERbeta expression was higher (p < 0.01) than that observed in not responsive patients and comparable to that of control subjects. Notably, ERbeta expression was markedly decreased in colonic mucosa of CD/UC patients with active disease, reflecting the alterations observed in peripheral blood T cells. ERbeta expression inversely correlated with interleukin (IL)-6 serum levels and exogenous exposure of both T lymphocytes and intestinal epithelial cells to this cytokine resulted in ERbeta downregulation. These results demonstrate that the ER profile is altered in active IBD patients at both mucosal and systemic levels, at least in part due to IL-6 dysregulation, and highlight the potential exploitation of T cell-associated ERbeta as a biomarker of endoscopic disease activity. PMID- 26497219 TI - Elucidating the band structure and free charge carrier dynamics of pure and impurities doped CH3NH3PbI(3-x)Cl(x) perovskite thin films. AB - CH3NH3PbI3-xClx perovskite material has been commonly used as the free charge generator and reservoir in highly efficient perovskite-based solid-state solar photovoltaic devices. However, many of the underlying fundamental photophysical mechanisms in this material such as the perovskite transition band structure as well as the dependent relationship between the carrier properties and lattice properties still lack sufficient understanding. Here, we elucidated the fundamental band structure of the pure CH3NH3PbI3-xClx pervoskite lattice, and then reported about the dependent relationship between the free charge carrier characteristic and the different CH3NH3PbI3-xClx pervoskite lattice thin films utilizing femtosecond time-resolved pump-probe technologies. The data demonstrated that the pure perovskite crystal band structure should only have one conduction and one valence band rather than dual valences, and the pure perovskite lattice could trigger more free charge carriers with a slower recombination rate under an identical pump intensity compared with the impurities doped perovskite crystal. We also investigated the perovskite film performance when exposed to moisture and water, the corresponding results gave us a dip in the optimization of the performance of perovskite based devices, and so as a priority this material should be isolated from moisture (water). This work may propose a deeper perspective on the comprehension for this material and it is useful for future optimization of applications in photovoltaic and light emission devices. PMID- 26497218 TI - Effectiveness of a brief psychoeducational group intervention for relatives on the course of disease in patients after inpatient depression treatment compared with treatment as usual--study protocol of a multisite randomised controlled trial. AB - BACKGROUND: Relapses and rehospitalisations are common after acute inpatient treatment in depressive disorders. Interventions for stabilising treatment outcomes are urgently needed. Psychoeducational group interventions for relatives were shown to be suitable for improving the course of disease in schizophrenia and bipolar disorders. A small Japanese monocentre randomised controlled trial also showed promising results for depressive disorders. However, the evidence regarding psychoeducation for relatives of patients with depressive disorders is unclear. METHODS/DESIGN: The study is conducted as a two-arm multisite randomised controlled trial to evaluate the incremental effect of a brief psychoeducational group intervention for relatives as a maintenance treatment on the course of disease compared to treatment as usual. Primary outcome is the estimated number of depression-free-days in patients within one year after discharge from inpatient treatment. 180 patients diagnosed with unipolar depressive disorders as well as one key relative per patient will be included during inpatient treatment and randomly allocated to the conditions at discharge. In the intervention group, relatives will participate in a brief psychoeducational group intervention following the patient's discharge. The intervention consists of four group sessions lasting 90 to 120 min each. Every group session contains informational parts as well as structured training in problem-solving. In both study conditions, patients will receive treatment as usual. Patients as well as relatives will be surveyed by means of questionnaires at discharge and three, six, nine and twelve months after discharge. In addition to the primary outcome, several patient-related and relative-related secondary outcomes will be considered and health economics will be investigated. DISCUSSION: Our study will provide evidence on the incremental effect of a brief psychoeducational intervention for relatives as a maintenance treatment after inpatient depression treatment. Positive results may have a major impact on health care for depression. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00006819; Trial registration date: 2014 Oktober 31; Universal Trial Number (UTN): U1111-1163-5391. PMID- 26497220 TI - Analysis of zebrafish (Danio rerio) behavior in response to bacterial infection using a self-organizing map. AB - BACKGROUND: Animal behavioral responses have been recently established as a suitable tool for detecting contaminants in the environment for risk assessment in situ. In this study, we observed movement behavior of zebrafish (Danio rerio) before and after infection with Edwardsiella tarda CK41 for 3 days until death. METHODS: Infection status of zebrafish was confirmed through PCR and colonization assay as time progressed and lesion development in the tails of zebrafish was also examined. Movement behaviors in response to bacterial infection were patterned by self-organizing map (SOM) based on movement parameters, including speed (mm/s), acceleration (mm/s (2) ), stop duration (t), stop number (n), locomotory rate (mm/s), turning rate (rad/s), and meander (rad/mm). RESULTS: According to SOM result, clusters were identified firstly according to time and secondly according to infection. Two movement patterns were observed in the early period of infection: one group with minimum turning rate and meander (i.e., stiff movement) and the other group with maximum strop number. Late infection was characterized by long stop duration. CONCLUSION: SOM was suitable for extracting complex behavioral data and thus can serve as a referencing system for diagnosing disease development in order to reveal the mechanism of the infection process. PMID- 26497221 TI - Rh-Catalyzed Asymmetric Hydrogenation of Cyclic alpha-Dehydroamino Ketones. AB - Catalyzed by a rhodium complex of P-stereogenic diphosphine trichickenfootphos, five-membered cyclic alpha-dehydroamino ketones bearing endocyclic acyl and endocyclic vinyl groups were hydrogenated to give chiral alpha-amino ketones with quantitative conversions and excellent enantioselectivities. PMID- 26497222 TI - The molecular characterisation of Escherichia coli K1 isolated from neonatal nasogastric feeding tubes. AB - BACKGROUND: The most common cause of Gram-negative bacterial neonatal meningitis is E. coli K1. It has a mortality rate of 10-15 %, and neurological sequelae in 30-50 % of cases. Infections can be attributable to nosocomial sources, however the pre-colonisation of enteral feeding tubes has not been considered as a specific risk factor. METHODS: Thirty E. coli strains, which had been isolated in an earlier study, from the residual lumen liquid and biofilms of neonatal nasogastric feeding tubes were genotyped using pulsed-field gel electrophoresis, and 7-loci multilocus sequence typing. Potential pathogenicity and biofilm associated traits were determined using specific PCR probes, genome analysis, and in vitro tissue culture assays. RESULTS: The E. coli strains clustered into five pulsotypes, which were genotyped as sequence types (ST) 95, 73, 127, 394 and 2076 (Achman scheme). The extra-intestinal pathogenic E. coli (ExPEC) phylogenetic group B2 ST95 serotype O1:K1:NM strains had been isolated over a 2 week period from 11 neonates who were on different feeding regimes. The E. coli K1 ST95 strains encoded for various virulence traits associated with neonatal meningitis and extracellular matrix formation. These strains attached and invaded intestinal, and both human and rat brain cell lines, and persisted for 48 h in U937 macrophages. E. coli STs 73, 394 and 2076 also persisted in macrophages and invaded Caco-2 and human brain cells, but only ST394 invaded rat brain cells. E. coli ST127 was notable as it did not invade any cell lines. CONCLUSIONS: Routes by which E. coli K1 can be disseminated within a neonatal intensive care unit are uncertain, however the colonisation of neonatal enteral feeding tubes may be one reservoir source which could constitute a serious health risk to neonates following ingestion. PMID- 26497223 TI - Screening and Identifying a Novel ssDNA Aptamer against Alpha-fetoprotein Using CE-SELEX. AB - Alpha-fetoprotein (AFP) is a liver cancer associated protein and has long been utilized as a serum tumor biomarker of disease progression. AFP is usually detected in HCC patients by an antibody based system. Recently, however, aptamers generated from systematic evolution of ligands by exponential enrichment (SELEX) were reported to have an alternative potential in targeted imaging, diagnosis and therapy. In this study, AFP-bound ssDNA aptamers were screened and identified using capillary electrophoresis (CE) SELEX technology. After cloning, sequencing and motif analysis, we successfully confirmed an aptamer, named AP273, specifically targeting AFP. The aptamer could be used as a probe in AFP immunofluorescence imaging in HepG2, one AFP positive cancer cell line, but not in A549, an AFP negative cancer cell line. More interesting, the aptamer efficiently inhibited the migration and invasion of HCC cells after in vivo transfection. Motif analysis revealed that AP273 had several stable secondary motifs in its structure. Our results indicate that CE-SELEX technology is an efficient method to screen specific protein-bound ssDNA, and AP273 could be used as an agent in AFP-based staining, diagnosis and therapy, although more works are still needed. PMID- 26497224 TI - Development and External Validation of Nomograms for Predicting Survival in Nasopharyngeal Carcinoma Patients after Definitive Radiotherapy. AB - The distant metastasis free survival (DMFS) and overall survival (OS) differ significantly among individuals even within the same clinical stages. The purpose of this retrospective study was to build nomograms incorporating plasma EBV DNA for predicting DMFS and OS of nasopharyngeal carcinoma (NPC) patients after definitive radiotherapy. A total of 1168 non-metastatic NPC patients from two institutions were included to develop the nomograms. Seven and six independent prognostic factors were identified to build the nomograms for OS and DMFS, respectively. The models were externally validated by a separate cohort of 756 NPC patients from the third institutions. For predicting OS, the c-index of the nomogram was significantly better than that of the TNM staging system (Training cohort, P = 0.005; validation cohort, P = 0.03). The c-index of nomogram for DMFS in the training and validation set were both higher than that of TNM classification with marginal significance (P = 0.048 and P = 0.057, respectively). The probability of 1-, 3-, and 5-year OS and DMFS showed optimal agreement between nomogram prediction and actual observation. The proposed stratification of risk groups based on the nomograms allowed significant distinction between Kaplan-Meier curves for survival outcomes. The prognostic nomograms could better stratify patients into different risk groups. PMID- 26497225 TI - Natural supramolecular protein assemblies. AB - Supramolecular protein assemblies are an emerging area within the chemical sciences, which combine the topological structures of the field of supramolecular chemistry and the state-of-the-art chemical biology approaches to unravel the formation and function of protein assemblies. Recent chemical and biological studies on natural multimeric protein structures, including fibers, rings, tubes, catenanes, knots, and cages, have shown that the quaternary structures of proteins are a prerequisite for their highly specific biological functions. In this review, we illustrate that a striking structural diversity of protein assemblies is present in nature. Furthermore, we describe structure-function relationship studies for selected classes of protein architectures, and we highlight the techniques that enable the characterisation of supramolecular protein structures. PMID- 26497226 TI - Management of acute coronary syndromes in a developing country; time for a paradigm shift? an observational study. AB - BACKGROUND: There are limited contemporary data on the presentation, management and outcomes of acute coronary syndromes (ACS) in Sri Lanka. We aimed to identify the critical issues that limit optimal management of ACS in Sri Lanka. METHODS: We performed a prospectively observational study of 256 consecutive patients who presented with ACS between November 2011 and May 2012 at a tertiary care general medical unit in Sri Lanka. RESULTS: We evaluated data on presentation, management, in-hospital mortality, and major adverse cardiovascular events (MACE) of participants. Smoking, alcohol abuse, and obesity were more common in patients with ST elevation myocardial infarction (STEMI) (P < 0.05). Discharge diagnoses were STEMI in 32.8 % (84/256) and unstable angina (UA)/non-ST elevation myocardial infarction [NSTEMI] in 67.1 % (172/256) of participants. The median time (IQR) from onset of pain to presentation was 60 (319) minutes for STEMI and 120 (420) for UA/NSTEMI (P = 0.058). A median delay of 240 min was noted in patients who had presented initially to smaller hospitals. Cardiac markers were assessed in only 35 % of participants. In-hospital anti-platelet use was high (>92 %). Only 70.2 % of STEMI patients received fibrinolytic therapy. Fewer than 20 % of patients were received fibrinolytic therapy within 30 min of arrival. Major adverse cardiac events (MACE) were recorded in 11.9 % of subjects with STEMI and 11.6 % of those with UA/NSTEMI (P = 0.5). According to logistic regression analysis, body mass index (P = 0.045) and duration of diabetes (P = 0.03) were significant predictors of in-hospital MACE. On discharge, aspirin, thienopyridine, and statins were prescribed to more than 90 % of patients. Only one patient underwent coronary angiography during the index admission. CONCLUSIONS: Delays in presentation and in initiation of thrombolytic therapy and coronary interventions are key hurdles that need attention to optimize ACS care in Sri Lanka. PMID- 26497228 TI - Evidence of covalent synergy in silicon-sulfur-graphene yielding highly efficient and long-life lithium-ion batteries. AB - Silicon has the potential to revolutionize the energy storage capacities of lithium-ion batteries to meet the ever increasing power demands of next generation technologies. To avoid the operational stability problems of silicon based anodes, we propose synergistic physicochemical alteration of electrode structures during their design. This capitalizes on covalent interaction of Si nanoparticles with sulfur-doped graphene and with cyclized polyacrylonitrile to provide a robust nanoarchitecture. This hierarchical structure stabilized the solid electrolyte interphase leading to superior reversible capacity of over 1,000 mAh g(-1) for 2,275 cycles at 2 A g(-1). Furthermore, the nanoarchitectured design lowered the contact of the electrolyte to the electrode leading to not only high coulombic efficiency of 99.9% but also maintaining high stability even with high electrode loading associated with 3.4 mAh cm(-2). The excellent performance combined with the simplistic, scalable and non-hazardous approach render the process as a very promising candidate for Li-ion battery technology. PMID- 26497227 TI - Impact of storage conditions on electromechanical, histological and histochemical properties of osteochondral allografts. AB - BACKGROUND: Osteochondral allograft transplantation has a good clinical outcome, however, there is still debate on optimization of allograft storage protocol. Storage temperature and nutrient medium composition are the most critical factors for sustained biological activity of grafts before implantation. In this study, we performed a time-dependent in vitro experiment to investigate the effect of various storage conditions on electromechanical, histological and histochemical properties of articular cartilage. METHODS: Osteochondral grafts derived from goat femoral condyles were frozen at -70 degrees C or stored at 4 degrees C and 37 degrees C in the medium supplemented with or without insulin-like growth factor-1 (IGF-1). After 14 and 28 days the cartilage samples were quantitatively analysed for electromechanical properties, glycosaminoglycan distribution, histological structure, chondrocyte viability and apoptosis. The results were compared between the experimental groups and correlations among different evaluation methods were determined. RESULTS: Storage at -70 degrees C and 37 degrees C significantly deteriorated cartilage electromechanical, histological and histochemical properties. Storage at 4 degrees C maintained the electromechanical quantitative parameter (QP) and glycosaminoglycan expression near the normal levels for 14 days. Although hypothermic storage revealed reduced chondrocyte viability and increased apoptosis, these parameters were superior compared with the storage at -70 degrees C and 37 degrees C. IGF-1 supplementation improved the electromechanical QP, chondrocyte viability and histological properties at 37 degrees C, but the effect lasted only 14 days. Electromechanical properties correlated with the histological grading score (r = 0.673, p < 0.001), chondrocyte viability (r = -0.654, p < 0.001) and apoptosis (r = 0.416, p < 0.02). In addition, apoptosis correlated with glycosaminoglycan distribution (r = -0.644, p < 0.001) and the histological grading score (r = 0.493, p = 0.006). CONCLUSIONS: Our results indicate that quality of allografts is better preserved at currently established 4 degrees C storage temperature. Storage at -70 degrees C or at 37 degrees C is unable to maintain cartilage function and metabolic activity. IGF-1 supplementation at 37 degrees C can enhance chondrocyte viability and improve electromechanical and histological properties of the cartilage, but the impact persists only 14 days. The correlations between cartilage electromechanical quantitative parameter (QP) and metabolic activity were detected. Our findings indicate that non-destructive assessment of cartilage by Arthro-BST is a simple and reliable method to evaluate allograft quality, and could be routinely used before implantation. PMID- 26497229 TI - Anti-inflammatory effects of 1,25-dihydroxyvitamin D3 in monocytes cultured in serum from patients with type 2 diabetes mellitus and diabetic nephropathy with uremia via Toll-like receptor 4 and nuclear factor-kappaB p65. AB - Type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) seriously affect the quality of human life. 1,25-dihydroxyvitamin D3 (VD3) is known to exert anti inflammatory and immunomodulatory effects. The present study investigated the effects of VD3 on Toll-like receptor 4 (TLR4) and nuclear factor (NF)-kappaB p65 expression in monocytes from patients with T2DM and investigated the underlying mechanisms. Serum from subjects of the control, T2DM and DN with uremia groups was isolated, and THP-1 monocytes were cultured in these sera with or without VD3. After treatment with lipopolysaccharide (LPS) and interleukin (IL)-15, monocytes and culture supernatants were collected. The expression of TLR4, TLR9 and IL-15 mRNA was detected using reverse-transcription polymerase chain reaction analysis. Furthermore, the protein expression of TLR4, NF-kappaB p65 and inhibitor of NF-kappaB (IkappaB) was determined using western blot analysis. The levels of IL-6 and monocyte chemotactic protein in culture supernatants were detected using ELISAs. The impact of LPS, IL-15 and VD3 on the TLR/NF-kappaB signaling pathway in the T2DM and DN uremia groups was also investigated. In the T2DM and DN uremia groups, LPS and IL-15 downregulated the expression of IkappaB and upregulated levels of proteins, including TLR4, NF-kappaB p65, IL-6 and monocyte chemoattractant protein 1, as well as TLR4 and IL-15 mRNA. There was no significant difference in TLR9 mRNA protein expression among the three groups. VD3 partially blocked the above effects; However, pre-treatment with VD3 had no significant effect on TLR4 mRNA expression, protein expression of NF-kappaB p65 and IkappaB, or the levels of associated inflammatory cytokines. In conclusion, the present study indicated that anti-inflammatory effects of VD3 in inflammatory immune responses in T2DM and DN uremia are associated with the TLR4/NF-kappaB p65 signaling pathway. PMID- 26497230 TI - The effect of branching in a semiconducting polymer on the efficiency of organic photovoltaic cells. AB - The impact of branching in a diketopyrrolopyrrole polymer on the performance of polymer-fullerene photovoltaic cells is investigated. Compared to the linear polymer, the branched polymer affords a more finely dispersed fibrillar network in the photoactive layer and as a result a large enhancement of the photocurrent and power conversion efficiency. PMID- 26497231 TI - The effect of toothbrush abrasion force on dentine hypersensitivity in-vitro. AB - OBJECTIVES: This study investigated the effect of tooth brushing force on changes in dentine tubule patency in an erosion-toothbrush abrasion model. METHODS: 60 dentine samples prepared with an artificial smear layer and divided randomly into control (no toothbrush), 100 g, 200 g or 400 g toothbrush groups. They were immersed in 3:1 artificial saliva/NaF 1450 ppm and either brushed (p35 soft tooth brush; 120 strokes) or not brushed. Then samples were subjected to agitated acid challenge (0.3% citric acid pH2.6 for 2 min). Finally, samples were re-brushed. Calibrated software calculated patent dentine tubules that cause DH in confocal microscopy images taken of samples at each stage. RESULTS: At baseline, mean patent tubules in all samples were 188 (SD54) with no significant inter-group differences. Following first brushing, mean patent tubules decreased using 100 g to 150 (SD32) (p<0.01) and increased using 400 g to 215 (SD45) (p=0.02). Following acid challenge, patent tubules increased to 218 (SD40) in all samples (p<0.01) with no significant inter-group differences. Following further brushing, mean patent tubules decreased using 100 g to 175 (SD72) (p<0.01), but increased with 400 g to 232 (SD52). CONCLUSIONS: At higher brushing forces (400 g), more tubules were exposed. At lower brushing forces (100 g), tubule patency decreased even post-acidic challenge. CLINICAL SIGNIFICANCE: It is often recommended to our patients with DH to brush using lighter brushing forces but our understanding of this force on dentine tubule patency is unknown. The management of DH requires lighter brushing forces to reduce the numbers of patent dentine tubules. PMID- 26497232 TI - Anti-biofilm activity of zinc oxide and hydroxyapatite nanoparticles as dental implant coating materials. AB - OBJECTIVES: Dental implants are prone to failure as a result of bacterial biofilm accumulation. Such biofilms are often resistant to traditional antimicrobials and the use of nanoparticles as implant coatings may offer a means to control infection over a prolonged period. The objective of this study was to determine the antibiofilm activity of nanoparticulate coated titanium (Ti) discs using a film fermenter based system. METHODS: Metal oxide nanoparticles of zinc oxide (nZnO), hydroxyapatite (nHA) and a combination (nZnO+nHA) were coated using electrohydrodynamic deposition onto Ti discs. Using human saliva as an inoculum, biofilms were grown on coated discs for 96 h in a constant depth film fermenter under aerobic conditions with artificial saliva and peri-implant sulcular fluid. Viability assays and biofilm thickness measurements were used to assess antimicrobial activity. RESULTS: Following 96 h, reduced numbers of facultatively anaerobic and Streptococcus spp. on all three nano-coated surfaces were demonstrated. The proportion of non-viable microorganisms was shown to be higher on nZnO and composite (nZnO+nHA) coated surfaces at 96 h compared with nHA coated and uncoated titanium. Biofilm thickness comparison also demonstrated that nZnO and composite coatings to be the most effective. CONCLUSIONS: The findings support the use of coating Ti dental implant surfaces with nZnO to provide an antimicrobial function. CLINICAL SIGNIFICANCE: Current forms of treatment for implant associated infection are often inadequate and may result in chronic infection requiring implant removal and resective/regenerative procedures to restore and reshape supporting tissue. The use of metal oxide nanoparticles to coat implants could provide osteoconductive and antimicrobial functionalities to prevent failure. PMID- 26497233 TI - Promethean Evolution: A Comparison of the Immune and Neural Systems. AB - In contrast to normal Darwinian evolution involving adaptation to past challenges, it has been suggested that evolution has devised two unique biological mechanisms to permit the host to anticipate future challenges: the adaptive immune response and neural memory functions. Certain phenomenological similarities, some sharing of names, and the participation in both systems of a group of physiologically active molecules suggested to many that the two might be intimately related. This article compares the two systems in terms of the familiar parlance of immunology-specificity, repertoire, degeneracy, memory, mediators, pathways, and genetics-to show that they differ in most respects, except insofar as they may utilize some of the same agents, many of which participate in the normal functions of other tissues and systems of the body. Indeed, this very difference provides a further demonstration of the wonders of the evolutionary process. PMID- 26497234 TI - The Perfect Storm: Preterm Birth, Neurodevelopmental Mechanisms, and Autism Causation. AB - A unifying model of autism causation remains elusive, and thus well-designed explanatory models are needed to develop appropriate therapeutic and preventive interventions. This essay argues that autism is not a static disorder, but rather an ongoing process. We discuss the link between preterm birth and autism and briefly review the evidence supporting the link between immune system characteristics and both prematurity and autism. We then propose a causation process model of autism etiology and pathogenesis, in which both neurodevelopment and ongoing/prolonged neuroinflammation are necessary pathogenetic component mechanisms. We suggest that an existing model of sufficient cause and component causes can be interpreted as a mechanistic view of etiology and pathogenesis and can serve as an explanatory model for autism causal pathways. PMID- 26497235 TI - George Engel's Epistemology of Clinical Practice. AB - George Engel's (1913-1999) biopsychosocial model, one of the most significant proposals for the renewal of medicine in the latter half of the 20th century, has been understood primarily as a multi-factorial approach to the etiology of disease and as a call to re-humanize clinical practice. This common reading of Engel's model misses the central aspect of his proposal, that the biopsychosocial model is an epistemology for clinical work. By stating the simple fact that the clinician is not dealing directly with a body, but first, and inevitably, with a person, Engel challenged the epistemology implicit in the classical clinical method-a method predicated on the possibility of direct access to the body. Framed in epistemological terms, the issue at stake is not the need to complement medical science with humane virtues, but rather to acknowledge that the object of clinical practice is not the body but the patient. PMID- 26497236 TI - Maimonides Reincarnated. AB - The writings of Maimonides, the 12th-century physician, Talmudic and philosophic scholar, are remarkably relevant for modern medicine. Whereas the specific medical recommendations are obviously outdated, Maimonides' perceptive insights into professional responsibilities and medical ethics remain as useful guides even in our postmodern era. PMID- 26497237 TI - Binding and Hoche's "Life Unworthy of Life": A Historical and Ethical Analysis. AB - The 1920 essay by German attorney Karl Binding and psychiatrist Alfred Hoche, "Permitting the Destruction of Life Unworthy of Life," is often characterized as a stepping-stone toward the Nazi genocide policies. A careful review of Binding and Hoche's arguments does reveal elements that foreshadow Nazi thinking, but it also contains points that fail to parallel--or that directly contradict--Nazi death practices. A proper ethical and historical analysis of this work requires a more nuanced discussion than it often receives. PMID- 26497238 TI - In Praise of Richard Asher (1912-1969). AB - This essay aims to stimulate a reawakening of interest in the writings of the physician Richard Asher (1912-1969), who is now best known for coining the term "Munchausen's syndrome." Asher's essays are as relevant now as when first published. His articles were a model of clarity, wit and elegance: he argued consistently for precision in thought and expression, for logic in clinical thinking, and for evidence in treatment. PMID- 26497239 TI - Catatonia in the History of Psychiatry: Construction and Deconstruction of a Disease Concept. AB - Catatonia is a psychomotor disorder that has gone through numerous descriptions since 1874, reflecting the many changes in psychiatric disease conceptualization that have occurred within that time frame. Catatonia has been variously described as a distinct disease entity, as a part of schizophrenia, and as a nonspecific manifestation of many disorders. Because of its association with schizophrenia, the description of catatonia was particularly affected by the psychopharmacological era, beginning in the 1950s, and by the development of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Changing trends in psychiatric research--especially the brain-based disease model, research methods favoured by the evidence-based medicine movement, and the codes and categories of the DSM--also profoundly influenced the evolving concept of catatonia. This paper discusses these important factors that affected recognition, treatment, and study of catatonia in order to reveal the biases and assumptions made when constructing a disease concept. PMID- 26497240 TI - Marino Ortolani: "Does That Baby's Hip Go Click?". AB - Marino Ortolani (1904-1983), a pediatrician from Ferrara, in northeastern Italy, was an outstanding pioneer in the early diagnosis and treatment of hip dysplasia. In 1935, while examining hip abduction-adduction in a six-month-old baby, Ortolani noted that a clearly audible and palpable "click" was sufficient to reveal congenital pre-dislocation of the hip, a condition he confirmed by an X ray of the pelvis. This discovery suggested that the sound alone could be used for early diagnosis and treatment of the condition. Ortolani's test is now a widespread diagnostic technique, described in all pediatric and orthopedic textbooks. To confirm his conjecture, Ortolani dissected many hip specimens in very young babies who had died of unrelated causes. He also collected excellent specimens of congenital hip pathology in fetuses at all stages of intrauterine development, proving that hip dysplasia may already occur in utero. After his death, his entire collection was donated to the Institute of Anatomy of the University of Padua, where it is now exhibited in a special showcase. This collection, very impressive for both the number and high anatomical quality of its specimens, is famous worldwide because it demonstrates the etiopathology of hip dysplasia so clearly. PMID- 26497241 TI - Hope Less: How a Healthy Dose of Realism Can Help in the ICU. AB - The author's father died recently after a sudden heart attack. This essay discusses how the family's experiences in the cardiac intensive care unit surprised her, even though she is a member of the Ethics Committee and the Ethics Consult Team at her local hospital, and how this led her to reconsider the ways in which families and hospital physicians communicate about the process of dying. How should doctors balance their messages of hope and realism when the situation is grim? Important judgment calls needed to be made, yet the family did not fully understand what they needed to know to make good decisions, especially the importance of the timing of their decisions. A conversation early on about what would happen if the patient became physically stable--no matter how impaired- while all options remained on the table might usefully (and mercifully) transform hope at the end. PMID- 26497242 TI - Responses from Palliative Care: Hope Is Like Water. PMID- 26497243 TI - Response: Hope Is in the Eye of the Beholder. PMID- 26497245 TI - The tryptophan metabolite picolinic acid suppresses proliferation and metabolic activity of CD4+ T cells and inhibits c-Myc activation. AB - Tryptophan metabolites, including kynurenine, 3-hydroxyanthranilic acid, and picolinic acid, are key mediators of immunosuppression by cells expressing the tryptophan-catabolizing enzyme indoleamine2,3-dioxygenase. In this study, we assessed the influence of picolinic acid on cell viability and effector functions of CD4(+)T cells following in vitro activation with agonistic anti-CD3/anti-CD28 antibodies. In contrast to kynurenine and 3-hydroxyanthranilic acid, exposure of T cells with picolinic acid did not affect cell viability, whereas proliferation and metabolic activity were suppressed in a dose-dependent manner. On the other hand, cytokine secretion and up-regulation of cell surface activation markers were not or only weakly inhibited by picolinic acid. Picolinic acid exposure induced a state of deep anergy that could not be overcome by the addition of exogenous IL-2 and inhibited Th cell polarization. On the molecular level, important upstream signaling molecules, such as the MAPKs ERK and p38 and the mammalian target of rapamycin target protein S6 ribosomal protein, were not affected by picolinic acid. Likewise, NFAT, NF-kappaB, and AP-1 promoter activity in Jurkat T cells was not influenced by exposure to picolinic acid. Whereas transcriptional levels of v-myc avian myelocytomatosis viral oncogene homolog were not affected by picolinic acid, phosphorylation at Ser62 was strongly reduced in picolinic acid-exposed T cells following activation. In conclusion, picolinic acid mediates a unique immunosuppressive program in T cells, mainly inhibiting cell cycle and metabolic activity, while leaving other effector functions intact. These functional features are accompanied by reduced phosphorylation of v-myc avian myelocytomatosis viral oncogene homolog. It remains to be determined whether this effect is mediated by direct inhibition of ERK activity or whether indirect mechanisms apply. PMID- 26497244 TI - Recombinant HE4 protein promotes proliferation of pancreatic and endometrial cancer cell lines. AB - Pancreatic adenocarcinoma is one of the most deadly malignancies, and endometrial cancer represents the most common gynecologic cancer in the USA. Better understanding on the pathologic mechanisms and pathways is required for effective treatment of these malignancies. Recently, human epididymis protein 4 (HE4 or WFDC2), a secretory glycoprotein, was found to be overexpressed in pancreatic and endometrial cancers. In addition, studies have shown that HE4 overexpression in endometrial cancer cell lines led to faster cancer progression in a mouse subcutaneous model. These findings raise a question on the role(s) of secretory, extracellular HE4 in cancer development. In the present study, we found that treatment of pancreatic and endometrial cancer cell lines with purified, extracellular HE4 protein led to a significant increase in cell viability and proliferation. Moreover, extracellular HE4 protein was able to increase DNA synthesis, and modulate the mRNA and protein levels of cell cycle marker PCNA and cell cycle inhibitor p21. These effects appeared to be robust and sustainable and required a relatively low concentration of HE4 protein. The findings indicated the secreted, extracellular HE4 may carry some physiopathological functions. Via paracrine/endocrine actions, circulatory HE4 produced by malignant cells may contribute to pancreatic and endometrial cancer progression and/or metastasis. PMID- 26497247 TI - Lack of support for relation between woman's masculinity preference, estradiol level and mating context. AB - It has been proposed that women's preferences for male facial sexual dimorphism are positively correlated with conception probability and differ between short- and long-term mating contexts. In this study, we tested this assumption by analyzing relationships between estradiol levels to the women's preferences of male faces that were manipulated to vary in masculinity. Estradiol was measured in daily saliva samples throughout the entire menstrual cycle collected by Polish women with regular menstrual cycles. In our analyses, we included the three most commonly used definitions of the fertile window in the literature. After computing the overall masculinity preference of each participant and measuring hormone levels, we found that i) the timing of ovulation varied greatly among women (between -11 and -17days from the onset of the next menses, counting backwards), ii) there was no relationship between daily, measured during the day of the test (N=83) or average for the cycle (N=115) estradiol levels and masculinity preferences, iii) there were no differences in masculinity preferences between women in low- and high-conception probability phases of the cycle, and iv) there were no differences in masculinity preferences between short and long-term mating contexts. Our results do not support the idea that women's preferences for a potential sexual partner's facial masculinity fluctuate throughout the cycle. PMID- 26497246 TI - Asparagine deprivation mediated by Salmonella asparaginase causes suppression of activation-induced T cell metabolic reprogramming. AB - Salmonellae are pathogenic bacteria that induce immunosuppression by mechanisms that remain largely unknown. Previously, we showed that a putative type II l asparaginase produced by Salmonella Typhimurium inhibits T cell responses and mediates virulence in a murine model of infection. Here, we report that this putative L-asparaginase exhibits L-asparagine hydrolase activity required for Salmonella Typhimurium to inhibit T cells. We show that L-asparagine is a nutrient important for T cell activation and that L-asparagine deprivation, such as that mediated by the Salmonella Typhimurium L-asparaginase, causes suppression of activation-induced mammalian target of rapamycin signaling, autophagy, Myc expression, and L-lactate secretion. We also show that L-asparagine deprivation mediated by the Salmonella Typhimurium L-asparaginase causes suppression of cellular processes and pathways involved in protein synthesis, metabolism, and immune response. Our results advance knowledge of a mechanism used by Salmonella Typhimurium to inhibit T cell responses and mediate virulence, and provide new insights into the prerequisites of T cell activation. We propose a model in which l-asparagine deprivation inhibits T cell exit from quiescence by causing suppression of activation-induced metabolic reprogramming. PMID- 26497248 TI - The type-1 cannabinoid receptor modulates the hydroelectrolytic balance independently of the energy homeostasis during salt load. AB - Hydroelectrolytic imbalances, such as saline load (SL), trigger behavioral and neuroendocrine responses, such as thirst, hypophagia, vasopressin (AVP) and oxytocin (OT) release and hypothalamus-pituitary-adrenal (HPA) axis activation. To investigate the participation of the type-1 cannabinoid receptor (CB1R) in these homeostatic mechanisms,male adult Wistar rats were subjected to SL (0.3MNaCl) for four days. SL induced not only increases in the water intake and plasma levels of AVP, OT and corticosterone, as previously described, but also increases in CB1R expression in the lamina terminalis, which integrates sensory afferents, aswell as in the hypothalamus, the main integrative and effector area controlling hydroelectrolytic homeostasis. A more detailed analysis revealed that CB1R-positive terminals are in close apposition with not only axons but also dendrites and secretory granules of magnocellular neurons, particularly vasopressinergic cells. In satiated and euhydrated animals, the intracerebroventricular administration of the CB1R selective agonist ACEA (0.1 MUg/5 MUL) promoted hyperphagia, but this treatment did not reverse the hyperosmolality-induced hypophagia in the SL group. Furthermore, ACEA pretreatment potentiated water intake in the SL animals during rehydration as well as enhanced the corticosterone release and prevented the increase in AVP and OT secretion induced by SL. The same parameters were not changed by ACEA in the animals whose daily food intake was matched to that of the SL group (Pair-Fed). These data indicate that CB1Rs modulate the hydroelectrolytic balance independently of the food intake during sustained hyperosmolality and hypovolemia. PMID- 26497249 TI - Luteinizing hormone downregulation but not estrogen replacement improves ovariectomy-associated cognition and spine density loss independently of treatment onset timing. AB - Age-related changes in reproductive hormone levels are a well-known risk factor for the development of cognitive dysfunction and dementia in women. We and others have shown an important contribution of gonadotropins in this process. Lowering serum gonadotropin levels is able to rescue cognitive function in Alzheimer's disease and menopause models, but whether this is time-dependent and the exact mechanism through which gonadotropins regulate cognitive function is unknown. We show that pharmacologically lowering serum levels of luteinizing hormone lead to cognitive improvement immediately after ovariectomy and with a 4month interval after ovariectomy, when the benefits of 17beta-estradiol are known to disappear in rodents. Importantly, we show that these improvements are associated with spine density changes at both time points. These findings suggest a role of luteinizing hormone in learning and memory and neuroplasticity processes as well as provide an alternative therapeutic strategy of menopause associated cognitive loss. PMID- 26497250 TI - Long-term continuous allopregnanolone elevation causes memory decline and hippocampus shrinkage, in female wild-type B6 mice. AB - Chronic stress in various forms increases the risk for cognitive dysfunction, dementia and Alzheimer's disease. While the pathogenesis behind these findings is unknown, growing evidence suggests that chronic increase in neurosteroid levels, such as allopregnanolone, is part of the mechanism. We treated wild-type C57BL/6J mice with allopregnanolone for 5months, using osmotic pumps. This treatment led to moderately increased levels of allopregnanolone, equivalent to that of mild chronic stress. After an interval of no treatment for 1month, female mice showed impaired learning and memory function in the Morris water maze (MWM) in combination with diminished hippocampus weight and increased cerebellum weight, both correlating to MWM performance. Male mice showed a minor reduction in memory function and no differences in brain structure. We conclude that chronic allopregnanolone elevation can lead to cognitive dysfunction and negative brain alterations. We suggest that allopregnanolone could play a key role in the pathogenesis of stress-induced cognitive disturbances and perhaps dementia. PMID- 26497251 TI - [Aggressive fibromatosis of the neck]. PMID- 26497252 TI - Evolution of metabolic disorder in rats fed high sucrose or high fat diet: Focus on redox state and mitochondrial function. AB - Glucotoxicity and lipotoxicity are major hallmarks of metabolic disorder. High consumption of fat or carbohydrate rich food is a major risk of metabolic disorder. However, the evolution of high fat or high carbohydrate diet-induced metabolic disorder is not clear. In the study, we tried to find distinguished and common ways involved in the pathogenesis of insulin resistance induced by high fat (HF) and high sucrose (HS) diet. We found that HS diet induced mild glucose intolerance (2month), followed by a "temporary non-symptom phase" (3month), and then induced significant metabolic abnormality (4month). HF diet induced an early "responsive enhancement phase" (2month), and then gradually caused severe metabolic dysfunction (3-4month). After a mild induction of mitochondrial ROS generation (2month), HS diet resulted in a "temporary non-symptom phase" (3month), and then induced a more significant mitochondrial ROS production (4month). The impairment of mitochondrial function induced by HS diet was progressive (2-4month). HF diet induced gradual mitochondrial ROS generation and hyperpolarization. HF diet induced an early "responsive enhancement" of mitochondrial function (2month), and then gradually resulted in severe decrease of mitochondrial function (3-4month). Despite the patterns of HS and HF diet induced insulin resistance were differential, final mitochondrial ROS generation combined with mitochondrial dysfunction may be the common pathway. These findings demonstrate a novel understanding of the mechanism of insulin resistance and highlight the pivotal role of mitochondrial ROS generation and mitochondrial dysfunction in the pathogenesis of metabolic disorder. PMID- 26497253 TI - Genes and associated peptides involved with aestivation in a land snail. AB - Some animals can undergo a remarkable transition from active normal life to a dormant state called aestivation; entry into this hypometabolic state ensures that life continues even during long periods of environmental hardship. In this study, we aimed to identify those central nervous system (CNS) peptides that may regulate metabolic suppression leading to aestivation in land snails. Mass spectral-based neuropeptidome analysis of the CNS comparing active and aestivating states, revealed 19 differentially produced peptides; 2 were upregulated in active animals and 17 were upregulated in aestivated animals. Of those, the buccalin neuropeptide was further investigated since there is existing evidence in molluscs that buccalin modulates physiology by muscle contraction. The Theba pisana CNS contains two buccalin transcripts that encode precursor proteins that are capable of releasing numerous buccalin peptides. Of these, Tpi buccalin-2 is most highly expressed within our CNS transcriptome derived from multiple metabolic states. No significant difference was observed at the level of gene expression levels for Tpi-buccalin-2 between active and aestivated animals, suggesting that regulation may reside at the level of post-translational control of peptide abundance. Spatial gene and peptide expression analysis of aestivated snail CNS demonstrated that buccalin-2 has widespread distribution within regions that control several physiological roles. In conclusion, we provide the first detailed molecular analysis of the peptides and associated genes that are related to hypometabolism in a gastropod snail known to undergo extended periods of aestivation. PMID- 26497254 TI - Multi-layer Flow-modulating Stents for Thoraco-abdominal and Peri-renal Aneurysms: The UK Pilot Study. AB - OBJECTIVE: There remains a population of patients with aortic aneurysms that cannot be treated by conventional endovascular means. Multi-layer flow modulating stents (MFMS) are a novel approach for the treatment of aortic aneurysm; this study reports outcomes of a UK pilot study of first-generation MFMS in thoraco abdominal (TAAA) and perirenal aneurysms (PAA) in patients who were also unfit for open surgery. METHODS: Patients with TAAA and PAA unfit for open surgery and with no conventional options for endovascular repair were recruited. Follow-up included CTA at 1, 3, 6, and 12 months, then annually. Outcome measures included 30 day mortality, growth-free survival, branch vessel patency, complications, re intervention, and maximal aortic diameter. RESULTS: MFMS were implanted in 14 patients (6 PAA, 8 TAAA) between October 2011 and March 2014 with one (7%) 30 day death and 11 (79%) surviving to 12 months. The median aneurysm growth was 9 mm in the first 12 months following implantation. On mean follow-up of 22.8 months, seven (50%) patients had died including one confirmed rupture. AAA diameter remained stable in only two of the surviving patients. Fifty of 51 covered aortic branches remained patent with no embolic episodes or symptoms of ischaemia in any patient. MFMS dislocation occurred in four patients, leading to re-intervention in two. A total of six re-interventions were performed in five patients (35%) with one post-re-intervention death. CONCLUSION: These first-generation MFMS were unstable and dislocated frequently. It is uncertain whether MFMS implantation influenced the natural history of these aneurysms as none decreased in size, but two remain stable after a mean of 22.8 months. Although side branch patency was maintained, our results do not support the continued use of these first generation devices. Further development is needed if this technology is to have a role in treatment of aortic aneurysm. PMID- 26497255 TI - Management of Aortic Sac Enlargement Following Successful EVAR in a Frail Patient. AB - BACKGROUND: An enlarging aneurysm after endovascular aneurysm repair (EVAR) without clear endoleak is a clinical challenge. Management of this problem is guided by the current evidence for adequate EVAR follow up and recommended thresholds for re-intervention. In a frail patient, careful risk assessment of aneurysm related mortality against the risks associated with examinations and interventions is required. METHODS: The literature was reviewed for imaging modalities for EVAR follow up and their advantages and disadvantages. The current evidence and guideline recommendations regarding follow up and re-intervention after EVAR were assessed in relation to the presented case. RESULTS: To detect sac expansion after EVAR, repeated examinations with the same imaging modality are needed. Verified expansion must be above the inter-observer variation of the method used. Although duplex ultrasound is an excellent modality for EVAR follow up, the finding of a significant expansion on duplex requires further examination, primarily with computed tomography angiography to assess sealing, stent graft integrity, and presence of endoleak. A frail patient should be assessed thoroughly before any kind of surgical intervention, the extent of which is related to the identified or suspected cause of expansion. CONCLUSION: Failure to totally exclude the aneurysm from continuing circulation, pressure and endoleak remains a potential shortcoming of EVAR. Significant sac expansion is an indication of EVAR failure. Decisions regarding further examinations or intervention are guided by the stability of the initial EVAR performed, the cause and extent of expansion, and the patient's comorbidities. PMID- 26497256 TI - Polybrominated diphenyl ethers in mussels (Mytilus galloprovincialis) collected from Central Adriatic Sea. AB - One-hundred and thirty-four samples of mussels (Mytilus galloprovincialis) collected along Central Adriatic Sea in 2013 were examined to determine the levels of fifteen congeners of polybrominated diphenyl ethers (PBDEs). The purified samples were analysed by gas-chromatography coupled to tandem mass spectrometry (GC-MS/MS) applying the isotopic dilution. Only four congeners (PBDE 47, PBDE 99, PBDE 49 and PBDE 100) were present above the established limits of quantification with mean concentrations equal to 73, 30, 19 and 18 pg g(-1), respectively. The concentrations of PBDEs (sum) ranged from 27 to 386 pg g(-1), with the highest levels around the coastal area of Ancona town. The here found levels were comparable to those measured in mussels collected along Southern Adriatic Sea. PMID- 26497257 TI - Sampling frequency of ciliated protozoan microfauna for seasonal distribution research in marine ecosystems. AB - Sampling frequency is important to obtain sufficient information for temporal research of microfauna. To determine an optimal strategy for exploring the seasonal variation in ciliated protozoa, a dataset from the Yellow Sea, northern China was studied. Samples were collected with 24 (biweekly), 12 (monthly), 8 (bimonthly per season) and 4 (seasonally) sampling events. Compared to the 24 samplings (100%), the 12-, 8- and 4-samplings recovered 94%, 94%, and 78% of the total species, respectively. To reveal the seasonal distribution, the 8-sampling regime may result in >75% information of the seasonal variance, while the traditional 4-sampling may only explain <65% of the total variance. With the increase of the sampling frequency, the biotic data showed stronger correlations with seasonal variables (e.g., temperature, salinity) in combination with nutrients. It is suggested that the 8-sampling events per year may be an optimal sampling strategy for ciliated protozoan seasonal research in marine ecosystems. PMID- 26497258 TI - Synergistic Combination Chemotherapy of Camptothecin and Floxuridine through Self Assembly of Amphiphilic Drug-Drug Conjugate. AB - Combination chemotherapy has been widely applied in cancer treatment; however, the cocktail administration of combination chemotherapy could cause the nonuniform biodistribution of anticancer agents, thus impairing the therapeutic efficacy. In the present study, to address this concern, we proposed a novel strategy of preparing self-assembled nanoparticles from amphiphilic drug-drug conjugate for synergistic combination chemotherapy. The conjugate was synthesized by two-step esterification of hydrophobic camptothecin (CPT) and hydrophilic floxuridine (FUDR) through a linker compound. Because of its amphiphilic nature, the CPT-FUDR conjugate self-assembled into stable nanoparticles which could simultaneously release fixed dosage of the two drugs in cancer cells. In vitro studies demonstrated synergistic anticancer efficacy of the CPT-FUDR nanoparticles including improved cell apoptosis, varied cell cycle arrest, as well as effective inhibition of cancer cell proliferation. PMID- 26497259 TI - Impact of Early-Life Exposures on Immune Maturation and Susceptibility to Disease. AB - Exiting from the largely sterile environment of the womb, the neonatal immune system is not fully mature, and thus neonatal immune cells must simultaneously mount responses against environmental stimuli while maturing. This dynamic process of immune maturation is driven by a variety of cell-intrinsic and extrinsic factors. Recent studies have focused on some of these factors and have shed light on the mechanisms by which they drive immune maturation. We review the interactions and consequences of immune maturation during the pre- and perinatal period. We discuss environmental signals in early life that are needed for healthy immune homeostasis, and highlight detrimental factors that can set an individual on a path towards disease. This early-life period of immune maturation could hold the key to strategies for setting individuals on trajectories towards health and reduced disease susceptibility. PMID- 26497261 TI - Prevalence, Patterns, and Predictors of Yoga Use: Results of a U.S. Nationally Representative Survey. AB - INTRODUCTION: The purpose of this study was to investigate the prevalence, patterns, and predictors of yoga use in the U.S. general population. METHODS: Using cross-sectional data from the 2012 National Health Interview Survey Family Core, Sample Adult Core, and Adult Complementary and Alternative Medicine questionnaires (N=34,525), weighted frequencies for lifetime and 12-month prevalence of yoga use and patterns of yoga practice were analyzed. Using logistic regression analyses, sociodemographic predictors of lifetime yoga use were analyzed. Analyses were conducted in 2015. RESULTS: Lifetime and 12-month prevalence of yoga use were 13.2% and 8.9%, respectively. Compared with nonpractitioners, lifetime yoga practitioners were more likely female, younger, non-Hispanic white, college educated, higher earners, living in the West, and of better health status. Among those who had practiced in the past 12 months, 51.2% attended yoga classes, 89.9% used breathing exercises, and 54.9% used meditation. Yoga was practiced for general wellness or disease prevention (78.4%), to improve energy (66.1%), or to improve immune function (49.7%). Back pain (19.7%), stress (6.4%), and arthritis (6.4%) were the main specific health problems for which people practiced yoga. CONCLUSIONS: About 31 million U.S. adults have ever used yoga, and about 21 million practiced yoga in the past 12 months. Disease prevention and back pain relief were the most important health reasons for yoga practice. Yoga practice is associated with age, gender, ethnicity, SES, and health status. PMID- 26497260 TI - Hirsutella sinensis mycelium attenuates bleomycin-induced pulmonary inflammation and fibrosis in vivo. AB - Hirsutella sinensis mycelium (HSM), the anamorph of Cordyceps sinensis, is a traditional Chinese medicine that has been shown to possess various pharmacological properties. We previously reported that this fungus suppresses interleukin-1beta and IL-18 secretion by inhibiting both canonical and non canonical inflammasomes in human macrophages. However, whether HSM may be used to prevent lung fibrosis and the mechanism underlying this activity remain unclear. Our results show that pretreatment with HSM inhibits TGF-beta1-induced expression of fibronectin and alpha-SMA in lung fibroblasts. HSM also restores superoxide dismutase expression in TGF-beta1-treated lung fibroblasts and inhibits reactive oxygen species production in lung epithelial cells. Furthermore, HSM pretreatment markedly reduces bleomycin-induced lung injury and fibrosis in mice. Accordingly, HSM reduces inflammatory cell accumulation in bronchoalveolar lavage fluid and proinflammatory cytokines levels in lung tissues. The HSM extract also significantly reduces TGF-beta1 in lung tissues, and this effect is accompanied by decreased collagen 3alpha1 and alpha-SMA levels. Moreover, HSM reduces expression of the NLRP3 inflammasome and P2X7R in lung tissues, whereas it enhances expression of superoxide dismutase. These findings suggest that HSM may be used for the treatment of pulmonary inflammation and fibrosis. PMID- 26497262 TI - Walmart and Other Food Retail Chains: Trends and Disparities in the Nutritional Profile of Packaged Food Purchases. AB - INTRODUCTION: Proliferation of food retail chains has created an environment in which a few food retailers account for the majority of U.S. packaged food purchases (PFPs). Despite the major potential for these food retail chains (FRCs) to impact what U.S. consumers buy and eat, little is known about the nutritional profile of PFPs from these retailers, particularly PFPs from Walmart, the largest U.S. grocer. METHODS: A data set of household PFPs from Nielsen Homescan was linked to data from the Nutrition Facts Panel (N=164,315), analyzed in 2014. Fixed effects models and inverse probability weights accounting for selectivity of shopping at a retailer were used to examine shifts in nutrient densities and key food groups purchased at Walmart and other FRCs from 2000 to 2013, and whether these changes differed for low-income or racial/ethnic-minority households. RESULTS: There were substantial declines in energy (-73 kcal/100 g); total sugar (-8 g/100 g); and sodium density (-33 mg/100 g) of Walmart PFPs, coupled with decreases in percentage volume purchased from sweets (-11%); grain based desserts (-2%); and savory snacks (-3%) and increases in fruits (+3%) and vegetables (+1%). PFPs from other FRCs had a more favorable nutritional profile than Walmart PFPs in 2000, but demonstrated smaller shifts over time. Disparities in the nutritional profile of Walmart PFPs by race/ethnicity but not by income level shrank over time. CONCLUSIONS: The nutritional profile of Walmart purchases has improved over time and in 2013 was similar to PFPs from other FRCs. PMID- 26497263 TI - Healthcare Stereotype Threat in Older Adults in the Health and Retirement Study. AB - INTRODUCTION: Healthcare stereotype threat is the threat of being personally reduced to group stereotypes that commonly operate within the healthcare domain, including stereotypes regarding unhealthy lifestyles and inferior intelligence. The objective of this study was to assess the extent to which people fear being judged in healthcare contexts on several characteristics, including race/ethnicity and age, and to test predictions that experience of such threats would be connected with poorer health and negative perceptions of health care. METHODS: Data were collected as part of the 2012 Health and Retirement Study (HRS). A module on healthcare stereotype threat, designed by the research team, was administered to a random subset (n=2,048 of the total 20,555) of HRS participants. The final sample for the present healthcare stereotype threat experiment consists of 1,479 individuals. Logistic regression was used to test whether healthcare stereotype threat was associated with self-rated health, reported hypertension, and depressive symptoms, as well as with healthcare related outcomes, including physician distrust, dissatisfaction with health care, and preventative care use. RESULTS: Seventeen percent of respondents reported healthcare stereotype threat with respect to one or more aspects of their identities. As predicted, healthcare stereotype threat was associated with higher physician distrust and dissatisfaction with health care, poorer mental and physical health (i.e., self-rated health, hypertension, and depressive symptoms), and lower odds of receiving the influenza vaccine. CONCLUSIONS: The first of its kind, this study demonstrates that people can experience healthcare stereotype threat on the basis of various stigmatized aspects of social identity, and that these experiences can be linked with larger health and healthcare-related outcomes, thereby contributing to disparities among minority groups. PMID- 26497265 TI - Enhanced Dispersion of TiO2 Nanoparticles in a TiO2/PEDOT:PSS Hybrid Nanocomposite via Plasma-Liquid Interactions. AB - A facile method to synthesize a TiO2/PEDOT:PSS hybrid nanocomposite material in aqueous solution through direct current (DC) plasma processing at atmospheric pressure and room temperature has been demonstrated. The dispersion of the TiO2 nanoparticles is enhanced and TiO2/polymer hybrid nanoparticles with a distinct core shell structure have been obtained. Increased electrical conductivity was observed for the plasma treated TiO2/PEDOT:PSS nanocomposite. The improvement in nanocomposite properties is due to the enhanced dispersion and stability in liquid polymer of microplasma treated TiO2 nanoparticles. Both plasma induced surface charge and nanoparticle surface termination with specific plasma chemical species are proposed to provide an enhanced barrier to nanoparticle agglomeration and promote nanoparticle-polymer binding. PMID- 26497264 TI - Receipt of Preventive Services After Oregon's Randomized Medicaid Experiment. AB - INTRODUCTION: It is predicted that gaining health insurance via the Affordable Care Act will result in increased rates of preventive health services receipt in the U.S., primarily based on self-reported findings from previous health insurance expansion studies. This study examined the long-term (36-month) impact of Oregon's 2008 randomized Medicaid expansion ("Oregon Experiment") on receipt of 12 preventive care services in community health centers using electronic health record data. METHODS: Demographic data from adult (aged 19-64 years) Oregon Experiment participants were probabilistically matched to electronic health record data from 49 Oregon community health centers within the OCHIN community health information network (N=10,643). Intent-to-treat analyses compared receipt of preventive services over a 36-month (2008-2011) period among those randomly assigned to apply for Medicaid versus not assigned, and instrumental variable analyses estimated the effect of actually gaining Medicaid coverage on preventive services receipt (data collected in 2012-2014; analysis performed in 2014-2015). RESULTS: Intent-to-treat analyses revealed statistically significant differences between patients randomly assigned to apply for Medicaid (versus not assigned) for 8 of 12 assessed preventive services. In intent-to treat analyses, Medicaid coverage significantly increased the odds of receipt of most preventive services (ORs ranging from 1.04 [95% CI=1.02, 1.06] for smoking assessment to 1.27 [95% CI=1.02, 1.57] for mammography). CONCLUSIONS: Rates of preventive services receipt will likely increase as community health center patients gain insurance through Affordable Care Act expansions. Continued effort is needed to increase health insurance coverage in an effort to decrease health disparities in vulnerable populations. PMID- 26497266 TI - Preschoolers' brains rely on semantic cues prior to the mastery of syntax during sentence comprehension. AB - Sentence comprehension requires the integration of both syntactic and semantic information, the acquisition of which seems to have different trajectories in the developing brain. Using functional magnetic resonance imaging, we examined the neural correlates underlying syntactic and semantic processing during auditory sentence comprehension as well as its development in preschool children by manipulating case marking and animacy hierarchy cues, respectively. A functional segregation was observed within Broca's area in the left inferior frontal gyrus for adults, where the pars opercularis was involved in syntactic processing and the pars triangularis in semantic processing. By contrast, five-year-old children sensitive to animacy hierarchy cues showed diffuse activation for semantic processing in the left inferior frontal and posterior temporal cortices. While no main effect of case marking was found in the left fronto-temporal language network, children with better syntactic skills showed greater neural responses for syntactically complex sentences, most prominently in the posterior superior temporal cortex. The current study provides both behavioral and neural evidence that five-year-old children compared to adults rely more on semantic information than on syntactic cues during sentence comprehension, but with the development of syntactic abilities, their brain activation in the left fronto-temporal network increases for syntactic processing. PMID- 26497267 TI - Optimized parallel transmit and receive radiofrequency coil for ultrahigh-field MRI of monkeys. AB - Monkeys are a valuable model for investigating the structure and function of the brain. To attain the requisite resolution to resolve fine anatomical detail and map localized brain activation requires radiofrequency (RF) coils that produce high signal-to-noise ratios (SNRs) both spatially (image SNR) and temporally. Increasing the strength of the static magnetic field is an effective method to improve SNR, yet this comes with commensurate challenges in RF coil design. First, at ultrahigh field strengths, the magnetic field produced by a surface coil in a dielectric medium is asymmetric. In neuroimaging of rhesus macaques, this complex field pattern is compounded by the heterogeneous structure of the head. The confluence of these effects results in a non-uniform flip angle, but more markedly, a suboptimal circularly polarized mode with reduced transmit efficiency. Secondly, susceptibility-induced geometric distortions are exacerbated when performing echo-planar imaging (EPI), which is a standard technique in functional studies. This requires receive coils capable of parallel imaging with low noise amplification during image reconstruction. To address these challenges at 7T, this study presents a parallel (8-channel) transmit coil developed for monkey imaging, along with a highly parallel (24-channel) receive coil. RF shimming with the parallel-transmit coil produced significant advantages the transmit field was 38% more uniform than a traditional circularly polarized mode and 54% more power-efficient, demonstrating that parallel-transmit coils should be used for monkey imaging at ultrahigh field strengths. The receive coil had the ability to accelerate along an arbitrary axis with at least a three-fold reduction factor, thereby reducing geometric distortions in whole-brain EPI. PMID- 26497269 TI - [Harvesting technique of chimeric multiple paddles fibular flap for wide oromandibular defects]. AB - Carcinological head and neck reconstruction still remains a challenge due to the volume and varied tissues needed. Large and wide oromandibular defects require, not just the bone but also soft tissues for the pelvilingual reconstruction and therefore, a second free flap may become necessary in addition to a fibular flap. The option of an unique chimeric flap based on the fibular artery and its branches is less known whereas it offers the advantage of a unique flap with bone, muscle and multiple skin paddles, independent of each other. The aim of this technical note is to present step by step the surgical procedure of this chimeric flap and share this method that avoids a second free flap. PMID- 26497268 TI - Randomised prior feedback modulates neural signals of outcome monitoring. AB - Substantial evidence indicates that decision outcomes are typically evaluated relative to expectations learned from relatively long sequences of previous outcomes. This mechanism is thought to play a key role in general learning and adaptation processes but relatively little is known about the determinants of outcome evaluation when the capacity to learn from series of prior events is difficult or impossible. To investigate this issue, we examined how the feedback related negativity (FRN) is modulated by information briefly presented before outcome evaluation. The FRN is a brain potential time-locked to the delivery of decision feedback and it is widely thought to be sensitive to prior expectations. We conducted a multi-trial gambling task in which outcomes at each trial were fully randomised to minimise the capacity to learn from long sequences of prior outcomes. Event-related potentials for outcomes (Win/Loss) in the current trial (Outcomet) were separated according to the type of outcomes that occurred in the preceding two trials (Outcomet-1 and Outcomet-2). We found that FRN voltage was more positive during the processing of win feedback when it was preceded by wins at Outcomet-1 compared to win feedback preceded by losses at Outcomet-1. However, no influence of preceding outcomes was found on FRN activity relative to the processing of loss feedback. We also found no effects of Outcomet-2 on FRN amplitude relative to current feedback. Additional analyses indicated that this effect was largest for trials in which participants selected a decision different to the gamble chosen in the previous trial. These findings are inconsistent with models that solely relate the FRN to prediction error computation. Instead, our results suggest that if stable predictions about future events are weak or non existent, then outcome processing can be determined by affective systems. More specifically, our results indicate that the FRN is likely to reflect the activity of positive affective systems in these contexts. Importantly, our findings indicate that a multifactorial explanation of the nature of the FRN is necessary and such an account must incorporate affective and motivational factors in outcome processing. PMID- 26497270 TI - Isolation, expression analysis and characterization of NEFA-interacting nuclear protein 30 and RING finger and SPRY domain containing 1 in skeletal muscle. AB - Muscle atrophy results from a range of physiological conditions, including immobilization, spinal cord damage, inflammation and aging. In this study we describe two genes, NEFA-interacting nuclear protein 30 (Nip30) and RING Finger and SPRY domain containing 1 (Rspry1), which have not previously been characterized or shown to be expressed in skeletal muscle. Furthermore, Nip30 and Rspry1 were transcriptionally induced in response to neurogenic muscle wasting in mice and were also found to be expressed endogenously at the RNA and protein level in C2C12 mouse muscle cells. Interestingly, during analysis of Nip30 and Rspry1 it was observed that these genes share a 230 base pair common regulatory region that contains several putative transcription regulatory elements. In order to assess the transcriptional activity of the Nip30 and Rspry1 regulatory regions, a fragment of the promoter of each gene was cloned, fused to a reporter gene, and transfected into cells. The Nip30 and Rspry1 reporters were both found to have significant transcriptional activity in cultured cells. Furthermore, the Nip30-Rspry1 common regulatory region contains a conserved E-box enhancer, which is an element bound by myogenic regulatory factors that function in the regulation of muscle-specific gene expression. Therefore, in order to determine if the predicted E-box was functional, Nip30 and Rspry1 reporters were transfected into cells ectopically expressing the myogenic regulatory factor, MyoD1, resulting in significant induction of both reporter genes. In addition, mutation of the conserved E-box element eliminated MyoD1 activation of the Nip30 and Rspry1 reporters. Finally, GFP-tagged Nip30 was found to localize to the nucleus, while GFP-tagged Rspry1 was found to localize to the cytoplasm of muscle cells. PMID- 26497271 TI - Dynamics of bacterial community structure on intertidal sandflat inhabited by the ghost shrimp Nihonotrypaea harmandi (Decapoda: Axiidea: Callianassidae) in Tomioka Bay, Amakusa, Japan. AB - Callianassid (ghost) shrimp has been claimed as an ecosystem engineer, as it is one of the most powerful bioturbating macrobenthos in intertidal sandflats. However, our knowledge about the relationship between areal distribution of bottom-dwelling ghost shrimps and dynamics of sediment microbial community structure remains obscured. We used automated ribosomal intergenic spacer analysis (ARISA) to reveal the bacterial community dynamics in the sediment of intertidal sandflat of Tomioka Bay, Kyushu, Japan, which is predominantly inhabited by a burrow-dwelling callianassid shrimp Nihonotrypaea harmandi. We found that the bacterial community structures of high and middle shrimp population areas were significantly differentiated from those of low population area (ANOSIM, R=0.10-0.18, p<0.01), while the former two areas were statistically indistinguishable (ANOSIM, R=-0.015, p>0.1). These results illustrated the potential importance of shrimp population density as a key factor in shaping the bacterial community structure and interpreting their dynamics in the sandflat. Furthermore, greater similarity between burrow and non-burrow communities was found in samples taken in autumn through winter than in those in summer (one-way ANOVA, p<0.05), whereas the phylotype richness was not simply differentiated by seasons. These results suggest not only that environmental variables including water temperature and salinity of the water column overlying the sandflat could exert notable impacts on the sediment bacterial community dynamics, but that the bio-irrigation and mixing by the ghost shrimp in permeable sandflat would strongly homogenize sediment particles, enhance solute transport surrounding the burrow and ambient subsurface substrate, and therefore reduce spatial differentiation of the bacterial community structure between the two sites. A comparison between present and previous studies of axiidean (former taxonomic group name, thalassinidean) ghost shrimps provides us with a comprehensive understanding of the shrimps' impacts on bacterial community dynamics, highlighting the importance of sediment permeability, a characteristic determined by the type of sediment, as a key controlling factor to shape spatial heterogeneity of bacterial community structure around burrow. PMID- 26497272 TI - The history of brucellosis in the Pacific Island Countries and Territories and its re-emergence. AB - There are few publications on brucellosis within the Pacific Island Countries and Territories (PICTs). The reason is possibly because the cattle population has been reportedly free of the disease for many years until a re-emergence occurred in the Fiji Islands (Viti Levu) in 2009. This paper reports on the outbreak of brucellosis in Fiji and its progression between 2009 and 2013 in the context of an overview of brucellosis in the Pacific Island community. Review of the literature found only 28 articles with the oldest record of brucellosis being in 1965 in Papua New Guinea (PNG) and from human cases in Tonga in 1980. The Fiji outbreak of Brucella abortus occurred in cattle in 2009 (Wainivesi basin) in the Tailevu province. Prior to the outbreak, Fiji declared freedom from B. abortus to OIE in 1996 after a successful eradication campaign. During the course of the outbreak investigation, serum samples were collected from between 9790 and 21,624 cattle per annum between 2009 and 2013 from 87 farms on the main island of Fiji (Viti Levu). Blood samples were tested for brucellosis using the Rose Bengal Test (RBT) in 2009 and the indirect ELISA test in subsequent years. At the time of the outbreak in Fiji (2009) the apparent prevalence in cattle was 1.50% and this has fluctuated since the outbreak. The True Prevalence (TP) for the main island in Fiji for the indirect ELISA tests was 2.40% in 2010, reached a peak of 3.49% in 2011 then reduced to 0.12% by 2013. The significant reduction in prevalence compared to 2010 is most likely due to the control programs being implemented in Fiji. The re-emergence of B. abortus in Fiji could be attributed to the lack of monitoring for the disease until 2009 combined with inadequate management of exposed animals, thus illustrating how important it is for authorities not to become complacent. Continued awareness and monitoring for brucellosis is essential if future outbreaks are to be avoided. PMID- 26497274 TI - Protein stability - an underappreciated but critical need for drug delivery systems. PMID- 26497273 TI - Dog and cat management through sterilization: Implications for population dynamics and veterinary public policies. AB - The present study aimed to compare different sterilization scenarios allowing the adoption of the most adequate strategy to control owned dog and cat population sizes as the official veterinary public policy for animal control in an urban area of Campinas municipality, Brazil. To achieve this goal, the vital parameters of the owned pet population were measured in a neighborhood of Campinas called Jardim Vila Olimpia through questionnaires used in two census studies performed in February 2012 and June 2013. Different hypothetical sterilization scenarios were compared with the scenario of a single sterilization campaign performed in the study area between the census studies. Using a deterministic mathematical model, population dynamics were simulated for these different scenarios. We have observed that for both owned dogs and cats, the impact on the population size achieved by a single sterilization campaign would be diluted over the years, equating to the impact achieved by the usual sterilization rate practiced before the sterilization campaign yearly. Moreover, using local and global sensitivity analyses, we assessed the relative influence on animal population evolution of each vital parameter used in the mathematical models. The more influential parameters for both species were the carrying capacity of the environment and sterilization rates of males and females (for both species). We observed that even with sterilizing 100% of the intact animals annually, it would not be possible to obtain proportions greater than 86% and 88% of sterilized dogs and cats, respectively, after 20 years due to the high introduction of new intact animals. There is no public dog and cat sterilization service in place in the city, and sporadic and local sterilization campaigns are performed with a prior communication to the owners to bring their animals to be sterilized in a selected veterinary facility. If a sterilization campaign was performed annually in the study area, it would have the most favorable cost effectiveness ratio after 20 years compared to the scenarios of 50% and 100% sterilization of intact animals annually. These results allowed the veterinary public policy stakeholders to make decisions based on scientific evidence to implement adequate control of dog and cat populations in urban areas, aiming to reduce zoonosis transmission to humans and other problems associated with uncontrolled animal populations. PMID- 26497275 TI - Aqueous photofate of crystal violet under simulated and natural solar irradiation: Kinetics, products, and pathways. AB - In this work photodegradation rates and pathways of an illegal veterinary drug, crystal violet, were studied under simulated and solar irradiation with the goal of assessing the potential of photolysis as a removal mechanism in the aquatic environment. Factors influencing the photodegradation process under simulated sunlight were investigated, including pH, humic acid, Fe(2+), Ca(2+), [Formula: see text] , and [Formula: see text] , of which favorable conditions were optimized by the orthogonal array design. The degradation processes of crystal violet conformed to pseudo first-order kinetics, with different rate constants under different conditions. Reactive oxygen species such as hydroxyl radical, singlet oxygen, and superoxide anion participated in the indirect photolysis process, leading to much higher decolorization efficiencies than those of direct photolysis and hydrolysis. Contrasting to simulated irradiation, solar irradiation led to complete decolorization. Sixty-four products were identified by high resolution liquid chromatography-time-of-flight mass spectrometry and gas chromatography-mass spectrometry, elucidating relatively complete mineralization through photolysis. Based on the analyses of the degradation products and calculations of the frontier electron density, transformation pathways were proposed as singlet oxygen addition, N-demethylation, hydroxyl addition, decomposition of conjugated structure, the removal of benzene ring and the ring opening reaction. As a result, small products generated as carboxylic acids, alcohols and amines, which were not likely to cause severe hazards to the environment. This study provided both a reference for photodegradation of crystal violet and future safety applications and predictions of decontamination of related triphenylmethane veterinary drug under environmental conditions. PMID- 26497276 TI - [Medical and economic evaluation of oncological inpatients in 14 Belgian hospitals]. AB - INTRODUCTION: A prospective payment system per DRG is announced in Belgium. Is this kind of financing system adequate for oncology? Objectives of this study are: to analyze medical and economical characteristics of oncological inpatients and evaluate the homogeneity of costs and length of stay per DRG. METHODS: The study was realized in 14 Belgian hospitals, with 2010 data. Inpatients with primary diagnosis of neoplasms were selected in medical and administrative databases. Characteristics of patients as well as length of stay and cost (hospital perspective) were analyzed. The homogeneity of costs and length of stay is measured by calculating the coefficient of variation (standard deviation divided by the mean). RESULTS: The length of stay (standard deviation) is 9.72 days (12.64). The variation is high per DRG. The average cost (standard deviation) is 7689.28? (10,418) and is also variable from one DRG to another one. There are 5% of high-length of stay outliers and 0.2% of low-length of stay outliers. There are 4.7% of high-cost outliers and 0.2% of low-cost outliers. The withdrawal of outliers improves the homogeneity of cost and length of stay per APR-DRG. DISCUSSION AND CONCLUSION: There is a homogeneity of costs and length of stay per DRG and per severity of illness. A prospective payment system per DRG would probably be applicable for these patients. It is however necessary to plan an appropriate and additional financing of all elements susceptible to stimulate innovation in the management of oncology and to stimulate the quality of care by adding financial stimulants. PMID- 26497277 TI - Peroxisomal protein import pores. AB - Peroxisomal protein import is essentially different to the translocation of proteins into other organelles. The molecular mechanisms by which completely folded or even oligomerized proteins cross the peroxisomal membrane remain to be disclosed. The identification of a water-filled pore that is mainly constituted by Pex5 and Pex14 led to the assumption that proteins are translocated through a large, probably transient, protein-conducting channel. Here, we will review the work that led to the identification of this translocation pore. In addition, we will discuss the main biophysical features of the pore and compare it with other protein-translocation channels. PMID- 26497278 TI - Structural and biochemical characterization of two heme binding sites on alpha1 microglobulin using site directed mutagenesis and molecular simulation. AB - BACKGROUND: alpha1-Microglobulin (A1M) is a reductase and radical scavenger involved in physiological protection against oxidative damage. These functions were previously shown to be dependent upon cysteinyl-, C34, and lysyl side chains, K(92, 118,130). A1M binds heme and the crystal structure suggests that C34 and H123 participate in a heme binding site. We have investigated the involvement of these five residues in the interactions with heme. METHODS: Four A1M-variants were expressed: with cysteine to serine substitution in position 34, lysine to threonine substitutions in positions (92, 118, 130), histidine to serine substitution in position 123 and a wt without mutations. Heme binding was investigated by tryptophan fluorescence quenching, UV-Vis spectrophotometry, circular dichroism, SPR, electrophoretic migration shift, gel filtration, catalase-like activity and molecular simulation. RESULTS: All A1M-variants bound to heme. Mutations in C34, H123 or K(92, 118, 130) resulted in significant absorbance changes, CD spectral changes, and catalase-like activity, suggesting involvement of these side-groups in coordination of the heme-iron. Molecular simulation support a model with two heme-binding sites in A1M involving the mutated residues. Binding of the first heme induces allosteric stabilization of the structure predisposing for a better fit of the second heme. CONCLUSIONS: The results suggest that one heme-binding site is located in the lipocalin pocket and a second binding site between loops 1 and 4. Reactions with the hemes involve the side-groups of C34, K(92, 118, 130) and H123. GENERAL SIGNIFICANCE: The model provides a structural basis for the functional activities of A1M: heme binding activity of A1M. PMID- 26497279 TI - Validation of the flooding dose technique to determine fractional rates of protein synthesis in a model bivalve species, the blue mussel (Mytilus edulis L.). AB - For the first time, use of the flooding dose technique using (3)H-Phenylalanine is validated for measuring whole-animal and tissue-specific rates of protein synthesis in the blue mussel Mytilus edulis (61mm shell length; 4.0g fresh body mass). Following injection, the phenylalanine-specific radioactivities in the gill, mantle and whole-animal free pools were elevated within one hour and remained elevated and stable for up to 6h following injection of (3)H phenylalanine into the posterior adductor muscle. Incorporation of (3)H phenylalanine into body protein was linear over time following injection and the non-significant intercepts for the regressions suggested incorporation into body protein occurred rapidly after injection. These results validate the technique for measuring rates of protein synthesis in mussels. There were no differences in the calculated rates following 1-6h incubation in gill, mantle or whole-animal and fractional rates of protein synthesis from the combined time course data were 9.5+/-0.8%d(-1) for the gill, 2.5+/-0.3%d(-1) for the mantle and 2.6+/-0.3%d(-1) for the whole-animal, respectively (mean values+/-SEM). The whole-animal absolute rate of protein synthesis was calculated as 18.9+/-0.6mg protein day(-1). The use of this technique in measuring one of the major components of maintenance metabolism and growth will provide a valuable and convenient tool in furthering our understanding of the protein metabolism and energetics of this keystone marine invertebrate and its ability to adjust and respond to fluctuations, such as that expected as a result of climate change. PMID- 26497280 TI - Untangling a role for tau in synucleinopathies. PMID- 26497281 TI - Behavioral interventions produce robust beneficial biological alterations. PMID- 26497282 TI - APOEepsilon4 and depression: following a winding road. PMID- 26497283 TI - Macrocyclic prolinyl acyl guanidines as inhibitors of beta-secretase (BACE). AB - The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented. PMID- 26497284 TI - Watson-Crick hydrogen bonding of unlocked nucleic acids. AB - We herein describe the synthesis of two new unlocked nucleic acid building blocks containing hypoxanthine and 2,6-diaminopurine as nucleobase moieties and their incorporation into oligonucleotides. The modified oligonucleotides were used to examine the thermodynamic properties of UNA against unmodified oligonucleotides and the resulting thermodynamic data support that the hydrogen bonding face of UNA is Watson-Crick like. PMID- 26497285 TI - Synthesis and evaluation of antibacterial activity of (R)-2-methylheptyl isonicotinate, a putative naturally occurring bioactive agent. AB - A putative antibacterial and antifungal compound, (R)-2-methylheptyl isonicotinate, was synthesized via reductive lactone alkylation of (R)-4 methyldihydrofuran-2(3H)-one. Structural characterisation data as well as bioassay results (with Bacillus subtilis or Escherichia coli) contradict those previously reported. PMID- 26497287 TI - Hepatitis D virus and hepatitis B virus infection in Amerindian communities of the Amazonas state, Colombia. AB - BACKGROUND: In Colombia, cases of Hepatitis D virus (HDV) infection have been officially described since 1985 mainly in Amerindian population from Sierra Nevada de Santa Marta (North Caribbean Coast), Uraba (North West), and Amazon (South East). The last official report of a clinical case of HDV infection in Colombia was registered in 2005. OBJECTIVES: The aims of this study were to identify cases of HDV and/or Hepatitis B virus (HBV) infection in asymptomatic Amerindians from Amazonas state, South East Colombia, and to describe the circulating viral genotypes in this population. STUDY DESIGN: The study population was recruited in 19 Amerindian communities in the Amazonas state. Individuals over 18 years old were screened by rapid test for Hepatitis B surface Antigen (HBsAg). Blood samples obtained from individuals positives for HBsAg in the rapid-test assay were analyzed for HBsAg, anti-HBc, anti-HDV IgM/IgG by ELISA. The detection of HBV DNA and HDV RNA was performed by PCR amplification. The viral genotype was determined by sequencing and phylogenetic analysis. RESULTS: A total of 23/861 individuals were positive for HBsAg detection by rapid test. Serological and/or molecular markers of HDV infection were demonstrated in 43.5 % (10/23) of samples from Amerindians. The phylogenetic analysis demonstrated the exclusive circulation of HBV subgenotype F1b of and HDV 3 in this population. CONCLUSIONS: A high frequency of HBV/HDV infection was found in Amerindian population from Amazonas State, Colombia (43.5 %, 10/23). Nine cases were identified in a population of 861 asymptomatic Amerindian individuals; one symptomatic case (with diagnosis of end-stage hepatic disease) was also identified in the study. The circulation of HDV 3 and HBV subgenotype F1b suggests a constant flow of these viral genotypes as a result of the interaction of the Amerindian populations from Amazon basin. Further studies are necessary to confirm whether HBV subgenotype F1b is the prevalent in the population from South East region in Colombia. PMID- 26497288 TI - Characterization of Diastereo- and Enantioselectivity in Degradation of Synthetic Pyrethroids in Soils. AB - Permethrin (PM), cypermethrin (CP), and cyfluthrin (CF) are three important synthetic pyrethroids, which contain two, four, and four enantiomeric pairs (diastereomers) and thus have four, eight, and eight stereoisomers, respectively. In this study, the stereo- and enantioselective degradation of PM, CP, and CF in a Shijiazhuang alkaline yellow soil and a Wuhan acidic red soil were studied in detail by a combination of achiral and chiral high-performance liquid chromatography (HPLC). The results showed that PM, CP, and CF degraded faster in Shijiazhuang soil than in Wuhan soil, and the dissipation rate followed an order of PM > CF > CP in both soils. The three pyrethroids exhibited similar diastereomer selectivity, while CP and CF showed higher enantioselectivity than PM. Moreover, the trans-diastereomers degraded faster, and showed higher enantioselectivity than the corresponding cis-diastereomers. For PM, the enantiomer 1S-trans-PM degraded most rapidly in both soils. As for CP and CF, the highest enantioselectivity was observed for diastereomer trans-3, and the insecticidally active enantiomer 1R-trans-alphaS degraded fastest among the 8 CP or CF stereoisomers in both soils. In addition, the Wuhan acidic soil displayed higher diastereomer and enantiomer selectivity than the Shijiazhuang alkaline soil for the three pyrethroids. Further incubation of CF in an alkaline-treated Wuhan soil showed that the dissipation rate greatly increased and the diastereo- and enantioselectivity significantly decreased after the alkaline treatment process. PMID- 26497286 TI - Protein stability: computation, sequence statistics, and new experimental methods. AB - Calculating protein stability and predicting stabilizing mutations remain exceedingly difficult tasks, largely due to the inadequacy of potential functions, the difficulty of modeling entropy and the unfolded state, and challenges of sampling, particularly of backbone conformations. Yet, computational design has produced some remarkably stable proteins in recent years, apparently owing to near ideality in structure and sequence features. With caveats, computational prediction of stability can be used to guide mutation, and mutations derived from consensus sequence analysis, especially improved by recent co-variation filters, are very likely to stabilize without sacrificing function. The combination of computational and statistical approaches with library approaches, including new technologies such as deep sequencing and high throughput stability measurements, point to a very exciting near term future for stability engineering, even with difficult computational issues remaining. PMID- 26497290 TI - Last issue of our 90th anniversary. PMID- 26497289 TI - Early deprivation and autonomic nervous system functioning in post institutionalized children. AB - The relations between early deprivation and the development of the neuroendocrine and central components of the mammalian stress response have been examined frequently. However, little is known about the impact of early deprivation on the developmental trajectories of autonomic function. Children adopted between 15-36 months from institutional care were examined during their first 16 months post adoption (N = 60). Comparison groups included same-aged peers reared in their birth families (N = 50) and children adopted internationally from overseas foster care (N = 46). The present study examined trajectories of baseline autonomic nervous system function longitudinally following entry into adopted families. Post-institutionalized children had higher sympathetic tone, measured by pre ejection period (PEP). Individual differences in PEP soon after adoption served as a mediator between early deprivation and parent-reported behavioral problems 2 years post-adoption. There were no group differences in parasympathetic function, indexed by respiratory sinus arrhythmia. All three groups showed similar trajectories of ANS function across the 16 month period. PMID- 26497292 TI - Refractive plasticity of the developing chick eye: a summary and update. AB - PURPOSE: To summarize the OPO 1992 Classic Paper: Refractive plasticity of the developing chick eye (12: 448-452) and discuss recent findings in refractive development. SUMMARY AND RECENT FINDINGS: The classic paper shows that when lightweight plastic goggles with rigid contact lens inserts are applied to the eyes of newly hatched chicks, the eye responds accurately to defocus between -10 and +20 D, although hyperopia develops more rapidly. While the changes largely are due to change in axial length, high levels of hyperopia are associated with corneal flattening. Also, newly hatched chicks are better able to compensate for the induced defocus than chicks that are 9 days old. In addition, astigmatism of 2-6 D can be produced by applying 9 D toric inducing lenses on the day of hatching, and the most myopic meridian coincides with the power meridian of the inducing lens. This astigmatism appears to be primarily due to corneal toricity. Furthermore, the greatest magnitude was produced when the plano meridian of the inducing lens was placed 45 degrees from the line of the palpebral fissure. Since our publication in 1992, it has been shown that similar results can be produced in a variety of species, including; tree shrews, marmosets, monkeys and fish. Considerable effort has been spent in trying to determine what the eye uses, if not the brain, as the signal to the sign of the defocus. Accommodation, chromatic aberration, diurnal variation, astigmatism and higher order monochromatic aberrations have all been considered. Choroidal thinning and thickening play a role in myopia and hyperopia development, respectively, in chicks. High light levels (15,000 lux) increase the rate at which chicks compensate for positive lenses and decrease the compensation rate for negative lenses. However these light levels do not prevent the eye from fully compensating for either type of lens. It has also been shown that brief periods of normal vision prevent the development of form deprivation myopia. Finally, the importance of the peripheral retina in refractive development has been explored and lenses designed to reduce relative peripheral hyperopia have resulted in variable effects as far as myopia control is concerned. CONCLUSIONS: A growing body of evidence, from both animal models and human clinical trials indicates that the development of myopia is related both to genetics and environment / lifestyle. Nevertheless, we are far from understanding how this interaction takes place. PMID- 26497293 TI - Differences in the accommodation stimulus response curves of adult myopes and emmetropes: a summary and update. AB - PURPOSE: To provide a summary of the classic paper "Differences in the accommodation stimulus response curves of adult myopes and emmetropes" published in Ophthalmic and Physiological Optics in 1998 and to provide an update on the topic of accommodation errors in myopia. SUMMARY: The accommodation responses of 33 participants (10 emmetropes, 11 early onset myopes and 12 late onset myopes) aged 18-31 years were measured using the Canon Autoref R-1 free space autorefractor using three methods to vary the accommodation demand: decreasing distance (4 m to 0.25 cm), negative lenses (0 to -4 D at 4 m) and positive lenses (+4 to 0 D at 0.25 m). We observed that the greatest accommodation errors occurred for the negative lens method whereas minimal errors were observed using positive lenses. Adult progressing myopes had greater lags of accommodation than stable myopes at higher demands induced by negative lenses. Progressing myopes had shallower response gradients than the emmetropes and stable myopes; however the reduced gradient was much less than that observed in children using similar methods. RECENT FINDINGS: This paper has been often cited as evidence that accommodation responses at near may be primarily reduced in adults with progressing myopia and not in stable myopes and/or that challenging accommodation stimuli (negative lenses with monocular viewing) are required to generate larger accommodation errors. As an analogy, animals reared with hyperopic errors develop axial elongation and myopia. Retinal defocus signals are presumably passed to the retinal pigment epithelium and choroid and then ultimately the sclera to modify eye length. A number of lens treatments that act to slow myopia progression may partially work through reducing accommodation errors. PMID- 26497294 TI - Clinical evaluation of the Shin-Nippon SRW-5000 autorefractor in adults: an update. AB - PURPOSE: The Shin-Nippon SRW-5000 is an open view autorefractor that superseded the Canon R-1 autorefractor in the mid-1990 s and has been used widely in optometry and vision science laboratories. It has been used to measure refractive error, accommodation responses both statically and dynamically, off-axis refractive error, and adapted to measure pupil size. This paper presents an overview of the original 2001 clinical evaluation of the SRW-5000 in adults (Mallen et al., Ophthal Physiol Opt 2001; 21: 101) and provides an update on the use and modification of the instrument since the original publication. RECENT FINDINGS: The SRW-5000 instrument, and the family of devices which followed, have shown excellent validity, repeatability, and utility in clinical and research settings. The instruments have also shown great potential for increased research functionality following a number of modifications. SUMMARY: The SRW-5000 and its derivatives have been, and continue to be, of significant importance in our drive to understand myopia progression, myopia control techniques, and oculomotor function in human vision. PMID- 26497295 TI - A commentary on 'Amplitude spectra of natural images'. AB - Tolhurst, Tadmor and Tang Chao (Ophthalmic Physiol Opt 1992; 12: 229-232) published their analyses of the Fourier spectra of 135 digitised monochrome photographs of everyday scenes. In 2015, this would be a trivial exercise, but in 1992, this stretched emerging computer technology to its desktop limits. The short paper made an impact because it provided a handle for extending vision science beyond laboratory stimuli such as sinewave gratings into a real world of real visual scenes and real visual tasks. PMID- 26497296 TI - Is it time to confine Snellen charts to the annals of history? AB - PURPOSE: A paper published by the author in 1988 in this journal provided some important findings about the lack of precision of visual acuity (VA) measures made with commonly used Snellen charts and the advantages of using letter charts designed using the principles proposed by Bailey and Lovie in 1976. That 1988 paper has been cited a number of times since, mostly supporting the findings. The purpose of this review is to examine the changes that have occurred in VA measurement in research and clinical practice since that earlier study. RECENT FINDINGS: While precise measures of VA using Bailey-Lovie or ETDRS charts are now commonly used in major, multi-centre research studies, it is disappointing to see that many research papers still report VA measured with Snellen charts and even use Snellen fractions, invalidly converted to logMAR notation, in parametric analyses of VA. Many studies have examined the test-retest variability (TRV) of VA measures in groups and individuals, but it is difficult to determine if clinicians or researchers determine patients' individual TRVs to more accurately detect real changes in VA for each individual. SUMMARY: This paper summarises the findings of the 1988 study: (1) Snellen charts and VA notations are not appropriate for accurate clinical and research measures of VA; (2) Charts employing the Bailey-Lovie design principles should be used to provide precise measures of VA. (3) Test-retest variability should be used to determine the limit for detecting significant change in VA. This author suggests that it is time for Snellen charts, Snellen fractions and decimal notation to be confined to the teaching of the history of VA measurement. A request is also made to stop the use of the redundant term 'best corrected' VA (BCVA). Recommended procedures are given for precise measures of VA and accurately monitoring changes in VA in clinical practice and research. PMID- 26497297 TI - Myopia revisited, 2010-2015. PMID- 26497298 TI - Metaphorical expressions used in Swedish news media narratives to portray the shortage of nurses and their working conditions. AB - AIM: The aim of the study is to uncover and reveal how nurses as a profession and their working conditions are dramatized and portrayed in Swedish media narratives about the shortage of nurses. BACKGROUND: The media is an arena where stakeholders can air their views of the healthcare sector in general and the situation for nurses in particular. The focus in this study is the debate in Sweden on the shortage of nurses. DESIGN: Qualitative discursive study. METHOD: A discourse analysis of media narratives about nurses and their working conditions published in several Swedish newspapers from 2009-2014. 1779 articles were included in the study. A selection (113 articles) of these articles was further analysed using a qualitative discursive psychological approach. FINDINGS: Nurses are portrayed as being good, concerned about and critical of healthcare managers and politicians for not taking action. The accused actors justify their actions by partially accepting or displacing responsibility. The shortage of nurses is framed as a social problem - a threat to patients' safety. Seven different types of metaphorical expression frame the problem as inevitable, beyond control, abstract, an individual and collegial problem and nurses as replaceable. In addition, nurses and patients are dehumanized and no-one is held responsible. CONCLUSIONS: This study analyses the role of the media in emphasizing the seriousness or obscurity of the problem and possible solutions to it. Alternative narratives are needed to re-frame the nursing shortage and to find sustainable solutions. PMID- 26497299 TI - Advanced glycation end-products induced VEGF production and inflammatory responses in human synoviocytes via RAGE-NF-kappaB pathway activation. AB - Aging and diabetes are known to be the major cause to affect the progression of osteoarthritis (OA). Advanced glycation end products (AGEs) have been observed to accumulate in various organs especially in joint tissue and do damage to the joint tissue during aging and diabetes. Synovial angiogenesis and inflammation are observed across the full range of OA severity. The signaling pathway of AGEs on vascular endothelial growth factor (VEGF) production and inflammatory responses in synoviocytes are still unclear. Here, we investigated the role of receptor for AGEs (RAGE) and the signaling pathway involved in AGEs-induced VEGF production and inflammatory responses in human synoviocytes. Human synoviocytes were cultured and treated with AGEs (25-100 ug/ml). AGEs significantly induced the protein expressions of cyclooxygenase-2 (COX-2) and VEGF and the productions of prostaglandin-E2 (PGE2), VEGF, interleukin-6 (IL-6), and metalloproteinase-13 (MMP-13) in human synoviocytes in a dose-dependent manner. Moreover, AGEs markedly activated the phosphorylations of IkappaB kinase (IKK)alpha/beta, IkappaBalpha, and nuclear factor (NF)-kappaB-p65 proteins in human synoviocytes in a time-dependent manner. Treatment with neutralizing antibody for RAGE statistically significantly decreased the AGEs-induced increase in COX-2, VEGF, PGE2, IL-6, and MMP13 and AGEs-activated NF-kappaB pathway activation. Taken together, these findings indicate that AGEs are capable of inducing VEGF production and inflammatory responses via RAGE-NF-kappaB pathway activation in human synoviocytes. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:791-800, 2016. PMID- 26497300 TI - Social-emotional instability in individuals with Rett syndrome: parents' experiences with second stage behaviour. AB - BACKGROUND: While the medical profession often terms behaviours in individuals with Rett syndrome (RTT) in the second stage as 'autistic-like', parents disagree with this description. The present study focuses on a comparison of parents' experiences with the social-emotional behaviour of the child with RTT in the second and subsequent stages. METHOD: In collaboration with the Dutch Rett Syndrome Organization, 51 parents of children with RTT in the Netherlands took part in the present study. Parents completed an online questionnaire to clarify their experiences of the social-emotional behaviour of their children during and after the second stage of RTT. Both quantitative and qualitative analysis techniques have been used. RESULTS: The results of the paired-samples t-test show that parents see significantly less social-emotional behaviour in the children during the second stage of RTT than in the subsequent stages. Parents reported that their children did not seek as much interaction. From the parents' descriptions, it would seem that the children are willing but unable to interact with their environment. CONCLUSIONS: Like previous research, our study leads to doubts about the appropriateness of the label 'autistic-like' for the behaviour of individuals in the second stage of RTT. While behaviours of individuals with autism and individuals with RTT may resemble each other, quality and intentions may differ. Still, future studies are needed for further clarification. PMID- 26497301 TI - From Lignin-derived Aromatic Compounds to Novel Biobased Polymers. AB - Nowadays, the synthesis of (semi)aromatic polymers from lignin derivatives is of major interest, as aromatic compounds are key intermediates in the manufacture of polymers and lignin is the main source of aromatic biobased substrates. Phenols with a variety of chemical structures can be obtained from lignin deconstruction; among them, vanillin and ferulic acid are the main ones. Depending on the phenol substrates, different chemical modifications and polymerization pathways are developed, leading to (semi)aromatic polymers covering a wide range of thermomechanical properties. This review discusses the synthesis and properties of thermosets (vinyl ester resins, cyanate ester, epoxy, and benzoxazine resins) and thermoplastic polymers (polyesters, polyanhydrides, Schiff base polymers, polyacetals, polyoxalates, polycarbonates, acrylate polymers) prepared from vanillin, ferulic acid, guaiacol, syringaldehyde, or 4-hydroxybenzoic acid. PMID- 26497302 TI - Identification of invasive fungal diseases in immunocompromised patients by combining an Aspergillus specific PCR with a multifungal DNA-microarray from primary clinical samples. AB - The increasing incidence of invasive fungal diseases (IFD), most of all invasive aspergillosis (IA) in immunocompromised patients emphasises the need to improve the diagnostic tools for detection of fungal pathogens. We investigated the diagnostic performance of a multifungal DNA-microarray detecting 15 different fungi [Aspergillus, Candida, Fusarium, Mucor, Rhizopus, Scedosporium and Trichosporon species (spp.)] in addition to an Aspergillus specific polymerase chain reaction (PCR) assay. Biopsies, bronchoalveolar lavage and peripheral blood samples of 133 immunocompromised patients (pts) were investigated by a multifungal DNA-microarray as well as a nested Aspergillus specific PCR assay. Patients had proven (n = 18), probable (n = 29), possible (n = 48) and no IFD (n = 38) and were mostly under antifungal therapy at the time of sampling. The results were compared to culture, histopathology, imaging and serology, respectively. For the non-Aspergillus IFD the microarray analysis yielded in all samples a sensitivity of 64% and a specificity of 80%. Best results for the detection of all IFD were achieved by combining DNA-microarray and Aspergillus specific PCR in biopsy samples (sensitivity 79%; specificity 71%). The molecular assays in combination identify genomic DNA of fungal pathogens and may improve identification of causative pathogens of IFD and help overcoming the diagnostic uncertainty of culture and/or histopathology findings, even during antifungal therapy. PMID- 26497303 TI - Lignocellulose degrading extremozymes produced by Pichia pastoris: current status and future prospects. AB - In this review article, extremophilic lignocellulosic enzymes with special interest on xylanases, beta-mannanases, laccases and finally cellulases, namely, endoglucanases, exoglucanases and beta-glucosidases produced by Pichia pastoris are reviewed for the first time. Recombinant lignocellulosic extremozymes are discussed from the perspectives of their potential application areas; characteristics of recombinant and native enzymes; the effects of P. pastoris expression system on recombinant extremozymes; and their expression levels and applied strategies to increase the enzyme expression yield. Further, effects of enzyme domains on activity and stability, protein engineering via molecular dynamics simulation and computational prediction, and site-directed mutagenesis and amino acid modifications done are also focused. Superior enzyme characteristics and improved stability due to the proper post-translational modifications and better protein folding performed by P. pastoris make this host favourable for extremozyme production. Especially, glycosylation contributes to the structure, function and stability of enzymes, as generally glycosylated enzymes produced by P. pastoris exhibit better thermostability than non glycosylated enzymes. However, there has been limited study on enzyme engineering to improve catalytic efficiency and stability of lignocellulosic enzymes. Thus, in the future, studies should focus on protein engineering to improve stability and catalytic efficiency via computational modelling, mutations, domain replacements and fusion enzyme technology. Also metagenomic data need to be used more extensively to produce novel enzymes with extreme characteristics and stability. PMID- 26497304 TI - A cecropin-like antimicrobial peptide with anti-inflammatory activity from the black fly salivary glands. AB - BACKGROUND: Several antimicrobial peptides (AMPs) belonging to the cecropin family have been identified from the salivary glands of different black fly species, however, the immunological functions for these molecules were poorly understood. METHODS: A novel cecropin-like antimicrobial peptide (SibaCec) was purified using reverse phase high-performance liquid chromatography (RP-HPLC) from the salivary glands of the black fly Simulium bannaense. The amino acid sequence of SibaCec was determined by a combination method of automated Edman degradation and cDNA sequencing. The morphologic changes of Gram-negative bacteria Escherichia coli treated with SibaCec were assessed by scanning electron microscopy (SEM). Quantitative PCR (qPCR) was performed to analyze the mRNA expression of the inducible NO synthase (iNOS) and pro-inflammatory cytokines. Nitric oxide (NO) generation was examined using a Griess assay and the secretion of pro-inflammatory cytokines was determined by an enzyme-linked immunosorbent assay (ELISA). The activation of extracellular signal-regulated kinase (ERK), p38, and the nuclear translocation of nuclear factor-kappaB (NF-kappaB) were assessed by Western blotting analysis. Circular dichroism (CD) spectroscopy was performed to evaluate the secondary structure of SibaCec in solvent environment. Interaction of SibaCec with lipopolysaccharide (LPS) was studied using fluorescein isothiocyanate (FITC)- conjugated LPS aggregates. Neutralization of LPS by SibaCec was assayed with the chromogenic limulus amebocyte lysate (LAL) test. qPCR was also used to analyze the expression of SibaCec mRNA in the salivary glands of insects after oral infection with the bacteria E.coli. RESULTS: SibaCec possessed potent antimicrobial activity against Gram-negative bacteria, and showed low cytotoxicity toward mammalian cells. SEM analysis indicated that SibaCec killed bacteria through the disruption of cell membrane integrity. Furthermore, SibaCec significantly inhibited lipopolysaccharide (LPS) induced production of NO and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interferon-1beta (IL-1beta) and interferon-6 (IL-6) by blocking the activation of MAPKs and NF-kappaB signaling pathways. It mainly adopted an alpha-helix conformation in membrane-mimetic environments. SibaCec could interact and neutralize LPS. Infection of black flies with bacteria caused an upregulation of the expression of SibaCec. CONCLUSIONS: These results demonstrated that in addition to the bactericidal capacity, SibaCec can function as immune regulator, inhibiting host secretion of inflammatory factors. PMID- 26497305 TI - AMPK activator AICAR promotes 5-FU-induced apoptosis in gastric cancer cells. AB - The aim of the present study was to determine the effect of AICAR, an AMPK activator, on apoptosis in gastric carcinoma cells (SGC-7901) with or without 5 fluorouracil (5-FU). SGC-7901 cells were treated with AICAR (0.2-5 mM, for 24-48 h) with or without 5-FU. Cell viability was determined using MTT assay, while apoptosis were measured through the evaluation of active caspase-3 activity and DNA fragmentation. Real-time PCR was employed to determine the expression of tumor suppressor and multi-drug resistant (mdr1) gene. Cleaved caspase-3 and phosphorylated AMPK (p-AMPK) were measured by Western blot. AICAR significant reduced cellular viability but increased apoptosis in a time- and dose-dependent manner, which is associated with an increase in p-AMPK levels. Importantly, AICAR enhanced the sensitivity to 5-FU-induced reduction of cellular viability and increased apoptosis in SGC-7901 cells. Furthermore, AICAR increased tumor suppressor genes [F-box and WD repeat domain containing 7 (FBXW7), semaphorin III/F (SEMA3F), and p21(Cip1) (p21)] but reduced mdr1 expression. Finally, p-AMPK levels were reduced in 5-FU-resistant gastric cancer cells compared to human immortalized gastric epithelial cell line and 5-FU-sensitive gastric cancer cells. AICAR not only induces apoptosis alone but also enhances pro-apoptotic effect of 5-FU in SGC-7901 cells, which lays an experimental foundation to develop AICAR as a chemotherapeutic sensitizer against gastric cancer. PMID- 26497306 TI - Correlation of hypothetical virulence traits of two Streptococcus uberis strains with the clinical manifestation of bovine mastitis. AB - Streptococcus uberis is a common cause of clinical and subclinical mastitis in dairy cattle. Several virulence mechanisms have been proposed to contribute to the species' ability to cause disease. Here, virulence characteristics were compared between S. uberis strains FSL Z1-048, which consistently caused clinical mastitis in a challenge model, and FSL Z1-124, which consistently failed to cause disease in the same model, to ascertain whether in vitro virulence characteristics were related to clinical outcome. Macrophages derived from bovine blood monocytes failed to kill FSL Z1-048 whilst reducing survival of FSL Z1-124 by 42.5%. Conversely, blood derived polymorphonuclear cells caused more reduction (67.1 vs. 44.2%, respectively) in the survival of FSL Z1-048 than in survival of FSL Z1-124. After 3 h of coincubation with bovine mammary epithelial cell line BME-UV1, 1000-fold higher adherence was observed for FSL Z1-048 compared to FSL Z1-124, despite presence of a frame shift mutation in the sua gene of FSL Z1-048 that resulted in predicted truncation of the S. uberis Adhesion Molecule (SUAM) protein. In contrast, FSL Z1-124 showed higher ability than FSL Z1-048 to invade BME-UV1 cells. Finally, observed biofilm formation by FSL Z1-124 was significantly greater than for FSL Z1-048. In summary, for several hypothetical virulence characteristics, virulence phenotype in vitro did not match disease phenotype in vivo. Evasion of macrophage killing and adhesion to mammary epithelial cells were the only in vitro traits associated with virulence in vivo, making them attractive targets for further research into pathogenesis and control of S. uberis mastitis. PMID- 26497307 TI - Influencing factors for high quality care on postpartum haemorrhage in the Netherlands: patient and professional perspectives. AB - BACKGROUND: Postpartum haemorrhage (PPH) remains a major contributor to maternal morbidity even in high resource settings, despite the development and dissemination of evidence-based guidelines and Advance-Trauma-Life-Support (ATLS) based courses for optimal management of PPH. We aimed to assess current influencing factors (obstacles and facilitators) for the delivery of high quality PPH-care from both patient and professional perspective. METHODS: We qualitatively explored influencing factors for delivering high quality PPH-care, by having individual interviews with PPH-patients and focus group interviews with the different types of professionals working in the delivery room. For both perspectives, the theoretical frameworks of Grol and Cabana were used to classify the influencing factors for optimal PPH-care (factors of the guidelines, of professionals, of patients, of the social setting and of the organisation). In order to assess the importance of the influencing factors found among the professionals, we quantified these factors in a web-based questionnaire. RESULTS: A total of 12 patients and 41 professionals participated in the interviews, and 315 complete surveys were analyzed. The main obstacle for high quality PPH-care identified by patients was the lack of information given by the professionals to the patient and partner before, during and after the PPH event. An informative patient website, a patient leaflet and a follow-up consultation were mentioned as facilitators. The main obstacles according to the professionals were: lack of clarity of the guidelines, lack of knowledge and failing team-communication. Team training and checklists/ flowcharts were considered facilitators. CONCLUSIONS: Different obstacles to the delivery of high quality PPH-care were identified by both patients and professionals. These data can be used to develop a focused strategy to improve PPH-care. TRIAL REGISTRATION: NCT 00928863. PMID- 26497308 TI - [Surgical decompression of the superficial radial nerve: Wartenberg syndrome]. AB - OBJECTIVE: Open decompression of the superficial radial nerve is performed at the distal forearm in cases of circumscript entrapment. Broad-based entrapments can be treated by endoscopically assisted decompression. INDICATIONS: Entrapment of the nerve along its course between the brachioradialis and extensor carpi radialis longus muscles or tendons. Persistent neuropathic pain with Tinel's sign. Numbness distal to the entrapment in accordance to nerval innervation. Futile conservative treatment. Pathological electrophysiological findings. CONTRAINDICATIONS: Endogeneous neuropathy, bleeding disorders, anticoagulation medication. SURGICAL TECHNIQUE: Longitudinal skin incision at the Tinel's sign at the forearm. The subcutaneous tissue is dissected until forearm fascia is detected. The fascia is opened cautiously under direct visualization and the superficial radial nerve is identified. In cases of broad-based entrapments, endoscopically assisted decompression can be performed. The dissector with attached optical device is introduced proximally and distally. Blunt mobilization using the dissector and preparation with the Metzenbaum scissors release the superficial radial nerve sufficiently. POSTOPERATIVE MANAGEMENT: Bandaging allowing immediate motion, removal of sutures after 14 days, avoidance of excessive use for 2 weeks. RESULTS: Surgical decompression of the superficial radial nerve yields good to excellent results regarding pain reduction and sensory function. PMID- 26497309 TI - Psychiatric Morbidity and Subjective Burden Among Carers of Outpatients of a Psychogeriatric Clinic in Southwestern Nigeria. AB - Few studies in Nigeria have investigated the burden of caring for elderly persons with mental illness. The aim of this study was to examine psychiatric morbidity and burden of care among caregivers of outpatients of a psychogeriatric clinic. Burden of care was evaluated with Zarit Burden Interview. A questionnaire was also used to elicit caregivers' sociodemographic and caregiving variables while psychological well-being was assessed with the General Health Questionnaire (GHQ). Overall, 52.3% had high care burden. High care burden was associated with financial difficulty (chi(2) = 9.37; df = 1; p = 0.002; OR = 3.1; 95% CI = 1.50 6.4), restrictions on caregivers' social activity (chi(2) = 4.87; df = 1; p = 0.027; OR = 2.4; 95% CI = 1.09-5.27), lack of support from relatives (chi(2) = 6.85; df = 1; p = 0.009; OR = 6.3; 95% CI = 1.35-29.6), physical health problems (chi(2) = 10.52; df = 1; p = 0.001; OR = 4.7; 95% CI = 1.75-12.7), and psychiatric morbidity (chi(2) = 4.05; df = 1; p = 0.044; OR = 2.62; 95% CI = 1.00 6.85). Psychiatric morbidity was predicted by physical health problems (OR = 3.0; 95% CI = 1.1-8.1), financial difficulty (OR = 17.2; 95% CI = 3.8-77.5), and job loss (OR = 5.3; 95% CI = 2.0-13.8). Care burden is a significant problem among caregivers of elderly persons with mental illness attending the clinic. This may have important implications for the mental well-being of the patients. PMID- 26497310 TI - Exploration of the wound healing effect of topical administration of nicotine in combination with collagen scaffold in a rabbit model. AB - Nicotine has been reported to prolong the wound healing; however, we showed that the topical application of 10(-4) M nicotine promoted murine wound healing. The objective of this study was to explore the wound healing effects of nicotine in combination with collagen scaffold using skin defects in rabbit. Three full thickness skin defects 8 mm in diameter were made on the rabbit auricle. Artificial dermis was applied to the defects, and 10 MUl of nicotine solution (10(-5), 10(-4), and10(-3) M), bFGF solution (0.5 MUg/10 MUl), and both bFGF and 10(-4) M nicotine solutions were injected into the artificial dermis once daily for 7 days. Rabbits were sacrificed on day 10, 15, or 20, and the wound healing process was evaluated. bFGF was superior in the formation of the dermis-like tissue and capillaries. In nicotine groups, the epithelial length and the dermis like tissue formations in the 10(-4) M group were superior, in contrast, those were inhibited in the 10(-3) M group. The synergistic effect of bFGF and 10(-4) M nicotine was not confirmed. This study suggests that the topical application of 10(-4) M nicotine promoted wound healing in rabbit, but the effect was not apparent compared with murine models. PMID- 26497311 TI - Genome-wide DNA methylome variation in two genetically distinct chicken lines using MethylC-seq. AB - BACKGROUND: DNA cytosine methylation is an important epigenetic modification that has significant effects on a variety of biological processes in animals. Avian species hold a crucial position in evolutionary history. In this study, we used whole-genome bisulfite sequencing (MethylC-seq) to generate single base methylation profiles of lungs in two genetically distinct and highly inbred chicken lines (Fayoumi and Leghorn) that differ in genetic resistance to multiple pathogens, and we explored the potential regulatory role of DNA methylation associated with immune response differences between the two chicken lines. METHODS: The MethylC-seq was used to generate single base DNA methylation profiles of Fayoumi and Leghorn birds. In addition, transcriptome profiling using RNA-seq from the same chickens and tissues were obtained to interrogate how DNA methylation regulates gene transcription on a genome-wide scale. RESULTS: The general DNA methylation pattern across different regions of genes was conserved compared to other species except for hyper-methylation of repeat elements, which was not observed in chicken. The methylation level of miRNA and pseudogene promoters was high, which indicates that silencing of these genes may be partially due to promoter hyper-methylation. Interestingly, the promoter regions of more recently evolved genes tended to be more highly methylated, whereas the gene body regions of evolutionarily conserved genes were more highly methylated than those of more recently evolved genes. Immune-related GO (Gene Ontology) terms were significantly enriched from genes within the differentially methylated regions (DMR) between Fayoumi and Leghorn, which implicates DNA methylation as one of the regulatory mechanisms modulating immune response differences between these lines. CONCLUSIONS: This study establishes a single-base resolution DNA methylation profile of chicken lung and suggests a regulatory role of DNA methylation in controlling gene expression and maintaining genome transcription stability. Furthermore, profiling the DNA methylomes of two genetic lines that differ in disease resistance provides a unique opportunity to investigate the potential role of DNA methylation in host disease resistance. Our study provides a foundation for future studies on epigenetic modulation of host immune response to pathogens in chickens. PMID- 26497312 TI - Nonlinear Ion Harmonics in the Paul Trap with Added Octopole Field: Theoretical Characterization and New Insight into Nonlinear Resonance Effect. AB - The nonlinear harmonics within the ion motion are the fingerprint of the nonlinear fields. They are exclusively introduced by these nonlinear fields and are responsible to some specific nonlinear effects such as nonlinear resonance effect. In this article, the ion motion in the quadrupole field with a weak superimposed octopole component, described by the nonlinear Mathieu equation (NME), was studied by using the analytical harmonic balance (HB) method. Good accuracy of the HB method, which was comparable with that of the numerical fourth order Runge-Kutta (4th RK), was achieved in the entire first stability region, except for the points at the stability boundary (i.e., beta = 1) and at the nonlinear resonance condition (i.e., beta = 0.5). Using the HB method, the nonlinear 3beta harmonic series introduced by the octopole component and the resultant nonlinear resonance effect were characterized. At nonlinear resonance, obvious resonant peaks were observed in the nonlinear 3beta series of ion motion, but were not found in the natural harmonics. In addition, both resonant excitation and absorption peaks could be observed, simultaneously. These are two unique features of the nonlinear resonance, distinguishing it from the normal resonance. Finally, an approximation equation was given to describe the corresponding working parameter, q nr , at nonlinear resonance. This equation can help avoid the sensitivity degradation due to the operation of ion traps at the nonlinear resonance condition. PMID- 26497314 TI - High-performance liquid chromatographic separations of stereoisomers of chiral basic agrochemicals with polysaccharide-based chiral columns and polar organic mobile phases. AB - The separation of the stereoisomers of 23 chiral basic agrochemicals was studied on six different polysaccharide-based chiral columns in high-performance liquid chromatography with various polar organic mobile phases. Along with the successful separation of analyte stereoisomers, emphasis was placed on the effect of the chiral selector and mobile phase composition on the elution order of stereoisomers. The interesting phenomenon of reversal of enantiomer/stereoisomer elution order function of the polysaccharide backbone (cellulose or amylose), type of derivative (carbamate or benzoate), nature, and position of the substituent(s) in the phenylcarbamate moiety (methyl or chloro) and the nature of the mobile phase was observed. For several of the analytes containing two chiral centers all four stereoisomers were resolved with at least one chiral selector/mobile phase combination. PMID- 26497313 TI - Cardiac involvement in systemic sclerosis: differences between clinical subsets and influence on survival. AB - Cardiac involvement (CI) is a known complication of SSc associated with increased mortality. Our objective was to describe a cohort of patients with SSc and CI and to assess the differences between cutaneous subsets regarding their presentation and survival. Three hundred and ninety-three Spanish patients from a single center, diagnosed with SSc, were retrospectively studied for evidence of CI using noninvasive and invasive tests from 1976 to 2011. Clinical, epidemiological, immunological and therapeutic features of patients with CI were compared to those without it and within the different cutaneous subsets of SSc. CI was present in 173 (44 %) patients. Mitral regurgitation (67 %), conduction alterations (45 %) and left ventricle diastolic dysfunction (40 %) were the most common findings. Pericardial involvement and heart failure were more frequent in diffuse SSc (dcSSc) than in limited or sine scleroderma SSc. CI accounted for 20 % of deaths, and it was an independent mortality risk factor (HR 2.1, P = 0.02), but once CI was established, classical dcSSc mortality risk factors determined mortality. Patients with dcSSc developed CI faster than limited (HR 1.9, P = 0.003) or sine SSc patients (HR 2.5, P = 0.002), specially during the first year after SSc onset. We found statistically significant differences between the 3 SSc subsets in the presentation of pericardial involvement and heart failure. CI increased the mortality and appeared at a higher rate, especially during the first year after SSc onset. Screening for heart involvement should be performed at diagnosis and during follow-up. PMID- 26497315 TI - Generative Mechanisms in Early Childhood Interventions: A Confirmatory Research Framework for Prevention. AB - This article reviews methodological and analytic approaches and impact evidence for understanding the mechanisms of effects of early childhood interventions, including delinquency and violence prevention. Illustrations from longitudinal studies of preschool preventive interventions are provided. We restrict our attention to preventive interventions for children from birth to age 5, including evidence from the Chicago Longitudinal Study (CLS), which investigates the impact of an established school-based early childhood intervention. Frameworks and evidence will be organized according to the Five-Hypothesis Model (5HM), which postulates that a variety of early childhood interventions impact later well being through the promotion of cognitive and scholastic advantages, motivational advantages, social adjustment, family support behaviors, and school supports. Recommendations are made for advancing confirmatory approaches for identifying the most effective prevention programs using identification of generative mechanisms as a major methodological criterion. PMID- 26497316 TI - A VL-linker-VH Orientation Dependent Single Chain Variable Antibody Fragment Against Rabies Virus G Protein with Enhanced Neutralizing Potency in vivo. AB - Lethal rabies can be prevented effectively by post-exposure prophylactic (PEP) with rabies immunoglobulin (RIG). Single-chain variable fragment (scFv), which is composed of a variable heavy chain (VH) and variable light chain (VL) connected by a peptide linker, may be developed as alternative to RIG for neutralizing rabies virus (RV). However, our previously constructed scFv (FV57S) with the (NH2) VH-linker-VL (COOH) orientation showed a lower neutralizing potency than its parent RIG. This orientation may inhibit FV57S from refolding into an intact and correct conformation. Therefore, the RFV57S protein with a VL-linker-VH orientation was constructed based on FV57S. A HIS tag was incorporated to aid in purification and detection of RFV57S and FV57S. However, abilities of RFV57S and FV57S to bind with the anti-HIS tag mAb were different. Therefore, a novel direct ELISA was established by utilizing a biotin-labeled truncated glycoprotein of RV. Although with similar stability and in vitro neutralizing potency as FV57S, RFV57S showed enhanced binding ability, affinity and in vivo protective efficacy against lethal dose of RV. Our studies support the feasibility of developing a scFv with reversed orientation and provide a novel method for evaluating the binding ability, stability and affinity of engineered antibodies recognizing linear epitope. PMID- 26497317 TI - Overexpression and Characterization of The C-Terminal Domain of Human Siva1, A Proapoptotic Factor and Cytoskeleton Binding Protein. AB - Siva1 protein interacts with tumor protein p53 and with the member of the tumor necrosis factor receptor superfamily, stathmin, among others. These proteins are related to several pathways involved in cancer and are therefore strong candidate targets for drug design. This study aimed to characterize the biophysical properties of Siva 1 C- terminal domain to contribute to the discovery of new target directed drugs. Siva1 protein interacts with tumor protein p53 and with the member of the tumor necrosis factor receptor superfamily, stathmin, among others. These proteins are related to several pathways involved in cancer and are therefore strong candidate targets for drug design. This study aimed to characterize the biophysical properties of Siva 1 C- terminal domain to contribute to the discovery of new target directed drugs. The C-terminus Siva1 domain (residues 84-175) was fused to glutathione Stransferase (GST) and expressed in an E coli system and the recombinant GST-Siva C-terminus was purified by GSTTagged Protein affinity and gel filtration chromatography. We tested the biological activity of the purified Siva Cterminus domain in a Jurkat extract cell line and found that the protein interacted with natural binders. Biophysical and biochemical assays have demonstrated monodispersion of the protein in solution with a predominant unfolded and elongated shape. However, at high concentrations, the protein showed a tendency to form soluble aggregates. These results are expected to lead to further progress in the understanding of Siva1 properties and target-directed drug design. PMID- 26497318 TI - A Comparison of Biological Activity of B Lymphocyte Stimulator (BLyS) Antagonist Peptibodies and the Elucidation of Possible BLyS Binding Sites. AB - B lymphocyte stimulator (BLyS) overexpression is associated with autoimmune diseases such as rheumatoid arthritis and lupus. BLyS antagonists are new effective therapeutic strategies that have been studied extensively. BLyS-binding peptides, BC originated from computer-aided drug design (CADD), 814 selected from the phage display library, as well as the 3-copy of BC (3-BC), were fused with human IgG1 Fc to constitute peptide-Fc fusion proteins, referred as peptibodies. BP-Fc, a peptibody possessing the identical sequence as BC-Fc but a His tag, was also constructed. The biological activities of these peptibodies were assessed by Enzyme-Linked Immuno Sorbent Assay (ELISA). Furthermore, the potential interacting orientations of BP and 814 with BLyS were studied. At 100 MUg/ml, BC Fc, BP-Fc, 814-Fc and 3-BC-Fc could distinctly inhibit 64 %, 50 %, 73 % and 56 % of the interaction of B cell maturation antigen (BCMA) with BLyS respectively. BP Fc demonstrated 15 % higher binding ratio with BLyS than BC-Fc at 100 MUg/ml. However, 814-Fc displayed at least 39 % higher BLyS-binding activity than BP-Fc at different concentrations. The binding capacity of 3-BC-Fc was slightly superior to BC-Fc. In addition, 814 and BP shared the identical domain on the surface of BLyS which involves in binding with BCMA, but owned the detached orientations. The discovery of possible locations of the BLyS-targeted peptides lays the foundation for the development of novel antagonists. Both BP-Fc and 3-BC Fc fusion proteins could bind to BLyS in a dose-dependent manner and inhibit BLyS biological activity significantly, which might act as candidate agents for autoimmune disease therapy. PMID- 26497319 TI - Designing and structure evaluation of multi-epitope vaccine against ETEC and EHEC, an in silico approach. AB - Diarrheal diseases represent a major health problem in developing countries. Several viruses and bacterial agents, such as Enterotoxigenic Escherichia coli (ETEC) and Enterohemorrhagic Escherichia coli (EHEC) are responsible for human enteric infections. In humans, EHEC infections result in bloody or non-bloody diarrhea, which may be complicated by haemorrhagic colitis and haemolytic uraemic syndrome (HUS). Infection by ETEC is accompanied by a non inflammatory watery diarrhea. E. coli follows a common strategy of infection: colonization on a mucosal site, evasion of host defenses, multiplication, and host damage. Intimin, Stx, Lt and Cfa proteins are the virulence factors expressed by these strains. Antibiotic treatment is generally not recommended for most cases of diarrhea, since antibiotic usage may lead to antibiotic resistance in ETEC and may also change the intestinal flora. We hypothesized that the chimeric forms of these effectors as vaccine candidates would reduce the colonization of bacteria. This study is based on an in silico analysis of chimeric protein structure and its stability and solubility. The secondary and tertiary structures of selected domains were also predicted. Moreover, T and B cell epitopes were mapped. Protein structure Prediction showed that each domain of antigen was separated completely also stable for recombinant expression. We believe that this chimeric vaccine candidate is effective for prevention of bacteria caused diarrheal diseases. PMID- 26497322 TI - Islet Xeno/transplantation and the risk of contagion: local responses from Canada and Australia to an emerging global technoscience. AB - This paper situates the public debate over the use of living animal organs and tissue for human therapies within the history of experimental islet transplantation. Specifically, the paper compares and contrasts the Canadian and Australian responses on xenotransplantation to consider what lessons can be learnt about the regulation of a complex and controversial biotechnology. Sobbrio and Jorqui described public engagement on xenotransplantation in these countries as 'important forms of experimental democracy.' While Canada experimented with a novel nation-wide public consultation, Australia sought public input within the context of a national inquiry. In both instances, the outcome was a temporary moratorium on all forms of clinical xenotransplantation comparable to the policies adopted in some European countries. In addition, the Australian xenotransplantation ban coincided with a temporary global ban on experimental islet allotransplantation in 2007. Through historical and comparative research, this paper investigates how public controversies over organ and tissue transplantation can inform our understanding of the mediation of interspeciality and the regulation of a highly contested technoscience. It offers an alternative perspective on the xenotransplantation controversy by exploring the ways in which coinciding moratoriums on islet allograft and xenograft challenge, complicate and confound our assumptions regarding the relationships between human and animal, between routine surgery and clinical experimentation, between biomedical science and social science, and between disease risks and material contagion. PMID- 26497323 TI - Relative importance of Microcystis abundance and diversity in determining microcystin dynamics in Lake Erie coastal wetland and downstream beach water. AB - AIMS: Microcystis population and microcystin (MC) dynamics were investigated in western Lake Erie coastal wetlands and downstream beach water. A three dimensional (3-D) model was developed to quantify how Microcystis population size and structure affect MCs. METHODS AND RESULTS: Real-time PCR, denaturing gradient gel electrophoresis (DGGE) and enzyme-linked immunoabsorbent assay (ELISA) were used. A moderate-low level of Microcystis abundance and MCs were detected with a significant increase along the wetland flow and the spatiotemporal homogeneity of Microcystis populations. The proportion of toxigenic and nontoxgenic genotypes appeared to be more affected by the variation in two major Microcystis PC-IGS genotypes. MC dynamics was associated with the changing Microcystis population size and structure. The 3-D model showed that Microcystis population with greater Microcystis PC-IGS abundance (and simultaneously higher diversity) had more MCs. CONCLUSION: Microcystin variation was significantly affected by Microcystis population size and structure. The 3-D model also revealed the relative importance of Microcystis population size and structure in determining MCs in the Lake Erie costal wetland and downstream beach water. SIGNIFICANCE AND IMPACT OF THE STUDY: This study enriches our understanding of Microcystis population and microcystin ecology in a western Lake Erie coastal wetland and downstream beach water. Our illustrative model brings a new perspective for understanding the ecological relationship between Microcystis population size and structure and MCs. PMID- 26497324 TI - Cut-off Scores and Clinical Change Indices for the Dutch Outcome Questionnaire (OQ-45) in a Large Sample of Normal and Several Psychotherapeutic Populations. AB - : The Outcome Questionnaire-45 (OQ-45; Lambert et al., ) has been designed for frequent assessment of a patient's functioning during the course of psychotherapy and has become one of the most frequently used outcome measures in the Netherlands. The OQ-45 was originally normed on outpatients in secondary care only, but is applied in a wide variety of patient populations. As such, it has become increasingly important to provide cut-off scores with the normal population, as well as between different patient populations. The present large scale Dutch study aims to provide cut-off scores between several populations. Data were collected from the normal population (n = 1810) and patients in five different treatment settings: outpatient primary care (n = 1581), outpatient secondary care (n = 9433), private practice (n = 457), day patient (n = 481) and inpatient therapies (n = 485), a total of more than 14.000 administrations. Reliable change indices and cut-off scores were calculated using the method of Jacobson and Truax (). The reliable change index for the patient population was calculated as 18 and the cut-off between the normal and patient population as 56. Sensitivity, specificity and area under the curves of cut-off scores between the normal population and the treatment settings were satisfactory and generally higher than 0.80. Between the patient populations, these measures were generally too low for strict use. The OQ-45 total score can satisfactorily discriminate between the normal and patient populations. For assignment to specific treatment types, the OQ-45 may help, but its use is somewhat limited in practice. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: The Dutch OQ-45 has satisfactory levels of reliability, sensitivity, specificity and area under the curve. The new overall cut-off score for normal function for the Dutch OQ-45 is 56 and the new reliable change index is 18. Cut-off scores for several therapeutic treatments are provided. PMID- 26497325 TI - A systematic review of mentorship programs to facilitate transition to post secondary education and employment for youth and young adults with disabilities. AB - PURPOSE: Youth with disabilities experience barriers in transitioning to Post Secondary Education (PSE) and employment. Mentorship programs provide a promising approach to supporting youth through those transitions. This paper aims to identify the effective components of mentorship programs and describe participants' experiences. METHOD: We undertook a systematic review of mentorship interventions for youth and young adults with disabilities. We searched seven electronic databases for peer-reviewed articles published in English between 1980 and 2014. We included articles that examined mentorship interventions focused on PSE or employment outcomes among youth, aged thirty or younger, with physical, developmental, or cognitive disabilities. RESULTS: Of the 5068 articles identified, 22 met the inclusion criteria. For seven mentorship interventions, at least one significant improvement was reported in school- or work-related outcomes. Mentorship programs with significant outcomes were often structured, delivered in group-based or mixed formats, and longer in duration (>6 months). Mentors acted as role models, offered advice, and provided mentees with social and emotional support. CONCLUSIONS: Evidence suggests that mentorship programs may be effective for helping youth with disabilities transition to PSE or employment. More rigorously designed studies are needed to document the impact of mentorship programs on school and vocational outcomes for youth with disabilities. Implications for Rehabilitation Mentorship interventions have the potential to effectively support youth with disabilities as they transition to post-secondary education and employment. Youth should consider participating in formal mentorship interventions, and clinicians and educators should encourage them to do so, to enhance social, educational, and vocational outcomes. When developing interventions, clinicians should consider incorporating the effective components (i.e. duration, content, format) of mentorship interventions identified in this paper. Future mentorship programs should also contain a rigorous evaluation component. Clinicians can help to create (build content, consult on accessibility), connect (youth to program, program to community agencies), and contribute to mentorship interventions. PMID- 26497326 TI - Physiological and transcriptional regulation in poplar roots and leaves during acclimation to high temperature and drought. AB - To elucidate the physiological and transcriptional regulatory mechanisms that underlie the responses of poplars to high temperature (HT) and/or drought in woody plants, we exposed Populus alba * Populus tremula var. glandulosa saplings to ambient temperature (AT) or HT under 80 or 40% field capacities (FC), or no watering. HT increased the foliar total carbon (C) concentrations, and foliar delta(13) C and delta(18) O. HT triggered heat stress signaling via increasing levels of abscisic acid (ABA) and indole-3-acetic acid (IAA) in poplar roots and leaves. After perception of HT, poplars initiated osmotic adjustment by increasing foliar sucrose and root galactose levels. In agreement with the HT induced heat stress and the changes in the levels of ABA and carbohydrates, we detected increased transcript levels of HSP18 and HSP21, as well as NCED3 in the roots and leaves, and the sugar transporter gene STP14 in the roots. Compared with AT, drought induced greater enhancement of foliar delta(13) C and delta(18) O in poplars at HT. Similarly, drought caused greater stimulation of the ABA and foliar glucose levels in poplars at HT than at AT. Correspondingly, desiccation led to greater increases in the mRNA levels of HSP18, HSP21, NCED3, STP14 and INT1 in poplar roots at HT than at AT. These results suggest that HT has detrimental effects on physiological processes and it induces the transcriptional regulation of key genes involved in heat stress responses, ABA biosynthesis and sugar transport and HT can cause greater changes in drought-induced physiological and transcriptional responses in poplar roots and leaves. PMID- 26497327 TI - Assessing and monitoring intratumor heterogeneity in glioblastoma: how far has multimodal imaging come? AB - Glioblastoma demonstrates imaging features of intratumor heterogeneity that result from underlying heterogeneous biological properties. This stems from variations in cellular behavior that result from genetic mutations that either drive, or are driven by, heterogeneous microenvironment conditions. Among all imaging methods available, only T1-weighted contrast-enhancing and T2-weighted fluid-attenuated inversion recovery are used in standard clinical glioblastoma assessment and monitoring. Advanced imaging modalities are still considered emerging techniques as appropriate end points and robust methodologies are missing from clinical trials. Discovering how these images specifically relate to the underlying tumor biology may aid in improving quality of clinical trials and understanding the factors involved in regional responses to treatment, including variable drug uptake and effect of radiotherapy. Upon validation and standardization of emerging MR techniques, providing information based on the underlying tumor biology, these images may allow for clinical decision-making that is tailored to an individual's response to treatment. PMID- 26497328 TI - Sialylation and glycosylation modulate cell adhesion and invasion to extracellular matrix in human malignant lymphoma: Dependency on integrin and the Rho GTPase family. AB - To determine the biological roles of cell surface glycosylation, we modified the surface glycosylation of human malignant lymphoma cell lines using glycosylation inhibitors. The O-glycosylation inhibitor, benzyl-alpha-GalNAc (BZ) enhanced the fibronectin adhesion of HBL-8 cells, a human Burkitt's lymphoma cell line, and of H-ALCL cells, a human anaplastic large cell lymphoma cell line, both of which were established in our laboratory. The N-glycosylation inhibitor, tunicamycin (TM) inhibited the surface expression of Phaseolus vulgaris leukoagglutinating (L PHA) lectin- and Canavalia ensiformis (ConA) lectin-reactive oligosaccharides in the HBL-8 cell line. Assay of the adhesion of HBL-8 cells to fibronectin showed that fibronectin adhesion is mediated by the integrin very late antigen (VLA)-4 and that not only BZ but also TM treatment enhanced HBL-8 cell adhesion to fibronectin. Furthermore, although BZ treatment also enhanced H-ALCL cell adhesion to fibronectin, this effect was not mediated by VLA-5 or the RGD sequence of fibronectin. We also showed that H-ALCL cell adhesion to galectin-3 was enhanced by pre-treatment with neuraminidase, which cleaves cell surface sialic acid. Additionally, H-ALCL cell adhesion to galectin-3 was inhibited by pre-treatment with the RGD peptide suggesting that cell adhesion to galectin-3 is mediated by integrin (VLA-5). Furthermore, H-ALCL cell invasion of galectin-1 and galectin-3 was inhibited by pre-treatment with the RGD peptide. Therefore, cell adhesion to and invasion of galectin-1 and galectin-3 are integrin-dependent. In addition to these findings, cell adhesion to galectin-3 was markedly inhibited by treatment with beta-lactose compared to treatment with sucrose. Therefore, interactions between integrins and galectin-3 may be mediated through beta galactose that is linked to glycans of integrins. AZA1, an inhibitor of Ras homolog oncoprotein (Rho) GTPase family proteins, RAS-related C3 botulinus toxin substrate 1 (Rac 1) and Cell division control protein 42 homolog (Cdc42) markedly inhibited cell invasion of galectin-1 and galectin-3 suggesting that Rac 1 and Cdc42 may be involved in the regulation of H-ALCL cell invasion of galectins. In conclusion, artificial modification of cell surface glycosylation revealed the biological roles of glycosylation in the adhesion to and invasion of the extracellular matrix (ECM) by human malignant lymphoma cell lines. These findings will provide new insight into the glycobiology of human malignant lymphoma. PMID- 26497329 TI - Glucose Fluctuations Aggravate Cardiac Susceptibility to Ischemia/Reperfusion Injury by Modulating MicroRNAs Expression. AB - BACKGROUND: The influence of glucose fluctuations (GF) on cardiovascular complications of diabetes mellitus (DM) has been attracting much attention. In the present study, whether GF increase susceptibility to ischemia/reperfusion in the heart was investigated. METHODS AND RESULTS: Male rats were randomly assigned to either a control, DM, and DM with GF group. DM was induced by an injection of streptozotocin, and glucose fluctuation was induced by starvation and insulin injection. One sequential program comprised 2 hypoglycemic episodes during 4 days. The isolated hearts were subjected to 20-min ischemia/30-min reperfusion. The infarct size was larger in hearts with GF than those with sustained hyperglycemia. Activities of catalase and superoxide dismutase were decreased, and expressions of NADPH oxidase and thioredoxin-interacting protein were upregulated by GF accompanied by an increase of reactive oxygen species (ROS). Swollen mitochondria with destroyed cristae were observed in diabetic hearts; they were further devastated by GF. Microarray analysis revealed that the expressions of microRNA (miRNA)-200c and miRNA-141 were abundant in those hearts with GF. Overexpression of miRNA-200c and miRNA-141 decreased mitochondrial superoxide dismutase and catalase activities, and increased ROS levels. Meanwhile, knockdown of miRNA-200c and miRNA-141 significantly decreased ROS levels in cardiomyocytes exposed to GF. CONCLUSIONS: GF increased ROS generation and enhanced ischemia/reperfusion injury in the diabetic heart. Upregulated miRNA 200c and miRNA-141 may account for the increased ROS. PMID- 26497330 TI - Epicardial Adipose Tissue Accumulation Is Associated With Renal Dysfunction and Coronary Plaque Morphology on Multidetector Computed Tomography. AB - BACKGROUND: Chronic kidney disease (CKD) is strongly associated with coronary artery disease (CAD), although the underlying pathophysiological mechanism remains unclear. Epicardial adipose tissue (EAT) has recently been recognized as an important source of various pro-inflammatory cytokines causing coronary atherosclerosis. This study investigated the relationship between CKD and EAT volume in association with high-risk plaque. METHODS AND RESULTS: The study included 275 patients with an estimated glomerular filtration rate (eGFR) >=30 ml/min/1.73 m(2)who underwent multidetector computed tomography (MDCT) for the evaluation of CAD. Patients were classified, according to eGFR, into a CKD group (30<=eGFR<60 ml/min/1.73 m(2)) or a non-CKD group (eGFR >=60 ml/min/1.73 m(2)). MDCT was used to assess coronary plaque morphology and EAT volume. One hundred and ten patients with CKD were more likely to be older, have higher prevalence of hypertension, lower serum HDL-C, higher serum CRP, and larger EAT volume, than those without CKD (all P<0.01). On multivariate analysis age, hypertension, and EAT volume were significantly associated with eGFR (all P<0.01). EAT volume was associated with the presence of high-risk plaque, independent of traditional CAD risk factors (P=0.003). CONCLUSIONS: Patients with CKD had significantly increased EAT volume, which could be associated with the presence of high-risk plaque. PMID- 26497331 TI - Successful Management of Guidewire Kinking in a Patient With Subaortic Septal Bulging Using the Pull-Through Technique During Transapical Transcatheter Aortic Valve Implantation. PMID- 26497332 TI - Suppression of Evi1 promotes the osteogenic differentiation and inhibits the adipogenic differentiation of bone marrow-derived mesenchymal stem cells in vitro. AB - Osteoporosis (OP) is considered a complex disease with a strong genetic impact, mainly affecting post-menopausal women and is also a common cause of fracture. Elucidating the molecular mechanisms that regulate the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) is crucial to developing treatment strategies to combat OP. In the present study, we found that ectopic viral integration site-1 (Evi1) was highly expressed during the process of adipogenesis of rat BMSCs. Notably, Evi1 levels markedly increased on day 3 of adipogenic differentiation following the addition of adipogenic induction supplements. In addition, we interfered with the expression of the Evi1 gene in the adipogenesis of BMSCs by supplementing adenoviral plasmids and measured the expression levels of bone sialoprotein (BSP), osteocalcin (OCN), osteopontin (OPN), peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and lipoprotein lipase (LPL) by RT-qPCR and western blot analysis. The mRNA and protein levels of osteogenic and adipogenic markers in the BMSCs were up- and downregulated, respectively following the silencing of siEvi1. Our experimental results substantiate that the suppression of Evi1 in BMSCs by RNA interference inhibits adipogenic differentiation, while it promotes osteogenic differentiation. The results from our study demonstrated that the Evi1 gene may be targeted as a therapeutic strategy for promoting bone formation. PMID- 26497333 TI - Administration of zinc complex of acetylsalicylic acid after the onset of myocardial injury protects the heart by upregulation of antioxidant enzymes. AB - We recently demonstrated that the pre-treatment of rats with zinc and acetylsalicylic acid complex in the form of bis(aspirinato)zinc(II) [Zn(ASA)2] is superior to acetylsalicylic acid in protecting the heart from acute myocardial ischemia. Herein, we hypothesized that Zn(ASA)2 treatment after the onset of an acute myocardial injury could protect the heart. The rats were treated with a vehicle or Zn(ASA)2 after an isoproterenol injection. Isoproterenol-induced cardiac damage [inflammatory infiltration into myocardial tissue, DNA-strand breakage evidenced by TUNEL-assay, increased 11-dehydro thromboxane (TX)B2 levels, elevated ST-segment, widened QRS complex and prolonged QT-interval] was prevented by the Zn(ASA)2 treatment. In isoproterenol-treated rats, load independent left ventricular contractility parameters were significantly improved after Zn(ASA)2. Furthermore, Zn(ASA)2 significantly increased the myocardial mRNA expression of superoxide dismutase-1, glutathione peroxidase-4 and decreased the level of Na(+)/K(+)/ATPase. Postconditioning with Zn(ASA)2 protects the heart from acute myocardial ischemia. Its mechanisms of action might involve inhibition of pro-inflammatory prostanoids and upregulation of antioxidant enzymes. PMID- 26497334 TI - Postnatal overnutrition in mice leads to impaired pulmonary mechanics in response to salbutamol. AB - Obesity increases the risk of respiratory disease, which is associated with airway hyperresponsiveness. Although the molecular underpinnings of this phenomenon are not well established, lung remodeling is known as an important factor in this process and could potentially explain compromised lung functions. In the present study, the obesity was induced by postnatal overnutrition in Swiss mice and we investigated the pulmonary mechanics after aerosolization of saline, methacholine, and salbutamol. The lungs were prepared for morphometric analysis. Obese animals showed bronchoconstriction in response to methacholine, as evidenced by airway and tissue resistance, tissue elastance, and hysteresivity. Salbutamol was effective at recovering the response only for airway resistance but not for tissue mechanics. We suggest that this impaired response in obese mice is related to collapsed alveolar, to inflammatory cells, and to elevated deposition collagen fibers in parenchymal tissue. PMID- 26497336 TI - Rhodiola rosea extends lifespan and improves stress tolerance in silkworm, Bombyx mori. AB - The root of Rhodiola rosea is widely used in Traditional Chinese Medicine. The extract from R. rosea is reported to extend the lifespan of yeast, nematode, and fruit fly. However, the molecular mechanism is not fully understood. Here, we tested whether R. rosea extends the lifespan of the silkworm. An aqueous extract of R. rosea significantly prolonged the lifespan of the silkworm, without affecting its daily food intake, body weight, or fecundity, suggesting that R. rosea did not exhibit obvious side effects. Rhodiola rosea extract also enhanced the stress resistance in the silkworm, against heat stress (37 degrees C) and starvation. The R. rosea extract increased the activity of the major antioxidant enzymes, glutathione S-transferase and catalase, and altered the content of glutathione and malondialdehyde. Rhodiola rosea increased the expression of BmFoxO, which is a downstream regulator of insulin/IGF-1 signaling (IIS) pathway in the silkworm. Our results showed that R. rosea extends lifespan, in which IIS pathway might be involved, and enhances stress resistance in the silkworm. Thus, the silkworm might be used as a novel animal model for lifespan study and efficacy evaluation of Traditional Chinese Medicines. PMID- 26497335 TI - Deteriorated glucose metabolism with a high-protein, low-carbohydrate diet in db mice, an animal model of type 2 diabetes, might be caused by insufficient insulin secretion. AB - PURPOSE: We previously showed the deleterious effects of increased dietary protein on renal manifestations and glucose metabolism in leptin receptor deficient (db) mice. Here, we further examined its effects on glucose metabolism, including urinary C-peptide. We also orally administered mixtures corresponding to low- or high-protein diets to diabetic mice. METHODS: In diet experiments, under pair-feeding (equivalent energy and fat) conditions using a metabolic cage, mice were fed diets with different protein content (L diet: 12 % protein, 71 % carbohydrate, 17 % fat; H diet: 24 % protein, 59 % carbohydrate, 17 % fat) for 15 days. In oral administration experiments, the respective mixtures (L mixture: 12 % proline, 71 % maltose or starch, 17 % linoleic acid; H mixture: 24 % proline, 59 % maltose or starch, 17 % linoleic acid) were supplied to mice. Biochemical parameters related to glucose metabolism were measured. RESULTS: The db-H diet mice showed significantly higher water intake, urinary volume, and glucose levels than db-L diet mice but similar levels of excreted urinary C-peptide. In contrast, control-H diet mice showed significantly higher C-peptide excretion than control-L diet mice. Both types of mice fed H diet excreted high levels of urinary albumin. When maltose mixtures were administered, db-L mixture mice showed significantly higher blood glucose after 30 min than db-H mixture mice. However, db mice administered starch-H mixture showed significantly higher blood glucose 120-300 min post-administration than db-L mixture mice, although both groups exhibited similar insulin levels. CONCLUSIONS: High-protein, low carbohydrate diets deteriorated diabetic conditions and were associated with insufficient insulin secretion in db mice. Our findings may have implications for dietary management of diabetic symptoms in human patients. PMID- 26497337 TI - MicroRNA-1 suppresses cardiac hypertrophy by targeting nuclear factor of activated T cells cytoplasmic 3. AB - Cardiomyocyte hypertrophy is a threat to human health due to the probability of sudden heart failure-induced mortality. Previous studies have demonstrated that nuclear factor of activated T cells cytoplasmic 3 (NFATC3) is important in the process of cardiomyocyte hypertrophy. However, the molecular mechanism underlying the alteration in the expression levels of NFATC3 during cardiomyocyte hypertrophy has remained to be fully elucidated. In order to shed light on the molecular mechanism, the present study employed several approaches, including the measurement of the cell surface area, analysis of the protein/DNA ratio, western blot analysis and a Luciferase reporter assay using isolated rat cardiomyocytes as model. The results showed that expression of microRNA-1 (miR-1) was reduced in patients diagnosed with cardiac hypertrophy and rat cardiomyocytes treated with pro-hypertrophic stimuli. The increase in the expression of miR-1 was able to inhibit the hypertrophic remodeling of cardiomyocytes. The suppression of miR-1 was sufficient to induce cardiomyocyte hypertrophy, and further experiments confirmed that NFATC3 was a target of miR-1 in cardiomyocytes. Forced expression of NFATC3 inhibited the protective activity of miR-1 against hypertrophic stimuli in the cardiomyocytes. These findings provided clarification of the regulatory signaling pathway underlying cardiac hypertrophy, and provided evidence that targeting the miR-1/NFATC3 pathway may be a promising strategy for the prevention and treatment of heart hypertrophy. PMID- 26497338 TI - Benign prostatic hyperplasia: epidemiology, economics and evaluation. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is arguably the most common benign disease of mankind. As men age, the prostate inexorably grows often causing troubling symptoms causing them to seek out care. While traditionally treated by transurethral resection or open surgical removal of the hypertrophied adenoma, today the urologist has numerous medical, surgical and minimally invasive techniques available. In this supplement The Canadian Journal of Urology provides a review of the various techniques and medications available today. MATERIALS AND METHODS: As an introduction to the supplement, the aim of this article is to review the epidemiology and economy of BPH as well as its natural history and diagnosis. A systematic review of available literature was looking for articles on BPH and its epidemiology, economics, natural history and management using PubMed database. RESULTS: The prevalence of this condition is increasing with the population aging and so does the economic burden. The exact etiology of this condition is unknown, but some risk factors have been identified. The diagnostic and treatment of this very common disease should rely on a strong collaboration between primary care physician and urologist. CONCLUSION: There are multiple options in treating BPH including medical, surgical and newer minimally invasive options. The challenge with having a variety of options is to review them with the patient and help the patient select the best treatment option for their condition. PMID- 26497339 TI - Medical therapy for benign prostatic hyperplasia: a review. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is a common disease that affects men as they age. Historically the treatment has been primarily surgical in nature, but over the past 25 years significant advances in medical therapy have been made, sparing some men from interventional procedures. MATERIALS AND METHODS: This article highlights the current state-of-the-art with respect to medical therapy for lower urinary tract symptoms secondary to BPH (BPH-LUTS) including a review of landmark studies and recent areas of research in the field. RESULTS: Alpha blockers are considered first line when treating BPH-LUTS in men with small prostates and 5-alpha reductase inhibitors (5-ARIs) are recommended in men with large symptomatic prostates. While, phosphodiesterase-5 (PDE-5) inhibitors are the mainstay of erectile dysfunction therapy, they also play a role in treating BPH-LUTS. If men have persistent irritative storage symptoms after first line BPH therapy then overactive bladder (OAB) medications can be added or substituted. Combination therapies can be used to provide short term symptom relief with long term disease management. CONCLUSIONS: Medical therapy remains the main treatment option for men suffering from BPH-LUTS. Numerous medical options are available that can be tailored to meet the individual's needs depending on their personal and prostate characteristics. An algorithmic approach, as we have defined within this article, can be a helpful guide to this decision-making process. PMID- 26497340 TI - Complementary and alternative medications for benign prostatic hyperplasia. AB - INTRODUCTION: The use of complementary and alternative medications has become a multi-million dollar business in the United States and comprises more than half of all filled prescriptions for benign prostatic hyperplasia (BPH) in Europe. For the practicing urologist, understanding the phytotherapeutic agents available, their proposed mechanism of action, the research supporting their use, and their safety profiles has become increasingly important as more patients inquire into their use. MATERIALS AND METHODS: A comprehensive literature search was conducted to identify pertinent articles pertaining to alternative and complementary treatment options for the management of BPH. Treatments demonstrating adequate clinical data, including Serona repens, Pygeum africanum, and Secale cereal, were selected for in depth review. RESULTS: Small clinical trials for each of the agents demonstrated mixed results while larger more soundly constructed studies found no significant benefit for the use of phytotherapy in the treatment of BPH. CONCLUSIONS: Based on the available literature, there is no evidence that phytotherapy significantly improves symptoms of BPH against placebo, despite being largely safe for ingestion. In patients with mild BPH symptoms who are reluctant to take standard pharmaceutical medications may try these agents provided that the patient understands their current limitations. Those with moderate or severe BPH should be discouraged from alternative and complementary treatments. PMID- 26497341 TI - Electrosurgical transurethral resection of the prostate and transurethral incision of the prostate (monopolar techniques). AB - INTRODUCTION: We summarize the current guidelines, techniques, efficacy and complications associated with monopolar transurethral resection of the prostate (TURP) and transurethral incision of the prostate (TUIP) for benign prostatic hyperplasia (BPH). Patients who elect to have endoscopic surgical bladder outlet reduction are faced with an abundance of evolving treatment options. As new technology comes and goes, TURP and TUIP remain the gold standard for which new treatments are compared. MATERIALS AND METHODS: A review of past and contemporary data including American and European guidelines was performed. Techniques, efficacy, durability, short term and long term complications of TURP and TUIP are summarized. RESULTS: Small prostate sizes < 30 mL without a median lobe can be effectively treated with TUIP with decreased perioperative complications and sexual side effects compared to TURP. Monopolar TURP demonstrates significant improvements in IPSS, peak flow rate (Qmax), and quality of life (QoL) with durable (8 year-22 year) outcomes. Secondary intervention increases by 1%-2% annually. Thirty-day mortality rate is low (0.1%) as well as incidence of TUR syndrome (< 1.1%). Short term and long term complications include bleeding requiring transfusion, clot retention, acute urinary retention (AUR), and urinary tract infections as well as incontinence, bladder neck contracture, urethral stricture, and sexual dysfunction. CONCLUSIONS: Monopolar TURP and TUIP are effective endoscopic treatments for BPH with durable long term results. While the short term and long term complication rates are acceptable, new technologies aim to increase tolerability of bladder outlet reduction by decreasing treatment related morbidity. PMID- 26497342 TI - Bipolar energy in the treatment of benign prostatic hyperplasia: a current systematic review of the literature. AB - INTRODUCTION: For decades, the monopolar transurethral resection of the prostate has been established as the minimally invasive surgical treatment for patients with benign prostatic hyperplasia (BPH). In recent years, new technologies and devices emerged to reduce the morbidity and improve outcomes for this treatment approach. Bipolar energy introduced the use of saline irrigation and laser technology increased the urological armamentarium to treat BPH. We performed a systematic review of the literature regarding bipolar technology for the treatment of BPH. MATERIALS AND METHODS: A MEDLINE database search using the PRISMA methodology. Selected literature was restricted to articles published in English and published between 2005 and 2015. Articles regarding techniques using bipolar energy were included, while manuscripts that used a different technique, hybrid techniques, or techniques other than bipolar resection, bipolar vaporization, and bipolar enucleation were excluded. RESULTS: The use of bipolar energy in the endoscopic treatment of BPH presented a significant reduction in operative time, perioperative complications, shorter catheterization time, reduced number of blood products transfused, and shorter hospital stay compared to standard techniques. Postoperative outcomes showed that bipolar energy was safe and offered significant outcome improvement when compared to traditional monopolar transurethral resection of the prostate (TURP). CONCLUSION: The use of bipolar energy in the surgical treatment of patients with BPH is safe and is associated with improvements in perioperative outcomes. Short and mid-term functional outcomes are comparable to standard techniques, but long term functional outcomes need better clinical evaluation. PMID- 26497343 TI - Photoselective laser ablation of the prostate: a review of the current 2015 tissue ablation options. AB - INTRODUCTION: Transurethral resection of the prostate (TURP) is still considered the gold standard to treat benign prostatic hyperplasia (BPH). However, photoselective vaporization of the prostate (PVP) has gained widespread acceptance as an alternative option requiring preoperative patient selection. Four laser systems are currently in use: holmium, thulium, diode and GreenLight. MATERIALS AND METHODS: The goal of this article is to review the physics and the basics behind laser prostatectomies, as well as to present the most current literature concerning the results, advantages, disadvantages and international recommendations for each vaporization procedure. RESULTS: Holmium laser ablation of the prostate (HoLAP) and GreenLight photoselective vaporization of the prostate are an alternative to TURP for small to medium-sized prostates, providing equivalent efficacy and safety. GreenLight is also safe and effective in large-sized prostates and especially beneficial in anti-coagulated individuals compared to TURP. Thulium vaporization of the prostate (ThuVAP) and diode vaporization both require additional randomized trials and long term studies before conclusion is made, despite promising initial results. Diode vaporization provides the best hemostasis overall, but at the cost of increased complication and re-treatment rate, and thus is not recommended except in severely anti coagulated patients. CONCLUSION: Laser vaporization is a safe and effective alternative to TURP in the treatment of benign prostatic hyperplasia (BPH) for carefully selected patients. However, further research is still needed to assess the durability of each technology. PMID- 26497344 TI - Laser prostate enucleation techniques. AB - INTRODUCTION: Laser treatment of benign prostatic hyperplasia (BPH) through enucleation techniques has become increasingly more utilized in the field of urology. Laser enucleation of the prostate (LEP) is a transurethral procedure that employs several different types of lasers to dissect the adenoma from the surgical capsule in a retrograde fashion. MATERIALS AND METHODS: We review basic laser physics and current laser prostate enucleation techniques. Holmium-LEP (HoLEP), Thulium-LEP (ThuLEP), Greenlight-LEP (GreenLEP) and Diode-LEP (DiLEP) applications are discussed. We summarize the current literature with respect to functional outcomes and complications. RESULTS: Although each laser device used for prostate enucleation has the same goal of removal of the adenoma from the surgical capsule, each has unique characteristics (i.e. wavelength, absorption rates) that must be understood by the practicing surgeon. Mastery of one LEP technique does not necessarily translate into facile use of an alternative enucleation energy source and/or approach. The various LEP techniques have demonstrated similar, if not superior, postoperative results to transurethral resection of the prostate (TURP), the current gold standard in the treatment of BPH. CONCLUSIONS: This article outlines the current LEP techniques and should serve as a quick reference for the practicing urologist. PMID- 26497345 TI - Prostatectomy for benign prostate disease: open, laparoscopic and robotic techniques. AB - INTRODUCTION: Prostatectomy for benign disease, also known as a 'simple prostatectomy', is neither simple in indication nor approach. In the post-Medical Therapy of Prostatic Symptoms (MTOPS), NCT00021814 trial era, the medical management of benign prostatic hyperplasia (BPH) and consequent bladder outlet obstruction (BOO) has shifted surgical intervention to those patients who are medical-non responders, present with advanced signs of BOO and obstructive uropathy, and those with prostate gland volumes beyond the size normally approachable with standard transurethral resection of the prostate (TURP). Simple prostatectomy through an open surgical approach is associated with improvements in BOO and lower urinary tract symptoms (LUTS) but at the expense of considerable surgical and perioperative morbidity. Advances in technology have made it possible for patients to be offered standard open surgical approaches as well as transurethral approaches with photon-based energy sources (i.e. laser prostatectomy) and laparoscopic simple prostatectomy. A review of the historical challenges of BPH and the standard-of-care of open prostatectomy will put into perspective the potential advantages and disadvantages of laparoscopic and robotic prostatectomy for the treatment of benign BOO due to BPH. MATERIALS AND METHODS: A careful review of the literature was performed utilizing PubMed and ClinicalKey searches to identify relevant articles. Search terms 'simple prostatectomy', 'robotic simple prostatectomy' and 'laparoscopic simple prostatectomy'. RESULTS: Over 14 series of open simple prostatectomies and over 20 minimally invasive series were identified and used as a reference. Additionally, several review articles were identified and incorporated. CONCLUSIONS: Simple prostatectomy may be performed safely in appropriately selected patients utilizing either open or minimally invasive approaches. Clinical criteria should be used to determine the appropriateness of either retropubic versus transvesical approach. PMID- 26497346 TI - Prostatic urethral lift: a novel approach for managing symptomatic BPH in the aging man. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is an obligate disorder of the aging male prostate with close associations to other metabolic conditions of aging including obesity. Clinical manifestations of this chronic disorder increase as men age suggesting that a growing number of older men will require intervention for progressive voiding symptoms or bladder dysfunction. MATERIALS AND METHODS: The Prostatic Urethral Lift (PUL) procedure represents a new endoscopic approach in which small permanent intraprostatic implants are positioned to correct bladder outlet obstruction without tissue destruction. An overview of the treatment modality, review of recent literature, and analysis of data in the context of cost considerations is presented. RESULTS: The mean symptom score improvement of the prospective, sham controlled, pivotal trial was 11 points, 88% greater than sham controls. Multiple studies have confirmed symptom score improvement of at least 52%. Durability has been established out to 3 years. A randomized comparison between PUL and transurethral resection of the prostate (TURP) established PUL as superior to TURP in terms of a composite BPH6 endpoint which incorporated symptom relief, quality of recovery, erectile function preservation, ejaculatory function preservation, continence preservation, and safety. The National Institute for Health and Care Excellence of the United Kingdom conducted an analysis that found PUL is less costly than TURP. Earlier management with PUL may even reduce overall cost for those patients managed with medication. CONCLUSION: Current reports have demonstrated rapid voiding symptom improvement with a low risk of adverse events suggesting that this procedure represents a safe and cost effective new paradigm for the early therapy for BPH/ LUTS. PMID- 26497347 TI - The management of prostatic obstruction with urethral stents. AB - INTRODUCTION: Elderly men with multiple comorbidities may be unfit to undergo surgical management of benign prostatic obstruction (BPO). Permanent and temporary prostatic stents have been developed as an alternative to chronic indwelling catheters in men unfit for surgery. MATERIALS AND METHODS: Herein we review the past and present literature on the role and effectiveness of prostatic stents in the treatment of BPO. RESULTS: Permanent prostatic stents have largely been abandoned in North America due to unfavorable outcomes and improved technologies to allow for treatment of BPO. Currently, the temporary Spanner stent is the only available stent on the market, but its effectiveness has mostly been documented for temporary relief of tissue edema following minimal invasive ablative treatments for BPO. CONCLUSIONS: The advent of well-tolerated surgical treatments for BPO (KTP laser vaporization, bipolar TURP, urethral lift devices) has diminished the need for permanent prostatic stents. The temporary Spanner stent is an alternative to urethral catheter, but requires adequate detrusor function and can cause irritative symptoms. PMID- 26497348 TI - Evolving and investigational therapies for benign prostatic hyperplasia. AB - INTRODUCTION: Lower urinary tract symptoms (LUTS) are common and are often caused by benign prostatic hyperplasia (BPH). Traditional surgical methods of open enucleation and transurethral resection of prostrate (TURP) have been efficacious in alleviating these symptoms however, these are operator dependent and often come with significant side effects. In this review, we will discuss upcoming new surgical techniques in management of BPH. MATERIALS AND METHODS: A systematic search of SCOPUS, MEDLINE, EMBASE and Cochrane databases were carried out using relevant key words. RESULTS: Intra-prostatic injections with a variety of agents have been explored as these can be readily performed under local anesthesia. Alcohol injections into the prostate have been abandoned due to potential side effects but there has been ongoing development of two alternative agents, NX-1207 and PRX-302. Both have shown good safety profiles and early efficacy in phase II studies. Thermal treatment with the Rezum device performed as an outpatient procedure has shown both safety and efficacy in phase I and II studies. Aquablation shows promise in phase II studies with few side effects and is a relatively an automated procedure, albeit requiring general anesthesia. Prostate artery embolization has been reported in a number of studies, but clinical outcomes have been unpredictable. Histotripsy has had a number of complications in animal models and despite technical improvement has not yet progressed beyond feasibility studies in humans. CONCLUSIONS: Some of the new techniques and technologies available for BPH have been shown to be relatively safe and efficacious and await validation with phase III studies. PMID- 26497349 TI - Management of complications after surgical outlet reduction for benign prostatic obstruction. AB - INTRODUCTION: Lower urinary tract symptoms are a common complaint. Surgery to debulk hyperplastic prostate tissue is indicated for men with symptoms refractory to medical therapy, or for those who cannot tolerate first-line medications. In recent decades, new endoscopic techniques have been developed to reduce the morbidity of transurethral resection of the prostate (TURP). Nonetheless, complications are still frequently encountered in the immediate, early, and remote postoperative setting. MATERIALS AND METHODS: In this review, we perform an in-depth examination of contemporary treatment strategies for long term complications of surgical outlet reduction procedures. Complications encountered in the remote postoperative setting such as erectile dysfunction (ED), urethral stricture, refractory incontinence, and bladder neck contracture were identified in the literature. RESULTS: Treatment strategies for ED after TURP do not differ from algorithms applied for ED due to other causes. Management of urethral stricture following TURP depends on the size and location of narrowing and can range from simple dilation to complex excision with grafting techniques or perineal urethrostomy. Refractory urinary incontinence requires a full diagnostic evaluation, and artificial urinary sphincter placement is efficacious for cases that do not respond to first-line medical therapy. Finally, numerous therapies for bladder neck contracture exist and vary in their invasiveness. CONCLUSION: Endoscopic reduction of the prostate for the male with benign prostatic obstruction via most contemporary modalities is a safe and effective means to decrease outlet resistance to urinary flow. However, late complications from these procedures still exist. Management of remote morbidity following TURP can be diagnostically and therapeutically complex, necessitating prompt referral to a genitourinary reconstruction specialist. PMID- 26497350 TI - Current status of African swine fever virus in a population of wild boar in eastern Poland (2014-2015). AB - African swine fever virus (ASFV) was detected in wild boar in eastern Poland in early 2014. So far, 65 cases of ASFV infection in wild boar have been recognised. The methods used for ASFV detection included highly specific real-time PCR with a universal probe library (UPL), enzyme-linked immunosorbent assay (ELISA), and an immunoperoxidase test (IPT) for identification of anti-ASFV antibodies. The positive ASF cases were located near the border with Belarus in Sokolka and Bialystok counties. Some of the countermeasures for disease prevention include early ASF diagnosis by ASFV DNA identification as well as detection of specific antibodies by systematic screening. The aim of this study was to assess the current ASF status in a Polish population of wild boar during the last two years (2014-2015). PMID- 26497351 TI - Novel hydroxybutyl chitosan nanoparticles for siRNA delivery targeting tissue factor inhibits proliferation and induces apoptosis in human vascular smooth muscle cells. AB - Chitosan, a polysaccharide isolated from shrimp and other crustacean shells, has been widely investigated for DNA and siRNA delivery. Despite substantial effort having been made to improve chitosan as a non-viral gene delivery vector, the application is severely limited by its poor solubility under physiological conditions. Hydroxybutyl chitosan (HBC), a modified chitosan, is soluble under neutral conditions. Tissue factor (TF) is involved in the pathogenesis of cardiovascular diseases by promoting thrombus formation and inducing the migration and proliferation of vascular smooth muscle cells. Targeting TF is an attractive therapeutic strategy for cardiovascular diseases. In the present study, the use of HBC for the transfer of TF-siRNAs into human umbilical vein smooth muscle cells (HUVSMCs) was investigated, and the effects of TF knockdown on cell proliferation and apoptosis were examined. HBC/siRNA nanoparticles were produced by mixing HBC and siRNA solutions with the assistance of tripolyphosphate buffer. The transfection efficiency with these nanoparticles was 74+/-2.5%, which was determined using a fluorescence-labeled siRNA under fluorescence microscopy. The delivery of HBC/TF-siRNA resulted in reductions in the production of cellular and soluble TF protein in HUVMSCs, which were measured using western blotting and enzyme-linked immunosorbent assay, respectively. TF knockdown led to inhibited cell proliferation, as assessed using a Cell Counting Kit-8 assay, and increased cell apoptosis, determined using Annexin V-fluorescein isothiocyanate staining. These findings suggested that HBC may be a promising vector for siRNA delivery, and that in vivo HBC/siRNA nanoparticle delivery targeting TF may be a potential option for the treatment of cardiovascular diseases, which warrants further investigation. PMID- 26497352 TI - Further evidence for preoperative chemoradiotherapy and transanal endoscopic surgery (TEM) in T2-3s,N0,M0 rectal cancer. AB - PURPOSE: Preoperative chemoradiotherapy and local excision via transanal endoscopic surgery (TEM) in T2-3s,N0,M0 rectal cancer achieve promising results in selected patients. We describe our long-term follow-up experience with this combination, and evaluate complete clinical and pathological responses, local recurrence and overall survival. METHODS: The prospective observational follow-up study carried out since 2007. Out of 476 consecutive patients treated with TEM, we selected those with adenocarcinoma of low or moderate grade of differentiation, clinical stages T2-superficial T3,N0,M0, who refused radical surgery. Preoperative chemoradiotherapy comprised 5-fluorouracil or capecitabine combined with radiotherapy at a dose of 50.4 Gy. TEM was performed after 8 weeks. Complications were recorded and long-term follow-up was conducted. RESULTS: Fifteen patients undergoing preoperative chemoradiotherapy and TEM (median age 76 years, 95 % CI 70.3-80.4, and median follow-up 38 months, 95 % CI 20-44) were studied. No local recurrence was observed, and only one patient (6.7 %) presented systemic relapse. The overall survival was 76 %. Complete clinical response was achieved in seven patients (46.7 %) and complete pathological response in four (26.7 %). With regard to toxicity associated with neoadjuvant treatment, four patients (26.7 %) developed grade 3 adverse effects; no grade 4 or 5 adverse effects were observed. There was no postoperative mortality. CONCLUSIONS: The results of our study, with a response rate of 26.7 % and without local relapse, support the treatment of T2-3s,N0,M0 of rectal cancer with preoperative chemoradiotherapy and local excision (TEM). PMID- 26497353 TI - Clinical significance of ECT2 expression in tissue and serum of gastric cancer patients. AB - The ECT2 (epithelial cell transforming sequence 2) oncogene acted as a guanine nucleotide exchange factor for RhoGTPases, and regulates cytokinesis; thus, it may play a role in the pathogenesis of gastric cancer. In this study, we investigated the expression ECT2 gene in tissues and serum of gastric cancer patients to explore its clinical significance. ECT2 mRNA expression levels in tissues and serum were examined by RT-PCR, and ECT2 protein expression in tissue was evaluated by Western blot, and was further validated by immunohistochemistry and enzyme-linked immunosorbent assay at serum level. ECT2 level was significantly increased in the GC tissues and serum compared to normal control. ECT2 expression was positively correlated with the histologic differentiation, stages of TNM, and lymph node metastasis in GC (P < 0.05). Our results suggest that ECT2 plays an important role during GC progression and it may become a new diagnostic marker and therapeutic molecular target for management of GC. PMID- 26497354 TI - SEOM clinical guidelines for the treatment of Hodgkin's lymphoma. AB - Hodgkin lymphoma (HL) is an uncommon B cell lymphoid malignancy representing approximately 10-15 % of all lymphomas. HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte-predominant HL. An accurate assessment of the stage of disease and prognostic factors that identify patients at low or high risk for recurrence are used to optimize therapy. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. Brentuximab vedotin should be considered for patients who fail HDCT with ASCT. PMID- 26497355 TI - Pin1 promotes prostate cancer cell proliferation and migration through activation of Wnt/beta-catenin signaling. AB - BACKGROUND: Recent evidence suggests that the peptidyl-prolyl isomerase Pin1 is an oncoprotein that acts as a novel therapeutic target in a variety of tumors. In this study, we investigated the clinical significance of Pin1 and its function in prostate cancer (PCa) tumor progression. METHODS: Immunohistochemical and quantitative RT-PCR analyses were performed to detect the expression of Pin1 in 86 PCa tissue samples. The functional role of Pin1 was evaluated by small interfering RNA-mediated depletion in PCa cells followed by analyses of cell proliferation and migration. Furthermore, the association between expression of Pin1 and levels of beta-catenin and cyclin D1 was also evaluated. RESULTS: Our results showed that the high expression of Pin1 staining was 66 of 86 (76.74 %) PCa samples, and in 25 of 86 (29.07 %) BPH tissues, the difference was statistically significant (P < 0.001). Pin1 was significantly elevated in all PCa cell lines when compared to the normal RWPE-1 cells. We observed that proliferation and migration of LNCaP cells were inhibited by Pin1 knockdown. The levels of beta-catenin and cyclin D1 in clinical PCa specimens were positively associated with Pin1 expression. CONCLUSIONS: Our results suggest that Pin1 plays an important role in tumorigenesis of PCa, suggesting that targeting Pin1 pathway could represent a potential modality for treating PCa. PMID- 26497356 TI - SEOM clinical guidelines in early-stage breast cancer 2015. AB - Breast cancer is a major public health problem. Despite remarkable advances in early diagnosis and treatment, one in three women may have metastases since diagnosis. Better understanding of prognostic and predictive factors allows us to select the most appropriate adjuvant therapy in each patient. In these guidelines, we summarize current evidence for the medical management of early stage breast cancer. PMID- 26497357 TI - Use of FDG-PET to detect a chronic odontogenic infection as a possible source of the brain abscess. AB - This study describes the use of (18)F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) to detect a chronic odontogenic infection as the possible origin of a brain abscess (BA). A 74-year-old man with esophageal carcinoma was referred to our department to determine the origin of a BA in his oral cavity. He had no acute odontogenic infections. The BA was drained, and bacteria of the Staphylococcus milleri group were detected. Whole body FDG-PET revealed that the only sites of definite uptake of FDG were the esophageal carcinoma and the left upper maxillary region (SUVmax: 4.5). These findings suggested that the BA may have originated from a chronic periodontal infection. Six teeth with progressive chronic periodontal disease were extracted to remove the possible source of BA. These findings excluded the possibility of direct spread of bacteria from the odontogenic infectious lesion to the intracranial cavity. After extraction, there was no relapse of BA. PMID- 26497358 TI - Hot-Injection Synthesis of Cu-Doped Cu2ZnSnSe4 Nanocrystals to Reach Thermoelectric zT of 0.70 at 450 degrees C. AB - As a new class of potential midrange temperature thermoelectric materials, quaternary chalcogenides like Cu2ZnSnS4 (CZTS) and Cu2ZnSnSe4 (CZTSe) suffer from low electrical conductivity due to insufficient doping. In this work, Cu-doped CZTSe nanocrystals consisting of polygon-like nanoparticles are synthesized with sufficient Cu doping contents. The hot-injection synthetic method, rather than the traditional one-pot method, in combination with the hot-pressing method is employed to produce the CZTSe nanocrystals. In Cu-doped CZTSe nanocrystals, the electrical conductivity is enhanced by substitution of Zn(2+) with Cu(+), which introduces additional holes as charge carriers. Meanwhile, the existence of boundaries between nanoparticles in as-synthesized CZTSe nanocrystals collectively results in intensive phonon-boundary scatterings, which remarkably reduce the lattice thermal conductivity. As a result, an average thermoelectric figure of merit of 0.70 is obtained at 450 degrees C, which is significantly larger than that of the state-of-the-art quaternary chalcogenides thermoelectric materials. The theoretical calculations from the Boltzmann transport equations and the modified effective medium approximation are in good agreement with the experimental data. PMID- 26497359 TI - Optimal speech motor control and token-to-token variability: a Bayesian modeling approach. AB - The remarkable capacity of the speech motor system to adapt to various speech conditions is due to an excess of degrees of freedom, which enables producing similar acoustical properties with different sets of control strategies. To explain how the central nervous system selects one of the possible strategies, a common approach, in line with optimal motor control theories, is to model speech motor planning as the solution of an optimality problem based on cost functions. Despite the success of this approach, one of its drawbacks is the intrinsic contradiction between the concept of optimality and the observed experimental intra-speaker token-to-token variability. The present paper proposes an alternative approach by formulating feedforward optimal control in a probabilistic Bayesian modeling framework. This is illustrated by controlling a biomechanical model of the vocal tract for speech production and by comparing it with an existing optimal control model (GEPPETO). The essential elements of this optimal control model are presented first. From them the Bayesian model is constructed in a progressive way. Performance of the Bayesian model is evaluated based on computer simulations and compared to the optimal control model. This approach is shown to be appropriate for solving the speech planning problem while accounting for variability in a principled way. PMID- 26497360 TI - Biosynthesis of fungal meroterpenoids. AB - Covering: up to September 2015. Meroterpenoids are hybrid natural products that partially originate from the terpenoid pathway. The meroterpenoids derived from fungi display quite diverse structures, with a wide range of biological properties. This review summarizes the molecular bases for their biosyntheses, which were recently elucidated with modern techniques, and also discusses the plausible biosynthetic pathways of other related natural products lacking genetic information. (Complementary to the coverage of literature by Geris and Simpson in Nat. Prod. Rep., 2009, 26, 1063-1094.). PMID- 26497361 TI - Fibrates for secondary prevention of cardiovascular disease and stroke. AB - BACKGROUND: Fibrates are a class of drugs characterised by mainly lowering high triglyceride, raising high-density lipoprotein (HDL) cholesterol, and lowering the small dense fraction of low-density lipoprotein (LDL) cholesterol. Their efficacy for secondary prevention of serious vascular events is unclear, and to date no systematic review focusing on secondary prevention has been undertaken. OBJECTIVES: To assess the efficacy and safety of fibrates for the prevention of serious vascular events in people with previous cardiovascular disease (CVD), including coronary heart disease and stroke. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2014) on the Cochrane Library, MEDLINE (OVID, 1946 to October week 1 2014), EMBASE (OVID, 1980 to 2014 week 41), the China Biological Medicine Database (CBM) (1978 to 2014), the Chinese National Knowledge Infrastructure (CNKI) (1979 to 2014), Chinese Science and Technique Journals Database (VIP) (1989 to 2014). We also searched other resources, such as ongoing trials registers and databases of conference abstracts, to identify further published, unpublished, and ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which a fibrate (for example gemfibrozil, fenofibrate) was compared with placebo or no treatment. We excluded RCTs with only laboratory outcomes. We also excluded trials comparing two different fibrates without a placebo or no-treatment control. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed risk of bias, and extracted the data. We contacted authors of trials for missing data. MAIN RESULTS: We included 13 trials involving a total of 16,112 participants. Eleven trials recruited participants with history of coronary heart disease, two trials recruited participants with history of stroke, and one trial recruited participants with a mix of people with CVD. We judged overall risk of bias to be moderate. The meta-analysis (including all fibrate trials) showed evidence for a protective effect of fibrates primarily compared to placebo for the primary composite outcome of non-fatal stroke, non fatal myocardial infarction (MI), and vascular death (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.94; participants = 16,064; studies = 12; I(2) = 45%, fixed effect). Fibrates were moderately effective for preventing MI occurrence (RR 0.86, 95% CI 0.80 to 0.93; participants = 13,942; studies = 10; I(2) = 24%, fixed effect). Fibrates were not effective against all-cause mortality (RR 0.98, 95% CI 0.91 to 1.06; participants = 13,653; studies = 10; I(2) = 23%), death from vascular causes (RR 0.95, 95% CI 0.86 to 1.05; participants = 13,653; studies = 10; I(2) = 11%, fixed effect), and stroke events (RR 1.03, 95% CI 0.91 to 1.16; participants = 11,719; studies = 6; I(2) = 11%, fixed effect). Excluding clofibrate trials, as the use of clofibrate was discontinued in 2012 due to safety concerns, the remaining class of fibrates were no longer effective in preventing the primary composite outcome (RR 0.90, 95% CI 0.79 to 1.03; participants = 10,320; studies = 7; I(2) = 50%, random effects). However, without clofibrate data, fibrates remained effective in preventing MI (RR 0.85, 95% CI 0.76 to 0.94; participants = 8304; studies = 6; I(2) = 47%, fixed effect). There was no increase in adverse events with fibrates compared to control. Subgroup analyses showed the benefit of fibrates on the primary composite outcome to be consistent irrespective of age, gender, and diabetes mellitus. AUTHORS' CONCLUSIONS: Moderate evidence showed that the fibrate class can be effective in the secondary prevention of composite outcome of non-fatal stroke, non-fatal MI, and vascular death. However, this beneficial effect relies on the inclusion of clofibrate data, a drug that was discontinued in 2002 due to its unacceptably large adverse effects. Further trials of the use of fibrates in populations with previous stroke and also against a background treatment with statins (standard of care) are required. PMID- 26497362 TI - Assessing the Efficacy of a Breastfeeding-Friendly Quality Improvement Project in a Large Federally Qualified Health Center Network. AB - BACKGROUND: Provider attitudes can influence breastfeeding decision making, initiation, and duration, although much of this research has suffered from a "hospital-limited view." OBJECTIVES: This study aimed to evaluate the effect of a Breastfeeding-Friendly Initiative (BFI) on knowledge and attitudes of providers and staff, as well as breastfeeding rates of patients within a large Federally Qualified Health Center network with no lactation consultants on staff. METHODS: We evaluated breastfeeding rates before and throughout the BFI. In addition, surveys of 136 primary care providers and staff before and after they were exposed to a breastfeeding education module were assessed to measure changes in breastfeeding knowledge and attitudes. RESULTS: Breastfeeding initiation and duration improved over the course of the BFI, with mean breastfeeding duration increasing by nearly 1 month following the education module compared with baseline rates (P = .01). Following participation in the breastfeeding education module, we observed a statistically significant improvement in provider and staff knowledge (P < .01) and attitudes (P < .01). These improvements were consistent across employment type, gender, geography, and personal experience as a parent. CONCLUSION: Implementing a BFI in a large multispecialty primary care network was found to improve breastfeeding initiation and duration up to 1 year, with a further increase in breastfeeding duration of 1 month following a 45-minute staff education module. After exposure to this module, health care providers and staff across our network improved in breastfeeding knowledge and attitudes. Given that expectant and new mothers regularly come into contact with staff and providers in primary care, sound knowledge and positive attitudes toward breastfeeding appear to have had a favorable effect on mothers that correlates with improved breastfeeding duration. PMID- 26497363 TI - Geographic disparities in late stage breast cancer incidence: results from eight states in the United States. AB - BACKGROUND: Late stage of cancer at diagnosis is an important predictor of cancer mortality. In many areas worldwide, cancer registry systems, available data and mapping technologies can provide information about late stage cancer by geographical regions, offering valuable opportunities to identify areas where further investigation and interventions are needed. The current study examined geographical variation in late stage breast cancer incidence across eight states in the United States with the objective to identify areas that might benefit from targeted interventions. METHODS: Data from the Surveillance Epidemiology and End Results Program on late stage breast cancer incidence was used as dependent variable in regression analysis and certain factors known to contribute to high rates of late stage cancer (socioeconomic characteristics, health insurance characteristics, and the availability and utilization of cancer screening) as covariates. Geographic information systems were used to map and highlight areas that have any combination of high late stage breast cancer incidence and significantly associated risk factors. RESULTS: The differences in mean rates of late stage breast cancer between eight states considered in this analysis are statistically significant. Factors that have statistically negative association with late stage breast cancer incidence across the eight states include: density of mammography facilities, percent population with Bachelor's degree and English literacy while percent black population has statistically significant positive association with late stage breast cancer incidence. CONCLUSIONS: This study describes geographic disparities in late stage breast cancer incidence and identifies areas that might benefit from targeted interventions. The results suggest that in the eight US states examined, higher rates of late stage breast cancer are more common in areas with predominantly black population, where English literacy, percentage of population with college degree and screening availability are low. The approach described in this work may be utilized both within and outside US, wherever cancer registry systems and technologies offer the same opportunity to identify places where further investigation and interventions for reducing cancer burden are needed. PMID- 26497364 TI - Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. AB - Accumulated evidence suggests that M2-like polarized tumor associated macrophages (TAMs) plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-like TAMs as an appealing target for therapy intervention. Here we found that metformin significantly suppressed IL-13 induced M2-like polarization of macrophages, as illustrated by reduced expression of CD206, down regulation of M2 marker mRNAs, and inhibition of M2-like macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPKalpha1 activation in macrophage and silencing of AMPKalpha1 partially abrogated the inhibitory effect of metformin in IL-13 induced M2-like polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-like polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-like macrophage was decreased and the area of pericyte-coated vessels was increased. Further, the anti-metastatic effect of metformin was abolished when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-like polarization of macrophages partially through AMPKalpha1, which plays an important role in metformin inhibited metastasis of Lewis lung cancer. PMID- 26497365 TI - beta2-adrenogenic signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1alpha. AB - Cigarette smoking is a risk factor for pancreatic cancer. It is suggested that 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, mediates the carcinogenic action of cigarette smoking by promoting cancer growth. In the present study, we show that smoking, HIF-1alpha expression and beta2-adrenogenic receptor (beta2-AR) expression are negatively correlated with the overall survival of pancreatic cancer patients. Moreover, HIF-1alpha expression and beta2-AR expression are positively correlated with smoking status, different histological differentiation and among the tumor node metastasis (TNM) stages in pancreatic cancer patients. NNK increases HIF-1alpha expression in pancreatic cancer in vitro and in vivo. Furthermore, knockdown of HIF-1alpha and ICI118, 551 (a beta2-AR selective antagonist) abrogates NNK-induced pancreatic cancer proliferation and invasion in vitro and inhibits NNK-induced pancreatic cancer growth in vivo. However, using CoCl2 (a HIF-1alpha stabilizing agent which decreases HIF-1alpha degradation under normoxia conditions) reverses ICI118, 551 induced effects under NNK exposure. Thus, our data indicate that beta2-AR signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1alpha. Taken together, beta2-AR signaling and HIF-1alpha may represent promising therapeutic targets for preventing smoking induced pancreatic cancer progression. PMID- 26497366 TI - Identification of hallmarks of lung adenocarcinoma prognosis using whole genome sequencing. AB - In conjunction with clinical characteristics, prognostic biomarkers are essential for choosing optimal therapies to lower the mortality of lung adenocarcinoma. Whole genome sequencing (WGS) of 7 cancerous-noncancerous tissue pairs was performed to explore the comparative copy number variations (CNVs) associated with lung adenocarcinoma. The frequencies of top ranked CNVs were verified in an independent set of 114 patients and then the roles of target CNVs in disease prognosis were assessed in 313 patients. The WGS yielded 2604 CNVs. After frequency validation and biological function screening of top 10 CNVs, 9 mutant driver genes from 7 CNVs were further analyzed for an association with survival. Compared with the PBXIP1 amplified copy number, unamplified carriers had a 0.62 fold (95%CI = 0.43-0.91) decreased risk of death. Compared with an amplified TERT, those with an unamplified TERT had a 35% reduction (95% CI = 3%-56%) in risk of lung adenocarcinoma progression. Cases with both unamplified PBXIP1 and TERT had a median 34.32-month extension of overall survival and 34.55-month delay in disease progression when compared with both amplified CNVs. This study demonstrates that CNVs of TERT and PBXIP1 have the potential to translate into the clinic and be used to improve outcomes for patients with this fatal disease. PMID- 26497367 TI - miR-124 and miR-506 inhibit colorectal cancer progression by targeting DNMT3B and DNMT1. AB - miR-124 and miR-506 are reportedly down-regulated and associated with tumor progression in many cancers, but little is known about their intrinsic regulatory mechanisms in colorectal cancer (CRC). In this study, we found that the miR-124 and miR-506 levels were significantly lower in human CRC tissues than in controls, as indicated by qRT-PCR and in situ hybridization histochemistry. We also found that the overexpression of miR-124 or miR-506 inhibited tumor cell progression and increased sensitivity to chemotherapy in vitro. Increased miR-124 or miR-506 expression also inhibited tumor cell proliferation and invasion in vivo. Luciferase reporter assays and western blotting were used to determine the association between miR-124, miR-506 and their target genes, DNMTs. We further identified that miR-124 and miR-506 directly targeted DNMT3B and indirectly targeted DNMT1. The overexpression of miR-124 and miR-506 reduced global DNA methylation and restored the expression of E-cadherin, MGMT and P16. In conclusion, our data showed that miR-124 and miR-506 inhibit progression and increase sensitivity to chemotherapy by targeting DNMT3B and DNMT1 in CRC. These findings may provide novel avenues for the development of targeted therapies. PMID- 26497369 TI - Near-ambient XPS characterization of interfacial copper species in ceria supported copper catalysts. AB - Catalysts based on combinations of copper and cerium oxides are interesting alternatives to noble metal ones for processes involved in the production/purification of hydrogen produced from hydrocarbons or biomass like the water-gas shift or the preferential oxidation of CO reactions. Active sites for such processes have been proposed to correspond to reduced species formed at the interface between both oxides. The present work provides direct evidence of reduced copper species located at the interface and observed during the course of near-ambient XPS experiments performed over samples of copper oxide supported on ceria nanospheres and nanocubes subjected to interaction with CO at different temperatures. The analysis of XPS results is based on DFT+U calculations employed as a complementary method for the analysis of redox properties of the catalysts and core-level shifts produced upon such redox changes. Differences observed in interfacial redox properties as a function of the ceria support morphology appear to be most useful to explain catalytic properties of this type of system for mentioned processes. PMID- 26497370 TI - Psychiatric comorbidities among Iranian elderly patients on methadone maintenance treatment. AB - BACKGROUND: Comorbidity of psychiatric disorders and substance abuse can intensify both conditions, and when advanced age is added to the combination, the patient will face a distinctive array of issues. This study evaluated the prevalence of psychiatric disorders in elderly substance users as well as certain related factors. METHODS: This cross-sectional study was performed on 160 consenting elderly substance users 60 years and over who had been on methadone maintenance. The subjects were selected from rehabilitation centers affiliated with the Welfare Organization in Tehran through convenience sampling, and were assessed for current or lifetime axis-I psychiatric disorders using the SCID questionnaire. RESULTS: In this study, 28.1% of substance abusers were diagnosed with at least one current psychiatric disorder. Psychiatric disorders were more common in subjects whose dependence had started prior to the age of 35, or those who had a family history of substance use. Also, 34.4% had a lifetime history of at least one psychiatric disorder, with a higher incidence among those simultaneously dependent on other substances in addition to opioids. Major depression was the most prevalent disorder among the study subjects. CONCLUSION: Based on the findings of the present study, axis-I psychiatric disorders are rather common among elderly substance users, and approximately a third of this population have a lifetime history of at least one such disorder. The type of abused substance can affect the incidence of psychiatric disorders, and simultaneous use of non-opioids and other substances can increase their prevalence. PMID- 26497368 TI - Mitochondrial translocation of EGFR regulates mitochondria dynamics and promotes metastasis in NSCLC. AB - Dysfunction of the mitochondria is well-known for being associated with cancer progression. In the present study, we analyzed the mitochondria proteomics of lung cancer cell lines with different invasion abilities and found that EGFR is highly expressed in the mitochondria of highly invasive non-small-cell lung cancer (NSCLC) cells. EGF induces the mitochondrial translocation of EGFR; further, it leads to mitochondrial fission and redistribution in the lamellipodia, upregulates cellular ATP production, and enhances motility in vitro and in vivo. Moreover, EGFR can regulate mitochondrial dynamics by interacting with Mfn1 and disturbing Mfn1 polymerization. Overexpression of Mfn1 reverses the phenotypes resulting from EGFR mitochondrial translocation. We show that the mitochondrial EGFR expressions are higher in paired samples of the metastatic lymph node as compared with primary lung tumor and are inversely correlated with the overall survival in NSCLC patients. Therefore, our results demonstrate that besides the canonical role of EGFR as a receptor tyrosine, the mitochondrial translocation of EGFR may enhance cancer invasion and metastasis through regulating mitochondria dynamics. PMID- 26497371 TI - Risk and protective factor for suicide attempt in Iran: a matched case-control study. AB - OBJECTIVE: In order to generate local evidence, a case-control study was designed to explore risk factors for suicide attempts (SA) in one of the larger cities in the southeast of Iran-Kerman. METHODS: From one of the main referral hospitals, 300 cases and 300 age- and sex-matched controls were recruited. On top of demographic variables, the following variables were compared in the two groups: personality traits, psychological condition, religiosity, coping skills, general health, and recent stressful events. RESULTS: Having adjusted for recent stressful events as the most important factor (OR = 1.66, P-value < 0.001), the main significant variables were: general health (1.04, P = 0.02), the support of friends (OR = 0.95, P-value = 0.04), being problem-focused mentality (OR = 0.88, P-value = 0.005), and intrinsic religiousness (OR = 0.86, P-value = 0.01). CONCLUSIONS: Although, recent stress increased the risk of SA considerably, other factors such as general health, friends' support, and being problem-focused may predispose subjects independently. Conversely, intrinsic religious beliefs and close social networks may have protective effects. Therefore, a multi disciplinary approach is recommended to minimize the burden of SA in Iran. PMID- 26497372 TI - Pediatric reference values for serum creatinine and estimated glomerular filtration rate in Iranians: Tehran Lipid and Glucose Study. AB - BACKGROUND: Serum creatinine is the most widely used marker for estimating glomerular filtration rate (GFR). The aim of this study was to determine pediatric reference values for serum creatinine levels and eGFR values using data from a population-based study in Iran. METHODS: Serum creatinine of 1594 subjects, aged 3 - 18 years, participating in phase 4 of the Tehran Lipid and Glucose Study (2008 - 2011) was measured using the conventional Jaffe method. The non-parametric method of Schwartz and Counahan-Barratt equations were used to calculate eGFR. CLSI/IFCC guidelines were used to determine reference values. RESULTS: In both genders, serum creatinine concentration was significantly increased with age and had a positive correlation with age (boys (r = 0.786, n = 778, P < 0.001) and girls (r = 0.638, n = 724, P < 0.001)). In addition, mean serum creatinine concentration was significantly higher in boys, compared to girls (0.86 +/- 0.01 vs. 0.80 +/- 0.01 mg/dL, P < 0.001). Based on these results, we proposed the following formula: serum creatinine (mg/dL) = k * age (year) + 0.5, where k was 0.03 for boys and 0.02 for girls. CONCLUSIONS: This study presents pediatric reference values in Iranian boys and girls for serum creatinine levels to be 0.6 - 1.20 mg/dL and 0.6 - 1.00 mg/dL and for eGFR values to be 81 - 154 mL/min/1.73 m(2) and 80 - 129 mL/min/1.73 m(2), respectively. These values can be used for diagnostic and therapeutic purposes. PMID- 26497373 TI - Investigation of ITGB2 gene in 12 new cases of leukocyte adhesion deficiency-type I revealed four novel mutations from Iran. AB - BACKGROUND: Leukocyte adhesion deficiency type I (LAD-I) is a rare, autosomal recessive inherited immunodeficiency disease. LAD-I is caused by mutations in the ITGB2 gene and characterized by recurrent severe bacterial infections, as well as impaired wound healing with lack of pus formation. METHODS: In this study, we investigated ITGB2 gene mutations in 12 patients and their parents. Genomic DNA was extracted from whole blood samples. All coding regions of the ITGB2 gene were amplified using PCR and followed by direct sequencing. RESULTS: Genetic analysis revealed 12 different homozygous mutations, including six missense (c.382G>A, c.2146G>C, c.715G>A, c.691G>C, c.1777C and new c.1686C>A), two new nonsense (c.1336G>T and c.1821C>A), three-frame shift (c.1143delc, c.1907delA and new c.474dupC) and a splice site (c.1877+2T>C). Flow cytometry analysis of CD11/CD18 expression on neutrophils revealed defect in CD18 in all twelve cases (1.4% to 42%), CD11a in ten cases (0.1% to 26.7%), CD11b in nine cases (1.2% to 58.8%), and CD11c in all cases (0 % to 18.1%). The patients' parents were both heterozygous carriers. CONCLUSION: Our findings showed four new mutations in the ITGB2 gene. These results can be used for decisive genetic diagnosis, genetic counseling, as well as prenatal diagnosis for all patients who are suspended to LADI. PMID- 26497374 TI - Study on association of peroxisome proliferator-activated receptor alpha with C reactive protein, and additional gene-gene interaction in Chinese Han. AB - BACKGROUND: The aim was to examine the association between 6 single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptors alpha (PPAR alpha) poly morphisms and C-reactive protein (CRP) level, as well as additional gene-gene interaction among the 6 SNPs. METHODS: A total of 1260 subjects (583 men, 677 women), with a mean age of 41.3 +/- 14.6 years old, were selected. Six SNPs of PPAR alpha were selected for genotyping in the study including: rs135539, rs135551, rs135549, rs1800206, rs1800243 and rs4253623. Linear regression analysis was performed to verify the polymorphism association between SNP with CRP levels. Generalized MDR (GMDR) was employed to analysis the interaction among six SNPs. RESULTS: Linear regression results indicated a significant negative correlation between mutation of rs1800206 and CRP level. The carriers of the V allele (LV + VV) of rs1800206 were associated with a significant decreased level of CRP (regression coefficients was -0.533, standard error was 0.148 (P < 0.001)). However, the other 5 SNPs in PPAR alpha were not significantly associated with CRP level before or after covariate adjustment. GMDR model indicated that there was a significant two-locus model (P = 0.0107) involving rs1800206 and rs135539, indicating a potential gene-gene interaction between rs1800206 and rs135539. Overall, the two- locus models had a cross-validation consistency of 10 of 10, respectively, and had the testing accuracy of 55.9%, respectively. CONCLUSIONS: Our results support an important association between rs1800206 minor allele (V) of PPAR alpha and lower CRP level. The interaction analysis showed a combined effect between rs1800206 and rs135539 on the lower CRP level. PMID- 26497375 TI - A simple and cost-effective method for isolation and expansion of human fetal pancreas derived mesenchymal stem cells. AB - BACKGROUND: Previous studies have suggested mesenchymal stem cells (MSCs) as a suitable source for cell replacement therapy in diabetes. MSCs have successfully isolated from different adult and fetal tissues, including the pancreas. In vitro studies have shown that human fetal pancreatic stem cells could be extensively expanded and differentiated into islet-like structures. Here, we introduce a simple and cost-effective method for the generation of MSCs from the human fetal pancreas (FPMSCs). METHODS: To isolate FPMSCs, pancreata from four aborted fetuses (second trimester) were processed with short collagenase digestion. The resulting tissue fragments were transferred to a basic media (DMEM+15%FBS) without adding any growth factor. RESULTS: After 10 to14 days, fibroblast-like cells were harvested and passaged six times for further evaluations. Flow cytometry analysis and three-lineage differentiation capacity have demonstrated that these cells have MSC-like properties. We also continuously passaged samples of FPMSCs and found no evidence for chromosomal instability and morphological changes until 10th subculture. Moreover, our cell culture protocol can be easily modified and translated into a GMP-compliant one. CONCLUSION: The results of current study demonstrated that our simple and inexpensive method could yield a pure population of FPMSCs that might be suitable for transplantation. PMID- 26497377 TI - Adherence to Mediterranean diet and risk of breast cancer in premenopausal and postmenopausal women. AB - BACKGROUND: Mediterranean diet (MD) has long been suspected to impact on health promotion. Epidemiologic studies reveal the protective role of adherence to this dietary pattern on cancer incidence. However, its association with breast cancer risk remains unclear. Therefore, we aimed to investigate whether adherence to Mediterranean dietary pattern influence on breast cancer risk in postmenopausal and premenopausal women. METHODS: We performed an electronic search of published studies earlier than Apr 2015 using Pubmed, Google scholar, Cochrane and Scopus databases. The search terms included: breast neoplasm, breast tumors, mammary carcinoma, mammary neoplasm, breast cancer, and Mediterranean diet. Study inclusion criteria were: 1) written in English; 2) with a study arm of MD intervention or MD style assessment; 3) reported the BC risk in premenopausal and postmenopausal women. RESULTS: We summarized the findings of 8 studies in this review, including five cohorts and three case-control studies. Although, cohort studies reported controversial results in this field, case-control studies resulted inverse relation between this Mediterranean dietary pattern and breast cancer risk in pre or/and postmenopausal women. CONCLUSIONS: It seems that there is no sufficient data to reach a conclusion about the effect of MD on breast cancer risk in pre and postmenopausal, but there are some evidences suggesting the protective association. More cohort studies in different parts of the world are needed to confirm these results. PMID- 26497376 TI - Impact of whole exome sequencing among Iranian patients with autosomal recessive retinitis pigmentosa. AB - BACKGROUND: Non-syndromic autosomal recessive Retinitis Pigmentosa (arRP) is a highly heterogeneous genetic visual disorder with a large number of causative genes. We aimed to determine the power of Whole Exome Sequencing (WES) in the identification of the genes responsible for non-syndromic arRP among Iranian patients. METHODS: We used WES, followed by the Sanger sequencing to identify the underlying gene mutations causing non-syndromic arRP. RESULTS: Our study revealed disease-causing mutations in known arRP genes for 10 of the 13 families studied (76.9%). These mutations included two-frameshift insertion/deletion in CRB1 and ABCA4, one splicing mutation in PDE6B, four missense mutations in RP1, CRB1, PANK2 and IFT140, as well as three stop codon mutations in RDH12, PRCD, and C2orf71. Three remaining families harbored no mutation in previously known RP genes. Of the 10 diseases causing mutations identified among the investigated Iranian patients with non-syndromic arRP, eight variants had not been reported previously. We confirmed segregation of all 10 mutations with disease phenotypes in our studied population. CONCLUSION: This study supports the genetic heterogeneity of non-syndromic arRP in Iranian patients, and provides an opportunity to show the effectiveness of WES in the identification of pathogenic mutations among patients with non-syndromic arRP born to consanguineous parents. PMID- 26497378 TI - Disseminated Kaposi's sarcoma. AB - Kaposi's Sarcomas (KS) have been associated with many conditions and also known as a typical complication of immunosuppression. It should be considered as an important differential diagnosis in skin lesions of patients after solid organ transplantation. This is a report of a 61-year-old man, who presented with disseminated KS and a history of renal transplantation. We suggest systemic evaluation and visceral assessment in patients with Cutaneous KS. PMID- 26497379 TI - Double incontinence as a first symptom of saddle embolism of the aorta leads to sudden paraplegia. AB - An aortic saddle embolus causing cauda equine syndrome followed by paraplegia is an exceedingly rare phenomenon in post-operative period in coronary artery bypass grafting. In non-CABG cases, reported documentation of neurological recovery from this event is even rarer. A 57-year-old male 8 days after uneventful OPCAP presented with severe lower extremity pain and sudden fecal and urinary incontinence, followed by the absence of pulsations in the lower limbs and paraplegia, during 20-minute period. He underwent immediate bilateral transfemoral embolectomy. The postoperative period was uneventful. The paraplegia recovered immediately after embolectomy and recovery from anesthesia. An angiography has been made to verify that a high origin of the great radicular artery above T12 level may be responsible for better recovery of paraplegia when its ostium obstructed by a saddle embolus relieved using embolectomy. Early surgical intervention in restoring the blood flow into the great radicular artery may prevent severe histological changes hitherto responsible for non-recovery from paraplegia in the earlier reports. Three unique characteristics of this article are as follows: 1) Occurrence of this complication in the post-operative period in off-pump CABG surgery; 2) Commencing of emboli with bizarre symptoms of double incontinence; 3) Combination of cauda equine syndrome and complete paralysis. PMID- 26497380 TI - Medical oncology, history and its future in Iran. AB - Systemic therapy is one of the cornerstones of cancer treatment. In 1972, following representations by American Society of Clinical Oncology (ASCO), the American Board of Internal Medicine (ABIM) recognized medical oncology as a new subspecialty of internal medicine. Subspecialty of Hematology and Medical Oncology was emerged in Iran in 1983. In the past, modern medical treatments and education were started in Dar Al-fonun school and then in Tehran University; now six universities in Iran are training in Subspecialty of Hematology and Medical Oncology. There are also ten active hematopoietic stem cell transplantation centers, thirty-one provincial medical schools use their specialized services. Future goals for Hematology and Medical Oncology in Iran include expansion and reinforcement of multidisciplinary teams across the country, early detection and prevention of cancer, providing educational program and conducting cancer researches. To achieve these goals, it is necessary to establish Cancer Hospitals in each province that link together through a network. PMID- 26497381 TI - Exploration of tetrahedral structures in silicate cathodes using a motif-network scheme. AB - Using a motif-network search scheme, we studied the tetrahedral structures of the dilithium/disodium transition metal orthosilicates A2MSiO4 with A = Li or Na and M = Mn, Fe or Co. In addition to finding all previously reported structures, we discovered many other different tetrahedral-network-based crystal structures which are highly degenerate in energy. These structures can be classified into structures with 1D, 2D and 3D M-Si-O frameworks. A clear trend of the structural preference in different systems was revealed and possible indicators that affect the structure stabilities were introduced. For the case of Na systems which have been much less investigated in the literature relative to the Li systems, we predicted their ground state structures and found evidence for the existence of new structural motifs. PMID- 26497384 TI - Peptide utilizing carbon starvation gene yjiY is required for flagella mediated infection caused by Salmonella. AB - Peptide metabolism forms an important part of the metabolic network of Salmonella and to acquire these peptides the pathogen possesses a number of peptide transporters. While various peptide transporters known in Salmonella are well studied, very little is known about the carbon starvation (cst) genes, cstA and yjiY, which are also predicted to be involved in peptide metabolism. We investigated the role of these genes in the metabolism and pathogenesis of Salmonella and demonstrated for the first time that cst genes actually participate in transport of specific peptides in Salmonella. Further, we established that the carbon starvation gene yjiY affects the expression of flagella leading to poor adhesion of the bacterium to host cells. In contrast with the previously reported role of the gene cstA in virulence of Salmonella in C. elegans, we showed that yjiY is required for successful colonization of Salmonella in the mouse gut. Thus, cst genes not only contribute to the metabolism of Salmonella but also influence its virulence. PMID- 26497385 TI - New cases of HIV in India could fall by 38% with early ART and better retention, finds study. PMID- 26497382 TI - Tumor-induced lymph node alterations detected by MRI lymphography using gadolinium nanoparticles. AB - Contrast-enhanced MRI lymphography shows potential to identify alterations in lymph drainage through lymph nodes (LNs) in cancer and other diseases. MRI studies have typically used low molecular weight gadolinium contrast agents, however larger gadolinium-loaded nanoparticles possess characteristics that could improve the specificity and sensitivity of lymphography. The performance of three gadolinium contrast agents with different sizes and properties was compared by 3T MRI after subcutaneous injection. Mice bearing B16-F10 melanoma footpad tumors were imaged to assess tumor-induced alterations in lymph drainage through tumor draining popliteal and inguinal LNs versus contralateral uninvolved drainage. Gadolinium lipid nanoparticles were able to identify tumor-induced alterations in contrast agent drainage into the popliteal LN, while lower molecular weight or albumin-binding gadolinium agents were less effective. All of the contrast agents distributed in foci around the cortex and medulla of tumor-draining popliteal LNs, while they were restricted to the cortex of non-draining LNs. Surprisingly, second-tier tumor-draining inguinal LNs exhibited reduced uptake, indicating that tumors can also divert LN drainage. These characteristics of tumor-induced lymph drainage could be useful for diagnosis of LN pathology in cancer and other diseases. The preferential uptake of nanoparticle contrasts into tumor-draining LNs could also allow selective targeting of therapies to tumor-draining LNs. PMID- 26497386 TI - Raman and infra-red microspectroscopy: towards quantitative evaluation for clinical research by ratiometric analysis. AB - Biomolecular structure elucidation is one of the major techniques for studying the basic processes of life. These processes get modulated, hindered or altered due to various causes like diseases, which is why biomolecular analysis and imaging play an important role in diagnosis, treatment prognosis and monitoring. Vibrational spectroscopy (IR and Raman), which is a molecular bond specific technique, can assist the researcher in chemical structure interpretation. Based on the combination with microscopy, vibrational microspectroscopy is currently emerging as an important tool for biomedical research, with a spatial resolution at the cellular and sub-cellular level. These techniques offer various advantages, enabling label-free, biomolecular fingerprinting in the native state. However, the complexity involved in deciphering the required information from a spectrum hampered their entry into the clinic. Today with the advent of automated algorithms, vibrational microspectroscopy excels in the field of spectropathology. However, researchers should be aware of how quantification based on absolute band intensities may be affected by instrumental parameters, sample thickness, water content, substrate backgrounds and other possible artefacts. In this review these practical issues and their effects on the quantification of biomolecules will be discussed in detail. In many cases ratiometric analysis can help to circumvent these problems and enable the quantitative study of biological samples, including ratiometric imaging in 1D, 2D and 3D. We provide an extensive overview from the recent scientific literature on IR and Raman band ratios used for studying biological systems and for disease diagnosis and treatment prognosis. PMID- 26497383 TI - Cross platform analysis of methylation, miRNA and stem cell gene expression data in germ cell tumors highlights characteristic differences by tumor histology. AB - BACKGROUND: Alterations in methylation patterns, miRNA expression, and stem cell protein expression occur in germ cell tumors (GCTs). Our goal is to integrate molecular data across platforms to identify molecular signatures in the three main histologic subtypes of Type I and Type II GCTs (yolk sac tumor (YST), germinoma, and teratoma). METHODS: We included 39 GCTs and 7 paired adjacent tissue samples in the current analysis. Molecular data available for analysis include DNA methylation data (Illumina GoldenGate Cancer Methylation Panel I), miRNA expression (NanoString nCounter miRNA platform), and stem cell factor expression (SABiosciences Human Embryonic Stem Cell Array). We evaluated the cross platform correlations of the data features using the Maximum Information Coefficient (MIC). RESULTS: In analyses of individual datasets, differences were observed by tumor histology. Germinomas had higher expression of transcription factors maintaining stemness, while YSTs had higher expression of cytokines, endoderm and endothelial markers. We also observed differences in miRNA expression, with miR-371-5p, miR-122, miR-302a, miR-302d, and miR-373 showing elevated expression in one or more histologic subtypes. Using the MIC, we identified correlations across the data features, including six major hubs with higher expression in YST (LEFTY1, LEFTY2, miR302b, miR302a, miR 126, and miR 122) compared with other GCT. CONCLUSIONS: While prognosis for GCTs is overall favorable, many patients experience resistance to chemotherapy, relapse and/or long term adverse health effects following treatment. Targeted therapies, based on integrated analyses of molecular tumor data such as that presented here, may provide a way to secure high cure rates while reducing unintended health consequences. PMID- 26497387 TI - Desialylation is associated with apoptosis and phagocytosis of platelets in patients with prolonged isolated thrombocytopenia after allo-HSCT. AB - BACKGROUND: Prolonged isolated thrombocytopenia (PT) is a frequent complication in patients who undergo allogeneic hematopoietic stem cell transplantation (allo HSCT), and it is associated with an adverse prognosis. In this study, we hypothesized that desialylation on platelet surfaces was associated with PT after allo-HSCT. The mechanisms participating in this process may include NEU1 translocation, platelet apoptosis, and phagocytosis by macrophages. METHODS: PT was defined as a peripheral platelet count less than 100 * 10(9)/L without sustained anemia or leukopenia for more than 3 months after allo-HSCT. 34 patients were identified consecutively from a cohort of 255 patients who underwent allo-HSCT for hematologic malignancies between May and October 2014 at Peking University Institute of Hematology. Desialylation, enzyme expression, and phagocytosis were detected using flow cytometry, immunofluorescence, RT-PCR, Western blot, and so on. RESULTS: Platelets from the PT patients had significantly fewer sialic acids (P = .001) and increased beta-galactose exposure indicative of desialylation on the surface (P = .042), and serum from the PT patients showed a higher sialic acid concentration (8.400 +/- 0.2209 MUmol/L, P < .001). The sialidase NEU1 was over-expressed from mRNA to protein levels, and its catalytic activity was increased in platelets from the PT patients. Desialylation of GPIbalpha in the PT patients was correlated with changes in 14-3-3zeta distribution, which, relative to Bad activation, modulated the expression of Bcl 2 family proteins, depolarized the inner membrane of the mitochondria, and initiated the intrinsic mitochondria-dependent pathway of apoptosis. Macrophages derived from the THP-1 cell line preferred to phagocytize desialylated platelets from the PT patients in vitro. We also revealed that oseltamivir (400 MUmol/L) could inhibit 50 % of the sialidase activity on platelets and could protect 20 % of platelets from phagocytosis in vitro. CONCLUSIONS: Desialylation of platelets was associated with platelet apoptosis and phagocytosis, whereas oseltamivir could reduce platelet destruction in the periphery, indicating a potential novel treatment for PT after allo-HSCT. PMID- 26497389 TI - Multiradionuclide evidence for the solar origin of the cosmic-ray events of A? 774/5 and 993/4. AB - The origin of two large peaks in the atmospheric radiocarbon ((14)C) concentration at AD 774/5 and 993/4 is still debated. There is consensus, however, that these features can only be explained by an increase in the atmospheric (14)C production rate due to an extraterrestrial event. Here we provide evidence that these peaks were most likely produced by extreme solar events, based on several new annually resolved (10)Be measurements from both Arctic and Antarctic ice cores. Using ice core (36)Cl data in pair with (10)Be, we further show that these solar events were characterized by a very hard energy spectrum with high fluxes of solar protons with energy above 100 MeV. These results imply that the larger of the two events (AD 774/5) was at least five times stronger than any instrumentally recorded solar event. Our findings highlight the importance of studying the possibility of severe solar energetic particle events. PMID- 26497388 TI - The impact of ginsenosides on cognitive deficits in experimental animal studies of Alzheimer's disease: a systematic review. AB - BACKGROUND: The efficacy of ginsenoside treatment on cognitive decline in individuals with Alzheimer's disease (AD) has yet to be investigated. In this protocal, we conducted a systematic review to evaluate the effect of ginsenosides on cognitive deficits in experimental rodent AD models. METHODS: We identified eligible studies by searching seven electronic databases spanning from January 1980 to October 2014. We assessed the study quality, evaluated the efficacy of ginsenoside treatment, and performed a stratified meta-analysis and meta regression analysis to assess the influence of the study design on ginsenoside efficacy. RESULTS: Twelve studies fulfilled our inclusion criteria from a total of 283 publications. The overall methodological quality of these studies was poor. The meta-analysis revealed that ginsenosides have a statistically significant positive effect on cognitive performance in experimental AD models. The stratified analysis revealed that ginsenoside Rg1 had the greatest effect on acquisition and retention memory in AD models. The effect size was significantly higher for both acquisition and retention memory in studies that used female animals compared with male animals. CONCLUSIONS: We conclude that ginsenosides might reduce cognitive deficits in AD models. However, additional well-designed and well-reported animal studies are needed to inform further clinical investigations. PMID- 26497390 TI - Contactin-associated protein-like 2 expression in SH-SY5Y cells is upregulated by a FOXP2 mutant with a shortened poly-glutamine tract. AB - The forkhead box protein P2 (FOXP2) gene encodes an important transcription factor that contains a polyglutamine (poly-Q) tract and a forkhead DNA binding domain. It has been observed that FOXP2 is associated with speech sound disorder (SSD), and mutations that decrease the length of the poly-Q tract were identified in the FOXP2 gene of SSD patients. However, the exact role of poly-Q reduction is not well understood. In the present study, constructs expressing wild-type and poly-Q reduction mutants of FOXP2 were generated by polymerase chain reaction (PCR) using lentiviral vectors and transfected into the SH-SY5Y neuronal cell line. Quantitative reverse transcription (qRT)-PCR and western blotting indicated that infected cells stably expressed high levels of FOXP2. Using this cell model, the impact of FOXP2 on the expression of contactin-associated protein-like 2 (CNTNAP2) were investigated, and CNTNAP2 mRNA expression levels were observed to be significantly higher in cells expressing poly-Q-reduced FOXP2. In addition, the expression level of CASPR2, a mammalian homolog of Drosophila Neurexin IV, was increased in cells expressing the FOXP2 mutant. Demonstration of regulation by FOXP2 indicates that CNTNAP2 may also be involved in SSD. PMID- 26497391 TI - Trauma-focused cognitive behavioral therapy with unaccompanied refugee minors: a case series. AB - BACKGROUND: Unaccompanied refugee minors (URMs) are a group who are vulnerable to developing posttraumatic stress symptoms (PTSS). However, they rarely receive the treatment that is indicated and there are no treatment studies focusing exclusively on this group of adolescents. This case study evaluates the feasibility of trauma-focused cognitive behavioral therapy (TF-CBT) for URMs with PTSS. METHOD: A health care utilization sample of N = 6 was assessed prior to and after treatment with TF-CBT. Therapists were asked to report differences in treatment application and content in comparison to TF-CBT standard protocol. RESULTS: We found moderate to high levels of PTSS at baseline and a clinically significant decrease in symptoms at posttest. Some modifications to the TF-CBT protocol were made with regard to affective modulation which required more sessions than usual whereas fewer caregiver sessions were conducted. CONCLUSION: TF-CBT is feasible in reducing PTSS in severely traumatized URMs. Further research with controlled trials is necessary. TRIAL REGISTRATION: The trial registration: ClinicalTrials.gov Identifier NCT01516827. Registered 13 December 2011. PMID- 26497392 TI - Detection and differentiation of Schmallenberg, Akabane and Aino viruses by one step multiplex reverse-transcriptase quantitative PCR assay. AB - BACKGROUND: Schmallenberg virus (SBV), Akabane virus (AKAV) and Aino virus (AINV) are members of the Simbu serogroup within the genus Orthobunyavirus, family Bunyaviridae, which can cause reproductive disorders including abortion, stillbirth and congenital malformation in ruminants. Because, the clinical signs are similar, confirmatory diagnosis requires viral detection to differentiate infection between these three viruses. METHODS: In this study, a one-step multiplex reverse-transcriptase quantitative PCR (one-step mRT-qPCR) was developed for the simultaneous detection and differentiation of SBV, AKAV and AINV. RESULTS: The detection limit of the one-step mRT-qPCR for SBV, AKAV and AINV were 2.4 copies (10 (0.6) TCID 50/ml), 96.2 copies (10 (1.5) TCID 50/ml) and 52.3 copies (10 (1.2) TCID 50/ml), respectively. Various field samples such as bovine serum, bovine whole blood, bovine brain, goat serum and Culicoides were analyzed using the one-step mRT-qPCR and compared with previously published RT qPCRs. The test results of the field samples were identical for the one-step mRT qPCR and RT-qPCRs, which showed all samples to be negative for SBV, AKAV and AINV, except for one bovine brain sample (1/123) that was positive for AKAV. CONCLUSION: The one-step mRT-qPCR allows for the simultaneous detection of three viral pathogens (SBV, AKAV and AINV) that cause reproductive failure. PMID- 26497393 TI - Incidence of viral respiratory infections in a prospective cohort of outpatient and hospitalized children aged <=5 years and its associated cost in Buenos Aires, Argentina. AB - BACKGROUND: Although information about the incidence of viral respiratory illnesses and their associated cost can help health officials explore the value of interventions, data are limited from middle-income countries. METHODS: During 2008-2010, we conducted a prospective cohort study and followed ~1,800 Argentinian children aged <=5 years to identify those children who were hospitalized or who sought care at an emergency room with any acute respiratory infection sign or symptom (e.g., rhinorrhea, cough, wheezing, tachypnea, retractions, or cyanosis). Respiratory samples were obtained for respiratory syncytial virus, influenza, parainfluenza, adenovirus, and metapneumovirus testing by immunofluorescence and for rhinovirus by real-time reverse transcription polymerase chain reaction. RESULTS: The incidence of respiratory syncytial virus (24/1000 children-years), human metapneumovirus (8/1000 children years), and influenza (8/1000 children-years) illnesses was highest among hospitalized children aged <6 months and decreased among older children. In contrast, the incidence of rhinovirus was highest (12/1000 children-years) among those aged 6-23 months. In the emergency room, the incidence of rhinovirus was 459; respiratory syncytial virus 352; influenza 185; parainfluenza 177; metapneumovirus 130; and adenovirus 73/1,000 children-years. The total cost of hospitalization was a median of US$529 (Interquartile range, US$362-789). CONCLUSIONS: Our findings indicate that respiratory viruses, in particular rhinovirus, respiratory syncytial virus, metapneumovirus, and influenza may be associated with severe illness causing substantial economic burden. PMID- 26497394 TI - Factors associated with 30-day readmission of patients with heart failure from a Japanese administrative database. AB - BACKGROUND: Numerous studies have been conducted in many countries to identify the factors associated with readmission of patients with heart failure (HF). However, there have been no such studies utilizing a large-scale administrative database in Japan. This study aimed to establish the factors associated with 30 day readmission of patients with HF using a Japanese nationwide administrative database. METHODS: Data of the index admissions of 68,257 patients discharged from 1057 participating hospitals between April 1, 2012 and March 31, 2013 were analyzed. Patients were divided into the 30-day readmission group and no readmission group according to whether unplanned HF readmission occurred within 30 days after discharge. Study variables included age, sex, New York Heart Association functional class (NYHA) at admission, Charlson Comorbidity Index (CCI), length of stay in hospital (LOS), body mass index (BMI) at admission, hospital volume reflected by the number of cases hospitalized with HF, and medical treatment at discharge. RESULTS: The 30-day readmission and no readmission groups included 4479 and 63,778 patients, respectively. The independent factors associated with the increase in 30-day readmission were older age, higher NYHA, higher CCI, and use of the following drugs at discharge: beta blockers, loop diuretics, thiazide, and nitrates. In contrast, the independent factors associated with the decrease in 30-day readmission were longer LOS, higher BMI, and the use of angiotensin converting enzyme inhibitors (ACEs) or angiotensin II receptor blockers (ARBs), calcium channel blockers, and spironolactone. CONCLUSIONS: The results suggest that, especially during the first few weeks after discharge, careful management of HF outpatients with advanced age, high disease severity, multiple comorbidities, or taking beta blockers, loop diuretics, thiazide, and nitrates at discharge may be crucial for reducing the 30-day readmission rate. PMID- 26497395 TI - Hip arthroscopy for the management of osteoid osteoma of the acetabulum: a systematic review of the literature and case report. AB - BACKGROUND: Intra-articular osteoid osteoma (OO) causes irreversible joint damage. Its treatment of choice is radiofrequency ablation (RFA); however, some areas of the acetabulum are hard to access. Therefore, hip arthroscopy was used to treat this tumor. We aim to systematically review the literature with regards to arthroscopic management of acetabular OO, and to report a further case in which hip arthroscopy was used for treatment. METHODS: PubMed and EMBASE were searched for articles relevant to the arthroscopic management of acetabular OO on December 2, 2014. All articles published on and before that date were reviewed, and studies which met our pre-determined inclusion criteria were included. Articles screening and data abstraction were done by two reviewers independently. We also presented a 31-year-old man with acetabular OO who underwent hip arthroscopy for the management of his tumor after failing to respond to medications and computed tomography scan (CT)-guided RFA. RESULTS: The initial search revealed 14 studies, of which ten met our inclusion criteria. A total of ten patients underwent hip arthroscopy for the management of acetabular OO. Only two patients were females, and the patients' age ranged from 7 to 47 years. Two patients underwent arthroscopic guided-RFA of the lesion, while the rest underwent excision. The follow-up period ranged from 6 months to 2 years. Success rate was 100 %, and no recurrence was reported. Minor complications (transient impotence and perineal numbness) developed in one patient (10 %). Arthroscopic guided RFA failed to eliminate the tumor in our additional case. A second trial of CT-guided RFA was successful in treating the patient's condition. CONCLUSIONS: Hip arthroscopy is an effective and safe option for the management of acetabular OO, with success rate exceeding 90 %. Studies of higher level of evidence are required. PMID- 26497396 TI - Multiple photosynthetic reaction centres of porphyrinic polypeptide-Li(+)@C60 supramolecular complexes. AB - Multiple photosynthetic reaction centres have been successfully constructed using strong supramolecular complexes of free base porphyrin polypeptides with lithium ion-encapsulated C60 (Li(+)@C60) as compared with those of C60. Efficient energy migration and electron transfer occur in the supramolecular complexes. PMID- 26497397 TI - Popeye deformity in rheumatoid arthritis. PMID- 26497398 TI - Atypical proliferative endometrioid tumor of ovary: Report of a rare case. AB - Borderline ovarian tumors represent 10-20% of epithelial ovarian neoplasms that typically have an excellent prognosis. Both the oncological behavior of this group of tumors and also the diagnostic histological criteria are intermediate between the specific criteria of benign and malignant. They usually occur in the third to fourth decade of women's lives and are limited to the ovary in 80% of cases. Atypical proliferative or borderline ovarian tumors constitute a group of epithelial tumors with an excellent prognosis due to the low aggressiveness, microscopic examination is mandatory in order to establish an accurate histological diagnosis in all cases of borderline ovarian tumors and to differentiate from well differentiated adenocarcinoma. We report a case of a 45 year old female who presented with irregular bleeding per vaginum and underwent hysterectomy with bilateral salpingo-oophorectomy. Atypical proliferative endometrioid tumor of the left ovary was an incidental finding, which is a very rare occurrence. PMID- 26497399 TI - Numerous linear metallic densities on radiograph: Gold threads. PMID- 26497400 TI - A Novel Soluble Peptide with pH-Responsive Membrane Insertion. AB - Several diseases, such as cancer, are characterized by acidification of the extracellular environment. Acidosis can be employed as a target to specifically direct therapies to the diseased tissue. We have used first principles to design an acidity-triggered rational membrane (ATRAM) peptide with high solubility in solution that is able to interact with lipid membranes in a pH-dependent fashion. Biophysical studies show that the ATRAM peptide binds to the surface of lipid membranes at pH 8.0. However, acidification leads to the peptide inserting into the lipid bilayer as a transmembrane alpha-helix. The insertion of ATRAM into membranes occurs at a moderately acidic pH (with a pK of 6.5), similar to the extracellular pH found in solid tumors. Studies with human cell lines showed a highly efficient pH-dependent membrane targeting, without causing toxicity. Here we show that it is possible to rationally design a soluble peptide that selectively targets cell membranes in acidic environments. PMID- 26497401 TI - Defining and achieving normal thyroid function during pregnancy. PMID- 26497402 TI - Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. AB - BACKGROUND: Thyroid hormone is involved in the regulation of early brain development. Since the fetal thyroid gland is not fully functional until week 18 20 of pregnancy, neuronal migration and other crucial early stages of intrauterine brain development largely depend on the supply of maternal thyroid hormone. Current clinical practice mostly focuses on preventing the negative consequences of low thyroid hormone concentrations, but data from animal studies have shown that both low and high concentrations of thyroid hormone have negative effects on offspring brain development. We aimed to investigate the association of maternal thyroid function with child intelligence quotient (IQ) and brain morphology. METHODS: In this population-based prospective cohort study, embedded within the Generation R Study (Rotterdam, Netherlands), we investigated the association of maternal thyroid function with child IQ (assessed by non-verbal intelligence tests) and brain morphology (assessed on brain MRI scans). Eligible women were those living in the study area at their delivery date, which had to be between April 1, 2002, and Jan 1, 2006. For this study, women with available serum samples who presented in early pregnancy (<18 weeks) were included. Data for maternal thyroid-stimulating hormone, free thyroxine, thyroid peroxidase antibodies (at weeks 9-18 of pregnancy), and child IQ (assessed at a median of 6.0 years of age [95% range 5.6-7.9 years]) or brain MRI scans (done at a median of 8.0 years of age [6.2-10.0]) were obtained. Analyses were adjusted for potential confounders including concentrations of human chorionic gonadotropin and child thyroid-stimulating hormone and free thyroxine. FINDINGS: Data for child IQ were available for 3839 mother-child pairs, and MRI scans were available from 646 children. Maternal free thyroxine concentrations showed an inverted U shaped association with child IQ (p=0.0044), child grey matter volume (p=0.0062), and cortex volume (p=0.0011). For both low and high maternal free thyroxine concentrations, this association corresponded to a 1.4-3.8 points reduction in mean child IQ. Maternal thyroid-stimulating hormone was not associated with child IQ or brain morphology. All associations remained similar after the exclusion of women with overt hypothyroidism and overt hyperthyroidism, and after adjustment for concentrations of human chorionic gonadotropin, child thyroid-stimulating hormone and free thyroxine or thyroid peroxidase antibodies (continuous or positivity). INTERPRETATION: Both low and high maternal free thyroxine concentrations during pregnancy were associated with lower child IQ and lower grey matter and cortex volume. The association between high maternal free thyroxine and low child IQ suggests that levothyroxine therapy during pregnancy, which is often initiated in women with subclinical hypothyroidism during pregnancy, might carry the potential risk of adverse child neurodevelopment outcomes when the aim of treatment is to achieve high-normal thyroid function test results. FUNDING: The Netherlands Organisation for Health Research and Development (ZonMw) and the European Community's Seventh Framework Programme. PMID- 26497404 TI - Aldosterone stimulates the cardiac sodium/bicarbonate cotransporter via activation of the g protein-coupled receptor gpr30. AB - Some cardiac non-genomic effects of aldosterone (Ald) are reported to be mediated through activation of the classic mineralocorticoid receptor (MR). However, in the last years, it was proposed that activation of the novel G protein-coupled receptor GPR30 mediates certain non-genomic effects of Ald. The aim of this study was to elucidate if the sodium/bicarbonate cotransporter (NBC) is stimulated by Ald and if the activation of GPR30 mediates this effect. NBC activity was evaluated in rat cardiomyocytes perfused with HCO3(-)/CO2 solution in the continuous presence of HOE642 (sodium/hydrogen exchanger blocker) during recovery from acidosis using intracellular fluorescence measurements. Ald enhanced NBC activity (% of DeltaJHCO3(-); control: 100+/-5.82%, n=7 vs Ald: 151.88+/-11.02%, n=5; P<0.05), which was prevented by G15 (GPR30 blocker, 90.53+/-7.81%, n=7). Further evidence for the involvement of GPR30 was provided by G1 (GPR30 agonist), which stimulated NBC (185.13+/-18.28%, n=6; P<0.05) and this effect was abrogated by G15 (124.19+/-10.96%, n=5). Ald- and G1-induced NBC stimulation was abolished by the reactive oxygen species (ROS) scavenger MPG and by the NADPH oxidase inhibitor apocynin. In addition, G15 prevented Ald- and G1-induced ROS production. Pre-incubation of myocytes with wortmannin (PI3K-AKT pathway blocker) prevented Ald- or G1-induced NBC stimulation. In summary, Ald stimulates NBC by GPR30 activation, ROS production and AKT stimulation. PMID- 26497403 TI - Thyroid stimulating hormone directly modulates cardiac electrical activity. AB - BACKGROUND: The electrocardiogram of hypothyroid patients shows a series of abnormalities of cardiac repolarization due to a reduction of some repolarizing K(+) currents and an increase of the L-type calcium current. Experimental and clinical works call into question the unique role of T3 and T4 in these mechanisms and correlate increased serum TSH levels with the repolarization abnormalities in patients with both subclinical and overt hypothyroidism. In this context, the aim of the present study was to investigate the direct effects of TSH upon cardiac electrical properties. METHODS: The action potential recording and the ion channel subunits mRNA expression were obtained from left ventricle of adult rats. Additionally, the repolarizing K(+) currents and the L-type Ca(2+) current (ICa-L) were recorded in isolated rat adult ventricular myocytes by the patch-clamp technique. RESULTS: 24h exposure to TSH lengthened the action potential and slightly depolarized the resting membrane potential. TSH- receptor activation causes a reduction of the amplitude of Ito and IK1 currents caused by a reduction in channels expression. However, TSH had no effect on ICa-L, IK or IKur. CONCLUSION: These results support the idea that some of the electrical disturbances seen in hypothyroid hearts, such as the Ito and IK1 current reduction, could be caused not by low T3 but by the elevation of circulating TSH. PMID- 26497405 TI - Effects of HPV-16 infection on hypopharyngeal squamous cell carcinoma and FaDu cells. AB - Hypopharyngeal squamous cell carcinoma is a common type of malignant tumor among head and neck squamous cell carcinomas (HNSCCs). Heavy smoking and/or drinking is associated with the development of HNSCC. However, HNSCC also occurs in individuals that do not drink or smoke, possibly due to infection with the human papilloma virus (HPV). HPV-16 has been shown to be closely associated with the occurrence of several types of cancers. However, its role in hypopharyngeal squamous cell carcinoma remains unclear. In the present study, we investigated the effects of HPV-16 on hypopharyngeal squamous cell carcinoma and FaDu cells. Lentiviral vectors were used to establish FaDu cells that expressed the E6 and E7 proteins of HPV-16. We used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays and western blotting to detect and determine the levels of expression for E6-E7 mRNAs and proteins. Cell Counting Kit-8 (CCK-8) assays, enzyme-linked immunosorbent assays (ELISA), Transwell assays, and flow cytometry were used to assess the effects of HPV-16 E6-E7 on the proliferation, invasion, metastasis and apoptosis of FaDu cells. Expression of microRNAs was analyzed by qRT-PCR. We found that the expression levels of HPV-16 E6-E7 were increased in FaDu cells transfected with the lentiviral vector compared with that observed in the control cells. In addition, the rates of apoptosis were decreased in the transfected cells, while proliferation was increased. The average numbers of cells penetrating the Matrigel were significantly higher than those for the controls. We detected miR-363 and miR-15a, and their expression levels were significantly increased in the HPV-16-positive patients and in FaDu cells expressing HPV-16 E6-E7. We found that HPV-16 E6-E7 appeared to inhibit apoptosis, and to increase cell proliferation, invasion and metastasis. Furthermore, miR-363 and miR-15a were overexpressed in the hypopharyngeal squamous cell carcinoma samples infected with HPV-16, and in FaDu cells stably expressing HPV-16 E6-E7. These findings may provide a new clue of the mechanisms involved in the pathogenesis of HPV-16-positive hypopharyngeal squamous cell carcinoma. PMID- 26497406 TI - Coq7p relevant residues for protein activity and stability. AB - Coenzyme Q (Q) is an isoprenylated benzoquinone electron carrier required for electronic transport in the mitochondrial respiratory chain, shuttling electrons from complexes I and II to complex III. Q synthesis requires proteins termed Coq (Coq1-Coq11). Coq7p is part of the multimeric complex involved in Q synthesis catalyzing the hydroxylation of demethoxy-Q6 (DMQ6), the last monooxygenase step in Q synthesis with a catalytic center containing a carboxylate-bridged di-iron at the active site of the enzyme. Here we indicate a group of Coq7p residues that modulate protein activity: D53, R57, V111 and S114. R57, V111 and S114 are very conserved residues; V111 and S114 are present in separated communities of amino acid correlation analysis. The coq7 double mutant V111G/S114A and S114E show respiratory deficiency at non permissive temperature, DMQ6 accumulation and lower content of Q6. Therefore we conclude that phosphomimetic S114E inhibit Coq7p activity, and propose that S114 phosphorylation is required to move a non structured loop of 25 amino acids between helix 2 and 3, and that affects the di iron coordination in Coq7p catalytic center. PMID- 26497408 TI - Androgen response to social competition in a shoaling fish. AB - Androgens respond to social challenges and this response has been interpreted as a way for males to adjust androgen-dependent behavior to social context. However, the androgen responsiveness to social challenges varies across species and a conceptual framework has been developed to explain this variation according to differences in the mating system and parental care type, which determines the regimen of challenges males are exposed to, and concomitantly the scope (defined as the difference between the physiological maximum and the baseline levels) of response to a social challenge. However, this framework has been focused on territorial species and no clear predictions have been made to gregarious species (e.g. shoaling fish), which although tolerating same-sex individuals may also exhibit intra-sexual competition. In this paper we extend the scope of this conceptual framework to shoaling fish by studying the endocrine response of zebrafish (Danio rerio) to social challenges. Male zebrafish exposed to real opponent agonistic interactions exhibited an increase in androgen levels (11 ketotestosterone both in Winners and Losers and testosterone in Losers). This response was absent in Mirror-fighters, that expressed similar levels of aggressive behavior to those of winners, suggesting that this response is not a mere reflex of heightened aggressive motivation. Cortisol levels were also measured and indicated an activation of the hypothalamic-pituitary-interrenal axis in Winners of real opponent fighters, but not Losers or in Mirror-fighters. These results confirm that gregarious species also exhibit an endocrine response to an acute social challenge. PMID- 26497407 TI - Androgen-primed castrate males are sufficient for methamphetamine-facilitated increases in proceptive behavior in female rats. AB - Methamphetamine (MA) is a psychomotor stimulant associated with increases in sex drive in both men and women. Women, however, are far more likely to face social disadvantages as a consequence of MA use, and their increased sexual motivation poses additional health concerns such as unplanned pregnancies. To better understand the mechanisms underlying MA-facilitated sexual motivation in females, we previously established a rodent model where a "binge"-type administration paradigm of MA to sexually receptive female rats significantly increases proceptive behavior in the presence of a sexually active, gonadally-intact male. Our previous work with this model has led us to consider whether the increases in proceptive behavior are truly indicative of increased sexual motivation, or instead a consequence of heightened motor responsivity. Here, we test whether MA induced increases in proceptive behaviors are specific to a sexually relevant stimulus. Females' sexual, social, exploratory behaviors, and interaction times were scored during the exposure to stimulus males, including castrates, and dihydrotestosterone (DHT)-treated castrates. MA-treated females demonstrated significant increases in proceptive behaviors toward DHT-treated castrate males but not toward castrate males. While the non-MA-treated females did display proceptive behavior, there was no significant difference between behaviors elicited by DHT-CX males compared to CX males. Our results support the hypothesis that MA facilitates proceptive behavior only in response to specific, androgen mediated sexually-relevant cues. PMID- 26497410 TI - Investing in nursing and midwifery enterprise to empower women and strengthen health services and systems: Commentary and context. PMID- 26497411 TI - Aluminum plasmonic photocatalysis. AB - The effectiveness of photocatalytic processes is dictated largely by plasmonic materials with the capability to enhance light absorption as well as the energy conversion efficiency. Herein, we demonstrate how to improve the plasmonic photocatalytic properties of TiO2/Al nano-void arrays by overlapping the localized surface plasmon resonance (LSPR) modes with the TiO2 band gap. The plasmonic TiO2/Al arrays exhibit superior photocatalytic activity boasting an enhancement of 7.2 folds. The underlying mechanisms concerning the radiative energy transfer and interface energy transfer processes are discussed. Both processes occur at the TiO2/Al interface and their contributions to photocatalysis are evaluated. The results are important to the optimization of aluminum plasmonic materials in photocatalytic applications. PMID- 26497409 TI - Hormonal stimulation and paternal experience influence responsiveness to infant distress vocalizations by adult male common marmosets, Callithrix jacchus. AB - Parental experience and hormones play a large role in the common marmoset (Callithrix jacchus) father's care of their offspring. We tested the effect of exogenous estradiol or testosterone on the responsiveness of common marmosets to respond to infant distress vocalizations and whether males who haven't become fathers yet (paired males) would have increased responsiveness to infant distress calls with either steroid or whether parental experience is the most important component for the onset of paternal care. Sixteen male marmosets (8 fathers, 8 paired males) received a vehicle, low dose or high dose of estradiol and additional 16 males were tested with testosterone at three doses for their response either to a vocal control or a recording of an infant distress call for 10min. Without steroid stimulation fathers were significantly more likely to respond to the infant distress stimulus than paired males. Low dose estradiol stimulation resulted in a significant increase in fathers' behavioral response towards the infant distress stimulus but not in paired males. Fathers also showed a significant increase in infant responsiveness from the vehicle dose to the estradiol low dose treatment, but not to the estradiol high dose treatment. Testosterone treatment did not show significant differences between infant responsiveness at either dose and between fathers and paired males. We suggest that neither steroid is involved in the onset of paternal care behaviors in the marmoset but that estradiol may be involved in facilitating paternal motivation in experienced fathers. PMID- 26497412 TI - Self-aligned, full solution process polymer field-effect transistor on flexible substrates. AB - Conventional techniques to form selective surface energy regions on rigid inorganic substrates are not suitable for polymer interfaces due to sensitive and soft limitation of intrinsic polymer properties. Therefore, there is a strong demand for finding a novel and compatible method for polymeric surface energy modification. Here, by employing the confined photo-catalytic oxidation method, we successfully demonstrate full polymer filed-effect transistors fabricated through four-step spin-coating process on a flexible polymer substrate. The approach shows negligible etching effect on polymeric film. Even more, the insulating property of polymeric dielectric is not affected by the method, which is vital for polymer electronics. Finally, the self-aligned full polymer field effect transistors on the flexible polymeric substrate are fabricated, showing good electrical properties and mechanical flexibility under bending tests. PMID- 26497413 TI - Acute respiratory distress due to post-tracheostomy tracheal rupture treated with venovenous extracorporeal membrane oxygenation and endotracheal prosthesis. PMID- 26497414 TI - Cigarette butts: The collateral effects of cigarettes on humans, animals and the environment. PMID- 26497415 TI - Tracheal stenosis and IgG4-related disease. PMID- 26497416 TI - Acceptance of telemedicine among healthcare professionals. PMID- 26497417 TI - Ulcerative pseudomembranous tracheobronchitis caused by Aspergillus fumigatus. PMID- 26497419 TI - The influence student placement experience can have on the employment choices of graduates: A paediatric nursing context. AB - This paper explores how the student placement experience may influence employment choices in the context of paediatric nursing. A qualitative research methodology was used. Data was collected using semi structured interviews at a tertiary teaching hospital. The sample group comprised of six newly qualified nurses who had completed their Bachelor of Nursing less than 12 months before the interview. They had completed at least one clinical placement at the site of data collection in their 2nd or 3rd year of undergraduate nursing studies. The main themes contributing to the student nurse experience within the context of paediatric nursing included the wish to work with children, a job being available, support during clinical placements and assistance with future career planning while on placement. The support experienced by student nurses during their clinical placement was seen to have a very positive influence on their future employment choices. Group de-briefing to support mutual understanding and sharing was seen to be a highly positive aspect of a clinical placement. Also how students were treated by clinical staff was a key factor that influenced future employment choices. PMID- 26497418 TI - Predictive Model for Anxiety and Depression in Spanish Patients with Stable Chronic Obstructive Pulmonary Disease. AB - INTRODUCTION: The association between chronic obstructive pulmonary disease (COPD) and anxiety and depression is not yet completely characterized, and differences between countries may exist. We used a predictive model to assess this association in a Spanish population. PATIENTS AND METHOD: Prospective transversal descriptive study of 204 patients with stable COPD. Concomitant anxiety or depression were diagnosed by psychiatric assessment, using the diagnostic criteria of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Sociodemographic, clinical and lung function parameters were analyzed. RESULTS: In total, 36% of stable COPD patients had psychiatric comorbidities, but 76% were unaware of their diagnosis. Nineteen percent had a pure anxiety disorder, 9.8% had isolated depression, and 7.3% had a mixed anxiety-depression disorder. Predictive variables in the multivariate analysis were younger age, higher educational level, lack of home support, higher BODE index, and greater number of exacerbations. The ROC curve of the model had an AUC of 0.765 (P<0.001). CONCLUSIONS: In COPD, concomitant psychiatric disorders are significantly associated with sociodemographic factors. Anxiety disorders are more common than depression. Patients with more severe COPD, according to BODE, younger patients and those with a higher educational level have a greater risk of being diagnosed with anxiety or depression in a structured psychiatric interview. In our population, most patients with psychiatric comorbidities remain unidentified. PMID- 26497420 TI - When molecules support morphology: Phylogenetic reconstruction of the family Onuphidae (Eunicida, Annelida) based on 16S rDNA and 18S rDNA. AB - Onuphid polychaetes are tubicolous marine worms commonly reported worldwide from intertidal areas to hadal depths. They often dominate in benthic communities and have economic importance in aquaculture and recreational fishing. Here we report the phylogeny of the family Onuphidae based on the combined analyses of nuclear (18S rDNA) and mitochondrial (16S rDNA) genes. Results of Bayesian and Maximum Likelihood analyses supported the monophyly of Onuphidae and its traditional subdivision into two monophyletic subfamilies: Onuphinae and Hyalinoeciinae. Ten of 22 recognized genera were monophyletic with strong node support; four more genera included in this study were either monotypic or represented by a single species. None of the genera appeared para- or polyphyletic and this indicates a strong congruence between the traditional morphology-based systematics of the family and the newly obtained molecular-based phylogenetic reconstructions. Intergeneric relationships within Hyalinoeciinae were not resolved. Two strongly supported monophyletic groups of genera were recovered within Onuphinae: ((Onuphis, Aponuphis), Diopatra, Paradiopatra) and (Hirsutonuphis, (Paxtonia, (Kinbergonuphis, Mooreonuphis))). A previously accepted hypothesis on the subdivision of Onuphinae into the Onuphis group of genera and the Diopatra group of genera was largely rejected. PMID- 26497421 TI - Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems. AB - Primary human hepatocytes (hHEP), human HepaRG and HepG2 cell lines are the most used human liver-based in vitro models for hepatotoxicity testing, including screening of drug-induced liver injury (DILI)-inducing compounds. hHEP are the reference hepatic in vitro system, but their availability is limited and the cells available for toxicology studies are often of poor quality. Hepatic cell lines on the other hand are highly proliferative and represent an inexhaustible hepatic cell source. However, these hepatoma-derived cells do not represent the population diversity and display reduced hepatic metabolism. Alternatively, stem cell-derived hepatic cells, which can be produced in high numbers and can differentiate into multiple cell lineages, are also being evaluated as a cell source for in vitro hepatotoxicity studies. Human skin-derived precursors (hSKP) are post-natal stem cells that, after conversion towards hepatic cells (hSKP HPC), respond to hepatotoxic compounds in a comparable way as hHEP. In the current study, four different human hepatic cell systems (hSKP-HPC, hHEP, HepaRG and HepG2) are evaluated for their capacity to predict hepatic toxicity. Their hepatotoxic response to acetaminophen (APAP) exposure is compared to data obtained from patients suffering from APAP-induced acute liver failure (ALF). The results indicate that hHEP, HepaRG and hSKP-HPC identify comparable APAP-induced hepatotoxic functions and that HepG2 cells show the slightest hepatotoxic response. Pathway analyses further points out that HepaRG cells show the highest predicted activation of the functional genes related to 'damage of liver', followed by hSKP-HPC and hHEP cells that generated similar results. HepG2 did not show any activation of this function. PMID- 26497422 TI - [Conclusion]. PMID- 26497424 TI - Metabolism-Activated Multitargeting (MAMUT): An Innovative Multitargeting Approach to Drug Design and Development. AB - Multitargeting is a valuable concept in drug design for the development of effective drugs for the treatment of multifactorial diseases. This concept has most frequently been realized by incorporating two or more pharmacophores into a single hybrid molecule. Many such hybrids, due to the increased molecular size, exhibit unfavorable physicochemical properties leading to adverse effects and/or an inappropriate ADME (absorption, distribution, metabolism, and excretion) profile. To avoid this limitation and achieve additional therapeutic benefits, here we describe a novel multitargeting strategy based on the synergistic effects of a parent drug and its active metabolite(s). The concept of metabolism activated multitargeting (MAMUT) is illustrated using a number of examples. PMID- 26497425 TI - Surface-Engineered Viral Vectors for Selective and Cell Type-Specific Gene Delivery. AB - Recent progress in gene transfer technology enables the delivery of genes precisely to the application-relevant cell type ex vivo on cultivated primary cells or in vivo on local or systemic administration. Gene vectors based on lentiviruses or adeno-associated viruses can be engineered such that they use a cell surface marker of choice for cell entry instead of their natural receptors. Binding to the surface marker is mediated by a targeting ligand displayed on the vector particle surface, which can be a peptide, single-chain antibody, or designed ankyrin repeat protein. Examples include vectors that deliver genes to specialized endothelial cells or lymphocytes, tumor cells, or particular cells of the nervous system with potential applications in gene function studies and molecular medicine. PMID- 26497426 TI - Central Nervous System and its Disease Models on a Chip. AB - Technologies for microfluidics and biological microelectromechanical systems have been rapidly progressing over the past decade, enabling the development of unique microplatforms for in vitro human central nervous system (CNS) and related disease models. Most fundamental techniques include manipulation of axons, synapses, and neuronal networks, and different culture conditions are possible, such as compartmental, co-culturing, and 3D. Various CNS disease models, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), epilepsy, N-methyl-D-aspartate receptor (NMDAR) encephalitis, migraine, diffuse axonal injury, and neuronal migration disorders, have been successfully established on microplatforms. In this review, we summarize fundamental technologies and current existing CNS disease models on microplatforms. We also discuss possible future directions, including application of these methods to pathological studies, drug screening, and personalized medicine, with 3D and personalized disease models that could generate more realistic CNS disease models. PMID- 26497427 TI - Possibilities in Germ Cell Research: An Engineering Insight. AB - Germ cells (GCs) are responsible for fertility and disruptions in their development or function cause infertility. However, current knowledge about the diverse mechanisms involved in GC development and function is still in its infancy. This is mainly because there are low numbers of GCs, especially during embryonic development. A deeper understanding of GCs would enhance our ability to produce them from stem cells. In addition, such information would enable the production of healthy gametes for infertile couples. In this regard, pluripotent stem cells (PSCs) demonstrated a promising ability to produce GCs in vitro. In this review, we highlight recent advances in the field of tissue engineering that suggest novel strategies to enhance GC research. PMID- 26497423 TI - [The reference site of the European Innovation Partnership on Active and Healthy Aging MACVIA-LR (the fight against chronic diseases for an active and healthy aging in Languedoc-Roussillon)]. PMID- 26497428 TI - A new three dimensional biomimetic hydrogel to deliver factors secreted by human mesenchymal stem cells in spinal cord injury. AB - Stem cell therapy with human mesenchymal stem cells (hMSCs) represents a promising strategy in spinal cord injury (SCI). However, both systemic and parenchymal hMSCs administrations show significant drawbacks as a limited number and viability of stem cells in situ. Biomaterials able to encapsulate and sustain hMSCs represent a viable approach to overcome these limitations potentially improving the stem cell therapy. In this study, we evaluate a new agarose/carbomer based hydrogel which combines different strategies to optimize hMSCs viability, density and delivery of paracrine factors. Specifically, we evaluate a new loading procedure on a lyophilized scaffold (soaked up effect) that reduces mechanical stress in encapsulating hMSCs into the hydrogel. In addition, we combine arginine-glycine-aspartic acid (RGD) tripeptide and 3D extracellular matrix deposition to increase the capacity to attach and maintain healthy hMSCs within the hydrogel over time. Furthermore, the fluidic diffusion from the hydrogel toward the injury site is improved by using a cling film that oriented efficaciously the delivery of paracrine factors in vivo. Finally, we demonstrate that an improved combination as here proposed of hMSCs and biomimetic hydrogel is able to immunomodulate significantly the pro-inflammatory environment in a SCI mouse model, increasing M2 macrophagic population and promoting a pro regenerative environment in situ. PMID- 26497429 TI - Synergistic therapeutic effects of Schiff's base cross-linked injectable hydrogels for local co-delivery of metformin and 5-fluorouracil in a mouse colon carcinoma model. AB - In situ formed hydrogels based on Schiff base reaction were formulated for the co delivery of metformin (ME) and 5-fluorouracil (5FU). The reactive aldehyde functionalized four-arm polyethylene glycol (PFA) was synthesized by end-capping of 4-arm PEG with 4-formylbenzoic acid (FA) and used as a cross-linking agent. The injectable hydrogels are designed through the quick gelation induced by the formation of covalent bonds via Schiff-base reaction of PFA with 4-arm poly (ethylene glycol)-b-poly (L-lysine) (PPLL). This formulation eliminated the need for metal catalysts and complicated processes in the preparation of in situ forming hydrogels. In vitro degradation and drug release studies demonstrated that both ME and 5FU were released through PFA/PPLL hydrogels in a controlled and pH-dependent manner. When incubated with mouse colon adenocarcinoma cells (C26), the ME/5FU-incorporated PFA/PPLL hydrogels had synergistic inhibitory effects on the cell cycle progression and cell proliferation in colon cancer cells. After a single subcutaneous injection of the hydrogel containing ME/5FU beside the tumors of BALB/c mice inoculated with C26 cells, the dual-drug-loaded hydrogels displayed superior therapeutic activity resulted from a combination of p53 mediated G1 arrest and apoptosis in C26 cells. Hence, the Schiff's base cross linked hydrogels containing ME and 5FU may have potential therapeutic applications in the treatments of colon cancer. PMID- 26497431 TI - Bright Green Stool in a Toddler's Diaper. Bromethalin rodenticide ingestion. PMID- 26497432 TI - Young Female With Diplopia and Crossed Eye. Chiari malformation. PMID- 26497433 TI - Labels. PMID- 26497430 TI - Synaptic plasticity as a cortical coding scheme. AB - Processing of auditory information requires constant adjustment due to alterations of the environment and changing conditions in the nervous system with age, health, and experience. Consequently, patterns of activity in cortical networks have complex dynamics over a wide range of timescales, from milliseconds to days and longer. In the primary auditory cortex (AI), multiple forms of adaptation and plasticity shape synaptic input and action potential output. However, the variance of neuronal responses has made it difficult to characterize AI receptive fields and to determine the function of AI in processing auditory information such as vocalizations. Here we describe recent studies on the temporal modulation of cortical responses and consider the relation of synaptic plasticity to neural coding. PMID- 26497434 TI - Dealing With the Difficult Patient. PMID- 26497435 TI - Annals of Emergency Medicine Journal Club. Blowing Smoke: Examining the Benefits of High-Flow Nasal Cannula in Hypoxic Respiratory Failure: November 2015 Annals of Emergency Medicine Journal Club. PMID- 26497436 TI - Young Woman With Chest Pain After Fall. Left posterior sternoclavicular dislocation. PMID- 26497437 TI - Chest Pain Bounce-Back: Posterior Sternoclavicular Dislocation. PMID- 26497438 TI - Ring Removal With a Surgical Tie: Further Considerations. PMID- 26497439 TI - Patient Selection Is Critical in Rate or Rhythm Control of Atrial Fibrillation or Flutter. PMID- 26497440 TI - In reply. PMID- 26497441 TI - Young Adult With Abdominal Pain. Gastric dilatation caused by anorexia nervosa. PMID- 26497442 TI - Does cigarette smoking relieve stress? Evidence from the event-related potential (ERP). AB - Previous studies have reported a paradox that cigarette smoking reduces stress psychologically; however, it increases the arousal level physiologically. To examine this issue, our study aimed to investigate whether cigarette smoking relieves stress by measuring the late positive potential (LPP), a component of the event-related potential (ERP). In Experiment 1, participants first watched emotionally neutral images; second, they received a break; and finally, they watched emotionally neutral images again. In the break, they smoked a cigarette (smoking condition) or simply rested without smoking (non-smoking condition). The procedure of Experiment 2 was the same as that of Experiment 1, except that the participants watched unpleasant images as stress stimuli before the break. In Experiment 1, the LPP decreased from before to after the break in the smoking condition, but not in the non-smoking condition, suggesting that smoking cigarettes in the neutral state reduces the arousal level. In Experiment 2, the LPP for 400-600 ms decreased from before to after the break, both in the smoking and non-smoking conditions; however, the LPP for 200-400 ms decreased from before to after the break only in the smoking condition. This suggests the possibility that cigarette smoking in the unpleasant state may facilitate a decrease in the arousal level faster than with non-smoking. In both Experiments 1 and 2, the subjective rating results also suggested that cigarette smoking decreased anxiety. Taken together, both the physiological (LPP) and the psychological responses from our study suggest that cigarette smoking perhaps relieves stress. PMID- 26497444 TI - Verteporfin photodynamic therapy for the treatment of sporadic retinal capillary haemangioblastoma. AB - PURPOSE: To assess the effectivity of photodynamic therapy (PDT) for the treatment of retinal capillary haemangiomas METHOD: Retrospective case note analysis of all patients with retinal angiomas treated with PDT between 2003 and 2010. RESULTS: Six eyes of 6 patients (3 male, 3 female) with a mean age of 50 years (range, 23-78) were identified in our database. The follow up period was between 24 and 60 months (mean, 36). Tumor regression was evident in two patients; three tumors showed no demonstrable response to treatment on ophthalmoscopy or ultrasonography and one tumor progressed despite PDT and subsequent cryotherapy. One patient developed retinal neovascularisations following a period of inattendence to our clinic. Visual acuity improved in two patients following PDT, deteriorated in three patients and remained stable in a one patient. CONCLUSION: The response of retinal haemangioblastomas to PDT is inconsistent. Other treatment modalities ought to be utilized for peripheral lesions, however PDT may be tried in juxtapapillary lesions where radiotherapy or cryotherapy is likely to result in concurrent visual loss. PMID- 26497443 TI - Antimicrobial photodynamic therapy-A discovery originating from the pre antibiotic era in a novel periodontal therapy. AB - Antimicrobial photodynamic therapy (aPDT) involves pathogens' destruction caused by means of toxic Reactive Oxygen Species (ROS) that are generated upon the interaction of a photoactivatable substance (photosensitizer), light of the appropriate wavelength and oxygen. Among many clinical applications, it is also used as a supplementary method of treatment of periodontal disease. Many in vitro studies confirmed, that a major periopathogenic bacterium, Porphyromonas gingivalis is susceptible to this method. Several animal model studies pointed, that even a single application of aPDT adjunctive to conventional scaling and root planning (SRP) promotes better tissue healing, reduces the inflammatory infiltrate and bone loss. The outcomes of clinical trials are, however, inconsistent. Although in several the superiority of combined treatment protocol (SRP+aPDT) over the conventional (SRP alone) was reported, it was not confirmed in other trials. Nonetheless, the reduction of bleeding indices favoring the combined therapy was observed in the majority of the studies. It indicates, that aPDT has an influence on the extent of inflammation and further studies are needed to establish an optimal protocol of treatment combining mechanical debridement with photochemotherapy in order to obtain good treatment outcomes in our patients. PMID- 26497445 TI - Effects of feed deprivation on the AMPK signaling pathway in skeletal muscle of broiler chickens. AB - The 5'-adenosine monophosphate-activated protein kinase (AMPK) plays a key role in rapid metabolic adaptations to maintain energy homeostasis in poultry. It remains unclear if AMPK is involved in muscular energy metabolism in broiler chickens. Hence, in the present study, seven-day-old male broilers were equally divided into three groups: fed ad libitum (control); feed-deprived for 24h (S24); feed-deprived for 24h and then refed for 24h (S24R24). Compared to the control group, the plasma levels of glucose, insulin, T3 and triglycerides in the S24 group were significantly lower (P<0.05), whereas the uric acid levels were significantly higher (P<0.01). Except for glucose, refeeding for 24h reversed the fasting-induced alterations in plasma metabolite. Fasting decreased the liver kinase B1 (LKB1), AMPK alpha 2 subunit (AMPKalpha2), and fatty acid synthase (FAS) mRNA levels (P<0.05) in M. pectoralis major (PM). Feed deprivation did not affect the phosphorylated AKT, mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K) in PM (P>0.05), but upregulated carnitine palmitoyltransferase 1 (CPT1) gene expression and increased phosphorylated LKB1 (0.050.05). However, refeeding after 24h of fasting increased the phosphorylated mTOR level in BF muscle which was in parallel with increased plasma insulin concentration. It was likely that increased phospho-mTOR level in the BF muscle was due to the higher sensitivity of BF to insulin. Together, the results suggested that the AMPK signaling pathway might be involved in the energy metabolism alterations in the skeletal muscles of broiler chickens and was also dependent upon the muscle fiber type. Furthermore, the regulatory effects of AMPK on energy metabolism in muscles of broiler chickens might be mediated by the AMPK/FAS pathway. PMID- 26497446 TI - Implicit and explicit measures of spider fear and avoidance behavior: Examination of the moderating role of working memory capacity. AB - BACKGROUND AND OBJECTIVES: Avoidance behavior is central to several anxiety disorders. The current study tested whether avoidance behavior for spiders depends on a dynamic interplay between implicit and explicit processes, moderated by the availability to exert control through working memory capacity (WMC). METHODS: A total of 63 participants completed an approach-avoidance task, an implicit association test, a spider fear questionnaire and a behavioral avoidance test that included an assessment of approach distance as well as approach speed. WMC was measured by a complex operation span task. It was hypothesized that in individuals with low WMC, implicit avoidance tendencies and implicit negative associations predict avoidance behavior for a spider better than the explicit measure, whereas in high WMC individuals, the explicit measure should better predict avoidance behavior than the implicit measures. RESULTS: Results revealed that WMC moderated the influence of implicit negative associations, but not implicit avoidance tendencies, on spider approach distance but not the speed of approaching. Although explicit spider fear directly influenced avoidance behavior, its impact was not modulated by WMC. LIMITATIONS: Participants in our study were from a non-clinical sample, which limits the generalizability of our findings. CONCLUSIONS: These findings suggest that implicit processes might become more pertinent for fear behavior as the ability to control such processes wanes, which may be particularly relevant for anxiety disorders given their association with lowered executive control functioning. As such, training procedures that specifically target implicit processes or control abilities might improve treatment outcomes for anxiety disorders. PMID- 26497447 TI - Positive valence reduces susceptibility to return of fear and enhances approach behavior. AB - BACKGROUND AND OBJECTIVES: Although exposure therapy is highly efficacious for anxiety disorders, many individuals do not respond. Drawing from the science of fear extinction and reinstatement, the current study evaluated whether a training designed to increase valence of the feared stimulus improved the longevity of treatment outcomes. METHODS: Participants were 61 undergraduate students with fear of spiders (>10 on Spider Phobia Questionnaire, M = 20.45, SD = 3.98) who were randomized to receive positive valence training or control training. Participants completed exposure over two days, with training conditions at the end of the first day. Tests of spontaneous recovery and reinstatement were conducted one week later. RESULTS: Compared to control, the Positive Valence Training group demonstrated significantly less subjective fear at test of spontaneous recovery and less behavioral avoidance after reinstatement. Change in valence predicted subjective fear at spontaneous recovery and after reinstatement but did not predict behavioral avoidance after reinstatement. LIMITATIONS: Due to the relatively small size and homogeneity of the sample, as well as the limited methods of training (i.e., film clips only) and outcome measurement (i.e., self report and behavioral measures), current results should be interpreted with caution. CONCLUSIONS: Adjunct positive valence training may enhance the longevity of exposure treatment. PMID- 26497448 TI - Interface pressure mapping pilot study to select surfaces that effectively redistribute pediatric occipital pressure. AB - AIM: The aim of this pilot study was to better inform clinical decisions to prevent pediatric occipital pressure ulcers with quantitative data to choose an appropriate reactive support surface. MATERIALS: A commercially available capacitive pressure mapping system (XSENSOR, X3 Medical Seat System, Calgary, Canada) was used to evaluate a standard pediatric mattress and four commercially available pressure-redistributing support surfaces. METHODS: The pressure mapping system was validated for use in the pediatric population through studies on sensitivity, accuracy, creep, and repeatability. Then, a pilot pressure mapping study on healthy children under 6 years old (n = 22) was performed to determine interface pressure and pressure distribution between the occipital region of the skull and each surface: standard mattress, gel, foam, air and fluidized. RESULTS: The sensor was adequate to measure pressure generated by pediatric occipital loading, with 0.5-9% error in accuracy in the 25-95 mmHg range. The air surface had the lowest mean interface pressure (p < .005) and lowest peak pressure index (PPI), defined as the peak pressure averaged over four sensels, (p < .005). Mean interface pressure for mattress, foam, fluidized, gel, and air materials were 24.8 +/- 4.42, 24.1 +/- 1.89, 19.4 +/- 3.25, 17.9 +/- 3.10, and 14.2 +/- 1.41 mmHg, respectively. The air surface also had the most homogenous pressure distribution, with the highest mean to PPI ratio (p < .005) and relatively high contact area compared to the other surfaces (p < .005). CONCLUSION: The air surface was the most effective pressure-redistributing material for pediatric occipital pressure as it had the lowest interface pressure and a homogeneous pressure distribution. This implies effective envelopment of the bony prominence of the occiput and increasing contact area to decrease peak pressure points. PMID- 26497449 TI - Spinach (Spinacia oleracea L.) modulates its proteome differentially in response to salinity, cadmium and their combination stress. AB - Cadmium (Cd) contamination and salinity are common stressors in agricultural soils all over the globe. Sensitivity and modulation of plant proteome lead to proper signal execution and adaptation to abiotic stress via molecular responses, which strengthen plant defence system. A comparative proteomic study, employing 2DE-MALDI TOF/TOF MS, of Spinacia oleracea plants exposed to cadmium (50 MUg CdCl2 g(-1) soil), salinity (10 mg NaCl g(-1) soil) and their combination (NaCl + Cd) was conducted to understand the minimum common adaptation to multiple stress. Analysis of 2D gel maps showed significant increase and decrease in relative abundance of 14 and 39 proteins by Cd; 11 and 46 by salinity and 22 and 37 by combined stress of Cd and salinity, respectively. Peptide mass fingerprinting (PMF) helped in the identification of maturase K and PPD4 with increased relative abundance under all stresses; whereas salinity stress and combination stress silenced the presence of one protein (polycomb protein EZ2) and two proteins (cellulose synthase-like protein and ubiquitin conjugation factor E4), respectively. The identified proteins were functionally associated with signal transduction (15%), protein synthesis (16%), stress response and defence (33%), photosynthesis (13%), plant growth/cell division (9%), energy generation (4%), transport (4%), secondary metabolism (3%), and cell death (3%); clearly indicating the importance and necessity of keeping a higher ratio of defence and disease-responsive proteins. The results suggest that plant may increase the abundance of defence proteins and may also lower the abundance of catabolic proteins. Proteins with altered ratios of abundance belonged to different functional categories, suggesting that plants have differential mechanisms to respond to Cd, salinity, and their combined stress, but with unique sets of proteins. PMID- 26497450 TI - The association of molecular typing, vancomycin MIC, and clinical outcome for patients with methicillin-resistant Staphylococcus aureus infections. AB - BACKGROUND/PURPOSE: There are reports of an increase in vancomycin minimum inhibitory concentration (MIC) against methicillin-resistant Staphylococcus aureus (MRSA) over time, a phenomenon referred to as "MIC creep", but some studies have conflicting results. The aim of this study is to evaluate the association of molecular typing, vancomycin MIC, and clinical outcome for patients with MRSA infections. METHODS: Thirty-two MRSA isolates from Taichung Veterans General Hospital (TCVGH), Taichung, Taiwan during the period of 2003 to 2008 were analyzed for the association of sequence typing, vancomycin MIC, and the correlated clinical outcome for patients with MRSA infections. The vancomycin MICs of 28 additional isolates from 2014 were used for the detection of MIC creep. RESULTS: Among the genotypes of 32 isolates, there were 17 (53.1%) isolates with ST239-SCCmecIII, seven (21.9%) isolates with ST5-SCCmecII, six (18.8%) isolates with ST59-SCCmecIV, and two (6.2%) isolates with ST59-SCCmecVT. Two isolates had an MIC of 2 MUg/mL and were identified as ST239-SCCmecIII. No statistically significant change in the distribution of MICs of all isolates was observed between 2003 and 2014 (p = 0.263). There was no significant difference in the mortality rates between two groups of patients with vancomycin MICs < 2 MUg/mL and >= 2 MUg/mL (p = > 0.99). CONCLUSION: There was no vancomycin MIC creep in the period from 2003 to 2014 in this study. Appropriate prognostic models for assessment of the association among sequence types, vancomycin MICs, and clinical outcome warrant further investigation. PMID- 26497451 TI - Solar Disinfection of Viruses in Polyethylene Terephthalate Bottles. AB - Solar disinfection (SODIS) of drinking water in polyethylene terephthalate (PET) bottles is a simple, efficient point-of-use technique for the inactivation of many bacterial pathogens. In contrast, the efficiency of SODIS against viruses is not well known. In this work, we studied the inactivation of bacteriophages (MS2 and phiX174) and human viruses (echovirus 11 and adenovirus type 2) by SODIS. We conducted experiments in PET bottles exposed to (simulated) sunlight at different temperatures (15, 22, 26, and 40 degrees C) and in water sources of diverse compositions and origins (India and Switzerland). Good inactivation of MS2 (>6 log inactivation after exposure to a total fluence of 1.34 kJ/cm(2)) was achieved in Swiss tap water at 22 degrees C, while less-efficient inactivation was observed in Indian waters and for echovirus (1.5-log inactivation at the same fluence). The DNA viruses studied, phiX174 and adenovirus, were resistant to SODIS, and the inactivation observed was equivalent to that occurring in the dark. High temperatures enhanced MS2 inactivation substantially; at 40 degrees C, 3-log inactivation was achieved in Swiss tap water after exposure to a fluence of only 0.18 kJ/cm(2). Overall, our findings demonstrate that SODIS may reduce the load of single-stranded RNA (ssRNA) viruses, such as echoviruses, particularly at high temperatures and in photoreactive matrices. In contrast, complementary measures may be needed to ensure efficient inactivation during SODIS of DNA viruses resistant to oxidation. PMID- 26497453 TI - Spatial Distribution of Lactococcus lactis Colonies Modulates the Production of Major Metabolites during the Ripening of a Model Cheese. AB - In cheese, lactic acid bacteria are immobilized at the coagulation step and grow as colonies. The spatial distribution of bacterial colonies is characterized by the size and number of colonies for a given bacterial population within cheese. Our objective was to demonstrate that different spatial distributions, which lead to differences in the exchange surface between the colonies and the cheese matrix, can influence the ripening process. The strategy was to generate cheeses with the same growth and acidification of a Lactococcus lactis strain with two different spatial distributions, big and small colonies, to monitor the production of the major ripening metabolites, including sugars, organic acids, peptides, free amino acids, and volatile metabolites, over 1 month of ripening. The monitored metabolites were qualitatively the same for both cheeses, but many of them were more abundant in the small-colony cheeses than in the big-colony cheeses over 1 month of ripening. Therefore, the results obtained showed that two different spatial distributions of L. lactis modulated the ripening time course by generating moderate but significant differences in the rates of production or consumption for many of the metabolites commonly monitored throughout ripening. The present work further explores the immobilization of bacteria as colonies within cheese and highlights the consequences of this immobilization on cheese ripening. PMID- 26497452 TI - The Microbiota of Freshwater Fish and Freshwater Niches Contain Omega-3 Fatty Acid-Producing Shewanella Species. AB - Approximately 30 years ago, it was discovered that free-living bacteria isolated from cold ocean depths could produce polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) (20:5n-3) or docosahexaenoic acid (DHA) (22:6n-3), two PUFA essential for human health. Numerous laboratories have also discovered that EPA- and/or DHA-producing bacteria, many of them members of the Shewanella genus, could be isolated from the intestinal tracts of omega-3 fatty acid-rich marine fish. If bacteria contribute omega-3 fatty acids to the host fish in general or if they assist some bacterial species in adaptation to cold, then cold freshwater fish or habitats should also harbor these producers. Thus, we undertook a study to see if these niches also contained omega-3 fatty acid producers. We were successful in isolating and characterizing unique EPA producing strains of Shewanella from three strictly freshwater native fish species, i.e., lake whitefish (Coregonus clupeaformis), lean lake trout (Salvelinus namaycush), and walleye (Sander vitreus), and from two other freshwater nonnative fish, i.e., coho salmon (Oncorhynchus kisutch) and seeforellen brown trout (Salmo trutta). We were also able to isolate four unique free-living strains of EPA-producing Shewanella from freshwater habitats. Phylogenetic and phenotypic analyses suggest that one producer is clearly a member of the Shewanella morhuae species and another is sister to members of the marine PUFA-producing Shewanella baltica species. However, the remaining isolates have more ambiguous relationships, sharing a common ancestor with non-PUFA producing Shewanella putrefaciens isolates rather than marine S. baltica isolates despite having a phenotype more consistent with S. baltica strains. PMID- 26497454 TI - Maturation of Fibrinolytic Bacillopeptidase F Involves both Hetero- and Autocatalytic Processes. AB - Bacillopeptidase F (Bpr) is a fibrinolytic serine protease produced by Bacillus subtilis. Its precursor is composed of a signal peptide, an N-terminal propeptide, a catalytic domain, and a long C-terminal extension (CTE). Several active forms of Bpr have been previously reported, but little is known about the maturation of this enzyme. Here, a gene encoding a Bpr (BprL) was cloned from B. subtilis LZW and expressed in B. subtilis WB700, and three fibrinolytic mature forms with apparent molecular masses of 45, 75, and 85 kDa were identified in the culture supernatant. After treatment with urea, the 75-kDa mature form had the same molecular mass as the 85-kDa mature form, from which we infer that they adopt different conformations. Mutational analysis revealed that while the 85-kDa mature form is generated via heterocatalytic processing of a BprL proform by an unidentified protease of B. subtilis, the production of the 75- and 45-kDa mature forms involves both hetero- and autocatalytic events. From in vitro analysis of BprL and its sequential C-terminal truncation variants, it appears that partial removal of the CTE is required for the initiation of autoprocessing of the N terminal propeptide, which is composed of a core domain (N*) and a 15-residue linker peptide, thereby yielding the 45-kDa mature form. These data suggest that the differential processing of BprL, either heterocatalytically or autocatalytically, leads to the formation of multiple mature forms with different molecular masses or conformations. PMID- 26497455 TI - A Dual Microscopy-Based Assay To Assess Listeria monocytogenes Cellular Entry and Vacuolar Escape. AB - Listeria monocytogenes is a Gram-positive bacterium and a facultative intracellular pathogen that invades mammalian cells, disrupts its internalization vacuole, and proliferates in the host cell cytoplasm. Here, we describe a novel image-based microscopy assay that allows discrimination between cellular entry and vacuolar escape, enabling high-content screening to identify factors specifically involved in these two steps. We first generated L. monocytogenes and Listeria innocua strains expressing a beta-lactamase covalently attached to the bacterial cell wall. These strains were then incubated with HeLa cells containing the Forster resonance energy transfer (FRET) probe CCF4 in their cytoplasm. The CCF4 probe was cleaved by the bacterial surface beta-lactamase only in cells inoculated with L. monocytogenes but not those inoculated with L. innocua, thereby demonstrating bacterial access to the host cytoplasm. Subsequently, we performed differential immunofluorescence staining to distinguish extracellular versus total bacterial populations in samples that were also analyzed by the FRET based assay. With this two-step analysis, bacterial entry can be distinguished from vacuolar rupture in a single experiment. Our novel approach represents a powerful tool for identifying factors that determine the intracellular niche of L. monocytogenes. PMID- 26497456 TI - Inhibitory Role of Greatwall-Like Protein Kinase Rim15p in Alcoholic Fermentation via Upregulating the UDP-Glucose Synthesis Pathway in Saccharomyces cerevisiae. AB - The high fermentation rate of Saccharomyces cerevisiae sake yeast strains is attributable to a loss-of-function mutation in the RIM15 gene, which encodes a Greatwall-family protein kinase that is conserved among eukaryotes. In the present study, we performed intracellular metabolic profiling analysis and revealed that deletion of the RIM15 gene in a laboratory strain impaired glucose anabolic pathways through the synthesis of UDP-glucose (UDPG). Although Rim15p is required for the synthesis of trehalose and glycogen from UDPG upon entry of cells into the quiescent state, we found that Rim15p is also essential for the accumulation of cell wall beta-glucans, which are also anabolic products of UDPG. Furthermore, the impairment of UDPG or 1,3-beta-glucan synthesis contributed to an increase in the fermentation rate. Transcriptional induction of PGM2 (phosphoglucomutase) and UGP1 (UDPG pyrophosphorylase) was impaired in Rim15p deficient cells in the early stage of fermentation. These findings demonstrate that the decreased anabolism of glucose into UDPG and 1,3-beta-glucan triggered by a defect in the Rim15p-mediated upregulation of PGM2 and UGP1 redirects the glucose flux into glycolysis. Consistent with this, sake yeast strains with defective Rim15p exhibited impaired expression of PGM2 and UGP1 and decreased levels of beta-glucans, trehalose, and glycogen during sake fermentation. We also identified a sake yeast-specific mutation in the glycogen synthesis-associated glycogenin gene GLG2, supporting the conclusion that the glucose-anabolic pathway is impaired in sake yeast. These findings demonstrate that downregulation of the UDPG synthesis pathway is a key mechanism accelerating alcoholic fermentation in industrially utilized S. cerevisiae sake strains. PMID- 26497457 TI - Biocontrol of the Potato Blackleg and Soft Rot Diseases Caused by Dickeya dianthicola. AB - Development of protection tools targeting Dickeya species is an important issue in the potato production. Here, we present the identification and the characterization of novel biocontrol agents. Successive screenings of 10,000 bacterial isolates led us to retain 58 strains that exhibited growth inhibition properties against several Dickeya sp. and/or Pectobacterium sp. pathogens. Most of them belonged to the Pseudomonas and Bacillus genera. In vitro assays revealed a fitness decrease of the tested Dickeya sp. and Pectobacterium sp. pathogens in the presence of the biocontrol agents. In addition, four independent greenhouse assays performed to evaluate the biocontrol bacteria effect on potato plants artificially contaminated with Dickeya dianthicola revealed that a mix of three biocontrol agents, namely, Pseudomonas putida PA14H7 and Pseudomonas fluorescens PA3G8 and PA4C2, repeatedly decreased the severity of blackleg symptoms as well as the transmission of D. dianthicola to the tuber progeny. This work highlights the use of a combination of biocontrol strains as a potential strategy to limit the soft rot and blackleg diseases caused by D. dianthicola on potato plants and tubers. PMID- 26497458 TI - The Connection between Persistent, Disinfectant-Resistant Listeria monocytogenes Strains from Two Geographically Separate Iberian Pork Processing Plants: Evidence from Comparative Genome Analysis. AB - The aim of this study was to investigate the basis of the putative persistence of Listeria monocytogenes in a new industrial facility dedicated to the processing of ready-to-eat (RTE) Iberian pork products. Quaternary ammonium compounds, which included benzalkonium chloride (BAC), were repeatedly used as surface disinfectants in the processing plant. Clean and disinfected surfaces were sampled to evaluate if resistance to disinfectants was associated with persistence. Of the 14 isolates obtained from product contact and non-product contact surfaces, only five different pulsed-field gel electrophoresis (PFGE) types were identified during the 27-month study period. Two of these PFGE types (S1 and S10-1) were previously identified to be persistent and BAC-resistant (BAC(r)) strains in a geographically separate slaughterhouse belonging to the same company. The remaining three PFGE types, which were first identified in this study, were also BAC(r). Whole-genome sequencing and in silico multilocus sequence typing (MLST) analysis of five BAC(r) isolates of the different PFGE types identified in this study showed that the isolate of the S1 PFGE type belonged to MLST sequence type 31 (ST31), a low-virulence type characterized by mutations in the inlA and prfA genes. The isolates of the remaining four PFGE types were found to belong to MLST ST121, a persistent type that has been isolated in several countries. The ST121 strains contained the BAC resistance transposon Tn6188. The disinfection-resistant L. monocytogenes population in this RTE pork product plant comprised two distinct genotypes with different multidrug resistance phenotypes. This work offers insight into the L. monocytogenes subtypes associated with persistence in food processing environments. PMID- 26497460 TI - Identification and Resolution of Microdiversity through Metagenomic Sequencing of Parallel Consortia. AB - To gain a predictive understanding of the interspecies interactions within microbial communities that govern community function, the genomic complement of every member population must be determined. Although metagenomic sequencing has enabled the de novo reconstruction of some microbial genomes from environmental communities, microdiversity confounds current genome reconstruction techniques. To overcome this issue, we performed short-read metagenomic sequencing on parallel consortia, defined as consortia cultivated under the same conditions from the same natural community with overlapping species composition. The differences in species abundance between the two consortia allowed reconstruction of near-complete (at an estimated >85% of gene complement) genome sequences for 17 of the 20 detected member species. Two Halomonas spp. indistinguishable by amplicon analysis were found to be present within the community. In addition, comparison of metagenomic reads against the consensus scaffolds revealed within species variation for one of the Halomonas populations, one of the Rhodobacteraceae populations, and the Rhizobiales population. Genomic comparison of these representative instances of inter- and intraspecies microdiversity suggests differences in functional potential that may result in the expression of distinct roles in the community. In addition, isolation and complete genome sequence determination of six member species allowed an investigation into the sensitivity and specificity of genome reconstruction processes, demonstrating robustness across a wide range of sequence coverage (9* to 2,700*) within the metagenomic data set. PMID- 26497459 TI - Influence of Salmonella enterica Serovar Typhimurium ssrB on Colonization of Eastern Oysters (Crassostrea virginica) as Revealed by a Promoter Probe Screen. AB - Although Salmonella has been isolated from 7.4 to 8.6% of domestic raw oysters, representing a significant risk for food-borne illness, little is known about the factors that influence their initial colonization by Salmonella. This study tested the hypothesis that specific regulatory changes enable a portion of the invading Salmonella population to colonize oysters. An in vivo promoter probe library screen identified 19 unique regions as regulated during colonization. The mutants in the nearest corresponding downstream genes were tested for colonization defects in oysters. Only one mutation, in ssrB, resulted in a significantly reduced ability to colonize oysters compared to that of wild-type Salmonella. Because ssrB regulates Salmonella pathogenicity island 2 (SPI-2) dependent infections in vertebrate macrophages, the possibility that ssrB mediated colonization of oyster hemocytes in a similar manner was examined. However, no difference in hemocyte colonization was observed. The complementary hypothesis that signal exchange between Salmonella and the oyster's native microbial community aids colonization was also tested. Signals that triggered responses in quorum sensing (QS) reporters were shown to be produced by oyster associated bacteria and present in oyster tissue. However, no evidence for signal exchange was observed in vivo. The sdiA reporter responded to salinity, suggesting that SdiA may also have a role in environmental sensing. Overall, this study suggests the initial colonization of live oysters by Salmonella is controlled by a limited number of regulators, including ssrB. PMID- 26497461 TI - Abiotic Stress and Phyllosphere Bacteria Influence the Survival of Human Norovirus and Its Surrogates on Preharvest Leafy Greens. AB - Foodborne outbreaks of human noroviruses (HuNoVs) are frequently associated with leafy greens. Because there is no effective method to eliminate HuNoV from postharvest leafy greens, understanding virus survival under preharvest conditions is crucial. The objective of this study was to evaluate the survival of HuNoV and its surrogate viruses, murine norovirus (MNV), porcine sapovirus (SaV), and Tulane virus (TV), on preharvest lettuce and spinach that were subjected to abiotic stress (physical damage, heat, or flood). We also examined the bacteria culturable from the phyllosphere in response to abiotic stress and in relation to viral persistence. Mature plants were subjected to stressors 2 days prior to inoculation of the viruses on leaves. We quantified the viral RNA, determined the infectivity of the surrogates, and performed bacterial counts on postinoculation days (PIDs) 0, 1, 7, and 14. For both plant types, time exerted significant effects on HuNoV, MNV, SaV, and TV RNA titers, with greater effects being seen for the surrogates. Infectious surrogate viruses were undetectable on PID 14. Only physical damage on PID 14 significantly enhanced HuNoV RNA persistence on lettuce, while the three stressors differentially enhanced the persistence of MNV and TV RNA. Bacterial counts were significantly affected by time and plant type but not by the stressors. However, bacterial counts correlated significantly with HuNoV RNA titers on spinach and with the presence of surrogate viruses on both plant types under various conditions. In conclusion, abiotic stressors and phyllosphere bacterial density may differentially influence the survival of HuNoV and its surrogates on lettuce and spinach, emphasizing the need for the use of preventive measures at the preharvest stage. PMID- 26497462 TI - Changing Feeding Regimes To Demonstrate Flexible Biogas Production: Effects on Process Performance, Microbial Community Structure, and Methanogenesis Pathways. AB - Flexible biogas production that adapts biogas output to energy demand can be regulated by changing feeding regimes. In this study, the effect of changes in feeding intervals on process performance, microbial community structure, and the methanogenesis pathway was investigated. Three different feeding regimes (once daily, every second day, and every 2 h) at the same organic loading rate were studied in continuously stirred tank reactors treating distiller's dried grains with solubles. A larger amount of biogas was produced after feeding in the reactors fed less frequently (once per day and every second day), whereas the amount remained constant in the reactor fed more frequently (every 2 h), indicating the suitability of the former for the flexible production of biogas. Compared to the conventional more frequent feeding regimes, a methane yield that was up to 14% higher and an improved stability of the process against organic overloading were achieved by employing less frequent feeding regimes. The community structures of bacteria and methanogenic archaea were monitored by terminal restriction fragment length polymorphism (T-RFLP) analysis of 16S rRNA and mcrA genes, respectively. The results showed that the composition of the bacterial community varied under the different feeding regimes, and the observed T-RFLP patterns were best explained by the differences in the total ammonia nitrogen concentrations, H2 levels, and pH values. However, the methanogenic community remained stable under all feeding regimes, with the dominance of the Methanosarcina genus followed by that of the Methanobacterium genus. Stable isotope analysis showed that the average amount of methane produced during each feeding event by acetoclastic and hydrogenotrophic methanogenesis was not influenced by the three different feeding regimes. PMID- 26497464 TI - Silver Nanoparticles Decrease the Viability of Cryptosporidium parvum Oocysts. AB - Oocysts of the waterborne protozoan parasite Cryptosporidium parvum are highly resistant to chlorine disinfection. We show here that both silver nanoparticles (AgNPs) and silver ions significantly decrease oocyst viability, in a dose dependent manner, between concentrations of 0.005 and 500 MUg/ml, as assessed by an excystation assay and the shell/sporozoite ratio. For percent excystation, the results are statistically significant for 500 MUg/ml of AgNPs, with reductions from 83% for the control to 33% with AgNPs. For Ag ions, the results were statistically significant at 500 and 5,000 MUg/ml, but the percent excystation values were reduced only to 66 and 62%, respectively, from 86% for the control. The sporozoite/shell ratio was affected to a greater extent following AgNP exposure, presumably because sporozoites are destroyed by interaction with NPs. We also demonstrated via hyperspectral imaging that there is a dual mode of interaction, with Ag ions entering the oocyst and destroying the sporozoites while AgNPs interact with the cell wall and, at high concentrations, are able to fully break the oocyst wall. PMID- 26497463 TI - Anodes Stimulate Anaerobic Toluene Degradation via Sulfur Cycling in Marine Sediments. AB - Hydrocarbons released during oil spills are persistent in marine sediments due to the absence of suitable electron acceptors below the oxic zone. Here, we investigated an alternative bioremediation strategy to remove toluene, a model monoaromatic hydrocarbon, using a bioanode. Bioelectrochemical reactors were inoculated with sediment collected from a hydrocarbon-contaminated marine site, and anodes were polarized at 0 mV and +300 mV (versus an Ag/AgCl [3 M KCl] reference electrode). The degradation of toluene was directly linked to current generation of up to 301 mA m(-2) and 431 mA m(-2) for the bioanodes polarized at 0 mV and +300 mV, respectively. Peak currents decreased over time even after periodic spiking with toluene. The monitoring of sulfate concentrations during bioelectrochemical experiments suggested that sulfur metabolism was involved in toluene degradation at bioanodes. 16S rRNA gene-based Illumina sequencing of the bulk anolyte and anode samples revealed enrichment with electrocatalytically active microorganisms, toluene degraders, and sulfate-reducing microorganisms. Quantitative PCR targeting the alpha-subunit of the dissimilatory sulfite reductase (encoded by dsrA) and the alpha-subunit of the benzylsuccinate synthase (encoded by bssA) confirmed these findings. In particular, members of the family Desulfobulbaceae were enriched concomitantly with current production and toluene degradation. Based on these observations, we propose two mechanisms for bioelectrochemical toluene degradation: (i) direct electron transfer to the anode and/or (ii) sulfide-mediated electron transfer. PMID- 26497465 TI - A Novel Bacteriophage Targeting Cronobacter sakazakii Is a Potential Biocontrol Agent in Foods. AB - Cronobacter sakazakii is an important pathogen that causes high mortality in infants. Due to its occasional antibiotic resistance, a bacteriophage approach might be an alternative effective method for the control of this pathogen. To develop a novel biocontrol agent using bacteriophages, the C. sakazakii-infecting phage CR5 was newly isolated and characterized. Interestingly, this phage exhibited efficient and relatively durable host lysis activity. In addition, a specific gene knockout study and subsequent complementation experiment revealed that this phage infected the host strain using the bacterial flagella. The complete genome sequence analysis of phage CR5 showed that its genome contains 223,989 bp of DNA, including 231 predicted open reading frames (ORFs), and it has a G+C content of 50.06%. The annotated ORFs were classified into six functional groups (structure, packaging, host lysis, DNA manipulation, transcription, and additional functions); no gene was found to be related to virulence or toxin or lysogen formation, but >80% of the predicted ORFs are unknown. In addition, a phage proteomic analysis using SDS-PAGE and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) revealed that seven phage structural proteins are indeed present, supporting the ORF predictions. To verify the potential of this phage as a biocontrol agent against C. sakazakii, it was added to infant formula milk contaminated with a C. sakazakii clinical isolate or food isolate, revealing complete growth inhibition of the isolates by the addition of phage CR5 when the multiplicity of infection (MOI) was 10(5). PMID- 26497466 TI - The CreC Regulator of Escherichia coli, a New Target for Metabolic Manipulations. AB - The CreBC (carbon source-responsive) two-component regulation system of Escherichia coli affects a number of functions, including intermediary carbon catabolism. The impacts of different creC mutations (a DeltacreC mutant and a mutant carrying the constitutive creC510 allele) on bacterial physiology were analyzed in glucose cultures under three oxygen availability conditions. Differences in the amounts of extracellular metabolites produced were observed in the null mutant compared to the wild-type strain and the mutant carrying creC510 and shown to be affected by oxygen availability. The DeltacreC strain secreted more formate, succinate, and acetate but less lactate under low aeration. These metabolic changes were associated with differences in AckA and LdhA activities, both of which were affected by CreC. Measurement of the NAD(P)H/NAD(P)(+) ratios showed that the creC510 strain had a more reduced intracellular redox state, while the opposite was observed for the DeltacreC mutant, particularly under intermediate oxygen availability conditions, indicating that CreC affects redox balance. The null mutant formed more succinate than the wild-type strain under both low aeration and no aeration. Overexpression of the genes encoding phosphoenolpyruvate carboxylase from E. coli and a NADH-forming formate dehydrogenase from Candida boidinii in the DeltacreC mutant further increased the yield of succinate on glucose. Interestingly, the elimination of ackA and adhE did not significantly improve the production of succinate. The diverse metabolic effects of this regulator on the central biochemical network of E. coli make it a good candidate for metabolic-engineering manipulations to enhance the formation of bioproducts, such as succinate. PMID- 26497467 TI - Sporulation Temperature Reveals a Requirement for CotE in the Assembly of both the Coat and Exosporium Layers of Bacillus cereus Spores. AB - The Bacillus cereus spore surface layers consist of a coat surrounded by an exosporium. We investigated the interplay between the sporulation temperature and the CotE morphogenetic protein in the assembly of the surface layers of B. cereus ATCC 14579 spores and on the resulting spore properties. The cotE deletion affects the coat and exosporium composition of the spores formed both at the suboptimal temperature of 20 degrees C and at the optimal growth temperature of 37 degrees C. Transmission electron microscopy revealed that DeltacotE spores had a fragmented and detached exosporium when formed at 37 degrees C. However, when produced at 20 degrees C, DeltacotE spores showed defects in both coat and exosporium attachment and were susceptible to lysozyme and mutanolysin. Thus, CotE has a role in the assembly of both the coat and exosporium, which is more important during sporulation at 20 degrees C. CotE was more represented in extracts from spores formed at 20 degrees C than at 37 degrees C, suggesting that increased synthesis of the protein is required to maintain proper assembly of spore surface layers at the former temperature. DeltacotE spores formed at either sporulation temperature were impaired in inosine-triggered germination and resistance to UV-C and H2O2 and were less hydrophobic than wild-type (WT) spores but had a higher resistance to wet heat. While underscoring the role of CotE in the assembly of B. cereus spore surface layers, our study also suggests a contribution of the protein to functional properties of additional spore structures. Moreover, it also suggests a complex relationship between the function of a spore morphogenetic protein and environmental factors such as the temperature during spore formation. PMID- 26497469 TI - The moderating effects of coping and self-esteem on the relationship between defeat, entrapment and suicidality in a sample of prisoners at high risk of suicide. AB - BACKGROUND: Research is sparse which examines pathways to suicide, and resilience to suicide, in people who are particularly vulnerable to suicide, for example, prison inmates. The purpose of this study was to examine the ways in which perceptions of self-esteem and coping ability interacted with defeat and entrapment to both amplify suicidal thoughts and feelings, and to act as a buffer against suicidal thoughts and feelings. METHODS: Participants were 65 male prisoners at high risk of suicide. A cross-sectional questionnaire design was used. Questionnaire measures of depression, defeat, entrapment, self-esteem, coping ability and suicidal probability were administered. RESULTS: For the hopelessness component of the suicide probability measure, high levels of coping ability together with low levels of defeat resulted in the lowest levels of suicidality indicative of a resilience factor. In contrast, low levels of coping skills together with high levels of entrapment were a high risk factor for this hopelessness component of suicide. This pattern of results pertained when controlling for depression levels. CONCLUSIONS: This is the first study to examine interactions between defeat, entrapment and appraisals of self-esteem and coping ability. Therapeutic interventions would benefit from boosting perceptions and appraisals of coping ability, in particular, in people who are at high risk for suicide. PMID- 26497468 TI - Bacillus cereus NVH 0500/00 Can Adhere to Mucin but Cannot Produce Enterotoxins during Gastrointestinal Simulation. AB - Adhesion to the intestinal epithelium could constitute an essential mechanism of Bacillus cereus pathogenesis. However, the enterocytes are protected by mucus, a secretion composed mainly of mucin glycoproteins. These may serve as nutrients and sites of adhesion for intestinal bacteria. In this study, the food poisoning bacterium B. cereus NVH 0500/00 was exposed in vitro to gastrointestinal hurdles prior to evaluation of its attachment to mucin microcosms and its ability to produce nonhemolytic enterotoxin (Nhe). The persistence of mucin-adherent B. cereus after simulated gut emptying was determined using a mucin adhesion assay. The stability of Nhe toward bile and pancreatin (intestinal components) in the presence of mucin agar was also investigated. B. cereus could grow and simultaneously adhere to mucin during in vitro ileal incubation, despite the adverse effect of prior exposure to a low pH or intestinal components. The final concentration of B. cereus in the simulated lumen at 8 h of incubation was 6.62 +/- 0.87 log CFU ml(-1). At that point, the percentage of adhesion was approximately 6%. No enterotoxin was detected in the ileum, due to either insufficient bacterial concentrations or Nhe degradation. Nevertheless, mucin appears to retain B. cereus and to supply it to the small intestine after simulated gut emptying. Additionally, mucin may play a role in the protection of enterotoxins from degradation by intestinal components. PMID- 26497471 TI - Outcomes of kidney retransplantation in recipients with prior post-transplant lymphoproliferative disorder. AB - Post-transplant lymphoproliferative disease (PTLD) is an uncommon but serious complication of solid organ transplantation. Reduction in immunosuppression is the mainstay of PTLD treatment, but it may precipitate graft loss. Retransplantation remains controversial, as immunosuppression resumption may trigger PTLD relapse. Herein, we describe the experience of eight patients who underwent kidney retransplantation after successful PTLD treatment. Epstein-Barr virus (EBV) serology was not known before the first transplantation. PTLD was diagnosed 62.5 months (range 5-323 months) after transplantation and was confined to the renal allograft (n = 1), lymph nodes (n = 2), gastrointestinal tract (n = 4), or central nervous system (n = 1). Immunosuppression tapering (8/8), chemotherapy (6/8), oral cavity lymphoma excision (1/8), and allograft nephrectomy (1/8) led to hematological remission in all patients. Retransplantation was performed at a median of 55.5 months (range 29-95 months) after PTLD diagnosis. After a median follow-up of 62.5 months (range 2-125 months) allograft survival was 87.5% (seven functioning grafts, one failed graft from chronic rejection), with no recurrence of PTLD. In all, five patients remain alive; the other three died from causes other than PTLD. In conclusion, kidney retransplantation appears to be safe in patients with prior PTLD and without major risk of hematological recurrence provided that PTLD has remitted. PMID- 26497470 TI - Differential impacts of duration of untreated psychosis (DUP) on cognitive function in first-episode schizophrenia according to mode of onset. AB - BACKGROUND: The mode of onset and the course of schizophrenia illness exhibit substantial individual variations. Previous studies have pointed out that the mode of onset affects the duration of untreated psychosis (DUP) and clinical outcomes, such as cognitive and social functioning. This study attempted to clarify the association between the DUP and clinical features, taking the different modes of onset into consideration, in a prospective longitudinal study examining patients with first-episode schizophrenia. METHODS: This study was conducted in six areas of Japan. Patients with first-episode schizophrenia were followed for over 18 months. Cognitive function, psychopathology, and social functioning were assessed at baseline and at 6, 12, and 18-month follow-up points. RESULTS: We identified 168 patients and sufficient information was available to determine the DUP and the mode of onset for 156 patients (92.9%): 79 had an acute onset, and 77 had an insidious onset. The DUP was significantly associated with quality of life (QOL), social functioning, and cognitive function at most of the follow-up points in the insidious-onset group. The DUP and negative symptoms at baseline were significant predictors of cognitive function at the 18-month follow-up in the insidious-onset group. CONCLUSIONS: The present results further support the hypothesis that the DUP affects QOL, social functioning, and cognitive function over the course of illness, especially in patients with an insidious onset. Effective strategies for detecting and caring for individuals with insidious onset early during the course of schizophrenia will be essential for achieving a full patient recovery. PMID- 26497472 TI - Bouts of steps: The organization of infant exploration. AB - Adults primarily walk to reach a new location, but why do infants walk? Do infants, like adults, walk to travel to a distant goal? We observed 30 13-month old and 30 19-month-old infants during natural walking in a laboratory playroom. We characterized the bout structure of walking-when infants start and stop walking-to examine why infants start and stop walking. Locomotor activity was composed largely of brief spurts of walking. Half of 13-month-olds' bouts and 41% of 19-month-olds' bouts consisted of three or fewer steps-too few to carry infants to a distant goal. Most bouts ended in the middle of the floor, not at a recognizable goal. Survival analyses of the distribution of steps per bout indicated that the probability of continuing to walk was independent of the length of the ongoing bout; infants were just as likely to stop walking after five steps as after 50 steps and they showed no bias toward bouts long enough to carry them across the room to a goal. However, 13-month-olds showed an increased probability of stopping after 1-3 steps, and they did not initiate walking more frequently to compensate for their surfeit of short bouts. We propose that infants' natural walking is not intentionally directed at distant goals; rather, it is a stochastic process that serves exploratory functions. Relations between the bout structure of walking and other measures of walking suggest that locomotor exploration is constrained by walking skill in younger infants, but not in older infants. PMID- 26497475 TI - Vancomycin Trough Concentration as a Predictor of Clinical Outcomes in Patients with Staphylococcus aureus Bacteremia: A Meta-analysis of Observational Studies. AB - STUDY OBJECTIVE: To determine the strength of evidence for better clinical outcomes in patients with Staphylococcus aureus bacteremia who had vancomycin trough levels of 15-20 mg/L. DESIGN: Meta-analysis of 14 observational cohort studies. PATIENTS: A total of 1677 patients, representing geriatric and unspecified inpatients, who received standard dosing of vancomycin for the treatment of S. aureus bacteremia and who had trough level goals of 15-20 mg/L. MEASUREMENTS AND MAIN RESULTS: The treatment variables examined in the analysis were vancomycin trough concentrations and 24-hour area under the concentration time curve to minimum inhibitory concentration ratio (AUC:MIC) values. The outcomes of interest were mortality, persistent bacteremia, and treatment failure. Mortality was defined as 30-day mortality, in-hospital mortality, or a comparable measure; persistent bacteremia was defined as bacteremia lasting at least 7 days after the initiation of vancomycin; treatment failure was defined as a composite end point that included at least persistent bacteremia and mortality, as previously defined. Higher vancomycin trough levels (15 mg/L or greater or based on MIC) were not associated with significantly reduced treatment failure, persistent bacteremia, or mortality. Higher AUC:MIC values were associated with significantly reduced treatment failure (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.31-0.53), persistent bacteremia (OR 0.53, 95% CI 0.33-0.86), and mortality (OR 0.47, 95% CI 0.33-0.65). The weighted mean +/- SD AUC:MIC threshold defined by regression analyses in the included studies was 418 +/- 88 hours, which supports the current goal of 400 hours or more. CONCLUSION: Vancomycin trough concentrations do not have sufficient evidence to support their use as the primary guide in vancomycin dosing. Dosing should instead focus on AUC:MIC values, which have strong evidence of benefit. PMID- 26497473 TI - A novel intrinsically fluorescent probe for study of uptake and trafficking of 25 hydroxycholesterol. AB - Cholesterol homeostasis is regulated not only by cholesterol, but also by oxygenated cholesterol species, referred to as oxysterols. Side-chain oxysterols, such as 25-hydroxycholesterol (25-HC), regulate cholesterol homeostasis through feedback inhibition and feed-forward activation of transcriptional pathways that govern cholesterol synthesis, uptake, and elimination, as well as through direct nongenomic actions that modulate cholesterol accessibility in membranes. Elucidating the cellular distribution of 25-HC is required to understand its biological activity at the molecular level. However, studying oxysterol distribution and behavior within cells has proven difficult due to the lack of fluorescent analogs of 25-HC that retain its chemical and physical properties. To address this, we synthesized a novel intrinsically fluorescent 25-HC mimetic, 25 hydroxycholestatrienol (25-HCTL). We show that 25-HCTL modulates sterol homeostatic responses in a similar manner as 25-HC. 25-HCTL associates with lipoproteins in media and is taken up by cells through LDL-mediated endocytosis. In cultured cells, 25-HCTL redistributes among cellular membranes and, at steady state, has a similar distribution as cholesterol, being enriched in both the endocytic recycling compartment as well as the plasma membrane. Our findings indicate that 25-HCTL is a faithful fluorescent 25-HC mimetic that can be used to investigate the mechanisms through which 25-HC regulates sterol homeostatic pathways. PMID- 26497474 TI - ABCA1-dependent sterol release: sterol molecule specificity and potential membrane domain for HDL biogenesis. AB - Mammalian cells synthesize various sterol molecules, including the C30 sterol, lanosterol, as cholesterol precursors in the endoplasmic reticulum. The build-up of precursor sterols, including lanosterol, displays cellular toxicity. Precursor sterols are found in plasma HDL. How these structurally different sterols are released from cells is poorly understood. Here, we show that newly synthesized precursor sterols arriving at the plasma membrane (PM) are removed by extracellular apoA-I in a manner dependent on ABCA1, a key macromolecule for HDL biogenesis. Analysis of sterol molecules by GC-MS and tracing the fate of radiolabeled acetate-derived sterols in normal and mutant Niemann-Pick type C cells reveal that ABCA1 prefers newly synthesized sterols, especially lanosterol, as the substrates before they are internalized from the PM. We also show that ABCA1 resides in a cholesterol-rich membrane domain resistant to the mild detergent, Brij 98. Blocking ACAT activity increases the cholesterol contents of this domain. Newly synthesized C29/C30 sterols are transiently enriched within this domain, but rapidly disappear from this domain with a half-life of less than 1 h. Our work shows that substantial amounts of precursor sterols are transported to a certain PM domain and are removed by the ABCA1-dependent pathway. PMID- 26497477 TI - The Microbiome in Mental Health: Potential Contribution of Gut Microbiota in Disease and Pharmacotherapy Management. AB - The gut microbiome is composed of ~10(13) -10(14) microbial cells and viruses that exist in a symbiotic bidirectional communicative relationship with the host. Bacterial functions in the gut have an important role in healthy host metabolic function, and dysbiosis can contribute to the pathology of many medical conditions. Alterations in the relationship between gut microbiota and host have gained some attention in mental health because new evidence supports the association of gut bacteria to cognitive and emotional processes. Of interest, illnesses such as major depressive disorder are disproportionately prevalent in patients with gastrointestinal illnesses such as inflammatory bowel disease, which pathologically has been strongly linked to microbiome function. Not only is the microbiome associated with the disease itself, but it may also influence the effectiveness or adverse effects associated with pharmacologic agents used to treat these disorders. This field of study may also provide new insights on how dietary agents may help manage mental illness both directly as well as though their influence on the therapeutic and adverse effects of psychotropic agents. PMID- 26497476 TI - Risk of Acute Cerebrovascular and Cardiovascular Events Among Users of Acetaminophen or an Acetaminophen-Codeine Combination in a Cohort of Patients with Osteoarthritis: A Nested Case-Control Study. AB - STUDY OBJECTIVE: To determine whether acetaminophen or an acetaminophen-codeine combination is associated with an increased risk of acute cerebrovascular and cardiovascular events (ACCEs) in patients with osteoarthritis. DESIGN: Nested case-control study. DATA SOURCE: Health Search IMS Health Longitudinal Patient Database. PATIENTS: A total of 36,754 adults with a diagnosis of osteoarthritis and an incident (first-time) prescription of nonsteroidal antiinflammatory drugs (NSAIDs) between January 2002 and June 2012 were identified; of these patients, cases were defined as those who had a diagnosis of an ACCE during the follow-up period (index date was the date of ACCE diagnosis; 2182 cases). For each case, up to five controls were randomly selected who were matched based on age, sex, month and year of cohort entry, and duration of follow-up (10,301 controls). Matched controls were assigned the same index date as their respective cases. MEASUREMENTS AND MAIN RESULTS: For each case and matched controls, all prescriptions of acetaminophen-containing medicines filled during follow-up were identified. The risk of ACCEs was investigated with respect to the recency of use of acetaminophen and/or an acetaminophen-codeine combination. Patients were classified as current (0-90 days preceding index date), recent (91-180 days), or past (181-365 days) acetaminophen users, or nonusers (longer than 365 days), with nonusers representing the reference category. Conditional logistic regression was estimated to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Of the 36,754 patients with osteoarthritis and newly prescribed NSAIDs, the incidence rate of ACCEs was 117.6 per 10,000 person-years. No significant association between exposure to acetaminophen-containing medications and ACCEs was observed in current (OR 1.22, 95% CI 0.96-1.55), recent (OR 1.12, 95% CI 0.80 1.55), or past users (OR 1.13, 95% CI 0.86-1.48). A secondary analysis evaluating exposure to acetaminophen monotherapy or acetaminophen-codeine combination therapy showed similar results for current users. CONCLUSION: Our findings indicate that no association can be made between the use of acetaminophen and/or an acetaminophen-codeine combination and the occurrence of ACCEs. This information contributes to support clinicians in the choice of acetaminophen therapy for osteoarthritis-related pain, especially in those patients presenting with cerebrovascular and cardiovascular morbidities or related risk factors. PMID- 26497478 TI - Peripherally Restricted Cannabinoids for the Treatment of Pain. AB - The use of cannabinoids for the treatment of chronic diseases has increased in the United States, with 23 states having legalized the use of marijuana. Although currently available cannabinoid compounds have shown effectiveness in relieving symptoms associated with numerous diseases, the use of cannabis or cannabinoids is still controversial mostly due to their psychotropic effects (e.g., euphoria, laughter) or central nervous system (CNS)-related undesired effects (e.g., tolerance, dependence). A potential strategy to use cannabinoids for medical conditions without inducing psychotropic or CNS-related undesired effects is to avoid their actions in the CNS. This approach could be beneficial for conditions with prominent peripheral pathophysiologic mechanisms (e.g., painful diabetic neuropathy, chemotherapy-induced neuropathy). In this article, we discuss the scientific evidence to target the peripheral cannabinoid system as an alternative to cannabis use for medical purposes, and we review the available literature to determine the pros and cons of potential strategies that can be used to this end. PMID- 26497479 TI - Liraglutide: A New Option for the Treatment of Obesity. AB - Obesity continues to pose a major public health risk to the United States and across the world, with an estimated one-third of adult Americans being defined as obese. Obesity treatment guidelines recommend the use of pharmacologic therapy in adults who have a body mass index (BMI) of 30 kg/m(2) or higher or in patients with a BMI of 27 kg/m(2) or higher who have at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, insulin resistance, type 2 diabetes mellitus). Liraglutide is a glucagon-like peptide-1 receptor agonist that has been successfully used in the treatment of type 2 diabetes for several years. Weight loss has been well described as an additional benefit with liraglutide therapy, which prompted the manufacturer to evaluate and develop a higher dose formulation specifically for the treatment of obesity. Liraglutide 3 mg/day was approved by the U.S. Food and Drug Administration for this indication in December 2014. We performed a search of the Medline database to identify relevant literature focused on liraglutide's role specifically in treating obesity. Five clinical trials with this primary end point were identified. Data demonstrated that liraglutide can successfully achieve weight-loss benchmarks of 5% or more and 10% or more loss from baseline. The most common adverse effects were gastrointestinal and mild to moderate in intensity. The cost of therapy is high, averaging over $1000/month for out-of-pocket expenses if insurance coverage is not available. Liraglutide is also available for delivery only by subcutaneous injection, which may represent a barrier for patients. Liraglutide 3 mg/day represents another pharmacologic option for the treatment of obesity. PMID- 26497480 TI - Dalbavancin and Oritavancin: An Innovative Approach to the Treatment of Gram Positive Infections. AB - Health care-associated infections, especially those caused by multidrug-resistant gram-positive organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), are a growing public health threat. In 2014, the U.S. Food and Drug Administration approved two new lipoglycopeptides, oritavancin and dalbavancin, for the treatment of acute bacterial skin and skin structure infections. The rationale for the development of these antimicrobials was partly to aid in the battle against vancomycin resistance in both Staphylococcus and Enterococcus. Considered a subclass of the glycopeptide antibiotics, the new lipoglycopeptides have similar mechanisms of action of binding to the carboxyl terminal d-alanyl-d alanine residue of the growing peptide chains but differ from their parent glycopeptides by the addition of lipophilic tails. This addition allows for these agents to have prolonged half-lives, giving them unique dosing profiles. In addition, by concentrating at the site of action, they have increased potency against MRSA compared with vancomycin, the current mainstay of therapy. In this review, we focus on comparing and contrasting these two new agents with regard to their pharmacology, mechanisms of action, spectrum of activity, safety profiles, dosage and administration, and drug and laboratory interactions, and we review the clinical trials evaluating their use. PMID- 26497481 TI - Infections Caused by Resistant Gram-Negative Bacteria: Epidemiology and Management. AB - Infections caused by resistant gram-negative bacteria are becoming increasingly prevalent and now constitute a serious threat to public health worldwide because they are difficult to treat and are associated with high morbidity and mortality rates. In the United States, there has been a steady increase since 2000 in rates of extended-spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem resistant Enterobacteriaceae, and multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii, particularly among hospitalized patients with intraabdominal infections, urinary tract infections, ventilator-associated pneumonia, and bacteremia. Colonization with resistant gram-negative bacteria is common among residents in long-term care facilities (particularly those residents with an indwelling device), and these facilities are considered important originating sources of such strains for hospitals. Antibiotic resistance is associated with a substantial clinical and economic burden, including increased mortality, greater hospital and antibiotic costs, and longer stays in hospitals and intensive care units. Control of resistant gram-negative infections requires a comprehensive approach, including strategies for risk factor identification, detection and identification of resistant organisms, and implementation of infection-control and prevention strategies. In treating resistant gram-negative infections, a review of surveillance data and hospital-specific antibiograms, including resistance patterns within local institutions, and consideration of patient characteristics are helpful in guiding the choice of empiric therapy. Although only a few agents are available with activity against resistant gram negative organisms, two recently released beta-lactam/beta-lactamase inhibitor combinations - ceftolozane/tazobactam and ceftazidime/avibactam - have promising activity against these organisms. In this article, we review the epidemiology, risk factors, and antibiotic resistance mechanisms of gram-negative organisms. In addition, an overview of treatment options for patients with these infections is provided. PMID- 26497482 TI - Immune Checkpoint Inhibitors: New Insights and Current Place in Cancer Therapy. AB - The treatment of cancer has largely relied on killing tumor cells with nonspecific cytotoxic therapies and radiotherapy. This approach, however, has limitations including severe systemic toxicities, bystander effects on normal cells, recurrence of drug-resistant tumor cells, and the inability to target micrometastases or subclinical disease. An increased understanding of the critical role of the immune system in cancer development and progression has led to new treatment strategies using various immunotherapies. It is now recognized that established tumors have numerous mechanisms of suppressing the antitumor immune response including production of inhibitory cytokines, recruitment of immunosuppressive immune cells, and upregulation of coinhibitory receptors known as immune checkpoints. This review focuses on the immune checkpoint inhibitors, a novel class of immunotherapy first approved in 2011. Our objective is to highlight similarities and differences among the three immune checkpoint inhibitors approved by the U.S. Food and Drug Administration-ipilimumab, pembrolizumab, and nivolumab-to facilitate therapeutic decision making. We conducted a review of the published literature and conference proceedings and present a critical appraisal of the clinical evidence supporting their use in the treatment of metastatic melanoma and advanced squamous non-small cell lung cancer (NSCLC). We also compare and contrast their current place in cancer therapy and patterns of immune-related toxicities, and discuss the role of dual immune checkpoint inhibition and strategies for the management of immune-related adverse events. The immune checkpoint inhibitors have demonstrated a dramatic improvement in overall survival in patients with advanced melanoma and squamous NSCLC, along with acceptable toxicity profiles. These agents have a clear role in the first line treatment of advanced melanoma and in the second-line treatment of advanced squamous NSCLC. PMID- 26497483 TI - Vedolizumab for the Treatment of Moderately to Severely Active Ulcerative Colitis. PMID- 26497484 TI - Successful Treatment of Propafenone Intoxication With Intravenous Lipid Emulsion. AB - Severe cardiac effects, including cardiac arrest, are a rare complication of high dose propafenone intake. Among patients who experience cardiac arrest, the survival rate is low. This report presents the case of a young female patient who developed cardiac arrest linked to propafenone intake. While spontaneous circulation was restored with cardiopulmonary resuscitation, vital signs did not recover despite supportive treatment. However, after the administration of intravenous lipid emulsion (ILE), vital signs and cardiac functions resolved and the patient survived. This case is the second to describe the successful use of ILE for propafenone intoxication. However, as all of the findings of this patient were clearly linked to propafenone, we believe the benefits of ILE were more clearly defined in this case than in the other. PMID- 26497485 TI - Catheter-Directed Low-Dose Tissue Plasminogen Activator for Treatment of Right Atrial Thrombus Caused by a Central Venous Catheter. AB - Catheter-related atrial thrombosis is a potentially deadly complication of central venous catheters. Options for treatment include surgical thrombectomy, systemic anticoagulation, and systemic thrombolysis, but the optimal method of treatment remains unknown. We describe a 48-year-old woman with a large right atrial thrombus who was successfully treated with localized recombinant tissue plasminogen activator (tPA). She was treated with an 18-hour infusion of localized low-dose tPA administered through her central venous catheter. The dimensions of the thrombus decreased from 30 * 16 * 22 mm to 10 * 8 * 5 mm after treatment with tPA, corresponding to an associated 96% reduction in thrombus volume. No major bleeding complications were observed. Catheter-directed thrombolysis provides the theoretical advantage of a decreased rate of major bleeding by reducing the exposure to and duration of high-dose systemic thrombolytic therapy. To our knowledge, this is the second case report describing the use of this novel therapy. Although no guidelines for the treatment of atrial thrombosis or consensus on the optimal regimen for catheter-directed thrombolysis (and intensity of concomitant anticoagulation) exist, we believe that this intervention may be a well-tolerated alternative to systemic thrombolysis and surgery in certain patients. PMID- 26497486 TI - Relationship between synovial fluid biomarkers of articular cartilage metabolism and the patient's perspective of outcome depends on the severity of articular cartilage damage following ACL trauma. AB - Anterior cruciate ligament (ACL) trauma often occurs in combination with injury to the articular cartilage of the knee, this can result in earlier radiographic evidence of post traumatic osteoarthritis (OA) of the knee compared to the contralateral, ACL intact knee; however, the biomechanical and biological mechanisms associated with the onset and progression of this disease are not understood. We sought to gain insight into the mechanisms by determining the relationship between articular cartilage injury associated with ACL trauma and the expression of synovial fluid biomarkers of articular cartilage metabolism, and to evaluate the relationship between these biomarkers and the patient's perspective of the outcomes. Synovial fluid samples were acquired from 39 ACL injured subjects at an average of 10 weeks after injury, and 32 control subjects with normal knees (documented with clinical exam and MRI assessment). Subjects in the ACL-injured group were classified as low-risk for future OA if they displayed an International Cartilage Repair Society (ICRS) Grade 2 articular cartilage lesion or less and high-risk for future OA if they had an ICRS Grade 3A articular cartilage lesion. The patient's perspective of the injury was evaluated with the Knee Injury and Osteoarthritis Outcomes Score (KOOS). There were no significant differences in mean concentrations of the markers of type II collagen metabolism (CPII, C2C, and C1,2C) or the aggrecan breakdown Alanine-Arginine-Glycine-Serine (ARGS) -fragment between control subjects and the subjects in the low- and high risk groups (p-value range: 0.80-0.43). Associations between ARGS-aggrecan concentration and KOOS subscales of symptoms and pain were significantly different between the low- and high-risk groups (p = 0.03 and p = 0.01, respectively). Likewise, there was strong evidence in support of an association between the markers of type II collagen metabolism (C1,2C and CPII concentrations) and the KOOS subscale of pain between the low- and high-risk groups (p = 0.051 and 0.077, correspondingly). In ACL injured subjects with concomitant Grade 3A articular cartilage injuries, concentrations of synovial fluid ARGS-aggrecan were directly associated with improvements in KOOS symptoms and pain. These findings suggest the possible involvement of ARGS-aggrecan in a localized tissue repair response involving an increase in aggrecan turnover following severe knee trauma. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:820-827, 2016. PMID- 26497487 TI - Assessment of reference gene stability in Rice stripe virus and Rice black streaked dwarf virus infection rice by quantitative Real-time PCR. AB - BACKGROUND: Stably expressed reference gene(s) normalization is important for the understanding of gene expression patterns by quantitative Real-time PCR (RT qPCR), particularly for Rice stripe virus (RSV) and Rice black streaked dwarf virus (RBSDV) that caused seriously damage on rice plants in China and Southeast Asia. METHODS: The expression of fourteen common used reference genes of Oryza sativa L. were evaluated by RT-qPCR in RSV and RBSDV infected rice plants. Suitable normalization reference gene(s) were identified by geNorm and NormFinder algorithms. RESULTS: UBQ 10 + GAPDH and UBC + Actin1 were identified as suitable reference genes for RT-qPCR normalization under RSV and RBSDV infection, respectively. When using multiple reference genes, the expression patterns of OsPRIb and OsWRKY, two virus resistance genes, were approximately similar with that reported previously. Comparatively, by using single reference gene (TIP41 Like), a weaker inducible response was observed. CONCLUSIONS: We proposed that the combination of two reference genes could obtain more accurate and reliable normalization of RT-qPCR results in RSV- and RBSDV-infected plants. This work therefore sheds light on establishing a standardized RT-qPCR procedure in RSV- and RBSDV-infected rice plants, and might serve as an important point for discovering complex regulatory networks and identifying genes relevant to biological processes or implicated in virus. PMID- 26497488 TI - Synthesis and Characterization of Coumarin-Containing Cyclic Polymer and Its Photoinduced Coupling/Dissociation. AB - Cyclic polystyrene (PS) with a pendant coumarin group is prepared by the combination of atom transfer radical polymerization and "click" chemistry. Fluorescence resonance energy transfer process is observed in the fluorescence measurement of coumarin-containing PS, and cyclic PS exhibits stronger emission than that of its linear precursor. When cyclic PS is irradiated under UV light at lambda = 365 nm, 8-shaped PS is achieved due to the dimerization of pendant coumarin group. Subsequently, 8-shaped PS can be divided into single macrocycle under UV irradiation at lambda = 254 nm via the photocleavage of coumarin dimer. The photoinduced coupling and dissociation are monitored by UV/vis spectra and gel permeation chromatography (GPC). PMID- 26497489 TI - How meaningful is meaningful use? PMID- 26497490 TI - SQUIRE 2.0 (Standards for QUality Improvement Reporting Excellence): revised publication guidelines from a detailed consensus process. AB - In the past several years, the science of health care improvement has advanced considerably. In this article, we describe the development of SQUIRE 2.0 and its key components. We undertook the revision between 2012 and 2015 using (1) interviews and focus groups to evaluate SQUIRE 1.0 plus feedback from an international steering group, (2) face-to-face consensus meetings to develop interim drafts, and (3) pilot testing with authors and a public comment period. SQUIRE 2.0 emphasizes 3 key components of systematic efforts to improve the quality, value, and safety of health care: formal and informal theory in planning, implementing, and evaluating improvement work; the context in which the work is done; and the study of the intervention(s). SQUIRE 2.0 is intended for reporting the range of methods used to improve health care, recognizing that they can be complex and multidimensional. It provides common ground to share these discoveries in the scholarly literature (www.squire-statement.org). PMID- 26497492 TI - A lipase with broad solvent stability from Burkholderia cepacia RQ3: isolation, characteristics and application for chiral resolution of 1-phenylethanol. AB - Using both polar and low polar organic solvents (DMSO and toluene) as screening stress, a solvent-stable bacterium Burkholderia cepacia RQ3 was newly isolated. An organic solvent-stable lipase from strain RQ3 was purified in a single step with 50.1% recovery by hydrophobic chromatography. The purified lipase was homogenous on SDS-PAGE and had an apparent molecular mass of 33 kDa. The gene of lipase RQ3 with an open reading frame of 1095 bp encoding 364-amino acid residues was cloned. The optimal pH and temperature for lipase activity were 9.0 and 40 degrees C. The lipase was stable in a wide pH range of 6.0-10.0 and at temperature below 50 degrees C. Strikingly, all the tested hydrophilic and hydrophobic organic solvents significantly extended the half-life of lipase RQ3 compared with that in a solvent-free system, which indicated that lipase RQ3 showed a broad solvent tolerance to various organic solvents. The lipase demonstrated excellent enantioselective transesterification toward the (S)-1 phenylethanol with a theoretical conversion yield of 50% and ee p of 99.9%, which made it an exploitable biocatalyst for organic synthesis and pharmaceutical industries. PMID- 26497493 TI - Dynamic tracking of functional gene modules in treated juvenile idiopathic arthritis. AB - BACKGROUND: We have previously shown that childhood-onset rheumatic diseases show aberrant patterns of gene expression that reflect pathology-associated co expression networks. In this study, we used novel computational approaches to examine how disease-associated networks are altered in one of the most common rheumatic diseases of childhood, juvenile idiopathic arthritis (JIA). METHODS: Using whole blood gene expression profiles derived from children in a pediatric rheumatology clinical trial, we used a network approach to understanding the impact of therapy and the underlying biology of response/non-response to therapy. RESULTS: We demonstrate that therapy for JIA is associated with extensive re ordering of gene expression networks, even in children who respond inadequately to therapy. Furthermore, we observe distinct differences in the evolution of specific network properties when we compare children who have been treated successfully with those who have inadequate treatment response. CONCLUSIONS: Despite the inherent noisiness of whole blood gene expression data, our findings demonstrate how therapeutic response might be mapped and understood in pathologically informative cells in a broad range of human inflammatory diseases. PMID- 26497494 TI - The risks and benefits of patients temporarily discontinuing medications in the event of an intercurrent illness: a systematic review protocol. AB - BACKGROUND: Acute kidney injury (AKI) is common and often leads to significant morbidity and/or death. The development of AKI, or complications associated with it, may be due to use of certain medications in at-risk patients experiencing an intercurrent illness. Implicated drugs include diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/direct renin inhibitors, non steroidal anti-inflammatory drugs (NSAIDs), metformin and sulfonylureas. Expert consensus opinion (and clinical guidelines) recommend considering discontinuation of diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/direct renin inhibitors, NSAIDs, metformin and sulfonylureas in the event of an intercurrent illness to prevent AKI onset or reduce severity or complications. However, the evidence base for these recommendations is very limited. This systematic review aims to address the available evidence for the temporary discontinuation of diuretics, ACE inhibitors, angiotensin receptor blockers, direct renin inhibitors, non-steroidal anti-inflammatories and metformin and sulfonylureas for those at risk of AKI or with newly diagnosed AKI. METHODS/DESIGN: Randomised controlled trials; non-randomised trials; cohort studies; case-control studies; interrupted time series studies; and before-and after studies featuring adults aged 18 and over in any setting currently taking diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/direct renin inhibitors, NSAIDs and metformin; experiencing an intercurrent illness; or undergoing a radiological/surgical procedure (planned or unplanned) will be searched for. Relevant trial registers and systematic review databases will be searched. Systematic reviews will be assessed for methodological quality using the ROBIS tool, trials will be assessed using the Cochrane risk of bias tool, and observational studies will be assessed using the ACROBAT-NRS tool. If sufficient studies assessing similar populations, study type, settings and outcomes are found, then a formal meta-analysis will be performed to estimate summary measures of effect. If not, a narrative synthesis will be adopted. DISCUSSION: This review will synthesise evidence for the efficacy of discontinuing diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/direct renin inhibitors, NSAIDs, metformin or sulfonylureas to prevent or delay onset of AKI or associated complications. Results will provide guidance on efficacy and safety of this strategy and potentially help to develop an intervention to test the best mechanism of guiding medication discontinuation in at-risk populations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015023210. PMID- 26497495 TI - Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management. AB - BACKGROUND: Treatment of patients with non-metastatic, locally advanced rectal cancer (LARC) includes pre-operative chemoradiation, total mesorectal excision (TME) and post-operative adjuvant chemotherapy. This trimodality treatment provides local tumor control in most patients; but almost one-third ultimately die from distant metastasis. Most survivors experience significant impairment in quality of life (QoL), due primarily to removal of the rectum. A current challenge lies in identifying patients who could safely undergo rectal preservation without sacrificing survival benefit and QoL. METHODS/DESIGN: This multi-institutional, phase II study investigates the efficacy of total neoadjuvant therapy (TNT) and selective non-operative management (NOM) in LARC. Patients with MRI-staged Stage II or III rectal cancer amenable to TME will be randomized to receive FOLFOX/CAPEOX: a) before induction neoadjuvant chemotherapy (INCT); or b) after consolidation neoadjuvant chemotherapy (CNCT), with 5-FU or capecitabine-based chemoradiation. Patients in both arms will be re-staged after completing all neoadjuvant therapy. Those with residual tumor at the primary site will undergo TME. Patients with clinical complete response (cCR) will receive non operative management (NOM). NOM patients will be followed every 3 months for 2 years, and every 6 months thereafter. TME patients will be followed according to NCCN guidelines. All will be followed for at least 5 years from the date of surgery or--in patients treated with NOM--the last day of treatment. DISCUSSION: The studies published thus far on the safety of NOM in LARC have compared survival between select groups of patients with a cCR after NOM, to patients with a pathologic complete response (pCR) after TME. The current study compares 3-year disease-free survival (DFS) in an entire population of patients with LARC, including those with cCR and those with pCR. We will compare the two arms of the study with respect to organ preservation at 3 years, treatment compliance, adverse events and surgical complications. We will measure QoL in both groups. We will analyze molecular indications that may lead to more individually tailored treatments in the future. This will be the first NOM trial utilizing a regression schema for response assessment in a prospective fashion. TRIAL REGISTRATION: NCT02008656. PMID- 26497496 TI - Ryanodine-receptor-driven intracellular calcium dynamics underlying spatial association of synaptic plasticity. AB - Synaptic modifications induced at one synapse are accompanied by hetero-synaptic changes at neighboring sites. In addition, it is suggested that the mechanism of spatial association of synaptic plasticity is based on intracellular calcium signaling that is mainly regulated by two types of receptors of endoplasmic reticulum calcium store: the ryanodine receptor (RyR) and the inositol triphosphate receptor (IP3R). However, it is not clear how these types of receptors regulate intracellular calcium flux and contribute to the outcome of calcium-dependent synaptic change. To understand the relation between the synaptic association and store-regulated calcium dynamics, we focused on the function of RyR calcium regulation and simulated its behavior by using a computational neuron model. As a result, we observed that RyR-regulated calcium release depended on spike timings of pre- and postsynaptic neurons. From the induction site of calcium release, the chain activation of RyRs occurred, and spike-like calcium increase propagated along the dendrite. For calcium signaling, the propagated calcium increase did not tend to attenuate; these characteristics came from an all-or-none behavior of RyR-sensitive calcium store. Considering the role of calcium dependent synaptic plasticity, the results suggest that RyR regulated calcium propagation induces a similar change at the synapses. However, according to the dependence of RyR calcium regulation on the model parameters, whether the chain activation of RyRs occurred, sensitively depended on spatial expression of RyR and nominal fluctuation of calcium flux. Therefore, calcium regulation of RyR helps initiate rather than relay calcium propagation. PMID- 26497497 TI - [Adjuvant radiotherapy significantly also reduces local recurrence rate for prognostically favorable DCIS]. PMID- 26497500 TI - Novel Moraxella catarrhalis prophages display hyperconserved non-structural genes despite their genomic diversity. AB - BACKGROUND: Moraxella catarrhalis is an important pathogen that often causes otitis media in children, a disease that is not currently vaccine preventable. Asymptomatic colonisation of the human upper respiratory tract is common and lack of clearance by the immune system is likely due to the emergence of seroresistant genetic lineages. No active bacteriophages or prophages have been described in this species. This study was undertaken to identify and categorise prophages in M. catarrhalis, their genetic diversity and the relationship of such diversity with the host-species phylogeny. RESULTS: This study presents a comparative analysis of 32 putative prophages identified in 95 phylogenetically variable, newly sequenced M. catarrhalis genomes. The prophages were genotypically classified into four diverse clades. The genetic synteny of each clade is similar to the group 1 phage family Siphoviridae, however, they form genotypic clusters that are distinct from other members of this family. No core genetic sequences exist across the 32 prophages despite clades 2, 3, and 4 sharing the most sequence identity. The analysis of non-structural prophage genes (coding the integrase, and terminase), and portal gene showed that the respective genes were identical for clades 2, 3, and 4, but unique for clade 1. Empirical analysis calculated that these genes are unexpectedly hyperconserved, under purifying selection, suggesting a tightly regulated functional role. As such, it is improbable that the prophages are decaying remnants but stable components of a fluctuating, flexible and unpredictable system ultimately maintained by functional constraints on non-structural and packaging genes. Additionally, the plate encoding genes were well conserved across all four prophage clades, and the tail fibre genes, commonly responsible for receptor recognition, were clustered into three major groups distributed across the prophage clades. A pan-genome of 283,622 bp was identified, and the prophages were mapped onto the diverse M. catarrhalis multi-locus sequence type (MLST) backbone. CONCLUSION: This study has provided the first evidence of putatively mobile prophages in M. catarrhalis, identifying a diverse and fluctuating system dependent on the hyperconservation of a few key, non-structural genes. Some prophages harbour virulence-related genes, and potentially influence the physiology and virulence of M. catarrhalis. Importantly our data will provide supporting information on the identification of novel prophages in other species by adding greater weight to the identification of non-structural genes. PMID- 26497502 TI - Effects of mental resource availability on looming task performance. AB - Past research has shown that the looming bias-the tendency to judge one's distance to an approaching object as shorter than in actuality-is stronger among people who are physically weak or vulnerable. The current study examined whether the looming bias would also be stronger among people who are mentally weak or vulnerable. We tested that hypothesis by subjecting 46 young adults to cognitive load and examining their perceptions of approaching objects distance. Participants completed two blocks of the looming task, once under high cognitive load (memorizing a seven-digit number) and once under low load (memorizing a two digit number). Participants exhibited a stronger looming bias under high load than under low load. These findings support the hypothesis that the looming bias will be stronger when people are weak or vulnerable-either physically or mentally and in need of a larger margin-of-safety. PMID- 26497501 TI - Biologic therapy for inflammatory arthritis and latent tuberculosis: real world experience from a high prevalence area in the United Kingdom. AB - Biologic therapies have resulted in a sea change in the management of inflammatory arthritis; however, a higher risk of opportunistic infection, particularly tuberculosis (TB), is well recognised. This has led to the development of TB screening guidelines. The aim of this study was to investigate the prevalence of latent TB in patients prescribed biologic therapy in an endemic area (prevalence of TB 50/100,000) and to assess the risk of subsequent reactivation. Retrospective case note review of all patients with inflammatory arthritis ever prescribed biologic therapy between 1998 and 2014 at our centre. Two hundred ninety-nine patients (109 men, 190 women) who had ever been prescribed biologic therapy over a 16-year period were included. Mean age upon commencing the biologic therapy was 51 years. Two hundred eighteen (73 %) patients were Caucasian with remaining from ethnic minorities. Two hundred thirty nine (80 %) prescriptions were for TNF inhibitors. Median duration of biologic therapy was 4.2 years for those who remained on treatment prior to stopping or switching therapies. During 1998-2007, 112 patients underwent clinical assessment, chest X-ray and check for BCG scar. One patient of Asian origin developed extrapulmonary TB within 6 weeks of adalimumab initiation. Following a year of anti-TB treatment, he restarted the biologic therapy with no ill effects. One hundred eighty-seven participants (who started on biologic therapy between 2008 and 2014) underwent additional interferon gamma release assays (IGRA) testing as part of a new TB screening protocol (T-spot test). Eighteen (10 %) had positive test with normal chest X-rays. Six patients were white, nine of Asian origin and three others. Three Caucasian patients had a borderline result. All had 3 months of isoniazid and rifampicin with simultaneous prescription of biologic agent (13 had TNF antagonist, 5 rituximab and 3 tocilizumab). No cases of active TB infection were observed. Overall prevalence of latent TB in patients with inflammatory arthritis prescribed biologic therapy in an endemic area is 10 %. The risk warrants careful screening and monitoring in all patients. Adherence to strict screening protocol reduces the risk of active TB infection irrespective of the biologic therapy employed. PMID- 26497503 TI - Correlation between conductivity and prognostic factors in invasive breast cancer using magnetic resonance electric properties tomography (MREPT). AB - PURPOSE: To investigate the correlation between conductivity and prognostic factors of invasive breast cancer using magnetic resonance electric properties tomography (MREPT). METHODS: This retrospective study was approved by the Institutional Review Board, and verbal informed consent was obtained prior to breast MRI. This study included 65 women with surgically confirmed invasive breast cancers measuring 1 cm or larger on T2-weighted fast spin echo (FSE). Phase-based MREPT and the coil combination technique were used to reconstruct conductivity. Simple and multiple linear regression analysis were used to find an independent factor associated with conductivity. RESULTS: In total tumours, tumours with HER-2 overexpression showed lower conductivity than those without, and HER-2 overexpression was independently associated with conductivity. In 37 tumours 2 cm or larger, tumours with high mitosis or PR positivity showed higher conductivity than those without, and high mitosis and PR positivity were independently associated with conductivity. In 28 tumours 1-2 cm in size, there were no differences in conductivity according to the prognostic factors. CONCLUSION: Conductivity values measured using MREPT are associated with the HER 2 overexpression status, and may provide information about mitosis and the PR status of invasive breast cancers 2 cm or larger. KEY POINTS: * In all tumours, HER-2 overexpression was independently associated with conductivity. * In tumours >= 2 cm, high mitosis and PR positivity were associated with conductivity. * Conductivity is associated with the HER-2 overexpression status of invasive breast cancers. PMID- 26497505 TI - Sugar Profile of Kernels as a Marker of Origin and Ripening Time of Peach (Prunus persicae L.). AB - Large amounts of fruit seeds, especially peach, are discarded annually in juice or conserve producing industries which is a potential waste of valuable resource and serious disposal problem. Regarding the fact that peach seeds can be obtained as a byproduct from processing companies their exploitation should be greater and, consequently more information of cultivars' kernels and their composition is required. A total of 25 samples of kernels from various peach germplasm (including commercial cultivars, perspective hybrids and vineyard peach accessions) differing in origin and ripening time were characterized by evaluation of their sugar composition. Twenty characteristic carbohydrates and sugar alcohols were determined and quantified using high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC/PAD). Sucrose, glucose and fructose are the most important sugars in peach kernels similar to other representatives of the Rosaceae family. Also, high amounts of sugars in seeds of promising hybrids implies that through conventional breeding programs peach kernels with high sugar content can be obtained. In addition, by the means of several pattern recognition methods the variables that discriminate peach kernels arising from diverse germplasm and different stage of maturity were identified and successful models for further prediction were developed. Sugars such as ribose, trehalose, arabinose, galactitol, fructose, maltose, sorbitol, sucrose, iso-maltotriose were marked as most important for such discrimination. PMID- 26497504 TI - Effects of the Dietary Addition of Amaranth (Amaranthus mantegazzianus) Protein Isolate on Antioxidant Status, Lipid Profiles and Blood Pressure of Rats. AB - The effects of the dietary addition of 2.5% (w/w) Amaranthus mantegazzianus protein isolate (AI) on blood pressure, lipid profiles and antioxidative status of Wistar rats were evaluated. Six diets were used to feed animals during 28 days: (base (AIN93G), Chol (cholesterol 1%, w/w), CE (alpha-tocopherol 0.005%, w/w), CholE (cholesterol 1% (w/w) + alpha-tocopherol 0.005%, w/w), CAI (AI 2.5% w/w), CholAI (cholesterol 1% (w/w) + AI 2.5%, w/w). Lipid profiles of plasma and liver and faecal cholesterol content were analyzed. Antioxidant status was evaluated by the ferric reducing activity of plasma (FRAP), the 2-thiobarbituric acid (TBA) assay and superoxide dismutase (SOD) activity in plasma and liver. Blood pressure was measured in the tail artery of rats. CholA group presented a significant (alpha < 0.05) reduction (16%) in the plasma total cholesterol. In liver, the intake of cholesterol (Chol group) induced a significant increment in cholesterol and triglycerides (2.5 and 2.3 times, respectively), which could be decreased (18% and 47%, respectively) by the addition of AI (CholA group). This last group also showed an increased faecal cholesterol excretion (20%). Increment (50%) in FRAP values, diminution of TBA value in plasma and liver (70% and 38%, respectively) and diminution of SOD activity (20%) in plasma of CholA group suggest an antioxidant effect because of the intake of AI. In addition, CA and CholA groups presented a diminution (18%) of blood pressure after 28 days. PMID- 26497506 TI - In vitro Antimicrobial Study for Biological Evaluation of Clerodendrum infortunatum Linn. AB - OBJECTIVE: To explore a scientific idea, this study was examined for evaluation of antimicrobial potency using root, leaf and stem of ethyl acetate and chloroform extracts of C. infortunatum (Verbenaceae) due to randomly use in traditional medicine to cure common ailments such as intestinal disorder, diarrhea, tuberculosis and respiratory problems etc. METHODS: The in vitro application was carried out by using disc diffusion, micro broth dilution and serial dilution techniques against clinically important life threatening organisms. RESULTS: All the extracts showed significant inhibitory activity over the bacteria and fungus comparable to the standard drug tetracycline and fluconazole. The maximum average diameter zone of inhibition was recorded to bacterial strains against B. megaterium, S. typhi, K. pneumoniae and to fungi against A. niger and C. albicans. The MIC values of ethyl acetate and chloroform root extract were determined 64 ug/ml to B. subtilis, and K. pneumoniae; to S. beta-haemolyticus and S. typhi for ethyl acetate extracts, 128 ug/ml to S. aureus, and E. coli for both ethyl acetate and chloroform root extracts but only S. typhi and S.-beta-haemolyticus for chloroform extract. CONCLUSION: The findings evidently appear promising antibacterial and antifungal properties of C. infortunatum against antagonistic pathogens. Leaf possess quite potent activity than root and stem specially root extract > leaf extract > stem extract. One of the more significant achievements of this study to follows and covers the most recent and important patents WO2009075290 (2009) which deals on yeast having immunopotentiating effect and food or feed. This study serves as basis for further research to lead compounds to be isolated so that may be as a template for the implications of these results for bioactivity and drug discovery potential of herbal products are discussed. PMID- 26497507 TI - Methicillin-Resistant Staphylococcus aureus: Treatment with Cultures of Non Drug Resistant Staphylococcus epidermidis. AB - The colonization and infection with methicillin-resistant Staphylococcus aureus is a major health problem in hospitals and long-term care facilities. Although bacteriaemias with MRSA (methicillin-resistant Staphylococcus aureus) can be treated with vancomycin and other reserve antibiotics, 20% of patients cannot be successfully cured. Inpatients colonized with MRSA are isolated in hospitals according to the guidelines of the Robert-Koch-Institute, although in long-term care facilities these patients are not urgently isolated. Active decolonization measures are taken to eradicate colonization with MRSA. In order to reduce MRSA colonization, it could be possible to administer cultures of Staphylococcus epidermidis which have no antibiotic resistance, so that physiological genes could be conferred from Staphylococcus epidermidis to MRSA bacteria. PMID- 26497509 TI - Fc Receptors: Introduction. PMID- 26497508 TI - Stress inhibits PYY secretion in obese and normal weight women. AB - The impact of stress on circulating levels of appetite-regulating hormones remains largely unknown. The aim of this study was to analyze the effect of acute psychosocial stress on the gut hormone peptide YY (PYY) secretion in obese and normal weight women. Therefore, we compared pre- and post-prandial plasma PYY secretion of 42 obese and 43 normal weight women in a repeated measure randomized controlled laboratory experiment. PYY and cortisol concentrations were measured and ratings of stress and satiety were also recorded in response to a psychological stressor (Trier Social Stress Test, TSST). PYY samples were collected in the fasting state both before participating in the TSST and before a control session. Participants had a standardized meal after the TSST and control session, respectively. PYY was measured both 30 and 60 min after the TSST and control session, respectively. Stress inhibited PYY secretion as well as food intake in all women, but did not influence subjective satiety perception. The present data indicate that despite of lower PYY levels the subjects' requirement to overeat was not increased. From an evolutionary perspective this finding is adaptive. After stress the organism is prepared for fight or flight reaction, whereas not primarily necessary functions are inhibited. Therefore, increased food intake during stress would be dysfunctional. PMID- 26497510 TI - Fcgamma receptors: genetic variation, function, and disease. AB - Fcgamma receptors (FcgammaRs) are key immune receptors responsible for the effective control of both humoral and innate immunity and are central to maintaining the balance between generating appropriate responses to infection and preventing autoimmunity. When this balance is lost, pathology results in increased susceptibility to cancer, autoimmunity, and infection. In contrast, optimal FcgammaR engagement facilitates effective disease resolution and response to monoclonal antibody immunotherapy. The underlying genetics of the FcgammaR gene family are a central component of this careful balance. Complex in humans and generated through ancestral duplication events, here we review the evolution of the gene family in mammals, the potential importance of copy number, and functionally relevant single nucleotide polymorphisms, as well as discussing current approaches and limitations when exploring genetic variation in this region. PMID- 26497511 TI - Mouse and human FcR effector functions. AB - Mouse and human FcRs have been a major focus of attention not only of the scientific community, through the cloning and characterization of novel receptors, and of the medical community, through the identification of polymorphisms and linkage to disease but also of the pharmaceutical community, through the identification of FcRs as targets for therapy or engineering of Fc domains for the generation of enhanced therapeutic antibodies. The availability of knockout mouse lines for every single mouse FcR, of multiple or cell-specific- 'a la carte'--FcR knockouts and the increasing generation of hFcR transgenics enable powerful in vivo approaches for the study of mouse and human FcR biology. This review will present the landscape of the current FcR family, their effector functions and the in vivo models at hand to study them. These in vivo models were recently instrumental in re-defining the properties and effector functions of FcRs that had been overlooked or discarded from previous analyses. A particular focus will be made on the (mis)concepts on the role of high-affinity IgG receptors in vivo and on results from antibody engineering to enhance or abrogate antibody effector functions mediated by FcRs. PMID- 26497512 TI - bIgG time for large eaters: monocytes and macrophages as effector and target cells of antibody-mediated immune activation and repression. AB - The mononuclear phagocytic system consists of a great variety of cell subsets localized throughout the body in immunological and non-immunological tissues. While one of their prime tasks is to detect, phagocytose, and kill intruding microorganisms, they are also involved in maintaining tissue homeostasis and immune tolerance toward self through removal of dying cells. Furthermore, monocytes and macrophages have been recognized to play a critical role for mediating immunoglobulin G (IgG)-dependent effector functions, including target cell depletion, tissue inflammation, and immunomodulation. For this, monocyte and macrophage populations are equipped with a complex set of Fc-receptors, enabling them to directly interact with pro- or anti-inflammatory IgG preparations. In this review, we will summarize the most recent findings, supporting a central role of monocytes and macrophages for pro- and anti-inflammatory IgG activity. PMID- 26497514 TI - Fc receptor inside-out signaling and possible impact on antibody therapy. AB - Fc receptors (FcR) are expressed on immune cells and bind to the Fc tail of antibodies. This interaction is essential for FcR-mediated signaling and triggering of cellular effector functions. FcR activation is tightly regulated to prevent immune responses by non-antigen bound antibodies or in the absence of 'danger signals'. FcR activity may be modulated at the plasma membrane via cross talk with integrins. In addition, cytokines at the site of infection/inflammation can increase FcR avidity, a process referred to as inside-out signaling. This regulatory mechanism has been described for FcgammaRI (CD64), FcgammaRIIa (CD32a), and FcalphaRI (CD89) and is also well-known for integrins. Key cellular events during inside-out signaling are (de)phosphorylation, clustering, cytoskeleton rearrangements, and conformational changes. The latter can be studied with antibodies that specifically recognize epitopes exposed by the active (high affinity) or inactive (low affinity) state of the FcR. These antibodies are important tools to investigate the role of FcR activation in disease settings. Research on FcR has gained momentum with the rise of monoclonal antibodies (mAb) entering the clinic for the treatment of cancer and other diseases. The clinical outcome of mAb therapy may be improved by increasing FcR avidity by cytokine stimulation. PMID- 26497515 TI - Fcgamma receptor pathways during active and passive immunization. AB - IgG antibodies are actively produced in response to antigenic challenge or passively administered as an effective form of immunotherapy to confer immunity against foreign antigens. Their protective activity is mediated through their bifunctional nature: a variable Fab domain mediates antigen-binding specificity, whereas the constant Fc domain engages Fcgamma receptors (FcgammaRs) expressed on the surface of leukocytes to mediate effector functions. While traditionally considered the invariant domain of an IgG molecule, the Fc domain displays remarkable structural heterogeneity determined primarily by differences in the amino acid sequence of the various IgG subclasses and by the composition of the complex, Fc-associated biantennary N-linked glycan. These structural determinants regulate the conformational flexibility of the IgG Fc domain and affect its capacity to interact with distinct types of FcgammaRs (type I or type II FcgammaRs). FcgammaR engagement activates diverse downstream immunomodulatory pathways with pleiotropic functional consequences including cytotoxicity and phagocytosis of IgG-coated targets, differentiation and activation of antigen presenting cells, modulation of T-cell activation, plasma cell survival, and regulation of antibody responses. These functions highlight the importance of FcgammaR-mediated pathways in the modulation of adaptive immune responses and suggest a central role for IgG-FcgammaR interactions during active and passive immunization. PMID- 26497513 TI - Of ITIMs, ITAMs, and ITAMis: revisiting immunoglobulin Fc receptor signaling. AB - Receptors for immunoglobulin Fc regions play multiple critical roles in the immune system, mediating functions as diverse as phagocytosis, triggering degranulation of basophils and mast cells, promoting immunoglobulin class switching, and preventing excessive activation. Transmembrane signaling associated with these functions is mediated primarily by two amino acid sequence motifs, ITAMs (immunoreceptor tyrosine-based activation motifs) and ITIMs (immunoreceptor tyrosine-based inhibition motifs) that act as the receptors' interface with activating and inhibitory signaling pathways, respectively. While ITAMs mobilize activating tyrosine kinases and their consorts, ITIMs mobilize opposing tyrosine and inositol-lipid phosphatases. In this review, we will discuss our current understanding of signaling by these receptors/motifs and their sometimes blurred lines of function. PMID- 26497516 TI - FcgammaR requirements leading to successful immunotherapy. AB - Monoclonal antibody (mAb) immunotherapy is currently experiencing an unprecedented amount of success, delivering blockbuster sales for the pharmaceutical industry. Having experienced several false dawns and overcoming technical issues which limited progress, we are now entering a golden period where mAbs are becoming a mainstay of treatment regimes for diseases ranging from cancer to autoimmunity. In this review, we discuss how these mAbs are most likely working and focus in particular on the key receptors that they interact with to precipitate their therapeutic effects. Although their targets may vary, their engagement with Fcgamma receptors (FcgammaRs) on numerous immune effector cells is almost universal, and here we review their roles in delivering successful immunotherapy. PMID- 26497517 TI - The era of the immunoglobulin A Fc receptor FcalphaRI; its function and potential as target in disease. AB - Immunoglobulin A (IgA) is the most prevalent antibody at mucosal sites, and has an important role in defense by preventing invasion of pathogens. Traditionally, IgA has been thought of as a non-inflammatory antibody that helps to maintain homeostasis in the mucosa. However, in the last decade it has become clear that IgA is a very potent stimulus to initiate pro-inflammatory cellular processes, especially after triggering the IgA Fc receptor (FcalphaRI) on neutrophils. It was furthermore described that FcalphaRI acts as a regulator between anti- and pro-inflammatory responses of IgA. Although neutrophil activation is beneficial in (mucosal) infections, abnormal or excessive IgA immune complexes can induce disproportionate neutrophil migration and in this way initiate a perpetuating neutrophil recruitment and activation loop, which will result in severe tissue damage. Increasing evidence on this process plays a detrimental role in several diseases, including autoimmune IgA blistering diseases, a subtype of rheumatoid arthritis and ulcerative colitis. Inhibiting FcalphaRI-mediated activation may dampen inflammation in these patients. This process also opens up the possibility of targeting FcalphaRI in antibody immunotherapy of cancer. Thus, interfering with IgA-mediated FcalphaRI activation may represent an attractive novel therapeutic strategy for multiple maladies. PMID- 26497519 TI - The many faces of FcgammaRI: implications for therapeutic antibody function. AB - Fcgamma receptor I (FcgammaRI or CD64) is the sole human Fc receptor with high affinity for monovalent IgG. While it contains an immunoreceptor tyrosine-based activation motif in its cytoplasmic domain, binding of FcgammaRI can result in a complex array of activating and inhibitory outcomes. For instance, binding of monomeric IgG provides a low-intensity tonic signal through FcgammaRI that is necessary for full interferon gamma receptor signaling in the same cell. Interaction of FcgammaRI with larger high-avidity complexes can result in phagocytosis, the generation of reactive oxygen species, as well as the synthesis and release of inflammatory cytokines. However, numerous reports also document potent anti-inflammatory effects brought about by FcgammaRI engagement with immune complexes such as the inhibition of IFNgamma and TLR4 signaling, and secretion of interleukin-10. This has led to conflicting hypotheses regarding the function of FcgammaRI, especially with regard to its role in the efficacy of several therapeutic monoclonal antibodies. While many of these issues are still unclear, continued characterization of the regulation and context dependence of FcgammaRI function, as well as the molecular mechanisms responsible for these various outcomes, will improve our understanding of FcgammaRI biology as well as the therapeutic strategies designed to harness or constrain its actions. PMID- 26497520 TI - The high-affinity receptor for IgG, FcgammaRI, of humans and non-human primates. AB - Non-human primate (NHP) models, especially involving macaques, are considered important models of human immunity and have been essential in preclinical testing for vaccines and therapeutics. Despite this, much less characterization of macaque Fc receptors has occurred compared to humans or mice. Much of the characterization of macaque Fc receptors so far has focused on the low-affinity Fc receptors, particularly FcgammaRIIIa. From these studies, it is clear that there are distinct differences between the human and macaque low-affinity receptors and their interaction with human IgG. Relatively little work has been performed on the high-affinity IgG receptor, FcgammaRI, especially in NHPs. This review will focus on what is currently known of how FcgammaRI interacts with IgG, from mutation studies and recent crystallographic studies of human FcgammaRI, and how amino acid sequence differences in the macaque FcgammaRI may affect this interaction. Additionally, this review will look at the functional consequences of differences in the amino acid sequences between humans and macaques. PMID- 26497521 TI - Structural mechanism of high affinity FcgammaRI recognition of immunoglobulin G. AB - Antibody-based immunotherapies are becoming powerful means of modern medicine for treating cancers and autoimmune diseases. The increasing popularity of antibody based treatment demands a better understanding of antibody functions and in particular, their interaction with Fc receptors as effectiveness of antibodies often depends on their ability to activate or avoid effector cell functions through Fc receptors. Until recently, our understanding of antibody recognition by Fc receptors is based on the structures of low affinity Fc receptor in complex with Fc. These structural studies provided significant insights to our understanding of how an IgG antibody generally docks on Fcgamma receptor and the requirement of immune complex formation for effector cell activations. They are less informative, however, to the molecular forces underlying the vast different affinities between antibodies and their Fcgamma receptors. Recently, the structure of the high affinity FcgammaRI in complex with IgG-Fc has been determined. This review will focus on the knowledge learned from the high affinity complex structural work and a potential receptor-glycan interaction as an important contribution to the receptor affinity. PMID- 26497522 TI - Structural analysis of Fc/FcgammaR complexes: a blueprint for antibody design. AB - The number of studies and the quality of the structural data of Fcgamma receptors (FcgammaRs) has rapidly increased in the last few years. Upon critical examination of the literature, we have extracted general conclusions that could explain differences in affinity and selectivity of FcgammaRs for immunoglobulin G (IgG) based on structural considerations. FcgammaRs employ a little conserved asymmetric surface of domain D2 composed of two distinct subsites to recognize the well-conserved lower hinge region of IgG1-Fc. The extent of the contact interface with the antibody in subsite 1 of the receptor (but not in subsite 2), the geometrical complementarity between antibody and receptor, and the number of polar interactions contribute decisively toward strengthening the binding affinity of the antibody for the receptor. In addition, the uncertain role of the N-linked glycan of IgG for the binding and effector responses elicited by FcgammaRs is discussed. The available data suggest that not only the non-covalent interactions between IgG and FcgammaRs but also their dynamic features are essential for the immune response elicited through these receptors. We believe that the integration of structural, thermodynamic, and kinetic data will be critical for the design and validation of the next generation of therapeutic antibodies with enhanced effector capabilities. PMID- 26497518 TI - Human IgG4: a structural perspective. AB - IgG4, the least represented human IgG subclass in serum, is an intriguing antibody with unique biological properties, such as the ability to undergo Fab arm exchange and limit immune complex formation. The lack of effector functions, such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, is desirable for therapeutic purposes. IgG4 plays a protective role in allergy by acting as a blocking antibody, and inhibiting mast cell degranulation, but a deleterious role in malignant melanoma, by impeding IgG1 mediated anti-tumor immunity. These findings highlight the importance of understanding the interaction between IgG4 and Fcgamma receptors. Despite a wealth of structural information for the IgG1 subclass, including complexes with Fcgamma receptors, and structures for intact antibodies, high-resolution crystal structures were not reported for IgG4-Fc until recently. Here, we highlight some of the biological properties of human IgG4, and review the recent crystal structures of IgG4-Fc. We discuss the unexpected conformations adopted by functionally important Cgamma2 domain loops, and speculate about potential implications for the interaction between IgG4 and FcgammaRs. PMID- 26497523 TI - Structure and dynamics of IgE-receptor interactions: FcepsilonRI and CD23/FcepsilonRII. AB - Immunoglobulin E (IgE) is well known for its role in allergic disease, the manifestations of which are mediated through its two Fc receptors, FcepsilonRI and CD23 (FcepsilonRII). IgE and its interactions with these receptors are therefore potential targets for therapeutic intervention, and exciting progress has been made in this direction. Furthermore, recent structural studies of IgE Fc, the two receptors, and of their complexes, have revealed a remarkable degree of plasticity at the IgE-CD23 interface and an even more remarkable degree of dynamic flexibility within the IgE molecule. Indeed, there is allosteric communication between the two receptor-binding sites, which we now know are located at some distance from each other in IgE-Fc (at opposite ends of the Cepsilon3 domain). The conformational changes associated with FcepsilonRI and CD23 binding to IgE-Fc ensure that their interactions are mutually incompatible, and it may be that this functional imperative has driven IgE to evolve such a dynamic structure. Appreciation of these new structural data has revised our view of IgE structure, shed light on the co-evolution of antibodies and their receptors, and may open up new therapeutic opportunities. PMID- 26497524 TI - The biology of the classical Fcgamma receptors in non-hematopoietic cells. PMID- 26497525 TI - The platelet Fc receptor, FcgammaRIIa. AB - Human platelets express FcgammaRIIa, the low-affinity receptor for the constant fragment (Fc) of immunoglobulin (Ig) G that is also found on neutrophils, monocytes, and macrophages. Engagement of this receptor on platelets by immune complexes triggers intracellular signaling events that lead to platelet activation and aggregation. Importantly these events occur in vivo, particularly in response to pathological immune complexes, and engagement of this receptor on platelets has been causally linked to disease pathology. In this review, we will highlight some of the key features of this receptor in the context of the platelet surface, and examine the functions of platelet FcgammaRIIa in normal hemostasis and in response to injury and infection. This review will also highlight pathological consequences of engagement of this receptor in platelet based autoimmune disorders. Finally, we present some new data investigating whether levels of the extracellular ligand-binding region of platelet glycoprotein VI which is rapidly shed upon engagement of platelet FcgammaRIIa by autoantibodies, can report on the presence of pathological anti-heparin/platelet factor 4 immune complexes and thus identify patients with pathological autoantibodies who are at the greatest risk of developing life-threatening thrombosis in the setting of heparin-induced thrombocytopenia. PMID- 26497526 TI - The multiple facets of FcRn in immunity. AB - The neonatal Fc receptor, FcRn, is best known for its role in transporting IgG in various tissues, providing newborns with humoral immunity, and for prolonging the half-life of IgG. Recent findings implicate the involvement of FcRn in a far wider range of biological and immunological processes, as FcRn has been found to bind and extend the half-life of albumin; to be involved in IgG transport and antigen sampling at mucosal surfaces; and to be crucial for efficient IgG mediated phagocytosis. Herein, the function of FcRn will be reviewed, with emphasis on its recently documented significance for IgG polymorphisms affecting the half-life and biodistribution of IgG3, on its role in phagocyte biology, and the subsequent role for the presentation of antigens to lymphocytes. PMID- 26497527 TI - Accelerating antibody discovery using transgenic animals overexpressing the neonatal Fc receptor as a result of augmented humoral immunity. AB - In recent years, there has been an increasing demand for the development of faster and more efficient technologies for the generation of monoclonal antibodies against challenging targets that are weakly immunogenic or available only in limited amounts. Typical classes of such targets are cell surface antigens such as G-protein related receptors (GPCRs) or ion channels. We have developed transgenic (Tg) mice and rabbits that overexpress the neonatal Fc receptor (FcRn), resulting in an augmented humoral immune response even if challenging antigens are used for immunization. The impressively enhanced FcRn mediated immune reactions are characterized by improved IgG protection and enhanced antigen presentation leading to greater number of antigen-specific T helper and B-cell activation in lymphoid organs. Notably, these animals do not show any sign of autoimmunity and can be efficiently bred. FcRn overexpression thus leads to a number of practical benefits for improved generation of monoclonal and polyclonal antibodies against multiple antigens, including weakly immunogenic epitopes or tiny amounts of proteins. This review summarizes our current understanding about the mechanisms by which FcRn overexpression leads to such a significantly enhanced humoral immune response. PMID- 26497528 TI - Immune regulation by Fcalpha/MU receptor (CD351) on marginal zone B cells and follicular dendritic cells. AB - Although both Fcalpha/MU receptor (Fcalpha/MUR) and polymeric Ig receptor (poly IgR) are Fc receptors for IgA and IgM and are functionally and genetically related, the expression profile of Fcalpha/MUR is unique. Unlike poly-IgR, Fcalpha/MUR is expressed on marginal zone (MZ) B cells and follicular dendritic cells, suggesting that Fcalpha/MUR plays an important role in humoral immune responses. Fcalpha/MUR mediates endocytosis of the IgM immune complex (IC). Recent research demonstrated that Fcalpha/MUR downregulated retention of the IgM IC with a T-independent (TI) antigen on MZ B cells and follicular dendritic cells due to endocytosis of the IgM IC, suppressing germinal center formation, affinity maturation, and memory B-cell generation in response to TI antigen challenge. In addition, Fcalpha/MUR physically associates with Toll-like receptor 4 (TLR4) and augments TLR4 oligomerization and signaling in MZ B cells upon lipopolysaccharide (LPS) challenge, leading to increased proinflammatory cytokine production by MZ B cells. Thus, Fcalpha/MUR is a unique Fc receptor that is involved in humoral immune responses and inflammation. PMID- 26497530 TI - Cross-talk between pathogen recognizing Toll-like receptors and immunoglobulin Fc receptors in immunity. AB - The individual role of pathogen-binding Toll-like receptors (TLRs) and antibody binding Fc receptors (FcRs) during pathogenic infections has been studied extensively. However, combined activation of these different receptor classes has received little attention, even though they are triggered simultaneously when immune cells bind antibody-opsonized pathogens. In the last few years, it has become evident that joined activation of TLRs and FcRs substantially tailors inflammatory immune responses, which is an efficient and controlled mechanism of the host to act upon invading pathogens. In this review, we discuss the mechanisms of cross-talk between different TLRs and FcRs and the resulting inflammatory immune responses. Furthermore, we propose how chronic activation via this cross-talk might be detrimental in inflammatory (auto) immune diseases. We conclude with the potential exploitation of the interplay between TLRs and FcRs for monoclonal antibody therapy to target tumors. Future interests in this field of research include establishing a more detailed and mechanistic understanding of the mode of action of TLR and FcR cross-talk and exploration of its physiological importance in health and disease. This may furthermore open up novel therapeutic options for intervention in inflammatory diseases or cancer. PMID- 26497529 TI - The role of Fc receptors in HIV prevention and therapy. AB - Over the past decade, a wealth of experimental evidence has accumulated supporting the importance of Fc receptor (FcR) ligation in antibody-mediated pathology and protection in many disease states. Here we present the diverse evidence base that has accumulated as to the importance of antibody effector functions in the setting of HIV prevention and therapy, including clinical correlates, genetic associations, viral evasion strategies, and a rapidly growing number of compelling animal model experiments. Collectively, this work identifies antibody interactions with FcR as important to both therapeutic and prophylactic strategies involving both passive and active immunity. These findings mirror those in other fields as investigators continue to work toward identifying the right antibodies and the right effectors to be present at the right sites at the right time. PMID- 26497532 TI - Fc receptors in antibody-dependent enhancement of viral infections. AB - Sensitization of the humoral immune response to invading viruses and production of antiviral antibodies forms part of the host antiviral repertoire. Paradoxically, for a number of viral pathogens, under certain conditions, antibodies provide an attractive means of enhanced virus entry and replication in a number of cell types. Known as antibody-dependent enhancement (ADE) of infection, the phenomenon occurs when virus-antibody immunocomplexes interact with cells bearing complement or Fc receptors, promoting internalization of the virus and increasing infection. Frequently associated with exacerbation of viral disease, ADE of infection presents a major obstacle to the prevention of viral disease by vaccination and is thought to be partly responsible for the adverse effects of novel antiviral therapeutics such as intravenous immunoglobulins. There is a growing body of work examining the intracellular signaling pathways and epitopes responsible for mediating ADE, with a view to aiding rational design of antiviral strategies. With in vitro studies also confirming ADE as a feature of infection for a growing number of viruses, challenges remain in understanding the multilayered molecular mechanisms of ADE and its effect on viral pathogenesis. PMID- 26497531 TI - TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity. AB - Antibodies are key molecules in the fight against infections. Although previously thought to mediate protection solely in the extracellular environment, recent research has revealed that antibody-mediated protection extends to the cytosolic compartment of cells. This postentry viral defense mechanism requires binding of the antibody to a cytosolic Fc receptor named tripartite motif containing 21 (TRIM21). In contrast to other Fc receptors, TRIM21 shows remarkably broad isotype specificity as it does not only bind IgG but also IgM and IgA. When viral pathogens coated with these antibody isotypes enter the cytosol, TRIM21 is rapidly recruited and efficient neutralization occurs before the virus has had the time to replicate. In addition, inflammatory signaling is induced. As such, TRIM21 acts as a cytosolic sensor that engages antibodies that have failed to protect against infection in the extracellular environment. Here, we summarize our current understanding of how TRIM21 orchestrates humoral immunity in the cytosolic environment. PMID- 26497534 TI - Novel genetic tools to tackle c-di-GMP-dependent signalling in Pseudomonas aeruginosa. AB - AIMS: To develop new genetic tools for studying 3',5'-cyclic diguanylic acid (c di-GMP) signalling in Pseudomonas aeruginosa. METHODS AND RESULTS: Plasmid pPcdrA::lux, carrying a transcriptional fusion between the c-di-GMP responsive promoter PcdrA and the luxCDABE reporter genes, has been generated and validated in purpose-built P. aeruginosa strains in which c-di-GMP levels can be increased or reduced upon arabinose-dependent induction of c-di-GMP synthetizing or degrading enzymes. CONCLUSIONS: The reporter systems described so far were able to detect a decrease in the c-di-GMP levels only in engineered strains overproducing c-di-GMP. Conversely, pPcdrA::lux could be used for studying any process or chemical compound expected to cause both an increase or a decrease with respect to the c-di-GMP levels produced by wild type P. aeruginosa. Another relevant aspect of this study has been the development of novel and improved genetic devices for the fine arabinose-dependent control of c-di-GMP levels in P. aeruginosa. SIGNIFICANCE AND IMPACT OF THE STUDY: The genetic tools developed and validated in this study could facilitate investigations tackling the c-di-GMP signalling process on different fields, from cellular physiology to drug discovery research. PMID- 26497535 TI - Enhancing CBT for Chronic Insomnia: A Randomised Clinical Trial of Additive Components of Mindfulness or Cognitive Therapy. AB - : Although cognitive behavioural therapy (CBT) for insomnia has resulted in significant reductions in symptoms, most patients are not classified as good sleepers after treatment. The present study investigated whether additional sessions of cognitive therapy (CT) or mindfulness-based therapy (MBT) could enhance CBT in 64 participants with primary insomnia. All participants were given four sessions of standard CBT as previous research had identified this number of sessions as an optimal balance between therapist guidance and patient independence. Participants were then allocated to further active treatment (four sessions of CT or MBT) or a no further treatment control. The additional treatments resulted in significant improvements beyond CBT on self-report and objective measures of sleep and were well tolerated as evidenced by no dropouts from either treatment. The effect sizes for each of these additional treatments were large and clinically significant. The mean scores on the primary outcome measure, the Insomnia Severity Index, were 5.74 for CT and 6.69 for MBT, which are within the good-sleeper range. Treatment effects were maintained at follow up. There were no significant differences between CT and MBT on any outcome measure. These results provide encouraging data on how to enhance CBT for treatment of insomnia. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: CBT treatments for insomnia can be enhanced using recent developments in cognitive therapy. CBT treatments for insomnia can be enhanced using mindfulness-based treatments. Both cognitive therapy and mindfulness produce additional clinically significant change. PMID- 26497536 TI - Self-assembly of Janus nanoparticles with a hydrophobic hemisphere in nanotubes. AB - We performed molecular simulations to investigate the morphologies and phase diagrams of self-assembled diblock Janus nanoparticles (JNPs) confined in nanotubes. A JNP is a unique anisotropic nanoparticle, which typically has more than two distinct surfaces, each with different properties. We derived qualitative phase diagrams of axial pressure versus the ratio of the diameter of the nanoparticle and the nanotube. Three distinct types of nanotube walls were considered: hydrophobic, hydrophilic, and hydroneutral. We observed diverse morphologies in JNP solutions, many of which have not been observed in bulk solutions. We also compared the self-assembled structures of diblock and triblock patchy particles. Under weak confinement, significant differences were observed between the different JNP designs. The orientation ordering and self-assembly behaviours of the JNPs can be qualitatively predicted based on the chemical nature of the nanotube wall and the JNP design. PMID- 26497533 TI - Pituitary adenomas: historical perspective, surgical management and future directions. AB - Pituitary adenomas are among the most common central nervous system tumors. They represent a diverse group of neoplasms that may or may not secrete hormones based on their cell of origin. Epidemiologic studies have documented the incidence of pituitary adenomas within the general population to be as high as 16.7%. A growing body of work has helped to elucidate the pathogenesis of these tumors. Each subtype has been shown to demonstrate unique cellular changes potentially leading to tumorigenesis. Surgical advancements over several decades have included microsurgery and the employment of the endoscope for surgical resection. These advancements increase the likelihood of gross-total resection and have resulted in decreased patient morbidity. PMID- 26497537 TI - Associations of maternal folic acid supplementation and folate concentrations during pregnancy with foetal and child head growth: the Generation R Study. AB - PURPOSE: Folic acid supplementation during pregnancy has been associated with a reduced risk of common neurodevelopmental delays in the offspring. However, it is unclear whether low folate status has effects on the developing brain. We evaluated the associations of maternal folic acid supplementation and folate concentrations during pregnancy with repeatedly measured prenatal and postnatal head circumference in the offspring. METHODS: Within a population-based prospective cohort, we measured maternal plasma folate concentrations at approximately 13 weeks of gestation (90 % range 10.5-17.2) and assessed folic acid supplementation by questionnaire (2001-2005). Up to 11 repeated measures of head circumference were obtained during foetal life (20 and 30 weeks of gestation) and childhood (between birth and age 6 years) in 5866 children (2002 2012). RESULTS: In unadjusted models, foetal head growth was 0.006 SD (95 % CI 0.003; 0.009, P < 0.001) faster per week per 1-SD higher maternal folate concentration. After adjustment for confounders, this association was attenuated to 0.004 SD per week (95 % CI 0.000; 0.007, P = 0.02; estimated absolute difference at birth of 2.7 mm). The association was independent of overall foetal growth. No associations were found between maternal folate concentrations and child postnatal head growth. Preconceptional start of folic acid supplementation was associated with larger prenatal head size, but not with prenatal or postnatal head growth. CONCLUSIONS: Our results suggest an independent, modest association between maternal folate concentrations in early pregnancy and foetal head growth. More research is needed to identify whether specific brain regions are affected and whether effects of folate on foetal head growth influence children's long term functioning. PMID- 26497538 TI - No association between blood telomere length and longitudinally assessed diet or adiposity in a young adult Filipino population. AB - PURPOSE: Telomeres, DNA-protein structures that cap and protect chromosomes, are thought to shorten more rapidly when exposed to chronic inflammation and oxidative stress. Diet and nutritional status may be a source of inflammation and oxidative stress. However, relationships between telomere length (TL) and diet or adiposity have primarily been studied cross-sectionally among older, overweight/obese populations and yielded inconsistent results. Little is known about the relationship between diet or body composition and TL among younger, low to normal-weight populations. It also remains unclear how cumulative exposure to a specific diet or body composition during the years of growth and development, when telomere attrition is most rapid, may be related to TL in adulthood. METHODS: In a sample of 1459 young adult Filipinos, we assessed the relationship between blood TL at ages 20.8-22.5 and measures of BMI z-score, waist circumference, and diet collected between the ages of 8.5 and 22.5. TL was measured using monochrome multiplex quantitative PCR, and diet was measured using multiple 24-h recalls. RESULTS: We found no associations between blood TL and any of the measures of adiposity or between blood TL and the seven dietary factors examined: processed meats, fried/grilled meats and fish, non-fried fish, coconut oil, fruits and vegetables, bread and bread products, and sugar-sweetened beverages. CONCLUSIONS: Considering the inconsistencies in the literature and our null results, small differences in body composition and consumption of any single pro- or anti-inflammatory dietary component may not by themselves have a meaningful impact on telomere integrity, or the impact may differ across distinct ecological circumstances. PMID- 26497539 TI - Attentional performance, impulsivity, and related neurotransmitter systems in apoE2, apoE3, and apoE4 female transgenic mice. AB - RATIONALE: The apolipoprotein E (apoE) genotype influences cognitive performance in humans depending on age and sex. While the detrimental role of the apoE4 isoform on spatial learning and memory has been well-established in humans and rodents, less is known on its impact on the executive functions. OBJECTIVES: We aimed to evaluate the effect of apoE isoforms (apoE2, apoE3, apoE4) on visuospatial attention and inhibitory control performance in female transgenic mice, and to determine the neurochemical and neuropharmacological basis of this potential relationship. METHODS: Female mice carrying apoE2, apoE3, and apoE4 were trained in the five-choice serial reaction time task (5-CSRTT). Upon a stable performance, we manipulated the inter-trial interval and the stimulus duration to elicit impulsive responding and engage attention respectively. We further performed a pharmacological challenge by administering cholinergic and GABAergic agents. Finally, we analyzed the levels of brain amino acids and monoamines by using reversed phase high-performance liquid chromatography (HPLC). RESULTS: ApoE4 mice showed a deficient inhibitory control as revealed by increased perseveration and premature responding. When attention was challenged, apoE4 mice also showed a higher drop in accuracy. The adverse effect of scopolamine on the task was attenuated in apoE4 mice compared to apoE2 and apoE3. Furthermore, apoE4 mice showed less dopamine in the frontal cortex than apoE2 mice. CONCLUSIONS: We confirmed that the apoE genotype influences attention and inhibitory control in female transgenic mice. The influence of apoE isoforms in the brain neuromodulatory system may explain the cognitive and behavioral differences attributable to the genotype. PMID- 26497540 TI - Biocompatibility of different nanostructured TiO2 scaffolds and their potential for urologic applications. AB - Despite great efforts in tissue engineering of the ureter, urinary bladder, and urethra, further research is needed in order to improve the patient's quality of life and minimize the economic burden of different lower urinary tract disorders. The nanostructured titanium dioxide (TiO2) scaffolds have a wide range of clinical applications and are already widely used in orthopedic or dental medicine. The current study was conducted to synthesize TiO2 nanotubes by the anodization method and TiO2 nanowires and nanospheres by the chemical vapor deposition method. These scaffolds were characterized with scanning electron microscopy (SEM) and X-ray diffraction (XRD) methods. In order to test the urologic applicability of generated TiO2 scaffolds, we seeded the normal porcine urothelial (NPU) cells on TiO2 nanotubes, TiO2 nanowires, TiO2 nanospheres, and on the standard porous membrane. The viability and growth of the cells were monitored everyday, and after 3 weeks of culturing, the analysis with scanning electron microscope (SEM) was performed. Our results showed that the NPU cells were attached on all scaffolds; they were viable and formed a multilayered epithelium, i.e., urothelium. The apical plasma membrane of the majority of superficial NPU cells, grown on all three different TiO2 scaffolds and on the porous membrane, exhibited microvilli; thus, indicating that they were at a similar differentiation stage. The maximal caliper diameter measurements of superficial NPU cells revealed significant alterations, with the largest cells being observed on nanowires and the smallest ones on the porous membrane. Our findings indicate that different nanostructured TiO2 scaffolds, especially nanowires, have a great potential for tissue engineering and should be further investigated for various urologic applications. PMID- 26497541 TI - Three-dimensional ultrasonography for visualization of muscular anomalies in type VI and VII radial polydactyly. AB - OBJECTIVE: To describe a technique and its clinical applications of three dimensional ultrasonography to type VI and VII radial polydactyly for identification of potential muscular anomalies. MATERIALS AND METHODS: Ultrasonographic examinations were performed at an out-patient department without sedation or an operative room prior to surgery. The palm was scanned in the transverse direction using a 18-MHz linear transducer under speed regulation at 3 mm/s. Sequential images acquired at 0.2 mm intervals were converted into volume data. After validation of the technique, patients with a radial polydactyly in association with triphalangism (type VII) or with polydactylies of metacarpal duplication (type VI) were included for the examination. RESULTS: Five hands of five patients, one with type VI and four with type VII, were included the study. All the patients were male and the ages at examination ranged from 7 months to 2 years. Of the five patients, four examinations were performed at an out-patient department without sedation and one was under anesthesia just prior to surgery. The muscular abnormalities identified were mal-positions of the thenar muscles in a type VI case and a deficiency of the abductor pollicis brevis muscle in a type VII case with a delta phalanx in the ulnar part. CONCLUSION: Three-dimensional ultrasound technique could be an aid to plan strategies in radial polydactyly if intrinsic muscular anomalies are suspected to be involved. PMID- 26497542 TI - Retrospective analysis of intravertebral collateral enhancement in patients with central venous obstruction. AB - OBJECTIVE: To compare prevalence and patterns of intravertebral collateral enhancement in patients with and without central venous obstruction (CVO). MATERIALS AND METHODS: Chest CTs performed between 1/1/2000 and 12/15/2012 with reports containing terms indicating CVO were identified. All contrast enhanced CTs were examined for the presence of CVO and collateral venous pathways. If intravertebral collateral enhancement was present, the pattern was recorded as nodular, linear, or both. RESULTS: In 209 suspected cases of CVO, 53 (25 %) were confirmed with obstruction and 156 (75 %) were without obstruction. In patients with CVO, 47 % (25/53) demonstrated collateral venous flow through an intravertebral marrow pathway compared to 5 % (8/156) of patients without CVO (P < 0.0001). The most common level of enhancement was the upper thoracic spine, involving only the vertebral body. Nodular, linear, and combined nodular-linear enhancement patterns were seen with similar frequency. Nodular intravertebral collateral enhancement was mistaken for sclerotic metastases in 33 % (3/9) of cases. CONCLUSION: Intravertebral collateral enhancement was seen in almost half the patients with CVO and when nodular enhancement is present, it is important to differentiate between metastatic lesions and enhancement related to CVO. PMID- 26497543 TI - The prognostic value of total lesion glycolysis via 18F-fluorodeoxyglucose PET-CT in surgically treated esophageal squamous cell carcinoma. AB - OBJECTIVE: In addition to staging, the identification of prognostic factors is important for predicting survival in patients with esophageal cancer after esophagectomy. The present study was performed to document the prognostic role of total lesion glycolysis (TLG) in postoperative patients. METHODS: We retrospectively reviewed the records of 50 patients with esophageal squamous cell carcinoma who underwent surgical resection and complete lymph node dissection after positron emission tomography-computed tomography (PET-CT). A volume of interest was drawn on the primary lesion and suspected metastatic lymph nodes, and the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), TLG of the primary lesion (TLGp), and whole-body TLG (TLGwb) were measured using an SUV cutoff of 2.5. RESULTS: The study population included 50 patients with a mean age of 63.14 +/- 8.18 years: 12 (24%) were reported as stage I, 13 (26%) as stage II, and 25 (50%) as stage III. The median follow-up period was 20.46 months, and recurrences occurred in 17 patients. The mean SUVmax, MTV, TLGp, and TLGwb were 11.11 +/- 6.40, 20.47 +/- 22.88, 122.54 +/- 180.98, and 129.37 +/- 193.66, respectively. On the multivariate analysis, TLGp was a risk factor for disease-free survival (DFS) [hazard ratio (HR) = 1.002, p = 0.026], and TLGwb was a risk factor for DFS (HR = 1.002, p = 0.021) and overall survival (OS) (HR = 1.002, p = 0.044). The 3-year OS rates were 66.1% in patients with low TLGwb (<= 41.45) and 33.3% in those with high TLGwb (>41.45; p = 0.004). The concordance index of the TLGwb was 0.752 (95% CI 0.659-0.845). CONCLUSION: TLGwb is a significant prognostic factor for OS and DFS in patients with surgically treated esophageal squamous cell carcinoma. PMID- 26497544 TI - Transanal total mesorectal excision for rectal cancer: a single center experience and systematic review of the literature. AB - PURPOSE: The present study aimed to compare the operative and oncologic results of transanal total mesorectum excision (Ta-TME) ("down-to-up") vs. laparoscopic TME (L-TME, "up-to-down") for low rectal cancer. Additionally, a systematic review of the literature was performed to assess the quality of the current body of evidence on Ta-TME. METHODS: The study population included 32 consecutive patients who underwent Ta-TME between January 2011 and December 2014 that were compared with a matched group of patients undergoing L-TME between January 2008 and December 2010. The literature search was performed following the PRISMA guidelines for a systematic review. RESULTS: Ta-TME was associated with significantly shorter operative time (195 vs. 225 min; p = 0.017) and hospital stay (7.8 vs. 9.7 days; p = 0.018) compared to L-TME. No group differences were observed for intra-/postoperative complications and oncologic outcomes. One patient in the Ta-TME and two patients in the L-TME group developed local recurrence. The estimated survival rate at 2 years was 95.5 % for the Ta-TME and 96.6 % for the L-TME group (p = 0.646). The literature search identified 22 relevant retrospective studies on 423 patients operated on Ta-TME or robotic assisted transanal TME for rectal cancer. The only two comparative studies found similar short-term oncologic outcomes between Ta-TME and L-TME. A complete mesorectum was observed in 85 % of Ta-TME cases. The conversion rate was estimated at 4.3 % and the postoperative complication rate at 30.4 %. CONCLUSIONS: Ta-TME appears to be safe and feasible. It may find special application in patients with anatomic constraints that could make L-TME highly challenging. PMID- 26497546 TI - Cardiovascular risk and white matter lesions after endocrine control of Cushing's syndrome. AB - OBJECTIVE: Cushing's syndrome (CS) is associated with high cardiovascular risk. White matter lesions (WML) are common on brain magnetic resonance imaging (MRI) in patients with increased cardiovascular risk. AIM: To investigate the relationship between cardiovascular risk, WML, neuropsychological performance and brain volume in CS. DESIGN/METHODS: Thirty-eight patients with CS (23 in remission, 15 active) and 38 controls sex-, age- and education-level matched underwent a neuropsychological and clinical evaluation, blood and urine tests and 3Tesla brain MRI. WML were analysed with the Scheltens scale. Ten-year cardiovascular risk (10CVR) and vascular age (VA) were calculated according to an algorithm based on the Framingham heart study. RESULTS: Patients in remission had a higher degree of WML than controls and active patients (P<0.001 and P=0.008 respectively), which did not correlate with cognitive performance in any group. WML severity positively correlated with diastolic blood pressure (r=0.659, P=0.001) and duration of hypertension (r=0.478, P=0.021) in patients in remission. Both patient groups (active and in remission) had higher 10CVR (P=0.030, P=0.041) and VA than controls (P=0.013, P=0.039). Neither the 10CVR nor the VA correlated with WML, although both negatively correlated with cognitive function and brain volume in patients in remission (P<0.05). Total brain volume and grey matter volume in both CS patient groups were reduced compared to controls (total volume: active P=0.006, in remission P=0.012; grey matter: active P=0.001, in remission P=0.003), with no differences in white matter volume between groups. CONCLUSIONS: Patients in remission of Cushing's syndrome (but not active patients) have more severe white matter lesions than controls, positively correlated with diastolic pressure and duration of hypertension. Ten-year cardiovascular risk and vascular age appear to be negatively correlated with the cognitive function and brain volume in patients in remission of Cushing's syndrome. PMID- 26497545 TI - Further insight into molecular mechanism underlying thoracic spinal cord injury using bioinformatics methods. AB - The present study aimed to explore the molecular mechanisms underlying the development of thoracic spinal cord injury (SCI). The gene expression profile of GSE20907, which included 12 thoracic non-injured spinal cord control samples and 12 thoracic transected spinal cord samples at different stages of SCI, was obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using the limma package in R/Bioconductor. DEG associated pathways were analyzed using the Kyoto encyclopedia of genes and genomes database. A protein-protein interaction (PPI) network was constructed and transcription factors (TFs) were predicted using cytoscape. Compared with the control samples, there were 1,942, 396, 188 and 396 DEGs identified at day 3 (d3), week 1 (wk1), wk2 and month 1 (m1), respectively. Cluster analysis indicated that the DEGs at m1 were similar to those in the control group. Downregulated DEGs were enriched in nervous system disease pathways, such as Parkinson's disease. Upregulated DEGs were enriched in immune response-associated pathways, such as Fc gamma R-mediated phagocytosis at early stages (d3 and wk1). Upregulated DEGs were enriched in pathways associated with cancer and pyrimidine metabolism at wk2 and m1, respectively. In the PPI network, nodes including RAC2, CD4, STAT3 and JUN were identified. Furthermore, ATF3, JUN and EGR1 were identified as TFs associated with SCI. In conclusion, the results of the present study showed that the number of DEGs decreased in a time-dependent manner following SCI. OLIG1, ATF3 and JUN may represent SCI regeneration-associated genes. Immune-associated inflammation was shown to be important in SCI, and SCI exhibits causal associations with other diseases, including cardiovascular disease and cancers. The present study provided novel insight into the molecular mechanisms of SCI regeneration, which may aid in the development of strategies to enhance recovery following SCI. PMID- 26497547 TI - Strong Photocurrent from Two-Dimensional Excitons in Solution-Processed Stacked Perovskite Semiconductor Sheets. AB - Room-temperature photocurrent measurements in two-dimensional (2D) inorganic organic perovskite devices reveal that excitons strongly contribute to the photocurrents despite possessing binding energies over 10 times larger than the thermal energies. The p-type (C6H9C2H4NH3)2PbI4 liberates photocarriers at metallic Schottky aluminum contacts, but incorporating electron- and hole transport layers enhances the extracted photocurrents by 100-fold. A further 10 fold gain is found when TiO2 nanoparticles are directly integrated into the perovskite layers, although the 2D exciton semiconducting layers are not significantly disrupted. These results show that strong excitonic materials may be useful as photovoltaic materials despite high exciton binding energies and suggest mechanisms to better understand the photovoltaic properties of the related three-dimensional perovskites. PMID- 26497548 TI - Determination of the mechanism of action of repetitive halothane exposure on rat brain tissues using a combined method of microarray gene expression profiling and bioinformatics analysis. AB - The present study aimed to investigate the gene expression profiles of rats brain tissues treated with halothane compared with untreated controls to improve current understanding of the mechanism of action of the inhaled anesthetic. The GSE357 gene expression profile was dowloaded from the Gene Expression Omnibus database, and included six gene chips of samples repeatedly exposed to halothane and 12 gene chips of untreated controls. The differentially expressed genes (DEGs) between these two groups were identified using the Limma package in R language. Subsequently, the Database for Annotation, Visualization and Integrated Discovery was used to annotate the function of these DEGs. In addition, the most significantly upregulated gene and downregulated gene were annotated, to reveal the functional interactions with other associated genes, in FuncBase database. A total of 44 DEGs were obtained between The control and halothane exposure samples. Following Gene Ontology functional classification, these DEGs were found to be involved predominantly in the circulatory system, regulation of cell proliferation and response to endogenous stimulus and corticosteroid stimulus processes. KRT31 and HMGCS2, which were identified as the most significantly downregulated and upregulated DEGs, respectively, were associated with the lipid metabolic process and T cell activation, respectively. These results provided a basis for the development of improved inhalational anesthetics with minimal side effects and are essential for optimization of inhaled anesthetic techniques for advanced surgical procedures. PMID- 26497549 TI - CDDO-Me inhibits tumor growth and prevents recurrence of pancreatic ductal adenocarcinoma. AB - Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) has shown potent antitumorigenic activity against a wide range of cancer cell lines in vitro and inhibited the growth of liver, lung and prostate cancer in vivo. In the present study, we examined the antitumor activity of CDDO-Me for pancreatic ductal adenocarcinoma (PDAC) cells with and without activating K-ras mutations. Treatment of K-ras mutant MiaPaCa-2 and K-ras normal BxPC-3 cells with CDDO-Me elicited strong antiproliferative and proapoptopic responses in both cell lines in culture. The inhibition of cell proliferation and induction of apoptosis was accompanied by the inhibition of antiapoptotic/prosurvival p-Akt, NF-kB and p mTOR signaling proteins. For testing efficacy of CDDO-Me in vivo heterotopic and orthotopic xenografts were generated by implanting BxPC-3 and MiaPaCa-2 cells subcutaneously and in the pancreatic tail, respectively. Treatment with CDDO-Me significantly inhibited the growth of BxPC-3 xenografts and reduced the levels of p-Akt and p-mTOR in tumor tissue. In mice with orthotopic MiaPaCa-2 xenografts, treatment with CDDO-Me prolonged the survival of mice when administered following the surgical resection of tumors. The latter was attributed to the eradication of residual PDAC remaining after resection of tumors. These preclinical data demonstrate the potential of CDDO-Me for treating primary PDAC tumors and for preventing relapse/recurrence through the destruction of residual disease. PMID- 26497550 TI - Blockade of telomerase reverse transcriptase enhances chemosensitivity in head and neck cancers through inhibition of AKT/ERK signaling pathways. AB - Head and Neck squamous cell carcinomas (HNSCC), characterized by the high frequency of local recurrence and distant metastases, is mostly related to highly malignant and resistant to apoptosis, resulting in significant insensitivity to chemotherapy. Telomerase reverse transcriptase (TERT), as the catalytic subunit of telomerase, was implicated in the telomerase-mediated cellular transformation, proliferation, stemness and cell survival. Moreover, overexpression of human TERT (hTERT) is reported to be correlated with advanced invasive stage of the tumor progression and poor prognosis. Here, we show that hTERT potentially mediated the apoptotic resistance and blockade of telomerase reverse transcriptase could enhance chemosensitivity in head and neck cancers. Mechanistically, hTERT interacts with the phosphorylation of AKT and ERK to suppress the expression of p53, ultimately, leading to modulation of the cellular sensitivity to chemotherapy. Thus, these findings suggest that hTERT targeting could be an attractive approach in combination with conventional chemotherapies for patients suffering from chemoinsensitivity or refractory HNSCC. PMID- 26497551 TI - FN14 and GRP94 expression are prognostic/predictive biomarkers of brain metastasis outcome that open up new therapeutic strategies. AB - Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83-9.71) and 2.55- (95%CI 1.52 4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis. PMID- 26497552 TI - Cytoskeletal protein Flightless I inhibits apoptosis, enhances tumor cell invasion and promotes cutaneous squamous cell carcinoma progression. AB - Flightless I (Flii) is an actin remodeling protein that affects cellular processes including adhesion, proliferation and migration. In order to determine the role of Flii during carcinogenesis, squamous cell carcinomas (SCCs) were induced in Flii heterozygous (Flii+/-), wild-type and Flii overexpressing (FliiTg/Tg) mice by intradermal injection of 3-methylcholanthrene (MCA). Flii levels were further assessed in biopsies from human SCCs and the human SCC cell line (MET-1) was used to determine the effect of Flii on cellular invasion. Flii was highly expressed in human SCC biopsies particularly by the invading cells at the tumor edge. FliiTg/Tg mice developed large, aggressive SCCs in response to MCA. In contrast Flii+/- mice had significantly smaller tumors that were less invasive. Intradermal injection of Flii neutralizing antibodies during SCC initiation and progression significantly reduced the size of the tumors and, in vitro, decreased cellular sphere formation and invasion. Analysis of the tumors from the Flii overexpressing mice showed reduced caspase I and annexin V expression suggesting Flii may negatively regulate apoptosis within these tumors. These studies therefore suggest that Flii enhances SCC tumor progression by decreasing apoptosis and enhancing tumor cell invasion. Targeting Flii may be a potential strategy for reducing the severity of SCCs. PMID- 26497553 TI - Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth. AB - A promising new strategy for cancer therapy is to target the autophagic pathway. In the current study, we demonstrate that the antimalarial drug Quinacrine (QC) reduces cell viability and promotes chemotherapy-induced cell death in an autophagy-dependent manner more extensively in chemoresistant cells compared to their isogenic chemosensitive control cells as quantified by the Chou-Talalay methodology. Our preliminary data, in vitro and in vivo, indicate that QC induces autophagy by downregulating p62/SQSTM1 to sensitize chemoresistant cells to autophagic- and caspase-mediated cell death in a p53-independent manner. QC promotes autophagosome accumulation and enhances autophagic flux by clearance of p62 in chemoresistant ovarain cancer (OvCa) cell lines to a greater extent compared to their chemosensitive controls. Notably, p62 levels were elevated in chemoresistant OvCa cell lines and knockdown of p62 in these cells resulted in a greater response to QC treatment. Bafilomycin A, an autophagy inhibitor, restored p62 levels and reversed QC-mediated cell death and thus chemosensitization. Importantly, our in vivo data shows that QC alone and in combination with carboplatin suppresses tumor growth and ascites in the highly chemoresistant HeyA8MDR OvCa model compared to carboplatin treatment alone. Collectively, our preclinical data suggest that QC in combination with carboplatin can be an effective treatment for patients with chemoresistant OvCa. PMID- 26497554 TI - Upregulated in Hepatitis B virus-associated hepatocellular carcinoma cells, miR 331-3p promotes proliferation of hepatocellular carcinoma cells by targeting ING5. AB - Hepatitis B virus (HBV) is a major risk factor for development and progression of hepatocellular carcinoma (HCC). It has been reported that viral infection can interfere with cellular microRNA (miRNA) expression and participate in the pathogenesis of oncogenicity. Our miRNAs array data indicated that miR-331-3p expression in HCC cell lines increased, but the relationship between miR-331-3p expression and HBV activity is unclear. Here, we observed elevated expression of miR-331-3p in different HCC cell lines expressing HBV. HBV, especially HBx, promotes miR-331-3p expression by enhancing its promoter activity. Using a miRNA target prediction database miRBase, we identified ING5 to be a novel target gene of miR-331-3p. miR-331-3p could inhibit ING5 expression by directly targeting its 3'-untranslated region (3'-UTR). As predicted, HBV was confirmed to repress ING5 at both mRNA and protein levels by promoting miR-331-3p expression. Our result indicated that miR-331-3p expression promotes proliferation of SMMC7721 cells by inhibiting ING5. ING5 overexpression promoted cell apoptosis in HCC cell lines. We also found ING5 expression was decreased in tumor tissue of HCC patient with HBV infection compared to its expression in para-carcinoma tissues. CONCLUSION: These results showed that miR-331-3p is upregulated by HBV and promotes proliferation of HCC cells though repression of ING5 expression. These data provide new insights for understanding the mechanisms of HBV-related HCC pathogenesis. PMID- 26497555 TI - ZNF32 protects against oxidative stress-induced apoptosis by modulating C1QBP transcription. AB - Reactive oxygen species (ROS)-driven oxidative stress has been recognized as a critical inducer of cancer cell death in response to therapeutic agents. Our previous studies have demonstrated that zinc finger protein (ZNF)32 is key to cell survival upon oxidant stimulation. However, the mechanisms by which ZNF32 mediates cell death remain unclear. Here, we show that at moderate levels of ROS, Sp1 directly binds to two GC boxes within the ZNF32 promoter to activate ZNF32 transcription. Alternatively, at cytotoxic ROS concentrations, ZNF32 expression is repressed due to decreased binding activity of Sp1. ZNF32 overexpression maintains mitochondrial membrane potential and enhances the antioxidant capacity of cells to detoxify ROS, and these effects promote cell survival upon pro oxidant agent treatment. Alternatively, ZNF32-deficient cells are more sensitive and vulnerable to oxidative stress-induced cell injury. Mechanistically, we demonstrate that complement 1q-binding protein (C1QBP) is a direct target gene of ZNF32 that inactivates the p38 MAPK pathway, thereby exerting the protective effects of ZNF32 on oxidative stress-induced apoptosis. Taken together, our findings indicate a novel mechanism by which the Sp1-ZNF32-C1QBP axis protects against oxidative stress and implicate a promising strategy that ZNF32 inhibition combined with pro-oxidant anticancer agents for hepatocellular carcinoma treatment. PMID- 26497556 TI - MicroRNA-107: a novel promoter of tumor progression that targets the CPEB3/EGFR axis in human hepatocellular carcinoma. AB - MicroRNAs (miRNAs) are dysregulated in many types of malignancies, including human hepatocellular carcinoma (HCC). MiR-107 has been implicated in several types of cancer regulation; however, relatively little is known about miR-107 in human HCC. In the present study, we showed that the overexpression of miR-107 accelerates the tumor progression of HCC in vitro and in vivo through its new target gene, CPEB3. Furthermore, our results demonstrated that CPEB3 is a newly discovered tumor suppressor that acts via the EGFR pathway. Therefore, our study demonstrates that the newly discovered miR-107/CPEB3/EGFR axis plays an important role in HCC progression and might represent a new potential therapeutic target for HCC treatment. PMID- 26497557 TI - Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome. AB - 5-azacytidine (5-aza) is a hypomethylating agent approved for the treatment of high-risk myelodysplastic syndrome (MDS). It is assumed to act by demethylating tumor suppressor genes and via direct cytotoxic effects on malignant cells. In vitro treatment with hypomethylating agents has profound effects on the expression of killer-cell immunoglobulin-like (KIR) receptors on natural killer (NK) cells, as these receptors are epigenetically regulated via methylation of the promoters. Here we investigated the influence of 5-aza on the NK-cell repertoire during cytokine-induced proliferation in vitro and homeostatic proliferation in vivo in patients with high-risk MDS. In vitro treatment of NK cells from both healthy donors and MDS patients with low doses of 5-aza led to a significant increase in expression of multiple KIRs, but only in cells that had undergone several rounds of cell division. Proliferating 5-aza exposed NK cells exhibited increased IFN-gamma production and degranulation towards tumor target cells. MDS patients had lower proportions of educated KIR-expressing NK cells than healthy controls but after systemic treatment with 5-aza, an increased proportion of Ki-67+ NK cells expressed multiple KIRs suggesting uptake of 5-aza in cycling cells in vivo. Hence, these results suggest that systemic treatment with 5-aza may shape the NK cell repertoire, in particular during homeostatic proliferation, thereby boosting NK cell-mediated recognition of malignant cells. PMID- 26497559 TI - Crop evapotranspiration-based irrigation management during the growing season in the arid region of northwestern China. AB - In arid northwestern China, water shortages have triggered recent regulations affecting irrigation water use in desert-oasis agricultural systems. In order to determine the actual water demand of various crops and to develop standards for the rational use of water resources, we analyzed meteorological data from the Fukang desert ecosystem observation and experiment station (FKD), the Cele desert grassland ecosystem observation and research station (CLD), and the Linze Inland River Basin Comprehensive Research Station (LZD), which all belong to the Chinese Ecosystem Research Network. We researched crop evapotranspiration (ETc) using the water balance method, the FAO-56 Penman-Monteith method, the Priestley-Taylor method, and the Hargreaves method, during the growing seasons of 2005 through 2009. Results indicate substantial differences in ETc, depending on the method used. At the CLD, the ETc from the soil water balance, FAO-56 Penman-Monteith, Priestley-Taylor, and Hargreaves methods were 1150.3+/-380.8, 783.7+/-33.6, 1018.3+/-22.1, and 611.2+/-23.3 mm, respectively; at the FKD, the corresponding results were 861.0+/-67.0, 834.2+/-83.9, 1453.5+/-47.1, and 1061.0+/-38.2 mm, respectively; and at the LZD, 823.4+/-110.4, 726.0+/-0.4, 722.3+/-29.4, and 1208.6+/-79.1 mm, respectively. The FAO-56 Penman-Monteith method provided a fairly good estimation of E Tc compared with the Priestley-Taylor and Hargreaves methods. PMID- 26497558 TI - Tumor-host signaling interaction reveals a systemic, age-dependent splenic immune influence on tumor development. AB - The concept of age-dependent host control of cancer development raises the natural question of how these effects manifest across the host tissue/organ types with which a tumor interacts, one important component of which is the aging immune system. To investigate this, changes in the spleen, an immune nexus in the mouse, was examined for its age-dependent interactive influence on the carcinogenesis process. The model is the C57BL/6 male mice (adolescent, young adult, middle-aged, and old or 68, 143, 551 and 736 days old respectively) with and without a syngeneic murine tumor implant. Through global transcriptome analysis, immune-related functions were found to be key regulators in the spleen associated with tumor progression as a function of age with CD2, CD3epsilon, CCL19, and CCL5 being the key molecules involved. Surprisingly, other than CCL5, all key factors and immune-related functions were not active in spleens from non tumor bearing old mice. Our findings of age-dependent tumor-spleen signaling interaction suggest the existence of a global role of the aging host in carcinogenesis. Suggested is a new avenue for therapeutic improvement that capitalizes on the pervasive role of host aging in dictating the course of this disease. PMID- 26497560 TI - Bioaccumulation of arsenic and selenium in bycatch fishes Diapterus peruvianus, Pseudupeneus grandisquamis, and Trachinotus kennedyi from shrimp trawling in the continental shelf of Guerrero, Mexico. AB - With the aim of determining arsenic (As) and selenium (Se) concentrations in bycatch fishes from SW Mexico and comparing elemental concentrations with limits for human consumption set in the national and international legislation, three fish species (Diapterus peruvianus, Pseudupeneus grandisquamis, and Trachinotus kennedyi) were collected from Guerrero state during trawling operations. Additionally, As and Se levels in muscle tissue were compared with similar species from diverse areas. The order of As and Se concentrations was T. kennedyi>P. grandisquamis>D. peruvianus. In Mexico, there is no regulation of As and Se levels in fish. In comparison to the legal limit (0.1 MUg g(-1) wet weight) set by legislation in Venezuela, As levels in the edible portion of T. kennedyi (0.632 MUg g(-1) wet weight), P. grandisquamis (0.166 MUg g(-1) wet weight), and D. peruvianus (0.157 MUg g(-1) wet weight) were above this limit. In the case of Se, average concentrations in T. kennedyi (0.323 MUg g(-1) wet weight) were above the maximum permissible limit (0.30 MUg g(-1) wet weight) set in the Chilean legislation. Se concentrations in Carangoides bajad from Saudi Arabia were comparable to values in T. kennedyi (this study). In relation to As, concentrations varied in magnitude orders; the highest As concentration (range 10.35 to 23.71 MUg g(-1) wet weight) corresponded to Mullus barbatus from the Iberian Mediterranean. PMID- 26497561 TI - The invasive macrophyte Pistia stratiotes L. as a bioindicator for water pollution in Lake Mariut, Egypt. AB - The present study was conducted to evaluate the potentiality of the aquatic macrophyte Pistia stratiotes to accumulate trace metals, perspective of phytoremediation, and the probability for using it as a bioindicator for the different pollution types. Plants were collected from the different Lake Mariut basins (main basin, south-west, north-west, and fish farm), through five quadrats each, for measuring some growth parameters such as plant density, rosette diameter and height, root length, number of living and dead leaves per individual, and leaf length and width. In addition, nutrients and heavy metals in plant organs as well as water samples were analyzed. The bioaccumulation and translocation factors of trace metals were calculated. Water physicochemical data of Lake Mariut showed significant variations of all variables, except temperature and pH as well as Cd metal, among the lake basins. Fish farm was characterized by the highest plant density, individual size, biomass, and the number of living leaves, while the north-west basin had the lowest, except the number of dead leaves. In contrast to trace metals, P. stratiotes accumulated concentrations of macronutrients in the leaves higher than in roots. The bioaccumulation factors of the investigated metals, except Cu, were greater than one, while the translocation factors (TFs) of all trace metals were less than unity, and this may render P. stratiotes suitable for rhizofiltration. In addition, the significant positive correlation of Ni and Cd in water with those in plant roots and leaves as well as the growth response of this plant to the different pollutants may suggest its potential use as bioindicator for these pollutants in water. PMID- 26497562 TI - Relation between increased oxidative stress and histological abnormalities in the ovaries of Alburnus tarichi in Lake Van, Turkey. AB - Recent studies have shown reproductively arrested gonad development in female Alburnus tarichi (Guldenstadt, 1814) (Cyprinidae) from the eastern coastline of Lake Van, Turkey, due to increasing pollution. In the reproductively arrested females (RAF), oocytes were developmentally blocked and arrested at the previtellogenic stage and gonadosomatic indices (GSI) were very low, while reproductively non-arrested females (RNF) found at the same site displayed relatively normal ovarian development and higher GSI. The present study investigated various oxidative stress biomarkers in the ovaries of RAF and RNF collected from a polluted site at Lake Van at the mid-vitellogenic phase, compared with reference fish from a non-polluted site (Lake Ercek). Ovarian total protein content, biometric indices, and histology were also evaluated. The oxidative stress biomarkers used were levels of lipid peroxidation (LPO) and glutathione (GSH), and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST). High levels of LPO and GSH and activities of SOD, GPx and GST were found in the ovaries of RAF compared with the reference fish. GSH content and activities of GPx and GST were also higher in the RNF. The total protein content and biometric indices decreased significantly in the RAF compared with the RNF and reference fish. The histology of the ovaries revealed atresia, melano-macrophage centers, encapsulated follicle cysts, and severe fibrosis in the RAF. The results of this study suggest that abnormalities in the ovaries of A. tarichi are causally related to increased oxidative stress as a result of pollution. PMID- 26497563 TI - Direct estimation of dissolved organic carbon using synchronous fluorescence and independent component analysis (ICA): advantages of a multivariate calibration. AB - Dissolved organic carbon (DOC) is frequently used as a diagnostic parameter for the identification of environmental contamination in aqueous systems. Since this organic matter is evolving and decaying over time. If samples are collected under environmental conditions, some sample stabilization process is needed until the corresponding analysis can be made. This may affect the analysis results. This problem can be avoided using the direct determination of DOC. We report a study using in situ synchronous fluorescence spectra, with independent component analysis to retrieve relevant major spectral contributions and their respective component contributions, for the direct determination of DOC. Fluorescence spectroscopy is a very powerful and sensitive technique to evaluate vestigial organic matter dissolved in water and is thus suited for the analytical task of direct monitoring of dissolved organic matter in water, thus avoiding the need for the stabilization step. We also report the development of an accurate calibration model for dissolved organic carbon determinations using environmental samples of humic and fulvic acids. The method described opens the opportunity for a fast, in locus, DOC estimation in environmental or other field studies using a portable fluorescence spectrometer. This combines the benefits of the use of fresh samples, without the need of stabilizers, and also allows the interpretation of various additional spectral contributions based on their respective estimated properties. We show how independent component analysis may be used to describe tyrosine, tryptophan, humic acid and fulvic acid spectra and, thus, to retrieve the respective individual component contribution to the DOC. PMID- 26497564 TI - Brain dopamine-serotonin vesicular transport disease presenting as a severe infantile hypotonic parkinsonian disorder. AB - Two male siblings from a consanguineous union presented in early infancy with marked truncal hypotonia, a general paucity of movement, extrapyramidal signs and cognitive delay. By mid-childhood they had made little developmental progress and remained severely hypotonic and bradykinetic. They developed epilepsy and had problems with autonomic dysfunction and oculogyric crises. They had a number of orthopaedic problems secondary to their hypotonia. Cerebrospinal fluid (CSF) neurotransmitters were initially normal, apart from mildly elevated 5 hydroxyindolacetic acid, and the children did not respond favourably to a trial of levodopa-carbidopa. The youngest died from respiratory complications at 10 years of age. Repeat CSF neurotransmitters in the older sibling at eight years of age showed slightly low homovanillic acid and 5-hydroxyindoleacetic acid levels. Whole-exome sequencing revealed a novel mutation homozygous in both children in the monoamine transporter gene SLC18A2 (p.Pro237His), resulting in brain dopamine serotonin vesicular transport disease. This is the second family to be described with a mutation in this gene. Treatment with the dopamine agonist pramipexole in the surviving child resulted in mild improvements in alertness, communication, and eye movements. This case supports the identification of the causal mutation in the original case, expands the clinical phenotype of brain dopamine-serotonin vesicular transport disease and confirms that pramipexole treatment may lead to symptomatic improvement in affected individuals. PMID- 26497565 TI - Response of 33 UK patients with infantile-onset Pompe disease to enzyme replacement therapy. AB - BACKGROUND: Enzyme replacement therapy (ERT) for infantile-onset Pompe disease has been commercially available for almost 10 years. We report the experience of its use in a cohort treated at three specialist lysosomal treatment centres in the UK. METHODS: A retrospective case-note review was performed, with additional data being gathered from two national audits on all such patients treated with ERT. The impact on the outcome of various characteristics, measured just prior to the initiation of ERT (baseline), was evaluated using logistic regression. RESULTS: Thirty-three patients were identified; 13/29 (45%) were cross-reactive immunological material (CRIM) negative, and nine were immunomodulated. At baseline assessment, 79% were in heart failure, 66% had failure to thrive and 70% had radiological signs of focal pulmonary collapse. The overall survival rate was 60%, ventilation-free survival was 40% and 30% of patients were ambulatory. Median follow-up of survivors was 4 years, 1.5 months (range 6 months to 13.5 years). As with previous studies, the CRIM status impacted on all outcome measures. However, in this cohort, baseline failure to thrive was related to death and lack of ambulation, and left ventricular dilatation was a risk factor for non-ventilator-free survival. CONCLUSION: The outcome of treated patients remains heterogeneous despite attempts at immunomodulation. Failure to thrive at baseline and left ventricular dilation appear to be associated with poorer outcomes. PMID- 26497566 TI - Emotional intelligence score and performance of dental undergraduates. AB - The purpose of this study was to investigate the relationship between emotional intelligence (EI) and undergraduate dental students' ability to deal with different situations of communication in a clinical dentistry practical training course of communication skills. Fourth-year students in 2012 and in 2013 at the Nippon Dental University School of Life Dentistry at Niigata participated in the survey. The total number of participating students was 129 (88 males and 41 females). The students were asked to complete the Japanese version of the Mayer Salovey-Caruso Emotional Intelligence Test in communication skills. Female students tended to have significantly higher EI score than males. The EI score in the group with high-grade academic performers was higher than in the low-grade group. The influence of EI on academic performance appeared to be mainly due to the students' ability to accurately perceiving emotions and to their ability to understand emotional issues. The importance of EI may also lie in its ability to parse out personality factors from more changeable aspects of a person's behavior. Although further studies are required, we believe that dental educators need to assume the responsibility to help students develop their emotional competencies that they will need to prosper in their chosen careers. In our conclusion, dental educators should support low achievers to increase their levels of self-confidence instead of concentrating mainly on improving their technical skill and academic performance. This may lead to upgrading their skills for managing emotions and to changing their learning approach. PMID- 26497567 TI - Pain control methods in use and perceived effectiveness by patients with Ehlers Danlos syndrome: a descriptive study. AB - PURPOSE: The purpose of this study was to assess the pain control methods in use by patients who have Ehlers-Danlos Syndrome (EDS), a group of connective tissue disorders, and their perceived effectiveness. METHOD: This descriptive study involved 1179 adults diagnosed with EDS who completed an anonymous on-line survey. The survey consisted of demographics information, the Patient Reported Outcomes Measurement Information System (PROMIS) Pain-Behavior, PROMIS Pain Interference, and Neuro QOL Satisfaction with Social Roles and Activities scales, as well as a modified version of the Pain Management Strategies Survey. RESULTS: Respondents reported having to seek out confirmation of their EDS diagnosis with multiple healthcare providers, which implies the difficulty many people with EDS face when trying to gain access to appropriate treatment. Patients with EDS experience higher levels of pain interference and lower satisfaction with social roles and activities compared to national norms. Among the treatment modalities in this study, those perceived as most helpful for acute pain control were opioids, surgical interventions, splints and braces, avoidance of potentially dangerous activities and heat therapy. Chronic pain treatments rated as most helpful were opioids, splints or braces and surgical interventions. For methods used for both acute and chronic pain, those perceived as most helpful were opioids, massage therapies, splints or braces, heat therapy and avoiding potentially dangerous activities. CONCLUSIONS: EDS is a complex, multi-systemic condition that can be difficult to diagnose and poses challenges for healthcare practitioners who engage with EDS patients in holistic care. Improved healthcare provider knowledge of EDS is needed, and additional research on the co-occurring diagnoses with EDS may assist in comprehensive pain management for EDS patients. IMPLICATIONS FOR REHABILITATION: Ehlers-Danlos Syndrome (EDS) is a group of connective tissue disorders associated with defective production of collagen, which can dramatically reduce musculoskeletal functioning by symptoms of joint laxity and frequent dislocations eventually leading to disability. Respondents to an on-line survey reported having to seek out confirmation of their EDS diagnosis with multiple physicians, which implies the difficulty many people with EDS face when trying to gain access to appropriate treatment. Participants with EDS reported the most helpful methods for managing acute pain were opioids, surgical interventions, splints and braces, heat therapy, nerve blocks and physical therapy, while chronic pain was treated most effectively with opioids, heat therapy, splints or braces and surgical interventions. PMID- 26497568 TI - The Role and Importance of Small Fiber Neuropathy in Fibromyalgia Pain. AB - Serious investigators of fibromyalgia (FM) realize the profound implications of finding features of small fiber neuropathy (SFN) in this disorder. For the first time, an easily reproducible and generally agreed upon, peripheral tissue lesion has been reported from multiple investigative centers. Understanding how this discovery relates to other features of FM, and how one might utilize it to better comprehend, and care for, afflicted patients' painful complaints remains a challenge, however. In this article we review how the SFN seen in FM may be placed in context, and suggest how such a tissue abnormality might be used to better understand the pathophysiology of FM, and plan for its effective treatment. We also suggest how finding SFN in FM implies the need for continued focused research within the area of neuropathic disease in FM. PMID- 26497570 TI - Developments in spontaneous and coherent Raman scattering microscopic imaging for biomedical applications. AB - First, the potential role of Raman-based techniques in biomedicine is introduced. Second, an overview about the instrumentation for spontaneous and coherent Raman scattering microscopic imaging is given with a focus of recent developments. Third, imaging strategies are summarized including sequential registration with laser scanning microscopes, line imaging and global or wide-field imaging. Finally, examples of biomedical applications are presented in the context of single cells, laser tweezers, tissue sections, biopsies and whole animals. PMID- 26497569 TI - Activin and TGFbeta use diverging mitogenic signaling in advanced colon cancer. AB - BACKGROUND: Understanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFbeta or activin-induced metastatic phenotype of colon cancer. METHOD: Mitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) -/- or wild type mice. Colon cancer cell lines (+/- SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays. RESULTS: In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFbeta/MEK/ERK pathway activation. Activin, but not TGFbeta, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFbeta increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFbeta induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling. CONCLUSION: Although activin and TGFbeta share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4 independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFbeta ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFbeta family receptors. PMID- 26497571 TI - Effect of Carbenoxolone on Arrhythmogenesis in Rat Ventricular Muscle. AB - BACKGROUND: Connexin43 (Cx43) is a major connexin that forms gap junction (GJ) channels in the heart and is also present in the cell membrane as unopposed/non junctional hemichannels and in the inner mitochondrial membrane. By using carbenoxolone (CBX), a blocker of Cx43, the effect of the blockade of Cx43 on Ca(2+)waves and triggered arrhythmias in the myocardium with non-uniform contraction was examined. METHODS AND RESULTS: Trabeculae were obtained from rat hearts. Force, [Ca(2+)]i, and the diffusion coefficient were measured. Non uniform contraction was produced with a 2,3-butanedione monoxime jet. Ca(2+)waves were induced by electrical stimulation. Inducibility of arrhythmias was estimated based on the minimal [Ca(2+)]oat which arrhythmias were induced. The Ca(2+)spark rate was measured in isolated single rat ventricular myocytes. CBX reduced the GJ permeability, whereas it did not change force and [Ca(2+)]itransients. CBX increased the Ca(2+)leak from the sarcoplasmic reticulum in trabeculae and increased the Ca(2+)spark rate in isolated single myocytes. CBX increased the velocity of Ca(2+)waves and further increased the inducibility of arrhythmias. Modulation of mitochondrial KATPchannels by diazoxide, cromakalim and 5 hydroxydecanoic acid affected the inducibility of arrhythmias increased by CBX. CONCLUSIONS: These results suggest that in diseased hearts, Cx43 plays an important role in the occurrence of triggered arrhythmias, probably under the modulation of mitochondrial KATPchannels. PMID- 26497572 TI - Effect of Respiratory Therapy on the Prognosis of Chronic Heart Failure Patients Complicated With Sleep-Disordered Breathing - A Pilot Efficacy Trial. AB - BACKGROUND: Sleep-disordered breathing (SDB) has been reported to influence mortality and occurrence of ventricular tachyarrhythmia in patients with chronic heart failure (CHF). It remains to be elucidated, however, whether respiratory therapy (RT) can affect the occurrence of fatal ventricular tachyarrhythmia in CHF patients with SDB. METHODS AND RESULTS: We prospectively examined whether the severity of SDB was associated with fatal cardiac events in CHF patients and, if so, whether RT for SDB improved prognosis. We enrolled 95 patients with stable CHF, in whom SDB was examined on overnight polygraphy. The severity of SDB was quantified using the apnea-hypopnea index (AHI). All patients with AHI >=10 (n=42) at initial evaluation were recommended to have RT, such as home oxygen therapy and continuous positive airway pressure, and 24 agreed to this. During the follow-up period of 29+/-17 months, 8 ventricular tachyarrhythmias occurred and 14 of the 95 patients died. On multivariate proportional hazard analysis AHI >=5 was a risk factor for fatal arrhythmic events (P=0.026). Although RT significantly reduced AHI, it did not significantly reduce the event rates, but 4 patients with AHI <5 on RT had no fatal arrhythmic events or death. CONCLUSIONS: SDB is an independent prognostic factor and thus an important therapeutic target in CHF patients. PMID- 26497573 TI - Safety of topical corticosteroids in pregnancy. AB - BACKGROUND: Topical corticosteroids are the most frequently prescribed dermatological treatment and are often used by pregnant women with skin conditions. However, little is known about their safety in pregnancy. OBJECTIVES: To assess the effects of topical corticosteroids on pregnancy outcomes in pregnant women. SEARCH METHODS: This is an update of a review previously published in 2009. We updated our searches of the following databases to July 2015: the Cochrane Skin Group Specialised Register, the Cochrane Pregnancy and Childbirth Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 6), MEDLINE, EMBASE, and LILACS. We also searched five trials registers and checked the reference lists of included studies, published reviews, articles that had cited the included studies, and one author's literature collection, for further references to relevant RCTs. SELECTION CRITERIA: Randomised controlled trials and cohort studies of topical corticosteroids in pregnant women, as well as case-control studies comparing maternal exposure to topical corticosteroids between cases and controls when studies reported pre-specified outcomes. The primary outcomes included mode of delivery, major congenital abnormality, birth weight, and preterm delivery (delivery before 37 completed weeks gestation); the secondary outcomes included foetal death, minor congenital abnormality, and low Apgar score (less than seven at 5 min). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two authors independently applied selection criteria, extracted data, and assessed the quality of the included studies. A third author was available for resolving differences of opinion. A further author independently extracted data from included studies that were conducted by authors of this systematic review. MAIN RESULTS: We included 7 new observational studies in this update, bringing the total number to 14, including 5 cohort and 9 case control studies, with 1,601,515 study subjects.Most studies found no causal associations between maternal exposure to topical corticosteroids of any potency and pregnancy outcomes when compared with no exposure. These outcomes included: mode of delivery (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.95 to 1.15, 1 cohort study, n = 9904, low quality evidence); congenital abnormalities, including orofacial cleft or cleft palate and hypospadias (where the urethral opening is on the underside of the penis) (RR 0.82, 95% CI 0.34 to 1.96, 2 cohort studies, n = 9512, low quality evidence; and odds ratio (OR) 1.07, 95% CI 0.71 to 1.60, 1 case-control study, n = 56,557); low birth weight (RR 1.08, 95% CI 0.86 to 1.36; n = 59,419, 4 cohort studies; very low quality evidence); preterm delivery (RR 0.93, 95% CI 0.81 to 1.08, 4 cohort studies, n = 59,419, low quality evidence); foetal death (RR 1.02, 95% CI 0.60 to 1.73, 4 cohort studies, n = 63,885, very low quality evidence); and low Apgar score (RR 0.84, 95% CI 0.54 to 1.31, 1 cohort study, n = 9220, low quality evidence).We conducted stratified analyses of mild or moderate potency, and potent or very potent topical corticosteroids, but we found no causal associations between maternal exposure to topical corticosteroid of any potency and congenital abnormality, orofacial clefts, preterm delivery, or low Apgar score. For low birth weight, although the meta-analysis based on study-level data was not significant for either mild to moderate corticosteroids (pooled RR 0.90, 95% CI 0.74 to 1.09, 3 cohort studies, n > 55,713) or potent to very potent corticosteroids (pooled RR 1.58, 95% CI 0.96 to 2.58, 4 cohort studies, n > 47,651), there were significant differences between the two subgroups (P = 0.04). The results from three of the individual studies in the meta-analysis indicated an increased risk of low birth weight in women who received potent to very potent topical corticosteroids. Maternal use of mild to moderate potency topical steroids was associated with a decreased risk of foetal death (pooled RR 0.70, 95% CI 0.64 to 0.77, 2 studies, n = 48,749; low quality evidence), but we did not observe this effect when potent to very potent topical corticosteroids were given during pregnancy (pooled RR 1.14, 95% CI 0.69 to 1.88, 3 studies, n = 37,086, low quality evidence).We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group approach to rate the overall quality of the evidence. Data from observational studies started at low quality. We further downgraded the evidence because of imprecision in low birth weight and inconsistency in foetal death. Lower quality evidence resulted in lower confidence in the estimate of effect for those outcomes. AUTHORS' CONCLUSIONS: This update adds more evidence showing no causal associations between maternal exposure to topical corticosteroids of all potencies and pregnancy outcomes including mode of delivery, congenital abnormalities, preterm delivery, foetal death, and low Apgar score, which is consistent with the previous version of this review. This update provides stratified analyses based on steroid potency; we found no association between maternal use of topical corticosteroids of any potency and an increase in adverse pregnancy outcomes, including mode of delivery, congenital abnormality, preterm delivery, foetal death, and low Apgar score. Similar to the previous version of the review, this update identified a probable association between low birth weight and maternal use of potent to very potent topical corticosteroids, especially when the cumulative dosage of topical corticosteroids throughout the pregnancy is very large, which warrants further investigation. The finding of a possible protective effect of mild to moderate topical corticosteroids on foetal death could also be examined. PMID- 26497574 TI - The nasopharyngeal microbiota of feedlot cattle. AB - The bovine nasopharyngeal tract plays an important role in animal health and welfare by acting as a site for the carriage of pathogens causing bovine respiratory disease, a condition which results in significant morbidity and mortality in feedlot cattle. We characterized the bacterial nasopharyngeal microbiota in cattle at feedlot entry (day 0) and day 60 using 454 pyrosequencing. We also identified the most frequently isolated aerobic bacteria from nasopharyngeal swabs after plating onto three types of media. The cattle nasopharyngeal microbiota was composed primarily of Proteobacteria (68.9%) and Firmicutes (19.2%). At the genus-level, there was more inter-individual variability and a total of 55 genera were identified. The genera Pseudomonas (23.7%), Shewanella (23.5%), Acinetobacter (17.5%), and Carnobacterium (12.2%) were most prevalent at entry, while after 60 days in the feedlot, Staphylococcus (20.8%), Mycoplasma (14.9%), Mannheimia (10.4%), and Moraxella (9.4%) were dominant. The nasopharyngeal microbiota also became more homogenous after 60 days in the feedlot and differed in structure at day 0 and 60. Using culture-based methods, the most frequently isolated bacteria from nasopharyngeal swabs were Bacillus, Staphylococcus, Moraxella, Pasteurella, and Mannheimia. These results provide insight into the nasopharyngeal microbiota of cattle and demonstrate that specific changes take place during feedlot production. PMID- 26497576 TI - Association of activated Galphaq to the tumor suppressor Fhit is enhanced by phospholipase Cbeta. AB - BACKGROUND: G proteins are known to modulate various growth signals and are implicated in the regulation of tumorigenesis. The tumor suppressor Fhit is a newly identified interaction partner of Gq proteins that typically stimulate the phospholipase C pathway. Activated Galphaq subunits have been shown to interact directly with Fhit, up-regulate Fhit expression and enhance its suppressive effect on cell growth and migration. Other signaling molecules may be involved in modulating Galphaq/Fhit interaction. METHODS: To test the relationship of PLCbeta with the interaction between Galphaq and Fhit, co-immunoprecipication assay was performed on HEK293 cells co-transfected with different combinations of Flag Fhit, Galpha16, Galpha16QL, pcDNA3 vector, and PLCbeta isoforms. Possible associations of Fhit with other effectors of Galphaq were also demonstrated by co immunoprecipitation. The regions of Galphaq for Fhit interaction and PLCbeta stimulation were further evaluated by inositol phosphates accumulation assay using a series of Galpha16/z chimeras with discrete regions of Galpha16 replaced by those of Galphaz. RESULTS: PLCbeta1, 2 and 3 interacted with Fhit regardless of the expression of Galphaq. Expression of PLCbeta increased the affinities of Fhit for both wild-type and activated Galphaq. Swapping of the Fhit-interacting alpha2-beta4 region of Galphaq with Galphai eliminated the association of Galphaq with Fhit without affecting the ability of the mutant to stimulate PLCbeta. Other effectors of Galphaq including RGS2 and p63RhoGEF were unable to interact with Fhit. CONCLUSIONS: PLCbeta may participate in the regulation of Fhit by Gq in a unique way. PLCbeta interacts with Fhit and increases the interaction between Galphaq and Fhit. The Galphaq/PLCbeta/Fhit complex formation points to a novel signaling pathway that may negatively regulate tumor cell growth. PMID- 26497577 TI - SKLB-677, an FLT3 and Wnt/beta-catenin signaling inhibitor, displays potent activity in models of FLT3-driven AML. AB - FLT3 has been identified as a valid target for the treatment of acute myeloid leukemia (AML), and some FLT3 inhibitors have shown very good efficacy in treating AML in clinical trials. Nevertheless, recent studies indicated that relapse and drug resistance are still difficult to avoid, and leukemia stem cells (LSCs) are considered one of the most important contributors. Here, we report the characterization of SKLB-677, a new FLT3 inhibitor developed by us recently. SKLB 677 exhibits low nanomolar potency in biochemical and cellular assays. It is efficacious in animal models at doses as low as 1mg/kg when administrated orally once daily. In particular, SKLB-677 but not first-generation and second generation FLT3 inhibitors in clinical trials has the ability to inhibit Wnt/beta catenin signaling; Wnt/beta-catenin signaling is required for the development of LSCs, but not necessary for the development of adult hematopoietic stem cells (HSCs). This compound indeed showed considerable suppression effects on leukemia stem-like cells in in vitro functional assays, but had no influence on normal HSCs. Collectively, SKLB-677 is an interesting lead compound for the treatment of AML, and deserves further investigations. PMID- 26497578 TI - Determination of Islet Viability Using a Zinc-Specific Fluorescent Dye and a Semiautomated Assessment Method. AB - Islet transplantation is an effective therapy that allows the achievement of insulin independence in patients with type 1 diabetes (T1D). To ensure successful transplantation, islet viability and function are of great importance. Viability assessments most often use fluorescein diacetate (FDA)/propidium iodide (PI) staining. However, results using this method often do not correlate well with graft function. Because FDA nonspecifically penetrates all cells present in the islet preparation, including islets and contaminating acinar cells, its use often complicates viability assessments of the overall cell population. Furthermore, the manual method for determining viability percentages is highly subjective. Shortcomings of the conventional islet viability assay can be potentially improved by staining cells with Newport Green (NG). NG, is a zinc-specific fluorescent dye that specifically reacts with zinc-rich beta cells. Two kinds of NG dyes, NG-DCF and NG-PDX, are currently available. We examined the zinc specificity of these NG dyes and compared NG staining with traditional FDA staining to explore the potential of NG dyes to improve islet viability assessment. Of the two NGs tested, NG-DCF showed the higher specificity toward a beta-cell line as well as human islets. NG-DCF accurately identified the islet area, even in low-purity islets, while neither FDA nor NG-PDX did. Although NG DCF staining required a longer incubation time, the addition of poloxamer F127 and incubation at 37 degrees C allowed viability assessment to take place within 30 min. Unlike FDA/PI staining, NG-DCF/PI staining allowed for islet-specific assessment. We also introduced a semiautomated measurement to determine NG-DCF/PI staining results, which enabled us to obtain objective and reproducible results. NG-DCF/PI staining is easy and reliable, and this method permits highly objective islet-specific viability assessments. PMID- 26497579 TI - Myocardial tissue engineering using electrospun nanofiber composites. AB - Emerging trends for cardiac tissue engineering are focused on increasing the biocompatibility and tissue regeneration ability of artificial heart tissue by incorporating various cell sources and bioactive molecules. Although primary cardiomyocytes can be successfully implanted, clinical applications are restricted due to their low survival rates and poor proliferation. To develop successful cardiovascular tissue regeneration systems, new technologies must be introduced to improve myocardial regeneration. Electrospinning is a simple, versatile technique for fabricating nanofibers. Here, we discuss various biodegradable polymers (natural, synthetic, and combinatorial polymers) that can be used for fiber fabrication. We also describe a series of fiber modification methods that can increase cell survival, proliferation, and migration and provide supporting mechanical properties by mimicking micro-environment structures, such as the extracellular matrix (ECM). In addition, the applications and types of nanofiber-based scaffolds for myocardial regeneration are described. Finally, fusion research methods combined with stem cells and scaffolds to improve biocompatibility are discussed. PMID- 26497580 TI - Rapamycin-resistant and torin-sensitive mTOR signaling promotes the survival and proliferation of leukemic cells. AB - The serine/threonine kinase mTOR is essential for the phosphoinositide 3-kinases (PI3K) signaling pathway, and regulates the development and function of immune cells. Aberrant activation of mTOR signaling pathway is associated with many cancers including leukemia. Here, we report the contributions of mTOR signaling to growth of human leukemic cell lines and mouse T-cell acute leukemia (T-ALL) cells. Torin, an ATP-competitive mTOR inhibitor, was found to have both cytotoxic and cytostatic effects on U-937, THP-1, and RPMI-8226 cells, but not on Jurkat or K-562 cells. All cells were relatively resistant to rapamycin even with suppressed activity of mTOR complex 1. Growth of T-ALL cells induced by Notch1 was profoundly affected by torin partially due to increased expression of Bcl2l11 and Bbc3. Of note, activation of Akt or knockdown of FoxO1 mitigated the effect of mTOR inhibition on T-ALL cells. Our data provide insight on the effect of mTOR inhibitors on the survival and proliferation of leukemic cells, thus further improving our understanding on cell-context-dependent impacts of mTOR signaling. PMID- 26497581 TI - Stem cell maintenance by manipulating signaling pathways: past, current and future. AB - Pluripotent stem cells only exist in a narrow window during early embryonic development, whereas multipotent stem cells are abundant throughout embryonic development and are retained in various adult tissues and organs. While pluripotent stem cell lines have been established from several species, including mouse, rat, and human, it is still challenging to establish stable multipotent stem cell lines from embryonic or adult tissues. Based on current knowledge, we anticipate that by manipulating extrinsic and intrinsic signaling pathways, most if not all types of stem cells can be maintained in a long-term culture. In this article, we summarize current culture conditions established for the long-term maintenance of authentic pluripotent and multipotent stem cells and the signaling pathways involved. We also discuss the general principles of stem cell maintenance and propose several strategies on the establishment of novel stem cell lines through manipulation of signaling pathways. PMID- 26497582 TI - The expression and functional roles of microRNAs in stem cell differentiation. AB - microRNAs (miRNAs) are key regulators of cell state transition and retention during stem cell proliferation and differentiation by post-transcriptionally downregulating hundreds of conserved target genes via seed-pairing in their 3' untranslated region. In embryonic and adult stem cells, dozens of miRNAs that elaborately control stem cell processes by modulating the transcriptomic context therein have been identified. Some miRNAs accelerate the change of cell state into progenitor cell lineages-such as myoblast, myeloid or lymphoid progenitors, and neuro precursor stem cells-and other miRNAs decelerate the change but induce proliferative activity, resulting in cell state retention. This cell state choice can be controlled by endogenously or exogenously changing miRNA levels or by including or excluding target sites. This control of miRNA-mediated gene regulation could improve our understanding of stem cell biology and facilitate their development as therapeutic tools. PMID- 26497584 TI - Cognitive improvement of compound danshen in an Abeta25-35 peptide-induced rat model of Alzheimer's disease. AB - BACKGROUND: Senile dementia mainly includes Alzheimer' s disease (AD) and vascular dementia (VD). AD is a progressive and irreversible neurodegenerative disorder that is accompanied with a great deal of social burden. The aim of this study was to investigate the effect of Compound Danshen (CDS) on learning and memory of alzheimer's disease (AD) rat model, as well as to explore the possible connection between CDS and the associated molecules of amyloid beta (Abeta). METHODS: Rats were injected with Abeta25-35 peptide intracerebroventricularly and CDS were subsequently administered once daily for 23 days. Rats' behavior was monitored using Morris water maze and passive avoidance. Real time PCR and Western blotting were used in determining amyloid precursor protein (APP), beta site APP cleaved enzyme-1(BACE1), Presenilin-1 (PS1), Insulin-degrading enzyme (IDE) and neprilysin (NEP) in hippocampus. RESULTS: The AD model group presented with spatial learning and memory impairments. CDS and donepezil administration significantly ameliorated the Abeta25-35 peptide-induced memory impairment in both Morris water maze (P < 0.05) and passive avoidance task (P < 0.01) compared to the AD model group. Real time PCR results suggested that CDS significantly decreased APP mRNA, PS1 mRNA and increased IDE and NEP mRNA levels. Western blotting analyses showed that CDS decreased the protein expression of APP and PS1 and increased IDE expression. CONCLUSION: CDS improved spatial learning and memory by down-regulating APP, PS1 levels and up-regulating IDE. In future, CDS may have significant therapeutic potential in the treatment of AD patients. PMID- 26497586 TI - School recess, social connectedness and health: a Canadian perspective. AB - Children need opportunities to establish positive social connections at school, yet many school playgrounds are challenged by social conflict that can undermine these connections. When children's social needs go unmet, the resultant feelings of loneliness, isolation and self-doubt can cumulatively lead to mental and physical illness. Because recess is typically the only time during the school day that children are free to socialize and play, we propose a more thoughtful way of thinking about it: from the lens of belongingness. Schools are, historically, designed for instruction. We argue, however, that we need to attend to children's social needs at school. We highlight current research from social neuroscience, belonging and social connectedness in order to delineate the pathways between daily school recess and developmental health trajectories. We then consolidate an array of research on play, social interaction and school change to suggest four areas that could benefit from consideration in research, practice and policy: (i) the culture of recess, (ii) the importance of healthy role models on the playground, (iii) the necessity of activities, options and variety during recess and (iv) the significance of space and spatial layout (indoor and outdoor). We bridge our discussion with the conception of health as described in the Ottawa Charter and emphasize the need to build alliances across sectors to assist schools in their efforts to support children's overall health needs. PMID- 26497585 TI - Canadian academic's call for moratorium on HPV vaccine sparks controversy. PMID- 26497583 TI - Small PARP inhibitor PJ-34 induces cell cycle arrest and apoptosis of adult T cell leukemia cells. AB - BACKGROUND: HTLV-I is associated with the development of an aggressive form of lymphocytic leukemia known as adult T-cell leukemia/lymphoma (ATLL). A major obstacle for effective treatment of ATLL resides in the genetic diversity of tumor cells and their ability to acquire resistance to chemotherapy regimens. As a result, most patients relapse and current therapeutic approaches still have limited long-term survival benefits. Hence, the development of novel approaches is greatly needed. METHODS: In this study, we found that a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), PJ-34, is very effective in activating S/G2M cell cycle checkpoints, resulting in permanent cell cycle arrest and reactivation of p53 transcription functions and caspase-3-dependent apoptosis of HTLV-I-transformed and patient-derived ATLL tumor cells. We also found that HTLV-I-transformed MT-2 cells are resistant to PJ-34 therapy associated with reduced cleaved caspase-3 activation and increased expression of RelA/p65. CONCLUSION: Since PJ-34 has been tested in clinical trials for the treatment of solid tumors, our results suggest that some ATLL patients may be good candidates to benefit from PJ-34 therapy. PMID- 26497587 TI - Television food advertising to children in Malta. AB - To undertake a cross-sectional survey of the extent and nature of food and beverage advertising to children on Maltese national television stations. Seven national free-to-air channels were recorded for seven consecutive days in March 2014 between 07:00 and 22:00 h. Advertisements were coded according to predefined categories, with a focus on advertisements aired during 'peak' children's viewing times, defined as periods during which more than 25% of children were likely to be watching television on any channel. Food and beverage advertisements were classified as core (healthy), non-core (unhealthy) or miscellaneous foods. Malta. Whole population, with a focus on children. Food and drinks were the most heavily advertised product category (26.9% of all advertisements) across all channels. The proportion of non-core food/drink advertisements was significantly greater during peak compared with non-peak children's viewing times (52 vs 44.6%; p <= 0.001). A majority of advertisements aimed at children are for non-core foods, and are typically shown during family-oriented programmes in the late evening rather than being restricted to children's programmes. 'Taste', 'enjoyment' and 'peer status' were the primary persuasive appeals used in adolescent and child focused advertisements. This first content analysis of television advertising in Malta suggests that there is scope for the implementation of statutory regulation regarding advertising of foods high in fat, sugar and salt (HFSS) during times when children are likely to watch television, rather than during children's programmes only. Ongoing, systematic monitoring is essential for evaluation of the effectiveness of regulations designed to reduce children's exposure to HFSS food advertising on television. PMID- 26497588 TI - Depression symptom and professional mental health service use. AB - BACKGROUND: Despite the sharp rise in antidepressant use, the underutilization of mental healthcare services for depression remains a concern. We investigated factors associated with the underutilization of mental health services for potential depression symptoms in the Republic of Korea, using a nationally representative sample. METHODS: Data were obtained from the Community Health Survey (2011-2012) conducted in the Republic of Korea. Participants comprised adults who reported potential depression symptoms during the year prior to the study (n = 21,644); information on professional mental healthcare use for their symptoms was obtained. The association of demographic, socioeconomic, and health related factors with consultation use was analysed via multiple logistic regression. Adjusted odds ratio and 95% confidence intervals were estimated. RESULTS: Among those reporting potential depression symptoms, only 17.4% had consulted a medical/mental health professional. Elderly individuals of both genders had significantly lower consultation rates compared to middle-aged individuals. Unmet healthcare needs and a history of diabetes mellitus were associated with lower consultation rates. After stratification by age, elderly individuals with the lowest education and income level were significantly less likely to seek professional mental health services. Married, separated, or divorced men had lower consultation rates compared to unmarried individuals, whereas married, separated, or divorced women had higher rates. CONCLUSIONS: The results suggest that target strategies for vulnerable groups identified in this study--including elderly individuals--need to be established at the community level, including strengthening social networks and spreading awareness to reduce the social stigma of depression. PMID- 26497590 TI - Trap-limited charge recombination in intrinsic perovskite film and meso superstructured perovskite solar cells and the passivation effect of the hole transport material on trap states. AB - Charge recombination dynamics in intrinsic perovskite film and in meso superstructured perovskite solar cells have been systematically studied, which are found to be mediated by the energetic distribution of intra-gap trap states as described by the trap-limited recombination theory. Besides, the passivation effect of the hole-transport material on trap states is discussed. PMID- 26497589 TI - Unusual severe cases of type 1 porcine reproductive and respiratory syndrome virus (PRRSV) infection in conventionally reared pigs in South Korea. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) causes a loss of approximately US$ 70 million every year to the South Korean pork industry. There are two distinct genotypes: European (type 1) and North American (type 2). In South Korea, type 1 and type 2 PRRSV are widely distributed and have evolved continuously since the infection was first described. Here, we present two field cases of type 1 PRRSV infection with unusually severe pathogenicity. CASE PRESENTATION: The first case farm was a two-site production system comprising farrow-to-grower and grower-to-finish units and was historically free from PRRSV infections. The PRRSV vaccine had not been used in both units. In October 2014, pigs in the grower-to-finish unit experienced severe respiratory distress with the mortality rate reaching to 22%. Despite antibiotic treatment, clinical signs were still noticed in most pigs. The second case farm was also a two-site production system, but had two separate farrow-to-grower units (unit A and unit B). Historically, type 1 PRRSV was continuously present in unit A, but unit B was free from PRRSV. Thus, all grower pigs of unit B were vaccinated before being moved to the grower-to-finish unit. In November 2014, severe respiratory distress was seen in pigs of the grower-to-finish unit. Significant respiratory distress was observed in only the grower herd moved from unit B, and the mortality of those pigs was ~50%. However, no disease was shown in the grower pigs from unit A. CONCLUSIONS: To our knowledge, the present study is the first observation of the cases of infection by highly pathogenic type 1 PRRSV in South Korea. The Korean type 1 PRRSV strains have undergone unique evolutionary dynamics for the last decade in this country. Although there are known to be three clusters of Korean type 1 PRRSV, their pathogenicity could not be categorized owing to their high level of genetic diversity. Therefore, further studies are needed to demonstrate the novel classification of Korean type 1 PRRSV strains according to their virulence factors. PMID- 26497591 TI - Bioactive peptide from Pyropia yezoensis and its anti-inflammatory activities. AB - Pyropia yezoensis (P. yezoensis) is an important marine algae. Its high protein content serves as a good source of biologically active peptides. Potent inhibitory effects on the production of inflammatory mediators were observed in a bioactive peptide derived from P. yezoensis (peptide from P. yezoensis; PPY1), as demonstrated in lipopolysaccharide (LPS)-stimulated macrophages. The present study showed that peptide concentrations ranging from 250 to 1,000 ng/ml had no significant cytotoxicity in the cell viability assay when applied to the RAW 264.7 cells for 24 h. PPY1 completely inhibited LPS-stimulated nitric oxide (NO) release in a dose-dependent manner. Fluorescence intensity, corresponding to intracellular reactive oxygen species (ROS) produced by 10 ng/ml LPS-stimulated cells, significantly shifted, indicating that the peptide reduced the level of ROS. Furthermore, PPY1 exerted potent inhibitory activity to reduce the release of pro-inflammatory cytokines (inducible NO synthase, cyclooxygenase-2, interleukin-1beta and tumor necrosis factor-alpha) in LPS-stimulated macrophages in a dose-dependent manner. These results also showed that the anti-inflammatory activity of PPY1 was associated with downregulation of extracellular signal regulated kinase, protein 38, and c-jun NH2-terminal kinase phosphorylation in the mitogen-activated protein kinase pathways. In conclusion, PPY1 can have a significant role as an anti-inflammatory agent, with a potential for use in marine products. PMID- 26497592 TI - The rs1803274 polymorphism of the BCHE gene is associated with an increased risk of coronary in-stent restenosis. AB - BACKGROUND: We sought to identify gene polymorphisms that confer susceptibility to in-stent restenosis after coronary artery bare-metal stenting in a Central European population. METHODS: 160 controls without post-percutaneous coronary intervention in-stent restenosis were matched for age, sex, vessel diameter, and diabetes to 160 consecutive cases involving in-stent restenosis of the target lesion within 12 months. Using real time polymerase chain reaction and melting curve analysis, we detected 13 single-nucleotide polymorphisms in 11 candidate genes - rs1803274 (BCHE gene), rs529038 (ROS1), rs1050450 (GPX1), rs1800849 (UCP3), rs17216473 (ALOX5AP), rs7412, rs429358 (ApoE), rs2228570 (VDR), rs7041, rs4588 (GC), rs1799986 (LRP1) and rs2228671 (LDLR). Multivariable logistic regression was used to test for associations. RESULTS: The rs1803274 polymorphism of BCHE was significantly associated with in-stent restenosis (OR 1.934; 95 % CI: 1.181-3.166; p = 0.009). No association was found with the other studied SNPs. CONCLUSIONS: The A allele of rs1803274 represents a risk factor for in-stent restenosis in Central European patients after percutaneous coronary intervention with bare-metal stent implantation. PMID- 26497593 TI - Presence of an intracompartmental septum detected by ultrasound is associated with the failure of ultrasound-guided steroid injection in de Quervain's syndrome. AB - The purpose of this study was to find clinical or ultrasound characteristics that might predict the failure of conservative treatment in de Quervain's syndrome. A total of 42 ultrasound-guided injections have been performed in 41 patients after clinical and ultrasound examination. Patients were immobilized for 3 weeks with a spica splint cast, and clinically evaluated at 3 and 6 weeks and by phone call at the end of the study. Ultrasound showed a septum between the tendons of the first comportment in 34% of the wrists. At last follow-up (mean 15.6 months after the injection) ten patients (24%) had undergone surgery. When comparing ultrasound and clinical characteristics of the operated and non-operated wrists, we found that patients with a high baseline visual analogue scale, with all positive clinical tests and with a persistent intracompartmental septum, had a significantly higher risk of failure following conservative treatment. LEVEL OF EVIDENCE: III. PMID- 26497594 TI - Transverse soft tissue distraction preceding separation of complex syndactylies. AB - Various surgical techniques are described for separation of syndactylies leading to good results. However, the use of standard techniques is limited in complex syndactylies with extensive bony fusion and tight soft tissues. The aim of this study was to assess the outcomes of a two-stage procedure involving progressive soft tissue distraction prior to syndactyly release. Between 1996 and 2012 we treated 168 complex syndactylies with this technique. The main indications were syndactylies in Apert syndrome. The digits were distracted through an external fixator at 0.5 mm/day. Distraction of 15-25 mm was achieved. Soft tissue distraction provided additional skin, a wider nail matrix and more bone in the form of callus. Thus subsequent modelling of the fingertips was improved, especially if they were closely fused. This technique facilitates treatment of complex cases and improves aesthetic outcome. LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26497595 TI - Clinical outcomes and molecular typing of heterogenous vancomycin-intermediate Staphylococcus aureus bacteremia in patients in intensive care units. AB - BACKGROUND: Staphylococcus aureus is one of most common pathogens in humans. Methicillin-resistant S. aureus (MRSA) accounts for 64 % of S. aureus bacteremia isolated in intensive care units (ICUs), and heteroresistant vancomycin intermediates S. aureus (hVISA) is a phenotype of MRSA. However, studies focusing on the hVISA impact on critically ill patients are scarce. METHODS: This was a retrospective study conducted in a tertiary medical center from January 2009 to December 2010. All adult patients in ICUs with MRSA bloodstream infection were eligible. A modified population analysis profile and area under the curve method was applied to all isolates to confirm hVISA phenotype. Multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec) and the accessory gene regulator (agr) typing were performed individually. Clinical outcomes including in-hospital mortality, length of stay in intensive care unit and hospital after MRSA bacteremia of the patients were also analyzed. RESULTS: A total of 48 patients were enrolled and 14 patients were confirmed to have the hVISA phenotype. The prevalence of hVISA was 29.2 %. There was no difference in the age, sex, comorbidity, Charlson's comorbidity score and previous vancomycin therapy between the hVISA and VSSA groups. The hVISA group had a significantly higher in-hospital mortality than the VSSA group (13/14 versus 22/34; p = 0.046). All of the 14 hVISA patients had an MIC = 2 mg/L by E-test and this represented a significant association between high MIC and the development of hVISA (p < 0.001). MLST analysis showed all the isolates in the hVISA group were ST239, while ST239 (14/34; 41.2 %) and ST5 (12/34; 35.3 %) were predominant in the VSSA group (p = 0.007). A comparison of the survivor and non-survivor group showed that the hVISA phenotype (OR 11.8; 95 % CI 1.1-126.99; p = 0.042) and sequential organ failure assessment (SOFA) score (OR 1.39; 95 % CI 1.07-1.81; p = 0.014) were independent factors significantly associated with in-hospital mortality. CONCLUSIONS: Patients in ICUs with MRSA bacteremia may have a higher in-hospital mortality if they have the hVISA phenotype. SOFA score is also predictor of mortality. PMID- 26497596 TI - Multi-level engineering facilitates the production of phenylpropanoid compounds in tomato. AB - Phenylpropanoids comprise an important class of plant secondary metabolites. A number of transcription factors have been used to upregulate-specific branches of phenylpropanoid metabolism, but by far the most effective has been the fruit specific expression of AtMYB12 in tomato, which resulted in as much as 10% of fruit dry weight accumulating as flavonols and hydroxycinnamates. We show that AtMYB12 not only increases the demand of flavonoid biosynthesis but also increases the supply of carbon from primary metabolism, energy and reducing power, which may fuel the shikimate and phenylalanine biosynthetic pathways to supply more aromatic amino acids for secondary metabolism. AtMYB12 directly binds promoters of genes encoding enzymes of primary metabolism. The enhanced supply of precursors, energy and reducing power achieved by AtMYB12 expression can be harnessed to engineer high levels of novel phenylpropanoids in tomato fruit, offering an effective production system for bioactives and other high value ingredients. PMID- 26497597 TI - Comparison of patients in three different rehabilitation settings after knee or hip arthroplasty: a natural observational, prospective study. AB - BACKGROUND: Patients after primary hip or knee replacement surgery can benefit from postoperative treatment in terms of improvement of independence in ambulation, transfers, range of motion and muscle strength. After discharge from hospital, patients are referred to different treatment destination and modalities: intensive inpatient rehabilitation (IR), cure (medically prescribed stay at a convalescence center), or ambulatory treatment (AT) at home. The purpose of this study was to 1) measure functional health (primary outcome) and function relevant factors in patients with hip or knee arthroplasty and to compare them in relation to three postoperative management strategies: AT, Cure and IR and 2) compare the post-operative changes in patient's health status (between preoperative and the 6 month follow-up) for three rehabilitation settings. METHODS: Natural observational, prospective two-center study with follow-up. Sociodemographic data and functional mobility tests, Timed Up and Go (TUG) and Iowa Level of Assistance Scale (ILOAS) of 201 patients were analysed before arthroplasty and at the end of acute hospital stay (mean duration of stay: 9.7 days +/- 3.9). Changes in health state were measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) before and 6 months after arthroplasty. RESULTS: Compared to patients referred for IR and Cure, patients referred for AT were significantly younger and less comorbid. Patients admitted to IR had the highest functional disability before arthroplasty. Before rehabilitation, mean TUG was 40.0 s in the IR group, 33.9 s in the Cure group, and 27.5 s in the AT group, and corresponding mean ILOAS was 16.0, 13.0 and 12.2 (50.0 = worst). At the 6 months follow-up, the corresponding effect sizes of the WOMAC global score were 1.32, 1.87, and 1.51 (>0 means improvement). CONCLUSIONS: Age, comorbidity and functional disability are associated with referral for intensive inpatient rehabilitation after hip or knee arthroplasty and partly affect health changes after rehabilitation. PMID- 26497598 TI - Regional roadmaps for reducing premature deaths from NCDs. PMID- 26497599 TI - Regional contributions of six preventable risk factors to achieving the 25 * 25 non-communicable disease mortality reduction target: a modelling study. AB - BACKGROUND: Countries have agreed to reduce premature mortality from the four main non-communicable diseases (NCDs) by 25% from 2010 levels by 2025 (referred to as the 25 * 25 target). Countries also agreed on a set of global voluntary targets for selected NCD risk factors. Previous analyses have shown that achieving the risk factor targets can contribute substantially towards meeting the 25 * 25 mortality target at the global level. We estimated the contribution of achieving six of the globally agreed risk factor targets towards meeting the 25 * 25 mortality target by region. METHODS: We estimated the effect of achieving the targets for six risk factors (tobacco and alcohol use, salt intake, obesity, and raised blood pressure and glucose) on NCD mortality between 2010 and 2025. Our methods accounted for multicausality of NCDs and for the fact that, when risk factor exposure increases or decreases, the harmful or beneficial effects on NCDs accumulate gradually. We used data for risk factor and mortality trends from systematic analyses of available country data. Relative risks for the effects of individual and multiple risks, and for change in risk after decreases or increases in exposure, were from reanalyses and meta-analyses of epidemiological studies. FINDINGS: The probability of dying between the ages 30 years and 70 years from the four main NCDs in 2010 ranged from 19% in the region of the Americas to 29% in southeast Asia for men, and from 13% in Europe to 21% in southeast Asia for women. If current trends continue, the probability of dying prematurely from the four main NCDs is projected to increase in the African region but decrease in the other five regions. If the risk factor targets are achieved, the 25 * 25 target will be surpassed in Europe in both men and women, and will be achieved in women (and almost achieved in men) in the western Pacific; the regions of the Americas, the eastern Mediterranean, and southeast Asia will approach the target; and the rising trend in Africa will be reversed. In most regions, a more ambitious approach to tobacco control (50% reduction relative to 2010 instead of the agreed 30%) will contribute the most to reducing premature NCD mortality among men, followed by addressing raised blood pressure and the agreed tobacco target. For women, the highest contributing risk factor towards the premature NCD mortality target will be raised blood pressure in every region except Europe and the Americas, where the ambitious (but not agreed) tobacco reduction would have the largest benefit. INTERPRETATION: No WHO region will meet the 25 * 25 premature mortality target if current mortality trends continue. Achieving the agreed targets for the six risk factors will allow some regions to meet the 25 * 25 target and others to approach it. Meeting the 25 * 25 target in Africa needs other interventions, including those addressing infection related cancers and cardiovascular disease. FUNDING: UK Medical Research Council. PMID- 26497600 TI - SERPINB12 Is a Slow-Binding Inhibitor of Granzyme A and Hepsin. AB - The clade B/intracellular serpins protect cells from peptidase-mediated injury by forming covalent complexes with their targets. SERPINB12 is expressed in most tissues, especially at cellular interfaces with the external environment. This wide tissue distribution pattern is similar to that of granzyme A (GZMA). Because SERPINB12 inhibits trypsin-like serine peptidases, we determined whether it might also neutralize GZMA. SERPINB12 formed a covalent complex with GZMA and inhibited the enzyme with typical serpin slow-binding kinetics. SERPINB12 also inhibited Hepsin. SERPINB12 may function as an endogenous inhibitor of these peptidases. PMID- 26497601 TI - Mitochondrial COI/tRNASer(UCN) G7444A mutation may be associated with aminoglycoside-induced and non-syndromic hearing impairment. AB - Mutations in mitochondrial DNA (mtDNA) have been reported to have important roles in aminoglycoside-induced hearing impairment; however, the underlying molecular mechanisms have remained largely elusive. The current study presented a case of a Chinese patient with maternally inherited aminoglycoside-induced hearing impairment. A profound hearing impairment was identified by clinical evaluation; furthermore, analysis of the mitochondrial genome sequence of the patient revealed the presence of an A1555G mutation in the 12S rRNA as well as a G7444A mutation in the COI/tRNASer(UCN) gene. As the G7444A mutation is highly conserved between various species, it may be a modifying factor with regard to the pathological effects of the A1555G mutation. PMID- 26497602 TI - Evidence, illness, and causation: an epidemiological perspective on the Russo Williamson Thesis. AB - According to the Russo-Williamson Thesis, causal claims in the health sciences need to be supported by both difference-making and mechanistic evidence. In this article, we attempt to determine whether Evidence-based Medicine (EBM) can be improved through the consideration of mechanistic evidence. We discuss the practical composition and function of each RWT evidence type and propose that exposure-outcome evidence (previously known as difference-making evidence) provides associations that can be explained through a hypothesis of causation, while mechanistic evidence provides finer-grained associations and knowledge of entities that ultimately explains a causal hypothesis. We suggest that mechanistic evidence holds untapped potential to add value to the assessment of evidence quality in EBM and propose initial recommendations for the integration of mechanistic and exposure-outcome evidence to improve EBM by robustly leveraging available evidence in support of good medical decisions. PMID- 26497603 TI - The regularity theory of mechanistic constitution and a methodology for constitutive inference. AB - This paper discusses a Boolean method for establishing constitutive regularity statements which, according to the regularity theory of mechanistic constitution, form the core of any mechanistic explanation in neuroscience. After presenting the regularity definition for the constitution relation, the paper develops a set of inference rules allowing one to establish constitutive hypotheses in light of certain kinds of empirical evidence. The general methodology consisting of these rules is characterized as having formed the basis of many successful explanatory projects in neuroscience. PMID- 26497604 TI - A specific immunoassay for proAMH, the uncleaved proprotein precursor of anti Mullerian hormone. AB - The utility of serum anti-Mullerian hormone (AMH) assays in assessment of female fertility have been investigated extensively but little is known about the biological activity of the hormone being studied. ProAMH is the proprotein precursor and is incapable of binding to the AMH-specific type II receptor. Proteolytic cleavage generates receptor-competent AMHN,C which is a non-covalent complex of the N- and C-terminal cleavage fragments. Commercially available AMH assays do not differentiate the two forms of AMH. Techniques were developed to dissociate the AMHN,C complex and abolish its two-site immunoassay immunoreactivity. This allowed specific quantification of proAMH. The surfactant sodium deoxycholate (DOC) dissociated AMHN,C without disrupting binding of proAMH to the capture-antibody with an optimal concentration of 0.1-0.2%w/v. The incorporation of a DOC incubation step into the AMH Gen II ELISA detected proAMH, with AMHN,C cross-detection conservatively estimated at 6.0% +/- 2.5% (mean +/- S.D.). The intra-assay and inter-assay variability were estimated at 8.0%CV and 13.0%CV respectively. The levels of proAMH and total AMH were assessed in 5 boys and 5 men and the proportion of proAMH was found to be significantly higher in boys (p = 0.005). This study will facilitate further investigation of the role of proteolytic cleavage in AMH signalling. PMID- 26497605 TI - Reproducibility of ambulatory blood pressure values and circadian blood pressure patterns in untreated subjects in a 1-11 month interval. AB - OBJECTIVE: To evaluate in untreated subjects the reproducibility of mean values and four circadian patterns between two ambulatory blood pressure monitoring (ABPM) recordings separated by 1-11 months. METHODS: We performed a retrospective analysis of 481 individuals (59% women) evaluated by ABPM on two occasions, visit 1 (V1) and 2 (V2), separated by 5.5+0.2 months. Four circadian patterns were defined by night/day systolic blood pressure (SBP) ratios: reverse dippers (RD), ratio >1.0; non-dippers (ND), ratio 0.9-1.0; dippers (D), ratio 0.8-<0.9; and extreme dippers (ED), ratio <0.8. Coefficients of correlation and concordance between the ABPM values at V1 and V2 and the reproducibility of the RD, ND, D and ED patterns were calculated by the percentage of the same profile from V1 to V2. RESULTS: Mean 24-h blood pressure (BP) at V1 and V2 was 126.8/75.9+/-0.5/0.5 vs. 126.5/75.7+/-0.5/0.4 mmHg (NS). Nighttime SBP fall was 9.8+/-0.4 (V1) and 9.6+/ 0.3% (V2) (NS). The correlation coefficient of ABPM data at V1 vs. at V2 was 0.41 0.69 (p<0.001) and the concordance coefficient was 0.34-0.57 (p<0.01). At V1, 38 subjects were classified as ED (7.9%); D, n=216 (44.9%), 187 as ND (38.9%) and 40 as RD (8.3%). At V2 only 26.3% of ED, 44.9% of D, 54.5% of ND and 40% of RD maintained the same profile as at V1. CONCLUSION: In untreated subjects ABPM has high reproducibility for mean values but only modest reproducibility for circadian profiles, thereby challenging the prognostic value of BP dipping patterns. PMID- 26497606 TI - Cardiogenic shock induced by Takotsubo cardiomyopathy: A new therapeutic option. AB - Takotsubo cardiomyopathy (TC) is characterized by the sudden onset of reversible left ventricular dysfunction, with a presentation similar to that of an acute coronary syndrome. Although cardiogenic shock is a rare occurrence in TC, if it does occur it may require the use of a left ventricular assist device. We report the use of extracorporeal life support (ECLS) in a patient with TC and refractory cardiogenic shock. With ECLS it was possible to reduce inotropic support, and a normal left ventricular ejection fraction was documented by echocardiography on day 2. This is, to our knowledge, the first reported case of TC with refractory cardiogenic shock treated with ECLS in Portugal. PMID- 26497607 TI - Do persons with asymmetric hip pain or radiographic hip OA have worse pain and structure outcomes in the knee opposite the more affected hip? Data from the Osteoarthritis Initiative. AB - PURPOSE: To determine if asymmetry between hips in pain or radiographic osteoarthritis (RHOA) is associated with worse pain and joint space narrowing (JSN) at baseline and longitudinally in knees contralateral to more affected hips. METHODS: We studied 279 participants in the Osteoarthritis Initiative with baseline asymmetry between hips in pain and 483 with asymmetry in RHOA none of whom had a hip replacement for >=4 years after baseline. RHOA assessed from pelvis radiographs was categorized as none, possible or definite and hip pain on most days of a month in the past year as present/absent. Knee pain (WOMAC scale) and JSN (fixed flexion radiographs) were categorized as none, mild and moderate severe. We compared knees contralateral and ipsilateral to more affected hips on baseline knee pain and JSN using clustered multinomial regression and on change in knee pain and JSN over 4-5 years using generalized linear and logistic estimating equations. RESULTS: Knees contralateral to painful hips had less baseline pain ("moderate-severe" vs "none", relative risk ratio [RRR]: 0.39, 95% CI = 0.27-0.57), but greater baseline JSN ("moderate-severe" vs "none", RRR: 1.62, 95% CI = 1.09-2.38) and greater worsening of pain during follow-up (P = 0.001). Knees contralateral to hips with worse RHOA had nonsignificant trends for greater baseline JSN (P = 0.10) and JSN progression (P = 0.17). CONCLUSION: These findings provide limited support for the hypothesis that early asymmetry in hip pain and RHOA is associated with worse pain and structural outcomes in knees contralateral to the more affected hip. PMID- 26497608 TI - Detecting new microRNAs in human osteoarthritic chondrocytes identifies miR-3085 as a human, chondrocyte-selective, microRNA. AB - OBJECTIVE: To use deep sequencing to identify novel microRNAs (miRNAs) in human osteoarthritic cartilage which have a functional role in chondrocyte phenotype or function. DESIGN: A small RNA library was prepared from human osteoarthritic primary chondrocytes using in-house adaptors and analysed by Illumina sequencing. Novel candidate miRNAs were validated by northern blot and qRT-PCR. Expression was measured in cartilage models. Targets of novel candidates were identified by microarray and computational analysis, validated using 3'-UTR-luciferase reporter plasmids. Protein levels were assessed by western blot and functional analysis by cell adhesion. RESULTS: We identified 990 known miRNAs and 1621 potential novel miRNAs in human osteoarthritic chondrocytes, 60 of the latter were expressed in all samples assayed. MicroRNA-140-3p was the most highly expressed microRNA in osteoarthritic cartilage. Sixteen novel candidate miRNAs were analysed further, of which six remained after northern blot analysis. Three novel miRNAs were regulated across models of chondrogenesis, chondrocyte differentiation or cartilage injury. One sequence (novel #11), annotated in rodents as microRNA-3085 3p, was preferentially expressed in cartilage, dependent on chondrocyte differentiation and, in man, is located in an intron of the cartilage-expressed gene CRTAC-1. This microRNA was shown to target the ITGA5 gene directly (which encodes integrin alpha5) and inhibited adhesion to fibronectin (dependent on alpha5beta1 integrin). CONCLUSION: Deep sequencing has uncovered many potential microRNA candidates expressed in human cartilage. At least three of these show potential functional interest in cartilage homeostasis and osteoarthritis (OA). Particularly, novel #11 (microRNA-3085-3p) which has been identified for the first time in man. PMID- 26497609 TI - Measures of hip morphology are related to development of worsening radiographic hip osteoarthritis over 6 to 13 year follow-up: the Johnston County Osteoarthritis Project. AB - OBJECTIVES: We sought to describe the effect of alterations in hip morphology with respect to worsening hip OA in a community-based sample including African American (AA) and white men and women. METHODS: This nested case-control study defined case hips as Kellgren Lawrence grade (KLG) <3 on baseline supine pelvis radiographs and KLG >=3 or THR for OA at the 1st or 2nd follow-up visit (mean 6 and 13 years, respectively); control hips had KLG <3 at both visits, with gender/race distribution similar to cases. Hip morphology was assessed using HipMorf software (Oxford, UK). Descriptive means and standard errors were obtained from generalized estimating equation (GEE) models. Sex-stratified GEE regression models (accounting for within-person correlation), adjusted for age, race, BMI, and side were then employed. RESULTS: A total of 120 individuals (239 hips; 71 case/168 control) were included (25% male, 26% AA, mean age 62 years, BMI 30 kg/m(2)). Case hips tended to have greater baseline AP alpha angles, smaller minimum joint space width (mJSW) and more frequent triangular index signs. Adjusted results among men revealed that higher AP alpha angle, Gosvig ratio, and acetabular index were positively associated with case hips; coxa profunda was negatively associated. Among women, greater AP alpha angle, smaller mJSW, protrusio acetabuli, and triangular index sign were associated with case hips. CONCLUSIONS: We confirmed an increased risk of worsening hip OA due to baseline features of cam deformity among men and women, as well as protrusio acetabuli among women, and provide the first estimates of these measures in AAs. PMID- 26497610 TI - Comparisons of Contraceptive Use between Rural and Urban Teens. AB - STUDY OBJECTIVE: The purpose of the study was to determine if barriers in rural areas might decrease an adolescent's likelihood of obtaining effective contraception. Previous studies have reported mixed results in comparisons of rural and urban contraception use. DESIGN: Electronic survey. SETTING: Midwestern Public University. PARTICIPANTS: Undergraduate and graduate women. INTERVENTIONS: Questionnaire. MAIN OUTCOME MEASURES: Participants retrospectively recalled their contraceptive use and barriers to contraceptive use between the 9th and 12th grades. RESULTS: A Barriers to Contraception Use Scale was created using exploratory factor analysis and yielded 31 questions with 1 underlying factor: barriers. Participants were identified as rural or urban using the Office of Management and Budget (OMB) definition and the participant's self-identification. Overall, rural participants endorsed more barriers to accessing contraceptives than urban participants using the OMB definition (chi(2) (2; n = 388) = 2.04; P < .05), and self-identification (chi(2) (2; n = 398) = 2.37; P < .05). However, no differences were found in contraception use according to the OMB definition, t (380) = -1.90; P = .06, or self-identification, t (380) = -2.11; P > .05. The Barriers to Contraception Use Scale total score predicted whether an individual would have a prescription for contraceptives 70.5% of the time compared to the base rate of 54.1%. CONCLUSION: Although no rural-urban differences in actual contraception use were found, rural participants reported more barriers to accessing contraception, and those who endorsed more barriers were less likely to obtain contraceptives while in high school. Pregnancy prevention programs should thus take these barriers into account when developing future interventions. PMID- 26497611 TI - [Associations of the work duration, sleep duration and number of holidays with an exaggerated blood pressure response during an exercise stress test among workers]. AB - AIM: It has been reported that an exaggerated systolic blood pressure (ESBP) response during exercise, even if resting blood pressure is normal, is associated with an increased risk of future hypertension and cardiovascular disease (CVD). This study was designed to investigate the relationships of work duration, sleep duration and number of holidays with blood pressure response during an exercise stress test among normotensive workers. SUBJECTS AND METHODS: The subjects were 362 normotensive workers (79 males and 283 females; age, 49.1 years). A multi stage graded submaximal exercise stress test was performed on each subject using an electric bicycle ergometer. The workload was increased every 3 minutes, and blood pressure was measured at rest and during the last 1 minute of each stage. In this study, an ESBP response during exercise was defined according to the criteria of the Framingham Study (peak systolic blood pressure >=210 mmHg in males, or >=190 mmHg in females). Working environments, work duration, sleep duration, number of holidays, and physical activity during commuting and work, and leisure time exercise duration were evaluated using a questionnaire. RESULTS: An ESBP response during exercise was observed in 94 (26.0%) workers. The adjusted odds ratio for the prevalence of an ESBP response during exercise was found to be significantly higher with an increase in work duration, decreases in sleep duration and number of holidays (p<0.05, respectively). Moreover, the highest work duration with lowest sleep duration and number of holidays groups had significantly higher adjusted odds ratio for the prevalence of an ESBP response during exercise than the lowest work duration with highest sleep duration and number of holidays groups (p<0.05, respectively). CONCLUSIONS: Based on our results, we consider that the assessment of blood pressure response during exercise and daily life are necessary to prevent the incidence of future hypertension, CVD and death due to overwork in workers with long-work duration, short sleep duration and small number of holidays. PMID- 26497613 TI - Should we treat heart failure with phosphatase inhibitors? Better to start at the end. PMID- 26497612 TI - A Highly Similar Mathematical Model for Cerebral Blood Flow Velocity in Geriatric Patients with Suspected Cerebrovascular Disease. AB - Cerebral blood flow velocity(CBFV) is an important parameter for study of cerebral hemodynamics. However, a simple and highly similar mathematical model has not yet been established for analyzing CBFV. To alleviate this issue, through TCD examination in 100 geriatric patients with suspected cerebrovascular disease (46 males and 54 females), we established a representative eighth-order Fourier function Vx(t) that simulates the CBFV. The measured TCD waveforms were compared to those derived from Vx(t), an illustrative Kolmogorov-Smirnov test was employed to determine the validity. The results showed that the TCD waves could been reconstructed for patients with different CBFVs by implementing their variable heart rates and the formulated maximum/minimum of Vx(t). Comparisons between derived and measured TCD waveforms suggest that the two waveforms are very similar. The results confirm that CBFV can be well-modeled through an eighth order Fourier function. This function Vx(t) can be used extensively for a prospective study of cerebral hemodynamics in geriatric patients with suspected cerebrovascular disease. PMID- 26497615 TI - Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance. AB - To elaborate the decisive role of surfactants in promotion of aceclofenac' skin absorption, potentially avoiding irritation, we developed non-ionic microemulsions varying natural or synthetic surfactants: sucrose esters (laurate or myristate) vs. polysorbate 80. A comprehensive physicochemical characterization indicated no significant influence of the solubilized nonsteroidal anti-inflammatory drug on the bicontinuous structure of blank formulations. To evaluate skin tolerability of isopropyl alcohol, a sucrose ester based microemulsion containing transcutol P as a cosurfactant was also developed. The measured skin parameters strongly depended on the (co)surfactant type, showing higher compatibility of the microemulsions containing sucrose ester and isopropyl alcohol. In vitro release results, in vivo tape stripping and pharmacokinetics in rats confirmed superiority of the sucrose ester- over polysorbate-based microemulsions (total amounts of aceclofenac penetrated 60.81+/ 5.97 and 60.86+/-3.67 vs. 27.00+/-5.09MUg/cm(2), and its maximum plasma concentrations 275.57+/-109.49 and 281.31+/-76.76 vs. 150.23+/-69.74ng/ml for sucrose laurate- and myristate- vs. polysorbate 80-based microemulsions, respectively). Hence, sugar-based excipients increased delivery of aceclofenac through stratum corneum by increasing its fluidity, showing overall more satisfying safety profiles. In conclusion, sucrose ester-based microemulsions proved to be promising carriers for dermal/transdermal aceclofenac delivery. PMID- 26497614 TI - A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes. AB - Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. However, the precise underlying mechanisms have not been fully delineated. Herein we report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy. In cultured CFs, Ang II treatment enhanced exosome release via the activation of Ang II receptor types 1 (AT1R) and 2 (AT2R), whereas lipopolysaccharide, insulin, endothelin (ET)-1, transforming growth factor beta (TGFbeta)1 or hydrogen peroxide did not. The CF-derived exosomes upregulated the expression of renin, angiotensinogen, AT1R, and AT2R, downregulated angiotensin-converting enzyme 2, and enhanced Ang II production in cultured cardiomyocytes. In addition, the CF exosome-induced cardiomyocyte hypertrophy was blocked by both AT1R and AT2R antagonists. Exosome inhibitors, GW4869 and dimethyl amiloride (DMA), inhibited CF-induced cardiomyocyte hypertrophy with little effect on Ang II-induced cardiomyocyte hypertrophy. Mechanistically, CF exosomes upregulated RAS in cardiomyocytes via the activation of mitogen-activated protein kinases (MAPKs) and Akt. Finally, Ang II-induced exosome release from cardiac fibroblasts and pathological cardiac hypertrophy were dramatically inhibited by GW4869 and DMA in mice. These findings demonstrate that Ang II stimulates CFs to release exosomes, which in turn increase Ang II production and its receptor expression in cardiomyocytes, thereby intensifying Ang II-induced pathological cardiac hypertrophy. Accordingly, specific targeting of Ang II-induced exosome release from CFs may serve as a novel therapeutic approach to treat cardiac pathological hypertrophy and heart failure. PMID- 26497616 TI - Two years' experience of implementing molecular screening of hepatitis B virus, hepatitis C virus and human immunodeficiency virus 1, 2 in Riyadh blood donors. AB - Molecular screening technologies have improved blood safety by reducing the number of window-period transmissions relative to serological screening. In the two years following the introduction of molecular testing in King Khalid University Hospital, Saudi Arabia, 25,920 donor samples were screened in parallel by both serological and molecular techniques for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). No HCV or HIV NAT yields were detected. However, molecular screening enabled the interdiction of two confirmed HBV NAT yields. This is only the second report of confirmed HBV NAT yield in the Kingdom of Saudi Arabia, and amongst the few reports in the wider Middle East and North Africa region. PMID- 26497617 TI - Malingering Imposed on Another: A Diagnosis That is Missing in Action? AB - BACKGROUND: Descriptions of malingering imposed on another, in which an individual induces or exaggerates symptoms in another for secondary gain (including financial benefit or access to medications), are remarkably scant in the current literature. We summarize reported cases of malingering imposed on another in order to underscore its relevance to practicing physicians. OBJECTIVE: We sought to review the available literature describing the creation or exaggeration of symptoms of illness, motivated by secondary gain, in another vulnerable individual. METHOD: A search of the literature using PubMed was undertaken searching the terms "malingering," "by proxy," and "imposed on another." RESULTS: Malingering imposed on another may be under-reported in the professional literature. Maintaining awareness that caregivers may misrepresent or embellish the symptoms of the identified patient for their own gain is an important consideration to forestall unnecessary testing, hospital admission, and exposure to adverse effects of treatments. PMID- 26497619 TI - Human Movement Science adopts Registered Reports for hypothesis-driven research. PMID- 26497620 TI - A simple optimization approach for improving target dose homogeneity in intensity modulated radiotherapy for sinonasal cancer. AB - Homogeneous target dose distribution in intensity-modulated radiotherapy (IMRT) for sinonasal cancer (SNC) is challenging to achieve. To solve this problem, we established and evaluated a basal-dose-compensation (BDC) optimization approach, in which the treatment plan is further optimized based on the initial plans. Generally acceptable initial IMRT plans for thirteen patients were created and further optimized individually by (1) the BDC approach and (2) a local-dose control (LDC) approach, in which the initial plan is further optimized by addressing hot and cold spots. We compared the plan qualities, total planning time and monitor units (MUs) among the initial, BDC, LDC IMRT plans and volumetric modulated arc therapy (VMAT) plans. The BDC approach provided significantly superior dose homogeneity/conformity by 23%-48%/6%-9% compared with both the initial and LDC IMRT plans, as well as reduced doses to the organs at risk (OARs) by up to 18%, with acceptable MU numbers. Compared with VMAT, BDC IMRT yielded superior homogeneity, inferior conformity and comparable overall OAR sparing. The planning of BDC, LDC IMRT and VMAT required 30, 59 and 58 minutes on average, respectively. Our results indicated that the BDC optimization approach can achieve significantly better dose distributions with shorter planning time in the IMRT for SNC. PMID- 26497618 TI - Matrine inhibits the proliferation, invasion and migration of castration resistant prostate cancer cells through regulation of the NF-kappaB signaling pathway. AB - Matrine is a naturally occurring alkaloid extracted from the Chinese herb Sophora flavescens. It has been demonstrated to exhibit antiproliferative properties, promote apoptosis and inhibit cell invasion in a number of cancer cell lines. It has also been shown to improve the efficacy of chemotherapy when it is combined with other chemotherapy drugs. However, the therapeutic efficacy of matrine for prostate cancer remains poorly understood. In the present study, we showed that matrine inhibited the proliferation, migration and invasion of both DU145 and PC 3 cells in a dose- and time-dependent manner. It also reduced the cell population at S phase and increased the cell population at sub-G1 phase. The increases in both the apoptotic cell population and cell population at S and sub-G1 phases consistently indicated a pro-apoptotic effect of matrine. Decreases in levels of P65, p-P65, IKKalpha/beta, p-IKKalpha/beta, IKBalpha and p-IKBalpha as detected by immunoblot analysis in the matrine-treated DU145 and PC-3 cells suggested an involvement of the NF-kappaB signaling pathway. Therefore, it is a novel promising addition to the current arsenal of chemotherapy drugs for the treatment of androgen-independent prostate cancer. PMID- 26497621 TI - Pathogen Resistance Mediated by IL-22 Signaling at the Epithelial-Microbiota Interface. AB - Intestinal colonization resistance to bacterial pathogens is generally associated, among other factors, with mucosal homeostasis that preserves the integrity of the intestinal barrier. Mucosal homeostasis depends on physical and molecular interactions between three components: the resident microbiota, the epithelial layer and the local immune system. The cytokine IL-22 helps to orchestrate this three-way interaction. IL-22 is produced by immune cells present beneath the epithelium and is induced by bacteria present in the intestine. IL-22 stimulates the epithelial cells via the IL-22RA1-IL-10R2 receptor complex inducing changes in the expression of genes involved in the maintenance of epithelial barrier integrity, with a variety of functions in pathogen resistance such as mucus layer modifications and hydration, tight junction fortification and the production of a broad range of bactericidal compounds. These mechanisms of pathogen resistance, in turn, affect the microbiota composition and create an environment that excludes pathogens. Here we highlight the role of IL-22 as key mediator in the give-and-take relationship between the microbiota and the host that impacts pathogen resistance. PMID- 26497622 TI - Nature-Inspired Multifunctional Ligands: Focusing on Amyloid-Based Molecular Mechanisms of Alzheimer's Disease. AB - The amyloidogenic pathway is a prominent feature of Alzheimer's disease (AD). However, growing evidence suggests that a linear disease model based on beta amyloid peptide (Abeta) alone is not likely to be realistic, which therefore calls for further investigations on the other actors involved in the play. The pro-oxidant environment induced by Abeta in AD pathology is well established, and a correlation among Abeta, oxidative stress, and conformational changes in p53 has been suggested. In this study, we applied a multifunctional approach to identify allyl thioesters of variously substituted trans-cinnamic acids for which the pharmacological profile was strategically tuned by hydroxy substituents on the aromatic moiety. Indeed, only catechol derivative 3 [(S)-allyl (E)-3-(3,4 dihydroxyphenyl)prop-2-enethioate] inhibited Abeta fibrilization. Conversely, albeit to different extents, all compounds were able to decrease the formation of reactive oxygen species in SH-SY5Y neuroblastoma cells and to prevent alterations in the conformation of p53 and its activity mediated by soluble sub-lethal concentrations of Abeta. This may support an involvement of oxidative stress in Abeta function, with p53 emerging as a potential mediator of their functional interplay. PMID- 26497623 TI - Impaired hippocampal activity at the goal zone on the place preference task in a DISC1 mouse model. AB - Learning deficit is a clinical feature of many mental disorders and is hypothesized to result from an inability to integrate information in neural systems. We showed that transgenic mice expressing a dominant-negative form of DISC1, a risk gene for neuropsychiatric disorders, exhibited impaired performance in a reward-place association task when combined with a mild isolation stress. CA1 cells in the mutant mice showed normal place cell properties, but their activity at the goal zone was diminished. This abnormality in hippocampal activity at the goal zone during the task may underlie the learning deficit observed in the DISC1 mutant mice. PMID- 26497625 TI - Controlled release of fibrin matrix-conjugated platelet derived growth factor improves ischemic tissue regeneration by functional angiogenesis. AB - Sustained, local, low dose growth factor stimulus of target tissues/cells is believed to be of imminent importance in tissue regeneration and engineering. Recently, a technology was developed to bind growth factors to a fibrin matrix using the transglutaminase (TG) activity of factor XIIIa, thus allowing prolonged release through enzymatic cleavage. In this study we aimed to determine whether TG-PDGF.AB in fibrin could improve tissue regeneration in a standard ischemic flap model. In vitro determination of binding and release kinetics of TG-PDGF.AB allowed proof of concept of the developed binding technology. A single spray application of TG-PDGF.AB in fibrin matrix at a concentration of 10 and 100ng/ml significantly reduced ischemia-induced flap tissue necrosis in vivo on day 7 after ischemic impact compared to controls. TG-PDGF.AB at a concentration of 100ng/ml fibrin induced distinct angiogenesis as reflected by significantly improved tissue perfusion assessed by laser Doppler imaging as well as enhanced von Willebrand factor (vWF) protein expression determined by immunohistochemical means. In addition, significantly more mature microvessels were observed with 100ng/ml TG-PDGF.AB in fibrin compared to control and vehicle groups as evidenced by an improved smooth muscle actin (sma)/vWF protein ratio. In conclusion, PDGF.AB in a conjugated fibrin matrix effectively reduced ischemia-induced tissue necrosis, increased tissue perfusion and induced the growth of a mature and functional neovasculature. The sealing properties of the fibrin matrix in conjunction with the prolonged growth factor stimulus enabled by the TG-hook binding technology may present an innovative and suitable tool in tissue regeneration. STATEMENT OF SIGNIFICANCE: In our experimental study we elucidated recombinant platelet derived growth factor (PDGF) as a potential candidate in inducing angiogenesis. To avoid preterm growth factor degradation in vivo PDGF.AB was covalently linked to a fibrin scaffold using a bi-domain functionalized peptide (FXIII substrate site and plasmin cleavage site). This allowed PDGF binding to fibrin during spray application to the donor site and subsequent prolonged release via endogenous plasmin. This resulted in a mature vascular network thus enhancing tissue perfusion and consequently improved clinical outcome. With our present work we could certainly provide researchers and clinicians with an innovative versatile and reproducible technology not only to induce functional vascularity but also to improve attempts in tissue engineering in general by e.g. using different growth factors. Hence, we believe that this approach studied in the present work may provide a valuable input in an effort to drive the aim forward bringing experimental work in tissue engineering to clinic by using a clinically well characterized and used fibrin scaffold in combination with a human recombinant growth factor (fibrin scaffold linked with the specific binding technology). PMID- 26497624 TI - Polymer microarray technology for stem cell engineering. AB - Stem cells hold remarkable promise for applications in tissue engineering and disease modeling. During the past decade, significant progress has been made in developing soluble factors (e.g., small molecules and growth factors) to direct stem cells into a desired phenotype. However, the current lack of suitable synthetic materials to regulate stem cell activity has limited the realization of the enormous potential of stem cells. This can be attributed to a large number of materials properties (e.g., chemical structures and physical properties of materials) that can affect stem cell fate. This makes it challenging to design biomaterials to direct stem cell behavior. To address this, polymer microarray technology has been developed to rapidly identify materials for a variety of stem cell applications. In this article, we summarize recent developments in polymer array technology and their applications in stem cell engineering. STATEMENT OF SIGNIFICANCE: Stem cells hold remarkable promise for applications in tissue engineering and disease modeling. In the last decade, significant progress has been made in developing chemically defined media to direct stem cells into a desired phenotype. However, the current lack of the suitable synthetic materials to regulate stem cell activities has been limiting the realization of the potential of stem cells. This can be attributed to the number of variables in material properties (e.g., chemical structures and physical properties) that can affect stem cells. Polymer microarray technology has shown to be a powerful tool to rapidly identify materials for a variety of stem cell applications. Here we summarize recent developments in polymer array technology and their applications in stem cell engineering. PMID- 26497626 TI - Resveratrol prevents alveolar bone loss in an experimental rat model of periodontitis. AB - Resveratrol is an antioxidant and anti-inflammatory polyphenol. Periodontitis is induced by oral pathogens, where a systemic inflammatory response accompanied by oxidative stress is the major event initiating disease. We investigated how resveratrol modulates cellular responses and the mechanisms related to this modulation in lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (hGFs). We also explored whether resveratrol protects rats against alveolar bone loss in an experimental periodontitis model. Periodontitis was induced around the first upper molar of the rats by applying ligature infused with LPS. Stimulating hGFs with 5MUg/ml LPS augmented the expression of cyclooxygenase-2, matrix metalloproteinase (MMP)-2, MMP-9, and Toll-like receptor-4. LPS treatment also stimulated the production of reactive oxygen species (ROS) and the phosphorylation of several protein kinases in the cells. However, the expression of heme oxygenase-1 (HO-1) and nuclear factor-E2 related factor 2 (Nrf2) was inhibited by the addition of LPS. Resveratrol treatment almost completely inhibited all of these changes in LPS-stimulated cells. Specifically, resveratrol alone augmented HO-1 induction via Nrf2-mediated signaling. Histological and micro-CT analyses revealed that administration of resveratrol (5mg/kg body weight) improved ligature/LPS-mediated alveolar bone loss in rats. Resveratrol also attenuated the production of inflammation-related proteins, the formation of osteoclasts, and the production of circulating ROS in periodontitis rats. Furthermore, resveratrol suppressed LPS-mediated decreases in HO-1 and Nrf2 levels in the inflamed periodontal tissues. Collectively, our findings suggest that resveratrol protects rats from periodontitic tissue damage by inhibiting inflammatory responses and by stimulating antioxidant defense systems. STATEMENT OF SIGNIFICANCE: The aims of this study were to investigate how resveratrol modulates cellular responses and the mechanisms related to this modulation in lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (hGFs) and protects rats against alveolar bone disruption in an experimental periodontitis model. Our findings suggest that resveratrol protects rats from periodontitic tissue damage by inhibiting inflammatory responses and by stimulating antioxidant defense systems. On the basis of our experiment studies, we proposed that resveratrol could be used as novel bioactive materials or therapeutic drug for the treatment of periodontitis or other inflammatory bone diseases like osteoporosis, arthritis etc. Furthermore, it could be also used for the modification or coating of implant materials as an antiinflammatory molecules which will help to accelerate bone formation. There are a few of reports suggesting antioxidant and anti-inflammatory potentials of resveratrol. However, our results highlight the cellular mechanisms by which resveratrol inhibits LPS mediated cellular damages using human-originated gingival fibroblasts and also support the potential of resveratrol to suppress periodontitis-mediated tissue damages. We believe that the present findings might improve a clinical approach of using of resveratrol on human, although further detailed experiments will be needed. PMID- 26497627 TI - Rational design of efficient modular cells. AB - The modular cell design principle is formulated to devise modular (chassis) cells. These cells can be assembled with exchangeable production modules in a plug-and-play fashion to build microbial cell factories for efficient combinatorial biosynthesis of novel molecules, requiring minimal iterative strain optimization steps. A modular cell is designed to be auxotrophic, containing core metabolic pathways that are necessary but insufficient to support cell growth and maintenance. To be functional, it must tightly couple with an exchangeable production module containing auxiliary metabolic pathways that not only complement cell growth but also enhance production of targeted molecules. We developed a MODCELL (modular cell) framework based on metabolic pathway analysis to implement the modular cell design principle. MODCELL identifies genetic modifications and requirements to construct modular cell candidates and their associated exchangeable production modules. By defining the degree of similarity and coupling metrics, MODCELL can evaluate which exchangeable production module(s) can be tightly coupled with a modular cell candidate. We first demonstrated how MODCELL works in a step-by-step manner for example metabolic networks, and then applied it to design modular Escherichia coli cells for efficient combinatorial biosynthesis of five alcohols (ethanol, propanol, isopropanol, butanol and isobutanol) and five butyrate esters (ethyl butyrate, propyl butyrate, isopropyl butyrate, butyl butyrate and isobutyl butyrate) from pentose sugars (arabinose and xylose) and hexose sugars (glucose, mannose, and galactose) under anaerobic conditions. We identified three modular cells, MODCELL1, MODCELL2 and MODCELL3, that can couple well with Group 1 of modules (ethanol, isobutanol, butanol, ethyl butyrate, isobutyl butyrate, butyl butyrate), Group 2 (isopropanol, isopropyl butyrate), and Group 3 (propanol, isopropanol), respectively. We validated the design of MODCELL1 for anaerobic production of ethanol, butanol, and ethyl butyrate using experimental data available in literature. PMID- 26497628 TI - Elucidating central metabolic redox obstacles hindering ethanol production in Clostridium thermocellum. AB - Clostridium thermocellum is an anaerobic, Gram-positive, thermophilic bacterium that has generated great interest due to its ability to ferment lignocellulosic biomass to ethanol. However, ethanol production is low due to the complex and poorly understood branched metabolism of C. thermocellum, and in some cases overflow metabolism as well. In this work, we developed a predictive stoichiometric metabolic model for C. thermocellum which incorporates the current state of understanding, with particular attention to cofactor specificity in the atypical glycolytic enzymes and the complex energy, redox, and fermentative pathways with the goal of aiding metabolic engineering efforts. We validated the model's capability to encompass experimentally observed phenotypes for the parent strain and derived mutants designed for significant perturbation of redox and energy pathways. Metabolic flux distributions revealed significant alterations in key metabolic branch points (e.g., phosphoenol pyruvate, pyruvate, acetyl-CoA, and cofactor nodes) in engineered strains for channeling electron and carbon fluxes for enhanced ethanol synthesis, with the best performing strain doubling ethanol yield and titer compared to the parent strain. In silico predictions of a redox-imbalanced genotype incapable of growth were confirmed in vivo, and a mutant strain was used as a platform to probe redox bottlenecks in the central metabolism that hinder efficient ethanol production. The results highlight the robustness of the redox metabolism of C. thermocellum and the necessity of streamlined electron flux from reduced ferredoxin to NAD(P)H for high ethanol production. The model was further used to design a metabolic engineering strategy to phenotypically constrain C. thermocellum to achieve high ethanol yields while requiring minimal genetic manipulations. The model can be applied to design C. thermocellum as a platform microbe for consolidated bioprocessing to produce ethanol and other reduced metabolites. PMID- 26497629 TI - Association between whole blood mercury and glucose intolerance among adult Inuit in Greenland. AB - OBJECTIVES: The Arctic diet is partly constituted by traditional food characterized by top predator animals such as whales, walrus, and seals with high mercury content. Mercury exposure has been associated with glucose intolerance in Western populations. We studied the association between whole blood mercury and glucose intolerance in a highly exposed non-Western population METHODS: Cross sectional study of 2640 Inuit (18+ years) with information on ancestry, smoking, waist circumference, total energy intake, and physical activity. Mercury, fasting and 2-h plasma glucose, insulin, and c-peptide were measured in blood. Fasting participants without diabetes were classified into normal glucose tolerance, impaired glucose tolerance, impaired fasting glycemia, or type 2 diabetes. We calculated hepatic insulin resistance with homoeostatic model assessment - insulin resistance index, peripheral insulin sensitivity by ISI0,120., and relative beta cell function by c-peptide/insulin ratio. We conducted adjusted linear- and logistic regression analyses. RESULTS: For an increase in whole blood mercury of 5 ug/L we found a positive association with fasting glucose [% change=0.25 (95% CI: 0.20; 0.30); p<0.001], and 2-h glucose [% change=0.23 (95% CI: 0.05; 0.40); p=0.01]. Mercury was weakly associated with impaired fasting glycemia [OR=1.03 (95% CI: 1.02; 1.05)], and type 2 diabetes [OR=1.02 (95% CI: 1.01; 1.04)]. CONCLUSION: While the study found a weak but statistically significant association between whole blood mercury and both impaired fasting glycemia and type 2 diabetes, no associations were found with measures of underlying disturbances in glucose homoeostasis. PMID- 26497630 TI - [Lung ultrasound as a tool to guide the administration of surfactant in premature neonates]. AB - OBJECTIVES: The aim of this study is to assess the usefulness of lung ultrasound (LUS) to estimate the endotracheal tube (ETT) depth position during the Intubation-Surfactant-Extubation (INSURE) procedure. MATERIAL AND METHODS: The ETT insertion depth was estimated using the weight (insertion depth (cm)=weight (kg)+5.5). After intubation two independent neonatologists using bilateral auscultation or LUS checked the ETT depth. RESULTS: Twelve newborns with respiratory distress syndrome were included. In two cases LUS helped to correctly replace the ETT. All the patients progressed well, with normal x-ray and LUS before discharge. CONCLUSIONS: LUS appears to be a safe and non-invasive technique and is useful in clinical situations were x-ray is not routinely performed, as it is fast and radiation free. PMID- 26497631 TI - [Congenital anomalies of the kidney and urinary tract. A vision for the paediatrician]. AB - The congenital abnormalities of kidney and urinary tract (CAKUT) are disorders with a high prevalence in the general population, with urinary tract dilations being the most frequent. CAKUT also account for the most important cause of chronic kidney disease in childhood. This paper focuses on the role of the primary care paediatrician in the diagnosis, assessment, and follow-up of children with CAKUT, with special emphasis on the associated urinary tract infections, the progression toward chronic renal failure, and the genetic basis. PMID- 26497632 TI - [Compartment syndrome in severe rhabdomyolysis]. PMID- 26497633 TI - [Acute intermittent porphyria in a paediatric population in the region of Murcia: Phenotype and prevalence]. PMID- 26497635 TI - PRC2 mediated H3K27 methylations in cellular identity and cancer. AB - The Polycomb Repressive Complex 2 (PRC2) is a multiprotein chromatin modifying complex that is essential for vertebrate development and differentiation. It is composed of a trimeric core of SUZ12, EED and EZH1/2 and is responsible for catalysing both di-methylation and tri-methylation of Histone H3 at lysine 27 (H3K27me2/3). Both H3K27 methylations contribute to the role of PRC2 in maintaining cellular identity. In all cell types, the H3K27me3 modification is associated with repression of genes encoding regulators of alternative lineages. The less well-characterised H3K27me2 modification is ubiquitous throughout the genome and is thought to act like a protective blanket to maintain the repression of non-H3K27me3 associated genes and cell-type-specific enhancers of alternative lineages. Recent cancer genome sequencing studies highlighted that several genes encoding PRC2 components as well as Histone H3 are mutated in multiple cancer types. Intriguingly, these cancers have changes in the global levels of the H3K27me2 and H3K27me3 modifications as well as genome-wide redistributions. Exciting new studies suggest that these changes confer context dependent blocks in cellular differentiation and increased vulnerability to aberrant cancer signalling pathways. PMID- 26497634 TI - The Peptide Oxytocin Antagonist F-792, When Given Systemically, Does Not Act Centrally in Lactating Rats. AB - Oxytocin secreted by nerve terminals in the posterior pituitary has important actions for ensuring a successful outcome of pregnancy: it stimulates uterine contractions that lead to birth and it is essential in the milk-ejection reflex, enabling milk to be expelled from the mammary glands into the mouths of suckling young. Oxytocin also has important actions in the brain: released from dendrites of neurones that innervate the posterior pituitary, oxytocin auto-excites the neurones to fire action potentials in co-ordinated bursts, causing secretion of pulses of oxytocin. Central oxytocin actions are blocked by an oxytocin antagonist given into the brain and, consequently, milk transfer stops. Systemic peptide oxytocin antagonist (atosiban) treatment is used clinically in management of pre-term labour, a major obstetric problem. Hence, it is important to know whether an oxytocin antagonist given peripherally can enter the brain and interfere with central oxytocin actions. In the present study, we tested F792, a peptide oxytocin antagonist. In urethane-anaesthetised suckled rats, we show that the mammary gland responsiveness to oxytocin is blocked by i.v. injections of 7 MUg/kg of F792, and the milk-ejection reflex is blocked when F792 is given directly into the brain at a dose of 0.2 MUg. To critically test whether F792 given systemically can enter the brain, we recorded the suckling- and oxytocin induced burst-firing of individual antidromically identified oxytocin neurones in the paraventricular nucleus. Given systemically at 100 MUg/kg i.v., F792 acted only peripherally, blocking the milk-ejecting actions of oxytocin, but not the burst-firing of oxytocin neurones during suckling (n = 5 neurones in five rats). Hence, this peptide oxytocin antagonist does not enter the brain from the circulation to interfere with an essential oxytocin function in the brain. Furthermore, the functions of oxytocin in the brain evidently cannot be explored with a systemic peptide antagonist. PMID- 26497636 TI - Incidence, etiology, and significance of acute kidney injury in the early post kidney transplant period. AB - Little is known about the incidence, causes, and significance of acute kidney injury (AKI) in the early transplant period. This study used a definition as >26 MUmol/L increase in creatinine within 48 h or >50% increase over a period >48 h. In 326 adult consecutive recipients of a solitary kidney transplant from 2006 to 2014 followed at this center, 21% developed AKI within the first six months. Most etiologies were CNI toxicity (33%) or unknown (26%), whereas acute rejection accounted for 17% and urinary tract obstruction for 10%. Those with AKI had a significantly lower glomerular filtration rate (GFR) at one-yr post-transplant (adjusted beta coefficient -5.5 mL/min/1.73 m(2) , 95% CI: -10.4, -0.7, p = 0.025) in a multivariable linear regression model. However, the AKI definition missed 6 of 19 episodes of acute rejection and 4 of 10 episodes of urinary tract obstruction. When acute rejection (including those that did not satisfy AKI criteria) was included in the model, other causes of AKI were not significantly associated with GFR at year 1. Although AKI, using current criteria, is likely to be a significant predictor of later outcomes, important causes are missed and the criteria are not sensitive for clinical decision-making. PMID- 26497637 TI - Regression models for expected length of stay. AB - In multi-state models, the expected length of stay (ELOS) in a state is not a straightforward object to relate to covariates, and the traditional approach has instead been to construct regression models for the transition intensities and calculate ELOS from these. The disadvantage of this approach is that the effect of covariates on the intensities is not easily translated into the effect on ELOS, and it typically relies on the Markov assumption. We propose to use pseudo observations to construct regression models for ELOS, thereby allowing a direct interpretation of covariate effects while at the same time avoiding the Markov assumption. For this approach, all we need is a non-parametric consistent estimator for ELOS. For every subject (and for every state of interest), a pseudo observation is constructed, and they are then used as outcome variables in the regression model. We furthermore show how to construct longitudinal (pseudo-) data when combining the concept of pseudo-observations with landmarking. In doing so, covariates are allowed to be time-varying, and we can investigate potential time-varying effects of the covariates. The models can be fitted using generalized estimating equations, and dependence between observations on the same subject is handled by applying the sandwich estimator. The method is illustrated using data from the US Health and Retirement Study where the impact of socio economic factors on ELOS in health and disability is explored. Finally, we investigate the performance of our approach under different degrees of left truncation, non-Markovianity, and right-censoring by means of simulation. PMID- 26497638 TI - Improving your genetic literacy in epilepsy-A new series. AB - Advances in epilepsy genetics have been rapid, and it is challenging for clinicians on the ground to keep pace with these advances. The International League Against Epilepsy (ILAE) Genetics Commission has thus crafted a new Genetic Literacy series targeted at busy clinicians. Our goal is to help provide a concise, accessible resource on epilepsy genetics for the busy, on-the-ground clinician so that he/she can apply that knowledge at point-of-care to help patients. This new series is grounded in educational theories and evidence to ensure that learning is effective and efficient. We hope that by promoting and encouraging continuing medical education in epilepsy genetics, this eventually translates to better patient management and therefore better patient health outcomes. PMID- 26497639 TI - The Brazilian 'Cracolandia' open drug scene and the challenge of implementing a comprehensive and effective drug policy. PMID- 26497640 TI - Open tubular-capillary electrochromatography: Developments and applications from 2013 to 2015. AB - Open tubular CEC (OT-CEC) separates analyte mixtures by a combination of electrophoretic, electro-osmotic, and/or chromatographic effects. OT-CEC research is an active and growing field, with studies encompassing a wide range of investigations related to new strategies for chemical modification of the inner surface of the capillary, leading to the introduction of novel stationary phase coatings. This review has examined the literature on OT-CEC from 2013 to August 2015 and highlights the developments in the fabrication of highly selective stationary phases, based on materials that include cyclodextrin chiral selectors, graphene and graphene oxide, metal-organic frameworks, molecularly imprinted polymers, nanoparticles, nanolatex particles, nanocomposites, in situ generated polymers, block polymers, tentacle-type polymers, polyelectrolyte multilayers, polysaccharides, phospholipids, and proteins. This review, while considering the development of novel OT-CEC coating materials, specifically examines different immobilization or coating methodologies and approaches and also discusses the separation mechanisms that occur with these new materials. These OT-CEC coatings are intended mainly to separate low molecular weight molecules relevant to the pharmaceutical, agricultural, and food industries as well as for use in environmental monitoring. PMID- 26497641 TI - Vascularized proximal fibula epiphyseal transfer for distal radius reconstruction in children: A systematic review. AB - PURPOSE: Reconstruction of the distal radius in children is cumbersome, requiring simultaneous restoration of joint function and axial growth. Vascularized proximal fibular epiphyseal transfers (VFET) have been popularized over non vascularized transfers and prosthesis. This systematic review aims to evaluate the effectiveness of VFET and its associated complications. METHODS: Electronic database of PubMed MEDLINE was searched between 1970 and 2014. Studies reporting VFET for distal radius reconstruction in children (<15 years old) with clear reporting of technique (vascular pedicle) and objective outcome measures were included. Outcomes of interest were rate of graft growth, bone union and complications. A one-way Analysis of Variance (ANOVA) test was used to compare growth rates between pedicle types. RESULTS: Fourteen studies met the inclusion criteria, representing 25 patients. Pedicles used were anterior tibial (44%), peroneal (16%), or bi-pedicled (40%) anastomosed in antegrade (64%) or reverse flow (36%) fashion. Among all pedicle types, best results were achieved using anterior tibial artery with reversed flow, yielding average growth rate of 0.83 cm/year (P = 0.01). Recipient complications included four premature epiphyseal plate closures, a flap loss, and six wrist radial deviations. Donor complications included six common peroneal nerve palsies (five temporary, a permanent), and a talocalcaneal instability. Overall complication rates between pedicle types were comparable (P = 0.062). CONCLUSION: VFET may be a surgical option capable of restoring joint function and axial growth potential in select patients. The reverse flow technique based on the anterior tibial artery may result in superior outcomes. However, the overall complication rate is high and permanent peroneal nerve palsy may result. LEVEL OF EVIDENCE: IV (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:705-711, 2016. PMID- 26497642 TI - Narrow, Intermediate, and Wide Complex Tachycardia: What Is the Mechanism? PMID- 26497643 TI - Histological and Histomorphometrical Evaluation of Postextractive Sites Grafted with Mg-Enriched Nano-Hydroxyapatite: A Randomized Controlled Trial Comparing 4 Versus 12 Months of Healing. AB - BACKGROUND: Tooth extraction generally results in an alveolar bone loss and structural changes in the overlying soft tissue. The amount of this relocation might jeopardize prosthetically driven implant placement. Thus, there is a high interest in techniques, materials and timing to minimizing tissue resorption, using postextraction ridge preservation procedures. PURPOSE: To assess by histological techniques, the outcomes of a socket preservation technique at 4 or 12 months after treatment with a magnesium-enriched hydroxyapatite (Mg-e HA). MATERIALS AND METHODS: Postextraction site in 20 patients underwent ridge preservation procedure. Mg-e HA granules were mixed with blood and grafted into the socket. A bone specimen was collected from each site before implant placement after 4 or 12 months randomly. Each biopsy was processed for undecalcified histological analysis. All ground sections were observed under light and polarized microscope. A semi-quantitative analysis by mean of stereological method was performed to evaluate the average volume fractions of bone, biomaterial and medullary spaces, and the percentage of blood vessels for both timepoints. Nonparametric Mann-Whitney U test for unpaired data was used to detect eventual statistical differences between groups. RESULTS: Histologically, the biomaterial appeared surrounded by newly formed bone in both groups without inflammatory infiltrate. At 4 months, the remodeling process of collagen matrix was starting from the apical portion toward coronal direction and was more active around grafted particles. At 12 months, the alveolar socket was completely regenerated and filled with mineralized and well-organized bone tissue around the residual biomaterial particles. In both groups, vessels were present to supply tissues around the graft (at 4 months: 4.95% +/- 2.49; at 12 months: 7.45% +/- 2.57). Tissue fractions at 4 versus 12 months were respectively: 31.85% +/- 6.99 versus 41.32% +/- 9.37 for bone (p = .021), 40.82% +/- 6.71 versus 26.28% +/- 11.49 for residual Mg-e HA (p = .009), and 27.33% +/- 7.72 versus 32.40% +/- 9.87 for medullary spaces. CONCLUSION: Data from the present study show that Mg-e HA allows the complete healing of the tissue. Additionally, graft material demonstrated to undergo significant resorption during the experimental time frame. PMID- 26497644 TI - Synthesis and mass spectrometry analysis of quaternary cryptando-peptidic conjugates. AB - The bicyclic amines in the form of cryptands, the crown ether analogs, were used in the synthesis of cryptando-peptidic conjugates with simultaneous formation of quaternary ammonium nitrogen moiety. A series of model cryptando-peptidic conjugates at the peptide N-terminus was efficiently prepared by the standard Fmoc solid phase synthesis. Tandem mass spectrometric analysis of the obtained conjugates has shown the specific fragmentation pattern during MS/MS experiment. The obtained cryptandic quaternary ammonium group undergoes the Hofmann elimination during collision-induced dissociation fragmentation followed by the ethoxyl group elimination. The presented quaternization of cryptands by iodoacetylated peptides is relatively easy and compatible with standard solid phase peptide synthesis. Additionally, the applicability of such peptide derivatives and their isotopologues selectively deuterated at the alpha-carbon in the quantitative LC-MS analysis was analyzed. PMID- 26497646 TI - DNA Hypomethylation, Ambient Particulate Matter, and Increased Blood Pressure: Findings From Controlled Human Exposure Experiments. PMID- 26497645 TI - Co-circulation of a novel phlebovirus and Massilia virus in sandflies, Portugal. AB - BACKGROUND: In Portugal, entomological surveys to detect phleboviruses in their natural vectors have not been performed so far. Thus, the aims of the present study were to detect, isolate and characterize phleboviruses in sandfly populations of Portugal. FINDINGS: From May to October 2007-2008, 896 female sandflies were trapped in Arrabida region, located on the southwest coast of Portugal. Phlebovirus RNA was detected by using a pan-phlebovirus RT-PCR in 4 out of 34 Phlebotomus perniciosus pools. Direct sequencing of the amplicons showed that 2 samples exhibited 72 % nucleotide identity with Arbia virus, and two showed 96 % nucleotide identity with Massilia virus. The Arbia-like virus (named Alcube virus) was isolated in cell culture and complete genomic sequences of one Alcube and two Massila viruses were determined using next-generation sequencing technology. Phylogenetic analysis demonstrated that Alcube virus clustered with members of the Salehabad virus species complex. Within this clade, Alcube virus forms a monophyletic lineage with the Arbia, Salehabad and Adana viruses sharing a common ancestor. Arbia virus has been identified as the most closely related virus with 20-28 % nucleotide and 10-27 % amino acid divergences depending on the analysed segment. CONCLUSIONS: We have provided genetic evidence for the circulation of a novel phlebovirus species named Alcube virus in Ph. perniciosus and co-circulation of Massilia virus, in Arrabida region, southwest of Portugal. Further epidemiological investigations and surveillance for sandfly-borne phleboviruses in Portugal are needed to elucidate their medical importance. PMID- 26497649 TI - Clinical Variables Associated with Hydration Status in Acute Ischemic Stroke Patients with Dysphagia. AB - Acute stroke patients with dysphagia are at increased risk for poor hydration. Dysphagia management practices may directly impact hydration status. This study examined clinical factors that might impact hydration status in acute ischemic stroke patients with dysphagia. A retrospective chart review was completed on 67 ischemic stroke patients who participated in a prior study of nutrition and hydration status during acute care. Prior results indicated that patients with dysphagia demonstrated elevated BUN/Cr compared to non-dysphagia cases during acute care and that BUN/Cr increased selectively in dysphagic patients. This chart review evaluated clinical variables potentially impacting hydration status: diuretics, parenteral fluids, tube feeding, oral diet, and nonoral (NPO) status. Exposure to any variable and number of days of exposure to each variable were examined. Dysphagia cases demonstrated significantly more NPO days, tube fed days, and parenteral fluid days, but not oral fed days, or days on diuretics. BUN/Cr values at discharge were not associated with NPO days, parenteral fluid days, oral fed days, or days on diuretics. Patients on modified solid diets had significantly higher mean BUN/Cr values at discharge (27.12 vs. 17.23) as did tube fed patients (28.94 vs. 18.66). No difference was noted between these subgroups at baseline (regular diet vs. modified solids diets). Any modification of solid diets (31.11 vs. 17.23) or thickened liquids (28.50 vs. 17.81) resulted in significantly elevated BUN/Cr values at discharge. Liquid or diet modifications prescribed for acute stroke patients with dysphagia may impair hydration status in these patients. PMID- 26497650 TI - Comparison of Two Methods for Inducing Reflex Cough in Patients With Parkinson's Disease, With and Without Dysphagia. AB - Aspiration pneumonia is a common cause of death in people with Parkinson's disease (PD). Dysfunctional swallowing occurs in the majority of people with PD, and research has shown that cough function is also impaired. Previous studies suggest that testing reflex cough by having participants inhale a cough-inducing stimulus through a nebulizer may be a reliable indicator of swallowing dysfunction, or dysphagia. The primary goal of this study was to determine the cough response to two different cough-inducing stimuli in people with and without PD. The second goal of this study was to compare the cough response to the two different stimuli in people with PD, with and without swallowing dysfunction. Seventy adults (49 healthy and 21 with PD) participated in the study. Aerosolized water (fog) and 200 MUM capsaicin were used to induce cough. Each substance was placed in a small, hand-held nebulizer, and presented to the participant. Each cough stimulus was presented three times. The total number of coughs produced to each stimulus trial was recorded. All participants coughed more to capsaicin versus fog (p < 0.001). A categorical 'responder' and 'non-responder' variable for the fog stimulus, defined as whether or not the participant coughed at least two times to two of three presentations of the stimulus, yields sensitivity of 77.8 % and a specificity of 90.9 % for identifying PD participants with and without dysphagia. The data show a differential response of the PD participants to the capsaicin versus fog stimuli. Clinically, this finding may allow for earlier identification of people with PD who are in need of a swallowing evaluation. As well, there are implications for the neural control of cough in this patient population. PMID- 26497651 TI - What we know: the inflammatory basis of hepatic encephalopathy. AB - Central Nervous System (CNS) degeneration appearing in patients with cirrhosis is responsible for cognitive and persistent motor impairments that lead to an important impact on life quality. Brain injury affects certain areas of the CNS that might affect two types of cells: neurons and astrocytes. The process leading to brain injury could be induced by portosystemic shunting accompanied by hyperammonemia and by the activation of peripheral inflammation, manifested as episodic encephalopathy. Hyperammonemia combined with a decrease on the BCA/AAA ratio induces alterations of energetic metabolism and the formation of free radicals in the CNS. This process would be stimulated by the activation of peripheral inflammatory mediators that could act on receptors of the blood brain barrier such as TLR4, activating inflammatory responses in the CNS. As a result, a persistent activation of microglia and an irreversible neuronal and astrocytic injury would be induced. A new knowledge of the mechanisms leading to brain injury in cirrhosis would develop protective strategies to correct changes of nitrogen metabolism and inflammation. PMID- 26497652 TI - HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer. AB - BACKGROUND: Understanding carboplatin resistance in ovarian cancer is critical for the improvement of patients' lives. Multipotent mesenchymal stem cells or an aggravated epithelial to mesenchymal transition phenotype of a cancer are integrally involved in pathways conferring chemo-resistance. Long non-coding RNA HOTAIR (HOX transcript antisense intergenic RNA) is involved in mesenchymal stem cell fate and cancer biology. METHODS: We analyzed HOTAIR expression and associated surrogate DNA methylation (DNAme) in 134 primary ovarian cancer cases (63 received carboplatin, 55 received cisplatin and 16 no chemotherapy). We validated our findings by HOTAIR expression and DNAme analysis in a multicentre setting of five additional sets, encompassing 946 ovarian cancers. Chemo sensitivity has been assessed in cell culture experiments. RESULTS: HOTAIR expression was significantly associated with poor survival in carboplatin-treated patients with adjusted hazard ratios for death of 3.64 (95 % confidence interval [CI] 1.78-7.42; P < 0.001) in the discovery and 1.63 (95 % CI 1.04-2.56; P = 0.032) in the validation set. This effect was not seen in patients who did not receive carboplatin (0.97 [95 % CI 0.52-1.80; P = 0.932]). HOTAIR expression or its surrogate DNAme signature predicted poor outcome in all additional sets of carboplatin-treated ovarian cancer patients while HOTAIR expressors responded preferentially to cisplatin (multivariate interaction P = 0.008). CONCLUSIONS: Non-coding RNA HOTAIR or its more stable DNAme surrogate may indicate the presence of a subset of cells which confer resistance to carboplatin and can serve as (1) a marker to personalise treatment and (2) a novel target to overcome carboplatin resistance. PMID- 26497653 TI - Improved intraocular bioavailability of ganciclovir by mucoadhesive polymer based ocular microspheres: development and simulation process in Wistar rats. AB - BACKGROUND: The poor ocular bioavailability of the conventional eye drops is due to lack of corneal permeability, nasolacrimal drainage and metabolic degradation. To overcome this issue, drug encapsulated in mucoadhesive polymer based ocular microspheres have the advantages of improved drug stability, easy administration in liquid form, diffuse rapidly and better ocular tissue internalization. METHODS: The ganciclovir chitosan microspheres (GCM) were prepared by modified water-in-oil emulsification method. The formulation was optimized and characterized by investigating in vitro release study, release kinetics, XRD and microspheres stability. Ocular irritancy, in vivo ocular pharmacokinetic parameters and histopathology study was evaluated in Wistar rats. The use of pharmacokinetic/pharmacodynamic indices and simulation process was carried out to further ensure clinical applicability of the formulation. RESULTS: The in vitro release study showed initial burst (nearly 50 %) in first few minutes and followed Fickian (R(2) = 0.9234, n-value = 0.2329) type of diffusion release mechanism. The XRD and stability studies showed favorable results. The Wistar rat eyes treated with GCM showed significant increase in ganciclovir AUC (~4.99-fold) and Cmax (2.69-fold) in aqueous humor compared to ganciclovir solution and delay in Tmax. The Cmax/MIC90, AUC0-24/MIC90, AUC above MIC90 and T above MIC90 were significantly higher in GCM group. The aqueous humor concentration-time profile of ganciclovir in GCM and ganciclovir solution was simulated with every 28.1 and 12.8 h, respectively. The simulated concentration-time profile shows that in duration of 75 h, the ganciclovir solution require six ocular instillations compared to three ocular instillations of the GCM formulation. The photomicrograph of GCM and ganciclovir solution treated rat retina showed normal organization and cytoarchitecture. CONCLUSIONS: Correlating with in vitro data, the formulation showed sustained drug release along with improved intraocular bioavailability of ganciclovir in Wistar rats. PMID- 26497655 TI - Recurrent multiple CNS hemangioblastomas with VHL disease treated with pazopanib: a case report and literature review. AB - Hemangioblastoma is a rare benign neoplasm, accounting for less than 2% of all primitive brain tumors. It may arise sporadically in a solitary form, or associated with Von Hippel-Lindau (VHL) disease with multiple tumors. Surgery is the mainstay treatment, but management is challenging in case of recurrent and/or multiple tumors. VHL protein is defective in both forms of hemangioblastoma, leading to the accumulation of hypoxia-inducible factor, stimulating angiogenesis via VEGF and PDGF mainly. Here, we report a 37-year-old woman's case with recurrent and rapidly progressive VHL-associated hemangioblastomas, causing severe disability. She was treated 24 months with pazopanib, a multityrosine kinase inhibitor (TKI) targeting VEGF and PDGF-beta pathways. Despite moderate radiological changes, progressive improvement in her clinical condition persisting over 3 years was observed. Inhibiting angiogenesis is a therapeutic option that may improve the quality of life and the autonomy of VHL patients disabled with multiple hemangioblastomas. PMID- 26497656 TI - [Prehospital analgesia by paramedics in Rhineland-Palatinate : Feasability, analgesic effectiveness and safety of intravenous paracetamol]. AB - BACKGROUND: In contrast to the widespread practice in life-threatening emergencies, delegation of medical pain therapy to paramedics by the medical director of Emergency Medical Services, EMS, are still the exception in Germany. This is due to the fact that in non-life-threatening situations, the expected benefit and potential side effects of drug therapy have to be carefully weighed. In addition, in Germany federal law generally restricts the administration of opiates to physicians. METHODS: In 2011 the medical directors of EMS in the German state of Rhineland- Palatinate (4 million inhabitants) developed and implemented a standard operating procedure (SOP) for paramedics related to the prehospital parenteral administration of paracetamol for patients with isolated limb trauma. After a 2 h training session and examination, paramedics were authorized to administer 1 g of paracetamol to patients with a pain score > 5 points on an 11-point numerical rating scale (NRS). For purposes of quality management, every administration of paracetamol had to be prospectively documented on a specific electronic mission form. RESULTS: A total of 416 mission forms could be analyzed. After administration of paracetamol the median NRS score decreased from 8 points (interquartile range: 6; 8) to 4 points (interquartile range: 3; 7). In 51.2 % of the patients the pain intensity was reduced by at least 3 NRS points and in 50.5 % of the patients the NRS was less than 5 points after treatment. The extent of pain reduction was positively correlated with the initial NRS value (r = 0.31, p < 0.0001). No serious side effects were noted. The percentage of patients with an initial heart rate > 100/min declined from 14.6 % to 5.2 % after the administration of paracetamol (p < 0.0001), 18.7 % of the patients received paracetamol for trauma not related to the extremities and 7 % of the patients for nontraumatic pain. An emergency physician was involved in 50 % of the EMS missions and 98.6 % of the patients were transported to a hospital for further diagnostics and treatment. CONCLUSION: The prehospital intravenous administration of paracetamol by paramedics to patients with limb trauma is simple, safe and in 50 % of the patients effective in achieving a NRS value < 5; however, further improvements in prehospital pain therapy initiated by paramedics are desirable, especially in patients with an initial NRS value > 7. PMID- 26497654 TI - Capecitabine and oxaliplatin combined with bevacizumab are feasible for treating selected Japanese patients at least 75 years of age with metastatic colorectal cancer. AB - BACKGROUND: Although number of elderly patients with metastatic colorectal cancer (mCRC) is rapidly increasing, this population is often underrepresented in clinical trials. Recently, a phase II trial demonstrated that capecitabine and oxaliplatin (XELOX) combined with bevacizumab XELOX plus bevacizumab was effective and well tolerated by elderly patients with mCRC who reside in Western countries. The aim of this study was to evaluate the safety and efficacy of XELOX plus bevacizumab for Japanese patients aged >= 75 years with mCRC. METHODS: This prospective, open-label phase II trial recruited patients aged >= 75 years with previously untreated mCRC between March 2010 and January 2012. Treatment consisted of 7.5 mg/kg of intravenous bevacizumab and 130 mg/m(2) of oxaliplatin on day 1 of each cycle combined with 2000 mg/m(2) of oral capecitabine per day on days 1-14 of each cycle. Treatment was repeated every 3 weeks until disease progression or termination of the study. The primary endpoint was progression free survival; the secondary endpoints were toxicity, overall response rate, time to-treatment failure, and overall survival. RESULTS: Thirty-six patients (male 58%; median age 78 years; colon cancer 67%) met all eligibility criteria and received at least one course of the planned treatment. The median time-to treatment failure was 7.0 months. Twelve patients (33.3%) experienced adverse effects (AEs) >= grade 3 and frequent AEs >= grade 3, including neutropenia (22.2%) and neuropathy (13.9%). Hypertension was the most frequent AE >= grade 3 associated with bevacizumab (11.1%). Low baseline creatinine clearance associated significantly with the incidence of AEs >= grade 3. Response and disease control rates were 55.6 and 91.7%, respectively. Median progression-free and overall survival times were 11.7 months (95% confidence interval, 8.0-13.4 months) and 22.9 months, respectively. CONCLUSION: XELOX combined with bevacizumab was well tolerated by selected Japanese patients aged >= 75 years with mCRC patients, and controlled clinical trials are now required to determine the survival benefit. PMID- 26497658 TI - Brownian microhydrodynamics of active filaments. AB - Slender bodies capable of spontaneous motion in the absence of external actuation in an otherwise quiescent fluid are common in biological, physical and technological contexts. The interplay between the spontaneous fluid flow, Brownian motion, and the elasticity of the body presents a challenging fluid structure interaction problem. Here, we model this problem by approximating the slender body as an elastic filament that can impose non-equilibrium velocities or stresses at the fluid-structure interface. We derive equations of motion for such an active filament by enforcing momentum conservation in the fluid-structure interaction and assuming slow viscous flow in the fluid. The fluid-structure interaction is obtained, to any desired degree of accuracy, through the solution of an integral equation. A simplified form of the equations of motion, which allows for efficient numerical solutions, is obtained by applying the Kirkwood Riseman superposition approximation to the integral equation. We use this form of equation of motion to study dynamical steady states in free and hinged minimally active filaments. Our model provides the foundation to study collective phenomena in momentum-conserving, Brownian, active filament suspensions. PMID- 26497657 TI - Multivariate classification of smokers and nonsmokers using SVM-RFE on structural MRI images. AB - Voxel-based morphometry (VBM) studies have revealed gray matter alterations in smokers, but this type of analysis has poor predictive value for individual cases, which limits its applicability in clinical diagnoses and treatment. A predictive model would essentially embody a complex biomarker that could be used to evaluate treatment efficacy. In this study, we applied VBM along with a multivariate classification method consisting of a support vector machine with recursive feature elimination to discriminate smokers from nonsmokers using their structural MRI data. Mean gray matter volumes in 1,024 cerebral cortical regions of interest created using a subparcellated version of the Automated Anatomical Labeling template were calculated from 60 smokers and 60 nonsmokers, and served as input features to the classification procedure. The classifier achieved the highest accuracy of 69.6% when taking the 139 highest ranked features via 10-fold cross-validation. Critically, these features were later validated on an independent testing set that consisted of 28 smokers and 28 nonsmokers, yielding a 64.04% accuracy level (binomial P = 0.01). Following classification, exploratory post hoc regression analyses were performed, which revealed that gray matter volumes in the putamen, hippocampus, prefrontal cortex, cingulate cortex, caudate, thalamus, pre-/postcentral gyrus, precuneus, and the parahippocampal gyrus, were inversely related to smoking behavioral characteristics. These results not only indicate that smoking related gray matter alterations can provide predictive power for group membership, but also suggest that machine learning techniques can reveal underlying smoking-related neurobiology. PMID- 26497659 TI - A novel intra-operative, high-resolution atrial mapping approach. AB - PURPOSE: A new technique is demonstrated for extensive high-resolution intra operative atrial mapping that will facilitate the localization of atrial fibrillation (AF) sources and identification of the substrate perpetuating AF. METHODS: Prior to the start of extra-corporal circulation, a 8 * 24-electrode array (2-mm inter-electrode distance) is placed subsequently on all the right and left epicardial atrial sites, including Bachmann's bundle, for recording of unipolar electrograms during sinus rhythm and (induced) AF. AF is induced by high frequency pacing at the right atrial free wall. A pacemaker wire stitched to the right atrium serves as a reference signal. The indifferent pole is connected to a steal wire fixed to subcutaneous tissue. Electrograms are recorded by a computerized mapping system and, after amplification (gain 1000), filtering (bandwidth 0.5-400 Hz), sampling (1 kHz) and analogue to digital conversion (16 bits), automatically stored on hard disk. During the mapping procedure, real-time visualization secures electrogram quality. Analysis will be performed offline. RESULTS: This technique was performed in 168 patients of 18 years and older, with coronary and/or structural heart disease, with or without AF, electively scheduled for cardiac surgery and a ventricular ejection fraction above 40 %. The mean duration of the entire mapping procedure including preparation time was 9 +/ 2 min. Complications related to the mapping procedure during or after cardiac surgery were not observed. CONCLUSIONS: We introduce the first epicardial atrial mapping approach with a high resolution of >=1728 recording sites which can be performed in a procedure time of only 9+/-2 mins. This mapping technique can potentially identify areas responsible for initiation and persistence of AF and hopefully can individualize both diagnosis and therapy of AF. PMID- 26497660 TI - Novel association of polymorphic genetic variants with predictors of outcome of catheter ablation in atrial fibrillation: new directions from a prospective study (DECAF). AB - PURPOSE: Non-pulmonary vein (non-PV) triggers and left atrial (LA) scars perpetuate atrial fibrillation (AF) and limit the success rate of catheter ablation. In order to understand the genetic basis of these risk factors, we examined the association of selected single nucleotide polymorphisms (SNPs) with scar and non-PV triggers. METHODS: Four hundred AF patients (67 %male, 62+/-12 years, LA size 45.3+/-7 mm, 64%non-paroxysmal) undergoing catheter ablation were prospectively enrolled. DNA extractions for16 AF-related SNPS from blood samples were performed of which 371 DNA samples were available for genotyping. Multivariate logistic regression analysis was used for assessing predictive role of individual SNP, and logistic kernel-machine approach was applied to test the cumulative effect of multiple SNPs as a group with non-PV triggers and LA scar. False discovery rate (FDR) was computed for all candidate SNPs to address multiple testing. RESULTS: SNPs rs6599230 and rs6843082 were inversely associated (OR 0.68, p=0.04, and 0.62, p=0.01, respectively) whereas rs1448817 (OR 1.74, p=0.04) and rs7193343 (OR 1.66, p=0.02) predicted higher risk of non-PV triggers. Genotypes for rs6599230 and rs6843082 conferred 51 % reduction in the odds for non-PV triggers (combined OR 0.49, p=0.019), while rs1448817 and rs7193343 demonstrated a combined OR of 1.93, p=0.025. FDR was controlled at 16 % to adjust for multiple testing. For LA scar, inverse association was observed with rs1448817 (OR 0.29, p=0.006), rs17042171 (OR 0.27, p=0.032), rs3807989 (OR 0.54, p=0.017), and rs6843082 (OR 0.56, p=0.009). Two SNPs were associated with increased scar risk: rs17375901 (OR 3.68, p=0.03) and rs7193343 (OR 1.74, p=0.037). For global association of SNPs with left atrial scar FDR was controlled at <=10 % to adjust for multiple testing. CONCLUSIONS: This study has a strong clinical significance as it provides important insights into the molecular basis of pertinent therapeutic targets. Our findings demonstrate that the presence of certain genetic polymorphisms increases the risk of scar and non-PV triggers in AF patients. Therefore, PVAI alone will not be enough to eliminate the arrhythmia and the operators may need to identify and isolate the non-PV foci to maximize procedural success in patients carrying these risk variants. Clinical trial registration clinicaltrials.gov (NCT01751607). PMID- 26497663 TI - Letter to the Editor: "Comparison of efficacy of kinesiological taping and subacromial injection therapy in subacromial impingement syndrome". PMID- 26497661 TI - Dendritic cell immunoreceptor 1 alters neutrophil responses in the development of experimental colitis. AB - BACKGROUND: Ulcerative colitis, an inflammatory bowel disease, is associated with the massive infiltration of neutrophils. Although the initial infiltration of neutrophils is beneficial for killing bacteria, it is presumed that persistent infiltration causes tissue damage by releasing antibacterial products as well as inflammatory cytokines. A murine C-type lectin receptor, dendritic cell immunoreceptor 1 (Dcir1), is expressed on CD11b(+) myeloid cells, such as macrophages, dendritic cells and neutrophils. It was reported that Dcir1 is required to maintain homeostasis of the immune system to prevent autoimmunity, but it is also involved in the development of infectious disease resulting in the enhanced severity of cerebral malaria. However, the role of Dcir1 in intestinal immune responses during colitis remains unclear. In this study, we investigated the role of Dcir1 in intestinal inflammation using an experimental colitis model induced with dextran sodium sulfate (DSS). RESULTS: In contrast to wild type (WT) mice, Dcir1 (-/-) mice exhibited mild body weight loss during the course of DSS colitis accompanied by reduced colonic inflammation. Dcir1 deficiency caused a reduced accumulation of neutrophils in the inflamed colon on day 5 of DSS colitis compared with WT mice. Consistently, the production of a neutrophil-attracting chemokine, MIP-2, was also decreased in the Dcir1 (-/-) colon compared with the WT colon on day 5. There were fewer myeloperoxidase-positive neutrophils in the inflamed colon of Dcir1 (-/-) mice than in that of WT mice. Moreover, bone marrow neutrophils from Dcir1 (-/-) mice produced less reactive oxygen species (ROS) by lipopolysaccharide stimulation than those from WT mice. This suggests that Dcir1 deficiency decreases the accumulation of tissue destructive neutrophils during DSS colitis. CONCLUSION: Dcir1 enhances the pathogenesis of DSS colitis by altering neutrophil recruitment and their functions. PMID- 26497664 TI - Co-morbidity index in rheumatoid arthritis: time to think. AB - Rheumatoid arthritis patients are clinically complex, and the interplay of their disease activity together with the other associated conditions may lead to increased morbidity and mortality. The recent advances in the disease management attracted the attention to its associated co-morbidities and highlighted the need for a tool to provide clinicians and potential payers with a clinically powerful measure of the disease burden and prognosis. Predicting outcome or co-morbidity probability has been previously implemented successfully for calculating 10-year fracture probability (FRAX) as well as for predicting 1-year patient mortality using co-morbidity data obtained (Charlson index). Developing a specific rheumatoid arthritis-independent tool able to predict morbidity, mortality, cost and hospitalization would be a step forward on the way to achieve full disease remission. The co-morbidity index should be used both at baseline as well as a continuous variable in analyses. It should be implemented regularly in the clinical assessment as a confounder of outcomes. This article will review the redefined health outcomes in rheumatoid arthritis and the concept of co-morbidity index for patients with inflammatory arthritis. It will also present a proposed co-morbidity index for rheumatoid arthritis patients. PMID- 26497665 TI - Effects of motivational enhancement therapy plus cognitive behaviour therapy on depressive symptoms and health-related quality of life in adults with type II diabetes mellitus: a randomised controlled trial. AB - OBJECTIVE: This paper evaluates the effectiveness of motivational enhancement therapy plus cognitive behavioural therapy on depressive symptoms, glycosylated haemoglobin, fasting glucose, body mass index (BMI), and health-related quality of life in type II diabetes patients. METHODS: A controlled trial was conducted to compare patients who received the behavioural intervention with untreated controls on measures of health outcomes. A total of 31 intervention group participants and 30 controls were selected from patients that met the inclusion criteria from a hospital-based endocrinology outpatient department. The outcome measures including depressive symptoms, glycosylated haemoglobin, fasting glucose, BMI, and both physical and mental quality of life were collected before (T1), after (T2), and after 90 days (T3) following the intervention. RESULTS: The experimental group showed a significant reduction in glycosylated haemoglobin, fasting glucose, and depressive symptoms and a significant increase in physical quality of life and mental quality of life at T2 and T3, while patients in the control group with usual care showed no changes over time. CONCLUSION: The behavioural intervention facilitated a significant improvement in psychological adjustment and glycemic control, thus strengthening diabetes control skills and leading to healthy outcomes. It is feasible that nurses and psychiatrists can deliver the behavioural intervention for diabetes patients to decrease their depressive symptoms. Sharing discussion and problem-solving experiences is particularly helpful method for self-control, and these will be beneficially influential on further research. PMID- 26497666 TI - Incidentally detected non-palpable testicular tumours in adults at scrotal ultrasound: impact of radiological findings on management Radiologic review and recommendations of the ESUR scrotal imaging subcommittee. AB - OBJECTIVES: The increasing detection of small testicular lesions by ultrasound (US) in adults can lead to unnecessary orchiectomies. This article describes their nature, reviews the available literature on this subject and illustrates some classical lesions. We also suggest recommendations to help characterization and management. METHODS: The ESUR scrotal imaging subcommittee searched for original and review articles published before May 2015 using the Pubmed and Medline databases. Key words used were 'testicular ultrasound', 'contrast enhanced sonography', 'sonoelastography', 'magnetic resonance imaging', 'testis sparing surgery', 'testis imaging', 'Leydig cell tumour', 'testicular cyst'. Consensus was obtained amongst the members of the subcommittee, urologist and medical oncologist. RESULTS: Simple cysts are frequent and benign, and do not require follow up or surgery. Incidentally discovered small solid testicular lesions detected are benign in up to 80 %, with Leydig cell tumours being the most frequent. However, the presence of microliths, macrocalcifications and hypoechoic areas surrounding the nodule are findings suggestive of malignant disease. CONCLUSION: Asymptomatic small testicular lesions found on ultrasound are mainly benign, but findings such as microliths or hypoechoic regions surrounding the nodules may indicate malignancy. Colour Doppler US remains the basic examination for characterization. The role of newer imaging modalities in characterization is evolving. KEY POINTS: * Characterization of testicular lesions is primarily based on US examination. * The role of MRI, sonoelastography, contrast-enhanced ultrasound is evolving. * Most small non palpable testicular lesions seen on ultrasound are benign simple cysts. * Leydig cell tumours are the most frequent benign lesions. * Associated findings like microliths or hypoechoic regions may indicate malignancy. PMID- 26497667 TI - Inhibition of integrin beta1 decreases the malignancy of ovarian cancer cells and potentiates anticancer therapy via the FAK/STAT1 signaling pathway. AB - Integrin beta1 (ITGB1) is frequently upregulated in ovarian cancer, and promotes ovarian tumorigenesis and cancer progression. However, the effects of ITGB1 inhibition on ovarian cancer progression and anticancer therapy remain to be elucidated. The results of the present study indicated that ITGB1 was upregulated in HO-8910 and HO-8910PM ovarian cancer cell lines, and knockdown of ITGB1 using short hairpin RNA markedly increased tumor cell apoptosis, decreased tumor cell adhesion and migration, and reduced tumor cell invasion by suppressing matrix metalloproteinase (MMP)-2 and MMP-9 expression. Furthermore, the results of the present study provided evidence regarding the role of ITGB1 inhibition in bevacizumab anticancer therapy. The activation of signal transducer and activator of transcription 1 (STAT1) by focal adhesion kinase (FAK) is involved in integrin mediated cell migration and adhesion. In the present study, the expression levels of FAK were markedly upregulated in ovarian cancer. The adherence and migratory potentials of ovarian cancer cells were significantly reduced when the FAK/STAT1 signaling pathway was inhibited by fludarabine. The results of the present study demonstrated that ITGB1 inhibition effectively reduced tumorigenesis and disease exacerbation, and contributed to bevacizumab anticancer therapy via the FAK/STAT1 signaling pathway, suggesting that inhibition of ITGB1 is a potential novel therapeutic strategy for ovarian carcinogenesis. PMID- 26497668 TI - Differences in leg muscle activity and body sway between elderly adults able and unable to maintain one-leg stance for 1 min: the effect of hand support. AB - BACKGROUND: One-leg stance (OLS) training is often used to prevent falls in the elderly. The burden imposed on the supporting lower limb during OLS may differ depending on whether hand support is used, particularly in patients with decreased lower-limb strength. AIMS: Here we examined the effect of hand support on leg muscle activity and body sway during OLS in elderly subjects able to maintain OLS for 1 min unaided [able group (AG), n = 13] and those who were unable to do so [unable group (UG), n = 11]. METHODS: All subjects performed OLS unaided and OLS with front support (OLS-FS) using one hand for 1 min each. We estimated leg muscle activity [mean and maximum % root mean square (%RMS)] and body sway (total, X-axis, and Y-axis path lengths) for both tests. %RMS was calculated according to the results of the maximum voluntary isometric contraction test. RESULT: The overall average mean and maximum %RMS for the tibialis anterior muscle was larger in UG than in AG. In AG, tibialis anterior muscle mean and maximum %RMS and body sway was larger during OLS than during OLS FS. Total and X-axis path lengths were larger during the first 20 s OLS phase in AG and the first 20 s OLS-FS phase in UG. CONCLUSION: These results highlight the need to differentiate between patients able and unable to perform OLS unaided for training because of differences in leg muscle activity. PMID- 26497669 TI - Risk factors of outcomes in elderly patients with acute ischemic stroke in China. AB - BACKGROUND: Stroke results in poor outcomes among elderly patients. However, the factors associated with outcome over different follow-up periods in this population are unknown. AIMS: To evaluate the outcomes and risk factors of outcomes in elderly patients after stroke. MATERIALS AND METHODS: Outcomes, including mortality, dependency (defined as a mRS >2), and recurrence rates, and associated risk factors were assessed at 3 and 12 months after stroke in patients aged >=80 years. RESULTS: There were 419 acute ischemic stroke patients aged >=80 years at 3 months, and 309 patients at 12 months; outcomes and relevant risk factors were assessed in these patients. Hypertension was more prevalent in women than in men. At 3 months, the mortality, dependency, and recurrence rates were 13.8, 54.2, and 18.1 %, respectively; the corresponding rates at 12 months were 26.9, 58.0, and 32.6 %, respectively. In the multivariate analysis, after adjusting by confounding factors, TOAST classification and stroke severity were associated with mortality and recurrence, while stroke severity was associated with dependency at 3 months. The mortality and dependency rates at 12 months were significantly associated with moderate and severe stroke, but severe stroke was an independent factor associated with recurrence. CONCLUSION: Stroke subtype and severity were associated with stroke outcomes among elderly patients in northern China. These findings suggest that it is crucial to highlight the affected factors of stroke outcome among elderly patients for reduce the burden of stroke in China. PMID- 26497670 TI - Investigation of the Interaction between Perovskite Films with Moisture via in Situ Electrical Resistance Measurement. AB - Organometal halide perovskites have recently emerged as outstanding semiconductors for solid-state optoelectronic devices. Their sensitivity to moisture is one of the biggest barriers to commercialization. In order to identify the effect of moisture in the degradation process, here we combined the in situ electrical resistance measurement with time-resolved X-ray diffraction analysis to investigate the interaction of CH3NH3PbI(3-x)Cl(x) perovskite films with moisture. Upon short-time exposure, the resistance of the perovskite films decreased and it could be fully recovered, which were ascribed to a mere chemisorption of water molecules, followed by the reversible hydration into CH3NH3PbI(3-x)Cl(x).H2O. Upon long-time exposure, however, the resistance became irreversible due to the decomposition into PbI2. The results demonstrated the formation of monohydrated intermediate phase when the perovskites interacted with moisture. The role of moisture in accelerating the thermal degradation at 85 degrees C was also demonstrated. Furthermore, our study suggested that the perovskite films with fewer defects may be more inherently resistant to moisture. PMID- 26497671 TI - Streptokinase-A Drug for Thrombolytic Therapy: A Patent Review. AB - Accumulation of fibrin in blood vessels significantly increases thrombosis, leading to myocardial infraction and other cardiovascular diseases. Microbial enzymes are one option for curing this pathological condition. Fibrinolytic enzymes such as urokinase (UK), tissue type plasminogen activator (t-PA) and streptokinase (SK) attracted much attention for thrombolytic therapy. Among them SK is preferable in low-resource settings because it is cost-effective. Therefore, the purpose of this review is to summarize recent patents related to the occurrence, mechanism of action, physico-chemical properties, cloning and expression, production, structure, immunogenicity, chemical modification, in vivo application and clinical trials of SK. This patent review considers the properties and characteristics of SK that make it a preferred agent for thrombolytic therapy. PMID- 26497672 TI - Substance P prevents 1-methyl-4-phenylpyridinium-induced cytotoxicity through inhibition of apoptosis via neurokinin-1 receptors in MES23.5 cells. AB - [Sar9, Met(O2)11] termed Substance P (SP), is an effective and selective agonist for the neurokinin-1 (NK-1) receptors, which are synthetic peptides, similar in structure to SP. SP is an important neurotransmitter or neuromodulator mediated by neurokinin receptors, namely the SP receptor in the central nervous system. The excitatory effects induced by SP may be selectively inhibited by a neurokinin 1 receptor antagonist, such as SR140333B. It has been proposed that Parkinson's disease (PD) is primarily caused by the loss of trophic peptidergic neurotransmitter, possibly SP, which may lead to the degeneration of neurons. In previous studies, 1-methyl-4-phenylpyridinium (MPP+) has been frequently utilized to establish animal or cell models of PD. In the present study, to further investigate the effects of SP in PD, MPP+ was employed to investigate the promising anti-apoptotic effects of SP, and examine the underlying mechanisms of the pathology in the MES23.5 dopaminergic cell line. The results indicated that MPP+-triggered apoptosis was prevented by treatment with SP. SP treatment also decreased the MPP+-triggered Ca2+ influx, caspase-3 re-activity, reactive oxygen species production and mitochondrial membrane potential decrease. Treatment with MPP+ also induced phosphorylation of c-Jun N-terminal kinase and p38 mitogen activated protein kinase. In addition, treatment with SP inhibited the MPP+ triggered neurotoxicity in MES23.5 cells. However, no changes were observed in SR140333B+SP+MPP+-treated MES23.5 cell lines. In conclusion, SP could protect the cells from MPP+-induced cytotoxicity by inhibiting the apoptosis via NK-1 receptors. PMID- 26497673 TI - Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation. AB - Breast cancer encompasses a heterogeneous group of diseases at the molecular level. It is known that chemosensitivity of breast cancer depends on its molecular subtype. We investigated the growth inhibitory effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, and the mechanism of this inhibition on four breast cancer cell lines with different molecular subtypes. The growth inhibitory effect of VPA in the four different breast cancer cell lines was investigated. The alteration of levels of p21 WAF1, cleaved caspase-3, acetylated Heat shock protein (Hsp) 90, acetylated Hsp70, and acetylated alpha tubulin by VPA was examined in VPA-sensitive, human epidermal receptor 2 (HER2) overexpressing SKBR3 cells. The cell growth inhibition of breast cancer cell lines was dependent on the dose and exposure time of VPA. The cell growth of HER2 overexpressing SKBR3 cell line was inhibited by VPA to a much greater degree than other cell lines studied. In SKBR3 cell line, VPA upregulated expression of p21 WAF1 and cleaved caspase-3 in the early phase. VPA markedly increased Hsp70 acetylation in a time-dependent manner but did not increase Hsp90 acetylation. Our data demonstrated that VPA inhibited cell proliferation and induced cell cycle arrest and apoptosis of HER2-overexpressing breast cancer cells. This anti proliferation effect might be the direct function of VPA as an HDAC inhibitor. We propose an alternative mechanism whereby acetylation of Hsp70 disrupts the function of Hsp90 and leads to downregulation of its client proteins, including HER2 that might be the indirect function of VPA, in the sense that non-histone proteins are acetylated. PMID- 26497674 TI - Histological evidence of chronic traumatic encephalopathy in a large series of neurodegenerative diseases. PMID- 26497675 TI - RCAN1 overexpression promotes age-dependent mitochondrial dysregulation related to neurodegeneration in Alzheimer's disease. AB - Aging is the largest risk factor for Alzheimer's disease (AD). Patients with Down syndrome (DS) develop symptoms consistent with early-onset AD, suggesting that overexpression of chromosome 21 genes such as Regulator of Calcineurin 1 (RCAN1) plays a role in AD pathogenesis. RCAN1 levels are increased in the brain of DS and AD patients but also in the human brain with normal aging. RCAN1 has been implicated in several neuronal functions, but whether its increased expression is correlative or causal in the aging-related progression of AD remains elusive. We show that brain-specific overexpression of the human RCAN1.1S isoform in mice promotes early age-dependent memory and synaptic plasticity deficits, tau pathology, and dysregulation of dynamin-related protein 1 (DRP1) activity associated with mitochondrial dysfunction and oxidative stress, reproducing key AD features. Based on these findings, we propose that chronic RCAN1 overexpression during aging alters DRP1-mediated mitochondrial fission and thus acts to promote AD-related progressive neurodegeneration. PMID- 26497676 TI - The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-beta1-induced growth inhibition by targeting Smad3 linker region. AB - Leukotriene B4 (LTB4) is a potent pro-inflammatory eicosanoid that is derived from arachidonic acid, and its signaling is known to have a tumor-promoting role in several cancer types. In this study, we investigated whether enhanced LTB4 signaling confers resistance to the cytostatic transforming growth factor-beta1 (TGF-beta1) response. We found that LTB4 pretreatment or ectopic expression of BLT1, a high affinity LTB4 receptor, fully abrogated TGF-beta1-induced cell cycle arrest and expression of p15INK4B and p27KIP1. Mechanism study revealed that LTB4 mediated suppression of TGF-beta1-induced Smad3 activation and growth inhibition was due to enhanced phosphorylation of Smad3 linker region (pSmad3L) through activation of BLT1-NAD(P)H oxidase (NOX)-reactive oxygen species (ROS)-epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3-K)-extracellular signal-activated kinase1/2 (ERK1/2)-linked signaling cascade. Furthermore, the LTB4/BLT1 signaling pathway leading to pSmad3L was constitutively activated in breast cancer cells and was correlated with TGF-beta1-resistant growth of the cells in vitro and in vivo. In human breast cancer tissues, the expression level of pSmad3L (Thr179) had a positive correlation with BLT1 expression. Collectively, our data demonstrate for the first time that the induction of pSmad3L through BLT1-NOX-ROS-EGFR-PI3K-ERK1/2 signaling pathway is a key mechanism by which LTB4 blocks the anti-proliferative responses of TGF-beta1, providing a novel mechanistic insight into the connection between enhanced inflammatory signal and cancer cell growth. PMID- 26497677 TI - Eribulin targets a ch-TOG-dependent directed migration of cancer cells. AB - Non-cytotoxic concentrations of microtubule targeting agents (MTAs) interfere with the dynamics of interphase microtubules and affect cell migration, which could impair tumor angiogenesis and metastasis. The underlying mechanisms however are still ill-defined. We previously established that directed cell migration is dependent on stabilization of microtubules at the cell leading edge, which is controlled by microtubule +end interacting proteins (+TIPs). In the present study, we found that eribulin, a recently approved MTA interacting with a new class of binding site on beta-tubulin, decreased microtubule growth speed, impaired their cortical stabilization and prevented directed migration of cancer cells. These effects were reminiscent of those observed when +TIP expression or cortical localization was altered. Actually, eribulin induced a dose-dependent depletion of EB1, CLIP-170 and the tubulin polymerase ch-TOG from microtubule +ends. Interestingly, eribulin doses that disturbed ch-TOG localization without significant effect on EB1 and CLIP-170 comets, had an impact on microtubule dynamics and directed migration. Moreover, knockdown of ch-TOG led to a similar inhibition of microtubule growth speed, microtubule capture and chemotaxis. Our data suggest that eribulin binding to the tip of microtubules and subsequent loss of ch-TOG is a priming event leading to alterations in microtubule dynamics and cancer cell migration. PMID- 26497678 TI - Therapeutic potential of targeting cell division cycle associated 5 for oral squamous cell carcinoma. AB - Molecularly targeted drugs are used in the treatment of a variety of malignant tumors, but this approach to developing novel therapies for oral squamous cell carcinoma (OSCC) has lagged behind the progress seen for other cancers. We have attempted to find appropriate molecular targets for OSCC and identified cell division cycle associated 5 (CDCA5) as a cancer-related gene which was overexpressed in all the human OSCC cells tested by microarray analysis. In this study, we investigated the expression and function of CDCA5 in OSCC. First, we confirmed that CDCA5 was overexpressed in 4 human OSCC cell lines by quantitative RT-PCR and Western blotting. We then tested the effect of synthetic small interfering RNAs specific for CDCA5 on the growth and invasion of human OSCC cells. Knockdown of CDCA5 markedly inhibited the growth of OSCC cells in vitro and in vivo. We also examined the expression of CDCA5 protein in 80 cases of OSCC immunohistochemically and found a significant association between CDCA5 expression levels and overall survival. These results suggest that CDCA5 functions as a critical gene supporting OSCC progression and that targeting CDCA5 may be a useful therapeutic strategy for OSCC. PMID- 26497679 TI - Tristetraprolin induces cell cycle arrest in breast tumor cells through targeting AP-1/c-Jun and NF-kappaB pathway. AB - The main characteristic of cancers, including breast cancer, is the ability of cancer cells to proliferate uncontrollably. However, the underlying mechanisms of cancer cell proliferation, especially those regulated by the RNA binding protein tristetraprolin (TTP), are not completely understood. In this study, we found that TTP inhibits cell proliferation in vitro and suppresses tumor growth in vivo through inducing cell cycle arrest at the S phase. Our studies demonstrate that TTP inhibits c-Jun expression through the C-terminal Zn finger and therefore increases Wee1 expression, a regulatory molecule which controls cell cycle transition from the S to the G2 phase. In contrast to the well-known function of TTP in regulating mRNA stability, TTP inhibits c-Jun expression at the level of transcription by selectively blocking NF-kappaB p65 nuclear translocation. Reconstitution of NF-kappaB p65 completely abolishes the inhibition of c-Jun transcription by TTP. Moreover, reconstitution of c-Jun in TTP-expressing breast tumor cells diminishes Wee1 overexpression and promotes cell proliferation. Our results indicate that TTP suppresses c-Jun expression that results in Wee1 induction which causes cell cycle arrest at the S phase and inhibition of cell proliferation. Our study provides a new pathway for TTP function as a tumor suppressor which could be targeted in tumor treatment. PMID- 26497680 TI - Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2. AB - Nrf2 is a key transcription factor for genes coding for antioxidants, detoxification enzymes, and multiple drug resistance and it also confers resistance to anticancer drugs. Here, we hypothesized that mutant p53 could upregulate Nrf2 expression at the transcriptional level, thereby conferring cisplatin resistance in non-small cell lung cancer (NSCLC). Luciferase reporter assays and real-time PCR analysis indicated that the Nrf2 promoter activity and its mRNA levels were markedly suppressed by wild-type p53, but not by mutant p53. Chromatin immunoprecipitation (ChIP) further confirmed that wild-type p53 binds at the p53 putative binding site to block Sp1 binding to the Nrf2 promoter and consequently to suppress the Nrf2 promoter activity. The MTT assay indicated that an increase in Nrf2 expression by mutant p53 is responsible for cisplatin resistance. Among the Nrf2 downstream genes, Bcl-2 and Bcl-xL contribute more strongly to Nrf2-mediated cisplatin resistance when compared with heme oxygenase 1 (HO-1). Cox regression analysis showed that patients with high-Nrf2, high-Bcl 2, high-Bcl-xL mRNA tumors were more commonly occurred unfavorable response to cisplatin-based chemotherapy than their counterparts. The prognostic significance of Nrf2 mRNA levels on OS and RFS was also observed in patients who have received cisplatin-based chemotherapy, particularly in p53-mutant patients. Collectively, mutant p53 may confer cisplatin resistance via upregulation of Nrf2 expression, and Nrf2 mRNA level may predict chemotherapeutic response and outcomes in NSCLC. PMID- 26497681 TI - Suppression of ATAD2 inhibits hepatocellular carcinoma progression through activation of p53- and p38-mediated apoptotic signaling. AB - The ATPase family, AAA domain containing 2 (ATAD2) is highly expressed in multiple cancers. We aim to understand the clinical and biological significance of ATAD2 over-expression in hepatocellular carcinoma (HCC), as a means to validate it as a therapeutic target in HCC. We demonstrated that ATAD2 was over expressed in HCC patients, where high ATAD2 levels were significantly correlated with aggressive phenotypes such as high AFP levels, advanced tumor stages, and vascular invasion. Using RNA interference, suppression of ATAD2 in HCC cell lines decreased cell viability, migration, and invasion, and induced apoptosis in vitro. Furthermore, we identified p53 and p38 as key proteins that mediate apoptosis induced by ATAD2 suppression. In HCC cells, we demonstrated that ATAD2 directly interacted with MKK3/6, which prevented p38 activation and therefore inhibited p38-mediated apoptosis. In vivo, suppression of ATAD2 impaired the growth of HepG2 and Hep3B subcutaneous xenografts, accompanied by enhanced apoptosis and p-p53 and p-p38 levels. Our results validate that ATAD2 is an important negative regulator of apoptosis, and that neutralizing its activity has promising anti-tumor effects in HCC cells. PMID- 26497682 TI - A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway. AB - Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum. PMID- 26497683 TI - A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation. AB - We previously described diaryl trifluorothiazoline compound 1a (hereafter referred to as fluorizoline) as a first-in-class small molecule that induces p53 independent apoptosis in a wide range of tumor cell lines. Fluorizoline directly binds to prohibitin 1 and 2 (PHBs), two proteins involved in the regulation of several cellular processes, including apoptosis. Here we demonstrate that fluorizoline-induced apoptosis is mediated by PHBs, as cells depleted of these proteins are highly resistant to fluorizoline treatment. In addition, BAX and BAK are necessary for fluorizoline-induced cytotoxic effects, thereby proving that apoptosis occurs through the intrinsic pathway. Expression analysis revealed that fluorizoline induced the upregulation of Noxa and Bim mRNA levels, which was not observed in PHB-depleted MEFs. Finally, Noxa(-/-)/Bim(-/-) MEFs and NOXA downregulated HeLa cells were resistant to fluorizoline-induced apoptosis. All together, these findings show that fluorizoline requires PHBs to execute the mitochondrial apoptotic pathway. PMID- 26497684 TI - Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. AB - The differential diagnosis of Parkinson's diseases (PD) is challenging, especially in the early stages of the disease. We developed a microRNA profiling strategy for exosomal miRNAs isolated from cerebrospinal fluid (CSF) in PD and AD. Sixteen exosomal miRNAs were up regulated and 11 miRNAs were under regulated significantly in PD CSF when compared with those in healthy controls (relative fold > 2, p < 0.05). MiR-1 and miR-19b-3p were validated and significantly reduced in independent samples. While miR-153, miR-409-3p, miR-10a-5p, and let-7g 3p were significantly over expressed in PD CSF exosome. Bioinformatic analysis by DIANA-mirPath demonstrated that Neurotrophin signaling, mTOR signaling, Ubiquitin mediated proteolysis, Dopaminergic synapse, and Glutamatergic synapse were the most prominent pathways enriched in quantiles with PD miRNA patterns. Messenger RNA (mRNA) transcripts [amyloid precursor protein (APP), alpha-synuclein (alpha syn), Tau, neurofilament light gene (NF-L), DJ-1/PARK7, Fractalkine and Neurosin] and long non-coding RNAs (RP11-462G22.1 and PCA3) were differentially expressed in CSF exosomes in PD and AD patients. These data demonstrated that CSF exosomal RNA molecules are reliable biomarkers with fair robustness in regard to specificity and sensitivity in differentiating PD from healthy and diseased (AD) controls. PMID- 26497685 TI - The combinatorial activation of the PI3K and Ras/MAPK pathways is sufficient for aggressive tumor formation, while individual pathway activation supports cell persistence. AB - A high proportion of human tumors maintain activation of both the PI3K and Ras/MAPK pathways. In basal-like breast cancer (BBC), PTEN expression is decreased/lost in over 50% of cases, leading to aberrant activation of the PI3K pathway. Additionally, BBC cell lines and tumor models have been shown to exhibit an oncogenic Ras-like gene transcriptional signature, indicating activation of the Ras/MAPK pathway. To directly test how the PI3K and Ras/MAPK pathways contribute to tumorigenesis, we deleted PTEN and activated KRas within non tumorigenic MCF-10A breast cells. Neither individual mutation was sufficient to promote tumorigenesis, but the combination promoted robust tumor growth in mice. However, in vivo bioluminescence reveals that each mutation has the ability to promote a persistent phenotype. Inherent in the concept of tumor cell dormancy, a stage in which residual disease is present but remains asymptomatic, viable cells with each individual mutation can persist in vivo during a period of latency. The persistent cells were excised from the mice and showed increased levels of the cell cycle arrest proteins p21 and p27 compared to the aggressively growing PTEN /-KRAS(G12V) cells. Additionally, when these persistent cells were placed into growth-promoting conditions, they were able to re-enter the cell cycle and proliferate. These results highlight the potential for either PTEN loss or KRAS activation to promote cell survival in vivo, and the unique ability of the combined mutations to yield rapid tumor growth. This could have important implications in determining recurrence risk and disease progression in tumor subtypes where these mutations are common. PMID- 26497686 TI - Decreased severity of collagen antibody and lipopolysaccharide-induced arthritis in human IL-32beta overexpressed transgenic mice. AB - Interleukin (IL)-32, mainly produced by T-lymphocytes, natural killer cells, epithelial cells, and blood monocytes, is dominantly known as a pro-inflammatory cytokine. However, the role of IL-32 on inflammatory disease has been doubtful according to diverse conflicting results. This study was designed to examine the role of IL-32beta on the development of collagen antibody (CAIA) and lipopolysaccharide (LPS)-induced inflammatory arthritis. Our data showed that the paw swelling volume and clinical score were significantly reduced in the CAIA and LPS-treated IL-32beta transgenic mice compared with non-transgenic mice. The populations of cytotoxic T, NK and dendritic cells was inhibited and NF-kappaB and STAT3 activities were significantly lowered in the CAIA and LPS-treated IL 32beta transgenic mice. The expression of pro-inflammatory proteins was prevented in the paw tissues of CAIA and LPS-treated IL-32beta transgenic mice. In addition, IL-32beta altered several cytokine levels in the blood, spleen and paw joint. Our data indicates that IL-32beta comprehensively inhibits the inflammation responses in the CAIA and LPS-induced inflammatory arthritis model. PMID- 26497687 TI - Inhibition of the miR-155 target NIAM phenocopies the growth promoting effect of miR-155 in B-cell lymphoma. AB - Several studies have indicated an important role for miR-155 in the pathogenesis of B-cell lymphoma. Highly elevated levels of miR-155 were indeed observed in most B-cell lymphomas with the exception of Burkitt lymphoma (BL). However, the molecular mechanisms that underlie the oncogenic role of miR-155 in B-cell lymphoma are not well understood. To identify the miR-155 targets relevant for B cell lymphoma, we performed RNA immunoprecipitation of Argonaute 2 in Hodgkin lymphoma (HL) cells upon miR-155 inhibition and in BL cells upon ectopic expression of miR-155. We identified 54 miR-155-specific target genes in BL cells and confirmed miR-155 targeting of DET1, NIAM, TRIM32, HOMEZ, PSIP1 and JARID2. Five of these targets are also regulated by endogenous miR-155 in HL cells. Both overexpression of miR-155 and inhibition of expression of the novel miR-155 target gene NIAM increased proliferation of BL cells. In primary B-cell lymphoma NIAM-positive cases have significant lower levels of miR-155 as compared to NIAM negative cases, suggesting that NIAM is also regulated by miR-155 in primary B cell lymphoma. Thus, our data indicate an oncogenic role for miR-155 in B-cell lymphoma which involves targeting the tumor suppressor NIAM. PMID- 26497688 TI - Flavokawain A induces deNEDDylation and Skp2 degradation leading to inhibition of tumorigenesis and cancer progression in the TRAMP transgenic mouse model. AB - S phase kinase-associated protein 2 (Skp2) has been shown to be required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb) deficient mice. Here we have demonstrated that flavokawain A (FKA), a novel chalcone from the kava plant, selectively inhibited the growth of pRb deficient cell lines and resulted in a proteasome-dependent and ubiquitination-mediated Skp2 degradation. Degradation of Skp2 by FKA was found to be involved in a functional Cullin1, but independent of Cdh1 expression. Further studies have demonstrated that FKA docked into the ATP binding pocket of the precursor cell expressed developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) complex, inhibited NEDD8 conjugations to both Cullin1 and Ubc12 in PC3 cells and Ubc12 NEDDylation in an in vitro assay. Finally, dietary feeding of the autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with FKA inhibited the formation of high-grade prostatic intra-epithelial neoplasia lesions (HG-PIN) and prostate adenocarcinomas, reduced the tumor burden and completely abolished distant organ metastasis. Immunohistochemistry studies revealed that dietary FKA feeding resulted in marked anti-proliferative and apoptotic effects via down-regulation of Skp2 and NEDD8 and up-regulation of p27/Kip1 in the prostate of TRAMP mice. Our findings therefore provide evidence that FKA is a promising NEDDylation inhibitor for targeting Skp2 degradation in prostate cancer prevention and treatment. PMID- 26497690 TI - Adjuvant treatment with tumor-targeting Salmonella typhimurium A1-R reduces recurrence and increases survival after liver metastasis resection in an orthotopic nude mouse model. AB - Colon cancer liver metastasis is often the lethal aspect of this disease. Well isolated metastases are candidates for surgical resection, but recurrence is common. Better adjuvant treatment is therefore needed to reduce or prevent recurrence. In the present study, HT-29 human colon cancer cells expressing red fluorescent protein (RFP) were used to establish liver metastases in nude mice. Mice with a single liver metastasis were randomized into bright-light surgery (BLS) or the combination of BLS and adjuvant treatment with tumor-targeting S. typhimurium A1-R. Residual tumor fluorescence after BLS was clearly visualized at high magnification by fluorescence imaging. Adjuvant treatment with S. typhimurium A1-R was highly effective to increase survival and disease-free survival after BLS of liver metastasis. The results suggest the future clinical potential of adjuvant S. typhimurium A1-R treatment after liver metastasis resection. PMID- 26497691 TI - Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward. AB - RATIONALE: Cigarette smoking is influenced by nicotine's effects on dopaminergic activity in the mesocorticolimbic pathway. This activity appears to be moderated by genetic variation, specifically a variable number tandem repeat (VNTR) polymorphism in the third exon of the dopamine receptor gene (DRD4). OBJECTIVE: We examined whether this polymorphism along with three DRD4 single-nucleotide polymorphisms (SNPs: rs936460, rs936461, and rs12280580) moderate the influence of nicotine on subjective responses to cigarettes. METHODS: White, non-Hispanic smokers (n = 96, cigarettes/day >=15) attended two double-blind, counterbalanced experimental sessions, each preceded by overnight smoking abstinence. Participants smoked four nicotine (8.9 mg) or placebo (1.0 mg) cigarettes per session, with each cigarette followed by completion of the modified Cigarette Evaluation Questionnaire (mCEQ). RESULTS: We examined the mCEQ composite score via 2 * 2 * 4 ANOVAs with genotype (major homozygotes versus minor carriers) as the between-subject factor and nicotine content and smoking bout as within subject factors. Although DRD4 VNTR variation did not moderate overall nicotine response, there was a moderation of nicotine response over successive cigarettes. Smokers with fewer than seven repeats for the DRD4 VNTR reported markedly reduced craving, increased satisfaction, and a greater calming effect in response to earlier smoked nicotine cigarettes, whereas those with seven or more repeats did not. In addition, minor carriers for all three DRD4 SNPs displayed blunted overall response to nicotine. CONCLUSION: These findings provide support for DRD4 variation as an informative predictor of subjective responses to nicotine. We discuss how these data may lead to improved tailoring of smoking cessation pharmacotherapies. PMID- 26497689 TI - Combination of circulating tumor cell enumeration and tumor marker detection in predicting prognosis and treatment effect in metastatic castration-resistant prostate cancer. AB - Although circulating tumor cell (CTC) enumeration in peripheral blood has already been validated as a reliable biomarker in predicting prognosis in metastatic castration-resistant prostate cancer (mCRPC), patients with favorable CTC counts (CTC < 5/7.5 ml) still experience various survival times. Assays that can reduce patients' risks are urgently needed. In this study, we set up a real-time quantitative polymerase chain reaction (RT-qPCR) method to detect epithelial mesenchymal transition (EMT) and stem cell gene expression status in peripheral blood to validate whether they could complement CTC enumeration. From January 2013 to June 2014 we collected peripheral blood from 70 mCRPC patients and enumerated CTC in these blood samples using CellSearch system. At the same time, stem cell-related genes (ABCG2, PROM1 and PSCA) and EMT-related genes (TWIST1 and vimentin) were detected in these peripheral blood samples using an RT-qPCR assay. Patient overall survival (OS) and treatment methods were recorded in the follow up. For patients who received first-line chemotherapy, docetaxel plus prednisone, PSA progression-free survival (PSA-PFS) and PSA response rate were recorded. At the time of analysis, 35 patients had died of prostate cancer with a median follow-up of 16.0 months. Unfavorable CTC enumerations (CTC >=5/7.5 ml) were predictive of shorter OS (p = 0.01). Also, positive stem cell gene expression indicated poor prognosis in mCRPC patients (p = 0.01). However, EMT gene expression status failed to show any prognostic value in OS (p = 0.78). A multivariate analysis indicated that serum albumin (p = 0.04), ECOG performance status (p < 0.01), CTC enumeration (p = 0.02) and stem cell gene expression status (p = 0.01) were independent prognostic factors for OS. For the 40 patients categorized into the favorable CTC enumeration group, positive stem cell gene expression also suggested poor prognosis (p < 0.01). A combined prognostic model consisting of stem cell gene expression and CTC enumeration increased the concordance probability estimated value from 0.716 to 0.889 in comparison with CTC enumeration alone. For patients who received docetaxel plus prednisone as first-line chemotherapy, positive stem cell gene expression suggested a poor PSA PFS (p = 0.01) and a low PSA response rate (p = 0.008). However, CTC enumeration and EMT gene expression status did not affect PSA-PFS or PSA response rates. As a result, detection of peripheral blood stem cell gene expression could complement CTC enumeration in predicting OS and docetaxel-based treatment effects in mCRPC patients. PMID- 26497692 TI - Selective effects of acute alcohol intake on the prospective and retrospective components of a prospective-memory task with emotional targets. AB - RATIONALE: Prospective memory involves remembering to do something in the future and has a prospective component (remembering that something must be done) and a retrospective component (remembering what must be done and when it must be done). Initial studies reported an impairment in prospective-memory performance due to acute alcohol consumption. Retrospective-memory studies demonstrated that alcohol effects vary depending on the emotionality of the information that needs to be learned. OBJECTIVES: The aim of the present study was to investigate possible differential effects of a mild acute alcohol dose (0.4 g/kg) on the prospective and retrospective components of prospective memory depending on cue valence. METHOD: Seventy-five participants were allocated to an alcohol or placebo group and performed a prospective-memory task in which prospective-memory cue valence was manipulated (negative, neutral, positive). The multinomial model of event based prospective memory (Smith and Bayen 2004) was used to measure alcohol and valence effects on the two prospective-memory components separately. RESULTS: Overall, no main effect of alcohol or valence on prospective-memory performance occurred. However, model-based analyses demonstrated a significantly higher retrospective component for positive compared with negative cues in the placebo group. In the alcohol group, the prospective component was weaker for negative than for neutral cues and the retrospective component was stronger for positive than for neutral cues. Group comparisons showed that the alcohol group had a significantly lower prospective component for negative cues and a lower retrospective component for neutral cues. CONCLUSION: This is the first study to demonstrate selective alcohol effects on prospective-memory components depending on prospective-memory cue valence. PMID- 26497693 TI - Terminalia arjuna bark extract alleviates nickel toxicity by suppressing its uptake and modulating antioxidative defence in rice seedlings. AB - Terminalia arjuna (Ta) bark contains various natural antioxidants and has been used to protect animal cells against oxidative stress. In the present study, we have examined alleviating effects of Ta bark aqueous extract against Ni toxicity in rice (Oryza sativa L.). When rice seedlings were raised for 8 days in hydroponics in Yoshida nutrient medium containing 200 MUM NiSO4, a decline in height, reduced biomass, increased Ni uptake, loss of root plasma membrane integrity, increase in the level of O2-, H2O2 and OH, increased lipid peroxidation, decline in photosynthetic pigments, increase in the level of antioxidative enzymes superoxide dismutase, catalase and glutathione peroxidase and alterations in their isoenzyme profile patterns were observed. Transmission electron microscopy (TEM) showed damage to chloroplasts marked by disorganised enlarged starch granules and disrupted thylakoids under Ni toxicity. Exogenously adding Ta bark extract (3.2 mg ml-1) to the growth medium considerably alleviated Ni toxicity in the seedlings by reducing Ni uptake, suppressing generation of reactive oxygen species, reducing lipid peroxidation, restoring level of photosynthesis pigments and ultrastructure of chloroplasts, and restoring levels of antioxidative enzymes. Results suggest that Ta bark extract considerably alleviates Ni toxicity in rice seedlings by preventing Ni uptake and reducing oxidative stress in the seedlings. PMID- 26497695 TI - Direct Synthesis of Thioethers from Carboxylates and Thiols Catalyzed by FeCl3. AB - A new and efficient method has been developed for the synthesis of thioethers from carboxylates and thiols. The reaction proceeds via a Fe(III)-catalyzed direct displacement of carboxylates from benzylic or allylic esters by heterocyclic thiols. Short reaction times, good to excellent yields of products, and few side reactions are the significant features of the new protocol. PMID- 26497694 TI - Floral micromorphology of the Australian carnivorous bladderwort Utricularia dunlopii, a putative pseudocopulatory species. AB - Flowers of sexually deceptive taxa generally possess a set of morphological and physiological characters that mimic their insect pollinators. These characters often include a specific insect-like floral configuration, together with scent glands (osmophores) that produce fragrances which chemically resemble insect sex pheromones. Furthermore, these flowers tend not to produce pollinator food rewards. According to some authors, flowers of the Australian bladderwort Utricularia dunlopii (and species of the Utricularia capilliflora complex) resemble insects, and pollination perhaps occurs by pseudocopulation. The aims of this paper are to compare the structure and distribution of floral glandular trichomes in the Australian carnivorous plant U. dunlopii with those of closely related species assigned to the same section and to discuss their putative function. Floral tissues of U. dunlopii P. Taylor, Utricularia paulinae Lowrie, Utricularia dichotoma Labill. and Utricularia uniflora R.Br. (section Pleiochasia) were investigated using light microscopy, scanning electron microscopy, transmission electron microscopy and histochemistry. In U. dunlopii, two long, erect, filiform appendages arising from the upper lip of the corolla, together with three arising from the lower lip, bear numerous glandular trichomes that may function as osmophores. In other species, such as U. uniflora and U. paulinae, glandular papillae on the corolla palate may also function as osmophores. The floral anatomical and morphological organisation of U. dunlopii differs from that of the other investigated species, indicating that its insect pollinators are also likely to differ. Morphological and ultrastructural observations, while generally contributing to our understanding of the flower of U. dunlopii, do not refute the possibility that pollination here may occur by pseudocopulation. Further field-based investigations, however, are now necessary to test this hypothesis. PMID- 26497696 TI - Using Animation to Improve Recovery from Acute Coronary Syndrome: A Randomized Trial. AB - Background: Recovery from myocardial infarction has been associated with patients' perceptions of damage to their heart. New technologies offer a way to show patients animations that may foster more accurate perceptions and encourage medication adherence, increased exercise and faster return to activities. PURPOSE: The purpose of this study was to investigate the effects of a brief animated intervention delivered at the patients' bedside on perceptions and recovery in acute coronary syndrome patients. METHODS: Seventy acute coronary syndrome patients were randomly assigned to the intervention or standard care alone. Illness perceptions, medication beliefs and recovery outcomes were measured. RESULTS: Post-intervention, the intervention group had significantly increased treatment control perceptions and decreased medication harm beliefs and concerns. Seven weeks later, intervention participants had significantly increased treatment control and timeline beliefs, decreased symptoms, lower cardiac avoidance, greater exercise and faster return to normal activities compared to control patients. CONCLUSIONS: A brief animated intervention may be clinically effective for acute coronary syndrome patients (Trial-ID: ACTRN12614000440628). PMID- 26497697 TI - Optimism and Spontaneous Self-affirmation are Associated with Lower Likelihood of Cognitive Impairment and Greater Positive Affect among Cancer Survivors. AB - BACKGROUND: Optimism and self-affirmation promote adaptive coping, goal achievement, and better health. PURPOSE: The aim of this study is to examine the associations of optimism and spontaneous self-affirmation (SSA) with physical, mental, and cognitive health and information seeking among cancer survivors. METHODS: Cancer survivors (n = 326) completed the Health Information National Trends Survey 2013, a national survey of US adults. Participants reported optimism, SSA, cognitive and physical impairment, affect, health status, and information seeking. RESULTS: Participants higher in optimism reported better health on nearly all indices examined, even when controlling for SSA. Participants higher in SSA reported lower likelihood of cognitive impairment, greater happiness and hopefulness, and greater likelihood of cancer information seeking. SSA remained significantly associated with greater hopefulness and cancer information seeking when controlling for optimism. CONCLUSIONS: Optimism and SSA may be associated with beneficial health-related outcomes among cancer survivors. Given the demonstrated malleability of self-affirmation, these findings represent important avenues for future research. PMID- 26497698 TI - In vivo biokinetic and metabolic characterization of the 68Ga-labelled alpha5beta1-selective peptidomimetic FR366. AB - PURPOSE: Integrins are transmembrane receptors responsible for cell-cell adhesion and cell-extracellular matrix binding and play an important role in angiogenesis and tumour metastasis. For this reason, integrins are increasingly used as targets for molecular imaging. Up to now interest has mostly been focused on the integrin subtype alphavbeta3. However, targeting of other subtypes such as the integrin alpha5beta1 is also of high interest due to its central role in colonization of metastatic cells, resistance of tumour cells to chemotherapy and ionizing radiation, and tumour aggressiveness. Recently, a highly active antagonist ligand (2,2'-(7-(1-carboxy-4-((6-((3-(4-(((S)-1-carboxy-2-(2-(3 guanidinobenzamido)acetamido)ethyl)carbamoyl)-3,5-dimethylphenoxy)propyl)amino)-6 oxohexyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid, FR366) for the integrin subtype alpha5beta1 with high selectivity versus alphavbeta3, has been developed and tested successfully in preliminary in vitro and in vivo experiments. Here, we present our results of an investigation of the use of (68)Ga-labelled alpha5beta1 ligand in PET imaging. METHODS: The free alpha5beta1 peptidomimetic ligand was functionalized with a spacer (6-aminohexanoic acid) and the bifunctional chelator 1-((1,3-dicarboxy)propyl)-4,7-(carboxymethyl)-1,4,7 triazacyclononane (NODAGA) to yield FR366 and labelled with (68)Ga. To confirm selective in vivo targeting of alpha5beta1, female BALB/c nude mice xenografted with alpha5beta1-expressing RKO cells in the right shoulder and alpha5beta1/alphavbeta3-expressing M21 cells in the left shoulder were subjected to PET/CT scans and biodistribution experiments. Specificity of tracer uptake was proven by blocking studies. Metabolic stability of the injected tracer was measured in urine and in plasma. RESULTS: MicroPET/CT scans with radiolabelled FR366 showed a good tumour-to-normal tissue ratio with low uptake in the liver (0.32 +/- 0.14 %ID/g) and good retention of (68)Ga-NODAGA-FR366 in the tumour (0.71 +/- 0.20 %ID/g and 0.40 +/- 0.12 %ID/g for RKO and M21 tumours, respectively, at 90 min after injection). Biodistribution experiments showed uptake in the alpha5beta1-expressing RKO tumour of 1.05 +/- 0.23 %ID/g at 90 min after injection. Specificity of tracer uptake was demonstrated by injection of 5 mg/kg unlabelled ligand 10 min prior to tracer injection, resulting in a 67 % reduction in uptake in the RKO tumour. The tracer was found to be metabolically stable in urine and plasma 30 min after injection. CONCLUSION: Our results show that PET imaging of alpha5beta1 expression with the (68)Ga-labelled alpha5beta1 specific ligand is feasible with good image quality. Thus, FR366 is a promising new tool for investigating the role of alpha5beta1 in angiogenesis and the influence of this integrin subtype on cancer aggressiveness and metastatic potential. PMID- 26497699 TI - (18)F-DOPA PET/CT in the diagnosis and localization of persistent medullary thyroid carcinoma. AB - PURPOSE: To evaluate the performance of (18)F-L-dihydroxyphenylalanine ((18)F DOPA) PET/CT in the detection of locoregional and distant medullary thyroid carcinoma (MTC) metastases and to compare imaging findings with histological data. METHODS: We retrospectively evaluated 86 MTC patients with persistently high serum calcitonin levels after initial surgery who had undergone (18)F-DOPA PET/CT between January 2007 and December 2014 in two referral centres. They were followed up for at least 6 months after the PET/CT assessment. The results were compared with histological data or with the findings obtained during follow-up using a complementary imaging modality. RESULTS: (18)F-DOPA PET/CT was positive in 65 of the 86 patients, corresponding to a patient-based sensitivity of 75.6 %. Distant metastatic disease (M1) was seen in 29 patients including 11 with previously unknown metastases revealed only by PET/CT. Among the 36 patients without distant metastatic spread, 25 had nodal involvement limited to the neck, and 10 of these 25 patients underwent reoperation. The lymph node compartment based sensitivity of (18)F-DOPA PET/CT was 100 % in the two institutions but lesion-based sensitivity was only 24 %. Preoperative and postoperative median calcitonin levels were 405 pg/mL (range 128 - 1,960 pg/mL) and 259 pg/mL (range 33 - 1,516 pg/mL), respectively. None of the patients achieved normalization of serum calcitonin after reoperation. CONCLUSION: (18)F-DOPA PET/CT enables early diagnosis of a significant number of patients with distant metastasis. It has a limited sensitivity in the detection of residual disease but provides high performance for regional analysis. A surgical compartment-oriented approach could be the approach of choice whatever the number of nodes revealed by (18)F-DOPA PET/CT. PMID- 26497701 TI - Gut dysbiosis in mania: A viable therapeutic target? PMID- 26497700 TI - The value of F-18 fluorodeoxyglucose positron emission tomography/computed tomography in asymptomatic examinees with unexplained elevated blood carcinoembryonic antigen levels. AB - PURPOSE: Cancer is still a clinical challenge, with many efforts invested in order to achieve timely detection. Unexplained elevated blood carcinoembryonic antigen levels are occasionally observed in an asymptomatic population and considered as a risk factor of cancers. The purpose of this study was to determine the validity of 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-18 FDG-PET/CT) for detecting cancer in an asymptomatic population with an unexplained elevation in blood carcinoembryonic antigen (CEA) levels. METHODS: This retrospective study included a total of 1920 asymptomatic examinees conducted from August 2011 through September 2013. The participants underwent CEA assay and conventional medical imaging (CEA conventional), or CEA assay and F-18 FDG-PET/CT (CEA-PET/CT). The validity of conventional medical imaging and CEA-PET/CT scanning for detecting cancer and early-stage cancer in an asymptomatic population with an unexplained elevation in blood CEA levels were evaluated. RESULTS: Sensitivity, specificity, cancer detection rate, missed cancer detection rate, early-stage cancer detection rate, and early-stage cancer ratio using the CEA-PET/CT scanning were 96.6 %, 100 %, 10.4 %, 0.4 %, 3.7 %, and 34.5 %, respectively. In contrast, the corresponding values obtained using the conventional medical imaging were 50.6 % (P < 0.0001), 100 % (P > 0.9999), 50.6 % (P < 0.0001), 99.9 % (P = 0.055), 2.6 % (P < 0.0001), 2.5 % (P = 0.04), 0.7 % (P = 0.0004), and 14.5 % (P = 0.002), respectively. CONCLUSION: The F-18 FDG-PET/CT scanning significantly improved the validity of the cancer detection program in the asymptomatic population with an unexplained elevation in CEA levels. PMID- 26497702 TI - Recurrent brief depressive disorder in Dhat syndrome: A biological or psychological phenomenon! PMID- 26497703 TI - Corticomedullary difference in the effects of dietary Ca2+ on tight junction properties in thick ascending limbs of Henle's loop. AB - The thick ascending limb of Henle's loop (TAL) drives an important part of the reabsorption of divalent cations. This reabsorption occurs via the paracellular pathway formed by the tight junction (TJ), which in the TAL shows cation selectivity. Claudins, a family of TJ proteins, determine the permeability and selectivity of this pathway. Mice were fed with normal or high-Ca(2+) diet, and effects on the reabsorptive properties of cortical and medullary TAL segments were analysed by tubule microdissection and microperfusion. Claudin expression was investigated by immunostaining and quantitative PCR. We show that the TAL adapted to high Ca(2+) load in a sub-segment-specific manner. In medullary TAL, transcellular NaCl transport was attenuated. The transepithelial voltage decreased from 10.9 +/- 0.6 mV at control diet to 8.3 +/- 0.5 mV at high Ca(2+) load, thereby reducing the driving force for Ca(2+) and Mg(2+) uptake. Cortical TAL showed a reduction in paracellular Ca(2+) and Mg(2+) permeabilities from 8.2 +/- 0.7 to 6.2 +/- 0.5 ? 10(-4) cm/s and from 4.8 +/- 0.5 to 3.0 +/- 0.2 . 10(-4) cm/s at control and high-Ca(2+) diet, respectively. Expression, localisation and regulation of claudins 10, 14, 16 and 19 differed along the corticomedullary axis: Towards the cortex, the main site of divalent cation reabsorption in TAL, high-Ca(2+) intake led to a strong upregulation of claudin-14 within TAL TJs while claudin-16 and -19 were unaltered. Towards the inner medulla, only claudin 10 was present in TAL TJ strands. In summary, high-Ca(2+) diet induced a reduction of divalent cation reabsorption via a diminution of NaCl transport and driving force in mTAL and via decreased paracellular permeabilities in cTAL. We reveal an important regulatory pattern along the corticomedullary axis and improve the understanding how the kidney disposes of detrimental excess Ca(2+). PMID- 26497704 TI - Salts of 5-amino-2-sulfonamide-1,3,4-thiadiazole, a structural and analog of acetazolamide, show interesting carbonic anhydrase inhibitory properties, diuretic, and anticonvulsant action. AB - Three salts of 5-amino-2-sulfonamide-1,3,4-thiadiazole (Hats) were prepared and characterized by physico-chemical methods. The p-toluensulfonate, the methylsulfonate, and the chlorhydrate monohydrate salts of Hats were evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) and as anticonvulsants and diuretics, since many CAIs are clinically used as pharmacological agents. The three Hats salts exhibited diuretic and anticonvulsant activities with little neurotoxicity. The human (h) isoforms hCA I, II, IV, VII, IX, and XII were inhibited in their micromolar range by these salts, whereas pathogenic beta and gamma CAs showed similar, weak inhibitory profiles. PMID- 26497705 TI - Enhanced photovoltaic performance and time varied controllable growth of a CuS nanoplatelet structured thin film and its application as an efficient counter electrode for quantum dot-sensitized solar cells via a cost-effective chemical bath deposition. AB - For the first time we report a simple synthetic strategy to prepare copper sulfide counter electrodes on fluorine-doped tin oxide (FTO) substrates using the inexpensive chemical bath deposition method in the presence of hydrochloric acid (HCl) at different deposition times. CuS nanoplatelet structures were uniformly grown on the FTO substrate with a good dispersion and optimized conditions. The growth process of the CuS nanoplatelets can be controlled by changing the deposition time in the presence of HCl. HCl acts as a complexing agent as well as improving S(2-) concentration against S atoms in this one-step preparation. The photovoltaic performance was significantly improved in terms of the power conversion efficiency (PCE), short-circuit density (J(sc)), open-circuit voltage (V(oc)), and the fill factor (FF). The optimized deposition time of CuS 60 min resulted in a higher PCE of 4.06%, J(sc) of 12.92 mA cm(-2), V(oc) of 0.60 V, and a FF of 0.52 compared to CuS 50 min, CuS 70 min, and a Pt CE. The superior performance of the 60 min sample is due to the greater electrocatalytic activity and low charge transfer resistance at the interface of the CE and the polysulfide electrolyte. The concentration of Cu/S also had an important role in the formation of the CuS nanoplatelet structures. The optical bandgaps for the CuS with different morphologies were measured to be in the range of 1.98-2.28 eV. This improved photovoltaic performance is mainly attributed to the greater number of active reaction sites created by the CuS layer on the FTO substrate, which results large specific surface, superior electrical conductivity, low charge transfer resistance, and faster electron transport in the presence of HCl. Cyclic voltammetry, electrochemical impedance spectroscopy and Tafel-polarization measurements were used to investigate the electrocatalytic activity of the CuS and Pt CEs. This synthetic procedure not only provides high electrocatalytic activity for QDSSCs but could also be a cost-effective way to fabricate flexible electrodes in dye-sensitized solar cells or supercapacitor applications. PMID- 26497706 TI - Prevalence and correlates of overweight status among Saudi school children. AB - BACKGROUND AND OBJECTIVES: There are limited data on changes in the prevalence of overweight among the Saudi school children and on associated risk factors. We compared recent prevalence data (2012) with early data (1994-98) and assessed risk factors. DESIGN AND SETTING: Data from a cross-sectional study of children in primary schools in two cities in Al-Qassim province. PATIENTS AND METHODS: Parental questionnaires were used to collect sociodemographic data and informa.tion on the child's diet/exercise behavior. Children's weight and height were measured. Current and previous data on overweight prevalence were compared and risk factors were assessed in a multiple logistic regression model. RESULTS: The sample consisted of 874 randomly chosen school children, aged 6-10 years; analysis was based on 601 with complete data. Current overweight prevalence was 16.9% and was higher in girls than in boys (29.7% vs. 11.7%, P value < .0001). Prevalence has risen in the last 15 years (overall: 16.9% vs. 10.1%; boys: 11.7% vs. 8.5%; girls: 29.7% vs. 11.5%; all P values < .05). Those who ate restaurant food >=2 times/week were 2.4 times more likely (95% CI=1.26, 4.64) to be overweight and those who engaged in sports >=2 hours/day were 0.5 times less likely to be overweight (95% CI=0.25, 1.20). CONCLUSION: The overweight prevalence in primary school children in Saudi Arabia has risen significantly. The focus should be on developing obesity prevention programs for this population. PMID- 26497707 TI - Effects of energy drink consumption on corrected QT interval and heart rate variability in young obese Saudi male university students. AB - BACKGROUND AND OBJECTIVES: Consumption of energy drinks has adverse effects on the heart that might be potentiated in obese individuals. Since the incidence of obesity and use of energy drinks is high among Saudi youth, we used non-invasive tests to study hemodynamic changes produced by altered autonomic cardiac activ.ity following consumption of energy drinks in obese male students. DESIGN AND SETTING: This cross-sectional study was carried out at Department of Physiology, College of Medicine, University of Dammam, Saudi Arabia, over a one year period from December 2013 to December 2014. SUBJECTS AND METHODS: In Saudi male university students we measured continuous ECG recordings and a one-minute deep breathing maneuver to measure the expiratory-to-inspiratory ratio, the mean heart rate range (MHRR), the mean percentage variability. (M%VHR) and the corrected QT interval (QTc) at 0, 30 and 60 minutes after consumption of energy drink. RESULTS: We enrolled 31 students (18 overweight/obese and 13 normal weights. QTc was significantly in.creased at 60 min as compared with the resting state in overweight/obese subjects (P=.006). Heart rate variability was significantly less in obese as compared with normal weight subjects at 60 minutes as indicated by E:I ratio, (P=.037), MHRR (P=.012), M%VHR (P=.040) after energy drink consumption. Significant increases in diastolic (P=.020) and mean arterial blood pressure (P=.024) were observed at 30 minutes in the obese group. CONCLUSION: Hemodynamic changes after intake of energy drinks in obese subjects indicate that obesity and energy drinks could synergistically induce harmful effects. This finding warrants efforts to caution the obese on intake of energy drinks and timely intervention to motivate changes in lifestyle. PMID- 26497708 TI - Quality of healthcare for hemodialysis patients in various health sectors in Jeddah, Saudi Arabia. AB - BACKGROUND AND OBJECTIVE: We compared the adequacy of the management of hemodialysis patients in different health sectors in a major city in Saudi Arabia. DESIGN AND SETTINGS: Cross-sectional analytic study conducted in three different health sectors in Jeddah, Saudi Arabia. METHODS: Data was collected from nine hemodialysis centers, which represent three sectors: Ministry of Health, governmental (but not health ministry) hospitals, and charity centers. A simple random sampling tech.nique was employed for gathering data from the participating centers. Medical records were reviewed and all the relevant data were retrieved using a pre-designed form. RESULTS: In the 587 subjects, hypertension, diabetes mellitus and an idiopathic etiology accounted for 85.3% of end-stage renal disease. Only 25.4% of the patients had a hemoglobin level of 110 120 g/L and 12.1% achieved target levels of ferritin and transferrin saturation. The percentage of patients meeting targeted levels of calcium (2.1-2.38 mmol/L), phosphorous (1.13-1.78 mmol/L) and albumin (>=40 g/L) were 54.2%, 38.7% and 23.5%, respectively. The variation between different health sectors was statistically significant (P < .001). Arteriovenous fistula was used for 84% of the patients and catheter for 15.7%. CONCLUSION: The quality of healthcare for hemodialysis patients in Jeddah needs improvement to meet the recommendations of the Kidney Disease Outcomes Quality Initiative guidelines. PMID- 26497709 TI - Improvement of glucose and lipid metabolism with pegylated interferon-a plus ribavirin therapy in Chinese patients chronically infected with genotype 1b hepatitis C virus. AB - BACKGROUND: Many epidemiological studies have demonstrated a significant association between Type 2 diabetes mellitus and abnormal lipid profiles with chronic HCV genotype 1 (GT1) infection. We examined the impact on glucose and lipid profiles of treating Chinese patients using pegylated interferon (Peg-IFN) a and ribavirin (RBV). METHODS: We conducted a hospital-based clinical study of Chinese patients chronically infected with GT1b HCV. All the patients were treated for 48 weeks (PR48) with Peg-IFN-a (180 micro g once per week) or Peg-IFN a (1.5 micro g/kg once per week) plus RBV (15 mg/kg per day). Fasting blood glucose (FBG), postprandial blood glucose (PBG-2h), glycosylated hemoglobin (HbA1c), total cholesterol (TC) and triglyceride (TG) levels, were measured at baseline, during therapy, at the end of therapy and at follow-up. In addition, liver stiffness (LS) by transient elastography, HCV RNA and ALT levels were also measured. RESULTS: We enrolled 116 patients. At the end of treatment (EOT) (week 48), HCV RNA was negative in all patients, 77.6% (90/116) of patients achieved sustained virologic response (SVR) 24 weeks after EOT, and 22.4% (26/116) did not achieve SVR. All parameters associated with liver inflammation, liver fibrosis, glucose and lipid metabolism had decreased significantly compared with baseline (P < .05) in SVR patients. However, there were no obvious changes in lipid metabolism in non-SVR patients. CONCLUSION: PR48 therapy is still the primary treatment for Chinese patients with GT1b HCV infection and will remain so until oral anti-HCV agents are approved. It is beneficial in amelioration of liver histological status and glucose metabolism regardless of post-treatment virologic response. PMID- 26497710 TI - Coronary artery calcium score in high-risk asymptomatic women in Saudi Arabia. AB - BACKGROUND AND OBJECTIVE: Coronary artery calcification (CAC) is indicated by calcium deposits in the coronary artery wall. Calcification is a component of atherosclerosis and coronary artery disease. Currently, there are no data on calcification in Saudi women at high risk of coronary artery disease. The aim of this study was to investigate the prevalence and percentiles of CAC score in high risk asymptotic women in Saudi Arabia with comparison of age-specific CAC percentiles derived from large population-based published study in the United States. DESIGN AND SETTING: Retrospective analysis of CAC scores (CACS) at a single tertiary care center. METHODS: Between January 2011 and April 2015, women referred for CAC screening because of the presence of one or more CAD risk factors were enrolled in the study. CT scans were interpreted by an experienced radiographic technologist, and confirmed by a radiologist. RESULTS: The study sample consisted of 918 women, mean (SD) age of 55 (11) years. All patients were asymp.tomatic and referred by their primary care physician or cardiologist for CAC screening because presence of one or more CAD risks factors. CAD risk factors included diabetes, hypertension, hypercholesterolemia, family history of CAD, and obesity. Baseline CAD risk factors were remarkably higher than in the US comparator group. CACS for 25th, 50th, 75th, and 90th percentiles were calculated. The 75th and 90th CACS percentiles in Saudi women were significantly higher than the US percentiles. Age and diabetes are the most independent predictor of severity of CAC. LIMITATIONS: A potential bias due to sample collection because data was from a single tertiary care center, the study was retrospective and the sample size was small. CONCLUSION: There are significantly higher CACS percentiles in Saudi women compared with international data. Application of available published percentiles to a local population is not applicable and underestimates the severity of subclinical atherosclerosis. A large local population-based study is warranted to establish local CACS percentiles for a better understanding CAD screening, diagnosis, and treatment. PMID- 26497711 TI - Long-term outcomes of antiretroviral therapy in an adult HIV program: a 10-year retrospective cohort study in Kano, Nigeria. AB - BACKGROUND: Treatment outcomes from HIV/AIDS programs in resource-limited settings mostly describe short-term follow-up. We report 10-year treatment outcomes in an HIV clinic in Kano, Nigeria. METHODS: Using paper medical charts, the authors conducted a retrospective cohort study of patients that initiated ART from June 1, 2004 to December 31, 2007, and were followed up until June 30, 2014. The authors abstracted data from patient case files and did a time-to-event analysis on ART failure and loss to follow-up, and determined immunologic trends. RESULTS: The authors studied 345 patient records (29,860 person months of follow up); 82 records (23.7%) indicated that patients failed their first-line ART regimen at the rate of 2.75 failures per 1000 person-months. The estimates of durability on first-line ART regimen were 99.1% at 1 year and 59.0% at 10 years. Of the studied patients, 83.0% were still in care at the end of the 10-year period. Only being on abacavir (hazard ratio: 8.0) was a positive predictor of ART failure. CD4 increment at 4 years (hazard ratio: 0.9) and 5 years (hazard ratio: 0.9) were negative predictors. CONCLUSION: A high rate of long-term ART durability and modest long-term retention in care were achieved among our cohort. Improved availability of low-cost virologic and immunologic monitoring tools and provision of resistance testing technology will go a long way in improving early detection of treatment failure in the developing world. PMID- 26497713 TI - Basal cell adenocarcinoma of the buccal minor salivary gland with liver metastases. AB - Basal cell adenocarcinomas (BCACs) of salivary glands are rare malignant neoplasms that mostly affect the major salivary glands. They are generally considered low-grade carcinomas that are locally destruc.tive and tend to recur, but only occasionally metastasize. Currently there are only a few reported cases of distant metastases from BCAC, and metastasis to the liver is not previously described. We report the first case of BCAC with histologically confirmed liver metastases. A 40-year-old man presented with a 2-month history of a painless swelling in the left buccal region. The lesion was completely resected, and the patient underwent postoperative radiotherapy. Permanent histology and immunohistochemical studies revealed a BCAC of the buccal minor salivary gland. After 14 months, two hepatic metastatic nodules were detected. The patient underwent a partial hepatectomy with adjuvant chemotherapy. No evidence of progressive disease or further recurrence was observed for 20 months after the hepatic metastasectomy. BCACs grow indolently and long-term survival can be expected. Surgery should be considered in selected patients as a therapeutic option in metastatic disease. PMID- 26497712 TI - Eosinophil-related markers and total immunoglobulin E as a predictive marker for antibiotic response in chronic rhinosinusitis. AB - BACKGROUND AND OBJECTIVES: Chronic rhinosinusitis (CRS) is a commonly diagnosed disease that has a significant impact on a child's quality of life. However, no useful biomarker is available to identify antibiotic-responsive CRS. We determined the significance of eosinophil-related markers and total IgE levels in childhood CRS with regard to antibiotic response. DESIGN AND SETTING: This was a case-control study of patients admitted to Uijeongbu St. Mary's Hospital between November 2010 and November 2011 and diagnosed with CRS. PATIENTS AND METHODS: In this analytical cross-sectional study, we identified children whose symptoms and radiologic abnormalities did not resolve after 12 weeks despite appropriate antibiotics (non-responder CRS group), children whose symptoms and radiologic abnormalities resolved after 12 weeks with appropriate antibiotics (responder CRS group), and healthy controls selected from clinic patients. Skin prick tests were performed along with serum total IgE, total eosinophil count (TEC), serum eosinophil cationic protein (ECP) level, and ImmunoCAP analysis for common allergens. RESULTS: This study included 36 responders, 22 nonresponders and 22 healthy controls. The prevalence of allergic diseases, atopy, and a family history of allergic diseases were significantly higher in the non-responder group than in the responder and control groups. TEC, ECP, and total IgE levels were significantly higher in the non-responder group than in the responder and control groups (all P < .05). Multiple linear regression analysis showed that no response to appropriate antibiotics and TEC was positively associated with ECP concentration. CONCLUSION: These findings suggest that there is a high prevalence of allergic diseases in the non-responder group, that the TEC and ECP levels in the non-responder group are significantly higher than those in the responder group and controls, and that no response to antibiotics may be due to eosinophilic inflammation. The measurement of serum ECP may be useful in monitoring the progress of childhood CRS with regard to antibiotic response. PMID- 26497714 TI - Multifocal giant cell reparative granuloma involving maxilla and mandible: a rare entity. AB - Giant cell reparative granuloma (GCRG) is a rare lesion that is a reactive process, not a true neoplasm. It was originally coined by Jaffe to describe lesions, which he believed were a response to intraosseous hemorrhage from jaw trauma. Regardless, GCRG is much more distinct from giant cell tumor (GCT) of bone, both histologically and clinically. We report a patient who presented with multiple facial swelling involving the facial skeleton that showed a multiloculated cystic appearance on CT involving the maxilla and mandible. The patient refused surgery, but after 6 months of follow up there was no progression. PMID- 26497715 TI - Perforated obturator Littr hernia in an elderly woman. AB - Obturator hernia is an uncommon condition. It carries the highest mortality amongst abdominal wall hernias, usually presenting in elderly, multiparous and thin ladies. Meckel diverticulum is a rare cause of intestinal obstruction and its existence in an obturator hernia is extremely rare; our literature search revealed only two reported cases. We report the case of a 70-year-old woman who presented with signs and symptoms of intestinal obstruction and peritonitis. An exploratory laparotomy led to diagnosis of a strangulated obturator hernia. The sac contents included a Meckel diverticulum with a perforation at its base and a loop of the ileum. The ischemic ileal segment including the Meckel diverticulum was resected and a loop ileostomy was created. PMID- 26497716 TI - Pleural myelomatous involvement in multiple myeloma: five cases. AB - Pleural myelomatous involvement in multiple myeloma (MM) is rare, occurring in less than 1% of cases. We retrospectively studied five cases of patients with MM who developed myelomatous pleural effusions. Three men and 2 women with a mean age of 61 years presented with myelomatous pleural effusion. The pleural fluid electrophoresis revealed a peak of IgG in three cases, of IgA in one case, and of lambda light chains in one case, which were identical to that in the sera of the patients. Detection of typical plasma cells in pleural fluid cytology was contributive, and histologic confirmation by pleural biopsy was positive in four cases. Treatment consisted of chemotherapy. The clinical outcome was initially good, but relapses occurred in all cases early and were complicated by fatal infections. Myelomatous pleural effusion is a rare affection. It is usually a late complication associated with poor prognosis. PMID- 26497717 TI - Regulatory roles of grass carp EpCAM in cell morphology, proliferation and migration. AB - Epithelial cell adhesion molecule (EpCAM) is a Ca(2+)-independent and relatively weak adhesion molecule, which has been extensively investigated in mammalian models. However, the functional roles of its fish homolog are largely unknown. In the present study, we explored the biological properties of grass carp EpCAM (gcEpCAM) in a fish kidney cell line (CIK) via overexpression of gcEpCAM or gcEpCAM intracellular domain (gcEpICD) deletion mutant. Results showed that gcEpCAM overexpression significantly changed the cell morphology, and the proliferation of the cells transfected with gcEpCAM was significantly decreased when compared to the control cells, which is unexpectedly opposite to the increasing effects induced by its mammalian homolog. Moreover, overexpression of gcEpICD deletion mutant had no effect on cell proliferation, indicating gcEpICD's involvement in the cell growth control that is concerted with its role in mammalian model. Additionally, gcEpCAM overexpression increased cell migration which is at least partially consistent with the findings in mammalian cells in which EpCAM expression both positively and negatively affects cell migration. It is worth noting that gcEpICD was not essential to the stimulatory effect of gcEpCAM on cell migration, but overexpression of human EpICD in tumor cells increases cell migration, suggesting the functional discrepancy of EpICD in fish and mammals. In conclusion, we elucidated the cellular functionality of EpCAM in fish cells which will be of benefit to defining the functions of fish EpCAM and also provide rewarding information on the functional evolution of EpCAM in vertebrates. PMID- 26497718 TI - A luminescent down-shifting and moth-eyed anti-reflective film for highly efficient photovoltaic devices. AB - Adhesive polydimethylsiloxane (PDMS) films were developed to increase the performance of photovoltaic devices. The films combined two separate features of moth-eye patterns to reduce the reflection of incident light at the film surface and luminescent down-shifting (LDS) CdZnS/ZnS-core/shell quantum dots (QDs) to convert ultraviolet (UV) radiation into visible light at 445 nm. The films were both flexible and self-adhesive, easily attachable to any surface of a solar cell module. By simply attaching the developed films on high-efficiency GaAs solar cells, the short circuit current density and power conversion efficiency of the solar cells increased to 33.8 mA cm(-2) and 28.7%, by 1.1 mA cm(-2) and 0.9 percentage points in absolute values, respectively. We showed that the enhancement of the GaAs solar cells was attributed to both the anti-reflection (AR) properties of the moth-eye patterns and the LDS of QDs using a scattering matrix method and external quantum efficiency measurements. The developed films are versatile in application for solar cells, and expected to aid in overcoming limits of material absorption and device structures. PMID- 26497719 TI - Oral budesonide for induction of remission in ulcerative colitis. AB - BACKGROUND: Corticosteroids are first-line therapy for induction of remission in ulcerative colitis. Although corticosteroids may improve symptoms, they have significant adverse effects. Steroids which act topically, with less systemic side-effects may be more desirable. Budesonide is a topically acting corticosteroid with extensive first pass hepatic metabolism. There are currently three formulations of budesonide: two standard formulations including a controlled-ileal release capsule and a pH-dependent capsule both designed to release the drug in the distal small intestine and right colon; and the newer Budesonide-MMX(r) capsule designed to release the drug throughout the entire colon. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in ulcerative colitis. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Group Specialised Register from inception to April 2015. We also searched reference lists of articles, conference proceedings and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials comparing oral budesonide to placebo or another active therapy for induction of remission in ulcerative colitis were considered eligible. There were no exclusions based on patient age or the type, dose, duration or formulation of budesonide therapy. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted data and assessed study quality. Methodological quality was assessed using the Cochrane risk of bias tool. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. The primary outcome was induction of remission (as defined by the primary studies) at week eight. Secondary outcomes included clinical, endoscopic and histologic improvement, adverse events and early withdrawal. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome and the mean difference (MD) and corresponding 95% CI for each continuous outcome. Data were analysed on an intention-to-treat basis. MAIN RESULTS: Six studies (1808 participants) were included. Four studies compared budesonide MMX(r) with placebo, one small pilot study looked at clinical remission at week four, and was subsequently followed by three large, studies that assessed combined clinical and endoscopic remission at week eight. Although two placebo controlled studies had mesalamine and Entocort (standard budesonide) treatment arms, these studies were not sufficiently powered to compare Budesonide-MMX(r) with these active comparators. One small study compared standard budesonide with prednisolone and one study compared standard budesonide to mesalamine. Four studies were rated as low risk of bias and two studies had an unclear risk of bias. A pooled analysis of three studies (900 participants) showed that budesonide-MMX(r) 9 mg was significantly superior to placebo for inducing remission (combined clinical and endoscopic remission) at 8 weeks. Fifteen per cent (71/462) of budesonide-MMX(r) 9 mg patients achieved remission compared to 7% (30/438) of placebo patients (RR 2.25, 95% CI 1.50 to 3.39). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (101 events). A subgroup analysis by concurrent mesalamine use suggests higher efficacy in the 442 patients who were not considered to be mesalamine-refractory (RR 2.89, 95% CI 1.59 to 5.25). A subgroup analysis by disease location suggests budesonide is most effective in patients with left-sided disease (RR 2.98, 95% CI 1.56 to 5.67; 289 patients). A small pilot study reported no statistically significant difference in endoscopic remission between budesonide and prednisolone (RR 0.75, 95% CI 0.23 to 2.42; 72 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to unclear risk of bias and very sparse data (10 events). Standard oral budesonide was significantly less likely to induce clinical remission than oral mesalamine after 8 weeks of therapy (RR 0.72, 95% CI 0.57 to 0.91; 1 study, 343 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (161 events). Another study found no difference in remission rates between budesonide-MMX(r) 9 mg and mesalamine (RR 1.48, 95% CI 0.81 to 2.71; 247 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (37 events). One study found no difference in remission rates between budesonide-MMX(r) 9 mg and standard budesonide 9 mg (RR 1.38, 95% CI 0.72 to 2.65; 212 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). Suppression of plasma cortisol was more common in prednisolone-treated patients (RR 0.02, 95% CI 0.0 to 0.33). While budesonide does appear to suppress morning cortisol to some extent, mean morning cortisol values remained within the normal range in 2 large studies (n = 899) and there was no difference in glucocorticoid-related side-effects across different treatment groups. Further, study withdrawal due to adverse events was not more common in budesonide compared with placebo treated patients (RR 0.85, 95% CI 0.53 to 1.38). Common adverse events included worsening ulcerative colitis, headache, pyrexia, insomnia, back pain, nausea, abdominal pain, diarrhoea, flatulence and nasopharyngitis. AUTHORS' CONCLUSIONS: Moderate quality evidence to supports the use of oral budesonide-MMX(r) at a 9 mg daily dose for induction of remission in active ulcerative colitis, particularly in patients with left-sided colitis. Budesonide-MMX(r) 9 mg daily is effective for induction of remission in the presence or absence of concurrent 5-ASA therapy. Further, budesonide-MMX(r) appears to be safe, and does not lead to significant impairment of adrenocorticoid function compared to placebo. Moderate quality evidence from a single study suggests that mesalamine may be superior to standard budesonide for the treatment of active ulcerative colitis. Low quality evidence from one study found no difference in remission rates between budesonide MMX(r) and mesalamine. Very low quality evidence from one small study showed no difference in endoscopic remission rates between standard budesonide and prednisolone. Low quality evidence from one study showed no difference in remission rates between budesonide-MMX(r) and standard budesonide. Adequately powered studies are needed to allow conclusions regarding the comparative efficacy and safety of budesonide versus prednisolone, budesonide-MMX(r) versus standard budesonide and budesonide versus mesalamine. PMID- 26497720 TI - Mechanical origin of aftershocks. AB - Aftershocks are the most striking evidence of earthquake interactions and the physical mechanisms at the origin of their occurrence are still intensively debated. Novel insights stem from recent results on the influence of the faulting style on the aftershock organisation in magnitude and time. Our study shows that the size of the aftershock zone depends on the fault geometry. We find that positive correlations among parameters controlling aftershock occurrence in time, energy and space are a stable feature of seismicity independently of magnitude range and geographic areas. We explain the ensemble of experimental findings by means of a description of the Earth Crust as an heterogeneous elastic medium coupled with a Maxwell viscoelastic asthenosphere. Our results show that heterogeneous stress distribution in an elastic layer combined with a coupling to a viscous flow are sufficient ingredients to describe the physics of aftershock triggering. PMID- 26497721 TI - Can anesthetic-analgesic technique during primary cancer surgery affect recurrence or metastasis? AB - PURPOSE: Mortality among cancer patients is more commonly due to the effects of metastasis and recurrence as opposed to the primary tumour. Various perioperative factors have been implicated in tumour growth, including anesthetic agents and analgesia techniques. In this narrative review, we integrate this information to present a summary of the best available evidence to guide the conduct of anesthesia for primary cancer surgery. SOURCE: We conducted a search of the PubMed database up to May 31, 2015 to identify relevant literature using the search terms "anesthesia and metastases", "anesthetic drugs and cancer", "volatile anesthetic agents and cancer", and "anesthetic technique and cancer". PRINCIPAL FINDINGS: There is conflicting evidence regarding volatile agents; however, the majority of studies are in vitro, suggesting that these agents are associated with enhanced expression of tumourigenic markers as well as both proliferation and migration of cancer cells. Nitrous oxide has not been shown to have any effect on cancer recurrence. Local anesthetic agents may reduce the incidence of cancer recurrence through systemic anti-inflammatory action in addition to direct effects on the proliferation and migration of cancer cells. Nonsteroidal anti-inflammatory drugs affect cancer cells via inhibition of cyclooxygenase 2 (COX-2), which leads to reduced resistance of the cancer cell to apoptosis and reduced production of prostaglandins by cancer cells. Nonsteroidal anti-inflammatory drugs also suppress the cancer cell growth cycle through effects independent of COX-2 inhibition. Opioids have been shown to inhibit the function of natural killer cells and to stimulate cancer cell proliferation through effects on angiogenesis and tumour cell signalling pathways. Supplemental oxygen at the time of surgery has a proangiogenic effect on micrometastases, while the use of perioperative dexamethasone does not affect overall rates of cancer survival. CONCLUSIONS: Current laboratory research suggests that perioperative interventions may impact recurrence or metastasis through effects on cancer cell signalling, the immune response, or modulation of the neuroendocrine stress response. Further evidence is awaited from prospective randomized-controlled trials. Meanwhile, with limited data upon which to make strong recommendations, anesthesiologists should seek optimal anesthesia and analgesia for their patients based on individual risk-benefit analysis and best available evidence on outcomes other than cancer recurrence. PMID- 26497722 TI - The prescription opioid epidemic: a call to action for our profession. PMID- 26497723 TI - Outcomes in neuroanesthesia: What matters most? AB - PURPOSE: The goal of this narrative review is to consider and categorize the clinically relevant outcomes that have been previously investigated in neuroanesthesia and to propose the essential outcomes and directions that deserve priority in clinical care and future outcome-oriented research. PRINCIPAL FINDINGS: The current body of neuroanesthesia research has created an important and comprehensive fundamental knowledge base by defining the effect of anesthetic care on various outcomes. The translation of animal data to patients has been limited, however, and must be done cautiously. The literature to date has focused on short-term perioperative outcomes but should now shift towards understanding the role of the neuroanesthesiologist in long-term and disease-specific outcomes that are of great concern to patients. In addition, the term "neurologic outcome" is nonspecific and deserves a better definition,possibly through the integration of multiple scales and measurements. CONCLUSIONS: Future endeavours in neuroanesthesia research should advocate prospective randomized trials that focus on long-term neurologic outcomes. These initiatives will require coordination of multiple centres through a clinical trials network. PMID- 26497724 TI - Perioperative complications in adults with a posterior mediastinal mass: a retrospective observational cohort study. AB - BACKGROUND: We studied the incidence of perioperative complications in patients presenting with a posterior mediastinal mass and the possible predictors of complications in these patients. METHODS: We conducted a review of the perioperative records of patients aged over 18 years with a posterior mediastinal mass confirmed by computed tomography (CT) who were admitted for surgical procedures relating to the mass during 2004-2014. Perioperative complications were defined as 1) hypoxemia (pulse oximetry < 90% at a fraction of inspired oxygen of 1.0), 2) difficult ventilation (peak pressure > 40 cm H2O or respiratory acidosis with PaCO2 > 60 mmHg), and 3) hemodynamic instability (systolic pressure < 70 mmHg, pulse rate < 40 beats.min(-1) and/or > 120 beats.min(-1) for over five minutes). The review also extended to the first 24 hr postoperatively for cardiovascular and respiratory instability. RESULTS: Forty three patients underwent 44 procedures, and the surgery entailed resection of the mediastinal mass in all but one patient. All patients received general anesthesia following intravenous induction. In 43 of 44 cases, intubation was achieved uneventfully with direct laryngoscopy after neuromuscular blockade. The incidence of perioperative cardiopulmonary complications was seven of 44 (16%) procedures. Four of these involved severe hypoxemia, two concerned hemodynamic instability, and two led to postoperative respiratory distress. No cardiovascular collapse or complete airway occlusion occurred. All occurrences of intraoperative complications transpired mid-surgery - six of the seven with the patient in the lateral position. Patients who developed complications were more likely to have a mass with a larger diameter and evidence of airway compression on the preoperative CT scan. CONCLUSION: The incidence of perioperative complications in patients with a posterior mediastinal mass is not insignificant; however, no catastrophic airway or cardiopulmonary event was encountered in this study. PMID- 26497725 TI - Functional and aesthetic rehabilitation with maxillary prosthesis supported by two zygomatic implants for maxillary defect resulting from cancer ablative surgery: a case report/technique article. AB - We report herein a case of functional and aesthetic rehabilitation with maxillary prosthesis supported by only two zygomatic implants for a patient with severe maxillary defect resulting from subtotal maxillectomy for malignant melanoma of the upper gingiva. A 76-year-old woman was referred to our facility with non painful discoloration of the upper gingiva. After several examinations, a clinical diagnosis of malignant melanoma of the upper gingiva (cT3N1M0 stage IVA, American Joint Committee on Cancer) was made. Subtotal maxillectomy utilizing Le Fort I osteotomy and functional neck dissection were performed. A conventional resection denture was made and employed postoperatively, but was unable to be suitably retained due to insufficient residual maxillary structures. Six months after tumor resection, two zygomatic implants were inserted into bilateral zygomatic bones. Magnetic attachments were applied as a mechanism for attaching the implants and resection denture. After application of these implants, retention and stability of the prosthesis was considerably improved. The patient became able to eat a normal diet. From an aesthetic perspective, the depressed upper lip was also properly restored, leading to an acceptable facial appearance. PMID- 26497726 TI - Risk of thromboembolic disease in men with prostate cancer undergoing androgen deprivation therapy. AB - OBJECTIVES: To investigate the risk of thromboembolic disease (TED) in men with prostate cancer (PCa) on androgen deprivation therapy (ADT), while accounting for known TED risk factors. MATERIALS AND METHODS: We assessed TED risk for 42 263 men with PCa who were receiving ADT compared with a matched cohort of 190 930 without PCa. The associations between ADT and deep vein thrombosis (DVT) or pulmonary embolism (PE) were analysed using multivariate Cox proportional hazard regression models, while accounting for previous PCa-related surgeries and the following proxies for disease progression: transurethral resection of the prostate, palliative radiotherapy and nephrostomy. RESULTS: Between 1997 and 2013, 11 242 men with PCa received anti-androgen monotherapy, 26 959 men received gonadotropin-releasing hormone (GnRH) agonists, 1 091 men received combined androgen blockade and 3 789 men underwent orchiectomy. When accounting for previous surgeries and proxies of disease progression, GnRH agonist users and surgically castrated men had a higher risk of TED than the comparison cohort: hazard ratios (HRs) 1.67 (95% confidence interval [CI] 1.40-1.98) and 1.61 (95% CI 1.15-2.28), respectively. Men on anti-androgen monotherapy had a lower risk: HR for DVT 0.49 (95% CI 0.33-0.74). TED risk was highest among those who switched from anti-androgen to GnRH agonists: HR for PE 2.55 (95% CI 1.76-3.70). This increased from 2.52 (95% CI 1.54-4.12) in year 1, to 4.05 (95% CI 2.51-6.55) in year 2. CONCLUSION: The incidence of TED among men on ADT increased with the duration of therapy and the risk was highest for those who switched regimen, suggesting that disease progression as well as ADT contribute to the propagation of TED risk. Nonetheless, these findings support the hypothesis that only men with a relevant indication should receive systemic ADT. PMID- 26497727 TI - Informed Consent in Implantable BCI Research: Identifying Risks and Exploring Meaning. AB - Implantable brain-computer interface (BCI) technology is an expanding area of engineering research now moving into clinical application. Ensuring meaningful informed consent in implantable BCI research is an ethical imperative. The emerging and rapidly evolving nature of implantable BCI research makes identification of risks, a critical component of informed consent, a challenge. In this paper, 6 core risk domains relevant to implantable BCI research are identified-short and long term safety, cognitive and communicative impairment, inappropriate expectations, involuntariness, affective impairment, and privacy and security. Work in deep brain stimulation provides a useful starting point for understanding this core set of risks in implantable BCI. Three further risk domains-risks pertaining to identity, agency, and stigma-are identified. These risks are not typically part of formalized consent processes. It is important as informed consent practices are further developed for implantable BCI research that attention be paid not just to disclosing core research risks but exploring the meaning of BCI research with potential participants. PMID- 26497728 TI - A population-based analysis of the risk of drug interaction between clarithromycin and statins for hospitalisation or death. AB - BACKGROUND: Clarithromycin, known as a potent inhibitor of the cytochrome P450 isoenzyme CYP3A, may increase the plasma concentration of statins metabolized by this pathway; therefore, increase the risk of interaction with statins in reference to pharmacokinetic studies. This study aimed to characterize whether the concomitant use of a statin with clarithromycin is associated with serious outcomes among adult persons. METHODS: Health claims data of adult persons in the Regional Sickness Fund of Burgenland, Austria, who filled a prescription for clarithromycin between July 1, 2009 and June 30, 2012 were reviewed retrospectively. We assumed that the risk of hospitalisation increases acutely with the indication for taking an antibiotic, whereas statin use can be considered a chronic exposure with a low constant effect on hospitalisation. When defining the population as persons taking clarithromycin and the use of statins as the exposure we could achieve a comparable effect in both groups from the acute condition on hospitalisation. Therefore, we defined exposed patients as those who had overlapping treatment with a statin and unexposed controls as those who had filled a prescription for clarithromycin without concomitant statin therapy. Outcome was defined as a composite of hospital admission or death within 30 days after starting clarithromycin. We used generalised linear regression to model an association between outcome and exposure to statins. RESULTS: Among 28,484 prescriptions of clarithromycin, 2317 persons were co-exposed to statins. Co-administration of CYP3A4 metabolized statins and clarithromycin was associated with a 2.11 fold increased risk of death or hospitalisation (95 % confidence interval [CI]: 1.79-2.48). This effect was explained by age, evidence of cardiovascular disease, diabetes mellitus and utilization of other antibiotics (multivariable adjusted risk ratio: 1.02, 95 % CI: 0.85-1.22). The sensitivity analyses did not change the significance of effect. CONCLUSIONS: The risk for hospitalisation or death in persons receiving clarithromycin increases with age and cardiovascular disease but is not causally associated with statin clarithromycine co-administration. PMID- 26497729 TI - The roles of lithium-philic giant nitrogen-doped graphene in protecting micron sized silicon anode from fading. AB - A stable Si-based anode with a high initial coulombic efficiency (ICE) for lithium-ion batteries (LIB) is critical for energy storage. In the present paper, a new scalable method is adopted in combination with giant nitrogen-doped graphene and micron-size electrode materials. We first synthesize a new type of freestanding LIB anode composed of micron-sized Si (mSi) particles wrapped by giant nitrogen-doped graphene (mSi@GNG) film. High ICE (>85%) and long cycle life (more than 80 cycles) are obtained. In the mSi@GNG composite, preferential formation of a stable solid electrolyte interphase (SEI) on the surface of graphene sheets is achieved. The formation and components of SEI are identified for the first time by using UV-resonance Raman spectroscopy and Raman mapping, which will revive the study of formation and evolution of SEI by Raman. New mechanism is proposed that the giant graphene sheets protect the mSi particles from over-lithiation and fracture. Such a simple and scalable method may also be applied to other anode systems to boost their energy and power densities for LIB. PMID- 26497730 TI - Developing and piloting a peer mentoring intervention to reduce teenage pregnancy in looked-after children and care leavers: an exploratory randomised controlled trial. AB - BACKGROUND: Looked-after children (LAC) are at greater risk of teenage pregnancy than non-LAC, which is associated with adverse health and social consequences. Existing interventions have failed to reduce rates of teenage pregnancy in LAC. Peer mentoring is proposed as a means of addressing many of the factors associated with the increased risk of teenage pregnancy in this group. OBJECTIVE: To develop a peer mentoring intervention to reduce teenage pregnancy in LAC. DESIGN: Phase I and II randomised controlled trial of a peer mentoring intervention for LAC; scoping exercise and literature search; national surveys of social care professionals and LAC; and focus groups and interviews with social care professionals, mentors and mentees. SETTING: Three local authorities (LAs) in England. PARTICIPANTS: LAC aged 14-18 years (mentees/care as usual) and 19-25 years (mentors). INTERVENTION: Recruitment and training of mentors; randomisation and matching of mentors to mentees; and 1-year individual peer mentoring. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: pregnancy in LAC aged 14-18 years. SECONDARY OUTCOMES: sexual attitudes, behaviour and knowledge; psychological health; help seeking behaviour; locus of control; and attachment style. A health economic evaluation was also carried out. RESULTS: In total, 54% of target recruitment was reached for the exploratory trial and 13 out of 20 mentors (65%) and 19 out of 30 LAC aged 14-18 years (63%) (recruited during Phases I and II) were retained in the research. The training programme was acceptable and could be manualised and replicated. Recruitment and retention difficulties were attributed to systemic problems and LA lack of research infrastructure and lack of additional funding to support and sustain such an intervention. Mentees appeared to value the intervention but had difficulty in meeting weekly as required. Only one in four of the relationships continued for the full year. A future Phase III trial would require the intervention to be modified to include provision of group and individual peer mentoring; internal management of the project, with support from an external agency such as a charity or the voluntary sector; funds to cover LA research costs, including the appointment of a dedicated project co-ordinator; a reduction in the lower age for mentee recruitment and an increase in the mentor recruitment age to 21 years; and the introduction of a more formal recruitment and support structure for mentors. CONCLUSIONS: Given the problems identified and described in mounting this intervention, a new development phase followed by a small-scale exploratory trial incorporating these changes would be necessary before proceeding to a Phase III trial. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 85. See the NIHR Journals Library website for further project information. PMID- 26497731 TI - The Effects of Grain Boundaries on the Current Transport Properties in YBCO Coated Conductors. AB - We report a detailed study of the grain orientations and grain boundary (GB) networks in Y2O3 films grown on Ni-5 at.%W substrates. Electron back scatter diffraction (EBSD) exhibited different GB misorientation angle distributions, strongly decided by Y2O3 films with different textures. The subsequent yttria stabilized zirconia (YSZ) barrier and CeO2 cap layer were deposited on Y2O3 layers by radio frequency sputtering, and YBa2Cu3O7-delta (YBCO) films were deposited by pulsed laser deposition. For explicating the effects of the grain boundaries on the current carry capacity of YBCO films, a percolation model was proposed to calculate the critical current density (J c) which depended on different GB misorientation angle distributions. The significantly higher J c for the sample with sharper texture is believed to be attributed to improved GB misorientation angle distributions. PMID- 26497732 TI - Preparation of Stabilizer-Free Silver Nanoparticle-Coated Micropipettes as Surface-Enhanced Raman Scattering Substrate for Single Cell Detection. AB - In this work, we established a convenient while reproduceable method for stabilizer-free silver nanoparticle (AgNP)-coated micropipettes by the combination of magnetron sputtering and surface coupling agent. The clear surfaces of the AgNPs are beneficial for absorbing biological or functional molecules on their surfaces. By optimizing the operating parameters, such as sputtering current and sputtering time, the tip of micropipettes coated with AgNPs exhibits excellent surface-enhanced Raman scattering (SERS) performance. Finally, the Raman spectra of a single A549 lung adenocarcinoma cell are successfully acquired by these advanced SERS-active micropipettes. PMID- 26497733 TI - Enhance photoelectrochemical hydrogen-generation activity and stability of TiO2 nanorod arrays sensitized by PbS and CdS quantum dots under UV-visible light. AB - We develop a composite photoanode by sensitizing TiO2 nanorod arrays with PbS quantum dots (QDs) and CdS QDs. Benefitted from additional introduced PbS QDs and CdS QDs onto TiO2, the absorption of the composite photoanodes are broaden from UV to visible region. The experimental results showed that the PbS sandwiched between TiO2 and CdS cannot only broad the absorption properties but also improve the stability. The stability can be explained by the hole facile transmission from PbS to CdS because of the valence band offsets between PbS and CdS which cause a small energy barrier and reduce the hole accumulation. The photocurrent density reached 1.35 mA cm(-2) at 0.9716 V vs. RHE (0 V vs. Ag/AgCl, under 60 mW cm(-2) illumination) for TiO2/PbS/CdS. The highest photocurrent of TiO2/PbS/CdS can be explained by the smallest of total resistance (138 Omega cm(-2)) compared to TiO2/CdS and pristine TiO2. PMID- 26497734 TI - Nanoscale Relationship Between CD4 and CD25 of T Cells Visualized with NSOM/QD Based Dual-Color Imaging System. AB - In this study, by using of near-field scanning optical microscopy (NSOM)/immune labeling quantum dot (QD)-based dual-color imaging system, we achieved the direct visualization of nanoscale profiles for distribution and organization of CD4 and CD25 molecules in T cells. A novel and interesting finding was that though CD25 clustering as nanodomains were observed on the surface of CD4(+)CD25(high) regulatory T cells, these CD25 nanodomains were not co-localized with CD4 nanodomains. This result presented that the formation of these CD25 nanodomains on the surface of CD4(+)CD25(high) T cells were not associated with the response of T cell receptor (TCR)/CD3-dependent signal transduction. In contrast, on the surface of CD4(+)CD25(low) T cells, CD25 molecules distributed randomly without forming nanodomains while CD4 clustering as nanodomains can be observed; on the surface of CD8(+)CD25(+) T cells, CD25 clustering as nanodomains and co localization with CD8 nanodomains were observed. Collectively, above these results exhibited that TCR/CD3-based microdomains were indeed required for TCR/CD3-mediated T cells activation and enhanced the immune activity of CD4(+)CD25(low) T cells or CD8(+)CD25(+) T cells. In particular, it was found that the formation of CD25 nanodomains and their segregation from TCR/CD3 microdomains were the intrinsic capability of CD4(+)CD25(high) T cells, suggesting this specific imaging feature of CD25 should be greatly associated with the regulatory activity of CD4(+)CD25(high) T cells. Importantly, this novel NSOM/QD-based dual-color imaging system will provide a useful tool for the research of distribution-function relationship of cell-surface molecules. PMID- 26497735 TI - Human Multipotent Mesenchymal Stromal Cells in the Treatment of Postoperative Temporal Bone Defect: An Animal Model. AB - Canal wall down mastoidectomy is one of the most effective treatments for cholesteatoma. However, it results in anatomical changes in the external and middle ear with a negative impact on the patient's quality of life. To provide complete closure of the mastoid cavity and normalize the anatomy of the middle and external ear, we used human multipotent mesenchymal stromal cells (hMSCs), GMP grade, in a guinea pig model. A method for preparing a biomaterial composed of hMSCs, hydroxyapatite, and tissue glue was developed. Animals from the treated group were implanted with biomaterial composed of hydroxyapatite and hMSCs, while animals in the control group received hydroxyapatite alone. When compared to controls, the group implanted with hMSCs showed a significantly higher ratio of new bone formation (p = 0.00174), as well as a significantly higher volume percentage of new immature bone (p = 0.00166). Our results proved a beneficial effect of hMSCs on temporal bone formation and provided a promising tool to improve the quality of life of patients after canal wall down mastoidectomy by hMSC implantation. PMID- 26497736 TI - Transcatheter pulmonary and tricuspid valve-in-valve replacement for bioprosthesis degeneration in carcinoid heart disease. PMID- 26497739 TI - Theoretical maximum efficiency of solar energy conversion in plasmonic metal semiconductor heterojunctions. AB - Plasmonics can enhance solar energy conversion in semiconductors by light trapping, hot electron transfer, and plasmon-induced resonance energy transfer (PIRET). The multifaceted response of the plasmon and multiple interaction pathways with the semiconductor makes optimization challenging, hindering design of efficient plasmonic architectures. Therefore, in this paper we use a density matrix model to capture the interplay between scattering, hot electrons, and dipole-dipole coupling through the plasmon's dephasing, including both the coherent and incoherent dynamics necessary for interactions on the plasmon's timescale. The model is extended to Shockley-Queisser limit calculations for both photovoltaics and solar-to-chemical conversion, revealing the optimal application of each enhancement mechanism based on plasmon energy, semiconductor energy, and plasmon dephasing. The results guide application of plasmonic solar-energy harvesting, showing which enhancement mechanism is most appropriate for a given semiconductor's weakness, and what nanostructures can achieve the maximum enhancement. PMID- 26497737 TI - Intracardiac echocardiography for guidance of transcatheter aortic valve implantation under monitored sedation: a solution to a dilemma? AB - Transcatheter aortic valve implantation (TAVI) has been established as a valuable alternative to surgical aortic valve replacement in patients deemed to have high or prohibitive perioperative risk. However, there are several technical constraints and procedural risks inherent to TAVI. These risks include annulus rupture, ventricular perforation, aortic dissection, coronary occlusion, and dislodgement or migration of the valve prosthesis to the aorta or the left ventricle (LV). Other complications may be related to inappropriate valve deployment and subsequent paravalvular leak. Most complications cannot be detected at an early stage without echocardiographic guidance. Although not addressed by current guidelines, some European centres have advocated a 'minimalist' approach with exclusively fluoroscopic and angiographic guidance. Transoesophageal echocardiography (TEE), including real-time three-dimensional (RT-3D) imaging, has been established as a standard approach for peri interventional guidance of TAVI. However, TEE monitoring almost always necessitates general anaesthesia and endotracheal intubation. A potential alternative to TEE is intracardiac echocardiography (ICE) that may provide a solution to a common dilemma: the most important advantage of ICE being the compatibility with monitored anaesthesia care without endotracheal intubation. Other advantages of ICE include uninterrupted monitoring, no fluoroscopic interference, and precise Doppler-based assessment of pulmonary artery pressures. Limitations of ICE include the need for additional venous access, the learning curve associated with a new device, and potentially increased cost. PMID- 26497740 TI - The NF-kappaB p65 and p50 homodimer cooperate with IRF8 to activate iNOS transcription. AB - BACKGROUND: Inducible nitric oxide synthase (iNOS) metabolizes L-arginine to produce nitric oxide (NO) which was originally identified in myeloid cells as a host defense mechanism against pathogens. Recent studies, however, have revealed that iNOS is often induced in tumor cells and myeloid cells in the tumor microenvironment. Compelling experimental data have shown that iNOS promotes tumor development in certain cellular context and suppresses tumor development in other cellular conditions. The molecular mechanisms underlying these contrasting functions of iNOS is unknown. Because iNOS is often induced by inflammatory signals, it is therefore likely that these contrasting functions of iNOS could be controlled by the inflammatory signaling pathways, which remains to be determined. METHODS: iNOS is expressed in colon carcinoma and myeloid cells in the tumor microenvironment. Colon carcinoma and myeloid cell lines were used to elucidate the molecular mechanisms underlying iNOS expression. Chromatin immunoprecipitation and electrophoretic mobility shift assay were used to determine the IFNgamma-activated pSTAT1 and NF-kappaB association with the chromatin DNA of the nos2 promoter. RESULTS: We show here that iNOS is dramatically up-regulated in inflammed human colon tissues and in human colon carcinoma as compared to normal colon tissue. iNOS is expressed in either the colon carcinoma cells or immune cells within the tumor microenvironment. On the molecular level, the proinflammatory IFNgamma and NF-kappaB signals induce iNOS expression in human colon cancer cells. We further demonstrate that NF-kappaB directly binds to the NOS2 promoter to regulate iNOS expression. Although neither the IFNgamma signaling pathway nor the NF-kappaB signaling pathway alone is sufficient to induce iNOS expression in myeloid cells, IFNgamma and NF-kappaB synergistically induce iNOS expression in myeloid cells. Furthermore, we determine that IFNgamma up-regulates IRF8 expression to augment NF-kappaB induction of iNOS expression. More interestingly, we observed that the p65/p65 and p50/p50 homodimers, not the canonical p65/p50 heterodimer, directly binds to the nos2 promoter to regulate iNOS expression in myeloid cells. CONCLUSIONS: IFNgamma-induced IRF8 acts in concert with NF-kappaB to regulate iNOS expression in both colon carcinoma and myeloid cells. In myeloid cells, the NF-kappaB complexes that bind to the nos2 promoter are p65/p65 and p50/p50 homodimers. PMID- 26497741 TI - Bushen Zhuangjin decoction inhibits TM-induced chondrocyte apoptosis mediated by endoplasmic reticulum stress. AB - Chondrocyte apoptosis triggered by endoplasmic reticulum (ER) stress plays a vital role in the pathogenesis of osteoarthritis (OA). Bushen Zhuangjin decoction (BZD) has been widely used in the treatment of OA. However, the cellular and molecular mechanisms responsible for the inhibitory effects of BZD on chondrocyte apoptosis remain to be elucidated. In the present study, we investigated the effects of BZD on ER stress-induced chondrocyte apoptosis using a chondrocyte in vitro model of OA. Chondrocytes obtained from the articular cartilage of the knee joints of Sprague Dawley (SD) rats were detected by immunohistochemical staining for type II collagen. The ER stress-mediated apoptosis of tunicamycin (TM) stimulated chondrocytes was detected using 4-phenylbutyric acid (4-PBA). We found that 4-PBA inhibited TM-induced chondrocyte apoptosis, which confirmed the successful induction of chondrocyte apoptosis. BZD enhanced the viability of the TM-stimulated chondrocytes in a dose- and time-dependent manner, as shown by MTT assay. The apoptotic rate and the loss of mitochondrial membrane potential (DeltaPsim) of the TM-stimulated chondrocytes treated with BZD was markedly decreased compared with those of chondrocytes not treated with BZD, as shown by 4',6-diamidino-2-phenylindole (DAPI) staining, Annexin V-FITC binding assay and JC-1 assay. To further elucidate the mechanisms responsible for the inhibitory effects of BZD on TM-induced chondrocyte apoptosis mediated by ER stress, the mRNA and protein expression levels of binding immunoglobulin protein (Bip), X-box binding protein 1 (Xbp1), activating transcription factor 4 (Atf4), C/EBP homologous protein (Chop), caspase-9, caspase-3, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were measured by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis. In the TM stimulated chondrocytes treated with BZD, the mRNA and protein expression levels of Bip, Atf4, Chop, caspase-9, caspase-3 and Bax were significantly decreased, whereas the mRNA and protein expression levels of Xbp1 and Bcl-2 were significantly increased compared with the TM-stimulated chondrocytes not treated with BZD. Additionally, all our findings demonstrated that there was no significant difference between the TM-stimulated chondrocytes treated with BZD and those treated with 4-PBA. Taken together, our results indicate that BZD inhibits TM-induced chondrocyte apoptosis mediated by ER stress. Thus, BZD may be a potential therapeutic agent for use in the treatment of OA. PMID- 26497742 TI - Antioxidant, antibacterial activity, and phytochemical characterization of Melaleuca cajuputi extract. AB - BACKGROUND: The threat posed by drug-resistant pathogens has resulted in the increasing momentum in research and development for effective alternative medications. The antioxidant and antibacterial properties of phytochemical extracts makes them attractive alternative complementary medicines. Therefore, this study evaluated the phytochemical constituents of Melaleuca cajuputi flower and leaf (GF and GL, respectively) extracts and their antioxidant and antibacterial activities. METHODS: Radical scavenging capacity of the extracts was estimated using 2,2-diphenyl-2-picrylhydrazyl and Fe(2+)-chelating activity. Total antioxidant activity was determined using ferric reducing antioxidant power assay. Well diffusion, minimum inhibitory concentration, and minimum bactericidal concentration assays were used to determine antibacterial activity against eight pathogens, namely Staphylococcus aureus, Escherichia coli, Bacillus cereus, Staphylococcus epidermidis, Salmonella typhimurium, Klebsiella pneumonia, Streptococcus pneumoniae, and Pasteurella multocida. We identified and quantified the phytochemical constituents in methanol extracts using liquid chromatography/mass spectrometry (LC/MS) and gas chromatography (GC)/MS. RESULTS: This study reports the antioxidant and radical scavenging activity of M. cajuputi methanolic extracts. The GF extract showed better efficacy than that of the GL extract. The total phenolic contents were higher in the flower extract than they were in the leaf extract (0.55 +/- 0.05 and 0.37 +/- 0.05 gallic acid equivalent per mg extract dry weight, respectively). As expected, the percentage radical inhibition by GF was higher than that by the GL extract (81 and 75 %, respectively). A similar trend was observed in Fe(2+)-chelating activity and beta carotene bleaching tests. The antibacterial assay of the extracts revealed no inhibition zones with the Gram-negative bacteria tested. However, the extracts demonstrated activity against B. cereus, S. aureus, and S. epidermidis. CONCLUSIONS: In this study, we found that M. cajuputi extracts possess antioxidant and antibacterial activities. The results revealed that both extracts had significant antioxidant and free radical-scavenging activity. Both extracts had antibacterial activity against S. aureus, S. epidermidis, and B. cereus. The antioxidant and antimicrobial activities could be attributed to high flavonoid and phenolic contents identified using GC/MS and LC/MS. Therefore, M. cajuputi could be an excellent source for natural antioxidant and antibacterial agents for medical and nutraceutical applications. PMID- 26497744 TI - Quasiparticle spin resonance and coherence in superconducting aluminium. AB - Conventional superconductors were long thought to be spin inert; however, there is now increasing interest in both (the manipulation of) the internal spin structure of the ground-state condensate, as well as recently observed long lived, spin-polarized excitations (quasiparticles). We demonstrate spin resonance in the quasiparticle population of a mesoscopic superconductor (aluminium) using novel on-chip microwave detection techniques. The spin decoherence time obtained (~100 ps), and its dependence on the sample thickness are consistent with Elliott Yafet spin-orbit scattering as the main decoherence mechanism. The striking divergence between the spin coherence time and the previously measured spin imbalance relaxation time (~10 ns) suggests that the latter is limited instead by inelastic processes. This work stakes out new ground for the nascent field of spin-based electronics with superconductors or superconducting spintronics. PMID- 26497743 TI - Complexity of FGFR signalling in metastatic urothelial cancer. AB - BACKGROUND: Urothelial cancers (UC) are the fourth most common tumours worldwide after prostate (or breast), lung and colorectal cancer. Despite recent improvements in their management, UC remain an aggressive disease associated with a poor outcome. Following disease progression on first-line platinum-based chemotherapy, very few effective treatment options are available and none of them have shown significant improvement in overall survival. Alterations of the fibroblast growth factor receptor (FGFR) pathway including amplification, mutations and overexpression are common in UC. Pre-clinical data suggest that the presence of such dysregulations may confer sensitivity to FGFR inhibitors. MATERIALS AND METHODS: We present here the case of a patient with a metastatic UC of the renal pelvis with lymph node metastases treated with the selective FGFR inhibitor AZD4547. RESULTS: To date, the patient has been on a study drug for 32 months with acceptable tolerance and maintained radiological partial response as per RECIST 1.1 criteria. Exploratory biomarker analysis showed FGFR3, FGFR1, FGF ligand and fibroblast growth factor receptor substrate 2 (FRS2) expression in the patient's tumour, together with the presence of a germ-line mutation in the FGFR3 extracellular binding domain. This is not a known hotspot mutation, and the functional significance remains unclear. CONCLUSIONS: The FGFR inhibitor AZD4547 exhibits antitumour activity in a metastatic urothelial cancer displaying FGFR1, FGFR3, FGF-ligand and FRS2 expression. This lends support to the further exploration of FGFR inhibitors in urothelial cancer. Further studies are required to determinate the most effective way to select those patients most likely to respond. PMID- 26497745 TI - Prevalence, associated factors and predictors of anxiety: a community survey in Selangor, Malaysia. AB - BACKGROUND: Anxiety is the most common mental health disorders in the general population. This study aimed to determine the prevalence of anxiety, its associated factors and the predictors of anxiety among adults in the community of Selangor, Malaysia. METHODS: A cross sectional study was carried out in three districts in Selangor, Malaysia. The inclusion criteria of this study were Malaysian citizens, adults aged 18 years and above, and living in the selected living quarters based on the list provided by the Department of Statistics Malaysia (DOS). Participants completed a set of questionnaires, including the validated Malay version of Generalized Anxiety Disorder 7 (GAD 7) to detect anxiety. RESULTS: Of the 2512 participants who were approached, 1556 of them participated in the study (61.90%). Based on the cut-off point of 8 and above in the GAD-7, the prevalence of anxiety was 8.2%. Based on the initial multiple logistic regression analysis, the predictors of anxiety were depression, serious problems at work, domestic violence and high perceived stress. When reanalyzed again after removing depression, low self-esteem and high perceived stress, six predictors that were identified are cancer, serious problems at work, domestic violence, unhappy relationship with family, non-organizational religious activity and intrinsic religiosity. CONCLUSION: This study reports the prevalence of anxiety among adults in the community of Selangor, Malaysia and also the magnitude of the associations between various factors and anxiety. PMID- 26497746 TI - The relationship between Fibroblast Growth Factor-21 and characteristic parameters related to energy balance in dairy cows. AB - BACKGROUND: Negative energy balance (NEB) is a common pathological foundation of ketosis and fatty liver. Liver and fat tissue are the major organs of lipid metabolism and take part in modulating lipid oxidative capacity and energy demands, which is also a key metabolic pathway that regulates NEB develop during perinatal period. Fibroblast growth factor-21 (FGF-21) is a recently discovered protein hormone that plays an important and specific regulating role in adipose lipid metabolism and liver gluconeogenesis for human and mouse. Our aim is to investigate the variation and relationship between serum FGF-21 concentration and characteristic parameters related to negative energy balance in different energy metabolism state. METHODS: In this research, five non-pregnant, non-lactating Holstein-Friesian dairy cows were randomly allocated into two groups. The interventions were a controlled-energy diet (30% of maintenance energy requirements) and a moderate-energy diet (120% of predicted energy requirements) that lasted for the duration of the experiment. We measured biochemical parameters, serum FGF-21, leptin and insulin levels by commercial ELISA kits. RESULTS: The results showed that serum FGF-21 levels were significantly higher in both groups treated with a controlled-energy diet, while FGF-21 levels in both groups treated with moderate-energy diet were low. FGF-21 levels exhibited a significant positive correlation with serum leptin levels, while an inverse relationship was found between FGF-21 and blood glucose and beta-hydroxybutyrate acid (BHBA) levels. CONCLUSION: An increase in FGF-21 levels after a controlled energy diet treatment may contribute to a positive metabolic effect which could result in a new theoretical and practical basis for the preventive strategy of dairy cows with NEB. PMID- 26497747 TI - Development and validation of the Comprehensive Quality of Life Outcome (CoQoLo) inventory for patients with advanced cancer. AB - BACKGROUND: The purpose of this study was to develop a scale capable of measuring comprehensive quality of life (QOL) outcomes based on the concept of a good death for patients with advanced cancer. METHODS: We conducted an anonymous cross sectional questionnaire survey on inpatients being treated at the Oncology Clinic in Saitama Medical University International Medical Center and seven palliative units throughout Japan. RESULTS: A total of 405 patients with cancer participated in this study. Factor analysis of scores on the Comprehensive Quality of Life Outcome (CoQoLo) inventory revealed 28 items and the following 10 subscales: physical and psychological comfort; staying in a favourite place; maintaining hope and pleasure; good relationships with medical staff; not being a burden to others; good relationships with family; independence; environmental comfort; being respected as an individual; and having a fulfilling life. The total CoQoLo score was moderately correlated with satisfaction (r=0.34) and overall QOL (r=0.34), and moderately correlated with feelings of support and security regarding cancer care (r=0.44). Cronbach's alpha and the intraclass correlation coefficient of the total score were 0.90 and 0.79, respectively. No significant correlation was found between the total CoQoLo score and self-reported Eastern Cooperative Oncology Group performance status (r=-0.01). CONCLUSIONS: These results suggest that the CoQoLo has sufficient reliability and validity and therefore provides an accurate measure of QOL outcomes independent of the general physical condition of the patient. PMID- 26497748 TI - Aiming for a representative sample: Simulating random versus purposive strategies for hospital selection. AB - BACKGROUND: A ubiquitous issue in research is that of selecting a representative sample from the study population. While random sampling strategies are the gold standard, in practice, random sampling of participants is not always feasible nor necessarily the optimal choice. In our case, a selection must be made of 12 hospitals (out of 89 Dutch hospitals in total). With this selection of 12 hospitals, it should be possible to estimate blood use in the remaining hospitals as well. In this paper, we evaluate both random and purposive strategies for the case of estimating blood use in Dutch hospitals. METHODS: Available population wide data on hospital blood use and number of hospital beds are used to simulate five sampling strategies: (1) select only the largest hospitals, (2) select the largest and the smallest hospitals ('maximum variation'), (3) select hospitals randomly, (4) select hospitals from as many different geographic regions as possible, (5) select hospitals from only two regions. Simulations of each strategy result in different selections of hospitals, that are each used to estimate blood use in the remaining hospitals. The estimates are compared to the actual population values; the subsequent prediction errors are used to indicate the quality of the sampling strategy. RESULTS: The strategy leading to the lowest prediction error in the case study was maximum variation sampling, followed by random, regional variation and two-region sampling, with sampling the largest hospitals resulting in the worst performance. Maximum variation sampling led to a hospital level prediction error of 15%, whereas random sampling led to a prediction error of 19% (95% CI 17%-26%). While lowering the sample size reduced the differences between maximum variation and the random strategies, increasing sample size to n = 18 did not change the ranking of the strategies and led to only slightly better predictions. CONCLUSIONS: The optimal strategy for estimating blood use was maximum variation sampling. When proxy data are available, it is possible to evaluate random and purposive sampling strategies using simulations before the start of the study. The results enable researchers to make a more educated choice of an appropriate sampling strategy. PMID- 26497749 TI - Transient neurological deficit due to a misplacement of central venous catheter despite ultrasound guidance and ultrasound assistance. AB - Central venous catheters (CVC) are frequently used in intensive care units (ICU), with a low incidence of complications, most of them being of mechanical origin and occurring during the insertion of the catheter. To avoid such complications, "ultrasound guidance" and "ultrasound assistance" are recommended. Nevertheless, even with trained and experienced physicians, mechanical complications of IJV access such as carotid punctures are still reported. We report the case of a 75 year-old woman, admitted into the ICU for CVC insertion due to impossibility of peripheral venous access. About 12 hours after the procedure, the patient presented a neurological deficit. The cervical and thoracic CT scan showed a transfixing path of the catheter from the left IJV into the left common carotid artery, with distal extremity of the catheter localized in the ascending aorta. The catheter was removed, and thereafter the neurological deficit immediately and definitely disappeared. Onset of a neurological deficit after CVC insertion into the IJV, regardless the time of occurrence after the procedure, should suggest complication due to the CVC insertion, even if procedure was uneventful and chest radiography confirmed the apparent accurate position of CVC. PMID- 26497750 TI - Modelling estimates of the burden of Respiratory Syncytial virus infection in adults and the elderly in the United Kingdom. AB - BACKGROUND: Growing evidence suggests respiratory syncytial virus (RSV) is an important cause of respiratory disease in adults. However, the adult burden remains largely uncharacterized as most RSV studies focus on children, and population-based studies with laboratory-confirmation of infection are difficult to implement. Indirect modelling methods, long used for influenza, can further our understanding of RSV burden by circumventing some limitations of traditional surveillance studies that rely on direct linkage of individual-level exposure and outcome data. METHODS: Multiple linear time-series regression was used to estimate RSV burden in the United Kingdom (UK) between 1995 and 2009 among the total population and adults in terms of general practice (GP) episodes (counted as first consultation >=28 days following any previous consultation for same diagnosis/diagnostic group), hospitalisations, and deaths for respiratory disease, using data from Public Health England weekly influenza/RSV surveillance, Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics. The main outcome considered all ICD-listed respiratory diseases and, for GP episodes, related symptoms. Estimates were adjusted for non specific seasonal drivers of disease using secular cyclical terms and stratified by age and risk group (according to chronic conditions indicating severe influenza risk as per UK recommendations for influenza vaccination). Trial registration NCT01706302 . Registered 11 October 2012. RESULTS: Among adults aged 18+ years an estimated 487,247 GP episodes, 17,799 hospitalisations, and 8,482 deaths were attributable to RSV per average season. Of these, 175,070 GP episodes (36 %), 14,039 hospitalisations (79 %) and 7,915 deaths (93 %) were in persons aged 65+ years. High- versus low-risk elderly were two-fold more likely to have a RSV-related GP episode or death and four-fold more likely be hospitalised for RSV. In most seasons since 2001, more GP episodes, hospitalisations and deaths were attributable to RSV in adults than to influenza. CONCLUSION: RSV is associated with a substantial disease burden in adults comparable to influenza, with most of the hospitalisation and mortality burden in the elderly. Treatment options and measures to prevent RSV could have a major impact on the burden of RSV respiratory disease in adults, especially the elderly. PMID- 26497751 TI - Delivery of HIV Transmission Risk-Reduction Services by HIV Care Providers in the United States-2013. AB - OBJECTIVES: Evidence-based guidelines have long recommended that HIV care providers deliver HIV transmission risk-reduction (RR) services, but recent data are needed to assess their adoption. METHODS: The authors surveyed a probability sample of 1234 US HIV care providers on delivery of 9 sexual behavior- and 7 substance use-related HIV transmission RR services and created an indicator of "adequate" delivery of services in each area, defined as performing approximately 70% or more of applicable services. RESULTS: Providers were most likely to encourage patients to disclose HIV status to all partners since HIV diagnosis (81%) and least likely to ask about disclosure to new sex and drug injection partners at follow-up visits (both 41%). Adequate delivery of sexual behavior- and substance use-related RR services was low (37% and 43%, respectively). CONCLUSION: The majority of US HIV care providers may need additional support to improve delivery of comprehensive HIV transmission RR services. PMID- 26497752 TI - Profile of differentially expressed miRNAs in high-grade serous carcinoma and clear cell ovarian carcinoma, and the expression of miR-510 in ovarian carcinoma. AB - Improved insight into the molecular and genetic profile of different types of epithelial ovarian cancer (EOC) is required for understanding the carcinogenesis of EOC and may potentially be exploited by future targeted therapies. The aim of the present study was to identify a unique microRNA (miRNA) patterns and key miRNAs, which may assist in predicting progression and prognosis in high-grade serous carcinoma (HGSC) and clear cell carcinoma (CCC). To identify unique miRNA patterns associated with HGSC and CCC, a miRNA microarray was performed using Chinese tumor bank specimens of patients with HGSC or CCC in a retrospective analysis. The expression levels of four deregulated miRNAs were further validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in an external cohort of 42 cases of HGSC and 36 cases of CCC. Kaplan-Meier analysis was performed to analyze the correlation between the expression levels of the four miRNAs and patient prognosis. Among these validated miRNAs, miR-510 was further examined in another cohort of normal ovarian tissues, as well as the HGSC, low-grade serous carcinoma (LGSC) and CCC specimens using RT-qPCR and in situ hybridization. The results revealed that, of the 768 miRNAs analyzed in the microarray, 33 and 50 miRNAs were significantly upregulated and downregulated, respectively, with at least a 2-fold difference in HGSC, compared with CCC. The quantitative analysis demonstrated that miR-510 and miR-129-3p were significantly downregulated, and that miR-483-5p and miR-miR-449a were significantly upregulated in CCC, compared with HGSC (P<0.05), which was consistent with the microarray results. Kaplan-Meier analysis revealed low expression levels of miR 510 and low expression levels of miR-129-3p, advanced International Federation of Gynecology and Obstetrics (FIGO) stage, lymphatic metastasis and that HGSC was significantly associated with the poorer overall survival rates (P<0.05). The expression of miR-510 was significantly higher in the LGSC and CCC tissues, compared with the HGSC and normal ovarian tissues. The results of the present study suggested that different subtypes of EOC have specific miRNA signatures, and that miR-510 may be involved differently in HGSC and CCC. Thus, miR-510 and miR-129-3p may be considered as potential novel candidate clinical biomarkers for predicting the outcome of EOC. PMID- 26497753 TI - Modeling Yeast Organelle Membranes and How Lipid Diversity Influences Bilayer Properties. AB - Membrane lipids are important for the health and proper function of cell membranes. We have improved computational membrane models for specific organelles in yeast Saccharomyces cerevisiae to study the effect of lipid diversity on membrane structure and dynamics. Previous molecular dynamics simulations were performed by Jo et al. [(2009) Biophys J. 97, 50-58] on yeast membrane models having six lipid types with compositions averaged between the endoplasmic reticulum (ER) and the plasma membrane (PM). We incorporated ergosterol, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol lipids in our models to better describe the unique composition of the PM, ER, and trans-Golgi network (TGN) bilayers of yeast. Our results describe membrane structure based on order parameters (SCD), electron density profiles (EDPs), and lipid packing. The average surface area per lipid decreased from 63.8 +/- 0.4 A(2) in the ER to 47.1 +/- 0.3 A(2) in the PM, while the compressibility modulus (KA) varied in the opposite direction. The high SCD values for the PM lipids indicated a more ordered bilayer core, while the corresponding lipids in the ER and TGN models had lower parameters by a factor of at least 0.7. The hydrophobic core thickness (2DC) as estimated from EDPs is the thickest for PM, which is in agreement with estimates of hydrophobic regions of transmembrane proteins from the Orientation of Proteins in Membranes database. Our results show the importance of lipid diversity and composition on a bilayer's structural and mechanical properties, which in turn influences interactions with the proteins and membrane-bound molecules. PMID- 26497754 TI - Needs Perceived by Parents of Preterm Infants: Integrating Care Into the Early Discharge Process. AB - The birth of a preterm infant can have a great emotional impact on the parents when the length of stay is long. Early discharge programs facilitate the transition to the home and have beneficial effects on both the parents and children. However, only a few studies have been conducted to identify the real needs of parents of preterm infants and to determine whether early discharge programs meet such needs. The main objective of this study was to identify the experiences and obstacles, during hospitalization and after discharge, of fathers and mothers of preterm infants who did or did not participate in an early discharge program. METHOD: A qualitative study using semi-structured interviews was performed and included 23 parents of preterm infants. Thematic analysis was performed with the assistance of Atlas.ti 6.2 software. RESULTS: Two main themes were identified: the emotional experience and obstacles to care during hospitalization and the emotional experiences and obstacles at home related to the early discharge program. The results indicated that preterm birth initially has a deep emotional impact on parents. DISCUSSION: There is a remarkable lack of coordination regarding the information provided to parents on their infant's health status. Being first-time parents seems to be an important factor, although further evidence supporting this notion should be provided. CONCLUSION: Parents considered early discharge programs to be very useful in addressing the emotional aspects of hospitalization and the acquisition of neonatal care skills. Parents claim that the coordination and the information provided should be improved. PMID- 26497755 TI - Altered Metabolic Profile With Sodium-Restricted Dietary Approaches to Stop Hypertension Diet in Hypertensive Heart Failure With Preserved Ejection Fraction. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as a distinct entity with unique pathophysiology. In the Dietary Approaches to Stop Hypertension in Diastolic Heart Failure (DASH-DHF) study, the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) was associated with improved blood pressure and cardiovascular function in 13 hypertensive patients with HFpEF. With the use of targeted metabolomics, we explored metabolite changes and their relationship with energy dependent measures of cardiac function in DASH-DHF. METHODS AND RESULTS: With the use of chromatography and mass spectrometry, 152 metabolites including amino acids, free fatty acids, phospholipids, diglycerides, triglycerides, cholesterol esters, and acyl carnitines were measured. Comparison of baseline and post DASH/SRD samples revealed increases in short-chain acetyl, butryl, and propionyl carnitines (P values .02, .03, .03, respectively). Increases in propionyl carnitine correlated with ventricular-arterial coupling ratio (Ees:Ea; r = 0.78; P = .005) and ventricular contractility (maximum rate of change of pressure normalized stress [dsigma*/dtmax]; r = 0.66; P = .03). Changes in L-carnitine also correlated with Ees:Ea (r = 0.62; P = .04) and dsigma*/dtmax (r = 0.60; P = .05) and inversely with ventricular stiffness (r = -0.63; P = .03). CONCLUSIONS: Metabolite profile changes of patients with HFpEF during dietary modification with the use of DASH/SRD suggest improved energy substrate utilization. Additional studies are needed to clarify connections between diet, metabolic changes, and myocardial function in HFpEF. PMID- 26497757 TI - Determining the Role of Thiamine Deficiency in Systolic Heart Failure: A Meta Analysis and Systematic Review. AB - BACKGROUND: Approximately 5.7 million Americans carry the diagnosis of systolic heart failure (HF), a major health care burden. HF is a known manifestation of thiamine deficiency (TD). HF patients are at unique risk for developing TD, which may contribute to further altered cardiac function and symptoms. METHODS AND RESULTS: We performed a systematic review of the literature and a meta-analysis to evaluate the prevalence of TD in HF patients, risk factors for and mechanisms of development of TD in HF population, and outcomes of thiamine supplementation in HF patients. We found 54 studies that met our selection criteria, 9 of which were suitable for meta-analysis. TD is more common in HF patients than control subjects (odds ratio 2.53, 95% confidence interval 1.65-3.87). Diuretic use, changes in dietary habits, and altered thiamine absorption and metabolism were identified as possible mechanisms of TD in HF patients. Small observational studies and randomized control trials suggest that thiamine supplementation in HF population may improve ejection fraction and reduce symptoms. CONCLUSIONS: Thiamine deficiency is more prevalent in the HF population, and its supplementation may be beneficial. The therapeutic role of thiamine in HF warrants further study. PMID- 26497756 TI - Effect of a Sodium-Restricted Diet on Intake of Other Nutrients in Heart Failure: Implications for Research and Clinical Practice. AB - BACKGROUND: Sodium restriction is the primary dietary therapy for heart failure (HF) patients. Currently, it is unknown if changing diets to reduce dietary sodium in HF causes secondary changes to the intake of other nutrients in this patient population already at nutritional risk. METHODS AND RESULTS: HF patients (n = 16; 52 +/- 12 years old; 78% male) followed a sodium-restricted diet for 1 week. Nutritional changes were documented at baseline and after a <2,000 mg/d sodium-restricted diet, as measured by food records before baseline and each day during the study. After a 49% reduction in dietary sodium (3,626 +/- 956 to 1,785 +/- 696 mg/d), we observed a significant reduction in calorie (2,467 +/- 748 to 1,931 +/- 388 kcal/d; P < .016), carbohydrate (293 +/- 108 to 232 +/- 56 g/d; P = .013), calcium (995 +/- 496 to 609 +/- 208 mg/d; P < .004), thiamine (2.0 +/- 0.8 to 1.5 +/- 0.8 mg/d; P = .020), and folate (412 +/- 192 to 331 +/- 172 MUg/d; P = .019) intakes. There was a decrease in saturated fat (32 +/- 18 to 21 +/- 6 g/d; P = .032) and a trend to lower total fat (89 +/- 34 to 68 +/- 19 g/d; P = .066) and higher potassium (1,262 +/- 328 to 1,405 +/- 268 mg/1,000 kcal; P = .055) intakes. CONCLUSIONS: We found multiple unintentional nutritional consequences with dietary sodium reduction in HF patients. These findings highlight the need to consider the whole diet when counseling HF patients to lower sodium intake. PMID- 26497758 TI - Association of Depressive Symptoms and Micronutrient Deficiency With Cardiac Event-Free Survival in Patients With Heart Failure. AB - BACKGROUND: Depressive symptoms and malnutrition independently predict cardiac events in heart failure (HF) patients. However, the relationships among depressive symptoms, nutritional intake, and cardiac event-free survival have not been examined. METHODS AND RESULTS: A total of 232 patients with HF completed the Patient Health Questionnaire 9 (PHQ-9) to measure depressive symptoms and a 3-day food diary to determine the number of micronutrient deficiencies. Patients were followed for 2 years to collect data on cardiac event-free survival. Patients were divided into 4 groups by a PHQ-9 score of 10 and the median value of micronutrient deficiencies. Cox regressions were used to determine the relationships among depressive symptoms, micronutrient deficiency, and cardiac event-free survival. Depressive symptoms conferred greater risk of cardiac events in patients with a high number of micronutrient deficiencies than in those with a low number of micronutrient deficiencies. Patients with a PHQ-9 score >=10 and number of micronutrient deficiencies >5 had 2.4 times higher risk for cardiac events compared with patients with a PHQ-9 score <10 and micronutrient deficiency <=5 (P = .005). CONCLUSIONS: There was a synergistic effect on the association of depressive symptoms with cardiac event-free survival in HF patients that differed by micronutrient deficiency. PMID- 26497760 TI - Inhibitory effects of trichostatin A on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT-20 cells. AB - Cushing's disease is primarily caused by adrenocorticotropic hormone (ACTH) producing pituitary adenomas. Pituitary tumor-transforming gene 1 (PTTG1) expression, a hallmark of pituitary tumors, stimulates pituitary cell proliferation. Histone deacetylases (HDACs) play an important role in regulating gene transcription and HDAC inhibitors induce cellular differentiation and suppress tumor cell proliferation. HDAC inhibitors also repress PTTG1 mRNA levels. Trichostatin A (TSA) is a potent cell-permeable HDAC inhibitor that blocks cell cycle progression. In the present study, we determined the effect of TSA on ACTH production and cellular proliferation in mouse AtT-20 corticotroph tumor cells. TSA decreased proopiomelanocortin (POMC) mRNA levels in AtT-20 cells and reduced ACTH levels in the culture medium of these cells. The TSA-induced decreases in POMC mRNA levels were not modulated when TSA and dexamethasone were simultaneously administered. Drug treatment also decreased AtT-20 cell proliferation, induced apoptosis, and increased the percentage of cells in G0/G1 phase using flow cytometry. TSA decreased PTTG1 mRNA levels. Furthermore, PTTG1 knockdown inhibited cellular proliferation. Its knockdown also inhibited POMC mRNA and ACTH levels. TSA inhibits ACTH production and corticotroph tumor cell proliferation. TSA may inhibit cellular proliferation, and ACTH synthesis and secretion by decreasing PTTG1 expression. PMID- 26497759 TI - Psychometric Evaluation of Two Appetite Questionnaires in Patients With Heart Failure. AB - BACKGROUND: Decreased appetite in heart failure (HF) may lead to undernutrition which could negatively influence prognosis. Appetite is a complex clinical issue that is often best measured with the use of self-report instruments. However, there is a lack of self-rated appetite instruments. The Council on Nutrition Appetite Questionnaire (CNAQ) and the Simplified Nutritional Appetite Questionnaire (SNAQ) are validated instruments developed primarily for elderly people. Yet, the psychometric properties have not been evaluated in HF populations. The aim of the present study was to evaluate the psychometric properties of CNAQ and SNAQ in patients with HF. METHODS AND RESULTS: A total of 186 outpatients with reduced ejection fraction and New York Heart Association (NYHA) functional classifications II-IV were included (median age 72 y; 70% men). Data were collected with the use of a questionnaire that included the CNAQ and SNAQ. The psychometric evaluation included data quality, factor structure, construct validity, known-group validity, and internal consistency. Unidimensionality was supported by means of parallel analysis and confirmatory factor analyses (CFAs). The CFA results indicated sufficient model fit. Both construct validity and known-group validity were supported. Internal consistency reliability was acceptable, with ordinal coefficient alpha estimates of 0.82 for CNAQ and 0.77 for SNAQ. CONCLUSIONS: CNAQ and SNAQ demonstrated sound psychometric properties and can be used to measure appetite in patients with HF. PMID- 26497761 TI - Active biopolymers in green non-conventional media: a sustainable tool for developing clean chemical processes. AB - The greenness of chemical processes turns around two main axes: the selectivity of catalytic transformations, and the separation of pure products. The transfer of the exquisite catalytic efficiency shown by enzymes in nature to chemical processes is an important challenge. By using appropriate reaction systems, the combination of biopolymers with supercritical carbon dioxide (scCO2) and ionic liquids (ILs) resulted in synergetic and outstanding platforms for developing (multi)catalytic green chemical processes, even under flow conditions. The stabilization of biocatalysts, together with the design of straightforward approaches for separation of pure products including the full recovery and reuse of enzymes/ILs systems, are essential elements for developing clean chemical processes. By understanding structure-function relationships of biopolymers in ILs, as well as for ILs themselves (e.g. sponge-like ionic liquids, SLILs; supported ionic liquids-like phases, SILLPs, etc.), several integral green chemical processes of (bio)catalytic transformation and pure product separation are pointed out (e.g. the biocatalytic production of biodiesel in SLILs, etc.). Other developments based on DNA/ILs systems, as pathfinder studies for further technological applications in the near future, are also considered. PMID- 26497762 TI - Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis. AB - Enhancing the radiosensitivity of cancer cells is one of the most important tasks in clinical radiobiology. Endocrine therapy and radiotherapy are two cancer treatment modalities which are often given together in patients with locally advanced breast cancer and positive hormone-receptor status. Oncostatic actions of melatonin are relevant on estrogen-dependent mammary tumors. In the present study, we wanted to evaluate the effects of the combination of ionizing radiation and melatonin on proteins involved in estrogen biosynthesis in breast cancer cells. We demonstrated a role of melatonin in mediating the sensitization of human breast cancer cells to the ionizing radiation by decreasing around 50% the activity and expression of proteins involved in the synthesis of estrogens in these cells. Thus, melatonin pretreatment before radiation reduces the amount of active estrogens at cancer cell level. Melatonin 1 nM induced a 2-fold change in p53 expression as compared to radiation alone. The regulatory action of melatonin on p53 could be a link between melatonin and its modulatory action on the sensitivity of breast cancer cells to ionizing radiation. These findings may have implications for designing clinical trials using melatonin and radiotherapy. PMID- 26497764 TI - Insights into Eukaryotic Translation Initiation from Mass Spectrometry of Macromolecular Protein Assemblies. AB - Translation initiation in eukaryotes requires the interplay of at least 10 initiation factors that interact at the different steps of this phase of gene expression. The interactions of initiation factors and related proteins are in general controlled by phosphorylation, which serves as a regulatory switch to turn protein translation on or off. The structures of initiation factors and a complete description of their post-translational modification (PTM) status are therefore required in order to fully understand these processes. In recent years, mass spectrometry has contributed considerably to provide this information and nowadays is proving to be indispensable when studying dynamic heterogeneous protein complexes such as the eukaryotic initiation factors. Herein, we highlight mass spectrometric approaches commonly applied to identify interacting subunits and their PTMs and the structural techniques that allow the architecture of protein complexes to be assessed. We present recent structural investigations of initiation factors and their interactions with other factors and with ribosomes and we assess the models generated. These models allow us to locate PTMs within initiation factor complexes and to highlight possible roles for phosphorylation sites in regulating interaction interfaces. PMID- 26497763 TI - The protective role of montelukast against intestinal ischemia-reperfusion injury in rats. AB - Several drugs are effective in attenuating intestinal ischemia-reperfusion injury (IRI); however little is known about the effect of montelukast. Fifty rats were randomly assigned to 3 groups: model group (operation with clamping), sham group (operation without clamping), and study group (operation with clamping and 0.2, 2 and 20 mg/kg montelukast pretreatment). Intestinal ischemia-reperfusion was performed by occlusion (clamping) of the arteria mesenterica anterior for 45 min, followed by 24 h reperfusion. Intestinal IRI in the model group led to severe damage of the intestinal mucosa, liver and kidney. The Chiu scores of the intestines from the study group (2 and 20 mg/kg) were lower than that of the model group. Intestinal IRI induced a marked increase in CysLTR1, Caspase-8 and 9 expression in intestine, liver and kidney, which were markedly reduced by preconditioning with 2 mg/kg montelukast. Preconditioning with 2 g/kg montelukast significantly attenuated hepatic tissue injury and kidney damage, and decreased plasma interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels in plasma after intestinal IRI. In conclusion, preconditioning with montelukast could attenuate intestinal IRI and the subsequent systemic inflammatory response in rats. PMID- 26497765 TI - Seasonal pattern of manic episode admissions among bipolar I disorder patients is associated with male gender and presence of psychotic features. AB - BACKGROUND: Bipolar I disorder (BD-I) patients demonstrate disrupted chronobiology expressed as seasonal variation in mood symptoms. The seasonal pattern (SP) specifier of mood disorders was recently extended by the DSM-5, to be applied to manic episodes. However, the significance of seasonality of manic episodes for the course of BD-I is unknown. In the present study we sought to identify clinical and demographic features that discriminate between BD-I patients with and without SP of manic admissions. METHODS: BD-I patients (n=148) admitted at least twice with the same mood exacerbation type, were retrospectively followed between 2005 and 2013. Demographic and clinical characteristics were compared between BD-I patients with or without SP of manic admissions. RESULTS: SP of manic episode admissions, found in 31 (26%) of 117 BD I patients with repeated manic episode admissions, was associated with higher rates of male gender (p=0.01), presence of psychotic features (p=0.01) and comorbid substance use disorder (p<0.05) compared to patients without SP. In a multivariate analysis, SP of manic episode admissions was associated with the presence of psychotic features (OR 8.42, 95% CI: 1.05-67.65, p<0.05) and male gender (OR 3.23, 95% CI: 1.08-9.65, p<0.05), but not with comorbidity of substance use disorder (OR 1.79, 95% CI: 0.71-4.50, p=0.24). LIMITATIONS: Seasonal psychological/environmental factors contributing to the emergent of mood episodes could not be ruled out. CONCLUSIONS: Our results suggest that SP of manic admissions is associated with male gender and the presence of psychotic features, thus might be associated with more severe form of the disorder. PMID- 26497766 TI - The genus Sida L. - A traditional medicine: Its ethnopharmacological, phytochemical and pharmacological data for commercial exploitation in herbal drugs industry. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sida L. (Malvaceae) has been used for centuries in traditional medicines in different countries for the prevention and treatment of different diseases such as diarrhea, dysentery, gastrointestinal and urinary infections, malarial and other fevers, childbirth and miscarriage problems, skin ailments, cardiac and neural problems, asthma, bronchitis and other respiratory problems, weight loss aid, rheumatic and other inflammations, tuberculosis, etc. AIMS OF THIS REVIEW: To assess the scientific evidence for therapeutic potential of Sida L. and to identify the gaps of future research needs. METHODS: The available information on the ethnomedicinal uses, phytochemistry, pharmacology and toxicology of Sida species was collected via a library and electronic searches in SciFinder, PubMed, ScienceDirect, Google Scholar for the period, 1933 2015. RESULTS: A variety of ethnomedicinal uses of Sida species have been found in India, China, Afrian and American countries. Phytochemical investigation of this genus has resulted in identification of about 142 chemical constituents, among which alkaloids, flavonoids and ecdysteroids are the predominant groups. The crude extracts and isolates have exhibited a wide spectrum of in vitro and in vivo pharmacological effects involving antimicrobial, analgesic, anti inflammatory, abortifacient, neuroprotective, cardiovascular and cardioprotective, antimalarial, antitubercular, antidiabetic and antiobesity, antioxidant and nephroprotective activities among others. Ethnopharmacological preparations containing Sida species as an ingredient in India, African and American countries possess good efficacy in health disorders. From the toxicity perspective, only three Sida species have been assessed and found safe for oral use in rats. CONCLUSIONS: Pharmacological results supported some of the uses of Sida species in the traditional medicine. Alkaloids, flavonoids, other phenolics and ecdysteroids were perhaps responsible for the activities of extracts of the plants of this genus. No clinical study was reported. The detailed study on mechanism of action of isolates and extracts and their clinical study are needed for their use in modern medicine. More attention should be paid to Sida acuta, Sida cordifolia, Sida spinosa, Sida rhombifolia and Sida veronicaefolia in the domain of diarrhea, dysentery, gastrointestinal and urinary infections, skin ailments, asthma, bronchitis and other respiratory problems, malaria, childbirth and miscarriage problems, cardiac and neural problems, weight loss aid, and rheumatic and other inflammations, etc. Furthermore, detailed study on quality and safety assurance data on available ethnopharmacological preparations is needed for their commercial exploitation in local and global markets. PMID- 26497767 TI - Effect of Pressure on Liver Stiffness During the Development of Liver Fibrosis in Rabbits. AB - This study was designed to investigate whether hepatic arterial pressure and portal pressure have an effect on liver stiffness during the development of liver fibrosis. Liver fibrosis was induced in 50 healthy New Zealand white rabbits. Laparotomy was performed to measure liver stiffness, and the portal vein and hepatic artery were successively ligated to repeat the measurements. A significant difference was observed among liver stiffness values measured at different time points (F = 22.82, p < 0.001). Differences between original liver stiffness and liver stiffness measured after portal ligation were positively correlated with portal pressure (r = 0.801, p < 0.001). In animals with grade 4 liver fibrosis, the increase in liver stiffness caused by pressure was greater than that caused by extracellular matrix accumulation (p = 0.002). In conclusion, hepatic arterial pressure and portal pressure have a significant effect on liver stiffness during the development of liver fibrosis. PMID- 26497768 TI - High Risk of Lateral Nodal Metastasis in Lateral Solitary Solid Papillary Thyroid Cancer. AB - We explored the relationship between ultrasonic intra-thyroidal location and neck node metastasis pattern in solitary solid papillary thyroid cancer (PTC). Data on 186 patients were retrospectively reviewed. The association between several characteristics and neck node metastasis pattern were analyzed. Among the 186 thyroid nodules, age >=45 y (p = 0.005), mass size >=2 cm (p = 0.001), presence of calcifications (p < 0.001) and lateral nodal metastasis (p = 0.001) were significantly related to central nodal metastasis in multivariate analysis. Mass size >=2 cm (p = 0.046) and central nodal metastasis (p = 0.002) were significantly related to lateral nodal metastasis in multivariate analysis. Location of an intra-thyroidal solitary solid PTC located non-adjacent to the trachea (lateral) was significantly related to lateral nodal metastasis (p = 0.043) compared with location of an intra-thyroidal solitary solid PTC adjacent to the trachea (medial or isthmus). Lateral lesions have a high risk of lateral nodal metastasis in solitary solid PTC. PMID- 26497769 TI - Quantitative Ultrasound Assessment of Cartilage Degeneration in Ovariectomized Rats with Low Estrogen Levels. AB - The aim of this study was to assess quantitatively the site-specific degeneration of articular cartilage in ovariectomized rats with low estrogen levels using a high-frequency ultrasound system. Fourteen female Sprague-Dawley rats were randomly divided into two groups (n = 7 per group): a sham group in which only the peri-ovarian fatty tissue was exteriorized and an ovariectomized group that underwent bilateral ovariectomy to create a menopause model with low estrogen levels. All animals were sacrificed at the end of the third week after ovariectomy. Hindlimbs were harvested. The articular cartilage from five anatomic sites (i.e., femoral caput [FC], medial femoral condyle [MFC], lateral femoral condyle [LFC], medial tibial plateau [MTP] and lateral tibial plateau [LTP]) was examined with ultrasound. Four parameters were extracted from the ultrasound radiofrequency data: reflection coefficient of the cartilage surface (RC1), reflection coefficient of the cartilage-bone interface (RC2), ultrasound roughness index (URI) and thickness of the cartilage tissue. The results indicated significant (p < 0.05) site dependence for cartilage thickness, URI and RC1 in the sham group. The 3-wk post-menopause ovariectomized rats exhibited significant increases (p < 0.05) in the URI at the LFC, MTP and LTP; significant decreases (p < 0.05) in RC1 at the FC, LFC and MTP; and significant decreases (p < 0.05) in cartilage thickness at the MFC, LFC, MTP and LTP. These results of this study suggest that post-menopausal estrogen reduction induces morphologic and acoustic alterations in the articular cartilage of the hip and knee joints in ovariectomized rats. PMID- 26497770 TI - Moving beyond a categorical diagnosis of autism. PMID- 26497771 TI - Diagnosis of autism spectrum disorder: reconciling the syndrome, its diverse origins, and variation in expression. AB - Recent discoveries about the pathogenesis and symptom structure of autism spectrum disorders (ASDs) are challenging traditional nosology and driving efforts to reconceptualise the diagnosis of autism, a goal made all the more pressing by new prospects for early identification, targeted intervention, and personalised-medicine approaches to specific autistic syndromes. Recognition that ASD represents the severe end of a continuous distribution of social communication abilities in the general population has stimulated attempts to standardise the measurement of autistic traits and to set appropriate clinical thresholds for diagnosis. Over the next decade, rapid advances in our understanding of symptom structure and the diversity of causes of ASD could be incorporated into the next evolution in the diagnosis of autism, with important implications for research, clinical practice, public health, and policy. As differential effects of personalised therapies are identified in relation to specific causes of autism, the benefits of an updated diagnostic nosology will translate into the delivery of more effective care for patients. PMID- 26497772 TI - Significance of lymphadenectomy with splenectomy in radical surgery for advanced (pT3/pT4) remnant gastric cancer. AB - BACKGROUND: To date, the optimal surgical strategy for remnant gastric cancer has not been determined. The purpose of this study was to clarify the significance of lymphadenectomy with splenectomy in remnant gastric cancer surgery. METHODS: This retrospective cohort study was conducted at the Kumamoto Regional Medical Center. The primary endpoint was overall survival after surgery. We retrospectively analyzed the clinicopathologic features, surgical treatments, and long-term prognosis of remnant gastric cancer patients treated with total gastrectomy. RESULTS: A total of 80 patients with gastric cancer in the remnant stomach after distal gastrectomy and who underwent total gastrectomy were enrolled in the study. Splenectomy was performed in 38 patients. Lymph node metastasis in the splenic hilum was not observed in the patients with pT1/pT2 tumors, whereas nodal metastasis at the splenic hilum was detected in 30.4% of the patients with pT3/pT4 tumors. The survival rate of the patients with pT3/pT4 tumors who underwent splenectomy was significantly higher than that of the patients who did not undergo splenectomy, although there was no difference in the patients with pT1/pT2 tumors. Among the patients classified as R0, the survival rate of the patients with pT3/pT4 tumors who underwent splenectomy was significantly higher than that of the patients who did not undergo splenectomy. CONCLUSION: Lymphadenectomy with splenectomy in radical surgery is beneficial for patients with advanced (pT3/pT4) remnant gastric cancer. PMID- 26497773 TI - Correlation between the promoter methylation status of ATP-binding cassette sub family G member 2 and drug sensitivity in colorectal cancer cell lines. AB - Resistance to chemotherapeutic agents has been considered as a major reason for the high incidence rate of recurrence and metastasis suffered by colorectal cancer (CRC) patients. ATP-binding cassette sub-family G member 2 (ABCG2) is involved in drug resistance. DNA methylation of the ABCG2 promoter site has a significant influence on the regulation of epigenetic gene expression. In the present study, we investigated whether the methylation status of the ABCG2 promoter is related to drug sensitivity in CRC cell lines. In order to examine the ABCG2 expression level and identify the methylation status, RT-PCR, qRT-PCR analysis, MS-PCR and bisulfite sequencing were conducted on 32 CRC cell lines. SNU-C4, LS174T and NCI-H716 were selected as low ABCG2-expressing and high promoter methylated cell lines. The cell proliferation assay for 5-fluorouracil, oxaliplatin and irinotecan was performed after 5-aza-2'-deoxycytidine (5-aza) treatment in these cell lines. In the 32 CRC cell lines, 25% of the cell lines expressed low or no ABCG2 expression. Of these cell lines, SNU-C4, LS174T and NCI H716 were hypermethylated at the promoter region, ~20%. Demethylation of ABCG2 was induced by 5-aza, which enhanced the ABCG2 expression level and influenced the cell proliferation similar to treatment with the anticancer agents. Our data suggest that the ABCG2 expression level regulated by methylation is related to anticancer drug sensitivity. Based on these results, it can be applied to predict the anticancer drug response. PMID- 26497774 TI - Mosapride, a selective serotonin 5-HT4 receptor agonist, and alogliptin, a selective dipeptidyl peptidase-4 inhibitor, exert synergic effects on plasma active GLP-1 levels and glucose tolerance in mice. AB - Pharmacologic stimulation of serotonin 5-HT4 receptors increased plasma active glucagon-like-peptide-1 (GLP-1) levels independent of feeding, and that pharmacologic stimulation of 5-HT4 receptors and pharmacologic inhibition of dipeptidyl peptidase-4 exerted synergic effects on plasma active GLP-1 levels and glucose tolerance in mice. PMID- 26497775 TI - Association between brain-muscle-ARNT-like protein-2 (BMAL2) gene polymorphism and type 2 diabetes mellitus in obese Japanese individuals: A cross-sectional analysis of the Japan Multi-institutional Collaborative Cohort Study. AB - AIMS: Brain-muscle-Arnt-like protein-1 (BMAL1) and BMAL2 genes are essential components of the circadian clock, and are considered to be involved in glucose homeostasis. We examined whether single nucleotide polymorphisms (SNPs) of BMAL1 and BMAL2 were associated with the prevalence of type 2 diabetes (T2DM) in the general Japanese population. METHODS: We studied 2467 subjects (1232 men and 1235 women, 35-69 years old), including 105 men and 57 women with T2DM, from the participants of the Japan Multi-institutional Collaborative Cohort Study. The association between SNPs in the BMAL1 (rs11022775 and rs2290035) and BMAL2 (rs7958822) genes and T2DM were analyzed by multiple logistic regression after adjustment for potential confounders. Analysis was also performed after stratification by body mass index (>=25 kg/m(2) and <25 kg/m(2)) to investigate an interaction between genotypes and obesity. RESULTS: The A/G and A/A genotypes of BMAL2 rs7958822 showed significantly higher adjusted odds ratios (OR) for T2DM than the G/G genotype among obese men (OR=2.2, 95% confidence intervals [CI] 1.1, 4.6, P for interaction=0.0495) and obese women (OR=2.7, 95% CI 1.1, 6.7, P for interaction=0.199). There were no significant associations between BMAL1 rs11022775 or rs2290035 genotypes and T2DM. CONCLUSIONS: To the best of our knowledge, this is the first study to show the significant association between BMAL2 rs7958822 genotype and T2DM among obese subjects. PMID- 26497777 TI - Highly selective detection of individual nuclear spins with rotary echo on an electron spin probe. AB - We consider an electronic spin, such as a nitrogen-vacancy center in diamond, weakly coupled to a large number of nuclear spins, and subjected to the Rabi driving with a periodically alternating phase. We show that by switching the driving phase synchronously with the precession of a given nuclear spin, the interaction to this spin is selectively enhanced, while the rest of the bath remains decoupled. The enhancement is of resonant character. The key feature of the suggested scheme is that the width of the resonance is adjustable, and can be greatly decreased by increasing the driving strength. Thus, the resonance can be significantly narrowed, by a factor of 10-100 in comparison with the existing detection methods. Significant improvement in selectivity is explained analytically and confirmed by direct numerical many-spin simulations. The method can be applied to a wide range of solid-state systems. PMID- 26497776 TI - Lyon bracing in adolescent females with thoracic idiopathic scoliosis: a prospective study based on SRS and SOSORT criteria. AB - BACKGROUND: The Lyon brace is commonly prescribed in many European countries to patients with thoracic curves and is based on the three-point pressure system. The purpose of this study was to evaluate the efficacy of Lyon bracing for the conservative treatment of adolescent females with idiopathic thoracic curves in a case series selected on the basis of the Scoliosis Research Society (SRS) Committee on Bracing and Nonoperative Management Standardization Criteria and followed the guidelines on management of idiopathic scoliosis with corrective braces, proposed by the International Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT). METHODS: Prospective study based on an ongoing database. From 1297 patients treated for idiopathic scoliosis between 1995 and 2014 fulfill the inclusion criteria 102 patients treated with Lyon brace. Of these, 69 patients had a definite outcome, 17 have abandoned treatment e 16 are still in treatment. The 104 patients were adolescent females with curvatures in the thoracic spine and a pre-treatment Risser score ranging from 0 to 2. All patients were prescribed with full-time Lyon bracing. The minimum duration of follow-up was 24 months after the end of weaning (mean: 41.64 +/- 31.45 months). Anteroposterior radiographs were used to estimate the curve magnitude (CM) at 5 time points: beginning of treatment (t1), one year after the beginning of treatment (t2), intermediate time between t1 and t4 (t3), end of weaning (t4), 2 year minimum follow-up from t4 (t5). Three outcomes were distinguished: curve correction, curve stabilization and curve progression. RESULTS: The results from our study showed that of the 69 patients with a definite outcome the CM mean value was 31.51 degrees +/- 4.34 SD at t1 and 20 degrees +/- 7.6 SD at t5. Curve correction was accomplished in 85.5 % of patients, curve stabilization was obtained in 13 % of patients and curve progression was evident in only 1.5 %. None of the patients were recommended surgery post-bracing. Of 17 patients who abandoned the treatment, at the time of abandonment (14.4 age) have achieved curve correction in 13 cases (77 %), stabilization in 53 cases (18 %) and progression in 1 case (5 %). CONCLUSION: The Lyon brace, through its biomechanical action on vertebral modeling, is highly effective in correcting thoracic curves in particularly when the SOSORT guidelines were adopted in addition to the SRS criteria. PMID- 26497778 TI - Alterations in Connectivity on Functional Magnetic Resonance Imaging with Provocation of Lower Urinary Tract Symptoms: A MAPP Research Network Feasibility Study of Urological Chronic Pelvic Pain Syndromes. AB - PURPOSE: Urological chronic pelvic pain syndromes have refractory bladder or pelvic pain as the dominant symptom. This has been attributed to changes in the central nervous system caused by a chronic barrage of noxious stimuli. We developed what is to our knowledge a novel challenge protocol that induced bladder distention in study participants to reproduce pain and urinary symptoms. We tested to see whether it could discriminate between persons with urological chronic pelvic pain syndrome-like symptoms and asymptomatic controls. MATERIALS AND METHODS: We recruited 10 female twin pairs who were discordant for urological chronic pelvic pain syndrome-like symptoms. Before scanning each twin urinated to completion and then consumed 500 cc water. Each twin was scanned with our resting state functional magnetic resonance imaging protocol immediately and approximately 50 minutes after consumption. Time series were extracted from the right and left periaqueductal gray, and the right and left amygdala subregions. We performed the repeated measures 2-sample t-test to assess differences in connectivity between symptomatic and asymptomatic twins before and after bladder distention. RESULTS: Group by condition interaction effects were found from the periaqueductal gray to the right cerebellum VIIIa, the amygdala, the right premotor cortex/supplementary motor area and the insular cortex, and between the amygdala and the frontal pole/medial orbital frontal cortex, the hypothalamus, the insular cortex, the thalamus and the anterior cingulate cortex. CONCLUSIONS: These findings demonstrate that our noninvasive bladder distention protocol can detect differences in the processing of urinary sensation between twins discordant for lower urinary tract pain. PMID- 26497780 TI - Emergency preservation and resuscitation for cardiac arrest from trauma. AB - The advent of cardiopulmonary resuscitation (CPR) revolutionized the care of patients with cardiac arrest, now allowing survival of up to 30% after out-of hospital arrest due to arrhythmia; however, outcomes for cardiac arrest after trauma remain dismal, with less than 10% survival despite the most aggressive modern resuscitation techniques. The short time interval between cardiac arrest and brain ischemia, the reduced efficacy of CPR in the patient with profound hypovolemia due to hemorrhage, and the speed of exsanguination from major vascular injury all conspire to limit the effectiveness of standard CPR in the critically injured patient. Beginning in the 1980s, researchers began to harness the effects of profound hypothermia in order to extend the window of survivability after traumatic arrest, allowing the critical time needed to obtain surgical hemostasis in otherwise lethal exsanguinating injuries. These studies have culminated in the emergency preservation and resuscitation (EPR) of the trauma patient. Rapid central arterial access is obtained and profound (<10 degrees C) hypothermia induced with aortic infusion of cold saline. During this window of up to 1 h, damage control surgical techniques are applied to control hemorrhage and repair injuries, followed by controlled rewarming and reperfusion using cardiopulmonary bypass. In this review, we trace these techniques from their early theoretical development, through refinement in clinically relevant animal models, and into their present application in a currently-enrolling human clinical trial of EPR for cardiac arrest from trauma (EPR-CAT), as well as examine current topics, ongoing challenges, and future directions for emergency preservation and resuscitation research. PMID- 26497779 TI - New insights about ORF1 coding regions support the proposition of a new genus comprising arthropod viruses in the family Totiviridae. AB - Analyzing the positions of 2A-like polypeptide cleavage sites in all available genomes of arthropod totiviruses we propose the limits of all ORF1 coding sequences and observed that two proteins previously predicted in infectious myonecrosis virus genome are unique in the arthropod totiviruses group. A putative protein cleavage site upstream the major capsid protein was also identified only in these genomes. In addition, protein models generated using ab initio and threading approaches revealed conserved structures possibly related to formation of viral protrusions and RNA packaging, clarifying the mechanisms involved in the extracellular transmission. These data appoints that the group formed by arthropod totiviruses are sufficient distinctive to be clustered in new genus belonging to the Totiviridae family, in agreement with previous phylogenetic analysis. PMID- 26497781 TI - Blunt cerebrovascular injuries in trauma. AB - Blunt cerebrovascular injury (BCVI) includes trauma to the carotid or vertebral vessels and is noted in 0.1% of hospitalized trauma patients without an initial screening system in place. Several important topics must be addressed including determination of the appropriate screening population, the best modality of screening for diagnosis, treatment types, and required follow-up of blunt cerebrovascular injuries. PMID- 26497782 TI - Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen glucose deprivation via PPARgamma and 5-HT1A receptors. AB - BACKGROUND AND PURPOSE: In vivo and in vitro studies have demonstrated a protective effect of cannabidiol (CBD) in reducing infarct size in stroke models and against epithelial barrier damage in numerous disease models. We aimed to investigate whether CBD also affects blood-brain barrier (BBB) permeability following ischaemia. EXPERIMENTAL APPROACH: Human brain microvascular endothelial cell (HBMEC) and human astrocyte co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. KEY RESULTS: CBD (10 MUM) prevented the increase in permeability caused by 4 h OGD. CBD was most effective when administered before the OGD, but protective effects were observed up to 2 h into reperfusion. This protective effect was inhibited by a PPARgamma antagonist and partly reduced by a 5-HT1A receptor antagonist, but was unaffected by antagonists of cannabinoid CB1 or CB2 receptors, TRPV1 channels or adenosine A2A receptors. CBD also reduced cell damage, as measured by LDH release and by markers of cellular adhesion, such as the adhesion molecule VCAM-1. In HBMEC monocultures, CBD decreased VCAM-1 and increased VEGF levels, effects which were inhibited by PPARgamma antagonism. CONCLUSIONS AND IMPLICATIONS: These data suggest that preventing permeability changes at the BBB could represent an as yet unrecognized mechanism of CBD-induced neuroprotection in ischaemic stroke, a mechanism mediated by activation of PPARgamma and 5-HT1A receptors. PMID- 26497783 TI - Retinal neurodegeneration in experimental glaucoma. AB - In rats and mice, limbar tissues of the left eye were laser-photocoagulated (LP) and ocular hypertension (OHT) effects were investigated 1 week to 6 months later. To investigate the innermost layers, retinas were examined in wholemounts using tracing from the superior colliculi to identify retinal ganglion cells (RGCs) with intact retrograde axonal transport, melanopsin immunodetection to identify intrinsically photosensitive RGCs (m(+)RGC), Brn3a immunodetection to identify most RGCs but not m(+)RGCs, RECA1 immunodetection to examine the inner retinal vessels, and DAPI staining to detect all nuclei in the GC layer. The outer retinal layers (ORLs) were examined in cross sections analyzed morphometrically or in wholemounts to study S- and L-cones. Innervation of the superior colliculi was examined 10 days to 14 weeks after LP with orthogradely transported cholera toxin subunit B. By 2 weeks, OHT resulted in pie-shaped sectors devoid of FG(+)RGCs or Brn3a(+)RGCs but with large numbers of DAPI(+)nuclei. Brn3a(+)RGCs were significantly greater than FG(+)RGCs, indicating the survival of large numbers of RGCs with their axonal transport impaired. The inner retinal vasculature showed no abnormalities that could account for the sectorial loss of RGCs. m(+)RGCs decreased to approximately 50-51% in a diffuse loss across the retina. Cross sections showed focal areas of degeneration in the ORLs. RGC loss at 1m diminished to 20-25% and did not progress further with time, whereas the S- and L-cone populations diminished progressively up to 6m. The retinotectal projection was reduced by 10 days and did not progress further. LP-induced OHT results in retrograde degeneration of RGCs and m(+)RGCs, severe damage to the ORL, and loss of retinotectal terminals. PMID- 26497784 TI - Retinal ganglion cell apoptotic pathway in glaucoma: Initiating and downstream mechanisms. AB - Apoptosis of retinal ganglion cells (RGCs) in glaucoma causes progressive visual field loss, making it the primary cause of irreversible blindness worldwide. Elevated intraocular pressure and aging, the main risk factors for glaucoma, accelerate RGC apoptosis. Numerous pathways and mechanisms were found to be involved in RGC death in glaucoma. Neurotrophic factors deprivation is an early event. Oxidative stress, mitochondrial dysfunction, inflammation, glial cell dysfunction, and activation of apoptotic pathways and prosurvival pathways play a significant role in RGC death in glaucoma. The most important among the involved pathways are the MAP-kinase pathway, PI-3 kinase/Akt pathway, Bcl-2 family, caspase family, and IAP family. PMID- 26497785 TI - The contribution of the sclera and lamina cribrosa to the pathogenesis of glaucoma: Diagnostic and treatment implications. AB - Glaucoma, the second most common cause of world blindness, results from loss of retinal ganglion cells (RGC). RGC die as a consequence of injury to their axons, as they pass through the transition between the environment within the eye and that of the retrobulbar optic nerve, as they course to central visual centers. At the optic nerve head (ONH), axonal transport becomes abnormal, at least in part due to the effect of strain induced by intraocular pressure (IOP) on the sclera and ONH. Animal glaucoma models provide the ability to study how alterations in ocular connective tissues affect this pathological process. New therapeutic interventions are being investigated to mitigate glaucoma blindness by modifying the remodeling of ocular tissues in glaucoma. Some genetically altered mice are resistant to glaucoma damage, while treatment of the sclera with cross-linking agents makes experimental mouse glaucoma damage worse. Inhibition of transforming growth factor beta activity is strikingly protective. Treatments that alter the response of ocular connective tissues to IOP may be effective in protecting those with glaucoma from vision loss. PMID- 26497786 TI - Autophagy dysregulation and the fate of retinal ganglion cells in glaucomatous optic neuropathy. AB - Glaucoma is a neurodegenerative disease caused by the progressive apoptotic death of retinal ganglion cells (RGCs). The mechanisms leading to the RGC loss are still unknown but it is now clear that, besides elevated intraocular pressure (IOP), which is considered the main risk factor, other IOP-independent determinants are responsible for the development of the optic neuropathy. Autophagy is a highly conserved catabolic pathway by which cellular components are degraded through the lysosomes. Dysfunctional autophagic pathway has been associated with several neuropathological conditions and a considerable number of studies have proved autophagy as a potential target for pharmacological modulation to achieve neuroprotection. Here, we review the current literature bridging the degeneration of RGCs to alterations of the autophagic pathway; we also discuss the possible role of autophagy in the pathogenesis and progression of glaucoma in view of the future application of autophagy modulators for glaucoma therapy. PMID- 26497787 TI - Advances in glaucoma genetics. AB - Glaucoma is presumed to be a complex progressive neurodegenerative disorder caused by genetic and environmental factors, and it is also one of the leading causes of irreversible blindness worldwide. Glaucoma is divided into two major forms: primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Familial linkage studies for POAG have been performed and identified causative POAG disease genes (e.g., MYOC, OPTN, and WDR36). Recent genome-wide association studies revealed a large number of susceptibility gene variants associated with both POAG (e.g., CDKN2BAS, CAV1/CAV2, and ATOH7) and PACG (e.g., PLEKHA7 and COL11A1 PCMTD1-ST18). In POAG, these genes were expressed in ocular tissues including retinal ganglion cells, ciliary body, trabecular meshwork, and the optic nerve head. A further functional analysis of these genes would provide the precise mechanism underlying glaucoma, including POAG and PACG. It might be possible to assess the personal future risk for glaucoma and facilitate therapeutic strategies through genetic studies. PMID- 26497788 TI - Oxidative stress and mitochondrial failure in the pathogenesis of glaucoma neurodegeneration. AB - This review focuses on oxidative stress and mitochondrial failure for understanding mechanisms of optic nerve damage in primary open-angle glaucoma. The chapter shows scientific evidence for the role of mitochondrial disbalance and reactive oxygen species in glaucoma neurodegeneration. Mitochondria regulate important cellular functions including reactive oxygen species generation and apoptosis. Mitochondrial alterations result from a wide variety of damaging sources. Reactive oxygen species formed by the mitochondria can act as signaling molecules, inducing lipid peroxidation and/or excitotoxicity with the result of cell lesion and death. Antioxidants may help to counteract oxidative stress and to promote neuroprotection. We provide information that may lead to a new way for diagnosing and treating glaucoma patients. PMID- 26497789 TI - Macro- and microglial responses in the fellow eyes contralateral to glaucomatous eyes. AB - Most studies employing experimental models of unilateral glaucoma have used the normotensive contralateral eye as the normal control. However, some studies have recently reported the activation of the retinal macroglia and microglia in the uninjured eye, suggesting that the eye contralateral to experimental glaucoma should not be used as a control. This review analyzes the studies describing the contralateral findings and discusses some of the routes through which the signals can reach the contralateral eye to initiate the glial reactivation. PMID- 26497790 TI - Retinal and optic nerve changes in glaucoma: From animal study to clinical implication. AB - Animal models of experimental glaucoma provide the ability to longitudinally characterize changes in the optic nerve head and surrounding retinal nerve fiber layer with various imaging modalities and compare them to histomorphometric changes. Analysis of the optic nerve head surface by confocal scanning laser tomography and structures deep to this by spectral domain optical coherence tomography allow for the detection of the earliest structural changes seen in glaucoma. Algorithms utilizing these parameters along with retinal nerve fiber layer measurement are likely to play an important role in the future of glaucoma progression monitoring. PMID- 26497791 TI - Lymphatic drainage from the eye: A new target for therapy. AB - Lowering intraocular pressure (IOP) has been central to glaucoma care for over a century. In order to prevent sight loss from disease, there has been considerable focus on medical and surgical methods to improve fluid drainage from the eye. In spite of this, our understanding of exactly how aqueous humor leaves the eye is not complete. Recently, lymphatic vessels have been discovered in the human uvea, with studies showing lymphatic fluid outflow in several models, in addition to evidence for their pharmacological enhancement. The presence of a lymphatic outflow system points to an exciting, expanded understanding of how fluid and particulate materials such as proteins move out of the eye, and how IOP may be regulated. We coin the term "uveolymphatic pathway"-to reflect a comprehensive and compelling new target for glaucoma and an exciting opportunity for future investigations to better understand the eye in health and disease. PMID- 26497792 TI - Retinal ganglion cell dendrite pathology and synapse loss: Implications for glaucoma. AB - Dendrites are exquisitely specialized cellular compartments that critically influence how neurons collect and process information. Retinal ganglion cell (RGC) dendrites receive synaptic inputs from bipolar and amacrine cells, thus allowing cell-to-cell communication and flow of visual information. In glaucoma, damage to RGC axons results in progressive neurodegeneration and vision loss. Recent data indicate that axonal injury triggers rapid structural alterations in RGC dendritic arbors, prior to manifest axonal loss, which lead to synaptic rearrangements and functional deficits. Here, we provide an update on recent work addressing the role of RGC dendritic degeneration in models of acute and chronic optic nerve damage as well as novel mechanisms that regulate RGC dendrite stability. A better understanding of how defects in RGC dendrites contribute to neurodegeneration in glaucoma might provide new insights into disease onset and progression, while informing the development of novel therapies to prevent vision loss. PMID- 26497793 TI - MicroRNA target prediction in glaucoma. AB - Glaucoma is a progressive optic neuropathy and is one of the leading causes of blindness in the industrialized countries. The aim of this study is to investigate microRNA (miRNA) regulation in glaucoma and other neurodegenerative diseases, that share similar pathways, by means of in silico approaches such as bibliographic search and access to bioinformatic resources. First of all, data mining was carried out on Human miRNA Disease Database (HMDD) and miR2Disease databases. Then, predictions of deregulated miRNAs were carried out accessing to microrna.org database. Finally, the potential combinatorial effect of miRNAs, on regulation of biochemical pathways, was studied by an enrichment analysis performed by DIANA-miRPath v.2.0. We found, from literature search, 8 deregulated miRNAs in glaucoma and 9 and 23 in age-related macular degeneration (AMD) and Alzheimer's disease (AD), respectively. One miRNA is commonly deregulated in glaucoma and AMD (miR-23a). Two miRNAs (miR-29a, miR-29b) are common to glaucoma and AD, and four miRNAs were identified to be commonly deregulated in AMD and AD (miR-9, miR-21, miR-34a, miR-146a). The match of the miRNA common to glaucoma and the other two neurodegenerative diseases (AMD and AD) did not generate any output. Enrichment of information has been reached through miRNAs prediction: 88 predicted miRNAs are common to glaucoma and AMD, 19 are common to glaucoma and AD, and 9 are common to AMD and AD. Indeed, predicted miRNAs common to the three neurodegenerative diseases are nine (miR-107, miR-137, miR-146a, miR-181c, miR 197, miR-21, miR-22, miR-590, miR-9). DIANA-miRPath predicted that those nine miRNAs might regulate pathways involved in inflammation. The findings hereby obtained provide a valuable hint to assess deregulation of specific miRNA, as potential biomarkers and therapeutic targets, in glaucoma and other neurodegenerative diseases by means of preclinical and clinical studies. PMID- 26497794 TI - Stem cell approaches to glaucoma: from aqueous outflow modulation to retinal neuroprotection. AB - Long-term pharmacological management of glaucoma currently relies on self administered drugs to regulate intraocular pressure (IOP). A number of approaches using stem cells have recently shown promise as potential future treatment strategies complementary to IOP lowering. Several sources of endogenous stem cells have been identified in the eye, some of which may be able to repair the damaged trabecular meshwork and restore functional regulation of aqueous outflow. Neural and mesenchymal stem cells secrete growth factors which provide neuroprotective effects, reducing loss of retinal ganglion cells (RGCs) in animal models. In the future, stem cells may even replace RGCs to reform functional connections between the eye and the brain, although the complexity of such a repair task is formidable. With advances in biomaterial cell scaffolds and concurrent efforts in other neural systems, stem cell therapies are becoming a realistic option for treating multiple eye diseases, and despite ongoing challenges, there are reasons for optimism that stem cells may play a role in the treatment of human glaucoma in the future. PMID- 26497795 TI - Natural compounds and retinal ganglion cell neuroprotection. AB - Glaucoma, the second leading cause of blindness in the world, is a chronic optic neuropathy often associated with increased intraocular pressure and characterized by progressive retinal ganglion cell (RGC) axons degeneration and death leading to typical optic nerve head damage and distinctive visual field defects. Although the pathogenesis of glaucoma is still largely unknown, it is hypothesized that RCGs become damaged through various insults/mechanisms, including ischemia, oxidative stress, excitotoxicity, defective axonal transport, trophic factor withdrawal, and neuroinflammation. In this review, we summarize the potential benefits of several natural compounds for RGCs neuroprotection. PMID- 26497797 TI - Preface. PMID- 26497796 TI - Rho kinase inhibitor AMA0526 improves surgical outcome in a rabbit model of glaucoma filtration surgery. AB - PURPOSE: First, to elucidate the effect of Rho kinase inhibitor, AMA0526, on Human Tenon Fibroblast (HTF) proliferation and transdifferentiation to myofibroblasts. Second, the effects of ROCK inhibition on the wound healing process and surgical outcome were investigated in a rabbit model of glaucoma filtration surgery. METHODS: After exposure of HTF to AMA0526 (0.1-25 MUM), a water-soluble tetrazolium salt-1 assay and caspase 3/7 activity assay were used to assess its effect on cell proliferation and to elucidate any toxic effects, respectively. Immunohistochemistry of alpha-smooth muscle actin expression was used to investigate fibroblast-to-myofibroblast differentiation induced by transforming growth factor-beta 1 (TGF-beta1) in the presence or absence of the ROCK inhibitor. The effect of topical treatment was studied in a rabbit model of glaucoma filtration surgery. Treatment outcome was studied by performing intraocular pressure (IOP) measurements and clinical investigation of the bleb area and survival. Immunohistological analysis for inflammation (CD45), angiogenesis (CD31), and collagen I was performed at day 8, 14, and 30 after surgery (n=5/time point). Separate control groups treated with vehicle were used as control. RESULTS: In vitro results showed that AMA0526 dose dependently inhibited proliferation of HTF (P<0.05) without the induction of caspase 3/7 activity. Incubation of HTF with the AMA0526 inhibited TGF-beta1 induced fibroblast-to-myofibroblast differentiation. In the rabbit model, topical treatment significantly improved surgical outcome. Compared to vehicle-treated eyes, AMA0526 resulted in increased bleb area (P<0.0001) and prolonged survival (P=0.0025). IOP remained significantly lower throughout the course of the experiment in the AMA0526 group (P<0.0001). Histological evaluation revealed that blebs treated with the ROCK inhibitor were characterized by reduced inflammation, angiogenesis, and collagen deposition at the site of filtration surgery (P<0.05). CONCLUSIONS: AMA0526 had profound effects on HTF proliferation and myofibroblast transition and improved glaucoma filtration surgery outcome by interfering at different levels of the wound healing process. Therefore, these data indicate that ROCK inhibitors may be considered as more physiological agents which specifically target the wound healing process to improve the outcome of glaucoma surgery. PMID- 26497798 TI - Heart failure: new approaches to an old problem. PMID- 26497799 TI - Latest developments in heart transplantation: a review. AB - PURPOSE: Heart transplantation (HT) remains the treatment of choice for advanced heart failure despite improvements in medical therapy and mechanical circulatory support. Significant developments have occurred in the field of HT over the past year, in particular the successful transplantation of donor hearts after circulatory determination of death. The purpose of this article was to review developments in HT published in 2014 and 2015. METHODS: Selected articles found using a MEDLINE search of the key term heart transplant were reviewed. FINDINGS: The year has seen improvements in the attenuation of ischemia and reperfusion injury, patient selection, immunosuppression, imaging of the transplanted heart, and donor organ preservation that hold promise for increasing the number of transplantations and improving outcomes in HT recipients. Advances in the detection and attenuation of cardiac rejection and allograft vasculopathy are highlighted. IMPLICATIONS: A number of significant advances over the past year hold promise for tangible improvements in outcomes in the field of HT. PMID- 26497800 TI - Run kinematics with and without a jogging stroller. AB - BACKGROUND: Jogging strollers have become increasingly popular as they allow a parent the freedom to run without having to leave their children. Few studies have examined the effects of running with a stroller and no study to date has examined the effects on joint kinematics. The aim of this study was to compare lower limb and trunk kinematics while running with and without a jogging stroller. METHODS: Participants (N=15) ran on a 16-metre indoor runway, with and without a stroller, at their self-selected comfortable training speed. Three dimensional trunk and lower limb kinematics were assessed using the CODA cx1 active marker system. FINDINGS: The jogging stroller led to reduced movement of the trunk in both the transverse [mean difference -11.4 degrees , 95% confidence interval (CI) (-14.8 degrees , -8.2 degrees ), p<0.001] and coronal [-2.9 degrees , 95% CI (-0.8 degrees , -4.9 degrees ), p=0.009] planes most likely due to fixing of the upper limbs. There was also a 6.7 degrees [95% CI (-9 degrees , 4.6 degrees ), p<0.001] increase in forward trunk lean, 2.8 degrees [95% CI ( 4.2 degrees , -1.7 degrees ), p<0.001] increase in anterior pelvic tilt and a 3 degrees [95% CI (-4.4 degrees , -1.5 degrees ), p=0.001] decrease in hip extension. There were no significant changes in knee or ankle kinematics and no changes in stride length, cadence or stance time. INTERPRETATION: Our data suggest that jogging strollers lead to minor changes in trunk, pelvis and hip kinematics with no significant changes at the knee and ankle. Due to the changes in kinematics we suggest that flexibility work for the spine, pelvis and hips may be recommended. PMID- 26497801 TI - Characteristic muscle activity patterns during gait initiation in the healthy younger and older adults. AB - It is thought that gait initiation (GI) might be an optimal task for identifying postural control deficiencies. Thus, the aim of this study was to clarify the strategies adopted by older subjects during this task. 16 healthy younger and 15 healthy older adults participated in the study. Subjects were instructed to begin forward stepping with their dominant limb in response to an auditory stimulus. The mean muscle activity, co-contraction index, and intra-subject coefficients of variation (intra-subject CVs) of dominant limb muscles in different phases of GI were measured. The level of association between the co-contraction index and intra-subject CV of muscles was also explored. This study showed that in the anticipatory phase, the younger group had larger amplitudes and more intra subject CVs than older the group, particularly for the tibialis anterior muscle. However, the co-contraction index was greater in older subjects relative to younger subjects. During the weight transition phase, tibialis anterior, semitendinosus and vastus lateralis muscles of older adults had a lower amplitude as compared to younger adults. However, during the locomotor phase, the activity of tibialis anterior was greater in comparison to younger adults. Also, during this phase, similar to the anticipatory phase, the co-contraction index between tibialis anterior and gastrocnemius muscles was greater in older subjects relative to younger subjects. Additionally, the larger co-contraction index of some muscles was associated with smaller intra-subject CV. These findings suggest that muscle behaviors are altered with aging and older adults employ different strategies in the different phases of GI as compared to younger adults. PMID- 26497802 TI - Advanced computational modeling for in vitro nanomaterial dosimetry. AB - BACKGROUND: Accurate and meaningful dose metrics are a basic requirement for in vitro screening to assess potential health risks of engineered nanomaterials (ENMs). Correctly and consistently quantifying what cells "see," during an in vitro exposure requires standardized preparation of stable ENM suspensions, accurate characterizatoin of agglomerate sizes and effective densities, and predictive modeling of mass transport. Earlier transport models provided a marked improvement over administered concentration or total mass, but included assumptions that could produce sizable inaccuracies, most notably that all particles at the bottom of the well are adsorbed or taken up by cells, which would drive transport downward, resulting in overestimation of deposition. METHODS: Here we present development, validation and results of two robust computational transport models. Both three-dimensional computational fluid dynamics (CFD) and a newly-developed one-dimensional Distorted Grid (DG) model were used to estimate delivered dose metrics for industry-relevant metal oxide ENMs suspended in culture media. Both models allow simultaneous modeling of full size distributions for polydisperse ENM suspensions, and provide deposition metrics as well as concentration metrics over the extent of the well. The DG model also emulates the biokinetics at the particle-cell interface using a Langmuir isotherm, governed by a user-defined dissociation constant, K(D), and allows modeling of ENM dissolution over time. RESULTS: Dose metrics predicted by the two models were in remarkably close agreement. The DG model was also validated by quantitative analysis of flash-frozen, cryosectioned columns of ENM suspensions. Results of simulations based on agglomerate size distributions differed substantially from those obtained using mean sizes. The effect of cellular adsorption on delivered dose was negligible for K(D) values consistent with non-specific binding (> 1 nM), whereas smaller values (<= 1 nM) typical of specific high-affinity binding resulted in faster and eventual complete deposition of material. CONCLUSIONS: The advanced models presented provide practical and robust tools for obtaining accurate dose metrics and concentration profiles across the well, for high-throughput screening of ENMs. The DG model allows rapid modeling that accommodates polydispersity, dissolution, and adsorption. Result of adsorption studies suggest that a reflective lower boundary condition is appropriate for modeling most in vitro ENM exposures. PMID- 26497803 TI - Natural variation of H3K27me3 modification in two Arabidopsis accessions and their hybrid. AB - Histone modifications affect gene expression, but the mechanism and biological consequence of natural variation in histone modifications remain unclear. Here, we generated genome-wide integrated maps of H3K27me3 modification and transcriptome for Col, C24 and their F1 hybrid. A total of 1,828 genomic regions showing variation in H3K27me3 modification between Col and C24 were identified, most of which were associated with genic regions. Natural variation of H3K27me3 modification between parents could result in allelic bias of H3K27me3 in hybrids. Furthermore, we found that H3K27me3 variation between Col and C24 was negatively correlated with gene expression differences between two accessions, especially with those arising from the cis-effect. Importantly, mutation of CLF, an Arabidopsis methyltransferase for H3K27, altered gene expression patterns between the parents. Together, these data provide insights into natural variation of histone modifications and their association with gene expression differences between Arabidopsis ecotypes. PMID- 26497805 TI - Rare Cause of Acute Dysphagia Associated with Dysphonia. PMID- 26497806 TI - An intercomparison done at NIRS, Japan on continuous monitors for measuring 220Rn concentration. AB - An intercomparison for continuous monitors that measure thoron ((220)Rn) concentration was carried out using a (220)Rn chamber of National Institute of Radiological Sciences (NIRS), Japan; eleven (220)Rn monitors (four types) from nine laboratories were evaluated. The (220)Rn detection principle was the same for the eleven instruments and one reference instrument, which were commercially available silicon semiconductor detectors using an electrostatic collection method. The intercomparison results showed that there was a negative deviation of more than 30% in measured (220)Rn concentrations given by the laboratories relative to the reference values, which were obtained by making a decay correction during the travel of (220)Rn through the sampling assembly (sample tube, filter and drying unit) and using a calibration factor. In order to elucidate the reason for this and then to investigate factors that affect the (220)Rn concentration measured with the monitors. As a result, it was necessary to make the decay-correction, in particular, when using a drying unit with a large inner volume and to use the calibration factor in order to better estimate the (220)Rn concentration. It was also found to be better to determine a calibration factor inherent to an individual monitor, because the calibration factor values ranged from 0.75 to 2.32, depending on the flow rate of the monitor pump (0.37-1.02 L min(-1)). It was concluded from this study that a periodical calibration of the monitor and a check of the monitor flow rate during measurements are necessary to maintain a consistent quality level of the (220)Rn measurement. PMID- 26497807 TI - Semi-empirical model for fluorescence lines evaluation in diagnostic x-ray beams. AB - Diagnostic x-ray beams are composed of bremsstrahlung and discrete fluorescence lines. The aim of this study is the development of an efficient model for the evaluation of the fluorescence lines. The most important electron ionization models are analyzed and implemented. The model results were compared with experimental data and with other independent spectra presented in the literature. The implemented peak models allow the discrimination between direct and indirect radiation emitted from tungsten anodes. The comparison with the independent literature spectra indicated a good agreement. PMID- 26497808 TI - Insecticide resistance in malaria-transmitting mosquitoes in Zimbabwe: a review. AB - Malaria is a global public health problem, with about 3.2 billion people at risk of infection. The populations at risk mainly reside in Africa, Asia and America, with African populations accounting for the largest burden of the disease. In 2013, close to 198 million malaria cases were reported, leading to 584,000 deaths. Much (90 %) of the mortality rates were recorded from the World Health Organization (WHO) database in the African region and 78 % of these occurred in children under the age of five. In Zimbabwe, approximately half of the population is at risk of infection with malaria.Insecticide residual spraying (IRS) has been documented as an effective way to control malaria and has been adopted globally by the WHO and national governments. However, both insecticide resistance and climate change threaten to reverse the progress made by IRS in malaria control. Resistance has been reported in all four classes of insecticides approved by the WHO for vector control intervention. Variability of environmental temperature is suspected to complicate the situation through alteration in the genetic structure, and enzyme and protein profiles of mosquitoes. In Zimbabwe, little research has been done on the interaction between climate change, temperature variability and insecticide resistance in malarial mosquitoes over time. Such information is important for informing policies on insecticide selection for IRS.We reviewed literature on insecticide sensitivity among malarial mosquitoes in Zimbabwe from 1972 to 2014. International peer-reviewed articles on insecticide sensitivity in Zimbabwe, published in English in this time period, were searched using MEDLINE(r) (PubMed), Google Scholar, Google and grey literature. Eight publications were eligible for the present study, with one of the articles being a review paper. Six articles covered insecticide resistance, while the other two articles, published in 2000, were about the absence of resistance. Contradicting resistance results were reported in 2014.The insecticide sensitivity status and distribution of insecticide resistance in mosquitoes are still under debate in Zimbabwe, as studies report differing results. The resistance trend in Zimbabwe is characterised by fluctuations in the status of the sensitivity of existing insecticides. Inconsistencies in data collection methods may be responsible for the inconsistencies in the results. None of the studies have determined a link between climate/temperature variability and insecticide resistance as yet. The current insecticide sensitivity status of mosquitoes still needs to be verified. PMID- 26497810 TI - Erratum to: Ferulic acid chronic treatment exerts antidepressant-like effect: role of antioxidant defense system. PMID- 26497809 TI - Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid exposure during adolescence. AB - Chronic exposure to cannabinoids during adolescence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the serotoninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were administered separately at 1 mg/kg and 20 mg/kg, and in combination at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor agonist WIN55,212-2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like memory in the open field and novel object recognition tests respectively 30 minutes after the last drug administration. Chronic WIN55,212-2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute administration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses. However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212-2. These findings give further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophrenia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease. PMID- 26497811 TI - Behavioral effects of Citrus paradisi in rats. AB - Anxiety and depression adversely affect behavior though these conditions may be handled through environmental and dietary changes. Diet rich in flavonoids and vitamins may support reducing anxiety and depression. Depression is most common but serious illness making life miserable; however the usage of dietary and herbal complements to treat anxiety and depression had been grown by the time. The purpose of this investigation was to characterize the behavioral properties of Citrus paradisi in rats at diverse doses i.e. 0.1, 0.3 and 0.5 ml/kg. Anxiolytic and antidepressant actions were particularly measured twice in 15 days through elevated plus maze, open field and forced swimming tests. C. paradisi, revealed increase in the locomotor activity and the exploratory skills of the animals, as assessed in the open-field. Indeed C. paradisi had a strong anxiolytic effect in elevated plus-maze, as assessed by an augmented number of entries and the proportion of time spent in the open arms. Moreover there was decline in duration of immobility and rise in duration of climbing during forced swimming test. At the tested doses these results suggest that C. paradisi have the potential to exert a range of CNS-mediated biological activities and thus encourage more investigations in this field. PMID- 26497812 TI - Does sexual selection shape sex differences in longevity and senescence patterns across vertebrates? A review and new insights from captive ruminants. AB - In most mammals, both sexes display different survival patterns, often involving faster senescence in males. Being under intense sexual competition to secure mating opportunities, males of polygynous species allocate resources to costly behaviors and conspicuous sexual traits, which might explain these observed differences in longevity and senescence patterns. However, comparative studies performed to date have led to conflicting results. We aimed to resolve this problem by first reviewing case studies of the relationship between the strength of sexual selection and age-specific survival metrics. Then, we performed a comprehensive comparative analysis to test whether such relationships exist among species of captive ruminants. We found that the strength of sexual selection negatively influenced the onset of actuarial senescence in males, with males senescing earlier in polygynous than in monogamous species, which led to reduced male longevity in polygynous species. Moreover, males of territorial species senesced earlier but slower, and have a shorter longevity than males of species displaying other mating tactics. We detected little influence of the strength of sexual selection on the rate of actuarial senescence. Our findings demonstrate that the onset of actuarial senescence, rather than its rate, is a side effect of physiological mechanisms linked to sexual selection, and potentially accounts for observed differences in longevity. PMID- 26497814 TI - [Substance use disorders as a cause and consequence of childhood abuse. Basic research, therapy and prevention in the BMBF-funded CANSAS-Network]. AB - Substance use disorders (SUDs) belong to the most frequent behavioural consequences of childhood abuse and neglect (CAN). In community samples, about 20% of adults with experiences of abuse or neglect in childhood have a lifetime diagnosis of an SUD. About 30% of individuals seeking treatment for a post traumatic disorder have an SUD and 24-67% of all patients in treatment for an SUD have a history of CAN. About 16% of all children and adolescents under the age of 20 in Germany grow up in families where an alcohol- and/or drug-dependence is present. The children of parents with SUDs have, in addition to other risks to their development in cognitive and psychosocial domains, an increased risk of experiencing violence and neglect. Regarding both perspectives, SUD as a cause and as a consequence of CAN, a better understanding of relevant mediators and risk factors is necessary to improve prevention and develop adequate treatments. The aims of the BMBF-funded research network CANSAS are: 1. To gain a better understanding of the relationships between these two important public health problems (basic research), 2. To provide evidence-based treatments for survivors of CAN with SUDs and to increase the awareness for the necessity to diagnose CAN in patients with SUDs in counselling and treatment facilities (research on diagnostics and therapy), 3. To improve the systematic evaluation of child welfare among children of parents with SUDs through counselling services and to promote links between addiction services and youth welfare services (prevention research and health services research). In a multidisciplinary approach, the CANSAS network brings together experts in the fields of trauma treatment, epidemiology, basic research, health services research, prevention research as well as addiction services. PMID- 26497815 TI - [Violence and discrimination in the workplace. The effects on health and setting-related approaches to prevention and rehabilitation]. AB - Violence in the workplace is a widespread problem that manifests itself in very different forms. The consequences for victims and companies are equally diverse. Sexual harassment is a special form of violence at the workplace. Violence may come from external perpetrators (attacks on cashiers) or from persons inside a company or establishment (colleagues, patients, people in care). Statutory accident insurance institutions in Germany (UV, "Unfallversicherungstrager") receive approximately 16,000 occupational injury reports per year that resulted from violence and led to extended incapacity to work. The numbers are increasing steadily. Particularly affected by violence are people working in healthcare and social welfare. Both psychological and physical violence can lead to severe disorders such as post-traumatic stress disorder (PTSD). To avoid violence, technical, organisational, and personal protective measures are needed. The training of de-escalation officers in the areas affected can be helpful. For victims of psychological and physical violence in the workplace, the UV offers special psychotherapeutic support and recommends the training of first-aiders. PMID- 26497813 TI - Colorectal liver metastatic disease: efficacy of irreversible electroporation--a single-arm phase II clinical trial (COLDFIRE-2 trial). AB - BACKGROUND: Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique that has shown promise for the ablation of lesions in proximity to vital structures such as blood vessels and bile ducts. The primary aim of the COLDFIRE-2 trial is to investigate the efficacy of IRE for unresectable, centrally located colorectal liver metastases (CRLM). Secondary outcomes are safety, technical success, and the accuracy of contrast-enhanced (ce)CT and (18)F-FDG PET-CT in the detection of local tumor progression (LTP). METHODS/DESIGN: In this single-arm, multicenter phase II clinical trial, twenty nine patients with (18)F-FDG PET-avid CRLM <= 3,5 cm will be prospectively included to undergo IRE of the respective lesion. All lesions must be unresectable and unsuitable for thermal ablation due to vicinity of vital structures. Technical success is based on ceMRI one day post-IRE. All complications related to the IRE procedure are registered. Follow-up consists of (18)F-FDG PET-CT and 4-phase liver CT at 3-monthly intervals during the first year of follow-up. Treatment efficacy is defined as the percentage of tumors successfully eradicated 12 months after the initial IRE procedure based on clinical follow-up using both imaging modalities, tumor marker and (if available) histopathology. To determine the accuracy of (18)F-FDG PET-CT and ceCT, both imaging modalities will be individually scored by two reviewers that are blinded for the final oncologic outcome. DISCUSSION: To date, patients with a central CRLM unsuitable for resection or thermal ablation have no curative treatment option and are given palliative chemotherapy. For these patients, IRE may prove a life-saving treatment option. The results of the proposed trial may represent an important step towards the implementation of IRE for central liver tumors in the clinical setting. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: NCT02082782. PMID- 26497816 TI - Influence of lactation stage and some flock management practices on sensory characteristics of goat milk from Brazilian Saanen breed. AB - This study evaluated the influence of lactation stage (early, middle, late) and management practices (milking hygiene and buck presence) on the sensory attributes of Saanen goat milk. Goats were randomly divided in four groups in respect of different milking sanitary procedures and the presence/absence of the buck in the barn. Milk samples were analyzed for sensory attributes including quantitative descriptive analysis (QDA) and acceptance. The milking hygiene practice caused no significant influence on microbiological parameters. Results of QDA revealed that the buck presence increased the characteristic odor of milk at the middle and late lactation stages. The off-odor and off-flavor descriptors showed a distinct response since a higher intensity of these sensory characteristics was noted in the samples obtained from goats maintained without the buck. Odor and flavor contributed most in characterizing the different samples regardless of the management practice and lactation stage. The acceptance of odor showed to be influenced only by the lactation stage, while the acceptance of flavor was only through the presence of the buck. Odor acceptance correlated negatively to off-odor and off-flavor, suggesting that these two sensory attributes impaired the preference for the aroma of the milk samples. PMID- 26497817 TI - The invasion of fatty liver disease in liver transplantation. PMID- 26497819 TI - Dielectrophoretic manipulation of particle mixtures employing asymmetric insulating posts. AB - A novel scheme for particle separation with insulator-based dielectrophoresis (iDEP) was developed. This technique offers the capability for an inverted order in particle elution, where larger particles leave the system before smaller particles. Asymmetrically shaped insulating posts, coupled with direct current (DC) biased low-frequency alternating current (AC) electric potentials, were used to successfully separate a mixture of 500 nm and 1 MUm polystyrene particles (size difference of 0.5 MUm in diameter). In this separation, the 1 MUm particles were eluted first, demonstrating the discriminatory potential of this methodology. To extend this technique to biological samples, a mixture containing Saccharomyces cerevisiae cells (6.3 MUm) and 2 MUm polystyrene particles was also separated, with the cells being eluted first. The asymmetric posts featured a shorter sharp half and a longer blunt half; this produced an asymmetry in the forces exerted on the particles. The negative DC offset produced a net displacement of the smaller particles toward the upstream direction, while the post asymmetry produced a net displacement of the larger particles toward the downstream direction. This new iDEP approach provides a setup where larger particles are quickly concentrated at the outlet of the post array and can be released first when in a mixture with smaller particles. This new scheme offers an extra set of parameters (alternating current amplitude, DC offset, post asymmetry, and shape) that can be manipulated to obtain a desired separation. This asymmetric post iDEP technique has potential for separations where it is important to quickly elute and enrich larger and more fragile cells in biological samples. PMID- 26497820 TI - The prevalence of statistical reporting errors in psychology (1985-2013). AB - This study documents reporting errors in a sample of over 250,000 p-values reported in eight major psychology journals from 1985 until 2013, using the new R package "statcheck." statcheck retrieved null-hypothesis significance testing (NHST) results from over half of the articles from this period. In line with earlier research, we found that half of all published psychology papers that use NHST contained at least one p-value that was inconsistent with its test statistic and degrees of freedom. One in eight papers contained a grossly inconsistent p value that may have affected the statistical conclusion. In contrast to earlier findings, we found that the average prevalence of inconsistent p-values has been stable over the years or has declined. The prevalence of gross inconsistencies was higher in p-values reported as significant than in p-values reported as nonsignificant. This could indicate a systematic bias in favor of significant results. Possible solutions for the high prevalence of reporting inconsistencies could be to encourage sharing data, to let co-authors check results in a so called "co-pilot model," and to use statcheck to flag possible inconsistencies in one's own manuscript or during the review process. PMID- 26497821 TI - Localization of Vascular Endothelial Growth Factor and Fibroblast Growth Factor 2 in the Ovary of the Ostrich (Struthio camelus). AB - Vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) play a paramount role in the regulation of normal and pathologic angiogenesis in the ovary of mammals. Very little is known on the expression of these two growth factors in the avian ovary. The aim of this study was to determine for the first time the localization of VEGF and FGF-2 in the ovary of the ostrich using immunohistochemical techniques to investigate the vascularization of the rapidly growing huge ostrich oocyte. At the oocyte periphery, distinct VEGF-positive granules are visible. In our opinion, the expression of VEGF in the growing oocytes, which does not occur in mammals such as bovines, does not significantly contribute to angiogenesis in the theca interna and externa, where all the original and developing vessels are located, but may contribute to the mitoses and survival of granulosa cells during folliculogenesis. A different immunostaining can be demonstrated for FGF-2: from late pre-vitellogenic follicles, FGF-2 immunopositivity can be observed at the inner perivitelline layer area. In the stroma, the smooth muscle cells of small arteries and the endothelial cells of venules and veins are positively stained for FGF-2. Another interesting finding of this study is the occurrence of a significant number of VEGF- and FGF-2 positive heterophilic granulocytes within the ovarian stroma, which migrate from the periphery of the ovary towards the growing follicles. We assume that the growth factors of the heterophilic granulocytes contribute significantly to the angiogenesis seen in both theca layers. PMID- 26497822 TI - Right ventricular strain by MR quantitatively identifies regional dysfunction in patients with arrhythmogenic right ventricular cardiomyopathy. AB - BACKGROUND: Analysis of regional wall motion of the right ventricle (RV) is primarily qualitative with large interobserver variation in clinical practice. Thus, the purpose of this study was to use feature tracking to analyze regional wall motion abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: We enrolled 110 subjects (39 overt ARVC [mutation+/phenotype+] (35.5%), 40 preclinical ARVC [mutation+/phenotype-] (36.3%), and 31 control subjects (28.2%)). Cine steady state free precession cardiac MR was performed with temporal resolution <=40 ms in the horizontal long axis (HLA), axial, and short axis directions. Regional strain was analyzed using feature tracking software and reproducibility was assessed by means of intraclass correlation coefficient. Dunnett's test was used in univariate analysis for comparisons to control subjects; cumulative odds logistic regression was used for minimally and fully adjusted multivariate models. RESULTS: Strain was significantly impaired in overt ARVC compared with control subjects both globally (P < 0.01) and regionally (all segments of HLA view, P < 0.01). In the HLA view, regional reproducibility was excellent within (intraclass correlation coefficient [ICC] = 0.81) and moderate between (ICC = 0.62) observers. Using a threshold of 31% subtricuspid strain in the HLA view, the sensitivity and specificity for overt ARVC were 75.0% and 78.2%, respectively. In multivariable analysis involving all three groups, subtricuspid strain less than -31% (beta = 1.38; P = 0.014) and RV end diastolic volume index (beta = 0.06; P = 0.001) were significant predictors of disease presence. CONCLUSION: RV strain can be reproducibly assessed with MR feature tracking, and regional strain is abnormal in overt ARVC compared with control subjects. PMID- 26497823 TI - Laparoscopic radical nephroureterectomy is associated with worse survival outcomes than open radical nephroureterectomy in patients with locally advanced upper tract urothelial carcinoma. AB - PURPOSE: To compare survival outcomes between laparoscopic radical nephroureterectomy (LRNU) and open radical nephroureterectomy (ORNU) in upper urinary tract urothelial carcinoma (UTUC) patients. METHODS: We retrospectively analyzed the data of 371 UTUC patients who underwent ORNU (n = 271) or LRNU (n = 100) between 1992 and 2012. The survival outcomes included intravesical recurrence (IVR)-free survival, overall survival (OS), and cancer-specific survival (CSS). The Kaplan-Meier method and log-rank test were used to estimate and compare survival curves between groups. Factors associated with survival outcomes were evaluated using univariable and multivariable Cox proportional hazard models. RESULTS: The three-year IVR-free survival rates were similar between the ORNU and LRNU groups (59.9 and 61.7 %, p = 0.267). However, the LRNU group showed worse five-year OS (59.1 vs. 75.2 %, p = 0.027) and CSS (66.1 vs. 80.2 %, p = 0.015) rates than the ORNU group. In particular, on stratifying the study cohort by pathological stages, significant differences in OS (p = 0.007) and CSS (p = 0.005) between the surgical approaches were observed only in locally advanced disease (pT3/T4). In multivariable analysis, LRNU was an independent predictor of worse OS (p = 0.001) and CSS (p = 0.006) than ORNU. Likewise, in multivariable analysis in patients with pT3/T4 stage, LRNU was significantly associated with worse OS (hazard ratio [HR] 2.59, p = 0.001) and CSS (HR 2.50, p = 0.005). CONCLUSIONS: Our data suggest that in UTUC patients, LRNU, compared to ORNU, is generally associated with unfavorable OS and CSS results. In particular, LRNU should be performed in locally advanced UTUC patients after careful consideration of its impact on patient survival. PMID- 26497824 TI - Clinical significance of residual fragments in 2015: impact, detection, and how to avoid them. AB - PURPOSE: Residual fragments are common after stone treatment. Little is known about clinical outcomes relevant to the patient. This comprehensive review of the literature highlights the impact of residual fragments, modes of detection, and treatment strategies to avoid residual fragments in shock wave therapy, ureteroscopy, and percutaneous nephrolithotomy. METHODS: A comprehensive review of current literature was performed using PubMed((r)), MEDLINE((r)), EmbaseTM, Ovid((r)), Google ScholarTM, and the Cochrane Library. Publications relevant to the subject were retrieved and critically appraised. RESULTS: Residual fragments after treatment for urinary stones have a significant impact on a patient's well being and future course. (Ultra-) low-dose non-contrast computed tomography detects small residuals most reliably. In shock wave lithotripsy, adherence to basic principles helps to improve results. Various techniques and devices facilitate complete stone clearance in conventional and miniaturized percutaneous nephrolithotomy and (flexible) ureteroscopy. Promising new technologies in shock waves, lasers, and robotics (and potentially microrobotics) are on the horizon. CONCLUSIONS: Residual fragments are relevant to patients. Contemporary treatment of urolithiasis should aim at complete stone clearance. PMID- 26497826 TI - Comparison of innate immunity mediators in peritoneal fluid and spleen between young and aged rats. AB - BACKGROUND: Aging of the innate immune system can result in a wide array of decreasing biological function. AIM: We investigated differences between young and old mice in the expression of the pattern-recognition receptors (PRRs). METHODS: mRNA levels for PRRs were quantified and compared in peritoneal fluid and spleens from old (36 months old) and young (1 month old) Wistar white rats (n = 8/group) using real-time reverse transcription-polymerase chain reaction. RESULTS: In old rats, TLR-5 and -7 were decreased in peritoneal fluid, whereas TLR 4/6/9 and Syk were increased in the spleen (p < 0.05). In young rats, TLR 2/4, dectin-1, and Trem-1 were increased in peritoneal fluid and decreased in the spleen (p < 0.05), but TLR 1/3/7/9/10 and Syk were vice versa (p < 0.05). DISCUSSION: Several parameters related to innate immunity may change with aging. CONCLUSION: Different expressions of mRNA for several PRRs are suggesting changes in innate immune responses in association with aging. PMID- 26497827 TI - An unusual finding of massive pulmonary embolism in a patient during treatment with high-dose ibuprofen. AB - Non-steroidal anti-inflammatory drugs have been associated with an increased risk of venous thromboembolism. We report for the first time, the case of a patient who developed massive pulmonary embolism after a long period of treatment with high doses of ibuprofen. A 65-year-old woman was admitted with severe dyspnea while on treatment with high doses of ibuprofen for diffuse spine pain due to arthrosis. A spiral computed tomography showed a massive pulmonary embolism. No other explanation for the thromboembolic disorder was found. She was successfully treated with therapeutic doses of low-molecular-weight heparin followed by rivaroxaban. Ibuprofen was discontinued and replaced by tramadol. High-dose ibuprofen is likely to have accounted for the life-threatening thromboembolic disorder. PMID- 26497825 TI - Treatment of muscle invasive bladder cancer in the elderly: navigating the trade offs of risk and benefit. AB - PURPOSE: Despite the fact that bladder cancer patients have the highest median age of any type of cancer, older patients with muscle invasion are often under treated. METHODS: In this review, we report the most up to date literature on the patterns of care and treatment of older patients with muscle invasive bladder cancer. Data on under-treatment, geriatric principles, cystectomy, perioperative chemotherapy, and bladder preservation for older patients are presented and analyzed. CONCLUSION: Chronologic age should not exclude patients from curative intent therapy. Functional age as determined by geriatric assessments and multidisciplinary evaluation can help clinicians decide on the best course of treatment for individual patients. Cystectomy, perioperative chemotherapy, and curative-intent bladder preservation are reasonable options in healthy older adults. Observation should be limited to patients with extremely poor performance status and very limited life expectancy. PMID- 26497828 TI - Oily fish consumption is inversely correlated with cerebral microbleeds in community-dwelling older adults: results from the Atahualpa Project. AB - BACKGROUND: Oily fish is a major dietary source of omega-3 polyunsaturated fatty acids (omega-3 PUFAs). These nutrients improve endothelial dysfunction, reduce beta-amyloid induced damage of neurovascular units, and might prevent the occurrence of cerebral microbleeds. However, this relationship has not been investigated so far. AIM: To evaluate the association between oily fish intake and cerebral microbleeds in a population of frequent fish consumers living in coastal Ecuador. METHODS: Cerebral microbleeds were identified by gradient-echo MRI and oily fish consumption was calculated in community-dwellers aged >=60 years enrolled in the Atahualpa Project. The association between cerebral microbleeds and fish servings was examined in regression models adjusted for relevant confounders. A predictive model was constructed using quintiles of fish servings to take into account the non-linearity in the relationship. RESULTS: Out of 311 eligible individuals, 293 (94 %) were enrolled. Cerebral microbleeds were recognized in 37 (13 %) individuals. Mean fish consumption was 8.8 +/- 5.4 servings per week (omega-3 PUFAs estimates: 10.2 +/- 7.1 g). Multivariate analysis showed an inverse relationship between cerebral microbleeds and fish consumption (p < 0.001). Predictive margins of CMB were higher for individuals in the lowest (<=4.3) than for those in the highest (>=13.1) quintile of fish servings (17.4 vs 2.3 %, p < 0.001). CONCLUSIONS: This study shows a lower cerebral microbleed presence among older adults eating large amounts of oily fish (13 servings per week, equivalent to about 15 g of omega-3 PUFAs). These high requirements can be more readily accomplished in other populations by taking fish oil preparations. Longitudinal studies are warranted to assess whether these interventions reduce incident cerebral microbleeds in high-risk individuals. PMID- 26497829 TI - White matter abnormalities are associated with chronic postconcussion symptoms in blast-related mild traumatic brain injury. AB - Blast-related mild traumatic brain injury (mTBI) is a common injury among Iraq and Afghanistan military veterans due to the frequent use of improvised explosive devices. A significant minority of individuals with mTBI report chronic postconcussion symptoms (PCS), which include physical, emotional, and cognitive complaints. However, chronic PCS are nonspecific and are also associated with mental health disorders such as posttraumatic stress disorder (PTSD). Identifying the mechanisms that contribute to chronic PCS is particularly challenging in blast-related mTBI, where the incidence of comorbid PTSD is high. In this study, we examined whether blast-related mTBI is associated with diffuse white matter changes, and whether these neural changes are associated with chronic PCS. Ninety Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans were assigned to one of three groups including a blast-exposed no--TBI group, a blast related mTBI without loss of consciousness (LOC) group (mTBI--LOC), and a blast related mTBI with LOC group (mTBI + LOC). PCS were measured with the Rivermead Postconcussion Questionnaire. Results showed that participants in the mTBI + LOC group had more spatially heterogeneous white matter abnormalities than those in the no--TBI group. These white matter abnormalities were significantly associated with physical PCS severity even after accounting for PTSD symptoms, but not with cognitive or emotional PCS severity. A mediation analysis revealed that mTBI + LOC significantly influenced physical PCS severity through its effect on white matter integrity. These results suggest that white matter abnormalities are associated with chronic PCS independent of PTSD symptom severity and that these abnormalities are an important mechanism explaining the relationship between mTBI and chronic physical PCS. PMID- 26497830 TI - Nitrogen detected TROSY at high field yields high resolution and sensitivity for protein NMR. AB - Detection of (15)N in multidimensional NMR experiments of proteins has sparsely been utilized because of the low gyromagnetic ratio (gamma) of nitrogen and the presumed low sensitivity of such experiments. Here we show that selecting the TROSY components of proton-attached (15)N nuclei (TROSY (15)NH) yields high quality spectra in high field magnets (>600 MHz) by taking advantage of the slow (15)N transverse relaxation and compensating for the inherently low (15)N sensitivity. The (15)N TROSY transverse relaxation rates increase modestly with molecular weight but the TROSY gain in peak heights depends strongly on the magnetic field strength. Theoretical simulations predict that the narrowest line width for the TROSY (15)NH component can be obtained at 900 MHz, but sensitivity reaches its maximum around 1.2 GHz. Based on these considerations, a (15)N detected 2D (1)H-(15)N TROSY-HSQC ((15)N-detected TROSY-HSQC) experiment was developed and high-quality 2D spectra were recorded at 800 MHz in 2 h for 1 mM maltose-binding protein at 278 K (tauc ~ 40 ns). Unlike for (1)H detected TROSY, deuteration is not mandatory to benefit (15)N detected TROSY due to reduced dipolar broadening, which facilitates studies of proteins that cannot be deuterated, especially in cases where production requires eukaryotic expression systems. The option of recording (15)N TROSY of proteins expressed in H2O media also alleviates the problem of incomplete amide proton back exchange, which often hampers the detection of amide groups in the core of large molecular weight proteins that are expressed in D2O culture media and cannot be refolded for amide back exchange. These results illustrate the potential of (15)NH-detected TROSY experiments as a means to exploit the high resolution offered by high field magnets near and above 1 GHz. PMID- 26497831 TI - Fish oil supplementation does not lower C-reactive protein or interleukin-6 levels in healthy adults. AB - BACKGROUND: The n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may prevent a range of chronic conditions through anti inflammatory actions. However, as clinical trials using these fatty acids for primary prevention are yet unavailable, their putative role in disease prevention rests, in part, on evidence of anti-inflammatory actions in healthy individuals. OBJECTIVE: To investigate in a double-blind, placebo-controlled clinical trial whether supplementation with a moderate dose of EPA+DHA reduces common biomarkers of chronic, systemic inflammation in healthy individuals. METHODS: A total of 261 healthy individuals aged 30-54 years who were free of inflammatory conditions and consumed <= 300 mg per day EPA+DHA were included in the study. Participants were randomly assigned to 18 weeks of either fish oil supplementation providing 1400 mg per day EPA+DHA or matching placebo. Outcome measures were serum levels of C reactive protein (CRP) and interleukin (IL)-6. In a substudy, ex vivo cytokine production was measured. Missing data for CRP and IL-6 were estimated using regression imputation. Data analyses conformed to intention-to-treat principles. RESULTS: Participant blinding was verified. Red blood cell EPA+DHA increased by 64% in the active treatment group, but serum CRP and IL-6 were not affected by supplementation (P >= 0.20). Findings were consistent with and without imputed values and across subgroups. Similarly, EPA+DHA supplementation did not alter ex vivo production of four pro-inflammatory cytokines (P >= 0.20). CONCLUSIONS: Supplementation with 1400 mg EPA+DHA did not reduce common markers of systemic inflammation in healthy adults. Whether this or a higher dose affects other measures of inflammation, oxidative stress or immune function warrants examination. PMID- 26497833 TI - Influence of preparation and football skill level on injury incidence during an amateur football tournament. AB - INTRODUCTION: Scientific studies on injury characteristics are rather common in professional football but not in amateur football despite the thousands of amateur football tournaments taking place worldwide each year. The purpose of this study was to evaluate the preparation and injury patterns of players of two different football skill levels who participated in an international amateur football tournament. METHODS: In a prospective cohort study, an international amateur football tournament of medical doctors in 2011 was analysed with regard to training and warm-up preparation, the level of football played before the tournament and injury data during the tournament by means of standardised injury definitions and data samples for football. RESULTS: Amateur players of registered football clubs had higher training exposure before the tournament (p < 0.001) than recreational players and had more frequently performed warm-up programmes (p < 0.001). Recreational football players showed a significantly higher overall injury incidence (p < 0.002), particularly of overuse injuries (p < 0.001), during the tournament than amateur players. In almost 75% of players in both groups, the body region most affected by injuries and complaints was the lower extremities. Orthopaedic and trauma surgeons had the lowest overall injury incidence and anaesthetists the highest (p = 0.049) during the tournament. CONCLUSION: For the first time, this study presents detailed information on the injury incidence and injury patterns of an amateur football tournament. Less trained recreational players sustained significantly more injuries than better trained amateur players, probably due to the lack of sufficient preparation before the tournament. Preventive strategies against overuse and traumatic injuries of recreational football players should start with regular training and warm-up programmes in preparation for a tournament. PMID- 26497836 TI - Differences in the Limits of Stability Between Older Rolling Walker Users and Older Single-Tip-Cane Users - A Preliminary Study. AB - PURPOSE: To identify the differences in the limits of stability (LOS) between older rolling walker and single-tip-cane users. DESIGN: This was a matched paired t-test design with repeated measure. METHODS: Eighteen older subjects were matched based on age, gender, and functional level. The subjects were assessed using the multidirectional reach test initially and 5-month later in four directions: forward, backward, leftward, and rightward. FINDINGS: Initially, there were no differences between cane users and rolling walker users in the LOS in all directions. However, 5-month later, the cane users who held their canes in their right hand had significantly better stability in forward and rightward reach than the walker users (p < .05). Further, the walker users demonstrated significantly decreased functional reach in forward reach (p < .05). CONCLUSION: Cane users might have better stability than walker users in the forward direction and in the direction toward the side holding the cane. This study may provide guide for clinicians including nurses for selecting appropriate rehabilitative interventions for older adults using walkers and canes. PMID- 26497835 TI - Inhibitory respiratory responses to progesterone and allopregnanolone in newborn rats chronically treated with caffeine. AB - KEY POINTS: In premature newborns, recurrent apnoea is systematically treated with caffeine to prevent long-term neurocognitive disorders, but a substantial percentage of apnoea persists particularly in neonates born before 28 weeks of gestation. Progesterone has been proposed as a respiratory stimulant potentially suitable for the treatment of newborn apnoea persistent to caffeine. Accordingly we asked whether acute progesterone administration reduces apnoea frequency in newborn rats treated with caffeine. Surprisingly our results show that in newborn rats treated with caffeine, administration of progesterone inhibits breathing and increases apnoea frequency. Additional experiments showed an enhanced GABAergic inhibitory drive on breathing after caffeine treatment, and that progesterone is converted to allopregnanolone (an allosteric modulator of GABAA receptors) to inhibit breathing. We conclude that combining progesterone and chronic caffeine is not an option in preterm neonates, unless the effects of allopregnanolone can be counteracted. ABSTRACT: Caffeine is the main treatment for apnoea in preterm neonates, but its interactions with other respiratory stimulants like progesterone are unknown. We tested the hypothesis that the addition of progesterone to caffeine treatments further stimulates ventilation. Newborn rats were treated with water (control) or caffeine (15 mg kg(-1)) by daily gavage between postnatal day (P)3 and P12. At P4 and P12, we measured apnoea frequency, ventilatory responses and metabolic parameters under both normoxia and hypoxia (12% O2, 20 min) following an acute administration of either saline or progesterone (4 mg kg(-1); i.p.). Progesterone injection increased the serum levels of both progesterone and its neuroactive metabolite allopregnanolone. Progesterone had no effect on ventilation in control rats under normoxia. Progesterone depressed ventilation in P12 caffeine-treated rats under normoxia and hypoxia and increased apnoea frequency in both P4 and P12 rats. Because allopregnanolone is an allosteric modulator of GABAA receptors and caffeine may enhance GABAergic inhibition in newborns, we studied the effects of the GABAA receptor antagonist bicuculline at 0, 1, 2 and 3 mg kg(-1) doses and allopregnanolone (10 mg kg(-1) dose) in P12 rats. In caffeine-treated rats, bicuculline enhanced ventilation, while allopregnanolone decreased ventilation and increased total apnoea time. Progesterone had no effect on ventilation and apnoea frequency in caffeine-treated rats injected with finasteride, which blocks the conversion of progesterone to allopregnanolone. We conclude that combining progesterone and chronic caffeine therapy is not an option for the treatment of persistent apnoea in preterm neonates, unless the effects of allopregnanolone can be counteracted. PMID- 26497834 TI - Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array. AB - Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 * 10(-8) ). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10(-5) . The effect of nine SNPs in the HLA region remained (P < 10(-5) ) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations. PMID- 26497837 TI - Recent Clinical Trials of Pharmacologic Cardiovascular Interventions in Patients with Chronic Kidney Disease: An Update. AB - As a consequence of both traditional and non-traditional risk factors, cardiovascular disease is over-represented, and the leading cause of mortality, among patients with Chronic Kidney Disease (CKD). Whilst recommendations for reducing cardiovascular risk in the general population exist, their applicability to the CKD population is questionable due to the exclusion of CKD patients from the majority of contemporary cardiovascular interventional studies. The aim of this review is to critically evaluate the literature regarding pharmacologic cardiovascular interventions in patients with CKD, with an emphasis on studies published since our 2008 review. Interventions discussed include erythropoiesis stimulating agents (TREAT, U.S. Normal Hematocrit, CHOIR, CREATE, Palmer meta analysis); statins (SHARP, AURORA, PPP, 4D, ALERT); Fibrates (VA-HIT); Folic Acid (ASFAST, US FOLIC acid trial, HOST); Antihypertensive Agents, Including Angiotensin-Converting Enzyme Inhibitors, angiotensin-receptor blockers, Beta blockers and Combination therapy (Cice et al, FOSDIAL, Agarwal et al, ONTARGET); sevelamer (DCOR); Cinacalcet (ADVANCE, EVOLVE, Cunningham meta-analysis); Anti oxidants (SPACE, HOPE, ATIC); Aspirin (HOT study re-analysis); vitamin D analogues (PRIMO); and multidisciplinary intervention (LANDMARK). Unfortunately, there remains a paucity of evidence in this area and a large number of methodologically poor quality studies with negative results. It is possible that these interventions do not have the same positive effect in CKD patients due to differences in the pathogenesis driving cardiovascular disease burden, such as altered bone metabolism and calcific vascular disease. Further well-designed studies with appropriately selected study populations and patient level outcomes are required. Until such time, physicians must consider on an individual patient basis the appropriateness of these interventions. PMID- 26497839 TI - Multi-residue fluorescent microspheres immunochromatographic assay for simultaneous determination of macrolides in raw milk. AB - A rapid, reliable, sensitive, and quantitative multi-residue fluorescent microspheres immunochromatographic assay (FMCA) was developed for simultaneous detection of four macrolides in raw milk. The IC50 value of the optimized FMCA was 1.36, 1.22, 1.01, and 1.39 ng/mL for erythromycin (ERY), spiramycin (SPI), tilmicosin (TIM), and tylosin (TYL), respectively. The limits of detection (LODs) for the four macrolides was 0.13 ng/mL. The recoveries of ERY, SPI, TIM, and TYL from spiked raw milk ranged from 91.8-109.2, 89.6-114.4, 84.8-111.6, and 85.8 115.2%, respectively, with coefficients of variation (CVs) of 5.4-11.3, 7.9-15.7, 6.2-13.7, and 3.2-14.9%, respectively. The whole testing process was completed within 20 min. The antibody-mixed labeled method was successfully applied to the FMCA, which greatly simplified the operation steps and saved a lot of time. Compared with the immunogold chromatographic assay (IGCA), the FMCA is more sensitive and stable and has less antibody consumption. A parallel analysis in blind raw milk samples was conducted by liquid chromatography-tandem mass spectrometry (LC-MS/MS); the results showed good correlation (r(2) = 0.99) between the two methods. Therefore, the developed multi-residue FMCA is reliable and can be easily applied to other antibiotics or other contaminants. PMID- 26497841 TI - Simultaneous determination of 18 D-amino acids in rat plasma by an ultrahigh performance liquid chromatography-tandem mass spectrometry method: application to explore the potential relationship between Alzheimer's disease and D-amino acid level alterations. AB - D-Amino acids are increasingly being recognized as important signaling molecules, and abnormal levels of D-amino acids have been implicated in the pathogenesis of Alzheimer's disease. To evaluate the potential relationship between Alzheimer's disease and D-amino acids, a simple, sensitive, and reliable UPLC-MS/MS method with pre-column derivatization was developed and validated for simultaneous determination of 18 D-amino acids in rat plasma. The analytes were extracted from plasma samples by a protein precipitation procedure, and then derivatized with (S)-N-(4-nitrophenoxycarbonyl) phenylalanine methoxyethyl ester [(S)-NIFE]. Chromatographic separation was achieved using an ACQUITY UPLC BEH C18 column (2.1 mm * 50 mm, 1.7 MUm) with a mobile phase composed of acetonitrile containing 8 mM ammonium hydrogen carbonate at a flow rate of 0.6 mL min(-1). The analytes were detected by electrospray ionization in positive ion multiple reaction monitoring modes. Under the optimum experimental conditions, all the linear regressions were acquired with r > 0.9932. The limits of quantitation of all derivatized D-amino acids were within 0.05-40.0 ng mL(-1) in rat plasma. The intra- and inter-day precisions, expressed as percentage relative standard deviations (%RSD), were within the range of 12.3 and 10.1%, respectively. The recoveries for all the analytes were observed over the range of 82.8-100.5% with RSD values less than 12.5%. Finally, the proposed method was successfully applied to simultaneous determination of the 18 D-amino acids in plasma from Alzheimer's disease rats and age-matched normal controls. Results showed that the concentrations of D-serine, D-aspartate, D-alanine, D-leucine, and D-proline in Alzheimer's disease rat plasma were significantly decreased compared with those in normal controls, while D-phenylalanine levels increased. It was revealed that some of these D-amino acids would be potential diagnostic biomarkers for Alzheimer's disease. PMID- 26497818 TI - Multilocus sequence typing of Streptococcus thermophilus from naturally fermented dairy foods in China and Mongolia. AB - BACKGROUND: Streptococcus thermophilus is a major dairy starter used for manufacturing of dairy products. In the present study, we developed a multilocus sequence typing (MLST) scheme for this important food bacterium. Sequences of 10 housekeeping genes (carB, clpX, dnaA, murC, murE, pepN, pepX, pyrG, recA, and rpoB) were obtained for 239 S. thermophilus strains, which were isolated from home-made fermented dairy foods in 18 different regions of Mongolia and China. METHODS: All 10 genes of S. thermophilus were sequenced, aligned, and defined sequence types (STs) using the BioNumerics Software. The nucleotide diversity was calculated by START v2.0. The population structure, phylogenetic relationships and the role of recombination were inferred using ClonalFrame v1.2, SplitsTree 4.0 and Structure v2.3. RESULTS: The 239 S. thermophilus isolates and 18 reference strains could be assigned into 119 different STs, which could be further separated into 16 clonal complexes (CCs) and 38 singletons. Among the 10 loci, a total of 132 polymorphic sites were detected. The standardized index of association (IAS=0.0916), split-decomposition and rho/theta (relative frequency of occurrence of recombination and mutation) and r/m value (relative impact of recombination and mutation in the diversification) confirms that recombination may have occurred, but it occurred at a low frequency in these 10 loci. Phylogenetic trees indicated that there were five lineages in the S. thermophilus isolates used in our study. MSTree and ClonalFrame tree analyses suggest that the evolution of S. thermophilus isolates have little relationship with geographic locality, but revealed no association with the types of fermented dairy product. Phylogenetic analysis of 36 whole genome strains (18 S. thermophilus, 2 S. vestibularis and 16 S. salivarius strains) indicated that our MLST scheme could clearly separate three closely related species within the salivarius group and is suitable for analyzing the population structure of the other two species in the salivarius group. CONCLUSIONS: Our newly developed MLST scheme improved the understanding on the genetic diversity and population structure of the S. thermophilus, as well as provided useful information for further studies on the genotyping and evolutionary research for S. thermophilus strains with global diversity. PMID- 26497843 TI - Identifying the Atomic-Level Effects of Metal Composition on the Structure and Catalytic Activity of Peptide-Templated Materials. AB - Bioinspired approaches for the formation of metallic nanomaterials have been extensively employed for a diverse range of applications including diagnostics and catalysis. These materials can often be used under sustainable conditions; however, it is challenging to control the material size, morphology, and composition simultaneously. Here we have employed the R5 peptide, which forms a 3D scaffold to direct the size and linear shape of bimetallic PdAu nanomaterials for catalysis. The materials were prepared at varying Pd:Au ratios to probe optimal compositions to achieve maximal catalytic efficiency. These materials were extensively characterized at the atomic level using transmission electron microscopy, extended X-ray absorption fine structure spectroscopy, and atomic pair distribution function analysis derived from high-energy X-ray diffraction patterns to provide highly resolved structural information. The results confirmed PdAu alloy formation, but also demonstrated that significant surface structural disorder was present. The catalytic activity of the materials was studied for olefin hydrogenation, which demonstrated enhanced reactivity from the bimetallic structures. These results present a pathway to the bioinspired production of multimetallic materials with enhanced properties, which can be assessed via a suite of characterization methods to fully ascertain structure/function relationships. PMID- 26497844 TI - Near work-induced transient myopia in Indian subjects. AB - PURPOSE: The aim was to determine the characteristics of near work-induced transient myopia (NITM) in asymptomatic Indian subjects and the influence of target size and contrast. METHODS: Two studies were conducted: First, 24 myopes and 24 emmetropes viewed four targets (N8 and N12 with 50 and 90 per cent contrasts) placed at 0.2 m for five minutes. The refractive status was assessed objectively, before and after carrying out the near task, with the Grand Seiko WAM-5500 open-field autorefractor under monocular viewing conditions. Second, a different group of 24 myopes and 24 emmetropes viewed a N12 target with 90 per cent contrast for 60 minutes with pre- and post-refractive state measurements repeated as above. NITM was defined as the difference between pre-task and post task distance refraction. RESULTS: In the first study, myopes demonstrated an initial post-task myopic shift of 0.21 D, whereas emmetropes demonstrated a small hyperopic shift of 0.07 D (p < 0.001). The myopes demonstrated a decay time constant of 6.07 seconds. There was no effect of target size or contrast on the magnitude of the NITM or the decay time constant (p > 0.05). In the second study, myopes showed a NITM of 0.31 D, which was significantly greater than emmetropes (p < 0.001). The myopes demonstrated a decay time constant of 8.16 seconds. CONCLUSION: The magnitude of the NITM was higher in myopes compared to emmetropes for both five minute and 60 minute viewing time. The NITM decayed slightly faster than that found in previous literature for some other ethnic groups. Potential reasons for these findings are discussed. PMID- 26497842 TI - Erectile dysfunction and its management in patients with diabetes mellitus. AB - Diabetes can be described as a syndrome of multiple closely related conditions induced by a chronic state of hyperglycaemia resulting from defective insulin secretion, insulin action or both. Chronic complications associated with diabetes (including neuropathy, vascular disease, nephropathy and retinopathy) are common, and of these, erectile dysfunction (ED) deserves special attention. ED and its correlation with cardiovascular disease require careful evaluation and appropriate treatment. PDE5 inhibitors (PDE5is) are an important tool for the treatment of ED, with new drugs coming onto the market since the late 90s. This review offers an overview of PDE5is and their use in treating ED in diabetes. We underline the differences between different types of PDE5i, focusing on available doses, duration of action, T 1/2, side effects and selectivity profiles in relation to patients with diabetes. We also discuss the link between diabetes and ED in presence of various associated cofactors (obesity, hypertension and its pharmacological treatments, atherosclerosis, hyperhomocysteinaemia, neuropathy, nephropathy, hypogonadism and depression). Finally a number of past and ongoing clinical trials on the use of PDE5is in patients with diabetes are presented to offer an overview of the appropriate treatment of ED in this condition. PMID- 26497845 TI - Toll-like receptor-2 and -4 are associated with hyperlipidemia. AB - Recent studies have suggested that toll-like receptors (TLRs) contribute to insulin resistance, and that fatty acids have a role in TLR activation. Other studies have found that TLR2 and TLR4 upregulation is consistent with an increase in serum lipid. Therefore, it was hypothesized that TLRs are associated with hyperlipidemia. The aim of the present study was to investigate whether TLR2 or TLR4 was associated with hyperlipidemia and to provide novel targets for hyperlipidemia therapy. Volunteers were selected at the Medical Examination Center of Hebei General Hospital (Shijiazhuang, China), including 43 patients with high triglyceride (TG) levels, 84 with high total cholesterol (TC) levels and 55 with high TG and high TC levels. In addition, 68 healthy volunteers were selected as a control group. For the animal study, the TLR gene and protein levels were assessed in the skeletal muscle of rats fed a high-fat diet. As expected, TLR2 and TLR4 gene expression were upregulated when TC increased, TG increased, or TC and TG increased. In rats fed a high-fat diet, the levels of gene and protein expression in the skeletal muscle of the two TLRs were all increased compared with the control group, this was consistent with an increase in TC and TG. In addition, in drug treatment groups the mRNA and protein expression levels of TLR in the skeletal muscle of rats fed a high fat diet were decreased, as were the TC and TG levels. In conclusion, these findings suggest that TLR2 and TLR4 are associated with hyperlipidemia. PMID- 26497846 TI - The application of low frequency dielectric spectroscopy to analyze the electrorheological behavior of monodisperse yolk-shell SiO2/TiO2 nanospheres. AB - Monodisperse SiO2/TiO2 yolk-shell nanospheres (YSNSs) with different SiO2 core sizes were fabricated and adopted as dispersing materials for electrorheological (ER) fluids to investigate the influence of the gradual structural change of disperse particles on ER properties. The results showed that the ER performance of the YSNS-based ER fluid prominently enhanced with the decrease of SiO2 core size, which was attributed to the enhancement of electric field force between YSNSs. Combined with the analysis of dielectric spectroscopy, it was found that the increase of permittivity at low frequency (10(-2)-10(0) Hz) was due to the increase of polarized charges caused by secondary polarization (Psp). Moreover, the number of Psp closely related to the distributing change of polarized particles in ER fluid was a critical factor to assess the ER performance. Additionally, a parameter K (the absolute value of the slope of permittivity curves at 0.01 Hz) could be utilized to characterize the efficiency of structural evolution of polarized particles in ER fluid. Compared with the ER performance, it could be concluded that the value of Deltaepsilon(100Hz-100kHz)' just demonstrated the initial intensity of the interface polarization in the ER fluid as the electric field was applied, which ignored the distributing evolution of polarized disperse particles in ER fluid. The polarizability Deltaepsilon(0.01Hz 100kHz)' obtained in the frequency range of 10(-2)-10(5) Hz should be more suitable for analyzing the system of ER fluid. The relationships between polarizability of disperse particles, parameter K and ER properties were discussed in detail. PMID- 26497847 TI - Expression of USP22 and Survivin is an indicator of malignant behavior in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor type, ranking as the third leading cause of all cancer-related deaths in the world. The post-surgical 5-year survival rate is low, largely due to the high recurrence rate. Therefore, the identification of target molecules that control the biological characteristics of HCC is of great importance. Ubiquitin-specific protease 22 (USP22) is a newly discovered deubiquitinating enzyme and is a cancer stem cell marker that plays a role in tumorigenesis, therapy resistance and cell cycle progression. Survivin is a member of the inhibitor of apoptosis protein (IAP) family and is known to function either as an inhibitor for apoptosis or as a regulator of cell division. Levels of survivin are correlated with the aggressiveness of tumors and a poor prognosis in various cancers including HCC. In the present study, we examined the USP22 expression and its association with survivin expression and clinicopathological features in HCC. First, we examined the expression of USP22 and survivin in 151 HCC cases by immunohistochemistry. High expression of USP22 and survivin was frequently observed in HCC cases, in comparison with normal adjacent liver tissues. Expression of USP22 and survivin was well correlated with malignant behavior including tumor size, stage and differentiation in HCC cases. Importantly, HCC patients with high expression of USP22 and survivin showed poor prognosis. USP22 expression was well correlated with survivin expression in HCC cases. This correlation was confirmed in HCC cell lines and tissues by RT-PCR and western blot analysis. Next, to investigate the biological role of USP22 in HCC, we examined the effect of USP22 knockdown on the cell growth and the expression of cell cycle-related protein including survivin in HCC cells. USP22 siRNA suppressed cell growth. Moreover, USP22 siRNA decreased survivin expression together with upregulation of CDK inhibitor, p21 and downregulation of cyclin B. These findings suggest that USP22 may be involved in HCC progression in cooperation with survivin. We suggest that USP22 can be useful as a new prognostic marker and therapeutic target in HCC patients. PMID- 26497848 TI - Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction. AB - AIM: Growth differentiation factor 15 (GDF15) is a cytokine highly expressed in states of inflammatory stress. We aimed to study the clinical correlates and prognostic significance of plasma GDF15 in heart failure with preserved ejection fraction (HFpEF) vs. reduced ejection fraction(HFrEF), compared with N-terminal pro-brain natriuretic peptide (NT-proBNP), an indicator of haemodynamic wall stress. METHODS: Plasma GDF15 and NT-proBNP were prospectively measured in 916 consecutive patients with HFrEF (EF <50%; n = 730) and HFpEF (EF >=50%; n = 186), and measured again at 6 months in 488 patients. Patients were followed up for a composite outcome of death or first HF rehospitalization. RESULTS: Median GDF15baseline values were similarly elevated in HFpEF [2862 (1812 represent the 25th percentile and 4176 represent the 75th percentile) ng/L] and HFrEF [2517 (1555, 4030) ng/L] (P = 0.184), whereas NT-proBNP was significantly lower in HFpEF than HFrEF (1119 ng/L vs. 2335 ng/L, P < 0.001). Independent correlates of GDF15baseline were age, systolic blood pressure, New York Heart Association (NYHA) class, diabetes, atrial fibrillation, sodium, haemoglobin, creatinine, diuretic therapy, high sensitivity troponin T (hsTnT) and NT-proBNP (all P < 0.05). During a median follow-up of 23 months, there were 379 events (307 HFrEF, 72 HFpEF). GDF15 remained a significant independent predictor for composite outcome even after adjusting for important clinical predictors including hsTnT and NT-proBNP (adjusted hazard ratio 1.76 per 1 Ln U, 95% confidence interval 1.39-2.21; P < 0.001), regardless of HF group (Pinteraction = 0.275). GDF15baseline provided incremental prognostic value when added to clinical predictors, hsTnT and NT-proBNP (area under receiver operating characteristic curve increased from 0.720 to 0.740, P < 0.019), with a net reclassification improvement of 0.183 (P = 0.004). Patients with >=20% GDF156months increase had higher risk for composite outcome (adjusted hazard ratio 1.68, 95% confidence interval 1.15-2.45; P = 0.007) compared with those with GDF156months within +/- 20% of baseline. CONCLUSIONS: The similarly elevated levels and independent prognostic utility of GDF15 in HFrEF and HFpEF suggest that beyond haemodynamic stress (NT-proBNP), inflammatory injury (GDF15) may play an important role in both HF syndromes. PMID- 26497849 TI - Myeloid-derived suppressor cells inhibit T cell proliferation in human extranodal NK/T cell lymphoma: a novel prognostic indicator. AB - The expansion of myeloid-derived suppressor cells (MDSCs) and its correlation with advanced disease stage have been shown in solid cancers. Here, we investigated the functional features and clinical significance of MDSCs in extranodal NK/T cell lymphoma (ENKL). A higher percentage of circulating HLA-DR( )CD33(+)CD11b(+) MDSCs was observed in ENKL patients than in healthy controls (P < 0.05, n = 32) by flow cytometry analysis. These MDSCs from ENKL patients (ENKL MDSCs) consisted of CD14(+) monocytic (Mo-MDSCs, >60 %) and CD15(+) granulocytic (PMN-MDSCs, <20 %) MDSCs. Furthermore, these ENKL-MDSCs expressed higher levels of Arg-1, iNOS and IL-17 compared to the levels of MDSCs from healthy donors, and they expressed moderate levels of TGFbeta and IL-10 but lower levels of CD66b. The ENKL-MDSCs strongly suppressed the anti-CD3-induced allogeneic and autologous CD4 T cell proliferation (P < 0.05), but they only slightly suppressed CD8 T cell proliferation (P > 0.05). Interestingly, ENKL-MDSCs inhibited the secretion of IFNgamma but promoted IL-10, IL-17 and TGFbeta secretion as well as Foxp3 expression in T cells. The administration of inhibitors of iNOS, Arg-1 and ROS significantly reversed the suppression of anti-CD3-induced T cell proliferation by MDSCs (P < 0.05). Importantly, based on multivariate Cox regression analysis, the HLA-DR(-)CD33(+)CD11b(+) cells and CD14(+) Mo-MDSCs were independent predictors for disease-free survival (DFS, P = 0.013 and 0.016) and overall survival (OS, P = 0.017 and 0.027). Overall, our results identified for the first time that ENKL-MDSCs (mainly Mo-MDSCs) have a prognostic value for patients and a suppressive function on T cell proliferation. PMID- 26497850 TI - Increased tumor infiltration by mucosal-associated invariant T cells correlates with poor survival in colorectal cancer patients. AB - The infiltration of tumors by lymphocytes is a prognosis factor in colorectal cancer (CRC). The magnitude and quality of this infiltration have emerged as important component of the clinical outcome in these patients. Specifically, markers associated with functional cell-mediated immunity, i.e., a Th1 immune response, are independent markers of better prognosis, whereas Th17-associated components are deleterious and correlate with poorer survival. Mucosal-associated invariant T (MAIT) cells are a recently described T cell subset with tissue homing properties. They display a restricted TCR repertoire specific for widely conserved microbial ligands, and display anti-bacterial properties upon release of Th1-like, Th17-like, and/or cytotoxic granules. MAIT-cell-specific transcripts have been found in kidney and brain cancer, but have not been studies in other sites. In this study, we retrospectively analyzed by confocal microscopy the presence of MAIT cells within colorectal tumors as compared with paired healthy tissues. We observed a significant although variable increase, both in density and in proportion of overall tumor-infiltrating T lymphocytes inside the tumors. Importantly, survival curves as well as multivariate analysis showed that patients displaying a higher recruitment of MAIT cells in their tumor, as compared with the neighboring healthy tissue, showed a less favorable clinical outcome. This study suggests that including MAIT-cell-specific markers or transcripts in the analysis of tumor-infiltrating lymphocytes could be a benefit to the diagnosis and follow-up of CRC patients. PMID- 26497851 TI - Hsa-miR-139-5p inhibits proliferation and causes apoptosis associated with down regulation of c-Met. AB - Hsa-miRNA-139-5p (miR-139-5p) has recently been discovered having anticancer efficacy in different organs. However, the role of miR-139-5p on lung cancer is still ambiguous. In this study, we investigated the role of miR-139-5p on development of lung cancer. Results indicated miR-139-5p was significantly down regulated in primary tumor tissues and very low levels were found in a non-small cell lung cancer (NSCLC) cell lines. Ectopic expression of miR-139-5p in NSCLC cell lines significantly suppressed cell growth through inhibition of cyclin D1 and up-regulation of p57(Kip2). In addition, miR-139-5p induced apoptosis, as indicated by up-regulation of key apoptosis gene cleaved caspase-3, and down regulation of anti-apoptosis gene Bcl2. Moreover, miR-139-5p inhibited cellular metastasis through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene c-Met was revealed to be a putative target of miR-139-5p, which was inversely correlated with miR-139-5p expression. Taken together, our results demonstrated that miR-139-5p plays a pivotal role in lung cancer through inhibiting cell proliferation, metastasis, and promoting apoptosis by targeting oncogenic c-Met. PMID- 26497852 TI - MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab. AB - The aim of our study was to investigate whether microRNAs (miRNAs) could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with RAS wild-type (wt-RAS) metastatic colorectal cancer (mCRC). Historical cohort of 93 patients with mCRC (2006-2009) was included and further divided into exploratory and validation cohorts. MiRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 28 patients of wt-RAS mCRC treated with cetuximab and 24 patients of wt-RAS mCRC treated with panitumumab. We identified 9 miRNAs with significantly different expression between responders and non responders to cetuximab therapy (P <= 0.01). These 9 miRNAs were further evaluated in two independent cohorts of patients and miR-31-3p (P < 0.001) and miR-31-5p (P < 0.001) were successfully confirmed as strongly associated with TTP in wt-RAS mCRC patients treated with cetuximab but not panitumumab. When evaluated on the complete cohort of cetuximab patients (N = 69), miR-31-3p (HR, 5.10; 95% CI, 2.52-10.32; P < 0.001) and miR-31-5p (HR, 4.80; 95% CI, 2.50-9.24; P < 0.001) were correlated with TTP on the comparable level of significance. There was no difference in miR-31-5p/3p expression levels in RAS mutated and wild type tumor samples. MiR-31-5p/3p are promising predictive biomarkers of cetuximab response in wt-RAS mCRC patients. PMID- 26497853 TI - Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma. AB - Melanoma harboring BRAF mutations frequently develop resistance to BRAF inhibitors, limiting the impact of treatment. Here, we establish a mechanism of resistance and subsequently identified a suitable drug combination to overcome the resistance. Single treatment of BRAF mutant melanoma cell lines with vemurafenib or dabrafenib (BRAF inhibitors) alone or in combination with trametinib (MEK1/2 inhibitor) resulted in overexpression of Mcl-1. Overexpression of Mcl-1 in A375 and SK-MEL-28 by transfection completely blocked BRAF and MEK1/2 inhibitor-mediated inhibition of cell survival and apoptosis. Melanoma cells resistant to BRAF inhibitors showed massive expression of Mcl-1 as compared to respective sensitive cell lines. Silencing of Mcl-1 using siRNA completely sensitized resistant melanoma cells to growth suppression and induction of apoptosis by BRAF inhibitors. In vivo, vemurafenib resistant A375 xenografts implanted in athymic nude mice showed substantial tumor growth inhibition when treated with a combination of vemurafenib and Mcl-1 inhibitor or siRNA. Immunohistochemistry and western blot analyses demonstrated enhanced expression of Mcl-1 and activation of ERK1/2 in vemurafenib-resistant tumors whereas level of Mcl-1 or p-ERK1/2 was diminished in the tumors of mice treated with either of the combination. Biopsied tumors from the patients treated with or resistant to BRAF inhibitors revealed overexpression of Mcl-1. These results suggest that the combination of BRAF inhibitors with Mcl-1 inhibitor may have therapeutic advantage to melanoma patients with acquired resistance to BRAF inhibitors alone or in combination with MEK1/2 inhibitors. PMID- 26497854 TI - Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome. AB - A thorough understanding of the idiopathic hypereosinophilic syndrome (IHES) and further optimization of diagnostic work-up procedures are warranted. We analyzed purified eosinophils from patients with IHES by next-generation whole-exome sequencing and compared DNA methylation profiles from reactive eosinophilic conditions to known clonal and suspected clonal eosinophilia. Somatic missense mutations in cancer-related genes were detected in three IHES patients. These included the spliceosome gene PUF60 and the cadherin gene CDH17. Furthermore, reactive eosinophilia samples could be differentiated from known- and suspected clonal eosinophilia samples based on 285 differentially methylated CpG sites corresponding to 128 differentially methylated genes. Using Ingenuity pathway analysis, we found that differentially methylated genes were highly enriched in functional pathways such as cancer, cell death and survival, and hematological disease. Our data show that a subset of IHES may be of clonal origin not related to the classical molecular aberrations of FGFR, PDGFRA/B, or T-cells, and that the initiating hits could be point mutations in a variety of genes, including spliceosome mutations or hypermethylated tumor suppressor genes. In addition, we identified a DNA methylation signature that is relevant for distinguishing clonal and suspected clonal eosinophilia from reactive eosinophilia per se, which may be useful in daily clinical work. PMID- 26497855 TI - MicroRNA-1 down-regulates proliferation and migration of breast cancer stem cells by inhibiting the Wnt/beta-catenin pathway. AB - We investigated the miRNA profiles of breast cancer stem cells (CSCs) and non-CSC tumor cells by miRNA microarray and determined the effect of altered miR-1 expression on proliferation and migration of breast CSCs. The potential targets of miR-1 in the Wnt/beta-catenin signaling were characterized by bioinformatics analysis and luciferase assay. We found that 14 miRNAs were up-regulated and 13 were down-regulated in the ESA+CD44+CD24-lineage- CSCs, related to ESA+CD44 CD24+lineage- non-CSC tumor cells. The miR-1 expression was associated inversely with aggressiveness of breast cancers. Furthermore, enhanced miR-1 expression decreased the percentages of SKBR3/CSCs and miR-1 inhibition increased the percentages of MCF-7/CSCs. Enhanced miR-1 expression significantly reduced the Frizzled 7 and Tankyrase-2 (TNKS2)-regulated luciferase activity in 293T cells and decreased Frizzled 7, TNKS2, c-Myc, octamer-binding transcription factor 4 (Oct4) and Nanog expression and the ratios of nuclear to cytoplasmic beta-catenin as well as beta-catenin-dependent luciferase activity in breast CSCs in vitro. miR-1 inhibited proliferation, migration and wound healing of breast CSCs in vitro. Enhanced miR-1 expression inhibited the growth of implanted MCF-7/CSCs while miR-1 inhibition promoted the growth of implanted MCF-7/CSCs in vivo. Our data indicate that miR-1 down-regulates breast CSC stemness, proliferation and migration by targeting the Frizzled 7 and TNKS2 to inhibit the Wnt/beta-catenin signaling. PMID- 26497856 TI - Immobilization of enzymes using non-ionic colloidal liquid aphrons (CLAs): Activity kinetics, conformation, and energetics. AB - This study seeks to examine the ability of non-ionic/non-polar Colloidial Liquid Aphrons (CLAs) to preserve enzyme functionality upon immobilization and release. CLAs consisting of micron-sized oil droplets surrounded by a thin aqueous layer stabilized by a mixture of surfactants, were formulated by direct addition (pre manufacture addition) using 1% Tween 80/mineral oil and 1% Tween 20 and the enzymes lipase, aprotinin and alpha-chymotrypsin. The results of activity assays for both lipase and alpha-chymotrypsin showed that kinetic activity increased upon immobilization by factors of 7 and 5.5, respectively, while aprotinin retained approximately 85% of its native activity. The conformation of the enzymes released through desorption showed no significant alterations compared to their native state. Changes in pH and temperature showed that optimum conditions did not change after immobilization, while analysis of activation energy for the immobilized enzyme showed an increase in activity at higher temperatures. Furthermore, the effect of bound water within the aphron structure allowed for some degree of enzyme hydration, and this hydration was needed for an active conformation with results showing a decrease in DeltaH* for the immobilized system compared to its native counterpart. PMID- 26497857 TI - Effects of cow milk versus extensive protein hydrolysate formulas on infant cognitive development. AB - Little research has focused on infant developmental effects, other than growth, of formulas that differ substantially in the form of protein. To examine development of infants fed formulas differing in free amino acid content, we randomized 0.5-month-old infants (n = 79) to either a control group who fed only cow milk formula (CMF) during the first 8 months (CMF8), or to one of two experimental groups: one experimental group fed extensively protein hydrolyzed formula (EHF) for 1-3 months during first 4.5 months (EHF1-3) of life, and the other fed EHF for 8 months (EHF8). The Mullen Scales of Early Learning were administered monthly from 1.5 to 8.5 months to assess fine (FM) and gross (GM) motor control, receptive (RL) and expressive (EL) language, visual reception (VR), and an early learning composite (ELC). Across the 5.5-8.5-month time period, when compared to CMF8 infants, GM scores in EHF1-3 infants averaged 1.5 points higher (95 % CI 0.1, 3.0) and in EHF8 infants 2.2 points higher (95 % CI 0.3, 4.0). Similarly, VR scores averaged 1.9 points higher (95 % CI 0.1, 3.8) in EHF1-3 infants and 2.2 points higher (95 % CI -0.2, 4.5) in EHF8 infants. EHF8 infants' RL scores averaged 1.8 points lower (95 % CI 0.1, 3.6) than CMF8 infants. These data suggest that the form of protein in infant formula may impact cognitive development and that the higher free amino acid content in breast milk may be a contributing factor to the differential cognitive development between breastfed and CMF-fed infants. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT00994747. PMID- 26497858 TI - Mammalian target of rapamycin/p70 ribosomal S6 protein kinase signaling is altered by sevoflurane and/or surgery in aged rats. AB - The mammalian target of rapamycin (mTOR)/p70 ribosomal S6 protein kinase (p70S6k) pathway exerts anti-apoptotic effects that may contribute to disease pathogenesis. The memory impairment in patients with Alzheimer's disease (AD) has been suggested to be contributed to by abnormal mTOR signaling. The aim of the current study was to investigate the association between sevoflurane and/or surgery and AD through the mTOR/p70S6K signaling pathway. Sprague-Dawley rats were randomly assigned to the sevoflurane, surgery or control groups. The animals in the surgery group received a partial hepatectomy under sevoflurane anesthesia. The hippocampal levels of phosphorylated (p)-mTOR, p-p70S6K, caspase-3 and p tau/total (t)-tau were analyzed. The Morris water maze (MWM) was used to evaluate cognitive function following treatment. The levels of p-mTOR and p-p70S6K were reduced, whereas caspase-3 levels were increased in the surgery group compared with the sevoflurane group. The p-tau/t-tau levels were increased, however, tau mRNA was unaffected by sevoflurane and/or surgery. The rats in the surgery group required a significantly longer time to locate the platform in the MWM test compared with the control and sevoflurane groups. Sevoflurane treatment and/or surgery reduced anti-apoptotic activity, and the postoperative cognitive dysfunction following surgery may be due to mTOR signaling pathway inhibition in aged rats. Increased neuronal apoptosis and tau phosphorylation are suggested to be involved in the association between anesthesia and AD occurrence. PMID- 26497859 TI - Disruption of diapause induction by TALEN-based gene mutagenesis in relation to a unique neuropeptide signaling pathway in Bombyx. AB - The insect neuropeptide family FXPRLa, which carries the Phe-Xaa-Pro-Arg-Leu-NH2 sequence at the C-terminus, is involved in many physiological processes. Although ligand-receptor interactions in FXPRLa signaling have been examined using in vitro assays, the correlation between these interactions and in vivo physiological function is unclear. Diapause in the silkworm, Bombyx mori, is thought to be elicited by diapause hormone (DH, an FXPRLa) signaling, which consists of interactions between DH and DH receptor (DHR). Here, we performed transcription activator-like effector nuclease (TALEN)-based mutagenesis of the Bombyx DH-PBAN and DHR genes and isolated the null mutants of these genes in a bivoltine strain. All mutant silkworms were fully viable and showed no abnormalities in the developmental timing of ecdysis or metamorphosis. However, female adults oviposited non-diapause eggs despite diapause-inducing temperature and photoperiod conditions. Therefore, we conclude that DH signaling is essential for diapause induction and consists of highly sensitive and specific interactions between DH and DHR selected during ligand-receptor coevolution in Bombyx mori. PMID- 26497860 TI - [Three Patients with Acute Myocardial Infarction Associated with Targeted Therapy of Sorafenib for Metastatic Renal Cell Carcinoma : Case Report]. AB - Sorafenib is a tyrosine kinase inhibitor (TKI) of the vascular endothelial growth factor receptor (VEGFR) used for advanced renal cell carcinoma. Treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal cell carcinoma. However, in spite of its therapeutic efficacy, sorafenib causes a wide range of adverse events. Cardiovascular adverse events have been observed when sorafenib was used with targeted agents. Although these adverse events like hypertension, reduced left ventricular ejection fraction, cardiac ischemia or infarction were manageable with standard medical therapies in most cases, some had a poor clinical outcome. We report three cases of acute myocardial infarction associated with sorafenib in patients with metastatic renal cell carcinoma. PMID- 26497861 TI - [A Case of Abdominal Wall Desmoid Tumor after Radical Nephrectomy for Renal Cancer]. AB - A 71-year-old man with a right renal tumor underwent nephrectomy. The procedure was converted from laparoscopy to open surgery due to profound bleeding from the renal vein. Pathological diagnosis was clear cell carcinoma G2pT3b v1 ly1 INFalpha. Three years after surgery, a 5 cm tumor in the abdominal wall was found on computed tomography (CT). A mild uptake was shown on positron emission tomography/CT and as the tumor was located near the surgical wound, recurrence of the renal cell carcinoma was suspected. However, desmoid tumor was suggested by the pathological examination of the tumor biopsy. En-bloc resection of the mass was carried out and the pathological examination showed an array of proliferating and tangling atypical spindle-shaped tumor cells. Immunohistochemical staining of the tumor cells was positive for vimentin, but negative for CD34, c-kit, and s100. Pathological diagnosis was desmoid tumor. There has been no recurrence so far. Desmoid tumor, despite its extremely low incidence, should be considered in a postoperative neoplasm. PMID- 26497862 TI - [Ex Vivo Partial Nephrectomy and Auto-Transplantation of a Solitary Kidney with Metastatic Renal Cell Carcinoma : A Case Report]. AB - A 68-year-old man underwent radical nephrectomy for renal cell carcinoma of the right kidney 12 years ago. He was diagnosed as having a recurrent tumor of the contralateral kidney and a single metastatic pulmonary lesion by diagnostic imaging on the annual checkup. He visited us in order to receive nephron sparing surgery. Since the preoperative abdominal computed tomography showed tumor thrombus invading into the intrarenal vein, ex vivo partial nephrectomy and auto transplantation was performed. Although he received transit hemodialysis during the postoperative 10 days, his renal function, thereafter became stable without hemodialysis. Eighty-seven days later he underwent right lower lobectomy. At postoperative 6 months he has no local recurrence or distant metastasis and maintains well-preserved renal function. PMID- 26497863 TI - [A Case of Partial Prostatectomy for Advanced Rectal Cancer Involving the Prostate in the Jack-Knife Position]. AB - A 72-year-old man was diagnosed with advanced rectal cancer possibly involving the prostate on magnetic resonance imaging (MRI) findings. Following neoadjuvant chemoradiotherapy (CRT), he underwent curative surgery. Confirming negative surgical margin through intraoperative pathological evaluation, colorectectomy with partial prostatectomy was performed in the jack-knife position. No evidence of local recurrence of the tumor was observed one year after surgery without symptoms of the urinary tract. Partial prostatectomy is a choice to be taken into account in the treatment of advanced rectal cancer achieving both the good surgical outcome and the patient's quality of life (QOL). PMID- 26497864 TI - [A Case of Rapidly Progressive Metastatic Castration-Resistant Prostate Cancer : Durable Control by Early Induction of Carboplatin and Paclitaxel]. AB - A 60-year-old man visited the previous hospital with difficulty of urination in July 2004. Serum prostate specific antigen (PSA) was 5.4 ng/ml and he was diagnosed with prostate adenocarcinoma, Gleason Score 4+4=8, cT1cN0M0. Although radical prostatectomy was recommended, he refused any treatment and never visited that hospital again. He was admitted to our hospital for exacerbation of dysuria with anal pain newly appeared in March 2005, when it was found that his disease had progressed to cT4N0M1b (thoracic spine, sacroiliac joint and ischium). Serum PSA decreased and the primary lesion shrunk after androgen deprivation therapy (ADT), whereas the left ischial lesion enlarged and serum carcinoembryonic antigen (CEA) and alkaline phosphatase (ALP) were elevated. For the castration resistant progression, 30 Gy of local irradiation to the left ischial lesion and systemic chemotherapy with carboplatin (CBDCA) and paclitaxel (PTX) were administered, which led the patient to complete radiological and biochemical remission. The chemotherapy was discontinued in 2009 after the 18th course, and then ADT was also discontinued in 2010. The patient remains free from radiological or biochemical evidence of disease at the latest follow up in December 2014. PMID- 26497865 TI - [Urethral Fistula and Scrotal Abscess Associated with Colovesical Fistula Due to the Sigmoid Colon Cancer]. AB - We report here a rare case of urethral fistula and scrotal abscess associated with colovesical fistula due to sigmoid colon cancer. An 84-year-old male was referred to our hospital complaining of macrohematuria, fecaluria, pneumaturia and micturitional pain. Computed tomography (CT) showed colovesical fistula. Other examinations, including colonoscopy and cystoscopy, did not reveal a clear cause for the colovesical fistula. Only an elevated serum level of the tumor marker CA19-9 suggested the possibility of sigmoid colon cancer. Eleven days after hospitalization, bilateral scrotal contents had swollen rapidly to the size of a goose egg. CT suggested urethral fistula with scrotal abscess formation. Drainage of scrotal abscess and colostomy were performed. Intraoperatively, the fistula of the bulbar urethra was revealed. Because increased serum CA19-9 suggested a diagnosis of sigmoid colon cancer, cystectomy and sigmoid colectomy with right nephrectomy were performed. Pathological examination revealed adenocarcinoma of sigmoid colon with bladder invasion. His condition was improved with rehabilitation 6 months after operation. PMID- 26497866 TI - Platinum-catalyzed reduction of amides with hydrosilanes bearing dual Si-H groups: a theoretical study of the reaction mechanism. AB - A platinum-catalyzed amide reduction through hydrosilylation with 1,2 bis(dimethylsilyl)benzene (BDSB) was investigated on a theoretical basis. While the platinum-catalyzed hydrosilylation of alkenes is well known, that of carbonyl groups rarely occurs. The only exception involves the use of bifunctional hydrosilanes having dual, closely located Si-H groups, which accelerate the hydrosilylation of carbonyl groups, leading to successful reduction of amides to amines under mild conditions. In the present study, we determined through density functional theory calculations that the platinum-catalyzed hydrosilylation of the C=O bond proceeds via a Pt(IV)-disilyl-dihydride intermediate with an associated activation energy of 29.6 kcal mol(-1). Although it was believed that the hydrosilylation of carbonyl groups does not occur via the classical Chalk-Harrod cycle, the computational results support a mechanism involving the insertion of the amide C=O bond into a Pt-H bond. This insertion readily occurs because a Pt-H bond in the Pt(IV)-disilyl-dihydride intermediate is highly activated due to the strong sigma-donating interaction of the silyl groups. The modified Chalk-Harrod mechanism that occurs preferentially in rhodium-catalyzed hydrosilylation as well as the ionic outer sphere mechanism associated with iridium-catalyzed amide reduction were both safely ruled out as mechanisms for this platinum-catalyzed amide reduction, because of the unexpectedly large activation barrier (>40 kcal mol(-1)) for the Si-O bond formation. PMID- 26497868 TI - Direct and continuous synthesis of VO2 nanoparticles. AB - Monoclinic VO2 nanoparticles are of interest due to the material's thermochromic properties, however, direct synthesis routes to VO2 nanoparticles are often inaccessible due to the high synthesis temperatures or long reaction times required. Herein, we present a two-step synthesis route for the preparation of monoclinic VO2 nanoparticles using Continuous Hydrothermal Flow Synthesis (CHFS) followed by a short post heat treatment step. A range of particle sizes, dependent on synthesis conditions, were produced from 50 to 200 nm by varying reaction temperatures and the residence times in the process. The nanoparticles were characterised by powder X-ray diffraction, Raman and UV/Vis spectroscopy, transmission electron microscopy (TEM), scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The nanoparticles were highly crystalline with rod and sphere-like morphologies present in TEM micrographs, with the size of both the rod and spherical particles being highly dependent on both reaction temperature and residence time. SEM micrographs showed the surface of the powders produced from the CHFS process to be highly uniform. The samples were given a short post synthesis heat treatment to ensure that they were phase pure monoclinic VO2, which led to them exhibiting a large and reversible switch in optical properties (at near-IR wavelengths), which suggests that if such materials can be incorporated into coatings or in composites, they could be used for fenestration in architectural applications. PMID- 26497867 TI - Subacute hepatic necrosis mimicking veno-occlusive disease in a patient with HFE H63D homozygosity after allogeneic hematopoietic cell transplantation with busulfan conditioning. AB - Busulfan is a commonly used chemotherapeutic agent in myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). It has been associated with sinusoidal-obstructive syndrome(SOS) as a life-threatening complication of myeloablative allo-HCT, yet it has not been found to cause severe hepatocellular injury, even in cases of significant accidental overdose.We report the case of a 31-year-old male with a history of high-risk myelodysplastic syndrome transitioning to acute myeloid leukemia, who in complete remission underwent allo-HCT using myeloablative busulfan-fludarabine conditioning, and who developed hepatic failure. While he met clinical criteria for SOS and was treated with defibrotide,liver biopsy demonstrated severe subacute hepatic necrosis and lacked characteristics of SOS. Further evaluation revealed that the patient was homozygous for the HFE H63D gene mutation, associated with hereditary hemochromatosis.Both Busulfan and iron overload related to HFE H63D homozygosity can cause oxidative stress resulting in cellular injury, and the cumulative effects of these risk factors are possibly responsible for the severe hepatocellular injury in this case, making our patient the first-known case of subacute hepatic necrosis related to busulfan administration. PMID- 26497869 TI - Synchronizing thermodilution cardiac output measurements with spontaneous breathing does not improve precision. AB - INTRODUCTION: Measuring cardiac output (CO) with the pulmonary artery catheter intermittent bolus thermodilution technique (PAC-IBTD) is less precise with spontaneous breathing compared to controlled ventilation. We aimed to test if precision could be improved in spontaneous breathing by synchronizing the measurement with respiration or using instructed respiration in 18 post-operative cardiac surgery patients. METHODS: We performed eight CO measurements with PAC IBTD using cold saline in three different situations; in random order: 1) random compared to respiration, 2) timed to the start of expiration, and 3) synchronized with a slow exhalation through a PEP-flute. We calculated the standard deviation (SD), coefficient of variation (CV), and precision in the total material and in the three situations using a linear mixed effects model. RESULTS: A total of 408 CO measurements were performed in 17 included patients. There were no differences between the three study situations regarding mean or precision. The overall CO was 6.0 +/- 1.4 l/min (mean +/- SD), CV 6.2% and precision 12.2% for single measurements. Averaging three measurements increased the precision to 7.0%. CONCLUSION: We could not improve the precision of PAC-IBTD in spontaneously breathing patients by synchronizing the measurements with respiration. PMID- 26497870 TI - Cloning, expression and biochemical characterization of a beta-carbonic anhydrase from the soil bacterium Enterobacter sp. B13. AB - A recombinant carbonic anhydrase (CA, EC 4.2.1.1) from the soil-dwelling bacterium Enterobacter sp. B13 was cloned and purified by Co(2+) affinity chromatography. Bioinformatic analysis showed that the new enzyme (denominated here B13-CA) belongs to the beta-class CAs and to possess 95% homology with the ortholog enzyme from Escherichia coli encoded by the can gene, whereas its sequence homology with the other such enzyme from E. coli (encoded by the cynT gene) was of 33%. B13-CA was characterized kinetically as a catalyst for carbon dioxide hydration to bicarbonate and protons. The enzyme shows a significant catalytic activity, with the following kinetic parameters at 20 degrees C and pH of 8.3: kcat of 4.8 * 10(5) s(-1) and kcat/Km of 5.6 * 10(7) M(-1) * s(-1). This activity was potently inhibited by acetazolamide which showed a KI of 78.9 nM. Although only this compound was investigated for the moment as B13-CA inhibitor, further studies may reveal new classes of inhibitors/activators of this enzyme which may show biomedical or environmental applications, considering the posssible role of this enzyme in CaCO3 biomineralization processes. PMID- 26497871 TI - Large-scale comparative phosphoprotein analysis of maize seedling leaves during greening. AB - MAIN CONCLUSION : Large-scale comparative phosphoprotein analysis in maize seedlings reveals a complicated molecular regulation mechanism at the phosphoproteomic level during de-etiolation. In the present study we report a phosphoproteomic study conducted on Zea mays etiolated leaves harvested at three time points during greening (etiolated seedlings and seedlings exposed to light for 6 or 12 h). We identified a total of 2483 phosphopeptides containing 2389 unambiguous phosphosites from 1339 proteins. The abundance of nearly 692 phosphorylated peptides containing 783 phosphosites was reproducible and profiled with high confidence among treatments. Comparisons with other large-scale phosphoproteomic studies revealed that 473 of the phosphosites are novel to this study. Of the 783 phosphosites identified, 171, 79, and 138 were identified in 0, 6, and 12 h samples, respectively, which suggest that regulation of phosphorylation plays important roles during maize seedling de-etiolation. Our experimental methods included enrichment of phosphoproteins, allowing the identification of a great number of low abundance proteins, such as transcription factors, protein kinases, and photoreceptors. Most of the identified phosphoproteins were involved in gene transcription, post-transcriptional regulation, or signal transduction, and only a few were involved in photosynthesis and carbon metabolism. It is noteworthy that tyrosine phosphorylation and calcium signaling pathways might play important roles during maize seedling de-etiolation. Taken together, we have elucidated a new level of complexity in light-induced reversible protein phosphorylation during maize seedling de-etiolation. PMID- 26497872 TI - Trends in stage-specific incidence of prostate cancer in Norway, 1980-2010: a population-based study. AB - OBJECTIVE: To estimate changes in the stage distribution of prostate cancer during the time period where opportunistic prostate-specific antigen (PSA) testing was introduced. PATIENTS AND METHODS: Cancer stage, age, and year of diagnosis were obtained for all men aged >50 years diagnosed with prostate cancer in Norway during the period 1980-2010. Three calendar-time periods (1980-1989, 1990-2000, and 2001-2010) and three age groups (50-65, 66-74, and >=75 years) were defined. Birth cohorts were categorised into four intervals: <=1915, 1916 1925, 1926-1940 and >=1941. We used Poisson regressions to conduct both a time period and cohort-based analysis of trends in the incidence of localised, regional, and distant cancer for each combination of age groups and calendar-time periods or birth cohorts, respectively. Additionally, we explored the effect of cohorts on the stage-specific incidence graphically with a Poisson regression using 5-year age groups, and by estimating cumulative incidence rates for each birth cohort. RESULTS: The annual incidence of localised cancers among men aged 50-65 and 66-74 years rose from 41.4 and 255.2 per 100 000, respectively, before the introduction of PSA testing to 137.9 and 418.7 in 2001-2010 afterwards, corresponding to 3.3 [95% confidence interval (CI) 3.1-3.5] and 1.6 (95% CI 1.6 1.7) fold increases. The incidence of regional cancers increased by a factor seven among men aged <75 years. The incidence of distant cancers in men aged >=75 years decreased by 29% (95% CI 25-33%). These findings were confirmed in the cohort-based approach. CONCLUSION: Opportunistic PSA testing substantially increased the incidence of localised and regional prostate cancers among men aged 50-74 years, which was not fully compensated by the 30% decrease in incidence of distant prostate cancers in older men. PMID- 26497873 TI - Intraspecific diversity among partners drives functional variation in coral symbioses. AB - The capacity of coral-dinoflagellate mutualisms to adapt to a changing climate relies in part on standing variation in host and symbiont populations, but rarely have the interactions between symbiotic partners been considered at the level of individuals. Here, we tested the importance of inter-individual variation with respect to the physiology of coral holobionts. We identified six genetically distinct Acropora palmata coral colonies that all shared the same isoclonal Symbiodinium 'fitti' dinoflagellate strain. No other Symbiodinium could be detected in host tissues. We exposed fragments of each colony to extreme cold and found that the stress-induced change in symbiont photochemical efficiency varied up to 3.6-fold depending on host genetic background. The S. 'fitti' strain was least stressed when associating with hosts that significantly altered the expression of 184 genes under cold shock; it was most stressed in hosts that only adjusted 14 genes. Key expression differences among hosts were related to redox signaling and iron availability pathways. Fine-scale interactions among unique host colonies and symbiont strains provide an underappreciated source of raw material for natural selection in coral symbioses. PMID- 26497874 TI - The karyotypes of five species of the Scinax perpusillus group (Amphibia, Anura, Hylidae) of southeastern Brazil show high levels of chromosomal stabilization in this taxon. AB - Based on morphological, bioacoustics, and morphological traits, the genus Scinax has been subdivided into two major clades: S. catharinae and S. ruber. The first clade includes S. catharinae and S. perpusillus groups, whereas the second clade includes S. rostratus and S. uruguayus groups. Chromosome morphology, NOR and C banding patterns of variation support these clades. This study aims the cytogenetic characterization of five species currently included in the S. perpusillus group: Scinax sp. (gr. perpusillus), S. arduous, S. belloni, S. cosenzai, and S. v-signatus, including standard cytogenetic techniques and repetitive DNA FISH probes. All species had 2n = 24 chromosomes. Nucleolar organizing regions occurred in chromosome pair 6 in all species, but differed in their locations among some species, suggesting a putative synaponomastic character for the clade. In S. belloni, the first chromosome pair was a metacentric, contrasting with the submetacentric first pair reported in all other species of the genus. Scinax sp. (gr. perpusillus) and S. v-signatus had similar karyotypic formulae, suggesting they are related species. Scinax cosenzai had a divergent C-banding pattern. Repetitive DNA probes hybridized more frequently in chromosomal subtelomeric regions in all species indicating recent cladogenesis in these species. Karyotypic evidence indicates unreported high levels of stabilization within S. perpusillus and in S. catharinae clade, resulting in a wealth of characters potentially informative for higher phylogenetic analyses. PMID- 26497875 TI - Genetic diversity and genetic structure of an endemic Mexican Dusky Rattlesnake (Crotalus triseriatus) in a highly modified agricultural landscape: implications for conservation. AB - It is necessary to determine genetic diversity of fragmented populations in highly modified landscapes to understand how populations respond to land-use change. This information will help guide future conservation and management strategies. We conducted a population genetic study on an endemic Mexican Dusky Rattlesnake (Crotalus triseriatus) in a highly modified landscape near the Toluca metropolitan area, in order to provide crucial information for the conservation of this species. There was medium levels of genetic diversity, with a few alleles and genotypes. We identified three genetically differentiated clusters, likely as a result of different habitat cover type. We also found evidence of an ancestral genetic bottleneck and medium values of effective population size. Inbreeding coefficients were low and there was a moderate gene flow. Our results can be used as a basis for future research and C. triseriatus conservation efforts, particularly considering that the Trans-Mexican Volcanic Belt is heavily impacted by destructive land-use practices. PMID- 26497876 TI - Role of non-Indigenous researchers in Indigenous health research in Australia: a review of the literature. AB - Objective This paper explores the body of knowledge around Indigenous health research and aims to outline what roles are appropriate for non-Indigenous researchers within Indigenous health research in Australia. Methods A literature review was conducted using CINAHL, PubMed and Scopus in May 2015. The search terms were 'non-Indigenous researchers' AND 'Indigenous health research' and other combinations of these terms. Additional documents were sourced by hand using the reference lists of key articles. Results Seven thematic categories were identified: (1) Closing the Gap: implications for research; (2) history of Indigenous research; (3) developing Indigenous research using a capacity-building approach; (4) the cultural interface between Western paradigms and Indigenous knowledge; (5) ethical Indigenous research; (6) culturally safe Indigenous research; and (7) positive roles for non-Indigenous researchers in Indigenous research. Conclusion It is important that non-Indigenous researchers become more aware of culturally appropriate ways in which to undertake Indigenous research and to ensure that the research undertaken is safe, ethical and useful for participants. Fostering partnerships between non-Indigenous academic organisations and researchers and Indigenous health researchers is an important development that can promote and enhance the emerging field of Indigenous inquiry. Actively contributing to capacity building with Indigenous researchers and research initiatives is a key role that non-Indigenous researchers and academic institutions can have in improving Indigenous health. Self-determination through health research capacity building and evidence-based advocacy may provide the most useful outcomes for Indigenous people. What is known about the topic? The health status of Indigenous Australians is well below that of other Australians. Historically, research about Indigenous health has been undertaken by non-Indigenous researchers using Western research paradigms. There is a need to identify appropriate roles for non-Indigenous researchers supportive of culturally safe and ethical research. What does this paper add? This paper synthesises available knowledge about the role of non-Indigenous researchers with Indigenous health research and provides suggestions for their contribution to Indigenous research practice. What are the implications for practitioners? Non Indigenous researchers need to: (1) focus on culturally safe research practices; (2) be willing to address power imbalances within the research process; and (3) advocate for change within academic institutions to support culturally safe research practices. PMID- 26497878 TI - Confocal laser endomicroscopy in breast surgery. PMID- 26497877 TI - Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2 negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor. AB - This phase I/II dose-escalation study evaluated the efficacy, safety, and pharmacokinetics of pilaralisib (SAR245408), a pan-class I phosphoinositide 3 kinase (PI3K) inhibitor, or voxtalisib (SAR245409), a PI3K and mammalian target of rapamycin inhibitor, in combination with letrozole in hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, non steroidal aromatase inhibitor-refractory, recurrent or metastatic breast cancer. Maximum tolerated doses (MTDs) were determined using a 3 + 3 design in phase I. Efficacy was evaluated at the MTDs in phase II. Twenty-one patients were enrolled in phase I; MTDs were determined to be pilaralisib tablets 400 mg once daily (QD) or voxtalisib capsules 50 mg twice daily in combination with letrozole tablets 2.5 mg QD. Fifty-one patients were enrolled in phase II; one patient had a partial response in the pilaralisib arm. Rates of progression-free survival at 6 months were 17 and 8 % in the pilaralisib and voxtalisib arms, respectively. The most frequently reported treatment-related grade >= 3 adverse events were aspartate aminotransferase increased (5 %) and rash (5 %) in the pilaralisib arm, and alanine aminotransferase increased (11 %) and rash (9 %) in the voxtalisib arm. Pilaralisib and voxtalisib did not interact pharmacokinetically with letrozole. Pilaralisib had a greater pharmacodynamic impact than voxtalisib, as demonstrated by its impact on glucose homeostasis. There was no association between molecular alterations in the PI3K pathway and efficacy. In summary, pilaralisib or voxtalisib, in combination with letrozole, was associated with an acceptable safety profile and limited efficacy in endocrine therapy-resistant HR+ , HER2-negative metastatic breast cancer. PMID- 26497879 TI - Anatomy of an Extensible Open Source PACS. AB - The conception and deployment of cost effective Picture Archiving and Communication Systems (PACS) is a concern for small to medium medical imaging facilities, research environments, and developing countries' healthcare institutions. Financial constraints and the specificity of these scenarios contribute to a low adoption rate of PACS in those environments. Furthermore, with the advent of ubiquitous computing and new initiatives to improve healthcare information technologies and data sharing, such as IHE and XDS-i, a PACS must adapt quickly to changes. This paper describes Dicoogle, a software framework that enables developers and researchers to quickly prototype and deploy new functionality taking advantage of the embedded Digital Imaging and Communications in Medicine (DICOM) services. This full-fledged implementation of a PACS archive is very amenable to extension due to its plugin-based architecture and out-of-the box functionality, which enables the exploration of large DICOM datasets and associated metadata. These characteristics make the proposed solution very interesting for prototyping, experimentation, and bridging functionality with deployed applications. Besides being an advanced mechanism for data discovery and retrieval based on DICOM object indexing, it enables the detection of inconsistencies in an institution's data and processes. Several use cases have benefited from this approach such as radiation dosage monitoring, Content-Based Image Retrieval (CBIR), and the use of the framework as support for classes targeting software engineering for clinical contexts. PMID- 26497880 TI - The association of cardiovascular risk factors with saturated fatty acids and fatty acid desaturase indices in erythrocyte in middle-aged Korean adults. AB - BACKGROUND: The quality of dietary fats is associated with risk of cardiovascular diseases (CVD). We aimed to investigate the association between fatty acids in erythrocyte membrane phospholipids and CVD risk factors in middle-aged Korean adults. METHODS: Fifty-five middle-aged adults who underwent health examinations were included in this retrospective and cross-sectional study. Anthropometry, serum lipids, clinical parameters, and erythrocyte membrane phospholipid fatty acid data were obtained from a registry. RESULTS: The proportion of C14:0 and C16:0 was greatly elevated in high quartile groups for triglyceride (TG) and systolic and diastolic blood pressure groups (SBP and DBP) (p = 0.042, p = 0.021, or p = 0.008 respectively) compared to low quartile groups. While C16:1n7 and/or C18:1n9 were positively associated with CVD risk factors, the delta 9 desaturase activity index (D9D) (C18:1n9/C18:0) was only significantly increased in high quartile groups for TG and blood pressures (p = 0.001, p = 0.002 or p = 0.003). Conversely, TG and blood pressures showed inverse relationships with C20:4n6 or D5D (C20:4n6/C20:3n6). C18:3n6 and/or D6D (C18:3n6/C18:2n6) were positively associated with insulin resistance and diabetic parameters. Particularly high D6D was detected in high quartile groups of FBS and insulin (p = 0.016 and p = 0.042). In linear regression analysis, D9D and/or C14:0 + C16:0 were significant contributors to serum TG and blood pressures. D6D was a contributing factor to FBS. CONCLUSIONS: The indices of D9D and D6D from erythrocyte membrane phospholipids and the proportion of saturated fatty acids were increased as the cardiovascular risk factors, including serum TG, blood pressures, and FBS increased their levels (IRB number C2014199 (1396)). PMID- 26497881 TI - Adverse Reactions to Metal on Metal Are Not Exclusive to Large Heads in Total Hip Arthroplasty. AB - BACKGROUND: There is some suggestion that smaller diameter heads in metal-on metal total hip arthroplasty (MoM THA) may be less prone to the adverse reactions to metal debris (ARMD) seen with large-diameter heads. QUESTIONS/PURPOSES: We reviewed our population of patients with small head (<= 32 mm) MoM THA to determine (1) the frequency of ARMD; (2) potential risk factors for ARMD in this population; and (3) the etiology of revision and Kaplan-Meier survivorship with revision for all causes. METHODS: Small-diameter head MoM devices were used in 9% (347 of 3753) of primary THAs during the study period (January 1996 to March 2005). We generally used these implants in younger, more active, higher-demand patients. Three hundred hips (258 patients) had MoM THA using a titanium modular acetabular component with a cobalt-chromium tapered insert and were available for review with minimum 2-year followup (mean, 10 years; range, 2-19 years). Complete followup was available in 86% of hips (300 of 347). Clinical records and radiographs were reviewed to determine the frequency and etiology of revision. Kaplan-Meier survivorship analysis was performed. RESULTS: ARMD frequency was 5% (14 of 300 hips) and represented 70% (14 of 20) of revisions performed. Using multivariate analysis, no variable tested, including height, weight, body mass index, age, cup diameter, cup angle, use of screws, stem diameter, stem type, head diameter, preoperative clinical score, diagnosis, activity level, or sex, was significant as a risk factor for revision. Twenty hips have been revised: two for infection, four for aseptic loosening, and 14 for ARMD. Kaplan-Meier analysis revealed survival free of component revision for all causes was 95% at 10 years (95% confidence interval [CI], 91%-97%), 92% at 15 years (95% CI, 87%-95%), and 72% at 19 years (95% CI, 43%-90%), and survival free of component revision for aseptic causes was 96% at 10 years (95% CI, 92%-98%), 92% at 15 years (95% CI, 88%-95%), and 73% at 19 years (95% CI, 43%-90%). CONCLUSIONS: The late onset and devastating nature of metal-related failures is concerning with this small diameter MoM device. Although the liner is modular, it cannot be exchanged and full acetabular revision is required. Patients with all MoM THA devices should be encouraged to return for clinical and radiographic followup, and clinicians should maintain a low threshold to perform a systematic evaluation. Symptomatic patients should undergo thorough investigation and vigilant observation for ARMD. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26497883 TI - Editorial-Going Global: CORR1 Best-paper Awards for China and Latin America in 2015. PMID- 26497882 TI - Does Postoperative Radiation Decrease Heterotopic Ossification After the Kocher Langenbeck Approach for Acetabular Fracture? AB - BACKGROUND: Controversy regarding heterotopic ossification (HO) prophylaxis exists after Kocher-Langenbeck for treatment of acetabular fracture. Prophylaxis options include antiinflammatory oral medications, single-dose radiation therapy, and debridement of gluteus minimus muscle. Prior literature has suggested single dose radiation therapy as the best prophylaxis to prevent HO formation. However, recent reports have emerged of radiation-induced sarcoma after radiotherapy for HO prophylaxis, which has led many surgeons to reconsider the risks and benefits of single-dose radiation therapy. We set out to determine if radiotherapy, in addition to standard debridement of gluteus minimus muscle, affected postoperative HO formation after a Kocher-Langenbeck approach for acetabular fracture. QUESTIONS/PURPOSES: (1) After the Kocher-Langenbeck approach and gluteus minimus debridement, is single-dose radiotherapy associated with a decreased risk of HO? (2) Does addition of single-dose radiotherapy prolong length of stay after a Kocher-Langenbeck approach and gluteus minimus debridement as compared with patients without radiotherapy? METHODS: After institutional review board approval, all adult patients treated for acetabular fracture by a single surgeon with a Kocher-Langenbeck approach between August 2011 and October 2014 were identified (n = 60). Debridement of gluteus minimus muscle caudal to the superior gluteal bundle was standard in all patients. Radiotherapy was given with a single dose of 700 cGy within 72 hours of surgery from August 2011 until April 2013. Patients treated subsequently did not receive radiotherapy. Patients treated with indomethacin (n = 1) and with fewer than 10 weeks followup were excluded (n = 12) because several studies suggest that most HO that develops is visible by that point in time. Our study group totaled 46 patients with 24 in the radiotherapy and debridement group and 22 in the debridement group. Charts were reviewed to determine length of stay. Attending orthopaedic trauma surgeons who were blinded to the patient's treatment group graded all followup radiographs according to the Brooker system, and Classes III and IV HO were considered clinically important Fisher's exact test was used to analyze clinically significant differences HO between the two groups. Length of stay was compared using a t-test. RESULTS: Single-dose radiotherapy is associated with a decreased risk of clinically important (Brooker III-IV) HO after a Kocher-Langenbeck approach and gluteus minimus debridement (radiotherapy: one of 24 [4%], no radiotherapy: seven of 22 [32%], relative risk: 0.131 [95% confidence interval {CI}, 0.018-0.981], p = 0.020). Addition of single-dose radiotherapy did not result in increased length of stay (radiotherapy: 12 +/- 7.0 days; no radiotherapy: 11 +/- 7.2 days; mean difference: 1.0 [95% CI, -3.2 to 5.2] days, p = 0.635). CONCLUSIONS: Single-dose radiation in combination with gluteus minimus debridement decreases the risk of clinically important HO compared with gluteus minimus debridement alone after a Kocher-Langenbeck approach for acetabular fracture. No differences in length of stay were seen. Surgeons who chose not to use radiotherapy as a result of concern for future sarcoma may see higher rates of clinically significant HO after a Kocher-Langenbeck approach for acetabular fracture fixation. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26497884 TI - From Bench to Bedside: A Perfect Fit? Osseointegration Can Improve Function for Patients with Amputations. PMID- 26497885 TI - Dipeptidyl Peptidase-4 Inhibitor-Associated Pancreatic Carcinoma: A Review of the FAERS Database. AB - BACKGROUND: To date, there is limited literature regarding the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and pancreatic carcinoma. OBJECTIVE: To describe the comparative incidence of DPP-4 inhibitors and pancreatic carcinoma as reportedly available in the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. The goal was to provide health care practitioners a general understanding of the drug-disease occurrence. METHODS: This is a case/noncase study utilizing Empirica Signal software to query FAERS from November 1968 to December 31, 2013. The software was used to calculate a disproportionality statistic--namely, the empirical Bayesian geometric mean (EBGM)--for reports of DPP-4 inhibitors-associated pancreatic carcinoma. The FDA considers an EBGM significant if the fifth percentile of the distribution is at least 2, defined as an EB05 >= 2. With use of a disproportionality analysis, DPP 4 inhibitors were compared with all agents listed in FAERS. RESULTS: A total of 156 patients experienced pancreatic carcinoma while receiving DPP-4 inhibitor therapy. An EB05 of 10.3 was determined for sitagliptin, 7.1 for saxagliptin, 4.9 for linagliptin, and 1.4 for alogliptin, compared with all other agents included in FAERS. Although an EB05 > 2 was achieved in 2 other antihyperglycemic agents, the findings were not consistent within their medication classes. CONCLUSION: There appears to be a statistical association between DPP-4 inhibitor use and pancreatic carcinoma. Causality cannot be inferred from the data provided. Additional clinical studies are needed to further explore this statistical association. PMID- 26497886 TI - Use of 4-Factor Prothrombin Concentrate (Kcentra) in Hospitalized Pediatric Patients. PMID- 26497887 TI - Melatonin as an Antioxidant for Stroke Neuroprotection. AB - Melatonin (N-acetyl-5-methoxytryptamine) is a hormone derived from the pineal gland that has a wide range of clinical applications. While melatonin was originally assessed as a hormone specializing in regulation of the normal circadian rhythm in mammals, it now has been shown to be an effective free radical scavenger and antioxidant. Current research has focused on central nervous system (CNS) disorders, stroke in particular, for potential melatonin based therapeutics. As of now, the realm of potential therapy regimens is focused on three main treatments: exogenously delivered melatonin, pineal gland grafting, and melatonin-mediated stem cell therapy. All therapies contain both costs and benefits, and current research is still focused on finding the best treatment plan. While comprehensive research has been conducted, more research regarding the safety of such therapies is needed in order to transition into the clinical level of testing. Antioxidants such as traditional Chinese medicine, (-) epigallocatechin-3-gallate (EGCG), and lavender oil, which have been used for thousands of years as treatment, are now gaining recognition as effective melatonin treatment alternatives. This review will further discuss relevant studies assessing melatonin-based therapeutics and provide evidence of other natural melatonin treatment alternatives for the treatment of stroke. PMID- 26497888 TI - Theoretical study of polyiodide formation and stability on monolayer and bilayer graphene. AB - The presence of polyiodide complexes have been reported several times when carbon based materials were doped by iodine molecules, but their formation mechanism remains unclear. By using first-principles calculations that include nonlocal correlation effects by means of a van der Waals density functional approach, we propose that the formation of triiodide (I3(-)) and pentaiodide (I5(-)) is due to a large density of iodine molecules (I2) in interaction with a carbonaceous substrate. As soon as the concentration of surface iodine reaches a threshold value of 12.5% for a graphene monolayer and 6.25% for a bilayer, these complexes spontaneously appear. The corresponding structural and energetic aspects, electronic structures and vibrational frequencies support this statement. An upshift of the Dirac point from the Fermi level with values of 0.45 and 0.52 eV is observed for adsorbed complexes on graphene and intercalated complexes between two layers, respectively. For doped-graphene, it corresponds to a graphene hole density of around 1.1 * 10(13) cm(-2), in quantitative agreement with experiments. Additionally, we have studied the thermal stability at room temperature of these adsorbed ions on graphene by means of ab initio molecular dynamics, which also shows successful p-doping with polyiodide complexes. PMID- 26497889 TI - Adhesio interthalamica and cavum septum pellucidum in mesial temporal lobe epilepsy. AB - The absence of the adhesio interthalamica (AI; also called interthalamic adhesion or massa intermedia) and the presence of a large cavum septum pellucidum (CSP) later in life have been related to neurodevelopmental alterations and have not been systematically investigated in epilepsy to date. This study carried out a MRI evaluation of the AI and CSP in a large sample with mesial temporal lobe epilepsy (MTLE). A total of 179 patients, classified according to the side of the epileptogenic focus, and 156 age- and sex-balanced healthy controls were assessed. Between-group comparisons of the prevalence and length of both AI and CSP were conducted. Neuropsychological assessments were also performed in 160 MTLE patients. The patients exhibited reduction in the AI prevalence (P < 0.05; FDR-uncorrected) and length (P < 0.05; FDR-corrected) when compared to controls. Patients without AI showed lower scores in a proportion of neuropsychological tests than patients with AI. No CSP differences were found between MTLE patients and controls. These results support that AI anomalies have clinical significance in MTLE, as well as indicate that neurodevelopmental alterations may be implicated in this disorder. PMID- 26497891 TI - Double inversion recovery imaging improves the evaluation of gray matter volume losses in patients with Alzheimer's disease and mild cognitive impairment. AB - Our goal was to investigate whether three-dimensional (3D) double inversion recovery (DIR) images can show alterations of gray matter volume (GMV) between Alzheimer's disease (AD) patients and nondemented controls and to compare alterations of GMV between groups using DIR images and those using 3D T1-weighted (T1W) images. We included 25 subjects with mild or probable AD, 25 subjects with amnestic mild cognitive impairment (MCI), and 25 elderly cognitively normal (CN) subjects. Group differences in GMV among CN, MCI, and AD patients were tested by voxel-wise, one-way ANOVA. Additional region-of-interest-based comparisons of GMV differences among the three groups for DIR and T1WI were performed using ANCOVA. Finally, ROC curve analysis was performed. In the AD group compared with the CN and MCI groups, GMV was decreased in both DIR and T1W images. However, the areas showing GMV loss were larger in DIR images compared to those in T1W images. Amygdala had the highest area under curve value for both DIR and T1W images. DIR images were sensitive for identifying GMV loss in patients with AD compared with MCI and CN subjects and areas showing GMV loss identified with DIR were extended to more brain areas than those identified with T1W. With DIR, amygdala GMV is the most sensitive in differentiating between subject groups. PMID- 26497890 TI - Differential dopamine function in fibromyalgia. AB - Approximately 30 % of Americans suffer from chronic pain disorders, such as fibromyalgia (FM), which can cause debilitating pain. Many pain-killing drugs prescribed for chronic pain disorders are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms reported by many patients. The neurobiological substrates of chronic pain are largely unknown, but evidence points to altered dopaminergic transmission in aberrant pain perception. We sought to characterize the dopamine (DA) system in individuals with FM. Positron emission tomography (PET) with [(18)F]fallypride (FAL) was used to assess changes in DA during a working memory challenge relative to a baseline task, and to test for associations between baseline D2/D3 availability and experimental pain measures. Twelve female subjects with FM and 11 female controls completed study procedures. Subjects received one FAL PET scan while performing a "2-back" task, and one while performing a "0-back" (attentional control, "baseline") task. FM subjects had lower baseline FAL binding potential (BP) in several cortical regions relative to controls, including anterior cingulate cortex. In FM subjects, self-reported spontaneous pain negatively correlated with FAL BP in the left orbitofrontal cortex and parahippocampal gyrus. Baseline BP was significantly negatively correlated with experimental pain sensitivity and tolerance in both FM and CON subjects, although spatial patterns of these associations differed between groups. The data suggest that abnormal DA function may be associated with differential processing of pain perception in FM. Further studies are needed to explore the functional significance of DA in nociception and cognitive processing in chronic pain. PMID- 26497893 TI - Oct4-induced oligodendrocyte progenitor cells enhance functional recovery in spinal cord injury model. AB - The generation of patient-specific oligodendrocyte progenitor cells (OPCs) holds great potential as an expandable cell source for cell replacement therapy as well as drug screening in spinal cord injury or demyelinating diseases. Here, we demonstrate that induced OPCs (iOPCs) can be directly derived from adult mouse fibroblasts by Oct4-mediated direct reprogramming, using anchorage-independent growth to ensure high purity. Homogeneous iOPCs exhibit typical small-bipolar morphology, maintain their self-renewal capacity and OPC marker expression for more than 31 passages, share high similarity in the global gene expression profile to wild-type OPCs, and give rise to mature oligodendrocytes and astrocytes in vitro and in vivo. Notably, transplanted iOPCs contribute to functional recovery in a spinal cord injury (SCI) model without tumor formation. This study provides a simple strategy to generate functional self-renewing iOPCs and yields insights for the in-depth study of demyelination and regenerative medicine. PMID- 26497894 TI - Salvia libanotica improves glycemia and serum lipid profile in rats fed a high fat diet. AB - BACKGROUND: Salvia libanotica (S. Libanotica) is a commonly used herb in folk medicine in Lebanon and the Middle East. The present study aimed to assess the scientific basis for the therapeutic use of S. libanotica in glycemia and to evaluate its effects on lipemia and abdominal fat. METHODS: Animals were fed a high-fat diet and allocated into a control and three experimental groups (GI, GII and GIII) receiving incremental doses of the plant water extract in drinking water (50, 150 and 450 mg/Kg body weight respectively) for six weeks. RESULTS: The intake of S. libanotica extract was associated with a significant decrease in fasting serum glucose (102.9 +/- 10.8 in GII and 87.5 +/- 6.4 in GIII vs. 152.1 +/- 7.9 mg/dl in controls) and a two fold increase in fasting serum insulin (GIII) and liver glycogen content (GII and GIII). Group III also had better glucose tolerance following intraperitoneal glucose challenges. Additionally, the plant extract intake produced a significant improvement in serum HDL (34.4 +/- 2.4 in GIII vs. 27.2 +/- 1.9 mg/dl in controls) and HDL/LDL cholesterol ratio (2.79 +/- 0.32 in GII and 3.02 +/- 0.31 in GIII vs. 1.74 +/- 0.18 in controls), as well as a decrease in abdominal fat. CONCLUSION: The current study is the first to demonstrate that the chronic intake of S. libanotica infusion helps in the prevention of high fat-induced hyperglycemia and dyslipidemia. This supports the plant use as a remedy for the prevention of type 2 diabetes and cardiovascular diseases. PMID- 26497895 TI - Effect of targeted ovarian cancer immunotherapy using ovarian cancer stem cell vaccine. AB - BACKGROUND: Accumulating evidence has shown that different immunotherapies for ovarian cancer might overcome barriers to resistance to standard chemotherapy. The vaccine immunotherapy may be a useful one addition to conditional chemotherapy regimens. The present study investigated the use of vaccine of ovarian cancer stem cells (CSCs) to inhibit ovarian cancer growth. METHODS: CD117(+)CD44(+)CSCs were isolated from human epithelial ovarian cancer (EOC) SKOV3 cell line by using a magnetic-activated cell sorting system. Pre inactivated CD117(+)CD44(+)CSC vaccine was vacccinated into athymic nude mice three times, and then the mice were challenged subcutaneously with SKOV3 cells. The anti-tumor efficacy of CSC vaccine was envaluated by in vivo tumorigenicity, immune efficient analysis by flow cytometer, and enzyme-linked immunosorbent assays, respectively. RESULTS: The CD117(+) CD44(+)CSC vaccine increased anti ovarian cancer efficacy in that it depressed ovarian cancer growth in the athymic nude mice. Vaccination resulted in enhanced serum IFN-gamma, decreased TGF-beta levels, and increased cytotoxic activity of natural killer cells in the CD117(+) CD44(+)CSC vaccine immunized mice. Moreover, the CSC-based vaccine significantly reduced the CD117(+)CD44(+)CSC as well as the aldehyde dehydrogenase 1 positive cell populations in the ovarian cancer tissues in the xenograft mice. CONCLUSION: The present study provided the first evidence that human SKOV3 CD117(+) CD44(+)CSC-based vaccine may induce the anti-ovarian cancer immunity against tumor growth by reducing the CD117(+)CD44(+)CSC population. PMID- 26497896 TI - Transcriptional profiles of pilocytic astrocytoma are related to their three different locations, but not to radiological tumor features. AB - BACKGROUND: Pilocytic astrocytoma is the most common type of brain tumor in the pediatric population, with a generally favorable prognosis, although recurrences or leptomeningeal dissemination are sometimes also observed. For tumors originating in the supra-or infratentorial location, a different molecular background was suggested, but plausible correlations between the transcriptional profile and radiological features and/or clinical course are still undefined. The purpose of this study was to identify gene expression profiles related to the most frequent locations of this tumor, subtypes based on various radiological features, and the clinical pattern of the disease. METHODS: Eighty six children (55 males and 31 females) with histologically verified pilocytic astrocytoma were included in this study. Their age at the time of diagnosis ranged from fourteen months to seventeen years, with a mean age of seven years. There were 40 cerebellar, 23 optic tract/hypothalamic, 21 cerebral hemispheric, and two brainstem tumors. According to the radiological features presented on MRI, all cases were divided into four subtypes: cystic tumor with a non-enhancing cyst wall; cystic tumor with an enhancing cyst wall; solid tumor with central necrosis; and solid or mainly solid tumor. In 81 cases primary surgical resection was the only and curative treatment, and in five cases progression of the disease was observed. In 47 cases the analysis was done by using high density oligonucleotide microarrays (Affymetrix HG-U133 Plus 2.0) with subsequent bioinformatic analyses and confirmation of the results by independent RT-qPCR (on 39 samples). RESULTS: Bioinformatic analyses showed that the gene expression profile of pilocytic astrocytoma is highly dependent on the tumor location. The most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes expression even within different compartments of the supratentorial region. Analysis of the genes potentially associated with radiological features showed much weaker transcriptome differences. Single genes showed association with the tendency to progression. CONCLUSIONS: Here we have shown that pilocytic astrocytomas of three different locations can be precisely differentiated on the basis of their gene expression level, but their transcriptional profiles does not strongly reflect the radiological appearance of the tumor or the course of the disease. PMID- 26497897 TI - Decreased expression of miR-204 in plasma is associated with a poor prognosis in patients with non-small cell lung cancer. AB - In order to identify novel non-invasive biomarkers with high accuracy for the screening of non-small cell lung cancer (NSCLC), we investigated the predictive power of 4 microRNAs (miR-146, miR-204, miR-106a and miR-124) in plasma samples obtained from patients with NSCLC and healthy controls (n=50; training phase) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). We found that the levels of miR-204 in the patients with NSCLC were significantly dysregulated compared with the healthy controls, and thus this miRNA was selected for further validation. For the validation phase, RT-qPCR was performed on plasma samples from patients with NSCLC and healthy controls (n=176) in order to examine the expression levels of the candidate miRNA, miR-204. The results revealed that the plasma levels of miR-204 were significantly downregulated in the patients with NSCLC compared with the healthy controls (p<0.001). The value of the area under the receiver operating characteristic (ROC) curve obtained for miR-204 was 0.809 (sensitivity, 76%; specificity, 82%), which was higher than the values obtained for carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19 9). The expression of miR-204 in plasma significantly correlated with the tumor stage (p=0.009) and distant metastasis (p=0.048). A log-rank test revealed that lower plasma levels of miR-204 were associated with a shorter overall survival and disease-free survival (p=0.006 and 0.0065, respectively). Both univariate and multivariate Cox regression analyses indicated that a lower miR-204 expression level in plasma was a prognostic factor with a relative risk of death of 1.936 and 1.712, respectively. On the whole, our results suggest that the decreased expression of miR-204 in plasma is a promising biomarker for the detection of NSCLC and the prediction of poor survival in patients with the disease. PMID- 26497898 TI - Embryo-scale tissue mechanics during Drosophila gastrulation movements. AB - Morphogenesis of an organism requires the development of its parts to be coordinated in time and space. While past studies concentrated on defined cell populations, a synthetic view of the coordination of these events in a whole organism is needed for a full understanding. Drosophila gastrulation begins with the embryo forming a ventral furrow, which is eventually internalized. It is not understood how the rest of the embryo participates in this process. Here we use multiview selective plane illumination microscopy coupled with infrared laser manipulation and mutant analysis to dissect embryo-scale cell interactions during early gastrulation. Lateral cells have a denser medial-apical actomyosin network and shift ventrally as a compact cohort, whereas dorsal cells become stretched. We show that the behaviour of these cells affects furrow internalization. A computational model predicts different mechanical properties associated with tissue behaviour: lateral cells are stiff, whereas dorsal cells are soft. Experimental analysis confirms these properties in vivo. PMID- 26497900 TI - Protective effects of camel milk against pathogenicity induced by Escherichia coli and Staphylococcus aureus in Wistar rats. AB - The aim of the present study was to investigate the protective effects of camel milk on hepatic pathogenicity induced by experimental infection with Escherichia (E. coli) and Staphylococcus aureus (S. aureus) in Wistar rats. The rats were divided into six groups: The control and camel milk groups received water and camel milk, respectively; two groups received camel milk for 2 weeks prior to intraperitoneal injection of either E. coli or S. aureus; and two groups were injected intraperitoneally with E. coli and S. aureus, respectively. All animals were maintained under observation for 7 days prior to biochemical and gene expression analyses. The rats treated with camel milk alone exhibited no changes in expression levels of glutamic-pyruvate transaminase (GPT) or glutamic oxaloacetic transaminase (GOT), compared with the water-treated group. The E. coli- and S. aureus-injected rats exhibited a significant increase in oxidative stress, and prior treatment with camel milk normalized the observed changes in the expression levels of GPT, GOT and malondialdehyde (MDA). Treatment with camel milk decreased the total bacterial count in liver tissue samples obtained from the rats injected with E. coli and S. aureus. Camel milk administration increased the expression levels of glutathione-S-transferase and superoxide dismutase, which were downregulated following E. coli and S. aureus injection. In addition, camel milk downregulated the increased expression of interleukin-6 and apoptosis associated genes. Of note, administration of camel milk alone increased the expression levels of the B cell lymphoma 2-associated X protein and survivin anti apoptotic genes, and supplementation prior to the injection of E. coli and S. aureus induced further upregulation, In conclusion, camel milk exerted protective effects against E. coli and S. aureus pathogenicity, by modulating the extent of lipid peroxidation, together with the antioxidant defense system, immune cytokines, apoptosis and the expression of anti-apoptotic genes in the liver of Wistar rats. PMID- 26497899 TI - Epidermal growth factor receptor status and Notch inhibition in non-small cell lung cancer cells. AB - BACKGROUND: Notch may behave as an oncogene or a tumor suppressor gene in lung cancer cells. Notch receptor undergoes cleavage by enzymes, including gamma secretase, generating the active Notch intracellular domain (NICD). The aim of the present study was to investigate the effect of DAPT, a gamma-secretase inhibitor, in non-small cell lung cancer (NSCLC) cells, as well as the impact of epidermal growth factor (EGF) that is over-expressed by NSCLC cells, on Notch signaling. H23, A549, H661 and HCC827 human NSCLC cell lines were used, expressing various NICD and EGF receptor (EGFR) protein levels. RESULTS: DAPT decreased the number of H661 cells in a concentration-dependent manner, while it had a small effect on H23 and A549 cells and no effect on HCC827 cells that carry mutated EGFR. Notch inhibition did not affect the stimulatory effect of EGF on cell proliferation, while EGF prevented DAPT-induced NICD decrease in H23 and H661 cells. The type of cell death induced by DAPT seems to depend on the cell type. CONCLUSIONS: Our data indicate that inhibition of Notch cleavage may not affect cell number in the presence of EGFR mutations and that EGFR may affect Notch signalling suggesting that a dual inhibition of these pathways might be promising in NSCLC. PMID- 26497901 TI - The contribution of illness perceptions to fatigue and sleep problems in youngsters with epilepsy. AB - PURPOSE: The present study aims to explore the extent to which gender, epilepsy severity and illness perceptions predict fatigue and sleep problems in youngsters with epilepsy. METHOD: Structured interviews were conducted in 100 young patients (Mage = 13,9, SD = 2.21; 41% girls) and data were analyzed by means of multiple hierarchical regression analyses. RESULTS: Most patients (91%) were well controlled by anti-epileptics; 3% had infrequent seizures and 6% were pharmacoresistant. At a multivariate level it appeared that youngsters with epilepsy who believe that they have less personal control over their illness and who feel that the illness has a high emotional impact on their lives reported higher levels of fatigue. In addition, more sleep problems were reported by youngsters who think they have less personal control over the disease, who believe that treatment controls epilepsy and report that the disease has a high emotional impact on their lives. CONCLUSION: Given the importance of illness perceptions, it is suggested that they are targets for future interventions that aim to reduce fatigue and sleep problems in youngsters with epilepsy. PMID- 26497903 TI - Understanding the complex determinants of height and adiposity in disadvantaged daycare preschoolers in Salvador, NE Brazil through structural equation modelling. AB - BACKGROUND: Earlier we reported on growth and adiposity in a cross-sectional study of disadvantaged Brazilian preschoolers. Here we extend the work on these children, using structural equation modelling (SEM) to gather information on the complex relationships between the variables influencing height and adiposity. We hope this information will help improve the design and effectiveness of future interventions for preschoolers. METHODS: In 376 preschoolers aged 3-6 years attending seven philanthropic daycares in Salvador, we used SEM to examine direct and indirect relationships among biological (sex, ethnicity, birth order, maternal height and weight), socio-economic, micronutrient (haemoglobin, serum selenium and zinc), and environmental (helminths, de-worming) variables on height and adiposity, as reflected by Z-scores for height-for-age (HAZ) and body mass index (BMIZ). RESULTS: Of the children, 11 % had HAZ < -1, 15 % had WHZ < -1, and 14 % had BMIZ > 1. Of their mothers, 8 % had short stature, and 50 % were overweight or obese. Based on standardized regression coefficients, significant direct effects (p < 0.05) for HAZ were maternal height (0.39), being white ( 0.07), having helminth infection (-0.09), and serum zinc (-0.11). For BMIZ, significant direct effects were maternal weight (0.21), extremely low SES ( 0.15), and haemoglobin (0.14). Indirect (p < 0.05) effects for HAZ were sex (being male) (-0.02), helminth infection (-0.01), de-worming treatment (0.01), and serum selenium (-0.02), and for BMIZ were extremely low SES (-0.001), helminth infection (-0.004), and serum selenium (0.02). CONCLUSIONS: Of the multiple factors influencing preschoolers' growth, helminth infection was a modifiable risk factor directly and indirectly affecting HAZ and BMIZ, respectively. Hence the WHO de-worming recommendation should include preschoolers living in at-risk environments as well as school-aged children. PMID- 26497904 TI - Practical Management Guide for Clinicians Who Treat Patients with Amiodarone. AB - Amiodarone, an iodinated benzofuran derivative with Class I, II, III, and IV antiarrhythmic properties, is the most commonly used antiarrhythmic drug used to treat supraventricular and ventricular arrhythmias. Appropriate use of this drug, with its severe and potentially life-threatening adverse effects, requires an essential understanding of its risk-benefit properties in order to ensure safety. The objective of this review is to afford clinicians who treat patients receiving amiodarone an appropriate management strategy for its safe use. The authors of this consensus management guide have thoroughly reviewed and evaluated the existing literature on amiodarone and apply this information, along with the collective experience of the authors, in its development. Provided are management guides on the intravenous and oral dosing of amiodarone, appropriate outpatient follow-up of patients taking the drug, its recognized adverse effects, and recommendations on when to consult specialists to help in patient management. All clinicians must be cognizant of the appropriate use, follow-up, and adverse reactions of amiodarone. The responsibility incurred by those treating such patients cannot be overemphasized. PMID- 26497902 TI - Feasibility of automated pre-screening for lifestyle and behavioral health risk factors in primary care. AB - BACKGROUND: Screening of primary care patients for unhealthy behaviors and mental health issues is recommended by numerous governing bodies internationally, yet evidence suggests that provider-initiated screening is not routine practice. The objective of this study was to implement systematic pre-screening of primary care patients for common preventive health issues on a large scale. METHODS: Patients registered for non-acute visits to one of 40 primary care providers from eight clinics in an Academic Medical Center health care network in the United States from May, 2012 to May, 2014 were contacted one- to three-days prior to their visit. Patients were invited to complete a questionnaire using an Interactive Voice Response (IVR) system. Six items assessed pain, smoking, alcohol use, physical activity, concern about weight, and mood. RESULTS: The acceptance rate among eligible patients reached by phone was 65.6 %, of which 95.5 % completed the IVR-Screen (N = 8,490; mean age 57; 57 % female). Sample demographics were representative of the overall primary care population from which participants were drawn on gender, race, and insurance status, but participants were slightly older and more likely to be married. Eighty-seven percent of patients screened positive on at least one item, and 59 % endorsed multiple problems. The majority of respondents (64.2 %) reported being never or only somewhat physically active. Weight concern was reported by 43.9 % of respondents, 36.4 % met criteria for unhealthy alcohol use, 23.4 % reported current pain, 19.6 % reported low mood, and 9.4 % reported smoking. CONCLUSIONS: The percent endorsement for each behavioral health concern was generally consistent with studies of screening using other methods, and contrasts starkly with the reported low rates of screening and intervention for such concerns in typical PC practice. Results support the feasibility of IVR-based, large-scale pre-appointment behavioral health/ lifestyle risk factor screening of primary care patients. Pre-screening in this population facilitated participation in a controlled trial of brief treatment for unhealthy drinking, and also could be valuable clinically because it allows for case identification and management during routine care. PMID- 26497905 TI - Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease. AB - Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease. PMID- 26497906 TI - Outcomes of Haploidentical Stem Cell Transplantation for Lymphoma with Melphalan Based Conditioning. AB - Haploidentical transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PTCy) is increasingly utilized for the treatment of lymphoma and almost exclusively with the nonmyeloablative fludarabine (Flu)/cyclophosphamide/total body irradiation (TBI) conditioning regimen. We present early results of a reduced-intensity (RIC) regimen utilizing fludarabine and melphalan (FM) for the treatment of advanced lymphoma. All patients with a diagnosis of lymphoma or chronic lymphocytic leukemia (CLL) who received Haplo SCT at the University of Texas MD Anderson Cancer Center between 2009 and 2014 were reviewed (N = 22). Patients received Flu 160 mg/m(2) and melphalan 100 mg/m(2) to 140 mg/m(2) with thiotepa 5 mg/kg or 2 Gy TBI. Because of concerns of increased treatment-related mortality (TRM) with the melphalan 140 mg/m(2) regimen (FM140), a RIC regimen with melphalan 100 mg/m(2) (FM100) was devised. Rituximab was included for CD20(+) disease. Graft-versus-host disease prophylaxis consisted of PTCy 50 mg/kg on days +3 and + 4, tacrolimus, and mycophenolate mofetil. Sixty-eight percent of all patients were not in complete remission at the time of transplantation. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire cohort were 54%, 1-year TRM was 19%, and the cumulative incidence of relapse at 2 years was 27%. Two-year PFS for Hodgkin lymphoma, non-Hodgkin lymphoma, and CLL/small lymphocytic lymphoma were 57%, 51%, and 75%. Patients treated with FM100 compared to FM140 had equivalent PFS (71% versus 37%, P = .246) and OS (71% versus 58%, P = .32). These early results establish Flu and melphalan 100 mg/m(2) with 2 Gy TBI or thiotepa 5 mg/kg as a very promising conditioning regimen for the treatment of advanced lymphoma with Haplo-SCT and PTCy. PMID- 26497907 TI - Adjusting Cyclophosphamide Dose in Obese Patients with Lymphoma Is Safe and Yields Favorable Outcomes after Autologous Hematopoietic Cell Transplantation. AB - No clear dosing guidelines exist for cyclophosphamide (Cy) dose adjustments in obese patients treated with high-dose chemoradiotherapy followed by autologous hematopoietic cell transplantation (HCT). We prospectively compared the outcomes of high-dose Cy/total body irradiation (TBI) conditioning in 147 non-Hodgkin lymphoma (NHL) patients in 3 weight groups: nonobese (<120% ideal body weight [IBW]; n = 72), overweight (120% to 149% IBW; n = 46), and obese (>=150% IBW; n = 29). Nonobese and overweight patients received Cy (120 mg/kg of total body weight, intravenously) and TBI (1320 cGy), whereas obese patients (median body mass index, 36) received an adjusted Cy dose based on IBW plus 50% of the difference between total body weight and IBW (AdjBW50). The median patient age was 57 years (range, 19 to 73). The most common diagnoses were diffuse large B cell lymphoma (n = 57) and mantle cell lymphoma (n = 51). Three-year overall survival was 61% (95% confidence interval [CI], 48% to 72%) for nonobese patients, 68% (95% CI, 52% to 82%) for overweight patients, and 80% (95% CI, 62% to 93%) for obese patients. Cumulative incidence of relapse (48%, 43%, and 38%, respectively) and nonrelapse mortality (~4%) were similar in all groups. Hemorrhagic cystitis and cardiac toxicity were rare events. Our data show that the AdjBW50 formula can be safely and effectively used for Cy dose adjustments in obese patients treated for NHL with high-dose Cy/TBI conditioning followed by autologous HCT. PMID- 26497909 TI - Co(II)-MOF: A Highly Efficient Organic Oxidation Catalyst with Open Metal Sites. AB - A porous Co(II)-MOF (1) was synthesized by the combination of a bent imidazole bridged ligand and p-phthalic acid (PTA) with Co(OAc)2 under solvothermal conditions. This Co(II)-MOF (1) is able to undergo a reversible MeOH substitution reaction on the Co(II) center via a single-crystal-to-single-crystal process. The desolvated Co(II)-MOF (2) with the open Co(II) sites is very stable (up to 350 degrees C). Furthermore, 2 is a highly active heterogeneous catalyst for various organic substrates oxidation in the presence of tert-butyl hydroperoxide (TBHP) under milder conditions. The importance of open Co(II) sites in 2 for the organic substrates oxidation is directly evidenced by the single-crystal X-ray diffraction. PMID- 26497910 TI - A highly enantioselective thiolation of sulfonyl indoles to access 3-sec-sulfur substituted indoles in water. AB - A highly enantioselective approach for the synthesis of 3-alkyl- indole or indoline derivatives with a functional thiol group is presented. The chemistry is based on the asymmetric 1,4-addition of thiol to vinylogous imine intermediates, which are generated in situ from sulfonylindoles. The broad substrate transformation proceeds with high yields (up to 96%) and enantioselectivity (up to 98% ee) in a water-compatible system. PMID- 26497908 TI - Protective immunity against acute toxoplasmosis in BALB/c mice induced by a DNA vaccine encoding Toxoplasma gondii elongation factor 1-alpha. AB - BACKGROUND: Toxoplasma gondii can infect almost all warm-blood animals including human beings. The high incidence and severe damage that can be caused by T. gondii infection clearly indicates the need for the development of a vaccine. T. gondii elongation factor 1-alpha (TgEF-1alpha) plays an important role in pathogenesis and host cell invasion for this parasite. The aim of this study was to evaluate the immune protective efficacy of a DNA vaccine encoding TgEF-1alpha gene against acute T. gondii infection in mice. METHODS: A DNA vaccine (pVAX-EF 1alpha) encoding T. gondii EF-1a (TgEF-1alpha) gene was constructed and its immune response and protective efficacy against lethal challenge in BALB/c mice were evaluated. RESULTS: Mice inoculated with the pVAX-EF-1alpha vaccine had a high level of specific anti-T. gondii antibodies and produced high levels of IFN gamma, interleukin (IL)-4, and IL-17. The expression levels of MHC-I and MHC-II molecules as well as the percentages of both CD4(+) and CD8(+) T cells in mice vaccinated with pVAX-EF-1alpha were significantly increased (p < 0.05), compared with those in all the mice from control groups (blank control, PBS, and pVAXI). Immunization with pVAX-EF-1alpha significantly (p < 0.05) prolonged mouse survival time to 14.1 +/- 1.7 days after challenge infection with the virulent T. gondii RH strain, compared with mice in the control groups which died within 8 days. CONCLUSIONS: DNA vaccination with pVAX-EF-1alpha triggered strong humoral and cellular responses and induced effective protection in mice against acute T. gondii infection, indicating that TgEF-1alpha is a promising vaccine candidate against acute toxoplasmosis. PMID- 26497911 TI - A novel RET gene mutation in a patient with apparently sporadic pheochromocytoma. AB - Pheochromocytoma (Pheo) is a chromaffin tumor arising from the adrenal medulla. The recent discovery of new germline mutations in RET, SDHA, SDHB, SDHC, SDHD, VHL, NF1, TMEM127, MAX genes, increased the rate of genetic disease from 10% to 28% in patients with apparently sporadic tumor. RET germline mutations cause multiple endocrine neoplasia type 2 syndrome (MEN 2A) characterized by complete penetrance of medullary thyroid cancer (MTC), and lower prevalence of Pheo and hyperparathyroidism. We describe the genetic etiology of an apparently sporadic case of monolateral Pheo in a 42-year-old male patient. A new (not previously reported) MEN 2A-associated germline RET mutation located in exon 11 (Glu632Gly, caused by an A>G point mutation at position 1895 of the RET cDNA) was found in the patient but not in his living first-degree relatives. This observation increases the number of possible germline RET mutations. Genotype-phenotype correlation of this new genetic alteration is unknown, but this rare mutation is probably associated with a low risk for MTC (usually the first tumor diagnosed in MEN 2A syndrome) and with the development of Pheo before the onset of MTC. Since we expect MTC to occur in our patient, strict follow-up is mandatory. Our findings emphasize the relevance of genetic testing in patients with Pheo, especially when the clinical presentation (family history, young age at diagnosis, multiple locations, malignant lesions, and bilateralism) is suggestive. PMID- 26497912 TI - Experience of negative emotions in Parkinson's disease: An fMRI investigation. AB - OBJECTIVE: Amygdala abnormalities have been discussed as a possible mechanism underlying reduced reactivity to negative stimuli in Parkinson's disease (PD). METHODS: The present investigation used functional magnetic resonance imaging (fMRI) in order to test this hypothesis. We compared brain activation of 17 nondepressed and nondemented PD patients with 22 healthy controls during the elicitation of negative affective states. The patients suffered from moderate motor symptoms for an average of 75 months and had stopped their antiparkinson medication 10-12h prior to the fMRI testing. All participants were shown images which depicted disgusting, fear-relevant and neutral contents and they answered self-report scales for the assessment of disgust proneness and trait anxiety. RESULTS: Both groups did not differ from each other in affective state and trait ratings. In line with the self-report, the fMRI data showed similar activation (including the amygdala) in both groups during disgust and fear elicitation. CONCLUSION: This fMRI investigation found no indication of diminished disgust and fear experience in PD. SIGNIFICANCE: Previously reported affective processing deficits in PD might be due to insufficiently controlled confounding variables (medication, depression, cognitive impairment). PMID- 26497913 TI - Increased ethanol consumption despite taste aversion in mice with a human tryptophan hydroxylase 2 loss of function mutation. AB - Polymorphisms in the gene encoding the brain serotonin synthesis enzyme Tph2 have been identified in mental illnesses, with co-morbidity of substance use disorder. However, little is known about the impact of Tph2 gene variants on addiction. Mice expressing a human Tph2 loss of function variant were used to investigate consequences of aversive conditions on ethanol intake. Mice were familiarized either with ethanol or a solution containing both ethanol and the bittering agent quinine. Effect of familiarization to ethanol or an ethanol-quinine solution was then evaluated using a two-bottles preference test in Tph2-KI and control littermates. Mice from both genotypes displayed similar levels of ethanol consumption and quinine avoidance when habituated to ethanol alone. In contrast, addition of quinine to ethanol during the familiarization period resulted in a reduction of avoidance for the quinine-ethanol solution only in mutant mice. These results indicate that loss of function mutation in Tph2 results in greater motivation for ethanol consumption under aversive conditions and may confer enhanced sensitivity to alcohol use disorder. PMID- 26497914 TI - A new method to effectively and rapidly generate neurons from SH-SY5Y cells. AB - It is well known that neurons differentiated from SH-SY5Y cells can serve as cell models for neuroscience research; i.e., neurotoxicity and tolerance to morphine in vitro. To differentiate SH-SY5Y cells into neurons, RA (retinoic acid) is commonly used to produce the inductive effect. However, the percentage of neuronal cells produced from SH-SY5Y cells is low, either from the use of RA treatment alone or from the combined application of RA and other chemicals. In the current study, we used CM-hNSCs (conditioned medium of human neural stem cells) as the combinational inducer with RA to prompt neuronal differentiation of SH-SY5Y cells. We found that neuronal differentiation was improved and that neurons were greatly increased in the differentiated SH-SY5Y cells using a combined treatment of CM-hNSCs and RA compared to RA treatment alone. The neuronal percentage was higher than 80% (about 88%) on the 3rd day and about 91% on the 7th day examined after a combined treatment with CM-hNSCs and RA. Cell maturation and neurite growth of these neuronal cells were also improved. In addition, the use of CM-hNSCs inhibited the apoptosis of RA-treated SH-SY5Y cells in culture. We are the first to report the use of CM-hNSCs in combination with RA to induce neuronal differentiation of RA-treated SH-SY5Y cells. Our method can rapidly and effectively promote the neuronal production of SH-SY5Y cells in culture conditions. PMID- 26497915 TI - Accuracy of Bedside Paediatric Early Warning System (BedsidePEWS) in a Pediatric Stem Cell Transplant Unit. AB - Hospital mortality in children who undergo stem cell transplant (SCT) is high. Early warning scores aim at identifying deteriorating patients and at preventing adverse outcomes. The bedside pediatric early warning system (BedsidePEWS) is a pediatric early warning score based on 7 clinical indicators, ranging from 0 (all indicators within normal ranges for age) to 26. The aim of this case-control study was to assess the performance of BedsidePEWS in identifying clinical deterioration events among children admitted to an SCT unit. Cases were defined as clinical deterioration events; controls were all the other patients hospitalized on the same ward at the time of case occurrence. BedsidePEWS was retrospectively measured at 4-hour intervals in cases and controls 24 hours before an event (T4-T24). We studied 19 cases and 80 controls. The score significantly increased in cases from a median of 4 at T24 to a median of 14 at T4. The proportion of correctly classified cases and controls was >90% since T8. The area under the curve receiver operating characteristic was 0.9. BedsidePEWS is an accurate screening tool to predict clinical deterioration in SCT patients. PMID- 26497916 TI - Exceptionally large entropy contributions enable the high rates of GTP hydrolysis on the ribosome. AB - Protein synthesis on the ribosome involves hydrolysis of GTP in several key steps of the mRNA translation cycle. These steps are catalyzed by the translational GTPases of which elongation factor Tu (EF-Tu) is the fastest GTPase known. Here, we use extensive computer simulations to explore the origin of its remarkably high catalytic rate on the ribosome and show that it is made possible by a very large positive activation entropy. This entropy term (TDeltaS(?)) amounts to more than 7 kcal/mol at 25 degrees C. It is further found to be characteristic of the reaction mechanism utilized by the translational, but not other, GTPases and it enables these enzymes to attain hydrolysis rates exceeding 500 s(-1). This entropy driven mechanism likely reflects the very high selection pressure on the speed of protein synthesis, which drives the rate of each individual GTPase towards maximal turnover rate of the whole translation cycle. PMID- 26497917 TI - An in silico model to demonstrate the effects of Maspin on cancer cell dynamics. AB - Most cancer treatments efficacy depends on tumor metastasis suppression, where tumor suppressor genes play an important role. Maspin (Mammary Serine Protease Inhibitor), an non-inhibitory serpin has been reported as a potential tumor suppressor to influence cell migration, adhesion, proliferation and apoptosis in in vitro and in vivo experiments in last two decades. Lack of computational investigations hinders its ability to go through clinical trials. Previously, we reported first computational model for maspin effects on tumor growth using artificial neural network and cellular automata paradigm with in vitro data support. This paper extends the previous in silico model by encompassing how maspin influences cell migration and the cell-extracellular matrix interaction in subcellular level. A feedforward neural network was used to define each cell behavior (proliferation, quiescence, apoptosis) which followed a cell-cycle algorithm to show the microenvironment impacts over tumor growth. Furthermore, the model concentrates how the in silico experiments results can further confirm the fact that maspin reduces cell migration using specific in vitro data verification method. The data collected from in vitro and in silico experiments formulates an unsupervised learning problem which can be solved by using different clustering algorithms. A density based clustering technique was developed to measure the similarity between two datasets based on the number of links between instances. Our proposed clustering algorithm first finds the nearest neighbors of each instance, and then redefines the similarity between pairs of instances in terms of how many nearest neighbors share the two instances. The number of links between two instances is defined as the number of common neighbors they have. The results showed significant resemblances with in vitro experimental data. The results also offer a new insight into the dynamics of maspin and establish as a metastasis suppressor gene for further molecular research. PMID- 26497918 TI - Clinical Factors Associated With a Short Survival Time After Percutaneous Nephrostomy for Ureteric Obstruction in Cancer Patients: An Updated Model. AB - CONTEXT: Patients with advanced cancer can develop ureteric obstruction. Percutaneous nephrostomy (PCN) tube insertion can relieve this obstruction and prevent renal failure. PCN is associated with complications and can worsen quality of life. Prognostic models of survival after PCN in cancer patients can help identify the patients who will most likely benefit from this intervention. This work updates a prognostic model to predict overall survival in cancer patients after receiving PCN. OBJECTIVES: The primary objective was to assess survival of patients with malignant urinary obstruction after PCN tube insertion. The secondary objective was to identify factors associated with poor prognosis in this group of patients and externally validate an existing model. METHODS: We conducted a retrospective analysis of 211 patients who had malignant urinary obstruction and received PCN tube insertion. RESULTS: The median survival was 5.05 months (95% CI = 3.87-7.11; range 2-963 days). On univariate analysis, the factors significantly associated with shorter survival were type of malignancy, bilateral hydronephrosis, serum albumin <3.5 mg/dL, presence of metastasis, ascites, and pleural effusion (P < 0.05). Multivariate analysis using a Cox proportional hazards regression model showed that type of malignancy, serum albumin <3.5 mg/dL, pleural effusion, and bilateral hydronephrosis were significantly associated with shorter survival (P < 0.05). Using the latter three factors, we stratified patients into four prognostic groups: zero risk factors (32 patients), one risk factor (85 patients), two risk factors (78 patients), and three risk factors (16 patients). Median survival for each group was 17.6 months, 7.7 months, 2.2 months, and 1.7 months, respectively (P < 0.0001). CONCLUSION: Survival in patients with malignant ureteric obstruction can range widely from a few days to a few years. The presented prognostic model is an updated model and can be used to identify patients with poor survival after PCN. PMID- 26497919 TI - C-reactive protein levels in girls with lower urinary tract symptoms. AB - INTRODUCTION: Daytime lower urinary tract (LUT) conditions are identified as daytime incontinence problems for children in whom any cause of neuropathy and uropathy has been excluded. C-reactive protein (CRP) is a common marker of acute or chronic inflammation and infection. Increased CRP levels have been detected in the studies conducted on adults diagnosed with overactive bladders and interstitial cystitis. OBJECTIVE: This study aimed to investigate the role of serum CRP levels in girls suffering from daytime LUT conditions. STUDY DESIGN: Out of the 752 patients who presented to the outpatient clinics with lower urinary tract symptoms, 709 were excluded due to: being boys, having previous urinary tract surgery, an active urinary tract infection, a neurological anomaly, a urinary system anomaly, having rheumatic disease, any chronic disease, any febrile infection over the past week, a history of constipation, and enuresis nocturna. Forty-three girls with LUT conditions and aged 8-10 years were included in the study as the patient group. Forty girls who attended the urology outpatient clinic without LUT conditions, or active urinary tract infections and any chronic disease requiring follow-up constituted the control group. Under the control of the parents, all subjects were asked to fill out 3-day voiding diaries. The voiding diaries identified frequency, urgency, urgency urinary incontinence, and functional bladder capacity data. All subjects also completed a dysfunctional voiding scoring system (DVSS). The serum CRP levels of all subjects were measured. RESULTS: There was a significant difference in serum CRP levels and DVSS between the patient group and the control group (P = 0.001, P = 0.001). The mean serum CRP levels showed a significant increase when frequency and urgency scores were >=8, the urge incontinence score was >=2 and the DVS score DVSS was >=14 in the voiding diaries of the patient group (Table). DISCUSSION: Lower urinary tract dysfunction is defined as a condition involving abnormalities of filling and/or emptying of the bladder. This frequently encountered problem constitutes >40% of all pediatric urology outpatient visits. The relationship between LUT conditions and serum CRP in both genders has been detected. However, it is believed that to our knowledge, this is the first study looking at the relationship between daytime LUTS and increased CRP levels in children. The most important limitations of the study were: having a small number of patients, and the sample consisting of only one gender and a specific age group. CONCLUSION: The serum CRP levels were significantly higher in the girls with daytime LUT conditions than in the control group. Also, the CRP levels significantly increased as DVSS, frequency, urgency, and urge incontinence scores increased. PMID- 26497921 TI - Should Prebiopsy Multiparametric Magnetic Resonance Imaging be Offered to All Biopsy-naive Men Undergoing Prostate Biopsy? PMID- 26497920 TI - Docetaxel for Castration-sensitive Prostate Cancer: Wrapping up Unfinished Business? PMID- 26497922 TI - Association Between RECIST Changes and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Receiving Docetaxel. AB - We explored the association between Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and 1.1 changes and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) from the control arms of the VENICE and MAINSAIL phase 3 trials, respectively, receiving docetaxel, prednisone, and placebo. We used Cox proportional hazards regression to evaluate the OS prognostic ability of RECIST changes after adjusting for prognostic factors. In the VENICE trial, the OS hazard ratio (HR) was 0.64 (95% confidence interval [CI] 0.42-0.99; p=0.045) for patients with a partial response (PR) compared to those without PR, and 1.78 (95% CI 1.07-2.95; p=0.026) for those with progressive disease (PD) compared to those without PD. After adjusting for prostate-specific antigen (PSA) changes, PD remained significant (HR 1.85, 95% CI 1.10-3.12; p=0.020). Data from the MAINSAIL trial corroborated the association of PR (HR 0.51, 95% CI 0.22-1.18; p=0.12) and PD (HR 3.51, 95% CI 1.92-6.43; p<0.001) with OS. After adjusting for PSA changes, PD was associated with poor OS (HR 2.36, 95% CI 1.11-5.04; p=0.026). Given the association between RECIST changes and OS, more frequent detection of measurable disease with current imaging techniques, and the poor reliability of bone scan and PSA changes, assessment of RECIST changes on treatment with novel agents in patients with measurable tumors may provide an objective signal of efficacy. PATIENT SUMMARY: In this study, we found an association between changes in objectively measurable tumors according to Response Evaluation Criteria in Solid Tumors (RECIST) and survival in patients with metastatic prostate cancer receiving docetaxel chemotherapy. Since bone scan and prostate-specific antigen changes are unreliable and measurable tumors are more frequently detected now because of better radiographic technology, a focus on RECIST changes should be considered during drug development to provide an objective signal of efficacy. PMID- 26497923 TI - The Impact of Adding Taxanes to Gemcitabine and Platinum Chemotherapy for the First-Line Therapy of Advanced or Metastatic Urothelial Cancer: A Systematic Review and Meta-analysis. AB - CONTEXT: Gemcitabine/platinum chemotherapy is the most widely used first-line regimen for metastatic urothelial carcinoma, and the potential improvement of adding taxanes needs to be clarified. OBJECTIVE: To study the survival impact of taxane plus gemcitabine/platinum compared with gemcitabine/platinum alone as upfront therapy. EVIDENCE ACQUISITION: Literature was searched for studies including gemcitabine/platinum +/- taxanes (paclitaxel or docetaxel only). We pooled trial level data including the median, proportions, and confidence intervals on response-rate, progression-free survival, overall survival (OS), and side effects. Univariable and multivariable regression models evaluated the prognostic role of addition of taxanes after adjusting for platinum type, performance status 2, and the presence of visceral metastases. Data were weighted by the logarithm of the trial sample size. EVIDENCE SYNTHESIS: Thirty-five arms of trials including 2,365 patients were selected (seven with taxanes [n=617], and 28 arms without taxanes [n=1,748]). Median OS was univariably significantly different (p=0.019) between trials with and without taxanes. Across trials, the median 'median OS' amongst trials containing taxanes was 15.5 mo, compared with 12.5 mo in trials which did not. Multivariably, visceral disease and performance status were significantly associated with OS, and the addition of taxanes trended toward significantly better OS (p=0.056) and increase in grade >= 3 neurotoxicity (p=0.051), regardless of specific platinum agent used. CONCLUSIONS: In this meta analysis, adding taxanes to gemcitabine and platinum showed a trend for improved OS and higher grade >= 3 neurotoxicity. Improvements in patient selection and the evaluation of a more potent and tolerable tubulin inhibitor in combination with gemcitabine/platinum in a well-powered trial are the critical next steps. PATIENT SUMMARY: In this report, a trend for improved overall survival and worse neurotoxicity was observed for adding a taxane to first-line gemcitabine/platinum chemotherapy for metastatic urothelial carcinoma. More effective taxanes should be investigated further in urothelial carcinoma in combination with gemcitabine/platinum. PMID- 26497924 TI - Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. AB - BACKGROUND: Early salvage radiation therapy (eSRT) represents a treatment option for patients who experience a prostate-specific antigen (PSA) rise after radical prostatectomy (RP); however, the optimal PSA level for eSRT administration is still unclear. OBJECTIVE: To test the impact of PSA level on cancer control after eSRT according to pathologic tumour characteristics. DESIGN, SETTING, AND PARTICIPANTS: The study included 716 node-negative patients with undetectable postoperative PSA who experienced a PSA rise after RP. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at PSA <= 0.5 ng/ml. Biochemical recurrence (BCR) after eSRT was defined as two consecutive PSA values >= 0.2 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Cox regression analysis tested the association between pre-eSRT PSA level and BCR after eSRT. Covariates consisted of pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (<= 6, 7, or >= 8), and surgical margin status (negative vs positive). We tested an interaction with PSA level and baseline pathologic risk for the hypothesis that BCR-free survival differed by pre-eSRT PSA level. Three pathologic risk factors were identified: pathologic stage pT3b or higher, pathologic Gleason score >= 8, and negative surgical margins. RESULTS AND LIMITATIONS: Median follow-up among patients who did not experience BCR after eSRT was 57 mo (interquartile range: 27 105). At 5 yr after eSRT, BCR-free survival rate was 82% (95% confidence interval [CI], 78-85). At multivariable Cox regression analysis, pre-eSRT PSA level was significantly associated with BCR after eSRT (hazard ratio: 4.89; 95% CI, 1.40 22.9; p < 0.0001). When patients were stratified according to the number of risk factors at final pathology, patients with at least two pathologic risk factors showed an increased risk of 5-yr BCR as high as 10% per 0.1 ng/ml of PSA level compared with only 1.5% in patients with one or no pathologic risk factors. CONCLUSIONS: In this retrospective study, cancer control after eSRT greatly depended on pretreatment PSA. The absolute PSA level had a different prognostic value depending on the pathologic characteristics of the tumour. In patients with more adverse pathologic features, eSRT conferred better cancer control when administered at the very first sign of PSA rise. Conversely, the benefit of eSRT was less evident in men with favourable disease at RP. PATIENT SUMMARY: In this retrospective study, cancer control after early salvage radiation therapy (eSRT) was influenced by pretreatment prostate-specific antigen (PSA) level. This effect was highest in men with at least two of the following pathologic features: pT3b/pT4 disease, pathologic Gleason score >= 8, and negative surgical margins. In these patients, eSRT conferred better cancer control when administered at the very first sign of PSA rise. PMID- 26497925 TI - Multidrug resistance-associated protein 4 is a determinant of arsenite resistance. AB - Although arsenic trioxide (arsenite, As(III)) has shown a remarkable efficacy in the treatment of acute promyelocytic leukemia patients, multidrug resistance is still a major concern for its clinical use. Multidrug resistance-associated protein 4 (MRP4), which belongs to the ATP-binding cassette (ABC) superfamily of transporters, is localized to the basolateral membrane of hepatocytes and the apical membrane of renal proximal tubule cells. Due to its characteristic localization, MRP4 is proposed as a candidate in the elimination of arsenic and may contribute to resistance to As(III). To test this hypothesis, stable HEK293 cells overexpressing MRP4 or MRP2 were used to establish the role of these two transporters in As(III) resistance. The IC50 values of As(III) in MRP4 cells were approximately 6-fold higher than those in MRP2 cells, supporting an important role for MRP4 in resistance to As(III). The capacity of MRP4 to confer resistance to As(III) was further confirmed by a dramatic decrease in the IC50 values with the addition of MK571, an MRP4 inhibitor, and cyclosporine A, a well-known broad spectrum inhibitor of ABC transporters. Surprisingly, the sensitivity of the MRP2 cells to As(III) was similar to that of the parent cells, although insufficient formation of glutathione and/or Se conjugated arsenic compounds in the MRP2 cells might limit transport. Given that MRP4 is a major contributor to arsenic resistance in vitro, further investigation into the correlation between MRP4 expression and treatment outcome of leukemia patients treated with arsenic-based regimens is warranted. PMID- 26497926 TI - The influence of red pepper powder on the density of Weissella koreensis during kimchi fermentation. AB - Weissella koreensis is a psychrophilic bacterium that is the dominant species found in kimchi and exhibits anti-obesity effects via its production of ornithine. In this study, we mined the genome of W. koreensis KACC15510 to identify species-specific genes that can serve as new targets for the detection and quantification of W. koreensis in kimchi. A specific polymerase chain reaction (PCR) primer set for the membrane protein-encoding gene of W. koreensis KACC15510 was designed and investigated to quantify its sensitivity and specificity for detecting the bacterium in kimchi. The specificity of the primer set was evaluated using genomic DNA from eight isolates of W. koreensis, 11 different species of Weissella and 13 other reference lactic acid bacterium (LAB) strains. In addition, red pepper powder was observed to strongly influence the density of W. koreensis during kimchi fermentation. PMID- 26497927 TI - Chronic effects of losartan on the muscles and the serologic profiles of mdx mice. AB - AIMS: Losartan, an angiotensin II type 1 receptor blocker, attenuates transforming growth factor-beta (TGF-beta) signaling, which inhibits myogenic regeneration. Although many researchers have demonstrated that losartan has anti fibrotic and protective effects on cardiac and skeletal muscles, for long-term administration to treat dystrophic disorders, it is essential to demonstrate not only the therapeutic effects of losartan on muscles but also its effects on other organs and on blood biochemistry. MAIN METHODS: Mdx mice, an animal model of Duchenne muscular dystrophy (DMD), were fed losartan dissolved in tap water. After 44weeks, the skeletal (gastrocnemius), cardiac, and diaphragm muscles of mdx mice were removed. Tissue and blood samples were collected from all experimental animals. Effects of losartan on muscle regeneration, fibrosis, and blood enzymatic profiles were evaluated. KEY FINDINGS: In histopathological findings and serum biochemistry analyses, chronic losartan administration showed muscular protective effects and inhibited fibrosis in skeletal (gastrocnemius), cardiac, and diaphragmatic muscles. In addition, losartan had no effects on other solid organs. Interestingly, losartan had beneficial effects on serum HDL ratio. SIGNIFICANCE: This study demonstrates the therapeutic effects of losartan on muscles and its effects on other organs and on blood biochemistry. In conclusion, our results provide useful information for consideration of chronic losartan administration be as a treatment of DMD. PMID- 26497929 TI - Clinical implications of aging. AB - Figure summarizes the major changes of aging and some key ways these changes affect pages. Though many changes occur with aging, under normal or resting conditions, there is usually very little functionally that is diminished solely on the basis of aging. The net effects are reductions in reserve capacity and placing geriatric patients at higher risk for adverse consequences related to medications and diseases. Interactions between lifestyle factors, such as exercise, diet, and environmental exposures, have a large impact on aging and lead to great individual variability. The interplay between these environmental factors, aging, and development of chronic diseases multiply the amount of variation seen as individual's age. PMID- 26497928 TI - Review of endocrine disorders associated with environmental toxicants and possible involved mechanisms. AB - Endocrine disrupting chemicals (EDC) are released into environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDC have major risks for human by targeting different organs and systems in the body. Multiple mechanisms are involved in targeting the normal system, through estrogen receptors, nuclear receptors and steroidal receptors activation. In this review, different methods by which xenobiotics stimulate signaling pathways and genetic mutation or DNA methylation have been discussed. These methods help to understand the results of xenobiotic action on the endocrine system. Endocrine disturbances in the human body result in breast cancer, ovarian problems, thyroid eruptions, testicular carcinoma, Alzheimer disease, schizophrenia, nerve damage and obesity. EDC characterize a wide class of compounds such as organochlorinated pesticides, industrial wastes, plastics and plasticizers, fuels and numerous other elements that exist in the environment or are in high use during daily life. The interactions and mechanism of toxicity in relation to human general health problems, especially endocrine disturbances with particular reference to reproductive problems, diabetes, and breast, testicular and ovarian cancers should be deeply investigated. There should also be a focus on public awareness of these EDC risks and their use in routine life. Therefore, the aim of this review is to summarize all evidence regarding different physiological disruptions in the body and possible involved mechanisms, to prove the association between endocrine disruptions and human diseases. PMID- 26497930 TI - Cytotoxicity of PEGylated liposomes co-loaded with novel pro-apoptotic drug NCL 240 and the MEK inhibitor cobimetinib against colon carcinoma in vitro. AB - The overactivation of signaling pathways, such as the PI3K and MAPK, which are crucial to cell growth and survival, is a common feature in many cancer types. Though a number of advances have been made in the development of molecular agents targeting these pathways, their application as monotherapies has not significantly improved clinical outcome. A novel liposomal preparation was developed, co-loaded with NCL-240, a small-molecule inhibitor of the PI3K/mTOR pathway, along with cobimetinib, a MEK/ERK pathway inhibitor. This combination drug-loaded nanocarrier, (N+C)-LP, was able to significantly enhance the cytotoxicity of these drugs against colon carcinoma cells in vitro demonstrating a clear synergistic effect (combination index of 0.79). The (N+C)-LP was also able to induce cell cycle arrest of the cells, specifically in the G1 phase thereby preventing their progression to the S-phase, typical of the action of MEK inhibitors. Analyzing the apoptotic events, it was found that this effect on cell cycle regulation is followed by the induction of apoptosis. The quantified distribution of apoptotic events showed that the (N+C)-LP induced apoptosis significantly by over 3-4 fold (P<0.001) compared to other treatment groups. The co-loaded liposomal preparation was also targeted to the transferrin receptor of cancer cells by modifying the surface of the liposome with transferrin. FACS analysis showed that transferrin-mediated targeting enhanced the association of liposomes to HCT 116 cells by almost 5-fold. This could potentially allow for cancer cell-specific effects in vivo thereby minimizing any non-specific interactions of the liposomes with non-cancerous cells. Taken together, this study clearly shows that the combined inhibition of the PI3K and MEK pathways correlates with a significant anti-proliferative effect, due to cell-cycle regulation leading to the induction of apoptosis. PMID- 26497931 TI - Extension of in vivo half-life of biologically active molecules by XTEN protein polymers. AB - XTENTM is a class of unstructured hydrophilic, biodegradable protein polymers designed to increase the half-lives of therapeutic peptides and proteins. XTEN polymers and XTEN fusion proteins are typically expressed in Escherichia coli and purified by conventional protein chromatography as monodisperse polypeptides of exact length and sequence. Unstructured XTEN polypeptides have hydrodynamic volumes significantly larger than typical globular proteins of similar mass, thus imparting a bulking effect to the therapeutic payloads attached to them. Since their invention, XTEN polypeptides have been utilized to extend the half-lives of a variety of peptide- and protein-based therapeutics. Multiple clinical and preclinical studies and related drug discovery and development efforts are in progress. This review details the most current understanding of physicochemical properties and biological behavior of XTEN and XTENylated molecules. Additionally, the development path and status of several advanced drug discovery and development efforts are highlighted. PMID- 26497932 TI - Cervical artery dissections and type A aortic dissection in a family with a novel missense COL3A1 mutation of vascular type Ehlers-Danlos syndrome. AB - Cervical artery dissection (CeAD) is a rare condition. One of the causes is the vascular type of Ehlers-Danlos syndrome (vEDS). A novel missense mutation in COL3A1 was found in a young patient with CeAD as the single manifestation of vEDS. This is a heterozygous c.953G > A mutation in exon 14, disrupting the normal Gly-X-Y repeats of type III procollagen, by converting glycine to aspartic acid. PMID- 26497933 TI - Epididymal anomalies in boys with undescended testis or hydrocele: Significance of testicular location. AB - BACKGROUND: Epididymal anomalies and patent processus vaginalis are frequently found in boys with cryptorchidism or hydrocele. We conducted this study to evaluate the association between epididymal anomalies and testicular location or patent processus vaginalis in boys with undescended testis or hydrocele. METHODS: Children undergoing surgery with undescended testis (group A, 136 boys and 162 testes) or communicating hydrocele (group B, 93 boys and 96 testes) were included. Testicular locations and epididymal anomalies were investigated prospectively. An anomalous epididymis was defined as anomalies of epididymal fusion that consisted of loss of continuity between the testis, the epididymis, and the long looping epididymis. The epididymis was considered normal when a normal, firm attachment between the testis, the caput, and the cauda epididymis was present. RESULTS: The mean ages of groups A and B were 24.6 +/- 19.7 (range, 8-52 months) and 31.4 +/- 20.6 months (range, 10-59 months). The incidence of epididymal anomalies was significantly higher in group A than that in group B (65.4 % vs. 13.5 %, P < .001). The incidence of epididymal anomalies in boys with undescended testis was significantly different according to testis location. Epididymal anomalies were observed in 100 %, 91.4 %, and 39.3 % of cases when the testis was located in the abdomen, inguinal canal, and distal to the external inguinal ring, respectively (P < 0.001). CONCLUSION: We conclude that epididymal anomalies were more frequent in boys with undescended testis than in boys with hydrocele, and that these anomalies were more frequent when undescended testis was at a higher level. These results suggest that testicular location is associated with epididymal anomalies rather than patent processus vaginalis. PMID- 26497934 TI - Elongation factor-1A1 is a novel substrate of the protein phosphatase 1-TIMAP complex. AB - TIMAP (TGF-beta inhibited membrane associated protein) is a protein phosphatase 1 (PP1) regulatory subunit highly abundant in endothelial cells and it is involved in the maintenance of pulmonary endothelial barrier function. It localizes mainly in the plasma membrane, but it is also present in the nuclei and cytoplasm. Direct interaction of TIMAP with the eukaryotic elongation factor 1 A1 (eEF1A1) is shown by pull-down, LC-MS/MS, Far-Western and immunoprecipitations. In connection with the so called moonlighting functions of the elongation factor, eEF1A is thought to establish protein-protein interactions through a transcription-dependent nuclear export motif, TD-NEM, and to aid nuclear export of TD-NEM containing proteins. We found that a TD-NEM-like motif of TIMAP has a critical role in its specific binding to eEF1A1. However, eEF1A1 is not or not exclusively responsible for the nuclear export of TIMAP. On the contrary, TIMAP seems to regulate membrane localization of eEF1A1 as the elongation factor co localized with TIMAP in the plasma membrane fraction of control endothelial cells, but it has disappeared from the membrane in TIMAP depleted cells. It is demonstrated that membrane localization of eEF1A1 depends on the phosphorylation state of its Thr residue(s); and ROCK phosphorylated eEF1A1 is a novel substrate for TIMAP-PP1 underlining the complex regulatory role of TIMAP in the endothelium. The elongation factor seems to be involved in the regulation of endothelial cell attachment and spreading as silencing of eEF1A1 positively affected these processes which were monitored by transendothelial resistance measurements. PMID- 26497935 TI - Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management. AB - SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended. PMID- 26497936 TI - 2D fluorescence spectroscopy for monitoring ion-exchange membrane based technologies - Reverse electrodialysis (RED). AB - Reverse electrodialysis (RED) is one of the emerging, membrane-based technologies for harvesting salinity gradient energy. In RED process, fouling is an undesirable operation constraint since it leads to a decrease of the obtainable net power density due to increasing stack electric resistance and pressure drop. Therefore, early fouling detection is one of the main challenges for successful RED technology implementation. In the present study, two-dimensional (2D) fluorescence spectroscopy was used, for the first time, as a tool for fouling monitoring in RED. Fluorescence excitation-emission matrices (EEMs) of ion exchange membrane surfaces and of natural aqueous streams were acquired during one month of a RED stack operation. Fouling evolvement on the ion-exchange membrane surfaces was successfully followed by 2D fluorescence spectroscopy and quantified using principal components analysis (PCA). Additionally, the efficiency of cleaning strategy was assessed by measuring the membrane fluorescence emission intensity before and after cleaning. The anion-exchange membrane (AEM) surface in contact with river water showed to be significantly affected due to fouling by humic compounds, which were found to cross through the membrane from the lower salinity (river water) to higher salinity (sea water) stream. The results obtained show that the combined approach of using 2D fluorescence spectroscopy and PCA has a high potential for studying fouling development and membrane cleaning efficiency in ion exchange membrane processes. PMID- 26497937 TI - Transport and retention of xanthan gum-stabilized microscale zero-valent iron particles in saturated porous media. AB - Microscale zero valent iron (mZVI) is a promising material for in-situ contaminated groundwater remediation. However, its usefulness has been usually inhibited by mZVI particles' low mobility in saturated porous media for sedimentation and deposition. In our study, laboratory experiments, including sedimentation studies, rheological measurements and transport tests, were conducted to investigate the feasibility of xanthan gum (XG) being used as a coating agent for mZVI particle stabilization. In addition, the effects of XG concentration, flow rate, grain diameter and water chemistry on XG-coated mZVI (XG-mZVI) particle mobility were explored by analyzing its breakthrough curves and retention profiles. It was demonstrated that XG worked efficiently to enhance the suspension stability and mobility of mZVI particles through the porous media as a shear thinning fluid, especially at a higher concentration level (3 g/L). The results of the column study showed that the mobility of XG-mZVI particles increased with an increasing flow rate and larger grain diameter. At the highest flow rate (2.30 * 10(-3) m/s) within the coarsest porous media (0.8-1.2 mm), 86.52% of the XG-mZVI flowed through the column. At the lowest flow rate (0.97 * 10(-4) m/s) within the finest porous media (0.3-0.6 mm), the retention was dramatically strengthened, with only 48.22% of the particles flowing through the column. The XG-mZVI particles appeared to be easily trapped at the beginning of the column especially at a low flow rate. In terms of two representative water chemistry parameters (ion strength and pH value), no significant influence on XG mZVI particle mobility was observed. The experimental results suggested that straining was the primary mechanism of XG-mZVI retention under saturated condition. Given the above results, the specific site-related conditions should be taken into consideration for the design of a successful delivery system to achieve a compromise between maximizing the radius of influence of the injection and minimizing the injection pressure. PMID- 26497938 TI - Attenuation of copper in runoff from copper roofing materials by two stormwater control measures. AB - Concerns have been raised over diffuse and non-point sources of metals including releases from copper (Cu) roofs during storm events. A picnic shelter with a partitioned Cu roof was constructed with two types of stormwater control measures (SCMs), bioretention planter boxes and biofiltration swales, to evaluate the ability of the SCMs to attenuate Cu in stormwater runoff from the roof. Cu was measured as it entered the SCMs from the roof as influent as well as after it left the SCMs as effluent. Samples from twenty-six storms were collected with flow-weighted composite sampling. Samples from seven storms were collected with discrete sampling. Total Cu in composite samples of the influent waters ranged from 306 to 2863 MUg L(-1) and had a median concentration of 1087 MUg L(-1). Total Cu in the effluent from the planter boxes ranged from 28 to 141 MUg L(-1), with a median of 66 MUg L(-1). Total Cu in effluent from the swales ranged from 7 to 51 MUg L(-1) with a median of 28 MUg L(-1). Attenuation in the planter boxes ranged from 85 to 99% with a median of 94% by concentration and in the swales ranged from 93 to 99% with a median of 99%. As the roof aged, discrete storm events showed a pronounced first-flush effect of Cu in SCM influent but this was less pronounced in the planter outlets. Stormwater retention time in the media varied with antecedent conditions, stormwater intensity and volume with median values from 6.6 to 73.5 min. Based on local conditions, a previously-published Cu weathering model gave a predicted Cu runoff rate of 2.02 g m(-2) yr(-1). The measured rate based on stormwater sampling was 2.16 g m(-2) yr(-1). Overall, both SCMs were highly successful at retaining and preventing offsite transport of Cu from Cu roof runoff. PMID- 26497939 TI - Subsurface intake systems: Green choice for improving feed water quality at SWRO desalination plants, Jeddah, Saudi Arabia. AB - An investigation of three seawater reverse osmosis facilities located along the shoreline of the Red Sea of Saudi Arabia that use well intake systems showed that the pumping-induced flow of raw seawater through a coastal aquifer significantly improves feed water quality. A comparison between the surface seawater and the discharge from the wells shows that turbidity, algae, bacteria, total organic carbon, most fractions of natural organic matter (NOM), and particulate and colloidal transparent exopolymer particles (TEP) have significant reductions in concentration. Nearly all of the algae, up to 99% of the bacteria, between 84 and 100% of the biopolymer fraction of NOM, and a high percentage of the TEP were removed during transport. The data suggest that the flowpath length and hydraulic retention time in the aquifer play the most important roles in removal of the organic matter. Since the collective concentrations of bacteria, biopolymers, and TEP in the intake seawater play important roles in the biofouling of SWRO membranes, the observed reductions suggest that the desalination facilities that use well intakes systems will have a potentially lower fouling rate compared to open-ocean intake systems. Furthermore, well intake system intakes also reduce the need for chemical usage during complex pretreatment systems required for operation of SWRO facilities using open-ocean intakes and reduce environmental impacts. PMID- 26497940 TI - How Bacteria Use Type IV Pili Machinery on Surfaces. AB - The bacterial type IV pilus (T4P) is a versatile molecular machine with a broad range of functions. Recent advances revealed that the molecular components and the biophysical properties of the machine are well conserved among phylogenetically distant bacterial species. However, its functions are diverse, and include adhesion, motility, and horizontal gene transfer. This review focusses on the role of T4P in surface motility and bacterial interactions. Different species have evolved distinct mechanisms for intracellular coordination of multiple pili and of pili with other motility machines, ranging from physical coordination to biochemical clocks. Coordinated behavior between multiple bacteria on a surface is achieved by active manipulation of surfaces and modulation of pilus-pilus interactions. An emerging picture is that the T4P actively senses and responds to environmental conditions. PMID- 26497941 TI - Brucella abortus Cell Cycle and Infection Are Coordinated. AB - Brucellae are facultative intracellular pathogens. The recent development of methods and genetically engineered strains allowed the description of cell-cycle progression of Brucella abortus, including unipolar growth and the ordered initiation of chromosomal replication. B. abortus cell-cycle progression is coordinated with intracellular trafficking in the endosomal compartments. Bacteria are first blocked at the G1 stage, growth and chromosome replication being resumed shortly before reaching the intracellular proliferation compartment. The control mechanisms of cell cycle are similar to those reported for the bacterium Caulobacter crescentus, and they are crucial for survival in the host cell. The development of single-cell analyses could also be applied to other bacterial pathogens to investigate their cell-cycle progression during infection. PMID- 26497942 TI - The ethics of neonatal research: An ethicist's and a parents' perspective. AB - The ethics of neonatal research are complex because vulnerable new parents are asked to provide consent on behalf of their fragile baby. Whereas clinical neonatal care has evolved to value personalized and shared decision-making, the goal of research ethics is still to standardize the informed consent process and make it as complete and thorough as possible. Ethicists, lawyers and physicians have shaped the field of research ethics and consent for research. The goal of detailed informed consent is to protect participants from harm, but procedures were developed without input from the principal stakeholders: ex-neonatal intensive care unit parents/patients. Empirical investigations examining patient and parental perspectives on research and research ethics are lacking. Rigorous investigations are needed to determine how parents of sick neonates want their families to be protected, knowing that a lack of research is also harmful. Large randomized controlled multicenter trials will always be needed to improve neonatal outcomes. These trials are costly and time-consuming. Currently, the way in which research is funded and regulated and the way in which academic merit is recognized lead to inefficiency and a waste of precious resources. Following a review of the history of research ethics, this article examines and discusses the ethics of research in neonatology. In addition, challenges and opportunities are identified and ideas for future investigations are proposed. PMID- 26497943 TI - Captures of MFO-resistant Cydia pomonella adults as affected by lure, crop management system and flight. AB - The main resistance mechanism of codling moth (Cydia pomonella) in the tree fruit area of Lleida (NE Spain) is multifunction oxidases (MFO). We studied the frequency of MFO-resistant adults captured by different lures, with and without pear ester, and flights in orchards under different crop management systems. The factor year affected codling moth MFO-resistance level, particularly in the untreated orchards, highlighting the great influence of codling moth migration on the spread of resistance in field populations. Chemical treatments and adult flight were also very important but mating disruption technique showed no influence. The second adult flight showed the highest frequency, followed by the first flight and the third flight. In untreated orchards, there were no significant differences in the frequency of MFO-resistant individuals attracted by Combo and BioLure. Red septa lures baited with pear ester (DA) captured sufficient insects only in the first generation of 2010, obtaining a significantly lower proportion of MFO-resistant adults than Combo and BioLure. In the chemically treated orchards, in 2009 BioLure caught a significantly lower proportion of MFO-resistant adults than Combo during the first and third flight, and also than DA during the first flight. No significant differences were found between the lures or flights in 2010. These results cannot support the idea of a higher attractiveness of the pear ester for MFO-resistant adults in the field but do suggest a high influence of the response to the attractant depending on the management of the orchard, particularly with regard to the use of chemical insecticides. PMID- 26497945 TI - Ultrasensitive Phototransistors Based on Few-Layered HfS2. AB - An ultrathin HfS2 -based ultrasensitive phototransistor is systematically studied. Au-contacted HfS2 phototransistors with ideal thickness ranging from 7 to 12 nm exhibit a high on/off ratio of ca. 10(7) , ultrahigh photoresponsivity over 890 A W(-1) , and photogain over 2300. Moreover, the response time is strongly dependent on the back-gate voltage and shows a reverse trend for Au and Cr metals. PMID- 26497944 TI - Contribution of Piezo2 to endothelium-dependent pain. AB - BACKGROUND: We evaluated the role of a mechanically-gated ion channel, Piezo2, in mechanical stimulation-induced enhancement of hyperalgesia produced by the pronociceptive vasoactive mediator endothelin-1, an innocuous mechanical stimulus induced enhancement of hyperalgesia that is vascular endothelial cell dependent. We also evaluated its role in a preclinical model of a vascular endothelial cell dependent painful peripheral neuropathy. RESULTS: The local administration of oligodeoxynucleotides antisense to Piezo2 mRNA, at the site of nociceptive testing in the rat's hind paw, but not intrathecally at the central terminal of the nociceptor, prevented innocuous stimulus-induced enhancement of hyperalgesia produced by endothelin-1 (100 ng). The mechanical hyperalgesia induced by oxaliplatin (2 mg/kg. i.v.), which was inhibited by impairing endothelial cell function, was similarly attenuated by local injection of the Piezo2 antisense. Polymerase chain reaction analysis demonstrated for the first time the presence of Piezo2 mRNA in endothelial cells. CONCLUSIONS: These results support the hypothesis that Piezo2 is a mechano-transducer in the endothelial cell where it contributes to stimulus-dependent hyperalgesia, and a model of chemotherapy induced painful peripheral neuropathy. PMID- 26497946 TI - Short-term outcomes of single-site robotic cholecystectomy versus four-port laparoscopic cholecystectomy: a prospective, randomized, double-blind trial. AB - BACKGROUND: Randomized studies could not demonstrate significant outcome benefit after single-incision laparoscopic cholecystectomy compared to classic four-port laparoscopic cholecystectomy (CLC). The new robotic single-site platform might offer potential benefits on local inflammation and postoperative pain due to its technological advantages. This prospective randomized double-blind trial compared the short-term outcomes between single-incision robotic cholecystectomy (SIRC) and CLC. METHODS: Two groups of 30 eligible patients were randomized for SIRC or CLC. During the first postoperative week, patients and study monitors were blinded to the type of procedure performed by four dressing tapes applied on the abdomen. Pain was assessed at 6 h and on day 1, 7 and 30 after surgery, along with a 1-10 cosmetic score. RESULTS: No significant difference in postoperative pain occurred in the two groups at any time point nor for any of the abdominal sites. Nineteen (63 %) SIRC patients reported early postoperative pain in extra umbilical sites. Intraoperative complications which might influence postoperative pain, such as minor bleeding and bile spillage, were similar in both groups and no conversions occurred. The cosmetic score 1 month postoperatively was higher for SIRC (p < 0.001). Two SIRC patients had wound infection, one of which developed an incisional hernia. CONCLUSIONS: SIRC does not offer any significant reduction of postoperative pain compared to CLC. SIRC patients unaware of their type of operation still report pain in extra-umbilical sites like after CLC. The cosmetic advantage of SIRC should be balanced against an increased risk of incisional hernias and higher costs. TRIAL REGISTRATION NUMBER: ACTRN12614000119695 ( http://www.anzctr.org.au ). PMID- 26497947 TI - A comparison of the efficacy and safety of endoscopic full-thickness resection and laparoscopic-assisted surgery for small gastrointestinal stromal tumors. AB - BACKGROUND AND AIM: Laparoscopic-assisted surgery (LAC) is an alternative to open surgery for gastrointestinal stromal tumors (GISTs). Endoscopic full-thickness resection (EFTR), a recently developed procedure, is increasingly used to resect GISTs originated from the muscularis propria. In this retrospective study, we aimed to compare EFTR with LAC as minimally invasive treatments for GISTs, especially those with a diameter <2 cm, originating from the muscularis propria. Moreover, we evaluated the clinical efficacy, safety, and feasibility of EFTR for GISTs. METHODS: The study included 68 patients with GISTs originating from the muscularis propria (35 patients who underwent EFTR, and 33 who underwent LAC) who were treated at the Affiliated Hospital of Guangdong Medical University (Zhanjiang, China) between January 2011 and December 2013. The therapeutic outcomes of EFTR and LAC were reviewed retrospectively. RESULTS: In the EFTR group, the mean tumor size was 13 +/- 5 mm, the mean procedure time was 91 +/- 63 min, and the complete resection rate was 100 %. There were 35 "artificial" perforations and four cases of intraoperative bleeding; all complications were successfully managed endoscopically without emergency surgery. In the LAC group, the mean tumor size was 16 +/- 4 mm, the mean operation time was 155 +/- 37 min, and complications included three wound infections and one anastomotic leakage. CONCLUSIONS: EFTR was associated with a lower complication rate than LAC, with favorable en bloc and sufficient tumor tissue for histological diagnosis. EFTR seems to be an efficacious, relatively safe, and minimally invasive treatment for GISTs and could replace LAC surgical resection in cases where the tumor is smaller than 2 cm in diameter. PMID- 26497949 TI - Genetic load, inbreeding depression, and hybrid vigor covary with population size: An empirical evaluation of theoretical predictions. AB - Reduced population size is thought to have strong consequences for evolutionary processes as it enhances the strength of genetic drift. In its interaction with selection, this is predicted to increase the genetic load, reduce inbreeding depression, and increase hybrid vigor, and in turn affect phenotypic evolution. Several of these predictions have been tested, but comprehensive studies controlling for confounding factors are scarce. Here, we show that populations of Daphnia magna, which vary strongly in genetic diversity, also differ in genetic load, inbreeding depression, and hybrid vigor in a way that strongly supports theoretical predictions. Inbreeding depression is positively correlated with genetic diversity (a proxy for Ne ), and genetic load and hybrid vigor are negatively correlated with genetic diversity. These patterns remain significant after accounting for potential confounding factors and indicate that, in small populations, a large proportion of the segregation load is converted into fixed load. Overall, the results suggest that the nature of genetic variation for fitness-related traits differs strongly between large and small populations. This has large consequences for evolutionary processes in natural populations, such as selection on dispersal, breeding systems, ageing, and local adaptation. PMID- 26497950 TI - Radical-Mediated Fluoroalkylations. AB - Recently, the development of eco-friendly radical processes has become of great interest in synthetic chemistry. In particular, visible-light photocatalysis has drawn tremendous attention for its environmental compatibility and versatility in promoting many synthetically important reactions. In addition, inorganic electrides as electron donors have emerged as new eco-friendly tools for radical transformations since they consist of non-toxic and naturally abundant main metals such as calcium. The design of new fluoroalkylation reactions has benefited greatly from recent advances in visible-light photocatalysis and the chemistry of inorganic electrides. Since adding fluoroalkyl groups can dramatically change the physical and chemical properties of organic compounds, using these processes to promote eco-friendly radical fluoroalkylations will have a major impact in areas such as pharmaceuticals, agrochemicals, and material sciences. This Personal Account reviews radical-mediated fluoroalkylations, such as trifluoromethylations and difluoroalkylations, recently developed in our laboratory. PMID- 26497948 TI - Utility of untimed single urine protein/creatinine ratio as a substitute for 24-h proteinuria for assessment of proteinuria in systemic lupus erythematosus. AB - INTRODUCTION: In this study, we determined: (1) the utility of an untimed sample of urine protein/creatinine ratio (PCR) as a screening test for proteinuria, (2) its ability to accurately measure proteinuria, and (3) cutoff values for PCR predicting protein content in a 24-h urine collection sample (24hP) of 0.5, 1.0, and 2.0 g/day. METHODS: Analysis was performed on data from a single lupus cohort (2008-2014). Proteinuria was measured in a 24hP and with PCR. On the basis of 24hP, samples were divided into 4 groups: group 1, <0.5 g/day; group 2, 0.5-0.99 g/day; group 3, 1-1.99 g/day; and group 4, >=2 g/day. To determine the validity of PCR in screening for proteinuria, the Pearson correlation coefficient was determined for the urine samples with normal PCR (<0.05 g/mmol) and normal 24hP (<0.5 g/day). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PCR were calculated. To determine the ability of PCR to accurately measure the level of proteinuria, in addition to the correlation between 24hP and PCR, agreement was determined by intraclass correlation coefficient, concordance correlation coefficient, and Bland-Altman plot between 24hP/24hC and PCR. The best cutoffs for PCR predicting a 24hP of 0.5, 1.0, and 2.0 g/day were determined with the receiver operating characteristic curve. RESULTS: The correlation of the samples with normal PCR as well as 24hP (n = 552) was 0.29 (p < 0.0001). PCR sensitivity and specificity against 24hP were 91 % and 83 %, respectively. The PPV was 82.5 %, and the NPV was 91.4 %. The correlation for all samples (n = 1233) was high, but low to moderate for groups 1, 2, 3, and 4. The agreement for all samples was appropriate but poor for groups 1, 2, 3, and 4. PCR cutoffs for 24hP of 0.5, 1.0, and 2.0 g/day were 0.08, 0.16, and 0.35 g/mmol, respectively. CONCLUSIONS: PCR can be used as a screening test for proteinuria, and the best cutoff value to predict a 24hP of 0.5 g/day is 0.08 g/mmol (800 mg/g). The accurate level of proteinuria should be measured by the gold standard test, 24hP. PMID- 26497951 TI - In-hospital logistics: what are the key aspects for succeeding in each of the steps of the process of controlled donation after circulatory death? AB - Donation after circulatory death (DCD) donors are becoming an increasingly important population of organ donors in Europe and worldwide. We report the state of the art regarding controlled DCD donation describing the organizational and technical aspects of establishing a controlled DCD programme and provide recommendations regarding the introduction and development of this type of programme. PMID- 26497952 TI - Effects of pre-slaughter stressor and feeding preventative Chinese medicinal herbs on glycolysis and oxidative stability in pigs. AB - A total of 64 5-month-old Pietrain pigs were randomly allocated to four treatments with four replicates per treatment according to body weight. The pigs were fed either a standard corn-soybean meal based control diet (treatments 1 and 2), the standard diet with 1% Lycium barbarum (LB) (treatment 3), or the standard diet with 1% Polygala tenuifolia Willd (PT) (treatment 4). Serum lactic acid and glucose concentrations were increased in stressed pigs (P < 0.05). Addition of the herbs in the diet had no effect on the serum lactic acid concentration, but 1% LB decreased (P < 0.05) serum glucose concentration in the stressed pigs. Pre slaughter stress also decreased (P < 0.01) liver glycogen concentration and the decrease could be inhibited by addition of 1% LB in the diet (P > 0.05). Pre slaughter stress increased the concentration of maleic dialdehyde (MDA) (P < 0.05) and decreased glutathione peroxidase (GSH-Px) activity in serum, while dietary 1% LB increased (P < 0.05) the activity of GSH-Px and decreased the concentration of MDA in the serum. In conclusion, pre-slaughter stress induces oxidative stress in pigs and dietary supplementation with 1% LB improves antioxidant capacity in stressed pigs before slaughtering. PMID- 26497953 TI - Anembryonic Gestation in Wild South American Sea Lion, Otaria flavescens. AB - We present the first record and description of an anembryonic gestation in a wild South America sea lion, Otaria flavescens (Carnivora, Pinniped). This is the first report of an anembryonic gestation in a wild marine mammal species. This description furthers the knowledge of general aspects of the reproduction of an otariid species, which presents the particularities of delayed implantation and polygynic breeding system, and adds information on a reproductive abnormality in marine mammals. PMID- 26497954 TI - Assessment of liver fibrosis in rats by MRI with apparent diffusion coefficient and T1 relaxation time in the rotating frame. AB - PURPOSE: To explore the value of T1 relaxation times in the rotating frame (T1 rho or T1 rho) for evaluating liver fibrosis stage, compared to apparent diffusion coefficients (ADCs). MATERIALS AND METHODS: Liver fibrosis in model rats (n = 50) was produced by carbon tetrachloride (CCl4 ) injection. Five rats died during the experiment. Surviving model rats (n = 45) and controls (n = 15) were subjected to 3.0T MRI and the ADCs (b-values: 0, 800 s/mm(2) ) and T1 rho values were determined. Liver fibrosis stage (F0-F4) was defined based on METAVIR scoring. Nonparametric statistical methods and receiver operating characteristic (ROC) curve analyses were employed to determine diagnostic accuracy. RESULTS: Mean ADC and T1 rho associated negatively (r = -0.732 P < 0.001) and positively (r = 0.863 P < 0.001), respectively, with severity of fibrosis stage. Analysis of ROC curves for fibrosis staging showed that the area under the curve (AUC) for T1 rho (stage F0 vs. F1-F4 = 0.976, stage F0-F1 vs. F2-F4 = 0.920, stage F0-F2 vs. F3-F4 = 0.938, and stage F0-F3 vs. F4 = 0.931) was larger than that for ADCs (0.917, 0.924, 0.842, and 0.781, respectively). CONCLUSION: ADC and T1 rho values correlate with liver fibrosis stage. The performance of the T1 rho parameter was superior to that of the ADC parameter in the differentiation of liver fibrosis stages in a CCl4 rat model. PMID- 26497955 TI - [Cryosurgery in dermatology]. AB - This article provides information on the clinical development of skin reactions after cryosurgery/cryotherapy and the indications, complications and contraindications of skin cryosurgery. Successful skin cryosurgery requires rapid freezing and slow thawing, minimum tissue temperature of -25 to -60C and, in malignant lesions, repetition of the freeze-thaw cycle. Frozen tissue reacts with peripheral erythema immediately after thawing, followed by edema, bulla formation, exudation and mumification. Lesions usually heal with a fine atrophic scar after approximately 4 weeks. Nowadays, cryosurgery is considered the treatment of choice in hypertrophic scars and keloids, granuloma annulare, small capillary infantile hemangioma and isolated actinic keratoses. It is also a valuable alternative therapy for various other skin diseases, including common warts, solar lentigo, superficial basal cell carcinoma and Kaposi's sarcoma. Cryosurgery is a safe regimen with relatively few adverse effects and contraindications. Pain during and/or shortly after treatment, bulla formation and local edema are the major temporary adverse effects; lesional hypopigmentation and/or peripheral hyperpigmentation is the most common long-term complication. PMID- 26497956 TI - Demethylation of HIN-1 reverses paclitaxel-resistance of ovarian clear cell carcinoma through the AKT-mTOR signaling pathway. AB - BACKGROUND: Methylation of HIN-1 is associated with poor outcomes in patients with ovarian clear cell carcinoma (OCCC), which is regarded to be an aggressive, chemo-resistant histological subtype. This study aimed to evaluate whether 5-aza 2-deoxycytidine (5-aza-2-dC) can reverse methylation of the HIN-1 gene to restore chemo-sensitivity of OCCC and the possible mechanism. METHODS: In vitro flow cytometric analysis and evaluation of caspase-3/7 activity of paclitaxel sensitive and resistant OCCC cell lines were performed. Methylation status and expression changes of HIN-1 in the OCCC cell lines treated with 5-aza-2-dC were evaluated, and immunohistochemical staining of HIN-1 in OCCC tissues was performed. In vivo tumor growth with or without 5-aza-2-dC treatment was analyzed, and Western blotting of AKT-mTOR signaling-related molecules was performed. RESULTS: G2-M phase arrest was absent in paclitaxel-resistant OCCC cells after treatment with the cytotoxic drug. The caspase activities of the chemo-resistant OCCC cells were lower than those of the chemo-sensitive OCCC cells when treated with paclitaxel. Methylation of HIN-1 was noted in paclitaxel resistant OCCC cell lines and cancerous tissues. 5-aza-2-dC reversed the methylation of HIN-1, re-activated the expression of HIN-1, and then suppressed the in vivo tumor growth of paclitaxel-resistant OCCC cells. Immunoblotting revealed that phospho-AKT473 and phospho-mTOR were significantly increased in HIN 1-methylated paclitaxel-resistant OCCC cell lines. However, the expressions of phospho-AKT at Ser473 and Thr308 and phospho-mTOR decreased in the OCCC cells with a high expression of HIN-1. CONCLUSIONS: Demethylating agents can restore the HIN-1 expression in paclitaxel-resistant OCCC cells through the HIN-1-AKT mTOR signaling pathway to inhibit tumor growth. PMID- 26497957 TI - Lifestyle factors associated with histologically derived human ovarian non growing follicle count in reproductive age women. AB - STUDY QUESTION: Are lifestyle factors (smoking, BMI, alcohol use and oral contraceptive pill use) associated with the human ovarian reserve as determined by the total ovarian non-growing follicle number? SUMMARY ANSWER: Light to moderate alcohol use was significantly associated with greater ovarian non growing follicle (NGF) count, whereas other lifestyle factors were not significantly related. WHAT IS KNOWN ALREADY: A single previous investigation has suggested that smoking and alcohol use are associated with lower ovarian follicle density. However, this investigation utilized follicle density as the outcome of interest rather than the estimated total ovarian NGF count. STUDY DESIGN, SIZE, DURATION: This cross-sectional investigation included a convenience sample of premenopausal women from two different academic sites, the University of Washington (n = 37, from 1999-2004) and the University of Oklahoma (n = 73, from 2004-2013), undergoing incidental oophorectomy at the time of hysterectomy (total n = 110, age range 21-52 years). PARTICIPANTS/MATERIALS, SETTING, METHODS: Prior to undergoing oophorectomy, participants completed detailed questionnaires regarding lifestyle exposures. Following surgery, total ovarian NGF counts were determined with systematic random sampling rules and a validated fractionator/optical dissector technique. Associations between lifestyle factors and log-transformed ovarian follicle counts were determined using multivariable linear regression. MAIN RESULTS AND THE ROLE OF CHANCE: After controlling for age, BMI, oral contraceptive pill (OCP) use, tobacco use and site of collection, cumulative alcohol use (measured in alcoholic drinks per day multiplied by years of drinking) was associated with ovarian NGF count. Women reporting light (>0 to <1 drink-years) and moderate (1-3 drink-years) alcohol use had greater NGF counts (beta = 0.75, P = 0.04, and beta = 1.00, P = 0.03; light and moderate use, respectively) as compared with non-users. Neither heavier alcohol use (>3 drink years), BMI, OCP use, nor tobacco use were significantly associated with the ovarian NGF count. Similar patterns of association with moderate cumulative alcohol use were observed when evaluating associations with pre-antral follicles and total follicle counts. LIMITATIONS, REASONS FOR CAUTION: All participants in this convenience sample had a benign indication for hysterectomy, and therefore may not be broadly representative of the population without such an indication. Additionally, lifestyle factors were self-reported, and the sample size of the present investigation limits our ability to detect associations of smaller magnitude. WIDER IMPLICATIONS OF THE FINDINGS: While our findings are in disagreement with a single investigation that utilized human follicle density as the outcome of interest, they are consistent with many studies investigating the relationship between lifestyle factors and the age of spontaneous menopause. Furthermore, they suggest a mechanism that does not involve accelerated follicular atresia to explain the association between smoking and an earlier age of menopause. STUDY FUNDING/COMPETING INTERESTS: This investigation was funded by NIA R29-HD37360-04 (N.A.K.) and OCAST HR04-115 (K.R.H.) and by the National Institute of General Medical Sciences, Grant 1 U54GM104938 (J.D.P.). There is no conflict of interest. PMID- 26497958 TI - Chromosomal integration vectors allowing flexible expression of foreign genes in Campylobacter jejuni. AB - BACKGROUND: Campylobacter jejuni is a major cause of human gastroenteritis yet there is limited knowledge of how disease is caused. Molecular genetic approaches are vital for research into the virulence mechanisms of this important pathogen. Vectors that allow expression of genes in C. jejuni via recombination onto the chromosome are particularly useful for genetic complementation of insertional knockout mutants and more generally for expression of genes in particular C. jejuni host backgrounds. METHODS: A series of three vectors that allow integration of genes onto the C. jejuni chromosome were constructed by standard cloning techniques with expression driven from three different strong promoters. Following integration onto the C. jejuni chromosome expression levels were quantified by fluorescence measurements and cells visualized by fluorescence microscopy. RESULTS: We have created plasmid, pCJC1, designed for recombination mediated delivery of genes onto the C. jejuni chromosome. This plasmid contains a chloramphenicol resistance cassette (cat) with upstream and downstream restriction sites, flanked by regions of the C. jejuni pseudogene Cj0223. Cloning of genes immediately upstream or downstream of the cat gene allows their subsequent introduction onto the C. jejuni chromosome within the pseudogene. Gene expression can be driven from the native gene promoter if included, or alternatively from the cat promoter if the gene is cloned downstream of, and in the same transcriptional orientation as cat. To provide increased and variable expression of genes from the C. jejuni chromosome we modified pCJC1 through incorporation of three relatively strong promoters from the porA, ureI and flaA genes of C. jejuni, Helicobacter pylori and Helicobacter pullorum respectively. These promoters along with their associated ribosome binding sites were cloned upstream of the cat gene on pCJC1 to create plasmids pCJC2, pCJC3 and pCJC4. To test their effectiveness, a green fluorescent protein (gfp) reporter gene was inserted downstream of each of the three promoters and following integration of promoter-gene fusions onto the C. jejuni host chromosome, expression levels were quantified. Expression from the porA promoter produced the highest fluorescence, from flaA intermediate levels and from ureI the lowest. Expression of gfp from the porA promoter enabled visualization by fluorescent microscopy of intracellular C. jejuni cells following invasion of HeLa cells. CONCLUSIONS: The plasmids constructed allow stable chromosomal expression of genes in C. jejuni and, depending on the promoter used, different expression levels were obtained making these plasmids useful tools for genetic complementation and high level expression. PMID- 26497959 TI - Endothelial cell activation by hemodynamic shear stress derived from arteriovenous fistula for hemodialysis access. AB - Intimal hyperplasia (IH) is the first cause of failure of an arteriovenous fistula (AVF). The aim of the present study was to investigate the effects on endothelial cells (ECs) of shear stress waveforms derived from AVF areas prone to develop IH. We used a cone-and-plate device to obtain real-time control of shear stress acting on EC cultures. We exposed human umbilical vein ECs for 48 h to different shear stimulations calculated in a side-to-end AVF model. Pulsatile unidirectional flow, representative of low-risk stenosis areas, induced alignment of ECs and actin fiber orientation with flow. Shear stress patterns of reciprocating flow, derived from high-risk stenosis areas, did not affect EC shape or cytoskeleton organization, which remained similar to static cultures. We also evaluated flow-induced EC expression of genes known to be involved in cytoskeletal remodeling and expression of cell adhesion molecules. Unidirectional flow induced a significant increase in Kruppel-like factor 2 mRNA expression, whereas it significantly reduced phospholipase D1, alpha4-integrin, and Ras p21 protein activator 1 mRNA expression. Reciprocating flow did not increase Kruppel like factor 2 mRNA expression compared with static controls but significantly increased mRNA expression of phospholipase D1, alpha4-integrin, and Ras p21 protein activator 1. Reciprocating flow selectively increased monocyte chemoattractant protein-1 and IL-8 production. Furthermore, culture medium conditioned by ECs exposed to reciprocating flows selectively increased smooth muscle cell proliferation compared with unidirectional flow. Our results indicate that protective vascular effects induced in ECs by unidirectional pulsatile flow are not induced by reciprocating shear forces, suggesting a mechanism by which oscillating flow conditions may induce the development of IH in AVF and vascular access dysfunction. PMID- 26497960 TI - At high cardiac output, diesel exhaust exposure increases pulmonary vascular resistance and decreases distensibility of pulmonary resistive vessels. AB - Air pollution has recently been associated with the development of acute decompensated heart failure, but the underlying biological mechanisms remain unclear. A pulmonary vasoconstrictor effect of air pollution, combined with its systemic effects, may precipitate decompensated heart failure. The aim of the present study was to investigate the effects of acute exposure to diesel exhaust (DE) on pulmonary vascular resistance (PVR) under resting and stress conditions but also to determine whether air pollution may potentiate acquired pulmonary hypertension. Eighteen healthy male volunteers were exposed to ambient air (AA) or dilute DE with a particulate matter of <2.5 MUm concentration of 300 MUg/m(3) for 2 h in a randomized, crossover study design. The effects of DE on PVR, on the coefficient of distensibilty of pulmonary vessels (alpha), and on right and left ventricular function were evaluated at rest (n = 18), during dobutamine stress echocardiography (n = 10), and during exercise stress echocardiography performed in hypoxia (n = 8). Serum endothelin-1 and fractional exhaled nitric oxide were also measured. At rest, exposure to DE did not affect PVR. During dobutamine stress, the slope of the mean pulmonary artery pressure-cardiac output relationship increased from 2.8 +/- 0.5 mmHg . min . l (-1) in AA to 3.9 +/- 0.5 mmHg . min . l (-1) in DE (P < 0.05) and the alpha coefficient decreased from 0.96 +/- 0.15 to 0.64 +/- 0.12%/mmHg (P < 0.01). DE did not further enhance the hypoxia-related upper shift of the mean pulmonary artery pressure-cardiac output relationship. Exposure to DE did not affect serum endothelin-1 concentration or fractional exhaled nitric oxide. In conclusion, acute exposure to DE increased pulmonary vasomotor tone by decreasing the distensibility of pulmonary resistive vessels at high cardiac output. PMID- 26497961 TI - Circadian variation of variability and irregularity of heart rate in patients with permanent atrial fibrillation: relation to symptoms and rate control drugs. AB - The aim of the present study was to evaluate diurnal variations of the variability and irregularity of heart rate (HR) in patients with permanent atrial fibrillation (AF) with and without rate control drugs. Thirty-eight patients with permanent AF were part of an investigator-blind crossover study comparing diltiazem, verapamil, metoprolol, and carvedilol. We analyzed five Holter recordings per patient: at baseline (no rate control drug) and with each of the four drug regimens. HR, variability (SD; percentages of interval differences of successive RR intervals of >20, 50, and 80 ms; and root of the mean squared differences of successive RR intervals), and irregularity (approximate and sample entropy) parameters were computed in 20-min long nonoverlapping segments. Circadian rhythmicity was evaluated using cosinor analysis to each parameter series, which is characterized by the 24-h mean [midline statistic of rhythm (MESOR)] and excursion over the mean (amplitude). Arrhythmia-related symptoms were assessed by a questionnaire measuring symptom severity and frequency. HR and variability parameters showed a significant circadian variation in most patients, whereas only a small minority of the patients had circadian variations of irregularity parameters. Patients with circadian approximate entropy n at baseline had more severe symptoms (symptom severity: 9 +/- 4 vs. 6 +/- 5, P < 0.05, circadian vs. noncircadian variations). All drugs decreased the MESOR of HR and increased the MESOR of variability parameters. Only carvedilol and metoprolol decreased the normalized amplitude over 24 h of all parameters and HR. In conclusion, HR and RR variability parameters present a circadian variation in patients with permanent AF, whereas few patients demonstrated circadian fluctuations in irregularity parameters, suggesting different physiological mechanisms. PMID- 26497962 TI - Cardiac and mitochondrial dysfunction following acute pulmonary exposure to mountaintop removal mining particulate matter. AB - Throughout the United States, air pollution correlates with adverse health outcomes, and cardiovascular disease incidence is commonly increased following environmental exposure. In areas surrounding active mountaintop removal mines (MTM), a further increase in cardiovascular morbidity is observed and may be attributed in part to particulate matter (PM) released from the mine. The mitochondrion has been shown to be central in the etiology of many cardiovascular diseases, yet its roles in PM-related cardiovascular effects are not realized. In this study, we sought to elucidate the cardiac processes that are disrupted following exposure to mountaintop removal mining particulate matter (PM MTM). To address this question, we exposed male Sprague-Dawley rats to PM MTM, collected within one mile of an active MTM site, using intratracheal instillation. Twenty four hours following exposure, we evaluated cardiac function, apoptotic indices, and mitochondrial function. PM MTM exposure elicited a significant decrease in ejection fraction and fractional shortening compared with controls. Investigation into the cellular impacts of PM MTM exposure identified a significant increase in mitochondrial-induced apoptotic signaling, as reflected by an increase in TUNEL positive nuclei and increased caspase-3 and -9 activities. Finally, a significant increase in mitochondrial transition pore opening leading to decreased mitochondrial function was identified following exposure. In conclusion, our data suggest that pulmonary exposure to PM MTM increases cardiac mitochondrial associated apoptotic signaling and decreases mitochondrial function concomitant with decreased cardiac function. These results suggest that increased cardiovascular disease incidence in populations surrounding MTM mines may be associated with increased cardiac cell apoptotic signaling and decreased mitochondrial function. PMID- 26497963 TI - The coiled-coil domain of MURC/cavin-4 is involved in membrane trafficking of caveolin-3 in cardiomyocytes. AB - Muscle-restricted coiled-coil protein (MURC), also referred to as cavin-4, is a member of the cavin family that works cooperatively with caveolins in caveola formation and function. Cavins are cytoplasmic proteins with coiled-coil domains and form heteromeric complexes, which are recruited to caveolae in cells expressing caveolins. Among caveolins, caveolin-3 (Cav3) is exclusively expressed in muscle cells, similar to MURC/cavin-4. In the heart, Cav3 overexpression contributes to cardiac protection, and its deficiency leads to progressive cardiomyopathy. Mutations in the MURC/cavin-4 gene have been identified in patients with dilated cardiomyopathy. In the present study, we show the role of MURC/cavin-4 as a caveolar component in the heart. In H9c2 cells, MURC/cavin-4 was localized at the plasma membrane, whereas a MURC/cavin-4 mutant lacking the coiled-coil domain (DeltaCC) was primarily localized to the cytoplasm. DeltaCC bound to Cav3 and impaired membrane localization of Cav3 in cardiomyocytes. Additionally, although DeltaCC did not alter Cav3 mRNA expression, DeltaCC decreased the Cav3 protein level. MURC/cavin-4 and DeltaCC similarly induced cardiomyocyte hypertrophy; however, DeltaCC showed higher hypertrophy-related fetal gene expression than MURC/cavin-4. DeltaCC induced ERK activation in cardiomyocytes. Transgenic mice expressing DeltaCC in the heart (DeltaCC-Tg mice) showed impaired cardiac function accompanied by cardiomyocyte hypertrophy and marked interstitial fibrosis. Hearts from DeltaCC-Tg mice showed a reduction of the Cav3 protein level and activation of ERK. These results suggest that MURC/cavin-4 requires its coiled-coil domain to target the plasma membrane and to stabilize Cav3 at the plasma membrane of cardiomyocytes and that MURC/cavin-4 functions as a crucial caveolar component to regulate cardiac function. PMID- 26497964 TI - 2-Deoxyadenosine triphosphate restores the contractile function of cardiac myofibril from adult dogs with naturally occurring dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is a major type of heart failure resulting from loss of systolic function. Naturally occurring canine DCM is a widely accepted experimental paradigm for studying human DCM. 2-Deoxyadenosine triphosphate (dATP) can be used by myosin and is a superior energy substrate over ATP for cross-bridge formation and increased systolic function. The objective of this study was to evaluate the beneficial effect of dATP on contractile function of cardiac myofibrils from dogs with naturally occurring DCM. We measured actomyosin NTPase activity and contraction/relaxation properties of isolated myofibrils from nonfailing (NF) and DCM canine hearts. NTPase assays indicated replacement of ATP with dATP significantly increased myofilament activity in both NF and DCM samples. dATP significantly improved maximal tension of DCM myofibrils to the NF sample level. dATP also restored Ca(2+) sensitivity of tension that was reduced in DCM samples. Similarly, dATP increased the kinetics of contractile activation (kACT), with no impact on the rate of cross-bridge tension redevelopment (kTR). Thus, the activation kinetics (kACT/kTR) that were reduced in DCM samples were restored for dATP to NF sample levels. dATP had little effect on relaxation. The rate of early slow-phase relaxation was slightly reduced with dATP, but its duration was not, nor was the fast-phase relaxation or times to 50 and 90% relaxation. Our findings suggest that myosin utilization of dATP improves cardiac myofibril contractile properties of naturally occurring DCM canine samples, restoring them to NF levels, without compromising relaxation. This suggests elevation of cardiac dATP is a promising approach for the treatment of DCM. PMID- 26497965 TI - Determinants of kinetic energy of blood flow in the four-chambered heart in athletes and sedentary controls. AB - The kinetic energy (KE) of intracardiac blood may play an important role in cardiac function. The aims of the present study were to 1) quantify and investigate the determinants of KE, 2) compare the KE expenditure of intracardiac blood between athletes and control subjects, and 3) quantify the amount of KE inside and outside the diastolic vortex. Fourteen athletes and fourteen volunteers underwent cardiac MRI, including four-dimensional phase-contrast sequences. KE was quantified in four chambers, and energy expenditure was calculated by determining the mean KE/cardiac index. Left ventricular (LV) mass was an independent predictor of diastolic LVKE (R(2) = 0.66, P < 0.001), whereas right ventricular (RV) end-diastolic volume was important for diastolic RVKE (R(2) = 0.76, P < 0.001). The mean KE/cardiac index did not differ between groups (control subjects: 0.53 +/- 0.14 mJ.l(-1).min.m(2) and athletes: 0.56 +/- 0.21 mJ.l(-1).min.m(2), P = 0.98). Mean LV diastolic vortex KE made up 70 +/- 1% and 73 +/- 2% of total LV diastolic KE in athletes and control subjects (P = 0.18). In conclusion, the characteristics of the LV as a pressure pump and the RV as a volume pump are demonstrated as an association between LVKE and LV mass and between RVKE and end-diastolic volume. This also suggests different filling mechanisms where the LV is dependent on diastolic suction, whereas the RV fills with a basal movement of the atrioventricular plane over "stationary" blood. Both groups had similar energy expenditure for intracardiac blood flow, indicating similar pumping efficiency, likely explained by the lower heart rate that cancels the higher KE per heart beat in athletes. The majority of LVKE is found within the LV diastolic vortex, in contrast to earlier findings. PMID- 26497966 TI - Consumer response to media information: the case of grapefruit-medicine interaction. AB - This study measured the effect of media exposure on grapefruit/grapefruit juice consumption changes, in particular grapefruit-medicine interaction. Respondents' attitudes about health news on television and the internet were measured to account for consumers exposed versus not exposed to such information. Results of a sample selection model show that consumer attitudes toward health news were significantly related to exposure to media information. Also, news exposure about grapefruit-medicine interaction has a tendency to result in reduced grapefruit consumption. Consumers who are directly affected by the medication interaction significantly react to the news, and the effect varies by age. Even though consumer's age was positively related to the probability of increased grapefruit consumption, when consumers took the medication, consumer's age was negatively related to the probability of increased grapefruit consumption. PMID- 26497967 TI - Benefits and risks of antihypertensive medications in the elderly. AB - Hypertension is highly prevalent in older age and accounts for a large proportion of cardiovascular (CV) morbidity and mortality worldwide. Isolated systolic hypertension is more common in the elderly than younger adults and associated with poor outcomes such as cerebrovascular disease and acute coronary events. International guidelines are inconsistent in providing recommendations on optimal blood pressure targets in hypertensive elderly patients as a result of the limited evidence in this population. Evidence from clinical trials supports the use of antihypertensive drugs in hypertensive elderly patients due to benefits in reducing CV disease and mortality. However, elderly participants in these trials may not be typical of elderly patients seen in routine clinical practice, and the potential risks associated with use of antihypertensive drugs in the elderly are not as well studied as younger participants. Therefore, the purpose of this review was to provide a comprehensive summary of the benefits and risks of the use of antihypertensive drugs in elderly patients (aged >=65 years), highlighting landmark clinical trials and observational studies. We will focus on specific outcomes relating to the benefits and risks of these medications in hypertensive elderly patients, such as CV disease, cognitive decline, dementia, orthostatic hypotension, falls, fractures, cancer and diabetes, in order to provide an update of the most relevant and current evidence to help inform clinical decision making. PMID- 26497968 TI - Wnt signaling and astrocytic brain tumors. PMID- 26497970 TI - Teaching to Teach: A Personality Disorders Curriculum. PMID- 26497969 TI - The prognostic impact of squamous and glandular differentiation for upper tract urothelial carcinoma patients after radical nephroureterectomy. AB - PURPOSE: To evaluate the association between tumor squamous and/or glandular differentiation and tumor biological characteristics and to validate the impact of these histologic variants on oncologic outcomes of UTUC patients. METHODS: We retrospectively analyzed the data of 687 UTUC patients who underwent radical nephroureterectomy in our institute, from Aug 1, 1999, to Dec 31, 2011. All pathologic sections were reevaluated for histologic differentiation variations (squamous and glandular). The clinicopathological variables of patients were reviewed. RESULTS: Among the 687 UTUC patients in our study, 53 (7.7 %) had squamous differentiation, 20 (2.9 %) had glandular differentiation and 8 (1.2 %) had both histologic variants. Patients with mixed histologic variant tended to have significant larger percentage of sessile tumor architecture (58.0 vs 18.2 %), presence of CIS (7.4 vs 2.3 %), advanced T stage, advanced tumor grade and lymph node metastasis (17.3 vs 6.6 %; all p < 0.05). Patients with squamous and/or glandular differentiation had significant worse cancer-specific survival than pure UTUC patients (p < 0.001), while significant difference of recurrence free survival between two groups was not observed (p = 0.126). Patients with both squamous and glandular differentiation did not show significantly worse CSS than those with single histologic variant. Univariate analyses revealed that tumor squamous and/or glandular differentiation was a significant factor on survival (p < 0.001). However, the influence did not remain significant after adjusted for other factors in the multivariate analyses (p = 0.076, HR 1.42). CONCLUSIONS: UTUC patients with squamous and/or glandular differentiation are more likely to have aggressive tumor biological features and tend to have worse postoperative outcomes. PMID- 26497971 TI - Mental Health Research in the Global Era: Training the Next Generation. PMID- 26497972 TI - Ketamine suppresses hypoxia-induced inflammatory responses in the late-gestation ovine fetal kidney cortex. AB - Acute fetal hypoxia is a form of fetal stress that stimulates renal vasoconstriction and ischaemia as a consequence of the physiological redistribution of combined ventricular output. Because of the potential ischaemia reperfusion injury to the kidney, we hypothesized that it would respond to hypoxia with an increase in the expression of inflammatory genes, and that ketamine (an N-methyl-D-aspartate receptor antagonist) would reduce or block this response. Hypoxia was induced for 30 min in chronically catheterized fetal sheep (125 +/- 3 days), with or without ketamine (3 mg kg(-1)) administered intravenously to the fetus 10 min prior to hypoxia. Gene expression in fetal kidney cortex collected 24 h after the onset of hypoxia was analysed using ovine Agilent 15.5k array and validated with qPCR and immunohistochemistry in four groups of ewes: normoxic control, normoxia + ketamine, hypoxic control and hypoxia + ketamine (n = 3-4 per group). Significant differences in gene expression between groups were determined with t-statistics using the limma package for R (P <= 0.05). Enriched biological processes for the 427 upregulated genes were immune and inflammatory responses and for the 946 downregulated genes were metabolic processes. Ketamine countered the effects of hypoxia on upregulated immune/inflammatory responses as well as the downregulated metabolic responses. We conclude that our transcriptomics modelling predicts that hypoxia activates inflammatory pathways and reduces metabolism in the fetal kidney cortex, and ketamine blocks or ameliorates this response. The results suggest that ketamine may have therapeutic potential for protection from ischaemic renal damage. PMID- 26497974 TI - Dual-phase steel structure visualized by extremely slow electrons. AB - Mechanical properties of complex steels are affected by their multi-phase structure. Scanning electron microscopy (SEM) is routinely used for characterizing dual-phase (DP) steels, although the identification of steel constituents is not straightforward. In fact, there are several ways of enabling the ferrite-martensite segmentation by SEM, and a wide range of electron energies can be utilized. This study demonstrates the phase identification of DP steels at high, low and extremely low landing energies of the primary electrons from tens of keV to tens of eV. Visualization of the specimen surface at very low landing energies has been achieved by inserting an earthed detector between the pole piece and the negatively biased specimen. This 'cathode lens mode' enables the use of the full energy range up to the primary electron energies. It has been found that extremely slow electrons (<100 eV) are exceptionally suitable for separation of the martensite from the ferrite matrix due to high surface sensitivity, enabling visualization of very fine features. Moreover, the channelling contrast is significantly suppressed at the landing energy of tens of eV of the primary electrons, which enables separation of the phases clearly even in the images acquired at low magnification. The contrast between the phases at tens of eV can be explained by the different thickness of native oxide covering the martensite and the ferrite phase. PMID- 26497973 TI - Assessing the Genetic Predisposition of Education on Myopia: A Mendelian Randomization Study. AB - Myopia is the largest cause of uncorrected visual impairments globally and its recent dramatic increase in the population has made it a major public health problem. In observational studies, educational attainment has been consistently reported to be correlated to myopia. Nonetheless, correlation does not imply causation. Observational studies do not tell us if education causes myopia or if instead there are confounding factors underlying the association. In this work, we use a two-step least squares instrumental-variable (IV) approach to estimate the causal effect of education on refractive error, specifically myopia. We used the results from the educational attainment GWAS from the Social Science Genetic Association Consortium to define a polygenic risk score (PGRS) in three cohorts of late middle age and elderly Caucasian individuals (N = 5,649). In a meta analysis of the three cohorts, using the PGRS as an IV, we estimated that each z score increase in education (approximately 2 years of education) results in a reduction of 0.92 +/- 0.29 diopters (P = 1.04 * 10(-3) ). Our estimate of the effect of education on myopia was higher (P = 0.01) than the observed estimate (0.25 +/- 0.03 diopters reduction per education z-score [~2 years] increase). This suggests that observational studies may actually underestimate the true effect. Our Mendelian Randomization (MR) analysis provides new evidence for a causal role of educational attainment on refractive error. PMID- 26497975 TI - Electrostatic Self-Assembly of Soft Matter Nanoparticle Cocrystals with Tunable Lattice Parameters. AB - Atomic crystal structure affects the electromagnetic and thermal properties of common matter. Similarly, the nanoscale structure controls the properties of higher length-scale metamaterials, for example, nanoparticle superlattices and photonic crystals. Electrostatic self-assembly of oppositely charged nanoparticles has recently become a convenient way to produce crystalline nanostructures. However, understanding and controlling the assembly of soft nonmetallic particle crystals with long-range translational order remains a major challenge. Here, we show the electrostatic self-assembly of binary soft particle cocrystals, consisting of apoferritin protein cages and poly(amidoamine) dendrimers (PAMAM), with very large crystal domain sizes. A systematic series of PAMAM dendrimers with generations from two to seven were used to produce the crystals, which showed a dendrimer generation dependency on the crystal structure and lattice constant. The systematic approach presented here offers a transition from trial-and-error experiments to a fundamental understanding and control over the nanostructure. The structure and stability of soft particle cocrystals are of major relevance for applications where a high degree of structural control is required, for example, protein-based mesoporous materials, nanoscale multicompartments, and metamaterials. PMID- 26497976 TI - Massive pulmonary embolism leading to cardiac arrest: one pathology, two different ECMO modes to assist patients. AB - Massive acute pulmonary embolism (MAPE) represents a significant risk for morbidity and mortality. The potential for sudden and fatal deterioration highlights the need for a prompt diagnosis and appropriate intervention. Using two cases reports, we describe two different modes of successful ECMO implantation (VA-ECMO vs. VV-ECMO) for MAPE leading to cardiac arrest. A 27-year old patient with a severe trauma presented with a MAPE leading to cardiac arrest. In this case, which had absolute contraindications of thrombolysis, a VA-ECMO was successfully implanted. Additionally, a 56-year-old patient presented with a MAPE leading to cardiac arrest. Although intravenous thrombolysis allowed for hemodynamic stabilization, the patient remained severely hypoxemic with RV dilation. A VV-ECMO was successfully implemented, leading to a rapid improvement in both oxygenation and RV function. ECMO can provide lifesaving hemodynamic and respiratory support in critically ill patients with a MAPE who are too unstable to tolerate other interventions or have failed other therapies. An important determinant of success in the use of ECMO for MAPE is the return of adequate RV function, which allows physicians to appropriately identify which type of ECMO to implant. PMID- 26497977 TI - A review of environmental risk factors for myopia during early life, childhood and adolescence. AB - Myopia is a significant public health problem worldwide, particularly in East Asian countries. The increasing prevalence of myopia poses a huge socio-economic burden and progressive high myopia can lead to sight-threatening ocular complications. Hence, the prevention of early-onset myopia progressing to pathological high myopia is important. Recent epidemiological studies suggest that increased outdoor time is an important modifiable environmental factor that protects young children from myopia. This protective effect may be due to high light intensity outdoors, the chromaticity of daylight or increased vitamin D levels. This review summarises the possible underlying biological mechanisms for the protective association between time outdoors and myopia, including the potential role of nicotinic acetylcholine receptors in refractive error development. Recent evidence for the role of other environmental risk factors such as near work, birth seasons, parental smoking and birth order are also summarised. PMID- 26497978 TI - Modulation of fatty acid metabolism is involved in the alleviation of isoproterenol-induced rat heart failure by fenofibrate. AB - Heart failure is a disease predominantly caused by an energy metabolic disorder in cardiomyocytes. The present study investigated the inhibitory effects of fenofibrate (FF) on isoproterenol (ISO)-induced hear failure in rats, and examined the underlying mechanisms. The rats were divided into CON, ISO (HF model), FF and FF+ISO (HF animals pretreated with FF) groups. The cardiac structure and function of the rats were assessed, and contents of free fatty acids and glucose metabolic products were determined. In addition, myocardial cells were isolated from neonatal rats and used in vitro to investigate the mechanisms by which FF relieves heart failure. Western blot analysis was performed to quantify the expression levels of peroxisome proliferator-activated receptor (PPAR)alpha and uncoupling protein 2 (UCP2). FF effectively alleviated the ISO-induced cardiac structural damage, functional decline, and fatty acid and carbohydrate metabolic abnormalities. Compared with the ISO group, the serum levels of brain natriuretic peptide (BNP), free fatty acids, lactic acid and pyruvic acid were decreased in the FF animals. In the cultured myocardial cells, lactic acid and pyruvic acid contents were lower in the supernatants obtained from the FF animals, with lower levels of mitochondrial ROS production and cell necrosis, compared with the ISO group, whereas PPARalpha upregulation and UCP2 downregulation occurred in the FF+ISO group. The results demonstrated that FF efficiently alleviated heart failure in the ISO-induced rat model, possibly via promoting fatty acid oxidation. PMID- 26497979 TI - Micro-phase separation in two dimensional suspensions of self-propelled spheres and dumbbells. AB - We use numerical simulations to study the phase behavior of self-propelled spherical and dumbbellar particles interacting via micro-phase separation inducing potentials. Our results indicate that under the appropriate conditions, it is possible to drive the formation of two new active states; a spinning cluster crystal, i.e. an ordered mesoscopic phase having finite size spinning crystallites as lattice sites, and a fluid of living clusters, i.e. a two dimensional fluid where each "particle" is a finite size living cluster. We discuss the dynamics of these phases and suggest ways of extending their stability under a wide range of active forces. PMID- 26497980 TI - Cetuximab-resistant oral squamous cell carcinoma cells become sensitive in anchorage-independent culture conditions through the activation of the EGFR/AKT pathway. AB - We have previously shown that growth of the oral squamous cell carcinoma cell line SAS, is resistant to cetuximab in monolayer culture conditions, even though epidermal growth factor receptor (EGFR) was phosphorylated, but the growth of SAS aggregates was sensitive to cetuximab. In the present study, we demonstrate differences in the EGFR signaling pathways utilized by SAS cells in monolayer and suspension cultures at the molecular level. Cetuximab treatment of SAS cells in monolayer cultures inhibits the phosphorylation of EGFR and ERK, and reduces the cell migratory potency, but not cell proliferation. AG1478 treatment reduces the phosphorylation of EGFR, ERK and AKT, and affects cell growth in monolayer cultures. The phosphorylation levels of EGFR and AKT are significantly higher in SAS cell aggregates compared to monolayer cultures. Treatment with cetuximab and AG1478 reduces the growth of SAS aggregates and eliminates the phosphorylation of EGFR and AKT. Furthermore, proliferation of SAS aggregates is also inhibited by LY294002 and MK2206, which are inhibitors of PI3K and AKT, respectively. In addition, treatment with the lipid raft disruptor filipin III reduced the phosphorylation levels of EGFR and Akt in SAS aggregates, but not in SAS monolayer culture. These results suggest the possibility that ligands in the serum stimulate the phosphorylation of EGFR localized in lipid rafts leading to PI3K-AKT activation, which results in the growth of SAS aggregates, therefore resulting in the sensitivity of SAS aggregates to cetuximab. PMID- 26497981 TI - Arthroscopic tenodesis versus tenotomy of the long head of biceps tendon in simultaneous rotator cuff repair. AB - INTRODUCTION: Full thickness rotator cuff tears are a common cause of shoulder pain and disability. While the role of the rotator cuff seems to be well known, the clinical significance of the biceps tendon for shoulder function has still been a subject of controversy. The aim of this study was to evaluate differences between tenodesis or tenotomy in simultaneous rotator cuff repair. METHODS: For this retrospective study 53 consecutive patients (25f/28m, O age 58 years) undergoing arthroscopic double row rotator cuff reconstruction and suture bridge repair were included. The LHB was treated with tenodesis (n = 24) or tenotomy (n = 29). Clinical examination was carried out for all patients after an average of 34 months (range 27-38) following arthroscopic surgery. The Constant score, level of pain, range of motion in flexion and abduction, and isometric force for the operated and healthy shoulder in flexion and abduction were recorded. RESULTS: Patients in the tenodesis and tenotomy group reached similar good result regarding the Constant score (86.6 +/- 11.9 vs. 81.3 +/- 12.2; P = 0.120), pain (median 0, range 0-8 vs. Median 0, range 0-10; P = 0.421), and range of motion (flexion: median 180 degrees , range 90 degrees -180 degrees vs. median 180 degrees , range 90 degrees -180 degrees ; P = 0.833; abduction: median 180 degrees , range 90 degrees -180 degrees vs. median 180 degrees , range 120 degrees -180 degrees ; P = 0.472). Postoperative popeye sign was found only in one patient (1.9 %). At the time of postoperative follow-up, no patient reported cramping of the biceps. Isometric forces in abduction of the tenotomy group (mean 4.7 +/- 2.9 kg; maximum 5.5 +/- 2.8 kg) was significant lower compared to the tenodesis group (mean 6.6 +/- 3.0 kg, P = 0.019; maximum 7.7 +/- 2.9 kg, P = 0.007) and compared to healthy shoulders (mean 6.1 +/- 3.0 kg P = 0.004; maximum 7.4 +/- 3.1 kg, P = 0.001), all other measurements were similar. CONCLUSION: According to our results arthroscopic biceps tenodesis and tenotomy are valuable procedures in simultaneous rotator cuff repair regarding function, pain, and range of motion. However, the tenotomy group showed reduced strength in abduction. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26497982 TI - Surgical interventions for meniscal tears: a closer look at the evidence. AB - INTRODUCTION: The aim of the present study was to compare the outcomes of various surgical treatments for meniscal injuries including (1) total and partial meniscectomy; (2) meniscectomy and meniscal repair; (3) meniscectomy and meniscal transplantation; (4) open and arthroscopic meniscectomy and (5) various different repair techniques. MATERIALS AND METHODS: The Bone, Joint and Muscle Trauma Group Register, Cochrane Database, MEDLINE, EMBASE and CINAHL were searched for all (quasi) randomized controlled clinical trials comparing various surgical techniques for meniscal injuries. Primary outcomes of interest included patient reported outcomes scores, return to pre-injury activity level, level of sports participation and persistence of pain using the visual analogue score. Where possible, data were pooled and a meta-analysis was performed. RESULTS: A total of nine studies were included, involving a combined 904 subjects, 330 patients underwent a meniscal repair, 402 meniscectomy and 160 a collagen meniscal implant. The only surgical treatments that were compared in homogeneous fashion across more than one study were the arrow and inside-out technique, which showed no difference for re-tear or complication rate. Strong evidence-based recommendations regarding the other surgical treatments that were compared could not be made. CONCLUSIONS: This meta-analysis illustrates the lack of level I evidence to guide the surgical management of meniscal tears. LEVEL OF EVIDENCE: Level I meta-analysis. PMID- 26497983 TI - Transition from brand to generic tacrolimus is associated with a decrease in trough blood concentration in pediatric heart transplant recipients. AB - There are limited data available on the bioequivalence of generic and brand-name tacrolimus in pediatric and heart transplant patients. We characterized changes in 12-hour trough concentrations and clinical outcomes after transition from brand to generic tacrolimus in pediatric thoracic organ transplant recipients. Patients with a pharmacy-confirmed date of switch between generic and brand tacrolimus were identified, as well as a matched control group that did not switch for comparison. We identified 18 patients with a confirmed date of switch, and in 12 patients that remained on the same dose, trough concentrations were 14% less than when they were on brand (p = 0.037). The average change was -1.15 +/- 1.76 ng/mL (p = 0.045). The control group did not experience a change in trough concentration and was different than the switched group (p = 0.005). There were no differences in dosage changes or kidney or liver function. In the year after switch, 24% of patients who were switched to generic experienced a rejection event vs. 18% in the patients on brand. We suggest a strategy of monitoring around the time of transition, and education of the patient/family to notify the care team when changes from brand to generic or between generics occur. PMID- 26497984 TI - Learning where to feed: the use of social information in flower-visiting Pallas' long-tongued bats (Glossophaga soricina). AB - Social learning is a widespread phenomenon among vertebrates that influences various patterns of behaviour and is often reported with respect to foraging behaviour. The use of social information by foraging bats was documented in insectivorous, carnivorous and frugivorous species, but there are little data whether flower-visiting nectarivorous bats (Phyllostomidae: Glossophaginae) can acquire information about food from other individuals. In this study, we conducted an experiment with a demonstrator-observer paradigm to investigate whether flower-visiting Pallas' long-tongued bats (Glossophaga soricina) are able to socially learn novel flower positions via observation of, or interaction with, knowledgeable conspecifics. The results demonstrate that flower-visiting G. soricina are able to use social information for the location of novel flower positions and can thereby reduce energy-costly search efforts. This social transmission is explainable as a result of local enhancement; learning bats might rely on both visual and echo-acoustical perception and are likely to eavesdrop on auditory cues that are emitted by feeding conspecifics. We additionally tested the spatial memory capacity of former demonstrator bats when retrieving a learned flower position, and the results indicate that flower-visiting bats remember a learned flower position after several weeks. PMID- 26497985 TI - The eukaryotic translation initiation factor 3f (eIF3f) interacts physically with the alpha 1B-adrenergic receptor and stimulates adrenoceptor activity. AB - BACKGROUND: eIF3f is a multifunctional protein capable of interacting with proteins involved in different cellular processes, such as protein synthesis, DNA repair, and viral mRNA edition. In human cells, eIF3f is related to cell cycle and proliferation, and its deregulation compromises cell viability. RESULTS: We here report that, in native conditions, eIF3f physically interacts with the alpha 1B-adrenergic receptor, a plasma membrane protein considered as a proto-oncogene, and involved in vasoconstriction and cell proliferation. The complex formed by eIF3f and alpha 1B-ADR was found in human and mouse cell lines. Upon catecholamine stimulation, eIF3f promotes adrenoceptor activity in vitro, independently of the eIF3f proline- and alanine-rich N-terminal region. CONCLUSIONS: The eIF3f/alpha adrenergic receptor interaction opens new insights regarding adrenoceptor-related transduction pathways and proliferation control in human cells. The eIf3f/alpha 1B-ADR complex is found in mammals and is not tissue specific. PMID- 26497986 TI - Sonoclot((r))-based method to detect iron enhanced coagulation. AB - Thrombelastographic methods have been recently introduced to detect iron mediated hypercoagulability in settings such as sickle cell disease, hemodialysis, mechanical circulatory support, and neuroinflammation. However, these inflammatory situations may have heme oxygenase-derived, coexistent carbon monoxide present, which also enhances coagulation as assessed by the same thrombelastographic variables that are affected by iron. This brief report presents a novel, Sonoclot-based method to detect iron enhanced coagulation that is independent of carbon monoxide influence. Future investigation will be required to assess the sensitivity of this new method to detect iron mediated hypercoagulability in clinical settings compared to results obtained with thrombelastographic techniques. PMID- 26497987 TI - Nadroparin for the prevention of venous thromboembolism in nonsurgical patients: a systematic review and meta-analysis. AB - Anticoagulant thromboprophylaxis with low molecular weight heparin is widely used in nonsurgical settings. To obtain best estimates of the effects of nadroparin for the prevention of venous thromboembolism (VTE) in nonsurgical patients, we conducted a systematic review and meta-analysis. Data sources were Medline, Embase, and Cochrane Library supplemented with conference abstracts, without language restrictions. Selection criteria were randomized controlled trials with nadroparin at prophylactic dose in adult nonsurgical patients. Main efficacy outcomes were major VTE (the composite of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, asymptomatic proximal deep vein thrombosis and VTE-related death) and symptomatic VTE. The main safety outcome was major bleeding. We expressed treatment effects as risk ratios. Ten studies (4 vs. placebo or no treatment, 4 vs. UFH, 1 vs. fondaparinux and 1 vs. warfarin) enrolling a total of 7658 patients were included. In comparison with placebo, nadroparin reduced major VTE by about one-half (RR 0.48, 95% CI 0.24-0.97) with a consistent effect on symptomatic VTE (RR 0.69, 95% CI 0.46-1.05) and no increase in major bleeding (RR 1.51, 95% CI 0.40-5.79). In comparison with other pharmacological prophylaxis, nadroparin was similarly efficacious for prevention of major VTE (RR 1.14, 95% CI 0.63-2.10) and symptomatic VTE (RR 1.10, 95% CI 0.51-2.35) and produced similar effects on major bleeding (RR 0.60, 95% CI 0.25 1.50). Five studies were open label, and for three of these the adjudication method was not described or not blinded. In nonsurgical populations at risk of VTE, nadroparin reduced VTE by about one half compared with placebo or no treatment and appeared similarly effective and safe as other prophylactic anticoagulants. PMID- 26497988 TI - The neural network of saccadic foreknowledge. AB - Foreknowledge about upcoming events may be exploited to optimize behavioural responses. In a previous work, using an eye movement paradigm, we showed that different types of partial foreknowledge have different effects on saccadic efficiency. In the current study, we investigated the neural circuitry involved in processing of partial foreknowledge using functional magnetic resonance imaging. Fourteen subjects performed a mixed antisaccade, prosaccade paradigm with blocks of no foreknowledge, complete foreknowledge or partial foreknowledge about stimulus location, response direction or task. We found that saccadic foreknowledge is processed primarily within the well-known oculomotor network for saccades and antisaccades. Moreover, we found a consistent decrease in BOLD activity in the primary and secondary visual cortex in all foreknowledge conditions compared to the no-foreknowledge conditions. Furthermore we found that the different types of partial foreknowledge are processed in distinct brain areas: response foreknowledge is processed in the frontal eye field, while stimulus foreknowledge is processed in the frontal and parietal eye field. Task foreknowledge, however, revealed no positive BOLD correlate. Our results show different patterns of engagement in the saccade-related neural network depending upon precisely what type of information is known ahead. PMID- 26497989 TI - Age effects on voluntary and automatic adjustments in anti-pointing tasks. AB - We examined the effects of age on automatic and voluntary motor adjustments in pointing tasks. To this end, young (20-25 years) and middle-aged adults (48-62 years) were instructed to point at a target that could unexpectedly change its location (to the left or right) or its color (to green or red) during the movement. In the location change conditions, participants were asked to either adjust their pointing movement toward the new location (i.e., normal pointing) or in the opposite direction (i.e., anti-pointing). In the color change conditions, participants were instructed to adjust their movement to the left or right depending on the change in color. The results showed that in a large proportion of the anti-pointing trials, participants made two adjustments: an early initial automatic adjustment in the direction of the target shift followed by a late voluntary adjustment toward the opposite direction. It was found that the late voluntary adjustments were delayed for the middle-aged participants relative to the young participants. There were no age differences for the fast automatic adjustment in normal pointing, but the early adjustment in anti-pointing tended to be later in the middle-aged adults. Finally, the difference in the onset of early and late adjustments in anti-pointing adjustments was greater among the middle-aged adults. Hence, this study is the first to show that aging slows down voluntary goal-directed movement control processes to greater extent than the automatic stimulus-driven processes. PMID- 26497990 TI - Directional specificity of postural threat on anticipatory postural adjustments during lateral leg raising. AB - This study explored the directional specificity of fear of falling (FoF) effects on the stabilizing function of anticipatory postural adjustments (APA). Participants (N = 71) performed a series of lateral leg raises from an elevated surface in three conditions: in the "Control condition", participants stood at the middle of the surface; in the two test conditions, participants were positioned at the lateral edge of the surface so that the shift of the whole-body centre-of-mass during APA for leg raising was directed towards the edge ("Approach condition") or was directed away from the edge ("Avoidance condition"). Results showed that the amplitude of APA was lower in the "Approach condition" than in the "Control condition" (p < .01); this reduction was compensated for by an increase in APA duration (p < .05), so that both postural stability and motor performance (in terms of peak leg velocity, final leg posture and movement duration) remained unchanged. These changes in APA parameters were not present in the "Avoidance condition". Participants further self-reported a greater FoF (p < .001) and a lower ability to avoid a fall (p < .001) in the "Approach condition" (but not in the "Avoidance condition") than in the "Control condition". The results of this study show that the effects of FoF do not solely depend on initial environmental conditions, but also on the direction of APA relative to the location of the postural threat. These results support the so called Motivational Direction Hypothesis, according to which approach and avoidance behaviours are primed by emotional state. PMID- 26497991 TI - Brain morphologic changes in asymptomatic C9orf72 repeat expansion carriers. AB - OBJECTIVE: To investigate possible effects of the C9orf72 repeat expansion before disease onset, we assessed brain morphology in asymptomatic carriers. METHODS: Aiming to diminish the effects of genetic variation between subjects, apart from the C9orf72 repeat expansion, 16 carriers of the repeat expansion were compared with 23 noncarriers from the same large family with a history of amyotrophic lateral sclerosis (ALS). Cortical thickness, subcortical volumes, and white matter connectivity, as assessed from high-resolution T1-weighted and diffusion weighted MRIs, were evaluated. For comparison, we included 14 C9orf72 carriers with ALS and 28 healthy, unrelated controls. RESULTS: We found temporal, parietal, and occipital regions to be thinner (p < 0.05) and the left caudate and putamen to be smaller (p < 0.05) in asymptomatic carriers compared with noncarriers. Cortical thinning of the primary motor cortex and decreased connectivity of white matter pathways (global, corticospinal tract, and corpus callosum) were observed in patients with C9orf72-associated ALS, but not in asymptomatic carriers. CONCLUSIONS: Asymptomatic C9orf72 carriers show cortical and subcortical differences compared with noncarriers from the same family, possibly effects of the C9orf72 repeat expansion on the brain. Of note, changes in the primary motor regions and motor-related tracts were found exclusively in patients with ALS, indicating that such motor changes may be a disease phenomenon. PMID- 26497992 TI - Histologic muscular history in steroid-treated and untreated patients with Duchenne dystrophy. AB - OBJECTIVE: Duchenne muscular dystrophy (DMD) is a lethal disease. The outcome measures used in numerous therapeutic trials include skeletal muscle biopsy. We studied the natural history of DMD from the standpoint of muscle histology with the aim of providing a reproducible tool for use in evaluating and comparing any histologic changes occurring in patients with DMD undergoing treatment and hence be able to determine how therapy modulates the histologic evolution of the disease. METHODS: Three independent operators analyzed 56 muscle biopsies from 40 patients not treated with steroids, aged 1 to 10 years and 16 individuals treated with steroids, aged 7 to 10 years. We analyzed morphologic measures, normalized every measure for the average number of fibers observed for each year of age, and calculated intraclass correlation coefficients. RESULTS: The average proportion of connective tissue in patients not treated with steroids was 16.98% from ages 1 to 6 years and 30% from ages 7 to 10 years (p < 0.0001). The average proportion in patients treated with steroids was 24.90%. Muscle fiber area mirrored that of connective tissue in both groups. CONCLUSIONS: Having provided a reproducible tool for evaluation and comparison of histologic changes occurring in patients undergoing clinical trials, it was observed that at ages 6 to 7 years, fibrotic tissue rapidly peaks to 29.85%; this is a crucial moment when muscle tissue loses its self-regeneration ability, veering toward fibrotic degeneration. These data should be considered when deciding the most suitable time to begin therapy. PMID- 26497993 TI - SCP2 mutations and neurodegeneration with brain iron accumulation. PMID- 26497994 TI - Structural similarities of human and mammalian lipocalins, and their function in innate immunity and allergy. AB - Owners and their domestic animals via skin shedding and secretions, mutually exchange microbiomes, potential pathogens and innate immune molecules. Among the latter especially lipocalins are multifaceted: they may have an immunomodulatory function and, furthermore, they represent one of the most important animal allergen families. The amino acid identities, as well as their structures by superposition modeling were compared among human lipocalins, hLCN1 and hLCN2, and most important animal lipocalin allergens, such as Can f 1, Can f 2 and Can f 4 from dog, Fel d 4 from cats, Bos d 5 from cow's milk, Equ c 1 from horses, and Mus m 1 from mice, all of them representing major allergens. The beta-barrel fold with a central molecular pocket is similar among human and animal lipocalins. Thereby, lipocalins are able to transport a variety of biological ligands in their highly conserved calyx-like cavity, among them siderophores with the strongest known capability to complex iron (Fe(3+) ). Levels of human lipocalins are elevated in nonallergic inflammation and cancer, associated with innate immunoregulatory functions that critically depend on ligand load. Accordingly, deficient loading of lipocalin allergens establishes their capacity to induce Th2 hypersensitivity. Our similarity analysis of human and mammalian lipocalins highlights their function in innate immunity and allergy. PMID- 26497995 TI - Prognostic significance of the combination of preoperative hemoglobin, albumin, lymphocyte and platelet in patients with gastric carcinoma: a retrospective cohort study. AB - Nutritional and immune status is important to the prognosis of patients with gastric carcinoma (GC). Here, we evaluated the prognostic significance of the combination of preoperative hemoglobin, albumin, lymphocyte and platelet (HALP) in patients with GC. From January 2005 to December 2011, 1332 patients with GC who underwent gastrectomy were randomly divided into the training (n = 888) and the validation sets (n = 444) by X-tile according to the sample size ratio 2:1. The cut-point of HALP was 56.8 and the patients were subsequently subdivided into HALP < 56.8 and HALP >= 56.8 groups in both two sets. Multivariate analysis revealed that gender (p < 0.001, p < 0.001), tumor size (p = 0.003, p = 0.035) and T stage (p < 0.001, p = 0.044) were independently related to HALP both in the training and the validation sets. Kaplan-Meier (p < 0.001, p = 0.003) and Cox regression (p = 0.043, p = 0.042) showed that the prognosis of HALP >= 56.8 group was significantly better than that of HALP < 56.8 group both in two sets (p < 0.001, p < 0.001). Nomograms of these two sets based on HALP were more accurate in prognostic prediction than TNM stage alone. Our findings suggested that HALP was closely associated with clinicopathological features and was an independent prognostic factor in GC patients. Nomogram based on HALP could accurately predict the prognosis of GC patients. PMID- 26497996 TI - IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide. AB - Prior studies implicate type 1 IGF receptor (IGF-1R) in mediating chemo resistance. Here, we investigated whether IGF-1R influences response to temozolomide (TMZ), which generates DNA adducts that are removed by O6 methylguanine-DNA methyltransferase (MGMT), or persist causing replication associated double-strand breaks (DSBs). Initial assessment in 10 melanoma cell lines revealed that TMZ resistance correlated with MGMT expression (r = 0.79, p = 0.009), and in MGMT-proficient cell lines, with phospho-IGF-1R (r = 0.81, p = 0.038), suggesting that TMZ resistance associates with IGF-1R activation. Next, effects of IGF-1R inhibitors (IGF-1Ri) AZ3801 and linsitinib (OSI-906) were tested on TMZ-sensitivity, cell cycle progression and DSB induction. IGF-1Ri sensitized BRAF wild-type and mutant melanoma cells to TMZ in vitro, an effect that was independent of MGMT. Cells harboring wild-type p53 were more sensitive to IGF-1Ri, and showed schedule-dependent chemo-sensitization that was most effective when IGF-1Ri followed TMZ. This sequence sensitized to clinically achievable TMZ concentrations and enhanced TMZ-induced apoptosis. Simultaneous or prior IGF-1Ri caused less effective chemo-sensitization, associated with increased G1 population and reduced accumulation of TMZ-induced DSBs. Clinically relevant sequential (TMZ -> IGF-1Ri) treatment was tested in mice bearing A375M (V600E BRAF, wild-type p53) melanoma xenografts, achieving peak plasma/tumor IGF 1Ri levels comparable to clinical Cmax, and inducing extensive intratumoral apoptosis. TMZ or IGF-1Ri caused minor inhibition of tumor growth (gradient reduction 13%, 25% respectively), while combination treatment caused supra additive growth delay (72%) that was significantly different from control (p < 0.01), TMZ (p < 0.01) and IGF-1Ri (p < 0.05) groups. These data highlight the importance of scheduling when combining IGF-1Ri and other targeted agents with drugs that induce replication-associated DNA damage. PMID- 26497997 TI - miRNA-regulated delivery of lincRNA-p21 suppresses beta-catenin signaling and tumorigenicity of colorectal cancer stem cells. AB - Cancer stem cells (CSCs) are key cellular targets for effective cancer therapy, due to their critical roles in cancer progression and chemo/radio-resistance. Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) are important players in the biology of cancers. However, it remains unknown whether lncRNAs could be exploited to target CSCs. We report that large intergenic non-coding RNA p21 (lincRNA-p21) is a potent suppressor of stem-like traits of CSCs purified from both primary colorectal cancer (CRC) tissues and cell lines. A novel lincRNA p21-expressing adenoviral vector, which was armed with miRNA responsive element (MRE) of miR-451 (Ad-lnc-p21-MRE), was generated to eliminate CRC CSCs. Integration of miR-451 MREs into the adenovirus efficiently delivered lincRNA-p21 into CSCs that contained low levels of miR-451. Moreover, lincRNA-p21 inhibited the activity of beta-catenin signaling, thereby attenuating the viability, self renewal, and glycolysis of CSCs in vitro. By limiting dilution and serial tumor formation assay, we demonstrated that Ad-lnc-p21-MRE significantly suppressed the self-renewal potential and tumorigenicity of CSCs in nude mice. Importantly, application of miR-451 MREs appeared to protect normal liver cells from off target expression of lincRNA-p21 in both tumor-bearing and naive mice. Taken together, these findings suggest that lncRNAs may be promising therapeutic molecules to eradicate CSCs and MREs of tumor-suppressor miRNAs, such as miR-451, may be exploited to ensure the specificity of CSC-targeting strategies. PMID- 26497998 TI - Host JDP2 expression in the bone marrow contributes to metastatic spread. AB - The c-Jun Dimerization Protein 2, JDP2, is a basic leucine zipper protein member of the activator protein-1 (AP-1) family of transcription factors. JDP2 typically suppresses gene transcription through multiple mechanisms and plays a dual role in multiple cellular processes, including cell differentiation and proliferation which is dependent on AP-1 function. Whereas the role of JDP2 expression within cancer cells has been studied, its role in stromal cells at the tumor microenvironment is largely unknown. Here we show that mice lacking JDP2 (JDP2-/ ) display a reduced rate of metastasis in Lewis lung carcinoma (LLC) and polyoma middle T-antigen (PyMT) breast carcinoma mouse models. The replacement of wild type bone marrow derived cells (BMDCs) with JDP2-deficient BMDCs recapitulates the metastatic phenotype of JDP2-/- tumor-bearing mice. In vitro, conditioned medium of wild-type BMDCs significantly potentiates the migration and invasion capacity of LLC cells as compared to that of JDP2-/- BMDCs. Furthermore, wild type BMDCs secrete CCL5, a chemokine known to contribute to metastasis, to a greater extent than JDP2-/- BMDCs. The supplementation of CCL5 in JDP2-/- BMDC conditioned medium was sufficient to potentiate the invasion capacity of LLC. Overall, this study suggests that JDP2-expressing BMDCs within the tumor microenvironment contribute to metastatic spread. PMID- 26497999 TI - Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells. AB - Autophagy defect has been shown to be correlated with malignant phenotype and poor prognosis of human cancers, however, the detailed mechanisms remain obscure. In this study, we investigated the biological changes induced by autophagy inhibition in gastric cancer. We showed that inhibition of autophagy in gastric cancer cells promotes epithelial-mesenchymal transition (EMT) and metastasis, alters metabolic phenotype from mitochondrial oxidative phosphorylation to aerobic glycolysis and converts cell phenotype toward malignant, which maybe further contribute to chemoresistance and poor prognosis of gastric cancer. We also identified that the EMT and metabolism alterations induced by autophagy inhibition were dependent on ROS-NF-kappaB-HIF-1alpha pathway. More importantly, scavenging of ROS by the antioxidant N-acetylcysteine (NAC) attenuated activation of NF-kappaB and HIF-1alpha in autophagy-deficient gastric cancer cells, and autophagy inhibition induced metastasis and glycolysis were also diminished by NAC in vivo. Taken together, our findings suggested that autophagy defect promotes metastasis and glycolysis of gastric cancer, and antioxidants could be used to improve disease outcome for gastric cancer patients with autophagy defect. PMID- 26498000 TI - Achieving complete nitrogen removal by coupling nitritation-anammox and methane dependent denitrification: A model-based study. AB - The discovery of denitrifying anaerobic methane oxidation (DAMO) processes enables the complete nitrogen removal from wastewater by utilizing the methane produced on site from anaerobic digesters. This model-based study investigated the mechanisms and operational window for efficient nitrogen removal by coupling nitritation-anaerobic ammonium oxidation (Anammox) and methane-dependent denitrification in membrane biofilm reactors (MBfRs). A mathematical model was applied to describe the microbial interactions among Anammox bacteria, DAMO archaea, and DAMO bacteria. The model sufficiently described the batch experimental data from an MBfR containing an Anammox-DAMO biofilm with different feeding nitrogen compositions, which confirmed the validity of the model. The effects of process parameters on the system performance and microbial community structure could therefore be reliably evaluated. The impacts of nitritation produced NO2(-)/NH4(+) ratio, methane supply, biofilm thickness and total nitrogen (TN) surface loading were comprehensively investigated with the model. Results showed that the optimum NO2(-)/NH4(+) ratio produced from nitritation for the Anammox-DAMO biofilm system was around 1.0 in order to achieve the maximum TN removal (over 99.0%), independent on TN surface loading. The corresponding optimal methane supply increased while the associated methane utilization efficiency decreased with the increase of TN surface loading. The cooperation between DAMO organisms and Anammox bacteria played the key role in the TN removal. Based on these results, the proof-of-concept feasibility of a single stage MBfR coupling nitritation-Anammox-DAMO for complete nitrogen removal was also tested through integrating the model with ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB) processes whilst controlling the dissolved oxygen (DO) concentration in the simulated system. The maximum TN removal was found to be achieved at the bulk DO concentration of around 0.17 g m(-3) under the simulation conditions, with the AOB, Anammox bacteria and DAMO organisms coexisting in the biofilm. PMID- 26498002 TI - AMBER-ii: New Combining Rules and Force Field for Perfluoroalkanes. AB - A molecular mechanics force field of the AMBER/OPLS family for perfluoroalkanes, noble gases, and their mixtures with alkanes has been proposed. We had to abandon the traditional Lorentz-Berthelot combining rules for the Lennard-Jones potential to be able to uniformly describe these substance classes and their mixtures. Instead, the Waldman-Hagler rules developed for noble gases were used for all of these elements except hydrogen. Hydrogen is considered to be a particular substance to which the usual Lorentz-Berthelot rules are applied. The proposed rules have little effect on the organic chemistry of H, C, N, and O elements but make it compliant with the chemistry of heavy elements. Because of assigning a relatively high partial charge of -0.37e to fluorine atoms, the new force field reproduces the mutual insolubility of higher liquid alkanes and perfluoroalkanes. PMID- 26498001 TI - Environmental neurotoxin interaction with proteins: Dose-dependent increase of free and protein-associated BMAA (beta-N-methylamino-L-alanine) in neonatal rat brain. AB - beta-Methylamino-L-alanine (BMAA) is implicated in the aetiology of neurodegenerative disorders. Neonatal exposure to BMAA induces cognitive impairments and progressive neurodegenerative changes including intracellular fibril formation in the hippocampus of adult rats. It is unclear why the neonatal hippocampus is especially vulnerable and the critical cellular perturbations preceding BMAA-induced toxicity remains to be elucidated. The aim of this study was to compare the level of free and protein-associated BMAA in neonatal rat brain and peripheral tissues after different exposures to BMAA. Ultra-high performance liquid chromatography-tandem mass spectrometry analysis revealed that BMAA passed the neonatal blood-brain barrier and was distributed to all studied brain areas. BMAA was also associated to proteins in the brain, especially in the hippocampus. The level in the brain was, however, considerably lower compared to the liver that is not a target organ for BMAA. In contrast to the liver there was a significantly increased level of protein-association of BMAA in the hippocampus and other brain areas following repeated administration suggesting that the degradation of BMAA-associated proteins may be lower in neonatal brain than in the liver. Additional evidence is needed in support of a role for protein misincorporation in the neonatal hippocampus for long-term effects of BMAA. PMID- 26498003 TI - Procyanidin B2 inhibits high glucose-induced epithelial-mesenchymal transition in HK-2 human renal proximal tubular epithelial cells. AB - Diabetic nephropathy (DN) is not only an important chronic complication of diabetes, but is also one of the predominant cause of renal failure. Previous studies have indicated that the process termed 'epithelial-mesenchymal transition' (EMT) results in fibrosis of renal tubular epithelial cells, and is key in DN. As an antioxidant, procyanidin B2 can inhibit cardiac fibrosis; however, whether it has an effect on the inhibition of renal fibrosis remains to be elucidated. The present study demonstrated that high glucose levels were able to activate EMT-associated changes, including the loss of E-cadherin and increase in alpha-smooth muscle actin (alpha-SMA), as determined by western blotting and immunofluorescence. Pre-treatment with procyanidin B2 reversed the high glucose induced morphological changes, upregulated the expression of E-cadherin and downregulated the expression levels of vimentin and alpha-SMA. Furthermore, procyanidin B2 decreased the phosphorylation of small mothers against decapentaplegic (Smad)2, Smad3 and P38, and upregulated the expression of phosphorylated-Smad7. In conclusion, the results of the present study suggested that procyanidin B2 inhibited high glucose-induced EMT through the inhibition of transforming growth factor-beta/Smad and mitogen-activated protein kinase/P38 signaling pathways. PMID- 26498004 TI - A structural and (1)H NMR relaxometric study on novel layered carboxyalkylaminophosphonate nanocrystals with Gd(III) ions located in the framework. AB - Novel Gd(III) carboxyalkylphosphonate nanocrystals were synthesized under mild hydrothermal conditions. Structural properties and (1)H NMR relaxometric behaviour in aqueous solution as a function of the magnetic field strength were investigated, aiming to evaluate the local chemical environment of the paramagnetic centres and their interaction and affinity with water molecules. PMID- 26498006 TI - Self-assembled polymeric nanocarriers for the targeted delivery of retinoic acid to the hair follicle. AB - Acne vulgaris is a highly prevalent dermatological disease of the pilosebaceous unit (PSU). An inability to target drug delivery to the PSU results in poor treatment efficacy and the incidence of local side-effects. Cutaneous application of nanoparticulate systems is reported to induce preferential accumulation in appendageal structures. The aim of this work was to prepare stable polymeric micelles containing retinoic acid (RA) using a biodegradable and biocompatible diblock methoxy-poly(ethylene glycol)-poly(hexylsubstituted lactic acid) copolymer (MPEG-dihexPLA) and to evaluate their ability to deliver RA to skin. An innovative punch biopsy sample preparation method was developed to selectively quantify follicular delivery; the amounts of RA present were compared to those in bulk skin, (i.e. without PSU), which served as the control. RA was successfully incorporated into micelle nanocarriers and protected from photoisomerization by inclusion of Quinoline Yellow. Incorporation into the spherical, homogeneous and nanometer-scale micelles (dn < 20 nm) increased the aqueous solubility of RA by >400-fold. Drug delivery experiments in vitro showed that micelles were able to deliver RA to porcine and human skins more efficiently than Retin-A((r)) Micro (0.04%), a marketed gel containing RA loaded microspheres, (7.1 +/- 1.1% vs. 0.4 +/- 0.1% and 7.5 +/- 0.8% vs. 0.8 +/- 0.1% of the applied dose, respectively). In contrast to a non-colloidal RA solution, Effederm((r)) (0.05%), both the RA loaded MPEG-dihexPLA polymeric micelles (0.005%) and Retin-A((r)) Micro (0.04%) displayed selectivity for delivery to the PSU with 2-fold higher delivery to PSU containing samples than to control samples. Moreover, the micelle formulation outperformed Retin-A((r)) Micro in terms of delivery efficiency to PSU presenting human skin (10.4 +/- 3.2% vs. 0.6 +/- 0.2%, respectively). The results indicate that the polymeric micelle formulation enabled an increased and targeted delivery of RA to the PSU, potentially translating to a safer and more efficient clinical management of acne. PMID- 26498005 TI - Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination. AB - We have previously reported two trials in non-small cell lung cancer (NSCLC) evaluating vaccine therapy with the telomerase peptide GV1001. The studies demonstrated considerable differences in survival among immune responders, highlighting that an immune response is not necessarily beneficial. In the present study, we conducted long-term clinical follow-up and investigated immunological factors hypothesized to influence clinical efficacy. Peripheral blood mononuclear cells from 33 NSCLC trial patients and 15 healthy donors were analyzed by flow cytometry for T regulatory cells (Tregs, CD4(+)CD25(+)CD127(low/ )FOXP3(+)) and two types of myeloid-derived suppressor cells (MDSCs, HLA-DR (low) CD14 (+) or Lin (-/lo) HLA-DR (-) CD33 (+) CD11b (+)). T cell cultures were analyzed for 17 cytokines. The results demonstrated that immune responders had increased overall survival (OS, p < 0.001) and progression-free survival (p = 0.003), compared to subjects without immunological response. The mean OS advantage was 54 versus 13 months. Six patients were still alive at the last clinical update, all belonging to the immune responders. No serious toxicity had developed (maximum observation 13 years). Most patients developed a polyfunctional cytokine profile, with high IFNgamma/IL-4 and IFNgamma/IL-10 ratios. Low Treg levels were associated with improved OS (p = 0.037) and a favorable cytokine profile, including higher IFNgamma/IL-10 ratios. High CD33(+) MDSC levels were associated with poorer immune response rate (p = 0.005). The levels of CD14(+) MDSC were significantly higher in patients than in healthy controls (p = 0.012). We conclude that a randomized GV1001 trial in NSCLC is warranted. The findings suggest that Tregs and MDSCs are associated with a tolerogenic cytokine milieu and impaired clinical efficacy of vaccine responses. PMID- 26498007 TI - Erratum to: Amino acids and autophagy: their crosstalk, interplay and interlock. PMID- 26498008 TI - Induction of Gametogenesis in the Cnidarian Endosymbiosis Model Aiptasia sp. AB - Endosymbiosis is widespread among cnidarians and is of high ecological relevance. The tropical sea anemone Aiptasia sp. is a laboratory model system for endosymbiosis between reef-building corals and photosynthetic dinoflagellate algae of the genus Symbiodinium. Here we identify the key environmental cues to induce reproducible spawning in Aiptasia under controlled laboratory conditions. We find that simulating a lunar cycle with blue-wavelength light is necessary to promote abundant gamete production and synchronous release in well-fed animals. Sexual reproduction rates are genetically determined and differ among clonal lines under similar conditions. We also find the inverse difference in rates of asexual reproduction. This study provides the requisite basis for further development of the Aiptasia model system, allowing analysis of basic cellular and molecular mechanisms in the laboratory as well as investigations of broad questions of ecological and evolutionary relevance. PMID- 26498009 TI - Surgimesh M-SLING((r)) transobturator and prepubic four-arm urethral sling for post-prostatectomy stress urinary incontinence: clinical prospective assessment at 24 months. AB - OBJECTIVE: To assess tolerance and mid-term clinical outcomes of treatment, with a new four-arm mesh sling, of post-prostatectomy incontinence (PPI) in men. MATERIAL AND METHODS: This was a French multicentre prospective study that included 93 patients who underwent radical prostatectomy at least 1 year before Surgimesh M-SLING((r)) implantation for the treatment of PPI. Data were collected preoperatively, and patients were followed at 3, 12 and 24 months postoperatively. Objective outcome measures included number of pads per day, 24-h pad-test, maximum urinary flow rate (Qmax ) and urinary retention. We also analysed Urinary Symptom Profile (USP((r)) ) score, degree of erectile dysfunction, patients' satisfaction level, postoperative pain and procedure complications. Length of catheterization and hospitalization periods were also recorded. Patients were considered cured if no protection was used and/or daily pad weight was <2 g. Patients whose condition was considered to have improved reduced their daily urinary losses by >50%. Those not included in any of the aforementioned groups were assessed as unchanged or to have deteriorated, and were considered as treatment failures. RESULTS: The mean hospitalization period was 1.57 +/- 0.70 days. All patients remained catheterized for 1.17 +/- 0.48 days. Intention-to-treat analysis at 24 months showed that 34.4% of patients were cured, 27.1% had improved, and 19.4% were considered failures. Two patients experienced transient urinary retention. USP questionnaire scores showed a significant decrease in incontinence and prevalence of hyperactive bladder. There was a nonsignificant tendency for reduced severe erectile dysfunction (ED), and a shift towards moderate ED was observed. No severe complications occurred. CONCLUSION: The Surgimesh M-SLING transobturator and prepubic four-arm urethral sling represents an easy-to-deploy, safe and durable therapeutic alternative for mild to moderate PPI. Its implantation did not have a negative influence on sexual performance outcomes. PMID- 26498011 TI - Primary Neurilemmoma of the Thyroid Gland Clinically Mimicking Malignant Thyroid Nodule. PMID- 26498010 TI - Molecular Dimensions of Gastric Cancer: Translational and Clinical Perspectives. AB - Gastric cancer is a global health burden and has the highest incidence in East Asia. This disease is complex in nature because it arises from multiple interactions of genetic, local environmental, and host factors, resulting in biological heterogeneity. This genetic intricacy converges on molecular characteristics reflecting the pathophysiology, tumor biology, and clinical outcome. Therefore, understanding the molecular characteristics at a genomic level is pivotal to improving the clinical care of patients with gastric cancer. A recent landmark study, The Cancer Genome Atlas (TCGA) project, showed the molecular landscape of gastric cancer through a comprehensive molecular evaluation of 295 primary gastric cancers. The proposed molecular classification divided gastric cancer into four subtypes: Epstein-Barr virus-positive, microsatellite unstable, genomic stable, and chromosomal instability. This information will be taken into account in future clinical trials and will be translated into clinical therapeutic decisions. To fully realize the clinical benefit, many challenges must be overcome. Rapid growth of high-throughput biology and functional validation of molecular targets will further deepen our knowledge of molecular dimensions of this cancer, allowing for personalized precision medicine. PMID- 26498012 TI - Clear Cell Adenocarcinoma Arising from Adenofibroma in a Patient with Endometriosis of the Ovary. AB - Ovarian clear cell adenocarcinomas (CCACs) are frequently associated with endometriosis and, less often with clear cell adenofibromas (CCAFs). We encountered a case of ovarian CCAC arising from benign and borderline adenofibromas of the clear cell and endometrioid types with endometriosis in a 53 year-old woman. Regions of the adenofibromas showed transformation to CCAC and regions of the endometriosis showed atypical endometriotic cysts. This case demonstrates that CCAC can arise from CCAF or endometriosis. PMID- 26498015 TI - Transient study of the oxygen reduction reaction on reduced Pt and Pt alloys microelectrodes: evidence for the reduction of pre-adsorbed oxygen species linked to dissolved oxygen. AB - Using chronoamperometry at preconditioned oxide-free Pt microdisc electrodes in aqueous media, we investigated the oxygen reduction reaction (ORR) on the millisecond timescale and obtained results consistent with the reduction of oxygen species which adsorb on the electrode before the ORR is electrochemically driven. Furthermore these adsorbed species are clearly linked to oxygen in solution. At long times, the amperometric response is solely controlled by the diffusion of dissolved oxygen towards the microelectrode. However, at short times, typically below 50 ms, the reduction of pre-adsorbed oxygen produces a large extra current whose magnitude depends on the oxygen concentration in solution, deliberate electrode poisoning and the rest time before the potential step. Using sampled current voltammetry we show that this extra current affects the entire potential range of the ORR. Using microdisc electrodes made with Pt alloys we find that the amperometric response is sufficiently sensitive to distinguish oxygen coverage differences between Pt, Pt0.9Rh0.1 and Pt0.9Ir0.1 microdiscs. These unexpected and, to our knowledge, never previously reported results provide new insight into the oxygen reduction reaction on Pt. The existence over a wide potential range of irreversibly adsorbed oxygen species arising from dissolved oxygen and different from Pt oxide is particularly relevant to the development of oxygen reduction catalysts for low temperature fuel cells. PMID- 26498014 TI - The stiffening of the cell walls observed during physiological softening of pears. AB - MAIN CONCLUSION: The Young's modulus of the primary cell walls of pears decreases linearly during the pre-harvest on-tree maturation and increases during postharvest storage, and does not correlate with firmness of fruit. The determination of mechanical properties of cell walls is indispensable for understanding the mechanism of physiological softening and deterioration of quality of fruits during postharvest storage. The Young's modulus of the primary cell walls from pear fruit (Pyrus communis L., cultivars 'Conference' and 'Xenia') during pre-harvest maturation and postharvest storage in an ambient atmosphere at 2 degrees C followed by shelf life was studied using atomic force microscopy (AFM). The results were related to the firmness of fruits, galacturonic acid content in water, chelator, sodium carbonate and insoluble pectin fractions, polygalacturonase and pectin methylesterase activities. The Young's modulus of the primary cell walls decreased linearly during the last month of pre-harvest maturation from 3.2 +/- 1.8 to 1.1 +/- 0.7 MPa for 'Conference' and from 1.9 +/- 1.2 to 0.2 +/- 0.1 MPa for 'Xenia' which correlated with linear firmness decrease. During postharvest storage the cell wall Young's modulus increased while firmness continued to decrease. Correlation analysis for the entire period of the experiment showed a lack of straightforward relation between the Young's modulus of primary cell walls and fruit firmness. The Young's modulus of cell walls correlated negatively either with galacturonic acid content in sodium carbonate soluble pectin ('Conference') or with insoluble pectin fractions ('Xenia') and positively with polygalacturonase activity. It was therefore evidenced that covalently linked pectins play the key role for the stiffness of fruit cell walls. Based on the obtained results, the model explaining the fruit transition from firm and crispy to soft and mealy was proposed. PMID- 26498013 TI - Controlled downregulation of the cannabinoid CB1 receptor provides a promising approach for the treatment of obesity and obesity-derived type 2 diabetes. AB - Increased activity of the endocannabinoid system has emerged as a pathogenic factor in visceral obesity, which is a risk factor for type 2 diabetes mellitus (T2DM). The endocannabinoid system is composed of at least two Gprotein-coupled receptors (GPCRs), the cannabinoid receptor type 1 (CB1), and the cannabinoid receptor type 2 (CB2). Downregulation of CB1 activity in rodents and humans has proven efficacious to reduce food intake, abdominal adiposity, fasting glucose levels, and cardiometabolic risk factors. Unfortunately, downregulation of CB1 activity by universally active CB1 inverse agonists has been found to elicit psychiatric side effects, which led to the termination of using globally active CB1 inverse agonists to treat diet-induced obesity. Interestingly, preclinical studies have shown that downregulation of CB1 activity by CB1 neutral antagonists or peripherally restricted CB1 inverse agonists provided similar anorectic effects and metabolic benefits without psychiatric side effects seen in globally active CB1 inverse agonists. Furthermore, downregulation of CB1 activity may ease endoplasmic reticulum and mitochondrial stress which are contributors to obesity induced insulin resistance and type 2 diabetes. This suggests new approaches for cannabinoid-based therapy in the management of obesity and obesity-related metabolic disorders including type 2 diabetes. PMID- 26498016 TI - Sexually transmissible infections in middle and high school students: experience rates, risk factors and relationship with mental health - results from the Korean youth risk behaviour web-based survey. AB - Background Sexually transmissible infections (STIs) in adolescents are an important heath problem. However, the understanding of STIs among adolescents is poor. Rates of and risk factors for ever having a STI and relationships between ever having a STI and mental health in adolescents was investigated. METHODS: Data from the Korea Youth Risk Behaviour Web-based Survey (KYRBS) were used. The KYRBS is an anonymous, self-administered online survey. To achieve a representative sample of Koreans, researchers used a stratification, clustering and multi-stage sampling method. Data from adolescents who had not had sexual intercourse and surveys with missing data concerning sexual experience were excluded. Finally, 31363 participants were included. RESULTS: The rate of ever having a STI was 10.0%. A total of 26.5% of adolescents who have had sexual experience report always using contraceptives, and condoms are the most popular contraceptives (69.0%). Contraceptive method (condom, OR: 0.601, 95% CI: 0.491 0.736) and elementary school sexual debut (elementary school, OR: 1.000, middle school, OR: 0.235, 95% CI: 0.181-0.305; high school, OR: 0.128, 95% CI: 0.094 0.173) were significantly correlated with ever having a STI in the multivariate analysis. Depressed mood (OR: 1.379, 95% CI: 1.130-1.683), suicidal ideation (OR: 1.358, 95% CI: 1.109-1.664) and suicide attempts (OR: 1.382, 95% CI: 1.029-1.856) were significantly associated with ever having a STI after adjusting for potential confounders. CONCLUSIONS: STIs are common diseases in adolescents who have sexual experience and are significantly associated with mental health. Development of preventive measures and treatment policies including mental counselling for adolescents with STI are needed. PMID- 26498017 TI - Phylogeography of specialist weevil Trichobaris soror: a seed predator of Datura stramonium. AB - Can the genetic structure of a specialist weevil be explained by the geological history of their distribution zone? We analyze the genetic variation of the weevil Trichobaris soror, a specialist seed predator of Datura stramonium, in order to address this question. For the phylogeographic analysis we used the COI gene, and assessed species identity in weevil populations through geometric morphometric approach. In total, we found 53 haplotypes in 413 samples, whose genetic variation supports the formation of three groups: (1) the Transmexican Volcanic Belt (TVB group), (2) the Sierra Madre Sur (SMS group) and (3) the Balsas Basin (BB group). The morphometric analysis suggests that BB group is probably not T. soror. Our results have two implications: first, the phylogeographic pattern of T. soror is explained by both the formation of the geological provinces where it is currently distributed and the coevolution with its host plant, because the TVB and SMS groups could be separated due to the discontinuity of altitude between the geological provinces, but the recent population expansion of TVB group and the high frequency of only one haplotype can be due to specialization to the host plant. Second, we report a new record of a different species of weevil in BB group parasitizing D. stramonium fruits. PMID- 26498018 TI - Extracardiac-Lodged Mesenchymal Stromal Cells Propel an Inflammatory Response Against Myocardial Infarction via Paracrine Effects. AB - Transplantation of stem cells, including mesenchymal stromal cells (MSCs), improves the recovery of cardiac function after myocardial infarction (MI) in experimental studies using animal models and in patients. However, the improvement of cardiac function following MSC transplantation remains suboptimal in both preclinical and clinical studies. Understanding the mechanism of cell therapy may improve its therapeutic outcomes, but the mode of action mediating stem cell promotion of cardiac repair is complex and not fully understood. Recent studies suggest that the immunomodulatory effects of MSCs on the macrophage M1/M2 subtype transition allow the transplanted stem cells to inhibit inflammation induced injury and promote cardiac repair in acute MI. However, equally compelling evidence shows that there is poor survival and minimal graft persistence of transplanted MSCs within the infarcted heart tissues, negating the view that graft survival per se is required for the observed high rate and long duration of the transition from proinflammatory M1 to reparative M2 macrophages in the infarcted myocardium. Therefore, we raised a novel hypothesis that the therapeutic effects of MSC transplantation for acute MI depends not primarily on the grafted cells in infarct myocardium, but that MSCs migrating to and being lodged in the extracardiac organs, demonstrating good graft survival and persistence, may render the therapeutic effects in MI. More specifically, MSC transplantation promotes the transition from M1 to M2 in extracardiac organs, such as spleen and bone marrow, and therapeutic effects are conferred to the infarcted myocardium via paracrine effects. In MSC transplantation, the conversion from proinflammatory M1 to anti-inflammatory M2 monocytes may occur remotely from the heart and may serve as one of the major pathways in regulating the dual effects of inflammation. This hypothesis, if proven valid, may represent an important new mechanism of action to be considered for the future of MSC transplantation in the treatment of MI. PMID- 26498019 TI - Optimal threshold for stromal tumor-infiltrating lymphocytes: its predictive and prognostic value in HER2-positive breast cancer treated with trastuzumab-based neoadjuvant chemotherapy. AB - The purpose of the present study was to determine the optimal threshold for stromal tumor-infiltrating lymphocytes (TILs) and investigate its predictive and prognostic value in HER2-positive breast cancer treated with trastuzumab-based neoadjuvant chemotherapy (NAC). Levels of stromal TILs were evaluated using hematoxylin and eosin-stained sections of core biopsies from 116 patients. We investigated the correlation between stromal TILs and pathological response to identify its optimal threshold. Using receiver operating characteristic curve analysis, a 30 % threshold best discriminated pathological complete response (pCR) from non-pCR subgroups (P < 0.001). Lymphocyte-rich breast cancer (LRBC) was defined as having >=30 % stromal TILs level, and was used for analysis. For analyses of predictive factors, multivariate analysis indicated that LRBC was a strong predictor of pCR with an odds ratio of 5.23 (P < 0.001). Negative hormone receptor (HR) status was also significantly associated with pCR (P = 0.028). LRBC significantly predicted pCR in both HR-positive and HR-negative tumors (P = 0.016 and 0.006, respectively). For survival analyses, LRBC was the only independent predictor of improved event-free survival (EFS) among baseline clinicopathological factors in multivariate analysis (P = 0.012). When pathological response was included, both LRBC and pCR were independent predictors of better EFS (P = 0.040 and 0.045, respectively). LRBC significantly predicted longer EFS in the non-pCR subgroup (P = 0.018), whereas LRBC was not significantly associated with EFS in the pCR subgroup (P = 0.825). A 30 % threshold for stromal TILs optimally identified response to trastuzumab-based NAC in HER2-positive breast cancer; its predictive and prognostic value was also validated in our study. PMID- 26498020 TI - Doing "nothing" for DCIS: a case report. PMID- 26498021 TI - Low signal-to-cutoff ratio (S/Co) in the diagnosis of hepatitis C: A diagnostic dilemma? PMID- 26498022 TI - Camel milk peptide improves wound healing in diabetic rats by orchestrating the redox status and immune response. AB - BACKGROUND: Diabetes mellitus alters oxidative stability and immune response. Here, we investigated the impact of a peptide extracted from camel milk (CMP) on the oxidative status, transcription factor kappa-B (NF-kB) and inflammatory cytokine in diabetic wounds. METHODS: Rats were assigned into three groups: control, diabetic induced (DM) and diabetic induced with multiple doses of CMP for a week (DM-CMP). RESULTS: DM showed a sharp decline in the activity of major antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) compared to the control. The DM-CMP group, however, showed a noticeable replenishment in the activity of these enzymes compared to the DM group. The CMP-treated group also showed a normal level of lipid peroxidation marker (MDA) compared to the DM rats. Furthermore, ELISA analysis of serum TNF alpha protein showed an elevated level in diabetic rats in comparison to control serum. However, RT-PCR analysis of locally wounded skin tissues revealed that diabetes down-regulates the RNA expression of both TNF-alpha and MIF genes in comparison to the control samples but that CMP was found to restore RNA expression significantly. Although it was elevated in CMP-treated rats after one day of wound incision, the NF-kB protein level was significantly decreased seven days after the incision in comparison to the animals in the diabetic group. CONCLUSION: CMP, therefore, can be seen an effective antioxidant and immune stimulant that induces oxidative stability and speeds up wound healing in diabetic model animals, making it a potential adjuvant in improving wound healing in those with diabetic conditions. PMID- 26498023 TI - Eukaryotic Expression and Purification of Native Form of Mouse Midkine from Pichia pastoris. AB - To confirm the treating effectiveness of midkine as an articular protective agent, mouse midkine (mMK) was produced for the pre-clinic long-term studies in mice. The protein was expressed under the control of the AOX1 gene promoter in Pichia pastoris, X-33 strain, and secreted into fermentation broth through high density fermentation. Approximately 380 mg mMK, containing authentic and truncated forms, was secreted into 1 liter induction medium and 280 mg mMK was obtained after one-step purification on a 50 ml SP Sepharose Fast Flow column. The purified protein was characterized and identified to be the mature, authentic form of mMK. N-terminal five amino acid sequence was determined to be K-K-K-E-K. SDS-PAGE analysis indicated that the molecular weight of the product was about 13 KDa. The purity of the purified rmMK protein was determined to be 99% by high performance liquid chromatography. The biological activity of final product was verified via migration assay on osteoblast-like UMR-106 cells. PMID- 26498024 TI - A Novel Optical Biosensing System Using Mach-Zehnder-Type Optical Waveguide for Influenza Virus Detection. AB - In order to minimize the damage from viral epidemics, early detection of the causative agent of a viral epidemic and prevention of its immediate spread are urgent social demands. Therefore, in this study, we evaluated the utility of a Mach-Zehnder-type optical waveguide as a sensing device for influenza virus detection. However, it is impossible to detect a 100-nm-size virus using a sol gel optical biosensor because sol-gel glass has a pore size of only a few nanometers, which makes it impossible for the virus to diffuse into the silica thin film. In order to construct the influenza-specific Mach-Zehnder optical biosensor for influenza detection, a stable antibody immobilization method with resulting high density on the sol-gel surface is strongly required. In this study, the sol-gel glass surface was modified with amino and carboxyl groups, and an anti-H1N1/HA1 antibody was covalently immobilized using a cross-linking agent. We successfully prepared a carboxyl-modified sol-gel surface, using NHS/EDC as the cross-linker, for antibody immobilization, and confirmed the detection of influenza virus using the antibody-immobilized sol-gel glass. After treatment with a 100 MUg/mL influenza virus solution for 15 min, a peak wavelength shift (~24 nm) was observed in the output light spectrum. PMID- 26498025 TI - Identification of the potential molecular targets for human intervertebral disc degeneration based on bioinformatic methods. AB - The present study aimed to explore potential molecular targets and gain further insights into the mechanism of intervertebral disc degeneration (IDD) progression. Microarray datasets of GSE19943, GSE15227 and GSE34095 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) in 3 IDD specimens compared with 3 controls in GSE34095, DEGs in 7 grade III and 3 grade IV samples compared with 5 grade II samples in GSE19943, and differentially expressed miRNAs in 3 degenerated samples compared with 3 controls in GSE15227 were screened. Grade III- and IV-specific networks were constructed and grade-specific genes were extracted. The network features were analyzed, followed by Gene Ontology (GO) enrichment analysis and pathway enrichment analysis of grade-specific genes and DEGs identified in GSE34095. Furthermore, miRNA-pathway interactions were analyzed using Fisher's exact test. Tumor protein p53 (TP53) was a hub gene in the grade III-specific network and ubiquitin C (UBC) was identified to be a hub gene in the grade IV-specific network. Six significant features were identified by grade-specific network topology analysis. Grade-specific genes and DEGs were involved in different GO terms and pathways. Differentially expressed miRNAs were identified to participate in 35 pathways, among which 6 pathways were significantly enriched by DEGs, including apoptosis. The present study identified that key genes (TP53 and UBC) and miR-129-5p may participate in the mechanism of IDD progression. Thus, they may be potential therapeutic targets for IDD. PMID- 26498026 TI - An orphan gene is necessary for preaxial digit formation during salamander limb development. AB - Limb development in salamanders differs from other tetrapods in that the first digits to form are the two most anterior (preaxial dominance). This has been proposed as a salamander novelty and its mechanistic basis is unknown. Salamanders are the only adult tetrapods able to regenerate the limb, and the contribution of preaxial dominance to limb regeneration is unclear. Here we show that during early outgrowth of the limb bud, a small cohort of cells express the orphan gene Prod1 together with Bmp2, a critical player in digit condensation in amniotes. Disruption of Prod1 with a gene-editing nuclease abrogates these cells, and blocks formation of the radius and ulna, and outgrowth of the anterior digits. Preaxial dominance is a notable feature of limb regeneration in the larval newt, but this changes abruptly after metamorphosis so that the formation of anterior and posterior digits occurs together within the autopodium resembling an amniote-like pattern. PMID- 26498028 TI - Do not let precision medicine be kidnapped. AB - Obama's precision medicine initiative made the medical community boil over after the initiative's release. Precision medicine has been advocated by the majority of scientists and doctors. However, some experts have questioned this concept. This article does not oppose precision medicine. However, the incentive of vigorously promoting precision medicine at present is a concern. PMID- 26498027 TI - Emerging roles of podoplanin in vascular development and homeostasis. AB - Podoplanin (PDPN) is a mucin-type O-glycoprotein expressed in diverse cell types, such as lymphatic endothelial cells (LECs) in the vascular system and fibroblastic reticular cells (FRCs) in lymph nodes. PDPN on LECs or FRCs activates CLEC-2 in platelets, triggering platelet activation and/or aggregation through downstream signaling events, including activation of Syk kinase. This mechanism is required to initiate and maintain separation of blood and lymphatic vessels and to stabilize high endothelial venule integrity within lymphnodes. In the vascular system, normal expression of PDPN at the LEC surface requires transcriptional activation of Pdpn by Prox1 and modification of PDPN with core 1 derived O-glycans. This review provides a comprehensive overview of the roles of PDPN in vascular development and lymphoid organ maintenance and discusses the mechanisms that regulate PDPN expression related to its function. PMID- 26498029 TI - In vivo knockdown of CXCR4 using jetPEI/CXCR4 shRNA nanoparticles inhibits the pulmonary metastatic potential of B16-F10 melanoma cells. AB - Metastasis is a key factor that limits survival in the majority of patients with cancer. Thus, numerous efforts have been made to elucidate the molecular mechanisms involved in this phenomenon. B16-F10 melanoma cells have been demonstrated to be highly metastatic to the lungs in mice. The aim of the current study was to investigate the role of CXC motif chemokine receptor 4 (CXCR4) in the metastatic potential of B16-F10 melanoma cells in mice. In vitro transfection of B16-F10 tumor cells with CXCR4 short hairpin RNA (shRNA) expressing plasmids (CXCR4 shRNA) significantly reduced the expression levels of CXCR4 mRNA (80%) and protein (68%), compared with the control. In addition, these results demonstrated that pulmonary metastasis was significantly inhibited (85%) in mice inoculated with CXCR4 shRNA-transfected B16-F10 melanoma cells. The polycation-based nanoparticle (jetPEI) was used to investigate the effect of CXCR4 knockdown in vivo on the metastatic potential of B16-F10 melanoma cells. The number of pulmonary metastatic nodules was significantly reduced (50%) in animals that received a retro-orbital injection of jetPEI-CXCR4-1 shRNA. The current study demonstrated that CXCR4 serves a role in the metastatic potential of B16-F10 melanoma cells. Currently there is a great interest in the development of antagonists for the therapeutic targeting of CXCR4 expression. Taking the results of the current study and the fact that CXCR4 is highly conserved between humans and mice into account, this experimental model of metastasis with B16-F10 melanoma cells may aid in the discovery of CXCR4 antagonists with clinical implications. PMID- 26498032 TI - Guest Editorial: Special issue on metabolomics. PMID- 26498033 TI - Position Statement on Breastfeeding from the Italian Pediatric Societies. AB - The 2015 Position Statement on Breastfeeding of The Italian Pediatric Societies (SIP, SIN, SICupp, SIGENP) recognizes breastfeeding as an healthy behaviour with many short and long term benefits for both mother and infant.While protecting, promoting and supporting breastfeeding, neonatologists and pediatricians need specific knowledge, skills and a positive attitude toward breastfeeding. In Maternity Hospitals and in Neonatal Units, appropriate organizative interventions should be applied in order to facilitate the beginning of breastfeeding and the use of mother's/human milk.The Italian Pediatric Societies indicate the desiderable goal of around 6 months exclusive breastfeeding if the infant grows properly according to WHO Growth Charts. In principle, complementary feeding should not be anticipated before 6 months as a nutritional strategy pretending to prevent allergy and/or celiac disease. Eventually, long term breastfeeding should be supported meeting mother's desire. PMID- 26498031 TI - Combined effect of G3139 and TSPO ligands on Ca(2+)-induced permeability transition in rat brain mitochondria. AB - Permeability of the mitochondrial outer membrane is determined by the activity of voltage-dependent anion channels (VDAC) which are regulated by many factors and proteins. One of the main partner-regulator of VDAC is the 18 kDa translocator protein (TSPO), whose role in the regulation of membrane permeability is not completely understood. We show that TSPO ligands, 1 MUM PPIX and PK11195 at concentrations of 50 MUM, accelerate opening of permeability transition pores (mPTP) in Ca(2+)-overloaded rat brain mitochondria (RBM). By contrast, PK11195 at 100 nM and anti-TSPO antibodies suppressed pore opening. Participation of VDAC in these processes was demonstrated by blocking VDAC with G3139, an 18-mer phosphorothioate oligonucleotides, which sensitized mitochondria to Ca(2+) induced mPTP opening. Despite the inhibitory effect of 100 nM PK11195 and anti TSPO antibodies alone, their combination with G3139 considerably stimulated the mPTP opening. Thus, 100 nM PK11195 and anti-TSPO antibody can modify permeability of the VDAC channel and mPTP. When VDAC channels are closed and TSPO is blocked, permeability of the VDAC for calcium seems to be the highest, which leads to accelerated pore opening. PMID- 26498034 TI - Antimicrobial potential of 27 plants consumed by chimpanzees (Pan troglodytes verus Blumenbach) in Ivory Coast. AB - BACKGROUND: Due to their genetic proximity, chimpanzees share with human several diseases including bacterial, fungal and viral infections, such as candidiasis, acquired immune deficiency syndrome (AIDS), Ebola virus disease. However, in its natural environment, chimpanzees are tolerant to several pathogens including simian immunodeficiency virus (SIV), virus related to human immunodeficiency virus (HIV) that contribute to the emergence of opportunistic diseases such as microbial infections. METHODS: Twenty seven species of plants consumed by chimpanzees were evaluated for their antimicrobial potential against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, Candida tropicalis and Candida glabrata using the agar diffusion technique and micro dilution in 96-well plates. In total 132 extracts (33 dichloromethane, 33 methanol, 33 ethyl acetate and 33 aqueous) were tested. RESULTS: The results showed that 24 extracts (18 %) showed activity against bacteria and 6 extracts (5 %) were active against yeasts. The minimal inhibitory concentrations (MICs) values of active extracts ranged between 23 and 750 MUg/ml for bacteria and between 188 and 1500 MUg/ml for yeasts. CONCLUSION: Tristemma coronatum was the most promising on the studied microorganisms followed by Beilschmiedia mannii. The extracts of the two plants indicated by chimpanzees have potential for antimicrobial use in human. PMID- 26498035 TI - Annexins are instrumental for efficient plasma membrane repair in cancer cells. AB - Plasma membrane stress can cause damage to the plasma membrane, both when imposed by the extracellular environment and by enhanced oxidative stress. Cells cope with these injuries by rapidly activating their plasma membrane repair system, which is triggered by Ca(2+) influx at the wound site. The repair system is highly dynamic, depends on both lipid and protein components, and include cytoskeletal reorganization, membrane replacements, and membrane fusion events. Cancer cells experience enhanced membrane stress when navigating through dense extracellular matrix, which increases the frequency of membrane injuries. In addition, increased motility and oxidative stress further increase the risk of plasma membrane lesions. Cancer cells compensate by overexpressing Annexin proteins including Annexin A2 (ANXA2). Annexin family members can facilitate membrane fusion events and wound healing by binding to negatively charged phospholipids in the plasma membrane. Plasma membrane repair in cancer cells depends on ANXA2 protein, which is recruited to the wound site and forms a complex with the Ca(2+)-binding EF-hand protein S100A11. Here they regulate actin accumulation around the wound perimeter, which is required for wound closure. In this review, we will discuss the requirement for Annexins, S100 proteins and actin cytoskeleton in the plasma membrane repair response of cancer cells, which reveals a novel avenue for targeting metastatic cancers. PMID- 26498037 TI - Coccolithophore biomineralization: New questions, new answers. AB - Coccolithophores are unicellular phytoplankton that are characterized by the presence intricately formed calcite scales (coccoliths) on their surfaces. In most cases coccolith formation is an entirely intracellular process - crystal growth is confined within a Golgi-derived vesicle. A wide range of coccolith morphologies can be found amongst the different coccolithophore groups. This review discusses the cellular factors that regulate coccolith production, from the roles of organic components, endomembrane organization and cytoskeleton to the mechanisms of delivery of substrates to the calcifying compartment. New findings are also providing important information on how the delivery of substrates to the calcification site is co-ordinated with the removal of H(+) that are a bi-product of the calcification reaction. While there appear to be a number of species-specific features of the structural and biochemical components underlying coccolith formation, the fluxes of Ca(2+) and a HCO3(-) required to support coccolith formation appear to involve spatially organized recruitment of conserved transport processes. PMID- 26498036 TI - cncRNAs: Bi-functional RNAs with protein coding and non-coding functions. AB - For many decades, the major function of mRNA was thought to be to provide protein coding information embedded in the genome. The advent of high-throughput sequencing has led to the discovery of pervasive transcription of eukaryotic genomes and opened the world of RNA-mediated gene regulation. Many regulatory RNAs have been found to be incapable of protein coding and are hence termed as non-coding RNAs (ncRNAs). However, studies in recent years have shown that several previously annotated non-coding RNAs have the potential to encode proteins, and conversely, some coding RNAs have regulatory functions independent of the protein they encode. Such bi-functional RNAs, with both protein coding and non-coding functions, which we term as 'cncRNAs', have emerged as new players in cellular systems. Here, we describe the functions of some cncRNAs identified from bacteria to humans. Because the functions of many RNAs across genomes remains unclear, we propose that RNAs be classified as coding, non-coding or both only after careful analysis of their functions. PMID- 26498038 TI - Clinical detection and categorization of uncommon and concomitant mutations involving BRAF. AB - BACKGROUND: Selective BRAF inhibitors, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, have been approved for treatment of metastatic melanomas with a BRAF p.V600E mutation. The clinical significance of non-codon 600 mutations remains unclear, in part, due to variation of kinase activity for different mutants. METHODS: In this study, we categorized BRAF mutations according to the reported mutant kinase activity. A total of 1027 lung cancer, colorectal cancer or melanoma specimens were submitted for clinical mutation detection by next generation sequencing. RESULTS: Non-codon 600 mutations were observed in 37% of BRAF-mutated tumors. Of all BRAF mutants, 75% were kinase activated, 15% kinase-impaired and 10% kinase-unknown. The most common kinase impaired mutant involves codon 594, specifically, p.D594G (c.1781A > G) and p.D594N (c.1780G > A). Lung cancers showed significantly higher incidences of kinase-impaired or kinase-unknown mutants. Kinase-impaired BRAF mutants showed a significant association with concomitant activating KRAS or NRAS mutations, but not PIK3CA mutations, supporting the reported interaction of these mutations. CONCLUSIONS: BRAF mutants with impaired or unknown kinase activity as well as concomitant kinase-impaired BRAF mutations and RAS mutations were detected in lung cancers, colorectal cancers and melanomas. Different therapeutic strategies based on the BRAF mutant kinase activity and the concomitant mutations may be worthwhile. PMID- 26498039 TI - Clinical Electroencephalographic Biomarker for Impending Epilepsy in Asymptomatic Tuberous Sclerosis Complex Infants. AB - BACKGROUND: We assessed the clinical utility of routine electroencephalography (EEG) in the prediction of epilepsy onset in asymptomatic infants with tuberous sclerosis complex. METHODS: This multicenter prospective observational study recruited infants younger than 7 months, seizure-free and on no antiepileptic drugs at enrollment, who all underwent serial physical examinations and video EEGs throughout the study. Parental education on seizure recognition was completed at the time of initial enrollment. Once seizure onset occurred, standard of care was applied, and subjects were followed up until 24 months. RESULTS: Forty patients were enrolled, 28 older than 12 months with completed EEG evaluation at the time of this interim analysis. Of those, 19 (67.8%) developed seizures. Epileptic spasms occurred in 10 (52.6%), focal seizures in five (26.3%), generalized tonic-clonic seizure in one (5.3%), and a combination of epileptic spasms and focal seizures in three (15.7%). Fourteen infants (73.6%) had the first emergence of epileptiform abnormalities on EEG at an average age 4.2 months, preceding seizure onset by a median of 1.9 months. Hypsarrhythmia or modified hypsarrhythmia was not found in any infant before onset of epileptic spasms. All children with epileptiform discharges subsequently developed epilepsy (100% positive predictive value), and the negative predictive value for not developing epilepsy after a normal EEG was 64%. CONCLUSIONS: Serial routine EEGs in infants with tuberous sclerosis complex is a feasible strategy to identify individuals at high risk for epilepsy. The most frequent clinical presentation was epileptic spasms followed by focal seizures, and then a combination of both seizure types. PMID- 26498040 TI - Asymmetric synthesis of 1H-pyrrol-3(2H)-ones from 2,3-diketoesters by combination of aldol condensation with benzilic acid rearrangement. AB - An efficient two-step protocol for the asymmetric synthesis of 1H-pyrrol-3(2H) one derivatives in 99% ee from conveniently accessed 2,3-diketoesters has been developed. PMID- 26498041 TI - Reactive oxygen species contribute to dysfunction of bone marrow hematopoietic stem cells in aged C57BL/6 J mice. AB - BACKGROUND: Stem cells of intensely regenerative tissues are susceptible to cellular damage. Although the response to this process in hematopoietic stem cells (HSCs) is crucial, the mechanisms by which hematopoietic homeostasis is sustained are not completely understood. Aging increases reactive oxygen species (ROS) levels and inflammation, which contribute to increased proliferation, senescence and/or apoptosis, leading to self-renewal premature exhaustion. In this study, we assessed ROS production, DNA damage, apoptosis, senescence and plasticity in young, middle and aged (2-, 12- and 24-month-old, respectively) C57BL/6 J mice. RESULTS: Aged HSCs showed an increase in intracellular superoxide anion (1.4-fold), hydrogen peroxide (2-fold), nitric oxide (1.6-fold), peroxynitrite/hidroxil (2.6-fold) compared with young cells. We found that mitochondria and NADPHox were the major sources of ROS production in the three groups studied, whereas CYP450 contributed in middle and aged, and xanthine oxidase only in aged HSCs. In addition, we observed DNA damage and apoptosis in the middle (4.2- and 2-fold, respectively) and aged (6- and 4-fold, respectively) mice; aged mice also exhibited a significantly shorter telomere length (-1.8 fold) and a lower expression of plasticity markers. CONCLUSION: These data suggest that aging impairs the functionality of HSCs and that these age associated alterations may affect the efficacy of aged HSC recovery and transplantation. PMID- 26498042 TI - Transgenic mouse offspring generated by ROSI. AB - The production of transgenic animals is an important tool for experimental and applied biology. Over the years, many approaches for the production of transgenic animals have been tried, including pronuclear microinjection, sperm-mediated gene transfer, transfection of male germ cells, somatic cell nuclear transfer and the use of lentiviral vectors. In the present study, we developed a new transgene delivery approach, and we report for the first time the production of transgenic animals by co-injection of DNA and round spermatid nuclei into non-fertilized mouse oocytes (ROSI). The transgene used was a construct containing the human CMV immediate early promoter and the enhanced GFP gene. With this procedure, 12% of the live offspring we obtained carried the transgene. This efficiency of transgenic production by ROSI was similar to the efficiency by pronuclear injection or intracytoplasmic injection of male gamete nuclei (ICSI). However, ICSI required fewer embryos to produce the same number of transgenic animals. The expression of Egfp mRNA and fluorescence of EGFP were found in the majority of the organs examined in 4 transgenic lines generated by ROSI. Tissue morphology and transgene expression were not distinguishable between transgenic animals produced by ROSI or pronuclear injection. Furthermore, our results are of particular interest because they indicate that the transgene incorporation mediated by intracytoplasmic injection of male gamete nuclei is not an exclusive property of mature sperm cell nuclei with compact chromatin but it can be accomplished with immature sperm cell nuclei with decondensed chromatin as well. The present study also provides alternative procedures for transgene delivery into embryos or reconstituted oocytes. PMID- 26498043 TI - Appropriateness of colonoscopy requests according to EPAGE-II in the Spanish region of Catalonia. AB - BACKGROUND: In a context of increasing demand and pressure on the public health expenditure, appropriateness of colonoscopy indications is a topic of discussion. The objective of this study is to evaluate the appropriateness of colonoscopy requests performed in a primary care (PC) setting in Catalonia. METHODS: Cross sectional descriptive study. Out-patients >14 years of age, referred by their reference physicians from PC or hospital care settings to the endoscopy units in their reference hospitals, to undergo a colonoscopy. Evaluation of the appropriateness of 1440 colonoscopy requests issued from January to July 2011, according to the EPAGE-II guidelines (European Panel on the Appropriateness of Gastrointestinal Endoscopy). RESULTS: The most frequent indications of diagnostic suspicion requests were: rectal bleeding (37.46 %), abdominal pain (26.54 %), and anaemia study (16.78 %). The most frequent indications of disease follow-up were adenomas (58.1 %), and CRC (31.16 %). Colonoscopy was appropriate in 73.68 % of the cases, uncertain in 16.57 %, and inappropriate in 9.74 %. In multivariate analysis, performed colonoscopies reached an OR of 9.9 (CI 95 % 1.16-84.08) for qualifying as appropriate for colorectal cancer (CRC) diagnosis, 1.49 (CI 95 % 1.1-2.02) when requested by a general practitioner, and 1.09 (CI 95 % 1.07-1.1) when performed on women. CONCLUSIONS: Appropriateness of colonoscopy requests in our setting shows a suitable situation in accordance with recognized standards. General practitioners contribute positively to this appropriateness level. It is necessary to provide physicians with simple and updated guidelines, which stress recommendations for avoiding colonoscopy requests in the most prevalent conditions in PC. PMID- 26498044 TI - Ankyrin exposure induced by activated protein kinase C plays a potential role in erythrophagocytosis. AB - BACKGROUND: In physiological and pathological conditions activated protein kinace C (PKC) has been observed in the erythrocytes. Externalization of ankyrin followed by Arg-Gly-Asp (RGD)/integrin recognition also triggers erythrophagocytosis. In the present study, to test whether activated PKC is associated with ankyrin exposure in erythrophagocytosis. METHODS: Phorbol 12 myristate-13-acetate (PMA)-induced PKC activation and ankyrin phosphorylation were tested, and under different treatment conditions the subpopulation of erythrocytes with ankyrin exposure and the levels of intracellular calcium were analyzed by flow cytometry. RESULTS: Results showed that treatment of erythrocytes with PMA in a calcium-containing buffer led to ankyrin exposure. In the absence of extracellular calcium, no ankyrin exposure was observed. PKC inhibition with calphostin C, a blocker of the PMA binding site, completely prevented the calcium entry, protein phosphorylation and ankyrin exposure. PKC inhibition with chelerythrine chloride, an inhibitor of the active site, diminished the level of ankyrin-exposing cells and ankyrin phosphorylation; however it even led to a higher percentage of cells with increased levels of calcium than with PMA treatment alone. Although PKC was activated and ankyrin phosphorylation occurred, no ankyrin exposure was observed in the absence of extracellular calcium. CONCLUSION: Analyses of results suggested that PMA induces calcium influx into the erythrocytes, leading to the activation of calcium dependent enzymes and the phosphorylation of membrane proteins, ultimately inducing ankyrin exposure and erythrophagocytosis. This study may provide insights into the molecular mechanisms of removing aged or diseased erythrocytes. PMID- 26498046 TI - Breast image pre-processing for mammographic tissue segmentation. AB - During mammographic image acquisition, a compression paddle is used to even the breast thickness in order to obtain optimal image quality. Clinical observation has indicated that some mammograms may exhibit abrupt intensity change and low visibility of tissue structures in the breast peripheral areas. Such appearance discrepancies can affect image interpretation and may not be desirable for computer aided mammography, leading to incorrect diagnosis and/or detection which can have a negative impact on sensitivity and specificity of screening mammography. This paper describes a novel mammographic image pre-processing method to improve image quality for analysis. An image selection process is incorporated to better target problematic images. The processed images show improved mammographic appearances not only in the breast periphery but also across the mammograms. Mammographic segmentation and risk/density classification were performed to facilitate a quantitative and qualitative evaluation. When using the processed images, the results indicated more anatomically correct segmentation in tissue specific areas, and subsequently better classification accuracies were achieved. Visual assessments were conducted in a clinical environment to determine the quality of the processed images and the resultant segmentation. The developed method has shown promising results. It is expected to be useful in early breast cancer detection, risk-stratified screening, and aiding radiologists in the process of decision making prior to surgery and/or treatment. PMID- 26498045 TI - Nonstandard working schedules and health: the systematic search for a comprehensive model. AB - BACKGROUND: Theoretical models on shift work fall short of describing relevant health-related pathways associated with the broader concept of nonstandard working schedules. Shift work models neither combine relevant working time characteristics applicable to nonstandard schedules nor include the role of rest periods and recovery in the development of health complaints. Therefore, this paper aimed to develop a comprehensive model on nonstandard working schedules to address these shortcomings. METHODS: A literature review was conducted using a systematic search and selection process. Two searches were performed: one associating the working time characteristics time-of-day and working time duration with health and one associating recovery after work with health. Data extracted from the models were used to develop a comprehensive model on nonstandard working schedules and health. RESULTS: For models on the working time characteristics, the search strategy yielded 3044 references, of which 26 met the inclusion criteria that contained 22 distinctive models. For models on recovery after work, the search strategy yielded 896 references, of which seven met the inclusion criteria containing seven distinctive models. Of the models on the working time characteristics, three combined time-of-day with working time duration, 18 were on time-of-day (i.e. shift work), and one was on working time duration. The model developed in the paper has a comprehensive approach to working hours and other work-related risk factors and proposes that they should be balanced by positive non-work factors to maintain health. Physiological processes leading to health complaints are circadian disruption, sleep deprivation, and activation that should be counterbalanced by (re-)entrainment, restorative sleep, and recovery, respectively, to maintain health. CONCLUSIONS: A comprehensive model on nonstandard working schedules and health was developed. The model proposes that work and non-work as well as their associated physiological processes need to be balanced to maintain good health. The model gives researchers a useful overview over the various risk factors and pathways associated with health that should be considered when studying any form of nonstandard working schedule. PMID- 26498047 TI - Manifold ranking based scoring system with its application to cardiac arrest prediction: A retrospective study in emergency department patients. AB - BACKGROUND: The recently developed geometric distance scoring system has shown the effectiveness of scoring systems in predicting cardiac arrest within 72h and the potential to predict other clinical outcomes. However, the geometric distance scoring system predicts scores based on only local structure embedded by the data, thus leaving much room for improvement in terms of prediction accuracy. METHODS: We developed a novel scoring system for predicting cardiac arrest within 72h. The scoring system was developed based on a semi-supervised learning algorithm, manifold ranking, which explores both the local and global consistency of the data. System evaluation was conducted on emergency department patients' data, including both vital signs and heart rate variability (HRV) parameters. Comparison of the proposed scoring system with previous work was given in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV). RESULTS: Out of 1025 patients, 52 (5.1%) met the primary outcome. Experimental results show that the proposed scoring system was able to achieve higher area under the curve (AUC) on both the balanced dataset (0.907 vs. 0.824) and the imbalanced dataset (0.774 vs. 0.734) compared to the geometric distance scoring system. CONCLUSIONS: The proposed scoring system improved the prediction accuracy by utilizing the global consistency of the training data. We foresee the potential of extending this scoring system, as well as manifold ranking algorithm, to other medical decision making problems. Furthermore, we will investigate the parameter selection process and other techniques to improve performance on the imbalanced dataset. PMID- 26498048 TI - Social Support and Supervisory Quality Interventions in the Workplace: A Stakeholder-Centered Best-Evidence Synthesis of Systematic Reviews on Work Outcomes. AB - BACKGROUND: There is controversy surrounding the impact of workplace interventions aimed at improving social support and supervisory quality on absenteeism, productivity and financial outcomes. OBJECTIVE: To determine the value of social support interventions for work outcomes. METHODS: Databases were searched for systematic reviews between 2000 and 2012 to complete a synthesis of systematic reviews guided by the PRISMA statement and the IOM guidelines for systematic reviews. Assessment of articles for inclusion and methodological quality was conducted independently by at least two researchers, with differences resolved by consensus. RESULTS: The search resulted in 3363 titles of which 3248 were excluded following title/abstract review, leaving 115 articles that were retrieved and underwent full article review. 10 articles met the set inclusion criteria, with 7 focusing on social support, 2 on supervisory quality and 1 on both. We found moderate and limited evidence, respectively, that social support and supervisory quality interventions positively impact workplace outcomes. CONCLUSION: There is moderate evidence that social support and limited evidence that supervisory quality interventions have a positive effect on work outcomes. PMID- 26498049 TI - A 'Balanced' Life: Work-Life Balance and Sickness Absence in Four Nordic Countries. AB - BACKGROUND: Little attention has been given to the relationship between work-life balance and sickness absence. OBJECTIVE: To investigate the association between poor work-life balance and sickness absence in 4 Nordic welfare states. METHODS: Multivariable logistic regression analysis was performed on pooled cross sectional data of workers aged 15-65 years from Denmark, Finland, Sweden, and Norway (n=4186) obtained from the 2010 European Working Conditions Survey (EWCS). Poor work-life balance was defined based on the fit between working hours and family or social commitments outside work. Self-reported sickness absence was measured as absence for >=7 days from work for health reasons. RESULTS: Poor work life balance was associated with elevated odds (OR 1.38, 95% CI 1.06 to 1.80) of self-reported sickness absence and more health problems in the 4 Nordic countries, even after adjusting for several important confounding factors. Work related characteristics, ie, no determination over schedule (OR 1.26, 95% CI 1.04 to 1.53), and job insecurity (OR 1.56, 95% CI 1.21 to 2.02) increased the likelihood of sickness absence, and household characteristics, ie, cohabitation status (OR 0.75, 95% CI 0.58 to 0.96) reduced this likelihood. The associations were non-significant when performed separately for women and men. CONCLUSION: Sickness absence is predicted by poor work-life balance. Findings suggest the need for implementation of measures that prevent employee difficulties in combining work and family life. PMID- 26498050 TI - Dimensions of Safety Climate among Iranian Nurses. AB - BACKGROUND: Workplace safety has been a concern of workers and managers for decades. Measuring safety climate is crucial in improving safety performance. It is also a method of benchmarking safety perception. OBJECTIVE: To develop and validate a psychometrics scale for measuring nurses' safety climate. METHODS: Literature review, subject matter experts and nurse's judgment were used in items developing. Content validity and reliability for new tool were tested by content validity index (CVI) and test-retest analysis, respectively. Exploratory factor analysis (EFA) with varimax rotation was used to improve the interpretation of latent factors. RESULTS: A 40-item scale in 6 factors was developed, which could explain 55% of the observed variance. The 6 factors included employees' involvement in safety and management support, compliance with safety rules, safety training and accessibility to personal protective equipment, hindrance to safe work, safety communication and job pressure, and individual risk perception. CONCLUSION: The proposed scale can be used in identifying the needed areas to implement interventions in safety climate of nurses. PMID- 26498051 TI - Validity and Reliability of Malay Version of the Job Content Questionnaire among Public Hospital Female Nurses in Malaysia. AB - BACKGROUND: The Job Content Questionnaire (M-JCQ) is an established self-reported instrument used across the world to measure the work dimensions based on the Karasek's demand-control-support model. OBJECTIVE: To evaluate the psychometrics properties of the Malay version of M-JCQ among nurses in Malaysia. METHODS: This cross-sectional study was carried out on nurses working in 4 public hospitals in Klang Valley area, Malaysia. M-JCQ was used to assess the perceived psychosocial stressors and physical demands of nurses at their workplaces. Construct validity of the questionnaire was examined using exploratory factor analysis (EFA). Cronbach's alpha values were used to estimate the reliability (internal consistency) of the M-JCQ. RESULTS: EFA showed that 34 selected items were loaded in 4 factors. Except for psychological job demand (Cronbach's alpha 0.51), the remaining 3 alpha values for 3 subscales (job control, social support, and physical demand) were greater than 0.70, indicating acceptable internal consistency. However, an item was excluded due to poor item-total correlation (r<0.3). The final M-JCQ was consisted of 33 items. CONCLUSION: The M-JCQ is a reliable and valid instrument to measure psychosocial and physical stressors in the workplace of public hospital nurses in Malaysia. PMID- 26498053 TI - The Deadly Heat Wave of Pakistan, June 2015. PMID- 26498054 TI - Deadly Heat Wave in Karachi, July 2015: Negligence or Mismanagement? PMID- 26498052 TI - Occupational Safety Precautions among Nurses at Four Hospitals, Nablus District, Palestine. AB - Occupational hazards, exposure to blood and body fluids (BBF) accidents and safety precautions constitute an important public health issue. We assessed the prevalence and determinants of exposure to occupational hazards among nurses, and their knowledge of occupational safety precautions. In a cross-sectional study, we surveyed 332 nurses working in 4 hospitals, Nablus, West Bank, Palestine, by a questionnaire. Bivariate analysis tested the associations between ever exposure and the high likelihood of BBF exposure and the independent socio-demographic and occupational variables. Binary logistic regression analysis was used to assess the associations between the same two exposures and selected independent variables (those significant in the bivariate analysis). Prevalence of ever exposure to BBF was 51.7%, and was associated with working in private and charitable hospitals (OR 2.62, 2.68, respectively), having 4-6 family members (OR 0.52) and "nursing" being as one's top career choice at university (OR 0.48). The prevalence of high likelihood of BBF exposure was 62.2%, and was associated with working in charitable and private hospitals (OR 7.81, 2.43, respectively) and "nursing" being as one's top career choice (OR 0.57). Regarding knowledge, most respondents believed it is necessary to enact laws and regulations regarding occupational safety precautions, reported the use of sharps containers, immediate disinfection after an accident, reporting an accident, and using personal protective equipment. Nurses had adequate knowledge of the risks of their hospital work. Nevertheless, they exhibited high prevalence of exposure to BBF accidents. Future studies are needed to re-evaluate existing occupational safety guidelines in hospitals, establish monitoring and evaluation protocols for health care workers' adherence to the guidelines, and institute well-defined policies for reporting occupational injury incidents so these can be handled appropriately. PMID- 26498055 TI - Neurogenic Lower Urinary Tract Dysfunction in Adults with Cerebral Palsy: Outcomes following a Conservative Management Approach. AB - PURPOSE: Cerebral palsy is characterized by motor impairment following injury to the developing brain. Neurogenic lower urinary tract dysfunction is estimated to affect at least a third of children with cerebral palsy. However there are limited data as patients transition to adulthood. We sought to describe the symptoms, sequelae and management of neurogenic lower urinary tract dysfunction in adults with cerebral palsy. MATERIALS AND METHODS: We retrospectively reviewed the charts of adult patients with cerebral palsy between 2011 and 2014. Patients with prior bladder reconstruction or catheterization based bladder drainage were excluded from study. Cerebral palsy severity was determined using GMFCS (Gross Motor Function Classification System). A conservative evaluation and treatment paradigm was used. Noninvasive treatments were encouraged. Specifically clean intermittent catheterization, which is often not feasible, is avoided unless urinary retention, hydronephrosis or refractory lower urinary tract symptoms develop. RESULTS: There were 121 patients included in final analysis. Median age was 25 and 61 patients (50%) had GMFCS level V. Noninvasive management failed in 28 of 121 patients (23%) as defined by hydronephrosis in 9, persistent urinary retention in 10 and refractory lower urinary tract symptoms/incontinence in 9. Urethral clean intermittent catheterization was poorly tolerated. Of all patients 25% showed evidence of urolithiasis during the study period. Surgical intervention was rare and associated with significant morbidity. CONCLUSIONS: Adults with cerebral palsy may present with variable signs and symptoms of neurogenic lower urinary tract dysfunction. Conservative treatment was successful in more than 75% of patients. Clean intermittent catheterization was poorly tolerated in patients in whom conservative treatment failed. Surgical intervention was rarely indicated and it should be reserved for select individuals. PMID- 26498057 TI - Effect of Testosterone Solution 2% on Testosterone Concentration, Sex Drive and Energy in Hypogonadal Men: Results of a Placebo Controlled Study. AB - PURPOSE: We determined the effect of testosterone solution 2% on total testosterone level and the 2 symptoms of hypogonadism, sex drive and energy level. MATERIALS AND METHODS: This was a randomized, multicenter, double-blind, placebo controlled, 16-week study to compare the effect of testosterone and placebo on the proportion of men with a testosterone level within the normal range (300 to 1,050 ng/dl) upon treatment completion. We also assessed the impact of testosterone on sex drive and energy level measured using SAID (Sexual Arousal, Interest and Drive scale) and HED (Hypogonadism Energy Diary), respectively. A total of 715 males 18 years old or older with total testosterone less than 300 ng/dl and at least 1 symptom of testosterone deficiency (decreased energy and/or decreased sexual drive) were randomized to 60 mg topical testosterone solution 2% or placebo once daily. RESULTS: Of study completers 73% in the testosterone vs 15% in the placebo group had a testosterone level within the normal range at study end point (p <0.001). Participants assigned to testosterone showed greater baseline to end point improvement in SAID scores (low sex drive subset p <0.001 vs placebo) and HED scores (low energy subset p = 0.02 vs placebo, not significant at prespecified p <0.01). No major adverse cardiovascular or venous thrombotic events were reported in the testosterone group. The incidence of increased hematocrit was higher with testosterone vs placebo (p = 0.04). CONCLUSIONS: Once daily testosterone solution 2% for 12 weeks was efficacious in restoring normal testosterone levels and improving sexual drive in hypogonadal men. Improvement was also seen in energy levels on HED though not at the prespecified p <0.01. No new safety signals were identified. PMID- 26498056 TI - Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2015. AB - PURPOSE: The purpose of this amendment is to incorporate relevant newly-published literature to better provide a rational basis for the management of patients with castration-resistant prostate cancer. MATERIALS AND METHODS: The original systematic review and meta-analysis of the published literature yielded 303 studies published from 1996 through 2013. This review informed the majority of the guideline statements. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence. In April 2014, the CRPC guideline underwent amendment based on an additional literature search, which retrieved additional studies published between February 2013 and February 2014. Thirty-seven studies from this search provided data relevant to the specific treatment modalities for CRPC. In March 2015, the CRPC guideline underwent a second amendment, which incorporated 10 additional studies into the evidence base published through February 2015. RESULTS: Guideline statements based on six index patients developed to represent the most common scenarios encountered in clinical practice were amended appropriately. The additional literature provided the basis for an update of current supporting text as well as the incorporation of new guideline statements for multiple index patients. CONCLUSIONS: Given the rapidly evolving nature of this field, this guideline should be used in conjunction with recent systematic literature reviews and an understanding of the individual patient's treatment goals. Patients' preferences and personal goals should be considered when choosing management strategies. This guideline will be continually updated as new literature emerges in the field. PMID- 26498058 TI - Increasing incidence of pertussis in Brazil: a retrospective study using surveillance data. AB - BACKGROUND: Many countries have reported an increase in the incidence of pertussis, which has become a global public health concern. METHODS: In this study, the epidemiology of pertussis in Brazil was assessed retrospectively using surveillance data gathered from case notification forms from 2007 to 2014. RESULTS: From 2007 to 2014, 80,068 suspected cases of pertussis were reported in Brazil. Of these, 24,612 (32 %) were confirmed by various criteria. The annual distribution of confirmed cases demonstrated a significant increase in incidence rate since 2012. A seasonal pattern in which cases occur most frequently between the end of spring and midsummer has been identified. Among the confirmed cases, 34.5 % occurred in infants aged 0-2 months, 22.4 % occurred in infants aged 3-6 months, 21 % occurred in children aged 7 months to 4 years, and 8 % were reported in adults >21 years. Of the confirmed cases, 47.2 % met only clinical criteria, 15.5 % met clinical and epidemiological criteria, and 36.6 % were confirmed in a laboratory. The overall case fatality rate was 2.1 %, reaching 4.7 % among infants aged 0-2 months. The complications most commonly reported in the notification forms were pneumonia, encephalitis, dehydration, otitis, and malnutrition. Of the confirmed cases, 23.1 % occurred in subjects who received at least 3 doses of the pertussis vaccine. Within this group, there were 1098 infants aged 7 to 15 months and 2079 children aged 16 months to 4 years. In 2012, 18 states did not achieve 95 % immunization coverage, a number that dropped to 10 and 6 in 2013 and 2014, respectively. CONCLUSIONS: Brazil's main challenges in facing pertussis resurgence will be to offer the best quality medical attention to reduce mortality, to improve the infrastructure for laboratory diagnosis and to increase vaccination coverage. Additional studies to assess the effectiveness of the current vaccination schedule and basic research on the genetics and evolution of circulating B. pertussis strains are also needed. PMID- 26498059 TI - Attributes and weights in health care priority setting: A systematic review of what counts and to what extent. AB - In most societies resources are insufficient to provide everyone with all the health care they want. In practice, this means that some people are given priority over others. On what basis should priority be given? In this paper we are interested in the general public's views on this question. We set out to synthesis what the literature has found as a whole regarding which attributes or factors the general public think should count in priority setting and what weight they should receive. A systematic review was undertaken (in August 2014) to address these questions based on empirical studies that elicited stated preferences from the general public. Sixty four studies, applying eight methods, spanning five continents met the inclusion criteria. Discrete Choice Experiment (DCE) and Person Trade-off (PTO) were the most popular standard methods for preference elicitation, but only 34% of all studies calculated distributional weights, mainly using PTO. While there is heterogeneity, results suggest the young are favoured over the old, the more severely ill are favoured over the less severely ill, and people with self-induced illness or high socioeconomic status tend to receive lower priority. In those studies that considered health gain, larger gain is universally preferred, but at a diminishing rate. Evidence from the small number of studies that explored preferences over different components of health gain suggests life extension is favoured over quality of life enhancement; however this may be reversed at the end of life. The majority of studies that investigated end of life care found weak/no support for providing a premium for such care. The review highlights considerable heterogeneity in both methods and results. Further methodological work is needed to achieve the goal of deriving robust distributional weights for use in health care priority setting. PMID- 26498060 TI - The effect of foetal bovine serum supplementation upon the lactate dehydrogenase cytotoxicity assay: Important considerations for in vitro toxicity analysis. AB - The lactate dehydrogenase (LDH) assay is a commonly-used tool for assessing toxicity in vitro. However, anecdotal reports suggest that foetal bovine serum (FBS) may contain LDH at concentrations significant enough to interfere with the assay and thus reduce its sensitivity. A series of experiments were performed to determine whether addition of FBS to culture medium significantly elevated culture media LDH content, and whether replacement of FBS with heat inactivated foetal bovine serum (HI-FBS) reduced LDH content and interfered with cell response to cytotoxic challenge. The addition of FBS at 5, 10 and 15% final concentrations increased culture medium LDH content in a dose-dependent manner. The substitution of HI-FBS for FBS reduced culture medium LDH content and increased the dynamic range of the assay. Cell viability of the SH-SY5Y human neuroblastoma and N27 rat mesencephalic neurone cell lines were significantly reduced as measured using the MTT reduction assay, whilst HI-FBS only affected toxicity response in a cell- and toxin-specific manner, although these effects were small. Hence, for cell lines with a high FBS requirement, the use of HI-FBS or alternative toxicity assays can be considered, or the use of alternative formulations, such as chemically-defined serum-free media, be adopted. PMID- 26498061 TI - Inhibitory effect 6-gingerol on adipogenesis through activation of the Wnt/beta catenin signaling pathway in 3T3-L1 adipocytes. AB - 6-Gingerol has been reported to inhibit adipogenesis and lipid content accumulation. However, the mechanism of its anti-adipogenic effect remains unclear. Our aim is to investigate the molecular mechanism of the anti-adipogenic effect of 6-gingerol. The lipid content in adipocytes was measured by Oil Red O staining and cell viability was analyzed by MTT assay. The extent of suppression of differentiation by 6-gingerol was characterized by measuring the triglyceride content and GPDH activity. The regulation of adipogenic markers and the components of the Wnt/beta-catenin pathway were analyzed by real-time PCR and Western blotting. The nuclear location of beta-catenin was identified using immunofluorescence assay. Small interfering RNA transfection was conducted to elucidate the crucial role of beta-catenin in anti-adipogenic effect of 6 gingerol. Our results showed that 6-gingerol inhibited the adipogenesis and lowered the mRNA expression levels of transcription factors and the key lipogenic enzymes in 3T3-L1 cells. The effect of 6-gingerol on adipogenic differentiation was accompanied by stimulating the activation of the Wnt/beta-catenin signaling. In addition, we found that 6-gingerol induced phosphorylations of glycogen synthase kinase-3beta(GSK-3beta), and promoted the nuclear accumulation of beta catenin. Importantly, the inhibitory effect of 6-gingerol on adipogenic differentiation was reversed after the siRNA knockdown of beta-catenin was added. Our findings demonstrated that 6-gingerol inhibits the adipogenic differentiation of 3T3-L1 cells through activating the Wnt/beta-catenin signaling pathway. PMID- 26498062 TI - Plasmodium falciparum malaria in migrants who transited Libya - Where did they contract malaria? PMID- 26498063 TI - Determining temperature distribution in tissue in the focal plane of the high (>100 W/cm(2)) intensity focused ultrasound beam using phase shift of ultrasound echoes. AB - In therapeutic applications of High Intensity Focused Ultrasound (HIFU) the guidance of the HIFU beam and especially its focal plane is of crucial importance. This guidance is needed to appropriately target the focal plane and hence the whole focal volume inside the tumor tissue prior to thermo-ablative treatment and beginning of tissue necrosis. This is currently done using Magnetic Resonance Imaging that is relatively expensive. In this study an ultrasound method, which calculates the variations of speed of sound in the locally heated tissue volume by analyzing the phase shifts of echo-signals received by an ultrasound scanner from this very volume is presented. To improve spatial resolution of B-mode imaging and minimize the uncertainty of temperature estimation the acoustic signals were transmitted and received by 8 MHz linear phased array employing Synthetic Transmit Aperture (STA) technique. Initially, the validity of the algorithm developed was verified experimentally in a tissue mimicking phantom heated from 20.6 to 48.6 degrees C. Subsequently, the method was tested using a pork loin sample heated locally by a 2 MHz pulsed HIFU beam with focal intensity ISATA of 129 W/cm(2). The temperature calibration of 2D maps of changes in the sound velocity induced by heating was performed by comparison of the algorithm-determined changes in the sound velocity with the temperatures measured by thermocouples located in the heated tissue volume. The method developed enabled ultrasound temperature imaging of the heated tissue volume from the very inception of heating with the contrast-to-noise ratio of 3.5-12 dB in the temperature range 21-56 degrees C. Concurrently performed, conventional B mode imaging revealed CNR close to zero dB until the temperature reached 50 degrees C causing necrosis. The data presented suggest that the proposed method could offer an alternative to MRI-guided temperature imaging for prediction of the location and extent of the thermal lesion prior to applying the final HIFU treatment. PMID- 26498064 TI - Frequency analysis of photoplethysmogram and its derivatives. AB - There are a limited number of studies on heat stress dynamics during exercise using the photoplethysmogram (PPG). We investigate the PPG signal and its derivatives for heat stress assessment using Welch (non-parametric) and autoregressive (parametric) spectral estimation methods. The preliminary results of this study indicate that applying the first and second derivatives to PPG waveforms is useful for determining heat stress level using 20-s recordings. Interestingly, Welch's and Yule-Walker's methods in agreement that the second derivative is an improved detector for heat stress. In fact, both spectral estimation methods showed a clear separation in the frequency domain between measurements before and after simulated heat-stress induction when the second derivative is applied. Moreover, the results demonstrate superior performance of the Welch's method over the Yule-Walker's method in separating before and after the three simulated heat-stress inductions. PMID- 26498065 TI - miRNA expression profile of vulvar squamous cell carcinoma and identification of the oncogenic role of miR-590-5p. AB - MicroRNAs (miRNAs), a class of small non-coding RNA molecules, are associated with a variety of human cancers. Currently, little data are available regarding miRNA expression in vulvar squamous cell carcinoma (VSCC); the mechanism of action of miRNAs in VSCC still requires investigation. The aim of the present study was to investigate the miRNA expression profile in VSCC using a miRCURYTM LNA array. The expression levels of selected miRNAs were quantified by RT-qPCR. The relationship between miR-590-5p expression and clinical pathology was assessed. The expression levels of crucial transforming growth factor-beta (TGF beta) and Smad pathway factors were detected. We further investigated the role of miR-590-5p via in vitro studies in the A431 human VSCC cell line. A total of 157 miRNAs showed significantly altered expression in this type of carcinoma. Of particular interest, miR-590-5p, miR-182-5p and miR-183-5p were upregulated, and miR-603, miR-103a-3p and miR-107 were downregulated. A positive relationship was found between miR-590-5p expression and lymph node metastasis. In VSCC, TGFbeta1 and TGFbeta2 were significantly overexpressed and TGFbetaRII and Smad4 were significantly underexpressed at both the RNA and protein levels. In A431 cells, overexpression of miR-590-5p promoted proliferation, migration and G1-S phase transition and downregulated TGFbetaRII. The knockdown of TGFbetaRII by siRNA promoted malignant behaviours in the A431 cells. In conclusion, we present the miRNA expression profile in VSCC, and our findings suggest that the upregulation of miR-590-5p promotes cellular malignant behaviours via the target gene TGFbetaRII. PMID- 26498067 TI - Purines in neurite growth and astroglia activation. AB - The mammalian nervous system is a complex, functional network of neurons, consisting of local and long-range connections. Neuronal growth is highly coordinated by a variety of extracellular and intracellular signaling molecules. Purines turned out to be an essential component of these processes. Here, we review the current knowledge about the involvement of purinergic signaling in the regulation of neuronal development. We particularly focus on its role in neuritogenesis: the formation and extension of neurites. In the course of maturation mammals generally lose their ability to regenerate the central nervous system (CNS) e.g. after traumatic brain injury; although, spontaneous regeneration still occurs in the peripheral nervous system (PNS). Thus, it is crucial to translate the knowledge about CNS development and PNS regeneration into novel approaches to enable neurons of the mature CNS to regenerate. In this context we give a general overview of growth-inhibitory and growth-stimulatory factors and mechanisms involved in neurite growth. With regard to neuronal growth, astrocytes are an important cell population. They provide structural and metabolic support to neurons and actively participate in brain signaling. Astrocytes respond to injury with beneficial or detrimental reactions with regard to axonal growth. In this review we present the current knowledge of purines in these glial functions. Moreover, we discuss organotypic brain slice co-cultures as a model which retains neuron-glia interactions, and further presents at once a model for CNS development and regeneration. In summary, the purinergic system is a pivotal factor in neuronal development and in the response to injury. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID- 26498066 TI - The inverted free energy landscape of an intrinsically disordered peptide by simulations and experiments. AB - The free energy landscape theory has been very successful in rationalizing the folding behaviour of globular proteins, as this representation provides intuitive information on the number of states involved in the folding process, their populations and pathways of interconversion. We extend here this formalism to the case of the Abeta40 peptide, a 40-residue intrinsically disordered protein fragment associated with Alzheimer's disease. By using an advanced sampling technique that enables free energy calculations to reach convergence also in the case of highly disordered states of proteins, we provide a precise structural characterization of the free energy landscape of this peptide. We find that such landscape has inverted features with respect to those typical of folded proteins. While the global free energy minimum consists of highly disordered structures, higher free energy regions correspond to a large variety of transiently structured conformations with secondary structure elements arranged in several different manners, and are not separated from each other by sizeable free energy barriers. From this peculiar structure of the free energy landscape we predict that this peptide should become more structured and not only more compact, with increasing temperatures, and we show that this is the case through a series of biophysical measurements. PMID- 26498068 TI - Sequential integrated antenatal screening for Down's syndrome, trisomy 18 and trisomy 13. AB - OBJECTIVE: To estimate the performance of antenatal sequential Integrated screening for Down's syndrome (DS), trisomy 18 (T18) and trisomy 13 (T13), in which women have first trimester testing for each disorder; those above specified risk cut-offs are screen-positive, and the remainder continue to Integrated testing, using first and second trimester screening markers together. METHODS: Published screening marker parameters and Monte Carlo simulation were used to calculate detection rates (DR's) and risk cut-off levels for specified false positive rates (FPR's), and DR's and FPR's for specified risk cut-offs. We compared this screening performance with that based on all women having Integrated tests. RESULTS: Sequential Integrated DS screening detects 71% of DS pregnancies at the first trimester stage at a 0.5% FPR. For an overall 2% FPR, the DS DR is 92%, the same screening performance as the Integrated test performed on all women. Sequential Integrated T18 and T13 screening detects 70% of T18 and 53% of T13 pregnancies at the first trimester stage at a 0.05% FPR for each. The overall T18 and T13 DR's are 96% and 72% respectively at 0.2% FPR, the same screening performance as with Integrated tests performed on all women. Increasing the overall FPR's does not materially increase the DR's for any of the three disorders. CONCLUSION: The performance of sequential Integrated screening is similar to the performance if all women have an Integrated test, but has the advantage of identifying most DS, T18, and T13 pregnancies a few weeks earlier. PMID- 26498069 TI - Growth and nutritional status in children with chronic kidney disease on maintenance dialysis in Poland. AB - PURPOSE: Despite vast availability of modern methods of treatment of chronic kidney disease and its complications, the short stature still is a major point of concern in adolescents with chronic kidney disease. The aim of the study was to assess changes in growth and nutritional status of Polish children on renal replacement therapy in the decade, 2004-2013. MATERIAL AND METHODS: The study was designed as a cross-sectional analysis of anthropometric values and selected indices of growth status amongst children receiving dialysis in Poland between the years 2004 and 2013. Data were acquired during two different multicentre studies on hypertension in dialyzed children in Poland. Basic anthropometric parameters (body weight, body height/length, body mass index - BMI), dialysis adequacy and duration of RRT were assessed. RESULTS: The study showed that anthropometric parameters of children undergoing renal replacement therapy had not significantly changed in the last 10 years of observation. Children on RRT were still of short stature despite availability of modern methods of hormonal therapy and nutrition. Median of height z-score was -2.10 in 2004 and -2.19 in 2013. Expected clinical improvement in these measures was not proven. CONCLUSIONS: The cause of chronic kidney disease, method of dialysis, time on dialysis or dialysis adequacy did not influence the anthropometric parameters significantly in dialyzed children in Poland. PMID- 26498070 TI - Cross-talk between alpha7 nAchR and NMDAR revealed by protein profiling. AB - Functional regulation of NMDA receptor (NMDAR) by the activation of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) has been reported, although the molecular signaling pathway underlying this process remains largely unknown. We employed a label-free quantitative proteomics approach to identify potential intracellular molecules and pathways that might be involved in the functional cross-talk between NMDAR and alpha7nAChR. 43 proteins showed significantly expression changes after choline treatment in which 35 out of 43 proteins was significantly altered by co-treatment with NMDA. Western blot analysis verified proteins expression determined by LC-MS. Furthermore, protein expression in vivo in neurons from fetal rats were visualized and quantified by Confocal microscopy,which showed consistency of relative changes of AHA-1 expressionmeasured by LC-MS and Western blot. Biological network analysis of differently expressed proteins found 21 kind of biological pathways involved. Of those pathways, 6 pathways were directly involved in regulation of neurotransmitters. Lastly, the levels of neurotransmitters (dopamine, glutamate, GABA and 5-HT) were measured by HPLC-ECD. Co-treatment choline/NMDA significantly enhances the release of dopamine, glutamate and GABA and dramatically decrease 5 HT to only 65% of control level, which is consist with this protein interaction network analysis, providing an additional evidence for the cross-talk between NMDAR and alpha7nAChR. PMID- 26498071 TI - Quantitative proteomics reveals the mechanism and consequence of gliotoxin mediated dysregulation of the methionine cycle in Aspergillus niger. AB - Gliotoxin (GT) is a redox-active metabolite, produced by Aspergillus fumigatus, which inhibits the growth of other fungi. Here we demonstrate how Aspergillus niger responds to GT exposure. Quantitative proteomics revealed that GT dysregulated the abundance of 378 proteins including those involved in methionine metabolism and induced de novo abundance of two S-adenosylmethionine (SAM) dependent methyltransferases. Increased abundance of enzymes S adenosylhomocysteinase (p=0.0018) required for homocysteine generation from S adenosylhomocysteine (SAH), and spermidine synthase (p=0.0068), involved in the recycling of Met, was observed. Analysis of Met-related metabolites revealed significant increases in the levels of Met and adenosine, in correlation with proteomic data. Methyltransferase MT-II is responsible for bisthiobis(methylthio)gliotoxin (BmGT) formation, deletion of MT-II abolished BmGT formation and led to increased GT sensitivity in A. niger. Proteomic analysis also revealed that GT exposure also significantly (p<0.05) increased hydrolytic enzyme abundance, including glycoside hydrolases (n=22) and peptidases (n=16). We reveal that in an attempt to protect against the detrimental affects of GT, methyltransferase-mediated GT thiomethylation alters cellular pathways involving Met and SAM, with consequential dysregulation of hydrolytic enzyme abundance in A. niger. Thus, it provides new opportunities to exploit the response of GT-naive fungi to GT. PMID- 26498072 TI - Interactive effects of chronic waterborne copper and cadmium exposure on tissue specific metal accumulation and reproduction in fathead minnow (Pimephales promelas). AB - The present study was carried out to examine the interactive effects of chronic waterborne copper (Cu) and cadmium (Cd) on tissue-specific metal accumulation and reproduction in fathead minnow (Pimephales promelas). Trios (1 male: 2 female; n=5) of fish were exposed for 21days to: (i) control (no added Cu or Cd), (ii) waterborne Cu (75MUg/L), (iii) waterborne Cd (5MUg/L), and (iv) Cu and Cd mixture (75 and 5MUg/L, respectively). Reproductive output (cumulative egg production) was significantly reduced by Cu but not by Cd. Interestingly however, no spawning occurred in fish exposed to the mixture of waterborne Cu and Cd. In general, both Cu and Cd accumulation in target tissues (gill, liver, gonad and carcass) increased significantly in fish exposed to Cu and Cd mixture, and no interaction between Cu and Cd accumulation was observed in any tissues, except in the liver where Cu accumulation was significantly reduced by Cd. The expression of female hepatic estrogen receptor genes (ER-alpha and ER-beta) was most significantly elevated in fish exposed to Cu and Cd mixture, whereas vitellogenin gene expression was reduced maximally in the same exposure. Similarly, the hepatic expression of the metallothionein gene was most significantly upregulated in fish exposed to Cu and Cd mixture. Moreover, the circulating estradiol level in females was significantly decreased only during the co-exposure of waterborne Cu and Cd. Overall, the present study indicates that the interaction of chronic waterborne Cu and Cd exposure may elicit greater than additive effect on reproductive output in fish. PMID- 26498073 TI - Aquatic animal models of human disease: Selected papers from the 7(th) Conference. Preface. PMID- 26498074 TI - Is altered behavior linked to cellular energy regulation in a freshwater mussel (Elliptio complanata) exposed to triclosan? AB - Environmental stress may alter the bioenergetic balance of organisms by resulting in greater energy investment into detoxification processes, which diverts energy from other biological functions. Here, we examine responses to triclosan (TCS) exposure in a freshwater mussel across multiple biological levels: behavioral (e.g., burrowing and movement activity), organismal (e.g., metabolic rate and heart rate), and subcellular (e.g., gene expression and protein abundance/activity). At the subcellular level, we employed both energetic (i.e., AMP-activated protein kinase (AMPK)) and traditional (i.e., heat shock protein (HSP70), superoxide dismutase (SOD), glutathione-S-transferase (GST)) biomarkers. We found a significant reduction in burrowing and movement behaviors, a 1.8-fold increase in total-AMPK protein abundance, and a 2.8-fold increase in AMPK activity after 21d. GST activity increased after 4d, but not after 21d. Our findings suggest that TCS exposure results in an energetic tradeoff between detoxification at the cellular level and whole-animal activity. PMID- 26498075 TI - Vesiculobullous and hemorrhagic erythema migrans: uncommon variants of a common disease. AB - BACKGROUND: The diagnosis of Lyme disease relies on the accurate diagnosis of erythema chronicum migrans (ECM) because serologic tests, culture, and polymerase chain reactions are often inaccurate. Although ECM is classically associated with a targetoid rash, there are many variants of this lesion. These variants of ECM are often initially diagnosed as cellulitis or spider bite reactions and treated with oral antibiotics. Inappropriate treatment further delays the diagnosis of Lyme disease, leading to late complications. METHODS: We present four cases of vesiculobullous and hemorrhagic ECM, a less common variant of ECM. RESULTS: All four patients had a history of exposure to wooded areas in Massachusetts during the summer months. In these patients, ECM presented with central vesicles and bullae with hemorrhage, crusting, and in some cases necrosis. Serologic testing was positive in three of the four cases at presentation. In one case, microscopic examination of a skin biopsy showed epidermal spongiosis with parakeratosis, focal necrosis, papillary dermal edema, erythrocyte extravasation, and a superficial and deep perivascular lymphocytic infiltrate with neutrophils and eosinophils of the dermis. No fungal organisms or bacteria were identified. All four patients were treated with doxycycline with complete resolution of symptoms. CONCLUSIONS: It is important to recognize the vesiculobullous and hemorrhagic variants of ECM in order to minimize the provision of inappropriate antibiotic treatment for other diagnoses. Early diagnosis of ECM and the initiation of appropriate antibiotics may prevent late complications of Lyme disease. PMID- 26498076 TI - Ebola and the Ophthalmologist. PMID- 26498077 TI - Papillomatous Compound Nevus. PMID- 26498078 TI - Should We Add Screening of Age-Related Macular Degeneration to Current Screening Programs for Diabetic Retinopathy? PMID- 26498079 TI - Ophthalmic Technology Assessments. PMID- 26498080 TI - Unusual Histopathological Views of Fuchs' Endothelial Dystrophy. PMID- 26498081 TI - Amelanotic Melanoma Arising within Conjunctival Melanocytic Intraepithelial Neoplasia Sine Pigmento. PMID- 26498082 TI - Conjunctival Melanoma with Intraocular Extension. PMID- 26498083 TI - Re: Peters et al.: Threat to fixation at diagnosis and lifetime risk of visual impairment in open-angle glaucoma (Ophthalmology 2015;122:1034-9). PMID- 26498084 TI - Reply: To PMID 25537196. PMID- 26498085 TI - Re: Yeh et al.: Ophthalmic Technology Assessment: therapies for macular edema associated with central retinal vein occlusion: a report by the American Academy of Ophthalmology (Ophthalmology 2015;122:769-78). PMID- 26498086 TI - Reply: To PMID 25576994. PMID- 26498087 TI - Re: Ueno et al.: Corneal thickness profile and posterior corneal astigmatism in normal corneas (Ophthalmology 2015;122:1072-8). PMID- 26498088 TI - Re: Koolwijk et al.: Outpatient cataract surgery: incident and procedural risk analysis do not support current clinical ophthalmology guidelines (Ophthalmology 2015;122:281-7). PMID- 26498089 TI - Reply: To PMID 25444350. PMID- 26498090 TI - Risk factors for surgical site infection after instrumented fixation in spine trauma. AB - Surgical site infection (SSI) represents a significant complication after instrumented fixation in spine trauma. Institutional practice changes have emphasized early fracture correction, shortened intraoperative times, early ambulation, and prompt nutritional supplementation. This retrospective study evaluates the senior author's experience of instrumented spinal trauma SSI occurring at a single Level I trauma center over two equal and contiguous time periods, 2005-2007 (before nutritional supplementation was added to the institutional protocol) and 2008-2010 (after nutritional supplementation was added). This study assessed whether SSI varied depending on the primary surgical site and/or by the chosen approach. Lastly, the incidence of SSI among demographic and other clinical variables was evaluated. In total, 358 patients underwent an index procedure for spinal trauma correction. Fourteen patients developed a SSI requiring reoperation for an incidence of 4.0%. In assessing nutritional supplementation, the probability of infection tended to be lower in the supplemented group (3.7%) than the pre-supplement group (4.3%), but this did not reach significance. The difference in approach for the cervical spine was statistically significant (p=0.045) with rates of infection via posterior approach at 8.1% and no infections via anterior approach. Presence of comorbidities (p=0.03) and time to surgery >3days (p=0.006) were predictors of developing SSI. Benefit is shown from early surgical correction of spinal trauma patients in the reduction of postoperative SSI. Nutritional supplementation may provide a small reduction in infections in the spine trauma population. PMID- 26498091 TI - Tuberous sclerosis complex coexistent with hippocampal sclerosis. AB - Tuberous sclerosis and hippocampal sclerosis are both well-defined entities associated with medically intractable epilepsy. To our knowledge, there has been only one prior case of these two pathologies being co-existent. We report a 7 month-old boy who presented with intractable seizures at 2 months of age. MRI studies showed diffuse volume loss in the brain with bilateral, multiple cortical tubers and subcortical migration abnormalities. Subependymal nodules were noted without subependymal giant cell astrocytoma. Genetic testing revealed TSC2 and PRD gene deletions. Histopathology of the hippocampus showed CA1 sclerosis marked by loss of neurons in the CA1 region. Sections from the temporal, parietal and occipital lobes showed multiple cortical tubers characterized by cortical architectural disorganization, gliosis, calcifications and increased number of large balloon cells. Focal white matter balloon cells and spongiform changes were also present. The patient underwent resection of the right fronto-parietal lobe and a subsequent resection of the right temporal, parietal and occipital lobes. The patient is free of seizures on anti-epileptic medication 69 months after surgery. Although hippocampal sclerosis is well documented to be associated with coexistent focal cortical dysplasia, the specific co-existence of cortical tubers and hippocampal sclerosis appears to be rare. PMID- 26498092 TI - Awake brain tumor resection during pregnancy: Decision making and technical nuances. AB - The co-occurrence of primary brain tumor and pregnancy poses unique challenges to the treating physician. If a rapidly growing lesion causes life-threatening mass effect, craniotomy for tumor debulking becomes urgent. The choice between awake craniotomy versus general anesthesia becomes complicated if the tumor is encroaching on eloquent brain because considerations pertinent to both patient safety and oncological outcome, in addition to fetal wellbeing, are involved. A 31-year-old female at 30 weeks gestation with twins presented to our hospital seeking awake craniotomy to resect a 7 * 6 * 5 cm left frontoparietal brain tumor with 7 mm left-to-right subfalcine herniation on imaging that led to word finding difficulty, dysfluency, right upper extremity paralysis, and right lower extremity weakness. She had twice undergone tumor debulking under general anesthesia during the same pregnancy at an outside hospital at 16 weeks and 28 weeks gestation. There were considerations both for and against awake brain tumor resection over surgery under general anesthesia. The decision-making process and the technical nuances related to awake brain tumor resection in this neurologically impaired patient are discussed. Awake craniotomy benefits the patient who harbors a tumor that encroaches on the eloquent brain by allowing a greater extent of resection while preserving the language and sensorimotor function. It can be successfully done in pregnant patients who are neurologically impaired. The patient should be motivated and well informed of the details of the process. A multidisciplinary and collaborative effort is also crucial. PMID- 26498093 TI - Exercise-induced changes of cerebrospinal fluid vascular endothelial growth factor in adult chronic hydrocephalus patients. AB - Vascular endothelial growth factor (VEGF) is a growth factor demonstrated to be a key factor in cerebral angiogenesis and neurogenesis. It has been considered a critical component in hippocampus neurogenesis and memory formation and has been observed to increase in the rat hippocampus after exercise. We previously found increased VEGF levels in experimental chronic hydrocephalus in several brain areas and cerebrospinal fluid (CSF), suggesting a role in the adaption to chronic hypoxia. Here we investigate the ability of moderate exercise to increase CSF VEGF levels in adult chronic hydrocephalus patients. Lumbar CSF samples were collected from 17 normal pressure hydrocephalus patients. During CSF collection, 11 patients (exercise group) underwent a standard in-room occupational therapy session; six patients (no-exercise group) did not undergo a physical therapy session. CSF-VEGF levels were evaluated for increase related to exercise and the clinical response to CSF drainage. CSF-VEGF levels in the exercise group demonstrated significant increases 1-3 hours post-exercise compared with the levels 1-2 hours pre-exercise (p=0.04), and also showed significantly higher levels than the no-exercise groups (p=0.03). The post-exercise CSF-VEGF level in the group that did not clinically improve was significantly higher than both their own pre-exercise level (p=0.02) and that seen in the clinically improving group (p=0.05) after exercise. We conclude that CSF-VEGF levels can increase after moderate exercise even in elderly hydrocephalus patients. This suggests that a potential benefit of exercise, especially in CSF drainage non-improved patients, may exist via a central VEGF mechanism. PMID- 26498094 TI - Comparison of the transport of the aggregates of nanoscale zerovalent iron under vertical and horizontal flow. AB - Direct injection of nanoscale zerovalent iron (NZVI) particles is being considered for remediation of contaminated sites. However, the transport characteristics of NZVI under horizontal flow conditions are not fully understood. In this study, NZVI particles were stabilized with carboxymethyl cellulose (CMC) and injected in vertical and horizontal columns to compare the effects of the flow direction on the transport. Columns were packed with sand of mean grain diameters of 180, 340 or 1140 um (referred to as fine, intermediate and coarse sand, respectively), and were injected with CMC-NZVI suspensions of 0.3, 1 or 3 g Fe L(-1). Experimental breakthrough curves showed that with the coarse and intermediate sands, the steady-state effluent concentration in the horizontal column were up to 84% lower than those in the vertical column regardless of the initial NZVI concentration. However, in the fine sand the differences were insignificant, except at the highest NZVI particle concentration. Additionally, in the horizontally-oriented columns containing the coarse or intermediated sand, NZVI aggregates particles were non-uniformly distributed in the cross-section of the columns and there higher deposition in the bottom-half of the cross-section due to gravity effects. These deposition patterns can be accounted for, in part, by the gravitational settling of the large aggregates of NZVI, especially at high NZVI concentrations. A particle trajectory analysis in three dimensions demonstrated that under horizontal flow, gravity forces resulted in lower deposition of NZVI on the bottom-half of a single collector, as particles approaching the bottom-half of the collector were deflected by gravity to collectors below. PMID- 26498096 TI - Characterization of solidifiers used for oil spill remediation. AB - The physical characteristics and chemical composition of oil spill solidifiers were studied, and correlation of these properties with product effectiveness enabled determination of characteristics that are desirable in a good solidifier. The analyses revealed that the commercial products were primarily comprised of organic polymers and a few trace elements. A natural sorbent, which was composed entirely of plant based matter, was also evaluated, and it had the highest oil removal capacity, but it did not produce a solid mat-like final product. Generally, solidifiers with a carbonate group, pore size greater than 5 MUm, and bulk densities lower than 0.3 g cm(-3) were found to have better efficiency and produced a cohesive rubbery final product that facilitated removal compared to sorbents. The importance of bulk density and pore size in the performance of the solidifier suggest that the primary mechanism of action was likely physical sorption. PMID- 26498095 TI - A case-control study of maternal exposure to chromium and infant low birth weight in China. AB - Exposure to chromium is increasing due to environmental pollution from industrial processes. Several epidemiological studies have investigated chromium exposure and reproductive outcomes, but few studies have investigated the association of chromium exposure and low birth weight (LBW). This study was designed to investigate whether maternal exposure to chromium during pregnancy is associated with an increased risk of LBW. Chromium concentrations in maternal urine samples collected at delivery were measured in 204 LBW cases and 612 matched controls recruited between 2012 and 2014 in Hubei Province, China. Risk of LBW was associated with higher levels of chromium in maternal urine [adjusted odds ratio (OR) = 1.77 for the medium tertile, 95% confidence interval (CI): 0.95, 3.29; adjusted OR = 2.48 for the highest tertile, 95% CI: 1.33, 4.61; P trend = 0.01]. The association was more pronounced among female infants (adjusted OR = 3.67 for the highest tertile, 95% CI: 1.50, 8.97) than among male infants (adjusted OR = 1.22 for the highest tertile, 95% CI = 0.48, 3.11) (p heterogeneity = 0.06). Our findings suggest that maternal exposure to higher levels of chromium during pregnancy may potentially increase the risk of delivering LBW infants, particularly for female infants. PMID- 26498097 TI - Acetic acid effects on methanogens in the second stage of a two-stage anaerobic system. AB - This study reports on biomass tolerance towards high concentrations of acetic acid (HAc) within the system. Biomass from the second stage of a two-stage anaerobic sludge digestion system was used for this study. Microbial community analysis by 454 pyrosequencing highlighted hydrogenotrophic Methanomicrobiales was the predominant archaeal population in the second stage (>99% of the total archaeal community). Second stage biomass degraded HAc up to 4200 mg HAc L(-1) without observable lag phase. However, at HAc-shock loading of 7400 mg HAc L(-1), it showed a one day lag phase associated with decreased biomass activity. After stepwise HAc-acclimation over 27 d, the biomass degraded HAc of up to 8200 mg HAc L(-1) without observable lag phase. The dominance of Methanomicrobiales had remained unchanged in proportion - while the total archaeal population increased during acclimation. This study showed stepwise acclimation could be an approach to accommodate HAc accumulation and hence higher concentrations resulting from an enhanced first stage. PMID- 26498098 TI - Associations of serum organohalogen levels and prostate cancer risk: Results from a case-control study in Singapore. AB - There is increasing evidence that elevated exposure to organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) may lead to an increased risk of prostate cancer. As part of a hospital-based case-control study of the Singaporean male population, we investigated associations between organohalogen exposure and risk of prostate cancer. Trace residue concentrations of 74 organohalogen contaminants, including several PCBs, OCPs and halogenated flame retardants (HFRs), were determined in serum samples (n = 120) using gas chromatography tandem mass spectrometry (GC-MS/MS). A variety of OCPs, PCBs and HFRs were detected in samples of both patients and controls. Mean concentrations of p,p' DDT, p,p' DDE, PCB 118, PCB 138, PCB 153 and PCB 187 were significantly higher (p < 0.05) in serum of patients. p,p' DDE measured in serum of patients was relatively high (mean:13,700 ng/g lipid, 95% CI:7000-26,800). Odds ratios (ORs) of OCPs and PCBs in many cases exceeded 1. ORs for p,p' DDE and PCB-153 at the highest tertile (>67th) were 5.67 (95% CI, 2.37-13.54) and 2.14 (95% CI, 0.99 to 4.66), respectively. The results suggest that exposure to DDTs and PCBs may be associated with prostate cancer risk in Singaporean males. No such association was observed for the organohalogen flame retardants studied, including polybrominated diphenyl ethers (PBDEs). The study provides novel information regarding the occurrence, levels and potential associations with prostate cancer risk for several organohalogen contaminants in the Singapore population. However, further investigation and analyses should be conducted to confirm these findings. PMID- 26498099 TI - Variations in the bioavailability of polycyclic aromatic hydrocarbons in industrial and agricultural soils after bioremediation. AB - The aim of this study was to demonstrate the variations in bioavailability remaining in industrial and agricultural soils contaminated by polycyclic aromatic hydrocarbons (PAHs) after bioremediation. After inoculation of Mycobacterium sp. and Mucor sp., PAH biodegradation was tested on a manufactured gas plant (MGP) soil and an agricultural soil. PAH bioavailability was assessed before and after biodegradation using solid-phase extraction (Tenax-TA extraction) and solid-phase micro-extraction (SPME) to represent bioaccessibility and chemical activity of PAHs, respectively. Only 3- and 4-ring PAHs were noticeably biodegradable in the MGP soil. PAH biodegradation in the agricultural soil was different from that in the MGP soil. The rapidly desorbing fractions (F(rap)) extracted by Tenax-TA and the freely dissolved concentrations of 3- and 4-ring PAHs determined by SPME from the MGP soil decreased after 30 days biodegradation; those values of the 5- and 6-ring PAHs changed to a lesser degree. For the agricultural soil, the F(rap) values of the 3- and 4-ring PAHs also decreased after the biodegradation experiment. The Tenax-TA extraction and the SPME have the potential to assess variations in the bioavailability of PAHs and the degree of biodegradation in contaminated MGP soils. In addition, Tenax-TA extraction is more sensitive than SPME when used in the agricultural soil. PMID- 26498100 TI - Concentrations and mass fluxes estimation of organochlorine pesticides in Three Gorges Reservoir with virtual organisms using in situ PRC-based sampling rate. AB - Organochlorine pesticides (OCP) are widely distributed environmental pollutants. Due to their persistence and toxicity, it is important to know their fluxes and spatial and temporal distribution in the environment. In this study, a new procedure to estimate OCP concentration based on a set of performance reference compounds (PRCs) was used. Their occurrence and mass fluxes were assessed on a regional scale ranging from Chonqging to Maoping in Three Gorges Reservoir (TGR) as part of Yangtze River. The results are based on three sampling campaigns in 2009 (twice) and 2011. Due to different factors, the measured concentrations varied from 410 to 1418 pg/L. The highest total OCP concentration was localized in Wanzhou while the lowest was downstream Maoping near the Three Gorges Dam (TGD). The highest load of OCP mass fluxes was observed at Wanhzou with 9.6 mg/s and the lowest load at Maoping with 2.97 mg/s. Studies at Maoping show an increase in OCP water concentration from 2009 to 2012. Comparison between free dissolved OCP water concentration and total OCP water concentration in TGR 2009, 2011 and 2012 show a slight variation, indicating the important role of dilution in the OCP removal process in TGR. PMID- 26498101 TI - Rapid degradation of azo dye methyl orange using hollow cobalt nanoparticles. AB - A rapid and efficient method for methyl orange degradation using hollow cobalt (Co) nanoparticles is reported. Hollow Co nanoparticles were fabricated by a galvanic replacement reaction using aluminum (Al) nanoparticles as the template material. The methyl orange degradation characteristics were investigated by measuring the time dependent UV-Vis absorption of the dye solution, which showed a very fast degradation rate under acidic conditions. At an initial methyl orange concentration of 100 mg/L (pH = 2.5) and Co nanoparticle dosage of 0.5 g/L, the azo dye degradation efficiency reached up to 99% within 4 min, and the degradation constant rate was up to 2.444 min(-1), which is the highest value among other studies. A comparison of the decolorization rates at similar conditions with several other azo dyes, including Congo red, Amaranth, and Orange G, showed that the dye with a simpler structure and lower molecular mass decolorized considerably faster than the ones having a more complicated structure (higher molecular mass). The methyl orange degradation was also conducted using hollow nickel (Ni) nanoparticles and commercially available solid spherical Co and Ni nanoparticles. The results showed that Co-based nanoparticles outperformed Ni-based nanoparticles, with the hollow Co nanoparticles exhibiting the fastest degradation rate. Using the hollow Co nanoparticles is a very promising approach for the remediation of methyl orange dye containing wastewater due to the fast degradation rate and high degradation efficiency. In addition, these hollow Co nanoparticles are easily recycled because of their magnetic property. PMID- 26498102 TI - Wildlife contamination with fluoroquinolones from livestock: Widespread occurrence of enrofloxacin and marbofloxacin in vultures. AB - There is much recent interest in the presence and impact of veterinary pharmaceuticals in wildlife. Livestock carcasses are often disposed of in supplementary feeding stations for avian scavengers, as a management and conservation tool for these species worldwide. In feeding stations, vultures and other scavengers can consume carcasses almost immediately after disposal, which implies the potential ingestion of veterinary pharmaceuticals as a non-target consequence of supplementary feeding. Using UPLC-MS/MS and HPLC-TOF, we evaluated the presence and concentration of fluoroquinolone residues in plasma of nestling vultures feeding on domestic livestock carrion. Three different fluoroquinolones (marbofloxacin, enrofloxacin and its metabolite ciprofloxacin) and a non-targeted beta-lactam (nafcillin) were detected in vulture plasma. The high proportion of individuals (92%) with fluoroquinolone residues at variable concentrations (up to ~20 MUg L(-1) of enrofloxacin and ~150 MUg L(-1) of marbofloxacin) sampled in several geographically distant colonies and on different dates suggests that these and other drugs were potentially ingested throughout nestling development. Contamination with veterinary fluoroquinolones and other pharmaceuticals should be considered as an unintended but alarming consequence of food management in threatened wildlife. PMID- 26498103 TI - Metal toxicity to freshwater organisms as a function of pH: A meta-analysis. AB - Acidification caused by climate change and seasonal fluctuation can have profound implications for chemical toxicity to freshwater organisms. The present study aims to address this challenging issue through a comprehensive meta-analysis by comparing acute median lethal or effect concentration data (LC50 or EC50) for 10 metals and metalloids for various freshwater species obtained at different pH values. Our results revealed that element toxicity generally follows three different models, including Model-I: decreasing toxicity with increasing pH, Model-II: increasing toxicity with increasing pH, and Model-III: minimal toxicity at intermediate (optimal) pH (pH(opt)) with increasing toxicity as pH increases or decreases from pH(opt). We further examined these observations by constructing pH-dependent species sensitivity distributions (SSDs). The results indicated that the 10(th) percentile hazardous concentrations (HC10s) for copper, lead, selenium and silver generally exhibited a positive linear relationship with pH, following the Model-I. The ability to accurately predict toxicity of elements to biota in natural waters as a function of pH may be limited, however, the pH-dependent SSD approach presented in this study facilitates and helps characterize the role of pH in water quality guidelines and ecological risk assessment. PMID- 26498104 TI - Occurrence of phthalate diesters (phthalates), p-hydroxybenzoic acid esters (parabens), bisphenol A diglycidyl ether (BADGE) and their derivatives in indoor dust from Vietnam: Implications for exposure. AB - Phthalate diesters (phthalates), esters of p-hydroxybenzoic acid (parabens), and bisphenol A diglycidyl ether (BADGE) are used in personal care products, food packages, household products, or pharmaceuticals. These compounds possess endocrine-disrupting potentials and have been reported to occur in the environment. Nevertheless, no previous studies have reported the occurrence of these compounds in indoor dust from Vietnam. In this study, nine phthalates, six parabens, and four BADGEs were determined in indoor dust samples collected from Hanoi, Hatinh, Hungyen, and Thaibinh, in Vietnam. Total concentrations of phthalates, parabens, and BADGEs in indoor dust ranged from 3440 to 106,000 ng/g (median: 22,600 ng/g), 40-840 ng/g (median: 123 ng/g), and 23 to 1750 ng/g (median: 184 ng/g), respectively. Based on the measured median concentration of phthalates, parabens, and BADGEs in indoor dust, we estimated human exposure doses to these compounds through indoor dust ingestion for various age groups. The exposure doses to phthalates, parabens, and BADGEs decreased with age and ranged from 19.4 to 90.4 ng/kg-bw/d, 0.113-0.528 ng/kg-bw/d, and 0.158-0.736 ng/kg-bw/d, respectively. This is the first study on the occurrence and human exposure of phthalates, parabens, and BADGEs in indoor dust from Vietnam. PMID- 26498105 TI - Daily self-sampling for high-risk human papillomavirus (HR-HPV) testing. AB - BACKGROUND: Self-sampling for HPV as part of primary screening is a well tolerated method for women not attending organized Pap smear screening and could increase coverage of cervical cancer screening. OBJECTIVE: To investigate if the prevalence of HR-HPV varies from day to day in infected women and if one single sample is reliable for detecting an ongoing infection. STUDY DESIGN: This is a prospective cohort study on 12 premenopausal and 13 postmenopausal women performing daily self-sampling for HR-HPV testing. They were all HR-HPV-positive 1-3 months ago. Postmenopausal women were sampled for 28 days and premenopausal women sampled during bleeding-free days in one menstrual cycle. A possible difference in viral load between the estrogen-dominated proliferative phase and the progesterone-dominated secretory phase was analyzed. RESULTS AND CONCLUSIONS: Consistent results throughout the sampling period were observed for 19 women, with either a daily presence of HPV (14 women) or no HPV at all during the sampling period (5 women). Of 607 samples from 25 women, 596 were consistently positive or negative for HPV during the sampling period and 11 were inconsistent (2%). There was no difference in HPV copy number between the estrogen dominated proliferative or progesterone dominated secretory menstrual cycle phases. The major finding was a high degree of consistency concerning HR-HPV positivity and negativity of HR-HPV in vaginal fluid during a sustained period of daily self sampling. It does not appear to matter whether the sample is collected in the proliferative or secretory phase. PMID- 26498106 TI - [Use of intravenous iron supplementation in chronic kidney disease: Interests, limits, and recommendations for a better practice]. AB - Iron deficiency is an important clinical concern in chronic kidney disease (CKD), giving rise to iron-deficiency anaemia, and various impaired cellular functions. Oral supplementation, in particular with ferrous salts, is associated with a high rate of gastro-intestinal side effects and is poorly absorbed, a problem that is avoided with intravenous (IV) irons. Recently, with the approval of the European Medicines Agency's Committee for Medicinal Products for Human Use, the French Agence nationale de securite du medicament et des produits de sante (ANSM) took adequate measures to minimize the risk of allergic reactions, by correction on the summary of intravenous iron products characteristics. All IV iron products should be prescribed, administered and injected, inside public or private hospitals exclusively, and a clinical follow-up after the infusion for at least 30 minutes is mandatory. The most stable intravenous iron complexes (low molecular weight iron dextran, ferric carboxymaltose, and iron isomaltoside 1000 [under agreement]) can be given in higher single doses and more rapidly than less recent preparations such as iron sucrose (originator or similars). Test doses are advisable for conventional low molecular weight iron dextrans, but are no more mandatory. Iron supplementation is recommended for all CKD patients with iron deficiency anaemia and those who receive erythropoiesis-stimulating agents, whether or not they require dialysis. Intravenous iron is the preferred route of administration in haemodialysis patients, with randomized trials showing a significantly greater increase in haemoglobin levels for intravenous versus oral iron and a low rate of treatment-related adverse events during these trials. According ANSM, physicians should apply the product's label recommendations especially the posology. In the non-dialysis CKD population, the erythropoietic response is also significantly higher using intravenous versus oral iron, and tolerability is at least as good. Moreover in some non-dialysis patients, intravenous iron supplementation might avoid or at least delay the need for erythropoiesis-stimulating agents. Following the new ANSM's recommendations, we now have the ability to achieve iron stores replenishment correctly and conveniently in dialysis dependent and non-dialysis dependent CKD patients without compromising safety using the various pharmaceutical forms of iron products especially intravenous compounds. PMID- 26498107 TI - Simplified scoring of the Actionable 8-item screening questionnaire for neurogenic bladder overactivity in multiple sclerosis: a comparative analysis of test performance at different cut-off points. AB - BACKGROUND: The Actionable questionnaire is an 8-item tool to screen patients with multiple sclerosis (MS) for neurogenic bladder problems, identifying those patients who might benefit from urological referral and bladder-specific treatment. The original scoring yields a total score of 0 to 24 with cut-off point 6. A simplified scoring, yielding a total score of 0 to 8 with cut-off point 3, has been developed in urogynaecological patients, but has not been investigated in MS. METHODS: One-hundred-and-forty-one MS patients completed the Actionable on two occasions. We compared the test performance of the simplified scoring with cut-off point 3 with that of cut-off point 2, using the original scoring with cut-off point 6 as a gold standard. The following measures were calculated: True Positives (TP), True Negatives (TN), False Positives (FP), False Negatives (FN), Sensitivity, Specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), and Accuracy. The associations between positive test result and urological treatment, and bladder-specific drug treatment were calculated. RESULTS: For cut-off point 3 the outcomes (Test 1, Test 2) were: TP 43.26 %, 40.88 %; TN 29.79 %, 32.85 %; FP 0.00 %, 0.00 %; FN 26.95 %, 26.28 %; Sensitivity 0.62, 0.61; Specificity 1.00, 1.00; PPV 1.00, 1.00; NPV 0.53, 0.55; Accuracy 0.73, 0.74; and for cut-off point 2: TP 59.57 %, 59.85 %; TN 26.95 %, 31.39 %; FP 2.84 %, 1.46 %; FN 10.63 %, 7.30 %; Sensitivity 0.85, 0.89; Specificity 0.90, 0.96; PPV 0.95, 0.98; NPV 0.72, 0.81; Accuracy 0.87, 0.91. Cut off 3 completely prevented FP outcomes, but wrongly classified 26 % of the patients as negative (FN). Cut-off 2 reduced the FN to 7-10 %, with low FP values (2.84-1.46 %). With cut-off 2, the percentage of patients screened positive was higher in the Progressive group (75.00 %) than in the Relapsing Remitting group (56.25 %) (P = 0.0331), which was not the case with cut-off 3. Only a positive test according to the original scoring was associated with both urological treatment (P = 0.0119) and bladder-specific medication (P = 0.0328). CONCLUSIONS: Our findings suggest that in MS patients the simplified Actionable scoring is more accurate with cut-off point 2 than with cut-off point 3, especially by substantially reducing FN outcomes; and that in MS the original Actionable scoring seems preferable. PMID- 26498109 TI - Investigation of the relationship between neutrophil-to-lymphocyte ratio and obstructive sleep apnoea syndrome. PMID- 26498108 TI - Three steps forward, two steps back: mechanistic insights into the assembly and disassembly of the SNARE complex. AB - Membrane fusion is a tightly controlled process in all eukaryotic cell types. The SNARE family of proteins is required for fusion throughout the exocytic and endocytic trafficking pathways. SNAREs on a transport vesicle interact with the cognate SNAREs on the target membrane, forming an incredibly stable SNARE complex that provides energy for the membranes to fuse, although many aspects of the mechanism remain elusive. Recent advances in single-molecule and high-resolution structural methods provide exciting new insights into how SNARE complexes assemble, including measurements of assembly energetics and identification of intermediates in the assembly pathway. These techniques were also key in elucidating mechanistic details into how the SNARE complex is disassembled, including details of the energetics required for ATP-dependent alpha-SNAP/NSF mediated SNARE complex disassembly, and the structural changes that accompany ATP hydrolysis by the disassembly machinery. Additionally, SNARE complex formation and disassembly are tightly regulated processes; innovative biochemical and biophysical characterization has deepened our understanding of how these regulators work to control membrane fusion and exocytosis. PMID- 26498110 TI - Prospective neonatal screening for severe T- and B-lymphocyte deficiencies in Seville. AB - BACKGROUND: Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected children. T-cell-receptor-excision circles (TRECs) and kappa-deleting recombination-excision circles (KRECs) determination from dried blood spots (DBS) identify neonates with severe T- and/or B-lymphopenia. No prospective data exist of the impact of gestational age (GA) and birth weight (BW) on TRECs and KRECs values. METHODS: TRECs and KRECs determination using triplex RT-PCR (TRECS-KRECS beta-actin-Assay) from prospectively collected DBS between 02/2014 and 02/2015 in three hospitals in Seville, Spain. Cut-off levels were TRECs < 6/punch, KRECs < 4/punch and -beta-actin>700/punch. Internal (SCID, XLA, ataxia telangiectasia) and external controls (NBS quality assurance program, CDC) were included. RESULTS: A total of 5160 DBS were tested. Re-punch was needed in 77 samples (1.5%) due to insufficient beta-actin (<700 copies/punch). Pre-term neonates (GA<37 weeks) and neonates with a BW<2500 g showed significantly lower TRECs and KRECs levels (p < 0.001). Due to repeat positive results five neonates were re called (<0.1%): Fatal chromosomopathy (n = 1; TRECs 1/KRECs 4); extreme pre maturity (n = 2; TRECs 0/KRECs 0 and TRECs 1/KRECs 20 copies/punch); neonates born to mothers receiving azathioprine during pregnancy (n = 2; TRECs 92/KRECs 1 and TRECs 154/KRECs 3 copies/punch). All internal and external controls were correctly identified. CONCLUSIONS: TRECS-KRECS-beta-actin-Assay correctly identifies T- and B-cell lymphopenias. Pre-maturity and low BW is associated with lower TREC and KREC levels. Extreme pre-maturity and maternal immune suppressive therapy may be a cause for false positive results of TRECs and KRECs values, respectively. To reduce the rate of insufficient samples, DBS extraction and storage need to be improved. PMID- 26498111 TI - Differentiating Between Attachment Styles and Behaviors and their Association with Marital Quality. AB - The purpose of this study was to distinguish between the influence of attachment styles and behaviors on marital quality for couples. Data were gathered from 680 couples in a married relationship. Results showed attachment style and behaviors predicted marital quality for both men and women, with higher levels of attachment related to greater quality. Attachment behaviors predicted more of the variance in quality than did styles. Specific implications regarding how therapists may wish to foster behaviors that promote attachment security in marriages are discussed. PMID- 26498112 TI - CpG oligodeoxynucleotides potentiate the antitumor activity of anti-BST2 antibody. AB - Numerous monoclonal antibodies (mAb) targeting tumor antigens have recently been developed. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) via effector cells such as tumor-infiltrating natural killer (NK) cells and macrophages are often involved in mediating the antitumor activity of mAb. CpG oligodeoxynucleotides (ODN) have a potent antitumor activity and are considered to increase tumor infiltration of NK cells and macrophages. Our group previously reported significant antitumor activity of anti-bone marrow stromal antigen 2 (BST2) mAb against BST2-positive endometrial cancer cells through ADCC. In this study, we evaluated the synergistic antitumor activity of combination therapy with anti-BST-2 mAb and CpG ODN using SCID mice and elucidated the mechanisms underlying this activity. Anti-BST2 mAb and CpG ODN monotherapy had a significant dose-dependent antitumor activity (P = 0.0135 and P = 0.0196, respectively). Combination therapy with anti-BST2 mAb and CpG ODN had a significant antitumor activity in SCID mice (P < 0.01), but not in NOG mice. FACS analysis revealed significantly increased numbers of NK cells and macrophages in tumors treated with a combination of anti-BST2 mAb and CpG ODN and with CpG ODN alone in SCID mice (P < 0.05 and P < 0.01, respectively). These results suggested that the combination therapy with anti-BST2 mAb and CpG ODN has a significant antitumor activity and induces tumor infiltration of NK cells and macrophages. Combination therapy with CpG ODN and anti-BST2 mAb or other antitumor mAb depending on ADCC may represent a new treatment option for cancer. PMID- 26498113 TI - Re: Determinants of participation in prostate cancer screening: A simple analytical framework to account for healthy-user bias. PMID- 26498114 TI - Correction. PMID- 26498118 TI - Incidence, Distribution and Morphology of Left Ventricular False Tendons in Cat Hearts. AB - The incidence, distribution, and macro- and microscopic structures of left ventricular false tendons (LVFTs) in the cat heart were studied using 25 normal and 57 diseased hearts. The fibrous bands were observed in the left ventricle of all 82 cat hearts examined and most commonly extended between the papillary muscles and the ventricular septum. Histologically, the LVFTs were composed of central Purkinje fibres and surrounding dense collagenous fibres covered by endothelium. There was no appreciable difference in the incidence, distribution or morphology of LVFTs between the normal and the diseased hearts, indicating that LVFTs are a common anatomic variant in the cat heart. PMID- 26498117 TI - MicroRNA circulating in the early aftermath of motor vehicle collision predict persistent pain development and suggest a role for microRNA in sex-specific pain differences. AB - BACKGROUND: Molecular mediators influencing the transition from acute to persistent musculoskeletal pain following common stress exposures such as motor vehicle collision (MVC) remain poorly understood. In this exploratory, proof of concept study, we compared circulating microRNA (miRNA) expression profiles in the early aftermath of MVC among individuals who did and did not subsequently develop persistent pain. Blood RNA samples were obtained from African American individuals (n = 53) who presented to the emergency department after MVC and were discharged to home after evaluation. The presence or absence of severe pain in the axial region, the most common and morbid region in which post-MVC pain occurs, was assessed 6 weeks following MVC via standardized questionnaire. miRNA expression was determined using miRNA-sequencing; nonparametric analyses were used to compare miRNA expression levels among individuals with and without persistent pain. RESULTS: Thirty-two mature miRNA were differentially expressed (p < 0.05) in those with and without severe axial pain at 6 weeks. miR-135a-5p, a regulator of the serotonin receptor that is known to be stress-responsive, differed most significantly between groups (p = 3 * 10(-4)). This miRNA, and miR 3613-3p (p = 0.001) survived correction for multiple testing (FDR = 0.15) in this small sample. Interestingly, differentially expressed miRNA were enriched for X chromosome location. In secondary analyses, the eight X chromosome miRNA were (a) more significantly associated with axial pain in women than men, (b) expressed more highly in the peripheral blood of women than men, and (c) predicted in pathway analyses (DIANA miRPath v 2.0) to regulate neuronal and neuroendocrine pathways previously implicated in various pain pathologies. CONCLUSIONS: These results show that circulating miRNA predict persistent severe axial pain after MVC and suggest that they may be involved in the pathogenesis of post-traumatic musculoskeletal pain. However, further studies are needed to determine if these miRNA play a direct causal role. PMID- 26498120 TI - A Dose-response relationship between severity of disc degeneration and intervertebral disc height in the lumbosacral spine. AB - INTRODUCTION: Varied definitions of disc pathology exist in the literature. Magnetic Resonance Imaging (MRI) classification systems incorporate several qualitative features including disc appearance, the distinction between the nucleus and the annulus, signal intensity and intervertebral disc height. The lack of a continuous measure has made it difficult to sensitively examine degenerative disc disease. This study sought to examine the relationship between disc degeneration and intervertebral disc height. METHODS: 72 community-based individuals not selected for low back pain had MRI from which the presence of lumbosacral disc degeneration was identified using the Pfirrmann grading system, and intervertebral disc height was measured. RESULTS: At each lumbosacral level, with higher grade of disc degeneration, intervertebral disc height was reduced (all p <= 0.003). Results remained unchanged when grade 5 disc degeneration, which necessitated a collapsed disc space, was excluded from analyses (all p <= 0.03). To quantify these associations, at each lumbosacral level, for every grade increase in disc degeneration, there was a reduction in intervertebral disc height, after adjusting for age, gender, Body mass index and smoking history (beta range from -0.98 mm to -1.60 mm, 95 % CI range from -2.37 to -0.31, all p <= 0.005). CONCLUSION: This study has demonstrated a negative dose-response relationship between increasing severity of disc degeneration with a reduction in intervertebral disc height. Although the assessment of disc degeneration incorporates a number of qualitative measures, these data substantiate the utility of intervertebral disc height as a quantitative and continuous outcome measure in epidemiological studies, and potentially clinical practice. PMID- 26498119 TI - Vitamin D in incident nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study. AB - BACKGROUND: Cross-sectional studies of children with prevalent nephrotic syndrome (NS) have shown 25-vitamin D (25(OH)D) deficiency rates of 20-100 %. Information on 25(OH)D status in incident patients or following remission is limited. This study aimed to assess 25(OH)D status of incident idiopathic NS children at presentation and longitudinally with short-term observation. METHODS: Multicenter longitudinal study of children (2-18 years old) from 14 centers across the Midwest Pediatric Nephrology Consortium with incident idiopathic NS. 25(OH)D levels were assessed at diagnosis and 3 months later. RESULTS: Sixty-one children, median age 5 (3, 11) years, completed baseline visit and 51 completed second visit labs. All 61 (100 %) had 25(OH)D < 20 ng/ml at diagnosis. Twenty seven (53 %) had 25(OH)D < 20 ng/ml at follow-up. Fourteen (28 %) children were steroid resistant. Univariate analysis showed that children prescribed vitamin D supplements were less likely to have 25(OH)D deficiency at follow-up (OR 0.2, 95 % CI 0.04, 0.6). Steroid response, age, and season did not predict 25(OH)D deficiency. Multivariable linear regression modeling showed higher 25(OH)D levels at follow-up by 13.2 ng/ml (SE 4.6, p < 0.01) in children supplemented with vitamin D. CONCLUSIONS: In this incident idiopathic NS cohort, all children at diagnosis had 25(OH)D deficiency and the majority continued to have a deficiency at 2-4 months. Supplemental vitamin D decreased the odds of 25(OH)D deficiency at follow-up, supporting a role for supplementation in incident NS. PMID- 26498121 TI - Synthesis and antimicrobial evaluation of novel 4-amino-6-(1,3,4-oxadiazolo/1,3,4 thiadiazolo)-pyrimidine derivatives. AB - A series of novel 4-amino-6-(1,3,4-oxadiazolo/1,3,4-thiadiazolo)-pyrimidine derivatives of biological interest were prepared by sequential amination, hydrazide formation, and hydrazine carbothioamidination followed by cyclization. All the synthesized compounds (6a-6h and 7a-7f) were screened for antibacterial and antifungal activity. From this group, compound 7f (MIC (MUg/mL MUg/mL )/Inhibition (mm): 6.25/23-30) showed good antibacterial and antifungal activity. Reagents and conditions: (a) Ethyl acetoacetate, 60% NaH, 1,4-dioxane, 60 degrees C, 6 h; (b) DIPEA, 1,4-dioxane, 100 degrees C, 14 h; (c) NH2NH2 ? H2O, EtOH, reflux, 14 h; (d) Tolyl isothiocyanatobenzene, DMF, RT, 2 h; (e) (if X = O) EDC? HCl, TEA, DMF, RT, 14 h; (f) (if X = S) Conc. H2O4, RT, 14h. PMID- 26498122 TI - Erratum to: Discovery of new Mycobacterium tuberculosis proteasome inhibitors using a knowledge-based computational screening approach. PMID- 26498123 TI - Functionalization of protected tyrosine via Sonogashira reaction: synthesis of 3 (1,2,3-triazolyl)-tyrosine. AB - 1,2,3-Triazol tyrosines were synthesized from tyrosine alkynes that were in turn prepared via Sonogashira cross-coupling reaction. The tyrosine alkynes were subjected to click-chemistry reaction conditions leading to the corresponding 3 (1,2,3-triazolyl)-tyrosines in yields ranging from moderate to good. PMID- 26498124 TI - Tripping out on TRPV4. PMID- 26498125 TI - Management and treatment of relapsed or refractory Ph(-) B-precursor ALL: a web based, double-blind survey of EU clinicians. AB - BACKGROUND: The prognosis for adult patients with Ph(-) B-precursor acute lymphoblastic leukaemia (ALL) who are refractory to treatment or experience relapse (R/R), is poor; over 90% of these patients die from the disease, typically within a few months. While there are some national guidelines published for the treatment of adult patients with ALL, and local working group recommendations do exist, there is very little detail and no preferred treatment regimens for adult patients with R/R Ph(-) B-precursor ALL. The aim of this study was to describe current real-world clinical practice in Europe for the management and treatment of adult R/R Ph(-) B-precursor ALL. METHODS: A web-based, double blind survey was conducted in November/December 2013 in France, Germany, Italy, Spain, and the UK. The survey was developed following consultation with specialist clinicians and a critical review of published literature. Eligible clinicians (15 per country) were board-certified in haemato-oncology or haematology; had at least 4 years of experience in their current role and had treated at least five patients with adult ALL in the 36 months before the survey, including at least one with R/R Ph(-) B-precursor ALL. RESULTS: Clinicians across the five countries consulted 16 guidelines and local working group recommendations for the diagnosis and treatment of R/R Ph(-) B-precursor ALL. Thirty three regimens for salvage therapy were reported; the most frequently cited was augmented hyper-CVAD (15%), with vincristine the most commonly used agent. Salvage therapy regimens involved a range of agents, and most respondents reported using at least one cytotoxic agent; across respondents 10 different cytotoxic agents were cited. All respondents reported that toxicity was common for the regimens they used to treat R/R Ph(-) B-precursor ALL. CONCLUSIONS: This study provides evidence of current management and treatment patterns of R/R Ph(-) B-precursor ALL in the real-world clinical practice in Europe. The approach to the treatment of R/R Ph(-) B-precursor ALL is heterogeneous, reflecting the lack of any clearly superior chemotherapeutic option, thus it appears that clinicians are trying a wide variety of therapies. These findings show a clear need for effective, tolerable treatments for R/R Ph(-) B-precursor ALL. PMID- 26498126 TI - Complete sequence and detailed analysis of the first indigenous plasmid from Xanthomonas oryzae pv. oryzicola. AB - BACKGROUND: Bacterial plasmids have a major impact on metabolic function and adaptation of their hosts. An indigenous plasmid was identified in a Chinese isolate (GX01) of the invasive phytopathogen Xanthomonas oryzae pv. oryzicola (Xoc), the causal agent of rice bacterial leaf streak (BLS). To elucidate the biological functions of the plasmid, we have sequenced and comprehensively annotated the plasmid. METHODS: The plasmid DNA was extracted from Xoc strain GX01 by alkaline lysis and digested with restriction enzymes. The cloned and subcloned DNA fragments in pUC19 were sequenced by Sanger sequencing. Sequences were assembled by using Sequencher software. Gaps were closed by primer walking and sequencing, and multi-PCRs were conducted through the whole plasmid sequence for verification. BLAST, phylogenetic analysis and dinucleotide calculation were performed for gene annotation and DNA structure analysis. Transformation, transconjugation and stress tolerance tests were carried out for plasmid function assays. RESULTS: The indigenous plasmid from Xoc strain GX01, designated pXOCgx01, is 53,206-bp long and has been annotated to possess 64 open reading frames (ORFs), including genes encoding type IV secretion system, heavy metal exporter, plasmid stability factors, and DNA mobile factors, i.e., the Tn3-like transposon. Bioinformatics analysis showed that pXOCgx01 has a mosaic structure containing different genome contexts with distinct genomic heterogeneities. Phylogenetic analysis indicated that the closest relative of pXOCgx01 is pXAC64 from Xanthomonas axonopodis pv. citri str. 306. It was estimated that there are four copies of pXOCgx01 per cell of Xoc GX01 by PCR assay and the calculation of whole genome shotgun sequencing data. We demonstrate that pXOCgx01 is a self transmissible plasmid and can replicate in some Xanthomonas spp. strains, but not in Escherichia coli DH5alpha. It could significantly enhance the tolerance of Xanthomonas oryzae pv. oryzae PXO99A to the stresses of heavy metal ions. The plasmid survey indicated that nine out of 257 Xoc Chinese isolates contain plasmids. CONCLUSIONS: pXOCgx01 is the first report of indigenous plasmid from Xanthomonas oryzae pv. oryzicola, and the first completely sequenced plasmid from Xanthomonas oryzae species. It is a self-transmissible plasmid and has a mosaic structure, containing genes for macromolecule secretion, heavy metal exportation, and DNA mobile factors, especially the Tn3-like transposon which may provide transposition function for mobile insertion cassette and play a major role in the spread of pathogenicity determinants. The results will be helpful to elucidate the biological significance of this cryptic plasmid and the adaptive evolution of Xoc. PMID- 26498127 TI - Vascular responsiveness determined by near-infrared spectroscopy measures of oxygen saturation. AB - Vascular impairments at the macro- and microcirculatory levels are associated with increased risk for cardiovascular disease. Flow-mediated dilation (FMD) is currently the most widely used method for non-invasive assessment of vascular endothelial function. Recently, near-infrared spectroscopy (NIRS)-derived measures of tissue oxygen saturation (StO2) have been used to characterize the dynamic response of local tissue perfusion to a brief period of ischaemia. The purpose of the present study was to establish correlations between the reperfusion rate of StO2 and FMD. Ultrasound-derived FMD was quantified after 5 min of distal cuff occlusion of the popliteal artery in 20 healthy young men (26 +/- 3 years old). Triplicate measurements of end-diastolic arterial diameter were made every 15 s after cuff release, and FMD response was calculated as the greatest percentage change in diameter from baseline (%FMD). The StO2 was measured using NIRS throughout the duration of each test. Two consecutive FMD tests were performed, separated by 30 min of rest, and were averaged for %FMD and StO2. The %FMD was significantly correlated with the reperfusion slope of StO2 after cuff release (slope 2 StO2; r = 0.63, P = 0.003). In conclusion, the present study established a correlation between slope 2 StO2 and %FMD in healthy young men. These data suggest that NIRS-derived slope 2 StO2 can be used as a measure of vascular endothelial function. PMID- 26498128 TI - Osteomyelitis of bilateral great toes: iatrogenic complication of nerve conduction study. PMID- 26498129 TI - The role of cyclo-oxygenase-1 in high-salt diet-induced microvascular dysfunction in humans. AB - KEY POINTS: Recent studies have shown that some of the deleterious effects of a high-salt (HS) diet are independent of elevated blood pressure and are associated with impaired endothelial function. Increased generation of cyclo-oxygenase (COX 1 and COX-2)-derived vasoconstrictor factors and endothelial activation may contribute to impaired vascular relaxation during HS loading. The present study aimed to assess the regulation of microvascular reactivity and to clarify the role of COX-1 and COX-2 in normotensive subjects on a short-term HS diet. The present study demonstrates the important role of COX-1 derived vasoconstrictor metabolites in regulation of microvascular blood flow during a HS diet. These results help to explain how even short-term HS diets may impact upon microvascular reactivity without changes in blood pressure and suggest that a vasoconstrictor metabolite of COX-1 could play a role in this impaired tissue blood flow. ABSTRACT: The present study aimed to assess the effect of a 1-week high-salt (HS) diet on the role of cyclo-oxygenases (COX-1 and COX-2) and the vasoconstrictor prostaglandins, thromboxane A2 (TXA2 ) and prostaglandin F2alpha (PGF2alpha ), on skin microcirculatory blood flow, as well as to detect its effect on markers of endothelial activation such as soluble cell adhesion molecules. Young women (n = 54) were assigned to either the HS diet group (N = 30) (~14 g day(-1) NaCl ) or low-salt (LS) diet group (N = 24) (<2.3 g day(-1) NaCl ) for 7 days. Post-occlusive reactive hyperaemia (PORH) in the skin microcirculation was assessed by laser Doppler flowmetry. Plasma renin activity, plasma aldosterone, plasma and 24 h urine sodium and potassium, plasma concentrations of TXB2 (stable TXA2 metabolite) and PGF2alpha , soluble cell adhesion molecules and blood pressure were measured before and after the diet protocols. One HS diet group subset received 100 mg of indomethacin (non selective COX-1 and COX-2 inhibitor), and another HS group subset received 200 mg of celecoxib (selective COX-2 inhibitor) before repeating laser Doppler flowmetry measurements. Blood pressure was unchanged after the HS diet, although it significantly reduced after the LS diet. Twenty-four hour urinary sodium was increased, and plasma renin activity and plasma aldosterone levels were decreased after the HS diet. The HS diet significantly impaired PORH and increased TXA2 but did not change PGF2alpha levels. Indomethacin restored microcirculatory blood flow and reduced TXA2 . By contrast, celecoxib decreased TXA2 levels but had no significant effects on blood flow. Restoration of of PORH by indomethacin during a HS diet suggests an important role of COX-1 derived vasoconstrictor metabolites in the regulation of microvascular blood flow during HS intake. PMID- 26498130 TI - Patterns of response to crizotinib in recurrent glioblastoma according to ALK and MET molecular profile in two patients. AB - Two patients with an unmethylated MGMT promoter and IDH1 (R132H) wild-type recurrent glioblastoma were treated with crizotinib. Prolonged stabilization of the disease (17 months) was achieved in the first case. Interestingly, anaplastic lymphoma kinase (ALK) expression and c-MET protein overexpression was observed. Conversely, no response to crizotinib was obtained in the second case with MET protein overexpression and c-MET amplification but no ALK expression or ALK gene amplification. These case studies suggest that novel targeted ALK inhibitors may provide relevant clinical benefit in selected cases in which driver mutations are demonstrable. PMID- 26498131 TI - Color Rendering Plasmonic Aluminum Substrates with Angular Symmetry Breaking. AB - We fabricate and characterize large-area plasmonic substrates that feature asymmetric periodic nanostructures made of aluminum. Strong coupling between localized and propagating plasmon resonances leads to characteristic Fano line shapes with tunable spectral positions and widths. Distinctive colors spanning the entire visible spectrum are generated by tuning the system parameters, such as the period and the length of the aluminum structures. Moreover, the asymmetry of the aluminum structures gives rise to a strong symmetry broken color rendering effect, for which colors are observed only from one side of the surface normal. Using a combination of immersed laser interference lithography and nanoimprint lithography, our color rendering structures can be fabricated on areas many inches in size. We foresee applications in anticounterfeiting, photovoltaics, sensing, displays, and optical security. PMID- 26498133 TI - Genetic Variants Influencing Joint Damage in Mexican Americans and European Americans With Rheumatoid Arthritis. AB - Joint destruction in rheumatoid arthritis (RA) is heritable, but knowledge on specific genetic determinants of joint damage in RA is limited. We have used the Immunochip array to examine whether genetic variants influence variation in joint damage in a cohort of Mexican Americans (MA) and European Americans (EA) with RA. We studied 720 MA and 424 EA patients with RA. Joint damage was quantified using a radiograph of both hands and wrists, scored using Sharp's technique. We conducted association analyses with the transformed Sharp score and the Immunochip single nucleotide polymorphism (SNP) data using PLINK. In MAs, 15 SNPs from chromosomes 1, 5, 9, 17 and 22 associated with joint damage yielded strong p values (p < 1 * 10(-4) ). The strongest association with joint damage was observed with rs7216796, an intronic SNP located in the MAP3K14 gene, on chromosome 17 (beta +/- SE = -0.25 +/- 0.05, p = 6.23 * 10(-6) ). In EAs, 28 SNPs from chromosomes 1, 4, 6, 9, and 21 showed associations with joint damage (p value < 1 * 10(-4) ). The best association was observed on chromosome 9 with rs59902911 (beta +/- SE = 0.86 +/- 0.17, p = 1.01 * 10(-6) ), a synonymous SNP within the CARD9 gene. We also observed suggestive evidence for some loci influencing joint damage in MAs and EAs. We identified two novel independent loci (MAP3K14 and CARD9) strongly associated with joint damage in MAs and EAs and a few shared loci showing suggestive evidence for association. PMID- 26498134 TI - Dyspnoea and chest pain as the presenting symptoms of pneumomediastinum: two cases and a review of the literature. AB - Pneumomediastinum is the presence of air in the mediastinum. It may occur as spontaneous, traumatic, or iatrogenic pneumomediastinum. Although spontaneous pneumomediastinum is usually observed in healthy young men, traumatic pneumomediastinum may be caused by blunt or penetrating trauma to the chest and neck. Pneumomediastinum is a clinical condition with potential complications that cause high morbidity and mortality rates. Pneumomediastinum also may develop without tracheal or oesophageal injury after spontaneous or blunt chest, neck and facial injuries, and it may be accompanied by pneumothorax. We treated two patients who had pneumomediastinum. Case 1 was a 20-year-old man who had pain and dyspnoea around the sternum for one hour, as a result of a blow from an elbow during a football match. Case 2 was a 23-year-old man who had a two-day history of dyspnoea and chest pain with no history of trauma. In both patients, diagnosis of pneumomediastinum was confirmed with thoracic computed tomography scans, and the condition resolved within five days of in-patient observation. In conclusion, the diagnosis of pneumomediastinum should be considered for all patients who present to the emergency department with chest pain and dyspnoea. PMID- 26498132 TI - A Meta-Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX. AB - Trabecular bone score (TBS) is a gray-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual-level data from 17,809 men and women in 14 prospective population based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow-up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. (c) 2015 American Society for Bone and Mineral Research. PMID- 26498135 TI - Age-stratified cut-off points for the nocturnal penile tumescence measurement using Nocturnal Electrobioimpedance Volumetric Assessment (NEVA((r)) ) in sexually active healthy men. AB - The current nocturnal penile tumescence (NPT) measurement is based on standard cut-off levels defined regardless of age. This study was conducted to provide age stratified cut-off points for NPT measurement. Forty sexually active healthy men between 20 and 60 years old were enrolled and divided equally into four groups defined by age (20-29, 30-39, 40-49 and 50-60 years.). None of the candidates had sexual dysfunction or sleep disturbance or used supportive medication to enhance sexual function. Erectile function was evaluated by using the 5-item version of the international index of erectile function (IIEF-5). NPT was observed using the nocturnal electrobioimpedance volumetric assessment (NEVA((r)) ). The NPT values of healthy men aged 20-60 years varied from 268.7% to 202.3%. The NPT differed significantly between age groups (P < 0.0009); however, no significant differences between men aged 30-39 and 40-49 (P = 0.593) were observed. Age was weakly associated with IIEF-5 scores (P = 0.004), whereas a strong and negative correlation between age and NPT (P < 0.0001) was found. IEF-5 scores were not significantly associated with NPT (P = 0.95). Therefore, the standard values for NPT testing should be considered in the evaluation of the nocturnal penile activity of men of all ages. PMID- 26498136 TI - Inhibitory effects of fasudil on renal interstitial fibrosis induced by unilateral ureteral obstruction. AB - Renal fibrosis is the major cause of chronic kidney disease, and the Rho/Rho associated coiled-coil kinase (ROCK) signaling cascade is involved in the renal fibrotic processes. Several studies have reported that ROCK inhibitors attenuate renal fibrosis. However, the mechanism of this process remains to be fully elucidated. The present study assessed the inhibitory effect of fasudil, a ROCK inhibitor using immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blot analyses, in vivo and in vitro, to elucidate the mechanisms underlying renal interstitial fibrosis. In mice induced with unilateral ureteral obstruction (UUO), collagen accumulation, the expression of fibrosis-associated genes and the content of hydroxyproline in the kidney increased 3, 7, and 14 days following UUO. Fasudil attenuated the histological changes, and the production of collagen and extracellular matrix in the UUO kidney. The expression of alpha-smooth muscle actin (alpha-SMA) and the transforming growth factor-beta (TGFbeta)-Smad signaling pathway, and macrophage infiltration were suppressed by fasudil in the kidneys of the UUO mice. The present study also evaluated the role of intrinsic renal cells and infiltrated macrophages using NRK-52E, NRK-49F and RAW264.7 cells. The mRNA and protein expression levels of collagen I and alpha-SMA increased in the NRK-52E and NRK 49F cells stimulated by TGF-beta1. Hydroxyfasudil, a bioactive metabolite of fasudil, attenuated the increase in the mRNA and protein expression levles of alpha-SMA in the two cell types. However, the reduction in the mRNA expression of collagen I was observed in the NRK-49F cells only. Hydroxyfasudil decreased the mRNA expression of monocyte chemoattractant protein-1 (MCP-1) induced by TGF beta1 in the NRK-52E cells, but not in the NRK-49F cells. In the RAW264.7 cells, the mRNA expression levels of MCP-1, interleukin (IL)-1beta, IL-6 and tumor necrosis factor alpha were increased significantly following lipopolysaccharide stimulation, and were not suppressed by hydroxyfasudil. These data suggested that the inhibition of ROCK activity by fasudil suppressed the transformation of renal intrinsic cells into the myofibroblast cells, and attenuated the infiltration of macrophages, without inhibiting the expression or the activation of cytokine/chemokines, in the progression of renal interstitial fibrosis. PMID- 26498137 TI - Curcumin-induced downregulation of Axl receptor tyrosine kinase inhibits cell proliferation and circumvents chemoresistance in non-small lung cancer cells. AB - Lung cancer is still in the first place in terms of both incidence and mortality. In the present study, we demonstrated the effect of curcumin, a phytochemical of the plant Curcuma longa, on expression and activation of Axl receptor tyrosine kinase (RTK) which plays an important role in cell survival, proliferation and anti-apoptosis. Curcumin treatment of non-small cell lung cancer (NSCLC) A549 and H460 cells, was found to decrease Axl protein as well as mRNA levels in a dose- and time-dependent manner. Axl promoter activity was also reduced by curcumin, indicating that curcumin downregulates Axl expression at the transcriptional level. Moreover, Axl phosphorylation in response to binding of its ligand, Gas6, was abrogated by curcumin, suggesting the inhibitory effect of curcumin on Gas6 induced Axl activation. We next found cytotoxic effect of cucumin on both the parental A549 and H460 cells, and their variants which are resistant to cisplatin (A549/CisR and H460/CisR) and paclitaxel (A549/TR and H460/TR). Exposure of these cells to curcumin resulted in dose-dependent decline of cell viability and clonogenic ability. It is further observed that the anti-proliferative effect of curcumin on A549 cells overexpressing Axl protein was reduced, while that on H460 cells transfected Axl specific siRNA was augmented, confirming that curcumin inhibits cell proliferation via downregulation of Axl expression. In addition, curcumin was found to cause the induction of p21, a cyclin-dependent kinase inhibitor, and reduction of X-linked inhibitor of apoptosis protein (XIAP), an anti-apoptotic molecule, in parental H460 cells as well as chemoresistant cells, H460/CisR and H460/TR. Taken together, our data imply that Axl RTK is a novel target of curcumin through which it exerts anti-proliferative effect in both parental and chemoresistant NSCLC cells. PMID- 26498139 TI - Test-retest reliability of schizoaffective disorder compared with schizophrenia, bipolar disorder, and unipolar depression--a systematic review and meta-analysis. AB - OBJECTIVES: Schizoaffective disorder is a frequent diagnosis, and its reliability is subject to ongoing discussion. We compared the diagnostic reliability of schizoaffective disorder with its main differential diagnoses. METHODS: We systematically searched Medline, Embase, and PsycInfo for all studies on the test retest reliability of the diagnosis of schizoaffective disorder as compared with schizophrenia, bipolar disorder, and unipolar depression. We used meta-analytic methods to describe and compare Cohen's kappa as well as positive and negative agreement. In addition, multiple pre-specified and post hoc subgroup and sensitivity analyses were carried out. RESULTS: Out of 4,415 studies screened, 49 studies were included. Test-retest reliability of schizoaffective disorder was consistently lower than that of schizophrenia (in 39 out of 42 studies), bipolar disorder (27/33), and unipolar depression (29/35). The mean difference in kappa between schizoaffective disorder and the other diagnoses was approximately 0.2, and mean Cohen's kappa for schizoaffective disorder was 0.50 (95% confidence interval: 0.40-0.59). While findings were unequivocal and homogeneous for schizoaffective disorder's diagnostic reliability relative to its three main differential diagnoses (dichotomous: smaller versus larger), heterogeneity was substantial for continuous measures, even after subgroup and sensitivity analyses. CONCLUSIONS: In clinical practice and research, schizoaffective disorder's comparatively low diagnostic reliability should lead to increased efforts to correctly diagnose the disorder. PMID- 26498138 TI - Kidney cancer focal cryoablation trend: does location or approach matter? AB - PURPOSE: We evaluated the current indications and surgical and survival outcomes for cryoablation (CA) using either a percutaneous (PCA) or a laparoscopic approach (LCA). We also investigated the ability of the PADUA score to predict the risk of complications and local recurrence. METHODS: A retrospective analysis was performed at two European tertiary referral centers. Parameters analyzed included size, location, approach, operative time, hospital stay, complications, and functional and oncologic outcomes. Univariate and multivariate analyses were performed. An ROC analysis was conducted to evaluate the accuracy of the PADUA score. RESULTS: Eighty patients were included. Mean tumor size was 2.6 cm. PCA was more often performed in posterior (95 vs. 60 %), inferior (72 vs. 32 %), and lateral (87 vs. 55 %) tumors. The global complication rate was 8.75 %, although proximity to the renal sinus resulted in a higher rate (30 vs. 4 %). Mean follow up was 34 and 23 months for LCA and PCA, respectively. The 5-year recurrence-free survival was 76 and 90 % for LCA and PCA, respectively. Multivariate analysis showed that tumor involvement of the collecting system was predictive of recurrence. Under ROC analysis, PADUA score was a mild predictor for complications (AUC = 0.601) and a good predictor for recurrence (AUC = 0.723); PADUA >=8 was identified as a cutoff for patients to a higher risk of recurrence. CONCLUSIONS: The percutaneous approach is confirmed to be the preferred CA technique for posterior and lateral tumors. CA in deeper renal lesions and tumors with PADUA score >=8 might entail a higher risk of recurrence, and closer follow up should be considered in these patients. PMID- 26498140 TI - Hospital-acquired acute kidney injury: an analysis of baseline estimated glomerular filtration rate and in-hospital mortality. AB - AIM: The objective of this study was to determine whether the baseline estimated glomerular filtration rate (eGFR) level was independently associated with in hospital mortality in generalized patients with hospital-acquired acute kidney injury (HA-AKI) in China. METHODS: All of the patients admitted to a tertiary medical center of Nanjing, China, between January 1, 2013, and December 31, 2013, were involved. Through the use of an electronic database and the Acute Kidney Injury Network (AKIN) classification, the patients with HA-AKI were indentified. We included the hospitalized adult patients with HA-AKI. Epidemiological information and in-hospital outcomes were collected and were analyzed according to different baseline eGFR strata of the included individual patients. RESULTS: Of the 42,664 admissions during the study period, 1327 patients were identified as AKI. The incidence of HA-AKI was 3.1 %. HA-AKI patients with a compromised baseline eGFR tended to be older and had a higher prevalence of various comorbid conditions. With the gradual deterioration of the baseline eGFR, the odds ratio of in-hospital mortality increased incrementally and a graded independent association between the baseline eGFR and in-hospital mortality was observed when the baseline eGFR dropped below 60 ml/min per 1.73 m(2). CONCLUSION: Baseline eGFR was a potential risk factor for in-hospital mortality in HA-AKI. Serum Creatinine (SCr)-based definition of AKI needs to incorporate baseline eGFR to optimize or refine risk stratification. PMID- 26498141 TI - Can a pill prevent HIV? Negotiating the biomedicalisation of HIV prevention. AB - This article examines how biomedicalisation is encountered, responded to and negotiated within and in relation to new biomedical forms of HIV prevention. We draw on exploratory focus group discussions on pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) to examine how the processes of biomedicalisation are affected by and affect the diverse experiences of communities who have been epidemiologically framed as 'vulnerable' to HIV and towards whom PrEP and TasP will most likely be targeted. We found that participants were largely critical of the perceived commodification of HIV prevention as seen through PrEP, although this was in tension with the construction of being medical consumers by potential PrEP candidates. We also found how deeply entrenched forms of HIV stigma and homophobia can shape and obfuscate the consumption and management of HIV-related knowledge. Finally, we found that rather than seeing TasP or PrEP as 'liberating' through reduced levels of infectiousness or risk of transmission, social and legal requirements of responsibility in relation to HIV risk reinforced unequal forms of biomedical self-governance. Overall, we found that the stratifying processes of biomedicalisation will have significant implications in how TasP, PrEP and HIV prevention more generally are negotiated. PMID- 26498142 TI - Rs488087 single nucleotide polymorphism as predictive risk factor for pancreatic cancers. AB - Pancreatic cancer (PC) is a devastating disease progressing asymptomatically until death within months after diagnosis. Defining at-risk populations should promote its earlier diagnosis and hence also avoid its development. Considering the known involvement in pancreatic disease of exon 11 of the bile salt-dependent lipase (BSDL) gene that encodes variable number of tandem repeat (VNTR) sequences, we hypothesized upon the existence of a genetic link between predisposition to PC and mutations in VNTR loci. To test this, BSDL VNTR were amplified by touchdown-PCR performed on genomic DNA extracted from cancer tissue or blood samples from a French patient cohort and amplicons were Sanger sequenced. A robust method using probes for droplet digital (dd)-PCR was designed to discriminate the C/C major from C/T or T/T minor genotypes. We report that the c.1719C > T transition (SNP rs488087) present in BSDL VNTR may be a useful marker for defining a population at risk of developing PC (occurrence: 63.90% in the PC versus 27.30% in the control group). The odds ratio of 4.7 for the T allele was larger than those already determined for other SNPs suspected to be predictive of PC. Further studies on tumor pancreatic tissue suggested that a germline T allele may favor Kras G12R/G12D somatic mutations which represent negative prognostic factors associated with reduced survival. We propose that the detection of the T allele in rs488087 SNP should lead to an in-depth follow-up of patients in whom an association with other potential risk factors of pancreatic cancer may be present. PMID- 26498143 TI - Allele frequencies of BRAFV600 mutations in primary melanomas and matched metastases and their relevance for BRAF inhibitor therapy in metastatic melanoma. AB - BACKGROUND: The detection of BRAFV600 mutations in patients with metastatic melanoma is important because of the availability of BRAF inhibitor therapy. However, the clinical relevance of the frequency of BRAFV600 mutant alleles is unclear. PATIENTS AND METHODS: Allele frequencies of BRAFV600 mutations were analyzed by ultra-deep next-generation sequencing in formalin-fixed, paraffin embedded melanoma tissue (75 primary melanomas and 88 matched metastases). In a second study, pretreatment specimens from 76 patients who received BRAF inhibitors were retrospectively analyzed, and BRAFV600 allele frequencies were correlated with therapeutic results. RESULTS: Thirty-five patients had concordantly BRAF-positive and 36 (48%) patients had concordantly BRAF-negative primary melanomas and matched metastases, and four patients had discordant samples with low allele frequencies (3.4-5.2%). Twenty-six of 35 patients with concordant samples had BRAFV600E mutations, three of whom had additional mutations (V600K in two patients and V600R in one) and nine patients had exclusively non-V600E mutations (V600K in eight patients and V600E -c.1799_1800TG > AA- in one patient). The frequency of mutated BRAFV600 alleles was similar in the primary melanoma and matched metastasis in 27/35 patients, but differed by >3 fold in 8/35 of samples. BRAFV600E allele frequencies in pretreatment tumor specimens were not significantly correlated with treatment outcomes in 76 patients with metastatic melanoma who were treated with BRAF inhibitors. CONCLUSIONS: BRAFV600 mutation status and allele frequency is consistent in the majority of primary melanomas and matched metastases. A small subgroup of patients has double mutations. BRAFV600 allele frequencies are not correlated with the response to BRAF inhibitors. PMID- 26498144 TI - miR-214/199a/199a* cluster levels predict poor survival in hepatocellular carcinoma through interference with cell-cycle regulators. AB - AIMS: To identify the clinical and functional association of miR-214/199a/199a* cluster in human hepatocellular carcinoma (HCC) and to clarify the mechanism of miR-214. METHODS: Kaplan-Meier and Cox proportional regression analyses were used to determine the association of miR-214/199a/199a* cluster levels with the survival of HCC patients. The role of miR-214 in regulating HCC cell proliferation was studied with miR-214 mimics/inhibitor-treated cells. Furthermore, the inhibition effect of miR-214 on E2F2, cyclin-dependent kinase (CDK) 3 and CDK6 expression was assessed in HCC cell lines with miR-214 mimics/inhibitors to increase/decrease miR-214 expression. Direct binding of miR 214 to the 3'-untranslated regions of E2F2, CDK3, and CDK6 was verified by dual luciferase reporter assay. RESULTS: In analyzing HCC clinical specimens and cell lines, we discovered a uniform decrease in miR-214/199a/199a* expression in comparison with noncancerous tissue or normal liver epithelial cell lines. Higher miR-214 levels were related with improved patient survival. Overexpression of miR 214 in HCC cells inhibited proliferation by inducing G1-S checkpoint arrest. Conversely, RNA interference-mediated silencing of miR-214 promoted cell-cycle progression and accelerated the proliferation of HCC cells. E2F2, CDK3 and CDK6 were each directly targeted for inhibition by miR-214, and restoring their expression reversed miR-214 inhibition of cell-cycle progression. The relationship between expression of miR-214 and its targets was confirmed in HCC tumor xenografts and clinical specimens. CONCLUSIONS: Our results demonstrate that miR-214 has tumor-suppressive activity in HCC through inhibition of E2F2, CDK3 and CDK6. PMID- 26498145 TI - Methimazole-induced cholestatic hepatitis: two cases report and literature review. AB - Methimazole is commonly prescribed for patients who are thyrotoxic. Cholestatic hepatitis is a rare but serious adverse event which may be associated with interventional therapy. In this case report, we present two Chinese women with cholestatic jaundice due to methimazole treatment. Both patients had a history of hyperthyroidism; initial laboratory studies of liver function were normal and cholestatic hepatitis occurred after treatment with methimazole. Concomitant liver disease, such as viral hepatitis (A, B, C, D, E), autoimmune hepatitis, primary biliary cirrhosis and calculus of bile duct, were excluded. Liver enzyme levels in both patients returned to normal after stopping methimazole therapy and taking hepatoprotective drugs. It is essential that patients are informed about the earliest symptoms of serious adverse effects of antithyroid drugs, such as hepatic toxicity, and that they are advised to stop taking the drug immediately and contact their physician if such symptoms occur. PMID- 26498147 TI - Microscale profiling of photosynthesis-related variables in a highly productive biofilm photobioreactor. AB - In the present study depth profiles of light, oxygen, pH and photosynthetic performance in an artificial biofilm of the green alga Halochlorella rubescens in a porous substrate photobioreactor (PSBR) were recorded with microsensors. Biofilms were exposed to different light intensities (50-1,000 MUmol photons m( 2) s(-1) ) and CO2 levels (0.04-5% v/v in air). The distribution of photosynthetically active radiation showed almost identical trends for different surface irradiances, namely: a relatively fast drop to a depth of about 250 um, (to 5% of the incident), followed by a slower decrease. Light penetrated into the biofilm deeper than the Lambert-Beer Law predicted, which may be attributed to forward scattering of light, thus improving the overall light availability. Oxygen concentration profiles showed maxima at a depth between 50 and 150 MUm, depending on the incident light intensity. A very fast gas exchange was observed at the biofilm surface. The highest oxygen concentration of 3.2 mM was measured with 1,000 MUmol photons m(-2) s(-1) and 5% supplementary CO2. Photosynthetic productivity increased with light intensity and/or CO2 concentration and was always highest at the biofilm surface; the stimulating effect of elevated CO2 concentration in the gas phase on photosynthesis was enhanced by higher light intensities. The dissolved inorganic carbon concentration profiles suggest that the availability of the dissolved free CO2 has the strongest impact on photosynthetic productivity. The results suggest that dark respiration could explain previously observed decrease in growth rate over cultivation time in this type of PSBR. Our results represent a basis for understanding the complex dynamics of environmental variables and metabolic processes in artificial phototrophic biofilms exposed to a gas phase and can be used to improve the design and operational parameters of PSBRs. PMID- 26498146 TI - Is lineage decision-making restricted during tumoral reprograming of haematopoietic stem cells? AB - Within the past years there have been substantial changes to our understanding of haematopoiesis and cells that initiate and sustain leukemia. Recent studies have revealed that developing haematopoietic stem and progenitor cells are much more heterogeneous and versatile than has been previously thought. This versatility includes cells using more than one route to a fate and cells having progressed some way towards a cell type retaining other lineage options as clandestine. These notions impact substantially on our understanding of the origin and nature of leukemia. An important question is whether leukemia stem cells are as versatile as their cell of origin as an abundance of cells belonging to a lineage is often a feature of overt leukemia. In this regard, we examine the coming of age of the "leukemia stem cell" theory and the notion that leukemia, like normal haematopoiesis, is a hierarchically organized tissue. We examine evidence to support the notion that whilst cells that initiate leukemia have multi-lineage potential, leukemia stem cells are reprogrammed by further oncogenic insults to restrict their lineage decision-making. Accordingly, evolution of a sub-clone of lineage-restricted malignant cells is a key feature of overt leukemia. PMID- 26498148 TI - Development of an incipient Stevens-Johnson reaction while on a stable dose of lamotrigine. AB - OBJECTIVE: To describe a case of a possible incipient Stevens-Johnson reaction while a patient had been on a stable dose of lamotrigine for several months and to consider the likely cause. METHODS: The history is recounted. RESULTS: One likely cause implicates differing effective doses of lamotrigine across differing brands and raises quality control issues. CONCLUSION: The patient's severe reaction may reflect changing to a brand of lamotrigine that precipitously generated a higher serum level of lamotrigine. PMID- 26498149 TI - The pivotal role of primary care in meeting the health needs of people recently released from prison. AB - OBJECTIVE: Australia's prison population is growing at a rate well in excess of population growth. Indigenous Australians are over-represented by a factor of 13. Prisoners are a profoundly marginalised group characterised by complex health and social needs. Despite improvements in health during incarceration, poor health outcomes after release are common, and the net effect of incarceration is usually health depleting. Given the need for effective care coordination, primary care plays a pivotal role in meeting the health needs of this population. In this paper we review what is known about patterns of primary care utilisation in ex prisoners, identify evidence-based strategies for increasing access to primary care in ex-prisoners, and consider how such contact may shape subsequent health service outcomes. CONCLUSIONS: Primary care is a necessary but not sufficient condition for effective post-release support. Positive outcomes may depend more on the quality than the quantity of care received. Given massive over representation of Indigenous people in Australia's prisons, and compelling evidence of preventable morbidity and mortality after release from prison, effective models of care for this population are an important component of closing the gap in Indigenous life expectancy. PMID- 26498150 TI - Research leadership: should clinical directors be distinguished researchers? AB - OBJECTIVES: Clinical directors established research-led healthcare by combining research, teaching and clinical excellence within the teaching hospitals. This research culture created high clinical standards, which benefited patients, the workforce and healthcare organisations. The current paper explores this research leadership role for clinical directors. It reviews studies arising from the theory of expert leadership, which focuses on the relationship between a leader's core knowledge and organisational performance. More specifically, we examine the expert leader's research track record, the associations with their organisation's performance, and the influence of research activity on clinical excellence. CONCLUSION: Distinguished researchers still lead the most prestigious teaching hospitals and the most trusted departments of psychiatry in the United States where the clinical directorate structure originated. It is also known that good scholars can improve research output when appointed to leadership positions. This suggests that the clinical director's research track record should be a consideration at a time when research is being embedded in Australia's local health networks. A clinical director's leadership may influence the research performance of their department and contribute to the quality of mental healthcare. PMID- 26498151 TI - Graduate-entry medical students: older and wiser but not less distressed. AB - OBJECTIVES: Australia has a growing number of graduate-entry medical courses. It is known that undergraduate medical students have high levels of psychological distress; however, little is known about graduate-entry medical students. We examined whether graduate-entry medical students had higher levels of psychological distress than the same-age general population. METHOD: Psychological distress was assessed in 122 graduate-entry medical students in an Australian graduate-entry medical school using the 21-item Depression Anxiety and Stress Scale. Mean scores and the proportion of students with scores in the highly distressed range were compared with non-clinical population norms. Scores were also compared across demographic characteristics. RESULTS: Medical students reported higher mean depression, anxiety and stress scores than the general population and were more likely to score in the moderate to extremely high range for anxiety (45% vs. 13%; p<0.001) and stress (17% vs. 13%; p=0.003). Anxiety and stress were higher in students aged >=30 years than in younger students. CONCLUSIONS: Despite their maturity, graduate-entry students experienced high psychological distress. Anxiety and stress were higher, not lower, with increasing age. Our results suggest that graduate-entry medical students warrant the same level of concern as their school-leaving counterparts. Further interventions to support these students during medical school are warranted. PMID- 26498152 TI - Rel8: demonstrating the feasibility of delivering an 8-week social skills program in a public mental health setting. AB - OBJECTIVE: As community mental health services integrate recovery-oriented practices, treatments that focus on skills development and social integration are desirable. This study aimed to examine the feasibility of implementing "Rel8", an 8-week social skills training group adapted to suit a public community mental health setting. METHOD: A retrospective audit was conducted of quantitative and qualitative data from four groups run between 2011 and 2013. Pre- and post-group measures were collected, assessing self-rated friendships and confidence with social skills and clinician-rated social skill performance. Qualitative feedback about group participation was also collected through use of a developed questionnaire. RESULTS: Analysis revealed significant improvements in participants' confidence with their social skills following group participation, with a trend also found for improved social skill performance. CONCLUSIONS: "Rel8", an adapted 8-week social skills training group, is a feasible program in the context of community mental health services. The program added to the recovery-centred practice of the community mental health service while also adding to the diversity of clinician skills for psychosocial-oriented practice. PMID- 26498153 TI - Aboriginal involvement in caring-for-country: an economic case study in primary preventative health. AB - OBJECTIVE: Firstly, to demonstrate the involvement of Aboriginal people in caring for-country as a case study of how appropriately targeted non-medical primary preventative health strategies can be a cost-effective approach to addressing chronic disease among Indigenous people. Secondly, to demonstrate the use of an analogous approach in addressing the global chronic disease pandemic. METHOD: A review of prior biomedical and economic research based on the involvement of Aboriginal people in caring-for-country is used to: (a) exemplifying the cost effectiveness of a non-medical preventative health intervention; and (b) the process by which such an approach might be applied across a broader context. RESULTS: The presented results demonstrate one non-medical primary preventative health approach to addressing the health burden affecting Indigenous peoples. CONCLUSIONS: The suggested steps in optimising the cost effectiveness of such an approach demonstrate how it could be applied in addressing the global chronic disease pandemic. PMID- 26498154 TI - Mast cell tryptase and chymase in the progress of cutaneous vasculitis. AB - In animal models of vasculitis, mast cells are essential in the pathogenesis, but their involvement in human skin vasculitis is obscure. Because tryptase and chymase are potent serine proteinases in the secretory granules of mast cells, the purpose was to examine the number of mast cells expressing tryptase and chymase during the progress of cutaneous vasculitis. These numbers were correlated with the appearance of immunoreactants (C3c, fibrin, IgM, IgA and IgG) in vessel walls. For this, skin biopsies were taken from the healthy-looking skin, initial petechial lesion (IP), and palpable purpura (PP) of the leg of patients with leukocytoclastic vasculitis (n = 10). The frozen biopsies were analysed using enzyme- and immunohistochemistry and direct immunofluorescence (IF) staining. The results show that there are no marked changes in the numbers of mast cells expressing chymase or tryptase proteins. Instead, chymase enzyme activity decreased, but the score of alpha1-antichymotrypsin staining increased, during the progress of vasculitis. The IF positivity of fibrin correlated positively with chymase activity (p = 0.01) and the ratio of chymase activity to tryptase protein in IP (p = 0.03), as well as with mast cells showing tryptase (p = 0.03) and chymase (p = 0.01) proteins in PP. The IF positivity of C3c correlated with the ratio of chymase activity to tryptase protein in IP (p = 0.01). In conclusion, chymase is partially inactivated in vasculitis possibly due to alpha1-antichymotrypsin. Several positive correlations between chymase and fibrin and/or C3c in IP or PP suggest that this enzyme is involved in the deposition of immunoreactants in the vessel wall. PMID- 26498155 TI - Do as I ... Did! Long-term memory of imitative actions in dogs (Canis familiaris). AB - This study demonstrates long-term declarative memory of imitative actions in a non-human animal species. We tested 12 pet dogs for their ability to imitate human actions after retention intervals ranging from 1 to 24 h. For comparison, another 12 dogs were tested for the same actions without delay between demonstration and recall. Our test consisted of a modified version of the Do as I Do paradigm, combined with the two-action procedure to control for non-imitative processes. Imitative performance of dogs remained consistently high independent of increasing retention intervals, supporting the idea that dogs are able to retain mental representations of human actions for an extended period of time. The ability to imitate after such delays supports the use of long-term declarative memory. PMID- 26498156 TI - Joint Effect of Genotypic and Phenotypic Features of Reproductive Factors on Endometrial Cancer Risk. AB - Prolonged estrogen exposure is believed to be the major cause of endometrial cancer. As possible markers of estrogen exposure, various menstrual and reproductive features, e.g., ages at menarche and menopause, are found to be associated with endometrial cancer risk. In order to assess their combined effects on endometrial cancer, we created the total number of menstrual cycles (TNMC) that a woman experienced during her life or up to the time of study and two genetic risk scores, GRS1 for age at menarche and GRS2 for age at menopause. Comparing 482 endometrial cancer patients with 571 population controls, we found TNMC was associated with endometrial cancer risk and that the association remained statistically significant after adjustment for obesity and other potential confounders. Risk increased by about 2.5% for every additional 10 menstrual-cycles. The study also showed that high GRS1 was associated with increased risk. This relationship, however, was attenuated after adjustment for obesity. Our study further indicated women with high TNMC and GRS1 had twice the risk of endometrial cancer compared to those low in both indices. Our results provided additional support to the involvement of estrogen exposure in endometrial cancer risk with regard to genetic background and lifestyle features. PMID- 26498157 TI - Sequence- and Temperature-Dependent Properties of Unfolded and Disordered Proteins from Atomistic Simulations. AB - We use all-atom molecular simulation with explicit solvent to study the properties of selected intrinsically disordered proteins and unfolded states of foldable proteins, which include chain dimensions and shape, secondary structure propensity, solvent accessible surface area, and contact formation. We find that the qualitative scaling behavior of the chains matches expectations from theory under ambient conditions. In particular, unfolded globular proteins tend to be more collapsed under the same conditions than charged disordered sequences of the same length. However, inclusion of explicit solvent in addition naturally captures temperature-dependent solvation effects, which results in an initial collapse of the chains as temperature is increased, in qualitative agreement with experiment. There is a universal origin to the collapse, revealed in the change of hydration of individual residues as a function of temperature: namely, that the initial collapse is driven by unfavorable solvation free energy of individual residues, which in turn has a strong temperature dependence. We also observe that in unfolded globular proteins, increased temperature also initially favors formation of native-like (rather than non-native-like) structure. Our results help to establish how sequence encodes the degree of intrinsic disorder or order as well as its response to changes in environmental conditions. PMID- 26498158 TI - Whole genome SNP genotype piecemeal imputation. AB - BACKGROUND: Despite ongoing reductions in the cost of sequencing technologies, whole genome SNP genotype imputation is often used as an alternative for obtaining abundant SNP genotypes for genome wide association studies. Several existing genotype imputation methods can be efficient for this purpose, while achieving various levels of imputation accuracy. Recent empirical results have shown that the two-step imputation may improve accuracy by imputing the low density genotyped study animals to a medium density array first and then to the target density. We are interested in building a series of staircase arrays that lead the low density array to the high density array or even the whole genome, such that genotype imputation along these staircases can achieve the highest accuracy. RESULTS: For genotype imputation from a lower density to a higher density, we first show how to select untyped SNPs to construct a medium density array. Subsequently, we determine for each selected SNP those untyped SNPs to be imputed in the add-one two-step imputation, and lastly how the clusters of imputed genotype are pieced together as the final imputation result. We design extensive empirical experiments using several hundred sequenced and genotyped animals to demonstrate that our novel two-step piecemeal imputation always achieves an improvement compared to the one-step imputation by the state-of-the art methods Beagle and FImpute. Using the two-step piecemeal imputation, we present some preliminary success on whole genome SNP genotype imputation for genotyped animals via a series of staircase arrays. CONCLUSIONS: From a low SNP density to the whole genome, intermediate pseudo-arrays can be computationally constructed by selecting the most informative SNPs for untyped SNP genotype imputation. Such pseudo-array staircases are able to impute more accurately than the classic one-step imputation. PMID- 26498159 TI - Expert cardiologists cannot distinguish between Brugada phenocopy and Brugada syndrome electrocardiogram patterns. AB - AIMS: Brugada phenocopies (BrPs) are electrocardiogram (ECG) patterns that are identical to true Brugada syndrome (BrS) but are induced by various clinical conditions. The concept that both ECG patterns are visually identical has not been formally demonstrated. The aim of our study was to determine if experts on BrS were able to accurately distinguish between the BrS and BrP ECG patterns. METHODS AND RESULTS: Six ECGs from confirmed cases of BrS and six ECGs from previously published cases of BrP were included in the study. Surface 12-lead ECGs were scanned, saved in JPEG format, and sent to 10 international experts on BrS for evaluation (no clinical history provided). Evaluators were asked to label each case as a Brugada ECG pattern or non-Brugada ECG pattern by visual interpretation alone. The overall accuracy was 53 +/- 33% for all cases. Within the BrS cases, the mean accuracy was 63 +/- 34% and within the BrP cases, the mean accuracy was 43 +/- 33%. Intra-observer repeatability was moderate (kappa = 0.56) and inter-observer agreement was fair (kappa = 0.36) while evaluator accuracy vs. the true diagnosis was only marginally better than chance (kappa = 0.05). Similarly, diagnostic operating characteristics were poor (sensitivity 62%, specificity 43%, +LR 1.1, -LR 0.9). CONCLUSION: Our results provide strong evidence that BrP and BrS ECG patterns are visually identical and indistinguishable. These findings support the use of systematic diagnostic criteria for differentiating BrP vs. BrS as an erroneous diagnosis may have a negative impact on patient morbidity and mortality. PMID- 26498161 TI - Bifocal left ventricular stimulation or the optimal left ventricular stimulation site in cardiac resynchronization therapy: a pressure-volume loop study. AB - AIMS: Several implantation strategies have been proposed to improve response to cardiac resynchronization therapy (CRT), including bifocal left ventricular (LV) stimulation and optimal single-LV lead placement. This study aimed to compare these two strategies during invasive pressure-volume (PV) loop measurements. METHODS AND RESULTS: Thirty-three patients eligible for CRT were included [21 (64%) men, 20 (61%) ischaemic aetiology, QRS 155 +/- 23 ms], and underwent cardiac magnetic resonance (CMR) imaging and invasive PV loop measurements. Left ventricular pump function was characterized by stroke work (SW) and dP/dtmax (5.1 +/- 3.4 L mmHg and 856 +/- 190 mmHg/s, respectively). Haemodynamic response was assessed during stimulation at single-LV sites and during bifocal LV [anterolateral and posterolateral (PL)] stimulation. Response during bifocal LV stimulation was not significantly higher compared with standard PL pacing (SW; beta = 9.4 +/- 5.4, P = 0.080; dP/dtmax, beta = 0.2 +/- 1.9, P = 0.922). However, mean pump function improvement was significantly higher during stimulation at the optimal LV site compared with bifocal LV stimulation (SW; beta = 12.7 +/- 5.1, P = 0.012; dP/dtmax, beta = 3.3 +/- 1.2, P = 0.020). Myocardial tissue properties were assessed by CMR tissue tagging. Mechanical activation at the optimal LV site was significantly more delayed compared with the worst LV site (431 +/- 93 ms vs. 326 +/- 127 ms; P = 0.004). CONCLUSION: Stimulation at the optimal LV site showed a significantly higher pump function improvement compared with bifocal LV stimulation. Mechanical activation at the optimal LV site was significantly more delayed compared with the non-optimal LV site. In general, these results suggest that implantation of a second LV lead yields no additional benefit over implantation of one optimally placed LV lead. However, a bifocal approach might be beneficial in the individual patient. PMID- 26498160 TI - Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing. AB - AIMS: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible. METHODS AND RESULTS: To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands. CONCLUSION: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution. PMID- 26498162 TI - Serum amine-based metabolites and their association with outcomes in primary prevention implantable cardioverter-defibrillator patients. AB - AIMS: Heart failure patients are at increased risk of ventricular arrhythmias and all-cause mortality. However, existing clinical and serum markers only modestly predict these adverse events. We sought to use metabolic profiling to identify novel biomarkers in two independent prospective cohorts of patients with implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death (SCD). METHODS AND RESULTS: Baseline serum was quantitatively profiled for 42 known biologically relevant amine-based metabolites among 402 patients from the Prospective Observational Study of Implantable Cardioverter Defibrillators (PROSE-ICD) Study (derivation group) and 240 patients from the Genetic Risk Assessment of Defibrillator Events (GRADE) Study (validation group) for ventricular arrhythmia-induced ICD shocks and all-cause mortality. Three amines, N-methyl-l-histidine, symmetric dimethylarginine (SDMA), and l kynurenine, were derived and validated to be associated with all-cause mortality. The hazard ratios of mortality in PROSE-ICD and GRADE were 1.48 (95% confidence interval 1.14-1.92) and 1.67 (1.22-2.27) for N-methyl-l-histidine, 1.49 (1.17 1.91) and 1.77 (1.27-2.45) for SDMA, 1.31 (1.06-1.63) and 1.73 (1.32-2.27) for l kynurenine, respectively. l-Histidine, SDMA, and l-kynurenine were associated with ventricular arrhythmia-induced ICD shocks in PROSE-ICD, but they did not reach statistical significance in the GRADE cohort. CONCLUSION: Utilizing metabolic profiling in two independent prospective cohorts of patients undergoing ICD implantation for primary prevention of SCD, we identified several novel amine markers that were associated with appropriate shock and mortality. These findings shed insight into the potential biologic pathways leading to adverse events in ICD patients. Further studies are needed to confirm the prognostic value of these findings. PMID- 26498163 TI - Impact of remote monitoring on reducing the burden of inappropriate shocks related to implantable cardioverter-defibrillator lead fractures: insights from a French single-centre registry. AB - AIMS: Lead fractures in implantable cardioverter-defibrillator (ICD) patients may cause inappropriate shocks (ISs). An early diagnosis is essential to prevent adverse clinical events. Implantable cardioverter-defibrillator remote monitoring (RM) permits prompt detection of lead fracture. Limited data define the impact of RM on ISs specifically related to lead fracture. We sought to compare the number of ISs related to lead fracture in patients with vs. without RM follow-up. METHODS AND RESULTS: We checked the registry of our institution and collected, between July 2007 and June 2014, 115 cases of right ventricular lead fractures. All relevant data were documented from patients' files, device-interrogation printouts and electronic records, and remote transmissions databases when applicable. We assessed the ISs that were related to lead fracture. The first study endpoint was the number of ISs per shocked patient. Among the 82 patients with conventional follow-up (CFU) and the 33 patients with RM, a first IS occurred to 32.9% (n = 27) and 30.3% (n = 10, P = 0.83) of the patients, respectively. Shocked patients in the RM group underwent significantly fewer ISs with a mean of 6 +/- 2 shocks per patient [median of 3.5 shocks (2-8)] than those in the CFU group with a mean of 18 +/- 5 shocks per patient [median of 10 shocks (5-22), P = 0.03]. CONCLUSION: Remote monitoring helps to reduce the burden of ISs related to ICD lead fractures. PMID- 26498164 TI - Arrhythmogenic right ventricular cardiomyopathy, clinical manifestations, and diagnosis. AB - This review aims to give an update on the pathogenesis, clinical manifestations, and diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Arrhythmogenic right ventricular cardiomyopathy is mainly an autosomal dominant inherited disease linked to mutations in genes encoding desmosomes or desmosome related proteins. Classic symptoms include palpitations, cardiac syncope, and aborted cardiac arrest due to ventricular arrhythmias. Heart failure may develop in later stages. Diagnosis is based on the presence of major and minor criteria from the Task Force Criteria revised in 2010 (TFC 2010), which includes evaluation of findings from six different diagnostic categories. Based on this, patients are classified as having possible, borderline, or definite ARVC. Imaging is important in ARVC diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting structural and functional abnormalities, but importantly these findings may occur after electrical alterations and ventricular arrhythmias. Electrocardiograms (ECGs) and signal-averaged ECGs are analysed for depolarization and repolarization abnormalities, including T-wave inversions as the most common ECG alteration. Ventricular arrhythmias are common in ARVC and are considered a major diagnostic criterion if originating from the RV inferior wall or apex. Family history of ARVC and detection of an ARVC-related mutation are included in the TFC 2010 and emphasize the importance of family screening. Electrophysiological studies are not included in the diagnostic criteria, but may be important for differential diagnosis including RV outflow tract tachycardia. Further differential diagnoses include sarcoidosis, congenital abnormalities, myocarditis, pulmonary hypertension, dilated cardiomyopathy, and athletic cardiac adaptation, which may mimic ARVC. PMID- 26498165 TI - Nanoparticle-Mediated Target Delivery of TRAIL as Gene Therapy for Glioblastoma. AB - Human tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) is an attractive cancer therapeutic because of its ability to induce apoptosis in tumor cells while having a negligible effect on normal cells. However, the short serum half-life of TRAIL and lack of efficient in vivo administration approaches have largely hindered its clinical use. Using nanoparticles (NPs) as carriers in gene therapy is considered as an alternative approach to increase TRAIL delivery to tumors as transfected cells would be induced to secrete TRAIL into the tumor microenvironment. To enable effective delivery of plasmid DNA encoding TRAIL into glioblastoma (GBM), we developed a targeted iron oxide NP coated with chitosan polyethylene glycol-polyethyleneimine copolymer and chlorotoxin (CTX) and evaluated its effect in delivering TRAIL in vitro and in vivo. NP-TRAIL successfully delivers TRAIL into human T98G GBM cells and induces secretion of 40 pg mL(-1) of TRAIL in vitro. Transfected cells show threefold increased apoptosis as compared to the control DNA bound NPs. Systemic administration of NP-TRAIL-CTX to mice bearing T98G-derived flank xenografts results in near-zero tumor growth and induces apoptosis in tumor tissue. Our results suggest that NP-TRAIL-CTX can potentially serve as a targeted anticancer therapeutic for more efficient TRAIL delivery to GBM. PMID- 26498167 TI - Molecular iodine adsorption within Hofmann-type structures M(L)[M'(CN)4] (M = Ni, Co; M' = Ni, Pd, Pt): impact of their composition. AB - A series of thermally stable Hofmann-type clathrate structures with the general formula M(pz)[M'(CN)4], where M and M' are bivalent metal ions M(II) = Ni(II), Co(II), M(II)' = Ni(II), Pd(II), Pt(II), and pz is the pyrazine bidentate ligand, was synthesized and investigated for the efficient entrapment of iodine (I2) in solution and in the gas phase. Iodine-containing clathrates thus prepared were analysed to determine the saturation capacity, thermal stability, guest-induced structural changes of the clathrate's lattice and the nature of the confined iodine according to the chemical composition of the host structure. An efficient confinement of about 1 I2 per unit cell is observed for the series of clathrates with the Ni(II) and Pd(II) ions in the square planar position whatever the bivalent metal ion in the octahedral position. Specific responses in the lattice adjustment are detected for Co(II) in the octahedral and Pd(II) in the square planar positions. PMID- 26498166 TI - Long-range energy transfer in self-assembled quantum dot-DNA cascades. AB - The size-dependent energy bandgaps of semiconductor nanocrystals or quantum dots (QDs) can be utilized in converting broadband incident radiation efficiently into electric current by cascade energy transfer (ET) between layers of different sized quantum dots, followed by charge dissociation and transport in the bottom layer. Self-assembling such cascade structures with angstrom-scale spatial precision is important for building realistic devices, and DNA-based QD self assembly can provide an important alternative. Here we show long-range Dexter energy transfer in QD-DNA self-assembled single constructs and ensemble devices. Using photoluminescence, scanning tunneling spectroscopy, current-sensing AFM measurements in single QD-DNA cascade constructs, and temperature-dependent ensemble devices using TiO2 nanotubes, we show that Dexter energy transfer, likely mediated by the exciton-shelves formed in these QD-DNA self-assembled structures, can be used for efficient transport of energy across QD-DNA thin films. PMID- 26498168 TI - Isolation and characteristics of CD133-/A2B5+ and CD133-/A2B5- cells from the SHG139s cell line. AB - In glioma tissues, there are small cell populations with the capability of sustaining tumor formation. These cells are referred to as glioma stem cells (GSCs). However, the presence of subpopulations of GSCs, and the differences between each subpopulation remain to be fully elucidated. In the present study, CD133-/A2B5- and CD133-/A2B5+ cells from the SHG139 GSC cell line (SHG139s) were isolated using magnetic-activated cell sorting. Following xenografting into nude mice, the two isolated subpopulations generated tumors. The characteristics of the two subpopulations were investigated extensively, and it was found that the two exhibited cancer stem cell characteristics. These cells expressed stem cell markers, exhibited a neurosphere-like appearance, and were found to exhibit self renewal and multipotency capabilities. Subsequently, the self-renewal and proliferation abilities of the two subpopulations were compared. It was found that the A2B5- cells had a higher proliferative index and a higher self-renewal ability, compared with the A2B5+ cells. In addition, the A2B5- cells exhibited increased angiogenic ability. However, the invasion ability of the A2B5+ cells was higher than that of the A2B5- cells. Taken together, the results of the present study suggested that there are different cell subpopulations in GSCs, and each subpopulation has its own properties. PMID- 26498169 TI - Denosumab Inhibition of RANKL and Insulin Resistance in Postmenopausal Women with Osteoporosis. AB - The tumor necrosis factor-related cytokine receptor activator of nuclear factor kappa B ligand (RANKL) has been proposed as predictor of incident type 2 diabetes mellitus, and experimental blockade of RANKL resulted in a marked improvement of glucose tolerance. Denosumab is a fully human monoclonal antibody that binds to RANKL and prevents osteoclast formation, function and survival, leading to fracture risk reduction. The aim of our study was to investigate glucometabolic parameters, insulin resistance, and lipid profile in non-diabetic women receiving denosumab. Forty-eight women with postmenopausal osteoporosis were enrolled and treated with a subcutaneous dose (60 mg) of denosumab. At baseline and after 4, 12, ad 24 weeks, insulin resistance was computed by homeostasis model assessment of insulin resistance (HOMA-IR) and total cholesterol, triglycerides and HDL cholesterol were also measured. At baseline and after 24 weeks, bone turn-over markers were also evaluated. After denosumab administration, with the exception of a slight reduction of insulin and HOMA-IR values after 4 weeks (p < 0.05), neither fasting plasma glucose nor insulin and insulin resistance were significantly changed. Lipid parameters remained unchanged at each time-points of this study. A reduction of C-telopeptide of type 1 collagen (-63%, p < 0.0001) and osteocalcin (-45%, p < 0.0001), as bone resorption and formation markers, respectively, were observed after 24 weeks. Baseline levels of bone biomarkers were not predictive of HOMA-IR, and changes of osteocalcin were not associated to markers of glucose control. In osteoporotic otherwise healthy postmenopausal women, denosumab was not associated with relevant modification of insulin resistance and lipid profile. PMID- 26498170 TI - Why develop antidotes and reversal agents for non-vitamin K oral anticoagulants? AB - Over the past several years, non-vitamin K oral anticoagulants (NOACs) have been introduced into clinical practice for the treatment of venous thromboembolism and prevention of stroke in patients with nonvalvular atrial fibrillation. Clinical trials have shown these agents to have similar or less risk of major bleeding as compared to warfarin therapy. Moreover, when patients do experience a major bleeding event administration of advanced factor products is rare, and post-bleed outcomes are similar in those receiving a NOAC compared to those receiving warfarin. However, there are situations where urgent reversal of NOAC anticoagulation would be desirable. The following review focuses on the outcomes and management strategies for patients experiencing a major bleed with warfarin or NOAC agents and describes the rationale for the development of therapies capable of targeted NOAC-reversal. PMID- 26498171 TI - Design and evaluation of gamma-sterilized vancomycin hydrochloride-loaded poly(E caprolactone) microspheres for the treatment of biofilm-based medical device related osteomyelitis. AB - CONTEXT: There is a great necessity to find and use accomplished terminal sterilization technique for industrial manufacturing, research and development studies. Gamma (gamma)-sterilization has been commonly employed for wide range of products as indicated by the pharmacopoeias. However, carefully examination should be performed prior to administration since gamma-radiation can cause changes in drug and polymer excipients. No information is available in literature about gamma-sterilization effects on vancomycin HCl-loaded poly (E-caprolactone) (PCL) microspheres. OBJECTIVE: Formulations were developed using a different preparation approach for the treatment of medical device-related osteomyelitis, and gamma-sterilization effects on the physicochemical characterization of the formulations were examined. METHODS: Water-in-oil-in-water (w/o/w) emulsion technique using polyvinyl alcohol (PVA) in inner and outer phase was applied to prepare formulations. Physicochemical properties of the formulations were investigated before and after gamma-sterilization and the antibacterial activity against Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) were measured. RESULTS: The particle size of the nonsterilized formulations were between 58 and 134 MUm. 60% or 20% of vancomycin HCl were released from 42.500 Mn or 70.000-90.000 Mn PCL microspheres, respectively, in 24 h. No difference was observed in the particle size, drug-loading efficiency, morphology, in vitro release and antimicrobial activity of the formulations after gamma-sterilization (p > 0.05). PMID- 26498172 TI - Identification of novel alleles of the rice blast resistance gene Pi54. AB - Rice blast is one of the most devastating rice diseases and continuous resistance breeding is required to control the disease. The rice blast resistance gene Pi54 initially identified in an Indian cultivar confers broad-spectrum resistance in India. We explored the allelic diversity of the Pi54 gene among 885 Indian rice genotypes that were found resistant in our screening against field mixture of naturally existing M. oryzae strains as well as against five unique strains. These genotypes are also annotated as rice blast resistant in the International Rice Genebank database. Sequence-based allele mining was used to amplify and clone the Pi54 allelic variants. Nine new alleles of Pi54 were identified based on the nucleotide sequence comparison to the Pi54 reference sequence as well as to already known Pi54 alleles. DNA sequence analysis of the newly identified Pi54 alleles revealed several single polymorphic sites, three double deletions and an eight base pair deletion. A SNP-rich region was found between a tyrosine kinase phosphorylation site and the nucleotide binding site (NBS) domain. Together, the newly identified Pi54 alleles expand the allelic series and are candidates for rice blast resistance breeding programs. PMID- 26498173 TI - Predictive Validity of a Cigarette Purchase Task in a Randomized Controlled Trial of Contingent Vouchers for Smoking in Individuals With Substance Use Disorders. AB - INTRODUCTION: A cigarette purchase task (CPT) is a behavioral economic measure of the reinforcing value of smoking in monetary terms (ie, cigarette demand). This study investigated whether cigarette demand predicted response to contingent monetary rewards for abstinence among individuals with substance use disorders. It also sought to replicate evidence for greater price sensitivity at whole dollar pack price transitions (ie, left-digit effects). METHODS: Participants (N = 338) were individuals in residential substance use disorder treatment who participated in a randomized controlled trial that compared contingent vouchers to noncontingent vouchers for smoking abstinence. Baseline demand indices were used to predict number of abstinent days during the 14-day voucher period (after the reduction lead-in) and at 1 and 3 months afterward. RESULTS: Demand indices correlated with measures of smoking and nicotine dependence. As measured by elasticity, intensity and O max, higher demand significantly predicted fewer abstinent exhaled carbon monoxide readings during voucher period for individuals in the noncontingent vouchers condition. Breakpoint exhibited a trend-level association with abstinent exhaled carbon monoxide readings. Demand indices did not predict abstinence in the contingent vouchers group, and did not predict abstinence at 1- and 3-month follow-ups. Left-digit price transitions were associated with significantly greater reductions in consumption. CONCLUSIONS: The association of cigarette demand with smoking behavior only in the group for whom abstinence was not incentivized indicates that CPT assesses the value of smoking more than the value of money per se and that vouchers counteract the effects of the intrinsic reinforcing value of cigarettes. Results provide initial short-term evidence of predictive validity for the CPT indices. IMPLICATIONS: This study provides the first evidence of the validity of the CPT for predicting early response to brief advice for smoking cessation plus nicotine replacement in smokers with substance dependence. However, demand for cigarettes did not predict voucher-based treatment response, indicating that incentives serve as a powerful motivator not to smoke that acts in opposition to the intrinsic reinforcing value of cigarettes and that the indices reflect the value of smoking more than the value of money per se. PMID- 26498174 TI - Atypical Case of a Painful Presacral Tumor. AB - BACKGROUND: Retention of surgical items after a surgical procedure is not only a medical error, but can also lead to various unexpected complications and additional surgery procedures even years after the initial operation. CASE REPORT: A 59-year old woman was referred to our hospital with intermittent pain in the lesser pelvis for about three months. She had undergone laparotomy for cholecystectomy 24 years ago and adnexectomy more than 30 years ago. CT-scan and MRI indicated a presacral tumor, most likely compatible with a presacral teratoma. A laparoscopic resection of the tumor was performed. Intraoperatively the tumor showed no clear capsule and could only be resected by fragments. The pathological report analyzed textile fibres, diagnosing a textiloma. The patient showed an uneventful postoperative follow-up. CONCLUSIONS: Most likely, the textile fibres originated from a sponge, which was retained during adnexectomy 33 years ago. There are numerous reports of retained surgical items discovered years after the initial operation. In literature, there are several reported cases of transmural migration of a sponge into the intestine, stomach and bladder. In our case, the sponge must have migrated to the deepest point of the retroperitoneum, which appears to be quite unusual, as no comparable case reports could be found. This case stresses the importance of the surgeon's awareness to particular appearances of a retained surgical sponge from a surgical procedure performed even decades ago. Additionally, this case report stresses the importance of meticulous analysis of individual patient medical history. PMID- 26498176 TI - Pressure-responsive mesoscopic structures in room temperature ionic liquids. AB - Among the most spectacular peculiarities of room temperature ionic liquids, their mesoscopically segregated structural organization keeps on attracting attention, due to its major consequences for the bulk macroscopic properties. Herein we use molecular dynamics simulations to explore the nm-scale architecture in 1-octyl-3 methylimidazolium tetrafluoroborate, as a function of pressure. This study reveals an intriguing new feature: the mesoscopic segregation in ionic liquids is characterized by a high level of pressure-responsiveness, which progressively vanishes upon application of high enough pressure. These results are in agreement with recent X-ray scattering data and are interpreted in terms of the microscopic organization. This new feature might lead to new methods of developing designer solvents for enhanced solvation capabilities and selectivity. PMID- 26498175 TI - Inhibition of osteolysis after local administration of osthole in a TCP particles induced osteolysis model. AB - PURPOSE: Wear debris-induced osteolysis and aseptic loosening are the most frequent late complications of total joint arthroplasty leading to revision of the prosthesis. However, no effective measures for the prevention and treatment of particles-induced osteolysis currently exist. Here, we investigated the efficacy of local administration of osthole on tricalcium phosphate (TCP) particles-induced osteolysis in a murine calvarial model. METHODS: TCP particles were implanted over the calvaria of ICR mice, and established TCP particles induced osteolysis model. On days one, four, seven, ten and thirteen post surgery, osthole (10 mg/kg) or phosphate buffer saline (PBS) were subcutaneously injected into the calvaria of TCP particles-implanted or sham-operated mice. Two weeks later, blood, the periosteum and the calvaria were collected and processed for bone turnover markers, pro-inflammatory cytokine, histomorphometric and molecular analysis. RESULTS: Osthole (10 mg/kg) markedly prevented TCP particles induced osteoclastogenesis and bone resorption in a mouse calvarial model. Osthole also inhibited the decrease of serum osteocalcin level and calvarial alkaline phosphatase (ALP) activity, and prevented the increase in the activity of tartrate resistant acid phosphatase (TRAP) and cathepsin K in the mouse calvaria. Furthermore, osthole obviously reduced the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) into the periosteum. Western blotting demonstrated TCP particles caused a remarkable endoplasmic reticulum (ER) stress response in the mouse calvaria, which was obviously blocked by osthole treatment. CONCLUSION: These results suggest that local administration of osthole inhibits TCP particles-induced osteolysis in the mouse calvarial in vivo, which may be mediated by inhibition of the ER stress signaling pathway, and it will be developed as a new drug in the prevention and treatment of destructive diseases caused by prosthetic wear particles. PMID- 26498177 TI - Predicting the chance of live birth for women undergoing IVF: a novel pretreatment counselling tool. AB - STUDY QUESTION: Which pretreatment patient variables have an effect on live birth rates following assisted conception? SUMMARY ANSWER: The predictors in the final multivariate logistic regression model found to be significantly associated with reduced chances of IVF/ICSI success were increasing age (particularly above 36 years), tubal factor infertility, unexplained infertility and Asian or Black ethnicity. WHAT IS KNOWN ALREADY: The two most widely recognized prediction models for live birth following IVF were developed on data from 1991 to 2007; pre dating significant changes in clinical practice. These existing IVF outcome prediction models do not incorporate key pretreatment predictors, such as BMI, ethnicity and ovarian reserve, which are readily available now. STUDY DESIGN, SIZE, DURATION: In this cohort study a model to predict live birth was derived using data collected from 9915 women who underwent IVF/ICSI treatment at any CARE (Centres for Assisted Reproduction) clinic from 2008 to 2012. Model validation was performed on data collected from 2723 women who underwent treatment in 2013. The primary outcome for the model was live birth, which was defined as any birth event in which at least one baby was born alive and survived for more than 1 month. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected from 12 fertility clinics within the CARE consortium in the UK. Multivariable logistic regression was used to develop the model. Discriminatory ability was assessed using the area under receiver operating characteristic (AUROC) curve, and calibration was assessed using calibration-in-the-large and the calibration slope test. MAIN RESULTS AND THE ROLE OF CHANCE: The predictors in the final model were female age, BMI, ethnicity, antral follicle count (AFC), previous live birth, previous miscarriage, cause and duration of infertility. Upon assessing predictive ability, the AUROC curve for the final model and validation cohort was (0.62; 95% confidence interval (CI) 0.61-0.63) and (0.62; 95% CI 0.60-0.64) respectively. Calibration-in-the-large showed a systematic over-estimation of the predicted probability of live birth (Intercept (95% CI) = -0.168 (-0.252 to 0.084), P < 0.001). However, the calibration slope test was not significant (slope (95% CI) = 1.129 (0.893-1.365), P = 0.28). Due to the calibration-in-the large test being significant we recalibrated the final model. The recalibrated model showed a much-improved calibration. LIMITATIONS, REASONS FOR CAUTION: Our model is unable to account for factors such as smoking and alcohol that can affect IVF/ICSI outcome and is somewhat restricted to representing the ethnic distribution and outcomes for the UK population only. We were unable to account for socioeconomic status and it may be that by having 75% of the population paying privately for their treatment, the results cannot be generalized to people of all socioeconomic backgrounds. In addition, patients and clinicians should understand this model is designed for use before treatment begins and does not include variables that become available (oocyte, embryo and endometrial) as treatment progresses. Finally, this model is also limited to use prior to first cycle only. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study to present a novel, up-to-date model encompassing three readily available prognostic factors; female BMI, ovarian reserve and ethnicity, which have not previously been used in prediction models for IVF outcome. Following geographical validation, the model can be used to build a user-friendly interface to aid decision-making for couples and their clinicians. Thereafter, a feasibility study of its implementation could focus on patient acceptability and quality of decision-making. STUDY FUNDING/COMPETING INTEREST: None. PMID- 26498178 TI - Placental characteristics in women with polycystic ovary syndrome. AB - STUDY QUESTION: Are macroscopic and microscopic placental characteristics in a heterogeneous group of women diagnosed with polycystic ovary syndrome (PCOS) different from those of a low-risk general population? SUMMARY ANSWER: Women with PCOS have significantly different microscopic placental characteristics compared with control women, independently from pregnancy complications. WHAT IS KNOWN ALREADY: Non-obese women with PCOS who conceived spontaneously have a significantly reduced placental volume and weight, with more chronic villitis and intervillositis compared with healthy controls. STUDY DESIGN, SIZE, DURATION: A subset of a large prospective cohort study of pregnant women with PCOS was used. Healthy (low-risk) women who delivered at term after an uncomplicated pregnancy were used as the reference population. The placentas of 73 women with PCOS were analysed and compared with 209 placentas of healthy women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Placentas were collected after delivery from women with PCOS who were followed from prior to conception until delivery. The placentas were macroscopically and microscopically analysed and compared with placentas of healthy women with either a spontaneous start of labour who delivered at term or who had an elective Caesarean section. MAIN RESULTS AND THE ROLE OF CHANCE: After adjusting for potential confounders, placentas from women with PCOS showed more chorioamnionitis (P < 0.001), funisitis (P = 0.019), villitis (P = 0.045), thrombosis (P = 0.018), infarction (P = 0.010), villous immaturity (P = 0.009) and nucleated fetal red blood cells (P < 0.001). In a subgroup analysis, among women with and without pregnancy complications within the PCOS group, only the occurrence of thrombosis was increased in pregnancies complicated by pregnancy-induced hypertension or pre-eclampsia (30%, versus 0% in gestational diabetes pregnancies and 13% in uncomplicated pregnancies; P = 0.008). LIMITATIONS, REASONS FOR CAUTION: There might be a small proportion of women with PCOS in the reference group, since this group was not screened for PCOS. As a result, the observed difference may be an underestimation of the true difference. Placentas were stored for up to 72 h at 4 degrees C, this is common practice but some degenerative changes cannot be ruled out absolutely. Also, there is possibility that baseline differences between the groups may in part explain some of the differences in placental pathology. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that, in general, women with PCOS can have placental alterations associated with an increased hypoxic state, which seems not to be caused by the increased incidence of pregnancy complications. PMID- 26498179 TI - Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis. AB - STUDY QUESTION: How does regulation of telomerase activity (TA) in human endometrial epithelial cells (EEC) by ovarian hormones impact on telomere lengths (TL) and cell proliferation? SUMMARY ANSWER: Healthy endometrial epithelial cell proliferation is characterized by high TA and endometrial TL changes according to the ovarian hormone cycle, with shortest TL observed in the progesterone dominant mid-secretory phase, when TA is lowest, implicating progesterone in the negative regulation of TA and TL. WHAT IS KNOWN ALREADY: Critical shortening of telomeres may result in permanent cell cycle arrest while the enzyme telomerase maintains telomere length (TL) and replicative capacity of cells. Telomerase expression and activity change in the human endometrium with the ovarian hormone cycle, however the effect of this on endometrial TL and cell growth is not known. STUDY DESIGN, SIZE, DURATION: A prospective observational study, which included endometrial and blood samples collected from 196 women. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied endometrial samples from five different groups of women. Endometrial and matched blood TL and circulating steroid hormones were studied in samples collected from 85 women (Group 1). Fresh epithelial and stromal cell isolation and culture in vitro for TL and TA was done on endometrial biopsies collected from a further 74 healthy women not on hormonal therapy (Group 2) and from 5 women on medroxyprogesterone acetate (MPA) for contraception (Group 3). The epithelial TL and telomerase protein expression was examined in active, peritoneal, ectopic endometriotic and matched uterine (eutopic) endometrial samples collected from 10 women with endometriosis (Group 4); the in vivo effect of mifepristone on telomerase protein expression by immunohistochemistry (IHC) was examined in endometrium from 22 healthy women in mid-secretory phase before (n = 8), and after administering 200 mg mifepristone (n = 14) (Group 5). TA was measured by telomere repeat amplification protocol (TRAP) assay; TL by qPCR, and Q-FISH; cell proliferation was assessed by immunoblotting of histone H3 and 3D culture to assess the ability of EECs to form spheroids; telomerase reverse transcriptase protein levels and Ki-67 (proliferative index) were assessed with IHC. MAIN RESULTS AND THE ROLE OF CHANCE: Endometrial TLs correlated negatively with serum progesterone levels (n = 58, r = -0.54) and were significantly longer than corresponding blood TLs (4893 +/- 929 bp versus 3955 +/- 557 bp, P = 0.002) suggesting a tissue-specific regulation. High TA and short TLs were observed in proliferating EECs in vivo and in vitro. During the progesterone dominant mid secretory phase endometrial TL were significantly shorter compared with the proliferative phase (P = 0.0002). Progestagen treatment suppressed EEC TA in vivo and reduced endometrial TA in explant (P = 0.01) and in vitro cultures (P = 0.02) compared with untreated cells. Mifepristone (progesterone receptor antagonist) increased telomerase protein levels in vivo (P < 0.05). In 2D culture, Imetelstat inhibited EEC TA (P = 0.03), proliferation (P = 0.009) and in 3D culture disrupted endometrial glandular architecture (P = 0.03). LIMITATIONS, REASONS FOR CAUTION: The in vitro telomerase inhibition data were tested in a mono-cellular system for a short-term. Further confirmation of the results in an in vivo model is necessary. The women in group 2 included a high proportion of women although with a regular menstrual cycle, with an increased BMI (>25) therefore this may affect extrapolation of data to other groups. WIDER IMPLICATIONS OF THE FINDINGS: The observed effects of telomerase inhibition in vitro on epithelial cell proliferation, suggest that telomerase might be an attractive target in developing new therapies for proliferative disorders of the endometrium, such as endometriosis. PMID- 26498180 TI - Zinc regulates a key transcriptional pathway for epileptogenesis via metal regulatory transcription factor 1. AB - Temporal lobe epilepsy (TLE) is the most common focal seizure disorder in adults. In many patients, transient brain insults, including status epilepticus (SE), are followed by a latent period of epileptogenesis, preceding the emergence of clinical seizures. In experimental animals, transcriptional upregulation of CaV3.2 T-type Ca(2+)-channels, resulting in an increased propensity for burst discharges of hippocampal neurons, is an important trigger for epileptogenesis. Here we provide evidence that the metal-regulatory transcription factor 1 (MTF1) mediates the increase of CaV3.2 mRNA and intrinsic excitability consequent to a rise in intracellular Zn(2+) that is associated with SE. Adeno-associated viral (rAAV) transfer of MTF1 into murine hippocampi leads to increased CaV3.2 mRNA. Conversely, rAAV-mediated expression of a dominant-negative MTF1 abolishes SE induced CaV3.2 mRNA upregulation and attenuates epileptogenesis. Finally, data from resected human hippocampi surgically treated for pharmacoresistant TLE support the Zn(2+)-MTF1-CaV3.2 cascade, thus providing new vistas for preventing and treating TLE. PMID- 26498182 TI - Reliability, factor structure, and validity of the German version of the Trauma Symptom Checklist for Children in a sample of adolescents. AB - BACKGROUND: The Trauma Symptom Checklist for Children (TSC-C) is the most widely used self-report scale to assess trauma-related symptoms in children and adolescents on six clinical scales. The purpose of the present study was to develop a German version of the TSC-C and to investigate its psychometric properties, such as factor structure, reliability, and validity, in a sample of German adolescents. METHOD: A normative sample of N=583 and a clinical sample of N=41 adolescents with a history of physical or sexual abuse aged between 13 and 21 years participated in the study. RESULTS: The Confirmatory Factor Analysis on the six-factor model (anger, anxiety, depression, dissociation, posttraumatic stress, and sexual concerns with the subdimensions preoccupation and distress) revealed acceptable to good fit statistics in the normative sample. One item had to be excluded from the German version of the TSC-C because the factor loading was too low. All clinical scales presented acceptable to good reliability, with Cronbach's alpha's ranging from .80 to .86 in the normative sample and from .72 to .87 in the clinical sample. Concurrent validity was also demonstrated by the high correlations between the TSC-C scales and instruments measuring similar psychopathology. TSC-C scores reliably differentiated between adolescents with trauma history and those without trauma history, indicating discriminative validity. CONCLUSIONS: In conclusion, the German version of the TSC-C is a reliable and valid instrument for assessing trauma-related symptoms on six different scales in adolescents aged between 13 and 21 years. PMID- 26498183 TI - Adipose differentiation-related protein is not involved in hypoxia inducible factor-1-induced lipid accumulation under hypoxia. AB - Increasing evidence has showed that hypoxia inducible factor-1 (HIF1) has an important role in hypoxia-induced lipid accumulation, a common feature of solid tumors; however, its role remains to be fully elucidated. Adipose differentiation related protein (ADRP), a structural protein of lipid droplets, is found to be upregulated under hypoxic conditions. In the present study, an MCF7 breast cancer cell line was used to study the role of ADRP in hypoxia-induced lipid accumulation. It was demonstrated that hypoxia induced the gene expression of ADRP in a HIF1-dependent manner. Increases in the mRNA and protein levels of ADRP was accompanied by increased HIF1A activity. In addition, a significant decrease in the mRNA and protein levels of ADRP were detected in presence of siRNA targeting HIF1A. Using a dual-luciferase reporting experiment and chromatin immunoprecipitation assay, the present study demonstrated that ADRP is a direct target gene of HIF1, and identified a functional hypoxia response element localized 33 bp upstream of the transcriptional start site of the ADRP gene. Furthermore, the present study demonstrated the role of ADRP in low density liporotein (LDL) and very-LDL uptake-induced lipid accumulation under hypoxia. The knockdown of ADRP did not reduce HIF1-induced lipid accumulation under hypoxia. Together, these results showed that ADRP may be not involved in HIF1 induced lipid accumulation. PMID- 26498181 TI - Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review). AB - The CCN family of proteins comprises the members CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6. They share four evolutionarily conserved functional domains, and usually interact with various cytokines to elicit different biological functions including cell proliferation, adhesion, invasion, migration, embryonic development, angiogenesis, wound healing, fibrosis and inflammation through a variety of signalling pathways. In the past two decades, emerging functions for the CCN proteins (CCNs) have been identified in various types of cancer. Perturbed expression of CCNs has been observed in a variety of malignancies. The aberrant expression of certain CCNs is associated with disease progression and poor prognosis. Insight into the detailed mechanisms involved in CCN-mediated regulation may be useful in understanding their roles and functions in tumorigenesis and cancer metastasis. In this review, we briefly introduced the functions of CCNs, especially in cancer. PMID- 26498184 TI - The challenges of managing coexistent disorders with phenylketonuria: 30 cases. AB - INTRODUCTION: The few published case reports of co-existent disease with phenylketonuria (PKU) are mainly genetic and familial conditions from consanguineous marriages. The clinical and demographic features of 30 subjects with PKU and co-existent conditions were described in this multi-centre, retrospective cohort study. METHODS: Diagnostic age of PKU and co-existent condition, treatment regimen, and impact of co-existent condition on blood phenylalanine (Phe) control and PKU management were reported. RESULTS: 30 patients (11 males and 19 females), with PKU and a co-existent condition, current median age of 14 years (range 0.4 to 40 years) from 13 treatment centres from Europe and Turkey were described. There were 21 co-existent conditions with PKU; 9 were autoimmune; 6 gastrointestinal, 3 chromosomal abnormalities, and 3 inherited conditions. There were only 5 cases of parental consanguinity. Some patients required conflicting diet therapy (n=5), nutritional support (n=7) and 5 children had feeding problems. There was delayed diagnosis of co-existent conditions (n=3); delayed treatment of PKU (n=1) and amenorrhea associated with Grave's disease that masked a PKU pregnancy for 12 weeks. Co-existent conditions adversely affected blood Phe control in 47% (n=14) of patients. Some co-existent conditions increased the complexity of disease management and increased management burden for patients and caregivers. CONCLUSIONS: Occurrence of co existent disease is not uncommon in patients with PKU and so investigation for co existent disorders when the clinical history is not completely consistent with PKU is essential. Integrating care of a second condition with PKU management is challenging. PMID- 26498185 TI - Comparison of subjective symptoms associated with exposure to low levels of formaldehyde between students enrolled and not enrolled in a gross anatomy course. AB - OBJECTIVES: This study aimed to evaluate students' subjective symptoms associated with exposure to low levels of formaldehyde (FA) during a gross anatomy course and to survey how the risk of subjective symptoms was affected by exposure to FA. METHODS: We conducted three questionnaire surveys of 125 students enrolled in an anatomy course (FA exposure group) and 124 students not enrolled in the course (FA nonexposure group) before, during, and 6 months after the course. The questionnaire included questions inquiring about subjective symptoms, sex, age, and allergies. We analyzed differences in the prevalence of subjective symptoms in distinct survey periods. Furthermore, we analyzed the relationship between the subjective symptoms and exposure to FA after adjusting for allergy, sex, and age using multiple logistic regression analysis. RESULTS: The prevalence of some of the ocular, nasal, and nonspecific symptoms in the FA exposure group was low before the course, increased during the course and decreased 6 months after the course. A significant positive relationship was observed between exposure to FA and some symptoms after adjusting for allergy, sex, and age. CONCLUSIONS: We identified some concrete symptoms associated with exposure to FA. We suggest that the exposure to low levels of FA influences students' subjective symptoms. PMID- 26498186 TI - Individualized medicine and demographic change as determining workload factors in pathology: quo vadis? AB - The advent of individualized medicine with novel guidelines, extended quality assessment as well as intensified conventional, immunohistochemical, and molecular characterization of diseases has led to a substantial increase of pathologists' workload. Furthermore, in industrialized countries, we are facing the challenges of demographic change with an aging population. This raises the question of how pathology will be affected by these developments in the future. We extracted German population data and data on the number of board-certified physicians and pathologists from official sources. These data were reviewed in the light of data on caseload, case complexity, auxiliary diagnostic procedures, and matching patient data from a large German pathology department serving as a sector independent regional service provider. The refinement of diagnostic procedures over the last decade has resulted in a 60 % increase in slide numbers per case, doubling of immunohistochemistry procedures, and more than tripling of molecular analyses. Correlation of this development to demographics suggests that an aging population will further increase the caseload and case complexity in the coming decades since patient age is tightly linked to both parameters. This development is currently not accompanied by a sufficient increase in the number of pathologists. Our data point toward an imbalance between the increase in pathology workload and the number of pathologists. Extrapolations suggest a further aggravation of this development in the future. Thus, healthcare systems need to address this problem urgently in order to cope with these challenges. PMID- 26498188 TI - Obituary: Derek Horton (1933-2015). PMID- 26498187 TI - Fluviicoccus keumensis gen. nov., sp. nov., isolated from freshwater. AB - A Gram-stain-negative, non-spore-forming and coccus-shaped bacterial strain, designated 4DR5T, was isolated from freshwater and its taxonomic position was investigated using a polyphasic approach. Growth occurred at 10-40 degrees C (optimum 30 degrees C), at pH 6-9 (optimum pH 7) and in the presence of 0-0.4 % (w/v) NaCl (optimum 0 %) on R2A agar. On the basis of 16S rRNA gene sequence similarity, strain 4DR5T was assigned to the family Moraxellaceae of the class Gammaproteobacteria, and its closest related taxa were species of the genera Perlucidibaca (93.67 % sequence similarity), Agitococcus (93.07 %), Paraperlucidibaca (92.31-92.38 %), Alkanindiges (91.79 %) and Acinetobacter (90.24-91.23 %). The predominant isoprenoid quinone detected in strain 4DR5T was Q-10. The major cellular fatty acids were a summed feature consisting of C16 : 1omega7c and/or C16 : 1omega6c, one consisting of C18 : 1omega7c and/or C18 : 1omega6c, and C16 : 0. The major polar lipid was phosphatidylethanolamine. The genomic DNA G+C content of the strain was 61.2 mol%. The phylogenetic, chemotaxonomic and biochemical data not only supported the affiliation of strain 4DR5T to the family Moraxellaceae, but also separated it from other established genera within the family. Therefore, the novel isolate evidently represents a novel species of a new genus of Moraxellaceae, for which the name Fluviicoccus keumensis gen. nov., sp. nov. is proposed. The type strain of Fluviicoccus keumensis is 4DR5T ( = KCTC 32475T = JCM 19370T). PMID- 26498189 TI - Single-molecule studies of the dynamics and interactions of bacterial OXPHOS complexes. AB - Although significant insight has been gained into biochemical, genetic and structural features of oxidative phosphorylation (OXPHOS) at the single-enzyme level, relatively little was known of how the component complexes function together in time and space until recently. Several pioneering single-molecule studies have emerged over the last decade in particular, which have illuminated our knowledge of OXPHOS, most especially on model bacterial systems. Here, we discuss these recent findings of bacterial OXPHOS, many of which generate time resolved information of the OXPHOS machinery with the native physiological context intact. These new investigations are transforming our knowledge not only of the molecular arrangement of OXPHOS components in live bacteria, but also of the way components dynamically interact with each other in a functional state. These new discoveries have important implications towards putative supercomplex formation in bacterial OXPHOS in particular. This article is part of a Special Issue entitled Organization and dynamics of bioenergetic systems in bacteria, edited by Conrad Mullineaux. PMID- 26498190 TI - Photosynthetic, respiratory and extracellular electron transport pathways in cyanobacteria. AB - Cyanobacteria have evolved elaborate electron transport pathways to carry out photosynthesis and respiration, and to dissipate excess energy in order to limit cellular damage. Our understanding of the complexity of these systems and their role in allowing cyanobacteria to cope with varying environmental conditions is rapidly improving, but many questions remain. We summarize current knowledge of cyanobacterial electron transport pathways, including the possible roles of alternative pathways in photoprotection. We describe extracellular electron transport, which is as yet poorly understood. Biological photovoltaic devices, which measure electron output from cells, and which have been proposed as possible means of renewable energy generation, may be valuable tools in understanding cyanobacterial electron transfer pathways, and enhanced understanding of electron transfer may allow improvements in the efficiency of power output. This article is part of a Special Issue entitled Organization and dynamics of bioenergetic systems in bacteria, edited by Conrad Mullineaux. PMID- 26498191 TI - Fast, cheap and out of control--Insights into thermodynamic and informatic constraints on natural protein sequences from de novo protein design. AB - The accumulated results of thirty years of rational and computational de novo protein design have taught us important lessons about the stability, information content, and evolution of natural proteins. First, de novo protein design has complicated the assertion that biological function is equivalent to biological structure - demonstrating the capacity to abstract active sites from natural contexts and paste them into non-native topologies without loss of function. The structure-function relationship has thus been revealed to be either a generality or strictly true only in a local sense. Second, the simplification to "maquette" topologies carried out by rational protein design also has demonstrated that even sophisticated functions such as conformational switching, cooperative ligand binding, and light-activated electron transfer can be achieved with low information design approaches. This is because for simple topologies the functional footprint in sequence space is enormous and easily exceeds the number of structures which could have possibly existed in the history of life on Earth. Finally, the pervasiveness of extraordinary stability in designed proteins challenges accepted models for the "marginal stability" of natural proteins, suggesting that there must be a selection pressure against highly stable proteins. This can be explained using recent theories which relate non equilibrium thermodynamics and self-replication. This article is part of a Special Issue entitled Biodesign for Bioenergetics--The design and engineering of electronc transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson. PMID- 26498192 TI - The circadian system as an organizer of metabolism. AB - The regulation of metabolism by circadian systems is believed to be a key reason for the extensive representation of circadian rhythms within the tree of life. Despite this, surprisingly little work has focused on the link between metabolism and the clock in Neurospora, a key model system in circadian research. The analysis that has been performed has focused on the unidirectional control from the clock to metabolism and largely ignored the feedback from metabolism on the clock. Recent efforts to understand these links have broken new ground, revealing bidirectional control from the clock to metabolism and vise-versa, showing just how strongly interconnected these two cellular systems can be in fungi. This review describes both well understood and emerging links between the clock and metabolic output of fungi as well as the role that metabolism plays in influencing the rhythm set by the clock. PMID- 26498193 TI - Quantitative relationship between the mRNA secondary structure of translational initiation region and the expression level of heterologous protein in Escherichia coli. AB - Translational efficiency in Escherichia coli is strongly influenced by mRNA secondary structure of translational initiation region (TIR). We have previously reported that the expression of heterologous protein is directly related to the minimal folding free energy (DeltaG) of the local secondary structure. However, identifying biologically relevant maximum and minimum levels of expression, or exploring the optimal level between them, is a key to successful optimization of heterologous protein expression. To systematically search a large range of the DeltaG of TIR, we now present a quantitative analysis of the relationship between expression level and these DeltaGs. The DeltaG of TIR in green fluorescent protein is found to be linearly correlated with the fluorescence intensity over a range of tenfold change. The result demonstrates that the increasing DeltaG of TIR can enhance the expression level linearly with no threshold or plateau. PMID- 26498195 TI - Development of compositional and contextual communicable congruence in robots by using dynamic neural network models. AB - The current study presents neurorobotics experiments on acquisition of skills for "communicable congruence" with human via learning. A dynamic neural network model which is characterized by its multiple timescale dynamics property was utilized as a neuromorphic model for controlling a humanoid robot. In the experimental task, the humanoid robot was trained to generate specific sequential movement patterns as responding to various sequences of imperative gesture patterns demonstrated by the human subjects by following predefined compositional semantic rules. The experimental results showed that (1) the adopted MTRNN can achieve generalization by learning in the lower feature perception level by using a limited set of tutoring patterns, (2) the MTRNN can learn to extract compositional semantic rules with generalization in its higher level characterized by slow timescale dynamics, (3) the MTRNN can develop another type of cognitive capability for controlling the internal contextual processes as situated to on-going task sequences without being provided with cues for explicitly indicating task segmentation points. The analysis on the dynamic property developed in the MTRNN via learning indicated that the aforementioned cognitive mechanisms were achieved by self-organization of adequate functional hierarchy by utilizing the constraint of the multiple timescale property and the topological connectivity imposed on the network configuration. These results of the current research could contribute to developments of socially intelligent robots endowed with cognitive communicative competency similar to that of human. PMID- 26498194 TI - Perceived discrimination and cancer screening behaviors in US Hispanics: the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study. AB - PURPOSE: Perceived discrimination has been associated with lower adherence to cancer screening guidelines. We examined whether perceived discrimination was associated with adherence to breast, cervical, colorectal, and prostate cancer screening guidelines in US Hispanic/Latino adults. METHODS: Data were obtained from the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study, including 5,313 Hispanic adults aged 18-74 from Bronx, NY, Chicago, IL, Miami, FL, and San Diego, CA, and those who were within appropriate age ranges for specific screening tests were included in the analysis. Cancer screening behaviors were assessed via self-report. Perceived discrimination was measured using the Perceived Ethnic Discrimination Questionnaire. Confounder-adjusted multivariable polytomous logistic regression models assessed the association between perceived discrimination and adherence to cancer screening guidelines. RESULTS: Among women eligible for screening, 72.1 % were adherent to cervical cancer screening guidelines and 71.3 %were adherent to breast cancer screening guidelines. In participants aged 50-74, 24.6 % of women and 27.0 % of men were adherent to fecal occult blood test guidelines; 43.5 % of women and 34.8 % of men were adherent to colonoscopy/sigmoidoscopy guidelines; 41.0 % of men were adherent to prostate-specific antigen screening guidelines. Health insurance coverage, rather than perceived ethnic discrimination,was the variable most associated with receiving breast, cervical,colorectal, or prostate cancer screening. CONCLUSIONS: The influence of discrimination as a barrier to cancer screening may be modest among Hispanics/Latinos in urban US regions. Having health insurance facilitates cancer screening in this population. Efforts to increase cancer screening in Hispanics/Latinos should focus on increasing access to these services, especially among the uninsured. PMID- 26498196 TI - Evaluation of the Mineral Concentration in Beef from Polish Native Cattle. AB - The aim of the study was to determine the content of macrominerals and microminerals in the longissimus lumborum (LL) and semitendinosus (ST) muscles of young bulls of five breeds-Polish Red (PR), White-Backed (WB), Polish Black-and White (PBW), Simmental (SIM) and Polish Holstein-Friesian (PHF). The meat of the Polish Holstein-Friesian bulls was found to contain significantly less K, Mg and Ca and more Mn than other breeds. The meat of the White-Backed bulls contained significantly (P < 0.01) more Ca and less Na than the meat of the Polish Red, Simmental and Polish Holstein-Friesian breeds. Moreover, the meat of White-Backed bulls showed a significantly (P < 0.01) higher level of Mn and Cu in comparison with other native breeds (Polish Red and Polish Black-and-White) and the Simmental breed. Similar content of macronutrients was found in the LL and ST muscles. However, in the case of micronutrients, the LL muscle contained significantly more Zn, Fe and Cu as well as Mn (P > 0.05). PMID- 26498197 TI - Effects of different cooking methods of oatmeal on preventing the diet-induced increase of cholesterol level in hypercholesterolemic rats. AB - BACKGROUND: The aim of present study is to investigate the influences of brewing and boiling on hypocholesterolemic effect of oatmeal in rats fed with a hypercholesterolemic diet. METHODS: Fifty-six male Sprague-Dawley rats were divided into 5 groups of 8 rats each with similar mean body weights and serum cholesterol concentrations. Rats were fed with the experimental diets containing 10% of oatmeal from two Chinese oat varieties which were brewed or boiled for 30 days. The lipids levels in serum, liver, and faeces were determined. RESULTS: The effects of feeding boiled oatmeal on lowering lipid concentrations in plasma and liver were more significant than that of brewed oatmeal (P < 0.05). Feeding boiled oatmeal was also more efficient in increasing fecal total lipids, cholesterol and bile acids as compared to feeding brewed oatmeal (P < 0.05). Boiled oatmeal had higher apparent viscosity and soluble beta-glucan content than the brewed oatmeal did (P < 0.05). CONCLUSION: These results indicated that the capability of boiled oatmeal in improving cholesterol metabolism is better than that of brewed oatmeal, which is mainly attributed to its higher soluble beta glucan content and apparent viscosity. PMID- 26498198 TI - Impact of stent length on clinical outcomes of first-generation and new generation drug-eluting stents. AB - The aim of this study is to compare first- and new-generation drug-eluting stents (DESs) which are implanted in long lesion. Stent length is known to be a predictor of adverse events after percutaneous coronary intervention (PCI), even with the first-generation DESs. The introduction of new-generation DESs has reduced the rates of adverse clinical events. However, the impact of stent length on long-term clinical outcomes is not well known. A total of 1181 consecutive patients who underwent PCI using either a first-generation DES (n = 885) or a new generation DES (n = 296) between 2004 and 2011 were investigated. In each of the stent groups, the patients were divided into two groups by stent length (>32 and <=32 mm) and compared. During the follow-up period, the incidence of major adverse cardiac events (MACEs) was significantly higher for patients with long stents implanted than with short stents (P < 0.01; log-rank test) in the first generation DES group. However, there was no difference in the incidence of MACEs between the long- and short-stent groups in the new-generation DES group (P = 0.24; log-rank test). On multivariate Cox regression analysis, stent length was not associated with adverse events in the new-generation DES groups [hazard ratio (HR) 0.87; 95 % confidence interval (95 % CI) 0.71-1.04; P = 0.14]. Implanted stent length was significantly associated with a higher risk of MACEs in patients who received first-generation DESs, but not in patients who received the new generation DESs. PMID- 26498199 TI - Ratio-controlled synthesis of CuNi octahedra and nanocubes with enhanced catalytic activity. AB - Non-noble bimetallic nanocrystals (NCs) have been widely explored due to not only their low cost and abundant content in the Earth's crust but also their outstanding performance in catalytic reactions. However, controllable synthesis of non-noble alloys remains a significant challenge. Here we report a facile synthesis of CuNi octahedra and nanocubes with controllable shapes and tunable compositions. Its success relies on the use of borane morpholine as a reducing agent, which upon decomposition generates a burst of H2 molecules to induce rapid formation of the nuclei. Specifically, octahedra switched to nanocubes with an increased amount of borane morpholine. In addition, the ratio of CuNi NCs could be facilely tuned by changing the molar ratio of both precursors. The obtained CuNi NCs exhibited high activity in aldehyde-alkyne-amine coupling reactions, and their performance is strongly facet- and composition-dependent due to the competition of the surface energy (enhanced by increasing the percent of Ni) and active sites (derived from Cu atoms). PMID- 26498200 TI - Anomalous adsorption of biomolecules on a Zn-based metal-organic framework obtained via a facile room-temperature route. AB - Herein, we report a new method for the crystal growth of two Zn-based MOFs at room temperature (known MOF-5 and a new modification of [{Zn2(TBAPy)(H2O)2}.3.5DEF]n (1)) by employing slow diffusion conditions. Employing both Zn-based MOFs with different pore morphology made it possible to discover an anomalous adsorption of L-histidine in of up to 24.3 * 10(15) molecules cm(-2) at 25 degrees C. This is one of the first reports aimed not only at describing a new method for the targeted formation of crystalline MOFs and coordination polymers, but also at demonstrating the use of Zn-based MOFs as potential drug delivery materials, with highly effective adsorption of l histidine given herein as an example. PMID- 26498202 TI - Expression dynamics of bovine MX genes in the endometrium and placenta during early to mid pregnancy. AB - MX belongs to a family of type I interferon (IFN)-stimulated genes, and the MX protein has antiviral activity. MX has at least two isoforms, known as MX1 and MX2, in mammals. Moreover, bovine MX1 has been found to have alternative splice variants-namely, MX1-a and MX1B. In ruminants, IFN-tau-a type I IFN-is temporarily produced from the conceptus before implantation and induces MX expression in the endometrium. However, the expression dynamics of MX after implantation are not clear. In the present study, we investigated the expression of MX1-a, MX1B and MX2 in the endometrium and placenta before and after implantation along with the expression of IFN-alpha, type I receptors (IFNAR1 and IFNAR2) and interferon regulatory factors (IRF3 and IRF9). Pregnant uterine samples were divided into five groups according to pregnancy days 14-18, 25-40, 50-70, 80-100, and 130-150. Tissue samples were collected from the intercaruncular endometrium (IC), caruncular endometrium (C) and fetal placenta (P). Although all the MX expressions were significantly higher in the IC and C at days 14-18, presumably caused by embryo-secreted IFN-tau stimulation, their expressions were also detectable in the IC, C and P after implantation. Furthermore, IFN-alpha expression was significantly higher in the IC. RT-PCR indicated IFNAR1, IFNAR2, IRF3 and IRF9 mRNA in all the tissues during pregnancy. These results suggest that all the MX genes are affected by the type I IFN pathway during pregnancy and are involved in an immune response to protect the mother and fetus. PMID- 26498203 TI - Expression and localization of epidermal growth factor, transforming growth factor-alpha and epidermal growth factor receptor in the canine testis. AB - Gene expression of epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha) and EGF receptor (EGF-R) and the localization of the corresponding proteins in the canine testis were studied. Levels of mRNA expressions were determined by semiquantitative reverse transcription polymerase chain reaction in the testes of the peripubertal (4-6 months), young adult (3-4 years), advanced adult (7-8 years) and senescent (11-16 years) groups. The EGF-R mRNA level in the testes of the peripubertal group was significantly higher than those in the other groups, whereas there was no difference in EGF and TGF-alpha mRNA levels among groups. Immunohistochemical stainings for EGF, TGF-alpha and EGF-R in the testis revealed that immunoreactivity in the seminiferous epithelium and Sertoli cell was weak and nonspecific for the stage of spermatogenesis, and distinct staining was found in Leydig cells. These results suggest that the EGF family of growth factors may be involved in testicular maturation and function in the dog. PMID- 26498204 TI - Cell proliferation potency is independent of FGF4 signaling in trophoblast stem cells derived from androgenetic embryos. AB - We previously established trophoblast stem cells from mouse androgenetic embryos (AGTS cells). In this study, to further characterize AGTS cells, we compared cell proliferation activity between trophoblast stem (TS) cells and AGTS cells under fibroblast growth factor 4 (FGF4) signaling. TS cells continued to proliferate and maintained mitotic cell division in the presence of FGF4. After FGF4 deprivation, the cell proliferation stopped, the rate of M-phase cells decreased, and trophoblast giant cells formed. In contrast, some of AGTS cells continued to proliferate, and the rate of M-phase cells did not decrease after FGF4 deprivation, although the other cells differentiated into giant cells. RO3306, an ATP competitor that selectively inhibits CDK1, inhibited the cell proliferation of both TS and AGTS cells. Under RO3306 treatment, cell death was induced in AGTS cells but not in TS cells. These results indicate that RO3306 caused TS cells to shift mitotic cell division to endoreduplication but that some of AGTS cells did not shift to endoreduplication and induced cell death. In conclusion, the paternal genome facilitated the proliferation of trophoblast cells without FGF4 signaling. PMID- 26498206 TI - Evaluation of the impact of cantharidin on rat CYP enzymes by using a cocktail of probe drugs. AB - The aim of this study was to assess the influence of cantharidin on the activities of the drug-metabolizing enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 in rats. The activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 were measured using specific probe drugs. After pretreatment for 1week with cantharidin or physiological saline (control group) by intraperitoneal injection, probe drugs phenacetin (5.0mg/kg; CYP1A2 activity), tolbutamide (1.0mg/kg; CYP2C9 activity), omeprazole (10mg/kg; CYP2C19 activity), metoprolol (20mg/kg; CYP2D6 activity) and midazolam (10mg/kg; CYP3A4 activity) were administered to rats by oral administration. The blood was then collected at different times for ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. The data showed that cantharidin exhibits an inhibitory effect on CYP2D6 and CYP3A4 by increasing t1/2, Cmax and AUC(0-infinity), and decreasing CL/F compared with those of the control group. In addition, cantharidin has induction effect on CYP2C9 activity. However, no significant changes in CYP1A2 and CYP2C19 activities were observed. In conclusion, the results indicated that cantharidin could inhibit CYP2D6 and CYP3A4, while induce CYP2C9, which may affect the disposition of medicines primarily dependent on these pathways. Our work may be the basis of related herb-drug interactions in the clinic. PMID- 26498205 TI - Decreased serum concentrations of sphingosine-1-phosphate in sepsis. AB - INTRODUCTION: Sphingosine-1-phosphate (S1P) is a signaling lipid that regulates pathophysiological processes involved in sepsis progression, including endothelial permeability, cytokine release, and vascular tone. The aim of this study was to investigate whether serum-S1P concentrations are associated with disease severity in patients with sepsis. METHODS: This single-center prospective observational study includes 100 patients with systemic inflammatory response syndrome (SIRS) plus infection (n = 40), severe sepsis (n = 30), or septic shock (n = 30) and 214 healthy blood donors as controls. Serum-S1P was measured by mass spectrometry. Blood parameters, including C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), lactate, and white blood cells (WBCs), were determined by routine assays. The Sequential Organ Failure Assessment (SOFA) score was generated and used to evaluate disease severity. RESULTS: Serum-S1P concentrations were lower in patients than in controls (P < 0.01), and the greatest difference was between the control and the septic shock groups (P < 0.01). Serum-S1P levels were inversely correlated with disease severity as determined by the SOFA score (P < 0.01) as well as with IL-6, PCT, CRP, creatinine, lactate, and fluid balance. A receiver operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for S1P compared with the SOFA score. In a multivariate logistic regression model calculated for prediction of septic shock, S1P emerged as the strongest predictor (P < 0.001). CONCLUSIONS: In patients with sepsis, serum-S1P levels are dramatically decreased and are inversely associated with disease severity. Since S1P is a potent regulator of endothelial integrity, low S1P levels may contribute to capillary leakage, impaired tissue perfusion, and organ failure in sepsis. PMID- 26498207 TI - Test-enhanced learning: analysis of an experience with undergraduate nursing students. AB - BACKGROUND: This study is based on the evidence that tests can be used as an educational tool to enhance learning, not just as an evaluation tool. There is a growing body of research that shows that participating in repeated testing improves learning, a phenomenon defined as Test-Enhanced Learning. The aim of the present study was to analyse the effect of the use of a test enhanced learning program integrated into a general psychology course for undergraduate nursing students and its interaction with the students' test anxiety. METHODS: 161 undergraduate nursing students attending a General Psychology course followed an educational program based on Test-Enhanced Learning methodology. Students were divided into two groups, an experimental group (TEL group) and a control group (Re-study group). TEL students took a multiple-choice test on the lecture topics. The Re-study group just read study material. Testing and re-study occurred at intervals of about a week after each lesson. TEL students received feedback immediately after each test. About two weeks after the end of the lessons, all the students took a final cumulative test on all the topics. Statistical analysis was used to analyse students' performances. After the administration of the cumulative unit test, all the students took a graded examination. RESULTS: Students in the TEL group performed better than the controls, both in the final cumulative test and in a graded examination. TEL participants experienced better final cumulative test results than students not tested (M TEL = 23.11, M Re-study = 20.47, t(109.86) = -2.57, p < 0.05, r = 0.24). Test-Enhanced Learning program participation has a positive impact on exam performance (betaG_Step1 = 0.46, p < 0.001). Finally, the analysis performed shows a slight moderating effect of test anxiety on Test-Enhanced Learning (betaGxTA_Step3 = 0.15, p < 0.05). DISCUSSION AND CONCLUSIONS: Test-Enhanced Learning can be an effective tool for promoting and enhancing learning. In fact, taking tests after studying produced better long term retention and then better final test performance than re-reading without testing. Both students in the TEL group and the Re-study group with a high test anxiety level perform less well than colleagues with lower test anxiety. Nevertheless, students with higher test anxiety may obtain more benefits from participating in a Test-Enhanced Learning process than people with lower test anxiety. Further studies on larger and more representative samples are necessary in order to investigate the effect of test anxiety on Test-Enhanced Learning. PMID- 26498208 TI - Microsatellite instability detected in tumor-related genes in C57BL/6J mice with thymic lymphoma induced by N-methyl-N-nitrosourea. AB - Microsatellite instability (MSI) has been observed within tumors and found to be closely associated with the degree of malignancy and prognosis in tumors. However, whether MSI in tumor-related genes can be induced by a chemical and whether a connection exists between MSI and tumors remain unclear. In the present study, we detected MSI in the tissues of N-methyl-N-nitrosourea (MNU) treated mice by targeting to 5, 29, 30 microsatellite loci in 3 mismatch repair (MMR) genes, 1 DNA repair gene, and 5 tumor suppressor (TS) genes, respectively. Among 26 mice survived in the MNU-group, 18 (69%) mice presented thymic lymphomas. Moreover, 61% (11/18) of the tumors metastasized to the other organs, including the liver, spleen, and kidney. We examined 104 tissues from MNU-treated mice using the 64 loci, and found 8 MSI events involved 4 loci in 4 tissues types. The MSI incidence in MMR, DNA repair, and TS genes was 67% (2/3), 0% (0/1) and 40% (2/5), respectively. MSI occurrence in tumor and non-tumor tissues was 5.6% (1/18) and 0% (0/8) and that in metastasis and non-metastasis tissues was 7.1% (1/14) and 9.4% (6/64), showing no significant difference. MSI loci in intronic regions of Atm, Msh6 and p21 and MSI in the 3'UTR of Pms2 were detected in MNU treated mice. Specifically, we found a loss of heterozygosity in intron of Atm (ATM-8) in one metastasis mouse. Four similar events occurred in p21 gene intron (P21-1) of another non-metastasis mouse. Another MSI was a heterozygous mutation existed in an Msh6 allele (MSH6-2) in metastasis mouse. We also found a homozygous 2-bp insertion in the 3'UTR of Pms2 in two non-metastasis mice. These results imply that MNU can induce MSI in MMR and TS genes in C57BL/6J mice. MSI frequency does not seem to be associated with tumorigenesis or metastasis. PMID- 26498209 TI - Prognostic significance of Epstein-Barr virus infection in gastric cancer: a meta analysis. AB - BACKGROUND: The prognostic significance of Epstein-Barr virus (EBV) infection in gastric cancer (GC) remains unclear. Recently, a number of studies have investigated the association between EBV infection and the prognosis of GC with controversial results. We therefore conducted a meta-analysis to assess its prognostic significance. METHODS: PubMed and EMBASE were searched for studies up to October 1, 2014. We investigated the association between EBV infection with survival in patients with GC. The pooled hazard ratio (HR) and its 95% confidence interval (CI) were calculated to evaluate risk. RESULTS: A final analysis of 8,336 patients with GC from 24 studies was performed. Our analysis results indicated that the pooled HR was 0.67 (95% CI: 0.55-0.79; Z = 11.18, P < 0.001). Subgroup analyses stratified by region revealed that the protective role of EBV infection only remained in the Asian population (HR: 0.62, 95% CI: 0.48-0.75; P < 0.001). When stratified by study quality and statistical methodology, the protective role could also be identified in high quality studies (HR: 0.67, 95% CI: 0.55-0.79) and in univariate analysis studies (HR: 0.62, 95% CI: 0.50-0.74). There was no evidence of significant heterogeneity and publication bias. CONCLUSIONS: The presence of EBV has a favorable impact on GC patient's survival, especially in an Asian population. Future updated studies, especially large-scale randomized controlled studies stratified by region, are warranted as validation studies. PMID- 26498210 TI - Chemical inhibition of DNA repair kinases as a promising tool in oncology. AB - BACKGROUND: DNA repair pathways play a major role in tumour resistance towards chemo- and radiotherapy. Therefore, inhibitors of specific DNA repair pathways might be advantageous when used in combination with DNA-damaging agents, such as ionizing radiation. This review put particular emphasis on the key DNA repair enzymes: DNA-dependent protein kinase (DNA-PK), ataxia-telangiectasia mutated kinase (ATM) and ATM-Rad3-related kinase (ATR) and their specific inhibitors in the context of radio-sensitization. RESULTS: We reviewed recent studies on novel and potent inhibitors and found evidence that inhibitors of DNA repair pathways such as small molecule inhibitors could be efficient and selective in tumour cells. Interpretation of recent literature results accompanied with implications for practice and further research are presented. CONCLUSIONS: The prospects of targeting DNA repair enzymes to treat cancer are optimistic, but future work will show if this approach has a significant in vivo efficacy, since we are still waiting for the inhibitor which would pass all phases in clinical trials. In spite of the fact that a number of drugs possess interesting synergy of radiotherapy in vitro, the future use will depend on developing compounds with improved solubility and the serum half-life. Normal tissue toxicity leading to a significant increase of radiotherapy efficiency remains a key question that might be answered only by clinical trials. PMID- 26498211 TI - Acute pancreatitis as the first manifestation of duodenal MALT lymphoma. AB - BACKGROUND: Possibly any tumor that can cause mechanical obstruction of the distal bile duct can induce acute pancreatitis. However, acute pancreatitis as the first clinical manifestation of duodenal lymphoma is extremely rare. OBJECTIVE: To report the case of a patient with acute pancreatitis as an extremely rare first manifestation of duodenal MALT lymphoma and possible association with erythema nodosum. METHODS: Case report of a 66-year-old woman who was diagnosed with acute pancreatitis caused by infiltration with duodenal lymphoma. RESULTS: Acute pancreatitis was confirmed by CT imaging. Detailed investigation revealed a duodenal mass causing pancreatic injury. Histological analysis established the diagnosis of MALT lymphoma. The patient's medical history also included erythema nodosum. Complete remission of the malignancy was achieved with chemotherapy. CONCLUSION: This is the first published case report of acute pancreatitis caused by the growth of duodenal MALT lymphoma. An association with erythema nodosum is possible. PMID- 26498212 TI - Refractory cardiogenic shock due to extensive anterior STEMI with covered left ventricular free wall rupture treated with awake VA-ECMO and LVAD as a double bridge to heart transplantation - collaboration of three cardiac centres. AB - AIM: To highlight an optimal collaborative strategy of three different levels of specialized care cardiac centres. BACKGROUND: Refractory cardiogenic shock is a life-threatening condition. A myocardial recovery is not achieved in many cases despite all efforts and subsequently the heart transplantation remains an ultimate option. Thereby, the use of extracorporeal membrane oxygenation (ECMO) followed by a ventricular assist device in staged bridging provides an attractive approach. CASE REPORT: We report on an optimal cooperation of PCI (percutaneous coronary intervention) centre with ELSO (extracorporeal life support organization) centre and transplant centre in a patient suffering from refractory cardiogenic shock due to acute myocardial infarction (RCSMI) complicated by left ventricle free wall rupture with pericardial tamponade. CONCLUSION: The interhospital collaboration can be essential in the context of patients with RCSMI. The use of ECMO enables safe interhospital transport and gains time for further diagnostic and therapeutic steps in such critically ill patients. PMID- 26498213 TI - Gastrointestinal comorbidities in patients with psoriasis in the Czech Republic: The results of 189 patients with psoriasis and 378 controls. AB - AIMS: The aim of the study was to investigate gastrointestinal comorbidities, identify risk factors and detect the early stages of autoimmune gastrointestinal diseases, such as Crohn's disease, ulcerative colitis and coeliac disease in patients with psoriasis. METHODS: This was a hospital-based case-control study. Patients with chronic plaque psoriasis were included as cases. The control group consisted of patients with other skin diseases and who complied with the same selection criteria as cases. Two controls were selected per one case. We analysed the following antibodies (ASCA, AEP, p-ANCA, AGC, EMA, ARA, tTG, AGA) and non specific signs of gastrointestinal diseases. RESULTS: There were significant differences between cases and controls in several parameters. Leucocyte count, CRP, total protein, transglutaminase IgA antibodies and p-ANCA were statistically significant between groups (P < 0.05). In the binary logistic model, leucocyte count and p-ANCA (for all parameters included in the logistic model P <= 0.001) were associated with psoriasis. CONCLUSION: Patients with psoriasis should be regularly screened for coeliac and inflammatory bowel disease. Early diagnosis of gastrointestinal diseases and risk factors may prevent complications and greatly improve the patient's quality of life. PMID- 26498214 TI - Absence of Borrelia burgdorferi in the myocardium of subjects with normal left ventricular systolic function: a study using PCR and electron microscopy. AB - BACKGROUND: Several studies have demonstrated the presence of the Borrelia burgdorferi (Bb) genome in the myocardium of patients with dilated cardiomyopathy (DCM). To further support a causal relationship between the presence of Bb in the heart muscle and the development of DCM, demonstration of the absence of Bb in the myocardium of subjects with normal left ventricular (LV) systolic function is needed. AIM: To determine the prevalence of Bb by polymerase chain reaction (PCR) and electron microscopy (EM) in individuals with normal LV systolic function and no history suggestive of myocarditis. METHODS: We investigated 50 patients (67 +/ 9 years, 15 women) with normal LV ejection fraction (EF) >= 50% undergoing cardiac surgery. During surgery, four samples from the right atrial appendage were obtained and subsequently examined by PCR and EM for the presence of Bb, and by immunohistochemistry to detect inflammatory cells. Serological testing of antibodies against Bb was also performed. RESULTS: Neither PCR nor EM detected Bb in any of the subjects. Immunohistological examination revealed myocardial inflammation in 2 individuals (4%). Serological analysis by enzyme-linked immunosorbent assay demonstrated IgM antibodies against Bb in 4% and IgG antibodies in 12% of the study cohort; Western blot revealed IgM as well as IgG positivity in 14% of patients. CONCLUSIONS: The absence of Bb in the myocardium of individuals who undergo cardiac surgery and have normal LV systolic function supports the idea of Bb pathogenicity in the development of DCM. PMID- 26498215 TI - Ten-year survival and prognostic markers in one thousand patients with advanced heart failure. A single-centre analysis. AB - AIM: Patients with advanced heart failure (HF) represent a pool of candidates for heart transplantation and long-term mechanical circulatory support devices. The aim of our study was to determine simple and reliable markers of one-year mortality for selection of the most suitable patients for heart replacement therapy. METHODS AND RESULTS: One thousand consecutive patients with HF (mean age 49 +/- 10.9 years; 86.8% males) referred to a single tertiary centre from January 1998 to January 2010 in order to assess the indication for heart transplantation were enrolled. Kaplan-Meier survival analysis was performed. Independent mortality predictors were established using logistic regression analysis. The mean follow-up was 4.3 +/- 2.7 years (range 1-12 years). Cumulative survival was as follows: 1-year survival 83%, 3-year 63%, 5-year 50%, 7-year 39%, and 10-year 23%. Independent predictors of 1-year mortality included coronary artery disease, left ventricular diastolic diameter >79 mm, plasma sodium <135 mmol/L, the need for intravenous treatment at hospital admission (diuretics and/or inotropes), and furosemide dose at discharge >240 mg/day. CONCLUSIONS: Short-term prognosis of HF patient can be estimated based on simple parameters. Patients with signs of poor prognosis should be referred to tertiary centres to be considered for heart replacement therapy. PMID- 26498216 TI - Optic nerve head segmentation using fundus images and optical coherence tomography images for glaucoma detection. AB - BACKGROUND: Glaucoma is a common causes of blindness. The associated elevation in intra ocular pressure leads to progressive degeneration of the optic nerve and resultant structural changes with functional failure of the visual field. Since, glaucoma is asymptomatic in the early stages and the associated vision loss is irreparable, its early detection and timely medical treatment is essential to prevent further visual damage. OBJECTIVE: This paper presents a novel method for glaucoma detection using digital fundus image and optical coherence tomography (OCT) image. METHOD: The first section focuses on the features such as cup to disc ratio (CDR) and the inferior superior nasal temporal (ISNT) ratio which were obtained from fundus images.The above features were used for classifying the normal and glaucoma condition using back propagation neural network (BPN) and Support Vector Machine (SVM) classifiers. In the second part of the article, features such as CDR and two novel features, cup depth and retinal thickness were obtained from the OCT image. These features were evaluated by the BPN and SVM classifier. RESULTS AND CONCLUSION: The combined features from fundus and OCT images were analyzed. The system proposed here is able to classify glaucoma automatically. The accuracy of BPN and SVM Classifiers was 90.76% and 96.92% respectively. PMID- 26498218 TI - High fat diet-induced inflammation and oxidative stress are attenuated by N acetylneuraminic acid in rats. AB - BACKGROUND: Serum sialic acid levels are positively correlated with coronary artery disease and inflammation. Although sialic acid is a non-specific marker, it is considered sensitive likely due to its influence in sialylation of glycoprotein structures all over the body. OBJECTIVES: We hypothesized that dietary supplementation with N-acetylneuraminic acid (Neu5Ac), a type of sialic acid, will have profound effects on high fat diet- (HFD-) induced inflammation and oxidative stress in view of the widespread incorporation of sialic acid into glycoprotein structures in the body. METHODS: HFD-fed rats with or without simvastatin or Neu5Ac (50 and 400 mg/kg/day) were followed up for 12 weeks. Lipid profiles, and markers of inflammation (C-reactive protein, interleukin-6, and tumor necrosis factor alpha), insulin resistance (serum insulin and adiponectin, oral glucose tolerance test and homeostatic model of insulin resistance) and oxidative stress (total antioxidant status and thiobarbituric acid reactive species) in the serum and liver were determined, while mRNA levels of hepatic antioxidant and inflammation genes were also quantified. Serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase, urea, creatinine and uric acid were also assessed. RESULTS: HFD feeding caused hyperlipidemia and insulin resistance, and worsened liver and kidney functions. HFD feeding also potentiated inflammation and oxidative stress, partly through modulation of hepatic gene expression, while Neu5Ac especially at higher doses and simvastatin attenuated HFD-induced changes, although Neu5Ac showed better outcomes. CONCLUSIONS: Based on the present results, we surmised that Neu5Ac can prevent HFD-induced inflammation and oxidative stress, and may in fact be useful in the prevention of hyperlipidemia-associated inflammation and oxidative stress. However, the translational implications of these findings can only be determined after long-term effects are established. Hence, the use of Neu5Ac on obesity related diseases requires additional attention. PMID- 26498219 TI - Improving the Transition from Pediatric to Adult Diabetes Healthcare: A Literature Review. AB - Effective transition to adult care is a significant component of an emerging adult's diabetes care. Poor transition places them at risk for disengagement with the health care system and for poor diabetes-related outcomes. The purpose of this paper was to review the literature to date on existing methods of transition care delivery for emerging adults with diabetes. We conducted a literature review using MEDLINE via OvidSP and searching the grey literature. Papers published in English between January 1, 2000 and March 25, 2015 that evaluated transition care programs for emerging adults with diabetes were included. 16 original studies, 1 study protocol and 1 technical brief describing transition programs were reviewed. Common components of care included transition care coordination, young adult clinics, transition preparation, familiarity with adult health care providers and support groups. Overall, when emerging adults are supported during the transition period, clinic attendance and glycemic control can be maintained or improved, and diabetes-related complications reduced. Despite widespread support in the literature for the need for structured transition care delivery, methodologically strong research evaluating transition care services remains limited. The literature to date encompasses a variety of care models that lack consistency in outcome measurements as well as lacking frameworks describing the interventions, which impedes comparison across studies. Further research, using a consistent framework for transition care program design, delivery and evaluation as well as reporting of outcomes, is needed to inform how best to deliver transition care services to this vulnerable population. PMID- 26498217 TI - Ibuprofen ameliorates fatigue- and depressive-like behavior in tumor-bearing mice. AB - AIMS: Cancer-related fatigue (CRF) is often accompanied by depressed mood, both of which reduce functional status and quality of life. Research suggests that increased expression of pro-inflammatory cytokines is associated with skeletal muscle wasting and depressive- and fatigue-like behaviors in rodents and cancer patients. We have previously shown that treatment with ibuprofen, a nonsteroidal anti-inflammatory drug, preserved muscle mass in tumor-bearing mice. Therefore, the purpose of the present study was to determine the behavioral effects of ibuprofen in a mouse model of CRF. MAIN METHODS: Mice were injected with colon-26 adenocarcinoma cells and treated with ibuprofen (10mg/kg) in the drinking water. Depressive-like behavior was determined using the forced swim test (FST). Fatigue like behaviors were determined using voluntary wheel running activity (VWRA) and grip strength. The hippocampus, gastrocnemius muscle, and serum were collected for cytokine analysis. KEY FINDINGS: Tumor-bearing mice showed depressive-like behavior in the FST, which was not observed in mice treated with ibuprofen. VWRA and grip strength declined in tumor-bearing mice, and ibuprofen attenuated this decline. Tumor-bearing mice had decreased gastrocnemius muscle mass and increased expression of IL-6, MAFBx and MuRF mRNA, biomarkers of protein degradation, in the muscle. Expression of IL-1beta and IL-6 was also increased in the hippocampus. Treatment with ibuprofen improved muscle mass and reduced cytokine expression in both the muscle and hippocampus of tumor-bearing mice. SIGNIFICANCE: Ibuprofen treatment reduced skeletal muscle wasting, inflammation in the brain, and fatigue- and depressive-like behavior in tumor-bearing mice. Therefore, ibuprofen warrants evaluation as an adjuvant treatment for CRF. PMID- 26498220 TI - Innovating in the Delivery of Diabetes Care. PMID- 26498222 TI - Oral direct factor Xa inhibitor versus enoxaparin for thromboprophylaxis after hip or knee arthroplasty: Systemic review, traditional meta-analysis, dose response meta-analysis and network meta-analysis. AB - OBJECTIVES: To analyze the efficacy and safety of direct factor Xa inhibitors for thromboprophylaxis after total hip or knee replacement. To delineate the dose response effect of direct factor Xa inhibitors. To compare the efficacy between any two direct factor Xa inhibitors. DESIGN: Systemic review, traditional meta analysis, dose-response meta-analysis and network meta-analysis. DATA SOURCE: PubMed, EMBASE and Cochrane Library. STUDY SELECTION: Randomized controlled trials of rivaroxaban, apixaban, betrixaban, darexaban and edoxaban were compared with enoxaparin for thromboprophylaxis after total hip or knee replacement. Two reviewers independently checked the quality of RCTs. Another two investigators independently extracted data. The primary efficacy outcomes (composite of deep venous thrombosis, non-fatal pulmonary embolism and death of all causes) and the primary bleeding outcomes (major bleeding and non-major but clinically relevant bleeding) were summarized for meta-analysis. Stata software was used for traditional meta-analysis and dose-response meta-analysis, and Winbugs software was used for network meta-analysis. RESULTS: Twenty trials with 38,507 subjects in the intention-to-treat population were included. Compared with enoxaparin, the risk of total venous thromboembolism was lower with rivaroxaban (relative risk 0.70, 95% confidence interval 0.60 to 0.81), apixaban (0.62, 0.47 to 0.81), and edoxaban (0.62, 0.39 to 0.97) and similar to darexaban (0.96, 0.84 to 1.11) and betrixaban (1.28, 0.97 to 1.68). Compared with enoxaparin, the risk of major or clinically relevant non-major bleeding was higher with rivaroxaban (1.52, 1.14 to 2.02), lower with betrixaban (0.34, 0.14 to 0.84) and similar to apixaban (0.88, 0.73 to 1.05), darexaban (0.85, 0.66 to 1.09) or edoxaban (1.30, 0.72 to 2.33). The risk of major and clinically relevant non-major bleeding of rivaroxaban had a linear relationship with its treatment doses; the risk of total venous thromboembolism of betrixaban and darexaban had linear relationships with their respective treatment doses. There was no linear nor non-liner relationships between the effect of apixaban and its treatment dose. The ranking of total venous thromboembolism risk from low to high was: rivaroxaban, apixaban, edoxaban, enoxaparin, darexaban, and betrixaban. The ranking of major and clinically relevant non-major bleeding from low to high was: betrixaban, enoxaparin, darexaban, edoxaban, apixaban, and rivaroxaban. CONCLUSIONS: Direct oral factor Xa inhibitors are more effective to prevent venous thromboembolism after total hip or knee replacement. Their anticoagulant effect was not necessarily compromised with a higher bleeding risk. Rivaroxaban, apixaban and edoxaban showed a better anticoagulant effect, as compared with enoxaparin. Rivaroxaban had a higher bleeding rate, while apixaban and edoxaban did not show significantly higher bleeding risks. PMID- 26498221 TI - Effectiveness of motivational interviewing in patients with dyslipidemia: a randomized cluster trial. AB - BACKGROUND: It is known that making people change their habits is challenging. It is crucial to identify the most effective approach that general practitioners (GPs) should use to help their patients change unhealthy habits. The objective this study was to assess the efficacy of a multifactorial intervention based on Motivational Interviewing performed by general practitioners to enhance lipid levels in patients with dyslipidemia, as compared to standard care. METHODS: A multicenter, controlled, randomized, cluster, two-parallel arm trial with a 12 month follow-up conducted in 25 community health centers of the Spanish. 38 GPs and 227 primary care patients with uncontrolled dyslipidemia were included in the trial. GPs performed an intervention based either on Motivational Interviewing (MI) or standard practice. Lipid levels were measured, and the control degree was analyzed based on the criteria of clinical guidelines. RESULTS: 107 were assigned to the Experimental Group (EG) and 120 to the Control Group (CG). An overall improvement was achieved in total cholesterol levels (Mean Difference -MD- = 19.60; 95 % CI: -15.33 at -23.87 mg/dl; p < 0.001), LDL-cholesterol levels (MD = 13.78; 95 % CI: -9.77 at -17.79 mg/dl; p < 0.001) and triglycerides (MD = -19.14; CI 95 %: -11.29 at -26.99 mg/dl; p < 0.001). No differences were found between the two groups. However, when we assessed the degree of lipid control by combining cholesterol <200 mg/dl and LDL-cholesterol < 130 mg/dl parameters, it was observed that a higher percentage of patients achieved target figures in the EG versus CG (13.1 % vs. 5.0 %; adjusted OR = 5.77, 95 % CI: 1.67-19.91). CONCLUSION: A Motivational Interviewing-based approach conducted by Primary Care physicians aimed at patients with dyslipidemia, achieved a significant reduction in all lipid parameters, cardiovascular risk, weight reduction and the adherence to the Mediterranean diet, similar to that obtained with the usual intervention and superior in the proportion of patients achieving combined lipid control goals and the level of physical exercise. TRIAL REGISTRATION: the trial is registered in ClinicalTrials.gov ( NCT01282190 ; January 21, 2011). PMID- 26498223 TI - Causal inference in multi-state models-sickness absence and work for 1145 participants after work rehabilitation. AB - BACKGROUND: Multi-state models, as an extension of traditional models in survival analysis, have proved to be a flexible framework for analysing the transitions between various states of sickness absence and work over time. In this paper we study a cohort of work rehabilitation participants and analyse their subsequent sickness absence using Norwegian registry data on sickness benefits. Our aim is to study how detailed individual covariate information from questionnaires explain differences in sickness absence and work, and to use methods from causal inference to assess the effect of interventions to reduce sickness absence. Examples of the latter are to evaluate the use of partial versus full time sick leave and to estimate the effect of a cooperation agreement on a more inclusive working life. METHODS: Covariate adjusted transition intensities are estimated using Cox proportional hazards and Aalen additive hazards models, while the effect of interventions are assessed using methods of inverse probability weighting and G-computation. RESULTS: Results from covariate adjusted analyses show great differences in sickness absence and work for patients with assumed high risk and low risk covariate characteristics, for example based on age, type of work, income, health score and type of diagnosis. Causal analyses show small effects of partial versus full time sick leave and a positive effect of having a cooperation agreement, with about 5 percent points higher probability of returning to work. CONCLUSIONS: Detailed covariate information is important for explaining transitions between different states of sickness absence and work, also for patient specific cohorts. Methods for causal inference can provide the needed tools for going from covariate specific estimates to population average effects in multi-state models, and identify causal parameters with a straightforward interpretation based on interventions. PMID- 26498224 TI - Construction of human single-chain variable fragment antibodies of medullary thyroid carcinoma and single photon emission computed tomography/computed tomography imaging in tumor-bearing nude mice. AB - Medullary thyroid carcinoma (MTC) is a rare tumor of the endocrine system with poor prognosis as it exhibits high resistance against conventional therapy. Recent studies have shown that monoclonal antibodies labeled with radionuclide have become important agents for diagnosing tumors. To elucidate whether single chain fragment of variable (scFv) antibody labeled with 131I isotope is a potential imaging agent for diagnosing MTC. A human scFv antibody library of MTC using phage display technique was constructed with a capacity of 3x10(5). The library was panned with thyroid epithelial cell lines and MTC cell lines (TT). Western blotting and enzyme-linked immunosorbent assay (ELISA) were used to identify the biological characteristics of the panned scFv. Methyl thiazolyl tetrazolium (MTT) assay was also used to explore the optimal concentration of the TT cell proliferation inhibition rate. They were categorized into TT, SW480 and control groups using phosphate-buffered saline. Western blotting showed that molecular weight of scFv was 28 kDa, cell ELISA showed that the absorbance of TT cell group was significantly increased (P=0.000??) vs. the other three groups, and MTT assay showed that the inhibition rate between the two cell lines was statistically significantly different (P<0.05) when the concentration of scFv was 0.1, 1 and 10 umol/l. The tumor uptake of 131I-scFv was visible at 12 h and clear image was obtained at 48 h using the single photon emission computed tomography. scFv rapidly and specifically target MTC cells, suggesting the potential of this antibody as an imaging agent for diagnosing MTC. PMID- 26498225 TI - Cell recognition based on topological sparse coding for microscopy imaging of focused ultrasound treatment. AB - BACKGROUND: Ultrasound is considered a reliable, widely available, non-invasive, and inexpensive imaging technique for assessing and detecting the development phases of cancer; both in vivo and ex vivo, and for understanding the effects on cell cycle and viability after ultrasound treatment. METHODS: Based on the topological continuity characteristics, and that adjacent points or areas represent similar features, we propose a topological penalized convex objective function of sparse coding, to recognize similar cell phases. RESULTS: This method introduces new features using a deep learning method of sparse coding with topological continuity characteristics. Large-scale comparison tests demonstrate that the RAW can outperform SIFT GIST and HoG as the input features with this method, achieving higher sensitivity, specificity, F1 score, and accuracy. CONCLUSIONS: Experimental results show that the proposed topological sparse coding technique is valid and effective for extracting new features, and the proposed system was effective for cell recognition of microscopy images of theMDA MB-231 cell line. This method allows features from sparse coding learning methods to have topological continuity characteristics, and the RAW features are more applicable for the deep learning of the topological sparse coding method than SIFT GIST and HoG. PMID- 26498226 TI - Global hotspots in the present-day distribution of ancient animal and plant lineages. AB - The current distribution of biotic lineages that emerged in the deep time has both theoretical and practical implications, in particular for understanding the processes that have forged present-day biodiversity and informing local and regional-scale conservation efforts. To date however, there has been no examination of such patterns globally across taxa and geological time. Here we map the diversity of selected extant seed plant and tetrapod vertebrate lineages that were already in existence either in the latest Triassic or latest Cretaceous. For Triassic-age lineages, we find concentrations in several regions both tropical and temperate - parts of North America, Europe, East and South east Asia, northern South America, and New Zealand. With Cretaceous-age lineages, high values are relatively uniformly distributed across the tropics, with peak the values along the Andes, in South-east Asia and Queensland, but also in the temperate Cape Mountains. These patterns result from a combination of factors, including land area, geographic isolation, climate stability and mass extinction survival ability. While the need to protect many of these lineages has been long recognised, a spatially-explicit approach is critical for understanding and maintaining the factors responsible for their persistence, and this will need to be taken forward across finer scales. PMID- 26498227 TI - Oxytocin enhances orienting to social information in a selective group of high functioning male adults with autism spectrum disorder. AB - OBJECTIVE: The study investigated the effects of nasally administered oxytocin on neurophysiological orienting to empathy-evoking pictures in normally intelligent male adults with and without an autism spectrum disorder (ASD). It further investigated whether these effects might be moderated by the individual's approach and avoidance tendencies. METHODS: All subjects participated in a randomised double-blind placebo controlled crossover trial where either oxytocin (OXT) or placebo was administered preceding the viewing of affective pictures.The pictures, selected from the International Affective Picture System (IAPS), represented a systematic variation of pleasant, unpleasant and neutral scenes with and without humans. Both cardiac (ECR) and cortical (LPP) evoked orienting responses were measured and both were enhanced for the pictures with humans, in particular for the unpleasant ones. RESULTS: No significant group differences were found, nor were there any treatment effects. Moderator analysis, however, demonstrated that OXT did enhance orienting to affective pictures with humansin male adults with ASD who are easily distressed when seeing others in stressful situations and in healthy males who are highly sensitive to anticipated punishment and criticism or have a low drive for goal achievement. CONCLUSION: Individual differences in stress-related avoidance tendencies should be taken into account when considering OXT as a treatment of social deficiencies in autism. PMID- 26498228 TI - Sleep patterns of co-sleeping and solitary sleeping infants and mothers: a longitudinal study. AB - OBJECTIVE: Controversies exist regarding the impact of co-sleeping on infant sleep quality. In this context, the current study examined: (a) the differences in objective and subjective sleep patterns between co-sleeping (mostly room sharing) and solitary sleeping mother-infant dyads; (b) the predictive links between maternal sleep during pregnancy and postnatal sleeping arrangement; (c) the bi-directional prospective associations between sleeping arrangement and infant/maternal sleep quality at three and six months postpartum. METHODS: The sample included 153 families recruited during pregnancy. Data were obtained in home settings during the third trimester of pregnancy and at three and six months postpartum. Mothers were asked to monitor their own sleep and their infants' sleep for five nights using actigraphy and sleep diaries. Questionnaires were used to assess sleeping arrangements, feeding methods, socio-demographic characteristics, and maternal depressive and anxiety symptoms. RESULTS: Mothers of co-sleeping infants reported more infant night-wakings than mothers of solitary sleeping infants. However, none of the objective sleep measures was significantly different between co-sleeping and solitary sleeping infants, after controlling for feeding techniques. Co-sleeping mothers had significantly more objective and subjective sleep disturbances than mothers in the solitary sleeping group. Moreover, poorer maternal sleep during pregnancy and at three months postpartum predicted higher levels of co-sleeping at six months. CONCLUSION: Mothers of co-sleeping infants report more infant night-wakings, and experience poorer sleep than mothers of solitary sleeping infants. The quality of maternal sleep should be taken into clinical consideration when parents consult about co sleeping. PMID- 26498229 TI - The effect of sleep deprivation on pain perception in healthy subjects: a meta analysis. AB - BACKGROUND: There is strong evidence indicating an interaction between sleep and pain. However, the size of this effect, as well as the clinical relevance, is unclear. Therefore, this meta-analysis was conducted to quantify the effect of sleep deprivation on pain perception. METHODS: A systematic literature search was conducted using the electronic databases PubMed, Cochrane, Psyndex, Psycinfo, and Scopus. By conducting a random-effect model, the pooled standardized mean differences (SMDs) of sleep deprivation on pain perception was calculated. Studies that investigated any kind of sleep deprivation in conjunction with a pain measurement were included. In cases of several pain measurements within a study, the average effect size of all measures was calculated. RESULTS: Five eligible studies (N = 190) for the between-group analysis and ten studies (N = 266) for the within-group analysis were identified. Sleep deprivation showed a medium effect in the between-group analysis (SMD = 0.62; CI95: 0.12, 1.12; z = 2.43; p = 0.015) and a large effect in the within-group analysis (SMD = 1.49; CI95: 0.82, 2.17; z = 4.35; p <0.0001). The test for heterogeneity was not significant in the between-group analysis (Q = 5.29; df = 4; p = 0.2584), but it was significant in the within-group analysis (Q = 53.49; df = 9; p <0.0001). CONCLUSION: This meta-analysis confirms a medium effect (SMD = 0.62) of sleep deprivation on pain perception. As this meta-analysis is based on experimental studies in healthy subjects, the clinical relevance should be clarified. PMID- 26498230 TI - Bad sleep? Don't blame the moon! A population-based study. AB - INTRODUCTION: The aim of this study was to evaluate if there is a significant effect of lunar phases on subjective and objective sleep variables in the general population. METHODS: A total of 2125 individuals (51.2% women, age 58.8 +/- 11.2 years) participating in a population-based cohort study underwent a complete polysomnography (PSG) at home. Subjective sleep quality was evaluated by a self rating scale. Sleep electroencephalography (EEG) spectral analysis was performed in 759 participants without significant sleep disorders. Salivary cortisol levels were assessed at awakening, 30 min after awakening, at 11 am, and at 8 pm. Lunar phases were grouped into full moon (FM), waxing/waning moon (WM), and new moon (NM). RESULTS: Overall, there was no significant difference between lunar phases with regard to subjective sleep quality. We found only a nonsignificant (p = 0.08) trend toward a better sleep quality during the NM phase. Objective sleep duration was not different between phases (FM: 398 +/- 3 min, WM: 402 +/- 3 min, NM: 403 +/- 3 min; p = 0.31). No difference was found with regard to other PSG derived parameters, EEG spectral analysis, or in diurnal cortisol levels. When considering only subjects with apnea/hypopnea index of <15/h and periodic leg movements index of <15/h, we found a trend toward shorter total sleep time during FM (FM: 402 +/- 4, WM: 407 +/- 4, NM: 415 +/- 4 min; p = 0.06) and shorter-stage N2 duration (FM: 178 +/- 3, WM: 182 +/- 3, NM: 188 +/- 3 min; p = 0.05). CONCLUSION: Our large population-based study provides no evidence of a significant effect of lunar phases on human sleep. PMID- 26498231 TI - The association between sleep duration and dry eye syndrome among Korean adults. AB - OBJECTIVE: The aim of the present study was to investigate the association between sleep duration and dry eye syndrome (DES) symptoms. METHODS: We investigated 15,878 subjects (male = 6684; female = 9194) aged 20 years and older who underwent physical examinations and completed a self-report questionnaire and other anthropometric variables from the fifth Korean National Health and Nutrition Examination Survey (KNHANES) 2010-2012. Odds ratios (OR) and 95% confidence intervals (95% CI) for DES according to sleep duration were calculated using multiple logistic regression models. RESULTS: Compared to that in an optimal sleep group (6-8 h/day), OR (95% CI) DES prevalence after adjusting for age, gender, sociodemographic factors (educational level, occupation, household income, and residence), and health behaviors (smoking habit, alcohol consumption, and level of exercise) was 1.20 (1.05-1.36) for a mild short sleep group (5 h/day) and 1.29 (1.08-1.55) for a severe short sleep group (<=4 h/day). CONCLUSION: Our results revealed that DES increased at shorter sleep durations. PMID- 26498233 TI - Open-label study of the efficacy and safety of intravenous ferric carboxymaltose in pregnant women with restless legs syndrome. AB - OBJECTIVE: The objective of this study was to test the efficacy and safety of intravenous ferric carboxymaltose (FCM) in pregnant women with restless legs syndrome (RLS) and iron deficiency or anemia. The open-label pilot study (exploratory) was performed at the University Hospital of Zurich and the Neurocenter of Southern Switzerland (Lugano). PATIENT AND METHODS: Nineteen women in the third trimester of pregnancy with moderate-to-severe RLS and serum ferritin levels <35 ug/l or hemoglobin (Hb) < 11.0 g/dl were included in the study. RLS was graded according to the International Restless Legs Syndrome (IRLS) Study Group rating scale. All participants had a score of >=20 or had RLS >=3 times/week. Based on the Hb levels, 500 or 700 mg of FCM was administered over 20 min. The primary end point was a >= 50% reduction in the mean IRLS score one week after FCM infusion. The secondary end points included periodic limb movements (PLMs; assessed using nocturnal foot actigraphy), sleep quality (assessed using the Pittsburgh Sleep Quality Index), and safety. RESULTS: The IRLS score decreased from 23 +/- 7 (baseline) to 13 +/- 7 (P <0.01), whereas the PLM index decreased from 35 +/- 26 (baseline) to 25 +/- 20 (P <0.001). Significant improvement in sleep quality was also reported (P <0.029), and treatment was well tolerated. Three serious adverse events were reported, but they were considered unrelated to treatment. CONCLUSIONS: These data provide promising evidence on the safety and efficacy of FCM for moderate-to-severe RLS in pregnant women with iron deficiency or anemia. Therefore, a future placebo controlled study is warranted. PMID- 26498232 TI - New approach for analyzing self-reporting of insomnia symptoms reveals a high rate of comorbid insomnia across a wide spectrum of chronic diseases. AB - BACKGROUND: Insomnia is increasingly recognized to be comorbid with one or more medical conditions. This study used an online research platform to characterize insomnia across different mental and physical conditions. METHODS: A custom cross sectional survey was fielded online to 31,208 users of the patient community PatientsLikeMe. The survey queried members on National Sleep Foundation-defined insomnia risk (waking up feeling unrefreshed, difficulty falling asleep, waking in the middle of the night, or waking too early). RESULTS: Complete results were obtained from 5256 patients with 11 comorbid conditions. Seventy-six percent of US-based respondents were at risk for insomnia. Patients who reported difficulty falling asleep were found to have nearly twice the odds of self-reporting insomnia (odds ratio [OR]: 1.84; 95% confidence interval [CI]: 1.5-2.1) when compared to those who do not have difficulty falling asleep, whereas those who reported waking during the night or waking up unrefreshed were no more likely (OR: 1.025 and 1.032, respectively) to report that they suffered from insomnia than those who did not experience these issues. Although insomnia was self reported as severe or very severe across most conditions, few respondents had actually been diagnosed with insomnia by a physician. After adjustment for age and gender, there was an independent and strong effect of primary condition severity on insomnia risk, and those with severe epilepsy (0.93), depressive disorders (0.92), and fibromyalgia (0.92) occupied the highest risk probabilities. CONCLUSIONS: The high rate of severity and frequency of insomnia across a multitude of mental and physical conditions reveals an opportunity for better disease management through enhanced insomnia awareness. PMID- 26498234 TI - Intraindividual long-term stability of sleep electroencephalography in school aged children. AB - OBJECTIVE: To examine the long-term stability of sleep duration, sleep continuity, and sleep architecture assessed via unattended home sleep electroencephalography (EEG) during middle childhood. METHODS: A total of 69 healthy children (18 girls and 51 boys) aged 8.2 years (standard deviation = 1.3 years) at T1 underwent unattended home sleep EEG on two nights separated by 18.5 months (standard deviation = 3.9 months). Of the children, 34 (49.3%) children were born prematurely (<32 gestational weeks; mean birth weight = 1367 g) and 35 (50.7%) children were born at term (mean birth weight = 3275 g). RESULTS: We found moderate to substantial stability (all p <0.001) for total sleep time (TST; intraclass correlation coefficient [ICC] = 0.65), slow wave sleep (SWS; min, %: ICC = 0.49), and stage 2 sleep (min; ICC = 0.47), and found fair stability (all p <0.013) for sleep efficiency (ICC = 0.28), nocturnal awakenings (ICC = 0.33), stage 2 sleep (%; ICC = 0.32), and rapid eye movement (REM) sleep (min: ICC = 0.33; %: ICC = 0.27). Prematurity status was not associated with stability of sleep EEG indices over time. CONCLUSIONS: Long-term follow-up of one night of unattended home sleep EEG during middle childhood reveals that TST, stage 2 sleep, and SWS are relatively stable, trait-like characteristics. This applies less strongly for sleep efficiency, nocturnal awakenings, and REM sleep. Stage 1 sleep and REM latency showed no stability. PMID- 26498235 TI - Phase-delay in the light-dark cycle impairs clock gene expression and levels of serotonin, norepinephrine, and their metabolites in the mouse hippocampus and amygdala. AB - OBJECTIVE: A number of animal studies have implicated circadian clock genes in the regulation of mood, anxiety, and reward. However, the effect of misalignment of the environmental light-dark and internal circadian clock on the monoamine system is not fully understood. In the present study, we examined whether an abnormal light-dark schedule would affect behavior-, circadian clock-, and monoamine-related gene expressions, along with monoamine contents in the amygdala and hippocampus of mice. METHODS: Mice were subjected to an 8-hour phase delay in the light-dark cycle (Shift) every two days for four weeks, and locomotor activity was continuously measured. We examined the circadian expression of clock genes (Per1, Per2, and Bmal1) and genes of the NE/5HT uptake transporters (Net and Sert). In addition, the levels of NE/5HT and their metabolites MHPG/5HIAA were analyzed in the amygdala and hippocampus. RESULTS: Locomotor activity showed a free-running phenotype with a longer period (>24 hours) and showed misalignment between the light-dark and inactive-active cycles. The amplitude of the day-night fluctuation of Bmal1 expression was reduced in the amygdala and hippocampus of light-dark-shifted mice. Net gene expression in the Shift group showed different profiles compared with the Control group. In addition, NE and 5HT levels in the amygdala of the Shift group increased during the active period. CONCLUSIONS: The present results suggest that misalignment of the internal and external clocks by continuous shifting of the light-dark cycle affects the circadian clocks and monoamine metabolism in the amygdala and hippocampus of mice. PMID- 26498236 TI - Genetic associations of periodic limb movements of sleep in the elderly for the MrOS sleep study. AB - OBJECTIVE: The objective of this study was to assess the relationship between single-nucleotide polymorphisms associated with restless legs syndrome and periodic limb movements of sleep in a population cohort of elderly individuals. METHODS: Single-nucleotide polymorphisms previously associated with periodic limb movements of sleep or restless legs syndrome were analyzed in 2356 white male participants in the Osteoporotic Fractures in Men Sleep Study cohort. The associations between single-nucleotide polymorphisms and polysomnographically measured periodic limb movement index >=15 were examined with logistic regression adjusted for age, ancestry markers, and periodic limb movements of sleep risk factors. RESULTS: Of the men in this cohort, 61% had a periodic limb movement index >=15. Significant associations were observed between a periodic limb movement index >=15 and the number of risk alleles for the two BTBD9 single nucleotide polymorphisms (rs9357271[T], odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.20-1.58; and rs3923809[A], OR = 1.43, 95% CI 1.26-1.63), one of the MEIS1 single-nucleotide polymorphisms (rs2300478[G], OR = 1.31, 95% CI 1.14 1.51) and the mitogen-activated protein kinase kinase 5 (MAP2K5)/Ski family transcriptional corepressor 1 (SKOR1) single-nucleotide polymorphism (rs1026732[G], OR = 1.16, 95% CI 1.02-1.31). In a multivariable model controlling for each of the two MEIS1 single-nucleotide polymorphisms, the rs6710341[A] single-nucleotide polymorphism became a significant risk allele (OR = 1.59, 95% CI 1.26-2.00). CONCLUSIONS: Our findings confirm an association between the BTBD9, MEIS1, and MAP2K5/SKOR1 single-nucleotide polymorphisms and periodic limb movements of sleep in an elderly cohort not selected for the presence of restless legs syndrome. PMID- 26498237 TI - Metabolic changes in normal- and underweight children with obstructive sleep disordered breathing. AB - OBJECTIVE: This study evaluates the metabolic profile of normal- and underweight children with sleep-disordered breathing (SDB) due to adenotonsillar hypertrophy. METHODS: A total of 39 children aged 3-15 years with SDB and 28 age- and gender matched controls were included in the study. Body mass index z score, blood pressure, and fasting serum levels of triglycerides (TGs), high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, very-low density lipoprotein (VLDL), blood glucose, plasma insulin, and homeostatic model assessment (HOMA) were determined in both case patients and controls. RESULTS: We observed significantly lower levels of fasting blood glucose (p = 0.015) and higher levels of HDL (p = 0.002), LDL (p = 0.002), and cholesterol (p = 0.001) in case patients than in controls. The mean values of fasting insulin and HOMA were higher in case patients (6.42 +/- 6.47 and 1.40 +/- 1.48) than in controls (5.31 +/- 3.40 and 1.20 +/- 0.84) respectively. No direct correlation between indices of severity of SDB and various metabolic and blood pressure parameters was found. When the effect of body weight was studied by subgrouping case patients according to normal weight and underweight, significant increases in the levels of fasting insulin (p = 0.039), HOMA (p = 0.017), and fasting blood glucose (p = 0.021) were observed. Also, a significant correlation was observed between the duration of illness and fasting insulin (p = 0.023), HOMA (p = 0.020), fasting glucose (p = 0.004), and diastolic blood pressure (p = 0.030). CONCLUSION: This study shows an independent effect of body weight and duration of illness on various metabolic and blood pressure parameters in normal- and underweight children with SDB. PMID- 26498238 TI - Response to placebo acupuncture in insomnia: a secondary analysis of three randomized controlled trials. AB - OBJECTIVE: To determine the patient characteristics that are associated with a response to noninvasive placebo acupuncture for insomnia. METHODS: We performed a secondary analysis of three randomized, double-blind, placebo-controlled trials of acupuncture for primary insomnia and residual insomnia associated with major depression. A total of 86 participants were randomized to receive placebo acupuncture three times per week for three consecutive weeks. Outcome was assessed at 1-week posttreatment. Response was defined as an Insomnia Severity Index (ISI) score improved by eight points or more from baseline to 1-week posttreatment. Sociodemographic, clinical, and baseline characteristics including sleep diary-derived and actigraph-derived sleep parameters as predictors of placebo response were examined using univariate and multivariate logistic regression. RESULTS: The effect size of placebo acupuncture was estimated at 0.18 for total sleep time, 0.08 for sleep efficiency, and 0.92 for ISI score. Eighteen (20.9%) of the 86 participants were responders. Responders had a higher ISI score (p = 0.03), higher sleep diary-derived total sleep time (p = 0.02), less discrepancy between sleep diary-derived and actigraph-derived total sleep time (p = 0.03), and higher expectation toward acupuncture (p = 0.03) at baseline compared to nonresponders. Multivariate regression analysis found that only ISI score remained significant (odds ratio = 1.23, 95% confidence interval = 1.02 1.50, p = 0.03). CONCLUSIONS: Baseline sleep parameters and perceived effectiveness were shown to predict the placebo response of acupuncture for insomnia. Although the study was limited by a small sample size, our findings highlighted the potential implication of sleep duration and sleep-state misperception in the treatment of insomnia. PMID- 26498240 TI - Night-shift work increases morbidity of breast cancer and all-cause mortality: a meta-analysis of 16 prospective cohort studies. AB - Night-shift work (NSW) has previously been related to incidents of breast cancer and all-cause mortality, but many published studies have reported inconclusive results. The aim of the present study was to quantify a potential dose-effect relationship between NSW and morbidity of breast cancer, and to evaluate the association between NSW and risk of all-cause mortality. The outcomes included NSW, morbidity of breast cancer, cardiovascular mortality, cancer-related mortality, and all-cause mortality. Sixteen investigations were included, involving 2,020,641 participants, 10,004 incident breast cancer cases, 7185 cancer-related deaths, 4820 cardiovascular end points, and 2480 all-cause mortalities. The summary risk ratio (RR) of incident breast cancer for an increase of NSW was 1.057 [95% confidence interval (CI) 1.014-1.102; test for heterogeneity p = 0.358, I(2) = 9.2%]. The combined RR (95% CI) of breast cancer risk for NSW vs daytime work was: 1.029 (0.969-1.093) in the <5-year subgroup, 1.019 (1.001-1.038) for 5-year incremental risk, 1.025 (1.006-1.044) for 5- to 10 year exposure times, 1.074 (1.010-1.142) in the 10- to 20-year subgroup, and 1.088 (1.012-1.169) for >20-year exposure lengths. The overall RR was 1.089 (95% CI 1.016-1.166) in a fixed-effects model (test for heterogeneity p = 0.838, I(2) = 0%) comparing rotating NSW and day work. Night-shift work was associated with an increased risk of cardiovascular death (RR 1.027, 95% CI 1.001-1.053), and all cause death 1.253 (95% CI 0.786-1.997). In summary, NSW increased the risk of breast cancer morbidity by: 1.9% for 5 years, 2.5% for 5-10 years, 7.4% for 10-20 years, and 8.8% for >20-years of NSW. Additionally, rotating NSW enhanced the morbidity of breast cancer by 8.9%. Moreover, NSW was associated with a 2.7% increase in cardiovascular death. PMID- 26498239 TI - Comparing subjective measures of behavioral sleep problems in children with ADHD: a cross-sectional study. AB - AIM: Behavioral sleep problems are ideally measured using a combination of objective and subjective measures. However, this is not always feasible. Thus, a global subjective measure has been used to assess sleep problems in children with attention deficit hyperactivity disorder (ADHD), yet it is unclear how this relates to more detailed multidimensional measures of sleep problems. In children with ADHD, parent report of a global measure of sleep problem severity (classified no/mild versus moderate/severe) is compared with the following: (1) a 7-Day Sleep Log and (2) the validated Children's Sleep Habits Questionnaire (CSHQ). METHOD: This study recruited 392 children with ADHD (aged 5-13 years) from 50 pediatric practices across Victoria, Australia. All caregivers completed the CSHQ, and 257 children prospectively completed the 7-Day Sleep Logs. RESULTS: Sleep log data identified distinct sleep patterns according to parent-reported sleep problem severity; children with moderate/severe sleep problems slept 30 min less per day, took longer to fall asleep, and experienced more night awakenings. This pattern was also repeated across the CSHQ, where children with moderate/severe sleep problems experienced more problematic sleep symptoms across all domains (effect sizes: 0.5-1.1; all p < 0.001). CONCLUSION: A subjective, global measure of sleep problem severity appears to be a useful tool for the initial assessment of sleep problems in children with ADHD when more extensive measures are not feasible, as it is reflective of well-established multidimensional measures. However, further research is required to determine its validity. PMID- 26498241 TI - Sleep interruption associated with house staff work schedules alters circadian gene expression. AB - BACKGROUND: Epidemiological studies indicate that disruption of circadian rhythm by shift work increases the risk of breast and prostate cancer. Our studies demonstrated that carcinogens disrupt the circadian expression of circadian genes (CGs) and circadian-controlled genes (CCGs) during the early stages of rat mammary carcinogenesis. A chemopreventive regimen of methylselenocysteine (MSC) restored the circadian expression of CGs and CCGs, including PERIOD 2 (PER2) and estrogen receptor beta (ERS2), to normal. The present study evaluated whether changes in CG and CCG expression in whole blood can serve as indicators of circadian disruption in shift workers. METHODS: Fifteen shift workers were recruited to a crossover study. Blood samples were drawn before (6 PM) and after (8 AM) completing a night shift after at least seven days on floating night-shift rotation, and before (8 AM), during (1 PM), and after (6 PM) completing seven days on day shift. The plasma melatonin level and messenger RNA (mRNA) expression of PER2, nuclear receptor subfamily 1, group d, member 1 (NR1D1), and ERS2 were measured, and the changes in levels of melatonin and gene expression were evaluated with statistical analyses. RESULTS: The mRNA expression of PER2 was affected by shift (p = 0.0079); the levels were higher in the evening for the night shift, but higher in the morning for the day shift. Increased PER2 expression (p = 0.034) was observed in the evening on the night versus day shifts. The melatonin level was higher in the morning for both day shifts (p = 0.013) and night shifts (p <0.0001). CONCLUSION: Changes in the level of PER2 gene expression can serve as a biomarker of disrupted circadian rhythm in blood cells. Therefore, they can be a useful intermediate indicator of efficacy in future MSC-mediated chemoprevention studies. PMID- 26498242 TI - Residual effects of zolpidem, triazolam, rilmazafone and placebo in healthy elderly subjects: a randomized double-blind study. AB - With current hypnotic agents, next-day residual effects are a common problem. The purpose of the present study was to evaluate the residual effects of the commercially available hypnotics - zolpidem, triazolam, and rilmazafone - on the physical and cognitive functions of healthy elderly people in the early morning and the day following drug administration. In this study, the next-day residual effects of zolpidem, triazolam, and rilmazafone, following bedtime dosing in elderly subjects, were evaluated. Women (n = 11) and men (n = 2) aged 60-70 years received a single dose (at 23:00) of one of these, zolpidem 5 mg, triazolam 0.125 mg, rilmazafone 1 mg and placebo in a randomized, double-blind, crossover design. Measures of objective parameters and psychomotor performances (Timed up and Go test, Functional Reach Test, body sway test, critical flicker fusion test, simple discrimination reaction test, short-term memory test) and subjective ratings were obtained at 04:00, 07:00, and the next time of the day. All hypnotics were generally well tolerated; there were no serious adverse side effects and no subjects discontinued the evaluations. Compared to placebo, zolpidem and rilmazafone had good results on the Functional Reach Test. Although subjective assessments tended to be poor in the early morning, rilmazafone significantly improved the body sway test in the other hypnotics. A single dose of zolpidem 5 mg and triazolam 0.125 mg did not have any next-day residual effects on healthy elderly subjects. Residual effects appeared to be related to the compound's half life and the dose used. Rilmazafone 1 mg exhibited steadiness in static and dynamic balance and seemed to be more favorable for the elderly with early morning awakening. PMID- 26498243 TI - Comparison of impact of insomnia on depression and quality of life in restless legs syndrome/Willis-Ekbom disease and primary insomnia patients. AB - BACKGROUND: Although insomnia is common among people with restless legs syndrome (RLS), its impact on the daily suffering of those with RLS remains unclear. This study aimed to compare the differential impact of clinical insomnia on depression and quality of life (QoL) among people with RLS, primary insomnia, and healthy controls. METHODS: A total of 148 people with RLS, 115 with primary insomnia, and 117 healthy controls were enrolled into this cross-sectional study. Participants completed sleep, depression, and QoL questionnaires. Clinical insomnia was defined as Korean version of the Insomnia Severity Index (K-ISI) >= 15. Correlation coefficients between sleep measures and both depression and QoL were calculated. Multivariate regression was used to identify the clinical factors that were most closely associated with depression and QoL among people with RLS and primary insomnia. RESULTS: Participants with RLS had insomnia and sleep quality at intermediate levels between the healthy controls and primary insomnia subjects, but those with clinical insomnia had equivalent depression and QoL scores regardless of RLS diagnosis. Insomnia severity correlated with depression and QoL in RLS and primary insomnia. Multivariate regression, however, revealed that RLS severity was the most overall predictive factor for depression and QoL among those with RLS. Insomnia severity was the strongest predictor in primary insomnia. CONCLUSION: Insomnia was more closely associated with depression and QoL among people with primary insomnia than those with RLS, but clinical insomnia may have a significant impact in RLS as well. Future RLS studies should account for sleep quality in addition to RLS symptom severity when investigating mood and QoL. PMID- 26498244 TI - The role of nocturnal pulse oximetry in the screening for obstructive sleep apnea in obese children and adolescents. AB - BACKGROUND AND AIM: Obesity is a known risk factor for the development of obstructive sleep apnea (OSA) in children. Early screening is essential because of the possible complications associated with OSA. At present, the gold standard for diagnosing OSA is polysomnography, which however has multiple limitations. The aim of this study is to examine the role of nocturnal oximetry as a screening tool for OSA in obese children and adolescents. MATERIALS AND METHODS: This retrospective study included obese children who underwent a polysomnography at the Antwerp University Hospital between November 2010 and May 2014. Their oximetries were scored manually, blinded for the polysomnography results, according to Brouilette et al. OSA was defined as an obstructive apnea-hypopnea index (oAHI) >= 2 on polysomnography. RESULTS: This study included 130 obese patients (38% boys, mean age 12 years). Polysomnography results determined 44 patients (34%) with a diagnosis of OSA. Oximetry results classified 16 patients as positive, 43 as negative, and 71 as inconclusive. Further analysis of the positive and negative oximetry results showed a sensitivity and specificity of 58% and 88%, respectively, with a negative and positive predictive value of 81% and 69%, respectively. A second analysis, using the oxygen desaturation index, showed inferior results in comparison to the score attained by Brouillette (sensitivity 57%, specificity 73%). CONCLUSIONS: These results suggest that oximetry alone is insufficient as a screening tool for OSA in obese children. Other screening methods need to be explored in the future. PMID- 26498245 TI - Association of low ferritin with PLM in the Wisconsin Sleep Cohort. AB - OBJECTIVE: The origins of periodic leg movements (PLMs), a strong correlate of restless legs syndrome (RLS), are uncertain. This study was performed to assess the relationship between PLMs and peripheral iron deficiency, as measured with ferritin levels corrected for inflammation. METHODS: We included a cross sectional sample of a cohort study of 801 randomly selected people (n = 1008 assays, mean age 58.6 +/- 0.3 years) from Wisconsin state employee agencies. A previously validated automatic detector was used to measure PLMs during sleep. The patients were categorized into RLS symptoms-positive and RLS symptoms negative based on a mailed survey response and prior analysis. Analyses were performed using a linear model with PLM category above and below 15 PLM/h (periodic leg movement index, PLMI) as the dependent variable, and adjusting for known covariates, including previously associated single-nucleotide polymorphisms (SNPs) within BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD. Ferritin and C-reactive protein (CRP) levels were measured in serum, and ferritin levels corrected for inflammation using CRP levels. RESULTS: After controlling for cofactors, PLMI >= 15 was associated with low (<=50 ng/mL) ferritin levels (OR = 1.55, p = 0.020). The best model was found using quasi-least squares regression of ferritin as a function of PLMI, with an increase of 0.0034 PLM/h predicted by a decrease of 1 ng/mL ferritin (p = 0.00447). CONCLUSIONS: An association was found between low ferritin and greater PLMs in a general population of older adults, independent of genetic polymorphisms, suggesting a role of low iron stores in the expression of these phenotypes. Patients with high PLMI may require to be checked for iron deficiency. PMID- 26498246 TI - Effects of fluid shift on upper airway patency and neck circumference in normal weight subjects. AB - BACKGROUND: Fluid shift from the lower body into the neck could narrow the upper airway (UA) and increase the propensity of its obstruction in people with obstructive sleep apnea. Although studies have demonstrated an increase in the neck circumference (NC) due to fluid shift, it remains unclear as to whether a large increase in NC means a large reduction in the cross-sectional area of the UA (CSA-UA). This study tested a hypothesis that a significant UA narrowing due to fluid redistribution is not necessarily linked to an apparent increase in NC, and vice versa. METHODS: Magnetic resonance imaging (MRI) studies were performed on 30 male and 20 female normal-weight subjects. Fluid shift was achieved by raising their legs by >50 degrees . The coordinates of the neck and UA boundaries were extracted from the MRI to calculate the NC and CSA-UA. RESULTS: After elevating the legs for 8 min, the CSA-UA was reduced by 27.6% while the NC increased by 1.5% in 50 subjects (p < 0.001). In 10% of the males and 10% of the females, NC was almost unchanged, while the reduction in CSA-UA was large. In 7% of the males and 20% of the females, the change in NC was large, while that in CSA-UA was small. The correlation coefficient between the changes in NC and CSA UA was -0.211, which was consistent with the hypothesis. CONCLUSIONS: The amount of NC increase should not be used to judge the degree of reduction in CSA-UA. Clinically, those people who have little NC increase after body position changes have more risk of CSA-UA reduction at bedtime. PMID- 26498247 TI - A cryptic paracentric inversion of MSH2 exons 2-6 causes Lynch syndrome. AB - Lynch syndrome is an autosomal dominant disorder that predisposes carriers of DNA mismatch repair (MMR) gene mutations to early-onset cancer. Germline testing screens exons and splice sites for mutations, but does not examine introns or RNA transcripts for alterations. Pathogenic mutations have not been detected in ~30% of suspected Lynch syndrome cases with standard screening practices. We present a 38-year-old male with a clinicopathological and family history consistent with Lynch syndrome, including loss of MSH2 expression in his tumor. Germline testing revealed normal MSH2 coding sequence, splice sites and exon copy number, however, cDNA sequencing identified an aberrant MSH2 transcript lacking exons 2-6. An inversion PCR on germline DNA identified an ~18kb unbalanced, paracentric inversion within MSH2, with breakpoints in a long terminal repeat in intron 1 and an Alu repeat in intron 6. The 3' end of the inversion had a 1.2 kb deletion and an 8 bp insertion at the junction with intron 6. Screening of 55 additional Australian patients presenting with MSH2-deficient tumors who were negative in germline genetic tests for MSH2 mutations identified another inversion-positive patient. We propose an Alu-mediated recombination model to explain the origin of the inversion. Our study illustrates the potential value of cDNA screening to identify patients with cryptic MMR gene rearrangements, clarifies why standard testing may not detect some pathogenic alterations, and provides a genetic test for screening individuals with suspected Lynch syndrome that present with unexplained MSH2-deficient tumors. PMID- 26498248 TI - Role of GADD45a in murine models of radiation- and bleomycin-induced lung injury. AB - We previously reported protective effects of GADD45a (growth arrest and DNA damage-inducible gene 45 alpha) in murine ventilator-induced lung injury (VILI) via effects on Akt-mediated endothelial cell signaling. In the present study we investigated the role of GADD45a in separate murine models of radiation- and bleomycin-induced lung injury. Initial studies of wild-type mice subjected to single-dose thoracic radiation (10 Gy) confirmed a significant increase in lung GADD45a expression within 24 h and persistent at 6 wk. Mice deficient in GADD45a (GADD45a(-/-)) demonstrated increased susceptibility to radiation-induced lung injury (RILI, 10 Gy) evidenced by increased bronchoalveolar lavage (BAL) fluid total cell counts, protein and albumin levels, and levels of inflammatory cytokines compared with RILI-challenged wild-type animals at 2 and 4 wk. Furthermore, GADD45a(-/-) mice had decreased total and phosphorylated lung Akt levels both at baseline and 6 wk after RILI challenge relative to wild-type mice while increased RILI susceptibility was observed in both Akt(+/-) mice and mice treated with an Akt inhibitor beginning 1 wk prior to irradiation. Additionally, overexpression of a constitutively active Akt1 transgene reversed RILI susceptibility in GADD45a(-/-) mice. In separate studies, lung fibrotic changes 2 wk after treatment with bleomycin (0.25 U/kg IT) was significantly increased in GADD45a(-/-) mice compared with wild-type mice assessed by lung collagen content and histology. These data implicate GADD45a as an important modulator of lung inflammatory responses across different injury models and highlight GADD45a mediated signaling as a novel target in inflammatory lung injury clinically. PMID- 26498249 TI - Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function. AB - Transendothelial hyperpermeability caused by numerous agonists is dependent on heat shock protein 90 (Hsp90) and leads to endothelial barrier dysfunction (EBD). Inhibition of Hsp90 protects and restores transendothelial permeability. Hyperacetylation of Hsp90, as by inhibitors of histone deacetylase (HDAC), suppresses its chaperone function and mimics the effects of Hsp90 inhibitors. In this study we assessed the role of HDAC in mediating lipopolysaccharide (LPS) induced transendothelial hyperpermeability and acute lung injury (ALI). We demonstrate that HDAC inhibition protects against LPS-mediated EBD. Inhibition of multiple HDAC by the general inhibitors panobinostat or trichostatin provided protection against LPS-induced transendothelial hyperpermeability, acetylated and suppressed Hsp90 chaperone function, and attenuated RhoA activity and signaling crucial to endothelial barrier function. Treatment with the HDAC3-selective inhibitor RGFP-966 or the HDAC6-selective inhibitor tubastatin A provided partial protection against LPS-mediated transendothelial hyperpermeability. Similarly, knock down of HDAC3 and HDAC6 by specific small-interfering RNAs provided significant protection against LPS-induced EBD. Furthermore, combined pharmacological inhibition of both HDAC3 and -6 attenuated the inflammation, capillary permeability, and structural abnormalities associated with LPS-induced ALI in mice. Together these data indicate that HDAC mediate increased transendothelial hyperpermeability caused by LPS and that inhibition of HDAC protects against LPS-mediated EBD and ALI by suppressing Hsp90-dependent RhoA activity and signaling. PMID- 26498250 TI - EET-dependent potentiation of pulmonary arterial pressure: sex-different regulation of soluble epoxide hydrolase. AB - We tested the hypothesis that suppression of epoxyeicosatrienoic acid (EET) metabolism via genetic knockout of the gene for soluble epoxide hydrolase (sEH KO), or female-specific downregulation of sEH expression, plays a role in the potentiation of pulmonary hypertension. We used male (M) and female (F) wild-type (WT) and sEH-KO mice; the latter have high pulmonary EETs. Right ventricular systolic pressure (RVSP) and mean arterial blood pressure (MABP) in control and in response to in vivo administration of U46619 (thromboxane analog), 14,15-EET, and 14,15-EEZE [14,15-epoxyeicosa-5(z)-enoic acid; antagonist of EETs] were recorded. Basal RVSP was comparable among all groups of mice, whereas MABP was significantly lower in F-WT than M-WT mice and further reduced predominantly in F KO compared with M-KO mice. U46619 dose dependently increased RVSP and MABP in all groups of mice. The increase in RVSP was significantly greater and coincided with smaller increases in MABP in M-KO and F-WT mice compared with M-WT mice. In F-KO mice, the elevation of RVSP by U46619 was even higher than in M-KO and F-WT mice, associated with the least increase in MABP. 14,15-EEZE prevented the augmentation of U46619-induced elevation of RVSP in sEH-KO mice, whereas 14,15 EET-induced pulmonary vasoconstriction was comparable in all groups of mice. sEH expression in the lungs was reduced, paralleled with higher levels of EETs in F WT compared with M-WT mice. In summary, EETs initiate pulmonary vasoconstriction but act as vasodilators systemically. High pulmonary EETs, as a function of downregulation or deletion of sEH, potentiate U46619-induced increases in RVSP in a female-susceptible manner. PMID- 26498252 TI - A systemic defect in Toll-like receptor 4 signaling increases lipopolysaccharide induced suppression of IL-2-dependent T-cell proliferation in COPD. AB - The susceptibility to bacterial infections is increased in chronic obstructive pulmonary disease (COPD). This promotes exacerbations. IL-2 triggers CD4(+)/Th1 cell proliferation, which is important for infection defense. Bacterial endotoxin (LPS) activates MyD88/IRAK and TRIF/IKKepsilon/TBK1 pathways via Toll-like receptor-4 (TLR4) in Th1 cells. Systemic defects in TLR pathways in CD4(+)/Th1 cells cause an impairment of IL-2-dependent immune responses to bacterial infections in COPD. Peripheral blood CD4(+) T cells of never smokers, smokers without COPD, and smokers with COPD (each n = 10) were ex vivo activated towards Th1 and stimulated with LPS. IL-2, MyD88, and TRIF expression, and cell proliferation was analyzed by ELISA, quantitative RT-PCR, and bromodeoxyuridine (BrdU) and trypan blue staining comparative among the cohorts. IL-2 release from activated T cells was increased in COPD vs. smokers and never smokers. LPS reduced IL-2 expression and T-cell proliferation. These effects were increased in COPD vs. never smokers and inversely correlated with FEV1 (%predicted). The MyD88/TRIF ratio was decreased in Th1 cells of COPD. The suppression of IL-2 by LPS was abolished by MyD88/IRAK blockade in never smokers but by TRIF/IKKepsilon/TBK1 blockade in COPD. Moxifloxacin restored IL-2 expression and T-cell proliferation in the presence of LPS by blocking p38 MAPK. The increased IL-2 release from Th1 cells in COPD might contribute to airway inflammation in disease exacerbations. A switch from MyD88/IRAK to TRIF/IKKepsilon/TBK1 signaling amplifies the suppression of IL-2-dependent proliferation of CD4(+) T cells by LPS in COPD. This molecular pathology is of systemic origin, might impair adaptive immune responses, and could explain the increased susceptibility to bacterial infections in COPD. Targeting TLR4-downstream signaling, for example, with moxifloxacin, might reduce exacerbation rates. PMID- 26498251 TI - Carbon monoxide in the treatment of sepsis. AB - Carbon monoxide (CO), a low-molecular-weight gas, is endogenously produced in the body as a product of heme degradation catalyzed by heme oxygenase (HO) enzymes. As the beneficial roles of HO system have been elucidated in vitro and in vivo, CO itself has also been reported as a potent cytoprotective molecule. Whereas CO represents a toxic inhalation hazard at high concentration, low-dose exogenous CO treatment (~250-500 parts per million) demonstrates protective functions including but not limited to the anti-inflammatory and antiapoptotic effects in preclinical models of human diseases. Of note, CO exposure confers protection in animal models of sepsis by inhibiting inflammatory responses and also enhancing bacterial phagocytosis in leukocytes. These unique functions of CO including both dampening inflammation and promoting host defense mechanism are mediated by multiple pathways such as autophagy induction or biosynthesis of specialized proresolving lipid mediators. We suggest that CO gas may represent a novel therapy for patients with sepsis. PMID- 26498253 TI - Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder. AB - Valproic acid administration during gestational period causes behavior and biochemical deficits similar to those observed in humans with autism spectrum disorder. Although worldwide prevalence of autism spectrum disorder has been increased continuously, therapeutic agents to ameliorate the social impairment are very limited. The present study has been structured to investigate the therapeutic potential of melatonin receptor agonist, agomelatine in prenatal valproic acid (Pre-VPA) induced autism spectrum disorder in animals. Pre-VPA has produced reduction in social interaction (three chamber social behavior apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, Pre-VPA has increased locomotor activity (actophotometer), anxiety, brain oxidative stress (thiobarbituric acid reactive species, glutathione, and catalase), nitrosative stress (nitrite/nitrate), inflammation (brain and ileum myeloperoxidase activity), calcium levels and blood brain barrier leakage in animals. Treatment with agomelatine has significantly attenuated Pre-VPA induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, agomelatine also attenuated Pre-VPA induced increase in locomotion, anxiety, brain oxidative stress, nitrosative stress, inflammation, calcium levels and blood brain barrier leakage. It is concluded that, Pre-VPA has induced autism spectrum disorder, which was attenuated by agomelatine. Agomelatine has shown ameliorative effect on behavioral, neurochemical and blood brain barrier alteration in Pre-VPA exposed animals. Thus melatonin receptor agonists may provide beneficial therapeutic strategy for managing autism spectrum disorder. PMID- 26498254 TI - PFKFB3-mediated glycolysis is involved in reactive astrocyte proliferation after oxygen-glucose deprivation/reperfusion and is regulated by Cdh1. AB - Reactive astrocyte proliferation is involved in many central degenerative diseases. The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), an allosteric activator of 6-phosphofructo-1-kinase (PFK1), controls glycolytic flux. Furthermore, APC/C-Cdh1 plays a crucial role in brain metabolism by regulating PFKFB3 expression. Previous studies have defined the roles of PFKFB3-mediated glycolysis in pathological angiogenesis, cell autophagy, and amyloid plaque deposition in proliferating cells. However, the role of PFKFB3 in reactive astrocyte proliferation after cerebral ischemia is unknown. In this study, we cultured rat primary cortical astrocytes and established an oxygen glucose deprivation/reperfusion (OGD/R) model to mimic cerebral ischemia in vivo. Astrocyte proliferation was measured by western blotting for proliferating cell nuclear antigen (PCNA) and by EdU incorporation. We found that OGD/R up-regulated PFKFB3 and PFK1 expression, which was accompanied by reactive astrocyte proliferation. Knockdown of PFKFB3 by siRNA transfection significantly inhibited reactive astrocyte proliferation and lactate release, an indicator of glycolysis. We found that PFKFB3 and PFK1 expression were down-regulated and lactate release was decreased when OGD/R-induced astrocyte proliferation was inhibited by a Cdh1 expressing lentivirus. Thus, reactive astrocyte proliferation can be effectively suppressed by down-regulation of PFKFB3 through control of glycolytic flux, which is downstream of APC/C-Cdh1. PMID- 26498255 TI - Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. AB - Ovarian endometriosis is a recognized risk for infertility and epithelial ovarian cancer, presumably due to iron overload resulting from repeated hemorrhage. To find a clue for early detection and prevention of ovarian endometriosis associated cancer, it is mandatory to evaluate catalytic (labile) ferrous iron (catalytic Fe(II)) and to study iron manipulation in ovarian endometriotic lesions. By the use of tissues from women of ovarian endometriosis as well as endometrial tissue from women with and without endometriosis, we for the first time performed histological analysis and cellular detection of catalytic Fe(II) with a specific fluorescent probe (HMRhoNox-M), and further evaluated iron transport proteins in the human specimens and in co-culture experiments using immortalized human eutopic/ectopic endometrial stromal cells (ESCs) in the presence or absence of epithelial cells (EpCs). The amounts of catalytic Fe(II) were higher in ectopic endometrial stromal cells (ecESCs) than in normal eutopic endometrial stromal cells (n-euESCs) both in the tissues and in the corresponding immortalized ESCs. ecESCs exhibited higher transferrin receptor 1 expression both in vivo and in vitro and lower ferroportin expression in vivo than n-euESCs, leading to sustained iron uptake. In co-culture experiments of ESCs with iron loaded EpCs, ecESCs received catalytic ferrous iron from EpCs, but n-euESCs did not. These data suggest that ecESC play a protective role for cancer-target epithelial cells by collecting excess iron, and that these characteristics are retained in the immortalized ecESCs. PMID- 26498256 TI - Maternal Depressive Symptoms and Attained Size Among Children in the First 2 Years of Life. AB - OBJECTIVE: To evaluate the relation of maternal depressive symptoms with attained size and whether it is stronger for young children in low-income families. METHODS: Secondary analysis was performed of longitudinal data from enrollment and parents surveys from the Healthy Steps for Young Children National Evaluation among 4745 children who made at least one visit to a Healthy Steps site. Length and weight data from medical records were converted to z scores and percentiles for length for age and weight for length at 6, 12, and 24 months using 2000 Centers for Disease Control and Prevention growth standards. Analyses evaluated the relation of maternal depressive symptoms at 2 to 4 months using a modified 14 item Center for Epidemiologic Depression Scale with attained size and child, maternal, and family characteristics. Regression models estimated the relation of symptoms with z scores and logistic regression the relation for short stature (below 10th percentile for length for age), adjusted for covariates. RESULTS: Maternal depressive symptoms were associated with z scores for length for age at 6, 12, and 24 months and short stature at 6 and 24 months for children in low/middle-income families. The z scores at 24 months remained significantly lower for children in low/middle-income families whose mothers reported depressive symptoms, after adjustment for covariates. The odds of short stature were significantly increased at 6 months in the total sample and among low/middle income families for children whose mothers reported symptoms. Other measures of attained size were not associated with depressive symptoms. CONCLUSIONS: The link between maternal symptoms and young children's risk of short stature reinforces recommendations for increased screening for postpartum depressive symptoms and for clinicians to review growth charts with parents for impaired/unfavorable patterns. PMID- 26498257 TI - Children's Environmental Health: A Brief History. AB - BACKGROUND: Children's environmental health (CEH), the branch of pediatrics that studies the influence of the environment on children's health, has grown substantially in the past 3 decades and become an increasingly visible and important component of pediatric medicine. GOALS: To trace the historical origins of CEH; to identify factors responsible for its recent growth. FINDINGS: CEH has historical roots in toxicology, epidemiology, and occupational medicine. It arose in the second half of the 20th century through a melding of insights from pediatric toxicology, nutritional epidemiology, and social science research. Convergent research in these 3 fields has documented children's unique sensitivities to chemical, nutritional, and psychosocial hazards during windows of vulnerability in early development and has shown that early-life exposures can produce disease and disability in childhood and across the life span. Key events in the development of CEH were: 1) formation by the American Academy of Pediatrics in 1957 of a committee on environmental health that has nurtured the growth of the field for 5 decades and evolved into the Council on Environmental Health; 2) observations made in the 1980s that nutritional deficiency in utero increased risk for adult-onset obesity, diabetes, and cardiovascular disease-work that led to the hypothesis of the developmental origins of health and disease; 3) social science research showing that early exposure to psychosocial stress and trauma increases risk for chronic illness; and 4) publication in 1993 by the National Academy of Sciences of a report, Pesticides in the Diets of Infants and Children, which elevated awareness among national policy makers of children's vulnerability to toxic hazards, moved US environmental policy toward protection of children's health, and catalyzed research investment in CEH in the United States and globally. CONCLUSIONS: CEH has made substantial progress but faces emerging challenges, including new chemicals and pesticides; increasing movement of polluting industries to poor countries where environmental and public health protections are few; and global climate change. In the future, CEH will require continued investment in research and education and will need to adopt an increasingly global perspective. PMID- 26498258 TI - Left ventricular lead position, mechanical activation, and myocardial scar in relation to left ventricular reverse remodeling and clinical outcomes after cardiac resynchronization therapy: A feature-tracking and contrast-enhanced cardiovascular magnetic resonance study. AB - BACKGROUND: Late mechanical activation (LMA) and viability in the left ventricular (LV) myocardium have been proposed as targets for LV pacing during cardiac resynchronization therapy (CRT). OBJECTIVE: The purpose of this study was to determine whether an LV lead position over segments with LMA and no scar improves LV reverse remodeling (LVRR) and clinical outcomes after CRT. METHODS: Feature-tracking and late gadolinium enhancement images were analyzed retrospectively in patients with heart failure (HF) (n = 89; mean age 66.8 +/- 10.8 years; LV ejection fraction = 23.1% +/- 9.9%) who underwent cardiovascular magnetic resonance (CMR) scanning before CRT implantation. Lead positions were classified as concordant (no scar and LMA [time to peak systolic circumferential strain]) or nonconcordant (scar and/or no LMA). RESULTS: LVRR occurred in 68% and 24% of patients with concordant and nonconcordant LV lead positions, respectively (P < .001). Over a median of 4.4 years (range 0.1-8.7 years), LV lead concordance predicted cardiac mortality (adjusted odds ratio [aOR] 0.27; 95% confidence interval [CI] 0.12-0.62) and cardiac mortality or HF hospitalizations (aOR 0.26, 95% CI 0.12-0.58). "No scar" in the paced segment predicted cardiac mortality (aOR 0.24; 95% CI 0.11-0.52) and cardiac mortality or HF hospitalizations (adjusted aOR 0.24; 95% CI 0.12-0.49). CONCLUSION: LV lead deployment over nonscarred LMA segments was associated with better LVRR and clinical outcomes after CRT. LVRR was primarily related to LMA, whereas events were primarily related to scar. These findings support the use of late gadolinium enhancement CMR and feature-tracking CMR in guiding LV lead deployment. PMID- 26498259 TI - Flecainide monotherapy for catecholaminergic polymorphic ventricular tachycardia: Perspectives and limitations. PMID- 26498260 TI - Long-term clinical outcomes of focal impulse and rotor modulation for treatment of atrial fibrillation: A multicenter experience. AB - BACKGROUND: New approaches to ablation of atrial fibrillation (AF) include focal impulse and rotor modulation (FIRM). Studies of this technology with short-term follow-up have shown favorable outcomes. OBJECTIVE: The purpose of this study was to characterize the long-term results of FIRM ablation in a cohort of patients treated at 2 academic medical centers. METHODS: All FIRM-guided ablation procedures (n = 43) at UCLA Medical Center and Virginia Commonwealth University Medical Center performed between January 2012 and October 2013 were included for analysis. During AF, FIRM software constructed phase maps from unipolar atrial electrograms to identify putative AF sources. These sites were targeted for ablation, along with pulmonary vein isolation in 77% of patients. RESULTS: AF was paroxysmal in 56%, and 67% had prior AF ablation. All patients had rotors identified (mean 2.6 +/- 1.2 per patient, 77% in LA). Prespecified acute procedural end-point was achieved in 47% of patients (n = 20): AF termination in 4, organization in 7, >10% slowing of AF cycle length in 9. Acute complications occurred in 4 patients (9.3%). At 18 +/- 7 months of follow-up, 37% were free from documented recurrent AF after a 3-month blanking period; 21% were free from documented atrial tachyarrhythmias and off antiarrhythmic drugs. Multivariate analysis did not reveal any significant predictors of AF recurrence, including pattern of AF, acute procedural success, or prior failed ablation. CONCLUSION: Long-term clinical results after FIRM ablation in this cohort of patients showed poor efficacy, different from previously published studies. Randomized studies are needed to evaluate the efficacy and clinical utility of this ablation approach for treating AF. PMID- 26498261 TI - Erythematous soft nodules on both ear helices. PMID- 26498263 TI - The clinical spectrum associated with myelin oligodendrocyte glycoprotein antibodies (anti-MOG-Ab) in Thai patients. AB - BACKGROUND: Myelin oligodendrocyte glycoprotein (anti-MOG) antibody was reported in anti-aquaporin-4 (anti-AQP4) seronegative neuromyelitis optica spectrum disorders (NMOSD) patients. OBJECTIVES: To describe clinical phenotypes associated with anti-MOG. METHODS: Seventy consecutive Thai patients with inflammatory idiopathic demyelinating central nervous system disorders (IIDCD) who were previously anti-AQP4 seronegative were tested for anti-MOG. RESULTS: Anti-MOG was positive in six patients, representing 20.7% of the IIDCD anti-AQP4 seronegative patients with a non-multiple sclerosis phenotype, and most had relapses. All first presented with optic neuritis with good visual recovery after treatment. CONCLUSIONS: Anti-MOG positive patients may have manifestations that mimic NMOSD but differ in their course and prognosis from anti-AQP4 positive NMOSD. PMID- 26498262 TI - IFT-Cargo Interactions and Protein Transport in Cilia. AB - The motile and sensory functions of cilia and flagella are indispensable for human health. Cilia assembly requires a dedicated protein shuttle, intraflagellar transport (IFT), a bidirectional motility of multi-megadalton protein arrays along ciliary microtubules. IFT functions as a protein carrier delivering hundreds of distinct proteins into growing cilia. IFT-based protein import and export continue in fully grown cilia and are required for ciliary maintenance and sensing. Large ciliary building blocks might depend on IFT to move through the transition zone, which functions as a ciliary gate. Smaller, freely diffusing proteins, such as tubulin, depend on IFT to be concentrated or removed from cilia. As I discuss here, recent work provides insights into how IFT interacts with its cargoes and how the transport is regulated. PMID- 26498264 TI - Coincidence of obesity associated with cardio-renal abnormalities in Thais obese population. AB - AIM: To investigate the patterns and relationship among the metabolic syndrome (MS), coronary heart disease (CHD) and kidney function. METHODS: A cross sectional secondary data set of 9359 individuals, age 30-74 years, receiving annual health check-up in 2012 were used in this studied. Identification of MS and CHD development was determined by International Diabetes Federation criteria and Framingham risk score, respectively, while kidney function was assessed by using the estimate glomerulus filtration rate (eGFR) and chronic kidney disease epidemiology (CKD-EPI) formula. RESULTS: The prevalence of MS was 16.1%. The majority pattern of MS in male displayed abnormalities of body mass index (BMI) plus triglyceride and blood pressure (BP). Most of them had high risk of CHD, and kidney function in stage 1 and 2. Furthermore, abnormalities of BMI plus BP and blood glucose were the main components related to high risk of CHD, and stage 1 of kidney function in female. CONCLUSION: This finding showed the cleared pattern of the sequential abnormality factors which potentially use for setting the activity and empowerment team to prevention, promotion, and treatment strategy in MS patients. Particularly, BMI is the first assessment and then follow by blood pressure and blood sugar which could be used as the guideline for reducing MS associated with CHD and kidney disorder in Thai population. PMID- 26498265 TI - Proteasome subunit and opioid receptor gene expression down-regulation induced by paraquat and maneb in human neuroblastoma SH-SY5Y cells. AB - Paraquat (PQ) and maneb (MB) are able to induce neurotoxic effects by promoting alpha-synuclein (alpha-syn) aggregates and altering tyrosine hydroxylase (TH), thus increasing the risk of Parkinson's disease (PD). These pesticides promote neurotoxic effects also by affecting proteasome function that normally regulate protein turnover. We investigated the effects of the two pesticides exposure on multiple targets involved in PD, using SH-SY5Y cells. First, we evaluated TH and alpha-syn protein levels following PQ and MB cell exposure and a significant increase of these protein levels was observed. Subsequently, since a relationship between ubiquitin/proteasome and opioid receptors has been proposed, the effects of pesticides on their gene expression have been investigated. A decrease of beta1 and Rpt3 proteasome subunit mRNA levels, together with the MU and delta opioid receptor down-regulation, was detected. The reported alterations, here simultaneously observed, help to clarify the involvement of multiple biological markers implicated in PD, often separately evaluated. PMID- 26498266 TI - Propolis aqueous extract preserves functional integrity of murine intestinal mucosa after exposure to ionizing radiation. AB - The ability of a specially prepared water propolis extract (PWE) to preserve the functional activity of the intestinal mucosa after radiation exposure was studied. PWE was given orally (650 mg/kg) to rats five days prior to irradiation by 6 Gy and continued for further two days. Rats were sacrificed 24h later, intestinal segments were examined histologically and homogenates were used to assess relevant biochemical parameters reflecting intestinal injury. Irradiation led to a rise in the histological damage score, a rise in tissue TNF-alpha and TBARS, and a decrease in sucrase, alkaline phosphatase, GSH and cholecystokinin as well as a decrease in plasma citrulline. The findings reflect a decrease in intestinal functional activity. PWE preserved the intestinal integrity and largely protected against the changes induced in the histology damage score and all parameters measured, possibly as a result of the antioxidant and anti inflammatory action of its caffeic acid content. PMID- 26498268 TI - Randomized controlled trial of group cognitive behavioral therapy compared to a discussion group for co-morbid anxiety and depression in older adults. AB - BACKGROUND: Co-morbid anxiety and depression in older adults is associated with worse physical and mental health outcomes and poorer response to psychological and pharmacological treatments in older adults. However, there is a paucity of research focused on testing the efficacy of the co-morbid treatment of anxiety and depression in older adults using psychological interventions. Accordingly, the primary objective of the current study was to test the effects of a group cognitive behavior therapy (CBT) program in treating co-morbid anxiety and depression in a sample of older age adults. METHOD: A total of 133 community dwelling participants aged ?60 years (mean age = 67.35, s.d. = 5.44, male = 59) with both an anxiety disorder and unipolar mood disorder, as assessed on the Anxiety Disorder Interview Schedule (ADIS), were randomly allocated to an 11-week CBT group or discussion group. Participants with Mini-Mental State Examination scores <26 were excluded. Participants were assessed pre-treatment, post treatment and at 6 months follow-up on the ADIS, a brief measure of well-being, Geriatric Anxiety Inventory and Geriatric Depression Scale. RESULTS: Both conditions resulted in significant improvements over time on all diagnostic, symptom and wellbeing measures. Significant group * time interaction effects emerged at post-treatment only for diagnostic severity of the primary disorder, mean severity of all anxiety disorders, mood disorders, and all disorders, and recovery rates on primary disorder. CONCLUSION: Group CBT produced faster and sustained improvements in anxiety and depression on diagnostic severity and recovery rates compared to an active control in older adults. PMID- 26498267 TI - Fucoidan ameliorates steatohepatitis and insulin resistance by suppressing oxidative stress and inflammatory cytokines in experimental non-alcoholic fatty liver disease. AB - Fucoidan, a sulfated polysaccharide derived from brown seaweeds, possesses a wide range of pharmacological properties. In the present study, we investigated the therapeutic effect of fucoidan on non-alcoholic fatty liver disease (NAFLD) in rats. Rats were fed a high-fat diet (HFD) for 12 weeks to induce NAFLD. Oral administrations of fucoidan (100mg/kg, orally), metformin (200mg/kg, orally) or the vehicle were started in the last four weeks. Results showed that administration of fucoidan for 4 weeks attenuated the development of NAFLD as evidenced by the significant decrease in liver index, serum liver enzymes activities, serum total cholesterol and triglycerides, fasting serum glucose, insulin, insulin resistance, and body composition index. Further, fucoidan decreased hepatic malondialdehyde as well as nitric oxide concentrations, and concomitantly increased hepatic reduced glutathione level. In addition, the effect of fucoidan was accompanied with significant decrease in hepatic mRNA expressions of tumor necrosis factor-alpha, interleukins-1beta and matrix metalloproteinase-2. Furthermore, histopathological examination confirmed the effect of fucoidan. In conclusion, fucoidan ameliorated the development of HFD induced NAFLD in rats that may be, at least partly, related to its hypolipidemic, insulin sensitizing, antioxidant and anti-inflammatory mechanisms. PMID- 26498269 TI - Wheat protein recognition pattern in tolerant and allergic children. AB - BACKGROUND: Wheat is one of the most common food allergens in early childhood. In contrast to other food allergies, wheat-specific IgE correlates badly with clinical symptoms and relevant components have been identified mostly for wheat depended exercise-induced anaphylaxis. Moreover, a high percentage of patients present with immediate type symptoms but wheat-specific IgE cannot be detected with commercial available systems. OBJECTIVE: We addressed the question whether the IgE recognition pattern between wheat allergic (WA) and clinically tolerant (WT) children differs in order to identify individual proteins useful for component-resolved diagnostics. METHODS: Sera of 106 children with suspected wheat allergy, of whom 44 children had clinical relevant wheat allergy and 62 were tolerant upon oral food challenge, were analyzed for wheat-specific IgE using the ImmunoCap system as well as immunoblots against water and salt soluble, and water-insoluble protein fractions. 40 randomly selected sera were analyzed for specific IgE to omega5-gliadin. RESULTS: Sixty-three percent of the WT and 86% of the WA children were sensitized to wheat with >0.35 kUA /l in ImmunoCAP analysis. We could confirm the role of alpha-, beta-, gamma-, and omega-gliadins, and LMW glutenin subunits as major allergens and found also IgE binding to a broad spectrum of water- and salt-soluble protein bands. It is of great importance that wheat allergic and tolerant patients showed IgE binding to the same protein bands. WT and WA did not significantly differ in levels of omega5 gliadin-specific IgE. CONCLUSIONS & CLINICAL RELEVANCE: Children with challenge proven clinical relevant food allergy and tolerant ones had a similar spectrum of IgE binding to the same protein bands. These findings imply that component resolved diagnostics might not be helpful in the diagnostic work-up of wheat allergy. PMID- 26498270 TI - To dry or not too dry: should we be more tolerant of stable subretinal fluid in patients receiving anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration? PMID- 26498272 TI - Printing Tablets with Fully Customizable Release Profiles for Personalized Medicine. AB - Personalizing the release profiles of drugs is important for different people with different medical and biological conditions. A technically simple and low cost method to fabricate fully customizable tablets that can deliver drugs with any type of release profile is described. The customization is intuitively straightforward: the desired profile can simply be "drawn" and printed by a 3D printer. PMID- 26498273 TI - Caregiver Expressed Emotion and Psychiatric Symptoms in African-Americans with Schizophrenia: An Attempt to Understand the Paradoxical Relationship. AB - Expressed emotion (EE) is a family environmental construct that assesses how much criticism, hostility, and/or emotional over-involvement a family member expresses about a patient (Hooley, Annual Review of Clinical Psychology, 2007, 3, 329). Having high levels of EE within the family environment has generally been associated with poorer patient outcomes for schizophrenia and a range of other disorders. Paradoxically, for African-American patients, high-EE may be associated with a better symptom course (Rosenfarb, Bellack, & Aziz, Journal of Abnormal Psychology, 2006, 115, 112). However, this finding is in need of additional support and, if confirmed, clarification. In line with previous research, using a sample of 30 patients with schizophrenia and their primary caregivers, we hypothesized that having a caregiver classified as low-EE would be associated with greater patient symptom severity. We also aimed to better understand why this pattern may exist by examining the content of interviews taken from the Five-Minute Speech Sample. Results supported study hypotheses. In line with Rosenfarb et al. (2006), having a low-EE caregiver was associated with greater symptom severity in African-American patients. A content analysis uncovered some interesting patterns that may help elucidate this finding. Results of this study suggest that attempts to lower high-EE in African Americans may, in fact, be counterproductive. PMID- 26498274 TI - Qualitative evaluation of a novel contingency management-related intervention for patients receiving supervised injectable opioid treatment. AB - AIM: To evaluate a novel contingency management (CM)-related intervention for people experiencing complex drug problems, thereby increasing understanding of CM implementation in real-world settings. Objectives are to provide new insights into (i) how context influences intervention delivery; (ii) aspects of intervention delivery that influence outcomes; and (iii) intervention outcomes. DESIGN: Qualitative realist evaluation of a novel CM-related intervention: conditional budgets (CB). SETTING: Supervised injectable opioid treatment (IOT) clinic in England (May 2014-March 2015). PARTICIPANTS: Twenty IOT clinic patients (14 men; six women); 10 IOT clinic staff (seven men; three women). MEASUREMENTS: Semi-structured interviews systematically coded relating to knowledge and views of the intervention, experiences of delivering/receiving the intervention, and effectiveness of the intervention. INTERVENTION: Personal budgets provided to patients who reduced their supervised IOT while demonstrating ongoing stability. FINDINGS: (i) Contextual factors influencing intervention delivery included patient motivation; clarity of intervention information; prior trust in the treatment system; patient and staff involvement in intervention design; stability of the treatment setting. (ii) Aspects of delivery influencing outcomes included transparency of the eligibility criteria, rules and operating processes; rule enforcement; continued verbal information about the intervention; speed of incentive processing and receipt. (iii) Reduced drug use was difficult to attribute to CBs, as patients who did well were those most motivated to change before the intervention started. Unintended outcomes were positive (improved patient psychological wellbeing, staff job satisfaction, staff/patient relationships) and negative (patient relapse, increased staff work-load, tensions in clinic relationships). CONCLUSIONS: A 'qualitative realist' evaluation of a contingency management intervention to help address complex substance use disorder problems suggests that the programmes need to have stakeholder input, implement consistent eligibility criteria, rules and processes and be introduced into stable treatment settings where relationships are trusting and patients and staff feel secure. PMID- 26498275 TI - Sacral neuromodulation for the treatment of neurogenic lower urinary tract dysfunction caused by multiple sclerosis: a single-centre prospective series. AB - BACKGROUND: Sacral neuromodulation is well established in the treatment of refractory, non-neurogenic lower urinary tract dysfunction, but its efficacy and safety in patients with lower urinary tract dysfunction of neurological origin is unclear. Only few case series have been reported for multiple sclerosis. We prospectively evaluated the efficacy and safety of sacral neuromodulation in patients with multiple sclerosis. METHODS: Seventeen patients (13 women, 4 men) treated with sacral neuromodulation for refractory neurogenic lower urinary tract dysfunction caused by multiple sclerosis were prospectively enrolled (2007-2011). Patients had to have stable disease and confirmed neurogenic lower urinary tract dysfunction. Voiding variables, adverse events, and subjective satisfaction were assessed. RESULTS: Sixteen (94 %) patients had a positive test phase with a >70 % improvement. After implantation of the pulse generator (InterStim II), the improvement in voiding variables persisted. At 3 years, the median voided volume had improved significantly from 125 (range 0 to 350) to 265 ml (range 200 to 350) (p < 0.001), the post void residual from 170 (range 0 to 730) to 25 ml (range 0 to 300) (p = 0.01), micturition frequency from 12 (range 6 to 20) to 7 (range 4 to 12) (p = 0.003), and number of incontinence episodes from 3 (range 0 to 10) to 0 (range 0 to 1) (p = 0.006). The median subjective degree of satisfaction was 80 %. Only two patients developed lack of benefit. No major complications occurred. CONCLUSIONS: Chronic sacral neuromodulation promises to be an effective and safe treatment of refractory neurogenic lower urinary tract dysfunction in selected patients with multiple sclerosis. PMID- 26498276 TI - Monitoring the John Cunningham virus throughout natalizumab treatment in multiple sclerosis patients. AB - BACKGROUND AND PURPOSE: Progressive multifocal leukoencephalopathy (PML) cases have arisen amongst multiple sclerosis patients treated with natalizumab. Our objective was to gain a better understanding of the mechanisms that underlie the John Cunningham virus (JCV) infection which causes PML. METHODS: A study was made of (i) the quarterly JCV DNA levels in peripheral blood mononuclear cells (PBMCs), serum and urine samples in 100 multiple sclerosis patients during their natalizumab treatment (3-39 months), (ii) the association between human leukocyte antigen (HLA) class II and the previous viral detection and (iii) the identification of the JCV variants in those patients suspected of having PML. RESULTS: (i) JCV DNA in PBMCs and/or serum was detected in 23% of our cohort. Patients with an intermittent JCV excretion in urine had a significant increase of the viral load and prevalence in this compartment during natalizumab treatment. (ii) The frequency of the DRB1*07/DQA1*02:01/DQB1*02:02 haplotype tended to be higher in patients with detectable versus undetectable JCV DNA in PBMCs (P(corrected) = 0.108). (iii) The variants in PBMCs and serum of the non PML patient matched the archetype. In the patient with non-fatal PML, the archetype and the same neurotropic variant in PBMCs, serum and cerebrospinal fluid was identified at the time PML was diagnosed, whereas in the patient with a worse PML prognosis, four neurotropic variants in the three previous compartments were found by the PML diagnosis. CONCLUSIONS: The detection of the neurotropic variant in blood during natalizumab treatment could be critical in the prevention of the development of severe PML, since this variant appears simultaneously with the clinical symptoms of PML and mutates quickly. PMID- 26498277 TI - Deep brain stimulation exacerbates hypokinetic dysarthria in a rat model of Parkinson's disease. AB - Motor symptoms of Parkinson's disease (PD) follow the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) treats some parkinsonian symptoms, such as tremor, rigidity, and bradykinesia, but may worsen certain medial motor symptoms, including hypokinetic dysarthria. The mechanisms by which DBS exacerbates dysarthria while improving other symptoms are unclear and difficult to study in human patients. This study proposes an animal model of DBS-exacerbated dysarthria. We use the unilateral, 6-hydroxydopamine (6-OHDA) rat model of PD to test the hypothesis that DBS exacerbates quantifiable aspects of vocalization. Mating calls were recorded from sexually experienced male rats under healthy and parkinsonian conditions and during DBS of the subthalamic nucleus. Relative to healthy rats, parkinsonian animals made fewer calls with shorter and less complex vocalizations. In the parkinsonian rats, putatively therapeutic DBS further reduced call frequency, duration, and complexity. The individual utterances of parkinsonian rats spanned a greater bandwidth than those of healthy rats, potentially reducing the effectiveness of the vocal signal. This utterance bandwidth was further increased by DBS. We propose that the parkinsonism associated changes in call frequency, duration, complexity, and dynamic range combine to constitute a rat analog of parkinsonian dysarthria. Because DBS exacerbates the parkinsonism-associated changes in each of these metrics, the subthalamic stimulated 6-OHDA rat is a good model of DBS-induced hypokinetic dysarthria in PD. This model will help researchers examine how DBS alleviates many motor symptoms of PD while exacerbating parkinsonian speech deficits that can greatly diminish patient quality of life. PMID- 26498278 TI - Prognostic significance of FAM3C in esophageal squamous cell carcinoma. AB - BACKGROUND: Family with sequence similarity 3, member C (FAM3C) has been identified as a novel regulator in epithelial-mesenchymal transition (EMT) and metastatic progression. However, the role of FAM3C in esophageal squamous cell carcinoma (ESCC) remains unexplored. The purpose of present study is to illustrate the role of FAM3C in predicting outcomes of patients with ESCC. METHODS: FAM3C expression was measured in ESCC tissues and the matched adjacent nontumorous tissues by quantitative real-time RT-PCR and Western blot analysis. The relationship between FAM3C expression and prognosis of ESCC patients was further evaluated by univariate and multivariate regression analyses. Univariate and multivariate analyses of the prognostic factors were performed using Cox proportional hazards model. RESULTS: The FAM3C mRNA expression was remarkably upregulated in ESCC compared with their nontumor counterparts (P < 0.001). In addition, high expression of FAM3C was significantly associated with pT stage (P = 0.014) , pN stage (P = 0.026) and TNM stage (P = 0.003). Kaplan-Meier analysis showed that the 7-year overall survival rate in the group with high expression of FAM3C was poorer than that in low expression group (32.0 versus 70.9 %; P < 0.001). Univariate and multivariate analyses demonstrated that FAM3C was an independent risk factor for overall survival. Moreover, Stratified analysis revealed that FAM3C expression could differentiate the prognosis of patients in early clinical stage (TNM stage I-II). CONCLUSIONS: FAM3C expression was dramatically increased in ESCC and might serve as a valuable prognostic indicator for ESCC patients after surgery. PMID- 26498279 TI - Lessons learned from the ESPN/ERA-EDTA Registry. AB - End-stage renal disease (ESRD) in children is a medically challenging condition. Due to its rarity and special features, methodologically sound collaborative studies are required. In 2007, a new European registry of pediatric renal replacement therapy (RRT), the ESPN/ERA-EDTA Registry, was launched. In recent years, the Registry has provided comprehensive data on incidence, prevalence, patient characteristics, RRT modalities, and mortality in pediatric ESRD, along with relevant insights into cardiovascular risk, anemia, nutrition and growth, transplantation outcomes, and rare diseases. In this review, we describe the study design and structure underlying the ESPN/ERA-EDTA Registry, summarize the major research findings from more than 20 publications, and discuss current limitations and the future challenges to overcome. PMID- 26498280 TI - Impact of the highly active antiretroviral therapy era on the epidemiology of primary HIV-associated thrombocytopenia. AB - BACKGROUND: Primary HIV-associated thrombocytopenia (PHAT) typically improves with highly active antiretroviral therapy (HAART); however, cases continue to occur. Data comparing the epidemiology of PHAT between the pre-HAART and HAART eras are limited. We retrospectively examined the incidence of PHAT over 28 years in the US Military HIV Natural History Study (NHS) from 1986 to 2013. RESULTS: Subjects had a nadir platelet count <100 * 10(9)/l with no other identifiable cause. Time periods were categorized as pre-HAART (1986-1995), early HAART (1996 2001), and later HAART (2002-2013). Incidence, demographic data, and CD4 count were compared across the three eras. A generalized estimating equations model was used to assess any association of platelet count and HIV viral load in cases diagnosed during the HAART eras. 218 participants met the case definition. 86.2 % of cases occurred prior to 2002. The incidence of PHAT per 1000 person-years of follow-up was 16.3, 4.6, and 1.9 during pre-HAART, early HAART and later HAART eras respectively. CD4 cell counts were significantly higher in the HAART eras at the time of thrombocytopenia (p < 0.001). Of patients diagnosed after 1996, 96.4 % were viremic within six months preceding the platelet nadir and over half were antiretroviral naive. Viral load (per log10 copies/ml) inversely correlated with platelet count throughout the HAART eras (p < 0.0001). CONCLUSIONS: The incidence of PHAT has markedly decreased in the HAART era. However, viremic individuals, including those with healthy CD4 cell counts, may be at risk. Achieving viral suppression as early as possible may decrease the incidence further. PMID- 26498281 TI - A novel stem cell culture model of recurrent glioblastoma. AB - Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults with average disease relapse at 9 months and median survival rarely extending beyond 15 months. Brain tumor stem cells (BTSCs) have been implicated in not only initiating GBM but also conferring resistance to therapy. However, it is not clear whether the BTSC population that initiates tumor growth is also responsible for GBM recurrence. In this study, we have developed a novel in vitro treatment model to profile the evolution of primary treatment-naive GBM BTSCs through chemoradiotherapy. We report that our in vitro model enriched for a CD15+/CD133- BTSC population, mirroring the phenotype of BTSCs in recurrent GBM. We also show that in vitro treatment increased stem cell gene expression as well as self-renewal capacity of primary GBMs. In addition, the chemoradiotherapy refractory gene signature obtained from gene expression profiling identified a hyper-aggressive subtype of glioma. The delivery of in vitro chemoradiotherapy to primary GBM BTSCs models several aspects of recurrent GBM biology, and could be used as a discovery and drug-screening platform to uncover new biological drivers and therapeutic targets in GBM. PMID- 26498283 TI - Patterns of resource utilization and cost for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer in Europe. AB - BACKGROUND: Healthcare resource utilization in breast cancer varies by disease characteristics and treatment choices. However, lack of clarity in guidelines can result in varied interpretation and heterogeneous treatment management and costs. In Europe, the extent of this variability is unclear. Therefore, evaluation of chemotherapy use and costs versus hormone therapy across Europe is needed. METHODS: This retrospective chart review (N = 355) examined primarily direct costs for chemotherapy versus hormone therapy in postmenopausal women with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer across 5 European countries (France, Germany, The Netherlands, Belgium, and Sweden). RESULTS: Total direct costs across the first 3 treatment lines were approximately ?10,000 to ?14,000 lower for an additional line of hormone therapy-based treatment versus switching to chemotherapy-based treatment. Direct cost difference between chemotherapy-based and hormone therapy-based regimens was approximately ?1900 to ?2500 per month. Chemotherapy-based regimens were associated with increased resource utilization (managing side effects; concomitant targeted therapy use; and increased frequencies of hospitalizations, provider visits, and monitoring tests). The proportion of patients taking sick leave doubled after switching from hormone therapy to chemotherapy. CONCLUSIONS: These results suggest chemotherapy is associated with increased direct costs and potentially with increased indirect costs (lower productivity of working patients) versus hormone therapy in HR+, HER2- advanced breast cancer. PMID- 26498282 TI - Angiotensin-converting enzyme 2 inhibits high-mobility group box 1 and attenuates cardiac dysfunction post-myocardial ischemia. AB - High-mobility group box 1 (HMGB1) triggers and amplifies inflammation cascade following ischemic injury, and its elevated levels are associated with adverse clinical outcomes in patients with myocardial infarction (MI). Angiotensin converting enzyme 2 (ACE2), a key member of vasoprotective axis of the renin angiotensin system (RAS), regulates cardiovascular functions and exerts beneficial effects in cardiovascular disease. However, the association between HMGB1 and ACE2 has not been studied. We hypothesized that overexpression of ACE2 provides cardioprotective effects against MI via inhibiting HMGB1 and inflammation. ACE2 knock-in (KI) mice and littermate wild-type (WT) controls were subjected to either sham or coronary artery ligation surgery to induce MI. Heart function was assessed 4 weeks after surgery using echocardiography and Millar catheterization. Tissues were collected for histology and analysis of the expression of HMGB1, RAS components, and inflammatory cytokines. ACE2 in the heart of the ACE2 KI mice was 58-fold higher than WT controls. ACE2-MI mice exhibited a remarkable preservation of cardiac function and reduction of infarct size in comparison to WT-MI mice. Notably, ACE2 overexpression significantly reduced the MI-induced increase in apoptosis, macrophage infiltration, and HMGB1 and proinflammatory cytokine expression (TNF-alpha and IL-6). Moreover, in an in vitro study, ACE2 activation prevented the hypoxia-induced cell death and upregulation of HMGB1 in adult cardiomyocytes. This protective effect is correlated with downregulation of HMGB1 and downstream proinflammatory cascades, which could be useful for the development of novel treatment for ischemic heart disease. PMID- 26498284 TI - Donor-derived tuberculosis after solid organ transplantation in two patients and a staff member. AB - Because of global mobility and migration resulting in a growing diversity of the donor pool, the risk for donor-derived tuberculosis in solid organ transplant recipients becomes more and more relevant, even in countries with a low overall tuberculosis incidence. Here, we describe a case series of donor-derived tuberculosis in 2 of 3 solid organ transplant recipients and one medical staff member in Germany resulting in the death of one recipient. This case series highlights the relevance of this topic to clinicians. It advocates for a better communication between organ procurement organizations and transplant centers regarding donor information and transplant recipient outcome. Furthermore, it underpins the necessity for a standardized critical incident reporting system in the german transplant system to improve short- and long-term recipient's safety, health and survival. PMID- 26498285 TI - Necrotizing fasciitis due to Serratia marcescens: case report and review of the literature. AB - BACKGROUND: Necrotizing fasciitis is a severe, life-threatening infection. Serratia marcescens, a Gram-negative bacterium, is an extremely rare cause of necrotizing fasciitis. METHODS: A case of S. marcescens necrotizing fasciitis is described, and a comprehensive review of the literature (1966-2015) of monomicrobial cases due to this organism performed. RESULTS: We report the first case of S. marcescens necrotizing fasciitis in the setting of calciphylaxis associated with end-stage renal disease. A comprehensive review of the literature of S. marcescens necrotizing fasciitis is provided to enhance the awareness of this increasingly recognized infection, and to provide a concise summary of risk factors, treatment, and outcome. CONCLUSIONS: Our case and review highlight the potential risk factors for S. marcescens necrotizing fasciitis, including underlying renal disease and open wounds, and demonstrate the emergence of this organism as a cause of severe, life-threatening soft tissue infections. PMID- 26498287 TI - The impact of an experimentally induced increase in arterial blood pressure on left ventricular twist mechanics. AB - The effects of isometric hand-grip exercise (IHG) coupled with a period of postexercise circulatory occlusion (OCC; known to sustain exercise-induced increases in blood pressure while facilitating a decrease in heart rate) on left ventricular (LV) twist mechanics was examined. Two-dimensional speckle-tracking echocardiography was used to assess LV apical and basal rotation and LV twist in 19 healthy participants (23 +/- 2 years old) at rest, during 3 min of IHG (performed at 40% maximal voluntary contraction) and 3 min of OCC immediately following IHG. The IHG elicited significant (P < 0.001) increases in mean arterial pressure (rest, 91 +/- 1 mmHg; IHG, 122 +/- 2 mmHg) and heart rate (rest, 65 +/- 2 beats min(-1); IHG, 91 +/- 4 beats min(-1)). Mean arterial pressure remained elevated during OCC (116 +/- 2 mmHg; P < 0.001 versus rest), whereas heart rate returned to resting levels (68 +/- 3 beats min(-1); P = 0.159 versus rest). Apical rotation decreased significantly (P < 0.01) by 10 +/- 5% during IHG and 21 +/- 4% during OCC, whereas basal rotation remained unchanged from rest. Left ventricular twist decreased from rest to IHG (12 +/- 5%; P = 0.015) and OCC (21 +/- 4%; P = 0.001), whereas a decrease in LV untwist rate was observed only during OCC. An increase in blood pressure generated by IHG, and maintained by a period of OCC, impairs aspects of LV twist mechanics. Postexercise circulatory occlusion isolated the effect of the arterial blood pressure rise (from heart rate), magnifying the impairment of LV twist mechanics when compared with IHG, whilst also negatively impacting LV relaxation. We propose that a protocol using isometric exercise followed by circulatory occlusion provides a method for studying the effects of blood pressure changes on LV twist mechanics. PMID- 26498286 TI - Changes in global gene expression of Vibrio parahaemolyticus induced by cold- and heat-stress. AB - BACKGROUND: Vibrio (V.) parahaemolyticus causes seafood-borne gastro-intestinal bacterial infections in humans worldwide. It is widely found in marine environments and is isolated frequently from seawater, estuarine waters, sediments and raw or insufficiently cooked seafood. Throughout the food chain, V. parahaemolyticus encounters different temperature conditions that might alter metabolism and pathogenicity of the bacterium. In this study, we performed gene expression profiling of V. parahaemolyticus RIMD 2210633 after exposure to 4, 15, 20, 37 and 42 degrees C to describe the cold and heat shock response. METHODS: Gene expression profiles of V. parahaemolyticus RIMD 2210633 after exposure to 4, 15, 20, 37 and 42 degrees C were investigated via microarray. Gene expression values and RT-qPCR experiments were compared by plotting the log2 values. Moreover, volcano plots of microarray data were calculated to visualize the distribution of differentially expressed genes at individual temperatures and to assess hybridization qualities and comparability of data. Finally, enriched terms were searched in annotations as well as functional-related gene categories using the Database for Annotation, Visualization and Integrated Discovery. RESULTS: Analysis of 37 degrees C normalised transcriptomics data resulted in differential expression of 19 genes at 20 degrees C, 193 genes at 4 degrees C, 625 genes at 42 degrees C and 638 genes at 15 degrees C. Thus, the largest number of significantly expressed genes was observed at 15 and 42 degrees C with 13.3 and 13%, respectively. Genes of many functional categories were highly regulated even at lower temperatures. Virulence associated genes (tdh1, tdh2, toxR, toxS, vopC, T6SS-1, T6SS-2) remained mostly unaffected by heat or cold stress. CONCLUSION: Along with folding and temperature shock depending systems, an overall temperature-dependent regulation of expression could be shown. Particularly the energy metabolism was affected by changed temperatures. Whole genome gene expression studies of food related pathogens such as V. parahaemolyticus reveal how these pathogens react to stress impacts to predict its behaviour under conditions like storage and transport. PMID- 26498288 TI - Vertebrobasilar artery fenestration with moyamoya disease. PMID- 26498289 TI - Repeated sessions of transcranial direct current stimulation for treatment of chronic subjective tinnitus: a pilot randomized controlled trial. AB - Subjective tinnitus is an auditory phantom sensation characterized by the perception of sound in the absence of an identifiable external source. This distressing audiological symptom can severely affect the quality of life. Transcranial direct current stimulation (tDCS) is a noninvasive technique that can induce short-term relief in tinnitus in some patients. The purpose of this pilot double-blind randomized controlled trial was to investigate whether repeated application of anodal tDCS over left temporoparietal area could induce long-lasting relief in patients with chronic tinnitus. Twenty-two patients with chronic tinnitus for at least 6 months were randomly allocated into two groups and received five sessions of anodal (N = 11) or sham (N = 11) stimulation in five consecutive days. A current intensity of 2 mA for 20 min was used for anodal stimulation. Outcomes were assessed using Persian version of tinnitus handicap inventory (THI), loudness and distress visual analog scale (VAS) scores and clinical global impression (CGI) scale. The trial is registered at the Iranian Registry of Clinical Trials (IRCT) with the reference ID of IRCT2014082018871N1. No statistically significant difference was found between anodal and sham stimulation regarding either immediate or long-lasting effects over the 2 weeks follow-up period. Deterioration of symptoms and alteration in tinnitus characteristics were reported by a few patients. There were no significant long term beneficial effects following tDCS of the left temporoparietal area. PMID- 26498291 TI - The protective role of DJ-1 in ultraviolet-induced damage of human skin: DJ-1 levels in the stratum corneum as an indicator of antioxidative defense. AB - DJ-1 is a multifunctional protein associated with Parkinson's disease and plays a significant role in protecting nerve cells from oxidative stress. DJ-1 is expressed in the skin, although its function there is unknown. In this study, we investigated DJ-1 function in keratinocytes. DJ-1 was induced by H2O2 exposure and UV irradiation in keratinocytes. DJ-1 knockdown with small interfering RNA (siRNA) increased reactive oxygen species (ROS) and lactate dehydrogenase (LDH) release after UVB irradiation, suggesting that DJ-1 reduces ROS and might protect skin cells from UV damage in vitro. To investigate the in vivo role of DJ-1 in the skin, we determined DJ-1 levels in human stratum corneum samples obtained by the tape-stripping method. DJ-1 levels in the stratum corneum (scDJ-1) correlated with total antioxidant capacity. We also examined the effect of scDJ-1 on changes in skin after UVB irradiation. DJ-1 was elevated in SC from the upper arm 1 to 2 weeks after UVB irradiation. One day after UVB irradiation, L* (brightness) and a* (redness) values, indicators of skin color, were altered regardless of scDJ-1 expression. However, these values recovered more quickly in subjects with high scDJ-1 expression than in those with low scDJ-1 expression. These data suggest that DJ-1 in skin plays a significant role in protection against UV radiation and oxidative stress, and that DJ-1 levels in the SC might be an indicator of antioxidative defense against UV-induced damage. PMID- 26498290 TI - Immunoadsorber for specific apheresis of autoantibodies in the treatment of bullous pemphigoid. AB - Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with autoantibodies against two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. As the pathogenic relevance of antibodies against the immunodominant NC16A domain of BP180 has been clearly demonstrated, specific removal of these antibodies should be a rational therapeutic approach. Here, we evaluated three recombinant forms of bacterially produced BP180 NC16A, a monomer, trimer, and tetramer, together with different matrices for their efficacy to specifically adsorb autoantibodies from BP plasma samples. An adsorber consisting of NC16A trimer coupled to NHS-activated Sepharose 4 Fast Flow revealed satisfying adsorption rates and a high specificity. The NC16A-trimer adsorber was regenerable and autoclavable. It has the potential to be used for specific immunoadsorption to treat severe and refractory BP and other pemphigoid diseases associated with BP180 NC16A reactivity. PMID- 26498292 TI - Japanese Cedar (Cryptomeria japonica) pollen allergen induces elevation of intracellular calcium in human keratinocytes and impairs epidermal barrier function of human skin ex vivo. AB - Cry j1 is the major peptide allergen of Japanese cedar (Sugi), Cryptomeria japonica. Since some allergens disrupt epidermal permeability barrier homeostasis, we hypothesized that Cry j1 might have a similar effect. Intracellular calcium level in cultured human keratinocytes was measured with a ratiometric fluorescent probe, Fura-2 AM. Application of Cry j1 significantly increased the intracellular calcium level of keratinocytes, and this increase was inhibited by trypsin inhibitor or a protease-activated receptor 2 (PAR-2) antagonist. We found that Cry j1 itself did not show protease activity, but application of Cry j1 to cultured keratinocytes induced a rapid (within 30 s) and transient increase of protease activity in the medium. This transient increase was blocked by trypsin inhibitor or PAR-2 antagonist. The effect of Cry j1 on transepidermal water loss (TEWL) of cultured human skin was measured in the presence and absence of a trypsin inhibitor and PAR-2 antagonist. Cry j1 significantly impaired the barrier function of human skin ex vivo, and this action was blocked by co-application of trypsin inhibitor or PAR-2 antagonist. Our results suggested that interaction of Cry j1 with epidermal keratinocytes leads to the activation of PAR-2, which induces elevation of intracellular calcium and disruption of barrier function. Blocking the interaction of Cry j1 with epidermal keratinocytes might ameliorate allergic reaction and prevent disruption of epidermal permeability barrier homeostasis. PMID- 26498293 TI - Neuron anatomy structure reconstruction based on a sliding filter. AB - BACKGROUND: Reconstruction of neuron anatomy structure is a challenging and important task in neuroscience. However, few algorithms can automatically reconstruct the full structure well without manual assistance, making it essential to develop new methods for this task. METHODS: This paper introduces a new pipeline for reconstructing neuron anatomy structure from 3-D microscopy image stacks. This pipeline is initialized with a set of seeds that were detected by our proposed Sliding Volume Filter (SVF), given a non-circular cross-section of a neuron cell. Then, an improved open curve snake model combined with a SVF external force is applied to trace the full skeleton of the neuron cell. A radius estimation method based on a 2D sliding band filter is developed to fit the real edge of the cross-section of the neuron cell. Finally, a surface reconstruction method based on non-parallel curve networks is used to generate the neuron cell surface to finish this pipeline. RESULTS: The proposed pipeline has been evaluated using publicly available datasets. The results show that the proposed method achieves promising results in some datasets from the DIgital reconstruction of Axonal and DEndritic Morphology (DIADEM) challenge and new BigNeuron project. CONCLUSION: The new pipeline works well in neuron tracing and reconstruction. It can achieve higher efficiency, stability and robustness in neuron skeleton tracing. Furthermore, the proposed radius estimation method and applied surface reconstruction method can obtain more accurate neuron anatomy structures. PMID- 26498296 TI - Erratum: CHEK2 1100DELC germline mutation: a frequency study in hereditary breast and colon cancer Brazilian families. AB - This corrects the article DOI: 10.1590/S0004-28032012000400008. PMID- 26498295 TI - Excess mortality attributable to chronic kidney disease. Results from the PIRP project. AB - Although chronic kidney disease (CKD) has a high mortality rate, the estimation of CKD mortality burden in the general population may be challenging because CKD is not always listed as a cause of death in mortality registries. To overcome this limitation, relative survival was used to estimate the excess mortality attributable to CKD as compared to the general population using data of patients registered in the Prevenzione Insufficienza Renale Progressiva (PIRP) registry since 2005 and were followed up until 2013. Relative survival was the ratio of survival observed in CKD patients to the expected survival of the general population. Multivariate parametric survival analysis was used to identify factors predicting excess mortality. The relative survival of CKD patients at 9 years was 0.708. Survival was significantly lower in CKD patients with cardiovascular comorbidities, proteinuria, diabetes, anemia and high phosphate levels and in advanced CKD stages, males, older patients and those who underwent dialysis. Relative survival is a viable method to determine mortality attributable to CKD. Study limitations are that patients are representative only of CKD patients followed by nephrologists and that our follow-up duration may be relatively short as a model for mortality. PMID- 26498294 TI - Glomerular diseases and cancer: evaluation of underlying malignancy. AB - Onconephrology is an emerging medical subspecialty focused on the numerous interconnections between cancer and kidney diseases. Patient with malignancies commonly experience kidney problems including acute kidney injury, tumor lysis syndrome, fluid and electrolyte disorders and chronic kidney disease, often as a consequence of the anti-cancer treatment. Conversely, a number of glomerulopathies, tubulopathies and vascular renal diseases can early signal the presence of an underlying cancer. Furthermore, the administration of immunosuppressive drugs, especially cytotoxic drugs and calcineurin inhibitors, may strongly impair the immune response increasing the risk of cancer. The objective of this review article is to: (i) discuss paraneoplastic glomerular disease, (ii) review cancer as an adverse effect of immunosuppressive agents used to treat glomerulopathies, and (iii) in the absence of international approved guidelines, propose a screening program based on expert opinion aimed at guiding nephrologists to early detect malignancies during their clinical practice. PMID- 26498297 TI - alpha-Tocopherol/Gallic Acid Cooperation in the Protection of Galactolipids Against Ozone-Induced Oxidation. AB - The protective ability of alpha-tocopherol (TOH) and gallic acid (GA) acting simultaneously at the moment of oxidizer application was evaluated by determination of galactolipid layers' oxidation degree. Addition of GA resulted in a significant decrease of ozone-derived radicals shifting the threshold of lipid sensitivity by an amount approximately corresponding to the GA intake in bulk reaction with ozone. TOH presence in lipid layers results in a change of the role of GA which additionally may be involved in the reduction of tocopheroxyl radical formed during oxidation. This leads to a decrease in effectiveness of GA in diminishing the amount of ozone radicals. Such an effect was not observed for mixed layers containing galactolipid and pre-oxidized tocopherol where the ozone threshold level was associated with a stoichiometry of GA + O3 reaction. It was concluded that probably subsequent transformations of tocopheroxyl radical to less reactive forms prevent its reaction with GA the entire quantity of which is used for radicals scavenging. This result shows the role of time parameter in systems where substrates are engaged in various reactions taking place simultaneously. The inactivation of 1,1-diphenyl-2-picrylhydrazyl radical by studied antioxidants in homogeneous system confirmed observations made on the basis of lipid layer properties indicating their antagonistic action (at least at studied conditions). Formation of layers in post-oxidation situation did not depend whether tocopherol was oxidized during oxidation of lipid/tocopherol mixture or was introduced as pre-oxidized. This may be interpreted as indication that products of tocopherol oxidation may stabilize lipid layers. PMID- 26498298 TI - Maize hybrids derived from GM positive and negative segregant inbreds are compositionally equivalent: any observed differences are associated with conventional backcrossing practices. AB - In this study, we show that compositional differences in grain harvested from genetically modified (GM) maize hybrids derived from near-isogenic trait-positive and trait-negative segregant inbreds are more likely related to backcrossing practices than to the GM trait. To demonstrate this, four paired GM trait positive (NK603: herbicide tolerance) and trait-negative near-isogenic inbred male lines were generated. These were crossed with two different females (testers) to create a series of trait-positive and trait-negative hybrid variants. The hypothesis was, that compositional variation within the hybrid variants would reflect differences associated with backcrossing practices and provide context to any observed differences between GM and non-GM hybrids. The F1 hybrids, as well as corresponding conventional comparator hybrids, were grown concurrently at four field sites across the United States during the 2013 season. Grain was harvested for compositional analysis; proximates (protein, starch, and oil), amino acids, fatty acids, minerals, tocopherols (alpha-, delta-, gamma-), beta-carotene, phytic acid, and raffinose were measured. Statistical analysis showed that within each hybrid tester set, there were very few significant (p < 0.05) differences between the paired trait-positive and trait-negative hybrids or between the conventional comparators and the trait-positive or trait-negative hybrids. Assessments of the magnitudes of differences and variance component analysis highlighted that growing location, and the tester used in hybrid formation, had a markedly greater effect on composition than did the GM trait. Significantly, for each tester set, compositional differences within the trait positive and trait-negative hybrid variants were greater than differences between the GM and non-GM comparators. Overall, GM trait insertion is not intrinsically a meaningful contributor to compositional variation, and observed differences between GM and non-GM comparators typically reflect incidental changes associated with conventional breeding practices. These results contribute to ongoing discussions on the relevance of negative segregants as comparators in GM assessments. PMID- 26498299 TI - Violence in general practice: a gendered risk? AB - This article focuses on the extent to which violence against family doctors in England is experienced in gendered terms. It draws on data from two studies: a postal survey of 1,300 general practitioners (GPs) (62% response rate) and in depth interviews with 26 doctors who have been assaulted or threatened; and 13 focus groups with primary care teams and 19 in-depth interviews with GPs who had expressed an interest in the topic of violence against doctors. Most GPs, regardless of gender, reported receiving verbal abuse over the last two years, often interpreted as a consequence of declining deference to professionals, while actual physical assaults and threats were much rarer and more likely to be reported by men. Overall, women GPs were much more likely to express concern about violence and to take personal precautions, although younger male GPs working in inner-city practices also had high levels of concern. The study shows how some aspects of family doctors' work has been organised on gendered lines and how these contribute to the differences in experience of violence. We suggest that the increasing proportion of women among family doctors may have implications for these, often tacit, organisational routines. PMID- 26498302 TI - Zygosity testing should be encouraged for all same-sex twins: FOR: A genetic test is essential to determine zygosity. PMID- 26498303 TI - Zygosity testing should be encouraged for all same-sex twins: AGAINST: Benefit of this knowledge should be weighed against potential pitfalls. PMID- 26498304 TI - The morbidly adherent placenta--a continuing diagnostic and management challenge. PMID- 26498305 TI - Authors' reply re: Stabilising the caesarean rate: which target population? PMID- 26498306 TI - Re: Stabilising the caesarean rate: which target population? PMID- 26498307 TI - Re: Pelvic organ prolapse and incontinence 15-23 years after first delivery: a cross-sectional study. PMID- 26498308 TI - Re: The Hayman uterine compression suture. PMID- 26498309 TI - Authors' reply re: Pelvic organ prolapse and incontinence 15-23 years after first delivery: a cross-sectional study. PMID- 26498310 TI - Re: The Hayman uterine compression suture. PMID- 26498312 TI - Corrigenda. PMID- 26498311 TI - A report from #BlueJC: 'Can induction of labour reduce risks to my baby?'. PMID- 26498313 TI - Blair Bell Research Society. PMID- 26498314 TI - Evidence Suggesting that the Buccal and Zygomatic Branches of the Facial Nerve May Contain Parasympathetic Secretomotor Fibers to the Parotid Gland by Means of Communications from the Auriculotemporal Nerve. AB - BACKGROUND: The auriculotemporal nerve is one of the peripheral nerves that communicates with the facial nerve. However, the function of these communications is poorly understood. Details of how these communications form and connect with each other are still unclear. In addition, a reliable anatomical landmark for locating these communications during surgery has not been sufficiently described. METHODS: Microdissection was performed on 20 lateral hemifaces of 10 soft embalmed cadavers to investigate facial-auriculotemporal nerve communications with emphasis on determining their function. The auriculotemporal nerve was identified in the retromandibular space and traced towards its terminations. The communicating branches were followed and the anatomical relationships to surrounding structures observed. RESULTS: The auriculotemporal nerve is suspended above the maxillary artery in the dense retromandibular fascia behind the mandibular ramus. It forms a knot and fans out, providing multiple branches in all directions in the sagittal plane. Inferiorly, it connects the maxillary periarterial plexus, while minute branches supply the temporomandibular joint anteriorly. The larger branches mainly communicate with the branches of the temporofacial division of the facial nerve, and the auricular branches enter the fascia of the auricular cartilage posteriorly. The temporal branches and occasionally the zygomatic branches arise superiorly to distribute within the temporoparietal fascia. The auriculotemporal nerve forms the parotid retromandibular plexus through two types of communication. It sends one to three branches to join the zygomatic and buccal branches of the facial nerve at the branching area of the temporofacial division. It also communicates with the periarterial plexus of the superficial temporal and maxillary arteries. This plexus continues anteriorly along the branches of the facial nerve and the periarterial plexus of the transverse facial artery as the parotid periductal autonomic plexus, supplying the branches of the parotid duct within the loop of the two main divisions of the parotid gland. CONCLUSION: A single cutaneous zygomatic branch arising from the auriculotemporal nerve in some specimens, the intraparotid communications with the zygomatic and the buccal trunks of the facial nerve, the retromandibular communications with the superficial temporal maxillary periarterial plexuses, and the periductal autonomic plexus between the loop of the two main facial divisions lead to the suggestion that these communications of the auriculotemporal nerve convey the secretomotor to the zygomatic and buccal branches of the facial nerve. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26498315 TI - Prohibitin promotes apoptosis of promyelocytic leukemia induced by arsenic sulfide. AB - Arsenic sulfide (As4S4), an oral form of arsenic agent, has been shown to have similar efficacy and safety to intravenous arsenic trioxide in the treatment of acute promyelocytic leukemia (APL). The aim of the present study was to identify proteins modulated by As4S4 and to determine their involvement in the apoptotic pathway. We used comparative proteomic analysis to screen and identify the proteins that were differentially expressed with As4S4 treatment. Prohibitin (PHB) was selected for its diverse role and its increased expression in the cells treated with As4S4. To examine whether PHB play a functional role, two clones of PHB-knockdown and PHB-overexpression were generated by transfection of NB4-R1 with vectors containing PHB gene sequences. In comparison with parental NB4-R1 cells, PHB overexpression showed an increase in baseline apoptosis and an enhanced response in As4S4-induced apoptosis. PML-RARalpha fusion protein was found to be reduced with PHB-overexpression, and following As4S4 treatment, a greater reduction of promyelocytic leukemia-retinoic acid receptor-alpha (PML RARalpha) fusion protein was seen in PHB-overexpression than that in parental cells. Consistently, PHB knockdown presented with a significant reduction in As4S4-induced apoptosis and a lesser degree of PML-RARalpha degradation. The results indicate the antitumor activity of PHB in promoting apoptosis of APL cells. PMID- 26498316 TI - Alcohol, drug and other prior crimes and risk of arrest in handgun purchasers: protocol for a controlled observational study. AB - BACKGROUND AND OBJECTIVE: Alcohol abuse is common in the USA and is a well established risk factor for violence. Other drug use and criminal activity are risk factors as well and frequently occur together with alcohol abuse. Firearm ownership is also common; there are >50 million firearm owners in the USA. This study assesses the relationships between alcohol and drug abuse and future violence among firearm owners, which no prior research has done. DESIGN AND STUDY POPULATION: This records-based retrospective cohort study will involve all persons who legally purchased handguns in California in 2001-approximately 116 000 individuals-with follow-up through the end of 2013. METHODS: The principal exposures include prior convictions for alcohol-related and drug-related offenses. The primary outcome measure is an arrest following handgun purchase for a violent Crime Index offense: homicide, rape, robbery or aggravated assault. Subjects will be considered at risk for outcome events for only as long as their residence in California can be established independently of outcome events. Covariates include individual characteristics (eg, age, sex, criminal history, firearm purchase history) and community characteristics (eg, demographics, socioeconomic measures, firearm ownership and alcohol outlet density). We will employ survival analytic methods, expressing effects as HRs. DISCUSSION: The results of this large-scale study are likely to be generalisable and to have important implications for violence prevention policies and programmes. PMID- 26498317 TI - Down-regulation of expression of retinoid acid-related orphan receptor C (RORC) in systemic lupus erythematosus. AB - CONTEXT: Retinoic acid-related orphan receptor C (RORC), the key factor orchestrating the transcription of genes encoding interleukin 17, plays a critical role in the regulation of inflammatory responses. OBJECTIVE: The objective of this study was to analyze the expression of RORC in the peripheral blood of patients with systemic lupus erythematosus (SLE) for a better understanding of the pathogenesis of SLE especially in relation to disease activity and clinical and biochemical findings. METHODS: The study included 24 patients with SLE and a control group of 18 healthy gender- and age-matched individuals. Evaluation of the level of expression of RORC mRNA was performed by real-time polymerase chain reaction. RESULTS: The results showed that patients with SLE had lower RORC gene expression levels compared with healthy subjects that were not correlated with disease activity. The down-regulation of RORC was significantly lower in patients with lupus nephritis in remission than active lupus nephritis and nonrenal patients. CONCLUSIONS: The findings suggest that RORC plays a significant role in the dysregulated immune response associated with SLE. Deciphering the intricate regulatory network and the target genes of RORC will help unravel new specific treatments for SLE. PMID- 26498318 TI - Psychological maladjustment of Asian and African peacekeepers in Liberia and its related factors. AB - This study aimed to investigate the maladjustment of Asian (Bangladeshi, Pakistani) and African (Nigerian, Namibian, Ghanaian) peacekeepers and its major influence factors. By random cluster sampling, 300 Asian peacekeepers and 271 African peacekeepers were administered the military psychological maladjustment scale (MPMS) and risk factors questionnaire. Investigation at Day 7 and Day 120 into the peacekeeping deployment period indicated that MPMS total score and factor scores of the Asian peacekeepers were significantly lower than those of the African peacekeepers (p < .01). The total score and each factor score of MPMS of the Asian peacekeepers significantly decreased (p < .01); for the African peacekeepers, only the factor score of emotional disorder of MPMS significantly decreased (p < .05). Stepwise regression analysis showed that the education duration was the influence factor for the emotional disorder factor score in the Asian peacekeepers, and the two factors were positively correlated. Age, military service duration, education duration and marital status were the major influence factors for the MPMS factors of the African peacekeepers, among which age was negatively correlated with the total score and each factor score, and military service duration, education duration and marital status were positively related. We conclude that the Asian peacekeepers are more adaptable and resilient than the African peacekeepers. Education duration was the major influence factor for Emotional Disorder in the Asian peacekeepers. The major influence factors for maladjustment in the African peacekeepers were age, military service duration, education duration and marital status. PMID- 26498319 TI - Printable Ultrathin Metal Oxide Semiconductor-Based Conformal Biosensors. AB - Conformal bioelectronics enable wearable, noninvasive, and health-monitoring platforms. We demonstrate a simple and straightforward method for producing thin, sensitive In2O3-based conformal biosensors based on field-effect transistors using facile solution-based processing. One-step coating via aqueous In2O3 solution resulted in ultrathin (3.5 nm), high-density, uniform films over large areas. Conformal In2O3-based biosensors on ultrathin polyimide films displayed good device performance, low mechanical stress, and highly conformal contact determined using polydimethylsiloxane artificial skin having complex curvilinear surfaces or an artificial eye. Immobilized In2O3 field-effect transistors with self-assembled monolayers of NH2-terminated silanes functioned as pH sensors. Functionalization with glucose oxidase enabled d-glucose detection at physiologically relevant levels. The conformal ultrathin field-effect transistor biosensors developed here offer new opportunities for future wearable human technologies. PMID- 26498320 TI - Phosphoinositide 3-kinase/Akt pathway is involved in pingyangmycin-induced growth inhibition, apoptosis and reduction of invasive potential in EOMA mouse hemangioendothelioma cells. AB - Pingyangmycin (PYM), a glycopeptide antibiotic, has been recommended as a stand treatment for hemangioma. However, the underlying mechanisms of its anti-tumor effects have remained elusive. The purpose of the present study was to explore the effects of PYM on the biological behavior of the EOMA mouse hemangioendothelioma cell line and investigate the possible mechanisms. The effects of PYM on EOMA cell viability were determined by an MTT assay, apoptosis was evaluated by Annexin V/propidium iodide staining and flow cytometric analysis, and cell invasion ability was determined using a Transwell invasion assay. In order to investigate the underlying mechanism of action of PYM, the expression of angiogenic signaling proteins was determined by western blot analysis. PYM treatment (0.5-500 ug/ml) inhibited cell growth in a time- and dose dependent manner. PYM at 100 ug/ml significantly induced apoptosis and reduced the invasive ability of EOMA cells. Effects of PYM on cell viability, apoptosis and invasion ability were completely blocked by co-treatment with phosphoinositide 3-kinase (PI3K) activator insulin-like growth factor-1 (IGF-1). Furthermore, treatment with PYM reduced the expression of PI3K and phosphorylated Akt. In conclusion, the present study indicated that the PI3K/Akt pathway is likely to be involved in the anti-cancer effects of PYM on EOMA cells. PMID- 26498321 TI - Acidithiobacillus ferriphilus sp. nov., a facultatively anaerobic iron- and sulfur-metabolizing extreme acidophile. AB - The genus Acidithiobacillus includes three species that conserve energy from the oxidation of ferrous iron, as well as reduced sulfur, to support their growth. Previous work, based on multi-locus sequence analysis, identified a fourth group of iron- and sulfur-oxidizing acidithiobacilli as a potential distinct species. Eleven strains of 'Group IV' acidithiobacilli, isolated from different global locations, have been studied. These were all shown to be obligate chemolithotrophs, growing aerobically by coupling the oxidation of ferrous iron or reduced sulfur (but not hydrogen) to molecular oxygen, or anaerobically by the oxidation of reduced sulfur coupled to ferric iron reduction. All strains were mesophilic, although some were also psychrotolerant. Strain variation was also noted in terms of tolerance to extremely low pH and to elevated concentrations of transition metals. One strain was noted to display far greater tolerance to chloride than reported for other iron-oxidizing acidithiobacilli. All of the strains were able to catalyse the oxidative dissolution of pyrite and, on the basis of some of the combined traits of some of the strains examined, it is proposed that these may have niche roles in commercial mineral bioprocessing operations, such as for low temperature bioleaching of polysulfide ores in brackish waters. The name Acidithiobacillus ferriphilus sp. nov. is proposed to accommodate the strains described, with the type strain being M20T ( = DSM 100412T = JCM 30830T). PMID- 26498322 TI - Genetic Transmission of Disease: A Legal Harm? AB - This paper considers whether existing law could potentially be used to criminalize the transmission of genetic disease. The paper argues that even if an offence could be made out, the criminal law should not be involved in this context for many reasons, including the need to protect reproductive liberty and pregnant women's rights. The paper also examines whether there might be scope for civil claims between reproductive partners for a 'failure to warn' of potential genetic harm and argues there are strong policy grounds for resisting such claims. If such a duty were to exist, there might, in the future, be scope for a child to bring a claim under the Congenital Disabilities (Civil Liability Act) 1976. Such a claim could be for the failure by the child's father to warn her mother, which in turn led to the loss of opportunity to have treatment in utero which could have prevented the disability. It is suggested that the same arguments which supported granting maternal immunity under the Act would also support paternal immunity and that, therefore the issue of the lack of paternal immunity under the Act should be revisited. PMID- 26498323 TI - Achieving Global Health and Justice: Practical and Philosophical Challenges. PMID- 26498324 TI - Temporal Trends of Cardiac Chambers Function with Trastuzumab in Human Epidermal Growth Factor Receptor II-Positive Breast Cancer Patients. AB - BACKGROUND: Trastuzumab has substantially improved overall survival and reduced the risk of disease recurrence in patients with human epidermal growth factor receptor type II (HER-II)-positive breast cancer. However, this benefit may be at the increased risk of cardiotoxicity. We aimed to explore the early subclinical left and right ventricular as well as atrial dysfunction, in trastuzumab-treated patients with HER-II-positive breast cancer, using velocity vector imaging. METHODS: Echocardiography images were acquired in 50 patients with HER-II positive breast cancer undergoing trastuzumab therapy. All patients had baseline and 3-6 months and 12-15 months of follow-up echocardiograms after initiation of trastuzumab therapy. Subendocardial borders of all the cardiac chambers were traced from the apical views to obtain volumetric and deformation indices. RESULTS: Mean age was 60 +/- 13 years. Left ventricular (LV) ejection fraction as well as conventional indices of right ventricular (RV) function did not change with trastuzumab. The RV peak systolic global longitudinal strain (GLepsilon) significantly decreased (-24.53 +/- 6.03 vs. -21.28 +/- 5.11 vs. -21.84 +/- 5.15, baseline vs. first and second follow-ups, P = 0.01). LV peak systolic GLepsilon was reduced by 1.19 at early follow-up (P < 0.05). Left atrial reservoir and booster pump functions as well as right atrial reservoir function were reduced through follow-up as well. CONCLUSIONS: The RV exhibited greater change in strain after trastuzumab treatment when compared to the LV. Atria function was reduced by trastuzumab as well. The repercussion of these findings and their potential implication will warrant further study. PMID- 26498325 TI - Synthetic pathway optimization for improved 1,2,4-butanetriol production. AB - 1,2,4-Butanetriol (BT) is an important non-natural chemical with a variety of industrial applications. Identifying the bottlenecks for BT biosynthesis is expected to contribute to improving the efficiency of this process. In this work, we first constructed a prototype strain for BT production by assembling a four step synthetic pathway and disrupting the competing pathways for xylose in Escherichia coli BW25113. Using this prototype strain, we conducted systematic fine-tuning of the pathway enzyme expression level to identify the potential bottlenecks and optimize the BT biosynthesis. Production conditions were also optimized by exploring the effects of temperature, pH and cell density on BT titer. BT production was increased by 4.3-fold from the prototype strain, achieved a final titer of 1.58 g/L with a yield of 7.9% after 72-h biotransformation. PMID- 26498326 TI - Nucleosome alterations caused by mutations at modifiable histone residues in Saccharomyces cerevisiae. AB - Nucleosome organization exhibits dynamic properties depending on the cell state and environment. Histone proteins, fundamental components of nucleosomes, are subject to chemical modifications on particular residues. We examined the effect of substituting modifiable residues of four core histones with the non-modifiable residue alanine on nucleosome dynamics. We mapped the genome-wide nucleosomes in 22 histone mutants of Saccharomyces cerevisiae and compared the nucleosome alterations relative to the wild-type strain. Our results indicated that different types of histone mutation resulted in different phenotypes and a distinct reorganization of nucleosomes. Nucleosome occupancy was altered at telomeres, but not at centromeres. The first nucleosomes upstream (-1) and downstream (+1) of the transcription start site (TSS) were more dynamic than other nucleosomes. Mutations in histones affected the nucleosome array downstream of the TSS. Highly expressed genes, such as ribosome genes and genes involved in glycolysis, showed increased nucleosome occupancy in many types of histone mutant. In particular, the H3K56A mutant exhibited a high percentage of dynamic genomic regions, decreased nucleosome occupancy at telomeres, increased occupancy at the +1 and -1 nucleosomes, and a slow growth phenotype under stress conditions. Our findings provide insight into the influence of histone mutations on nucleosome dynamics. PMID- 26498327 TI - Modeling and verification of process parameters for the production of tannase by Aspergillus oryzae under submerged fermentation using agro-wastes. AB - Tannase production by Aspergillus oryzae using various agro-wastes as substrates by submerged fermentation was studied in this research. The microbe was isolated from degrading corn kernel obtained from the corn fields at Tiruchengode, India. The microbial identification was done using 18S rRNA gene analysis. The agro wastes chosen for the study were pomegranate rind, Cassia auriculata flower, black gram husk, and tea dust. The process parameters chosen for optimization study were substrate concentration, pH, temperature, and incubation period. During one variable at a time optimization, the pomegranate rind extract produced maximum tannase activity of 138.12 IU/mL and it was chosen as the best substrate for further experiments. The quadratic model was found to be the effective model for prediction of tannase production by A. oryzae. The optimized conditions predicted by response surface methodology (RSM) with genetic algorithm (GA) were 1.996% substrate concentration, pH of 4.89, temperature of 34.91 degrees C, and an incubation time of 70.65 H with maximum tannase activity of 138.363 IU/mL. The confirmatory experiment under optimized conditions showed tannase activity of 139.22 IU/mL. Hence, RSM-GA pair was successfully used in this study to optimize the process parameters required for the production of tannase using pomegranate rind. PMID- 26498328 TI - Assessing the influence of biofilm surface roughness on mass transfer by combining optical coherence tomography and two-dimensional modeling. AB - Imaging and modeling are two major approaches in biofilm research to understand the physical and biochemical processes involved in biofilm development. However, they are often used separately. In this study we combined these two approaches to investigate substrate mass transfer and mass flux. Cross-sectional biofilm images were acquired by means of optical coherence tomography (OCT) for biofilms grown on carriers. A 2D biofilm model was developed incorporating OCT images as well as a simplified biofilm geometry serving as structural templates. The model incorporated fluid flow, substrate transfer and biochemical conversion of substrates and simulated the hydrodynamics surrounding the biofilm structure as well as the substrate distribution. The method allowed detailed analysis of the hydrodynamics and mass transfer characteristics at the micro-scale. Biofilm activity with respect to substrate fluxes was compared among different combinations of flow, substrate availability and biomass density. The combined approach revealed that higher substrate fluxes at heterogeneous biofilm surface under two conditions: pure diffusion and when high flow velocity along the biofilms surface renders the whole liquid-biofilm interface to be highly active. In-between the two conditions the substrate fluxes across the surface of smooth biofilm geometry were higher than that of the heterogeneous biofilms. PMID- 26498329 TI - Assessment of Serum Trace Elements in Diarrheic Yaks (Bos grunniens) in Hongyuan, China. AB - Diarrhea is one of the main causes of animal deaths especially in neonatal calves. The objective of this study was to investigate the blood serum for cobalt (Co), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), Molybdenum (Mo), selenium (Se), and zinc (Zn) concentrations in yak serum samples by inductively coupled plasma mass spectrometry (ICP-MS) from 35 yaks consisting of 10 healthy and 25 diarrheic ones. Our observations indicated that the concentrations of Mn, Zn, and Fe in yak affected with diarrhea had statistically significant reduced levels as compared to the control group (P < 0.05). The mean concentration of Cu in blood serum of diarrheic yaks was found significantly higher than the normal ones (P < 0.05). The Mn and Zn in the serum of diarrheic groups were observed significantly different (P < 0.05) with different ages. These findings can provide for some valuable information for the investigation on relationship between trace elements in the serum of normal and diarrheic yaks. PMID- 26498330 TI - Interactions of genetic variants reveal inverse modulation patterns of dopamine system on brain gray matter volume and resting-state functional connectivity in healthy young adults. AB - Different genotypic combinations of COMT and DRD2 can generate multiple subgroups with different levels of dopamine signaling. Its modulations on brain properties can be investigated by analyzing the combined gene effects of COMT and DRD2. However, the inherent association between modulation patterns of the dopamine system on structural and functional properties of the brain remains unknown. In 294 healthy young adults, we investigated both additive and non-additive interactions of COMT and DRD2 on gray matter volume (GMV) and resting-state functional connectivity (rsFC) using a voxel-based analysis. We found a significant non-additive COMT * DRD2 interaction in the right dorsal anterior cingulate cortex (dACC), exhibiting an inverted U-shape modulation by dopamine signaling. We also found a significant non-additive COMT * DRD2 interaction in the rsFC between the right dACC and precuneus, displaying a U-shape modulation by dopamine signaling. Moreover, this rsFC was negatively correlated with the GMV of the right dACC. Although the additive interaction did not pass corrections for multiple comparisons, we also found a trend towards an inverse modulation pattern and a negative correlation between the GMV and rsFC of the right inferior frontal gyrus. No genotypic differences were detected in any assessments of the cognition, mood and personality. These findings suggest that healthy young adults without optimal dopamine signaling may maintain their normal behavioral performance via a functional compensatory mechanism in response to structural deficit due to genetic variation. PMID- 26498331 TI - [Positive impact on the Expanded Program on Immunization when sending call-back SMS through a Computerized Immunization Register, Bobo Dioulasso (Burkina Faso)]. AB - The impact of a Computerized Immunization Register (CIR) on Expanded Program on Immunization (EPI), with sending SMS to parents before immunization sessions, has never been studied in sub-Saharan Africa. The objective of this study is to measure EPI quickness and completeness of vaccinations after sending call-back SMS to parents through CIR put in place in a health center. In a health center, chosen at random (Colma 1) in the city of Bobo Dioulasso, Burkina Faso, West Africa, mothers, at first EPI session, if they had a mobile phone available at hand or in her surrounding, were randomized for receiving, or not, a call-back SMS before following EPI sessions, after child registration on a Francophone CIR (Siloxane's Intervax (c)). Mothers, which were sent SMS and did not correctly followed sessions were asked through mobile phone why their child was late for EPI. 523 newborns were included in the study, with 253 whose parents were sent SMS, and 268 being informed of sessions only by ordinary methods. At second EPI session at 2 months of age, there was a statistical significant increase of coverage for children whose parents received SMS (p<0.001). Quickness to come also to this session was significantly shorter when parents received SMS (p=0.03). At third EPI session at 3 months of age, attendance to EPI for children whose parents were sent SMS was significantly better (p<0.001). Quickness to come to this session was shorter for children with SMS (p=0.02). At fourth EPI session at 4 months of age, attendance for children with SMS was significantly better for children whose parents were sent SMS (p<0.001). Quickness to come to this session was better but not significantly different (p=0.49). Out of 101 children registered as late for EPI sessions in Colma 1 CIR, even with call-back SMS, 19 (19%) parents could not be reached on the telephone. 31/82 (38%) mothers had shifted for EPI to a more proximate vaccination center (Colma 2), and 5 (6%) to private or civil servants clinic. 14/82 (17%) mothers had been travelling far from health center. Ten (12%) admitted neglect of EPI sessions. Two (2%) children had deceased, and one mother did not come back to Colma 1 after her child's AEFI. One child has been dismissed two times of vaccination following recommendation not to open a measles multi-dose vial for a single child, and did not come back. Of 523 children registered in CIR, 77 (14.7%) could not be found in the paper registers of Colma 1. Quickness and completeness for EPI is increased by sending SMS with help of CIR. An official number should be given for each child registered in CIR, consulted by health staff admitting children in urgency, allowing EPI vaccinations completion. With CIR safeguards, CIR should replace paper registers and should be used to send EPI reports by internet at central levels, helping MOH coverage determination and MAPI surveillance. The fall of coverage due to restriction policy not to open a multidose vial for a single child is low. Health staff should institute telephone call-back for badly immunized children registered on CIR and incorporate in it, with SMS call-back, pregnant women, to better complete prenatal sessions and tetanus vaccination. PMID- 26498332 TI - Resveratrol ameliorates hepatic steatosis and inflammation in methionine/choline deficient diet-induced steatohepatitis through regulating autophagy. AB - BACKGROUND: Non-alcoholic steatohepatitis (NASH) is one of the leading causes of chronic liver disease that can progress to liver fibrosis, cirrhosis and eventually hepatocellular carcinoma. Resveratrol, a naturally occurring phytoalexin, is believed to have therapeutic effects on hepatic steatosis. However, the effect of resveratrol on NASH and the underlying mechanism is not fully illustrated. In the present study, we aimed to exam the effect of resveratrol on methionine/choline-deficient (MCD) diet or medium-induced hepatic steatosis, oxidation and inflammation, and to explore the possible mechanism. METHODS: C57BL/6 mice and AML12 cells were treated with MCD alone or in combination with different concentrations of resveratrol (100 mg/kg/day or 250 mg/kg/day for mice and 25 MUmol/L, 50 MUmol/L, or 100 MUmol/L for cells). Levels of aminotransferases (ALT), interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) were measured, concentrations of triglyceride (TG) and thiobarbituric acid reactive substances (TBARs) were determined, and expressions of proteins involved in autophagy were analyzed. RESULTS: The results indicate that MCD diet or medium induced NASH in mouse and AML12 cell, which was confirmed by the elevated levels of TG, TNF-alpha, IL-1beta, IL-6, ALT and TBARS in mice serum or cell culture medium. Resveratrol administration slowed down NASH progression, decreased the levels of ALT, TG, TBARS, IL-1beta, IL-6, downregulated mRNA expressions of TNF-alpha, IL-1beta, IL-6, and regulated the expressions of proteins involved in autophagy, both in vitro and in vivo. However, an autophagical inhibitor significantly impaired the protective role of resveratrol on liver injury and inflammation. CONCLUSIONS: Resveratrol can attenuate hepatic steatosis and inflammation in MCD-induced NASH by regulating autophagy. Thus, resveratrol may be a promising agent for inhibiting lipid accumulation and inflammatory processes associated with NASH. PMID- 26498333 TI - Effects of recombinant lipoxygenase on the rheological properties of dough and the quality of noodles. AB - BACKGROUND: The effects of purified recombinant lipoxygenase (ana-rLOX) on the rheological properties of dough and the quality of noodles made from wheat flour with low protein content (Yanmai 15) were studied. RESULTS: The addition of ana rLOX increased dough stability time, decreased the degree of softening within 12 min, enhanced the resistance to extension, and increased the extensibility with 135 min of resting time. The mechanical spectra of the dough showed an increase in both storage modulus (G') and loss modulus (G") with increasing ana-rLOX levels. The L(*) values of the noodle sheets increased by 2.34 compared with the control after storing for 1 h at room temperature. The textural parameters of noodles improved after ana-rLOX addition, including hardness, gumminess, chewiness and springiness. The wheat flour treated with the ana-rLOX had a higher cooking yield and lower cooking loss for the resulting noodles. The scanning electron microscopy results revealed that gluten was formed in the noodle samples that were treated with ana-rLOX. CONCLUSION: In this study, ana-rLOX was applied to noodles during the noodle-making process, and both dough rheological characteristics and noodle quality were improved. (c) 2015 Society of Chemical Industry. PMID- 26498334 TI - Tale of a hairy tail: Rapunzel Syndrome. PMID- 26498337 TI - Evaluation of a home treatment program for cold hypersensitivity using a classical conditioning procedure in patients with hand and arm injuries. AB - STUDY DESIGN: Case series. INTRODUCTION: A home treatment program using a classical conditioning procedure to decrease cold hypersensitivity has potential to reduce symptoms. PURPOSE: To evaluate a home treatment program for cold hypersensitivity using a classical conditioning procedure in patients who are cold hypersensitive after hand and arm injuries. METHODS: A series of 22 patients followed a classical conditioning procedure consisting of exposing the body to cold outdoor temperatures and immersing the hands in warm water, every other day, for five weeks. The McCabe Cold Sensitivity Severity scale (CSS) was used to measure cold hypersensitivity twice before treatment, at four weeks, and at one year after treatment; Likert scales was used for the patients ratings of improvements. A cold stress test was performed to evaluate rewarming capacity in injured fingers. RESULTS: From the 20 patients, who returned questionnaires at all assessment points, 9 reported a small and three reported a moderate improvement in cold hypersensitivity after treatment. There was a trend toward improvement in the CSS (median 36; interquartile range--19 to 60) and in the rewarming pattern of fingers that were initially slow to rewarm. The improvements were sustained or increased at one-year follow-up. CONCLUSION: These preliminary results suggest that the classical conditioning procedure to treat cold hypersensitivity has potential and should be further explored in a trial with more rigorous design. PMID- 26498335 TI - Prognostic value of cardiac biomarkers in the risk stratification of syncope: a systematic review. AB - The role of cardiac biomarkers in risk stratification of syncope is unclear. We undertook a systematic review to assess their predictive value for short-term major adverse cardiovascular events (MACE). We conducted a systematic review using MEDLINE, EMBASE, DARE and Cochrane databases from inception to July 2014. We included studies involving adult syncope patients that evaluated cardiac biomarker levels for risk stratification during acute management and excluded case reports, reviews and studies involving children. Primary outcome (MACE) included death, cardiopulmonary resuscitation, myocardial infarction (MI), structural heart disease, pulmonary embolism, significant hemorrhage or cardiac procedural interventions. Secondary outcome analysis assessed for prediction of MI, cardiac syncope and death. Two reviewers extracted patient-level data based on the cut-off reported. Pooled sensitivities and specificities were calculated using patient-level data. A total of 1862 articles were identified, and 11 studies with 4246 patients were included. Studies evaluated 3 biomarkers: contemporary troponin (2693 patients), natriuretic peptides (1353 patients) and high-sensitive troponin (819 patients). The pooled sensitivities and specificities for MACE were: contemporary troponin 0.29 (95 % CI 0.24, 0.34) and 0.88 (95 % CI 0.86, 0.89); natriuretic peptides 0.77 (95 % CI 0.69, 0.85) and 0.73 (95 % CI 0.70, 0.76); high-sensitive troponin 0.74 (95 % CI 0.65, 0.83) and 0.65 (95 % CI 0.62, 0.69), respectively. Natriuretic peptides and high-sensitive troponin showed good diagnostic characteristics for both primary and secondary outcomes. Natriuretic peptides and high-sensitive troponin might be useful in risk stratification. PMID- 26498338 TI - Knockdown of eukaryotic translation initiation factor 4E suppresses cell growth and invasion, and induces apoptosis and cell cycle arrest in a human lung adenocarcinoma cell line. AB - Eukaryotic translation initiation factor 4E (eIF4E) was shown to be upregulated in malignant human tumors. To assess the effect of downregulation of eIF4E on the proliferation and invasiveness of a human lung adenocarcinoma cell line, a short hairpin (sh)RNA targeting eIF4E was constructed and transfected into A549 human lung adenocarcinoma cells. The expression of eIF4E was determined by reverse transcription-quantitative polymerase chain reaction and western blotting. Cell viability was assessed using a Cell Counting kit-8, and apoptosis levels and cell cycle distribution were assessed by flow cytometry. Invasiveness was assessed using Transwell chambers. Transfection of the A549 cells with eIF4E targeting shRNA reduced the mRNA and protein expression levels of eIF4E by >70% 48 and 72 h following transfection, and eIF4E targeting shRNA-transfected cells were significantly less viable compared with the cells transfected with scrambled shRNA. The rate of apoptosis was also significantly increased, significantly more cells were in the G0/G1 phase and fewer were in the S phase, indicating cell cycle arrest. The fraction of transfected cells migrating across Transwell inserts were also reduced. In conclusion, inhibition of eIF4E suppressed cell growth and invasion, induced apoptosis and cell cycle arrest, suggesting that eIF4E may be a potential therapeutic target in lung adenocarcinoma. PMID- 26498339 TI - Automatic aortic root landmark detection in CTA images for preprocedural planning of transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation is currently a well-established minimal invasive treatment option for patients with severe aortic valve stenosis. CT Angiography is used for the pre-operative planning and sizing of the prosthesis. To reduce the inconsistency in sizing due to interobserver variability, we introduce and evaluate an automatic aortic root landmarks detection method to determine the sizing parameters. The proposed algorithm detects the sinotubular junction, two coronary ostia, and three valvular hinge points on a segmented aortic root surface. Using these aortic root landmarks, the automated method determines annulus radius, annulus orientation, and distance from annulus plane to right and left coronary ostia. Validation is performed by the comparison with manual measurements of two observers for 40 CTA image datasets. Detection of landmarks showed high accuracy where the mean distance between the automatically detected and reference landmarks was 2.81 +/- 2.08 mm, comparable to the interobserver variation of 2.67 +/- 2.52 mm. The mean annulus to coronary ostium distance was 16.9 +/- 3.3 and 17.1 +/- 3.3 mm for the automated and the reference manual measurements, respectively, with a mean paired difference of 1.89 +/- 1.71 mm and interobserver mean paired difference of 1.38 +/- 1.52 mm. Automated detection of aortic root landmarks enables automated sizing with good agreement with manual measurements, which suggests applicability of the presented method in current clinical practice. PMID- 26498340 TI - Segmental assessments of coronary plaque morphology and composition by virtual histology intravascular ultrasound and fractional flow reserve. AB - Fractional flow reserve (FFR) is an index for identifying functionally significant stenotic lesions. A FFR value of <=0.75 is considered clinically significant and indicative of physiological ischemia. Focal lesions with 30-80 % stenosis by angiography with lesion lengths of less than 20 mm were selected from left anterior descending arteries of 74 patients. The analysis for the total lesion was processed first, and then each lesion was divided into three segments to assess the each segment. Data on plaque geometry and composition of two FFR groups, FFR <= 0.75 and FFR > 0.75, were compared by total and segmental analysis. Lesions with FFR <= 0.75 had more fibrofatty tissue (13.5 +/- 7.4 vs. 10.2 +/- 6.5%, p = 0.05) and less dense calcium (7.2 +/- 5.3 vs. 11.9 +/- 7.5%, p = 0.01) compared to lesions with FFR > 0.75. The content of necrotic core in mid segments was higher compared to proximal and distal segments (22.9 +/- 10.6, 20.2 +/- 10.9, 17.1 +/- 11.2%, respectively, p = 0.032) in lesions with FFR > 0.75 but the difference was less obvious in lesions with FFR <= 0.75 (17.9 +/- 9.9, 18.7 +/- 9.9, 15.8 +/- 9.0%, respectively, p = 0.533). Coronary lesions with FFR > 0.75 have larger content of dense calcium and slightly less fibrofatty tissue compared to lesions with FFR <= 0.75. While segmental plaque compositions for each segment show noticeable variations in lesions with FFR > 0.75 such as high concentrations of necrotic core in mid segment, these differences in each segment become obscure in FFR <= 0.75 and are evenly distributed across the lesion. PMID- 26498341 TI - "I wanted to communicate my feelings freely": a descriptive study of creative responses to enhance reflection in palliative medicine education. AB - BACKGROUND: The recent growth of arts and humanities in medical education shows recognition that these disciplines can facilitate a breadth of thinking and result in personal and professional growth. However creative work can be a challenge to incorporate into a busy curriculum. Offering the option of creative media as a way of reflecting is an example of how this can occur. This study aimed to examine the medical student response to being given this option to explore a visit to a patient in a hospice. METHODS: This was a mainly qualitative study. In the 2012 academic programme, the class of 86 students were given the option of using a creative medium to explore their responses to both the visit and their developing communication skills. Students were required to write an accompanying commentary if submitting the creative work option. Sixty-four percent of the class chose a creative medium e.g. poetry, visual art, narrative prose, music. These students were asked to take part in research including completing a short on-line survey and consenting for their creative work and commentaries to be further examined. The creative works were categorised by genre and the commentaries analysed using inductive thematic analysis. RESULTS: Seventeen students completed the on-line survey and fifteen consented to their work being used for this research. Thematic analysis of the student commentaries revealed the following themes: effectiveness for expressing emotion or ideas that are difficult to articulate; engaging and energising quality of the task; time for reflection; flexibility for individual learning styles and therapeutic value. CONCLUSIONS: Teaching the art of communicating at end-of-life is challenging especially when it involves patients, and teachers want to ensure students gain as much as possible from the experience. Offering the option to use creative media means that students can choose a medium for reflection that best suits them as individuals and that can enable them to benefit as much as possible from their experience. PMID- 26498343 TI - Thermal conductivity from hierarchical heat sinks using carbon nanotubes and graphene nanosheets. AB - The in-plane (kip) and through-plane (ktp) thermal conductivities of heat sinks using carbon nanotubes (CNTs), graphene nanosheets (GNs), and CNT/GN composites are extracted from two experimental setups within the 323-373 K temperature range. Hierarchical three-dimensional CNT/GN frameworks display higher kip and ktp values, as compared to the CNT- and GN-based heat sinks. The kip and ktp values of the CNT/GN-based heat sink reach as high as 1991 and 76 W m(-1) K(-1) at 323 K, respectively. This improved thermal conductivity is attributed to the fact that the hierarchical heat sink offers a stereo thermal conductive network that combines point, line, and plane contact, leading to better heat transport. Furthermore, the compression treatment provided an efficient route to increase both kip and ktp values. This result reveals that the hierarchical carbon structures become denser, inducing more thermal conductive area and less thermal resistivity, i.e., a reduced possibility of phonon-boundary scattering. The correlation between thermal and electrical conductivity (epsilon) can be well described by two empirical equations: kip = 567 ln(epsilon) + 1120 and ktp = 20.6 ln(epsilon) + 36.1. The experimental results are obtained within the temperature range of 323-373 K, suitably complementing the thermal management of chips for consumer electronics. PMID- 26498342 TI - Ambulatory Medical Assistance--After Cancer (AMA-AC): A model for an early trajectory survivorship survey of lymphoma patients treated with anthracycline based chemotherapy. AB - BACKGROUND: Cancer survivorship has emerged as an important aspect of oncology due to the possibility of physical and psychosocial complications. The purpose of this study was to assess the feasibility of the Ambulatory Medical Assistance for After Cancer (AMA-AC) procedure for monitoring lymphoma survivorship during the first year after chemotherapy. METHODS: AMA-AC is based on systematic general practitioner (GP) consultations and telephone interventions conducted by a nurse coordinator (NC) affiliated to the oncology unit, while an oncologist acts only on demand. Patients are regularly monitored for physical, psychological and social events, as well as their health-related quality of life (HRQoL). Inclusion criteria were patients newly diagnosed with non-Hodgkin or Hodgkin lymphomas, who had been treated with anthracycline-based chemotherapy and were in complete remission after treatment. RESULTS: All 115 patients and 113 collaborating GPs agreed to participate in the study. For patients who achieved one year of disease free survival (n = 104) their assessments (438 in total) were fully completed. Eleven were excluded from analysis (9 relapses and 2 deaths). The most frequent complications when taking into account all grades were arthralgia (64.3%) and infections (41.7%). About one third of patients developed new diseases with cardiovascular complications as the most common. Psychological disorders such as anxiety, depression and post-traumatic stress disorder were diagnosed in 42.6% of patients. The data collected showed that Hodgkin lymphoma patients, females, and patients with lower HRQoL (mental component) at study entry were at greater risk for developing at least one psychological disorder. CONCLUSION: This study showed that AMA-AC is a feasible and efficient procedure for monitoring lymphoma survivorship in terms of GP and patient participation rates and adherence, and provides a high quality of operable data. Hence, the AMA-AC procedure may be transferable into clinical daily practice as an alternative to standard oncologist-based follow-up. PMID- 26498344 TI - Recombinant human PDCD5 exhibits an antitumor role in hepatocellular carcinoma cells via clathrin-dependent endocytosis. AB - Liver cancer is the fifth most frequently diagnosed type of cancer in men worldwide. Recombinant human programmed cell death 5 (rhPDCD5) has been shown to enter a variety of cells by clathrin-independent endocytosis. Tissue specimens from 32 hepatocellular carcinoma (HCC) patients were collected for analysis of PDCD5 expression using ELISA. It was confirmed that the pre-operative serum levels of PDCD5 protein in patients with HCC were significantly lower than the post-operative serum levels. Moreover, the serum PDCD5 levels were significantly correlated with portal invasion and lymph node metastasis. rhPDCD5 inhibited cell proliferation as indicated by an MTT assay, and induced apoptosis and S-phase arrest in HCC cells as demonstrated by flow cytometric analysis. Furthermore, rhPDCD5 suppressed tumor growth in established xenograft tumor models. In addition, Pitstop2 was used to block clathrin-dependent endocytosis (CDE), which confirmed that the anti-tumor effect of rhPDCD5 in HCC cells is mediated via CDE. PMID- 26498346 TI - New daily persistent headache: A lack of an association with white matter abnormalities on neuroimaging. AB - OBJECTIVE: To provide results from the largest study of new daily persistent headache patients to date and specifically evaluate if patients with primary new daily persistent headache develop white matter abnormalities or infarct-like lesions on neuroimaging. METHODS: Retrospective analysis of patient medical records utilizing an electronic medical record system. All patients were seen at a headache specialty clinic by a single headache neurologist and diagnosed with primary new daily persistent headache during the time period of January 2009 to January 2013. RESULTS: Altogether, 97 patients were diagnosed with primary new daily persistent headache (65 women and 32 men). The mean average age of onset was slightly younger in women than men: 32.4 years vs. 35.8 years. In total, 84 of the 97 new daily persistent headache patients had no white matter abnormalities or infarct-like lesions on magnetic resonance imaging with a gender distribution of 56 women and 28 men. The mean age of onset of this white matter negative subgroup was 31.1 years. Of these individuals, 36% had cardiovascular/cerebrovascular risk factors and 44% had a history of migraine. Only 13 new daily persistent headache patients (nine women, four men) demonstrated white matter abnormalities on magnetic resonance imaging. None had infarct-like lesions. The mean age of onset of this white matter positive subgroup was 54.2 years, significantly older than the white matter negative population (p < .05). All new daily persistent headache patients in the white matter positive subgroup had cardiovascular/cerebrovascular risk factors and dual risk factors were noted in seven of 13 patients. Only 23% had a migraine history. Almost 40% of the patients in the white matter negative group were imaged 3 years after headache onset and at least six patients were imaged at least 9 years or more after onset of new daily persistent headache. Triggering events in both white matter lesion positive and negative populations were typical of the new daily persistent headache population as a whole and not specific to the presence or absence of brain imaging lesions except for a post-surgery trigger, which was significantly more likely to occur in the white matter positive group. Migraine associated symptoms occurred in 77% of the white matter negative subgroup compared with 46% of the white matter positive subgroup, which was a significant difference. CONCLUSION: White matter abnormalities and infarct-like lesions do not appear to occur in primary new daily persistent headache patients. Only new daily persistent headache patients with risk factors (cardiovascular/cerebrovascular or migraine) developed white matter abnormalities on brain magnetic resonance imaging. No patient with new daily persistent headache developed infarct-like lesions. New daily persistent headache triggering events (outside of possibly post-surgery) or the presence of migrainous symptoms did not appear to enhance the development of white matter abnormalities. PMID- 26498345 TI - Lymphocyte senescence in COPD is associated with decreased histone deacetylase 2 expression by pro-inflammatory lymphocytes. AB - BACKGROUND: Histone acetyltransferases (HAT) and histone deacetylases (HDAC) are enzymes that upregulate and down-regulate pro-inflammatory gene transcription respectively. HDAC2 is required by corticosteroids to switch off activated inflammatory genes and is reduced in lung macrophages in COPD. We have shown that COPD patients have increased steroid resistant CD28null (senescent) pro inflammatory T and NKT-like peripheral blood cells (particularly CD8+ subsets) and we hypothesized that these changes would be associated with a loss of HDAC2 from these senescent pro-inflammatory lymphocytes. METHODS: Blood was collected from 10 COPD and 10 aged-matched controls. Intracellular pro-inflammatory cytokines, IFNgamma and TNFalpha, and expression of CD28, HDAC2 and HAT, were determined in lymphocyte subsets in the presence of +/- 5 mg/ml theophylline (HDAC2 activator), 10 MUM prednisolone and 2.5 ng/ml cyclosporine A (immunosuppressant), using flow cytometry. RESULTS: There was a loss of HDAC2 from CD28null CD8+ T and NKT-like cells in COPD. There was a significant negative correlation between HDAC2 expression and the percentage of CD28null CD8+ T and NKT-like cells producing IFNgamma or TNFalpha in all subjects (eg, COPD: R = .763, p < 0.001 for T-cell IFNgamma). There was a synergistic upregulation of HDAC2 and associated decrease in pro-inflammatory cytokine production in CD28nullCD8+ T and NKT-like cells in the presence of 5 mg/L theophylline + 10(-6) M prednisolone or 2.5 ng/mL cyclosporine A (CsA). CONCLUSIONS: Lymphocyte senescence in COPD is associated with loss of HDAC2 in CD28nullCD8+ T and NKT like cells. Alternative treatment options such as combined theophylline with low dose CsA, that inhibit these pro-inflammatory cells, may reduce systemic inflammation in COPD. PMID- 26498347 TI - Test-retest reliability of visual-evoked potential habituation. AB - OBJECTIVE: Habituation of visual-evoked potentials (VEPs) is typically described as deficient interictally in migraine patients, supposedly indicating altered cortical excitability. Use of this parameter for monitoring changes over time, e.g. under treatment, requires demonstration of test-retest reliability. METHODS: VEPs were recorded interictally in 41 episodic migraine patients and 40 controls. N75-P100 amplitudes were measured over six consecutive blocks of 75 VEPs each. Amplitude regression slopes and block ratios were used to quantify VEP habituation. Test-retest reliability was assessed over 15 minutes and two to three weeks. RESULTS: Controls showed significantly more negative VEP habituation slopes than migraine patients (-0.21 +/- 0.40 vs. 0.04 +/- 0.46 uV/block, p < 0.05). Results were similar for block ratios, though, in the migraine group, VEP habituation significantly increased from test to two- to three-week retest (p < 0.05). In addition, VEP habituation test-retest correlations were mostly poor both in migraine patients and controls (intraclass correlation coefficients, 15 minutes: -0.13 to 0.30, two to three weeks: 0.07 to 0.59). CONCLUSIONS: Deficient VEP habituation in migraine was confirmed. However, the test-retest reliability of VEP habituation was rather weak. Therefore, we suggest that VEP habituation should be used for evaluation of cortical excitability under treatment only at the group level and only when a control group with sham treatment is included. PMID- 26498348 TI - Variability of the characteristics of a migraine attack within patients. AB - BACKGROUND: Migraine attacks may present different features in different patients and also within the same patient. The percentage of patients reporting stereotyped attacks and those reporting attacks with different phenotypes has not been the object of specific investigations. OBJECTIVE: The objective of this article is to evaluate the percentage of migraine patients reporting the same characteristics, in terms of phenotype and response to symptomatic medications on three consecutive migraine attacks. METHODS: Thirty patients with migraine without aura prospectively recorded the features of three consecutive attacks in a headache diary. Characteristics recorded were: pain intensity, presence of nausea, vomiting, photophobia, phonophophia, osmophobia, allodynia, cranial autonomic symptoms (at least one), and premonitory symptoms. Patients were allowed to take frovatriptan as symptomatic medication, whose efficacy was evaluated as the two hours pain-free status. RESULTS: None of the patients presented identical characteristics on the three studied attacks. This was still the case if we reduced the number of variables evaluated from 11 to seven of the eight core features indicated by the ICHD. Considering just six variables: unilaterality and quality of pain, presence/absence of nausea, vomiting, photophobia and phonophobia, only two patients (6%) had identical features on three consecutive attacks.With respect to the response to frovatriptan, 39% of patients had the same response, either positive (i.e. pain free after two hours) or negative (i.e. not pain free after two hours) on three consecutive attacks. CONCLUSION: Migraine attacks show a high variability not just among patients, but also within the same patient. Our data indicate that stereotypy of attacks is uncommon, and reinforces the underlying logic of the current operational classification system. PMID- 26498349 TI - Particular Distribution of Enterobacter cloacae Strains Isolated from Urinary Tract Infection within Clonal Complexes. AB - BACKGROUND: Based on biochemical properties, Enterobacter cloacae represents a large complex of at least 13 variant species, subspecies, and genotypes that progressively identified as the most species causing hospital-acquired infections. The aim of this study was to determine the relevance between phylogenetically related strains within the E. cloacae complex and the frequency of urinary tract infection caused by them. METHODS: A 268-bp fragment was obtained from hsp60 gene for 50 clinical E. cloacae isolates from urine cultures of inpatients that admitted to six hospitals in Tehran, Iran during December 2012 to November 2013. The 107 nucleotide sequences were analyzed and the evolutionary distances of sequences were computed and neighbor-joining tree was calculated. RESULTS: It showed that all of the genetic clusters have not an equal involvement in pathogenesis of urinary tract infections. Three superior clusters were found, together representing more than two third (80%) of the isolates (cluster VI with 25 members; clusters III and VIII with 9 and 6 members, respectively) and some genetic clusters were absent (IV, X, XII, and xiii), some of which are supposed to be associated with plants and no human infection has been reported. CONCLUSIONS: This study, for the first time, reports the unequal contribution of E. cloacae complex subspecies and clusters in urinary tract infections in Iran and together with studies from other countries suggest that the subspecies of E.hormaechei subsp. Oharae is the most prevalent E. cloacae complex subspecies regardless of country under study. PMID- 26498350 TI - Hepatic TLR4 signaling is activated by LPS from digestive tract during SARA, and epigenetic mechanisms contribute to enforced TLR4 expression. AB - Subacute ruminal acidosis (SARA) is known to trigger a systemic inflammatory response that is possibly caused by the translocation of lipopolysaccharides (LPS) from the gastrointestinal tract into the bloodstream. The aim of this study is to investigate this causal relationship between the increases of circulating LPS and liver inflammation. Here we found that SARA goats exhibited significantly increased LPS concentrations in both the rumen and portal vein. The livers of these goats exhibited increased mRNA concentrations of pro-inflammatory genes that indicated inflammation. Meanwhile, the occurrence of liver inflammation was further validated by the enhanced protein expression of those cytokines in the livers of SARA goats. These increased expressions of detected pro-inflammatory genes were likely mediated by enforced TLR4 signaling because SARA increased the concentrations of TLR4 mRNA and protein in the liver and the abundance of both the NF-kB-p65 factor and its active phosphorylated variant. We also verified that the enhanced TLR4 expression was accompanied by chromatin decompaction and demethylation of the proximal TLR4 promoter. Hence, epigenetic mechanisms are involved in the enforced expression of immune genes during SARA, and these findings open innovative routes for interventions via the modulation of these epigenetic mechanisms. PMID- 26498352 TI - Metabolic plasticity of cancer stem cells. PMID- 26498351 TI - MiR-21-5p and miR-126a-3p levels in plasma and circulating angiogenic cells: relationship with type 2 diabetes complications. AB - Innovative biomarkers are required to manage type 2 diabetic patients (T2DM). We focused our study on miR-126-3p and miR-21-5p levels, as biomarkers of endothelial function and inflammation. MiRNAs levels were measured in plasma from 107 healthy subjects (CTR) and 193 diabetic patients (T2DM), 76 without (T2DM NC) and 117 with (T2DM C) complications. When diabetic complication were analysed as a whole, miR-126-3p and miR-21-5p levels declined significantly from CTR to T2DM NC and T2DM C patients. When miRNAs levels were related to specific complications, significantly higher miR-21-5p levels (0.46 +/- 0.44 vs. 0.26 +/- 0.33, p < 0.001) and significant lower miR-126-3p levels (0.21 +/- 0.21 vs. 0.28 +/- 0.22, p = 0.032) were found in T2DM with previous major cardiovascular events (MACE) vs. all the others T2DM patients. To confirm these results we focused on circulating angiogenic cells (CACs) from a subgroup of 10 CTR, 15 T2DM NC and 15 T2DM patients with MACE. CACs from T2DM patients expressed higher miR-21-5p and lower miR-126-3p levels than CACs from CTR. Furthermore, CACs from T2DM + MACE showed the highest levels of miR-21-5p. Circulating miR-21-5p and miR-126-3p emerge as dynamic biomarkers of systemic inflammatory/angiogenic status. Their expression levels in CACs from T2DM with MACE suggest a shift from a proangiogenic to a proinflammatory profile. PMID- 26498353 TI - Molecular and functional interactions between AKT and SOX2 in breast carcinoma. AB - The transcription factor SOX2 is a key regulator of pluripotency in embryonic stem cells and plays important roles in early organogenesis. Recently, SOX2 expression was documented in various cancers and suggested as a cancer stem cell (CSC) marker. Here we identify the Ser/Thr-kinase AKT as an upstream regulator of SOX2 protein turnover in breast carcinoma (BC). SOX2 and pAKT are co-expressed and co-regulated in breast CSCs and depletion of either reduces clonogenicity. Ectopic SOX2 expression restores clonogenicity and in vivo tumorigenicity of AKT inhibited cells, suggesting that SOX2 acts as a functional downstream AKT target. Mechanistically, we show that AKT physically interacts with the SOX2 protein to modulate its subcellular distribution. AKT kinase inhibition results in enhanced cytoplasmic retention of SOX2, presumably via impaired nuclear import, and in successive cytoplasmic proteasomal degradation of the protein. In line, blockade of either nuclear transport or proteasomal degradation rescues SOX2 expression in AKT-inhibited BC cells. Finally, AKT inhibitors efficiently suppress the growth of SOX2-expressing putative cancer stem cells, whereas conventional chemotherapeutics select for this population. Together, our results suggest the AKT/SOX2 molecular axis as a regulator of BC clonogenicity and AKT inhibitors as promising drugs for the treatment of SOX2-positive BC. PMID- 26498354 TI - Greater efficacy of chemotherapy plus bevacizumab compared to chemo- and targeted therapy alone on non-small cell lung cancer patients with brain metastasis. AB - Control of non-small-cell lung cancer (NSCLC) with brain metastasis is clinically challenging. This study retrospectively evaluated the efficacy of different adjuvant therapies for 776 cases of advanced NSCLCs with brain metastasis who treated with chemotherapy, chemotherapy plus bevacizumab, tyrosine kinase inhibitor (TKI) alone, or supportive care. The median progression-free survival (mPFS) and median overall survival (mOS) of patients treated with chemotherapy plus bevacizumab were 8.5 and 10.5 months, respectively, which were better than those of patients treated with other three therapies(P < 0.01). For patients with EGFR-mutated NSCLC, the efficacy of TKI treatment was not statistically better than that of chemotherapy plus bevacizumab but was significantly better than that of other therapies. Moreover, for patients with EGFR wild-type NSCLC, the mPFS and mOS after chemotherapy plus bevacizumab were greater than those with other two therapies (P < 0.01). The local response rate (RR)and disease control rate (DCR)with regimen including pemetrexed were greater than those with regimen including paclitaxel (P < 0.05). Chemotherapy plus bevacizumab was more effective for NSCLC patients with brain metastasis. Further studies will investigate the benefit of TKI alone for patients with EGFR-mutated. For patients with EGFR wild type, chemotherapy plus bevacizumab did improve PFS and OS. Furthermore, regimens including pemetrexed led to a greater RR. PMID- 26498355 TI - FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3beta/beta- catenin signaling cascade via FGFR4 activation. AB - Compelling evidence suggests that the epithelial-mesenchymal transition (EMT) correlates with aggressiveness of tumors and poor survival. FGF19 has been shown to be involved in EMT in cholangiocarcinoma and colorectal cancer, however, molecular mechanisms underlying FGF19-induced EMT process in hepatocellular carcinoma (HCC) remain largely unknown. Here, we show the expression of FGF19 is significantly elevated and negatively associated with the expression of E cadherin in HCC tissues and cell lines. Ectopic FGF19 expression promotes EMT and invasion in epithelial-like HCC cells through repression of E-cadherin expression, whereas FGF19 knockdown enhances E-cadherin expression and hence diminishes EMT traits in mesenchymal-like HCC cells, suggesting FGF19 exerts its tumor progressing functions as an EMT inducer. Interestingly, depletion of FGF19 cannot abrogate EMT traits in the presence of GSK3beta inhibitors. Furthermore, FGF19-induced EMT can be markedly attenuated when FGFR4 is knocked out. These observations clearly indicate that FGFR4/GSK3beta/beta-catenin axis may play a pivotal role in FGF19-induced EMT in HCC cells. As FGF19 and its specific receptor FGFR4 are frequently amplified in HCC cells, selective targeting this signaling node may lend insights into a potential effective therapeutic approach for blocking metastasis of HCC. PMID- 26498356 TI - Cigarette smoking during pregnancy and preeclampsia risk: a systematic review and meta-analysis of prospective studies. AB - Although evidence from epidemiological studies evaluating the association between cigarette smoking during pregnancy and preeclampsia risk has been systematically reviewed, the findings have been out of date. To further clarify the relationship, we conducted this comprehensive meta-analysis of prospective studies. We searched PubMed and Web of Science up to August 2015 to identify prospective studies that evaluated the association between cigarette smoking during pregnancy and preeclampsia risk. Random-effects models were used to estimate summarized relative risk (RR) and 95% confidence intervals (CIs). Seventeen prospective studies involving 62,089 preeclampsia patients from a total of approximately 1.8 million subjects were included. Overall, there was a significant negative association between smoking during pregnancy and incidence of preeclampsia (RR = 0.67, 95% CI: 0.60-0.75), with significant heterogeneity (I2 = 91.7%). Such an inverse association was also detected in strata of subgroup analyses according to study location, study sample size, parity of populations, singleton pregnancy, and adjustment for potential confounders including maternal age, diabetes mellitus, chronic hypertension, body mass index, and gender of infant. In summary, this meta-analysis suggests that smoking during pregnancy is inversely associated with incidence of preeclampsia. Further large scale multi center prospective studies are warranted to validate our findings. PMID- 26498357 TI - Amplification of ACK1 promotes gastric tumorigenesis via ECD-dependent p53 ubiquitination degradation. AB - Amplification or over-expression of an activated Cdc42-associated kinase 1 (ACK1) gene is common in breast, lung and ovarian cancers. However, little is known about the role of ACK1 in gastric tumorigenesis. Here, we found that DNA copy numbers of the ACK1 gene and its mRNA expression levels were significantly increased in gastric cancer (GC) compared to normal gastric tissues. Additionally, silencing ACK1 inhibited GC cell proliferation and colony formation, induced G2/M arrest and cellular apoptosis in vitro, and suppressed tumor growth in vivo. Gene Ontology annotation revealed that 147 differential proteins regulated by ACK1 knockdown were closely related with cellular survival. A cell cycle regulator, ecdysoneless homolog (ECD), was found to be significantly down-regulated by ACK1 knockdown. Silencing of ECD inhibited colony formation and induced G2/M arrest and cell apoptosis, which is similar to the effects of ACK1 knockdown. Silencing of ECD did not further enhance the effects of ACK1 knockdown on G2/M arrest and apoptosis, while silencing of ECD blocked the enhancement of colony formation by ACK1 over-expression. Over-expression of ACK or ECD promoted the ubiquitination of tumor suppressor p53 protein and decreased p53 levels, while silencing of ACK1 or ECD decreased the p53 ubiquitination level and increased p53 levels. Silencing of ECD attenuated the ubiquitination enhancement of p53 induced by ACK1 over-expression. Collectively, we demonstrate that amplification of ACK1 promotes gastric tumorigenesis by inducing an ECD-dependent ubiquitination degradation of p53. PMID- 26498358 TI - Negative regulation of EB1 turnover at microtubule plus ends by interaction with microtubule-associated protein ATIP3. AB - The regulation of microtubule dynamics is critical to ensure essential cell functions. End binding protein 1 (EB1) is a master regulator of microtubule dynamics that autonomously binds an extended GTP/GDP-Pi structure at growing microtubule ends and recruits regulatory proteins at this location. However, negative regulation of EB1 association with growing microtubule ends remains poorly understood. We show here that microtubule-associated tumor suppressor ATIP3 interacts with EB1 through direct binding of a non-canonical proline-rich motif. Results indicate that ATIP3 does not localize at growing microtubule ends and that in situ ATIP3-EB1 molecular complexes are mostly detected in the cytosol. We present evidence that a minimal EB1-interacting sequence of ATIP3 is both necessary and sufficient to prevent EB1 accumulation at growing microtubule ends in living cells and that EB1-interaction is involved in reducing cell polarity. By fluorescence recovery of EB1-GFP after photobleaching, we show that ATIP3 silencing accelerates EB1 turnover at microtubule ends with no modification of EB1 diffusion in the cytosol. We propose a novel mechanism by which ATIP3-EB1 interaction indirectly reduces the kinetics of EB1 exchange on its recognition site, thereby accounting for negative regulation of microtubule dynamic instability. Our findings provide a unique example of decreased EB1 turnover at growing microtubule ends by cytosolic interaction with a tumor suppressor. PMID- 26498359 TI - Glucocorticoid-induced leucine zipper (GILZ) in immuno suppression: master regulator or bystander? AB - Induction of glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids has been reported to be essential for their anti-inflammatory actions. At the same time, GILZ is actively downregulated under inflammatory conditions, resulting in an enhanced pro-inflammatory response. Two papers published in the recent past showed elevated GILZ expression in the late stage of an inflammation. Still, the manuscripts suggest seemingly contradictory roles of endogenous GILZ: one of them suggested compensatory actions by elevated corticosterone levels in GILZ knockout mice, while our own manuscript showed a distinct phenotype upon GILZ knockout in vivo. Herein, we discuss the role of GILZ in inflammation with a special focus on the influence of endogenous GILZ on macrophage responses and suggest a cell-type specific action of GILZ as an explanation for the conflicting results as presented in recent reports. PMID- 26498360 TI - MiR-542-5p is a negative prognostic factor and promotes osteosarcoma tumorigenesis by targeting HUWE1. AB - Recent evidence has demonstrated that microRNAs (miRNAs) are involved in the proliferation and metastasis of osteosarcoma. Using miRNA microarray and functional screening methods to compare miRNA expression profiles in osteosarcoma cell lines treated with Trichostatin A (TSA), overexpression of miR-542-5p was determined to be involved in the proliferation of osteosarcoma. We used isobaric tags for relative and absolute quantitation (iTRAQ) and nanoscale liquid chromatography-mass spectrometry (NanoLC-MS/MS) to identify differentially expressed proteins in MNNG/HOS and U2OS osteosarcoma cell lines transfected with miR-542-5p; in both cell lines, seven proteins were downregulated, and nine were upregulated. HUWE1 was found to be a direct target of miR-542-5p in both osteosarcoma cell lines, and was negatively correlated with miR-542-5p levels in human osteosarcoma tissues. Moreover, the expression of miR-542-5p was upregulated in human osteosarcoma tissue compared with non-tumor adjacent tissue. Kaplan-Meier analysis revealed that overexpression of miR-542-5p predicted poor prognosis for osteosarcoma patients. Taken together, our results indicated that miR-542-5p plays a critical role in the proliferation of osteosarcoma and targets HUWE1. PMID- 26498362 TI - Is magnetic resonance/ultrasound fusion prostate biopsy better than systematic prostate biopsy? An updated meta- and trial sequential analysis. AB - We systematically reviewed the literature to determine whether Magnetic Resonance/Ultrasound (MR/US) fusion prostate biopsy is better than systematic biopsy for making a definitive diagnosis of prostate cancer. The two strategies were also compared for their ability to detect lesions with different degrees of suspicion on MRI and clinically significant prostate cancer, and the number of cores needed for diagnosis. The Cochrane Library, Embase, Web of Knowledge, and Medline were searched from inception until May 1, 2015. Meta-analysis was conducted via RevMan 5.2 software. Data was expressed as risk ratio (RR) and 95% confidence interval. Trial sequential analysis was used to assess risk of random errors. Fourteen trials were included, encompassing a total of 3105 participants. We found that MR/US fusion biopsy detected more prostate cancers than systematic biopsy (46.9% vs. 44.2%, p=0.03). In men with moderate/high MRI suspicion, MR/US fusion biopsy did better than systematic biopsy (RR = 1.46; p < 0.05) for making a diagnosis. Moreover, MR/US fusion biopsy detected more clinically significant cancers than systematic biopsy (RR = 1.19; p < 0.05). We recommend that MR/US fusion prostate biopsy be used to better detect prostate cancer, particularly in patients with moderate/high suspicion lesions on MRI. PMID- 26498361 TI - Can active components of licorice, glycyrrhizin and glycyrrhetinic acid, lick rheumatoid arthritis? AB - OBJECTIVES: This review stated the possible application of the active components of licorice, glycyrrhizin (GL) and glycyrrhetinic acid (GA), in rheumatoid arthritis (RA) treatment based on the cyclooxygenase (COX)-2/thromboxane A2 (TxA2) pathway. METHODS: The extensive literature from inception to July 2015 was searched in PubMed central, and relevant reports were identified according to the purpose of this study. RESULTS: The active components of licorice GL and GA exert the potential anti-inflammatory effects through, at least in part, suppressing COX-2 and its downstream product TxA2. Additionally, the COX-2/TxA2 pathway, an auto-regulatory feedback loop, has been recently found to be a crucial mechanism underlying the pathogenesis of RA. However, TxA2 is neither the pharmacological target of non-steroidal anti-inflammatory drugs (NSAIDs) nor the target of disease modifying anti-rheumatic drugs (DMARDs), and the limitations and side effects of those drugs may be, at least in part, attributable to lack of the effects on the COX-2/TxA2 pathway. Therefore, GL and GA capable of targeting this pathway hold the potential as a novel add-on therapy in therapeutic strategy, which is supported by several bench experiments. CONCLUSIONS: The active components of licorice, GL and GA, could not only potentiate the therapeutic effects but also decrease the adverse effects of NSAIDs or DMARDs through suppressing the COX-2/TxA2 pathway during treatment course of RA. PMID- 26498363 TI - Comprehensive multiplatform biomarker analysis of 199 anal squamous cell carcinomas. AB - Anal squamous cell carcinoma (ASCC) is a rare, HPV-associated malignancy typically diagnosed in early stages and definitively treated with chemoradiation. In situations where patients exhibit metastatic or recurrent disease, treatment options are severely limited. In this study, molecular alterations were identified that could be used to aid in therapeutic decisions for patients with metastatic or recurrent anal squamous cell carcinoma. Specimens from patients with this cancer were tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing, protein expression by immunohistochemistry, and gene amplification with in situ hybridization. Utilizing these techniques, novel treatment strategies that could be explored were identified, including potential benefit with anti-EGFR therapies, immune checkpoint inhibitors, topoisomerase inhibitors, and taxanes. The frequency of overexpression of proteins that mark resistance to chemotherapeutic drugs, such as MRP1 (chemotherapy efflux pump), ERCC1 (resistance to platinum-based chemotherapy), and thymidylate synthase (resistance to fluoropyrimidines) were also identified, suggesting a lack of benefit. This multiplatform strategy could be explored for its potential to generate a personalized treatment selection for patients with advanced ASCC, provide a guide for future therapeutic development for this cancer, and be extended to other rare cancer types as well. PMID- 26498364 TI - RNA-binding protein CELF1 promotes tumor growth and alters gene expression in oral squamous cell carcinoma. AB - The RNA binding protein CELF1 (also known as CUGBP1) is emerging as a critical regulator of cancer cell proliferation and apoptosis. Here, to provide a global prospective of CELF1 regulation of oral squamous cell carcinoma, we performed RNA sequencing in oral cancer cells and CELF1 overexpression analysis in non malignant human oral keratinocytes. Our approaches identified 1283 mRNAs differentially regulated as a function of CELF1 expression and more importantly CELF1 promoted alternative splicing of several target pre-mRNAs, which are known to be involved in various cancer biological processes. Overexpression of CELF1 in non-malignant human oral keratinocytes protected cells against oxidative damage and altered gene expression patterns. Finally, we provide evidence that reduction of CELF1 protein using a xenograft tumorigenesis mouse model decreased tumor growth. Altogether, these data provided a comprehensive view of the CELF1 mRNA regulatory network in oral cancer and suggests that CELF1 and/or its target mRNAs are viable candidates for therapeutic intervention. PMID- 26498366 TI - Oxocomplexes of Mo(VI) and W(VI) with 8-hydroxyquinoline-5-sulfonate in solution: structural studies and the effect of the metal ion on the photophysical behaviour. AB - Multinuclear ((1)H, (13)C, (95)Mo and (183)W) NMR spectroscopy, combined with DFT calculations, provides detailed information on the complexation between the Mo(VI) and W(VI) oxoions and 8-hydroxyquinoline-5-sulfonate (8-HQS) in aqueous solution. Over the concentration region studied, Mo(VI) and W(VI) oxoions form three homologous complexes with 8-HQS in water in the pH range 2-8. Two of these, detected at pH < 6, are mononuclear 1 : 2 (metal : ligand) isomers, with the metal centre (MO2(2+)) coordinated to two 8-HQS ligands. An additional complex, dominant at slightly higher pH values (5-8) for solutions with a 1 : 1 metal : ligand molar ratio, has a binuclear M2O5(2+) centre coordinated to two 8-HQS ligands. The two metal atoms are bridged by three oxygen atoms, two coming from 8 HQS, together with the M-O-M bridge of the bimetallic centre. We show that the long-range exchange corrected BOP functional with local response dispersion (LCBOPLRD), together with explicit solvent molecules, leads to geometries that readily converge to equilibrium structures having realistic bridging O8-HQS-M bonds. Previous attempts to calculate the structures of such binuclear complexes using DFT with the B3LYP functional have failed due to difficulties in treating the weak interaction in these bridged structures. We believe that the LCBOPLRD method may be of more general application in theoretical studies in related binuclear metal complexes. UV/visible absorption and luminescence spectra of all the complexes have also been recorded. The complex between Mo(vi) and 8-HQS is only weakly luminescent, in contrast to what has been observed with this ligand and many other metal ions. We suggest that this is due to the presence of low lying ligand-to-metal charge transfer (LMCT) states close to the emitting ligand based level which quench the emission. However, with W(VI), DFT calculations show that the LMCT states are now much higher in energy than the ligand based levels, leading to a marked increase in fluorescence. PMID- 26498365 TI - Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle. AB - BACKGROUND: Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. RESULTS: Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. CONCLUSIONS: This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought. PMID- 26498367 TI - Associations between active travel and adiposity in rural India and Bangladesh: a cross-sectional study. AB - BACKGROUND: Data on use and health benefits of active travel in rural low- and middle- income country settings are sparse. We aimed to examine correlates of active travel, and its association with adiposity, in rural India and Bangladesh. METHODS: Cross sectional study of 2,122 adults (>=18 years) sampled in 2011-13 from two rural sites in India (Goa and Chennai) and one in Bangladesh (Matlab). Logistic regression was used to examine whether >=150 min/week of active travel was associated with socio-demographic indices, smoking, oil/butter consumption, and additional physical activity. Adjusting for these same factors, associations between active travel and BMI, waist circumference and waist-to-hip ratio were examined using linear and logistic regression. RESULTS: Forty-six percent of the sample achieved recommended levels of physical activity (>=150 min/week) through active travel alone (range: 33.1 % in Matlab to 54.8 % in Goa). This was more frequent among smokers (adjusted odds ratio 1.36, 95 % confidence interval 1.07 1.72; p = 0.011) and those that spent >=150 min/week in work-based physical activity (OR 1.71, 1.35-2.16; p < 0.001), but less frequent among females than males (OR 0.25, 0.20-0.31; p < 0.001). In fully adjusted analyses, >=150 min/week of active travel was associated with lower BMI (adjusted coefficient -0.39 kg/m(2), -0.77 to -0.02; p = 0.037) and a lower likelihood of high waist circumference (OR 0.77, 0.63-0.96; p = 0.018) and high waist-to-hip ratio (OR 0.72, 0.58-0.89; p = 0.002). CONCLUSIONS: Use of active travel for >=150 min/week was associated with being male, smoking, and higher levels of work-based physical activity. It was associated with lower BMI, and lower risk of a high waist circumference or high waist-to-hip ratio. Promotion of active travel is an important component of strategies to address the growing prevalence of overweight in rural low- and middle- income country settings. PMID- 26498368 TI - Direct observation of many-body charge density oscillations in a two-dimensional electron gas. AB - Quantum interference is a striking manifestation of one of the basic concepts of quantum mechanics: the particle-wave duality. A spectacular visualization of this effect is the standing wave pattern produced by elastic scattering of surface electrons around defects, which corresponds to a modulation of the electronic local density of states and can be imaged using a scanning tunnelling microscope. To date, quantum-interference measurements were mainly interpreted in terms of interfering electrons or holes of the underlying band-structure description. Here, by imaging energy-dependent standing-wave patterns at noble metal surfaces, we reveal, in addition to the conventional surface-state band, the existence of an 'anomalous' energy band with a well-defined dispersion. Its origin is explained by the presence of a satellite in the structure of the many-body spectral function, which is related to the acoustic surface plasmon. Visualizing the corresponding charge oscillations provides thus direct access to many-body interactions at the atomic scale. PMID- 26498369 TI - Endocytosis of fluorescent cyclodextrins by intestinal Caco-2 cells and its role in paclitaxel drug delivery. AB - Cyclodextrins are widely used excipients in pharmaceutical formulations. They are mainly utilized as solubilizers and absorption enhancers, but recent results revealed their effects on cell membranes and pharmacological barriers. In addition to the growing knowledge on their interaction with plasma membranes, it was confirmed that cyclodextrins are able to enter cells by endocytosis. The number of the tested cyclodextrins was limited, and the role of this mechanism in drug absorption and delivery is not known. Our aim was to examine the endocytosis of fluorescently labeled hydroxypropyl-beta-cyclodextrin, random methyl-beta cyclodextrin and soluble beta-cyclodextrin polymer, and the cellular uptake of the fluorescent paclitaxel derivative-random methyl-beta-cyclodextrin complex. The studied cyclodextrin derivatives were able to enter Caco-2 intestinal cells and localized in vesicles in the cytoplasm, while their permeability was very limited through Caco-2 monolayers. We demonstrated for the first time that the fluorescent paclitaxel derivative and rhodamine-labeled random methyl-beta cyclodextrin were detected in the same intracellular vesicles after treating cells with their inclusion complex. These results indicate that the endocytosis of cyclodextrin complexes can contribute to drug absorption processes. PMID- 26498370 TI - Modified local diatomite as potential functional drug carrier--A model study for diclofenac sodium. AB - Diatomite makes a promising candidate for a drug carrier because of its high porosity, large surface area, modifiable surface chemistry and biocompatibility. Herein, refined diatomite from Kolubara coal basin, which complied with the pharmacopoeial requirements for heavy metals content and microbiological quality, was used as a starting material. Inorganic modification of the starting material was performed through a simple, one-step procedure. Significant increase in adsorbent loading with diclofenac sodium (DS) was achieved after the modification process (~373mg/g) which enabled the preparation of comprimates containing therapeutic dose of the adsorbed drug. Adsorption of DS onto modified diatomite resulted in the alteration of the drug's XRD pattern and FTIR spectrum. In vitro drug release studies in phosphate buffer pH 7.5 demonstrated prolonged DS release over 8h from comprimates containing DS adsorbed on modified diatomite (up to 37% after 8h) and those containing physical mixture of the same composition (up to 45% after 8h). The results of in vivo toxicity testing on mice pointed on potential safety of both unmodified (starting) and modified diatomite. All these findings favor the application of diatomite as a potential functional drug carrier. PMID- 26498371 TI - Interactions of dendritic glycopolymer with erythrocytes, red blood cell ghosts and membrane enzymes. AB - Interactions between maltose functionalized hyperbranched poly(ethylene imine)s (95% maltose decoration denoted as Mal-PEI A; 33% maltose decoration denoted as Mal-PEI B) and red blood cells (RBCs) and between red blood cell membranes were investigated. We monitored the degree of hemolysis, the change in cell shape, the influence of polymers on the fluidity of the cell membrane and some cell membrane enzymes to determine their possible cytotoxic impact on them. To observe the extent of hemolysis, the RBCs were incubated with different concentrations of Mal PEIs. The first significant lysis of RBCs was observed after 6h of incubation. Prolongation of the incubation time increased the number of ruptured cells. Moreover, we observed that Mal-PEI B was more hemolytic than Mal-PEI A in buffer solution. In contrast, an incubation of RBCs with Mal-PEIs in human plasma significantly decreased the hemolytic process and showed higher hemolytic property of Mal-PEI A compared to Mal-PEI B. Also several changes in the shape of the RBCs occurred after incubation with Mal-PEIs. Some of the erythrocytes shrank (echinocytes), but their morphology generally remained unchanged during the incubation. As shown by fluorescence experiments, both polymers induced the increase of fluidity of RBCs membranes. In summary, both types of hyperbranched poly(ethylene imine)s were practically non-hemolytic even at high polymer concentrations. Mal-PEI B was slightly more noxious than the Mal-PEI A in a buffer solution, while in blood plasma, the situation was opposite. Decrease of Na+/K+ ATPase and total ATPase enzymes activity was related with molecule size and number of maltose groups on the surface of molecule. The low hemolytic properties only observed at higher concentration (100MUM and 400MUM) indicated that Mal-PEIs are promising macromolecules in the area of drug delivery systems. PMID- 26498372 TI - Effect of sterilization on the physical stability of brimonidine-loaded solid lipid nanoparticles and nanostructured lipid carriers. AB - Nanoparticulate delivery systems have recently been under consideration for topical ophthalmic drug delivery. Brimonidine base-loaded solid lipid nanoparticles and nanostructured lipid carrier formulations were prepared using glyceryl monostearate as solid lipid and were evaluated for their physical stability following sterilization by autoclaving at 121 degrees C for 15min. The objective of this work was to evaluate the effect of autoclaving on the physical appearance, particle size, polydispersity index, zeta potential, entrapment efficiency and particle morphology of the prepared formulations, compared to non autoclaved ones. Results showed that, autoclaving at 121 degrees C for 15min allowed the production of physically stable formulations in nanometric range, below 500nm suitable for ophthalmic application. Moreover, the autoclaved samples appeared to be superior to non-autoclaved ones, due to their increased zeta potential values, indicating a better physical stability. As well as, increased amount of brimonidine base entrapped in the tested formulations. PMID- 26498373 TI - Dramatic Response of BRAF V600E Mutant Papillary Craniopharyngioma to Targeted Therapy. AB - We recently reported that BRAF V600E is the principal oncogenic driver of papillary craniopharyngioma, a highly morbid intracranial tumor commonly refractory to treatment. Here, we describe our treatment of a man age 39 years with multiply recurrent BRAF V600E craniopharyngioma using dabrafenib (150mg, orally twice daily) and trametinib (2mg, orally twice daily). After 35 days of treatment, tumor volume was reduced by 85%. Mutations that commonly mediate resistance to MAPK pathway inhibition were not detected in a post-treatment sample by whole exome sequencing. A blood-based BRAF V600E assay detected circulating BRAF V600E in the patient's blood. Re-evaluation of the existing management paradigms for craniopharyngioma is warranted, as patient morbidity might be reduced by noninvasive mutation testing and neoadjuvant-targeted treatment. PMID- 26498374 TI - Could it be colorectal cancer? General practitioners' use of the faecal occult blood test and decision making--a qualitative study. AB - BACKGROUND: Abdominal complaints are common reasons for contacting primary care physicians, and it can be challenging for general practitioners (GPs) to identify patients with suspected colorectal cancer (CRC) for referral to secondary care. The immunochemical faecal occult blood test (iFOBT) is used as a diagnostic aid in primary care, but it is unclear how test results are interpreted. Studies show that negative tests are associated with a risk of delayed diagnosis of CRC and that some patients with positive tests are not investigated further. The aim of this study was to explore what makes GPs suspect CRC and to investigate their practices regarding investigation and referral, with special attention on the use of iFOBTs. METHOD: Semi-structured individual interviews were conducted with eleven purposely selected GPs and registrars in Region Jamtland Harjedalen, Sweden, and subjected to qualitative content analysis. RESULTS: In the analysis of the interviews four categories were identified that described what made the physicians suspect CRC and their practices. Careful listening-with awareness of the pitfalls: Attentive listening was described as essential, but there was a risk of being misled by, for example, the patient's own explanations. Tests can help-the iFOBT can also complicate the diagnosis: All physicians used iFOBTs to various extents. In the absence of guidelines, all found their own ways to interpret and act on the test results. To refer or not to refer-safety margins are necessary: Uncertainty was described as a part of everyday work and was handled in different ways. Common vague symptoms could be CRC and thus justified referral with safety margins. Growing more confident-but also more humble: With increasing experience, the GPs described becoming more confident in their decisions but they were also more cautious. CONCLUSIONS: Listening carefully to the patient's history was essential. The iFOBT was frequently used as support, but there were considerable variations in the interpretation and handling of the results. The diagnostic process can be described as navigating uncertain waters with safety margins, while striving to keep the patient's best interests in mind. The iFOBT may be useful as a diagnostic aid in primary care, but more research and evidence-based guidelines are needed. PMID- 26498376 TI - A highly enantioselective Biginelli reaction using self-assembled methanoproline thiourea organocatalysts: asymmetric synthesis of 6-isopropyl-3,4 dihydropyrimidines. AB - An efficient self-assembled methanoproline-thiourea organocatalyst for the synthesis of optically active 6-isopropyl-3,4-dihydro-pyrimidines via an asymmetric Biginelli reaction was developed, which is superior to the individual precatalyst. A wide range of optically active 6-isopropyl-3,4-dihydropyrimidines with remarkable pharmacological interest was obtained in high yields with excellent enantioselectivities (up to 99% ee). A plausible transition state has been proposed to explain the origin of the activation and the asymmetric induction. PMID- 26498375 TI - Five miRNAs Considered as Molecular Targets for Predicting Esophageal Cancer. AB - BACKGROUND: Esophageal cancer (EC) is one of the most aggressive malignant gastrointestinal tumors; however the traditional therapies for EC are not effective enough. Great improvements are needed to explore new and valid treatments for EC. We aimed to screen the differentially expressed miRNAs (DEMs) in esophageal cancer and explore the pathogenesis of esophageal cancer along with functions and pathways of the target genes. MATERIAL AND METHODS: miRNA high throughput sequencing data were downloaded from The Cancer Genome Atlas (TCGA), then the DEMs underwent principal component analysis (PCA) based on their expression value. Following that, TargetScan software was used to predict the target genes, and enrichment analysis and pathway annotation of these target genes were done by DAVID and KEGG, respectively. Finally, survival analysis between the DEMs and patient survival time was done, and the miRNAs with prediction potential were identified. RESULTS: A total of 140 DEMs were obtained, 113 miRNAs were up-regulated including hsa-mir-153-2, hsa-mir-92a-1 and hsa-mir 182; while 27 miRNAs were down-regulated including hsa-mir comprising 29a, hsa mir-100 and hsa-mir-139 and so on. Five miRNAs (hsa-mir-103-1, hsa-mir-18a, hsa mir-324, hsa-mir-369 and hsa-mir-320b-2) with diagnostic and preventive potential were significantly correlated with survival time. CONCLUSIONS: The crucial molecular targets such as p53 may provide great clinical value in treatment, as well to provide new ideas for esophageal cancer therapy. The target genes of miRNA were found to play key roles in protein phosphorylation, and the functions of the target genes during protein phosphorylation should be further studied to explore novel treatment of EC. PMID- 26498377 TI - Patient-specific compensation for Co-60 TBI treatments based on Monte Carlo design: A feasibility study. AB - PURPOSE: To develop an AP-PA treatment technique for the delivery of total body irradiation (TBI) at extended SSD using a modified Co-60 unit equipped with flattening filter and patient-specific compensators supported by Monte Carlo (MC) simulations and measurements. METHODS: An existing Eldorado-78 Co-60 teletherapy unit was stripped of its original collimator and equipped with two beam-defining cerrobend blocks. An acrylic flattening filter was numerically designed based on detailed mapping of the dose distribution of the large open field at a 10 cm depth in water using a primary radiation attenuation calculation. An EGSnrc/BEAMnrc MC model of the resulting unit was developed and experimentally validated and was used to calculate MC dose distributions in whole-body supine and prone CT images of a patient. AP-PA patient-specific compensators were designed based on the supine and prone mid-plane dose distributions. RESULTS: The designed flattening filter flattens the beam to within +/-2% over a 200 cm * 70 cm area at 10 cm depth in water. Experimental validation of the calculated dose profiles in the open and flattened beams shows agreement of better than 2% and 1%, respectively. Patient MC dose calculations in the flattened, uncompensated beam showed dose deviations from prescription dose most notably in lung, neck and extremities ranging from -5% to +25%. The use of patient-specific compensators reduced inhomogeneities to within -5% to +10%. CONCLUSIONS: This work demonstrates that a Co-60 TBI setup upgraded with patient-specific compensators, numerically designed using MC patient dose calculations, is feasible and considerably improves the dose homogeneity. PMID- 26498378 TI - Multicentre treatment planning inter-comparison in a national context: The liver stereotactic ablative radiotherapy case. AB - PURPOSE: To compare five liver metastasis stereotactic ablative radiotherapy (SABR) plans optimised in fourteen centres with 3D-Conformal-RT, IMRT, VMAT, CyberKnife and Tomotherapy and identify possible dosimetric differences. METHODS: Dose prescription was 75 Gy in 3 fractions, normalised at 67%-95% isodose. RESULTS: Excluding few cases, all institutions achieved the planning objectives. Differences up to 40% and 25% in mean dose to liver and PTV were found. No significant correlations between technological factors and DVH for target and OARs were observed; the optimisation strategies selected by the planners played a key role in the planning procedure. CONCLUSIONS: The human factor and the constraints imposed to the target volume have a greater dosimetric impact than treatment planning and radiation delivery technology in stereotactic treatment of liver metastases. Significant differences found both in terms of dosimetric target coverage and OAR sparing should be taken into consideration before starting a multi-institutional SARB clinical trial. PMID- 26498379 TI - Effects of extremity positioning on radiographic evaluation of femoral tunnel location with digitally reconstructed femoral lateral radiographs after anterior cruciate ligament reconstruction. AB - BACKGROUND: Radiographic imaging is a valuable tool in clinical practice for quick anatomical assessment. We aimed to radiographically assess (A) the anterior cruciate ligament (ACL) graft tunnel location after anatomic single-bundle (SB) reconstruction and (B) the effects of extremity positioning on the localization of the orifice of the tunnel in the distal femur in comparison with Blumensaat's line (BL). METHODS: Three-dimensional computed tomography (3D CT) scan examinations of 22 knees of 22 subjects were evaluated. The 3D CT scan data was used to digitally reconstruct the true lateral radiographs. Graft tunnel location on the distal femoral shaft along the Blumensaat's line and perpendicular to it were assessed on these radiographs. The femur was digitally rotated to simulate varus, valgus, internal rotation and external rotation in 5-degree increments from 0 to 20-degree. At each incremental rotated position of the femur, position of the ACL graft tunnel was calculated relative to BL and the difference from the true lateral x-ray was estimated. RESULTS: The position of the tunnel in the distal femur was 30.6 (+/-4.4) % along BL and 33.1 (+/-5.4) % perpendicular to BL. Ten and more degree of external, internal, valgus and varus rotations significantly affected the estimates of tunnel position (P < 0.05). CONCLUSIONS: Femoral tunnel location can be reliably estimated from lateral radiographs after anatomic SB ACL reconstruction. Although, ten or more degree of rotations can introduce significant inaccuracies in tunnel location estimates, our study suggests that BL is overall reliable for assessing location of the distal femoral tunnel. LEVEL OF EVIDENCE: Level 2b (Retrospective Cohort Study). PMID- 26498380 TI - Total saponins from Aralia taibaiensis protect against myocardial ischemia/reperfusion injury through AMPK pathway. AB - It was previously shown that total saponins extracted from Aralia taibaiensis (sAT) have potent antioxidant activities for treating diabetes mellitus and attenuate d-galactose-induced aging. Since diabetes mellitus and aging are closely associated with cardiac dysfunction, particularly ischemic heart disease, sAT may have potential protective activity against myocardial ischemia/reperfusion injury (MI/RI). However, the anti-MI/RI effects of sAT have yet to be examined, and the possible molecular mechanisms remain to be determined. The present study was undertaken to investigate the anti-MI/RI activities of sAT and to elucidate the mechanisms underlying these effects in rats using TUNEL and Hoechst 33258 staining. The results confirmed the cardioprotective effects in vivo and elucidated the potential molecular mechanisms of sAT in vitro. Pretreatment with sAT significantly reduced infarct size, decreased the levels of lactate dehydrogenase and creatine kinase in the serum and blocked apoptosis. In addition, sAT inhibited A/R-induced apoptosis by decreasing DNA strand breaks, caspase-3 activity and cytochrome c release in H9c2 cells. Furthermore, sAT markedly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase and elevated the Bcl2/Bcl-2 associated X protein ratio. These effects were blocked by compound C. The results suggested that sAT pretreatment exerts protective effects on myocardial cells in vitro and in vivo against MI/RI-induced apoptosis by activating AMPK pathway. PMID- 26498382 TI - Origins of Regioselectivity in Iridium Catalyzed Allylic Substitution. AB - Detailed studies on the origin of the regioselectivity for formation of branched products over linear products have been conducted with complexes containing the achiral triphenylphosphite ligand. The combination of iridium and P(OPh)3 was the first catalytic system shown to give high regioselectivity for the branched product with iridium and among the most selective for forming branched products among any combination of metal and ligand. We have shown the active catalyst to be generated from [Ir(COD)Cl]2 and P(OPh)3 by cyclometalation of the phenyl group on the ligand and have shown such species to be the resting state of the catalyst. A series of allyliridium complexes ligated by the resulting P,C ligand have been generated and shown to be competent intermediates in the catalytic system. We have assessed the potential impact of charge, metal-iridium bond length, and stability of terminal vs internal alkenes generated by attack at the branched and terminal positions of the allyl ligand, respectively. These factors do not distinguish the regioselectivity for attack on allyliridium complexes from that for attack on allylpalladium complexes. Instead, detailed computational studies suggest that a series of weak, attractive, noncovalent interactions, including interactions of H-bond acceptors with a vinyl C-H bond of the alkene ligand, favor formation of the branched product with the iridium catalyst. This conclusion underscores the importance of considering attractive interactions, as well as repulsive steric interactions, when seeking to rationalize selectivities. PMID- 26498381 TI - Phenotypic, Morphological and Adhesive Differences of Human Hematopoietic Progenitor Cells Cultured on Murine versus Human Mesenchymal Stromal Cells. AB - Xenogenic transplantation models have been developed to study human hematopoiesis in immunocompromised murine recipients. They still have limitations and therefore it is important to delineate all players within the bone marrow that could account for species-specific differences. Here, we evaluated the proliferative capacity, morphological and physical characteristics of human CD34(+) hematopoietic stem and progenitor cells (HSPCs) after co-culture on murine or human bone marrow-derived mesenchymal stromal cells (MSCs). After seven days, human CD34(+)CD133(-) HSPCs expanded to similar extents on both feeder layers while cellular subsets comprising primitive CD34(+)CD133(+) and CD133(+)CD34(-) phenotypes are reduced fivefold on murine MSCs. The number of migrating HSPCs was also reduced on murine cells suggesting that MSC adhesion influences cellular polarization of HSPC. We used atomic force microscopy-based single-cell force spectroscopy to quantify their adhesive interactions. We found threefold higher detachment forces of human HSPCs from murine MSCs compared to human ones. This difference is related to the N-cadherin expression level on murine MSCs since its knockdown abolished their differential adhesion properties with human HSPCs. Our observations highlight phenotypic, morphological and adhesive differences of human HSPCs when cultured on murine or human MSCs, which raise some caution in data interpretation when xenogenic transplantation models are used. PMID- 26498383 TI - Mono-(2-ethylhexyl) phthalate (MEHP) affects intercellular junctions of Sertoli cell: A potential role of oxidative stress. AB - We analyzed the potential role of oxidative stress induced by mono (2-ethylhexyl) phthalate (MEHP) in adherent cell junction protein expression of prepubertal rat Sertoli cells (SC) in vitro. Five-day SC cultures were treated with MEHP (200MUM) for 24h and compared to cells in basal conditions. Western blot and immunofluorescent (IF) analyses showed that MEHP induced increase of N-cadherin and catenin expression, modifying its distribution. Concomitantly, Cx-43 expression decreased significantly and delocalization of the IF signal for tight junction proteins (occludin, claudin-11 and ZO-1) occurred. Indicative of oxidative stress, MEHP induced in SC an increase of lipoperoxides, a decrease in glutathione (GSH) levels and a concomitant increase in Glutathione S-Transferases (GST) activity. Antioxidant N-acetyl-cysteine (1mM) treatment prevented GSH decrease and N-cadherin and alpha-catenin up-regulation induced by MEHP. Our data suggest that oxidative stress signaling is a mechanism involved in adherent cell junctions disruption induced by MEHP in SC cultures. PMID- 26498384 TI - Asymptotic stability of tri-trophic food chains sharing a common resource. AB - One of the key results of the food web theory states that the interior equilibrium of a tri-trophic food chain described by the Lotka-Volterra type dynamics is globally asymptotically stable whenever it exists. This article extends this result to food webs consisting of several food chains sharing a common resource. A Lyapunov function for such food webs is constructed and asymptotic stability of the interior equilibrium is proved. Numerical simulations show that as the number of food chains increases, the real part of the leading eigenvalue, while still negative, approaches zero. Thus the resilience of such food webs decreases with the number of food chains in the web. PMID- 26498385 TI - Trophic Cascades by Large Carnivores: A Case for Strong Inference and Mechanism. AB - Studies on trophic cascades involving large carnivores typically are limited by a lack of replication and control, giving rise to a spirited debate over the ecological role of these iconic species. We argue that much of this debate can be resolved by decomposing the trophic cascade hypothesis into three constituent interactions, quantifying each interaction individually, and accommodating alternative hypotheses. We advocate for a novel approach that couples the rigor characterizing foundational work on trophic cascades (i.e., from studies carried out in mesocosm and whole lake systems) with the conservation relevance of large carnivore-dominated food webs. Because of their iconic status, it is crucial that inferences about the ecological role of large carnivores rise to meet the same rigorous standards to which other studies in community ecology are held. PMID- 26498386 TI - Roflumilast for asthma: Efficacy findings in placebo-controlled studies. AB - BACKGROUND: The role of roflumilast as a potential asthma treatment is not yet fully understood. A series of placebo-controlled trials were undertaken in order to investigate the safety and efficacy of roflumilast in asthma. AIM: To evaluate the efficacy of roflumilast in nine randomized proof-of-concept, placebo controlled monotherapy and combination therapy phase II and III clinical studies performed between 1997 and 2005. METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 24 weeks. Data were analyzed from 4873 patients, 12-70 years of age, of whom 2668 received roflumilast. At randomization patients had a forced expiratory flow (FEV1) of 45-90%. Roflumilast was investigated at doses of 125, 250 and 500 MUg versus placebo. In two studies, 500 MUg roflumilast was added on top of standard therapy with inhaled corticosteroids (ICS), 250 MUg fluticasone propionate, or 400 MUg beclomethasone dipropionate (BDP). Improvement in FEV1 from baseline was the primary endpoint in seven studies. Key secondary endpoints included asthma symptom scores and time to first severe exacerbation. RESULTS: Roflumilast consistently improved FEV1 across the nine studies compared with placebo, reaching statistical significance in three studies. When given in addition to ICS, roflumilast provided additional improvements in FEV1 which was statistically significant for 500 MUg roflumilast/400 MUg BDP versus placebo/400 MUg BDP. CONCLUSION: Together these studies show that roflumilast has potential as an effective anti-inflammatory therapy for the treatment of asthma. Additional beneficial effects are observed when given in combination with ICS, which warrant further investigation. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177, NCT00076076, NCT00163527. PMID- 26498388 TI - Strong orbital deformation due to CH-pi interaction in the benzene-methane complex. AB - The orbital distribution and composition of the benzene-methane complex have been investigated systemically using ab initio calculations for the first time. Surprisingly, we find strong deformation in the HOMO-4 and LUMO+2 induced by CH pi interaction, extending the general view that nonbonding interaction does not cause orbital change of molecules. PMID- 26498387 TI - Cough reflex sensitization from esophagus and nose. AB - The diseases of the esophagus and nose are among the major factors contributing to chronic cough although their role in different patient populations is debated. Studies in animal models and in humans show that afferent C-fiber activators applied on esophageal or nasal mucosa do not initiate cough, but enhance cough induced by inhaled irritants. These results are consistent with the hypothesis that activation of esophageal and nasal C-fibers contribute to cough reflex hypersensitivity observed in chronic cough patients with gastroesophageal reflux disease (GERD) and chronic rhinitis, respectively. The afferent nerves mediating cough sensitization from the esophagus are probably the neural crest-derived vagal jugular C-fibers. In addition to their responsiveness to high concentration of acid typical for gastroesophageal reflux (pH < 5), esophageal C-fibers also express receptors for activation by weakly acidic reflux such as receptors highly sensitive to acid and receptors for bile acids. The nature of sensory pathways from the nose and their activators relevant for cough sensitization are less understood. Increased cough reflex sensitivity was also reported in many patients with GERD or rhinitis who do not complain of cough indicating that additional endogenous or exogenous factors may be required to develop chronic coughing in these diseases. PMID- 26498389 TI - The development of cat testicular sperm cryopreservation protocols: Effects of tissue fragments or sperm cell suspension. AB - In endangered animals that have been found dead or sterilized for medical reasons, testis is the ultimate source of haploid DNA or sperm. Thus, preservation of testicular sperm may be performed to rescue their genetics. The aim of this study was to evaluate protocols for testicular sperm freezing: as tissue fragments or cell suspension in domestic cats as a model. A pair of testes from each cat (n = 9) were cut into eight equal pieces. Four randomly selected pieces were cryopreserved as: (1) tissue pieces using two-step freezing; (2) tissue pieces using a slow passive cooling device (CoolCell); (3) sperm suspension after single-layer centrifugation (SLC) through colloids; and (4) sperm suspension without being processed through SLC. A testicular piece from each cat served as fresh control. Testicular sperm membrane and DNA integrity were evaluated before, and after, the cryopreservation process. In addition, spermatogenic cell types (testicular sperm, spermatogonia, spermatocyte, and spermatid) present in the suspension samples were counted before and after SLC. The results found that testicular sperm membrane integrity in the suspension after SLC process was higher than that in the fragment form neither using the two step nor CoolCell freezing, both before and after freezing (before freezing: 92.3 +/- 3.4 vs. 81 +/- 4.5 and 80.0 +/- 7.0; after freezing: 84.5 +/- 4.6 vs. 71.2 +/ 12 and 76.2 +/- 4.6; P <= 0.05). Testicular sperm DNA integrity was, however, not different among groups. Furthermore, the samples processed through the SLC had higher ration of sperm cells: other spermatogenic cells than those were not processed through the SLC (88.9 +/- 3.8 vs. 30 +/- 7.9; P <= 0.05). In summary, testicular sperm cryopreserved as a minced suspension is considered suitable in terms of preventing sperm membrane integrity, and SLC is considered a selection tool for enriching haploid sperm cells from castrated or postmortem cats. PMID- 26498390 TI - Total plasma magnesium in healthy and critically ill foals. AB - Abnormalities in total Mg (tMg) concentration in plasma and/or serum are common in critically ill humans, and the association with increased mortality has been documented in several clinical studies in adults and newborns with hypoxic ischemic encephalopathy. Abnormalities in tMg were studied in hospitalized dogs, cats, and adult horses. Newborn foals were scarcely studied with regard to Mg concentration. The aims of the present study were: (1) to compare two analytical methods for the determination of tMg in plasma: the automated colorimetric method and the atomic absorption spectrometry; (2) to measure plasma tMg in healthy foals during the first 72 hours after birth and in sick foals during the first 72 hours of hospitalization; (3) to compare total plasma Mg concentration among healthy foals, foals affected by perinatal asphyxia syndrome (PAS), prematurity and/or dismaturity, and sepsis; (4) to evaluate tMg plasma concentration in surviving and non-surviving foals. One hundred seventeen foals were included in the study: 20 healthy and 97 sick foals. The automated method used in clinical practice probably overestimates plasma tMg. Due to its higher sensitivity and specificity, the atomic absorption spectrometry should be considered the method of choice from an analytical point of view, but requires an instrumentation not easily available in any laboratory and specific technical skills and competencies. Plasma tMg in healthy foals were included in the range 0.52 to 1.01 mmol/L and did not show any time-dependent change during the first 72 hours of life. In sick foals, tMg evaluated at T0 was statistically higher than tMg measured at subsequent times. Foals affected by PAS had a tMg at T0 significantly higher (P < 0.01) than healthy, septic, and premature and/or dysmature foals. The t test found significantly higher (P < 0.01) plasma tMg measured at T0 in non surviving than in surviving foals. Plasma tMg could be a useful parameter for the diagnosis of PAS and the formulation of the prognosis in critically ill foals. PMID- 26498391 TI - Resveratrol sensitizes glioblastoma-initiating cells to temozolomide by inducing cell apoptosis and promoting differentiation. AB - Glioblastoma-initiating cells play crucial roles in the origin, growth, and recurrence of glioblastoma multiforme. The elimination of glioblastoma-initiating cells is believed to be a key strategy for achieving long-term survival of glioblastoma patients due to the highly resistant property of glioblastoma initiating cells to temozolomide. Resveratrol, a naturally occurring polyphenol, has been widely studied as a promising candidate for cancer prevention and treatment. Whether resveratrol could enhance the sensitivity of glioblastoma initiating cells to temozolomide therapy has not yet been reported. Here, using patient-derived glioblastoma-initiating cell lines, we found that resveratrol sensitized glioblastoma-initiating cells to temozolomide both in vitro and in vivo. Furthermore, we showed that resveratrol enhanced glioblastoma-initiating cells to temozolomide-induced apoptosis through DNA double-stranded breaks/pATM/pATR/p53 pathway activation, and promoted glioblastoma-initiating cell differentiation involving p-STAT3 inactivation. Our results propose that temozolomide and resveratrol combination strategy may be effective in the management of glioblastoma patients, particularly for those patients who have been present with a high abundance of glioblastoma-initiating cells in their tumors and show slight responsiveness to temozolomide. PMID- 26498392 TI - Evaluation of enzyme immobilization methods for paper-based devices--A glucose oxidase study. AB - Paper-based sensors gained almost explosive attention during the last few years. A large number of systems, often destined to resource limited settings is based on enzymatic reactions. Choice of an adequate immobilization method could significantly prolong the shelf-life of such sensors, especially in applications, where exposure to high temperatures during storage and transport is more than a threat. We are seeking to compare a variety of immobilization methods based on different phenomena (adsorption, entrapment in gel, microencapsulation, covalent linkage), with total of 33 methods tested. Glucose oxidase was used as a model enzyme. Enzymatic activity of immobilized samples was accompanied for a period of 24 weeks considering two sets of samples, one stored in 4 degrees C and other in ambient temperature. PMID- 26498393 TI - New natural product carbonic anhydrase inhibitors incorporating phenol moieties. AB - Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. They represent a typical example of enzyme convergent evolution, as six genetically unrelated families of such enzymes were described so far. The need to find selective CA inhibitors (CAIs) triggered the investigation of natural product libraries, which proved to be a valid source of agents with such an activity, as demonstrated for the phenols, polyamines and coumarins. Herein we report an in vitro inhibition study of human (h) CA isoforms hCAs I, II, IV, VII and XII with a panel of natural polyphenols including flavones, flavonols, flavanones, flavanols, isoflavones and depsides, some of which extracted from Quercus ilex and Salvia miltiorrhiza. Several of the investigated derivatives showed interesting inhibition activity and selectivities for inhibiting some important isoforms over the off-target ones hCA I and II. PMID- 26498394 TI - Inhibition of mammalian carbonic anhydrase isoforms I-XIV with a series of phenolic acid esters. AB - A series of phenolic acid esters incorporating caffeic, ferulic, and p-coumaric acid, and benzyl, m/p-hydroxyphenethyl- as well as p-hydroxy-phenethoxy-phenethyl moieties were investigated for their inhibitory effects against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Many of the mammalian isozymes of human (h) or murine (m) origin, hCA I-hCA XII, mCA XIII and hCA XIV, were inhibited in the submicromolar range by these derivatives (with KIs of 0.31-1.03 MUM against hCA VA, VB, VI, VII, IX and XIV). The off-target, highly abundant isoforms hCA I and II, as well as hCA III, IV and XII were poorly inhibited by many of these esters, although the original phenolic acids were micromolar inhibitors. These phenols, like others investigated earlier, possess a CA inhibition mechanism distinct of the sulfonamides/sulfamates, clinically used drugs for the treatment of a multitude of pathologies, but with severe side effects due to hCA I/II inhibition. Unlike the sulfonamides, which bind to the catalytic zinc ion, phenols are anchored at the Zn(II)-coordinated water molecule, binding more externally within the active site cavity, and making contacts with amino acid residues at the entrance of the active site. As this is the region with the highest variability between the many CA isozymes found in mammals, this class of compounds shows isoform-selective inhibitory profiles, which may be exploited for obtaining pharmacological agents with less side effects compared to other classes of inhibitors. PMID- 26498395 TI - Five-wave-packet quantum error correction based on continuous-variable cluster entanglement. AB - Quantum error correction protects the quantum state against noise and decoherence in quantum communication and quantum computation, which enables one to perform fault-torrent quantum information processing. We experimentally demonstrate a quantum error correction scheme with a five-wave-packet code against a single stochastic error, the original theoretical model of which was firstly proposed by S. L. Braunstein and T. A. Walker. Five submodes of a continuous variable cluster entangled state of light are used for five encoding channels. Especially, in our encoding scheme the information of the input state is only distributed on three of the five channels and thus any error appearing in the remained two channels never affects the output state, i.e. the output quantum state is immune from the error in the two channels. The stochastic error on a single channel is corrected for both vacuum and squeezed input states and the achieved fidelities of the output states are beyond the corresponding classical limit. PMID- 26498396 TI - Pore-forming toxins: Properties, diversity, and uses as tools to image sphingomyelin and ceramide phosphoethanolamine. AB - Pore-forming toxins (PFTs) represent a unique class of highly specific lipid binding proteins. The cytotoxicity of these compounds has been overcome through crystallographic structure and mutation studies, facilitating the development of non-toxic lipid probes. As a consequence, non-toxic PFTs have been utilized as highly specific probes to visualize the diversity and dynamics of lipid nanostructures in living and fixed cells. This review is focused on the application of PFTs and their non-toxic analogs as tools to visualize sphingomyelin and ceramide phosphoethanolamine, two major phosphosphingolipids in mammalian and insect cells, respectively. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale. PMID- 26498397 TI - An intimate link between antimicrobial peptide sequence diversity and binding to essential components of bacterial membranes. AB - Antimicrobial peptides and proteins (AMPs) are widespread in the living kingdom. They are key effectors of defense reactions and mediators of competitions between organisms. They are often cationic and amphiphilic, which favors their interactions with the anionic membranes of microorganisms. Several AMP families do not directly alter membrane integrity but rather target conserved components of the bacterial membranes in a process that provides them with potent and specific antimicrobial activities. Thus, lipopolysaccharides (LPS), lipoteichoic acids (LTA) and the peptidoglycan precursor Lipid II are targeted by a broad series of AMPs. Studying the functional diversity of immune effectors tells us about the essential residues involved in AMP mechanism of action. Marine invertebrates have been found to produce a remarkable diversity of AMPs. Molluscan defensins and crustacean anti-LPS factors (ALF) are diverse in terms of amino acid sequence and show contrasted phenotypes in terms of antimicrobial activity. Their activity is directed essentially against Gram-positive or Gram negative bacteria due to their specific interactions with Lipid II or Lipid A, respectively. Through those interesting examples, we discuss here how sequence diversity generated throughout evolution informs us on residues required for essential molecular interaction at the bacterial membranes and subsequent antibacterial activity. Through the analysis of molecular variants having lost antibacterial activity or shaped novel functions, we also discuss the molecular bases of functional divergence in AMPs. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID- 26498398 TI - Outcome of Patients with Long-Lasting Cerebral Vasospasm After Subarachnoid Hemorrhage: Is Prolonged Treatment for Cerebral Vasospasm Worthwhile? A Matched Pair Analysis. AB - OBJECTIVE: Cerebral vasospasm (CVS) occurs regularly between days 3 and 12 after subarachnoid hemorrhage (SAH). Yet, some patients suffering from SAH have long lasting cerebral vasospasm (LL-CVS, i.e., longer than 14 days). The outcome of these patients with a very long treatment is unknown. METHODS: Patients with SAH were entered into a prospectively collected database. In unconscious patients, CVS was treated until a reversal of CVS was confirmed by imaging. Outcome was assessed with the modified Rankin Scale (mRS; favorable [mRS 0-2] and unfavorable [mRS 3-6]) 6 months after SAH. Data were compared by matched pair analysis. RESULTS: Of 1126 patients, 106 had LL-CVS (9.4%). The mean of treatment was until day 20 (range, 15-42). Of these patients, more than 30% needed treatment longer than 21 days after SAH; 29% had a small intracerebral hematoma (ICH; <50 mL). Hydrocephalus that required external ventricular drainage was present in 81%. Outcomes were favorable in 60%, and 8% died. In the multivariate logistic regression analysis, risk factors for an unfavorable outcome were elderly patients, poor admission status, and the presence of small ICH. Compared with the matched control group, who had "regular-lasting" CVS, patients with LL-CVS had a significant better outcome (60% vs. 49%) and a significant lower mortality rate (8% vs. 27%). CONCLUSION: Patients with LL-CVS had a significant better outcome than patients with "regular-lasting" CVS. Risk factors for worse outcome of patients with LL-CVS were a worse admission status, elderly age, and the presence of small ICH. We recommend using an objective method to validate the reversal of CVS in unconscious patients. PMID- 26498399 TI - Outcomes for Patients with Poor-Grade Subarachnoid Hemorrhage: To Treat or Not To Treat? PMID- 26498400 TI - beta-carotene and retinol contents in the meat of herbivorous ungulates with a special reference to their public health importance. AB - The aim of this study was to estimate total carotenoids, beta-carotene and retinol concentrations in the livers and muscles of some ungulates (cattle, buffalo, sheep, goats and horses) in comparison with the Wistar rats as a control. Cattle and horses had the highest contents of total carotenoids and beta carotene. Unexpectedly, sheep was the highest accumulator of retinol with a mean concentration of 203 +/- 23.34 ug/g, while the least accumulator was buffalo, having a mean value of 58.28 +/- 13.77 ug/g. Livers had higher contents of the examined phytochemicals than muscles. Consumption of these tissues may provide human with some needs from these important phytochemicals, though ingestion of livers, especially that of the sheep, is not advisable for the pregnant women. PMID- 26498401 TI - Serological survey of caprine arthritis-encephalitis virus infection in Japan. AB - A serological survey of caprine arthritis-encephalitis virus (CAEV) infection was conducted from September 2006 to February 2007 in Japan. A total of 857 serum samples were collected from 113 herds in 28 prefectures and were analyzed for the presence of CAEV antibodies using agar gel immunodiffusion test. The seroprevalence of CAEV infection at the herd and animal levels was 15.0% (17/113) and 10.0% (86/857), respectively. Large farms with more than 10 goats and with animals for dairy and breeding purposes had higher seroprevalence (P<0.05). The results of this study provide useful information to consider effective control programs against CAEV infection in Japan. PMID- 26498402 TI - Growth kinetics of Salmonella enterica in Hajna tetrathionate broth, Rappaport broth and modified semisolid Rappaport agar. AB - To determine the appropriate method for isolating Salmonella enterica, we compared the growth of S. enterica serovars using three selective enrichment media. S. enterica was more successfully isolated from artificially contaminated fecal samples after enrichment in Hajna tetrathionate broth or modified semisolid Rappaport agar than in Rappaport broth. Since most bacteria (other than motile S. enterica) do not migrate on modified semisolid Rappaport agar, the growth characteristics of S. enterica can be interpreted easily and quickly. Two S. enterica isolates did not migrate on modified semisolid Rappaport agar, but did grow in Hajna tetrathionate broth, which suggests that the combined use of these selective enrichment media is appropriate for isolating S. enterica. PMID- 26498403 TI - Contrast-enhanced ultrasonographic findings in three dogs with lung lobe torsion. AB - Lung lobe torsion is rare but life-threatening condition in the dog. Thoracic radiographs and conventional ultrasonography cannot be conclusive for the diagnosis, and computed tomography is useful but is limited by cost and availability. This report describes the findings of contrast-enhanced ultrasonography in 3 dogs with lung lobe torsion. Contrast-enhanced ultrasonography showed the absence or reduction of pulmonary vascularization secondary to twisting of the lung lobe around its bronchovascular pedicle in all three dogs. Moreover, contrast-enhanced ultrasonography distinguished partial pulmonary atelectasis from a lung lobe torsion. These preliminary results suggest that contrast-enhanced ultrasonography can improve the accuracy of conventional ultrasonography for detection of pulmonary blood flow compromise in dogs with lung lobe torsion. PMID- 26498404 TI - Interdisciplinary lifestyle intervention for weight management in a community population (HealthTrack study): Study design and baseline sample characteristics. AB - BACKGROUND: Integrating professional expertise in diet, exercise and behavioural support may provide more effective preventive health services but this needs testing. We describe the design and baseline results of a trial in the Illawarra region of New South Wales, Australia. METHODS: The HealthTrack study is a 12 month randomised controlled trial testing effects of a novel interdisciplinary lifestyle intervention versus usual care. The study recruited overweight and obese adults 25-54 years resident in the Illawarra. Primary outcomes were weight, and secondary outcomes were disease risk factors (lipids, glucose, blood pressure), and behaviour (diet, activity, and psychological factors). Protocols, recruitment and baseline characteristics are reported. RESULTS: Between May 2014 and April 2015, 377 participants were recruited and randomised. The median age (IQR) of the mostly female sample (74%) was 45 (37-51) years. The sample comprised obese (BMI 32 (29-35) kg/m(2)) well educated (79% post school qualifications) non-smokers (96%). A high proportion reported suffering from anxiety (26.8%) and depression (33.7%). Metabolic syndrome was identified in 34.9% of the sample. CONCLUSIONS: The HealthTrack study sample was recruited to test the effectiveness of an interdisciplinary approach to preventive healthcare in self-identified overweight adults in the Illawarra region. The profile of participants gives some indication of those likely to use services similar to the trial design. PMID- 26498405 TI - What qualitative research can contribute to a randomized controlled trial of a complex community intervention. AB - Using the case of a large-scale, multi-site Canadian Housing First research demonstration project for homeless people with mental illness, At Home/Chez Soi, we illustrate the value of qualitative methods in a randomized controlled trial (RCT) of a complex community intervention. We argue that quantitative RCT research can neither capture the complexity nor tell the full story of a complex community intervention. We conceptualize complex community interventions as having multiple phases and dimensions that require both RCT and qualitative research components. Rather than assume that qualitative research and RCTs are incommensurate, a more pragmatic mixed methods approach was used, which included using both qualitative and quantitative methods to understand program implementation and outcomes. At the same time, qualitative research was used to examine aspects of the intervention that could not be understood through the RCT, such as its conception, planning, sustainability, and policy impacts. Through this example, we show how qualitative research can tell a more complete story about complex community interventions. PMID- 26498406 TI - Critical role of the Mac1/NOX2 pathway in mediating reactive microgliosis generated chronic neuroinflammation and progressive neurodegeneration. AB - As average life expectancy rises throughout the world, neurodegenerative diseases have emerged as one of the greatest global public heath challenges in modern times. Substantial efforts have been made in researching neurodegenerative diseases over the last few decades, yet their predominantly sporadic nature has made uncovering their etiologies challenging. Mounting evidence has suggested that factors like damage-associated molecular patterns (DAMPs) released by stressed and dying neurons are likely involved in disease pathology and in stimulating chronic activation of microglia that contributes to neuronal oxidative stress and degeneration. This review focuses on how the microglial integrin receptor Mac1 and its downstream effector NADPH oxidase (NOX2) contribute to maintaining chronic neuroinflammation and are crucial in inflammation-driven neurotoxicity in neurodegenerative diseases. Our hope is to provide new insights on novel targets and therapies that could slow or even halt neurodegeneration. PMID- 26498407 TI - Alveolar ridge dimensional changes following ridge preservation procedure: part-2 - CBCT 3D analysis in non-human primate model. AB - AIM: The aim of this study was to evaluate the efficacy of ridge preservation involving novel devices used for obturation of socket orifice (Socket cap; SocketKAP(TM) ) and resorbable cage used for space maintenance in sites with facial wall dehiscence (Socket cage; SocketKAGE(TM) ). MATERIAL AND METHODS: Eight teeth were extracted in each of six Macaca fascicularis non-human primates. Six intervention groups consisted of the following: Group A: intact socket negative control. Group B: intact socket: socket cap. Group C: intact socket filled with anorganic bovine bone mineral (ABBM) + socket cap. Group D: dehiscence: negative control. Group E: dehiscence: socket cap + socket cage. Group F: dehiscence: filled with ABBM + socket cap + socket cage. CBCT scans were obtained preoperatively and at 6 and 12 weeks following intervention. The pre- and postoperative scans were superimposed, to quantify 3D volumetric alveolar bone changes. RESULTS: Volumetric bone loss occurred in all sockets, not only within the cretal zone (0-3 mm) to the ridge crest, as has been commonly reported by other investigators, but significant bone loss was also detected in the zone which was 3-6 mm apical to the alveolar crest. For intact sockets, socket cap + ABBM led to significantly greater percentages of remaining bone volume when compared to groups A and B. A significant difference favoring socket cap + socket cage + ABBM treatment was observed for sockets with facial dehiscence defects compared to groups D and E. CONCLUSIONS: Socket cap in conjunction with ABBM appears effective in limiting post-extraction volumetric bone loss in intact sockets, while socket cap + socket cage + ABBM appears effective in limiting post extraction bone loss in sockets with dehiscence defects. PMID- 26498408 TI - microRNA level is raised in the hair shafts of patients with dematomyositis in comparison with normal subjects and patients with scleroderma. AB - BACKGROUND: The diagnosis of dermatomyositis is sometimes difficult. We tried to evaluate the possibility that levels of Homo sapiens microRNA-214 (hsa-miR-214) in hair roots or hair shafts can be a useful marker of the disease. METHODS: A single hair root and five pieces of hair shafts were obtained from nine patients with dermatomyositis, 15 normal subjects, and 18 patients with scleroderma before treatment. RNAs were purified from the hair roots and hair shafts using commercially available kits. cDNA was synthesized from the RNA, and miR-214 levels were measured with quantitative real-time polymerase chain reaction. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic performance of hair microRNA levels. RESULTS: The levels of miR-214 in hair shafts of patients with dermatomyositis were significantly higher than those of normal subjects and patients with scleroderma. By receiver operator curve analysis of hair shaft miR-214 levels to distinguish patients with dermatomyositis from normal subjects, the area under the curve was 0.90. The duration between symptom onset and the first visit to the hospital was significantly shorter in patients with elevated hair shafts miR-214 levels, suggesting that they have more severe subjective symptoms. On the other hand, we could not find significant differences in hair root miR-214 levels among normal subjects and patients with dermatomyositis and scleroderma. CONCLUSIONS: Hair shaft miR-214 levels are useful for diagnosis and evaluating the disease severity of dermatomyositis. Hair microRNA levels may have potential to be a novel and less invasive biomarker. PMID- 26498409 TI - The role of Nrf2 in protection against Pb-induced oxidative stress and apoptosis in SH-SY5Y cells. AB - Lead exerts severe adverse effects on the nervous system in which oxidative stress might mediate impairments. In this study, we focused on Nrf2, which has been identified to significantly influence the protection of a cellular system against many xenobiotic compounds. We found that PbAc exhibited neurotoxicity mainly through oxidant-based processes and could be inhibited by NAC and DPI in SH-SY5Y cells. As a defense response, Nrf2 was activated when exposed to PbAc, thereby inducing a rapid increase in Nrf2 nuclear accumulation, as well as Nrf2 ARE binding activities in a ROS-dependent manner. Analysis of Nrf2-regulated gene expression and protein showed that PbAc could induce the mRNA transcription of HO 1, GSTalpha1, GCLM, GCLC, and NQO1, as well as the protein expression of HO-1 and gamma-GCS. The responses of these genes to PbAc were regulated by Nrf2. Silencing Nrf2 expression in SH-SY5Y cells inhibited PbAc-induced gene transcription and protein expression. Overexpression of Nrf2 led to decreased ROS production and cell apoptosis, as well as increased cell viability under PbAc exposure. These results indicated that the Nrf2-ARE system exhibited a protective role in Pb induced neurotoxicity, providing potential therapeutic strategies for the prevention and treatment of Pb-related diseases. PMID- 26498410 TI - Sub-chronic (13-week) oral toxicity study, preceded by an in utero exposure phase and genotoxicity studies with fish source phosphatidylserine in rats. AB - The safety of fish phosphatidylserine (PS) conjugated to DHA (InCogTM) was examined in a series of toxicology studies as first step to support future use in infants and general population using in vitro genotoxicity tests and in a sub chronic toxicity study with an in-utero exposure phase. PS is a major lipid in the cell membrane, active in various membrane-mediated processes. PS-DHA, present in human milk, has been suggested to be important for early brain development. Rats were exposed to diets containing 1.5%, 3% or 4.5% InCog or two control diets. Parental (F0) animals were fed throughout mating, gestation and lactation. Subsequently, a subchronic, 13-week study was conducted on the F1 animals followed by 4 weeks of recovery. The genotoxicity tests showed no mutagenicity potential. No significant toxicological findings were found in the F0 rats or the F1 pups. In the 13-weeks study, an increase in the presence of renal minimal-mild multifocal corticomedullary mineralization was noted in nine females of the high dose group. This change was not associated with any inflammatory or degenerative changes in the kidneys. The no-observed-adverse-effect level (NOAEL) in the present study was placed at 3% in the diet (mid-dose group), equivalent to an overall intake of at least 2.1 g InCog/kg bw/day in the F1 generation. PMID- 26498411 TI - Protective effect of gastrodin on bile duct ligation-induced hepatic fibrosis in rats. AB - Gastrodin has been showed to possess many beneficial physiological functions, including protection against inflammation and oxidation and apoptosis. Studies showed inflammation and oxidation play important roles in producing liver damage and initiating hepatic fibrogenesis. However, it has not been reported whether gastrodin has a protective effect against hepatic fibrosis or not. This is first ever made attempts to test gastrodin against liver fibrosis in bile duct ligation (BDL) rats. The aim of the present study is to evaluate the effect of gastrodin on BDL-induced hepatic fibrosis in rats. BDL rats were divided into two groups, BDL alone group, and BDL-gastrodin group treated with gastrodin (5 mg/ml in drinking water). The effects of gastrodin on BDL-induced hepatic injury and fibrosis in rats were estimated by assessing serum, urine, bile and liver tissue biochemistry followed by liver histopathology (using hematoxylin & eosin and sirius red stain) and hydroxyproline content measurement. The results showed that gastrodin treatment significantly reduced collagen content, bile duct proliferation and parenchymal necrosis after BDL. The serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) decreased with gastrodin treatment by 15.1 and 23.6 percent respectively in comparison to BDL group did not receive gastrodin. Gastrodin also significantly increased the level of serum high density lipoprotein (HDL) by 62.5 percent and down-regulated the elevated urine total bilirubin (TBIL) by 56.5 percent, but had no effect on total bile acid (TBA) in serum, bile and liver tissues. The immunohistochemical assay showed gastrodin remarkably reduced the expressions of CD68 and NF-kappaB in BDL rats. Hepatic SOD levels, depressed by BDL, were also increased by gastrodin by 8.4 percent. In addition, the increases of hepatic MDA and NO levels in BDL rats were attenuated by gastrodin by 31.3 and 38.7 percent separately. Our results indicate that gastrodin significantly attenuated the severity of BDL-induced hepatic injury and fibrosis by attenuating oxidative stress and inflammation. Taken together, these findings suggest that gastrodin might be an effective antifibrotic drug in cholestatic liver disease. PMID- 26498412 TI - Improving advance care planning and bereavement outcomes. PMID- 26498413 TI - Functional status metrics in kidney transplantation: implications for patients, programs, and policy makers. PMID- 26498414 TI - Progress in emergency preparedness for dialysis care 10 years after Hurricane Katrina. PMID- 26498415 TI - Timing of dialysis initiation, duration and frequency of hemodialysis sessions, and membrane flux: a systematic review for a KDOQI clinical practice guideline. AB - BACKGROUND: In 2006, NKF-KDOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) published clinical practice guidelines for hemodialysis adequacy. Recent studies evaluating hemodialysis adequacy as determined by initiation timing, frequency, duration, and membrane type and prompted an update to the guideline. STUDY DESIGN: Systematic review and evidence synthesis. SETTING & POPULATION: Patients with advanced chronic kidney disease receiving hemodialysis. SELECTION CRITERIA FOR STUDIES: We screened publications from 2000 to March 2014, systematic reviews, and references and consulted the NKF KDOQI Hemodialysis Adequacy Work Group members. We included randomized or controlled clinical trials in patients undergoing long-term hemodialysis if they reported outcomes of interest. INTERVENTIONS: Early versus late dialysis therapy initiation; more frequent (>3 times a week) or longer duration (>4.5 hours) compared to conventional hemodialysis; low- versus high-flux dialyzer membranes. OUTCOMES: All-cause and cardiovascular mortality, myocardial infarction, stroke, hospitalizations, quality of life, depression or cognitive function scores, blood pressure, number of antihypertensive medications, left ventricular mass, interdialytic weight gain, and harms or complications related to vascular access or the process of dialysis. RESULTS: We included 32 articles reporting on 19 trials. Moderate-quality evidence indicated that earlier dialysis therapy initiation (at estimated creatinine clearance [eClcr] of 10-14mL/min) did not reduce mortality compared to later initiation (eClcr of 5-7mL/min). More than thrice-weekly hemodialysis and extended-length hemodialysis during a short follow up did not improve clinical outcomes compared to conventional hemodialysis and resulted in a greater number of vascular access procedures (very low-quality evidence). Hemodialysis using high-flux membranes did not reduce all-cause mortality, but reduced cardiovascular mortality compared to hemodialysis using low-flux membranes (moderate-quality evidence). LIMITATIONS: Few studies were adequately powered to evaluate mortality. Heterogeneity of study designs and interventions precluded pooling data for most outcomes. CONCLUSIONS: Limited data indicate that earlier dialysis therapy initiation and more frequent and longer hemodialysis did not improve clinical outcomes compared to conventional hemodialysis. PMID- 26498416 TI - KDOQI Clinical Practice Guideline for Hemodialysis Adequacy: 2015 update. AB - The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) has provided evidence-based guidelines for all stages of chronic kidney disease (CKD) and related complications since 1997. The 2015 update of the KDOQI Clinical Practice Guideline for Hemodialysis Adequacy is intended to assist practitioners caring for patients in preparation for and during hemodialysis. The literature reviewed for this update includes clinical trials and observational studies published between 2000 and March 2014. New topics include high-frequency hemodialysis and risks; prescription flexibility in initiation timing, frequency, duration, and ultrafiltration rate; and more emphasis on volume and blood pressure control. Appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Limitations of the evidence are discussed and specific suggestions are provided for future research. PMID- 26498417 TI - A jar of encouragement: a nurse's point of view of depression in the hemodialysis setting. PMID- 26498418 TI - Quiz page November 2015: hematuria in a child with tuberous sclerosis. PMID- 26498419 TI - AJKD Atlas of Renal Pathology: IgA nephropathy. PMID- 26498420 TI - AJKD Atlas of Renal Pathology: Fabry nephropathy. PMID- 26498421 TI - AJKD Atlas of Renal Pathology: diabetic nephropathy. PMID- 26498422 TI - AJKD Atlas of Renal Pathology: acute antibody-mediated rejection. PMID- 26498423 TI - AJKD Atlas of Renal Pathology: chronic antibody-mediated rejection. PMID- 26498424 TI - Who are gynandromorphophilic men? Characterizing men with sexual interest in transgender women. AB - BACKGROUND: Gynandromorphophilia (GAMP) is sexual interest in gynandromorphs (GAMs; colloquially, shemales). GAMs possess a combination of male and female physical characteristics. Thus, GAMP presents a challenge to conventional understandings of sexual orientation as sexual attraction to the male v. female form. Speculation about GAMP men has included the ideas that they are homosexual, heterosexual, or especially, bisexual. METHOD: We compared genital and subjective sexual arousal patterns of GAMP men with those of heterosexual and homosexual men. We also compared these groups on their self-ratings of sexual orientation and sexual interests. RESULTS: GAMP men had arousal patterns similar to those of heterosexual men and different from those of homosexual men. However, compared to heterosexual men, GAMP men were relatively more aroused by GAM erotic stimuli than by female erotic stimuli. GAMP men also scored higher than both heterosexual and homosexual men on a measure of autogynephilia. CONCLUSIONS: Results provide clear evidence that GAMP men are not homosexual. They also indicate that GAMP men are especially likely to eroticize the idea of being a woman. PMID- 26498425 TI - Targeting lysosomal Ca2+ to reduce reperfusion injury. PMID- 26498426 TI - Anti-inflammatory effects of potato extract on a rat model of cigarette smoke induced chronic obstructive pulmonary disease. AB - OBJECTIVE: This study aimed to evaluate the therapeutic effects of potato extract (PE) on cigarette smoke (CS)-induced chronic obstructive pulmonary disease (COPD). METHODS: PE was first prepared by frozen centrifugation, and its amino acid composition was detected. Toxicity of PE was analyzed by changes in morphology, behavior, routine blood indexes, and biochemical criteria of mice. Then, the COPD rat model was established by CS exposure, and PE, doxofylline, and prednisolone acetate were used to treat these rats. After 45 days of treatment, the morphology and behavior of rats were recorded. In addition, the histopathology of lung tissue was evaluated by chest x-ray and hematoxylin and eosin staining. The expression of interleukine-10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and granulocyte colony-stimulating factor (G-CSF) was detected in serum and lung tissue by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. RESULTS: Various amino acids were identified in PE, and no toxicity was exhibited in mice. The CS-induced COPD rat model was successfully established, which exhibited significant thickened and disordered lung markings on 90% of the rats. After administering doxofylline and prednisolone acetate, inflammation symptoms were improved. However, side effects such as emaciation, weakness, and loosening of teeth appeared. In the PE group, obviously improved histopathology was observed in lung tissues. Meanwhile, it was revealed that PE could increase the expression of IL-10 and reduce the expression of TNF-alpha and G-CSF in COPD rats, and doxofylline and prednisolone acetate also elicited similar results. CONCLUSION: Our study suggests PE might be effective in the treatment of CS-induced COPD by inhibiting inflammation. PMID- 26498427 TI - Carbohydrate ingestion but not mouth rinse maintains sustained attention when fasted. AB - Carbohydrate (CHO) receptors in the mouth signal brain areas involved in cognitive tasks relying upon motivation and task persistence; however, the minimal CHO dose that improves mental activity is unclear. PURPOSE: To determine if CHO (via ingestion or oral rinse) influences sustained attention without eliciting glycemic responses when in a fasted state. METHODS: Study A: Six healthy adults completed five treatment trials, ingesting 0-6% CHO solutions to evaluate glycemic response. Peak blood glucose for 6% and 1.5% CHO was greater (p<0.05) than 0% and 0.4% CHO; thus, the low 0.4% CHO was evaluated further. Study B: Following an overnight fast, ten healthy adults completed three trials in a crossover design: 1) 400 ml 0.4% CHO ingested serially via 25 ml boluses, 2) 375 ml 0% CHO control (CON) ingested followed by one 25 ml 6% CHO isocaloric (1.5 g CHO) mouth rinse, and 3) CON ingest followed by CON rinse. Following treatments, a 20 min Continuous Performance Task (CPT) was performed to assess accuracy and precision. RESULTS: Accuracy and precision were not different during the first 5 min of CPT. However, accuracy was maintained with CHO ingest (p=1.0) but decreased over 20 min (p<0.05) with both CHO and CON rinse treatments. Precision tended to decline over 20 min CPT with CON (p=0.06) and CHO rinse (p=0.05) but were maintained with CHO ingest (p=1.0). No differences in glycemic responses were observed between treatments. CONCLUSIONS: Compared to mouth rinsing CON or CHO (1.5 g in 6% CHO), ingestion of an isocaloric low-CHO drink maintained sustained attention over a mentally fatiguing task and appears effective after fasting without eliciting a glycemic response. PMID- 26498428 TI - Switching from constant voltage to constant current in deep brain stimulation: a multicenter experience of mixed implants for movement disorders. AB - BACKGROUND AND PURPOSE: For many years deep brain stimulation (DBS) devices relied only on voltage-controlled stimulation (CV), but recently current controlled devices have been developed and approved for new implants as well as for replacement of CV devices after battery drain. Constant-current (CC) stimulation has been demonstrated to be effective in new implanted parkinsonian and dystonic patients, but the effect of switching to CC therapy in patients chronically stimulated with CV implantable pulse generators (IPGs) has not been assessed. This report shows the results of a consecutive retrospective data collection performed at five Italian centers before and after replacement of constant-voltage with constant-current DBS devices, in order to verify the clinical efficacy and safety of this procedure. METHODS: Nineteen patients with Parkinson's disease or dystonic syndrome underwent DBS IPG CV/CC replacement. Clinical features and therapy satisfaction were assessed before surgery, 1 week after and 3 and 6 months after replacement. Programming settings and impedances were recorded before removing the CV device and when the CC IPGs were switched on. RESULTS: The clinical outcome of CC stimulation was similar to that obtained with CV devices and remained stable at 3 and 6 months of follow-up. Impedance values recorded for CV and CC IPGs were similar. Ninety-five percent of patients and physicians were satisfied with mixed implants. No adverse events occurred after IPG replacement. CONCLUSION: Replacing CV with CC IPGs is a safe and effective procedure. Longer follow-up is necessary to better clarify the impact of CC stimulation on clinical outcome after chronic stimulation in CV mode. PMID- 26498429 TI - Temporal changes in alcohol-related mortality and morbidity in Australia. AB - BACKGROUND AND AIMS: Alcohol consumption is an avoidable risk factor for morbidity and mortality. Studies have examined relative risks and outcomes of alcohol-related harms in Australia at discrete times, limiting the ability to examine changes across time. This paper examined alcohol consumption and its contribution to deaths, illness and injury at two time-points, 2001 and 2010. DESIGN: Alcohol consumption was modelled based on the 2001 and 2010 National Drug Strategy Household Survey, upshifted to reflect alcohol sales data. SETTING: All data reported are from Australian sources. MEASUREMENTS: Based on relative risk estimates obtained from meta-analysis, alcohol-attributable fractions were estimated for 42 disease and injury categories in 2001 and 2010 separately for conditions that were not 100% alcohol-attributable. Deaths and hospital separations attributable to alcohol were calculated in 2001 and 2010. FINDINGS: There was a relatively stable per capita consumption of alcohol across time, with males reporting higher levels of consumption compared with females. While there were increases in the number of abstainers from alcohol across time, the proportion of heavy alcohol consumers also increased. This corresponded with an observed increase in alcohol-attributable burden. For example, alcohol attributable deaths increased from 4957 [95% confidence interval (CI) = 2867 8770] to 5610 (95% CI = 3398-9408) during the study period. CONCLUSION: The findings demonstrate that there has been an increase in alcohol-attributable harms between 2001 and 2010 in Australia without a corresponding increase in per capita consumption. PMID- 26498430 TI - Bioelectrical activity of the pelvic floor muscles during synchronous whole-body vibration--a randomized controlled study. AB - BACKGROUND: More and more frequently stress urinary incontinence affects young healthy women. Hence, early implementation of effective preventive strategies in nulliparous continent women is essential, including pelvic floor muscle training. An initial evaluation based on the bioelectrical activity of the pelvic floor muscles (PFM) during whole-body vibration (WBV) would help to devise the best individualized training for prevention of stress urinary incontinence in woman. We hypothesized that synchronous WBV enhances bioelectrical activity of the PFM which depends on vibration frequency and peak-to-peak vibration displacement. METHODS: The sample consisted of 36 nulliparous continent women randomly allocated to three comparative groups. Group I and II subjects participated in synchronous whole-body vibrations on a vibration platform; the frequency and peak to-peak displacement of vibration were set individually for each group. Control participants performed exercises similar to those used in the study groups but without the concurrent application of vibrations. Pelvic floor surface electromyography (sEMG) activity was recorded using a vaginal probe during three experimental trials limited to 30s, 60s and 90 s. The mean amplitude and variability of the signal were normalized to the Maximal Voluntary Contraction - MVC. RESULTS: Friedman's two-way ANOVA revealed a statistically significant difference in the mean normalized amplitudes (%MVC) of the sEMG signal from the PFM during 60s- and 90 s-trials between the group exposed to high-intensity WBV and control participants (p < 0.05). Longer trial duration was associated with a statistically significant decrease in the variability of sEMG signal amplitude in the study and control groups (p < 0.05). CONCLUSIONS: Synchronous high-intensity WBV (40 Hz, 4 mm) of long duration (60s, 90 s) significantly enhances the activation of the PFM in young continent women. Prolonged maintenance of a static position significantly decreases the variability of sEMG signal amplitude independent of whole-body vibrations. Single whole-body vibrations in nulliparous continent women does not cause pelvic floor muscle fatigue. TRIAL REGISTRATION: The trial was registered in the Australian and New Zealand Clinical Trials Registry (no. ACTRN12615000966594); registration date: 15/09/2015. PMID- 26498432 TI - Consideration Sets and Their Role in Modelling Doctor Recommendations About Contraceptives. AB - Decisions about prescribed contraception are typically the result of a consultation between a woman and her doctor. In order to better understand contraceptive choice within this environment, stated preference methods are utilized to ask doctors about what contraceptive options they would discuss with different types of women. The role of doctors is to confine their discussion to a subset of products that best match their patient. This subset of options forms the consideration set from which the ultimate recommendation is made. Given the existence of consideration sets we address the issue of how to model appropriately the ultimate recommendations. The estimated models enable us to characterize doctor recommendations and how they vary with patient attributes and to highlight where recommendations are clear and when they are uncertain. The results also indicate systematic variation in recommendations across different types of doctors, and in particular we observe that some doctors are reluctant to embrace new products and instead recommend those that are more familiar. Such effects are one possible explanation for the relatively low uptake of more cost effective longer acting reversible contraceptives and indicate that further education and training of doctors may be warranted. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26498433 TI - Subcortical Volume Loss in the Thalamus, Putamen, and Pallidum, Induced by Traumatic Brain Injury, Is Associated With Motor Performance Deficits. AB - BACKGROUND: Traumatic brain injury (TBI) has been associated with altered microstructural organization of white matter (WM) and reduced gray matter (GM). Although disrupted WM organization has been linked to poorer motor performance, the predictive value of GM atrophy for motor impairments in TBI remains unclear. OBJECTIVE: Here, we investigated TBI-induced GM volumetric abnormalities and uniquely examined their relationship with bimanual motor impairments. METHODS: 22 moderate to severe TBI patients (mean age = 25.9 years, standard deviation [SD] = 4.9 years; time since injury = 4.7 years, SD = 3.7 years) and 27 age- and gender matched controls (mean age = 23.4 years; SD = 3.8 years) completed bimanual tasks and a structural magnetic resonance imaging scan. Cortical and subcortical GM volumes were extracted and compared between groups using FreeSurfer. The association between bimanual performance and GM volumetric measures was investigated using partial correlations. RESULTS: Relative to controls, patients performed significantly poorer on the bimanual tasks and demonstrated significantly smaller total GM as well as overall and regional subcortical GM. However, the groups did not show significant differences in regional cortical GM volume. The majority of the results remained significant even after excluding TBI patients with focal lesions, suggesting that TBI-induced volume reductions were predominantly caused by diffuse injury. Importantly, atrophy of the thalamus, putamen, and pallidum correlated significantly with poorer bimanual performance within the TBI group. CONCLUSIONS: Our results reveal that GM atrophy is associated with motor impairments in TBI, providing new insights into the etiology of motor control impairments following brain trauma. PMID- 26498431 TI - Breaking Down the Bilingual Cost in Speech Production. AB - Bilinguals have been shown to perform worse than monolinguals in a variety of verbal tasks. This study investigated this bilingual verbal cost in a large-scale picture-naming study conducted in Spanish. We explored how individual characteristics of the participants and the linguistic properties of the words being spoken influence this performance cost. In particular, we focused on the contributions of lexical frequency and phonological similarity across translations. The naming performance of Spanish-Catalan bilinguals speaking in their dominant and non-dominant language was compared to that of Spanish monolinguals. Single trial naming latencies were analyzed by means of linear mixed models accounting for individual effects at the participant and item level. While decreasing lexical frequency was shown to increase naming latencies in all groups, this variable by itself did not account for the bilingual cost. In turn, our results showed that the bilingual cost disappeared when naming words with high phonological similarity across translations. In short, our results show that frequency of use can play a role in the emergence of the bilingual cost, but that phonological similarity across translations should be regarded as one of the most important variables that determine the bilingual cost in speech production. Low phonological similarity across translations yields worse performance in bilinguals and promotes the bilingual cost in naming performance. The implications of our results for the effect of phonological similarity across translations within the bilingual speech production system are discussed. PMID- 26498435 TI - Renal-type clear cell carcinoma of the prostate: a diagnostic challenge. AB - A 72-year-old male presented with urinary symptoms. His serum prostate specific antigen level was 65.2 ng/ml. His radical prostatectomy specimen showed clear cell lesion reminiscent of the clear cell renal cell carcinoma along with acinar type of prostatic adenocarcinoma, Gleason score 4 + 4. The lesional clear cells were positive for pancytokeratin, epithelial membrane antigen, CD10, vimentin, and AMACR while negative for 34betaE12, CK7, prostate specific antigen, and PAX8. The final diagnosis was renal-type clear cell carcinoma of the prostate. A follow up of 20 months did not show metastasis. We herein report fifth case of renal type clear cell carcinoma of the prostate. PMID- 26498434 TI - The Effects of Stroke Type, Locus, and Extent on Long-Term Outcome of Gait Rehabilitation: The LEAPS Experience. AB - Background Paresis in stroke is largely a result of damage to descending corticospinal and corticobulbar pathways. Recovery of paresis predominantly reflects the impact on the neural consequences of this white matter lesion by reactive neuroplasticity (mechanisms involved in spontaneous recovery) and experience-dependent neuroplasticity, driven by therapy and daily experience. However, both theoretical considerations and empirical data suggest that type of stroke (large vessel distribution/lacunar infarction, hemorrhage), locus and extent of infarction (basal ganglia, right-hemisphere cerebral cortex), and the presence of leukoaraiosis or prior stroke might influence long-term recovery of walking ability. In this secondary analysis based on the 408 participants in the Locomotor Experience Applied Post-Stroke (LEAPS) study database, we seek to address these possibilities. Methods Lesion type, locus, and extent were characterized by the 2 neurologists in the LEAPS trial on the basis of clinical computed tomography and magnetic resonance imaging scans. A series of regression models was used to test our hypotheses regarding the effects of lesion type, locus, extent, and laterality on 2- to 12-month change in gait speed, controlling for baseline gait speed, age, and Berg Balance Scale score. Results Gait speed change at 1 year was significantly reduced in participants with basal ganglia involvement and prior stroke. There was a trend toward reduction of gait speed change in participants with lacunar infarctions. The presence of right-hemisphere cortical involvement had no significant impact on outcome. Conclusions Type, locus, and extent of lesion, and the loss of substrate for neuroplastic effect as a result of prior stroke may affect long-term outcome of rehabilitation of hemiparetic gait. PMID- 26498437 TI - Evolution and challenges of dynamic global vegetation models for some aspects of plant physiology and elevated atmospheric CO2. AB - Dynamic global vegetation models (DGVMs) simulate surface processes such as the transfer of energy, water, CO2, and momentum between the terrestrial surface and the atmosphere, biogeochemical cycles, carbon assimilation by vegetation, phenology, and land use change in scenarios of varying atmospheric CO2 concentrations. DGVMs increase the complexity and the Earth system representation when they are coupled with atmospheric global circulation models (AGCMs) or climate models. However, plant physiological processes are still a major source of uncertainty in DGVMs. The maximum velocity of carboxylation (Vcmax), for example, has a direct impact over productivity in the models. This parameter is often underestimated or imprecisely defined for the various plant functional types (PFTs) and ecosystems. Vcmax is directly related to photosynthesis acclimation (loss of response to elevated CO2), a widely known phenomenon that usually occurs when plants are subjected to elevated atmospheric CO2 and might affect productivity estimation in DGVMs. Despite this, current models have improved substantially, compared to earlier models which had a rudimentary and very simple representation of vegetation-atmosphere interactions. In this paper, we describe this evolution through generations of models and the main events that contributed to their improvements until the current state-of-the-art class of models. Also, we describe some main challenges for further improvements to DGVMs. PMID- 26498438 TI - A joint latent class model for classifying severely hemorrhaging trauma patients. AB - BACKGROUND: In trauma research, "massive transfusion" (MT), historically defined as receiving >=10 units of red blood cells (RBCs) within 24 h of admission, has been routinely used as a "gold standard" for quantifying bleeding severity. Due to early in-hospital mortality, however, MT is subject to survivor bias and thus a poorly defined criterion to classify bleeding trauma patients. METHODS: Using the data from a retrospective trauma transfusion study, we applied a latent-class (LC) mixture model to identify severely hemorrhaging (SH) patients. Based on the joint distribution of cumulative units of RBCs and binary survival outcome at 24 h of admission, we applied an expectation-maximization (EM) algorithm to obtain model parameters. Estimated posterior probabilities were used for patients' classification and compared with the MT rule. To evaluate predictive performance of the LC-based classification, we examined the role of six clinical variables as predictors using two separate logistic regression models. RESULTS: Out of 471 trauma patients, 211 (45 %) were MT, while our latent SH classifier identified only 127 (27 %) of patients as SH. The agreement between the two classification methods was 73 %. A non-ignorable portion of patients (17 out of 68, 25 %) who died within 24 h were not classified as MT but the SH group included 62 patients (91 %) who died during the same period. Our comparison of the predictive models based on MT and SH revealed significant differences between the coefficients of potential predictors of patients who may be in need of activation of the massive transfusion protocol. CONCLUSIONS: The traditional MT classification does not adequately reflect transfusion practices and outcomes during the trauma reception and initial resuscitation phase. Although we have demonstrated that joint latent class modeling could be used to correct for potential bias caused by misclassification of severely bleeding patients, improvement in this approach could be made in the presence of time to event data from prospective studies. PMID- 26498439 TI - Neurocognitive effects of proton radiation therapy in adults with low-grade glioma. AB - To understand neurocognitive effects of proton radiation therapy (PRT) in patients with low-grade glioma, we evaluated 20 patients who received this therapy prospectively and over 5 years with a comprehensive neuropsychological battery. 20 patients were evaluated at baseline and at yearly intervals for up to 5 years with a battery of neuropsychological measures that assessed intellectual, attention, executive, visuospatial and memory functions as well as mood and functional status. We evaluated change in cognitive functioning over time. We analyzed the relationship between cognitive performance and tumor location and also examined whether patients' performance differed from that reported in a study of normative practice effects. Overall, patients exhibited stability in cognitive functioning. Tumor location played a role in performance; those with tumors in the left hemisphere versus in the right hemisphere were more impaired at baseline on verbal measures (p < .05). However, we found greater improvement in verbal memory over time in patients with left than with right hemisphere tumors (p < .05). Results of our study, the first to investigate, in depth, neurocognitive effects of PRT in adults with low-grade gliomas, are promising. We hypothesize that the conformal advantage of PRT may contribute to preservation of cognitive functioning, although larger sample sizes and a longer period of study are required. Our study also highlights the need to consider normative practice effects when studying neurocognitive functioning in response to treatment over time, and the need to utilize comprehensive neuropsychological batteries given our findings that differentiate patients with left and right hemisphere tumors. PMID- 26498440 TI - Diachronic analysis of genetic diversity in rice landraces under on-farm conservation in Yunnan, China. AB - KEY MESSAGE: Diachronic analysis showed no significant changes in the level of genetic diversity occurred over the past 27 years' domestication, which indicated genetic diversity was successfully maintained under on-farm conservation. Rice (Oryza sativa L.) is one of the earliest domesticated crop species. Its genetic diversity has been declining as a result of natural and artificial selection. In this study, we performed the first analysis of the levels and patterns of nucleotide variation in rice genomes under on-farm conservation in Yunnan during a 27-year period of domestication. We performed large-scale sequencing of 600 rice accessions with high diversity, which were collected in 1980 and 2007, using ten unlinked nuclear loci. Diachronic analysis showed no significant changes in the level of genetic diversity occurring over the past 27 years' domestication, which indicated genetic diversity was successfully maintained under on-farm conservation. Population structure revealed that the rice landraces could be grouped into two subpopulations, namely the indica and japonica groups. Interestingly, the alternate distribution of indica and japonica rice landraces could be found in each ecological zone. The results of AMOVA showed that on-farm conservation provides opportunities for continued differentiation and variation of landraces. Therefore, dynamic conservation measures such as on-farm conservation (which is a backup, complementary strategy to ex situ conservation) should be encouraged and enhanced, especially in crop genetic diversity centers. The results of this study offered accurate insights into short-term evolutionary processes and provided a scientific basis for on-farm management practices. PMID- 26498441 TI - Identification of stable QTLs causing chalk in rice grains in nine environments. AB - KEY MESSAGE: A novel QTL cluster for chalkiness on Chr04 was identified using single environment analysis and joint mapping across 9 environments in Asia and South American. QTL NILs showed that each had a significant effect on chalk. Chalk in rice grains leads to a significant loss in the proportion of marketable grains in a harvested crop, leading to a significant financial loss to rice farmers and traders. To identify the genetic basis of chalkiness, two sets of recombinant inbred lines (RILs) derived from reciprocal crosses between Lemont and Teqing were used to find stable QTLs for chalkiness. The RILs were grown in seven locations in Asia and Latin American and in two controlled environments in phytotrons. A total of 32 (21) and 46 (22) QTLs for DEC and PGWC, most of them explaining more than 10% of phenotypic variation, were detected based on single environment analysis in T/L (L/T) population, respectively. Seven (2) and 7 (3) QTLs for DEC and PGWC were identified in the T/L (L/T) population using joined analysis across all environments, respectively. Six major QTLs clusters were found on five chromosomes: 1, 2, 4, 5 and 11. The biggest cluster at id4007289 RM252 on Chr04 was a novelty, including 16 and 4 QTLs detected by single environment analysis and joint mapping across all environments, respectively. The detected digenic epistatic QTLs explained up to 13% of phenotypic variation, suggesting that epistasis play an important role in the genetic control of chalkiness in rice. QTL NILs showed that each QTL cluster had a significant effect on chalk. These chromosomal regions could be targets for MAS, fine mapping and map-based cloning for low chalkiness breeding. PMID- 26498443 TI - Student-directed retrieval practice is a predictor of medical licensing examination performance. AB - INTRODUCTION: A large body of evidence indicates that retrieval practice (test enhanced learning) and spaced repetition increase long-term information retention. Implementation of these strategies in medical curricula is unfortunately limited. However, students may choose to apply them autonomously when preparing for high-stakes, cumulative assessments, such as the United States Medical Licensing Examination Step 1. We examined the prevalence of specific self directed methods of testing, with or without spaced repetition, among preclinical students and assessed the relationship between these methods and licensing examination performance. METHODS: Seventy-two medical students at one institution completed a survey concerning their use of user-generated (Anki) or commercially available (Firecracker) flashcards intended for spaced repetition and of boards style multiple-choice questions (MCQs). Other information collected included Step 1 score, past academic performance (Medical College Admission Test [MCAT] score, preclinical grades), and psychological factors that may have affected exam preparation or performance (feelings of depression, burnout, and test anxiety). RESULTS: All students reported using practice MCQs (mean 3870, SD 1472). Anki and Firecracker users comprised 31 and 49 % of respondents, respectively. In a multivariate regression model, significant independent predictors of Step 1 score included MCQs completed (unstandardized beta coefficient [B] = 2.2 * 10- 3, p < 0.001), unique Anki flashcards seen (B = 5.9 * 10- 4, p = 0.024), second-year honours (B = 1.198, p = 0.002), and MCAT score (B = 1.078, p = 0.003). Test anxiety was a significant negative predictor (B= - 1.986, p < 0.001). Unique Firecracker flashcards seen did not predict Step 1 score. Each additional 445 boards-style practice questions or 1700 unique Anki flashcards was associated with an additional point on Step 1 when controlling for other academic and psychological factors. CONCLUSIONS: Medical students engage extensively in self initiated retrieval practice, often with spaced repetition. These practices are associated with superior performance on a medical licensing examination and should be considered for formal support by educators. PMID- 26498444 TI - Is assessment good for learning or learning good for assessment? A. Both? B. Neither? C. It depends? PMID- 26498442 TI - Whole exome sequencing of microdissected splenic marginal zone lymphoma: a study to discover novel tumor-specific mutations. AB - BACKGROUND: Splenic marginal zone lymphoma (SMZL) is an indolent B-cell non Hodgkin lymphoma and represents the most common primary malignancy of the spleen. Its precise molecular pathogenesis is still unknown and specific molecular markers for diagnosis or possible targets for causal therapies are lacking. METHODS: We performed whole exome sequencing (WES) and copy number analysis from laser-microdissected tumor cells of two primary SMZL discovery cases. Selected somatic single nucleotide variants (SNVs) were analyzed using pyrosequencing and Sanger sequencing in an independent validation cohort. RESULTS: Overall, 25 nonsynonymous somatic SNVs were identified, including known mutations in the NOTCH2 and MYD88 genes. Twenty-three of the mutations have not been associated with SMZL before. Many of these seem to be subclonal. Screening of 24 additional SMZL for mutations at the same positions found mutated in the WES approach revealed no recurrence of mutations for ZNF608 and PDE10A, whereas the MYD88 L265P missense mutation was identified in 15% of cases. An analysis of the NOTCH2 PEST domain and the whole coding region of the transcription factor SMYD1 in eight cases identified no additional case with a NOTCH2 mutation, but two additional cases with SMYD1 alterations. CONCLUSIONS: In this first WES approach from microdissected SMZL tissue we confirmed known mutations and discovered new somatic variants. Recurrence of MYD88 mutations in SMZL was validated, but NOTCH2 PEST domain mutations were relatively rare (10 % of cases). Recurrent mutations in the transcription factor SMYD1 have not been described in SMZL before and warrant further investigation. PMID- 26498445 TI - Marine bacteria from the French Atlantic coast displaying high forming-biofilm abilities and different biofilm 3D architectures. AB - BACKGROUND: Few studies have reported the species composition of bacterial communities in marine biofilms formed on natural or on man-made existing structures. In particular, the roles and surface specificities of primary colonizers are largely unknown for most surface types. The aim of this study was to obtain potentially pioneering bacterial strains with high forming-biofilm abilities from two kinds of marine biofilms, collected from two different surfaces of the French Atlantic coast: an intertidal mudflat which plays a central role in aquaculture and a carbon steel structure of a harbour, where biofilms may cause important damages. RESULTS: A collection of 156 marine heterotrophic aerobic bacteria isolated from both biofilms was screened for their ability to form biofilms on polystyrene 96-well microtiter plates. Out of 25 strains able to build a biofilm in these conditions, only four bacteria also formed a thick and stable biofilm on glass surfaces under dynamic conditions. These strains developed biofilms with four different three-dimensional architectures when observed by confocal laser scanning microscopy: Flavobacterium sp. II2003 biofilms harboured mushroom-like structures, Roseobacter sp. IV3009 biofilms were quite homogeneous, Shewanella sp. IV3014 displayed hairy biofilms with horizontal fibres, whereas Roseovarius sp. VA014 developed heterogeneous and tousled biofilms. CONCLUSIONS: This work led for the first time to the obtaining of four marine bacterial strains, potentially pioneering bacteria in marine biofilms, able to adhere to at least two different surfaces (polystyrene and glass) and to build specific 3D biofilms. The four selected strains are appropriate models for a better understanding of the colonization of a surface as well as the interactions that can occur between bacteria in a marine biofilm, which are crucial events for the initiation of biofouling. PMID- 26498447 TI - [Acute unilateral paracentral scotoma]. PMID- 26498446 TI - [In Process Citation]. PMID- 26498448 TI - [Ease of handling of first and second generation rebound tonometers]. AB - PURPOSE: To evaluate the ease of handling of two rebound tonometers, which are designed for self-measurement of intraocular pressure (IOP) in a clinical setting by untrained patients. METHODS: After self-measurement of the IOP with the rebound tonometers iCare ONE and iCare HOME, participants were asked to complete a questionnaire containing different subitems concerning ease of operation using a visual analog scale (1 = very good to 5 = very poor). Moreover, the feasibility and duration of measurement were tested. RESULTS: A total of 147 subjects participated in this study. The mean score for general handling ability was 2.79 +/- 1.01 for the iCare ONE and 1.85 +/- 0.87 for the iCare HOME (p < 0.001). The evaluation of the subitems sense of safety (iCare ONE: 2.71 +/- 1.03 and iCare HOME: 1.87 +/- 0.81, p < 0.001) and comfort of measurement (iCare ONE: 2.07 +/- 1.01 and iCare HOME: 1.66 +/- 0.72, p < 0.001) also showed a significant discrepancy between the two tonometers. Participants needed significantly less time for a single valid measurement when using the iCare HOME tonometer (mean 66.14 +/- 61.54 s) compared to the iCare ONE tonometer (mean 81.54 +/- 69.51 s, p < 0.001). CONCLUSIONS: A better handling of the iCare HOME rebound tonometer in comparison to the iCare ONE tonometer can be deduced on the basis of the subjective assessments of patients and the shorter duration of measurements. Moreover, the iCare HOME received a significantly better evaluation for all subitems. The accuracy of measurements using the iCare HOME still needs to be clarified. PMID- 26498449 TI - Influence of different Er,Cr:YSGG laser parameters on long-term dentin bond strength of self-etch adhesive. AB - The aim of the present study was to evaluate the effects of erbium, chromium: yattrium-scandium-gallium-garnet (Er,Cr:YSGG) laser frequency on microtensile bond strength (MUTBS) of a self-etch adhesive to dentin after 15-month water storage. The Er,Cr:YSGG laser can safely be used on dental hard tissue. However, no study has compared the effects of Er,Cr:YSGG laser parameters and aging by water storage on the bonding effectiveness of self-etch adhesives to dentin. Thirty-five bovine teeth were randomly assigned to the following seven groups (n = 5): group I (diamond bur with high-speed handpiece (control)), group II (Er,Cr:YSGG laser 3 W/50 Hz), group III (Er,Cr:YSGG laser 3 W/35 Hz), group IV (Er,Cr:YSGG laser 3 W/20 Hz), group V (Er,Cr:YSGG laser 6 W/50 Hz), group VI (Er,Cr:YSGG laser 6 W/35 Hz), and group VII (Er,Cr:YSGG laser 6 W/20 Hz). Clearfil SE Bond was applied to the prepared dentin, and the composites were placed and cured. Resin-dentin sticks with an approximate cross-sectional area of 0.8 mm(2) were obtained, and bond strength tests were performed at 24 h and 15 months of water storage after bonding. Data were analyzed with Kruskal-Wallis and Mann-Whitney U tests (p < 0.05). Laser irradiation resulted in significantly lower bond strengths when compared to bur treating. Fifteen-month water storage reduced bond strength for all groups. There was no significant difference among the effects of different laser frequencies on bond strength. It can be concluded that Er,Cr:YSGG laser used at the tested parameters may alter the dentin bond durability of self-etch adhesive. PMID- 26498450 TI - Atomic force microscopy investigation of the interaction of low-level laser irradiation of collagen thin films in correlation with fibroblast response. AB - Low-level red laser (LLRL)-tissue interactions have a wide range of medical applications and are garnering increased attention. Although the positive effects of low-level laser therapy (LLLT) have frequently been reported and enhanced collagen accumulation has been identified as one of the most important mechanisms involved, little is known about LLRL-collagen interactions. In this study, we aimed to investigate the influence of LLRL irradiation on collagen, in correlation with fibroblast response. Atomic force microscopy (AFM) and fluorescence spectroscopy were used to characterize surfaces and identify conformational changes in collagen before and after LLRL irradiation. Irradiated and non-irradiated collagen thin films were used as culturing substrates to investigate fibroblast response with fluorescence microscopy. The results demonstrated that LLRL induced small alterations in fluorescence emission and had a negligible effect on the topography of collagen thin films. However, fibroblasts cultured on LLRL-irradiated collagen thin films responded to LRLL. The results of this study show for the first time the effect of LLRL irradiation on pure collagen. Although irradiation did not affect the nanotopography of collagen, it influenced cell behavior. The role of collagen appears to be crucial in the LLLT mechanism, and our results demonstrated that LLRL directly affects collagen and indirectly affects cell behavior. PMID- 26498451 TI - Treatment of hypertrophic scars and keloids by fractional carbon dioxide laser: a clinical, histological, and immunohistochemical study. AB - Treatment of keloids (K) and hypertrophic scars (HTS) is challenging. A few case reports reported good results in HTS treated by fractional CO2 laser. The aim of the present study was the assessment of the clinical response as well as histological changes in K and HTS treated by fractional CO2 laser and the role of matrix metalloproteinase 9 (MMP9) in the response. A randomized half of the scar was treated by fractional CO2 laser in 30 patients (18 K, 12 HTS) for a total of four sessions 6 weeks apart. Vancouver scar score (VSS) was done before and 1, 3, and 6 months after the last laser session by a blinded observer. Biopsies taken from normal skin, untreated scar, and treated scar tissue 1 and 3 months after the laser sessions were stained by HX & E for histological changes and Masson trichrome for collagen fiber arrangement. Immunohistochemical staining for MMP9 was done in before and 1 month after samples. Quantitative morphometric analysis was done for collagen and MMP9 by image analyzer. Nineteen patients completed the 6-month follow-up period (12 K, 7 HTS). VSS score was significantly lower in the treated compared to untreated areas after 3 and 6 months in both K and HTS but was mainly due to improved pliability of the scar. Histologically, dense inflammatory infiltrate and increased vascularity was apparent 1 month after laser sessions and disappeared at 3 months. Thinner better organized collagen bundle could be seen in 3 months after samples. MMP9 was significantly increased in after treatment samples but without significant correlation with VSS. Fractional CO2 resurfacing is safe but affects mainly pliability of K and HTS with collagen remodeling apparent 3 months after therapy. MMP9 may play a role in mechanism of action of CO2 laser in K and HTS. PMID- 26498452 TI - Analysis of experimental tendinitis in rats treated with laser and platelet-rich plasma therapies by Raman spectroscopy and histometry. AB - The objective of this controlled experimental study was to analyze the changes in the Achilles tendons of rats with experimentally induced tendinitis after treatment with platelet-rich plasma (PRP) and/or laser therapies by histometry to quantify fibroblasts and by Raman spectroscopy to determine the biochemical concentration of collagen types I and III. Fifty-four male Wistar rats were divided into six treatment groups: control (G1); PRP only (G2); irradiation with 660 nm laser (G3); irradiation with 830 nm laser (G4); PRP plus 660 nm laser irradiation (G5); and PRP plus 830 nm laser irradiation (G6). Injuries (partial tenotomy) were inflicted in the middle third of the Achilles tendon, with PRP added prior to suture in the appropriate experimental groups. A diode laser (model Laser Flash(r) III, DMC Equipamentos Ltda, Sao Carlos, SP, Brazil) that can be operated in two wavelengths 660 and 830 nm was used for irradiation treatments. The irradiation protocol was energy density of 70 J/cm2, 20 s irradiation time, and 0.028 cm2 spot area, per point in three points in the injured. The histometry was made in micrographical images of the H&E stained sections and evaluated by ImageJ (version 1.46r)(r). Raman spectra were collected using a dispersive spectrometer at 830 nm excitation, 200 mW power, and 10 s integration time (P-1 Raman system, Lambda Solutions, Inc. MA, USA). The relative amount of type I collagen was significantly greater in the PRP plus 830 nm laser irradiation group (468 +/- 188) than in the control (147 +/- 137), 630 nm laser only (191 +/- 117), and 830 nm laser only (196 +/- 106) groups (p < 0.01), while the quantity of type III collagen was significantly greater in the PRP-only group compared to both irradiated groups without PRP (p < 0.05). Treatment with PRP combined with irradiation at 830 nm resulted in a larger number of fibroblasts and increased concentration of type I collagen, thus accelerating the healing of the injured tendon. PMID- 26498453 TI - Pre-stimulation of CD81 expression by resting B cells increases proliferation following EBV infection, but the overexpression of CD81 induces the apoptosis of EBV-transformed B cells. AB - Hepatitis C virus (HCV) E2 protein binds to CD81, which is a component of the B cell co-stimulatory complex. The E2-CD81 interaction leads to B cell proliferation, protein tyrosine phosphorylation and to the hypermutation of immunoglobulin genes. Epidemiological studies have reported a high prevalence of B cell non-Hodgkin lymphoma (NHL) in HCV-positive patients, suggesting a potential association between HCV and Epstein-Barr virus (EBV) in the genesis of B lymphocyte proliferative disorders. In the present study, in order to investigate the association between EBV and HCV in B cells, we created an in vitro EBV-induced B cell transformation model. CD81 was gradually overexpressed during transformation by EBV. B cells isolated from HCV-positive patients grew more rapidly and clumped together earlier than B cells isolated from healthy donors following EBV infection. Pre-stimulation of CD81 expressed by resting B cells with anti-CD81 monoclonal antibody (mAb) or HCV E2 accelerated the generation of lymphoblastoid cell lines (LCLs) by EBV infection. These cells proliferated prominently through the early expression of interleukin-10 and intracellular latent membrane protein (LMP)-l. By contrast, the overexpression of CD81 on EBV-transformed B cells by anti-CD81 mAb or HCV E2 protein induced apoptosis through reactive oxygen species (ROS)-mediated mitochondrial dysfunction. These results suggest that the engagement of CD81 expressed by B cells has differential effects on B cell fate (proliferation or apoptosis) according to EBV infection and the expression level of CD81. PMID- 26498454 TI - QCScreen: a software tool for data quality control in LC-HRMS based metabolomics. AB - BACKGROUND: Metabolomics experiments often comprise large numbers of biological samples resulting in huge amounts of data. This data needs to be inspected for plausibility before data evaluation to detect putative sources of error e.g. retention time or mass accuracy shifts. Especially in liquid chromatography-high resolution mass spectrometry (LC-HRMS) based metabolomics research, proper quality control checks (e.g. for precision, signal drifts or offsets) are crucial prerequisites to achieve reliable and comparable results within and across experimental measurement sequences. Software tools can support this process. RESULTS: The software tool QCScreen was developed to offer a quick and easy data quality check of LC-HRMS derived data. It allows a flexible investigation and comparison of basic quality-related parameters within user-defined target features and the possibility to automatically evaluate multiple sample types within or across different measurement sequences in a short time. It offers a user-friendly interface that allows an easy selection of processing steps and parameter settings. The generated results include a coloured overview plot of data quality across all analysed samples and targets and, in addition, detailed illustrations of the stability and precision of the chromatographic separation, the mass accuracy and the detector sensitivity. The use of QCScreen is demonstrated with experimental data from metabolomics experiments using selected standard compounds in pure solvent. The application of the software identified problematic features, samples and analytical parameters and suggested which data files or compounds required closer manual inspection. CONCLUSIONS: QCScreen is an open source software tool which provides a useful basis for assessing the suitability of LC-HRMS data prior to time consuming, detailed data processing and subsequent statistical analysis. It accepts the generic mzXML format and thus can be used with many different LC-HRMS platforms to process both multiple quality control sample types as well as experimental samples in one or more measurement sequences. PMID- 26498455 TI - The effect of primary midwife-led care on women's experience of childbirth: results from the COSMOS randomised controlled trial. AB - OBJECTIVE: To determine the effect of primary midwife-led care ('caseload midwifery') on women's experiences of childbirth. DESIGN: Randomised controlled trial. SETTING: Tertiary care women's hospital in Melbourne, Australia. POPULATION: A total of 2314 low-risk pregnant women. METHODS: Women randomised to caseload care received antenatal, intrapartum and postpartum care from a primary midwife, with some care provided by a 'back-up' midwife. Women in standard care received midwifery-led care with varying levels of continuity, junior obstetric care or community-based medical care. MAIN OUTCOME MEASURES: The primary outcome of the study was caesarean section. This paper presents a secondary outcome, women's experience of childbirth. Women's views and experiences were sought using seven-point rating scales via postal questionnaires 2 months after the birth. RESULTS: A total of 2314 women were randomised between September 2007 and June 2010; 1156 to caseload and 1158 to standard care. Response rates to the follow-up questionnaire were 88 and 74%, respectively. Women in the caseload group were more positive about their overall birth experience than women in the standard care group (adjusted odds ratio 1.50, 95% CI 1.22-1.84). They also felt more in control during labour, were more proud of themselves, less anxious, and more likely to have a positive experience of pain. CONCLUSIONS: Compared with standard maternity care, caseload midwifery may improve women's experiences of childbirth. TWEETABLE ABSTRACT: Primary midwife-led care ('caseload midwifery') improves women's experiences of childbirth. PMID- 26498456 TI - Synthesis and Fluorescence Properties of new Monastrol Analogs Conjugated Fluorescent Coumarin Scaffolds. AB - A mild and efficient method has been used for the synthesis of ethyl 4-(3 hydroxphenyl)-6-methyl-2-thioxo-1,3-dihydroprimidine-5-carboxylate (monastrol) (2), via Biginelli reaction. Alkylation of 2 with the fluorescent coumarin 3 afforded the new thioether analog 4. Similarly, ethyl 4-(6,8-dichloro-2-oxo-2 H chromen-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate (6) was prepared. The synthesized compounds are fluorescent active and show wavelength of maximum absorption (lambdamax) in UV or visible region in MeOH at room temperature. PMID- 26498457 TI - White Light Emission by Dy3+ Doped Phosphor Matrices: A Short Review. AB - In this review we have studied number of research papers related to white light emission from Dy3+ doped different host matrices. It is observed that most of the Dy3+doped aluminates, silicates, borates etc., emitted blue, green and red colour with specific intensities so that CIE coordinates, appeared near to white light. Correlated Colour Temperature(CCT) values of these phosphors expressed that the white light emission produced, was adaptable to human eyes. Dy3+ ions act as activator in each case. Four peaks at approximately 480,575, 670, and 757 nm could be seen in most of the Dy3+ doped phosphors. Expected transition responsible for these peaks are 4F9/2 -> 6H15/2 (Blue Colour), 4F9/2 -> 6H13/2 (Green-Yellow Colour), 4F9/2 -> 6H11/2 (Red Colour) and 4F9/2 -> 6H9/2(Brownish Red Colour). Few of the discussed phosphors exhibited long phosphorescence, starting from several minutes to few hours. Mechanism responsible for long lasting white light emission was also discussed. Five different factors, to recognize the phosphors for its suitability as commercial white light phosphor have been discussed. PMID- 26498458 TI - Dual-reporter Imaging and its Potential Application in Tracking Studies. AB - By tracking reporter molecules such as green fluorescent protein and luciferase, researchers can determine physiological status and follow processes both in vitro and in vivo.Here, we describe a dual-reporter imaging method, in which a fusion of eGFP and Luc2 is introduced into hosts using lentiviral particles based on HIV 1. The fusion molecule is both fluorescent and bioluminescent, and is therefore ideal as an optical marker in clinical and research applications.We characterized multiple technical indices of the molecule,including sensibility, biocompatibility, lifetime, and others.Lentiviral particles carrying the reporter were strongly infective in endothelial progenitor (EPC) and GL261 glioma cells,as well as in live mice. By transforming Luc2-eGFP into hosts, morphological and quantitative data can be collected not only from tissue specimens but also from live animal models. PMID- 26498459 TI - A New Star-shaped Carbazole Derivative with Polyhedral Oligomeric Silsesquioxane Core: Crystal Structure and Unique Photoluminescence Property. AB - A new inorganic-organic hybrid material based on polyhedral oligomeric silsesquioxane (POSS) capped with carbazolyl substituents, octakis[3-(carbazol-9 yl)propyldimethylsiloxy]-silsesquioxane (POSS-8Cz), was successfully synthesized and characterized. The X-ray crystal structure of POSS-8Cz were described. The photophysical properties of POSS-8Cz were investigated by using UV vis,photoluminescence spectroscopic analysis. The hybrid material exhibits blue emission in the solution and the solid film.The morphology and thermal stablity properties were measured by X-ray diffraction (XRD) and TG-DTA analysis. PMID- 26498460 TI - Herd-level prevalence and risk factors for bovine viral diarrhea virus infection in cattle in the State of Paraiba, Northeastern Brazil. AB - Serological surveys based on a planned sampling on bovine viral diarrhea virus (BVDV) infection in Brazilian cattle herds are scarce. A cross-sectional study was carried out to determine herd- and animal-level seroprevalences and to identify risk factors associated with herd-level seroprevalence for BVDV infection in the State of Paraiba, Northeastern Brazil, from September 2012 to January 2013. The state was divided into three sampling strata, and for each stratum, the prevalence of herds infected with BVDV and the prevalence of seropositive animals was estimated by a two-stage sampling survey. In total, 2443 animals were sampled from 478 herds. A virus-neutralization test was used for BVDV antibody detection. A herd was considered positive when at least one seropositive animal was detected. The herd- and animal-level prevalences in the State of Paraiba were 65.5% (95% confidence interval (CI) = 61.1-69.7%) and 39.1% (95% CI = 33.1-45.6%), respectively. The frequency of seropositive animals per herd ranged from 10 to 100% (median of 50%). The risk factors identified were as follows: more than six calves aged <=12 months (odds ratio (OR) = 3.72; 95% CI = 2.08-6.66), animal purchasing (OR = 1.66; 95% CI = 1.08-2.55), pasture rental (OR = 2.15; 95% CI = 1.35-3.55), and presence of veterinary assistance (OR = 2.04; 95% CI = 1.10-3.79). Our findings suggest that the implementation of control and prevention measures among farmers, with the aim of preventing dissemination of the agent in the herds, is necessary. Special attention should be given to addressing the identified risk factors, such as sanitary control prior to animal purchasing and to discourage the pasture rental, as well as to encourage the vaccination in the herds. PMID- 26498461 TI - Induction of IkappaB-zeta by Epstein-Barr virus latent membrane protein-1 and CD30. AB - Activation of nuclear factor-kappaB (NF-kappaB) in Burkitt's lymphoma (BL) and Hodgkin's lymphoma (HL) cells is important in the transformation and development process of these lymphomas. Epstein-Barr virus (EBV) latent membrane protein-1 (LMP-1) and ligand-independent signaling by overexpressed CD30 are known to cause permanent activation of NF-kappaB in lymphomas. However, hyperactivation of NF kappaB triggers cellular senescence and apoptosis. Here, we show that IkappaB zeta, an inducible regulator of NF-kappaB, is constitutively expressed in BL and HL cell lines. In addition, immunohistochemical staining identified nuclear IkappaB-zeta-positive BL cells, and Hodgkin and Reed-Sternberg cells in lymph nodes. Expression of LMP-1 and CD30 increased IkappaB-zeta expression at the transcriptional level. IkappaB-zeta promoter was regulated by activation of the NF-kappaB-inducing kinase (NIK)/IkappaB kinase/NF-kappaB pathway via the carboxyl terminal tumor necrosis factor (TNF) receptor-associated factor (TRAF) interacting regions of LMP-1 and CD30. Interestingly, IkappaB-zeta inhibited NF kappaB activation by LMP-1 and CD30. The results suggest that NF-kappaB-induced IkappaB-zeta negatively modulates NF-kappaB hyperactivation, resulting in a fine balance that ultimately endows a net evolutionary benefit to the survival of BL and HL cells. PMID- 26498462 TI - Promoting Food Security for All Children. AB - Sixteen million US children (21%) live in households without consistent access to adequate food. After multiple risk factors are considered, children who live in households that are food insecure, even at the lowest levels, are likely to be sick more often, recover from illness more slowly, and be hospitalized more frequently. Lack of adequate healthy food can impair a child's ability to concentrate and perform well in school and is linked to higher levels of behavioral and emotional problems from preschool through adolescence. Food insecurity can affect children in any community, not only traditionally underserved ones. Pediatricians can play a central role in screening and identifying children at risk for food insecurity and in connecting families with needed community resources. Pediatricians should also advocate for federal and local policies that support access to adequate healthy food for an active and healthy life for all children and their families. PMID- 26498463 TI - Terpenoids from the roots of Alangium chinense. AB - Two new norditerpenoids (1 and 2), four new sesquiterpenoids (3-6), and 22 known compounds (7-28) were isolated from an ethanolic extract of roots of Alangium chinense. The absolute configurations of 1-6 were assigned by experimental and calculated ECD spectra. The skeleton of the compounds (1 and 2) has been reported only one time so far. Compounds 1, 13, and 23 exhibited antiviral activity against coxsackie virus B3 with IC50 values of 38-67 MUM. Compounds 8 and 9 displayed neuritis inhibitory activity against microglial inflammation factor, with IC50 values of 6.4 and 10.1 MUM, respectively. None of the compounds were cytotoxic in the MTT assay. PMID- 26498464 TI - Down-regulation of TGF-b1, TGF-b receptor 2, and TGF-b-associated microRNAs, miR 20a and miR-21, in skin lesions of sulfur mustard-exposed Iranian war veterans. AB - Sulfur mustard (SM) affects divergent cellular pathways including cell cycle, apoptosis, necrosis, and inflammatory responses. SM-induced lesions in skin include late-onset hyper-pigmentation, xerosis, and atrophy. It seems that TGF-b signaling pathway is a major player for SM pathogenesis. Here, we have employed a real-time polymerase chain reaction (PCR) approach to evaluate the expression alterations of all TGF-b variants and their receptors in skin biopsies obtained from 10 Iran-Iraq war veterans. Using specific LNA primers, the expression alteration of a TGF-bR2 regulator, miR-20a, and TGF-b downstream target, miR-21, was also assessed in the same samples Our real-time PCR data revealed a significant down-regulation of TGF-b1 and TGF-bR2, the major mediators of TGF-b signaling pathway, in skin biopsies of SM-exposed patients (p = 0.0015 and p = 0.0115, respectively). Down-regulation of TGF-b signaling pathway seems to contribute in severe inflammation observed in SM-exposed patients' tissues. MiR 20a and miR-21, as two important TGF-b associated microRNAs (miRNAs), were also down-regulated in SM-exposed skin lesions, compared to those of control group (p = 0.0003). Based on our findings, these miRNAs could be directly or indirectly involve in the pathogenesis of SM. Altogether, our data suggest the suitability of TGF-b1, TGF-bR2, as well as miR-20a and miR-21 as potential biomarkers for diagnosis and treatment of SM-exposed patients. PMID- 26498465 TI - Clinical Significance of Hu-Antigen Receptor (HuR) and Cyclooxygenase-2 (COX-2) Expression in Human Malignant and Benign Thyroid Lesions. AB - Hu-antigen R (HuR) is considered to play a crucial role in tumor formation and growth by binding to mRNAs encoding proteins such as Cyclooxygenase-2 (COX-2) and inducing their expression via mRNA stabilization and/or altered translation. The present study aimed to evaluate the clinical significance of HuR and COX-2 proteins' expression in human benign and malignant thyroid lesions. HuR and COX-2 proteins' expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 98 patients with benign (n = 48) and malignant (n = 50) lesions and was statistically analyzed with clinicopathological parameters, follicular cells' proliferative capacity and recurrence risk rate. Enhanced HuR and COX-2 expression was significantly more frequently observed in malignant compared to benign thyroid lesions (p = 0.0073 and p = 0.0016, respectively), as well as in papillary carcinomas compared to hyperplastic nodules (p = 0.0039 and p = 0.0009, respectively). Positive associations of both HuR and COX-2 expression with follicular cells' proliferation rate were also noted (p = 0.0087 and p = 0.0127, respectively). In malignant thyroid lesions, elevated COX-2 expression was significantly associated with female patients' gender (p = 0.0381) and the presence of lymph node metastases (p = 0.0296). The present data support evidence that both HuR and COX-2 may be involved in the malignant state of thyroid neoplasia and may be utilized in the diagnosis of malignant thyroid tumors. PMID- 26498466 TI - Lysobacter hankyongensis sp. nov., isolated from activated sludge and Lysobacter sediminicola sp. nov., isolated from freshwater sediment. AB - Two novel strains, designated KTCe-2T and 7C-9T, isolated from an activated sludge and freshwater sediment, respectively in South Korea, were characterized by a polyphasic approach to clarify their taxonomic positions. Phylogenetic analysis based on 16S rRNA gene sequences indicated that both isolates belong to the genus Lysobacter and are most closely related to 'Lysobacter daecheongensis' Dae 08 (98.5 % and 97.6 % similarity for strains KTCe-2T and 7C-9T, respectively), Lysobacter brunescens KCTC 12130T (98.4 % and 97.2 %), and Lysobacter oligotrophicus JCM 18257T (97.1 % and 96.8 %). The G+C content of the genomic DNA of strains KTCe-2T and 7C-9T was 68.6 % and 71.5 mol%, respectively. Strains KTCe-2T and 7C-9T possessed ubiquinone-8 as the sole respiratory quinone, and a fatty acid profile with iso-C15 : 0 and iso-C16 : 0 as the major fatty acids supported the affiliation of the two strains to the genus Lysobacter. Moreover, the physiological and biochemical results and low DNA-DNA relatedness values allowed the phenotypic and genotypic differentiation of strains KTCe-2T and 7C-9T from other species of the genus Lysobacter with validly published names. Therefore, the two isolates represent two novel species of the genus Lysobacter, for which the name Lysobacter hankyongensis sp. nov. (type strain KTCe-2T = JCM 18204T = KACC 16618T) and Lysobacter sediminicola sp. nov. (type strain 7C-9T = JCM 18205T = KACC 16617T) are proposed. PMID- 26498467 TI - Imagining Global Health with Justice: In Defense of the Right to Health. AB - The singular message in Global Health Law is that we must strive to achieve global health with justice--improved population health, with a fairer distribution of benefits of good health. Global health entails ensuring the conditions of good health--public health, universal health coverage, and the social determinants of health--while justice requires closing today's vast domestic and global health inequities. These conditions for good health should be incorporated into public policy, supplemented by specific actions to overcome barriers to equity. A new global health treaty grounded in the right to health and aimed at health equity--a Framework Convention on Global Health (FCGH)- stands out for its possibilities in helping to achieve global health with justice. This far-reaching legal instrument would establish minimum standards for universal health coverage and public health measures, with an accompanying national and international financing framework, require a constant focus on health equity, promote Health in All Policies and global governance for health, and advance the principles of good governance, including accountability. While achieving an FCGH is certainly ambitious, it is a struggle worth the efforts of us all. The treaty's basis in the right to health, which has been agreed to by all governments, has powerful potential to form the foundation of global governance for health. From interpretations of UN treaty bodies to judgments of national courts, the right to health is now sufficiently articulated to serve this role, with the individual's right to health best understood as a function of a social, political, and economic environment aimed at equity. However great the political challenge of securing state agreement to the FCGH, it is possible. States have joined other treaties with significant resource requirements and limitations on their sovereignty without significant reciprocal benefits from other states, while important state interests would benefit from the FCGH. And from integrating the FCGH into the existing human rights system to creative forms of compliance and enforcement and strengthened domestic legal and political accountability mechanisms, the treaty stands to improve right to health compliance. The potential for the FCGH to bring the right to health nearer universal reality calls for us to embark on the journey towards securing this global treaty. PMID- 26498468 TI - [(Very) high Creatinkinase concentration after exertional whole-body electromyostimulation application: health risks and longitudinal adaptations]. AB - Due to its individualization, time-efficiency and effectiveness Whole-body Electromyo-stimulation (WB-EMS) becomes increasingly popular. However, recently (very) high Creatin-kinase concentration were reported, at least after initial WB EMS-application. Thus, the aim of the study was to determine (1) WB-EMS induced increases of CK-concentration, (2) their impact on corresponding health parameters and (3) training-induced changes of CK-levels.Twenty-six healthy, sportive volunteers without previous experience with WB-EMS were included. Initial high intense WB-EMS application (bipolar, 85 Hz; 350 ms; intermittent, 20 min) led to an increase of the CK-level by the 117fold (28.545 +/- 33.611 IU/l) of baseline. CK-peaks were detected after 72-96 h. Despite this pronounced "exertional rhabdomyolysis", we did not determine rhabdomyolysis-induced complications (e.g. acute renal failure, hyperkalemia, hypocalcaemia). After 10 weeks of WB-EMS (1 session/week) CK-reaction to intensive WB-EMS-Application was significantly blunted (906 +/- 500 IE/l) and averaged in the area of conventional resistance exercise.In summary, intensity of WB-EMS should be carefully increased during the initial sessions. PMID- 26498469 TI - Various Echocardiographic Patterns of Left Ventricular Systolic Dysfunction Induced by Carbon Monoxide Intoxication. AB - Carbon monoxide (CO) intoxication could cause significant cardiac injury. Although cardiac dysfunction after CO intoxication can be presented, the echocardiographic findings after CO intoxication are poorly defined. The purpose of this study was to evaluate the clinical patterns of left ventricular (LV) systolic dysfunction using echocardiography. A total of 132 CO-intoxicated patients were enrolled. Clinical, demographic and laboratory data and echocardiographic findings were analyzed. The LV dysfunction group (29 patients) showed higher lactate level (5.8 +/- 3.3 vs. 4.1 +/- 3.5 mmol/L, p = 0.024) and lower base excess (BE) (-8.2 +/- 6.0 vs. -4.8 +/- 4.7 mEq/L, p = 0.001) compared with normal LV function group. Among the LV dysfunction group, three different echocardiographic patterns were presented. Regional wall motion abnormality was presented in 14 patients. Apical ballooning, typical finding of stress-induced cardiomyopathy, was presented in eight patients. Global hypokinesia of LV was presented in seven patients. Laboratory findings indicating the severity of CO intoxication, such as lactate level, pH value, BE and aspartate aminotransferase, showed statistical significance according to the patterns of LV dysfunction (p = 0.033, 0.022, 0.02 and 0.006, respectively). Our results demonstrate that CO intoxication could induce various patterns of LV dysfunction. The patterns of LV dysfunction might affect subsequent clinical outcomes. PMID- 26498471 TI - Molecular characterization of BK virus in patients infected with human immunodeficiency virus. AB - Immunosuppression seems to be the most important cause of BKPyV reactivation. Recently, a spectrum of diseases associated with BKPyV infection has been reported in HIV-infected patients. BKPyV isolates can be classified into four subtypes based on nucleotide polymorphisms within VP1 coding region. Mutations within the BC loop of the VP1 may be associated with an increase in the viral pathogenicity. The aims of this study were to determine prevalence and distribution of BKPyV subtypes, sequence variation and mutations within VP1 among HIV-infected patients and healthy donors. Urine samples from 114 HIV-infected patients and 120 healthy donors were collected. PCR followed by sequence analysis was carried out using primers specific for VP1 and NCRR of the virus genome. The predominant BKPyV subtype was I, followed by IV. In isolates from HIV-infected patients, the majority of non-synonymous alterations were located within the BC loop. BKV sequences from healthy donors showed non-synonymous alterations outside of the receptor loops in the beta-sheets. The higher frequency of mutations in the BC loop of VP1 protein was detected among HIV-infected patients. The most frequent mutation was E82D. All HIV-infected patients who harbored mutations had CD4(+) cell counts less than 200 cell/mm(3). It seems that immunosuppression is a very important factor for BKPyV reactivation that can increase viral replication rate and leads to higher frequency of mutations in the BC loop of the VP1. These mutations may change receptor specificity, and further studies are needed to determine the effect of these mutations on the biological properties of the BKPyV. PMID- 26498472 TI - Evaluating Survivorship Experiences and Needs Among Rural African American Breast Cancer Survivors. AB - Disparities in cancer survivorship exist among specific populations of breast cancer survivors, specifically rural African American breast cancer survivors (AA BCS). While effective survivorship interventions are available to address and improve quality of life, interventions must be culturally tailored for relevance to survivors. Here, we report the results of our formative research using focus groups and in-depth interview to better understand unique rural AA-BCS survivorship experiences and needs in the Alabama Black Belt. Surveys were used to gather sociodemographic and cancer treatment data. Fifteen rural AA-BCS shared their experiences and concerns about keeping their cancer a secret, lack of knowledge about survivorship, lingering symptoms, religion and spirituality, cancer surveillance, and general lack of survivorship education and support. Rural AA-BCS were unwilling to share their cancer diagnosis, preferring to keep it a secret to protect family and friends. Quality-of-life issues like lymphedema body image and sexuality were not well understood. They viewed spirituality and religion as essential in coping and accepting cancer. Participants also discussed the importance of and barriers to maintaining health through regular check-ups. They needed social support from family and friends and health care providers. Overall, rural AA-BCS expressed their need for knowledge about survivorship self management by providing a vivid picture of the realities of cancer survival based on shared concerns for survivorship support and education within the context of culture. PMID- 26498473 TI - Trypsin- and low pH-mediated fusogenicity of avian metapneumovirus fusion proteins is determined by residues at positions 100, 101 and 294. AB - Avian metapneumovirus (aMPV) and human metapneumovirus (hMPV) are members of the genus Metapneumovirus in the subfamily Pneumovirinae. Metapneumovirus fusion (F) protein mediates the fusion of host cells with the virus membrane for infection. Trypsin- and/or low pH-induced membrane fusion is a strain-dependent phenomenon for hMPV. Here, we demonstrated that three subtypes of aMPV (aMPV/A, aMPV/B, and aMPV/C) F proteins promoted cell-cell fusion in the absence of trypsin. Indeed, in the presence of trypsin, only aMPV/C F protein fusogenicity was enhanced. Mutagenesis of the amino acids at position 100 and/or 101, located at a putative cleavage region in aMPV F proteins, revealed that the trypsin-mediated fusogenicity of aMPV F proteins is regulated by the residues at positions 100 and 101. Moreover, we demonstrated that aMPV/A and aMPV/B F proteins mediated cell cell fusion independent of low pH, whereas the aMPV/C F protein did not. Mutagenesis of the residue at position 294 in the aMPV/A, aMPV/B, and aMPV/C F proteins showed that 294G played a critical role in F protein-mediated fusion under low pH conditions. These findings on aMPV F protein-induced cell-cell fusion provide new insights into the molecular mechanisms underlying membrane fusion and pathogenesis of aMPV. PMID- 26498474 TI - Super-resolution Microscopy of Clickable Amino Acids Reveals the Effects of Fluorescent Protein Tagging on Protein Assemblies. AB - The advent of super-resolution microscopy (nanoscopy) has set high standards for fluorescence tagging. Fluorescent proteins (FPs) are convenient tags in conventional imaging, but their use in nanoscopy has been questioned due to their relatively large size and propensity to form multimers. Here, we compared the nanoscale organization of proteins with or without FP tags by introducing the unnatural amino acid propargyl-L-lysine (PRK) in 26 proteins known to form multimolecular arrangements and into their FP-tagged variants. We revealed the proteins by coupling synthetic fluorophores to PRK via click chemistry and visualized them using ground-state depletion microscopy followed by individual molecule return, as well as stimulated emission depletion microscopy. The arrangements formed by the FP-tagged and nontagged proteins were similar. Mild, but statistically significant differences were observed for only six proteins (23% of all proteins tested). This suggests that FP-based nanoscopy is generally reliable. Unnatural amino acids should be a reliable alternative for the few proteins that are sensitive to FP tagging. PMID- 26498475 TI - Giant Hydatid Cyst of the Interventricular Septum. PMID- 26498476 TI - Two-dimensional speckle tracking for the assessment of coronary artery disease during dobutamine stress echo: clinical tool or merely research method. AB - BACKGROUND: Two-dimensional speckle tracking provides valuable information for regional wall motion abnormalities. The purpose of this study was to determine the diagnostic value of left ventricular longitudinal strain and torsion to diagnose coronary artery disease during dobutamine stress echocardiography. METHODS: We studied 100 patients (mean age 60.8 +/- 10.7 years, 72 male) with known or suspected coronary artery disease, excluding those with prior history of transmural infraction. All of them underwent dobutamine stress echo and coronary angiography within one month. Wall-motion score index, left ventricular global longitudinal strain and torsion were measured at rest and peak stress. Additionally, the respective differences between rest and stress were also calculated. Optimal cut-offs were derived from receiver operating characteristic curves for strain and torsion values. RESULTS: Mean left ventricular ejection fraction was 55 +/- 5.4 %. Coronary angiography revealed significant lesions in 67 patients. Values regarding sensitivity, and specificity for wall motion score index difference were 78 % and 88 % respectively (area under curve 0.84). Global longitudinal strain difference (median 0.5 %) illustrated 81 % sensitivity and 72 % specificity for disease detection (area under curve 0.80, cut-off value <=0 %). The respective values for torsion difference (median 4.7 degrees ) were 81 % and 82 % (area under curve 0.76, cut-off value <=6.5 degrees ). Combination of wall motion score index difference and torsion difference for disease detection showed 91 % sensitivity and 79 % specificity (area under curve 0.85). CONCLUSIONS: The implementation of speckle tracking during dobutamine stress echo could serve as an adjunct method for coronary artery disease assessment, providing quantitative diagnostic information. PMID- 26498477 TI - Identification of key genes associated with the human abdominal aortic aneurysm based on the gene expression profile. AB - The present study was aimed at screening the key genes associated with abdominal aortic aneurysm (AAA) in the neck, and to investigate the molecular mechanism underlying the development of AAA. The gene expression profile, GSE47472, including 14 AAA neck samples and eight donor controls, was downloaded from the Gene Expression Omnibus database. The total AAA samples were grouped into two types to avoid bias. Differentially expressed genes (DEGs) were screened in patients with AAA and subsequently compared with donor controls using linear models for microarray data, or the Limma package in R, followed by gene ontology enrichment analysis. Furthermore, a protein-protein interaction (PPI) network based on the DEGs was constructed to detect highly connected regions using a Cytoscape plugin. In total, 388 DEGs in the AAA samples were identified. These DEGs were predominantly associated with limb development, including embryonic limb development and appendage development. Nuclear receptor co-repressor 1 (NCOR1), histone 4 (H4), E2F transcription factor 4 (E2F4) and hepatocyte nuclear factor 4alpha (HNF4A) were the four transcription factors associated with AAA. Furthermore, HNF4A indirectly interacted with the other three transcription factors. Additionally, six clusters were selected from the PPI network. The DEG screening process and the construction of an interaction network enabled an understanding of the mechanism of AAA to be gleaned. HNF4A may exert an important role in AAA development through its interactions with the three other transcription factors (E2F4, NCOR1 and H4), and the mechanism of this coordinated regulation of the transcription factors in AAA may provide a suitable target for the development of therapeutic intervention strategies. PMID- 26498478 TI - Qualitative grading of aortic regurgitation: a pilot study comparing CMR 4D flow and echocardiography. AB - Over the past 10 years there has been intense research in the development of volumetric visualization of intracardiac flow by cardiac magnetic resonance (CMR).This volumetric time resolved technique called CMR 4D flow imaging has several advantages over standard CMR. It offers anatomical, functional and flow information in a single free-breathing, ten-minute acquisition. However, the data obtained is large and its processing requires dedicated software. We evaluated a cloud-based application package that combines volumetric data correction and visualization of CMR 4D flow data, and assessed its accuracy for the detection and grading of aortic valve regurgitation using transthoracic echocardiography as reference. Between June 2014 and January 2015, patients planned for clinical CMR were consecutively approached to undergo the supplementary CMR 4D flow acquisition. Fifty four patients(median age 39 years, 32 males) were included. Detection and grading of the aortic valve regurgitation using CMR4D flow imaging were evaluated against transthoracic echocardiography. The agreement between 4D flow CMR and transthoracic echocardiography for grading of aortic valve regurgitation was good (j = 0.73). To identify relevant,more than mild aortic valve regurgitation, CMR 4D flow imaging had a sensitivity of 100 % and specificity of 98 %. Aortic regurgitation can be well visualized, in a similar manner as transthoracic echocardiography, when using CMR 4D flow imaging. PMID- 26498479 TI - Cost-effectiveness of peer role play and standardized patients in undergraduate communication training. AB - BACKGROUND: The few studies directly comparing the methodological approach of peer role play (RP) and standardized patients (SP) for the delivery of communication skills all suggest that both methods are effective. In this study we calculated the costs of both methods (given comparable outcomes) and are the first to generate a differential cost-effectiveness analysis of both methods. METHODS: Medical students in their prefinal year were randomly assigned to one of two groups receiving communication training in Pediatrics either with RP (N = 34) or 19 individually trained SP (N = 35). In an OSCE with standardized patients using the Calgary-Cambridge Referenced Observation Guide both groups achieved comparable high scores (results published). In this study, corresponding costs were assessed as man-hours resulting from hours of work of SP and tutors. A cost effectiveness analysis was performed. RESULTS: Cost-effectiveness analysis revealed a major advantage for RP as compared to SP (112 vs. 172 man hours; cost effectiveness ratio .74 vs. .45) at comparable performance levels after training with both methods. CONCLUSIONS: While both peer role play and training with standardized patients have their value in medical curricula, RP has a major advantage in terms of cost-effectiveness. This could be taken into account in future decisions. PMID- 26498480 TI - KIT exon 10 variant (c.1621 A > C) single nucleotide polymorphism as predictor of GIST patient outcome. AB - BACKGROUND: Tumor genotype plays a crucial role in clinical management of GIST. Whether genetic polymorphism of KIT may influence GIST patient outcome is unclear. METHODS: We investigated the biological and clinical significance of the presence of KIT exon 10 variant (c.1621 A > C), KIT (L541), in a transfected cell line (3 T3 L541) and in two retrospectively collected series of 109 GIST patients in total. The control group consisted of 60 healthy donors collected at the French department of blood transfusion. RESULTS: In the 3 T3 L541 cell line, KIT(L541) protein exhibited a spontaneous phosphorylation status comparable to that of wild-type KIT but displayed a phosphorylation pattern of AKT and ERK1/2 that was found similar to that of the classical mutated forms of the KIT receptor. Of 109 patients enrolled in this retrospective translational research study, 24 (22%) harboured KIT (L541), similarly to the control group of healthy donors (n = 10 of 60, 17%). A higher prevalence of the variant KIT (L541) was observed in patients with metastatic status at diagnosis (KIT (L541) correlated nine of 22 versus 15 of 87, p = 0.02). In addition, patients with KIT (L541) and localized GIST had a higher rate of relapse at 5 years and lower relapse free survival at 5 years in univariate, as well as in multivariate analysis. Response rate and duration of response to imatinib was similar in KIT (L541) and KIT (M541) patients. CONCLUSION: KIT (L541) genotype is associated with a higher risk of metastasis at diagnosis and a higher risk of relapse in GIST patients. PMID- 26498482 TI - Metabolic engineering of E. coli for the production of isoflavonoid-7-O methoxides and their biological activities. AB - Isoflavonoid representatives such as genistein, daidzein are high potent anti cancer, anti-bacterial, anti-oxidant agents. It have been demonstrated that methylation of flavonoids enhanced the transporting ability, which lead to facilitated absorption and greatly increased bioavailability. In this paper, genetically engineered Escherichia coli was reconstructed by harboring E. coli K12-derived metK encoding S-adenosylmethionine (SAM) synthase (accession number: K02129) for enhancement of SAM as precursor and a Streptomyces avermitilis originated SaOMT2 (O-methyltransferase, accession number: NP_823558) for methylation of daidzein and genistein as preferred substrates. The formation of desired products via biotransformation including 7-O-methyl-genistein and 7-O methyl-daidzein were confirmed individually by chromatographical data such as HPLC, LC-TOF-MS and NMR (1 H and 13 C) as well. Furthermore, substrates concentration, incubation time and media parameters were optimized using flask culture. Finally, the most fit conditions were applied for fed-batch fermentation with scale up to 3 L (working volume) to obtain the maximum yield of the products including 164.25 MUM (46.81 mg/L) and 382.50 MUM (102.88 mg/L) for 7-O-methyl genistein and 7-O-methyl daidzein, respectively. In particular, potent inhibitory activities of those isoflavonoid methoxides against the growth of cancer line (B16F10, AGS and HepG2) and endothelical (HUVEC) cells were investigated and demonstrated. Taken together this research work described the production of isoflavonoid-7-O-methoxides by E. coli engineering, improvement of production, characterization of produced compounds and preliminary in vitro biological activities of the these flavonoids being manufactured. This article is protected by copyright. All rights reserved. PMID- 26498481 TI - Increased cyclooxygenase-2 and nuclear factor-kappaB/p65 expression in mouse hippocampi after systemic administration of tetanus toxin. AB - Brain inflammation has a crucial role in various diseases of the central nervous system. The hippocampus in the mammalian brain exerts an important memory function, which is sensitive to various insults, including inflammation induced by exo/endotoxin stimuli. Tetanus toxin (TeT) is an exotoxin with the capacity for neuronal binding and internalization. The present study investigated changes in inflammatory mediators in the mouse hippocampus proper (CA1-3 regions) and dentate gyrus (DG) after TeT treatment. The experimental mice were intraperitoneally injected with TeT at a low dosage (100 ng/kg), while the control mice were injected with the same volume of saline. At 6, 12 and 24 h after TeT treatment, changes in the hippocampal levels of inflammatory mediators cyclooxygenase-2 (COX-2) and nuclear factor kappa-B (NF-kappaB/p65) were assessed using immunohistochemical and western blot analysis. In the control group, moderate COX-2 immunoreactivity was observed in the stratum pyramidal (SP) of the CA2-3 region, while almost no expression was identified in the CA1 region and the DG. COX-2 immunoreactivity was increased by TeT in the SP and granule cell layer (GCL) of the DG in a time-dependent manner. At 24 h post-treatment, COX-2 immunoreactivity in the SP of the CA1 region and in the GCL of the DG was high, and COX-2 immunoreactivity in the SP of the CA2/3 region was highest. Furthermore, the present study observed that NF-kappaB/p65 immunoreactivity was obviously increased in the SP and GCL at 6, 12 and 24 h after TeT treatment. In conclusion, the present study demonstrated that systemic treatment with TeT significantly increased the expression of COX-2 and NF-kappaB/p65 in the mouse hippocampus, suggesting that increased COX-2 and NF-kappaB/65 expression may be associated with inflammation in the brain induced by exotoxins. PMID- 26498483 TI - Cigarette smoke differentially modulates dendritic cell maturation and function in time. AB - BACKGROUND: Dendritic cells (DCs) as professional antigen presenting cells (APCs) play a critical role in the regulation of host immune responses. DCs evolve from immature, antigen-capturing cells, to mature antigen-presenting cells. The relative contribution of DCs to cigarette smoke-induced inflammation is not well documented. In the current study, we investigated a modulatory effect of cigarette smoke extract (CSE) on differentiation, maturation and function of DCs. METHODS: Primary murine DCs were grown from bone marrow cells with GM-CSF. Development of DC was analyzed by expression of CD11c, MHCII, CD86, CD40 and CD83 using flow cytometry. Murine DC's and human L428 cells were co-cultured with CSE for various periods of time. Functional activity was analyzed by measuring FITC dextran uptake, cytokine production and the ability to stimulate T cell activation in a mixed lymphocyte reaction. RESULTS: Our results show that short term CSE stimulation (~24 h) influence the maturation status of newly differentiated and immature DCs towards more mature cells as revealed by upregulation of MHCII, CD83, CD86, CD40, reduction in antigen up-take capacity and enhanced secretion of pro-inflammatory (IL-12, IL-6 and TNF-alpha) cytokines. Interestingly, long-term CSE exposure, time- and concentration-dependently, suppressed the development of functional DCs. This suppression was demonstrated by a decline in CD11c/MHCII, CD83, CD86 and CD40 expression, the production of cytokines and ability to stimulate T lymphocytes. Moreover, CSE significantly suppressed the endocytosis function of mouse DCs which was not due to diminished DC viability. Similar to mouse DCs, long-term co-culturing of the human L428 DC cell line with CSE time-dependently suppressed the expression of CD54. CONCLUSIONS: The present study provides evidence that CSE modulates DC-mediated immune responses via affecting both the function and maturation of DCs. The suppressive effects of cigarette smoke on DC function might lead to impaired immune responses to various infections. PMID- 26498484 TI - Scaffold and scaffold-free self-assembled systems in regenerative medicine. AB - Self-assembly in tissue engineering refers to the spontaneous chemical or biological association of components to form a distinct functional construct, reminiscent of native tissue. Such self-assembled systems have been widely used to develop platforms for the delivery of therapeutic and/or bioactive molecules and various cell populations. Tissue morphology and functional characteristics have been recapitulated in several self-assembled constructs, designed to incorporate stimuli responsiveness and controlled architecture through spatial confinement or field manipulation. In parallel, owing to substantial functional properties, scaffold-free cell-assembled devices have aided in the development of functional neotissues for various clinical targets. Herein, we discuss recent advancements and future aspirations in scaffold and scaffold-free self-assembled devices for regenerative medicine purposes. Biotechnol. Bioeng. 2016;113: 1155 1163. (c) 2015 Wiley Periodicals, Inc. PMID- 26498485 TI - Case report of malignant pulmonary parenchymal glomus tumor: imaging features and review of the literature. AB - Glomus tumor is rare tumor which arises from glomus body and is most frequently found in the soft tissue of the extremities. The lung is a rare ectopic site, and a malignant glomus tumor arising from pulmonary parenchyma is particularly uncommon. To deepen our understanding on their imaging features, we report a case of malignant glomus tumor of pulmonary parenchyma confirmed with surgical histopathology and immunochemistry and review the medical literature on pulmonary parenchymal glomus tumors with emphasis on their imaging features. PMID- 26498487 TI - Flexible and fragmentable tandem photosensitive nanocrystal skins. AB - We proposed and demonstrated the first account of large-area, semi-transparent, tandem photosensitive nanocrystal skins (PNSs) constructed on flexible substrates operating on the principle of photogenerated potential buildup, which avoid the need for applying an external bias and circumvent the current-matching limitation between junctions. We successfully fabricated and operated the tandem PNSs composed of single monolayers of colloidal water-soluble CdTe and CdHgTe nanocrystals (NCs) in adjacent junctions on a Kapton polymer tape. Owing to the usage of a single NC layer in each junction, noise generation was significantly reduced while keeping the resulting PNS films considerably transparent. In each junction, photogenerated excitons are dissociated at the interface of the semi transparent Al electrode and the NC layer, with holes migrating to the contact electrode and electrons trapped in the NCs. As a result, the tandem PNSs lead to an open-circuit photovoltage buildup equal to the sum of those of the two single junctions, exhibiting a total voltage buildup of 128.4 mV at an excitation intensity of 75.8 MUW cm(-2) at 350 nm. Furthermore, we showed that these flexible PNSs could be bent over 3.5 mm radius of curvature and cut out in arbitrary shapes without damaging the operation of individual parts and without introducing any significant loss in the total sensitivity. These findings indicate that the NC skins are promising as building blocks to make low-cost, flexible, large-area UV/visible sensing platforms with highly efficient full spectrum conversion. PMID- 26498486 TI - Cerebralcare Granule(r) attenuates cognitive impairment in rats continuously overexpressing microRNA-30e. AB - Previous studies have demonstrated that dysregulation of micro (mi)RNAs is associated with the etiology of various neuropsychiatric disorders, including depression and schizophrenia. Cerebralcare Granule(r) (CG) is a Chinese herbal medicine, which has been reported to have an ameliorative effect on brain injury by attenuating blood-brain barrier disruption and improving hippocampal neural function. The present study aimed to evaluate the cognitive behavior of rats continuously overexpressing miRNA-30e (lenti-miRNA-30e), prior to and following the administration of CG. In addition, the mechanisms underlying the ameliorative effects of CG were investigated. The cognitive ability of the rats was assessed using an open-field test and a Morris water maze spatial reference/working memory test. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to detect neuronal apoptosis in the dentate gyrus of the hippocampus. Immunohistochemical analysis and western blotting were conducted to detect the expression levels of B-cell lymphoma 2 (BCL-2) and ubiquitin-conjugating enzyme 9 (UBC9), in order to examine neuronal apoptosis. The lenti-miRNA-30e rats exhibited increased signs of anxiety, depression, hyperactivity and schizophrenia, which resulted in a severe impairment in cognitive ability. Furthermore, in the dentate gyrus of these rats, the expression levels of BCL-2 and UBC9 were reduced and apoptosis was increased. The administration of CG alleviated cognitive impairment, enhanced the expression levels of BCL-2 and UBC9, and reduced apoptosis in the dentate gyrus in the lenti-miRNA-30e rats. No significant differences were detected in behavioral indicators between the lenti miRNA-30e rats treated with CG and the normal controls. These findings suggested that CG exerts a potent therapeutic effect, conferred by its ability to enhance the expression levels of BCL-2 and UBC9, which inhibits the apoptotic process in neuronal cells. Therefore, CG may be considered a potential therapeutic strategy for the treatment of cognitive impairment in mental disorders. PMID- 26498488 TI - Antidiabetic and Antihyperlipidemic Effects of Ethanol Extract of Rosa canina L. fruit on Diabetic Rats: An Experimental Study With Histopathological Evaluations. AB - Rosa canina L. (Rosaceae) has been traditionally used as a medicinal plant. This study was undertaken to evaluate the antidiabetic and antihyperlipidemic effects of Rosa canina fruit extract in streptozotocin induced diabetic rats. The results showed oral administration of Rosa canina fruit extract significantly ameliorated the high levels of blood glucose compared with the control group. Serum triglyceride levels significantly decreased by the administration of Rosa canina extract compared with control. Histopathological examinations showed that the Rosa canina extract improved islets necrotic and regenerated pancreatic islet cells. Rosa canina extract has the antihyperglycemic and antihyperlipidemic effects in streptozotocin-induced diabetic rats. PMID- 26498489 TI - Understanding gate adsorption behaviour of CO2 on elastic layer-structured metal organic framework-11. AB - We demonstrate that CO2 gate adsorption behaviour of elastic layer-structured metal-organic framework-11 (ELM-11: [Cu(BF4)2(4,4'-bipyridine)2]), which is a family of soft porous crystals (SPCs), can be described by a thermodynamic model by free energy analysis with the aid of an adsorption experiment and a molecular simulation. The structures of ELM-11 (closed structure) at 273 K after its evacuation and CO2-encapsulated ELM-11 (open structure) at 195-298 K were determined by the Rietveld analysis using in situ synchrotron X-ray powder diffraction data. We then performed grand canonical Monte Carlo (GCMC) simulations for CO2 adsorption on the open host framework structures of ELM-11 from the Rietveld analysis. The temperature dependence of the Helmholtz free energy change of host DeltaF(host) from the closed structure to the open structure was obtained by the free energy analysis using the GCMC data. We show that there is a linear correlation between DeltaF(host) and temperature, and thus, the internal energy and entropy changes of host, DeltaU(host) and DeltaS(host), respectively, can be obtained. The obtained DeltaU(host) value is in good agreement with that obtained from the quantum chemical calculations using the closed and open host framework structures, which demonstrates that the thermodynamic model for gate adsorption is highly appropriate. Moreover, our result suggests that the gate adsorption pressure depends on not only the guest host interaction and the internal energy change of host, but also the entropy change of host, which should be one of the key factors for the tailored synthesis of SPCs. PMID- 26498490 TI - The first aurochs genome reveals the breeding history of British and European cattle. AB - The first genome sequence of the extinct European wild aurochs reveals the genetic foundation of native British and Irish landraces of cattle.See related Research article: www.dx.doi.org/10.1186/s13059-015-0790-2. PMID- 26498491 TI - Association between XRCC3 Thr241Met Polymorphism and Risk of Breast Cancer: Meta Analysis of 23 Case-Control Studies. AB - BACKGROUND: Studies have shown that gene and environmental factors, such as BRCA1/2 mutations, ionized radiation, and chemical carcinogens, are related with breast cancer. X-ray repair cross-complementing group 3 (XRCC3) is involved in homologous repair of double DNA breaks. It was reported that Thr241Met single nucleotide polymorphism (SNP) in XRCC3 is associated with increased risk of breast cancer. However, the finding remains controversial. The current meta analysis aims to determine whether XRCC3 Thr241Met polymorphism is associated with increased risk of breast cancer. MATERIAL AND METHODS: We performed a meta analysis of association between XRCC3 T241M polymorphism and the risk of breast cancer. Crude odds ratios (ORs) together with 95% confidence intervals (CIs) were used to assess the strength of association in dominant, recessive, and homozygote models. RESULTS: We included 23 studies consisting of 13513 cases and 14100 controls in our study. For meta-analysis on the entire database, association of the SNP and breast cancer risk was observed in recessive (OR=1.10, 95% CI: 1.03 1.18, p=0.005) and homozygote (OR=1.09, 95% CI: 1.01-1.18, p=0.023) models. For the analysis on the Asian population subgroup, association of the SNP and breast cancer risk was also observed in recessive (OR=1.615, 95% CI: 1.17-2.228, p=0.004) and homozygote (OR=1.609, 95% CI: 1.154-2.241, p=0.005) models. For the evaluation of the patients without family history of breast cancer, association of the SNP and breast cancer risk was observed in dominant (OR=1.364, 95% CI: 1.096-1.698, p=0.005), recessive (OR=1.336, 95% CI: 0.999-1.788, p=0.051) and homozygote (OR=1.492, 95% CI: 1.085-2.051, p=0.014) models. CONCLUSIONS: We can conclude that XRCC3 Thr241Met polymorphism might be associated with breast cancer risk, especially in Asian populations and in patients without family history of breast cancer. PMID- 26498492 TI - Effects of 6 weeks oral administration of Phyllanthus acidus leaf water extract on the vascular functions of middle-aged male rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Leaves of Phyllanthus acidus (PA) have been used in Thai traditional medicine for the treatment of hypertension. We have previously shown that chronic treatment of a PA water extract to middle-aged male rats caused a lowering of the body and serum lipids, two of the parameters that are implicated in cardiovascular disease. AIM OF THE STUDY: To investigate if chronic treatment of middle-aged male rats with a PA water extract affected the perivascular (aortic) adipose tissue (PVAT) and/or their vascular functions MATERIALS AND METHODS: Fresh leaves of PA were extracted with water and orally gavaged to the middle-aged male rats for 6 weeks. Vascular functions were studied in vitro using isolated thoracic aorta with and without PVAT, and mesenteric rings in Krebs Heinseleit solution with results recorded with a Polygraph or a Myograph system. The amount of blood vessel eNOS and CSE (cystathionine-gamma lyase) expression was measured by Western blotting. RESULTS: PA treatment caused a lower maximal contractile response to phenylephrine (Phe) of the endothelium intact aortic ring than that of the control group. This effect was abolished by N(G)-nitro-l-arginine (l-NA) or by denudation of the endothelium. dl propargylglycine (PAG, H2S inhibitor) and TEA (Ca(2+)-activated K(+) channel blocker), but not glybenclamide (ATP-activated K(+) channel blocker), caused a similar increase in the baseline of the endothelium-intact aortic ring in the presence of l-NA in both the PA-treated and control aortic rings. This effect sequentially resulted in a greater contractile response of the aortic rings of both groups to Phe. Glybenclamide also caused a similar increase in the maximal contraction of the endothelium-intact blood vessels with l-NA to both groups. PAG, TEA or glybenclamide did not modify the phenylephrine C-R curves for either group of the PVAT-endothelium-intact aortic rings preincubated with l-NA. The CSE levels of the thoracic aorta and at the PVAT were not different between the PA treated and the control group. Relaxation of the Phe-precontracted thoracic aortic ring to acetylcholine, but not to glyceryl trinitrate, was higher for the PA-treated than for the control aortic rings and this effect was abolished by l NA. The mesenteric rings of the PA treated group showed a lower sensitivity on the contractile response to Phe than that of the control group, and this effect was abolished by l-NA. Vasodilatation to acetylcholine, but not to glyceryl trinitrate, of the PA treated-mesenteric ring was more sensitive than that of the control group and this effect was abolished by l-NA. The expression of eNOS by the PA treated thoracic aorta and the mesenteric arteries was higher than the control group. These results demonstrated that chronic treatment with a PA water extract to middle-aged rats affected their vascular functions by increasing the nitric oxide production from the endothelial cells and also modulated the responsiveness of the thoracic aortic- and mesenteric rings to phenylephrine and acetylcholine. PMID- 26498493 TI - A review of commercially important African medicinal plants. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Data on the relative importance and research status of commercially relevant African medicinal plants are needed for developing new research strategies in order to stimulate much-needed ethnopharmacological research and to promote the commercialization of African plants. AIM OF THE STUDY: To present an illustrated bird's eye view and comparative analysis of the relative popularity and importance of commercialized African medicinal plants. A comparison is made between the general popularity and commercial importance of the species (as indicated by their footprint on the World Wide Web) and their scientific popularity and importance (as indicated by the number of research publications). The inventory and review is strongly focussed to cover all or most of the medicinal plant raw materials in the international trade that are exported from African countries, with less emphasis on those that are regularly traded on local and regional markets within Africa. MATERIALS AND METHODS: The review is based on literature data, Scopus and Google searches, commercial information and the author's own experience and observations. RESULTS: More than 5400 plant species are used in traditional medicine in Africa, of which less than 10% have been commercially developed to some extent. Africa is home to more than 80 valuable commercial species that are regularly traded on international markets, including phytomedicines (e.g. Harpagophytum procumbens and Pelargonium sidoides), functional foods (e.g. Adansonia digitata and Hibiscus sabdariffa) and sources of pure chemical entities (e.g. caffeine from Coffea arabica and yohimbine from Pausinystalia johimbe). According to the Scopus results, about 60% of all recent publications on African medicinal plants appeared in the last decade, with an average of 280 papers (28 per year) for 85 prominent species of international trade. The most popular African species for research (number of publications in brackets) were: Ricinus communis (5187), Aloe vera (2832), Catharanthus roseus (2653), Sesamum indicum (2534), Strophanthus gratus (2514), Coffea arabica (2431), Citrullus lanatus (2215), Momordica charantia (2047), Withania somnifera (1767), Trigonella foenum graecum (1687), Acacia senegal (1373), Centella asiatica (1355), Griffonia simplicifolia (1010), Hibiscus sabdariffa (987), Tamarindus indica (973) and Catha edulis (947). The top species in terms of recent research interest (% of publications in last decade) were: Hoodia gordonii (95%), Cyclopia genistoides (93%), Sceletium tortuosum (90%), Agathosma betulina (89%), Pelargonium sidoides (86%), Boswellia papyrifera (85%), Lessertia (Sutherlandia) frutescens (84%), Boswellia sacra (83%), Mondia whitei (81%), Hibiscus sabdariffa (80%), Hypoxis hemerocallidea (80%) and Tylosema esculentum (80%). Both lists reflect the recent interest in functional foods and dietary supplements. CONCLUSION: Despite a marked recent increase in the number of publications on indigenous medicinal plants and dietary supplements, Africa lags behind Europe and Asia in terms of the number of products that have been commercialised and the percentage of the flora that is utilized for international trade. There is a tremendous potential for developing new crops and new products but much work remains to be done to generate more focussed and relevant pre-clinical data and convincing proof of concept through clinical studies. PMID- 26498494 TI - JCU medical graduates' preparedness for remote practice. PMID- 26498495 TI - Corrigendum: genome-wide association study of colorectal cancer identifies six new susceptibility loci. PMID- 26498497 TI - Nickel as a co-catalyst for photocatalytic hydrogen evolution on graphitic-carbon nitride (sg-CN): what is the nature of the active species? AB - The nature of a nickel-based co-catalyst deposited on a sol-gel prepared porous graphitic-carbon nitride (sg-CN), for photocatalytic H2 production from water, has been investigated. The formation of the active catalytic species, charge separation and recombination of the photogenerated electrons and holes during photochemical H2 evolution has been determined for the first time using in situ EPR spectroscopy. PMID- 26498496 TI - During Stably Suppressive Antiretroviral Therapy Integrated HIV-1 DNA Load in Peripheral Blood is Associated with the Frequency of CD8 Cells Expressing HLA DR/DP/DQ. AB - BACKGROUND: Characterising the correlates of HIV persistence improves understanding of disease pathogenesis and guides the design of curative strategies. This study investigated factors associated with integrated HIV-1 DNA load during consistently suppressive first-line antiretroviral therapy (ART). METHOD: Total, integrated, and 2-long terminal repeats (LTR) circular HIV-1 DNA, residual plasma HIV-1 RNA, T-cell activation markers, and soluble CD14 (sCD14) were measured in peripheral blood of 50 patients that had received 1-14 years of efavirenz-based or nevirapine-based therapy. RESULTS: Integrated HIV-1 DNA load (per 10(6) peripheral blood mononuclear cells) was median 1.9 log10 copies (interquartile range 1.7-2.2) and showed a mean difference of 0.2 log10 copies per 10 years of suppressive ART (95% confidence interval - 0.2, 0.6; p = 0.28). It was positively correlated with total HIV-1 DNA load and frequency of CD8(+)HLA DR/DP/DQ(+) cells, and was also higher in subjects with higher sCD14 levels, but showed no correlation with levels of 2-LTR circular HIV-1 DNA and residual plasma HIV-1 RNA, or the frequency of CD4(+)CD38(+) and CD8(+)CD38(+) cells. Adjusting for pre-ART viral load, duration of suppressive ART, CD4 cell counts, residual plasma HIV-1 RNA levels, and sCD14 levels, integrated HIV-1 DNA load was mean 0.5 log10 copies higher for each 50% higher frequency of CD8(+)HLA-DR/DP/DQ(+) cells (95% confidence interval 0.2, 0.9; p = 0.01). CONCLUSIONS: The observed positive association between integrated HIV-1 DNA load and frequency of CD8(+)DR/DP/DQ(+) cells indicates that a close correlation between HIV persistence and immune activation continues during consistently suppressive therapy. The inducers of the distinct activation profile warrant further investigation. PMID- 26498498 TI - Perceived stress and musculoskeletal pain are prevalent and significantly associated in adolescents: an epidemiological cross-sectional study. AB - BACKGROUND: Long-term musculoskeletal pain and negative stress are health risks with adverse long-term health effects, and these health risks seem to increase among young people. The mechanisms behind this are unclear. There is a need for a better understanding of perceived stress and musculoskeletal pain among adolescents, in order to improve health promotion and treatment approaches in this group. METHODS: Objectives were to evaluate the current prevalence of perceived stress and musculoskeletal pain in 15 and 16 year olds, to explore stress-pain associations and the probability that perceived stress (PSQ) was related to the reporting of pain and variations in pain, and to investigate possible differences in stress between different types of musculoskeletal pain in the adolescents. A cross-sectional study was conducted. Elementary schools participated. The outcomes were stress (Perceived stress questionnaire; PSQ) and musculoskeletal pain (pain/no pain, pain sites, pain duration and pain intensity (Visual analogue scale; VAS). RESULTS: Fifty-one point two percent (N = 422) reported pain, of which 70.8 % reported long-term pain. Some more girls (57.9 %) reported pain. 22.0 % of the study population reported moderate to severe stress (PSQ >= 0.45), of which 79.6 % were bothered by pain (Pearson Chi-square 38.47, p <= .001). All stress and pain variables were significantly associated (p < .01). The strongest association appeared between pain intensity (VAS) and stress (PSQ) (r = 0.40). Perceived stress (PSQ) was associated with the reporting of pain among the adolescents (Odds Ratio [OR] 1.68) and could explain some of the variation in pain intensity (VAS; beta = 0.15, p < .001) and number of pain sites (beta = 0.14, p < .01), according to the regression analyses. There were no mean differences in stress (PSQ) between different types of musculoskeletal pain. CONCLUSIONS: There was high prevalence of musculoskeletal pain, long-term pain and moderate to severe stress (PSQ >= 0.45) in this study sample. Perceived stress (PSQ) was related to the reporting of musculoskeletal pain among the adolescents and could explain some of the variation in pain intensity (VAS) and number of pain sites. There were no differences in stress levels (PSQ) between different types of musculoskeletal pain in the adolescents. PMID- 26498500 TI - Magnetic graphene-carbon nanotube iron nanocomposites as adsorbents and antibacterial agents for water purification. AB - One of the biggest challenges of the 21st century is to provide clean and affordable water through protecting source and purifying polluted waters. This review presents advances made in the synthesis of carbon- and iron-based nanomaterials, graphene-carbon nanotubes-iron oxides, which can remove pollutants and inactivate virus and bacteria efficiently in water. The three-dimensional graphene and graphene oxide based nanostructures exhibit large surface area and sorption sites that provide higher adsorption capacity to remove pollutants than two-dimensional graphene-based adsorbents and other conventional adsorbents. Examples are presented to demonstrate removal of metals (e.g., Cu, Pb, Cr(VI), and As) and organics (e.g., dyes and oil) by grapheme-based nanostructures. Inactivation of Gram-positive and Gram-negative bacterial species (e.g., Escherichia coli and Staphylococcus aureus) is also shown. A mechanism involving the interaction of adsorbents and pollutants is briefly discussed. Magnetic graphene-based nanomaterials can easily be separated from the treated water using an external magnet; however, there are challenges in implementing the graphene based nanotechnology in treating real water. PMID- 26498501 TI - Interfacial behavior of asphaltenes. AB - We review the existing literature on asphaltenes at various types of interfaces: oil-water, air-water, gas-oil and solid-liquid, with more emphasis on the oil water interfaces. We address the role of asphaltene aggregation, recently clarified for asphaltenes in bulk by the Yen-Mullins model. We discuss the questions of adsorption reversibility and interfacial rheology, especially in connection with emulsion stability. PMID- 26498499 TI - Carbon Nanotubes Act as Contaminant Carriers and Translocate within Plants. AB - Nanotechnology permits broad advances in agriculture. However, as it is still at a relatively early stage of development, the potential risks remain unclear. Herein, for the first time, we reveal the following: 1) the impact of multi walled carbon nanotubes (MWCNTs) on the accumulation/depuration behaviors of contaminants in crop, mustard (Brassica juncea), and 2) the permeability and transportability of MWCNTs in intact mature mustard plants. Using an in vivo sampling technique, the kinetic accumulation/depuration processes of several contaminants in mustard plans exposed to MWCNTs were traced, and an enhancement of contaminant accumulation in living plants was observed. Meanwhile, we observed that the MWCNTs permeated into the roots of intact living plants (three months old) and were then transported to the upper organs under the force of transpiration steam. This study demonstrated that MWCNTs can act as contaminant carriers and be transported to the edible parts of crops. PMID- 26498502 TI - Studies of the symptom dyspnoea: a systematic review. AB - BACKGROUND: To deal with patients suffering from dyspnoea, it is crucial for general practitioners to know the prevalences of different diseases causing dyspnoea in the respective area and season, the likelihood of avoidable life threatening conditions and of worsening or recovery from disease. AIM: Aim of our project was to conduct a systematic review of symptom-evaluating studies on the prevalence, aetiology, and prognosis of dyspnoea as presented to GPs in a primary care setting. METHODS: We did a systematic review of symptom-evaluating studies on dyspnoea in primary care. For this we included all studies investigating the complaint "dyspnoea" as a primary or secondary consulting reason in general practice. Apart from qualitative studies, all kind of study designs independent from type of data assessment, outcome measurement or study quality were included. Symptom-evaluating studies from other settings than primary care and studies which exclusively included children (age <18 years) were excluded from the review. Studies selecting patients prior to recruitment, e.g. because of an increased probability for a particular diagnosis, were also excluded. RESULTS: This systematic review identified 6 symptom evaluating studies on dyspnoea in the primary care setting. The prevalence of dyspnoea as reason for consultation ranges from 0.87 to 2.59 % in general practice. Among all dyspnoea patients 2.7 % (CI 2.2-3.3) suffer from pneumonia. Further specification of underlying aetiologies seems difficult due to the studies' heterogeneity showing a great variety of probabilities. CONCLUSION: There is a great lack of empirical evidence on the prevalence, aetiology and prognosis of dyspnoea in general practice. This might yield uncertainty in diagnosis and evaluation of dyspnoea in primary care. PMID- 26498503 TI - Thoracic Radiotherapy for Extensive Stage Small-Cell Lung Cancer: A Meta Analysis. AB - BACKGROUND: Thoracic radiotherapy (TRT) has been evaluated as a means of improving overall survival and progression-free survival in patients with extensive stage small-cell lung cancer (ES-SCLC). METHODS: A systematic review of Medline and Embase (inception to January 2015) was undertaken to identify studies of extensive stage SCLC patients receiving platinum-based chemotherapy and randomized to receive TRT versus no TRT. Studies were screened by title (n = 2343) and then abstract (n = 72), with subsequent full-text review (n = 16). Effect estimates (hazard ratios [HR] and confidence intervals) were abstracted, with a random-effects model created to estimate treatment effects. Cochrane's Q and I(2) statistics were used to assess study heterogeneity. RESULTS: Two randomized studies were identified, including a total of 604 patients (302 TRT; 302 non-TRT). All patients received prophylactic cranial irradiation. The weighted median age was 62 years, and 56% were male. TRT was delivered as 30 Gy/10 fractions (n = 247) or 54 Gy twice daily/36 fractions (n = 55). Overall, the delivery of TRT was associated with improved overall survival (HR, 0.81; 95% confidence interval, 0.69-0.96; P = .014) and progression-free survival (HR, 0.74; 95% confidence interval, 0.64-0.87, P < .001). For both end points, the studies were not found to be heterogeneous (P = .439 and P = .638 respectively, I(2) = 0). Bronchopulmonary toxicity (grade 3 or higher) was similar in both groups (<= 2%). Esophageal toxicity (grade 3 or higher) was 6.6% in the TRT arm and 0% in the non-TRT arm (P < .001). CONCLUSION: This systematic review with meta-analysis of 2 randomized trials indicates that TRT improves overall survival and progression-free survival in patients with extensive stage SCLC, with a small incremental risk of esophageal toxicity. PMID- 26498505 TI - Capture of reactive monophosphine-ligated palladium(0) intermediates by mass spectrometry. AB - A long-sought-after reactive monophosphine-ligated palladium(0) intermediate, Pd(0)L (L = phosphine ligand), was detected for the first time from the activation of the Buchwald precatalyst with base. The detection was enabled using desorption electrospray ionization mass spectrometry (DESI-MS) in combination with online reaction monitoring. The subsequent oxidative addition of Pd(0)L with aryl halide and C-N coupling with amine via reductive elimination was also probed using DESI-MS. PMID- 26498504 TI - Disease Control Rate at 8 Weeks Predicts Subsequent Survival in Platinum-Treated Extensive Stage Small-Cell Lung Cancer: Results From the Southwest Oncology Group (SWOG) Database. AB - BACKGROUND: Overall response rate is frequently used as an end point in phase 2 trials of platinum-treated extensive stage (ES) small-cell lung cancer (SCLC). We hypothesized that disease control rate (DCR) would be a superior surrogate for subsequent survival outcomes. METHODS: Updated patient-level data from Southwest Oncology Group (SWOG) trials in second- and/or third-line ES-SCLC patients were pooled. Landmark analysis was performed among patients alive at 8 weeks for overall survival (OS) measured from the 8-week landmark. Association of clinical prognostic factors with DCR was assessed using logistic regression. A Cox proportional hazard model was used to assess the associations between DCR at the landmark time and subsequent OS, adjusted for prognostic factors. RESULTS: Of the 319 ES-SCLC patients, 263 were alive at the 8-week landmark and constituted the pooled study population. Only 8 patients had a response. Disease control at 8 weeks was seen in 98 patients. Bivariate analysis of OS from the 8-week landmark revealed that DCR (hazard ratio [HR], 0.47; P < .0001) and elevated lactate dehydrogenase (HR, 1.70; P = .0004) were significantly associated with OS. In multivariable analysis, DCR remained an independent predictor of subsequent survival from the 8-week landmark (HR, 0.50; P < .0001). CONCLUSION: In this large second- and third-line ES-SCLC database, DCR at 8 weeks was found to be a significant predictor of subsequent survival in patients receiving investigational therapy. These results have critical implications in the selection of surrogate end points in future prospective ES-SCLC trials. PMID- 26498506 TI - Dopamine-dependent CB1 receptor dysfunction at corticostriatal synapses in homozygous PINK1 knockout mice. AB - Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset Parkinson's disease (PD). We investigated the interaction between endocannabinoid (eCB) and dopaminergic transmission at corticostriatal synapses in PINK1 deficient mice. Whole-cell patch-clamp and conventional recordings of striatal medium spiny neurons (MSNs) were made from slices of PINK1(-/-), heterozygous PINK1(+/-) mice and wild-type littermates (PINK1(+/+)). In PINK1(+/+) mice, CB1 receptor (CB1R) activation reduced spontaneous excitatory postsynaptic currents (sEPSCs). Likewise, CB1R agonists (ACEA, WIN55,212-3 and HU210) induced a dose-dependent reduction of cortically-evoked excitatory postsynaptic potential (eEPSP) amplitude. While CB1R agonists retained their inhibitory effect in heterozygous PINK1(+/-) mice, conversely, in PINK1(-/-) mice they failed to modulate sEPSC amplitude. Similarly, CB1R activation failed to reduce eEPSP amplitude in PINK1(-/-) mice. Parallel biochemical measurements revealed no significant difference in the levels of the two main eCBs, 2 arachidonoylglycerol (2-AG) and anandamide (AEA) in PINK1(-/-) striata. Similarly, no change was observed in the enzymatic activity of both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), responsible for eCB hydrolysis. Instead, a significant reduction of binding ability of CB1R agonists was found in PINK1(-/-) mice. Notably, the CB1R-dependent inhibition of synaptic activity was restored either by amphetamine or after chronic treatment with the D2 dopamine receptor agonist quinpirole. Additionally, CB1R binding activity returned to control levels after chronic pretreatment with quinpirole. Consistent with the hypothesis of a close interplay with dopaminergic neurotransmission, our findings show a CB1R dysfunction at corticostriatal synapses in PINK1(-/-), but not in PINK1(+/-) mice, and provide a mechanistic link to the distinct plasticity deficits observed in both genotypes. PMID- 26498507 TI - Genome-wide association study on reproductive traits in Jinghai Yellow Chicken. AB - To identify molecular markers and candidate genes associated with reproductive traits, a genome-wide analysis was performed in Jinghai Yellow Chickens to analyze body weight at first oviposition (BWF), age at first oviposition (AFE), weight of the egg at first oviposition (FEW), egg weight at the age of 300 days (EW300), number of eggs produced by 300 days of age (EN300), egg hatchability (HA) and multiple selection index for egg production (MSI). The results showed that seven single nucleotide polymorphisms (SNPs) were associated with reproductive traits (P<1.80E-6, Bonferroni correction). The P-values of the seven SNPs were 5.62E-10, 3.45E-08, 9.76E-07, 8.90E-07, 1.12E-06, 1.42E-07 and 1.48E 07, respectively. These SNPs were located in close proximity to or within the sequence of the five candidate genes, including FAM184B, TTL, RGS1, FBLN5 and PCNX. An additional 46 SNPs that could be associated with reproductive traits were identified (P<3.59E-5, Bonferroni correction). Identification of the candidate genes as well as genome-wide SNPs that may be associated with reproductive traits will greatly advance the understanding of the genetic basis and molecular mechanisms underlying reproductive traits and may have practical significance in breeding programs for the improvements of reproductive traits in the Jinghai Yellow Chicken. PMID- 26498508 TI - Are Antibiotics Effective in the Treatment of Acute Maxillary Sinusitis? PMID- 26498509 TI - Enhanced stability of Zn2SnO4 with N719, N3 and eosin Y dye molecules for DSSC application. AB - In view of the increased prospects of Zn2SnO4 as an alternative photoanode for dye sensitized solar cells (DSSCs), we synthesized phase pure Zn2SnO4 nanostructures by a cost effective sonochemical technique. In order to establish the stability of this alternative photoanode in DSSCs, we further explored the interaction of the synthesized Zn2SnO4 with commonly used photosensitizers in DSSCs, such as N3, N719 and eosin Y. Based on the time dependent optical studies we could establish the prominence of anchoring groups in controlling the dye loading. Optical studies confirmed an enhanced stable interaction of Zn2SnO4 with all the studied sensitizers which could be beneficial in designing DSSC devices in future. In addition, we also established contact angle measurement as an indirect tool to understand the surface characteristics and thereby optimize the dye loading and stability of the photoanode surface. With the help of contact angle data, we could unequivocally establish the stability of the Zn2SnO4 photoanode surface modified with N3 and N719 dye molecules. Our studies further suggest the enhanced and superior stability of the prepared Zn2SnO4 compared to ZnO in different chemical environments. The quenching of the fluorescence and the abrupt decrease in the contact angle owing to an increase in the surface roughness further strengthen the above conclusion. To our best knowledge, this probably is the first report on the synthesis of Zn2SnO4 by a sonochemical process and its interaction with various photosensitizers. An exceptionally high open circuit voltage of >0.8 V was observed for all the devices fabricated with the synthesized ZTO as a photoanode. Our studies could pave way to future developments in the area of DSSCs using Zn2SnO4 as a photoanode. PMID- 26498510 TI - Quantitative prediction of genome-wide resource allocation in bacteria. AB - Predicting resource allocation between cell processes is the primary step towards decoding the evolutionary constraints governing bacterial growth under various conditions. Quantitative prediction at genome-scale remains a computational challenge as current methods are limited by the tractability of the problem or by simplifying hypotheses. Here, we show that the constraint-based modeling method Resource Balance Analysis (RBA), calibrated using genome-wide absolute protein quantification data, accurately predicts resource allocation in the model bacterium Bacillus subtilis for a wide range of growth conditions. The regulation of most cellular processes is consistent with the objective of growth rate maximization except for a few suboptimal processes which likely integrate more complex objectives such as coping with stressful conditions and survival. As a proof of principle by using simulations, we illustrated how calibrated RBA could aid rational design of strains for maximizing protein production, offering new opportunities to investigate design principles in prokaryotes and to exploit them for biotechnological applications. PMID- 26498511 TI - Viscoelastic properties, creep behavior and degree of conversion of bulk fill composite resins. AB - OBJECTIVES: The aim of this study was to investigate the viscoelastic properties and creep behavior of bulk fill composites under different conditions and evaluate their degree of conversion. METHODS: Seven bulk fill composites were examined: everX Posterior (EV), SDR (SD), SonicFill (SF), Tetric EvoCeram Bulk Fill (TE), Venus Bulk Fill (VE), x-tra base (XB) and x-tra fil (XF). Each material was tested at 21 degrees C, 37 degrees C and 50 degrees C under dry and wet conditions by applying a constant torque for static and creep testing and dynamic torsional loading for dynamic testing. Degree of conversion (%DC) was measured on the top and bottom surfaces of composites with ATR-FTIR spectroscopy. Statistical analysis was performed with two-way ANOVA, Bonferroni's post hoc test and Pearson's correlation coefficient. RESULTS: Shear modulus G ranged from 2.17GPa (VE) to 8.03GPa (XF) and flexural modulus E from 6.16GPa (VE) to 23GPa (XF) when the materials were tested dry at 21 degrees C. The increase of temperature and the presence of water lead to a decline of these properties. Flowable materials used as base composites in restorations showed significantly lower values (p<0.05) than non-base composites, while being more prone to creep deformation. %DC ranged from 47.25% (XF) to 66.67% (SD) at the top material surface and 36.06% (XF) to 63.20% (SD) at the bottom. SIGNIFICANCE: Bulk fill composites exhibited significant differences between them with base flowable materials showing in most cases inferior mechanical properties and higher degree of conversion than restorative bulk fill materials. PMID- 26498513 TI - Promoter hypermethylation of PTPL1, PTPN6, DAPK, p16 and 5-azacitidine inhibits growth in DLBCL. AB - Aberrant hypermethylation of CpG islands of tumor suppressor is one of the mechanisms for epigenetic loss of gene function. In the present study, the methylation status of the promoter regions of protein tyrosine phosphatase (PTPN) 6, DAPK, and p16 were studied using methylation-specific polymerase chain reaction (MSP) in 26 diffuse large B cell lymphoma (DLBCL) lymphomas. In OCI-LY1 cell line, gene methylation status, expression of PTPL1 and its reactivation by DNA demethylation was determined by PCR and on the protein level by western blotting. ELISA-like reaction was used to detect global DNA methylation measurement. Induction of apoptosis by 5-azacitidine was analyzed by Annexin V/PI staining and flow cytometry. Our results show that hypermethylation of the PTPN6 gene promoter region was found in 15.4% (4/26), the DAPK gene promoter region in 30.8% (8/26), the p16 gene promoter region in 7.7% (2/26). Notably, we identified that PTPL1 was hypermethylated and transcriptionally silenced in OCI-LY1 cell line. The expression of PTPL1 was re-inducible by 5-azacytidine. 5-azacytidine also inhibits the proliferation and decreases the global methylation level of the OCI-LY1 cell line. We can conclude from our study that a higher prevalence of methylation of PTPL1, PTPN6, DAPK and p16 occur in DLBCL. Our data also highlights 5-azacytidine as a potential therapeutic candidate for DLBCL. Further studies are required to substantiate the role of methylation of PTPL1, PTPN6, DAPK and p16 as a marker in diffuse large B cell lymphoma. PMID- 26498514 TI - Positron emission tomography-computed tomography versus positron emission tomography-magnetic resonance imaging for diagnosis of oral squamous cell carcinoma: A pilot study. AB - Diagnostic imaging of head and neck cancer has made enormous progress during recent years. Next to morphological imaging modalities (computed tomography [CT] and magnetic resonance imaging [MRI]), there are also hybrid imaging systems that combine functional and morphological information (positron emission tomography [PET]/CT and PET/MRI). The aim of this study was to compare the diagnostic accuracy of PET/MRI in the diagnosis of head and neck cancer with other imaging modalities (MRI, CT, PET/CT). Ten patients (nine male and one female) with histologically proven oral squamous cell carcinoma participated in an 18 F-FDG PET/CT scan and an additional 18 F-FDG PET/MRI scan prior to surgery. The morphological and functional results were compared with the histological results. Inclusion criteria were histologically proven oral squamous cell carcinoma and no prior surgical intervention, medical therapy, or local external radiation. There was no significant correlation between tumor differentiation and maximum standard uptake values. Functional imaging showed a slightly better correlation with the measurement of the maximal tumor diameter, whereas pure morphological imaging showed a better correlation with the measurement of infiltration depth. Only with PET/MRI could correct lymph node staging be reached; the other imaging tools showed false-negative or false-positive results. In conclusion, we showed in our limited patient cohort that PET/MRI is superior to the morphological imaging modalities, especially for lymph node staging. PMID- 26498512 TI - Establishing disease causality for a novel gene variant in familial dilated cardiomyopathy using a functional in-vitro assay of regulated thin filaments and human cardiac myosin. AB - BACKGROUND: As next generation sequencing for the genetic diagnosis of cardiovascular disorders becomes more widely used, establishing causality for putative disease causing variants becomes increasingly relevant. Diseases of the cardiac sarcomere provide a particular challenge in this regard because of the complexity of assaying the effect of genetic variants in human cardiac contractile proteins. RESULTS: In this study we identified a novel variant R205Q in the cardiac troponin T gene (TNNT2). Carriers of the variant allele exhibited increased chamber volumes associated with decreased left ventricular ejection fraction. To clarify the causal role of this variant, we generated recombinant variant human protein and examined its calcium kinetics as well as the maximally activated ADP release of human beta-cardiac myosin with regulated thin filaments containing the mutant troponin T. We found that the R205Q mutation significantly decreased the calcium sensitivity of the thin filament by altering the effective calcium dissociation kinetics. CONCLUSIONS: The development of moderate throughput post-genomic assays is an essential step in the realization of the potential of next generation sequencing. Although technically challenging, biochemical and functional assays of human cardiac contractile proteins of the thin filament can be achieved and provide an orthogonal source of information to inform the question of causality for individual variants. PMID- 26498515 TI - Consensus or controversy? The classification and treatment decision-making by 491 maxillofacial surgeons from around the world in three cases of a unilateral mandibular condyle fracture. AB - PURPOSE: Many studies are available in the literature on both classification and treatment of unilateral mandibular condyle fractures. To date however, controversy regarding the best treatment for unilateral mandibular condyle fractures remains. MATERIAL AND METHODS: In this study, an attempt was made to quantify the level of agreement between a sample of maxillofacial surgeons worldwide, on the classification and treatment decisions in three different unilateral mandibular condyle fracture cases. RESULTS: In total, 491 of 3044 participants responded. In all three mandibular condyle fracture cases, a fairly high level of disagreement was found. Only in the case of a subcondylar fracture, assuming dysocclusion was present, more than 81% of surgeons agreed that the best treatment would be open reduction and internal fixation. CONCLUSIONS: Based on the study results, there is considerable variation among surgeons worldwide with regard to treatment of unilateral mandibular condyle fracture. 3D imaging in higher fractures tends to lead to more invasive treatment decisions. PMID- 26498516 TI - Fuzzy zoning for feature matching technique in 3D reconstruction of nasal endoscopic images. AB - 3D reconstruction from nasal endoscopic images greatly supports an otolaryngologist in examining nasal passages, mucosa, polyps, sinuses, and nasopharyx. In general, structure from motion is a popular technique. It consists of four main steps; (1) camera calibration, (2) feature extraction, (3) feature matching, and (4) 3D reconstruction. Scale Invariant Feature Transform (SIFT) algorithm is normally used for both feature extraction and feature matching. However, SIFT algorithm relatively consumes computational time particularly in the feature matching process because each feature in an image of interest is compared with all features in the subsequent image in order to find the best matched pair. A fuzzy zoning approach is developed for confining feature matching area. Matching between two corresponding features from different images can be efficiently performed. With this approach, it can greatly reduce the matching time. The proposed technique is tested with endoscopic images created from phantoms and compared with the original SIFT technique in terms of the matching time and average errors of the reconstructed models. Finally, original SIFT and the proposed fuzzy-based technique are applied to 3D model reconstruction of real nasal cavity based on images taken from a rigid nasal endoscope. The results showed that the fuzzy-based approach was significantly faster than traditional SIFT technique and provided similar quality of the 3D models. It could be used for creating a nasal cavity taken by a rigid nasal endoscope. PMID- 26498517 TI - Three dimensional imaging of gold-nanoparticles tagged samples using phase retrieval with two focus planes. AB - Optical sectioning microscopy can provide highly detailed three dimensional (3D) images of biological samples. However, it requires acquisition of many images per volume, and is therefore time consuming, and may not be suitable for live cell 3D imaging. We propose the use of the modified Gerchberg-Saxton phase retrieval algorithm to enable full 3D imaging of gold-particle tagged samples using only two images. The reconstructed field is free space propagated to all other focus planes using post processing, and the 2D z-stack is merged to create a 3D image of the sample with high fidelity. Because we propose to apply the phase retrieving on nano particles, the regular ambiguities typical to the Gerchberg Saxton algorithm, are eliminated. The proposed concept is presented and validated both on simulated data as well as experimentally. PMID- 26498518 TI - Intrathecal Versus Oral Baclofen: A Matched Cohort Study of Spasticity, Pain, Sleep, Fatigue, and Quality of Life. AB - BACKGROUND: Baclofen commonly is used to manage spasticity caused by central nervous system lesions or dysfunction. Although both intrathecal and oral delivery routes are possible, no study has directly compared clinical outcomes associated with these 2 routes of treatment. OBJECTIVE: To compare spasticity levels, pain, sleep, fatigue, and quality of life between individuals receiving treatment with intrathecal versus oral baclofen. DESIGN: Cross-sectional matched cohort survey study. SETTING: Urban academic rehabilitation outpatient clinics. PARTICIPANTS: Adult patients with spasticity, treated with intrathecal or oral baclofen for at least 1 year, matched 1:1 for age, gender, and diagnosis. METHODS: Standardized surveys were administered during clinic appointments or by telephone. MAIN OUTCOME MEASURES: Surveys included the Penn Spasm Frequency Scale, Brief Pain Inventory, Epworth Sleepiness Scale, Fatigue Severity Scale, Life Satisfaction Questionnaire, and Diener Satisfaction with Life Scale. RESULTS: A total of 62 matched subjects were enrolled. The mean (standard deviation [SD]) age was 46 (11) years with a mean duration of intrathecal baclofen or oral baclofen treatment of 11 (6) and 13 (11) years, respectively. There were 40 (64%) male and 22 (36%) female subjects. Primary diagnoses included spinal cord injury (n = 38), cerebral palsy (n = 10), stroke (n = 10), and multiple sclerosis (n = 4). The mean (SD) dose of intrathecal and oral baclofen at the time of survey were 577 (1429) MUg/day and 86 (50) mg/day, respectively. Patients receiving intrathecal compared with oral baclofen experienced significantly fewer (1.44 [0.92] versus 2.37 [1.12]) and less severe (1.44 [0.92] versus 2.16 [0.83]) spasms, respectively as measured by the Penn Spasm Frequency Scale (P < .01; P < .01). There were no significant differences in pain, sleep, fatigue, and quality of life between groups. Subanalysis of patients with SCI mirrored results of the entire study sample, with significant decreases in spasm frequency and severity associated with intrathecal compared to oral baclofen (P < .01; P < .01), but no other between group differences. The mean (SD) percent change in dose of oral (21% [33%]) compared with intrathecal (3% [28%]) baclofen was significantly larger two years prior to the date of survey (P = .02). CONCLUSIONS: Long-term treatment with intrathecal compared with oral baclofen is associated with reduced spasm frequency and severity as well as greater dose stability. These benefits must be weighed against the risks of internal pump and catheter placement in patients considering intrathecal baclofen therapy. PMID- 26498520 TI - Tri-iodothyronine preconditioning protects against liver ischemia reperfusion injury through the regulation of autophagy by the MEK/ERK/mTORC1 axis. AB - BACKGROUND AND OBJECTIVES: The autophagy pathway has previously been suggested as an important protective factor in liver injury. The purpose of this study is to demonstrate the protective, autophagy-modulating effect of tri-iodothyronine (T3) on liver ischemia reperfusion injury. METHODS: Liver ischemia reperfusion was induced in male C57BL/6 mice after T3 administration. Liver function, histological damage, inflammatory infiltration, cytokine production, oxidative stress, antioxidant capacity, autophagy changing, and autophagy-associated intracellular signaling pathway were assessed to evaluate the impact of antecedent T3 treatment on ischemia reperfusion induced liver injury. RESULTS: After 70% liver ischemia reperfusion injury, mice that were preconditioned with appropriate T3 displayed significantly preserved liver function, less histological damage, less apoptosis, and enhanced antioxidant capacity. Further studies revealed that mice which were preconditioned with T3 before IR induction exhibited an increased level of autophagy mediated by MEK/ERK/mTORC1. CONCLUSIONS: Our results provide the first line of evidence indicating that antecedent T3 injection can provide protection for the liver against ischemia reperfusion induced injury by enhancing autophagy. Therefore, T3 preconditioning could be a potential therapeutic approach to prevent liver IR injury related to various clinical conditions. PMID- 26498519 TI - RLIP76 regulates Arf6-dependent cell spreading and migration by linking ARNO with activated R-Ras at recycling endosomes. AB - R-Ras small GTPase enhances cell spreading and motility via RalBP1/RLIP76, an R Ras effector that links GTP-R-Ras to activation of Arf6 and Rac1 GTPases. Here, we report that RLIP76 performs these functions by binding cytohesin-2/ARNO, an Arf GTPase guanine exchange factor, and connecting it to R-Ras at recycling endosomes. RLIP76 formed a complex with R-Ras and ARNO by binding ARNO via its N terminus (residues 1-180) and R-Ras via residues 180-192. This complex was present in Rab11-positive recycling endosomes and the presence of ARNO in recycling endosomes required RLIP76, and was not supported by RLIP76(Delta1-180) or RLIP76(Delta180-192). Spreading and migration required RLIP76(1-180), and RLIP76(Delta1-180) blocked ARNO recruitment to recycling endosomes, and spreading. Arf6 activation with an ArfGAP inhibitor overcame the spreading defects in RLIP76-depleted cells or cells expressing RLIP76(Delta1-180). Similarly, RLIP76(Delta1-180) or RLIP76(Delta180-192) suppressed Arf6 activation. Together these results demonstrate that RLIP76 acts as a scaffold at recycling endosomes by binding activated R-Ras, recruiting ARNO to activate Arf6, thereby contributing to cell spreading and migration. PMID- 26498521 TI - Mitogen-activated protein kinase kinase kinase (MAPKKK) 4 from rapeseed (Brassica napus L.) is a novel member inducing ROS accumulation and cell death. AB - MAPKKK is the largest family of MAPK cascade, which is known to play important roles in plant growth, development and immune responses. So far, only a few have been functionally characterized even in the model plant, Arabidopsis due to the potential functional redundancy of MAPKKK. We previously identified and cloned a few MAPKKK family genes from rapeseed. In this study, BnaMAPKKK4 was characterized as a member in eliciting accumulation of reactive oxygen species (ROS) and hypersensitive response (HR)-like cell death. This is accompanied with accumulation of malondialdehyde (MDA), anthocyanin as well as nuclear DNA fragmentation. The transcript abundance of a series of ROS accumulation, cell death, and defense response related genes were up-regulated by the expression of MAPKKK4. Further investigation identified BnaMAPKKK4 elicited ROS through the downstream MPK3. These results indicate that BnaMAPKKK4 and its downstream components function in the ROS-induced cell death. PMID- 26498522 TI - Oxidized low-density lipoprotein attenuated desmoglein 1 and desmocollin 2 expression via LOX-1/Ca(2+)/PKC-beta signal in human umbilical vein endothelial cells. AB - Numerous studies have reported the presence of oxidized LDL (ox-LDL) and expression of its lectin-like receptor, LOX-1, have been shown in atherosclerotic regions. The present study aims to investigate the effects of ox-LDL on expression of desmoglein 1 (DSG1) and desmocollin 2 (DSC2) in endothelial cells, and to explore the role of LOX-1 mediated signal in the permeability injury associated with DSG1 and DSC2 disruption induced by oxidized lipoprotein. RT-PCR and Western blotting were applied to determine the mRNA and protein expression levels of DSG1 and DSC2 in human umbilical vein endothelial cells (HUVECs) respectively. Immunoreactivities of DSG1 and DSC2 were detected by laser scanning confocal microscope (LSCM). HUVEC monolayers permeability was evaluated by FITC labeled LDL in transwell assay system. The possible signal was assessed using in vitro blocking LOX-1 or Ca(2+) channel or PKC. The DSG1 and DSC2 expression were decreased by ox-LDL in concentration- and time-dependent manner. The effects of ox-LDL were mediated by its endothelial receptor, LOX-1. In parallel experiments, ox-LDL increased the influx of extracellular calcium, activation of protein kinase C (PKC) and permeability to LDL, which was inhibited by the LOX-1blocking antibody (10 MUg/ml), Ca(2+) channel blocker (Diltiazem, 50 MUmol/L) and PKC-beta inhibitor (hispidin, 4 MUmol/L). These results suggested that ox-LDL-induced decrease in DSG1 and DSC2 expression and monolayer barrier injury via calcium uptake and PKC-beta activation following up-regulation of LOX-1 is one of the mechanisms of inducing greater permeability in HUVECs. PMID- 26498523 TI - beta-Amyrin induces angiogenesis in vascular endothelial cells through the Akt/endothelial nitric oxide synthase signaling pathway. AB - beta-Amyrin is a pentacyclic triterpene found in various plants and has a variety of biological and pharmacological activities. However, the angiogenic effects of beta-amyrin in vascular endothelial cells have not been elucidated. Herein, we investigated the effects of beta-amyrin on angiogenesis and evaluated the underlying molecular mechanisms. beta-Amyrin treatment had no cytotoxic effect on cultured human umbilical vein endothelial cells (HUVECs). It promoted the formation of tube-like structures and enhanced HUVEC migration and the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) in HUVECs. Pre-treatment with a PI3 kinase or NOS inhibitor blocked beta-amyrin-induced phosphorylation of Akt and eNOS. beta-Amyrin treatment significantly induced nitric oxide (NO) production in HUVECs. Furthermore, pre-treatment with a PI3 kinase or NOS inhibitor significantly inhibited beta-amyrin-induced tube-like structures formation of vascular endothelial cells and HUVEC migration. These data indicate that beta-amyrin-induced angiogenesis in vascular endothelial cells may be mediated by Akt-eNOS signaling-dependent mechanisms. These findings suggest that beta-amyrin could be a novel therapeutic agent for ischemic vascular diseases. PMID- 26498524 TI - MiR-564 functions as a tumor suppressor in human lung cancer by targeting ZIC3. AB - Although miR-564 was reported to be dysregulated in human malignancy, the function and mechanism of miR-564 in tumorigenesis remains unknown. In the present study, we found that miR-564 frequently downregulated in lung cancer cells and significantly inhibited cell proliferation, cell cycle progression, motility, and the tumorigenicity of lung cancer cells. Moreover, we identified zic family member 3 (ZIC3) as a direct target of miR-564. ZIC3 overexpression impaired the suppressive effects of miR-564 on the capacity of lung cancer cells for proliferation and motility. Finally, we detected the expression level of miR 564 and ZIC3 protein in tissue specimens, and found a significant negative correlation between them. Patients with low levels of miR-564 showed a poorer overall survival. Taken together, our present study revealed the tumor suppressor role of miR-564, indicating restoration of miR-564 as a potential therapeutic strategy for the treatment of lung cancer. PMID- 26498525 TI - Sphere formation of adipose stem cell engineered by poly-2-hydroxyethyl methacrylate induces in vitro angiogenesis through fibroblast growth factor 2. AB - A number of researchers have been reporting a wide range of in vitro and in vivo studies of cell engraftment to enhance angiogenesis using stem cells. Despite these efforts, studies involving three-dimensional (3D) culture method that mimics in vivo environment have not reached its peak yet. In this study, we investigated the change and effects on cellular angiogenic growth factors through sphere formation of adipose stem cell (ASC) which is engineered by poly-2 hydroxyethyl methacrylate (Poly-HEMA). First of all, we successfully induced sphere formation of ASC (sph-ASC) on Poly-HEMA coated plates. sph-ASC represented significantly higher expression levels of anti-apoptotic and hypoxic factors compared to monolayer adherent ASC (adh-ASC). Interestingly, sph-ASC showed higher mRNA levels of the following genes; CD31, CD144, vWF, IGF-2, MCP-1, PDGF A, VEGF-A, VEGF-C, and FGF-2. In addition, mRNA expressions of angiogenic growth factor receptors such as Flk1, FGFR1, FGFR2, and Tie2 were elevated in sph-ASC. In protein level, Cytokine/Chemokines antibody array revealed a significant increase of FGF-2 in sph-ASC (3.17-fold) compared to adh-ASC. To investigate the effects of FGF-2 on sph-ASC, Matrigel angiogenic invasion assay showed significant reduced level of FGF-2 in FGF-2 siRNA transfected sph-ASC (2.27-fold) compared to negative control siRNA transfected sph-ASC. These findings suggest that Poly-HEMA coated plates induce sphere formation of ASC which has significantly higher expression of FGF-2, and plays a critical role as a major regulating growth factor of in vitro angiogenesis. PMID- 26498526 TI - The bisphosphonate zoledronic acid effectively targets lung cancer cells by inhibition of protein prenylation. AB - Aberrant activation of oncoproteins such as members of the Ras family is common in human lung cancers. The proper function of Ras largely depends on a post translational modification termed prenylation. Bisphosphonates have been shown to inhibit prenylation in cancer cells. In this study, we show that zoledronic acid, a third generation bisphosphonate, is effective in targeting lung cancer cells. This is achieved by the induction of apoptosis and inhibition of proliferation, through suppressing the activation of downstream Ras and EGFR signalling by zoledronic acid. The combination of zoledronic acid and paclitaxel or cisplatin (commonly used chemotherapeutic drugs for lung cancer) augmented the activity of either drug alone in in vitro lung cancer cellular system and in vivo lung xenograft mouse model. Importantly, zoledronic acid inhibits protein prenylation as shown by the increased levels of unprenylated Ras and Rap1A. In addition, the effects of zoledronic acid were reversed in the presence of geranylgeraniol and farnesol, further confirming that mechanism of zoledroinc acid's action in lung cancer cells is through prenylation inhibition. Since zoledronic acid is already available for clinic use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of lung cancer. PMID- 26498527 TI - Dunnione ameliorates cisplatin-induced small intestinal damage by modulating NAD(+) metabolism. AB - Although cisplatin is a widely used anticancer drug for the treatment of a variety of tumors, its use is critically limited because of adverse effects such as ototoxicity, nephrotoxicity, neuropathy, and gastrointestinal damage. Cisplatin treatment increases oxidative stress biomarkers in the small intestine, which may induce apoptosis of epithelial cells and thereby elicit damage to the small intestine. Nicotinamide adenine dinucleotide (NAD(+)) is a cofactor for various enzymes associated with cellular homeostasis. In the present study, we demonstrated that the hyper-activation of poly(ADP-ribose) polymerase-1 (PARP-1) is closely associated with the depletion of NAD(+) in the small intestine after cisplatin treatment, which results in downregulation of sirtuin1 (SIRT1) activity. Furthermore, a decrease in SIRT1 activity was found to play an important role in cisplatin-mediated small intestinal damage through nuclear factor (NF)-kappaB p65 activation, facilitated by its acetylation increase. However, use of dunnione as a strong substrate for the NADH:quinone oxidoreductase 1 (NQO1) enzyme led to an increase in intracellular NAD(+) levels and prevented the cisplatin-induced small intestinal damage correlating with the modulation of PARP-1, SIRT1, and NF-kappaB. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological NQO1 substrates could be a promising therapeutic approach for protecting against cisplatin-induced small intestinal damage. PMID- 26498528 TI - Expression pattern and function of tyrosine receptor kinase B isoforms in rat mesenteric arterial smooth muscle cells. AB - Tyrosine receptor kinaseB (TrkB) is a high affinity receptor for brain-derived neurotrophic factor (BDNF). TrkB isoforms involve full length TrkB (TrkB FL) and truncated TrkB type1 (TrkB T1) and type 2 (TrkB T2) in rats. The aim of present study was to explore their expression pattern and function in mesenteric arterial smooth muscle cells (MASMCs). The expression of TrkB isoform protein and mRNA was examined by Western blotting, immunofluorescence and quantitative RT-PCR analyses. Cell proliferation was measured by a bromodeoxyuridine (BrdU) incorporation assay. Cell migration was measured by a Boyden chamber assay. Cell morphology was observed with a phase-contrast microscope. Protein and mRNA expression of BDNF and TrkB isoforms was confirmed in MASMCs. Expression level of TrkB FL was less, while that of TrkB T1 was the highest in MASMCs. Although BDNF increased phosphorylation of ERK, it had no influence on migration and proliferation of MASMCs. TrkB T1 gene knockdown by a RNA interference induced morphological changes and reduced expression level of alpha-smooth muscle actin (alpha-SMA) in MASMCs. Similar morphological changes and reduced alpha-SMA expression were induced in MASMCs by a Rho kinase inhibitor, Y-27632. In conclusion, we for the first time demonstrate that TrkB T1 expressed highly in MASMCs contributes to maintain normal cell morphology possibly via regulation of Rho activity. This study firstly defined expression level of TrkB isoforms and partly revealed their functions in peripheral vascular cells. PMID- 26498529 TI - MicroRNA, miR-374b, directly targets Myf6 and negatively regulates C2C12 myoblasts differentiation. AB - Myogenesis is a complex process including myoblast proliferation, differentiation and myotube formation and is controlled by myogenic regulatory factors (MRFs), MyoD, MyoG, Myf5 and Myf6 (also known as MRF4). MicroRNA is a kind of ~22 nt-long non-coding small RNAs, and act as key transcriptional or post-transcriptional regulators of gene expression. Identification of miRNAs involved in the regulation of muscle genes could improve our understanding of myogenesis process. In this study, we investigated the regulation of Myf6 gene by miRNAs. We showed that miR-374b specifically bound to the 3'untranslated region (UTR) of Myf6 and down-regulated the expression of Myf6 gene at both mRNA and protein level. Furthermore, miR-374b is ubiquitously expressed in the tissues of adult C57BL6 mouse, and the mRNA abundance increases first and then decreases during C2C12 myoblasts differentiation. Over-expression of miR-374b impaired C2C12 cell differentiation, while inhibiting miR-374b expression by 2'-O-methyl antisense oligonucleotides promoted C2C12 cell differentiation. Taken together, our findings identified miR-374b directly targets Myf6 and negatively regulates myogenesis. PMID- 26498530 TI - UDP-glucose pyrophosphorylase Ugp1 is involved in oxidative stress response and long-term survival during stationary phase in Saccharomyces cerevisiae. AB - Ugp1, UDP-glucose pyrophosphorylase, plays an important role in carbohydrate metabolism because it provides UDP-glucose that is a pivotal metabolite in several metabolic pathways in Saccharomyces cerevisiae. In this study, we show that a considerable reduction of glycogen and trehalose content in ugp1 knockdown cells is rescued by complementing the expression of Ugp1, indicating that Ugp1 is required for the production of storage carbohydrates. Because of the specific function of trehalose as a stress protectant, Ugp1 expression contributed to oxidative stress response and long-term cell survival during stationary phase. Furthermore, the modulation of Ugp1 level readjusted glycogen and trehalose accumulation in the protein kinase A (PKA)-related gene mutants. The PKA dependent phenotypes of oxidative stress resistance and long-term cell survival were also alleviated via adjustment of Ugp1 level. Collectively, our data suggest that the regulation of UPG1 influences several PKA-dependent processes by adjusting the levels of various carbohydrates. PMID- 26498531 TI - DEC1 negatively regulates AMPK activity via LKB1. AB - Basic helix-loop-helix (bHLH) transcription factor DEC1 (bHLHE40/Stra13/Sharp2) is one of the clock genes that show a circadian rhythm in various tissues. AMP activated protein kinase (AMPK) activity plays important roles in the metabolic process and in cell death induced by glucose depletion. Recent reports have shown that AMPK activity exhibited a circadian rhythm. However, little is known regarding the regulatory mechanisms involved in the circadian rhythm of AMPK activity. The aim of this study is to investigate whether there is a direct correlation between DEC1 expression and AMPK activity. DEC1 protein and AMPK activity showed a circadian rhythm in the mouse liver with different peak levels. Knocking down DEC1 expression increased AMPK activity, whereas overexpression of DEC1 decreased it. Overexpressing the DEC1 basic mutants had little effect on the AMPK activity. DEC1 bound to the E-box of the LKB1 promoter, decreased LKB1 activity and total protein levels. There was an inverse relationship between DEC1 expression and AMPK activity. Our results suggest that DEC1 negatively regulates AMPK activity via LKB1. PMID- 26498532 TI - Continuous angiotensin-(1-7) infusion improves myocardial calcium transient and calcium transient alternans in ischemia-induced cardiac dysfunction rats. AB - The aim of this study was to evaluate the impact of Ang-(1-7) on calcium transient (CaT) in cardiomyocytes during the pathogenesis of heart failure. Cardiac dysfunction was induced by ligation of left anterior descending coronary artery in adult SD rats. Randomly selected rats were ligated and continuously infused with Ang-(1-7) [HF + Ang-(1-7) group] or saline (HF + saline group) via osmotic minipumps. After 28 days, hemodynamic parameters, the CaT, and the heart rate threshold of CaT alternans (CaT-Alt) were measured. Continuous Ang-(1-7) treatment could attenuate the impairment of cardiac function following LAD ligation. The amplitudes (F/F0) and 50%/90% recovery time of CaT were significantly different among HF + saline, HF + Ang-(1-7) and Sham-operated group. Compared to the Sham-operated group, the HF + saline group showed decreased CaT amplitude, and a prolonged 50%/90% CaT recovery time; Ang-(1-7) significantly improved these abnormalities. Compared with Sham-operated group, heart rate thresholds of CaT-Alt significantly reduced in HF + saline group, and Ang-(1-7) partly restored it. These findings indicate that Ang-(1-7) attenuates the CaT disturbance and increases the heart rate threshold of CaT-Alt during the pathogenesis of ischemic heart failure. PMID- 26498534 TI - A novel Bunyavirus from the soft tick, Argas vespertilionis, in Japan. AB - Soft ticks, Argas vespertilionis, were collected from feces of bats in Japan. Cytopathic effect (CPE) was observed after inoculating the homogenates of ticks to Vero cells. Sequencing of RNA extracted from the cell supernatant was performed by next generation sequencer. The contigs had identity to segments of Bunyaviruses, Issyk-Kul virus. The identities of segment L, M and S were only 77, 76 and 79% to Issyk-Kul virus, respectively. Therefore, we named this novel virus Soft tick bunyavirus (STBV). In the phylogenetic tree, segment L of STBV was closely related to a cluster consisting of the genus Nairovirus of the family Bunyaviridae. PMID- 26498533 TI - Further evaluation of an ELISA kit for detection of antibodies to a nonstructural protein of foot-and-mouth disease virus. AB - An ELISA kit for detection of antibodies to a nonstructural protein of foot-and mouth disease (FMDV) was further evaluated using sequentially collected serum samples of experimentally infected animals, because the sensitivity of the kit used in a previous study was significantly low in field animals. The kit fully detected antibodies in infected animals without vaccination; however, the first detections of antibodies by the kit were later than those by the liquid-phase blocking ELISA that is used for serological surveillance in the aftermath of outbreaks in Japan, for detection of antibodies to structural proteins of FMDV. Additionally, although the kit effectively detected antibodies in infected cattle with vaccination, there were several infected pigs with vaccination for which the kit did not detect antibodies during the experimental period. Taken together, the kit may not be suitable for serological surveillance after an FMD outbreak either with or without emergency vaccination in FMD-free countries. PMID- 26498536 TI - Electrocardiographic correlates of mechanical dyssynchrony in recipients of cardiac resynchronization therapy devices. AB - BACKGROUND: The relationship between electrical and mechanical indices of cardiac dyssynchronization in systolic heart failure (HF) remains poorly understood. OBJECTIVES: We examined retrospectively this relationship by using the daily practice tools in cardiology in recipients of cardiac resynchronization therapy (CRT) systems. METHODS: We studied 119 consecutive patients in sinus rhythm and QRS >= 120 ms (mean: 160 +/- 17 ms) undergoing CRT device implantation. P wave duration, PR, ePR (end of P wave to QRS onset), QT, RR-QT, JT and QRS axis and morphology were putative predictors of atrioventricular (diastolic filling time [DFT]/RR), interventricular mechanical dyssynchrony (IVMD) and left intraventricular mechanical dyssynchrony (left ventricular pre-ejection interval [PEI] and other measures) assessed by transthoracic echocardiography (TTE). Correlations between TTE and electrocardiographic measurements were examined by linear regression. RESULTS: Statistically significant but relatively weak correlations were found between heart rate (r=-0.5), JT (r=0.3), QT (r=0.3), RR QT intervals (r=0.5) and DFT/RR, though not with PR and QRS intervals. Weak correlations were found between: (a) QRS (r=0.3) and QT interval (r=0.3) and (b) IVMD > 40 ms; and between (a) ePR (r=-0.2), QRS (r=0.4), QT interval (r=0.3) and (b) LVPEI, though not with other indices of intraventricular dyssynchrony. CONCLUSIONS: The correlations between electrical and the evaluated mechanical indices of cardiac dyssynchrony were generally weak in heart failure candidates for CRT. These data may help to explain the discordance between electrocardiographic and echocardiographic criteria of ventricular dyssynchrony in predicting the effect of CRT. PMID- 26498535 TI - Tricuspid valve and percutaneous approach: No longer the forgotten valve! AB - Tricuspid valve disease is mainly represented by tricuspid regurgitation (TR), which is a predictor of poor outcome. TR is usually secondary, caused by right ventricle pressure or volume overload, the leading cause being left-sided heart valve diseases. Tricuspid surgery for severe TR is recommended during left valve surgery, and consists of either a valve replacement or, most often, a tricuspid repair with or without prosthetic annuloplasty. When TR persists or worsens after left valvular surgery, redo isolated tricuspid surgery is associated with high mortality. In addition, a sizeable proportion of patients present with tricuspid surgery deterioration over time, and need a reintervention, which is associated with high morbi-mortality rates. In this context, and given the recent major breakthrough in the percutaneous treatment of aortic and mitral valve diseases, the tricuspid valve appears an appealing challenge, although it raises specific issues. The first applications of transcatheter techniques for tricuspid valve disease were valve-in-valve and valve-in-ring implantation for degenerated bioprosthesis or ring annuloplasty. Some concerns remain regarding prosthesis sizing, rapid ventricular pacing and the best approach, but these procedures appear to be safe and effective. More recently, bicuspidization using a transcatheter approach for the treatment of native tricuspid valve has been published, in two patients. Finally, other devices are in preclinical development. PMID- 26498537 TI - Circulating microribonucleic acids miR-1, miR-21 and miR-208a in patients with symptomatic heart failure: Preliminary results. AB - BACKGROUND: Cardiomyocytes produce a wide variety of bioactive molecules that regulate numerous physiological and pathophysiological processes. Recently, it has been recognized that changes in microribonucleic acid (miRNA) expression may lead to cardiac dysfunction. AIMS: To assess the expression of circulating miRNAs (miR-1, miR-21 and miR-208a) in patients with symptomatic heart failure (HF), and to investigate the relationship between expression of these miRNAs and secretion of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and galectin-3. METHODS: Thirty-five patients in New York Heart Association (NYHA) class II/III (age: 68.8 +/- 13.0 years) and 26 patients in NYHA class IV (age: 72.0 +/- 10.4 years) hospitalized in the intensive coronary care unit participated in the study. Serum concentrations of miRNAs were measured by quantitative real-time polymerase chain reaction. Basic biochemical assays were carried out, and NT-proBNP and galectin-3 concentrations were measured in all serum samples. RESULTS: miR-1 was downregulated in patients with symptomatic HF and its expression decreased with severity of NYHA class (P=0.007). In contrast, overexpression of miR-21 was seen in all patients, independent of HF severity. Results suggest no miR-208a leakage into the circulation in patients with symptomatic HF. There was an inverse relationship between miR-1 expression and NT-proBNP concentration (Spearman's rank correlation coefficient [r]=-0.389; P=0.023) in patients in NYHA class II/III. Overexpression of miR-21 correlated significantly with galectin-3 concentration (r=0.422; P=0.032). CONCLUSION: Dysregulation of miR-1 and miR-21 expression may be essential for the development of HF; miR-1 might become a biomarker for predicting HF exacerbation. PMID- 26498538 TI - Everything Changes Always in Favor of Our Patients. PMID- 26498539 TI - Uterine Arteriovenous Malformation: Hysteroscopic Identification Is Possible. PMID- 26498540 TI - Letter to the Editor Regarding Zupi E, Centini G, Lazzeri L, et al. Hysteroscopic Endometrial Resection Versus Laparoscopic Supracervical Hysterectomy for Abnormal Uterine Bleeding : Long-Term Follow-up of a Randomized Trial. PMID- 26498541 TI - Management of Elbow Trauma: Anatomy and Exposures. AB - The elbow is a complex joint from the anatomic and biomechanical point of view. A thorough understanding of elbow anatomy greatly aids the surgeon in dealing with elbow trauma. The close vicinity of neurovascular structures should always be kept in mind when selecting a surgical approach. Any approach to the elbow needs to be safe and versatile. Knowledge of the attachment and orientation of elbow ligaments reduces the risk of inadvertent intraoperative injury and/or postoperative instability. Surgeons dealing with elbow trauma should have a good working understanding of elbow anatomy and the available approaches to effectively and efficiently conduct the surgical procedure to maximize outcomes and minimize complications. PMID- 26498542 TI - Simple Elbow Dislocation. AB - Simple elbow dislocation refers to those elbow dislocations that do not involve an osseous injury. A complex elbow dislocation refers to an elbow that has dislocated with an osseous injury. Most simple elbow dislocations are treated nonoperatively. Understanding the importance of the soft tissue injury following a simple elbow dislocation is a key to being successful with treatment. PMID- 26498543 TI - Fractures of the Radial Head. AB - Radial head fractures are the most common fractures around the elbow. Because they are often accompanied by ligamentous injuries, we recommend considering them to be osteoligamentous injuries rather than simple fractures, even in undisplaced or minimally displaced fractures. Surgeons should always suspect and actively exclude concomitant ligament tears. The incidence of these associated injuries increases with greater severity of the radial head fracture. However, the standard Mason classification system does not adequately address this problem, and all attempts to establish a new classification system that provides concise treatment algorithms have failed. This article discusses the current treatment options and the current controversies in nonsurgical therapy, open reduction and internal fixation (ORIF) and radial head replacement. PMID- 26498544 TI - Complex Elbow Instability: Radial Head and Coronoid. AB - A standardized and systematic approach for the management of an acute complex elbow dislocation involving the radial head and coronoid will maximize clinical outcomes. The cornerstones of surgical management include primary restoration of the ulnohumeral joint by reduction of the intact joint or coronoid fracture fixation, followed by radial head fixation or replacement. The lateral ulnar collateral ligament complex is then repaired before assessing elbow stability within a functional sagittal arc of motion. PMID- 26498545 TI - Varus Posteromedial Instability. AB - Varus posteromedial instability of the elbow is a result of traumatic injury to the medial facet of the coronoid and usually the lateral collateral ligament. Treatment of these fractures is usually surgical; poor outcomes have been described with nonoperative treatment. Surgical management consists of coronoid fracture fixation with plates, screws, or sutures and radial collateral ligament repair. Outcomes of these injuries are mixed, but most series report fair to good objective scores. The purpose of this article is to describe the pathophysiology of varus posteromedial instability, discuss the management of this injury, and report the outcomes of treatment. PMID- 26498546 TI - Adult Monteggia and Olecranon Fracture Dislocations of the Elbow. AB - Monteggia fractures and olecranon fracture dislocations represent complex injuries with distinct patterns of bony and soft tissue involvement. Fractures of the proximal ulna and olecranon process may lead to disruption of the proximal radioulnar joint and/or ulnohumeral joint. The keys to treatment are recognition of the pattern of injury and formation of an algorithmic surgical plan to address all components of the injury process. Complications are common and may be related to the injury spectrum itself and/or inadequate fracture alignment or fixation. PMID- 26498547 TI - Olecranon Fractures. AB - Olecranon fractures are common upper extremity injuries, with all but nondisplaced fractures treated surgically. There has been a recent shift in the surgical management of these fractures from tension band wiring to locking plate fixation and intramedullary nailing; however, this comes with increased implant cost. Although most patients can expect good outcomes after these various techniques, there is little information to guide a surgeon's treatment plan. This article reviews the epidemiology, classification, treatment, and outcomes of olecranon fractures. PMID- 26498548 TI - Distal Humerus Fractures: Open Reduction Internal Fixation. AB - Distal humerus fractures are challenging injuries for the upper extremity surgeon. However, recent techniques in open reduction internal fixation have been powerful tools in getting positive outcomes. To get such results, the surgeon must be aware of how to properly use these techniques in their respective practices. The method of fixation depends on the fracture, taking the degree of comminution and the restoration of the columns and articular surface into account. This article helps surgeons understand the concepts behind open reduction internal fixation of the distal humerus and makes them aware of pitfalls that may lead to negative results. PMID- 26498549 TI - Total Elbow Arthroplasty for Distal Humerus Fractures. AB - Total elbow arthroplasty is a good treatment alternative for selected patients with distal humerus fractures. Its attractiveness is related to several factors, including the possibility of performing the procedure; leaving the extensor mechanism intact; faster, easier rehabilitation compared with internal fixation; and overall good outcomes reported in terms of both pain relief and function. Implant failure leading to revision surgery does happen, and patients must comply with certain limitations to extend the longevity of their implant. Development of high-performance implants may allow expanding the indications of elbow arthroplasty for fractures. PMID- 26498550 TI - Capitellar and Trochlear Fractures. AB - Fractures of the capitellum and trochlea account for a small proportion of elbow trauma. Clinicians need to be vigilant in their assessment as they are commonly associated with other injuries about the elbow. To optimize outcomes, the goals of management include a stable, anatomic reduction and early range of motion. Closed reduction of noncomminuted fractures may be successful but requires close follow-up. Open reduction and internal fixation is the preferred management of displaced capitellum-trochlear fractures. Elbow stiffness is the most commonly reported complication in operatively treated fractures. Arthroscopic-assisted reduction and internal fixation and arthroplasty are evolving management options. PMID- 26498551 TI - Distal Biceps Injuries. AB - A review of distal biceps tendon injuries is presented. Notable and recent studies on the incidence, presentation, diagnosis, and treatment are outlined. The benefits and risks of 1- and 2-incision techniques for repair are discussed, and classic studies are reviewed. PMID- 26498552 TI - Distal Triceps Tendon Injuries. AB - Acute triceps ruptures are an uncommon entity, occurring mainly in athletes, weight lifters (especially those taking anabolic steroids), and following elbow trauma. Accurate diagnosis is made clinically, although MRI may aid in confirmation and surgical planning. Acute ruptures are classified on an anatomic basis based on tear location and the degree of tendon involvement. Most complete tears are treated surgically in medically fit patients. Partial-thickness tears are managed according to the tear severity, functional demands, and response to conservative treatment. We favor an anatomic footprint repair of the triceps to provide optimal tendon to bone healing and, ultimately, functional outcome. PMID- 26498553 TI - Arthroscopic Management of Elbow Fractures. AB - Several types of elbow fractures are amenable to arthroscopic or arthroscopic assisted fracture fixation, including fractures of the coronoid, radial head, lateral condyle, and capitellum. Other posttraumatic conditions may be treated arthroscopically, such as arthrofibrosis or delayed radial head excision. Arthroscopy can be used for assessment of stability or intra-articular fracture displacement. The safest portals are the midlateral (soft spot portal), proximal anteromedial, and proximal anterolateral. Although circumstances may vary according to the injury pattern, a proximal anteromedial portal is usually established first. Arthroscopy enables a less invasive surgical exposure that facilitates visualization of the fracture fragments in select scenarios. PMID- 26498554 TI - Elbow Trauma in the Athlete. AB - In caring for athletes, the physician must be able to accurately diagnose and appropriately treat all forms of elbow injuries. Traumatic injuries to the elbow are common in the athlete. The late cocking phase of throwing produces tremendous valgus stress on the elbow that can lead to medial epicondyle avulsion fractures in adolescents or rupture of the medial ulnar collateral ligament in skeletally mature overhead throwers, such as baseball pitchers and javelin throwers. Common traumatic elbow injuries suffered by athletes, surgical techniques for operative repair of these injuries, as well as postoperative rehabilitation protocols and the clinical results are presented. PMID- 26498555 TI - Complications of Elbow Trauma. AB - The elbow is a highly congruent trochoginglymoid joint allowing motion in both flexion-extension and pronosupination across 3 articulations. Therefore, treatment of fractures of the elbow can be technically challenging to manage, even after initial surgery. The posttraumatic elbow is prone to complications such as stiffness associated with heterotopic ossification, instability or subluxation (posterolateral rotatory instability and varus posteromedial instability patterns), and wound complications. This article discusses the pathoanatomy, prevention, and treatment of these complications. PMID- 26498557 TI - Elbow Trauma--It's All in the Details. PMID- 26498556 TI - Soft-Tissue Coverage for Elbow Trauma. AB - The elbow is particularly prone to trauma, and soft-tissue reconstruction can be challenging given the inherent motion, pressure, and lack of local tissue laxity. Small wounds and those without exposure of vital structures may be amenable to primary repair. Large wounds and those requiring more substantial structural or anatomic repair may require local, regional or free flap-based reconstruction. A comprehensive review of soft-tissue reconstruction of the elbow is provided to offer surgeons alternative options in complicated upper extremity wounds. PMID- 26498558 TI - Towards in vitro DT/DNT testing: Assaying chemical susceptibility in early differentiating NT2 cells. AB - Human pluripotent embryonal carcinoma (NT2) cells are increasingly considered as a suitable model for in vitro toxicity testing, e.g. developmental toxicity and neurotoxicity (DT/DNT) studies, as they undergo neuronal differentiation upon stimulation with retinoic acid (RA) and permit toxicity testing at different stages of maturation. NT2 cells have recently been reported to show specific changes in dielectric resistance profiles during differentiation which can be observed as early as 24h upon RA-stimulation. These observations suggest altered susceptibility to chemicals at an early stage of differentiation. However, chemical susceptibility of early differentiating NT cells has not yet been studied. To address this question, we have established a cell fitness screening assay based on the analysis of intracellular ATP levels and we applied the assay in a large-scale drug screening experiment in NT2 stem cells and early differentiating NT2 cells. Subsequent analysis of ranked fitness phenotypes revealed 19 chemicals with differential toxicity profile in early differentiating NT2 cells. To evaluate whether any of the identified drugs have previously been associated with DT/DNT, we conducted a literature search on the identified molecules and quantified the fraction of chemicals assigned to the FDA (Food and Drug Administration) pregnancy risk categories (PRC) N, A, B, C, D, and X in the hit list and the small molecule library. While the fractions of the categories N and B were decreased (0.81 and 0.35-fold), the classes C, D and X were increased (1.35, 1.47 and 3.27-fold) in the hit list compared to the chemical library. From these data as well as from the literature review, identifying large fractions of chemicals being directly (~42%) and indirectly associated with DT/DNT (~32%), we conclude that our method may be beneficial to systematic in vitro-based primary screening for developmental toxicants and neurotoxicants and we propose cell fitness screening in early differentiating NT2 cells as a strategy for evaluating chemical susceptibility at different stages of differentiation to reduce animal testing in the context of the 3Rs. PMID- 26498560 TI - Decoding the mechanical fingerprints of biomolecules. AB - The capacity of biological macromolecules to act as exceedingly sophisticated and highly efficient cellular machines - switches, assembly factors, pumps, or motors - is realized through their conformational transitions, that is, their folding into distinct shapes and selective binding to other molecules. Conformational transitions can be induced, monitored, and manipulated by pulling individual macromolecules apart with an applied force. Pulling experiments reveal, for a given biomolecule, the relationship between applied force and molecular extension. Distinct signatures in the force-extension relationship identify a given biomolecule and thus serve as the molecule's 'mechanical fingerprints'. But, how can these fingerprints be decoded to uncover the energy barriers crossed by the molecule in the course of its conformational transition, as well as the associated timescales? This review summarizes a powerful class of approaches to interpreting single-molecule force spectroscopy measurements - namely, analytically tractable approaches. On the fundamental side, analytical theories have the power to reveal the unifying principles underneath the bewildering diversity of biomolecules and their behaviors. On the practical side, analytical expressions that result from these theories are particularly well suited for a direct fit to experimental data, yielding the important parameters that govern biological processes at the molecular level. PMID- 26498559 TI - The role of Eph receptors and Ephrins in the skin. AB - Eph receptors and Ephrin ligands are widely expressed in the skin. Various studies have been carried out to identify the effects of these molecules on many aspects of skin development. Here we summarize the literature that has identified roles for Eph receptors and Ephrins in the skin, focusing mainly on the epidermis, hair follicles, and cutaneous innervation. This review may help direct and focus further investigations into the role of Eph receptors and Ephrins in the development, maintenance, and repair processes in cutaneous biology. PMID- 26498561 TI - Effects of thread size in the implant neck area on peri-implant hard and soft tissues: an animal study. AB - OBJECTIVES: The aim of this animal study was to examine the effects of thread size in the implant neck area on peri-implant tissues in terms of BIC and hard- and soft-tissue dimensions. MATERIALS AND METHODS: Six Beagle dogs received experimental implants in the mandible 3 month after the removal of premolars and first molars (P2, P3, P4, and M1). Two different types of implants were installed in each animal: Anyone microthread((r)) as Group 1 and Anyone((r)) as Group 2. Resonance frequency test, intraoral radiography, micro-CT, and histomorphometry were used to evaluate peri-implant tissue after implantation periods of 4 and 8 weeks. RESULTS: No remarkable complication was observed during the healing period in either group. Resonance frequency testing revealed no significant difference between groups. In radiographic evaluation, Group 2 showed more bone loss than Group 1. However, this difference was not statistically significant. In the micro CT analysis, BIC and BIV values and soft-tissue height were not significant in both groups. Histological analysis revealed no significant difference in BIC ratio, bone density, or bone loss between groups. However, soft-tissue height was significantly greater in Group 2 than in Group 1 (P = 0.0004). CONCLUSION: No difference in peri-implant hard or soft tissues was observed according to thread size in the implant neck area. PMID- 26498562 TI - Opiates in Enhanced Recovery After Surgery: still not convinced. PMID- 26498563 TI - Prediction in pancreatic cancer. PMID- 26498564 TI - Resected stomach after sleeve gastrectomy. PMID- 26498565 TI - Emergency and pre-surgical band deflation in patients with laparoscopic adjustable gastric bands: variations in practice. PMID- 26498566 TI - Urethral calculus originating from ureterocele and causing urinary retention. PMID- 26498567 TI - Re: Use of fine-needle aspiration cytology in the diagnosis of parotid neoplasms. PMID- 26498568 TI - Core-Scaffold-Inspired Asymmetric Synthesis of Polysubstituted Chiral Hexahydropyridazines that Potently Inhibit Breast Cancer Cell Proliferation by Inducing Apoptosis. AB - The highly enantioselective preparation of pharmacologically interesting hexahydropyridazine derivatives based on a multicomponent cascade reaction is described. This one-pot approach utilizes an organocatalytic Michael reaction followed by intermolecular alpha-amination and intramolecular hemiaminalization to yield a chiral pyridazine backbone with contiguous stereogenic centers and multiple functional groups in good yield and with high stereoselectivity. Compounds synthesized by this method potently inhibited proliferation of MCF-7 breast cancer cells. Mechanistic studies suggest that compound 5 c exerts these anticancer effects by inducing apoptosis through extracellular signal related kinase (ERK)- and poly(adenosine diphosphate ribose) polymerase (PARP)-regulated pathways, as well as mitochondrial pathways. PMID- 26498569 TI - State-of-the-art of small molecule inhibitors of the TAM family: the point of view of the chemist. AB - The TAM family of tyrosine kinases receptors (Tyro3, Axl and Mer) is implicated in cancer development, autoimmune reactions and viral infection and is therefore emerging as an effective and attractive therapeutic target. To date, only a few small molecules have been intentionally designed to block the TAM kinases, while most of the inhibitors were developed for blocking different protein kinases and then identified through selectivity profile studies. This minireview will examine in terms of chemical structure the different compounds able to act on either one, two or three TAM kinases with details about structure-activity relationships, drug-metabolism and pharmacokinetics properties where they exist. PMID- 26498570 TI - Design, synthesis and evaluation of diarylpiperazine derivatives as potent anti tubercular agents. AB - Molecular hybridization is an emerging approach to design novel ligands by combination of two or more pharmacophoric subunits of known bioactive compounds. In the present study, we have designed a novel series of diarylpiperazine analogues, synthesized, characterized using FTIR, (1)H NMR, Mass, Elemental analysis and evaluated their in-vitro anti-tubercular activity. Among the reported sixteen diarylpiperazines, eleven analogues exhibited significant anti tubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC values below 6.25 MUg/mL and good selectivity index. Structure activity relationship studies concluded that, ortho-para directing group (except para chloro) substitution on ortho and para position of piperazine attached phenyl ring favored anti-tubercular activity. PMID- 26498572 TI - Discovery of a new class of antiviral compounds: camphor imine derivatives. AB - A new class of compounds featuring a camphor moiety has been discovered that exhibits potent inhibitory activity against influenza A(H1N1)pdm09 and A(H5N1) viruses. The synthesized compounds were characterized by spectroscopic analysis; in addition the structures of compound 2 and 14 were elucidated by the X-ray diffraction technique. Structure-activity relationship studies have been conducted to identify the 1,7,7-trimethylbicyclo[2.2.1]heptanes2-ylidene group as the key functional group responsible for the observed antiviral activity. The most potent antiviral compound is imine 2 with therapeutic index more than 500. PMID- 26498571 TI - Synthesis and pharmacological screening of a large library of 1,3,4 thiadiazolines as innovative therapeutic tools for the treatment of prostate cancer and melanoma. AB - Antimitotic agents are widely used in cancer chemotherapy but the numerous side effects and the onset of resistance limit their clinical efficacy. Therefore, with the purpose of discovering more selective and efficient anticancer agents to be administered alone or in combination with traditional drugs, we synthesized a large library of 1,3,4-thiadiazoline analogues, maintaining the pharmacophoric structure of an antiproliferative compound known as K858: this is a new inhibitor of kinesin Eg5, able to induce the mitotic arrest in colorectal cancer cells and in xenograft ovarian cancer cells. We screened 103 compounds to assess their antiproliferative activity on PC3 prostate cancer cell line. Two derivatives, compounds 32 (corresponding to K858) and 33, have shown to be the most effective against prostate tumor cells and also towards two melanoma cell lines (SK-MEL-5 and SK-MEL-28) at low micromolar concentrations, confirming the pharmacological activity of this scaffold and revealing the potential role of 1,3,4 thiadiazolines in the management of cancer. PMID- 26498573 TI - Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme. AB - Aggressive behavior and diffuse infiltrative growth are the main features of Glioblastoma multiforme (GBM), together with the high degree of resistance and recurrence. Evidence indicate that GBM-derived stem cells (GSCs), endowed with unlimited proliferative potential, play a critical role in tumor development and maintenance. Among the many signaling pathways involved in maintaining GSC stemness, tumorigenic potential, and anti-apoptotic properties, the PDK1/Akt pathway is a challenging target to develop new potential agents able to affect GBM resistance to chemotherapy. In an effort to find new PDK1/Akt inhibitors, we rationally designed and synthesized a small family of 2-oxindole derivatives. Among them, compound 3 inhibited PDK1 kinase and downstream effectors such as CHK1, GS3Kalpha and GS3Kbeta, which contribute to GCS survival. Compound 3 appeared to be a good tool for studying the role of the PDK1/Akt pathway in GCS self-renewal and tumorigenicity, and might represent the starting point for the development of more potent and focused multi-target therapies for GBM. PMID- 26498574 TI - Spitz nevus arising in the eyelid of a teenager. AB - A 16-year-old boy developed over a 2-month interval a lightly pigmented left upper eyelid lesion measuring 1.5 mm in greatest diameter that, when excised, microscopically was hypercellular and composed almost exclusively of nonpigmented epithelioid cells that created florid, large intraepidermal junctional nests and sheets and nests of subepidermal cells. The diagnosis was a Spitz nevus. HMB-45, MART-1, and microphthalmia-associated transcription factor were all positive and established the melanocytic nature of the benign tumor. The Ki-67 proliferation index (5%) and 2 mitoses/mm(2) were both low; p16 protein was immunohistochemically identified in the nevoid cells. We review the clinical, histopathologic, and other immunohistochemical features of this entity and provide a brief differential diagnosis (including separation from a Spitzoid melanoma). This is only the third eyelid Spitz nevus reported in the literature and is the most fully characterized immunohistochemically. At their present stage of development, contemporary immunohistochemical biomarkers, while providing supplemental information, nonetheless remain less than definitive in terms of reliably distinguishing benign from malignant Spitz lesions. PMID- 26498575 TI - Relationship between ultrasonographic nerve morphology and severity of diabetic sensorimotor polyneuropathy. AB - BACKGROUND AND PURPOSE: In the current study, the aim was to characterize the nerve ultrasound cross-sectional areas (CSAs) of type 2 diabetic patients with diabetic sensorimotor polyneuropathy (DSP) of different severities. METHODS: A hundred symptomatic DSP patients and 40 age-matched healthy controls were prospectively recruited. DSP severity was ascertained through the Toronto Clinical Scoring System (TCCS). Nerve electrophysiology and ultrasound were performed on both lower limbs and the non-dominant upper limb. RESULTS: The sural nerve was inexcitable in 19.1% of mild, 40.0% of moderate and 69.0% of severe DSP groups. In contrast, CSAs were measurable in all nerves of DSP patients and were significantly larger compared to controls. Patients with severe DSP had significantly larger ulnar, peroneal, tibial and sural nerves compared to mild DSP patients. By receiver operating characteristic curve analysis, the cut-off value for the sural nerve at 2 mm(2) was a good discriminator (area under the curve 0.88) between the presence and absence of DSP (sensitivity 0.90; specificity 0.74) but performed less well in discriminating between the severity of DSP (cut-off 2.75 mm(2); area under the curve 0.62; sensitivity 0.59; specificity 0.73). Significant correlations were demonstrated between TCSS scores, most neurophysiology parameters and CSAs of the ulnar, peroneal, tibial and sural nerves. CONCLUSION: Nerve ultrasound in DSP reveals enlarged CSAs and these changes worsen with increasing disease severity, thus serving as a useful diagnostic tool especially when neurophysiology is unrevealing. PMID- 26498576 TI - Women's perceptions of antenatal, delivery, and postpartum services in rural Tanzania. AB - BACKGROUND: Maternal health care provision remains a major challenge in developing countries. There is agreement that the provision of quality clinical services is essential if high rates of maternal death are to be reduced. However, despite efforts to improve access to these services, a high number of women in Tanzania do not access them. The aim of this study is to explore women's views about the maternal health services (pregnancy, delivery, and postpartum period) that they received at health facilities in order to identify gaps in service provision that may lead to low-quality maternal care and increased risks associated with maternal morbidity and mortality in rural Tanzania. DESIGN: We gathered qualitative data from 15 focus group discussions with women attending a health facility after child birth and transcribed it verbatim. Qualitative content analysis was used for analysis. RESULTS: 'Three categories emerged that reflected women's perceptions of maternal health care services: "mothers perceive that maternal health services are beneficial," "barriers to accessing maternal health services" such as availability and use of traditional birth attendants (TBAs) and the long distances between some villages, and "ambivalence regarding the quality of maternal health services" reflecting that women had both positive and negative perceptions in relation to quality of health care services offered'. CONCLUSIONS: Mothers perceived that maternal health care services are beneficial during pregnancy and delivery, but their awareness of postpartum complications and the role of medical services during that stage were poor. The study revealed an ambivalence regarding the perceived quality of health care services offered, partly due to shortages of material resources. Barriers to accessing maternal health care services, such as the cost of transport and the use of TBAs, were also shown. These findings call for improvement on the services provided. Improvements should address, accessibility of services, professionals' attitudes and stronger promotion of the importance of postpartum check-ups, both among health care professionals and women. PMID- 26498578 TI - Erratum. PMID- 26498580 TI - Codon bias and gene ontology in holometabolous and hemimetabolous insects. AB - The relationship between preferred codon use (PCU), developmental mode, and gene ontology (GO) was investigated in a sample of nine insect species with sequenced genomes. These species were selected to represent two distinct modes of insect development, holometabolism and hemimetabolism, with an aim toward determining whether the differences in developmental timing concomitant with developmental mode would be mirrored by differences in PCU in their developmental genes. We hypothesized that the developmental genes of holometabolous insects should be under greater selective pressure for efficient translation, manifest as increased PCU, than those of hemimetabolous insects because holometabolism requires abundant protein expression over shorter time intervals than hemimetabolism, where proteins are required more uniformly in time. Preferred codon sets were defined for each species, from which the frequency of PCU for each gene was obtained. Although there were substantial differences in the genomic base composition of holometabolous and hemimetabolous insects, both groups exhibited a general preference for GC-ending codons, with the former group having higher PCU averaged across all genes. For each species, the biological process GO term for each gene was assigned that of its Drosophila homolog(s), and PCU was calculated for each GO term category. The top two GO term categories for PCU enrichment in the holometabolous insects were anatomical structure development and cell differentiation. The increased PCU in the developmental genes of holometabolous insects may reflect a general strategy to maximize the protein production of genes expressed in bursts over short time periods, e.g., heat shock proteins. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 686-698, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26498577 TI - Advancing patient-centered care for structurally vulnerable drug-using populations: a qualitative study of the perspectives of people who use drugs regarding the potential integration of harm reduction interventions into hospitals. AB - AIMS: To explore the perspectives of structurally vulnerable people who use drugs (PWUD) regarding: (1) the potential integration of harm reduction interventions (e.g. supervised drug consumption services, opioid-assisted treatment) into hospitals; and (2) the implications of these interventions for patient-centered care, hospital outcomes and drug-related risks and harms. DESIGN: Semi-structured qualitative interviews. SETTING: Vancouver, Canada. PARTICIPANTS: Thirty structurally vulnerable PWUD who had been discharged from hospital against medical advice within the past 2 years, and hospitalized multiple times over the past 5 years. MEASUREMENTS: Semi-structured interview guide including questions to elicit perspectives on hospital-based harm reduction interventions. FINDINGS: Participant accounts highlighted that hospital-based harm reduction interventions would promote patient-centered care by: (1) prioritizing hospital care access and risk reduction over the enforcement of abstinence-based drug policies; (2) increasing responsiveness to subjective health needs (e.g. pain and withdrawal symptoms); and (3) fostering 'culturally safe' care. CONCLUSIONS: Hospital-based harm reduction interventions for people who use drugs, such as supervised drug consumption services and opioid-assisted treatment, can potentially improve hospital care retention, promote patient-centered care and reduce adverse health outcomes among people who use drugs. PMID- 26498581 TI - Regression Trees Identify Relevant Interactions: Can This Improve the Predictive Performance of Risk Adjustment? AB - Risk equalization formulas have been refined since their introduction about two decades ago. Because of the complexity and the abundance of possible interactions between the variables used, hardly any interactions are considered. A regression tree is used to systematically search for interactions, a methodologically new approach in risk equalization. Analyses are based on a data set of nearly 2.9 million individuals from a major German social health insurer. A two-step approach is applied: In the first step a regression tree is built on the basis of the learning data set. Terminal nodes characterized by more than one morbidity group-split represent interaction effects of different morbidity groups. In the second step the 'traditional' weighted least squares regression equation is expanded by adding interaction terms for all interactions detected by the tree, and regression coefficients are recalculated. The resulting risk adjustment formula shows an improvement in the adjusted R2 from 25.43% to 25.81% on the evaluation data set. Predictive ratios are calculated for subgroups affected by the interactions. The R2 improvement detected is only marginal. According to the sample level performance measures used, not involving a considerable number of morbidity interactions forms no relevant loss in accuracy. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26498582 TI - Conference report: the 2015 SHOT symposium and report--what's new? PMID- 26498583 TI - Decellular Nerve Allografts. AB - Multiple treatment options are available for patients who have peripheral nerve injuries with a gap. Decellular nerve allografts are one option and provide an extracellular scaffold for neuronal cells to migrate for axonal regrowth. Immunosuppression is not needed because improved nerve processing technologies have rendered decellular nerve allografts nonimmunogenic. These allografts have also shown promising results in both animal and human studies as an alternative repair option. PMID- 26498584 TI - Update on the Diagnosis and Management of Cervical Spondylotic Myelopathy. AB - Spondylotic degeneration in the cervical spine may result in static and/or dynamic spinal cord compression that can lead to the associated signs and symptoms of myelopathy. Clinical examination combined with appropriate imaging studies help to confirm the diagnosis. Classic natural history and basic science studies suggest a pernicious course of demyelination and neurologic decline in a large subset of patients. The characterization of disease severity and progression in patients with cervical spondylotic myelopathy has improved in recent years with imaging and data from prospective and multicenter studies. Additionally, advances in surgical techniques, implants, and imaging modalities have improved the identification of surgical candidates with cervical spondylotic myelopathy and associated treatment strategies. Surgical treatment, via an anterior, posterior, or a combined approach, is primarily intended to arrest neurologic progression, although it can improve function in many patients. Alignment and the characteristics and location of spinal cord compression help determine the ideal surgical approach. Distinct complications associated with each technique may be mitigated by appropriate patient selection and should be discussed preoperatively to ensure informed decision making. PMID- 26498585 TI - High Ankle Sprains and Syndesmotic Injuries in Athletes. AB - Treatment of athletes with ligamentous injuries of the tibiofibular syndesmosis can be problematic. The paucity of historic data on this topic has resulted in a lack of clear guidelines to aid in imaging and diagnosing the injury, assessing injury severity, and making management decisions. In recent years, research on this topic has included an abundance of epidemiologic, clinical, and basic science investigations of syndesmotic injuries that are purely ligamentous or associated with ankle fracture. Several classification systems can be used to classify ligamentous injury to the syndesmosis. These systems integrate clinical and radiographic findings but do not address the location of the injury or its severity. Injury to the syndesmosis can be purely ligamentous; however, many unstable syndesmotic injuries are associated with fractures. Nonsurgical management can be used for stable ligamentous injuries without frank diastasis, but surgical management, including screw or suture-button fixation, is indicated for fractures with unstable syndesmotic injuries. PMID- 26498586 TI - Injuries of the Scapholunate Interosseous Ligament: An Update. AB - The scapholunate ligament is both a key ligament in the stability of the carpus and one of the most frequently injured. Thorough understanding of the anatomy, biomechanics, and pathophysiology of the wrist is important in treating injuries to the scapholunate ligament. The presentation of scapholunate instability often includes a vague injury history and pain with grip, wrist extension, and sport or labor. Identified injuries are classified based on dynamic and static radiographic findings, chronicity, and the presence or absence of arthrosis. Surgical options for the treatment of low- and high-grade injuries include both open and arthroscopic procedures and can be broadly classified into four categories: limited arthroscopic procedures, primary ligament repair, reconstructive procedures, and salvage procedures. No strong evidence currently supports any one treatment. Decision making is largely based on expert opinion and surgeon experience. Prognosis is often guarded, and patient expectations should be tempered. PMID- 26498587 TI - Preventing Hospital Readmissions and Limiting the Complications Associated With Total Joint Arthroplasty. AB - Total joint arthroplasty is a highly successful surgical procedure for patients with painful arthritic joints. The increasing prevalence of the procedure is generating significant expenditures in the American healthcare system. Healthcare payers, specifically the Center for Medicare and Medicaid Services, currently target total joint arthroplasty as an area for healthcare cost-savings initiatives, resulting in increased scrutiny surrounding orthopaedic care, health resource utilization, and hospital readmissions. Identifying the complications associated with total hip and total knee arthroplasty that result in readmissions will be critically important for predictive modeling and for decreasing the number of readmissions following total joint arthroplasty. Additionally, improving perioperative optimization, providing seamless episodic care, and intensifying posthospital coordination of care may result in a decreasing number of unnecessary hospital readmissions. Identified modifiable risk factors that significantly contribute to poor clinical outcome following total joint arthroplasty include morbid obesity; poorly controlled diabetes and nutritional deficiencies; Staphylococcus aureus colonization; tobacco use; venous thromboembolic disease; cardiovascular disease; neurocognitive, psychological, and behavioral problems; and physical deconditioning and fall risk. Both clinical practice and research will be enhanced if there is standardization of defined total joint arthroplasty complications and utilization of stratification schemes to identify high-risk patients. Subsequently, clinical intervention would be warranted to address modifiable risk factors before proceeding with total joint arthroplasty. PMID- 26498588 TI - Shikonin as an inhibitor of the LPS-induced epithelial-to-mesenchymal transition in human breast cancer cells. AB - Shikonin (SK), a natural naphthoquinone isolated from the Chinese medicinal herb, has been known to suppress the proliferation of several cancer cells. However, its role in the epithelial mesenchymal transition (EMT) has yet to be demonstrated. The aim of the present study was to examine the effects of SK on EMT. Lipopolysaccharide (LPS) induced EMT-like phenotypic changes, enhancing cell migration and invasion. SK markedly reduced the expression of the LPS-induced EMT markers, including N-cadherin in MDA-MB-231 cells, and increased the expression of E-cadherin in MCF-7 cells. SK also inhibited cell migration and invasion in vitro. The effects of SK on the LPS-induced EMT were mediated by the inactivation of the NF-kappaB-Snail signaling pathway. The results provided new evidence that SK suppresses breast cancer cell invasion and migration by inhibiting the EMT. Therefore, SK is a potentially effective anticancer agent for breast tumors, by inhibiting metastasis. PMID- 26498589 TI - Classification of EA1-box proteins and new insights into their role during reproduction in grasses. AB - KEY MESSAGE: EA1-box protein classification. Success in reproduction and vegetative development in flowering plants strongly depends on precise cell-to cell signaling events mediated by secreted peptides.A small peptide family named as EA1-like (EAL) has been first described 10 years ago and includes EA1 involved in pollen tubes attraction by the female gametophyte and EAL1-regulating germ cell identity in maize. EALs consist of an N-terminal endoplasmic reticulum targeting motif, the highly conserved EA1-box and a short C-terminal alanine-rich domain. Whereas EAL peptides are exclusively found in the Gramineae, the EA1-box is widely distributed throughout the plant kingdom. Based on in silico analysis and subcellular localization studies, we report here a new classification of EA1 box proteins in flowering plants. They can be distinguished into three protein classes: the already defined EAL proteins, the EAG (EA1-box glycine-rich) proteins and the EAC (EA1-box containing)proteins. While fusion proteins of EAL and EAC classes locate to the secretory pathway, EAGs are cytoplasmic and locate also to the nucleus. Moreover, we further show that the third EAL protein of Zea mays, EAL2, appears to be also involved in processes related to late embryogenic development as its peptide level increases after formation of leaf primordia. Immunohistochemical studies indicate its presence in the scutellar parenchyma and around the vasculature, where it is secreted to the extracellular space. In conclusion, the members of the maize EAL family possess very diverse functions during reproduction and it will now be exciting to elucidate the functions of EAGs and EACs in plants. PMID- 26498590 TI - Impact of cognitive function on communication in patients with primary or secondary brain tumours. AB - Communication support tools (CST) improve patient outcomes in oncology including: knowledge, satisfaction, self-management, and adherence to planned treatment. Little is known about communication support tools use in patients with primary or secondary brain tumours. We aimed to explore cognitive function and communication support tool use in this population. This prospective survey involved patients, caregivers and health professionals. Questionnaires were completed after initial brain radiotherapy consultation and 1-2 weeks later. Patients completed the Montreal Cognitive Assessment (MoCA). Descriptive statistics are reported. Fifty three patients participated, median age 62 years, ECOG status 0-2 (90 %), with 75 % having secondary brain metastasis. 21/53 (40 %) patients reported needing help reading medical information. Only 28 % patients had normal cognition (MoCA score >= 26/30). Initially, 82 % of patients and 87 % of caregivers reported the consultation was 'extremely/quite clear, and 69 % of their health professionals thought consultation 'extremely/quite clear' to patient. At follow-up, fewer patients (75 %) reported health professionals' explanation as 'extremely/quite clear'. Although patients recalled discussed illness and treatment details, 82 % recalled treatment-related side effects and management thereof by 46 %. CST use was reported by 22 % patients, 19 % caregivers, and 27 %health professionals. When used, tools improved understanding according to 92 % patients, 100 % caregivers, and 91 % health professionals. The majority of patients have some level of cognitive impairment. Information discussed appears clear to most patients, but this is not sustained, and recall of treatment toxicity management is poor. Few CSTs are used in consultations, but when used, are reported as helpful by all. PMID- 26498591 TI - Hemoperitoneum in a patient with spontaneous rupture of the posterior wall of an unscarred uterus in the second trimester of pregnancy. AB - BACKGROUND: Hemoperitoneum resulting from a rupture of an unscarred uterus is a rare condition. Uterine rupture in patients without evident risk factors is associated with non-specific signs and symptoms that can delay the diagnosis. This is a report of spontaneous rupture of posterior wall of the uterus in the second trimester of pregnancy presented as intra-abdominal bleeding. CASE PRESENTATION: Here, we report the case of a 31-year-old Caucasian multiparous female (gravida 3, para 1) who had a sudden onset of abdominal pain at 28 weeks of gestation. The patient had no history of caesarean section. Exploratory laparotomy was performed due to deterioration of the patient's clinical condition, and ultrasound results were suspicious for hemoperitoneum. Uterine rupture in the posterior wall with active bleeding from the defect was confirmed. A caesarean section was performed, and a live female infant weighing 1000 g, with an Apgar score of three, was delivered. A hysterectomy was performed during the caesarean section. CONCLUSION: Diagnostic difficulties arise from the rarity of the disease, a nonspecific clinical picture and the absence of the main risk factors. Uterine rupture should be considered in the differential diagnosis of hemoperitoneum in patients with an unscarred uterus. PMID- 26498592 TI - Diabetes at the crossroads: relevance of disease classification to pathophysiology and treatment. AB - Diabetes is not a single homogeneous disease but composed of many diseases with hyperglycaemia as a common feature. Four factors have, historically, been used to identify this diversity: the age at onset; the severity of the disease, i.e. degree of loss of beta cell function; the degree of insulin resistance and the presence of diabetes-associated autoantibodies. Our broad understanding of the distinction between the two major types, type 1 diabetes mellitus and type 2 diabetes mellitus, are based on these factors, but it has become apparent that they do not precisely capture the different disease forms. Indeed, both major types of diabetes have common features, encapsulated by adult-onset autoimmune diabetes and maturity-onset diabetes of the young. As a result, there has been a repositioning of our understanding of diabetes. In this review, drawing on recent literature, we discuss the evidence that autoimmune type 1 diabetes has a broad clinical phenotype with diverse therapeutic options, while the term non autoimmune type 2 diabetes obscures the optimal management strategy because it encompasses substantial heterogeneity. Underlying these developments is a general progression towards precision medicine with the need for precise patient characterisation, currently based on clinical phenotypes but in future augmented by laboratory-based tests. PMID- 26498593 TI - Carbon and sulfur isotopic signatures of ancient life and environment at the microbial scale: Neoarchean shales and carbonates. AB - An approach to coordinated, spatially resolved, in situ carbon isotope analysis of organic matter and carbonate minerals, and sulfur three- and four-isotope analysis of pyrite with an unprecedented combination of spatial resolution, precision, and accuracy is described. Organic matter and pyrite from eleven rock samples of Neoarchean drill core express nearly the entire range of delta(13) C, delta(34) S, Delta(33) S, and Delta(36) S known from the geologic record, commonly in correlation with morphology, mineralogy, and elemental composition. A new analytical approach (including a set of organic calibration standards) to account for a strong correlation between H/C and instrumental bias in SIMS delta(13) C measurement of organic matter is identified. Small (2-3 MUm) organic domains in carbonate matrices are analyzed with sub-permil accuracy and precision. Separate 20- to 50-MUm domains of kerogen in a single ~0.5 cm(3) sample of the ~2.7 Ga Tumbiana Formation have delta(13) C = -52.3 +/- 0.10/00 and -34.4 +/- 0.10/00, likely preserving distinct signatures of methanotrophy and photoautotrophy. Pyrobitumen in the ~2.6 Ga Jeerinah Formation and the ~2.5 Ga Mount McRae Shale is systematically (13) C-enriched relative to co-occurring kerogen, and associations with uraniferous mineral grains suggest radiolytic alteration. A large range in sulfur isotopic compositions (including higher Delta(33) S and more extreme spatial gradients in Delta(33) S and Delta(36) S than any previously reported) are observed in correlation with morphology and associated mineralogy. Changing systematics of delta(34) S, Delta(33) S, and Delta(36) S, previously investigated at the millimeter to centimeter scale using bulk analysis, are shown to occur at the micrometer scale of individual pyrite grains. These results support the emerging view that the dampened signature of mass-independent sulfur isotope fractionation (S-MIF) associated with the Mesoarchean continued into the early Neoarchean, and that the connections between methane and sulfur metabolism affected the production and preservation of S-MIF during the first half of the planet's history. PMID- 26498594 TI - Circulating tumor cells (Ctc) and kras mutant circulating free Dna (cfdna) detection in peripheral blood as biomarkers in patients diagnosed with exocrine pancreatic cancer. AB - BACKGROUND: Pancreatic cancer remains one of the most difficult cancers to treat with the poorest prognosis. The key to improving survival rates in this disease is early detection and monitoring of disseminated and residual disease. However, this is hindered due to lack reliable diagnostic and predictive markers which mean that the majority of patients succumb to their condition within a few months. METHODS: We present a pilot study of the detection circulating free DNA (cfDNA) combined with tumor specific mutation detection by digital PCR as a novel minimally invasive biomarker in pancreatic ductal adenocarcinoma (PDAC). This was compared to the detection of CTC by the CellSearch(r) system and a novel CTC enrichment strategy based on CD45 positive cell depletion. The aim of the study was to assess tumor specific DNA detection in plasma and CTC detection as prognostic markers in PDAC. RESULTS: We detected KRAS mutant cfDNA in 26% of patients of all stages and this correlated strongly with Overall Survival (OS), 60 days (95% CI: 19-317) for KRAS mutation positive vs 772 days for KRAS mutation negative (95% CI: 416-1127). Although, the presence of CTC detected by the CellSearch(r) system did correlate significantly with OS, 88 days (95% CI: 27 206) CTC positive vs 393 days CTC negative (95% CI: 284-501), CTC were detected in only 20% of patients, the majority of which had metastatic disease, whereas KRAS mutant cfDNA was detected in patients with both resectable and advanced disease. CONCLUSIONS: Tumor specific cfDNA detection and CTC detection are promising markers for the management of patients with PDAC, although there is a need to validate these results in a larger patient cohort and optimize the detection of CTC in PDAC by applying the appropriate markers for their detection. PMID- 26498595 TI - Antimicrobial resistance and virulence signatures of Listeria and Aeromonas species recovered from treated wastewater effluent and receiving surface water in Durban, South Africa. AB - BACKGROUND: Treated wastewater effluent has been found to contain high levels of contaminants, including disease-causing bacteria such as Listeria and Aeromonas species. The aim of this study was to evaluate the antimicrobial resistance and virulence signatures of Listeria and Aeromonas spp. recovered from treated effluents of two wastewater treatment plants and receiving rivers in Durban, South Africa. METHODS: A total of 100 Aeromonas spp. and 78 Listeria spp. were positively identified based on biochemical tests and PCR detection of DNA region conserved in these genera. The antimicrobial resistance profiles of the isolates were determined using Kirby Bauer disc diffusion assay. The presence of important virulence genes were detected via PCR, while other virulence determinants; protease, gelatinase and haemolysin were detected using standard assays. RESULTS: Highest resistance was observed against penicillin, erythromycin and nalidixic acid, with all 78 (100%) tested Listeria spp displaying resistance, followed by ampicillin (83.33%), trimethoprim (67.95%), nitrofurantoin (64.10%) and cephalosporin (60.26%). Among Aeromonas spp., the highest resistance (100%) was observed against ampicillin, penicillin, vancomycin, clindamycin and fusidic acid, followed by cephalosporin (82%), and erythromycin (58%), with 56% of the isolates found to be resistant to naladixic acid and trimethoprim. Among Listeria spp., 26.92% were found to contain virulence genes, with 14.10, 5.12 and 21% harbouring the actA, plcA and iap genes, respectively. Of the 100 tested Aeromonas spp., 52% harboured the aerolysin (aer) virulence associated gene, while lipase (lip) virulence associated gene was also detected in 68% of the tested Aeromonas spp. CONCLUSIONS: The presence of these organisms in effluents samples following conventional wastewater treatment is worrisome as this could lead to major environmental and human health problems. This emphasizes the need for constant evaluation of the wastewater treatment effluents to ensure compliance to set guidelines. PMID- 26498596 TI - How educational innovations and attention to competencies in postgraduate medical education relate to preparedness for practice: the key role of the learning environment. AB - INTRODUCTION: Many training programmes in postgraduate medical education (PGME) have introduced competency frameworks, but the effects of this change on preparedness for practice are unknown. Therefore, we explored how elements of competency-based programmes in PGME (educational innovations, attention to competencies and learning environment) were related to perceived preparedness for practice among new consultants. METHODS: A questionnaire was distributed among 330 new consultants. Respondents rated how well their PGME training programme prepared them for practice, the extent to which educational innovations (portfolio, Mini-CEX) were implemented, and how much attention was paid to CanMEDS competencies during feedback and coaching, and they answered questions on the learning environment and general self-efficacy. Multiple regression and mediation analyses were used to analyze data. RESULTS: The response rate was 43 % (143/330). Controlling for self-efficacy and gender, the learning environment was the strongest predictor of preparedness for practice (B = 0.42, p < 0.001), followed by attention to competencies (B = 0.29, p < 0.01). Educational innovations were not directly related to preparedness for practice. The overall model explained 52 % of the variance in preparedness for practice. Attention to competencies mediated the relationship between educational innovations and preparedness for practice. This mediation became stronger at higher learning environment values. CONCLUSIONS: The learning environment plays a key role in determining the degree to which competency-based PGME prepares trainees for independent practice. PMID- 26498597 TI - Do research findings on schema-based instruction translate to the classroom? AB - INTRODUCTION: Schema-based instruction has been shown to improve diagnostic performance and reduce cognitive load. However, to date, this has only been studied in controlled research settings. More distractions in classrooms may limit generalizability to real-world settings. We evaluated whether schema-based instruction would maintain its effects on cognitive load optimization and performance in a classroom. METHODS: Focused on the approach of interpreting cardiac auscultation findings, 101 first-year medical students at Western University were randomized to receive a traditional (n = 48) or a schema-based lecture (n = 53). Students completed four written questions to test diagnostic performance and a cognitive load assessment at the end of the lecture. Diagnostic performance and cognitive load were compared with independent t-tests. RESULTS: Schema-based instruction was associated with increased diagnostic performance on written questions (64 +/- 22 % vs 44 +/- 25 % p < 0.001) and reduced intrinsic cognitive load (mean difference = 15 %, standard error 3 %, p < 0.001). There was no significant difference in reported extraneous (p = 0.36) or germane (p = 0.42) cognitive load. CONCLUSIONS: Our results demonstrate that schema-based instruction can be used to reduce intrinsic load and improve diagnostic performance in a real-world classroom setting. The results would be strengthened by replication across other locations and topics. PMID- 26498598 TI - Worked examples in the classroom. PMID- 26498600 TI - Toll-like receptor 9 agonist stimulation enables osteogenic differentiation without altering the immune status of umbilical cord mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) possess three characteristics critical to tissue regeneration; multipotency, low immunogenicity and an undifferentiated status, providing plasticity. However, increasing evidence has indicated that induction of an immune response in vivo can injure and reject MSC-based tissues. Toll-like receptors (TLRs) are a family of pathogen-associated pattern recognition receptors, which are important in bridging the innate and adaptive immune responses. TLRs have been demonstrated to exhibit important MSC biological regulatory functions in previous studies. To confirm the role of TLR9 in the immune status maintenance of MSCs isolated from umbilical cords, the present study performed assessments to detect agonist effects. Following addition of the TLR9 agonist, CpG, to an umbilical cord mesenchymal stem cell (UCMSC) culture medium, a number of methods were used to detect the changes in the biological function of the UCMSCs. Reverse transcription-quantitative polymerase chain reaction indicated increased levels of pro-inflammatory molecules and decreased expression levels of stem cell markers following exposure to the TLR9 agonist. However, flow cytometry revealed that activation of TLR9 had no effect on the proliferation of peripheral blood leukocytes or the expression of surface markers. The present study also identified that CpG-oligodeoxynucleotide promoted MSC osteogenic differentiation, while inhibiting MSC proliferation and migration. These results indicated that TLRs and their ligands may serve as regulators of MSC proliferation and differentiation, and affect the maintenance of MSC multipotency. PMID- 26498599 TI - Phosphorylation increases the catalytic activity of rainbow trout gill cytosolic carbonic anhydrase. AB - Cytoplasmic carbonic anhydrase (CAc) in the gill of teleost fish contributes to ionic regulation and acid-base balance by catalyzing the reversible reaction of CO2 and water, CO2 + H2O <-> H(+) + HCO3(-). Regulation of CAc abundance and activity therefore is expected to fine-tune responses to ionic or acid-base challenges. The present study investigated the potential for gill CAc of rainbow trout, Oncorhynchus mykiss (tCAc), to undergo reversible phosphorylation. The activity of tCAc was approximately doubled by phosphorylation achieved through in vitro stimulation of endogenous protein kinases; kinase stimulation doubled phospho-threonine content from that observed in tCAc isolated under conditions where both kinases and protein phosphatases were inhibited. In vitro incubation to preferentially stimulate specific kinases implicated protein kinase G (PKG) in mediating the increase in tCAc activity. The kinetic parameters of turnover number (k cat) and substrate affinity (K m) were similarly affected by stimulation of either kinase or phosphatase action. However, phosphorylation via kinase stimulation significantly increased the efficiency of tCAc (V max /K m), and this factor may have contributed to the elevation of tCAc activity. In addition, phosphorylation of tCAc by kinase stimulation significantly increased the inhibition constant (K i) for acetazolamide. These results demonstrate that tCAc is subject to reversible phosphorylation; future work should focus on identifying the physiological situation(s) in which phosphorylation of trout branchial CAc occurs. PMID- 26498601 TI - In vitro effectiveness of 455-nm blue LED to reduce the load of Staphylococcus aureus and Candida albicans biofilms in compact bone tissue. AB - The aim of this study was to evaluate the effectiveness of a 455-nm blue light emitting diode (LED), at different application times, to reduce the load of Staphylococcus aureus and Candida albicans biofilms applied to compact bone tissue. The microorganisms S. aureus (ATCC 25923) and C. albicans (ATCC 18804) were used to form biofilms on 160 specimens of compact bones that had been divided into eight experimental groups (n = 10) for each microorganism, according to the times of application of the 455-nm blue LED (1, 2, 3, 4, 5, 7, and 10 min) with an irradiance of 75 mW/cm2. After LED application, decimal dilutions of microorganisms were performed, plated on BHI or Sabouraud agar and incubated for 24 h/35 degrees C to obtain CFU/mL counts. The findings were statistically analyzed using a ANOVA 5 %. For the group of S. aureus biofilms, all groups of 455-nm LED application differ compared with the control group (p < 0.05), in which no treatment was given. The largest reduction was obtained in the group receiving LED for 10 min (p = 0.00); within this group, a 3.2 log reduction was observed. For the C. albicans biofilms, only those samples receiving 3, 7, and 10 min of LED application presented a significant difference compared with the control group (p < 0.00), indicating that longer application times are required to achieve efficacy. The results of this study show that 455-nm LED light was effective to reduce the load of S. aureus and C. albicans biofilms, especially during 10 min of application. PMID- 26498602 TI - Velamentous cord insertion as a risk factor for obstetric outcome: a retrospective case-control study. AB - PURPOSE: Velamentous umbilical cord insertion (VCI) is associated with adverse pregnancy outcomes. Literature lacks data on Doppler. We aimed to evaluate obstetric outcomes and results of uterine and umbilical artery Doppler flowmetry associated with VCI. MATERIALS AND METHODS: In a retrospective case-control study, 108 singleton pregnancies with VCI were age- and body mass index-matched to 108 singleton pregnancies without VCI. The main outcome parameters were obstetric outcome, pregnancy-related complications, uterine artery flowmetry at the second-trimester screening, and umbilical artery flowmetry before delivery. Statistical analysis was accomplished using Pearson's Chi-square test or Fisher's exact test, and the Mann-Whitney U test, where appropriate. RESULTS: Pregnancies with VCI revealed a significantly higher PI in the umbilical artery during the last measurement before delivery (1.00 +/- 0.25 vs. 0.90 +/- 0.10; p = 0.001). Gestational age at this measurement did not differ between the groups. Fetal malformations and intrauterine fetal death were more common in pregnancies with VCI (12.7 vs. 0 %; p < 0.001, and 6.5 vs. 0 %; p = 0.014, respectively). Patients with VCI delivered significantly earlier (36.2 +/- 4.5 vs. 38.4 +/- 2.6; p < 0.001). CONCLUSION: Higher rates of (early) preterm delivery were found in pregnancies with VCI. Fetuses with VCI also suffered from malformations and IUFD more frequently. The last pulsatility index value in the umbilical artery, before delivery, was significantly higher in pregnancies with VCI, which is of uncertain clinical value. PMID- 26498603 TI - Short-course postpartum (6-h) magnesium sulfate therapy in severe preeclampsia. AB - OBJECTIVE: To assess the efficacy of short-course postpartum (6-h) magnesium sulfate therapy versus 24-h conventional magnesium sulfate therapy in severe preeclampsia. METHODS: Cases of severe preeclampsia were randomly allocated to group A (n = 76) and group B (n = 43). Group A and group B received magnesium sulfate loading dose (4 g) followed by infusion for 6 and 24 h postpartum (1 gm/h), respectively. Cases in both the groups were monitored closely after the initiation of therapy. t test and Chi-square test were used for data analysis. RESULTS: No occurrence of convulsions was noted in both group A and group B. The mean amount of magnesium sulfate used in the study group was 15.1 +/- 5.4 g as against 42.3 +/- 7.3 g in controls. The duration of Foley catheterization and monitoring was significantly less in group A (mean 11.3 +/- 5.1 and 11.1 +/- 4.9 h, respectively) as compared to group B (mean 38.3 +/- 7.3 and 38.4 +/- 7.2 h, respectively). The mean duration of hospital stay was 2.7 +/- 0.7 days in cases delivered vaginally and 7.5 +/- 1.6 days in those who underwent cesarean section in group A, while it was 4.04 +/- 1.47 and 11.11 +/- 3.14 days, respectively, in group B. CONCLUSION: Short-course, i.e., 6-h, postpartum magnesium sulfate therapy is as effective as conventional 24-h postpartum magnesium sulfate therapy in preventing convulsions in severe preeclampsia. PMID- 26498605 TI - Maternal super-obesity. AB - PURPOSE: Pregnant women with a body-mass-index (BMI) above 50 are referred to as "super-obese". For these women adverse pregnancy outcome and a higher risk of fetal congenital defects are major issues. This report focuses on the ratio development of super-obesity in pregnant women, as well as on prenatal ultrasound and pregnancy outcome in the super-obese gravida. METHODS: We reviewed data of all women with a BMI above 30 who delivered at our unit in a 15-year period between January 2000 and December 2014. Data of obese but not super-obese mothers were evaluated in comparison. RESULTS: Final evaluation comprised 69/20,711 pregnancies of super-obese mothers. Forty out of 69 women suffered from a preexisting condition requiring medical treatment. Fetal ultrasound evaluation revealed severe congenital defects in four cases. There were no missed and no false positive diagnoses. Elective cesarean section (c-section) took place in 26/69 cases, 21/69 had a secondary c-section. Twenty-two out of 69 women delivered vaginally. Mean gestational age at delivery was 38(+6) gestational weeks. Pregnancy was complicated by macrosomia in 17/69 pregnancies. Severe neonatal hypoglycemia occurred in 6/69 cases. The number of deliveries by super obese mothers showed no marked variation during the study period. In contrast the rate of deliveries by obese, but not super-obese, mothers showed an increase. CONCLUSIONS: Maternal super-obesity poses a high-risk situation for mother and child which generally demands a higher amount of perinatal care. The number of deliveries by super-obese mothers remained stable over the study period. Primary c-section was the most frequent mode of delivery. Of the parturients who opted for vaginal delivery nearly half of the deliveries had to be completed by secondary c-section. Over-all peripartal maternal complications did not exceed average. PMID- 26498604 TI - F-18 fluoro-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in planning of surgery and sentinel lymph node screening in vulvar cancers. AB - PURPOSE: To determine the effectiveness of FDG-PET/CT in the assessment of inguinofemoral lymph node (IFLN) in patients with vulvar cancer by comparing FDG PET/CT results, sentinel lymph node (SLN) screening with gamma probe, and the results of frozen section and definitive pathology in these lymph nodes. STUDY DESIGN: This prospective study included eight patients, who were diagnosed with vulvar cancer at the Gynecology and Obstetrics Department of Erciyes University, Turkey. All patients underwent FDG-PET/CT before surgery. Local excision and IFLN dissection were planned by assessing IFLN involvement with SLN screening with Tc 99m nanocolloid plus frozen section. Intraoperatively, SLN screening was performed by using a gamma probe, and these lymph nodes were excised and then evaluated by frozen section. Regardless of the frozen section results, the IFLNs were totally excised. The FDG-PET/CT scan results, SLN plus frozen section results and definitive pathology results of the inguinal lymph nodes were compared. RESULTS: The mean age was 64.50 +/- 13.25 years (min-max 43-79 years). All tumors were squamous cell carcinomas. FDG-PET/CT scan determined vulvar lesions accurately in all patients (8/8; 100 %). When inguinal lymph nodes were assessed by FDG uptake and SUVmax values, lymph nodes were interpreted as reactive in four patients (4/8; 50 %) and metastatic in the others (4/8; 50 %). In all patients frozen section confirmed the FDG-PET-CT results and definitive histopathology results confirmed the frozen section and FDG-PET-CT results (8/8; 100 %). CONCLUSIONS: In light of these data, FDG-PET/CT scanning is an effective method for the detection of primary tumor in vulvar cancer. Although it seems to be an effective method for the detection of IFLN metastasis, these findings must be supported by further studies with larger sample size for use in the planning of primary surgery and inguinal lymph node dissection without SLN dissection and frozen section, as a minimal invasive method. PMID- 26498606 TI - DiSNPindel: improved intra-individual SNP and InDel detection in direct amplicon sequencing of a diploid. AB - BACKGROUND: Amplicon re-sequencing based on the automated Sanger method remains popular for detection of single nucleotide polymorphisms (SNPs) and insertion deletion polymorphisms (InDels) for a spectrum of genetics applications. However, existing software tools for detecting intra-individual SNPs and InDels in direct amplicon sequencing of diploid samples are insufficient in analyzing single traces and their accuracy is still limited. RESULTS: We developed a novel computation tool, named DiSNPindel, to improve the detection of intra-individual SNPs and InDels in direct amplicon sequencing of a diploid. Neither reference sequence nor additional sample was required. Using two real datasets, we demonstrated the usefulness of DiSNPindel in its ability to improve largely the true SNP and InDel discovery rates and reduce largely the missed and false positive rates as compared with existing detection methods. CONCLUSIONS: The software DiSNPindel presented here provides an efficient tool for intra individual SNP and InDel detection in diploid amplicon sequencing. It will also be useful for identification of DNA variations in expressed sequence tag (EST) re sequencing. PMID- 26498607 TI - Celiac Disease: Background and Historical Context. AB - Medical descriptions of celiac disease date to the first century BC, and the first modern description was published in 1888. Further insights were gained throughout the 1900s, culminating in the identification of the dietary component, the major genetic determinant, and the autoantigen by the turn of the century. Understanding of the age of onset, population prevalence, and the extent of subclinical celiac disease developed in tandem. Thanks to advances in genomics, currently established loci account for over 50 % of the genetic risk. Nonetheless, much remains to be discovered. Advances in high-throughput genomic, biochemical, and cell analyses, as well as the bioinformatics needed to process the data, promise to deepen our understanding further. Here we present a primer of celiac disease, viewing the condition in turn from the historical, epidemiological, immunological, molecular, and genetic points of view. Research into any ailment has specific requirements: study subjects must be identified and relevant tissue samples collected and stored with the appropriate timing and conditions. These requirements are summarized. To conclude, a short discussion of future prospects is presented. PMID- 26498608 TI - Celiac Disease: Diagnosis. AB - Historically the diagnosis of celiac disease has relied upon clinical, serological, and histological evidence. In recent years the use of sensitive serological methods has meant an increase in the diagnosis of celiac disease. The heterogeneous nature of the disorder presents a challenge in the study and diagnosis of the disease with patients varying from subclinical or latent disease to patients with overt symptoms. Furthermore the related gluten-sensitive disease dermatitis herpetiformis, while distinct in some respects, shares clinical and serological features with celiac disease. Here we summarize current best practice for the diagnosis of celiac disease and briefly discuss newer approaches. The advent of next-generation assays for diagnosis and newer clinical protocols may result in more sensitive screening and ultimately the possible replacement of the intestinal biopsy as the gold standard for celiac disease diagnosis. PMID- 26498610 TI - Study Designs for Exploring the Non-HLA Genetics in Celiac Disease. AB - Since the breakthrough of genome-wide association studies and genetic studies of common complex diseases like celiac disease have been able to finally identify reproducible gene regions affecting risk of developing disease. Before it was possible to perform genome-wide association analysis, the field struggled with genome-wide linkage analysis to identify gene regions. Genome-wide linkage had been very successful in identifying genes underlying monogenic diseases, but common complex polygenic diseases did not prove so tractable. This chapter will describe the genome-wide methods available for genetic analyses of families today and compare these with the previous analyses performed in the 1990s and early twenty-first century. PMID- 26498609 TI - Generating Transgenic Mouse Models for Studying Celiac Disease. AB - This chapter provides a brief overview of current animal models for studying celiac disease, with a focus on generating HLA transgenic mouse models. Human Leukocyte Antigen class II molecules have been a particular target for transgenic mice due to their tight association with celiac disease, and a number of murine models have been developed which had the endogenous MHC class II genes replaced with insertions of disease susceptible HLA class II alleles DQ2 or DQ8. Additionally, transgenic mice that overexpress interleukin-15 (IL-15), a key player in the inflammatory cascade that leads to celiac disease, have also been generated to model a state of chronic inflammation. To explore the contribution of specific bacteria in gluten-sensitive enteropathy, the nude mouse and rat models have been studied in germ-free facilities. These reductionist mouse models allow us to address single factors thought to have crucial roles in celiac disease. No single model has incorporated all of the multiple factors that make up celiac disease. Rather, these mouse models can allow the functional interrogation of specific components of the many stages of, and contributions to, the pathogenic mechanisms that will lead to gluten-dependent enteropathy. Overall, the tools for animal studies in celiac disease are many and varied, and provide ample space for further creativity as well as to characterize the complete and complex pathogenesis of celiac disease. PMID- 26498611 TI - Twenty-Four Hour Ex Vivo Culture of Celiac Duodenal Biopsies. AB - Organ culture is a valuable technique in celiac disease research. It provides the opportunity to examine interactions between different cell types during the disease process without the need for invasive in vivo studies. Biopsies are maintained in an oxygen-rich environment, in contact with, but not submerged in, culture medium. A very straightforward and successful method of organ culture is described here. PMID- 26498612 TI - Isolation and Cloning of Gluten-Specific T Cells in Celiac Disease. AB - In patients with celiac disease, but not in healthy controls, gluten-specific CD4 T cells are present in the small intestinal lamina propria. Specific stimulation of these T cells due to gluten consumption leads to the release of pro inflammatory cytokines, in particular IFNgamma and IL-21. This leads to tissue damage, the typical morphological alterations like the flattening of the intestinal epithelium, and a variety of disease-associated symptoms including malnutrition, diarrhea, stomach ache, and failure to thrive. Removal of gluten from the diet eliminates the trigger for these CD4 T cells and leads to recovery. These CD4 T cells thus play a crucial role in the disease pathogenesis. Here we describe how such T cells can be isolated and characterized. PMID- 26498613 TI - Flow Cytometric Analysis of Human Small Intestinal Lymphoid Cells. AB - Flow cytometry is a powerful technique allowing simultaneous analysis of numerous morphological and phenotypic characteristics of cells and cellular constituents. Improvements in cell isolation techniques in recent years have enabled flow cytometric analyses of cells derived from tissue biopsies. Here we describe a method for isolating and analyzing small intestinal lymphoid cells using flow cytometry. PMID- 26498614 TI - Adaptation of a Cell-Based High Content Screening System for the In-Depth Analysis of Celiac Biopsy Tissue. AB - The IN Cell Analyzer 1000 possesses several distinguishing features that make it a valuable tool in research today. This fully automated high content screening (HCS) system introduced quantitative fluorescent microscopy with computerized image analysis for use in cell-based analysis. Previous studies have focused on live cell assays, where it has proven to be a powerful and robust method capable of providing reproducible, quantitative data. Using HCS as a tool to investigate antigen expression in duodenal biopsies, we developed a novel approach to tissue positioning and mapping. We adapted IN Cell Analyzer 1000's image acquisition and analysis software for the investigation of tissue transglutaminase (tTG) and smooth muscle alpha-actin (SM alpha-actin) staining in paraffin-embedded duodenal tissue sections from celiac patients and healthy controls. These innovations allowed a quantitative analysis of cellular structure and protein expression. The results from routine biopsy material indicated the intensity of protein expression was altered in celiac disease compared to normal biopsy material. PMID- 26498615 TI - HLA Genotyping: Methods for the Identification of the HLA-DQ2,-DQ8 Heterodimers Implicated in Celiac Disease (CD) Susceptibility. AB - In this chapter we will present the principal technical methods to genotype the HLA-DQA1* and -DQB1* alleles associated with celiac disease (CD), corresponding to the serological heterodimers HLA-DQ2 and -DQ8. We will present the methods specific for the genotyping of these heterodimers, which represents a common request from consultant doctors. Because these alleles are also common in healthy subjects, their presence is not diagnostic for CD. Conversely, their absence is more important because it excludes the disease, since CD patients negative for these heterodimers are very rare. Accordingly, HLA typing has been included as a useful test to exclude celiac disease in the ESPGHAN guidelines for diagnosis of celiac disease. The methods for HLA typing described in the present chapter are based on the following techniques: PCR-SSP (Polymerase Chain Reaction-Sequence Specific Primers): PCR with primers specific for HLA alleles encoding the CD risk heterodimers, whose presence is revealed through the electrophoresis of PCR products. Reverse PCR-SSOP (PCR-Sequence Specific Oligonucleotide Probes): PCR with primers specific for a single locus or a large group of alleles followed by hybridization with enzyme-conjugated probes specific for a single allele, immobilized on different supports (i.e., nitrocellulose strips), in which DNA probes binding is revealed by the production of a colored precipitate derived from the enzymatic modification of a specific substrate. Real-Time PCR (RT-PCR): PCR with locus or allelic specific primers whose amplification is revealed by particular probes (i.e., Taqman probes) hybridizing the DNA template within the two PCR primers and emitting fluorescent while the PCR reaction occurs. PMID- 26498616 TI - Detecting Allelic Expression Imbalance at Candidate Genes Using 5' Exonuclease Genotyping Technology. AB - Genetic variation along the length of a chromosome can influence the transcription of a gene. In a heterozygous individual, this may lead to one chromosome producing different levels of RNA, compared to its paired chromosome, for a given gene. Allelic differences in gene expression can offer insight into the role of variation in transcription, and subsequently infer a route to conferring disease risk. This phenomenon is known as allele expression imbalance or AEI, which may be assayed using a PCR-based method that includes the quantification of the relative dosage of each allele (e.g., 5' exonuclease assays, TaqManTM). Importantly, in heterozygous individuals the resolution of expression imbalance is performed within a controlled system; the comparison of the alternate allele is reported relative to the wild-type, as the experiment can be performed within a single sample, controlled for background genetic information. Alternative methods for the detection of AEI include Primer extension MALDI-TOF (Sequenom MassARRAY((r))), Next-Generation Sequencing, and SNP genotyping arrays. Here we present the methods used for the TaqManTM approach and include a description of the SNP identification, allele-specific PCR, and analytic methods to convert allele amplification metrics to relative allele dosage. PMID- 26498617 TI - Gene Expression Profiling of Celiac Biopsies and Peripheral Blood Monocytes Using Taqman Assays. AB - Quantitative real-time PCR (qPCR) allows for highly sensitive, rapid, and reproducible quantification of mRNA: it has become an established technology for the quantification of gene expression with the 5' nuclease assay using TaqMan((r)) probes. It is used for a broad range of applications, including quantification of gene expression, measuring RNA interference, biomarker discovery, pathogen detection, and drug target validation. When studying gene expression with qPCR, scientists usually investigate changes-increases or decreases-in the quantity of particular gene products or a set of gene products. Investigations typically evaluate gene response to biological conditions such as disease states, exposure to pathogens or chemical compounds, organ or tissue location, and cell cycle or differentiation status. Here we describe this technique applied to molecular profiling of candidate genes in celiac biopsies and peripheral blood monocytes. Using data obtained by gene expression experiments, a discriminant equation has been developed that allows the correct classification of Celiac Disease (CD) patients compared to healthy controls, CD patients on a Gluten Free Diet (GFD), and other disease controls. PMID- 26498618 TI - Cloning Gene Variants and Reporter Assays. AB - Recent advances have identified new genetic markers associated with the inheritance of celiac disease. These non-HLA target regions remain to be fully categorized. Investigation of associated SNPs indicates that the causal variants may alter specific gene expression. Thus, closer examination of potential causal variants found within regulatory regions could provide data relating to the mechanistic association. Molecular cloning is an established fundamental tool that enables investigators to examine the differential potential at a variant site. In conjunction with reporter gene assays, SNPs affecting gene expression can be uncovered and contribute to our understanding of the underlying pathogenic mechanisms. This chapter outlines the protocols necessary to clone risk variants and transfect these constructs into a T cell line for reporter assay analysis. PMID- 26498619 TI - Epigenetic Methodologies for the Study of Celiac Disease. AB - Epigenetic regulation of gene expression is an important event for normal cellular homeostasis. Gene expression may be "switched" on or "turned" off via epigenetic means through adjustments in the architecture of DNA. These structural alterations result from histone posttranslation modifications such as acetylation and methylation on key arginine and lysine residues, or by alterations to DNA methylation. Other known epigenetic mechanisms invoke histone variant exchange or utilize noncoding RNAs (lncRNA/miRNA). Drugs which can target the epigenetic regulatory machinery are currently undergoing clinical trials in a wide variety of autoimmune diseases and cancer. Here we describe RNA isolation and the subsequent Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) methods, post epigenetic drug treatment, to identify genes, which may be responsive to such epigenetic targeting agents. In addition, we depict a chromatin immunoprecipitation (ChIP) assay to determine the association between chromatin transcription markers and DNA following pretreatment of cell cultures with a histone deacetylase inhibitor (HDi). This assay allows us to determine whether treatment with an HDi dynamically remodels the promoter region of genes, as judged by the differences in the PCR product between our treated and untreated samples. Finally we describe two commonly used methodologies for analyzing DNA methylation. The first, methylation-sensitive high resolution melt analysis (MS HRM) is used for methylation screening of regions of interest, to identify potential epigenetic "hotspots." The second, quantitative methylation specific PCR (qMSP) is best applied when these hotspots are known, and offers a high throughput, highly sensitive means of quantifying methylation at specific CpG dinucleotides. PMID- 26498620 TI - Candidate Gene Knockdown in Celiac Disease. AB - RNA interference (RNAi) is a powerful genetic tool that has created new opportunities in cell biology by allowing the specific modulation of gene expression under controlled conditions. Knockdown of genes associated with disease can provide valuable information pertaining to their function and potentially their role in the disease etiology. In the context of celiac disease, it allows us to examine closely the cellular changes that occur when the expression levels of genes of interest are reduced. Utilizing informative assays that demonstrate changes in cell behavior or other measurable endpoints such as cytokine production or migratory phenotypes can further our understanding of the pathogenic mechanisms in this prevalent autoimmune disorder. This chapter outlines protocols for examining the effects of RNAi on candidate genes and subsequent changes to migratory phenotype, transmigration, and adhesion. PMID- 26498621 TI - Perl One-Liners: Bridging the Gap Between Large Data Sets and Analysis Tools. AB - Computational analyses of biological data are becoming increasingly powerful, and researchers intending on carrying out their own analyses can often choose from a wide array of tools and resources. However, their application might be obstructed by the wide variety of different data formats that are in use, from standard, commonly used formats to output files from high-throughput analysis platforms. The latter are often too large to be opened, viewed, or edited by standard programs, potentially leading to a bottleneck in the analysis. Perl one-liners provide a simple solution to quickly reformat, filter, and merge data sets in preparation for downstream analyses. This chapter presents example code that can be easily adjusted to meet individual requirements. An online version is available at http://bioinf.gen.tcd.ie/pol. PMID- 26498622 TI - Bioinformatic Analysis of Antigenic Proteins in Celiac Disease. AB - Investigation of the chemistry of the gliadin proteins has played an important role in our comprehension of how celiac disease (CoD) develops and progresses as a response to challenge with this immune stimulus. Studies in this area have implicated gut enzymes, tissue transglutaminase-mediated deamidation, and peptide binding affinity for the HLA-DQ2 and DQ8 molecules in disease pathogenesis. As the number and availability of prolamin sequences increases, the complexity and cost of laboratory analysis will similarly increase. Freely available tools to bioinformatically analyze candidate protein sequences can be employed as a low cost, high-return preliminary mechanism to focus one's laboratory analyses on the most rewarding sequences. This chapter describes the use of antigen prediction, deamidation prediction, and protease cleavage prediction as may be applied to CoD research. PMID- 26498623 TI - Quality Control Procedures for High-Throughput Genetic Association Studies. AB - Genome-wide association (GWA) studies provide an unbiased approach to discovering the role of genetic determinants of disease across the human genome. The case control design, the most frequently used GWA study design employed to date, compares allele frequencies in affected patients to those of unaffected controls. Several large-scale GWA studies have identified numerous risk variants for celiac disease (CD). However, due to their low marker density, the early GWA arrays failed to adequately capture much of the genetic variance associated with CD. The Immunochip, a custom Illumina Infinium high-density array containing 196,524 common and rare polymorphisms, was developed to allow deep replication and fine mapping of the previously established GWA significant loci identified in 12 major autoimmune and inflammatory diseases, including CD. It has the advantage of allowing uniform sets of genetic markers to be compared across all diseases. This chapter describes the methods used to perform Immunochip genotyping and the bioinformatics steps necessary for quality control and analysis of the resulting data. PMID- 26498624 TI - Quality Control and Analysis of NGS RNA Sequencing Data. AB - Transcriptome sequencing, where RNA is isolated, converted to library of cDNA fragments, and sequenced using next-generation sequencing technology, has become the method of choice for the genome-wide characterization of mRNA levels. It offers a more accurate quantification of transcript levels than array-based methods, but also has the added benefit of allowing the discovery of novel gene/transcripts, alternative splice junctions, and novel RNAs. In addition, RNA sequencing may be used to investigate differential gene expression, allelic imbalance, eQTL mapping, RNA editing, RNA-protein interactions, and alternative splicing. A number of statistical methods and tools are available for differential expression analysis using RNA sequencing data and these are continually being developed and improved to handle more complex experimental designs. This chapter describes an example workflow for the quality control and analysis of raw RNA sequencing reads for the purposes of differential gene expression analysis, followed by pathway/enrichment analysis of significantly different genes. The methods and tools described are just one example of how this analysis can be conducted, but they can be applied to most standard RNA sequencing studies of differential gene expression. The methods covered are based on Illumina HiSeq single-end 50 bp reads. However, all programs used are capable of working with paired-end data, subsequent to minor adaptations. PMID- 26498625 TI - Cell wall reconstruction and DNA damage repair play a key role in the improved salt tolerance effects of He-Ne laser irradiation in tall fescue seedlings. AB - The improved salt tolerance effects of He-Ne laser were further studied through the estimation of ROS levels, cell viability, DNA damage phenomena, physicochemical properties, and monosaccharide compositions of cell wall polysaccharides in tall fescue seedlings. Salt stress produced deleterious effects on seedlings growth and development. ROS levels and genomic DNA damage were markedly increased compared with controls. Physicochemical activities and monosaccharide proportions of cell wall polysaccharide were also pronouncedly altered. He-Ne laser irradiation improved plant growth retardation via increasing cell viability and reverting physicochemical parameters. According to the results of Fourier transform infrared (FTIR) scanning spectra and DNA apopladder analysis, He-Ne laser was showed to efficiently ameliorate cell wall polysaccharide damage and DNA fragmentation phenomena. The treatment with DNA synthesis inhibitor further demonstrated that DNA damage repair was correlated with the improvement effects of the laser. Therefore, our data illustrated that He-Ne laser irradiation resulted in cell wall reconstruction and genomic DNA injury repair in vivo in salt-stressed seedlings, then enhanced salt tolerance probably via interactions between plant cell wall and related resistance gene expression pattern. PMID- 26498626 TI - Three new compounds from Cinnamomum cassia. AB - Three new compounds, including two new diterpenoids, named epianhydrocinnzeylanol (1) and cinnacasiol H (2), and one hydroxylasiodiplodin, (3R,4S,6R)-4,6-dihydroxy de-O-methyllasiodiplodin (3), together with five known diterpenoids (4-8) and two known phenolic glycosides (9-10) were isolated from the barks of Cinnamomum cassia. Their structures were elucidated by extensive spectroscopic analysis and comparison of the chemical shift values with those of related known compounds. The anti-inflammatory activities of the isolates were evaluated on nitric oxide production in lipopolysaccharide-induced BV-2 microglial cells and the compounds showed weak inhibition activities. PMID- 26498627 TI - DNA Folding Transition in Presence of Naphthylhydroxamic Acids as Revealed by Fluorescence Microscopic Single Molecule Observation Method. AB - Fluorescence microscopy is a field of growing applications in various fields as it can be used to study immunofluorescence,fluorescent proteins techniques, live cell imaging and many more. The present investigation is based on this single molecule observation technique to observe the effect of N-arylhydroxamic acids on lambda plasmid DNA and linear Bacteriophage T7 DNA. The compounds under present investigation include N-1-naphthyl-o-methylbenzohydroxamic acid,N-1-naphthyl-p methylbenzohydroxamic acid, N-1-naphthyl ethoxy benzo hydroxamic acid, N-1 naphthylphenylacetohydroxamic acid and N-1-naphthyl valero hydroxamic acid. The hydrodynamic radius, RH of lambda DNA and long-axis length, l of T7 DNA were determined from the direct observation of Brownian motion of the DNA molecules in the absence and presence of hydroxamic acids. Folding transition was observed for lambda DNA as well as T7 DNA in the presence of naphthyl hydroxamic acids. N-1 naphthylvalerohydroxamic acid was found to be most effective. PMID- 26498628 TI - Effect of Aptamer Binding on the Electron-Transfer Properties of Redox Cofactors. AB - In vitro selection or SELEX has allowed for the identification of functional nucleic acids (FNAs) that can potentially mimic and replace protein enzymes. These FNAs likely interact with cofactors, just like enzymes bind cofactors in their active sites. Investigating how FNA binding affects cofactor properties is important for understanding how an active site is formed and for developing useful enzyme mimics. Oxidoreductase enzymes contain cofactors in their active sites that allow the enzymes to do redox chemistry. In certain applications, these redox cofactors act as electron-transfer shuttles that transport electrons between the enzymes' active sites and electrode surfaces. Three redox cofactors commonly found in oxidoreductases are flavin adenine dinucleotide, nicotinamide adenine dinucleotide (NAD(+)), and pyrroloquinoline quinone (PQQ). We are interested in investigating how DNA aptamers that bind these cofactors influence the cofactors' redox abilities and if these aptamer-cofactor complexes could serve as redox catalysts. We employed cyclic voltammetry and amperometry to study the electrochemical properties of NAD(+) and PQQ when bound to DNA aptamers. Our results suggest that the aptamers provide a stable environment for the cofactor to participate in redox reactions, although enhanced redox activity was not observed. This work provides a foundation for the development of new FNAs capable of redox activity. PMID- 26498629 TI - Serum neutrophil gelatinase-associated lipocalin is associated with cardiovascular events in patients with chronic kidney disease. AB - BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin family best known as a novel and early marker of acute kidney injury (AKI). Recent data suggest that NGQueryAL is not only a marker of AKI, but also an important player in the vascular remodeling, atherosclerotic plaque stability and thrombus formation. We conducted this study to investigate the association of serum NGAL levels with fatal and composite (fatal and non-fatal) cardiovascular events (CVE) in a cohort of patients with stage 1-5 CKD. METHODS: This was an observational cohort study in which serum NGAL was obtained from 298 CKD (stages 1-5) patients. Fatal and composite CVE were recorded for a median 41 months. We examined alteration of serum NGAL through CKD groups as well as association with inflammatory markers. We also performed a Cox regression analysis to determine the association of NGAL with predefined clinical outcomes. RESULTS: The median value of NGAL was 50.5 ng/mL (IR 47.6-54.9 ng/mL), and higher NGAL values were recorded in diabetic patients. In a multiple linear regression model, including all univariate associates of NGAL, only log eGFR, log hs-CRP and log HDL cholesterol maintained an independent association with log NGAL. During the observational period, 30 patients died due to cardiovascular causes and 69 non fatal CVE were registered. In the fully adjusted model, we observed a 2.08-fold increase in the risk of fatal CVE and a 1.50-fold increase in the risk of fatal and non-fatal CVE for each increment of 1 SD in log NGAL values. CONCLUSIONS: This is the first study that shows that serum NGAL is associated with cardiovascular events (fatal and non-fatal) in patients with CKD, independently of traditional risk factors, renal function and inflammation. PMID- 26498630 TI - The effect of thermochemotherapy with mitomycin C on normal bladder urothelium, an experimental study. AB - PURPOSE: To investigate the effects of thermochemotherapy with mitomycin C (MMC) on normal rabbit bladder urothelium and to compare it with standard intravesical MMC and hyperthermia with normal saline. METHODS: Twenty-four male New Zealand rabbits, with a mean weight of 2.7 kg (in weight of 2.1-4.3 kg), were divided into three groups, each containing eight rabbits. Thermotherapy with only normal saline was performed in the first group, standard intravesical MMC was performed in the second group, and thermotherapy with MMC was performed in the last group. A week after the primary procedure, total cystectomy was performed and tissue samples were evaluated. RESULTS: The presence of epithelial vacuolar degeneration (p = 0.001), epithelial hyperplasia (p = 0.000), subepithelial fibrosis (p = 0.001) and hemorrhagic areas in the connective tissue (p = 0.002) was observed statistically significantly higher in the standard MMC group than in thermotherapy with normal saline group. There was almost a significant difference among standard MMC and normal saline group in terms of vascular congestion in the connective tissue (p = 0.08). Presence of epithelial vacuolar degeneration (p = 0.002), epithelial hyperplasia (p = 0.002), subepithelial fibrosis (p = 0.030), hemorrhagic areas (p = 0.011) and vascular congestion (p = 0.36) in the connective tissue was observed statistically significantly higher in the thermochemotherapy with MMC group than in standard intravesical MMC group. Polymorphonuclear cell infiltration was not considerable in any of the groups, and there was no significant difference between each groups (p = 0.140). CONCLUSION: Administration of intravesical MMC causes a toxic effect on the normal urothelium of the bladder rather than an inflammatory reaction. Heating MMC significantly increased this effect. PMID- 26498631 TI - Excellent graft and patient survival after renal transplantation from donors after brain death with acute kidney injury: a case-control study. AB - BACKGROUND: Whether organs from donors after brain death (DBD) with acute kidney injury (AKI) should be accepted for transplantation is still a matter of debate. METHODS: This was a retrospective, center-based, matched cohort study of 33 renal transplant patients who received a renal allograft from a DBD with AKI. Sixty five kidney transplants without donor AKI transplanted directly before and after the index transplantation served as controls. RESULTS: All AKI donors were classified according to RIFLE criteria: 9.1 % Risk, 54.6 % Injury, and 36.4 % Failure. Mean serum creatinine was 2.41 +/- 0.88 mg/dL at procurement and 1.06 +/ 0.32 mg/dL on admission. AKI donors had lower 24-h urine production (3.22 +/- 1.95 vs. 4.59 +/- 2.53 L, p = 0.009) and received more frequently noradrenaline (93.9 vs. 72.3 %, p = 0.02) and/or adrenaline (15.2 vs. 1.5 %, p = 0.02). Recipient and transplant characteristics were similar except a more favorable HLA match in control patients (p = 0.01). Hemodialysis posttransplant was more frequently used in AKI recipients (14/33 [42.4 %] vs. 18/65 [27.7 %], p = 0.17). While significant elevations in serum creatinine were noted in these patients until 10 days after transplantation, this difference lost statistical significance by day 14. One-year graft survival was very similar when comparing the groups (93.6 % [95 % CI 76.8-98.4 %] vs. 90.3 % [95 % CI 79.6-95.5 %], log rank p = 0.58). CONCLUSIONS: Kidneys from AKI donors can be transplanted with excellent intermediate prognosis and should not be discarded. PMID- 26498634 TI - Transverse Anderson localization of light near Dirac points of photonic nanostructures. AB - We perform a comparative study of the Anderson localization of light beams in disordered layered photonic nanostructures that, in the limit of periodic layer distribution, possess either a Dirac point or a Bragg gap in the spectrum of the wavevectors. In particular, we demonstrate that the localization length of the Anderson modes increases when the width of the Bragg gap decreases, such that in the vanishingly small bandgap limit, namely when a Dirac point is formed, even extremely high levels of disorder are unable to localize the optical modes residing near the Dirac point. A comparative analysis of the key features of the propagation of Anderson modes formed in the Bragg gap or near the Dirac point is also presented. Our findings could provide valuable guidelines in assessing the influence of structural disorder on the functionality of a broad array of optical nanodevices. PMID- 26498632 TI - Ibandronate in stable renal transplant recipients with low bone mineral density on long-term follow-up. AB - BACKGROUND: Bone mineral density (BMD) has been reported to increase without specific treatment in long-term renal transplant recipients. The aim of this study was to evaluate the effect of ibandronate on BMD and kidney function in long-term renal transplant recipients as compared to a control group. Furthermore, we searched for a gender-specific treatment effect of ibandronate on BMD. METHODS: In a retrospective, matched case-control study 60 stable renal transplant recipients were included on long-term follow-up. The patient cohort was divided into two groups. The control group (n = 30) comprised patients with close-to-normal bone mineral density who did not receive ibandronate treatment and the treatment group (n = 30) comprised patients with reduced bone mineral density who received ibandronate treatment. The groups were matched for sex, age at the time of renal transplantation, use of steroids, renal transplant function and time lag between the dual-energy X-ray absorptiometry (DEXA) measurements and renal transplantation. Patients of the treatment group were treated with 12.0 +/- 6.7 g ibandronate. Treatment cycles lasted 19.3 +/- 11.0 months. The first bone mineral density testing was performed 55.3 +/- 60.2 months after renal transplantation followed by a second measurement 26.8 +/- 12.1 months later. RESULTS: Both groups did not differ in absolute (g/cm(2)) or relative (%) changes in BMD at the lumbar spine (0.033 +/- 0.079 vs. 0.055 +/- 0.066 g/cm(2), p = 0.217 and 3.6 +/- 7.8 vs. 6.4 +/- 8.1 %, p = 0.124) or femoral neck (0.013 +/- 0.106 vs. 0.025 +/- 0.077 g/cm(2), p = 0.647 and 3.2 +/- 13.6 vs. 5.0 +/- 13.1 %, p = 0.544) over the study period. There was no correlation of ibandronate dosages with changes in BMD (LS: r = -0.089; p = 0.639 and FN: r =+0.288; p = 0.445). We could neither determine a negative effect of ibandronate on renal transplant function over the study period, estimated via the CKD-EPI formula (-2.9 +/- 7.6 vs. -2.7 +/- 10.6 mL/min/1.73 m(2), p = 0.900) nor a gender-specific action of ibandronate on bone mass changes. CONCLUSIONS: Ibandronate treatment was safe with respect to renal transplant function but did not result in a significant additive improvement in bone mineral density as compared to the untreated control group. A gender-specific action of ibandronate on BMD at the LS or FN could not be determined either. PMID- 26498635 TI - A Comparison of Photocurrent Mechanisms in Quasi-Metallic and Semiconducting Carbon Nanotube pn-Junctions. AB - We present a comparative study of quasi-metallic (Eg ~ 100 meV) and semiconducting (Eg ~ 1 eV) suspended carbon nanotube pn-junctions introduced by electrostatic gating. While the built-in fields of the quasi-metallic carbon nanotubes (CNTs) are 1-2 orders of magnitude smaller than those of the semiconducting CNTs, their photocurrent is 2 orders of magnitude higher than the corresponding semiconducting CNT devices under the same experimental conditions. Here, the large exciton binding energy in semiconducting nanotubes (~400 meV) makes it difficult for excitons to dissociate into free carriers that can contribute to an externally measured photocurent. As such, semiconducting nanotubes require a phonon to assist in the exciton dissociation process, in order to produce a finite photocurrent, while quasi-metallic nanotubes do not. The quasi-metallic nanotubes have much lower exciton binding energies (~50 meV) as well as a continuum of electronic states to decay into and, therefore, do not require the absorption of a phonon in order to dissociate, making it much easier for these excitons to produce a photocurrent. We performed detailed simulations of the band energies in quasi-metallic and semiconducting nanotube devices in order to obtain the electric field profiles along the lengths of the nanotubes. These simulations predict maximum built-in electric field strengths of 2.3 V/MUm for semiconducting and 0.032-0.22 V/MUm for quasi-metallic nanotubes under the applied gate voltages used in this study. PMID- 26498636 TI - Fruit, vegetable and vitamin C intakes and plasma vitamin C: cross-sectional associations with insulin resistance and glycaemia in 9-10 year-old children. AB - AIM: To examine whether low circulating vitamin C concentrations and low fruit and vegetable intakes were associated with insulin resistance and other Type 2 diabetes risk markers in childhood. METHODS: We conducted a cross-sectional, school-based study in 2025 UK children aged 9-10 years, predominantly of white European, South-Asian and black African origin. A 24-h dietary recall was used to assess fruit, vegetable and vitamin C intakes. Height, weight and fat mass were measured and a fasting blood sample collected to measure plasma vitamin C concentrations and Type 2 diabetes risk markers. RESULTS: In analyses adjusting for confounding variables (including socio-economic status), a one interquartile range higher plasma vitamin C concentration (30.9 MUmol/l) was associated with a 9.6% (95% CI 6.5, 12.6%) lower homeostatic model assessment of insulin resistance value, 0.8% (95% CI 0.4, 1.2%) lower fasting glucose, 4.5% (95% CI 3.2, 5.9%) lower urate and 2.2% (95% CI 0.9, 3.4%) higher HDL cholesterol. HbA1c concentration was 0.6% (95% CI 0.2, 1.0%) higher. Dietary fruit, vegetable and total vitamin C intakes were not associated with any Type 2 diabetes risk markers. Lower plasma vitamin C concentrations in South-Asian and black African Caribbean children could partly explain their higher insulin resistance. CONCLUSIONS: Lower plasma vitamin C concentrations are associated with insulin resistance and could partly explain ethnic differences in insulin resistance. Experimental studies are needed to establish whether increasing plasma vitamin C can help prevent Type 2 diabetes at an early stage. PMID- 26498637 TI - The pharmacological and hormonal therapy of hot flushes in breast cancer survivors. AB - The side effects of oncological treatment, which appear during or after therapy, are sometimes very annoying for patients and are not adequately treated by physicians. Among the symptoms experienced by breast cancer patients are hot flushes, which result from a natural or cancer therapy-induced menopause. The intensity of hot flushes in breast cancer patients may be more severe than those experienced by women undergoing a natural menopause. Taking into account the incidence of breast cancer and long-lasting hormone-suppression therapies, the problem of hot flushes will affect many women. Hormonal replacement therapy, the most effective therapeutic means for alleviating hot flushes, is usually contraindicated for breast cancer patients. For intense and severe hot flushes, pharmacological treatment using agents from a group of selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors such as venlafaxine or citalopram may be introduced. Other agents from different pharmacological groups, such as clonidine, gabapentin, or pregabalin, have also proved to be effective in treating hot flushes. The efficacy of phytoestrogens has not been proven in randomized clinical trials. The importance of the placebo effect in decreasing vasomotor symptoms has also been reported in many research papers. Educating breast cancer patients in lifestyle changes which decrease the frequency and intensity of vasomotor symptoms can offer significant help too. This paper reviews the current state of research in order to assess the options for the treatment of hot flushes in breast cancer survivors. PMID- 26498638 TI - Tackling in Youth Football. AB - American football remains one of the most popular sports for young athletes. The injuries sustained during football, especially those to the head and neck, have been a topic of intense interest recently in both the public media and medical literature. The recognition of these injuries and the potential for long-term sequelae have led some physicians to call for a reduction in the number of contact practices, a postponement of tackling until a certain age, and even a ban on high school football. This statement reviews the literature regarding injuries in football, particularly those of the head and neck, the relationship between tackling and football-related injuries, and the potential effects of limiting or delaying tackling on injury risk. PMID- 26498640 TI - KDM3A confers metastasis and chemoresistance in epithelial ovarian cancer. AB - The aim of the present study was to investigate the association between KDM3A expression and the clinicopathological parameters of patients with epithelial ovarian cancer (EOC). KDM3A expression was analyzed using immunohistochemistry in EOC tissue microarray containing 90 paired cases of EOC and matched normal control. The expression level of KDM3A protein in EOC tissues was significantly higher than that of adjacent normal control tissues. In addition, positive expression of KDM3A correlated with the metastases. Furthermore, Kaplan-Meier survival analysis showed that a high expression level of KDM3A resulted in a significantly poor prognosis of EOC patients. Knock-down of KDM3A could suppress both the proliferation, migration and invasion in vitro EOC cell lines OV-2008 and ES-2. Additionally, knock-down of KDM3A not only could enhance cellular apoptosis induced by Cisplatin and Paclitaxel, but also induced some pro apoptotic genes expression. Our data is the first to demonstrate that increased KDM3A expression in EOC is significantly associated with metastases and poor prognosis; and that KDM3A promotes the proliferation, migration and invasion of EOC cells. Knock-down of KDM3A may be an important complement to EOC that is resistant or refractory to chemotherapy. PMID- 26498639 TI - Suppression of A549 cell proliferation and metastasis by calycosin via inhibition of the PKC-alpha/ERK1/2 pathway: An in vitro investigation. AB - The migration and invasion of lung cancer cells into the extracellular matrix contributes to the high mortality rates of lung cancer. The protein kinase C (PKC) and downstream signaling pathways are important in the invasion and migration of lung cancer cells. Calycosin (Cal), an effector chemical from Astragalus has been reported to affect the recurrence and metastasis of cancer cells via the regulation of the protein expression of matrix metalloproteinases (MMPs). The inhibition of Cal on the migration and invasion of A549 cells was investigated in the present study. Cell viability and apoptosis assays were performed using MTT and flow cytometric analyses. A wound healing assay and Transwell invasion assay were performed to evaluate the effect of Cal on A549 cell migration and invasion. Invasion-associated proteins, including MMP-2, MMP 9, E-cadherin (E-cad), integrin beta1, PKC-alpha and extracellular signal regulated kinase 1/2 (ERK1/2) were detected using western blotting. In addition, PKC-alpha inhibitor, AEB071, and ERK1/2 inhibitor, PD98059, were used to determine the association between the suppression of PKC-alpha /ERK1/2 and invasion, MMP-2, MMP-9, E-cad and integrin beta1. Cal was observed to suppress cell proliferation and induce apoptosis. There were significant differences between the phorbol-12-myristate-13-acetate (TPA)-induced A549 cells treated with Cal and the untreated cells in the rates of migration and invasion. The levels of MMP-2, MMP-9, E-cad and integrin beta1 in the TPA-induced A549 cells changed markedly, compared with the untreated cells. In addition, the suppression of Cal was affected by the PKC inhibitor, AEB071, an ERK1/2 inhibitor, PD98059. The results of the present study indicated that Cal inhibited the proliferation, adhesion, migration and invasion of the TPA-induced A549 cells. The Cal-induced repression of PKC-alpha/ERK1/2, increased the expression of E-Cad and inhibited the expression levels of MMP-2, MMP-9 and integrin beta1, which possibly demonstrates the mechanism underlying the biological anticancer effects of Cal. PMID- 26498641 TI - alpha7nAChR is expressed in satellite cells at different myogenic status during skeletal muscle wound healing in rats. AB - Recent study has reported that alpha7 nicotine acetylcholine receptor (alpha7nAChR) is expressed in regenerated multinucleated myotubes. But the distribution of alpha7nAChR in satellite cells in different myogenic status is unknown. A preliminary study on the dynamic distribution of alpha7nAChR in satellite cells was performed by double indirect immunofluorescent procedures during skeletal muscle wound healing in rats. An animal model of skeletal muscle contusion was established in 40 Sprague-Dawley male rats. Samples were taken at 1, 3, 5, 7, 9, 13, 17 and 21 days after injury, respectively (five rats in each posttraumatic interval). Five rats were employed as control. In normal muscle specimens, weak immunoreactivity for alpha7nAChR was detected in a few satellite cells (considered as quiescent). alpha7nAChR-positive signals were observed in proliferated and differentiated satellite cells and regenerated multinucleated myotubes in the wounded areas. By morphometric analysis, the average number of alpha7nAChR+/Pax7+ and alpha7nAChR+/MyoD+ cells climaxed at 5 days post-injury. The average number of alpha7nAChR+/myogenin+ cells was significantly increased from 3 to 9 days post-injury as compared with other posttraumatic intervals. The protein level of alpha7nAChR maximized at 9 days post-injury, which implies that alpha7nAChR was associated with the satellite cells status. Our observations on expression of alpha7nAChR in satellite cells from quiescence to myotube formation suggest that alpha7nAChR may be involved in muscle regeneration by regulating satellite cell status. PMID- 26498642 TI - Two-year results of combined intravitreal ranibizumab and photodynamic therapy for retinal angiomatous proliferation. AB - PURPOSE: The aim of this study was clarify the efficacy of combination therapy of intravitreal ranibizumab (IVR) injections and photodynamic therapy (PDT) in patients with symptomatic retinal angiomatous proliferation (RAP) over 24 months. METHODS: We retrospectively reviewed 37 naive eyes of 31 patients treated with three consecutive monthly IVR injections (0.5 mg/0.05 ml) and PDT and followed for at least 24 months. RESULTS: The mean logarithm of the minimum angle of resolution best-corrected visual acuity levels improved significantly (P < 0.0001) from 0.63 at baseline to 0.39 at 24 months. Geographic atrophy (GA) involving the fovea developed in nine (24%) eyes, with a significant (P = 0.036) decrease in VA at 24 months and a high (100%) prevalence of reticular pseudodrusen (RPD) at baseline. Complete occlusion of the retinal-retinal anastomosis seen in 35 eyes was achieved in 33 eyes at month 24. The central retinal thickness decreased significantly (P < 0.0001) from 415 to 129 MUm at 24 months. The mean number of treatments during 24 months was 2.5 PDT and 5.5 IVR injections. CONCLUSIONS: Combination therapy comprising IVR injections and PDT is generally effective in maintaining or improving VA and retinal morphology within 2 years in eyes with RAP, except for eyes with baseline RPD, which are likely to develop GA in the fovea resulting in reduced VA. PMID- 26498643 TI - Organic and inorganic mercurials have distinct effects on cellular thiols, metal homeostasis, and Fe-binding proteins in Escherichia coli. AB - The protean chemical properties of the toxic metal mercury (Hg) have made it attractive in diverse applications since antiquity. However, growing public concern has led to an international agreement to decrease its impact on health and the environment. During a recent proteomics study of acute Hg exposure in E. coli, we also examined the effects of inorganic and organic Hg compounds on thiol and metal homeostases. On brief exposure, lower concentrations of divalent inorganic mercury Hg(II) blocked bulk cellular thiols and protein-associated thiols more completely than higher concentrations of monovalent organomercurials, phenylmercuric acetate (PMA) and merthiolate (MT). Cells bound Hg(II) and PMA in excess of their available thiol ligands; X-ray absorption spectroscopy indicated nitrogens as likely additional ligands. The mercurials released protein-bound iron (Fe) more effectively than common organic oxidants and all disturbed the Na(+)/K(+) electrolyte balance, but none provoked efflux of six essential transition metals including Fe. PMA and MT made stable cysteine monothiol adducts in many Fe-binding proteins, but stable Hg(II) adducts were only seen in CysXxx(n)Cys peptides. We conclude that on acute exposure: (a) the distinct effects of mercurials on thiol and Fe homeostases reflected their different uptake and valences; (b) their similar effects on essential metal and electrolyte homeostases reflected the energy dependence of these processes; and (c) peptide phenylmercury-adducts were more stable or detectable in mass spectrometry than Hg(II)-adducts. These first in vivo observations in a well-defined model organism reveal differences upon acute exposure to inorganic and organic mercurials that may underlie their distinct toxicology. PMID- 26498645 TI - The outcome of children with selective mutism following cognitive behavioral intervention: a follow-up study. AB - Selective mutism (SM) is a relatively rare childhood disorder and is underdiagnosed and undertreated. The purpose of the retrospective naturalistic study was to examine the long-term outcome of children with SM who were treated with specifically designed modular cognitive behavioral therapy (MCBT). Parents of 36 children who met diagnostic criteria of SM that received MCBT treatment were invited for a follow-up evaluation. Parents were interviewed using structured scales and completed questionnaires regarding the child, including the Selective Mutism Questionnaire (SMQ). Twenty-four subjects were identified and evaluated. Their mean age +/- SD of onset of SM symptoms, beginning of treatment, and age at follow-up were 3.4 +/- 1.4, 6.4 +/- 3.1, and 9.3 +/- 3.4 years, respectively. There was robust improvement from beginning of treatment to follow up evaluation in SM, social anxiety disorder, and specific phobia symptoms. The recovery rate from SM was 84.2 %. CONCLUSION: SM-focused MCBT is feasible in children and possibly effective in inducing long-term reduction of SM and comorbid anxiety symptoms. WHAT IS KNOWN: * There are limited empirical data on selective mutism (SM) treatment outcome and specifically on cognitive-behavioral therapy, with the majority of studies being uncontrolled case reports of 1 to 2 cases each. * There is also limited data on the long-term outcome of children with SM following treatment. What is New: * Modular cognitive behavioral treatment is a feasible and possibly effective treatment for SM. Intervention at a younger age is more effective comparing to an older age. * Treatment for SM also decreases the rate of psychiatric comorbidities, including separation anxiety disorder and specific phobia. PMID- 26498644 TI - Advances in Isolation Methods for Spermatogonial Stem Cells. AB - Stem cell research has led to many remarkable achievements in recent years, but progress in the study of spermatogonial stem cells (SSCs) has been relatively slow, partly due to the slow development of techniques for spermatogonial stem cell isolation. The major accomplishments of SSC sorting and identification occurred approximately 10 years ago, and since that time, these techniques have been widely used without major improvements. In this article, we briefly introduce the biological properties of SSCs before reviewing the development of sorting techniques for SSCs in the past decades. We then summarize recent achievements in SSC sorting and finally discuss the advantages and disadvantages of SSC isolation methods, to provide new insight into techniques and research related to spermatogonial stem cells and promote the development of reproductive biology. PMID- 26498646 TI - The perfusion index of healthy term infants during transition at birth. AB - Perfusion index is a continuous parameter provided by pulse oximetry and might be useful for evaluating hemodynamic changes at birth and identifying transitional problems. The objective was to describe perfusion index values in term infants immediately after birth. Perfusion index of 71 healthy term born infants were recorded during the first 10 min after birth, using a pulse oximetry sensor placed preductally. A Wilcoxon signed-rank test was used to compare between time points. No significant trend in perfusion index could be observed in term delivered infants. There was a significant difference between 2 and 3 min (2.4 (1.6-5.0) vs. 2.3 (1.6-3.7), p = 0.05) and between 3 and 4 min after birth (2.3 (1.6-3.7) vs. 2.1 (1.4-3.2), p < 0.001). There was no significant change in median PI values in the following 8 min. CONCLUSION: Perfusion index does not change significantly during transition at birth in healthy term infants born by normal vaginal delivery or cesarean section. Large variation in perfusion index causes monitoring this parameter to have limited value. WHAT IS KNOWN: * Perfusion index is a non-invasive indicator for peripheral perfusion. * Perfusion index values <1.24 are seen as an accurate predictor for severity of illness for infants admitted to the neonatal intensive care unit. What is new: * Although significant physiological changes occur during birth, perfusion index remains stable. * Large variation in perfusion index causes monitoring of this value to have limited value as an additional parameter for evaluating transition at birth. PMID- 26498647 TI - Patients with anorectal malformation and upper limb anomalies: genetic evaluation is warranted. AB - The objective of this study was to compare the prevalence of genetic disorders in anorectal malformation (ARM) patients with upper limb anomalies to that in ARM patients with other associated anomalies. A retrospective case study was performed in two pediatric surgery centers. All patients born between 1990 and 2012 were included. VACTERL (vertebral defects (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula with esophageal atresia (TE), renal dysplasia (R), and limb anomalies (L)) was defined as at least three components present. We included 700 ARM patients: 219 patients (31 %) had isolated ARM, 43 patients (6 %) had a major upper limb anomaly, and 438 patients (63 %) had other associated anomalies. The most prevalent upper limb anomalies were radial dysplasia (n = 12) and hypoplastic thumb (n = 11). Ten of the 43 patients (23 %) with an upper limb anomaly were diagnosed with a genetic disorder-nine also met the VACTERL criteria-vs. 9 % of ARM patients with other anomalies (p = 0.004, chi squared test). CONCLUSION: Genetic disorders are twice as frequently diagnosed in ARM patients with upper limb anomalies than in those with other anomalies. As they also frequently meet the VACTERL criteria, it is important to consider VACTERL as a diagnosis per exclusionem. Genetic counseling is certainly warranted in these patients. WHAT IS KNOWN: * Anorectal malformations (ARMs) often co-occur with other congenital anomalies, including upper limb anomalies, mainly of pre axial origin. * Co-occurrence of ARMs and upper limb anomalies is seen in disorders such as Townes-Brocks syndrome, Fanconi anemia, and VACTERL association. What is New: * ARM patients with a major upper limb anomaly-with or without other congenital anomalies-have a twofold greater chance of a genetic disorder than have non-isolated ARM patients without upper limb anomalies. * Not all upper limb anomalies in ARM patients are part of the VACTERL association; a workup for genetic evaluation is proposed. PMID- 26498648 TI - Epidemiology of haemolytic uremic syndrome in children. Data from the North Italian HUS network. AB - Despite the severity of HUS and the fact that it represents a leading cause of acute kidney injury in children, the general epidemiology of HUS is all but well documented. The present study provides updated, population-based, purely epidemiological information on HUS in childhood from a large and densely populated area of northern Italy (9.6 million inhabitants, 1.6 million children). We systematically reviewed the files concerning patients with STEC-HUS and atypical HUS (aHUS) over a 10-year observation period (January 2003-December 2012). We included all incident cases with a documented first episode of HUS before the age of 18 years. We identified 101 cases of HUS during the 10 years. The overall mean annual incidence was 6.3 cases/million children aged <18 years (range 1.9-11.9), and 15.7/million of age-related population (MARP) among subjects aged <5 years; aHUS accounted for 11.9 % of the cases (mean incidence 0.75/MARP). The overall case fatality rate was 4.0 % (3.4 % STEC-HUS, 8.3 % aHUS). CONCLUSION: Given the public health impact of HUS, this study provides recent, population-based epidemiological data useful for healthcare planning and particularly for estimating the financial burden that healthcare providers might have to face in treating HUS, whose incidence rate seems to increase in Northern Italy. WHAT IS KNOWN: * HUS is a rare disease, but it represents the leading cause of acute kidney injury in children worldwide. * STEC-HUS (also called typical, D + HUS) is more common compared to atypical HUS, but recent, population based epidemiological data (incidence) are scanty. What is New: * Comprehensive, population-based epidemiological data concerning both typical and atypical HUS based on a long observational period. PMID- 26498649 TI - Do Men Receive Information Required for Shared Decision Making About PSA Testing? Results from a National Survey. AB - Most professional organizations, including the American College of Physicians and U.S. Preventive Services Task Force, emphasize that screening for prostate cancer with the prostate-specific antigen (PSA) test should only occur after a detailed discussion between the health-care provider and patient about the known risks and potential benefits of the test. In fact, guidelines strongly advise health-care providers to involve patients, particularly those at elevated risk of prostate cancer, in a "shared decision making" (SDM) process about PSA testing. We analyzed data from the National Cancer Institute's Health Information National Trends Survey 2011-2012-a nationally representative, cross-sectional survey-to examine the extent to which health professionals provided men with information critical to SDM prior to PSA testing, including (1) that patients had a choice about whether or not to undergo PSA testing, (2) that not all doctors recommend PSA testing, and (3) that no one is sure if PSA testing saves lives. Over half (55 %) of men between the ages of 50 and 74 reported ever having had a PSA test. However, only 10 % of men, regardless of screening status, reported receiving all three pieces of information: 55 % reported being informed that they could choose whether or not to undergo testing, 22 % reported being informed that some doctors recommend PSA testing and others do not, and 14 % reported being informed that no one is sure if PSA testing actually saves lives. Black men and men with lower levels of education were less likely to be provided this information. There is a need to improve patient-provider communication about the uncertainties associated with the PSA test. Interventions directed at patients, providers, and practice settings should be considered. PMID- 26498650 TI - Expansion of quiescent lung adenocarcinoma CD8+ T cells by MUC1-8-mer peptide-T2 cell-beta2 microglobulin complexes. AB - Adoptive immunotherapy requires the isolation of CD8+ T cells specific for tumor associated antigens, their expansion in vitro and their transfusion to the patient to mediate a therapeutic effect. MUC1 is an important adenocarcinoma antigen immunogenic for T cells. The MUC1-derived SAPDTRPA (MUC1-8-mer) peptide is a potent epitope recognized by CD8+ T cells in murine models. Likewise, the T2 cell line has been used as an antigen-presenting cell to activate CD8+ T cells, but so far MUC1 has not been assessed in this context. We evaluated whether the MUC1-8-mer peptide can be presented by T2 cells to expand CD25+CD8+ T cells isolated from HLA-A2+ lung adenocarcinoma patients with stage III or IV tumors. The results showed that MUC1-8-mer peptide-loaded T2 cells activated CD8+ T cells from cancer HLA-A2+ patients when anti-CD2, anti-CD28 antibodies and IL-2 were added. The percentage of CD25+CD8+ T cells was 3-fold higher than those in the non-stimulated cells (P=0.018). HLA-A2+ patient cells showed a significant difference (2.3-fold higher) in activation status than HLA-A2+ healthy control cells (P=0.04). Moreover, 77.6% of MUC1-8-mer peptide-specific CD8+ T cells proliferated following a second stimulation with MUC1-8-mer peptide-loaded T2 cells after 10 days of cell culture. There were significant differences in the percentage of basal CD25+CD8+ T cells in relation to the cancer stage; this difference disappeared after MUC1-8-mer peptide stimulation. In conclusion, expansion of CD25+CD8+ T cells by MUC1-8 peptide-loaded T2 cells plus costimulatory signals via CD2, CD28 and IL-2 can be useful in adoptive immunotherapy. PMID- 26498651 TI - Design and optimization of peptide nanoparticles. AB - BACKGROUND: Various supra-molecular structures form by self-assembly of proteins in a symmetric fashion. Examples of such structures are viruses, some bacterial micro-compartments and eukaryotic vaults. Peptide/protein-based nanoparticles are emerging in synthetic biology for a variety of biomedical applications, mainly as drug targeting and delivery systems or as vaccines. Our self-assembling peptide nanoparticles (SAPNs) are formed by a single peptide chain that consists of two helical coiled-coil segments connected by a short linker region. One helix is forming a pentameric coiled coil while the other is forming a trimeric coiled coil. RESULTS: Here, we were studying in vitro and in silico the effect of the chain length and of point mutations near the linker region between the pentamer and the trimer on the self-assembly of the SAPNs. 60 identical peptide chains co assemble to form a spherical nanoparticle displaying icosahedral symmetry. We have stepwise reduced the size of the protein chain to a minimal chain length of 36 amino acids. We first used biochemical and biophysical methods on the longer constructs followed by molecular dynamics simulations to study eleven different smaller peptide constructs. We have identified one peptide that shows the most promising mini-nanoparticle model in silico. CONCLUSIONS: An approach of in silico modeling combined with in vitro testing and verification yielded promising peptide designs: at a minimal chain length of only 36 amino acids they were able to self-assemble into proper nanoparticles. This is important since the production cost increases more than linearly with chain length. Also the size of the nanoparticles is significantly smaller than 20 nm, thus reducing the immunogenicity of the particles, which in turn may allow to use the SAPNs as drug delivery systems without the risk of an anaphylactic shock. PMID- 26498652 TI - Obestatin stimulates differentiation and regulates lipolysis and leptin secretion in rat preadipocytes. AB - Obestatin is a 23-amino acid peptide encoded by the ghrelin gene, which regulates food intake, body weight and insulin sensitivity. Obestatin influences glucose and lipid metabolism in mature adipocytes in rodents. However, the role of this peptide in rat preadipocytes remains to be fully understood. The current study characterized the effects of obestatin on lipid accumulation, preadipocyte differentiation, lipolysis and leptin secretion in rat primary preadipocytes. Obestatin enhanced lipid accumulation in rat preadipocytes and increased the expression of surrogate markers of preadipocyte differentiation. At the early stage of differentiation, obestatin suppressed lipolysis. By contrast, lipolysis was stimulated at the late stage of adipogenesis. Furthermore, obestatin stimulated the release of leptin, a key satiety hormone. Overall, the results indicated that obestatin promotes preadipocyte differentiation. Obestatin increased leptin release in preadipocytes, while the modulation of lipolysis appears to depend upon the stage of differentiation. PMID- 26498653 TI - Cardiac CTA for evaluation of cardiac function in patients with congenital heart disease: the good, the bad and the ugly. PMID- 26498654 TI - Left atrial minimum volume is more strongly associated with N-terminal pro-B-type natriuretic peptide than the left atrial maximum volume in a community-based sample. AB - Previous data have demonstrated that left atrial (LA) minimum volume indexed for body surface area (LAVImin) is more strongly associated with the Doppler echocardiographic E/e' ratio than LA maximum volume index (LAVImax). We sought to explore if LAVImin was more closely related to serum levels of NT-proBNP than LAVImax and E/e' in the community. A community-based sample of 730 subjects underwent echocardiographic examinations and NT-proBNP measurements. The mean age of the participants was 66.3 years (range 38-86) and 72% were men. Age (Spearman correlation [rho] 0.533), LAVImin (rho 0.460), LAVImax (rho 0.360), estimated glomerular filtration rate (rho -0.349), and E/e' (rho 0.301; all P < 0.001) were strongly correlated with log-NT-proBNP. In a multiple linear regression model with log-NT-proBNP as dependent variable and LAVImin, LAVImax, E/e' ratio, and potential confounders as predictors, an adjusted R(2) of 44.9% was obtained. When excluding either of LAVImin (R(2) 42.6%, P < 0.001) or E/e' (R(2) 44.6%, P = 0.019) the model fit was significantly reduced. In contrast, when LAVImax was excluded the model fit was preserved (R(2) 45.0%, P = 0.69). To detect an NT proBNP level of >125 ng/L, LAVImin yielded a significantly larger area under the receiver operating characteristic curve (AUC) of 0.749 than LAVImax (AUC 0.701; P < 0.001) and E/e' (AUC 0.661; P < 0.001). In our community-based sample, LAVImin was more strongly associated with NT-proBNP than LAVImax. Moreover, the discriminatory power to detect an elevated NT-proBNP level was stronger in LAVImin than in LAVImax and E/e'. Our findings support previous data that LAVImin may be more closely related to LV filling function than LAVImax. PMID- 26498656 TI - Advanced abdominal pregnancy with successful outcome. PMID- 26498655 TI - Stent fracture and longitudinal compression detected on coronary CT angiography in the first- and new-generation drug-eluting stents. AB - To evaluated prevalence and clinical implication of stent fracture and longitudinal compression in first- and new-generation drug-eluting stents (DES) using coronary computed tomography angiography (CCTA). The incidence of stent fracture and longitudinal compression were compared between first- and new generation DES in 374 patients who underwent coronary stenting using DES and follow-up CCTA due to recurrent angina. 235 and 139 patients received 322 first- and 213 new-generation DES, respectively. The crude per-stent incidence of longitudinal compression (6.1 vs. 0.3 %, p < 0.001) was higher after new- than first-generation DES implantation using CCTA and the incidence of stent fracture (11.3 vs. 8.1 %, p = 0.23) was comparable. On follow-up coronary angiography for 347 stents, stent fracture (3.2 %) and longitudinal compression (0.9 %) were less detected than those on CCTA. Ostial stenting was a risk factor of longitudinal compression (p < 0.001). Stent fracture was associated with younger patients (p = 0.03), longer stent (p = 0.010), and excessively tortuous lesions (p = 0.001). The presence of stent fracture or longitudinal compression was not associated with poor clinical outcomes. The longitudinal compression more frequently occurred after new-generation DES implantation. The stent fracture was comparable between two DES. However, the occurrence of such mechanical deformities did not translate into a poor clinical outcome. PMID- 26498657 TI - Erratum to: Prognostic relevance of microsatellite instability in pT3N0M0 colon cancer: a population-based study. PMID- 26498658 TI - The impacts of prolonged emergency department length of stay on clinical outcomes of patients with ST-segment elevation myocardial infarction after reperfusion. AB - Emergency department and hospital crowding have become an increasing problem. The clinical outcomes of prolonged emergency department (ED) length of stay in acute ST-segment elevation myocardial infarction (STEMI) patients after reperfusion are still unknown. Between January 2008 and December 2011, 432 consecutive patients with STEMI undergoing primary PCI were recruited. Patients were divided into two groups: the immediate admission group (length of ED stay <8 h; IA group) and the prolonged ED stay group (length of ED stay ?8 h; PS group). The median lengths of ED stay of the patients in both groups were 29.97 h in the PS group (n = 145, 33.6%) and 1.78 h in the IA group (n = 287, 66.4%), respectively. The age, gender, risk factors of coronary artery disease, characteristic of coronary angiography, and TIMI risk score did not differ between the two groups. During nearly 4-year clinical follow-up, the short-term and long-term clinical outcomes were similar between the two groups. B-blocker and statins were used infrequently in the ED. In addition, patients with high TIMI risk score in the PS group had higher incidence of 1-year re-MI (6.8 vs. 1.8%; p = 0.045). In the era of primary PCI for STEMI patients after reperfusion, prolonged ED length of stay may not influence clinical outcomes. Patients with high TIMI risk score in the PS group still had a trend toward worse clinical outcome after long ED stays. PMID- 26498659 TI - Effect of smoking status on coronary artery disease among Chinese post-menopausal women. AB - Smoking is a prominent risk factor of cardiovascular diseases. The occurrence of myocardial infarction and mortality in smokers with cardiovascular diseases is several times higher than that in non-smokers. Smoking is associated with gender independent enhanced mortality. We determined the effect of smoking status on coronary artery disease (CAD) and coronary computed tomography angiography (CCTA) in Chinese post-menopausal women. Among these patients, those with significant CAD (>=50 % luminal narrowing) were further classified into one-, two-, or three vessel disease according to CCTA results. The following events were recorded: all cause mortality, non-fatal infarction and unstable angina. 2332 patients evaluated with CCTA included 1668 never smokers (71.5 %), 475 former smokers (20.4 %), and 189 current smokers (8.1 %). The current smokers exhibit greater luminal narrowing as observed on CCTA (p < 0.001) than the other subjects. During the median 685 +/- 269.8 days follow-up period, never-smoking women have a low incidence of events, whereas former and current smokers are associated with an increased incidence of such event (p < 0.001). Furthermore, current smoking and the presence of multiple-vessel disease on CCTA are independently associated with the events in the logistic regression analysis. Smoking status is related to significant CAD and luminal narrowing on CCTA in the Chinese post-menopausal smoking women. In addition, current smoking and the presence of multiple-vessel disease on CCTA can independently predict events of all-cause mortality, non fatal infarction or unstable angina. PMID- 26498660 TI - Biomimetic sensor design. AB - Detection of desired target chemicals in a sensitive and selective manner is critically important to protect human health, environment and national security. Nature has been a great source of inspiration for the design of sensitive and selective sensors. In this mini-review, we overview the recent developments in bio-inspired sensor development. There are four major components of sensor design: design of receptors for specific targets; coating materials to integrate receptors to transducing machinery; sensitive transducing of signals; and decision making based on the sensing results. We discuss the biomimetic methods to discover specific receptors followed by a discussion about bio-inspired nanocoating material design. We then review the recent developments in phage based bioinspired transducing systems followed by a discussion of biomimetic pattern recognition-based decision making systems. Our review will be helpful to understand recent approaches to reverse-engineer natural systems to design specific and sensitive sensors. PMID- 26498661 TI - Hospital pharmacists' perceptions of the suitability of doctor of pharmacy graduates in hospital settings in Thailand. AB - BACKGROUND: Thai pharmacy education has moved to an all Doctor of Pharmacy (PharmD) programme. However, there has been no previous research about the perceptions regarding the suitability of PharmD graduates employed in hospital settings, which is the major pharmacy workforce in Thailand. METHODS: A cross sectional survey questionnaire was distributed to 180 hospital pharmacists at the 2013 Association of Hospital Pharmacy (Thailand) conference. This study aimed to explore Thai hospital pharmacists' perceptions concerning the suitability of the PharmD graduates employed in hospital settings and the competency differences between the Bachelor of Pharmacy (BPharm) and PharmD graduates. Descriptive statistics were used to present the participants' demographics and their perceptions. An inductive thematic analysis was used to analyse the open-ended written answers. RESULTS: Ninety-eight valid responses were included in the data analysis (response rate of 55.6 %). The majority of the respondents (76.5 %) felt that the PharmD graduates were suited for the hospital setting and addressed its need for more professionals working in pharmaceutical care and with multi disciplinary teams. Approximately 55 % of respondents agreed that there were competency differences between the BPharm and PharmD graduates. Major themes emerged in response to the open-ended written answers showing that PharmD graduates had high competency in patient care services and readiness to work, particularly in large hospitals, due to their training to work in specialised areas (e.g., special clinics, ward rounds). However, PharmD graduates require more training in health promotion and humanistic skills and need the system to promote the role of PharmD in pharmaceutical care. CONCLUSIONS: PharmD graduates were suited for hospital settings. However, there were concerns regarding the suitability of the PharmD graduates for the community hospital and primary care hospital settings because of their insufficient training in health promotion and disease prevention. Half of the respondents perceived PharmD graduates as having higher competencies in clinical activities and being more prepared to work than BPharm graduates. However, the other half of the respondents perceived the competency of both pharmacy qualifications as being similar, as PharmD graduates provide non-clinical activities similar to BPharm graduates due to the high workload in dispensing services and the shortage of hospital pharmacists, which prevent PharmD graduates from providing direct pharmaceutical care services. PMID- 26498663 TI - Structure and properties of Al-MIL-53-ADP, a breathing MOF based on the aliphatic linker molecule adipic acid. AB - The new aluminium based metal-organic framework [Al(OH)(O2C-C4H8-CO2)].H2O denoted as Al-MIL-53-ADP-lp (lp stands for large pore) was synthesised under solvothermal conditions. This solid is an analogue of the archetypical aluminium terephthalate Al-MIL-53 based on the aliphatic single-chain linker molecule adipic acid (H2ADP, hexanedioic acid). In contrast to its aromatic counterparts, Al-MIL-53-ADP exhibits a structural breathing behaviour solely upon dehydration/rehydration. The crystal structure of the anhydrous compound denoted as Al-MIL-53-ADP-np (np stands for narrow pore) was determined by a combination of forcefield-based computations and Rietveld refinement of the powder X-ray diffraction data while the structure of the hydrated form Al-MIL-53-ADP-lp was derived computationally by a combination of force field based methods and Density Functional Theory calculations. Both structures were further supported by (1)H, (13)C and (27)Al high-resolution NMR MAS 1D data coupled again with simulations. Al-MIL-53-ADP was further characterised by means of vibrational spectroscopy, elemental analysis, thermogravimetry and water vapour sorption. PMID- 26498662 TI - The unique transcriptional response produced by concurrent estrogen and progesterone treatment in breast cancer cells results in upregulation of growth factor pathways and switching from a Luminal A to a Basal-like subtype. AB - BACKGROUND: In breast cancer, progesterone receptor (PR) positivity or abundance is positively associated with survival and treatment response. It was initially believed that PR was a useful diagnostic marker of estrogen receptor activity, but increasingly PR has been recognised to play an important biological role in breast homeostasis, carcinogenesis and metastasis. Although PR expression is almost exclusively observed in estrogen receptor positive tumors, few studies have investigated the cellular mechanisms of PR action in the context of ongoing estrogen signalling. METHODS: In this study, we contrast PR function in estrogen pretreated ZR-75-1 breast cancer cells with vehicle treated ZR-75-1 and T-47D breast cancer cells using expression microarrays and chromatin immunoprecipitation-sequencing. RESULTS: Estrogen cotreatment caused a dramatic increase in the number of genes regulated by progesterone in ZR-75-1 cells. In T 47D cells that have naturally high levels of PR, estrogen and progesterone cotreatment resulted in a reduction in the number of regulated genes in comparison to treatment with either hormone alone. At a genome level, estrogen pretreatment of ZR-75-1 cells led to a 10-fold increase in the number of PR DNA binding sites detected using ChIP-sequencing. Time course assessment of progesterone regulated genes in the context of estrogen pretreatment highlighted a series of important regulatory pathways, including those driven by epithelial growth factor receptor (EGFR). Importantly, progesterone applied to cells pretreated with estradiol resulted in switching of the PAM50-determined intrinsic breast cancer subtype from Luminal A to Basal-like, and increased the Oncotype DX(r) Unscaled Recurrence Score. CONCLUSION: Estrogen pretreatment of breast cancer cells increases PR steady state levels, resulting in an unequivocal progesterone response that upregulates key members of growth factor pathways. The transformative changes progesterone exerts on the breast cancer subtype suggest that these subtyping tools should be used with caution in premenopausal women. PMID- 26498664 TI - TCEA3 Attenuates Gastric Cancer Growth by Apoptosis Induction. AB - BACKGROUND: The aim of this study was to investigate and interpret the expression level and potential function of TCEA3 in gastric cancer. MATERIAL AND METHODS: qRT-PCR was used to determine the expression level of TCEA3 in gastric cancer tissues. Pearson chi2 test was performed to clarify the correlation between TCEA3 expression and patients' clinicopathologic characteristics. Biological function of TCEA3 was tested by proliferation assay and colony formation assay. Flow cytometry was used to study the potential function of TCEA3 in apoptosis induction. RESULTS: TCEA3 expression was significantly downregulated in gastric cancer tissues compared with paired normal tissues. Poor prognoses were observed in the low TCEA3 expression group of patients in contrast to the high TCEA3 expression group. Functionally, upregulation of TCEA3 inhibited gastric cancer cell proliferation and colony formation. We also found that TCEA3 may attenuate cell growth through apoptosis induction. CONCLUSIONS: Our findings suggest that TCEA3 attenuates the proliferation and induces apoptosis of gastric cancer cells. PMID- 26498666 TI - 2015 ACC/AHA/SCAI Focused Update on Primary Percutaneous Coronary Intervention for Patients With ST-Elevation Myocardial Infarction: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention and the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. PMID- 26498665 TI - Quantification of Plasmodium ex vivo drug susceptibility by flow cytometry. AB - BACKGROUND: The emergence and spread of multidrug-resistant Plasmodium falciparum and Plasmodium vivax highlights the need for objective measures of ex vivo drug susceptibility. Flow cytometry (FC) has potential to provide a robust and rapid quantification of ex vivo parasite growth. METHODS: Field isolates from Papua, Indonesia, underwent ex vivo drug susceptibility testing against chloroquine, amodiaquine, piperaquine, mefloquine, and artesunate. A single nucleic acid stain (i.e., hydroethidine (HE) for P. falciparum and SYBR Green I (SG) for P. vivax) was used to quantify infected red blood cells by FC-based signal detection. Data derived by FC were compared to standard quantification by light microscopy (LM). A subset of isolates was used to compare single and double staining techniques. RESULTS: In total, 57 P. falciparum and 23 P. vivax field isolates were collected for ex vivo drug susceptibility testing. Reliable paired data between LM and FC was obtained for 88 % (295/334) of these assays. The median difference of derived IC50 values varied from -5.4 to 6.1 nM, associated with 0.83-1.23 fold change in IC50 values between LM and FC. In 15 assays (5.1 %), the derived difference of IC50 estimates was beyond the 95 % limits of agreement; in eleven assays (3.7 %), this was attributable to low parasite growth (final schizont count < 40 %), and in four assays (1.4 %) due to low initial parasitaemia at the start of assay (<2000 ul(-1)). In a subset of seven samples, LM, single and double staining FC techniques generated similar IC50 values. CONCLUSIONS: A single staining FC-based assay using a portable cytometer provides a simple, fast and versatile platform for field surveillance of ex vivo drug susceptibility in clinical P. falciparum and P. vivax isolates. PMID- 26498667 TI - Moraxella catarrhalis bacteraemia and prosthetic valve endocarditis. AB - Moraxella catarrhalis, once considered a non-pathogenic coloniser of the oropharynx, has now been recognised as a true pathogen and is reported in cases of bacteraemia. A 63-year-old man with an aortic bioprosthetic valve was brought to the emergency room with altered mental status. Initial blood cultures revealed Gram-negative diplococci on Gram stain; echocardiogram showed a 5 mm vegetation on the aortic bioprosthetic valve. The blood cultures grew M. catarrhalis and the patient was treated medically for prosthetic valve endocarditis with 6 weeks of ceftriaxone and had a favourable clinical outcome. M. catarrhalis has a high prevalence of beta-lactamase production and hence the patient was treated with ceftriaxone. This case highlights the importance of considering M. catarrhalis as a pathogen in cases of invasive disease. PMID- 26498668 TI - Extramedullary plasmacytoma mimicking colon carcinoma: an unusual presentation and review of the literature. AB - A 72-year-old woman presented to outpatient clinic with fatigue, light headedness, dyspnoea and dark stool suggestive of lower gastrointestinal bleeding. She was previously diagnosed with multiple myeloma and completed 9 cycles of chemotherapy with bortezomib, lenalidomide and dexamethasone. She had very good partial response. A CT scan of the abdomen revealed a 9 cm mass at the hepatic flexure of the large intestine with an apple core deformity causing a marked narrowing of the lumen. Colonoscopy confirmed a large, nearly obstructing ulcerative mass in the distal right colon. The patient underwent a right hemicolectomy, distal ileal resection and lymph node dissection. Histopathology confirmed the mass as a plasmacytoma. Postoperatively, the patient was started with bortezomib and liposomal doxorubicin followed by carfilzomib. She showed excellent response to the chemotherapy. PMID- 26498669 TI - Two rare cases of head and neck tuberculosis. AB - Tuberculosis is an infectious disease, which is the leading cause of mortality and morbidity and is still a serious health concern. The fact that extra pulmonary tuberculosis does not have specific examination and radiographic findings and that clinical findings vary depending on the organ in which it is detected cause diagnostic difficulties. The head and neck region is an uncommon site for tuberculosis and tuberculosis can localise in many different places of the head and neck region. In this article, the authors present a case of nasopharyngeal tuberculosis, which clinically mimics nasopharyngeal carcinoma and rare cutaneous tuberculosis of the pinna. A wide knowledge of head and neck tuberculosis, including the disease in the differential diagnosis and carrying out microbiological examinations are necessary for accurate diagnosis. PMID- 26498670 TI - Down syndrome--novel associations: antenatal strawberry-shaped skull, severe neonatal hepatitis and an unusual form of portosystemic hepatic shunt. PMID- 26498671 TI - Life-threatening ACE inhibitor-induced angio-oedema successfully treated with icatibant: a bradykinin receptor antagonist. AB - We present a case of a 75-year-old woman treated with an ACE inhibitor, who presented with angio-oedema of the tongue and had difficulty speaking. No symptoms of anaphylaxis or urticaria were present. The patient was treated intravenously with antihistamine and glucocorticoid in combination with adrenaline inhalations. After 6 h in the hospital the swelling progressed, and the patient was admitted to the intensive care unit and treated with one injection of icatibant-a bradykinin receptor antagonist. The patient reported subjective relief after 20-30 min and the swelling resolved within 2 h. Although the angio-oedema was potentially life threatening, the patient avoided intubation and mechanical ventilation. ACE inhibitor-induced angio-oedema is most likely caused by an accumulation of bradykinin and substance P. Consequently, a bradykinin receptor antagonist is the rational treatment of choice instead of antiallergic medications, which have no proven efficacy in this condition. PMID- 26498672 TI - Predictors of tooth loss due to periodontal disease in patients following long term periodontal maintenance. AB - AIM: To analyse patient-related factors (PRFs) and tooth-related factors (TRFs) associated with tooth loss due to periodontal disease (TLPD) in patients undergoing periodontal maintenance (PM). MATERIAL AND METHODS: The sample consisted of 500 patients (mean follow-up of 20 years). The impact of PRFs on TLPD was analysed with Poisson regression and multivariate logistic regression. The simultaneous impact of PRFs and TRFs was analysed with multilevel logistic regression and Cox regression. RESULTS: Tooth loss due to periodontal disease was 515 (mean 0.05 patient/year). The significant PRFs were severe periodontitis (p < 0.001), aggressive periodontitis (p < 0.001), smoking (p = 0.018), bruxism (p = 0.022) and baseline number of teeth (p = 0.001). These PRFs allowed characterizing patients losing more teeth. The whole TRFs analysed were significant, depending on the type of tooth and the category of each factor (e.g. mobility 0, 1, 2, and 3). The significant PRFs increased the risk of TLPD by 2 to 3 times while TRFs increased the risk to a higher extent. Mobility was the main TRF. CONCLUSIONS: Severe periodontitis, aggressive periodontitis, smoking, bruxism and baseline number of teeth, as well as the whole TRFs analysed, were associated with TLPD. PMID- 26498673 TI - Water insecurity in Canadian Indigenous communities: some inconvenient truths. AB - INTRODUCTION: Canada has the second highest per capita water consumption in the world. However, little is known about complex socio-economic and cultural dynamics of water insecurities in Indigenous communities and the multiple health consequences. Most studies have concentrated on a simplified interpretation of accessibility, availability and quality issues, including some common water-borne infections as the only health outcomes. Thus, several government initiatives on potable water supply, particularly for remotely located communities, have failed to sustain and promote a healthy lifestyle. The objective was to explore the water insecurity, coping strategies and associated health risks in a small and isolated sub-Arctic Indigenous (Inuit) community in Canada. METHODS: The study was based on a community-based survey (2013) in one of the most remote Inuit communities of Labrador. In-depth, open-ended key informant (KI) interviews (community leader (1), woman (1), nurse (1), teacher (1), and elder (1)) and focus group discussions (FGDs) were conducted with community leaders (5), community members (25), women (5), and high school students (8). Convenience sampling was followed in selection of the subjects for FGDs and approached some KIs. All the water sources (five in April and seven in October) were visited and tested for their physical, chemical and microbiological parameters. The FGDs and KI interviews were audio recorded and transcribed. In the analysis, the data (qualitative and quantitative) were broadly categorized into (a) water sources, access and quality, (b) coping, (c) health risks and (d) challenges to run a public water system. RESULTS: The community did not have any piped water supply. Their regular sources of water consisted of several unmonitored local streams, brooks, and ponds. The public water system was not affordable to the majority of community members who solely depended on government aid. Animal fecal contamination (in natural sources such as streams, brooks, and ponds) and the presence of disinfection by-products (in the public water system) were the major quality issues. Gastro-intestinal infections were the most common disease in the community. Per capita water consumption was less than one-third of the Canadian national average (274 L/day/person), severely compromising personal hygiene and water intake. High-sugar-content beverages were the most common alternative to lack of accessible and affordable potable water, particularly for children. Mental stress due to water insecurity and chronic back and shoulder injuries due to carrying heavy water buckets every day were the commonly encountered adverse health outcomes. CONCLUSIONS: Water insecurity has put the community at risk of multiple serious adverse health outcomes. The scenario is not unique in Canada. There are many remote Indigenous communities facing similar kinds of water insecurity. PMID- 26498674 TI - Alterations in ductus venosus velocity indices in relation to umbilical venous pulsations and perinatal outcome. AB - INTRODUCTION: Abnormal blood velocity in the ductus venosus is more frequently detected than pulsations in the umbilical vein, but both are considered to be indicators of fetal compromise. The aim of this study was to investigate blood flow patterns in the ductus venosus and the association between individual blood velocity ratios and pulsations in the umbilical vein and perinatal outcome. MATERIAL AND METHODS: Retrospective cohort study on Doppler ultrasound examination of ductus venosus and umbilical venous blood velocity in 358 high risk pregnancies. Ductus venosus blood velocity pattern was analyzed for pulsatility index and the following velocity ratios: S/ES, S/a and ES/a (where S is systole, ES is end-systole, and a is atrial contraction). Ductus venosus ratio z-scores were calculated and related to pulsations in the umbilical vein and adverse perinatal outcome. RESULTS: Systolic ratios in the ductus venosus were less frequently abnormal than ratios taking into account diastolic velocities, particularly at full-term. High S/ES, ES/a ratios and pulsatility index (z-score >2), were all related to presence of pulsations in the umbilical vein. Umbilical venous pulsations were the best indicator of adverse perinatal outcome. CONCLUSIONS: Changes in ductus venosus blood flow during systole occur more rarely than diastolic changes, and alterations in end-diastolic blood velocity in the ductus venosus might give false-positive indications of worsening fetal condition. Umbilical venous pulsations seem to better predict adverse outcome of pregnancy than do indices in the ductus venosus. PMID- 26498675 TI - Association of TLR2 S450S and ICAM1 K469E polymorphisms with polycystic ovary syndrome (PCOS) and obesity. AB - Toll-like receptors (TLRs) are activated by inflammatory stimuli and influence endothelial functions, contributing to the pathogenesis of atherosclerosis. We investigate the influence of polymorphisms in the genes encoding toll-like receptor 2 (TLR2) and 4 (TLR4) and endothelial adhesion molecules on polycystic ovary syndrome (PCOS) and its interaction with obesity. Ten single nucleotide polymorphisms were genotyped in 305 women with PCOS and 166 non-hyperandrogenic control women. In obese women, TLR2 S450S and ICAM1 K469E polymorphisms differently influenced metabolic variables and PCOS, respectively. Irrespective of PCOS, variant alleles of TLR2 S450S increased triglycerides, fasting insulin levels, and insulin resistance in obese women. TLR2 S450S interacted with obesity and PCOS on androstenedione levels, mutant alleles were associated with increased androstenedione concentrations in all women, with the exception of obese patients with PCOS (P=0.034). Regarding ICAM1 K469E, homozygosis for K469 alleles was more frequent in PCOS, but only in obese women (P=0.014). K469 alleles were also related to increased body mass index (P=0.017) and diastolic blood pressure (P=0.034). Moreover, ICAM1 K469E interacted with obesity and PCOS on serum triglyceride levels (P=0.019) and with PCOS on serum sex hormone-binding globulin concentrations (P=0.006). In conclusion, TLR2 S450S and ICAM1 K469E polymorphisms may be associated with PCOS and metabolic comorbidities in obese women. PMID- 26498676 TI - Corrigendum: identification of a novel actin-dependent signal transducing module allows for the targeted degradation of GLI1. PMID- 26498678 TI - Dynamic configuration of reduced graphene oxide in aqueous dispersion and its effect on thin film properties. AB - The dynamic configuration of reduced graphene oxide (rGO) in an aqueous dispersion is revealed by several characterization methods, showing a spontaneous and seemingly irreversible configuration transition from flat to highly corrugated sheets over time. Such dynamic behaviour of rGO leads to a tailored porous structure of graphene-based thin films. This affects their permeation and electrochemical properties, as well as future industry adoption of graphene. PMID- 26498677 TI - Promoter-like epigenetic signatures in exons displaying cell type-specific splicing. AB - BACKGROUND: Pre-mRNA splicing occurs mainly co-transcriptionally, and both nucleosome density and histone modifications have been proposed to play a role in splice site recognition and regulation. However, the extent and mechanisms behind this interplay remain poorly understood. RESULTS: We use transcriptomic and epigenomic data generated by the ENCODE project to investigate the association between chromatin structure and alternative splicing. We find a strong and significant positive association between H3K9ac, H3K27ac, H3K4me3, epigenetic marks characteristic of active promoters, and exon inclusion in a small but well defined class of exons, representing approximately 4 % of all regulated exons. These exons are systematically maintained at comparatively low levels of inclusion across cell types, but their inclusion is significantly enhanced in particular cell types when in physical proximity to active promoters. CONCLUSION: Histone modifications and other chromatin features that activate transcription can be co-opted to participate in the regulation of the splicing of exons that are in physical proximity to promoter regions. PMID- 26498679 TI - Radiotherapy in Gorlin Syndrome: Can It Be Safe and Effective in Adult Patients? AB - Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is a rare autosomal dominant disorder with multiple manifestations including early onset of cutaneous basal cell carcinomas (BCCs). Radiotherapy has traditionally been contraindicated due to reports of BCC induction. We describe here a patient treated successfully with radiotherapy with no tumour induction at 57 months of follow-up. A comprehensive literature review of radiotherapy outcomes in patients with Gorlin syndrome suggests radiotherapy may be a feasible treatment option for adult patients with treatment refractory lesions or surgical contraindication. PMID- 26498680 TI - CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma. AB - Oscillations in intracellular Ca2+ concentrations ([Ca2+]i) mediate various cellular function. Although it is known that [Ca2+]i oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca2+]i oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca2+]i oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca2+]i oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca2+ release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca2+]i oscillations. Furthermore, CD147 accelerates ER Ca2+refilling and enhances the frequency of [Ca2+]i oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147 promoted ER Ca2+ release and refilling are tightly regulated by changing [Ca2+]i. CD147 may activate IP3R1 channel under low [Ca2+]i conditions and CD147 may activate SERCA pump under high [Ca2+]i conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca2+]i oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca2+]i oscillations to promote oncogenic progression in HCC. PMID- 26498681 TI - Tunicamycin enhances the antitumor activity of trastuzumab on breast cancer in vitro and in vivo. AB - Trastuzumab, a humanized monoclonal antibody targeting HER2, has demonstrated clinical benefits for women with HER2-positive breast cancer; however, trastuzumab resistance remains the biggest clinical challenge. In this study, results showed that tunicamycin, an inhibitor of N-glycosylation, synergistically enhanced the antitumor activity of trastuzumab against HER2-overexpressing breast cancer cells through induction of cell cycle arrest and apoptosis. Combined treatment of tunicamycin with trastuzumab dramatically decreased the expression of EGFR family and its down signaling pathway in SKBR3 and MCF-7/HER2 cells. Tunicamycin dose-dependently inhibited tumor growth in both of SKBR3 xenografts and MCF-7/HER2 xenografts. Optimal tunicamycin without inducing ER stress in liver tissue significantly increased the antitumor effect of trastuzumab in MCF 7/HER2 xenografts. Combinations of trastuzumab with N-glycosylation inhibitors tunicamycin may be a promising approach for improving clinical efficacy of trastuzumab. PMID- 26498682 TI - MiR-652 inhibits acidic microenvironment-induced epithelial-mesenchymal transition of pancreatic cancer cells by targeting ZEB1. AB - Recent evidences suggest that the acidic microenvironment might facilitate epithelial mesenchymal transition (EMT) of tumor cells, while the effects of acidity on EMT of pancreatic cancer (PC) remain undefined. The present study demonstrated that acidity suppressed miR-652 expression, which further promoted EMT process by absenting inhibition on the transcriptional factor ZEB1 expression. At first, we found that acidity remarkably enhanced invasion ability of PC cells accompanying with increased mesenchymal and decreased epithelial markers. Meanwhile, miRNAs-microarray showed that miR-652, the potential regulator of ZEB1, was distinctly decreased in acidity-treated PC cells. Furthermore, restoration of miR-652 reversed acidity-induced EMT by inhibiting ZEB1 expression, while miR-652 inhibitor induced EMT in normal PC cells through promoting ZEB1 expression. Nevertheless, knockdown of ZEB1 significantly suppressed acidity-induced EMT in PC cells, but ZEB1 overexpression rescued the EMT which was inhibited by miR-652 overexpression. The in vivo results showed that the tumor growth and liver metastasis were remarkably retarded by both miR 652 overexpression and ZEB1 knockdown. The clinical samples further revealed that miR-652 was decreased in PC tissues and antagonistically correlated with ZEB1 expression, associating with late tumor stage, lymphatic invasion and metastasis. In conclusion, our study indicated a novel acidity/miR-652/ZEB1/EMT axis in the tumorigenesis of PC. PMID- 26498683 TI - Three-dimensional structure discrepancy between HLA alleles for effective prediction of aGVHD severity and optimal selection of recipient-donor pairs: a proof-of-concept study. AB - The optimal selection of recipient-donor pair and accurate prediction of acute graft-versus-host disease (aGVHD) severity are always the two most crucial works in allogeneic hematopoietic stem cell transplantation (allo-HSCT), which currently rests mostly with HLA compatibility, the most polymorphic loci in the human genome, in clinic. Thus, there is an urgent need for a rapid and reliable quantitative system for optimal recipient-donor pairs selection and accurate prediction of aGVHD severity prior to allo-HSCT. For these reasons, we have developed a new selection/prediction system for optimal recipient-donor selection and effective prediction of aGVHD severity based on HLA three-dimensional (3D) structure modeling (HLA-TDSM) discrepancy, and applied this system in a pilot randomized clinical allo-HSCT study. The 37 patient-donor pairs in the study were typed at low- and high-resolution levels for HLA-A/-B/-DRB1/-DQB1 loci. HLA-TDSM system covering the 10000 alleles in HLA class I and II consists of the revised local and coordinate root-mean-square deviation (RMSD) values for each locus. Its accuracy and reliability were confirmed using stably transfected Hmy2.CIR-HLA-B cells, TCR Vbeta gene scan, and antigen-specific alloreactive cytotoxic lymphocytes. Based on the preliminary results, we theoretically defined all HLA acceptable versus unacceptable mismatched alleles. More importantly, HLA-TDSM enabled a successful retrospective verification and prospective prediction for aGVHD severity in a pilot randomized clinical allo-HSCT study of 32 recipient donor transplant pairs. There was a strong direct correlation between single/total revised RMSD and aGVHD severity (92% in retrospective group vs 95% in prospective group). These results seem to be closely related to the 3D structure discrepancy of mismatched HLA-alleles, but not the number or loci of mismatched HLA-alleles. Our data first provide the proof-of-concept that HLA-TDSM is essential for optimal selection of recipient-donor pairs and effective prediction of aGVHD severity before allo-HSCT. PMID- 26498684 TI - The 5'-untranslated region of p16INK4a melanoma tumor suppressor acts as a cellular IRES, controlling mRNA translation under hypoxia through YBX1 binding. AB - CDKN2A/p16INK4a is an essential tumor suppressor gene that controls cell cycle progression and replicative senescence. It is also the main melanoma susceptibility gene. Here we report that p16INK4a 5'UTR mRNA acts as a cellular Internal Ribosome Entry Site (IRES). The potential for p16INK4a 5'UTR to drive cap-independent translation was evaluated by dual-luciferase assays using bicistronic and monocistronic vectors. Results of reporters' relative activities coupled to control analyses for actual bicistronic mRNA transcription, indicated that the wild type p16INK4a 5'UTR could stimulate cap-independent translation. Notably, hypoxic stress and the treatment with mTOR inhibitors enhanced the translation-stimulating property of p16INK4a 5'UTR. RNA immunoprecipitation performed in melanoma-derived SK-Mel-28 and in a patient-derived lymphoblastoid cell line indicated that YBX1 can bind the wild type p16INK4a mRNA increasing its translation efficiency, particularly during hypoxic stress. Modulation of YBX1 expression further supported its involvement in cap-independent translation of the wild type p16INK4a but not a c.-42T>A variant. RNA SHAPE assays revealed local flexibility changes for the c.-42T>A variant at the predicted YBX1 binding site region. Our results indicate that p16INK4a 5'UTR contains a cellular IRES that can enhance mRNA translation efficiency, in part through YBX1. PMID- 26498685 TI - Practice of traditional Chinese medicine for psycho-behavioral intervention improves quality of life in cancer patients: A systematic review and meta analysis. AB - BACKGROUND: Cancer patients suffer from diverse symptoms, including depression, anxiety, pain, and fatigue and lower quality of life (QoL) during disease progression. This study aimed to evaluate the benefits of Traditional Chinese Medicine psycho-behavioral interventions (TCM PBIs) on improving QoL by meta analysis. RESULTS: The six TCM PBIs analyzed were acupuncture, Chinese massage, Traditional Chinese Medicine five elements musical intervention (TCM FEMI), Traditional Chinese Medicine dietary supplement (TCM DS), Qigong and Tai Chi. Although both TCM PBIs and non-TCM PBIs reduced functional impairments in cancer patients and led to pain relief, depression remission, reduced time to flatulence following surgery and sleep improvement, TCM PBIs showed more beneficial effects as assessed by reducing both fatigue and gastrointestinal distress. In particular, acupuncture relieved fatigue, reduced diarrhea and decreased time to flatulence after surgery in cancer patients, while therapeutic Chinese massage reduced time to flatulence and time to peristaltic sound. METHODS: Electronic literature databases (PubMed, CNKI, VIP, and Wanfang) were searched for randomized, controlled trials conducted in China. The primary intervention was TCM PBIs. The main outcome was health-related QoL (HR QoL) post-treatment. We applied standard meta analytic techniques to analyze data from papers that reached acceptable criteria. CONCLUSION: These findings demonstrate the efficacy of TCM PBIs in improving QoL in cancer patients and establish that TCM PBIs represent beneficial adjunctive therapies for cancer patients. PMID- 26498686 TI - Prostaglandins induce early growth response 1 transcription factor mediated microsomal prostaglandin E2 synthase up-regulation for colorectal cancer progression. AB - Cyclooxygenase2 (COX2) has been associated with cell growth, invasiveness, tumor progression and metastasis of colorectal carcinomas. However, the downstream prostaglandin (PG)-PG receptor pathway involved in these effects is poorly characterized.We studied the PG-pathway in gene expression databases and we found that PTGS2 (prostaglandin G/H synthase and cyclooxygenase) and PTGES (prostaglandin E synthase) are co-expressed in human colorectal tumors. Moreover, we detected that COX2 and microsomal Prostaglandin E2 synthase 1 (mPGES1) proteins are both up-regulated in colorectal human tumor biopsies.Using colon carcinoma cell cultures we found that COX2 overexpression significantly increased mPGES1 mRNA and protein. This up-regulation was due to an increase in early growth response 1 (EGR1) levels and its transcriptional activity. EGR1 was induced by COX2-generated PGF2alpha. A PGF2alpha receptor antagonist, or EGR1 silencing, inhibited the mPGES1 induction by COX2 overexpression. Moreover, using immunodeficient mice, we also demonstrated that both COX2- and mPGES1 overexpressing carcinoma cells were more efficient forming tumors.Our results describe for the first time the molecular pathway correlating PTGS2 and PTGES in colon cancer progression. We demonstrated that in this pathway mPGES1 is induced by COX2 overexpression, via autocrine PGs release, likely PGF2alpha, through an EGR1-dependent mechanism. This signaling provides a molecular explanation to PTGS2 and PTGES association and contribute to colon cancer advance, pointing out novel potential therapeutic targets in this oncological context. PMID- 26498687 TI - Myeloma cells can corrupt senescent mesenchymal stromal cells and impair their anti-tumor activity. AB - Senescent cells secrete several molecules that help to prevent the progression of cancer. However, cancer cells can also misuse these secreted elements to survive and grow. Since the molecular and functional bases of these different elements remain poorly understood, we analyzed the effect of senescent mesenchymal stromal cell (MSC) secretome on the biology of ARH-77 myeloma cells. In addition to differentiating in mesodermal derivatives, MSCs have sustained interest among researchers by supporting hematopoiesis, contributing to tissue homeostasis, and modulating inflammatory response, all activities accomplished primarily by the secretion of cytokines and growth factors. Moreover, senescence profoundly affects the composition of MSC secretome. In this study, we induced MSC senescence by oxidative stress, DNA damage, and replicative exhaustion. While the first two are considered to induce acute senescence, extensive proliferation triggers replicative (i.e., chronic) senescence. We cultivated cancer cells in the presence of acute and chronic senescent MSC-conditioned media and evaluated their proliferation, DNA damage, apoptosis, and senescence. Our findings revealed that senescent secretomes induced apoptosis or senescence, if not both, to different extents. This anti-tumor activity became heavily impaired when secretomes were collected from senescent cells previously in contact (i.e., primed) with cancer cells. Our analysis of senescent MSC secretomes with LC-MS/MS followed by Gene Ontology classification further indicated that priming with cancer profoundly affected secretome composition by abrogating the production of pro-senescent and apoptotic factors. We thus showed for the first time that compared with cancer-primed MSCs, naive senescent MSCs can exert different effects on tumor progression. PMID- 26498688 TI - PIK3CA mutation detection in metastatic biliary cancer using cell-free DNA. AB - PIK3CA mutation is considered a good candidate for targeted therapies in cancers, especially biliary tract cancer (BTC). We evaluated the utility of cell free DNA (cfDNA) from serum by using droplet digital PCR (ddPCR) as an alternative source for PIK3CA mutation analysis. To identify matching archival tumour specimens from serum samples of advanced BTC patients, mutation detection using ddPCR with Bio Rad's PrimePCR mutation and wild type assays were performed for PIK3CA p.E542K, p.E545K, and p.H1047R. Thirty-eight patients with metastatic BTC were enrolled. Only one (BTC 29T) sample (n = 38) was positive for PIK3CA p.E542K and another (BTC 27T) for p.H1047R mutation; none was positive for PIK3CA p.E545K. Matched serum sample (BTC 29P) was positive for PIK3CA p.E542K with 28 mutant copies detected, corresponding to 48 copies/ml of serum and an allelic prevalence of 0.3%. Another matched serum sample (BTC 27P) was positive for PIK3CA p.H1047R with 10 mutant copies detected, i.e. 18 copies/ml and an allelic frequency of 0.2%. High correlation was noted in the PIK3CA mutation status between tumour gDNA and serum cfDNA. Low-level PIK3CA mutations were detectable in the serum indicating the utility of cfDNA as a DNA source to detect cancer-derived mutations in metastatic biliary cancers. PMID- 26498690 TI - Frizzled-7 promoter is highly active in tumors and promoter-driven Shiga-like toxin I inhibits hepatocellular carcinoma growth. AB - Frizzled-7 protein plays a significant role in the formation of several malignant tumors. Up regulation of the Frizzled-7 in cancer cell lines is associated with nuclear accumulation of wild-type beta-catenin from the Wnt/beta-catenin pathway which is frequently activated in tumors. To analyze activity of the Frizzled-7 promoter in tumor cells, we constructed two recombinant plasmid vectors in which the Frizzled-7 promoter was used to drive the expression of green fluorescent protein (GFP) and Shiga-like toxin I (Stx1) (pFZD7-GFP/Stx1) genes. The Frizzled 7 protein was found to be expressed in the cancer cell lines but not in the normal cell lines. The GFP expression was restricted to the cancer cell lines and xenografts in the BALB/C mice but not to normal cell lines. Moreover, cell proliferation and tumor growth decreased significantly after transfection with the pFZD7-Stx1. Results from this study will help determine a highly effective strategy for gene therapy of tumors. PMID- 26498689 TI - Key contribution of eIF4H-mediated translational control in tumor promotion. AB - Dysregulated expression of translation initiation factors has been associated with carcinogenesis, but underlying mechanisms remains to be fully understood. Here we show that eIF4H (eukaryotic translation initiation factor 4H), an activator of the RNA helicase eIF4A, is overexpressed in lung carcinomas and predictive of response to chemotherapy. In lung cancer cells, depletion of eIF4H enhances sensitization to chemotherapy, decreases cell migration and inhibits tumor growth in vivo, in association with reduced translation of mRNA encoding cell-proliferation (c-Myc, cyclin D1) angiogenic (FGF-2) and anti-apoptotic factors (CIAP-1, BCL-xL). Conversely, each isoform of eIF4H acts as an oncogene in NIH3T3 cells by stimulating transformation, invasion, tumor growth and resistance to drug-induced apoptosis together with increased translation of IRES containing or structured 5'UTR mRNAs. These results demonstrate that eIF4H plays a crucial role in translational control and can promote cellular transformation by preferentially regulating the translation of potent growth and survival factor mRNAs, indicating that eIF4H is a promising new molecular target for cancer therapy. PMID- 26498691 TI - SF3A1 and pancreatic cancer: new evidence for the association of the spliceosome and cancer. AB - A two-stage case-control study was conducted to examine the association between six candidate U2-depedent spliceosome genes (SRSF1, SRSF2, SF3A1, SF3B1, SF1 and PRPF40B) and pancreatic cancer (PC). Subjects with one or two T alleles at rs2074733 in SF3A1 had a lower risk of PC compared to those with two C alleles in combined two populations (OR: 0.59, 95% confidence interval: 0.48-0.73, False discovery rate (FDR)-P = 1.5E-05). Moreover, the presence of the higher-risk genotype at rs2074733 plus smoking or drinking had synergic effects on PC risk. These findings illustrate that RNA splicing-related genes appear to be associated with the occurrence of PC, and show synergic interactions with smoking and drinking in the additive model. In the future, our novel findings should be further confirmed by functional studies and independent large-scale population studies. PMID- 26498692 TI - miR-149 represses metastasis of hepatocellular carcinoma by targeting actin regulatory proteins PPM1F. AB - microRNAs have been implicated in hepatocellular carcinoma (HCC) metastasis, which is predominant cause of high mortality in these patients. Although an increasing body of evidence indicates that miR-149 plays an important role in the growth and metastasis of multiple types of cancers, its role in the progression of HCC remains unknown. Here, we demonstrated that miR-149 was significantly down regulated in HCC, which was correlated with distant metastasis and TNM stage with statistical significance. A survival analysis showed that decreased miR-149 expression was correlated with a poor prognosis of HCC as well. We found that over-expression of miR-149 suppressed migration and invasion of HCC cells in vitro. In addition, we identified PPM1F (protein phosphatase, Mg(2+)/Mn(2+) dependent, 1F) as a direct target of miR-149 whose expression was negatively correlated with the expression of miR-149 in HCC tissues. The re-expression of PPM1F rescued the miR-149-mediated inhibition of cell migration and invasion. miR 149 regulated formation of stress fibers to inhibit migration, and re-expression of PPM1F reverted the miR-149-mediated loss of stress fibers. Moreover, we demonstrated that over-expression of miR-149 reduced pMLC2, a downstream effector of PPM1F, in MHCC-97H cells. In vivo studies confirm inhibition of HCC metastasis by miR-149. Taken together, our findings indicates that miR-149 is a potential prognostic biomarker of HCC and that the miR-149/PPM1F regulatory axis represents a novel therapeutic target for HCC treatment. PMID- 26498693 TI - Downregulation of RPL15 may predict poor survival and associate with tumor progression in pancreatic ductal adenocarcinoma. AB - Early diagnosis and treatment in pancreatic ductal adenocarcinoma (PDAC) is still a challenge worldwide. The poor survival of PDAC patients mainly due to early metastasis when first diagnosed and lack of prognostic biomarker. Ribosomal protein L15 (RPL15), an RNA-binding protein, is a component of ribosomal 60S subunit. It was reported that RPL15 is dysregulated in various type of cancers. However, little is known about the role of RPL15 in PDAC carcinogenesis and progression. Herein, we clarified RPL15 expression status may serve as an independent prognostic biomarker in three independent PDAC patient cohorts. We found that RPL15 was dramatically decreased in PDAC tissues and cell lines. The high expression of RPL15 was inversely correlated with TNM stage, histological differentiation, T classification and vascular invasion. Low expression of RPL15 was significantly associated with poor overall survival of PDAC patients. Furthermore, we demonstrated that the reduction of RPL15 may promote invasion ability of pancreatic cell by inducing EMT process. In conclusion, decreased RPL15 expression is associated with invasiveness of PDAC cells, and RPL15 expression status may serve as a reliable prognostic biomarker in PDAC patients. PMID- 26498694 TI - In-situ characterization of nanoparticle beams focused with an aerodynamic lens by Laser-Induced Breakdown Detection. AB - The Laser-Induced Breakdown Detection technique (LIBD) was adapted to achieve fast in-situ characterization of nanoparticle beams focused under vacuum by an aerodynamic lens. The method employs a tightly focused, 21 MUm, scanning laser microprobe which generates a local plasma induced by the laser interaction with a single particle. A counting mode optical detection allows the achievement of 2D mappings of the nanoparticle beams with a reduced analysis time thanks to the use of a high repetition rate infrared pulsed laser. As an example, the results obtained with Tryptophan nanoparticles are presented and the advantages of this method over existing ones are discussed. PMID- 26498695 TI - Molecular characterization of antitumor effects of the rhizome extract from Curcuma zedoaria on human esophageal carcinoma cells. AB - Curcuma zedoaria has been used as a traditional agent against malignant diseases. To elucidate detailed mechanisms producing such an activity, characterization and determination of molecular mechanisms of its antitumor effects was conducted. Inhibiting activities against cell proliferation, invasion and colony formation, and expression levels of corresponding molecules were investigated using human esophageal cancer TE-8 cells treated with the rhizome extract from C. zedoaria. Antitumor effect of the extract administered orally was also examined in tumor bearing mice. The extract possessed strong anti-proliferation and invasion activities against TE-8 cells. Further, upregulated PTEN and downregulated phosphorylated Akt, mTOR and STAT3 expressions in the cells were induced shortly after treatment with the extract, followed by attenuation of FGFR1 and MMP-2, activation of caspase-9, caspase-3 and PARP, and suppression of Bcl-2 expressions, which led the cells to apoptotic cell death. Furthermore, tumor formation in mice was significantly suppressed through the oral administration of the extract. Taken together, these results suggest that the C. zedoaria extract could be a promising agent against esophageal cancer. PMID- 26498696 TI - ST-Segment Elevation With Exercise. PMID- 26498698 TI - Experimental and Mechanistic Understanding of Aldehyde Hydrogenation Using Au25 Nanoclusters with Lewis Acids: Unique Sites for Catalytic Reactions. AB - The catalytic activity of Au25(SR)18 nanoclusters (R = C2H4Ph) for the aldehyde hydrogenation reaction in the presence of a base, e.g., ammonia or pyridine, and transition-metal ions M(z+), such as Cu(+), Cu(2+), Ni(2+) and Co(2+), as a Lewis acid is studied. The addition of a Lewis acid is found to significantly promote the catalytic activity of Au25(SR)18/CeO2 in the hydrogenation of benzaldehyde and a number of its derivatives. Matrix-assisted laser desorption ionization (MALDI) and electrospray ionization (ESI) mass spectrometry in conjunction with UV-vis spectroscopy confirm the generation of new species, Au25-n(SR)18-n (n = 1 4), in the presence of a Lewis acid. The pathways for the speciation of Au24(SR)17 from its parent Au25(SR)18 nanocluster as well as its structure are investigated via the density functional theory (DFT) method. The adsorption of M(z+) onto a thiolate ligand "-SR-" of Au25(SR)18, followed by a stepwise detachment of "-SR-" and a gold atom bonded to "-SR-" (thus an "Au-SR" unit) is found to be the most likely mechanism for the Au24(SR)17 generation. This in turn exposes the Au13-core of Au24(SR)17 to reactants, providing an active site for the catalytic hydrogenation. DFT calculations indicate that M(z+) is also capable of adsorbing onto the Au13-core surface, producing a possible active metal site of a different kind to catalyze the aldehyde hydrogenation reaction. This study suggests, for the first time, that species with an open metal site like adducts [nanoparticle-M]((z-1)+) or fragments Au25-n(SR)18-n function as the catalysts rather than the intact Au25(SR)18. PMID- 26498699 TI - Preference evaluation and perceived sensory comparison of fluticasone furoate and mometasone furoate intranasal sprays in allergic rhinitis. AB - OBJECTIVE: Intranasal corticosteroid sprays (INCSs) are commonly used for therapy of allergic rhinitis (AR). Adherence to regular use of INCSs is influenced by patient perception and preferences of products. The study objective was to compare perceived sensory attributes of fluticasone furoate nasal spray (FFNS) and mometasone furoate nasal spray (MFNS) in AR patients. METHODS: In a multicenter, randomized, crossover, prospective study, 40 seasonal AR patients were administered both FFNS and MFNS for 2 weeks each in a crossover fashion, for a total of 4 weeks. Patients completed questionnaires for each product regarding perceived sensory attributes at the end of each two-week period of product administration. RESULTS: FFNS was significantly preferred over MFNS. Significantly, fewer subjects perceived a bitter taste (p=0.01), medication running down their throat (p=0.033), and medication running out of their nose (p=0.002) with FFNS. MFNS was more frequently reported to induce nasal irritation (p=0.012), sneezing (p=0.017), and rhinorrhea (p=0.007) compared to FFNS. Interestingly, these findings were markedly observed in females. Medicine dripping out of the nose and nasal shooting were the most common problems reported for MFNS with a higher proportion of subjects who felt moderate-to severe discomfort. Overall, 52.5% of patients expressed a preference for FFNS compared with 22.5% for MFNS. CONCLUSION: Several perceived sensory attributes of FFNS were rated significantly superior to MFNS. FFNS may contribute to enhanced treatment outcomes in AR patients due to improved treatment adherence. PMID- 26498700 TI - Associations between temperament and gene polymorphisms in the brain dopaminergic system and the adrenal gland of sheep. AB - Sheep of calm or nervous temperament differ in their physiological (cortisol secretion) and behavioural (motor activity) responses to stressors, perhaps due to variation in genes that regulate glucocorticoid synthesis or brain dopamine activity. Using ewes that had been selected over 20 generations for nervous (n=58) or calm (n=59) temperament, we confirmed the presence of a polymorphism in a gene specifically involved in cortisol production (CYP17), and identified polymorphisms in three genes specifically associated with personality and behavioural traits: dopamine receptors 2 and 4 (DRD2, DRD4), and monoamine oxidase A (MAOA). The calm and nervous lines differed in their frequencies of CYP17 SNP628 (single nucleotide A-G mutation at position 628) and DRD2 SNP939 (single nucleotide T-C mutation at position 939), but not for other SNPs detected in DRD2 or MAOA. In a second experiment, we then genotyped a large, non-selected flock of ewes for DRD2 SNP939 and CYP17 SNP628. Responses to the 'arena' and 'isolation box' challenges were associated with the DRD2 SNP939 genotype and the response to ACTH challenge was associated with the CYP17 SNP628 genotype. We conclude that, for sheep, a combination of the DRD2 SNP939 C allele and the CYP17 SNP628 A/A genotype could be used as a genetic marker for nervous temperament, and that a combination of DRD2 SNP939 T/T and CYP17 SNP628 G/G could be used as a genetic marker for calm temperament. PMID- 26498697 TI - Operational Definition of Active and Healthy Aging (AHA): The European Innovation Partnership (EIP) on AHA Reference Site Questionnaire: Montpellier October 20-21, 2014, Lisbon July 2, 2015. AB - A core operational definition of active and healthy aging (AHA) is needed to conduct comparisons. A conceptual AHA framework proposed by the European Innovation Partnership on Active and Healthy Ageing Reference Site Network includes several items such as functioning (individual capability and underlying body systems), well-being, activities and participation, and diseases (including noncommunicable diseases, frailty, mental and oral health disorders). The instruments proposed to assess the conceptual framework of AHA have common applicability and availability attributes. The approach includes core and optional domains/instruments depending on the needs and the questions. A major common domain is function, as measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). WHODAS 2.0 can be used across all diseases and healthy individuals. It covers many of the AHA dimensions proposed by the Reference Site network. However, WHODAS 2.0 does not include all dimensions proposed for AHA assessment. The second common domain is health related quality of life (HRQoL). A report of the AHA questionnaire in the form of a spider net has been proposed to facilitate usual comparisons across individuals and groups of interest. PMID- 26498701 TI - The influence of social capital on employers' use of occupational health services: a qualitative study. AB - BACKGROUND: Occupational health services may have a strategic role in the prevention of sickness absence, as well as in rehabilitation and return to work after sick leave, because of their medical expertise in combination with a close connection to workplaces. The purpose of this study was to explore how employers and occupational health service providers describe their business relations and the use of occupational health services in rehabilitation in relation to the organization of such services. The study uses a theoretical framework based on social capital to analyse the findings. METHODS: Interviews and focus groups with managers with Swedish public employers (n = 60), and interviews with occupational health services professionals (n = 25). RESULTS: Employers emphasized trustful relationships, local workplace knowledge, long-term contracts and dialogue about services for good relationships with occupational health providers. Occupational health providers strove to be strategic partners to employers, promoting preventive work, which was more easily achieved in situations where the services were organized in-house. Employers with outsourced occupational health services expressed less trust in their providers than employers with internal occupational health provision. CONCLUSIONS: Social capital emerges as central to understanding the conditions for cooperation and collective action in the use of occupational health services, with reference to structural (e.g. contracts), relational (e.g. trust) as well as cognitive (e.g. shared vision) dimensions. The study suggests that attention to the quality of relationships is imperative for developing purposeful occupational health service delivery in rehabilitation and return to work. PMID- 26498702 TI - Relative and absolute reliability of measures of linoleic acid-derived oxylipins in human plasma. AB - Modern analytical techniques allow for the measurement of oxylipins derived from linoleic acid in biological samples. Most validatory work has concerned extraction techniques, repeated analysis of aliquots from the same biological sample, and the influence of external factors such as diet and heparin treatment upon their levels, whereas less is known about the relative and absolute reliability of measurements undertaken on different days. A cohort of nineteen healthy males were used, where samples were taken at the same time of day on two occasions, at least 7 days apart. Relative reliability was assessed using Lin's concordance correlation coefficients (CCC) and intraclass correlation coefficients (ICC). Absolute reliability was assessed by Bland-Altman analyses. Nine linoleic acid oxylipins were investigated. ICC and CCC values ranged from acceptable (0.56 [13-HODE]) to poor (near zero [9(10)- and 12(13)-EpOME]). Bland Altman limits of agreement were in general quite wide, ranging from +/-0.5 (12,13 DiHOME) to +/-2 (9(10)-EpOME; log10 scale). It is concluded that relative reliability of linoleic acid-derived oxylipins varies between lipids with compounds such as the HODEs showing better relative reliability than compounds such as the EpOMEs. These differences should be kept in mind when designing and interpreting experiments correlating plasma levels of these lipids with factors such as age, body mass index, rating scales etc. PMID- 26498704 TI - Determination of the thermodynamic activities of LiF and ThF4 in the Li(x)Th(1 x)F(4-3x) liquid solution by Knudsen effusion mass spectrometry. AB - Knudsen effusion mass spectrometry (KEMS) has been used to investigate the vapour pressure over the molten LiF-ThF4 salt and determine the thermodynamic activity of LiF and ThF4 in the liquid solution. As part of the study, the vaporization of pure LiF and pure ThF4 was examined and the results were compared with the literature values finding a good agreement. Next, the vapour pressure of the LixTh1-xF4-3x liquid solution was investigated by measuring four samples having different compositions (XLiF~ 0.2, 0.4, 0.6, 0.8 mol%). In order to determine the thermodynamic activities, the vapour pressure of LiF and ThF4 species over the liquid solution, as calculated from our results, were compared with the vapour pressure over the pure LiF(l) and pure ThF4(l) systems. A strong deviation from the Raoult's law was observed, more evident in case of LiF species, in agreement with the predictions by our thermodynamic model. PMID- 26498703 TI - Decreasing Clostridium difficile health care-associated infections through use of a launderable mattress cover. AB - BACKGROUND: The annual incidence of Clostridium difficile infection (CDI) in the United States is estimated to be 330,000 cases. We evaluated the impact of using a launderable mattress and bed deck cover on the incidence of hospital-onset CDI in 2 long-term acute care hospitals (LTACHs). METHODS: Two LTACHs began using a launderable mattress and bed deck cover on beds starting in May 2013. One facility had 74 beds, and the other had 30 beds. Covers were changed after every patient. The covers were laundered using hot water, detergent, and chlorine. Rates for CDIs were compared using Poisson regression between the 16 months before use of the launderable cover and the 14 months after the cover started being used. RESULTS: At hospital A, the use of bedcovers reduced the rate of infection by 47.8% (95% confidence interval [CI], 47.1-48.6), controlling for the rate of handwashing compliance and length of stay in days. At hospital B, the use of bedcovers reduced the rate of infection by 50% (95% CI, 47.5-52.7), controlling for the rate of handwashing compliance and length of stay in days. CONCLUSION: The use of a launderable cover for mattresses and bed decks of hospital beds was associated with a decreased rate of health care-associated CDI in 2 LTACHs. PMID- 26498705 TI - Universal access to medicines. PMID- 26498707 TI - Pyogenic granuloma-like Kaposi's sarcoma. PMID- 26498708 TI - Reduced lymphocyte count as an early marker for predicting infected pancreatic necrosis. AB - BACKGROUND: Early occurrence of immunosuppression is a risk factor for infected pancreatic necrosis (IPN) in the patients with acute pancreatitis (AP). However, current measures for the immune systems are too cumbersome and not widely available. Significantly decreased lymphocyte count has been shown in patients with severe but not mild type of AP. Whereas, the correlation between the absolute lymphocyte count and IPN is still unknown. We conduct this study to reveal the exact relationship between early lymphocyte count and the development of IPN in the population of AP patients. METHODS: One hundred and fifty-three patients with acute pancreatitis admitted to Jinling Hospital during the period of January 2012 to July 2014 were included in this retrospective study. The absolute lymphocyte count and other relevant parameters were measured on admission. The diagnosis of IPN was based on the definition of the revised Atlanta classification. RESULTS: Patients were divided into two groups according to the presence of IPN. Thirty patients developed infected necrotizing pancreatitis during the disease course. The absolute lymphocyte count in patients with IPN was significantly lower on admission (0.62 * 10(9)/L, interquartile range [IQR]: 0.46-0.87 * 10(9)/L vs. 0.91 * 10(9)/L, IQR: 0.72-1.27 * 10(9)/L, p < 0.001) and throughout the whole clinical course than those without IPN. Logistic regression indicated that reduced lymphocyte count was an independent risk factor for IPN. The optimal cut-offs from ROC curve was 0.66 * 10(9)/L giving sensitivity of 83.7 % and specificity of 66.7 %. CONCLUSIONS: Reduced lymphocyte count within 48 h of AP onset is significantly and independently associated with the development of IPN. PMID- 26498709 TI - Snail-induced EMT promotes cancer stem cell-like properties in head and neck cancer cells. AB - Epithelial-mesenchymal transition (EMT) is a key process involved in the invasion and metastasis of cancer cells. Furthermore, EMT can induce a cancer stem cell (CSC)-like phenotype in a number of tumor types. We demonstrated that Snail is one of the master regulators that promotes EMT and mediates cancer cell migration and invasion in many types of malignancies including head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated the role of Snail in inducing and maintaining CSC-like properties through EMT in HNSCC. We established HNSCC cell lines transfected with Snail. Stem cell markers were evaluated with real-time RT-PCR and western blot analysis. CSC properties were assessed using sphere formation and WST-8 assays as well as chemosensitivity and chick chorioallantoic membrane in vivo invasion assays. Introduction of Snail induced EMT properties in HNSCC cells. Moreover, Snail-induced EMT maintained the CSC like phenotype, and enhanced sphere formation capability, chemoresistance and invasive ability. These data suggest that Snail could be one of the critical molecular targets for the development of therapeutic strategies for HNSCC. PMID- 26498710 TI - Reactive oxygen species: Reactions and detection from photosynthetic tissues. AB - Reactive oxygen species (ROS) have long been recognized as compounds with dual roles. They cause cellular damage by reacting with biomolecules but they also function as agents of cellular signaling. Several different oxygen-containing compounds are classified as ROS because they react, at least with certain partners, more rapidly than ground-state molecular oxygen or because they are known to have biological effects. The present review describes the typical reactions of the most important ROS. The reactions are the basis for both the detection methods and for prediction of reactions between ROS and biomolecules. Chemical and physical methods used for detection, visualization and quantification of ROS from plants, algae and cyanobacteria will be reviewed. The main focus will be on photosynthetic tissues, and limitations of the methods will be discussed. PMID- 26498711 TI - Cryo-imaging of photosystems and phycobilisomes in Anabaena sp. PCC 7120 cells. AB - Primary photosynthetic reactions take place inside thylakoid membrane where light to-chemical energy conversion is catalyzed by two pigment-protein complexes, photosystem I (PSI) and photosystem II (PSII). Light absorption in cyanobacteria is increased by pigment-protein supercomplexes--phycobilisomes (PBSs) situated on thylakoid membrane surfaces that transfer excitation energy into both photosystems. We have explored the localization of PSI, PSII and PBSs in thylakoid membrane of native cyanobacteria cell Anabaena sp. 7120 by means of cryogenic confocal microscopy. We have adapted a conventional temperature controlling stage to an Olympus FV1000 confocal microscope. The presence of red shifted emission of chlorophylls from PSI has been confirmed by spectral measurements. Confocal fluorescence images of PSI (in a spectral range 710-750 nm), PSII (in a spectral range 690-705 nm) and PBSs (in a spectral range 650-680 nm) were recorded at low temperature. Co-localization of images showed spatial heterogeneity of PSI, PSII and PBSs over the thylakoid membrane, and three dominant areas were identified: PSI-PSII-PBS supercomplex area, PSII-PBS supercomplex area and PSI area. The observed results were discussed with regard to light-harvesting regulation in cyanobacteria. PMID- 26498712 TI - Genetics, sleep and memory: a recall-by-genotype study of ZNF804A variants and sleep neurophysiology. AB - BACKGROUND: Schizophrenia is a complex, polygenic disorder for which over 100 genetic variants have been identified that correlate with diagnosis. However, the biological mechanisms underpinning the different symptom clusters remain undefined. The rs1344706 single nucleotide polymorphism within ZNF804A was among the first genetic variants found to be associated with schizophrenia. Previously, neuroimaging and cognitive studies have revealed several associations between rs1344706 and brain structure and function. The aim of this study is to use a recall-by-genotype (RBG) design to investigate the biological basis for the association of ZNF804A variants with schizophrenia. A RBG study, implemented in a population cohort, will be used to evaluate the impact of genetic variation at rs1344706 on sleep neurophysiology and procedural memory consolidation in healthy participants. METHODS/DESIGN: Participants will be recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) on the basis of genotype at rs1344706 (n = 24). Each participant will be asked to take part in two nights of in-depth sleep monitoring (polysomnography) allowing collection of neurophysiological sleep data in a manner not amenable to large-scale study. Sleep questionnaires will be used to assess general sleep quality and subjective sleep experience after each in-house recording. A motor sequencing task (MST) will be performed before and after the second night of polysomnography. In order to gather additional data about habitual sleep behaviour participants will be asked to wear a wrist worn activity monitor (actiwatch) and complete a sleep diary for two weeks. DISCUSSION: This study will explore the biological function of ZNF804A genotype (rs1344706) in healthy volunteers by examining detailed features of sleep architecture and physiology in relation to motor learning. Using a RBG approach will enable us to collect precise and detailed phenotypic data whilst achieving an informative biological gradient. It would not be feasible to collect such data in the large sample sizes that would be required under a random sampling scheme. By dissecting the role of individual variants associated with schizophrenia in this way, we can begin to unravel the complex genetic mechanisms of psychiatric disorders and pave the way for future development of novel therapeutic approaches. PMID- 26498713 TI - Personal Sound Amplifiers for Adults with Hearing Loss. AB - Age-related hearing loss is highly prevalent and often untreated. Use of hearing aids has been associated with improvements in communication and quality of life, but such treatment is unaffordable or inaccessible for many adults. The purpose of this review is to provide a practical guide for physicians who work with older adults who are experiencing hearing and communication difficulties. Specifically, we review direct-to-consumer amplification products that can be used to address hearing loss in adults. Helping adults with hearing loss navigate hearing loss treatment options ranging from being professionally fitted with hearing aids to using direct-to-consumer amplification options is important for primary care clinicians to understand given our increasing understanding of the impact of hearing loss on cognitive, social, and physical functioning. PMID- 26498714 TI - Negative Secular Trends in Medicine: Summary. PMID- 26498715 TI - Grain Boundary Plane Orientation Fundamental Zones and Structure-Property Relationships. AB - Grain boundary plane orientation is a profoundly important determinant of character in polycrystalline materials that is not well understood. This work demonstrates how boundary plane orientation fundamental zones, which capture the natural crystallographic symmetries of a grain boundary, can be used to establish structure-property relationships. Using the fundamental zone representation, trends in computed energy, excess volume at the grain boundary, and temperature dependent mobility naturally emerge and show a strong dependence on the boundary plane orientation. Analysis of common misorientation axes even suggests broader trends of grain boundary energy as a function of misorientation angle and plane orientation. Due to the strong structure-property relationships that naturally emerge from this work, boundary plane fundamental zones are expected to simplify analysis of both computational and experimental data. This standardized representation has the potential to significantly accelerate research in the topologically complex and vast five-dimensional phase space of grain boundaries. PMID- 26498716 TI - Catheter ablation of atrial fibrillation in patients with diabetes mellitus: a systematic review and meta-analysis. AB - AIMS: Diabetes mellitus (DM) and atrial fibrillation (AF) share pathophysiological links, as supported by the high prevalence of AF within DM patients. Catheter ablation of AF (AFCA) is an established therapeutic option for rhythm control in drug resistant symptomatic patients. Its efficacy and safety among patients with DM is based on small populations, and long-term outcome is unknown. The present systematic review and meta-analysis aims to assess safety and long-term outcome of AFCA in DM patients, focusing on predictors of recurrence. METHODS AND RESULTS: A systematic review was conducted in MEDLINE/PubMed and Cochrane Library. Randomized controlled trials, clinical trials, and observational studies including patients with DM undergoing AFCA were screened and included if matching inclusion and exclusion criteria. Fifteen studies were included, adding up to 1464 patients. Mean follow-up was 27 (20-33) months. Overall complication rate was 3.5 (1.5-5.0)%. Efficacy in maintaining sinus rhythm at follow-up end was 66 (58-73)%. Meta-regression analysis revealed that advanced age (P < 0.001), higher body mass index (P < 0.001), and higher basal glycated haemoglobin level (P < 0.001) related to higher incidence of arrhythmic recurrences. Performing AFCA lead to a reduction of patients requiring treatment with antiarrhythmic drugs (AADs) from 55 (46-74)% at baseline to 29 (17 41)% (P < 0.001) at follow-up end. CONCLUSIONS: Catheter ablation of AF safety and efficacy in DM patients is similar to general population, especially when performed in younger patients with satisfactory glycemic control. Catheter ablation of AF reduces the amount of patients requiring AADs, an additional benefit in this population commonly exposed to adverse effects of AF pharmacological treatments. PMID- 26498717 TI - Ventricular tachycardia originating from the right ventricular outflow tract in a patient with dextrocardia. PMID- 26498718 TI - Current ablation techniques for persistent atrial fibrillation: results of the European Heart Rhythm Association Survey. AB - The aim of this survey was to provide insight into current practice regarding ablation of persistent atrial fibrillation (AF) among members of the European Heart Rhythm Association electrophysiology research network. Thirty centres responded to the survey. The main ablation technique for first-time ablation was stand-alone pulmonary vein isolation (PVI): in 67% of the centres for persistent but not long-standing AF and in 37% of the centres for long-standing persistent AF as well. Other applied techniques were ablation of fractionated electrograms, placement of linear lesions, stepwise approach until AF termination, and substrate mapping and isolation of low-voltage areas. However, the percentage of centres applying these techniques during first ablation did not exceed 25% for any technique. When stand-alone PVI was performed in patients with persistent but not long-standing AF, the majority (80%) of the centres used an irrigated radiofrequency ablation catheter whereas 20% of the respondents used the cryoballoon. Similar results were reported for ablation of long-standing persistent AF (radiofrequency 90%, cryoballoon 10%). Neither rotor mapping nor one-shot ablation tools were used as the main first-time ablation methods. Systematic search for non-pulmonary vein triggers was performed only in 10% of the centres. Most common 1-year success rate off antiarrhythmic drugs was 50-60%. Only 27% of the centres knew their 5-year results. In conclusion, patients with persistent AF represent a significant proportion of AF patients undergoing ablation. There is a shift towards stand-alone PVI being the primary choice in many centres for first-time ablation in these patients. The wide variation in the use of additional techniques and in the choice of endpoints reflects the uncertainties and lack of guidance regarding the most optimal approach. Procedural success rates are modest and long-term outcomes are unknown in most centres. PMID- 26498706 TI - Availability and affordability of cardiovascular disease medicines and their effect on use in high-income, middle-income, and low-income countries: an analysis of the PURE study data. AB - BACKGROUND: WHO has targeted that medicines to prevent recurrent cardiovascular disease be available in 80% of communities and used by 50% of eligible individuals by 2025. We have previously reported that use of these medicines is very low, but now aim to assess how such low use relates to their lack of availability or poor affordability. METHODS: We analysed information about availability and costs of cardiovascular disease medicines (aspirin, beta blockers, angiotensin-converting enzyme inhibitors, and statins) in pharmacies gathered from 596 communities in 18 countries participating in the Prospective Urban Rural Epidemiology (PURE) study. Medicines were considered available if present at the pharmacy when surveyed, and affordable if their combined cost was less than 20% of household capacity-to-pay. We compared results from high-income, upper middle-income, lower middle-income, and low-income countries. Data from India were presented separately given its large, generic pharmaceutical industry. FINDINGS: Communities were recruited between Jan 1, 2003, and Dec 31, 2013. All four cardiovascular disease medicines were available in 61 (95%) of 64 urban and 27 (90%) of 30 rural communities in high-income countries, 53 (80%) of 66 urban and 43 (73%) of 59 rural communities in upper middle-income countries, 69 (62%) of 111 urban and 42 (37%) of 114 rural communities in lower middle-income countries, eight (25%) of 32 urban and one (3%) of 30 rural communities in low income countries (excluding India), and 34 (89%) of 38 urban and 42 (81%) of 52 rural communities in India. The four cardiovascular disease medicines were potentially unaffordable for 0.14% of households in high-income countries (14 of 9934 households), 25% of upper middle-income countries (6299 of 24,776), 33% of lower middle-income countries (13,253 of 40,023), 60% of low-income countries (excluding India; 1976 of 3312), and 59% households in India (9939 of 16,874). In low-income and middle-income countries, patients with previous cardiovascular disease were less likely to use all four medicines if fewer than four were available (odds ratio [OR] 0.16, 95% CI 0.04-0.57). In communities in which all four medicines were available, patients were less likely to use medicines if the household potentially could not afford them (0.16, 0.04-0.55). INTERPRETATION: Secondary prevention medicines are unavailable and unaffordable for a large proportion of communities and households in upper middle-income, lower middle income, and low-income countries, which have very low use of these medicines. Improvements to the availability and affordability of key medicines is likely to enhance their use and help towards achieving WHO's targets of 50% use of key medicines by 2025. FUNDING: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries. PMID- 26498719 TI - Regulation of human (adrenal) androgen biosynthesis-New insights from novel throughput technology studies. AB - Androgens are precursors for sex steroids and are predominantly produced in the human gonads and the adrenal cortex. They are important for intrauterine and postnatal sexual development and human reproduction. Although human androgen biosynthesis has been extensively studied in the past, exact mechanisms underlying the regulation of androgen production in health and disease remain vague. Here, the knowledge on human androgen biosynthesis and regulation is reviewed with a special focus on human adrenal androgen production and the hyperandrogenic disorder of polycystic ovary syndrome (PCOS). Since human androgen regulation is highly specific without a good animal model, most studies are performed on patients harboring inborn errors of androgen biosynthesis, on human biomaterials and human (tumor) cell models. In the past, most studies used a candidate gene approach while newer studies use high throughput technologies to identify novel regulators of androgen biosynthesis. Using genome wide association studies on cohorts of patients, novel PCOS candidate genes have been recently described. Variant 2 of the DENND1A gene was found overexpressed in PCOS theca cells and confirmed to enhance androgen production. Transcriptome profiling of dissected adrenal zones established a role for BMP4 in androgen synthesis. Similarly, transcriptome analysis of human adrenal NCI-H295 cells identified novel regulators of androgen production. Kinase p38alpha (MAPK14) was found to phosphorylate CYP17 for enhanced 17,20 lyase activity and RARB and ANGPTL1 were detected in novel networks regulating androgens. The discovery of novel players for androgen biosynthesis is of clinical significance as it provides targets for diagnostic and therapeutic use. PMID- 26498720 TI - Inhibitory effects of SKF96365 on the activities of K(+) channels in mouse small intestinal smooth muscle cells. AB - In order to investigate the effects of SKF96365 (SKF), which is a non-selective cationic channel blocker, on K(+) channel currents, we recorded currents through ATP sensitive K(+) (IKATP), voltage-gated K(+) (IKv) and Ca(2+) activated K(+) channels (IBK) in the absence and presence of SKF in single small intestinal myocytes of mice with patch-clamp techniques. SKF (10 uM) reversibly abolished IKATP that was induced by cromakalim (10 uM), which is a selective ATP sensitive K(+) channel opener. These inhibitory effects were induced in a concentration dependent and voltage-independent manner. The 50% inhibitory concentration (IC50) was 0.85 uM, which was obviously lower than that reported for the muscarinic cationic current. In addition, SKF (1 uM ~ the IC50 value in IKATP suppression) reversibly inhibited the IKv that was induced by repetitive depolarizing pulses from -80 to 20 mV. However, the extent of the inhibitory effects was only ~30%. In contrast, SKF (1 uM) had no significant effects on spontaneous transient IBK and caffeine-induced IBK. These results indicated that SKF inhibited ATP sensitive K(+) channels and voltage-gated K(+) channels, with the ATP sensitive K(+) channels being more sensitive than the voltage-gated K(+) channels. These inhibitory effects on K(+) channels should be considered when SKF is used as a cationic channel blocker. PMID- 26498721 TI - Population screening in Asia: A unique opportunity to enhance early detection of psychosis? AB - A recent article in this journal (Razali et al., 2015) reports the results of a 2 stage study screening for psychosis risk in Malaysia. The researchers incorporated both selective and indicated prevention strategies and included self report items probing non-specific "early" experiences as well as attenuated psychotic symptoms associated with the prodromal phase of schizophrenia. Given that increased stigma and reduced services may reduce help-seeking in many Asian countries, population screening may be more important to early detection of individuals at risk for psychosis. In fact, the availability of large population centers and greater trust of providers may make Asian research centers uniquely suited for conducting badly needed research on screening strategies and the role of cultural factors in the emergence of psychosis. PMID- 26498722 TI - Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India. AB - AIM: To assess the attitude of psychiatrists towards clozapine and also to evaluate the prescription practices of psychiatrists for clozapine. METHODOLOGY: An email survey was sent to 3381 psychiatrists from India, of whom 548 (16.2%) responded. RESULTS: Mean number of years in clinical practice was 12.59 (SD-10.1) for participating psychiatrists. Majority of the participants rated their knowledge about clozapine to be good (61.5%)/very good (34.5%). The primary indication for use of clozapine for almost all the participants was treatment resistance and most of the psychiatrists initiated clozapine either in the dose of 25mg OD (44.3%) or 12.5mg OD (37%). Half (51.8%) of the psychiatrists preferred to use clozapine as BD dosing schedule, and median doses required to stabilize the patients ranged from 137.5 to 400mg/day. Once the clozapine dose had been stabilized, about half (51%) of the psychiatrists advised blood monitoring at monthly intervals. Almost all psychiatrists rated effectiveness of clozapine to be better than other antipsychotics. In terms of tolerability, 45.3% of the psychiatrists rated it as 'same as other antipsychotics' and 15.9% rated it as better than other antipsychotics. Most common patient and therapist related factors associated with reluctance to start clozapine were history of poor medication compliance and need for monitoring, respectively. Upon reviewing the prescription of other psychiatrists, participating psychiatrists reported that in about 28.46% of patients clozapine was not prescribed though indicated. CONCLUSIONS: This survey suggests that clozapine is underused in India, although psychiatrists have adequate knowledge about the drug but many psychiatrists have negative attitude towards clozapine. PMID- 26498723 TI - The effect of Mycobacterium tuberculosis CRISPR-associated Cas2 (Rv2816c) on stress response genes expression, morphology and macrophage survival of Mycobacterium smegmatis. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) are present in the genome of 40% bacteria and 90% archaea. CRISPR and accompanying Cas proteins constitute an adaptive immune system against disruptive mobile genetic elements. Two CRISPRs and 9 genes encoding CRISPR-associated proteins have been found in the genome of Mycobacterium tuberculosis. The CRISPR-associated Cas2 is an endoribonuclease required for the acquisition of new spacers. In this study, Cas2 encoded by Rv2816c was expressed in Mycobacterium smegmatis lacking CRISPR-Cas system and its role in stress responses of M. smegmatis in vitro and within macrophages was studied. We found that Cas2 mediated M. smegmatis stress response changes were associated with the altered expression of sigma factors which involved in mycobacterial stress response and virulence. We also found that Cas2 decreased the survival of M. smegmatis within macrophages. This study provides new insights on the role of Cas2. PMID- 26498725 TI - Patient perceived burden of implant placement compared to surgical tooth removal and apicectomy. AB - OBJECTIVE: To assess how patients actually perceive implant placement, to evaluate whether patients' perceived burdens are related to specific stages during implant placement, and to compare patients' perceptions during implant placement with other surgical procedures. METHODS: A sample of 287 patients was consecutively recruited. Only patients with implantations (n=45), surgical tooth removal (n=147), or apicectomies (n=95) were included. Patients' perceptions during oral surgery and implantation were assessed using the Burdens in Oral Surgery Questionnaire (BiOS-Q). Effects of treatment on BiOS-Q total and domain scores were assessed using multivariate linear regression analyses, and effect sizes (Cohen's d) were computed. RESULTS: Overall, patients' perceived burdens during oral surgery were low indicated by a mean BiOS-Q total score of 28.5 points, with lowest scores for Side effects (19.4) and highest scores for Anesthesia (34.1). Among treatment groups, implantation was perceived least unpleasant. This was related to lower burdens during Bone and soft tissue manipulation during implantation than during surgical tooth removal (difference: 14.8 points; d=0.8) or apicectomy (difference: 13.1 points; d=0.7). CONCLUSIONS: Implantation has a low overall perceived burden and is significantly less burdensome during bone and soft tissue manipulation than surgical tooth removal or apicectomy. CLINICAL SIGNIFICANCE: Patients can be informed that implant placement is less unpleasing than other commonly performed oral surgery procedures. PMID- 26498724 TI - Predictors of Self-Reported Adherence to Antiretroviral Medication in a Multisite Study of Ethnic and Racial Minority HIV-Positive Youth. AB - OBJECTIVE: To test social cognitive predictors of medication adherence in racial/ethnic minority youth living with HIV using a conceptual model. METHODS: Youth were participants in two descriptive studies by the Adolescent Trials Network for HIV/AIDS Interventions. Minority youth ages 16-24 years who were prescribed antiretroviral medication were included (N = 956). Data were collected through chart extraction and/or laboratory testing and by Audio Computer-Assisted Self-Interview. RESULTS: 39% of youth reported suboptimal adherence. Path analysis was used to explore predictors of medication adherence. Higher self efficacy predicted higher readiness and adherence. Greater social support predicted higher self-efficacy. Psychological symptoms and substance use were associated with several predictors and lower adherence. CONCLUSIONS: The model provided a plausible framework for understanding adherence in this population. Culturally competent, but individually tailored, interventions focused on increasing self-efficacy to take medication and reducing risk behaviors (e.g., substance use) may be helpful for racial or ethnic minority youth with HIV. PMID- 26498726 TI - Identification of acid-resistant proteins in acquired enamel pellicle. AB - OBJECTIVES: This study characterized the proteome profile of the acquired pellicle formed in vivo on enamel. Changes in this proteome profile after exposure to lactic or citric acid were also evaluated. METHODS: Volunteers (n=8) were subjected to dental prophylaxis. After 2 h to allow the formation of the acquired pellicle, the teeth were isolated with cotton rolls and 1 mL of citric acid (1%, pH 2.5) or lactic acid (0.1 M pH 4.8) or deionized water was gently applied with a pipette on the anterior teeth (both maxillary and mandibular) for 10 s. In sequence, the pellicle was collected with an electrode filter paper soaked in 3% citric acid. This procedure was repeated for two additional days following a crossover protocol. Proteins were subjected to reverse phase liquid chromatography coupled to mass spectrometry (nLC-ESI-MS/MS). MS/MS data were processed and submitted to Proteome Discoverer software. Searches were done using SWISS-PROT and TrEMBL databases for human proteins. RESULTS: In total, seventy two proteins were present in all groups and were submitted to quantitative analysis (SIEVE). Some of these proteins were increased more than two-fold after exposure to the acids. Among them, cystatin-B was increased 20- and 13-fold after exposure to citric and lactic acids, respectively. Additionally, some proteins were identified in only one of the groups (18, 5, and 11 proteins for deionized water, citric and lactic acids, respectively). CONCLUSIONS: Our results open new insights regarding potentially acid-resistant proteins that could be added to dental products to prevent acidic dissolution of the teeth. PMID- 26498728 TI - Disclaimer labels on fashion magazine advertisements: Impact on visual attention and relationship with body dissatisfaction. AB - Globally there is increasing advocacy for the implementation of laws requiring disclaimer labels to be attached to media images that have been digitally altered, with the goal of reducing the known negative effects of exposure to unrealistic thin ideal imagery for women. The current study used eye tracking technology to establish how digital alteration disclaimer labels affect women's visual attention to fashion magazine advertisements, and the interrelationship with body dissatisfaction and state appearance comparison. Participants were 120 female undergraduate students who viewed four thin ideal advertisements with either no disclaimer, a generic disclaimer, or a more detailed specific disclaimer. It was found that women did attend to the disclaimers. Specifically worded disclaimers directed visual attention towards target body areas, which resulted in increased body dissatisfaction, while state appearance comparison predicted increased body dissatisfaction. Further research is imperative to provide guidance on the most effective use of disclaimer labels. PMID- 26498727 TI - Monomer elution in relation to degree of conversion for different types of composite. AB - OBJECTIVES: The aim of this study was to determine the degree of conversion (DC) and the monomer release of three composite types when employed following a layer- and bulk-filling technique. METHODS: The release of monomers from a 'conventional paste-like' (Filtek Z250), a 'conventional flowable' (Filtek Supreme XTE Flowable) and a 'bulk-fill' flowable composite (Filtek Bulk Fill Flowable) from the same manufacturer (3M ESPE, Seefeld, Germany) was determined. Ten cylindrical specimens per composite were built, either in two 2-mm layers or in one 4-mm bulk. DC was measured at the specimen top and bottom surface using micro-Raman spectroscopy, after which the specimens were immersed in 2 ml absolute ethanol for 24 h at 37 degrees C. This solution was refreshed weekly during six weeks and the concentration of BisGMA, BisEMA(6), BisPMA, UDMA, TEGDMA and BPA was determined by liquid chromatography/mass spectroscopy. RESULTS: DC at the specimen top and bottom was similar except for the bulk-fill technique, which resulted in significantly lower DC at the specimen bottom. The release of BisGMA and TEGDMA was initially very high, but rapidly dropped in the second week. In contrast, the release of BisPMA and UDMA increased initially, but then declined towards the sixth week. BisEMA(6) release was relatively steady over time. All composites released small amounts of BPA. The total monomer release was significantly lower for the layer- than the bulk-filling technique. CONCLUSIONS: The slightly reduced degree of conversion at 4-mm depth resulted in a higher monomer elution when the composite was applied following a bulk-fill application method. CLINICAL SIGNIFICANCE: Applying a flowable and a bulk-fill composite following a bulk-fill application method resulted in a significantly reduced degree of conversion at the bottom of polymerized composite specimens when compared to a layer-application method. This reduced polymerization degree was reflected in significantly increased monomer release. PMID- 26498729 TI - Effect of excimer laser treatment on vitiliginous areas with leukotrichia after confirmation by dermoscopy. AB - BACKGROUND: Leukotrichia is clinically common in patients with vitiligo, and dermoscopy is useful for finding white vellus hair. The use of phototherapy in the repigmentation of vitiliginous areas with leukotrichia is usually difficult because of a deficient melanocyte reservoir. OBJECTIVES: We sought to evaluate the effect of leukotrichia on the clinical outcomes of excimer laser treatment. METHODS: We treated 77 patients with vitiligo using excimer laser therapy. Vitiligo is classified into two types: segmental vitiligo (SV) and nonsegmental vitiligo (NSV). Before starting the treatment, we confirmed the leukotrichia of vitiliginous lesions by dermoscopy and then treated the areas once weekly for 24 weeks. At the beginning and 24 weeks later, we took clinical pictures and graded the repigmentation from 1 to 4. Grades 1 and 2 were defined as a poor response and grades 3 and 4 as a good response. RESULTS: Thirty-one of 77 patients with vitiligo had SV. Among those with SV, 24 (77.4%) had leukotrichia, and these patients showed a poor response compared to those without leukotrichia (P = 0.272). Three of 24 patients with SV and leukotrichia showed a good response. Among the 46 patients with NSV, 18 (39.1%) had leukotrichia and showed a poor response. Twenty-eight (60.9%) of the 46 patients with NSV without leukotrichia showed a good response in contrast to those with leukotrichia (P < 0.01). Comparison of the response to the excimer laser treatment, regardless of vitiligo type, showed that leukotrichia was a significant negative factor in the repigmentation of vitiliginous areas (P < 0.01). CONCLUSION: Excimer laser therapy was satisfactory in patients with vitiligo, including SV. Confirming the presence of leukotrichia in patients with vitiligo before excimer laser treatment would be helpful in predicting the response to treatment. PMID- 26498730 TI - Healthcare-Associated Transmission of Plasmodium falciparum in New York City. AB - A patient with no risk factors for malaria was hospitalized in New York City with Plasmodium falciparum infection. After investigating all potential sources of infection, we concluded the patient had been exposed to malaria while hospitalized less than 3 weeks earlier. Molecular genotyping implicated patient to-patient transmission in a hospital setting. Infect. Control Hosp. Epidemiol. 2015;37(1):113-115. PMID- 26498731 TI - Abundance and generalisation in mutualistic networks: solving the chicken-and-egg dilemma. AB - A frequent observation in plant-animal mutualistic networks is that abundant species tend to be more generalised, interacting with a broader range of interaction partners than rare species. Uncovering the causal relationship between abundance and generalisation has been hindered by a chicken-and-egg dilemma: is generalisation a by-product of being abundant, or does high abundance result from generalisation? Here, we analyse a database of plant-pollinator and plant-seed disperser networks, and provide strong evidence that the causal link between abundance and generalisation is uni-directional. Specifically, species appear to be generalists because they are more abundant, but the converse, that is that species become more abundant because they are generalists, is not supported by our analysis. Furthermore, null model analyses suggest that abundant species interact with many other species simply because they are more likely to encounter potential interaction partners. PMID- 26498732 TI - "My dirty little habit": Patient constructions of antidepressant use and the 'crisis' of legitimacy. AB - Discontents surrounding depression are many, and include concerns about a creeping appropriation of everyday kinds of misery; divergent opinions on the diagnostic category(ies); and debates about causes and appropriate treatments. The somewhat mixed fortunes of antidepressants - including concerns about their efficacy, overuse and impacts on personhood - have contributed to a moral ambivalence around antidepressant use for people with mental health issues. Given this, we set out to critically examine how antidepressant users engage in the moral underpinnings of their use, especially how they ascribe legitimacy (or otherwise) to this usage. Using a modified constant comparative approach, we analyzed 107 narrative interviews (32 in UKa, 36 in UKb, 39 in Australia) collected in three research studies of experiences of depression in the UK (2003 4 UKa, and 2012 UKb) and in Australia (2010-11). We contend that with the precariousness of the legitimacy of the pharmaceutical treatment of depression, participants embark on their own legitimization work, often alone and while distressed. We posit that here, individuals with depression may be particularly susceptible to moral uncertainty about their illness and pharmaceutical interventions, including concerns about shameful antidepressant use and deviance (e.g. conceiving medication as pseudo-illicit). We conclude that while people's experiences of antidepressants (including successful treatments) involve challenges to illegitimacy narratives, it is difficult for participants to escape the influence of underlying moral concerns, and the legitimacy quandary powerfully shapes antidepressant use. PMID- 26498734 TI - Transurethral Bipolar Enucleation of the Prostate Is an Effective Treatment Option for Men With Urinary Retention. AB - OBJECTIVE: To evaluate outcomes of transurethral bipolar enucleation (TuBE) of the prostate in patients with refractory lower urinary tract symptoms. MATERIALS AND METHODS: A retrospective analysis was performed on patients who underwent TuBE from July 2014 to March 2015. Perioperative factors evaluated included International Prostate Symptom Score, Sexual Health Inventory for Men score, prostate-specific antigen, postvoid residual volume, transrectal ultrasound volume measurement, estimated blood loss, operative time, pathologic weight, and complications. Postoperative evaluation was performed at 6 weeks and 3 months. RESULTS: Forty-nine patients were identified. Mean age was 67 years and mean follow-up was 4.4 months. Twenty-eight patients (57%) were in retention. Preoperative, 6-week, and 3-month mean postvoid residual volumes were 278 mL, 66 mL, and 87 mL (P < .01); mean International Prostate Symptom Scores were 22, 9, and 8 (P < .01); mean quality of life scores were 5.0, 1.9, and 1.9; and Sexual Health Inventory for Men scores were 7.1, 8.4, and 7.0 (P = .35), respectively. Twenty-eight patients (57%) were able to have erections preoperatively and were still able to postoperatively. All (100%) of the patients in retention were able to void postoperatively. Mean operative time was 93 minutes, estimated blood loss was 49 mL, and pathologic weight was 18 g. Urinary tract infection occurred in 3 patients (6%), urethral stricture in 1 (2%), and bladder neck contracture in 2 (4%). Mean prostate-specific antigen decreased from 3.2 ng/dL to 0.9 ng/dL at 3 months (P < .01). CONCLUSION: TuBE is an effective operation for refractory urinary tract symptoms including those who are in urinary retention. PMID- 26498735 TI - Verumontanum Cyst Associated With Lower Urinary Tract Symptoms in an Adolescent. AB - Urinary tract polyps occur anywhere from the renal pelvis to the anterior urethra. Lower tract polyps occur less frequently than upper tract polyps and are a rare finding in children. Symptoms include obstruction, dysfunctional voiding, or hematuria. We report the case of a 17-year-old male who presented with persistent leakage of urine following voiding. Ultrasound demonstrated a small cystic lesion in the posterior aspect of the prostate and a voiding cystourethrogram was suggestive of a utricular cyst or polyp. He underwent a cystoscopy that demonstrated a large cystic structure originating from the verumontanum, nearly obstructing the prostatic urethra. PMID- 26498736 TI - Impact of price display on provider ordering: A systematic review. AB - BACKGROUND: Displaying order prices to physicians is 1 potential strategy to reduce unnecessary health expenditures, but its impact on patterns of care is unclear. OBJECTIVE: To review characteristics of previous price display interventions, impact on order costs and volume, effects on patient safety, acceptability to physicians, and the quality of this evidence. DESIGN: Systematic review of studies that showed numeric prices of laboratory tests, imaging studies, or medications to providers in real time during the ordering process and evaluated the impact on provider ordering. Two investigators independently extracted data for each study and evaluated study quality using a modified Downs and Black checklist. RESULTS: Of 1494 studies reviewed, 19 met inclusion criteria, including 5 randomized trials, 13 pre-post intervention studies, and 1 time series analysis. Studies were published between 1983 and 2014. Of 15 studies reporting the quantitative impact of price display on aggregate order costs or volume, 10 demonstrated a statistically significant decrease in the intervention group. Price display was found to decrease aggregate order costs (9 of 13 studies) more frequently than order volume (3 of 8 studies). Patient safety was evaluated in 5 studies and was unaffected by price display. Provider acceptability tended to be positive, although evidence was limited. Study quality was mixed, with checklist scores ranging from 5/21 to 20/21. CONCLUSIONS: Provider price display likely reduces order costs to a modest degree. Patient safety appeared unchanged, though evidence was limited. More high-quality evidence is needed to confirm these findings within a modern context. PMID- 26498737 TI - A Graphene-Based Bimorph Structure for Design of High Performance Photoactuators. AB - A photoactuator based on a tubular-shaped graphene composite bimorph is fabricated and shows reversible photoactuation with fast response and large deformation (deformation angle of ca. 479 degrees in only 3.6 s), which is mostly attributed to the interfacial thermal stress. Various photoactuator devices based on the tubular bimorph, including a smart box and crawler-type robot that can mimic tank-track motion, are designed. PMID- 26498733 TI - Clinical dissection of childhood occipital epilepsy of Gastaut and prognostic implication. AB - BACKGROUND AND PURPOSE: Our aim was to describe the clinical and electrical features and the long-term evolution of childhood occipital epilepsy of Gastaut (COE-G) in a cohort of patients and to compare long-term prognosis between patients with and without other epileptic syndromes. METHODS: This was a retrospective analysis of the long-term outcome of epilepsy in 129 patients with COE-G who were referred to 23 Italian epilepsy centres and one in Austria between 1991 and 2004. Patients were evaluated clinically and with electroencephalograms for 10.1-23.0 years. The following clinical characteristics were evaluated: gender, patient age at seizure onset, history of febrile seizures and migraine, family history of epilepsy, duration and seizure manifestations, circadian distribution and frequency of seizures, history of medications including the number of drugs, therapeutic response and final outcome. RESULTS: Visual hallucinations were the first symptom in 62% and the only manifestation in 38.8% of patients. Patients were subdivided into two groups: group A with isolated COE G; group B with other epileptic syndromes associated with COE-G. The most significant (P < 0.05) difference concerned antiepileptic therapy: in group A, 45 children responded to monotherapy; in group B only 15 children responded to monotherapy. At the end of follow-up, the percentage of seizure-free patients was significantly higher in group A than in group B. CONCLUSIONS: Childhood occipital epilepsy of Gastaut has an overall favourable prognosis and a good response to antiepileptic therapy with resolution of seizures and of electroencephalogram abnormalities. The association of typical COE-G symptoms with other types of seizure could be related to a poor epilepsy outcome. PMID- 26498738 TI - A SNP in the porcine chemokine (C-X-C motif) ligand 10 gene is associated with blood hemoglobin concentration. PMID- 26498739 TI - Novel postzygotic KRAS mutation in a Japanese case of epidermal nevus syndrome presenting with two distinct clinical features, keratinocytic epidermal nevi and sebaceous nevi. PMID- 26498740 TI - Measuring benefits of opioid misuse treatment for economic evaluation: health related quality of life of opioid-dependent individuals and their spouses as assessed by a sample of the US population. AB - AIMS: To understand how the general public views the quality of life effects of opioid misuse and opioid use disorder on an individual and his/her spouse, measured in terms used in economic evaluations. DESIGN: Cross-sectional internet survey of a US population-representative respondent panel conducted December 2013 January 2014. SETTING: United States. PARTICIPANTS: A total of 2054 randomly selected adults; 51.1% male (before weighting). MEASUREMENTS: Mean (95% confidence interval) and median health 'utility' for six opioid misuse and treatment outcomes: active injection misuse; active prescription misuse; methadone maintenance therapy at initiation and when stabilized in treatment; and buprenorphine therapy at initiation and when stabilized. Utility is a numerical representation of health-related quality of life used in economic evaluations to 'adjust' estimated survival to include peoples' preferences for health states. Utilities are determined by surveying the general population to estimate the value they assign to particular health states on a scale where 0 = the value of being dead and 1.0 = the value of being in perfect health. Spouse spillover utility is assigned to a spouse of an individual who is in a particular health state. FINDINGS: Mean individual utility ranged from 0.574 [95% confidence interval (CI) = 0.538, 0.611] for active injection opioid misuse to 0.766 for stabilized buprenorphine therapy (95% CI = 0.738, 0.795), with other states in between. Female respondents assigned higher utility to the active prescription misuse and buprenorphine therapy at initiation states than did males (P < 0.05); all other states did not differ by respondent gender. Mean spousal utilities were significantly lower than 1.0 but mostly higher than individual utility, and were similar between male and female respondents. CONCLUSIONS: In the opinion of the US public, injection opioid misuse results in worse health-related quality of life than prescription misuse, and methadone therapy results in worse health related quality of life than buprenorphine therapy. Spouses are negatively affected by their partner's opioid misuse and early treatment. PMID- 26498741 TI - Substance use, health status and service utilisation of older clients attending specialist drug and alcohol services. AB - INTRODUCTION AND AIMS: The number of older clients attending drug and alcohol (D&A) services is increasing, although there is insufficient knowledge regarding service needs for this group. The aim of this study was to document the patterns of substance use, health status, cognition, social conditions, and health service utilisation of older clients in D&A treatment. DESIGN AND METHODS: A cross sectional observational study of 99 clients aged >=50 years (M = 55, SD = 4.5; 77% male) attending specialist D&A services (N = 30 alcohol treatment, N = 69 opioid treatment) in Sydney, Australia. Participants completed a confidential research interview. Findings were compared to aggregated data from younger opioid substitution treatment (OST) clients attending the same services (N = 214). RESULTS: Alcohol (46%), benzodiazepines (40%) and cannabis (38%) were the most commonly reported substances used in the past 4 weeks; 23% reported no recent substance use, and 17% reported using three or more drugs. Participants reported high levels of physical and mental health problems, social isolation, low levels of employment, and a third reported difficulties with daily living activities. Forty percent had been injured in a fall in the past 12 months. The mean Addenbrooke's Cognitive Examination-R score was 82.4 +/- 9.6, with 40% performing at a level consistent with severe cognitive impairment. A significantly higher proportion of older participants used alcohol and benzodiazepines than younger clients, and older participants had significantly poorer psychological health, physical health and quality of life. DISCUSSION AND CONCLUSIONS: D&A services will require strategies to address the complex physical, mental, cognitive and social problems of older clients. PMID- 26498742 TI - Medical Malpractice Damage Caps and Provider Reimbursement. AB - A common state legislative maneuver to combat rising healthcare costs is to reform the tort system by implementing caps on noneconomic damages awardable in medical malpractice cases. Using the implementation of caps in several states and large database of private insurance claims, I estimate the effect of damage caps on the amount providers charge to insurance companies as well as the amount that insurance companies reimburse providers for medical services. The amount providers charge insurers is unresponsive to tort reform, but the amount that insurers reimburse providers decreases for some procedures. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26498743 TI - Cloning and characterization of the pepper CaPAO gene for defense responses to salt-induced leaf senescence. AB - BACKGROUND: Pheophorbide a oxygenase (PAO) is an important enzyme in the chlorophyll catabolism pathway and is involved in leaf senescence. It opens the porphyrin macrocycle of pheophorbide a and finally forms the primary fluorescent chlorophyll catabolite. Previous studies have demonstrated the function of PAO during cell death. However, the characterizaton of PAO during leaf senescence induced by environmental factors is not well understood. METHODS: Homology-based cloning and RACE techniques were used to obtain the full-length cDNA of the CaPAO gene. CaPAO expression was determined by quantitative real-time PCR. Function of CaPAO gene were studied using virus-induced gene silencing and transgenic techniques with tobacco plants (Nicotiana tabacum). RESULTS: A novel PAO gene CaPAO was isolated from pepper (Capsicum annuum L.). The full-length CaPAO cDNA is comprised of 1838 bp, containing an open reading frame of 1614 bp, and encodes a 537 amino acid protein. This deduced protein belongs to the Rieske-type iron sulfur superfamily, containing a conserved Rieske cluster. CaPAO expression, as determined by quantitative real-time PCR, was higher in leaves than roots, stems and flowers. It was upregulated by abscisic acid, methyl jasmonate and salicylic acid. Moreover, CaPAO was significantly induced by high salinity and osmotic stress treatments and also was regulated by Phytophthora capsici. The virus induced gene silencing technique was used to silence the CaPAO gene in pepper plants. After 3 days of high salt treatment, the chlorophyll breakdown of CaPAO silenced pepper plants was retarded. RD29A promoter-inducible expression vector was constructed and transferred into tobacco plant. After 7 days of salt treatment, the leaves of transgenic plants were severely turned into yellow, the lower leaves showed necrotic symptom and chlorophyll content was significantly lower than that in the control plants. CONCLUSIONS: The expression of CaPAO gene was induced in natural senescence and various stresses. The CaPAO gene may be related to defense responses to various stresses and play an important role in salt-induced leaf senescence. PMID- 26498744 TI - Behind the scenes of the PRIME intervention: designing a complex intervention to improve malaria care at public health centres in Uganda. AB - BACKGROUND: In Uganda, health system challenges limit access to good quality healthcare and contribute to slow progress on malaria control. We developed a complex intervention (PRIME), which was designed to improve quality of care for malaria at public health centres. OBJECTIVE: Responding to calls for increased transparency, we describe the PRIME intervention's design process, rationale, and final content and reflect on the choices and challenges encountered during the design of this complex intervention. DESIGN: To develop the intervention, we followed a multistep approach, including the following: 1) formative research to identify intervention target areas and objectives; 2) prioritization of intervention components; 3) review of relevant evidence; 4) development of intervention components; 5) piloting and refinement of workshop modules; and 6) consolidation of the PRIME intervention theories of change to articulate why and how the intervention was hypothesized to produce desired outcomes. We aimed to develop an intervention that was evidence-based, grounded in theory, and appropriate for the study context; could be evaluated within a randomized controlled trial; and had the potential to be scaled up sustainably. RESULTS: The process of developing the PRIME intervention package was lengthy and dynamic. The final intervention package consisted of four components: 1) training in fever case management and use of rapid diagnostic tests for malaria (mRDTs); 2) workshops in health centre management; 3) workshops in patient-centred services; and 4) provision of mRDTs and antimalarials when stocks ran low. CONCLUSIONS: The slow and iterative process of intervention design contrasted with the continually shifting study context. We highlight the considerations and choices made at each design stage, discussing elements we included and why, as well as those that were ultimately excluded. Reflection on and reporting of 'behind the scenes' accounts of intervention design may improve the design, assessment, and generalizability of complex interventions and their evaluations. PMID- 26498745 TI - Global surgery in a postconflict setting--5-year results of implementation in the Russian North Caucasus. AB - BACKGROUND: Collaborations for global surgery face many challenges to achieve fair and safe patient care and to build sustainable capacity. The 2004 terrorist attack on a school in Beslan in North Ossetia in the Russian North Caucasus left many victims with complex otologic barotrauma. In response, we implemented a global surgery partnership between the Vladikavkaz Children's Hospital, international surgical teams, the North Ossetian Health Ministry, and civil society organizations. This study's aim was to describe the implementation and 5 year results of capacity building for complex surgery in a postconflict, mid income setting. DESIGN: We conducted an observational study at the Children's Hospital in Vladikavkaz in the autonomous Republic of North Ossetia-Alania, part of the Russian Federation. We assessed the outcomes of 15 initial patients who received otologic surgeries for complex barotrauma resulting from the Beslan terrorism attack and for other indications, and report the incidence of intra- and postoperative complications. RESULTS: Patients were treated for trauma related to terrorism (53%) and for indications not related to violence (47%). None of the patients developed peri- or postoperative complications. Three patients (two victims of terrorism) who underwent repair of tympanic perforations presented with re-perforations. Four junior and senior surgeons were trained on site and in Germany to perform and teach similar procedures autonomously. CONCLUSIONS: In mid-income, postconflict settings, complex surgery can be safely implemented and achieve patient outcomes comparable to global standards. Capacity building can build on existing resources, such as operation room management, nursing, and anesthesia services. In postconflict environments, substantial surgical burden is not directly attributable to conflict-related injury and disease, but to health systems weakened by conflicts. Extending training and safe surgical care to include specialized interventions such as microsurgery are integral components to strengthen local capacity and ownership. Our experience identified strategies for fair patient selection and might provide a model for potentially sustainable surgical system building in postconflict environments. PMID- 26498747 TI - Antimicrobial stewardship: are we failing in cross-specialty clinical engagement? AB - BACKGROUND: Antimicrobial resistance (AMR) is a public health priority and leading patient safety issue. Globally, antimicrobial stewardship (AMS) has been integral in promoting therapeutic optimization whilst minimizing harmful antimicrobial use. A cross-sectional, observational study was undertaken to investigate the coverage of AMS and antibacterial resistance across clinical scientific conferences in 2014, as a surrogate marker for current awareness and attributed importance. METHODS: Clinical specialties were identified, and the largest corresponding clinical scientific/research conferences in 2014 determined (i) within the UK and (ii) internationally. Conference characteristics and abstracts were interrogated and analysed to determine those related to AMS and AMR. Inter-specialty variation was assessed using chi(2) or Fisher's exact statistical analysis. RESULTS: In total, 45 conferences from 23 specialties were analysed representing 59,682 accepted abstracts. The UK had a significantly greater proportion of AMS-AMR-related abstracts compared with international conferences [2.8% (n = 221/7843) compared with 1.8% (n = 942/51,839); P < 0.001]. Infection conferences contained the greatest proportion of AMS-AMR abstracts, representing 20% (732/3669) of all abstracts [UK 66% (80/121) and international 18% (652/3548); P < 0.0001]. AMS-AMR coverage across all general specialties was poor [intensive care 9% (116/1287), surgical 1% (8/757) and medical specialties 0.64% (332/51,497)] despite high usage of antimicrobials across all. CONCLUSIONS: Despite current AMS-AMR strategies being advocated by infection specialists and discussed by national and international policy makers, AMS-AMR coverage remained limited across clinical specialty scientific conferences in 2014. We call for further intervention to ensure specialty engagement with AMS programmes and promote the AMR agenda across clinical practice. PMID- 26498746 TI - Effectiveness of an intervention to facilitate the implementation of healthy eating and physical activity policies and practices in childcare services: a randomised controlled trial. AB - BACKGROUND: The primary aim of this study was to evaluate the effectiveness of an intervention to increase the implementation of healthy eating and physical activity policies and practices by centre-based childcare services. The study also sought to determine if the intervention was effective in improving child dietary intake and increasing child physical activity levels while attending childcare. METHODS: A parallel group, randomised controlled trial was conducted in a sample of 128 childcare services. Intervention strategies included provision of implementation support staff, securing executive support, staff training, consensus processes, academic detailing visits, tools and resources, performance monitoring and feedback and a communications strategy. The primary outcome of the trial was the proportion of services implementing all seven healthy eating and physical activity policies and practices targeted by the intervention. Outcome data were collected via telephone surveys with nominated supervisors and room leaders at baseline and immediately post-intervention. Secondary trial outcomes included the differences between groups in the number of serves consumed by children for each food group within the Australian Guide to Healthy Eating and in the proportion of children engaged in sedentary, walking or very active physical activity assessed via observation in a random subsample of 36 services at follow up. RESULTS: There was no significant difference between groups for the primary trial outcome (p = 0.44). Relative to the control group, a significantly larger proportion of intervention group services reported having a written nutrition and physical activity policy (p = 0.05) and providing adult-guided activities to develop fundamental movement skills (p = 0.01). There were no significant differences between groups at follow-up on measures of child dietary intake or physical activity. CONCLUSIONS: The findings of the trial were equivocal. While there was no significant difference between groups for the primary trial outcome, the intervention did significantly increase the proportion of intervention group services implementing two of the seven healthy eating and physical activity policies and practices. High levels of implementation of a number of policies and practices at baseline, significant obesity prevention activity in the study region and higher than previously reported intra-class correlation of child behaviours may, in part, explain the trial findings. TRIAL REGISTRATION: Australian Clinical Trials Registry (reference ACTRN12612000927820 ). PMID- 26498748 TI - Piloting prostate cancer patient-reported outcomesin clinical practice. AB - PURPOSE: The expanded prostate cancer index composite-26 (EPIC-26) instrument is a validated research tool used for capturing patient-reported quality-of-life outcomes related to the domains of bowel, bladder, and sexual functioning for men undergoing curative treatment for prostate cancer. The purpose of this pilot study was to explore the perceptions and experiences of clinicians with using EPIC-26 in a clinical setting for patients receiving curative radiotherapy. METHODS: Ten clinicians reviewed EPIC-26 scores either before or during weekly clinical encounters with patients receiving curative radiation treatment for prostate cancer. After a period of 2 months, clinicians underwent individual semi structured interviews where they were asked about their views on measuring patient-reported outcomes in practice, the value of EPIC-26, impressions on patient acceptability, and operational issues. RESULTS: There was a general willingness and acceptance by clinicians to use EPIC-26 for routine clinical practice. Clinician participants found EPIC-26 to be generally informative, and added value to the clinical encounter by providing additional information that was specific to prostate cancer patients. EPIC-26 was also felt to improve overall communication and provide additional insight into the patient experience. CONCLUSIONS: Our qualitative findings suggest that there may be a role for incorporating patient-reported outcome measure assessment tools like EPIC-26 routinely into clinical practice. However, further qualitative and quantitative research is required in order to assess the impact of patient-reported outcome information on communication, patient and clinician satisfaction, and how these and other related outcomes can be used for guiding treatment decision-making. PMID- 26498749 TI - A situation analysis of inter-professional education and practice for ethics and professionalism training at Makerere University College of Health Sciences. AB - BACKGROUND: Students at Makerere University College of Health Sciences (MakCHS) are introduced to ethics and professionalism using the inter-professional education (IPE) model. Ethics and professionalism should be running themes throughout succeeding years of study during which students are expected to develop qualities and skills for future inter-professional practice (IPP). We performed a situation analysis of IPE and IPP among students and teaching health professionals at MakCHS to guide development of a relevant training curriculum of ethics and professionalism. METHODS: A cross sectional study with quantitative and qualitative methods which included questionnaires, focus group discussions and key informant interviews. RESULTS: We interviewed 236 undergraduate students (148, 63 % male) and 32 teaching health professionals (25, 78 % male). Two hundred fifteen (91 %) students indicated they had joint learning activities with students of other professions and 166 (70 %) stated there was benefit in having an IPE model training curriculum. Most students (140, 59 %) strongly agreed that learning with other students will make them more effective members of the health team. Whereas the respondents reported inter professionalism as being well articulated in their course curricula, more than half said IPE is only implemented in the pre-clinical years of study. They noted that IPE and IPP concepts were not well programmed, health professionals engaged in teaching had poor attitudes towards IPE and IPP, there were limited numbers of skilled health care workers to implement IPP and there was poor communication between students and teaching health professionals. Majority of teaching health professionals noted challenges in implementation of IPE such as poor coordination and large student population and major factors influencing ethics and professionalism in healthcare such as limited government support, low pay for the health care workers, disrespect and lack of appreciation of the health workers by the public. CONCLUSIONS: Our findings demonstrate that IPE, IPP, ethics and professionalism are not emphasized in the clinical years of study at MakCHS. We recommend increased sensitization on the concepts of IPE and IPP plus enhanced mentorship for both students and teaching health professionals. Innovative strategies of implementation of IPE and IPP for training in ethics and professionalism must be introduced. PMID- 26498750 TI - Use of extracorporeal membrane oxygenation in an awake patient after a major trauma with an incidental finding of tuberculosis. AB - We report the use of extracorporeal membrane oxygenation (ECMO) in a trauma patient with an incidental finding of open tuberculosis (TB). Sedation was reduced during extracorporeal support and awake veno-venous ECMO was successfully performed. Subsequently, accidental cannula removal caused major blood loss which required the administration of cardiopulmonary resuscitation (CPR). Our case report demonstrates that the incidental finding of open TB is an important hint for differential diagnosis and that it should still be considered in high-income countries. In addition, awake ECMO appears to be a feasible therapeutic option in non-transplant patients, although the described case demonstrates that patient compliance and nursing care are important for therapeutic success to avoid complications, for example, inadvertent decannulation. PMID- 26498751 TI - Longitudinal predictors of informal and formal caregiving time in community dwelling dementia patients. AB - PURPOSE: Care provided in the community for dementia patients on an individual basis may be very time consuming. Yet, little is known about the factors affecting caregiving time for community-dwelling dementia patients. Thus, we aimed to investigate the predictors of informal and formal caregiving time for these patients in a longitudinal approach. METHOD: Caregiving time for n = 126 community-dwelling dementia patients was assessed by proxy interviews in four assessments at 6-month intervals (1.5 years of longitudinal follow-up; AgeCoDe study). Measurement of informal caregiving time was based on a German adaptation of the Resource Utilization in Dementia questionnaire. Dementia severity was measured by the Clinical Dementia Rating (CDR). We used random effects models to estimate the effects of sociodemographic variables (age, gender, marital status and education), comorbidity and dementia severity on informal and formal caregiving time. RESULTS: At the first assessment, mean age was 85.0 years (+/ 3.2 years). The majority of patients was female (65.9 %), not married (divorced, single, widowed: 55.6 %) and had primary education (63.5 %). Furthermore, mean GDS was 4.4 (+/-0.8) and mean MMSE was 20.1 (+/-5.1). According to CDR, 43 individuals had very mild dementia, 55 individuals had mild dementia and 28 individuals had moderate/severe dementia. Moreover, mean total caregiving time was 3.4 h per day (+/-4.0). Thereof the main part represents informal caregiving time (2.3 h +/- 3.4), whereas formal caregiving time was 1.2 h (+/-2.4). Dementia severity was associated with total caregiving time, mainly influenced by informal caregiving time. Age was positively associated with total caregiving time, driven by formal caregiving time, while being married was positively associated with total caregiving time, mainly affected by informal caregiving time. All need categories of informal caregiving time were strongly related to dementia severity, whereas none of the categories of formal caregiving time were related to dementia severity. CONCLUSIONS: Our findings extend previous studies that found an association between informal caregiving time and dementia severity. Moreover, our findings highlight the role of informal care for community-dwelling dementia patients in Germany. Informal caregiving time strongly increases with dementia severity. Consequently, as the number of patients suffering from dementia is expected to increase considerably in the next decades, there is a paramount need to strengthen the informal care system to meet patients' needs. PMID- 26498752 TI - Early psychosis research at Orygen, The National Centre of Excellence in Youth Mental Health. AB - BACKGROUND: Specialised early intervention (SEI) programs have offered individuals with psychotic disorders and their families new hope for improving illness trajectories and outcomes. The Early Psychosis Prevention and Intervention Centre (EPPIC) was one of the first SEI programs developed in the world, providing services for young people experiencing their first episode of psychosis. METHODS: We conducted a narrative synthesis of controlled and uncontrolled studies that have been conducted at EPPIC. DISCUSSION: The history of the EPPIC model is first described. This is followed by a discussion of clinical research emerging from EPPIC, including psychopharmacological, psychotherapeutic trials and outcome studies. Neurobiological studies are also described. Issues pertaining to the conduct of clinical research and future research directions are then described. Finally, the impact of the EPPIC model on the Australian environment is discussed. PMID- 26498753 TI - Tumorigenic hybrids between mesenchymal stem cells and gastric cancer cells enhanced cancer proliferation, migration and stemness. AB - BACKGROUND: Emerging evidence indicates that inappropriate cell-cell fusion might contribute to cancer progression. Similarly, mesenchymal stem cells (MSCs) can also fuse with other cells spontaneously and capable of adopting the phenotype of other cells. The aim of our study was to investigate the role of MSCs participated cell fusion in the tumorigenesis of gastric cancer. METHODS: We fused human umbilical cord mesenchymal stem cells (hucMSCs) with gastric cancer cells in vitro by polyethylene glycol (PEG), the hybrid cells were sorted by flow cytometer. The growth and migration of hybrids were assessed by cell counting, cell colony formation and transwell assays. The proteins and genes related to epithelial- mesenchymal transition and stemness were tested by western blot, immunocytochemistry and real-time RT-PCR. The expression of CD44 and CD133 was examined by immunocytochemistry and flow cytometry. The xenograft assay was used to evaluation the tumorigenesis of the hybrids. RESULTS: The obtained hybrids exhibited epithelial- mesenchymal transition (EMT) change with down-regulation of E-cadherin and up-regulation of Vimentin, N-cadherin, alpha-smooth muscle actin (alpha-SMA), and fibroblast activation protein (FAP). The hybrids also increased expression of stemness factors Oct4, Nanog, Sox2 and Lin28. The expression of CD44 and CD133 on hybrid cells was stronger than parental gastric cancer cells. Moreover, the migration and proliferation of heterotypic hybrids were enhanced. In addition, the heterotypic hybrids promoted the growth abilities of gastric xenograft tumor in vivo. CONCLUSIONS: Taken together, our results suggest that cell fusion between hucMSCs and gastric cancer cells could contribute to tumorigenic hybrids with EMT and stem cell-like properties, which may provide a flexible tool for investigating the roles of MSCs in gastric cancer. PMID- 26498754 TI - Impact of efflux in the development of multidrug resistance phenotypes in Staphylococcus aureus. AB - BACKGROUND: Efflux has been recognized as a resistance mechanism to antimicrobials in Staphylococcus aureus; however its role on the development of clinically relevant resistance is still poorly characterized. This study aimed to examine the impact of efflux on development of resistance to fluoroquinolones and other antimicrobials in S. aureus strains representing relevant phenotypes in terms of antibiotic susceptibility and efflux activity. METHODS: Two closely related methicillin- and ciprofloxacin-resistant Staphylococcus aureus clinical strains, with different efflux capacity and the pan-susceptible strain ATCC25923 were exposed to constant concentrations of the efflux pump (EP) substrates ciprofloxacin, ethidium bromide and cetrimide. Parental and exposed strains were tested regarding their susceptibility towards antibiotics, biocides and ethidium bromide, efflux capacity and levels of EP gene expression. Occurrence of resistance-associated mutations was screened by sequencing. RESULTS: Multidrug resistance phenotypes emerged upon exposure, independently of the substrate or its concentration, which were correlated with increased efflux capacity of the exposed strains. The temporal pattern of EP gene expression disclosed an early response with high expression of several genes, followed by a late-response, characterized by overexpression of specific genes. The overall cell response was more pronounced for strains with an initial basal efflux activity. Remarkably, detection of the IS256 element in the promoter regions of mgrA and norA, in some cases associated with increased gene expression, suggests that these genes may be hot spots for IS256 insertion events. The results obtained with exposure of ATCC25923 to ciprofloxacin were particularly striking, revealing a step-wise development of fluoroquinolone resistance, with a first efflux-mediated response, followed by the occurrence of a mutation in grlA that resulted in phenotypic resistance. Additionally, challenge by non-fluoroquinolone agents, particularly cetrimide, promoted cross resistance to fluoroquinolones, revealing the potential role of biocides as selective pressure for the emergence of resistance to these antibiotics. CONCLUSIONS: This study reveals efflux as a significant component of S. aureus resistance to fluoroquinolones and biocides and as a primary mechanism to withstand stress imposed by antimicrobials. This efflux-mediated response can result in the emergence of multidrug resistance in healthcare environments and should be taken into account in the management of this major pathogen. PMID- 26498755 TI - Partially anaortic clampless off-pump coronary artery bypass prevents neurologic injury compared to on-pump coronary surgery: a propensity score-matched study on 286 patients. AB - Anaortic coronary artery bypass proved to prevent early neurologic injury compared to on-pump CABG. The Cardica PAS-Port((r)) is a fully automated device that might be able to perform proximal aorto-venous anastomoses without an increased embolic risk. We evaluated early post-operative neurologic outcome in a matched population following clampless OPCAB (CCAB: either "all-arterial" or with automatically anastomosed venous grafts) or on-pump CABG. 366 consecutive patients were submitted to isolated coronary bypass by a single surgeon experienced in both off and on-pump procedures between January 2009 and December 2013. Of these patients, 223 underwent a clampless off-pump revascularization. After propensity score matching, 143 pairs were selected, who received either off pump or on-pump surgery. In the off-pump group, CCAB was performed with an all arterial approach (n = 33) or with automated proximal anastomosis of the venous graft(s) by means of the Cardica PAS-Port((r)) connector (n = 110). Neurologic injury was defined as non-reversible (NRNI: lethal coma or stroke) or reversible (RNI: TIA or delirium). Operative mortality was 2.4 % (CCAB 1.4 %; CABG 3.5 %; p = 0.14). The global rate of early neurologic injury was 5.6 % (CCAB 2.1 vs. CABG 9.1 %; p = 0.006). Incidence was 1.4 % for NRNI (CCAB 0 vs. CABG 2.8 %; p = 0.04) and 4.2 % for RNI (CCAB 2.1 vs. CABG 6.3 %; p = 0.06). No differences were found among other major perioperative outcomes. CCAB prevents both early post-operative RNI and NRNI. This result can be achieved with a totally anaortic strategy and also with the aid of a fully automated device for proximal aorto-venous anastomoses. PMID- 26498756 TI - Association of serum cystatin C levels with myocardial perfusion and cardiac functional recovery in patients with anterior wall ST elevation myocardial infarction treated with primary coronary intervention. AB - This study sought to investigate the association of baseline serum cystatin C levels with myocardial perfusion and cardiac functional recovery in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). 108 patients with a first anterior STEMI who underwent PPCI were enrolled. Serum cystatin C was measured by immunoturbidimetric method. Patients were divided into two groups according to the median cystatin C levels on admission: group 1 (>=median, n = 54) and group 2 (=33.7 U also had significantly higher cystatin C levels. The WMSI showed a greater improvement in group 2 than in group 1 and there was a significant negative correlation between improvement of WMSI and the cystatin C levels. There was no significant difference in MACEs between the 2 groups. However, congestive heart failure (CHF) was observed significantly more frequent in group 1 than in group 2 (18.5 vs. 5.6 %, p = 0.022). Multivariate logistic regression analysis demonstrated that cystatin C levels at admission were a significant independent predictor of angiographic no-reflow and the development of CHF at 6-month follow up. Elevated cystatin C levels at admission were independently associated with impaired myocardial perfusion, poor cardiac functional recovery and development of CHF in patients with anterior STEMI undergoing PPCI. PMID- 26498757 TI - Efficacy and toxicity profile of pegylated liposomal doxorubicin in patients with advanced ovarian cancer. AB - BACKGROUND: The prognosis of patients with non-platinum-sensitive recurrent ovarian cancer is poor. There is a need for salvage therapies with anti-tumor activity and acceptable toxicity for maintaining quality of life. Pegylated liposomal doxorubicin (PLD, Caelyx((r))) is a promising drug fulfilling these demands. We present retrospective data of patients with advanced epithelial ovarian cancer (EOC) who were treated with pegylated liposomal doxorubicin at the University of Heidelberg between 2007 and 2009. PATIENTS AND METHODS: Eligible patients for this retrospective study had advanced ovarian cancer and were treated in a palliative setting with PLD at the university hospital of Heidelberg, Germany. Primary objectives were toxicity and efficacy of PLD. 34 patients were included in this study between November 2007 and December 2009; one patient received PLD twice as palliative treatment. RESULTS: The median age of the 34 patients enrolled in this study was 59.9 years (range 27-77 years). The median weight of the patients was 69 kg (range 47-109 kg), the median height 164 cm (range 140-176 cm). Pegylated liposomal doxorubicin was administered every 4 weeks with a dosage of 40 mg/m(2) body surface. PLD was administered for three cycles in median (range 1-9 cycles). Dose reduction was necessary in only four patients. In our study time to progression and overall survival was 8.74 and 14.23 months. CONCLUSIONS: In conclusion, this retrospective study showed the efficacy and low toxicity of pegylated liposomal doxorubicin in patients with advanced EOC. Further observations are needed to confirm these preliminary experiences on a larger number of patients. PMID- 26498759 TI - The nationality of Ibni Sina (Avicenna). PMID- 26498758 TI - The number of removed lymph nodes by inguinofemoral lymphadenectomy: impact on recurrence rates in patients with vulva carcinoma. AB - OBJECTIVE: Inguinal lymph node (LN) metastasis is a crucial prognostic factor in vulva carcinoma. The aim of this study was to determine the prognostic value of the number of resected LNs in patients with vulvar carcinoma on recurrence rates. METHODS: This retrospective study includes patients with vulvar squamous cell carcinoma who underwent inguinofemoral lymphadenectomy (IFL) between 1998 and 2011. Dissected groins were stratified by the number of removed lymph nodes (<6 LNs versus >=6 LNs) or inguinal LN metastasis (pN- versus pN+) and analyzed according to groin, local and distance recurrence rates. RESULTS: In total 45 patients were identified and 79 groins were eligible for this analysis. 11 patients underwent ipsilateral IFL and 34 bilateral IFL. The median age was 58 years (range 31-80). The median tumor size was 2 cm (range 0.1-7.9). A median of 8 (range 0-19) LNs were resected per groin. Overall in 11 groins LN metastases were found. Groin recurrences occurred in four patients, local recurrence in six patients and distant metastasis in one patient. We did not observe any significant improvement in groin recurrence rates, local recurrence rates and distant recurrence rates if more than six LNs were removed per groin. Notably, patients with LN metastasis did not show higher recurrence rates compared to unaffected LNs. CONCLUSION: In this cohort we demonstrated that resection of more than six LNs per groin does not improve the recurrence rates in patients with carcinoma of the vulva. Further prospective studies with more individuals are needed to evaluate the role of resected LNs in vulvar carcinoma. PMID- 26498760 TI - Is endometrial ablation protective against endometrial cancer? A retrospective observational study. AB - STUDY OBJECTIVES: Endometrial ablation has been increasingly used over the last 30 years to manage patients with dysfunctional uterine bleeding. Of primary concern, however, is the potential of the procedure to mask the presence or delay the diagnosis of endometrial cancer. The aim of this study is to assess the long term effects of endometrial ablation and its association with the development of endometrial cancer. METHODS: This is a retrospective observational study that was conducted at Bradford Teaching Hospitals in the United Kingdom. The study included all women who had different types of endometrial ablative procedures in the period of January 1994 to December 2011. Analysis of the data was performed using SPSS for windows (V9) software package. RESULTS: Over 18 years period, 1521 women had endometrial ablative procedures for dysfunctional uterine bleeding. During their long-term follow-up, none of the women developed endometrial cancer later in life. This incidence is much lower than the lifetime risk of endometrial cancer in the general population (RR 0.0135; 95 % CI 0.0007-0.2801; P = 0.0054). CONCLUSION: To our knowledge, this is the largest study to examine the long-term incidence of endometrial cancer in women who had endometrial ablative procedures. It shows that the development of endometrial cancer does not seem to be associated with endometrial ablative procedures. PMID- 26498761 TI - A loss-of-function and H2B-Venus transcriptional reporter allele for Gata6 in mice. AB - BACKGROUND: The GATA-binding factor 6 (Gata6) gene encodes a zinc finger transcription factor that often functions as a key regulator of lineage specification during development. It is the earliest known marker of the primitive endoderm lineage in the mammalian blastocyst. During gastrulation, GATA6 is expressed in early cardiac mesoderm and definitive endoderm progenitors, and is necessary for development of specific mesoderm and endoderm-derived organs including the heart, liver, and pancreas. Furthermore, reactivation or silencing of the Gata6 locus has been associated with certain types of cancer affecting endodermal organs. RESULTS: We have generated a Gata6(H2B-Venus) knock-in reporter mouse allele for the purpose of labeling GATA6-expressing cells with a bright nuclear-localized fluorescent marker that is suitable for live imaging at single-cell resolution. CONCLUSIONS: Expression of the Venus reporter was characterized starting from embryonic stem (ES) cells, through mouse embryos and adult animals. The Venus reporter was not expressed in ES cells, but was activated upon endoderm differentiation. Gata6(H2B-Venus/H2B-Venus) homozygous embryos did not express GATA6 protein and failed to specify the primitive endoderm in the blastocyst. However, null blastocysts continued to express high levels of Venus in the absence of GATA6 protein, suggesting that early Gata6 transcription is independent of GATA6 protein expression. At early post implantation stages of embryonic development, there was a strong correlation of Venus with endogenous GATA6 protein in endoderm and mesoderm progenitors, then later in the heart, midgut, and hindgut. However, there were discrepancies in reporter versus endogenous protein expression in certain cells, such as the body wall and endocardium. During organogenesis, detection of Venus in specific organs recapitulated known sites of endogenous GATA6 expression, such as in the lung bud epithelium, liver, pancreas, gall bladder, stomach epithelium, and vascular endothelium. In adults, Venus was observed in the lungs, pancreas, liver, gall bladder, ovaries, uterus, bladder, skin, adrenal glands, small intestine and corpus region of the stomach. Overall, Venus fluorescent protein under regulatory control of the Gata6 locus was expressed at levels that were easily visualized directly and could endure live and time-lapse imaging techniques. Venus is co expressed with endogenous GATA6 throughout development to adulthood, and should provide an invaluable tool for examining the status of the Gata6 locus during development, as well as its silencing or reactivation in cancer or other disease states. PMID- 26498763 TI - The Effects of Molecular Properties on Ready Biodegradation of Aromatic Compounds in the OECD 301B CO2 Evolution Test. AB - Ready biodegradation is the primary biodegradability of a compound, which is used for discriminating whether a compound could be rapidly and readily biodegraded in the natural ecosystems in a short period and has been applied extensively in the environmental risk assessment of many chemicals. In this study, the effects of 24 molecular properties (including 2 physicochemical parameters, 10 geometrical parameters, 6 topological parameters, and 6 electronic parameters) on the ready biodegradation of 24 kinds of synthetic aromatic compounds were investigated using the OECD 301B CO2 Evolution test. The relationship between molecular properties and ready biodegradation of these aromatic compounds varied with molecular properties. A significant inverse correlation was found for the topological parameter TD, five geometrical parameters (Rad, CAA, CMA, CSEV, and N c), and the physicochemical parameter K ow, and a positive correlation for two topological parameters TC and TVC, whereas no significant correlation was observed for any of the electronic parameters. Based on the correlations between molecular properties and ready biodegradation of these aromatic compounds, the importance of molecular properties was demonstrated as follows: geometrical properties > topological properties > physicochemical properties > electronic properties. Our study first demonstrated the effects of molecular properties on ready biodegradation by a number of experiment data under the same experimental conditions, which should be taken into account to better guide the ready biodegradation tests and understand the mechanisms of the ready biodegradation of aromatic compounds. PMID- 26498762 TI - GM1 Ganglioside is Involved in Epigenetic Activation Loci of Neuronal Cells. AB - Gangliosides are sialic acid-containing glycosphingolipids that are most abundant in the nerve tissues. The quantity and expression pattern of gangliosides in brain change drastically throughout development and are mainly regulated through stage-specific expression of glycosyltransferase (ganglioside synthase) genes. We previously demonstrated that acetylation of histones H3 and H4 on the N acetylgalactosaminyltransferase I (GalNAcT, GA2/GM2/GD2/GT2-synthase) gene promoter resulted in recruitment of trans-activation factors. In addition, we reported that epigenetic activation of the GalNAcT gene was also detected as accompanied by an apparent induction of neuronal differentiation in neural stem cells responding to an exogenous supplement of ganglioside GM1. Here, we present evidence supporting the concept that nuclear GM1 is associated with gene regulation in neuronal cells. We found that nuclear GM1 binds acetylated histones on the promoters of the GalNAcT and NeuroD1 genes in differentiated neurons. Our study demonstrates for the first time that GM1 interacts with chromatin via acetylated histones at the nuclear periphery of neuronal cells. PMID- 26498764 TI - Prenatal diagnosis of right-sided diaphragmatic hernia and ipsilateral intrathoracic kidney in a female fetus: a rare observation. AB - Congenital diaphragmatic hernia is a rare congenital malformation, as well as kidney ectopia. Among kidney ectopias, the intrathoracic one is the rarest. Those malformations concern more frequently boys, and affected more the left than the right side. Their association is poorly reported in the literature. We report the rare case of an early sonographic prenatal diagnosis of intrathoracic kidney at 22 weeks of gestation in a female fetus, completed on the follow-up by the diagnosis of an associated diaphragmatic hernia at 33 weeks of gestation. If chest mass is diagnosed prenatally or in neonate, ITK should be considered in a differential diagnosis, all the more if the ipsilateral renal fossa is empty. An associated DH should be searched if ITK is confirmed. Isolated ITK usually requires no specific treatment, in contrast with ITK associated with DH. PMID- 26498766 TI - MicroRNA-33a disturbs influenza A virus replication by targeting ARCN1 and inhibiting viral ribonucleoprotein activity. AB - In order to explore the roles of microRNA(s) [miRNA(s)] in the influenza A virus life cycle, we compared the miRNA profiles of 293T and HeLa cell lines, as influenza A virus can replicate efficiently in 293T cells but only poorly in HeLa cells. We analysed differentially expressed miRNAs and identified five, including miR-33a, that could disturb influenza A virus replication significantly. Using TargetScan analysis, we found that ARCN1 could be a potential target of miR-33a. To confirm whether miR-33a could truly target ARCN1, we generated a luciferase reporter for the ARCN1 3' untranslated region (UTR) and performed a luciferase assay. The data indicated that miR-33a could suppress the luciferase activity of the reporter for the ARCN1 3' UTR but not a reporter in which the predicted miR 33a targeting sites on ARCN1 3' UTR were mutated. We performed immunoblotting to confirm that miR-33a could downregulate the protein level of ARCN1. Consistently, the level of ARCN1 protein in HeLa cells was significantly lower than that in 293T cells. We also demonstrated that ectopic expression of ARCN1 could partially rescue the inhibitory effect of miR-33a on virus replication. Furthermore, we demonstrated that miR-33a could impede virus replication at the stage of virus internalization, which was similar to the pattern for knockdown of ARCN1, indicating that miR-33a inhibits influenza virus infection by suppressing ARCN1 expression. In addition, we found that miR-33a could also weaken the viral ribonucleoprotein activity in an ARCN1-independent manner. In conclusion, we found that miR-33a is a novel inhibitory factor for influenza A virus replication. PMID- 26498765 TI - Linking Essential Tremor to the Cerebellum: Neurochemical Evidence. AB - The pathophysiology and the exact anatomy of essential tremor (ET) is not well known. One of the pillars that support the cerebellum as the main anatomical locus in ET is neurochemistry. This review examines the link between neurochemical abnormalities found in ET and cerebellum. The review is based on published data about neurochemical abnormalities described in ET both in human and in animal studies. We try to link those findings with cerebellum. gamma aminobutyric acid (GABA) is the main neurotransmitter involved in the pathophysiology of ET. There are several studies about GABA that clearly points to a main role of the cerebellum. There are few data about other neurochemical abnormalities in ET. These include studies with noradrenaline, glutamate, adenosine, proteins, and T-type calcium channels. One single study reveals high levels of noradrenaline in the cerebellar cortex. Another study about serotonin neurotransmitter results negative for cerebellum involvement. Finally, studies on T-type calcium channels yield positive results linking the rhythmicity of ET and cerebellum. Neurochemistry supports the cerebellum as the main anatomical locus in ET. The main neurotransmitter involved is GABA, and the GABA hypothesis remains the most robust pathophysiological theory of ET to date. However, this hypothesis does not rule out other mechanisms and may be seen as the main scaffold to support findings in other systems. We clearly need to perform more studies about neurochemistry in ET to better understand the relations among the diverse systems implied in ET. This is mandatory to develop more effective pharmacological therapies. PMID- 26498767 TI - Neptunism and Transformism: Robert Jameson and other Evolutionary Theorists in Early Nineteenth-Century Scotland. AB - This paper sheds new light on the prevalence of evolutionary ideas in Scotland in the early nineteenth century and establish what connections existed between the espousal of evolutionary theories and adherence to the directional history of the earth proposed by Abraham Gottlob Werner and his Scottish disciples. A possible connection between Wernerian geology and theories of the transmutation of species in Edinburgh in the period when Charles Darwin was a medical student in the city was suggested in an important 1991 paper by James Secord. This study aims to deepen our knowledge of this important episode in the history of evolutionary ideas and explore the relationship between these geological and evolutionary discourses. To do this it focuses on the circle of natural historians around Robert Jameson, Wernerian geologist and professor of natural history at the University of Edinburgh from 1804 to 1854. From the evidence gathered here there emerges a clear confirmation that the Wernerian model of geohistory facilitated the acceptance of evolutionary explanations of the history of life in early nineteenth-century Scotland. As Edinburgh was at this time the most important center of medical education in the English-speaking world, this almost certainly influenced the reception and development of evolutionary ideas in the decades that followed. PMID- 26498768 TI - Prognosis of Primary and Recurrent Chondrosarcoma of the Rib. AB - BACKGROUND: Chondrosarcoma of the rib is a rare disease. Although surgery is the only curative treatment option, rib resection with an adequate margin can be challenging and local recurrence is a frequent problem. In this study, the prognosis of primary and recurrent chondrosarcoma of the rib is reported. METHODS: Retrospective analysis was performed of patients treated for chondrosarcoma of the rib between 1984 and 2014 in three major tertiary referral centers in The Netherlands. Clinical and histopathological features were analyzed for their prognostic value using Kaplan-Meier and Cox proportional hazard analysis. Endpoints were set at local recurrent disease, metastasis rate, or death. RESULTS: Overall, 76 patients underwent a resection for a primary chondrosarcoma, and 26 patients underwent a resection for a recurrent chondrosarcoma. Five-year overall survival in the primary group was 90%, local recurrence rate was 17%, and metastasis rate was 12%. The 5-year outcome after recurrent chondrosarcoma was lower, with an overall survival of 65%, local recurrence rate of 27%, and metastasis rate of 27%. For primary chondrosarcoma, tumor size >5 cm and a positive resection margin were correlated with worse overall survival [hazard ratio (HR) 3.28, 95% confidence interval (CI) 1.03 10.44; HR 2.92, 95% CI 1.03-8.25). A higher histological grade was correlated with a higher local recurrence and metastasis rate (HR 5.92, 95% CI 1.11-31.65; HR 6.96, 95% CI 1.15-42.60). CONCLUSION: Surgical resection of both primary and recurrent chondrosarcoma of the rib is an effective treatment strategy. The oncological outcome after surgery is worse in tumors >5 cm, in tumors with positive resection margins and grade 3 chondrosarcoma. PMID- 26498769 TI - Postoperative bleeding risk for oral surgery under continued rivaroxaban anticoagulant therapy. AB - OBJECTIVES: The purpose of this study was to assess the risk of postoperative bleeding complications after oral procedures performed under continued mono or dual anticoagulation therapy with rivaroxaban (and aspirin). METHODS: This retrospective single-center observational study included 52 oral procedures performed under continued oral anticoagulant therapy with rivaroxaban (20 mg/day). Among them, two procedures were performed under continued dual therapy with aspirin (100 mg/day) added to the regimen. Postoperative bleeding events were compared with 285 oral procedures in patients without any anticoagulation/antiplatelet therapy. RESULTS: Postoperative bleeding complications after oral surgery occurred significantly more often in patients under continued rivaroxaban therapy (11.5 %) than in the control cases without anticoagulation/antiplatelet medication (0.7 %). All of the bleeding events were manageable: Two of them were treated with local compression, three by applying new fibrin glue with (one case) or without (two cases) secondary sutures, one occurred during a weekend and was therefore treated under inpatient conditions with suture replacement. All postoperative bleeding episodes occurred during the first postoperative week. CONCLUSIONS: According to our data, continued anticoagulation therapy with rivaroxaban significantly increases postoperative bleeding risk for oral surgical procedures, although the bleeding events were manageable. CLINICAL RELEVANCE: Oral surgeons, cardiologists, general physicians, and patients should be aware of the increased bleeding risk after oral surgical procedures. Close observation up to 1 week postoperatively is advisable to prevent excessive bleeding. PMID- 26498770 TI - Apical pressure created during irrigation with the GentleWaveTM system compared to conventional syringe irrigation. AB - OBJECTIVES: The purpose of this study is to compare pressures at the apical foramen created by conventional syringe irrigation and the GentleWaveTM System, which releases high-velocity degassed irrigants to the pulp chamber and uses broad-spectrum sound energy for cleaning. MATERIALS AND METHODS: The apical pressure generated during irrigation was measured for palatal and distobuccal root canals of four extracted maxillary molars after no instrumentation, minimal instrumentation to a size #15/.04, instrumentation to a size #40/.04 taper, and after perforating the apical foramen to size #40. The root canals opened into an air-tight custom fixture coupled to a piezoresistive pressure transducer. Apical pressures were measured for the GentleWaveTM System and syringe-needle irrigation at different irrigant flow rates, with the needle tip at 1 and 3 mm from the apical foramen using 30-gauge (G) open-ended or side-vented safety tip needles. RESULTS: The GentleWaveTM System generated negative apical pressures (P < 0.001 compared with syringe irrigation); the mean pressures were between -13.07 and 17.19 mmHg. The 30 G needles could not reach the 1 and 3 mm from the working length in uninstrumented and 1 mm in minimally instrumented canals. The mean positive pressures between 6.46 and 110.34 mmHg were measured with needle irrigation depending on the flow rate, needle insertion depth, and size of the root canal. CONCLUSIONS: The GentleWaveTM System creates negative pressure at the apical foramen during root canal cleaning irrespective of the size of canal instrumentation. Positive apical pressures were measured for syringe irrigation. CLINICAL RELEVANCE: Negative pressure during irrigation contributes to improved safety as compared to high-positive pressure. PMID- 26498771 TI - Macrophage Polarization and Bone Formation: A review. AB - The contribution of inflammation to bone loss is well documented in arthritis and other diseases with an emphasis on how inflammatory cytokines promote osteoclastogenesis. Macrophages are the major producers of cytokines in inflammation, and the factors they produce depend upon their activation state or polarization. In recent years, it has become apparent that macrophages are also capable of interacting with osteoblasts and their mesenchymal precursors. This interaction provides growth and differentiation factors from one cell that act on the other and visa versa-a concept akin to the requirement for a feeder layer to grow hemopoietic cells or the coupling that occurs between osteoblasts and osteoclasts to maintain bone homeostasis. Alternatively, activated macrophages are the most likely candidates to promote bone formation and have also been implicated in the tissue repair process in other tissues. In bone, a number of factors, including oncostatin M, have been shown to promote osteoblast formation both in vitro and in vivo. This review discusses the different cell types involved, cellular mediators, and how this can be used to direct new bone anabolic approaches. PMID- 26498773 TI - Analysis of outcomes of percutaneous coronary intervention in metastatic cancer patients with acute coronary syndrome over a 10-year period. AB - BACKGROUND: Early medical palliative care has been shown to improve overall survival of patients with metastatic cancer, but the role of cardiac surgical interventions in such patients is not clear. The limited life expectancy of these patients often poses a dilemma to clinicians and involves a detailed analysis of the risks and benefits of such interventions. This study examines the outcomes of percutaneous coronary intervention (PCI) in patients with metastatic cancer. METHODS: The National Inpatient Database of USA was used to identify patients aged >= 1 8 years who had a diagnosis of metastatic cancer and acute coronary syndrome (ACS) between 2000 and 2009 using ICD-9-CM codes. These were categorized into ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI). The utilization of PCI was also identified using ICD-9-CM codes. The outcomes studied were in-hospital mortality, length of hospital stay and discharge disposition. The association between various outcomes and use of cardiac catheterization was assessed using multivariate regression models. RESULTS: There were 49,515 patients with metastatic disease who were discharged with a diagnosis of ACS. Of these, 15,964 had STEMI and 33,551 had NSTEMI. 3981 patients (24.9%) with STEMI and 3209 patients (9.6%) with NSTEMI received percutaneous coronary intervention. Caucasian male patients under age 65 years were more likely to receive PCI in the setting of an ACS. The hospital characteristics associated with higher use of PCI included academic affiliation, large bedsize, private for-profit hospitals and Midwestern and Western regions of USA. The adjusted odds of receiving PCI in this group of patient have gradually increased by 1.14 every year in last decade (95% CI 1.11-1.16). The beneficial effect of PCI on in-hospital mortality has declined in NSTEMI such that by 2009, there was no significant difference between patients who received PCI and those who did not receive PCI. This has remained unchanged for STEMI patients.C ONCLUSIONS: In metastatic cancer patients with ACS, the rate of PCI has increased over the last decade. In the current era, metastatic cancer patients with NSTEMI may perform equally well without PCI in terms of in-hospital mortality. The decision to provide such care may be considered on an individual basis based on the extent of their medical comorbidity and tumor burden. PMID- 26498772 TI - Upregulation of nuclear transporter, Kpnbeta1, contributes to accelerated cell proliferation- and cell adhesion-mediated drug resistance (CAM-DR) in diffuse large B-cell lymphoma. AB - BACKGROUND: The Karyopherin proteins are involved in the shuttling of cargo proteins, and certain RNAs, across the nuclear pore complex into and out of the cell nucleus. Karyopherin beta1 (Kpnbeta1) is a member of the Karyopherin beta superfamily of nuclear transport proteins. In addition to the nuclear import function, Kpnbeta1 is associated with the occurrence of tumors. This study investigated the expression and biologic function of Kpnbeta1 in diffuse large B cell lymphoma (DLBCL). METHODS: The prognostic value of Kpnbeta1 expression was evaluated using immunohistochemical staining. The role of Kpnbeta1 on cell proliferation- and cell adhesion-mediated drug resistance (CAM-DR) was also determined. RESULTS: We demonstrated that Kpnbeta1 mRNA and protein expression levels were significantly higher in DLBCL B-cells and DLBCL cell lines than in normal CD19 purified B-cells. Immunohistochemical analysis suggested that the expression of Kpnbeta1 was correlated with Ki-67 (P < 0.001). Kaplan-Meier curve showed that high expression of Kpnbeta1 was significantly associated with shorter overall survival. In addition, Kpnbeta1 was associated with the proliferation of DLBCL cells. Importantly, we found that Kpnbeta1 could interact with p65 and promote CAM-DR via accelerating NF-kappaB activation in DLBCL. CONCLUSIONS: Patients with tumors highly expressing Kpnbeta1 have poorer overall survivals. Kpnbeta1 interacts with p65 and enhances CAM-DR. PMID- 26498774 TI - Integrated care in ovarian cancer "IgV Ovar": results of a German pilot for higher quality in treatment of ovarian cancer. AB - INTRODUCTION: Late-stage ovarian cancer patient's survival depends on complete cytoreduction and chemotherapy. Complete cytoreduction is more often achieved in institutions with a case volume of >20 cases per year. The Integrated care program Ovar (IgV Ovar) was founded in 2005 and started recruiting in 2006 with 21 health insurances and six expert centers of ovarian cancer treatment as a quality initiative. Results of the pilot and outcomes of patients of three participating centers will be presented here. METHODS: Data of 1038 patients with ovarian cancer were collected. Adjuvant patients (n = 505) stage FIGO IIB-IV (n = 307) were analyzed for cytoreduction and survival. FIGO IIIC patients were analyzed separately. RESULTS: Median follow-up was 32.7 months. Progression-free survival (PFS) was 23.1 months and overall survival (OS) was 53.6 months for stage IIB-IV. Patients with FIGO IIIC were completely cytoreduced in 48 %. PFS was 21, 29 months if completely cytoreduced. OS was 47.4, 64.9 months if completely cytoreduced.D ISCUSSION: Although the IgV Ovar Rhineland proved to have some structural problems with recruitment and prospective data collection, cytoreduction rates and outcome of patients prove treatment of patients in expert centers is superior to the national and international mean. Therefore, a new quality initiative will be started to bring more awareness to women and to their gynecologists and general practitioners of just how important a good referral strategy is. PMID- 26498775 TI - Adjuvant radiotherapy for vulvar cancer with close or positive surgical margins. AB - BACKGROUND: The survival effect of adjuvant radiotherapy (RT) for vulvar cancer has been poorly investigated. PATIENTS AND METHODS: We performed a multicentre retrospective register study of 257 patients with primary squamous vulvar cancer. The survival effect of adjuvant RT was investigated in two groups of patients, dependent on surgical margins. The outcome measure was overall survival. All statistical tests were two-sided. RESULTS: Of the 257 patients investigated, 192 had negative resection margins, while positive and/or close surgical margins were observed in 65 cases. Margin status was associated with unfavourable overall survival. The five-year overall survival was 66.1 and 49.2% in patients with negative and positive/close resection margins, respectively. Adjuvant RT directed to the vulva was associated with improved survival in patients with positive/close resection margins but not in patients with negative surgical margins. The 5-year overall survival of patients with positive/close surgical margins without RT was 29%, whereas with RT it increased to 67.6%. Notably, patients with positive/close surgical margins who received RT of the vulva had a 5-year survival rate similar to the patients with negative margins (67.6%). Multivariate analysis adjusted for age, stage of disease, tumour grade and lymph node metastases showed that adjuvant RT significantly reduced the mortality risk in patients with positive/close resection margins (HR 0.36, CI 0.14-0.94, p = 0.038). In the group of patients with negative resection margins, the involvement of lymph nodes was the strongest unfavourable prognostic factor. CONCLUSIONS: Adjuvant RT should be used for patients with positive/close surgical margins to improve their outcome. PMID- 26498776 TI - Identification of differentially expressed genes associated with burn sepsis using microarray. AB - The aim of the present study was to identify the potential target biomarkers associated with burn sepsis using microarray. GSE1781 was downloaded from Gene Expression Omnibus and included a collective of three biological replicates for each of the three conditions: Sham-Sham, Sham-cecal ligation and puncture (CLP) and Burn-CLP. Subsequently, limma was applied to screen the differentially expressed genes (DEGs). Additionally, functional annotations were predicted by pathway enrichment. Furthermore, the transcription factors were screened according to the transcriptional regulation from patterns to profiles database. Furthermore, the interaction associations of the proteins were obtained from the STRING database and the protein-protein interaction (PPI) network was constructed using Cytoscape. Finally, the gene co-expression analysis was conducted using CoExpress. In total, compared with Sham-Sham, a total of 476 DEGs and 682 DEGs were obtained in Sham-CLP and Burn-CLP, respectively. Additionally, 230 DEGs were screened in Burn-CLP compared with Sham-CLP. Acadm, Ehhadh and Angptl4 were significantly enriched in the PPAR signaling pathway. Additionally, Gsta3, Gstm2 and Gstt1 in Burn-CLP were significantly enriched in glutathione metabolism. In the PPI network, the transcription factor Ppargc1a interacted with Angptl4, while Acadm interacted with Ehhadh. The gene co-expression analysis showed that Ehhadh could be co-expressed with Aqp8. In conclusion, Acadm, Ehhadh, Aqp8, Gsta3, Gstm2, Gstt1, Ppargc1a and Angptl4 may be potential target genes for the treatment of burn sepsis. PMID- 26498777 TI - Long-Term Live Cell Imaging of Cell Migration: Effects of Pathogenic Fungi on Human Epithelial Cell Migration. AB - Long-term live cell imaging was used in this study to determine the responses of human epithelial cells to pathogenic biofilms formed by Candida albicans. Epithelial cells of the skin represent the front line of defense against invasive pathogens such as C. albicans but under certain circumstances, especially when the host's immune system is compromised, the skin barrier is breached. The mechanisms by which the fungal pathogen penetrates the skin and invade the deeper layers are not fully understood. In this study we used keratinocytes grown in culture as an in vitro model system to determine changes in host cell migration and the actin cytoskeleton in response to virulence factors produced by biofilms of pathogenic C. albicans. It is clear that changes in epithelial cell migration are part of the response to virulence factors secreted by biofilms of C. albicans and the actin cytoskeleton is the downstream effector that mediates cell migration. Our goal is to understand the mechanism by which virulence factors hijack the signaling pathways of the actin cytoskeleton to alter cell migration and thereby invade host tissues. To understand the dynamic changes of the actin cytoskeleton during infection, we used long-term live cell imaging to obtain spatial and temporal information of actin filament dynamics and to identify signal transduction pathways that regulate the actin cytoskeleton and its associated proteins. Long-term live cell imaging was achieved using a high resolution, multi-mode epifluorescence microscope equipped with specialized light sources, high-speed cameras with high sensitivity detectors, and specific biocompatible fluorescent markers. In addition to the multi-mode epifluorescence microscope, a spinning disk confocal long-term live cell imaging system (Olympus CV1000) equipped with a stage incubator to create a stable in vitro environment for long-term real-time and time-lapse microscopy was used. Detailed descriptions of these two long-term live cell imaging systems are provided. PMID- 26498778 TI - Live-Cell Imaging of Mitochondria and the Actin Cytoskeleton in Budding Yeast. AB - Maintenance and regulation of proper mitochondrial dynamics and functions are necessary for cellular homeostasis. Numerous diseases, including neurodegeneration and muscle myopathies, and overall cellular aging are marked by declining mitochondrial function and subsequent loss of multiple other cellular functions. For these reasons, optimized protocols are needed for visualization and quantification of mitochondria and their function and fitness. In budding yeast, mitochondria are intimately associated with the actin cytoskeleton and utilize actin for their movement and inheritance. This chapter describes optimal approaches for labeling mitochondria and the actin cytoskeleton in living budding yeast cells, for imaging the labeled cells, and for analyzing the resulting images. PMID- 26498779 TI - Imaging of the Actin Cytoskeleton and Mitochondria in Fixed Budding Yeast Cells. AB - The budding yeast Saccharomyces cerevisiae is widely used as a model system to study the organization and function of the cytoskeleton. In the past, its small size, rounded shape, and rigid cell wall created obstacles to explore the cell biology of this model eukaryote. It is now possible to acquire and analyze high resolution and super-resolution multidimensional images of the yeast cell. As a result, imaging of yeast has emerged as an important tool in eukaryotic cell biology. This chapter describes labeling methods and optical approaches for visualizing the cytoskeleton and interactions of the actin cytoskeleton with mitochondria in fixed yeast cells using wide-field and super-resolution fluorescence microscopy. PMID- 26498780 TI - Imaging of the Cytoskeleton Using Live and Fixed Drosophila Tissue Culture Cells. AB - In recent years, the convergence of multiple technologies and experimental approaches has led to the expanded use of cultured Drosophila cells as a model system. Their ease of culture and maintenance, susceptibility to RNA interference, and imaging characteristics have led to extensive use in both traditional experimental approaches as well as high-throughput RNAi screens. Here we describe Drosophila S2 cell culture and preparation for live-cell and fixed cell fluorescence microscopy and scanning electron microscopy. PMID- 26498781 TI - Imaging Cytoskeleton Components by Electron Microscopy. AB - The cytoskeleton is a complex of detergent-insoluble components of the cytoplasm playing critical roles in cell motility, shape generation, and mechanical properties of a cell. Fibrillar polymers-actin filaments, microtubules, and intermediate filaments-are major constituents of the cytoskeleton, which constantly change their organization during cellular activities. The actin cytoskeleton is especially polymorphic, as actin filaments can form multiple higher order assemblies performing different functions. Structural information about cytoskeleton organization is critical for understanding its functions and mechanisms underlying various forms of cellular activity. Because of the nanometer-scale thickness of cytoskeletal fibers, electron microscopy (EM) is a key tool to determine the structure of the cytoskeleton. This article describes application of rotary shadowing (or metal replica) EM for visualization of the cytoskeleton. The procedure is applicable to thin cultured cells growing on glass coverslips and consists of detergent extraction of cells to expose their cytoskeleton, chemical fixation to provide stability, ethanol dehydration and critical point drying to preserve three-dimensionality, rotary shadowing with platinum to create contrast, and carbon coating to stabilize replicas. This technique provides easily interpretable three-dimensional images, in which individual cytoskeletal fibers are clearly resolved, and individual proteins can be identified by immunogold labeling. More importantly, replica EM is easily compatible with live cell imaging, so that one can correlate the dynamics of a cell or its components, e.g., expressed fluorescent proteins, with high resolution structural organization of the cytoskeleton in the same cell. PMID- 26498782 TI - Purification and Localization of Intraflagellar Transport Particles and Polypeptides. AB - The growth and maintenance of almost all cilia and flagella are dependent on the proper functioning of the process of intraflagellar transport (IFT). This includes the primary cilia of most human cells that are in the Go phase of the cell cycle. The model system for the study of IFT is the flagella of the biflagellate green alga Chlamydomonas. It is in this organism that IFT was first discovered, and genetic data from a Chlamydomonas mutant first linked the process of IFT to polycystic kidney disease in humans. The information provided in this chapter addresses procedures to purify IFT particles from flagella and localize these particles, and their associated motor proteins, in flagella using light and electron microscopic approaches. PMID- 26498783 TI - Fluorescence Imaging of the Cytoskeleton in Plant Roots. AB - During the past two decades the use of live cytoskeletal probes has increased dramatically due to the introduction of the green fluorescent protein. However, to make full use of these live cell reporters it is necessary to implement simple methods to maintain plant specimens in optimal growing conditions during imaging. To image the cytoskeleton in living Arabidopsis roots, we rely on a system involving coverslips coated with nutrient supplemented agar where the seeds are directly germinated. This coverslip system can be conveniently transferred to the stage of a confocal microscope with minimal disturbance to the growth of the seedling. For roots with a larger diameter such as Medicago truncatula, seeds are first germinated in moist paper, grown vertically in between plastic trays, and roots mounted on glass slides for confocal imaging. Parallel with our live cell imaging approaches, we routinely process fixed plant material via indirect immunofluorescence. For these methods we typically use non-embedded vibratome sectioned and whole mount permeabilized root tissue. The clearly defined developmental regions of the root provide us with an elegant system to further understand the cytoskeletal basis of plant development. PMID- 26498785 TI - Basic Methods to Visualize Actin Filaments In Vitro Using Fluorescence Microscopy for Observation of Filament Severing and Bundling. AB - Dynamics of actin filaments are regulated by a number of actin-binding proteins. To understand the function of an actin-binding protein, it is necessary to characterize effects of the protein on actin filament dynamics in vitro. This chapter describes basic microscopic methods to visualize fluorescently labeled actin filaments using commonly available fluorescence microscope settings. Direct microscopic observation of actin filaments provides strong evidence for severing or bundling of actin filaments. PMID- 26498784 TI - Microtubules in Plant Cells: Strategies and Methods for Immunofluorescence, Transmission Electron Microscopy, and Live Cell Imaging. AB - Microtubules (MTs) are required throughout plant development for a wide variety of processes, and different strategies have evolved to visualize and analyze them. This chapter provides specific methods that can be used to analyze microtubule organization and dynamic properties in plant systems and summarizes the advantages and limitations for each technique. We outline basic methods for preparing samples for immunofluorescence labeling, including an enzyme-based permeabilization method, and a freeze-shattering method, which generates microfractures in the cell wall to provide antibodies access to cells in cuticle laden aerial organs such as leaves. We discuss current options for live cell imaging of MTs with fluorescently tagged proteins (FPs), and provide chemical fixation, high-pressure freezing/freeze substitution, and post-fixation staining protocols for preserving MTs for transmission electron microscopy and tomography. PMID- 26498786 TI - An In Vitro Model System to Test Mechano-microbiological Interactions Between Bacteria and Host Cells. AB - The aim of this chapter is to present an innovative technique to visualize changes of the f-actin cytoskeleton in response to locally applied force. We developed an in vitro system that combines micromanipulation of force by magnetic tweezers with simultaneous live cell fluorescence microscopy. We applied pulling forces to magnetic beads coated with the Neisseria gonorrhoeae Type IV pili in the same order of magnitude than the forces generated by live bacteria. We saw quick and robust f-actin accumulation at the sites where pulling forces were applied. Using the magnetic tweezers we were able to mimic the local response of the f-actin cytoskeleton to bacteria-generated forces. In this chapter we describe our magnetic tweezers system and show how to control it in order to study cellular responses to force. PMID- 26498787 TI - Reconstitution of a Minimal Actin Cortex by Coupling Actin Filaments to Reconstituted Membranes. AB - A thin layer of actin filaments in many eukaryotic cell types drives pivotal aspects of cell morphogenesis and is generally cited as the actin cortex. Myosin driven contractility and actin cytoskeleton membrane interactions form the basis of fundamental cellular processes such as cytokinesis, cell migration, and cortical flows. How the interplay between the actin cytoskeleton, the membrane, and actin binding proteins drives these processes is far from being understood. The complexity of the actin cortex in living cells and the hardly feasible manipulation of the omnipotent cellular key players, namely actin, myosin, and the membrane, are challenging in order to gain detailed insights about the underlying mechanisms. Recent progress in developing bottom-up in vitro systems where the actin cytoskeleton is combined with reconstituted membranes may provide a complementary route to reveal general principles underlying actin cortex properties. In this chapter the reconstitution of a minimal actin cortex by coupling actin filaments to a supported membrane is described. This minimal system may be very well suited to study for example protein interactions on membrane bound actin filaments in a very controlled and quantitative manner as it may be difficult to perform in living systems. PMID- 26498788 TI - Use of Nanobodies to Localize Endogenous Cytoskeletal Proteins and to Determine Their Contribution to Cancer Cell Invasion by Using an ECM Degradation Assay. AB - There are numerous ways to study actin cytoskeletal structures, and thereby identify the underlying mechanisms of organization and their regulating proteins. Traditional approaches make use of protein overexpression or siRNA. However to study or modulate resident endogenous proteins, complementary methods are required. Since the discovery of nanobodies in 1993, they have proven to represent interesting tools in a variety of applications due to their high affinity, solubility, and stability. Especially their intracellular functionality makes them ideally suited for the study of actin cytoskeletal regulation. Here we provide a protocol to clone nanobody cDNAs in frame with an EGFP or mCherry fluorescent tag. We explain how to transfect this fusion protein in eukaryotic (cancer) cells and how to perform immunofluorescence. This allows microscopic analysis of endogenous (cytoskeletal) proteins and gives insight into their endogenous localization. Moreover, we outline an extracellular matrix (ECM) degradation assay as an application of the general protocol. By seeding cells onto a fluorescently labeled gelatin matrix, degradation can be quantified by means of a matrix degradation index. This assay demonstrates the contribution of a protein during cancer cell invasiveness in vitro and the potential of a nanobody to inhibit this degradation through modulation of its target. PMID- 26498790 TI - Quantitative Motion Analysis in Two and Three Dimensions. AB - This chapter describes 2D quantitative methods for motion analysis as well as 3D motion analysis and reconstruction methods. Emphasis is placed on the analysis of dynamic cell shape changes that occur through extension and retraction of force generating structures such as pseudopodia and lamellipodia. Quantitative analysis of these structures is an underutilized tool in the field of cell migration. Our intent, therefore, is to present methods that we developed in an effort to elucidate mechanisms of basic cell motility, directed cell motion during chemotaxis, and metastasis. We hope to demonstrate how application of these methods can more clearly define alterations in motility that arise due to specific mutations or disease and hence, suggest mechanisms or pathways involved in normal cell crawling and treatment strategies in the case of disease. In addition, we present a 4D tumorigenesis model for high-resolution analysis of cancer cells from cell lines and human cancer tissue in a 3D matrix. Use of this model led to the discovery of the coalescence of cancer cell aggregates and unique cell behaviors not seen in normal cells or normal tissue. Graphic illustrations to visually display and quantify cell shape are presented along with algorithms and formulae for calculating select 2D and 3D motion analysis parameters. PMID- 26498789 TI - Actin-Dynamics in Plant Cells: The Function of Actin-Perturbing Substances: Jasplakinolide, Chondramides, Phalloidin, Cytochalasins, and Latrunculins. AB - This chapter gives an overview of the most common F-actin-perturbing substances that are used to study actin dynamics in living plant cells in studies on morphogenesis, motility, organelle movement, or when apoptosis has to be induced. These substances can be divided into two major subclasses: F-actin-stabilizing and -polymerizing substances like jasplakinolide and chondramides and F-actin severing compounds like chytochalasins and latrunculins. Jasplakinolide was originally isolated form a marine sponge, and can now be synthesized and has become commercially available, which is responsible for its wide distribution as membrane-permeable F-actin-stabilizing and -polymerizing agent, which may even have anticancer activities. Cytochalasins, derived from fungi, show an F-actin severing function and many derivatives are commercially available (A, B, C, D, E, H, J), also making it a widely used compound for F-actin disruption. The same can be stated for latrunculins (A, B), derived from red sea sponges; however the mode of action is different by binding to G-actin and inhibiting incorporation into the filament. In the case of swinholide a stable complex with actin dimers is formed resulting also in severing of F-actin. For influencing F-actin dynamics in plant cells only membrane permeable drugs are useful in a broad range. We however introduce also the phallotoxins and synthetic derivatives, as they are widely used to visualize F-actin in fixed cells. A particular uptake mechanism has been shown for hepatocytes, but has also been described in siphonal giant algae. In the present chapter the focus is set on F-actin dynamics in plant cells where alterations in cytoplasmic streaming can be particularly well studied; however methods by fluorescence applications including phalloidin and antibody staining as well as immunofluorescence-localization of the inhibitor drugs are given. PMID- 26498791 TI - Measurement of Cell Motility Using Microgrooved Substrates. AB - Cells migrate to perform specific functions such as tissue/organ formation during development or to repair injured tissue. Therefore, the study of cell migration is important not only for fundamental cell biology research, but also to understand tissue morphogenesis and wound healing. In this chapter, we describe a method developed in our laboratory to measure cell migration in a uniaxial direction. In this approach, linear microgrooves, fabricated on a transparent poly(dimethylsiloxane) (PDMS) substrate, allow cells to move in a uniaxial direction, in contrast to the random movement of cells in all directions on a smooth substrate surface. This chapter describes in detail the materials and methods needed to measure cell movement using microgrooved substrates, as well as applications of this method. PMID- 26498792 TI - The Study of Cell Motility by Cell Traction Force Microscopy (CTFM). AB - Migration is a vital characteristic of various cell types and enables various cellular functions during development and wound healing. Cell movement can be measured by monitoring cell traction forces, which are generated by individual cells and transmitted to the substrate below the migrant cells. This method, termed cell traction force microscopy (CTFM), has the advantage of directly measuring the "cause" (i.e., cell traction forces, CTFs) of cell movement rather than the "effect" (i.e., cell movement itself). This chapter details the methods involved in measuring cell traction forces. Several examples are also given to illustrate various applications of CTFM in cell biology research. PMID- 26498793 TI - Melanosome Motility in Fish Retinal Pigment Epithelial (RPE) Cells. AB - Several model systems have been developed to investigate mechanism and regulation of intracellular organelle motility. The fish retinal pigment epithelial (RPE) cell represents a novel yet simple system for the study of organelle motility. Primary cultures of dissociated RPE cells are easily prepared and amenable to motility studies. In vivo, melanin-containing pigment granules (melanosomes) within fish RPE migrate distances up to 100 MUm in response to light flux. When dissociated from the epithelial layer and cultured in vitro, RPE cells attach to the substrate with the apical projections extending radially from the central cell body. Melanosomes can be chemically triggered to aggregate or disperse throughout the projections, and are easily observed using phase contrast microscopy. Melanosome migration in RPE apical projections is dependent on actin filaments, and thus renders this model system useful for investigations of actin dependent organelle motility. PMID- 26498794 TI - Analysis of Stem Cell Motility In Vivo Based on Immunodetection of Planarian Neoblasts and Tracing of BrdU-Labeled Cells After Partial Irradiation. AB - Planarian flatworms have become an important system for the study of stem cell behavior and regulation in vivo. These organisms are able to regenerate any part of their body upon damage or amputation. A crucial cellular event in the process of planarian regeneration is the migration of pluripotent stem cells (known as neoblasts) to the site of injury. Here we describe two approaches for analyzing migration of planarian stem cells to an area where these have been ablated by localized X-ray irradiation. The first approach involves immunolabeling of mitotic neoblasts, while the second is based on tracing stem cells and their progeny after BrdU incorporation. The use of planarians in studies of cell motility is suitable for the identification of factors that influence stem cell migration in vivo and is amenable to RNA interference or pharmacological screening. PMID- 26498795 TI - Chemotaxis: Under Agarose Assay. AB - The unicellular eukaryote Dictyostelium discoideum represents a superb model for examining chemotaxis. Under vegetative conditions, the amoebae are chemotactically responsive to pterins, such as folate. Under starved conditions, they lose their sensitivity to pterins, and become chemotactically responsive to cAMP. As an NIH model system, Dictyostelium offers a variety of advantages in studying chemotaxis, including its conservation of mammalian signaling pathways, its ease of growth, and its genetic tractability. In this chapter, we describe the use of the under agarose chemotaxis assay to identify proteins involved in controlling motility and directional sensing in Dictyostelium discoideum. Given the similarities between Dictyostelium and mammalian cells, this allows us to dissect the conserved pathways involved in eukaryotic chemotaxis. PMID- 26498796 TI - Functional Analysis of Actin-Binding Proteins in the Central Nervous System of Drosophila. AB - Using Drosophila actin-binding protein Dunc-115 as model system, this chapter describes a MARCM (mosaic analysis with a repressible cell marker)-based method for analyzing cytoskeletal components for their functions in the nervous system. Following a concise description about the principle, a step-by-step protocol is provided for generating the needed stocks and for histological analysis. Additional details and explanations have been given in the accompanying notes. Together, this should form a practical and sufficient recipe for performing at the single-cell-level loss-of-function and gain-of-function analyses of proteins associated with the cytoskeleton. PMID- 26498797 TI - Proteomic Analysis of Cytoskeleton Proteins in Fish. AB - In this chapter, we describe laboratory protocols for rearing fish and a simple and efficient method of extracting and identifying pathogen and host proteins that may be involved in entry and replication of commercially important fish viruses. We have used the common carp (Cyprinus carpio L.) and goldfish (Cyprinus auratus) as a model system for studies of proteins involved in viral entry and replication. The chapter describes detailed protocols for maintenance of carp, cell culture, antibody purification of proteins, and use of electrospray ionization mass spectrometry analysis to screen and identify cytoskeleton and other proteins that may be involved in viral infection and propagation in fish. PMID- 26498798 TI - Using a Handheld Gene Gun for Genetic Transformation of Tetrahymena thermophila. AB - This chapter describes protocols for using a handheld gene gun to deliver transformation vectors for overexpression of genes or gene replacement in the macronucleus of Tetrahymena thermophila. The protocols provide helpful information for preparing Tetrahymena for biolistic bombardment, preparation of vector-coated microcarriers, and basic gene gun operating procedures. PMID- 26498799 TI - Proteomic Tools for the Analysis of Cytoskeleton Proteins. AB - Proteomic analyses have become an essential part of the toolkit of the molecular biologist, given the widespread availability of genomic data and open source or freely accessible bioinformatics software. Tools are available for detecting homologous sequences, recognizing functional domains, and modeling the three dimensional structure for any given protein sequence. Although a wealth of structural and functional information is available for a large number of cytoskeletal proteins, with representatives spanning all of the major subfamilies, the majority of cytoskeletal proteins remain partially or totally uncharacterized. Moreover, bioinformatics tools provide a means for studying the effects of synthetic mutations or naturally occurring variants of these cytoskeletal proteins. This chapter discusses various freely available proteomic analysis tools, with a focus on in silico prediction of protein structure and function. The selected tools are notable for providing an easily accessible interface for the novice, while retaining advanced functionality for more experienced computational biologists. PMID- 26498800 TI - Homology Modeling Procedures for Cytoskeletal Proteins of Tetrahymena and Other Ciliated Protists. AB - In recent years there has been an explosive increase in the number of annotated protein sequences available through genome sequencing, as well as an accumulation of published protein structural data based on crystallographic and NMR methods. When taken together with the development of computational methods for the prediction of protein structural and functional properties through homology modeling, an opportunity exists for prediction of properties of cytoskeletal proteins in a suitable model organism, such as Tetrahymena thermophila and its ciliated protist relatives. In particular, the recently sequenced genome of T. thermophila, long a model for cytoskeletal studies, provides a good starting point for undertaking such homology modeling studies. Homology modeling can produce functional predictions, for example regarding potential molecular interactions, that are of great interest to the drug industry and Tetrahymena is an attractive model system in which to follow up computational predictions with experimental analyses. We provide here procedures that can be followed to gain entry into this promising avenue of analysis. PMID- 26498801 TI - Spectroscopic Investigation and Photophysics of a D-pi-A-pi-D Type Styryl Pyrazine Derivative. AB - E,E-2,5-bis(3,4-dimethoxystyryl)pyrazine (BDSP)has been prepared by aldol condensation between 2,5-dimethypyrazine and 3,4-dimthoxybenzaldehyde and characterized by IR, 1HNMR, 13C NMR and X-ray crystallography.The electronic absorption and emission properties of BDSP were studied in different solvents. BDSP displays a strong solvatochromic effect of the emission spectrum that is reflected by large red shifts of its fluorescence emission maximum on increasing the solvent polarity, indicating a large change in dipole moment of BDSP upon excitation due to photoinduced intramolecular charge transfer (PICT). Excited state intermolecular hydrogen bonding affects the energy of emission spectrum and fluorescence quantum yield of BDSP dye. The dye solutions (1*10(-4) M) in DMSO, DMF, CH3CN and dioxane give laser emission in green region upon excitation by a 337.1 nm nitrogen pulse (lambda=337 nm). The tuning range, gain coefficient (alpha), emission cross - section (sigmae) and half-life energy (E1/2) has been determined. Ground and electronic excited states geometric optimization were performed using density functional theory (DFT) and time-dependent density functional theory (TD-DFT), respectively. A DFT natural bond analysis complemented the ICT. BDSP dye displays fluorescence quenching by colloidal silver nanoparticles(AgNPs). The fluorescence data reveal that radiative and non radiative energy transfer play a major role in the fluorescence quenching mechanism. PMID- 26498802 TI - Pushing the limits of nickel detection to nanomolar range using a set of engineered bioluminescent Escherichia coli. AB - The detection of nickel in water is of great importance due to its harmfulness for living organism. A way to detect Ni is the use of whole-cell biosensors. The aim of the present work was to build a light-emitting bacterial biosensor for the detection of Ni with high specificity and low detection limit properties. For that purpose, the regulatory circuit implemented relied on the RcnR Ni/Co metallo regulator and its rcnA natural target promoter fused to the lux reporter genes. To convert RcnR to specifically detect Ni, several mutations were tested and the C35A retained. Deleting the Ni efflux pump rcnA and introducing genes encoding several Ni-uptake systems lowered the detection thresholds. When these constructs were assayed in several Escherichia coli strains, it appeared that the detection thresholds were highly variable. The TD2158 wild-type E. coli gave rise to a biosensor ten times more active and sensitive than its W3110 E. coli K12 equivalent. This biosensor was able to confidently detect Ni concentrations as little as 80 nM (4.7 MUg l-1), which makes its use compatible with the norms governing the drinking water quality. PMID- 26498803 TI - Correlation studies on nitrogen for sunflower crop across the agroclimatic variability. AB - Nitrogen (N) fertilizer is an important yield limiting factor for sunflower production. The correlation between yield components and growth parameters of three sunflower hybrids (Hysun-33, Hysun-38, Pioneer-64A93) were studied with five N rates (0, 60, 120, 180, 240 kg ha(-1)) at three different experimental sites during the two consecutive growing seasons 2008 and 2009. The results revealed that total dry matter (TDM) production and grain yield were positively and linearly associated with leaf area index (LAI), leaf area duration (LAD), and crop growth rate (CGR) at all three sites of the experiments. The significant association of yield with growth components indicated that the humid climate was most suitable for sunflower production. Furthermore, the association of these components can be successfully used to predict the grain yield under diverse climatic conditions. The application of N at increased rate of 180 kg ha(-1) resulted in maximum yield as compared to standard rate (120 kg ha(-1)) at all the experimental sites. In this way, N application rate was significantly correlated with growth and development of sunflower under a variety of climatic conditions. Keeping in view such relationship, the N dose can be optimized for sunflower crop in a particular region to maximize the productivity. Multilocation trails help to predict the input rates precisely while taking climatic variations into account also. In the long run, results of this study provides basis for sustainable sunflower production under changing climate. PMID- 26498804 TI - Identification of nitrate leaching loss indicators through regression methods based on a meta-analysis of lysimeter studies. AB - This study presents a meta-analysis of 12 experiments that quantify nitrate-N leaching losses from grazed pasture systems in alluvial sedimentary soils in Canterbury (New Zealand). Mean measured nitrate-N leached (kg N/ha * 100 mm drainage) losses were 2.7 when no urine was applied, 8.4 at the urine rate of 300 kg N/ha, 9.8 at 500 kg N/ha, 24.5 at 700 kg N/ha and 51.4 at 1000 kg N/ha. Lismore soils presented significantly higher nitrate-N losses compared to Templeton soils. Moreover, a multiple linear regression (MLR) model was developed to determine the key factors that influence nitrate-N leaching and to predict nitrate-N leaching losses. The MLR analyses was calibrated and validated using 82 average values of nitrate-N leached and 48 explanatory variables representative of nitrogen inputs and outputs, transport, attenuation of nitrogen and farm management practices. The MLR model (R (2) = 0.81) showed that nitrate-N leaching losses were greater at higher urine application rates and when there was more drainage from rainfall and irrigation. On the other hand, nitrate leaching decreased when nitrification inhibitors (e.g. dicyandiamide (DCD)) were applied. Predicted nitrate-N leaching losses at the paddock scale were calculated using the MLR equation, and they varied largely depending on the urine application rate and urine patch coverage. PMID- 26498806 TI - Optimization of silica removal with magnesium chloride in papermaking effluents: mechanistic and kinetic studies. AB - The reuse of deinking paper mill effluent based on reverse osmosis is limited by silica scaling on the membranes. The removal of silica during softening processes is one of the most used approaches as it can treat large volumes of water at low cost, but when the water hardness is low, the addition of magnesium compounds is necessary. In the present investigation, MgCl2.6H2O was selected as magnesium source to analyze the effect of pH, dosage, temperature, and contact time on silica removal. Moreover, the silica removal mechanism was analyzed under different operational conditions. The results show that it is possible to obtain high silica removal rates (>70%) at an intermediate dosage (750 mg/L of MgCl2.6H2O) either at high pH (12.0) and ambient temperature (20 degrees C) or lower pHs, i.e., pH = 10.5, but at higher temperatures 35-50 degrees C. The kinetic study demonstrates that contact times lower than 30 min are enough for silica removal with independence of the temperature. SEM-energy-dispersive X-ray spectroscopy (EDX) and Fourier transform infrared spectroscopy (FTIR) analysis of the solids obtained confirms that silica is removed through the formation of magnesium silicates. The EDX analysis showed that, independently of the operational conditions, the atomic Si/Mg ratio was around 0.7 which indicates that antigorite (Mg3Si2O5(OH)4) is the predominant specie formed. PMID- 26498805 TI - Arsenopyrite weathering under conditions of simulated calcareous soil. AB - Mining activities release arsenopyrite into calcareous soils where it undergoes weathering generating toxic compounds. The research evaluates the environmental impacts of these processes under semi-alkaline carbonated conditions. Electrochemical (cyclic voltammetry, chronoamperometry, EIS), spectroscopic (Raman, XPS), and microscopic (SEM, AFM, TEM) techniques are combined along with chemical analyses of leachates collected from simulated arsenopyrite weathering to comprehensively examine the interfacial mechanisms. Early oxidation stages enhance mineral reactivity through the formation of surface sulfur phases (e.g., S n (2-)/S(0)) with semiconductor properties, leading to oscillatory mineral reactivity. Subsequent steps entail the generation of intermediate siderite (FeCO3)-like, followed by the formation of low-compact mass sub-micro ferric oxyhydroxides (alpha, gamma-FeOOH) with adsorbed arsenic (mainly As(III), and lower amounts of As(V)). In addition, weathering reactions can be influenced by accessible arsenic resulting in the formation of a symplesite (Fe3(AsO4)3)-like compound which is dependent on the amount of accessible arsenic in the system. It is proposed that arsenic release occurs via diffusion across secondary alpha, gamma-FeOOH structures during arsenopyrite weathering. We suggest weathering mechanisms of arsenopyrite in calcareous soil and environmental implications based on experimental data. PMID- 26498807 TI - Comparison of the properties of periphyton attached to modified agro-waste carriers. AB - Periphyton is a valuable, environmentally benign resource widely used in environmental remediation. A protocol for reusing agro-wastes to improve the metabolic activity and versatility of periphyton was tested in this study. Peanut shell (PS), decomposed peanut shell (DPS), acidified peanut shell (APS), rice husks (RHs), acidified rice husks (ARHs), and a commonly used synthetic carrier, ceramsite (C), were used to support periphyton attachment and growth. The results show that the modified carriers have more hydrophilic groups, higher periphyton biomass, and autotrophic indices than the unmodified carriers. As a consequence, they promote the metabolic versatility of periphyton microbial communities. Thus, the periphyton attached to modified agro-wastes (DPS, APS, and ARH) grew in a stable and sustainable manner. This study suggests that modified PS and RH are effective and environmentally benign carriers that enhance periphyton activity and functionality. Development of periphytic carriers using agro-wastes is also a sustainable method of reusing these materials. PMID- 26498808 TI - Stakeholder consultations and opportunities for integrating socio-behavioural factors into the pesticide risk analysis process. AB - The pesticide risk analysis process is well regulated in the EU, especially in relation to placing on the market authorisation procedures, but in order to avoid risks for human health and environment in the use phase, information on how these substances are employed and on socio-behavioural factors that can influence the exposure have to be taken into account. To better explore reasons about the gap between risk assessment and risk management, within the EU FP7 Health and Environmental Risks: Organisation, Integration and Cross-fertilisation of Scientific Knowledge (HEROIC) project, a stepwise stakeholder's consultation process was developed using a mixed approach in two different phases (survey and roundtable). We elicited stakeholder views regarding factors that could limit the pesticide risk assessment phase linked on how the knowledge is produced and the way the data are used in risk management and in risk communication, also taking into account qualitative factors such as responsibility, trust and behaviours, which could have impact on risk assessment policies. Activities deployed indicate that some changes and interaction are needed to better define the problems at the formulation stage, and the type of information risk assessor has to provide, to better inform risk manager in addressing different societal needs, to strengthen the credibility of the process of risk assessment and improve the effectiveness of policies. Integrations between disciplines may initially increase the complexity but in turn will provide a better and more useful estimation of the risk, reinforce transparency and drive a more efficient use of risk management resources. PMID- 26498810 TI - The co-occurrence of the demosponge Hymeniacidon perlevis and the edible mussel Mytilus galloprovincialis as a new tool for bacterial load mitigation in aquaculture. AB - Pollutants in marine coastal areas are mainly a consequence of anthropogenic inputs, and microorganisms often play a major role in determining the extent of this pollution. Thus, practical and eco-friendly techniques are urgently required in order to control or minimise the pathogenic bacterial problem. The bacterial accumulation of Mytilus galloprovincialis (Lamarck 1919) in the presence or absence of another filter feeder, the demosponge Hymeniacidon perlevis (Montagu 1818) on sewage flowing into the Northern Ionian Sea has been estimated in a laboratory study. On account of the interesting results obtained, we also evaluated the bioremediation capability of the sponges when reared in co-culture with mussels. Specimens of M. galloprovincialis and H. perlevis were collected from the Mar Grande and from the Second Inlet of the Mar Piccolo of Taranto (Northern Ionian Sea, Italy), respectively. In the laboratory, we detected the bacterial abundances in the sewage, in sponge homogenates (both sponges alone and sponges that have been added to sewage with mussels) and in mussel homogenates (both mussels alone and mussels that have been added to sewage with sponges). In the field, we estimated the bacterial concentration in both the seawater within the mussels culture and the seawater collected where mussels were reared in co culture with sponges. The bacteriological analyses were performed analysing the following parameters: the density of culturable heterotrophic bacteria by spread plate on marine agar, total culturable bacteria at 37 degrees C on plate count agar and vibrios on thiosulphate-citrate-bile-sucrose-salt (TCBS) agar. Total coliforms, Escherichia coli and intestinal streptococci concentrations were detected by the MPN method. The study demonstrates a higher efficiency of the sponges in removing all the considered bacterial groups compared to the mussels. Due to the conspicuous bacterial accumulation by the sponge, we can conclude that the co-occurrence of the filter-feeder H. perlevis with M. galloprovincialis is a powerful tool in reducing the bacterial load in shellfish culture areas thus playing a role in mitigating the health hazard related to the consumption of edible mussels. PMID- 26498809 TI - Degradation of monocrotophos by Starkeya novella YW6 isolated from paddy soil. AB - A bacteria strain, YW6, capable of utilizing monocrotophos (MCP) as the sole carbon and nitrogen sources for growth was isolated from paddy soil and identified as Starkeya novella. Strain YW6 completely degraded 0.2 mM MCP within 36 h without any lag period. Addition of carbon source resulted in slowing down of the initial rate of degradation of MCP, while the presence of a more favorable source of nitrogen enhanced the degradation of MCP. In addition to the degradation of MCP, strain YW6 was also able to degrade a wide range of organophosphorus pesticides (OPs) containing P-O-C bond, but not dimethoate, which has P-S-C bond. A MCP degradation pathway was proposed on the basis of metabolite production patterns and identification of the metabolites. MCP is hydrolyzed at the P-O-C bond to form N-methylacetoacetamide and dimethyl phosphate; N-methylacetoacetamide is transformed to N-methyl-4-oxo-pentanamide, which was subsequently converted to 5-(methylamino)-5-oxo-pentanoic acid, and 5 (methylamino)-5-oxo-pentanoic acid is cleaved to glutaric acid and methylamine. These findings provide new insights into the microbial metabolism of MCP. To the best of our knowledge, this is the first report on the degradation of MCP by Starkeya bacteria. PMID- 26498811 TI - Best available techniques (BATs) for oil spill response in the Mediterranean Sea: calm sea and presence of economic activities. AB - An oil spill is the accidental or intentional discharge of petroleum products into the environment due to human activities. Although oil spills are actually just a little percent of the total world oil pollution problem, they represent the most visible form of it. The impact on the ecosystems can be severe as well as the impact on economic activities. Oil spill cleanup is a very difficult and expensive activity, and many techniques are available for it. In previous works, a methodology based on different kinds of criteria in order to come to the most satisfactory technique was proposed and the relative importance of each impact criterion on the basis of the Saaty's Analytic Hierarchy Process (AHP) was also evaluated. After a review of the best available techniques (BATs) available for oil spill response, this work suggests criteria for BATs' selection when oil spills occur in the Mediterranean Sea under well-defined circumstances: calm sea and presence of economic activities in the affected area. A group of experts with different specializations evaluated the alternative BATs by means of AHP method taking into account their respective advantages and disadvantages. PMID- 26498812 TI - Biodegradation of polycyclic aromatic hydrocarbons by Trichoderma species: a mini review. AB - Fungi belonging to Trichoderma genus are ascomycetes found in soils worldwide. Trichoderma has been studied in relation to diverse biotechnological applications and are known as successful colonizers of their common habitats. Members of this genus have been well described as effective biocontrol organisms through the production of secondary metabolites with potential applications as new antibiotics. Even though members of Trichoderma are commonly used for the commercial production of lytic enzymes, as a biological control agent, and also in the food industry, their use in xenobiotic biodegradation is limited. Trichoderma stands out as a genus with a great range of substrate utilization, a high production of antimicrobial compounds, and its ability for environmental opportunism. In this review, we focused on the recent advances in the research of Trichoderma species as potent and efficient aromatic hydrocarbon-degrading organisms, as well as aimed to provide insight into its potential role in the bioremediation of soils contaminated with heavy hydrocarbons. Several Trichoderma species are associated with the ability to metabolize a variety of both high and low molecular weight polycyclic aromatic hydrocarbons (PAHs) such as naphthalene, phenanthrene, chrysene, pyrene, and benzo[a]pyrene. PAH-degrading species include Trichoderma hamatum, Trichoderma harzianum, Trichoderma reesei, Trichoderma koningii, Trichoderma viride, Trichoderma virens, and Trichoderma asperellum using alternate enzyme systems commonly seen in other organisms, such as multicooper laccases, peroxidases, and ring-cleavage dioxygenases. Within these species, T. asperellum stands out as a versatile organism with remarkable degrading abilities, high tolerance, and a remarkable potential to be used as a remediation agent in polluted soils. PMID- 26498813 TI - Airborne microorganisms cultivable on naturally ventilated document repositories of the National Archive of Cuba. AB - The quality of the indoor air can provide very useful information for the artwork conservation. The aim of the study was to evaluate the microbial concentration inside six document repositories of the National Archive of the Republic of Cuba in two months of 1 year. The repositories are large, high, and have a natural cross-ventilation system. The microbial sampling was done in July 2010 (summer or rainy month) and February 2011 (winter or dry month) using the SAS Super 100 biocollector at 100 L/min. An appropriate selective culture media were used to isolate fungi and bacteria. A high total microbial concentration on the north side of the building in two studied months was observed. The fungal concentrations were significantly higher in July 2010 in all repositories, while the bacterial concentrations were significantly higher mostly in February 2011 only in repositories located on the first and second floor of the building. Eight fungal genera in the indoor air of all environments were isolated. Regardless of the side of the analyzed building, Penicillium, Aspergillus, and Cladosporium were the predominant genera. Aspergillus flavus and Aspergillus niger were the species isolated in almost all of the analyzed repositories in the studied months. Gram-positive bacteria prevailed among bacterial groups isolated from indoor air repositories, and some percentages corresponded to the genera Bacillus and Streptomyces. In Cuba, the temperature and relative humidity are high during the whole year but the natural ventilation plays an important role in retarding microbial growth on materials. PMID- 26498814 TI - 'End to end' planktonic trophic web and its implications for the mussel farms in the Mar Piccolo of Taranto (Ionian Sea, Italy). AB - The Mar Piccolo is a semi-enclosed basin subject to different natural and anthropogenic stressors. In order to better understand plankton dynamics and preferential carbon pathways within the planktonic trophic web, an integrated approach was adopted for the first time by examining all trophic levels (virioplankton, the heterotrophic and phototrophic fractions of pico-, nano- and microplankton, as well as mesozooplankton). Plankton abundance and biomass were investigated during four surveys in the period 2013-2014. Beside unveiling the dynamics of different plankton groups in the Mar Piccolo, the study revealed that high portion of the plankton carbon (C) pool was constituted by small-sized (<2 MUm) planktonic fractions. The prevalence of small-sized species within micro- and mesozooplankton communities was observed as well. The succession of planktonic communities was clearly driven by the seasonality, i.e. by the nutrient availability and physical features of the water column. Our hypothesis is that beside the 'bottom-up' control and the grazing pressure, inferred from the C pools of different plankton groups, the presence of mussel farms in the Mar Piccolo exerts a profound impact on plankton communities, not only due to the important sequestration of the plankton biomass but also by strongly influencing its structure. PMID- 26498815 TI - Cadmium stress alters the redox reaction and hormone balance in oilseed rape (Brassica napus L.) leaves. AB - In order to understand the physiological response of oilseed rape (Brassica napus L.) leaves to cadmium (Cd) stress and exploit the physiological mechanisms involved in Cd tolerance, macro-mineral and chlorophyll concentrations, reactive oxygen species (ROS) accumulation, activities of enzymatic antioxidants, nonenzymatic compounds metabolism, endogenous hormonal changes, and balance in leaves of oilseed rape exposed to 0, 100, or 200 MUM CdSO4 were investigated. The results showed that under Cd exposure, Cd concentrations in the leaves continually increased while macro-minerals and chlorophyll concentrations decreased significantly. Meanwhile, with increased Cd stress, superoxide anion (O2(* -)) production rate and hydrogen peroxide (H2O2) concentrations in the leaves increased significantly, which caused malondialdehyde (MDA) accumulation and oxidative stress. For scavenging excess accumulated ROS and alleviating oxidative injury in the leaves, the activity of enzymatic antioxidants, such as superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), was increased significantly at certain stress levels. However, with increased Cd stress, the antioxidant enzyme activities all showed a trend towards reduction. The nonenzymatic antioxidative compounds, such as proline and total soluble sugars, accumulated continuously with increased Cd stress to play a long-term role in scavenging ROS. In addition, ABA levels also increased continuously with Cd stress while ZR decreased and the ABA/ZR ratio increased, which might also be providing a protective role against Cd toxicity. PMID- 26498816 TI - The biosorption capacity of biochar for 4-bromodiphengl ether: study of its kinetics, mechanism, and use as a carrier for immobilized bacteria. AB - Polybrominated diphenyl ethers (PBDEs) are known as ubiquitous pollutants in ecological systems and thus pose a great threat to the health of humans and other organisms due to their bioamplification and bioaccumulation along the food chain. The present study was designed to investigate the biosorption capacity of biochar for the removal of 4-monobromodiphengl ether and its synergistic effect when used as a carrier to immobilize the 4-monobromodiphengl ether-degrading strain Sphingomonas sp. DZ3. The raw biochar material was prepared by pyrolyzing maize straw at 350 degrees C under oxygen-limited conditions. The maximum biosorption capacity of biochar for 4-bromodiphengl ether was determined to be 50.23 mg/L under an initial concentration of 800 mg/L at pH 7.0 and 40 degrees C. The data obtained from the biosorption studies were fitted successfully with the pseudo first-order kinetic and Freundlich isotherm models. The Weber-Morris model analysis indicated that intraparticle diffusion was the limiting step in the biosorption of 4-bromodiphengl ether onto the biosorbent. The values of thermodynamic parameters ?G0 were calculated as -24.61 kJ/mol (20 degrees C), 24.35 kJ/mol (30 degrees C), and -23.98 kJ/mol (40 degrees C), ?S(0) was -8.45 kJ/mol/K, and ?H(0) was 21.36 kJ/mol. The artificial neural network analysis indicated that the initial concentration appeared to be the most influential parameter on the biosorption processes. The removal rate of 4-bromodiphengl ether achieved using the biochar-microorganism system was increased by 63 and 83% compared with the rates obtained with biochar and the strain individually, respectively. The morphology of the biochar and immobilized strain was determined using a scanning electron microscope, and information of the surface functional groups of biochar was obtained through an infrared spectra study. PMID- 26498817 TI - Mitigation of cadmium and arsenic in rice grain by applying different silicon fertilizers in contaminated fields. AB - A field experiment was established to support the hypothesis that application of different silicon (Si) fertilizers can simultaneously reduce cadmium (Cd) and arsenic (As) concentration in rice grain. The "semi-finished product of Si-potash fertilizer" treatment at the high application of 9000 kg/ha (NP+S-KSi9000) significantly reduced the As concentration in rice grain by up to 20.1%, compared with the control. Si fertilization reduces the Cd concentration in rice considerably more than the As concentration. All Si fertilizers apart from sodium metasilicate (Na2SiO3) exhibited a high ability to reduce Cd concentration in rice grain. The Si-calcium (CaSi) fertilizer is the most effective in the mitigation of Cd concentration in rice grain. The CaSi fertilizer applied at 9000 kg/ha (NPK+CaSi9000) and 900 kg/ha (NPK+CaSi900) reduced the Cd concentration in rice grain about 71.5 and 48.0%, respectively, while the Si-potash fertilizer at 900 kg/ha (NP+KSi900), the semi-finished product of Si-potash fertilizer at both 900 kg/ha (NP+S-KSi900) and 9000 kg/ha (NP+S-KSi9000), and the rice straw (NPK+RS) treatments reduced the Cd concentration in rice grain about 42, 26.5, 40.7, and 23.1%, respectively. The results of this investigation demonstrated the potential effects of Si fertilizers in reducing Cd and As concentrations in rice grain. PMID- 26498818 TI - Cu retention in an acid soil amended with perlite winery waste. AB - The effect of perlite waste from a winery on general soil characteristics and Cu adsorption was assessed. The studied soil was amended with different perlite waste concentrations corresponding to 10, 20, 40 and 80 Mg ha(-1). General soil characteristics and Cu adsorption and desorption curves were determined after different incubation times (from 1 day to 8 months). The addition of perlite waste to the soil increased the amounts of organic matter as well as soil nutrients such as phosphorus and potassium, and these increments were stable with time. An increase in Cu adsorption capacity was also detected in the perlite waste-amended soils. The effect of perlite waste addition to the soil had special relevance on its Cu adsorption capacity at low coverage concentrations and on the energy of the soil-Cu bonds. PMID- 26498819 TI - Effect of resin content and substrate on the emission of BTEX and carbonyls from low-VOC water-based wall paint. AB - The primary aim of this work is to explore the effect of resin content and the effect of substrate on the emission of benzene, toluene, ethylbenzene, and xylene (BTEX) and carbonyls from low-VOC water-based wall paint. Four low-volatile organic compound (VOC) paints include paints A (20% acrylic), B (30% acrylic), C (20% polyvinyl acetate), and D (30% polyvinyl acetate) were painted on stainless steel specimen for the study of resin effect. Green calcium silicate, green cement, and stainless steel were painted with paints A and C for the study of substrate effect. Concentrations of the VOCs in the chamber decreased with the elapsed time. Both resin type and resin quantity in paint had effects on VOC emissions. Paints with acrylic resin emitted less BTEX and carbonyls than paints with polyvinyl acetate resin. However, the effects of resin quantity varied with VOCs. Porous substrates were observed to interact more strongly with paints than inert substrates. Both green calcium silicate and green cement substrates have strong power of adsorption of VOCs from wall paints, namely toluene, formaldehyde, acetaldehyde, 2-butanone, methacrolein, butyraldehyde, and benzaldehyde. Some compounds like toluene, formaldehyde, and butyaldehyde were desorbed very slowly from green calcium silicate and green cement substrates. PMID- 26498820 TI - Biological properties of Alsidium corallinum and its potential protective effects against damage caused by potassium bromate in the mouse liver. AB - In the course of searching for hepatoprotective agents from natural sources, the protective effect of chemical constituents of the marine red alga Alsidium corallinum (A. corallinum) against potassium bromate (KBrO3)-induced liver damage in adult mice was investigated. The in vitro antioxidant and antibacterial properties of A. corallinum were firstly investigated. Then, A. corallinum was tested in vivo for its potential protective effects against damage caused by KBrO3 in mice models divided into four groups: controls, KBrO3, KBrO3 + A. corallinum, and A. corallinum. Our results demonstrated the rich composition of A. corallinum in antioxidant compounds like phenolics, flavonoids, anthocyanins, polysaccharides, chlorophyll and carotenoids. Its antioxidant activity was also confirmed using beta-carotene bleaching by linoleic acid assay, reducing sugar test and trolox equivalent antioxidant capacity. The ethanolic extract of A. corallinum also showed good inhibition of the tested bacteria. The coadministration of the red alga associated to the KBrO3 alleviated hepatotoxicity as monitored by the improvement of hepatic oxidative stress biomarkers and plasma biochemical parameters, when compared to the KBrO3-treated mice. These results were confirmed by the improvement of histological and molecular changes. Treatment with A. corallinum prevented liver damage induced by KBrO3, thus protecting the body against free radicals and reducing inflammation and hypercholesterolemia risks. PMID- 26498822 TI - Quality means decency-on the quality of teaching through accreditation of the course? AB - The term "accreditation" applies to the attempts in various fields of scientific work and administration. It refers to an acknowledgement of some particular positive (wanted) property being present in or brought about by either a procedure or technical system, an acknowledgement which is then formally issued by some authority generally accepted to be able to prove and file such statements. Bioindication & Biomonitoring (B&B) technologies are highly influenced by accreditation procedures, because both B&B technologies are often related to accreditation during the overall instrumental measurement processes applied. As an example, tuna fish used for (bio) monitoring salt water systems on pollution by Pb will be presented. Analytical measurement results from the International Measurement Evaluation Programme (IMEP 20) and additionally the construction of the university course "Integrative sustainable management: quality, environmental, health, safety and risk management (QUAR)" are reviewed in this respect. It was a serious finding by the multi-participant IMEP study that neither quality control measures nor accreditation actually ensure improved quality of measurement results, i.e. data produced by analytical laboratories. Accordingly, even though the accreditation of study curricula is often done with utmost diligence and precision, and while it is fairly important for making study curricula throughout Europe (and the World) fitting and comparable to each other to get study results produced and tested at university X also be accepted when changing to university Y, we cannot assume or take for granted that the mere protocol of accreditation will do anything positive to improve the chance to get better or "more correct" results. A single member of lab staff or professor changing to some other position might seriously compromise the turnout of some analytical lab or university course at least in the short term regardless of whether accreditation was done or not. As consequence, data obtained by B&B technologies have to be discussed and handled with the highest care to reach acceptable and scientifically sound goals of quality. PMID- 26498821 TI - An improved effective microorganism (EM) soil ball-making method for water quality restoration. AB - Soil balls containing the so-called effective microorganisms (EM) have been applied to improve water quality of small ponds, lakes, and streams worldwide. However, neither the physical conditions facilitating their proper application nor the diversity of microbial community in such soil balls have been investigated. In this study, the application of 0.75% of hardener to the soil balls exerted almost neutral pH (pH 7.3) which caused up to a fourfold increased hardness of the soil ball. Moreover, the 0.75% of hardener in the soil ball also improved the water quality due to a significant reduction in dissolved oxygen, total phosphorus, and total nitrogen contents. Metagenomic analysis of the microbial community in the soil ball with 0.75% hardener was compared with control (traditional soil ball) through next-generation sequencing. The traditional soil ball microbial community comprised 96.1% bacteria, 2.7% eukaryota, and 1% archaea, whereas the soil ball with 0.75% hardener comprised 71.4% bacteria, 27.9% eukaryota, and 0.2% viruses. Additionally, metagenomic profiles for both traditional and improved soil balls revealed that the various xenobiotic biodegradation, such as those for caprolactam, atrazine, xylene, toluene, styrene, bisphenol, and chlorocyclohexane might be responsible for organic waste cleanup. PMID- 26498823 TI - A comparison of medical litigation filed against obstetrics and gynecology, internal medicine, and surgery departments. AB - BACKGROUND: The aim of this study was to review the typical factors related to physician's liability in obstetrics and gynecology departments, as compared to those in internal medicine and surgery, regarding a breach of the duty to explain. METHODS: This study involved analyzing 366 medical litigation case reports from 1990 through 2008 where the duty to explain was disputed. We examined relationships between patients, physicians, variables related to physician's explanations, and physician's breach of the duty to explain by comparing mean values and percentages in obstetrics and gynecology, internal medicine, and surgical departments with the t-test and chi(2) test. RESULTS: When we compared the reasons for decisions in cases where the patient won, we found that the percentage of cases in which the patient's claim was recognized was the highest for both physician negligence, including errors of judgment and procedural mistakes, and breach of the duty to explain, in obstetrics and gynecology departments; breach of the duty to explain alone in internal medicine departments; and mistakes in medical procedures alone in surgical departments (p = 0.008). When comparing patients, the rate of death was significantly higher than that of other outcomes in precedents where a breach of the duty to explain was acknowledged (p = 0.046). The proportion of cases involving obstetrics and gynecology departments, in which care was claimed to be substandard at the time of treatment, and that were not argued as breach of a duty to explain, was significantly higher than those of other evaluated departments (p <0.001). However, internal medicine and surgical departments were very similar in this context. In obstetrics and gynecology departments, the proportion of cases in which it had been conceded that the duty to explain had been breached when seeking patient approval (or not) was significantly higher than in other departments (p = 0.002). CONCLUSION: It is important for physicians working in obstetrics and gynecology departments to carefully explain the risk of death associated with any planned procedure, and to obtain genuinely informed patient consent. PMID- 26498824 TI - Cerium oxide nanoparticles attenuate acute kidney injury induced by intra abdominal infection in Sprague-Dawley rats. AB - BACKGROUND: Intra-abdominal infection or peritonitis is a cause for great concern due to high mortality rates. The prognosis of severe intra-abdominal infection is significantly diminished in the presence of acute kidney injury (AKI) which is often characterized by renal tubular cell death that can lead to renal failure. The purpose of the current study is to examine the therapeutic efficacy of cerium oxide (CeO2) nanoparticles for the treatment of peritonitis-induced AKI by polymicrobial insult. RESULTS: A one-time administration of CeO2 nanoparticles (0.5 mg/kg) in the absence of antibiotics or other supportive care, attenuated peritonitis-induced tubular dilatation and the loss of brush border in male Sprague-Dawley rats. These improvements in renal structure were accompanied by decreases in serum cystatin-C levels, reduced renal oxidative stress, diminished Stat-3 phosphorylation and an attenuation of caspase-3 cleavage suggesting that the nanoparticle treatment improved renal glomerular filtration rate, diminished renal inflammation and reduced renal apoptosis. Consistent with these data, further analysis demonstrated that the CeO2 nanoparticle treatment diminished peritonitis-induced increases in serum kidney injury molecule-1 (KIM-1), osteopontin, beta-2 microglobulin and vascular endothelial growth factor-A (VEGF A) levels. In addition, the nanoparticle attenuated peritonitis-induced hyperglycemia along with increases in blood urea nitrogen (BUN), serum potassium and sodium. CONCLUSION: CeO2 nanoparticles scavenge reactive oxygen species and attenuate polymicrobial insult induced increase in inflammatory mediators and subsequent AKI. Taken together, the data indicate that CeO2 nanoparticles may be useful as an alternative therapeutic agent or in conjunction with standard medical care for the treatment of peritonitis induced acute kidney injury. PMID- 26498825 TI - A framework for retinal vasculature segmentation based on matched filters. AB - BACKGROUND: Automatic fundus image processing plays a significant role in computer-assisted retinopathy diagnosis. As retinal vasculature is an important anatomical structure in ophthalmic images, recently, retinal vasculature segmentation has received considerable attention from researchers. A segmentation method usually consists of three steps: preprocessing, segmentation, post processing. Most of the existing methods emphasize on the segmentation step. In our opinion, the vessels and background can be easily separable when suitable preprocessing exists. METHODS: This paper represents a new matched filter-based vasculature segmentation method for 2-D retinal images. First of all, a raw segmentation is acquired by thresholding the images preprocessed using weighted improved circular gabor filter and multi-directional multi-scale second derivation of Gaussian. After that, the raw segmented image is fine-tuned by a set of novel elongating filters. Finally, we eliminate the speckle like regions and isolated pixels, most of which are non-vessel noises and miss-classified fovea or pathological regions. RESULTS: The performance of the proposed method is examined on two popularly used benchmark databases: DRIVE and STARE. The accuracy values are 95.29 and 95.69 %, respectively, without a significant degradation of specificity and sensitivity. CONCLUSION: The performance of the proposed method is significantly better than almost all unsupervised methods, in addition, comparable to most of the existing supervised vasculature segmentation methods. PMID- 26498826 TI - HiFive: a tool suite for easy and efficient HiC and 5C data analysis. AB - The chromatin interaction assays 5C and HiC have advanced our understanding of genomic spatial organization, but analysis approaches for these data are limited by usability and flexibility. The HiFive tool suite provides efficient data handling and a variety of normalization approaches for easy, fast analysis and method comparison. Integration of MPI-based parallelization allows scalability and rapid processing time. In addition to single-command analysis of an entire experiment from mapped reads to interaction values, HiFive has been integrated into the open-source, web-based platform Galaxy to connect users with computational resources and a graphical interface. HiFive is open-source software available from http://taylorlab.org/software/hifive/ . PMID- 26498827 TI - Validity of a two-item physical activity questionnaire for assessing attainment of physical activity guidelines in youth. AB - BACKGROUND: As physical activity is important for health and well-being, it is essential to monitor population prevalence of physical activity. Surveillance is dependent on the use of valid and reliable measurement tools. The PACE+ questionnaire is used globally in youth and has acceptable reliability; however it has not been validated in a European sample. The purpose of this study is to validate this instrument in a sample of 10-18 year old Irish youth. METHODS: Participants (n = 419, 45.7 % male) completed the PACE+ two-item questionnaire and were asked to wear an Actigraph accelerometer for eight consecutive days. Freedson cut-points were used to estimate moderate to vigorous physical activity from accelerometer counts. Analyses compared self-report and accelerometry data in participants with (1) >=5 and (2) seven valid accelerometer days. Calculations were performed for the whole sample, and were stratified by sex and school level (primary; post-primary). RESULTS: Spearman correlations between self-reported physical activity levels and accelerometry derived minutes of moderate-to vigorous physical activity per day were small (r = 0.27; seven valid days) to moderate (r = 0.34; >=5 valid days). Higher correlations were found in older participants (post-primary r = 0.39; primary r = 0.24) and females (r = 0.39; males r = 0.27) using >=5 valid days. The agreement level was high (68-96 %). The accuracy of classifying those not meeting the guidelines (specificity) was moderate to high (59-100 %). CONCLUSIONS: The PACE+ self-report instrument has acceptable validity for assessing non-achievement of the adolescent physical activity recommendations. The validity is higher in females and increases with age. The continued use of the tool is recommended and will allow for comparability between studies, tracking of physical activity over time including trends in youth population prevalence. PMID- 26498828 TI - Advanced Sodium Ion Battery Anode Constructed via Chemical Bonding between Phosphorus, Carbon Nanotube, and Cross-Linked Polymer Binder. AB - Maintaining structural stability is a great challenge for high-capacity conversion electrodes with large volume change but is necessary for the development of high-energy-density, long-cycling batteries. Here, we report a stable phosphorus anode for sodium ion batteries by the synergistic use of chemically bonded phosphorus-carbon nanotube (P-CNT) hybrid and cross-linked polymer binder. The P-CNT hybrid was synthesized through ball-milling of red phosphorus and carboxylic group functionalized carbon nanotubes. The P-O-C bonds formed in this process help maintain contact between phosphorus and CNTs, leading to a durable hybrid. In addition, cross-linked carboxymethyl cellulose-citric acid binder was used to form a robust electrode. As a result, this anode delivers a stable cycling capacity of 1586.2 mAh/g after 100 cycles, along with high initial Coulombic efficiency of 84.7% and subsequent cycling efficiency of ~99%. The unique electrode framework through chemical bonding strategy reported here is potentially inspirable for other electrode materials with large volume change in use. PMID- 26498829 TI - An Ester of beta-Hydroxybutyrate Regulates Cholesterol Biosynthesis in Rats and a Cholesterol Biomarker in Humans. AB - In response to carbohydrate deprivation or prolonged fasting the ketone bodies, beta-hydroxybutyrate (betaHB) and acetoacetate (AcAc), are produced from the incomplete beta-oxidation of fatty acids in the liver. Neither betaHB nor AcAc are well utilized for synthesis of sterols or fatty acids in human or rat liver. To study the effects of ketones on cholesterol homeostasis a novel betaHB ester (KE) ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) was synthesized and given orally to rats and humans as a partial dietary carbohydrate replacement. Rats maintained on a diet containing 30-energy % as KE with a concomitant reduction in carbohydrate had lower plasma cholesterol and mevalonate (-40 and -27 %, respectively) and in the liver had lower levels of the mevalonate precursors acetoacetyl-CoA and HMG-CoA (-33 and -54 %) compared to controls. Whole liver and membrane LDL-R as well as SREBP-2 protein levels were higher (+24, +67, and +91 %, respectively). When formulated into a beverage for human consumption subjects consuming a KE drink (30-energy %) had elevated plasma betaHB which correlated with decreased mevalonate, a liver cholesterol synthesis biomarker. Partial replacement of dietary carbohydrate with KE induced ketosis and altered cholesterol homeostasis in rats. In healthy individuals an elevated plasma betaHB correlated with lower plasma mevalonate. PMID- 26498830 TI - Increased lymphangiogenesis in lung metastases from colorectal cancer is associated with early lymph node recurrence and decreased overall survival. AB - Pulmonary metastasectomy (PM) is an accepted treatment modality in colorectal cancer (CRC) patients with pulmonary tumor spread. Positive intrathoracic lymph nodes at the time of PM are associated with a poor prognosis and 5-year survival rates of <20 %. Increased lymphangiogenesis in pulmonary metastases might represent an initial step for a subsequent lymphangiogenic spreading. We aimed to evaluate the presence of lymphangiogenesis in clinically lymph node negative patients undergoing PM and its impact on outcome parameters. 71 patients who underwent PM for CRC metastases were included in this dual-center study. Tissue specimens of pulmonary metastases and available corresponding primary tumors were assessed by immunohistochemistry for lymphatic microvessel density (LMVD) and lymphovascular invasion (LVI). Results were correlated with clinical outcome parameters. LMVD was 13.9 +/- 8.1 and 13.3 +/- 8.5 microvessels/field (mean +/- SD) in metastases and corresponding primary CRC; LVI was evident in 46.5 and 58.6 % of metastases and corresponding primary CRC, respectively. Samples with high LMVD had a higher likelihood of LVI. LVI was associated with early tumor recurrence in intrathoracic lymph nodes and a decreased overall survival (p < 0.001 and p = 0.029). Herein, we present first evidence in a well-defined patient collective that increased lymphangiogenesis is already present in a subtype of pulmonary metastases of patients staged as N0 at the time of PM. This lymphangiogenic phenotype has a strong impact on patients' prognosis. Our findings may have impact on the post-surgical therapeutic management of CRC patients with pulmonary spreading. PMID- 26498831 TI - Internal jugular vein duplication and fenestration: Case series and literature review. AB - We present three cases of duplicated or fenestrated internal jugular veins in patients undergoing neck dissection, including the first known case of concomitant bovine aortic arch. The prevalence of this anomaly is 1.0% (three out of 295 patients). Internal jugular vein duplication and fenestration may risk iatrogenic injury to the vasculature and spinal accessory nerve during neck dissection. The existence of this anatomic abnormality should be considered when variation of the internal jugular vein is encountered. The objective of this report is to discuss the presentation, clinical implications, and literature pertaining to internal jugular vein duplication and fenestration. Laryngoscope, 126:1585-1588, 2016. PMID- 26498832 TI - Community Socioeconomic Disadvantage in Midlife Relates to Cortical Morphology via Neuroendocrine and Cardiometabolic Pathways. AB - Residing in communities of socioeconomic disadvantage confers risk for chronic diseases and cognitive aging, as well as risk for biological factors that negatively affect brain morphology. The present study tested whether community disadvantage negatively associates with brain morphology via 2 biological factors encompassing cardiometabolic disease risk and neuroendocrine function. Participants were 448 midlife adults aged 30-54 years (236 women) who underwent structural neuroimaging to assess cortical and subcortical brain tissue morphology. Community disadvantage was indexed by US Census data geocoded to participants' residential addresses. Cardiometabolic risk was indexed by measurements of adiposity, blood pressure, glucose, insulin, and lipids. Neuroendocrine function was indexed from salivary cortisol measurements taken over 3 days, from which we computed the cortisol awakening response, area-under the-curve, and diurnal cortisol decline. Community disadvantage was associated with reduced cortical tissue volume, cortical surface area, and cortical thickness, but not subcortical morphology. Moreover, increased cardiometabolic risk and a flatter (dysregulated) diurnal cortisol decline mediated the associations of community disadvantage and cortical gray matter volume. These effects were independent of age, sex, and individual-level socioeconomic position. The adverse risks of residing in a disadvantaged community may extend to the cerebral cortex via cardiometabolic and neuroendocrine pathways. PMID- 26498833 TI - The usefulness of C-reactive protein and neutrophil-to-lymphocyte ratio for predicting the outcome in hospitalized patients with liver cirrhosis. AB - BACKGROUND: The role of clinical parameters such as systemic inflammatory response syndrome (SIRS) criteria in predicting the infection remains unclear in cirrhosis patients. The aim was to evaluate the usefulness of inflammatory markers including C-reactive protein (CRP) and the neutrophil-to-lymphocyte ratio (NLR) for diagnosis of infection and predicting the outcomes in hospitalized cirrhotic patients. METHODS: The study included 184 cirrhotic patients consecutively hospitalized from 2011 to 2012. The presence of overt infection and survival was evaluated. CRP concentration, NLR, Model for End-Stage Liver Disease (MELD) score and the presence of SIRS were assessed. RESULTS: The main cause of admission was uncontrolled ascites (36.4 %), followed by varix bleeding (23.9 %), and hepatic encephalopathy (13.6 %). Fifty-eight patients (31.5 %) had overt infection during hospitalization and thirty-two patients (17.4 %) expired during the follow up period (median 38 months). Ninety-two patients (52.2 %) fulfilled the SIRS criteria and among them, only 32 patients (38.5 %) had the overt infection. For diagnose of the infection, baseline CRP concentration was a significant factor compared to the presence of SIRS (odds ratio 1.202, P = 0.003). For predicting one-month short-term survival, MELD score, NLR and WBC count were significant factors but in Child-Pugh class C patients, NLR was only an independent factor. CONCLUSIONS: CRP was a significant indicator of infection in hospitalized cirrhotic patients and a NLR was a useful predictor of 1-month survival, particularly in Child-Pugh class C patients. This study suggests that the inflammatory markers such as CRP and NLR can help identify cirrhotic patients at risk of unfavorable outcomes. PMID- 26498834 TI - LDL cholesterol is not a good marker of cardiovascular risk in Type 1 diabetes. AB - AIM: LDL cholesterol (LDL-C) is considered an important cardiovascular disease (CVD) risk factor. Less is known in Type 1 diabetes. We assessed LDL-C and total cholesterol to HDL cholesterol ratio (TC/HDL-C) as predictors of CVD in Type 1 diabetes. METHODS: The study monitored 30 778 people with Type 1 diabetes, baseline 2003-2006, to 31 December 2011. Cox regression analyses were performed with LDL-C and TC/HDL-C as predictors of fatal/non-fatal CVD. Models were adjusted for traditional CVD risk factors. RESULTS: Hazard ratios (HR) (with 95% CI) per 1 mmol/l increase in LDL-C for CVD were 1.09 (1.01-1.18) in people without lipid-lowering medication and 1.02 (0.95-1.09) in people with lipid lowering medication (P = 0.02 and 0.65). In people aged 40 years or older having a CVD risk factor, and in people with a history of CVD, HR was 1.07 (0.99-1.16) and 1.02 (0.92-1.13) (P = 0.07 and 0.66). HR per 1 unit increase in TC/HDL-C was 1.12 (1.05-1.20) in people without lipid-lowering medication and 1.08 (1.02-1.15) in people with lipid-lowering medication (P < 0.001 and 0.01). For people aged 40 or older and people with a history of CVD, HR was 1.16 (1.09-1.24) and 1.04 (0.95 1.14) (P < 0.001 and 0.43). Broken down into octiles, LDL-C was not a significant predictor of CVD in any group. Higher octiles of TC/HDL-C were significant predictors for CVD in people without lipid-lowering medication and in those aged 40 years or older. CONCLUSION: In this study of people with Type 1 diabetes in clinical practice, LDL-C was not a good predictor of CVD. We found no support for an LDL-C cut-off point < 2.6 mmol/l. TC/HDL-C seems more reliable as a marker for CVD risk when considering primary prevention. PMID- 26498836 TI - The guest-dependent thermal response of the flexible MOF Zn2(BDC)2(DABCO). AB - The guest-dependent thermal response of the flexible MOF Zn2(BDC)2(DABCO) (1) has been studied. A series of temperature-dependent single crystallographic analyses revealed inherent structural thermal responses of 1. The guest-free framework 1 exhibited interesting thermal responses including anisotropic thermal expansion (negative thermal expansion (NTE) along the a- and b-axes, positive thermal expansion (PTE) along the c-axis) and disorder-order phase transition. In addition, inclusion of guest molecules (DMF and benzene) brought distinct thermal responses to 1 from host-guest interactions. 1.4DMF showed altered thermal responses, presenting disorder-order phase transitions at a higher temperature and PTE along the a- and b-axes. Meanwhile, 1.3benzene displayed a quite different type of thermal response such as a hinge like motion (breathing) without a symmetry change. PMID- 26498835 TI - NADPH oxidase 3-associated oxidative stress and caspase 3-dependent apoptosis in the cochleae of D-galactose-induced aged rats. AB - Oxidative damage to mitochondrial DNA (mtDNA) and cell apoptosis are heavily implicated in aging. Our previous study established a mimetic rat model of aging in the cochleae using D-galactose (D-gal), and revealed that chronic injection of D-gal can increase oxidative stress and mtDNA common deletions (CD). The aim of the present study was to investigate the sources of reactive oxygen species and the occurrence of apoptosis in the cochleae of rats following 8 weeks of D-gal exposure. The results of the present study indicated that an elevated accumulation of the mtDNA CD and mitochondrial ultrastructural damage occurred in the cochleae of rats injected with D-gal for 8 weeks. In addition, the levels of 8-hydroxy-2-deoxyguanosine, NADPH oxidase (NOX) 3, P22phox and cleaved caspase 3, and the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end-labelling-positive cells were increased in the cochleae of D-gal-treated rats, compared with the controls. These findings suggested that nitric oxide synthase NOX3-associated oxidative stress may contribute to the accumulation of mtDNA mutations and activate a caspase 3-dependent apoptotic signalling pathway in the cochleae during aging. The present study also provided novel insights into the development of age-associated hearing loss, also termed presbycusis. PMID- 26498837 TI - Charge transfer state emission dynamics in blue-emitting functionalized silicon nanocrystals. AB - We explore the dynamics of blue emission from dodecylamine and ammonia functionalized silicon nanocrystals (Si NCs) with average diameters of ~3 and ~6 nm using time-resolved photoluminescence (TRPL) spectroscopy. The Si NCs exhibit nanosecond PL decay dynamics that is independent of NC size and uniform across the emission spectrum. The TRPL measurements reveal complete quenching of core state emission by a charge transfer state that is responsible for the blue PL with a radiative recombination rate of ~5 * 10(7) s(-1). A detailed picture of the charge transfer state emission dynamics in these functionalized Si NCs is proposed. PMID- 26498838 TI - The inflammatory milieu within the pancreatic cancer microenvironment correlates with clinicopathologic parameters, chemoresistance and survival. AB - BACKGROUND: The tumor microenvironment impacts pancreatic cancer (PC) development, progression and metastasis. How intratumoral inflammatory mediators modulate this biology remains poorly understood. We hypothesized that the inflammatory milieu within the PC microenvironment would correlate with clinicopathologic findings and survival. METHODS: Pancreatic specimens from normal pancreas (n = 6), chronic pancreatitis (n = 9) and pancreatic adenocarcinoma (n = 36) were homogenized immediately upon resection. Homogenates were subjected to multiplex analysis of 41 inflammatory mediators. RESULTS: Twenty-three mediators were significantly elevated in adenocarcinoma specimens compared to nonmalignant controls. Increased intratumoral IL-8 concentrations associated with larger tumors (P = .045) and poor differentiation (P = .038); the administration of neoadjuvant chemotherapy associated with reduced IL-8 concentrations (P = .003). Neoadjuvant therapy was also associated with elevated concentrations of Flt-3 L (P = .005). Elevated levels of pro-inflammatory cytokines IL-1beta (P = .017) and TNFalpha (P = .033) were associated with a poor histopathologic response to neoadjuvant therapy. Elevated concentrations of G-CSF (P = .016) and PDGF-AA (P = .012) correlated with reduced overall survival. Conversely, elevated concentrations of FGF-2 (P = .038), TNFalpha (P = .031) and MIP-1alpha (P = .036) were associated with prolonged survival. CONCLUSION: The pancreatic cancer microenvironment harbors a unique inflammatory milieu with potential diagnostic and prognostic value. PMID- 26498840 TI - The method used to culture host cells (Sf9 cells) can affect the qualities of baculovirus budding particles expressing recombinant proteins. AB - Budded virus (BV) particles of baculovirus (Autographa californica nucleopolyhedrovirus, AcNPV) are harvested from the supernatant of liquid culture of Sf9 host cells by ultracentrifugation. Using polyacrylamide gel electrophoresis, Western blot and transmission electron microscopy (TEM) of BV samples fractionated closely by sucrose density gradient centrifugation, we observed that BVs exhibited different qualities depending on whether they had been harvested from the supernatant from a standing (static), shaking (suspension), or standing/shaking (pre-/post-infection) culture of Sf9 cells. The amount of BV protein apparently increased in the order of standing, standing/shaking, and shaking procedure, and the yield of intact particles showed an opposite trend. TEM observation clearly showed that appropriate fractions of the standing and standing/shaking cultures contained more intact BV particles than those from the shaking culture. These results suggest that the qualities of recombinant BV particles may be related to the culture conditions of the host cells. PMID- 26498839 TI - Age modifies respiratory complex I and protein homeostasis in a muscle type specific manner. AB - Changes in mitochondrial function with age vary between different muscle types, and mechanisms underlying this variation remain poorly defined. We examined whether the rate of mitochondrial protein turnover contributes to this variation. Using heavy label proteomics, we measured mitochondrial protein turnover and abundance in slow-twitch soleus (SOL) and fast-twitch extensor digitorum longus (EDL) from young and aged mice. We found that mitochondrial proteins were longer lived in EDL than SOL at both ages. Proteomic analyses revealed that age-induced changes in protein abundance differed between EDL and SOL with the largest change being increased mitochondrial respiratory protein content in EDL. To determine how altered mitochondrial proteomics affect function, we measured respiratory capacity in permeabilized SOL and EDL. The increased mitochondrial protein content in aged EDL resulted in reduced complex I respiratory efficiency in addition to increased complex I-derived H2 O2 production. In contrast, SOL maintained mitochondrial quality, but demonstrated reduced respiratory capacity with age. Thus, the decline in mitochondrial quality with age in EDL was associated with slower protein turnover throughout life that may contribute to the greater decline in mitochondrial dysfunction in this muscle. Furthermore, mitochondrial-targeted catalase protected respiratory function with age suggesting a causal role of oxidative stress. Our data clearly indicate divergent effects of age between different skeletal muscles on mitochondrial protein homeostasis and function with the greatest differences related to complex I. These results show the importance of tissue-specific changes in the interaction between dysregulation of respiratory protein expression, oxidative stress, and mitochondrial function with age. PMID- 26498841 TI - Steroidal saponins from the rhizomes of Polygonatum prattii. AB - Seven steroidal saponins including two new furostanol glycosides were isolated from the rhizomes of Polygonatum prattii collected from Panzhihua, Sichuan province of China. The new compounds were determined as 26-O-beta-d glucopyranosyl-(25R)-3beta,22xi-dihydroxy-furost-5-en-7-one (pratioside G) and 26 O-beta-D-glucopyranosyl-(25R)-22xi-hydroxy-furost-5-en-3beta-O-beta-D glucopyranosyl-(1->2)-beta-D-glucopyranosyl-(1->2)-[beta-D-xylopyranosyl-(1->3)] beta-D-glucopyranosyl-(1->4)-beta-D-galactopyranoside (pratioside H), on the basis of detailed spectroscopic and chemical analysis. PMID- 26498842 TI - Unusual localization of glomus tumor of the knee. AB - Glomus tumor is an uncommon benign neuromyoarterial tumor. The extradigital location at the knee is unusual. Ignorance of this disease characterized by atypical clinical signs and the absence of specific imaging are responsible for a significant diagnostic delay in these forms localized in the knee. Complete resection of the tumor results in an immediate resolution of the pain. We report three rare locations of glomus tumor in the knee with an exceptional location in the quadriceps tendon and discuss epidemiological, diagnostic and therapeutic aspects of these tumors. PMID- 26498844 TI - Disentangling the effects of solar radiation, wrack macroalgae and beach macrofauna on associated bacterial assemblages. AB - Wrack detritus plays a significant role in shaping community dynamics and food webs on sandy beaches. Macroalgae is the most abundant beach wrack, and it is broken down by the combination of environmental processes, macrofauna grazing, and microbial degradation before returning to the sea as nutrients. The role of solar radiation, algal species and beach macrofauna as ecological drivers for bacterial assemblages associated to wrack was investigated by experimental manipulation of Laminaria ochroleuca and Sargassum muticum. We examined the effects of changes in solar radiation on wrack-associated bacterial assemblages by using cut-off filters: PAR + UVA + UVB (280-700 nm; PAB), PAR + UVA (320-700 nm; PA), PAR (400-700 nm; P), and a control with no filter (C). Results showed that moderate changes in UVR are capable to promote substantial differences on bacterial assemblages so that wrack patches exposed to full sunlight treatments (C and PAB) showed more similar assemblages among them than compared to patches exposed to treatments that blocked part of the solar radiation (P and PA). Our findings also suggested that specific algal nutrient quality-related variables (i.e. nitrogen, C:N ratio and phlorotannins) are main determinants of bacterial dynamics on wrack deposits. We showed a positive relationship between beach macrofauna, especially the most abundant and active wrack-users, the amphipod Talitrus saltator and the coleopteran Phaleria cadaverina, and both bacterial abundance and richness. Moderate variations in natural solar radiation and shifts in the algal species entering beach ecosystems can modify the role of wrack in the energy-flow of nearshore environments with unknown ecological implications for coastal ecosystems. PMID- 26498846 TI - Lyme disease and juvenile idiopathic arthritis - A pediatric case report. PMID- 26498843 TI - Intermedin protects against renal ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress. AB - BACKGROUND: Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene related peptide family. Endoplasmic reticulum stress (ERS) has been implicated in the pathology of renal ischemia/reperfusion (IRI). In the present study, we investigated whether IMD could reduce ERS damage after renal ischemia. METHODS: The kidneys of SD rats were subjected to 45 min of warm ischemia followed by 24 h of reperfusion. The hypoxia/reoxygenation(H/R) model in NRK-52E cells consisted of hypoxia for 1 h and reoxygenation for 2 h. IMD was over-expressed in vivo and in vitro using the vector pcDNA3.1-IMD. The serum creatinine concentration and lactate dehydrogenase (LDH) activity in the plasma were determined. Histologic examinations of renal tissues were performed with PAS staining. Real-time PCR and Western blotting were used to determine the mRNA and protein levels, respectively. Additionally, ER staining was used to detect the ERS response. RESULTS: In the rat renal IRI model, we found that IMD gene transfer markedly improved renal function and pathology and decreased LDH activity and cell apoptosis compared with the kidneys that were transfected with the control plasmid. IMD significantly attenuated the ERS stress parameters compared with IRI group. Indeed, IMD down-regulated glucose-regulated protein 78 (GRP78), C/EBP homologous protein(CHOP), and caspase 12 protein and mRNA levels. Moreover, in the NRK-52E cell H/R model, IMD overexpression prevented the apoptosis induced by H/R. Furthermore, IMD ameliorated the ER structural changes and concomitantly decreased the levels of GRP78, CHOP and caspase-12. CONCLUSION: This study revealed that IMD protects against renal IRI by suppressing ERS and ERS-related apoptosis. PMID- 26498848 TI - The MRTF-A/B function as oncogenes in pancreatic cancer. AB - Despite evidence that MRTF-A/B, co-activators of serum response factor (SRF), promotes tumor cell invasion and metastasis in cancer, there are no studies describing MRTF-A/B in pancreatic cancer. To clarify involvement of MRTF-A/B expression in pancreatic cancer, we used quantitative reverse transcription polymerase chain reaction and western blot analysis to detect MRTF-A/B in pancreatic cancer, intraductal papillary mucinous neoplasm (IPMN) and non neoplastic pancreata. MRTF-A/B expression differs significantly between cancer and non-neoplastic tissues as well as between non-neoplastic tissues and IPMN bulk tissues. Next, we studied the roles of MRTF-A/B in vitro. Overexpression of MRTF-A/B promoted epithelial-mesenchymal transition (EMT) and generated stem cell like cells in normal pancreatic cells. We performed quantitative reverse transcription-polymerase chain reaction to detect the level of MRTF-A/B in 19 pancreatic cancer cell lines. We found that their expression was associated with gemcitabine resistance. Like in normal pancreatic cells, MRTF-A/B also promoted EMT and promoted formation of stem cell-like cells in pancreatic cancer and they could regulate microRNA expression associated with EMT and CICs. Finally, to further demonstrate the roles of MRTF-A/B in vivo, we performed nude mouse model of s.c. xenograft and found that overexpression of MRTF-A and MRTF-B promoted pancreatic cancer growth. Elucidating the roles of MRTF-A/B will help us to further understand molecular basis of the disease and offer new gene targets for effective therapies. PMID- 26498849 TI - Surface air plasma-induced cell death and cytokine release of human keratinocytes in the context of psoriasis. AB - BACKGROUND: Cold atmospheric plasma (CAP) has shown promise for wound healing, although little is understood of the underpinning mechanisms. Little has been reported so far of its potential use in the treatment of immune-mediated diseases such as psoriasis. OBJECTIVES: To study CAP-induced cell death and cytokine release in human keratinocytes as a first assessment of possible CAP use for psoriasis. METHODS: Using a CAP generator free of energetic ions, we observed its effects on keratinocytes in terms of morphology, cell viability and apoptosis, intracellular and mitochondrial reactive oxygen species (ROS), lysosomal integrity and mitochondrial membrane potential; and on secretion and expression of eight cytokines at protein and gene levels. RESULTS: CAP-induced reduced cell viability, apoptotic death and production of intracellular and mitochondrial ROS in dose-dependent manner. Mitochondrial dysfunction and lysosomal leakage were found in CAP-treated cells. It also induced release of interleukin (IL)-6, IL-8, tumour necrosis factor (TNF)-alpha and vascular endothelial growth factor (VEGF), and enhanced the mRNA expression of IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, interferon-gamma and VEGF. By contrast, IL-12 declined monotonically. CONCLUSIONS: The results suggest that with appropriate control of its dose, physical plasma could induce cell death via apoptotic pathways and enable simultaneous reduction in IL-12. These effects may be used to suppress keratinocyte hyperproliferation and to target T-cell activation to control amplification of inflammation. This provides an initial basis for further studies of CAP as a potential therapeutic option for inflammatory and immune-related diseases in dermatology, including psoriasis. PMID- 26498850 TI - Modified Cut-Off Value of the Urine Protein-To-Creatinine Ratio Is Helpful for Identifying Patients at High Risk for Chronic Kidney Disease: Validation of the Revised Japanese Guideline. AB - Chronic kidney disease (CKD) is a global public health issue, and strategies for its early detection and intervention are imperative. The latest Japanese CKD guideline recommends that patients without diabetes should be classified using the urine protein-to-creatinine ratio (PCR) instead of the urine albumin-to creatinine ratio (ACR); however, no validation studies are available. This study aimed to validate the PCR-based CKD risk classification compared with the ACR based classification and to explore more accurate classification methods. We analyzed two previously reported datasets that included diabetic and/or cardiovascular patients who were classified into early CKD stages. In total, 860 patients (131 diabetic patients and 729 cardiovascular patients, including 193 diabetic patients) were enrolled. We assessed the CKD risk classification of each patient according to the estimated glomerular filtration rate and the ACR-based or PCR-based classification. The use of the cut-off value recommended in the current guideline (PCR 0.15 g/g creatinine) resulted in risk misclassification rates of 26.0% and 16.6% for the two datasets. The misclassification was primarily caused by underestimation. Moderate to substantial agreement between each classification was achieved: Cohen's kappa, 0.56 (95% confidence interval, 0.45-0.69) and 0.72 (0.67-0.76) in each dataset, respectively. To improve the accuracy, we tested various candidate PCR cut-off values, showing that a PCR cut off value of 0.08-0.10 g/g creatinine resulted in improvement in the misclassification rates and kappa values. Modification of the PCR cut-off value would improve its efficacy to identify high-risk populations who will benefit from early intervention. PMID- 26498851 TI - Clinical significance of Anoctamin-1 gene at 11q13 in the development and progression of head and neck squamous cell carcinomas. AB - This study investigates the clinical significance of Anoctamin-1 gene mapping at 11q13 amplicon in both the development and progression of head and neck squamous cell carcinomas (HNSCC). ANO1 protein expression was evaluated by immunohistochemistry in a cohort of 372 surgically treated HNSCC patients and also in 35 laryngeal precancerous lesions. ANO1 gene amplification was determined by real-time PCR in all the laryngeal premalignancies and 60 of the HNSCCs, and molecular data correlated with clinical outcome. ANO1 gene amplification was frequently detected in both premalignant lesions (63%) and HNSCC tumours (58%), whereas concomitant ANO1 expression occurred at a much lower frequency (20 and 22%). Interestingly, laryngeal dysplasias harbouring ANO1 gene amplification showed a higher risk of malignant transformation (HR = 3.62; 95% CI 0.79-16.57; P = 0.097; Cox regression). ANO1 expression and gene amplification showed no significant associations with clinicopathological parameters in HNSCC. However, remarkably ANO1 expression differentially influenced patient survival depending on the tumour site. Collectively, this study provides original evidence demonstrating the distinctive impact of ANO1 expression on HNSCC prognosis depending on the tumour site. PMID- 26498852 TI - Opportunities to improve antimicrobial use in paediatric intensive care units: a nationwide survey in Spain. AB - Improving antimicrobial use is a complex process that requires an accurate assessment of ongoing problems and barriers. Paediatric intensive care units (PICU) have seldom been assessed from this perspective. Two Internet-based, self administered surveys were conducted nationwide in Spain between January and February 2014. The first survey aimed to assess those characteristics of Spanish PICUs that could influence antimicrobial prescribing or antimicrobial stewardship. The second survey targeted Spanish PICU physicians and pursued to assess their attitudes and perceptions regarding antimicrobial resistance and antimicrobial use. Information about 29/39 contacted PICUs was obtained. A total of 114/206 (55.3%) paediatric intensivists responded. PICUs were heterogeneous regarding years since foundation, number of beds, type of patients admitted and staffing. Only 11 (37.9%) PICUs had available e-prescribing systems. Procalcitonin was available in 24 (89.1%) PICUs, but there were no procalcitonin based protocols in 14 (60.9%) of them. Half of surveyed PICUs had implemented antimicrobial stewardship activities. Ninety-eight of the 114 PICU physicians (86%) who participated considered that antimicrobial resistance was a significantly relevant problem for their daily and that improving antimicrobial use in their PICU should be a priority (103; 90.4%). The main perceived problems regarding antimicrobial use were the excessive use of antimicrobials in patients with nonconfirmed infections and excessive use of broad-spectrum antimicrobials. The most valued antimicrobial stewardship interventions were the implementation of protocols to guide antimicrobial therapy. Spanish PICU doctors are aware of the relevance of the problem of antimicrobial resistance and the need to improve antimicrobial use. Targeted interventions should take into account their difficulties and preferences when feasible. PMID- 26498853 TI - Identification of candidate target genes for human peripheral arterial disease using weighted gene co-expression network analysis. AB - The aim of the present study was to identify the potential treatment targets of peripheral arterial disease (PAD) and provide further insights into the underlying mechanism of PAD, based on a weighted gene co-expression network analysis (WGCNA) method. The mRNA expression profiles (accession. no. GSE27034), which included 19 samples from patients with PAD and 18 samples from normal control individuals were extracted from the Gene Expression Omnibus database. Subsequently, the differentially expressed genes (DEGs) were obtained using the Limma package and the co-expression network modules were screened using the WGCNA approach. In addition, the protein-protein interaction network for the DEGs in the most significant module was constructed using Cytoscape software. Functional enrichment analyses of the DEGs in the most significant module were also performed using the Database for Annotation, Visualization and Integrated Discovery and Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology-Based Annotation System, respectively. A total of 148 DEGs were identified in PAD, which were used to construct the WGCN, in which two modules (gray module and turquoise module) were identified, with the gray module exhibiting a higher gene significance (GS) value than the turquoise module. In addition, a co-expression network was constructed for 60 DEGs in the gray module. The functional enrichment results showed that the DEGs in the gray module were enriched in five Gene Ontology terms and four KEGG pathways. For example, cyclin-dependent kinase inhibitor 1A (CDKN1A), FBJ murine osteosarcoma viral oncogene homolog (FOS) and prostaglandin-endoperoxide synthase 2 (PTGS2) were enriched in response to glucocorticoid stimulus. The results of the present study suggested that DEGs in the gray module, including CDKN1A, FOS and PTGS2, may be associated with the pathogenesis of PAD, by modulating the cell cycle, and may offer potential for use as candidate treatment targets for PAD. PMID- 26498855 TI - Protein Phosphorylation: A Major Switch Mechanism for Metabolic Regulation. AB - Metabolism research is undergoing a renaissance because many diseases are increasingly recognized as being characterized by perturbations in intracellular metabolic regulation. Metabolic changes can be conferred through changes to the expression of metabolic enzymes, the concentrations of substrates or products that govern reaction kinetics, or post-translational modification (PTM) of the proteins that facilitate these reactions. On the 60th anniversary since its discovery, reversible protein phosphorylation is widely appreciated as an essential PTM regulating metabolism. With the ability to quantitatively measure dynamic changes in protein phosphorylation on a global scale - hereafter referred to as phosphoproteomics - we are now entering a new era in metabolism research, with mass spectrometry (MS)-based proteomics at the helm. PMID- 26498854 TI - Self-efficacy and progression of periodontal disease: a prospective cohort study. AB - AIM: The purpose of this longitudinal study was to investigate whether self efficacy scale for self-care (SESS) was related to changes in oral health behaviours and progression of periodontal disease in Japanese university students. MATERIAL AND METHODS: Students (n = 533) who were interested in receiving oral health examinations before entering the university and before graduation were included in the analysis. Self-efficacy was assessed using SESS, which uses three subscales: self-efficacy for brushing of the teeth (SE-BR), for dentist consultations (SE-DC) and for dietary habits. The informations about oral health behaviours were also collected. For all participants, oral hygiene instructions was performed at baseline. After 3 years, the oral health behaviours and the periodontal condition were re-assessed. RESULTS: The progression of periodontal disease was related to low baseline SE-BR. Logistic regression analysis showed that progression of periodontal disease risk during a 3-year period was associated with low baseline SE-BR (OR: 1.516; 95% CI: 1.010-2.275; p < 0.05). The increase in the score of SE-DC was related to the increase in regular dental checkups (p < 0.05). CONCLUSION: Low SESS was associated with progression of periodontal disease and improvement of oral health behaviours in university students who received oral hygiene instructions at baseline. PMID- 26498856 TI - The PHD2 oxygen sensor paves the way to metastasis. PMID- 26498858 TI - Beyond gamma-secretase activity: The multifunctional nature of presenilins in cell signalling pathways. AB - The presenilins are the catalytic subunit of the membrane-embedded tetrameric gamma-secretase protease complexes. More that 90 transmembrane proteins have been reported to be gamma-secretase substrates, including the widely studied amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-beta peptides and biologically active APP intracellular domain (AICD) and Notch intracellular domain (NICD). The diversity of gamma secretase substrates highlights the importance of presenilin-dependent gamma secretase protease activities as a regulatory mechanism in a range of biological systems. However, there is also a growing body of evidence that supports the existence of gamma-secretase-independent functions for the presenilins in the regulation and progression of an array of cell signalling pathways. In this review, we will present an overview of current literature that proposes evolutionarily conserved presenilin functions outside of the gamma-secretase complex, with a focus on the suggested role of the presenilins in the regulation of Wnt/beta-catenin signalling, protein trafficking and degradation, calcium homeostasis and apoptosis. PMID- 26498857 TI - Protein-protein interactions of PDE4 family members - Functions, interactions and therapeutic value. AB - The second messenger cyclic adenosine monophosphate (cAMP) is ubiquitous and directs a plethora of functions in all cells. Although theoretically freely diffusible through the cell from the site of its synthesis it is not evenly distributed. It rather is shaped into gradients and these gradients are established by phospodiesterases (PDEs), the only enzymes that hydrolyse cAMP and thereby terminate cAMP signalling upstream of cAMP's effector systems. Miles D. Houslay has devoted most of his scientific life highly successfully to a particular family of PDEs, the PDE4 family. The family is encoded by four genes and gives rise to around 20 enzymes, all with different functions. M. Houslay has discovered many of these functions and realised early on that PDE4 family enzymes are attractive drug targets in a variety of human diseases, but not their catalytic activity as that is encoded in conserved domains in all family members. He postulated that targeting the intracellular location would provide the specificity that modern innovative drugs require to improve disease conditions with fewer side effects than conventional drugs. Due to the wealth of M. Houslay's work, this article can only summarize some of his discoveries and, therefore, focuses on protein-protein interactions of PDE4. The aim is to discuss functions of selected protein-protein interactions and peptide spot technology, which M. Houslay introduced into the PDE4 field for identifying interacting domains. The therapeutic potential of PDE4 interactions will also be discussed. PMID- 26498859 TI - Diploic vessels and computed tomography: Segmentation and comparison in modern humans and fossil hominids. AB - OBJECTIVES: The diploic channels appear to be more developed in humans than in nonhuman primates, suggesting they may be relevant in evolutionary biology. This study is aimed at providing a segmentation procedure for diploic channels and CT analysis, a quantitative description of their variation in modern humans, and paleoanthropological case-studies. MATERIALS AND METHODS: CT data were used for the 2D and 3D visualization, rendering, and measure, of diploic channels in modern and fossil hominids. We analyzed 20 modern human skulls and three Neanderthals. The effect of different resolution factors was evaluated. A specific protocol was designed to segment the vascular network and localize the main branches, reducing the noise of the cancellous bone. RESULTS: We provide a quantitative description of the frontal, parietal, and occipital diploic networks in modern humans and in three Neanderthals. There is a correlation in the degree of vascularization among the different vault areas. No side differences can be detected. The diploic network is commonly connected with the meningeal artery at the temporal fossa, with the emissary veins at the occipital bone, and with the venous sinuses at the parieto-occipital areas. The channels are more developed in the parietal areas. The three Neanderthals show a vascular development, which is in the lower range of the modern human variation. CONCLUSIONS: Modern humans display a large variation in their morphological patterns, being the parietal area the most vascularized. The pattern of the diploic channels may be relevant in anthropology, medicine, and paleontology, taking into account their possible involvement in thermoregulation. PMID- 26498861 TI - High-throughput genotyping of CRISPR/Cas9-mediated mutants using fluorescent PCR capillary gel electrophoresis. AB - Recent advances in the engineering of sequence-specific synthetic nucleases provide enormous opportunities for genetic manipulation of gene expression in order to study their cellular function in vivo. However, current genotyping methods to detect these programmable nuclease-induced insertion/deletion (indel) mutations in targeted human cells are not compatible for high-throughput screening of knockout clones due to inherent limitations and high cost. Here, we describe an efficient method of genotyping clonal CRISPR/Cas9-mediated mutants in a high-throughput manner involving the use of a direct lysis buffer to extract crude genomic DNA straight from cells in culture, and fluorescent PCR coupled with capillary gel electrophoresis. This technique also allows for genotyping of multiplexed gene targeting in a single clone. Overall, this time- and cost-saving technique is able to circumvent the limitations of current genotyping methods and support high-throughput screening of nuclease-induced mutants. PMID- 26498860 TI - Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate-specific phospholipase A1 activity. AB - Vibrio cholerae, responsible for acute gastroenteritis secretes a large multifunctional-autoprocessing repeat-in-toxin (MARTX) toxin linked to evasion of host immune system, facilitating colonization of small intestine. Unlike other effector domains of the multifunctional toxin that target cytoskeleton, the function of alpha-beta hydrolase (ABH) remained elusive. This study demonstrates that ABH is an esterase/lipase with catalytic Ser-His-Asp triad. ABH binds with high affinity to phosphatidylinositol-3-phosphate (PtdIns3P) and cleaves the fatty acid in PtdIns3P at the sn1 position in vitro making it the first PtdIns3P specific phospholipase A1 (PLA1). Expression of ABH in vivo reduces intracellular PtdIns3P levels and its PtdIns3P-specific PLA1 activity blocks endosomal and autophagic pathways. In accordance with recent studies acknowledging the potential of extracellular pathogens to evade or exploit autophagy to prevent their clearance and facilitate survival, this is the first report highlighting the role of ABH in inhibiting autophagy and endosomal trafficking induced by extracellular V. cholerae. PMID- 26498862 TI - Autoregulation and neurovascular coupling in the optic nerve head. AB - Impairments of autoregulation and neurovascular coupling in the optic nerve head play a critical role in ocular pathologies, especially glaucomatous optic neuropathy. We critically review the literature in the field, integrating results obtained in clinical, experimental, and theoretical studies. We address the mechanisms of autoregulation and neurovascular coupling in the optic nerve head, the current methods used to assess autoregulation--including measurements of optic nerve head blood flow (or volume and velocity)--blood flow data collected in the optic nerve head as pressure or metabolic demand is varied in healthy and pathologic conditions, and the current status and potential of mathematical modeling work to further the understanding of the relationship between ocular blood flow mechanisms and diseases such as glaucoma. PMID- 26498863 TI - Sulforaphane inhibits hypoxia-induced HIF-1alpha and VEGF expression and migration of human colon cancer cells. AB - The effects of sulforaphane (a natural product commonly found in broccoli) was investigated on hypoxia inducible factor-1alpha (HIF-1alpha) expression in HCT116 human colon cancer cells and AGS human gastric cancer cells. We found that hypoxia-induced HIF-1alpha protein expression in HCT116 and AGS cells, while treatment with sulforaphane markedly and concentration-dependently inhibited HIF 1alpha expression in both cell lines. Treatment with sulforaphane inhibited hypoxia-induced vascular endothelial growth factor (VEGF) expression in HCT116 cells. Treatment with sulforaphane modulated the effect of hypoxia on HIF-1alpha stability. However, degradation of HIF-1alpha by sulforaphane was not mediated through the 26S proteasome pathway. We also found that the inhibition of HIF 1alpha by sulforaphane was not mediated through AKT and extracellular signal regulated kinase phosphorylation under hypoxic conditions. Finally, hypoxia induced HCT116 cell migration was inhibited by sulforaphane. These data suggest that sulforaphane may inhibit human colon cancer progression and cancer cell angiogenesis by inhibiting HIF-1alpha and VEGF expression. Taken together, these results indicate that sulforaphane is a new and potent chemopreventive drug candidate for treating patients with human colon cancer. PMID- 26498864 TI - Surgical Revascularization of the Left Anterior Descending Artery with Multiple Failed Overlapping Stents. AB - BACKGROUND: Multiple stents make standard coronary artery bypass techniques difficult. We describe our surgical approach, in patients undergoing coronary artery bypass grafting (CABG), in left anterior descending arteries (LAD) with multiple failed overlapping stents. METHODS: We retrospectively reviewed the data of six patients undergoing CABG with multiple failed overlapping stents in the LAD. All patients were operated on electively. After removal of the stents with an open endarterectomy, the long segmental arteriotomy of the LAD was reconstructed with a saphenous vein patch. Afterwards the left internal mammary artery was anastomosed to the vein patch. RESULTS: The mean age was 61.5 +/- 7.9 years. Five patients (83.3%) were in Canadian Cardiovascular Society Class III or IV. Four patients (66.6%) had suffered a remote myocardial infarction (>1 month). The average hospital stay was 6.5 +/- 1.1 days. Postoperative electrocardiograms showed no specific changes and no myocardial enzyme elevations were noted. Early postoperative angiography showed that all grafts including the endarterectomized LAD were patent. There was no mortality within the 30 days. Patients' mean follow up time was 35.6 +/- 36.7 months. CONCLUSIONS: CABG with open stent endarterectomy is a valuable alternative option for patients with "full-metal jacket" diseased LAD that are not graftable using standard surgical techniques. PMID- 26498865 TI - Age-related decline in global form suppression. AB - Visual selection of illusory 'Kanizsa' figures, an assembly of local elements that induce the percept of a whole object, is facilitated relative to configurations composed of the same local elements that do not induce a global form--an instance of 'global precedence' in visual processing. Selective attention, i.e., the ability to focus on relevant and ignore irrelevant information, declines with increasing age; however, how this deficit affects selection of global vs. local configurations remains unknown. On this background, the present study examined for age-related differences in a global-local task requiring selection of either a 'global' Kanizsa- or a 'local' non-Kanizsa configuration (in the presence of the respectively other configuration) by analyzing event-related lateralizations (ERLs). Behaviorally, older participants showed a more pronounced global-precedence effect. Electrophysiologically, this effect was accompanied by an early (150-225 ms) 'positivity posterior contralateral' (PPC), which was elicited for older, but not younger, participants, when the target was a non-Kanizsa configuration and the Kanizsa figure a distractor (rather than vice versa). In addition, timing differences in the subsequent (250-500 ms) posterior contralateral negativity (PCN) indicated that attentional resources were allocated faster to Kanizsa, as compared to non Kanizsa, targets in both age groups, while the allocation of spatial attention seemed to be generally delayed in older relative to younger age. Our results suggest that the enhanced global-local asymmetry in the older age group originated from less effective suppression of global distracter forms on early processing stages--indicative of older observers having difficulties with disengaging from a global default selection mode and switching to the required local state of attentional resolution. PMID- 26498866 TI - Poly-adenine-based programmable engineering of gold nanoparticles for highly regulated spherical DNAzymes. AB - Enzyme complexes are assembled at the two-dimensional lipid membrane or prearranged on three-dimensional scaffolding proteins to regulate their catalytic activity in cells. Inspired by nature, we have developed gold nanoparticle-based spherical DNAzymes (SNAzymes) with programmably engineered activities by exploiting poly-adenine (polyA)-Au interactions. In a SNAzyme, AuNPs serve as the metal core, which is decorated with a functional shell of DNAzymes. Conventional thiolated DNAzyme-based assembly leads to disordered structures with suppressed activity. In contrast, by using an anchoring block of polyA tails, we find that the activity of SNAzymes can be programmably regulated. By using a polyA30 tail, SNAzymes demonstrated remarkably enhanced binding affinity compared to the thiolated DNAzyme-based assembly (~75-fold) or individual DNAzymes in the solution phase (~10-fold). More significantly, this increased affinity is directly translated to the sensitivity improvement in the SNAzyme-based lead sensor. Hence, this design of SNAzymes may provide new opportunities for developing biosensors and bioimaging probes for theranostic applications. PMID- 26498867 TI - Mechanism Switching of Ammonia Synthesis Over Ru-Loaded Electride Catalyst at Metal-Insulator Transition. AB - The substitution of electrons for O(2-) anions in the crystallographic cages of [Ca24Al28O64](4+)(O(2-))2 was investigated to clarify the correlation between the electronic properties and catalytic activity for ammonia synthesis in Ru-loaded [Ca24Al28O64](4+)(O(2-))2-x(e(-))2x (0 <= x <= 2). This catalyst has low catalytic performance with an electron concentration (Ne) lower than 1 * 10(21) cm(-3) and a high apparent activation energy (Ea) for ammonia synthesis comparable to that for conventional Ru-based catalysts with a basic promoter such as alkali or alkaline earth compounds. Replacement of more than half of the cage O(2-) anions with electrons (Ne ~ 1 * 10(21) cm(-3)) significantly changes the reaction mechanism to yield a catalytic activity that is an order higher and with half the Ea. The metal-insulator transition of [Ca24Al28O64](4+)(O(2-))2-x(e( ))2x also occurs at Ne ~ 1 * 10(21) cm(-3) and is triggered by structural relaxation of the crystallographic cage induced by the replacement of O(2-) anions with electrons. These observations indicate that the metal-insulator transition point is a boundary in the catalysis between Ru-loaded [Ca24Al28O64](4+)(O(2-))2 and [Ca24Al28O64](4+)(e(-))4. It is thus demonstrated that whole electronic properties of the support material dominate catalysis for ammonia synthesis. PMID- 26498868 TI - Validation of the Seattle Heart Failure Model in Japanese heart failure patients. PMID- 26498869 TI - Diagnostic value of the six-minute walk test (6MWT) in grown-up congenital heart disease (GUCH): Comparison with clinical status and functional exercise capacity. AB - BACKGROUND: Exercise testing for the assessment of functional capacity plays an important role in long-term follow-up of GUCH patients. CPX is the favored modality for decision-making recommended in the current guidelines. In contrast to this complex method, the 6 MWT is a simple, easy-to-perform, safe, and commonly available exercise test. Although well-established in various cardiopulmonary diseases, the diagnostic impact of the 6 MWT in GUCH patients is not known so far. METHODS: 102 GUCH patients were evaluated by 6 MWT and CPX simultaneously. Clinical symptoms were assessed, according to the NYHA classification. Additionally, an echocardiography study, and selected cardiac blood tests (N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive Troponin T) were performed. RESULTS: Ranges of six-minute walk distance (6 MWD) and peak oxygen consumption (peakVO2) were 116-765 m and 6.4-36.2 ml/kg/min, respectively. 6 MWD and peakVO2 showed a close correlation (r=0.72, 95% CI, 0.63 to 0.79). Patients with a peakVO2 of <= 15.5 ml/kg/min were excellently identified by 6 MWT (c-value=0.82). A cut-off value of 482 m was optimal to predict reduced peakVO2. In multivariate regression analysis, 6 MWD and NYHA class were identified as relevant predictors of peakVO2. In subgroup analysis, Eisenmenger patients achieved the shortest 6 MWD (280, SD 178 m). CONCLUSION: In our study population of GUCH patients, the 6 MWD shows a close correlation to peakVO2, and an excellent prediction of reduced peakVO2. Thus, it seems to be an easy-to-perform and reliable screening parameter to evaluate functional capacity of these patients (Controlled Clinical Trials number, NCT02193243). PMID- 26498870 TI - Office blood pressure is a predictor of aortic elastic properties and urinary protein excretion in subjects with white coat hypertension. AB - BACKGROUND: White coat hypertension (WCH) is related to target organ damage and increased cardiovascular risk. Arterial elastic properties and urinary protein excretion are determinants of cardiovascular performance and predictors of outcomes. We investigated whether office blood pressure (BP) is a better determinant of arterial and renal function than the ambulatory BP in WCH patients. METHODS: We studied 440 consecutive untreated non-diabetic patients with WCH (office BP >140/90 mmHg, mean daytime ambulatory BP <135/85 mmHg). Arterial function was evaluated with carotid-femoral pulse wave velocity (cfPWV), an index of aortic stiffness, and aortic augmentation index (AIx), a composite marker of aortic stiffness and wave reflections. In 24-hour urine, albumin excretion and albumin/creatinine ratio (ACR) were measured as markers of glomerular function and urinary alpha1-microglobulin was measured as a marker of renal tubular function. RESULTS: In univariate analysis, office systolic BP correlated significantly with cfPWV (r=0.245, P<0.001), AIx (r=0.31, P<0.001), albumin (r=0.134, P=0.005), ACR (r=0.199, P<0.001) and alpha1-microglobulin (r=0.118, P=0.013). In contrast, mean ambulatory systolic BP did not correlate with arterial function or urinary proteins (all P>0.5). Hierarchical multilevel linear regression analysis showed that office systolic BP is an independent determinant of cfPWV (P=0.050), AIx (P=0.029), albumin (P=0.002) and ACR (P=0.001) and has a borderline association with alpha1-microglobulin (P=0.088). CONCLUSIONS: In non-diabetic WCH individuals, office systolic BP is an independent predictor of aortic elastic properties and urinary protein excretion, whereas ambulatory BP is not. This finding suggests that office BP may be a marker of cardiovascular risk in subjects with WCH. PMID- 26498871 TI - Right heart size in orthotopic heart transplant population: Influence of donor and recipient gender, race, and body surface area. PMID- 26498872 TI - CTG-repeat expansions in the DMPK gene do not cause takotsubo syndrome. PMID- 26498873 TI - MicroRNA-101 inhibits proliferation of pulmonary microvascular endothelial cells in a rat model of hepatopulmonary syndrome by targeting the JAK2/STAT3 signaling pathway. AB - Hepatopulmonary syndrome (HPS) is one of the reasons for the mortality of patients with perioperative liver disease. Intrapulmonary vascular dilatation is the most important mechanism underlying HPS, and it primarily occurs due to cell proliferation. Inhibiting the proliferation of pulmonary microvascular endothelial cells (PMVECs) may provide a novel strategy to prevent HPS. MicroRNAs (miRNAs) regulate gene expression and are crucial in cell proliferation. To investigate the mechanism underlying the proliferation of PMVECs in HPS, PMVECs were isolated from rat models of HPS. It was demonstrated that interleukin (IL)-6 could stimulate the janus kinase 2 (JAK2)/ signal transducer and activator of transcription (STAT3) signaling pathway, which promotes the cell proliferation of PMVECs. JAK2 is a novel target gene of miR-101 and it was shown that miR-101 could inhibit cell proliferation by targeting the IL-6/JAK2/STAT3 signal pathway. In conclusion, the present study demonstrated that miR-101 could inhibit the proliferation of PMVECs by targeting the IL-6/JAK2/STAT3 signaling pathway. This clarifies the role of miR-101 in HPS and provides the theoretical basis of the pathogenesis of HPS. PMID- 26498874 TI - Jumonji domain containing 2A predicts prognosis and regulates cell growth in lung cancer depending on miR-150. AB - Lung cancer has become the most common cancer worldwide, of which non-small cell lung cancer (NSCLC) accounts for over 80%. Previous studies have shown that the Jumonji domain containing 2A (JMJD2A) was aberrantly expressed in various tumors and involved in the regulation of tumor progression, but the role of JMJD2A on the tumorigenesis in NSCLC and the underlying mechanisms are still unclear. In the present study, we first identified the expression of JMJD2A in NSCLC tissues and cell lines through quantitative RT-PCR (qRT-PCR) and western blotting. Next, the effects of JMJD2A on the progression of NSCLC were analyzed. MTT assay was performed to measure the cell numbers and fluorescence-activated cell sorting (FACS) was adopted to evaluate cell apoptosis. Finally, the relationship between JMJD2A and miR-150 involved in NSCLC was studied. Our results suggested that JMJD2A was significantly overexpressed in NSCLC samples and cell lines. Kaplan Meier analysis showed that high level of JMJD2A predicted a poor prognosis. Knockdown of JMJD2A inhibited tumor growth and promoted cell apoptosis in NSCLC cells. Additionally, miR-150 was upregulated in NSCLC tissues and positively related with JMJD2A expression. Significant downregulation of miR-150 was observed with JMJD2A knockdown. Furthermore, JMJD2A knockdown inhibited NSCLC cell proliferation while the silencing of miR-150 attenuated the inhibition effect on cell proliferation, suggesting that the effect of JMJD2A on NSCLC cell growth was dependent on miR-150. Thus, our findings identified that JMJD2A played an oncogenic role in NSCLC via regulating miR-150. JMJD2A could possibly serve as a prognostic factor and potential target for NSCLC therapy. PMID- 26498875 TI - Facile synthesis of carbon dots in an immiscible system with excitation independent emission and thermally activated delayed fluorescence. AB - Herein, we present a one-pot microwave-assisted preparative method for water soluble carbon dots (CDs) in an immiscible system. CDs demonstrated uniform morphology, high quantum yield and excitation-independent fluorescence emission. Moreover, we first reported the observation of thermally activated delayed fluorescence from CDs. PMID- 26498876 TI - Photodynamic inactivation of Candida albicans by a tetracationic tentacle porphyrin and its analogue without intrinsic charges in presence of fluconazole. AB - The photodynamic inactivation mediated by 5,10,15,20-tetrakis[4-(3-N,N dimethylaminopropoxy)phenyl]porphyrin (TAPP) and 5,10,15,20-tetrakis[4-(3-N,N,N trimethylaminepropoxy)phenyl]porphyrin (TAPP(4+)) were compared in Candida albicans cells. A strong binding affinity was found between these porphyrins and the yeast cells. Photosensitized inactivation of C. albicans increased with both photosensitizer concentration and irradiation time. After 30 min irradiation, a high photoinactivation (~5 log) was found for C. albicans treated with 5 MUM porphyrin. Also, the photoinactivation of yeast cells was still elevated after two washing steps. However, the photocytotoxicity decreases with an increase in the cell density from 10(6) to 10(8) cells/mL. The high photodynamic activity of these porphyrins was also established by growth delay experiments. This C. albicans strain was susceptible to fluconazole with a MIC of 1.0 MUg/mL. The effect of photosensitization and the action of fluconazole were combined to eradicate C. albicans. After a PDI treatment with 1 MUM porphyrin and 30 min irradiation, the value of MIC decreased to 0.25 MUg/mL. In addition, a complete arrest in cell growth was found by combining both effects. TAPP was similarly effective to photoinactivate C. albicans than TAPP(4+). This porphyrin without intrinsic positive charges contains basic amino groups, which can be protonated at physiological pH. Moreover, an enhancement in the antifungal action was found using both therapies because lower doses of the agents were required to achieve cell death. PMID- 26498877 TI - Adaptive myelination from fish to man. AB - Myelinated axons with nodes of Ranvier are an evolutionary elaboration common to essentially all jawed vertebrates. Myelin made by Schwann cells in our peripheral nervous system and oligodendrocytes in our central nervous system has been long known to facilitate rapid energy efficient nerve impulse propagation. However, it is now also clear, particularly in the central nervous system, that myelin is not a simple static insulator but that it is dynamically regulated throughout development and life. New myelin sheaths can be made by newly differentiating oligodendrocytes, and mature myelin sheaths can be stimulated to grow again in the adult. Furthermore, numerous studies in models from fish to man indicate that neuronal activity can affect distinct stages of oligodendrocyte development and the process of myelination itself. This begs questions as to how these effects of activity are mediated at a cellular and molecular level and whether activity driven adaptive myelination is a feature common to all myelinated axons, or indeed all oligodendrocytes, or is specific to cells or circuits with particular functions. Here we review the recent literature on this topic, elaborate on the key outstanding questions in the field, and look forward to future studies that incorporate investigations in systems from fish to man that will provide further insight into this fundamental aspect of nervous system plasticity. This article is part of a Special Issue entitled SI: Myelin Evolution. PMID- 26498878 TI - Glial restricted precursors maintain their permissive properties after long-term expansion but not following exposure to pro-inflammatory factors. AB - Glial restricted precursors (GRP) are a promising cellular source for transplantation therapy of spinal cord injury (SCI), capable of creating a permissive environment for axonal growth and regeneration. However, there are several issues regarding the nature of their permissive properties that remain unexplored. For example, cellular transplantation strategies for spinal cord repair require the preparation of a large number of cells, but it is unknown whether the permissive properties of GRP are maintained following the process of in vitro expansion. We used rat GRP isolated from the embryonic day 13.5 spinal cord to compare the properties of early (10-20 days) and late (120-140 days) passage GRP. We found that late passage GRP showed comparable effects on neurite outgrowth of adult rat DRG to early passage GRP in both in vitro co-culture and conditioned medium experiments. In addition, to further examine the effects of the inflammatory cascade activated in the aftermath of SCI on the microenvironment, we studied the direct effects of strong inflammatory mediators, Lipopolysaccharide and interferon gamma (LPS and IFN?, respectively), on the properties of GRP. We showed that exposure to these pro-inflammatory mediators altered GRP phenotype and attenuated their growth-promoting effects on neurite outgrowth in a dose dependent manner. Taken together, our data suggest that GRP maintain their growth-promoting properties following extensive in vitro passaging and underscore the importance of modulating the inflammatory environment at the injured spinal cord. PMID- 26498879 TI - Nesfatin-1, a potent anorexic agent, decreases exploration and induces anxiety like behavior in rats without altering learning or memory. AB - The anorectic neuropeptide nesfatin-1 has recently been characterized as a potential mood regulator, but the accurate effect of nesfatin-1 on anxiety and learning and memory behavior and the possible mechanisms remains unknown. In the present study, to test the hypothesis that nesfatin-1 might affect the anxiety like and learning and memory behaviors in rats via ERK/CREB/BDNF pathway, nesfatin-1 was administered intraperitoneally to rats with the doses (10, 20, 40MUg/kg), and the behavioral performance was tested using the open field task, the Morris water maze (MWM), and the Y maze. Moreover, the protein expression of brain-derived neurotrophic factor (BDNF), total and phosphorylated-ERK in the hippocampus and the prefrontal cortex (PFC) were evaluated. The results showed that chronic administration of nesfatin-1 could decrease the moving distance, the duration in the center, and the frequencies of rearing and grooming in the open field task, decrease the moving distance, frequency, and the preference index of new arm in the Y maze, although there was no significant difference of the performance in the MWM task among groups. Furthermore, 3 weeks' consecutive administration of nesfatin-1 resulted in the decrease of protein expression of BDNF and phosphorylated-ERK in the hippocampus and the PFC. These results provided evidence that exogenous nesfatin-1 could decrease exploration and induce anxiety-like behavior in rats, the mechanism of which might be related to the reduced protein expression of BDNF and phosphorylated-ERK in the hippocampus and the PFC. PMID- 26498881 TI - Unicompartmental isoelastic resurfacing prosthesis for malignant tumor of the distal radius: A case report with a 3-year follow-up. AB - We report a case of 74-year-old man in whom a unicompartmental isoelastic resurfacing prosthesis was used to reconstruct the distal radius after en-bloc resection of a malignant tumor. Thirty-nine months after the operation, on a visual analogic scale, pain score was 0/10 and range of motion was 25 degrees of flexion, 5 degrees of extension, 70 degrees of pronation, 45 degrees of supination, 20 degrees of radial deviation, and 30 degrees of ulnar deviation. The Quick DASH functional score was 72.72/100. With radiographic finding, the prosthesis was well-aligned, with no evidence of loosening but with slightly implant conflict with the lunate. This case report indicates that unicompartmental isoelastic resurfacing prosthesis seems a simple and reliable technique for distal radius reconstruction after en-bloc resection of malignant tumor. PMID- 26498882 TI - Radial nerve palsy in surgical revision of total elbow arthroplasties: A study of 4 cases and anatomical study, possible aetiologies and prevention. AB - BACKGROUND: Damage to the radial nerve in the arm during revision of total elbow arthroplasty is a serious complication; which is still not well documented. The aim of this study was to define a way on how to avoid this complication and to prevent it. PATIENTS AND METHODS: Four patients underwent radial palsy after revision of total elbow arthroplasty. An anatomical study on 20 upper limbs was performed to define landmarks for the radial nerve in the arm and elbow. RESULTS: Radial nerve damage occurred near the proximal tip of the stem in all four patients, due to cement seepage caused by cortical effraction in two patients, and to damage caused by the retractors in the two other patients. The anatomical study made it possible to specify landmarks for the radial nerve in relation to the humerus. A high-risk area located 14cm away from the tip of the olecranon fossa, and 15.5cm from the medial epicondyle, was identified. CONCLUSION: A high risk area for the radial nerve was defined and suggested targeted landmarks with a posterior proximal counter-incision situated at about 14cm above the olecranon fossa. LEVEL OF EVIDENCE: IV. PMID- 26498883 TI - Chondrosarcoma of the femur in Mazabraud's syndrome: A first case study. AB - Malignant transformation of fibrous dysplasia (FD) in long bones is rare (less than 1% of cases) and occurs in the form of osteosarcomas. They can occur on FD associated with multiple myxomas, which corresponds to Mazabraud syndrome. To our knowledge, only six cases of FD malignant transformation into osteosarcoma in the context of Mazabraud syndrome have been described. Here, we describe the first case of malignant transformation of femur FD into chondrosarcoma in a 51-year-old female patient. The patient had significant changes in the size and number of myxomas around the femur before the malignant transformation into chondrosarcoma. She underwent complete femur replacement with a favourable result after 4 years' follow-up. Close surveillance is strongly recommended in this syndrome, particularly when the number and size of myxomas increase. PMID- 26498884 TI - Fate of the unrevised cemented stem following cup only revision: 227 hips at an average of 6 years follow-up. AB - BACKGROUND: After primary total hip replacement, aseptic loosening of the acetabular cup is more common than loosening of the femoral stem. Removal of a well-fixed stem adds to operative time, blood loss, risk of bone loss and fracture. There is limited evidence that isolated cup revision can be a safe option in revision hip arthroplasty. We question the following regarding the unrevised cemented stem after isolated cup revision: 1) Does the unrevised stem require revision after isolated cup revision? 2) When is the stem subsequently revised? 3) Why is the stem subsequently revised? 4) Do unrevised stems exhibit radiographic loosening? HYPOTHESIS: We hypothesise that after isolated cup revision most unrevised stems do not need subsequent revision, and that most do not exhibit evidence of radiographic loosening. PATIENTS AND METHODS: A retrospective analysis of all patients who underwent revision of the acetabular component only during revision hip arthroplasty between March 1970 and July 2013 was carried out. We assessed survival of the unrevised stem, reasons for subsequent revision, plus radiographic analysis for stem loosening. RESULTS: Two hundred and twenty-seven hips were included [215 patients with an average age at the time of primary surgery was 47 (13-70) years]. The Charnley stem was used in 161 cases; C-stem 65, Howse 1. Average time between primary surgery and cup revision was 15.9 (1.6-33.4) years. Average follow-up for all stems post-isolated cup revision was 6.1 (0.1-30.7) years. Twenty-eight stems (12.3%) were subsequently revised 5.1 (0.1-12.6) years after the isolated cup revision. Reasons for subsequent revision were: aseptic loosening (10); infection (8); dislocation (6); unreconstructable joint post-loose cup removal (2); fracture (2). Radiographic review was possible on 140 cases. Five femoral stems were revised and 2 others showed evidence of possible radiological loosening but were not revised. CONCLUSION: To our knowledge this is the largest series showing that isolated cup revision in the place of a well-fixed cemented stem is safe and is associated with ongoing good long-term survival of the stem. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26498880 TI - The scales and tales of myelination: using zebrafish and mouse to study myelinating glia. AB - Myelin, the lipid-rich sheath that insulates axons to facilitate rapid conduction of action potentials, is an evolutionary innovation of the jawed-vertebrate lineage. Research efforts aimed at understanding the molecular mechanisms governing myelination have primarily focused on rodent models; however, with the advent of the zebrafish model system in the late twentieth century, the use of this genetically tractable, yet simpler vertebrate for studying myelination has steadily increased. In this review, we compare myelinating glial cell biology during development and regeneration in zebrafish and mouse and enumerate the advantages and disadvantages of using each model to study myelination. This article is part of a Special Issue entitled SI: Myelin Evolution. PMID- 26498885 TI - Response to the letter by D. Goutallier. PMID- 26498886 TI - Clinical experience with Angiojet: a comprehensive review. AB - The development of various sophisticated mechanical thrombectomy devices and the amassed experience of physicians in minimal invasive therapy produced a paradigm shift in vascular access management toward percutaneous declotting procedures, using pharmaceutical thrombolysis, mechanical thrombectomy, balloon thrombectomy, and a combination of the above techniques. In this setting, in the last years, AngioJetTM (Possis, Minneapolis, MN, USA) rheolytic thrombectomy (RT) showed an increasing use in emergency and election patients. The purpose of this review is to present the current status of percutaneous rheolytic thrombectomy in different fields of applications. PMID- 26498887 TI - Surgical complications of carotid body tumors surgery: a review. AB - Carotid body tumor (CBT) is a rare neoplasm, although it represents about 65% of head and neck paragangliomas. Surgical excision is considered the appropriate therapy for CBTs. The aim of this study was to evaluate surgical outcomes on a large scale. We reviewed 19 studies between 2004 to 2014 with a total of 625 procedures. We observed a higher number of cases in women (62%). Only 3 (0,48%) deaths were reported as surgical complication. Total cranial nerve injuries were 302 (48,32%) of which 194 (31,04%) were transient and 108 (17,28%) were permanent. We found a total of 174 (27,84%) arterial injuries, most of which are external carotid artery (ECA) injuries. Cerebrovascular accident due to surgery were 15 (2,4%). We concluded that surgical resection remains the treatment of choice for these disease despite the related morbidity. PMID- 26498888 TI - Vascular anomalies of the large bowel. AB - Vascular anomalies of the large bowel, commonly known as vascular malformations of the colon (VMC), constitute a rare but important condition, potentially causing significant morbidity and mortality. Our aim is to provide an up-to-date, practical summary evaluating this disease entity, focussing on pathogenesis, as well as diagnostic and therapeutic modalities. We reviewed available data in the literature, and discussed it in the form of a narrative, readily applicable review. Most VMC (over 70%) are detected in the caecum and ascending colon, and affect people aged over 50 years. VMC are almost always symptomatic, presenting with lower bleeding. Endoscopy is crucial to identify and locate VMC, and to treat the lesions. In patients who fail or do not fit endoscopic treatment, aggressive approaches (interventional angiology or surgery) are mandatory. Up to 40% of patients may have relapse in the long term. VMC are rare but potentially life-threatening. Advances in endoscopic imaging and therapy have improved the results of treatment. Long-term follow-up after treatment is recommended. PMID- 26498889 TI - Ethylene-vinyl alcohol polymer trans-arterial embolization in emergency peripheral active bleeding: initial experience. AB - AIM: The aim of this paper was to evaluate the efficacy, safety, and clinical outcomes of superselective embolization using ethylene-vinyl alcohol copolymer (Onyx Liquid Embolic System; ev3 Neurovascular, Irvine, CA, USA) as the primary treatment in active peripheral emergency arterial bleeding. METHODS: Between January 2014 and June 2014, all patients with active peripheral arterial bleeding who were treated by embolization were retrospectively analyzed. We selected 15 (age 37-91 year old) patients embolized with Onyx, chosen as embolic agent in an intention-to-treat fashion. Multidetector computed tomography was performed in all patients. RESULTS: Active bleeding was detected in all cases. Digital subtraction angiography confirmed CT findings in all cases. The causes of bleeding were traumatic in 8 patients, angiodysplasia in 1 patient, duodenal ulcer in 1, chronic pancreatitis in 1 and unknown in 4 patients. Nine patients were under anticoagulant or antiplatelet therapy. Embolization was possible in all patients. The technical success rate was 100%. The immediate bleeding control rate was 100%. No rebleeding at 30 days occurred (0%). There were no major complications, or deaths attributable to the treatment. No patient needed surgery or new embolization during a mean follow-up period of 5.1 months (range, 4.5-6 months). CONCLUSION: Control of massive active peripheral emergency arterial bleeding using superselective embolization with Onyx is feasible and safe. PMID- 26498890 TI - Renovascular anatomic variants at CT angiography. AB - AIM: The aim of this paper was to assess the origin and course variations of vessels forming the renal vascular pedicle. METHODS: The IRB approved study retrospectively evaluated 921 consecutive patients (503 females, 418 males; mean age, 54 years), who underwent multidetector computed tomographic (MDCT) of the abdomen for various purposes at our Department of Radiology, between January 2012 and December 2013. Multiplanar and volumetric reformations were performed in all cases. For each set of images, the locations of renal artery origins and renal venous drainage, such as all renal vessels variations, including division variations and presence of extrarenal vessels, were investigated. RESULTS: The tract of the aorta between the upper margin of L1 and the lower margin of L2 originated 96% of main renal arteries and 72% of extra renal arteries. The most common location for renal artery origin was the L1- L2 intervertebral disc level. Sixty-nine percent of patients showed a single renal artery, with multiple arteries in 31%, bilateral multiple arteries in 11%, and early division in 6% of cases. Additional renal arteries were detected on the right side in 5% and on the left side in 12% of cases. With regard to the venous drainage, 89.8% of patients showed a single renal vein, with multiple vein in 10.2%, while 23.8% showed a retro-aortic course of the renal vein. CONCLUSION: Renal arteries and veins variations of origin and course are not infrequent. Extrarenal vessels may compromise renal surgery. The awareness of any possible renovascular anomaly is crucial in case of a non-invasive diagnostic search for renal artery stenosis, and when renal surgery related to renal arteries is performed, such as in case of interventional radiological procedures, urological and vascular operations, and renal transplantation. PMID- 26498893 TI - Endogenously elevated bilirubin modulates kidney function and protects from circulating oxidative stress in a rat model of adenine-induced kidney failure. AB - Mildly elevated bilirubin is associated with a reduction in the presence and progression of chronic kidney disease and related mortality, which may be attributed to bilirubin's antioxidant properties. This study investigated whether endogenously elevated bilirubin would protect against adenine-induced kidney damage in male hyperbilirubinaemic Gunn rats and littermate controls. Animals were orally administered adenine or methylcellulose solvent (vehicle) daily for 10 days and were then monitored for 28 days. Serum and urine were assessed throughout the protocol for parameters of kidney function and antioxidant/oxidative stress status and kidneys were harvested for histological examination upon completion of the study. Adenine-treated animals experienced weight-loss, polyuria and polydipsia; however, these effects were significantly attenuated in adenine-treated Gunn rats. No difference in the presence of dihydroadenine crystals, lymphocytic infiltration and fibrosis were noted in Gunn rat kidneys versus controls. However, plasma protein carbonyl and F2-isoprostane concentrations were significantly decreased in Gunn rats versus controls, with no change in urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine or kidney tissue F2 isoprostane concentrations. These data indicated that endogenously elevated bilirubin specifically protects from systemic oxidative stress in the vascular compartment. These data may help to clarify the protective relationship between bilirubin, kidney function and cardiovascular mortality in clinical investigations. PMID- 26498891 TI - Retinal Changes in Pediatric Glaucoma and Nonglaucomatous Optic Atrophy. AB - PURPOSE: To describe the incidence and significance of retinal changes in pediatric eyes with glaucoma and nonglaucomatous optic atrophy by optical coherence tomography (OCT). DESIGN: Retrospective observational case series. METHODS: OCT scans performed on children with either glaucoma or nonglaucomatous optic atrophy were retrospectively reviewed. Excluded were poor-quality scans and diagnoses of ocular hypertension or glaucoma suspects. RESULTS: Included were 227 eyes (227 children), 151 with glaucoma and 76 with nonglaucomatous optic atrophy. Outer retinal changes were present in 20 of 151 glaucoma eyes (13.2%) (12 prior intraocular surgery, 5 uveitis, 3 primary retinopathy) and 6 of 76 nonglaucomatous optic atrophy eyes (7.9%) (1 retinal vasculitis, 3 papilledema, 2 infiltrative optic neuropathy). Excluding eyes with outer retinal changes, isolated inner nuclear layer (INL) cysts were found in 6 of 131 eyes with glaucoma (4.6%) (3 uveitis, 1 prior hydrocephalus, 1 uveitis and pars plana vitrectomy, and 1 juvenile open-angle glaucoma) and 21 of 70 eyes with nonglaucomatous optic atrophy (30%) (5 optic neuritis, 11 anterior visual pathway tumors, 2 papilledema, 3 other) (P < .0001). Compared to eyes without INL cysts, those with INL cysts had thinner average retinal nerve fiber layer (RNFL) (78.2 +/- 1.8 MUm vs 52.0 +/- 4.8 MUm, P < .0001) and worse vision (logMAR = 0.33 +/- 0.04 vs 0.65 +/- 0.09, P < .002). CONCLUSIONS: INL cysts are more frequent in pediatric nonglaucomatous optic atrophy than glaucoma; they are associated with worse vision and thinner RNFL. Outer retinal changes were exclusively seen in pathology that directly affected the retina. In children, INL cysts and/or outer retinal changes without prior history of intraocular surgery or uveitis should prompt further evaluation. PMID- 26498894 TI - Association of clinical properties and compatibility of the QuantiFERON-TB Gold In-Tube test with the tuberculin skin test in patients with psoriasis. AB - BACKGROUND: Individuals with psoriasis show conflicting responses to the tuberculin skin test (TST), a commonly used screening test for latent tuberculosis infection. An alternative to TST is QuantiFERON-TB Gold In-Tube test (QFT-GIT), an in vitro interferon-gamma release assay. This study aimed to determine the effect of the clinical properties of psoriasis (disease severity and koebnerization status) on TST results and the agreement between the TST and QFT-GIT results in psoriatic patients. METHODS: One hundred patients with mild to severe psoriasis were enrolled in this prospective cross-sectional study. Psoriasis properties, including disease severity (psoriasis area and severity index score and koebnerization status), latent tuberculosis infection risk factors, and bacillus Calmette-Guerin vaccination history, were recorded. All patients underwent a TST and QFT-GIT. TST positivity cut-off point was >=10 mm for bacillus Calmette-Guerin-vaccinated patients and >=5 mm for non-vaccinated patients. RESULTS: Psoriasis area and severity index scores and koebnerization status did not correlate with TST diameters. Only one of the 23 koebnerization positive patients developed koebnerization in response to TST. QFT-GIT positivity was prominently higher in the TST-positive group, and this was the only factor that differed between the TST-positive and TST-negative groups (P < 0.001). CONCLUSION: Tuberculin skin test results were not affected by psoriasis severity or koebnerization status. QFT-GIT positivity was prominently higher in the TST positive group (P < 0.001). Overall agreement between TST and QFT-GIT results was moderate (kappa = 0.413). Concurrent negativity (44%) was higher than concurrent positivity (27%). PMID- 26498895 TI - [The need for a paradigm shift in radiotherapy]. AB - The status and indications of radiotherapy have significantly changed in the past decade because novel techniques, radiobiological research and major advances in informatics have made better local control possible. Using supplemented marking of the target volume with computer tomography based other image-making methods adapted made it possible to define the tumor and intact surrounding tissues more precisely. With novel radiotherapy techniques the dosage of the homogenity and the covering in the target volume can be raised optimally, especially with intensity modulated arc radiotherapy (volumetric modulated arc therapy) without causing radiation injury or damage to intact surrounding tissues. Furthermore, with novel techniques and target volume marking, new indications have appeared in clinical practice and besides stereotactic radiotherapy for intracranial metastases, the extracranial so-called oligometastic conditions can be maintained close to a curative state (or in remission) for many years. Among these, perhaps the most striking is the stereotactic radiotherapy treatment of liver, lung and spinal cord metastases in one or more fractions, for which the indispensable condition is the image or respiratory guided technique. PMID- 26498896 TI - [Thousand faces of Streptococcus pneumonia (pneumococcus) infections]. AB - Incidence and mortality rates of infections caused by Streptococcus pneumoniae (pneumococcus) are high worldwide and in Hungary among paediatric as well as adult populations. Pneumococci account for 35-40% of community acquired adult pneumonias requiring hospitalization, while 25-30% of Streptococcus pneumoniae pneumonias are accompanied by bacteraemia. 5-7% of all infections are fatal but this rate is exponentially higher in high risk patients and elderly people. Mortality could reach 20% among patients with severe invasive pneumococcal infections. Complications may develop despite administration of adequate antibiotics. The authors summarize the epidemiology of pneumococcal infections, pathogenesis of non-invasive and invasive disease and present basic clinical aspects through demonstration of four cases. Early risk stratification, sampling of hemocultures, administration of antibiotics and wider application of active immunization could reduce the mortality of invasive disease. Anti-pneumococcal vaccination is advisable for adults of >=50 years and high risk patients of >=18 years who are susceptible to pneumococcal disease. PMID- 26498897 TI - [Palliative endoscopic treatment of malignant gastroduodenal obstructions with uncovered enteral stents]. AB - INTRODUCTION: Palliative treatment of malignant gastroduodenal obstructions with enteral stents is an effective and safe method, and a viable alternative to gastroenterostomy. AIM: The authors present the most common malignancies behind gastroduodenal obstructions, the aspects of stent selections, insertion techniques, technical and clinical success rates, and possible procedure-related complications. METHOD: Between 1 March, 2013 and 9 April, 2015 nineteen patients were treated with uncovered, self-expandable enteral stents. Out of the 19 patients, 6 were females and 13 males, with an average age of 67 years. Indications of stenting were peripyloric ventricular tumour in five cases, malignancies of the duodenum, gastroenteralis anastomosis, Vater papilla and gallbladder in one case respectively, pancreatic tumor in seven cases and bile duct malignancies in three cases. RESULTS: The technical success rate of stent placement was 100%. The evaluation of clinical success was analised on the basis of the Gastric Outlet Obstruction Scoring System. CONCLUSIONS: The use of enteral stents in malignant gastroduodenal obstructions is a reliable and safe method, which promptly decreases symptoms of the patients and improves their quality of life. PMID- 26498899 TI - [Pregnancy and delivery with transfer of vitrified blastocysts following trophectoderm biopsy]. AB - Application of preimplantation genetic diagnosis makes it possible to transfer only embryos unaffected by a certain genetic disorder. The authors have applied the combination of trophectoderm biopsy and vitrification in order to detect a monogenic disorder. Previously diagnosed type 1 neurofibromatosis of the woman was the indication for genetic examination. In vitro fertilisation and embryo culture was performed using sequential culture mediums. Seven blastocysts could be sampled on the fifth day and were vitrified subsequently. Two blastocysts turned out to be genetically normal based on the result of genetic examination using polimerase chain reaction. A healthy boy was delivered following the transfer of warmed blastocysts and an uneventful singleton pregnancy. PMID- 26498900 TI - [Prof. Dr. Dezso Tanka (1927-2015). ]. PMID- 26498898 TI - [Antimicrobial effect on some zoonotic bacteria, of the cell-free fermentation fluid and purified peptide fraction of the entomopathogenic bacterium, Xenorhabdus budapestensis]. AB - INTRODUCTION: Many multi-resistant patogens appear continuously resulting in a permanent need for the development of novel antibiotics. A large number of antibiotics introduced in clinical and veterinary practices are not effective. Antibacterial peptides with unusual mode of action may represent a promising option against multi-resistant pathogens. The entomopathogenic Xenorhabdus budapestensis bacteria produce several different antimicrobial peptides compounds such as bicornutin-A and fabclavin. AIM: The aim of the authors was to evaluate the in vitro antibacterial effect of Xenorhabdus budapestensis using zoonotic patogen bacteria. METHOD: Cell-free conditioned media and purified peptide fractions of Xenorhabdus budapestensis were tested on Gram-positive (Rhodococcus equi, Erysipelothrix rhusiopathia, Staphylococcus aureus, Streptococcus equi, Corynebacterium pseudotuberculosis, Listeria monocytagenes) and Gram-negative bacteria (Salmonella gallinarum, Salmonella derbi, Bordatella bronchoseptica, Escherichia coli, Pasteurella multocida, Aeromonas hydrophila) using agar diffusion test on blood agar plates. RESULTS: It was found that Xenorhabdus budapestensis bacteria produced compounds with strong and dose-dependent effects on the tested organisms. Purified peptid fraction exerted a more marked effect than cell free conditioned media. Gram-positive bacteria were more sensitive to this antibacterial effect than Gram-negative bacteria. CONCLUSIONS: Antibacterial peptide compound from Xenorhabdus budapestensis exert marked antibacterial effect on zoonotic patogen bacteria and they should be further evaluated in future for their potential use in the control or prevention of zoonoses. PMID- 26498902 TI - Time for a Campus Tour. PMID- 26498903 TI - Infectious Diseases Pharmacotherapy for Children With Cystic Fibrosis. AB - Cystic fibrosis (CF) affects several organs, most notably the lungs, which become predisposed to infections with potentially severe consequences. Because of physiologic changes and infection characteristics, unique approaches to antimicrobial agent selection, dosing, and administration are needed. To provide optimal acute and long-term care, pediatric health care providers must be aware of these patient features and common approaches to antimicrobial therapy in CF, which can differ significantly from those of other infectious diseases. The purpose of this article is to review common respiratory pathogens, pharmacology of commonly used antimicrobial agents, and unique pharmacokinetics and dosing strategies often used when treating children with CF. PMID- 26498904 TI - Transcatheter closure of perimembranous ventricular septal defects with the Amplatzer Vascular Plug-II. AB - OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of the Amplatzer Vascular Plug-II used for the closure of perimembranous ventricular septal defects. BACKGROUND: There are no FDA-approved transcatheter devices for the closure of perimembranous ventricular septal defects. Several studies have reported on the use of various devices either off-label or under clinical trial protocols. However these reports have described significant adverse events including residual shunts, complete heart block, arrhythmia, and new valve regurgitations. Thus far, no study on the Amplatzer Vascular Plug-II has been reported. METHODS: We conducted a 4-year retrospective chart review from August, 2010 to August, 2014, of patients with perimembranous ventricular septal defects associated with ventricular septal aneurysm who underwent transcatheter closure using the Amplatzer Vascular Plug-II. RESULTS: A total of 16 patients underwent Amplatzer Vascular Plug-II transcatheter closure of their perimembranous ventricular septal defects. The median age was 2.56 years (range: 0.5-27.3). Their median weight was 13.0 kg (range: 6.9-71.6). The left ventricular median defect size was 9.3 mm (range: 5.9-14.4). The right ventricular median defect size was 3.6 mm (range: 2.3-5.8). All the patients underwent successful device implantation with 83% of the patients having complete echocardiographic closure at the 1-year follow-up; however, one procedure was complicated by early device embolisation. The device was successfully retrieved and replaced with a larger device. There were no device-related outflow tract obstructions, rhythm abnormalities, or haemolysis. CONCLUSION: Application of the Amplatzer Vascular Plug-II for closure of perimembranous ventricular septal defects appears to be a safe and effective treatment option. Prospective clinical trials and longer follow-up periods are warranted. PMID- 26498905 TI - Phosphorylation-Dependent Regulation of G-Protein Cycle during Nodule Formation in Soybean. AB - Signaling pathways mediated by heterotrimeric G-protein complexes comprising Galpha, Gbeta, and Ggamma subunits and their regulatory RGS (Regulator of G protein Signaling) protein are conserved in all eukaryotes. We have shown that the specific Gbeta and Ggamma proteins of a soybean (Glycine max) heterotrimeric G-protein complex are involved in regulation of nodulation. We now demonstrate the role of Nod factor receptor 1 (NFR1)-mediated phosphorylation in regulation of the G-protein cycle during nodulation in soybean. We also show that during nodulation, the G-protein cycle is regulated by the activity of RGS proteins. Lower or higher expression of RGS proteins results in fewer or more nodules, respectively. NFR1 interacts with RGS proteins and phosphorylates them. Analysis of phosphorylated RGS protein identifies specific amino acids that, when phosphorylated, result in significantly higher GTPase accelerating activity. These data point to phosphorylation-based regulation of G-protein signaling during nodule development. We propose that active NFR1 receptors phosphorylate and activate RGS proteins, which help maintain the Galpha proteins in their inactive, trimeric conformation, resulting in successful nodule development. Alternatively, RGS proteins might also have a direct role in regulating nodulation because overexpression of their phospho-mimic version leads to partial restoration of nodule formation in nod49 mutants. PMID- 26498906 TI - Mitigation of Insulin Resistance by Mangiferin in a Rat Model of Fructose-Induced Metabolic Syndrome Is Associated with Modulation of CD36 Redistribution in the Skeletal Muscle. AB - Mangiferin is one of the prominent active components responsible for the antidiabetic property of many traditional herbs, but its underlying mechanisms of action remain unclear. CD36 in skeletal muscle is known to contribute to the etiology of insulin resistance by facilitating fatty acid uptake. This study investigated the effect of mangiferin on insulin resistance. The results showed that treatment of Wistar-Kyoto rats with mangiferin (15 mg/kg, once daily, by oral gavage) for 7 weeks inhibited chronic liquid fructose consumption-induced increases in plasma insulin concentrations at the baseline and during oral glucose tolerance test (OGTT), and the homeostasis model assessment of insulin resistance index. It also suppressed the increases in fasted plasma nonesterified fatty acid (NEFA) concentration and the adipose tissue insulin resistance index. Mechanistically, mangiferin neither affected intakes of fructose and chow, and the increase in epididymal and perirenal fat, nor attenuated fructose-induced hypertension. In contrast, mangiferin attenuated fructose-induced acceleration of plasma NEFA clearance during OGTT, and tended to decrease excessive triglyceride accumulation in gastrocnemius. Immunofluorescence staining and subsequent rating of CD36-expressing fibers in gastrocnemius revealed that mangiferin restored fructose-stimulated sarcolemmal CD36 overexpression and decreased intracellular CD36 distribution. In addition, the effects of mangiferin on the parameters associated with insulin resistance and abnormal fatty acid metabolism were absent in the spontaneously hypertensive rats carrying numerous nonfunctional mutations in the CD36 gene. Thus, these results suggest that mangiferin treatment mitigates insulin resistance in a rat model of fructose-induced metabolic syndrome by modulating sarcolemmal and intracellular CD36 redistribution in the skeletal muscle. PMID- 26498907 TI - Cardiovascular care research for immigrant or ethnic groups. PMID- 26498908 TI - Factors influencing the decision of older adults to be assessed for transcatheter aortic valve implantation: An exploratory study. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is the recommended therapy for patients with severe symptomatic aortic stenosis at increased surgical risk and likely to derive benefit. Multimodality and multidisciplinary assessment is required for the heart team to determine eligibility for TAVI in a primarily older population. Little is known about patients' motivation and perspectives on making the decision to undergo the complex assessment. AIMS: To explore factors influencing patients' decision making to undergo TAVI eligibility assessment to inform practice, programme development, health policy and future research. METHODS: An exploratory qualitative approach was used. Semistructured interviews were conducted with 15 patients at the time of their referral for assessment to a quaternary cardiac and high volume TAVI centre. RESULTS: Multiple, intersecting factors that included biomedical, functional, social and environmental considerations influenced patients' decision. The six distinct factors were symptom burden, participants' perception as 'experienced' patients, expectations of benefit and risks, healthcare system and informal support, logistical barriers and facilitators, and obligations and responsibilities. CONCLUSIONS: The decision to undergo TAVI eligibility assessment is multifaceted and complex. Programmatic processes of care must be in place to facilitate appropriate and patient-centered decision making and access to TAVI. Strategies are required to mitigate the risks associated with the rapid deterioration of severe aortic stenosis, address patient and referring physicians' education needs, and provide individualised care and equitable access. Future research must focus on patients' experiences throughout the trajectory of TAVI care. PMID- 26498911 TI - How does metabolism affect cell death in cancer? AB - In cancer research, identifying a specificity of tumor cells compared with 'normal' proliferating cells for targeted therapy is often considered the Holy Grail for researchers and clinicians. Although diverse in origin, most cancer cells share characteristics including the ability to escape cell death mechanisms and the utilization of different methods of energy production. In the current paradigm, aerobic glycolysis is considered the central metabolic characteristic of cancer cells (Warburg effect). However, recent data indicate that cancer cells also show significant changes in other metabolic pathways. Indeed, it was recently suggested that Kreb's cycle, pentose phosphate pathway intermediates, and essential and nonessential amino acids have key roles. Renewed interest in the fact that cancer cells have to reprogram their metabolism in order to proliferate or resist treatment must take into consideration the ability of tumor cells to adapt their metabolism to the local microenvironment (low oxygen, low nutrients). This variety of metabolic sources might be either a strength, resulting in infinite possibilities for adaptation and increased ability to resist chemotherapy-induced death, or a weakness that could be targeted to kill cancer cells. Here, we discuss recent insights showing how energetic metabolism may regulate cell death and how this might be relevant for cancer treatment. PMID- 26498912 TI - Avoidable tragedies: Disparities in healthcare access among medically underserved women diagnosed with cervical cancer. AB - BACKGROUND: The purpose was to identify barriers including logistical and health belief correlates of late stage presentation of cervical cancer (CxCa) among medically underserved women presenting to a safety net health care system. METHODS: Women presenting with newly diagnosed CxCa were asked to complete a detailed health belief survey that included questions about barriers to care and their knowledge of CxCa. All information was collected prior to initiating cancer treatment. Comparisons were made among women diagnosed at early stages of disease amendable to surgical treatment (<=IB1) and those diagnosed at a stage requiring local-regional or systemic/palliative treatment (>=IB2). RESULTS: Among the 138 women, 21.7% were diagnosed with <=lB1 disease, while 78.3% were diagnosed with >=IB2 disease. Late-stage diagnosis was associated with a greater number of emergency room (ER) visits (p<.001) and blood transfusions (p<.001) prior to diagnosis. Compared to 88% with <=lB1 disease, only 53% of patients with >=IB2 disease had a car (p=.003). Women with >=IB2 disease were more likely to be without a primary care provider (75.0% vs. 42.3%, p=.001). CONCLUSION: Access to transportation and lack of a regular primary care provider or a medical home are associated with late-stage of CxCa at diagnosis. Many medically underserved women continue to use the ER as their primary source of health care, and as a result their CxCa is diagnosed in advanced stages, with higher medical costs and lower chances of cure. The lack of Medicaid expansion in Texas may result in a worsening of this situation. PMID- 26498913 TI - Peripheral neuropathy associated with levodopa-carbidopa intestinal infusion: a long-term prospective assessment. AB - BACKGROUND AND PURPOSE: Subacute and chronic peripheral neuropathies (PNP) have been reported in Parkinson's disease (PD) patients treated with levodopa/carbidopa intestinal gel infusion (LCIG), although several aspects of their incidence and pathogenesis still remain to be clarified. This study main objective is to prospectively report the 2-year incidence of PNP in patients treated with LCIG. METHODS AND RESULTS: The clinical, hematological, nutritional and electrophysiological assessments of 33 consecutive patients have been prospectively collected and evaluated. At baseline (before the start of LCIG therapy), 3/33 (9%) patients showed symptomatic PNP and 7/33 (21%) subclinical PNP. During a follow-up of 24.36 +/- 12.18 months, 2/23 patients with normal baseline clinical-electrophysiological assessment developed a subacute PNP, 2/23 developed a chronic PNP and 7/23 developed a subclinical PNP. LCIG was immediately halted in the subacute cases, while the infusion therapy was not interrupted in chronic and subclinical forms. All PNP were supplemented with vitamin B1 and B12, showing a clinical improvement and/or substantial stability at the following evaluations. Higher levodopa-equivalent daily dose (P: 0.024) and homocysteine levels (P: 0.041) were found in chronic PNP, while no correlations were observed with vitamin B12, folate and UPDRS values. A trend towards BMI reduction was observed in both PNP and unaffected subjects and one patient developed a symptomatic PNP associated with a relevant weight loss. CONCLUSIONS: Serial clinical-electrophysiological evaluations are mandatory in patients treated with LCIG, given the possible risk of subacute and chronic PNP. No clear causative factors has been recognized in the subacute forms, whilst homocysteine-mediated neurotoxicity seems to underlie the pathogenesis of chronic forms. PMID- 26498915 TI - Patient with extensive Mongolian spots, nevus flammeus and nevus vascularis mixtus: A novel case of phacomatosis pigmentovascularis. PMID- 26498914 TI - MicroRNA expression and its implications for diagnosis and therapy of tongue squamous cell carcinoma. AB - Tongue squamous cell carcinoma (TSCC) is the most common type of oral squamous cell carcinomas and is well known for its high rate of lymph nodal metastasis. Despite the identification of many molecular mechanisms in TSCC, the number of deaths associated with TSCC increased during the past 5 years. MicroRNAs (miRNAs) are a family of small non-coding RNA molecules, which regulate gene expression by either translational inhibition or mRNA degradation. miRNAs have been proven to be key regulators of various biological and pathological processes including cell proliferation, development and tumourigenesis. Increasing evidence has demonstrated that the deregulated miRNAs are implicated in the diagnosis and treatment of TSCC. In this review, we summarized the expressions and roles of miRNAs in TSCC and comment on the potential roles of miRNAs in diagnosis, prognosis and treatment of this malignancy. PMID- 26498916 TI - First off-time treatment prostate-specific antigen kinetics predicts survival in intermittent androgen deprivation for prostate cancer. AB - BACKGROUND: Prostate-specific antigen (PSA) doubling time is relying on an exponential kinetic pattern. This pattern has never been validated in the setting of intermittent androgen deprivation (IAD). Objective is to analyze the prognostic significance for PCa of recurrent patterns in PSA kinetics in patients undergoing IAD. METHODS: A retrospective study was conducted on 377 patients treated with IAD. On-treatment period (ONTP) consisted of gonadotropin-releasing hormone agonist injections combined with oral androgen receptor antagonist. Off treatment period (OFTP) began when PSA was lower than 4 ng/ml. ONTP resumed when PSA was higher than 20 ng/ml. PSA values of each OFTP were fitted with three basic patterns: exponential (PSA(t) = lambda.e(alphat)), linear (PSA(t) = a.t), and power law (PSA(t) = a.t(c)). Univariate and multivariate Cox regression model analyzed predictive factors for oncologic outcomes. RESULTS: Only 45% of the analyzed OFTPs were exponential. Linear and power law PSA kinetics represented 7.5% and 7.7%, respectively. Remaining fraction of analyzed OFTPs (40%) exhibited complex kinetics. Exponential PSA kinetics during the first OFTP was significantly associated with worse oncologic outcome. The estimated 10-year cancer-specific survival (CSS) was 46% for exponential versus 80% for nonexponential PSA kinetics patterns. The corresponding 10-year probability of castration-resistant prostate cancer (CRPC) was 69% and 31% for the two patterns, respectively. Limitations include retrospective design and mixed indications for IAD. CONCLUSION: PSA kinetic fitted with exponential pattern in approximately half of the OFTPs. First OFTP exponential PSA kinetic was associated with a shorter time to CRPC and worse CSS. PMID- 26498917 TI - Microparticles from apoptotic RAW 264.7 macrophage cells carry tumour necrosis factor-alpha functionally active on cardiomyocytes from adult mice. AB - After ischaemic injury and in patients with atherosclerosis, the pool of inflammatory macrophages is enlarged in the heart and in atherosclerotic plaques. Monocyte/macrophage-derived microparticles (MPs) are part of the pathological process of unstable atherosclerotic plaques. The present study focused on effects of MPs, produced by apoptotic murine RAW 264.7 macrophage cell line, in adult murine cardiomyocytes. Flow cytometry and western blot analysis showed that these MPs contained the soluble form of tumour necrosis factor alpha (TNF-alpha). Cardiomyocyte sarcomere shortening amplitudes and kinetics were reduced within 5 min of exposure to these MPs. Conversely, Ca(2+) transient amplitude and kinetics were not modified. The contractile effects of MPs were completely prevented after pretreatment with nitric oxide synthase, guanylate cyclase or TNF-alpha inhibitors as well as blocking TNF-alpha receptor 1 with neutralizing antibody. Microscopy showed that, after 1 h, MPs were clearly surrounding rod-shaped cardiomyocytes, and after 2 h they were internalized into cardiomyocytes undergoing apoptosis. After 4 h of treatment with MPs, cardiomyocytes expressed increased caspase-3, caspase-8, Bax and cytochrome C. Thus, MPs from apoptotic macrophages induced a negative inotropic effect and slowing of both contraction and relaxation, similar to that observed in the presence of TNF-alpha. The use of specific inhibitors strongly suggests that TNF-alpha receptors and the guanylate cyclase/cGMP/PKG pathway were involved in the functional responses to these MPs and that the mitochondrial intrinsic pathway was implicated in their proapoptotic effects. These data suggest that MPs issued from activated macrophages carrying TNF-alpha could contribute to propagation of inflammatory signals leading to myocardial infarction. PMID- 26498918 TI - Clinical implementation of routine screening for fetal trisomies in the UK NHS: cell-free DNA test contingent on results from first-trimester combined test. AB - OBJECTIVES: Cell-free DNA (cfDNA) analysis of maternal blood for detection of trisomies 21, 18 and 13 is superior to other methods of screening but is expensive. One strategy to maximize performance at reduced cost is to offer cfDNA testing contingent on the results of the first-trimester combined test that is used currently. The objectives of this study were to report the feasibility of implementing such screening, to examine the factors affecting patient decisions concerning their options for screening and decisions on the management of affected pregnancies and to report the prenatal diagnosis of fetal trisomies and outcome of affected pregnancies following the introduction of contingent screening. METHODS: We examined routine clinical implementation of contingent screening in 11,692 singleton pregnancies in two National Health Service (NHS) hospitals in the UK. Women with a risk >= 1 in 100 (high-risk group) were offered options of invasive testing, cfDNA testing or no further testing, and those with a risk between 1 in 101 and 1 in 2500 (intermediate-risk group) were offered cfDNA testing or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or by examination of the neonates. RESULTS: In the study population of 11,692 pregnancies, there were 47 cases of trisomy 21 and 28 of trisomies 18 or 13. Screening with the combined test followed by invasive testing for all patients in the high-risk group potentially could have detected 87% of trisomy 21 and 93% of trisomies 18 or 13, at a false-positive rate of 3.4%; the respective values for cfDNA testing in the high- and intermediate-risk groups were 98%, 82% and 0.25%. However, in the high risk group, 38% of women chose invasive testing and 60% chose cfDNA testing; in the intermediate-risk group 92% opted for cfDNA testing. A prenatal diagnosis was made in 43 (91.5%) pregnancies with trisomy 21 and all pregnancies with trisomies 18 or 13. In many affected pregnancies the parents chose to avoid testing or termination and 32% of pregnancies with trisomy 21 resulted in live births. CONCLUSIONS: Screening for fetal trisomies by cfDNA analysis of maternal blood, contingent on the results of the combined test, can be implemented easily in routine clinical practice. In the high-risk group from the combined test, most but not all women chose cfDNA testing rather than invasive testing. Performance of screening for trisomy 21 was superior by the cfDNA test than by the combined test. However, prenatal detection of trisomies and pregnancy outcome depend not only on performance of screening tests but also on parental choice. PMID- 26498919 TI - Predictors of 10-year smoking abstinence in smokers abstinent for 1 year after treatment. AB - AIMS: To identify factors predicting long-term relapse to smoking in people attending smoking treatment services who have maintained at least 1 year abstinence. DESIGN: Observational, prospective study with multiple logistic regression used to model predictors of relapse between 1 and 10 years from cessation using variables measured pre-cessation. SETTING AND PARTICIPANTS: Among smokers receiving behavioural support for cessation in a clinic in Spain, in some cases with nicotine patches or bupropion, 366 had remained abstinent after 1 year of follow-up and were included into the study. MEASUREMENTS: Predictive measures (disease history, psychological disorder, age of starting smoking, years of smoking, cigarette dependence and smoking cessation treatment used) were obtained at the time of the quit attempt, and 'failure' (defined as reported smoking, loss to follow-up, died or an expired air carbon monoxide reading of > 5 parts per million) was assessed 10 years later. FINDINGS: At follow-up, abstinence status was confirmed in 50.5% (n = 185) of participants, while 21.0% (n = 77) reported that they had resumed smoking, and 28.5% (n = 104) were lost to follow-up (also counted as having resumed smoking). In the multiple regression model, the main factor that predicted relapse had a psychological disorder (odds ratio = 1.85, 95% confidence interval = 1.13-3.05; P < 0.02). CONCLUSIONS: Having a psychological disorder at the time of stopping smoking is a risk factor for relapse to smoking, even after more than 1 year of abstinence. PMID- 26498920 TI - Pathway to a phenocopy: Heat stress effects in early embryogenesis. AB - BACKGROUND: Heat shocks applied at the onset of gastrulation in early Drosophila embryos frequently lead to phenocopies of U-shaped mutants-having characteristic failures in the late morphogenetic processes of germband retraction and dorsal closure. The pathway from nonspecific heat stress to phenocopied abnormalities is unknown. RESULTS: Drosophila embryos subjected to 30-min, 38 degrees C heat shocks at gastrulation appear to recover and restart morphogenesis. Post-heat shock development appears normal, albeit slower, until a large fraction of embryos develop amnioserosa holes (diameters > 100 um). These holes are positively correlated with terminal U-shaped phenocopies. They initiate between amnioserosa cells and open over tens of minutes by evading normal wound healing responses. They are not caused by tissue-wide increases in mechanical stress or decreases in cell-cell adhesion, but instead appear to initiate from isolated apoptosis of amnioserosa cells. CONCLUSIONS: The pathway from heat shock to U shaped phenocopies involves the opening of one or more large holes in the amnioserosa that compromise its structural integrity and lead to failures in morphogenetic processes that rely on amnioserosa-generated tensile forces. The proposed mechanism by which heat shock leads to hole initiation and expansion is heterochonicity, i.e., disruption of morphogenetic coordination between embryonic and extra-embryonic cell types. PMID- 26498921 TI - Defining the complementarities between antibodies and haptens to refine our understanding and aid the prediction of a successful binding interaction. AB - BACKGROUND: Low molecular weight haptens (<1000 Da) cannot be recognized by the immune system unless conjugated to larger carrier molecules. Antibodies to these exceptionally small antigens can still be generated with exquisite sensitivity. A detailed understanding at the molecular level of this incredible ability of antibodies to recognize haptens, is still limited compared to other antigen classes. METHODS: Different hapten targets with a broad range of structural flexibility and polarity were conjugated to carrier proteins, and utilized in sheep immunization. Three antibody libraries were constructed and used as potential pools to isolate specific antibodies to each target. The isolated antibodies were analysed in term of CDR length, canonical structure, and binding site shape and electrostatic potential. RESULTS: The simple, chemically naive structure of squalane (SQA) was recognized with micromolar sensitivity. An increase in structural rigidity of the hydrophobic and cyclic coprostane (COP) did not improve this binding sensitivity beyond the micromolar range, whilst the polar etioporphyrin (POR) was detected with nanomolar sensitivity. Homoserine lactone (HSL) molecules, which combine molecular flexibility and polarity, generated super-sensitive (picomolar) interactions. To better understand this range of antibody-hapten interactions, analyses were extended to examine the binding loop canonical structures and CDR lengths of a series of anti-hapten clones. Analyses of the pre and post- selection (panning of the phage displayed libraries) sequences revealed more conserved sites (123) within the post selection sequences, when compared to their pre-selection counterparts (28). The strong selection pressure, generated by panning against these haptens resulted in the isolation of antibodies with significant sequence conservation in the FW regions, and suitable binding site cavities, representing only a relatively small subset of the available full repertoire sequence and structural diversity. As part of this process, the important influence of CDR H2 on antigen binding was observed through its direct interaction with individual antigens and indirect impact on the orientation and the pocket shape, when combined with CDRs H3 and L3. The binding pockets also displayed electrostatic surfaces that were complementary to the hydrophobic nature of COP, SQA, and POR, and the negatively charged HSL. CONCLUSIONS: The best binding antibodies have shown improved capacity to recognize these haptens by establishing complementary binding pockets in terms of size, shape, and electrostatic potential. PMID- 26498922 TI - Simultaneous perturbation of the MAPK and the PI3K/mTOR pathways does not lead to increased radiosensitization. AB - BACKGROUND: The mitogen-activated protein kinases (MAPK) and the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are intertwined on various levels and simultaneous inhibition reduces tumorsize and prolonges survival synergistically. Furthermore, inhibiting these pathways radiosensitized cancer cells in various studies. To assess, if phenotypic changes after perturbations of this signaling network depend on the genetic background, we integrated a time series of the signaling data with phenotypic data after simultaneous MAPK/ERK kinase (MEK) and PI3K/mTOR inhibition and ionizing radiation (IR). METHODS: The MEK inhibitor AZD6244 and the dual PI3K/mTOR inhibitor NVP-BEZ235 were tested in glioblastoma and lung carcinoma cells, which differ in their mutational status in the MAPK and the PI3K/mTOR pathways. Effects of AZD6244 and NVP-BEZ235 on the proliferation were assessed using an ATP assay. Drug treatment and IR effects on the signaling network were analyzed in a time-dependent manner along with measurements of phenotypic changes in the colony forming ability, apoptosis, autophagy or cell cycle. RESULTS: Both inhibitors reduced the tumor cell proliferation in a dose-dependent manner, with NVP-BEZ235 revealing the higher anti-proliferative potential. Our Western blot data indicated that AZD6244 and NVP-BEZ235 perturbed the MAPK and PI3K/mTOR signaling cascades, respectively. Additionally, we confirmed crosstalks and feedback loops in the pathways. As shown by colony forming assay, the AZD6244 moderately radiosensitized cancer cells, whereas NVP-BEZ235 caused a stronger radiosensitization. Combining both drugs did not enhance the NVP-BEZ235-mediated radiosensitization. Both inhibitors caused a cell cycle arrest in the G1-phase, whereas concomitant IR and treatment with the inhibitors resulted in cell line- and drug-specific cell cycle alterations. Furthermore, combining both inhibitors synergistically enhanced a G1-phase arrest in sham-irradiated glioblastoma cells and induced apoptosis and autophagy in both cell lines. CONCLUSION: Perturbations of the MEK and the PI3K pathway radiosensitized tumor cells of different origins and the combination of AZD6244 and NVP-BEZ235 yielded cytostatic effects in several tumor entities. However, this is the first study assessing, if the combination of both drugs also results in synergistic effects in terms of radiosensitivity. Our study demonstrates that simultaneous treatment with both pathway inhibitors does not lead to synergistic radiosensitization but causes cell line-specific effects. PMID- 26498923 TI - Esophageal motility after peroral endoscopic myotomy for achalasia. AB - BACKGROUND: Peroral endoscopic myotomy (POEM) has been introduced as a novel endoscopic treatment for achalasia. The aim of this work is to assess the changes in esophageal motility caused by POEM in patients with achalasia. METHODS: Forty one patients with achalasia underwent POEM from September 2012 to November 2014. Esophageal motility of all patients was evaluated preoperatively and 1 month after POEM utilizing high-resolution manometry, which was performed with ten water swallows, ten steamed bread swallows, and multiple rapid swallows (MRS). RESULTS: In single swallows, including liquid swallows and bread swallows, all the parameters of lower esophagus sphincter resting pressure (LESP), 4-s integrated relaxation pressure (4sIRP), and intra-bolus pressure (IBP) were decreased between pre- and post-POEM patients (all p < 0.05). Postoperatively, the trend of distal contractile integral (DCI) and distal esophageal peristaltic amplitude declined in subtype II and subtype III (subtype II: p < 0.05; subtype III: p > 0.05), but increased in subtype I (subtype I: p > 0.05). In liquid swallows, the Eckardt score of subtype II patients decreased with DCI, and distal esophageal peristaltic amplitude after POEM was significantly lower compared with those showing increased values of those two parameters (p < 0.05). In MRS, the rate of LES relaxation increased from 66.67 to 95.24%, but without normal response in all achalasia patients. CONCLUSIONS: POEM reduces LES pressure in achalasia, and partly restores esophageal motility. POEM displayed varying effect on esophageal motility in patients with different patterns of swallowing. In addition, the changes in parameters associated with esophageal peristalsis correlated with decreases in Eckardt score. PMID- 26498924 TI - The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice. AB - Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan nuclear receptor Nur77 [also known as TR3 or nuclear receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77-deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77-deficient mice. There was no difference in the number of intimal apoptotic cells between the groups. Taken together, our results indicate that Nur77 may be a sensor of oxidative stress and an inhibitor of vascular remodeling induced by low shear stress. Nur77, as well as its downstream cell signals, may thus be a potential therapeutic target for the suppression of vascular remodeling. PMID- 26498925 TI - A cross-cultural investigation into the dimensional structure and stability of the Barriers to Research and Utilization Scale (BARRIERS Scale). AB - BACKGROUND: It is important that scales exhibit strong measurement properties including those related to the investigation of issues that impact evidence-based practice. The validity of the Barriers to Research Utilization Scale (BARRIERS Scale) has recently been questioned in a systematic review. This study investigated the dimensional structure and stability of the 28 item BARRIERS Scale when completed by three groups of participants from three different cross cultural environments. METHOD: Data from the BARRIERS Scale completed by 696 occupational therapists from Australia (n = 137), Taiwan (n = 413), and the United Kingdom (n = 144) were analysed using principal components analysis, followed by Procrustes Transformation. Poorly fitting items were identified by low communalities, cross-loading, and theoretically inconsistent primary loadings, and were systematically removed until good fit was achieved. The cross cultural stability of the component structure of the BARRIERS Scale was examined. RESULTS: A four component, 19 item version of the BARRIERS Scale emerged that demonstrated an improved dimensional fit and stability across the three participant groups. The resulting four components were consistent with the BARRIERS Scale as originally conceptualised. CONCLUSION: Findings from the study suggest that the four component, 19 item version of the BARRIERS Scale is a robust and valid measure for identifying barriers to research utilization for occupational therapists in paediatric health care settings across Australia, United Kingdom, and Taiwan. The four component 19 item version of the BARRIERS Scale exhibited good dimensional structure, internal consistency, and stability. PMID- 26498927 TI - Self-reported stigma and its association with socio-demographic factors and physical disability in people with intellectual disabilities: results from a cross-sectional study in England. AB - PURPOSE: The aim of this study was to investigate whether socio-demographic variables and physical disability (e.g. sensory impairment and mobility problems) were associated with self-reported stigma in people with intellectual disabilities (ID), and to examine whether age, sex and ethnicity modified the relationship between severity of intellectual disability and self-reported stigma. METHODS: 229 participants with mild or moderate intellectual disabilities were recruited from 12 centres/sites in England from community intellectual disability services, day centres, supported housing schemes, voluntary organisations and invitation letters. Information on physical disability and socio-demographic variables were obtained using a structured data collection form. Self-reported stigma was measured using a validated questionnaire. RESULTS: Age was associated with self-reported stigma, with older adults reporting more stigmatising experiences. Participants with moderate intellectual disabilities were more likely to report being treated differently such as being made fun of and being treated like children. Physical disability such as sensory, mobility and speech problems were not associated with self-reported stigma. Gender modified the relationship between severity of ID and self-reported stigma as participants who were male and had moderate ID were more likely to report stigma compared to females with moderate ID. Categorical age also modified the relationship between severity of ID and self-reported stigma as older participants who had moderate ID were more likely to report stigma compared to younger people with moderate ID. CONCLUSIONS: Older adults and those with moderate ID are potentially at higher risk of being targets of public stigma or are more likely to report stigma. Interventions to help individuals cope with stigma could be targeted to this group. PMID- 26498926 TI - Illness perception, help-seeking attitudes, and knowledge related to obsessive compulsive disorder across different ethnic groups: a community survey. AB - PURPOSE: Despite similar prevalence rates across ethnicities, ethnic minorities with obsessive-compulsive disorder (OCD) are under-represented in research and clinical settings. The reasons for this disproportion have been sparsely studied. We explored potential differences in illness perception, help-seeking attitudes, illness knowledge, and causal attributions that could help explain the lower uptake of treatment for OCD amongst ethnic minorities. METHODS: Two-hundred and ninety-three parents (139 White British, 61 Black African, 46 Black Caribbean, and 47 Indian) were recruited from the general population in South-East London, UK. Using a text vignette methodology, participants completed a survey including questions on illness perception, help-seeking attitudes, OCD knowledge, and causal attributions. RESULTS: The groups did not differ in socio-demographic characteristics and family history of OCD. White British parents perceived that the OCD difficulties would have more negative impact on their children and that treatment would be more helpful, compared to the ethnic minorities; the largest differences were observed between White British and Indian parents. Ethnic minorities were more prone to say that would seek help from their religious communities. Black African parents were more in favor of not seeking help for the described difficulties and, in general, perceived more treatment barriers. White British parents seemed to be better informed about OCD than ethnic minority parents. CONCLUSIONS: The results offer some plausible explanations for the large inequalities in access to services amongst ethnic minorities with OCD. Clinicians and policy-makers need to be aware of these socio-cultural factors when designing strategies to encourage help-seeking behaviors in these populations. PMID- 26498928 TI - Abnormalities in the meibomian glands in patients with oral administration of anticancer combination drug-capsule TS-1((r)): a case report. AB - BACKGROUND: The anticancer TS-1((r)) combination capsules of tegafur, gimeracil, and oteracil potassium (Taiho Pharmaceutical Co. Ltd, Japan) causes side effects, i. e., corneal epithelial disorder and dacryostenosis. However, its side effect on meibomian gland had not been reported. We observed morphological changes in the meibomian gland in patients taking TS-1((r)) who exhibited punctate corneal epithelial defects to examine if dysfunction of meibomian glands is involved in the corneal epitheliopathy. CASE PRESENTATION: Patients comprised two males and one female (age, 59-81 years). After starting oral TS-1((r)) administration, patients developed subjective symptoms such as decreased visual acuity. Corneal epithelial disorder was seen in all six eyes of the three subjects exhibited, and lacrimal duct disorder was seen in one eye. Furthermore, meibomian gland loss and contraction were observed in all six eyes that exhibited meibomian gland disorder upon examination by using the MeiboPen((r)). CONCLUSIONS: Results suggested that oral administration of TS-1((r)) may cause meibomian gland disorder which potentially affect corneal epithelial homeostasis. PMID- 26498929 TI - Quinolone resistance mutations in the faecal microbiota of Swedish travellers to India. AB - BACKGROUND: International travel contributes to the spread of antibiotic resistant bacteria over the world. Most studies addressing travel-related changes in the faecal flora have focused on specific mobile resistance genes, or depended on culturing of individual bacterial isolates. Antibiotic resistance can, however, also spread via travellers colonized by bacteria carrying chromosomal antibiotic resistance mutations, but this has received little attention so far. Here we aimed at exploring the abundance of chromosomal quinolone resistance mutations in Escherichia communities residing in the gut of Swedish travellers, and to determine potential changes after visiting India. Sweden is a country with a comparably low degree of quinolone use and quinolone resistance, whereas the opposite is true for India. METHODS: Massively parallel amplicon sequencing targeting the quinolone-resistance determining region of gyrA and parC was applied to total DNA extracted from faecal samples. Paired samples were collected from 12 Swedish medical students before and after a 4-15 week visit to India. Twelve Indian residents were included for additional comparisons. Methods known resistance mutations were common in Swedes before travel as well as in Indians, with a trend for all mutations to be more common in the Indian sub group. There was a significant increase in the abundance of the most common amino acid substitution in GyrA (S83L, from 44 to 72%, p=0.036) in the samples collected after return to Sweden. No other substitution, including others commonly associated with quinolone resistance (D87N in GyrA, S80I in ParC) changed significantly. The number of distinct genotypes encoded in each traveller was significantly reduced after their visit to India for both GyrA (p=0.0020) and ParC (p=0.0051), indicating a reduced genetic diversity, similar to that found in the Indians. CONCLUSIONS: International travel can alter the composition of the Escherichia communities in the faecal flora, favouring bacteria carrying certain resistance mutations, and, thereby, contributes to the global spread of antibiotic resistance. A high abundance of specific mutations in Swedish travellers before visiting India is consistent with the hypothesis that these mutation have no fitness cost even in the absence of an antibiotic selection pressure. PMID- 26498930 TI - Leveraging local ancestry to detect gene-gene interactions in genome-wide data. AB - BACKGROUND: Although genome-wide association studies have successfully identified thousands of variants associated to complex traits, these variants only explain a small amount of the entire heritability of the trait. Gene-gene interactions have been proposed as a source to explain a significant percentage of the missing heritability. However, detecting gene-gene interactions has proven to be very difficult due to computational and statistical challenges. The vast number of possible interactions that can be tested induces very stringent multiple hypotheses corrections that limit the power of detection. These issues have been mostly highlighted for the identification of pairwise effects and are even more challenging when addressing higher order interaction effects. In this work we explore the use of local ancestry in recently admixed individuals to find signals of gene-gene interaction on human traits and diseases. RESULTS: We introduce statistical methods that leverage the correlation between local ancestry and the hidden unknown causal variants to find distant gene-gene interactions. We show that the power of this test increases with the number of causal variants per locus and the degree of differentiation of these variants between the ancestral populations. Overall, our simulations confirm that local ancestry can be used to detect gene-gene interactions, solving the computational bottleneck. When compared to a single nucleotide polymorphism (SNP)-based interaction screening of the same sample size, the power of our test was lower on all settings we considered. However, accounting for the dramatic increase in sample size that can be achieve when genotyping only a set of ancestry informative markers instead of the whole genome, we observe substantial gain in power in several scenarios. CONCLUSION: Local ancestry-based interaction tests offer a new path to the detection of gene-gene interaction effects. It would be particularly useful in scenarios where multiple differentiated variants at the interacting loci act in a synergistic manner. PMID- 26498931 TI - Effects of Vessel Tortuosity on Coronary Hemodynamics: An Idealized and Patient Specific Computational Study. AB - Although coronary tortuosity can influence the hemodynamics of coronary arteries, the relationship between tortuosity and flow has not been thoroughly investigated partly due to the absence of a widely accepted definition of tortuosity and the lack of patient-specific studies that analyze complete coronary trees. Using a computational approach we investigated the effects of tortuosity on coronary flow parameters including pressure drop, wall shear stress, and helical flow strength as measured by helicity intensity. Our analysis considered idealized and patient specific geometries. Overall results indicate that perfusion pressure decreases with increased tortuosity, but the patient-specific results show that more tortuous vessels have higher physiological wall shear stress values. Differences between the idealized and patient-specific results reveal that an accurate representation of coronary tortuosity must account for all relevant geometric aspects, including curvature imposed by the heart shape. The patient-specific results exhibit a strong correlation between tortuosity and helicity intensity, and the corresponding helical flow contributes directly to the observed increase in wall shear stress. Therefore, helicity intensity may prove helpful in developing a universal parameter to describe tortuosity and assess its impact on patient health. Our data suggest that increased tortuosity could have a deleterious impact via a reduction in coronary perfusion pressure, but the attendant increase in wall shear stress could afford protection against atherosclerosis. PMID- 26498932 TI - Exploring the relationship between quality of life and mental health problems in children: implications for measurement and practice. AB - Quality of life is typically reduced in children with mental health problems. Understanding the relationship between quality of life and mental health problems and the factors that moderate this association is a pressing priority. This was a cross-sectional study involving 45,398 children aged 8-13 years from 880 schools in England. Self-reported quality of life was assessed using nine items from the KIDSCREEN-10 and mental health was assessed using the Me and My School Questionnaire. Demographic information (gender, age, ethnicity, socio-economic status) was also recorded. Quality of life was highest in children with no problems and lowest in children with both internalising and externalising problems. There was indication that quality of life may be reduced in children with internalising problems compared with externalising problems. Approximately 12 % children with mental health problems reported high quality of life. The link between mental health and quality of life was moderated by gender and age but not by socio-economic status or ethnicity. This study supports previous work showing mental health and quality of life are related but not synonymous. The findings have implications for measuring quality of life in child mental health settings and the need for approaches to support children with mental health problems that are at particular risk of poor quality of life. PMID- 26498933 TI - Mallet finger: a simulation and analysis of hyperflexion versus hyperextension injuries. AB - The goal of this study was to simulate the mechanisms of hyperflexion and hyperextension injuries of the distal interphalangeal (DIP) joint of the hand and to analyze the resulting extensor tendon injury patterns. The hypotheses were raised that hyperflexion trauma leads to a plastic deformation of the extensor tendon aponeurosis, with or without a small bony avulsion fragment but without joint surface involvement, and that hyperextension injuries can create a shear fracture of the dorsal lip of the distal phalanx, without injury to the extensor tendon aponeurosis. Loading was applied with a swinging pendulum impacting the distal phalanx in 103 human specimens in either an extended or flexion position. After loading, injury patterns were analyzed radiologically and histologically. There was evidence that hyperflexion trauma leads to a plastic deformation or rupture of the extensor tendon. Bony tendon avulsion was evident in 12.2 % of cases. With hyperextension, the extensor tendon remained intact in all cases, but there were large fracture fragments involving the articular surface in 4.1 % of cases. The results of the study show that force on the flexed joint leads to overstretching of the extensor tendon, and to an associated dorsal bony avulsion with intact joint line. Force applied to the joint in extension can lead to a bony dorsal edge fracture with articular involvement and with it, a palmar DIP joint capsule rupture. The results illuminate a direct correlation between the mechanism of injury and the pattern of injury in the clinical picture of mallet finger. PMID- 26498934 TI - The extracranial to intracranial anastomotic channel through the parietal foramen: delineation with magnetic resonance imaging. AB - PURPOSE: Parietal foramina (PFs) are openings of fine canals that perforate the parietal bone. However, few studies have investigated the entire canals and their emissary vessels (EVs). Here, we explore the EVs with magnetic resonance imaging. METHODS: A total of 104 patients who underwent contrast examinations and exhibited an intact scalp, skull, dura mater, and superior sagittal sinus were enrolled in this study. Imaging data were obtained as thin-sliced, seamless sagittal sections and were transferred to a workstation for analysis. RESULTS: A total of 116 EVs passing through the PF and inner canals (parietal canal) were identified in 78 patients (75 %). All the EVs were found to perforate each layer of the parietal bone. Of 104 patients, 68 % exhibited one EV, 30 % two EVs, and 2 % three EVs. In 85.3 %, the EV was entirely delineated in one sagittal slice, 10.3 % were covered by two slices, and 4.3 % by three slices. In 68 %, the EV connected to the upper surface of the superior sagittal sinus (SSS) with variable courses from near-vertical to horizontal inclinations. CONCLUSIONS: EVs perforate the skull with variable inclinations, while showing a highly consistent course in the sagittal dimension. The PF and EV can be used as landmarks of the SSS lying immediately below. PMID- 26498935 TI - Forsythiaside A Exhibits Anti-inflammatory Effects in LPS-Stimulated BV2 Microglia Cells Through Activation of Nrf2/HO-1 Signaling Pathway. AB - Inflammation and oxidative stress have been reported to play critical roles in the pathogenesis of neurodegenerative disease. Forsythiaside A, a phenylethanoside product isolated from air-dried fruits of Forsythia suspensa, has been reported to have anti-inflammatory and antioxidant effects. In this study, the anti-inflammatory effects of forsythiaside A on LPS-stimulated BV2 microglia cells and primary microglia cells were investigated. The production of inflammatory mediators TNF-alpha, IL-1beta, NO and PGE2 were detected in this study. NF-kappaB, nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) expression were detected by western blot analysis. Our results showed that forsythiaside A significantly inhibited LPS-induced inflammatory mediators TNF-alpha, IL-1beta, NO and PGE2 production. LPS-induced NF-kappaB activation was suppressed by forsythiaside A. Furthermore, forsythiaside A was found to up-regulate the expression of Nrf2 and HO-1. In conclusion, this study demonstrates that forsythiaside A inhibits LPS-induced inflammatory responses in BV2 microglia cells and primary microglia cells through inhibition of NF-kappaB activation and activation of Nrf2/HO-1 signaling pathway. PMID- 26498936 TI - Attenuation of Acute Phase Injury in Rat Intracranial Hemorrhage by Cerebrolysin that Inhibits Brain Edema and Inflammatory Response. AB - The outcome of intracerebral hemorrhage (ICH) is mainly determined by the volume of the hemorrhage core and the secondary brain damage to penumbral tissues due to brain swelling, microcirculation disturbance and inflammation. The present study aims to investigate the protective effects of cerebrolysin on brain edema and inhibition of the inflammation response surrounding the hematoma core in the acute stage after ICH. The ICH model was induced by administration of type VII bacterial collagenase into the stratum of adult rats, which were then randomly divided into three groups: ICH + saline; ICH + Cerebrolysin (5 ml/kg) and sham. Cerebrolysin or saline was administered intraperitoneally 1 h post surgery. Neurological scores, extent of brain edema content and Evans blue dye extravasation were recorded. The levels of pro-inflammatory factors (IL-1beta, TNF-alpha and IL-6) were assayed by Real-time PCR and Elisa kits. Aquaporin-4 (AQP4) and tight junction proteins (TJPs; claudin-5, occludin and zonula occluden 1) expression were measured at multiple time points. The morphological and intercellular changes were characterized by Electron microscopy. It is found that cerebrolysin (5 ml/kg) improved the neurological behavior and reduced the ipsilateral brain water content and Evans blue dye extravasation. After cerebrolysin treated, the levels of pro-inflammatory factors and AQP4 in the peri hematomal areas were markedly reduced and were accompanied with higher expression of TJPs. Electron microscopy showed the astrocytic swelling and concentrated chromatin in the ICH group and confirmed the cell junction changes. Thus, early cerebrolysin treatment ameliorates secondary injury after ICH and promotes behavioral performance during the acute phase by reducing brain edema, inflammatory response, and blood-brain barrier permeability. PMID- 26498938 TI - Atrial rhythm influences catheter tissue contact during radiofrequency catheter ablation of atrial fibrillation: comparison of contact force between sinus rhythm and atrial fibrillation. AB - Catheter tissue contact force (CF) is an important factor for durable lesion formation during radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). Since CF varies in the beating heart, atrial rhythm during RFCA may influence CF. A high-density map and RFCA points were obtained in 25 patients undergoing RFCA of AF using a CF-sensing catheter (Tacticath, St. Jude Medical). The operators were blinded to the CF information. Contact type was classified into three categories: constant, variable, and intermittent contact. Average CF and contact type were analyzed according to atrial rhythm (SR vs. AF) and anatomical location. A total of 1364 points (891 points during SR and 473 points during AF) were analyzed. Average CFs showed no significant difference between SR (17.2 +/- 11.3 g) and AF (17.2 +/- 13.3 g; p = 0.99). The distribution of points with an average CF of >=20 and <10 g also showed no significant difference. However, the distribution of excessive CF (CF >=40 g) was significantly higher during AF (7.4 %) in comparison with SR (4.2 %; p < 0.05). At the anterior area of the right inferior pulmonary vein (RIPV), the average CF during AF was significantly higher than during SR (p < 0.05). Constant contact was significantly higher during AF (32.2 %) when compared to SR (9.9 %; p < 0.01). Although the average CF was not different between atrial rhythms, constant contact was more often achievable during AF than it was during SR. However, excessive CF also seems to occur more frequently during AF especially at the anterior part of RIPV. PMID- 26498939 TI - Short- and long-term inhibition of cardiac inward-rectifier potassium channel current by an antiarrhythmic drug bepridil. AB - Bepridil is an effective antiarrhythmic drug on supraventricular and ventricular arrhythmias, and inhibitor of calmodulin. Recent investigations have been elucidating that bepridil exerts antiarrhythmic effects through its acute and chronic application for patients. The aim of this study was to identify the efficacy and the potential mechanism of bepridil on the inward-rectifier potassium channel in neonatal rat cardiomyocytes in acute- and long-term conditions. Bepridil inhibited inward-rectifier potassium current (I K1) as a short-term effect with IC50 of 17 MUM. Bepridil also reduced I K1 of neonatal cardiomyocytes when applied for 24 h in the culture medium with IC50 of 2.7 MUM. Both a calmodulin inhibitor (W-7) and an inhibitor of calmodulin-kinase II (KN93) reduced I K1 when applied for 24 h as a long-term effect in the same fashion, suggesting that the long-term application of bepridil inhibits I K1 more potently than that of the short-term application through the inhibition of calmodulin kinase II pathway in cardiomyocytes. PMID- 26498940 TI - Body mass index is associated with prognosis in Japanese elderly patients with atrial fibrillation: an observational study from the outpatient clinic. AB - The relationship between body mass index (BMI) and the prognosis of elderly patients with atrial fibrillation (AF) is unknown. We aimed to examine the association of body weight with the clinical outcomes among Japanese elderly patients with a history of documented AF. This observational study of AF patients from an outpatients clinic in Nagoya University Hospital included 413 patients >=70 years old (99 obese: BMI >=25 kg/m(2); 256 normal weight: BMI 18.5-24.9 kg/m(2); and 58 underweight patients: BMI <18.5 kg/m(2)). The mean age was 77.5 +/- 5.6 years. During a mean follow-up of 19.0 months, all-cause death occurred in 23 patients (obese 1 %, normal weight 5.1 %, and underweight 16 %). The major adverse events including all-cause death, stroke or transient ischemic attack, heart failure requiring admission, and acute coronary syndrome were observed in 53 patients (obese 5.1 %, normal weight 13 %, and underweight 26 %). After adjusting for confounding factors, the underweight group had a significantly greater risk for all-cause death [hazard ratio (HR) 2.91, 95 % confidence interval (CI) 1.12-7.60, p = 0.029], and major adverse events (HR 2.45, 95 % CI 1.25-4.78, p = 0.009) than the normal weight group. In contrast, the obese group had a better prognosis in major adverse events compared with the normal weight group (HR 0.34, 95 % CI 0.13-0.89, p = 0.029). In conclusion, lower BMI was independently associated with poor outcomes among older AF patients. The association between obesity and better prognosis in elderly AF patients was also found. PMID- 26498941 TI - Electrocardiographic changes associated with takotsubo cardiomyopathy in a patient with pre-existing left bundle branch block. AB - An 81-year-old man was referred to our emergency department with severe persistent chest pain. One year before presentation at our department, his 12 lead electrocardiogram (ECG) revealed a normal QRS pattern during the period of normal conduction with intermittent left bundle branch block (LBBB). His ECG immediately after arrival showed deep T-wave inversion in the precordial leads during normal conduction. During LBBB, there was mild ST-segment elevation with poor R-wave progression across the precordial leads. Emergent cardiac catheterization was performed to rule out acute coronary syndrome. Coronary angiography showed no significant stenosis, and coronary spasm was not provoked by the administration of intracoronary ergonovine. Left ventriculography demonstrated persistent left ventricular apical akinesis with systolic ballooning. Based on these findings, the patient was diagnosed to have takotsubo cardiomyopathy (TCM). After 6 months, echocardiography demonstrated the recovery of the left ventricular regional wall motion abnormality. An ECG performed 6 months after the presentation showed incomplete resolution of T-wave inversion in the periods of normal conduction. ST elevation and poor R-wave progression were improved during LBBB. In a case with acute chest pain and an ECG changes incompatible with acute ischemia superimposed on a pattern of LBBB, TCM should be considered as a differential diagnosis. PMID- 26498937 TI - Temporal cardiac remodeling post-myocardial infarction: dynamics and prognostic implications in personalized medicine. AB - Despite dramatic improvements in short-term mortality rates following myocardial infarction (MI), long-term survival for MI patients who progress to heart failure remains poor. MI occurs when the left ventricle (LV) is deprived of oxygen for a sufficient period of time to induce irreversible necrosis of the myocardium. The LV response to MI involves significant tissue, cellular, and molecular level modifications, as well as substantial hemodynamic changes that feedback negatively to amplify the response. Inflammation to remove necrotic myocytes and fibroblast activation to form a scar are key wound healing responses that are highly variable across individuals. Few biomarkers of early remodeling stages are currently clinically adopted. The discovery of underlying pathophysiological mechanisms and associated novel biomarkers has the potential of improving prognostic capability and therapeutic monitoring. Combining these biomarkers with other prominent ones could constitute a powerful diagnostic and prognostic tool that directly reflects the pathophysiological remodeling of the LV. Understanding temporal remodeling at the tissue, cellular, and molecular level and its link to a well-defined set of biomarkers at early stages post-MI is a prerequisite for improving personalized care and devising more successful therapeutic interventions. Here we summarize the integral mechanisms that occur during early cardiac remodeling in the post-MI setting and highlight the most prominent biomarkers for assessing disease progression. PMID- 26498942 TI - Antioxidant Rescue of Selenomethionine-Induced Teratogenesis in Zebrafish Embryos. AB - Selenium (Se) is an essential micronutrient that can be found at toxic concentrations in surface waters contaminated by runoff from agriculture and coal mining. Zebrafish (Danio rerio) embryos were exposed to aqueous Se in the form of selenate, selenite, and l-selenomethionine (SeMet) in an attempt to determine if oxidative stress plays a role in selenium embryo toxicity. Selenate and selenite exposure did not induce embryo deformities (lordosis and craniofacial malformation). l-selenomethionine, however, induced significantly higher deformity rates at 100 ug/L compared with controls. SeMet exposure induced a dose dependent increase in the catalytic subunit of glutamate-cysteine ligase (gclc) and reached an 11.7-fold increase at 100 ug/L. SeMet exposure also reduced concentrations of TGSH, RGSH, and the TGSH:GSSG ratio. Pretreatment with 100 uM N acetylcysteine significantly reduced deformities in the zebrafish embryos secondarily treated with 400 ug/L SeMet from approximately 50-10 % as well as rescued all three of the significant glutathione level differences seen with SeMet alone. Selenite exposure induced a 6.6-fold increase in expression of the glutathione-S-transferase pi class 2 (gstp2) gene, which is involved in xenobiotic transformation and possibly oxidative stress. These results suggest that aqueous exposure to SeMet can induce significant embryonic teratogenesis in zebrafish that are at least partially attributed to oxidative stress. PMID- 26498944 TI - Light Chain Amyloidosis: Patient Experience Survey from the Amyloidosis Research Consortium. AB - INTRODUCTION: Information detailing the experience of patients with light chain (AL) amyloidosis is lacking. The primary aim of this study was to gather data on the patient experience to understand the challenges in diagnosis and to gain insight into barriers to accessing appropriate care. METHODS: Patients with amyloidosis, family members, and caregivers were invited to participate in an online 16-question survey (available from January 29 to February 5, 2015). Participants with AL amyloidosis were sent an eight-question follow-up survey. RESULTS: The initial survey was completed by 533 participants (follow-up survey completed by 201 participants). AL amyloidosis was the most common diagnosis. For 37.1% of respondents, the diagnosis of amyloidosis was not established until >= 1 year after the onset of initial symptoms. Diagnosis was received after visits to 1, 2, 3, 4, or >= 5 physicians by 7.6%, 23.5%, 20.3%, 16.8%, and 31.8% of respondents, respectively. Correct diagnosis was most often made by hematologists/oncologists (34.1%). Treatments included chemotherapy (63.1%) and stem cell transplantation (38.9%) and were difficult to tolerate for 54.1% of respondents. A significant number of respondents felt uninformed about clinical trials. Nevertheless, approximately half (46.1%) believed that enrolling in a trial would enhance their care. CONCLUSIONS: Establishing a diagnosis of amyloidosis is difficult. Current treatments are difficult to tolerate and do not substantially improve quality of life for most patients. There is an urgent need for well-tolerated therapies with clear treatment benefit. Patient awareness of clinical trials can be improved, especially given that respondents indicated high willingness to participate. PMID- 26498943 TI - Development of a Consensus Statement for the Definition, Diagnosis, and Treatment of Acute Exacerbations of Idiopathic Pulmonary Fibrosis Using the Delphi Technique. AB - INTRODUCTION: There is a lack of agreed and established guidelines for the treatment of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). This reflects, in part, the limited evidence-base underpinning the management of AE IPF. In the absence of high-quality evidence, the aim of this research was to develop a clinician-led consensus statement for the definition, diagnosis and treatment of AE-IPF. METHODS: A literature review was conducted to obtain published material on the definition and treatment of AE-IPF. The results of this review were circulated to an online panel of clinicians for review. Statements were then shared with ten expert respiratory clinicians who regularly treat patients with IPF. A Delphi technique was then used to develop a consensus statement for the definition, diagnosis and treatment of AE-IPF. During the first round of review, clinicians rated the clarity of each statement, the extent to which the statement should be included and provided comments. In two subsequent rounds of review, clinicians were provided with the group median inclusion rating for each statement, and any revised wording of statements to aid clarity. Clinicians were asked to repeat the clarity and inclusion ratings for the revised statements. RESULTS: The literature review, online panel discussion, and face-to face meeting generated 65 statements covering the definition, diagnosis, and management of AE-IPF. Following three rounds of blind review, 90% of clinicians agreed 39 final statements. These final statements included a definition of AE IPF, approach to diagnosis, and treatment options, specifically: supportive measures, use of anti-microbials, immunosuppressants, anti-coagulants, anti fibrotic therapy, escalation, transplant management, and long-term management including discharge planning. CONCLUSION: This clinician-led consensus statement establishes the 'best practice' for the management and treatment of AE-IPF based on current knowledge, evidence, and available treatments. PMID- 26498945 TI - Tobacco rattle virus 16K silencing suppressor binds ARGONAUTE 4 and inhibits formation of RNA silencing complexes. AB - The cysteine-rich 16K protein of tobacco rattle virus (TRV), the type member of the genus Tobravirus, is known to suppress RNA silencing. However, the mechanism of action of the 16K suppressor is not well understood. In this study, we used a GFP-based sensor strategy and an Agrobacterium-mediated transient assay in Nicotiana benthamiana to show that 16K was unable to inhibit the activity of existing small interfering RNA (siRNA)- and microRNA (miRNA)-programmed RNA induced silencing effector complexes (RISCs). In contrast, 16K efficiently interfered with de novo formation of miRNA- and siRNA-guided RISCs, thus preventing cleavage of target RNA. Interestingly, we found that transiently expressed endogenous miR399 and miR172 directed sequence-specific silencing of complementary sequences of viral origin. 16K failed to bind small RNAs, although it interacted with ARGONAUTE 4, as revealed by bimolecular fluorescence complementation and immunoprecipitation assays. Site-directed mutagenesis demonstrated that highly conserved cysteine residues within the N-terminal and central regions of the 16K protein are required for protein stability and/or RNA silencing suppression. PMID- 26498946 TI - Subclinical Cushing's syndrome in patients with bilateral compared to unilateral adrenal incidentalomas: a systematic review and meta-analysis. AB - The purpose of this study was to systematically review the literature for studies that have investigated possible differences in the prevalence of subclinical Cushing's syndrome (SCS) and related clinical implications between patients with unilateral (UAI) and bilateral adrenal incidentalomas (BAI) and to meta-analyze the best evidence available. Electronic databases PubMed and EMBASE were systematically searched. Main study outcome was the prevalence of SCS in patients with UAI and BAI. Secondary outcomes were the prevalence of obesity, diabetes, glucose intolerance, hypertension, dyslipidemia, and osteoporosis in patients with UAI and BAI. Risk differences (RD) or mean differences (MD) and 95 % confidence intervals (CIs) were calculated. Meta-analysis was conducted using Review Manager (RevMan 5.3). Six studies were included in the meta-analysis involving in total 1239 patients, 968 with UAI, and 271 with BAI. Patients with UAI had lower prevalence of SCS compared with those with BAI [RD (95 % CI) -0.13 (-0.22 to -0.05), I (2) = 42 %]. The mass diameter of UAI did not differ from BAI (the size of the largest lesion) [MD (95 % CI) -0.45 (-1.09 to 0.19), I (2) = 91 %]. The prevalence of obesity [MD (95 % CI) 0.42 (-0.53 to 1.37), I (2) = 4 %], diabetes [RD (95 % CI) -0.04 (-0.11 to 0.04), I (2) = 0 %], hypertension [RD (95 % CI) 0.00 (-0.18 to 0.18), I (2) = 75 %], and dyslipidemia [RD (95 % CI) -0.02 ( 0.16 to 0.13), I (2) = 50 %] did not differ between UAI and BAI. The present meta analysis provided evidence that patients with BAI present a higher prevalence of SCS compared to patients with UAI. PMID- 26498947 TI - Comparison of in-plane and out-of-plane needle insertion with vs. without needle guidance. AB - PURPOSE: First comparison of two methods of needle insertion: long axis ("in plane") versus short axis ("out-of-plane") approach, each with and without a prototype needle guidance system (NGS). MATERIALS AND METHODS: 24 medical students without prior experience punctured an ultrasound phantom (transparent except for the decklayer) in four conditions, with the goal of achieving as many accurate punctures as possible within a fixed time. RESULTS: Out-of-plane with NGS led to substantially more hits at first attempt than punctures without NGS (p < 0.001), as well as to a greater total number of hits (p = 0.004), and participants were faster to hit the target the first time (p = 0.009). CONCLUSIONS: Thus, navigation increases accuracy as well as efficiency of ultrasound guided punctures on the phantom. It could prove advantageous in clinical applications for fine needle biopsies, musculoskeletal injections, vascular access, and in regional anesthesia. PMID- 26498948 TI - Cochlear implantation for hearing rehabilitation in single-sided deafness after translabyrinthine vestibular schwannoma surgery. AB - The aim of the study was to investigate the option of cochlear implantation (CI) in resultant single-sided deafness associated with unilateral translabyrinthine resection of sporadic vestibular schwannoma (VS). This is a retrospective study performed at Tertiary Care Academic Centre. Following extensive counselling regarding the potential for delayed CI, translabyrinthine VS resection was performed and an intracochlear placeholder was inserted to allow later CI in 11 patients who showed intraoperative microscopic confirmation of preserved cochlear nerve anatomy. Follow-up magnetic resonance imaging (MRI) and promontory testing were performed 1 year after surgery to confirm the absence of VS recurrence and viable cochlea. Confirmed CI candidates underwent a second procedure where the placeholder was removed and the CI inserted (4/11). Preimplant unaided and CI aided evaluations at 12 and 24 months were performed for subjective and objective hearing outcomes. Tinnitus suppression was also measured for implant on and off effects. Available audiological data for three patients demonstrated significant hearing benefits for 'speech from deaf/implanted side, noise from the normal hearing side' in all three patients and localisation ability improved for 2/3 patients. Subjective findings presented similar results. For the two patients with preimplant tinnitus, complete suppression occurred during active CI. CI is beneficial for hearing rehabilitation and tinnitus reduction in SSD patients with remaining viable cochlear nerve after translabyrinthine VS surgery. Counselling on the risks of intracochlear placeholder insertion and the inherent limitations for ongoing MRI investigations of VS recurrence is essential. PMID- 26498949 TI - Intensity modulated perioperative HDR brachytherapy for recurrent and/or advanced head and neck metastases. AB - Recurrent neck metastases following surgery and full dose adjuvant radiotherapy of squamous cell head and neck cancer remain a clinical challenge. After revision neck dissection and chemotherapy re-irradiation dosage is often limited and survival prognosis deteriorates. Here, adjuvant high-dose rate intensity modulated perioperative brachytherapy (HDR IMBT) offers a second full radiation dose with a limited volume of normal tissue radiation in the neck. In this retrospective study patients were identified who underwent revision surgery and perioperative HDR IMBT for recurrent neck metastases. Survival rates were estimated and the scarce literature on interstitial brachytherapy of the neck was reviewed. From 2006 to 2014, nine patients were treated for recurrent or palliative neck metastases using salvage surgery and HDR IMBT. Eight patients received previous surgery and external beam radiotherapy with or without chemotherapy. Two and five year overall survival was calculated to be 78 and 67 %, respectively. HDR IMBT is a salvage treatment option for selected cases in the neck following surgical revision or last-line treatment strategies. In the literature and this small cohort radiation toxicity and the risk of "carotid blow out" seemed to be low. PMID- 26498951 TI - Mitochondrial DNA in the regulation of innate immune responses. AB - Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and considered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor's, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA (mtDNA) activates several innate immune pathways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibacterial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production,mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity. PMID- 26498950 TI - Minor salivary gland carcinoma: a review of 35 cases. AB - Minor salivary gland carcinomas represent a heterogeneous group of tumors with broad variation in clinical appearance and histopathology. Clinical data of patients with small salivary gland malignancies were collected from the medical records. Tissue microarray was constructed to determine the expression pattern of 24 proteins in 35 patients with minor salivary gland carcinomas. The choice of markers was based on involvement in neoangiogenesis, cell-to-cell contact, cell cycle regulation and carcinogenesis. Protein expression data were correlated to patients' clinical data. Overexpression of patched (p = 0.046) and Smo (p = 0.032) was linked to a better overall survival and Glutathione S-transferase pi overexpression was linked to prolonged disease-free survival (p = 0.005). Cox-1 (p = 0.035) and VEGFR2 (p = 0.009) were significantly linked to decreased survival for recurrent disease. Bcl-x (84 %), beta-catenin (87 %) and Cox-2 (87 %) were significantly overexpressed in minor salivary gland carcinomas. We have shown that Smo resulted in a better overall survival, whereas Gstpi in improved disease-free survival. VEGFR2 was a prognostic factor for survival after recurrence in patients with minor salivary gland carcinomas. Cyclooxygenase inhibitors and anti-Wnt-1 antibodies might be a potential therapeutic option in an adjuvant setting or for patients with unresectable tumors of the minor salivary glands. PMID- 26498952 TI - TH and DCX mRNAs in peripheral blood and bone marrow predict outcome in metastatic neuroblastoma patients. AB - PURPOSE: In metastatic neuroblastoma (NB) patients, accurate risk stratification and disease monitoring would reduce relapse probabilities. This study aims to evaluate the independent prognostic significance of detecting tyrosine hydroxylase (TH) and doublecortin (DCX) mRNAs by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in peripheral blood (PB) and bone marrow (BM) samples from metastatic NB patients. PROCEDURES: RT-qPCR was performed on PB and BM samples from metastatic NB patients at diagnosis, post induction therapy and at the end of treatment for TH and DCX mRNAs detection. RESULTS: High levels of TH and DCX mRNAs when detected in PB and BM at diagnosis independently predicted worse outcome in a cohort of 162 metastatic NB. In the subgroup of high-risk metastatic NB, TH mRNA detected in PB remained as independent predictor of EFS and OS at diagnosis. After the induction therapy, high levels of TH mRNA in PB and DCX mRNA in BM independently predicted poor EFS and OS. Furthermore TH mRNA when detected in BM predicted worse EFS. TH mRNA in PB samples at the end of treatment is an independent predictor of worse outcome. CONCLUSION: TH and DCX mRNAs levels in PB and BM assessed by RT-qPCR should be considered in new pre-treatment risk stratification strategies to reliable estimate outcome differences in metastatic NB patients. In those high-risk metastatic NB, TH and DCX mRNA quantification could be used for the assessment of response to treatment and for early detection of progressive disease or relapses. PMID- 26498953 TI - Changes in chlamydia control activities in Europe between 2007 and 2012: a cross national survey. AB - BACKGROUND: In 2012, the levels of chlamydia control activities including primary prevention, effective case management with partner management and surveillance were assessed in 2012 across countries in the European Union and European Economic Area (EU/EEA), on initiative of the European Centre for Disease Control (ECDC) survey, and the findings were compared with those from a similar survey in 2007. METHODS: Experts in the 30 EU/EEA countries were invited to respond to an online questionnaire; 28 countries responded, of which 25 participated in both the 2007 and 2012 surveys. Analyses focused on 13 indicators of chlamydia prevention and control activities; countries were assigned to one of five categories of chlamydia control. RESULTS: In 2012, more countries than in 2007 reported availability of national chlamydia case management guidelines (80% vs. 68%), opportunistic chlamydia testing (68% vs. 44%) and consistent use of nucleic acid amplification tests (64% vs. 36%). The number of countries reporting having a national sexually transmitted infection control strategy or a surveillance system for chlamydia did not change notably. In 2012, most countries (18/25, 72%) had implemented primary prevention activities and case management guidelines addressing partner management, compared with 44% (11/25) of countries in 2007. CONCLUSION: Overall, chlamydia control activities in EU/EEA countries strengthened between 2007 and 2012. Several countries still need to develop essential chlamydia control activities, whereas others may strengthen implementation and monitoring of existing activities. PMID- 26498954 TI - Modelling the cost-effectiveness of impact-absorbing flooring in Swedish residential care facilities. AB - OBJECTIVE: Fall-related injuries among the elderly, specifically hip fractures, cause significant morbidity and mortality as well as imposing a substantial financial cost on the health care system. Impact-absorbing flooring has been advocated as an effective method for preventing hip fractures resulting from falls. This study identifies the cost-effectiveness of impact-absorbing flooring compared to standard flooring in residential care facilities for the elderly in a Swedish setting. METHOD: An incremental cost-effectiveness analysis was performed comparing impact-absorbing flooring to standard flooring using a Markov decision model. A societal perspective was adopted and incremental costs were compared to incremental gains in quality-adjusted life years (QALYs). Data on costs, probability transitions and health-related quality of life measures were retrieved from the published literature and from Swedish register data. Probabilistic sensitivity analysis was performed through a Monte Carlo simulation. RESULTS: The base-case analysis indicates that the impact-absorbing flooring reduces costs and increases QALYs. When allowing for uncertainty we find that 60% of the simulations indicate that impact-absorbing flooring is cost saving compared to standard flooring and an additional 20% that it has a cost per QALY below a commonly used threshold value CONCLUSIONS: : Using a modelling approach, we find that impact-absorbing flooring is a dominant strategy at the societal level considering that it can save resources and improve health in a vulnerable population. PMID- 26498955 TI - Tobacco use among prison staff in Germany: a cross-sectional study. AB - BACKGROUND: Studies on tobacco in the prison environment report high prevalence of use among detainees, but little data regarding staff are available. An observational study addressing tobacco control in German prisons was conducted in 2011. It involved multiple strands (quantitative and qualitative components) both among detainees and staff. This article presents quantitative results regarding staff. METHODS: Cross-sectional study among prison employees in 16 different institutions in nine regions (Lander) in Germany. Tobacco use and second-hand smoke (SHS) exposure (primary outcomes) were assessed by a questionnaire designed specifically. Logistic regression models were used to assess the risk factors associated with each outcome. RESULTS: Among 704 participants (60.6% male, mean age 43.9 years +/- 9.33), 27.7% are smokers and 68% declared to be exposed to SHS. Independent factors associated with smoking were female gender [odds ratio (OR) 1.49,P= 0.026], an age below 45 years (OR 1.35,P= 0.08) and working in areas other than administration (ORP= 0.08). An age below 45 was associated with a higher degree of self-reported SHS exposure. The association between SHS and gender was different depending on occupational area with significantly more men exposed to SHS in administrative area and more women in health/social area (interaction between gender and occupational area,P= 0.02). CONCLUSION: Importance of SHS exposure among prison employees and confirm the need for a comprehensive tobacco control policy including support to smoking cessation and better enforcement of the smoke-free regulation, especially where staff contributes to SHS. Particular attention has to be given to female employees. PMID- 26498956 TI - Shortened version of the work ability index to identify workers at risk of long term sickness absence. AB - BACKGROUND: The Work Ability Index (WAI) identifies non-sicklisted workers at risk of future long-term sickness absence (LTSA). The WAI is a complicated instrument and inconvenient for use in large-scale surveys. We investigated whether shortened versions of the WAI identify non-sicklisted workers at risk of LTSA. METHODS: Prospective study including two samples of non-sicklisted workers participating in occupational health checks between 2010 and 2012. A heterogeneous development sample (N= 2899) was used to estimate logistic regression coefficients for the complete WAI, a shortened WAI version without the list of diseases, and single-item Work Ability Score (WAS). These three instruments were calibrated for predictions of different (>=2, >=4 and >=6 weeks) LTSA durations in a validation sample of non-sicklisted workers (N= 3049) employed at a steel mill, differentiating between manual (N= 1710) and non-manual (N= 1339) workers. The discriminative ability was investigated by receiver operating characteristic analysis. RESULTS: All three instruments under-predicted the LTSA risks in both manual and non-manual workers. The complete WAI discriminated between individuals at high and low risk of LTSA >=2, >=4 and >=6 weeks in manual and non-manual workers. Risk predictions and discrimination by the shortened WAI without the list of diseases were as good as the complete WAI. The WAS showed poorer discrimination in manual and non-manual workers. CONCLUSIONS: The WAI without the list of diseases is a good alternative to the complete WAI to identify non-sicklisted workers at risk of future LTSA durations >=2, >=4 and >=6 weeks. PMID- 26498957 TI - Jasmonic acid involves in grape fruit ripening and resistant against Botrytis cinerea. AB - Fruit ripening is a complex process that is regulated by a signal network. Whereas the regulatory mechanism of abscisic acid has been studied extensively in non-climacteric fruit, little is know about other signaling pathways involved in this process. In this study, we performed that plant hormone jasmonic acid plays an important role in grape fruit coloring and softening by increasing the transcription levels of several ripening-related genes, such as the color-related genes PAL1, DFR, CHI, F3H, GST, CHS, and UFGT; softening-related genes PG, PL, PE, Cell, EG1, and XTH1; and aroma-related genes Ecar, QR, and EGS. Lastly, the fruit anthocyanin, phenol, aroma, and cell wall materials were changed. Jasmonic acid positively regulated its biosynthesis pathway genes LOS, AOS, and 12 oxophytodienoate reductase (OPR) and signal pathway genes COI1 and JMT. RNA interference of grape jasmonic acid pathway gene VvAOS in strawberry fruit appeared fruit un-coloring phenotypes; exogenous jasmonic acid rescued this phenotypes. On the contrary, overexpression of grape jasmonic acid receptor VvCOI1 in the strawberry fruit accelerated the fruit-ripening process and induced some plant defense-related gene expression level. Furthermore, jasmonic acid treatment or strong jasmonic acid signal pathway in strawberry fruit make the fruit resistance against Botrytis cinerea. PMID- 26498958 TI - Platelet-Rich Plasma Injection With Arthroscopic Acromioplasty for Chronic Rotator Cuff Tendinopathy: A Randomized Controlled Trial. AB - BACKGROUND: Platelet-rich plasma (PRP) has been proposed to augment tendon healing through improving tissue structure during the initial repair phase. PURPOSE: To investigate both the clinical and tissue effects of the coapplication of PRP injection with arthroscopic acromioplasty (AA) in patients with chronic rotator cuff tendinopathy. DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: The study comprised 60 randomized patients diagnosed with rotator cuff tendinopathy (55% women) aged between 35 and 75 years. Patients were randomized to AA alone or in combination with an injection of autologous PRP into the subacromial bursa (AA + PRP). Efficacy of treatment was assessed by analysis of patient-reported outcomes up to 2 years after treatment (Oxford Shoulder Score [OSS]) and by analysis of tendon biopsy specimens taken 12 weeks after treatment. RESULTS: There was no significant difference in the OSS between AA alone and AA + PRP at any time point in the study. From 12 weeks onward, there was a significant increase in the OSS for both groups compared with their baseline scores (P < .001). Bonar scoring determined no significant change in tissue structure with the coapplication of PRP compared with surgery alone. The number of blood vessels and tendon cellularity were significantly decreased in tissue biopsy specimens taken from PRP-treated patients. The expression of p53-positive apoptotic cells increased after AA + PRP but decreased after AA alone. CONCLUSION: Arthroscopic acromioplasty significantly improves long-term clinical outcomes up to 2 years. The coapplication of PRP did not affect clinical outcomes. PRP significantly alters the tissue characteristics in tendons after surgery with reduced cellularity and vascularity and increased levels of apoptosis. CLINICAL RELEVANCE: The coapplication of PRP did not improve clinical outcomes and may have potential deleterious effects on healing tendons. REGISTRY NUMBER: ISRCTN 10464365. PMID- 26498959 TI - Micheli Anterior Cruciate Ligament Reconstruction in Skeletally Immature Youths: A Retrospective Case Series With a Mean 3-Year Follow-up. AB - BACKGROUND: The management of anterior cruciate ligament (ACL) tears in the skeletally immature patient remains controversial. Outcomes on a physeal-sparing technique using the iliotibial band for combined intra-articular and extra articular ACL reconstruction, called the Micheli technique, have been described and reported by the original authors. PURPOSE: To evaluate the clinical outcomes of a physeal-sparing technique using the iliotibial band for combined intra articular and extra-articular ACL reconstruction. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between 2005 and 2011, all patients who underwent Micheli ACL reconstruction performed by a single surgeon were identified. A minimum of 3 years' growth remaining was a prerequisite for Micheli reconstruction. Patients were excluded if postoperative follow-up was less than 1 year. Patients were evaluated for functional outcomes, satisfaction, graft survival, radiographic and clinical evidence of growth disturbance, and the need for additional procedures. RESULTS: Twenty-one patients (22 knees) met the inclusion criteria for this study. The mean age at the time of surgery was 11.8 years (range, 9.9-14.0 years). All patients were male. There were 4 concomitant meniscal repairs and 5 partial meniscectomies performed. All patients (100%) completed follow-up at a mean duration of 3.0 years (range, 1.0-6.9 years). Overall, 6 knees (27%) underwent reoperation. Of these, 3 knees (14%) underwent revision ACL surgery: 2 revision reconstructions at 2.8 and 4.0 years postoperatively and 1 graft shrinkage at 4.7 months postoperatively. Three knees (14%) underwent subsequent meniscal procedures, including 2 partial meniscectomies and 1 meniscal repair. Of the 19 knees that did not require revision ACL surgery, the median patient satisfaction score was 10 (range, 9-10). The mean Pediatric International Knee Documentation Committee score was 96.5 +/- 2.9, and the mean Lysholm score was 95.0 +/- 6.1. The median preinjury Tegner activity level was 8 (range, 6-10), and the median postoperative Tegner activity level was 8 (range, 6-10). Of the 19 knees that did not require revision ACL surgery, all had a normal Lachman test result, with a firm endpoint and normal pivot shift. At follow-up, 53% of knees had closed physes. There were no angular deformities or limb-length discrepancies. CONCLUSION: At a mean 3-year follow-up, the study findings confirmed excellent functional outcomes, a low ACL revision rate, and no growth disturbances. Patients returned to their preoperative activity level after reconstruction. This procedure offers a safe and effective ACL reconstruction option in children with several years of growth remaining. PMID- 26498960 TI - Electrical Changes in Resting, Exercise, and Holter Electrocardiography in Fabry Cardiomyopathy. AB - BACKGROUND: In Fabry cardiomyopathy, little is known about the interaction between its key feature of myocardial replacement fibrosis and changes in resting, Holter, and exercise electrocardiography (-ECG). METHODS AND RESULTS: Resting ECG, 24-h Holter ECG, and exercise ECG were performed in 95 patients (50 women) with Fabry disease, staged using cardiac magnetic resonance imaging to measure left ventricular fibrosis. With resting ECG, T alterations were seen in patients with cardiac fibrosis, while time intervals and rhythm were unchanged (except for a longer QRS duration in patients with severe fibrosis). All patients with severe fibrosis showed T inversion, ST alteration, or both. With Holter ECG, maximum and minimum heart rate did not differ with fibrosis severity. Patients without fibrotic tissue showed less ventricular premature beats (VPB) (median 5/24 h) compared to those with mild (median 11/24 h) or severe fibrosis (median 115/24 h; P < 0.05, respectively). Fibrosis was a strong predictor of VPB burden (r 2 = 0.5; P < 0.001). During exercise, patients with severe fibrosis had the least increase in systolic blood pressure (sBP) (47 +/- 22 mmHg vs. 62 +/- 25 mmHg, P < 0.05) and the lowest maximum heart rate (113 +/- 18/min; P < 0.05). Patients with mild fibrosis had a high sBP during exercise (198 +/- 37 mmHg; P < 0.05). Decreased diastolic blood pressure (>10 mmHg) occurred in some patients with no (3/41) or mild fibrosis (3/34) but not in patients with severe fibrosis (0/20; P < 0.01). CONCLUSIONS: Our data suggest that cardiac replacement fibrosis is responsible for repolarization abnormalities on resting ECG and increased VPB with Holter ECG. During exercise ECG, advanced cardiomyopathy is characterized by chronotropic incompetence with limitations on blood pressure and heart rate increase. PMID- 26498961 TI - Key factors in children's competence to consent to clinical research. AB - BACKGROUND: Although law is established on a strong presumption that persons younger than a certain age are not competent to consent, statutory age limits for asking children's consent to clinical research differ widely internationally. From a clinical perspective, competence is assumed to involve many factors including the developmental stage, the influence of parents and peers, and life experience. We examined potential determining factors for children's competence to consent to clinical research and to what extent they explain the variation in competence judgments. METHODS: From January 1, 2012 through January 1, 2014, pediatric patients aged 6 to 18 years, eligible for clinical research studies were enrolled prospectively at various in- and outpatient pediatric departments. Children's competence to consent was assessed by MacArthur Competence Assessment Tool for Clinical Research. Potential determining child variables included age, gender, intelligence, disease experience, ethnicity and socio-economic status (SES). We used logistic regression analysis and change in explained variance in competence judgments to quantify the contribution of a child variable to the total explained variance. Contextual factors included risk and complexity of the decision to participate, parental competence judgment and the child's or parents decision to participate. RESULTS: Out of 209 eligible patients, 161 were included (mean age, 10.6 years, 47.2 % male). Age, SES, intelligence, ethnicity, complexity, parental competence judgment and trial participation were univariately associated with competence (P < 0.05). Total explained variance in competence judgments was 71.5 %. Only age and intelligence significantly and independently explained the variance in competence judgments, explaining 56.6 % and 12.7 % of the total variance respectively. SES, male gender, disease experience and ethnicity each explained less than 1 % of the variance in competence judgments. Contextual factors together explained an extra 2.8 % (P > 0.05). CONCLUSIONS: Age is the factor that explaines most of to the variance in children's competence to consent, followed by intelligence. Experience with disease did not affect competence in this study, nor did other variables. CLINICAL TRIAL REGISTRATION: Development and use of a standardized instrument for assessing children's competence to consent in drug trials: Are legally established age limits valid?, NTR3918. PMID- 26498962 TI - Oxidative degradation of diclofenac by thermally activated persulfate: implication for ISCO. AB - Diclofenac (DCF), one of the typically recalcitrant pharmaceuticals, has been frequently detected in groundwater in recent years. This work investigated the performance of DCF degradation by thermally activated persulfate (PS) to further understand its application in in situ chemical oxidation (ISCO) for DCF contaminated groundwater. The effects of various factors, including activation temperature, solution pH, PS/DCF ratio, and common constitutes, e.g., HCO3(-), Cl(-) and humic acid, and the toxicity of transformation products were evaluated. The results indicated that the oxidation of DCF was well-fitted with a pseudo first-order kinetic model, and the rate constants increased with the elevated temperatures. The rate constants from 50-70 degrees C were further fitted to the Arrhenius equation, yielding an activation energy of 157.63 kJ.mol(-1). In addition, the oxidation of DCF was highly pH-dependent, with the rate constants rapidly decreased from pH 5 to 7, then slightly increased at the alkaline pH. The presence of a low dosage of Cl(-)(0-10 mM) promoted the degradation of DCF, whereas high Cl(-) addition (>10 mM) inhibited DCF degradation. HCO3(-) exhibited a negligible effect on DCF removal, while natural organic matters, e.g., humic acids, lightly inhibited DCF degradation. The rapid degradation of DCF was also confirmed in the real groundwater sample, which might be attributed to the pH drop during the reaction. Moreover, the radical quenching experiments revealed that sulfate radicals (SO4.-)) was the dominant reactive species for DCF oxidation. Finally, the acute toxicity of the DCF solution, as tested with a bioluminescent assay, was gradually decreased during the reaction, indicating that a thermally activated PS oxidation was a promising alternative approach for DCF-contaminated groundwater remediation. PMID- 26498963 TI - Development and applications of a DNA labeling method with magnetic nanoparticles to study the role of horizontal gene transfer events between bacteria in soil pollutant bioremediation processes. AB - Horizontal gene transfers are critical mechanisms of bacterial evolution and adaptation that are involved to a significant level in the degradation of toxic molecules such as xenobiotic pesticides. However, understanding how these mechanisms are regulated in situ and how they could be used by man to increase the degradation potential of soil microbes is compromised by conceptual and technical limitations. This includes the physical and chemical complexity and heterogeneity in such environments leading to an extreme bacterial taxonomical diversity and a strong redundancy of genes and functions. In addition, more than 99 % of soil bacteria fail to develop colonies in vitro, and even new DNA-based investigation methods (metagenomics) are not specific and sensitive enough to consider lysis recalcitrant bacteria and those belonging to the rare biosphere. The objective of the ANR funded project "Emergent" was to develop a new culture independent approach to monitor gene transfer among soil bacteria by labeling plasmid DNA with magnetic nanoparticles in order to specifically capture and isolate recombinant cells using magnetic microfluidic devices. We showed the feasibility of the approach by using electrotransformation to transform a suspension of Escherichia coli cells with biotin-functionalized plasmid DNA molecules linked to streptavidin-coated superparamagnetic nanoparticles. Our results have demonstrated that magnetically labeled cells could be specifically retained on micromagnets integrated in a microfluidic channel and that an efficient selective separation can be achieved with the microfluidic device. Altogether, the project offers a promising alternative to traditional culture based approaches for deciphering the extent of horizontal gene transfer events mediated by electro or natural genetic transformation mechanisms in complex environments such as soil. PMID- 26498964 TI - Application of veterinary antibiotics in China's aquaculture industry and their potential human health risks. AB - China contributes to more than 60 % of the global aquaculture production, and its aquaculture industry has become one of the main players in food security. A large amount of antibiotics is believed to be used in fish cultivation for ensuring adequate production. The use of antibiotics as disease control agents and growth promoter in aquaculture in China has raised significant concerns recently because of the potential threats to human health. The extensive use of antibiotics in aquaculture may result in water and sediment contamination and the development of antibiotic resistance genes. In this review, the role of aquaculture in antibiotic contamination of the environment as well as the emerging concern of antibiotic resistance genes in China is discussed. Based on this review, it has been concluded that more information regarding the types and quantities of antibiotics used by Chinese fish farmers is required. Studies about the contribution of antibiotic usage in aquaculture to environmental levels in surface water, their potential risks on environment and human health, and the existence and spread of antibiotic resistance genes in aquaculture are needed. PMID- 26498965 TI - Inoculation of paperboard mill sludge versus mixed culture bacteria for hydrogen production from paperboard mill wastewater. AB - A comparative evaluation of paperboard mill sludge (PMS) versus mixed culture bacteria (MCB) as inoculum for hydrogen production from paperboard mill wastewater (PMW) was investigated. The experiments were conducted at different initial cultivation pHs, inoculums to substrate ratios (ISRs gVS/gCOD), and hydraulic retention times (HRTs). The peak hydrogen yield (HY) of 5.29 +/- 0.16 and 1.22 +/- 0.11 mmol/gCODinitial was occurred at pH = 5 for MCB and PMS, respectively. At pH of 5, the HY and COD removal achieved the highest values of 2.26 +/- 0.14 mmol/gCODinitial and 86 +/- 1.6% at ISR = 6 for MCB, and 2.38 +/- 0.25 mmol/gCODinitial and 60.4 +/- 2.5% at ISRs = 3 for PMS. The maximum hydrogen production rate was 93.75 +/- 8.9 mmol/day at HRT = 9.6 h from continuous upflow anaerobic reactor inoculated with MCB. Meanwhile, the 16S ribosomal RNA (rRNA) gene fragments indicated a dominance of a novel hydrogen-producing bacterium of Stenotrophomonas maltophilia for PMS microbial community. On the other hand, Escherichia fergusonii and Enterobacter hormaechei were the predominant species for MCB. PMID- 26498966 TI - Uptake of polybrominated diphenyl ethers by carrot and lettuce crops grown in compost-amended soils. AB - The uptake of polybrominated diphenyl ethers (PBDEs) by carrot and lettuce was investigated. Degradation of PBDEs in soil in the absence of the plants was discarded. Different carrot (Nantesa and Chantenay) and lettuce (Batavia Golden Spring and Summer Queen) varieties were grown in fortified or contaminated compost-amended soil mixtures under greenhouse conditions. After plant harvesting, roots (core and peel) and leaves were analyzed separately for carrot, while for lettuce, leaves and hearts were analyzed together. The corresponding bioconcentration factors (BCFs) were calculated. In carrots, a concentration gradient of 2,2',3,4,4',5'-hexabromodiphenyl ether (BDE-138) became evident that decreased from the root peel via root core to the leaves. For decabromodiphenyl ether (BDE-209) at the low concentration level (7 and 20 ng g(-1)), the leaves incorporated the highest concentration of the target substance. For lettuce, a decrease in the BCF value (from 0.24 to 0.02) was observed the higher the octanol water partition coefficient, except in the case of BDE-183 (BCF = 0.51) and BDE 209 (BCF values from 0.41 to 0.74). Significant influence of the soils and crop varieties on the uptake could not be supported. Metabolic debromination, hydroxylation or methylation of the target PBDEs in the soil-plant system was not observed. PMID- 26498967 TI - Quinolone co-resistance in ESBL- or AmpC-producing Escherichia coli from an Indian urban aquatic environment and their public health implications. AB - Quinolone and beta-lactam antibiotics constitute major mainstay of treatment against infections caused by pathogenic Escherichia coli. Presence of E. coli strains expressing co-resistance to both these antibiotic classes in urban aquatic environments which are consistently being used for various anthropogenic activities represents a serious public health concern. From a heterogeneous collection of 61 E. coli strains isolated from the river Yamuna traversing through the National Capital Territory of Delhi (India), those harboring blaCTX-M 15 (n = 10) or blaCMY-42 (n = 2) were investigated for co-resistance to quinolones and the molecular mechanisms thereof. Resistance was primarily attributed to amino acid substitutions in the quinolone resistance-determining regions (QRDRs) of GyrA (S83L +/- D87N) and ParC (S80I +/- E84K). One of the E. coli strains, viz., IPE, also carried substitutions in GyrB and ParE at positions Ser492->Asn and Ser458->Ala, respectively. The phenotypically susceptible strains nevertheless carried plasmid-mediated quinolone resistance (PMQR) gene, viz., qnrS, which showed co-transfer to the recipient quinolone-sensitive E. coli J53 along with the genes encoding beta-lactamases and led to increase in minimal inhibitory concentrations of quinolone antibiotics. To the best of our knowledge, this represents first report of molecular characterization of quinolone co resistance in E. coli harboring genes for ESBLs or AmpC beta-lactamases from a natural aquatic environment of India. The study warrants true appreciation of the potential of urban aquatic environments in the emergence and spread of multi-drug resistance and underscores the need to characterize resistance genetic elements vis-a-vis their public health implications, irrespective of apparent phenotypic resistance. PMID- 26498970 TI - Presented Abstracts from the Thirty Fourth Annual Education Conference of the National Society of Genetic Counselors (Pittsburgh, PA, October 2015). PMID- 26498968 TI - Accumulation of heavy metals and As in liver, hair, femur, and lung of Persian jird (Meriones persicus) in Darreh Zereshk copper mine, Iran. AB - Rodents frequently serve as bioindicator to monitor the quality of the environment. Concentrations of 11 elements (Cd, Co, Ti, Fe, Mn, Cu, Sb, As, Sr, Ni, and Cr) were investigated and compared in liver, hair, femur, and lung of the Persian jird (Meriones persicus) from Darreh Zereshk copper mine, Iran. Metals were determined in different tissues of 39 individuals of Persian jird, collected by snap trap in 2014 from five areas of Darreh Zereshk copper mine. Samples were prepared by wet digestion method, and the contents of elements were analyzed with ICP-OES (VARIAN, 725-ES) instrument. Cadmium, Sb, and Co were below the limit of detection, and Mn and As were found only in hair and liver tissues. We detected the highest concentration of Cu, As, Ti, Fe, Mn, Cr, and Ni in hair in comparison with other tissues. Significant higher levels of Ti in femur and hair; Fe in liver and hair; Mn in liver; As in hair; Sr in lung; Cr in lung, hair, femur, and liver; Cu in femur; and Ni in liver and lung tissues were observed in females. Nearly all element concentrations in the tissues of Persian jird from flotation site, Darreh Zereshk and Hasan Abad villages and leaching site (mining areas) were higher than those from tailing dump site (reference site). We found the highest concentrations of As in liver and hair; Ni and Cr in liver, hair, and lung; and Sr in lung and hair tissues of Persian jird in leaching site. We tried to specify the status of elements before fully exploitation of Darreh Zereshk copper mine by using bioindicator species. Based on our achievements, initial activities did not strongly pollute the surrounded environment of the mine. The high abundance of Persian jird as well as their several proper features makes them a suitable species for biomonitoring programs especially for further studies will be performed after full exploitation of Darreh Zereshk copper mine. PMID- 26498969 TI - Soybean plant growth study conducted using purified protein hydrolysate-based fertilizer made from chrome-tanned leather waste. AB - Leather processing discharges enormous amount of chrome containing leather solid waste which creates a major disposal problem. Chrome-tanned leather solid waste is a complex of collagen and chromium. The presence of chromium limits protein application in fertilizer industry. The purified protein hydrolysate with zero chromium could be used as a nitrogen source for fertilizer formulation. In this study, an attempt has been made to employ purified protein hydrolysate derived from chrome-tanned leather shavings (CTLS) in formulation of fertilizer. The formulated fertilizer (1-3 t ha(-1)) is employed as nitrogen source in production of soybean. Plant growth study demonstrates that formulated fertilizer dosage 3 t ha(-1) produced similar effects of commercial fertilizer-treated plants. Application of formulated fertilizer yielded higher seed in plant than commercial fertilizer. PMID- 26498971 TI - Development, Experience, and Expression of Meaning in Genetic Counselors' Lives: an Exploratory Analysis. AB - Genetic counselors routinely engage with patients and families who grapple with questions of meaning while making decisions about genetic risk. Research and theory demonstrate genetic counselors gain important personal insights through their work and develop professionally from self-reflective practice regarding their beliefs and values. Data are lacking, however, about the nature of the meaning genetic counselors bring to their profession and how they directly experience and/or navigate issues of meaning within clinical practice over time. Accordingly, a national sample (N = 298) of practicing genetic counselors completed a brief survey assessing their demographic characteristics and willingness to participate in a semi-structured telephone interview exploring their views on meaning as they relate to their clinical work and professional development. Sixty-eight individuals of varied experience levels were interviewed about: 1) how they define a meaningful life for themselves; 2) lifetime sources of influence on their sense of meaning; 3) how they experience meaning within both personal and professional contexts; 4) work-related contexts that reaffirm and challenge their sense of meaning; and 5) how their sense of meaning has changed over time. Twenty-five interviews were analyzed using Consensual Qualitative Research methods, at which point, data saturation was reached. Five themes, 32 domains, and 29 categories were extracted. Common findings include: importance of satisfying relationships; helping others; personal fulfillment; personal and patient experiences of illness and loss; religious and/or spiritual foundations; value conflicts; competing obligations; challenges to meaning; development of empathy; resiliency; and increased humility. Results suggest the importance of professional venues for discussions of meaning (e.g., genetic counseling program curricula, continuing education, and peer supervision/consultation). Additional findings, practice implications, and research recommendations are presented. PMID- 26498973 TI - Objective assessment of Myringotomy and tympanostomy tube insertion: A prospective single-blinded validation study. AB - OBJECTIVES/HYPOTHESIS: Despite the transition to competency-based education in surgery, few standardized assessment tools exist in otolaryngology training. In particular, myringotomy and tympanostomy tube insertion (M+T) is a common surgical procedure with few validated assessment tools available. Our objectives were to develop an objective structured assessment of operative skills in M+T and to provide validity evidence for the developed assessment tool within otolaryngology training. STUDY DESIGN: Prospective study involving the evaluation of an assessment tool. METHODS: Through consultation with a panel of experts in otolaryngology and medical education we developed a Task-Specific Checklist and Global Rating Scale for M+T. Postgraduate year 2 junior residents, postgraduate year 3 senior residents, and attending otolaryngologists were video recorded performing M+T at a tertiary care pediatric hospital. The videos were subsequently reviewed and independently evaluated by three blinded raters from an unaffiliated academic institution. RESULTS: The average score of junior residents, senior residents, and attending otolaryngologists using the Task Specific Checklist was 21.7/30 (+/-7.1), 26.3/30 (+/-3.5), and 27.3/30 (+/-6.2), respectively (P = .04). For the Global Rating Scale, the scores for junior residents, senior residents, and attending surgeons were 27.7/50 (+/-11.2), 34.5/50 (+/-9.5), and 45.1/50 (+/-4.6), respectively (P < .001). The inter-rater and intrarater reliability were both above 0.88. CONCLUSIONS: The Task-Specific Checklist and Global Rating Scale for M+T appear reliable, with validity evidence supporting their use in otolaryngology training. LEVEL OF EVIDENCE: NA Laryngoscope, 126:2140-2146, 2016. PMID- 26498974 TI - Scanning Electrospray Microscopy with Nanopipets. AB - Electrospray from nanopipets is used to realize scanning electrospray microscopy (SESM). This technique provides an ambient, noncontact method to investigate surface topography with distance dependence of electrospray current as feedback for imaging. SESM approach curves, line scans, and images are reported. Salt deposition on the sample surface from SESM is also characterized. PMID- 26498972 TI - Nanoparticle based insulin delivery system: the next generation efficient therapy for Type 1 diabetes. AB - Diabetic cases have increased rapidly in recent years throughout the world. Currently, for type-1 diabetes mellitus (T1DM), multiple daily insulin (MDI) injections is the most popular treatment throughout the world. At this juncture, researchers are trying to develop different insulin delivery systems, especially through oral and pulmonary route using nanocarrier based delivery system. This next generation efficient therapy for T1DM may help to improve the quality of life of diabetic patients who routinely employ insulin by the subcutaneous route. In this paper, we have depicted various next generation nanocarrier based insulin delivery systems such as chitosan-insulin nanoparticles, PLGA-insulin nanoparticles, dextran-insulin nanoparticles, polyalkylcyanoacrylated-insulin nanoparticles and solid lipid-insulin nanoparticles. Modulation of these insulin nanocarriers may lead to successful oral or pulmonary insulin nanoformulations in future clinical settings. Therefore, applications and limitations of these nanoparticles in delivering insulin to the targeted site have been thoroughly discussed. PMID- 26498975 TI - The double-edged sword of genetic accounts of criminality: causal attributions from genetic ascriptions affect legal decision making. AB - Much debate exists surrounding the applicability of genetic information in the courtroom, making the psychological processes underlying how people consider this information important to explore. This article addresses how people think about different kinds of causal explanations in legal decision-making contexts. Three studies involving a total of 600 Mechanical Turk and university participants found that genetic, versus environmental, explanations of criminal behavior lead people to view the applicability of various defense claims differently, perceive the perpetrator's mental state differently, and draw different causal attributions. Moreover, mediation and path analyses highlight the double-edged nature of genetic attributions-they simultaneously reduce people's perception of the perpetrator's sense of control while increasing people's tendencies to attribute the cause to internal factors and to expect the perpetrator to reoffend. These countervailing relations, in turn, predict sentencing in opposite directions, although no overall differences in sentencing or ultimate verdicts were found. PMID- 26498976 TI - Biased Sex Ratios Influence Fundamental Aspects of Human Mating. AB - The operational sex ratio-the ratio of men to women in a given population-affects a range of social processes. The current research demonstrates that biased sex ratios (greater numbers of one sex than the other) influence fundamental aspects of people's mating strategy. When the sex ratio was favorable (one's own sex was in the minority), both sexes adopted strong sex-typical sociosexual orientations (relatively restricted for women; relatively unrestricted for men). When the sex ratio was unfavorable (one's own sex was in the majority), both sexes shifted toward the orientation typically favored by the other sex: Women became more unrestricted and men became more restricted (Experiment 1). When the sex ratio was unfavorable (relative to favorable), participants also displayed greater aggression toward a romantically desirable (but not undesirable) same-sex partner (Experiment 2). Exploratory analyses suggested that the sex ratio effect was present for unprovoked aggression but not provoked aggression (given the exploratory nature of that analysis, the aggression effect should be considered with some caution). Findings suggest that people's mating strategies are adaptively calibrated to contingencies within the local mating ecology. PMID- 26498977 TI - Changes in Self-Definition Impede Recovery From Rejection. AB - Previous research highlights how adept people are at emotional recovery after rejection, but less research has examined factors that can prevent full recovery. In five studies, we investigate how changing one's self-definition in response to rejection causes more lasting damage. We demonstrate that people who endorse an entity theory of personality (i.e., personality cannot be changed) report alterations in their self-definitions when reflecting on past rejections (Studies 1, 2, and 3) or imagining novel rejection experiences (Studies 4 and 5). Further, these changes in self-definition hinder post-rejection recovery, causing individuals to feel haunted by their past, that is, to fear the recurrence of rejection and to experience lingering negative affect from the rejection. Thus, beliefs that prompt people to tie experiences of rejection to self-definition cause rejection's impact to linger. PMID- 26498978 TI - Assessment of stress and autonomic nervous activity in Japanese female ambulance paramedics working 24-hour shifts. AB - OBJECTIVES: We studied the physical and mental conditions of 8 healthy young female ambulance paramedics working 24-hour shifts during their menstrual cycle, including assessment of cardiac autonomic nervous system activity by heart rate variability power spectral analysis. METHODS: The autonomic activity during the awake period of on- and off-duty days in the follicular, late luteal, and menstruation phases was measured. Questionnaires regarding fatigue and menstrual distress were administered and correlated with the autonomic profile. RESULTS: While degrees of fatigue significantly increased after work, the changes in autonomic activity during the awake period on on-duty days were not significantly different from those on off-duty days (LF/HF, p=0.123; HF/(HF+LF), p=0.153). As for the sleeping period, there were no significant differences. Although the Menstrual Distress Questionnaire (MDQ) revealed the presence of mild menstrual discomfort in the late luteal and menstruation phases, no significant difference was observed in the autonomic profile of the three menstrual cycle phases. No significant correlation was observed between the degree of menstrual distress and autonomic profile, though there was a significant correlation in the late luteal phase between degree of menstrual distress and fatigue after work (p<0.01). CONCLUSION: These results showed that, while subjects experienced menstrual discomfort and fatigue after work, their autonomic profile did not alter in the menstrual cycle. It is suggested that healthy young female ambulance paramedics may tolerate 24-hour shifts, though attention should be paid to subjective menstrual symptoms and fatigue. PMID- 26498979 TI - Predictors for chronic neck and low back pain in office workers: a 1-year prospective cohort study. AB - OBJECTIVE: All occupations expose workers to varied and unique conditions. The nature of work has been recognized as influencing the health of workers. Whether predictors for chronic neck and low back pain would be occupation-specific is unknown. This study aimed to identify predictors for chronic neck and low back pain in a cohort of office workers. METHODS: A prospective study was carried out among 669 healthy office workers. At baseline, risk factors were assessed using a questionnaire and standardized physical examination. A symptomatic case was defined as an individual who reported pain greater than 30 mm on a 100-mm VAS, and chronic pain was defined as experiencing ongoing neck or low back pain for greater than 3 months over the past 6 months. Two regression models were built to analyze the risk factors for developing chronic neck and low back pain. RESULTS: Of the sample, 17 and 27% of office workers who reported a new onset of neck or low back pain developed chronicity, respectively. Predictors for chronic neck pain were high body mass index, frequent neck extension during the work day, high initial pain intensity, and high psychological job demands. The development of chronic low back pain was associated with history of low back pain and high initial pain intensity. CONCLUSIONS: The findings suggest that predictors for chronic musculoskeletal pain in a subpopulation may be a subset of predictors identified in a general population or occupation specific. Successful management to prevent chronic musculoskeletal pain may also need to consider the patient's occupation. PMID- 26498980 TI - Changes in the immunohistochemical localization of the glycine receptor in the superior olivary complex of adult circling mice. AB - Circling mice is a mutant model of spontaneous deafness exhibiting degenerated spiral ganglion cells in the cochlea and loss of organ of Corti. The balance between glycinergic inhibition and glutamatergic excitation in the lateral superior olive (LSO) is essential for the detection of interaural level differences. Long term weakening of glycinergic synaptic inhibition in the LSO may lead to the downregulation of synaptic release of glycine in dorsal cochlear nucleus and downregulation of postsynaptic glycine receptor (GlyR) activity in the LSO, which may contribute to hearing loss. The present study utilized an immunohistochemical method to assess changes in GlyR immunoreactivity (IR) and the cell number in the superior olivary complex (SOC) of heterozygote (+/cir) and homozygote (cir/cir) circling mice. A significant decrease in the IR was observed in all nuclei of the SOC of homozygous mice. Loss of GlyR immunoreactive cells and a decrement in cell size was also observed in the homozygotes. A decrease in the GlyR IR in the neurons and neuropils, cell number and size of the cir/cir, may lead to profound changes in inhibitory transmission and the functional properties in the SOC nuclei. Therefore, the functional loss of inhibitory neurotransmitters in the brainstem may result in deafness of adult cir/cir mice. PMID- 26498981 TI - Electron microscopic recording of myosin head power stroke in hydrated myosin filaments. AB - Muscle contraction results from cyclic attachment and detachment between myosin heads and actin filaments, coupled with ATP hydrolysis. Despite extensive studies, however, the amplitude of myosin head power stroke still remains to be a mystery. Using the gas environmental chamber, we have succeeded in recording the power stroke of position-marked myosin heads in hydrated mixture of actin and myosin filaments in a nearly isometric condition, in which myosin heads do not produce gross myofilament sliding, but only stretch adjacent elastic structures. On application of ATP, individual myosin heads move by ~3.3 nm at the distal region, and by ~2.5 nm at the proximal region of myosin head catalytic domain. After exhaustion of applied ATP, individual myosin heads return towards their initial position. At low ionic strength, the amplitude of myosin head power stroke increases to >4 nm at both distal and proximal regions of myosin heads catalytic domain, being consistent with the report that the force generated by individual myosin heads in muscle fibers is enhanced at low ionic strength. The advantages of the present study over other in vitro motility assay systems, using myosin heads detached from myosin filaments, are discussed. PMID- 26498982 TI - Release profile of insulin from pH-sensitive hydrogel and its hypoglycemic effect by oral administration. AB - The purpose of this study was to investigate the release profile and in vivo hypoglycemic effect of insulin (INS)-loaded pH-sensitive hydrogel (INS-TPM950) administrated by oral route. TPM950 was fabricated via a free polymerization method and its inner morphology was observed with a scanning electron microscope (SEM). INS was encapsulated into TPM950 by an adsorption method, and the in vitro release profiles of INS from INS-TPM950 were revealed in pH 1.2 and 6.8. To investigate the hypoglycemic effect of INS-TPM950, Male Wistar rats were used in modeling of diabetes mellitus by multiple intraperitoneal injection of alloxan. The in vivo hypoglycemic effect of oral INS-TPM950 was studied, and the optimal dosage was also determined. SEM photograph showed that abundant 3D meshes were distributed in the inner of TPM950 hydrogel. INS release profile suggested that only 18.2 +/- 11.3% INS was released in pH 1.2, but over 88.8 +/- 4.9% was delivered into phosphate buffer solution in pH 6.8. After injection to the diabetic rats, the released INS solution from INS-TPM950 exhibited an obvious hypoglycemic effect. Oral administration of 50.0 I.U./kg of INS-TPM950 showed a slow but effective hypoglycemic effect, and the lowest blood glucose level was reached to 47.5 +/- 5.5% of the original level. Therefore, this formulation had a potential application in diabetes treatment via oral ingestion. PMID- 26498983 TI - Temporal changes in the prevalence of diagnosed diabetes, undiagnosed diabetes and prediabetes: findings from the German Health Interview and Examination Surveys in 1997-1999 and 2008-2011. AB - AIMS: Nationally representative data on temporal changes in the prevalence of diagnosed diabetes, as well as undiagnosed diabetes and prediabetes, have been lacking in Germany as in most other European countries. We aimed to fill this gap using data from nationwide examination surveys of German adults. METHODS: The study population comprised 18-79-year-old participants from the German Health Interview and Examination Surveys in 1997-1999 (GNHIES98, n = 6655) and 2008-2011 (DEGS1, n = 7017). Participants were classified as having diagnosed diabetes based on self-reported physician-diagnosed diabetes or the use of anti-diabetes agents. Among those without diagnosed diabetes, HbA1c measures were used to define undiagnosed diabetes [>= 48 mmol/mol (>= 6.5%)] or prediabetes [39-47 mmol/mol (5.7-6.4%)]. RESULTS: Although the age- and sex-standardized prevalence of total diabetes remained stable between 1997-1999 at 9.3% (95% CI 8.3-10.5%) and 2008-2011 at 9.2% (8.3-10.3%), the prevalence of diagnosed diabetes increased from 5.6% (4.9-6.3%) to 7.2% (6.5-8.0%), whereas the prevalence of undiagnosed diabetes decreased from 3.8% (3.1-4.6%) to 2.0% (1.5-2.7%), resulting in a decreased proportion of undiagnosed diabetes (40.9% vs. 21.7%). Over the same period, the prevalence of prediabetes decreased from 27.7% (25.6-29.8%) to 20.8% (18.2-23.7%). Observed temporal changes were not explained by changes in BMI, sport activity and educational level. CONCLUSIONS: The two nationwide surveys indicate a shift from undiagnosed to diagnosed diabetes. However, the unchanged prevalence of total diabetes and the considerably high proportion of prediabetes strongly call for a continued and concerted effort in diabetes prevention among German adults. PMID- 26498984 TI - Simultaneous enhancements in photon absorption and charge transport of bismuth vanadate photoanodes for solar water splitting. AB - n-Type bismuth vanadate has been identified as one of the most promising photoanodes for use in a water-splitting photoelectrochemical cell. The major limitation of BiVO4 is its relatively wide bandgap (~2.5 eV), which fundamentally limits its solar-to-hydrogen conversion efficiency. Here we show that annealing nanoporous bismuth vanadate electrodes at 350 degrees C under nitrogen flow can result in nitrogen doping and generation of oxygen vacancies. This gentle nitrogen treatment not only effectively reduces the bandgap by ~0.2 eV but also increases the majority carrier density and mobility, enhancing electron-hole separation. The effect of nitrogen incorporation and oxygen vacancies on the electronic band structure and charge transport of bismuth vanadate are systematically elucidated by ab initio calculations. Owing to simultaneous enhancements in photon absorption and charge transport, the applied bias photon to-current efficiency of nitrogen-treated BiVO4 for solar water splitting exceeds 2%, a record for a single oxide photon absorber, to the best of our knowledge. PMID- 26498985 TI - A tirucallane and two pairs of tetranortriterpene 23-epimers from the Thai mangrove Xylocarpus moluccensis. AB - A new tirucallane, 3beta-hydroxy-3-decarbonyl-24-epi-piscidinol A (1), and two new pairs of tetranortriterpene 23-epimers, named thaimoluccepimers A (2) and B (3), were isolated from the seeds of a Thai mangrove, Xylocarpus moluccensis. The structures of these compounds were elucidated by HRESIMS and NMR spectroscopic analysis. PMID- 26498986 TI - Particle size distribution of workplace aerosols in manganese alloy smelters applying a personal sampling strategy. AB - Air samples were collected by personal sampling with five stage Sioutas cascade impactors and respirable cyclones in parallel among tappers and crane operators in two manganese (Mn) alloy smelters in Norway to investigate PM fractions. The mass concentrations of PM collected by using the impactors and the respirable cyclones were critically evaluated by comparing the results of the parallel measurements. The geometric mean (GM) mass concentrations of the respirable fraction and the <10 MUm PM fraction were 0.18 and 0.39 mg m(-3), respectively. Particle size distributions were determined using the impactor data in the range from 0 to 10 MUm and by stationary measurements by using a scanning mobility particle sizer in the range from 10 to 487 nm. On average 50% of the particulate mass in the Mn alloy smelters was in the range from 2.5 to 10 MUm, while the rest was distributed between the lower stages of the impactors. On average 15% of the particulate mass was found in the <0.25 MUm PM fraction. The comparisons of the different PM fraction mass concentrations related to different work tasks or different workplaces, showed in many cases statistically significant differences, however, the particle size distribution of PM in the fraction <10 MUm d(ae) was independent of the plant, furnace or work task. PMID- 26498987 TI - Functional genomics to discover antibiotic resistance genes: The paradigm of resistance to colistin mediated by ethanolamine phosphotransferase in Shewanella algae MARS 14. AB - Shewanella algae MARS 14 is a colistin-resistant clinical isolate retrieved from bronchoalveolar lavage of a hospitalised patient. A functional genomics strategy was employed to discover the molecular support for colistin resistance in S. algae MARS 14. A pZE21 MCS-1 plasmid-based genomic expression library was constructed in Escherichia coli TOP10. The estimated library size was 1.30*10(8) bp. Functional screening of colistin-resistant clones was carried out on Luria Bertani agar containing 8 mg/L colistin. Five colistin-resistant clones were obtained after complete screening of the genomic expression library. Analysis of DNA sequencing results found a unique gene in all selected clones. Amino acid sequence analysis of this unique gene using the Integrated Microbial Genomes (IMG) and KEGG databases revealed that this gene encodes ethanolamine phosphotransferase (EptA, or so-called PmrC). Reverse transcription PCR analysis indicated that resistance to colistin in S. algae MARS 14 was associated with overexpression of EptA (27-fold increase), which plays a crucial role in the arrangement of outer membrane lipopolysaccharide. PMID- 26498989 TI - A resurgence of beta-lactamase inhibitor combinations effective against multidrug resistant Gram-negative pathogens. AB - beta-Lactamase inhibitors (BLIs) have played an important role in combatting beta lactam resistance in Gram-negative bacteria, but their effectiveness has diminished with the evolution of diverse and deleterious varieties of beta lactamases. In this review, a new generation of BLIs and inhibitor combinations is presented, describing epidemiological information, pharmacodynamic studies, resistance identification and current clinical status. Novel serine BLIs of major interest include the non-beta-lactams of the diazabicyclo[3.2.1]octanone (DBO) series. The DBOs avibactam, relebactam and RG6080 inhibit most class A and class C beta-lactamases, with selected inhibition of class D enzymes by avibactam. The novel boronic acid inhibitor RPX7009 has a similar inhibitory profile. All of these inhibitors are being developed in combinations that are targeting primarily carbapenemase-producing Gram-negative pathogens. Two BLI combinations (ceftolozane/tazobactam and ceftazidime/avibactam) were recently approved by the US Food and Drug Administration (FDA) under the designation of a Qualified Infectious Disease Product (QIDP). Other inhibitor combinations that have at least completed phase 1 clinical trials are ceftaroline fosamil/avibactam, aztreonam/avibactam, imipenem/relebactam, meropenem/RPX7009 and cefepime/AAI101. Although effective inhibitor combinations are in development for the treatment of infections caused by Gram-negative bacteria with serine carbapenemases, better options are still necessary for pathogens that produce metallo-beta-lactamases (MBLs). The aztreonam/avibactam combination demonstrates inhibitory activity against MBL-producing enteric bacteria owing to the stability of the monobactam to these enzymes, but resistance is still an issue for MBL-producing non fermentative bacteria. Because all of the inhibitor combinations are being developed as parenteral drugs, an orally bioavailable combination would also be of interest. PMID- 26498988 TI - Activity of fosfomycin and comparison of several susceptibility testing methods against contemporary urine isolates. AB - Fosfomycin is recommended as first-line treatment for acute uncomplicated cystitis in women. It has demonstrated in vitro activity against a variety of pathogens; however, a paucity of data are available from the USA. We determined the susceptibility of a collection of urine isolates to fosfomycin and compared multiple methods of susceptibility testing. Consecutive non-duplicate Enterobacteriaceae, enterococci and Pseudomonas aeruginosa isolates were collected from the clinical microbiology laboratory between August 2013 and January 2014. Isolates represented hospitalised or emergency department patients with monomicrobial bacteriuria. Fosfomycin MICs were determined in duplicate, on separate days, by Etest and disk diffusion and results were compared with agar dilution. Nitrofurantoin and ciprofloxacin were used as comparators. MIC results were categorised using Clinical and Laboratory Standards Institute interpretive criteria for Escherichia coli and Enterococcus faecalis. Correlation between the three testing methods was evaluated. Overall susceptibility to fosfomycin was 94.4%, 93.5% and 87.9% by agar dilution, disk diffusion and Etest, respectively. Five fosfomycin-resistant isolates were identified, including two Morganella morganii, one P. aeruginosa, one Proteus mirabilis and one Enterobacter aerogenes. Across all organisms, rates of essential agreement, categorical agreement, minor errors, major errors and very major errors for Etest/disk diffusion compared with agar dilution were 77.3%/NA, 89.5/93.8%, 7.1/5.0%, 3.6/1.3% and 0/0%, respectively. Fosfomycin displayed fairly consistent activity against a majority of isolates collected when using the susceptibility breakpoint of 64 MUg/mL. MICs for E. coli were particularly low (<=2 MUg/mL). These data lend support to current guidelines that recommend fosfomycin as empirical first line therapy for uncomplicated UTI. PMID- 26498990 TI - Theoretical demonstration of the potentiality of boron nitride nanotubes to encapsulate anticancer molecule. AB - Anticancer drug transport is now becoming an important scientific challenge since it would allow localizing the drug release near the tumor cell, avoiding secondary medical effects. We present theoretical results, based on density functional theory and molecular dynamics simulations, which demonstrate the stability of functionalized single (10,10) boron nitride nanotubes (BNNTs) filled with anticancer molecule such as carboplatin (CPT). For this functionalized system we determine the dependence of the adsorption energy on the molecule displacement near the inner BNNTs surface, together with their local morphological and electrical changes and compare the values to the adsorption energy obtained on the outer surface. Quantum simulations show that the most stable physisorption state is located inside the nanotube, with no net charge transfer. This demonstrates that chemotherapeutic encapsulation is the most favorable way to transport drug molecules. The solvent effect and dispersion repulsion contributions are then taken into account using molecular dynamics simulations. Our results confirm that carboplatin therapeutic agents are not affected when they are adsorbed inside BNNTs by the surrounding water molecules. PMID- 26498991 TI - A new approach for presurgical margin assessment by reflectance confocal microscopy of basal cell carcinoma. AB - BACKGROUND: Surgical excision represents the most common elective treatment for basal cell carcinoma (BCC). Several noninvasive approaches have been proposed for in vivo determination of tumour margin, in order to achieve radical removal. OBJECTIVES: To propose a new approach through the combination of dermoscopy and reflectance confocal microscopy (RCM) for lateral margin detection in BCC. METHODS: Ten patients with lesions clinically suggestive of nonpigmented BCCs with ill-defined margins were enrolled. All BCCs were dermoscopically evaluated first and the ill-defined margins were marked with a superficial cut and then inspected using RCM. RESULTS: RCM evaluation showed BCC foci beyond the presurgical marker in three out of 10 lesions. Histology confirmed the RCM results: the presence of BCC features across the cut, corresponding to two superficial BCCs and a morpheaform BCC. CONCLUSIONS: This new procedure helped to improve the identification of proper margins for surgical excision in nonpigmented BCC with clinically and dermoscopically ill-defined margins. PMID- 26498992 TI - Anti-cancer effects of 2-oxoquinoline derivatives on the HCT116 and LoVo human colon cancer cell lines. AB - The present study demonstrated the anti-tumor effects of the quinoline derivative [5-(3-chloro-oxo-4-phenyl-cyclobutyl)-quinoli-8-yl-oxy] acetic acid hydrazide (CQAH) against colorectal carcinoma. Substantial apoptotic effects of CQAH on HCT116 and LoVo human colon cancer cell lines were observed. Apoptosis was identified based on cell morphological characteristics, including cell shrinkage and chromatin condensation as well as Annexin V/propidium iodide double staining followed by flow cytometric analysis and detection of apoptosis-associated proteins by western blot analysis. CQAH induced caspase-3 and PARP cleavage, reduced the expression of the anti-apoptotic proteins myeloid cell leukemia-1 and B-cell lymphoma (Bcl) extra large protein and elevated the expression of the pro apoptotic protein Bcl-2 homologous antagonist killer. In addition, pharmacological inhibition of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase or p38, significantly reduced CQAH-mediated cell death as well as cleavage of caspase-3 and PARP. Co-treatment of CQAH with the commercial chemotherapeutics 5-fluorouracil and camptothecin-11 significantly improved their efficacies. Comparison of the apoptotic effects of CQAH with those of two illustrated structure-activity associations for this compound type, indicating that substitution at position-4 of the azetidine phenyl ring is pivotal for inducing apoptosis. In conclusion, the results of the present study indicated CQAH and its analogues are potent candidate drugs for the treatment of colon carcinoma. PMID- 26498993 TI - Complications after microdermal piercing in the hand: Report of two cases. PMID- 26498994 TI - The dynamic process and microscopic mechanism of extraordinary terahertz transmission through perforated superconducting films. AB - Superconductor is a compelling plasmonic medium at terahertz frequencies owing to its intrinsic low Ohmic loss and good tuning property. However, the microscopic physics of the interaction between terahertz wave and superconducting plasmonic structures is still unknown. In this paper, we conducted experiments of the enhanced terahertz transmission through a series of superconducting NbN subwavelength hole arrays, and employed microscopic hybrid wave model in theoretical analysis of the role of hybrid waves in the enhanced transmission. The theoretical calculation provided a good match of experimental data. In particular, we obtained the following results. When the width of the holes is far below wavelength, the enhanced transmission is mainly caused by localized resonance around individual holes. On the contrary, when the holes are large, hybrid waves scattered by the array of holes dominate the extraordinary transmission. The surface plasmon polaritions are proved to be launched on the surface of superconducting film and the excitation efficiency increases when the temperature approaches critical temperature and the working frequency goes near energy gap frequency. This work will enrich our knowledge on the microscopic physics of extraordinary optical transmission at terahertz frequencies and contribute to developing terahertz plasmonic devices. PMID- 26498995 TI - Selecting molecular therapeutic drug targets based on the expression profiles of intrahepatic cholangiocarcinomas and miRNA-mRNA regulatory networks. AB - The incidence of intrahepatic cholangiocarcinoma (ICC) is increasing yearly, making it the second most common carcinoma after hepatocellular carcinoma among primary malignant liver tumors. Integrated miRNA and mRNA analysis is becoming more frequently used in antitumor ICC treatment. However, this approach generates vast amounts of data, which leads to difficulties performing comprehensive analyses to identify specific therapeutic drug targets. In this study, we provide an in-depth analysis of ICC function, identifying potential highly potent antitumor drugs for antitumor therapy. Two sets of whole genome expression profiles were obtained from the Gene Expression Omnibus (GEO) database. Using modular bioinformatic analysis, six core functional modules were identified for ICC. Based on a Fisher's test of the Cmap small molecule drug database, 65 drug components were identified that regulated the genes of these six core modules. Literature mining was then used to identify 15 new potential antitumor drugs. PMID- 26498996 TI - Palliative Arterial Switch for Congenitally Corrected Transposition of the Great Arteries with Ventricular Septal Defect and Subaortic Hypoplasia. AB - We present a case of palliative arterial switch with aortic arch reconstruction performed as the first stage of anatomical correction in a patient with congenitally corrected transposition of great arteries (ccTGA), ventricular septal defect (VSD), duct-dependent aortic coartation, and hypoplasia of the ascending aorta and subaortic tract. PMID- 26498997 TI - Knockdown of eIF4E suppresses cell proliferation, invasion and enhances cisplatin cytotoxicity in human ovarian cancer cells. AB - Eukaryotic initiation factor 4E (eIF4E) plays an important role in cap-dependent translation. The overexpression of eIF4E gene has been found in a variety of human malignancies. In this study, we attempted to identify the potential effects of eIF4E and explore the possibility of eIF4E as a therapeutic target for the treatment of human ovarian cancer. First the activation of eIF4E protein was detected with m7-GTP cap binding assays in ovarian cancer and control cells. Next, the eIF4E-shRNA expression plasmids were used to specifically inhibit eIF4E activity in ovarian cancer cells line A2780 and C200. The effects of knockdown eIF4E gene on cell proliferation, migration and invasion were investigated in vitro. Moreover, the changes of cell cycle and apoptosis of ovarian cancer cells were detected by flow cytometry. Finally, we investigated the effect of knockdown of eIF4E on the chemosensitivity of ovarian cancer cells to cisplatin in vitro. Our results show there is elevated activation of eIF4E in ovarian cancer cells compared with normal human ovarian epithelial cell line. The results of BrdU incorporation and FCM assay indicate that knockdown of eIF4E efficiently suppressed cell growth and induce cell cycle arrest in G1 phase and subsequent apoptosis in ovarian cancer cells. From Transwell assay analysis, knockdown eIF4E significantly decrease cellular migration and invasion of ovarian cancer cells. We also confirmed that knockdown eIF4E could synergistically enhance the cytotoxicity effects of cisplatin to cancer cells and sensitized cisplatin resistant C200 cells in vitro. This study demonstrates that the activation of eIF4E gene is an essential component of the malignant phenotype in ovarian cancer, and aberration of eIF4E expression is associated with proliferation, migration, invasion and chemosensitivity to cisplatin in ovarian cancer cells. Knockdown eIF4E gene can be used as a potential therapeutic target for the treatment of human ovarian cancer. PMID- 26498998 TI - Clinical importance of median mandibular flexure in oral rehabilitation: a review. AB - The mandible has a property to flex inwards around the mandibular symphysis with change in shape and decrease in mandibular arch width during opening and protrusion of the mandible. The mandibular deformation may range from a few micrometres to more than 1 mm. The movement occurs because of the contraction of lateral pterygoid muscles that pulls mandibular condyles medially and causes a sagittal movement of the posterior segments. This movement of mandible can have a profound influence on prognosis and treatment outcome for various restorative, endodontics, fixed, removable and implant-related prosthesis. The review unfolds the causes, importance and clinical implications of median mandibular flexure in oral rehabilitation. This review also highlights the appropriate preventive measures and techniques that should be adopted by clinicians to minimise the effect of flexural movement of the jaw during oral rehabilitation. This would not only help clinicians to achieve a good prosthesis with accurate fit and longevity but also maintain the health of the surrounding periodontal or periimplant gingival tissues and bone. PMID- 26498999 TI - Nonoccupational Postexposure Prophylaxis (nPEP) Visits: Opportunities Beyond HIV PEP. PMID- 26499000 TI - Digital breast tomosynthesis and breast ultrasound: Additional roles in dense breasts with category 0 at conventional digital mammography. AB - PURPOSE: To compare the diagnostic performances of digital breast tomosynthesis (DBT) and ultrasound for the dense breasts with category 0 at conventional digital mammography. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. Among the 1103 patients who underwent screening digital mammography at our institution, 769 (69.7%) patients had dense breasts. Of the 769 patients, 229 (29.8%) lesions were categorized as 0. DBT, breast ultrasound and digital mammography were performed in 108 (47.2%) patients. BI-RADS final assessments for DBT and ultrasound were recorded. Categories 1-3 were clinically considered as benign, and categories 4 and 5 were clinically considered as malignant. The diagnostic performances of breast ultrasound and DBT were correlated with final pathologic reports or follow up images. RESULTS: Among 108 lesions, 17 (15.7%) were malignant and 91 (84.3%) were benign. Sensitivity was 100% for both ultrasound (17/17) and DBT (17/17) and negative predictive value was also 100% for both ultrasound (49/49) and DBT (74/74). Specificity and positive predictive value for ultrasound were 53.9% (49/91) and 28.8% (17/59), respectively. Specificity and positive predictive value for DBT were 81.3% (74/91) and 50% (17/34), respectively. DBT showed higher diagnostic accuracy than that of breast ultrasound (DBT: 84.3%, 91/108; ultrasound: 61.1%, 66/108; p<0.001). The benign biopsy rate of DBT (50%, 17/34) was lower than that of ultrasound (71.2%, 42/59). CONCLUSION: DBT showed better diagnostic performance than breast ultrasound for dense breasts with category 0. DBT may reduce the benign biopsy rate and short term follow-up. PMID- 26499001 TI - Letter to the Editor: Reply to Dunbar et al. (2015). PMID- 26499002 TI - Journey of a Girl Child in India During Health and Disease. PMID- 26499003 TI - Vaccination Policy for Japanese Encephalitis in India: Tread with Caution! AB - Live attenuated SA-14-14-2 vaccine against Japanese encephalitis (JE) was introduced in the routine immunization under Universal Immunization Program in the 181 endemic districts of India. Recently, the Government of India has announced the introduction of one dose of JE vaccine for adults in endemic districts. The policy to mass vaccinate adults has raised several concerns that are discussed in this write-up. Apart from adult vaccination, the continuation of large scale JE vaccination program despite it being a very focal problem, and continued neglect of some other serious public health illnesses have also been highlighted. The issue of lack of authentic data on effectiveness of currently employed SA-14-14-2 JE vaccine has also been discussed. PMID- 26499004 TI - Management of Recurrent Abdominal Pain: Have we Reached the end of the Tunnel? PMID- 26499005 TI - Drotaverine for Recurrent Abdominal Pain in Children. PMID- 26499006 TI - Outcome of Infants with Prenatally Diagnosed Congenital Heart Defects. PMID- 26499007 TI - Efficacy and Safety of Drotaverine Hydrochloride in Children with Recurrent Abdominal Pain: A Randomized Placebo Controlled Trial. AB - OBJECTIVE: To evaluate the efficacy and safety of Drotaverine hydrochroride in children with recurrent abdominal pain. DESIGN: Double blind, randomized placebo controlled trial. SETTING: Pediatric Gastroenterology clinic of a teaching hospital. PARTICIPANTS: 132 children (age 4-12 y) with recurrent abdominal pain (Apley Criteria) randomized to receivedrotaverine (n=66) or placebo (n=66) orally. INTERVENTION: Children between 4-6 years of age received 10 mL syrup orally (20 mg drotaverine hydrochloride or placebo) thrice daily for 4 weeks while children >6 years of age received one tablet orally (40 mg drotaverine hydrochloride or placebo) thrice daily for 4 weeks. OUTCOME MEASURES: Primary: Number of episodes of pain during 4 weeks of use of drug/placebo and number of pain-free days. Secondary: Number of school days missed during the study period, parental satisfaction (on a Likert scale), and occurrence of solicited adverse effects. RESULTS: Reduction in number of episodes of abdominal pain [mean (SD) number of episodes 10.3 (14) vs 21.6 (32.4); P=0.01] and lesser school absence [mean (SD) number of school days missed 0.25 (0.85) vs 0.71 (1.59); P=0.05] was noticed in children receiving drotaverine in comparison to those who received placebo. The number of pain-free days, were comparable in two groups [17.4 (8.2) vs 15.6 (8.7); P=0.23]. Significant improvement in parental satisfaction score was noticed on Likert scale by estimation of mood, activity, alertness, comfort and fluid intake. Frequency of adverse events during follow-up period was comparable between children receiving drotaverine or placebo (46.9% vs 46.7%; P=0.98). CONCLUSION: Drotaverine hydrochloride is an effective and safe pharmaceutical agent in the management of recurrent abdominal pain in children. PMID- 26499008 TI - Outcomes of Infants with Prenatally Diagnosed Congenital Heart Disease Delivered in a Tertiary-care Pediatric Cardiac Facility. AB - OBJECTIVE: To report short-term outcomes of infants with prenatally diagnosed Congenital Heart Disease (CHD) delivered in a tertiary-care cardiac facility. DESIGN: Retrospective study. SETTING: Tertiary-care referral hospital. PARTICIPANTS: Children with prenatally diagnosed CHDs who underwent delivery at study centre during the period January 2008 - December 2013 were included. Outcomes tracked from hospital records and direct follow-up. RESULTS: Of the 552 fetuses diagnosed to have CHD, 121 (22%) were delivered at the study centre. Fetuses undergoing a planned delivery were diagnosed in late gestation (mean gestational age 31.5 +/- 5.1 wk). 74 fetuses (61.2%) had simple CHD and rest were complex. 96 (79.3%) neonates received cardiac care; 30 (24.8%) required surgery while 5 received catheter-based interventions. 11 patients underwent surgery on follow-up. Neonatal survival in cardiac care group was 93.8%; on follow-up (12.5 +/- 13.1 mo); 83 (86.4%) of these infants were alive. All infants undergoing neonatal surgery or catheter-based interventions survived. 25 patients (20.6%) received comfort care (Complex CHD, associated co-morbidities); 14 (56%) survived neonatal period and 6 (24%) were alive on follow-up. CONCLUSIONS: Infants with prenatal diagnosis of CHD and planned delivery in a cardiac facility had satisfactory immediate outcomes, expecially in those receiving specialized post natal cardiac care. PMID- 26499009 TI - Association of Perceived Weight Status versus Body Mass Index on Adherence to Weight-modifying plan Among Iranian Children and Adolescents: The CASPIAN-IV Study. AB - OBJECTIVE: To identify risk-groups adhering to weight-changing plans for body dissatisfaction in a National sample of Iranian students. DESIGN: Cross sectional. SETTING: Primary, Middle and high-schools. PARTICIPANTS: 13486 students (mean age, 12.5 y). MAIN OUTCOME MEASURES: Demographic and anthropometric characteristics were collected via valid instruments. Body image and adherence to weight- changing diets were assessed by using validated questionnaires. RESULTS: 46.5% students were satisfied with their weight and12.5% declared that they had attempts for weight control, this was significantly higher among adolescent girls (13.8%, P=0.0005). Participants who perceived themselves as overweight and obese, were more likely (OR= 5.32) to follow weight-reduction diets than their peers with normal-weight perception. Actual overweight-BMI and obese-BMI individuals had greater odds for being on a diet (1.3 and 1.47, respectively) compared to their normal-BMI counterparts. CONCLUSION: Promoting strategies to improve body image concerns and prevent adverse outcomes of chronic dieting among adolescents are necessary. PMID- 26499010 TI - Maternal Overt Hypothyroidism and Neurobehavioral Outcome of Neonates: A Cohort Study from an Iodine-deficient Area of Northern India. AB - OBJECTIVE: To study the relation between maternal overt hypothyroidism and neurodevelopmental outcome of neonates in iodine-deficient region of Northern India (Kashmir Valley). DESIGN: Prospective cohort study. SETTING: Endocrinology department of a tertiary-care hospital. PARTICIPANTS: 82 hypothyroid pregnant women were enrolled and followed up till delivery. The neonates born to this group represented the case neonates. 51 euthyroid healthy pregnant women were selected as control group. The neonates born to these mothers served as controls. MAIN OUTCOME MEASURES: Early neonatal behavioral assessment at 3-4 weeks of age. RESULTS: The mean TSH and free T4 in neonates of mothers with well controlled hypothyroidism was significantly different from those born to mothers with poorly controlled hypothyroidism and controls in 1st trimester, but the difference was statistically insignificant for 2nd and 3rd trimester values. CONCLUSION: Overt maternal hypothyroidism in iodine-deficient area constitutes a risk factor for an abnormal neurobehavioral development of affected child. PMID- 26499011 TI - Determinants of Nutritional Anemia in Adolescents. AB - OBJECTIVES: To associate the severity of nutritional anaemia with serum levels of ferritin, vitamin B12 and folate; and to determine demographic, socio-economic and nutritional correlates for nutritional anemia in adolescents. METHODS: Cross sectional hospital-based study among 200 adolescents (10-18 y) with anemia. Dietary intake (24-h recall), and serum levels of folate, vitamin B12 and ferritin were estimated. RESULTS: Iron, folate and vitamin B12 deficiency was present in 30.5% 79.5% and 50% of adolescents, respectively. Statistically significant association was observed between severity of anemia and serum vitamin B12 levels, iron intake, folate intake, Vitamin B12 intake, vegetarian diet, attainment of menarche and history of worm infestation. CONCLUSIONS: Folate and vitamin B12 deficiencies are more common than iron deficiency in anemic adolescents. Low dietary intake of these nutrients seems to be a significant determinant of their deficiencies. PMID- 26499012 TI - Recent Trends in the Diagnosis and Management of Biliary Atresia in Developing Countries. AB - NEED AND PURPOSE OF REVIEW: Biliary atresia is a progressive obstructive cholangiopathy and is fatal if left untreated within 2 years of life. Delay in referral is because of difficulties in differentiating it from physiologic jaundice and identifying an abnormal stool color. This paper presents an overview on the diagnosis and discusses the current strategies in the management of this disease in developing countries. METHODS: Articles were retrieved from the PubMed database using the terms biliary atresia, Kasai portoenterostomy and pediatric liver transplantation. Contents of the article are also based on personal experience of the authors. CONCLUSION: A national screening program using stool color cards as part of standard care in the neonatal period will greatly improve early detection of biliary atresia. Outcomes will improve if it is diagnosed at the earliest after birth, the child is referred to an experienced pediatric hepatobiliary unit for evaluation, and undergoes an early Kasai procedure. If an early Kasai portoenterostomy is performed, nearly half of all children survive into adolescence, and about one-third are likely to have a long-term, symptom free life with normal liver biochemistry. Sequential treatment combining Kasai as first line and liver transplantation as second line results in 90% survival for children with biliary atresia. PMID- 26499013 TI - Tetanus--A Tale of 50 Years. PMID- 26499014 TI - Is Antibiotic Exposure Associated With Newly Diagnosed Juvenile Idiopathic Arthritis? PMID- 26499017 TI - Adult Form of Scimitar Syndrome Presenting as Severe Pulmonary Hypertension in a Child. AB - BACKGROUND: Scimitar syndrome is a rare association of congenital cardiopulmonary anomalies; the adult form is not usually is associated with pulmonary hypertension. CASE CHARACTERISTICS: 6-year-old girl with recurrent episodes of cough and breathlessness, along with features of right heart enlargement. Computed tomography angiogram revealed right pulmonary veins draining into inferior vena cava with dextroposition of heart. OUTCOME: Successfully managed with surgical correction. MESSAGE: Scimitar syndrome should be considered in any child with unexplained pulmonary hypertension and dextroposed heart. PMID- 26499018 TI - Scrub Typhus Co-infection in an Adolescent Girl with Varicella. AB - BACKGROUND: Co-infections with scrub typhus have been described quite frequently in adults but less frequently in children. CASE CHARACTERISTICS: An adolescent girl with varicella infection who had persistent fever. Associated clinical features like pain abdomen, vomiting, and features of third space losses made us suspect a co-infection. IgM and IgG antibodies by ELISA in acute and convalescent serum were suggestive of scrub typhus. OUTCOME: She recovered following a course of oral doxycycline. MESSAGE: In unexplained prolonged fever or atypical clinical manifestations not explainable by the primary disease process, co-infection needs to be considered. PMID- 26499019 TI - Ex-utero Intrapartum Treatment (EXIT) Procedure for Giant Fetal Epignathus. AB - BACKGROUND: Large fetal oropharyngeal tumors are rare, and have the potential to cause airway obstruction during birth. CASE CHARACTERISTICS: A 35-year-old woman with antenatally diagnosed large heterogenous mass in fetal neck displacing trachea and filling up the orophanygeal space. INTERVENTION: The infant was delivered at 31 weeks of gestation by ex-utero intrapartum therapy procedure to secure the airway. OUTCOME: Tumor was resected successfully on day 8 of life. Histopathology revealed mixed teratoma. MESSAGE: Ex-utero intrapartum therapy for fetuses with severe upper airway compromise may prove life-saving. PMID- 26499020 TI - Shanghai Fever: A Fatal Form of Pseudomonas Aeruginosa Enteric Disease. AB - BACKGROUND: Outcome of pseudomonas enteric fever is unpredictable as multiple systemic lethal complications occur abruptly. CASE CHARACTERISTICS: A 9-month-old girl with multiple ileal perforations, leukocoria, ecthyma gangrenosum, hemiplegia and a perforated ulcer in the soft palate. Blood culture suggested Pseudomonas aeruginosa infection. Operative repair of multiple ileal perforations and multidisciplinary management was provided. OUTCOME: On 10th post-operative day, patient succumbed to multiple organ dysfunction syndrome. MESSAGE: Early detection and management of complications of P. aeruginosa enteric disease is important. PMID- 26499021 TI - Isolated Congenital Absence of Sternum in a Newborn. PMID- 26499022 TI - Brevundimonas Septicemia: A Rare Infection with Rare Presentation. PMID- 26499023 TI - Volume Guarantee Ventilation in Neonates and Trouble Shooting. PMID- 26499024 TI - Effective Strategy for Newborn Screening for Congenital Hypothyroidism. PMID- 26499025 TI - Effective Strategy for Newborn Screening for Congenital Hypothyroidism: Author's Reply. PMID- 26499026 TI - Temporal Lobe Epilepsy Masquerading as Tetany. PMID- 26499027 TI - Disclosure of HIV Status to Children. PMID- 26499028 TI - Competency-based Medical Education: The Next Steps. PMID- 26499029 TI - Why was there no Vaccine-associated Intussusception in Indian Rotavirus Vaccine Trial? PMID- 26499030 TI - The Dilemma of Reactive NS1 Antigen test in Dengue Fever. PMID- 26499031 TI - Reply to Letter to the Editor - The impact of weight loss and low BMI on mortality of nursing home residents - Results from the nutritionDay in nursing homes. PMID- 26499032 TI - Prenatal markers of neonatal fat mass: A systematic review. AB - BACKGROUND: Environmental influences during pregnancy are able to affect off spring phenotype with lifelong effects. Clinical applicable markers are needed to identify foetuses at risk for neonatal adiposity. This systematic review aims to 1) review the current literature on prenatal markers of neonatal fat mass, and 2) appraise the clinical applicability of the assessed markers. METHODS: A systematic literature search was conducted to identify studies meeting the following inclusion criteria: 1) original research papers in English; 2) research on dynamic and measurable prenatal markers of neonatal fat mass; 3) neonatal fat mass measurement within one month after birth, using the four-compartment model, magnetic resonance imaging, dual-energy X-ray absorptiometry or air displacement plethysmography. Two reviewers independently performed study selection, assessment of methodological (QUADAS-II) and statistical quality and appraisal of clinical applicability. RESULTS: Of 2333 studies primarily identified by the search strategy, 16 studies were included. Four of these were both methodologically and statistically of moderate or high quality. Prenatal markers investigated were ultrasound parameters, maternal biochemical markers and maternal characteristics. Markers of predefined interest were maternal pre pregnancy body mass index, fasting glucose and HbA1c, showing varying results. A meta-analysis was not possible due to substantial methodological heterogeneity. Clinically applicability of all markers was rated poor. CONCLUSIONS: Although associations were found, no useful marker was identified, due to lack of methodological and statistical quality, inconsistent results and poor clinical applicability. No markers were investigated in the periconceptional and embryonic period. PMID- 26499033 TI - Adherence to the Mediterranean diet is inversely associated with visceral abdominal tissue in Caucasian subjects. AB - BACKGROUND: & aim: Adherence to the Mediterranean dietary pattern (MDP) is inversely related with abdominal adiposity as detected by waist circumference but the specific association to subcutaneous and visceral abdominal tissue has not been investigated. To this purpose we evaluated the association between MDP, visceral (VAT) and subcutaneous (SAT) abdominal tissue in a large sample of Italian adults. METHODS: A cross-sectional study was carried out on 4388 consecutive adults (73.2% women) followed as outpatients at Nutritional Research Centre in Milan, ICANS. VAT and SAT were measured by ultrasonography. MDP was evaluated using a Mediterranean dietary score (MEDscore) obtained from a validated 14-item questionnaire. RESULTS: At multiple linear regression adjusted for sex, age, smoking and physical activity, a 1-unit increase in MEDscore was associated with a -0.118 kg/m(2) decrease in BMI (p < 0.01), a -0.292 cm decrease in waist circumference (p < 0.01), a -0.002 cm:cm decrease in waist to height ratio (p < 0.001), a -1.125 mm decrease in the sum of 4 skinfolds (p < 0.001), and with a -0.045 cm decrease in VAT (p < 0.05). MEDscore was, however, not associated with SAT. Finally, the adherence to the MDP was a protective factor for obesity (OR = 0.717, 95%CI: 0.555-0.922) and VAT excess (OR = 0.717, 95%CI: 0.530-0.971). CONCLUSION: Our study confirms the inverse association between MDP, BMI and waist circumference and adds that the association with abdominal obesity as detected by waist circumference is due to an association with VAT and not with SAT. PMID- 26499034 TI - Post-discharge formula feeding in preterm infants: A systematic review mapping evidence about the role of macronutrient enrichment. AB - BACKGROUND & AIMS: Preterm infants are a heterogeneous group and many accumulate growth deficits before and after initial hospital discharge. Although this is associated with worse cognitive outcome, recent meta-analyses suggest that nutrient fortification of breast milk, or the use of nutrient and energy rich formulae after discharge exert little effect on growth and neurodevelopment. However, the complexity of study design, inclusion criteria and outcome parameters, combined with differences in formula composition mean that meta analysis may overlook important effects of differing interventions in sub-groups. METHODS: We systematically identified evidence and mapped the information on Participants, Intervention, Comparator, and Outcome (PICO) from 31 published studies illustrating the marked heterogeneity in study design and interventions next to outcomes on (quality of) growth and neurodevelopment. RESULTS: Despite significant heterogeneity in study design, we found that nutrient enriched diets after discharge show no negative effects but frequently improve growth parameters at some point in the course of the study, in particular for boys. The data indicates that when energy requirements are adequate, increased protein results in increased growth and lean mass (LM) accretion; In particular, higher protein to energy ratios lead to increased lean mass accretion, and increased head circumference (HC) at one year. However, improvements in neurodevelopmental outcome were rarely seen. CONCLUSION: This comprehensive evidence mapping approach to the field provides a broad but detailed overview of the currently available evidence. Furthermore, we identified key gaps in existing knowledge on the role of nutrient enrichment in the post-discharge period. PMID- 26499035 TI - Dynamics of SI epidemic with a demographic Allee effect. AB - In this paper, we present an extended SI model of Hilker et al. (2009). In the presented model the birth rate and the death rate are both modeled as quadratic polynomials. This approach provides ample opportunity for taking into account the major contributors to an Allee effect and effectively captures species' differential susceptibility to the Allee effects. It is shown that, the behaviors (persistence or extinction) of the model solutions are characterized by the two essential threshold parameters lambda0 and lambda1 of the transmissibility lambda and a threshold quantity MU(*) of the disease pathogenicity MU. If lambdalambda0 and MUlambda1 and MU>MU(*), the disease derives the host population to extinction with origin as the only global attractor. For the special cases of the model, verifiable conditions for host population persistence (with or without infected individuals) and host extinction are derived. Interestingly, we show that if the values of the parameters alpha and beta of the extended model are restricted, then the two models are similar. Numerical simulations show how the parameter beta affects the dynamics of the model with respect to the host population persistence and extinction. PMID- 26499036 TI - A theoretical analysis of the Allee effect in wind-pollinated cordgrass plant invasions. AB - A new individual-based model is presented for investigating an important group of invasive plant species, from the genus Spartina, that threaten biodiversity in coastal and intertidal habitats around the world. The role of pollen limitation in influencing the early development of an invasion is explored in order to gain a greater understanding of the mechanistic basis for an apparent Allee effect (causal relationship between population size/density and mean individual fitness) observed in populations of invasive Spartina species. The model is used to explore how various factors such as atmospheric stability, wind direction/speed, pollen characteristics and spatial structure of the population affect the overall invasion dynamics and reproductive success. Comparisons were also made between invasive species of Spartina (S. alterniflora, S. anglica) and a non-invasive species (S. foliosa), showing a reduced Allee effect was associated with invasion success. Furthermore, the conclusions drawn here may give insights into some of the fundamental processes affecting the growth and population dynamics of other invasive wind-pollinated plants. PMID- 26499037 TI - Major vault protein regulates cell growth/survival signaling through oxidative modifications. AB - Major vault protein forms a hollow, barrel-like structure in the cell called the vault, whose functions and regulation are not well understood. The present study reports that major vault protein regulates growth/survival signaling in human airway smooth muscle cells through oxidative modifications. The promotion of protein S-glutathionylation by asthma mediators such as interleukin-22 and platelet-derived growth factor or by knocking down glutaredoxin-1 or thioredoxin activated cell growth signaling. Mass spectrometry identified that major vault protein is glutathionylated. Major vault protein knockdown enhanced cell death and inhibited STAT3 and Akt signaling. We identified a protein partner of major vault protein that is regulated by glutaredoxin-1, namely myosin-9, which was found to serve as a cell death factor. Knocking down myosin-9 or promoting protein S-glutathionylation by knocking down glutaredoxin-1 inhibited the death of airway smooth muscle cells by heating to simulate bronchial thermoplasty, a clinically successful procedure for the treatment of severe asthma. These results establish a novel signaling pathway in which ligand/receptor-mediated oxidation promotes the S-glutathionylation of major vault protein, which in turn binds to myosin-9 to suppress the heating-induced death of airway smooth muscle cells. PMID- 26499038 TI - FHL3 differentially regulates the expression of MyHC isoforms through interactions with MyoD and pCREB. AB - In skeletal muscle, muscle fiber types are defined by four adult myosin heavy chain (MyHC) isoforms. Four and a half LIM domain protein 3 (FHL3) regulates myoblasts differentiation and gene expression by acting as a transcriptional co activator or co-repressor. However, how FHL3 regulates MyHC expression is currently not clear. In this study, we found that FHL3 down-regulated the expression of MyHC 1/slow and up-regulated the expression of MyHC 2a and MyHC 2b, whereas no significant effect was found on MyHC 2x expression. MyoD and phosphorylated cAMP response element binding protein (pCREB) played important roles in the regulation of MyHC 1/slow and MyHC 2a expression by FHL3, respectively. FHL3 could interact with MyoD, CREB and pCREB in vivo. pCREB had stronger interaction with the cyclic AMP-responsive elements (CRE) of the MyHC 2a promoter compared with CREB, and FHL3 significantly affected the binding capacity of pCREB to CRE. We established a model in which FHL3 promotes the expression of MyHC 2a through CREB-mediated transcription and inhibits the expression of MyHC 1/slow by inhibiting MyoD transcription activity during myogenesis. Our data support the notion that FHL3 plays important roles in the regulation of muscle fiber type composition. PMID- 26499039 TI - A fast transfer-free synthesis of high-quality monolayer graphene on insulating substrates by a simple rapid thermal treatment. AB - The transfer-free synthesis of high-quality, large-area graphene on a given dielectric substrate, which is highly desirable for device applications, remains a significant challenge. In this paper, we report on a simple rapid thermal treatment (RTT) method for the fast and direct growth of high-quality, large scale monolayer graphene on a SiO2/Si substrate from solid carbon sources. The stack structure of a solid carbon layer/copper film/SiO2 is adopted in the RTT process. The inserted copper film does not only act as an active catalyst for the carbon precursor but also serves as a "filter" that prevents premature carbon dissolution, and thus, contributes to graphene growth on SiO2/Si. The produced graphene exhibits a high carrier mobility of up to 3000 cm(2) V(-1) s(-1) at room temperature and standard half-integer quantum oscillations. Our work provides a promising simple transfer-free approach using solid carbon sources to obtain high quality graphene for practical applications. PMID- 26499040 TI - Kinetics of lentiviral vector transduction in human CD34(+) cells. AB - Unlike cell lines, human hematopoietic stem cells (HSCs) are less efficiently transduced with HIV-1 vectors, potentially limiting this approach. To investigate which step (internalization, reverse transcription, nuclear transport, and integration) limits lentiviral transduction, we evaluated the kinetics of lentiviral transduction in human CD34(+) cells. We transduced HeLa and CD34(+) cells with self-inactivating HIV-1 vector at low and tenfold higher multiplicity of infection (MOI) and evaluated vector amounts at various time points based on the rationale that if a given step was not limiting, tenfold greater vector amounts would be obtained at the tenfold higher MOI. We observed slower internalization (>60 min), a peak in reverse transcription at 24 hours, and completion of integration at 3 days in CD34(+) cells. In HeLa cells, there were approximately tenfold greater amounts at high MOI at all time points. When compared with HeLa cells, CD34(+) cells exhibited larger differences in vector amounts between high and low MOIs at 2-6 hours and a smaller difference at 12 hours to 10 days, revealing a limitation in human CD34(+) cell transduction around 12 hours, which corresponds to reverse transcription. In serial measurements of reverse transcription at 24 hours, vector amounts did not decrease once detected among CD34(+) cells. When using an HSC expansion medium, we observed less limitation for starting reverse transcription and more efficient transduction among CD34(+) cells in vitro and in xenografted mice. These data suggest that it is the initiation of reverse transcription that limits lentiviral transduction of human CD34(+) cells. Our findings provide an avenue for optimizing human CD34(+) cell transduction. PMID- 26499041 TI - Long-Term Passivation of Strongly Interacting Metals with Single-Layer Graphene. AB - The long-term (>18 months) protection of Ni surfaces against oxidation under atmospheric conditions is demonstrated by coverage with single-layer graphene, formed by chemical vapor deposition. In situ, depth-resolved X-ray photoelectron spectroscopy of various graphene-coated transition metals reveals that a strong graphene-metal interaction is of key importance in achieving this long-term protection. This strong interaction prevents the rapid intercalation of oxidizing species at the graphene-metal interface and thus suppresses oxidation of the substrate surface. Furthermore, the ability of the substrate to locally form a passivating oxide close to defects or damaged regions in the graphene overlayer is critical in plugging these defects and preventing oxidation from proceeding through the bulk of the substrate. We thus provide a clear rationale for understanding the extent to which two-dimensional materials can protect different substrates and highlight the key implications for applications of these materials as barrier layers to prevent oxidation. PMID- 26499042 TI - Kinetics of the establishment of HIV-1 viral interference and comprehensive analysis of the contribution of viral genes. AB - Viral interference defines the reduced susceptibility of an infected cell to reinfection. For HIV-1, both receptor-dependent and independent pathways were described. The relative importance of different receptor-independent pathways has not been addressed. We have used reporter viruses to quantify the percentage of single- and double-infected cells, as a function of the delay between the two infections. For co-infection experiments, the frequency of double infected cells was higher than expected for independent events. By delaying the second infection, this frequency progressively diminished, resulting in significant interference after 18h. Interference measured here was largely receptor independent. By individually deleting viral genes or expressing them in isolation, we demonstrate that the viral protein Rev plays a dominant role, while other viral proteins contributes to optimal interference. Our study defines the kinetics of early HIV-1 interference, describing the transition from higher susceptibility to double-infection to viral interference, and identifies Rev as its dominant effector. PMID- 26499043 TI - Arterivirus RNA-dependent RNA polymerase: Vital enzymatic activity remains elusive. AB - All RNA viruses encode an RNA-dependent RNA polymerase (RdRp), which in arteriviruses is expressed as the C-terminal domain of nonstructural protein 9 (nsp9). Previously, potent primer-dependent RdRp activity has been demonstrated for the homologous polymerase subunit (nsp12) of the distantly related coronaviruses. The only previous study focusing on the in vitro activity of nsp9 of an arterivirus (equine arteritis virus; EAV) reported weak de novo polymerase activity on homopolymeric RNA templates. However, this activity was not retained when Mn(2+) ions were omitted from the assay or when biologically relevant templates were supplied, which prompted us to revisit the biochemical properties of this polymerase. Based on the properties of active-site mutants, we conclude that the RNA-synthesizing activities observed in de novo and primer-dependent polymerase and terminal transferase assays cannot be attributed to recombinant EAV nsp9-RdRp. Our results illustrate the potential pitfalls of characterizing polymerases using highly sensitive biochemical assays. PMID- 26499044 TI - Adenoviral vectors elicit humoral immunity against variable loop 2 of clade C HIV 1 gp120 via "Antigen Capsid-Incorporation" strategy. AB - Adenoviral (Ad) vectors in combination with the "Antigen Capsid-Incorporation" strategy have been applied in developing HIV-1 vaccines, due to the vectors' abilities in incorporating and inducing immunity of capsid-incorporated antigens. Variable loop 2 (V2)-specific antibodies were suggested in the RV144 trial to correlate with reduced HIV-1 acquisition, which highlights the importance of developing novel HIV-1 vaccines by targeting the V2 loop. Therefore, the V2 loop of HIV-1 has been incorporated into the Ad capsid protein. We generated adenovirus serotype 5 (Ad5) vectors displaying variable loop 2 (V2) of HIV-1 gp120, with the "Antigen Capsid-Incorporation" strategy. To assess the incorporation capabilities on hexon hypervariable region1 (HVR1) and protein IX (pIX), 20aa or full length (43aa) of V2 and V1V2 (67aa) were incorporated, respectively. Immunizations with the recombinant vectors significantly generated antibodies against both linear and discontinuous V2 epitopes. The immunizations generated durable humoral immunity against V2. This study will lead to more stringent development of various serotypes of adenovirus-vectored V2 vaccine candidates, based on breakthroughs regarding the immunogenicity of V2. PMID- 26499045 TI - ICAM-1 regulates the survival of influenza virus in lung epithelial cells during the early stages of infection. AB - Intercellular cell adhesion molecule-1 (ICAM-1) is an inducible cell surface glycoprotein that is expressed on many cell types. Influenza virus infection enhanced ICAM-1 expression and messenger RNA levels. Human bronchial epithelial cells (HBEpC) and nasal epithelial cells, on exposure to different strains of influenza virus (H1N1, H3N2, and H9N1) showed significant increase in ICAM-1 gene expression (p<0.001) along with the ICAM-1 protein levels (surface and secreted). Depleting ICAM-1 in HBEpC with ICAM-1 siRNA and subsequently infecting with H1N1 showed increased viral copy numbers. Influenza virus infection in HBEpC resulted in up-regulation of NF-KB protein and the lack of ICAM-1 decreased NF-KB activity in NF-KB luciferase reporter assay. Addition of exogenous IL-1beta to HBEpC induced the ICAM-1 expression and decreased matrix gene copy number. Taken together, HBEpC induced ICAM-1 plays a key role in modulating the influenza virus survival possibly through the NF-KB pathway. PMID- 26499046 TI - Surface modification via strain-promoted click reaction facilitates targeted lentiviral transduction. AB - As a result of their ability to integrate into the genome of both dividing and non-dividing cells, lentiviruses have emerged as a promising vector for gene delivery. Targeted gene transduction of specific cells and tissues by lentiviral vectors has been a major goal, which has proven difficult to achieve. We report a novel targeting protocol that relies on the chemoselective attachment of cancer specific ligands to unnatural glycans on lentiviral surfaces. This strategy exhibits minimal perturbation on virus physiology and demonstrates remarkable flexibility. It allows for targeting but can be more broadly useful with applications such as vector purification and immunomodulation. PMID- 26499047 TI - Target lesion evaluation by multiple modalities in vivo: near-infrared spectroscopy (NIRS), virtual histology intravascular ultrasound, optical coherence tomography, and angioscopy. PMID- 26499048 TI - Multiple mycotic aneurysms of the right coronary artery. PMID- 26499049 TI - A curly case: dissecting giant arteriovenous anomaly - left main coronary artery shunting to superior vena cava. PMID- 26499050 TI - Successful surgical treatment of a pronounced myocardial bridge of the left anterior descending artery with ischaemia on a two-year-old child. PMID- 26499051 TI - Double atrial septum or redundant Eustachian valve: procedural management during atrial septal defect occlusion. PMID- 26499052 TI - Robotic nephrectomy for living donation: surgical technique and literature systematic review. AB - BACKGROUND: As compared with traditional laparoscopy, robotic-assisted surgery provides better EndoWrist instruments and three-dimensional visualization of the operative field. Studies published so far indicate that living donor nephrectomy using the robot-assisted technique is safe, feasible, and provides remarkable advantages for the patients. METHODS: From 5 papers reporting detailed descriptions of surgical technique for robotic assisted nephrectomy (RAN) in living donor kidney transplantation, we have gathered information about the surgical techniques as well as about patients' intra- and postoperative outcome. Data from these articles were analyzed together with the data from our own experience (33 cases) so that the total number of analyzed cases was 292. RESULTS: In the analyzed populations, no case of donor death occurred, and no case developed complication above grade 2 of Clavien score. Perioperative complications occurred in 37 of the 292 patients (12.6%). Accidental acute hemorrhage occurred in 5 of the 292 cases (1.7%). The average overall intraoperative blood loss was 67.8 mL (range 10 to 1,500). The average warm ischemia time was 3.5 minutes (range .58 to 7.6). Conversion to the open technique occurred in only 4 cases (1.3%). The average overall operative time was 192 minutes (range 60 to 400). The average length of the hospital stay was 2.7 days (range 1 to 10). CONCLUSIONS: Safety and feasibility of RAN are pointed out in all the reviewed article, both as hand-assisted and as totally robotic technique. RAN appears to be significantly easier for the surgeons and the results are comparable with the ones obtained with the pure laparoscopic technique. PMID- 26499053 TI - Comparison of one-stage vs two-stage prosthesis-based breast reconstruction: a systematic review and meta-analysis. AB - BACKGROUND: The aim of this review is to comprehensively compare the outcomes of one-stage and two-stage prosthesis-based breast reconstruction via meta-analytic methodology. DATA SOURCES: Seventeen studies comparing one-stage and two-stage prosthesis-based breast reconstruction were reviewed. The analysis divided the outcomes into 3 categories: complications, esthetic satisfaction, and total cost for completing reconstruction. CONCLUSIONS: The one-stage reconstruction group was at significantly higher risk for reconstruction failure and overall complications than the two-stage group. No significant difference was observed between the 2 groups in the results of nipple-sparing mastectomy. The esthetic result analysis demonstrated that both methods showed comparably positive outcomes. The one-stage group incurred lower cost for completing reconstruction than the two-stage group, despite the higher cost for treatment-related complications. Our results suggest that the risks for adverse outcome in patients undergoing one-stage reconstruction may be comparable with that of two-stage reconstruction when performed in patients receiving a nipple-sparing mastectomy. However, further well-controlled studies are required to draw more solid conclusions. PMID- 26499054 TI - Abscess due to perforated appendicitis: factors associated with successful percutaneous drainage. AB - BACKGROUND: Percutaneous drainage is the standard treatment for perforated appendicitis with abscess. We studied factors associated with complete resolution (CR) with percutaneous drainage alone. METHODS: Ninety-eight patients underwent percutaneous drainage for acute appendicitis complicated by abscess (October 1990 to September 2010). CR was defined as clinical recovery, resolution of the abscess on imaging, and drain removal without recurrence. Patients achieving CR were compared with patients not achieving CR. RESULTS: The rate of CR was 78.6% (n = 77). Abscess grade was the only radiological factor associated with CR (P = .007). The CR rate was higher with transgluteal drainage (90.9% vs 79.2%) than with other anatomic approaches (P = .018) and higher with computed tomography guided drainage than with ultrasound-guided drainage (82.7% vs 64.3%, P = .046). CONCLUSION: CR was more likely to be achieved in patients with lower abscess grade, computed tomography-guided drainage, and a transgluteal approach. PMID- 26499055 TI - Surgical repair of pectus excavatum relieves right heart chamber compression and improves cardiac output in adult patients--an intraoperative transesophageal echocardiographic study. AB - BACKGROUND: Cardiac compression in pectus excavatum (PE) deformity and effect of PE surgery on cardiac function in adults have been debated. We examined the effect of PE correction on right heart size and cardiac output. METHODS: A retrospective evaluation was performed of 168 adult patients who underwent a modified Nuss PE repair with intraoperative transesophageal echocardiography from 2011 to 2014. Seventeen patients with prior PE repair undergoing bar removal acted as controls. RESULTS: Mean age was 33.0 years (range, 18 to 71 years). There was an increase in right atrium (15.1%), tricuspid annulus (10.9%), and right ventricular outflow tract (6.1%) size after surgery (all P < .0001). Right ventricular cardiac output measured in a subset of 42 patients improved by 38%. No change in chamber size or cardiac output occurred before and after bar removal surgery in the control group. CONCLUSIONS: Surgical correction of PE deformity caused a significant improvement in right heart chamber size and cardiac output. PMID- 26499056 TI - [Corrigendum] Effects of rotigaptide (ZP123) on connexin43 remodeling in canine ventricular fibrillation. PMID- 26499058 TI - Time-multiplexed two-channel capacitive radiofrequency hyperthermia with nanoparticle mediation. AB - BACKGROUND: Capacitive radiofrequency (RF) hyperthermia suffers from excessive temperature rise near the electrodes and poorly localized heat transfer to the deep-seated tumor region even though it is known to have potential to cure ill conditioned tumors. To better localize heat transfer to the deep-seated target region in which electrical conductivity is elevated by nanoparticle mediation, two-channel capacitive RF heating has been tried on a phantom. METHODS: We made a tissue-mimicking phantom consisting of two compartments, a tumor-tissue-mimicking insert against uniform background agarose. The tumor-tissue-mimicking insert was made to have higher electrical conductivity than the normal-tissue-mimicking background by applying magnetic nanoparticle suspension to the insert. Two electrode pairs were attached on the phantom surface by equal-angle separation to apply RF electric field to the phantom. To better localize heat transfer to the tumor-tissue-mimicking insert, RF power with a frequency of 26 MHz was delivered to the two channels in a time-multiplexed way. To monitor the temperature rise inside the phantom, MR thermometry was performed at a 3T MRI intermittently during the RF heating. Finite-difference-time-domain (FDTD) electromagnetic and thermal simulations on the phantom model were also performed to verify the experimental results. RESULTS: As compared to the one-channel RF heating, the two channel RF heating with time-multiplexed driving improved the spatial localization of heat transfer to the tumor-tissue-mimicking region in both the simulation and experiment. The two-channel RF heating also reduced the temperature rise near the electrodes significantly. CONCLUSIONS: Time-multiplexed two-channel capacitive RF heating has the capability to better localize heat transfer to the nanoparticle-mediated tumor region which has higher electrical conductivity than the background normal tissues. PMID- 26499059 TI - Imatinib mesylate induces mitochondria-dependent apoptosis and inhibits invasion of human pigmented villonodular synovitis fibroblast-like synovial cells. AB - Pigmented villonodular synovitis (PVNS) is a rare sarcoma-like disorder characterized by synovial lesions proliferation and invasion to articular cartilage for which no effective treatments are available. Imatinib mesylate (IM) is known to exert antitumor activity in some tumors, but its effects on PVNS fibroblast-like synoviocytes (PVNS-FLS) and the specific mechanism involved remain to be established. In the present study, the in vitro effects of IM on cell proliferation and survival rates were investigated in PVNS-FLS. Apoptosis induction was assessed via acridine orange/ethidium bromide (AO)/(EB) and Annexin V/PI staining as well as western blotting. The invasion ability of PVNS-FLS was evaluated by Transwell invasion chambers. IM significantly inhibited survival and invasion ability of PVNS-FLS in a dose- and time-dependent manner. The drug treated cell groups exhibited markedly higher apoptosis, which was blocked upon pretreatment with the specific caspase-9 inhibitor Z-LEHD-FMK. Expression of cleaved caspase-9 was significantly increased and the Bcl-2 family and caspase-3 were activated following treatment with IM. Our results collectively demonstrated that IM has a strong antiproliferative effect on PVNS-FLS in vitro, attributable to induction of mitochondrial-dependent apoptosis in association with activation of caspase-9/-3 and the Bcl-2/Bax family, and exhibits significant inhibition on the invasion ability of PVNS-FLS, suggesting that IM may be useful as a novel treatment of this disease. PMID- 26499057 TI - Cognitive computer training in children with attention deficit hyperactivity disorder (ADHD) versus no intervention: study protocol for a randomized controlled trial. AB - BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder characterized by symptoms of inattention and impulsivity and/or hyperactivity and a range of cognitive dysfunctions. Pharmacological treatment may be beneficial; however, many affected individuals continue to have difficulties with cognitive functions despite medical treatment, and up to 30 % do not respond to pharmacological treatment. Inadequate medical compliance and the long-term effects of treatment make it necessary to explore nonpharmacological and supplementary treatments for ADHD. Treatment of cognitive dysfunctions may prove particularly important because of the impact of these dysfunctions on the ability to cope with everyday life. Lately, several trials have shown promising results for cognitive computer training, often referred to as cognitive training, which focuses on particular parts of cognition, mostly on the working memory or attention but with poor generalization of training on other cognitive functions and functional outcome. Children with ADHD have a variety of cognitive dysfunctions, and it is important that cognitive training target multiple cognitive functions. METHODS/DESIGN: This multicenter randomized clinical superiority trial aims to investigate the effect of "ACTIVATETM," a computer program designed to improve a range of cognitive skills and ADHD symptoms. A total of 122 children with ADHD, aged 6 to 13 years, will be randomized to an intervention or a control group. The intervention group will be asked to use ACTIVATETM at home 40 minutes per day, 6 days per week for 8 weeks. Both intervention and control group will receive treatment as usual. Outcome measures will assess cognitive functions, symptoms, and behavioral and functional measures before and after the 8 weeks of training and in a 12- and 24-week follow up. DISCUSSION: Results of this trial will provide useful information on the effectiveness of computer training focusing on several cognitive functions. Cognitive training has the potential to reduce cognitive dysfunctions and to become a new treatment option, which can promote a more normal neural development in young children with ADHD and thus reduce cognitive dysfunctions and symptoms. This could help children with ADHD to perform better in everyday life and school. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01752530 , date of registration: 10 December 2012. PMID- 26499060 TI - Hypertrophic aortic branches can potentially cause critical problems during minimally invasive cardiac surgery. AB - Here we present two cases in which hypertrophic aortic branches caused trouble during minimally invasive cardiac surgery. We performed mitral valvuloplasty with the Maze procedure in Case 1 and mitral valvuloplasty with aortic valve replacement in Case 2 via mini-thoracotomy. In preoperative computed tomography scan, we did not note a hypertrophic bronchial artery in Case 1 or a dilated intercostal artery in Case 2. The right atrium was distended after aortic cross clamping and perioperative myocardial infarction occurred in Case 1. Whereas, we could effectively deal with this situation in Case 2. The increased pulmonary blood flow can potentially cause critical problems during minimally invasive surgery. Sufficient venting of the right ventricle and secure myocardial protection is the key to perform safe surgery in the presence of dilated aortic branches. However, surgeons should not hesitate to convert to sternotomy under poor surgical exposure despite sufficient venting. PMID- 26499061 TI - The effects of narrative versus non-narrative information in school health education about alcohol drinking for low educated adolescents. AB - BACKGROUND: Traditionally most health education materials are written in an expository non-narrative format. Scholars have argued that the effectiveness of materials may increase when these texts are replaced by narrative texts, and that the non-narrative texts should be replaced by narrative texts. However, no previous studies have tested these claims in the context of school health education for low educated adolescents. This study aims to do so for an existing preventive health education intervention about alcohol for low educated adolescents. Based on the empirical findings of previous studies, it is expected that the claims about narratives being more effective than non-narrative texts are not true for effects on knowledge. Instead non-narrative texts are expected to have a stronger impact on this outcome variable. For attitude towards alcohol and intention to drink alcohol the claims are expected to be true, because participants are expected to be less aware of the persuasive intent of the narrative texts, which would make them less resistant. As a result, narrative texts are expected to have a stronger effect on attitude and intention. METHODS: This study compares the effects on knowledge, attitude towards alcohol, and intention to drink alcohol of both information formats in a two-condition (non narrative vs. narrative information) experiment with repeated measures (pre measurement, immediate post-measurement, and delayed post-measurement). The experiment was conducted amongst 296 students of the two lowest levels of the Dutch secondary education system. RESULTS: The results showed immediate effects on knowledge and attitude towards alcohol, which did not differ between conditions and school levels. These effects did not persist over time. There were no effects on intention to drink alcohol. CONCLUSION: It is concluded non narrative and narrative information are equally effective in the context of school health education, suggesting the claims that scholars have made about the superior effects of narrative texts are not true. Given the fact that narrative texts are more expensive to develop, policy makers may not be advised to prefer these types of texts over the traditionally used non-narrative texts. PMID- 26499062 TI - Problem-Solving Coping and Social Support as Mediators of Academic Stress and Suicidal Ideation Among Malaysian and Indian Adolescents. AB - This study examined whether productive coping styles and social support were significant mediators of the relationship between academic stress and suicidal ideation. The survey was performed on a sample of 300 Malaysian and 300 Indian college students. The participants completed psychological assessments of productive coping styles, social support, academic stress, and suicidal ideation. Significant cultural and demographic differences emerged. Indian students reported higher suicidal ideation and academic stress than did Malaysian students, and Malaysian students received more social support and had better problem-solving coping styles than did Indian students. Overall, students who were male, non-religious, and from low-income families reported more academic stress and more suicidal ideation. Productive coping styles and overall social support strongly affected the relationship between academic stress and suicidal ideation among both countries' participants. PMID- 26499063 TI - Self-assembly of the anti-fungal polyene amphotericin B into giant helically twisted nanotapes. AB - The amphiphilic polyene amphotericin B, a powerful treatment for systemic fungal infections, is shown to exhibit a critical aggregation concentration, and to form giant helically-twisted nanostructures via self-assembly in basic aqueous solution. PMID- 26499064 TI - How does age affect the care dependency risk one year after stroke? A study based on claims data from a German health insurance fund. AB - BACKGROUND: The objective of this study is to investigate the effect of age on care dependency risk 1 year after stroke. Two research questions are addressed: (1) How strong is the association between age and care dependency risk 1 year after stroke and (2) can this association be explained by burden of disease? METHODS: The study is based on claims data from a German statutory health insurance fund. The study population was drawn from all continuously insured members with principal diagnoses of ischaemic stroke, hemorrhagic stroke, or transient ischaemic attack in 2007 who survived for 1 year after stroke and who were not dependent on care before their first stroke (n = 2864). Data were collected over a 1-year period. People are considered to be dependent on care if they, due to a physical, mental or psychological illness or disability, require substantial assistance in carrying out activities of daily living for a period of at least 6 months. Burden of disease was assessed by stroke subtype, history of stroke, comorbidities as well as geriatric multimorbidity. Regression models were used for data analysis. RESULTS: 21.6 % of patients became care dependent during the observation period. Post-stroke care dependency risk was significantly associated with age. Relative to the reference group (0-65 years), the odds ratio of care dependency was 11.30 (95 % CI: 7.82-16.34) in patients aged 86+ years and 5.10 (95 % CI: 3.88-6.71) in patients aged 76-85 years. These associations were not explained by burden of disease. On the contrary, age effects became stronger when burden of disease was included in the regression model (by between 1.1 and 28 %). CONCLUSIONS: Our results show that age has an effect on care dependency risk that cannot be explained by burden of disease. Thus, there must be other underlying age-dependent factors that account for the remaining age effects (e.g., social conditions). Further studies are needed to explore the causes of the strong age effects observed. PMID- 26499065 TI - A high-throughput liquid bead array-based screening technology for Bt presence in GMO manipulation. AB - The number of species and planting areas of genetically modified organisms (GMOs) has been rapidly developed during the past ten years. For the purpose of GMO inspection, quarantine and manipulation, we have now devised a high-throughput Bt based GMOs screening method based on the liquid bead array. This novel method is based on the direct competitive recognition between biotinylated antibodies and beads-coupled antigens, searching for Bt presence in samples if it contains Bt Cry1 Aa, Bt Cry1 Ab, Bt Cry1 Ac, Bt Cry1 Ah, Bt Cry1 B, Bt Cry1 C, Bt Cry1 F, Bt Cry2 A, Bt Cry3 or Bt Cry9 C. Our method has a wide GMO species coverage so that more than 90% of the whole commercialized GMO species can be identified throughout the world. Under our optimization, specificity, sensitivity, repeatability and availability validation, the method shows a high specificity and 10-50 ng/mL sensitivity of quantification. We then assessed more than 1800 samples in the field and food market to prove capacity of our method in performing a high throughput screening work for GMO manipulation. Our method offers an applicant platform for further inspection and research on GMO plants. PMID- 26499067 TI - Electrochemical impedance based chiral analysis of anti-ascorbutic drug: l Ascorbic acid and d-ascorbic acid using C-dots decorated conductive polymer nano composite electrode. AB - Clinical manifestations owing to l-ascorbic acid for scurvy as comparison to d ascorbic acid and challenges of chiral purity are overcome by using chiral selective conductive polymer nanocomposite which mimics antibodies and enzymes. A novel chiral selective imprinted polyaniline-ferrocene-sulfonic acid film has been electrochemically fabricated on C-dots modified pencil graphite electrode. The performance of the obtained l-ascorbic acid or d-ascorbic acid chiral selective sensor was investigated by electrochemical impedance spectroscopy, cyclic and differential pulse voltammetry. The surface characteristics of the C dots, chiral sensor before and after the de-doping of chiral d- and l-ascorbic acid were characterized by scanning electron microscopy, Raman spectroscopy and X ray diffraction spectroscopy. Excellent recognition results were obtained by difference in electron transfer resistance. The proposed chiral sensor is capable of measuring d-ascorbic acid or l-ascorbic acid in aqueous as well as in real and commercial samples within the range of 0.020-0.187 nM and 0.003-0.232 nM with detection limit of 0.00073 nM and 0.00016 nM, respectively. The proposed method has also been examined for the chiral selective recognition of ascorbic acid isomers (d- and l-) quantitatively, in complicated matrices of real samples. PMID- 26499066 TI - Potentiometric bioimaging with a large-scale integration (LSI)-based electrochemical device for detection of enzyme activity. AB - This paper describes potentiometric bioimaging for enzyme activity using a large scale integration (LSI)-based electrochemical device with 400 sensors. Potentiometric detection is useful for bioimaging because redox species are not consumed or produced during the detection process; therefore, there is no effect on cell activity and the detectable signal is sustained. In this study, the potentiometer mode of the LSI-based device was applied for the detection of glucose oxidase (GOx) and alkaline phosphatase (ALP) activity. The enzyme activities were quantitatively detected within the concentration ranges of 25-250 MUg/mL and 0.10-5.0 ng/mL. In addition, GOx activity in hydrogels and the ALP activity of embryoid bodies (EBs) from embryonic stem (ES) cells were successfully imaged based on detection of the open circuit potentials of individual sensors in real time. To the best of our knowledge, this is the first report of potentiometric imaging using LSI-based electrochemical arrays to detect enzyme activity in ES cells. The LSI-based device is thus demonstrated to be a promising tool for bioimaging of enzyme activity. PMID- 26499068 TI - A Direct Link between Abscisic Acid Sensing and the Chromatin-Remodeling ATPase BRAHMA via Core ABA Signaling Pathway Components. AB - Optimal response to drought is critical for plant survival and will affect biodiversity and crop performance during climate change. Mitotically heritable epigenetic or dynamic chromatin state changes have been implicated in the plant response to the drought stress hormone abscisic acid (ABA). The Arabidopsis SWI/SNF chromatin-remodeling ATPase BRAHMA (BRM) modulates response to ABA by preventing premature activation of stress response pathways during germination. We show that core ABA signaling pathway components physically interact with BRM and post-translationally modify BRM by phosphorylation/dephosphorylation. Genetic evidence suggests that BRM acts downstream of SnRK2.2/2.3 kinases, and biochemical studies identified phosphorylation sites in the C-terminal region of BRM at SnRK2 target sites that are evolutionarily conserved. Finally, the phosphomimetic BRM(S1760D S1762D) mutant displays ABA hypersensitivity. Prior studies showed that BRM resides at target loci in the ABA pathway in the presence and absence of the stimulus, but is only active in the absence of ABA. Our data suggest that SnRK2-dependent phosphorylation of BRM leads to its inhibition, and PP2CA-mediated dephosphorylation of BRM restores the ability of BRM to repress ABA response. These findings point to the presence of a rapid phosphorylation based switch to control BRM activity; this property could be potentially harnessed to improve drought tolerance in plants. PMID- 26499069 TI - Hypercalcemia in metastatic GIST caused by systemic elevated calcitriol: a case report and review of the literature. AB - BACKGROUND: Hypercalcemia is the most common oncologic metabolic emergency but very rarely observed in patients with gastrointestinal stromal tumour, which is a rare mesenchymal malignancy of the gastrointestinal tract. We describe a case of hypercalcemia caused by elevated levels of activated vitamin D in a patient with gastrointestinal tumour. Prior to this case report, only one paper has reported an association between hypercalcemia, gastrointestinal stromal tumours and elevated levels of vitamin D. CASE PRESENTATION: An otherwise healthy 70-year-old Caucasian woman, previously treated for duodenal gastrointestinal stromal tumour, was diagnosed with liver metastasis, and relapse of gastrointestinal stromal tumour was confirmed by biopsy. At presentation, the patient suffered from severe symptoms of hypercalcemia. The most common causes of hypercalcemia, hyperparathyrodism, parathyroid hormone-related peptide secretion from tumour cells, and metastatic bone disease, were all dismissed as the etiology. Analysis of vitamin D subtypes revealed normal levels of both 25-OH Vitamin D2 and 25-OH Vitamin D3, whereas the level of activated vitamin D, 1,25 OH Vitamin D3, also referred to as calcitriol, was elevated. CONCLUSION: The fact that plasma calcitriol decreased after initiation of oncological treatment and the finding that hypercalcemia did not recur during treatment support the conclusion that elevated calcitriol was a consequence of the gastrointestinal stromal tumour. We suggest that gastrointestinal stromal tumours should be added to the list of causes of humoral hypercalcemia in malignancy, and propose that gastrointestinal stromal tumour tissue may have high activity of the specific enzyme 1alpha hydroxylase, which can lead to increased levels of calcitriol and secondarily hypercalcemia. PMID- 26499070 TI - Traditional medicine practices among community members with chronic kidney disease in northern Tanzania: an ethnomedical survey. AB - BACKGROUND: In sub-Saharan Africa, chronic kidney disease (CKD) is being recognized as a non-communicable disease (NCD) with high morbidity and mortality. In countries like Tanzania, people access many sources, including traditional medicines, to meet their healthcare needs for NCDs, but little is known about traditional medicine practices among people with CKD. Therefore, we sought to characterize these practices among community members with CKD in northern Tanzania. METHODS: Between December 2013 and June 2014, we administered a previously-developed survey to a random sample of adult community-members from the Kilimanjaro Region; the survey was designed to measure traditional medicine practices such as types, frequencies, reasons, and modes. Participants were also tested for CKD, diabetes, hypertension, and HIV as part of the CKD-AFRiKA study. To identify traditional medicines used in the local treatment of kidney disease, we reviewed the qualitative sessions which had previously been conducted with key informants. RESULTS: We enrolled 481 adults of whom 57 (11.9 %) had CKD. The prevalence of traditional medicine use among adults with CKD was 70.3 % (95 % CI 50.0-84.9 %), and among those at risk for CKD (n = 147; 30.6 %), it was 49.0 % (95 % CI 33.1-65.0 %). Among adults with CKD, the prevalence of concurrent use of traditional medicine and biomedicine was 33.2 % (11.4-65.6 %). Symptomatic ailments (66.7 %; 95 % CI 17.3-54.3), malaria/febrile illnesses (64.0 %; 95 % CI 44.1-79.9), and chronic diseases (49.6 %; 95 % CI 28.6-70.6) were the most prevalent uses for traditional medicines. We identified five plant-based traditional medicines used for the treatment of kidney disease: Aloe vera, Commifora africana, Cymbopogon citrullus, Persea americana, and Zanthoxylum chalybeum. CONCLUSIONS: The prevalence of traditional medicine use is high among adults with and at risk for CKD in northern Tanzania where they use them for a variety of conditions including other NCDs. Additionally, many of these same people access biomedicine and traditional medicines concurrently. The traditional medicines used for the local treatment of kidney disease have a variety of activities, and people with CKD may be particularly vulnerable to adverse effects. Recognizing these traditional medicine practices will be important in shaping CKD treatment programs and public health policies aimed at addressing CKD. PMID- 26499071 TI - Bisnaphthalimidopropyl diaminodicyclohexylmethane induces DNA damage and repair instability in triple negative breast cancer cells via p21 expression. AB - Bisnaphthalimidopropyl diaminodicyclohexylmethane (BNIPDaCHM) bisintercalates to DNA and is a potential anti-cancer therapeutic. In an attempt to elucidate the mechanism(s) underlying the potential of BNIPDaCHM; earlier work was extended to investigate its effect on DNA damage and repair as well as cell cycle modulation, in a triple negative breast cancer (TNBC) cell line in vitro. BNIPDaCHM significantly decreased cell viability in a concentration (>= 5 MUM) and time (>= 24 h) dependent manner. The mechanism of this growth inhibition involved alterations to cell cycle progression, an increase in the sub-G1 population and changes to plasma membrane integrity/permeability observed by flow cytometry and fluorescence microscopy with acridine orange/ethidium bromide staining. Using single cell gel electrophoresis (Comet assay) and fluorescence microscopy to detect gamma-H2AX-foci expression; it was found that after 4 h, >= 0.1 MUM BNIPDaCHM treatment-induced significant DNA double strand breaks (DSBs). Moreover, exposure to a non-genotoxic concentration of BNIPDaCHM induced a significant decrease in the repair of oxidative DNA strand breaks induced by hydrogen peroxide. Also, BNIPDaCHM-treatment induced a significant time dependent increase in p21(Waf/Cip1) mRNA expression but, did not alter p53 mRNA expression. In conclusion, BNIPDaCHM treatment in MDA-MB-231 cells was associated with a significant induction of DNA DSBs and inhibition of DNA repair at non-genotoxic concentrations via p53-independent expression of p21(Waf1/Cip1). The latter may be a consequence of novel interactions between BNIPDaCHM and MDA-MB-231 cells which adds to the spectrum of therapeutically relevant activities that may be exploited in the future design and development of naphthalimide-based therapeutics. PMID- 26499072 TI - S100A4 upregulation suppresses tissue ossification and enhances matrix degradation in experimental periodontitis models. AB - AIM: S100A4, also known as fibroblast-specific protein 1 or metastasin 1, is not only highly expressed in growth-stimulated cultured cells and metastatic tumor cells, but also in the periodontal ligament. The aim of this study was to investigate the roles of S100A4 in the pathogenesis of periodontitis and its regulatory mechanisms in inflammatory milieu. METHODS: Experimental periodontitis was induced in rats by submarginal silk ligatures. TRAP activity and S100A4 expression in periodontal ligaments were examined using immunohistochemistry and immunofluorescence methods. IL-1beta-treated human periodontal ligament cells (hPDLCs) were used as in vitro model of experimental periodontitis. S100A4 mRNA and protein were assessed using qRT-PCR and Western blot, respectively. hPDLCs were transfected with either S100A4 overexpression plasmids or shRNAs plasmids. The mineralization in hPDLCs was evaluated with a 12-d osteogenic induction assay, and the expression of ALP, OCN, MMP-2 and MMP-13 was analyzed by qRT-PCR. RESULTS: In the periodontal ligaments of rats with experimental periodontitis, TRAP activity and S100A4 protein staining were considerably more intense compared with those in the control rats. Treatment of hPDLCs with IL-1beta (10, 50 and 100 ng/mL) dose-dependently increased the mRNA and protein levels of S100A4. Transfection with shRNAs markedly increased mineralized nodule formation and the osteogenic-related markers ALP and OCN levels in hPDLCs, whereas the overexpression of S100A4 significantly reduced mineralized nodule formation, and increased the matrix degradation enzymes MMP-2 and MMP-13 levels in hPDLCs. CONCLUSION: S100A4 is upregulated in the experimental rat periodontitis and in IL 1beta-treated hPDLCs, where S100A4 suppresses osteogenic differentiation and enhances matrix degradation. Thus, S100A4 is a potential target for the treatment of periodontitis. PMID- 26499073 TI - Increased levels of adenosine and ecto 5'-nucleotidase (CD73) activity precede renal alterations in experimental diabetic rats. AB - The pathogenesis of diabetic nephropathy (DN) has not been clearly established, making diagnosis and patient management difficult. Recent studies using experimental diabetic models have implicated adenosine signaling with renal cells dysfunction. Therefore, the study of the biochemical mechanisms that regulate extracellular adenosine availability during DN is of emerging interest. Using streptozotocin-induced diabetic rats we demonstrated that urinary levels of adenosine were early increased. Further analyses showed an increased expression of the ecto 5'-nucleotidase (CD73), which hydrolyzes AMP to adenosine, at the renal proximal tubules and a higher enzymatic activity in tubule extracts. These changes precede the signs of diabetic kidney injury recognized by significant proteinuria, morphological alterations and the presence of the renal fibrosis markers alpha smooth muscle actin and fibronectin, collagen deposits and thickening of the glomerular basement membrane. In the proximal tubule cell line HK2 we identified TGF-beta as a key modulator of CD73 activity. Importantly, the increased activity of CD73 could be screened in urinary sediments from diabetic rats. In conclusion, the increase of CD73 activity is a key component in the production of high levels of adenosine and emerges as a new tool for the early diagnosis of tubular injury in diabetic kidney disease. PMID- 26499074 TI - Transduction of Oct6 or Oct9 gene concomitant with Myc family gene induced osteoblast-like phenotypic conversion in normal human fibroblasts. AB - INTRODUCTION: Osteoblasts play essential roles in bone formation and regeneration, while they have low proliferation potential. Recently we established a procedure to directly convert human fibroblasts into osteoblasts (dOBs). Transduction of Runx2 (R), Osterix (X), Oct3/4 (O) and L-myc (L) genes followed by culturing under osteogenic conditions induced normal human fibroblasts to express osteoblast-specific genes and produce calcified bone matrix both in vitro and in vivo Intriguingly, a combination of only two factors, Oct3/4 and L-myc, significantly induced osteoblast-like phenotype in fibroblasts, but the mechanisms underlying the direct conversion remains to be unveiled. MATERIALS AND METHODS: We examined which Oct family genes and Myc family genes are capable of inducing osteoblast-like phenotypic conversion. RESULTS: As result Oct3/4, Oct6 and Oct9, among other Oct family members, had the capability, while N-myc was the most effective Myc family gene. The Oct9 plus N-myc was the best combination to induce direct conversion of human fibroblasts into osteoblast-like cells. DISCUSSION: The present findings may greatly contribute to the elucidation of the roles of the Oct and Myc proteins in osteoblast direct reprogramming. The results may also lead to establishment of novel regenerative therapy for various bone resorption diseases. PMID- 26499075 TI - Fisetin induces Sirt1 expression while inhibiting early adipogenesis in 3T3-L1 cells. AB - Fisetin (3,7,3',4'-tetrahydroxyflavone) is a naturally found flavonol in many fruits and vegetables and is known to have anti-aging, anti-cancer and anti-viral effects. However, the effects of fisetin on early adipocyte differentiation and the epigenetic regulator controlling adipogenic transcription factors remain unclear. Here, we show that fisetin inhibits lipid accumulation and suppresses the expression of PPARgamma in 3T3-L1 cells. Fisetin suppressed early stages of preadipocyte differentiation, and induced expression of Sirt1. Depletion of Sirt1 abolished the inhibitory effects of fisetin on intracellular lipid accumulation and on PPARgamma expression. Mechanistically, fisetin facilitated Sirt1-mediated deacetylation of PPARgamma and FoxO1, and enhanced the association of Sirt1 with the PPARgamma promoter, leading to suppression of PPARgamma transcriptional activity, thereby repressing adipogenesis. Lowering Sirt1 levels reversed the effects of fisetin on deacetylation of PPARgamma and increased PPARgamma transactivation. Collectively, our results suggest the effects of fisetin in increasing Sirt1 expression and in epigenetic control of early adipogenesis. PMID- 26499076 TI - O-Linked N-acetylglucosaminylation of Sp1 interferes with Sp1 activation of glycolytic genes. AB - Glycolysis, the primary pathway metabolizing glucose for energy production, is connected to the hexosamine biosynthetic pathway (HBP) which produces UDP-N acetylglucosamine (UDP-GlcNAc), a GlcNAc donor for O-linked GlcNAc modification (O-GlcNAc), as well as for traditional elongated glycosylation. Thus, glycolysis and O-GlcNAc are intimately associated. The present study reports the transcriptional activation of glycolytic genes by the transcription factor Sp1 and the O-GlcNAc-mediated suppression of Sp1-dependent activation of glycolytic genes. O-GlcNAc-deficient mutant Sp1 stimulated the transcription of nine glycolytic genes and cellular production of pyruvate, the final product of glycolysis, to a greater extent than wild-type Sp1. Consistently, this mutant Sp1 increased the protein levels of the two key glycolytic enzymes, phosphofructokinase (PFK) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), to a greater extent than wild-type Sp1. Finally, the mutant Sp1 occupied GC-rich elements on PFK and GAPDH promoters more efficiently than wild-type Sp1. These results suggest that O-GlcNAcylation of Sp1 suppresses Sp1-mediated activation of glycolytic gene transcription. PMID- 26499077 TI - Decreased RECQL5 correlated with disease progression of osteosarcoma. AB - Human RecQ helicase family, consisting of RECQL, RECQL4, RECQL5, BLM and WRN, has critical roles in genetic stability and tumorigenesis. Although RECQL5 has been reported to correlate with the susceptibility to malignances including osteosarcoma, the specific effect on tumor genesis and progression is not yet clarified. Here we focused on the relationship between RECQL5 expression and osteosarcoma disease progression, and further investigated the function of RECQL5 on MG-63 cell proliferation and apoptosis. By immunohistochemical analysis, qRT PCR and western blot, we found that RECQL5 expression was downregulated in osteosarcoma tissues and cells. Patients with advanced tumor stage and low grade expressed lower RECQL5. To construct a stable RECQL5 overexpression osteosarcoma cell line (MG-63-RECQL5), RECQL5 gene was inserted into the human AAVS1 safe harbor by CRISPR/Cas9 system. The overexpression of RECQL5 was verified by qRT PCR and western blot. Cell proliferation, cell cycle and apoptosis assay revealed that RECQL5 overexpression inhibited proliferation, induced G1-phase arrest and promoted apoptosis in MG-63 cells. Collectively, our results suggested RECQL5 as a tumor suppressor in osteosarcoma and may be a potential therapeutic target for osteosarcoma treatment. PMID- 26499078 TI - Macrophage-derived microvesicles promote proliferation and migration of Schwann cell on peripheral nerve repair. AB - BACKGROUND: Macrophages have been implicated in peripheral nerve regeneration. However, whether macrophages-derived microvesicles (MVs) are involved in this process remains unknown. In the present study, the effects of macrophages-derived MVs on proliferation and migration of Schwann cells (SCs) were evaluated in both in vitro and in vivo. METHODS: Human monocytic leukaemia cell line (THP-1) was successfully driven to M1 and M2 phenotypes by delivery of either IFN-gamma or IL 4, respectively. SCs incubated with M1 or M2 macrophages-derived MVs, the cell migration and proliferation were assessed, and expression levels of nerve growth factor (NGF) and Laminin were measured. A rat model of sciatic nerve was established and the effects of macrophages-derived MVs on nerve regeneration were investigated. RESULTS: M2-derived MVs elevated migration, proliferation, NFG and Laminin protein levels of SCs compared with M1-or M0-derived MVs. The relative expression levels of miR-223 were also increased in M2 macrophages and M2-derived MVs. Transfected M2 macrophages with miR-223 inhibitor then co-incubated with SCs, an inhibition of cell migration and proliferation and a down-regulated levels of NFG and Laminin protein expression were observed. In vivo, M2-derived MVs significantly increased the infiltration and axon number of SCs. CONCLUSION: M2-derived MVs promoted proliferation and migration of SCs in vitro and in vivo, which provided a therapeutic strategy for nerve regeneration. PMID- 26499079 TI - SENP1 inhibits the IH-induced apoptosis and nitric oxide production in BV2 microglial cells. AB - To reveal SUMOylation and the roles of Sentrin-specific proteases (SENP)s in microglial cells under Intermittent hypoxia (IH) condition would provide more intensive view of understanding the mechanisms of IH-induced central nervous system (CNS) damage. Hence, in the present study, we detected the expression levels of SENPs in microglial cells under IH and normoxia conditions via RT-PCR assay. We found that SENP1 was significantly down-regulated in cells exposure to IH. Subsequently, the effect of IH for the activation of microglia and the potential roles of SENP1 in the SENP1-overexpressing cell lines were investigated via Western blotting, RT-PCR and Griess assay. The present study demonstrated the apoptosis-inducing and activating role of IH on microglia. In addition, we revealed that the effect of IH on BV-2 including apoptosis, nitric oxide synthase (iNOS) expression and nitric oxide (NO) induction can be attenuated by SENP1 overexpression. The results of the present study are of both theoretical and therapeutic significance to explore the potential roles of SENP1 under IH condition and elucidated the mechanisms underlying microglial survival and activation. PMID- 26499081 TI - Quality of life in patients with calluses. PMID- 26499080 TI - Ezh2 is involved in radial neuronal migration through regulating Reelin expression in cerebral cortex. AB - Radial migration of pyramidal neurons is an important event during the development of cerebral cortex. Neurons experience series of morphological and directional transitions to get to their final laminar positions. Here we report that the histone methyltransferase enhancer of zest homolog 2 (Ezh2) is involved in the regulation of cortical radial migration. We show that Ezh2 knockdown leads to disturbed neuronal orientation, which results in the impairment of radial migration. Further results reveal that this migration deficiency may be due to the derepression of Reelin transcription in the migrating neurons. Our study provides evidence that epigenetic regulation of Reelin by Ezh2 maintains appropriate Reelin expression pattern to fulfill proper orientation of migrating neurons. PMID- 26499082 TI - Complement Component 3 Is Associated with Metabolic Comorbidities in Older HIV Positive Adults. AB - Our objective was to evaluate the association of plasma inflammatory biomarkers with MetS in an older population of treated HIV-infected (HIV(+)) as compared to age-matched HIV-negative (HIV(-)) adults. This was done in a retrospective observational study. Plasma concentrations of complement component 3 (C3), cystatin C, fibroblast growth factor 1, interleukin 6, oxidized LDL, soluble RAGE, soluble CD163, soluble CD14, and osteopontin were measured in 79 HIV(+) participants on combination antiretroviral treatment (cART) with a suppressed HIV viral load and 47 HIV(-) participants with a median age of 59 (range 50 to 79). Outcomes were individual MetS components (hypertension, type II diabetes, dyslipidemia, and obesity) and MetS. Covariates were screened for inclusion in multivariable models. Odds ratios are reported per 50 mg/dl increase in C3. In the HIV(+) group, higher C3 levels were associated with MetS (OR 3.19, p = 0.004), obesity (OR 2.02, p = 0.01), type II diabetes (OR 1.93, p = 0.02), and at a trend level with dyslipidemia (OR 1.87, p = 0.07) and hypertension (OR 1.66, p = 0.09). C3 levels were significantly higher in HIV(+) participants with MetS compared to those without MetS (p = 0.002). C3 was higher among HIV(+) patients with three or four MetS components as compared to those with one or two (p = 0.04) and those with none (p = 0.002). No associations were found between C3 and the outcomes for HIV(-) participants. C3 is strongly associated with both MetS and MetS components in an older HIV(+) sample on cART compared to HIV(-) controls. C3 warrants further investigation as a marker of cardiometabolic risk among persons aging with HIV. PMID- 26499083 TI - The role of the opioid system in binge eating disorder. AB - Binge eating disorder is characterized by excessive, uncontrollable consumption of palatable food within brief periods of time. Excessive intake of palatable food is thought to be driven by hedonic, rather than energy homeostatic, mechanisms. However, reward processing does not only comprise consummatory actions; a key component is represented by the anticipatory phase directed at procuring the reward. This phase is highly influenced by environmental food associated stimuli, which can robustly enhance the desire to eat even in the absence of physiological needs. The opioid system (endogenous peptides and their receptors) has been strongly linked to the rewarding aspects of palatable food intake, and perhaps represents the key system involved in hedonic overeating. Here we review evidence suggesting that the opioid system can also be regarded as one of the systems that regulates the anticipatory incentive processes preceding binge eating hedonic episodes. PMID- 26499084 TI - Structural analysis of a Dioclea sclerocarpa lectin: Study on the vasorelaxant properties of Dioclea lectins. AB - Lectins are proteins that show a variety of biological activities. However, they share in common at least one domain capable of recognizing specific carbohydrates reversibly without changing its structure. The legume lectins family is the most studied family of plant lectins, in particular the Diocleinae subtribe, which possesses high degree of structural similarity, but variable biological activities. This variability lies in small differences that can be analyzed in studies based on structures. In particular, Dioclea sclerocarpa seed lectin (DSL) presents low ability to relax endothelialized rat aorta in comparison with other Dioclea lectins such as Dioclea violacea (DVL), Dioclea virgata (DvirL) and Dioclea rostrata (DRL). The DSL relaxation mechanism relies on nitric oxide production and carbohydrate recognition domain (CRD). This feature can be explained by structural differences, since DSL has a carbohydrate recognition domain design less favorable. In addition, the presence of a glutamate residue at position 205 proved to be a decisive factor for the low relaxant effect of Dioclea lectins. PMID- 26499085 TI - Bioengineered quantum dot/chitosan-tripeptide nanoconjugates for targeting the receptors of cancer cells. AB - Nanobiomaterials can be engineered to recognize cancer-specific receptors at the cellular level for diagnostic and therapeutic purposes. In this work, we report the synthesis of novel multifunctional nanoconjugates composed of fluorescent inorganic semiconductor quantum dot (QD) cores and tripeptide-modified polysaccharide organic shells. These structures were designed for targeting and imaging the alphavbeta3 integrin receptors of cancer cells. Initially, chitosan was covalently bound with the RGD peptide using a crosslinker to form bioconjugates (RGD-chitosan), which were later utilized as capping ligands for the production of surface-functionalized CdS QDs via a single-step process in aqueous media at room temperature. These core-shell nanostructures were extensively characterized by UV-vis spectroscopy, photoluminescence (PL) spectroscopy, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), zeta potential (ZP) and dynamic light scattering (DLS). The TEM images and the UV-vis absorption results indicated the formation of ultra-small CdS QD nanocrystals with average diameters between 2.0 and 3.0 nm. In addition, the PL results demonstrated that the nanobioconjugates exhibited intense green fluorescence under excitation. The CdS-RGD-chitosan systems were effective at specific targeting integrin when assayed in vitro using two model cell cultures, HEK 293 (non-cancerous human embryonic kidney cell) and SAOS (cancerous sarcoma osteogenic-derived cells) imaged using fluorescence microscopy. PMID- 26499086 TI - Evaluation of antioxidants in protein formulation against oxidative stress using various biophysical methods. AB - To evaluate the biophysical stability of protein against oxidative stress, hydrogen peroxide (H2O2) was used to induce non-site-specific protein oxidation. Various biophysical methods were utilized including RP-HPLC, DSC, DLS, and CD. Lysozyme was chosen as a model protein and three different antioxidants (ascorbic acid, N-acetyl-l-cysteine, and l-methionine) were selected to observe their effect. Significant increase in hydrodynamic size, decrease in alpha-helix propensity, and increase in beta-sheet content evident with increasing H2O2 concentration and temperature suggested methionine residues as the most probable site of oxidation. Among the three anti-oxidants, methionine proved superior in suppressing protein oxidation with its increasing concentration. Methionine reacted with H2O2 to form methionine sulfoxide, which aided in decreasing the oxidant concentration to react with the protein. The hydrodynamic size of methionine containing protein was retained when incubated at 40 degrees C after 14 days with unchanged transition temperature (Tm). In contrast, RP-HPLC revealed oxidation alterations when the same samples were stored at 40 degrees C, highlighting the significant impact of temperature on kinetics. N-acetyl-l cysteine and ascorbic acid were relatively less protective. Their hydrodynamic size was increased with decreasing Tm compared to the reference. In summary, methionine was a superior antioxidant, implicating a promising component in the protein formulation for suppressing oxidation. PMID- 26499087 TI - Crystal structure and biochemical characterization of a 3-ketoacyl-CoA thiolase from Ralstoniaeutropha H16. AB - The protein ReH16_B0759 from Ralstoniaeutropha is a 3-ketoacyl-coenzyme A (CoA) thiolase that catalyzes the fourth step of the beta-oxidation degradative pathways by converting 3-ketoacyl-CoAto acyl-CoA. The crystal structures of ReH16_B0759 in its apo form and as a complex with its CoA substrate have been determined. Although ReH16_B0759 exhibited an overall structure similar to the ReH16_A1887 isozyme, the proteindoes not make a complex for beta-oxidation. Similar to other degradative thiolases, ReH16_B0759 functions as a dimer, and the monomer comprises three subdomains. Unlike ReH16_A1887, a substantial structural change was not observed upon the binding of the CoA substrate in ReH16_B0759. Exceptionally, the Arg220 residue moved about 5.00A to make room for the binding of the adenosine ring. Several charged residues including Arg220 are involved in the stabilization of CoA through hydrogen bond interactions. At the active site of ReH16_B0759, highly conserved residues such as Cys89, His347, and Cys377 were located near the thiol-group of CoA, suggesting that ReH16_B0759 may catalyze the thiolase reaction in a manner similar to that of other degradative thiolases. The residues involved in substrate binding and enzyme catalysis were further confirmed by site-directed mutagenesis. PMID- 26499088 TI - Optimization of extraction, characterization and antioxidant activity of polysaccharides from Brassica rapa L. AB - The root of Brassica rapa L. has been traditionally used as a Uyghur folk medicine to cure cough and asthma by Uyghur nationality in Xinjiang Uygur Autonomous Region of China. In the present study, therefore, extraction optimization, characterization and antioxidant activity in vitro of polysaccharides from the root of B. rapa L. (BRP) were investigated. The optimal extraction conditions with an extraction yield of 21.48 +/- 0.41% for crude BRP were obtained as follows: extraction temperature 93 degrees C, extraction time 4.3h and ratio of extraction solvent (water) to raw material 75 mL/g. The crude BRP was purified by chromatographic columns of DEAE-52 cellulose and Sephadex G 100, affording three purified fractions of BRP-1-1, BRP-2-1 and BRP-2-2 with average molecular weight of 1510, 1110 and 838 kDa, respectively. Monosaccharide composition analysis indicated that BRP-1-1 was composed of mannose, rhamnose, glucose, galactose and arabinose, BRP-2-1 was composed of rhamnose, galacturonic acid, galactose and arabinose, and BRP-2-2 was composed of rhamnose and galacturonic acid in a molar ratio of 1.27: 54.92. Furthermore, the crude BRP exhibited relatively higher antioxidant activity in vitro than purified fractions; hence, it could be used as a natural antioxidant in functional foods or medicines. PMID- 26499089 TI - The N-terminal pre-A region of Mycobacterium tuberculosis 2/2HbN promotes NO dioxygenase activity. AB - A unique defense mechanisms by which Mycobacterium tuberculosis protects itself from nitrosative stress is based on the O2 -dependent NO-dioxygenase (NOD) activity of truncated hemoglobin 2/2HbN (Mt2/2HbN). The NOD activity largely depends on the efficiency of ligand migration to the heme cavity through a two tunnel (long and short) system; recently, it was also correlated with the presence at the Mt2/2HbN N-terminus of a short pre-A region, not conserved in most 2/2HbNs, whose deletion results in a drastic reduction of NO scavenging. In the present study, we report the crystal structure of Mt2/2HbN-DeltapreA, lacking the pre-A region, at a resolution of 1.53 A. We show that removal of the pre-A region results in long range effects on the protein C-terminus, promoting the assembly of a stable dimer, both in the crystals and in solution. In the Mt2/2HbN DeltapreA dimer, access of heme ligands to the short tunnel is hindered. Molecular dynamics simulations show that the long tunnel branch is the only accessible pathway for O2 -ligand migration to/from the heme, and that the gating residue Phe(62)E15 partly restricts the diameter of the tunnel. Accordingly, kinetic measurements indicate that the kon value for peroxynitrite isomerization by Mt2/2HbN-DeltapreA-Fe(III) is four-fold lower relative to the full-length protein, and that NO scavenging by Mt2/2HbN-DeltapreA-Fe(II)-O2 is reduced by 35 fold. Therefore, we speculate that Mt2/2HbN evolved to host the pre-A region as a mechanism for preventing dimerization, thus reinforcing the survival of the microorganism against the reactive nitrosative stress in macrophages. DATABASE: Coordinates and structure factors have been deposited in the Protein Data Bank under accession number 5AB8. PMID- 26499090 TI - Familial aggregation of stroke amongst young patients in Lund Stroke Register. AB - BACKGROUND AND PURPOSE: The known monogenic forms of stroke are rare. The aim of this study was to analyze pedigrees of young stroke patients regarding possible monogenic cerebrovascular disease and to evaluate the possibility of genetic stroke in these families. This may contribute to a better understanding of disease mechanism in stroke. METHODS: Lund Stroke Register includes consecutive patients with first-ever stroke from a defined geographical area in southern Sweden. Early-onset (<=55 years) stroke patients were systematically screened with regard to family history (FHx), and families with stroke aggregation were compiled. Participants provided information in a questionnaire on occurrence of stroke or transient ischaemic attack (TIA) in their families. Information on cardiovascular risk factors (VRFs) and clinical stroke subtype was collected. FHx for stroke was considered positive when the patient reported either >=1 first degree relative with stroke/TIA, or no first-degree relative but >=3 second- or third-degree relatives with stroke/TIA in a distribution compatible with monogenic inheritance. RESULTS: Of 4103 stroke patients registered, 426 (10%) had first-ever stroke at <=55 years and 338 (79%) of these answered the questionnaire. Of them, 159 (47%) reported a positive FHx. Twenty-eight (18%) of the probands with positive FHx had no known VRFs. Thirty-two families with >=4 members with stroke were identified. In all these larger families the affected individuals with stroke were present in more than one generation. CONCLUSION: Aggregation of stroke in families of early-onset stroke patients is not uncommon. Genetic factors with impact on stroke risk, including monogenic causes, need to be evaluated in future stroke studies. PMID- 26499091 TI - ToRCH "co-infections" are associated with increased risk of abortion in pregnant women. AB - ToRCH infections (toxoplasmosis, rubella, cytomegalovirus and Herpes simplex virus) have long been known to be associated with bad obstetric outcomes. However, little information is available about the impact of ToRCH co-infections on the outcome of pregnancy. Hence, we tested the IgG and IgM antibodies to Toxoplasma gondii, Rubella, Cytomegalovirus and Herpes Simplex Virus among 81 pregnant women with abortion (case group) and 98 pregnant women with normal delivery (control group). In the single-infection model, only CMV-IgM seropositivity was significantly increased in case than control group (25.9% in case and 12.2 % in control, OR = 2.5, P = 0.019). In the co-infection model, 14 patterns were recognized, but two patterns were significantly increased in the case than the control group. Co-infection of T. gondii IgG + CMV IgM was 9.1-fold increased in the case than the control group (8.6% in the case and 1% in control, OR = 9.1; P = 0.024). Also, co-infection of T. gondii IgG + HSV IgG + CMV IgM was 7.7-fold increased in case than the control group (7.4% in case and 1 % in control, OR = 7.7; P = 0.04). Although the OR of other co-infections was higher in the case than the control group, the difference was not statistically significant. These findings indicate that ToRCH co-infections are associated with increased risk of abortion than single infection. Hence, the rates of co infections should be considered in prenatal screening of ToRCH infections. PMID- 26499092 TI - The effect of protein restriction during the growing period on carcass, meat and fat quality of heavy barrows and gilts. AB - Nutritional strategies are being researched in pigs to increase fatness and then to improve quality of dry-cured products. A total of 160 Duroc*(Landrace*Large White) pigs, 50% barrows and 50% gilts, were used in a trial. During the growing period (73-118d of age), four feeds were formulated with decreasing levels of crude protein (CP; 21.6, 17.7, 14.7 and 13.5%) to achieve 1.10, 0.91, 0.78 and 0.52% of total Lysine, respectively. From 118d until slaughter, at 123kg (183, 181, 178 or 192d of age, respectively), a common diet was provided (17.7% CP and 0.91% Lysine). Barrows had fatter carcasses than gilts but intramuscular fat (IMF) proportion was similar for both. Dietary CP restriction promoted wider backfat depth and pork with higher IMF percentage which was more monounsaturated and less polyunsaturated. We conclude that CP restriction during the grower period improves desirable carcass and meat traits in barrows and gilts intended for dry-cured products. PMID- 26499093 TI - Ex vivo proteomics of Campylobacter jejuni 81-176 reveal that FabG affects fatty acid composition to alter bacterial growth fitness in the chicken gut. AB - Campylobacter jejuni is one of the leading causes of foodborne gastrointestinal illness worldwide. Here we performed ex vivo proteomic analysis of C. jejuni 81 176 in chicken, a main reservoir for human infection. At 0, 1 and 4 weeks post infection (p.i.) with the GFP-expressing 81-176 strain, inocula were recovered from chicken ceca by cell sorting using flow cytometry. iTRAQ-coupled 2D-LC-MS/MS analyses that detected 55 C. jejuni proteins, among which either 3 (FabG, HydB, CJJ81176_0876) or 7 (MscS, CetB, FlhF, PurH, PglJ, LpxC, Icd) proteins exhibited >1.4-fold-increased expression at 1 or 4 week(s) p.i. compared with those at 0 weeks p.i., respectively. Deletion of the fabG gene clearly decreased the proportion of bacterial unsaturated fatty acids (UFAs) and chicken colonization. The UFA proportion of the parental strain was not altered when grown at 42 degrees C. These findings suggest that FabG might play a pivotal role in UFA production, linked to bacterial adaptation in the poultry host. To our knowledge, this is the first example of ex vivo C. jejuni proteomics, in which fatty acid metabolism might affect bacterial adaptation to the chicken host. PMID- 26499094 TI - Diet drives quick changes in the metabolic activity and composition of human gut microbiota in a validated in vitro gut model. AB - The aim of this study was to screen how rapidly the human gut microbiota responds to diet in an in vitro model of the proximal colon (TIM-2 system). Two experimental diets were provided to the gut bacteria: a high carbohydrate and a high protein diet. The metabolic response and the composition of the microbiota were compared to a control diet simulating an average western meal. Short-chain and branched-chain fatty acids (SCFA and BCFA, respectively) production, in addition to changes in the community composition (profiling), were measured. The activity of the microbiota reflected differences between diets, exhibiting a trade-off between saccharolytic and proteolytic fermentation when compared to the control. Diversity analysis revealed a phylum-specific response depending on the diet tested. Most changes in the microbiome composition occurred during the first 24 h of the experiment. The outcome of this study elucidates the fact that human gut bacteria quickly respond to changes in diet. In addition, it confirms that variations in the concentration of carbohydrates and proteins modify the activity and composition of the microbiota, and these changes can potentially have an impact on the health of the host. PMID- 26499095 TI - A discrete role for FNR in the transcriptional response to moderate changes in oxygen by Haemophilus influenzae Rd KW20. AB - The survival by pathogenic bacteria within the specific conditions of an anatomical niche is critical for their persistence. These conditions include the combination of toxic chemicals, such as reactive oxygen (ROS) and reactive nitrogen species (RNS), with factors relevant to cell growth, such as oxygen. Haemophilus influenzae senses oxygen levels largely through the redox state of the intracellular fumarate-nitrate global regulator (FNR). H. influenzae certainly encounters oxygen levels that fluctuate, but in reality, these would rarely reach a state that results in FNR being fully reduced or oxidized. We were therefore interested in the response of H. influenzae to ROS and RNS at moderately high or low oxygen levels and the corresponding role of FNR. At these levels of oxygen, even though the growth rate of an H. influenzae fnr mutant was similar to wild type, its ROS and RNS tolerance was significantly different. Additionally, the subtle changes in oxygen did alter the whole cell transcriptional profile and this was different between the wild type and fnr mutant strains. It was the changed whole cell profile that impacted on ROS/RNS defence, but surprisingly, the FNR-regulated, anaerobic nitrite reductase (NrfA) continued to be expressed and had a role in this phenotype. PMID- 26499097 TI - Edge-Hydroxylated Boron Nitride Nanosheets as an Effective Additive to Improve the Thermal Response of Hydrogels. AB - Upon flowing hot steam over hexagonal boron nitride (h-BN) bulk powder, efficient exfoliation and hydroxylation of BN occur simultaneously. Through effective hydrogen bonding with water and N-isopropylacrylamide, edge-hydroxylated BN nanosheets dramatically improve the dimensional change and dye release of this temperature-sensitive hydrogel and thereby enhance its efficacy in bionic, soft robotic, and drug-delivery applications. PMID- 26499096 TI - Pharmacological induction of ferritin prevents osteoblastic transformation of smooth muscle cells. AB - Vascular calcification is a frequent complication of atherosclerosis, diabetes and chronic kidney disease. In the latter group of patients, calcification is commonly seen in tunica media where smooth muscle cells (SMC) undergo osteoblastic transformation. Risk factors such as elevated phosphorus levels and vitamin D3 analogues have been identified. In the light of earlier observations by our group and others, we sought to inhibit SMC calcification via induction of ferritin. Human aortic SMC were cultured using beta-glycerophosphate with activated vitamin D3 , or inorganic phosphate with calcium, and induction of alkaline phosphatase (ALP) and osteocalcin as well as accumulation of calcium were used to monitor osteoblastic transformation. In addition, to examine the role of vitamin D3 analogues, plasma samples from patients on haemodialysis who had received calcitriol or paricalcitol were tested for their tendency to induce calcification of SMC. Addition of exogenous ferritin mitigates the transformation of SMC into osteoblast-like cells. Importantly, pharmacological induction of heavy chain ferritin by 3H-1,2-Dithiole-3-thione was able to inhibit the SMC transition into osteoblast-like cells and calcification of extracellular matrix. Plasma samples collected from patients after the administration of activated vitamin D3 caused significantly increased ALP activity in SMC compared to the samples drawn prior to activated vitamin D3 and here, again induction of ferritin diminished the osteoblastic transformation. Our data suggests that pharmacological induction of ferritin prevents osteoblastic transformation of SMC. Hence, utilization of such agents that will cause enhanced ferritin synthesis may have important clinical applications in prevention of vascular calcification. PMID- 26499098 TI - Comparative Effects of Diet-Induced Lipid Lowering Versus Lipid Lowering Along With Apo A-I Milano Gene Therapy on Regression of Atherosclerosis. AB - Apolipoprotein A-1 (Apo A-I) Milano, a naturally occurring Arg173to Cys mutant of Apo A-1, has been shown to reduce atherosclerosis in animal models and in a small phase 2 human trial. We have shown the superior atheroprotective effects of Apo A I Milano (Apo A-IM) gene compared to wild-type Apo A-I gene using transplantation of retrovirally transduced bone marrow in Apo A-I/Apo E null mice. In this study, we compared the effect of dietary lipid lowering versus lipid lowering plus Apo A IM gene transfer using recombinant adeno-associated virus (rAAV) 8 as vectors on atherosclerosis regression in Apo A-I/Apo E null mice. All mice were fed a high cholesterol diet from age of 6 weeks until week 20, and at 20 weeks, 10 mice were euthanized to determine the extent of atherosclerosis. After 20 weeks, an additional 20 mice were placed on either a low-cholesterol diet plus empty rAAV (n = 10) to serve as controls or low-cholesterol diet plus 1 single intravenous injection of 1.2 * 10(12)vector genomes of adeno-associated virus (AAV) 8 vectors expressing Apo A-IM (n = 10). At the 40 week time point, intravenous AAV8 Apo A IM recipients showed a significant regression of atherosclerosis in the whole aorta (P< .01), aortic sinuses (P< .05), and brachiocephalic arteries (P< .05) compared to 20-week-old mice, whereas low-cholesterol diet plus empty vector control group showed no significant regression in lesion size. Immunostaining showed that compared to the 20-week-old mice, there was a significantly reduced macrophage content in the brachiocephalic (P< .05) and aortic sinus plaques (P< .05) of AAV8 Apo A-IM recipients. These data show that although dietary-mediated cholesterol lowering halts progression of atherosclerosis, it does not induce regression, whereas combination of low-cholesterol diet and AAV8 mediated Apo A-I Milano gene therapy induces rapid and significant regression of atherosclerosis in mice. These data provide support for the potential feasibility of this approach for atherosclerosis regression. PMID- 26499099 TI - Time-trend analysis of prevalence, incidence and traditional Chinese medicine use among children with asthma: a population-based study. AB - BACKGROUND: This study determined annual prevalence and incidence trends of asthma among children in Taiwan from 2002 to 2008. Risk factors and traditional Chinese medicine (TCM) use were examined. METHODS: A random sample was selected for a population-based study with a selection probability of 0.5 from all 3-18 years insurants. The annual prevalence and incidence of asthma were estimated according to age, sex, insurance premium and degree of urbanization. RESULTS: The prevalence of asthma increased from 12.99% in 2002 to 16.86% in 2008. The increase was greatest in 2008, among boys, 11-15 years, >=medium insurance premium, and high- and medium-density urban area. TCM use in asthma-prevalent children decreased from 1.16% in 2002 to 0.59% in 2008. The incidence fluctuated, ranging from 1.01% in 2002 to 1.49% in 2005. The highest was in 2005, among boys, 3-5 years, >=medium insurance premium and high-density urban area. TCM use in asthma-incident children decreased from 3.59% in 2002 to 1.69% in 2008. CONCLUSION: This study demonstrated a substantial increase in annual prevalence of asthma among children in Taiwan from 2002 to 2008. The incidence fluctuated. The TCM use showed a decreasing linear trend and was higher in incident than in prevalent cases. PMID- 26499100 TI - Myopericytoma proliferating in an unusual anastomosing multinodular fashion. AB - We herein describe a case of myopericytoma that proliferated in an unusual fashion. Myopericytoma is described as a group of rare, benign, dermal or subcutaneous tumors that are characterized histologically by a striking, concentric, perivascular proliferation of spindle cells and showing apparent differentiation towards perivascular myoid cells. Myopericytoma forms a morphological continuum with myofibroma/myofibromatosis, glomus tumor and angioleiomyoma. The patient was a 64-year-old woman who demonstrated a recurrent ulcer on an atrophic plaque on her left shin. A histopathological examination of the plaque demonstrated that tumor cells proliferated in an anastomosing multinodular fashion along the vessels in the dermis and subcutaneous tissue. In those nodules, there were numerous, small, concentric proliferations of myoid appearing spindle cells around small vascular lumina. The present case is an unusual example of myopericytoma, manifesting in a characteristic anastomosing, multinodular, infiltrating fashion. PMID- 26499101 TI - Alert dwell time: introduction of a measure to evaluate interruptive clinical decision support alerts. AB - Metrics for evaluating interruptive prescribing alerts have many limitations. Additional methods are needed to identify opportunities to improve alerting systems and prevent alert fatigue. In this study, the authors determined whether alert dwell time-the time elapsed from when an interruptive alert is generated to when it is dismissed-could be calculated by using historical alert data from log files. Drug-drug interaction (DDI) alerts from 3 years of electronic health record data were queried. Alert dwell time was calculated for 25,965 alerts, including 777 unique DDIs. The median alert dwell time was 8 s (range, 1-4913 s). Resident physicians had longer median alert dwell times than other prescribers (P < 001). The 10 most frequent DDI alerts (n = 8759 alerts) had shorter median dwell times than alerts that only occurred once (P < 001). This metric can be used in future research to evaluate the effectiveness and efficiency of interruptive prescribing alerts. PMID- 26499102 TI - Cheminformatics-aided pharmacovigilance: application to Stevens-Johnson Syndrome. AB - OBJECTIVE: Quantitative Structure-Activity Relationship (QSAR) models can predict adverse drug reactions (ADRs), and thus provide early warnings of potential hazards. Timely identification of potential safety concerns could protect patients and aid early diagnosis of ADRs among the exposed. Our objective was to determine whether global spontaneous reporting patterns might allow chemical substructures associated with Stevens-Johnson Syndrome (SJS) to be identified and utilized for ADR prediction by QSAR models. MATERIALS AND METHODS: Using a reference set of 364 drugs having positive or negative reporting correlations with SJS in the VigiBase global repository of individual case safety reports (Uppsala Monitoring Center, Uppsala, Sweden), chemical descriptors were computed from drug molecular structures. Random Forest and Support Vector Machines methods were used to develop QSAR models, which were validated by external 5-fold cross validation. Models were employed for virtual screening of DrugBank to predict SJS actives and inactives, which were corroborated using knowledge bases like VigiBase, ChemoText, and MicroMedex (Truven Health Analytics Inc, Ann Arbor, Michigan). RESULTS: We developed QSAR models that could accurately predict if drugs were associated with SJS (area under the curve of 75%-81%). Our 10 most active and inactive predictions were substantiated by SJS reports (or lack thereof) in the literature. DISCUSSION: Interpretation of QSAR models in terms of significant chemical descriptors suggested novel SJS structural alerts. CONCLUSIONS: We have demonstrated that QSAR models can accurately identify SJS active and inactive drugs. Requiring chemical structures only, QSAR models provide effective computational means to flag potentially harmful drugs for subsequent targeted surveillance and pharmacoepidemiologic investigations. PMID- 26499103 TI - Text message reminders do not improve hepatitis B vaccination rates in an Australian sexual health setting. AB - OBJECTIVE: To evaluate the impact of text message reminders (short messaging service (SMS)) on hepatitis B virus (HBV) vaccination completion among high risk sexual health center attendees. MATERIALS AND METHODS: In September 2008, Sydney Sexual Health Centre implemented an SMS reminder system. The authors assessed the impact of the reminder system on HBV vaccination rates among patients who initiated a course. The authors used a chi-square test and multivariate logistic regression to determine if SMS reminders were associated with second and third dose vaccine completion, compared with patients prior to the intervention. RESULTS: Of patients sent SMS reminders in 2009 (SMS group), 54% (130/241) received 2 doses and 24% (58/241) received 3 doses, compared to 56% (258/463) (P = 0.65) and 30% (141/463) (P = 0.07) in the pre-SMS group (2007), respectively. Findings did not change after adjusting for baseline characteristics significantly different between study groups. There were no significant differences in completion rates among people who injected drugs, HIV-negative gay and bisexual men (GBM), and HIV-positive GBM. Among sex workers, travelers, and people who reported sex overseas, second and third dose completion rates were significantly lower in the SMS group compared to the pre-SMS group. In the SMS group, 18% of those who only had one dose attended the clinic within 1-18 months and 30% of those who had 2 doses attended in 6-18 months, but vaccination was missed. DISCUSSION: SMS reminders did not increase second or third vaccine dose completion in this population. CONCLUSION: Clinician prompts to reduce missed opportunities and multiple recall interventions may be needed to increase HBV vaccination completion in this high risk population. PMID- 26499104 TI - Provider variation in responses to warnings: do the same providers run stop signs repeatedly? AB - OBJECTIVE: Variation in the use of tests and treatments has been demonstrated to be substantial between providers and geographic regions. This study assessed variation between outpatient providers in overriding electronic prescribing warnings. METHODS: Responses to warnings were prospectively logged. Random effects models were used to calculate provider-to-provider variation in the rates for the decisions to override warnings in 6 different clinical domains: medication allergies, drug-drug interactions, duplicate drugs, renal recommendations, age-based recommendations, and formulary substitutions. RESULTS: A total of 157 482 responses were logged. Differences between 1717 providers accounted for 11% of the overall variability in override rates, so that while the average override rate was 45.2%, individual provider rates had a wide range with a 95% confidence interval (CI) (13.7%-76.7% ). The highest variations between providers were observed in the categories age-based (25.4% of total variability; average override rate 70.2% [95% CI, 29.1%-100% ]) and renal recommendations (24.2%; average 70% [95% CI, 29.5%-100% ]), and provider responses within these 2 categories were most often clinically inappropriate according to prior work. Among providers who received at least 10 age-based recommendations, 64 of 238 (27%) overrode >= 90% of the warnings and 13 of 238 (5%) overrode all of them. Of those who received at least 10 renal recommendations, 36 of 92 (39%) overrode >= 90% of the alerts and 9 of 92 (10%) overrode all of them. CONCLUSIONS: The decision to override prescribing warnings shows variation between providers, and the magnitude of variation differs among the clinical domains of the warnings; more variation was observed in areas with more inappropriate overrides. PMID- 26499105 TI - Characterization of a novel metastatic prostate cancer cell line of LNCaP origin. AB - BACKGROUND: The LNCaP cell line was originally isolated from the lymph node of a patient with metastatic prostate cancer. Many cell lines have been derived from LNCaP by selective pressures to study different aspects of prostate cancer progression. When injected subcutaneously into male athymic nude mice, LNCaP and its derivatives rarely metastasize. METHODS: Here, we describe the characteristics of a new LNCaP derivative, JHU-LNCaP-SM, which was generated by long term passage in normal cell culture conditions. RESULTS: Short tandem repeat (STR) analysis and genomic sequencing verified JHU-LNCaP-SM derivation from parental LNCaP cells. JHU-LNCaP-SM cells express the same mutated androgen receptor (AR) but unlike LNCaP, are no longer androgen dependent for growth. The cells demonstrate an attenuated androgen responsiveness in transcriptional assays and retain androgen sensitive expression of PSA, AR, and PSMA. Unlike parental LNCaP, JHU-LNCaP-SM cells quickly form subcutaneous tumors in male athymic nude mice, reliably metastasize to the lymph nodes and display a striking intra tumoral and spreading hemorrhagic phenotype as tumor xenografts. CONCLUSIONS: The JHU-LNCaP-SM cell line is a new isolate of LNCaP, which facilitates practical, preclinical studies of spontaneous metastasis of prostate cancer through lymphatic tissues. PMID- 26499106 TI - Problem drug use prevalence estimation revisited: heterogeneity in capture recapture and the role of external evidence. AB - BACKGROUND AND AIMS: Capture-recapture (CRC) analysis is recommended for estimating the prevalence of problem drug use or people who inject drugs (PWID). We aim to demonstrate how naive application of CRC can lead to highly misleading results, and to suggest how the problems might be overcome. METHODS: We present a case study of estimating the prevalence of PWID in Bristol, UK, applying CRC to lists in contact with three services. We assess: (i) sensitivity of results to different versions of the dominant (treatment) list: specifically, to inclusion of non-incident cases and of those who were referred directly from one of the other services; (ii) the impact of accounting for a novel covariate, housing instability; and (iii) consistency of CRC estimates with drug-related mortality data. We then incorporate formally the drug-related mortality data and lower bounds for prevalence alongside the CRC into a single coherent model. RESULTS: Five of 11 models fitted the full data equally well but generated widely varying prevalence estimates, from 2740 [95% confidence interval (CI) = 2670, 2840] to 6890 (95% CI = 3740, 17680). Results were highly sensitive to inclusion of non incident cases, demonstrating the presence of considerable heterogeneity, and were sensitive to a lesser extent to inclusion of direct referrals. A reduced data set including only incident cases and excluding referrals could be fitted by simpler models, and led to much greater consistency in estimates. Accounting for housing stability improved model fit considerably more than did the standard covariates of age and gender. External data provided validation of results and aided model selection, generating a final estimate of the number of PWID in Bristol in 2011 of 2770 [95% credible interval (Cr-I) = 2570, 3110] or 0.9% (95% Cr-I = 0.9, 1.0%) of the population aged 15-64 years. CONCLUSIONS: Steps can be taken to reduce bias in capture-recapture analysis, including: careful consideration of data sources, reduction of lists to less heterogeneous subsamples, use of covariates and formal incorporation of external data. PMID- 26499107 TI - SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants. AB - Niemann-Pick Types A and B (NPA/B) diseases are autosomal recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase (ASM) because of the mutations in the SMPD1 gene. Here, we provide a comprehensive updated review of already reported and newly identified SMPD1 variants. Among them, 185 have been found in NPA/B patients. Disease-causing variants are equally distributed along the SMPD1 gene; most of them are missense (65.4%) or frameshift (19%) mutations. The most frequently reported mutation worldwide is the p.R610del, clearly associated with an attenuated NP disease type B phenotype. The available information about the impact of 52 SMPD1 variants on ASM mRNA and/or enzymatic activity has been collected and whenever possible, phenotype/genotype correlations were established. In addition, we created a locus-specific database easily accessible at http://www.inpdr.org/genes that catalogs the 417 SMPD1 variants reported to date and provides data on their in silico predicted effects on ASM protein function or mRNA splicing. The information reviewed in this article, providing new insights into the genotype/phenotype correlation, is extremely valuable to facilitate diagnosis and genetic counseling of families affected by NPA/B. PMID- 26499108 TI - Osseointegrated implants placed at supracrestal level may harbour higher counts of A. gerencseriae and S. constellatus - a randomized, controlled pilot study. AB - PURPOSE: This study aimed at evaluating the bacterial colonization in dental implants inserted in the crestal or supracrestal position and correlated it to radiographic bone measurements. METHODS: Thirty-five implants with regular platform in nine patients (mean age 62.4+/-11.2 years) were inserted either at the bone crest level (control group) or at a suprecrestal level (test group). Radiographic examination was performed at baseline (implant installation) and after 6 months. Clinical and microbiological data were collected after 6 months. Digital radiography was used to assess bone remodeling (marginal bone loss and optical alveolar density). Bacterial profile was analyzed by checkerboard DNA-DNA hybridization, including a panel of 40 bacterial species. RESULTS: After 6 months, there were significantly higher counts of Actinomyces gerencseriae (p=0.009) and Streptococcus constellatus (p=0.05) in the test group. No significant differences between test and control groups were observed for marginal bone loss (p=0.725) and optical alveolar density (p=0.975). Probing depth was similar in both groups. CONCLUSION: Significantly higher counts of A. gerencseriae and S. constellatus were found in implants placed at the supracrestal level compared to the ones placed at the bone level. No relation was found between the installation level of dental implants and peri-implant bone remodeling. PMID- 26499109 TI - Induction of dissociated cytokine profiles by ISRAA with selective critical involvement of ERK1/2 in its signaling functions. AB - The immune system-released activating agent (ISRAA) is an immune mediator activated as a result of a nerve stimulus initiated by immune challenge. We have previously demonstrated that ISRAA and tumor necrosis factor (TNF) receptor 1 (TNFR1) share an interspecies-conserved motif (72% homology) that induces the apoptosis and proliferation of human peripheral blood mononuclear cells (hPBMCs) in a dose-dependent manner. In the present study, cytokine profiles were examined in response to the stimulation of hPBMCs with ISRAA. Furthermore, the signaling pathways induced by ISRAA were mapped. The results revealed high measurable levels of TNF-alpha, interleukin (IL)-6, IL-8, IL-10 and interferon (IFN)-gamma, but not IL-4, IL-17 (IL-17A) or transforming growth factor (TGF)-beta. The analysis of signaling pathways revealed the activation of extracellular-regulated protein kinase (ERK)1/2 as a downstream signal in the mitogen-activated protein kinase (MAPK) pathway during TNF-alpha and IL-6 production and apoptosis, but not during proliferation following stimulation with ISRAA by triggering the Fas associated protein with death domain (FADD). STAT3 was found to be unphosphorylated in the ISRAA-stimulated hPBMCs, and STAT3 was ubiquitously expressed in unstimulated cells, suggesting that ISRAA has a protein inhibitor of activated STAT (PIAS)-like activity, by functioning as a negative regulator of the effects of STAT3 on the Janus kinase (JAK)/STAT pathway. The determination of the nature of cytokine responses together with the signaling pathways of cellular activity induced by ISRAA paves the way for the investigation of a potential target of ISRAA and for the development of novel therapeutic approaches for the treatment of immune-regulated disorders. PMID- 26499110 TI - Transcriptome study and identification of potential marker genes related to the stable expression of recombinant proteins in CHO clones. AB - BACKGROUND: Chinese hamster ovary (CHO) cells have become the host of choice for the production of recombinant proteins, due to their capacity for correct protein folding, assembly, and posttranslational modifications. The most widely used system for recombinant proteins is the gene amplification procedure that uses the CHO-Dhfr expression system. However, CHO cells are known to have a very unstable karyotype. This is due to chromosome rearrangements that can arise from translocations and homologous recombination, especially when cells with the CHO Dhfr expression system are treated with methotrexate hydrate. The present method used in the industry for testing clones for their long-term stability of recombinant protein production is empirical, and it involves their cultivation over extended periods of time prior to the selection of the most suitable clone for further bioprocess development. The aim of the present study was the identification of marker genes that can predict stable expression of recombinant genes in particular clones early in the development stage. RESULTS: The transcriptome profiles of CHO clones with stable and unstable recombinant protein production were investigated over 10-weeks of cultivation, using a DNA microarray. We identified 14 genes that were differentially expressed between the stable and unstable clones already at 2 weeks from the beginning of the cultivation. Their expression was validated by reverse-transcription quantitative real-time PCR (RT-qPCR). Furthermore, the k-nearest neighbour algorithm approach shows that the combination of the gene expression patterns of only five of these 14 genes is sufficient to predict stable recombinant protein production in clones in the early phases of cell-line development. CONCLUSIONS: The exact molecular mechanisms that cause unstable recombinant protein production are not fully understood. However, the expression profiles of some genes in clones with stable and unstable recombinant protein production allow prediction of such instability early in the cell-line development stage. We have thus developed a proof-of concept for a novel approach to eliminate unstable clones in the CHO-Dhfr expression system, which saves time and labour-intensive work in cell-line development. PMID- 26499111 TI - A retrospective study of californium-252 neutron brachytherapy combined with EBRT versus 3D-CRT in the treatment of esophageal squamous cell cancer. AB - BACKGROUND: We conducted a retrospective analysis on 884 patients who were diagnosed with esophageal squamous cell carcinoma (ESCC) and treated with either the neutron brachytherapy in combination with external beam radiotherapy (NBT + EBRT) or 3-dimensional conformal radiation therapy (3D-CRT) to determine the differences in efficacy and morbidity between the two treatment groups. METHODS: The 884 ESCC patients treated with either NBT + EBRT or 3D-CRT between 2002 and 2012 were retrospectively reviewed and analyzed. Multivariable Cox regression was used to compare oncologic outcomes of the two groups of patients in the context of other clinically relevant variables. The acute and chronic toxicities associated with the two groups were compared using Fisher exact and log-rank tests, respectively. RESULTS: Among the 884 patients, 545 received NBT + EBRT and 339 received 3D-CRT (i.e. EBRT-only). The age range is 39-95 years (median 66). The follow-up time range is 3-145 months (median 32). The analysis shows that the NBT + EBRT group has higher overall survival rate and local control rate than that of the 3D-CRT group. The acute toxicity effects were acceptable for both groups of patients with the NBT + EBRT group showing higher rates of leukopenia and thrombocytopenia and the 3D-CRT group showing higher rates on fistula and massive bleeding. CONCLUSIONS: The patients treated with NBT + EBRT showed better oncologic outcomes than those treated with 3D-CRT. The toxicity effects were acceptable for both groups with the NBT + EBRT group showing higher rates on the acute effects and the 3D-CRT group showing higher rates on the late effects. PMID- 26499112 TI - Effect of cooled hyperbaric bupivacaine on unilateral spinal anesthesia success rate and hemodynamic complications in inguinal hernia surgery. AB - PURPOSE: We hypothesized that cooling hyperbaric bupivacaine from 23 to 5 degrees C may limit the intrathecal spread of bupivacaine and therefore increase the success rate of unilateral spinal anesthesia and decrease the rate of hemodynamic complications. METHODS: A hundred patients scheduled for elective unilateral inguinal hernia surgery were randomly allocated to receive 1.8 ml of 0.5 % hyperbaric bupivacaine intrathecally at either 5 degrees C (group I, n = 50) or at 23 degrees C (group II, n = 50). Following spinal block at the L2-3 interspace, the lateral decubitus position was maintained for 15 min. Unilateral spinal anesthesia was assessed and confirmed at 15 and 30 min. The levels of sensory and motor block on the operative side were evaluated until complete resolution. RESULTS: The rate of unilateral spinal anesthesia at 15 and 30 min was significantly higher in group I (p = 0.015 and 0.028, respectively). Hypotensive events and bradycardia were significantly rarer in group I (p = 0.014 and 0.037, respectively). The density and viscosity of the solution at 5 degrees C was significantly higher than at 23 degrees C (p < 0.0001). Compared with group II, sensory block peaked later in group I (17.4 vs 12.6 min) and at a lower level (T9 vs T7), and two-segment regression of sensory block (76.4 vs 84.3 min) and motor block recovery was shorter (157.6 vs 193.4 min) (p < 0.0001). CONCLUSIONS: Cooling of hyperbaric bupivacaine to 5 degrees C increased the density and viscosity of the solution and the success rate of unilateral spinal anesthesia, and decreased the hemodynamic complication rate. PMID- 26499113 TI - Knowledge of stroke a study from a sex perspective. AB - BACKGROUND: Public health is increasingly concerned with recognising factors that lead to sex differences in stroke. We conducted a study to determine the effect of sex on knowledge of stroke risk factors and warning signs, and how both are perceived, in a representative sample of adults. METHODS: A representative sample of the population of Extremadura, Spain was selected using a double randomisation technique. Previously trained medical students carried out face-to-face interviews using a structured questionnaire. RESULTS: 2409 subjects were interviewed [59.9 % women; mean age (SD) 49.0 (18.7) years]. Seventy-three percent of all subjects reported at least one correct warning sign of stroke (OR: 1.01; 95 % CI: 0.84-1.21). The most frequently mentioned warning signs were sudden weakness, dizziness, and headache. There were no sex differences regarding the types of warning symptoms that respondents listed. Women displayed better knowledge of risk factors than men (OR: 1.23; 95 % CI: 1.05-1.46). Women were more likely to name hypertension as a risk factor for stroke whereas men more frequently listed smoking, alcohol consumption and a sedentary lifestyle as risk factors. In response to stroke, women were significantly less likely than men to choose to call an ambulance or to go immediately to hospital (OR: 0.69; 95 % CI: 0.60-0.85). CONCLUSIONS: Stroke knowledge is suboptimal in both men and women. We detected better knowledge of stroke risk factors in women, as well as differences in the type of risk factors listed by men and women. There were significant sex differences regarding response to stroke or to its warning signs. PMID- 26499114 TI - Self-harm and life problems: findings from the Multicentre Study of Self-harm in England. AB - PURPOSE: Self-harm is a major clinical problem and is strongly linked to suicide. It is important to understand the problems faced by those who self-harm to design effective clinical services and suicide prevention strategies. We investigated the life problems experienced by patients presenting to general hospitals for self-harm. METHODS: Data for 2000-2010 from the Multicentre Study of Self-harm in England were used to investigate life problems associated with self-harm and their relationship to patient and clinical characteristics, including age, gender, repeat self-harm and employment status. RESULTS: Of 24,598 patients (36,431 assessed episodes), 57% were female and with a mean age of 33.1 years (SD 14.0 years), 92.6% were identified as having at least one contributing life problem. The most frequently reported problems at first episode of self-harm within the study period were relationship difficulties (especially with partners). Mental health issues and problems with alcohol were also very common (especially in those aged 35-54 years, and those who repeated self-harm). Those who repeated self-harm were more likely to report problems with housing, mental health and dealing with the consequences of abuse. CONCLUSIONS: Self-harm usually occurs in the context of multiple life problems. Clinical services for self-harm patients should have access to appropriate care for provision of help for relationship difficulties and problems concerning alcohol and mental health issues. Individualised clinical support (e.g. psychological therapy, interventions for alcohol problems and relationship counselling) for self-harm patients facing these life problems may play a crucial role in suicide prevention. PMID- 26499118 TI - A Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneous Quantitation of 10 Bioactive Components in Rhus verniciflua Extracts. AB - The purpose of this study was to develop a simultaneous method to quantify 10 bioactive compounds in Rhus verniciflua extracts using high-performance liquid chromatography-tandem mass spectrometry. The chromatographic separation was performed using a C18 column under gradient elution with 0.1% formic acid and acetonitrile as the mobile phase solvents. The analytes were detected in the negative-ion mode using multiple-reaction monitoring detection with an electrospray ionization interface. The calibration curves for all the analytes showed good linearity (r(2) >0.997) over the concentration range of 1-1,000 ng/mL. The recovery values were within 89.53-110.14%, and the intra- and interday coefficients of variation were <4.86% for all the tested compounds. The developed method was successfully applied to a quality assessment of the R. verniciflua extract samples. PMID- 26499116 TI - Can Peto's paradox be used as the null hypothesis to identify the role of evolution in natural resistance to cancer? A critical review. AB - BACKGROUND: Carcinogenesis affects not only humans but almost all metazoan species. Understanding the rules driving the occurrence of cancers in the wild is currently expected to provide crucial insights into identifying how some species may have evolved efficient cancer resistance mechanisms. Recently the absence of correlation across species between cancer prevalence and body size (coined as Peto's paradox) has attracted a lot of attention. Indeed, the disparity between this null hypothesis, where every cell is assumed to have an identical probability to undergo malignant transformation, and empirical observations is particularly important to understand, due to the fact that it could facilitate the identification of animal species that are more resistant to carcinogenesis than expected. Moreover it would open up ways to identify the selective pressures that may be involved in cancer resistance. However, Peto's paradox relies on several questionable assumptions, complicating the interpretation of the divergence between expected and observed cancer incidences. DISCUSSIONS: Here we review and challenge the different hypotheses on which this paradox relies on with the aim of identifying how this null hypothesis could be better estimated in order to provide a standard protocol to study the deviation between theoretical/theoretically predicted and observed cancer incidence. We show that due to the disproportion and restricted nature of available data on animal cancers, applying Peto's hypotheses at species level could result in erroneous conclusions, and actually assume the existence of a paradox. Instead of using species level comparisons, we propose an organ level approach to be a more accurate test of Peto's assumptions. SUMMARY: The accuracy of Peto's paradox assumptions are rarely valid and/or quantifiable, suggesting the need to reconsider the use of Peto's paradox as a null hypothesis in identifying the influence of natural selection on cancer resistance mechanisms. PMID- 26499117 TI - Dichlorvos exposure results in large scale disruption of energy metabolism in the liver of the zebrafish, Danio rerio. AB - BACKGROUND: Exposure to dichlorvos (DDVP), an organophosphorus pesticide, is known to result in neurotoxicity as well as other metabolic perturbations. However, the molecular causes of DDVP toxicity are poorly understood, especially in cells other than neurons and muscle cells. To obtain a better understanding of the process of non-neuronal DDVP toxicity, we exposed zebrafish to different concentrations of DDVP, and investigated the resulting changes in liver histology and gene transcription. RESULTS: Functional enrichment analysis of genes affected by DDVP exposure identified a number of processes involved in energy utilization and stress response in the liver. The abundance of transcripts for proteins involved in glucose metabolism was profoundly affected, suggesting that carbon flux might be diverted toward the pentose phosphate pathway to compensate for an elevated demand for energy and reducing equivalents for detoxification. Strikingly, many transcripts for molecules involved in beta-oxidation and fatty acid synthesis were down-regulated. We found increases in message levels for molecules involved in reactive oxygen species responses as well as ubiquitination, proteasomal degradation, and autophagy. To ensure that the effects of DDVP on energy metabolism were not simply a consequence of poor feeding because of neuromuscular impairment, we fasted fish for 29 or 50 h and analyzed liver gene expression in them. The patterns of gene expression for energy metabolism in fasted and DDVP-exposed fish were markedly different. CONCLUSION: We observed coordinated changes in the expression of a large number of genes involved in energy metabolism and responses to oxidative stress. These results argue that an appreciable part of the effect of DDVP is on energy metabolism and is regulated at the message level. Although we observed some evidence of neuromuscular impairment in exposed fish that may have resulted in reduced feeding, the alterations in gene expression in exposed fish cannot readily be explained by nutrient deprivation. PMID- 26499115 TI - Neuronal response in Alzheimer's and Parkinson's disease: the effect of toxic proteins on intracellular pathways. AB - Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deterioration and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and alpha-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed. PMID- 26499119 TI - Evaluation of the Effects of Ketoconazole and Voriconazole on the Pharmacokinetics of Oxcarbazepine and Its Main Metabolite MHD in Rats by UPLC-MS MS. AB - Oxcarbazepine (OXC), a second-generation antiepileptic drug, undergoes rapid reduction with formation of the active metabolite 10,11-dihydro-10-hydroxy carbazepine (MHD) in vivo. In this study, a method for simultaneous determination of OXC and MHD in rat plasma using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS-MS) was developed and validated. Under given chromatographic conditions, OXC, MHD and internal standard diazepam were separated well and quantified by electrospray positive ionization mass spectrometry in the multiple reaction monitoring transitions mode. The method validation demonstrated good linearity over the range of 10-2,000 ng/mL for OXC and 5-1,000 ng/mL for MHD. The lower limit of quantification was 5 ng/mL for OXC and 2.5 ng/mL for MHD, respectively. The method was successfully applied to the evaluation of the pharmacokinetics of OXC and MHD in rats, with or without pretreatment by ketoconazole (KET) and voriconazole (VOR). Statistics indicated that KET and VOR significantly affected the disposition of OXC and MHD in vivo, whereas VOR predominantly interfered with the disposition of MHD. This method is suitable for pharmacokinetic study in small animals. PMID- 26499120 TI - One Step to Separate Five Alkaloids from Hypecoum leptocarpum by High-Speed Counter-Current Chromatography. AB - High-speed counter-current chromatography (CCC) was firstly and successfully applied for the preparative separation and purification of alkaloids from crude extract of Hypecoum leptocarpum. After the measurement of partition coefficient of five target alkaloids in the two-phase solvent systems, the CCC was performed well with a two-phase solvent system composed of tetrachloromethane-chloroform methanol-0.1 M HCl at a volume ratio of 1.5 : 2.5 : 3 : 2 (V/V/V/V). The upper phase was used as the stationary phase, and the lower phase was used as the mobile phase. From 120 mg crude extract, 5 mg leptopidine, 32 mg oxohydrastinine, 27 mg (-)-N-methylanadine, 7 mg N-feruloyltyramine and 3 mg hypecoleptopine could be successfully separated. The amides alkaloid, N-feruloyltyramine, was firstly separated from H. leptocarpum. High-performance liquid chromatography analysis showed that the purity of each of the five target alkaloids was over 92%. Their chemical structures were confirmed by (1)H-NMR and (13)C-NMR data. PMID- 26499122 TI - Modeling the Potential Impact of the 2014 American Academy of Pediatrics Respiratory Syncytial Virus Prophylaxis Guidance on Preterm Infant RSV Outcomes. AB - INTRODUCTION: The American Academy of Pediatrics (AAP) Committee on Infectious Diseases issued updated guidance on respiratory syncytial virus (RSV) prophylaxis in 2014. This report models the potential impact of the new guidance on RSV outcomes in preterm infants 29-34 weeks' gestational age (wGA) without chronic lung disease in the United States. METHODS: The number of preterm infants was estimated using 2012 natality data. Palivizumab utilization prior to the 2014 guidance update was estimated using 2013-2014 specialty pharmacy utilization data. Low, moderate, and high RSV hospitalization (RSVH) rates as well as average hospital length of stay, intensive care unit (ICU) admissions and mechanical ventilation (MV) frequencies were derived from published observational studies. Palivizumab efficacy was derived from two randomized clinical trials. RSV events that would be attributable to the 2014 guidance change were calculated for preterm infants 29-31 and 32-34 wGA. RESULTS: Annual number of infants 29-34 wGA surviving the neonatal period was estimated at 123,687. Of these, an estimated 44,712 (37%) would receive palivizumab based on the 2012 guidance. The annual number of RSVH among infants 29-34 wGA would increase from 3580 under the 2012 guidance to 6166 under the 2014 guidance based on moderate rates. This would result in an additional 24,440 hospitalization days, 1162 ICU admissions, and 584 MV events among this population. CONCLUSIONS: Based on published historical and contemporary data on RSVH rates in preterm infants 29-34 wGA, the 2014 AAP guidance is expected to result in additional burden to the healthcare system and families of preterm infants. The impact of the new guidance will be difficult to detect among the overall infant population, particularly in settings without routine testing for RSV, but the impact will be substantial for the small high risk population affected by the changes. FUNDING: AstraZeneca. PMID- 26499121 TI - Validation of HPLC-UV Assay of Caffeic Acid in Emulsions. AB - An accurate, sensitive, precise and rapid reversed-phase high-performance liquid chromatographic method was successfully developed and validated for the determination of caffeic acid (CA) in emulsions. The best separation was achieved on a 250 * 4.6 mm, 5.0 um particle size RP18 XDB Waters column using ethanol and purified water (40:60 v/v) adjusted to pH 2.5 with acetic acid as the mobile phase at a flow rate of 0.7 mL/min. Ultraviolet detection was performed at 325 nm at ambient column temperature (25 degrees C). The method was linear over the concentration range of 10-60 ug/mL (r(2) = 0.9999) with limits of detection and quantification of 1.44 and 4.38 ug/mL, respectively. CA was subjected to oxidation, acid, base and neutral degradation, as well as photolysis and heat as stress conditions. There were no interfering peaks at or near the retention time of CA. The method was applied to the determination of CA in standard and pharmaceutical products with excellent recoveries. The method is applicable in the quality control of CA. PMID- 26499124 TI - A novel thermostable protein-tag: optimization of the Sulfolobus solfataricus DNA alkyl-transferase by protein engineering. AB - In the last decade, a powerful biotechnological tool for the in vivo and in vitro specific labeling of proteins (SNAP-tagTM technology) was proposed as a valid alternative to classical protein-tags (green fluorescent proteins, GFPs). This was made possible by the discovery of the irreversible reaction of the human alkylguanine-DNA-alkyl-transferase (hAGT) in the presence of benzyl-guanine derivatives. However, the mild reaction conditions and the general instability of the mesophilic SNAP-tagTM make this new approach not fully applicable to (hyper )thermophilic and, in general, extremophilic organisms. Here, we introduce an engineered variant of the thermostable alkylguanine-DNA-alkyl-transferase from the Archaea Sulfolobus solfataricus (SsOGT-H5), which displays a catalytic efficiency comparable to the SNAP-tagTM protein, but showing high intrinsic stability typical of proteins from this organism. The successful heterologous expression obtained in a thermophilic model organism makes SsOGT-H5 a valid candidate as protein-tag for organisms living in extreme environments. PMID- 26499123 TI - Adolescent HIV Risk Reduction in the Bahamas: Results from Two Randomized Controlled Intervention Trials Spanning Elementary School Through High School. AB - To address global questions regarding the timing of HIV-prevention efforts targeting youth and the possible additional benefits of parental participation, researchers from the USA and The Bahamas conducted two sequential longitudinal, randomized trials of an evidence-based intervention spanning the adolescent years. The first trial involved 1360 grade-6 students and their parents with three years of follow-up and the second 2564 grade-10 students and their parents with two years of follow-up. Through grade-12, involvement in the combined child and parent-child HIV-risk reduction interventions resulted in increased consistent condom-use, abstinence/protected sex, condom-use skills and parent child communication about sex. Receipt of the grade-6 HIV-prevention intervention conferred lasting benefits regarding condom-use skills and self-efficacy. Youth who had not received the grade-six intervention experienced significantly greater improvement over baseline as a result of the grade-10 intervention. The HIV-risk reduction intervention delivered in either or both grade-6 and grade-10 conferred sustained benefits; receipt of both interventions appears to confer additional benefits. PMID- 26499125 TI - Persistent trigeminal artery: a cross-sectional study based on over 3 years conventional angiography, CT angiography and MR angiography images. AB - PURPOSE: The trigeminal artery is one of the four primitive anastomosis established between the internal carotid artery and the vertebrobasilar system that regresses at the sixth week of embryonic development. Its persistence in adult life (PTA) is usually found incidentally. The aim of this study is to determine its prevalence, main characteristics and clinical significance. METHODS: A cross-sectional study was performed over the last 3 years, 2012-2014, to analyze images performed on conventional angiography, CT angiography and MR angiography of patients who attended the Neuroradiology Department of the Hospital Universitario Doce de Octubre in Madrid, Spain, to control their underlying pathology. RESULTS: Nine cases of PTA were found (prevalence 0.37 %, two men, seven women; three right, six left; age range 13-88 years). Eight PTA emerged from the cavernous ICA and one from the petrous segment. Six cases were lateral or petrosal type and one was medial or sphenoidal type. The whole PTAs anastomosed the BA, six at the middle third and three at the distal third. Weon et al.'s type 3 was predominant. CVD incidence was 55.6 % and aneurysm incidence was 22 %. CONCLUSIONS: PTA prevalence was similar to those previously reported, being commonly left-sided, Salas et al.'s lateral or petrosal type, Weon et al.'s type 3 and with no gender predominance. CVD and aneurysms incidence in the presence of a PTA were higher than in general population. Its anatomical relations make it essential to consider its presence and directional blood flow when planning endovascular and neurosurgical treatments. PMID- 26499126 TI - Evolution of Autocatalytic Sets in Computational Models of Chemical Reaction Networks. AB - Several computational models of chemical reaction networks have been presented in the literature in the past, showing the appearance and (potential) evolution of autocatalytic sets. However, the notion of autocatalytic sets has been defined differently in different modeling contexts, each one having some shortcoming or limitation. Here, we review four such models and definitions, and then formally describe and analyze them in the context of a mathematical framework for studying autocatalytic sets known as RAF theory. The main results are that: (1) RAF theory can capture the various previous definitions of autocatalytic sets and is therefore more complete and general, (2) the formal framework can be used to efficiently detect and analyze autocatalytic sets in all of these different computational models, (3) autocatalytic (RAF) sets are indeed likely to appear and evolve in such models, and (4) this could have important implications for a possible metabolism-first scenario for the origin of life. PMID- 26499128 TI - A rare complication of wasp sting: acute cervical dystonia. PMID- 26499127 TI - Classification and diagnosis of pulmonary hypertension. AB - Pulmonary hypertension has been classified into five major subgroups in order to better understand and apply knowledge from the areas of molecular biology, pathophysiology and clinical science. Accurate classification of the patient not only optimizes diagnostic approach but also confers the best benefit, as therapeutic approaches are applied accurately. Current diagnostic strategies begin with a detailed history and physical, which are directed to elucidate symptoms that may increase the degree of suspicion. Subsequent application of a logical approach to progress through the diagnostic algorithm , with understanding of the complexity of this process, allows for best possible outcomes. Proper diagnosis and classification will eventually increase the potential for appropriate research and progress toward of a possible cure for this fatal disease. PMID- 26499130 TI - Toxicology of Marine Mammals: New Developments and Opportunities. AB - It is widely recognized that marine mammals are exposed to a wide variety of pollutants, with a weight of evidence indicating impacts on their health. Since hundreds of new chemicals enter the global market every year,the methods, approaches and technologies used to characterize pollution levels or impacts are also in a constant state of flux. However, legal and ethical constraints often limit the type and extent of toxicological research being carried out in marine mammals. Nevertheless, new and emerging in vivo, in vitro as well as in silico research opportunities abound in the field of marine mammal toxicology. In the application of findings to population-, species-, or habitat-related risk assessments, the identification of causal relationships which inform source apportionment is important. This, in turn, is informed by a comprehensive understanding of contaminant classes, profiles and fate overspace and time. Such considerations figure prominently in the design and interpretation of marine mammal (eco)-toxicology research. This mini-review attempts to follow the evolution behind marine mammal toxicology until now,highlight some of the research that has been done and suggest opportunities for future research. This Special Issue will showcase new developments in marine mammal toxicology, approaches for exposure-effect research in risk assessment as well as future opportunities. PMID- 26499129 TI - Antibiotic prophylaxis for shunt surgery of children: a systematic review. AB - OBJECTIVE: The object of this study was to evaluate the clinical effectiveness of antibiotic prophylaxis in children who underwent placement of intracranial ventricular shunts. METHODS: In this paper, the authors report a systematic review and meta-analysis of infection rate for pediatric shunt implantation surgery. Randomized or non-randomized controlled trials for comparing the use of prophylactic antibiotics in intracranial ventricular shunt procedures with placebo or no antibiotics were included in the review. RESULTS: Seven published reports of eligible studies involving 694 participants meet the inclusion criteria. Compared with the control group, antibiotic prophylaxis had made a significant difference in infection rate (RR = 0.59, 95% CI = 0.38, 0.90, P < 0.05). CONCLUSION: Although current evidence demonstrates that antibiotic prophylaxis can lead to a significant reduction of the infection rate of shunt surgery, more evidence from advanced multi-center studies is needed to provide instruction for the use of prophylactic antibiotics. PMID- 26499131 TI - Posterior fontanelle approach for uncinectomy and middle meatal antrostomy in endoscopic sinus surgery. PMID- 26499132 TI - Prevalence of Brick Tea-Type Fluorosis in the Tibet Autonomous Region. AB - BACKGROUND: The prevalence of brick tea-type fluorosis is high in Tibet because of the habit of drinking brick tea in this region. Brick tea-type fluorosis has become an urgent public health problem in China. METHODS: A cross-sectional survey was conducted to investigate prevalence of brick tea-type fluorosis in all districts of Tibet using a stratified cluster sampling method. Dental fluorosis in children aged 8-12 years and clinical skeletal fluorosis in adults were diagnosed according to the national criteria. A total of 423 children and 1320 adults participated in the study. Samples of drinking water, brick tea, brick tea infusion (or buttered tea), and urine were collected and measured for fluoride concentrations by the fluoride ion selective electrode method. RESULTS: The fluoride level in all but one of the brick tea samples was above the national standard. The average daily fluoride intake from drinking brick tea in all seven districts in Tibet was much higher than the national standard. The prevalence of dental fluorosis was 33.57%, and the prevalence of clinical skeletal fluorosis was 46.06%. The average daily fluoride intake from drinking brick tea (r = 0.292, P < 0.05), urine fluoride concentrations in children (r = 0.134, P < 0.05), urine fluoride concentrations in adults (r = 0.162, P < 0.05), and altitude (r = 0.276, P < 0.05) were positively correlated with the prevalence of brick tea-type fluorosis. Herdsmen had the highest fluoride exposure and the most severe skeletal fluorosis. CONCLUSIONS: Brick tea-type fluorosis in Tibet is more serious than in other parts of China. The altitude and occupational factors are important risk factors for brick tea-type fluorosis. PMID- 26499133 TI - Candesartan ameliorates acute myocardial infarction in rats through inducible nitric oxide synthase, nuclear factor-kappaB, monocyte chemoattractant protein-1, activator protein-1 and restoration of heat shock protein 72. AB - Candesartan, an angiotensin II type 1 receptor antagonist, has a variety of biological activities, including antioxidant, anti-inflammatory and anticancer activities, with specific pharmacological effects. The present study investigated the mechanisms and protective effect of candesartan on acute myocardial infarction in rats. Male Wistar rats (8-week-old) were induced as a model of acute myocardial infarction and treated with candesartan (0.25 mg/kg) for 2 weeks. The present study first measured the activities of casein kinase (CK), the MB isoenzyme of creatine kinase (CK-MB) and lactate dehydrogenase (LDH), the level of cardiac troponin T (cTnT) and infarct size. Subsequently, western blot analysis was performed to analyze the protein expression levels of inducible nitric oxide synthase (iNOS) and heat shock protein 72 (HSP72) in the rats. An enzyme linked immunosorbent assay was used to detect iNOS and nuclear factor kappaB (NF-kappaB) activity. In addition, gene expression levels of monocyte chemotactic protein-1 (MCP-1) and activating protein-1 (AP-1) were determined using reverse transcription-quantitative polymerase chain reaction analysis. Finally, the activities of caspase-3 and caspase-9 were examined using colorimetric assay kits. In the serum of the rat model of acute myocardial infarction, candesartan significantly increased the activities of CK, CK-MB and LDH, and the level of cTnT. The infarction size was perfected by candesartan treatment. Candesartan significantly reduced the protein expression and activity of iNOS, the activity of NF-kappaB p65, and the gene expression levels of MCP-1 and AP-1 in the rat model of acute myocardial infarction. Candesartan increased the protein expression of HSP-72 in the acute myocardial infarction rat model. However, candesartan did not effect the levels of caspase-3 or caspase-9 in the rat model of acute myocardial infarction. These results suggested that candesartan ameliorates acute myocardial infarction in rats through iNOS, NF kappaB, MCP-1 and AP-1, and the restoration of HSP72. PMID- 26499134 TI - Extracting Accurate Precursor Information for Tandem Mass Spectra by RawConverter. AB - Extraction of data from the proprietary RAW files generated by Thermo Fisher mass spectrometers is the primary step for subsequent data analysis. High resolution and high mass accuracy data obtained by state-of-the-art mass spectrometers (e.g., Orbitraps) can significantly improve both peptide/protein identification and quantification. We developed RawConverter, a stand-alone software tool, to improve data extraction on RAW files from high-resolution Thermo Fisher mass spectrometers. RawConverter extracts full scan and MS(n) data from RAW files like its predecessor RawXtract; most importantly, it associates the accurate precursor mass-to-charge (m/z) value with the tandem mass spectrum. RawConverter accepts RAW data generated by either data-dependent acquisition (DDA) or data-independent acquisition (DIA). It generates output into MS1/MS2/MS3, MGF, or mzXML file formats, which fulfills the format requirements for most data identification and quantification tools. Using the tandem mass spectra extracted by RawConverter with corrected m/z values, 32.8%, 27.1%, and 84.1%, peptide spectra matches (PSMs) produce 17.4% (13.0%), 14.4% (11.5%), and 45.7% (36.2%) more peptide (protein) identifications than ProteoWizard, pXtract, and RawXtract, respectively. RawConverter is implemented in C# and is freely accessible at http://fields.scripps.edu/rawconv. PMID- 26499136 TI - Erratum: STAT3 regulated ARF expression suppresses prostate cancer metastasis. PMID- 26499135 TI - Gold Nanoparticle Aggregation as a Probe of Antifreeze (Glyco) Protein-Inspired Ice Recrystallization Inhibition and Identification of New IRI Active Macromolecules. AB - Antifreeze (glyco)proteins are found in polar fish species and act to slow the rate of growth of ice crystals; a property known as ice recrystallization inhibition. The ability to slow ice growth is of huge technological importance especially in the cryopreservation of donor cells and tissue, but native antifreeze proteins are often not suitable, nor easily available. Therefore, the search for new materials that mimic this function is important, but currently limited by the low-throughout assays associated with the antifreeze properties. Here 30 nm gold nanoparticles are demonstrated to be useful colorimetric probes for ice recrystallization inhibition, giving a visible optical response and is compatible with 96 well plates for high-throughout studies. This method is faster, requires less infrastructure, and has easier interpretation than the currently used 'splat' methods. Using this method, a series of serum proteins were identified to have weak, but specific ice recrystallization inhibition activity, which was removed upon denaturation. It is hoped that high-throughput tools such as this will accelerate the discovery of new antifreeze mimics. PMID- 26499137 TI - Protective effects of trigonelline against indomethacin-induced gastric ulcer in rats and potential underlying mechanisms. AB - The present study was undertaken to explore gastroprotective effects of trigonelline (TRG) and to determine the potential mechanisms involved in this action. In order to evaluate the gastroprotective efficiency of TRG, an indomethacin-induced ulcer model has been applied. Antioxidants, cytokines, adhesion markers and apoptosis levels have been analyzed for the biochemical mechanism involved in TRG activity. TRG (45 mg kg(-1)) pretreated rats significantly inhibited gastric lesions by 81.71%. Indomethacin administration raises the levels of leukotriene B4 (LTB4), lipid peroxidation and myeloperoxidase (MPO) with the significant declines of prostaglandin E2 (PGE2), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px) levels. Conversely, TRG (45 mg kg(-1)) pretreated animals showed significant rises in PGE2 and antioxidant levels along with substantial reductions in LTB4, lipid peroxidation and MPO levels. Indomethacin-induced rats also exhibited considerable increases of pro-inflammatory cytokines including interleukin-6 (IL 6), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) levels and decreases of anti-inflammatory cytokines such as interleukin-10 (IL-10) and interleukin-4 (IL-4), but these imbalances were normalized through treatment of TRG. The protective activity of TRG against indomethacin-induced gastric ulcer has been ascribed to three important mechanisms: (1) anti-inflammatory; (2) antioxidant; (3) anti-apoptotic pathways. PMID- 26499139 TI - [Clinical efficacy of paclitaxel combined with S-1 in the prevention and treatment of gastric cancer with peritoneal metastasis]. AB - Peritoneal dissemination is the most common metastasis form in patients with highly advanced gastric cancer(AGC) or with recurrence after radical gastrectomy. The median survival time after manifestation of peritoneal carcinomatosis is about 4-6 months. Most systemic chemotherapeutic agents are not effective for peritoneal metastasis because of the blood-peritoneum barrier, although some adjuvant chemotherapy definitely improves overall survival. In this regard, neoadjuvant intraperitoneal-systemic chemotherapy(NIPS) has been recently considered as an additional adjuvant therapy for AGC with peritoneal metastasis. Combined chemotherapy of intravenous and intraperitoneal paclitaxel with oral S-1 has been confirmed by pharmacokinetic and pharmacodynamic studies to be well tolerated and well effective in gastric cancer patients with peritoneal metastasis. In this article, authors make a comprehensive introduction to clinical efficacy by adopting paclitaxel and S-1 to gastric cancer patients with peritoneal metastasis. PMID- 26499138 TI - [Gastrointestinal surgeons should master the adjuvant therapy of colorectal cancer]. AB - The diagnosis and treatment of colorectal cancer is one of the main diseases of gastrointestinal surgeons. It is very important to master the adjuvant chemotherapy of colorectal cancer for gastrointestinal surgeons. In recent years, with the development of a number of clinical trials and the appearance of new drugs, fluorouracil combined with oxaliplatin had been established as the standard regimen of adjuvant chemotherapy for colorectal cancer. In the current guidelines, stage III( colon cancer is the indication for adjuvant chemotherapy, while stage II( colon cancer should receive adjuvant chemotherapy is uncertain. Unlike colon cancer, adjuvant therapy of rectal cancer is not evidence-based. Especially, the indication and duration of adjuvant chemotherapy for rectal cancer after neoadjuvant chemoradiotherapy remain controversial. Adjuvant therapy of colorectal cancer still needs further investigation. PMID- 26499140 TI - [Current status and research progress of perioperative chemotherapy in advanced gastric cancer]. AB - Recently the standard treatment for advanced gastric cancer is the multimodal therapies associated with complete surgical resection of cancer (D2 dissection) and now more and more clinical attentions have been paid to chemotherapy. It has been confirmed by several randomized phase III( clinical trials that adjuvant chemotherapy after D2 dissection can significantly improve patients' survival. But it is still in debate that perioperative chemotherapy(adjuvant and neoadjuvant) and postoperative radiotherapy can really bring survival benefits for gastric cancer patients who received curative D2 dissections. Based on these questions, investigators designed different ongoing clinical trials in order to define subsets of patients who will more likely benefit from specific therapies and optimize the regimens and sequence. Meanwhile, along with the deep research of gastric cancer biomarkers and introduction of novel molecular subtypes of gastric cancer based on cancer genome atlas project, personalized or individual chemotherapy treatment will come into reality for improving survival and having better life quality for gastric cancer patients. PMID- 26499141 TI - [Advantages and disadvantages of postoperative radiotherapy in locally advanced gastric cancer]. AB - Gastric cancer is one of the most common cancers worldwide. Radical surgery remains the cornerstone of the treatment, however, outcomes are poor. As an effective, non-invasive treatment modality, radiotherapy constitutes an important part of the comprehensive therapy for locally advanced gastric cancer. The improved target coverage and accuracy of intensity-modulated radiotherapy allow for selective sparing of critical structures and reduce toxicity. With the use of new anti-cancer drugs and the progression of radiotherapy techniques, chemoradiotherapy may be of value in the future. This paper discusses the advantages and disadvantages of adjuvant radiotherapy in gastric cancer based on efficacy and toxicity. PMID- 26499142 TI - [Current status of hepatic resection for patients with colorectal liver metastasis]. AB - Liver metastasis is responsible for the majority of death of patients with colorectal cancer. The hepatic resection is curative standard treatment of colorectal liver metastasis. More and more patients with liver metastases from colorectal cancer were indicated to be resected because of progress in both surgical technique and systemic therapies. As a result, many surgeons take a more aggressive attitude towards the management of liver metastasis. In addition, multidisciplinary team of colorectal liver metastasis has helped to standardize clinical practice of synchronous and metachronous liver metastases. PMID- 26499143 TI - [Molecular phenotypes of colorectal cancer is critical in clinical individual treatment]. AB - Colorectal cancer (CRC) is not a single disease, but a group of wide spectrum of heterogeneous diseases, and tumors with similar clinicopathological features may react differently to treatments and have diverse prognosis. So complementary risk evaluation, or based on molecular biomarkers to further stratify colorectal cancer beyond TNM staging is necessary. Understanding mechanism of carcinogenesis is good for subtyping colorectal cancer as well as drug development. So far, 3 major pathways are thought to be related to CRC carcinogenesis, chromosome instability, microsatellite instability and CpG island hypermethylation. High throughput profiling enables to study the molecular basis for CRC more comprehensively and systemically. Several studies have defined 3-6 subtypes. Colorectal Cancer Subtype Consortium has made consensus to divide CRC into 5 subtypes based on pool analysis of available profiling data. Further validation is ongoing. There are only a few biomarkers which can be applied in daily practice, including MSI, RAS, BRAF, PI3KCA and HER2. PMID- 26499144 TI - [Three procedures of transanal minimally invasive surgery (TAMIS) for advanced mid-low rectal tumor]. AB - Transanal minimally invasive surgery (TAMIS) is a novel minimally invasive procedure which is performed by normal laparoscopic instruments through the single port transanally. Three kinds of procedures have been performed based on the TAMIS platform by now, including TAMIS-TME(total mesorectal excision), TAMIS APE(Abdominoperineal excision) and TAMIS-Hartmann. Transanal total mesorectal excision (taTME) with dissection from bottom to up through the platform of TAMIS is also called TAMIS-TME. The greatest advantage of TAMIS-TME is that it increases the quality of specimen and decrease the adverse injury due to the sufficient vision of lower part of mesorectum in the operation. TAMIS-APE and TAMIS-Hartmann procedures emerge after the experience of TAMIS-TME. TAMIS-APE procedure not only firstly make the dissection of perineal phase minimally invasive, but also make the perineal vision more clear, the resection of levator ani muscle more precise, eventually the tailored APE procedure comes true under the laparoscopy of perineal phase. The dissection of mid-low mesorectum for recurrent tumor is usually difficult just from above, TAMIS facilitates the resection through entering the normal anatomical space under the tumor. If the tumor has the risk of recurrence, distal rectum is closed and proximal colostomy is made, we firstly performed this procedure and name it TAMIS-Hartmann. Therefore, TAMIS is not only a platform for taTME, but also it provides a transanal approach and a "button to up" conception for the mid-low rectal tumor. PMID- 26499145 TI - [Upper arm vein versus subclavian vein for totally implantable venous access ports for patients with gastrointestinal malignancy: a retrospective comparison of complications]. AB - OBJECTIVE: To compare two different routes of totally implantable venous access ports (TIVPs) from the upper arm vein and the subclavian vein in terms of complications for patients with gastrointestinal malignancy. METHODS: Patients who underwent implantations of TIVPs from September 2013 to January 2015 were retrospectively evaluated. The outcome measurements were rates and types of postprocedural early-stage and long-term complications. RESULTS: A total of 208 patients(upper arm vein group, 86; subclavian vein group, 122) were included in this study. All TIVPs were implanted successfully. The rate of catheter displacement was higher in upper arm vein group(14.0% vs 5.7%, P=0.04), while other postprocedural early-stage complications had no significant difference between the two groups. The occurrence of transfusion obstacle and rates of overall postprocedural long-term complications were significantly lower in upper arm vein group than that in subclavian vein group(1.2% vs. 9.8%, P=0.02; 7.0% vs. 27.0%, P=0.01, respectively). CONCLUSION: Compared with subclavian vein group, upper arm vein group has lower postprocedural long-term complication rates and is recommended as a safe and comfortable choice for port implantation. PMID- 26499146 TI - [Safety evaluation of intraoperative peritoneal chemotherapy with Lobaplatin for advanced colorectal cancers]. AB - OBJECTIVE: To observe the impact of intraoperative peritoneal chemotherapy with Lobaplatin on the safety of postoperative bowel function and complications in patients with advanced colorectal cancer. METHODS: A total of 103 colorectal cancer patients undergoing surgical operations in our department between October 2013 and October 2014 were prospectively enrolled in this study and were randomly divided into peritoneal chemotherapy group(55 cases) and control group(48 cases) according to the random table. In therapy group, patients were treated with peritoneal implantation of 40 mg Lobaplatin intraoperatively and followed by intravenous chemotherapy using FOLFOX regimen with Oxaliplatin, Fluorouracil and Leucovorin. In control group, only FOLFOX regimen was fulfilled. Then the recovery time of bowel function, the incidence of adverse reactions and complications, and the pre- and post-chemotherapy routine blood tests and hepatorenal functions were compared. RESULTS: The recovery time of bowel function in peritoneal chemotherapy group and control group was(72.1+/-11.8) h and(68.7+/ 13.4) h respectively without significant difference(P>0.05). Each group had 6 cases with incisional fat liquefaction(10.9% vs. 12.5%, P>0.05). There was no serious infection in both groups. During intravenous chemotherapy, in peritoneal chemotherapy group and control group, the incidence of nausea and vomit(42 cases, 76.4% vs. 40 cases, 83.3%), constipation(38 cases, 69.1% vs. 29 cases, 60.4%), and diarrhea(4 cases, 7.3% vs. 5 cases, 10.4%) were observed and there were no significant differences(all P>0.05). It was noted that all these side effects vanished after chemotherapy or cured by symptomatic treatment. There were no significant differences between two groups in indexes of white blood cell, platelet, alanine aminotransferase, aspartate transaminase, and creatinine(all P>0.05), neither after operation nor after chemotherapy. CONCLUSION: Peritoneal implantation of Lobaplatin as intraoperative chemotherapy for advanced colorectal cancer is safe and tolerable. PMID- 26499147 TI - [Study on prognosis relationship between ABO blood groups of patients with gastric cancer]. AB - OBJECTIVE: To investigate the relationship of ABO blood group with the clinicopathological characteristics in patients with gastric cancer and to assess whether the ABO blood group was associated with prognosis. METHOD: Clinicopathological and follow-up data of 2838 patients with gastric cancer who underwent radical gastrectomy in our department from June 2008 to October 2013 were analyzed retrospectively. The distribution of ABO blood group under different clinicopathological characteristics and the overall 5-year survival of ABO blood group were compared. RESULTS: There were no significant differences in clinicopathological characteristics among patients with different ABO blood groups (all P>0.05). The 5-year overall survival(OS) rates were 57.3% for patients with blood type A, 54.7% for type B, 57.4% for type O, and 53.5% for type AB. Though there was no significance difference of survival among ABO blood groups(P=0.722), while the subgroup analysis indicated that stage III( patients of blood group Non-AB had a poorer OS compared to those of blood group AB(25.2% vs. 44.7%, P=0.014); smoking patients of blood group Non-AB had a poorer OS compared to those of blood group AB(53.4% vs. 74.9%, P=0.044). CONCLUSION: Neither clinicopathological characteristics nor overall survival are associated with the ABO blood group, however, stage III( and smoking patients of blood group Non-AB have a poorer OS compared to those of blood group AB. PMID- 26499148 TI - [Analysis of risk factors associate with lymph node metastasis of T1 and T2 rectal cancer]. AB - OBJECTIVE: To investigate the risk factors associated with lymph node metastasis of T1 and T2 rectal cancer. METHODS: Clinicopathological data of 576 patients with stage T1 to T2 rectal cancer without serosal invasion confirmed by pathology undergoing curative resection in Changhai Hospital from January 1999 to December 2013 were analyzed retrospectively. The relationship of clinicopathological factors of overall patients and stage T1 patients with lymph node metastasis was analyzed by univariate or multivariate analysis. RESULTS: The lymph node metastasis rate of stage T2 rectal cancer was significantly higher than that of stage T1[22.9% (108/463) vs. 9.7%(11/113), P=0.002], and the difference of stage T2a and T2b was not significant[22.0%(38/173) vs. 23.4% (68/290), P=0.733]. Multivariate analysis showed that poor differentiation(HR=1.54, 95% CI:1.12 to 2.13), abnormal carbohydrate antigen (CA) 199 level (HR=2.05, 95% CI:1.16 to 3.62), ulcerative mass (HR=1.58, 95% CI:1.05 to 2.39) and invasion of muscle (of inner ring muscle HR=3.55, 95% CI:1.79 to 7.02; of outer longitudinal muscle, HR=2.35, 95% CI:1.21 to 4.60) were independent risk factors of lymph node metastasis in patients with stage T1-T2 rectal cancer(all P<0.05). Meanwhile poor differentiation(HR=4.43, 95% CI:1.51 to 13.03), abnormal carcinoembryonic antigen(CEA) level (HR=4.66, 95% CI:1.18 to 20.11) and ulcerative mass (HR=6.23, 95% CI:1.51 to 25.66) were risk factors of lymph node metastasis in patients with stage T1 rectal cancer. CONCLUSION: Poor differentiation, preoperative high CA199, ulcerated tumor, invasion of inner ring muscle or outer longitudinal muscle are risk factors of lymph node metastasis in patients with stage T1-T2 rectal cancer, while the invasion depth of muscularis propria is not risk factor. Besides, poor differentiation, abnormal CEA level, ulcerated tumor are risk factors of lymph node metastasis in stage T1 rectal cancer patients, which can be used as reference for local excision in patients with stage T1 rectal cancer. PMID- 26499149 TI - [Comparative study on computed tomography features of gastrointestinal schwannomas and gastrointestinal stromal tumors]. AB - OBJECTIVE: To compare the CT image of gastrointestinal schwannomas (GIS) and gastrointestinal stromal tumors(GIST), and to find the CT features to be helpful for differentiation of GIS from GIST. METHODS: Clinical and iconography data of 15 GIS patients and 50 GIST patients who underwent stomach CT scan with postoperatively confirmed histopathology between January 2000 and July 2014 in our department were collected retrospectively. CT findings of these two tumors were compared. Then the ROC curve was drawn based on the significant CT findings and area under the curve (AUC) was calculated to assess the sensibility and specificity for the differential diagnosis of GIS and GIST. RESULT: CT findings, such as the tumor size, shape, cystic change, perilesional lymph nodes, vessel seeding, enhancement pattern and degree, absolute and standardized CT value were significantly different between GIS and GIST(all P<0.05). Among the CT findings, tumor size, cystic change, perilesional lymph nodes, enhancement pattern and arterial phase standardized CT value (Sa) were better differential than others (all AUC>0.7). Tumor size showed the highest sensibility(90%), and cystic change and Sa showed the highest specificity(87%). CONCLUSIONS: GIS seems to show a homogeneous tumor more frequently, presenting light and moderate enhancement pattern and obvious enhancement of perilesional lymph nodes, while GIST seems to reveal malignant features, such as abundant blood supply, larger volume, frequent necrosis and cystic change. Cystic change and Sa value possess the better differential ability in diagnosis of these two tumors. PMID- 26499150 TI - [Clinical characteristics and prognosis of colon cancer patient with extremely elevated carcinoembryonic antigen level]. AB - OBJECTIVE: To explore the clinicopathological characteristics and prognosis of colon cancer patients with extremely elevated serum carcinoembryonic antigen(CEA) level before operation(>50 MUg/L). METHODS: Clinicopathological and follow-up data of 1250 patients with colonic adenocarcinoma undergoing primary tumor resection between January 2001 and December 2011 were retrospectively analyzed. All the patients were divided into three groups according to the preoperative serum CEA levels as normal group (0-5 MUg/L, 721 cases), elevated group(5-50 MUg/L, 408 cases) and extremely elevated(>50 MUg/L, 121 cases). Kaplan-Meier method was used to analyze the overall survival and disease-free survival. Log rank test was used to compare the survival between groups. Cox regression was used to screen the independent prognostic factors of colon cancer. RESULTS: Compared with normal and elevated groups, patients with extremely elevated CEA had more advanced T,N,M stages (P<0.01), more palliative surgery (P<0.01) and more lymphovascular invasion(P<0.01). During the follow-up, patients with extremely elevated CEA demonstrated significantly higher ratio of distant metastases and liver metastases (both P=0.001). After radical surgery, 5-year overall survival rate of patients with normal, elevated and extremely elevated CEA levels was 70.1%, 54.4% and 42%, respectively, with statistically significant difference among three groups (P<0.001). Multivariate analysis showed that tumor differentiation, TNM staging, preoperative CEA levels, lymphovascular invasion and adjuvant chemotherapy were independent prognostic factors for colon cancer (all P<0.01). CONCLUSIONS: Colon cancer patients with extremely elevated preoperative CEA levels are associated with more unfavorable pathological factors, advanced TNM stage and more distant metastases (especially the liver metastases) during the follow-up. The elevated degree of preoperative CEA level is an independent poor prognostic factor of patients with colon cancer. PMID- 26499151 TI - [Expression of MACC1 protein in colorectal cancer and its relationship with clinicopathological characteristics]. AB - OBJECTIVE: To investigate the expression of metastasis-associated colon cancer 1 (MACC1) protein in colorectal cancer and its clinical significance. METHODS: Immunohistochemistry method was used to determine the expression of MACC1 protein in colorectal cancer and normal colorectal mucosal tissues (>5 cm distance to cancer tissue). Statistic analysis was performed to investigate the association between clinicopathologic features and MACC1 expression. RESULTS: The positive rate of MACC1 protein in colorectal cancer tissues was significantly higher than that in normal tissues [75%(72/96) vs. 14.6%(14/96), P<0.01, chi(2)=68.43]. Expression of MACC1 protein was associated with TNM staging (P<0.01, chi(2)=16.82) and distant metastasis (P<0.01, chi(2)=10.53), but not with age, gender, tumor size, differentiation degree, invasion depth, and lymph node metastasis(all P>0.05). Positive rate of MACC1 expression increased with the advanced TNM staging. When distant metastasis occurred, high expression of MACC1 protein in cancer tissues was found. During median 13(4 to 21) months of follow up, 7 patients died, including 6(8.3%, 6/72) with high expression and 1(4.2%, 1/24) with low expression. Distant metastasis occurred in 9 patients, including 7 with high expression and 2 with low expression. Two patients had local relapse, whose MACC1 expressions were both high. CONCLUSION: MACC1 protein is highly expressed in colorectal cancer tissues, which may be associated with the invasion and metastasis of colorectal cancer. PMID- 26499152 TI - [Expression of NEK-6 in gastric cancer and its clinical significance]. AB - OBJECTIVE: To explore the NEK-6 expression in gastric cancer tissue and its relationship with clinicopathological features. METHODS: Fluorescent quantification PCR and Western blotting were used to examine the NEK-6 expression in 36 samples of fresh gastric cancer tissues and para-cancer gastric mucosal tissues, human gastric cancer cell lines(BGC-823, MKN-28, SGC-7901, MGC-803, HGC 27, AGS), and human normal gastric epithelial cell line (GES-1). Gastric cancer cell lines with the highest expression level were selected to perform the invasion and migration tests, and the effect of down-regulated NEK-6 expression by siRNA transfection on above invasion and migration tests were observed. Meanwhile NEK-6 expression in 94 paraffin samples of gastric cancer tissues was examined by immunohistochemistry and its positivity was compared among different clinicopathologic features. RESULTS: Fluorescent quantification PCR revealed gastric cancer tissues had significantly higher NEK-6 expression than para-cancer tissues(0.002 80+/-0.001 36 vs. 0.001 91+/-0.001 48, P<0.05), NEK-6 expression was up-regulated in 31 gastric cancer tissues (86.1%), and human gastric cancer cell lines had significantly higher NEK-6 expression than GES-1 cells, among whom BGC-823 and AGS cell lines were the highest. Invasion and migration tests showed that as compared to negative siRNA control group, ability of invasion and migration in BGC-823 and AGS cells after siRNA transfection was obviously decreased. In 94 paraffin samples, positive expression rate of NEK-6 was 60.6%(57/94), and NEK-6 expression was significantly associated with gastric cancer distant metastasis, lymph nodes metastasis and TNM staging(all P<0.05). CONCLUSIONS: NEK-6 expression is up-regulated in gastric cancer tissues, which is significantly associated with distant metastasis, lymph nodes metastasis and TNM staging. Down-regulation of NEK-6 expression can inhibit the ability of invasion and migration in gastric cancer cells. PMID- 26499153 TI - [Expression and proliferative regulation of miR-204 related to mitochondrial transcription factor A in colon cancer]. AB - OBJECTIVE: To screen the microRNAs involved in colon cancer proliferation and to investigate the expression and regulating function of target miRNA in colon cancer. METHODS: Mitochondrial transcription factor A(TFAM), which was proved to be an oncogene to colon cancer in prior study, was used as target gene. The microRNAs involved in colon cancer proliferation were screened with miRWalk 2.0 software. The expression of screened miRNAs was examined in 30 samples of colon cancer tissue, para-cancer tissue, normal colon cell strain, and 3 colon cancer strains (SW480, HT-29, and HCT116) by real-time PCR. MiR-204 presenting lowest expression was selected to further study in SW480 cells. Dual luciferase reporter assays was performed to examine the association of TFAM with miR-204. Anti-miR 204 lentivirus and miR-240 lentivirus were used to down-regulate and up-regulate miR-204 expression respectively. Change of TFAM protein expression in SW480 cells was detected by Western blotting, and change of SW480 cells proliferation was detected by MTT and BrdU assay after lentivirus transfection. RESULTS: After screening, the candidate miRNAs were miR-204, miR-211, miR-214, miR-381 and miR 590-3p. Expressions of miR-204, miR-211, miR-214 and miR-381 were lower, but miR 590-3p expression was higher, in colon cancer tissues than those in para-cancer tissues(all P<0.05). Meanwhile expressions of above 4 miRNAs(miR-204, miR-211, miR-214 and miR-381) were also lower, but miR-590-3p expression was higher as well, in SW480, HT-29 and HCT116 cells compared to normal colon cells(all P<0.05). Among above 4 miRNAs, miR-204 showed the lowest expression in both colon cancer tissues and cell lines. Expression of miR-204 was negatively correlated with TFAM expression in colon cancer tissues(P<0.05). Dual luciferase reporter assays revealed TFAM could be integrated with miR-204 directly, suggesting TFAM as the direct target of miR-204. After up-regulating miR-204 by lentivirus, expression of TFAM decreased and proliferation increased in SW480 cells(all P<0.05). After down-regulating miR-204 by lentivirus, expression of TFAM increased and proliferation decreased in SW480 cells(all P<0.05). CONCLUSION: MiR 204 inhibits TFAM expression and up-regulates the proliferation of colon cancer cells SW480. PMID- 26499154 TI - [Analysis of gastric cancer tissues genome methylation by DNA methylation chip]. AB - OBJECTIVE: To detect the methylation status of gastric cancer tissue genome by DNA methylation chip. METHODS: Methylation status of 6 samples of gastric cancer tissues and their matched adjacent tissues was analyzed using methylated DNA immunoprecipitation(MeDIP) combined with NibleGen chip. Significantly different methylated genes in promoter region and CpG island between two tissues were searched. Functions of these significantly different methylated genes were analyzed by Gene Ontology and Pathway assays. RESULTS: In gene promoter regions, 113 significantly different methylated genes were identified in gastric cancer tissues, such as SHP1, FGF8 and CSF2RA, while 161 significantly different methylated genes were identified in their matched adjacent tissues, such as TNF, IGF2 and BMP7. In the CpG islands, 123 significantly different methylated genes were identified in gastric cancer tissues, such as WNT2B, JAK2 and TPT1, while 139 significantly different methylated genes were identified in their matched adjacent tissues, such as TNFRSF4, HOXC8 and NFYA. These genes located on different chromosomes. In gastric cancer tissues, the 1st and the 4th chromosomes had the most (both 11), the 18th and the 20th chromosomes had the least(both 1). In matched adjacent normal tissues, the 11th chromosome had the most (17), and no significantly different methylated gene was found on Y chromosome. These genes involved in many functions, such as protein phosphorylation, regulating cellular catabolism, ion transport, enzyme activity, transcriptional regulation, cell division, cell cycle regulation, and signal transduction. CONCLUSIONS: There are significant differences between gastric cancer tissues and their matched adjacent tissues in DNA methylation. DNA methylation genes locate on different chromosomes, and their number and distribution vary widely. These genes may be associated with many pathways in carcinogenesis. PMID- 26499155 TI - [Association of prognosis with insulin-like growth factor receptor type I expression in gastric cancer patients: a meta-analysis]. AB - OBJECTIVE: To systemically evaluate the relationship between the expression of insulin-like growth factor receptor type I (IGF-1R) and prognosis in gastric cancer (GC) patients. METHODS: A literature search was conducted from PubMed, EMBASE, Web of Science, CNKI, Wanfang and VIP databases to retrieve the clinical studies relevant to IGF-1R expression and its prognostic value in GC patients. Meta-analysis was performed using STATA 12.0 software. The methodology was assessed according to the European Lung Cancer Working Party Quality Scale for Biological Prognostic Factors for Lung Cancer. The quality of studies was assessed using the Newcastle-Ottawa scale. RESULTS: Four eligible studies including 685 patients were enrolled for this meta-analysis. Analysis results suggested that up-regulation of IGF-1R in GC patients was significantly associated with TNM staging (OR=5.20, 95%CI:1.12 to 24.15, P=0.035), lymph node metastasis(OR=8.24, 95%CI:2.68 to 25.34, P=0.000) and distant metastasis(OR=17.34, 95%CI:6.52 to 46.15, P=0.000). Moreover, up-regulated IGF-1R expression was significantly associated with poor overall survival of gastric cancer patients(HR=2.63, 95% CI:1.29 to 5.40, Z=2.64, P=0.008). CONCLUSION: High IGF-1R expression may be an adverse prognostic factor in gastric cancer patients. PMID- 26499156 TI - [Research progress of serum markers in the early diagnosis of acute mesenteric ischemia]. AB - Acute mesenteric ischemia is an insidious and sudden disease with high mortality, whose good prognosis depends on early diagnosis. This review summarizes the analyses of related serum markers about acute mesenteric ischemia in recent years, and investigates the sensitivity and specificity of the diagnosis, in order to help clinicians to assess the function of intestinal barrier. PMID- 26499157 TI - Fourth Circuit Upholds $237 Million Judgment Against Tuomey Healthcare System. PMID- 26499158 TI - The Candidate as Convict. PMID- 26499159 TI - Best Practice for Safe and Effective Administration of Epinephrine for the Treatment of Anaphylaxis in the Radiology Department. PMID- 26499160 TI - Awareness, Utilization, and Education of the ACR Appropriateness Criteria: A Review and Future Directions. AB - PURPOSE: With the overall rise in the use of medical imaging over the past two decades, overutilization has become a major concern. The ACR Appropriateness Criteria (AC) are an evidence-based, web-based, peer-reviewed resource designed to assist clinicians in making the most appropriate imaging decisions. In this literature review, the authors assess the current knowledge, utilization, and education of the AC among undergraduate and graduate medical education trainees and practicing physicians in both radiologic and nonradiologic specialties. METHODS: A comprehensive literature search was completed using the PubMed, Cochrane, and MedEdPORTAL databases with the query "American College of Radiology Appropriateness Criteria." Articles written in English and published from 1993, the year when the AC were introduced, to present were included for review. Retrieved articles were reviewed for relevance. RESULTS: The published literature is sparse. A review suggests a low rate of incorporation of the AC into clinical practice. Formal training in appropriate imaging ordering practices in both undergraduate and graduate medical education is lacking. The several studies targeting the use of the AC demonstrate that educational interventions increase awareness of the criteria as a decision tool. CONCLUSIONS: The low rate of incorporation of the AC into clinical practice may reflect the lack of formal training in appropriate imaging order practices, specifically in the use of the AC, in both undergraduate and graduate medical education. The integration of the AC into decision support may reduce overutilization, but this has not been fully studied. Greater integration of the AC into medical training would require more universal physician buy-in to use the AC as a resource to optimize imaging utilization. This further requires sustained efforts to improve the "user friendliness" of the AC and maximization of collaboration with nonradiology specialties in the development of the AC. PMID- 26499161 TI - Carpe Datum: A Consideration of the Barriers and Potential of Data-Driven PET Innovation. PMID- 26499162 TI - Surveying Fourth-Year Medical Students Regarding the Choice of Diagnostic Radiology as a Specialty. AB - PURPOSE: The aim of this study was to survey fourth-year medical students, both those choosing and those not choosing diagnostic radiology as their specialty, regarding factors influencing their choice of specialty and their perceptions of radiology. METHODS: A voluntary anonymous online survey hyperlink was sent to 141 US medical schools for distribution to fourth-year students. Topics included demographics, radiology education, specialty choice and influencing factors, and opinions of radiology. RESULTS: A representative sampling (7%) of 2015 fourth year medical students (n = 1,219; 51% men, 49% women) participated: 7% were applying in radiology and 93% were not. For respondents applying in radiology, the most important factor was intellectual challenge. For respondents applying in nonradiology specialties, degree of patient contact was the most important factor in the decision not to choose radiology; job market was not listed as a top-three factor. Women were less likely than men to apply in radiology (P < .001), with radiology selected by 11.8% of men (56 of 476) and only 2.8% of women (13 of 459). Respondents self-identifying as Asian had a significantly higher (P = .015) likelihood of selecting radiology (19 of 156 [12.2%]) than all other races combined (44 of 723 [6.1%]). Respondents at medical schools with required dedicated medical imaging rotations were more likely to choose radiology as a specialty, but most schools still do not require the clerkship (82%). CONCLUSIONS: The reasons fourth-year medical students choose, or do not choose, diagnostic radiology as a specialty are multifactorial, but noncontrollable factors, such as the job market, proved less compelling than controllable factors, such as taking a radiology rotation. PMID- 26499163 TI - ABR Core Examination Changes That Affect Residency Candidate Decisions. AB - PURPOSE: The recent restructuring of the ABR core examination has prompted changes to radiology residency training. The purpose of this study is to determine how factors related to the core examination restructuring influenced radiology applicants' match decisions. METHODS: We surveyed 626 applicants to our institution's radiology residency, after the 2014 match. Applicants rated 21 factors on a 5-point scale. Eight of the factors pertained to the core examination. The respondents additionally listed the top three factors in order of importance. RESULTS: The response rate was 153 of 626 (24.4%). The three most influential factors were current resident satisfaction (average score: 4.74 of 5.00 [95% confidence interval (CI) = 4.64-4.83]), quality of faculty (4.63 [95% CI = 4.52-4.73]) and quality of educational curriculum and clinical training (4.60 [95% CI = 4.50-4.70]). Of factors related to the core examination, the highest rated were core examination pass rate (4.21 [95% CI = 4.07-4.35]) and program resources/time off for external review courses (3.92 [95% CI = 3.79 4.04]). Core examination pass rate (16 of 459 [3.5%]) and time off from clinical duties to study for the examination (6 of 459 [1.3%]) appeared infrequently in respondents' lists of the top three most influential factors. CONCLUSIONS: Factors influencing candidates' choice of radiology program are similar to those reported previously, despite the addition of topics related to core examination restructuring. Although programs vary in how they have addressed the changes, these issues are less important to candidates than are more traditional factors. PMID- 26499164 TI - Medical Student Performance After a Vertically Integrated Radiology Clerkship. AB - PURPOSE: Proper selection of imaging examinations and basic image interpretation skills are essential for all physicians, yet only approximately 25% of US medical schools require clerkships in radiology. Although there is limited time in most medical school curricula to allow the addition of a required radiology clerkship, the authors developed one that is vertically integrated over a two-year period. This clerkship includes one week of contact with radiologists distributed over the M2 and M3 years, podcasts, online modules, required readings, and presentations. A standard national examination is administered at the end of the clerkship period. This clerkship was designed to address the educational needs of students while occupying minimal time in the curriculum. The purpose of this study was to determine if students completing this clerkship perform as well on a national radiology examination as students from other medical schools, regardless of their curricula. METHODS: At the end of the M3 year, these students take a computer-based radiology examination developed by the Alliance of Medical Student Educators in Radiology and used by students at multiple medical schools nationally. The mean and median scores of these students were compared with those of students at these other institutions. RESULTS: The mean and median scores of the students were 74% and 74% (standard deviation, 7.5%) compared with 74% and 50% (standard deviation, 8.4%) at other institutions. CONCLUSIONS: Students completing this vertically integrated radiology clerkship had test scores comparable with those of students at other medical schools. PMID- 26499165 TI - Radiology's Social Media Hashtag Ontology: Codifying Online Data. PMID- 26499166 TI - Effectiveness of Policies on Reducing Exposure to Ionizing Radiation From Medical Imaging: A Systematic Review. AB - PURPOSE: The use of medical imaging has expanded greatly in the past three decades, raising concern about potential unwanted carcinogenic harms associated with exposure to ionizing radiation among patients. This study summarizes evidence of efficacy of interventions that have prompted policies, and structural level interventions aimed at reducing radiation dose and risk of cancer, especially among women. METHODS: Using standard terms, we conducted searches in MEDLINE, Scopus, and Web of Science, and de-duplicated retrieved citations. We hand-searched the reference section of eligible studies and contacted radiology experts to identify studies missed from electronic searches. Two reviewers screened retrieved citations based on predefined eligibility criteria, to identify relevant studies, extract key information from each, rate the quality of evidence, and summarize data in tabular and graphical format. RESULTS: From a total of 1,543 unique citations identified from all sources, 16 were included for data extraction. Half of the studies focused on reduction of ionizing exposure from CT, and half on x-ray or fluoroscopy. Identified interventions were broadly categorized as: policy or structural intervention (two; 13%); multipronged (four; 25%); dose-feedback system (five; 31%); provision of training (four; 25%); and quality-control audit (one; 6%). In general, multipronged programs had a higher range for dose reduction (22%-74%), followed by policy/structural interventions (37%-50%). CONCLUSIONS: Existing evidence on the effectiveness of policies aimed at reducing patient radiation dose is disperse and low in quality. Compared with other approaches, multipronged efforts may offer more patient protection. PMID- 26499167 TI - Preparation of gamma-aminopropyltriethoxysilane cross-linked poly(aspartic acid) superabsorbent hydrogels without organic solvent. AB - Poly(aspartic acid) (PASP) hydrogel is a type of biodegradable and biocompatible polymer with high water absorbing ability. Traditionally, the production of PASP hydrogel is expensive, complex, environmentally unfriendly, and consumes a large amount of organic solvents, e.g. dimethylformamide or dimethylsulfoxide. This study introduces a one-step synthesis of PASP resin, in which the organic phase was replaced by distilled water and gamma-aminopropyltriethoxysilane was used as the cross-linker. Absorbent ability and characteristics were determined by swelling ratio, FTIR, (13)C SSNMR, and SEM. In vitro cytotoxicity evaluation and animal skin irritation tests showed the hydrogel has body-friendly properties. Preparing PASP hydrogel in aqueous solution is promising and finds its use in many applications. PMID- 26499168 TI - Three new sativene sesquiterpenoids from cultures of endophytic fungus Bipolaris eleusines. AB - Three new sativene sesquiterpenoids, bipolenins A-C (1-3), together with two known analogs (4 and 5), were obtained from cultures of endophytic fungus Bipolaris eleusines. The structures of new compounds were elucidated on the basis of extensive spectroscopic analyses. Compound 2 showed weak inhibitory activities against lung cancer A-549 and breast cancer MCF-7 with IC50 values of 33.2 and 19.1 MUmol, respectively. PMID- 26499169 TI - Periplanosides A-C: new insect-derived dihydroisocoumarin glucosides from Periplaneta americana stimulating collagen production in human dermal fibroblasts. AB - Three new dihydroisocoumarin glucosides, termed periplanosides A-C (1-3), a known analog, pericanaside (4), and the other twenty known compounds were isolated from the insect Periplaneta americana. Their structures including absolute configurations were determined by comprehensive spectroscopic analyses and computational methods. Biological evaluation showed that compound 2 could stimulate collagen production by 31.2% in human dermal fibroblasts-adult (HDFa) at the concentration of 30 MUM, indicating its significance in skin repair and ulcer. PMID- 26499170 TI - Predictors of low diabetes risk perception in a multi-ethnic cohort of women with gestational diabetes mellitus. AB - AIM: To determine what proportion of women with gestational diabetes underestimate their diabetes risk and identify factors associated with low diabetes risk perception. METHODS: Participants included pregnant adult women with gestational diabetes between 2009 and 2012 across seven diabetes clinics in Ontario, Canada. Data were collected through chart review and a survey that included a diabetes risk perception question. RESULTS: Of the 614 of 902 women (68% response rate) with gestational diabetes, 89% correctly responded that gestational diabetes increases the risk for developing diabetes. However, 47.1% of women perceived themselves to be at low risk for developing diabetes within 10 years. On multivariable analysis, BMI < 25 kg/m(2) , absent previous gestational diabetes history, absent diabetes family history and absent insulin use were appropriately associated with low diabetes risk perception. However, compared with Caucasian ethnicity, high-risk ethnicity (Aboriginal, Latin American, West Indian, South Asian, Middle Eastern, Filipino, Black, Pacific Islander) [odds ratio (OR) 2.07; 95% CI 1.30-3.31] and East and South East Asian ethnicity (OR 2.01; 1.10-3.67) were associated with low diabetes risk perception. After further adjustment for immigration, only high-risk ethnicity remained a predictor of low diabetes risk perception (OR 1.86; 1.09-3.19), whereas East and South East Asian ethnicity did not (OR 1.67; 0.86-3.22). CONCLUSIONS: Although the majority of women recognized gestational diabetes as a risk factor for diabetes, almost half underestimated their personal high diabetes risk despite prenatal care. Furthermore, women from high-risk ethnic groups were more likely to underestimate their risk, even after adjusting for immigration. Interventions tailored to these groups are necessary to enhance perceived diabetes risk. PMID- 26499171 TI - Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats. AB - Over 180 million people consume cannabis globally. Cannabis use peaks during adolescence with a trend for continued consumption by adults. Notably, several studies have shown that long-term and heavy cannabis use during adolescence can impair brain maturation and predispose to neurodevelopmental disorders, although the neurobiological mechanisms underlying this association remain largely unknown. In this study, we evaluated whether, in female rats, chronic administration of increasing doses of the psychotropic plant-derived cannabis constituent, delta-9-tetrahydrocannabinol (THC), during adolescence (PND 35-45) could affect microglia function in the long-term. Furthermore, we explored a possible contribution of microglia to the development of THC-induced alterations in mood and cognition in adult female rats. Present data indicate that adolescent THC administration induces a persistent neuroinflammatory state specifically localized within the adult prefrontal cortex (PFC), characterized by increased expression of the pro-inflammatory markers, TNF-alpha, iNOS and COX-2, and reduction of the anti-inflammatory cytokine, IL-10. This neuroinflammatory phenotype is associated with down-regulation of CB1 receptor on neuronal cells and up-regulation of CB2 on microglia cells, conversely. Interestingly, blocking microglia activation with ibudilast during THC treatment significantly attenuates short-term memory impairments in adulthood, simultaneously preventing the increases in TNF-alpha, iNOS, COX-2 levels as well as the up-regulation of CB2 receptors on microglia cells. In contrast, THC-induced depressive-like behaviors were unaffected by ibudilast treatment. Our findings demonstrate that adolescent THC administration is associated with persistent neuroinflammation within the PFC and provide evidence for a causal association between microglial activation and the development long-term cognitive deficits induced by adolescent THC treatment. PMID- 26499172 TI - S100B interacts with the serotonin 5-HT7 receptor to regulate a depressive-like behavior. AB - The serotonin 5-HT7 receptor (5-HT7) is an emerging target for psychiatric pharmacotherapy. Recent observations in rodent models and humans suggest that its blockade mediates antidepressant efficacy. In the present study, we identify the Ca(2+)-binding protein S100B as an interacting partner of 5-HT7 and show that S100B negatively regulates inducible cyclic AMP (cAMP) accumulation in transfected HeLa cells and mouse cortical astrocytes. Overexpression of S100B causes brain region-specific dysregulation of the cAMP pathway in vivo, such that concentrations of cAMP in the frontal cortex are higher in S100B transgenic female mice compared to wild-types. Finally, S100B transgenic female mice show depressive-like behavior in the forced swim test (FST) and pharmacological blockade of 5-HT7 with SB269970 normalizes FST behavior. Taken together, our results show that S100B affects behavioral despair in female mice through functional interaction with the 5-HT7 receptor. Furthermore, we identify S100B as a cAMP-regulatory protein in cultured astrocytes and the murine frontal cortex. Future experiments will clarify whether there is a direct link between the 5-HT7 associated and cAMP-regulatory actions of S100B. PMID- 26499173 TI - NCAM-deficient mice show prominent abnormalities in serotonergic and BDNF systems in brain - Restoration by chronic amitriptyline. AB - Mood disorders are associated with alterations in serotonergic system, deficient BDNF (brain-derived neurotrophic factor) signaling and abnormal synaptic plasticity. Increased degradation and reduced functions of NCAM (neural cell adhesion molecule) have recently been associated with depression and NCAM deficient mice show depression-related behavior and impaired learning. The aim of the present study was to investigate potential changes in serotonergic and BDNF systems in NCAM knock-out mice. Serotonergic nerve fiber density and SERT (serotonin transporter) protein levels were robustly reduced in the hippocampus, prefrontal cortex and basolateral amygdala of adult NCAM(-)(/-) mice. This SERT reduction was already evident during early postnatal development. [(3)H]MADAM binding experiments further demonstrated reduced availability of SERT in cell membranes of NCAM(-)(/-) mice. Moreover, the levels of serotonin and its major metabolite 5-HIAA were down regulated in the brains of NCAM(-)(/-) mice. NCAM( )(/-) mice also showed a dramatic reduction in the BDNF protein levels in the hippocampus and prefrontal cortex. This BDNF deficiency was associated with reduced phosphorylation of its receptor TrkB. Importantly, chronic administration of antidepressant amitriptyline partially or completely restored these changes in serotonergic and BDNF systems, respectively. In conclusion, NCAM deficiency lead to prominent and persistent abnormalities in brain serotonergic and BDNF systems, which likely contributes to the behavioral and neurobiological phenotype of NCAM( /-) mice. PMID- 26499174 TI - Generalized Muller-Kern formula for equilibrium thickness of a wetting layer with respect to the dependence of the surface energy of island facets on the thickness of the 2D layer. AB - Experimental results indicate a particular importance of such a value as the equilibrium thickness of the wetting layer during epitaxial growth according to the Stranski-Krastanow mechanism in systems with a lattice mismatch. In this paper the change in free energy during the transition of atoms from the wetting layer to the island in such systems is considered. Recent experimental results also show that the surface energy of the island's facets depends upon the thickness of the deposited material. So, in this paper the equilibrium thickness of the wetting layer, at which transition from 2D to 3D growth becomes energetically favorable, is calculated with the assumption that the specific energy of the island's facets depends upon the wetting layer thickness. In this approximation a new generalized Muller-Kern formula is obtained. As an illustration of the proposed method, an example of a numerical calculation according to the new formula for the material system of germanium on a silicon (001) surface is given. The result for the found equilibrium thickness of the wetting layer is rather unexpected since it differs from the value obtained in the bounds of the traditional Muller-Kern model. PMID- 26499175 TI - A randomized, phase IIa exploratory trial to assess the safety and preliminary efficacy of LEO 43204 in patients with actinic keratosis. AB - BACKGROUND: LEO 43204 is a novel ingenol derivative in development for the treatment of actinic keratosis. OBJECTIVES: To compare the safety and preliminary efficacy of three doses of LEO 43204 with ingenol mebutate in actinic keratoses (AKs). METHODS: Patients with at least three visible, discrete, nonkeratotic AKs on four separate selected treatment areas on the forearms received LEO 43204 gel (0.025%, 0.05% and 0.075%) and ingenol mebutate 0.05% gel, by investigator blinded, randomized allocation, for 2 consecutive days. Patients were assessed at 8 weeks. Primary outcomes included maximum composite local skin response (LSR) score and adverse events (AEs). Secondary outcomes included a reduction in the number of visible AKs. RESULTS: Forty patients completed the trial. For all treatments, mean LSR scores peaked at week 1, and were below baseline by week 8. Mean maximum composite LSR scores for LEO 43204 0.025%, 0.05% and 0.075% were 9.2 (Dunnett adjusted P = 0.02), 10.1 (Dunnett adjusted P = 0.90) and 11.2 (Dunnett adjusted P < 0.01), respectively, vs. ingenol mebutate 0.05% gel (10.0). The most frequent AEs across all treatments were application site pruritus, burning sensation and tenderness. Mean reduction in the number of AKs was comparable for ingenol mebutate and the two lowest doses of LEO 43204 (71.9-73.1%), but LEO 43204 0.075% gave a significantly larger reduction (81.8%; Dunnett adjusted P = 0.04). CONCLUSIONS: LEO 43204 had a similar safety profile to ingenol mebutate and a dose-response relationship for LSRs was demonstrated. The highest LEO 43204 dose (0.075%) significantly reduced the AK count when compared with ingenol mebutate. PMID- 26499176 TI - Use of Insulin Lispro Protamine Suspension in Pregnancy. AB - Maternal metabolism changes substantially during pregnancy, which poses numerous challenges to physicians managing pregnancy in women with diabetes. Insulin is the agent of choice for glycemic control in pregnant women with diabetes, and the insulin analogs are particularly interesting for use in pregnancy. These agents may reduce the risk of hypoglycemia and promote a more physiological glycemic profile than regular human insulin in pregnant women with type 1 (T1D), type 2 (T2D), or gestational (GDM) diabetes. However, there have been concerns regarding potential risk for crossing the placental barrier, mitogenic stimulation, teratogenicity, and embryotoxicity. Insulin lispro protamine suspension (ILPS), an intermediate- to long-acting insulin, has a stable and predictable pharmacological profile, and appears to have a favorable time-action profile and produce desirable basal and postprandial glycemic control. As the binding of insulin lispro is unaffected by the protamine molecule, ILPS is likely to have the same mitogenic and immunogenic potential as insulin lispro. Insulin lispro produces similar outcomes to regular insulin in pregnant women with T1D, T2D, or GDM, does not cross the placental barrier, and is considered a useful treatment option for pregnant women with diabetes. Clinical data support the usefulness of ILPS for basal insulin coverage in non-pregnant patients with T1D or T2D, and suggest that the optimal regimen, in terms of balance between efficacy and hypoglycemic risk, is a once-daily injection, especially in patients with T2D. Available data concerning use of ILPS in pregnant women are currently derived from retrospective analyses that involved, in total, >1200 pregnant women. These analyses suggest that ILPS is at least as safe and effective as neutral protamine Hagedorn insulin. Thus, available experimental and clinical data suggest that ILPS once daily is a safe and effective option for the management of diabetes in pregnant women. PMID- 26499177 TI - Current Management of Primary Immune Thrombocytopenia. AB - Primary immune thrombocytopenia is an autoimmune disorder of unknown cause affecting both children and adults. The low peripheral blood platelet count is caused by premature platelet destruction by self-reacting antibodies in addition to an impairment of platelet production. The disease is heterogeneous in its pathophysiology, clinical features and responses to treatment. To date, most of the treatments used have been immune-modulating drugs and these contribute to increased morbidity and mortality in patients. A new class of drugs, the thrombopoietin receptor agonists, has been developed for use in ITP. These have gone through randomised controlled trials in large numbers of patients with ITP. These drugs have high efficacy and are well tolerated. In addition, around 30% of patients receiving these drugs are able to stop them and maintain a safe or normal platelet count. Older treatments such as splenectomy are being used less than before, largely because of the introduction of the thrombopoietin receptor agonists. Currently there are trials underway evaluating novel therapies for ITP that will become available over the next few years once the trials are complete. PMID- 26499179 TI - Anxiety, depression and autonomy-connectedness: The mediating role of alexithymia and assertiveness. AB - OBJECTIVE: Autonomy-connectedness (self-awareness, sensitivity to others, and capacity for managing new situations) reflects the capacity for self-governance, including in social relationships. Evidence showed that autonomy-connectedness is related to anxiety and depression. Little is known about the underlying mechanisms. We hypothesized that alexithymia and assertiveness would mediate the relationships between autonomy-connectedness and anxiety and depression. METHOD: Relationships among the variables were investigated in 100 patients with a mean age of 42.2 suffering from anxiety and/or depression using a cross-sectional design. RESULTS: The relationship between self-awareness and both anxiety and depression was mediated by alexithymia. For anxiety, there was also a direct effect of sensitivity to others that was not explained by either alexithymia or assertiveness. Assertiveness did not have any mediational effect. CONCLUSIONS: The results indicate that particularly alexithymia explains the association of autonomy-connectedness with anxiety and depression. PRACTITIONER POINTS: The study confirmed the relevance of autonomy-connectedness in anxiety and depression. In treating symptoms of anxiety, it is advisable to give attention to normalizing the patient's sensitivity to others. Treatment of patients with symptoms of anxiety and depression should include assessment of emotional awareness and, in the case of impaired emotional awareness, should be tailored as to promote increased awareness. PMID- 26499180 TI - MicroRNA-200a suppresses epithelial-to-mesenchymal transition in rat hepatic stellate cells via GLI family zinc finger 2. AB - Hepatic stellate cells (HSCs) have an important role in liver fibrosis. Epithelial-to-mesenchymal transition (EMT), which is promoted by the Hedgehog (Hh) signaling pathway, is involved in the activation of HSCs. MicroRNAs (miRNAs/miRs) have been reported to be involved in the progression of liver fibrosis. A previous study indicated that the activation of HSCs was suppressed by miR-200a via targeting transforming growth factor-beta2 and beta-catenin. However, whether miR-200a is able to regulate the EMT in HSCs has remained elusive. The present study revealed that miR-200a was decreased in vitro and in vivo during liver fibrosis. Furthermore, miR-200a overexpression resulted in the inhibition of proliferation, alpha-SMA expression and extracellular matrix production of activated HSCs. Of note, miR-200a overexpression reduced myofibroblastic markers, including alpha-SMA, type I collagen and desmin, and increased the epithelial cell marker E-cadherin. These results were further confirmed by immunofluorescence staining. Further study showed that the expression of genes associated with Hh signaling, including Hhip, Shh and Gli1, were not affected by miR-200a. However, Gli2, a downstream signaling protein of the Hh pathway, was inhibited by miR-200a and confirmed as a target of miR-200a using a dual luciferase reporter assay. In addition, the inhibition of the Hh pathway by miR-200a resulted in an increase of BMP-7 and Id2 as well as a reduction of Snai1 and S100A4. Collectively, the results of the present study demonstrated that miR-200a suppressed the EMT process in HSCs, at least in part, via Gli2. PMID- 26499181 TI - Vascular nitric oxide: Beyond eNOS. AB - As the first discovered gaseous signaling molecule, nitric oxide (NO) affects a number of cellular processes, including those involving vascular cells. This brief review summarizes the contribution of NO to the regulation of vascular tone and its sources in the blood vessel wall. NO regulates the degree of contraction of vascular smooth muscle cells mainly by stimulating soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), although cGMP-independent signaling [S-nitrosylation of target proteins, activation of sarco/endoplasmic reticulum calcium ATPase (SERCA) or production of cyclic inosine monophosphate (cIMP)] also can be involved. In the blood vessel wall, NO is produced mainly from l-arginine by the enzyme endothelial nitric oxide synthase (eNOS) but it can also be released non-enzymatically from S-nitrosothiols or from nitrate/nitrite. Dysfunction in the production and/or the bioavailability of NO characterizes endothelial dysfunction, which is associated with cardiovascular diseases such as hypertension and atherosclerosis. PMID- 26499178 TI - Prevalence, Treatment, and Control of Hypercholesterolemia in High Cardiovascular Risk Patients: Evidences from a Systematic Literature Review in Spain. AB - INTRODUCTION: Cardiovascular diseases (CVDs) represent a major Public Health burden. High serum cholesterol levels have been linked to major CV risk. The objectives of this study were to review the epidemiology of hypercholesterolemia in high risk CV patients from Spain, by assessing its prevalence, the proportion of diagnosed patients undergoing pharmacological treatment and the degree of attained lipid control. METHODS: A systematic literature review was carried out using Medline and two Spanish databases. Manuscripts containing information on hypercholesterolemia in several high CV risk groups [diabetes mellitus (DM), Systematic COronary Risk Evaluation (SCORE) risk >5, or documented CVD], published between January 2010 and October 2014, were included. RESULTS: Of the 1947 published references initially retrieved, a full-text review was done on 264 manuscripts and 120 were finally included. Prevalence of hypercholesterolemia ranged from 50 to 84% in diabetics, 30-60% in patients with DM or elevated SCORE risk, 64-74% with coronary heart disease, 40-70% in stroke patients, and 60-80% in those with peripheral artery disease. Despite the finding that most of them were on pharmacological treatment, acceptable control of serum lipids was very variable, ranging from 15% to 65%. Among those with heterozygous familial hypercholesterolemia, 95-100% received treatment but less than 50% achieved their therapeutic goals. CONCLUSIONS: An elevated prevalence of hypercholesterolemia can be found in targeted groups at high CV risk. Although most patients are receiving pharmacological treatment, rates of lipid control continue to be low, both in primary and secondary prevention. PMID- 26499182 TI - Involvement of calpain in 4-hydroxynonenal-induced disruption of gap junction mediated intercellular communication among fibrocytes in primary cultures derived from the cochlear spiral ligament. AB - The endocochlear potential in the inner ear is essential for hearing ability, and maintained by various K(+) transport apparatuses including Na(+), K(+)-ATPase and gap junction-mediated intercellular communication (GJ-IC) in the lateral wall structures of the cochlea. Noise-induced hearing loss is known at least in part due to disruption of GJ-IC resulting from an oxidative stress-induced decrease in connexins (Cxs) level in the lateral wall structures. The purpose of this study was to investigate, using primary cultures of fibrocytes from the cochlear spiral ligament of mice, the mechanism underlying GJ-IC disruption induced by 4 hydroxynonenal (4-HNE), which is formed as a mediator of oxidative stress. An exposure to 4-HNE produced the following events: i.e., an increase in 4-HNE adducted proteins; a decrease in the protein levels of Cx43, beta-catenin, and Cx43/beta-catenin complex along with intracellular translocation of this complex from the cell membrane to the cytoplasm; enhanced calpain-dependent degradation of endogenous alpha-fodrin; and disruption of GJ-IC. The 4-HNE-induced decrease in these protein levels and disruption of GJ-IC were most completely abolished by the calpain inhibitor PD150606. Taken together, our data suggest that 4-HNE disrupted GJ-IC through calpain-mediated degradation of Cx43 and beta-catenin in primary cultures of fibrocytes derived from the cochlear spiral ligament. PMID- 26499183 TI - Nationwide trophic cascades: changes in avian community structure driven by ungulates. AB - In recent decades, many ungulate populations have changed dramatically in abundance, resulting in cascading effects across ecosystems. However, studies of such effects are often limited in their spatial and temporal scope. Here, we contrast multi-species composite population trends of deer-sensitive and deer tolerant woodland birds at a national scale, across Britain. We highlight the divergent fates of these two groups between 1994 and 2011, and show a striking association between the calculated divergence and a composite population trend of woodland deer. Our results demonstrate the link between changes in deer populations and changes in bird communities. In a period when composite population trends for deer increased by 46%, the community population trend across deer-sensitive birds (those dependent on understory vegetation) declined much more than the community trend for deer-tolerant birds. Our findings suggest that ongoing changes in the populations of herbivorous ungulates in many countries worldwide may help explain patterns of community restructuring at other trophic levels. Ungulate impacts on other taxa may require more consideration by conservation practitioners than they currently receive. PMID- 26499184 TI - Methylation-induced silencing of miR-34a enhances chemoresistance by directly upregulating ATG4B-induced autophagy through AMPK/mTOR pathway in prostate cancer. AB - miR-34a is downregulated and a regulator of drug resistance in prostate cancer (PCa). However, the mechanism of miR-34a in chemoresistance of PCa remains largely unknown. In the present study, we first confirmed the hypermethylation induced downregulation of miR-34a in PCa tissues and cell lines, PC-3 and DU145. Additionally, transfection of miR-34a mimics and demethylation by 5-azacytidine both resulted in the upregulation of miR-34a expression, which further induced declined cell proliferation and the enhanced apoptosis in PCa cells. Upregulation of miR-34a enhanced the chemosensitivity of PC-3 and DU145 cells. Furthermore, overexpression of miR-34a reduced the expression of autophagy-related proteins, ATG4B, Beclin-1 and LC3B II/I in PCa cells and demethylation treatment showed similar effect. ATG4B was confirmed directly by miR-34a targeting in PCa. Finally, downregulated p-AMPK and upregulated p-mTOR were detected in miR-34a overexpressed PCa cells. Collectively, miR-34a enhances chemosensitivity by directly downregulating ATG4B-induced autophagy through AMPK/mTOR pathway in PCa. PMID- 26499185 TI - Entomopoxvirus infection induces changes in both juvenile hormone and ecdysteroid levels in larval Mythimna separata. AB - Insect viruses are among the most important pathogens of lepidopteran insects. Virus-infected larvae often show developmental defects including a prolonged larval period and a failure to pupate, but the mechanisms by which insect viruses regulate host development need further investigation. In this study, the regulation of host endocrinology by a lepidopteran entomopoxvirus (EPV), Mythimna separata EPV (MySEV), was examined. When fourth instar M. separata were inoculated with MySEV occlusion bodies, pupation was prevented and the insects died during the final (sixth) larval instar. Liquid chromatography-MS analysis revealed that juvenile hormone (JH) titres in the haemolymph of MySEV-infected sixth instars were higher than those in mock-infected larvae. JH esterase (JHE) activity was also examined by kinetic assay using a colorimetric substrate. The level of JHE activity in the haemolymph of MySEV-infected larvae was generally lower than that found in mock-infected larvae. In contrast, ecdysteroid titre in the haemolymph of final-instar MySEV-infected larvae was lower than that found in mock-infected larvae when measured by radioimmunoassay. A statistically significant difference in the release of ecdysteroids from prothoracic glands (PGs) that were dissected from MySEV- or mock-infected sixth instar Day 3 larvae was not found following prothoracicotropic hormone (PTTH) exposure. Our results indicate that the release of ecdysteroids was reduced not by infection of the PGs by MySEV, but by reduced PTTH production from the brain. Taken together our study suggests that EPVs retard host development by both reducing ecdysone titre and maintaining status quo levels of JH by preventing its metabolism. PMID- 26499186 TI - Ethical issues surrounding the provider initiated opt--Out prenatal HIV screening practice in Sub-Saharan Africa: a literature review. AB - BACKGROUND: Prevention of mother to child transmission of HIV remains a key public health priority in most developing countries. The provider Initiated Opt - Out Prenatal HIV Screening Approach, recommended by the World Health Organization (WHO) lately has been adopted and translated into policy in most Sub - Saharan African countries. To better ascertain the ethical reasons for or against the use of this approach, we carried out a literature review of the ethics literature. METHODS: Papers published in English and French Languages between 1990 and 2015 from the following data bases were searched: Pubmed, Cochrane literature, Embase, Cinhal, Web of Science and Google Scholar. After screening from 302 identified relevant articles, 21 articles were retained for the critical review. DISCUSSION: Most authors considered this approach ethically justifiable due to its potential benefits to the mother, foetus and society (Beneficence). The breaching of respect for autonomy was considered acceptable on the grounds of libertarian paternalism. Most authors considered the Opt - Out approach to be less stigmatizing than the Opt - In. The main arguments against the Opt - Out approach were: non respect of patient autonomy, informed consent becoming a meaningless concept and the HIV test becoming compulsory, risk of losing trust in health care providers, neglect of social and psychological implications of doing an HIV test, risk of aggravation of stigma if all tested patients are not properly cared for and neglect of sociocultural peculiarities. CONCLUSIONS: The Opt - Out approach could be counterproductive in case gender sensitive issues within the various sociocultural representations are neglected, and actions to offer holistic care to all women who shall potentially test positive for HIV were not effectively ascertained. The Provider Initiated Opt - Out Prenatal HIV Screening option remains ethically acceptable, but deserves caution, active monitoring and evaluation within the translation of this approach into to practice. PMID- 26499187 TI - Coronary Vasospasm Due to Compression of a Pseudoaneurysm of the Ascending Aorta After Heart Surgery. PMID- 26499189 TI - Hepatic tuberculosis: a multimodality imaging review. AB - OBJECTIVES: We aim to illustrate the multimodal imaging spectrum of hepatic involvement in tuberculosis (TB). Whilst disseminated tuberculosis on imaging typically manifests as multiple small nodular lesions scattered in the liver parenchyma, isolated hepatic tuberculosis remains a rare and intriguing entity. METHODS: Indubitably, imaging is the mainstay for detection of tubercular hepatic lesions which display a broad spectrum of imaging manifestations on different modalities. While sonography and computed tomography (CT) findings have been described in some detail, there is a paucity of literature on magnetic resonance imaging (MRI) features. Due to a significant overlap with other commoner and similar appearing hepatic lesions, hepatic tuberculosis is often either misdiagnosed or labelled as indeterminate lesions. This article is a compendium of cases highlighting the spectrum of imaging patterns that can be encountered in patients with isolated primary hepatic tuberculosis as well as disseminated (secondary) disease. Rare patterns of primary disease such as tubercular cholangitis, hypervascular liver masses, and those with vascular complications are also illustrated and discussed. CONCLUSIONS: Imaging plays a valuable role in the detection of tubercular hepatic lesions. Also, imaging can be helpful in their characterisation and for assessing associated complications. TEACHING POINTS: * Hepatic TB has myriad imaging manifestations and is often confounded with neoplastic lesions. * Imaging patterns include miliary TB, macronodular TB, serohepatic TB and tubercular cholangitis. * Concurrent splenic, nodal or pulmonary involvements are helpful pointers towards the diagnosis. * Miliary calcifications along the bile ducts are characteristic of tubercular cholangitis. * Histological/microbiological confirmation is often necessary to confirm the diagnosis. PMID- 26499188 TI - Ocular vestibular-evoked myogenic potentials using air-conducted sound: test parameters and normative data in healthy children; effect of body position on threshold. AB - In the present prospective study, we both investigated positioning techniques for the enhancement of oVEMP procedures and the viability of oVEMP testing in a healthy children population. A total of 41 healthy children were enrolled in this study. 21 were boys and 20 were girls, with their ages ranging from 4 to 16 years. All children underwent audiometry and tympanometry prior to oVEMP test in upright and supine position. All subjects had normal hearing. The procedure was well tolerated by all children. Typical biphasic oVEMPs presented in 97.56 % in upright position and 90.25 % in the supine position. No statistically significant difference could be found concerning which position elicits the best or worst responses. However, a trend towards the supine position was noticed. It may be concluded that oVEMP test proved to be a well-tolerated examination of the vestibular system in children aged above 4 years old. Our results did not show a statistical difference on the oVEMP thresholds between the two body positions. However, further larger studies are needed to confirm these findings. PMID- 26499190 TI - ATP-binding cassette sub-family C member 4 (ABCC4) is overexpressed in human NK/T cell lymphoma and regulates chemotherapy sensitivity: Potential as a functional therapeutic target. AB - Nasal-type natural killer/T-cell (NK/T-cell) lymphomas are subtypes of non Hodgkin's lymphoma (NHL), which are typically more clinically aggressive. There is, however relatively little understanding of nasal-type NK/T-cell lymphoma molecular pathogenesis. Thus, in this study we applied RNA sequencing to systematically screen for altered gene expression in human NK/T-cell lymphoma cell lines YTS and SNK-6 versus normal NK cells. We found that ATP-binding cassette sub-family C Member 4 (ABCC4) levels were significantly upregulated both in human NK/T-cell lymphoma YTS and SNK-6 cells, as compared with normal NK cells. These expression levels were further confirmed by real-time PCR. Protein levels of ABCC4 were also significantly higher in YTS and SNK-6 cells as compared with normal NK cells. Clinically relevant, ABCC4 expression levels were significantly higher in human NK/T-cell lymphoma tissues as compared with control nasal mucosa tissues, confirmed by immunohistochemical staining. In addition, we explored the biological function of such ABCC4 upregulation. Overexpression of ABCC4 by lentivirus transfection induced chemotherapy resistance to epirubicin (EPI) and cisplatin (DDP) in YTS cells. In contrast, knockdown of ABCC4 expression by shRNA contributed to chemotherapy sensitivity by both EPI and DDP. Furthermore, overexpression of ABCC4 inhibited, while downregulation of ABCC4 increased, YTS cell apoptosis following treatment by EPI or DDP. Therefore, the present study identified ABCC4 to be overexpressed in human NK/T-cell lymphoma cells, to regulate chemotherapy sensitivity to EPI and DDP, and possibly to be a functional therapeutic target. These findings may provide a basic rationale for new approaches in the effort to develop anti-tumor therapeutics for NK/T-cell lymphoma. PMID- 26499191 TI - Differential item functioning (DIF) of SF-12 and Q-LES-Q-SF items among french substance users. AB - BACKGROUND: Differential Item Functioning (DIF) is investigated to ensure that each item displays a consistent pattern of responses irrespective of the characteristics of the respondents. Assessing DIF helps to understand the nature of instruments, to assess the quality of a measure and to interpret results. This study aimed to examine whether the items of the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) and Short-Form 12 (SF-12) exhibit DIF. METHOD: A total of 124 outpatients diagnosed with substance dependence participated in a cross-sectional, multicenter study. In addition to the Q-LES-Q-SF and SF-12 results, demographic data such as age, sex, type of substance dependence and education level were collected. Rasch analysis was conducted (using RUMM2020 software) to assess DIF of the Q-LES-Q-SF and SF-12 items. RESULTS: For SF-12, significant age-related uniform DIF was found in two of the 12 items, and sex-related DIF was found in one of the 12 items. All of the observed DIF effects in SF-12 were found among the mental health items. Three items showed DIF on the Q-LES-Q-SF; however, the impact of DIF item on the delta score calculation for the comparisons of self-reported health status between the groups was minimal in the SF-12 and small in the Q-LES-Q-SF. CONCLUSION: These results indicated that no major measurement bias affects the validity of the self reported health status assessed using the Q-LES-Q-SF or SF-12. Thus, these questionnaires are largely robust measures of self-reported health status among substance users. PMID- 26499193 TI - Caffeine and saliva steroids in young healthy recreationally trained women: impact of regular caffeine intake. PMID- 26499192 TI - False positive diagnosis on (131)iodine whole-body scintigraphy of differentiated thyroid cancers. AB - (131)Iodine is used both to ablate any residual thyroid tissue or metastatic disease and to obtain whole-body diagnostic images after total thyroidectomy for differentiated thyroid cancer (DTC). Even though whole-body scan is highly accurate in showing thyroid residues as well as metastases of DTC, false positive results can be found, possibly leading to diagnostic errors and unnecessary treatments. This paper reviews the physiological and pathological processes involved as well as the strategy to recognize and rule out false positive radioiodine images. PMID- 26499195 TI - Statistical challenges for central monitoring in clinical trials: a review. AB - Recently, the complexity and costs of clinical trials have increased dramatically, especially in the area of new drug development. Risk-based monitoring (RBM) has been attracting attention as an efficient and effective trial monitoring approach, which can be applied irrespectively of the trial sponsor, i.e., academic institution or pharmaceutical company. In the RBM paradigm, it is expected that a statistical approach to central monitoring can help improve the effectiveness of on-site monitoring by prioritizing and guiding site visits according to central statistical data checks, as evidenced by examples of actual trial datasets. In this review, several statistical methods for central monitoring are presented. It is important to share knowledge about the role and performance capabilities of statistical methodology among clinical trial team members (i.e., sponsors, investigators, data managers, monitors, and biostatisticians) in order to adopt central statistical monitoring for assessing data quality in the actual clinical trial. PMID- 26499194 TI - Investigation of common and rare genetic variation in the BAMBI genomic region in light of human obesity. AB - The aim of this study was to confirm the previously identified link between BAMBI and human obesity by means of a genetic and functional analysis. We performed both a mutation analysis, using high-resolution melting curve analysis, and a genetic association study, including 8 common tagSNPs in the BAMBI gene region. Three of the identified genetic variants (R151W, H201R, and C229R) were evaluated for their Wnt signaling enhancing capacity in a Wnt luciferase reporter assay. Mutation screening of the BAMBI coding region and exon-intron boundaries on our population of 677 obese children and adolescents and 529 lean control subjects resulted in the identification of 18 variants, 10 of which were not previously reported and 12 of which were exclusively found in obese individuals. The difference in variant frequency, not taking into account common polymorphisms, between obese (3.1 %) and lean (0.9 %) subjects was statistically significant (p = 0.004). Our Wnt luciferase assay, using WT and mutant BAMBI constructs, showed a significantly reduced activity for all of the investigated variants. Logistic and linear regression analysis on our Caucasian population of 1022 obese individuals and 606 lean controls, did not identify associations with obesity parameters (p values >0.05). We found several rare genetic variations, which represent the first naturally occurring missense variants of BAMBI in obese patients. Three variants (R151W, H201R, and C229R) were shown to reduce Wnt signaling enhancing capacity of BAMBI and we believe this result should encourage further study of this gene in other obese populations. In addition, we did not find evidence for the involvement of BAMBI common variation in human obesity in our population. PMID- 26499196 TI - Effects of sediment dredging on nitrogen cycling in Lake Taihu, China: Insight from mass balance based on a 2-year field study. AB - Sediment dredging can permanently remove pollutants from an aquatic ecosystem, which is considered an effective approach to aquatic ecosystem restoration. In this work, a 2-year field simulation test was carried out to investigate the effect of dredging on nitrogen cycling across the sediment-water interface (SWI) in Lake Taihu, China. The results showed that simulated dredging applied to an area rich in total organic carbon (TOC) and total nitrogen (TN) slightly reduced the NH4(+)-N release from sediments while temporarily enhanced the NH4(+)-N release in an area with lower TOC and/or TN (in the first 180 days), although the application had a limited effect on the fluxes of NO2(-)-N and NO3(-)-N in both areas. Further analysis indicated that dredging induced decreases in nitrification, denitrification, and anaerobic ammonium oxidation (anammox) in sediments, notably by 76.9, 49.0, and 89.9%, respectively, in the TOC and/or TN rich area. Therefore, dredging slowed down nitrogen cycling rates in sediments but did not increase N loading to overlying water. The main reason for the above phenomenon could be attributed to the removal of the surface sediments enriched with more TOC and/or TN (compared with the bottom sediments). Overall, to minimize internal N pollution, dredging may be more applicable to nutrient-rich sediments. PMID- 26499197 TI - Formation of hydroxyl radicals and kinetic study of 2-chlorophenol photocatalytic oxidation using C-doped TiO2, N-doped TiO2, and C,N Co-doped TiO2 under visible light. AB - This work reports on synthesis, characterization, adsorption ability, formation rate of hydroxyl radicals (OH(*)), photocatalytic oxidation kinetics, and mineralization ability of C-doped titanium dioxide (TiO2), N-doped TiO2, and C,N co-doped TiO2 prepared by the sol-gel method. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and UV-visible spectroscopy were used to analyze the titania. The rate of formation of OH(*) for each type of titania was determined, and the OH-index was calculated. The kinetics of as-synthesized TiO2 catalysts in photocatalytic oxidation of 2-chlorophenol (2-CP) under visible light irradiation were evaluated. Results revealed that nitrogen was incorporated into the lattice of titania with the structure of O-Ti-N linkages in N-doped TiO2 and C,N co-doped TiO2. Carbon was joined to the Ti-O-C bond in the C-doped TiO2 and C,N co-doped TiO2. The 2-CP adsorption ability of C,N co-doped TiO2 and C doped TiO2 originated from a layer composed of a complex carbonaceous mixture at the surface of TiO2. C,N co-doped TiO2 had highest formation rate of OH(*) and photocatalytic activity due to a synergistic effect of carbon and nitrogen co doping. The order of photocatalytic activity per unit surface area was the same as that of the formation rate of OH(*) unit surface area in the following order: C,N co-doped TiO2 > C-doped TiO2 > N-doped TiO2 > undoped TiO2. PMID- 26499198 TI - Development of a dynamic mathematical model for membrane bioelectrochemical reactors with different configurations. AB - Membrane bioelectrochemical reactors (MBERs) integrate membrane filtration into bioelectrochemical systems for sustainable wastewater treatment and recovery of bioenergy and other resource. Mathematical models for MBERs will advance the understanding of this technology towards further development. In the present study, a mathematical model was implemented for predicting current generation, membrane fouling, and organic removal within MBERs. The relative root-mean-square error was used to examine the model fit to the experimental data. It was found that a constant to determine how fast the internal resistance responds to the change of the anodophillic microorganism concentration could have a dominant impact on current generation. Hydraulic cross-flow exhibited a minor effect on membrane fouling unless it was reduced below 0.5 m s(-1). This MBER model encourages further optimization and eventually can be used to guide MBER development. PMID- 26499199 TI - Encystment/excystment response and serotypic variation in the gastropod parasite Tetrahymena rostrata (Ciliophora, Tetrahymenidae). AB - Tetrahymena rostrata, which is characterized by a particular encystment excystment cycle involving autogamy, has been recently found infecting the kidney of edible Helix aspersa snails under farming conditions. In this work, the effects of several factors on its encystment/excystment behaviour and the occurrence of different serotypes were investigated. The encystment/excystment response under starvation conditions was seriously affected by temperature. While a peak of encystment at 48 h followed by a progressive spontaneous excystment was observed at 18 and 25 degrees C, the encystment response was practically inhibited at 5 degrees C and clearly slowed down at 10 degrees C. At 30 degrees C, most of surviving ciliates remained encysted throughout the experiment, with spontaneous excystment being detected only after switching the temperature to 18 degrees C. Soil components also affected the encystment/excystment behaviour at 18 degrees C, with spontaneous excystment occurring in the presence of a sterile-filtered soil extract or mineral water but being strongly minimized with a non-filtered soil extract. Resting cysts formed in the latter extract exhibited a 3-4 times thicker and ultrastructurally more complex wall than that formed in mineral water and retained the excystment ability for about 4 weeks. Incomplete desiccation did not affect significantly the encystment response, while the mucus and kidney extracts from snails as well as a ciliate extract strongly stimulated a rapid excystment. Finally, two different serotypes infecting H. aspersa in heliciculture farms of Galicia (NW Spain) were identified, but no differences were observed between the encystment/excystment responses exhibited by two isolates belonging to each serotype. PMID- 26499200 TI - Curcumin inhibits cancer-associated fibroblast-driven prostate cancer invasion through MAOA/mTOR/HIF-1alpha signaling. AB - Cancer-associated fibroblasts (CAFs) are key determinants in the malignant progression of cancer, supporting tumorigenesis and metastasis. CAFs also mediate epithelial to mesenchymal transition (EMT) in tumor cells and their achievement of stem cell traits. Curcumin has recently been found to possess anticancer activities via its effect on a variety of biological pathways involved in cancer progression. In this study, we found that CAFs could induce prostate cancer cell EMT and invasion through a monoamine oxidase A (MAOA)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1alpha (HIF-1alpha) signaling pathway, which exploits reactive oxygen species (ROS) to drive a migratory and aggressive phenotype of prostate carcinoma cells. Moreover, CAFs was able to increase CXC chemokine receptor 4 (CXCR4) and interleukin-6 (IL-6) receptor expression in prostate cancer cells. However, curcumin abrogated CAF-induced invasion and EMT, and inhibited ROS production and CXCR4 and IL-6 receptor expression in prostate cancer cells through inhibiting MAOA/mTOR/HIF-1alpha signaling, thereby supporting the therapeutic effect of curcumin in prostate cancer. PMID- 26499202 TI - Integrated molecular pathology: the Belfast model. PMID- 26499201 TI - Gambling Risk Amongst Adolescents: Evidence from a School-Based Survey in the Malaysian Setting. AB - There has been emerging evidence regarding gambling experiences of young people in Asia recently, but to date, none in Malaysia. This study aimed to estimate the prevalence of gambling, and to identify individual, familial and high-risk behaviours factors among Malaysian adolescents. A cross-sectional study was conducted over 4 months at randomly selected secondary schools in Seremban in Negeri Sembilan state. A total of 2265 self-administered, anonymous questionnaires were distributed to the students. The students completed the questionnaire consisting of sociodemographic and family background, gambling behaviours, high risk behaviours and mental health questions. Approximately 29.6 % (95 % CI 27.7-31.5) of respondents reported participating in some forms of gambling activities in the previous 12 months. Among these, 3.6 % (95 % CI 2.8 4.3) of them were problem gamblers. Parental gambling was the strongest correlate with adolescent gambling behaviour. Signification association was found between gambling behaviour and gender (being males), but interestingly, not with ethnicity. Adolescents who reported engaging in high risk behaviours (such as smoking, alcohol consumption, involvement in physical fights, illegal vehicular racing) were also more likely to gamble. Gambling is not an uncommon phenomenon amongst Malaysian adolescents. Public awareness campaign, health education to targeted groups, revision of existing laws, and screening at primary care level should be implemented to address the issue of gambling among adolescents. This study also highlights the need to examine the national scope of the problem in Malaysia. PMID- 26499203 TI - Homosexuality as a Discrete Class. AB - Previous research on the latent structure of sexual orientation has returned conflicting results, with some studies finding a dimensional structure (i.e., ranging quantitatively along a spectrum) and others a taxonic structure (i.e., categories of individuals with distinct orientations). The current study used a sample (N = 33,525) from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). A series of taxometric analyses were conducted using three indicators of sexual orientation: identity, behavior, and attraction. These analyses, performed separately for women and men, revealed low-base-rate same-sex oriented taxa for men (base rate = 3.0%) and women (base rate = 2.7%). Generally, taxon membership conferred an increased risk for psychiatric and substance-use disorders. Although taxa were present for men and women, women demonstrated greater sexual fluidity, such that any level of same-sex sexuality conferred taxon membership for men but not for women. PMID- 26499204 TI - Toxoplasma gondii seroprevalence: 30-year trend in an HIV-infected US military cohort. AB - To determine if Toxoplasma gondii IgG antibody prevalence is declining in HIV infected persons, we analyzed data (1984-2013) from the US Military HIV Natural History Study. We found that T. gondii seroprevalence at enrollment was associated with age and decreased significantly after 1995 (P=0.004), similar to the general US population. PMID- 26499205 TI - What's burning got to do with it? Primate foraging opportunities in fire-modified landscapes. AB - OBJECTIVES: Anecdotal and formal evidence indicate that primates take advantage of burned landscapes. However, little work has been done to quantify the costs and benefits of this behavior. Using systematic behavioral observations from a population of South African vervet monkeys (Chlorocebus aethiops pygerythrus), we evaluate differences in food availability and energetics before and after controlled burns altered vegetation near their home range. We aim to determine whether burned habitats offer improved foraging opportunities. METHODS: We collected feeding data from foraging individuals and analyzed common plant foods for their energetic content. We then used the feeding and energetic data to calculate postencounter profitabilities and encounter rates for food types. Using negative binomial and mixed linear regression models we compared data from burned and unburned habitats. RESULTS: Our results show significantly improved encounter rates in burned landscapes for two prey items, invertebrates and grasses. However, postencounter profitabilities in burned areas were not significantly different than those achieved in unburned areas. CONCLUSIONS: Results suggest that improved encounters alone can motivate changes in foraging behavior. These foraging benefits enable the exploitation of burned savanna habitats, likely driving postburn range expansions observed among populations of vervet monkeys. Thus quantified, these results may serve as a foundation for hypotheses regarding the evolution of fire-use in our own lineage. PMID- 26499206 TI - Resveratrol alleviates diabetes-induced testicular dysfunction by inhibiting oxidative stress and c-Jun N-terminal kinase signaling in rats. AB - Diabetes adversely affects reproductive functions in humans and animals. The present study investigated the effects of Resveratrol on diabetes-induced alterations in oxidative stress, c-Jun N-terminal kinase (JNK) signaling and apoptosis in the testis. Adult male Wistar rats (13-15 weeks; n=6/group) were segregated into 1) normal control, 2) Resveratrol-treated (5mg/kg; ip; given during last 3 weeks), 3) Streptozotocin-induced diabetic and, 4) Resveratrol treated diabetic groups, and euthanized on day 42 after the confirmation of diabetes. Resveratrol did not normalize blood glucose levels in diabetic rats. Resveratrol supplementation recovered diabetes-induced decreases in reproductive organ weights, sperm count and motility, intra-testicular levels of superoxide dismutase, catalase, and glutathione peroxidase and an increase in 4 hydroxynonenal activities (P<0.05). Resveratrol also recovered diabetes-induced increases in JNK signaling pathway proteins, namely, ASK1 (apoptosis signal regulating kinase 1), JNKs (46 and 54 kDa isoforms) and p-JNK to normal control levels (P<0.05). Interestingly, the expression of a down-stream target of ASK1, MKK4 (mitogen-activated protein kinase kinase 4) and its phosphorylated form (p MKK4) did not change in experimental groups. Resveratrol inhibited diabetes induced increases in AP-1 (activator protein-1) components, c-Jun and ATF2 (activating transcription factor 2), but not their phosphorylated forms, to normal control levels (P<0.05). Further, Resveratrol inhibited diabetes-induced increase in cleaved-caspase-3 to normal control levels. In conclusion, Resveratrol alleviates diabetes-induced apoptosis in testis by modulating oxidative stress, JNK signaling pathway and caspase-3 activities, but not by inhibiting hyperglycemia, in rats. These results suggest that Resveratrol supplementation may be a useful strategy to treat diabetes-induced testicular dysfunction. PMID- 26499207 TI - The Trifluoromethyl Anion. AB - First evidence for the existence of free trifluoromethyl anion CF3 (-) has been obtained. The 3D-caged potassium cation in [K(crypt-222)](+) is inaccessible to CF3 (-) , thus rendering it uncoordinated ("naked"). Ionic [K(crypt-222)](+) CF3 (-) has been characterized by single-crystal X-ray diffraction, solution NMR spectroscopy, DFT calculations, and reactivity toward electrophiles. PMID- 26499208 TI - Tailoring dye-sensitized upconversion nanoparticle excitation bands towards excitation wavelength selective imaging. AB - One of the key roadblocks in UCNP development is its extremely limited choices of excitation wavelengths. We report a generic design to program UCNPs to possess highly tunable dye characteristic excitation bands. Using such distinctive properties, we were able to develop a new excitation wavelength selective security imaging. This work unleashed the greater freedom of the excitation wavelengths of the upconversion nanoparticles and we believe it is a game-changer in the field and this method will enable numerous applications that are currently limited by existing UCNPs. PMID- 26499209 TI - Latifolicinin A from a Fermented Soymilk Product and the Structure-Activity Relationship of Synthetic Analogues as Inhibitors of Breast Cancer Cell Growth. AB - The functional components in soymilk may vary depending upon the fermentation process. A fermented soymilk product (FSP) obtained by incubation with the microorganisms of intestinal microflora was found to reduce the risk of breast cancer. Guided by the inhibitory activities against breast cancer cells, two cytotoxic compounds, daidzein and (S)-latifolicinin A, were isolated from the FSP by repetitive extraction and chromatography. Latifolicinin A is the n-butyl ester of beta-(4-hydroxyphenyl)lactic acid (HPLA). A series of the ester and amide derivatives of (S)-HPLA and L-tyrosine were synthesized for evaluation of their cytotoxic activities. In comparison, (S)-HPLA derivatives exhibited equal or superior inhibitory activities to their L-tyrosine counterparts, and (S)-HPLA amides showed better cytotoxic activities than their corresponding esters. In particular, (S)-HPLA farnesyl amide was active to triple-negative MDA-MB-231 breast cancer cells (IC50 = 27 MUM) and 10-fold less toxic to Detroit-551 normal cells. PMID- 26499210 TI - More on sunitinib 2 weeks on/1 week off schedule: the Rainbow analysis. PMID- 26499211 TI - Improved in vitro evaluation of novel antimicrobials: potential synergy between human plasma and antibacterial peptidomimetics, AMPs and antibiotics against human pathogenic bacteria. AB - Stable peptidomimetics mimicking natural antimicrobial peptides (AMPs) have emerged as a promising class of potential novel antibiotics. In the present study, we aimed at determining whether the antibacterial activity of two alpha peptide/beta-peptoid peptidomimetics against a range of bacterial pathogens was affected by conditions mimicking in vivo settings. Their activity was enhanced to an unexpected degree in the presence of human blood plasma for thirteen pathogenic Gram-positive and Gram-negative bacteria. MIC values typically decreased 2- to 16-fold in the presence of a human plasma concentration that alone did not damage the cell membrane. Hence, MIC and MBC data collected in these settings appear to represent a more appropriate basis for in vivo experiments preceding clinical trials. In fact, concentrations of peptidomimetics and peptide antibiotics (e.g. polymyxin B) required for in vivo treatments might be lower than traditionally deduced from MICs determined in laboratory media. Thus, antibiotics previously considered too toxic could be developed into usable last-resort drugs, due to ensuing lowered risk of side effects. In contrast, the activity of the compounds was significantly decreased in heat-inactivated plasma. We hypothesize that synergistic interactions with complement proteins and/or clotting factors most likely are involved. PMID- 26499212 TI - miRNAfe: A comprehensive tool for feature extraction in microRNA prediction. AB - miRNAfe is a comprehensive tool to extract features from RNA sequences. It is freely available as a web service, allowing a single access point to almost all state-of-the-art feature extraction methods used today in a variety of works from different authors. It has a very simple user interface, where the user only needs to load a file containing the input sequences and select the features to extract. As a result, the user obtains a text file with the features extracted, which can be used to analyze the sequences or as input to a miRNA prediction software. The tool can calculate up to 80 features where many of them are multidimensional arrays. In order to simplify the web interface, the features have been divided into six pre-defined groups, each one providing information about: primary sequence, secondary structure, thermodynamic stability, statistical stability, conservation between genomes of different species and substrings analysis of the sequences. Additionally, pre-trained classifiers are provided for prediction in different species. All algorithms to extract the features have been validated, comparing the results with the ones obtained from software of the original authors. The source code is freely available for academic use under GPL license at http://sourceforge.net/projects/sourcesinc/files/mirnafe/0.90/. A user friendly access is provided as web interface at http://fich.unl.edu.ar/sinc/web demo/mirnafe/. A more configurable web interface can be accessed at http://fich.unl.edu.ar/sinc/web-demo/mirnafe-full/. PMID- 26499213 TI - The identification of cis-regulatory elements: A review from a machine learning perspective. AB - The majority of the human genome consists of non-coding regions that have been called junk DNA. However, recent studies have unveiled that these regions contain cis-regulatory elements, such as promoters, enhancers, silencers, insulators, etc. These regulatory elements can play crucial roles in controlling gene expressions in specific cell types, conditions, and developmental stages. Disruption to these regions could contribute to phenotype changes. Precisely identifying regulatory elements is key to deciphering the mechanisms underlying transcriptional regulation. Cis-regulatory events are complex processes that involve chromatin accessibility, transcription factor binding, DNA methylation, histone modifications, and the interactions between them. The development of next generation sequencing techniques has allowed us to capture these genomic features in depth. Applied analysis of genome sequences for clinical genetics has increased the urgency for detecting these regions. However, the complexity of cis regulatory events and the deluge of sequencing data require accurate and efficient computational approaches, in particular, machine learning techniques. In this review, we describe machine learning approaches for predicting transcription factor binding sites, enhancers, and promoters, primarily driven by next-generation sequencing data. Data sources are provided in order to facilitate testing of novel methods. The purpose of this review is to attract computational experts and data scientists to advance this field. PMID- 26499214 TI - [Dobutamine-related coronary spasm among patients with false positive dobutamine stress echocardiography: Prevalence and predictors]. AB - BACKGROUND AND OBJECTIVE: Dobutamine stress echocardiography (DSE) is being consistently used as an exercise-independent stress modality aimed at the detection of coronary artery disease (CAD) and the evaluation of myocardial ischemia. It may though occasionally induce coronary vasospasm. In this study, we aimed to evaluate the prevalence and predictors of dobutamine-related coronary spasm in patients without known CAD and false positive DSE (positive DSE but no significant coronary lesions on angiogram). METHODS: Three thousand nine hundred and fifty-two patients referred to our echocardiography laboratory for DSE between January 2010 and May 2012 were prospectively investigated. Those with positive DSE underwent coronary angiograms with systematic methylergometrine intracoronary injection in case of absence of significant coronary stenosis or spontaneous occlusive coronary spasm. Patients with spontaneous occlusive coronary spasm or positive methylergometrine test but no significant stenoses were enrolled and compared with those with positive DSE but no coronary lesions nor spontaneous or induced spasm ("true" false positive DSE). RESULTS: Twenty nine patients with DSE-related vasospasm (19.4% of positive DES without known CAD) were compared with 56 patients with no lesions and no spasm ("true" false positive DSE). They were more frequently smokers (72.4% vs 37.5%; P=0.003); they had more frequently dyslipidemia (79.3% vs 43%; P=0.001); they also had a larger ischemic area at peak DSE (3.4 segments vs 2.7 segments; P=0.05). On multivariate analysis, dyslipidemia (HR=10.7; 95% CI=[2.7-42.1]; P=0.001) and active smoking (HR=6.1; 95% CI=[1.7-21.1]; P=0.004) were found to be independent predictors of spasm-related DSE rather than "true" false positive DSE. CONCLUSION: DSE-related coronary spasm is present in a significant proportion of patients with erroneously labelled "false" positive DSE and should systematically be ruled out. Dyslipidemia and active smoking were independent predictors of spasm rather than "true" false positive DSE. PMID- 26499215 TI - [Corrigendum] Effects of miR-19b knockdown on the cardiac differentiation of P19 mouse embryonic carcinoma cells. PMID- 26499216 TI - The next step for mitral valve treatment: moving to early percutaneous intervention to prevent irreversible damage. PMID- 26499217 TI - The triad of residual ischaemia, plaque burden, and plaque vulnerability: a known known?...a known unknown?...or an unknown unknown? PMID- 26499218 TI - Clips and chutes: combined solutions to combined problems. PMID- 26499219 TI - The effect of complete percutaneous revascularisation with and without intravascular ultrasound guidance in the drugeluting stent era. AB - AIMS: Our aim was to compare the outcomes of complete revascularisation (CR) and incomplete revascularisation (IR) in multivessel coronary artery disease (CAD), with and without intravascular ultrasound (IVUS) guidance, in the drug-eluting stent (DES) era. METHODS AND RESULTS: Overall, 2,132 consecutive patients with multivessel CAD, defined as at least two epicardial vessels with >70% stenosis, had at least one DES implant. Chronic total occlusions were not analysed. Successful treatment of epicardial vessels and significant branches was termed CR; otherwise, treatment was defined as IR. CR and IR were further categorised according to the use of IVUS. The primary outcome was death or Q-wave myocardial infarction (QWMI). Secondary outcomes included the rates of non-QWMI and repeat revascularisation, the latter assessed as either target vessel revascularisation (TVR) or target lesion revascularisation (TLR) at one year. CR was associated with lower rates of death/QWMI (HR 0.66 [0.4-0.9]; p=0.048) and non-QWMI at one year (1.1% vs. 2.6%; p=0.017). Completeness of revascularisation was not independently associated with repeat intervention, but rates of both TVR (89% vs. 93%; p<0.001) and TLR (91% vs. 95%; p<0.001) were higher with CR than IR. IVUS decreased the rates of TLR irrespective of completeness of revascularisation (p interaction=0.75). CONCLUSIONS: CR in selected patients gives better outcomes than IR in multivessel CAD at one year. IVUS guidance can further improve results by reducing rates of repeat intervention irrespective of completeness of revascularisation. PMID- 26499220 TI - The effectiveness of stenting of coarctation of the aorta: a systematic review. AB - AIMS: Stent placement as treatment for coarctation of the aorta (CoA) has become a more common choice in the last 20 years. Clinical results of CoA stenting are usually reported in small retrospective case series. This systematic review provides an overview of clinical experience with stenting for CoA. METHODS AND RESULTS: A systematic review of the reports published between January 1990 and December 2014 after stenting a CoA was performed with a focus on relief of obstruction and lowering of blood pressure. Study and patient characteristics were extracted, as well as pre- and post-stenting aortic diameter in mm, systolic pressure gradient (SPG) and pre- and post-stenting systolic blood pressure (mmHg), periprocedural and follow-up complications. Forty-five articles met the inclusion criteria. Three outcomes were extracted from the articles - aortic diameter, systolic pressure gradient and blood pressure. Diameter increased from 6.4 mm (5.6, 7.3) to 15.1 mm (14.5, 15.7), pressure gradients decreased from 40 mmHg (35, 42) to 4 mmHg (3, 5) and systolic blood pressure decreased from 153 mmHg (148, 158) to 132 mmHg (127, 136). Stent migration was the most common periprocedural complication (2.4%), and mortality was low (0.4%). CONCLUSIONS: Stenting is an effective treatment with regard to immediate relief of obstruction and direct lowering effect on blood pressure. However, there is a lack of evidence regarding late effectiveness concerning durable blood pressure lowering, and limited information on periprocedural and late complications. This observation calls for a systematic and longer prospective follow-up of patients after CoA stenting. PMID- 26499221 TI - New Braile Inovare transcatheter aortic prosthesis: clinical results and follow up. AB - AIMS: Transcatheter aortic valve implantation has emerged as an alternative to conventional aortic valve replacement in high-risk patients. Diverse prostheses are currently under investigation. The aim of this study was the clinical, safety and efficacy assessment of Braile Inovare Transcatheter Aortic Prosthesis usage. METHODS AND RESULTS: Ninety high-risk or inoperable patients underwent transcatheter aortic valve implantation. The mean logistic EuroSCORE was 39.3%. All patients presented calcified aortic stenosis. The procedures were performed under fluoroscopic and echocardiographic guidance. Prostheses were implanted through the transapical approach under rapid ventricular pacing. Echocardiographic and angiographic controls were included. Implantation was feasible in 87 cases. There was only one case of operative mortality, and 30-day mortality was 13.3%. The median transvalvular aortic gradient was reduced from 44.8+/-15.3 to 14.1+/-8.0 mmHg. Left ventricular function improved in the first seven postoperative days. Paravalvular aortic regurgitation was present in 29.7% of cases, mostly trace. One case presented a major vascular complication, and there were two cases of permanent pacemaker implantation. Two cases of major stroke occurred. CONCLUSIONS: Transcatheter aortic valve replacement using the Braile Inovare prosthesis is able to provide encouraging results with significant functional and structural cardiac improvement. It is mandatory to continue follow up to measure the benefits of this device as well as to improve selection criteria of patients. PMID- 26499222 TI - Comparison of suture-based vascular closure devices in transfemoral transcatheter aortic valve implantation. AB - AIMS: The aim of this study was to compare outcomes with the use of two haemostasis strategies after transfemoral transcatheter aortic valve implantation (TAVI) - one Prostar(r) vs. two ProGlide(r) devices (Abbott Vascular Inc., Santa Clara, CA, USA). METHODS AND RESULTS: This was a retrospective study enrolling consecutive patients undergoing fully percutaneous transfemoral TAVI in our centre (Ferrarotto Hospital, Catania, Italy) from January 2012 to October 2014. All patients were dichotomised according to the vascular closure device (VCD) used for common femoral artery haemostasis (Prostar vs. ProGlide). All outcomes were defined according to VARC-2 criteria. The study population encompassed a total of 278 patients. Of these, 153 (55.1%) underwent TAVI using the Prostar, and 125 (44.9%) using two ProGlide devices. Vascular complications occurred in 48 patients (17.3%), being more frequent in the ProGlide group (11.8% vs. 24.0%, p=0.007). Patients who had TAVI using the ProGlide were also more likely to have a higher rate of percutaneous closure device failure (4.6% vs. 12.8%, p=0.013). Percutaneous peripheral intervention was performed in 13.7% and 28.0% of Prostar and ProGlide cases, respectively (p=0.003). CONCLUSIONS: Patients undergoing transfemoral TAVI had significantly lower rates of vascular complications and percutaneous closure device failures when the Prostar was used compared with two ProGlide devices. PMID- 26499224 TI - Getting maximum information out of a continuous outcome: applying linear regression. PMID- 26499223 TI - Percutaneous ventricular restoration (PVR) therapy using the Parachute device in 100 subjects with ischaemic dilated heart failure: one-year primary endpoint results of PARACHUTE III, a European trial. AB - AIMS: This prospective, non-randomised, observational study conducted in Europe was designed in order to assess the long-term safety and efficacy of the Parachute device in ischaemic heart failure subjects as a result of left ventricle remodelling after anterior wall myocardial infarction. METHODS AND RESULTS: One hundred subjects with New York Heart Association Class II-IV ischaemic heart failure (HF), ejection fraction (EF) between 15% and 40%, and dilated akinetic or dyskinetic anterior-apical wall without the need to be revascularised were enrolled. The primary safety endpoint was procedural- or device-related major adverse cardiac cerebral events (MACCE). The secondary safety endpoint was the composite of mortality and morbidity. Secondary efficacy endpoints included haemodynamic measurements determined by echocardiography, LV volume indices, and assessment of functional improvement measured by a standardised six-minute walk test. Of the 100 subjects enrolled, device implantation was successful in 97 (97%) subjects. The one-year rates of the primary and secondary safety endpoints were 7% and 32.3%, respectively. The secondary endpoints, LV volume reduction (p<0.0001) and six-minute walk distance improvement (p<0.01), were achieved. CONCLUSIONS: The favourable outcomes observed in this high-risk population provide reassuring safety and efficacy data to support adoption of this technology as a therapeutic option for HF subjects. PMID- 26499225 TI - How should I treat a patient with a proximal left anterior descending large plaque burden embolising plaque? PMID- 26499226 TI - Union rate after operative treatment of humeral shaft nonunion--A systematic review. AB - INTRODUCTION: Humeral shaft nonunions can lead to morbidity from subsequent operations, complications and impaired function. Currently there is no evidenced based consensus for treatment of humeral shaft nonunions. AIM: We aimed to summarize and analyze union rates and complications after operative treatment for humeral shaft nonunion. METHODS: Studies investigating operative treatment strategies for humeral shaft nonunion were identified by searching: EMBASE, MEDLINE, Ovid SP, Web of Science, Cochrane Central, PubMed and Google Scolar up to October 24, 2014. Studies were eligible if: (1) outcome of operative treatment for humeral shaft nonunion was reported; (2) at least ten adult patients with humeral shaft nonunion included; (3) full text article available; (4) written in English, German or Dutch; and (5) nonunion was defined as no bone-bridging between the fracture ends after 6 months. RESULTS: Thirty-six studies were included. A union rate of 98% was found in patients (n=672) who underwent plate fixation with autologous bone grafting (ABG), 95% in plate fixation without ABG (n=19), 88% in intramedullary nailing with ABG (n=164), 66% in intramedullary nailing without ABG (n=78), 92% in bone strut fixation (n=91) and 98% in external fixation (n=152). A total complication rate of 12% was found in patients treated with plate fixation combined with ABG, 15% in intramedullary nail with ABG and 8% intramedullary nailing without ABG, 20% in bone strut fixation and 22% in external fixation. CONCLUSION: Plate fixation with ABG was recommended for humeral shaft nonunion, since the union rate is highest and the complication rate is relatively low. LEVEL OF EVIDENCE: Level IV. PMID- 26499227 TI - Aggressive operative neurosurgical management in patients with extra-axial mass lesion and Glasgow Coma Scale of 3 is associated with survival benefit: A propensity matched analysis. AB - INTRODUCTION: Prognosis in patients with traumatic brain injury (TBI) and Glasgow Coma Scale (GCS) score of 3 is poor, raising concern regarding the utility of aggressive operative neurosurgical management. Our purpose was to describe outcomes in a propensity matched population with TBI and GCS3 treated with operative neurosurgical procedures of craniotomy or craniectomy (CRANI). METHODS: We conducted a five-year, multicenter retrospective cohort study of patients with an ED GCS 3 and a positive head CT identified by ICD-9CM diagnosis codes. Two populations were examined: (1) patients with extra-axial mass lesion (subdural or epidural haematoma), (2) patients without mass lesion (subarachnoid and intraparenchymal haemorrhage including contusion, other intracerebral haemorrhage or intracranial injury including diffuse axonal injury). In patients with extra axial mass lesion, propensity score techniques were used to match patients 1:1 by CRANI, and the following outcomes were analysed with conditional logistic regression: survival, favourable hospital disposition to home or rehabilitation, and development of complications. RESULTS: There were 541 patients with TBI and GCS3; 19% had a CRANI, 83% were initiated within 4h. In those with mass lesion, 27% (91/338) had a CRANI; after matching, a significant survival benefit was observed with CRANI vs. without CRANI (65% vs. 34% survival, OR: 3.9 (1.6-10.5) p<0.001). There was borderline increased odds of favourable disposition (43% vs. 26%, OR: 2.4 (0.99-6.3, p=0.052) with CRANI vs. without CRANI, and no difference in developing a complication (58% vs. 48%, OR: 1.5 (0.7-3.4), p=0.30). CONCLUSIONS: Survival was achieved in 65% of patients that underwent surgical intervention for subdural and epidural haematoma, despite a presenting GCS of 3. These results demonstrate prompt operative neurosurgical management of mass lesion is warranted for selected patients with a GCS of 3, contributing to a significant 4-fold survival benefit. In the absence of mass lesion the effect of immediate neurosurgery on outcomes is inconclusive. PMID- 26499228 TI - [Corrigendum] Trastuzumab and docetaxel in a preclinical organotypic breast cancer model using tissue slices from mammary fat pad: Translational relevance. PMID- 26499229 TI - [Five percent of Italian smokers use also e-cigs]. PMID- 26499230 TI - [HPV vaccination in males: a lost chance for technicians and decision-makers]. PMID- 26499231 TI - [The challenge of big databases for comparative impact evaluation...adelante, con juicio]. PMID- 26499232 TI - [Oncogenesis: theories and facts]. PMID- 26499233 TI - [EpiChange. Epidemiological study on the health status of residents in Manfredonia (Italy). Phase 2. Scenarios and implications]. AB - This is the second paper on the Project Manfredonia Environment and Health launched on February 2015 and based on a participatory approach. After a serious industrial accident on 1976 with release of several tons of arsenic, the management of environmental issues produced distrust and suspicion towards institutions and these feelings are still alive in the civil society. The Project is therefore based on a strong public engagement on each phase of the epidemiological investigation. In this article we report the second phase in which all the stakeholders consider all possible analysis results and the implications in terms of public health action plans. This step is relevant in order to acknowledge the limitation of the epidemiologic study due to uncertainties and assure transparency to the decision processes. PMID- 26499234 TI - [EpiChange. Epidemiological study on the health status of residents in Manfredonia (Italy). Phase 2. Epidemiological questions]. PMID- 26499235 TI - [Evaluation of the cancer co-pay fee exemption data source (048 code) to estimate cancer incidence]. AB - OBJECTIVES: to assess whether the data source of cancer exemption ticket (code 048) correctly estimate the cancer incidence produced by Cancer registries (CR). DESIGN: comparison between incidence estimates produced by cancer exemptions ticket and cases registered by CR. SETTING AND PARTICIPANTS: six CRs provided incidence data for one year in the five-year period from 2007 to 2011 and for the previous five years, the exemptions provided for the same year and for the previous five years. MAIN OUTCOME MEASURES: incidence distribution by gender, age and tumour site, exemptions 048/incident cancers ratio, and trend estimates. RESULTS: out of 14,586 patients with 048 exemption, a first group was present in the CR database in the same reference year (No. 8,015) and a second group in the previous 6 months (No. 1,696). Of the remaining 4,875, only 2,771 were prevalent cases and 2,104 were manually re-valued: 514 non-cancer; 710 non malignant/noninfiltrating tumours, 250 non-residents, 532 unknown, and 98 lost at CR. The exemption/ tumours ratio was 32%in males and 37% in females. Out of 27,632 cancer patients in CR, only 29% had a 048 exemption. Among linked cases, there is a case-mix problem: the exemptions overestimated the weight of some cancer sites (breast, prostate), but underestimate the weight of other sites (stomach, liver, lung) and the burden of tumours in the elderly.The trend estimated from the exemptions underestimates the true incidence of tumours and presents fluctuations, because of local administrative and organisational issues. CONCLUSIONS: the 048 codes are an accessory source for CRs, but when used as single flow they are not able to estimate the true incidence of tumours and, therefore, do not provide useful information on cancer trends. PMID- 26499236 TI - [A population study to evaluate the efficacy of influenza vaccination, 2014 2015]. AB - OBJECTIVES: to analyse the efficacy of influenza vaccination in the period 2014- 2015 in a population of a Local Health Authority of the Province of Milan (949,162 residents) in terms of reduction of short term mortality, hospital admissions, and access to emergency room. DESIGN: retrospective study, based on current health databases, comparing vaccinated subjects with non-vaccinated subject with a study design based on optimal caliper widths for propensity-score matching. SETTINGAND PARTICIPANTS: 74,250 subjects aged >=65 years and 12,090 subjects aged l <65 years undergoing influenza vaccination, from November to December 2014, were compared with 74,250 and 22,090 unvaccinated subjects aged >=65 years or <65 years, respectively (1:1). MAIN OUTCOME MEASURES: deaths, hospitalizations in ordinary regimen, and the accesses to the emergency room for all causes and for specific causes that occurred from the inclusion in the study at 31.06.2015, with a temporal window of 6 months from vaccination, were identified. STATISTICAL METHODS: the association between vaccination and health events was quantified by estimating hazard ratios (HR) and the corresponding 95% confidence intervals by using Cox models. For admissions and access to the emergency room, the approach based on multiple outcome according to Prentice was also used. RESULTS: vaccination reduces by 34% the risk of decease (HR: 0.66; 95%CI 0.61-0.71) and about 9% of hospitalization (HR: 0.91 for first event and 0.92 for multiple events, both significant). It does not exist, however, any reduction in the risk for access to the emergency room. The analysis of all-cause and the cause-specific one yield similar results. Analysis stratified by age and number of comorbidities found that subjects aged over 65 and with at least one comorbidity shows the greater risk reduction. CONCLUSIONS: influenza vaccination reduces the risk of decease and access to hospital admissions. These results, although coming from an observational study, given the need to further confirm the effectiveness of influenza vaccination and the difficulty to have results from randomised trials, must be used to reassure people of the advantage derived from some prevention practices and should open a debate on the use of current data for the rapid evaluation of interventions in public health. PMID- 26499237 TI - [Introduction of a centralised system (Service) for collecting clinical data in cancer screening programmes in Piedmont (Northern Italy): a pre-post assessment of a hub&spoke model]. AB - OBJECTIVES: evaluation of a centralised collection of clinical data (Service) within cancer screening programmes in Piedmont based on a hub&spoke model and its impact on process indicators. DESIGN: assessment of an organisational intervention, through a non-controlled pre-post design. SETTING AND PARTICIPANTS: organised screening programmes within the Piedmont Region, divided into 9 departments. MAIN OUTCOME MEASURES: clinical data (extracted from medical charts for mammography screening and from excision histology reports for cervical screening) obtained through the Service were quantified and their completeness was assessed. The Service impact on the detection rate (DR) was evaluated, comparing the DR pre- (2005-2008) and post-Service (2009- 2012) within breast screening; the DR was computed through histological diagnosis made during colposcopy (pre-Service method) or through the worst diagnosis between the latter and that reported from excision histology (post-Service method) within cervical screening (data available for department 1, year 2013). Some hints on human resources employed in pre- and post-Service periods were reported. RESULTS: within mammography screening, the Service obtained 53.1% of extra-department medical charts and 45.8% of extra-region ones; the percentage of missing diagnoses changed from 5.5% (pre- Service) to 3.7% (post-Service). The age standardised DR for malignant tumours in the post-Service period is 1.3 times the DR of the pre-Service period per 1,000 screening tests. Within cervical screening, 51.7% of histological reports was recorded. Crude DR for high-grade lesions changed from 3.9 (pre-Service) to 4.7 (post-Service) per 1,000 screened women. The system centralisation did not imply an increase in the dedicated personnel. CONCLUSION: the Service is an operational core which coordinates the collection of clinical data, impacting on process indicators without an increase in human resources at departmental level. PMID- 26499238 TI - [Investigation on the health effects of traffic-related air pollution from Mestre motorway (Veneto Region, Northern Italy)]. AB - OBJECTIVES: to evaluate whether living near motorway A57 (Mestre motorway, Veneto Region, Northern Italy) might have affected the residents' health status. DESIGN: longitudinal cohort study. SETTING AND PARTICIPANTS: 148,673 residents on the mainland in the Municipality of Venice (Mestre) who never changed their residence during the follow- up period (2002-2009). MAIN OUTCOMES MEASURES: the 2001 Italian census data were linked with the data sources of the epidemiological integrated system which includes: population registry, death certificates, hospital discharges, drug prescriptions, and tax exemption. Mortality and incidence for several subgroups of causes, incidence of acute myocardial infarction and stroke, and prevalence of asthma, chronic obstructive pulmonary disease, ischemic cardiopathy and diabetes were estimated. The ADMS-Urban model was adopted to define three different exposure areas based on PM10 emissions from the motorway: A (highly exposed), B (moderately exposed) used as a comparison for the analysis, C (unexposed). Hazard ratios (HR) for incidence and mortality were estimated from Cox proportional hazard models adjusted for calendar period, age, gender, and instruction level. The relationship between the exposure area and prevalence was investigated by multiple logistic regression analysis adjusted for the same covariates. RESULTS: compared with B area (23.25%of the population under study), people living in A area (3.16% of the population under study) had an increased incidence of acute myocardial infarction (HR: 1.43; 95%CI 1.03-1.97) in females, and prevalence of ischemic cardiopathy (odds ratio - OR: 1.12; 95%CI 1.01-1.26) in both genders. Results were borderline for COPD in males (OR: 1.17; 95%CI 0.97-1.41). Positive but nonsignificant associations were found with pneumonia and respiratory recoveries. CONCLUSIONS: this study showed that residents who live near Mestre motorway had an increased prevalence of some cardiorespiratory diseases, particularly ischemic cardiopathy. PMID- 26499239 TI - [Theory and testing of an accident risk assessment system based on prior experience]. AB - OBJECTIVES: to improve the "National Project: Integrated investigations for an indepth analysis of cases of Fatal Accidents", a project which, on one hand, is too open to interpretation of events, while, on the other, does not offer the possibility to analyse external factors which are often at the basis of accidents in the workplace. METHODS: identification and weighting criteria regarding causes of accident have been established and correlated by means of a specific algorithm, with the aim of making them numerically measurable. This has made it possible to use them as indicators to identify lines of priority in prevention planning. The theoretical model has been tested in an analysis of 35 work accidents which occurred in a firm in Mantova. RESULTS: the model has been evaluated in comparison to the analysis which was previously used to examine cases of work-related accidents and it has proved to be more efficient in the move towards establishing preventative action at the beginning of a chain of events. CONCLUSIONS: While maintaining the "Learning from mistakes" model, the method here proposed represents an extension and an implementation of previous practices. It is an effective operative method for companies, offering both a qualitative and quantitative analysis of work-related accidents with a view to their prevention. PMID- 26499240 TI - [Eating habits and physical activity improve thanks to the interventions of Italian schools]. PMID- 26499241 TI - [Cancer survival in Italy in 2000-2007 is better than in Europe]. PMID- 26499242 TI - Expanding the scope of alkyne-mediated bioconjugations utilizing unnatural amino acids. AB - The importance of bioconjugates within the field of chemistry drives the need for novel methodologies for their preparation. Well-defined and stable bioconjugates are easily accessible via the utilization of unnatural amino acids (UAAs). As such, we have synthesized and incorporated two new UAAs into green fluorescent protein, and optimized a novel Cadiot-Chodkiewicz bioconjugation, effectively expanding the toolbox of chemical reactions that can be employed in the preparation of bioconjugates. PMID- 26499243 TI - Tracking Austronesian expansion into the Pacific via the paper mulberry plant. PMID- 26499244 TI - Developmental biologist Eric H. Davidson, 1937-2015. PMID- 26499245 TI - Chromatin extrusion explains key features of loop and domain formation in wild type and engineered genomes. AB - We recently used in situ Hi-C to create kilobase-resolution 3D maps of mammalian genomes. Here, we combine these maps with new Hi-C, microscopy, and genome editing experiments to study the physical structure of chromatin fibers, domains, and loops. We find that the observed contact domains are inconsistent with the equilibrium state for an ordinary condensed polymer. Combining Hi-C data and novel mathematical theorems, we show that contact domains are also not consistent with a fractal globule. Instead, we use physical simulations to study two models of genome folding. In one, intermonomer attraction during polymer condensation leads to formation of an anisotropic "tension globule." In the other, CCCTC binding factor (CTCF) and cohesin act together to extrude unknotted loops during interphase. Both models are consistent with the observed contact domains and with the observation that contact domains tend to form inside loops. However, the extrusion model explains a far wider array of observations, such as why loops tend not to overlap and why the CTCF-binding motifs at pairs of loop anchors lie in the convergent orientation. Finally, we perform 13 genome-editing experiments examining the effect of altering CTCF-binding sites on chromatin folding. The convergent rule correctly predicts the affected loops in every case. Moreover, the extrusion model accurately predicts in silico the 3D maps resulting from each experiment using only the location of CTCF-binding sites in the WT. Thus, we show that it is possible to disrupt, restore, and move loops and domains using targeted mutations as small as a single base pair. PMID- 26499246 TI - Evolvability and nonevolvability of allometric slopes. PMID- 26499247 TI - Sequential divergence and the multiplicative origin of community diversity. AB - Phenotypic and genetic variation in one species can influence the composition of interacting organisms within communities and across ecosystems. As a result, the divergence of one species may not be an isolated process, as the origin of one taxon could create new niche opportunities for other species to exploit, leading to the genesis of many new taxa in a process termed "sequential divergence." Here, we test for such a multiplicative effect of sequential divergence in a community of host-specific parasitoid wasps, Diachasma alloeum, Utetes canaliculatus, and Diachasmimorpha mellea (Hymenoptera: Braconidae), that attack Rhagoletis pomonella fruit flies (Diptera: Tephritidae). Flies in the R. pomonella species complex radiated by sympatrically shifting and ecologically adapting to new host plants, the most recent example being the apple-infesting host race of R. pomonella formed via a host plant shift from hawthorn-infesting flies within the last 160 y. Using population genetics, field-based behavioral observations, host fruit odor discrimination assays, and analyses of life history timing, we show that the same host-related ecological selection pressures that differentially adapt and reproductively isolate Rhagoletis to their respective host plants (host-associated differences in the timing of adult eclosion, host fruit odor preference and avoidance behaviors, and mating site fidelity) cascade through the ecosystem and induce host-associated genetic divergence for each of the three members of the parasitoid community. Thus, divergent selection at lower trophic levels can potentially multiplicatively and rapidly amplify biodiversity at higher levels on an ecological time scale, which may sequentially contribute to the rich diversity of life. PMID- 26499248 TI - Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters. AB - Natural product biosynthetic pathways generate molecules of enormous structural complexity and exquisitely tuned biological activities. Studies of natural products have led to the discovery of many pharmaceutical agents, particularly antibiotics. Attempts to harness the catalytic prowess of biosynthetic enzyme systems, for both compound discovery and engineering, have been limited by a poor understanding of the evolution of the underlying gene clusters. We developed an approach to study the evolution of biosynthetic genes on a cluster-wide scale, integrating pairwise gene coevolution information with large-scale phylogenetic analysis. We used this method to infer the evolution of type II polyketide gene clusters, tracing the path of evolution from the single ancestor to those gene clusters surviving today. We identified 10 key gene types in these clusters, most of which were swapped in from existing cellular processes and subsequently specialized. The ancestral type II polyketide gene cluster likely comprised a core set of five genes, a roster that expanded and contracted throughout evolution. A key C24 ancestor diversified into major classes of longer and shorter chain length systems, from which a C20 ancestor gave rise to the majority of characterized type II polyketide antibiotics. Our findings reveal that (i) type II polyketide structure is predictable from its gene roster, (ii) only certain gene combinations are compatible, and (iii) gene swaps were likely a key to evolution of chemical diversity. The lessons learned about how natural selection drives polyketide chemical innovation can be applied to the rational design and guided discovery of chemicals with desired structures and properties. PMID- 26499249 TI - Management of complicated chronic anal fissures with high-dose circumferential chemodenervation (HDCC) of the internal anal sphincter. AB - BACKGROUND: Botulinum toxin injection into the internal anal sphincter (IAS) is gaining popularity as a second line therapy for chronic anal fissures after patients fail medical therapy. The dosage of Botulinum toxin reported in the literature ranged from 20 to 50 IU. Complicated chronic anal fissure is defined as persistent fissure concurrent with other perianal pathology. We report a new approach involving high-dose circumferential chemodenervation (HDCC) of 100 IU in treating these complicated chronic anal fissures. AIM: The aim of this study was to evaluate the fissure healing, complication, and recurrence rates with HDCC. METHODS: Complicated anal fissure was defined as fissure with other perianal pathologies including skin tag, hypertrophied papilla, fistula, symptomatic hemorrhoids, anal condylomata, and abscess. Between 2008 and 2012, 62 consecutive patients (28 Blacks, 33 Whites, 1 Hispanic) with complete follow-up data were included in this single arm study. These patients underwent HDCC-IAS with addition interventions by a single colorectal surgeon. Follow up data were obtained by chart review and office follow up. RESULTS: Of the 62 patients, the overall success rate was greater than 70% at 3 months follow-up. A few patients developed transient flatus or fecal incontinence, but shortly resolved. There was no major complication following HDCC-IAS. CONCLUSIONS: Combination therapy involving HDCC-IAS and local anorectal surgery for associated condition is both safe and effective for fissure healing. PMID- 26499250 TI - Would transcranial direct current stimulation (tDCS) enhance the effects of working memory training in older adults with mild neurocognitive disorder due to Alzheimer's disease: study protocol for a randomized controlled trial. AB - BACKGROUND: There has been longstanding interesting in cognitive training for older adults with cognitive impairment. In this study, we will investigate the effects of working memory training, and explore augmentation strategies that could possibly consolidate the effects in older adults with mild neurocognitive disorder. Transcranial direct current stimulation (tDCS) has been demonstrated to affect the neuronal excitability and reported to enhance memory performance. As tDCS may also modulate cognitive function through changes in neuroplastic response, it would be adopted as an augmentation strategy for working memory training in the present study. METHODS/DESIGN: This is a 4-week intervention double-blind randomized controlled trial (RCT) of tDCS. Chinese older adults (aged 60 to 90 years) with mild neurocognitive disorder due to Alzheimer's disease (DSM-5 criteria) would be randomized into a 4-week intervention of either tDCS-working memory (DCS-WM), tDCS-control cognitive training (DCS-CC), and sham tDCS-working memory (WM-CD) groups. The primary outcome would be working memory test - the n-back task performance and the Chinese version of the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog). Secondary outcomes would be test performance of specific cognitive domains and mood. Intention-to treat analysis would be carried out. Changes of efficacy indicators with time and intervention would be tested with mixed effect models. DISCUSSION: This study adopts the theory of neuroplasticity to evaluate the potential cognitive benefits of non-invasive electrical brain stimulation, working memory training and dual stimulation in older adults at risk of cognitive decline. It would also examine the tolerability, program adherence and adverse effects of this novel intervention. Information would be helpful for further research of dementia prevention studies. TRIAL REGISTRATION: ChiCTR-TRC- 14005036 Date of registration: 31 July 2014. PMID- 26499251 TI - Motion tracking and gait feature estimation for recognising Parkinson's disease using MS Kinect. AB - BACKGROUND: Analysis of gait features provides important information during the treatment of neurological disorders, including Parkinson's disease. It is also used to observe the effects of medication and rehabilitation. The methodology presented in this paper enables the detection of selected gait attributes by Microsoft (MS) Kinect image and depth sensors to track movements in three dimensional space. METHODS: The experimental part of the paper is devoted to the study of three sets of individuals: 18 patients with Parkinson's disease, 18 healthy aged-matched individuals, and 15 students. The methodological part of the paper includes the use of digital signal-processing methods for rejecting gross data-acquisition errors, segmenting video frames, and extracting gait features. The proposed algorithm describes methods for estimating the leg length, normalised average stride length (SL), and gait velocity (GV) of the individuals in the given sets using MS Kinect data. RESULTS: The main objective of this work involves the recognition of selected gait disorders in both the clinical and everyday settings. The results obtained include an evaluation of leg lengths, with a mean difference of 0.004 m in the complete set of 51 individuals studied, and of the gait features of patients with Parkinson's disease (SL: 0.38 m, GV: 0.61 m/s) and an age-matched reference set (SL: 0.54 m, GV: 0.81 m/s). Combining both features allowed for the use of neural networks to classify and evaluate the selectivity, specificity, and accuracy. The achieved accuracy was 97.2 %, which suggests the potential use of MS Kinect image and depth sensors for these applications. CONCLUSIONS: Discussion points include the possibility of using the MS Kinect sensors as inexpensive replacements for complex multi-camera systems and treadmill walking in gait-feature detection for the recognition of selected gait disorders. PMID- 26499252 TI - Assessing information needs on bone health in cancer survivors. AB - PURPOSE: Bone health education and implementation of preventive measures are key to effective management of osteoporosis. We assessed areas of knowledge deficits with respect to bone health in breast and prostate cancer survivors and the preferred source of health information METHODS: We used a mixed methods approach. We conducted 20 semi-structured interviews in breast or prostate cancer survivors receiving hormonal therapy. Responses were independently coded by 2 researchers and explored under 3 content areas: osteoporosis knowledge, behaviors for self management, and preferred learning tools. Another 20 participants responded to a structured questionnaire that comprised modified versions of the Osteoporosis Knowledge Questionnaire (OPQ) and Osteoporosis Knowledge Assessment Tool (OKAT). The OPQ and OKAT were analyzed as summary scores, and areas of knowledge deficits (i.e., where >=60 % of participants failed to give the right response) were identified. RESULTS: Median age of participants was 67 (range 48-92) and 78 % were White. Awareness of osteoporosis was high, but detailed knowledge was low. Bone healthy behaviors perceived by participants as most important include good nutrition, exercising, calcium and vitamin D supplementation and avoidance of falls. The Internet was the most preferred source of information. Areas of knowledge deficit revealed by the OPQ and OKAT included general information, risk factors, prevention, and treatment of osteoporosis. CONCLUSION: There is a desire for information on osteoporosis, specifically tailored for cancer survivors. Good nutrition, supplement intake, exercise, and avoidance of falls were perceived as key behaviors for self-management. The Internet was an important source of information for breast and prostate cancer patients. Implication for Cancer Survivors An educational website addressing the bone health information needs of cancer survivors could effectively improve behaviors for self-management. PMID- 26499253 TI - Paradoxical effects of thyroid function on glomerular filtration rate estimated from serum creatinine or standardized cystatin C in patients with Japanese Graves' disease. AB - BACKGROUND: Estimated glomerular filtration rate (eGFR) is clinically valuable for evaluating renal function. Recently, serum cystatin C (sCysC) measurement has been standardized and has demonstrated utility as a novel indicator of renal function. Thyroid hormone is known to affect serum creatinine (sCr) and sCysC, however, the clinical significance of post-treatment renal function evaluation is yet to be completely elucidated. This study examined the effects of thyroid hormones on eGFR by sCr (eGFRCr), and standardized sCysC (eGFRCysC) in patients with Japanese Graves' disease (GD). METHODS: Serum samples were obtained from 113 outpatients with GD. Following pharmacotherapy, 41 of the 113 outpatients with GD achieved remission. Renal function was evaluated by eGFRCr and eGFRCysC. Reference method used Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. RESULTS: eGFRCr levels significantly increased whereas eGFRCysC levels significantly decreased with elevated FT3 and FT4 levels in patients with GD. In the remission group, eGFRCr levels significantly decreased and eGFRCysC levels significantly increased. No significant differences between eGFRCr and eGFRCysC levels were observed. Furthermore, CKD-EPI equations show a similar trend and eGFRCr-CysC levels were no significant differences regardless of before and after treatment. CONCLUSIONS: Renal function evaluation by eGFRCr and eGFRCysC had clinical utility in post-treatment euthyroidism. PMID- 26499254 TI - Social activity, cognitive decline and dementia risk: a 20-year prospective cohort study. AB - BACKGROUND: Identifying modifiable lifestyle correlates of cognitive decline and risk of dementia is complex, particularly as few population-based longitudinal studies jointly model these interlinked processes. Recent methodological developments allow us to examine statistically defined sub-populations with separate cognitive trajectories and dementia risks. METHODS: Engagement in social, physical, or intellectual pursuits, social network size, self-perception of feeling well understood, and degree of satisfaction with social relationships were assessed in 2854 participants from the Paquid cohort (mean baseline age 77 years) and related to incident dementia and cognitive change over 20-years of follow-up. Multivariate repeated cognitive information was exploited by defining the global cognitive functioning as the latent common factor underlying the tests. In addition, three latent homogeneous sub-populations of cognitive change and dementia were identified and contrasted according to social environment variables. RESULTS: In the whole population, we found associations between increased engagement in social, physical, or intellectual pursuits and increased cognitive ability (but not decline) and decreased risk of incident dementia, and between feeling understood and slower cognitive decline. There was evidence for three sub-populations of cognitive aging: fast, medium, and no cognitive decline. The social-environment measures at baseline did not help explain the heterogeneity of cognitive decline and incident dementia diagnosis between these sub-populations. CONCLUSIONS: We observed a complex series of relationships between social-environment variables and cognitive decline and dementia. In the whole population, factors such as increased engagement in social, physical, or intellectual pursuits were related to a decreased risk of dementia. However, in a sub-population analysis, the social-environment variables were not linked to the heterogeneous patterns of cognitive decline and dementia risk that defined the sub-groups. PMID- 26499255 TI - Implications of newborn amygdala connectivity for fear and cognitive development at 6-months-of-age. AB - The first year of life is an important period for emergence of fear in humans. While animal models have revealed developmental changes in amygdala circuitry accompanying emerging fear, human neural systems involved in early fear development remain poorly understood. To increase understanding of the neural foundations of human fear, it is important to consider parallel cognitive development, which may modulate associations between typical development of early fear and subsequent risk for fear-related psychopathology. We, therefore, examined amygdala functional connectivity with rs-fcMRI in 48 neonates (M=3.65 weeks, SD=1.72), and measured fear and cognitive development at 6-months-of-age. Stronger, positive neonatal amygdala connectivity to several regions, including bilateral anterior insula and ventral striatum, was prospectively associated with higher fear at 6-months. Stronger amygdala connectivity to ventral anterior cingulate/anterior medial prefrontal cortex predicted a specific phenotype of higher fear combined with more advanced cognitive development. Overall, findings demonstrate unique profiles of neonatal amygdala functional connectivity related to emerging fear and cognitive development, which may have implications for normative and pathological fear in later years. Consideration of infant fear in the context of cognitive development will likely contribute to a more nuanced understanding of fear, its neural bases, and its implications for future mental health. PMID- 26499256 TI - The effectiveness and cost effectiveness of the PAtient-Centred Team (PACT) model: study protocol of a prospective matched control before-and-after study. AB - BACKGROUND: The present study protocol describes the evaluation of a comprehensive integrated care model implemented at two hospital sites at the University Hospital of North Norway (UNN). The PAtient Centred Team (PACT) model includes proactive, patient-centred interdisciplinary teams that aim to improve the continuum and quality of care of frail elderly patients and reduce health care costs. The main objectives of the evaluation are to analyse the effectiveness and cost effectiveness of using patient-centred teams as part of routine service provision for this patient group. The evaluation will analyse the effect on patient health and functional status, patient experiences and hospital utilisation, and it will conduct an economic evaluation. This paper describes the PACT model and the rationale for and design of the planned effectiveness and cost effectiveness study. METHODS/DESIGN: This is a prospective, non-randomised matched control before-and-after intervention study. Patients in the intervention group will be recruited from the hospital sites that have implemented the PACT model. The controls will be recruited from two hospitals without the model. The control patients and the index patients will be matched according to sex, age and number of long-term conditions. The study aims to include 600 patients in each group, which will provide sufficient power to detect a clinical change in the primary outcome. The primary outcome is the physical dimension of the Short Form Health Survey (SF-36). Secondary outcomes are the Patient Generated Index (PGI), the Patient Activation Measure (PAM), the Patient Assessment of Chronic Illness Care (PACIC), hospitalisation and length of stay. The cost-effectiveness study takes a health provider perspective and calculates the cost per quality-adjusted life-years (QALYs) gained. The data will be collected at baseline, 6 and 12 months. The data will be analysed using techniques and models that recognise the lack of randomisation and the correlation of cost and effect data. DISCUSSION: The study results will provide knowledge about whether the integrated care model implemented at UNN improves the quality of care for the frail elderly with multiple conditions. The study will establish whether the PAC. T model improves health and functional status and is cost effective compared to the usual care for this patient group. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02541474. PMID- 26499257 TI - Antithymocyte globulin treatment at the time of transplantation impairs donor hematopoietic stem cell engraftment. AB - Antithymocyte globulin (ATG) is often included in the conditioning regimen to prevent graft vs. host disease in allogeneic hematopoietic stem cell (HSC) transplantation. However, because ATG contains antibodies targeting a wide range of antigens on human cells, its potential off-target effects remain a concern. Here, we explored this question in humanized mice that permit the analysis of human cell depletion in tissues. We showed that ATG binds to almost all lineages of human hematopoietic cells including HSCs, and accordingly it is capable of depleting almost all human hematopoietic cells. Interestingly, the efficacy of ATG was highly variable depending on the tissue of residence, with human cells in bone marrow significantly less susceptible than those in the blood and spleen. Recovery of multilineage human lymphohematopoietic reconstitution in humanized mice that received ATG 3 weeks after HSC transplantation indicates that ATG had a minimal effect on human HSCs that have settled in bone marrow niches. However, efficient human HSC depletion and engraftment failure were seen in mice receiving ATG at the time of transplantation. Our data indicate that the efficacy of ATG is tissue-dependent, and suggest a potential risk of impairing donor hematopoietic engraftment when ATG is used in preparative conditioning regimens. PMID- 26499258 TI - Fluctuation amplitude and local synchronization of brain activity in the ultra low frequency band: An fMRI investigation of continuous feedback of finger force. AB - Functional magnetic resonance imaging (fMRI) studies of motor feedback have suggested that brain activity in the ultra-low frequency band (0-0.01Hz) may be physiologically significant for various feedback conditions, i.e., real and sham feedback. However, the functional role of the ultra-low frequency band of brain activity during the feedback procedure remains unclear. Here, we carried out an fMRI study of continuous feedback (8min) of finger force and assessed two important properties of brain activity: the fluctuation amplitude and local synchronization in the ultra-low frequency band. Two intriguing results were obtained: (1) real feedback recruited a stronger fluctuation amplitude and local synchronization in the basal ganglia compared with sham feedback; however, no significant correlation was found between the two properties across subjects; and (2) the behavioral performance was significantly correlated with the fluctuation amplitude but was not correlated with local synchronization in the basal ganglia. These findings contribute to characterization of the functional role of brain activity in the ultra-low frequency band and further suggest that the fluctuation amplitude and local synchronization in the basal ganglia may contribute differently to motor feedback. PMID- 26499259 TI - Embodied simulation and ambiguous stimuli: The role of the mirror neuron system. AB - According to the "embodied simulation theory," exposure to certain visual stimuli would automatically trigger action simulation in the mind of the observer, thereby originating a "feeling of movement" modulated by the mirror neuron system (MNS). Grounded on this conceptualization, some of us recently suggested that when exposed to the Rorschach inkblots, in order to see a human movement (e.g., "a person running") in those ambiguous stimuli, the observer would need to experience a "feeling of movement" via embodied simulation. The current study used repetitive transcranial magnetic stimulation (rTMS) to further test this hypothesis. Specifically, we investigated whether temporarily interfering with the activity of the left inferior frontal gyrus (LIFG; a putative MNS area) using rTMS would decrease the propensity to see human movement (M) in the Rorschach inkblots. Thirty-six participants were exposed to the Rorschach stimuli twice, i.e., during a baseline (without rTMS) and soon after inhibitory rTMS. As for the rTMS condition, half of the sample was stimulated over the LIFG (experimental group) and the other half over the Vertex (control group). In line with our hypothesis, the application of rTMS over LIFG, but not over Vertex, yielded a statistically significant reduction in the attribution of M to the ambiguous stimuli, with large effect size. These findings may be interpreted as being consistent with the hypothesis that there is a link between the MNS and the "feeling of movement" people may experience, when observing ambiguous stimuli such as the Rorschach cards. PMID- 26499260 TI - Equal effects of typical environmental and specific social enrichment on posttraumatic cognitive functioning after fimbria-fornix transection in rats. AB - Enriched environment (EE) has been shown to have beneficial effects on cognitive recovery after brain injury. Typical EE comprises three components: (i) enlarged living area providing physical activation, (ii) sensory stimulation, and (iii) social stimulation. The present study assessed the specific contribution of the social stimulation. Animals were randomly divided into groups of (1) a typical EE, (2) pure social enrichment (SE), or (3) standard housing (SH) and subjected to either a sham operation or transection of the fimbria-fornix (FF). The effect of these conditions on acquisition of a delayed alternation task in a T-maze was assessed. The sham control groups were not affected by housing conditions. In the lesioned groups, both typical EE and SE improved the task acquisition, compared to SH. A baseline one-hour activity measurement confirmed an equal level of physical activity in the EE and SE groups. After delayed alternation testing, pharmacological challenges (muscarinergic antagonist scopolamine and dopaminergic antagonist SKF-83566) were used to assess cholinergic and dopaminergic contributions to task solution. Scopolamine led to a marked impairment in all groups. SKF-83566 significantly enhanced the performance of the lesioned group subjected to SE. The results demonstrate that housing in a typical as well as atypical EE can enhance cognitive recovery after mechanical injury to the hippocampus. The scopolamine challenge revealed a cholinergic dependency during task performance in all groups, regardless of lesion and housing conditions. The dopaminergic challenge revealed a difference in the neural substrates mediating recovery in the lesioned groups exposed to different types of housing. PMID- 26499261 TI - Listening to music in a risk-reward context: The roles of the temporoparietal junction and the orbitofrontal/insular cortices in reward-anticipation, reward gain, and reward-loss. AB - Artificial rewards, such as visual arts and music, produce pleasurable feelings. Popular songs in the verse-chorus form provide a useful model for understanding the neural mechanisms underlying the processing of artificial rewards, because the chorus is usually the most rewarding element of a song. In this functional magnetic resonance imaging (fMRI) study, the stimuli were excerpts of 10 popular songs with a tensioned verse-to-chorus transition. We examined the neural correlates of three phases of reward processing: (1) reward-anticipation during the verse-to-chorus transition, (2) reward-gain during the first phrase of the chorus, and (3) reward-loss during the unexpected noise followed by the verse-to chorus transition. Participants listened to these excerpts in a risk-reward context because the verse was followed by either the chorus or noise with equal probability. The results showed that reward-gain and reward-loss were associated with left- and right-biased temporoparietal junction activation, respectively. The bilateral temporoparietal junctions were active during reward-anticipation. Moreover, we observed left-biased lateral orbitofrontal activation during reward anticipation, whereas the medial orbitofrontal cortex was activated during reward gain. The findings are discussed in relation to the cognitive and emotional aspects of reward processing. PMID- 26499262 TI - A parabolic model of drag coefficient for storm surge simulation in the South China Sea. AB - Drag coefficient (Cd) is an essential metric in the calculation of momentum exchange over the air-sea interface and thus has large impacts on the simulation or forecast of the upper ocean state associated with sea surface winds such as storm surges. Generally, Cd is a function of wind speed. However, the exact relationship between Cd and wind speed is still in dispute, and the widely-used formula that is a linear function of wind speed in an ocean model could lead to large bias at high wind speed. Here we establish a parabolic model of Cd based on storm surge observations and simulation in the South China Sea (SCS) through a number of tropical cyclone cases. Simulation of storm surges for independent Tropical cyclones (TCs) cases indicates that the new parabolic model of Cd outperforms traditional linear models. PMID- 26499263 TI - Plasma levels of natriuretic peptides and development of chronic kidney disease. AB - BACKGROUND: Plasma levels of atrial and brain natriuretic peptides (ANP and BNP) are increased in patients with chronic kidney disease (CKD) complicated with deteriorated kidney function, but the relationship between the plasma level of ANP or BNP and the future development of CKD is unclear. METHODS: We measured the plasma ANP and BNP levels of 294 local residents without CKD in a Japanese community (56.5 +/- 10.4 years, mean +/- S.D.), who were followed up for the development of CKD over the next 7 years. RESULTS: Sixty-three residents developed CKD during the follow-up period, and the baseline level of plasma ANP of these residents was significantly higher than in those without CKD development. Kaplan-Meier analysis showed that the residents with higher ANP than the median value developed CKD more frequently than those with lower ANP. The association between plasma ANP level and CKD development was found to be independent of baseline estimated glomerular filtration rate by a Cox proportional hazards model, while this association became insignificant when adjusted by age; plasma ANP was significantly correlated with age. Compared with ANP, the relationship between plasma BNP and CKD development was unclear in these analyses. CONCLUSIONS: Age-related elevation of plasma ANP levels preceded the development of CKD in the general population of Japan, raising a possibility for ANP being involved in the development of CKD. PMID- 26499264 TI - Cancer-testis antigen cyclin A1 is broadly expressed in ovarian cancer and is associated with prolonged time to tumor progression after platinum-based therapy. AB - BACKGROUND: Cyclin A1 is essential for male gametopoiesis. In acute myeloid leukemia, it acts as a leukemia-associated antigen. Cyclin A1 expression has been reported in several epithelial malignancies, including testicular, endometrial, and epithelial ovarian cancer (EOC). We analyzed Cyclin A1 expression in EOC and its correlation with clinical features to evaluate Cyclin A1 as a T-cell target in EOC. METHODS: Cyclin A1 mRNA expression in EOC and healthy tissues was quantified by microarray analysis and quantitative real-time PCR (qRT-PCR). Protein expression in clinical samples was assessed by immunohistochemistry (IHC) and was correlated to clinical features. RESULTS: Cyclin A1 protein was homogeneously expressed in 43 of 62 grade 3 tumor samples and in 1 of 10 grade 2 specimens (p < 0.001). Survival analysis showed longer time to progression (TTP) among patients with at least moderate Cyclin A1 expression (univariate: p = 0.018, multivariate: p = 0.035). FIGO stage, grading, age, macroscopic residual tumor after debulking, and peritoneal carcinomatosis / distant metastasis had no impact on TTP or overall survival (OS). CONCLUSION: Cyclin A1 is highly expressed in most EOCs. The mechanism behind the prolonged TTP in patients with high Cyclin A1 expression warrants further investigation. The frequent, selectively high expression of Cyclin A1 in EOC makes it a promising target for T-cell therapies. PMID- 26499265 TI - Dysregulated development of IL-17- and IL-21-expressing follicular helper T cells and increased germinal center formation in the absence of RORgammat. AB - Interleukin 17-producing helper T (Th17) cells have been widely defined by the lineage transcription factor retinoid-related orphan receptor (ROR)gammat. Pathophysiologically, these cells play a crucial role in autoimmune diseases and have been linked to dysregulated germinal center (GC) reactions and autoantibody production. In this study, we used gene expression and flow cytometric analyses for the characterization of Rorgammat(-/-) and Rorgammat(-/-)Il21(RFP/+) mice to demonstrate a previously unknown transcriptional flexibility in the development of IL-17-producing Th-cell subsets. We found an accumulation of follicular Th (Tfh) cells by 5.2-fold, spontaneous 13-fold higher GC formation, decreased frequency of follicular Foxp3(+) T-regulatory (Treg) cells (50%), and a 3.4-fold increase in the number of proliferating follicular B cells in RORgammat-deficient vs. wild-type mice. Dysregulated B-cell responses were associated with enhanced production of IL-17 (6.4-fold), IL-21 (2.2-fold), and B-cell-activating factor (BAFF) (2-fold) and were partially rescued by adoptive transfer of Treg cells. In an unexpected finding, we detected RORgammat-independent IL-17 expression in ICOS(+)CXCR5(+)Tfh and in ICOS(+)CXCR5(-)Th cells. Based on the observed high Irf4 and Batf gene expression, we suggest that CD4(+) T-cell transcription factors other than RORgammat can cooperatively induce differentiation of IL-17 producing Th cells, including Th17-like Tfh-cell subsets. We conclude that the occurrence of aberrant Tfh and follicular Treg cells support spontaneous GC formation and dysregulated B-cell responses in RORgammat-deficient mice. PMID- 26499266 TI - The constitutive activity of the adhesion GPCR GPR114/ADGRG5 is mediated by its tethered agonist. AB - Adhesion GPCRs (aGPCRs) form the second largest, yet most enigmatic class of the GPCR superfamily. Although the physiologic importance of aGPCRs was demonstrated in several studies, the majority of these receptors is still orphan with respect to their agonists and signal transduction. Recent studies reported that aGPCRs are activated through a tethered peptide agonist, coined the Stachel sequence. The Stachel sequence is the most C-terminal part of the highly conserved GPCR autoproteolysis-inducing domain. Here, we used cell culture-based assays to investigate 2 natural splice variants within the Stachel sequence of the orphan Gs coupling aGPCR GPR114/ADGRG5. There is 1 variant constitutively active in cAMP assays (~25-fold over empty vector) and sensitive to mechano-activation. The other variant has low basal activity in cAMP assays (6-fold over empty vector) and is insensitive to mechano-activation. In-depth mutagenesis studies of these functional differences revealed that the N-terminal half of the Stachel sequence confers the agonistic activity, whereas the C-terminal part orientates the agonistic core sequence to the transmembrane domain. Sequence comparison and functional testing suggest that the proposed mechanism of Stachel-mediated activation is relevant not only to GPR114 but to aGPCRs in general. PMID- 26499267 TI - Intrauterine low-functional programming of IGF1 by prenatal nicotine exposure mediates the susceptibility to osteoarthritis in female adult rat offspring. AB - This study aimed to evaluate whether female adult offspring born with intrauterine growth retardation induced by prenatal nicotine exposure (PNE) are susceptible to osteoarthritis (OA) and to explore the underlying programming mechanisms. Pregnant rats were treated with nicotine or saline at 2.0 mg/kg/d from gestational d 11 to 20. The female adult offspring with or without PNE were forced with a strenuous treadmill running for 6 wk to induce OA. Nicotine's effects on fetal articular chondrocytes were studied by exposing chondrocytes to nicotine for 10 d, and dihydro-beta-erythroidine, a selective alpha4beta2 nicotinic acetylcholine receptor (nAChR) inhibitor, was used to identify the change of nicotine's effect. For adult offspring, increased cartilage destruction and accelerated OA progression were observed in the PNE group with running; the expression of alpha1 chain of type II collagen (Col2A1), aggrecan, SRY-type high mobility group box 9 (Sox9), and IGF1 signaling molecules in the cartilage of PNE offspring were decreased. For fetuses, elevated serum corticosteroid and nicotine levels and suppressed IGF1 levels were observed; expression of Col2A1, aggrecan, Sox9, and IGF1 were reduced. The result of chondrocytes revealed that nicotine impeded the expression of Col2A1, aggrecan, and IGF1; blocking alpha4beta2-nAChR rescued nicotine's suppression. In conclusion, PNE increases the susceptibility of adult offspring to OA; the potential mechanism involves IGF1 low-functional programming in articular cartilage caused directly by the action of nicotine on alpha4beta2-nAChR. PMID- 26499268 TI - Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling. AB - Lithium chloride (LiCl) exhibits significant therapeutic potential as a treatment for osteoarthritis. Hedgehog signaling is activated in osteoarthritis, where it promotes chondrocyte hypertrophy and cartilage matrix catabolism. Hedgehog signaling requires the primary cilium such that maintenance of this compartment is essential for pathway activity. Here we report that LiCl (50 mM) inhibits Hedgehog signaling in bovine articular chondrocytes such that the induction of GLI1 and PTCH1 expression is reduced by 71 and 55%, respectively. Pathway inhibition is associated with a 97% increase in primary cilia length from 2.09 +/ 0.7 MUm in untreated cells to 4.06 +/- 0.9 MUm in LiCl-treated cells. We show that cilia elongation disrupts trafficking within the axoneme with a 38% reduction in Arl13b ciliary localization at the distal region of the cilium, consistent with the role of Arl13b in modulating Hedgehog signaling. In addition, we demonstrate similar increases in cilia length in human chondrocytes in vitro and after administration of dietary lithium to Wistar rats in vivo. Our data provide new insights into the effects of LiCl on chondrocyte primary cilia and Hedgehog signaling and shows for the first time that pharmaceutical targeting of the primary cilium may have therapeutic benefits in the treatment of osteoarthritis. PMID- 26499269 TI - A clinical report of Chediak-Higashi syndrome in infancy with a novel genotype from the Indian subcontinent. AB - Chediak-Higashi syndrome (CHS; OMIM no. 214500) is an inherited multisystem disorder presenting with hypopigmentation and a propensity to infections due to immunological dysfunction. CHS generally presents in infancy with a fatal outcome, but less severe cases can present in adulthood. Treatment with bone marrow transplantation can be life-saving, so establishing a correct diagnosis is critical. The presence of large granules on examination of peripheral blood smears is suggestive of the diagnosis of CHS in most centers. However, sequencing of the lysosomal trafficking, LYST, gene confirms the diagnosis and can provide a prognosis regarding disease severity. In the case presented here, we performed molecular testing to identify the causative mutation and tabulated published mutation data from 2009 to 2014. We found a novel frameshift mutation in our case and concluded that frameshift and nonsense are the most common types of mutation in CHS, but this may be biased due to underdiagnosis of the milder and atypical forms of the disease. PMID- 26499270 TI - Effects of Pegylated Interferon/Ribavirin on Bone Turnover Markers in HIV/Hepatitis C Virus-Coinfected Patients. AB - HIV/hepatitis C virus (HCV) patients have a 3-fold increased fracture incidence compared to uninfected patients. The impact of HCV therapy on bone health is unclear. We evaluated bone turnover markers (BTM) in well-controlled (HIV RNA <50 copies/ml) HIV/HCV-coinfected patients who received pegylated interferon-alpha and ribavirin (PEG-IFN/RBV) in ACTG trial A5178. Early virologic responders (EVR: >=2 log HCV RNA drop at week 12) continued PEG-IFN/RBV and non-EVRs were randomized to continuation of PEG-IFN alone or observation. We assessed changes in C-terminal telopeptide of type 1 collagen (CTX; bone resorption marker) and procollagen type I intact N-terminal propeptide (P1NP; bone formation marker), and whether BTM changes were associated with EVR, complete early virologic response (cEVR: HCV RNA <600 IU/ml at week 12), or PEG-IFN treatment. A total of 192 subjects were included. After 12 weeks of PEG-IFN/RBV, CTX and P1NP decreased: -120 pg/ml and -8.48 MUg/liter, respectively (both p < 0.0001). CTX declines were greater in cEVR (N = 91; vs. non-cEVR (N = 101; p = 0.003). From week 12 to 24, CTX declines were sustained among EVR patients who continued PEG IFN/RBV (p = 0.027 vs. non-EVR) and among non-EVR patients who continued PEG-IFN alone (p = 0.022 vs. Observation). Median decreases of P1NP in EVR vs. non-EVR were similar at weeks 12 and 24. PEG-IFN-based therapy for chronic HCV markedly reduces bone turnover. It is unclear whether this is a direct IFN effect or a result of HCV viral clearance, or whether they will result in improved bone mineral density. Further studies with IFN-free regimens should explore these questions. PMID- 26499271 TI - Evolution of Movement Disorders Surgery Leading to Contemporary Focused Ultrasound Therapy for Tremor. AB - Progressively less invasive neurosurgical approaches for the treatment of movement disorders have evolved, beginning with open craniotomy for placement of lesions within pyramidal structures followed by refined stereotactic ablation of extrapyramidal targets that encouraged nondestructive electrode stimulation of deep brain structures. A noninvasive approach using transcranial high-energy focused ultrasound has emerged for the treatment of intractable tremor. The ability to target discreet intracranial sites millimeters in size through the intact skull using focused acoustic energy marks an important milestone in movement disorders surgery. This article describes the evolution of magnetic resonance-guided focused ultrasound for ventrolateral thalamotomy for tremor. PMID- 26499272 TI - Magnetic Resonance Imaging-Guided Spine Interventions. AB - MR imaging-guided interventions for treatment of low back pain and for diagnosis and treatment of soft tissue and bony spinal lesions have been shown to be feasible, effective, and safe. Advantages of this technique include the absence of ionizing radiation, the high tissue contrast, and multiplanar imaging options. Recent advancements in MR imaging systems allow improved image qualities and real time guidance. One exciting application is MR imaging-guided cryotherapy of spinal lesions, including treating such lesions as benign osteoid osteomas and malignant metastatic disease in patients who are not good surgical candidates. This particular technique shows promise for local tumor control and pain relief in appropriate patients. PMID- 26499273 TI - 3-Tesla High-Field Magnetic Resonance Neurography for Guiding Nerve Blocks and Its Role in Pain Management. AB - Interventional magnetic resonance (MR) neurography is a minimally invasive technique that affords targeting of small nerves in challenging areas of the human body for highly accurate nerve blocks and perineural injections. This cross sectional technique uniquely combines high tissue contrast and high-spatial resolution anatomic detail, which enables the precise identification and selective targeting of peripheral nerves, accurate needle guidance and navigation of the needle tip within the immediate vicinity of a nerve, as well as direct visualization of the injected drug for the assessment of appropriate drug distribution and documentation of the absence of spread to confounding nearby nerves. PMID- 26499275 TI - Magnetic Resonance Imaging-Guided Cardiac Interventions. AB - Performing intraoperative cardiovascular procedures inside an MR imaging scanner can potentially provide substantial advantage in clinical outcomes by reducing the risk and increasing the success rate relative to the way such procedures are performed today, in which the primary surgical guidance is provided by X-ray fluoroscopy, by electromagnetically tracked intraoperative devices, and by ultrasound. Both noninvasive and invasive cardiologists are becoming increasingly familiar with the capabilities of MR imaging for providing anatomic and physiologic information that is unequaled by other modalities. As a result, researchers began performing animal (preclinical) interventions in the cardiovascular system in the early 1990s. PMID- 26499274 TI - Magnetic Resonance Imaging-Guided Breast Interventions: Role in Biopsy Targeting and Lumpectomies. AB - Contrast-enhanced breast MR imaging is increasingly being used to diagnose breast cancer and to perform biopsy procedures. The American Cancer Society has advised women at high risk for breast cancer to have breast MR imaging screening as an adjunct to screening mammography. This article places special emphasis on biopsy and operative planning involving MR imaging and reviews use of breast MR imaging in monitoring response to neoadjuvant chemotherapy. Described are peer-reviewed data on currently accepted MR imaging-guided procedures for addressing benign and malignant breast diseases, including intraoperative imaging. PMID- 26499276 TI - Magnetic Resonance-guided Active Catheter Tracking. AB - Several advantages of MR imaging compared with other imaging modalities have provided the rationale for increased attention to MR-guided interventions, including its excellent soft tissue contrast, its capability to show both anatomic and functional information, and no use of ionizing radiation. An important aspect of MR-guided intervention is to provide visualization and navigation of interventional devices relative to the surrounding tissues. This article focuses on the methods for MR-guided active tracking in catheter-based interventions. Practical issues about implementation of active catheter tracking in a clinical setting are discussed and several current application examples are highlighted. PMID- 26499278 TI - Magnetic Resonance-Guided Thermal Therapy for Localized and Recurrent Prostate Cancer. AB - The advent of focal therapies theoretically offers new treatment options for patients with localized prostate cancer. The goal of prostate cancer treatment is effective long-term cure with minimal impact on health-related quality of life. Multiparametric MR imaging of the prostate is being increasingly used for diagnosis, image-guided targeted biopsy, guidance for targeted focal and regional therapy, and monitoring the effectiveness of treatments for prostate cancer of all stages. In this article, the use of prostate MRI in the burgeoning domain of thermal ablative therapy for localized and recurrent prostate cancer is reviewed. PMID- 26499277 TI - Magnetic Resonance-Guided Passive Catheter Tracking for Endovascular Therapy. AB - The use of MR guidance for endovascular intervention is appealing because of its lack of ionizing radiation, high-contrast visualization of vessel walls and adjacent soft tissues, multiplanar capabilities, and potential to incorporate functional information such as flow, fluid dynamics, perfusion, and cardiac motion. This review highlights state-of-the-art imaging techniques and hardware used for passive tracking of endovascular devices in interventional MR imaging, including negative contrast, passive contrast, nonproton multispectral, and direct current techniques. The advantages and disadvantages of passive tracking relative to active tracking are also summarized. PMID- 26499279 TI - Magnetic Resonance-Guided Prostate Biopsy. AB - The optimal strategy for prostate cancer diagnosis is to avoid overdiagnosis, defined as diagnosis of clinically insignificant disease, and undersampling of the gland, which leads to missing clinically significant disease. Targeted prostate biopsy is a potential solution for decreasing the rate of both overdiagnosis and undersampling of prostate cancer. We focus here on different techniques for targeting prostate lesions identified on multiparametric MR imaging and review different clinical settings in which MR imaging-targeted prostate biopsies are performed. PMID- 26499280 TI - Magnetic Resonance-Guided Gynecologic Brachytherapy. AB - Gynecologic brachytherapy consists of positioning radioactive sources in catheters implanted inside a tumor. MR imaging provides tumor visibility and is ideal for image-guided insertions and treatment planning. It is important at first insertion and during treatment of large residual tumors potentially needing interstitial needles. Clear visibility of the tumor and the catheters is necessary for MR-guided brachytherapy. T2 sequences are ideal for tumor visibility but catheter visualization may be difficult. Active tracking and alternative sequences to improve catheter visibility have been explored. The use of digital applicator models, dummy markers, and CT-MR fusion is reviewed. PMID- 26499281 TI - Magnetic Resonance-Guided Drug Delivery. AB - The use of clinical imaging modalities for the guidance of targeted drug delivery systems, known as image-guided drug delivery (IGDD), has emerged as a promising strategy for enhancing antitumor efficacy. MR imaging is particularly well suited for IGDD applications because of its ability to acquire images and quantitative measurements with high spatiotemporal resolution. The goal of IGDD strategies is to improve treatment outcomes by facilitating planning, real-time guidance, and personalization of pharmacologic interventions. This article reviews basic principles of targeted drug delivery and highlights the current status, emerging applications, and future paradigms of MR-guided drug delivery. PMID- 26499282 TI - Update on Clinical Magnetic Resonance-Guided Focused Ultrasound Applications. AB - In this review, several clinical applications of magnetic resonance (MR)-guided focused ultrasound (FUS) are updated. MR-guided FUS is used clinically for thermal ablation of uterine fibroids and bone metastases. Thousands of patients have successfully been treated. Transcranial MR-guided FUS has received CE certification for ablation of deep, central locations in the brain. Thermal ablation of specific parts of the thalamus can result in relief of the symptoms in a number of neurological disorders. Several approaches have been proposed for ablation of prostate and breast cancer and clinical trials should show the potential of MR-guided FUS for these and other applications. PMID- 26499284 TI - Interventional Magnetic Resonance Imaging Clinic: The Emory University Experience. AB - In this article, we share our experience in establishing a clinic-based practice for MR imaging-guided interventions. Clinic resources and operational logistics are described and our institutional cost analysis for supporting the clinic activity is provided. We highlight the overall value of the clinic model in transitioning the field of interventional MR imaging from the "proof-of-concept" to the "working model" era and engage in a detailed discussion of our experience with the positive impact of the clinic on streamlining the procedural workflow, increasing awareness of the technology, expanding referral bases, and boosting the satisfaction of both patients and referring services. PMID- 26499283 TI - Magnetic Resonance Sequences and Rapid Acquisition for MR-Guided Interventions. AB - Interventional MR uses rapid imaging to guide diagnostic and therapeutic procedures. One of the attractions of MR-guidance is the abundance of inherent contrast mechanisms available. Dynamic procedural guidance with real-time imaging has pushed the limits of MR technology, demanding rapid acquisition and reconstruction paired with interactive control and device visualization. This article reviews the technical aspects of real-time MR sequences that enable MR guided interventions. PMID- 26499285 TI - Magnetic Resonance-Guided Interventions: The State of the Art. PMID- 26499287 TI - Foreword. PMID- 26499290 TI - The relation between input-output transformation and gastrointestinal nematode infections on dairy farms. AB - Efficiency analysis is used for assessing links between technical efficiency (TE) of livestock farms and animal diseases. However, previous studies often do not make the link with the allocation of inputs and mainly present average effects that ignore the often huge differences among farms. In this paper, we studied the relationship between exposure to gastrointestinal (GI) nematode infections, the TE and the input allocation on dairy farms. Although the traditional cost allocative efficiency (CAE) indicator adequately measures how a given input allocation differs from the cost-minimising input allocation, they do not represent the unique input allocation of farms. Similar CAE scores may be obtained for farms with different input allocations. Therefore, we propose an adjusted allocative efficiency index (AAEI) to measure the unique input allocation of farms. Combining this AAEI with the TE score allows determining the unique input-output position of each farm. The method is illustrated by estimating efficiency scores using data envelopment analysis (DEA) on a sample of 152 dairy farms in Flanders for which both accountancy and parasitic monitoring data were available. Three groups of farms with a different input-output position can be distinguished based on cluster analysis: (1) technically inefficient farms, with a relatively low use of concentrates per 100 l milk and a high exposure to infection, (2) farms with an intermediate TE, relatively high use of concentrates per 100 l milk and a low exposure to infection, (3) farms with the highest TE, relatively low roughage use per 100 l milk and a relatively high exposure to infection. Correlation analysis indicates for each group how the level of exposure to GI nematodes is associated or not with improved economic performance. The results suggest that improving both the economic performance and exposure to infection seems only of interest for highly TE farms. The findings indicate that current farm recommendations regarding GI nematode infections could be improved by also accounting for the allocation of inputs on the farm. PMID- 26499289 TI - Cell death at the intestinal epithelial front line. AB - The intestinal epithelium represents the largest epithelial surface in our body. This single-cell-layer epithelium mediates important functions in the absorption of nutrients and in the maintenance of barrier function, preventing luminal microorganisms from invading the body. Due to its constant regeneration the intestinal epithelium is a tissue not only with very high proliferation rates but also with very prominent physiological and pathophysiological cell death induction. The normal physiological differentiation and maturation of intestinal epithelial cells leads to their shedding and apoptotic cell death within a few days, without disturbing the epithelial barrier integrity. In contrast excessive intestinal epithelial cell death induced by irradiation, drugs and inflammation severely impairs the vital functions of this tissue. In this review we discuss cell death processes in the intestinal epithelium in health and disease, with special emphasis on cell death triggered by the tumour necrosis factor receptor family. PMID- 26499288 TI - An integrated pan-tropical biomass map using multiple reference datasets. AB - We combined two existing datasets of vegetation aboveground biomass (AGB) (Proceedings of the National Academy of Sciences of the United States of America, 108, 2011, 9899; Nature Climate Change, 2, 2012, 182) into a pan-tropical AGB map at 1-km resolution using an independent reference dataset of field observations and locally calibrated high-resolution biomass maps, harmonized and upscaled to 14 477 1-km AGB estimates. Our data fusion approach uses bias removal and weighted linear averaging that incorporates and spatializes the biomass patterns indicated by the reference data. The method was applied independently in areas (strata) with homogeneous error patterns of the input (Saatchi and Baccini) maps, which were estimated from the reference data and additional covariates. Based on the fused map, we estimated AGB stock for the tropics (23.4 N-23.4 S) of 375 Pg dry mass, 9-18% lower than the Saatchi and Baccini estimates. The fused map also showed differing spatial patterns of AGB over large areas, with higher AGB density in the dense forest areas in the Congo basin, Eastern Amazon and South East Asia, and lower values in Central America and in most dry vegetation areas of Africa than either of the input maps. The validation exercise, based on 2118 estimates from the reference dataset not used in the fusion process, showed that the fused map had a RMSE 15-21% lower than that of the input maps and, most importantly, nearly unbiased estimates (mean bias 5 Mg dry mass ha(-1) vs. 21 and 28 Mg ha(-1) for the input maps). The fusion method can be applied at any scale including the policy-relevant national level, where it can provide improved biomass estimates by integrating existing regional biomass maps as input maps and additional, country-specific reference datasets. PMID- 26499291 TI - Mycoplasma bovis-derived lipid-associated membrane proteins activate IL-1beta production through the NF-kappaB pathway via toll-like receptor 2 and MyD88. AB - Mycoplasma bovis causes pneumonia, otitis media, and arthritis in young calves, resulting in economic losses to the cattle industry worldwide. M. bovis pathogenesis results in part from excessive immune responses. Lipid-associated membrane proteins (LAMPs) can potently induce host innate immunity. However, interactions between M. bovis-derived LAMPs and Toll-like receptors (TLRs), or signaling pathways eliciting active inflammation and NF-kappaB activation, are incompletely understood. Here, we found that IL-1beta expression was induced in embryonic bovine lung (EBL) cells stimulated with M. bovis-derived LAMPs. Subcellular-localization analysis revealed nuclear p65 translocation following EBL cell stimulation with M. bovis-derived LAMPs. An NF-kappaB inhibitor reversed M. bovis-derived LAMP-induced IL-1beta expression. TLR2 and myeloid differentiation primary response gene 88 (MyD88) overexpression increased LAMP dependent IL-1beta induction. TLR2-neutralizing antibodies reduced IL-1beta expression during LAMP stimulation. LAMPs also inhibited IL-1beta expression following overexpression of a dominant-negative MyD88 protein. These results suggested that M. bovis-derived LAMPs activate IL-1beta production through the NF kappaB pathway via TLR2 and MyD88. PMID- 26499292 TI - Follow-up study on the relationship between alopecia areata and risk of autoimmune diseases. PMID- 26499293 TI - The Density of States and the Transport Effective Mass in a Highly Oriented Semiconducting Polymer: Electronic Delocalization in 1D. AB - The determination of the band structure along k parallel to the chain direction demonstrates significant electronic delocalization. The small effective mass [m* = 0.106mo ] is consistent with the high measured mobility. PMID- 26499294 TI - Editorial. PMID- 26499295 TI - Foetal trauma, body memory and early infant communication: a case illustration. AB - This paper presents the complex case of a male patient who started life as an unwanted pregnancy and adoptee in an era of socio-cultural shame and blame. When able to contact his birth mother later in life, he experienced a number of confronting synchronicities as well as visions which he felt were related to failed abortion attempts and to other pre- and post-natal events. The case material lends weight not only to Freud's, Ehrenwald's and FitzHerbert's assertions that the earliest form of mother-infant communications is telepathic in nature but that this mode of communication can be retained if emotional trauma inhibits normal developmental processes. Contemporary neuroscience research is presented supporting the hypothesis that emotional memory can become imbedded in the psyche/soma of the foetus. Such memory traces can later emerge into imagery and/or words if the traumatic impingement has been substantial enough and if other defensive strategies are in place. Clinical implications are then suggested regarding analysts' attention to the emotional conditions underpinning their patients' conceptions and foetal development; the connection to projective identification components of the countertransference as being aspects of the earliest telepathic mother/infant communication channel and the need for reductive analyses in analyst training programmes. PMID- 26499296 TI - Acoustic resonance at the dawn of life: musical fundamentals of the psychoanalytic relationship. AB - This paper uses a case vignette to show how musical elements of speech are a crucial source of information regarding the patient's emotional states and associated memory systems that are activated at a given moment in the analytic field. There are specific psychoacoustic markers associated with different memory systems which indicate whether a patient is immersed in a state of creative intersubjective relatedness related to autobiographical memory, or has been triggered into a traumatic memory system. When a patient feels immersed in an atmosphere of intersubjective mutuality, dialogue features a rhythmical and tuneful form of speech featuring improvized reciprocal imitation, theme and variation. When the patient is catapulted into a traumatic memory system, speech becomes monotone and disjointed. Awareness of such acoustic features of the traumatic memory system helps to alert the analyst that such a shift has taken place informing appropriate responses and interventions. Communicative musicality (Malloch & Trevarthen 2009) originates in the earliest non-verbal vocal communication between infant and care-giver, states of primary intersubjectivity. Such musicality continues to be the primary vehicle for transmitting emotional meaning and for integrating right and left hemispheres. This enables communication that expresses emotional significance, personal value as well as conceptual reasoning. PMID- 26499297 TI - The making of a tragedy: perversion in the perception of truth. AB - A type of wilful blindness can pervert an individual's perception of truth or reality, not because that reality is too much to hold, but because it is distasteful. Undesired. The case of Adam will be used to explore perversion as it twists an analytic process, affecting the transference and countertransference in ways that are difficult to see. Theorists of Freudian, Kleinian, Lacanian, and Jungian traditions are drawn from to explore potential roots to this perverted turn, and the way it can rigidify an individuation process. The anxiety that haunts this case echoes Jung's anxiety as he wondered if the stone saw him or he saw the stone. Object and observer blend when both analyst and patient hide from themselves and one another, knowing the truth of what is being discussed but blind to it. PMID- 26499298 TI - Supervising the uncanny: the play within the play. AB - The writer offers a combined experience in analysis and the performing arts to explore uncanny aspects of the unconscious subtext of the patient's inner drama; subtext which can remain hidden from view in supervision. Freud and Jung's understanding of uncanny experience is considered together with a painting from medieval alchemy and Matte Blanco's conceptions concerning the symmetrical nature of unconscious process. Theatre and the work of the theatre director and actor in approaching the multidimensional aspects of a play are then introduced. Finally clinical case material from group supervision demonstrates how the 'theatre of therapy' and the work of the supervisory couple and group promote the emergence of a more authentic conscious asymmetrical response to the patient's 'script' that can break the 'spell' of the transference/countertransference relationship. This in turn brings meaning to the underlying and implicit 'stage directions' that the patient has been unconsciously communicating. PMID- 26499299 TI - Two in one or one in two? Pushing off from Jung with Wolfgang Giegerich. AB - This paper responds to a recent paper by Wolfgang Giegerich entitled 'Two Jungs: apropos a paper by Mark Saban'. Giegerich disputes my assertion that the 'rigorous notion' at the heart of his psychology 'finds no source in Jung's psychology, implicit or explicit'. In order to do this he posits the existence of two Jungs, an exoteric Jung and an esoteric Jung. The implications of Giegerich's binary scission of Jung are explored in this paper, and show that the tendency to exalt one Jung while disparaging the other betrays a comprehensive blindness toward the contradictory complexity of Jung's psychology as a whole. It is suggested that this blindness is the consequence of Giegerich's systematic prioritization of a neo-Hegelian agenda that is in profound conflict with the telos of Jung's psychology. PMID- 26499300 TI - Reflections on the Jungian nature of psychology as the discipline of interiority: a response to Saban's 'Misunderstandings'. AB - Psychology as the discipline of interiority is the name of the psychology that has developed from Wolfgang Giegerich's work in the field of analytical psychology. This article offers a counterview to that of Mark Saban's claim that Giegerich's psychology is 'irrelevant' to Jungians today and is based on a fundamental misunderstanding of the nature of Jungian psychology. It will be shown that, in fact, it is a fundamental misunderstanding of Giegerich's work that has led Saban to form erroneous conclusions. Links between Jung's and Giegerich's conceptions of the 'objective psyche' will be highlighted, along with other examples of how, contrary to Saban's conclusions, psychology as the discipline of interiority has obvious connections to, and grounding in, Jungian psychology. PMID- 26499301 TI - Horror films and the attack on rationality. PMID- 26499302 TI - Melancholia. PMID- 26499303 TI - James Grotstein (8 November 1925 - 30 May 2015). PMID- 26499307 TI - The perioperative time course and clinical significance of the chemokine CXCL16 in patients undergoing cardiac surgery. AB - The chemokine CXCL16 and its receptor CXCR6 have been linked to the pathogenesis of acute and chronic cardiovascular disease. However, data on the clinical significance of CXCL16 in patients undergoing cardiac surgery with acute myocardial ischemia/reperfusion (I/R) are still lacking. Therefore, we determined CXCL16 in the serum of cardiac surgery patients and investigated its kinetics and association with the extent of organ dysfunction. 48 patients underwent conventional cardiac surgery with myocardial I/R and the use of cardiopulmonary bypass (CPB) were consecutively enrolled in the present study. We investigated the peri- and post-operative profile of CXCL16. Clinical relevant data were assessed and documented throughout the entire observation period. To identify the influence of myocardial I/R and CPB on CXCL16 release data were compared to those received from patients that underwent off-pump procedure. Pre-operative serum CXCL16 levels were comparable to those obtained from healthy volunteers (1174 +/- 55.64 pg/ml versus 1225 +/- 70.94). However, CXCL16 levels significantly increased during surgery (1174 +/- 55.64 versus 1442 +/- 75.42 pg/ml; P = 0.0057) and reached maximum levels 6 hrs after termination of surgery (1174 +/- 55.64 versus 1648 +/- 74.71 pg/ml; P < 0.001). We revealed a positive correlation between the intraoperative serum levels of CXCL16 and the extent of organ dysfunction (r(2) = 0.356; P = 0.031). Patients with high CXCL16 release showed an increased extent of organ dysfunction compared to patients with low CXCL16 release. Our study shows that CXCL16 is released into the circulation as a result of cardiac surgery and that high post-operative CXCL16 levels are associated with an increased severity of post-operative organ dysfunctions. PMID- 26499308 TI - PDLIM2 suppression efficiently reduces tumor growth and invasiveness of human castration-resistant prostate cancer-like cells. AB - BACKGROUND: Although PDLIM2 gene may have a context-dependent role in various human malignancies and can be a potential therapeutic target, only a limited number of in vitro studies addressed the molecular functions of PDLIM2 in prostate cancer. Here, we aimed to explore the role of PDLIM2 and the effect of the PDLIM2 gene suppression on oncogenic phenotypes of human castration-resistant prostate cancer (CRPC)-like cells. METHODS: We used human CRPC-like cell lines (PC3, DU145, and C4-2B) for our experiments. Transcription levels of PDLIM2 and relevant genes were measured by real time-PCR and protein expression was analyzed by western blot. Cell viability, proliferation, clonogenic growth, and tumor sphere formation were examined after a specific inhibition of PDLIM2 using RNA interference. Flow cytometry was used to examine apoptotic cell death and cell cycle disturbances. Wound healing and transwell migration assays were performed to investigate the invasion capabilities of CRPC-like cells. Additionally, key oncogenic signaling pathways were examined using western blot. Lastly, we evaluated the in vivo efficacy of PDLIM2 suppression on tumor growth of human CRPC xenografts in mice. RESULTS: We observed a significant enhancement of PDLIM2 expression in human CRPC-like cell lines, while a specific inhibition of PDLIM2 reduced cell viability and proliferation due to apoptotic cell death. Conversely, PDLIM2 overexpression significantly reduced cell proliferation compared to the negative control in androgen-sensitive LNCaP cells. Moreover, PDLIM2 suppression led to a decrease of clonogenic growth and tumor sphere formation in three dimensional cultures with the G2/M cell cycle arrest in human CRPC-like cells. PDLIM2 inhibition also attenuated cellular migration and invasion capabilities of human CRPC-like cells, and reduced the expression of mesenchymal marker. Among several oncogenic signaling pathways, only the MAPK/ERK signaling cascade was decreased by PDLIM2 inhibition and reciprocally, ERK inhibition down-regulated PDLIM2 expression. Importantly, PDLIM2 inhibition remarkably compromised tumor growth in a human CRPC xenograft model. CONCLUSION: In summary, the suppression of PDLIM2 significantly reduced such oncogenic phenotypes as proliferation, clonogenicity, invasiveness, and tumor cell growth in human CRPC-like cells both in vitro and in vivo, indicating that PDLIM2 may be considered a novel therapeutic target gene for treating human CRPC. PMID- 26499310 TI - Impacts of COPD on family carers and supportive interventions: a narrative review. AB - Caring for a relative with chronic disease influences multiple dimensions of family carers' lives. This study aimed to provide an overview of the impacts of chronic obstructive pulmonary disease (COPD) on family carers and identify interventions aimed at supporting them. A narrative review was conducted. Searches were performed in electronic databases using a combination of keywords. Articles were screened for relevance and selected articles were analysed in two groups considering the study aims. Eighteen articles were selected. Fifteen studies evaluated the impacts of COPD on family carers and three studies presented interventions aimed at supporting them. Carers reported negative impacts of caring on physical health, emotional, social, relational and financial/employment life dimensions. Positive aspects of care-giving were reported in four studies and were related to carers' personal growth and satisfaction in being able to do something useful for their relatives. The existing interventions were directed at both patients and carers; however, studies provided limited information on how carers were involved, hindering the interpretation of findings. In conclusion, COPD poses several unique challenges to family carers related to the specificities of the disease. Further research with appropriate intervention studies is needed to promote carers' healthy adjustment to the disease. PMID- 26499309 TI - Use of solubilizers in preclinical formulations: Effect of Cremophor EL on the pharmacokinetic properties on early discovery compounds. AB - The aim of the present study was to determine whether Cremophor EL is a suitable surfactant that can be routinely applied to pharmacokinetic (PK) studies in early drug discovery without influencing the intrinsic PK characteristics of the new chemical entities (NCEs). Cremophor EL, a polyoxyl 35 castor oil, has been used as a solubilization aid for water-insoluble compounds in pre-clinical drug discovery. The effect of Cremophor EL on the PK properties of NCEs was examined in seven structurally diverse discovery compounds after intravenous administration. Significant effects of Cremophor EL on plasma volume of distribution (Vss) and plasma clearance (CL) were observed in compounds with moderate to high Vss or CL. The plasma Vss decreased more than 2-fold and the Vss binning category decreased by one unit (e.g. from moderate to low Vss) in 6 of 7 test compounds. Two to five-fold reduction of CL was observed with these 6 compounds. Effect on the terminal half-life (T1/2) was minimal. Using one of these 7 NCEs, concentration dependent effect of Cremophor EL in the vehicle was also determined. Higher percentage of Cremophor EL in vehicle resulted in progressively increased alterations on the plasma CL and Vss. Taken together, these findings indicated that Cremophor EL altered the intrinsic PK properties of these discovery compounds in a concentration dependent manner. PMID- 26499311 TI - Facing the next frontier of fetal magnetic resonance imaging. PMID- 26499312 TI - Sensilla on different organs of female and male Telenomus dendrolimusi Chu (Hymenoptera: Scelionidae). AB - Telenomus dendrolimusi Chu is a dominant egg parasitoid of Dendrolimus, which is the most serious conifer defoliator in China. However, the host locating mechanism of T. dendrolimusi is unclear. To take better advantage of this kind of parasitoid, it is necessary to clarify the basic knowledge of the organization of the wasp's sensory system. In this study, the external morphologies of the sensilla on the entire female and male T. dendrolimusi body were described using scanning electron microscopy. Antennae shape and sensilla types were sexually dimorphic. Ten segments and nine types of sensilla were found on the female antenna, including basiconic sensillum (BS), chaeticum sensillum (ChS), trichoid sensillum type 1 (TS1), trichoid sensillum type 2 (TS2), trichoid curvata sensillum (TCS), sickle-shaped sensillum (SSS), multiporous gustatory sensillum (MGS), campaniform sensillum (CS), and styloconica sensillum (STS). The distribution of the sensilla was directional on female antenna. The male antenna consisted of 12 segments, and 1-3 segments were similar to those of the female. Five types of sensilla were found on male antenna, including BS, ChS, TS1, TCS, and STS. The mouthparts, thoracic legs, eyes, mesonotum, and wings were all covered with longitudinally fluted TSs without hole. A tympana structure appeared on the thoracic legs. Special crevice-shaped structures were found on the abdomens of both T. dendrolimusi sexes. Possible sensilla functions are discussed according to their morphology. These results provide a solid basis for further researches about the parasitic mechanisms of T. dendrolimusi. PMID- 26499313 TI - Multiple functions of the first EGF domain in matrilin-3: Secretion and endoplasmic reticulum stress. AB - Mutations in matrilin-3 are associated with common skeletal diseases, such as hand osteoarthritis (HOA), as well as rare chondrodysplasias, such as multiple epiphyseal dysplasia (MED) and spondyloepimetaphyseal dysplasia (SEMD). In the present study, we constructed the mutations R116W [at the von Willebrand factor, type A (vWFA) domain], T298M [at the first epidermal growth factor (EGF) domain] and C299S (at the first EGF domain), according to the mouse sequence, which are associated with human MED, HOA and SEMD, respectively, by overlap extension PCR and inserted them into an expression vector (pcDNA3.1/v5-His). We transfected these contructs into the COS-1 or MCT cells, and the results revealed that the HOA-related matrilin-3 mutation (T298M) leads to a high expression level of growth arrest DNA damage-inducible gene 153 (GADD153, also known as CHOP; an endoplasmic reticulum stress marker), as shown by western blot analysis and does not significantly affect protein secretion, as shown by immunofluorescence staining; however, osteochondroplasia, i.e., MED-related (R116W) and SEMD-related (C299S) mutations lead to both high levels of GADD153 expression and protein trafficking into the cytoplasm and form multiple vacuoles in cells, which in turn leads to insufficient protein secretion. PMID- 26499314 TI - Care interaction adding challenges to old patients' well-being during surgical hospital treatment. AB - Today, hospitals offer surgical treatment within a short hospital admission. This brief interaction may challenge the well-being of old patients. The aim of this study was to explore how the well-being of old hospitalized patients was affected by the interaction with staff during a fast-track surgical treatment and hospital admission for colon cancer. We used an ethnographic methodology with field observations and unstructured interviews focusing on one patient at a time (n=9) during a full day; the hours ranging from 7:45 a.m. to 8 p.m. Participants were between 74 and 85 years of age and of both sexes. The study was reported to the Danish Data Protection Agency with reference number (2007-58-0010). The encounter between old patients and the staff was a main theme in our findings elucidating a number of care challenges. The identified care challenges illustrated "well-being as a matter of different perspectives," "vulnerability in contrast to well being," and "staff mix influencing the care encounter." The experience of well being in old cancer patients during hospital admission was absent or challenged when staff did not acknowledge their individual vulnerability and needs. PMID- 26499315 TI - Kimura's disease: an uncommon cause of head and neck masses with potentially serious sequelae. AB - Kimura's disease (KD) typically presents as a mass in the head and neck region in association with eosinophilia and elevated serum IgE. Excisional biopsy is often required in order to obtain an adequate sample for histological diagnosis and exclude malignancy. If suspected, patients should also be investigated for renal involvement as this may complicate KD. Treatment options include surgical excision and medical therapies such as corticosteroids depending on the extent and severity of disease. PMID- 26499316 TI - Children's Impact on Adults' Substance Use Problem Awareness and Treatment Optimism: The Role of Harm. AB - Substance abuse is associated with a host of harmful consequences to the substance user as well as other individuals and society as a whole. Although harm is an integral component of substance abuse, there is a dearth of research that investigates the relationship between harm and substance use problems. The goal of this study was to explore recovering substance users' retrospective perceptions of harm caused to self and others during periods of substance abuse and the resulting association with the development of problem awareness and treatment perspectives. The present study found that perceptions of harming children demonstrated a significant impact on adults' substance use problem awareness and treatment optimism. Perceived harm caused to a child during periods of substance abuse was associated with increased substance use problem awareness and treatment optimism. Findings suggest that harming children as a consequence of adult substance abuse may play an impactful role on adults' recovery process. Implications for future research are discussed. PMID- 26499317 TI - Low immediate postoperative serum-cortisol nadir predicts the short-term, but not long-term, remission after pituitary surgery for Cushing's disease. AB - BACKGROUND: Cushing's disease is an ACTH-producing pituitary adenoma, and the primary treatment is microscopic or endoscopic transsphenoidal selective adenectomy. The aims of the present study were to evaluate whether the early postoperative S-cortisol level can serve as a prognostic marker for short- and long-term remission, and retrospectively review our own short and long term results after surgery for Cushing's disease. METHODS: This single centre, retrospective study consists of 19 consecutive patients with Cushing's disease who underwent transsphenoidal surgery. S-cortisol was measured every 6 h after the operation without any glucocorticoid replacement. We have follow-up on all patients, with a mean follow-up of 68 months. RESULTS: At the three-month follow up, 16 patients (84 %) were in remission; at 12 months, 18 (95 %) were in remission and at the final follow-up (mean 68 months), 13 (68 %) were in remission. Five-years recurrence rate was 26 %. The mean postoperative S-cortisol nadir was significantly lower in the group of patients in remission than in the non-remission group at 3 months, but there was no difference between those in long-term remission compared to those in long-term non-remission. The optimal cut off value for classifying 3-month remission was 74 nmol/l. CONCLUSION: We achieved a 95 % 1-year remission rate with transsphenoidal surgery for Cushing's disease in this series of consecutive patients. However, the 5-year recurrence rate was 26 %, showing the need for regular clinical and biochemical controls in this patient group. The mean postoperative serum-cortisol nadir was significantly lower in patients in remission at 3 months compared to patients not in remission at 3 months, but a low postoperative S-cortisol did not predict long-term remission. PMID- 26499318 TI - Passive proton therapy vs. IMRT planning study with focal boost for prostate cancer. AB - BACKGROUND: Exploiting biologic imaging, studies have been performed to boost dose to gross intraprostatic tumor volumes (GTV) while reducing dose elsewhere in the prostate. Interest in proton beams has increased due to superior normal tissue sparing they afford. Our goal was to dosimetrically compare 3D conformal proton boost plans with intensity-modulated radiation therapy (IMRT) plans with respect to target coverage and avoiding organs at risk. METHODS: Treatment planning computer tomography scans of ten patients were selected. For each patient, two hypothetical but realistic GTVs each with a fixed volume were contoured in different anatomical locations of the prostate. IMRT and proton beam plans were created with a prescribed dose of 50.4 Gy to the initial planning target volume (PTV) including the PTV of the seminal vesicles (PSV), 70.2 Gy to the PTV of the prostate (PPS), and 90 Gy to the PTV of the gross tumor volumes (PGTVs). For proton plans, uncertainties of range and patient setup were accounted for; apertures were adjusted until the dose-volume coverage of PTVs matched that of the IMRT plan. For both plans, prescribed PTV doses were made identical to allow for comparing normal-tissue doses. RESULTS: Protons delivered more homogeneous but less conformal doses to PGTVs than IMRT did and comparable doses to PSV and PPS. Volumes of bladder and rectum receiving doses higher than 65 Gy were similar for both plans. However, volumes receiving less than 65 Gy were significantly reduced, i.e., protons reduced integral dose by 45.6 % and 26.5 % for rectum and bladder, respectively. This volume-sparing was also seen in femoral heads and penile bulb. CONCLUSIONS: Protons delivered comparable doses to targets in dose homogeneity and conformity and spared normal tissues from intermediate-to-low doses better than IMRT did. Further improvement of dose sparing and changes in homogeneity and conformity may be achieved by reducing proton range uncertainties and from implementing intensity modulation. PMID- 26499319 TI - Optimal length of the pre-inserted tracheal tube for excellent view in nasal fiberoptic intubation. AB - PURPOSE: Inexperienced physicians frequently have difficulty performing nasal fiberoptic intubation. A pre-inserted tracheal tube of the appropriate length allows an excellent view of the laryngeal opening. The purpose of this study was to determine the ideal length of a pre-inserted tracheal tube for nasal fiberoptic intubation and to investigate if it could be predicted from easily measureable patient parameters. METHODS: This was an observational study in which data on adult patients (n = 150) requiring nasal intubation were collected and analyzed by stepwise regression. During the pre-anesthesia examination, a right angled gauge was used to measure the distance from the mid-point of the lateral border of the nares to the tragus of the ear (NT distance) and to the mandibular angle (NM distance). The distance from the tragus to the mandibular angle (TM distance) was also measured. The age, sex, height, and weight of each patient were recorded. After induction of anesthesia, the minimum and maximum lengths of the pre-inserted tracheal tube that provided an excellent view of laryngeal opening during nasal fiberoptic intubation were measured. The optimal length was calculated, and an equation was derived through stepwise regression analysis. RESULTS: The optimal length for each patient could be reliably predicted using the equation (distances in cm, weight in kg): optimal length (cm) = 1.952 + 0.051 * height (cm) + 0.354 * NM distance (cm) - 0.011 * weight (kg) (r (2) = 0.460, P < 0.001). CONCLUSION: The optimal length of pre-inserted tracheal tube for nasal fiberoptic intubation can be predicted using a newly developed formula with three patient parameters, namely, height, the NM distance, and weight. Application of this equation in the clinical setting should facilitate nasal fiberoptic intubation. PMID- 26499320 TI - Implementing enhanced recovery after bariatric surgery protocol: a retrospective study. AB - While the demand for bariatric surgery is increasing, hospital capacity remains limited. The ERABS (Enhanced Recovery After Bariatric Surgery) protocol has been implemented in a number of bariatric centers. We retrospectively compared the operating room logistics and postoperative complications between pre-ERABS and ERABS periods in an academic hospital. The primary endpoint was the length of stay in hospital. The secondary endpoints were turnover times-the time required for preparing the operating room for the next case, induction time (from induction of anesthesia until a patient is ready for surgery), surgical time (duration of surgery), procedure time (duration of stay in the operating room), and the incidence of re-admissions, re-operations and complications during admission and within 30 days after surgery. Of a total of 374 patients, 228 and 146 received surgery following the pre-ERABS and ERABS protocols, respectively. The length of hospital stay was significantly shortened from 3.7 (95 % confidence interval [CI] 3.1-4.7) days to 2.1 (95 % CI 1.6-2.6) days (P < 0.001). Procedure (surgical) times were shortened by 15 (7) min and 12 (5) min for gastric bypass and gastric sleeve surgery, respectively (P < 0.001 for both), by introducing the ERABS protocol. Induction times were reduced from 15.2 (95 % CI 14.3-16.1) min to 12.5 (95 % CI 11.7-13.3) min (P < 0.001).Turnover times were shortened significantly from 38 (95 % CI 44-32) min to 11 (95 % CI 8-14) min. The incidence of re-operations, re-admissions and complications did not change. PMID- 26499321 TI - Predictors of postoperative pain and analgesic requirements following abdominal hysterectomy: an observational study. AB - PURPOSE: A prospective observational study is conducted to identify independent predictors of pain and morphine consumption following abdominal hysterectomy. METHODS: Preoperative State Trait Anxiety Inventory (STAI), Numerical Rating Scales (NRS) for anxiety and pain expectations, thermal pain thresholds and pain scores at forearm and incision site, and pain scores generated from the insertion of an intravenous catheter were measured in female patients undergoing abdominal hysterectomy. Pearson correlations between the predictors and the two outcome measures postoperative pain scores and morphine consumption were studied and multiple regression analysis was conducted to identify independent predictors (primary outcome). Secondary outcomes included cut-off values of predictive tools for morphine consumption. RESULTS: Data from 60 patients were analyzed. STAI state anxiety, NRS pain expectations, and NRS anxiety scores were identified as independent predictors of postoperative morphine consumption. We identified a cut off value of 4.5 (sensitivity 90 %, specificity of 60 %) for the NRS anxiety and a cut-off of 42.5 (sensitivity 70 %, specificity 70 %) for the state anxiety STAI score for increased postoperative morphine consumption. CONCLUSIONS: Preoperative STAI state anxiety scores and NRS pain expectations are independent predictors for increased morphine consumption following hysterectomy. The STAI state anxiety tool and NRS 0-10 anxiety tool can be used interchangeably. The NRS 0-10 anxiety is a much simpler tool than STAI state anxiety and is associated with a higher sensitivity for high morphine consumption. Thermal pain thresholds and IV pain scores were not predictive of postoperative morphine consumption. PMID- 26499322 TI - Light Emitting Diode Fluorescence Microscopy increased the detection of smear positives during follow-up of Tuberculosis patients in India: program implications. AB - BACKGROUND: In India, since July 2012, at designated Microscopy Centers (DMCs) in 200 medical colleges, sputum smear examination for tuberculosis bacilli changed from Ziehl Neelsen (ZN) method to auramine based Light Emitting Diode Fluorescent Microscopy (LED-FM) method. We assessed the additional yield of smear positives among patients undergoing follow-up sputum examination during TB treatment before and after deploying LED-FM. METHODS: This was a before and after comparison study in eight conveniently selected medical college DMCs across North India. We extracted data from TB laboratory registers on number of TB patients examined for follow-up and their smear microscopy results including the grades by ZN (before; July-December 2011) and LED-FM (after; July-December 2012) and compared them. RESULTS: Altogether, 2868 TB patients were examined by LED-FM and 2740 were examined by ZN during follow-up. LED-FM increased the proportion of follow-up smear positives from 5.0 % (n = 136) to 7.4 % (n = 213) with an additional yield of 77 follow-up smear-positives-with the highest increase in smears graded scanty (2.6 vs 1.2 %) (p value <0.05). CONCLUSIONS: Since all smear positives during follow-up are considered 'presumptive multidrug resistant (MDR)-TB patients' in India, introduction of LED-FM would result in additional number of patients eligible for MDR-TB testing, which would have otherwise been missed by ZN. PMID- 26499323 TI - Assessing the Effects of Acidification on N Dynamics in Jiyun River System of Tianjin, China. AB - Alterations in pH have significant effects on nitrification and denitrification processes in aquatic systems. The Jiyun River in northern China experiences significant acid precipitation, and as such was selected to investigate the effects of decreasing pH (river pH at 8.2, pH at 6 and 5) on N dynamics via incubation experiments (35 and 10 degrees C). Statistical results indicated that the NO3 (-) concentrations of the control (pH at 8.2) were either significantly lower (at 35 degrees C) or significantly higher (at 10 degrees C) than the treatments of pH at 6 and 5 at the alpha level of 0.05 in the incubation. However, the NO3 (-) concentrations of the two pH treatments showed significant difference during part of the reaction stage at 35 degrees C and no difference at 10 degrees C. Analysis indicated that nitrification and coupled nitrification aerobic denitrification occurred for all treatments, which resulted in NO3 (-) being either accumulated or removed at the end of the incubation. PMID- 26499324 TI - Ecological Risk Assessment of EDTA-Assisted Phytoremediation of Cd Under Different Cultivation Systems. AB - A long-term field experiment was designed to assess remediation efficiency and ecological risk of phytoremediation of Cd under different cultivation systems with or without ethylene diamine tetraacetic acid (EDTA). EDTA can significantly improve the phytoremediation effectiveness of a historically polluted e-waste dismantling site through enhancing Cd uptake by plants in all cultivation systems along with higher ecological risks to different receptors especially in the presence of Cicer arietinum (chickpea). Moisture content at each layer of soil profile under Eucalyptus globules L. cultivated sites was consistently lower than under chickpea monoculture as a result of E. globules' high water use efficiency. Besides low soil moisture, E. globules can intercept more Cd-rich leachate than chickpea regardless of the presence of EDTA. E. globules could be used for Cd phytoremediation as they can take full advantage of EDTA and decrease ecological risk caused by the chelator. PMID- 26499325 TI - Photodegradation of Mefenamic Acid in Aqueous Media: Kinetics, Toxicity and Photolysis Products. AB - The present study investigated the photolytic behavior and photodegradation products of mefenamic acid (MEF) under ultraviolet-C irradiation. The results demonstrated that the photodegradation of MEF followed pseudo-first-order kinetics and the direct photolysis quantum yield of mefenamic acid was observed to be 2.63 +/- 0.28 * 10-3. Photodegradation of MEF included degradation by direct photolysis and by self-sensitization that the contribution rates of self sensitized photodegradation were 5.70, 11.25 and 18.96 % for .OH, 1O2 and O.2- , respectively. Primary transformation products of MEF were identified using ultra performance liquid chromatography and quadrupole time-of-flight mass spectrometer (UPLC-Q-TOF-MS). The identified transformation products suggested three possible pathways of MEF photodegradation: dehydrogenation, hydroxylation, and ketonized reactions. Toxicity of phototransformation products were evaluated using the Microtox test, which revealed that photodegradation likely provides a critical pathway for MEF toxicity reduction in drinking water and wastewater treatment facilities. PMID- 26499328 TI - Genome-wide association analysis reveals loci associated with resistance against Piscirickettsia salmonis in two Atlantic salmon (Salmo salar L.) chromosomes. AB - BACKGROUND: Pisciricketssia salmonis is the causal agent of Salmon Rickettsial Syndrome (SRS), which affects salmon species and causes severe economic losses. Selective breeding for disease resistance represents one approach for controlling SRS in farmed Atlantic salmon. Knowledge concerning the architecture of the resistance trait is needed before deciding on the most appropriate approach to enhance artificial selection for P. salmonis resistance in Atlantic salmon. The purpose of the study was to dissect the genetic variation in the resistance to this pathogen in Atlantic salmon. METHODS: 2,601 Atlantic salmon smolts were experimentally challenged against P. salmonis by means of intra-peritoneal injection. These smolts were the progeny of 40 sires and 118 dams from a Chilean breeding population. Mortalities were recorded daily and the experiment ended at day 40 post-inoculation. Fish were genotyped using a 50K Affymetrix(r) Axiom(r) myDesignTM Single Nucleotide Polymorphism (SNP) Genotyping Array. A Genome Wide Association Analysis was performed on data from the challenged fish. Linear regression and logistic regression models were tested. RESULTS: Genome Wide Association Analysis indicated that resistance to P. salmonis is a moderately polygenic trait. There were five SNPs in chromosomes Ssa01 and Ssa17 significantly associated with the traits analysed. The proportion of the phenotypic variance explained by each marker is small, ranging from 0.007 to 0.045. Candidate genes including interleukin receptors and fucosyltransferase have been found to be physically linked with these genetic markers and may play an important role in the differential immune response against this pathogen. CONCLUSIONS: Due to the small amount of variance explained by each significant marker we conclude that genetic resistance to this pathogen can be more efficiently improved with the implementation of genetic evaluations incorporating genotype information from a dense SNP array. PMID- 26499326 TI - Polymorphisms and minihaplotypes in the VvNAC26 gene associate with berry size variation in grapevine. AB - BACKGROUND: Domestication and selection of Vitis vinifera L. for table and wine grapes has led to a large level of berry size diversity in current grapevine cultivars. Identifying the genetic basis for this natural variation is paramount both for breeding programs and for elucidating which genes contributed to crop evolution during domestication and selection processes. The gene VvNAC26, which encodes a NAC domain-containing transcription factor, has been related to the early development of grapevine flowers and berries. It was selected as candidate gene for an association study to elucidate its possible participation in the natural variation of reproductive traits in cultivated grapevine. METHODS: A grapevine collection of 114 varieties was characterized during three consecutive seasons for different berry and bunch traits. The promoter and coding regions of VvNAC26 gene (VIT_01s0026g02710) were sequenced in all the varieties of the collection, and the existing polymorphisms (SNP and INDEL) were detected. The corresponding haplotypes were inferred and used for a phylogenetic analysis. The possible associations between genotypic and phenotypic data were analyzed independently for each season data, using different models and significance thresholds. RESULTS: A total of 30 non-rare polymorphisms were detected in the VvNAC26 sequence, and 26 different haplotypes were inferred. Phylogenetic analysis revealed their clustering in two major haplogroups with marked phenotypic differences in berry size between varieties harboring haplogroup specific alleles. After correcting the statistical models for the effect of the population genetic stratification, we found a set of polymorphisms associated with berry size explaining between 8.4 and 21.7% (R(2)) of trait variance, including those generating the differentiation between both haplogroups. Haplotypes built from only three polymorphisms (minihaplotypes) were also associated with this trait (R(2): 17.5 - 26.6%), supporting the involvement of this gene in the natural variation for berry size. CONCLUSIONS: Our results suggest the participation of VvNAC26 in the determination of the grape berry final size. Different VvNAC26 polymorphisms and their combination showed to be associated with different features of the fruit. The phylogenetic relationships between the VvNAC26 haplotypes and the association results indicate that this nucleotide variation may have contributed to the differentiation between table and wine grapes. PMID- 26499329 TI - Genetic architecture of growth traits in Populus revealed by integrated quantitative trait locus (QTL) analysis and association studies. AB - Deciphering the genetic architecture underlying polygenic traits in perennial species can inform molecular marker-assisted breeding. Recent advances in high throughput sequencing have enabled strategies that integrate linkage-linkage disequilibrium (LD) mapping in Populus. We used an integrated method of quantitative trait locus (QTL) dissection with a high-resolution linkage map and multi-gene association mapping to decipher the nature of genetic architecture (additive, dominant, and epistatic effects) of potential QTLs for growth traits in a Populus linkage population (1200 progeny) and a natural population (435 individuals). Seventeen QTLs for tree height, diameter at breast height, and stem volume mapped to 11 linkage groups (logarithm of odds (LOD) >= 2.5), and explained 2.7-18.5% of the phenotypic variance. After comparative mapping and transcriptome analysis, 187 expressed genes (10 046 common single nucleotide polymorphisms (SNPs)) were selected from the segmental homology regions (SHRs) of 13 QTLs. Using multi-gene association models, we observed 202 significant SNPs in 63 promising genes from 10 QTLs (P <= 0.0001; FDR <= 0.10) that exhibited reproducible associations with additive/dominant effects, and further determined 11 top-ranked genes tightly linked to the QTLs. Epistasis analysis uncovered a uniquely interconnected gene-gene network for each trait. This study opens up opportunities to uncover the causal networks of interacting genes in plants using an integrated linkage-LD mapping approach. PMID- 26499327 TI - Prognostic significance of Traf2- and Nck- interacting kinase (TNIK) in colorectal cancer. AB - BACKGROUND: The potential of expression profiling using microarray analysis as a tool to predict the prognosis for different types of cancer has been realized. This study aimed to identify a novel biomarker for colorectal cancer (CRC). METHODS: The expression profiles of cancer cells in 152 patients with stage I-III CRC were examined using microarray analysis. High expression in CRC cells, especially in patients with distant recurrences, was a prerequisite to select candidate genes. Thus, we identified seventeen candidate genes, and selected Traf2- and Nck-interacting kinase (TNIK), which was known to be associated with progression in CRC through Wnt signaling pathways. We analyzed the protein expression of TNIK using immunohistochemistry (IHC) and investigated the relationship between protein expression and patient characteristics in 220 stage I-III CRC patients. RESULTS: Relapse-free survival was significantly worse in the TNIK high expression group than in the TNIK low expression group in stage II (p = 0.028) and stage III (p = 0.006) patients. In multivariate analysis, high TNIK expression was identified as a significant independent risk factor of distant recurrence in stage III patients. CONCLUSION: This study is the first to demonstrate the prognostic significance of intratumoral TNIK protein expression in clinical tissue samples of CRC, in that high expression of TNIK protein in primary tumors was associated with distant recurrence in stage II and III CRC patients. This TNIK IHC study might contribute to practical decision-making in the treatment of these patients. PMID- 26499330 TI - Lasik Xtra(r) Provides Corneal Stability and Improved Outcomes. AB - A new procedure which combines LASIK and corneal cross-linking (Lasik Xtra(r)) has been proposed as an alternative to traditional LASIK. It is aimed at restoring strength to the cornea, increasing stability in visual outcomes, increasing the accuracy of the refractive correction, and potentially lowering enhancement rates. This article reviews the current clinical evidence which has been published on the topic and reviews both the safety and efficacy argument for the procedure. PMID- 26499331 TI - Antiinflammatory Activities of Crebanine by Inhibition of NF-kappaB and AP-1 Activation through Suppressing MAPKs and Akt Signaling in LPS-Induced RAW264.7 Macrophages. AB - Crebanine, an aporphine alkaloid, displays various biological activities such as anticancer and antimicrobial activities. In this study, we further investigated the suppressive effect of crebanine on lipopolysaccharide (LPS)-induced expression of proinflammatory mediators and the molecular mechanisms underlying these activities in RAW264.7 macrophages. Crebanine inhibited the production of proinflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor-alpha in LPS-induced RAW264.7 cells. Moreover, crebanine suppressed LPS induced inducible nitric oxide (iNO) and prostaglandin E2 and reduced the expression of iNO synthase and cyclooxygenase-2 in RAW264.7 cells. Crebanine suppressed LPS-induced phosphorylation of Akt and mitogen-activated protein kinases (MAPKs), including extracellular signaling-regulated kinase 1/2, c-Jun NH2-terminal kinase, and p38 MAPK signaling. In addition, the specific inhibitor of MAPKs and Akt reduced the expression of IL-6 and NO production in LPS-induced macrophages. Furthermore, crebanine inhibited LPS-induced nuclear factor kappa B (NF-kappaB) activation by reducing the phosphorylation of p65 at Ser536 but not the p65 translocation to the nucleus and inhibitory factor kappa B alpha degradation. Crebanine also suppressed phosphorylation and nucleus translocation of activator protein-1 (AP-1). These observations suggest that the antiinflammatory properties of crebanine may stem from the inhibition of proinflammatory mediators via suppression of the NF-kappaB, AP-1, MAPKs, and Akt signaling pathways. PMID- 26499332 TI - Small-sized gold nanoparticles inhibit the proliferation and invasion of SW579 cells. AB - The present study reported on an intrinsic property of gold nanoparticles (Au NPs), namely their ability to inhibit the proliferation and invasion of thyroid carcinoma cells. Au-NPs of various sizes (5-60 nm) were synthesized and their uptake into the SW579 human thyroid carcinoma cell line was verified using transmission electron microscopy (TEM). The viability, apoptosis, cell cycle distribution and invasive capacity of SW579 cells were assessed following treatment with Au-NPs using a Cell Counting Kit-8 assay, flow cytometric analysis and a Transwell as well as a fluorometric invasion assay. TEM demonstrated that all sizes of Au-NPs could be taken up by the SW579 cells. The results showed that small-sized Au-NPs (5 and 10 nm) significantly suppressed the proliferation and invasion of SW579 cells and induced apoptosis as well as cell cycle arrest in G0/G1 phase, while larger-sized gold nanoparticles (20-60 nm) did not exert these effects, therefore suggesting that the effects of Au-NPs on SW579 cells were highly associated with their particle size. The reduction of the invasive capacity of SW579 cells following treatment with Au-NPs may be attributed to decreases in the expression of matrix metalloproteinase-2 and -9, which were observed using western blot and reverse-transcription quantitative polymerase chain reaction analyses. The present study was the first to demonstrate that small-sized Au-NPs inhibit the proliferation and invasion of thyroid carcinoma cells, which may contribute to the advancement of biomedical applications of Au NPs. PMID- 26499333 TI - Eya4 Induces Hypertrophy via Regulation of p27kip1. AB - BACKGROUND: E193, a heterozygous truncating mutation in the human transcription cofactor Eyes absent 4 (Eya4), causes hearing impairment followed by dilative cardiomyopathy. METHODS AND RESULTS: In this study, we first show Eya4 and E193 alter the expression of p27(kip1) in vitro, suggesting Eya4 is a negative regulator of p27. Next, we generated transgenic mice with cardiac-specific overexpression of Eya4 or E193. Luciferase and chromatin immunoprecipitation assays confirmed Eya4 and E193 bind and regulate p27 expression in a contradictory manner. Activity and phosphorylation status of the downstream molecules casein kinase-2alpha and histone deacetylase 2 were significantly elevated in Eya4- but significantly reduced in E193-overexpressing animals compared with wild-type littermates. Magnetic resonance imaging and hemodynamic analysis indicate Eya4-overexpression results in an age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 animals develop onset of dilative cardiomyopathy as seen in human E193 patients. Both cardiac phenotypes were aggravated on pressure overload. Finally, we identified a new heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein as seen with E193. CONCLUSIONS: Our results implicate Eya4/Six1 regulates normal cardiac function via p27/casein kinase-2alpha/histone deacetylase 2 and indicate that mutations within this transcriptional complex and signaling cascade lead to the development of cardiomyopathy. PMID- 26499334 TI - Alcohol Use Problems and Sexual Risk Among Young Adult African American Mothers. AB - Studies have documented high levels of alcohol use and sexual risk among young mothers. We examined parenting satisfaction and self-efficacy in relation to alcohol use problems and sexual risk among 346 young African American women enrolled in an HIV prevention trial, 41 % (n = 141) of whom were mothers. Among mothers, greater parenting satisfaction was associated with a reduced likelihood of problematic alcohol use, having multiple sex partners, and testing positive for Trichomonas vaginalis. Relative to non-parenting women, mothers reported lower condom use. Compared to non-parenting women, mothers with the highest parenting satisfaction reported fewer alcohol use problems; mothers with the lowest parenting satisfaction reported lower condom use and were more likely to have multiple partners and test positive for T. vaginalis. Parenting self efficacy was not associated with the outcomes examined. Future research investigating relationships between parenting satisfaction, alcohol use and sexual risk may be useful for improving multiple maternal health outcomes. PMID- 26499335 TI - Social Cohesion Among Sex Workers and Client Condom Refusal in a Canadian Setting: Implications for Structural and Community-Led Interventions. AB - Community empowerment can be a powerful determinant of HIV risk among sex workers (SWs). This study modeled the impact of social cohesion on client condom refusal among SWs in Vancouver. Longitudinal data were drawn from a prospective cohort of SWs (2010-2013). Lippman and colleagues' Social Cohesion Scale measured SWs' connectedness (i.e., perception of mutual aid, trust, support). Multivariable logistic regression examined the independent effect of social cohesion on client condom refusal. Of 654 SWs, 22 % reported baseline client condom refusal and 34 % over 3 years. The baseline median social cohesion score was 24 (IQR 20-29, range 4-45). In the final confounding model, for every one-point increase in the social cohesion score, average odds of condom refusal decreased by 3 % (AOR 0.97; 95 % CI 0.95-0.99). Community empowerment can have a direct protective effect on HIV risk. These findings highlight the need for a legal framework that enables collectivization and SW-led efforts in the HIV response. PMID- 26499338 TI - Lithographically Patterned PEDOT Nanowires for the Detection of Iron(III) with Nanomolar Sensitivity. AB - Arrays of nanowires of an electronically conductive polymeric affinity medium tailored to the detection of Fe(III) are prepared, and their properties for detecting Fe(III) are evaluated. This polymeric affinity medium consists of poly(3,4-ethylenedioxythiophene) (PEDOT) into which an iron chelator, deferoxamine (DFA), has been doped during the polymerization process. PEDOT-DFA nanowires are potentiostatically deposited from a solution containing both EDOT and DFA using lithographically patterned nanowire electrodeposition (LPNE). The through-nanowire electrical resistance of PEDOT-DFA nanowires is measured as a function of the Fe(III) concentration. In parallel with measurements on PEDOT-DFA nanowire arrays, the electrochemical impedance of PEDOT-DFA films is characterized as a function of the Fe(III) concentration and the frequency of the impedance measurement in order to better understand the mechanism of transduction. PEDOT-DFA nanowires detect Fe(III) from 10(-4) to 10(-8) M with a limit of detection of 300 pM (calculated) and 10 nM (measured). PMID- 26499337 TI - A Web 2.0 and Epidemiology Mash-Up: Using Respondent-Driven Sampling in Combination with Social Network Site Recruitment to Reach Young Transwomen. AB - Respondent-driven sampling (RDS) peer referral has been proven to be an effective recruitment method for hard-to-reach populations; however, its application in diverse populations is limited. Recruitment occurred in two phases: RDS-only followed by development and implementation of an online social network strategy in combination with RDS peer referral (RDS + SNS). Compared to RDS-only, RDS + SNS reached a sample that was younger (chi(2) = 9.19, P = .03), more likely to identify with a non-binary gender identity (chi(2) = 10.4247, P = .03), with less housing instability (50.5 vs. 68.6 %, chi(2) = 9.0038, P = .002) and less sex work (19.7 vs. 31.4 %, chi(2) = 5.0798, P = .02). Additionally, we describe lessons learned as a result of implementing our online social network strategy. Our findings underscore the importance of integrating Internet-driven strategies to meet challenges in sample diversity and recruitment of young transwomen. PMID- 26499336 TI - Which Clinician Questions Elicit Accurate Disclosure of Antiretroviral Non adherence When Talking to Patients? AB - This study evaluated how clinicians assess antiretroviral (ARV) adherence in clinical encounters, and which questions elicit accurate responses. We conducted conversation analysis of audio-recorded encounters between 34 providers and 58 patients reporting ARV non-adherence in post-encounter interviews. Among 42 visits where adherence status was unknown by providers, 4 providers did not discuss ARVs (10 %), 6 discussed ARVs but did not elicit non-adherence disclosure (14 %), and 32 discussed ARVs which prompted disclosure (76 %). Questions were classified as: (1) clarification of medication ("Are you still taking the Combivir?"); (2) broad ("How's it going with your meds?"); (3) positively-framed ("Are you taking your medications regularly?"); (4) negatively-framed ("Have you missed any doses?"). Clinicians asked 75 ARV-related questions: 23 clarification, 12 broad, 17 positively-framed, and 23 negatively-framed. Negatively-framed questions were 3.8 times more likely to elicit accurate disclosure than all other question types (p < 0.0001). Providers can improve disclosure probability by asking directly about missed doses. PMID- 26499339 TI - Control of litchi downy blight by zeamines produced by Dickeya zeae. AB - Zeamines (ZMS), a class of polyamine-polyketide-nonribosomal peptide produced by bacterial isolate Dickeya zeae, were shown recently to be potent antibiotics against some bacterial pathogens. In this study, the results indicated that ZMS showed antifungal activity against Peronophythora litchii and other fungal pathogens. The activity of ZMS against the oomycete pathogen P. litchi, which causes the devastating litchi downy blight, was further investigated under in vitro and in vivo conditions. ZMS displayed potent inhibitory activity against the mycelial growth and sporangia germination of P. litchii. At a concentration of 2 MUg/mL, about 99% of the sporangia germination was inhibited. Scanning electron microscopy and transmission electron microscopy analyses showed that treatment with ZMS could cause substantial damages to the oomycete endomembrane system. Furthermore, treatment of litchi fruits with ZMS solution significantly (P < 0.05) reduced the fruits decay and peel browning caused by P. litchii infection during storage at 28 degrees C. Taken together, our results provide useful clues on the antifungal mechanisms of ZMS, and highlight the promising potentials of ZMS as a fungicide, which in particular, may be useful for prevention and control of litchi fruits decay and browning caused by P. litchii infection during storage and transportation. PMID- 26499340 TI - Fidelity Variants and RNA Quasispecies. AB - By now, it is well established that the error rate of the RNA-dependent RNA polymerase (RdRp) that replicates RNA virus genomes is a primary driver of the mutation frequencies observed in RNA virus populations-the basis for the RNA quasispecies. Over the last 10 years, a considerable amount of work has uncovered the molecular determinants of replication fidelity in this enzyme. The isolation of high- and low-fidelity variants for several RNA viruses, in an expanding number of viral families, provides evidence that nature has optimized the fidelity to facilitate genetic diversity and adaptation, while maintaining genetic integrity and infectivity. This chapter will provide an overview of what fidelity variants tell us about RNA virus biology and how they may be used in antiviral approaches. PMID- 26499341 TI - Corrigendum: macroscopic ordering of helical pores for arraying guest molecules noncentrosymmetrically. PMID- 26499342 TI - Tenuigenin exhibits anti-inflammatory activity via inhibiting MAPK and NF-kappaB and inducing Nrf2/HO-1 signaling in macrophages. AB - Tenuigenin (TNG), isolated from the root of the Chinese herb Polygala tenuifolia, possesses various biological and pharmacological activities, including anti oxidation and anti-inflammation activities. In this study, we aimed to further investigate whether its anti-inflammatory activity is associated with the inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Our results showed that TNG treatment dramatically reduced prostaglandin E2 (PGE2) and NO production, decreased iNOS and COX-2 gene expression, inhibited JNK1/2, ERK1/2, p38 and NF-kappaB (p65) phosphorylation, and blocked IkappaBalpha phosphorylation and degradation. Further studies revealed that TNG dramatically up-regulated heme oxygenase (HO)-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression, which was related to the induction of Nrf2 nuclear translocation and decreased Keap1 protein expression. Additionally, treatment with JNK1/2, ERK1/2 or p38 inhibitors had no effect on the TNG-induced HO-1 protein expression. Furthermore, the LPS-induced iNOS and COX-2 expression levels were inhibited by TNG, which was partially reversed by the HO-1-siRNA and HO-1 inhibitors. Together, these results showed that TNG's anti-inflammatory activity is related to the inhibition of iNOS and COX-2 expression via down-regulation of the MAPK and NF-kappaB, and up-regulation of the Nrf2/HO-1 signaling pathways. PMID- 26499344 TI - Changes in survival rate of multiple myeloma after the introduction of bortezomib: a single institutional experience over 20 years. AB - The data of factors on the changes in survival before and after the introduction of bortezomib in unselected multiple myeloma (MM) patients is scarce in Asian population. We analyzed the clinical features and treatment outcomes of 270 consecutive MM patients admitted to our hospital between January 1995 and August 2014. The patients were divided into two groups, 1995-2005 (n=106) and 2006-2014 (n=164), based on bortezomib availability. There were no differences in baseline characteristics between the groups, except age and percentage of patients receiving autologous stem cell transplantation (auto-SCT). The proportion of patients obtaining >=very good partial response (VGPR) was higher in the recent cohort, which was translated as better overall survival in both younger and older patients (36.1 vs. 79.8 months, P=0.024, and 40.0 vs. 110.7 months, respectively). Patients receiving bortezomib early after diagnosis showed significantly better survival. However, there was no difference in survival between patients obtaining >=VGPR in the two groups. On multivariate analysis, age >=75 and lactate dehydrogenase (LDH) >normal were associated with shorter survival, while early bortezomib use and auto-SCT were associated with longer survival. On Cox regression analysis, International Staging System (ISS) stage III, LDH, and treatment response =2.0 mg/dL, and treatment response 75 ppb) of copper enhanced oxidative effects of ascorbic acid, whereas other tested metals did not comparably promote oxidation. During oxidation, protein destabilization indicated by loss of the full-length protein, positively correlated with the increase in protein aggregation. However, levels of aggregation did not always correlate with the levels of protein carbonylation. At comparable carbonylation levels, addition of copper produced greater protein destabilization and aggregation than addition of iron. CONCLUSIONS: The results strongly suggest that ascorbic acid with traces of metals, especially copper, can promote therapeutic protein carbonylation and potentially aggregation. At similar carbonylation levels, some oxidative conditions may lead to greater protein destabilization than others. PMID- 26499345 TI - Echinocystic Acid Inhibits IL-1beta-Induced COX-2 and iNOS Expression in Human Osteoarthritis Chondrocytes. AB - Echinocystic acid (EA), a pentacyclic triterpene isolated from the fruits of Gleditsia sinensis Lam, displays a range of pharmacological activities including anti-inflammatory and antioxidant effects. However, the effect of EA on IL-1beta stimulated osteoarthritis chondrocyte has not been reported. The purpose of this study was to assess the effects of EA on IL-1beta-stimulated human osteoarthritis chondrocyte. Chondrocytes were stimulated with IL-1beta in the absence or presence of EA. NO and PGE2 production were measured by Griess reagent and ELISA. The expression of COX-2, iNOS, nuclear factor-kappaB (NF-kappaB), inhibitory kappa B (IkappaBalpha), c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK) were detected by Western blot analysis. The results showed that EA suppressed IL-1beta-induced collagenase-3 (MMP-13), NO, and PGE2 production in a dose-dependent manner. IL-1beta up-regulated the expression of COX-2 and iNOS, and the increase was inhibited by EA. Furthermore, IL-1beta induced NF-kappaB and mitogen-activated protein kinase (MAPK) activation were inhibited by EA. In conclusion, EA effectively attenuated IL-1beta-induced inflammatory response in osteoarthritis chondrocyte which suggesting that EA may be a potential agent in the treatment of osteoarthritis. PMID- 26499346 TI - A spectrum of intracranial vascular high-flow arteriovenous shunts in RASA1 mutations. AB - PURPOSE AND BACKGROUND: We describe three paediatric cases with different intracranial fast-flow shunts presenting early in life, all with capillary malformation-arteriovenous malformation syndrome and RASA1 verified mutations. Intracranial arteriovenous fast-flow shunts are rare vascular malformations typically presenting early in life and have been associated with cutaneous capillary malformations, characterized as capillary malformation-arteriovenous malformation syndrome. Heterozygous RASA1 gene mutations have been found to be disease causing with high penetrance for the typical cutaneous findings, but only some individuals with the syndrome have intracranial lesions. CASES: One infant presented with a vein of Galen malformation responsible for hydrodynamic disorders, one neonate suffered from severe cardiac insufficiency related to a superior sagittal sinus dural malformation with high-flow fistulas, and one baby was treated at infant age of a choroidal arteriovenous fistula discovered antenatally. RESULTS AND CONCLUSIONS: We report the follow-up of these three cases with RASA1 gene mutation and comment on the possible role of evaluation for vascular lesions and capillary malformation-arteriovenous malformation syndrome in patients and their families, with intracranial fast-flow shunts. PMID- 26499347 TI - A case of acute onset succinic semialdehyde dehydrogenase deficiency: neuroimaging findings and literature review. AB - BACKGROUND: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of gamma-aminobutyric acid metabolism, leading to elevated levels of gamma-aminobutyric acid and gamma-hydroxybutyric acid in cerebrospinal fluid. PATIENT: We describe the neuroimaging findings of a previously healthy 6-month-old girl with acute onset of lethargy, hypotonia, and choreiform movements, and a subsequent diagnosis of SSADH deficiency. Magnetic resonance (MR) imaging of the brain revealed symmetric T2 hyperintense signal abnormalities and reduced diffusivity of the globus pallidi bilaterally. Arterial spin-labeling perfusion MR imaging suggested bilateral hyperperfusion of the globus pallidi. MR spectroscopy of the thalamus and frontal lobe white matter revealed increased signal intensity in the glutamate and glutamine region of the spectra between 2.1 and 2.4 ppm. CONCLUSION: The unique early imaging findings described here may be attributable to bioenergetic failure and deficiency in mitochondrial energy metabolism and are consistent with SSADH-knockout mice studies. PMID- 26499348 TI - A commentary to the manuscript awareness and uptake of measures for preventing CNS birth defects among mothers of affected children in a sub-Saharan African neurosurgeon's practice. PMID- 26499349 TI - Comparison between the antero-posterior and posterior only approaches for treating thoracolumbar tuberculosis (T10-L2) with kyphosis in children: a minimum 3-year follow-up. AB - PURPOSE: There are few papers in the literature comparing outcomes between antero posterior and posterior-only approaches for treating thoracolumbar tuberculosis (T10-L2) in children. METHODS: We performed a retrospective review of 47 children who were diagnosed and treated as thoracolumbar tuberculosis (T10-L2) in our department from January 2005 to June 2009. Forty-seven cases of thoracolumbar tuberculosis were treated by two different surgical approaches. All the cases were divided into two groups: 25 cases in group A underwent one-stage posterior debridement, transforaminal fusion, and instrumentation, and 22 cases in group B underwent anterior debridement, bone graft, and posterior instrumentation in a single- or two-stage procedure. Two approaches were compared in terms of average operative time, blood loss, hospitalizations, bony fusion, intraoperative and postoperative complications, the Oswestry disability index score, neurological status, and the angle of kyphosis. RESULTS: All 47 patients (24 M/23F), averaged 9.1 +/- 2.6 years old (range 5 to 14 years), who were followed up for mean of 49.3 +/- 8.6 months (range 36 to 65 months). Spinal tuberculosis (TB) was completely cured, and the grafted bones were fused in 9 months in all cases. It was obviously that the average operative time, blood loss, hospitalization, and complication rate of group A was less than those of group B. Good clinical outcomes were achieved in both groups. CONCLUSIONS: Both the antero-posterior and posterior approaches can effectively heal T10-L2 vertebral tuberculosis, but the average surgical time, blood loss, complications, and hospital stay following the posterior approach are prominently less than those following the antero-posterior approach. It might be a better surgical treatment for thoracic spinal tuberculosis in children with poor health status, especially for cases in early phase of bone destruction and/or mild and moderate kyphosis. PMID- 26499350 TI - Bariatric surgery as a treatment for idiopathic intracranial hypertension: a systematic review. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is a chronic neurologic disease that may result in persistent and debilitating symptoms that are refractory to conventional treatments. OBJECTIVES: The aim of this study was to systematically review the effect of bariatric weight reduction surgery as a treatment for IIH. METHODS: A comprehensive literature search was conducted using the following databases: MEDLINE, EMBASE, PubMed, Scopus, Web of Sciences, and the Cochrane Library. No restrictions were placed on these searches, including the date of publication. RESULTS: A total of 85 publications were identified, and after initial appraisal, 17 were included in the final review. Overall improvement in symptoms of IIH after bariatric surgery was observed in 60 of the 65 patients observed (92%). Postoperative lumbar puncture opening pressure was shown to decrease by an average of 18.9 cmH2O in the 12 patients who had this recorded. CONCLUSION: Bariatric surgery for weight loss is associated with alleviation of IIH symptoms and a reduction in intracranial pressure. Furthermore, an improvement was observed in patients where conventional treatments, including neurosurgery, were ineffective. Further prospective randomized studies with control groups and a larger number of participants are lacking within the published studies to date. There is, therefore, a strong rationale for the use of bariatric surgery in individuals with IIH for the effective treatment of this condition, as well as the efficacy of weight loss for various other obesity co-morbidities. PMID- 26499351 TI - Life-threatening late complication after laparoscopic adjustable gastric banding: two cases of gastric necrosis. PMID- 26499352 TI - Effect of probiotics on postoperative quality of gastric bypass surgeries: a prospective randomized trial. AB - BACKGROUND: Gastric bypass surgery is the recommended treatment for severely obese patients. However, postoperative symptomatic gastrointestinal (GI) episodes are common complaints. OBJECTIVES: To determine if administration of probiotics improves symptomatic GI episodes after gastric bypass surgery. SETTING: Hospital based bariatric center. METHODS: This double-blind, randomized trial was conducted between March 2010 and September 2010 with 60 patients who underwent gastric bypass for severe obesity and experienced postoperative symptomatic GI episodes. Patients were randomly assigned to the probiotics group A (n = 20; 1 g Clostridium butyricum MIYAIRI twice daily); probiotics group B (n = 20; Bifidobacterium longum BB536 twice daily); or digestive enzymes group (n = 20; Aczym, containing 100 mg takadiastase N, 20 mg cellulase AP, 50 mg lipase MY, and 100 mg pancreatin, twice daily). Quality of life was measured using the modified Gastrointestinal Quality of Life Index (mGIQLI) before and after the 2-week intervention. RESULTS: Preintervention patient characteristics and mGIQLI scores were similar among the 3 groups. After the 2-week intervention, the mean mGIQLI score improved from 57.4 to 63.9 points in the entire sample and also within each group for 7 items specifically for 7: excessive passage of gas, foul smell of flatulence, belching, heartburn, abdominal noises, abdominal bloating, and abdominal pain. CONCLUSIONS: Administration of probiotics or digestive enzymes may improve symptomatic GI episodes after gastric bypass surgeries and improve quality of life, at least initially. PMID- 26499353 TI - A video case report of LRYGB in a patient with a left ventricular assist device. PMID- 26499354 TI - Beriberi: an uncommon complication of sleeve gastrectomy. PMID- 26499355 TI - Distal small bowel bypass for weight regain after gastric bypass: safety and efficacy threshold occurs at <70% bypass. AB - BACKGROUND: For patients with poor weight loss (WL) after Roux-en-Y gastric bypass (RYGB) there are few well-tolerated and effective surgical options. Revision to distal bypass by shortening of the common channel (CC) induces significant WL but often produces protein calorie malnutrition (PCM) and severe diarrhea. OBJECTIVE: The aim of this study was to identify a safe and effective threshold for distal small bowel bypass when done for revision of gastric bypass. SETTING: Academic Institution, United States. METHODS: We performed revision of RYGB for WL in 20 patients by shortening the CC to a new length of 120-300 cm. The Roux limb length was unchanged. WL and PCM were monitored. A threshold for percent of small bowel bypassed at which PCM was avoided was retrospectively determined. WL was then compared in patients above and below this threshold. Five patients completed a 250-kcal mixed meal challenge before and 3 months after revision to determine selected gut hormone responses. RESULTS: Bypassing >=70% small bowel resulted in PCM in 4 of 10 patients but in none of 10 patients below that threshold. PCM was observed as late as 2 years after revision and necessitated rerevision by lengthening of the CC in 3 patients. Additionally, nocturnal diarrhea was more common and more intractable when >=70% bypass was done. Both groups had significant excess body WL over 2 years, but it was greater in patients with >=70% bypass (47+/-19 versus 26+/-17; P<.05). A favorable gut hormone response was observed with 3-hour decrease in glucose-dependent insulinotropic peptide (GIP) by 25% and increase in glucagon-like peptide-1 (GLP 1) by 25%, whereas fasting peptide-YY (PYY) increased by 71% (P<.05 for all). CONCLUSIONS: Revision of RYGB to distal bypass when it is <70% of a patient's small bowel length results in an acceptable balance of WL and a positive safety profile. WL may be mediated through an enhanced gut hormone effect, an aversion to ingested fat, and possibly other mechanisms. PMID- 26499356 TI - An Evidence-Based Approach to Defining Fetal Macrosomia. AB - OBJECTIVE: This study aims to determine the risk of adverse outcomes associated with the current diagnostic criteria for fetal macrosomia. Study DESIGN: We evaluated three techniques for characterizing birth weight as a predictor of shoulder dystocia or third- or fourth-degree laceration in 79,879 vaginal deliveries. First, we compared deliveries with birth weights above or below 4,500 g. We then performed logistic regression using birth weight as a continuous predictor, both with and without fractional polynomial transformation. Finally, we calculated the number of cesarean sections required to prevent one incident of the interrogated outcomes (number needed to treat [NNT]). RESULTS: Rates of adverse intrapartum outcomes increase incrementally with increasing birth weight and are predicted most accurately with logistic regression following fractional polynomial transformation. The NNT for third- or fourth-degree laceration dropped from 14.3 (95% confidence interval [CI], 13.9-14.7) at a birth weight of 3,500 g to 6.4 (95% CI, 6.1-6.8) at 4,500 g and, for shoulder dystocia, from 54.9 (95% CI, 51.5-58.6) at 3,500 g to 5.6 (95% CI, 5.2-6.0) at 4,500 g. CONCLUSION: The conventional distinction between "normal" and "macrosomic" does not reflect the incremental effect of increasing birth weight on the risk of obstetric morbidity. Outcomes analysis can inform fetal growth standards to better reflect relevant thresholds of risk. PMID- 26499357 TI - Prostaglandin Availability and Association with Outcomes for Infants with Congenital Heart Disease. AB - Data regarding availability of prostaglandin E1 (PGE) and its impact on the stabilization, transport, critical care course, and surgical outcome of infants with ductal-dependent congenital heart disease in the current pediatric healthcare environment are unknown. We sought to determine the proportion of hospitals in Texas that stock PGE and to investigate associations between PGE availability and clinical outcomes. All birth institutions listed with the Texas Department of Health and Human Services were contacted to determine PGE availability as of 2011. Outcomes of all infants admitted to our institution from 2007 to 2012 who received PGE for ductal-dependent lesions were evaluated. PGE was stocked in 50 % (n = 139) of hospitals that performed deliveries in Texas in 2011 representing 79.1 % (303, 481) of births. Hospitals that did not stock PGE had less annual births and were located a further distance from a center that provided pediatric cardiac surgical services. Patients born at a hospital that did not stock PGE had significantly greater serum lactate and creatinine (p = 0.002) and serum lactate on admission (p < 0.001). The PGE availability was not associated with hospital length of stay, postoperative length of stay, or mortality. When stratifying in TGA and HLHS subgroups, lack of PGE availability remained associated with higher creatinine, higher lactate, lower glucose, and lower pH. PGE is not universally available in all healthcare institutions providing obstetrical services. Lack of availability of PGE at an outlying hospital was associated with increased morbidity, but was not associated with mortality or length of stay. PMID- 26499358 TI - Changes in Myocardial Contractility and Electromechanical Interval During the First Month of Life in Healthy Neonates. AB - This study aims at documenting the changes in ventricular tissue velocities, longitudinal strain and electromechanical coupling during the first month of life. During the neonatal period, when the ventricular myocardium is not yet fully maturated, the heart is subjected to significant hemodynamic changes. We studied the ventricular performance of 16 healthy neonates at three time points over the first month of life: on days 2 (IQR [2;2]), 13 [12;14] and 27 [25;29]. We found that systolic and diastolic tissue velocities increased significantly in both left and right ventricle (by 1.2-1.7 times, p < 0.001). Congruently, we found that peak systolic longitudinal strain of the right and left ventricles increased significantly. However, no significant changes in longitudinal strain rate were observed. Finally, QS-intervals shortened during the neonatal period: being measured at 12 points throughout the left ventricle, time to peak systolic velocity decreased on average to 89 % in the second and to 80 % in the fourth week of life (22.3 +/- 0.2 vs. 19.8 +/- 0.3 vs. 17.8 +/- 0.5 ms, r = -0.564, p < 0.001). When comparing opposing walls of the left ventricle, no dyssynchrony in left ventricular contraction was found. In addition to increasing systolic and diastolic tissue velocities during the first month of life, the time to peak systolic contraction shortens in the neonatal heart, which may reflect an increasing efficiency of the excitation-contraction coupling in the maturing myocardium. While there appears to be no dyssynchrony in ventricular contraction, these findings may extend our appreciation of the immature neonatal heart and certain disease states. PMID- 26499359 TI - Elevated Inducible Nitric Oxide Levels and Decreased Hydrogen Sulfide Levels Can Predict the Risk of Coronary Artery Ectasia in Kawasaki Disease. AB - Kawasaki disease (KD) is a vasculitis disease in children that is associated with coronary artery ectasia (CAE). We investigated whether inducible nitric oxide synthase (i-NOS) and hydrogen sulfide (H2S) could be used to predict CAE secondary to KD. We enrolled 65 children with KD (35 cases with CAE and 30 cases without CAE), 33 healthy children, and 32 children with fever but without vasculitis disease (febrile group). We measured plasma nitric oxide (NO), total nitric oxide synthase (Total-NOS), i-NOS, constructive nitric oxide synthase (c NOS) levels, and H2S content in all patients. Plasma NO, Total-NOS, i-NOS, and H2S were higher in KD children than in healthy and febrile children (P < 0.05). The i-NOS level was higher in KD children with CAE compared to those without CAE, while the H2S was lower (both P < 0.05). Using a combination of i-NOS (higher than 10 U/mL) and H2S (lower than 3.31 MUmol/L) to predict CAE had 80 % sensitivity and 81 % specificity (P < 0.05). Elevated plasma i-NOS and decreased plasma H2S levels in the acute phase of KD have good predictive value for CAE and may be used to guide appropriate clinical treatment and prevent future cardiovascular complications. PMID- 26499360 TI - Rapidly rising incidence of Type 1 diabetes in children and adolescents aged 0-19 years in Zhejiang, China, 2007 to 2013. AB - AIMS: To investigate the incidence rates and trends in Type 1 diabetes in children and adolescents aged 0-19 years in the registered Zhejiang population over the period 2007-2013 by age, sex and calendar year. METHODS: In total, 611 individuals with newly diagnosed Type 1 diabetes were identified from 30 districts in Zhejiang province over the study period. Annual incidence and 95% confidence intervals (CI) by age group and sex were calculated per 100 000 person years. Trends in diabetes incidence and the associations of age and sex with Type 1 diabetes were assessed using Poisson regression models. RESULTS: The mean annual age-standardized incidence of diabetes was 2.02/100 000 person-years (95% CI: 1.92-2.12), with an average annual increase of 12.0% (95% CI: 7.6-16.6%) over the study period. The risk for Type 1 diabetes in girls was estimated to be 1.25 (95% CI: 1.07-1.47) times higher than that in boys. Compared with those aged 0-4 years, the 5-9, 10-14 and 15-19 years age groups were at significantly greater risk, with adjusting incidence rate ratios of 3.54, 6.58 and 5.39, respectively. The mean age at diagnosis decreased significantly from 12.85 years in 2007 to 11.21 years in 2013. A steep rise in diabetes incidence was observed in the under 5 years age group, which showed the greatest increase at 33.61%. CONCLUSIONS: The incidence of diabetes in Zhejiang was relatively low, although rapidly rising trends have been found in recent years, particularly in younger children. Further monitoring and research are urgently required to better understand possible environmental risk factors and formulate preventive strategies. PMID- 26499361 TI - Modeling of interstitial fluid movement in soft tissue under negative pressure- relevance to treatment of tissue swelling. AB - Exact physiological mechanisms behind the potential positive treatment effects of pathological tissue swelling (edema), such as increased interstitial fluid flow, are poorly understood. Finite-element model was created and the model response was matched with the deformation data from the negative pressure (suction) measurements in human (N = 11) forearm. Two experimental suction protocols were simulated to evaluate their impact on interstitial fluid flow in soft tissues. Simulated continuous suction was up to 27 times more efficient in fluid transportation compared to the cyclic suction. The continuous suction that transports the interstitial fluid effectively may help to decrease soft tissue edema. PMID- 26499362 TI - Applications of DQ-DRENAR for the structural analysis of phosphate glasses. AB - A new solid state NMR technique entitled DQ-DRENAR (Double-Quantum based Dipolar Recoupling Effects Nuclear Alignment Reduction) has been recently described for measuring homonuclear dipole-dipole interactions in multi-spin-1/2 systems under magic-angle spinning conditions. As in rotational echo double resonance (REDOR), the homonuclear dipole-dipole coupling constant can be extracted from a plot of a normalized difference signal (S0-S')/S0 versus dipolar mixing time, where S is the signal amplitude with the DQ-Hamiltonian present, and S0 is the signal amplitude in the absence of the DQ-Hamiltonian, which is used for normalization. Within the range of (S0-S)/S0<=0.3-0.5 such "homonuclear REDOR curves" can be approximated by simple parabolae, yielding effective squared dipole-dipole coupling constants ?bjk(2) summed over all the pairwise interactions present. The effect of glassy disorder has been studied by simulations, replacing singular valued internuclear distances by Gaussian distance distributions with the same central value. This situation results in a systematic over-estimation effect, which tends to compensate the implicit under-estimation effect caused by the parabolic fitting approach. The present contribution describes applications to a number of phosphate-based glasses and glass ceramics. The method turns out to be well suited for the differentiation of the various Q((n)) phosphate species, for characterizing the spatial distribution of isolated orthophosphate ions and for the detection of incipient nano-segregation and/or phase separation effects in glass ceramics. PMID- 26499363 TI - Divalent metal ion-mediated assembly of spherical nucleic acids: the case study of Cu(2.). AB - Despite the critical functions of divalent metal ions (M(2+)s) in association with duplex DNA, fundamental and general interactions of M(2+)s with spherical nucleic acids (SNAs) composed of single-stranded DNA have rarely been investigated. We have explored that the coordinative nature of the M(2+)-SNA binding mediates the temperature- and base composition-dependent reversible assemblies of SNAs even without the need of complementary counterparts for duplex interconnection, additional monovalent metal ions for charge screening, or pre designed sequences for any non-Watson-Crick base-pairing, all of which are essential for the conventional assembly of SNAs. Cu(2+) has been identified to maximize the reversible assembly properties in relation to this M(2+)-mediated DNA bond, and has been further qualitatively and quantitatively investigated in detail as a model system. PMID- 26499364 TI - Unilateral hyperhidrosis and hypothermia: symptoms of an intrathoracic tumour. PMID- 26499365 TI - Substance P enhances the activation of AMPK and cellular lipid accumulation in 3T3-L1 cells in response to high levels of glucose. AB - The rescue of glucose tolerance and insulin-sensitivity in peripheral tissues, including adipose tissue, is essential in therapeutic strategies for diabetes. The present study demonstrated that substance P (SP) increases the accumulation of lipids in 3T3-L1 cells during their differentiation into adipocytes in response to a high concentration of glucose. SP reciprocally regulated the activities of AMP-activated protein kinase (AMPK) and Akt: SP enhanced the activation of AMPK, although the activity of Akt was downregulated. Notably, SP induced an increase in the expression level of glucose transporter 4 in the 3T3 L1 adipocytes. Therefore, it is possible that SP leads to an increase in glucose uptake and the accumulation of lipids in adipocytes, and may contribute towards the rescue of insulin-sensitivity in diabetes. PMID- 26499366 TI - Modelling the effects of cerebral microvasculature morphology on oxygen transport. AB - The cerebral microvasculature plays a vital role in adequately supplying blood to the brain. Determining the health of the cerebral microvasculature is important during pathological conditions, such as stroke and dementia. Recent studies have shown the complex relationship between cerebral metabolic rate and transit time distribution, the transit times of all the possible pathways available dependent on network topology. In this paper, we extend a recently developed technique to solve for residue function, the amount of tracer left in the vasculature at any time, and transit time distribution in an existing model of the cerebral microvasculature to calculate cerebral metabolism. We present the mathematical theory needed to solve for oxygen concentration followed by results of the simulations. It is found that oxygen extraction fraction, the fraction of oxygen removed from the blood in the capillary network by the tissue, and cerebral metabolic rate are dependent on both mean and heterogeneity of the transit time distribution. For changes in cerebral blood flow, a positive correlation can be observed between mean transit time and oxygen extraction fraction, and a negative correlation between mean transit time and metabolic rate of oxygen. A negative correlation can also be observed between transit time heterogeneity and the metabolic rate of oxygen for a constant cerebral blood flow. A sensitivity analysis on the mean and heterogeneity of the transit time distribution was able to quantify their respective contributions to oxygen extraction fraction and metabolic rate of oxygen. Mean transit time has a greater contribution than the heterogeneity for oxygen extraction fraction. This is found to be opposite for metabolic rate of oxygen. These results provide information on the role of the cerebral microvasculature and its effects on flow and metabolism. They thus open up the possibility of obtaining additional valuable clinical information for diagnosing and treating cerebrovascular diseases. PMID- 26499368 TI - Resveratrol induces human keratinocyte damage via the activation of class III histone deacetylase, Sirt1. AB - Human skin diseases are various and induce chronic inflammatory disorders, including psoriasis, atopic dermatitis and certain forms of ichthyosis. Psoriasis is a chronic inflammatory skin disease characterized by circumscribed, red, thickened plaques. Regulation of the balance between growth, differentiation and death is critical to keratinocytes; when altered, epidermal keratinocytes undergo hyperproliferation, abnormal differentiation and inflammatory infiltration. In the present study, we focused on the effects of resveratrol, found in red wine and peanuts, on the cell death of keratinocytes. We additionally studied the mechanism of resveratrol on Sirt1, a class III histone deacetylase, and Akt phosphorylation. Resveratrol caused apoptosis and increased Sirt1 expression in human HaCaT keratinocytes, following a decrease in the p62 protein level. Inhibition of Sirt1 by Sirt1 inhibitor restored cell viability and protein levels. Furthermore, we showed that resveratrol-induced Sirt1 blocked Akt phosphorylation. The present results indicated that resveratrol inhibited the Akt pathways by inducing Sirt1, thus leading to cell death. These data suggest that resveratrol-mediated activation of Sirt1 histone deacetylase may be a potential therapeutic target for skin diseases including psoriasis. PMID- 26499367 TI - Interaction between PVY HC-Pro and the NtCF1beta-subunit reduces the amount of chloroplast ATP synthase in virus-infected tobacco. AB - The photosynthetic rate of virus-infected plants is always reduced. However, the molecular mechanism underlying this phenomenon remains unclear. The helper component-proteinase (HC-Pro) of Potato virus Y (PVY) was found in the chloroplasts of PVY-infected tobacco, indicating some new function of HC-Pro in the chloroplasts. We generated HC-Pro transgenic plants with a transit peptide to target the protein to chloroplast. The HC-Pro transgenic tobacco showed a decreased photosynthetic rate by 25% at the light intensity of 600 MUmol m(-2) s( 1). Using a yeast two-hybrid screening assay to search for chloroplast proteins interacting with HC-Pro, we identified that PVY HC-Pro can interact with the chloroplast ATP synthase NtCF1beta-subunit. This interaction was confirmed by GST pull-down and co-immunoprecipitation assays. HC-Pro didn't interfere with the activity of assembled ATP synthase in vitro. The HC-Pro/NtCF1beta-subunit interaction might affect the assembly of ATP synthase complex. Quantitative western blot and immunogold labeling of the ATP synthase indicated that the amount of ATP synthase complex was decreased in both the HC-Pro transgenic and the PVY-infected tobacco. These results demonstrate that HC-Pro plays an important role in reducing the photosynthetic rate of PVY-infected plants, which is a completely new role of HC-Pro besides its multiple known functions. PMID- 26499369 TI - Evaluation of Quantitative Real-Time PCR as a Hepatitis C Virus Supplementary Test After RIBA Discontinuation. AB - Laboratory testing plays a major role in hepatitis C virus (HCV) diagnosis and patient follow-up. The high false positive rates of HCV screening tests require confirmation through a supplementary test. According to the 2003 CDC guidelines, recombinant immunoblot assay (RIBA) is indispensible to confirm positive screening results and differentiate biologic false positivity from true HCV exposure. However, RIBA has been permanently discontinued since 2011. In the 2013 update of its guidelines, CDC called for further studies on HCV laboratory testing without RIBA. In this study, we analyzed the applicability of quantitative real-time PCR (qPCR) as a supplementary HCV diagnostic test. By comparing our HCV testing performances before and after RIBA discontinuation, we found that omitting RIBA has no significant effect on the accurate and efficient identification of HCV infection, provided that HCV antibody signal-to-cutoff ratio is considered. Furthermore, we proposed a new HCV testing algorithm that incorporates semiquantitative assessment of HCV antibody positivity and HCV viral load measurement by qPCR. By following the algorithm, we were able to address confirmation of positive HCV screening results and to provide useful information generally required by clinicians, including the needs of further laboratory testing or clinical follow-up, as well as HCV viral titers. PMID- 26499371 TI - Reprint of "Decision-making in child protective services: Influences at multiple levels of the social ecology". AB - Decision-making in the child protection system is influenced by multiple factors; agency and geographic contexts, caseworker attributes, and families' unique circumstances all likely play a role. In this study, we use the second cohort of the National Survey of Child and Adolescent Well-Being to explore how these factors are associated with two key case decisions-substantiation and removal to out-of-home care. Analyses are conducted using weighted hierarchical linear models. We find that substantiation is strongly influenced by agency factors, particularly constraints on service accessibility. Substantiation is less likely when agencies can provide services to unsubstantiated cases and when collaboration with other social institutions is high. This supports the concept that substantiation may be a gateway to services in some communities. Agency factors contributed less to the probability of removal among substantiated cases, though time resources and constraints on decision-making had some influence. For both substantiation and removal risks, county, caseworker, and child characteristics were less influential than agency characteristics and family risk factors. PMID- 26499370 TI - Gastrointestinal symptoms and disorders in patients with eating disorders. AB - The two most clinically serious eating disorders are anorexia nervosa and bulimia nervosa. A drive for thinness and fear of fatness lead patients with anorexia nervosa either to restrict their food intake or binge-eat then purge (through self-induced vomiting and/or laxative abuse) to reduce their body weight to much less than the normal range. A drive for thinness leads patients with bulimia nervosa to binge-eat then purge but fail to reduce their body weight. Patients with eating disorders present with various gastrointestinal disturbances such as postprandial fullness, abdominal distention, abdominal pain, gastric distension, and early satiety, with altered esophageal motility sometimes seen in patients with anorexia nervosa. Other common conditions noted in patients with eating disorders are postprandial distress syndrome, superior mesenteric artery syndrome, irritable bowel syndrome, and functional constipation. Binge eating may cause acute gastric dilatation and gastric perforation, while self-induced vomiting can lead to dental caries, salivary gland enlargement, gastroesophageal reflux disease, and electrolyte imbalance. Laxative abuse can cause dehydration and electrolyte imbalance. Vomiting and/or laxative abuse can cause hypokalemia, which carries a risk of fatal arrhythmia. Careful assessment and intensive treatment of patients with eating disorders is needed because gastrointestinal symptoms/disorders can progress to a critical condition. PMID- 26499373 TI - The CD8+ cell non-cytotoxic antiviral response affects RNA polymerase II-mediated human immunodeficiency virus transcription in infected CD4+ cells. AB - A CD8+ cell non-cytotoxic antiviral response (CNAR), mediated by a CD8+ cell antiviral factor (CAF), is associated with a long-term healthy state in human immunodeficiency virus (HIV) infection. CNAR/CAF reduces viral transcription without a known effect on specific viral sequences in the HIV genome. In studies to define the mechanism involved in the block in viral transcription, we now report that transcription from the HIV-LTR reporter is reduced in infected CD4+ cells upon treatment with CAF. In agreement with this observation, the amount of RNA polymerase II (RNAPII) on the HIV promoter and other viral regions was strongly diminished in HIV-infected CD4+ cells co-cultivated with CNAR-expressing CD8+ cells. These results demonstrate further that CNAR/CAF has a specific role in regulating HIV transcription and a step during the preinitiation complex assembly appears to be sensitive to CNAR/CAF. PMID- 26499372 TI - Childhood trauma and neighborhood-level crime interact in predicting adult posttraumatic stress and major depression symptoms. AB - Previous research has identified several individual-level factors that modify the risk of childhood trauma on adult psychiatric symptoms, including symptoms of major depression (MD) and posttraumatic stress (PTS). Neighborhood-level factors also influence the impact of individual-level exposures on adult psychopathology. However, no prior studies to our knowledge have explored cross-level interactions between childhood trauma and neighborhood-level factors on MD and PTS symptoms. The purpose of this study was therefore to explore cross-level interactions between a neighborhood-level factor - neighborhood-level crime - and childhood trauma on MD and PTS symptoms. Participants in this study (N=3192) were recruited from a large public hospital, and completed self-report inventories of childhood trauma and MD and PTS symptoms. Participant addresses were mapped onto 2010 census tracts, and data on crime within each tract were collected. Multilevel models found a significant cross-level interaction between childhood trauma and neighborhood crime on MD symptoms, such that the influence of high levels of childhood trauma on MD symptoms was enhanced for participants living in high crime neighborhoods. Supplementary analyses found variation in the strength of cross-level interaction terms by types of childhood trauma and crime, with the strongest associations including emotional neglect paired with personal and property crime. The results provide preliminary support for interventions that help childhood trauma survivors find housing in less vulnerable neighborhoods and build skills to cope with neighborhood crime. PMID- 26499374 TI - Targeted silencing of CXCL1 by siRNA inhibits tumor growth and apoptosis in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is an aggressive malignancy and a major cause of cancer-related mortality worldwide. Our previous study shows that chemokine (C-X C motif) ligand 1 (CXCL1) was upregulated and CXCR1 was downregulated in tumor tissues as compared to peritumor tissues by chemotaxis assay. As the status of CXCL subgroups and their receptors affect progression of HCC, we evaluated potential mechanisms of CXCL1 associated with anticancer effects in HCC based on our previous study. The effects of targeting CXCL1 by RNA interference (RNAi) on the proliferation and apoptosis of CBRH-7919 cells were observed in vitro and in vivo. Additionally, whether CXCL1 knockdown significantly reduce the activity of STAT3, NF-kappaB and HIF-1 or not were also estimated. RNAi of CXCL1 in the CBRH 7919 cells decreased the growth of tumors in nude mice by inhibited cells proliferation and induced apoptosis. In conclusion, these findings suggest that CXCL1 plays critical roles in the growth and apoptosis of HCC. RNAi of CXCL1 inhibits the growth and apoptosis of tumor cells, which indicates that CXCL1 may be a potential molecular target for use in HCC therapy. PMID- 26499375 TI - An analysis of policy levers used to implement mental health reform in Australia 1992-2012. AB - BACKGROUND: Over the past two decades, mental health reform in Australia has received unprecedented government attention. This study explored how five policy levers (organisation, regulation, community education, finance and payment) were used by the Australian Federal Government to implement mental health reforms. METHODS: Australian Government publications, including the four mental health plans (published in 1992, 1998, 2003 and 2008) were analysed according to policy levers used to drive reform across five priority areas: [1] human rights and community attitudes; [2] responding to community need; [3] service structures; [4] service quality and effectiveness; and [5] resources and service access. RESULTS: Policy levers were applied in varying ways; with two or three levers often concurrently used to implement a single initiative or strategy. For example, changes to service structures were achieved using various combinations of all five levers. Attempts to improve service quality and effectiveness were instead made through a single lever-regulation. The use of some levers changed over time, including a move away from prescriptive, legislative use of regulation, towards a greater focus on monitoring service standards and consumer outcomes. CONCLUSIONS: Patterns in the application of policy levers across the National Mental Health Strategy, as identified in this analysis, represent a novel way of conceptualising the history of mental health reform in Australia. An improved understanding of the strategic targeting and appropriate utilisation of policy levers may assist in the delivery and evaluation of evidence-based mental health reform in the future. PMID- 26499377 TI - Abdomen disease diagnosis in CT images using flexiscale curvelet transform and improved genetic algorithm. AB - This paper presents an abdomen disease diagnostic system based on the flexi-scale curvelet transform, which uses different optimal scales for extracting features from computed tomography (CT) images. To optimize the scale of the flexi-scale curvelet transform, we propose an improved genetic algorithm. The conventional genetic algorithm assumes that fit parents will likely produce the healthiest offspring that leads to the least fit parents accumulating at the bottom of the population, reducing the fitness of subsequent populations and delaying the optimal solution search. In our improved genetic algorithm, combining the chromosomes of a low-fitness and a high-fitness individual increases the probability of producing high-fitness offspring. Thereby, all of the least fit parent chromosomes are combined with high fit parent to produce offspring for the next population. In this way, the leftover weak chromosomes cannot damage the fitness of subsequent populations. To further facilitate the search for the optimal solution, our improved genetic algorithm adopts modified elitism. The proposed method was applied to 120 CT abdominal images; 30 images each of normal subjects, cysts, tumors and stones. The features extracted by the flexi-scale curvelet transform were more discriminative than conventional methods, demonstrating the potential of our method as a diagnostic tool for abdomen diseases. PMID- 26499376 TI - Paranasal sinus opacification at MRI in lower airway disease (the HUNT study MRI). AB - The study builds on the concept of united airways, which describes the link between the upper and lower airways. Explorations of this concept have mainly related to asthma and less to chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate paranasal sinus opacification at magnetic resonance imaging (MRI) in COPD, self-reported asthma and respiratory symptoms. In this cross-sectional study, 880 randomly selected participants in the Nord Trondelag health survey (HUNT) (mean age 57.7 years, range 50-66 years, 463 women) were investigated using MRI of the paranasal sinuses. Participants were allocated to four mutually exclusive groups: (1) COPD (n = 20), (2) asthma (n = 89), (3) respiratory symptoms (n = 199), and (4) reference group (n = 572). Paranasal sinus opacifications were categorised as mucosal thickening, polyps and retention cysts, and fluid. In each participant, measurements >=1 mm from all sinuses were summed to give a total for each category of opacities. The sums for these three categories were further added together, and referred to as the total sum. Using the 75th percentile cut-off values, the likelihood of having paranasal sinus opacifications was more than six times higher in participants with COPD and twice as high in participants with asthma than among the reference group. Respiratory symptoms were only associated with mucosal thickening. The present study shows that paranasal sinus opacification is associated not only with asthma, but also with COPD and respiratory symptoms. This is in accordance with the united airways hypothesis, and should be kept in mind when handling patients with these conditions. PMID- 26499379 TI - Highly Decoupled Graphene Multilayers: Turbostraticity at its Best. AB - The extraordinary properties of graphene are truly observable when it is suspended, being free from any substrate influence. Here, a new type of multilayer graphene is reported wherein each layer is turbostratically decoupled, resembling suspended graphene in nature, while maintaining high degree of 2D crystallinity. Such defect-free graphene multilayers have been made over large areas by Joule heating of a Ni foil coated with a solid hydrocarbon. Raman spectra measured on thick flakes of turbostratically single layer graphene (T SLG) (100-250 nm) have shown characteristics similar to suspended graphene with very narrow 2D bands (~16 cm(-1)) and I2D/IG ratios up to 7.4, importantly with no D band intensity. Electron diffraction patterns showed sets of diffraction spots spread out with definite angular spacings, reminiscent of the angular deviations from the AB packing which are responsible for keeping the layers decoupled. The d-spacing derived from X-ray diffraction was larger (by ~0.04 A) compared to that in graphite. Accordingly, the c-axis resistance values were three orders higher, suggesting that the layers are indeed electronically decoupled. The high 2D crystallinity observed along with the decoupled nature should accredit the observed graphene species as a close cousin of suspended graphene. PMID- 26499378 TI - Lack of IL7Ralpha expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD). AB - Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Ralpha) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Ralpha expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients. PMID- 26499380 TI - Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/beta-catenin signaling pathway. AB - BACKGROUND: Klotho is a discovered aging suppressor gene, and its overexpression in mice extends the life span of the animal. Recently, Klotho is also identified as a tumor suppressor gene in variety of tumors; however, the potential role and the antitumor mechanism remain unclarified in liver cancers. METHODS: RT-PCR and western blotting analysis were used to detect the expression of Klotho, beta catenin, C-myc, and Cyclin D1. MTT assay was used to detect the survival rates of HepG2 and SMMC-7721 cells. Colony formation assay was used to test the proliferation ability in Klotho transfected cells. FACS was used to detect the cell apoptosis rate in different groups. RESULTS: The results showed that lower expression of Klotho were found in liver cancer cell lines than the immortalized liver cell L02. Also, MTT assay results found that overexpression or recombinant Klotho administration suppressed the proliferation of liver cancer cells HepG2 and SMMC-7721. Moreover, the colony formation assay results showed that the number of colonies was significantly lower in the cells with transfection with pCMV-Klotho than the controls. Thus, functional analysis demonstrated that Klotho expression inhibited the proliferation of liver cancer cells and Klotho worked as an important antitumor gene in tumor progression. Next, the mechanism was partly clarified that Klotho expression induced cell apoptosis in HepG2 and SMMC-7721 cells, and this phenomenon was mainly involved in the Wnt/beta-catenin signaling pathway. The western blotting analysis revealed that overexpression or recombinant administration of Klotho obviously decreased the expression levels of beta-catenin, C-myc, and Cyclin D1 in HepG2 cells. Most importantly, the antitumor mechanism for Klotho due to that overexpression of Klotho not only decreased the endogenous beta-catenin levels but also inhibited the nuclear translocation of beta-catenin to delay the cell cycle progression. CONCLUSIONS: Klotho was a tumor suppressor gene, and overexpression of Klotho suppressed the proliferation of liver cancer cells partly due to negative regulation of Wnt/beta catenin signaling pathway. So, Klotho might be used as a potential target, and the study will contribute to treatment for therapy of liver cancer patients. PMID- 26499381 TI - Association between HCV infection and diabetes type 2 in Egypt: is it time to split up? AB - PURPOSE: There is a conflicting evidence about the association between hepatitis C virus (HCV) infection and diabetes mellitus. The objective of this study was to assess this association in Egypt, the country with the highest HCV prevalence in the world. METHODS: The source of data was from the Egypt Demographic and Health Survey conducted in 2008. Using multivariable logistic regression analyses to account for known confounders, the association was investigated at two levels']: (1) HCV exposure (HCV antibody status) and diabetes mellitus and (2) diabetes mellitus and chronic HCV infection (HCV RNA status) among HCV-exposed individuals. RESULTS: We found no evidence for an association between HCV antibody status and diabetes (adjusted odds ratio [OR] = 0.87; 95% confidence interval [CI], 0.63-1.19). However, among HCV-exposed individuals, we found an evidence for an association between diabetes and active HCV infection (adjusted OR = 2.44, 95% CI, 1.30-4.57). CONCLUSIONS: Although it does not appear that HCV exposure and diabetes are linked, there might be an association between diabetes and chronic HCV infection. The HCV-diabetes relationship may be more complex than previously anticipated. Therefore, a call for an "amicable divorce" to the HCV diabetes relationship could be premature. PMID- 26499383 TI - Wellens' syndrome in a 22-year-old man. PMID- 26499382 TI - Optimal strength and timing of steroids in the management of erlotinib-related skin toxicities in a post-marketing surveillance study (POLARSTAR) of 9909 non small-cell lung cancer patients. AB - BACKGROUND: Skin toxicities, such as rash, are the most common adverse reactions associated with erlotinib. Steroids are a key treatment option for rash management; however, optimal timing of administration and selection of steroid strength have not been fully established. In this surveillance study of Japanese non-small-cell lung cancer (NSCLC) patients treated with erlotinib, rash management using topical steroids was analyzed in routine clinical practice. METHODS: From December 2007 to October 2009, all recurrent/advanced NSCLC patients in Japan treated with erlotinib were enrolled into this study (POst Launch All-patient Registration Surveillance in TARceva). The observation period was 12 months, and data for all adverse events were collected. Erlotinib-related rash, interventions for the symptoms, and outcomes of the interventions were analyzed. RESULTS: A total of 9909 patients were evaluated. Rash occurred in 67.4 % of patients; grade 1, 2, and 3 rash were observed in 26.8 %, 32.4 %, and 7.2 % of patients, respectively. The most common management strategy was topical steroids in 75.0 % of patients with rash. Regardless of rash grade, earlier initiation of steroids resulted in quicker recovery. In those for whom topical steroids were initiated more than 21 days after rash onset, median recovery time was more than 100 days regardless of rash grade, compared with those treated before rash onset, whose median time to recovery was 35-51 days, depending on rash grade. Median time to recovery of rash in the group initiated on medium-rank steroids then changed to strong-rank steroids was 47, 98, and 103 days for those with grade 1, 2, and 3 rash, respectively, compared with 39, 53, and 73 days median recovery for grade 1, 2, and 3 rash, respectively, in patients initiated on strong-rank steroids. CONCLUSION: Earlier initiation of topical steroids for the management of rash with strong or higher-rank steroids could achieve faster improvement. PMID- 26499384 TI - Impact of sex differences in brain response to infection with Plasmodium berghei. AB - Malaria is considered to be one of the most prevalent diseases in the world. Severity of the disease between males and females is very important in clinical research areas. In this study, we investigated the impact of sex differences in brain response to infection with Plasmodium berghei. Male and female C57Bl/6 mice were infected with P. berghei-infected erythrocytes. The infection induced a significant change in weight loss in males (-7.2 % +/- 0.5) than females (-4.9 % +/- 0.6). The maximum parasitemia reached about 15 % at day 9 postinfection. Also, P. berghei infection caused histopathological changes in the brain of mice. These changes were in the form of inflammation, hemorrhage, and structural changes in Purkinje cells. In addition, P. berghei was able to induce a marked oxidative damage in mice brain. The infection induced a significant increase in male brain glutathione than females while the brain catalase level was significantly increased in infected females than infected males. Moreover, the change in brain neurotransmitters, dopamine, epinephrine, norepinephrine, and serotonin, was more in infected males than infected females. At the molecular level, P. berghei was able to induce upregulations of Adam23, Cabp1, Cacnb4, Glrb, and Vdac3-mRNA in the brain of mice. These genes were significantly upregulated in infected males than in infected females. In general, P. berghei could induce structural, biochemical, and molecular alterations in mice brain. Severity of these alterations was different according to sex of mice. PMID- 26499385 TI - Barriers to Receiving Follow-Up Eye Care and Detection of Non-Glaucomatous Ocular Pathology in the Philadelphia Glaucoma Detection and Treatment Project. AB - This cross-sectional study aimed to evaluate adherence rates and identify barriers to receiving follow-up eye care in participants diagnosed with significant non-glaucomatous eye pathology in the Philadelphia Glaucoma Detection and Treatment Project. This community-based project aimed to improve detection, management, treatment, and follow-up eye care of individuals at high risk for glaucoma in community-based settings. Participants throughout Philadelphia, Pennsylvania, USA were enrolled. After a comprehensive eye examination, follow-up recommendations were given to each participant. A telephone survey was administered to individuals diagnosed with non-glaucomatous ocular pathology 3 months after initial eye examination to assess rates of follow-up and to evaluate potential barriers to follow-up. Of the 1649 participants enrolled in this project, 249 (15 %) were diagnosed with significant non-glaucomatous ocular pathology requiring follow-up care. There were 143 (57 %) who responded to the telephone survey. Respondents had a median age of 72 years, and were predominately female (69 %) and African-American (64 %). Of the respondents, 36 (25 %) attended a follow-up appointment. Participants who did not remember the results of their examinations, did not remember their recommendations, and had not seen an eye doctor within the past year were less likely to make a follow-up appointment (P = 0.04, 0.001 and 0.005, respectively). The Philadelphia Glaucoma Detection and Treatment Program was able to detect a significant amount of non glaucomatous ocular pathology requiring follow-up care. Actual follow-up rates were sub-optimal. Further research is needed to determine interventions to overcome barriers and increase adherence with follow-up recommendations. PMID- 26499386 TI - Suture anchors to fix free flaps in oral and oropharyngeal reconstruction. PMID- 26499387 TI - A new approach to control haemorrhage during lower lip shave. PMID- 26499388 TI - Smartphone photography in oral and maxillofacial surgery. AB - An increasing number of staff in oral and maxillofacial surgery (OMFS) departments take clinical photographs with their personal phones. We report the results of a survey on the use of smartphone photography in OMFS departments in the United Kingdom, and highlight the guidelines that govern their use and the associated ethical and medicolegal implications. PMID- 26499389 TI - Processing context: Asymmetric interference of visual form and texture in object and scene interactions. AB - Substantive evidence has demonstrated that scene-centered global image features influence the processing of objects embedded in complex visual scenes. Conversely, a growing body of work suggests that relevant object information may inherently influence diagnostic global scene statistics used in rapid scene categorization. Here, we investigate the potential effects of interference in object-scene perception when attending to form and texture in both simple figure ground representations and more complex object-background scenes. Results reveal asymmetric interference in the perception of form and texture in object and scene processing: Inconsistent scene texture interfered with the classification of object texture, and inconsistent object form interfered with the classification of scene form, but not vice versa. These findings contribute to our understanding of the interactions between an object and its environment, and further inform our knowledge of the visual features which influence interactivity in object and scene perception. PMID- 26499390 TI - Preparation and Evaluation of the Chelating Nanocomposite Fabricated with Marine Algae Schizochytrium sp. Protein Hydrolysate and Calcium. AB - Marine algae have been becoming a popular research topic because of their biological implication. The algae peptide-based metal-chelating complex was investigated in this study. Schizochytrium sp. protein hydrolysate (SPH) possessing high Ca-binding capacity was prepared through stepwise enzymatic hydrolysis to a degree of hydrolysis of 22.46%. The nanocomposites of SPH chelated with calcium ions were fabricated in aqueous solution at pH 6 and 30 degrees C for 20 min, with the ratio of SPH to calcium 3:1 (w/w). The size distribution showed that the nanocomposite had compact structure with a radius of 68.16 +/- 0.50 nm. SPH was rich in acidic amino acids, accounting for 33.55%, which are liable to bind with calcium ions. The molecular mass distribution demonstrated that the molecular mass of SPH was principally concentrated at 180 2000 Da. UV scanning spectroscopy and Fourier transform infrared spectroscopy suggested that the primary sites of calcium-binding corresponded to the carboxyl groups, carbonyl groups, and amino groups of SPH. The results of fluorescent spectroscopy, size distribution, atomic force microscope, and (1)H nuclear magnetic resonance spectroscopy suggested that calcium ions chelated with SPH would cause intramolecular and intermolecular folding and aggregating. The SPH calcium chelate exerted remarkable stability and absorbability under either acidic or basic conditions, which was in favor of calcium absorption in the gastrointestinal tracts of humans. The investigation suggests that SPH-calcium chelate has the potential prospect to be utilized as a nutraceutical supplement to improve bone health in the human body. PMID- 26499391 TI - Protein nanorings organized by poly(styrene-block-ethylene oxide) self-assembled thin films. AB - This study explores the use of block copolymer self-assembly to organize Lsmalpha, a protein which forms stable doughnut-shaped heptameric structures. Here, we have explored the idea that 2-D crystalline arrays of protein filaments can be prepared by stacking doughnut shaped Lsmalpha protein into the poly(ethylene oxide) blocks of a hexagonal microphase-separated polystyrene-b polyethylene oxide (PS-b-PEO) block copolymer. We were able to demonstrate the coordinated assembly of such a complex hierarchical nanostructure. The key to success was the choice of solvent systems and protein functionalization that achieved sufficient compatibility whilst still promoting assembly. Unambiguous characterisation of these structures is difficult; however AFM and TEM measurements confirmed that the protein was sequestered into the PEO blocks. The use of a protein that assembles into stackable doughnuts offers the possibility of assembling nanoscale optical, magnetic and electronic structures. PMID- 26499392 TI - Arbuscular mycorrhizal fungi: effects on plant terpenoid accumulation. AB - Arbuscular mycorrhizal fungi (AMF) are a diverse group of soil-dwelling fungi that form symbiotic associations with land plants. AMF-plant associations promote the accumulation of plant terpenoids beneficial to human health, although how AMF mediate terpenoid accumulation is not fully understood. A critical assessment and discussion of the literature relating to mechanisms by which AMF influence plant terpenoid accumulation, and whether this symbiosis can be harnessed in horticultural ecosystems was performed. Modification of plant morphology, phosphorus availability and gene transcription involved with terpenoid biosynthetic pathways were identified as key mechanisms associated with terpenoid accumulation in AMF-colonised plants. In order to exploit AMF-plant symbioses in horticultural ecosystems it is important to consider the specificity of the AMF plant association, the predominant factor affecting terpenoid accumulation, as well as the end use application of the harvested plant material. Future research should focus on resolving the relationship between ecologically matched AMF genotypes and terpenoid accumulation in plants to establish if these associations are effective in promoting mechanisms favourable for plant terpenoid accumulation. PMID- 26499393 TI - pH dependence of cyanide and imidazole binding to the heme domains of Sinorhizobium meliloti and Bradyrhizobium japonicum FixL. AB - Equilibrium and kinetic properties of cyanide and imidazole binding to the heme domains of Sinorhizobium meliloti and Bradyrhizobium japonicum FixL (SmFixLH and BjFixLH) have been investigated between pH5 and 11. KD determinations were made at integral pH values, with the strongest binding at pH9 for both ligands. KD for the cyanide complexes of BjFixLH and SmFixLH is 0.15+/-0.09 and 0.50+/-0.20MUM, respectively, and 0.70+/-0.01mM for imido-BjFixLH. The association rate constants are pH dependent with maximum values of 443+/-8 and 252+/-61M(-1)s(-1) for cyano complexes of BjFixLH and SmFixLH and (5.0+/-0.3)*10(4) and (7.0+/-1.4)*10(4)M( 1)s(-1) for the imidazole complexes. The dissociation rate constants are essentially independent of pH above pH5; (1.2+/-0.3)*10(-4) and (1.7+/-0.3)*10( 4)s(-1) for the cyano complexes of BjFixLH and SmFixLH, and (73+/-19) and (77+/ 14) s(-1) for the imidazole complexes. Two ionizable groups in FixLH affect the rate of ligand binding. The more acidic group, identified as the heme 6 propionic acid, has a pKa of 7.6+/-0.2 in BjFixLH and 6.8+/-0.2 in SmFixLH. The second ionization is due to formation of hydroxy-FixLH with pKa values of 9.64+/-0.05 for BjFixLH and 9.61+/-0.05 for SmFixLH. Imidazole binding is limited by the rate of heme pocket opening with maximum observed values of 680 and 1270s(-1) for BjFixLH and SmFixLH, respectively. PMID- 26499394 TI - The Impact of Maternal Body Mass Index and Gestational Age on the Detection of Uterine Contractions by Tocodynamometry: A Retrospective Study. AB - OBJECTIVE: To examine the impact of maternal body mass index (BMI) and gestational age (GA) on uterine contraction detection by tocodynamometry. METHODS: Gravidas with preterm labor (PTL) complaints who were evaluated by tocodynamometry, discharged from Labor and Delivery triage, and subsequently readmitted for preterm delivery were studied. Forty-six patients in whom contractions were detected (group 1) were compared to 49 women in whom contractions were not detected (group 2) with respect to BMI and GA at both evaluation and delivery. Multivariable logistic regression was used to adjust for confounders. RESULTS: Group 2 had a higher mean BMI (31.7 vs 26.1, P < .001), were more likely to be obese (57.1% vs 19.6%, P < .001), and were more likely to have been evaluated in the mid-trimester (36.7% vs 17.4%, P = .04) compared to group 1. Independent risk factors for the inability of the tocodynamometer to detect contractions were obesity (odds ratio [OR] 0.18, 95% confidence interval [CI] 0.07-0.46) and evaluation in the mid-trimester (OR 0.33, 95% CI 0.13-0.84). CONCLUSION: Our study provides evidence that the effectiveness of tocodynamometry diminishes with increasing maternal BMI. Efficacy of tocodynamometry is also decreased at earlier GA, most pronounced below 25 weeks. To evaluate women with PTL symptoms in the mid-trimester or symptomatic obese women at any GA, a modality other than tocodynamometry could be valuable to more accurately assess uterine activity. PMID- 26499395 TI - Effects of melatonin and its analogues on neural stem cells. AB - Neural stem cells (NSCs) are multipotent cells which are capable of self replication and differentiation into neurons, astrocytes or oligodendrocytes in the central nervous system (CNS). NSCs are found in two main regions in the adult brain: the subgranular zone (SGZ) in the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ). The recent discovery of NSCs in the adult mammalian brain has fostered a plethora of translational and preclinical studies to investigate novel approaches for the therapy of neurodegenerative diseases. Melatonin is the major secretory product synthesized and secreted by the pineal gland and shows both a wide distribution within phylogenetically distant organisms from bacteria to humans and a great functional versatility. Recently, accumulated experimental evidence showed that melatonin plays an important role in NSCs, including its proliferation, differentiation and survival, which are modulated by many factors including MAPK/ERK signaling pathway, histone acetylation, neurotrophic factors, transcription factors, and apoptotic genes. The purpose of this review is to summarize the beneficial effects of melatonin on NSCs and further to discuss the potential usage of melatonin and its derivatives or analogues in the treatment of CNS neurodegenerative diseases. PMID- 26499396 TI - Identification of a novel fusion transcript between human relaxin-1 (RLN1) and human relaxin-2 (RLN2) in prostate cancer. AB - Simultaneous expression of highly homologous RLN1 and RLN2 genes in prostate impairs their accurate delineation. We used PacBio SMRT sequencing and RNA-Seq in LNCaP cells in order to dissect the expression of RLN1 and RLN2 variants. We identified a novel fusion transcript comprising the RLN1 and RLN2 genes and found evidence of its expression in the normal and prostate cancer tissues. The RLN1 RLN2 fusion putatively encodes RLN2 isoform with the deleted secretory signal peptide. The identification of the fusion transcript provided information to determine unique RLN1-RLN2 fusion and RLN1 regions. The RLN1-RLN2 fusion was co expressed with RLN1 in LNCaP cells, but the two gene products were inversely regulated by androgens. We showed that RLN1 is underrepresented in common PCa cell lines in comparison to normal and PCa tissue. The current study brings a highly relevant update to the relaxin field, and will encourage further studies of RLN1 and RLN2 in PCa and broader. PMID- 26499398 TI - Acidosis differently modulates the inflammatory program in monocytes and macrophages. AB - Inflammation, ischemia or the microenvironment of solid tumors is often accompanied by a reduction of extracellular pH (acidosis) that stresses the cells and acts on cellular signaling and transcription. The effect of acidosis on the expression of various inflammatory markers, on functional parameters (migration, phagocytic activity) and on signaling pathways involved was studied in monocytic cells and macrophages. In monocytic cell lines acidosis led to a reduction in expression of most of the inflammatory mediators, namely IL-1beta, IL-6, TNF alpha, MCP-1, COX-2 and osteopontin. In primary human monocytes MCP-1 and TNF alpha were reduced but COX-2 and IL-6 were increased. In RAW264.7 macrophage cell line IL-1beta, COX-2 and iNOS expression was increased, whereas MCP-1 was reduced similar to the effect in monocytic cells. For primary human monocyte-derived macrophages the regulation of inflammatory markers by acidosis depended on activation state, except for the acidosis-induced downregulation of MCP-1 and TNF alpha. Acidosis affected functional immune cell behavior when looking at phagocytic activity which was increased in a time-dependent manner, but cellular motility was not changed. Neither ERK1/2 nor CREB signaling was stimulated by the reduction of extracellular pH. However, p38 was activated by acidosis in RAW264.7 cells and this activation was critical for the induction of IL-1beta, COX-2 and iNOS expression. In conclusion, acidosis may impede the recruitment of immune cells, but fosters inflammation when macrophages are present by increasing the level of COX-2 and iNOS and by functionally forcing up the phagocytic activity. PMID- 26499399 TI - [Lp-PLA2, a biomarker of vascular inflammation and vulnerability of atherosclerosis plaques]. AB - A chronic inflammation is involved in various stages of development of the atherosclerotic plaques. Among the emerging biomarkers of atherogenesis, the lipoprotein-associated phospholipase A2 (Lp-PLA2), formerly known as PAF acetylhydrolase (McIntyre et al., 2009), hydrolyses the oxidized short chain phospholipids of low-density lipoproteins (LDL), thereby releasing pro inflammatory mediators (lysophospholipids and oxidized fatty acids). Lp-PLA2, produced by monocytes/macrophages and T-lymphocytes, and mainly associated with LDL (Gazi et al., 2005), is predominantly expressed in the necrotic center of the atherosclerotic plaques and in the macrophage-rich areas (Kolodgie et al., 2006). It would have a predictive role of cardiovascular (CV) events in relation to the vulnerability of atherosclerotic plaques. Determination of Lp-PLA2 has been proposed in the assessment of the CV risk, to ensure a better stratification of populations at intermediate risk for targeted therapy (Davidson et al., 2008). Its proatherogenic role suggested that inhibition of its activity could ensure a better vascular protection in combination with cholesterol-lowering agents. Nevertheless, Lp-PLA2 is not yet a fully validated marker for use in daily clinical practice, especially since the studies using an inhibitor of Lp-PLA2 (darapladib) (STABILITY Investigators et al., 2014; O'Donoghue et al., 2014) did not show any reduction in coronary events. Lp-PLA2 could have a site-specific role in plaque inflammation and development (Fenning et al., 2015). High Lp-PLA2 activity could reflect a response to pro-inflammatory stress characteristic of atherosclerosis (Marathe et al., 2014). This presentation aims at clarifying the involvement of Lp-PLA2 in the pathophysiology of atherosclerosis, and at assessing its interest both as a biomarker for the onset of CV events and as a therapeutic target. PMID- 26499397 TI - Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease. AB - Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer's disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the 'glymphatic' system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26499400 TI - [Corrigendum] Lentivirus vector-mediated gene transduction of CNGRC peptide in rat adipose stem cells. PMID- 26499401 TI - Prospective observational study of near-miss obstetric events at two tertiary hospitals in Mumbai, Maharashtra, India. AB - OBJECTIVE: To review the incidence and patterns of near-miss obstetric events (defined as "A woman who nearly died but survived a complication that occurred during pregnancy, childbirth or within 42 days of termination of pregnancy"), as well as studying the classification criteria for near-miss events. METHODS: A prospective observational study was conducted in two tertiary hospitals in Mumbai. Women with near-miss obstetric events were interviewed during the period September 2012-August 2013. RESULTS: There were 884 near-miss events among 877 women, with seven patients readmitted. Clinical-criteria for near-miss events, accounting for 701 (79.3%) cases, were the commonest among the three classifications of near-miss events. Among the cases observed, hypertensive disorders of pregnancy (472 [53.4%]), severe anemia (185 [20.9%]), and postpartum hemorrhage 68 [7.7%]) were the most common causes of near-miss events. The most common problem encountered by patients prior to hospital admission for the near miss cases was the unavailability of treatment at lower-level health facilities, affecting 598 (68.2%) of the 877 study participants. CONCLUSION: Hypertensive disorders of pregnancy, postpartum hemorrhage, and severe anemia remain important determinants in maternal morbidity. Facilities and training at first-referral units should be improved so that they can respond better to basic obstetric emergencies such as sepsis, hemorrhage, and shock. PMID- 26499403 TI - Self-healing supramolecular heterometallic gels based on the synergistic effect of the constituent metal ions. AB - Supramolecular heterometallic gels with synergistic properties were prepared for the first time using ligand with Co(2+) and Ni(2+), and their macroscopic self healing has been achieved by improving the unfavorable viscoelasticity of each monometallic gel. PMID- 26499402 TI - A retrospective cohort study of the association between midwifery experience and perinatal mortality. AB - OBJECTIVE: To determine whether experience of midwife-only and nurse-midwife lead maternity carers (LMCs) is related to perinatal mortality. METHODS: In a retrospective analysis, routinely collected data were obtained for all pregnancies resulting in live births (or stillbirth at >=20weeks or weighing >400g) in New Zealand in 2005-2009. An anonymized dataset of date of midwife registration was used. The main outcome measure was perinatal mortality (fetal deaths and neonatal deaths <=27days). RESULTS: Among 233215 eligible births, 84043 were linked to a midwife-only LMC and 150172 to a nurse-midwife LMC. Among pregnancies with midwife-only LMCs, perinatal mortality was higher when the midwife had less than 1year of experience than when the midwife had 5-9years' experience (rate ratio 1.33; 95% confidence interval 1.02-1.73), an absolute difference of two additional deaths per 1000 births. There was a decreasing rate of perinatal mortality with increasing experience (P=0.031). Perinatal mortality rates did not differ by experience in the nurse-midwife group. CONCLUSION: Pregnancies cared for by early-career (<1year) midwife-only LMCs were associated with a 33% increase in perinatal mortality. No association between experience and perinatal mortality was found for nurse-midwives. Midwife-only trained LMCs could require additional training and/or supervision in their first year of practice. PMID- 26499404 TI - Phosphorus and water recovery by a novel osmotic membrane bioreactor-reverse osmosis system. AB - An osmotic membrane bioreactor-reverse osmosis (OMBR-RO) hybrid system integrated with periodic microfiltration (MF) extraction was evaluated for simultaneous phosphorus and clean water recovery from raw sewage. In this hybrid system, the forward osmosis membrane effectively retained inorganic salts and phosphate in the bioreactor, while the MF membrane periodically bled them out for phosphorus recovery with pH adjustment. The RO process was used for draw solute recovery and clean water production. Results show that phosphorus recuperation from the MF permeate was most effective when the solution pH was adjusted to 10, whereby the recovered precipitate contained 15-20% (wt/wt) of phosphorus. Periodic MF extraction also limited salinity build-up in the bioreactor, resulting in a stable biological performance and an increase in water flux during OMBR operation. Despite the build-up of organic matter and ammonia in the draw solution, OMBR-RO allowed for the recovery of high quality reused water. PMID- 26499406 TI - Underserved Areas and Pediatric Resident Characteristics: Is There Reason for Optimism? AB - OBJECTIVE: To examine whether resident characteristics and experiences are related to practice in underserved areas. METHODS: Cross-sectional survey of a national random sample of pediatric residents (n = 1000) and additional sample of minority residents (n = 223) who were graduating in 2009 was conducted. Using weighted logistic regression, we examined relationships between resident characteristics (background, values, residency experiences, and practice goals) and reported 1) expectation to practice in underserved area and 2) postresidency position in underserved area. RESULTS: Response rate was 57%. Forty-one percent of the residents reported that they had an expectation of practicing in an underserved area. Of those who had already accepted postresidency positions, 38% reported positions in underserved areas. Service obligation in exchange for loans/scholarships and primary care/academic pediatrics practice goals were the strongest predictors of expectation of practicing in underserved areas (respectively, adjusted odds ratio 4.74, 95% confidence interval 1.87-12.01; adjusted odds ratio 3.48, 95% confidence interval 1.99-6.10). Other significant predictors include hospitalist practice goals, primary care practice goals, importance of racial/ethnic diversity of patient population in residency selection, early plan (before medical school) to care for underserved families, mother with a graduate or medical degree, and higher score on the Universalism value scale. Service obligation and primary care/academic pediatrics practice goal were also the strongest predictors for taking a postresidency job in underserved area. CONCLUSIONS: Trainee characteristics such as service obligations, values of humanism, and desire to serve underserved populations offer the hope that policies and public funding can be directed to support physicians with these characteristics to redress the maldistribution of physicians caring for children. PMID- 26499405 TI - Niclosamide inhibits the inflammatory and angiogenic activation of human umbilical vein endothelial cells. AB - OBJECTIVE: Niclosamide is known to have anti-cancer and anti-inflammatory activities; however, its therapeutic mechanism has not been defined. In this study, to explain the therapeutic mechanism of niclosamide, we examined the effect of niclosamide on endothelial cell activation,leukocyte integration, proliferation, migration and angiogenesis in vitro. METHODS: Endothelia-leukocyte adhesion assays were used to assess primary cultures of human umbilical vein endothelial cells' (HUVECs) activation following TNF-alpha treatment. Each step of angiogenesis was evaluatedin vitro, including endothelial cell proliferation, migration and tube formation. Proliferation was examined using EdU assays, while wound migration assays and transwell assays were used to evaluate cell migration; cord like structure formation assays on Matrigel were used to assess tube formation. In vivo matrigel plug assay was used to assess angiogenesis. The protein expression was measured using western blot. RESULTS: Niclosamide reduced the adhesion of human monocyte cells to HUVECs. Niclosamide also reduced protein expression of VCAM-1 and ICAM1 in HUVECs.Niclosamide significantly inhibited HUVEC proliferation,migration and cord-like structure formation. Niclosamide also suppresses VEGF-induced angiogenesis in vivo.Niclosamide attenuated IKK-mediated activation of NF-kappaB pathway in TNFalpha-induced endothelial cells. Niclosamide also suppresses VEGF-induced endothelial VEGFR2 activation and downstream P-AKT, P-mTOR and P-p70S6K. CONCLUSIONS: Niclosamide exerted a potent effect on HUVECs activation, suggesting that it might function via an endothelia based mechanism in the treatment of various diseases, including rheumatoid arthritis and cancer. PMID- 26499407 TI - Efficacy and safety of a 21/7-active combined oral contraceptive with continuous low-dose ethinyl estradiol. AB - OBJECTIVE: Substituting low-dose ethinyl estradiol (EE) for the hormone-free interval in combined oral contraceptives (COCs) may enhance ovarian suppression and improve tolerability. This noncomparative phase 3 study evaluated the efficacy and safety of a 21/7-active COC regimen including 21days of desogestrel (DSG)/EE followed by 7days of EE. STUDY DESIGN: This multicenter, open-label, phase 3, single-arm study enrolled sexually active women aged 18-40years at risk for pregnancy. Women received up to 1year, or 13 consecutive 28-day cycles, of DSG 150mcg/EE 20mcg for 21days and EE 10mcg alone for 7days. Participants kept diaries to record compliance, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index (PI) and life-table approach. Safety and tolerability were assessed primarily through reported adverse events (AEs). RESULTS: A total of 2858 women enrolled and 1680 completed the study. Forty-six pregnancies in 2401 women aged 18-35years occurred after COC initiation and up to 7days after last DSG/EE or EE-only tablet was taken. When cycles in which another contraceptive method was used were excluded, the PI was 2.68 [95% confidence interval (CI), 1.96-3.57]. The cumulative pregnancy rate after 1year of treatment was 2.47% (95% CI, 1.85-3.29) for all users aged 18-35years. When only cycles during which women considered compliant were included, the PI was 2.00 (95% CI, 1.39-2.80). AEs were similar to those seen with other oral contraceptives. CONCLUSIONS: This 21/7-active DSG/EE COC with 7days of low-dose EE was efficacious and well tolerated for pregnancy prevention. IMPLICATIONS STATEMENT: This phase 3 open-label study demonstrated that a 21/7-active COC regimen including 21days of DSG 150mcg/EE 20mcg and 7days of EE 10mcg was efficacious and well tolerated for pregnancy prevention. PMID- 26499408 TI - Milan 2015: creating a safer, healthier, and sustainable world. PMID- 26499409 TI - Green areas and public health: improving wellbeing and physical activity in the urban context. AB - INTRODUCTION: The green areas play an important role in improving the environmental quality and climate of the city. However, despite the undoubted importance of these areas, the benefits to public health are still under investigation. RESULTS: The Authors perform a review of studies on the relationship between health and green areas and describe the main areas for which evidence on this relationship is currently available. They include: effects on air quality, on social cohesion, on mental health, with particular reference to the stress, and on physical activity. CONCLUSIONS: Most of the evidence comes from cross-sectional and descriptive studies and the approaches used to measure the association show themselves to be often unsatisfactory. The Authors conclude the review stressing the need for greater integration between the different professionals involved in urban planning and in health care analysis in order to identify research approaches more appropriate to understand such complex issues, striving toward a planning design of green areas that will satisfy both environmental sustainability and health requirements. PMID- 26499410 TI - Incidence of infection-associated cancers in Italy and prevention strategies. AB - Chronic infections and infestations represent major causes of cancer. Overall, Helicobacter pylori, HPV, HBV, and HCV are estimated to account for 15% of all human cancers. We have estimated that cancers associated with 6 pathogens in Italy account for 31,000 yearly cases, 42.0%of which is attributable to H. pylori, 34.7%to HBV and HCV, 19.8%to HPV, 2.9%to KSHV, and 0.2% to EBV. These figures represent 8.5% of all incident cases of cancer in Italy. The implementation of anti-HBV vaccination programs in countries with high endemicity resulted in a significant impact on the incidence of hepatocellular carcinoma, and the availability of antiviral drugs is a real opportunity to drastically reduce the cases attributable to HCV. Primary prevention of cervical cancer mainly involves HPV vaccination; two vaccines (bivalent and quadrivalent) are available and a new vaccine (9-valent) has recently been approved by the FDA. Secondary prevention is based on screening programs that include Pap smear cytology and/or HPV test. To reduce the burden of HIV-associated cancers, prevention programs include primary prevention of HIV infection, early diagnosis and treatment, restoration of immune function, reduction in the prevalence of associated infections and risk factors, and secondary prevention. To date, anti HBV and anti-HPV vaccinations, eradication of H. pylori infection, treatment of HCV and HIV carriers with antivirals, and HPV-related cancer screening prove to be the most effective strategies for the prevention of infection-associated cancers. PMID- 26499411 TI - Molecular epidemiology tools in the management of healthcare-associated infections: towards the definition of recommendations. AB - INTRODUCTION: Healthcare-Associated Infections (HAIs) are an important cause of morbidity and mortality worldwide and have a significant economic impact for health systems. Molecular epidemiology tools have a central role in HAI prevention programs. In order to give an overview of their specific advantages and disadvantages we reported current and new molecular typing methods for HAI outbreak detection and epidemiological surveillance. METHODS: The current review was drafted as a short version of a longer document written by the Public Health Genomics (GSP) working group, and the Italian Study Group of Hospital Hygiene (GISIO), entitled Molecular epidemiology of Healthcare Associated Infections: recommendations from the Italian Society of Hygiene, Preventive Medicine and Public Health (SItI). This text considers various aspects related to HAIs: the role of genotyping and bioinformatics, the organizational levels of laboratories, as well as ethical and economic aspects. CONCLUSIONS: The use of molecular epidemiology represents a key tool in the management of HAIs, to be used as a complement to conventional control measures. The present contribution aims to increase knowledge on the proper use of such methods, given the major challenge HAI represents for National Health systems. PMID- 26499412 TI - Appropriate perioperative antibiotic prophylaxis: challenges, strategies, and quality indicators. AB - INTRODUCTION: Surgical site infections (SSIs) are common surgical complications and perioperative antibiotic prophylaxis (PAP) contributes to the reduction of the associated risk. The aim of the present review article is to summarize the most recently published studies with a special focus on challenges, strategies and quality indicators of PAP. METHODS: Literature searches in the Medline database, using PubMed, were carried out for studies published from January 2011 to April 2015. Inclusion criteria were all types of epidemiological studies investigating: i. compliance with PAP recommendations at different levels by using process indicators, and ii. the effect of different interventions conducted in order to improve PAP compliance. RESULTS: A total of 28 studies were retrieved. Overall compliance with all included PAP indicators ranged from 9.4% to 80%. Generally, compliance with the PAP process indicators significantly improved after interventions. CONCLUSIONS: The present review summarizes the recent published studies and indicates an overall inadequate compliance with PAP recommendations, underlining the need to develop and to implement successful strategies to improve adherence to guidelines. Different interventions were found efficacious in order to increase compliance with appropriate PAP administration. PMID- 26499413 TI - Professional competencies in health promotion and public health: what is common and what is specific? Review of the European debate and perspectives for professional development. AB - According to the Nairobi Call to Action, the growth of practitioners' skills can be favoured by setting accreditation standards and by reorienting professional competencies of current and future health workers. This will make it possible to develop a critical mass of competent practitioners, foster training, and increase visibility of the professional field. Through a review of the literature, the authors offer an overview of competency-based strategies for professional development in health promotion. The main research questions discussed were as follows: Is there a shared definition of public health?; Is there a shared definition of health promotion?; Who are the main stakeholders for public health and health promotion in Europe?; What is the meaning of professional competencies in education and practice for public health and health promotion?; Is there a shared system of professional core competencies in public health and health promotion?;What is common and what is specific between the two systems of professional competencies?; Is it useful and feasible to create specific strategies of professional development for public health and health promotion? A transformative use of competencies makes it possible to inform students, professionals, employers, and political decision-makers about what is expected from a specific profession and its values. PMID- 26499414 TI - How to choose health technologies to be assessed by HTA? A review of criteria for priority setting. AB - INTRODUCTION: Health Technology Assessment (HTA) plays a key role in the policy and decision-making process. Nevertheless, it is time- and resource-consuming, and therefore requires proper resource allocation. Priority setting, as a best way to organize effective and explicit resource allocation systems, may be applied even in this field. OBJECTIVE: The aim of this study was to provide an overview of criteria used for priority setting in HTA at European level. METHODS: A systematic review of the scientific literature was performed through PubMed alongside consultation of the websites of the European HTA Agencies belonging to the INAHTA. The search was limited to papers written in English and provided with the full text. Documents were considered eligible if providing criteria for priority setting in HTA. RESULTS: Seven scientific articles were retrieved from PubMed and 14 European HTA Agencies released prioritization criteria were analysed. The most relevant criteria were: frequency/burden of disease, economic impact and costs, potential benefits, impact on ethical, social, cultural and/or legal aspects. CONCLUSION: This work is meant to contribute to supranational discussion on priority setting at European level and shows that, despite the available evidence, work still needs to be done toward harmonization and sharing of the criteria to adopt. PMID- 26499415 TI - Genetic testing and economic evaluations: a systematic review of the literature. AB - OBJECTIVES: To identify those studies in which economic analysis of predictive genetic and pharmacogenetic testing programs have been carried out. Since the Italian National Prevention Plan 2014-2018 foresees the implementation of genetic testing for inherited breast cancer, special attention was given to the cost effectiveness of BRCA1/2 testing programs. METHODS: A systematic review of primary economic evaluations (EEs) of predictive genetic and pharmacogenetic testing programs and an overview of previously published systematic reviews of economic evaluations (ERs) was performed. RESULTS: Overall 128 EEs and 11 ERs were identified. The methodological quality of both EEs and ERs was good on average. Both predictive genetic and pharmacogenetic testing programs were mainly concerned with oncological diseases. Seventeen percent of genetic testing programs are cost-saving, while a further 44% of cost/QALY ratios fall under the commonly used threshold of ?37,000 per QALY. For BRCA1/2 testing, only cascade genetic screening programs, targeted to close relatives of carriers, show clear evidence of cost-effectiveness. CONCLUSION: Despite some limitations, EEs and ERs are powerful tools that provide indications to policy-makers on which genetic testing programs might be introduced into health care systems and public health practice. PMID- 26499416 TI - HPV vaccination for boys? A systematic review of economic studies. AB - INTRODUCTION: HPV vaccination is recommended in many countries, including Italy, for girls in their twelfth year of age. In some countries, the goal of vaccination coverage has not been reached, and extension to boys has thus been debated. OBJECTIVE: Aim of this study is to perform a systematic review of pharmaco-economic studies considering the extension of HPV vaccination to boys. METHODS: An electronic literature search was performed on Pubmed to identify studies published from 2005 to 2015 in English and Italian. Four search strategies were used, including the terms "HPV", "boys", "vaccination", "economic evaluation", "cost effectiveness", and "epidemiological impact". Screening of titles, abstracts, and full texts was conducted, and economical evaluation of the extension of HPV vaccination to males was considered a criteria of inclusion. A total of 289 articles were identified. Only 15 articles were finally considered pertinent. RESULTS: The extension of HPV vaccination to boys was cost-effective or potentially cost-effective in 53%and 7%of the studies, respectively. Six studies did not positively evaluate the implementation of this intervention. However, taking into account both the new two-dose vaccination schedule available for all subjects <=13 years, and the dramatic reduction in the price of vaccines in the last few years, the advantages of universal vaccination are more consistent. CONCLUSION: The extension of HPV vaccination to boys is therefore foreseen to become increasingly implemented in the near future. PMID- 26499417 TI - Antimeningococcal and antipneumococcal vaccination determinants: a European systematic literature review. AB - BACKGROUND: ESCULAPIO is a multicenter project, funded by the Italian Centre for Disease Prevention and Control, aimed at implementing communication strategies to improve vaccination knowledge and attitudes among different target populations. OBJECTIVE: The objective of the Sicilian research unit was, in the first phase, to identify, through systematic literature revision, which vaccination determinants play a role in the uptake of recommended vaccines included in the Italian Vaccination Plan. DESIGN: A systematic literature review was carried out on studies describing the determinants underlying pneumococcal and meningococcal vaccination uptake. The analysis was limited to papers published in English from 2000 to date. RESULTS: A total of 188 (meningococcal) and 731 (pneumococcal) papers were found. After selection by publication data, country (Europe), article type (original article), target population (healthy subjects), 7 (meningococcal) and 4 ( pneumococcal) manuscripts were finally included in the analysis. For meningococcal vaccination a better socioeconomic status is related to vaccination acceptance, whereas distance from immunization service is a negative determinant. For pneumococcal vaccination the determinants related to vaccination uptake are older parental age and a strong vaccine recommendation. Conversely, when the vaccine needs to be paid for, a refusal is more likely. CONCLUSIONS: Our results show that payment for vaccination is a major barrier and communication about meningococcal and pneumococcal vaccination should be targeted towards specific population groups, especially through the counseling activities by health professionals. PMID- 26499418 TI - From surveillance to development of nutritional guidelines. AB - In Italy, like in most parts of the world, 30% of children and almost 50% of adults are overweight. This condition is one of the causes of non-communicable diseases responsible for over two thirds of DALYs, deaths and costs for healthcare. Current surveys confirm that overweight and obesity are associated with food habits which have changed, in Italy, in the last fifty years. Fewer and fewer people have been following a Mediterranean diet, which is considered an effective diet for the prevention of many diseases. The consumption of fruit, vegetables, legumes, whole cereals, and EVO oil has decreased, while the consumption of food with high energetic density and rich in sugar, salt, and added fat has increased, especially when eating out. Schools and workplaces are the best places to promote healthy food habits and an active lifestyle. The aim is to involve families (including low-income families), educators, and catering services. This type of intervention is not new to the National Health System and has already led to improvements: however, it is still possible to improve the use of resources and coordination between social, educational, and health services bringing the community to become its own health promoter. Health operators have to be more aware of overweight as a health threat. The National Health Plan represents a commitment for Italy, the country hosting EXPO 2015, to fulfill the targets of the "Action Plan European Strategy for the Prevention and Control of Non-communicable Diseases 2012-2016" entrusting the Departments of Prevention with the interventions and development of a network of stakeholders. PMID- 26499419 TI - The importance of indicators in monitoring water quality according to European directives. AB - Directive 2000/60/EC and subsequent legislation provide a list of priority substances to be measured and monitored in EU water bodies and require the adoption of analytical methods that ensure comparability of the data collected in all Member States. These regulations and standards have gradually improved water quality in the EU. However, new drugs, whose effects on ecosystems and health are still to be determined, are detected with growing frequency. The Member States are now called upon to characterize and monitor these pollutants in view of their possible inclusion in the priority substance list. PMID- 26499420 TI - Migrant health: the Apulian model. AB - INTRODUCTION: Since the 1990s Puglia has been totally involved in the reception and assistance of refugees. The prevention of infectious diseases among migrants, especially those residing in communities, is an important concern for public health authorities, since infectious diseases eliminated in Europe may still be widespread in the migrants' countries of origin, and other diseases may have a higher incidence than in European countries. Thus immigrants may contribute to the burden and spread of infectious diseases. OBJECTIVE: We describe the Apulian model of management and prevention of infectious disease among the population of Asylum Seeker Centres (CARA). It consists of a number of activities: surveillance of Poliovirus circulation, tuberculosis screening, seroprevalence studies of viral hepatitis and HIV, an immunization program for children, and syndromic surveillance. All the activities are organized and carried out by the Regional Observatory for Epidemiology among refugees hosted in the Bari Palese CARA. RESULTS: Surveillance of Poliovirus circulation has been carried out periodically since 2008 by assessing the presence of wild poliovirus or Sabin-like poliovirus in stool samples and seroprevalence studies. Data did not show circulation of poliovirus and indicated a good level of immunization against polio among refugees. Seroprevalence studies of viral hepatitis and HIV were carried out in 2008 and involved 529 refugees; 44 individuals (8.3%) were HBsAg positive, 24 (4.5%) were anti-HCV positive, 8 (1.5%) were HIV positive. Tuberculosis screening started in 2009 after a refugee's death due to tuberculosis and has been ongoing since then. The Mantoux tuberculin skin test is used and cutipositive migrants are examined by chest X-ray. Around 50% of migrants have been found to be cutipositive and 10% showed TB sequelae. Syndromic surveillance and an immunization program began in 2011 because of the significant increase in migration flow following civil unrest in North Africa; respiratory tract infection and diarrhoea were the most frequent notified syndromes. The immunization program involved 129 children coming from 23 countries: all received the appropriate vaccinations. The program also includes an annual special session to vaccinate all refugees against flu. CONCLUSIONS: The results confirmed some traditional concerns about migrant health and especially about the control of infectious diseases among these populations and the need, from our point of view, to strengthen screening to aid the development of trust between migrants and resident population. PMID- 26499421 TI - Evidence-based approach for continuous improvement of occupational health. AB - INTRODUCTION: It was recognized early on that an Evidence-Based Medicine (EBM) approach could be applied to Public Health (PH), including the area of Occupational Health (OH). The aim of Evidence-Based Occupational Health (EBOH) is to ensure safety, health, and well-being in the workplace. Currently, high quality research is necessary in order to provide arguments and scientific evidence upon which effective, efficient, and sustainable preventive measures and policies are to be developed in the workplace in Western countries. Occupational physicians need to integrate available scientific evidence and existing recommendations with a framework of national employment laws and regulations. OBJECTIVE: This paper addresses the state of the art of scientific evidence available in the field (i.e., efficacy of interventions, usefulness of education and training of workers, and need of a multidisciplinary strategy integrated within the national PH programs) and the main critical issues for their implementation. CONCLUSIONS: Promoting good health is a fundamental part of the smart, inclusive growth objectives of Europe 2020 - Europe's growth strategy: keeping people healthy and active for longer has a positive impact on productivity and competitiveness. It appears clear that health quality and safety in the workplace play a key role for smart, sustainable, and inclusive growth in Western countries. PMID- 26499422 TI - Monitoring the web to support vaccine coverage: results of two years of the portal VaccinarSi. AB - OBJECTIVES: The increasingly widespread use of the Internet by the population to collect information regarding health and medical treatments and the circulation of many non-scientific documents on the effectiveness and safety of vaccines has led the Italian Society of Hygiene (SItI), in 2013, to promote a portal to provide scientific information that is verified and easily understood to counteract the rampant misinformation on health treatments and combat the phenomenon of vaccine hesitancy. METHODS: The project was launched in May 2013 and provides a portal with six main sections (vaccine preventable diseases, registered vaccines, benefits and risks of vaccination, against misinformation, pros & cons and travel immunizations) and other headings that relate to scientific events, comics and news coverage concerning vaccines. The contents are validated and evaluated by a scientific committee of high profile scientists and experts in computer-mediated communication. RESULTS: In the first two years of activity, the portal has published more than 250 web pages on all aspects related to vaccinations. The number of individual users was 860,411, with a constant increase over time. Of these, about 21.7% returned to the website at least once. The total visits in 24 months were 1,099,670, with a total page count of 2,530,416. The frequency of contact was almost exclusively Italian (95.6%), with a higher proportion of males (54.1%) and younger age groups (25-34 years, 33.5%, and18-24 years, 27.5%). The data also show a significant position of the website in the major web search engines. The website has been certified by the Health On the Net Foundation. It is connected with the main social networks and it has recently opened its first regional section (Veneto). CONCLUSIONS: The strong, progressive increase in web contacts, the involvement of several institutional bodies, and the appreciation of various stakeholders give an absolutely positive assessment of the first two years of the VaccinarSi project. The success of the website suggests future developments, with updates, sections devoted to regional problems, in-depth news analysis, and international expansion. The authors conclude that initiatives like this are to be implemented and constitute an effective way to counteract vaccine hesitancy. PMID- 26499424 TI - Management of women at high risk of hereditary breast cancer in the Veneto Regional Program for Prevention. AB - INTRODUCTION: Today it is well-known that high risk of genetic breast cancer concerns a very limited part of the population: no more than 2-3 women are affected every thousand and this condition as a whole accounts for no more than 3%-5% of all breast cancers. OBJECTIVES AND METHODS: Following the directions contained in the 2014-2018 National Prevention Plan, Veneto's 2014-2018 Regional Program of Prevention (PRP), approved by Regional Council Resolution (DGR) No. 749 of 14.5.2015, consolidation of a pathway of diagnosis, observation, and prophylaxis for women at high risk of hereditary breast carcinoma is thus proposed. The principal activities of this policy will be the following: creation of a regional working group, survey of currently existing pathways for the identification of women at risk of hereditary breast cancer and adoption of the same, approval and consolidation of a structured regional pathway for women at high risk of hereditary breast and/or ovarian cancer, from paths of oncogenetic consultation and genetic testing to management of disease risk. Subsequent to the recognition of the pathway of diagnosis, observation, and prophylaxis for women at high risk of hereditary breast carcinoma, the Veneto region undertakes to develop a co-ordinated program of information and training on this pathway directed at the population and healthcare workers. CONCLUSIONS: It is firmly hoped that with the inclusion of a program for the management of women at high risk of hereditary breast cancer within the Veneto PRP this topic may become more defined and structured in terms of sustainability, integration with the existing regional networks (mammography network, Breast Unit), contrasting inequality, monitoring and evaluation, in this way pursuing the objectives of a reduction of cause-specific mortality and improvement of quality of life. PMID- 26499423 TI - Antibiotic consumption and resistance: results of the SPIN-UTI project of the GISIO-SItI. AB - OBJECTIVE: To evaluate trends and association between antibiotic consumption and resistance during an eight-year period, from 2006 to 2013. DESIGN: Prospective multicenter study. SETTING AND PARTICIPANTS: Intensive Care Units (ICUs) participating in the four editions of the Italian nosocomial infections surveillance in the ICU Network (Sorveglianza Prospettica delle Infezioni Nosocomiali nelle Unita di Terapia Intensiva, SPIN-UTI project). MAIN OUTCOME MEASURES: The isolation density of selected species of microorganisms, antibiotic resistance rates (RRs), incidence density of resistant isolates and antimicrobial usage density were calculated. RESULTS: RRs of carbapenem-resistant Acinetobacter baumannii, of carbapenem-resistant Klebsiella pneumoniae, of third-generation cephalosporin (3GC)-resistant K. pneumoniae and of 3GC-resistant Escherichia coli showed significant increasing trends (p <=0.001). The consumption of each antibiotic class varied with years, although not significantly. Significant strongly positive correlations were detected between RRs and antibiotic consumption. CONCLUSIONS: The present study describes high RRs and increasing trends of resistant microorganisms and highlights the need for continuous comprehensive strategies targeting not only the prudent use of antibiotics, but also infection control measures to limit the epidemic spread of resistant isolates. PMID- 26499426 TI - Malnutrition decreases the odds of attaining motor milestones in HIV exposed children: results from a paediatric DREAM cohort. AB - OBJECTIVE: HIV and malnutrition are the two major causes of infant mortality in Sub-Saharan Africa. The study describes the impact of malnutrition on motor milestone development in HIV-exposed children. DESIGN: Randomized community intervention trial (SMAC, Safe Milk for African Children). SETTING AND PARTICIPANTS: Growth, motor development, and malnutrition were assessed in a sample of 76 HIV-exposed children, aged 0-24 months, at the Blantyre Dream Centre in Malawi. MAIN OUTCOME MEASURES: We assessed growth and selected motor milestone achievement in agreement with WHO/UNICEF criteria. Odds ratios and 95%confidence intervals were calculated according to motor milestones and malnutrition indices. Multivariable logistic regression was performed with 18 months data. RESULTS: High rates of malnutrition were observed. Underweight increased by 6.7/9.2 and 3.2/5.5 the odds of not standing alone and not walking alone at 15 and 18 months. Stunting increased by 9.7 the odds of not standing alone at 11 months and by 6.1 the odds of not walking alone at 18 months. Wasting increased by 5.5/10.3 the odds for not walking with assistance at 12 and 18 months. Low weight for age was associated with delay in walking at 18 months (HR=2.9). CONCLUSION: Malnutrition in HIV-exposed children decreases the likelihood of adequate development. PMID- 26499425 TI - Increased incidence of childhood leukemia in urban areas: a population-based case control study. AB - OBJECTIVE: We carried out a population-based case-control study to assess the possibility of an excess risk of childhood leukemia in urban areas, independently from road traffic pollution. METHODS: Study subjects were the 111 cases of childhood leukemia diagnosed from 1998 to 2011 among residents of two provinces of the northern Italian Emilia-Romagna region, and 444 controls matched by age and sex. Through mapping of the region carried out by remote sensing, we examined the percentage of urban or rural area in the 100-meter circular buffer around each child's house. We also modeled annual average exposure to benzene and PM10 from vehicular traffic at each residence. RESULTS: In a multivariate model adjusting for benzene and PM10, the odds ratio of leukemia associated with residence in a highly urbanized area and residential area (>=95% land use of this type near the child's home) was 1.4 (95% confidence intervals 0.8-2.4) and 1.3 (0.8-2.2), respectively. An increased risk was also found in association with the proximity to "dumps, scrap yards, and building sites". No association emerged with residence in rural areas or near industrial plants. CONCLUSIONS: These results indicate that children living in urban areas experience an excess leukemia risk, independently from exposure to pollutants from vehicles. PMID- 26499427 TI - Reducing external drainage-related cerebrospinal fluid infections through implementation of a multidisciplinary protocol: experience in a paediatric hospital. AB - OBJECTIVE: To assess the frequency of external cerebrospinal fluid (CSF) drain related CNS infections before and after implementation of a protocol for their prevention. DESIGN: Quasi-experimental study, with comparison of incidence before and after the implementation of the intervention. SETTING AND PARTICIPANTS: Bambino Gesu Children's Hospital in Rome, Italy. Children receiving an external cerebrospinal fluid drain from 1 January 2013 to 31 March 2015. MAIN OUTCOME MEASURES: Drain-related infections. RESULTS: Fifty-two patients were included in the study. Before protocol implementation, cumulative incidence was 14 per 100 drains. Incidence rate was 8/1,000 catheter-days. After protocol implementation, cumulative incidence and incidence rate were 6.7 per 100 drains and 4.6 per 1,000 catheter-days (p=0.61 and p=0.2 versus the pre-intervention period, respectively). Infected patients were significantly younger (median age: 16.5 days vs 13.4 months; p=0.026), had a significantly higher number of procedures (5 vs 1 procedure per patient; p <0.0001) and were most frequently affected by post haemorrhagic hydrocephalus of premature newborns (50% vs 16.7%; p=0.039), compared to non-infected patients. CONCLUSIONS: After protocol implementation, we observed a reduction of incidence of CSF drain-related infections, though the short post-intervention period limited the power of the study to detect a significant difference. Patients <1 year of age, with multiple interventions and post-haemorrhagic hydrocephalus had higher risk of CSF drain-related infections. PMID- 26499429 TI - The first italian validation of the most widespread health literacy assessment tool: the Newest Vital Sign. AB - OBJECTIVE: This work represents the first attempt to validate, for the Italian population, the most widespread health literacy assessment tool: the Newest Vital Sign (NVS). DESIGN: The UK version of this tool was adapted for Italy using a translation/back-translation process. A web-based survey was then administered to a multidisciplinary panel of experts to assess its face validity. Finally, a preliminary study of construct validity was conducted, focusing on efficiency, comprehensibility, reliability, and sensitivity of the items of the test. For the evaluation of these dimensions we adopted Pearson's r correlation and calculated the average scores obtained for the subscales. RESULTS: Data analysis shows that the NVS-IT can be considered, under every aspect, an adequate tool for the assessment of individual health literacy grade level, given the optimal correlation among the experts' judgments and the average scores above the acceptability threshold. CONCLUSION: Our study aims to encourage use of the NVS for the Italian population and, furthermore, introduce a scientific approach to health literacy, an issue that is gaining interest even in our country, though, to date, this has mainly resulted in the production of theoretical works. PMID- 26499428 TI - Assessment of the effectiveness of the universal varicella vaccination program in Toscana (Italy), in the period 2010-2013. AB - OBJECTIVE: To assess the effectiveness of the varicella vaccination program in Toscana after one dose of vaccine, in the birth cohorts 2008-2011. DESIGN: Varicella vaccine effectiveness (VE) was calculated using the "screening method", based on vaccine coverage (VC) at 24 months and proportion of vaccinated subjects among varicella notified cases (PVC), verified through the Local Health Units' (LHUs) immunization registries. Breakthrough varicella (BV) was defined as a case of varicella occurring in a child vaccinated >=42 days before the date of disease onset. SETTING AND PARTICIPANTS: The study was conducted in the 12 Tuscan LHUs and included all varicella cases notified in 2010-2013 in children of the birth cohorts 2008-2011. MAIN OUTCOME MEASURES: BV cases; VE after one dose of varicella vaccine; time interval between varicella vaccination and symptom onset. RESULTS: VC was 79.8%, VE reached 90.8%(95%CI 89.5%-92.0%) and the proportion of BV among notified cases was 26.6%. The median time interval between vaccination and symptom onset was 25 months. CONCLUSIONS: The very low rate of BV cases among vaccinated children confirms the high effectiveness even of a single dose of varicella vaccine and does not support a change of the current immunization schedule. PMID- 26499430 TI - Molecular typing of XDR Acinetobacter baumannii strains in an Italian ICU. AB - OBJECTIVE: To investigate the antimicrobial susceptibility and clonal relationship of Acinetobacter baumannii strains isolated in an Italian ICU. DESIGN: Epidemiological, observational, retrospective, longitudinal study. SETTING AND PARTICIPANTS: The ICU of the University Hospital of Sassari, Italy. MAIN OUTCOME MEASURES: Pulsed Field Gel Electrophoresis (PFGE) and Multi Locus Sequence Typing (MLST) were used to evaluate the genomic features of the isolated strains. RESULTS: Drug susceptibility testing for all isolated strains showed the same resistance pattern, characterized by resistance to the most important antibiotics, with the only exception of colistin. PFGE showed a very poor between strain variability; three distinct clusters, 11, 4, and 1 isolates in size, were identified (Dice's coefficient: 92.11%). MLST showed that all isolated strains belonged to sequence type 2 (ST2). All isolates collected from the environment and the human samples were positive for the following genes: blaOXA-23, blaOXA-51 like, blaVIM-like, blaIMP-like, andISAba1; however, blaOXA-24-like, blaOXA-58 like, and blaNDM-like were not detected. CONCLUSIONS: The survey identified XDR strains belonging to the same cell clone, confirming the wide circulation and environmental persistence of this microorganism. PMID- 26499431 TI - Invasive pneumococcal disease in children and adults in seven Italian regions after the introduction of the conjugate vaccine, 2008-2014. AB - OBJECTIVE: To describe the trend of invasive pneumococcal disease in the years 2008-2014; to verify the impact of the conjugate vaccine and monitor the occurrence of serotype replacement. DESIGN: Prospective observational study based on data from the national surveillance for invasive bacterial diseases coordinated by the Istituto superiore di sanita. SETTING AND PARTICIPANTS: Seven Italian regions (A.P. Bolzano, A.P. Trento, Emilia-Romagna, Friuli-Venezia Giulia, Lombardia, Piemonte, Veneto), accounting for 43% of the national population. MAIN OUTCOME MEASURES: Number of cases and incidence of invasive pneumococcal diseases: global, stratified by age groups and by serotypes included or not in the PCV13. RESULTS: In 2008-2014, in the 0-4 age group IPD incidence for all serotypes decreased from 7.1 to 2.9/100,000; incidence for vaccine serotypes (VT) decreased from 5.5 to 1.1/100,000, while incidence for non-vaccine serotypes (NVT) increased from 1.6 to 2.0/100,000 (2.5 in 2013). In the >64 age group, IPD incidence increased from 5.3 to 7.5/100,000; VT incidence decreased from 3.9 to 3.2 (4.9 in 2010 and 4.3 in 2013), whereas NVT incidence increased from 1.4 to 4.4/100,000. CONCLUSION: Use of the conjugate vaccine has reduced the number of cases of IPD by VT in children; the increase in IPD by NVT, above all in older age groups, suggests a serotype replacement. PMID- 26499432 TI - Influenza and immunization: a quantitative study of media coverage in the season of the "Fluad case". AB - BACKGROUND: Seasonal influenza generates serious health and economic losses. In the last influenza season, the report of three deaths originally blamed on the Fluad vaccine drew widespread attention from the media and is likely to have had a major negative impact on vaccine uptake. OBJECTIVE: We quantitatively analyzed media coverage on influenza and immunization-related topics on all published issues of the Italian newspaper ranking first in circulation, over one year. DESIGN: We retrieved relevant key words and articles, reporting on article topic, length, position, and approach to immunization, and on other selected indicators' summary statistics, trends, and correspondence with key events. RESULTS: Selected key words were retrieved 798 times over the study period, 34% specifically focusing on influenza. The average number of influenza-related key words per issue was 96%higher in the four-day "uncertainty" period from when the deaths were first reported to the release of the test results disproving any causal association between the deaths and the vaccine (time frame #1), as compared to the whole study period. Ninety relevant articles were included in the analysis, 51%focusing on influenza, the average number/issue being 97%higher during time frame #1. During time frame #1, articles were also longer and located in the main sections of the newspapers. No articles were published at the launch of the seasonal influenza immunization campaign. CONCLUSION: We propose an analytic model of media monitoring that could be effectively applied to support health authorities and representatives of the scientific community in conveying health education messages through the media. PMID- 26499433 TI - Vaccine coverage in Italy and assessment of the 2012-2014 National Immunization Prevention Plan. AB - BACKGROUND: In 2012, the ItalianMinistry of Health issued the National Immunization Prevention Plan (Piano Nazionale Prevenzione Vaccinale, or PNPV 2012 2014), with the aim of harmonizing immunization strategies across the country and ensuring equitable access to infectious disease prevention to all citizens. The Plan defines the immunization standards all regions should comply with. OBJECTIVE AND METHODS: As new evidence has accumulated in the field of immunization, and the new National Immunization Prevention Plan is about to be launched, the aim of the current study is to: i. present immunization coverage data (2000-2014) for 14 vaccines included in the PNPV to be offered to the general population, ii. assess to what extent the PNPV coverage targets and objectives have been met, and iii. report on how the PNPV was transposed into regional immunization programs. Data are also available for the eight regions that piloted varicella immunization. RESULTS: The 2012-2014 PNPV first introduced a "lifecourse" approach to vaccination at the institutional level, and has been a milestone for prevention in the Italian health policy agenda. However, infant vaccine coverage rates have been decreasing over the last years, as has influenza immunization in the elderly. HPV vaccine coverage has been increasing for all birth cohorts, but is still far below the targets set in the Plan. Promising preliminary data show that pneumococcal and meningococcal C conjugate vaccines were well introduced in regional immunization schedules. CONCLUSION: The 2012-2014 PNPV objectives have only been partially met, due to several factors, in particular increase in vaccine hesitancy. Strengthened efforts are needed to promote immunization. The new National Immunization Prevention Plan should introduce new vaccines and extend immunization programs to other target populations on the basis of the most recent scientific evidence available. It is of crucial importance that interventions of proven efficacy be planned and implemented to contrast the growing phenomenon of vaccine hesitancy and ultimately increase immunization uptake. PMID- 26499434 TI - Authors' response to the letter on the article "Partial laryngectomy as salvage surgery after radiotherapy: Oncological and functional outcomes and impact on quality of life. A retrospective study of 20 cases". PMID- 26499435 TI - Survival of a micro-vascular free flap after a prolonged cardiac arrest. PMID- 26499436 TI - 3-D imaging of islets in obesity: formation of the islet-duct complex and neurovascular remodeling in young hyperphagic mice. AB - BACKGROUND: Obesity and insulin resistance lead to islet hyperplasia. However, how the islet remodeling influences the pancreatic environment and the associated neurovascular networks is largely unknown. The lack of information is primarily due to the difficulty of global visualization of the hyperplasic islet (>200 MUm) and the neurovascular environment with high definition. METHODS: We modulated the pancreatic optical property to achieve 3-dimensional (3-D) whole-islet histology and to integrate transmitted light microscopy (which provides the ground-truth tissue information) with confocal fluorescence imaging. The new optical and imaging conditions were used to globally examine the hyperplastic islets of the young (2 months) obese db/db and ob/ob mice, which otherwise cannot be easily portrayed by the standard microtome-based histology. The voxel-based islet micrographs were digitally processed for stereo projection and qualitative and quantitative analyses of the islet tissue networks. RESULTS: Paired staining and imaging of the pancreatic islets, ducts and neurovascular networks reveal the unexpected formation of the 'neuro-insular-ductal complex' in the young obese mice. The complex consists of the peri- and/or intra-islet ducts and prominent peri-ductal sympathetic nerves; the latter contributes to a marked increase in islet sympathetic innervation. In vascular characterization, we identify a decreased perivascular density of the ob/ob islet pericytes, which adapt to ensheathing the dilated microvessels with hypertrophic processes. CONCLUSIONS: Modulation of pancreatic optical property enables 3-D panoramic examination of islets in the young hyperphagic mice to reveal the formation of the islet-duct complex and neurovascular remodeling. On the basis of the morphological proximity of the remodeled tissue networks, we propose a reactive islet microenvironment consisting of the endocrine cells, ductal epithelium and neurovascular tissues in response to the metabolic challenge that is experienced early in life. PMID- 26499437 TI - Impaired atrial natriuretic peptide-mediated lipolysis in obesity. AB - BACKGROUND: Catecholamines and natriuretic peptides (NPs) are the only hormones with pronounced lipolytic effects in human white adipose tissue. Although catecholamine-induced lipolysis is well known to be impaired in obesity and insulin resistance, it is not known whether the effect of NPs is also altered. METHODS: Catecholamine- and atrial NP (ANP)-induced lipolysis was investigated in abdominal subcutaneous adipocytes in vitro and in situ by microdialysis. RESULTS: In a cohort of 122 women, both catecholamine- and ANP-induced lipolysis in vitro was markedly attenuated in obesity (n=87), but normalized after substantial body weight loss (n=52). The impairment of lipolysis differed between the two hormones when expressing lipolysis per lipid weight, the ratio of stimulated over basal (spontaneous) lipolysis rate or per number of adipocytes. Thus, while the response to catecholamines was lower when expressed as the former two measures, it was higher when expressed per cell number, a consequence of the significantly larger fat cell size in obesity. In contrast, although ANP-induced lipolysis was also attenuated when expressed per lipid weight or the ratio stimulated/basal, it was similar between non-obese and obese subjects when expressed per cell number suggesting that the lipolytic effect of ANP may be even more sensitive to the effects of obesity than catecholamines. Obesity was characterized by a decrease in the protein expression of the signaling NP A receptor (NPRA) and a trend toward increased levels of the clearance receptor NPRC. The impairment in ANP induced lipolysis observed in vitro was corroborated by microdialysis experiments in situ in a smaller cohort of lean and overweight men. CONCLUSIONS: ANP- and catecholamine-induced lipolysis is reversibly attenuated in obesity. The pro lipolytic effects of ANP are relatively more impaired compared with that of catecholamines, which may in part be due to specific changes in NP receptor expression. PMID- 26499439 TI - Inhibition of mitochondrial beta-oxidation by miR-107 promotes hepatic lipid accumulation and impairs glucose tolerance in vivo. AB - BACKGROUND: Hepatic expression of microRNA-107 is ubiquitously upregulated in various metabolic diseases. In our previous study, we had demonstrated that fatty acid synthase (FASN) is a target of miR-107. miR-107-FASN interaction, by inducing endoplasmic reticulum (ER) stress, promotes lipid accumulation in hepatocytes. Here, we explore the possible mechanism(s) of the miR-107-FASN-ER stress on hepatic lipid metabolism. METHODS: HepG2 cells were transfected with the scramble or miR-107 and/or its inhibitor. Transcript levels of lipid droplet membrane proteins, apolipoproteins and beta-oxidation genes were quantified by quantitative reverse transcription-PCR. Cells were treated with tunicamycin (Tm, 1 h) and 4-PBA (4-phenyl butyric acid, 8 h) or transfected with hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, apha subunit (HADHA) short interfering RNA or its overexpression vector. Mice were injected with the scramble or mmu-miR-107 (2.5 mg kg(-1) body weight) and random glucose levels were measured and oral glucose tolerance test was performed. Serum levels of cholesterol, triglyceride and serum glutamic oxaloacetic transaminase/serum glutamic-pyruvic transaminase (SGOT/SGPT) were evaluated. Hepatic tissues were collected to estimate levels of miR-107 and mitochondrial beta-oxidation genes. Six-micrometer-thick cryosections of hepatic tissues were prepared and stained with Oil Red O for lipid accumulation. RESULTS: miR-107 does not alter the expression of lipid metabolism-related transcription factors, lipid droplet components and apolipiprotein B. miR-107 significantly decreased the levels of the mitochondrial beta-oxidation enzyme, HADHA in HepG2 cells (P<0.01), which was prevented by the miR-107 inhibitor. Similar decrease was observed with Tm (P<0.001), suggesting that HADHA inhibition is promoted by ER stress induction. Interestingly, miR-107-mediated HADHA suppression was rescued by the ER stress inhibitor, 4-PBA (P<0.01). HADHA overexpression rescued miR-107-induced lipid accumulation (P<0.01). miR-107 injection in mice increased random blood glucose levels (P<0.05) and impaired glucose tolerance (P<0.05). Hepatic levels of Hadha were significantly decreased (P<0.001 and P<0.05) accompanied by increased lipid accumulation (P<0.001). CONCLUSIONS: miR-107 promotes hepatic lipid accumulation by suppressing transcript levels of HADHA, induces hyperglycemia and impairs glucose tolerance. We conclude that miR-107 regulation of fatty acid oxidation is an important contributor toward hepatic lipid accumulation. PMID- 26499440 TI - Lower core body temperature and greater body fat are components of a human thrifty phenotype. AB - BACKGROUND/OBJECTIVES: In small studies, a thrifty human phenotype, defined by a greater 24-hour energy expenditure (EE) decrease with fasting, is associated with less weight loss during caloric restriction. In rodents, models of diet-induced obesity often have a phenotype including a reduced EE and decreased core body temperature. We assessed whether a thrifty human phenotype associates with differences in core body temperature or body composition. SUBJECTS/METHODS: Data for this cross-sectional analysis were obtained from 77 individuals participating in one of two normal physiology studies while housed on our clinical research unit. Twenty-four-hour EE using a whole-room indirect calorimeter and 24-h core body temperature were measured during 24 h each of fasting and 200% overfeeding with a diet consisting of 50% carbohydrates, 20% protein and 30% fat. Body composition was measured by dual X-ray absorptiometry. To account for the effects of body size on EE, changes in EE were expressed as a percentage change from 24 hour EE (%EE) during energy balance. RESULTS: A greater %EE decrease with fasting correlated with a smaller %EE increase with overfeeding (r=0.27, P=0.02). The %EE decrease with fasting was associated with both fat mass and abdominal fat mass, even after accounting for covariates (beta=-0.16 (95% CI: -0.26, -0.06) %EE per kg fat mass, P=0.003; beta=-0.0004 (-0.0007, -0.00004) %EE kg(-1) abdominal fat mass, P=0.03). In men, a greater %EE decrease in response to fasting was associated with a lower 24- h core body temperature, even after adjusting for covariates (beta=1.43 (0.72, 2.15) %EE per 0.1 degrees C, P=0.0003). CONCLUSIONS: Thrifty individuals, as defined by a larger EE decrease with fasting, were more likely to have greater overall and abdominal adiposity as well as lower core body temperature consistent with a more efficient metabolism. PMID- 26499438 TI - Altered gut and adipose tissue hormones in overweight and obese individuals: cause or consequence? AB - The aim of this article is to review the research into the main peripheral appetite signals altered in human obesity, together with their modifications after body weight loss with diet and exercise and after bariatric surgery, which may be relevant to strategies for obesity treatment. Body weight homeostasis involves the gut-brain axis, a complex and highly coordinated system of peripheral appetite hormones and centrally mediated neuronal regulation. The list of peripheral anorexigenic and orexigenic physiological factors in both animals and humans is intimidating and expanding, but anorexigenic glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), peptide YY (PYY) and orexigenic ghrelin from the gastrointestinal tract, pancreatic polypeptide (PP) from the pancreas and anorexigenic leptin from adiposites remain the most widely studied hormones. Homeostatic control of food intake occurs in humans, although its relative importance for eating behaviour is uncertain, compared with social and environmental influences. There are perturbations in the gut-brain axis in obese compared with lean individuals, as well as in weight-reduced obese individuals. Fasting and postprandial levels of gut hormones change when obese individuals lose weight, either with surgical or with dietary and/or exercise interventions. Diet-induced weight loss results in long-term changes in appetite gut hormones, postulated to favour increased appetite and weight regain while exercise programmes modify responses in a direction expected to enhance satiety and permit weight loss and/or maintenance. Sustained weight loss achieved by bariatric surgery may in part be mediated via favourable changes to gut hormones. Future work will be necessary to fully elucidate the role of each element of the axis, and whether modifying these signals can reduce the risk of obesity. PMID- 26499441 TI - Breastfeeding during the first 6 months of life, adiposity rebound and overweight/obesity at 8 years of age. AB - BACKGROUND: The question of whether breastfeeding protects the child from obesity is a still debated issue; however, the relationship between early adiposity rebound and higher risk of obesity is well known. This study was aimed at evaluating whether breastfeeding (without formula supplement) during the first 6 months of life delays the time of adiposity rebound and consequently reduces the rates of obesity at the age of 8. METHODS: This retrospective cohort study included 1812 children born in Gran Canaria in 2004, with follow-up until they were 8 years of age. Anthropometrical data had been taken during routine visits to the doctor and were extracted from medical record databases. Only children with breastfeeding for the first 6 months of life (173 children) and children without breastfeeding (192 children) were included. Children with mixed feeding and children whose data were not available were excluded. RESULTS: No body mass index (BMI) differences were found between children with breastfeeding (17.7) or without breastfeeding (17.3) during the first 6 months of life. The percentages of children with normal weight, overweight and obesity were similar in both groups, as well as the age of adiposity rebound breastfeeding 3.61 years; formula 3.64 years). Early adiposity rebound was associated with increased BMI at the age of 8, both in male and female children. CONCLUSIONS: Breastfeeding during the first 6 months of life was not demonstrated to delay the age of the adiposity rebound, in our study. PMID- 26499442 TI - Prenatal notch1 receptor blockade by protein delta homolog 1 (DLK1) modulates adipocyte size in vivo. AB - INTRODUCTION/OBJECTIVES: The protein delta homolog 1 (DLK1) has been reported to have an important role as inhibitor of adipogenesis. Understanding its mode of action can be a promising approach to cope with the formation of obesity. However, data on DLK1 signaling are not consistent, and especially its role as negative regulator of Notch receptors is discussed controversially. METHODS: DLK1 effects have been investigated in differentiated 3T3-L1 cells by Adipokine Profiler Array, enzyme-linked immunosorbent assay and quantitative real-time PCR (qRT-PCR). In vivo effects of DLK1 on adipogenesis have been studied by the DLK1 treatment of pregnant C57BL/6NTac mice and the phenotypical characterization of the offspring fed on chow or high-fat diet (HFD). Furthermore, gene expression of key adipogenesis genes in adipose tissue (AT) samples was observed by qRT-PCR. RESULTS: In 3T3-L1 cells, DLK1 was found to be an inhibitor of Notch1 signaling. Gene expression of Notch1 and Hes1 was lowered by 53% and 65%, respectively, and the expression of protein target PAI-1 was decreased by 51%. The offspring of DLK1-treated pregnant mice were fed chow or HFD starting from week 4. At week 18, a larger proportion of visceral AT was determined on HFD after DLK1 treatment (P=0.011), whereas adipocyte size was reduced (P=0.007 for maximal size). This was affiliated to an upregulation of adipocyte differentiation. The underlying mechanism was found in an increased expression of the Notch1 receptor gene and protein in AT of the offsprings independently of the diet. However, feeding a chow diet resulted in a decreased expression of Notch1 target genes Hes1 and RBP Jkappa, whereas under HFD these genes were upregulated. CONCLUSIONS: Treatment of mice with recombinant human DLK1 during pregnancy has significant effects on AT of the offspring. This can be associated with counter-regulatory changes in the Notch1 signaling cascade. PMID- 26499443 TI - Surgical removal of inflamed epididymal white adipose tissue attenuates the development of non-alcoholic steatohepatitis in obesity. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is strongly associated with abdominal obesity. Growing evidence suggests that inflammation in specific depots of white adipose tissue (WAT) has a key role in NAFLD progression, but experimental evidence for a causal role of WAT is lacking. METHODS: A time-course study in C57BL/6J mice was performed to establish which WAT depot is most susceptible to develop inflammation during high-fat diet (HFD)-induced obesity. Crown-like structures (CLS) were quantified in epididymal (eWAT), mesenteric (mWAT) and inguinal/subcutaneous (iWAT) WAT. The contribution of inflamed WAT to NAFLD progression was investigated by surgical removal of a selected WAT depot and compared with sham surgery. Plasma markers were analyzed by enzyme-linked immunosorbent assay (cytokines/adipokines) and lipidomics (lipids). RESULTS: In eWAT, CLS were formed already after 12 weeks of HFD, which coincided with maximal adipocyte size and fat depot mass, and preceded establishment of non-alcoholic steatohepatitis (NASH). By contrast, the number of CLS were low in mWAT and iWAT. Removal of inflamed eWAT after 12 weeks (eWATx group), followed by another 12 weeks of HFD feeding, resulted in significantly reduced NASH in eWATx. Inflammatory cell aggregates (-40%; P<0.05) and inflammatory genes (e.g., TNFalpha, -37%; P<0.05) were attenuated in livers of eWATx mice, whereas steatosis was not affected. Concomitantly, plasma concentrations of circulating proinflammatory mediators, viz. leptin and specific saturated and monounsaturated fatty acids, were also reduced in the eWATx group. CONCLUSIONS: Intervention in NAFLD progression by removal of inflamed eWAT attenuates the development of NASH and reduces plasma levels of specific inflammatory mediators (cytokines and lipids). These data support the hypothesis that eWAT is causally involved in the pathogenesis of NASH. PMID- 26499444 TI - Less favorable body composition and adipokines in South Asians compared with other US ethnic groups: results from the MASALA and MESA studies. AB - BACKGROUND: Small studies have shown that South Asians (SAs) have more total body, subcutaneous, visceral and hepatic fat and abnormal adipokine levels compared with Whites. However, comprehensive studies of body composition and adipokines in SAs compared with other ethnic groups are lacking. METHODS: Using harmonized data, we performed a cross-sectional analysis of two community-based cohorts: Mediators of Atherosclerosis of South Asians Living in America (MASALA, n=906) and Multi-Ethnic Study of Atherosclerosis (MESA which included 2622 Whites, 803 Chinese Americans, 1893 African Americans and 1496 Latinos). General linear models were developed to assess the ethnic differences in ectopic fat (visceral, intermuscular and pericardial fat; and hepatic attenuation), lean muscle mass and adipokines (adiponectin and resistin). Models were adjusted for age, sex, site, alcohol use, smoking, exercise, education, household income and body mass index. Ectopic fat models were additionally adjusted for hypertension, diabetes, high-density lipoprotein and triglycerides. Adipokine models were adjusted for subcutaneous, visceral, intermuscular and pericardial fat; and hepatic attenuation. RESULTS: Compared with all ethnic groups in MESA (Whites, Chinese Americans, African Americans and Latinos), SAs had greater intermuscular fat (pairwise comparisons with each MESA group, P<0.01), lower hepatic attenuation (P<0.001) and less lean mass (P<0.001). SAs had greater visceral fat compared with Chinese Americans, African Americans and Latinos (P<0.05) and greater pericardial fat compared with African Americans (P<0.001). SAs had lower adiponectin levels compared with other ethnic groups (P<0.01; except Chinese Americans) and higher resistin levels than all groups (P<0.001), even after adjusting for differences in body composition. CONCLUSION: There are significant ethnic differences in ectopic fat, lean mass and adipokines. A less favorable body composition and adipokine profile in SAs may partially explain the increased predisposition to cardiometabolic disease. The mechanisms that underlie these differences warrant further investigation. PMID- 26499445 TI - GM3 ganglioside and phosphatidylethanolamine-containing lipids are adipose tissue markers of insulin resistance in obese women. AB - AIMS: The association between central obesity and insulin resistance reflects the properties of visceral adipose tissue. Our aim was to gain further insight into this association by analysing the lipid composition of subcutaneous and omental adipose tissue in obese women with and without insulin resistance. METHODS: Subcutaneous and omental adipose tissue and serum were obtained from 29 obese non diabetic women, 13 of whom were hyperinsulinemic. Histology, lipid and gene profiling were performed. RESULTS: In omental adipose tissue of obese, insulin resistant women, adipocyte hypertrophy and macrophage infiltration were accompanied by an increase in GM3 ganglioside and its synthesis enzyme ST3GAL5; in addition, phosphatidylethanolamine (PE) lipids were increased and their degradation enzyme, phosphatidylethanolamine methyl transferase (PEMT), decreased. ST3GAL5 was expressed predominantly in adipose stromovascular cells and PEMT in adipocytes. Insulin resistance was also associated with an increase in PE lipids in serum. INTERPRETATION: The relevance of these findings to insulin resistance in humans is supported by published mouse studies, in which adipocyte GM3 ganglioside, increased by the inflammatory cytokine tumour necrosis factor alpha, impaired insulin action and PEMT was required for adipocyte lipid storage. Thus in visceral adipose tissue of obese humans, an increase in GM3 ganglioside secondary to inflammation may contribute to insulin resistance and a decrease in PEMT may be a compensatory response to adipocyte hypertrophy. PMID- 26499446 TI - DNA methylation and gene expression patterns in adipose tissue differ significantly within young adult monozygotic BMI-discordant twin pairs. AB - BACKGROUND: Little is known about epigenetic alterations associated with subcutaneous adipose tissue (SAT) in obesity. Our aim was to study genome-wide DNA methylation and gene expression differences in SAT in monozygotic (MZ) twin pairs who are discordant for body mass index (BMI). This design completely matches lean and obese groups for genetic background, age, gender and shared environment. METHODS: 14We analyzed DNA methylome and gene expression from SAT, together with body composition (magnetic resonance imaging/spectroscopy) and glucose tolerance test, lipids and C-reactive protein from 26 rare BMI-discordant (intrapair difference in BMI ?3 kg m(-2)) MZ twin pairs identified from 10 birth cohorts of young adult Finnish twins. RESULTS: We found 17 novel obesity associated genes that were differentially methylated across the genome between heavy and lean co-twins. Nine of them were also differentially expressed. Pathway analyses indicated that dysregulation of SAT in obesity includes a paradoxical downregulation of lipo/adipogenesis and upregulation of inflammation and extracellular matrix remodeling. Furthermore, CpG sites whose methylation correlated with metabolically harmful fat depots (intra-abdominal and liver fat) also correlated with measures of insulin resistance, dyslipidemia and low-grade inflammation, thus suggesting that epigenetic alterations in SAT are associated with the development of unhealthy obesity. CONCLUSION: This is the first study in BMI-discordant MZ twin pairs reporting genome-wide DNA methylation and expression profiles in SAT. We found a number of novel genes and pathways whose methylation and expression patterns differ within the twin pairs, suggesting that the pathological adaptation of SAT to obesity is, at least in part, epigenetically regulated. PMID- 26499448 TI - Pentoxifylline as a modulator of anticancer drug doxorubicin. Part I: Reduction of doxorubicin DNA binding. AB - Pentoxifylline--biologically active aromatic compound--has a well established capability to sequester aromatic ligands, such as an anticancer drug--doxorubicin -in mixed stacking aggregates. Formation of such hetero-complexes may influence biological activity of secluded drug. Presented work shows assessment of pentoxifylline influence on doxorubicin direct interactions with DNA employing biophysical methods. Achievement of this goal required statistical thermodynamical model allowing numerical four-parameter analysis of experimental mixture--an issue that was successfully tackled by merging McGhee--von Hippel and Kapuscinski--Kimmel models. Results obtained with new model are well in agreement with data obtained with separate experiments with each of these two models and show reduction of doxorubicin in free (monomeric, dimeric) and complexed with DNA forms in favor of doxorubicin-pentoxifylline complexes with increasing pentoxifylline concentration. Developed model appears to be a universal tool allowing numerical analysis of mixtures containing self-aggregating ligand, DNA, and modulating agent. PMID- 26499447 TI - Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome. AB - OBJECTIVE: Dietary fructose is implicated in metabolic syndrome, but intervention studies are confounded by positive caloric balance, changes in adiposity, or artifactually high amounts. This study determined whether isocaloric substitution of starch for sugar would improve metabolic parameters in Latino (n = 27) and African-American (n = 16) children with obesity and metabolic syndrome. METHODS: Participants consumed a diet for 9 days to deliver comparable percentages of protein, fat, and carbohydrate as their self-reported diet; however, dietary sugar was reduced from 28% to 10% and substituted with starch. Participants recorded daily weights, with calories adjusted for weight maintenance. Participants underwent dual-energy X-ray absorptiometry and oral glucose tolerance testing on Days 0 and 10. Biochemical analyses were controlled for weight change by repeated measures ANCOVA. RESULTS: Reductions in diastolic blood pressure (-5 mmHg; P = 0.002), lactate (-0.3 mmol/L; P < 0.001), triglyceride, and LDL-cholesterol (-46% and -0.3 mmol/L; P < 0.001) were noted. Glucose tolerance and hyperinsulinemia improved (P < 0.001). Weight reduced by 0.9 +/- 0.2 kg (P < 0.001) and fat-free mass by 0.6 kg (P = 0.04). Post hoc sensitivity analysis demonstrates that results in the subcohort that did not lose weight (n = 10) were directionally consistent. CONCLUSIONS: Isocaloric fructose restriction improved surrogate metabolic parameters in children with obesity and metabolic syndrome irrespective of weight change. PMID- 26499449 TI - Detecting and Diagnosing Atrial Fibrillation (D2AF): study protocol for a cluster randomised controlled trial. AB - BACKGROUND: Atrial fibrillation is a common cause of stroke and other morbidity. Adequate treatment with anticoagulants reduces the risk of stroke by 60 %. Early detection and treatment of atrial fibrillation could prevent strokes. Atrial fibrillation is often asymptomatic and/or paroxysmal. Case-finding with pulse palpation is an effective screening method, but new methods for detecting atrial fibrillation have been developed. To detect paroxysmal atrial fibrillation ambulatory rhythm recording is needed. This study aims to determine the yield of case-finding for atrial fibrillation in primary care patients. In addition, it will determine the diagnostic accuracy of three different case-finding methods. METHODS/DESIGN: In a multicenter cluster randomised controlled trial, we compare an enhanced protocol for case-finding of atrial fibrillation with usual care. We recruit 96 practices. We include primary care patients aged 65 years or older not diagnosed with atrial fibrillation. Within each practice, a cluster of 200 patients is randomly selected and marked. Practices are evenly randomised to intervention or control group. The allocation is not blinded. When a marked patient visits an intervention practice, the case-finding protocol starts, consisting of: pulse palpation, sphygmomanometer with automated atrial fibrillation detection and handheld single-lead electrocardiogram (ECG). All patients with at least 1 positive test and a random sample of patients with negative tests receive a 12-lead ECG. Patients without atrial fibrillation on the 12-lead ECG, undergo additional continuous Holter and use the handheld single lead ECG at home for 2 weeks. Control practices provide care as usual. The study runs for 1 year in each cluster. The primary outcomes are the difference in detection rate of new AF between intervention and control practices and the accuracy of three index tests to diagnose AF. We are currently recruiting practices. The 'Detecting and Diagnosing Atrial Fibrillation' (D2AF) study will determine the yield of an intensive case-finding strategy and the diagnostic accuracy of three index tests to diagnose atrial fibrillation in a primary care setting. TRIAL REGISTRATION: Netherlands Trial Register: NTR4914 , registered on the 25 of November 2014. PMID- 26499450 TI - Use of ordinal information by fish. AB - Mammals and birds can process ordinal numerical information which can be used, for instance, for recognising an object on the basis of its position in a sequence of similar objects. Recent studies have shown that teleost fish possess numerical abilities comparable to those of other vertebrates, but it is unknown if they can also learn ordinal numerical relations. Guppies (Poecilia reticulata) learned to recognise the 3(rd) feeder in a row of 8 identical ones even when inter-feeder distance and feeder positions were varied among trials to prevent the use of any spatial information. To assess whether guppies spontaneously use ordinal or spatial information when both are simultaneously available, fish were then trained with constant feeder positions and inter-feeder distance. In probe trials where these two sources of information were contrasted, the subjects selected the correct ordinal position significantly more often than the original spatial position, indicating that the former was preferentially encoded during training. Finally, a comparison between subjects trained on the 3(rd) and the 5(th) position revealed that guppies can also learn the latter discrimination, but the larger error rate observed in this case suggests that 5 is close to the upper limit of discrimination in guppies. PMID- 26499451 TI - Cerebral venous thrombosis: comparing characteristics of infective and non infective aetiologies: a 12-year retrospective study. AB - BACKGROUND: Most cases of cerebral venous thrombosis (CVT) have non-infective causes. Infective CVT, though less common, often results in a catastrophic outcome. The distinctive clinical characteristics of infection-associated CVT (IACVT) and non-infection-associated CVT (NIACVT) would facilitate early detection and proper management. OBJECTIVE: To compare the characteristics of IACVT and NIACVT. METHODS: All patients with CVT admitted to Songklanagarind Hospital between January 2002 and December 2013 with the ICD10 codes I636, I676, O225 and G08 were identified and recruited. We compared the clinical presentations, neuroimaging results and hospital outcomes for patients with IACVT and those with NIACVT. We analysed the differences using descriptive statistics. Additionally, for patients with IACVT, we described the primary sites of infection, associated CVT, host immune status and microbiological results. RESULTS: Twenty of the 83 patients with CVT (24.1%) had IACVT. Male gender (70.0% vs 34.9%) and pre-existing diabetes mellitus (35.0% vs 4.8%) were significantly more prevalent in the IACVT than the NIACVT group. Additionally, cavernous sinus thrombosis predominated in IACVT (80.0% vs 11.1%), whereas focal neurological syndrome was more common among patients with NIACVT (50.8% vs 15.0%). Paracranial infections, mostly sinusitis and orbital cellulitis, were common primary infections (80.0%) among patients with IACVT. Lastly, fungus was a devastating causative pathogen in IACVT-five of six patients with fungal infection had intracranial complications. CONCLUSIONS: Cavernous sinus thrombosis is a distinctive clinical presentation of IACVT, whereas focal neurological syndrome is a hallmark feature of NIACVT. Paracranial fungal infections are highly virulent and frequently associated with intracranial complications. PMID- 26499452 TI - Quantification of confocal fluorescence microscopy for the detection of cervical intraepithelial neoplasia. AB - BACKGROUND: Cervical cancer remains a major health problem, especially in developing countries. Colposcopic examination is used to detect high-grade lesions in patients with a history of abnormal pap smears. New technologies are needed to improve the sensitivity and specificity of this technique. We propose to test the potential of fluorescence confocal microscopy to identify high-grade lesions. METHODS: We examined the quantification of ex vivo confocal fluorescence microscopy to differentiate among normal cervical tissue, low-grade Cervical Intraepithelial Neoplasia (CIN), and high-grade CIN. We sought to (1) quantify nuclear morphology and tissue architecture features by analyzing images of cervical biopsies; and (2) determine the accuracy of high-grade CIN detection via confocal microscopy relative to the accuracy of detection by colposcopic impression. Forty-six biopsies obtained from colposcopically normal and abnormal cervical sites were evaluated. Confocal images were acquired at different depths from the epithelial surface and histological images were analyzed using in-house software. RESULTS: The features calculated from the confocal images compared well with those features obtained from the histological images and histopathological reviews of the specimens (obtained by a gynecologic pathologist). The correlations between two of these features (the nuclear-cytoplasmic ratio and the average of three nearest Delaunay-neighbors distance) and the grade of dysplasia were higher than that of colposcopic impression. The sensitivity of detecting high-grade dysplasia by analysing images collected at the surface of the epithelium, and at 15 and 30 MUm below the epithelial surface were respectively 100, 100, and 92 %. CONCLUSIONS: Quantitative analysis of confocal fluorescence images showed its capacity for discriminating high-grade CIN lesions vs. low grade CIN lesions and normal tissues, at different depth of imaging. This approach could be used to help clinicians identify high-grade CIN in clinical settings. PMID- 26499453 TI - Management of the knees in arthrogryposis. AB - Arthrogryposis is defined as limited range of motion in three or more joints in two or more body parts. This article will describe treatment options for the arthrogrypotic knee. In all types of arthrogryposis, and in both extension and flexion deformities, very early treatment is favorable. Just after birth, traction and mobilization followed by serial casting could often greatly improve the range of motion. In the hyperextended knee, surgical lengthening of the extensor apparatus may be needed. Flexion deformities could be improved with temporary physeal arrest of the anterior distal femur by fixing two-hole plates over the physis on both sides of patella. The plates will result in a constrained growth of the anterior physis, and thus a very slow extension of the knee, which will give the nerves and vessels time to adjust. Pterygium, webbing of the knee joint, is a special subgroup that in selected mild cases could be treated with extensive surgical release of the webbing and orthotics. Arthrogrypotic knees can be treated with early reduction and maintenance with orthotics. PMID- 26499454 TI - Is percutaneous proximal gracilis tenotomy as effective and safe as the open procedure? AB - PURPOSE: There is currently an increasing trend for percutaneous surgical interventions mainly in children with cerebral palsy (CP). The purpose of this study was to evaluate the effectiveness and safety of percutaneous proximal gracilis tenotomy (PPGT) in children with CP scheduled for hip adductor tenotomy. METHODS: This is a prospective study of 59 hips in 31 consecutive patients with CP scheduled for hip adductor tenotomy in the setting of multilevel tenotomies or hip osteotomy (femoral or Dega). A pediatric orthopedic surgeon conducted a percutaneous adductor longus and gracilis tenotomy through the same stab wound. Another surgeon extended the wound to explore what had been cut during the PPGT, and completed the tenotomy if necessary (open proximal gracilis tenotomy; OPGT). Hip abduction with the hip and knee extended (HA) was assessed by a third surgeon (1) immediately before PPGT, i.e., directly after percutaneous adductor longus tenotomy (prePPGT), (2) after PPGT (postPPGT), and (3) following OPGT (postOPGT), using a goniometer, in a standardized reproducible manner. All three surgeons were blinded to each other's findings. Primary end-points included the percentage of muscle portion sectioned percutaneously and the improvement of HA angle. Comparison between HA before and after PPGT was performed using a paired t test with 95 % confidence interval (CI), and comparison between HA after PPGT and OPGT was performed using a Student's t-test with 95 % CI. The bleeding was assessed and other iatrogenic lesions were identified. The relationship between HA after PPGT and the percentage of muscle portion sectioned percutaneously was evaluated by calculating the Pearson correlation coefficient (p < 0.01). RESULTS: Mean HA measured 33.71 degrees prePPGT and increased to 45.90 degrees postPPGT (p < 0.0001). The postOPGT HA averaged 48.71 degrees with no statistically significant gain compared with postPPGT (p = 0.21). The muscular portion of gracilis origin was cut to an average of 91.95 %; completely in only 14 hips, between 90 and 100 % in 35 hips, between 70 and 90 % in 9 hips, and between 60 and 70 % in 1 hip. The gain in HA did not correlate with the extent of the muscular portion sectioned percutaneously (R = -0.043). Minimal accidental section of adductor brevis postPPGT was encountered in 39 hips. Considerable bleeding postPPGT with hematoma formation requiring hemostasis during the open control procedure occurred in 30 hips. Partial iatrogenic injury of the anterior branch of the obturator nerve was encountered in one patient bilaterally with severe adductor contracture, due to an anatomic too medial variant. CONCLUSIONS: This is the only prospective study concerning the outcome of PPGT. Although PPGT is fast, simple and effective, it is not as safe as the open procedure even when performed correctly by an experienced surgeon, mainly because of the increased risk of bleeding. The findings of the current study do not support its use as a 'standard of-care' technique in children with hip adductor contracture. LEVEL OF EVIDENCE: Level II therapeutic study-prospective comparative study. PMID- 26499455 TI - Long-term outcome for patients with arthrogryposis multiplex congenita. AB - PURPOSE: To access the long-term outcomes for patients with arthrogryposis multiplex congenita at adult age. MATERIALS AND METHODS: The cases were traced for most of them thanks to direct contact maintained from child hood, from colleagues interested from other parts of the country, and from the list from Alliance arthrogryposis association (parents and patients). The methods used were: mostly direct clinical examination, some phone calls or email. All answered a questionnaire for general life and mainly for function. One of these questions was: what is the function you missed most during your life? RESULTS: 65 patients( 41 females and 24 males) were reviewed at adult age from 22 to 65 years. For the personal life: 38 are married and had 34 children with only 4 having arthrogryposis. Only 27 (15 F/12 M) were living alone. Self-sufficiency was observed in 35, partial in 20, total dependence in 10 people. 38 reached university level, 20 had secondary school level, 10 had primary school level. Ambulation was made possible with wheelchair: permanent for 18, partial for 9 ambulating at home only, 8 ambulating outside with crutches and 29 were free walkers. 36 patients out of 65 were driving a car sometimes modified with special equipment. The involvement of spine was seen in 26 patients requiring surgical treatment sometimes complex combining anterior and posterior approach in 14 cases. Surgery of the lower limbs (hips, knee, feet) was very often repeated, with almost always stability, pain free and function. The most important finding was that 52 patients had more or less severe involvement of the upper limbs which was considered by the majority of the patients to be the most disabling, more than the absence of walking! CONCLUSION: Finally, it appeared that for the care of these patients, priority goes to the upper limbs function, because majority of these patients have a high level of intelligence. A remarkable fact is that many of these patients had to spend a lot of time during infancy and childhood in rehabilitation centers with education adapted for schools and teachers. Finally, they are grateful for that, telling often that it would have been much more difficult if not impossible to have such a treatment and education at home. PMID- 26499456 TI - Does physical therapy prevent post-operative delay in return of function following tension-band plating? AB - PURPOSE: The clinical outcomes and complications of tension-band plating have been well documented, and commonly include a post-operative delay in return of function. We performed a retrospective comparison study to evaluate the capacity of immediate post-operative physical therapy to prevent this post-operative delay in return of function. METHODS: Sixty-seven consecutive growth-deformity patients who were treated with tension-band plating at a single institution fulfilled the study criteria. Patients were allocated into two treatment groups: no post operative physical therapy and immediately post-operative physical therapy. All patients were evaluated for delayed return of function, which was defined as use of crutches, lack of >90 degrees flexion and full extension of the knee, or persistent pain requiring medication at the initial 2-week follow-up visit. Rates of delayed function were compared between the two treatment groups. RESULTS: Among the study participants, 48 patients had no physical therapy and 19 patients had immediate post-operative physical therapy. Eighteen patients in the no physical therapy group reported a delay (37.5 %) while only 2 patients in the physical therapy treatment group reported a delay (10.5 %); p = 0.0386. CONCLUSIONS: Delayed return of function dramatically affects pediatric patients, causing unnecessary absence from school and strain on the caregiver. Therefore, it is important to identify treatment modalities to help mitigate the complications of surgery. We conclude that the use of immediate post-operative physical therapy statistically significantly helps patients to return more rapidly to their functional level. PMID- 26499457 TI - Erratum to: Cytotoxic effects of 4-octylphenol on fish hepatocytes. PMID- 26499458 TI - When children play, they feel better: organized activity participation and health in adolescents. AB - BACKGROUND: Participation in organized leisure-time activities (OLTA) has been linked to healthy youth development. This study aimed to assess whether participation in OLTA is associated with both physical and mental health in adolescents, and whether this association differs by pattern of activity participation, age and gender. METHODS: The present study was based on data from the 2013/2014 Health Behaviour in School-aged Children study in the Czech Republic. This data concerned 10,503 adolescents (49.2 % boys) aged 11, 13 and 15. A cluster analysis was carried out to obtain patterns of activity participation and yielded five groups (all-rounders, artists, individual sports, team sports and inactive). The association between participation in types of OLTA and physical and mental health was analysed using logistic regression models adjusted for age and gender. We also assessed interactions between types of OLTA and gender and age. RESULTS: Participation in OLTA was associated with better self-rated health and higher life satisfaction regardless of gender or age. Participation in team or individual sports was associated with better general health and less frequent health complaints in boys, while participation in art activities was associated with lower occurrence of health complaints in girls and 11-year-olds. CONCLUSION: Participation in OLTA is associated with better physical and mental health in adolescents. The association varies by pattern of activity participation and is partly gender- and age-specific. PMID- 26499459 TI - Self-perceived memory loss is associated with an increased risk of hip fracture in the elderly: a population-based NOREPOS cohort study. AB - BACKGROUND: An early detection of memory loss may hold great value as a predictor for dementia. Dementia has already been associated with higher risk of hip fracture. Our aim was to examine the prospective association between self reported memory-loss and the risk of subsequent hip fracture in the elderly. METHODS: A population-based prospective cohort study design was used. Information on four self-perceived memory loss questions was obtained from questionnaires in 3 health surveys performed in Norway during the years 2000-2001. A total of 7154 men and 2462 women aged 67-77 years old were followed for a median of 7.8 years. Hip fracture information (n = 287 in men, and n = 237 in women) was obtained from NORHip (a database including all hip fractures treated in Norway from year 1994). Cox survival analysis was performed to estimate HR (hazard ratio). RESULTS: The risk of sustaining a hip fracture were higher in those who reported to forget things they had just heard or read, with a HR of 1.52 (1.19--1.95) in men and HR 1.60 (1.23--2.07) in women after adjustment for relevant confounders. Women reporting to forget where they had put things also had higher risk of later hip fracture with a HR of 1.58 (1.20--2.07). Answering yes in both questions showed stronger association with sustaining a first hip fracture compared with those who gave a negative response in both questions, with a multivariate adjusted HR of 1.41 (IC 95 % 1.06--1.88) in men and 1.90 (IC 95 % 1.39--2.60) in women. The two last questions did not show a significant association with hip fracture. CONCLUSIONS: There was a higher risk of hip fracture in elderly who reported self perceived memory loss. Due to the serious implications of sustaining a hip fracture, early detection of risk groups is important for preventive interventions. PMID- 26499460 TI - Self-reported tattoo reactions in a cohort of 448 French tattooists. AB - BACKGROUND: Self-reported complaints in people having tattoos, including swelling, itch, and photosensitivity, are frequent. Tattooists are usually heavily tattooed with multiple extended colored tattoos and constitute a specific population of interest. OBJECTIVES: To assess the prevalence of cutaneous complications on tattoos among a cohort of French tattooists. METHODS: An observational self-reported internet survey was performed among the tattooists of the French Tattoo Union in November 2013 to report on complaints about their tattoos. RESULTS: Of the 448 respondents, 42.6% reported a "tattoo reaction" on a least one of their previous tattoos: transient itch (45.7%), wax-and-waning swelling (57%), and swelling after sun exposure (23%). A tattoo "allergy" on one color of the tattoo was found in 8%. Permanent itch, swelling, and cutaneous infection were rare. No skin cancer on tattoos was reported. The binary regression analysis revealed that the area of the tattooed body surface was the main driver of the risk of developing a tattoo reaction, mainly transient or permanent swelling triggered by sun exposure or not. The tattoo reaction, transient itch, and swelling on tattoos seemed to be associated with the sun protection habits of the tattooed individuals. CONCLUSION: Professional tattooists have a high prevalence of minor complaints (transient itch and swelling) and photosensitivity on their tattoos such as in the general tattooed population. PMID- 26499461 TI - Short Communication: CXCL12 rs1029153 Polymorphism Is Associated with the Sustained Virological Response in HIV/Hepatitis C Virus-Coinfected Patients on Hepatitis C Virus Therapy. AB - The immune response against HIV and hepatitis C virus (HCV) infection partly depends on chemokine-mediated recruitment of specific T cells. CXCL12 polymorphisms have been associated with AIDS progression and survival, but there are no data related to HCV infection. The aim of this study was to determine whether CXCL12 polymorphisms are related so as to achieve sustained virological response (SVR) after HCV therapy with pegylated-interferon-alpha/ribavirin (pegIFN-alpha/ribavirin) in HIV/HCV-coinfected patients. We carried out a retrospective study in 319 naive patients who started HCV treatment. The CXCL12 (rs266093, rs1029153, and rs1801157) and IL28B (rs12980275) polymorphisms were genotyped by using the GoldenGate assay. Genetic data were analyzed under an additive inheritance model. The overall rates of the SVR were 54.9% (175/319) and 41.5% (90/217) in GT1/4 patients and 83.2% (84/101) in GT2/3 patients. Patients with a favorable CXCL12 rs1029153 T allele had higher SVR rates than patients with the rs1029153 CC genotype (44% CC, 49% CT, and 61.3% TT; p = 0.025). No significant results for the rs266093 and rs1801157 polymorphisms were found. Patients harboring the favorable rs1029153 T allele had significantly increased odds of achieving SVR [adjusted odds ratio (aOR) = 1.55; 95% confidence interval (95% CI) = 1.01; 2.40; p = 0.047]. Moreover, no significant association was found when the study population was stratified by HCV genotype (data not shown), possibly due to the low number of patients in each group. In conclusion, in this study we found that the favorable CXCL12 rs1029153 T allele seems to be related so as to achieve an SVR in HIV/HCV-coinfected patients on pegIFN-alpha/ribavirin therapy. PMID- 26499462 TI - Understanding the experiences and needs of individuals with Spinal Muscular Atrophy and their parents: a qualitative study. AB - BACKGROUND: The clinical features of SMA, which range along a spectrum of severity, are relatively well described. In contrast, the literature on how individuals with SMA and their families experience this condition is limited. To address this gap, we undertook a qualitative study with individuals affected by SMA Types I, II and III, parents of those affected, and clinicians. METHODS: We completed 16 focus group sessions and 37 interviews in the US with 96 participants including: 21 with individuals with SMA; 64 parents of individuals affected by SMA; and 11 clinicians who specialize in the care of SMA patients. RESULTS: The Diagnostic Journey: Families reported substantial diagnostic delays owing to: 1) lack of awareness and knowledge about SMA; 2) the difficulty of distinguishing normal from abnormal development; and 3) the challenge of differential diagnosis. Lack of sensitivity in how clinicians communicated this potentially devastating diagnosis compounded parents' negative impressions. Newborn Screening: Parents generally held positive views about adding SMA to newborn screening panels. For example, it would: 1) enable earlier access to care; 2) shorten the diagnostic journey; and 3) give families more time to prepare to care for a disabled child. Some noted negative outcomes such as prematurely affecting a parent's relationship with a child before symptoms are evident. The Psychosocial Impact of Living with SMA: Ten thematic areas characterized the impact: 1) confronting premature death; 2) making difficult treatment choices; 3) fearing the loss of functional ability; 4) coming to terms with lost expectations; 5) loss of sleep and stress; 6) stigma; 7) limitations on social activities; 8) independence; 9) uncertainty and helplessness; and 10) family finances. CONCLUSIONS: The results of this study suggest high levels of burden experienced by individuals with SMA and their families. The difficulties of living with SMA begin with the long and often arduous process of finding a diagnosis for their child. Newborn screening for SMA is seen as an important step toward shortening this journey. The psychosocial effects of coping with SMA are substantial and wide ranging both for the individual living with this condition and family members of affected individuals. PMID- 26499463 TI - Putative stem cell markers in cervical squamous cell carcinoma are correlated with poor clinical outcome. AB - BACKGROUND: The aim of this study was to elucidate the value of putative cancer stem cell markers Musashi-1, ALDH1, Sox2, and CD49f in predicting the prognosis in cervical squamous cell carcinoma (CSCC). METHODS: Real-time PCR and immunohistochemistry staining was performed to examine Musashi-1, ALDH1, Sox2, and CD49f expression in archived specimens of CSCC patients with postoperative chemotherapy. Kaplan-Meier analysis and Cox proportional hazards model were used to assess the prognostic impact of CSC markers for overall survival (OS) and recurrent-free survival (RFS). RESULTS: The Real-time PCR data showed that the expression of all markers were increased in CSCC tissues compared with in paired normal cervical tissues (P < 0.05). The IHC result showed that high expression of Msi1, ALDH1, Sox2, and CD49f was found in 25.7%, 43.0%, 62.0% and 29.0% CSCC samples, respectively. Moreover, high expression of Msi1 (P = 0.033 and P = 0.003, respectively), ALDH1 (P = 0.015 and P = 0.002, respectively), and Sox2 (P = 0.005 and P = 0.003, respectively), and low expression of CD49f (P = 0.027 and P = 0.025, respectively) were correlated with poor OS and PFS in CSCC patients. Interestingly, tumors with Msi1(high)/CD49f(low) expression had the poorest prognosis according to Msi1/CD49f stratification. In multivariate Cox regression analysis, Sox2 expression (P = 0.047 and P = 0.018, respectively), ALDH1 expression (P = 0.013 and P = 0.003, respectively), and CD49f expression (P = 0.008 and P = 0.003, respectively) were independent prognostic markers for both OS and RFS. CONCLUSIONS: Our results suggest that cancer stem cell markers are linked with poor prognosis of CSCC patients. PMID- 26499464 TI - Construction of a novel twin-arginine translocation (Tat)-dependent type expression vector for secretory production of heterologous proteins in Corynebacterium glutamicum. AB - Corynebacterium glutamicum is recognized as a favorable host for the secretory production of heterologous proteins. However, there are few secretion-type expression vectors available for protein production in C. glutamicum. In this study, we constructed a shuttle expression vector pAU3, which harbors the strong promoter tac-M for constitutive gene transcription, the consensus RBS sequence for protein translation, and the strong cgR_0949 signal sequence for protein secretion via the Tat pathway in C. glutamicum. The applicability of pAU3 was confirmed by the highly efficient expression and secretion of the CAT protein in C. glutamicum. The vector pAU3 is highly useful for secretory production of heterologous proteins in C. glutamicum. PMID- 26499465 TI - Growth responses of breast and leg muscles to essential amino acids in broiler chicks. AB - The first three essential amino acids (EAA) for broilers including methionine (Met), lysine (Lys) and threonine (Thr) may greatly influence the growth of chick muscles at early stages of life. In order to survey the potential effects of those EAA on growth muscles, a rotatable three-variable central composite design (CCD) was conducted to track the interrelationships of dietary digestible Met (dMet), Lys (dLys) and Thr (dThr) for optimization of processing yields in broiler chicks using response surface methodology. A total of 60 floor pens of six birds each were assigned to 15 dietary treatments based on CCD containing five levels of dMet (0.416% to 0.584% of diet), dLys (0.881% to 1.319% of diet) and dThr (0.532% to 0.868% of diet) from 3 to 16 days of age. Experimental treatments significantly affected breast mass (BM) and leg mass (LM) of the birds (P<0.05) in which the main effect of dLys on BM was threefold higher than the main effect of dThr, and interaction effect between dMet and dLys was observed on BM (P<0.05). However, in the case of LM, the main effect of dThr was higher than the main effects of dMet and dLys and highest interaction effect exist between dThr and dMet (P<0.05). The second-order models for BM and LM were fitted by least squares regression. Canonical analysis revealed that the stationary points for carcass components were saddle points, thus ridge analysis was performed for getting optimal values of each EAA. Ridge analyses of BM and LM models showed that the maximum BM point may be obtained with 0.58%, 1.05% and 0.76% of dMet, dLys and dThr, respectively, in diet, and maximum LM point may be achieved with 0.58%, 1.09% and 0.70% of dMet, dLys and dThr, respectively, in diet. The resultant ideal ratios of dMet and dThr to dLys were 55% and 72% for BM; 53% and 64% for LM. Moreover, sensitivity analysis showed that the most important amino acids in BM and LM models were Lys and Thr, respectively. In conclusion, providing these three amino acid for BM optimization may warrant LM optimization and higher ideal ratios of dMet and dThr for breast muscle may indicate the higher importance of these EAA in this muscle than those in thigh muscle. PMID- 26499466 TI - Case of photosensitivity caused by fenofibrate after photosensitization to ketoprofen. PMID- 26499467 TI - Anti-inflammatory and anti-arthritic effects of pentacyclic triterpenoids maslinic acid through NF-kappaB inactivation. AB - SCOPE: Consumption of olives (Olea europaea L.), including table olives and oil, is associated with low incidence of inflammation-related diseases. In this study, the effects of maslinic acid (MA), the main constituent of olive pomace, on the expression of genes and proteins involved in inflammatory activity in RAW 264.7 cells were investigated. Furthermore, the effect of MA on carrageenan-induced paw edema and collagen antibody induced arthritis in mice was determined. METHODS AND RESULTS: We confirmed the suppressive effects of MA on LPS-induced tumor necrosis factor alpha production and on the expression of inflammatory response associated genes in RAW 264.7 cells. We also clarified the suppressive effect of MA on LPS induced nuclear factor-kappa B activation as well as the phosphorylation of IkappaB-alpha. Furthermore, MA (200 mg/kg in the edema model or 100 mg/kg in the arthritis model) exerted anti-inflammatory and antiarthritis effects as shown by the suppression of paw edema, arthritis score, inflammatory cells, and destruction of synovium in knee joints. CONCLUSION: Olive products containing MA are useful as a new preventive and therapeutic food ingredient for inflammatory and arthritic diseases. PMID- 26499468 TI - Editorial. PMID- 26499469 TI - Cultural competence dimensions and outcomes: a systematic review of the literature. AB - It has been widely suggested that cultural competence is an individual's core requirement for working effectively with culturally diverse people. However, there is no consensus regarding the definition or the components of this concept and there is a dearth of empirical proof indicating the benefits of cultural competence. Therefore, a systematic review was conducted to identify the most common cultural competence dimensions proposed in recent publications and to identify whether sufficient evidence exists regarding the efficacy of cultural competence in the healthcare context. A total of 1204 citations were identified through an electronic search of databases, of which 18 publications included cultural competence frameworks, and 13 studies contained empirical data on cultural competence outcomes. The overarching themes of the review were centred around the challenges faced by the healthcare sector in many countries due to growing cultural diversity, but lack of cultural competence, leading to predicaments that arise during intercultural interactions between patients and clinicians. This review will benefit researchers exploring cultural competence as one of the research variables impacting research outcomes. PMID- 26499470 TI - Intrathymic and other anomalous courses of the left brachiocephalic vein in the fetus. AB - OBJECTIVE: The left brachiocephalic vein (LBCV), or innominate vein, connects the left jugular vein to the right superior vena cava. Its course is posterior to the thymus and directly anterior and superior to the aortic arch. Pediatric and adult cardiology studies have reported on the subaortic or retrotracheal courses of the LBCV and the presence of double LBCV. We observed recently in the fetus that the LBCV may have a course through the thymus (intrathymic) or be absent in the presence of a left superior vena cava. The aim of this study was to report the prevalence of isolated intrathymic and absent LBCV in normal fetuses undergoing second-trimester ultrasound screening, as well as the prevalence of other courses in association with cardiac anomalies. METHODS: In the prospective part of this study, consecutive second-trimester ultrasound examinations were evaluated to assess the presence and course of the fetal LBCV. In the retrospective case control part of this study, the databases of two fetal medicine centers were reviewed for cardiac anomalies and the pattern and prevalence of anomalous courses of the LBCV were reported. RESULTS: One thousand four hundred and eighteen consecutive fetuses were examined prospectively. An intrathymic course of the LBCV with a typical bent shape was found in 1.76% (1 : 57) of cases and the absence of a LBCV in association with a persistent left superior vena cava (LSVC) was found in 0.28% (1 : 350). All fetuses with an isolated intrathymic course or absence of the LBCV had a normal outcome. Over a period of 4.5 years, a total of 1544 fetuses with cardiac malformations were reviewed at two centers. Among these, an anomalous course of the LBCV was noted in eight (0.5%) cases: six subaortic, one retrotracheal and one double LBCV. CONCLUSION: An intrathymic LBCV is a common condition and appears to be a normal variant in the fetus. The prevalence of a LSVC in our screening population was similar to that reported in previous studies. Anomalous courses of the LBCV are seen occasionally in cases with cardiac malformation. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26499471 TI - Association between apical periodontitis lesions and plasmatic levels of C reactive protein, interleukin 6 and fibrinogen in hypertensive patients. AB - AIM: To test the null hypothesis of association between chronic apical periodontitis (CAP) and plasmatic levels of the C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen in a population of severely hypertensive patients. METHODOLOGY: One hundred and seventy patients with severe refractory hypertension were selected. All patients were submitted to radiographic, clinical and periodontal evaluation. Plasmatic levels of CRP, IL-6 and fibrinogen were measured on the morning of the first periodontal appointment using commercially available kits. Multiple linear regression analyses were carried out to appraise the effect of the co-variables on the plasmatic levels of the inflammatory markers assessed. RESULTS: Of the 170 subjects who participated, 105 (61.8%) were females and the median age of the participants was 53 years (range: 40-78). The adjusted multiple linear analyses demonstrated that plasmatic levels of CRP levels were associated with the body mass index (BMI) (r = 0.259, P < 0.001) and residual tooth roots (RTR) (r = 0.191, P = 0.041). IL-6 and fibrinogen levels showed associated with BMI (r = 0.400, P < 0.001 and r = 0.214, P = 0.002 respectively). CAP correlated weakly with CRP (r = 0.250, P = 0.005), IL-6 (r = 0.174, P = 0.020) and fibrinogen (r = 0.393, P < 0.001) levels. CONCLUSION: The null hypothesis was rejected in favour of the alternative hypothesis. In other words, the presence of chronic apical periodontitis was associated with higher plasmatic levels of CRP, IL-6 and fibrinogen, in a population of severely hypertensive patients. However, the weak association between CAP and each dependent variable suggests a modest participation of endodontic infection on the plasmatic levels of biomarkers. PMID- 26499472 TI - A case of familial central precocious puberty caused by a novel mutation in the makorin RING finger protein 3 gene. AB - BACKGROUND: Central precocious puberty (CPP) is often familial but its genetic cause is largely unknown. Very recently, the makorin RING finger protein 3 (MKRN3) gene, located on chromosome 15 in the Prader-Willi syndrome (PWS) associated region (15q11-q13), has been found mutated in 5 families with familial precocious puberty. The MKRN3 is a maternal imprinted gene and the phenotype is expressed only when the MKRN3 mutations are localized on the allele inherited from the father. The function of this gene is not completely known and the phenotype caused by its defect is not yet fully elucidated. We report a new MKRN3 mutation (Pro160Cysfs*14) causing familial CPP. CASE PRESENTATION: The index case is a 7 years old girl showing Tanner stage 3 and pubic hair stage 1. Her bone age evaluated by TW2 method was 10.3 years. Her hormonal data confirmed the diagnosis of central precocious puberty. Familial medical history revealed precocious puberty in a cousin on paternal side. Paternal grandmother had menarche at the age of 9 years and 6 months and premature menopause when she was 36 years old. Genetic analysis revealed a new mutation (c477_485del; Pro160Cysfs*14) in the maternally imprinted MKRN3. Puberty onset was at 5 years in the other affected female family member. Precocious puberty was well controlled by pharmacological therapy. CONCLUSION: We expand the number of the MKRN3 mutations associated with CPP and highlight the importance of an accurate family medical history to disclose the peculiar pattern of inheritance of this gene. PMID- 26499473 TI - Prostate motion during radiotherapy of prostate cancer patients with and without application of a hydrogel spacer: a comparative study. AB - BACKGROUND AND PURPOSE: The use of a tissue expander (hydrogel) for sparing of the rectum from increased irradiation during prostate radiotherapy is becoming popular. The goal of this study is to investigate the effect of a tissue expander (hydrogel) on the intrafraction prostate motion during radiotherapy. METHODS AND MATERIAL: Real time prostate motion was analysed for 26 patients and 742 fractions; 12 patients with and 14 patients without hydrogel (SpaceOARTM). The intra-fraction motion was quantified and compared between the two groups. RESULTS: The average (+/-standard deviation) of the mean motion during the treatment for patients with and without hydrogel was 1.5 (+/-0.8 mm) and 1.1 (+/ 0.9 mm) respectively (p < 0.05). The average time of motion >3 mm for patients with and without hydrogel was 7.7 % (+/-1.1 %) and 4.5 % (+/-0.9 %) respectively (p > 0.05). The hydrogel age, fraction number and treatment time were found to have no effect (R (2) < 0.05) on the prostate motion. CONCLUSIONS: Differences in intrafraction motion in patients with hydrogel and without hydrogel were within measurement uncertainty (<1 mm). This result confirms that the addition of a spacer does not negate the need for intrafraction motion management if clinically indicated. PMID- 26499474 TI - Morphology of sealant/enamel interface after surface treatment with bioactive glass. AB - The purpose of this study was to analyze, by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM), the morphology of sealant/enamel interface after surface treatment with Biosilicate. Before pits and fissures sealing, the occlusal surfaces of 10 sound human molars were sectioned perpendicularly at the fissures in order to obtain three slices for each tooth. Slices were randomly assigned into three groups (n = 10) according to sealing protocol: Group 1- Acid etching + Biosilicate + glass ionomer-based sealant (Clinpro XT Varnish, 3M ESPE); Group 2- Acid etching + glass ionomer-based sealant (Clinpro XT Varnish, 3M ESPE); Group 3- No sealing. All slices were subjected to thermal cycling (5,000 cycles; 5-55 degrees C; dwell time: 30s). Half of the slices from each group (n = 5) were analyzed by CLSM and the other half by SEM. Groups 1 and 2 were also submitted to EDS analysis and their data were evaluated by Two-Way ANOVA e Tukey's test (alpha=5%). EDS data analysis showed higher amounts of silicon (Si) ions than calcium (Ca) ions in Group 1 (P < 0.05); Group 2 presented higher amounts (P < 0.05) of Ca ions than Si ions. It may be concluded that the use of Biosilicate for surface treatment did not affect the morphology of glass ionomer-based sealant/enamel interfaces. PMID- 26499475 TI - Effects of fentanyl on serotonin syndrome-like behaviors in rats. AB - Emerging evidence from case reports suggests that fentanyl may precipitate potentially life-threatening serotonin syndrome in patients taking serotonergic drugs. However, the underlying mechanism of the association between serotonin syndrome and fentanyl remains under investigation. We therefore investigated the pharmacological effects of an analgesic dose of fentanyl (0.2 mg/kg) injected subcutaneously (s.c.) on serotonergic toxicity-like responses in rats. Rats were s.c. injected with 0.75 mg/kg 8-OH-DPAT, a full 5-HT1A agonist, as an animal model of serotonin syndrome. The 8-OH-DPAT-treated rats showed well-characterized serotonin syndrome-like behaviors (low body posture, forepaw treading), hyperlocomotion, and decreased body temperature. Rats injected s.c. with fentanyl alone showed no significant changes in any of the parameters measured, while concomitant administration of fentanyl + 8-OH-DPAT resulted in exaggerated 8-OH DPAT-induced serototoxic responses. A separate dose-response experiment showed that the serototoxic effect of fentanyl was dose-dependent. Pretreatment with naloxone [2.0 mg/kg, intraperitoneal (i.p.) injection], an opioid receptor antagonist, failed to antagonize the fentanyl-induced exaggerated serotonin syndrome-like behaviors. In contrast, pretreatment with WAY-100653, a serotonin 5 HT1A receptor antagonist (0.5 mg/kg, i.p. injection) completely inhibited all responses. Our findings provide preclinical proof-of-concept that an analgesic dose of fentanyl enhances serotonin toxicity, likely via its serotonin-reuptake inhibitory activity, independently of interaction with the opioid receptors. PMID- 26499476 TI - Redundancy in Glucose Sensing: Enhanced Accuracy and Reliability of an Electrochemical Redundant Sensor for Continuous Glucose Monitoring. AB - BACKGROUND: Current electrochemical glucose sensors use a single electrode. Multiple electrodes (redundancy) may enhance sensor performance. We evaluated an electrochemical redundant sensor (ERS) incorporating two working electrodes (WE1 and WE2) onto a single subcutaneous insertion platform with a processing algorithm providing a single real-time continuous glucose measure. METHODS: Twenty-three adults with type 1 diabetes each wore two ERSs concurrently for 168 hours. Post-insertion a frequent sampling test (FST) was performed with ERS benchmarked against a glucose meter (Bayer Contour Link). Day 4 and 7 FSTs were performed with a standard meal and venous blood collected for reference glucose measurements (YSI and meter). Between visits, ERS was worn with capillary blood glucose testing >=8 times/day. Sensor glucose data were processed prospectively. RESULTS: Mean absolute relative deviation (MARD) for ERS day 1-7 (3,297 paired points with glucose meter) was (mean [SD]) 10.1 [11.5]% versus 11.4 [11.9]% for WE1 and 12.0 [11.9]% for WE2; P < .0001. ERS Clarke A and A+B were 90.2% and 99.8%, respectively. ERS day 4 plus day 7 MARD (1,237 pairs with YSI) was 9.4 [9.5]% versus 9.6 [9.7]% for WE1 and 9.9 [9.7]% for WE2; P = ns. ERS day 1-7 precision absolute relative deviation (PARD) was 9.9 [3.6]% versus 11.5 [6.2]% for WE1 and 10.1 [4.4]% for WE2; P = ns. ERS sensor display time was 97.8 [6.0]% versus 91.0 [22.3]% for WE1 and 94.1 [14.3]% for WE2; P < .05. CONCLUSIONS: Electrochemical redundancy enhances glucose sensor accuracy and display time compared with each individual sensing element alone. ERS performance compares favorably with 'best-in-class' of non-redundant sensors. PMID- 26499477 TI - Organizational characteristics, outcomes, and resource use in 78 Brazilian intensive care units: the ORCHESTRA study. AB - PURPOSE: Detailed information on organization and process of care in intensive care units (ICU) in emerging countries is scarce. Here, we investigated the impact of organizational factors on the outcomes and resource use in a large sample of Brazilian ICUs. METHODS: Retrospective cohort study of 59,693 patients (medical admissions, 67 %) admitted to 78 ICUs during 2013. We retrieved patients' data from an ICU quality registry and surveyed ICUs regarding structure, organization, staffing patterns, and process of care. We used multilevel logistic regression analysis to identify factors associated with hospital mortality. Efficient resource use was assessed by estimating standardized resource use and mortality rates adjusted for the SAPS 3 score. RESULTS: ICUs were mostly medical-surgical (79 %) and located at private hospitals (86 %). Median nurse to bed ratio was 0.20 (IQR, 0.15-0.28) and board certified intensivists were present 24/7 in 16 (21 %) of ICUs. Multidisciplinary rounds occurred in 67 (86 %) and daily checklists were used in 36 (46 %) ICUs. Most frequent protocols focused on sepsis management and prevention of healthcare associated infections. Hospital mortality was 14.4 %. In multivariable analysis, the number of protocols was the only organizational characteristic associated with mortality [odds ratio = 0.944 (95 % CI 0.904-0.987)]. The effects of protocols were consistent across subgroups including surgical and medical patients as well as the SAPS 3 tertiles. We also observed a significant trend toward efficient resource use as the number of protocols increased. CONCLUSIONS: In emerging countries such as Brazil, organizational factors, including the implementation of protocols, are potential targets to improve patient outcomes and resource use in ICUs. PMID- 26499478 TI - Understanding lung protection. PMID- 26499479 TI - Protocols: help for improvement but beware of regression to the mean and mediocrity. PMID- 26499480 TI - The road forward in the management of Acinetobacter infections in the ICU. PMID- 26499481 TI - Does high-pressure, high-frequency oscillation shake the foundations of lung protection? PMID- 26499482 TI - The case for stronger regulation of private practitioners to control tuberculosis in low- and middle-income countries. AB - Tuberculosis case management practices of private practitioners in low- and middle-income countries are commonly not in compliance with treatment guidelines, thus increasing the risk of drug resistance. National Tuberculosis control programs have long been encouraged to collaborate with private providers to improve compliance, but there is no example yet of a sustained, large scale collaborations with private practitioners in these settings. Regulations have long been realized as a potential response to poor quality care, however there has been a lack of interest from the international actors to invest in stronger regulation of private providers in these countries due to limited evidence and many implementation challenges. Regulatory strategies have now evolved beyond the costly conventional form of command and control. These new strategies need to be tested for addressing the challenge of poor quality care among private providers. Multilateral and bilateral funding agencies committed to tuberculosis control need to invest in facilitating strengthening government's capacity to effectively regulate private providers. PMID- 26499483 TI - Whole transcriptome analysis of Penicillium digitatum strains treatmented with prochloraz reveals their drug-resistant mechanisms. AB - BACKGROUND: Penicillium digitatum is one of the most destructive postharvest pathogen of citrus fruits, causing fruit decay and economic loss. The emergence of fungicide-resistant strains made the control of P. digitatum more difficult. While the genome of P. digitatum is available, there has been few reports about its resistant mechanism from the transcriptome perspective and there has been no large-scale functional annotation of the genome using expressed genes derived from transcriptomes. METHODS: Total RNA of P. digitatum strain HS-F6 (prochloraz resistant strain) and HS-E3 (prochloraz-susceptible strain) before and after prochloraz-treatment were extracted and sequenced on an Illumina Hiseq 2000 platform. The transcriptome data of four samples were compared and analyzed using differential expression analysis, novel transcripts prediction and alternative splicing analysis, SNP analysis and quantitative real-time PCR. RESULTS: We present a large scale analysis about the transcriptome data of P. digitatum. The whole RNA was extracted from a prochloraz-resistant strain (HS-F6) and a prochloraz-susceptible strain (HS-E3) before and after prochloraz-treatment and sequenced by Illumina technology. A total of more than 100 million reads were generated and de novo assembled into 9760 transcripts that contained annotated genes after quality control and sequence assembling. 6625 single nucleotide variations (SNVs) were identified from the sequences aligned against the reference genome. Gene expression profiling analysis was performed upon prochloraz treatment in HS-F6 and HS-E3, and differential expression analysis was used to identify genes related to prochloraz-response and drug-resistance: there are 224 differentially expressed genes in HS-E3 and 1100 differentially expressed genes in HS-F6 after prochloraz-treatment. Moreover, gene expression profile in prochloraz-resistant strain HS-F6 is quite different from that in HS-E3 before prochloraz-treatment, 1520 differential expression genes were identified between the two strains. Gene ontology (GO) term enrichment and KEGG enrichment were then performed to classify the differential expression genes. Among these genes, there are a lot of transporter encoding genes including 14 MFS (Major Facilitator Superfamily) transporters, 8 ABC (ATP-binding cassette transporter) and 3 MATE (multidrug and toxic compound extrusion family) transporters. Meanwhile, the roles of typical MFS, ABC and MATE proteins in prochloraz resistance were investigated using real-time quantitative PCR. CONCLUSIONS: The sequencing-based transcriptome data of P. digitatum demonstrate differences between prochloraz resistant and prochloraz-susceptible strains with prochloraz-treatment. The differences existed in expressed transcripts, splice isoforms and GO categories, which would contribute to our knowledge on the molecular mechanisms involved in drug resistance of P. digitatum. PMID- 26499484 TI - The microbiome of Folsomia candida: an assessment of bacterial diversity in a Wolbachia-containing animal. AB - The springtail Folsomia candida is an important model organism for soil ecology, ecotoxicology and ecogenomics. The decomposer activities of soil invertebrates like Folsomia depend on their relationship with microbial communities including gut symbionts. In this paper, we apply high-throughput sequencing to provide a detailed characterization of the bacterial community associated with parthenogenetic F. candida. First, we evaluated a method to suppress the amplification of DNA from the endosymbiont Wolbachia, to prevent it from interfering with the identification of less abundant operational taxonomic units (OTUs). The suppression treatment applied was effective against Wolbachia and did not interfere with the detection of the most abundant OTUs (59 OTUs, contributing over 87% of the reads). However, this method did affect the inferred community composition. Significant differences were subsequently observed in the composition of bacterial communities associated with two different strains of F. candida. A total of 832 OTUs were found, of which 45% were only present in one strain and 17% only in the other. Among the 20 most abundant OTUs, 16 were shared between strains. Denaturing gradient gel electrophoresis and clone libraries, although unable to capture the full diversity of the bacterial community, provided results that supported the NGS data. PMID- 26499485 TI - 16S rRNA assessment of the influence of shading on early-successional biofilms in experimental streams. AB - Elevated nutrient levels can lead to excessive biofilm growth, but reducing nutrient pollution is often challenging. There is therefore interest in developing control measures for biofilm growth in nutrient-rich rivers that could act as complement to direct reductions in nutrient load. Shading of rivers is one option that can mitigate blooms, but few studies have experimentally examined the differences in biofilm communities grown under shaded and unshaded conditions. We investigated the assembly and diversity of biofilm communities using in situ mesocosms within the River Thames (UK). Biofilm composition was surveyed by 454 sequencing of 16S amplicons (~400 bp length covering regions V6/V7). The results confirm the importance of sunlight for biofilm community assembly; a resource that was utilized by a relatively small number of dominant taxa, leading to significantly less diversity than in shaded communities. These differences between unshaded and shaded treatments were either because of differences in resource utilization or loss of diatom-structures as habitats for bacteria. We observed more co-occurrence patterns and network interactions in the shaded communities. This lends further support to the proposal that increased river shading can help mitigate the effects from macronutrient pollution in rivers. PMID- 26499486 TI - Confocal Raman microspectroscopy reveals a convergence of the chemical composition in methanogenic archaea from a Siberian permafrost-affected soil. AB - Methanogenic archaea are widespread anaerobic microorganisms responsible for the production of biogenic methane. Several new species of psychrotolerant methanogenic archaea were recently isolated from a permafrost-affected soil in the Lena Delta (Siberia, Russia), showing an exceptional resistance against desiccation, osmotic stress, low temperatures, starvation, UV and ionizing radiation when compared to methanogens from non-permafrost environments. To gain a deeper insight into the differences observed in their resistance, we described the chemical composition of methanogenic strains from permafrost and non permafrost environments using confocal Raman microspectroscopy (CRM). CRM is a powerful tool for microbial identification and provides fingerprint-like information about the chemical composition of the cells. Our results show that the chemical composition of methanogens from permafrost-affected soils presents a high homology and is remarkably different from strains inhabiting non-permafrost environments. In addition, we performed a phylogenetic reconstruction of the studied strains based on the functional gene mcrA to prove the different evolutionary relationship of the permafrost strains. We conclude that the permafrost methanogenic strains show a convergent chemical composition regardless of their genotype. This fact is likely to be the consequence of a complex adaptive process to the Siberian permafrost environment and might be the reason underlying their resistant nature. PMID- 26499487 TI - Developing expressed sequence tag libraries and the discovery of simple sequence repeat markers for two species of raspberry (Rubus L.). AB - BACKGROUND: Due to a relatively high level of codominant inheritance and transferability within and among taxonomic groups, simple sequence repeat (SSR) markers are important elements in comparative mapping and delineation of genomic regions associated with traits of economic importance. Expressed sequence tags (ESTs) are a source of SSRs that can be used to develop markers to facilitate plant breeding and for more basic research across genera and higher plant orders. METHODS: Leaf and meristem tissue from 'Heritage' red raspberry (Rubus idaeus) and 'Bristol' black raspberry (R. occidentalis) were utilized for RNA extraction. After conversion to cDNA and library construction, ESTs were sequenced, quality verified, assembled and scanned for SSRs. Primers flanking the SSRs were designed and a subset tested for amplification, polymorphism and transferability across species. ESTs containing SSRs were functionally annotated using the GenBank non-redundant (nr) database and further classified using the gene ontology database. RESULTS: To accelerate development of EST-SSRs in the genus Rubus (Rosaceae), 1149 and 2358 cDNA sequences were generated from red raspberry and black raspberry, respectively. The cDNA sequences were screened using rigorous filtering criteria which resulted in the identification of 121 and 257 SSR loci for red and black raspberry, respectively. Primers were designed from the surrounding sequences resulting in 131 and 288 primer pairs, respectively, as some sequences contained more than one SSR locus. Sequence analysis revealed that the SSR-containing genes span a diversity of functions and share more sequence identity with strawberry genes than with other Rosaceous species. CONCLUSION: This resource of Rubus-specific, gene-derived markers will facilitate the construction of linkage maps composed of transferable markers for studying and manipulating important traits in this economically important genus. PMID- 26499489 TI - Three genetic groups of the Eucalyptus stem canker pathogen Teratosphaeria zuluensis introduced into Africa from an unknown source. AB - The Eucalyptus stem canker pathogen Teratosphaeria zuluensis was discovered in South Africa in 1988 and it has subsequently been found in several other African countries as well as globally. In this study, the population structure, genetic diversity and evolutionary history of T. z uluensis were analysed using microsatellite markers to gain an enhanced understanding of its movement in Africa. Isolates were collected from several sites in Malawi, Mozambique, Uganda and Zambia. Data obtained were compared with those previously published for a South African population. The data obtained from 334 isolates, amplified across eight microsatellite loci, were used for assignment, differentiation and genetic diversity tests. STRUCTURE analyses, theta st and genetic distances revealed the existence of two clusters, one dominated by isolates from South Africa and the other by isolates from the Zambezi basin including Malawi, Mozambique and Zambia. High levels of admixture were found within and among populations, dominated by the Mulanje population in Malawi. Moderate to low genetic diversity of the populations supports the previously held view that the pathogen was introduced into Africa. The clonal nature of the Ugandan population suggests a very recent introduction, most likely from southern Africa. PMID- 26499488 TI - Puquitinib mesylate (XC-302) induces autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in nasopharyngeal cancer cells. AB - There are numerous studies that demonstrate the anti-neoplastic activity of phosphatidylinositol 3-kinase (PI3K) inhibitors and the mechanisms of inducing autophagy in cancer cells. The new anticancer drug puquitinib mesylate (XC-302) is a molecular-targeted drug, which suppresses the activity of PI3K directly. However, it remains unclear whether XC-302 can develop an antitumor effect by inducing autophagy in nasopharyngeal cancer cells. The MTT assay was used to study the anti-proliferative effects of XC-302. Subsequently, autophagy was determined by monodansylcadaverine (MDC) staining, punctate localization of green fluorescent protein (GFP)-light chain 3 (LC3), LC3 protein blotting and electron microscopy. The expression levels of beclin 1, p62, protein kinase B (AKT), phospho (p)-AKT, mechanistic target of rapamycin (mTOR) and p-mTOR in XC-302 induced autophagy were detected. Autophagy inhibition was assayed by 3 methyladenine (3-MA) or small interfering RNA (siRNA) silencing of beclin 1. XC 302 inhibited the viability of CNE-2 in a dose-dependent manner and the IC50 of 72 h was 5.2 umol/l. After cells were exposed to XC-302 for 24 h, MDC-labeled autophagolysosomes were evident in CNE-2 cells by fluorescence microscope. Autophagosomes and autolysosomes were identified by transmission electron microscopy. Following transfection with GFP-LC3, XC-302 induced a significant accumulation of GFP-LC3, as monitored by a confocal microscope, which was reduced by 3-MA. XC-302 induced the formation of LC3-II, increased beclin 1 levels and decreased the expression of p62. Additionally, the expression levels of p-AKT and p-mTOR were reduced with the elevation of XC-302. Knockdown of beclin 1 with siRNA or co-treatment with 3-MA enhanced significantly the survival of CNE-2 and promoted the ability of clone formation. XC-302 also induced apoptosis in CNE-2, and when autophagy was inhibited by 3-MA, the apoptosis rate was decreased. The present data provides the evidence that XC-302 can induce autophagy in CNE-2, which promotes the program of cell death and inhibits the PI3K/AKT/mTOR signaling pathway. Furthermore, XC-302 also promoted apoptosis in CNE-2 cells, which could be reduced when autophagy was suppressed, meaning that autophagy may interact with apoptosis to induce cell death. PMID- 26499490 TI - Molecular mechanism of anti-cancer activity of phycocyanin in triple-negative breast cancer cells. AB - BACKGROUND: Triple-negative breast cancers represent an important clinical challenge, as these cancers do not respond to conventional endocrine therapies or other available targeted agents. Phycocyanin (PC), a natural, water soluble and non-toxic molecule is shown to have potent anti-cancer property. METHODS: In this study, we determined the efficacy of PC as an anti-neoplastic agent in vitro on a series of breast cancer cell lines. We studied effects of PC in inducing DNA damage and apoptosis through western blot and qPCR. Also, anti-metastatic and anti-angiogenic properties were studied by classic wound healing and vasculogenic mimicry assays. RESULTS: We found that triple negative MDA-MB-231 cells were most sensitive to PC (IC50 : 5.98 +/- 0.95 MUM) as compared to other cells. They also showed decreased cell proliferation and reduced colony formation ability upon treatment with PC. Profile of Cell cycle analysis showed that PC caused G1 arrest which could be attributed to decreased mRNA levels of Cyclin E and CDK-2 and increased p21 levels. Mechanistic studies revealed that PC induced apoptosis as evident by increase in percentage of annexin positive cells, increase in gamma H2AX levels, and by changing the Bcl-2/Bax ratio followed by release of cytochrome C and increased Caspase 9 levels. MDA MB 231 cells treated with PC resulted in decreased cell migration and increased cell adhesive property and also showed anti-angiogenic effects. We also observed that PC suppressed cyclooxygenase-2 (COX-2) expression and prostaglandin E(2) production. All these biological effects of phycocyanin on MDA MB 231 cells could be attributed to decreased MAPK signaling pathway. We also observed that PC is non-toxic to non malignant cells, platelets and RBC's. CONCLUSION: Taken together, these findings demonstrate, for the first time, that PC may be a promising anti-neoplastic agent for treatment of triple negative breast cancers. PMID- 26499491 TI - Brain mechanisms of sympathetic activation in heart failure: Roles of the renin angiotensin system, nitric oxide and pro-inflammatory cytokines (Review). AB - Patients with chronic heart failure (CHF) have an insufficient perfusion to the peripheral tissues due to decreased cardiac output. The compensatory mechanisms are triggered even prior to the occurrence of clinical symptoms, which include activation of the sympathetic nervous system (SNS) and other neurohumoral factors. However, the long-term activation of the SNS contributes to progressive cardiac dysfunction and has toxic effects on the cardiomyocytes. The mechanisms leading to the activation of SNS include changes in peripheral baroreceptor and chemoreceptor reflexes and the abnormal regulation of sympathetic nerve activity (SNA) in the central nervous system (CNS). Recent studies have focused on the role of brain mechanisms in the regulation of SNA and the progression of CHF. The renin-angiotensin system, nitric oxide and pro-inflammatory cytokines were shown to be involved in the abnormal regulation of SNA in the CNS. The alteration of these neurohumoral factors during CHF influences the activity of neurons in the autonomic regions and finally increase the sympathetic outflow. The present review summarizes the brain mechanisms contributing to sympathoexcitation in CHF. PMID- 26499492 TI - cryo-EM structures of the E. coli replicative DNA polymerase reveal its dynamic interactions with the DNA sliding clamp, exonuclease and tau. AB - The replicative DNA polymerase PolIIIalpha from Escherichia coli is a uniquely fast and processive enzyme. For its activity it relies on the DNA sliding clamp beta, the proofreading exonuclease epsilon and the C-terminal domain of the clamp loader subunit tau. Due to the dynamic nature of the four-protein complex it has long been refractory to structural characterization. Here we present the 8 A resolution cryo-electron microscopy structures of DNA-bound and DNA-free states of the PolIII-clamp-exonuclease-tauc complex. The structures show how the polymerase is tethered to the DNA through multiple contacts with the clamp and exonuclease. A novel contact between the polymerase and clamp is made in the DNA bound state, facilitated by a large movement of the polymerase tail domain and tauc. These structures provide crucial insights into the organization of the catalytic core of the replisome and form an important step towards determining the structure of the complete holoenzyme. PMID- 26499493 TI - Circularization restores signal recognition particle RNA functionality in Thermoproteus. AB - Signal recognition particles (SRPs) are universal ribonucleoprotein complexes found in all three domains of life that direct the cellular traffic and secretion of proteins. These complexes consist of SRP proteins and a single, highly structured SRP RNA. Canonical SRP RNA genes have not been identified for some Thermoproteus species even though they contain SRP19 and SRP54 proteins. Here, we show that genome rearrangement events in Thermoproteus tenax created a permuted SRP RNA gene. The 5'- and 3'-termini of this SRP RNA are located close to a functionally important loop present in all known SRP RNAs. RNA-Seq analyses revealed that these termini are ligated together to generate circular SRP RNA molecules that can bind to SRP19 and SRP54. The circularization site is processed by the tRNA splicing endonuclease. This moonlighting activity of the tRNA splicing machinery permits the permutation of the SRP RNA and creates highly stable and functional circular RNA molecules. PMID- 26499494 TI - Nonlinear circuits for naturalistic visual motion estimation. AB - Many animals use visual signals to estimate motion. Canonical models suppose that animals estimate motion by cross-correlating pairs of spatiotemporally separated visual signals, but recent experiments indicate that humans and flies perceive motion from higher-order correlations that signify motion in natural environments. Here we show how biologically plausible processing motifs in neural circuits could be tuned to extract this information. We emphasize how known aspects of Drosophila's visual circuitry could embody this tuning and predict fly behavior. We find that segregating motion signals into ON/OFF channels can enhance estimation accuracy by accounting for natural light/dark asymmetries. Furthermore, a diversity of inputs to motion detecting neurons can provide access to more complex higher-order correlations. Collectively, these results illustrate how non-canonical computations improve motion estimation with naturalistic inputs. This argues that the complexity of the fly's motion computations, implemented in its elaborate circuits, represents a valuable feature of its visual motion estimator. PMID- 26499495 TI - Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. AB - Current therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets by selective targeting of the molecular networks that support sarcoma cell proliferation. Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and disruption of Cdkn2a. ASNS silencing in mouse and human sarcoma cell lines reduced the percentage of S phase cells and impeded new polypeptide synthesis. These effects of ASNS silencing were reversed by exogenous supplementation with asparagine. Also, asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo. Asparagine reliance of sarcoma cells may represent a metabolic vulnerability with potential anti-sarcoma therapeutic value. PMID- 26499496 TI - Pharmacophore modeling, 3D-QSAR, and docking study of pyrozolo[1,5-a]pyridine/4,4 dimethylpyrazolone analogues as PDE4 selective inhibitors. AB - Phosphodiesterases 4 enzyme is an attractive target for the design of anti inflammatory and bronchodilator agents. In the present study pharmacophore and atom based 3D-QSAR studies were carried out for pyrozolo[1,5-a]pyridine/4,4 dimethylpyrazolone analogues. A five point pharmacophore model was developed using 52 molecules having pIC50 values ranging from 9.959 to 3.939. The best predictive pharmacophoric hypothesis AHHRR.3 was characterized by survival score (2.944), cross validated (r(2) = 0.8147), regression coefficient (R(2) = 0.9545) and Fisher ratio (F =173) with 4 component PLS factor. Results explained that one hydrogen bond acceptor, two aromatic rings and two hydrophobic groups are crucial for the PDE4 inhibition. The docking studies of all selected inhibitors in the active site of PDE4 showed crucial hydrogen bond interactions with Asp392, Asn395 Tyr233, and Gln443 residues. The pharmacophoric features R15 and R16 exhibited pi pi stacking with His234, Phe414, and Phe446 residues. The generated model was further validated by carrying out the decoy test. The binding free energies of these inhibitors in the catalytic domain of 1XMU were calculated by the molecular mechanics/generalized Born surface area VSGB 2.0 method. The results of molecular dynamics simulation confirmed the extra precision docking-predicted priority for binding sites, the accuracy of docking, and the reliability of active conformations. Pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues in this study showed lower binding affinity toward PDE3A in comparison to PDE4. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity. Graphical Abstract Pyrozolo[1,5-a]pyridines/4,4 dimethylpyrazolones. PMID- 26499497 TI - Optimization of enrofloxacin-imprinted polymers by computer-aided design. AB - Recently, a series of computational and combinatorial approaches were employed to improve the efficiency of screening for optimal molecularly imprinted polymer (MIP) systems. In the present work, we investigated MIP systems based on enrofloxacin (ENRO) as the template molecule and either 2-vinyl-4,6-diamino-1,3,5 triazine (VDAT), 4-vinylpyridine (4-Vpy), acrylamide (AM), or trifluoromethacrylic acid (TFMAA) as the functional monomer. The optimized geometries of these systems, the optimal molar ratios of template to functional monomer, and the active sites in the systems were all identified using density functional theory (DFT) at the B3LYP/6-31G(d,p) level of theory. The imprinting mechanism was investigated by calculating the hydrogen nuclear magnetic resonance ((1)H NMR) spectra of the systems. The simulated results revealed that the MIP system corresponding to a 1:7 complex of TFMAA and ENRO contained the most H bonds and presented the lowest (i.e., most negative) binding energy and the strongest interactions. MIPs of ENRO with the four functional monomers were prepared based on the optimal molar ratios of template to functional monomer determined in the simulations. Adsorption experiments suggested that TFMAA has the highest affinity (saturated adsorption 30.25 mg/g) among the four monomers for the template. Thus, we determined the optimal monomer and imprinting ratio for ENRO-imprinted MIPs and predicted their adsorption characteristics. Graphical Abstract The preparation and extraction processes of MIPs with ENRO as template, TFMAA as functional monomer, and EDMA as cross-linker. PMID- 26499498 TI - Unraveling the performance of dispersion-corrected functionals for the accurate description of weakly bound natural polyphenols. AB - Long-range non-covalent interactions play a key role in the chemistry of natural polyphenols. We have previously proposed a description of supramolecular polyphenol complexes by the B3P86 density functional coupled with some corrections for dispersion. We couple here the B3P86 functional with the D3 correction for dispersion, assessing systematically the accuracy of the new B3P86 D3 model using for that the well-known S66, HB23, NCCE31, and S12L datasets for non-covalent interactions. Furthermore, the association energies of these complexes were carefully compared to those obtained by other dispersion-corrected functionals, such as B(3)LYP-D3, BP86-D3 or B3P86-NL. Finally, this set of models were also applied to a database composed of seven non-covalent polyphenol complexes of the most interest. Graphical abstract Weakly bound natural polyphenols?. PMID- 26499499 TI - Molecular modeling studies demonstrate key mutations that could affect the ligand recognition by influenza AH1N1 neuraminidase. AB - The goal of this study was to identify neuraminidase (NA) residue mutants from human influenza AH1N1 using sequences from 1918 to 2012. Multiple alignment studies of complete NA sequences (5732) were performed. Subsequently, the crystallographic structure of the 1918 influenza (PDB ID: 3BEQ-A) was used as a wild-type structure and three-dimensional (3-D) template for homology modeling of the mutated selected NA sequences. The 3-D mutated NAs were refined using molecular dynamics (MD) simulations (50 ns). The refined 3-D models were used to perform docking studies using oseltamivir. Multiple sequence alignment studies showed seven representative mutations (A232V, K262R, V263I, T264V, S367L, S369N, and S369K). MD simulations applied to 3-D NAs showed that each NA had different active-site shapes according to structural surface visualization and docking results. Moreover, Cartesian principal component analyses (cPCA) show structural differences among these NA structures caused by mutations. These theoretical results suggest that the selected mutations that are located outside of the active site of NA could affect oseltamivir recognition and could be associated with resistance to oseltamivir. PMID- 26499500 TI - Integrated physiologic assessment of ischemic heart disease in real-world practice using index of microcirculatory resistance and fractional flow reserve: insights from the International Index of Microcirculatory Resistance Registry. AB - BACKGROUND: The index of microcirculatory resistance (IMR) is a quantitative and specific index for coronary microcirculation. However, the distribution and determinants of IMR have not been fully investigated in patients with ischemic heart disease (IHD). METHODS AND RESULTS: Consecutive patients who underwent elective measurement of both fractional flow reserve (FFR) and IMR were enrolled from 8 centers in 5 countries. Patients with acute myocardial infarction were excluded. To adjust for the influence of collateral flow, IMR values were corrected with Yong's formula (IMRcorr). High IMR was defined as greater than the 75th percentile in each of the major coronary arteries. FFR<=0.80 was defined as an ischemic value. 1096 patients with 1452 coronary arteries were analyzed (mean age 61.1, male 71.2%). Mean FFR was 0.84 and median IMRcorr was 16.6 U (Q1, Q3 12.4 U, 23.0 U). There was no correlation between IMRcorr and FFR values (r=0.01, P=0.62), and the categorical agreement of FFR and IMRcorr was low (kappa value= 0.04, P=0.10). There was no correlation between IMRcorr and angiographic % diameter stenosis (r=-0.03, P=0.25). Determinants of high IMR were previous myocardial infarction (odds ratio [OR] 2.16, 95% confidence interval [CI] 1.24 3.74, P=0.01), right coronary artery (OR 2.09, 95% CI 1.54-2.84, P<0.01), female (OR 1.67, 95% CI 1.18-2.38, P<0.01), and obesity (OR 1.80, 95% CI 1.31-2.49, P<0.01). Determinants of FFR <=0.80 were left anterior descending coronary artery (OR 4.31, 95% CI 2.92-6.36, P<0.01), angiographic diameter stenosis >=50% (OR 5.16, 95% CI 3.66-7.28, P<0.01), male (OR 2.15, 95% CI 1.38-3.35, P<0.01), and age (per 10 years, OR 1.21, 95% CI 1.01-1.46, P=0.04). CONCLUSIONS: IMR showed no correlation with FFR and angiographic lesion severity, and the predictors of high IMR value were different from those for ischemic FFR value. Therefore, integration of IMR into FFR measurement may provide additional insights regarding the relative contribution of macro- and microvascular disease in patients with ischemic heart disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02186093. PMID- 26499501 TI - A comprehensive intervention for adverse drug reactions identification and reporting in a Pediatric Emergency Department. AB - BACKGROUND: Physicians identify from 45.7 to 96.2 % of Adverse Drug Reactions (ADRs) in their patients, with under-reporting ranging from 6 to 100 %. In order to improve ADR reporting, several interventions have been evaluated in different studies, but not with regard to ADR identification. In addition, it is not known whether some patient characteristics might influence on ADR identification and reporting by physicians. OBJECTIVES: (a) To assess the effectiveness of a comprehensive intervention directed to Emergency Department physicians and coordinated by a pharmacist in a tertiary care pediatric hospital on ADR identification and reporting. (b) To assess if some of the children's characteristics might influence on ADR identification and reporting. Setting The Emergency Department of the Hospital Infantil de Mexico "Federico Gomez", which is a national pediatric institute of health in Mexico. METHODS: A Quasi experimental, pre-post test trial was designed. During the intervention, the pharmacist gave talks on Pharmacovigilance and on the program for electronic capture of data, took part in patient visits, left reminders, improved accessibility to ADR report format and performed feedback activities. To classify and quantify correctly identified ADRs and ADRs reported to the Institutional Pharmacovigilance Center (IPC), 1136 clinical records were reviewed. The models were adjusted for patient variables. MAIN OUTCOME MEASURES: Total ADRs, ADRs correctly identified by physicians, ADRs reported to the IPC by physicians. Results Before the intervention, 97 % of ADRs were correctly identified and 6.1 % reported by physicians. During the intervention, 99.6 % were correctly identified and 41.2 % were reported, and after the intervention, 99.6 and 41.7 %, respectively. Identification during the intervention showed a sevenfold increase with regard to preintervention and was maintained post-intervention. ADR reporting during the intervention showed a 14-fold increase with regard to pre intervention and was maintained during post-intervention. CONCLUSION: Physicians do identify ADRs, but fail to report them. The intervention increased ADR correct identification and reporting. The effect was maintained after the intervention. PMID- 26499502 TI - The structural and process aspects of pharmacy quality: older adults' perceptions. AB - BACKGROUND: Patients are increasingly playing an active role in healthcare and their definitions of healthcare quality are becoming more important to understand. The Donabedian model has been used to understand patients' perceptions of quality in healthcare settings including hospitals and nursing homes; no research has applied the model to understand patients' perceptions of pharmacy quality. OBJECTIVE: To describe older adults' perception of a quality pharmacy including their expectations of a quality pharmacy and their preferences in a quality pharmacy. SETTING: Six focus groups held in community centers and senior residence facilities in Wisconsin. METHODS: The design was a descriptive, exploratory study. Participants were adults 65 years and older who filled a prescription at a community pharmacy in the 90 days prior to being contacted. Donabedian's assessment of healthcare quality based on 'structure,' 'process' and 'outcome' was used to organize and categorize the focus group themes. MAIN OUTCOME MEASURE: The focus groups explored older adults' perceptions and expectations of a quality pharmacy. The factors that influenced their pharmacy choice were also examined. Results The older adults' description of a quality pharmacy was based on the 'structure' and 'process' domain of the Donabedian model. However, most responses were focused on the 'process' domains and related to the application of patient-centered care (e.g., pharmacist interaction and communication) versus the structure domains (e.g., staff availability). The most frequently reported factor in the choice of pharmacies was the pharmacy's location with some participants also reporting that their relationship and rapport with the pharmacist were also important. Older adults' expectations were focused on the 'process' features of quality, including the provision of medication-related information, and the pharmacist facilitating medication safety and medication adherence. CONCLUSIONS: In describing pharmacy quality, older adults mostly refer to the 'process' aspects of quality. Older adults perceive a quality pharmacy as one where the pharmacist provides patient-centered care. While location is important in pharmacy choices, the pharmacist's patient centeredness, and the quality features of the pharmacy are also relevant. Older adults' expectations were related to their perception of a quality pharmacy. Pharmacists should publicize their pharmacies' 'process' features in quality reporting systems. PMID- 26499503 TI - Pharmaceutical care of elderly patients with poorly controlled type 2 diabetes mellitus: a randomized controlled trial. AB - BACKGROUND: Care of the elderly with diabetes is more complicated than that for other age groups. The elderly and/or those with multiple comorbidities are often excluded from randomized controlled trials of treatments for diabetes. The heterogeneity of health status of the elderly also increases the difficulty in diabetes care; therefore, diabetes care for the elderly should be individualized. Motivated patients educated about diabetes benefit the most from collaborating with a multidisciplinary patient-care team. A pharmacist is an important team member by serving as an educator, coach, healthcare manager, and pharmaceutical care provider. OBJECTIVE: To evaluate the effects of pharmaceutical care on glycemic control of ambulatory elderly patients with type 2 diabetes. SETTING: A 421-bed district hospital in Nantou City, Taiwan. METHOD: We conducted a randomized controlled clinical trial involving 100 patients with type 2 diabetes with poor glycemic control (HbA1c levels of >=9.0 %) aged >=65 years over 6 months. Participants were randomly assigned to a standard-care (control, n = 50) or pharmaceutical-care (intervention, n = 50) group. Pharmaceutical care was provided by a certified diabetes-educator pharmacist who identified and resolved drug-related problems and established a procedure for consultations pertaining to medication. The Mann-Whitney test was used to evaluate nonparametric quantitative data. Statistical significance was defined as P < 0.05. MAIN OUTCOME MEASURE: The change in the mean HbA1c level from the baseline to the next level within 6 months after recruiting. RESULTS: Nonparametric data (Mann-Whitney test) showed that the mean HbA1c level significantly decreased (0.83 %) after 6 months for the intervention group compared with an increase of 0.43 % for the control group (P <= 0.001). Medical expenses between groups did not significantly differ (-624.06 vs. -418.7, P = 0.767). There was no significant difference in hospitalization rates between groups. CONCLUSION: The pharmacist intervention program provided pharmaceutical services that improved long-term, safe control of blood sugar levels for ambulatory elderly patients with diabetes and did not increase medical expenses. PMID- 26499504 TI - An exploration of health professionals' experiences of medicines management in elderly, hospitalised patients in Abu Dhabi. AB - BACKGROUND: Given the multiplicity of issues relating to medicines in the elderly, the structures and processes of medicines management should be clearly defined and described to optimise patient outcomes. There is a paucity of research which provides an in-depth exploration of these elements of medicines management for elderly patients. OBJECTIVES: This study explored health professionals' experiences of medicines management for elderly, hospitalised patients in Abu Dhabi. Setting The research was conducted in five major hospitals in Abu Dhabi, the United Arab Emirates. METHOD: Responses to an online sampling questionnaire were used to purposively select nurses, pharmacists and physicians for interview. A semi-structured interview schedule was developed with reference to normalization process theory (NPT) and the theoretical domains framework (TDF) to explore issues of medicines management structures, processes and outcomes. Face-to-face interviews of 20-30 min were audio-recorded, transcribed verbatim and analysed using the Framework Approach. MAIN OUTCOME MEASURES: Health professionals' in-depth experiences of structures, processes and outcomes relating to medicines management. Results Saturation of themes was deemed to occur at interview 27 (7 nurses, 13 pharmacists, 7 physicians). Six key themes and several subthemes emerged from the qualitative analysis, which pertained to the need for: appropriate polypharmacy; a systematic approach to medicines history taking; improved communication and documentation; improved patients' adherence to medicines; guidelines and policies to support medicines selection, and an educated and trained multidisciplinary team. The most dominant TDF behavioural determinants were issues around: professional role and identity; beliefs about capabilities; beliefs about consequences; environmental context and resources; knowledge, and goals. NPT construct identified little evidence of coherence, cognitive participation, collective action and reflexive monitoring. CONCLUSION: The key themes identified in this research indicate the need to develop a more structured approach to medicines management in elderly hospitalised patients in Abu Dhabi. The NPT constructs and the TDF behavioural determinants can be utilised as part of service development and implementing change. PMID- 26499505 TI - Survey of pharmacists' antibiotic dosing recommendations for sustained low efficiency dialysis. AB - BACKGROUND: The use of hybrid renal replacement therapies like sustained low efficiency dialysis (SLED) is increasing in ICUs worldwide. However, pharmacokinetic studies designed to inform therapeutic antibiotic dosing in critically ill patients receiving SLED are limited. SLED operational characteristics vary across institutions. Pharmacists in institutions that utilize SLED are challenged to recommend therapeutic doses for antibiotics. OBJECTIVE: To characterize pharmacist-recommended antibiotic regimens for SLED. METHODS: An electronic survey was sent to pharmacist members of the American College of Clinical Pharmacy in the Nephrology or Critical Care Practice and Research Network. Dosing recommendations for a hypothetical critically ill septic patient were collected for cefepime, ceftaroline, daptomycin, levofloxacin, meropenem, and piperacillin/tazobactam. Main outcome measure Antibiotic regimens for the six antibiotics, their frequency, pharmacist's experience with renal replacement therapies (RRT), post-graduate training, years of clinical experience, number of staffed beds in their hospital, and RRT employed in their ICUs. RESULTS: The survey was completed by 69 clinical pharmacists who had 8.5 +/ 7.5 (mean +/- SD) years of experience. All pharmacists had experience dosing medications for patients receiving RRT. The most frequently recommended regimen for each antibiotic was: cefepime 1000 mg every 24 h, ceftaroline 200 mg every 12 h, daptomycin 6 mg/kg every 24 h, levofloxacin 500 mg every 24 h, meropenem 1000 mg every 12 h, and piperacillin/tazobactam 2250 mg every 8 h. Up to nine distinct regimens were recommended for each antibiotic, and the total daily dose between these regimens ranged by as much as a 12-fold. Neither pharmacist's experience with SLED, post-graduate training, nor years of clinical experience were significantly associated with particular dosing recommendations for the antibiotics. CONCLUSION: Pharmacists working in institutions that utilize SLED make antibiotic dosing recommendations that vary 4-12-fold depending on the drug. Published research does not provide adequate guidance to optimally dose antibiotics in patients receiving SLED. More SLED pharmacokinetic trials, real time serum concentration monitoring and advanced pharmacokinetic modeling techniques are necessary to ensure therapeutic dosing in patients receiving SLED. PMID- 26499506 TI - Outcomes of allogeneic hematopoietic cell transplantation in patients with biphenotypic acute leukemia. AB - The outcomes of allogeneic hematopoietic cell transplantation (HSCT) in patients with biphenotypic acute leukemia (BAL) remain unclear. We retrospectively analyzed the outcomes of HSCT in BAL patients in Japan in comparison to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) using the registration data from a nationwide database. The data of 90, 5371, and 3301 patients with BAL, AML, and ALL, respectively, were included in the analysis. The median follow-up period was 1481.5 days (range: 0-5556). The 5-year overall survival (OS) of the BAL, AML, and ALL patients were 39.6, 41.8, and 42.0 %, respectively (BAL vs. AML, P = 0.98 BAL vs. ALL, P = 0.77). A multivariate analysis revealed that, in comparison to BAL, AML with a better-risk karyotype was associated with superior OS. An analysis of the prognostic factors of BAL patients showed that OS was significantly longer in patients who were in their first complete remission in comparison to patients who were not in remission. Our data suggest that HSCT is an effective treatment for BAL patients, regardless of the presence of any known poor prognostic factors other than a non-remission status. PMID- 26499507 TI - The Wilms Tumor-1 (WT1) rs2234593 variant is a prognostic factor in normal karyotype acute myeloid leukemia. AB - The single-nucleotide polymorphism (SNP) within Wilms tumor-1 (WT1) exon 7, rs16754, has been arguably reported to be implicated in acute myeloid leukemia (AML) prognosis. We assessed the potential association of selected WT1 SNPs as well as WT1 mutations in normal karyotype (NK)-AML and evaluated the prognostic value of these normal gene variants. Diagnostic samples from a series of 474 young adult NK-AML patients were used to genotype five WT1 SNPs using TaqMan assays and to directly sequence WT1 exons 7 and 9. Analysis of five WT1 gene variants showed an association of rs2234593 allele C with WT1 Ex7 mutation. Prognostic study of the same variants identified rs2234593 significantly associated with relapse and overall survival (OS). Patients with rs2234593AA/AC showed significantly higher 10-year OS (50 vs 36 %, hazard ratio (HR) = 0.69 (0.52-0.90), p = 0.006) and lower cumulative incidence of relapse (CIR) (36 vs 51 %, HR = 0.62 (0.45-0.86), p = 0.004) compared to those with rs2234593CC. The effect of AA genotype on CIR remained significant after adjustment for basic covariates including FLT3 internal-tandem duplication (FLT3-ITD) and nucleophosmin 1 (NPM1) mutations (HR = 0.60 (0.41-0.89), p = 0.009), with some evidence of improved survival (HR = 0.75 (0.55-1.03), p = 0.07). A multivariate analysis showed WT1 Ex7-mutant as the major relapse predictor, with a tendency for rs2234593-A effect after allowing for Ex7 mutation (p = 0.07). No adjusted risk benefit was found for previously reported rs16754-G. In conclusion, WT1 normal gene variant rs2234593 is associated with mutational status of WT1 Ex7 and is a further prognostic marker independent from FLT3-ITD and NPM1 mutations in NK AML. PMID- 26499508 TI - Phylogeographic breaks within Asian butternuts indicate the existence of a phytogeographic divide in East Asia. AB - East Asia has been hypothesized to be subdivided into two distinct northern and southern areas, separated by a band of dry climate that was far more severe in the early Tertiary but still exists today. However, this biogeographic hypothesis has rarely been tested using a molecular phylogeographic approach. We genotyped 70 populations throughout the distributional range of Asian butternuts (Juglans section Cardiocaryon) using eight chloroplast DNA regions, one single-copy nuclear gene, and 17 nuclear microsatellite loci, supplemented with paleodistribution modeling of the major genetic clades. The genetic data consistently identified two clades, one northern, comprising Juglans mandshurica and Juglans ailantifolia, and one southern, comprising Juglans cathayensis. The two clades diverged through climate-induced vicariance of an ancestral northern range during the mid-Miocene and remained mostly separate thereafter, with geographical isolation of the Japanese Islands and refugial isolation or secondary contacts in the late Pleistocene producing further subdivision within the northern clade. But beyond all that, we also discovered a role of environmental adaptation in maintaining and/or reinforcing the north-south divergence. Asian butternuts offer a strong case for the existence of a biogeographic divide between the northern and southern parts of East Asia during the Neogene and into the Pleistocene. PMID- 26499509 TI - Love really is in the eye of the beholder. PMID- 26499510 TI - 20 g PPV with indocyanine green-assisted ILM peeling versus 23 g PPV with brilliant blue G-assisted ILM peeling for epiretinal membrane. AB - To compare the anatomical and visual outcomes of 20 gauge (g) pars plana vitrectomy (PPV) with indocyanine green (ICG)-assisted internal limiting membrane (ILM) peeling and 23 g PPV with brilliant blue G (BBG)-assisted ILM peeling for idiopathic epiretinal membrane (ERM). 38 eyes of 38 patients with idiopathic ERM were included. They were divided in two groups: group 1 (18 eyes) underwent 20 g PPV with ICG-assisted ILM peeling and group 2 (20 eyes) 23 g PPV with BBG assisted ILM peeling. Postoperative best-corrected visual acuity (BCVA) and central macular thickness (CMT) were compared. Average BCVA in group 1 improved significantly from 0.60 logarithm of the minimal angle of resolution (log MAR) at baseline to 0.3 log MAR postoperatively. Average BCVA in group 2 improved significantly from 0.60 log MAR at baseline to 0.3 log MAR postoperatively. Mean CMT reduced significantly from 473 to 375 MUm in group 1 and from 486 to 396 MUm in group 2. There were no significant differences in the BCVA and CMT between the groups. Both surgical methods appeared to be safe and provided similar anatomical and visual outcomes. PMID- 26499511 TI - A Role for Diminished GABA Transporter Activity in the Cortical Discharge Phenotype of MeCP2-Deficient Mice. AB - Cortical network hyper-excitability is a common phenotype in mouse models lacking the transcriptional regulator methyl-CPG-binding protein 2 (MeCP2). Here, we implicate enhanced GABAB receptor activity stemming from diminished cortical expression of the GABA transporter GAT-1 in the genesis of this network hyper excitability. We found that administering the activity-dependent GABAB receptor allosteric modulator GS-39783 to female Mecp2(+/-) mice at doses producing no effect in wild-type mice strongly potentiated their basal rates of spontaneous cortical discharge activity. Consistently, administering the GABAB receptor antagonist CGP-35348 significantly decreased basal discharge activity in these mice. Expression analysis revealed that while GABAB or extra-synaptic GABAA receptor prevalence is preserved in the MeCP2-deficient cortex, the expression of GAT-1 is significantly reduced from wild-type levels. This decrease in GAT-1 expression is consequential, as low doses of the GAT-1 inhibitor NO-711 that had no effects in wild-type mice strongly exacerbated cortical discharge activity in female Mecp2(+/-) mice. Taken together, these data indicate that the absence of MeCP2 leads to decreased cortical levels of the GAT-1 GABA transporter, which facilitates cortical network hyper-excitability in MeCP2-deficient mice by increasing the activity of cortical GABAB receptors. PMID- 26499512 TI - Dietary fibre-rich resistant starches promote ammonia detoxification in the human colon as measured by lactose-[15N2]ureide. AB - Three resistant starches (RSs), namely fibre of potatoes (FP), wrinkle pea starch (WPS), and high amylose maize starch (HAMS) with different dietary fibre contents, were supplemented in adults to evaluate their effects on urinary nitrogen and ammonia excretion as well as on faecal nitrogen excretion by means of lactose-[(15)N2]ureide ((15)N-LU) degradation. Twenty subjects received a regular diet either without or with the supplementation of FP, WPS, and HAMS in a randomized order. After administration of (15)N-LU, urine and faeces were collected over 48 and 72 h, respectively, whereas blood was collected after 6 h. The (15)N-abundances were measured by isotope ratio mass spectrometry. In comparison to the dry run, supplementation with RS significantly lowered renal (15)N-excretion (dry run: 43.2%, FP: 34.6%, WPS: 37.9%, HAMS: 36.4%) as well as the corresponding (15)NH3-excretion (dry run: 0.08%, FP: 0.06%, HAMS: 0.05%), clearly indicating a reduced colonic nitrogen generation at high dietary fibre intake. PMID- 26499513 TI - High Frequency of Detection by PCR of Viral Nucleic Acid in The Blood of Infants Presenting with Clinical Myocarditis. AB - Specific viruses are associated with pediatric myocarditis, but the prevalence of viral DNAemia detected by blood polymerase chain reaction (PCR) is unknown. We evaluated the prevalence of known cardiotropic viruses (enterovirus, adenovirus, human herpesvirus 6, and parvovirus B19) in children with clinical myocarditis (n = 21). Results were compared to pediatric controls with similar viral PCR testing. The majority of positive PCR (89 %) was noted in children <=12 months of age at diagnosis compared to older children. Infant myocarditis patients (8/10) had increased the prevalence of PCR positivity compared to infant pediatric controls (4/114) (p < 0.0001). Other than age, patient characteristics at diagnosis were similar between PCR-positive and PCR-negative patients. Both PCR negative myocarditis infants had clinical recovery at follow-up. Of the PCR positive myocarditis infants, 4 had clinical recovery, 2 developed chronic cardiomyopathy, 1 underwent heart transplant, and 1 died. Infants with clinical myocarditis have a high rate of blood viral positivity, which is higher compared to older children with myocarditis and healthy infant controls. Age-related differences in PCR positivity may be due to differences in host and/or virus characteristics. Our findings suggest that viral blood PCR may be a useful diagnostic tool and identify patients who would potentially benefit from virus specific therapy. PMID- 26499514 TI - Clinical Features and Surgical Outcomes of Coronary Sinus Orifice Atresia. AB - This study aimed to review clinical features and surgical outcomes of coronary sinus orifice atresia (CSOA). From 2003 to 2015, 6 patients were diagnosed with CSOA. Median age at diagnosis was 2 years (range 0.2-73). CSOA was preoperatively diagnosed in 2 patients, intraoperatively in 3, and postoperatively in 1. Coronary venous blood flow drained into innominate vein through the left superior vena cava (LSVC) in 2, into the atrium through Thebesian veins in 2, and into both in 2. Three patients required surgical treatment. The first patient with a congenitally corrected transposition of great arteries had undergone ligation of the LSVC and a cutback of the proximal LSVC into the functional right atrium during the double-switch operation. The second patient with tricuspid atresia gradually developed hypoxia after the Fontan operation due to the increase in veno-venous shunt blood flow from the Fontan pathway to the right atrium through the LSVC and Thebesian veins, so that the LSVC was ligated and the coronary sinus was unroofed 6 years after Fontan operation. The other functional single ventricle patient had undergone ligation of the LSVC and a cutback of the proximal LSVC into the left atrium during the Fontan operation. There were no mortalities at the median follow-up of 9 years (1-11). CSOA should be suspected when the LSVC and usual-sized innominate vein were presented. Surgical treatment is required if the postoperative hemodynamics would affect coronary venous perfusion, like single ventricular palliation (244 words). PMID- 26499515 TI - Food matrix and processing influence on carotenoid bioaccessibility and lipophilic antioxidant activity of fruit juice-based beverages. AB - The biological activity of carotenoids depends on their bioaccessibility and solubilization in the gastrointestinal tract. These compounds are poorly dispersed in the aqueous media of the digestive tract due to their lipophilic nature. Thus, it is important to analyze the extent to which some factors, such as the food matrix and food processing, may improve their bioaccessibility. Beverages formulated with a blend of fruit juices and water (WB), milk (MB) or soymilk (SB) were treated by high-intensity pulsed electric fields (HIPEF) (35 kV cm(-1) with 4 MUs bipolar pulses at 200 Hz for 1800 MUs), high-pressure processing (HPP) (400 MPa at 40 degrees C for 5 min) or thermal treatment (TT) (90 degrees C for 1 min) in order to evaluate the influence of food matrix and processing on the bioaccessibility of carotenoids and on the lipophilic antioxidant activity (LAA). The bioaccessibility of these compounds diminished after applying any treatment (HIPEF, HPP and TT), with the exception of cis violaxanthin + neoxanthin, which increased by 79% in HIPEF and HPP beverages. The lowest carotenoid bioaccessibility was always obtained in TT beverages (losses up to 63%). MB was the best food matrix for improving the bioaccessibility of carotenoids, as well as the LAA. The results demonstrate that treatment and food matrix modulated the bioaccessibility of carotenoids as well as the lipophilic antioxidant potential of beverages. Additionally, HIPEF and HPP could be considered as promising technologies to obtain highly nutritional and functional beverages. PMID- 26499516 TI - Central venous pressure as an adjunct to flow-guided volume optimisation after induction of general anaesthesia. AB - BACKGROUND: Although the central venous pressure (CVP) is often used as a guide to volume status in major surgery and intensive care, fluid therapy should be guided by the response of the stroke volume (SV) to a fluid bolus. The present study evaluates whether the central venous pressure (CVP) can serve as an adjunct to decisions of whether or not fluid should be infused. METHODS: Stroke volume (SV) and stroke volume variation (SVV) was monitored with FloTrac/Vigileo and the CVP were measured in 80 patients just before general anaesthesia was induced (baseline) and then, before each of three successive bolus infusions of 3 mL kg-1 of 6% hydroxyethyl starch 130/0.4. A patient showed fluid responsiveness and was denoted a "responder" if SV increased by >=10% from the bolus infusion. RESULTS: The CVP was higher in non-responders (mean 7.2 mm Hg) than in responders (mean 5.8 mm Hg, P < 0.0001). In non-responders but not in responders, the absence or presence of a rise in CVP improved the prediction of whether the patient would show fluid responsiveness during the next fluid bolus. For example, if no rise in CVP occurred the chance was 48% of subsequent fluid responsiveness, while this chance was only 9% for those who had an increase in CVP (P < 0.004). There was only a fair concordance between fluid responsiveness as indicated by SV and SVV (Cohen's kappa 0.28). CONCLUSIONS: A low CVP suggests that the patient is lower on the Frank-Starling curve than indicated by SV as measured by FloTrac/Vigileo. PMID- 26499518 TI - Study of Ion Transfer Coupling with Electron Transfer by Hydrophilic Droplet Electrodes. AB - In a hydrophilic droplet three-electrode system, electroactive species within the droplet play very important roles in the electron-transfer (ET) process on the solid/electrolyte interface, which can then induce an ion-transfer (IT) reaction at the liquid/liquid interface. In this work, several redox couples and electroactive species are chosen to study ET-IT coupling processes at the water/1,2-dichloroethane (W/DCE) interface by cyclic voltammetry (CV) and Osteryoung square wave voltammetry (OSWV). Among them, the redox couple Ru(NH3)6(3+/2+) has been found to have the widest useful potential window of about 1.2 V. A hydrophilic droplet three-electrode system using a single electroactive molecule instead of a redox couple has been confirmed to be stable and has similar functionality to a redox couple. In addition, the lipophilicity of antiplatelet drug clopidogrel at the W/DCE interface is investigated and its ionic partition diagram has been constructed. Protonated clopidogrel is detected in a linear concentration range of 5.0-50 MUM and the limit of detection (LOD) is calculated to be 3.0 MUM by using the hydrophilic droplet system Ru(NH3)6(3+/2+) and OSWV. PMID- 26499517 TI - Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation. AB - Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative disorders such as Parkinson's disease (PD). gamma Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, has recently been shown to play an inhibitory role in the immune system. Tiagabine, a piperidine derivative, enhances GABAergic transmission by inhibiting GABA transporter 1 (GAT 1). In the present study, we found that tiagabine pretreatment attenuated microglial activation, provided partial protection to the nigrostriatal axis and improved motor deficits in a methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The protective function of tiagabine was abolished in GAT 1 knockout mice that were challenged with MPTP. In an alternative PD model, induced by intranigral infusion of lipopolysaccharide (LPS), microglial suppression and subsequent neuroprotective effects of tiagabine were demonstrated. Furthermore, the LPS-induced inflammatory activation of BV-2 microglial cells and the toxicity of conditioned medium toward SH-SY5Y cells were inhibited by pretreatment with GABAergic drugs. The attenuation of the nuclear translocation of nuclear factor kappaB (NF-kappaB) and the inhibition of the generation of inflammatory mediators were the underlying mechanisms. Our results suggest that tiagabine acts as a brake for nigrostriatal microglial activation and that it might be a novel therapeutic approach for PD. PMID- 26499519 TI - [Not Available]. PMID- 26499520 TI - [Not Available]. PMID- 26499521 TI - [Not Available]. PMID- 26499522 TI - [Not Available]. PMID- 26499523 TI - [Not Available]. PMID- 26499525 TI - [Not Available]. PMID- 26499524 TI - [Not Available]. PMID- 26499526 TI - [Not Available]. PMID- 26499527 TI - [Not Available]. PMID- 26499529 TI - [Not Available]. PMID- 26499528 TI - [Not Available]. PMID- 26499530 TI - [Not Available]. PMID- 26499532 TI - [Not Available]. 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PMID- 26499748 TI - Panoscopically optimized thermoelectric performance of a half-Heusler/full Heusler based in situ bulk composite Zr(0.7)Hf(0.3)Ni(1+x)Sn: an energy and time efficient way. AB - All scale hierarchical architecturing, matrix/inclusion band alignment and intra matrix electronic structure engineering, the so called panoscopic approach for thermoelectric materials has been demonstrated to be an effective paradigm for optimizing high ZT. To achieve such hierarchically organized microstructures, composition engineering has been considered to be an efficient strategy. In this work, such a panoscopic concept has been extended to demonstrate for the first time in the case of half-Heusler based thermoelectric materials via a composition engineering route. A series of new off-stoichiometric n-type Zr0.7Hf0.3Ni1+xSn (0 <=x<= 0.10) HH compositions have been modified to derive HH(1 -x)/full-Heusler (FH)(x) composite with an all scale hierarchically modified microstructure with FH inclusions within the matrix to study the temperature dependent thermoelectric properties. The structural analysis employing XRD, FE-SEM and HR-TEM of these materials reveal a composite of HH and FH, with hierarchically organized microstructures. In such a submicron/nano-composite, the electronic properties are observed to be well optimized yielding a large power factor; alpha(2)sigma (~30.7 * 10(-4) W m(-1) K(-2) for Zr0.7Hf0.3Ni1.03Sn) and reduced thermal conductivity (~2.4 W m(-1) K(-1) for Zr0.7Hf0.3Ni1.03Sn) yielding a high ZT~ 0.96 at 773 K for composition Zr0.7Hf0.3Ni1.03Sn which is ~250% larger than the normal HH Zr0.7Hf0.3NiSn (ZT~ 0.27 at 773 K). The enhancement in ZT of these composites has been discussed in terms of primary electron filtering, electron injection and several phonon scattering mechanisms such as alloy scattering, point defect scattering, and grain boundary scattering. The Bergman and Fel model is used to calculate effective thermoelectric parameters of these composites for comparing the experimental results. PMID- 26499750 TI - Response to "Comments on 'Lateral Subcutaneous Brow Lift: Updated Technique'". PMID- 26499749 TI - Comments on "Lateral Subcutaneous Brow Lift: Updated Technique". PMID- 26499751 TI - Simultaneous Double Eyelid Blepharoplasty and Ptosis Correction with a Single Knot, Continuous, Nonincisional Technique: A Five-Year Review. AB - BACKGROUND: Double eyelid blepharoplasty is one of the most popular facial cosmetic surgeries performed in patients with Asian eyelids. Although most patients choose to undergo blepharoplasty for cosmetic purposes, rather than functional reasons, these patients frequently present with concomitant mild-to moderate blepharoptosis. OBJECTIVES: Performing nonincisional double eyelid surgery without correcting the ptosis tends to lead to unsatisfactory results. The authors introduce our new method for simultaneous correction of blepharoptosis during double eyelid blepharoplasty. METHODS: For 5 years, the authors have performed a single-knot continuous nonincisional technique for simultaneous correction of blepharoptosis during double eyelid blepharoplasty. The medical charts of 127 patients (254 eyelids) were retrospectively reviewed. Muller muscle tagging suture was utilized to achieve the accurate amount of Muller tucking during the surgery. RESULTS: There was a statistically significant difference between pretreatment MRD1 (1.62 +/- 0.57 mm), and postoperative MRD1 (3.97 +/- 0.81 mm; P < .001, Wilcoxon signed rank test, nonparametric paired comparison). The mean duration of surgery for both eyelids was 14.8 minutes (range, 14.1-19.7 minutes), and the mean extent of Muller muscle tucking was 7.8 mm (range, 6.0-10.0 mm). The majority of patients showed favorable results during long-term follow-up, with minimal complications. CONCLUSIONS: There are no previously published articles documenting simultaneous double eyelid blepharoplasty and ptosis correction, using a single-knot continuous nonincisional technique. The authors suggest our simple and effective method is a good option for double eyelid blepharoplasty in cases with mild-to-moderate blepharoptosis.' LEVEL OF EVIDENCE 4: Therapeutic. PMID- 26499752 TI - Response to "Seroma Prevention in Abdominoplasty: Eliminating the Cause". PMID- 26499753 TI - Response to "Seroma Prevention in Abdominoplasty: Eliminating the Cause". PMID- 26499754 TI - Seroma Prevention in Abdominoplasty: Eliminating the Cause. PMID- 26499755 TI - Prevention of colorectal cancer: How many tools do we have in our basket? AB - Prevention is the main strategy in order to reduce colorectal cancer incidence and mortality. It can be accomplished through primary prevention, using measures affecting factors known to confer higher risk of colorectal cancer, or through secondary prevention, aimed at early diagnosis of cancer or preneoplastic lesions in groups of subjects at increased risk of cancer. Although primary prevention should be the goal for future years, because it acts on the probable causes of colorectal cancer, at present it seems that secondary prevention is more effective on colorectal cancer survival, and the approaches which have yielded the most satisfying results, in terms of reduced mortality for cancer, are those aimed at detecting preneoplastic lesions, or cancer at an early stage in selected groups of subjects at average or increased risk of colorectal cancer. These groups are subjects aged 50years or older, affected individuals (gene carriers) or family members of hereditary colorectal cancer syndromes (i.e., Lynch syndrome and familial adenomatous polyposis), and patients with inflammatory bowel diseases. The most effective procedures used, though with some drawbacks, are fecal occult blood tests and colonoscopy. Future research should be addressed to find new approaches that will render preventive strategies more acceptable for the population, and more cost-effective. PMID- 26499757 TI - Gastric motor dysfunctions in Parkinson's disease: Current pre-clinical evidence. AB - Parkinson's disease (PD) is associated with several non-motor symptoms, such as behavioral changes, urinary dysfunction, sleep disorders, fatigue and, above all, gastrointestinal (GI) dysfunction, including gastric dysmotility, constipation and anorectal dysfunction. Delayed gastric emptying, progressing to gastroparesis, is reported in up to 100% of patients with PD, and it occurs at all stages of the disease with severe consequences to the patient's quality of life. The presence of alpha-synuclein (alpha-syn) aggregates in myenteric neurons throughout the digestive tract, as well as morpho-functional alterations of the enteric nervous system (ENS), have been documented in PD. In particular, gastric dysmotility in PD has been associated with an impairment of the brain-gut axis, involving the efferent fibers of the vagal pathway projecting directly to the gastric myenteric plexus. The present review intends to provide an integrated overview of available knowledge on the possible role played by the ENS, considered as a semi-autonomous nervous network, in the pathophysiology of gastric dysmotility in PD. Particular attention has been paid review how translational evidence in humans and studies in pre-clinical models are allowing a better understanding of the functional, neurochemical and molecular alterations likely underlying gastric motor abnormalities occurring in PD. PMID- 26499756 TI - Influence of dietary protein on postprandial blood glucose levels in individuals with Type 1 diabetes mellitus using intensive insulin therapy. AB - AIM: To determine the effects of protein alone (independent of fat and carbohydrate) on postprandial glycaemia in individuals with Type 1 diabetes mellitus using intensive insulin therapy. METHODS: Participants with Type 1 diabetes mellitus aged 7-40 years consumed six 150 ml whey isolate protein drinks [0 g (control), 12.5, 25, 50, 75 and 100] and two 150 ml glucose drinks (10 and 20 g) without insulin, in randomized order over 8 days, 4 h after the evening meal. Continuous glucose monitoring was used to assess postprandial glycaemia. RESULTS: Data were collected from 27 participants. Protein loads of 12.5 and 50 g did not result in significant postprandial glycaemic excursions compared with control (water) throughout the 300 min study period (P > 0.05). Protein loads of 75 and 100 g resulted in lower glycaemic excursions than control in the 60-120 min postprandial interval, but higher excursions in the 180-300 min interval. In comparison with 20 g glucose, the large protein loads resulted in significantly delayed and sustained glucose excursions, commencing at 180 min and continuing to 5 h. CONCLUSIONS: Seventy-five grams or more of protein alone significantly increases postprandial glycaemia from 3 to 5 h in people with Type 1 diabetes mellitus using intensive insulin therapy. The glycaemic profiles resulting from high protein loads differ significantly from the excursion from glucose in terms of time to peak glucose and duration of the glycaemic excursion. This research supports recommendations for insulin dosing for large amounts of protein. PMID- 26499758 TI - Association of type 2 diabetes GWAS loci and the risk of Parkinson's and Alzheimer's diseases. AB - BACKGROUND: Insulin and insulin-like growth factor contribute to normal brain function. Recent experimental and clinical studies showed that type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD) or Alzheimer's disease (AD) share several dysregulated pathways. OBJECTIVE: We aimed to investigate whether genome wide significant loci of T2DM are associated with the risk of PD and AD as well as the severity of cognitive impairment. METHODS: Study subjects were 500 PD patients, 400 AD patients, and 500 unrelated controls. We selected 32 genetic variants from 11 genes (CDC123, CDKAL1, CDKN2B, FTO, GLIS3, HHEX, IGF2BP2, KCNJ11, KCNQ1, SLC30A8, and TCF7L2) and intergenic regions based on results of recent genome-wide association studies (GWAS) in T2DM. These variants were reported to be T2DM-susceptibility loci and have been replicated in other independent studies. All association analyses were performed using logistic regression models, adjusting for age and sex. RESULTS: KCNQ1 SNP rs163182 showed the strongest association with AD, but it was not significant after Bonferroni correction (OR = 1.30, 95% CI = 1.07-1.59, Pcorrected = 0.32). In PD patients, CDC123 SNP rs11257655 showed modest association with MMSE score <26, and CDKN2B SNPs (rs2383208, rs10965250, and rs10811661) showed modest association with MoCA score <26, which were not significant after Bonferroni correction. Other genetic variants had no association with the risk of PD or AD and the severity of cognitive impairment. CONCLUSIONS: Our results suggest that genome-wide significant loci of T2DM play no major role in the risk and cognitive impairment of PD and AD. PMID- 26499759 TI - MicroRNA-22 functions as a tumor suppressor by targeting SIRT1 in renal cell carcinoma. AB - Accumulating evidence demonstrates that microRNA-22 (miR-22) was deregulated in many types of cancers and was involved in various cellular processes related to carcinogenesis. However, the exact roles and mechanisms of miR-22 remain unknown in human renal cell carcinoma (RCC). Here, the relationship between miR-22 expression pattern and clinicopathological features of patients with EOC were determined by real-time quantitative RT-PCR (qRT-PCR). Furthermore, the role of miR-22 and possible molecular mechanisms in EOC were investigated by several in vitro approaches and in a nude mouse model. Results from qRT-PCR showed that miR 22 was significantly downregulated in RCC samples compared with corresponding non cancerous tissues, which was significantly associated with tumor stage and lymph node metastasis. Functional study demonstrated that enforced overexpression of miR-22 in renal cancer cells inhibited proliferation, migration and invasion, and induced cell apoptosis in vitro, and suppressed tumor growth in vivo. In addition, SIRT1 was identified as a direct target of miR-22 by a luciferase reporter assay. Overexpression of miR-22 activated p53 and its downstream target p21 and PUMA, and the apoptosis markers cleaved CASP3 and PARP, and inhibited epithelial-mesenchymal transition (EMT). These findings showed that miR-22 functioned as tumor suppressor in RCC and blocked RCC growth and metastasis by directly targeting SIRT1 in RCC, indicating a potential novel therapeutic role in RCC treatment. PMID- 26499761 TI - Calculation and word problem-solving skills in primary grades - Impact of cognitive abilities and longitudinal interrelations with task-persistent behaviour. AB - BACKGROUND: Primary school math skills form a basis for academic success down the road. Different math skills have different antecedents and there is a reason to believe that more complex math tasks require better self-regulation. AIMS: The study aimed to investigate longitudinal interrelations of calculation and problem solving skills, and task-persistent behaviour in Grade 1 and Grade 3, and the effect of non-verbal intelligence, linguistic abilities, and executive functioning on math skills and task persistence. SAMPLE: Participants were 864 students (52.3% boys) from 33 different schools in Estonia. METHODS: Students were tested twice - at the end of Grade1 and at the end of Grade 3. Calculation and problem-solving skills, and teacher-rated task-persistent behaviour were measured at both time points. Non-verbal intelligence, linguistic abilities, and executive functioning were measured in Grade 1. RESULTS: Cross-lagged structural equation modelling indicated that calculation skills depend on previous math skills and linguistic abilities, while problem-solving skills require also non verbal intelligence, executive functioning, and task persistence. Task-persistent behaviour in Grade 3 was predicted by previous problem-solving skills, linguistic abilities, and executive functioning. Gender and mother's educational level were added as covariates. CONCLUSIONS: The findings indicate that math skills and self regulation are strongly related in primary grades and that solving complex tasks requires executive functioning and task persistence from children. Findings support the idea that instructional practices might benefit from supporting self regulation in order to gain domain-specific, complex skill achievement. PMID- 26499760 TI - Niche differentiation of bacterial communities at a millimeter scale in Shark Bay microbial mats. AB - Modern microbial mats can provide key insights into early Earth ecosystems, and Shark Bay, Australia, holds one of the best examples of these systems. Identifying the spatial distribution of microorganisms with mat depth facilitates a greater understanding of specific niches and potentially novel microbial interactions. High throughput sequencing coupled with elemental analyses and biogeochemical measurements of two distinct mat types (smooth and pustular) at a millimeter scale were undertaken in the present study. A total of 8,263,982 16S rRNA gene sequences were obtained, which were affiliated to 58 bacterial and candidate phyla. The surface of both mats were dominated by Cyanobacteria, accompanied with known or putative members of Alphaproteobacteria and Bacteroidetes. The deeper anoxic layers of smooth mats were dominated by Chloroflexi, while Alphaproteobacteria dominated the lower layers of pustular mats. In situ microelectrode measurements revealed smooth mats have a steeper profile of O2 and H2S concentrations, as well as higher oxygen production, consumption, and sulfate reduction rates. Specific elements (Mo, Mg, Mn, Fe, V, P) could be correlated with specific mat types and putative phylogenetic groups. Models are proposed for these systems suggesting putative surface anoxic niches, differential nitrogen fixing niches, and those coupled with methane metabolism. PMID- 26499762 TI - Head-To-Head Assessment of Diagnostic Performance of Testosterone Immunoassays in Patients With Polycystic Ovary Syndrome. AB - BACKGROUND: Determination of plasma testosterone is critical for the proper diagnosis of polycystic ovary syndrome (PCOS), but the interpretation of biochemical tests is hampered by inadequate specificity and precision of available immunoassays. We here compared the diagnostic performance of three testosterone immunoassays (Advia Centaur, Immulite 2000 XPi, Cobas e411) in PCOS patients using receiver operator characteristics curve analysis. METHODS AND RESULTS: Plasma levels of testosterone, androstendione, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, estradiol, progesterone, steroid hormone binding globulin, luteinizing hormone, and follicular stimulating hormone were determined in 188 patients with PCOS and 202 controls. Free testosterone (fT) levels and free androgen index (FAI) were calculated. Testosterone levels measured on Advia Centaur, Immulite 2000 XPi, and Cobas e411 showed clear linear relationship to each other. Testosterone measured with Advia Centaur showed discriminatory performance superior to Immulite 2000 XPi and Cobas e411. Calculation of fT or FAI improved the performance of Advia Centaur and Immulite 2000 XPi, which nevertheless performed better than Cobas e411. The performance of other parameters was inferior to that of testosterone, fT, and FAI. CONCLUSION: Present study documents striking differences between testosterone immunoassays with respect to their capacity to identify PCOS patients and favors the use of calculated parameters reflecting active testosterone in plasma. PMID- 26499763 TI - Involvement of epithelial-to-mesenchymal transition and associated transforming growth factor-beta/Smad signaling in paraquat-induced pulmonary fibrosis. AB - Paraquat (PQ) is a highly toxic herbicide which is able to induce pulmonary fibrosis in humans and animals. The epithelial-to-mesenchymal transition (EMT) was demonstrated to be an important factor in pulmonary fibrosis. However, it has remained elusive whether PQ induces pulmonary fibrosis via EMT, which was therefore investigated in the present study. In addition, the underlying mechanisms of PQ-induced EMT were examined in vitro. Hematoxylin and eosin staining of rat lung tissues demonstrated that PQ induced pulmonary fibrosis in vivo. Western blot analysis then revealed that the expression of epithelial cell marker E-cadherin was significantly decreased, while the expression of mesenchymal markers alpha-smooth-muscle actin and vimentin was significantly increased in rat lung tissues and A549 cells following PQ treatment. Transforming growth factor (TGF)-beta/Smad signaling was also induced by PQ as evidenced by increased expression of TGF-beta1 and Smad2. However, PQ-induced EMT in A549 cells was abolished by transfection with TGF-beta1-specific small hairpin RNA. In conclusion, the present study demonstrated that PQ induced EMT in vivo and in vitro, which may be an important process in the development of PQ-induced pulmonary fibrosis. In addition, TGF-beta/Smad signaling was involved in PQ induced EMT. PMID- 26499765 TI - Introduction. PMID- 26499764 TI - Newborn screening and the era of medical genomics. AB - Across the span of the last 75+ years, technological and conceptual advances in genetics have found rapid implementation at the beginning of human life. From karyotype testing, to molecular cytogenetics, to gene panel testing, and now to whole exome and whole genome sequencing, each iterative expansion of our capability to acquire genetic data on the next generation has been implemented quickly in the clinical setting. In tandem, our continuously expanding ability to acquire large volumes of genetic data has generated its own challenges in terms of interpretation, clinical utility of the information, and concerns over privacy and discrimination; for the first time, we are faced with the possibility of having complete access to our genetic data from birth, if not shortly after conception. Here, we discuss the evolution of the field toward this new reality and we consider the potentially far-reaching consequences and, at present, an unclear path toward developing best practices for implementation. PMID- 26499766 TI - Goniothalamin enhances TRAIL-induced apoptosis in colorectal cancer cells through DR5 upregulation and cFLIP downregulation. AB - The combination of TNF-related apoptosis-inducing ligand (TRAIL) and bioactive compound to enhance apoptosis in TRAIL-resistant cancer is one of cancer treatment strategies. TRAIL possesses the unique capacity to selectively induce apoptosis in cancer cells both in vitro and in vivo with little effect on normal cells. Recent studies have reported that there are many TRAIL-resistant cancers. Thus, bioactive compounds that enhance cytotoxicity of TRAIL would be potential candidates for cancer therapeutic application. This study evaluated the cytotoxic and apoptosis induction upon combined treatment of TRAIL and goniothalamin, the natural styryl-lactone compound extracted from plant Goniothalamus spp., in LoVo cells. The results showed that a combination of goniothalamin and TRAIL enhanced caspase-dependent apoptosis induction in LoVo cells via both death receptor- and mitochondrial-mediated apoptosis pathways. In addition, goniothalamin enhanced TRAIL-induced apoptosis through increased death receptor DR5 expression and decreased anti-apoptotic regulator cFLIP. Interestingly, goniothalamin increased translocation of DR5 to cell surface and consequently contributed to the enhancement of TRAIL-induced apoptosis. In conclusion, this is the first report showing the combined treatment of goniothalamin and TRAIL was able to effectively enhance TRAIL-mediated apoptosis induction in TRAIL-refractory colorectal cancer, LoVo cells. Therefore, this study may offer a strategic cancer treatment against TRAIL-resistant cancers. PMID- 26499768 TI - A Review on Novel Breast Cancer Therapies: Photodynamic Therapy and Plant Derived Agent Induced Cell Death Mechanisms. AB - This review article presents an extensive examination of risk factors for breast cancer, treatment strategies with special attention to photodynamic therapy and natural product based treatments. Breast cancer remains the most commonly occurring cancer in women worldwide and the detection, treatment, and prevention are prominent concerns in public health. Background information on current developments in treatment helps to update the approach towards risk assessment. Breast cancer risk is linked to many factors such as hereditary, reproductive and lifestyle factors. Minimally invasive Photodynamic therapy (PDT) can be used in the management of various cancers; it uses a light sensitive drug (a photosensitizer, PS) and a light of visible wavelength, to destroy targeted cancer cells. State of the art analyses has been carried out to investigate advancement in the search for the cure and control of cancer progression using natural products. Traditional medicinal plants have been used as lead compounds for drug discovery in modern medicine. Both PDT and plant derived drugs induce cell death via different mechanisms including apoptosis, necrosis, autophagy, cell cycle regulation and even the regulation of various cell signalling pathways. PMID- 26499767 TI - Risk of infectious complications associated with blood transfusion in elective spinal surgery-a propensity score matched analysis. AB - BACKGROUND CONTEXT: Although the negative aspects of blood transfusion are increasingly recognized, less is known about transfusion-related risks in spinal surgery. PURPOSE: This study was designed to determine whether perioperative allogeneic blood transfusion is associated with increased risk of infectious complications after elective spinal surgery. STUDY DESIGN: A retrospective cohort study with propensity score matched analysis was carried out. PATIENT SAMPLE: Data of patients with spinal canal stenosis and spondylolisthesis who underwent elective lumbar surgeries (decompression or fusion) were obtained from the Diagnosis Procedure Combination database, a nationwide administrative inpatient database in Japan. OUTCOME MEASURES: Clinical outcomes included in-hospital death and the occurrence of infectious complications (surgical site infection [SSI], respiratory tract infection, urinary tract infection, and sepsis). METHODS: Patients' clinical information, including sex, age, type of hospital, preoperative comorbidities, duration of anesthesia, cell saver use, and volume of allogeneic blood transfused, were investigated. Patients transfused with >840 mL (6 units) were excluded. Propensity scores for receiving transfusion were calculated, with one-to-one matching based on estimated propensity scores to adjust for patients' baseline characteristics. The proportions of complications were compared in patients with and without transfusions. This study was funded by grants from the Ministry of Health, Labour and Welfare, Japan. RESULTS: Of the 84,650 patients identified, 5,289 patients (6.1%) received transfusions, with 4,436 (5.2%) receiving up to 840 mL. One-to-one propensity score matching resulted in 4,275 pairs with and without transfusion. Patients transfused were at increased risk of SSI (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.4 2.5; p<.001) and urinary tract infection (OR, 2.5; 95% CI, 1.5-4.2; p<.001) than those not transfused. CONCLUSIONS: Allogeneic blood transfusion after elective lumbar surgery was associated with increased risks of SSI and urinary tract infection. PMID- 26499769 TI - ASNC Leaves Its Mark. PMID- 26499770 TI - Evaluation of attenuation correction in cardiac PET using PET/MR. AB - BACKGROUND: Simultaneous acquisition Positron emission tomography/magnetic resonance (PET/MR) is a new technology that has potential as a tool both in research and clinical diagnosis. However, cardiac PET acquisition has not yet been validated using MR imaging for attenuation correction (AC). The goal of this study is to evaluate the feasibility of PET imaging using a standard 2-point Dixon volume interpolated breathhold examination (VIBE) MR sequence for AC. METHODS AND RESULTS: Evaluation was performed in both phantom and patient data. A chest phantom containing heart, lungs, and a lesion insert was scanned by both PET/MR and PET/CT. In addition, 30 patients underwent whole-body 18F fluorodeoxyglucose PET/CT followed by simultaneous cardiac PET/MR. Phantom study showed 3% reduction of activity values in the myocardium due to the non-inclusion of the phased array coil in the AC. In patient scans, average standardized uptake values (SUVs) obtained by PET/CT and PET/MR showed no significant difference (n = 30, 4.6 +/- 3.5 vs 4.7 +/- 2.8, P = 0.47). There was excellent per patient correlation between the values acquired by PET/CT and PET/MR (R 2 = 0.97). CONCLUSIONS: Myocardial SUVs PET imaging using MR for AC shows excellent correlation with myocardial SUVs obtained by standard PET/CT imaging. The 2-point Dixon VIBE MR technique can be used for AC in simultaneous PET/MR data acquisition. PMID- 26499771 TI - Case vignettes based on EQ-5D to elicit stated preferences for health services utilization from the insurees' perspective. AB - BACKGROUND: There is little evidence as to why or why not insurees decide to seek medical services. Steps prior to the entry of the insuree into the professional health care system have not been sufficiently examined and can only be partially described by secondary data of the statutory health insurance (SHI). We report the first investigation using case vignettes based on the generic health-related quality of life questionnaire EQ-5D as part of a choice study to assess insurees' stated preferences in health services utilization. METHODS: We invited 1500 randomly selected citizens (age 30 to 70 years) from the East German state of Saxony-Anhalt by postal mail to participate in the choice study. Attributes of the case vignettes involved in choice tasks were the five dimensions of the EQ 5D. We used multilevel mixed effects logit regression analysis with the dependent variables: preference to seek medical services (model 1) and preferred time until consultation (model 2) for the assessed case vignette. The EQ-5D attributes of the case vignettes and participant characteristics served as the independent variables. We also included the respondent's certainty of choosing from the choice set, and the order of questions of the questionnaire as control variables. RESULTS: Of the 1500 questionnaires 683 were evaluable (net response rate 48.0%). On the level of the case vignettes, problems in all five dimensions of the EQ-5D were statistically significant factors of the estimated likelihood to seek medical services (model 1). On the respondent level, there was a significant relationship between the preference for medical consultation for the assessed case vignette and the respondent's gender, age, educational level, the existence of a regular doctor, and the certainty of choosing from the choice set. Problems in four of the five dimensions of the EQ-5D (except anxiety/depression) of the case vignettes were significantly associated with the preferred time until consultation (model 2). On the respondent level, gender, educational level, the certainty of choosing from the choice set, and the order of questions of the questionnaire were significant determinants of the time until consultation. CONCLUSIONS: Our study offers a promising new approach for the national and cross national study of preferences in health services utilization from the insurees' perspective. PMID- 26499772 TI - Turning Back the Clock on Women's Health in Medically Underserved Communities. PMID- 26499774 TI - Phase Space Structures Explain Hydrogen Atom Roaming in Formaldehyde Decomposition. AB - We re-examine the prototypical roaming reaction--hydrogen atom roaming in formaldehyde decomposition--from a phase space perspective. Specifically, we address the question "why do trajectories roam, rather than dissociate through the radical channel?" We describe and compute the phase space structures that define and control all possible reactive events for this reaction, as well as provide a dynamically exact description of the roaming region in phase space. Using these phase space constructs, we show that in the roaming region, there is an unstable periodic orbit whose stable and unstable manifolds define a conduit that both encompasses all roaming trajectories exiting the formaldehyde well and shepherds them toward the H2...CO well. PMID- 26499773 TI - Treated versus non-treated subjects with depression from a 30-year cohort study: prevalence and clinical covariates. AB - The aim of this study was to determine prevalence rates of several components of depression (unipolar and bipolar major, minor, recurrent brief depression, and dysthymia) and to identify covariates of treatment. We analysed a representative population-based, long-term prospective cohort study from age 20 to 50. Across the seven semi-structured interviews, generalized estimating equations examined the associations between diagnoses and treatment status during the course. The results show that the mean annual treatment rate across 30 years in persons with MDE was 39.2%. The weighted treatment prevalence for any depressive disorder was 23.4% (15.7% for MDE, 4.3% for minor depressive disorders and 3.4% for non diagnosed subjects). Persons were more likely to seek treatment as they grew older. Women with MDE had triple the treatment prevalence of men (23.8 vs. 7.4%). Variables of distress/suffering under depression (OR 1.36-1.52) and the number of diagnostic depressive symptoms (OR 1.47) were statistically significant predictors of treatment, as were episode duration (OR 2.21) and various variables assessing impairment due to depression (OR 4.65-8.02). In conclusion, only a minority of persons with depressive disorders seek professional treatment in the year of disorder onset. Women and subjects suffering from high levels of depressive symptoms, frequent episodes, long episode duration and consecutive high distress and impairment were more likely to seek treatment. PMID- 26499775 TI - Disparities in Adherence to Pediatric Sepsis Guidelines across a Spectrum of Emergency Departments: A Multicenter, Cross-Sectional Observational In Situ Simulation Study. AB - BACKGROUND: Each year in the United States, 72,000 pediatric patients develop septic shock, at a cost of $4.8 billion. Adherence to practice guidelines can significantly reduce mortality; however, few methods to compare performance across a spectrum of emergency departments (EDs) have been described. OBJECTIVES: We employed standardized, in situ simulations to measure and compare adherence to pediatric sepsis guidelines across a spectrum of EDs. We hypothesized that pediatric EDs (PEDs) would have greater adherence to the guidelines than general EDs (GEDs). We also explored factors associated with improved performance. METHODS: This multi-center observational study examined in situ teams caring for a simulated infant in septic shock. The primary outcome was overall adherence to the pediatric sepsis guideline as measured by six subcomponent metrics. Characteristics of teams were compared using multivariable logistic regression to describe factors associated with improved performance. RESULTS: We enrolled 47 interprofessional teams from 24 EDs. Overall, 21/47 teams adhered to all six sepsis metrics (45%). PEDs adhered to all six metrics more than GEDs (93% vs. 22%; difference 71%, 95% confidence interval [CI] 43-84). Adherent teams had significantly higher Emergency Medical Services for Children readiness scores, MD composition of physicians to total team members, teamwork scores, provider perceptions of pediatric preparedness, and provider perceptions of sepsis preparedness. In a multivariable regression model, only greater composite team experience had greater adjusted odds of achieving an adherent sepsis score (adjusted odds ratio 1.38, 95% CI 1.01-1.88). CONCLUSIONS: Using standardized in situ scenarios, we revealed high variability in adherence to the pediatric sepsis guideline across a spectrum of EDs. PEDs demonstrated greater adherence to the guideline than GEDs; however, in adjusted analysis, only composite team experience level of the providers was associated with improved guideline adherence. PMID- 26499776 TI - Biomechanics of posterior instrumentation in L1-L3 lateral interbody fusion: Pedicle screw rod construct vs. transfacet pedicle screws. AB - BACKGROUND: The use of pedicle screws is the gold standard for supplemental posterior fixation in lateral interbody fusion. Information about the performance of transfacet pedicle screws compared to standard pedicle screws and rods in the upper lumbar spine with or without a lateral interbody fusion device in place is limited. METHODS: Fifteen fresh frozen human cadaveric lumbar spine segments (T12 L4) were studied using standard pure moment flexibility tests. Specimens were divided into two groups to receive either bilateral transfacet pedicle screws (n=8) or bilateral pedicle screws (n=14). Stability of each motion segment (L1-L2 and L2-L3) was evaluated intact, with posterior instrumentation with an intact disc, with posterior instrumentation and a lateral interbody fusion device in place, and following cyclic loading with the interbody device and posterior instrumentation still in place. Both raw values of motion (range of motion, lax zone and stiff zone) and normalized mobility (ratios to intact) were analyzed for each case. FINDINGS: In terms of immediate stability, transfacet pedicle screws performed equivalent to similarly sized pedicle screws, both with intact disc and with lateral interbody fusion device in all directions of loading. Stability following cyclic loading decreased significantly during lateral bending and axial rotation. INTERPRETATION: Posterior fixation with transfacet pedicle screws provides equivalent immediate stability to similarly sized pedicle screws. However, in the presence of a lateral interbody fusion device, pedicle screws seem to resist loosening more and may be a better option for fusion in the upper lumbar spine. PMID- 26499777 TI - The STORM trial and beyond: narrowing the horizon of adjuvant sorafenib for postoperative hepatocellular carcinoma. PMID- 26499778 TI - Simple laboratory score improves the preoperative diagnosis of adnexal mass. AB - We assessed the diagnostic accuracy of a newly developed laboratory score-based on CA125, platelet count (PLT), C-reactive protein (CRP), and fibrinogen levels in the preoperative diagnosis of adnexal mass. In this retrospective single center study, we analyzed records of 142 patients with 54 malignant (38 %) and 88 benign (62 %) ovarian tumors. Preoperative levels of CA125, PLT, CRP, and fibrinogen were dichotomized according to the common cutoff values (CA125, 35 U/ml; PLT, 350/nl; CRP, 5.0 mg/l; fibrinogen, 400 mg/dl), resulting in "1" for results above the cutoff and "0" for results within the normal ranges. The values (1 or 0) were summarized to a "low" (0-2) or "high" (3-4) score. Its diagnostic accuracy was compared to the "gold standard," CA125. All parameters differed significantly between malignant and benign cases. The score was false positive in 5/88 (5.7 %) and false negative in 13/54 (24 %) of cases. Conversely, CA125 was false positive in 18/88 (20.4 %) and false negative in 4/54 (7.4 %). The diagnostic accuracy of CA125 (>35 U/ml) was sensitivity 0.93, specificity 0.80, positive predictive value (PPV) 0.74, negative predictive value (NPV) 0.95, and positive likelihood ratio (weighted by prevalence) (+LH/p) 2.78. The diagnostic accuracy of the score was sensitivity 0.76, specificity 0.94, PPV 0.89, NPV 0.86, and +LH/p 8.2. In conclusion, the score is easy to use and generates no additional costs. It provides a better specificity, PPV, and +LH/p than CA125. The sensitivity and NPV are lower, but acceptable. A validation of the score in a large patient cohort is needed. PMID- 26499779 TI - RRP12 is a crucial nucleolar protein that regulates p53 activity in osteosarcoma cells. AB - RRP12 (ribosomal RNA processing 12 homolog), a nucleolar protein, plays important roles in cell cycle progression and the response to deoxyribonucleic acid (DNA) damage in yeast cells. However, its role has not been investigated in mammalian cells that possess p53, which has close functional association to nucleolus. We explored the role of RRP12 in nucleolar stress condition using an osteosarcoma cell line, U2OS. To induce DNA damage and nucleolar disruption, two cytotoxic drugs, doxorubicin and actinomycin D were used. Cytotoxic stress resulted nucleolar disruption induced cell cycle arrest and apoptosis in U2OS cells. However, RRP12 overexpression promoted resistance to cytotoxic stress. In contrast, RRP12 silencing enhanced susceptibility to cytotoxic stress. During drug treatment, p53 activity and cell death were suppressed by RRP12 overexpression but promoted by RRP12 silencing. This study demonstrated that RRP12 was crucial for cell survival during cytotoxic stress via the repression of p53 stability. Thus, targeting RRP12 may enhance chemotherapeutic effect in cancers. PMID- 26499780 TI - Role of miR-138 in the regulation of larynx carcinoma cell metastases. AB - The cases of larynx carcinoma (LC) with poor prognosis largely result from the distal metastases of the primary tumor. Since microRNAs (miRNAs) play critical roles during cancer metastases, determination of the involved miRNAs in the regulation of the LC metastases may provide novel therapeutic targets for LC treatment. Here, we studied the LC specimens from the patients and found that the levels of miR-138 were significantly decreased and the levels of ZEB2, a critical factor that regulates cancer cell invasiveness, were significantly increased in LC, compared to the paired normal larynx tissue. Metastatic LC appeared to contained lower levels of miR-138. Moreover, miR-138 and ZEB2 inversely correlated in LC specimens. Bioinformatics analyses showed that miR-138 targeted the 3'-untranslated region (3'-UTR) of ZEB2 mRNA to inhibit its translation, which was confirmed in a luciferase reporter assay. Further, miR-138 overexpression inhibited ZEB2-mediated cell invasiveness, while miR-138 depletion increased ZEB2-mediated cell invasiveness in LC cells. Together, our data suggest that miR-138 suppression in LC cells may promote ZEB2-mediated cancer metastases. Thus, miR-138 appears to be an intriguing therapeutic target to prevent metastases of LC. PMID- 26499781 TI - Diagnostic and prognostic values of tissue hsa-miR-30c and hsa-miR-203 in prostate carcinoma. AB - Prostate cancer (PCa) has become a prevalent malignant disease in males globally. Accumulating data suggested that hsa-microRNAs (miRNAs) could be potential biomarkers for tumor diagnosis due to their important roles in the cell cycle. This study investigated the diagnostic and prognostic values of hsa-miR-203 and hsa-miR-30c in PCa tissues. There were 44 pathologically confirmed PCa patients who were enrolled in this study. Tissue samples were collected from both tumor tissues and adjacent normal tissues. RNA was extracted and the expression levels of hsa-miR-203 and hsa-miR-30c in tumor and normal tissues were compared. The receiver operating characteristic (ROC) curves were plotted to evaluate the reliability of hsa-miR-203 and hsa-miR-30c in detecting PCa. All subjects in this study were followed up by 36 months, and the Kaplan-Meier method was conducted to investigate the survival status of PCa patients. The average relative expressions of hsa-miR-203 and hsa-miR-30c in tumor tissues were significantly different from those in adjacent normal tissues (P < 0.001), and the predictive power of the two hsa-miRNAs for PCa prognosis was reliable. Besides that, the average survival times of low-hsa-miR-30c and high-hsa-miR-203 groups were significantly lower than those of the corresponding groups with the log-rank P of 0.015 and 0.023, respectively. In summary, our study suggested that both hsa-miR-203 and hsa-miR 30c are potential biomarkers for detection and prognosis of PCa. PMID- 26499782 TI - Clinical effects of autologous dendritic cells combined with cytokine-induced killer cells followed by chemotherapy in treating patients with advanced colorectal cancer: a prospective study. AB - The objective of this study was to evaluate the effects of dendritic cell and cytokine-induced killer (DC-CIK) cell-based immunotherapy combined with chemotherapy on the treatment of patients with advanced colorectal cancer. We prospectively included patients with advanced colorectal cancer and assessed the efficacy of DC-CIK cell-based immunotherapy combined with chemotherapy compared to treatment with chemotherapy alone. T cell subtypes, progression-free survival (PFS), overall survival (OS), and adverse events were evaluated in each group. In total, 134 patients were included in the DC-CIK group and 121 patients were included in the control group. No significant differences were observed in the percentages of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), and NK cells after DC-CIK cell based immunotherapy compared to before chemotherapy in the DC-CIK group. The median PFS and OS in the DC-CIK treatment group were 8.8 months (95 % CI 8.4-9.1) and 14.7 months (95 % CI 13.9-15.5), respectively, which were significantly improved compared to the PFS and OS in the control group. The frequencies of grade III and IV leukopenia (8.2 vs. 19.0 %, P = 0.011), grade III and IV anemia (3.0 vs. 9.1 %, P = 0.039), and grade III and IV thrombocytopenia (3.7 vs. 10.7 %, P = 0.029) were significantly lower in the DC-CIK group compared to the control group. DC-CIK cell-based immunotherapy could induce an immune response against colorectal cancer and prolong PFS and OS. DC-CIK cell-based immunotherapy combined with chemotherapy had a significant benefit in terms of survival in patients with colorectal cancer compared to chemotherapy alone. PMID- 26499783 TI - Green tea polyphenol EGCG suppresses osteosarcoma cell growth through upregulating miR-1. AB - (-)-Epigallocatechin-3-gallate (EGCG), the most abundant and active polyphenol in green tea, has been demonstrated to have anticancer effects in a wide variety of human cancer. MicroRNAs (miRNAs) are a class of short noncoding RNAs and play important role in gene regulation and are critically involved in the pathogenesis and progression of human cancer. This study aims to investigate the effects of EGCG on osteosarcoma (OS) cells and elucidate the underlying mechanism. Cellular function assays revealed that EGCG inhibited cell proliferation, induced cell cycle arrest and promoted apoptosis of OS cells in vitro, and also inhibited the growth of transplanted tumors in vivo. By miRNA microarray and RT-qPCR analysis, miR-1 was found to be significantly upregulated in MG-63 and U-2OS treated by EGCG in dose- and time-dependent manners, and miR-1 downregulation by inhibitor mimics attenuated EGCG-induced inhibition on cell growth of OS cells. We also confirmed that miR-1 was also frequently decreased in clinical OS tumor tissues. Moreover, both EGCG and miR-1 mimic inhibited c-MET expression, and combination treatment with EGCG and c-MET inhibitor (crizotinib) had enhanced inhibitory effects on the growth of MG-63 and U-2OS cells. Taken together, these results suggest that EGCG has an anticancer effect on OS cells, at least partially, through regulating miR-1/c-MET interaction. PMID- 26499784 TI - MiR-613: a novel diagnostic and prognostic biomarker for patients with esophageal squamous cell carcinoma. AB - MicroRNA-613 (miR-613) plays important roles in tumorigenesis and cancer progression. We aimed to evaluate its expression level and potential for diagnosis and prognosis in esophageal squamous cell cancer (ESCC). We examined miR-613 expression in 60 pairs of ESCC cancerous and matched paracancerous tissues, serum samples from 75 ESCC patients and 75 healthy volunteers, and 105 formalin-fixed paraffin-embedded (FFPE) tissue samples using quantitative reverse transcription polymerase chain reaction. Receiver-operating characteristic (ROC) curve analysis, Kaplan-Meier method, and Cox regression were applied to analyze its diagnostic and prognostic value. MiR-613 was significantly decreased in ESCC tissue compared with paracancerous tissue (P < 0.001). Moreover, the expression level of miR-613 was significantly reduced with increased T stage of ESCC. Statistically significant difference between ESCC patients and healthy controls in expression level of miR-613 (0.89 +/- 0.73 vs. 1.71 +/- 1.03, P < 0.001) was found. The area under the ROC curve (AUC) based on serum miR-613 was 0.767 +/- 0.040. We also performed analysis on early-stage patients and revealed that the AUC value was 0.728 +/- 0.052 (P < 0.001). The Kaplan-Meier curve revealed that the downregulation of miR-613 was related to worse overall survival (OS) and progression-free survival (PFS) of ESCC patients (P = 0.018 and P = 0.035, respectively). Furthermore, the multivariate analysis identified miR-613 to be an independent prognostic factor for OS and PFS (P = 0.031 and P = 0.006, respectively) In conclusion, miR-613 is significantly reduced in cancerous tissue and serum samples of ESCC patients. It can serve as an ideal indicator for the diagnosis and prognosis of ESCC. PMID- 26499785 TI - Is revisional surgery mandatory when an unexpected sarcoma diagnosis is made following primary surgery? AB - BACKGROUND: Soft tissue sarcomas (STS) are often diagnosed unexpectedly after surgery, and many excisions are incomplete. As histopathological assessments are challenging, patients later referred to comprehensive cancer centers (CCC) often come with an unclear status. This can make treatment planning problematic. We investigated the reliability of primary histopathological assessments, whether revisional surgery improved resection status, and the prognostic value of residual tumor at re-excision. METHODS: We analyzed the demographic and clinical characteristics of all patients referred to our CCC between 2003 and 2013. We compared patients treated exclusively at our CCC with those who had primary surgery elsewhere, and focused on resection margins, re-excision type, residual tumor, resection status after re-excision, and oncological outcome. RESULTS: Over half (n = 110) of all patients (n = 204) were referred from elsewhere. Seventy one had undergone an excision without suspicion of malignancy. Resection status in referred patients was significantly inferior to the CCC group (p < 0.0001), although the latter had significantly more serious tumors and advanced disease stages (p < 0.05). The residual tumor rate was 53.13%, with a significantly higher probability in an upper extremity (p = 0.001). Initial histopathological classification was misleading in 46.9% of cases. Re-excision improved resection status in 69% of cases. Residual tumor presumably leads to higher rates of local recurrence (p = 0.057) and significantly shorter times to recurrence (p < 0.05). CONCLUSIONS: Re-excision should always follow unplanned STS excisions. Resection margins and histopathological assessments from referring institutions are often unreliable and unsuitable for treatment planning. Residual tumor is a risk factor for earlier and more likely local recurrence. PMID- 26499786 TI - Living Kidney Donors With Adrenal Incidentalomas: Are They Appropriate Donors? AB - OBJECTIVE: To determine the incidence of adrenal incidentalomas (AIs) in a single center series of living renal donors, to describe an evaluation algorithm for AIs in this patient population, and to compare the complication rates of hand assisted laparoscopic donor nephrectomy (HALDN) with those of combined HALDN and adrenalectomy. METHODS: We performed a single-center, retrospective study of consecutive living kidney donors who underwent laparoscopic nephrectomy for transplantation, with or without simultaneous ipsilateral adrenalectomy, between January 2008 and September 2014. RESULTS: During the study period, AIs were detected in 18 of 1033 potential living renal donors who underwent computerized tomographic angiography. Application of additional donor selection criteria and of an adrenal mass assessment algorithm resulted in 849 HALDN, of which 13 were combined with simultaneous adrenalectomy. The hospital length of stay (2.4 vs 2.6 days), perioperative (0.025 vs 0.077), early (0.073 vs 0.077), and late (0.014 vs 0.077) postoperative complication rates, and conversion to open donor nephrectomy (0.008 vs 0.00) were not significantly different. Mean operative time was significantly longer in the adrenalectomy group. None of the adrenal masses were malignant. CONCLUSION: Here, we presented our algorithm to manage the living kidney donors with AIs. Although donor population with AIs was relatively small in number, simultaneous adrenalectomy and ipsilateral nephrectomy seemed to be technically safe and conferred no identifiable increased risk of malignancy for the kidney transplant donor, when the incidentaloma is nonfunctional and less than or equal to 4 cm as assessed by preoperative imaging. PMID- 26499787 TI - Preparation and Characterization of Ultrarapidly Dissolving Orodispersible Films for Treating and Preventing Iodine Deficiency in the Pediatric Population. AB - Iodine deficiency is a public health problem that is easily prevented in many countries through having a salt iodization program. However, the World Health Organization (WHO) recommends that particular population groups including infants and young children have a sufficient level of daily iodine intake, while also reducing salt consumption in their diet. While many iodine supplements are available, swallowing tablet supplements is physically difficult for young children; thus, there is a need for the development of novel iodine delivery systems for pediatric patients. In this study a novel, ultrarapidly dissolving, nanofiber-based orodispersible film formulation containing iodine which is constructed from nanofibers was manufactured using an electrospinning technique. The potassium iodate (KIO3)-loaded poly(ethylene oxide) (PEO) fiber orodispersible films dissolve within seconds on wetting (applying on the tongue) without the need for the consumption of water. The electrospinning process and KIO3 loading did not alter the crystallinity and conformation of PEO. With high loading, KIO3 nanocrystals are present in the fibers. This formulation design allows easy administration of iodine for preventing childhood iodine deficiency. We have also described a novel and easy method for producing and harvesting nanocrystals of inorganic salts that can be potentially adopted for use in other relevant fields. PMID- 26499788 TI - Covalent bonding of YIGSR and RGD to PEDOT/PSS/MWCNT-COOH composite material to improve the neural interface. AB - The development of coating materials for neural interfaces has been a pursued to improve the electrical, mechanical and biological performances. For these goals, a bioactive coating was developed in this work featuring a poly(3,4 ethylenedioxythiophene) (PEDOT)/carbon nanotube (CNT) composite and covalently bonded YIGSR and RGD. Its biological effect and electrical characteristics were assessed in vivo on microwire arrays (MWA). The coated electrodes exhibited a significantly higher charge storage capacity (CSC) and lower electrochemical impedance at 1 kHz which are desired to improve the stimulating and recording performances, respectively. Acute neural recording experiments revealed that coated MWA possess a higher signal/noise ratio capturing spikes undetected by uncoated electrodes. Moreover, coated MWA possessed more active sites and single units, and the noise floor of coated electrodes was lower than that of uncoated electrodes. There is little information in the literature concerning the chronic performance of bioactively modified neural interfaces in vivo. Therefore in this work, chronic in vivo tests were conducted and the PEDOT/PSS/MWCNT-polypeptide coated arrays exhibited excellent performances with the highest mean maximal amplitude from day 4 to day 12 during which the acute response severely compromised the performance of the electrodes. In brief, we developed a simple method of covalently bonding YIGSR and RGD to a PEDOT/PSS/MWCNT-COOH composite improving both the biocompatibility and electrical performance of the neural interface. Our findings suggest that YIGSR and RGD modified PEDOT/PSS/MWCNT is a promising bioactivated composite coating for neural recording and stimulating. PMID- 26499789 TI - Different combinations of morpho-physiological traits are responsible for tolerance to drought in wild tomatoes Solanum chilense and Solanum peruvianum. AB - Herbaceous species can modify leaf structure during the growing season in response to drought stress and water loss. Evolution can select combinations of traits in plants for efficient water use in restricted environments. We investigated plant traits that mediate adaptation and acclimation to water stress in two herbaceous drought-tolerant species. Anatomical, morphological and physiological traits related to stems and leaves were examined under optimal watering (OW) and a long period of restricted watering (RW) in 11 accessions from three Solanaceae species (Solanum chilense, S. peruvianum and S. lycopersicum). The relationships between these traits were tested using linear regression and PCA. There were significant differences in anatomical traits between the species under both OW and RW, where leaf area correlated with stem diameter. Proline and total carbohydrates accumulated highly in S. chilense and S. peruvianum, respectively, and these osmolytes were strongly correlated with increased osmotic potential. Stomatal density varied between species but not between acclimation treatments, while stomatal rate was significantly higher in wild tomatoes. There was a strong positive relationship between stem growth rate and a group of traits together expressed as total stomatal number. Total stomata is described by integration of leaf area, stomatal density, height and internode length. It is proposed that constitutive adaptations and modifications through acclimation that mediate RW play an important role in tolerance to drought stress in herbaceous plants. The capacity for growth under drought stress was not associated with any single combination of traits in wild tomatoes, since the two species differed in relative levels of expression of various phenotypic traits. PMID- 26499790 TI - Fatal subarachnoid hemorrhage associated with internal carotid artery dissection resulting from whiplash trauma. AB - Spinal injury following inertial loading of the head and neck (whiplash) is a common sequel of low speed traffic crashes. A variety of non-musculoskeletal injuries have been described in association with injury to the spine following whiplash trauma, including traumatic brain injury, vestibular derangement, and cranial nerve injury, among others. Vascular injuries in the head and neck have, however, only rarely been described. We present the case of a middle-aged male who sustained an ultimately fatal injury that resulted from injury to the internal carotid artery (ICA) and intracerebral vascular structures following a hard braking maneuver, with no direct head- or neck contact with the vehicular interior. Based on this unusual mechanism of injury we reviewed hospital data from the United States nationwide inpatient database (NIS) to assess the frequency of similar injuries reportedly resulting from traffic crashes. The post mortem examination revealed a left internal carotid artery dissection associated with subarachnoid hemorrhage (SAH). Based on the close temporal association, the absent prior history, and the plausibility of the injury mechanism, the injury was attributed to the braking maneuver. An analysis of NIS data demonstrated that the prevalence of subarachnoid hemorrhage is significantly higher when there is a traumatic etiology, and higher yet when the trauma is a traffic crash (odds ratio 3.3 and 4.3, respectively). The presented case, together with the hospital inpatient data analysis, indicate that although SAH in combination with ICA dissection is relatively rare, it is substantially more probable following a traffic crash. In a clinical or forensic setting the inference that magnitude of a trauma was low should not serve as a basis for either excluding a cervical artery dissection from a differential diagnosis, or for excluding the trauma as a cause of a diagnosed dissection. This case report illustrates a rare fatal outcome of inertial load to the head and neck induced by a sudden braking event in a commonly experienced non-collision traffic incident. The likely mechanism of injury resulted from interaction between the occupant and the 3-point seat belt. These findings indicate that ICA dissections are substantially more likely to be associated with SAH following head and neck trauma, regardless of the magnitude of the traumatic event or whether an impact was involved. PMID- 26499791 TI - Short-term outcome of percutaneous posterior tibial nerve stimulation (PTNS) for the treatment of faecal incontinence. AB - BACKGROUND: The aim of the present study was to establish the efficacy of percutaneous posterior tibial nerve stimulation (PTNS) in treating flatal, urge and passive faecal incontinence (FI). METHODS: A prospective study with 55 patients with FI was carried out. Clinical anamnesis, physical examination, a reverse visual analogue scale (VAS) score, Wexner score and the American Society of Colon and Rectal Surgeons quality of life score were recorded at baseline and 6 months, along with an incontinence diary. Subjects underwent one weekly session for 12 consecutive weeks and then continued with six additional fortnightly sessions. An intention-to-treat analysis was performed. RESULTS: Fifty-five patients (44 females; mean age 58.62 +/- 10.74 years) with FI were treated with PTNS. The origins of the incontinence were obstetric (52.7 %) and perineal surgery (34.5 %). Eight patients did not continue with the second stage of treatment. The median Wexner baseline value was 9.98. After 6 months, it had decreased to 4.55 (p < 0.001). The visual analogue scale (VAS) increased from 4.94 to 6.80 (p < 0.001). There was a significant improvement in lifestyle, coping/behaviour, depression/self-perception and embarrassment scores. With respect to different types of FI, there was an improvement in the Wexner score both in patients with true passive FI and in those with urge or mixed FI. CONCLUSIONS: PTNS is an effective treatment for FI. Patients with passive or urge FI can benefit from this therapy, with improvement of the Wexner score and quality of life variables. PMID- 26499792 TI - Functional Characterization of Monomeric GTPase Rab1 in the Secretory Pathway of Leishmania. AB - Leishmania secretes a large number of its effectors to the extracellular milieu. However, regulation of the secretory pathway in Leishmania is not well characterized. Here, we report the cloning, expression, and characterization of the Rab1 homologue from Leishmania. We have found that LdRab1 localizes in Golgi in Leishmania. To understand the role of LdRab1 in the secretory pathway of Leishmania, we have generated transgenic parasites overexpressing GFP-LdRab1:WT, GFP-LdRab1:Q67L (a GTPase-deficient dominant positive mutant of Rab1), and GFP LdRab1:S22N (a GDP-locked dominant negative mutant of Rab1). Surprisingly, our results have shown that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N does not disrupt the trafficking and localization of hemoglobin receptor in Leishmania. To determine whether the Rab1-dependent secretory pathway is conserved in parasites, we have analyzed the role of LdRab1 in the secretion of secretory acid phosphatase and Ldgp63 in Leishmania. Our results have shown that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N significantly inhibits the secretion of secretory acid phosphatase by Leishmania. We have also found that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N retains RFP-Ldgp63 in Golgi and blocks the secretion of Ldgp63, whereas the trafficking of RFP-Ldgp63 in GFP LdRab1:WT-expressing cells is unaltered in comparison with control cells. Taken together, our results have shown that the Rab1-regulated secretory pathway is well conserved, and hemoglobin receptor trafficking follows an Rab1-independent secretory pathway in Leishmania. PMID- 26499793 TI - The PTK7 and ROR2 Protein Receptors Interact in the Vertebrate WNT/Planar Cell Polarity (PCP) Pathway. AB - The non-canonical WNT/planar cell polarity (WNT/PCP) pathway plays important roles in morphogenetic processes in vertebrates. Among WNT/PCP components, protein tyrosine kinase 7 (PTK7) is a tyrosine kinase receptor with poorly defined functions lacking catalytic activity. Here we show that PTK7 associates with receptor tyrosine kinase-like orphan receptor 2 (ROR2) to form a heterodimeric complex in mammalian cells. We demonstrate that PTK7 and ROR2 physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. In the Xenopus embryo, Ptk7 functionally interacts with Ror2 to regulate protocadherin papc expression and morphogenesis. Furthermore, we show that Ptk7 is required for papc activation induced by Wnt5a. Interestingly, we find that Wnt5a stimulates the release of the tagged Ptk7 intracellular domain, which can translocate into the nucleus and activate papc expression. This study reveals novel molecular mechanisms of action of PTK7 in non-canonical WNT/PCP signaling that may promote cell and tissue movements. PMID- 26499794 TI - Utilization of Dioxygen by Carotenoid Cleavage Oxygenases. AB - Carotenoid cleavage oxygenases (CCOs) are non-heme, Fe(II)-dependent enzymes that participate in biologically important metabolic pathways involving carotenoids and apocarotenoids, including retinoids, stilbenes, and related compounds. CCOs typically catalyze the cleavage of non-aromatic double bonds by dioxygen (O2) to form aldehyde or ketone products. Expressed only in vertebrates, the RPE65 sub group of CCOs catalyzes a non-canonical reaction consisting of concerted ester cleavage and trans-cis isomerization of all-trans-retinyl esters. It remains unclear whether the former group of CCOs functions as mono- or di-oxygenases. Additionally, a potential role for O2 in catalysis by the RPE65 group of CCOs has not been evaluated to date. Here, we investigated the pattern of oxygen incorporation into apocarotenoid products of Synechocystis apocarotenoid oxygenase. Reactions performed in the presence of (18)O-labeled water and (18)O2 revealed an unambiguous dioxygenase pattern of O2 incorporation into the reaction products. Substitution of Ala for Thr at position 136 of apocarotenoid oxygenase, a site predicted to govern the mono- versus dioxygenase tendency of CCOs, greatly reduced enzymatic activity without altering the dioxygenase labeling pattern. Reevaluation of the oxygen-labeling pattern of the resveratrol-cleaving CCO, NOV2, previously reported to be a monooxygenase, using a purified enzyme sample revealed that it too is a dioxygenase. We also demonstrated that bovine RPE65 is not dependent on O2 for its cleavage/isomerase activity. In conjunction with prior research, the results of this study resolve key issues regarding the utilization of O2 by CCOs and indicate that dioxygenase activity is a feature common among double bond-cleaving CCOs. PMID- 26499795 TI - D-Amino Acid Probes for Penicillin Binding Protein-based Bacterial Surface Labeling. AB - Peptidoglycan is an essential and highly conserved mesh structure that surrounds bacterial cells. It plays a critical role in retaining a defined cell shape, and, in the case of pathogenic Gram-positive bacteria, it lies at the interface between bacterial cells and the host organism. Intriguingly, bacteria can metabolically incorporate unnatural D-amino acids into the peptidoglycan stem peptide directly from the surrounding medium, a process mediated by penicillin binding proteins (PBPs). Metabolic peptidoglycan remodeling via unnatural D-amino acids has provided unique insights into peptidoglycan biosynthesis of live bacteria and has also served as the basis of a synthetic immunology strategy with potential therapeutic implications. A striking feature of this process is the vast promiscuity displayed by PBPs in tolerating entirely unnatural side chains. However, the chemical space and physical features of this side chain promiscuity have not been determined systematically. In this report, we designed and synthesized a library of variants displaying diverse side chains to comprehensively establish the tolerability of unnatural D-amino acids by PBPs in both Gram-positive and Gram-negative organisms. In addition, nine Bacillus subtilis PBP-null mutants were evaluated with the goal of identifying a potential primary PBP responsible for unnatural D-amino acid incorporation and gaining insights into the temporal control of PBP activity. We empirically established the scope of physical parameters that govern the metabolic incorporation of unnatural D-amino acids into bacterial peptidoglycan. PMID- 26499796 TI - The Stable Interaction Between Signal Peptidase LepB of Escherichia coli and Nuclease Bacteriocins Promotes Toxin Entry into the Cytoplasm. AB - LepB is a key membrane component of the cellular secretion machinery, which releases secreted proteins into the periplasm by cleaving the inner membrane bound leader. We showed that LepB is also an essential component of the machinery hijacked by the tRNase colicin D for its import. Here we demonstrate that this non-catalytic activity of LepB is to promote the association of the central domain of colicin D with the inner membrane before the FtsH-dependent proteolytic processing and translocation of the toxic tRNase domain into the cytoplasm. The novel structural role of LepB results in a stable interaction with colicin D, with a stoichiometry of 1:1 and a nanomolar Kd determined in vitro. LepB provides a chaperone-like function for the penetration of several nuclease-type bacteriocins into target cells. The colicin-LepB interaction is shown to require only a short peptide sequence within the central domain of these bacteriocins and to involve residues present in the short C-terminal Box E of LepB. Genomic screening identified the conserved LepB binding motif in colicin-like ORFs from 13 additional bacterial species. These findings establish a new paradigm for the functional adaptability of an essential inner-membrane enzyme. PMID- 26499797 TI - The Blockade of NF-kappaB Activation by a Specific Inhibitory Peptide Has a Strong Neuroprotective Role in a Sprague-Dawley Rat Kernicterus Model. AB - Kernicterus, the permanent nerve damage occurring as a result of bilirubin precipitation, still occurs worldwide and may lead to death or permanent neurological impairments. However, the underlying mechanisms remain unclear, and effective therapeutic strategies are lacking. The present study aims to investigate the activation of NF-kappaB and to identify the effect of NF-kappaB inhibition on the newborn rat kernicterus model. The NF-kappaB essential modifier binding domain peptide (NBD), coupled with the HIV trans-activator of transcription peptide (TAT) was used to inhibit NF-kappaB. NF-kappaB was significantly activated in the cerebrum at 1 and 3 h (p < 0.05) after the model was established, as measured by EMSA. NF-kappaB activation was inhibited by intraperitoneal administration of TAT-NBD. The general conditions of the TAT-NBD treated rats were improved; meanwhile, these rats performed much better on the neurological evaluation, the rotarod test, and the Morris water maze test (p < 0.05) than the vehicle-treated rats at 28 days. Furthermore, the morphology of the nerve cells was better preserved in the TAT-NBD group, and these cells displayed less neurodegeneration and astrocytosis. Simultaneously, apoptosis in the brain was attenuated, and the levels of the TNF-alpha and IL-1beta proteins were decreased (p < 0.01). These results suggested that NF-kappaB was activated, and inhibition of NF-kappaB activation by TAT-NBD not only attenuated the acute neurotoxicity, apoptosis, and inflammation, but also improved the long term neurobehavioral impairments in the kernicterus model rats in vivo. Thus, inhibiting NF-kappaB activation might be a potential therapeutic approach for kernicterus. PMID- 26499798 TI - Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells. AB - WW domain-containing oxidoreductase (WWOX), originally marked as a likely tumor suppressor gene, has over the years become recognized for its role in a much wider range of cellular activities. Phenotypic effects displayed in animal studies, along with resolution of WWOX's architecture, fold, and binding partners, point to the protein's multifaceted biological functions. Results from a series of complementary experiments seem to indicate WWOX's involvement in metabolic regulation. More recently, clinical studies involving cases of severe encephalopathy suggest that WWOX also plays a part in controlling CNS development, further expanding our understanding of the breadth and complexity of WWOX behavior. Here we present a short overview of the various approaches taken to study this dynamic gene, emphasizing the most recent findings regarding WWOX's metabolic- and CNS-associated functions and their underlying molecular basis. PMID- 26499799 TI - Probing the Mec1ATR Checkpoint Activation Mechanism with Small Peptides. AB - Yeast Mec1, the ortholog of human ATR, is the apical protein kinase that initiates the cell cycle checkpoint in response to DNA damage and replication stress. The basal activity of Mec1 kinase is activated by cell cycle phase specific activators. Three distinct activators stimulate Mec1 kinase using an intrinsically disordered domain of the protein. These are the Ddc1 subunit of the 9-1-1 checkpoint clamp (ortholog of human and Schizosaccharomyces pombe Rad9), the replication initiator Dpb11 (ortholog of human TopBP1 and S. pombe Cut5), and the multifunctional nuclease/helicase Dna2. Here, we use small peptides to determine the requirements for Mec1 activation. For Ddc1, we identify two essential aromatic amino acids in a hydrophobic environment that when fused together are proficient activators. Using this increased insight, we have been able to identify homologous motifs in S. pombe Rad9 that can activate Mec1. Furthermore, we show that a 9-amino acid Dna2-based peptide is sufficient for Mec1 activation. Studies with mutant activators suggest that binding of an activator to Mec1 is a two-step process, the first step involving the obligatory binding of essential aromatic amino acids to Mec1, followed by an enhancement in binding energy through interactions with neighboring sequences. PMID- 26499800 TI - Coupling between Nutrient Availability and Thyroid Hormone Activation. AB - The activity of the thyroid gland is stimulated by food availability via leptin induced thyrotropin-releasing hormone/thyroid-stimulating hormone expression. Here we show that food availability also stimulates thyroid hormone activation by accelerating the conversion of thyroxine to triiodothyronine via type 2 deiodinase in mouse skeletal muscle and in a cell model transitioning from 0.1 to 10% FBS. The underlying mechanism is transcriptional derepression of DIO2 through the mTORC2 pathway as defined in rictor knockdown cells. In cells kept in 0.1% FBS, there is DIO2 inhibition via FOXO1 binding to the DIO2 promoter. Repression of DIO2 by FOXO1 was confirmed using its specific inhibitor AS1842856 or adenoviral infection of constitutively active FOXO1. ChIP studies indicate that 4 h after 10% FBS-containing medium, FOXO1 binding markedly decreases, and the DIO2 promoter is activated. Studies in the insulin receptor FOXO1 KO mouse indicate that insulin is a key signaling molecule in this process. We conclude that FOXO1 represses DIO2 during fasting and that derepression occurs via nutritional activation of the PI3K-mTORC2-Akt pathway. PMID- 26499801 TI - Fasting and Systemic Insulin Signaling Regulate Phosphorylation of Brain Proteins That Modulate Cell Morphology and Link to Neurological Disorders. AB - Diabetes is strongly associated with cognitive decline, but the molecular reasons are unknown. We found that fasting and peripheral insulin promote phosphorylation and dephosphorylation, respectively, of specific residues on brain proteins including cytoskeletal regulators such as slit-robo GTPase-activating protein 3 (srGAP3) and microtubule affinity-regulating protein kinases (MARKs), in which deficiency or dysregulation is linked to neurological disorders. Fasting activates protein kinase A (PKA) but not PKB/Akt signaling in the brain, and PKA can phosphorylate the purified srGAP3. The phosphorylation of srGAP3 and MARKs were increased when PKA signaling was activated in primary neurons. Knockdown of PKA decreased the phosphorylation of srGAP3. Furthermore, WAVE1, a protein kinase A-anchoring protein, formed a complex with srGAP3 and PKA in the brain of fasted mice to facilitate the phosphorylation of srGAP3 by PKA. Although brain cells have insulin receptors, our findings are inconsistent with the down-regulation of phosphorylation of target proteins being mediated by insulin signaling within the brain. Rather, our findings infer that systemic insulin, through a yet unknown mechanism, inhibits PKA or protein kinase(s) with similar specificity and/or activates an unknown phosphatase in the brain. Ser(858) of srGAP3 was identified as a key regulatory residue in which phosphorylation by PKA enhanced the GAP activity of srGAP3 toward its substrate, Rac1, in cells, thereby inhibiting the action of this GTPase in cytoskeletal regulation. Our findings reveal novel mechanisms linking peripheral insulin sensitivity with cytoskeletal remodeling in neurons, which may help to explain the association of diabetes with neurological disorders such as Alzheimer disease. PMID- 26499802 TI - Endoplasmic Reticulum (ER) Stress Induces Sirtuin 1 (SIRT1) Expression via the PI3K-Akt-GSK3beta Signaling Pathway and Promotes Hepatocellular Injury. AB - Sirtuin 1 (SIRT1), an NAD(+)-dependent histone deacetylase, plays crucial roles in various biological processes including longevity, stress response, and cell survival. Endoplasmic reticulum (ER) stress is caused by dysfunction of ER homeostasis and exacerbates various diseases including diabetes, fatty liver, and chronic obstructive pulmonary disease. Although several reports have shown that SIRT1 negatively regulates ER stress and ER stress-induced responses in vitro and in vivo, the effect of ER stress on SIRT1 is less explored. In this study, we showed that ER stress induced SIRT1 expression in vitro and in vivo. We further determined the molecular mechanisms of how ER stress induces SIRT1 expression. Surprisingly, the conventional ER stress-activated transcription factors XBP1, ATF4, and ATF6 seem to be dispensable for SIRT1 induction. Based on inhibitor screening experiments with SIRT1 promoter, we found that the PI3K-Akt-GSK3beta signaling pathway is required for SIRT1 induction by ER stress. Moreover, we showed that pharmacological inhibition of SIRT1 by EX527 inhibited the ER stress induced cellular death in vitro and severe hepatocellular injury in vivo, indicating a detrimental role of SIRT1 in ER stress-induced damage responses. Collectively, these data suggest that SIRT1 expression is up-regulated by ER stress and contributes to ER stress-induced cellular damage. PMID- 26499803 TI - Evaluation of the basic functions of six calcium-dependent protein kinases in Toxoplasma gondii using CRISPR-Cas9 system. AB - Toxoplasma gondii, an important protozoan parasite, infects almost all warm blooded animals and humans. Although treatments in T. gondii are limited by the lack of effective drugs, some calcium-dependent kinases were demonstrated as the promising drug targets to chemotherapy against T. gondii due to their essential roles in T. gondii and absence from their hosts. The objectives of the present study were to investigate the functions of six calcium-dependent protein kinases (CDPK4, CDPK4A, CDPK5, CDPK6, CDPK8, and CDPK9) in T. gondii to assess whether they are suitable for designing as drug targets. We used the CRISPR-Cas9 system to disrupt six CDPK genes successfully by insertion of DHFR* at the guide RNA targeted region in the six endogenous CDPK loci and successfully obtained the six knockout (KO)-CDPK strains. The biological characteristics of the six strains were evaluated by plaque assays, invasion, egress, replication, and virulence assays, respectively. The results indicated that there was no significant difference between the six KO-CDPK strains and wild-type strain in virulence and the lytic cycle including invasion, egress, and replication. The conclusion was the six CDPKs are not essential for T. gondii lytic cycle and also not virulence factors for mice, suggesting that the six CDPKs may participate in other functions in T. gondii. PMID- 26499804 TI - Biosynthesis, characterization, and acute toxicity of Berberis tinctoria fabricated silver nanoparticles against the Asian tiger mosquito, Aedes albopictus, and the mosquito predators Toxorhynchites splendens and Mesocyclops thermocyclopoides. AB - Aedes albopictus is an important arbovirus vector, including dengue. Currently, there is no specific treatment for dengue. Its prevention solely depends on effective vector control measures. In this study, silver nanoparticles (AgNPs) were biosynthesized using a cheap leaf extract of Berberis tinctoria as reducing and stabilizing agent and tested against Ae. albopictus and two mosquito natural enemies. AgNPs were characterized by using UV-vis spectrophotometry, X-ray diffraction, and scanning electron microscopy. In laboratory conditions, the toxicity of AgNPs was evaluated on larvae and pupae of Ae. albopictus. Suitability Index/Predator Safety Factor was assessed on Toxorhynchites splendens and Mesocyclops thermocyclopoides. The leaf extract of B. tinctoria was toxic against larval instars (I-IV) and pupae of Ae. albopictus; LC50 was 182.72 ppm (I instar), 230.99 ppm (II), 269.65 ppm (III), 321.75 ppm (IV), and 359.71 ppm (pupa). B. tinctoria-synthesized AgNPs were highly effective, with LC50 of 4.97 ppm (I instar), 5.97 ppm (II), 7.60 ppm (III), 9.65 ppm (IV), and 14.87 ppm (pupa). Both the leaf extract and AgNPs showed reduced toxicity against the mosquito natural enemies M. thermocyclopoides and T. splendens. Overall, this study firstly shed light on effectiveness of B. tinctoria-synthesized AgNPs as an eco-friendly nanopesticide, highlighting the concrete possibility to employ this newer and safer tool in arbovirus vector control programs. PMID- 26499806 TI - Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. AB - Multidrug resistance (MDR) is a serious phenomenon employed by cancer cells which hampers the success of cancer pharmacotherapy. One of the common mechanisms of MDR is the overexpression of ATP-binding cassette (ABC) efflux transporters in cancer cells such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) that limits the prolonged and effective use of chemotherapeutic drugs. Researchers have found that developing inhibitors of ABC efflux transporters as chemosensitizers could overcome MDR. But the clinical trials have shown that most of these chemosensitizers are merely toxic and only show limited or no benefits to cancer patients, thus new inhibitors are being explored. Recent findings also suggest that efflux pumps of the ABC transporter family are subject to epigenetic gene regulation. In this review, we summarize recent findings of the role of ABC efflux transporters in MDR. PMID- 26499805 TI - Moonlighting proteins in cancer. AB - Since the 1980s, growing evidence suggested that the cellular localization of proteins determined their activity and biological functions. In a classical view, a protein is characterized by the single cellular compartment where it primarily resides and functions. It is now believed that when proteins appear in different subcellular locations, the cells surpass the expected activity of proteins given the same genomic information to fulfill complex biological behavior. Many proteins are recognized for having the potential to exist in multiple locations in cells. Dysregulation of translocation may cause cancer or contribute to poorer cancer prognosis. Thus, quantitative and comprehensive assessment of dynamic proteins and associated protein movements could be a promising indicator in determining cancer prognosis and efficiency of cancer treatment and therapy. This review will summarize these so-called moonlighting proteins, in terms of a coupled intracellular cancer signaling pathway. Determination of the detailed biological intracellular and extracellular transit and regulatory activity of moonlighting proteins permits a better understanding of cancer and identification of potential means of molecular intervention. PMID- 26499808 TI - Connectometry: A statistical approach harnessing the analytical potential of the local connectome. AB - Here we introduce the concept of the local connectome: the degree of connectivity between adjacent voxels within a white matter fascicle defined by the density of the diffusing spins. While most human structural connectomic analyses can be summarized as finding global connectivity patterns at either end of anatomical pathways, the analysis of local connectomes, termed connectometry, tracks the local connectivity patterns along the fiber pathways themselves in order to identify the subcomponents of the pathways that express significant associations with a study variable. This bottom-up analytical approach is made possible by reconstructing diffusion MRI data into a common stereotaxic space that allows for associating local connectomes across subjects. The substantial associations can then be tracked along the white matter pathways, and statistical inference is obtained using permutation tests on the length of coherent associations and corrected for multiple comparisons. Using two separate samples, with different acquisition parameters, we show how connectometry can capture variability within core white matter pathways in a statistically efficient manner and extract meaningful variability from white matter pathways, complements graph-theoretic connectomic measures, and is more sensitive than region-of-interest approaches. PMID- 26499807 TI - The common genetic influence over processing speed and white matter microstructure: Evidence from the Old Order Amish and Human Connectome Projects. AB - Speed with which brain performs information processing influences overall cognition and is dependent on the white matter fibers. To understand genetic influences on processing speed and white matter FA, we assessed processing speed and diffusion imaging fractional anisotropy (FA) in related individuals from two populations. Discovery analyses were performed in 146 individuals from large Old Order Amish (OOA) families and findings were replicated in 485 twins and siblings of the Human Connectome Project (HCP). The heritability of processing speed was h(2)=43% and 49% (both p<0.005), while the heritability of whole brain FA was h(2)=87% and 88% (both p<0.001), in the OOA and HCP, respectively. Whole brain FA was significantly correlated with processing speed in the two cohorts. Quantitative genetic analysis demonstrated a significant degree to which common genes influenced joint variation in FA and brain processing speed. These estimates suggested common sets of genes influencing variation in both phenotypes, consistent with the idea that common genetic variations contributing to white matter may also support their associated cognitive behavior. PMID- 26499809 TI - Altered thalamocortical and intra-thalamic functional connectivity during light sleep compared with wake. AB - The transition from wakefulness into sleep is accompanied by modified activity in the brain's thalamocortical network. Sleep-related decreases in thalamocortical functional connectivity (FC) have previously been reported, but the extent to which these changes differ between thalamocortical pathways, and patterns of intra-thalamic FC during sleep remain untested. To non-invasively investigate thalamocortical and intra-thalamic FC as a function of sleep stage we recorded simultaneous EEG-fMRI data in 13 healthy participants during their descent into light sleep. Visual scoring of EEG data permitted sleep staging. We derived a functional thalamic parcellation during wakefulness by computing seed-based FC, measured between thalamic voxels and a set of pre-defined cortical regions. Sleep differentially affected FC between these distinct thalamic subdivisions and their associated cortical projections, with significant increases in FC during sleep restricted to sensorimotor connections. In contrast, intra-thalamic FC, both within and between functional thalamic subdivisions, showed significant increases with advancement into sleep. This work demonstrates the complexity and state specific nature of functional thalamic relationships--both with the cortex and internally--over the sleep/wake cycle, and further highlights the importance of a thalamocortical focus in the study of sleep mechanisms. PMID- 26499810 TI - Improved determination of the myelin water fraction in human brain using magnetic resonance imaging through Bayesian analysis of mcDESPOT. AB - Myelin water fraction (MWF) mapping with magnetic resonance imaging has led to the ability to directly observe myelination and demyelination in both the developing brain and in disease. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) has been proposed as a rapid approach for multicomponent relaxometry and has been applied to map MWF in the human brain. However, even for the simplest two-pool signal model consisting of myelin associated and non-myelin-associated water, the dimensionality of the parameter space for obtaining MWF estimates remains high. This renders parameter estimation difficult, especially at low-to-moderate signal-to-noise ratios (SNRs), due to the presence of local minima and the flatness of the fit residual energy surface used for parameter determination using conventional nonlinear least squares (NLLS)-based algorithms. In this study, we introduce three Bayesian approaches for analysis of the mcDESPOT signal model to determine MWF. Given the high dimensional nature of the mcDESPOT signal model, and, therefore the high dimensional marginalizations over nuisance parameters needed to derive the posterior probability distribution of the MWF, the Bayesian analyses introduced here use different approaches to reduce the dimensionality of the parameter space. The first approach uses normalization by average signal amplitude, and assumes that noise can be accurately estimated from signal-free regions of the image. The second approach likewise uses average amplitude normalization, but incorporates a full treatment of noise as an unknown variable through marginalization. The third approach does not use amplitude normalization and incorporates marginalization over both noise and signal amplitude. Through extensive Monte Carlo numerical simulations and analysis of in vivo human brain datasets exhibiting a range of SNR and spatial resolution, we demonstrated markedly improved accuracy and precision in the estimation of MWF using these Bayesian methods as compared to the stochastic region contraction (SRC) implementation of NLLS. PMID- 26499811 TI - Regional growth and atlasing of the developing human brain. AB - Detailed morphometric analysis of the neonatal brain is required to characterise brain development and define neuroimaging biomarkers related to impaired brain growth. Accurate automatic segmentation of neonatal brain MRI is a prerequisite to analyse large datasets. We have previously presented an accurate and robust automatic segmentation technique for parcellating the neonatal brain into multiple cortical and subcortical regions. In this study, we further extend our segmentation method to detect cortical sulci and provide a detailed delineation of the cortical ribbon. These detailed segmentations are used to build a 4 dimensional spatio-temporal structural atlas of the brain for 82 cortical and subcortical structures throughout this developmental period. We employ the algorithm to segment an extensive database of 420 MR images of the developing brain, from 27 to 45weeks post-menstrual age at imaging. Regional volumetric and cortical surface measurements are derived and used to investigate brain growth and development during this critical period and to assess the impact of immaturity at birth. Whole brain volume, the absolute volume of all structures studied, cortical curvature and cortical surface area increased with increasing age at scan. Relative volumes of cortical grey matter, cerebellum and cerebrospinal fluid increased with age at scan, while relative volumes of white matter, ventricles, brainstem and basal ganglia and thalami decreased. Preterm infants at term had smaller whole brain volumes, reduced regional white matter and cortical and subcortical grey matter volumes, and reduced cortical surface area compared with term born controls, while ventricular volume was greater in the preterm group. Increasing prematurity at birth was associated with a reduction in total and regional white matter, cortical and subcortical grey matter volume, an increase in ventricular volume, and reduced cortical surface area. PMID- 26499812 TI - In vivo mapping of macroscopic neuronal projections in the mouse hippocampus using high-resolution diffusion MRI. AB - Recent developments in diffusion magnetic resonance imaging (MRI) make it a promising tool for non-invasive mapping of the spatial organization of axonal and dendritic networks in gray matter regions of the brain. Given the complex cellular environments, in which these networks reside, evidence on the capability of diffusion MRI-based tractography to study these networks is still lacking. In this study, we used a localized diffusion MRI approach to acquire high spatial and angular resolution images of the live mouse hippocampus. The diffusion MRI and tractography results were compared with histology and the Allen mouse brain connectivity atlas using a multi-step image registration pipeline. The results demonstrated that in vivo diffusion MRI data at 0.1mm isotropic resolution revealed the organization of axonal and dendritic networks in the hippocampus and the tractography results shared remarkable similarity with the viral tracer data in term of their spatial projection patterns. Quantitative analysis showed significant correlations between tractography- and tracer-based projection density measurements in the mouse hippocampus. These findings suggest that high resolution diffusion MRI and tractography can reveal macroscopic neuronal projections in the mouse hippocampus and are important for future development of advanced tractography methods. PMID- 26499813 TI - Resource atlases for multi-atlas brain segmentations with multiple ontology levels based on T1-weighted MRI. AB - Technologies for multi-atlas brain segmentation of T1-weighted MRI images have rapidly progressed in recent years, with highly promising results. This approach, however, relies on a large number of atlases with accurate and consistent structural identifications. Here, we introduce our atlas inventories (n=90), which cover ages 4-82years with unique hierarchical structural definitions (286 structures at the finest level). This multi-atlas library resource provides the flexibility to choose appropriate atlases for various studies with different age ranges and structure-definition criteria. In this paper, we describe the details of the atlas resources and demonstrate the improved accuracy achievable with a dynamic age-matching approach, in which atlases that most closely match the subject's age are dynamically selected. The advanced atlas creation strategy, together with atlas pre-selection principles, is expected to support the further development of multi-atlas image segmentation. PMID- 26499815 TI - Reliability of Modern Scores to Predict Long-Term Mortality After Isolated Aortic Valve Operations. AB - BACKGROUND: Contemporary scores for estimating perioperative death have been proposed to also predict also long-term death. The aim of the study was to evaluate the performance of the updated European System for Cardiac Operative Risk Evaluation II, The Society of Thoracic Surgeons Predicted Risk of Mortality score, and the Age, Creatinine, Left Ventricular Ejection Fraction score for predicting long-term mortality in a contemporary cohort of isolated aortic valve replacement (AVR). We also sought to develop for each score a simple algorithm based on predicted perioperative risk to predict long-term survival. METHODS: Complete data on 1,444 patients who underwent isolated AVR in a 7-year period were retrieved from three prospective institutional databases and linked with the Italian Tax Register Information System. Data were evaluated with performance analyses and time-to-event semiparametric regression. RESULTS: Survival was 83.0% +/- 1.1% at 5 years and 67.8 +/- 1.9% at 8 years. Discrimination and calibration of all three scores both worsened for prediction of death at 1 year and 5 years. Nonetheless, a significant relationship was found between long-term survival and quartiles of scores (p < 0.0001). The estimated perioperative risk by each model was used to develop an algorithm to predict long-term death. The hazard ratios for death were 1.1 (95% confidence interval, 1.07 to 1.12) for European System for Cardiac Operative Risk Evaluation II, 1.34 (95% CI, 1.28 to 1.40) for the Society of Thoracic Surgeons score, and 1.08 (95% CI, 1.06 to 1.10) for the Age, Creatinine, Left Ventricular Ejection Fraction score. CONCLUSIONS: The predicted risk generated by European System for Cardiac Operative Risk Evaluation II, The Society of Thoracic Surgeons score, and Age, Creatinine, Left Ventricular Ejection Fraction scores cannot also be considered a direct estimate of the long term risk for death. Nonetheless, the three scores can be used to derive an estimate of long-term risk of death in patients who undergo isolated AVR with the use of a simple algorithm. PMID- 26499814 TI - Examining the relationships between cortical maturation and white matter myelination throughout early childhood. AB - Cortical development and white matter myelination are hallmark processes of infant and child neurodevelopment, and play a central role in the evolution of cognitive and behavioral functioning. Non-invasive magnetic resonance imaging (MRI) has been used to independently track these microstructural and morphological changes in vivo, however few studies have investigated the relationship between them despite their concurrency in the developing brain. Further, because measures of cortical morphology rely on underlying gray-white matter tissue contrast, which itself is a function of white matter myelination, it is unclear if contrast-based measures of cortical development accurately reflect cortical architecture, or if they merely represent adjacent white matter maturation. This may be particularly true in young children, in whom brain structure is rapidly maturing. Here for the first time, we investigate the dynamic relationship between cortical and white matter development across early childhood, from 1 to 6years. We present measurements of cortical thickness with respect to cortical and adjacent myelin water fraction (MWF) in 33 bilateral cortical regions. Significant results in only 14 of 66 (21%) cortical regions suggest that cortical thickness measures are not heavily driven by changes in adjacent white matter, and that brain imaging studies of cortical and white matter maturation reflect distinct, but complimentary, neurodevelopmental processes. PMID- 26499816 TI - Basic Cardiac Surgery Skills on Sale for $22.50: An Aortic Anastomosis Simulation Curriculum. AB - BACKGROUND: Current resident and student duty-hour restrictions necessitate efficient training, which may be aided by simulation. Data on the utility of low cost simulation in cardiothoracic surgery are scant. We evaluated the effect and value of a low-cost, low-fidelity aortic anastomosis simulation curriculum. METHODS: Twenty participants (11 medical students, 9 residents) completed an aortic anastomosis on a porcine heart as a pretest. Participants were then provided access to a 14-minute online video created by a cardiac surgeon and given a low-cost task trainer for self-directed practice. Five weeks later, participants performed another aortic anastomosis on a porcine heart as a posttest. Pretest and posttest performances were filmed, deidentified, and graded blindly and independently by two cardiac surgeons using a standardized assessment tool (perfect score, 110; passing score, 58 or higher). Participants were surveyed anonymously after the posttest. RESULTS: The mean (SD) aortic anastomosis performance score improved significantly from pretest (53.3 [25.3]) to posttest (83.6 [15.3]; p < 0.001). Pass rates also improved significantly (35% versus 95%, p < 0.001). Medical students' scores improved most (p = 0.01). All 20 participants reported improved confidence in performing the task, and 18 believed that the online video was essential to better performance. The cost of the curriculum totaled $22.50 per participant, with 6 hours of total staff time required for assessment. CONCLUSIONS: An aortic anastomosis training and simulation curriculum improves the skills of student and resident trainees with minimal expense and staff time commitment. Such a curriculum may be of great value to both cardiothoracic training programs and their trainees. PMID- 26499817 TI - Can consumption of antioxidant rich mushrooms extend longevity?: antioxidant activity of Pleurotus spp. and its effects on Mexican fruit flies' (Anastrepha ludens) longevity. AB - The variability of antioxidant capacity of 14 strains of the edible oyster mushroom Pleurotus spp. was determined, and the effect of selected mushroom supplements on the longevity of the Mexican fruit fly, Anastrepha ludens, was evaluated. The antioxidant capacity of the fruiting bodies was determined by three different methods, measuring the free radical scavenging activity of methanolic extracts, the OH radical scavenging capacity, and the total phenol content. The inhibition percentage of the DPPH radical varied between 32.6 and 85.7% and total phenols varied between 30.6 and 143.3 mg/g. The strains with the highest (Pleurotus djamor ECS-0142) and lowest (Pleurotus ostreatus ECS-1123) antioxidant capacity were selected to study their effect on the survival, life expectancy, and mortality of the Mexican fruit fly A. ludens. The results demonstrated differing responses between male and female flies. High concentrations of mushrooms (5 and 20%) in the diet resulted in a decrease in life expectancy. However, flies on the diet with 1% P. djamor ECS-0142 showed slightly but significantly greater survival than those on the control diet. The possible adverse effect of protein content in mushroom extracts is discussed. PMID- 26499818 TI - Prenatal and childhood growth and physical performance in old age--findings from the Helsinki Birth Cohort Study 1934-1944. AB - Health in adulthood is in part a consequence of development and growth taking place during sensitive periods in early life. It has not been explored previously whether early growth is associated with physical performance in old age from a life course perspective taking into account health-related behavior, biological risk factors, and early life experiences. At a mean age of 71 years, physical performance was assessed using the Senior Fitness Test (SFT) in 1078 individuals belonging to the Helsinki Birth Cohort Study. We used multiple linear regression analysis to assess the association between the SFT physical fitness scores and individual life course measurements. Several adult characteristics were associated with physical performance including socioeconomic status, lifestyle factors, and adult anthropometry. Higher birth weight and length were associated with better physical performance, even after adjusting for potential confounders (all p values <0.05). The strongest individual association between life course measurements and physical performance in old age was found for adult body fat percentage. However, prenatal growth was independently associated with physical performance seven decades later. These findings suggest that physical performance in old age is at least partly programmed in early life. PMID- 26499820 TI - Validation of the self-reporting questionnaire (SRQ 20) in British Pakistani and White European population in the United Kingdom. AB - BACKGROUND: The incidence of depression is difficult to determine because of low clinical depression detection rates in the primary care setting. This low level of detection is a significantly greater problem in people from ethnic minority communities. The availability of culturally validated screening questionnaires might help to improve the detection and treatment of depression. METHOD: The aim of the study was to assess the validity of the self-reporting questionnaire SRQ 20, (English and Urdu versions) in white Europeans and British Pakistanis and to determine the optimum cut-off scores for detecting depression. Validation of the English and Urdu versions of the SRQ was conducted with a sample of white Europeans and British Pakistani participants. The semi-structured Schedule for Clinical Assessment in Neuropsychiatry (SCAN) was used as the gold standard diagnostic interview, and receiver operating characteristic analysis was used to evaluate SRQ test performance. RESULTS: The SRQ was completed by 1856 participants out of whom 651 completed the SCAN interview. The SRQ sensitivity, specificity, and predictive values versus SCAN indicated a cut-off score of 7 as optimum for white Europeans and a cut-off score of 6 for British Pakistanis. LIMITATIONS: This study focused on depression alone and did not take into consideration comorbid conditions such as anxiety which might have affected the way respondents answered the questions and contributed to comparatively lower optimum cut-off scores in British Pakistanis. CONCLUSIONS: The findings of this validation study provide evidence for high sensitivity and specificity of SRQ amongst both white Europeans and British Pakistanis. The SRQ can be used as a routine screening questionnaire for depression in English and Urdu speaking populations in the UK. PMID- 26499821 TI - Screening and analysis of mutation hot-spots in deafness-associated genes among adolescents with hearing loss. AB - The present study aimed to screen the hot-spot deafness gene mutations of adolescents with non-syndromic hearing loss in Yongchuan, Chongqing (CQ-YC ANSHL), aiming to preliminarily understand the region's spectrum and occurrence frequency of deafness gene mutation hot-spots. A total of 60 CQ-YC ANSHL were selected from the Special Education School of Yongchuan, Chongqing and the nine most common mutations of four deafness genes among the Chinese population were detected and associated with the patients' medical history as well as family history of deafness. Deafness gene mutations were detected in 22 cases, among which the detection rates of GJB2, mitochondrial 12S ribosomal ribonucleic acid and SLC26A4 mutations were 23.73% (14/59), 10.17% (6/59) and 5.08% (3/59), respectively, while no GJB3 mutation was detected. The carrying rate of deafness gene mutations in CQ-YC ANSHL was high; therefore, based on the deafness gene diagnosis, the combination of medication guidance, pre-natal diagnosis and clinical interventions may be able to effectively reduce the incidence of deafness in this region. PMID- 26499819 TI - Effect of resistance training on C-reactive protein, blood glucose and lipid profile in older women with differing levels of RT experience. AB - The purpose of this study was to analyze the effects of a progressive resistance training (RT) program on C-reactive protein (CRP), blood glucose (GLU), and lipid profile in older women with differing levels of RT experience. Sixty-five older women (68.9 +/- 6.1 years, 67.1 +/- 13.1 kg) were separated according to RT experience: an advanced group composed by 35 participants who previously carried out 24 weeks of RT and a novice group composed by 30 participants without previous experience in RT (n = 30). Both groups performed a RT program comprised of eight exercises targeting all the major muscles. Training was carried out 3 days/week for 8 weeks. Serum triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), GLU, and CRP concentrations were determined pre- and post- intervention after 12 h fasting. A significant group by time interaction (P < 0.05) for the TC (novice = -1.9% vs. advanced = 1.0%), and CRP (novice = -22.9% vs. advanced = 54.5%) was observed. A main effect of time (P < 0.05) was identified for the GLU (novice = -2.6% vs. advanced = -6.6%), TG (novice = -12.9% vs. advanced = -5.7%), HDL-C (novice = +6.7% vs. advanced = +2.6%), and LDL-C (novice = -34.0% vs. advanced = -25.4%). These results suggest that RT improves the metabolic profile of older women and that training for a longer period of time seems to produce more pronounced reductions mainly on CRP. PMID- 26499822 TI - A Review of Drowning Prevention Interventions for Children and Young People in High, Low and Middle Income Countries. AB - Globally, drowning is one of the ten leading causes of child mortality. Children aged <5 years are particularly at risk, and children and young people continue to be overrepresented in drowning statistics. Accordingly, evidence informed interventions to prevent children drowning are of global importance. This review aimed to identify, assess and analyse public health interventions to reduce child drowning and investigate the use of behavioural theories and evaluation frameworks to guide child drowning prevention. Thirteen databases were searched for relevant peer reviewed articles. The systematic review was guided by the PRISMA criteria and registered with PROSPERO. Fifteen articles were included in the final review. Studies were delivered in high, middle and low income countries. Intervention designs varied, one-third of studies targeted children under five. Almost half of the studies relied on education and information to reduce drowning deaths, only three studies used a multi-strategy approach. Minimal use of behavioural theories and/or frameworks was found and just one third of the studies described formative evaluation. This review reveals an over reliance on education and information as a strategy to prevent drowning, despite evidence for comprehensive multi-strategy approaches. Accordingly, interventions must be supported that use a range of strategies, are shaped by theory and planning and evaluation frameworks, and are robust in intervention design, delivery and evaluation methodology. This approach will provide sound evidence that can be disseminated to inform future practice and policy for drowning prevention. PMID- 26499823 TI - 111In-pentetreotide scintigraphy and 18F FDG PET-CT in differentiated thyroid carcinoma metastases with negative whole body radioiodine scan. AB - Metastases of differentiated thyroid cancer (DTC) can lose affinity to radioiodine with the passage of time, with resultant difficulty in management. Thyroid tumors are known to express somatostatin receptors and therefore 111In pentetreotide, somatostatin analogue, can visualize tumors with high concentration of somatostatin receptors. We report a case of I-131 whole body scan (WBS) negative recurrent metastatic papillary thyroid carcinoma with positive 18F FDG PET-CT and 111In-pentetreotide scan. Somatostatin receptor scintigraphy (SRS) with 111In-pentetreotide may be useful both in the staging and monitoring of patients with non-iodine avid carcinoma of the thyroid. 111In pentetreotide scan positive patients are potential candidates for somatostatin receptor-targeted therapy. PMID- 26499824 TI - Incidental splenic littoral cell angioma complicating a case of Rolon cancer: A case report. AB - Littoral cell angioma (LCA) is a recently described rare generally benign primary vascular neoplasm of the spleen originating from the lining cells of the splenic red pulp sinuses that is usually discovered incidentally. LCA may be associated with epithelial malignancies and may itself also have malignant potential. We report the case of a 71-year-old woman who presented with intraoperative bleeding from the spleen during sigmoidectomy for colonic adenocarcinoma. Histopathological examination of the removed spleen revealed multiple haemorrhagic lesions diagnosed as littoral cell angioma. This case has been reported due to its rarity and to highlight how its accidental detection, unique and unexpected presentation complicated a case of colonic carcinoma. Individuals diagnosed with this tumour must be carefully evaluated to exclude primary, secondary and synchronous malignancies. PMID- 26499825 TI - A 65-year old female with synchronous HIV and Extramedullary Plasmacytoma of Maxillary sinus. AB - Extramedullary plasmacytoma in the head and neck region is a rare malignant neoplasm comprising approximately 3% of all the plasma cell neoplasms and less than 1% of head and neck tumors. This extraskeletal lesion is a unifocal, monoclonal, neoplastic proliferation of plasma cells. Some investigators believe that this lesion represents the least aggressive part of the spectrum of plasma cell neoplasms which extends to multiple myeloma. Therefore, plasmacytoma is believed to have clinical importance. We report a case of extramedullary plasmacytoma in the right maxillary sinus of a 65-year-old HIV positive female as a clinical rarity with review of the relevant literature. PMID- 26499826 TI - Spinal metastasis of breast cancer presenting after 25 years: An extremely rare presentation. AB - Breast cancer is the most frequently diagnosed cancer in females of the developed world and is gradually becoming the leading cause in the developing world as well. The innate biology of breast cancer is marked by varied presentations, characteristics, response, recurrence and metastatic phenomenon. Even an early stage breast cancer has the potential to recur and/or metastasize after extremely long duration and this possibility should be borne in the clinician's mind. PMID- 26499827 TI - Solid tumors after chronic lymphocytic leukemia patients: Report of six cases and review of the literature. AB - INTRODUCTION: Malignancies have been reported to occur with increased frequency in chronic lymphocytic Leukemia (CLL) patients. The aim of this study was to describe which second malignancies occur in patients with CLL, whether these malignancies are related to CLL, its treatment, or both. We also attempt to study factors predicting the development of other malignancies. PATIENTS AND METHODS: Between 1995 and 2009, six cases of CLL associated with solid tumor were diagnosed in Hematology Department of Military Hospital of Tunis. The diagnosis of CLL was made by immunophenotyping of peripheral blood circulating B cells, and the diagnosis of solid tumors was made by biopsy with anatomopathological exam and immunohistochemical study. RESULTS: The mean age of patients was 71 years. Five patients were male. The CLL was classified Stage A in one case, Stage B in three cases and Stage C in two cases. Two patients had abnormal karyotype. Three patients have not received specific treatment for their CLL. Solid tumors were represented by skin cancer in three cases, lung cancer in two cases and breast cancer in one case. The median time between diagnosis of CLL and that of solid tumor was 53 months. CONCLUSION: Patients with CLL have an increased risk of developing a second cancer. Awareness of risk factors could permit early detection. PMID- 26499828 TI - Bevacizumab in clinical practice. AB - The development of targeted therapies and especially angiogenesis inhibitor drugs is undoubtedly a major advancement in the treatment of cancer in the 21st century. Bevacizumab is a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor that was approved for the treatment of multiple solid tumors, we have reviewed the side effects cited in clinical trials of bevacizumab and the guidelines for their management and we can conclude that bevacizumab, is generally well tolerated but is associated with increase in some adverse side effects for which monitoring is required particularly vascular and renal side effects including hypertension, proteinuria, thromboembolic events and hemorrhage. The better understanding of bevacizumab toxicity profile and the guidelines for their optimal management as well as the education of patients may allow prolonged therapy and thus improved clinical outcomes. PMID- 26499829 TI - Targeted therapies in the management of breast cancer. AB - The incidence of cancer is increasing in the United Kingdom. Breast cancer is the most commonly diagnosed cancer among women in the UK with an age standardised rate of 124 per 100,000 women. It accounts for almost one-third of all female cases of cancer in the UK and it is the most common form of cancer among women in both developing and developed countries. There are many management options for cancer such as surgery, chemotherapy and radiotherapy. Surgery has been the main treatment option for many solid tumours for several decades. However, research has shown that attacking specific targets within tumours such as receptors, intracellular proteins and genes could result in better clinical outcome. Promising therapeutic targets that have been identified include Raf kinase, Src, HER2, epidermal growth factor receptor and vascular endothelial growth factor receptor. After several decades of intensive research, it appears that we are finally hitting cancer where it hurts. It is very likely that in the near future, more targets for potential therapies would be identified and ultimately, there would be significant reduction in morbidity and mortality from cancers, including breast cancer. PMID- 26499830 TI - Primary Surgery in Treatment of Stages II and III Wilms' Tumour: A Developing Countries' Experience. AB - BACKGROUND: Treatment options for Wilms' tumour (WT) are costly and it affects the country's health budget and resources if adopted and implemented at the national level especially in developing countries with low or resource-challenged settings. AIM: The objective of this study is to evaluate the role and effectiveness of primary surgery in the treatment of stage II and III pediatric WT following the schedule indicated in the National Wilms' Tumor Study (NWTS-4) in the institutes of two developing countries. PATIENTS AND METHODS: The study enrolled 40 children who were primarily diagnosed as stage II and III WT. They were divided into 2 equal groups. Group I (n = 20) included those children who have undergone neoadjuvant chemotherapy followed by surgery and postoperative chemotherapy, while group II (n = 20) included those children who have undergone primary surgery as an initial management followed by chemotherapy. After a mean postoperative follow-up period of 20+/-5 months, clinical and radiological evaluation was performed for all patients. RESULTS: In group I, 15 patients were preoperatively diagnosed as stage II and 5 patients as stage III while in group II, 16 patients were proved to be stage II and 4 patients were stage III. After a follow up period, clinical and radiological evaluation using CT was performed on all patients. In patients with stage II, evidence of recurrence was noted in 4 patients of group I whereas no patient showed any evidence of recurrence in group II. In patients with stage III, rebound increase in size was seen in 2 patients in group I and only one patient in group II. CONCLUSION: Primary surgery with appropriate adjuvant therapy improves the treatment results compared to the neoadjuvant chemotherapy and delayed surgery for children primarily diagnosed as stage II and III WT. It may be used as a safe and effective tool in treating WT patients with relatively no changes from the long administration schedules. This will have a highly positive impact in lowering treatment cost in developing countries. PMID- 26499831 TI - Utility of fine needle aspiration cytology in evaluation of lymphadenopathy - An audit from a Cancer Centre in South India. AB - BACKGROUND: Cytological evaluation and diagnosis of lymphadenopathy plays an important role in distinction between reactive hyperplasia and malignancy.Being a tertiary cancer care centre, lymph node enlargement clinically suspected to be due to malignancy constitute the commonest indication for fine needle aspiration cytology (FNAC) at our centre. The aim of this study was to determine the utility of FNAC in evaluating enlarged lymph nodes and to categorizethe causes of lymphadenopathy diagnosed byFNAC at our centre. MATERIAL AND METHODS: Data was collected from the records of department of Pathology over a period of three months from January to March 2014. The data was analyzed and various parameters studied. RESULTS: There were 2000 aspirates over a period of three months of which 270 (13.5%) were from lymph nodes. Of these, 130 cases (48.2%) have metastatic deposits.We also came across 16 cases (5.9%) of lymphoma, 5 cases (1.9%) of granulomatous lymphadenitis, 2 cases (0.7%) of suppurative lesion and 99 cases (36.7%) of reactive hyperplasia during this period. In 3 cases (1.1%), the lesion turned out to be of salivary gland origin. Aspirates were suboptimal for diagnosis in 15 cases (5.5%). Aspirates were more in males (181) as compared to females (89). The most common site of aspiration was the cervical lymph node(64.5%),followed by supraclavicular=81(30%), inguinal=33(12.22%), axillary=19(7.04%) sub mental=1(0.37%) and others=7(2.59%). Apart from metastatic carcinomas other metastatic malignancies we came across were malignant melanoma, neuroblastoma, germ cell tumor and synovial sarcoma. CONCLUSION: FNAC of lymph nodes helps in rapid diagnosis of lymphadenopathy.Categorizingthe cause of lymph node enlargement as metastatic malignancy,lymphoma, reactive change, inflammatory cause,suppuration etc. can be done by FNAC.In patients with known histologically proven malignancy in whom a subsequent enlargement of lymph node occurs,a cytological diagnosis of metastasis helps in avoiding unwanted surgery for confirming metastasis.In patients without a previous diagnosis of malignancy, FNAC not only confirm metastatic deposit but in most conditions give a clue regarding site of primary. The use of immunocytochemistry and cell block preparations have increased the scope of FNAC. PMID- 26499832 TI - Level of awareness of lung cancer risk factors, signs, symptoms and safe practices among college teachers of different states in India: Do awareness programmes have an impact on adoption of safe practices? AB - Lung cancer is the one of the most common cause of cancer mortality among men in India where incidence rates are increasing although they are largely preventable diseases. In India, late presentation is generally responsible for high mortality and morbidity rates and early detection is one of the best ways to control it. The purpose of this study is to measure the level of awareness on lung cancer among women represented by a sample of college teachers in India and the impact of awareness programs in changing or adopting safer practices and the prevention and early detection of the disease. MATERIAL AND METHODS: The assessment was conducted during a Pink Chain Campaign on cancer awareness in 2011 in various women colleges in India. Pre-test related to lung cancer was followed by awareness programs. Posttest using the same questionnaire was conducted at the end of interactive session, at 1 year and 6 months. RESULTS: A total of 156 out of 182 teachers participated in the study (overall response rate was 85.7%). Mean age of the study population was 42.4 years (range- 28-59 yrs). There was a significant increase in level of knowledge regarding lung cancer at 6 months and this was sustained at 1 year. Magazines and newspapers were the primary source for information regarding risk factors, signs and symptoms of lung cancer in more than 60% of teachers whereas more than 30% teachers were educated by doctors. At post-awareness after 1 year and 6 months, there was a significant change in alcohol and smoking habits. The main reasons for not undergoing screening tests are: ignorance (50%), lethargic attitude (44.8 %) and lack of time (34.6 %). CONCLUSION: Knowledge about lung cancer was very low among teachers. Overall awareness of risk factors, signs and symptoms, and screening modalities of lung cancer have improved after 1 year along with practices related to smoking and alcohol consumption. There was a significant improvement in people undergoing regular check-up's. Improved means of communication, access to information and effective warnings about cigarette smoking are necessary to increase public awareness. To ensure the adoption of safe practices in the lifestyle of people who smoke and consume alcohol, awareness programmes such as the pink chain campaign should be conducted regularly, frequently and more widely in various areas of India. PMID- 26499833 TI - Characteristics and outcomes of acute kidney injury resulting in hospital admission in patients with solid tumor: Experience of a single center. AB - AIM: To describe the characteristics and outcomes of acute kidney injury (AKI) resulting in hospital admission in cancer patients managed at a comprehensive cancer center. METHODS: This was a prospective observational study conducted between December 2011 and July 2012. Patients admitted to the solid tumor service were screened to identify those who met the criteria of AKI upon admission. The identified cases were reviewed by two clinicians to determine the cause of AKI and to determine if AKI was the major cause for admission. Patient demographics, past medical and medication history were recorded. In addition, we evaluated patients for resolution of AKI. RESULTS: During the study period, 103 cases were identified, 57.3% were males, mean age was 64 years+/-11.2 (SD), 24 patients 23.3%) have diabetes, and 55 patients (53.4%) have hypertension. The most common causes of AKI were dehydration, medications, and tumor-related, reported in 40 (38.8%), 34 (33%), and 23 (22.3%) of these cases respectively. The most common medications associated with AKI were chemotherapy (n=13, 42%), mainly cisplatin (76.9%), followed by non-steroidal anti-inflammatory drugs (n=12, 38.7%). Eleven patients (10.7%) progressed to chronic renal failure and three patients required hemodialysis. In the remaining cases, AKI resolved after a mean of 6.39 days+/ 3.73(SD). Transfer to the intensive care unit was required for 4 patients and death was reported in 3 patients. CONCLUSION: AKI in cancer patients was mostly due to dehydration, medications, and the tumor. Measures to reduce the incidence of AKI are necessary to prevent unnecessary admission and the potential for further complications. PMID- 26499834 TI - Outcome of HER2 positive luminal operable breast cancer in comparison with outcome of other operable luminal breast cancer patients: Long follow-up of single center randomized study. AB - INTRODUCTION: In clinical practice, there is increasing recognition that HER2 positive breast cancer patients are not a homogeneous group. Especially patients with luminal B breast cancers which are now subdivided to more than two groups. AIM OF THE STUDY: The aim of this study is to know the effect of HER2 positivity on luminal breast cancer patients by comparing disease free survival DFS luminal of HER2 positive breast cancer patients with other luminal cases with HER2 negative disease. Also we explored the effect of HER2 positivity on different risk factors for breast cancer. PATIENTS AND METHODS: We compared the outcome of 25 HER2 positive luminal breast cancer patients with a control group of other luminal operable breast cancer at the same period of time with the same eligibility and exclusive criteria. RESULTS: Total of 59 operable luminal breast cancer patients were eligible for the study, 25 of them were luminal HER2 positive and the 34 were control group of luminal HER2 negative. We found that HER2 positive luminal breast cancer patients were having more unfavorable risk factors and have more incidence of relapse mainly after 48 months follow-up than other luminal patients: after 24 months follow-up period HER2 positive luminal patients have cumulative DFS of 91% compared with 93% in luminal HER2 negative patients but after 48 months follow-up the difference between the two groups became more obvious as it was 66% for luminal HER2 positive group and 90 % for the control group. High risk patients for luminal HER2 positive breast cancer patients have higher risk of relapse (60% compared with 86%), and this appeared also in other subgroups. CONCLUSION: HER2 positive luminal breast cancer patients have a higher incidence of relapse compared with other luminal breast cancer, and this difference appear mainly after 48 months of follow-up. High risk patients for luminal HER2 positive breast cancer have higher risk of relapse than high risk patients of other luminal patients. PMID- 26499835 TI - Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein Protein Interaction Data. AB - High content protein interaction screens have revolutionized our understanding of protein complex assembly. However, one of the major challenges in translation of high content protein interaction data is identification of those interactions that are functionally relevant for a particular biological question. To address this challenge, we developed a relevance ranking platform (RRP), which consist of modular functional and bioinformatic filters to provide relevance rank among the interactome proteins. We demonstrate the versatility of RRP to enable a systematic prioritization of the most relevant interaction partners from high content data, highlighted by the analysis of cancer relevant protein interactions for oncoproteins Pin1 and PME-1. We validated the importance of selected interactions by demonstration of PTOV1 and CSKN2B as novel regulators of Pin1 target c-Jun phosphorylation and reveal previously unknown interacting proteins that may mediate PME-1 effects via PP2A-inhibition. The RRP framework is modular and can be modified to answer versatile research problems depending on the nature of the biological question under study. Based on comparison of RRP to other existing filtering tools, the presented data indicate that RRP offers added value especially for the analysis of interacting proteins for which there is no sufficient prior knowledge available. Finally, we encourage the use of RRP in combination with either SAINT or CRAPome computational tools for selecting the candidate interactors that fulfill the both important requirements, functional relevance, and high confidence interaction detection. PMID- 26499838 TI - Correction: Coordination-directed self-assembly of a simple benzothiadiazole fused tetrathiafulvalene to low-bandgap metallogels. AB - Correction for 'Coordination-directed self-assembly of a simple benzothiadiazole fused tetrathiafulvalene to low-bandgap metallogels' by Anneliese M. Amacher et al., Chem. Commun., 2015, 51, 15063-15066. PMID- 26499836 TI - Comparative Phosphoproteomics Reveals the Role of AmpC beta-lactamase Phosphorylation in the Clinical Imipenem-resistant Strain Acinetobacter baumannii SK17. AB - Nosocomial infectious outbreaks caused by multidrug-resistant Acinetobacter baumannii have emerged as a serious threat to human health. Phosphoproteomics of pathogenic bacteria has been used to identify the mechanisms of bacterial virulence and antimicrobial resistance. In this study, we used a shotgun strategy combined with high-accuracy mass spectrometry to analyze the phosphoproteomics of the imipenem-susceptible strain SK17-S and -resistant strain SK17-R. We identified 410 phosphosites on 248 unique phosphoproteins in SK17-S and 285 phosphosites on 211 unique phosphoproteins in SK17-R. The distributions of the Ser/Thr/Tyr/Asp/His phosphosites in SK17-S and SK17-R were 47.0%/27.6%/12.4%/8.0%/4.9% versus 41.4%/29.5%/17.5%/6.7%/4.9%, respectively. The Ser-90 phosphosite, located on the catalytic motif S(88)VS(90)K of the AmpC beta lactamase, was first identified in SK17-S. Based on site-directed mutagenesis, the nonphosphorylatable mutant S90A was found to be more resistant to imipenem, whereas the phosphorylation-simulated mutant S90D was sensitive to imipenem. Additionally, the S90A mutant protein exhibited higher beta-lactamase activity and conferred greater bacterial protection against imipenem in SK17-S compared with the wild-type. In sum, our results revealed that in A. baumannii, Ser-90 phosphorylation of AmpC negatively regulates both beta-lactamase activity and the ability to counteract the antibiotic effects of imipenem. These findings highlight the impact of phosphorylation-mediated regulation in antibiotic resistant bacteria on future drug design and new therapies. PMID- 26499839 TI - Administration of tauroursodeoxycholic acid enhances osteogenic differentiation of bone marrow-derived mesenchymal stem cells and bone regeneration. AB - It is known that osteogenic differentiation of mesenchymal stem cells (MSCs) can be promoted by suppression of adipogenesis of MSCs. We have recently found that the chemical chaperone tauroursodeoxycholic acid (TUDCA) significantly reduces adipogenesis of MSCs. In the present study, we examined whether TUDCA can promote osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs) by regulating Integrin 5 (ITGA5) associated with activation of ERK1/2 signal pathway and thereby enhance bone tissue regeneration by reducing apoptosis and the inflammatory response. TUDCA treatment promoted in vitro osteogenic differentiation of BMMSCs and in vivo bone tissue regeneration in a calvarial defect model, as confirmed by micro-computed tomography, histological staining, and immunohistochemistry for osteocalcin. In addition, TUDCA treatment significantly decreased apoptosis and the inflammatory response in vivo and in vitro, which is important to enhance bone tissue regeneration. These results indicate that TUDCA plays a critical role in enhancing osteogenesis of BMMSCs, and is therefore a potential alternative drug for bone tissue regeneration. PMID- 26499840 TI - Active control of the nucleation temperature enhances freezing survival of multipotent mesenchymal stromal cells. AB - Cryopreservation is a technique that has been extensively used for storage of multipotent mesenchymal stromal cells (MSCs) in regenerative medicine. Therefore, improving current cryopreservation procedures in terms of increasing cell viability and functionality is important. In this study, we optimized the cryopreservation protocol of MSCs derived from the common marmoset Callithrix jacchus (cj), which can be used as a non-human primate model in various pathological and transplantation studies and have a great potential for regenerative medicine. We have investigated the effect of the active control of the nucleation temperature using induced nucleation at a broad range of temperatures and two different dimethylsulfoxide concentrations (Me2SO, 5% (v/v) and 10%, (v/v)) to evaluate the overall effect on the viability, metabolic activity and recovery of cells after thawing. Survival rate and metabolic activity displayed an optimum when ice formation was induced at -10 degrees C. Cryomicroscopy studies indicated differences in ice crystal morphologies as well as differences in intracellular ice formation with different nucleation temperatures. High subzero nucleation temperatures resulted in larger extracellular ice crystals and cellular dehydration, whereas low subzero nucleation temperatures resulted in smaller ice crystals and intracellular ice formation. PMID- 26499837 TI - Proteomic Analysis Revealed the Important Role of Vimentin in Human Cervical Carcinoma HeLa Cells Treated With Gambogic Acid. AB - Gambogic acid (GA) is an anticancer agent in phase IIb clinical trial in China. In HeLa cells, GA inhibited cell proliferation, induced cell cycle arrest at G2/M phase and apoptosis, as showed by results of MTT assay and flow cytometric analysis. Possible target-related proteins of GA were searched using comparative proteomic analysis (2-DE) and nine proteins at early (3 h) stage together with nine proteins at late (24 h) stage were found. Vimentin was the only target related protein found at both early and late stage. Results of both 2-DE analysis and Western blotting assay suggested cleavage of vimentin induced by GA. MS/MS analysis of cleaved vimentin peptides indicated possible cleavage sites of vimentin at or near ser51 and glu425. Results of targeted proteomic analysis showed that GA induced change in phosphorylation state of the vimentin head domain (aa51-64). Caspase inhibitors could not abrogate GA-induced cleavage of vimentin. Over-expression of vimentin ameliorated cytotoxicity of GA in HeLa cells. The GA-activated signal transduction, from p38 MAPK, heat shock protein 27 (HSP27), vimentin, dysfunction of cytoskeleton, to cell death, was predicted and then confirmed. Results of animal study showed that GA treatment inhibited tumor growth in HeLa tumor-bearing mice and cleavage of vimentin could be observed in tumor xenografts of GA-treated animals. Results of immunohistochemical staining also showed down-regulated vimentin level in tumor xenografts of GA-treated animals. Furthermore, compared with cytotoxicity of GA in HeLa cells, cytotoxicity of GA in MCF-7 cells with low level of vimentin was weaker whereas cytotoxicity of GA in MG-63 cells with high level of vimentin was stronger. These results indicated the important role of vimentin in the cytotoxicity of GA. The effects of GA on vimentin and other epithelial-to-mesenchymal transition (EMT) markers provided suggestion for better usage of GA in clinic. PMID- 26499841 TI - An ultra-rapid cryo-technique for complex organisms. AB - The soil nematode Caenorhabditis elegans is an excellent research model in cell biology, human disease and developmental studies. In this study, a novel cryopreservation technique based on a rapid cooling procedure, previously established for juveniles, was applied to adult-worms. Here we demonstrated that adults of C. elegans, a complex metazoan organism, survive to a rapid cooling and storage in liquid nitrogen (-196 degrees C) with a very high survival percentage (85%). The procedure relies on a Low CryoProtectant Technique (LCPT) and Ultra Rapid Cooling (URC). The high cooling rate is achieved through the reduction of sample volumes and the effectiveness of a nylon carrier. Our technique complies with the requirements for vitrification to occur. The main distinctive characters of this cryopreservation technique compared to other methods, e.g. Slow Freezing and Vitrification, are presented. Our results show that this cryopreservation method is valid for both unicellular and multicellular organisms; it is suitable for short or long time storage in liquid-nitrogen. This technique promises to be a unique and simpler method for cryostorage of cells, organisms and tissues. PMID- 26499842 TI - Combined Percutaneous Mitral Valve Implantation and Paravalvular Leak Closure in a High-risk Patient With Severe Mitral Regurgitation. PMID- 26499843 TI - Coronary Hematoma After Thoracic Trauma. PMID- 26499844 TI - Polychlorinated biphenyls in umbilical cord serum of newborns from Rio Grande do Sul state, Brazil. AB - BACKGROUND: Polychlorinated biphenyls (PCBs) are food-chain contaminants that have been shown to contaminate foods worldwide. The newborn are exposed to these organochlorine compounds across the placenta and through breastfeeding. They are proven to be carcinogenic and may contribute to congenital malformation etiology. METHODS: This study examined levels of five PCB congeners (28, 52, 138, 153 and 180) in umbilical cord serum samples from 148 newborns from Rio Grande do Sul state, Brazil. Serum concentrations of PCBs were analyzed by gas chromatography with electron capture detection and mass spectrometry. RESULTS: Levels of ?PCBs ranged from 0.35 to 55.17 ng/ml in umbilical cord serum positive samples, and PCB 138 was the most prevalent congener. Only 7.4% of samples presented no PCB congener. CONCLUSIONS: Some PCB congener cord serum levels were related to the locale of the mothers' residence, smoking and drinking habits, fruit consumption, and congenital malformation. PMID- 26499845 TI - Methotrexate normalized keratinocyte activation cycle by overturning abnormal keratins as well as deregulated inflammatory mediators in psoriatic patients. AB - BACKGROUND: In psoriatic skin, epidermal keratinocytes undergo deregulated inflammatory response that leads to prolonged expression of inflammatory mediators as well as abnormal keratins. Methotrexate (MTX) is an immunosuppressive agent used as a standard drug to treat severe psoriasis. The aim of the study is to find the pharmacological effect of MTX on abnormal keratin and deregulated inflammatory mediators. METHODS: Fifty-eight psoriasis vulgaris patients were recruited for this study. Skin biopsies of psoriatic patients were collected and analyzed for activation signal such as TNF-alpha and IFN-gamma and deactivation signal such as TGF-beta1. Also, protein and gene expression of normal keratins K14 and K10 and abnormal keratins K16 and K17 were analyzed in skin biopsies before (day 0) and after (at the end of 6 and 12 weeks) MTX treatment. RESULTS: Results show a significant decrease in tissue TNF-alpha and IFN-gamma and increase in TGF-beta1 after MTX treatment when compared with before MTX treatment in psoriasis patients (p<0.001). Protein and gene expression of K14, K16 and K17 decreased after MTX treatment, whereas the expression of differentiation marker K10 increased after MTX treatment. CONCLUSION: MTX resolves deregulated inflammatory markers and maintains normal keratin phenotype on hyperproliferating KC, thereby controlling acanthosis in psoriasis patients. PMID- 26499848 TI - RNA polymerase III autoantibodies may indicate renal and more severe skin involvement in systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is a multiorgan autoimmune disorder characterized by sclerosis of the skin and organs as well as the presence of antinuclear autoantibodies. Several types of antinuclear autoantibodies have been described in SSc, associated with distinct disease entities and differences in prognosis. METHODS: The aim of this study was to screen for the presence of antibodies reacting with RNA polymerase III (anti-RNAP3) in a large cohort of patients with SSc treated at a tertiary referral center and to evaluate correlations with disease severity. RESULTS: Anti-RNAP3 antibodies were detected in 11 of 158 patients (7.0%). Eight of the 11 (72.7%) anti-RNAP3-positive patients had diffuse cutaneous SSc (P < 0.01). A higher modified Rodnan skin score, associated with diffuse SSc, correlated with the presence of anti-RNAP3 (P < 0.0001). The detection of anti-RNAP3 antibodies strongly correlated with the presence of renal involvement (P < 0.0001). The odds ratio of RNAP3-positive patients to develop renal involvement was 80.1 (95% CI 9.3-690.1). CONCLUSIONS: This study demonstrates that the detection of anti-RNAP3 antibodies in patients with SSc correlates with renal crisis and severe cutaneous involvement. The possibility to detect specific antibodies with a prognostic value can lead to a better risk management of patients with SSc. PMID- 26499849 TI - Nutrient availability, the microbiome, and intestinal transport during pregnancy. AB - Adequate adaptation of the gastrointestinal tract is important during pregnancy to ensure that the increased metabolic demands by the developing fetus are met. These include changes in surface area mediated by villus hypertrophy and enhanced functional capacity of individual nutrient receptors, including those transporting glucose, fructose, leucine, and calcium. These processes are regulated either by the enhanced nutrient demand or are facilitated by changes in the secretion of pregnancy hormones. Our review also covers recent research into the microbiome, and how pregnancy could lead to microbial adaptations, which are beneficial to the mother, yet are also similar to those seen in the metabolic syndrome. The potential role of diet in modulating the microbiome during pregnancy, as well as the potential for the intestinal microbiota to induce pregnancy complications, are examined. Gaps in the current literature are highlighted, including those where only historical evidence is available, and we suggest areas that should be a priority for further research. In summary, although a significant degree of adaptation has been described, there are both well-established processes and more recent discoveries, such as changes within the maternal microbiome, that pose new questions as to how the gastrointestinal tract effectively adapts to pregnancy, especially in conjunction with maternal obesity. PMID- 26499847 TI - Vagal modulation of high mobility group box-1 protein mediates electroacupuncture induced cardioprotection in ischemia-reperfusion injury. AB - Excessive release of high mobility group box-1 (HMGB1) protein from ischemic cardiomyocytes activates inflammatory cascades and enhances myocardial injury after reperfusion. Here we report evidence that electroacupuncture of mice at Neiguan acupoints can inhibit the up-regulation of cardiac HMGB1 following myocardial ischemia and attenuate the associated inflammatory responses and myocardial injury during reperfusion. These benefits of electroacupuncture were partially reversed by administering recombinant HMGB1 to the mice, and further potentiated by administering anti-HMGB1 antibody. Electroacupuncture-induced inhibition of HMGB1 release was markedly reduced by unilateral vagotomy or administration of nicotinic receptor antagonist, but not by chemical sympathectomy. The cholinesterase inhibitor neostigmine mimicked the effects of electroacupuncture on HMGB1 release and myocardial ischemia reperfusion injury. Culture experiments with isolated neonatal cardiomyocytes showed that acetylcholine, but not noradrenaline, inhibited hypoxia-induced release of HMGB1 via a alpha7nAchR-dependent pathway. These results suggest that electroacupuncture acts via the vagal nerve and its nicotinic receptor-mediated signaling to inhibit HMGB1 release from ischemic cardiomyocytes. This helps attenuate pro-inflammatory responses and myocardial injury during reperfusion. PMID- 26499846 TI - Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression. AB - Metabolic reprogramming is widely observed during cancer development to confer cancer cells the ability to survive and proliferate, even under the stressed, such as nutrient-limiting, conditions. It is famously known that cancer cells favor the "Warburg effect", i.e., the enhanced glycolysis or aerobic glycolysis, even when the ambient oxygen supply is sufficient. In addition, deregulated anabolism/catabolism of fatty acids and amino acids, especially glutamine, serine and glycine, have been identified to function as metabolic regulators in supporting cancer cell growth. Furthermore, extensive crosstalks are being revealed between the deregulated metabolic network and cancer cell signaling. These exciting advancements have inspired new strategies for treating various malignancies by targeting cancer metabolism. Here we review recent findings related to the regulation of glucose, fatty acid and amino acid metabolism, their crosstalk, and relevant cancer therapy strategy. PMID- 26499850 TI - Cortisol, blood pressure, and heart rate responses to food intake were independent of physical fitness levels in women. AB - This research tested the hypothesis that women who had higher levels of physical fitness will have lower hypothalamo-pituitary-adrenal axis (cortisol) and sympatho-adrenal medullary system (blood pressure and heart rate) responses to food intake compared with women who had low levels of physical fitness. Lower fitness (n = 22; maximal oxygen consumption = 27.4 +/- 1.0 mL?kg(-1).min(-1)) and higher fitness (n = 22; maximal oxygen consumption = 41.9 +/- 1.6 mL?kg(-1).min( 1)) women (aged 30-50 years; in the follicular phase of the menstrual cycle) who participated in levels of physical activity that met (lower fitness = 2.7 +/- 0.5 h/week) or considerably exceeded (higher fitness = 7.1 +/- 1.4 h/week) physical activity guidelines made their own lunch using standardised ingredients at 1200 h. Concentrations of cortisol were measured in blood samples collected every 15 min from 1145-1400 h. Blood pressures and heart rate were also measured every 15 min between 1145 h and 1400 h. The meal consumed by the participants consisted of 20% protein, 61% carbohydrates, and 19% fat. There was a significant overall response to lunch in all of the parameters measured (time effect for all, p < 0.01). The cortisol response to lunch was not significantly different between the groups (time * treatment, p = 0.882). Overall, both groups showed the same pattern of cortisol secretion (treatment p = 0.839). Systolic blood pressure, diastolic blood pressure, mean arterial pressure, or heart rate responses (time * treatment, p = 0.726, 0.898, 0.713, and 0.620, respectively) were also similar between higher and lower fitness women. Results suggest that the physiological response to food intake in women is quite resistant to modification by elevated physical fitness levels. PMID- 26499852 TI - Development and validation of the Australian Aboriginal racial identity and self esteem survey for 8-12 year old children (IRISE_C). AB - INTRODUCTION: In Australia, there is little empirical research of the racial identity of Indigenous children and youth as the majority of the current literature focuses on adults. Furthermore, there are no instruments developed with cultural appropriateness when exploring the identity and self-esteem of the Australian Aboriginal population, especially children. The IRISE_C (Racial Identity and Self-Esteem of children) inventory was developed to explore the elements of racial identity and self-esteem of urban, rural and regional Aboriginal children. This paper describes the development and validation of the IRISE_C instrument with over 250 Aboriginal children aged 8 to 12 years. METHODS: A pilot of the IRISE C instrument was combined with individual interviews and was undertaken with 35 urban Aboriginal children aged 8-12 years. An exploratory factor analysis was performed to refine the survey and reduce redundant items in readiness for the main study. In the main study, the IRISE C was employed to 229 Aboriginal children aged 6-13 years across three sites (rural, regional and urban) in Western Australia. An exploratory factor analysis using Principal axis factoring was used to assess the fit of items and survey structure. A confirmatory factor analysis was then employed using LISREL (diagonally weighted least squares) to assess factor structures across domains. Internal consistency and reliability of subscales were assessed using Cronbach's co-efficient alpha. RESULTS: The pilot testing identified two key concepts - children's knowledge of issues related to their racial identity, and the importance, or salience, that they attach to these issues. In the main study, factor analyses showed two clear factors relating to: Aboriginal culture and traditions; and a sense of belonging to an Aboriginal community. Principal Axis Factoring of the Knowledge items supported a 2-factor solution, which explained 38.7% of variance. Factor One (Aboriginal culture) had a Cronbach's alpha of 0.835; Factor 2 (racial identity) had a Cronbach's alpha of 0.800, thus demonstrating high internal reliability of the scales. CONCLUSION: The IRISE_C has been shown to be a valid instrument useful of exploring the development of racial identity of Australian Aboriginal children across the 8-12 year old age range and across urban, rural and regional geographical locations. PMID- 26499853 TI - Body Satisfaction Among Girls With Obesity: A Strong Case for #Loveyourbody. PMID- 26499854 TI - The Cause and Consequence of Mental Health Problems Among At-Risk Youth. PMID- 26499851 TI - An emerging role for prdm family genes in dorsoventral patterning of the vertebrate nervous system. AB - The embryonic vertebrate neural tube is divided along its dorsoventral (DV) axis into eleven molecularly discrete progenitor domains. Each of these domains gives rise to distinct neuronal cell types; the ventral-most six domains contribute to motor circuits, while the five dorsal domains contribute to sensory circuits. Following the initial neurogenesis step, these domains also generate glial cell types-either astrocytes or oligodendrocytes. This DV pattern is initiated by two morphogens-Sonic Hedgehog released from notochord and floor plate and Bone Morphogenetic Protein produced in the roof plate-that act in concentration gradients to induce expression of genes along the DV axis. Subsequently, these DV restricted genes cooperate to define progenitor domains and to control neuronal cell fate specification and differentiation in each domain. Many genes involved in this process have been identified, but significant gaps remain in our understanding of the underlying genetic program. Here we review recent work identifying members of the Prdm gene family as novel regulators of DV patterning in the neural tube. Many Prdm proteins regulate transcription by controlling histone modifications (either via intrinsic histone methyltransferase activity, or by recruiting histone modifying enzymes). Prdm genes are expressed in spatially restricted domains along the DV axis of the neural tube and play important roles in the specification of progenitor domains, as well as in the subsequent differentiation of motor neurons and various types of interneurons. Strikingly, Prdm proteins appear to function by binding to, and modulating the activity of, other transcription factors (particularly bHLH proteins). The identity of key transcription factors in DV patterning of the neural tube has been elucidated previously (e.g. the nkx, bHLH and pax families), but it now appears that an additional family is also required and that it acts in a potentially novel manner. PMID- 26499855 TI - Childhood Adversities and Educational Attainment in Young Adulthood: The Role of Mental Health Problems in Adolescence. AB - PURPOSE: The aims of this study were to examine whether the association between childhood adversities and educational attainment in young adulthood can be explained by mental health problems in adolescence and whether associations and pathways differ for boys and girls. METHODS: Data were used of 2,230 participants from the Tracking Adolescents' Individual Lives Survey, a Dutch prospective cohort study with a 9-year follow-up. Childhood adversities were measured at age 11 years, mental health problems (i.e., externalizing, internalizing and attention problems with Youth Self-Report) at age 16 years, and educational attainment at age 19 years. Structural equation modeling was performed to analyze the data, overall and stratified by gender. RESULTS: Only among boys, childhood adversities were associated with low educational attainment in young adulthood. Externalizing problems in adolescence explained 5% of the association between childhood adversities and educational attainment. Furthermore, for both boys and girls, externalizing problems in adolescence had a direct effect on educational attainment in young adulthood. CONCLUSIONS: Among boys, childhood adversities are associated with poorer educational outcomes of young adults. A part of this association runs via adolescent externalizing problems. The results suggest that boys, compared with girls, are less capable to cope with childhood adversities. Monitoring of exposed boys to childhood adversities is of utmost importance. PMID- 26499856 TI - Psychologists and the Transition From Pediatrics to Adult Health Care. AB - PURPOSE: Guidelines for optimal transition call for multidisciplinary teams, including psychologists, to address youth and young adults' multifactorial needs. This study aimed to characterize psychologists' roles in and barriers to involvement in transition from pediatric to adult health care. METHODS: Psychologists were invited via professional listservs to complete an online survey about practice settings, roles in transition programming, barriers to involvement, and funding sources. Participants also responded to open-ended questions about their experiences in transition programs. RESULTS: One hundred participants responded to the survey. Involvement in transition was reported at multiple levels from individual patient care to institutional transition programming, and 65% reported more than one level of involvement. Direct clinical care (88%), transition-related research (50%), and/or leadership (44%) involvement were reported, with 59% reporting more than one role. Respondents often described advocating for their involvement on transition teams. Various sources of funding were reported, yet, 23% reported no funding for their work. Barriers to work in transition were common and included health care systems issues such as poor coordination among providers or lack of a clear transition plan within the clinic/institution. CONCLUSIONS: Psychologists assume numerous roles in the transition of adolescents from pediatric to adult health care. With training in health care transition-related issues, psychologists are ideally positioned to partner with other health professionals to develop and implement transition programs in multidisciplinary settings, provided health care system barriers can be overcome. PMID- 26499857 TI - Prevalence of Sexual Experience and Initiation of Sexual Intercourse Among Adolescents, Rakai District, Uganda, 1994-2011. AB - PURPOSE: The purpose of the study was to identify risk factors and time trends for sexual experience and sexual debut in rural Uganda. METHODS: Using population based, longitudinal data from 15- to 19-year olds in Rakai, Uganda, we examined temporal trends in the prevalence of sexual experience and potential risk factors for sexual experience (n = 31,517 person-round observations) using logistic regression. We then identified factors associated with initiation of sex between survey rounds, using Poisson regression to estimate incidence rate ratios (IRR; n = 5,126 person-year observations). RESULTS: Sexual experience was more common among adolescent women than men. The prevalence of sexual experience rose for most age-gender groups after 1994 and then declined after 2002. Factors associated with higher prevalence of sexual experience (without adjustment for other factors) included age, not enrolled in school, orphanhood, lower socioeconomic status, and drinking alcohol in the past 30 days; similar factors were associated with initiation of sex. Factors independently associated with initiation of sex included older age, nonenrollment in school (IRR = 1.7 for women and 1.8 for men), alcohol use (IRR = 1.3 for women and men), and being a double orphan among men (IRR = 1.2). Sexual experience began to decline around 2000, whereas increases in school enrollment began as early as 1994 and declines in orphanhood occurred after 2004 (as antiretroviral therapy became available). CONCLUSIONS: Sexual experience among youth in Rakai was associated with social factors particularly school enrollment. Changes in these social factors also appear to influence change over time in sexual experience. PMID- 26499858 TI - Perceived Discrimination and Heavy Episodic Drinking Among African-American Youth: Differences by Age and Reason for Discrimination. AB - PURPOSE: The purpose of this study was to examine whether associations between perceived discrimination and heavy episodic drinking (HED) vary by age and by discrimination type (e.g., racial, age, physical appearance) among African American youth. METHODS: National data from the Panel Study of Income Dynamics Transition to Adulthood Study were analyzed. Youth participated in up to four interviews (2005, 2007, 2009, 2011; n = 657) between ages 18 and 25 years. Respondents reported past-year engagement in HED (four or more drinks for females, five or more drinks for males) and frequency of discriminatory acts experienced (e.g., receiving poor service, being treated with less courtesy). Categorical latent growth curve models, including perceived discrimination types (racial, age, and physical appearance) as a time-varying predictors of HED, were run. Controls for gender, birth cohort, living arrangement in adolescence, familial wealth, parental alcohol use, and college attendance were explored. RESULTS: The average HED trajectory was curvilinear (increasing followed by flattening), whereas perceived discrimination remained flat with age. In models including controls, odds of HED were significantly higher than average around ages 20-21 years with greater frequency of perceived racial discrimination; associations were not significant at other ages. Discrimination attributed to age or physical appearance was not associated with HED at any age. CONCLUSIONS: Perceived racial discrimination may be a particularly salient risk factor for HED around the ages of transition to legal access to alcohol among African-American youth. Interventions to reduce discrimination or its impact could be targeted before this transition to ameliorate the negative outcomes associated with HED. PMID- 26499859 TI - Incidence and Course of Adolescent Deliberate Self-Harm in Victoria, Australia, and Washington State. AB - PURPOSE: There have been few longitudinal studies of deliberate self-harm (DSH) in adolescents. This cross-national longitudinal study outlines risk and protective factors for DSH incidence and persistence. METHODS: Seventh and ninth grade students (average ages 13 and 15 years) were recruited as state representative cohorts, surveyed, and then followed up 12 months later (N = 3,876), using the same methods in Washington State and Victoria, Australia. The retention rate was 99% in both states at follow-up. A range of risk and protective factors for DSH were examined using multivariate analyses. RESULTS: The prevalence of DSH in the past year was 1.53% in Grade 7 and .91% in Grade 9 for males and 4.12% and 1.34% for Grade 7 and Grade 9 females, respectively, with similar rates across states. In multivariate analyses, incident DSH was lower in Washington State (odds ratio [OR] = .67; 95% confidence interval [CI] = .45-1.00) relative to Victoria 12 months later. Risk factors for incident DSH included being female (OR = 1.93; CI = 1.35-2.76), high depressive symptoms (OR = 3.52; CI = 2.37-5.21), antisocial behavior (OR = 2.42; CI = 1.46-4.00), and lifetime (OR = 1.85; CI = 1.11-3.08) and past month (OR = 2.70; CI = 1.57-4.64) alcohol use relative to never using alcohol. CONCLUSIONS: Much self-harm in adolescents resolves over the course of 12 months. Young people who self-harm have high rates of other health risk behaviors associated with family and peer risks that may all be targets for preventive intervention. PMID- 26499860 TI - Six-months follow-up of a cluster randomized trial of school-based smoking prevention education programs in Aceh, Indonesia. AB - BACKGROUND: Smoking prevention programs have been taught in schools to reduce the high smoking prevalence and its related problems among adolescent populations. Although short-term benefits have been observed, the long-term effectiveness of such programs appear to be inconsistent. This study aims at investigating the long-term impact of both health and Islamic focused interventions amongst students in Indonesia. METHODS: At 6 months after completion of the interventions, 427 of the original 447 participants (control group = 128, intervention groups = 299) from a school-based cluster randomized control trial were re-assessed for their smoking knowledge, attitudes, intentions and behaviours using a self-report questionnaire. Data was analyzed according to the study's 2 * 2 factorial design with adjustment for baseline scores, school and classroom clustering effects and multiple comparisons. RESULTS: Compared to the control group, significant long term effects were found for the health-based intervention program in improved health (beta = 4.3 +/- 0.4, p < 0.001), Islamic (beta = 1.1 +/- 0.4, p = 0.01) knowledge and a reduction of smoking attitudes (beta = -11.5 +/- 1.8, p < 0.001). For the Islamic-based intervention programs there was an improvement of health (beta = 3.7 +/- 0.4, p < 0.001) and Islamic (beta = 2.2 +/- 0.5, p < 0.001) knowledge and a reduction towards smoking attitude (beta = -6.0 +/- 1.9, p < 0.01) and smoking behaviors in the past month (OR = 0.1, 95 % CI = 0.0-0.8, p = 0.03). The effects were greater but less than additive in the combined group for health (beta = -3.2 +/- 0.9, p < 0.001 for interaction) and Islamic knowledge (beta = -2.3 +/- 0.9, p = 0.01 for interaction) but were additive for smoking attitudes (beta = 6.1 +/- 3.2, p = 0.07 for interaction). No significant effects on smoking intentions were observed at 6 months follow-up in the health or Islamic-based intervention programs. CONCLUSION: School-based programs can provide long term benefits on Indonesian adolescents' smoking knowledge and attitudes. Tailoring program intervention components with participants' religious background might maximise program effectiveness. A larger and more encompassing study is now required to confirm the effectiveness of this new Indonesia culturally-based program. Adolescents in similar areas might also benefit from this type of school-based smoking cessation program. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, ACTRN12612001070820. PMID- 26499861 TI - Cytotoxic, anti-proliferative and apoptotic effects of silver nitrate against H ras transformed 5RP7. AB - Metal based drugs have successfully been used in both the detection and treatment of different disease states. The antibacterial features of metal ion silver are well documented. Most recently, metal ion silver has been tested and applied in anticancer activity. The present study observed the cytotoxic, anti-proliferative and apoptotic effects of metal complex silver nitrate in H-ras transformed 5RP7 cell lines for 24 h. In addition, the toxic effects of silver nitrate was investigated on NIH/3T3 primary mouse embryonic fibroblast cells for 24 h. Cytotoxic effects were determined by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2H-tetrazolium bromide) assay. Apoptosis and necrosis were evaluated by flow cytometric analysis (Annexin-V FITC/PI). Caspase-3 activation was researched by flow cytometric analysis. Apoptotic morphology was observed by DAPI staining. Structure and ultra-structure changes of cells were assessed using transmission electron microscopy. The results indicate silver nitrate has high cytotoxicity and a strong capacity to induce apoptosis in H-ras 5RP7 cells. Furthermore silver nitrate was not toxic against NIH/3T3 primary mouse embryonic fibroblast cells at low doses for 24 h. PMID- 26499862 TI - Spontaneous remission of fully symptomatic visceral leishmaniasis. AB - BACKGROUND: Visceral leishmaniasis (VL), i.e., infection with Leishmania sp. associated with high fever, weight loss, massive splenomegaly and markedly altered laboratory parameters, is generally fatal if untreated. The possibility of transient spontaneous remission of fully symptomatic visceral leishmaniasis (VL) has been mentioned but, to our knowledge) has never been documented. CASE PRESENTATION: We report the first documented history of a patient with overt, confirmed VL experiencing a complete remission in the absence of any anti leishmanial therapy. The diagnosis of VL at the time of the self-resolving episode was strongly suspected based on clinical presentation and presence of antileishmanial antibody, then unequivocally confirmed years later by the presence of an amastigote on a stored smear and the positive quantitative PCR with Leishmania-specific primers from the material scraped from this same slide CONCLUSION: This report demonstrates that complete spontaneous remission may occur in patients with overt, fully symptomatic VL. VL should therefore be considered in cases of self-resolving or relapsing episodes of fever of unknown origin. Confirmation should be based on both serological tests and specific PCR on a blood sample. PMID- 26499863 TI - The Vat-AIEC protease promotes crossing of the intestinal mucus layer by Crohn's disease-associated Escherichia coli. AB - The aetiology of Crohn's disease (CD) involves disorders in host genetic factors and intestinal microbiota. Adherent-invasive Escherichia coli (AIEC) are receiving increased attention because in studies of mucosa-associated microbiota, they are more prevalent in CD patients than in healthy subjects. AIEC are associated both with ileal and colonic disease phenotypes. In this study, we reported a protease called Vat-AIEC from AIEC that favours the mucosa colonization. The deletion of the Vat-AIEC-encoding gene resulted in an adhesion impaired phenotype in vitro and affected the colonization of bacteria in contact with intestinal epithelial cells in a murine intestinal loop model, and also their gut colonization in vivo. Furthermore, unlike LF82Deltavat-AIEC, wild-type AIEC reference strain LF82 was able to penetrate a mucus column extensively and promoted the degradation of mucins and a decrease in mucus viscosity. Vat-AIEC transcription was stimulated by several chemical conditions found in the ileum environment. Finally, the screening of E. coli strains isolated from CD patients revealed a preferential vat-AIEC association with AIEC strains belonging to the B2 phylogroup. Overall, this study revealed a new component of AIEC virulence that might favour their implantation in the gut of CD patients. PMID- 26499864 TI - Epigenome-Wide Association Study of Tic Disorders. AB - Tic disorders are moderately heritable common psychiatric disorders that can be highly troubling, both in childhood and in adulthood. In this study, we report results obtained in the first epigenome-wide association study (EWAS) of tic disorders. The subjects are participants in surveys at the Netherlands Twin Register (NTR) and the NTR biobank project. Tic disorders were measured with a self-report version of the Yale Global Tic Severity Scale Abbreviated version (YGTSS-ABBR), included in the 8th wave NTR data collection (2008). DNA methylation data consisted of 411,169 autosomal methylation sites assessed by the Illumina Infinium HumanMethylation450 BeadChip Kit (HM450k array). Phenotype and DNA methylation data were available in 1,678 subjects (mean age = 41.5). No probes reached genome-wide significance (p < 1.2 * 10(-7)). The strongest associated probe was cg15583738, located in an intergenic region on chromosome 8 (p = 1.98 * 10(-6)). Several of the top ranking probes (p < 1 * 10(-4)) were in or nearby genes previously associated with neurological disorders (e.g., GABBRI, BLM, and ADAM10), warranting their further investigation in relation to tic disorders. The top significantly enriched gene ontology (GO) terms among higher ranking methylation sites included anatomical structure morphogenesis (GO:0009653, p = 4.6 * 10-(15)) developmental process (GO:0032502, p = 2.96 * 10( 12)), and cellular developmental process (GO:0048869, p = 1.96 * 10(-12)). Overall, these results provide a first insight into the epigenetic mechanisms of tic disorders. This first study assesses the role of DNA methylation in tic disorders, and it lays the foundations for future work aiming to unravel the biological mechanisms underlying the architecture of this disorder. PMID- 26499865 TI - Organization and genomic complexity of sheep immunoglobulin light chain gene loci. AB - Sheep is the representative of the artiodactyla and is an agriculturally important animal, but limited knowledge is available with regard to its immunoglobulin genes and their expression mechanisms in the sheep. Based on the recently released sheep genome, we have characterized the genomic organization of the sheep immunoglobulin light gene loci. The sheep Iglambda locus, located on chromosome 17, contains 2Clambda segments each preceded by a Jlambda, but the Clambda2 appears to be a pseudogene. A total of 42 Vlambda segments (14 potentially functional genes, 1 ORF and 27 pseudogenes) were identified. In contrast, the Igkappa locus on chromosome 3 contains only a single Ckappa gene, 3 Jk segments and 13 Vkappa segments (8 potentially functional genes and 5 pseudogenes). Analysis of junctions of the recombined VJ transcripts revealed a restricted Vlambda4-Jlambda1-Clambda1 recombination and Vk6-Jk3-Ckappa recombination, respectively encode most of lambda and kappa chain antibody repertoire in the sheep despite more potential germline encoded combinatorial diversity. Therefore, the sheep may use gene conversion in combination with somatic hypermutation for antibody repertoire formation. PMID- 26499866 TI - Two cases of eosinophilic pustular folliculitis associated with pregnancy. PMID- 26499868 TI - A mitochondria-targeted ratiometric fluorescent probe for rapid, sensitive and specific detection of biological SO2 derivatives in living cells. AB - In this study, we report a ratiometric fluorescent probe (CZBI) for sulfur dioxide (SO2) derivatives based on the conjugate of carbazole and benzo[e]indolium, which displays colorimetric and ratiometric fluorescence dual response to HSO3(-). The probe can quantitatively detect HSO3(-) with high specificity, fast response (within 40s) as well as low detection limit (10nM). A 1,4-nucleophilic addition reaction was proposed for the sensing mechanism of this probe, which was confirmed by (1)H NMR and HR-MS spectra. Fluorescence co localization studies demonstrated that CZBI was a specific mitochondria-targeted fluorescent probe for SO2 derivatives with excellent cell membrane permeability. Furthermore, fluorescence imaging of HeLa cells indicated that CZBI could be used for monitoring the intrinsically generated intracellular SO2 derivatives in living cells by ratiometric fluorescence imaging. Thus, CZBI has a great potential application for exploring the role played by SO2 derivatives in biology. PMID- 26499867 TI - Do cognitive measures and brain circuitry predict outcomes of exercise in Parkinson Disease: a randomized clinical trial. AB - BACKGROUND: There is emerging research detailing the relationship between balance/gait/falls and cognition. Imaging studies also suggest a link between structural and functional changes in the frontal lobe (a region commonly associated with cognitive function) and mobility. People with Parkinson's disease have important changes in cognitive function that may impact rehabilitation efficacy. Our underlying hypothesis is that cognitive function and frontal lobe connections with the basal ganglia and brainstem posture/locomotor centers are responsible for postural deficits in people with Parkinson's disease and play a role in rehabilitation efficacy. The purpose of this study is to 1) determine if people with Parkinson's disease can improve mobility and/or cognition after partaking in a cognitively challenging mobility exercise program and 2) determine if cognition and brain circuitry deficits predict responsiveness to exercise rehabilitation. METHODS/DESIGN: This study is a randomized cross-over controlled intervention to take place at a University Balance Disorders Laboratory. The study participants will be people with Parkinson's disease who meet inclusion criteria for the study. The intervention will be 6 weeks of group exercise (case) and 6 weeks of group education (control). The exercise is a cognitively challenging program based on the Agility Boot Camp for people with PD. The education program is a 6-week program to teach people how to better live with a chronic disease. The primary outcome measure is the MiniBESTest and the secondary outcomes are measures of mobility, cognition and neural imaging. DISCUSSION: The results from this study will further our understanding of the relationship between cognition and mobility with a focus on brain circuitry as it relates to rehabilitation potential. TRIAL REGISTRATION: This trial is registered at clinical trials.gov (NCT02231073). PMID- 26499869 TI - Ratiometric electrochemiluminescent strategy regulated by electrocatalysis of palladium nanocluster for immunosensing. AB - This work designed a novel ratiometric electrochemiluminescence (ECL) immunosensing approach based on two different ECL emitters: CdS quantum dots (QDs) as cathodic emitter and luminol as anodic emitter. The ECL immunosensor was constructed by a layer-by-layer modification of CdS QDs, Au nanoparticles and capture antibody on a glassy carbon electrode. With hydrogen peroxide as ECL coreactant, the immunosensor showed a cathodic ECL emission of CdS QDs at -1.5 V (vs Ag/AgCl) in air-saturated pH 8.0 buffer. Upon the formation of sandwich immunoassay, the lumiol/palladium nanoclusters (Pd NCs)@graphene oxide probe was introduced to the electrode. Therefore, the cathodic ECL intensity decreased and luminol anodic ECL emission was appeared at +0.3 V (vs Ag/AgCl) owing to the competition of the coreactant of hydrogen peroxide. Using carcino-embryonic antigen as model, this ratiometric ECL strategy could be used for immunoassay with a linear range of 1.0-100 pg mL(-1) and a detection limit of 0.62 pg mL(-1). The enhanced ratiometric ECL signal resulted from the high density and excellent electrocatalysis of the loaded Pd NCs. The immunosensor exhibited good stability and acceptable fabrication reproducibility and accuracy, showing a great promising for clinical application. This electrocatalysis-regulated ratiometric ECL provides a new concept for ECL measurement, and could be conveniently extended for detection of other protein biomarkers. PMID- 26499870 TI - Intense charge transfer surface based on graphene and thymine-Hg(II)-thymine base pairs for detection of Hg(2.). AB - In this article, we developed an electrochemiluminescence (ECL) sensor with a high-intensity charge transfer interface for Hg(2+) detection based on Hg(II) induced DNA hybridization. The sensor was fabricated by the following simple method. First, graphene oxide (GO) was electrochemically reduced onto a glassy carbon electrode through cyclic voltammetry. Then, amino-labeled double-stranded (ds)DNA was assembled on the electrode surface using 1-pyrenebutyric acid N hydroxysuccinimide as a linker between GO and DNA. The other terminal of dsDNA, which was labeled with biotin, was linked to CdSe quantum dots via biotin-avidin interactions. Reduced graphene oxide has excellent electrical conductivity. dsDNA with T-Hg(II)-T base pairs exhibited more facile charge transfer. They both accelerate the electron transfer performance and sensitivity of the sensor. The increased ECL signals were logarithmically linear with the concentration of Hg(II) when Hg(2+) was present in the detection solution. The linear range of the sensor was 10(-11) to 10(-8)mol/L (R=0.9819) with a detection limit of 10( 11)mol/L. This biosensor exhibited satisfactory results when it was used to detect Hg(II) in real water samples. The biosensor with high-intense charge transfer performance is a prospect avenue to pursue more and more sensitive detection method. PMID- 26499871 TI - Multifunctional catalytic platform for peroxidase mimicking, enzyme immobilization and biosensing. AB - A hybrid platform based on ionic liquid-based alkoxysilane functionalized mesoporous silica was applied for the synthesis of supported Pt nanoparticles with peroxidase-like catalytic activity. The positively charged groups (imidazolium) chemically bonded to the surface provide dual-functionality as ion exchangers to the hybrid material, firstly used for the in situ synthesis of the highly dispersed Pt nanostructures and, secondly, for the immobilization of biological species aiming biosensing purposes. The peroxidase-like catalytic activity of the SiO2/Imi/Pt material was evaluated towards the H2O2-mediated oxidation of a chromogenic peroxidase substrate (TMB), allowing the colorimetric detection of H2O2. Finally, to further explore the practical application of this nanomaterial-based artificial system, glucose oxidase (GOx) was immobilized on the catalytic porous platform and a bioassay for the colorimetric determination of glucose was successfully conducted as a model system. The enzyme-like catalytic properties of the SiO2/Imi/Pt as well as its ability to immobilize and keep active biological entities on the porous structure indicate that this hybrid porous platform is potentially useful for the development of biosensing devices. PMID- 26499872 TI - Tumour necrosis factor-alpha-mediated disruption of cerebrovascular endothelial barrier integrity in vitro involves the production of proinflammatory interleukin 6. AB - The co-involvement of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) during blood-brain barrier (BBB) injury has been reported in various models of neuroinflammation, although the precise functional interplay between these archetypal proinflammatory cytokines remains largely undefined within this context. In the current paper, we tested the hypothesis that TNF-alpha-mediated BBB disruption is measurably attributable in-part to induction of microvascular endothelial IL-6 production. In initial experiments, we observed that treatment of human brain microvascular endothelial cells (HBMvECs) with TNF-alpha (0-100 ng/mL, 0-24 h) robustly elicited both time- and dose-dependent induction of IL-6 expression and release, as well as expression of the IL-6 family receptor, GP130. Further experiments demonstrated that the TNF-alpha-dependent generation of reactive oxygen species, down-regulation of adherens/tight junction proteins, and concomitant elevation of HBMvEC permeability, were all significantly attenuated by blockade of IL-6 signalling using either an anti-IL-6 neutralizing antibody or an IL-6 siRNA. Based on these observations, we conclude that TNF-alpha treatment of HBMvECs in vitro activates IL-6 production and signalling, events that were shown to synergize with TNF-alpha actions to elicit HBMvEC permeabilization. These novel findings offer a constructive insight into the specific contribution of downstream cytokine induction to the injurious actions of TNF-alpha at the BBB microvascular endothelium interface. The co-involvement of tumour necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) during blood-brain barrier (BBB) injury has been widely reported. Using human brain microvascular endothelial cells (HBMvEC), we show that TNF-alpha-mediated BBB disruption is measurably attributable in-part to induction of endothelial IL-6 production and signalling. We demonstrate that the TNF-alpha-dependent generation of reactive oxygen species (ROS), down-regulation of interendothelial junctions, and concomitant elevation of HBMvEC permeability, could be significantly attenuated by using either an IL-6 neutralizing antibody or an IL-6-specific siRNA. These findings provide insight into the complex nature of proinflammatory cytokine injury at the BBB microvascular endothelium interface. PMID- 26499874 TI - Editorial Comment from Dr Haddad and Dr Margulis to Prognostic factors of recurrent disease in upper urinary tract urothelial cancer after radical nephroureterectomy: Subanalysis of the multi-institutional national database of the Japanese Urological Association. PMID- 26499875 TI - Central corneal sensitivity after small incision lenticule extraction versus femtosecond laser-assisted LASIK for myopia: a meta-analysis of comparative studies. AB - BACKGROUND: The aim of this study was to evaluate central corneal sensitivity after small incision lenticule extraction (SMILE) versus femtosecond laser assisted laser in situ keratomileusis (FS-LASIK) for myopia. METHODS: Eligible studies were identified by systematically searching PubMed, the Cochrane Library, Embase and the Chinese Biomedicine Database. Central corneal sensitivity after SMILE versus FS-LASIK was assessed by the pooled weighted mean differences (WMDs) of the reduction from pre-operation levels to 1 week, 1, 3 and 6 months following the operation. The quality of the included literature was assessed by the Quality Index. Data were synthesized by Stata 12.0 SE for Windows. RESULTS: Five studies involving 245 patients (363 eyes; 189 eyes in the FS-LASIK group and 174 eyes in the SMILE group) were included in the meta-analysis. The pooled results showed that there were no significant differences in central corneal sensitivity between FS-LASIK and SMILE before surgery (WMD = 0 mm, 95 % CI: -0.23 to -0.23, p = 0.998). At 1 week, 1 and 3 months after surgery, the central corneal sensitivity after FS-LASIK was lower than with SMILE (WMD = -17.35 mm, 95 % CI: -26.54 to 8.16, p <0.001; WMD = -17.52 mm, 95 % CI: -25.10 to -9.94, p <0.001; WMD = -14.64 mm, 95 % CI: -20.08 to -9.21, p <0.001, respectively). However, central corneal sensitivity after FS-LASIK was similar with SMILE 6 months after surgery (WMD = 2.02 mm, 95 % CI: -4.23 to 0.19, p = 0.074). CONCLUSION: Central corneal sensitivity exhibited a small decrease and a faster recovery after the SMILE procedure compared to FS-LASIK during the first three postoperative months. Corneal sensitivity after SMILE and FS-LASIK was similar at 6 months after surgery. However, these results should be interpreted with caution due to the limited number of studies. PMID- 26499877 TI - Entropy of corneal nerve fibers distribution observed by laser scanning confocal microscopy: A noninvasive quantitative method to characterize the corneal innervation in Sjogren's syndrome patients. AB - Sjogren's syndrome (SS) is a progressive autoimmune condition mainly affecting the salivary and lacrimal glands with an incidence of primary SS between 1/100 and 1/1,000. SS implies an alteration in the epithelium and subepithelium innervation, with consequent reduction of corneal sensitivity. It is necessary to have noninvasive quantitative methods to characterize the status of the corneal nerve fibers of the patients in order to choose and follow the best therapy. Entropy (information dimension) of the nerve corneal fibers distribution observed by confocal microscopy was evaluated in patients with primary SS (n = 30, 6 males, 24 females, 21-81 years), diagnosed by biopsy of salivary gland and blood tests and in sex- age-matched healthy subjects (n = 12). Corneal nerve fiber density, Langerhans cell count, and cell density in the nerve plexus images were also evaluated. In selected patients salivary gland atrophy degree was also evaluated. Nerve corneal distribution observed by confocal microscopy is fractal. Entropy of the corneal nerve distribution statistically distinguishes between SS patients and healthy subjects: patients present a lower value of information dimension of the corneal nerve fibers distribution than healthy individuals (P < 0.001). Percentage of grouped cases classified by entropy according to the subjects (selected patients vs. healthy) showed a 100% sensitivity and 96% specificity, P < 0.0001 with a low value of coefficient of variation among the individuals (6-7 times lower than the other morphometric indexes). Entropy correlated with the severity of the disease (salivary gland atrophy degree, P < 0.01). Evaluation of entropy of the corneal nerve distribution observed by a laser confocal microscopy appears to quantitatively and noninvasively characterize an aspect of the SS patients in relation to the recognition of an impairment of their ocular surface, giving us for the first time a method to objectively and precisely characterize the corneal innervation status in the SS patients. PMID- 26499876 TI - Quercetin suppresses immune cell accumulation and improves mitochondrial gene expression in adipose tissue of diet-induced obese mice. AB - SCOPE: To examine the effect of dietary quercetin on the function of epididymal adipose tissue (EAT) in Western diet-induced obese mice. METHODS AND RESULTS: C57BL/6J mice were fed a control diet; a Western diet high in fat, cholesterol, and sucrose; or the same Western diet containing 0.05% quercetin for 18 weeks. Supplementation with quercetin suppressed the increase in the number of macrophages, the decrease in the ratio of CD4(+) to CD8(+) T cells in EAT, and the elevation of plasma leptin and tumor necrosis factor alpha levels in mice fed the Western diet. Comprehensive gene expression analysis revealed that quercetin suppressed gene expression associated with the accumulation and activation of immune cells, including macrophages and lymphocytes in EAT. It also improved the expression of the oxidative stress-sensitive transcription factor NFkappaB, NADPH oxidases, and antioxidant enzymes. Quercetin markedly increased gene expression associated with mitochondrial oxidative phosphorylation and mitochondrial DNA content. CONCLUSION: Quercetin most likely universally suppresses the accumulation and activation of immune cells, including antiinflammatory cells, whereas it specifically increased gene expression associated with mitochondrial oxidative phosphorylation. Suppression of oxidative stress and NFkappaB activity likely contributed to the prevention of the accumulation and activation of immune cells and resulting chronic inflammation. PMID- 26499878 TI - Association between ultrasound features of adenomyosis and severity of menstrual pain. AB - OBJECTIVE: To investigate the association between the ultrasound features of adenomyosis and the severity of menstrual pain. METHODS: This was a prospective observational study set in the general gynecology clinic of a university teaching hospital between January 2009 and January 2010. A total of 718 consecutive premenopausal women aged between 17 and 55 years attended the clinic and underwent structured clinical and transvaginal ultrasound examinations in accordance with the study protocol. Morphological features of adenomyosis on ultrasound scan were recorded systematically. A quantitative assessment of menstrual pain was made by completion of a numerical rating scale (NRS). RESULTS: One hundred and fifty-seven (21.9% (95% CI, 18.8-24.9%)) women were diagnosed with adenomyosis on ultrasound. Multiple linear regression analysis showed that an ultrasound diagnosis of adenomyosis and ultrasound and laparoscopic diagnoses of endometriosis were significantly associated with menstrual pain when measured by an NRS. In addition, there was a statistically significant positive correlation between the severity of menstrual pain and the number of ultrasound features of adenomyosis seen. CONCLUSIONS: Women with ultrasound features of adenomyosis have more severe menstrual pain than do women without these features. The positive correlation between the number of ultrasound features of adenomyosis and the severity of menstrual pain could form the basis of a clinically relevant grading system for adenomyosis. A classification of severity of adenomyosis based on the number of ultrasound features present is a novel concept that should be evaluated prospectively in different populations. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26499879 TI - General practice and specialist palliative care teams: an exploration of their working relationship from the perspective of clinical staff working in New Zealand. AB - With the future focus on palliative and end-of-life care provision in the community, the role of the general practice team and their relationship with specialist palliative care providers is key to responding effectively to the projected increase in palliative care need. Studies have highlighted the potential to improve co-ordination and minimise fragmentation of care for people living with palliative care need through a partnership between generalist services and specialist palliative care. However, to date, the exact nature of this partnership approach has not been well defined and debate exists about how to make such partnerships work successfully. The aim of this study was to explore how general practice and specialist palliative care team (SPCT) members view their relationship in terms of partnership working. Five focus group discussions with general practices and SPCT members (n = 35) were conducted in 2012 in two different regions of New Zealand and analysed using a general inductive approach. The findings indicate that participants' understanding of partnership working was informed by their identity as a generalist or specialist, their existing rules of engagement and the approach they took towards sustaining the partnership. Considerable commitment to partnership working was shown by all participating teams. However, their working relationship was based primarily on trust and personal liaison, with limited formal systems in place to enable partnership working. Tensions between the cultures of 'generalism' and 'specialism' also provided challenges for those endeavouring to meet palliative care need collaboratively in the community. Further research is required to better understand the factors associated with successful partnership working between general practices and specialist palliative care in order to develop robust strategies to support a more sustainable model of community palliative care. PMID- 26499880 TI - Influence of oval and circular post placement using different resin cements on push-out bond strength and void volume analysed by micro-CT. AB - AIM: To evaluate the percentage volume of voids within cement layers, to determine the push-out bond strength of circular and oval fibre posts luted with different commercial resin cements in oval cross-sectional root canals, and to correlate push-out bond strength values and volume of voids of circular and oval fibre posts. METHODOLOGY: Seventy-two mandibular premolars with oval-shaped root canals were selected. The specimens were divided into two main groups according to the post type (oval and circular). Groups were further divided into three subgroups (n = 24) according to resin cement type: Maxcem Elite, Rely-X Unicem and Duo-Link. The volumes of voids within the cements were analysed by micro computed tomography (micro-CT). The bond strength was then measured using a push out test with an Instron universal testing machine. The failure modes were evaluated. Statistical analyses were performed using a three-way anova, Tukey's post hoc, Pearson's correlation and chi-square test (P = 0.05). RESULTS: The push out bond strength values were significantly affected by root canal region, post type and cement type (P < 0.001). Root canal region, post type and cement type also significantly affected void volume (P < 0.001). There was a significant interaction between post type and cement type (P < 0.001). The most frequent failure type was adhesive failure in all the groups. There was no significant correlation between the push-out bond strength and void volume (P > 0.05). CONCLUSIONS: Void volume did not affect push-out bond strength of oval and circular posts luted in oval canals. PMID- 26499882 TI - Three-dimensional motions of distal syndesmosis during walking. AB - INTRODUCTION: The motion of the distal syndesmosis correlates highly with the instability, while an accurate kinematic description of the distal tibiofibular joint during normal gait has not previously been presented. MATERIAL AND METHODS: Sixteen healthy syndesmoses of sixteen living subjects (8 male and 8 female) were studied during stance phase of the normal gait. Data of CT scanning were collected first and used to create the 3D models of the distal tibia and fibula. The lateral X-ray images of the syndesmosis were captured by fluoroscopy when the subject was walking. Seven key-pose images were selected for subsequent 3D to 2D bone model registration and six degrees-of-freedom (DOF) motions of syndesmosis were then calculated. A validation experiment was also conducted to confirm the accuracy of the 3D/2D technique for the syndesmosis. RESULTS: During the stance phase, the distal tibiofibular joint exhibited with 2.98 +/- 1.10 degrees of dorsi/plantarflexion, 5.94 +/- 1.52 degrees of inversion/eversion, and 5.99 +/- 2.00 degrees of internal/external rotation; 2.63 +/- 1.05 mm on medial/lateral, 3.86 +/- 1.65 mm on anterior/posterior, and 4.12 +/- 1.53 mm on superior/inferior translation. From heel strike to mid-stance, the syndesmosis demonstrated 1.69 degrees of dorsiflexion, 3.61 degrees of eversion, and 3.95 degrees of external rotation. Likewise, from mid-stance to heel-off, the syndesmosis presented 1.04 degrees of plantarflexion, 4.95 degrees of inversion, and 5.13 degrees of internal rotation. CONCLUSION: During the stance phase of normal gait, internal/external rotation and vertical motion play dominant roles in terms of rotation and translation, respectively. PMID- 26499881 TI - Lower limb biomechanical characteristics of patients with neuropathic diabetic foot ulcers: the diabetes foot ulcer study protocol. AB - BACKGROUND: Foot ulceration is the main precursor to lower limb amputation in patients with type 2 diabetes worldwide. Biomechanical factors have been implicated in the development of foot ulceration; however the association of these factors to ulcer healing remains less clear. It may be hypothesised that abnormalities in temporal spatial parameters (stride to stride measurements), kinematics (joint movements), kinetics (forces on the lower limb) and plantar pressures (pressure placed on the foot during walking) contribute to foot ulcer healing. The primary aim of this study is to establish the biomechanical characteristics (temporal spatial parameters, kinematics, kinetics and plantar pressures) of patients with plantar neuropathic foot ulcers compared to controls without a history of foot ulcers. The secondary aim is to assess the same biomechanical characteristics in patients with foot ulcers and controls over-time to assess whether these characteristics remain the same or change throughout ulcer healing. METHODS/DESIGN: The design is a case-control study nested in a six month longitudinal study. Cases will be participants with active plantar neuropathic foot ulcers (DFU group). Controls will consist of patients with type 2 diabetes (DMC group) and healthy participants (HC group) with no history of foot ulceration. Standardised gait and plantar pressure protocols will be used to collect biomechanical data at baseline, three and six months. Descriptive variables and primary and secondary outcome variables will be compared between the three groups at baseline and follow-up. DISCUSSION: It is anticipated that the findings from this longitudinal study will provide important information regarding the biomechanical characteristic of type 2 diabetes patients with neuropathic foot ulcers. We hypothesise that people with foot ulcers will demonstrate a significantly compromised gait pattern (reduced temporal spatial parameters, kinematics and kinetics) at base line and then throughout the follow up period compared to controls. The study may provide evidence for the design of gait-retraining, neuro-muscular conditioning and other approaches to off-load the limbs of those with foot ulcers in order to reduce the mechanical loading on the foot during gait and promote ulcer healing. PMID- 26499883 TI - Mycorrhiza alters the profile of root hairs in trifoliate orange. AB - Root hairs and arbuscular mycorrhiza (AM) coexist in root systems for nutrient and water absorption, but the relation between AM and root hairs is poorly known. A pot study was performed to evaluate the effects of four different AM fungi (AMF), namely, Claroideoglomus etunicatum, Diversispora versiformis, Funneliformis mosseae, and Rhizophagus intraradices on root hair development in trifoliate orange (Poncirus trifoliata) seedlings grown in sand. Mycorrhizal seedlings showed significantly higher root hair density than non-mycorrhizal seedlings, irrespective of AMF species. AMF inoculation generally significantly decreased root hair length in the first- and second-order lateral roots but increased it in the third- and fourth-order lateral roots. AMF colonization induced diverse responses in root hair diameter of different order lateral roots. Considerably greater concentrations of phosphorus (P), nitric oxide (NO), glucose, sucrose, indole-3-acetic acid (IAA), and methyl jasmonate (MeJA) were found in roots of AM seedlings than in non-AM seedlings. Levels of P, NO, carbohydrates, IAA, and MeJA in roots were correlated with AM formation and root hair development. These results suggest that AMF could alter the profile of root hairs in trifoliate orange through modulation of physiological activities. F. mosseae, which had the greatest positive effects, could represent an efficient AM fungus for increasing fruit yields or decreasing fertilizer inputs in citrus production. PMID- 26499884 TI - Speckle tracking analysis allows sensitive detection of stress cardiomyopathy in severe aneurysmal subarachnoid hemorrhage patients. AB - PURPOSE: Stress cardiomyopathy is a common life-threatening complication after aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that left ventricular (LV) longitudinal strain alterations assessed with speckle tracking could identify early systolic function impairment. METHODS: This was an observational single-center prospective pilot controlled study conducted in a neuro-intensive care unit. Forty-six patients with severe SAH with a World Federation of Neurological Surgeons grade (WFNS) >= III were included. Transthoracic echocardiography (TTE) was performed on day 1, day 3, and day 7 after the patient's admission. A cardiologist blinded to the patient's management analyzed the LV global longitudinal strain (GLS). The control group comprised normal subjects matched according to gender and age. RESULTS: On day 1 median (25th-75th percentile) GLS was clearly impaired in SAH patients compared to controls [-16.7 (-18.7/-13.7) % versus -20 (-22/-19) %, p < 0.0001], whereas LVEF was preserved [65 (59-70) %]. GLS was severely impaired in patients with a WFNS score of V versus III-IV [-15.6 (-16.9/-12.3) % versus -17.8 (-20.6/-15.8) %, p = 0.008]. Seventeen (37 %) patients had a severe GLS alteration (>- 16 %). In these patients, GLS improved from day 1 [-12.4 (-14.8/-10.9) %] to last evaluation [ 16.2 (-19/-14.6) %, p = 0.0007] in agreement with the natural evolution of stress cardiomyopathy. CONCLUSIONS: On the basis of LV GLS assessment, we demonstrated for the first time that myocardial alteration compatible with a stress cardiomyopathy is detectable in up to 37 % of patients with severe SAH while LVEF is preserved. GLS could be used for sensitive detection of stress cardiomyopathy. This is critical because cardiac impairment remains a major cause of morbidity and mortality after SAH. PMID- 26499885 TI - Prevalence of obesity and overweight and associated factors among financial institution workers in Accra Metropolis, Ghana: a cross sectional study. AB - BACKGROUND: Certain professions are associated with low physical activity. Workers in such professions spend the most part of their adult working lives less engaged in physical activity if they don't consciously exercise outside of working hours. This increases their risk of obesity and its associated diseases. This study determined the prevalence of obesity and overweight and associated factors among workers of a financial institution in Accra Metropolis, Ghana. METHODS: A cross-sectional study was conducted among 180 workers of a financial institution in Accra using the World Health Organization's STEPS (STEPwise approach) instrument for non-communicable disease risk factor surveillance. Relevant sociodemographic information were recorded and BMI was computed for each respondent. RESULTS: The overall prevalence of obesity and overweight among the bank workers was 55.6 % (17.8 % obese and 37.8 % overweight). After adjusting for other variables, physical activity (OR = 0.34, 95 % CI = 0.13-0.89, p = 0.03), alcohol consumption (OR = 3.00, 95 % CI = 1.35, 6.68, p = 0.007), marital status (OR = 2.74, 95 % CI = 0.96-7.85, p = 0.04), sex (OR = 2.78, 95 % CI = 1.23-6.33, p = 0.01), and age (OR = 1.10, 95 % CI = 1.01-1.20, p = 0.036) were significantly associated with obesity and overweight. CONCLUSION: Being physically inactive, consumption of alcohol, being married and a female, in addition to old age, increase the risk of obesity and overweight significantly. These factors should inform policy makers in developing strategies to reduce the burden of obesity and overweight among this category of workers. PMID- 26499886 TI - Suppressive effects of microRNA-16 on the proliferation, invasion and metastasis of hepatocellular carcinoma cells. AB - miR-16 is known to be abnormally expressed in hepatocellular carcinoma (HCC) cells, and the overexpression of miR-16 inhibits the proliferation, invasion and metastasis of various cancer cells. MicroRNAs (miRNAs or miRs) are closely related to the proliferation, invasion and metastasis of HCC. The present study aimed to explore the effects of miR-16 on the proliferation, invasion and metastasis of HCC cells, and to elucidate the mechanisms involved. A cell line with moderate levels of miR-16 expression was selected from the SMMC-7721, HepG2, SK-Hep-1 and Huh-7 HCC cells and validated by reverse transcription-PCR (RT-PCR). The effects of miR-16 on HCC cell viability were determined by MTT assay; cell migration and invasion were determined by Transwell cell invasion assay, and apoptosis was determined by flow cytometery (FCM). Western blot analysis was used to measure the expression levels of the apoptosis-related proteins, Bax, Bcl-2, matrix metalloproteinase (MMP)-2, MMP-9, as well as to examine epithelial mesenchymal transition (EMT), and E-cadherin, vimentin, and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway-related protein expression. The mRNA expression levels of miR-16 were highest in the SMMC-7721 cells and lowest in the SK-Hep-1 and Huh-7 cells; moderate levels were observed in the HepG2 cells. The HepG2 cell line was selected as the cell line for use in the follow-up experiments, where we measured cell viability, and the expression of PI3k/Akt, Bax, Bcl-2, MMP-2 and MMP-9, and E-cadherin and vimentin. miR-16 overexpression significantly inhibited the proliferation, invasion and metastasis of the HepG2 cells, as shown by western blot analysis. This was achieved through the upregulation of Bax expression, the downregulation of Bcl-2 expression and the decrease in the expression of MMP-2 and MMP-9. In addition the expression of E cadherin increased and vimentin expression decreased. miR-16 overexpression inhibited PI3K expression and Akt phosphorylation. The results of this study suggest that the overexpression of miR-16 inhibits the proliferation, invasion and metastasis of HepG2 HCC cells, and that these effects are associated with the PI3K/Akt signaling pathway. PMID- 26499887 TI - Transcriptome analysis of Brassica napus pod using RNA-Seq and identification of lipid-related candidate genes. AB - BACKGROUND: Brassica napus is an important oilseed crop. Dissection of the genetic architecture underlying oil-related biological processes will greatly facilitates the genetic improvement of rapeseed. The differential gene expression during pod development offers a snapshot on the genes responsible for oil accumulation in. To identify candidate genes in the linkage peaks reported previously, we used RNA sequencing (RNA-Seq) technology to analyze the pod transcriptomes of German cultivar Sollux and Chinese inbred line Gaoyou. METHODS: The RNA samples were collected for RNA-Seq at 5-7, 15-17 and 25-27 days after flowering (DAF). Bioinformatics analysis was performed to investigate differentially expressed genes (DEGs). Gene annotation analysis was integrated with QTL mapping and Brassica napus pod transcriptome profiling to detect potential candidate genes in oilseed. RESULTS: Four hundred sixty five and two thousand, one hundred fourteen candidate DEGs were identified, respectively, between two varieties at the same stages and across different periods of each variety. Then, 33 DEGs between Sollux and Gaoyou were identified as the candidate genes affecting seed oil content by combining those DEGs with the quantitative trait locus (QTL) mapping results, of which, one was found to be homologous to Arabidopsis thaliana lipid-related genes. DISCUSSION: Intervarietal DEGs of lipid pathways in QTL regions represent important candidate genes for oil-related traits. Integrated analysis of transcriptome profiling, QTL mapping and comparative genomics with other relative species leads to efficient identification of most plausible functional genes underlying oil-content related characters, offering valuable resources for bettering breeding program of Brassica napus. CONCLUSIONS: This study provided a comprehensive overview on the pod transcriptomes of two varieties with different oil-contents at the three developmental stages. PMID- 26499889 TI - Monocot and dicot MLO powdery mildew susceptibility factors are functionally conserved in spite of the evolution of class-specific molecular features. AB - BACKGROUND: Specific members of the plant Mildew Locus O (MLO) protein family act as susceptibility factors towards powdery mildew (PM), a worldwide-spread fungal disease threatening many cultivated species. Previous studies indicated that monocot and dicot MLO susceptibility proteins are phylogenetically divergent. METHODS: A bioinformatic approach was followed to study the type of evolution of Angiosperm MLO susceptibility proteins. Transgenic complementation tests were performed for functional analysis. RESULTS: Our results show that monocot and dicot MLO susceptibility proteins evolved class-specific conservation patterns. Many of them appear to be the result of negative selection and thus are likely to provide an adaptive value. We also tested whether different molecular features between monocot and dicot MLO proteins are specifically required by PM fungal species to cause pathogenesis. To this aim, we transformed a tomato mutant impaired for the endogenous SlMLO1 gene, and therefore resistant to the tomato PM species Oidium neolycopersici, with heterologous MLO susceptibility genes from the monocot barley and the dicot pea. In both cases, we observed restoration of PM symptoms. Finally, through histological observations, we demonstrate that both monocot and dicot susceptibility alleles of the MLO genes predispose to penetration of a non-adapted PM fungal species in plant epidermal cells. CONCLUSIONS: With this study, we provide insights on the evolution and function of MLO genes involved in the interaction with PM fungi. With respect to breeding research, we show that transgenic complementation assays involving phylogenetically distant plant species can be used for the characterization of novel MLO susceptibility genes. Moreover, we provide an overview of MLO protein molecular features predicted to play a major role in PM susceptibility. These represent ideal targets for future approaches of reverse genetics, addressed to the selection of loss-of-function resistant mutants in cultivated species. PMID- 26499888 TI - Co-expression of the carbamoyl-phosphate synthase 1 gene and its long non-coding RNA correlates with poor prognosis of patients with intrahepatic cholangiocarcinoma. AB - The mechanisms leading to high rates of malignancy and recurrence of human intrahepatic cholangiocarcinoma (ICC) remain unclear. It is difficult to diagnose and assess the prognosis of patients with ICC in the clinic due to the lack of specific biomarkers. In addition, long non-coding RNAs (lncRNAs) have been reported to serve important roles in certain types of tumorigenesis however a role in ICC remains to be reported. The aim of the current study was to screen for genes and lncRNAs that are abnormally expressed in ICC and to investigate their biological and clinicopathological significance in ICC. The global gene and lncRNA expression profiles in ICC were measured using bioinformatics analysis. Carbamoyl-phosphate synthase 1 (CPS1) and its lncRNA CPS1 intronic transcript 1 (CPS1-IT1) were observed to be upregulated in ICC. The expression of CPS1 and CPS1-IT1 was measured in 31 tissue samples from patients with ICC and a number of cell lines. The effects of CPS1 and CPS1-IT1 on the proliferation and apoptosis of the ICC-9810 cell line were measured. In addition, the clinicopathological features and survival rates of patients with ICC with respect to the gene and lncRNA expression status were analyzed. CPS1 and CPS1-IT1 were co-upregulated in ICC tissues compared with non-cancerous tissues. Knockdown of CPS1 andor CPS1-IT1 reduced the proliferation and increased the apoptosis of ICC-9810 cells. Additionally, clinical analysis indicated that CPS1 and CPS1-IT1 were associated with poor liver function and reduced survival rates when the relative expression values were greater than 4 in cancer tissues. The comparisons between the high CPS1 expression group and the low expression group indicated significant differences in international normalized ratio (P=0.048), total protein (P=0.049), indirect bilirubin (P=0.025), alkaline phosphatase (P=0.003) and disease-free survival (P=0.034). In addition, there were differential trends in CA19-9 (P=0.068), globulin (P=0.052) and total bilirubin (P=0.066). The comparisons between the high CPS1-IT1 expression group and the low expression group indicated significant differences in lymphatic invasion (P=0.045), carbohydrate antigen 19 9 (P=0.044), disease-free survival (P=0.026), and non-significant differential trends in alkaline phosphatase were observed (P=0.085). In conclusion, CPS1 and CPS1-IT1 may serve an important role in ICC development by promoting the proliferation of ICC cells. Furthermore, CPS1 and CPS1-IT1 were associated with poor liver function and reduced survival rates. Thus, CPS1 and CPS1-IT1 may be potential prognostic indicators for patients with ICC. PMID- 26499890 TI - Adequacy of Help Received by Individuals with Severe Mental Disorders After a Major Healthcare Reform in Quebec: Predictors and Changes at 5-Year Follow-Up. AB - This study assessed predictors and changes in adequacy of help received (AHR), as perceived by 204 individuals with severe mental disorders (SMDs) transferred from a mental health institution to the community following a key healthcare reform. Adjusted perceived AHR remained stable after 2 years (T1), but decreased at 5 year follow-up (T2). Predictors of higher adjusted perceived AHR are age, severity of needs, help received from services and relatives, and number of health professionals consulted. Community mental health services need to address the two major predictors of adjusted perceived AHR: severity of needs among individuals with SMDs and level of help from services. PMID- 26499891 TI - Self-establishing communities enable cooperative metabolite exchange in a eukaryote. AB - Metabolite exchange among co-growing cells is frequent by nature, however, is not necessarily occurring at growth-relevant quantities indicative of non-cell autonomous metabolic function. Complementary auxotrophs of Saccharomyces cerevisiae amino acid and nucleotide metabolism regularly fail to compensate for each other's deficiencies upon co-culturing, a situation which implied the absence of growth-relevant metabolite exchange interactions. Contrastingly, we find that yeast colonies maintain a rich exometabolome and that cells prefer the uptake of extracellular metabolites over self-synthesis, indicators of ongoing metabolite exchange. We conceived a system that circumvents co-culturing and begins with a self-supporting cell that grows autonomously into a heterogeneous community, only able to survive by exchanging histidine, leucine, uracil, and methionine. Compensating for the progressive loss of prototrophy, self establishing communities successfully obtained an auxotrophic composition in a nutrition-dependent manner, maintaining a wild-type like exometabolome, growth parameters, and cell viability. Yeast, as a eukaryotic model, thus possesses extensive capacity for growth-relevant metabolite exchange and readily cooperates in metabolism within progressively establishing communities. PMID- 26499892 TI - Small nucleolar RNA U91 is a new internal control for accurate microRNAs quantification in pancreatic cancer. AB - BACKGROUND: RT-qPCR quantification of miRNAs expression may play an essential role in pancreatic ductal adenocarcinoma (PDAC) diagnostics. RT-qPCR-based experiments require endogenous controls for the result normalization and reliability. However, expression instability of reference genes in tumors may introduce bias when determining miRNA levels. METHODS: We investigated expression of 6 miRNAs, isolated from FFPE samples of pancreatic adenocarcinomas. Four internal controls were utilized for RT-qPCR result normalization: artificial miR 39 from C. elegans, U6 snRNA, miR-16 and snoRNA U91. RESULTS: We found miR-21, miR-155 or miR-217 expression values in tumors may differ up to several times, depending on selected internal controls. Moreover, different internal controls can produce controversial results for miR-96, miR-148a or miR-196a quantification. Also, expression of our endogenous controls varied significantly in tumors. U6 demonstrated variation from -1.03 to 8.12-fold, miR-16 from -2.94 up to 7.38-fold and the U91 from -3.05 to 4.36-fold respectively. On the other hand, the most stable gene, determined by NormFinder algorithm, was U91. Each miRNA normalized relatively to the spike or U91, demonstrated similar expression values. Thus, statistically significant and insignificant differences between tumors and normal tissues for miRNAs were equal for the spike and the U91. Also, the differences between the spike and U91 were statistically insignificant for all of miRs except miR-217. Among three endogenous controls, U91 had the lowest average expression values and standard deviation in cancer tissues. CONCLUSIONS: We recommend U91 as a new normalizer for miRNA quantification in PDACs. PMID- 26499893 TI - Bacterial RNAs activate innate immunity in Arabidopsis. AB - The common molecular patterns of microbes play a critical role in the regulation of plant innate immunity. However, little is known about the role of nucleic acids in this process in plants. We pre-infiltrated Arabidopsis leaves with total RNAs from Pseudomonas syringae pv. tomato DC3000 (Pto DC3000) and subsequently inoculated these plants with the same bacterial cells. Total Pto DC3000 RNAs pre infiltrated into Arabidopsis leaves elicited plant immune responses against Pto DC3000. However, sheared RNAs and RNase A application failed to induce immunity, suggesting that intact bacterial RNAs function in plant innate immunity. This notion was supported by the positive regulation of superoxide anion levels, callose deposition, two mitogen-activated protein kinases and defense-related genes observed in bacterial RNA-pre-treated leaves. Intriguingly, the Pto DC3000 population was not compromised in known pattern recognition receptor mutants for chitin, flagellin and elongation factor-Tu (EF-Tu). Plant defense-related mutant analyses further revealed that bacterial RNA-elicited innate immunity was normally required for salicylic and jasmonic acid signaling. Notably, among total RNAs, the abundant bacterial RNA species 16S and 23S ribosomal RNAs were the major determinants of this response. Our findings provide evidence that bacterial RNA serves as a microbe-associated molecular pattern in plants. PMID- 26499896 TI - A new polyketide, penicillolide from the marine-derived fungus Penicillium sacculum. AB - A new polyketide, penicillolide (1) was isolated from the fermentation broth of the marine-derived fungus Penicillium sacculum GT-308. Compound 1 is a polyketide with a unique carbon skeleton. The structure of this compound was established via extensive spectroscopic analyses including 1D-, 2D-NMR, and HRESI-MS. PMID- 26499894 TI - c-di-GMP signalling and the regulation of developmental transitions in streptomycetes. AB - The complex life cycle of streptomycetes involves two distinct filamentous cell forms: the growing (or vegetative) hyphae and the reproductive (or aerial) hyphae, which differentiate into long chains of spores. Until recently, little was known about the signalling pathways that regulate the developmental transitions leading to sporulation. In this Review, we discuss important new insights into these pathways that have led to the emergence of a coherent regulatory network, focusing on the erection of aerial hyphae and the synchronous cell division event that produces dozens of unigenomic spores. In particular, we highlight the role of cyclic di-GMP (c-di-GMP) in controlling the initiation of development, and the role of the master regulator BldD in mediating c-di-GMP signalling. PMID- 26499897 TI - Arylation with Diaryliodonium Salts. AB - This chapter focuses on recent developments in metal-free and metal-catalyzed arylations with diaryliodonium salts (diaryl-lambda3-iodanes). Synthetic routes to diaryliodonium salts are briefly described, and chemoselectivity trends with unsymmetric iodonium salts are discussed. PMID- 26499895 TI - Gut biogeography of the bacterial microbiota. AB - Animals assemble and maintain a diverse but host-specific gut microbial community. In addition to characteristic microbial compositions along the longitudinal axis of the intestines, discrete bacterial communities form in microhabitats, such as the gut lumen, colonic mucus layers and colonic crypts. In this Review, we examine how the spatial distribution of symbiotic bacteria among physical niches in the gut affects the development and maintenance of a resilient microbial ecosystem. We consider novel hypotheses for how nutrient selection, immune activation and other mechanisms control the biogeography of bacteria in the gut, and we discuss the relevance of this spatial heterogeneity to health and disease. PMID- 26499898 TI - Health care professionals' and students' attitude toward collaboration between pharmacists and physicians in Croatia. AB - BACKGROUND: As traditional roles of pharmacists and physicians seem nowadays insufficient to ensure patient safety and therapy effectiveness, interprofessional collaboration has been suggested to improve health outcomes. OBJECTIVE: To assess and compare the attitudes of physicians and pharmacists, as well as medical and pharmacy students in Croatia, toward interprofessional collaboration in primary health care. METHODS: The study included 513 pharmacists and physicians, and 365 students of pharmacy and medicine from Croatia. The validated questionnaire, Scale of Attitudes Toward Physician-Pharmacist Collaboration, was translated in Croatian and completed, anonymously and voluntarily, by all participants. Results Pharmacists showed a more positive attitude toward collaboration than physicians (53.8 +/- 4.8 vs. 50.7 +/- 5.0). Pharmacy students expressed the most positive attitude (56.2 +/- 4.9), while medical students showed the remarkably lowest attitude toward collaboration (44.6 +/- 6.2). CONCLUSION: Pharmacists and physicians in Croatia expressed a relatively positive attitude toward their collaboration, comparable with their colleges in the USA. On the other hand, medical students expressed a 21 % less positive attitude than pharmacy students which could have an effect on interprofessional collaboration in the future when those students start working as health care professionals. Future studies, focusing on the promotion of this collaboration, on both under-graduated and post-graduated level, are warranted. PMID- 26499899 TI - Elevated circulating monocyte chemoattractant protein 1 (MCP-1/CCL-2) level may be an unfavorable predictive factor to platinum- and taxane-based combination chemotherapy in patients with gastric cancer. AB - PURPOSE: Monocyte chemoattractant protein 1 (MCP-1/CCL-2) is a member of the CC chemokine family and a potent chemotactic factor for monocytes that regulate migration and infiltration of monocytes and macrophages. It plays an important role in the pathogenesis of multiple malignancies, and its expression strongly also affects the outcomes of cancer patients. The objective of this study was to determine the clinical significance of the serum levels of MCP-1/CCL-2 in gastric cancer patients. MATERIALS AND METHODS: A total of 78 patients diagnosed with gastric cancer were enrolled in this study. Serum MCP-1/CCL-2 concentrations were determined by the solid-phase sandwich ELISA method. Age- and sex-matched 30 healthy controls were included in the analysis. RESULTS: The median age at diagnosis was 60 years, range 21-84 years. The baseline serum MCP-1/CCL-2 concentrations of the gastric cancer patients were significantly higher than of healthy subjects (p < 0.001). The known clinical variables including gender, age, site of lesion, histopathology, tumor size, lymph node involvement, and stage of disease were not found to be correlated with serum MCP-1/CCL-2 concentrations (p > 0.05). However, a significant relationship was shown between serum MCP-1/CCL-2 levels and response to chemotherapy (p = 0.05). Chemotherapy non-responsive patients had higher serum MCP-1/CCL-2 concentrations. Serum MCP-1/CCL-2 concentrations were not associated with prognosis on both progression-free and overall survival (p = 0.53 and p = 0.39, respectively). CONCLUSION: Elevated circulating MCP-1/CCL-2 level may be an unfavorable predictive factor to chemotherapy based on platinum and taxane in patients with gastric cancer. However, serum MCP-1/CCL-2 concentrations were not associated with prognosis on both progression-free and overall survival. PMID- 26499900 TI - Phase 1a/1b and pharmacogenetic study of docetaxel, oxaliplatin and capecitabine in patients with advanced cancer of the stomach or the gastroesophageal junction. AB - PURPOSE: The prognosis of gastroesophageal cancer is poor, and current regimens are associated with limited efficacy. The purpose of this study was to explore the safety and preliminary efficacy of docetaxel, oxaliplatin plus capecitabine for advanced cancer of the stomach or the gastroesophageal junction (GEJ). Secondary objectives included pharmacokinetic and pharmacogenetic analyses. METHODS: Patients were treated in escalating dose levels with docetaxel and oxaliplatin (both on day 1), plus capecitabine b.i.d. on days 1-14 every 3 weeks, to determine the dose-limiting toxicity and maximum tolerated dose (MTD). An expansion cohort was treated at the MTD. A total of ten polymorphisms in pharmacokinetic and pharmacodynamic candidate genes were analyzed and tested for association with treatment outcome. RESULTS: A total of 34 evaluable patients were enrolled. The MTD was docetaxel 50 mg/m(2), oxaliplatin 100 mg/m(2) plus capecitabine 850 mg/m(2) b.i.d. The median number of treatment cycles was 6 (range 2-8). Grade >= 3 toxicities included neutropenia (24 %), leukocytopenia (15 %), febrile neutropenia (12 %), fatigue (9 %) and diarrhea (6 %). The overall response rate was 45 %; two patients achieved a complete response. Median progression-free survival and overall survival were 6.5 months (95 % CI 5.4-7.6) and 11.0 months (95 % CI 7.9-14.1), respectively. The polymorphisms ERCC1 354C>T, TYMS 1053C>T and rs2612091 in ENOSF1 were associated with severe toxicity; ERCC1 354C>T and ERCC2 2251A>C were associated with poor progression-free survival. CONCLUSION: Docetaxel, oxaliplatin plus capecitabine are a well-tolerable, safe and effective treatment regimen for patients with advanced cancer of the stomach or GEJ. Pharmacogenetic markers in pharmacokinetic and pharmacodynamic candidate genes may be predictive for treatment outcome. PMID- 26499901 TI - The isoflavone content of two new alfalfa-derived products for instant beverage preparation. AB - The frequent use of plant-based products to promote health leads to the search for scientific information related to efficacy and safety of those products for human consumption. Two alfalfa-derived products (ADP), freeze-dried juice (FDJ) and dehydrated powder (DP), from alfalfa harvested in Mexico, are being developed as new possible nutraceuticals. To the best of our knowledge, any study reports the real composition of such products used to prepare instant beverages in what concerns isoflavone contents. Seven isoflavones (glycitein, formononetin, biochanin A, daidzein, genistein, daidzin and genistin) were assessed by HPLC-DAD analysis as well as its variation in five different batches of these products. Different solvents were tested in order to choose the best one to extract isoflavones. The results showed the presence of daidzein, genistein, genistin and daidzin in most samples while glycitein, formononetin and biochanin A were not detected. Significant differences between isoflavone contents were found with different solvent systems. Water was the best option to extract daidzein (0.40 1.08 mg per unit and 1.30-4.90 mg per unit for DP and FDJ, respectively) whereas the water-methanol-formic acid mixture was efficient to extract genistein (0.19 0.43 mg per unit and 0.15-0.72 mg per unit for DP and FDJ, respectively). In all cases, the total isoflavone content was higher in freeze-dried juices than in dehydrated powders. Genistein and daidzein were the more abundant isoflavones quantified. Further physiological and nutritional studies are needed to complete the validation of effectiveness and safety of these products. PMID- 26499903 TI - Detection of Mycobacterium tuberculosis with nested polymerase chain reaction analysis in enucleated eye ball in Eales' disease. AB - Nested polymerase chain reaction (nPCR) was performed on enucleated eyeball for detection of Mycobacterium tuberculosis (M. tb) genome in a patient with Eales' disease. PCR analysis in all previous studies has been done mainly using aqueous, vitreous and epiretinal membranes from these patients. Paraffin wax embedded tissue section of the enucleated eyeball was analyzed by histopathology and nPCR targeting MPB64 gene and IS6110 region of M. tb genome. Lymphocytic infiltration was seen in the vitreous, iris and the retinal tissue. Ziehl Neelsen stain was negative for acid fast bacilli. Caseation necrosis was not seen in any section. Agarose gel electrophoretogram showed positive results with 200 bp specific amplified product targeting MPB64 gene, whereas nPCR targeting IS6110 region was negative. Since biopsy proven M. tb is extremely difficult in ocular tissues due to extensive necrosis, the nPCR technique aided in the diagnosis. PMID- 26499904 TI - Surface-Induced Dissociation Mass Spectra as a Tool for Distinguishing Different Structural Forms of Gas-Phase Multimeric Protein Complexes. AB - One attractive feature of ion mobility mass spectrometry (IM-MS) lies in its ability to provide experimental collision cross section (CCS) measurements, which can be used to distinguish different conformations that a protein complex may adopt during its gas-phase unfolding. However, CCS values alone give no detailed information on subunit structure within the complex. Consequently, structural characterization typically requires molecular modeling, which can have uncertainties without experimental support. One method of obtaining direct experimental evidence on the structures of these intermediates is utilizing gas phase activation techniques that can effectively dissociate the complexes into substructures while preserving the native topological information. The most commonly used activation method, collision-induced dissociation (CID) with low mass target gases, typically leads to unfolding of monomers of a protein complex. Here, we describe a method that couples IM-MS and surface-induced dissociation (SID) to dissociate the source-activated precursors of three model protein complexes: C-reactive protein (CRP), transthyretin (TTR), and concanavalin A (Con A). The results of this study confirm that CID involves the unfolding of the protein complex via several intermediates. More importantly, our experiments also indicate that retention of similar CCS between different intermediates does not guarantee retention of structure. Although CID spectra (at a given collision energy) of source-activated, mass-selected precursors do not distinguish between native-like, collapsed, and expanded forms of a protein complex, dissociation patterns and/or average charge states of monomer products in SID of each of these forms are unique. PMID- 26499905 TI - Rational regional distribution of sugarcane cultivars in China. AB - Knowing yield potential and yield stability of sugarcane cultivars is of significance in guiding sugarcane breeding and rationalising regional distribution of sugarcane cultivars. In the present study, a heritability adjusted genotype main effect plus genotype * environment (HA-GGE) biplot program was used to analyze the cane and sucrose yields of 44 newly released sugarcane cultivars at eight pilot test sites. The cane and sucrose yields of nine cultivars were higher than those of the control cultivar ROC22. From the perspective of cane yield, cultivars FN 40 and YZ 06-407 were well adapted to a wider range of conditions and produced relatively high cane yields in several pilot sites. From the perspective of sucrose yield, cultivars LC 03-1137, FN 38, FN 41, MT 01-77 and LC 05-136 were well adapted to a wide range of conditions and produced relatively high sucrose yields. Based on these results, three high yielding and widely adapted cultivars, namely, FN 39, LC 05-136, and YZ 05-51 were recommended for production in three major Chinese sugarcane planting areas. The results will provide a theoretical basis for recommending the effective use and rational regional distribution of sugarcane cultivars in China. PMID- 26499907 TI - Bifunctional Ce(1-x)Eu(x)O2 (0 <=x<= 0.3) nanoparticles for photoluminescence and photocatalyst applications: an X-ray absorption spectroscopy study. AB - Ce1-xEuxO2 (0 <=x<= 0.3) nanoparticles (NPs) were synthesized by the chemical precipitation method. The microstructures and morphology were characterized by synchrotron X-ray diffraction and high resolution transmission electron microscopy. X-ray absorption near edge structure (XANES) spectra at the Eu M5,4 edge and atomic-multiplet calculations revealed that Eu(3+) was predominantly present in the CeO2 lattice and Eu(2+) was negligibly present within the entire doping range. The detailed analysis of the Ce M5,4-edge and the O K-edge has shown strong dependence of the Ce(3+)/Ce(4+) ratio and oxygen vacancy with Eu content. Extended X-ray absorption fine structure (EXAFS) spectra at the Ce K edge, along with theoretical fitting, have shown systematic variation in the coordination number, bond length and Debye-Waller factor with Eu doping. A blue shift in the absorption edge was observed which implies a net increase in the charge transfer gap between the O 2p and Ce 4f bands due to the increased number of Ce(3+) ions in the Eu doped samples. The excitation and emission spectra of pure CeO2 NPs did not show any photoluminescence (PL) characteristic; however, Ce1-xEuxO2 (x = 0.1-0.3) NPs showed significant improvements in the 4f-4f, (5)D0 (7)F2 and (5)D0-(7)F1 transitions induced luminescence properties. Eu doping has two major effects on the electronic structure and optical properties of CeO2 NPs: the first, at an Eu content of 10 mol%, is the formation of Ce(4+)-O-Eu(3+) networks, i.e., Eu(3+) ions substitute the Ce(4+) ions and introduce oxygen vacancies and Ce(3+) ions in the host lattice, which favors the (5)D0-(7)F2 induced PL properties. The other, at an Eu doping over 10 mol%, is the formation of both Ce(4+)-O-Eu(3+) and Ce(3+)-O-Eu(3+), i.e., Eu(3+) ions not only take substitutional sites of Ce(4+) ions but also replace a fraction of Ce(3+) ions in the CeO2 lattice which favors (5)D0-(7)F1 induced PL properties. As an application of CeO2 NPs towards the degradation of water pollutants, we demonstrated that the Ce1-xEuxO2 (0 <=x<= 0.3) NPs can serve as effective photocatalyst materials towards the degradation of the methyl-orange aqueous pollutant dye under UV light irradiation. PMID- 26499906 TI - Usefulness of Intraoperative Computer Tomography-Assisted Thoracoscopic Segmentectomy for Small-Sized Lung Cancer. AB - We report the case of a patient who had synchronous primary lung cancers in the left upper lobe (S(1+2)a, S(1+2)c), and underwent S(1+2) segmentectomy. The lesion in S(1+2)c was non-palpable, and the location was confirmed using intraoperative computed tomography (CT) scan. After A(1+2) and B(1+2) had been cut, the intersegmental border was marked with clips and intraoperative CT was performed. After confirming the correct anatomical intersegmental border and the resection margin was sufficient, we cut the intersegmental border. The two lesions were both adenocarcinomas. Intraoperative CT was useful for confirming the locations of non-palpable lesions and anatomical intersegmental borders. PMID- 26499910 TI - A microsimulation model for the development and progression of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a chronic lung disease that is thought to affect over one million people in Great Britain. The main factor contributing to the development of COPD is tobacco smoke. This paper presents a microsimulation model for the development of COPD, incorporating population dynamics and trends in smoking. The model simulates a population longitudinally throughout their lifetimes, providing projections of future COPD prevalence and evaluation of the effects of changes in risk factor prevalence such as smoking. Sensitivity analysis provides information on the most influential model parameters. The model-predicted prevalence of COPD in 2040 was 17% in males over the age of 35 years (13% amongst non-smokers and 22% amongst smokers), and a modest decline over the next 25 years due to recent trends in smoking rates. The simulation model provides us with valuable information on current and future trends in COPD in Great Britain. It was developed primarily to enable easy extension to evaluate the effects of occupational and environmental exposures on lung function and the prevalence of COPD and to allow evaluation of interventions, such as introducing health surveillance or policy changes. As longitudinal studies for investigating COPD are difficult due to the lengthy follow-up time required and the potentially large number of drop-outs, we anticipate that the model will provide a valuable tool for health impact assessment. An extended model for occupational exposures is under development and will be presented in a subsequent paper. PMID- 26499911 TI - A replication study of 49 Type 2 diabetes risk variants in a Punjabi Pakistani population. AB - AIM: The burden of Type 2 diabetes is alarmingly high in South Asia, a region that has many genetically diverse ethnic populations. Genome-wide association studies (GWAS) conducted largely in European populations have identified a number of loci predisposing to Type 2 diabetes risk, however, the relevance of such genetic loci in many South Asian sub-ethnicities remains elusive. The aim of this study was to replicate 49 single nucleotide polymorphisms (SNPs) previously identified through GWAS in Punjabis living in Pakistan. METHODS: We examined the association of 49 SNPs in 853 Type 2 diabetes cases and 1945 controls using additive logistic regression models after adjusting for age and gender. RESULTS: Of the 49 SNPs investigated, eight showed a nominal association (P < 0.05) that also remained significant after controlling for the false discovery rate. The most significant association was found for rs7903146 at the TCF7L2 locus. For a per unit increase in the risk score comprising of all the 49 SNPs, the odds ratio in association with Type 2 diabetes risk was 1.16 (95% CI 1.13-1.19, P < 2.0E 16). CONCLUSION: These results suggest that some Type 2 diabetes susceptibility loci are shared between Europeans and Punjabis living in Pakistan. PMID- 26499912 TI - MicroRNA-616 promotes the migration, invasion and epithelial-mesenchymal transition of HCC by targeting PTEN. AB - MicroRNAs, which can post-transcriptionally regulate gene expression by binding to the 3'-untranslated regions of the mRNAs, have been found to be the critical regulators of the development and progression of hepatocellular carcinoma (HCC). The present study demonstrated for the first time that microRNA-616 (miR-616) was markedly upregulated in HCC tissues, and was associated with the recurrence and metastasis of HCC. Elevated level of miR-616 was correlated with adverse clinicopathological features and poor prognosis of HCC patients. Gain- and loss of-function studies revealed that miR-616 could potentiate the migration, invasion and the epithelial-mesenchymal transtion (EMT) phenotype of HCC cells. Phosphatase and tensin homolog (PTEN), the predicted target of miR-616 by bioinformatics analysis, was confirmed as a direct downstream target of miR-616 through western blotting, luciferase reporter and immunohistochemical assays. Furthermore, we demonstrated that miR-616 exerted the promoting effects on EMT and metastatic ability of HCC cells through suppressing PTEN expression. Based on these results, we conclude that miR-616 is a promising prognostic biomarker of HCC and targeting miR-616 may be a potential option to prevent the progression of HCC. PMID- 26499913 TI - Screening and identification of five serum proteins as novel potential biomarkers for cured pulmonary tuberculosis. AB - Rapid and efficient methods for the determination of cured tuberculosis (TB) are lacking. A total of 85 differentially expressed serum proteins were identified by iTRAQ labeling coupled with two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) analysis (fold change >1.50 or <0.60, P < 0.05). We validated albumin (ALB), Rho GDP-dissociation inhibitor 2 (ARHGDIB), complement 3 (C3), ficolin-2 (FCN2), and apolipoprotein (a) (LPA) using the enzyme-linked immunosorbent assay (ELISA) method. Significantly increased ALB and LPA levels (P = 0.036 and P = 0.012, respectively) and significantly reduced ARHGDIB, C3, and FCN2 levels (P < 0.001, P = 0.035, and P = 0.018, respectively) were observed in cured TB patients compared with untreated TB patients. In addition, changes in ALB and FCN2 levels occurred after 2 months of treatment (P < 0.001 and P = 0.030, respectively). We established a cured TB model with 87.10% sensitivity, 79.49% specificity, and an area under the curve (AUC) of 0.876. The results indicated that ALB, ARHGDIB, C3, FCN2, and LPA levels might serve as potential biomarkers for cured TB. Our study provides experimental data for establishing objective indicators of cured TB and also proposes potential markers for evaluating the efficacy of anti-TB drugs. PMID- 26499914 TI - Laparoscope-assisted intestinal lengthening using an anterior flap in jejunal atresia. AB - BACKGROUND: Jejunal atresia with short bowel syndrome is an unusual type of jejunoileal atresia. They present with jejunal atresia near the ligament of Treitz and a foreshortened small bowel. In this paper, we report our preliminary experience to emphasize the advantages and feasibility of enteroplasty for intestinal lengthening and primary anastomosis with an anterior flap in jejunal atresia with short bowel syndrome in neonates. METHODS: Between January 2014 and December 2014, four neonates with jejunal atresia and short bowel syndrome were submitted to this procedure in our hospital. Enteroplasty for intestinal lengthening procedures was accomplished in all the neonates by laparoscopic assisted procedure. The procedure was manually performed after exteriorization of the atretic bowel via the slightly enlarged umbilical port site incision. RESULTS: The mean operative time was 80 min (range 65-110 min). Blood loss was minimal. There was no mortality or surgical complication so far. The median follow-up duration was 14.5 months (range 9-20 months). In all the cases, the autonomy for oral/enteric feeding was obtained within 1 month after surgery. One neonate was readmitted because of associated cholestasis 1 month after the operation, and was cured by conservative therapy. CONCLUSIONS: Enteroplasty for intestinal lengthening and primary anastomosis with an anterior flap is a safe and feasible technique that could allow increased tolerance to oral/enteric feeding, thereby improves their chances for quality survival. PMID- 26499916 TI - Effects of comprehensive intensive therapies on the change of intima-media thickness of carotid arteries in type 2 diabetic patients: A report of 4-year follow-up with a literature review. AB - BACKGROUND: The aim was to evaluate the effect of comprehensive intensive therapy on the carotid and femoral arteries of intima-media thickness in patients with type 2 diabetes mellitus after 4-year follow-up. METHODS: In this prospective 4 year study, patients (N = 210) with newly diagnosed type 2 diabetes received either comprehensive intensive therapy (n = 110) or conventional therapy (n = 100). Blood pressure, blood glucose and lipid levels were monitored every 3-6 months, and carotid and femoral arteries of intima-media thickness were monitored with ultrasonography. For the literature review, various databases were searched until 20 December 2014 for studies that evaluated effects of intensive multi factorial therapies on comprehensive intensive therapy in type 2 diabetes mellitus patients. RESULTS: The comprehensive intensive therapy group had a smaller rate of carotid intima-media thickness increase than the conventional therapy (control) group (p < 0.05). The carotid intima-media thickness in comprehensive intensive therapy group remained stable while the adjusted rate of carotid intima-media thickness increase was 12.55% in the control group. The femoral intima-media thickness change was also smaller in comprehensive intensive therapy group but the difference over time did not reach significance. CONCLUSION: The carotid intima-media thickness remained stable in type 2 diabetes mellitus patients who received comprehensive intensive therapy, suggesting that multi-factorial intensive therapies might have potential in reducing macro vascular events in these patients. PMID- 26499915 TI - Magnitude, treatment, and impact of diabetes mellitus in patients hospitalized with non-ST segment elevation myocardial infarction: A community-based study. AB - PURPOSE OF THE STUDY: To examine differences in the characteristics, treatment practices and in-hospital outcomes of patients with and without previously diagnosed diabetes hospitalized for non-ST segment elevation myocardial infarction. KEY METHODS: The study cohort consisted of 3916 patients diagnosed with non-ST segment elevation myocardial infarction at all 11 central MA medical centres between 1999 and 2009, of whom 1475 (38%) had been previously diagnosed with diabetes. MAIN RESULTS: Diabetic patients were more likely to have received treatment with effective cardiac medications, and to have undergone coronary bypass surgery, but were less likely to have received a percutaneous coronary intervention, than non-diabetic patients. Patients with a history of diabetes were more likely to have developed cardiogenic shock, heart failure and died during their index hospitalization than non-diabetic patients. MAIN CONCLUSION: Diabetic patients presenting with non-ST segment elevation myocardial infarction remain at high risk of developing significant clinical complications during hospitalization. PMID- 26499917 TI - Prevalence of macro- and microvascular complications in patients with type 2 diabetes and kidney disease with or without albuminuria in a single Chinese Diabetes Centre. AB - OBJECTIVE: To investigate the relationship between diabetic retinopathy, neuropathy and low ankle-brachial index in mild-to-moderate chronic kidney disease of type 2 diabetic patients. METHODS: We enrolled 875 type 2 diabetic patients who were divided into two phenotypes (with or without albuminuria) and stratified into three groups (stage 1 with estimated glomerular filtration rate ? 90 mL/min/1.73 m(2), stage 2 with estimated glomerular filtration rate of 60-89, stage 3 with estimated glomerular filtration rate of 30-59). The prevalence of diabetic retinopathy, neuropathy and low ankle-brachial index was compared and the risk factors of renal impairment were determined. RESULTS: Among chronic kidney disease stages, the prevalence of diabetic retinopathy increased from 42.5%, 56.6% to 66.7% in albuminuric subjects and from 29.4%, 33.0% to 50.0% with no significant trend in normoalbuminuric subjects (p = 0.005, 0.007 and 0.399 compared with albuminuric subjects in each stage). There was a significantly increased prevalence of low ankle-brachial index (17.5%, 22.6% and 44.4%) in normoalbuminuric subjects but no significant trend in albuminuric subjects. Diabetic retinopathy (odds ratio = 2.474, 95% confidence interval = 1.009-6.068) was an independent risk factor of declining kidney function in albuminuric patients. CONCLUSION: The prevalence of diabetic retinopathy was graded according to the estimated glomerular filtration rate declining in albuminuric patients while the prevalence of low ankle-brachial index was gradually increased in normoalbuminuric patients, indicating the diverse underlying mechanisms of mild to moderate chronic kidney disease between these two phenotypes. PMID- 26499918 TI - Vancomycin AUC24 /MIC Ratio in Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia. AB - BACKGROUND: Vancomycin is the treatment of choice for serious methicillin resistant Staphylococcus aureus (MRSA) infections. The area under the concentration-time curve from 0 to 24 hr (AUC24 )/minimum inhibitory concentration (MIC) ratio was recently introduced as a parameter for assessing clinical outcome by S. aureus. This study was purposed to apply the vancomycin AUC24 /MIC in patients with MRSA pneumonia. METHODS: Forty-seven patients with confirmed lower respiratory infection caused by MRSA during 2011 were enrolled. All patients were treated with vancomycin. Clinical characteristics and laboratory data were collected. AUC24 /MIC values were calculated as previously reported and patients were divided into two groups based on the bacteriologic response, which was eradicated or not, and an AUC24 /MIC value (above or below 400). RESULTS: MRSA infections were eradicated in 39 patients but 8 patients had persistent MSRA infection in the following cultures. The mean AUC24 /MIC values and vancomycin concentrations were not statistically different between patients with and without MRSA eradication. All 13 patients with a vancomycin MIC of 2 mg/L had an AUC24 /MIC below 400. CONCLUSION: AUC24 /MIC might not be a reliable indicator for assessing treatment response of vancomycin in MRSA pneumonia. Relationship between vancomycin AUC24 /MIC and therapeutic outcome needs to undergo further studies, including sufficiently large sample size. PMID- 26499919 TI - MicroRNA-519 enhances HL60 human acute myeloid leukemia cell line proliferation by reducing the expression level of RNA-binding protein human antigen R. AB - Previous studies have demonstrated that microRNAs (miRs) are involved in cell apoptosis. However, the role of miR-519 in acute myeloid leukemia (AML) has yet to be elucidated. The present study identified the effects of miR-519 on HL60 human acute myeloid leukemia cell growth and apoptosis. The expression levels of miR-519 were examined in AML cells, as well as AML tissue samples. Furthermore, cell viability and apoptosis were examined in HL60 cells transfected with miR-519 mimics, miR-519 inhibitors or a negative control. In addition, the effects of human antigen R (HuR) on cell apoptosis were investigated using specific small interfering RNA targeting HuR. The results demonstrated that the expression levels of miR-519 were significantly increased in the AML cells and the tissue samples, suggesting that miR-519 may contribute to abnormal HL60 cell proliferation. Upregulation of miR-519 expression decreased HL60 cell viability and induced cell apoptosis. Furthermore, knockdown of HuR reduced cell migration and enhanced cell apoptosis. The results of the present study indicate that miR 519 may contribute to HL60 cell apoptosis by regulating the expression of HuR. PMID- 26499921 TI - A Phase 1 Study of Intravitreous E10030 in Combination with Ranibizumab in Neovascular Age-Related Macular Degeneration. AB - PURPOSE: To assess the safety and tolerability of E10030 (Fovista; Ophthotech, New York, NY), a platelet-derived growth factor (PDGF) antagonist, when administered in combination with an anti-vascular endothelial growth factor (VEGF) agent, ranibizumab (Lucentis; Genentech, South San Francisco, CA) 0.5 mg, by intravitreal injection in participants with neovascular age-related macular degeneration (NVAMD). DESIGN: Prospective phase 1 clinical trial. PARTICIPANTS: A total of 23 participants diagnosed with NVAMD and aged 50 years or older were enrolled. METHODS: Part 1 included 15 participants. Three participants received a single intravitreal E10030 (0.03 mg) injection and were subsequently given intravitreal ranibizumab (0.5 mg) injections at weeks 2, 6, and 10. Twelve participants (3 per group) received E10030 (0.03, 0.3, 1.5, or 3.0 mg) in combination with ranibizumab (0.5 mg) at day 0, month 1, and month 2 in an ascending manner. In Part 2 (8 participants), E10030 (0.3, 1.5, or 3.0 mg) in combination with ranibizumab (0.5 mg) was injected at day 0, month 1, and month 2. MAIN OUTCOME MEASURES: Safety at week 12 was the primary outcome and included assessment of vital signs, laboratory tests, and serial eye examinations. Other safety metrics included assessment through week 24 of Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity (VA) and biomarker changes evaluated by optical coherence tomography (OCT) and fluorescein angiography (FA). RESULTS: All doses of intravitreal E10030 administered in combination with ranibizumab were well tolerated. No dose-limiting toxicities or relevant safety events were noted at any dose level during the study. Investigators did not report adverse events related to E10030 or ranibizumab. Mean VA change was a gain of 14 letters, and 59% of participants gained >=15 letters from baseline at week 12. On FA at week 12, there was an 85.5% mean reduction from baseline in choroidal neovascularization (CNV) size. On OCT at the week 12 visit, there was a mean decrease in center point thickness and central subfield thickness of 38.9% and 33.7%, respectively. CONCLUSIONS: Intravitreal E10030 administered at doses up to 3 mg in combination with ranibizumab was well tolerated without evidence of systemic or ocular toxicity in participants with NVAMD. The changes in both mean VA and imaging biomarkers suggest a favorable short-term safety profile for the combination therapy of E10030 and ranibizumab. PMID- 26499922 TI - Inhibitory effect of carbonyl reductase 1 on ovarian cancer growth via tumor necrosis factor receptor signaling. AB - We investigated the mechanisms of the inhibitory effect of carbonyl reductase 1 (CR1) on ovarian cancer growth mediated by the activation of the tumor necrotic factor receptor (TNFR) pathway. OVCAR-3 and TOV21G cells overexpressing CR1 were constructed by transfecting them with CR1 cDNA by lipofection. CR1-overexpressing and control OVCAR-3 and TOV21G cells were injected subcutaneously into nude mice and the tumor growth was compared between the two groups for 3-4 weeks. The expression of TNFR1 and TNFR2 in tumors was examined immunohistochemically at the end of the experiment. Expression levels of caspase-8 and -3 activated by TNFR1, c-Jun activated by TNFR2, and NF-kappaB activated by both TNFR1 and TNFR2 were determined using immunohistochemistry and western blot analysis. Tumor growth was significantly suppressed in mice injected with CR1-overexpressing cells. Tumor volume in the CR1 induction group decreased temporarily until 2 weeks. Tumor cell membranes in both CR1 induction and control groups were positive for TNFR1 expression; however, total protein levels did not differ between the two groups. TNFR-2 expression was comparatively weak in both groups. The expression of NF kappaB and c-Jun was weaker in the CR1 induction group than in control. In contrast, caspase-8 and -3 expression was higher in the CR1 induction group. Furthermore, the number of apoptotic cells was significantly greater in tumors that appeared after injections of both types of CR1-overexpressing cells than in those of control cancer cells. These results suggest that CR1 induces apoptosis by activating the caspase pathway via binding to TNFR1. PMID- 26499920 TI - Cataract Surgery Outcomes in Uveitis: The Multicenter Uveitis Steroid Treatment Trial. AB - PURPOSE: To assess the visual outcomes of cataract surgery in eyes that received fluocinolone acetonide implant or systemic therapy with oral corticosteroids and immunosuppression during the Multicenter Uveitis Steroid Treatment (MUST) Trial. DESIGN: Nested prospective cohort study of patients enrolled in a randomized clinical trial. PARTICIPANTS: Patients that underwent cataract surgery during the first 2 years of follow-up in the MUST Trial. METHODS: Visual outcomes of cataract surgery were evaluated 3, 6, and 9 months after surgery using logarithmic visual acuity charts. Change in visual acuity over time was assessed using a mixed-effects model. MAIN OUTCOME MEASURES: Best-corrected visual acuity. RESULTS: After excluding eyes that underwent cataract surgery simultaneously with implant surgery, among the 479 eyes in the MUST Trial, 117 eyes (28 eyes in the systemic, 89 in the implant group) in 82 patients underwent cataract surgery during the first 2 years of follow-up. Overall, visual acuity increased by 23 letters from the preoperative visit to the 3-month visit (95% confidence interval [CI], 17-29 letters; P < 0.001) and was stable through 9 months of follow-up. Eyes presumed to have a more severe cataract, as measured by inability to grade vitreous haze, gained an additional 42 letters (95% CI, 34-56 letters; P < 0.001) beyond the 13-letter gain in eyes that had gradable vitreous haze before surgery (95% CI, 9-18 letters; P < 0.001) 3 months after surgery, making up for an initial difference of -45 letters at the preoperative visit (95% CI, -56 to -34 letters; P < 0.001). Black race, longer time from uveitis onset, and hypotony were associated with worse preoperative visual acuity (P < 0.05), but did not affect postsurgical recovery (P > 0.05, test of interaction). After adjusting for other risk factors, there was no significant difference in the improvement in visual acuity between the 2 treatment groups (implant vs. systemic therapy, 2 letters; 95% CI, -10 to 15 letters; P = 0.70). CONCLUSIONS: Cataract surgery resulted in substantial, sustained, and similar visual acuity improvement in the eyes of patients with uveitis treated with the fluocinolone acetonide implant or standard systemic therapy. PMID- 26499923 TI - Dynamic balance in elite karateka. AB - In karate, balance control represents a key performance determinant. With the hypothesis that high-level athletes display advanced balance abilities, the purpose of the current study was to quantitatively investigate the motor strategies adopted by elite and non-elite karateka to maintain balance control in competition. The execution of traditional karate techniques (kihon) in two groups of elite Masters (n = 6, 31 +/- 19 years) and non-elite Practitioners (n = 4, 25 +/- 9 years) was compared assessing body center of mass (CoM) kinematics and other relevant parameters like step width and angular joint behavior. In the considered kihon sequence, normalized average CoM height was 8% lower (p < 0.05), while CoM displacement in the horizontal direction was significantly higher in Masters than in Practitioners (2.5 vs. 1.9 m, p < 0.05), as well as CoM average velocity and rms acceleration (p < 0.05). Step width was higher in Masters in more than half of the sequence steps (p < 0.05). Results suggest that elite karateka showed a refined dynamic balance control, obtained through the increase of the base of support and different maneuvers of lower limbs. The proposed method could be used to objectively detect talented karateka, to measure proficiency level and to assess training effectiveness. PMID- 26499924 TI - Low Prevalence of Hypomagnesemia in Long-term Recipients of Proton Pump Inhibitors in a Managed Care Cohort. AB - BACKGROUND & AIMS: Chronic intake of proton pump inhibitors (PPI) has been associated with hypomagnesemia, but prevalence of PPI-associated hypomagnesemia is not known. METHODS: We examined the prevalence of hypomagnesemia among long term PPI recipients by using a large health maintenance organization database. We collected data on 10,167 participants eligible for chronic drug prescriptions from 2008 through 2013. Adult subjects receiving continuous PPI therapy for >= 6 months between 2008 and 2013 and >= 1 serum magnesium determination(s) were identified. Patients with any magnesium levels less than 1.6 mg/dL were selected for analysis; those with recognizable causes of altered magnesium homeostasis were excluded. RESULTS: Five hundred ninety participants received long-term PPIs, and 414 (70.2%) met the inclusion criteria for a total exposure of 2293 PPI-years (average, 5.7 years/subject). Of these patients, 57 (13.8%) had >= 1 low serum magnesium; 5 were no longer on PPIs, and 44 had other recognizable causes for hypomagnesemia (25 receiving diuretics, 8 with chronic diarrhea, 8 with chronic kidney disease, and 3 with malignancies). Of the 8 remaining patients (7 female; mean age, 71.2 +/- 13.4 years; mean daily medications, 5.4 +/- 1.1), mild hypomagnesemia (range, 1.2-1.5 mg/dL) was noted in 13.9% of 289 measurements. All 8 patients had normal serum levels of magnesium at their final measurement. CONCLUSIONS: In the absence of known precipitating factors, chronic PPI use does not appear to be associated with hypomagnesemia. PMID- 26499925 TI - Identification of Quality Measures for Performance of and Interpretation of Data From Esophageal Manometry. AB - BACKGROUND & AIMS: Esophageal manometry is the standard for the diagnosis of esophageal motility disorders. Variations in the performance and interpretation of esophageal manometry result in discrepant diagnoses and unnecessary repeated procedures, and could have negative effects on patient outcomes. We need a method to benchmark the procedural quality of esophageal manometry; as such, our objective was to formally develop quality measures for the performance and interpretation of data from esophageal manometry. METHODS: We used the RAND University of California Los Angeles Appropriateness Method (RAM) to develop validated quality measures for performing and interpreting esophageal manometry. The research team identified potential quality measures through a literature search and interviews with experts. Fourteen experts in esophageal manometry ranked the proposed quality measures for appropriateness via a 2-round process on the basis of RAM. RESULTS: The experts considered a total of 29 measures; 17 were ranked as appropriate and were as follows: related to competency (2), assessment before the esophageal manometry procedure (2), the esophageal manometry procedure itself (3), and interpretation of data (10). The data interpretation measures were integrated into a single composite measure. Eight measures therefore were found to be appropriate quality measures for esophageal manometry . Five other factors also were endorsed by the experts, although these were not ranked as appropriate quality measures. CONCLUSIONS: We identified 8 formally validated quality measures for the performance and interpretation of data from esophageal manometry on the basis of RAM. These measures represent key aspects of a high quality esophageal manometry study and should be adopted uniformly. These measures should be evaluated in clinical practice to determine how they affect patient outcomes. PMID- 26499926 TI - Large Sessile Serrated Polyps Can Be Safely and Effectively Removed by Endoscopic Mucosal Resection. AB - BACKGROUND & AIMS: As many as 50% of large sessile serrated adenomas/polyps (SSPs) are removed incompletely, which is significant because SSPs have been implicated in the development of interval cancers. It is unclear if endoscopic mucosal resection (EMR) is an optimal method for removal of SSPs. We assessed the efficacy and safety of removal of SSPs 10 mm and larger using a standardized inject-and-cut EMR technique. METHODS: We performed a retrospective analysis of colonoscopy data, collected over 7 years (2007-2013) at 2 centers, from 199 patients with proximal colon SSPs 10 mm and larger (251 polyps) removed by EMR by 4 endoscopists. The primary outcome measure was local recurrence. The secondary outcome measure was safety. RESULTS: At the index colonoscopy, patients had a median of 1 serrated lesion (range, 1-12) and 1 nonserrated neoplastic lesion (range, 0-15). The mean SSP size was 15.9 +/- 5.3 mm; most were superficially elevated (84.5%) and located in the ascending colon (51%), and 3 SSPs (1.2%) had dysplasia. Surveillance colonoscopies were performed on 138 patients (69.3%) over a mean follow-up period of 25.5 +/- 17.4 months. Of these patients, 5 had local recurrences (3.6%; 95% confidence interval, 0.5%-6.7%), detected after 17.8 +/- 15.4 months, with a median size of 4 mm. No patients developed postprocedural bleeding, perforation, or advanced colon cancer, or had a death related to the index colorectal lesion during the study period. CONCLUSIONS: Inject-and-cut EMR is a safe and effective technique for the resection of SSPs. Less than 5% of patients have a local recurrence, which is usually small and can be treated endoscopically. PMID- 26499927 TI - Association Between Plasma Level of Galectin-9 and Survival of Patients With Drug Induced Acute Liver Failure. AB - BACKGROUND & AIMS: Fewer than 50% of patients with acute liver failure (ALF) recover spontaneously, and ALF has high mortality without liver transplantation. Kupffer cells have been reported to mediate liver inflammation during drug induced injury. Galectin-9 is produced by Kupffer cells and has diverse roles in regulating immunity. We investigated whether plasma levels of galectin-9 are associated with outcomes of patients with ALF. METHODS: We analyzed plasma samples (collected at time of hospital admission) and clinical data from 149 patients included in the Acute Liver Failure Study Group from July 2006 through November 2010 (110 had acetaminophen-induced hepatotoxicity and 39 had nonacetaminophen drug-induced liver injury). We compared data with those from all patients enrolled in the study (from July 1, 2006 through October 30, 2013), and from healthy individuals of similar ages with no evidence of liver disease (control subjects). Plasma levels of galectin-9 were measured using a polyclonal antibody and colorimetric assay. RESULTS: Patients with ALF had statistically higher plasma levels of galectin-9 than control subjects, but levels did not differ significantly between patients with acetaminophen-induced liver injury and drug-induced liver injury. A level of galectin-9 above 690 pg/mL was associated with a statistically significant increase in risk for mortality or liver transplantation caused by ALF. Competing risk analyses associated level of galectin-9 with transplant-free survival, independently of Model For End-Stage Liver Disease score or systemic inflammatory response syndrome. CONCLUSIONS: A one-time measurement of plasma galectin-9 level can be used to assign patients with ALF to high-, intermediate-, and low-risk groups. The combination of galectin-9 level and Model For End-Stage Liver Disease score was more closely associated with patient outcome than either value alone. These data might be used to determine patient prognoses and prioritize patients for liver transplantation. ClinicalTrials.gov ID NCT00518440. PMID- 26499928 TI - Poor Documentation of Inflammatory Bowel Disease Quality Measures in Academic, Community, and Private Practice. AB - BACKGROUND & AIMS: Quality measures are used to standardize health care and monitor quality of care. In 2011, the American Gastroenterological Association established quality measures for inflammatory bowel disease (IBD), but there has been limited documentation of compliance from different practice settings. METHODS: We reviewed charts from 367 consecutive patients with IBD seen at academic practices, 217 patients seen at community practices, and 199 patients seen at private practices for compliance with 8 outpatient measures. Records were assessed for IBD history, medications, comorbidities, and hospitalizations. We also determined the number of patient visits to gastroenterologists in the past year, whether patients had a primary care physician at the same institution, and whether they were seen by a specialist in IBD or in conjunction with a trainee, and reviewed physician demographics. A univariate and multivariate statistical analysis was performed to determine which factors were associated with compliance of all core measures. RESULTS: Screening for tobacco abuse was the most frequently assessed core measure (89.6% of patients; n = 701 of 783), followed by location of IBD (80.3%; n = 629 of 783), and assessment for corticosteroid sparing therapy (70.8%; n = 275 of 388). The least-frequently evaluated measures were pneumococcal immunization (16.7% of patients; n = 131 of 783), bone loss (25%; n = 126 of 505), and influenza immunization (28.7%; n = 225 of 783). Only 5.8% of patients (46 of 783) had all applicable core measures documented (24 in academic practice, none in clinical practice, and 22 in private practice). In the multivariate model, year of graduation from fellowship (odds ratio [OR], 2.184; 95% confidence interval [CI], 1.522-3.134; P < .001), year of graduation from medical school (OR, 0.500; 95% CI, 0.352-0.709; P < .001), and total number of comorbidities (OR, 1.089; 95% CI, 1.016-1.168; P = .016) were associated with compliance with all core measures. CONCLUSIONS: We found poor documentation of IBD quality measures in academic, clinical, and private gastroenterology practices. Interventions are necessary to improve reporting of quality measures. PMID- 26499929 TI - Increased Risk of Oral Cancer in Patients With Inflammatory Bowel Diseases. AB - BACKGROUND & AIMS: Epidemiology studies have consistently found an increased risk of oral malignancies in organ transplant recipients, patients with graft-versus host disease, and people with human immunodeficiency virus infection. We assessed the risk of oral cancer in patients with inflammatory bowel diseases (IBD). METHODS: We collected data on 7294 patients with IBD (3785 women) seen at Mount Sinai Medical Center, New York, from 2000 through 2011. The expected incidence of oral cancer was calculated for each sex-specific and 5-year age-specific stratum by specific incidence rates using the Surveillance, Epidemiology and End Results 18 registry data (2000-2011), adjusted for age to the 2000 United States population (census P25-1130). RESULTS: Eleven patients (7 men) were found to have biopsy-proven oral cancer. Six patients had cancer of the tongue; 2 patients had cancer of the hard palate; and the remaining 3 had tonsillar, buccal, or mandibular sarcoma. Before the cancer diagnosis, IBD had been treated in 4 patients with azathioprine or mercaptopurine, in 1 patient with infliximab, and 3 in patients with combination of biologic agents and azathioprine; 4 of the patients had not been treated for IBD. The age- and sex-adjusted standardized incidence ratio (SIR) for oral cancer in patients with IBD was 9.77 (95% confidence interval [CI], 5.14-16.98). In women, the SIR was 12.07 (95% CI, 3.84 29.11), and in men the SIR was 8.49 (95% CI, 3.71-16.78). The age-adjusted SIR for tongue cancer was 18.91 (95% CI, 7.66-39.33): 17.06 for men (95% CI, 5.42 41.15) and 22.10 for women (95% CI, 3.70-73.01). CONCLUSIONS: We found patients with IBD to be at increased risk for oral cancers, especially tongue cancer. Women are at higher risk than men. PMID- 26499930 TI - Ability of King's College Criteria and Model for End-Stage Liver Disease Scores to Predict Mortality of Patients With Acute Liver Failure: A Meta-analysis. AB - BACKGROUND & AIMS: Several prognostic factors are used to identify patients with acute liver failure (ALF) who require emergency liver transplantation. We performed a meta-analysis to determine the accuracy of King's College criteria (KCC) versus the model for end-stage liver disease (MELD) scores in predicting hospital mortality among patients with ALF. METHODS: We performed a systematic search of the literature for articles published from 2001 through 2015 that compared the accuracy of the KCC with MELD scores in predicting hospital mortality in patients with ALF. We identified 23 studies (comprising 2153 patients) and assessed the quality of data, and then performed a meta-analysis of pooled sensitivity and specificity values, diagnostic odds ratios (DORs), and summary receiver operating characteristic curves. Subgroups analyzed included study quality, era, location (Europe vs non-Europe), and size; ALF etiology (acetaminophen-associated ALF [AALF] vs nonassociated [NAALF]); and whether or not the study included patients who underwent liver transplantation and if the study center was also a transplant center. RESULTS: The DOR for the KCC was 5.3 (95% confidence interval [CI], 3.7-7.6; 57% heterogeneity) and the DOR for MELD score was 7.0 (95% CI, 5.1-9.7; 48% heterogeneity), so the MELD score and KCC are comparable in overall accuracy. The summary area under the receiver operating characteristic curve values was 0.76 for the KCC and 0.78 for MELD scores. The KCC identified patients with AALF who died with 58% sensitivity (95% CI, 51%-65%) and 89% specificity (95% CI, 85%-93%), whereas MELD scores identified patients with AALF who died with 80% sensitivity (95% CI, 74%-86%) and 53% specificity (95% CI, 47%-59%). The KCC predicted hospital mortality in patients with NAALF with 58% sensitivity (95% CI, 54%-63%) and 74% specificity (95% CI, 69%-78%), whereas MELD scores predicted hospital mortality in patients with NAALF with 76% sensitivity (95% CI, 72%-80%) and 73% specificity (95% CI, 69%-78%). In patients with AALF, the KCC's DOR was 10.4 (95% CI, 4.9-22.1) and the MELD score's DOR was 6.6 (95% CI, 2.1-20.2). In patients with NAALF, the KCC's DOR was 4.16 (95% CI, 2.34-7.40) and the MELD score's DOR was 8.42 (95% CI, 5.98-11.88). CONCLUSIONS: Based on a meta-analysis of studies, the KCC more accurately predicts hospital mortality among patients with AALF, whereas MELD scores more accurately predict mortality among patients with NAALF. However, there is significant heterogeneity among studies and neither system is optimal for all patients. Given the importance of specificity in decision making for listing for emergency liver transplantation, MELD scores should not replace the KCC in predicting hospital mortality of patients with AALF, but could have a role for NAALF. PMID- 26499931 TI - Notalgia paraesthetica: A pilot study of treatment with simple exercises and stretches. AB - Notalgia paraesthetica is a distressing condition for which current treatments are either poorly effective or have unacceptable adverse effects. The aim of this pilot study was to evaluate the effectiveness of a programme of simple exercises and stretches for this condition. In total, 12 patients participated in a trial of simple exercises and stretches over 12 weeks, designed to relieve the sensory neuropathy caused by paraspinal muscle entrapment. Of the 12 patients 11 achieved satisfactory amelioration of their symptoms with no adverse effects. Our pilot study was unblinded and consisted of small patient numbers. Further research to evaluate this approach is warranted. PMID- 26499932 TI - Knowledge as an interactional tool in the management of client empowerment. AB - OBJECTIVE: To examine the way speaker and recipient knowledge is managed in interaction by a call taker at a mental-health information line, to achieve the institutional goals of information provision and client empowerment. METHODS: This study utilizes conversation analysis in the analysis of a single call to the line. RESULTS: Analysis demonstrates the ways in which a call taker produces turns-at-talk that construct a caller as knowing what help they wanted prior to that moment in the interaction, and that invoke 'common' knowledge of sources of such help. CONCLUSION: Talk that orients to knowledge is used as an interactional resource that allows the call taker to avoid talk that may be considered advice, and to be heard to achieve the goal of client empowerment. The asymmetric identities of help-seeker and help-provider are managed in this process. PRACTICE IMPLICATIONS: Client empowerment can be seen as something interactionally achieved and managed in talk-in-interaction, while not necessarily objectively experienced by the client. PMID- 26499933 TI - Spatio-temporal behavior of brightness temperature in Tel-Aviv and its application to air temperature monitoring. AB - This study applies remote sensing technology to assess and examine the spatial and temporal Brightness Temperature (BT) profile in the city of Tel-Aviv, Israel over the last 30 years using Landsat imagery. The location of warmest and coldest zones are constant over the studied period. Distinct diurnal and temporal BT behavior divide the city into four different segments. As an example of future application, we applied mixed regression models with daily random slopes to correlate Landsat BT data with monitored air temperature (Tair) measurements using 14 images for 1989-2014. Our preliminary results show a good model performance with R(2) = 0.81. Furthermore, based on the model's results, we analyzed the spatial profile of Tair within the study domain for representative days. PMID- 26499934 TI - Estimating ground-level PM(10) in a Chinese city by combining satellite data, meteorological information and a land use regression model. AB - Development of exposure assessment model is the key component for epidemiological studies concerning air pollution, but the evidence from China is limited. Therefore, a linear mixed effects (LME) model was established in this study in a Chinese metropolis by incorporating aerosol optical depth (AOD), meteorological information and the land use regression (LUR) model to predict ground PM10 levels on high spatiotemporal resolution. The cross validation (CV) R(2) and the RMSE of the LME model were 0.87 and 19.2 MUg/m(3), respectively. The relative prediction error (RPE) of daily and annual mean predicted PM10 concentrations were 19.1% and 7.5%, respectively. This study was the first attempt in China to estimate both short-term and long-term variation of PM10 levels with high spatial resolution in a Chinese metropolis with the LME model. The results suggested that the LME model could provide exposure assessment for short-term and long-term epidemiological studies in China. PMID- 26499935 TI - Vulvar lichen sclerosus: A new regenerative approach through fat grafting. AB - OBJECTIVE. The aim of this study was to evaluate the efficacy of fat grafting in the treatment of severe vulvar lichen sclerosus (LS). Our primary outcome was to assess the improvement of mucocutaneous trophism, the resolution/reduction of symptoms, and the histological features of the vulvar skin after treatment. The secondary outcome was to evaluate the improvement in life quality, and in resumption and quality of sexual life. METHODS. Between 2011 and 2014, 36 patients were offered fat grafting to treat LS. Inclusion criteria were age between 25 and 80 years, histopathologic diagnosis of LS, good health, failure of previous first line treatments. RESULTS. 34 out of 36 patients (94%) showed a better vulvar trophismof the skin and mucosae; 27 (75%) had an improvement in caliber and elasticity of the vaginal introitus; clitoris burying degree was reduced in 18 patients (50%), 30 (83%) reported an increased volume of labia major a and minor a, 34 (94%) had a complete disappearance of scratching lesions, and 28 (78%) showed a remission of white lesions. Eventually 34 patients (95%) stopped using topical corticosteroids routinely. The improvement in life quality was significant for both DLQI (p b 0001) and FSFI (p b 0001). CONCLUSIONS. Fat grafting may have a role as a support and completion treatment in selected cases of women with vulvar LS who do not respond to first line therapy or in severe cases where the anatomical impairment does not allow a regular sexual function and a good quality of life. PMID- 26499936 TI - Reduction in ERRalpha is associated with lichen sclerosus and vulvar squamous cell carcinoma. AB - OBJECTIVE: ERRs (estrogen-related receptors) regulate energy metabolism, the cell cycle and inflammatory processes in both normal and cancer cells. Chronic inflammation induced by lichen sclerosus (LS) or human papilloma virus (HPV) precedes vulvar squamous cell carcinoma (vulvar SCC). We investigated the expression of ERRalpha, ERRbeta and ERRgamma in normal vulvar skin, LS as well as LS-dependent and LS-independent/HPV-related vulvar SCC. METHODS: A total of 203 samples were analyzed for ERRalpha, ERRbeta and ERRgamma by using immunohistochemistry. These included 37 normal vulvar skin samples, 110 LS samples, 6 vulvar intraepithelial neoplasia (VIN) samples and 50 vulvar SCC samples. RESULTS: A substantial reduction in or disappearance of ERRalpha was detected in all vulvar SCC samples. A total of 79% of childhood-onset LS and 51% of adulthood-onset LS lesions showed decreases in ERRalpha staining. A gradual reduction in ERRalpha cytoplasmic staining was observed from healthy vulvar skin to precursor lesions and further to SCC. Nuclear ERRalpha staining was observed in 8/33 (24%) LS-dependent and 10/17 (59%) LS-independent SCC samples. CONCLUSIONS: ERRalpha, a key regulator of cell energy metabolism, may play a role in the pathogenesis of both LS and vulvar SCC. PMID- 26499937 TI - Design, Synthesis, and Acaricidal/Insecticidal Activities of Oxazoline Derivatives Containing a Sulfur Ether Moiety. AB - On the basis of etoxazole, a series of novel 2-(2,6-difluorophenyl)-4-(4 substituted phenyl)-1,3-oxazolines containing a sulfur ether moiety were designed and synthesized via the key intermediate N-(1-(4-(bromomethyl)phenyl)-2 chloroethyl)-2,6-difluorobenzamide. The bioassay results showed that most of these designed target compounds exhibited excellent acaricidal activity against both the eggs and larvae of Tetranychus cinnabarinus, especially the eggs. Among compounds with high activity against the eggs of mites, the LC50 values of 2, 11, 17, and 19 were 0.0003, 0.0002, 0.0005, and 0.0008 mg L(-1), respectively, much lower than that of etoxazole (0.0089 mg L(-1)). Compound 2 was chosen to evaluate the acaricidal activity in the field, and the results displayed that at a concentration of 22 mg kg(-1), 2 had a much better control effect than etoxazole against both T. cinnabarinus and P. latus on eggplant. Some compounds also showed good insecticidal activities against oriental armyworm and mosquito. On the basis of our research, the newly found structure-activity relationship may guide the development of new acaricides/pesticides that are required in the agriculture market. PMID- 26499938 TI - The role of the domain size and titanium dopant in nanocrystalline hematite thin films for water photolysis. AB - Here we develop a novel technique for preparing high quality Ti-doped hematite thin films for photoelectrochemical (PEC) water splitting, through sputtering deposition of metallic iron films from an iron target embedded with titanium (dopants) pellets, followed by a thermal oxidation step that turns the metal films into doped hematite. It is found that the hematite domain size can be tuned from ~10 nm to over 100 nm by adjusting the sputtering atmosphere from more oxidative to mostly inert. The better crystallinity at a larger domain size ensures excellent PEC water splitting performance, leading to record high photocurrent from pure planar hematite thin films on FTO substrates. Titanium doping further enhances the PEC performance of hematite photoanodes. The photocurrent is improved by 50%, with a titanium dopant concentration as low as 0.5 atom%. It is also found that the role of the titanium dopant in improving the PEC performance is not apparently related to the films' electrical conductivity which had been widely believed, but is more likely due to the passivation of surface defects by the titanium dopants. PMID- 26499939 TI - Driving skills in unmedicated first- and recurrent-episode schizophrenic patients. AB - The present study was designed to examine driving skills according to regulations of the German guidelines for road and traffic safety in unmedicated schizophrenic inpatients. A total of 13 first-episode (FES) and 13 recurrent-episode (RES) schizophrenic inpatients were included in the analysis and compared with a group of 20 healthy controls (HC). Data were collected with the computerised Wiener Testsystem measuring visual perception, reactivity and stress tolerance, concentration and vigilance. Analysis of data indicates that a great proportion (58 %) of schizophrenic patients were impaired in psychomotor functions related to driving skills. FES and RES significantly differed with respect to driving ability with a greater proportion in the FES (38 %) showing severe impairments when compared with RES (25 %). Differences with respect to HC performance were most pronounced in concentration and for the FES additionally in visual perception. Analysis of our data indicates that a great proportion of schizophrenic patients are impaired in psychomotor functions related to driving skills that cannot be attributed to adverse side effects of psychopharmacological treatment. Besides, we cannot confirm a chronical decline of psychomotor functions related to driving skills at least in the early course of schizophrenic illness. PMID- 26499940 TI - A 10-year population-based study of people with multiple sclerosis in Stockholm, Sweden: use of and satisfaction with care and the value of different factors in predicting use of care. AB - BACKGROUND: The national strategy for treatment of chronic diseases - including MS - and changes in the Swedish welfare system, call for analyses of the use of, and patient satisfaction with, care in a long-term perspective. The aim was therefore to explore the use of care and the predictive value of personal factors, disease-specific factors and functioning on the use of care and to explore patient satisfaction with care in a 10-year perspective. METHODS: Information regarding personal factors, disease-specific factors, functioning and satisfaction with care was collected by home-visits; use of care was collected from the Stockholm County Council computerised register. RESULT: Data from 121 people with MS (PwMS) was collected. Primary care accounted for the majority of all care. Neurology and Rehabilitation Departments together accounted for two thirds of all hospital outpatient care. Rehabilitation Departments accounted for one-third of the total number of inpatient days. Lower coping capacity, impaired manual dexterity and activity of daily living dependency at baseline, together with progress in MS disability predicted a higher use of care. Overall, patient satisfaction with care was stable over time. CONCLUSION: The extensive use of care offers challenges to care coordination. Implementation of person-centred care could be a strategy to increase efficacy/outcome of care. PMID- 26499942 TI - Labia Minora, Labia Majora, and Clitoral Hood Alteration: Experience-Based Recommendations. AB - Aesthetic alteration of the genitalia is increasingly sought by women unhappy with the size, shape, and appearance of their vulva. Although the labia minora are usually the focus of concern, the entire anatomic region--minora, labia majora, clitoral hood, perineum, and mons pubis--should be evaluated in a preoperative assessment of women seeking labiaplasty. Labiaplasty is associated with high patient satisfaction and low complication rates. The three basic labia minora reduction techniques--edge excision, wedge excision, and central deepithelialization--as well as their advantages and disadvantages are discussed to assist the surgeon in tailoring technique selection to individual genital anatomy and aesthetic desires. We present key points of the preoperative anatomic evaluation, technique selection, operative risks, perioperative care, and potential complications for labia minora, labia majora, and clitoral hood alterations, based on a large operative experience. Labiaplasty competency should be part of the skill set of all plastic surgeons. PMID- 26499941 TI - Interaction Between Breast Cancer Cells and Adipose Tissue Cells Derived from Fat Grafting. AB - BACKGROUND: Adipose tissue transplantation has the benefit of providing both regenerative and aesthetic outcomes in breast cancer treatment. However, the transplanted tissue can stimulate the growth of residual cancer cells. OBJECTIVES: The aim of this study is to identify the interactions between adipose tissue cell subpopulations and human cancer cell lines. METHODS: Intact adipose tissue from lipofilling procedures as well as fibroblasts derived from adipose tissue, were cocultured in the presence of MDA-MB-231, MCF-7 e ZR-75-1 breast cancer cell lines. The influence on cancer cell lines of fibroblasts, induced to differentiate into specific adipocytes, was also assayed. RESULTS: All cancer cell lines displayed a significant increase in proliferation rate when cocultured in the presence of either intact adipose tissue or induced adipocytes. To a lesser extent, uninduced fibroblasts stimulate breast cancer cell proliferation. CONCLUSIONS: Recent studies have shown that the microenvironment surrounding breast cancer cells may stimulate growth and promote progression of residual cancer cells when surgery is performed on the main tumor mass. Accordingly, the graft of adipose tissue could potentially promote or accelerate the development of a subclinical tumor or support its locoregional recurrence. Our data suggest that adipocytes have a remarkable influence on the proliferation of cancer cell lines. The oncological safety of the lipofilling procedure outcome is still debated; thus, further studies and consistent follow-up examination are needed. PMID- 26499943 TI - Mitotic arrest deficient-like 1 is correlated with poor prognosis in small-cell lung cancer after surgical resection. AB - Mitotic arrest deficient-like 1 (MAD1L1) whose dysfunction is associated with chromosomal instability plays a pathogenic role in a few human cancers. However, the status of MAD1L1 expression in small-cell lung cancer (SCLC) remains unknown. Immunohistochemistry was used to determine the expression of MAD1L1 protein in 32 lymph node metastasis (LN-M) tissues and 88 primary SCLCs compared with 32 adjacent noncancerous tissues. The associations of MAD1L1 protein expression with the clinicopathologic features and clinical outcomes in patients with SCLC were analyzed. The ratio of MAD1L1 positive expression was higher in primary SCLC tissues (39.8 %) and LN-M tissues (46.9 %) compared with adjacent noncancerous tissues (9.4 %). MAD1L1 positive expression was associated with tumor-node metastasis (TNM) stage (P = 0.003), International Association for the Study of Lung Cancer (IASLC) stage (P = 0.004), tumor size (P = 0.015), lymph node metastasis (P = 0.014), and recurrence (P < 0.001). Multivariate analysis suggested that MAD1L1 positive expression was an independent factor for overall survival (hazard ratio (HR) 2.002; 95 % confidence interval (CI) 1.065-3.763; P = 0.031) and recurrence-free survival (HR 2.263; 95 % CI 1.197-4.276; P = 0.012). To sum up, MAD1L1 positive expression may be associated with tumour progression and metastasis in SCLCs and may thus serve as a new biomarker for prognosis in these patients. PMID- 26499944 TI - HMGB1 promotes HCC progression partly by downregulating p21 via ERK/c-Myc pathway and upregulating MMP-2. AB - High-mobility group box 1 (HMGB1) was found to be over-expressed in many kinds of human cancer, which binds with several receptors and activates RAGE-Ras-MAPK, Toll-like receptors, NF-kappaB, and Src family kinase signaling pathways and plays a crucial role in tumorigenesis and cancer progression. However, the function and mechanism of HMGB1 in hepatocellular carcinoma (HCC) remain unclear. The aim of this study was to investigate the effect of HMGB1 on HCC progression and explore new molecular mechanism. HMGB1 transient knockdown, stable knockdown, and re-expression were performed by transfection with specific siRNA, shRNA, or expression vector in HCCLM3 cells. Results showed that transient knockdown HMGB1 prevented cell proliferation, promoted apoptosis, induced S phase arrest, and inhibited migration and invasion in vitro, and stable knockdown HMGB1 inhibited xenograft growth in Balb/c athymic mice in vivo. Molecular mechanism investigation revealed that knockdown HMGB1 significantly reduced the activation of MAPKs, including ERK1/2, p38, SAPK/JNK, as well as MAPKKs (MEK1/2, SEK1) and its substrates (c-Jun, c-Myc); downregulated NF-kappaB/p65 expression and phosphorylation level; decreased MMP-2 expression and activity; and upregulated p21 expression. Interestingly, c-Myc was firstly found to be involved in the promoting function of HMGB1 on HCC progression, which provided a novel clue for the inhibitory effect of HMGB1 on p21 expression by a p53-independent pathway. Collectively, these findings indicated that HMGB1 promoted HCC progression partly by enhancing the ERK1/2 and NF-kappaB pathways, upregulating MMP-2, and downregulating p21 via an ERK/c-Myc pathway. PMID- 26499945 TI - Role of estrogen receptor alpha in human cervical cancer-associated fibroblasts: a transcriptomic study. AB - Cancer-Associated Fibroblasts (CAFs) are crucial in genesis and progression of tumors; however, cervical CAFs (C-CAFs) are not well characterized. Estradiol (E2) has been implicated as a cofactor in human papillomavirus (HPV)-mediated cervical cancer (CxCa), both in animal models and in women using oral contraceptives; however, the exact role of the hormone is unclear. Human C-CAFs have recently been shown to express estrogen receptor alpha (ER-alpha). We investigated gene expression patterns in ex vivo cultured early and late stage C CAFs in the context of E2. CAFs were isolated from four patients with early and two patients with late stage CxCa. ER-alpha expression in CxCa tissues was localized to stromal fibroblast-like cells and confirmed in ex vivo cultured C CAFs. Two ER antagonists (ICI 182,780 and Methyl Piperidino Pyrazole) were used to unravel ER signaling in CAFs. Microarray technology was used for expression profiling and validated by quantitative reverse transcription PCR. The transcriptomes of C-CAFs across stages indicated their activated state. C-CAFs had gene expression patterns associated with both pro-tumorigenic and pro inflammatory signaling. Late-stage C-CAFs compared to those of early stage appeared to be more actively metabolizing and cycling but expressed fewer genes related to immune function. We report differential expression profiles between C CAFs: early vs. late stage and in the presence of ER antagonists. Both ER antagonists seemed to modulate C-CAF function by down regulating genes associated with cell cycle and metabolism, affecting angiogenesis and cancer progression. This study characterized C-CAFs from early and late stage disease, and experiments with ER inhibitors emphasized the probable importance of canonical ER alpha signaling. Interfering with paracrine signaling through fibroblast ER-alpha is worth exploiting as a targeted therapy in CxCa management. PMID- 26499946 TI - The alpha7-nicotinic acetylcholine receptor mediates the sensitivity of gastric cancer cells to taxanes. AB - Gastric cancer is difficult to cure because most patients are diagnosed at an advanced disease stage. Systemic chemotherapy remains an important therapy for gastric cancer, but both progression-free survival and disease-free survival associated with various combination regimens are limited because of refractoriness and chemoresistance. Accumulating evidence has revealed that the homomeric alpha7-nicotinic acetylcholine receptor (A7-nAChR) promotes human gastric cancer by driving cancer cell proliferation, migration, and metastasis. Therefore, A7-nAChR may serve as a potential therapeutic target for gastric cancer. However, the role of A7-nAChR in taxane therapy for gastric cancer was unclear. Cells were subjected to A7-nAChR knockdown (A7-nAChR KD) using short interfering RNA (siRNA). The anti-proliferative effects of taxane were assessed via 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL), and cell cycle distribution assays. A7-nAChR-KD cells exhibited low resistance to docetaxel and paclitaxel treatment, as measured by the MTT assay. Following paclitaxel treatment, the proportion of apoptotic cells was higher among A7-nAChR-KD cells than among scrambled control cells, as measured by cell cycle distribution and TUNEL assays. Further molecular analyses showed a reduction in the pAKT levels and a dramatic increase in the Bad levels in paclitaxel-treated A7-nAChR-KD cells but not in scrambled control cells. Following paclitaxel treatment, the level of Bax was slightly increased in both cell populations, whereas Poly (ADP-ribose) polymerase (PARP) cleavage was increased only in A7-nAChR-KD cells. These findings indicate that A7-nAChR-KD cells are more sensitive to paclitaxel treatment. We conclude that A7-nAChR may be a key biomarker for assessing the chemosensitivity of gastric cancer cells to taxane. PMID- 26499947 TI - Long-term outcomes of concurrent chemoradiotherapy versus radiotherapy alone in stage II nasopharyngeal carcinoma treated with IMRT: a retrospective study. AB - This study aimed to evaluate the efficacy of concurrent chemoradiotherapy (CCRT) for stage II nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiation therapy (IMRT). A total of 249 patients were retrospectively reviewed. All patients were treated with IMRT. One hundred forty-three patients treated with CCRT and 106 patients treated with IMRT alone. With a median follow up of 59.4 months, adding concurrent chemotherapy did not statistically significantly improve the 5-year overall survival (OS) (89.7 % vs 99.0 %, p = 0.278), locoregional relapse-free survival (LRFS) (94.8 % vs 89.3 %, p = 0.167), and distant metastases-free survival (DMFS) (93.4 % vs 97.5 %, p = 0.349). The patients with CCRT significantly experienced more acute toxic effects. The main grades 3-4 toxicity reactions were mucositis (26.6 % vs 15.1 %, p = 0.03) and leukopenia/neutropenia (9.1 % vs 0.9 %, p = 0.005). In subgroup analysis of patients with concurrent platinum single-agent chemotherapy the 5-year OS (98.4 % vs 81.9 %, p = 0.013) and DMFS (96.9 % vs 84.4 %, p = 0.043) of patients with platinum every 3 weeks (Q3W) were significantly higher than those with platinum weekly (QW) and no significant difference for LRFS (96.8 % vs 90.4 %, p = 0.150). CCRT did not improve the survival of patients with stage II NPC but increased the acute toxicity reactions. Patients with platinum Q3W improved the 5-year OS and DMFS, compared with those with platinum QW. PMID- 26499948 TI - Function analysis of rs9589207 polymorphism in miR-92a in gastric cancer. AB - MiR-92a was identified as an essential oncogene by promoting the cell proliferation through FBXW7 in gastric cancer (GC). The function of the single nucleotide polymorphism (SNP) located in the mature region of miR-92a (rs9589207) has not been investigated. We found that rs9589207 in miR-92a was involved in the occurrence of GC by acting as a tumor protective factor and was highly associated with tumor size in GC patients instead of tumor number or metastasis in 554 GC patients and 531 cancer-free controls. Besides, the AA genotype in miR-92a could attenuate the promoting function of miR-92a in cell proliferation with an incapacitation in downregulating the expression of FBXW7. In conclusion, rs9589207 in miR-92a was highly associated with a decreased risk of GC in Chinese Han population and might serve as a novel biomarker for the disease. PMID- 26499950 TI - Role and use of evidence in policymaking: an analysis of case studies from the health sector in Nigeria. AB - BACKGROUND: Health policymaking is a complex process and analysing the role of evidence is still an evolving area in many low- and middle-income countries. Where evidence is used, it is greatly affected by cognitive and institutional features of the policy process. This paper examines the role of different types of evidence in health policy development in Nigeria. METHODS: The role of evidence was compared between three case studies representing different health policies, namely the (1) integrated maternal neonatal and child health strategy (IMNCH); (2) oral health (OH) policy; and (3) human resource for health (HRH) policy. The data was collected using document reviews and 31 in-depth interviews with key policy actors. Framework Approach was used to analyse the data, aided by NVivo 10 software. RESULTS: Most respondents perceived evidence to be factual and concrete to support a decision. Evidence was used more if it was perceived to be context-specific, accessible and timely. Low-cost high-impact evidence, such as the Lancet series, was reported to have been used in drafting the IMNCH policy. In the OH and HRH policies, informal evidence such as experts' experiences and opinions, were reported to have been useful in the policy drafting stage. Both formal and informal evidence were mentioned in the HRH and OH policies, while the development of the IMNCH was revealed to have been informed mainly by more formal evidence. Overall, respondents suggested that formal evidence, such as survey reports and research publications, were most useful in the agenda-setting stage to identify the need for the policy and thus initiating the policy development process. International and local evidence were used to establish the need for a policy and develop policy, and less to develop policy implementation options. CONCLUSION: Recognition of the value of different evidence types, combined with structures for generating and using evidence, are likely to enhance evidence informed health policy development in Nigeria and other similar contexts. PMID- 26499949 TI - Upregulation of long non-coding RNA TUG1 correlates with poor prognosis and disease status in osteosarcoma. AB - The pathogenesis of osteosarcoma involves complex genetic and epigenetic factors. This study was to explore the impact and clinical relevance of long non-coding RNA (lncRNA), Taurine up-regulated gene 1 (TUG1) on patients with osteosarcoma. Seventy-six osteosarcoma tissues and matched adjacent normal tissues were included for analysis. The plasma samples were obtained from 29 patients with osteosarcoma at pre-operation and post-operation, 42 at newly diagnosed, 18 who experienced disease progression or relapse, 45 post-treatment, 36 patients with benign bone tumor, and 20 healthy donors. Quantitative real-time reverse transcript polymerase chain reactions were used to assess the correlation of the expression levels of TUG1 with clinical parameters of osteosarcoma patients. TUG1 was significantly overexpressed in the osteosarcoma tissues compared with matched adjacent normal tissues (P < 0.01) and was closely correlated with tumor size, post-operative chemotherapy, and Enneking surgical stage. Upregulation of TUG1 strongly correlated with poor prognosis and was an independent prognostic indicator for overall survival (HR = 2.78, 95% CI = 1.29-6.00, P = 0.009) and progression-free survival (HR = 1.81, 95% CI = 1.01-3.54, P = 0.037). Our constructed nomogram containing TUG1 had more predictive accuracy than that without TUG1 (c-index 0.807 versus 0.776, respectively). In addition, for plasma samples, TUG1 expression levels were obviously decreased in post-operative patients (mean DeltaCT -4.98 +/- 0.22) compared with pre-operation patients (mean DeltaCT -6.09 +/- 0.74), and the changes of TUG1 expression levels were significantly associated with disease status. Receiver operating characteristic (ROC) curve analysis demonstrated that TUG1 could distinguish patients with osteosarcoma from healthy individuals compared with alkaline phosphatase (ALP) (the area under curve 0.849 versus 0.544). TUG1 was overexpressed in patients with osteosarcoma and strongly correlated with disease status. In addition, TUG1 may serve as a molecular indicator in maintaining surveillance and forecasting prognosis. PMID- 26499951 TI - Clinical and genetic characteristics of Japanese nephronophthisis patients. AB - BACKGROUND: Nephronophthisis (NPH) accounts for 4-5 % of end-stage renal disease occurring in childhood. METHOD: We investigated the clinical context and characteristics of renal and extrarenal symptoms, as well as the NPHP genes, in 35 Japanese patients with clinical and histologic features suggesting NPH. RESULTS: NPH occurred fairly uniformly throughout Japan irrespective of region or gender. In three families, NPH affected siblings. The median age of patients was 12.5 years. Renal abnormalities attributable to NPH discovered through mass screening, such as urine tests in school. However, NPH accounted for less than 50 % of children with abnormal findings, including incidentally discovered renal dysfunction during evaluation of extrarenal symptoms or during routine check-ups. Typical extrarenal manifestations leaded to discovery including anemia and delayed physical development. The urine often showed low gravity specific density and low molecular weight proteinuria. Frequent renal histologic findings included cystic dilation of tubules, mainly in the medulla, and irregularity of tubular basement membranes. Genetically abnormalities of NPHP1 were not common, with large deletions frequently noted. Compound heterozygotes showing single abnormalities in each of NPHP1, NPHP3, and NPHP4 were observed. CONCLUSIONS: Our findings resemble those reported in Western populations. PMID- 26499952 TI - Prevalence and predictors for musculoskeletal discomfort in Malaysian office workers: Investigating explanatory factors for a developing country. AB - Musculoskeletal disorders (MSDs) are a major occupational health issue for workers in developed and developing countries, including Malaysia. Most research related to MSDs has been undertaken in developed countries; given the different regulatory and cultural practices it is plausible that contributions of hazard and risk factors may be different. A population of Malaysian public service office workers were surveyed (N = 417, 65.5% response rate) to determine prevalence and associated predictors of MSD discomfort. The 6-month period prevalence of MSD discomfort was 92.8% (95%CI = 90.2-95.2%). Akaike's Information Criterion (AIC) analyses was used to compare a range of models and determine a model of best fit. Contributions associated with MSD discomfort in the final model consisted of physical demands (61%), workload (14%), gender (13%), work home balance (9%) and psychosocial factors (3%). Factors associated with MSD discomfort were similar in developed and developing countries but the relative contribution of factors was different, providing insight into future development of risk management strategies. PMID- 26499953 TI - Identifying suspects by matching hand photographs with video evidence. AB - Reports by minors of sexual relations against their will are not rare, and in some cases pornographic photography is a part of the abuse. Such material can be used to help identify the perpetrator. In this study we examined the efficacy of visual comparison between two databases. One consisted of blinded still images of the back of the right hand of 51 males from video recordings, the other of blinded high quality camera images of the back of the right hand from the same 51 individuals. The images were compared in pairs (2601 combinations) and a judgment was made about whether they were a highly likely, possible or unlikely match, using several anatomical features as markers for comparison. Using this method all 51 high quality images were correctly matched with the video image from the same person, though in some cases there was up to 5 other samples that could not be excluded as possible matches. In total there were no false positive "highly possible" matches, but there were 50 false positive "possible" matches. Visual comparison of the back of the hand is a valuable addition to the burden of evidence in a judicial setting, but should not be used as a standalone method to establish proof of identity. The applicability of the method is dependent on the existence of a database of images; the degree of certainty of the identification is directly correlated to the size of the database. PMID- 26499954 TI - Diet, Depression, and Destiny in Heart Failure. PMID- 26499955 TI - Effects of simvastatin on the osteogenic differentiation and immunomodulation of bone marrow mesenchymal stem cells. AB - The present study aimed to investigate the effects of simvastatin on the bone differentiation capacity and immunological characteristics of bone marrow mesenchymal stem cells (BMSCs). BMSCs were isolated and cultured in medium containing 1.0 umol/ml simvastatin. The alkaline phosphatase activity, mRNA expression levels of osteocalcin and bone sialoprotein, and calcium nodule formation were assessed to determine the osteogenic differentiation capability of BMSCs. To investigate alterations in the immunological properties of simvastation treated BMSCs, the immunogenicity of these cells and the effect of BMSCs on phytohemagglutinin-stimulated lymphocyte proliferation were also assessed. Following treatment with simvastatin, the alkaline phosphatase activity, and mRNA expression levels of osteocalcin and bone sialoprotein were increased significantly in the BMSCs. In addition, von Kossa staining revealed a brown calcium-positive reaction zone in simvastatin-treated cells. Simvastatin-induced BMSCs revealed no affect on the proliferation of allogeneic lymphocytes, however, inhibited phytohemagglutinin-induced lymphocyte proliferation. Collectively, simvastatin promoted the osteogenic differentiation of BMSCs significantly without affecting their immunosuppressive properties. PMID- 26499956 TI - Genome-wide identification and expression analysis of the expansin gene family in tomato. AB - Plant expansins are capable of inducing pH-dependent cell wall extension and stress relaxation. They may be useful as targets for crop improvement to enhance fruit development and stress resistance. Tomato is a major agricultural crop and a model plant for studying fruit development. Because only some tomato expansins have been studied, a genome-wide analysis of the tomato expansin family is necessary. In this study, we identified 25 SlEXPAs, eight SlEXPBs, one SlEXLA, four SlEXLBs, and five short homologs in the tomato genome. 25 of these genes were identified as being expressed. Bioinformatic analysis showed that although tomato expansins share similarities with those from other plants, they also exhibit specific features regarding genetic structure and amino acid sequences, which indicates a unique evolutionary process. Segmental and tandem duplication events have played important roles in expanding the tomato expansin family. Additionally, the 3-exon/2-intron structure may form the basic organization of expansin genes. We identified new expansin genes preferentially expressed in fruits (SlEXPA8, SlEXPB8, and SlEXLB1), roots (SlEXPA9, SlEXLB2, and SlEXLB4), and floral organs. Among the analyzed genes those that were inducible by hormone or stress treatments, including SlEXPA3, SlEXPA7, SlEXPB1-B2, SlEXPB8, SlEXLB1 LB2, and SlEXLB4. Our findings may further clarify the biological activities of tomato expansins, especially those related to fruit development and stress resistance, and contribute to the genetic modification of tomato plants to improve crop quality and yield. PMID- 26499957 TI - Isolation and characterization of cDNAs and genomic DNAs encoding ADP-glucose pyrophosphorylase large and small subunits from sweet potato. AB - Sweet potato [Ipomoea batatas (L.) Lam.], the world's seventh most important food crop, is also a major industrial raw material for starch and ethanol production. In the plant starch biosynthesis pathway, ADP-glucose pyrophosphorylase (AGPase) catalyzes the first, rate-limiting step and plays a pivotal role in regulating this process. In spite of the importance of sweet potato as a starch source, only a few studies have focused on the molecular aspects of starch biosynthesis in sweet potato and almost no intensive research has been carried out on the AGPase gene family in this species. In this study, cDNAs encoding two small subunits (SSs) and four large subunits (LSs) of AGPase isoforms were cloned from sweet potato and the genomic organizations of the corresponding AGPase genes were elucidated. Expression pattern analysis revealed that the two SSs were constitutively expressed, whereas the four LSs displayed differential expression patterns in various tissues and at different developmental stages. Co-expression of SSs with different LSs in Escherichia coli yielded eight heterotetramers showing different catalytic activities. Interactions between different SSs and LSs were confirmed by a yeast two-hybrid experiment. Our findings provide comprehensive information about AGPase gene sequences, structures, expression profiles, and subunit interactions in sweet potato. The results can serve as a foundation for elucidation of molecular mechanisms of starch synthesis in tuberous roots, and should contribute to future regulation of starch biosynthesis to improve sweet potato starch yield. PMID- 26499958 TI - Sigma-1 receptor activation inhibits osmotic swelling of rat retinal glial (Muller) cells by transactivation of glutamatergic and purinergic receptors. AB - Water accumulation in retinal glial (Muller) and neuronal cells resulting in cellular swelling contributes to the development of retinal edema and neurodegeneration. Sigma (sigma) receptor activation is known to have neuroprotective effects in the retina. Here, we show that the nonselective sigma receptor agonist ditolylguanidine, and the selective sigma1 receptor agonist PRE 084, inhibit the osmotic swelling of Muller cell somata induced by superfusion of rat retinal slices with a hypoosmotic solution containing barium ions. In contrast, PRE-084 did not inhibit the osmotic swelling of bipolar cell somata. The effects of sigma receptor agonists on the Muller cell swelling were abrogated in the presence of blockers of metabotropic glutamate and purinergic P2Y1 receptors, respectively, suggesting that sigma receptor activation triggers activation of a glutamatergic-purinergic signaling cascade which is known to prevent the osmotic Muller cell swelling. The swelling-inhibitory effect of 17beta-estradiol was prevented by the sigma1 receptor antagonist BD1047, suggesting that the effect is mediated by sigma1 receptor activation. The data may suggest that the neuroprotective effect of sigma receptor activation in the retina is in part mediated by prevention of the cytotoxic swelling of retinal glial cells. PMID- 26499959 TI - Amyotrophic lateral sclerosis-associated mutant profilin 1 increases dendritic arborisation and spine formation in primary hippocampal neurons. AB - Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and familial ALS accounts for 10% of cases. The identification of familial ALS mutations in the actin-binding protein profilin 1 directly implicates actin dynamics and regulation in the pathogenesis of ALS. The mechanism by which these mutations cause ALS is unknown. In this study we show that expression of the ALS associated actin-binding deficient mutant of PFN1 (PFN1(C71G)) results in increased dendritic arborisation and spine formation, and cytoplasmic inclusions in cultured mouse hippocampal neurons. PMID- 26499960 TI - Parental health shocks, child labor and educational outcomes: Evidence from Tanzania. AB - This paper examines the impact of parental illness on children's education. We find that only father's illness decreases children's school attendance. Father's illness also has long-term impacts on child education, as it decreases children's likelihood of completing primary school and leads to fewer years of schooling. However, we find no evidence that father's illness affects schooling through increased child labor. Instead, father's illness decreases household's income and reduces school attendance possibly because of the reduced ability of the family to afford education. In contrast, mother's illness and illness of other household members have no effect on children's schooling. PMID- 26499961 TI - Smoothing the Bumpy Road to Antiarrhythmic Drug Development. PMID- 26499962 TI - Long-Standing Persistent Atrial Fibrillation: Can We Distinguish Ectopic Activity From Reentry by Epicardial Mapping? PMID- 26499963 TI - Simultaneous Biatrial High-Density (510-512 Electrodes) Epicardial Mapping of Persistent and Long-Standing Persistent Atrial Fibrillation in Patients: New Insights Into the Mechanism of Its Maintenance. AB - BACKGROUND: The mechanism(s) of persistent and long-standing persistent (LSP) atrial fibrillation (AF) is/are poorly understood. We performed high-density, simultaneous, biatrial, epicardial mapping of persistent and LSP AF in patients undergoing open heart surgery (1) to test the hypothesis that persistent and LSP AF are due to >= 1 drivers, either focal or reentrant, and (2) to characterize associated atrial activation. METHODS AND RESULTS: Twelve patients with persistent and LSP AF (1 month to 9 years duration) were studied at open heart surgery. During AF, electrograms were recorded from both atria simultaneously for 1 to 5 minutes from 510 to 512 epicardial electrodes with ECG lead II. Thirty-two consecutive seconds of activation sequence maps were produced per patient. During AF, multiple foci (QS unipolar atrial electrograms) of different cycle lengths (mean, 175 +/- 18 ms) were present in both atria in 11 of 12 patients. Foci (2-4 per patient, duration 5-32 s) were either sustained or intermittent, were predominantly found in the lateral left atrial free wall, and likely acted as drivers. Random and nonrandom breakthrough activation sites (initial r or R in unipolar atrial electrograms) were also found. In 1 of 12 patients, only breakthrough sites were found. All wave fronts emanated from foci and breakthrough sites, and largely either collided or merged with each other at variable sites. Repetitive focal QS activation occasionally generated repetitive wannabe reentrant activation in 5 of 12 patients. No actual reentry was found. CONCLUSIONS: During persistent and LSP AF in 12 patients, wave fronts emanating from foci and breakthrough sites maintained AF. No reentry was demonstrated. PMID- 26499964 TI - Potassium Channel Blockade Enhances Atrial Fibrillation-Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade. AB - BACKGROUND: The development of effective and safe antiarrhythmic drugs for atrial fibrillation (AF) rhythm control is an unmet clinical need. Multichannel blockers are believed to have advantages over single-channel blockers for AF, but their development has been completely empirical to date. We tested the hypothesis that adding K(+)-channel blockade improves the atrium-selective electrophysiological profile and anti-AF effects of optimized Na(+)-channel blockers. METHODS AND RESULTS: Realistic cardiomyocyte-, tissue-, and state-dependent Na(+)-channel block mathematical models, optical mapping, and action potential recording were used to study the effect of Na(+)-current (INa) blockade with or without concomitant inhibition of the rapid or ultrarapid delayed-rectifier K(+) currents (IKr and IKur, respectively). In the mathematical model, maximal AF selectivity was obtained with an inactivated-state Na(+)-channel blocker. Combining optimized Na(+)-channel blocker with IKr block increased rate-dependent and atrium selective peak INa reduction, increased AF selectivity, and more effectively terminated AF compared with optimized Na(+)-channel blocker alone. Combining optimized Na(+)-channel blocker with IKur block had similar effects but without IKr block-induced ventricular action potential prolongation. Consistent with the mathematical model, in coronary-perfused canine hearts, the addition of dofetilide (selective IKr blocker) to pilsicainide (selective INa blocker) produced enhanced atrium-selective effects on maximal phase 0 upstroke and conduction velocity. Furthermore, pilsicainide plus dofetilide had higher AF termination efficacy than pilsicainide alone. Pilsicainide alone had no statistically significant effect on AF inducibility, whereas pilsicainide plus dofetilide rendered AF noninducible. CONCLUSIONS: K(+)-channel block potentiates the AF-selective anti-AF effects obtainable with optimized Na(+)-channel blockade. Combining optimized Na(+)-channel block with blockade of atrial K(+) currents is a potentially valuable AF-selective antiarrhythmic drug strategy. PMID- 26499965 TI - Informatics framework of traditional Sino-Japanese medicine (Kampo) unveiled by factor analysis. AB - Kampo, an empirically validated system of traditional Sino-Japanese medicine, aims to treat patients holistically. This is in contrast to modern medicine, which focuses in principle on treating the affected parts of the body of the patient. Kampo medicines formulated as combinations of crude drugs are prescribed based on a Kampo-specific diagnosis called Sho (in Japanese), defined as the holistic condition of each patient. Therefore, the medication system is very complex and is not well understood from a modern scientific perspective. Here, we show the informatics framework of Kampo medication by multivariate factor analysis of the elements constituting Kampo medication. First, the variation of Kampo formulas projected by principal component analysis (PCA) indicated that the combination patterns of crude drugs were highly correlated with Sho diagnoses of Deficiency and Excess. In an opposite way, partial least squares projection to latent structures (PLS) regression analysis could also predict Deficiency/Excess only from the composed crude drugs. Secondly, to chemically verify the correlation between Deficiency/Excess and crude drugs, we performed mass spectrometry (MS)-based metabolome analysis of Kampo prescriptions. PCA and PLS regression analysis of the metabolome data also suggested that Deficiency/Excess could be theoretically explained based on the variation in chemical fingerprints of Kampo medicines. Our results show that factor analysis of Kampo concepts and of the metabolomes of Kampo medicines enables interpretation of the complex system of Kampo. This study will theoretically form the basis for establishing traditionally and empirically based medications worldwide, leading to systematically personalized medicine. PMID- 26499966 TI - Diabetes Prevention and Weight Loss with a Fully Automated Behavioral Intervention by Email, Web, and Mobile Phone: A Randomized Controlled Trial Among Persons with Prediabetes. AB - BACKGROUND: One-third of US adults, 86 million people, have prediabetes. Two thirds of adults are overweight or obese and at risk for diabetes. Effective and affordable interventions are needed that can reach these 86 million, and others at high risk, to reduce their progression to diagnosed diabetes. OBJECTIVE: The aim was to evaluate the effectiveness of a fully automated algorithm-driven behavioral intervention for diabetes prevention, Alive-PD, delivered via the Web, Internet, mobile phone, and automated phone calls. METHODS: Alive-PD provided tailored behavioral support for improvements in physical activity, eating habits, and factors such as weight loss, stress, and sleep. Weekly emails suggested small step goals and linked to an individual Web page with tools for tracking, coaching, social support through virtual teams, competition, and health information. A mobile phone app and automated phone calls provided further support. The trial randomly assigned 339 persons to the Alive-PD intervention (n=163) or a 6-month wait-list usual-care control group (n=176). Participants were eligible if either fasting glucose or glycated hemoglobin A1c (HbA1c) was in the prediabetic range. Primary outcome measures were changes in fasting glucose and HbA1c at 6 months. Secondary outcome measures included clinic-measured changes in body weight, body mass index (BMI), waist circumference, triglyceride/high-density lipoprotein cholesterol (TG/HDL) ratio, and Framingham diabetes risk score. Analysis was by intention-to-treat. RESULTS: Participants' mean age was 55 (SD 8.9) years, mean BMI was 31.2 (SD 4.4) kg/m(2), and 68.7% (233/339) were male. Mean fasting glucose was in the prediabetic range (mean 109.9, SD 8.4 mg/dL), whereas the mean HbA1c was 5.6% (SD 0.3), in the normal range. In intention-to-treat analyses, Alive-PD participants achieved significantly greater reductions than controls in fasting glucose (mean -7.36 mg/dL, 95% CI -7.85 to -6.87 vs mean -2.19, 95% CI -2.64 to -1.73, P<.001), HbA1c (mean -0.26%, 95% CI -0.27 to -0.24 vs mean -0.18%, 95% CI -0.19 to -0.16, P<.001), and body weight (mean -3.26 kg, 95% CI -3.26 to -3.25 vs mean -1.26 kg, 95% CI -1.27 to -1.26, P<.001). Reductions in BMI, waist circumference, and TG/HDL were also significantly greater in Alive-PD participants than in the control group. At 6 months, the Alive-PD group reduced their Framingham 8-year diabetes risk from 16% to 11%, significantly more than the control group (P<.001). Participation and retention was good; intervention participants interacted with the program a median of 17 (IQR 14) of 24 weeks and 71.1% (116/163) were still interacting with the program in month 6. CONCLUSIONS: Alive PD improved glycemic control, body weight, BMI, waist circumference, TG/HDL ratio, and diabetes risk. As a fully automated system, the program has high potential for scalability and could potentially reach many of the 86 million US adults who have prediabetes as well as other at-risk groups. TRIAL REGISTRATION: Clinicaltrials.gov NCT01479062; https://clinicaltrials.gov/ct2/show/NCT01479062 (Archived by WebCite at http://www.webcitation.org/6bt4V20NR). PMID- 26499967 TI - Development of a Modified Version of the Spinal Function Sort (M-SFS): A Mixed Method Approach. AB - Purpose To develop a modified version of the spinal function sort (M-SFS) by measuring work-related self-efficacy beliefs in patients with chronic low back pain. Methods A mixed method design consisting of three different methods (M1-3) was performed. In semi-structured interviews participants were asked how often they performed the activities of the 50 SFS items in 1 week, and which spinal postures and movements were associated with their back pain (M1). Quantitative analysis of previously obtained SFS data investigated internal consistency, unidimensionality, item response, and floor and ceiling effect (M2). Experts rated the SFS items based on their relevance (M3). The findings from these methods were used within a final scoring system for item reduction. Results From semi-structured interviews with 17 participants, eight new items emerged (M1). Quantitative analysis of 565 data sets (M2) revealed very high internal consistency of all items (Cronbach's alpha = 0.98) indicating item redundancy; unidimensionality of the SFS was supported by principal component analysis; good item response was confirmed by Rasch analysis; and a floor effect of four items depicting very heavy material handling was found. Experts agreed on 8 out of the 50 SFS as relevant (M3). From the original SFS, 12 items met the predefined summary score of 9. Conclusions A modified version of the SFS with 20 items has been developed. Feasibility, reliability and validity of this modified version must be tested before it can be used in clinical practice. PMID- 26499968 TI - Instrumentation and automation for the separation sciences. PMID- 26499969 TI - Reciprocating free-flow isoelectric focusing device for preparative separation of proteins. AB - The traditional recycling free-flow isoelectric focusing (RFFIEF) suffered from complex structure, tedious operations and poor extensibility as well as high cost. To address these issues, a novel reciprocating free-flow isoelectric focusing device (ReFFIEF) was developed for proteins or peptides pre fractionation. In the new device, a reciprocating background flow was for the first time introduced into free flow electrophoresis (FFE) system. The gas cushion injector (GCI) used in the previous continuous free-flow electrophoresis (CFFE) was redesigned for the reciprocating background flow. With the GCI, the reciprocating background flow could be achieved between the GCI, separation chamber and transient self-balance collector (tSBC). In a run, process fluid flowed to and from, forming a stable reciprocating fluid flow in the separation chamber. A pH gradient was created within the separation chamber, and at the same time proteins were focused repeatedly when passing through the chamber under perpendicular electric field. The ReFFIEF procedure was optimized for fractionations of three model proteins, and the optimized method was further used for pre-fractionation of model human serum samples. As compared with the traditional RFFIEF devices developed about 25 years ago, the new ReFFIEF system showed several merits, such as simple design and structure, user-friendly operation and easy to extend as well as low cost. PMID- 26499970 TI - Application of Asymmetric Flow Field-Flow Fractionation hyphenations for liposome antimicrobial peptide interaction. AB - Asymmetric Flow Field-Flow Fractionation (AF4) combined with multidetector analysis form a promising technique in the field of nanoparticle characterization. This system is able to measure the dimensions and physicochemical properties of nanoparticles with unprecedented accuracy and precision. Here, for the first time, this technique is optimized to characterize the interaction between an archetypal antimicrobial peptide and synthetic membranes. By using charged and neutral liposomes it is possible to mimic some of the charge characteristics of biological membranes. The use of AF4 system allows determining, in a single analysis, information regarding the selectivity of the peptides, the quantity of peptides bound to each liposome, the induced change in the size distribution and morphology of the liposomes. The results obtained provide relevant information for the study of structure-activity relationships in the context of membrane-induced antimicrobial action. This information will contribute to the rational design of potent antimicrobial agents in the future. Moreover, the application of this method to other liposome systems is straightforward and would be extremely useful for a comprehensive characterization with regard to size distribution and protein interaction in the nanomedicine field. PMID- 26499971 TI - Determination of total acid content in biomass hydrolysates by solvent-assisted and reaction based headspace gas chromatography. AB - This work reports on a novel method for the determination of total acid (TA) in biomass hydrolysates by a solvent-assisted and reaction-based headspace gas chromatography (HS-GC). The neutralization reaction between the acids in hydrolysates and bicarbonate in an ethanol (50%) aqueous solution was performed in a closed headspace sample vial, from which the carbon dioxide generated from the reaction was detected by HS-GC. It was found that the addition of ethanol can effectively eliminate the precipitation of some organic acids in the biomass hydrolysates. The results showed that the reaction and headspace equilibration can be achieved within 45min at 70 degrees C; the method has a good precision (RSD<3.27%) and accuracy (recovery of 97.4-105%); the limit of quantification is 1.36MUmol. The present method is quite suitable to batch analysis of TA content in hydrolysate for the biorefinery related research. PMID- 26499972 TI - Tracking and identification of antibacterial components in the essential oil of Tanacetum vulgare L. by the combination of high-performance thin-layer chromatography with direct bioautography and mass spectrometry. AB - Two tansy (Tanacetum vulgare L.) essential oils were obtained by steam distillation of the capitula with subsequent liquid-liquid extraction (oil 1) or with use of an auxiliary phase for the trapping of the steam components (oil 2). These oils were investigated against Bacillus subtilis F1276, B. subtilis spizizenii (DSM 618), Xanthomonas euvesicatoria, Pseudomonas syringae pv. maculicola, Ralstonia solanacearum strain GMI1000 and Aliivibrio fischeri, using the coupling of high-performance thin-layer chromatography to direct bioautography (HPTLC-DB). Using this method with the potato and tomato pathogen R. solanacearum is shown for the first time. Due to the advanced extraction process, oil 2 was richer in components and provided more inhibition zones. The main bioactive components were identified by scanning HPTLC-Direct Analysis in Real Time mass spectrometry (HPTLC-DART-MS) and solid-phase microextraction gas chromatography electron impact MS (SPME-GC-EI-MS) as cis- and trans-chrysanthenol as well as trans-chrysanthenyl acetate. cis-Chrysanthenol exhibited antibacterial effects against all tested bacteria, whereas trans-chrysanthenol inhibited B. subtilis, R. solanacearum and A. fischeri. trans-Chrysanthenyl acetate was an inhibitor for X. euvesicatoria, R. solanacearum and A. fischeri. Although HPTLC DART-MS resulted in a comparable fragmentation, the ionization characteristics and the recorded mass spectra clearly showed that DART is a softer ionization technique than EI. It is also more affected by ambient conditions and thus prone to additional oxidation products. PMID- 26499973 TI - Application of graphitic sorbent for online microextraction of drugs in human plasma samples. AB - In the present work a new sorbent based on graphitized carbon (CarbonX((r)) COA) was evaluated in microextraction by packed sorbent (MEPS) for extraction of lidocaine and ropivacaine from human plasma samples. The new graphitic sorbent showed high recoveries of lidocaine and ropivacaine compared to C18 sorbent. In the present study the G-MEPS (syringe packed with graphitic sorbent) was connect online with liquid chromatography tandem mass spectrometry (LC-MS/MS). In order to obtain a fast and reliable method different factors affecting MEPS performance were investigated. The extraction efficiency of the graphitic sorbent was compared with silica-based sorbents used in MEPS. The G-MEPS was also evaluated for reuse (50-100 times). The recoveries of lidocaine and ropivacaine from plasma samples were 79% and 82%; respectively. The method was validated according to FDA (Food and Drug Administration) guideline for bioanalytical method validation. Linearity was assessed in the range 5-2000nmol/L, with coefficient of determination r(2)>0,995 (n=3) for lidocaine and r(2)>0.997 (n=3) for ropivacaine. The lower limit of quantification (LLOQ) was 5nmol/L and the limit of detection (LOD) was 1nmol/L for studied analytes in plasma samples. For both analytes considered in this study the accuracy values in plasma samples were ranged from 86% to 113%. The Inter-day precisions, expressed as relative standard deviation (%RSD), at three different concentrations (QC-samples) ranged from 8% to 9% for lidocaine, and from 4% to 11% for ropivacaine. PMID- 26499974 TI - Highly efficient capillary columns packed with superficially porous particles via sequential column packing. AB - Highly efficient capillary columns packed with superficially porous particles were created for use in ultrahigh pressure liquid chromatography. Superficially porous particles around 1.5MUm in diameter were packed into fused silica capillary columns with 30, 50, and 75MUm internal diameters. To create the columns, several capillary columns were serially packed from the same slurry, with packing progress plots being generated to follow the packing of each column. Characterization of these columns using hydroquinone yielded calculated minimum reduced plate heights as low as 1.24 for the most efficient 30MUm internal diameter column, corresponding to over 500,000plates/m. At least one highly efficient column (minimum reduced plate height less than 2) was created for all three of the investigated column inner diameters, with the smallest diameter columns having the highest efficiency. This study proves that highly efficient capillary columns can be created using superficially porous particles and shows the efficiency potential of these particles. PMID- 26499975 TI - A computational study of the self-assembly of the RFFFR peptide. AB - The beta-amyloid peptide sequence, LVFFA, inspired the investigation of the fiber formation potential of the RFFFR peptide. The self-assembly was studied in silico by coarse grained-, atomistic molecular dynamics simulations and semi-empirical quantum mechanical calculations. The fiber formation was found to occur according to a three step process starting with the emergence of small aggregates that join together and form fiber segments that eventually form one continuous fiber. From a series of simulations the critical fiber concentration was determined to be in the interval between 70 mM and 100 mM. To obtain more structural information of the stable fiber, the final coarse grained configuration was backtransformed to atomistic detail. Based on this structure a 10 ns atomistic simulation was performed, which suggests that the fiber is stabilized by hydrogen bonds and water mediated hydrogen bonds. These stabilizing bonds are, however, reduced by competitive protein-water hydrogen bonds. Hence, pi-stacking is suspected to play a larger role in fiber stabilization. The pi-stacking of intermolecular Phe residues are found to favor a T-shaped stacking mode, while intramolecular pi stacking interactions assume a broad variety of modes from the parallel displaced mode to the T-shaped stacking mode and modes in between, with equal probability. Selected snapshots from the atomistic simulation were geometry optimized using semi-empirical quantum mechanical methods to validate the fiber stability and pi stacking configuration. An average Calpha-RMSD was determined to be 2.68 A. These findings indicate that the fiber may be used as a novel model system for the study of amyloid fibers or self-assembled conductive biowires, respectively. PMID- 26499976 TI - Bradykinin in ischemic conditioning-induced tissue protection: Evidences and possible mechanisms. AB - Ischemic conditioning is an intrinsic protective mechanism in which repeated short episodes of reversible ischemia protects the tissue and increases its tolerance against a subsequent longer period of ischemia (index ischemia). Bradykinin is a physiologically and pharmacologically active peptide of the kallikrein-kinin system. Besides the involvement of bradykinin in a variety of physiological and pathological responses such as pain, inflammation and in cardiovascular system as a potent vasodilator, it also acts as an endogenous cytoprotective mediator in the ischemic tissue. Pretreatment with various pharmacological modulators of bradykinin has confirmed the involvement of bradykinin in ischemic conditioning-induced protection. The protective actions of bradykinin in three major paradigms of ischemic conditioning i.e. ischemic preconditioning, ischemic postconditioning and remote ischemic preconditioning involves activation and regulation of various endogenous signaling cascades to render the heart resistant to infarction. In ischemic preconditioning, bradykinin exerts cardioprotective effect via activation of PI3K/Akt/eNOS signaling pathway and regulation of redox state via NO release. The role of bradykinin and its B2 receptors in ischemic-postconditioning induced neuroprotection has been described mainly due to its increased redox signaling cascade and activation of mitochondrial anti-apoptotic pathway. Furthermore, its cardioprotective role during remote ischemic preconditioning has been associated with activation of B2 receptors mediated neurogenic pathway and internalization of B2 receptors along with the formation of signalosomes that activates intracellular cytoprotective transduction pathways. The present review focuses on the potential role of bradykinin in mediating different forms of ischemic conditioning (pre/post/remote)-induced cardioprotection and neuroprotection along with the possible mechanisms. PMID- 26499977 TI - Role of connexin 43 in cardiovascular diseases. AB - Gap junctions (GJs) channels provide the basis for intercellular communication in the cardiovascular system for maintenance of the normal cardiac rhythm, regulation of vascular tone and endothelial function as well as metabolic interchange between the cells. They allow the transfer of small molecules and may enable slow calcium wave spreading, transfer of "death" or of "survival" signals. In the cardiomyocytes the most abundant isoform is Connexin 43 (Cx43). Alterations in Cx43 expression and distribution were observed in myocardium disease; i.e. in hypertrophic cardiomyopathy, heart failure and ischemia. Recent reports suggest the presence of Cx43 in the mitochondria as well, at least in the inner mitochondrial membrane, where it plays a central role in ischemic preconditioning. In this review, the current knowledge on the relationship between the remodeling of cardiac gap junctions and cardiac diseases are summarized. PMID- 26499978 TI - Liquid B2O3 up to 1700 K: x-ray diffraction and boroxol ring dissolution. AB - Using high energy x-ray diffraction, the structure factors of glassy and molten B2O3 were measured with high signal-to-noise, up to a temperature of T = 1710(20) K. The observed systematic changes with T are shown to be consistent with the dissolution of hexagonal [B3O6] boroxol rings, which are abundant in the glass, whilst the high-T (>~1500 K) liquid can be more closely described as a random network structure based on [BO3] triangular building blocks. We therefore argue that diffraction data are in fact qualitatively sensitive to the presence of small rings, and support the existence of a continuous structural transition in molten B2O3, for which the temperature evolution of the 808 cm-1 Raman scattering band (boroxol breathing mode) has long stood as the most emphatic evidence. Our conclusions are supported by both first-principles and polarizable ion model molecular dynamics simulations which are capable of giving good account of the experimental data, so long as steps are taken to ensure a ring fraction similar to that expected from Raman spectroscopy. The mean thermal expansion of the B-O bond has been measured directly to be alphaBO = 3.7(2) * 10-6 K-1, which accounts for a few percent of the bulk expansion just above the glass transition temperature, but accounts for greater than one third of the bulk expansion at temperatures in excess of 1673 K. PMID- 26499979 TI - Serum levels of TWEAK in patients with psoriasis vulgaris. AB - Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of a variety of inflammatory disorders and autoimmune diseases. However, studies conducted on the relationship of TWEAK and psoriasis patients are limited. In this study, we aimed to explore the serum levels of TWEAK and investigated whether TWEAK levels are associated with clinical variables and expression of other well-known psoriasis-related cytokines including IL-6, IL-23 and TNF-alpha. Forty-five patients with chronic plaque psoriasis and 43 controls were enrolled in this study. The severity of psoriasis was assessed by the Psoriasis Area and Severity Index (PASI). Serum levels of cytokines were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits. The mean TWEAK, IL-6, IL-23, and TN-alpha levels were significantly higher in psoriasis patients than in control subjects. However, there were no significant correlations between the psoriasis severity, the illness duration and serum cytokine levels. This study shows that TWEAK may be associated with the pathogenesis of psoriasis, like TNF-alpha, IL-6, and IL-23. PMID- 26499983 TI - Ebola: what it teaches us about medical ethics. A response to Angus Dawson. PMID- 26499981 TI - Estimation of changes in the force of infection for intestinal and urogenital schistosomiasis in countries with schistosomiasis control initiative-assisted programmes. AB - BACKGROUND: The last decade has seen an expansion of national schistosomiasis control programmes in Africa based on large-scale preventative chemotherapy. In many areas this has resulted in considerable reductions in infection and morbidity levels in treated individuals. In this paper, we quantify changes in the force of infection (FOI), defined here as the per (human) host parasite establishment rate, to ascertain the impact on transmission of some of these programmes under the umbrella of the Schistosomiasis Control Initiative (SCI). METHODS: A previous model for the transmission dynamics of Schistosoma mansoni was adapted here to S. haematobium. These models were fitted to longitudinal cohort (infection intensity) monitoring and evaluation data. Changes in the FOI following up to three annual rounds of praziquantel were estimated for Burkina Faso, Mali, Niger, Tanzania, Uganda, and Zambia in sub-Saharan Africa (SSA) according to country, baseline endemicity and schistosome species. Since schistosomiasis transmission is known to be highly focal, changes in the FOI at a finer geographical scale (that of sentinel site) were also estimated for S. mansoni in Uganda. RESULTS: Substantial and statistically significant reductions in the FOI relative to baseline were recorded in the majority of, but not all, combinations of country, parasite species, and endemicity areas. At the finer geographical scale assessed within Uganda, marked heterogeneity in the magnitude and direction of the relative changes in FOI was observed that would not have been appreciated by a coarser-scale analysis. CONCLUSIONS: Reductions in the rate at which humans acquire schistosomes have been achieved in many areas of SSA countries assisted by the SCI, while challenges in effectively reducing transmission persist in others. Understanding the underlying heterogeneity in the impact and performance of the control intervention at the level of the transmission site will become increasingly important for programmes transitioning from morbidity reduction to elimination of infection. Such analyses will require a fine-scale approach. The lack of association found between programmatic variables, such as therapeutic treatment coverage (recorded at district level) and changes in FOI (at sentinel site level) is discussed and recommendations are made. PMID- 26499982 TI - A qualitative analysis of the attitudes of Irish patients towards participation in genetic-based research. AB - BACKGROUND: Progress in diagnostic and therapeutic strategies in medicine is dependent upon high-quality biomedical research. Technological advances have facilitated improved understanding of disease aetiology, and rapidly emerging data promises further progress. Translating this potential into the clinic depends on patient participation in innovative clinical trials. We investigated attitudes to genetic research in Ireland, particularly with respect to commercial and financial implications. METHODS: A multi-centre, cross-sectional survey study was performed. Consecutive out-patients attending four clinics were asked to complete paper-based questionnaires. The same questionnaire was publicly available in electronic format on www.surveymonkey.com for 72 h. Data were analysed using SPSS. RESULTS: 351 questionnaires were completed (99 paper, 252 electronic). The majority of respondents were female (n = 288, 82 %), and highly educated, with 244 (70 %) attending college/university. Most participants supported genetic research (267, 76 %), more frequently for common diseases (274, 78 %) than rare disorders (204, 58 %, p < 0.001, chi 2). 103 (29 %) had participated in scientific research, and 57 (16 %) had donated material to a bio bank. The majority (n = 213, 61 %) would not support research with potential financial/commercial gain. 106 (30 %) would decline to participate in research if researchers would benefit financially, compared to 49 (14 %) if the research was supported by a pharmaceutical company (p < 0.001, chi 2). Respondents would provide buccal samples (258, 74 %) more readily than tissue (225, 64 %) or blood (222, 63 %). CONCLUSIONS: A high level of support for genetic research exists among the Irish population, but active participation is dependent upon a number of factors, notably, type of biological material required, frequency of the disease in question, and commercial interest of the researchers. PMID- 26499984 TI - Emotional reactions to human reproductive cloning. AB - BACKGROUND: Extant surveys of people's attitudes towards human reproductive cloning focus on moral judgements alone, not emotional reactions or sentiments. This is especially important given that some (especially Leon Kass) have argued against such cloning on the ground that it engenders widespread negative emotions, like disgust, that provide a moral guide. OBJECTIVE: To provide some data on emotional reactions to human cloning, with a focus on repugnance, given its prominence in the literature. METHODS: This brief mixed-method study measures the self-reported attitudes and emotions (positive or negative) towards cloning from a sample of participants in the USA. RESULTS: Most participants condemned cloning as immoral and said it should be illegal. The most commonly reported positive sentiment was by far interest/curiosity. Negative emotions were much more varied, but anxiety was the most common. Only about a third of participants selected disgust or repugnance as something they felt, and an even smaller portion had this emotion come to mind prior to seeing a list of options. CONCLUSIONS: Participants felt primarily interested and anxious about human reproductive cloning. They did not primarily feel disgust or repugnance. This provides initial empirical evidence that such a reaction is not appropriately widespread. PMID- 26499980 TI - Sonic hedgehog patterning during cerebellar development. AB - The morphogenic factor sonic hedgehog (Shh) actively orchestrates many aspects of cerebellar development and maturation. During embryogenesis, Shh signaling is active in the ventricular germinal zone (VZ) and represents an essential signal for proliferation of VZ-derived progenitors. Later, Shh secreted by Purkinje cells sustains the amplification of postnatal neurogenic niches: the external granular layer and the prospective white matter, where excitatory granule cells and inhibitory interneurons are produced, respectively. Moreover, Shh signaling affects Bergmann glial differentiation and promotes cerebellar foliation during development. Here we review the most relevant functions of Shh during cerebellar ontogenesis, underlying its role in physiological and pathological conditions. PMID- 26499985 TI - An unusual case of acute respiratory failure in a patient with pulmonary veins stenosis late after catheter ablation of atrial fibrillation: a case report and the review of the literature. AB - BACKGROUND: Atrial fibrillation (AF) can be treated with percutaneous catheter ablation procedures into the left atrium. Pulmonary veins stenosis (PV) stenosis is a severe complication of this procedure. CASE PRESENTATION: we report a case of late hemoptysis secondary to severe PV stenosis in a man who underwent AF ablation 9 months before onset of symptoms. He presented four episodes of bleeding and developed an acute respiratory failure (ARF). Parameters of respiratory mechanics and medical investigation did not show any abnormalities. Only computed tomography (CT) angiography showed stenosis of 3 out of 4 native PVs. PV balloon dilatation in all affected PVs and a stent was implanted in 1 of the 3 PVs with full restoration of respiratory function during 1 year follow-up. CONCLUSION: PV stenosis may be the underlying cause of recurrent haemoptysis after AF ablation in the presence of normal respiratory parameters. This diagnosis can be confirmed by means of CT angiography and magnetic resonance imaging can provide accurate localization of stenosis. PMID- 26499986 TI - Effects of Donor Age and Cold Ischemia on Liver Transplantation Outcomes According to the Severity of Recipient Status. AB - BackgroundProlonged cold ischemic time (CIT) and increased donor age are well known factors negatively influencing outcomes after liver transplantation (LT). AIMS: The aim of this study was to evaluate whether the magnitude of their negative effects is related to recipient model for end-stage liver disease (MELD) score. METHODS: This retrospective study was based on a cohort of 1402 LTs, divided into those performed in low-MELD (<10), moderate-MELD (10-20), and high MELD (>20) recipients. RESULTS: While neither donor age (p = 0.775) nor CIT (p = 0.561) was a significant risk factor for worse 5-year graft survival in low-MELD recipients, both were found to yield independent effects (p = 0.003 and p = 0.012, respectively) in moderate-MELD recipients, and only CIT (p = 0.004) in high-MELD recipients. However, increased donor age only triggered the negative effect of CIT in moderate-MELD recipients, which was limited to grafts recovered from donors aged >=46 years (p = 0.019). Notably, utilization of grafts from donors aged >=46 years with CIT >=9 h in moderate-MELD recipients (p = 0.003) and those with CIT >=9 h irrespective of donor age in high-MELD recipients (p = 0.031) was associated with particularly compromised outcomes. CONCLUSIONS: In conclusion, the negative effects of prolonged CIT seem to be limited to patients with moderate MELD receiving organs procured from older donors and to high-MELD recipients, irrespective of donor age. Varying effects of donor age and CIT according to recipient MELD score should be considered during the allocation process in order to avoid high-risk matches. PMID- 26499987 TI - Rotavirus-associated mild encephalopathy with a reversible splenial lesion (MERS) case report and review of the literature. AB - BACKGROUND: Rotavirus is the most common cause of severe gastroenteritis in children under the age of 5 years worldwide. It is well recognised that rotavirus can cause signs and symptoms beyond the gastrointestinal tract, including neurological manifestations such as encephalopathy. Mild encephalopathy with a reversible splenial lesion (MERS) is a clinico-radiological syndrome that has been associated with rotavirus. We report a case of a 4-year-old boy with clinically mild encephalopathy, who had an isolated splenial lesion in the corpus callosum on neuroimaging, and rotavirus RNA detected in faeces. We use this case as an opportunity to review the literature on rotavirus-associated MERS. CASE PRESENTATION: A previously healthy 4-year-old boy presented with a 2-day history of vomiting, diarrhoea, and fever, complicated by reduced level of consciousness. Magnetic resonance imaging of the brain showed a marked hyperintensity in the splenium of the corpus callosum on T2 and diffusion-weighted images. Rotavirus genome was detected by polymerase chain reaction in a stool specimen, but not in the cerebrospinal fluid. The genotype was identified as G1P8. His clinical condition improved with gradual resolution of his symptoms. No neurological complications were evident upon discharge and the patient had no recurring symptoms or significant residual defects when followed up 2 months later. CONCLUSION: MERS is a novel clinic-radiological syndrome first described in Japan. A transient splenial lesion with reduced diffusion that appears as a high signal intensity in diffusion-weighted MRI is the main diagnostic feature. Rotavirus is one of the most common agents associated with MERS, although to our knowledge only one previous case has been reported from Europe. The majority of patients appear to achieve full recovery following rotavirus-associated MERS, irrespective of treatment. This case, together with other published reports, supports the hypothesis that rotavirus-associated MERS is unlikely to be the result of direct viral invasion of the CNS. It has been suggested that MERS may be caused by intra-myelinic axonal oedema or local inflammatory cell infiltration; however, the pathogenesis remains incompletely understood. PMID- 26499988 TI - The individual, the government and the global community: sharing responsibility for health post-2015 in Vanuatu, a small island developing state. AB - INTRODUCTION: The end of 2015 will see the creation of the sustainable development goals - the new global framework for development. The process of creating universally relevant goals has involved community consultation throughout the world. Within this process it is vital that Pacific Island countries are included as they face particular development challenges due to their size and geographical location. As small island developing states, many Pacific Island countries struggle to overcome high rates of poverty and poor health outcomes. In order to include Pacific voices in the new health related sustainable development goals, Vanuatu was selected as a representative of the Pacific for this qualitative study. This paper presents the perspectives of communities throughout Vanuatu on their essential health needs and how best to meet them. METHODS: This paper examines the perspectives of 102 individuals from throughout Vanuatu. Ten focus group discussions and 2 individual interviews were conducted within communities in September 2013. Discussions focused on community perceptions of health, essential health needs, and responsibility in achieving health needs. Discussions were audio recorded and transcribed. The transcripts were then analysed using a theoretical thematic approach in order to identify central themes and subthemes. RESULTS: Individuals in this study demonstrated a comprehensive understanding of health, defining health in a holistic manner. Participants identified clear environmental and societal factors that impact upon health, and emphasized failures within the current health system as important barriers to attaining good health. Participants described the challenges faced in taking responsibility for one's health, and pointed to both the government and the international community as key players in meeting the essential health needs of communities. CONCLUSIONS: As a small island developing state, Vanuatu faces accentuated development challenges - particularly as globalisation and climate change progress. The individuals and communities in this study demonstrate a clear understanding of their needs, and show a strong desire for change. They point to both the government and the international community to assist in meeting health needs, and stress that respect for traditional governance and community involvement in decision-making are vital in this process. In order to ensure that the new health goals effectively meet local needs in Vanuatu such factors must be incorporated into policy and implementation decision-making. PMID- 26499989 TI - "Microglial nodules" and "newly forming lesions" may be a Janus face of early MS lesions; implications from virus-induced demyelination, the Inside-Out model. AB - BACKGROUND: Although the precise mechanism of initial lesion development in multiple sclerosis (MS) remains unclear, two different neuropathological findings have been reported as a potential early pathology of MS: "microglial nodules" and "newly forming lesions", both of which contain neither T cell infiltration nor demyelination. In microglial nodules, damaged axons were associated with a small number of aggregated macrophages/microglia, while oligodendrocyte apoptosis was a characteristic in newly forming lesions. However, is the presence of "microglial nodules" and "oligodendrogliopathy" mutually exclusive? Might these two different observations be the same neuropathology (as proposed by the concept, "preactive lesions"), but interpreted differently based on the different theories of early MS lesion development, using different staining methods? DISCUSSION: Since two studies are looking at two distinct aspects of early MS pathogenesis (one focused on axons and the other on oligodendrocytes), in a sense, one can say that these two studies are complementary. On the other hand, experimentally, Wallerian degeneration (WD) has been demonstrated to induce both microglial nodules and oligodendrocyte apoptosis in the central nervous system (CNS). Here, when encephalitogenic T cells are present in the periphery in both autoimmune and viral models of MS, induction of WD in the CNS has been shown to result in the recruitment of T cells along the degenerated tract, leading to demyelination (Inside-Out model). These experimental findings are consistent with early MS pathology described by both "microglial nodules" and "newly forming lesions". CONCLUSIONS: The differences between the two neuropathological findings may be based on the preference of staining methods, where one group observed axonal and microglial pathology and the other observed oligodendrocyte apoptosis; a Janus face that is looked at from the two different sides. PMID- 26499990 TI - Ameliorative effect of butylated hydroxyanisole against ferric nitrilotriacetate induced hepatotoxicity and oxidative stress in rats. AB - Ferric nitrilotriacetate (Fe-NTA) is a known renal carcinogen and has been shown to adversely induce oxidative stress and tissue toxicity after both acute and chronic exposure. Present studies were designed to study the hepatoprotective and antioxidant potential of butylated hydroxyanisole (BHA), a phenolic antioxidant used in foods on ferric nitrilotriacetate (Fe-NTA) induced hepatotoxicity in rats. Male albino rats of Wistar strain (4-6 weeks old) weighing 125-150 g were used in this study. Animals were given a single dose of Fe-NTA (9 mg/kg body weight, intraperitoneal) after a week's treatment with BHA. BHA was administered orally once daily for 7 days at doses of 1 and 2 mg/animal/day. The hepatoprotective activity was assessed using various biochemical parameters as serum transaminases (alanine transaminase (ALT), aspartate transaminase (AST)) and lactate dehydrogenase (LDH). Fe-NTA treatment increased ALT, AST, and LDH levels significantly when compared to the corresponding saline-treated group (p < 0.001). Fe-NTA also depleted the levels of glutathione and the activities of antioxidant enzymes namely glutathione reductase and glutathione-S-tranferase (p < 0.05). Pretreatment with BHA significantly decreased ALT, AST and LDH levels in a dose-dependent manner (p < 0.05). BHA also increased antioxidant enzymes level and decreased lipid peroxidation and hydrogen peroxide generation to 1.3-1.5-fold as compared to Fe-NTA-treated group. The results show the strong hepatoprotective activity of BHA which could be due to its potent antioxidant effects. PMID- 26499991 TI - Determination of genotoxic effects of boron and zinc on Zea mays using protein and random amplification of polymorphic DNA analyses. AB - In this research, we aimed to determine genotoxic effects of boron (B) and zinc (Zn) on Zea mays by using total soluble protein content and random amplification of polymorphic DNA (RAPD) analyses. For the RAPD analysis, 16 RAPD primers were found to produce unique polymorphic band profiles on treated maize seedlings. With increased Zn and B concentrations, increased polymorphism rate was observed, while genomic template stability and total soluble protein content decreased. The treatment with Zn was more effective than that of B groups on the levels of total proteins. The obtained results from this study revealed that the total soluble protein levels and RAPD profiles were performed as endpoints of genotoxicity and these analyses can offer useful biomarker assays for the evaluation of genotoxic effects on Zn and B polluted plants. PMID- 26499992 TI - Role of cysteinyl leukotriene receptor-1 antagonists in treatment of experimentally induced mammary tumor: does montelukast modulate antitumor and immunosuppressant effects of doxorubicin? AB - It has been reported that a leukotriene (LT)-D4 receptor (i.e. cysteinyl LT1 receptor; CysLT1R) has an important role in carcinogenesis. The current study was carried out to assess the possible antitumor effects of montelukast (MON), a CysLT1R antagonist, in a mouse mammary carcinoma model, that is, a solid Ehrlich carcinoma (SEC). Effects of MON on tumor-induced immune dysfunction and the possibility that MON may modulate the antitumor and immunomodulatory effects of doxorubicin (DOX) were also studied. The effects in tumor-bearing hosts of several dosings with MON (10 mg/kg, per os), with and without the added presence of DOX (2 mg/kg, intraperitoneal), were investigated in vivo; end points evaluated included assessment of tumor volume, splenic lymphocyte profiles/functionality, tumor necrosis factor-alpha content, as well as apoptosis and expression of nuclear factor-kappaB (NF-kappaB) among the tumor cells. The data indicate that MON induced significant antitumor activity against the SEC. MON treatments also significantly mitigated both tumor- and DOX-induced declines in immune parameters assessed here. Moreover, MON led to decreased NF-kappaB nuclear expression and, in doing so, appeared to chemosensitize these tumor cells to DOX-induced apoptosis. PMID- 26499993 TI - Biodegradable collagen matrix (OlogenTM) implant and conjunctival autograft for scleral necrosis after pterygium excision: two case reports. AB - BACKGROUND: Scleromalacia, in the form of scleral thinning, melting, and necrosis, is a potentially serious complication of pterygium excision. This study introduces a new biodegradable material, OlogenTM collagen matrix (OCM), to repair scleral thinning as an alternative to preserved scleral tissue, and evaluates the long-term outcomes of OCM for ocular surface reconstruction surgery. CASE PRESENTATION: Two cases of possibly mitomycin C (MMC)-associated marked scleral thinning after pterygium excision with 0.02 % topical MMC for 2 weeks were included in this study. An OCM graft at the scleral thinning area and conjunctival autograft (CAU) were performed on both patients. The scleral defect size was measured and its margin was marked with a biopsy punch. The margin of the scleral thinning area was trimmed by Vannas scissors and the OCM was cut using a circular-shape biopsy punch of the same size. The OCM was sutured with a recipient scleral wall using 10-0 nylon interrupted sutures. Free CAU was harvested from the superonasal bulbar conjunctiva with a punch biopsy 1-mm larger in diameter than that of the OCM. The previously sutured OCM bed was covered with CAU and the graft was secured with 10-0 nylon interrupted sutures. Both patients were examined periodically for over two years by assessing graft thickness and surface vascularization using a slit lamp biomicroscope. Reepithelialization of the ocular surface was observed within three to six days after surgery. Ocular discomfort and inflammation ceased in both patients as the ocular surface quickly stabilized. The entire graft site remained intact and provided a good healthy ocular surface with fluorescein stain negative intact epithelium and good vascularization of grafted conjunctiva. Epithelial defects and scleral thinning did not recur in either patient over the two year follow-up period. CONCLUSION: For treatment of a possibly MMC-associated scleral necrosis following the surgical excision of the pterygium, an OCM graft with CAU is highly recommended for good clinical outcomes and low recurrence rates. With the clinical results of this study, the new biodegradable OlogenTM collagen matrix qualifies as an alternative treatment to scleral tissue for ocular surface reconstruction. PMID- 26499994 TI - How temperature-induced variation in musculoskeletal anatomy affects escape performance and survival of zebrafish (Danio rerio). AB - Fishes are particularly sensitive to the effects of environmental conditions during early development, which can significantly impact adult morphology, performance, and survival. Previous research has highlighted the sensitivity of fishes to the effects of temperature during early development on vertebral number and muscle composition, which are both important determinants of an individual's swimming performance. In this study, we investigated the effect of developmental temperature on vertebral and muscle variation, and the subsequent effect of any variation on burst swimming performance in zebrafish (Danio rerio). Following development at a range of temperatures, all individuals were shifted to and maintained at a common temperature before startle responses were recorded and individuals were analyzed for either vertebral number or muscle composition. Our results indicate that developmental temperature does not significantly affect muscle composition, but can affect an individual's vertebral number, and that individuals with more vertebrae achieved greater displacement and velocities during C-start performance. To determine the ecological importance of this vertebral variation and to identify the potential selective factors behind it, we exposed populations of zebrafish with various vertebral numbers to native predators, needlenose garfish (Xenentodon cancila). We found that only caudal vertebral number was related to survival, and that survivors had the same caudal vertebral number across developmental temperatures. Overall, this work highlights the importance of including variation in musculoskeletal anatomy when investigating what is driving selection in fishes. J. Exp. Zool. 325A:25-40, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26499995 TI - Gut microbiota and probiotics: Focus on diabetes mellitus. AB - The characterization of gut microbiota has become an important area of research in several clinical conditions, including type 2 diabetes (T2DM). Changes in the composition and/or metabolic activity of the gut microbiota can contribute to human health. Thus, this review discusses the effects of probiotics and gut microbiota on metabolic control in these individuals. Relevant studies were obtained from electronic databases such as PubMed/Medline and ISI Web of Science. The main probiotics used in these studies belonged to the genera Lactobacillus and Bifidobacterium. The authors found seven randomized placebo-controlled clinical trials and 13 experimental studies directly related to the effect of probiotics on metabolic control in the context of T2DM. The hypothesis that gut microbiota plays a role in the development of diabetes indicates an important beginning, and the potential of probiotics to prevent and reduce the severity of T2DM is better observed in animal studies. In clinical trials, the use of probiotics in glycemic control presented conflicting results, and only few studies have attempted to evaluate factors that justify metabolic changes, such as markers of oxidative stress, inflammation, and incretins. Thus, further research is needed to assess the effects of probiotics in the metabolism of diabetic individuals, as well as the main mechanisms involved in this complex relationship. PMID- 26499996 TI - The measurement of intraocular pressure over positive soft contact lenses by rebound tonometry. AB - PURPOSE: To investigate if the accuracy of intraocular pressure (IOP) measurements using rebound tonometry over disposable hydrogel (etafilcon A) contact lenses (CL) is affected by the positive power of the CLs. METHODS: The experimental group comprised 26 subjects, (8 male, 18 female). IOP measurements were undertaken on the subjects' right eyes in random order using a Rebound Tonometer (ICare). The CLs had powers of +2.00D and +6.00D. Measurements were taken over each contact lens and also before and after the CLs had been worn. RESULTS: The IOP measure obtained with both CLs was significantly lower compared to the value without CLs (t test; p<0.001) but no significant difference was found between the two powers of CLs. CONCLUSIONS: Rebound tonometry over positive hydrogel CLs leads to a certain degree of IOP underestimation. This result did not change for the two positive lenses used in the experiment, despite their large difference in power and therefore in lens thickness. Optometrists should bear this in mind when measuring IOP with the rebound tonometer over plus power contact lenses. PMID- 26499997 TI - Survey mode influence on patient-reported outcome scores in orthopaedic surgery: telephone results may be positively biased. AB - PURPOSE: Patient-reported outcome (PRO) scores are used to evaluate treatment modalities in orthopaedic surgery. The method of PRO collection may introduce bias to reported surgical outcomes due to the presence of an interviewer. This study evaluates post-operative PROs for variation of outcomes between survey methods-in-person, online, or telephone. METHODS: From 2008 to 2011, 456 patients underwent arthroscopic surgical treatment for acetabular labral tears. All pre operative surveys were completed in the clinic during pre-operative visit. Two year follow-up questionnaires were completed by 385 (84 %) patients. The PRO data were prospectively collected pre- and post-operatively using five tools: modified Harris Hip Score (mHHS), Hip Outcome Score Activities of Daily Living (HOS-ADLS), Hip Outcome Score Sports-Specific Subscale (HOS-SSS), Non-Arthritic Hip Score (NAHS), and visual analog scale. Patients were grouped according to method of 2 year follow-up: in-person during follow-up visit (102 patients, 26 %), online by email prompt (138 patients, 36 %), or telephone with an interviewer (145 patients, 38 %). RESULTS: Pre-operative baseline PRO scores demonstrated no statistically significant difference between groups for mHHS, HOS-ADLS, HOS-SSS, and NAHS. Two-year post-operative PRO scores obtained by telephone were statistically greater than scores obtained in-person or online for mHHS (p < 0.001), HOS-ADLS (p < 0.001), and HOS-SSS (p < 0.01). CONCLUSION: This study demonstrates higher patient-reported outcome scores and greater improvement by telephone surveys compared to in-person or online. The variation of results between collection methods is indicative of a confounding variable. Clinically, it is important to understand these confounding variables in order to assess patient responses and guide treatment. LEVEL OF EVIDENCE: IV. PMID- 26499998 TI - Femoral rotation in total knee arthroplasty: a comparison of patient individualized jigs with gap balancing in relation to anatomic landmarks. AB - PURPOSE: The purpose of our study was to compare the accuracy of the rotational position of the femoral component in total knee arthroplasty aligned with patient individualized jigs (PSJ) to a gap balancing technique (GBT). METHODS: A consecutive series of 21 osteoarthritic patients were treated with 22 cruciate retaining total knee prostheses. During surgery, the rotation of the femoral component pinholes was recorded for all knees using PSJ and GBT and transferred to computer tomograms (CT). The rotational differences between PSJ and GBT relative to the transepicondylar axis were analysed. RESULTS: The medium rotation of the femoral component pinholes was 1.3 degrees +/- 5.1 degrees (min = -6.3 degrees ; max = 14.4 degrees ) for PSJ and 0.1 +/- 1.4 degrees (min = -1.6 degrees ; max = 3.4 degrees ) for GBT. Outliers of more than 3 degrees were found more frequently with PSJ in 12 cases but only in one for GBT. CONCLUSION: Based on our study, we would not recommend relying intra-operatively solely on the CT-based PSJ without the option to adjust or control femoral rotation. LEVEL OF EVIDENCE: II. PMID- 26499999 TI - Patterns and predictors of early mortality among emergency department patients in Addis Ababa, Ethiopia. AB - BACKGROUND: Ethiopian emergency department (ED) patients have a considerable burden of illness and injury for which all-cause mortality rates have not previously been published. This study sought to characterize the burden of and to identify predictors for early all-cause mortality among patients presenting to the Tikur Anbessa Specialized Hospital ED (TASH-ED) in Ethiopia. METHODS: Data was prospectively collected from the records of all patients who died within 72 h of ED presentation. Pearson's Chi square and Fisher's exact tests were used to investigate associations between two outcome variables: (a) time to death and (b) immediate cause of death in relation to specific demographic and clinical factors. Time from ED presentation to death was dichotomized as 'very early' mortality within <=6 h and death >6-72 h and logistic regression was used to assess the adjusted impact of these demographic and clinical variables on the probability of dying within 6 h of ED presentation. RESULTS: Between October 2012 and May 2013, 9956 patients visited the ED and 220 patients died within 72 h of admission. After excluding patients dead on arrival (n = 34), the average age of death was 43.1 years and the overall mortality rate was 1.9 %. Head injury (21.5 %) and sepsis (18.8 %) were the most common causes of death. Relative to medical patients, trauma patients were more likely to be male (p < 0.01), less likely to have had prior recent ED visits (p < 0.01) and more likely to be triaged as higher acuity (p = 0.04). The sole statistically significant predictor of death within 6 h from our multivariable logistic regression model was symptom duration less than 4 h (4-48 h vs. <4 h: OR = 0.20, 95 % CI 0.07, 0.53, p < 0.01; >48 h vs. <4 h: OR = 0.27, 95 % CI 0.09, 0.81, p = 0.02). CONCLUSIONS: The mortality burden of trauma and sepsis in the TASH-ED is substantial, and mortality patterns differ between these groups. As emergency medicine develops as a specialty in the Ethiopian health system, the potential impact of context-specific clinical care protocol development, trauma prevention advocacy and ED care re-organization initiatives to reduce mortality among these young, previously well patients warrants exploration. PMID- 26500000 TI - Recurrent nocturnal hypoglycaemia as a cause of morning fatigue in treated Addison's disease--favourable response to dietary management: a case report. AB - BACKGROUND: Addison's disease, or primary adrenal insufficiency, is often associated with reduced well-being and fatigue despite use of currently recommended adrenal hormone replacement. Hypoglycaemia is a known manifestation of glucocorticoid deficiency, but is generally considered rare in adults and not relevant to troubling ongoing symptoms in patients with Addison's disease. CASE PRESENTATION: A 43 year old woman with a three year history of Addison's disease complained of severe morning fatigue and headaches, despite standard glucocorticoid replacement therapy in the form of thrice daily hydrocortisone and mineralocorticoid replacement with fludrocortisone. Alternative glucocorticoid replacement regimens and the addition of dehydroepiandrosterone replacement therapy had no effect. Nocturnal hypoglycaemia was suspected and a 4-day continuous glucose monitor system (CGMS) revealed hypoglycaemia (interstitial glucose < 2.2 mmol/L) between 0200-0400 h on 3 of 4 days. The patient was counselled to take an evening snack designed to ensure slow absorption of ingested carbohydrates. Nocturnal hypoglycaemia was then absent on follow up CGMS assessment. The patient noted a marked symptomatic improvement in morning symptoms, but with persistent fatigue during the day. CONCLUSION: Currently, the best strategy for control of non-specific symptoms in treated Addison's disease is unknown, but it may be that investigation for hypoglycaemia and treatment, where necessary, could assist some sufferers to achieve improved wellbeing. A systematic study of this phenomenon in Addison's disease is required. PMID- 26500001 TI - Lungs exposed to 1 hour warm ischemia without heparin before harvesting might be suitable candidates for transplantation. AB - BACKGROUND: The limiting factor for lung transplantation is the lack of donor organs. The usage of lungs from donation after cardiac death (DCD) would dramatically increase donor availability. In the present paper we wanted to investigate lungs exposed to 1 h of warm ischemia without heparin followed by flush-perfusion and cold storage compared to lungs harvested from heart beating donors (HBD) using standard harvesting technique. METHODS: Twelve Swedish domestic pigs were randomized into two groups. Six pigs (DCD group) underwent ventricular fibrillation and were then left untouched for 1 h after declaration of death. They did not receive heparin. The lungs were then harvested and flush perfused with Perfadex(r) solution and the organs were stored at 8 degrees C for 4 h. Six pigs (HBD group) received heparin and the lungs were harvested and flush perfused with Perfadex(r) solution and the organs were stored at 8 degrees C for 4 h. Lung function was evaluated, using ex vivo lung perfusion (EVLP), with blood gases at different oxygen levels, pulmonary vascular resistance (PVR), lung weight, and macroscopic appearance. RESULTS: At FiO2 1.0, the PaO2 in the DCD group was 51.7 +/- 2.0 kPa and in the HBD group 68.6 +/- 2.4 kPa (p < 0.01). Significantly lower PVR levels were measured in the DCD group (372 +/- 31 dyne x s/cm(5)) compared to the HBD group (655 +/- 45 dyne x s/cm(5)) (p < 0.001). There was no significant difference between groups in weight, compliance or signs of pulmonary thrombosis or embolization. CONCLUSIONS: It seems as if DCD lungs exposed to 1 h of warm ischemia before 4 h of cold storage has satisfying oxygenation capacity, low PVR, normal weight and no signs of thrombosis or embolization. According to our study it seems as lungs exposed to 1 h warm ischemia without heparin might be good candidates for transplantation. PMID- 26500002 TI - Multicenter analytical performance evaluation of a fully automated anti-Mullerian hormone assay and reference interval determination. AB - OBJECTIVES: Anti-Mullenria hormone (AMH) is an established biomarker for assessing ovarian reserve and predicting response to controlled ovarian stimulation. Its routine clinical use is hampered by the variability and low throughput of available enzyme-linked immunosorbent assays (ELISA). The presented study examined if a fully automated AMH electrochemiluminescence assay (ECLIA; Elecsys(r) AMH assay, Roche Diagnostics) was suitable for measuring AMH levels in healthy women and in those diagnosed with polycystic ovary syndrome (PCOS). DESIGN AND METHODS: Five European laboratories evaluated the Elecsys(r) AMH assay independently under routine conditions over eight months. Within-run imprecision, repeatability, intermediate precision, linearity and functional sensitivity were assessed. The Elecsys(r) AMH assay was compared to a manual ELISA microtiter plate format test (AMH Gen II ELISA, modified version; Beckman Coulter Inc.) using 1729 routine serum samples. AMH reference intervals were determined in 887 healthy women with regular menstrual cycle aged 20-50 years, and 149 women diagnosed with PCOS. RESULTS: The fully automated Elecsys(r) AMH assay showed excellent precision, linearity, and functional sensitivity. The coefficient of variation was 1.8% for repeatability and 4.4% for intermediate precision. Values measured with the Elecsys(r) AMH assay were highly correlated with the manual ELISA method (modified version) but 24-28% lower. Reference intervals showed the expected AMH decline with age in healthy women and increased AMH levels in women with PCOS. CONCLUSIONS: The Elecsys(r) AMH assay demonstrated good precision under routine conditions, and is suitable for determining AMH levels in serum and lithium-heparin plasma. PMID- 26500003 TI - N-acetylcysteine interference of Trinder-based assays. AB - OBJECTIVES: The primary objective of this study was to evaluate potential interference of Trinder-based chemistry assays by N-acetylcysteine (NAC). A secondary objective was to look for evidence of interference in patients treated with NAC for acetaminophen (APAP) overdose. DESIGN AND METHODS: Dilutions of NAC in plasma were tested for interference using the following Roche Diagnostics Trinder-based assays on a cobas 8000 system: enzymatic creatinine (Cr), cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), triglycerides (TRIG), and uric acid (UA). Two non-Trinder Roche assays - urea nitrogen (BUN) and glucose (GLUC) - were tested as controls. Sekisui N-geneous(r) low-density lipoprotein cholesterol (LDL-C) reagent was also evaluated. Retrospective chart review of APAP overdose cases over 49months was conducted to look for differences in plasma Cr before and after intravenous (IV) NAC administration. RESULTS: NAC concentrations (shown in parentheses) that caused >=10% inhibition for individual assays were (in order of sensitivity to interference): TRIG (570mg/L)>CHOL (740mg/L)~Cr (790mg/L)>UA (1100mg/L)>HDL-C (1760mg/L)>LDL-C (2900mg/L). Neither BUN nor GLUC achieved significant inhibition up to 10,000mg/L NAC. Evidence for relatively minor inhibition of Cr was observed in patients after NAC administration. CONCLUSIONS: NAC inhibition of the assays investigated typically occurs at concentrations higher than expected during IV and oral NAC therapy. PMID- 26500004 TI - Identification and frequencies of cystic fibrosis mutations in central Argentina. AB - BACKGROUND: The Argentinian population is mainly of Caucasian origin, with a small contingent of indigenous descent. The aim of this study is to test the hypothesis that a panel of mutations designed for European countries is not optimal as a first-line molecular diagnosis for routine use in this country of mixed European origin. METHODS: Phenotype analyses combined with a European screening panel of 71 mutations followed by Sanger sequencing and large rearrangement study, were used to characterize the identification and distribution of CFTR mutations in the Santa Fe province of Argentina. RESULTS: Clinical review of 121 subjects suspected of CF during childhood led to selection of 83 unrelated patients. Thirty four different mutations, including two new ones, c.2554dupT and p.Leu49Pro, were detected. The total sensitivity was 91% (n = 151/166 alleles). CONCLUSIONS: Frequencies of CFTR mutations in Argentinian populations differ from those of their European ancestry. A new first line panel of 21 CFTR mutations with a sensitivity of 84% is proposed for routine use in central Argentina. PMID- 26500005 TI - Erectile dysfunction and diabetes: Association with the impairment of lipid metabolism and oxidative stress. AB - OBJECTIVES: To test the hypothesis that exists an association of non-diabetic and diabetic patients suffering from erectile dysfunction (ED) with lipid metabolism and oxidative stress. DESIGN AND METHODS: Clinical and laboratory characteristics in non-diabetic (n = 30, middle age range: 41-55.5 years; n = 25, old age range: 55.5-73), diabetic ED patients (n = 30, age range: 55.5-75 years) and diabetic patients (n = 25, age range: 56-73.25), were investigated. Proteomic analysis was performed to identify differentially expressed plasma proteins and to evaluate their oxidative posttranslational modifications. RESULTS: A decreased level of high-density lipoproteins in all ED patients (P < 0.001, C.I. 0.046-0.10), was detected by routine laboratory tests. Proteomic analysis showed a significant decreased expression (P < 0.05) of 5 apolipoproteins (i.e. apolipoprotein H, apolipoprotein A4, apolipoprotein J, apolipoprotein E and apolipoprotein A1) and zinc-alpha-2-glycoprotein, 50% of which are more oxidized proteins. Exclusively for diabetic ED patients, oxidative posttranslational modifications for prealbumin, serum albumin, serum transferrin and haptoglobin markedly increased. CONCLUSIONS: Showing evidence for decreased expression of apolipoproteins in ED and the remarkable enhancement of oxidative posttranslational modifications in diabetes-associated ED, considering type 2 diabetes mellitus and age as independent risk factors involved in the ED pathogenesis, lipid metabolism and oxidative stress appear to exert a complex interplay in the disease. PMID- 26500006 TI - Heat shock protein 70 and antibodies to heat shock protein 60 are associated with cerebrovascular atherosclerosis. AB - OBJECTIVES: Heat shock proteins (Hsps) are produced by all cells, including vascular, to ensure stress protection. Damaged cells release Hsps in their local environment and systemic circulation. The aim of this study was to investigate the involvement and prognostic utility of serum Hsp60 and Hsp70, and the respective antibodies anti-Hsp60 and anti-Hsp70 in subjects with advanced atherosclerosis resulting in high degree of cerebrovascular stenosis. DESIGN AND METHODS: Ultrasound Doppler examination of carotid arteries was used to discriminate between control and cerebrovascular atherosclerosis subjects. Twenty eight subjects without carotid obstruction were selected as controls. Fifty patients with obstruction of cerebrovascular blood flow were evaluated for the degree of stenosis of cerebral arteries by digital subtraction angiography. In parallel, serum concentrations of Hsp60, Hsp70, anti-Hsp60 and anti-Hsp70 were measured by ELISA kits. RESULTS: Anti-Hsp60 was significantly higher (P=0.003) in the atherosclerosis group than in the control group (23.62ng/L vs. 15.28ng/L, respectively, expressed as median). Circulating Hsp70 was lower in the atherosclerosis than in the control group (P=0.048), with respective median values of 0.00MUg/L vs. 0.22MUg/L. Concentrations of Hsp60 and anti-Hsp70 did not differ significantly between the control and atherosclerosis group. CONCLUSIONS: Higher circulating anti-Hsp60 is associated with advanced cerebrovascular atherosclerosis as a consequence of the autoimmunity part of the inflammation and bursting of atherosclerosis. Higher levels of Hsp70 observed in the control group could be protective in the development of atherosclerotic changes. PMID- 26500008 TI - Erratum to: Phenylephrine Pharmacokinetics and First-Pass Metabolism: What Is an Ideal Pharmacokinetic Surrogate? PMID- 26500007 TI - Pedicle screw placement accuracy in thoracic and lumbar spinal surgery with a patient-matched targeting guide: a cadaveric study. AB - PURPOSE: Pedicle screw placement is an increasingly common procedure for the correction of spine degenerative disease, deformity and trauma. However, screw placement is demanding, with complications resulting from inaccurate screw placement. While several different techniques have been developed to improve accuracy, they all have their limitations. METHODS: We examined the MySpine (Medacta International SA, Castel San Pietro, CH) patient-matched pedicle targeting guide in three cadaveric spine specimens operated on by three surgeons. A three-dimensional (3D) preoperative plan was constructed from spinal computed tomography scans, from which individualised guides were developed for the placement of Medacta Unconstrained Screw Technology pedicle screws. Following screw placement, the 3D positioning of the screws was compared to the preoperative plan against a series of pre-defined criteria. RESULTS: Of 46 inserted screws eligible for assessment, 91.3 % were fully inside the pedicle. There were no cases of Grade B (2-4 mm) or C (>4 mm) pedicle perforation. The mean deviation between the planned and actual screw position at the midpoint of the pedicle was 0.70 mm, the mean horizontal deviation was 0.60 mm and the mean vertical deviation was 0.77 mm. The mean angular deviation in the sagittal plane was 1.74 degrees , versus 1.32 degrees in the transverse plane. The mean deviation in screw depth was 1.55 mm. On all measures, the accuracy of screw placement was within the predefined criteria. CONCLUSIONS: Our cadaver study indicates that pedicle screw placement with the system is accurate and should be investigated in larger in vitro and in vivo studies. PMID- 26500009 TI - The Greek financial crisis: maintaining medical education against the odds. PMID- 26500010 TI - Pediatric Emergency Care Applied Research Network head injury clinical prediction rules are reliable in practice. AB - OBJECTIVE: The Pediatric Emergency Care Applied Research Network (PECARN) traumatic brain injury (TBI) age-based clinical prediction rules identify children at very low risk of a significant head injury who can safely avoid CT. Our goal was to independently validate these prediction rules. DESIGN: Cross sectional study. SETTING: Two paediatric emergency departments located in USA and in Italy. PATIENTS: All children presenting within 24 h of a head injury with a Glasgow Coma Score of >= 14. INTERVENTION: Assessment of PECARN TBI clinical predictors. MAIN OUTCOME MEASURE: Clinically important TBI defined as head injury resulting in death, intubation for >24 h, neurosurgery or two or more nights of hospitalisation for the management of head trauma. RESULTS: During the study period, we included 2439 children (91% of eligible patients), of which 959 (39%) were < 2 years of age and 1439 (59%) were male. Of the study patients, 373 (15%) had a CT performed, 69 (3%) had traumatic findings on their CT and 19 (0.8%) had a clinically important TBI. None of the children with a clinically important TBI were classified as very low risk by the PECARN TBI prediction rules (overall sensitivity 100%; 95% CI 83.2% to 100%, specificity 55%, 95% CI 52.5% to 56.6%, and negative predictive value 100%, 95% CI 99.6% to 100%). CONCLUSIONS: In our external validation, the age-based PECARN TBI prediction rules accurately identified children at very low risk for a clinically significant TBI and can be used to assist CT decision making for children with minor blunt head trauma. PMID- 26500011 TI - Minocycline-induced pigmentation of the skin and nails. PMID- 26500012 TI - Guidelines and Mindlines. PMID- 26500013 TI - Astroglial beta-Arrestin1-mediated Nuclear Signaling Regulates the Expansion of Neural Precursor Cells in Adult Hippocampus. AB - Adult hippocampal neurogenesis is crucial for preserving normal brain function, but how it is regulated by niche cells is uncertain. Here we show that beta arrestin 1 (beta-arr1) in dentate gyrus (DG) regulates neural precursor proliferation. beta-arr1 knockout (KO) mice show reduced neural precursor proliferation in subgranular zone (SGZ) which could be rescued by selective viral expression of beta-arr1 but not its nuclear-function-deficient mutants under control of hGFAP promotor in DG. Compared with wild type astrocytes, beta-arr1 KO astrocytes nurture less neurospheres, and this may be attributed to changed activity of soluble, heat-sensitive excretive factors, such as BMP2. RNA sequencing reveals that beta-arr1 KO DG astrocytes exhibit an aberrant gene expression profile of niche factors, including elevated transcription of Bmp2. Taken together, our data suggest that beta-arr1 mediated nuclear signaling regulates the production of excretive factors derived from niche astrocytes and expansion of neural precursors in DG, thus maintaining homeostasis of adult hippocampal neurogenesis. PMID- 26500014 TI - Guidelines for quantification of noise-induced hearing loss in a medicolegal context. AB - OBJECTIVES: Guidelines published in 2000 by the authors are widely used by medical and legal professionals in the UK for diagnosis of noise-induced hearing loss in a medicolegal context. However, they cannot be used for quantification of the noise-induced hearing loss, which is required in most cases. This requirement is addressed. DESIGN: A method is developed here to quantify noise-induced hearing loss, thereby overcoming this shortcoming. SETTING: Assessment of noise induced hearing loss in medicolegal cases. PARTICIPANTS: A consecutive series of 124 cases of noise-induced hearing loss is used for evaluation. MAIN OUTCOME MEASURE: Magnitude of noise-induced hearing loss based on hearing threshold levels averaged over the frequencies 1, 2 and 3 kHz. RESULTS: The rationale of the method, practical application and three worked examples are developed. A simpler short-cut method is developed and shown to be equivalent to the full method in most cases. CONCLUSIONS: The method offers a practical approach to quantification of noise-induced hearing loss. PMID- 26500015 TI - Changes in soil oribatid communities associated with conversion from conventional to organic agriculture. AB - We investigated the effects of switching from conventional management to organic management on the abundance and community composition of soil-living oribatid mites in clover fields in an experimental agricultural station at Al-Fayoum, Egypt. The site had two adjacent fields with identical vegetation cover but different management. Fifteen random soil samples were collected monthly from each of three plots per field, from October to March. We characterized the soils with respect to various physicochemical variables as well as fungal community composition, and estimated mite densities through core sampling. Organic fields had a significantly more abundant oribatid community than did conventional fields. Also the abundance of soil fungi was greater in the organically managed field. Organic management promoted common oribatid mite species with a wide ecological amplitude that already had a high abundance where such common species are more responsive to changes in agricultural management. However, some species of mite responded indifferent or negative to the switch from conventional to organic management. Overall, the differences between the two ecological systems were mainly quantitative. Species diversities of both mite and fungal communities did not differ much between the two management systems. Diversity (H0) and equitability (E) of soil oribatid communities were higher in conventional plots than in the organic plots during the first 2 months but indistinguishable thereafter. Our study confirmed that organic management stimulates soilorganic matter build-up, with positive effects on both fungal and oribatid mite abundance and possible long-term effects on soil function. PMID- 26500016 TI - The diagnostic utility of exome sequencing in Joubert syndrome and related disorders. PMID- 26500017 TI - FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion. PMID- 26500018 TI - The NAC transcription factor family in maritime pine (Pinus Pinaster): molecular regulation of two genes involved in stress responses. AB - BACKGROUND: NAC transcription factors comprise a large plant-specific gene family involved in the regulation of diverse biological processes. Despite the growing number of studies on NAC transcription factors in various species, little information is available about this family in conifers. The goal of this study was to identify the NAC transcription family in maritime pine (Pinus pinaster), to characterize ATAF-like genes in response to various stresses and to study their molecular regulation. METHODS: We have isolated two maritime pine NAC genes and using a transient expression assay in N. benthamiana leaves estudied the promoter jasmonate response. RESULTS: In this study, we identified 37 NAC genes from maritime pine and classified them into six main subfamilies. The largest group includes 12 sequences corresponding to stress-related genes. Two of these NAC genes, PpNAC2 and PpNAC3, were isolated and their expression profiles were examined at various developmental stages and in response to various types of stress. The expression of both genes was strongly induced by methyl jasmonate (MeJA), mechanical wounding, and high salinity. The promoter regions of these genes were shown to contain cis-elements involved in the stress response and plant hormonal regulation, including E-boxes, which are commonly found in the promoters of genes that respond to jasmonate, and binding sites for bHLH proteins. Using a transient expression assay in N. benthamiana leaves, we found that the promoter of PpNAC3 was rapidly induced upon MeJA treatment, while this response disappeared in plants in which the transcription factor NbbHLH2 was silenced. CONCLUSION: Our results suggest that PpNAC2 and PpNAC3 encode stress responsive NAC transcription factors involved in the jasmonate response in pine. Furthermore, these data also suggest that the jasmonate signaling pathway is conserved between angiosperms and gymnosperms. These findings may be useful for engineering stress tolerance in pine via biotechnological approaches. PMID- 26500020 TI - Erythematous and edematous plaques on the bilateral extremities in an immunocompromised patient. Protothecosis. PMID- 26500019 TI - A randomized controlled trial of web-based cognitive behavioral therapy for severely fatigued breast cancer survivors (CHANGE-study): study protocol. AB - BACKGROUND: About one third of breast cancer survivors suffer from persistent severe fatigue after completion of curative cancer treatment. Face-to-face cognitive behavioral therapy (F2F CBT), especially designed for fatigue in cancer survivors, was found effective in reducing fatigue. However, this intervention is intensive and treatment capacity is limited. To extend treatment options, a web based version of CBT requiring less therapist time was developed. This intervention is aimed at changing fatigue-perpetuating cognitions and behaviors. The efficacy of web-based CBT will be examined in a multicenter randomized controlled trial. METHODS: In total, 132 severely fatigued breast cancer survivors will be recruited and randomized to either an intervention condition or care as usual (ratio 1:1). Participants will be assessed at baseline and 6 months thereafter. The intervention group will receive web-based CBT, consisting of three F2F sessions and maximally eight web-based modules over a period of 6 months. The care as usual group will be on a waiting list for regular F2F CBT. The total duration of the waiting list is 6 months. The primary outcome of the study is fatigue severity. Secondary outcomes are functional impairments, psychological distress and quality of life. DISCUSSION: If web-based CBT is effective, it will provide an additional treatment option for fatigue in breast cancer survivors. Web-based CBT is expected to be less time-consuming for therapists than regular F2F CBT, which would result in an increased treatment capacity. Moreover, the intervention would become more easily accessible for a larger number of patients, and patients can save travel time and costs. TRIAL REGISTRATION: Dutch Trial Registry--NTR4309. PMID- 26500021 TI - Heparin-binding EGF-like growth factor (HB-EGF) stimulates the proliferation of Muller glia-derived progenitor cells in avian and murine retinas. AB - Muller glia can be stimulated to de-differentiate, proliferate and form Muller glia-derived progenitor cells (MGPCs) that regenerate retinal neurons. In the zebrafish retina, heparin-binding EGF-like growth factor (HB-EGF) may be one of the key factors that stimulate the formation of proliferating MGPCs. Currently nothing is known about the influence of HB-EGF on the proliferative potential of Muller glia in retinas of birds and rodents. In the chick retina, we found that levels of both hb-egf and egf-receptor are rapidly and transiently up-regulated following NMDA-induced damage. Although intraocular injections of HB-EGF failed to stimulate cell-signaling or proliferation of Muller glia in normal retinas, HB EGF stimulated proliferation of MGPCs in damaged retinas. By comparison, inhibition of the EGF-receptor (EGFR) decreased the proliferation of MGPCs in damaged retinas. HB-EGF failed to act synergistically with FGF2 to stimulate the formation of MGPCs in the undamaged retina and inhibition of EGF-receptor did not suppress FGF2-mediated formation of MGPCs. In the mouse retina, HB-EGF stimulated the proliferation of Muller glia following NMDA-induced damage. Furthermore, HB EGF not only stimulated MAPK-signaling in Muller glia/MGPCs, but also activated mTor- and Jak/Stat-signaling. We propose that levels of expression of EGFR are rate-limiting to the responses of Muller glia to HB-EGF and the expression of EGFR can be induced by retinal damage, but not by FGF2-treatment. We conclude that HB-EGF is mitogenic to Muller glia in both chick and mouse retinas, and HB EGF is an important player in the formation of MGPCs in damaged retinas. PMID- 26500022 TI - Activation of inflammasome by attenuated Salmonella typhimurium in bacteria mediated cancer therapy. AB - Escherichia coli and attenuated Salmonella both naturally accumulate in a tumor mass, yet have distinct therapeutic efficacy: the E. coli K-12 strain (MG1655) cannot induce as significant a tumor suppression as attenuated Salmonella typhimurium, despite similar levels of accumulation in the tumor. To elucidate the mechanism of the robust antitumor effect of S. typhimurium, the cytokine profiles elicited by bacterial colonization in tumors were analyzed. C57BL/6 mice bearing MC38 tumors were injected with Salmonella or MG1655 in the tail vein. Tumors were collected 3 days post-infection and homogenized. Inflammasome-related signals were measured by real-time PCR, ELISA and western blot analysis. Only attenuated Salmonella triggered significant levels of the inflammatory cytokine IL-1beta in the tumor, whereas tumor growth was significantly suppressed. In addition, transcript levels of the core molecules of inflammasome signaling, IPAF, NLRP3 and P2X7, were significantly elevated only in Salmonella-treated tumors. Upon direct interaction between Salmonella and BMDM, BMDM expressed inflammasome-related proteins such as NLRP3, IPAF and caspase-1 p10, and secreted a significant amount of IL-1beta in supernatants. Coincubation assays with BMDM and Salmonella-treated MC38 cells (damaged cancer cells) revealed secretion of IL 1beta only when TLR4 and inflammasome were activated by both LPS and damaged cancer cells. ATP released from damaged cancer cells was also identified as a mechanism of NLRP3 activation. In conclusion, Salmonella activate the inflammasome pathway using damage signals released from cancer cells and through direct interaction with macrophages. PMID- 26500023 TI - Cross-Talk Between Ionic and Nanoribbon Current Signals in Graphene Nanoribbon Nanopore Sensors for Single-Molecule Detection. AB - Nanopores are now being used not only as an ionic current sensor but also as a means to localize molecules near alternative sensors with higher sensitivity and/or selectivity. One example is a solid-state nanopore embedded in a graphene nanoribbon (GNR) transistor. Such a device possesses the high conductivity needed for higher bandwidth measurements and, because of its single-atomic-layer thickness, can improve the spatial resolution of the measurement. Here measurements of ionic current through the nanopore are shown during double stranded DNA (dsDNA) translocation, along with the simultaneous response of the neighboring GNR due to changes in the surrounding electric potential. Cross-talk originating from capacitive coupling between the two measurement channels is observed, resulting in a transient response in the GNR during DNA translocation; however, a modulation in device conductivity is not observed via an electric field-effect response during DNA translocation. A field-effect response would scale with GNR source-drain voltage (Vds), whereas the capacitive coupling does not scale with Vds . In order to take advantage of the high bandwidth potential of such sensors, the field-effect response must be enhanced. Potential field calculations are presented to outline a phase diagram for detection within the device parameter space, charting a roadmap for future optimization of such devices. PMID- 26500024 TI - Pediatric sleep-disordered breathing: New evidence on its development. AB - Sleep-disordered breathing (SDB) in children could be resolved by adenotonsillectomy (T&A). However, incomplete results are often noted post surgery. Because of this partial resolution, long-term follow-up is needed to monitor for reoccurrence of SDB, which may be diagnosed years later through reoccurrence of complaints or in some cases, through systematic investigations. Children undergoing T&A often have small upper airways. Genetics play a role in the fetal development of the skull, the skull base, and subsequently, the size of the upper airway. In non-syndromic children, specific genetic mutations are often unrecognized early in life and affect the craniofacial growth, altering functions such as suction, mastication, swallowing, and nasal breathing. These developmental and functional changes are associated with the development of SDB. Children without genetic mutations but with impairment of the above said functions also develop SDB. When applied early in life, techniques involved in the reeducation of these functions, such as myofunctional therapy, alter the craniofacial growth and the associated SDB. This occurs as a result of the continuous interaction between cartilages, bones and muscles involved in the growth of the base of the skull and the face. Recently collected data show the impact of the early changes in craniofacial growth patterns and how these changes lead to an impairment of the developmental functions and consequent persistence of SDB. The presence of nasal disuse and mouth breathing are abnormal functions that are easily amenable to treatment. Understanding the dynamics leading to the development of SDB and recognizing factors affecting the craniofacial growth and the resulting functional impairments, allows appropriate treatment planning which may or may not include T&A. Enlargement of lymphoid tissue may actually be a consequence as opposed to a cause of these initial dysfunctions. PMID- 26500025 TI - Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF). AB - In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primary AML blasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML cell lines. Cytotoxicity of PrAgU2/LF appeared to be nonapoptotic and was associated with MAPK activation and urokinase activity because all the PrAgU2/LF-sensitive cell lines showed both uPAR expression and high levels of MEK1/2 phosphorylation. Inhibition of uPAR or desensitization of cells to MEK1/2 inhibition blocked toxicity of PrAgU2/LF, indicating requirement for both uPAR expression and MAPK activation for activity. PrAgU2/LF was also cytotoxic to primary blasts from AML patients, with blasts from four out of five patients showing a cytotoxic response to PrAgU2/LF. Cytotoxicity of primary AML blasts was also dependent on uPAR expression and phos-MEK1/2 levels. CD34(+) bone marrow blasts and peripheral blood mononuclear cells lacked uPAR expression and were resistant to PrAgU2/LF, demonstrating the lack of toxicity to normal hematological cells and, therefore, the tumor selectivity of this approach. Dose escalation in mice revealed that the maximal tolerated dose of PrAgU2/LF is at least 5.7-fold higher than that of the wild-type anthrax lethal toxin, PrAg/LF, further demonstrating the increased safety of this molecule. We have shown, in this study, that PrAgU2/LF is a novel, dual-specific molecule for the selective targeting of AML. PMID- 26500026 TI - A Preclinical Model of Inflammatory Breast Cancer to Study the Involvement of CXCR4 and ACKR3 in the Metastatic Process. AB - Inflammatory breast cancer (IBC) is an aggressive and invasive tumor, accounting for 2.5% of all breast cancer cases, and characterized by rapid progression, regional and distant metastases, younger age of onset, and lower overall survival. Presently, there are no effective therapies against IBC and a paucity of model systems. Our aim was to develop a clinically relevant IBC model that would allow investigations on the role of chemokine receptors in IBC metastasis. Primary cultures of tumor cells were isolated from pleural exudates of an IBC patient and grown as spheres or monolayers. We developed a human xenograft model where patient-derived IBC cells, stably transduced with lentiviral vectors expressing fluorescent and bioluminescent markers, were inoculated directly into the left ventricle of mice. Our in vivo data show that these IBC cells (FC IBC02A) are able to seed and proliferate into various organs, including brain, lungs, lymph nodes, and bone, closely replicating the metastatic spread observed in IBC patients. Moreover, cells were able to generate tumors when grafted in the mammary fat pad of mice. RT-PCR and microscopy studies revealed expression of both CXCR4 and ACKR3 receptors in FC-IBC02A cells. Furthermore, CXCL12 (the endogenous chemokine ligand of these receptors) induced transendothelial migration of these cells and stimulated signaling pathways involved in cell survival and migration - an effect reduced by CXCR4 or ACKR3 antagonists. This new model can be used to develop chemokine-based pharmacological approaches against the IBC metastatic process. This work also provides the first evidence of ACKR3 expression in IBC cells. PMID- 26500027 TI - Targeting Suppressor of Variegation 3-9 Homologue 2 (SUV39H2) in Acute Lymphoblastic Leukemia (ALL). AB - Although recent progress in understanding the biology and optimizing the treatment of acute lymphoblastic leukemia (ALL) has improved cure rates of childhood ALL to nearly 90%, the cure rate in adult ALL remains less than 50%. The poor prognosis in adult ALL has in part been attributed to larger proportion of high-risk leukemia showing drug resistance. Thus, identifying novel therapeutic targets in ALL is needed for further improvements in treatment outcomes of adult ALL. Genetic aberration of chromatin-modifying molecules has been recently reported in subtypes of ALL, and targeting components of chromatin complexes has shown promising efficacy in preclinical studies. Suppressor of variegation 3-9 homologue 2 (SUV39H2), also known as KMT1B, is a SET-domain containing histone methyltransferase that is upregulated in solid cancers, but its expression is hardly detectable in normal tissues. Here, we show that SUV39H2 is highly expressed in ALL cells but not in blood cells from healthy donors and also that SUV39H2 mRNA is expressed at significantly higher levels in bone marrow or blood cells from patients with ALL obtained at diagnosis compared with those obtained at remission (P = .007). In four ALL cell lines (Jurkat and CEM derived from T-ALL and RS4;11 and REH derived from B-ALL), SUV39H2 knockdown resulted in a significant decrease in cell viability (~77%, P < .001), likely through induction of apoptosis. On the other hand, SUV39H2 overexpression made cells more resistant to chemotherapy. We conclude that SUV39H2 is a promising therapeutic target and further investigation of this therapeutic approach in ALL is warranted. PMID- 26500028 TI - Overcoming Chemoresistance of Pediatric Ependymoma by Inhibition of STAT3 Signaling. AB - The long-term clinical outcome of pediatric intracranial epepdymoma is poor with a high rate of recurrence. One of the main reasons for this poor outcome is the tumor's inherent resistance to chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is overactive in many human cancers, and inhibition of STAT3 signaling is an emerging area of interest in oncology. In this study, the possibility of STAT3 inhibition as a treatment was investigated in pediatric intracranial ependymoma tissues and cell lines. STAT3 activation status was checked in ependymoma tissues. The responses to conventional chemotherapeutic agents and a STAT3 inhibitor WP1066 in primarily cultured ependymoma cells were measured by cell viability assay. Apoptosis assays were conducted to reveal the cytotoxic mechanism of applied agents. Knockdown of STAT3 was tried to confirm the effects of STAT3 inhibition in ependymoma cells. High levels of phospho-STAT3 (p-STAT3) expression were observed in ependymoma tissue, especially in the anaplastic histology group. There was no cytotoxic effect of cisplatin, ifosfamide, and etoposide. Both brain tumor-initiating cells (BTICs) and bulk tumor cells (BCs) showed considerably decreased viability after WP1066 treatment. However, BTICs had fewer responses than BCs. No additive or synergistic effect was observed for combination therapy of WP1066 and cisplatin. WP1066 effectively abrogated p-STAT3 expression. An increased apoptosis and decreased Survivin expression were observed after WP1066 treatment. Knockdown of STAT3 also decreased cell survival, supporting the critical role of STAT3 in sustaining ependymoma cells. In this study, we observed a cytotoxic effect of STAT3 inhibitor on ependymoma BTICs and BCs. There is urgent need to develop new therapeutic agents for pediatric ependymoma. STAT3 inhibitors may be a new group of drugs for clinical application. PMID- 26500029 TI - Polycomb Repressor Complex 1 Member, BMI1 Contributes to Urothelial Tumorigenesis through p16-Independent Mechanisms. AB - Urothelial carcinoma (UC) causes significant morbidity and remains the most expensive cancer to treat because of the need for repeated resections and lifelong monitoring for patients with non-muscle-invasive bladder cancer (NMIBC). Novel therapeutics and stratification approaches are needed to improve the outlook for both NMIBC and muscle-invasive bladder cancer. We investigated the expression and effects of B Lymphoma Mo-MLV Insertion Region 1 (BMI1) in UC. BMI1 was found to be overexpressed in most UC cell lines and primary tumors by quantitative real-time polymerase chain reaction and immunohistochemistry. In contrast to some previous reports, no association with tumor stage or grade was observed in two independent tumor panels. Furthermore, upregulation of BMI1 was detected in premalignant bladder lesions, suggesting a role early in tumorigenesis. BMI1 is not located within a common region of genomic amplification in UC. The CDKN2A locus (which encodes the p16 tumor suppressor gene) is a transcriptional target of BMI1 in some cellular contexts. In UC cell lines and primary tissues, no correlation between BMI1 and p16 expression was observed. Retroviral-mediated overexpression of BMI1 immortalized normal human urothelial cells (NHUC) in vitro and was associated with induction of telomerase activity, bypass of senescence, and repression of differentiation. The effects of BMI1 on gene expression were identified by expression microarray analysis of NHUC BMI1. Metacore analysis of the gene expression profile implicated downstream effects of BMI1 on alpha4/beta1 integrin-mediated adhesion, cytoskeleton remodeling, and CREB1-mediated transcription. PMID- 26500030 TI - Increased Expression of CAP2 Indicates Poor Prognosis in Hepatocellular Carcinoma. AB - CAP2 has been suggested as a potential diagnostic biomarker for early hepatocellular carcinoma (HCC). However, its prognostic significance in HCC remains unclear. Here, we show that CAP2 expression is much higher in HCC tissues than that in paracarcinoma tissues, at both mRNA and protein levels. Data of immunohistochemistry (IHC) revealed that CAP2 was markedly up-regulated in 77.3% of HCC cases. High CAP2 expression, defined by the median score of IHC, was present in 53.3% of the patients. Kaplan-Meier analysis indicated that high CAP2 expression was associated with poor overall survival (P < .0001), disease-free survival (P = .013) and recurrence probability (P = .004) in a training cohort of 312 HCC patients. The prognostic implication of CAP2 in HCC was further confirmed in a validation cohort of 208 HCC patients and by stratified survival analysis. Multiple Cox regression analysis indicated CAP2 as an independent predictor for overall survival (hazard ratio (HR) = 1.615, 95% confidence interval: 1.345 1.938, P < .001). Collectively, we conclude that CAP2 is increased in HCC and is a novel unfavorable biomarker for prognostic prediction for patients with this deadly disease. PMID- 26500031 TI - Detection of Clonal and Subclonal Copy-Number Variants in Cell-Free DNA from Patients with Breast Cancer Using a Massively Multiplexed PCR Methodology. AB - We demonstrate proof-of-concept for the use of massively multiplexed PCR and next generation sequencing (mmPCR-NGS) to identify both clonal and subclonal copy number variants (CNVs) in circulating tumor DNA. This is the first report of a targeted methodology for detection of CNVs in plasma. Using an in vitro model of cell-free DNA, we show that mmPCR-NGS can accurately detect CNVs with average allelic imbalances as low as 0.5%, an improvement over previously reported whole genome sequencing approaches. Our method revealed differences in the spectrum of CNVs detected in tumor tissue subsections and matching plasma samples from 11 patients with stage II breast cancer. Moreover, we showed that liquid biopsies are able to detect subclonal mutations that may be missed in tumor tissue biopsies. We anticipate that this mmPCR-NGS methodology will have broad applicability for the characterization, diagnosis, and therapeutic monitoring of CNV-enriched cancers, such as breast, ovarian, and lung cancer. PMID- 26500032 TI - Changes in Nuclear Orientation Patterns of Chromosome 11 during Mouse Plasmacytoma Development. AB - Studying changes in nuclear architecture is a unique approach toward the understanding of nuclear remodeling during tumor development. One aspect of nuclear architecture is the orientation of chromosomes in the three-dimensional nuclear space. We studied mouse chromosome 11 in lymphocytes of [T38HxBALB/c]N mice with a reciprocal translocation between chromosome X and 11 (T38HT(X;11)) exhibiting a long chromosome T(11;X) and a short chromosome T(X;11) and in fast onset plasmacytomas (PCTs) induced in the same strain. We determined the three dimensional orientation of chromosome 11 using a mouse chromosome 11 specific multicolor banding probe. We also examined the nuclear position of the small translocation chromosome T(X;11) which contains cytoband 11E2 and parts of E1. Chromosomes can point either with their centromeric or with their telomeric end toward the nuclear center or periphery, or their position is found in parallel to the nuclear border. In T38HT(X;11) nuclei, the most frequently observed orientation pattern was with both chromosomes 11 in parallel to the nuclear border ("PP"). PCT cells showed nuclei with two or more copies of chromosome 11. In PCTs, the most frequent orientation pattern was with one chromosome in parallel and the other pointing with its centromeric end toward the nuclear periphery ("CP"). There is a significant difference between the orientation patterns observed in T38HT(X;11) and in PCT nuclei (P < .0001). PMID- 26500033 TI - Sex Steroid Hormone Receptor Expression Affects Ovarian Cancer Survival. AB - BACKGROUND AND AIMS: Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival in epithelial ovarian cancer. METHODS: Immunohistochemical stainings for ERalpha, ERbeta, PR, and AR were assessed in relation to survival in 118 serous and endometrioid ovarian cancers. Expression of the genes encoding the four receptors was studied in relation to prognosis in the molecular subtypes of ovarian cancer in an independent data set, hypothesizing that the expression levels and prognostic impact may differ between the subtypes. RESULTS: Expression of PR or AR protein was associated with improved 5-year progression-free (P=.001 for both) and overall survival (P<.001 for both, log-rank test). ERalpha and ERbeta did not provide prognostic information. Patients whose tumors coexpressed PR and AR had the most favorable prognosis, and this effect was retained in multivariable analyses. Analyses of the corresponding genes using an independent data set revealed differences among the molecular subtypes, but no clear relationship between high coexpression of PGR and AR and prognosis. CONCLUSIONS: A favorable outcome was seen for patients whose tumors coexpressed PR and AR. Gene expression data suggested variable effects in the different molecular subtypes. These findings demonstrate a prognostic role for PR and AR in ovarian cancer and support that tumors should be stratified based on molecular as well as histological subtypes in future studies investigating the role of endocrine treatment in ovarian cancer. PMID- 26500035 TI - Enhancement of the Carbon Dots/K2S2O8 Chemiluminescence System Induced by Triethylamine. AB - Triethylamine (TEA), a common coreactant for electrochemiluminescence (ECL), is first utilized as a coreactant for chemiluminescence (CL). The CL intensity of carbon dots/K2S2O8 could be increased by ~20 times in the presence of TEA. On the basis of this fascinating phenomenon, a room temperature operated senor is constructed for the fast, selective, and sensitive determination of TEA. A wide linear relationship between CL intensity and TEA concentration from 1 MUM to 1000 MUM (R(2) = 0.9995) was found with the detection limit down to 1 MUM. The enhancement mechanism of TEA to this CL system is carefully investigated. Experimental results reveal that the forming of TEA free radical is what indeed induced the enhancement of the CL efficiency of CDs. PMID- 26500034 TI - Isolation and Characterization of the Lytic Cold-Active Bacteriophage MYSP06 from the Mingyong Glacier in China. AB - As unique ecological systems, glaciers are characterized by low temperatures and low nutrient levels, which allow them to be considered as "living fossils" for the purpose of researching the evolution of life and the environmental evolution of the earth. Glaciers are also natural microbial "reservoirs". In this work, a lytic cold-active bacteriophage designated MYSP06 was isolated from Janthinobacterium sp. MYB06 from the Mingyong Glacier in China, and its major characteristics were determined. Electron microscopy revealed that bacteriophage MYSP06 had an isometric head (74 nm) and a long tail (10 nm in width, 210 nm in length). It was classified as a Siphoviridae with an approximate genome size of 65-70 kb. A one-step growth curve revealed that the latent and burst periods were 95 and 65 min, respectively, with an average burst size of 16 bacteriophage particles per infected cell. The bacteriophage particles (100 %) adsorbed to the host cells within 10 min after infection. Moreover, the pH value and thermal stability of bacteriophage MYSP06 were also investigated. The maximum stability of the bacteriophage was observed at the optimal pH 7.0, and the bacteriophage became completely unstable at the extremely alkaline pH 11.0; however, it was comparatively stable at the acidic alkaline pH 6.0. As MYSP06 is a cold-active bacteriophage with a lower production temperature, its characterization and its relationship with its host Janthinobacterium sp. MYB06 deserve further study. PMID- 26500037 TI - A Genome-Wide Scan of DNA Methylation Markers for Distinguishing Monozygotic Twins. AB - Identification of individuals within pairs of monozygotic (MZ) twins remains unresolved using common forensic DNA typing technology. For some criminal cases involving MZ twins as suspects, the twins had to be released due to inability to identify which of the pair was the perpetrator. In this study, we performed a genome-wide scan on whole blood-derived DNA from four pairs of healthy phenotypically concordant MZ twins using the methylated DNA immunoprecipitation sequencing technology to identify candidate DNA methylation markers with capacity to distinguish MZ twins within a pair. We identified 38 differential methylation regions showing within-pair methylation differences in all four MZ pairs. These are all located in CpG islands, 17 of which are promoter-associated, 17 are intergenic islands, and four are intragenic islands. Genes associated with these markers are related with cell proliferation, differentiation, and growth and development, including zinc finger proteins, PRRX2, RBBP9, or are involved in G protein signaling, such as the regulator of G-protein signaling 16. Further validation studies on additional MZ twins are now required to evaluate the broader utility of these 38 markers for forensic use. PMID- 26500036 TI - Clinical impact of alcohol-related cirrhosis in the next decade: estimates based on current epidemiological trends in the United States. AB - BACKGROUND: Identifying changes in the epidemiology of liver disease is critical for establishing healthcare priorities and allocating resources to develop therapies. The projected contribution of different etiologies toward development of cirrhosis in the United States was estimated based on current publications on epidemiological data and advances in therapy. Given the heterogeneity of published reports and the different perceptions that are not always reconcilable, a critical overview rather than a formal meta-analysis of the existing data and projections for the next decade was performed. METHODS: Data from the World Health Organization Global Status Report on Alcohol and Health of 2014, Scientific Registry of Transplant Recipients from 1999 to 2012, National Institute on Alcohol Abuse and Alcoholism, and the Centers for Disease Control and Prevention were inquired to determine future changes in the epidemiology of liver disease. RESULTS: Alcohol consumption has increased over the past 60 years. In 2010, transplant-related costs for liver recipients were the highest for hepatitis C (~$124 million) followed by alcohol-related cirrhosis (~$86 million). We anticipate a significant reduction in incidence cirrhosis due to causes other than alcohol because of the availability of high efficiency antiviral agents for hepatitis C, universal and effective vaccination for hepatitis B, relative stabilization of the obesity trends in the United States, and novel, potentially effective therapies for nonalcoholic steatohepatitis. The proportion of alcohol related liver disease is therefore likely to increase in both the population as a whole and the liver transplant wait list. CONCLUSIONS: Alcohol-related cirrhosis and alcohol-related liver disorders will be the major cause of liver disease in the coming decades. There is an urgent need to allocate resources aimed toward understanding the pathogenesis of the disease and its complications so that effective therapies can be developed. PMID- 26500038 TI - Luminex xMAP combined with Western blot improves HIV diagnostic sensitivity. AB - Currently, Western blot is used to confirm the initial serodiagnosis of HIV infection by antibody detection. However, a major deficiency of the Western blot relates to a lack of sufficient sensitivity in detecting HIV antibodies. This report describes a simple, sensitive and inexpensive bead-based assay for detection of early HIV infection. A panel of 138 positive specimens including 105 blood donors and 33 MSM with known Western blot results were evaluated using Luminex xMAP at Tianjin Centers for Disease Control and Prevention (CDC). We demonstrate a superior sensitivity of Luminex xMAP compared with Western blot. Of the 87 confirmed HIV positive blood donors, Western blot only confirmed 65 cases with 74.7% (65/87) sensitivity while Luminex xMAP identified 72 cases with 82.8% (72/87) sensitivity (p<0.05). Western blot and Luminex xMAP verified 13 and 19 of 33 MSM specimens, respectively. The sensitivity was 39.4% (13/33) for Western blot and 57.6% (19/33) for Luminex xMAP (p<0.1). Luminex xMAP combined with Western blot improves the diagnostic sensitivity of HIV infection at an early stage, and reduces the chances of missed diagnosis. PMID- 26500039 TI - Erratum to: Successful treatment with adalimumab for severe multifocal choroiditis and panuveitis in presumed (early-onset) ocular sarcoidosis. PMID- 26500040 TI - Lewis-Acid-Mediated Stereospecific Radical Polymerization of Acrylimides Bearing Chiral Oxazolidinones. AB - Lewis acid (MgBr2)-catalyzed radical polymerization of acrylimides bearing chiral oxazolidinones gave highly isotactic polyacrylimides with up to >99% meso tetrad (mmm) selectivity. Polymerization in the absence of Lewis acid gave atactic polymers with 80% racemo diad (r) selectivity; the selectivity was deliberately tuned from 80% r to >99% mmm by varying the polymerization conditions. The polyacrylimide was quantitatively converted to corresponding polyacrylates while preserving the stereoregularity, thus providing a general method for the synthesis of atactic to isotactic polyacrylates. PMID- 26500041 TI - Human factors--recognising and minimising errors in our day to day practice. AB - A significant cause of mistakes in healthcare and which are potentially harmful or fatal to patients can result from both individual clinicians and their employing organisations. The understanding and recognition of the role of human error within the healthcare setting is improving, but we still have much to learn when compared with other high-risk organisations such as aviation where such errors can be devastating at a much larger scale. The importance of both organisational issues and human factor issues at a more personal level including tiredness, the effect of emotions and the role of situational awareness, needs to be understood by all those involved in healthcare. Potential mistakes can be reduced with simple measures which need to be recognised by, emphasised and embedded in both teams and individuals. In this review, we address the need for greater awareness of human factors, assessing the path to error and how this can be reduced to minimum levels in clinical practice. PMID- 26500042 TI - Response to Re: Reconsideration of the clinical and histopathological significance of angiogenesis in prostate cancer: Usefulness and limitations of microvessel density measurement. PMID- 26500043 TI - Pro-angiogenic microRNA-296 upregulates vascular endothelial growth factor and downregulates Notch1 following cerebral ischemic injury. AB - The present study examined the association between microRNA (miR)-296 and angiogenesis following cerebral ischemic injury, and the underlying mechanisms. A cerebral ischemic model was established in rats via right middle cerebral artery occlusion. The animals were randomly divided into four groups (baseline, 1 day, 3 day and 7 day). Quantitative polymerase chain reaction and western blot analyses were performed to examine the expression levels of miR-296 and hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), respectively. Angiogenesis was assessed by examining microvessel density. The results demonstrated that miR-296 and angiogenesis were significantly upregulated, while HGS was significantly downregulated following ischemic injury. Adenovirus-mediated overexpression of miR-296 markedly enhanced the formation of capillary-like structures in human umbilical vein endothelial cells, parallel with significantly increased expression levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2, and reduced expression levels of DLL4 and Notch1. The results of the present study provided in vivo and in vitro evidence suggesting that miR-296 promotes angiogenesis in the ischemic brain through upregulating VEGF and downregulating Notch1 following cerebral ischemic injury. PMID- 26500045 TI - Gastrointestinal actions of glucagon-like peptide-1-based therapies: glycaemic control beyond the pancreas. AB - The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) lowers postprandial glucose concentrations by regulating pancreatic islet-cell function, with stimulation of glucose-dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP-1 are at least as important for glucose lowering. GLP-1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP-1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP-1 receptor agonists, which mimic the effects of GLP-1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP-1 receptor agonists can be broadly categorized as short- or long-acting, with each having unique islet-cell and gastrointestinal effects that lower glucose levels. Short-acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long-acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual beta-cell function. PMID- 26500044 TI - Chronic and progressive Parkinson's disease MPTP model in adult and aged mice. AB - Despite the different animal models of Parkinson's disease developed during the last years, they still present limitations modelling the slow and progressive process of neurodegeneration. Here, we undertook a histological, neurochemical and behavioural analysis of a new chronic parkinsonian mouse model generated by the subcutaneous administration of low doses of MPTP (20 mg/kg, 3 times per week) for 3 months, using both young adult and aged mice. The MPTP-induced nigrostriatal neurodegeneration was progressive and was accompanied by a decrease in striatal dopamine levels and motor impairment. We also demonstrated the characteristic neuroinflammatory changes (microglial activation and astrogliosis) associated with the neurodegenerative process. Aged animals showed both a faster time course of neurodegeneration and an altered neuroinflammatory response. The long-term systemic application of low MPTP doses did not induce any increase in mortality in either young adult or aged mice and better resembles the slow evolution of the neurodegenerative process. This treatment could be useful to model different stages of Parkinson's disease, providing a better understanding of the pathophysiology of the disease and facilitating the testing of both protective and restorative treatments. Here, we show a new chronic and progressive parkinsonian mouse model, in young and aged mice. This model produces a stable degeneration of the dopaminergic nigrostriatal pathway, continuous neuroinflammatory reaction and motor deficits. Aged animals showed a faster neurodegeneration and an altered neuroinflammatory response. This treatment could be useful to model different stages of PD and to test both protective and restorative therapeutic approaches. PMID- 26500046 TI - A microfluidic bubble trap and oscillator. AB - A new approach to trap air bubbles before they enter microfluidic systems is presented. The bubble trap is based on the combined interaction of surface tension and hydrodynamic forces. The design is simple, easy to fabricate and straightforward to use. The trap is made of tubes of different sizes and can easily be integrated into any microfluidic setup. We describe the general working principle and derive a simple theoretical model to explain the trapping. Furthermore, the natural oscillations of trapped air bubbles created in this system are explained and quantified in terms of bubble displacement over time and oscillation frequency. These oscillations may be exploited as a basis for fluidic oscillators in future microfluidic systems. PMID- 26500047 TI - Overexpression of mitochondrial Hsp75 protects neural stem cells against microglia-derived soluble factor-induced neurotoxicity by regulating mitochondrial permeability transition pore opening in vitro. AB - Microglia (MG)-induced neurotoxicity, a major determinant of Alzheimer's disease, is closely related to the survival of neural stem cells (NSCs). Heat shock protein 75 (Hsp75) has been reported to exert protective effects against environmental stresses; however, whether or not it protects NSCs against MG derived soluble factor-induced neurotoxicity remains unclear. In the present study, we constructed NSCs that overexpressed human Hsp75 protein and established a co-culture system in order to elucidate the role of Hsp75 in NSC-MG interactions. The results obtained indicated that Hsp75 expression increased after 12 h of soluble factor induction and continued to increase for up to 36 h of treatment. The overexpression of Hsp75 decreased NSC apoptosis and preserved mitochondrial membrane potential. Further experiments revealed that the overexpression of Hsp75 inhibited the formation of cyclophilin D (CypD)-dependent mitochondrial permeability transition pore (mPTP) involvement in neurotoxicity mediated mitochondrial dysfunction and suppressed the activation of the mitochondrial apoptotic cascade, as demonstrated by the inhibition of the release of cytochrome c (Cytc) and the activation of caspase-3. The findings of this study demonstrate that Hsp75 overexpression prevents the impairment of NSCs induced by MG-derived soluble factors by regulating the opening of mPTP. Thus, Hsp75 warrants further investigation as a potential candidate for protection against neurotoxicity. PMID- 26500050 TI - [In Process Citation]. PMID- 26500048 TI - Trans-presentation of IL-15 modulates STAT5 activation and Bcl-6 expression in TH1 cells. AB - During infection, naive CD4(+) T helper cells differentiate into specialized effector subsets based upon environmental signals propagated by the cytokine milieu. Recently, this paradigm has been complicated by the demonstration that alterations in the cytokine environment can result in varying degrees of plasticity between effector T helper cell populations. Therefore, elucidation of the mechanisms by which cytokines regulate T helper cell differentiation decisions is increasingly important. The gamma common cytokine IL-15 is currently undergoing clinical trials for the treatment of malignancies, due to its well established role in the regulation of natural killer and CD8(+) T cell immune responses. However, the effect of IL-15 signaling on CD4(+) T cell activity is incompletely understood. One mechanism by which IL-15 activity is conferred is through trans-presentation via the IL-15 receptor alpha subunit. Here, we demonstrate that differentiated TH1 cells are responsive to trans-presented IL 15. Importantly, while trans-presentation of IL-15 results in STAT5 activation and maintenance of the TH1 gene program, IL-15 treatment alone allows for increased Bcl-6 expression and the upregulation of a TFH-like profile. Collectively, these findings describe a novel role for IL-15 in the modulation of CD4(+) T cell responses and provide valuable insight for the use of IL-15 in immunotherapeutic approaches. PMID- 26500049 TI - SL4, a chalcone-based compound, induces apoptosis in human cancer cells by activation of the ROS/MAPK signalling pathway. AB - OBJECTIVES: SL4, a chalcone-based compound, exhibits clearly inhibitory effects on HIF-1 and has been shown to effectively suppress tumour invasion and angiogenesis in vitro and in vivo. Here, studies were conducted to determine SL4's anti-apoptotic effects and its underlying mechanisms, in human cancer cells. MATERIALS AND METHODS: Cytotoxicity, apoptotic induction and its involved mechanisms of SL4 were investigated using normal cells, cancer cells and mouse xenograft models. The role of reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) signalling in SL4-induced apoptosis was explored by manipulating specific scavenger or signalling inhibitors, in cultured cells. RESULTS: SL4 significantly inhibited cell population growth of human cancer cell lines but exhibited lower cytotoxicity against normal cells. In addition, SL4 effectively induced apoptosis of Hep3B and MDA-MB-435 cells by activating procaspase-8, -9 and -3, and down-regulating expression levels of XIAP, but did not affect HIF-1 apoptosis-related targets, Survivin and Bcl-XL. Further study showed that SL4 also reduced mitochondrial membrane potential and promoted generation of ROS. ROS generation and apoptotic induction by SL4 were blocked by NAC, a scavenger of ROS, suggesting SL4-induced apoptosis via ROS accumulation. We also found that MAPKs, JNK and p38, but not ERK1/2, to be critical mediators in SL4-induced apoptosis. SP600125 and SB203580, specific inhibitors of JNK kinase and p38 kinase, significantly retarded apoptosis induced by SL4. Moreover, anti-oxidant NAC blocked activation of JNK and p38 induced by SL4, indicating that ROS may act as upstream signalling of JNK and p38 activation. It is noteworthy that animal studies revealed dramatic reduction (49%) in tumour volume after 11 days SL4 treatment. CONCLUSIONS: These data demonstrate that SL4 induced apoptosis in human cancer cells through activation of the ROS/MAPK signalling pathway, suggesting that it may be a novel lead compound, as a cancer drug candidate, with polypharmacological characteristics. PMID- 26500051 TI - Modulated CMOS camera for fluorescence lifetime microscopy. AB - Widefield frequency-domain fluorescence lifetime imaging microscopy (FD-FLIM) is a fast and accurate method to measure the fluorescence lifetime of entire images. However, the complexity and high costs involved in construction of such a system limit the extensive use of this technique. PCO AG recently released the first luminescence lifetime imaging camera based on a high frequency modulated CMOS image sensor, QMFLIM2. Here we tested and provide operational procedures to calibrate the camera and to improve the accuracy using corrections necessary for image analysis. With its flexible input/output options, we are able to use a modulated laser diode or a 20 MHz pulsed white supercontinuum laser as the light source. The output of the camera consists of a stack of modulated images that can be analyzed by the SimFCS software using the phasor approach. The nonuniform system response across the image sensor must be calibrated at the pixel level. This pixel calibration is crucial and needed for every camera settings, e.g. modulation frequency and exposure time. A significant dependency of the modulation signal on the intensity was also observed and hence an additional calibration is needed for each pixel depending on the pixel intensity level. These corrections are important not only for the fundamental frequency, but also for the higher harmonics when using the pulsed supercontinuum laser. With these post data acquisition corrections, the PCO CMOS-FLIM camera can be used for various biomedical applications requiring a large frame and high speed acquisition. PMID- 26500052 TI - Association of Torsion With Testicular Cancer: A Retrospective Study. AB - Testicular torsion is a medical emergency that usually requires surgical exploration. However, testicular malignancy has been anecdotally reported with the association of torsion in surgical specimens, and the published data remain scant on the association of torsion with testicular tumors. By retrospective medical record review, we identified 32 patients who had been diagnosed with testicular torsion, 20 of whom had undergone orchiectomy. Of these 20 patients, 2 were diagnosed with a malignancy. Our study, the largest case series to date, has shown an association between testicular torsion and testicular cancer of 6.4%. BACKGROUND: Testicular torsion is a medical emergency that usually requires surgical exploration. However, testicular malignancy has been anecdotally reported in association with torsion in surgical specimens. However, the published data remain scant on the association between torsion and the presence of testicular tumors. The present retrospective study explored the association between torsion and testicular cancer in patients with testicular torsion undergoing orchiectomy during scrotal exploration. MATERIALS AND METHODS: A medical record review was performed of patients who had had a diagnosis of testicular torsion from January 2003 to February 2015. The clinicopathologic characteristics of the patients were recorded. RESULTS: A total of 32 patients were identified. Their mean age was 21.1 years (range, 7-39 years). All the patients had unilateral testicular torsion, which affected the left side in 17 and the right side in 15. Manual detorsion was successful in 6 patients, and 26 patients underwent emergency surgery with testicular detorsion (6 fixation surgery and 20 orchiectomy). The type of incision was scrotal in 6, inguinal in 10, and unspecified in 4. Pathologic examination of the orchiectomy specimens showed malignancy in 2 cases (seminoma and malign mixed germ cell tumor). CONCLUSION: To the best of our knowledge, the present single-center case series is the largest case series to date of testicular torsion and showed an association between testicular torsion and testicular cancer of 6.4%. However, further larger series of the association between testicular torsion and cancer are needed to explore the relationship between testicular torsion and testicular cancer. PMID- 26500054 TI - Chemical constituents and antioxidant activity of essential oil and organic extract from the peel and kernel parts of Citrus japonica Thunb. (kumquat) from Iran. AB - The constituents of essential oils and organic extracts from peel and kernels of Citrus japonica were analysed by GC and GC/MS. The content of essential oil in peel and kernel was 1.1 and 0.8% based on dry weight. The essential oil of C. japonica peel and kernel was characterised by a higher amount of limonene (51.0 and 47.1%) and germacrene D (12.1 and 6.3%), and the hexane extracts of its peel and kernel were characterised by a higher amount of dodecanol-1(12.9 and 20.8%) and linolenic acid (13.1 and 16.3%), respectively. The antioxidant activities of oils were evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) method. The results indicate that both oils from different parts of C. japonica possess considerable antioxidant activity. The fruit peel and kernel essential oil could thus be useful in the industries, chiefly in the food and pharmaceutical industries. PMID- 26500053 TI - Gaps in the evidence on improving social care outcomes: findings from a meta review of systematic reviews. AB - Adult social care continues to be a central policy concern in the UK. The Adult Social Care Outcomes Framework (ASCOF) is a range of measures nationally available to drive forward improvement on outcomes and quality in local councils. While there is an emphasis on improving transparency, quality and outcomes, drawing on research evidence to achieve these aims is often difficult because the evidence is not easily identifiable, is disparate or of variable quality. We conducted a meta-review to analyse and summarise systematic review-level evidence on the impact of interventions on the four outcomes set out in the ASCOF: quality of life, delaying and reducing the need for services, satisfaction with services and safeguarding of vulnerable adults. This paper focuses on the availability of review-level evidence and the presence of significant gaps in this evidence base. A range of health and social care databases were searched, including MEDLINE, ASSIA and The Cochrane Library in January and February 2012. All systematic reviews evaluating the efficacy of social care interventions for improving ASCOF outcomes for older people, people with long-term conditions, mental health problems or physical and/or learning disabilities were eligible. Two reviewers independently screened systematic reviews for quality and relevance and extracted data; 43 systematic reviews were included, the majority of which examined the impact of interventions on quality of life (n = 34) and delaying and reducing the need for support (n = 25). Limited systematic review-level evidence was found regarding satisfaction with services and safeguarding. There were also significant gaps in relation to key social care interventions and population groups. Research priorities include addressing these gaps and the collation of data on interventions, outcomes and populations more closely related to social care. Overall, a more relevant, comprehensive and robust evidence base is required to support improvement of outcomes for recipients of adult social care. PMID- 26500055 TI - Are the three hydroxyphenyl radical isomers created equal?--The role of the phenoxy radical. AB - We have investigated the thermal decomposition of the three hydroxyphenyl radicals (C6H4OH) in a heated microtubular reactor. Intermediates and products were identified isomer-selectively applying photoion mass-selected threshold photoelectron spectroscopy with vacuum ultraviolet synchrotron radiation. Similarly to the phenoxy radical (C6H5-O), hydroxyphenyl decomposition yields cyclopentadienyl (c-C5H5) radicals in a decarbonylation reaction at elevated temperatures. This finding suggests that all hydroxyphenyl isomers first rearrange to form phenoxy species, which subsequently decarbonylate, a mechanism which we also investigate computationally. Meta- and para-radicals were selectively produced and spectroscopically detectable, whereas the ortho isomer could not be traced due to its fast rethermalization and rapid decomposition in the reactor. A smaller barrier to isomerization to phenoxy was found to be the reason for this observation. Since hydroxyphenyl species may be present under typical sooting conditions in flames, the resonantly stabilized cyclopentadienyl radical adds to the hydrocarbon pool and can contribute to the formation of polycyclic aromatic hydrocarbons, which are precursors in soot formation. PMID- 26500056 TI - The aryl hydrocarbon receptor links integrin signaling to the TGF-beta pathway. AB - Glioblastoma is the most common and aggressive form of intrinsic brain tumor. Transforming growth factor (TGF)-beta represents a central mediator of the malignant phenotype of these tumors by promoting invasiveness and angiogenesis, maintaining tumor cell stemness and inducing profound immunosuppression. Integrins, which are highly expressed in glioma cells, interact with the TGF-beta pathway. Furthermore, a link has been described between activity of the transcription factor aryl hydrocarbon receptor (AhR) and TGF-beta expression. Here we demonstrate that integrin inhibition, using alphav, beta3 or beta5 neutralizing antibodies, RNA interference-mediated integrin gene silencing or pharmacological inhibition by the cyclic RGD peptide EMD 121974 (cilengitide) or the non-peptidic molecule GLPG0187, inhibits AhR activity. These effects are independent of cell detachment or cell density. While AhR mRNA expression was not affected by integrin inhibition, AhR total and nuclear protein levels were reduced, suggesting that integrin inhibition-mediated regulation of AhR may occur at a post-transcriptional level. AhR-null astrocytes, AhR-null hepatocytes or glioblastoma cells with a transiently silenced AhR gene showed reduced sensitivity to integrin inhibition-mediated alterations in TGF-beta signaling, indicating that AhR mediates integrin control of the TGF-beta pathway. Accordingly, there was a significant correlation of alphav integrin levels with nuclear AhR and pSmad2 levels as determined by immunohistochemistry in human glioblastoma in vivo. In summary, this study identifies a signaling network comprising integrins, AhR and TGF-beta and validates integrin inhibition as a promising strategy not only to inhibit angiogenesis, but also to block AhR- and TGF-beta-controlled features of malignancy in human glioblastoma. PMID- 26500057 TI - Peroxiredoxin II promotes hepatic tumorigenesis through cooperation with Ras/Forkhead box M1 signaling pathway. AB - The current study was carried out to define the involvement of Peroxiredoxin (Prx) II in progression of hepatocellular carcinoma (HCC) and the underlying molecular mechanism(s). Expression and function of Prx II in HCC was determined using H-ras(G12V)-transformed HCC cells (H-ras(G12V)-HCC cells) and the tumor livers from H-ras(G12V)-transgenic (Tg) mice and HCC patients. Prx II was upregulated in H-ras(G12V)-HCC cells and H-ras(G12V)-Tg mouse tumor livers, the expression pattern of which highly similar to that of forkhead Box M1 (FoxM1). Moreover, either knockdown of FoxM1 or site-directed mutagenesis of FoxM1-binding site of Prx II promoter significantly reduced Prx II levels in H-ras(G12V)-HCC cells, indicating FoxM1 as a direct transcription factor of Prx II in HCC. Interestingly, the null mutation of Prx II markedly decreased the number and size of tumors in H-ras(G12V)-Tg livers. Consistent with this, knockdown of Prx II in H-ras(G12V)-HCC cells reduced the expression of cyclin D1, cell proliferation, anchorage-independent growth and tumor formation in athymic nude mice, whereas overexpression of Prx II increased or aggravated the tumor phenotypes. Importantly, the expression of Prx II was correlated with that of FoxM1 in HCC patients. The activation of extracellular signal-related kinase (ERK) pathway and the expression of FoxM1 and cyclin D1 were highly dependent on Prx II in H ras(G12V)-HCC cells and H-ras(G12V)-Tg livers. Prx II is FoxM1-dependently expressed antioxidant in HCC and function as an enhancer of Ras(G12V) oncogenic potential in hepatic tumorigenesis through activation of ERK/FoxM1/cyclin D1 cascade. PMID- 26500058 TI - Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90 EGFR association. AB - Secondary mutation of epidermal growth factor receptor (EGFR) resulting in drug resistance is one of the most critical issues in lung cancer therapy. Several drugs are being developed to overcome EGFR tyrosine kinase inhibitor (TKI) resistance. Here, we report that pyruvate kinase M2 (PKM2) stabilized mutant EGFR protein by direct interaction and sustained cell survival signaling in lung cancer cells. PKM2 silencing resulted in markedly reduced mutant EGFR expression in TKI-sensitive or -resistant human lung cancer cells, and in inhibition of tumor growth in their xenografts, concomitant with downregulation of EGFR-related signaling. Mechanistically, PKM2 directly interacted with mutant EGFR and heat shock protein 90 (HSP90), and thus stabilized EGFR by maintaining its binding with HSP90 and co-chaperones. Stabilization of EGFR relied on dimeric PKM2, and the protein half-life of mutant EGFR decreased when PKM2 was forced into its tetramer form. Clinical levels of PKM2 positively correlated with mutant EGFR expression and with patient outcome. These results reveal a previously undescribed non-glycolysis function of PKM2 in the cytoplasm, which contribute to EGFR-dependent tumorigenesis and provide a novel strategy to overcome drug resistance to EGFR TKIs. PMID- 26500060 TI - A novel pVHL-independent but NEMO-driven pathway in renal cancer promotes HIF stabilization. AB - Activation of hypoxia-inducible factor (HIF) is due to loss of von Hippel-Lindau protein (pVHL) function in most clear cell renal cell carcinomas (ccRCCs). Here we describe a novel pVHL-independent mechanism of HIF regulation and identify nuclear factor (NF)-kappaB essential modulator (NEMO) as a hitherto unknown oncogenic factor influencing human ccRCC progression. Over 60% of human ccRCCs (n=157) have negative or weak NEMO protein expression by immunohistochemistry. Moderate/strong NEMO protein expression is more frequent in VHL wild-type ccRCCs. We show that NEMO stabilizes HIFalpha via direct interaction and independently of NF-kappaB signaling in vitro. NEMO prolongs tumor cell survival via regulation of apoptosis and activation of epithelial-to-mesenchymal transition, facilitating tumor metastasis. Our findings suggest that NEMO-driven HIF activation is involved in progression of ccRCC. Therefore, NEMO may represent a clinically relevant link between NF-kappaB and the VHL/HIF pathways. Targeting NEMO with specific inhibitors in patients with metastatic ccRCC could be a novel treatment approach in patients with ccRCC expressing functional pVHL. PMID- 26500059 TI - CDK6-a review of the past and a glimpse into the future: from cell-cycle control to transcriptional regulation. AB - The G1 cell-cycle kinase CDK6 has long been thought of as a redundant homolog of CDK4. Although the two kinases have very similar roles in cell-cycle progression, it has recently become apparent that they differ in tissue-specific functions and contribute differently to tumor development. CDK6 is directly involved in transcription in tumor cells and in hematopoietic stem cells. These functions point to a role of CDK6 in tissue homeostasis and differentiation that is partially independent of CDK6's kinase activity and is not shared with CDK4. We review the literature on the contribution of CDK6 to transcription in an attempt to link the new findings on CDK6's transcriptional activity to cell-cycle progression. Finally, we note that anticancer therapies based on the inhibition of CDK6 kinase activity fail to take into account its kinase-independent role in tumor development. PMID- 26500061 TI - PI3K-p110alpha mediates resistance to HER2-targeted therapy in HER2+, PTEN deficient breast cancers. AB - Human epidermal growth factor receptor-2 (HER2) amplification/overexpression (HER2+) frequently co-occurs with PI3K pathway activation in breast tumors. PI3K signaling is most often activated by PIK3CA mutation or PTEN loss, which frequently results in sensitivity to p110alpha or p110beta inhibitors, respectively. To examine the p110 isoform dependence in HER2+, PTEN-deficient tumors, we generated genetic mouse models of breast tumors driven by concurrent Her2 activation and Pten loss coupled with deletion of p110alpha or p110beta. Ablation of p110alpha, but not p110beta, significantly impaired the development of Her2+/Pten-null tumors in mice. We further show that p110alpha primarily mediates oncogenic signaling in HER2+/PTEN-deficient human cancers while p110beta conditionally mediates PI3K/AKT signaling only upon HER2 inhibition. Combined HER2 and p110alpha inhibition effectively reduced PI3K/AKT signaling and growth of cancer cells both in vitro and in vivo. Addition of the p110beta inhibitor to dual HER2 and p110alpha inhibition induced tumor regression in a xenograft model of HER2+/PTEN-deficient human cancers. Together, our data suggest that combined inhibition of HER2 and p110alpha/beta may serve as a potent and durable therapeutic regimen for the treatment of HER2+, PTEN-deficient breast tumors. PMID- 26500062 TI - Sleeping Beauty transposon screen identifies signaling modules that cooperate with STAT5 activation to induce B-cell acute lymphoblastic leukemia. AB - Signal transducer and activator of transcription 5 (STAT5) activation occurs frequently in human progenitor B-cell acute lymphoblastic leukemia (B-ALL). To identify gene alterations that cooperate with STAT5 activation to initiate leukemia, we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice in which a mutagenic Sleeping Beauty transposon (T2/Onc) was mobilized only in B cells. Stat5b-CA mice typically do not develop B-ALL (<2% penetrance); in contrast, 89% of Stat5b-CA mice in which the T2/Onc transposon had been mobilized died of B-ALL by 3 months of age. High-throughput sequencing approaches were used to identify genes frequently targeted by the T2/Onc transposon; these included Sos1 (74%), Kdm2a (35%), Jak1 (26%), Bmi1 (19%), Prdm14 or Ncoa2 (13%), Cdkn2a (10%), Ikzf1 (8%), Caap1 (6%) and Klf3 (6%). Collectively, these mutations target three major cellular processes: (i) the Janus kinase/STAT5 pathway (ii) progenitor B-cell differentiation and (iii) the CDKN2A tumor-suppressor pathway. Transposon insertions typically resulted in altered expression of these genes, as well as downstream pathways including STAT5, extracellular signal-regulated kinase (Erk) and p38. Importantly, expression of Sos1 and Kdm2a, and activation of p38, correlated with survival, further underscoring the role these genes and associated pathways have in B-ALL. PMID- 26500064 TI - High-selenium lentil diet protects against arsenic-induced atherosclerosis in a mouse model. AB - BACKGROUND: Cardiovascular disease (CVD) is a major cause of death worldwide, and arsenic (As) intake, mainly through drinking water, is a well-known risk factor for CVD as well as other health problems. Selenium (Se) is a known antagonist to As toxicity. OBJECTIVE: We tested the potential of high-Se lentils from the Canadian prairies as a therapeutic food to alter the outcome of As-enhanced atherosclerosis. MATERIALS AND METHODS: Male ApoE(-/-) mice exposed to a moderate level of As (200ppb) in their drinking water, and control mice on tap water received one of three lentil diets: Se-deficient (0.009mg/kg), Se-adequate (0.16mg/kg) or Se-high (0.3mg/kg). After 13weeks, lesion formation in the aortic arch and sinus were assessed. Intralesional cellular composition, serum lipid levels and hepatic oxidative stress were assessed as well. RESULTS: Arsenic exacerbated plaque formation was reduced in the sinus and completely abolished in the aortic arch of mice on the Se-fortified lentil diet, whereas lesions were increased in As-exposed mice on both the Se-deficient and Se-adequate diets. Notably, Se deficiency contributed to proatherogenic composition of serum lipids in As-exposed mice as indicated by high-density lipoprotein:low-density lipoprotein. At least adequate Se status was crucial for counteracting As-induced oxidative stress. CONCLUSION: This study is the first to show the potential of high-Se lentils to protect against As-triggered atherosclerosis, and this invites further investigations in human populations at risk from As contamination of their drinking water. PMID- 26500065 TI - A meta-analysis on selective versus comprehensive neck dissection in oral squamous cell carcinoma patients with clinically node-positive neck. AB - OBJECTIVE: Properly management of cervical lymph node metastases is a critical treatment for patients with oral squamous cell carcinoma (OSCC). However there is no consensus on the optimal treatment for oral cancer patients with clinically node-positive (cN+) neck. This study aims to access the feasibility of selective neck dissection in oral cancer patients with cN+neck. METHOD: We searched PubMed and EMBASE up to April 2015 to identify the studies which compared selective neck dissection (SND) with comprehensive neck dissection (CND) in OSCC patients with cN+neck. Data were extracted by two authors. The meta-analysis was conducted with regional recurrence and disease specific death as primary endpoints. RESULT: Five studies with a total of 443 patients met our inclusion criteria. No significant difference was found regarding regional recurrence, disease specific death or overall death between the SND and CND group. CONCLUSION: These findings suggest that cN+OSCC patients treated with SND in conjunction with adjuvant therapy got comparable clinical outcome to CND. PMID- 26500063 TI - The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes. AB - Cellular senescence is an antiproliferative response with essential functions in tumor suppression and tissue homeostasis. Here we show that SIX1, a member of the SIX family of homeobox transcriptional factors, is a novel repressor of senescence. Our data show that SIX1 is specifically downregulated in fibroblasts upon oncogenic stress and other pro-senescence stimuli, as well as in senescent skin premalignant lesions. Silencing of SIX1 in human fibroblasts suffices to trigger senescence, which is mediated by p16INK4A and lacks a canonical senescence-associated secretory phenotype. Interestingly, SIX1-associated senescence is further characterized by the expression of a set of development and differentiation-related genes that significantly overlap with genes associated with SIX1 in organogenesis or human tumors, and show coincident regulation in oncogene-induced senescence. Mechanistically, we show that gene regulation by SIX1 during senescence is mediated, at least in part, by cooperation with Polycomb repressive complexes. In summary, our results identify SIX1, a key development regulator altered in human tumors, as a critical repressor of cellular senescence, providing a novel connection between senescence, differentiation and tumorigenesis. PMID- 26500066 TI - Efficient synthesis of stably adenylated DNA and RNA adapters for microRNA capture using T4 RNA ligase 1. AB - MicroRNA profiling methods have become increasingly important due to the rapid rise of microRNA in both basic and translational sciences. A critical step in many microRNA profiling assays is adapter ligation using pre-adenylated adapters. While pre-adenylated adapters can be chemically or enzymatically prepared, enzymatic adenylation is preferred due to its ease and high yield. However, previously reported enzymatic methods either require tedious purification steps or use thermostable ligases that can generate side products during the subsequent ligation step. We have developed a highly efficient, template- and purification free, adapter adenylation method using T4 RNA ligase 1. This method is capable of adenylating large amounts of adapter at ~100% efficiency and can efficiently adenylate both DNA and RNA bases. We find that the adenylation reaction speed can differ between DNA and RNA and between terminal nucleotides, leading to bias if reactions are not allowed to run to completion. We further find that the addition of high PEG levels can effectively suppress these differences. PMID- 26500067 TI - Scopulariopsis sp. and Fusarium sp. in the Documentary Heritage: Evaluation of Their Biodeterioration Ability and Antifungal Effect of Two Essential Oils. AB - Fungi produce pigments and acids, generating particular local conditions which modify the physicochemical properties of materials. The aims of this work are (i) to investigate bioadhesion, foxing production and biofilm formation by Scopulariopsis sp. and Fusarium sp. isolated from document collections under laboratory conditions; (ii) to verify attack on cellulose fibres and (iii) to study the possibility of reducing fungal growth using natural products. Biofilm formation and extracellular polymeric substance (EPS) production by fungi were demonstrated in laboratory assays and by scanning electron microscopy (SEM) observations. The biocidal activity of two essential oils of Origanum vulgare L. and Thymus vulgaris L. was evaluated using the microatmosphere method. SEM observations showed that these strains were able to attach to paper and form biofilms, causing damage on them, which demonstrates the biodeterioration ability of these microorganisms. Scopulariopsis sp. and Fusarium sp. isolated from paper books showed the formation of fox-like reddish-brown colour spots, attack to the paper structure and pigment production on aged paper samples. The strains tested produced a decrease in the pH of one unit. This would substantiate the effect of the strains in paper biodeterioration. The microatmosphere method showed that volatile compounds of the essential oils have antifungal activity. PMID- 26500068 TI - Carbohydrate-Deficient Transferrin Determination in a Clinical Setting: Consistency Between Capillary Electrophoresis Assays and Utility of HPLC as a Confirmatory Test. AB - BACKGROUND: Carbohydrate-deficient transferrin (CDT) is used to assess chronic alcohol consumption in administrative and forensic context. The aim of the present study was the optimization of the diagnostic strategy for CDT determination in a clinical laboratory setting. METHODS: Two capillary zone electrophoresis (CZE) assays, the CEofix CDT (Analis, Suarlee, Belgium) run on single capillary MDQ instrument and the muticapillary (Sebia, Lisses, France), were compared as screening methods and a commercial high-performance liquid chromatography (HPLC) assay (Recipe, Munich, Germany) was used for confirmation. RESULTS: In total, 367 serum samples were analyzed by both CZE assays with concordant classification in 92% of cases. All discordant samples were classified as negative by HPLC, as did 2/3 of those that could not be classified by either CZE assay. Classification of samples with CDT values close to cut-off by CZE was confirmed by HPLC in 95-100% of negative samples but only in 28.6-33.3% of positive samples. CONCLUSIONS: Both CZE assays proved suitable for CDT screening. HPLC was useful for discriminating CDT value in most of samples that could not be interpreted by CZE due to analytical interferences. Considering the implication of CDT testing, HPLC assay may also be helpful for the confirmation of positive results close to the cut-off value of CZE assays. PMID- 26500069 TI - Dynamic expression of miR-206-3p during mouse skin development is independent of keratinocyte differentiation. AB - MicroRNA-206 (miR-206), the homolog of which in mice is termed miR-206-3p, is a muscle-specific miRNA known to be important in the development of skeletal muscle, and is involved in smooth muscle innervation of the airway through the post-transcriptional suppression of brain-derived neurotrophic factor (Bdnf). miR 206-3p is also expressed at significant levels in adult and embryonic skin; however, its functional roles in adult skin and during skin development remain to be fully elucidated. In the present study, the spatiotemporal expression of miR 206-3p and its target-gene, Bdnf, during mouse skin development were investigated. The expression level of miR-206-3p increased from 13.5 days postcoitus (dpc), peaked at 17.5 dpc and declined following birth. The observed temporal profile of the expression of miR-206-3p was accompanied by an inverse change in the protein expression levels of BDNF. However, the mRNA expression levels of Bdnf did not parallel those of BDNF protein. The localization of the expression of miR-206-3p was similar, or located near that of ubiquitin carboxyl terminal hydrolase L1 during skin development. An in vitro keratinocyte model demonstrated no significant differences between primary and differentiated keratinocytes in the expression levels of either miR-206-3p (P=0.227) or Bdnf (mRNA, P=0.118; mature BDNF, P=0.106; pro-BDNF, P=0.905). These findings indicate a potential role for miR-206-3p in cutaneous innervation, which largely relies on BDNF neurotrophic support and is independent of keratinocyte differentiation. The results of the present study suggested that this novel mechanism may be targeted for developing potential therapeutic approaches. PMID- 26500070 TI - Ability to use the wait-and-see strategy in pathological gamblers. AB - Pathological gamblers (PGs) perform differently on neurocognitive tests than do healthy controls (HC). The aim of this study was to assess "waiting ability" - a major components of inhibition control-using a modified Stop Signal Task (SST) in a population of male PGs (N=55), and HCs (N=53). Results indicated no differences between PGs and HCs in reaction times, intra-individual response variability, or number of false alarms and misses. In conclusion, PGs were not impaired in their ability to manipulate their on-line response strategy during the experimental task and were instead able to change their strategy to decrease the number of false alarms. However, much more empirical and theoretical work needs to be carried out in order to understand the key neural basis of impulsivity among PGs. PMID- 26500071 TI - Vitamin D status in psychotic disorder patients and healthy controls--The influence of ethnic background. AB - Vitamin D deficiency is common among patients with psychotic disorders and could be due to unknown disease mechanisms or contingent factors. However most studies are performed in chronic patients and have often failed to address the influence of ethnicity on vitamin D levels in clinical samples. We investigated serum concentrations of 25-hydroxy vitamin D (S-25 OH D) in first episode patients compared to patients with multi episodes and healthy controls; with a specific focus on differences between visible ethnic minorities and participants from the majority population. A total of 284 participants were included in this cross sectional study. First episode patients with a DSM-IV psychotic disorder were matched on age, gender and ethnicity to participants from a multi episode patient sample (1:1) and healthy controls (1:2). We did not find any differences between either patient groups or the healthy controls, but participants from visible ethnic minorities had significantly lower S-25 OH D than participants from the majority population. This implies that S-25 OH D should be routinely measured in persons from visible ethnic minorities since low levels are associated with higher levels of depressive symptoms. PMID- 26500072 TI - Physical activity in the treatment of Post-traumatic stress disorder: A systematic review and meta-analysis. AB - People with PTSD experience high levels of cardiovascular disease and comorbid mental health problems. Physical activity (PA) is an effective intervention in the general population. We conducted the first systematic review and meta analysis to determine the effect of PA on PTSD. We searched major electronic databases from inception till 03/2015 for RCTs of PA interventions among people with PTSD. A random effects meta-analysis calculating hedges g was conducted. From a potential of 812 hits, four unique RCTs met the inclusion criteria (n=200, mean age of participants 34-52 years). The methodological quality of included trials was satisfactory, and no major adverse events were reported. PA was significantly more effective compared to control conditions at decreasing PTSD and depressive symptoms among people with PTSD. There was insufficient data to investigate the effect on anthropometric or cardiometabolic outcomes. Results suggest that PA may be a useful adjunct to usual care to improve the health of people with PTSD. Although there is a relative paucity of data, there is reason to be optimistic for including PA as an intervention for people with PTSD, particularly given the overwhelming evidence of the benefits of PA in the general population. Robust effectiveness and implementation studies are required. PMID- 26500073 TI - Sedanolide induces autophagy through the PI3K, p53 and NF-kappaB signaling pathways in human liver cancer cells. AB - Sedanolide (SN), a phthalide-like compound from celery seed oil, possesses antioxidant effects. However, the effect of SN on cell death in human liver cancer cells has yet to be determined. In this study, cell viability determination, monodansylcadaverine (MDC) fluorescent staining and immunoblot analysis were performed to determine autophagy induction and autophagy-induced protein expression changes via molecular examination after human liver cancer (J5) cells were treated with SN. Our studies demonstrate that SN suppressed J5 cell viability by inducing autophagy. Phosphoinositide 3-kinase (PI3K)-I, mammalian target of rapamycin (mTOR) and Akt protein levels decreased, whereas PI3K-III, LC3-II and Beclin-1 protein levels increased following SN treatment in J5 cells. In addition, SN treatment upregulated nuclear p53 and damage-regulated autophagy modulator (DRAM) and downregulated cytosolic p53 and Tp53-induced glycolysis and apoptosis regulator (TIGAR) expression in J5 cells. Furthermore, the cytosolic phosphorylation of inhibitor of kappa B (IkappaB) and nuclear p65 and the DNA-binding activity of NF-kappaB increased after SN treatment. These results suggest that SN induces J5 cell autophagy by regulating PI3K, p53 and NF kappaB autophagy-associated signaling pathways in J5 cells. PMID- 26500074 TI - Designer exosomes as next-generation cancer immunotherapy. AB - Exosomes are small 40-120 nm vesicles secreted by nearly all cells and are an important form of intercellular communication. Exosomes are abundant, stable, and highly bioavailable to tissues in vivo. Increasingly, exosomes are being recognized as potential therapeutics as they have the ability to elicit potent cellular responses in vitro and in vivo. Patient-derived exosomes have been employed as a novel cancer immunotherapy in several clinical trials, but at this point lack sufficient efficacy. Still other researchers have focused on modifying the content and function of exosomes in various ways, toward the end-goal of specialized therapeutic exosomes. Here we highlight major advances in the use of exosomes for cancer immunotherapy and exosome bioengineering followed by a discussion of focus areas for future research to generate potent therapeutic exosomes. From the Clinical Editor: Exosomes are small vesicles used by cells for intercellular communication. In this short article, the authors described the current status and the potential use of exosomes in the clinical setting. PMID- 26500075 TI - Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in pediatric ovarian tumors: a novel treatment approach. AB - PURPOSE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been used in adults with ovarian carcinoma proving overall survival benefit in randomized trials, but measured in months. Diffuse peritoneal disease from pediatric type ovarian tumors is rare. We applied CRS and HIPEC to pediatric girls with diffuse peritoneal disease as part of a clinical trial. METHODS: In all patients complete cytoreduction was followed by HIPEC using 100 mg/m2 of cisplatin for 90 min in a closed technique. All received neoadjuvant chemotherapy. Patients with disease outside of the abdominal cavity were excluded. RESULTS: Of 101 pediatric CRS and HIPEC operations, 8 had ovarian primary tumors and multifocal peritoneal disease. There were three yolk sac tumors (germ cell, mixed teratoma), one Sertoli-Leydig, one PNET of the ovary, one choriocarcinoma, one juvenile granulosa cell tumor and one adenocarcinoma. Age ranged 4-18 years. Three of the 8 (37 %) recurred and died. The remaining 63 % are disease free 2-6 years post HIPEC. Overall survival and relapse-free survival in this cohort was 64 and 62 %, respectively [CI 0.64 (0.34, 1); 0.62 (0.37, 1)]. CONCLUSIONS: This is the first report of CRS and HIPEC in pediatric ovarian tumors. HIPEC may be effective in pediatric-type ovarian tumors. More study is needed in a larger cohort. PMID- 26500076 TI - Obstructive jaundice secondary to Morgagni hernia in an infant with Fontan circulation. AB - The vast majority of congenital diaphragmatic cases present with severe respiratory distress in the immediate neonatal period. Obstructive jaundice secondary to CDH is a rare presenting symptom, previously unreported with Morgagni type hernias which comprise 2% of all CDHs. Although the safety of minimally invasive repair for CDH has been shown previously, there has been little data on its safety for patients with complex congenital cardiac disease. In this case report, we present an 18-month old infant with Fontan circulation presenting with jaundice secondary to Morgagni hernia who ultimately underwent laparoscopic repair. A brief discussion of the safety of laparoscopic surgery in patients post-Fontan is included. PMID- 26500077 TI - The "Dose-Effect" Relationship Between 25-Hydroxyvitamin D and Muscle Strength in Hemodialysis Patients Favors a Normal Threshold of 30 ng/mL for Plasma 25 Hydroxyvitamin D. AB - OBJECTIVE: Muscle strength is weakened in maintenance hemodialysis patients. Strength is both a measure of a functional parameter and of frailty as it is independently associated with mortality. In the general population, observational studies show that plasma 25-hydroxyvitamin D (25[OH]D) is positively correlated with muscle strength and function. We analyzed the determinants of muscle strength measured by handgrip and 25(OH)D in a maintenance hemodialysis population. METHODS: In this observational cross-sectional study, data from all hemodialysis patients from our nephrology department were recorded in July 2014. Daily nutritional oral intake, handgrip strength, body composition measured by bioimpedancemetry analysis, as well as biological and dialysis parameters, were obtained from medical files. We used a linear regression model to assess nutritional, biological, and dialysis parameters as well as body composition associated with handgrip strength. RESULTS: The median age (interquartile range) of the 130 included patients was 77.3 (69.5-84.7) years, 57.7% were men, and 50.8% had diabetes mellitus. Median handgrip strength value (interquartile range) was 14.3 (10.6-22.2) kg. In univariate analyses, the factors associated with handgrip strength were age, gender, albumin, transthyretin, predialysis creatinine and urea, normalized protein nitrogen appearance, lean mass, and muscle mass measured by bioimpedancemetry analysis as well as phase angle, and 25(OH)D. In multivariate analyses, lower age, male gender, higher albumin, higher muscle mass, and 25(OH)D level >= 30 ng/mL were independently correlated with muscle strength measured by handgrip. CONCLUSIONS: This study found a positive correlation between plasma 25(OH)D and muscle strength measured by handgrip in hemodialysis patients. We report a "dose-effect" relationship between 25(OH)D and handgrip strength under 30 ng/mL, which is no more present above 30 ng/mL. Prospective randomized studies are needed to prove that supplementation with cholecalciferol, leading to 25(OH)D levels >= 30 ng/mL, improves muscle strength in hemodialysis patients. PMID- 26500078 TI - Appraisal of the Missing Proteins Based on the mRNAs Bound to Ribosomes. AB - Considering the technical limitations of mass spectrometry in protein identification, the mRNAs bound to ribosomes (RNC-mRNA) are assumed to reflect the mRNAs participating in the translational process. The RNC-mRNA data are reasoned to be useful for appraising the missing proteins. A set of the multiomics data including free-mRNAs, RNC-mRNAs, and proteomes was acquired from three liver cancer cell lines. On the basis of the missing proteins in neXtProt (release 2014-09-19), the bioinformatics analysis was carried out in three phases: (1) finding how many neXtProt missing proteins have or do not have RNA seq and/or MS/MS evidence, (2) analyzing specific physicochemical and biological properties of the missing proteins that lack both RNA-seq and MS/MS evidence, and (3) analyzing the combined properties of these missing proteins. Total of 1501 missing proteins were found by neither RNC-mRNA nor MS/MS in the three liver cancer cell lines. For these missing proteins, some are expected higher hydrophobicity, unsuitable detection, or sensory functions as properties at the protein level, while some are predicted to have nonexpressing chromatin structures on the corresponding gene level. With further integrated analysis, we could attribute 93% of them (1391/1501) to these causal factors, which result in the expression products scarcely detected by RNA-seq or MS/MS. PMID- 26500079 TI - Neuroendocrine neoplasms of the lung: Concepts and terminology. AB - Neuroendocrine neoplasms of the lung continue to undergo scrutiny, with respect to the diagnostic terminology recommended for them and details of their clinicopathologic profiles. This overview considers the nosological evolution of such lesions and presents current views on classification schemes that pertain to them. PMID- 26500080 TI - Developing Theory to Guide Building Practitioners' Capacity to Implement Evidence Based Interventions. AB - Public health and other community-based practitioners have access to a growing number of evidence-based interventions (EBIs), and yet EBIs continue to be underused. One reason for this underuse is that practitioners often lack the capacity (knowledge, skills, and motivation) to select, adapt, and implement EBIs. Training, technical assistance, and other capacity-building strategies can be effective at increasing EBI adoption and implementation. However, little is known about how to design capacity-building strategies or tailor them to differences in capacity required across varying EBIs and practice contexts. To address this need, we conducted a scoping study of frameworks and theories detailing variations in EBIs or practice contexts and how to tailor capacity building to address those variations. Using an iterative process, we consolidated constructs and propositions across 24 frameworks and developed a beginning theory to describe salient variations in EBIs (complexity and uncertainty) and practice contexts (decision-making structure, general capacity to innovate, resource and values fit with EBI, and unity vs. polarization of stakeholder support). The theory also includes propositions for tailoring capacity-building strategies to address salient variations. To have wide-reaching and lasting impact, the dissemination of EBIs needs to be coupled with strategies that build practitioners' capacity to adopt and implement a variety of EBIs across diverse practice contexts. PMID- 26500081 TI - Larvicidal and acetylcholinesterase inhibitory activities of apiaceae plant essential oils and their constituents against aedes albopictus and formulation development. AB - This study evaluated the larvicidal activity of 12 Apiaceae plant essential oils and their components against the Asian tiger mosquito, Aedes albopictus, and the inhibition of acetylcholine esterase with their components. Of the 12 plant essential oils tested, ajowan (Trachyspermum ammi), caraway seed (Carum carvi), carrot seed (Daucus carota), celery (Apium graveolens), cumin (Cuminum cyminum), dill (Anethum graveolens), and parsley (Petroselinum sativum) resulted in >90% larval mortality when used at 0.1 mg/mL. Of the compounds identified, alpha phellandrene, alpha-terpinene, p-cymene, (-)-limonene, (+)-limonene, gamma terpinene, cuminaldehyde, neral, (S)-+-carvone, trans-anethole, thymol, carvacrol, myristicin, apiol, and carotol resulted in >80% larval mortality when used at 0.1 mg/mL. Two days after treatment, 24.69, 3.64, and 12.43% of the original amounts of the celery, cumin, and parsley oils, respectively, remained in the water. Less than 50% of the original amounts of alpha-phellandrene, 1,8 cineole, terpinen-4-ol, cuminaldehyde, and trans-antheole were detected in the water at 2 days after treatment. Carvacrol, alpha-pinene, and beta-pinene inhibited the activity of Ae. albopictus acetylcholinesterase with IC50 values of 0.057, 0.062, and 0.190 mg/mL, respectively. A spherical microemulsion of parsley essential oil-loaded poly(vinyl alcohol) (PVA) was prepared, and the larvicidal activity of this formulation was shown to be similar to that of parsley oil. PMID- 26500082 TI - Omega-3 polyunsaturated fatty acid blood biomarkers increase linearly in men and women after tightly controlled intakes of 0.25, 0.5, and 1 g/d of EPA + DHA. AB - Blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been related to coronary heart disease risk. Understanding the response of EPA + DHA in blood to dietary intake of EPA + DHA would facilitate the use of blood measures as markers of adherence and enable the development of dietary recommendations. The objective of this study is examine the blood response to intakes of EPA + DHA <=1 g/d with an intervention designed for dietary adherence. It was hypothesized this relationship would be linear and that intakes of EPA + DHA <1 g/d would result in blood levels below those associated with the highest level of protection for cardiovascular events. Background EPA + DHA intake of men and women (n = 20) was determined by food frequency questionnaire and adherence was monitored by weekly fingertip blood sampling for fatty acid determinations. Participants consumed nutraceuticals to achieve intakes of 0.25 g/d and 0.5 g/d EPA + DHA for successive four-week periods. A subgroup (n = 5) had intakes of 1.0 g/d EPA + DHA for an additional 4 weeks. Fatty acid composition of whole blood, erythrocytes, and plasma phospholipids were determined at each time point. Blood levels of EPA and DHA increased linearly in these pools. A comprehensive review of the literature was used to verify the blood-intake relationship. Blood levels of long chain omega-3 polyunsaturated fatty acids reached blood levels associated with the highest levels of primary cardiac arrest reduction and sudden cardiac death risk only with intakes of 1.0 g/d of EPA + DHA. The blood biomarker response to intakes of EPA + DHA <=1 g/d is linear in a small but highly adherent study sample and this information can assist in determining adherence in clinical studies and help identify dietary intake targets from associations between blood and disease. PMID- 26500084 TI - Cervical cancer screening among women >=70 years of age in the United States-A referral problem or patient choice. AB - OBJECTIVE: Clinical guidelines recommend that women with a history of adequate screening and not otherwise at high risk may discontinue cervical cancer screening after 65 years of age. However, screening remains common among US women over 65 years old. This study was conducted to examine whether overutilization was attributable to provider's recommendation or patient choice. METHOD: This cross-sectional study used data from 1752 female participants (70+ years) from the 2013 National Health Interview Survey (NHIS). We quantitatively assessed the proportions of provider-recommended and patient self-initiated Pap smears. RESULTS: Among female respondents, 40.8% had a Pap smear within the past 3 years, 19.4% had a Pap smear in the last year, and 39.7% reported receiving a recommendation for a Pap smear from their provider in the past year. Among women who received a recommendation to obtain a Pap smear, 39.8% did so within the past 12 months compared to 5.9% of women who did not receive a recommendation (adjusted odds ratio 10.5, 95% confidence interval 7.39-15.0). About 70% of women who visited an obstetrician/gynecologist and reported receiving a recommendation to have a Pap smear did so in the past year, while 32.3% of women who visited an obstetrician/gynecologist but did not receive a recommendation obtained one. CONCLUSION: Pap smears were common among women >=70 years of age. Health care providers may need additional education on current guidelines regarding indications for Pap smears in this age group to help reduce screening of patients who may not benefit. PMID- 26500085 TI - Gout and its comorbidities in the total population of Stockholm. AB - OBJECTIVE: Study of prevalence of gout with concomitant diseases. METHODS: Study population included all living persons in Stockholm County, Sweden, on January 1st 2013 (N=2,124,959). A diagnosis of gout was identified during 2013-2014, with information of diabetes mellitus and insulin resistance, hypertension, chronic heart failure, chronic kidney disease, alcohol abuse, and malignancies. Age adjusted odds ratios (ORs) with 95% confidence intervals (95% CI) for women and men with gout, using individuals without gout as referents, were calculated. RESULTS: Age-adjusted odds of co-morbidities among individuals with gout vs. those without gout were: diabetes mellitus and insulin resistance 3.97 (95% CI 3.65-4.31) in women and 1.88 (95% CI 1.78-1.99) in men; hypertension 4.02 (95% CI 3.69-4.37) in women and 3.21 (95% CI 3.06-3.37) in men; chronic heart failure 4.72 (95% CI 4.31-5.19) in women and 2.84 (95% CI 2.66-3.04) in men; chronic kidney disease 2.08 (95% CI 1.50-2.87) in women and 2.39 (95% CI 2.15-2.66) in men; alcohol abuse 8.98 (95% CI 8.15-9.80) in women and 4.38 (95% CI 4.10-4.69) in men; and malignancies 1.32 (95% CI 1.17-1.48) in women and 1.13 (95% CI 1.06 1.21) men. CONCLUSION: Gout is a warning sign for concomitant diseases, e.g. alcoholism, diabetes, cardiovascular diseases, and cancer. KEY MESSAGES. PMID- 26500083 TI - Orally delivered beta-glucans aggravate dextran sulfate sodium (DSS)-induced intestinal inflammation. AB - beta-Glucans have beneficial health effects due to their immune modulatory properties. Oral administration of beta-glucans affects tumour growth, microbial infection, sepsis, and wound healing. We hypothesized that pre-treatment with orally delivered soluble and particulate beta-glucans could ameliorate the development of aggravate dextran sulfate sodium (DSS) induced intestinal inflammation. To study this, mice were orally pre-treated with beta-glucans for 14 days. We tested curdlan (a particulate beta-(1,3)-glucan), glucan phosphate (a soluble beta-(1,3)-glucan), and zymosan (a particle made from Saccharomyces cerevisiae, which contains around 55% beta-glucans). Weight loss, colon weight, and feces score did not differ between beta-glucan and vehicle treated groups. However, histology scores indicated that beta-glucan-treated mice had increased inflammation at a microscopic level suggesting that beta-glucan treatment worsened intestinal inflammation. Furthermore, curdlan and zymosan treatment led to increased colonic levels of inflammatory cytokines and chemokines, compared to vehicle. Glucan phosphate treatment did not significantly affect cytokine and chemokine levels. These data suggest that particulate and soluble beta-glucans differentially affect the intestinal immune responses. However, no significant differences in other clinical colitis scores between soluble and particulate beta glucans were found in this study. In summary, beta-glucans aggravate the course of dextran sulfate sodium (DSS)-induced intestinal inflammation at the level of the mucosa. PMID- 26500086 TI - The gap between expectations and reality of exercise-induced weight loss is associated with discouragement. AB - BACKGROUND: Exercise interventions result in modest weight loss, yet exercise is frequently prescribed for weight loss. PURPOSE: To identify individuals who become discouraged when exercise fails to achieve weight loss. METHODS: Representative samples of U.S. adults were recruited using Google Consumer Surveys in August-October 2014. Respondents were asked about beliefs and potential discouragement regarding the role of exercise and weight loss. An analysis of variance was performed to predict individuals that become discouraged if exercise does not lead to weight loss. RESULTS: The belief that exercise is a very effective way to lose weight was common (71% of respondents). Stronger belief that exercise is an effective way to lose weight (p<0.001) in individuals with higher weight status (p=0.04) positively predicted discouragement with exercise. Higher weight status combined with the belief that exercise reduces weight was a significant positive predictor of discouragement (p=0.01). CONCLUSIONS: Individuals with higher weight status that believe that exercise is an effective way to lose weight are more likely to become discouraged when exercise does not lead to weight loss. Prescribing exercise for weight loss might contribute to discouragement. Future studies should evaluate ways to encourage exercise without promoting the belief that exercise will yield weight loss. PMID- 26500087 TI - Ultrafast colorimetric determination of predominant protein structure evolution with gold nanoplasmonic particles. AB - The intracellular and extracellular accumulation of disordered proteins and aggregated proteins occurs in many protein conformational diseases, such as aging related neurodegeneration and alcoholic liver diseases. However, the conventional methods to study protein structural changes are limited for the rapid detection and monitoring of protein aggregation because of long incubation times (i.e., usually several days), complicated sample pretreatment steps, and expensive instrumentation. Here, we describe an ultrafast colorimetric method for the real time monitoring of protein structure evolution and the determination of predominant structures via nanoparticle-assisted protein aggregation. During the aggregation process, nanoparticles act as nucleation cores, which form networks depending on the structures of the protein aggregates, and accelerate the kinetics of the protein aggregation. Simultaneously, these nanoparticles exhibit colorimetric responses according to their embedded shapes (e.g., fibrillar and amorphous) on the protein aggregates. We observed distinct spectral shifts and concomitant colorimetric responses of concentration- and type-dependent protein aggregation with the naked eye within a few minutes (<2 min) under acidic conditions. Moreover, the morphological transitions from small aggregates to larger aggregates of nanoparticle-assisted protein aggregates were visualized with dark-field microscope imaging, which show a similar trend with that of protein aggregates formed without the aid of nanoparticles. Finally we show that our proposed method can be utilized to screen the protein aggregation propensity under a variety of conditions such as different pH levels, high temperature, and chemicals. These findings suggest that the proposed method is an easy way to study the molecular biophysics of protein aggregation and to rapidly screen anti aggregation drugs for protein conformational diseases. PMID- 26500088 TI - Inhibition of Flavobacterium psychrophilum adhesion in vitro. AB - Flavobacterium psychrophilum, a bacterium known for its adhesion ability to surfaces, has recently been shown to express phenotypic variation, as smooth and rough colony types in vitro. The aim of this study was to assess the effect of different compounds on adhesion of both phenotypes of F. psychrophilum to polystyrene surfaces of 96-well microtiter plates. Cells of F. psychrophilum of both phenotypes (10(8) CFU ml(-1)) were treated with different compounds for 1 h at 15 degrees C and were subsequently allowed to adhere to polystyrene surfaces. The adhered cells were stained with crystal violet and optical density measured at 595 nm. The compounds were classified as non, weak, moderate or strong inhibitors of the F. psychrophilum adhesion. The results showed that a combination of selected carbohydrates, D- and L-amino acids, phytochemicals, an ion chelating agent (EDTA) and proteinase K strongly inhibited the adhesion of mainly smooth cells. We suggest that the compounds inhibit the cell adhesion by presumably disrupting the protein-protein interactions that hold smooth cells together and by negatively affecting the surface hydrophobicity of smooth cells. In contrast, rough cells exhibit resistance to most inhibitor compounds. PMID- 26500089 TI - EheA from Exiguobacterium sp. yc3 is a novel thermostable DNase belonging to HNH endonuclease superfamily. AB - The HNH endonuclease superfamily usually contains a conserved HNH motif in the sequence, and the second subfamily of it uses N to replace the second H in the HNH motif. A bacterium with extracellular thermostable DNase was isolated and identified as Exiguobacterium sp. yc3. A 20 kDa putative DNase was later purified and the encoding gene of it was amplified and sequenced, the deduced amino acid sequence analysis showed that the protein belongs to the HNH endonuclease superfamily, and therefore it was named as EheA ( E: xiguobacterium H: NH E: ndonuclease). Characterization of the recombinant EheA confirmed that EheA is a DNase. By site-directed mutation method, H116, N141 and N156 were proved to be essential for the DNase activity. EheA is the first experimentally determined bacterial source endonuclease belonging to the second subfamily of HNH superfamily. Further bioinformatic analysis showed that EheA homologue genes are conserved in the Exiguobacterium species, which suggests their possible important functions for Exiguobacterium species. And as a thermostable DNase, EheA also has a promising future in many application fields. PMID- 26500090 TI - Perceived Work Ability in the Light of Long-Term and Stress-Related Unhealthy Behaviors-a Prospective Cohort Study. AB - BACKGROUND: Most of the few studies that exist on the longitudinal associations between health behaviors and work ability target to single health behaviors. PURPOSE: To investigate how lifetime clusters of unhealthy behaviors associate with perceived work ability in early midlife. METHODS: The study population consisted of 46-year-old men and women (n = 3107) born in Northern Finland in 1966. Their current perceived work ability compared to lifetime best, and their unhealthy behaviors (physical inactivity, smoking, and alcohol consumption) were assessed by questionnaires. We determined clusters of unhealthy behaviors at the ages of 14, 31, and 46 and created lifetime development trajectories of health behaviors. We also assessed stress-related eating and drinking at the ages of 31 and 46. Cross-tabulations and multivariate logistic regression models were used to investigate the associations between clusters of health behaviors, stress related eating and drinking, and work ability at 46 years. The analyses were controlled for basic education and physical strenuousness of work, psychosocial job characteristics, perceived work ability, and BMI (kg/m(2)) at 31 years. RESULTS: Four health behavior trajectories emerged: always healthy, moderate (reference group), deteriorated. and always unhealthy. Among men, always unhealthy behaviors [OR (95 % confidence interval) 2.81 (1.35, 5.86)], and among women, deteriorated health behaviors [1.67 (1.07, 2.58)] associated with poor perceived work ability at 46 years. In addition, stress-related eating and drinking associated independently with poor perceived work ability at 46 years [men 2.58 (1.62, 4.12) and women 2.48 (1.70, 3.61)]. CONCLUSION: Long-lasting and stress-related unhealthy behaviors increase the risk of poor work ability in midlife. PMID- 26500091 TI - Searching for biological traces on different materials using a forensic light source and infrared photography. AB - Because biological traces often play an important role in the investigation process of criminal acts, their detection is essential. As they are not always visible to the human eye, tools like a forensic light source or infrared photography can be used. The intention of the study presented was to give advice how to visualize biological traces best. Which wavelengths and/or filters give the best results for different traces on different fabrics of different colors? Therefore, blood (undiluted and diluted), semen, urine, saliva, and perspiration have been examined on 29 different materials. PMID- 26500092 TI - Fatal methadone intoxication in an infant listed as a homicide. AB - Voluntary methadone administration for the purpose of sedation eventually resulting in the infant's death is extremely infrequent, though it has been observed. In this report, we describe an autopsy case pertaining to a 32-month old infant who was repeatedly exposed to methadone by his parents. Autopsy revealed a coarctation of the aorta with a focal stenosis located at the junction of the distal aortic arch and the descending aorta. Left ventricular hypertrophy was also observed. Both these findings were considered to not have played a role in the child's death. Methadone was detected in the femoral blood (0.633 mg/l), urine (5.25 mg/l), bile (2.64 mg/l), and gastric contents (1.08 mg). A segmental hair analysis showed the presence of methadone and morphine in both the proximal and distal portion of the lock. Methadone was also detected in nail samples. A segmental hair analysis performed on the younger brother of the deceased revealed the presence of methadone and morphine in both the proximal and distal segments, as well as the presence of 6-monoacetylmorphine exclusively in the distal portion. Though the parents denied any involvement in methadone administration or exposure for the purpose of sedation, the manner of death was listed as homicide. The case emphasizes the usefulness of hair analysis to identify threatening situations for the children of drug-dependent parents and possibly support measures by the authorities to recognize and intervene in these potentially fatal situations. PMID- 26500093 TI - Indications and Results of HLA-Identical Sibling Hematopoietic Cell Transplantation for Sickle Cell Disease. AB - Although a number of published trials exist of HLA-identical sibling hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) that span 2 decades, when and for whom this therapy should be pursued is a subject of debate. Assessments of the risks of transplant-related complications that include infertility and debilitating graft-versus-host disease and long-term quality of life after successful HCT are difficult to perform without prospective trials in transplant and nontransplant cohorts. However, it is possible to assess the risk of mortality and to compare published rates of survival in individuals with SCD treated and not treated by HCT. In this brief review, projections about mortality risk based on recent published reports are reviewed and summarized. The published data show overall survival and event-free survival rates of 95% and 92%, respectively, in children treated by HLA-identical sibling HCT. The overall survival rates in the Center for International Blood and Marrow Transplant Research (N = 412) and European Blood and Marrow Transplant (N = 487) registries were 91% and 95%, respectively. These results provide broad support for the therapeutic value of HLA-identical sibling HCT for children with SCD and serve as the basis for a strong recommendation in favor of the option of HCT when a suitable donor is available. The experience of HLA-identical sibling HCT in adults with SCD is limited but appears to be similar to results in children. These preliminary observations, however, warrant further investigation. PMID- 26500094 TI - Upregulation of RICTOR gene transcription by the proinflammatory cytokines through NF-kappaB pathway contributes to the metastasis of renal cell carcinoma. AB - Metastasis accounts for more than 50 % of deaths among renal cell carcinoma (RCC) patients, and therefore, it is important to study the biology of metastasis and identify metastasis-associated biomarkers for risk prognosis and stratification of patients for an individualized therapy of RCC. In cultured RCC cells, knockdown of Rictor by short hairpin RNA (shRNA) inhibited cell migration and invasion, probably due to impairments in activation of Akt. Pretreatment with tumor necrosis factor alpha (TNFalpha) or interleukin 6 (IL-6) enhanced the expression of Rictor and the migration of renal cancer cells. Mechanistic analysis showed that TNFalpha induced the activation of NF-kappaB in RCC cells. Luciferase reporter analysis revealed a NF-kappaB responding element (-301 to -51 bp) at the promoter region of Rictor. Chromatin immunoprecipitation (ChIP) analysis further confirmed that TNFalpha-induced binding of p65 with the promoter of Rictor. In a xenograft model, knockdown of Rictor-blocked RCC cells metastasis to the mouse lungs and livers. Taken together, our results suggest that the proinflammatory cytokine TNFalpha promotes the expression of Rictor through the NF-kappaB pathway. PMID- 26500095 TI - The combination of thymoquinone and paclitaxel shows anti-tumor activity through the interplay with apoptosis network in triple-negative breast cancer. AB - Thymoquinone (TQ) is the active ingredient of Nigella sativa which has a therapeutic potential in cancer therapy and prevention. In this study, TQ has been shown to induce specific cytotoxicity and apoptosis and to inhibit wound healing in triple-negative breast cancer cell line. TQ also inhibited cancer growth in a mouse tumor model. Moreover, TQ and paclitaxel (Pac) combination inhibited cancer growth in cell culture and in mice. Genes involved in TQ and TQ Pac-mediated cytotoxicity were studied using focused real-time PCR arrays. After bioinformatic analysis, genes in apoptosis, cytokine, and p53 signaling categories were found to be modulated with a high significance in TQ-treated cells (p < 10(-28), p < 10(-8), and p < 10(-6), respectively). Important to note, TQ has been found to regulate the genes involved in the induction of apoptosis through death receptors (p = 5.5 * 10(-5)). Additionally, tumor suppressor genes such as p21, Brca1, and Hic1 were highly upregulated by TQ and TQ-Pac combination. Interestingly, when cells were treated with high dose TQ, several growth factors such as Vegf and Egf were upregulated and several pro-apoptotic factors such as caspases were downregulated possibly pointing out key pathways manipulated by cancer cells to resist against TQ. In cells treated with the combination of TQ and Pac, genes in apoptosis cascade (p < 10(-12)), p53 signaling (p = 10(-5)), and JAK-STAT signaling (p < 10(-3)) were differentially expressed. TQ has also been shown to induce protein levels of cleaved Caspase-3, Caspase-7, and Caspase-12 and PARP and to reduce phosphorylated p65 and Akt1. The in vivo therapeutic potential of TQ-Pac combination and the genetic network involved in this synergy have been shown for the first time to the best of our knowledge. PMID- 26500096 TI - Circulating tumor cells as trigger to hematogenous spreads and potential biomarkers to predict the prognosis in ovarian cancer. AB - Despite several improvements in the surgical field and in the systemic treatment, ovarian cancer (OC) is still characterized by high recurrence rates and consequently poor survival. In OC, there is still a great lack of knowledge with regard to cancer behavior and mechanisms of recurrence, progression, and drug resistance. The OC metastatization process mostly occurs via intracoelomatic spread. Recent evidences show that tumor cells generate a favorable microenvironment consisting in T regulatory cells, T infiltrating lymphocytes, and cytokines which are able to establish an "immuno-tolerance mileau" in which a tumor cell can become a resistant clone. When the disease responds to treatment, immunoediting processes and cancer progression have been stopped. A similar inhibition of the immunosuppressive microenvironment has been observed after optimal cytoreductive surgery as well. In this scenario, the early identification of circulating tumor cells could represent a precocious signal of loss of the immune balance that precedes cancer immunoediting and relapse. Supporting this hypothesis, circulating tumor cells have been demonstrated to be a prognostic factor in several solid tumors such as colorectal, pancreatic, gastric, breast, and genitourinary cancer. In OC, the role of circulating tumor cells is still to be defined. However, as opposed to healthy women, circulating tumor cells have been demonstrated in peripheral blood of OC patients, opening a new research field in OC diagnosis, treatment monitoring, and follow-up. PMID- 26500097 TI - Impact of use of angiotensin II receptor blocker on all-cause mortality in hemodialysis patients: prospective cohort study using a propensity-score analysis. AB - BACKGROUND: It is controversial whether treatment with an angiotensin II receptor blocker (ARB) or a calcium channel blocker (CCB) improves prognosis of hemodialysis (HD) patients. METHODS: This study was designed as a multicenter prospective cohort study. HD patients (n = 1071) were enrolled from 22 institutes in January 2009 and followed up for 3 years. Patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204) were excluded, and 867 patients contributed to analysis of mortality. Propensity score (PS) for use of ARB and that for CCB was calculated using a multiple logistic regression model. RESULTS: ARB and CCB were prescribed in 45.6 and 54.7 % of patients at enrollment. During the 3-year follow-up period, all-cause mortality and cardiovascular mortality rates were 18.8 and 5.1 %, respectively. Kaplan-Meier curves showed that all-cause and cardiovascular mortality rates were lower in the ARB group than in the non-ARB group, though the mortality rates were similar in the CCB group and non-CCB group. In PS-stratified Cox regression analysis, ARB treatment was associated with 34 and 45 % reduction of all-cause death and cardiovascular death, respectively. In PS matching analysis, ARB treatment was associated with a significant reduction (46 % reduction) in the risk of all-cause death. A significant impact of CCB treatment on all-cause or cardiovascular mortality was not detected in PS analysis. CONCLUSIONS: The use of an ARB, but not a CCB, is associated with reduced all-cause and cardiovascular mortalities in patients on HD. PMID- 26500098 TI - Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. AB - BACKGROUND: Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and nephrolithiasis. Type 1 is caused by a loss-of function mutation in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9). METHODS AND RESULTS: In this article we present clinical, biochemical and molecular genetics of two Czech patients. The serum uric acid in the probands was 57 and 98 umol/l and expressed as an increase in the fractional excretion of uric acid (40 and 18 %). The sequencing analysis of SLC22A12 and SLC2A9 revealed novel variants p.R92C and p.R203C in URAT1 and p.G72D in GLUT9. Functional studies were performed for these novel variants and for previously reported variants p.I118HfsX27, p.G216R and p.N333S in GLUT9 responsible for renal hypouricemia in three probands from Czech Republic and United Kingdom. Functional studies showed significantly decreased urate uptake for all variants. However, urate uptake of GLUT9 variants prepared for both isoforms were not significantly different. CONCLUSIONS: This is the first complex function characterization of non-synonymous allelic variants in patients with renal hypouricemia regarding both GLUT9 isoforms. Our finding of defects in the SLC2A9 and SLC22A12 genes show the following: renal hypouricemia is not restricted to East Asia populations; urate uptake of GLUT9 variants prepared for both isoforms were not significantly different; renal hypouricemia type 2 has more wide clinical variability than type 1; the phenotypic severity of renal hypouricemia is not correlated with results of functional characterizations of URAT1 and GLUT9 variants. PMID- 26500099 TI - Mechanisms of disease: The human N-glycome. AB - BACKGROUND: The majority of human proteins are being modified by covalent attachment of complex oligosaccharides--glycans. Both glycans and polypeptide parts of a protein contribute to its structure and function, but contrary to polypeptide that is defined by the sequence of nucleotides in the corresponding gene, glycans are shaped by complex dynamic interactions between hundreds of enzymes, transcription factors, ion channels and other proteins. SCOPE OF REVIEW: An overview of current knowledge about the importance of N-glycans in normal human physiology and disease mechanisms, exemplified by IgG N-glycans. MAJOR CONCLUSIONS: Recent technological development enabled systematic analysis of glycome composition in large epidemiological cohorts and clinical studies. However, the majority of these studies is still missing any glycomic component, and consequently also lacks this layer of biological information. Individual variation in glycosylation is potentially important for individualized disease risk, disease course and response to therapy. Evidence in support of this hypothesis is accumulating, but further studies are needed to enable understanding of the role of changes in protein glycosylation in disease. GENERAL SIGNIFICANCE: Glycans are involved in virtually all physiological processes. Inter-individual variation in glycome composition is large, and these differences associate with disease risk, disease course and the response to therapy. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. PMID- 26500100 TI - EUS-Guided Transgastric Drainage of Perihepatic Biloma After Laparoscopic Liver Metastasectomy from Colon Cancer. PMID- 26500101 TI - Cannabinoid WIN55, 212-2 induces cell cycle arrest and inhibits the proliferation and migration of human BEL7402 hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is the leading cause of cancer-associated mortality worldwide; however, only limited therapeutic treatments are currently available. The present study aimed to investigate the effects of cannabinoids as novel therapeutic targets in HCC. In addition, the mechanism underlying the effects of a synthetic cannabinoid, WIN55, 212-2, on the BEL7402 HCC cell line was investigated. The results demonstrated that WIN55, 212-2 induced cell cycle arrest of the BEL7402 cells at the G0/G1 phase via cannabinoid receptor 2 (CB2) mediated downregulation of phosphorylated-extracellular signal-regulated kinases (ERK)1/2, upregulation of p27, and downregulation of cyclin D1 and cyclin dependent kinase 4. Furthermore, inhibition of CB2 with the CB2 antagonist AM630 abrogated WIN55, 212-2-induced cell cycle arrest. Inhibition of ERK1/2 also resulted in cell cycle dysregulation and cell cycle arrest at the G0/G1 phase, which subsequently resulted in cell growth inhibition. In addition, the present study detected a significant reduction in matrix metalloproteinase-9, retinoblastoma protein and E2F1 expression, and migration inhibition by WIN treatment. These results suggested that cannabinoid receptor agonists, including WIN, may be considered as novel therapeutics for the treatment of HCC. PMID- 26500102 TI - Endogenous Acetylcholine Controls the Severity of Polymicrobial Sepsisassociated Inflammatory Response in Mice. AB - Acetylcholine (ACh) is the main mediator associated with the anti-inflammatory cholinergic pathway. ACh plays an inhibitory role in several inflammatory conditions. Sepsis is a severe clinical syndrome characterized by bacterial dissemination and overproduction of inflammatory mediators. The aim of the current study was to investigate the participation of endogenous ACh in the modulation of inflammatory response induced by a model of polymicrobial sepsis. Wild type (WT) and vesicular acetylcholine transporter knockdown (VAChT(KD)) mice were exposed to cecal ligation and perforation- induced sepsis. Levels of Tumor Necrosis Factor Alpha (TNF-alpha) and bacterial growth in peritoneal cavity and serum, and neutrophil recruitment into peritoneal cavity were assessed. The concentration of TNF-alpha in both compartments was higher in VAChT(KD) in comparison with WT mice. VAChT(KD) mice presented elevated burden of bacteria in peritoneum and blood, and impairment of neutrophil migration to peritoneal cavity. This phenotype was reversed by treatment with nicotine salt. These findings suggest that endogenous ACh plays a major role in the control of sepsis associated inflammatory response. PMID- 26500103 TI - Reversal in Cognition Impairments, Cholinergic Dysfunction, and Cerebral Oxidative Stress Through the Modulation of Ryanodine Receptors (RyRs) and Cysteinyl Leukotriene-1 (CysLT1) Receptors. AB - Chronic cerebral hypoperfusion (CCH) is a general pathophysiological condition occurring in vascular dementia (VaD) associated with negative impact on cognitive functions. Ryanodine as well as cysteinyl leukotriene-1 receptors (RyRs and CysLT1Rs) are extensively present in the central nervous system, where they participate in regulation of cognition, motivation, inflammation and neurodegeneration. The purpose of this study is to examine the role of ruthenium red; a selective RyR blocker as well as montelukast; a specific CysLT1 antagonist in CCH induced VaD in mice. Two vessel occlusion (2VO) or permanent ligation of bilateral common carotid arteries technique was used to induce CCH in mice. Animals with bilateral carotid arteries occlusion have revealed impaired learning and memory (Morris water maze), cholinergic dysfunction (increased acetylcholinesterase activity) as well as increased brain oxidative stress (reduction in brain superoxide dismutase, glutathione and catalase with an increase in thiobarbituric acid reactive substance level), with increased brain infarct size (2,3,5-triphenylterazolium chloride staining). While, administration of ruthenium red and montelukast considerably attenuated CCH induced cognitive impairments, cholinergic dysfunction, brain oxidative stress as well as brain damage. The results suggest that bilateral carotid arteries occlusion induced CCH has brought out VaD, which was attenuated by treatment with ruthenium red and montelukast. Therefore, modulation of RyRs as well as CysLT1 receptors may provide help in conditions involving CCH such as cognitive impairment and VaD. PMID- 26500104 TI - Genome-wide identification and comparative analysis of grafting-responsive mRNA in watermelon grafted onto bottle gourd and squash rootstocks by high-throughput sequencing. AB - Grafting is an important agricultural technique widely used to improve plant growth, yield, and adaptation to either biotic or abiotic stresses. However, the molecular mechanisms underlying grafting-induced physiological processes remain unclear. Watermelon (Citrullus lanatus L.) is an important horticultural crop worldwide. Grafting technique is commonly used in watermelon production for improving its tolerance to stresses, especially to the soil-borne fusarium wilt disease. In the present study, we used high-throughput sequencing to perform a genome-wide transcript analysis of scions from watermelon grafted onto bottle gourd and squash rootstocks. Our transcriptome and digital gene expression (DGE) profiling data provided insights into the molecular aspects of gene regulation in grafted watermelon. Compared with self-grafted watermelon, there were 787 and 3485 genes differentially expressed in watermelon grafted onto bottle gourd and squash rootstocks, respectively. These genes were associated with primary and secondary metabolism, hormone signaling, transcription factors, transporters, and response to stimuli. Grafting led to changes in expression of these genes, suggesting that they may play important roles in mediating the physiological processes of grafted seedlings. The potential roles of the grafting-responsive mRNAs in diverse biological and metabolic processes were discussed. Obviously, the data obtained in this study provide an excellent resource for unraveling the mechanisms of candidate genes function in diverse biological processes and in environmental adaptation in a graft system. PMID- 26500106 TI - Disrupting Electronic Health Records Systems: The Next Generation. AB - The health care system suffers from both inefficient and ineffective use of data. Data are suboptimally displayed to users, undernetworked, underutilized, and wasted. Errors, inefficiencies, and increased costs occur on the basis of unavailable data in a system that does not coordinate the exchange of information, or adequately support its use. Clinicians' schedules are stretched to the limit and yet the system in which they work exerts little effort to streamline and support carefully engineered care processes. Information for decision-making is difficult to access in the context of hurried real-time workflows. This paper explores and addresses these issues to formulate an improved design for clinical workflow, information exchange, and decision making based on the use of electronic health records. PMID- 26500105 TI - TIPE2 Play a Negative Role in TLR4-Mediated Autoimmune T Helper 17 Cell Responses in Patients with Myasthenia Gravis. AB - Th17-related cytokines have been suggested to play a crucial role in myasthenia gravis (MG) pathogenesis.The tumor necrosis factor (TNF)-alpha-induced protein 8 like-2 (TNFAIP8L2 or TIPE2), is a newly identified member of the tumor necrosis TNFAIP8 family which is an essential negative regulator of both innate and adaptive immunity. In the present study, the expression of TIPE2 mRNA and protein in peripheral blood mononuclear cells (PBMC) from healthy and MG subjects were detected by Real-time PCR and Western blotting.The serum IL-6, IL-17 and IL-21 levels were tested by ELISA. Furthermore, PBMC from MG patients were purified and stimulated with LPS (TLR4 agonist) with or without transfection of TIPE2 expressing adenovirus, then the expression of TIPE2 and Th17-specific transcriptional factor RORgammat and the IL-6, IL-17 and IL-21 levels of supernatant were analized. Our data demonstrated that the expression of TIPE2 mRNA and protein was reduced in MG compared with normal controls, with lower expression in generalized patients than in ocular ones. Furthermore, TIPE2 mRNA presents a significantly negative correlation with the serum levels of IL-6, IL 17 and IL-21 in either generalized patients or ocular patients. In cultured MG PBMC, TLR4 activation led to the down-regulation of TIPE2, while the expression of RORgammat and production of IL-6, IL-17 and IL-21 were significantly increased. However, when TIPE2 was overexpressed, these TLR4 activation-induced effects were significantly abrogated. Overall, our results indicated for the first time that TIPE2 may participate in the development of MG through negatively regulation of TLR4-mediated autoimmune T helper 17 cell responses. PMID- 26500108 TI - Gluten Introduction to Infant Feeding and Risk of Celiac Disease: Systematic Review and Meta-Analysis. AB - OBJECTIVE: To assess the evidence regarding the effect of time of gluten introduction and breastfeeding on the risk of developing celiac disease (CD). STUDY DESIGN: We included randomized controlled trials and observational studies evaluating the proper timing for introducing gluten to the infant diet, the appropriate quantity of gluten consumption at weaning, and the effect of breastfeeding on CD risk. Studies were located through the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), EMBASE (Ovid), and System for Information on Grey Literature in Europe (SIGLE). Two independent authors collected the data. RESULTS: A total of 1982 studies were identified, 15 of which were eligible for data extraction. A meta-analysis was performed on 2 randomized controlled trials, 10 cohort studies, and 1 case control study. There was a 25% increase in CD risk with late (>6 months) vs recommended (4-6 months) gluten introduction (risk ratio [RR], 1.25; 95% CI, 1.08 1.45). There was no significant effect of breastfeeding vs no breastfeeding on CD risk (OR, 0.55; 95% CI, 0.28-1.10), with substantial heterogeneity (I(2) = 92%) among studies. CONCLUSION: There is currently no evidence to support that early introduction of gluten to the infant diet increases the risk of CD; however, late introduction of gluten may be associated with increased risk of CD. More studies are needed that control for potential confounders and that evaluate environmental factors in low-risk families. PMID- 26500109 TI - Differential gene expression in human, murine, and cell line-derived macrophages upon polarization. AB - The mechanisms by which macrophages control the inflammatory response, wound healing, biomaterial-interactions, and tissue regeneration appear to be related to their activation/differentiation states. Studies of macrophage behavior in vitro can be useful for elucidating their mechanisms of action, but it is not clear to what extent the source of macrophages affects their apparent behavior, potentially affecting interpretation of results. Although comparative studies of macrophage behavior with respect to cell source have been conducted, there has been no direct comparison of the three most commonly used cell sources: murine bone marrow, human monocytes from peripheral blood (PB), and the human leukemic monocytic cell line THP-1, across multiple macrophage phenotypes. In this study, we used multivariate discriminant analysis to compare the in vitro expression of genes commonly chosen to assess macrophage phenotype across all three sources of macrophages, as well as those derived from induced pluripotent stem cells (iPSCs), that were polarized towards four distinct phenotypes using the same differentiation protocols: M(LPS,IFN) (aka M1), M(IL4,IL13) (aka M2a), M(IL10) (aka M2c), and M(-) (aka M0) used as control. Several differences in gene expression trends were found among the sources of macrophages, especially between murine bone marrow-derived and human blood-derived M(LPS,IFN) and M(IL4,IL13) macrophages with respect to commonly used phenotype markers like CCR7 and genes associated with angiogenesis and tissue regeneration like FGF2 and MMP9. We found that the genes with the most similar patterns of expression among all sources were CXCL-10 and CXCL-11 for M(LPS,IFN) and CCL17 and CCL22 for M(IL4,IL13). Human PB-derived macrophages and human iPSC-derived macrophages showed similar gene expression patterns among the groups and genes studied here, suggesting that iPSC-derived monocytes have the potential to be used as a reliable cell source of human macrophages for in vitro studies. These findings could help select appropriate markers when testing macrophage behavior in vitro and highlight those markers that may confuse interpretation of results from experiments employing macrophages from different sources. PMID- 26500110 TI - Aberrant miR-21 and miR-200b expression and its pro-fibrotic potential in hypertrophic scars. AB - The post-traumatic hypertrophic scar (HS) is a fibrotic disease with excessive extracellular matrix (ECM) production by fibroblasts in response to tissue injury. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNA in hypertrophic scar formation is unclear. Abnormal expression of miRNA in fibrosis has been investigated in several studies. The transforming growth factor beta1 (TGF-beta1) promotes fibroblasts proliferation, the synthesis of collagen and other extracellular matrix, and ultimately leads to the formation of the HS by inducing excessive deposition of ECM. We identified two miRNAs whose expression was correlated with fibrotic diseases: miR-21 and miR-200b. This study further confirmed that after stimulation with TGF-beta1, the expression of miR-21 was increased, whereas the mRNA level of SMAD7 was decreased in fibroblasts. TGF-beta1 reduced the expression of miR-200b, while it augmented that of Zinc finger E-box-binding homeobox 1(Zeb1). Our experiments demonstrated that the expression of miR-21 and miR-200b are related to a disorder, and the TGF-beta/miR-21/Smad7 and TGF beta/miR200b/Zeb1 pathways might participate in the pathogenesis of HS. Thus, a novel, beyond the traditional methods, approach for HS treatment via miRNA therapeutics could have been provided. PMID- 26500111 TI - Visualizing cell-cycle kinetics after hypoxia/reoxygenation in HeLa cells expressing fluorescent ubiquitination-based cell cycle indicator (Fucci). AB - Hypoxia induces G1 arrest in many cancer cell types. Tumor cells are often exposed to hypoxia/reoxygenation, especially under acute hypoxic conditions in vivo. In this study, we investigated cell-cycle kinetics and clonogenic survival after hypoxia/reoxygenation in HeLa cells expressing fluorescent ubiquitination based cell cycle indicator (Fucci). Hypoxic treatment halted cell-cycle progression during mid-S to G2 phase, as determined by the cell cycle-regulated E3 ligase activities of SCF(Skp2) and APC/C(Cdh1), which are regulators of the Fucci probes; however, the DNA content of the arrested cells was equivalent to that in G1 phase. After reoxygenation, time-lapse imaging and DNA content analysis revealed that all cells reached G2 phase, and that Fucci fluorescence was distinctly separated into two fractions 24h after reoxygenation: red cells that released from G2 arrest after repairing DNA double-strand breaks (DSBs) exhibited higher clonogenic survival, whereas most cells that stayed green contained many DSBs and exhibited lower survival. We conclude that hypoxia disrupts coordination of DNA synthesis and E3 ligase activities associated with cell-cycle progression, and that DSB repair could greatly influence cell-cycle kinetics and clonogenic survival after hypoxia/reoxygenation. PMID- 26500112 TI - A structural insight into the inhibitory mechanism of an orally active PI3K/mTOR dual inhibitor, PKI-179 using computational approaches. AB - The PI3K/AKT/mTOR signaling pathway has been identified as an important target for cancer therapy. Attempts are increasingly made to design the inhibitors against the key proteins of this pathway for anti-cancer therapy. The PI3K/mTOR dual inhibitors have proved more effective than the inhibitors against only single protein targets. Recently discovered PKI-179, an orally effective compound, is one such dual inhibitor targeting both PI3K and mTOR. This anti cancer compound is efficacious both in vitro and in vivo. However, the binding mechanisms and the molecular interactions of PKI-179 with PI3K and mTOR are not yet available. The current study investigated the exact binding mode and the molecular interactions of PKI-179 with PI3Kgamma and mTOR using molecular docking and (un)binding simulation analyses. The study identified PKI-179 interacting residues of both the proteins and their importance in binding was ranked by the loss in accessible surface area, number of molecular interactions of the residue, and consistent appearance of the residue in (un)binding simulation analysis. The key residues involved in binding of PKI-179 were Ala-805 in PI3Kgamma and Ile 2163 in mTOR as they have lost maximum accessible surface area due to binding. In addition, the residues which played a role in binding of the drug but were away from the catalytic site were also identified using (un)binding simulation analyses. Finally, comparison of the interacting residues in the respective catalytic sites was done for the difference in the binding of the drug to the two proteins. Thus, the pairs of the residues falling at the similar location with respect to the docked drug were identified. The striking similarity in the interacting residues of the catalytic site explains the concomitant inhibition of both proteins by a number of inhibitors. In conclusion, the docking and (un)binding simulation analyses of dual inhibitor PKI-179 with PI3K and mTOR will provide a suitable multi-target model for studying drug-protein interactions and thus help in designing the novel drugs with higher potency. PMID- 26500107 TI - Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide. AB - OBJECTIVE: To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Extremely low GA newborn infants (GA <=28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction. RESULTS: A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 +/- 164 g), GA (25.2 +/- 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks. CONCLUSION: Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580. PMID- 26500113 TI - Experimental and theoretical study of alpha-Eu2(MoO4)3 under compression. AB - The compression process in the alpha-phase of europium trimolybdate was revised employing several experimental techniques. X-ray diffraction (using synchrotron and laboratory radiation sources), Raman scattering and photoluminescence experiments were performed up to a maximum pressure of 21 GPa. In addition, the crystal structure and Raman mode frequencies have been studied by means of first principles density functional based methods. Results suggest that the compression process of alpha-Eu2(MoO4)3 can be described by three stages. Below 8 GPa, the alpha-phase suffers an isotropic contraction of the crystal structure. Between 8 and 12 GPa, the compound undergoes an anisotropic compression due to distortion and rotation of the MoO4 tetrahedra. At pressures above 12 GPa, the amorphization process starts without any previous occurrence of a crystalline-crystalline phase transition in the whole range of pressure. This behavior clearly differs from the process of compression and amorphization in trimolybdates with [Formula: see text]-phase and tritungstates with alpha-phase. PMID- 26500115 TI - Relamorelin to Treat Constipation: "Pusher" or Pushover? PMID- 26500114 TI - Acculturative Dissonance and Risks for Proactive and Reactive Aggression Among Latino/a Adolescents: Implications for Culturally Relevant Prevention and Interventions. AB - There is a dearth of studies concerning the functions of aggression among Latino/a youth despite the fact they are one of the fastest growing youth populations in the United States. We examined individual, peer, cultural, and community level indicators of reactive and proactive aggression and determined whether these relationships were moderated by acculturative dissonance (e.g., culturally specific family conflicts arising from the acculturation process) among a sample of Latino/a adolescents who were predominantly of Mexican heritage. Consistent with prior evidence, results revealed that peer delinquency was uniquely associated with proactive aggression, whereas impulsivity was uniquely associated with reactive aggression. Further, acculturative dissonance was uniquely associated with proactive but not reactive aggression. No moderating effects for acculturative dissonance were found, indicating that the significant risk factors in our study were associated with proactive and reactive aggression regardless of the level of acculturative dissonance experienced. Notably, acculturative dissonance was a unique risk factor for proactive aggression and thus may be an important target for prevention and interventions among Latino/a youth. Consequently, interventions designed to prevent culturally specific family conflicts and promote family functioning may be particularly useful in mitigating the risk of aggression intended to achieve social and material awards among in this population. PMID- 26500116 TI - Glucagon Is a Safe and Inexpensive Initial Strategy in Esophageal Food Bolus Impaction. AB - BACKGROUND: Controversy exists about the utility of pharmacologic agents and endoscopic technique used for esophageal food bolus impaction. AIM: To evaluate the utility of glucagon and the technique used for endoscopic removal, including the rate of success and the adverse events of the techniques. METHODS: The database of the largest healthcare provider in southeastern Wisconsin was retrospectively reviewed for patients presenting with esophageal food bolus impaction. Data extracted included glucagon administration and its success rate, outcome of radiographic studies, and the endoscopic method of removal and adverse events associated with it, including 30-day mortality. RESULTS: A total of 750 patients were identified with food bolus impaction from 2007 to 2012. Glucagon was administered in 440 patients and was successful in 174 (39.5%). Endoscopic removal was performed in 470 patients and was successful in 469 (99.8%). The push technique was utilized in 209 patients, reduction in the bolus size by piecemeal removal followed by the push technique was utilized in 97 patients, and the pull technique was utilized in 107 patients. There were no perforations with endoscopic removal. Only 4.5% of the X-rays performed reported a possible foreign body within the esophagus. Glucagon was a significantly less-expensive strategy than endoscopic therapy (p < 0.0001). CONCLUSION: Glucagon is low cost, is moderately effective, and may be considered as an initial strategy. Endoscopic removal regardless of technique is safe and effective. The yield of radiography is poor in the setting of food bolus impaction. PMID- 26500117 TI - Akt2-Dependent Phosphorylation of Radixin in Regulation of Mrp-2 Trafficking in WIF-B Cells. AB - BACKGROUND: The dominant ezrin/radixin/moesin protein in hepatocytes is radixin, which plays an important role in mediating the binding of F-actin to the plasma membrane after a conformational activation by phosphorylation at Thr564. AIM: Here we have investigated the importance of Akt-mediated radixin Thr564 phosphorylation on Mrp-2 distribution and function in WIF-B cells. Mrp-2 is an adenosine triphosphate (ATP)-binding cassette transporter that plays an important role in detoxification and chemoprotection by transporting a wide range of compounds, especially conjugates of lipophilic substances with glutathione, organic anions, and drug metabolites such as glucuronides. METHODS: Akt1 and Akt2 expression were manipulated using dominant active and negative constructs as well as Akt1 and Akt2 siRNA. Cellular distribution of radixin and Mrp-2 was visualized by fluorescence microscopy. A 5-chloromethylfluorescein diacetate, which is a substrate of the Mrp-2 and is actively transported in canalicular lumina, was used to measure Mrp-2 function. RESULTS: Radixin phosphorylation was significantly increased in wild-type and dominant active Akt2 transfected cells. Furthermore, radixin and Mrp-2 were localized at the canalicular membrane, similar to control cells. In contrast, overexpression of dominant negative Akt2, siRNA knockdown of Akt2 and a specific Akt inhibitor prevented radixin phosphorylation and led to alteration of normal radixin and Mrp-2 localization; inhibition of Akt2, but not Akt1 function led to radixin localization to the cytoplasmic space. In addition, dominant negative and Akt2 knockdown led to a dramatically impaired hepatocyte secretory response, while wild-type and dominant active Akt2 transfected cells exhibited increased 5-chloromethylfluorescein diacetate excretion. In contrast to Akt2, Akt1 was not associated with radixin phosphorylation. CONCLUSIONS: These studies, therefore, identify Akt2 as a critical kinase that regulates radixin phosphorylation and leads to Mrp-2 translocation and function. PMID- 26500118 TI - PKM2 Promotes Cell Survival and Invasion Under Metabolic Stress by Enhancing Warburg Effect in Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: Pyruvate kinase isoenzyme M2 (PKM2) is an essential enzyme involved in the regulation of aerobic glycolysis in cancer cells and promotes the translation between glycolytic flux and biosynthesis of cellular building blocks. AIM: Our present study aims to explore the expression pattern and underlying cellular functions of PKM2 in pancreatic ductal adenocarcinoma (PDAC) under metabolic stress. METHODS: Oncomine database and a tissue microarray (n = 90) were used to investigate the expression pattern of PKM2 and its clinicopathological findings. In vitro proliferation, apoptosis and invasion assays were used to determine the role and related mechanism of PKM2 in PDAC. RESULTS: Data from Oncomine database and our tissue microarray show that PKM2 is significantly elevated in PDAC specimens compared with the corresponding normal tissues. Kaplan-Meier survival analysis shows that higher expression of PKM2 is closely correlated with a poor prognosis of patients with PDAC. Under metabolic stress, suppression of PKM2 expression in PANC-1 and AsPC-1 cells results in decreased cell survival, increased caspase-3/7 activity, and reduced invasive potential, and these effects can be reversed by reintroduction of PKM2. Furthermore, sh-PKM2 cells show a significant decreased Warburg effect compared with sh-Ctrl cells as demonstrated by reduced glucose consumption and lactate production. Treatment with 2-deoxy-D-glucose, a glycolysis inhibitor, completely blocks the influences of PKM2 on cell survival and invasion. CONCLUSIONS: Our study reveals that silencing of PKM2 exhibits a tumor-suppressive role through altered Warburg effect and suggests that targeting PKM2 might serve as a potential therapeutic target for PDAC. PMID- 26500121 TI - Morphine modulates the effects of histamine H1 and H3 receptors on seizure susceptibility in pentylenetetrazole-induced seizure model of mice. AB - Histamine regulates release of neurotransmitters such as dopamine, serotonin, gamma-aminobutyric acid (GABA), glutamate and also is involved in several functions in central nervous system (CNS). It has been shown that histamine participates in disorders like seizure. It has been well documented that morphine dose-dependently induces anti or proconvulsant effects. In the current study, we firstly showed that morphine (1mg/kg) exerts anticonvulsant effects which significantly reversed by naltrexone administration. Secondly, we determined seizure threshold for H1 and H3 receptors agonists and antagonists in mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. Our results showed that activation of H1 receptors by 2-(2-Pyridyl)-ethylamine exerts anticonvulsant properties while inhibition of H1 receptors by pyrilamine maleate induced proconvulsant effects. Furthermore, we showed that immepip dihydrobromide, a H3 receptor agonist, increased seizure susceptibility to PTZ whereas thioperamide, a H3 receptor antagonist increased seizure threshold. We also revealed that pretreatment with morphine potently reversed the effects of histaminergic system on seizure threshold suggesting the involvement of opioid system in alteration of seizure threshold by histaminergic drugs. PMID- 26500122 TI - Nursing staff shortfalls make special measures more likely. PMID- 26500123 TI - Boosting immunity: new vaccines for children. PMID- 26500124 TI - Seizures: awareness and observation in the ward environment. AB - The preconceived 'foaming' and 'violent' seizure stereotypes are misrepresentations, particularly by non-specialist health professionals. Thus the vast semiology (signs and symptoms) of seizures and their subtle signs too easily go unrecognised by the untrained eye. Nevertheless, a significant proportion of adult patients admitted to the ward for treatment of their current illness will have a pre-existing seizure disorder (epilepsy). Furthermore, such hospitalised patients are more likely to suffer a seizure within the ward environment as triggering factors are unavoidably present. Thus, it is essential that nurses are prepared to encounter seizures, irrespective of the reason for admission. This article discusses the clinical semiology of the various seizure types in association with the underpinning neuropathophysiology, as well as the potential seizure triggers. It thereby enhances nurses' awareness and observations of seizure activity in patients in the ward environment. PMID- 26500125 TI - Nurses' perceptions of self-management in renal care. AB - Self-management is vital for patients with long-term conditions in order to ensure wellbeing. It needs to be supported by a healthcare workforce who are knowledgeable and able to work in collaboration with individuals. In this study, ten nurses were selected by means of exclusion/inclusion criteria and then interviewed with a semi-structured approach. Following analysis of the data with an open, axial and selective coding process, clear themes emerged: expectation of roles, lack of confidence and concerns with risk-taking. There were a number of concerns around engaging with self-management for this group of nurses, including a lack of knowledge and skills to assess the suitability of patients for self management and subsequently to offer support, and concerns that self-management would be too unsafe in a renal setting. This study suggests that nurses would need education in strategies to support and implement self-management. Further studies should be undertaken to explore this possibility with renal patients admitted to the ward. PMID- 26500126 TI - Comparing palliative care provision in India and the UK. AB - The Prince & Princess of Wales Hospice in Glasgow is committed to developing culturally competent, sensitive services to meet the needs of local ethnic minority communities. The clinical nurse specialist for widening access travelled to India, funded by a travel scholarship from the Florence Nightingale Foundation. The main rationale for this visit was to observe and compare palliative care practice in India in community, hospice and hospital settings with the current service provision by the hospice/hospital palliative care teams in Glasgow. A second focus was to study the cultural differences and potential challenges of providing palliative care to a diverse Indian population from multi faith communities and different socio-economic classes. Throughout the visit the barriers to accessing palliative care services in India were observed as well as cultural norms that might impact on clinical practice in the UK. PMID- 26500127 TI - Taking care of our children and young people. AB - John Tingle discusses two reports looking at the health, care and wellbeing of children. PMID- 26500128 TI - Will the UK Supreme Court allow assisted dying? AB - MPs overwhelmingly voted against passing the Assisted Dying Bill into law in September 2015. The Bill was defeated by a majority of 212, despite the heartfelt pleas of many MPs to pass it into law. The size of the defeat means that it is unlikely that Parliament will consider a similar law for many years. Yet many considered the Bill their last opportunity to make assisted dying lawful. There is, however, one further possible way assisted dying could become lawful in the UK--and that would be where the Supreme Court allowed it. In this article, the author reviews the Supreme Court's decision in R (on the application of Nicklinson v Ministry of Justice [2014] and considers how likely it is that the Supreme Court will now sanction assisted dying following Parliament's refusal to enact an assisted dying law. PMID- 26500129 TI - Is the nursing profession ready for revalidation? AB - Emeritus professor Alan Glasper, from the University of Southampton, discusses progress made by the Nursing and Midwifery Council (NMC) on plans to introduce revalidation for nurses in 2016. PMID- 26500130 TI - To whistleblow, or not--and dealing with the repercussions. AB - In this month's column, Aysha Mendes discusses the moral distress a nurse may experience when witnessing care that he or she feels is not up to standard-and being faced with the decision about whether or not to blow the whistle, as well as what the consequences could be. PMID- 26500131 TI - Preparing students to deliver integrated care. PMID- 26500132 TI - Writing for publication: from staff nurse to nurse consultant. PMID- 26500133 TI - Bridging the generation gap to aid recruitment and retention. PMID- 26500134 TI - Is There Still a Role for Low-Dose All-Transretinoic Acid in the Treatment of Acute Promyelocytic Leukemia in the Arsenic Trioxide Era? AB - BACKGROUND: Low-dose all-transretinoic acid (LD-ATRA) has shown similar peak plasma concentrations and a mean area under the concentration time curve in comparison with standard doses of ATRA. We evaluated the efficacy of LD-ATRA plus anthracycline-based chemotherapy in patients with newly diagnosed acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Patients diagnosed with APL during the period of 2002 to 2014 were included. They received ATRA 25 mg/m(2) plus anthracycline (doxorubicin or mitoxantrone) as induction chemotherapy, followed by 3 consolidations with LD-ATRA and anthracycline and maintenance therapy with intermittent LD-ATRA and oral chemotherapy for 2 years. RESULTS: Twenty-two patients with a median age of 28 years (range, 18-55 years) were included; 17 (77%) were in the low-risk group. Complete remission occurred in 86%, and the early death rate was 9%. At a median follow-up of 32 months (range, 4-126 months) disease-free survival (DFS) was 75% and overall survival (OS) was 86%, with a relapse rate of 27% for the entire follow-up period. CONCLUSION: LD ATRA plus anthracycline is safe and effective in achieving CR of APL. The early death rate is similar to that of treatment with standard doses, but it appears to be inferior in preventing relapses. PMID- 26500135 TI - Prognostic Factors, Response to Treatment, and Survival in Patients With Chronic Myeloid Leukemia in Blast Phase: A Single-Institution Survey. AB - INTRODUCTION: Data from 51 patients (23 women) with chronic myeloid leukemia (CML) in blast phase (BP) were analyzed in order to identify prognostic factors for complete hematologic response (CHR) and survival. PATIENTS AND METHODS: Forty four patients experienced disease progression from chronic or accelerated phase, and 7 cases presented as CML-BP. Thirteen patients (25.5%) had extramedullary involvement at diagnosis, and 71% were myeloid BP. Clonal evolution was identified in 53% of the cases, and the abnormalities most frequently observed were isochromosome (17q), double Philadelphia chromosome, and trisomy 8. Forty five patients received treatment: 60% chemotherapy (CT) alone and 40% CT plus tyrosine kinase inhibitors (TKI) or TKI alone; 42% of them experienced CHR. RESULTS: Median overall survival (OS) in patients whose disease responded to treatment was 7 months (95% confidence interval, 1.7-6.2 months), with a median disease-free survival of 5 months (95% confidence interval, 2.8-5.8 months). One out of 3 patients who underwent hematopoietic stem-cell transplantation remains alive. Multivariate analysis revealed that lymphoid BP and TKI therapy had a statistically significant positive impact as prognostic factors for CHR. In the multivariate analysis, age > 60 years, hemoglobin < 10 g/dL, and complex karyotype were statistically significant negative prognostic factors for OS. There was no statistical significant difference in OS between patients who received only CT (1988-2002) with those treated with CT plus TKI (2003-2013). CONCLUSION: This is the first study in Mexico to report prognostic factors associated with CHR and OS in patients with CML-BP. PMID- 26500136 TI - A comparison of open and endovascular treatment strategies for the management of splenic artery aneurysms. AB - Splenic artery aneurysms are rare with an incidence of less than 0.8%. Evidence to support an endovascular management strategy over open surgical repair for SAA is limited. We used the Nationwide Inpatient Sample to compare open to endovascular SAA repair by assessing postoperative outcomes, length of hospital stay, and mortality. Multivariate logistic regression analysis was done to determine predictors of postoperative complications. There were 2316 admissions with a diagnosis code for SAA [347 (14.9%) endovascular repair and 112 (4.8%) open surgery]. There was a statistically significant lower rate of cardiac (2.3% vs 6.9%, P = 0.05) and pulmonary (8.9% vs 16.1%, P = 0.05) complications for the endovascular repair group. The risk of surgical site infection was also lower (0.6% vs 5.1%, P = 0.01) in the endovascular group. Median in-hospital LOS was greater for open repairs (6 vs. 4 days, P = 0.01). There were no statistically significant differences across procedures for renal complications (8.9%, P = 0.88) or in-hospital mortality (3%, P = 0.99). Regression analysis established procedure type to be independent predictor of postoperative complications. Endovascular repair of SAA is therefore associated with a lower complication rate and less resource utilization but no difference in mortality peri-operatively. This may justify an endovascular first treatment strategy in the management of SAA. PMID- 26500137 TI - Surface soil phytoliths as vegetation and altitude indicators: a study from the southern Himalaya. AB - Phytoliths represent one of the few available altitudinal vegetation proxies for mountain ecosystems. This study analyzed 41 topsoil phytolith samples collected from five altitudinal zones in the southern Himalaya as far as, and beyond, the timberline, from tropical forest (up to 1,000 m a.s.l.) to subtropical forest (1,000-2,000 m a.s.l.), to temperate forest (2,000-3,000 m a.s.l.), to subalpine forest (3,000-4,100 m a.s.l.) and finally to alpine scrub (4,100-5,200 m a.s.l.). The statistical results show a good correlation between phytolith assemblages and these five altitudinal vegetation zones: the five phytolith assemblages identified effectively differentiated these five altitudinal vegetation zones. In particular, coniferous phytoliths accurately indicated the timberline. Additionally, we tested the phytolith index Ic (a proxy for estimating the percentage of Pooideae vis-a-vis the total grass content) as a quantifier of phytolith variety versus altitude. Ic increased along altitude, as expected. An investigation of phytoliths provided an initial basis for the analysis of the composition of gramineous vegetation. Furthermore, redundancy analysis and discriminant analysis also suggested a significant correlation between phytolith assemblages and altitude. Our research therefore provides an up-to-date analogue for the reconstruction of changes to palaeovegetation and palaeoaltitude in mountainous areas. PMID- 26500138 TI - Thrombocytopenia in MDS: epidemiology, mechanisms, clinical consequences and novel therapeutic strategies. AB - Thrombocytopenia is commonly seen in myelodysplastic syndrome (MDS) patients, and bleeding complications are a major cause of morbidity and mortality. Thrombocytopenia is an independent factor for decreased survival and has been incorporated in newer prognostic scoring systems. The mechanisms of thrombocytopenia are multifactorial and involve a differentiation block of megakaryocytic progenitor cells, leading to dysplastic, hypolobated and microscopic appearing megakaryocytes or increased apoptosis of megakaryocytes and their precursors. Dysregulated thrombopoietin (TPO) signaling and increased platelet destruction through immune or nonimmune mechanisms are frequently observed in MDS. The clinical management of patients with low platelet counts remains challenging and approved chemotherapeutic agents such as lenalidomide and azacytidine can also lead to a transient worsening of thrombocytopenia. Platelet transfusion is the only supportive treatment option currently available for clinically significant thrombocytopenia. The TPO receptor agonists romiplostim and eltrombopag have shown clinical activity in clinical trials in MDS. In addition to thrombopoietic effects, eltrombopag can inhibit leukemic cell proliferation via TPO receptor-independent effects. Other approaches such as treatment with cytokines, immunomodulating drugs and signal transduction inhibitors have shown limited activity in selected groups of MDS patients. Combination trials of approved agents with TPO agonists are ongoing and hold promise for this important clinical problem. PMID- 26500139 TI - Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion. AB - After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA. PMID- 26500141 TI - A novel Lin-CD34+CD38- integrin alpha2- bipotential megakaryocyte-erythrocyte progenitor population in the human bone marrow. PMID- 26500140 TI - FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas. AB - The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P<0.05). FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL patients (n=150), reduced HLA-DRA (<90% frequency) expression correlated with inferior overall survival (P=0.0003) and progression-free survival (P=0.0012) and with non-GCB subtype stratified by the Hans, Choi or Visco-Young algorithms (all P<0.01). In non-GCB DLBCL cases with <90% HLA-DRA, there was an inverse correlation with the frequency (P=0.0456) and intensity (P=0.0349) of FOXP1 expression. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients. PMID- 26500143 TI - Long-term complete clinical and hematological responses of the TEMPI syndrome after autologous stem cell transplantation. PMID- 26500144 TI - Kaposi varicelliform eruption in patients with autoimmune bullous dermatoses. AB - BACKGROUND: Viral superinfection of skin affected by preceding dermatosis has been studied extensively in eczema and reported anecdotally in pemphigus. Little is known about its involvement and complications in patients with other immunobullous diseases. METHODS: To investigate clinical features and complications of viral superinfection in patients with immunobullous diseases, we performed a retrospective chart review. RESULTS: We identified 12 patients with immunobullous diseases (linear immunoglobulin A bullous dermatosis, n = 2; pemphigoid, n = 3; pemphigus, n = 7) and superinfection by herpes simplex virus 1 (n = 9) or 2 (n = 3). Complications included inpatient hospitalization for intensive management of skin lesions during viral flare (n = 6), herpes keratitis (n = 1), and death due to sepsis (n = 1). Five patients previously had a skin swab negative for herpes simplex virus polymerase chain reaction before a positive test. Nine patients were taking systemic corticosteroids or corticosteroid-sparing agents at herpetic infection; two with linear immunoglobulin A bullous dermatosis and one with a new diagnosis of pemphigus vulgaris had not. CONCLUSIONS: Viral superinfection is a potentially serious complication in patients with immunobullous diseases. Clinicians should have a high index of suspicion for this phenomenon, even when patients are not otherwise immunosuppressed or when previous viral skin assays have been negative. PMID- 26500142 TI - Reprogramming human B cells into induced pluripotent stem cells and its enhancement by C/EBPalpha. AB - B cells have been shown to be refractory to reprogramming and B-cell-derived induced pluripotent stem cells (iPSC) have only been generated from murine B cells engineered to carry doxycycline-inducible Oct4, Sox2, Klf4 and Myc (OSKM) cassette in every tissue and from EBV/SV40LT-immortalized lymphoblastoid cell lines. Here, we show for the first time that freshly isolated non-cultured human cord blood (CB)- and peripheral blood (PB)-derived CD19+CD20+ B cells can be reprogrammed to iPSCs carrying complete VDJH immunoglobulin (Ig) gene monoclonal rearrangements using non-integrative tetracistronic, but not monocistronic, OSKM expressing Sendai Virus. Co-expression of C/EBPalpha with OSKM facilitates iPSC generation from both CB- and PB-derived B cells. We also demonstrate that myeloid cells are much easier to reprogram than B and T lymphocytes. Differentiation potential back into the cell type of their origin of B-cell-, T-cell-, myeloid- and fibroblast-iPSCs is not skewed, suggesting that their differentiation does not seem influenced by 'epigenetic memory'. Our data reflect the actual cell autonomous reprogramming capacity of human primary B cells because biased reprogramming was avoided by using freshly isolated primary cells, not exposed to cytokine cocktails favoring proliferation, differentiation or survival. The ability to reprogram CB/PB-derived primary human B cells offers an unprecedented opportunity for studying developmental B lymphopoiesis and modeling B-cell malignancies. PMID- 26500145 TI - Development of an aptasensor for electrochemical detection of exosomes. AB - Exosomes are small (50-100 nm in diameter) vesicles secreted from various mammalian cells. Exosomes have been correlated with tumor antigens and anti-tumor immune responses and may represent cancer biomarkers. Herein, we report on the development of an aptamer-based electrochemical biosensor for quantitative detection of exosomes. Aptamers specific to exosome transmembrane protein CD63 were immobilized onto gold electrode surfaces and incorporated into a microfluidic system. Probing strands pre-labeled with redox moieties were hybridized onto aptamer molecules anchored on the electrode surface. In the presence of exosomes these beacons released probing strands with redox reporters causing electrochemical signal to decrease. These biosensors could be used to detect as few as 1*10(6) particles/mL of exosomes, which represents 100-fold decrease in the limit of detection compared to commercial immunoassays relying on anti-CD63 antibodies. Given the importance of exosome-mediated signal transmission among cells, our study may represent an important step towards development of a simple biosensor that detects exosomes without washing or labeling steps in complex media. PMID- 26500146 TI - Microdialysis measurements of equine lamellar perfusion and energy metabolism in response to physical and pharmacological manipulations of blood flow. AB - REASONS FOR PERFORMING STUDY: A suitable method for evaluating lamellar perfusion changes and their metabolic consequences is currently lacking. OBJECTIVES: To examine perfusion changes in lamellar tissue using serial microdialysis measurements of urea clearance and energy metabolites. STUDY DESIGN: Randomised, controlled (within subject) experimental trial. METHODS: Nine Standardbred horses were instrumented with microdialysis probes in the foot lamellar tissue and skin (over the tail base). Urea (20 mmol/l) was added to the perfusate and its clearance was used to estimate local perfusion. Samples were collected every 15 min for a 1 h control period, then during application of a distal limb tourniquet, during periods when norepinephrine or potassium chloride (KCl) were included in both skin and lamellar perfusates, and after systemic (intravenous) acetylpromazine. Dialysate concentrations of glucose, lactate, pyruvate and urea were measured and lactate:glucose (L:G) and lactate:pyruvate (L:P) ratios calculated. Values were compared with pre-intervention baseline and also between simultaneous skin and lamellar samples using nonparametric statistical methods. RESULTS: Lamellar glucose decreased and lactate, urea, L:G and L:P increased significantly with tourniquet application, without significant changes in skin dialysate values. Lamellar and skin glucose decreased and L:G increased significantly during norepinephrine infusion, but mild increases in urea were not significant at either site. KCl caused significant decreases in lamellar and skin L:G, and an increase in skin glucose, but did not affect urea clearance. Acetylpromazine caused profound decreases in lamellar glucose and L:P, with increased L:G and pyruvate, but did not affect urea clearance or any skin dialysate values. CONCLUSIONS: Significant changes in microdialysis urea clearance only occurred with severe lamellar hypoperfusion. However, changes in dialysate metabolite concentrations reflected less profound fluctuations in perfusion. This method may be useful for examining lamellar perfusion and energy balance during laminitis development and for the evaluation of vasoactive therapeutics. PMID- 26500147 TI - Simultaneous determination of benzene, toluene, ethylbenzene, and xylene metabolites in human urine using electromembrane extraction combined with liquid chromatography and tandem mass spectrometry. AB - For the first time, electromembrane extraction combined with liquid chromatography and tandem mass spectrometry was applied for the determination of urinary benzene, toluene, ethylbenzene, and xylene metabolites. S Phenylmercapturic acid, hippuric acid, phenylglyoxylic acid, and methylhippuric acid isomers were extracted from human urine through a supported liquid membrane consisting of 1-octanol into an alkaline acceptor solution filling the inside of a hollow fiber by application of an electric field. Various extraction factors were investigated and optimized using response surface methodology, the statistical method. The optimum conditions were established to be 300 V applied voltage, 15 min extraction time, 1500 rpm stirring speed, and 5 mM ammonium acetate (pH 10.2) acceptor solution. The method was validated with respect to selectivity, linearity, accuracy, precision, limit of detection, limit of quantification, recovery, and reproducibility. The results showed good linearity (r(2) > 0.995), precision, and accuracy. The extract recoveries were 52.8-79.0%. Finally, we applied this method to real samples and successfully measured benzene, toluene, ethylbenzene, and xylene metabolites. PMID- 26500148 TI - Editorial. PMID- 26500150 TI - Active-Metal Template Synthesis of a Halogen-Bonding Rotaxane for Anion Recognition. AB - The synthesis of an all-halogen-bonding rotaxane for anion recognition is achieved by using active-metal templation. A flexible bis-iodotriazole-containing macrocycle is exploited for the metal-directed rotaxane synthesis. Endotopic binding of a Cu(I) template facilitates an active-metal CuAAC iodotriazole axle formation reaction that captures the interlocked rotaxane product. Following copper-template removal, exotopic coordination of a more sterically demanding rhenium(I) complex induces an inversion in the conformation of the macrocycle component, directing the iodotriazole halogen-bond donors into the rotaxane's interlocked binding cavity to facilitate anion recognition. PMID- 26500149 TI - Modulation of vincristine and doxorubicin binding and release from silk films. AB - Sustained release drug delivery systems remain a major clinical need for small molecule therapeutics in oncology. Here, mechanisms of small molecule interactions with silk protein films were studied with cationic oncology drugs, vincristine and doxorubicin, with a focus on hydrophobicity (non-ionic surfactant) and charge (pH and ionic strength). Interactions were primarily driven by charge interactions between the positively charged drugs and the negatively charged groups within the silk films. Exploiting chemical modifications of silk further modulated the drug interactions in a controlled fashion. Increasing anionic side groups via carboxylate- and sulfonate modifications of tyrosine side chains in the silk protein using diazonium coupling chemistry, increased drug binding and altered drug release. The effects of silk film protein crystallinity, beta sheet content, on drug binding and release were also explored. Lower crystallinity supported more rapid drug binding when compared to higher crystalline silk films. The drug release kinetics were governed by the protonation state of vincristine and doxorubicin and were tunable based on silk crystallinity and chemistry. These studies depict an approach to characterize small molecule-silk protein interactions and methods to tune drug binding and release kinetics from this protein delivery matrix. PMID- 26500151 TI - The Meaning of 'choice and control' for People with Intellectual Disabilities who are Planning their Social Care and Support. AB - BACKGROUND: This paper questions consumerist assumptions in current English social care policy and aims to look behind the processes of personalization to interrogate what 'choice and control' means in the lives of a diverse group of people with intellectual disabilities. METHODS: Data were from multiple interviews and direct practice recordings with nine people using personal budgets and were analysed using an interpretative approach. RESULTS: Identity, other people and personal budget processes were all important for choice and control. People needed to build confidence in themselves as decision-makers, both through peer support and through joint decisions with trusted others. CONCLUSIONS: Practitioners need to take into account the spectrum of ways in which people may make decisions. Action needs to be taken both at the micro level of support interactions and at the macro level, with a clearer articulation of independent living in policy and strategy for people with intellectual disabilities. PMID- 26500152 TI - funtooNorm: an R package for normalization of DNA methylation data when there are multiple cell or tissue types. AB - MOTIVATION: DNA methylation patterns are well known to vary substantially across cell types or tissues. Hence, existing normalization methods may not be optimal if they do not take this into account. We therefore present a new R package for normalization of data from the Illumina Infinium Human Methylation450 BeadChip (Illumina 450 K) built on the concepts in the recently published funNorm method, and introducing cell-type or tissue-type flexibility. RESULTS: funtooNorm is relevant for data sets containing samples from two or more cell or tissue types. A visual display of cross-validated errors informs the choice of the optimal number of components in the normalization. Benefits of cell (tissue)-specific normalization are demonstrated in three data sets. Improvement can be substantial; it is strikingly better on chromosome X, where methylation patterns have unique inter-tissue variability. AVAILABILITY AND IMPLEMENTATION: An R package is available at https://github.com/GreenwoodLab/funtooNorm, and has been submitted to Bioconductor at http://bioconductor.org. PMID- 26500153 TI - The minimum evolution problem is hard: a link between tree inference and graph clustering problems. AB - MOTIVATION: Distance methods are well suited for constructing massive phylogenetic trees. However, the computational complexity for Rzhetsky and Nei's minimum evolution (ME) approach, one of the earliest methods for constructing a phylogenetic tree from a distance matrix, remains open. RESULTS: We show that Rzhetsky and Nei's ME problem is NP-complete, and so probably computationally intractable. We do this by linking the ME problem to a graph clustering problem called the quasi-clique decomposition problem, which has recently also been shown to be NP-complete. We also discuss how this link could potentially open up some useful new connections between phylogenetics and graph clustering. PMID- 26500154 TI - BGT: efficient and flexible genotype query across many samples. AB - BGT is a compact format, a fast command line tool and a simple web application for efficient and convenient query of whole-genome genotypes and frequencies across tens to hundreds of thousands of samples. On real data, it encodes the haplotypes of 32 488 samples across 39.2 million SNPs into a 7.4 GB database and decodes up to 420 million genotypes per CPU second. The high performance enables real-time responses to complex queries. AVAILABILITY AND IMPLEMENTATION: https://github.com/lh3/bgt. PMID- 26500155 TI - 'Start to finish trans-institutional transdisciplinary care': a novel approach improves colorectal surgical results in frail elderly patients. AB - AIM: The frail elderly surgical patient is at increased risk of morbidity after major surgery. A transdisciplinary Geriatric Surgery Service (GSS) has been shown to produce consistently positive results in our institution. A trans institutional transdisciplinary Start to Finish (STF) programme was initiated incorporating seamless prehabilitation and rehabilitation to enhance the outcome further. METHOD: Patients who underwent major colorectal resection in Khoo Teck Puat Hospital and were managed under the GSS from January 2007 to December 2014 were included in this prospective study. The STF programme was initiated from January 2012. The surgical outcome of patients managed under the GSS before the initiation of STF was compared with that after its implementation. RESULTS: There were 57 patients after the initiation of the STF programme compared with 60 patients managed before STF. There were 26.4% and 25% of frail patients in the STF group compared with the non-STF group (P = 0.874). The mean length of hospital stay was significantly shorter in the STF group (8.4 days vs 11.0 days, P = 0.029). Functional recovery in patients available for follow-up at 6 weeks showed 100% (46/46) recovery in the elective STF group who received prehabilitation and 95.7% (45/47) in the elective non-STF group who did not (P = 0.157). There were no significant differences in a Clavien-Dindo complication score of Grade 3 or more and 30-day mortality between the two groups. CONCLUSION: Through a trans-institutional transdisciplinary approach, we managed to achieve a significantly shorter hospital stay in frail patients having colorectal surgery. All elective patients who received prehabilitation achieved full functional recovery. PMID- 26500156 TI - Male vagina is a more accurate term than prostatic utricle. PMID- 26500158 TI - Erratum. PMID- 26500157 TI - Mitochondrial dysfunction in a transgenic mouse model expressing human amyloid precursor protein (APP) with the Arctic mutation. AB - Accumulation of amyloid beta-peptide (Abeta) in the brain is an important event in the pathogenesis of Alzheimer disease. We have used a transgenic mouse model expressing human amyloid precursor protein (APP) with the Arctic mutation to investigate whether Abeta deposition is correlated with mitochondrial functions in these animals. We found evidence of mitochondrial dysfunction (i.e., decreased mitochondrial membrane potential, increased production of reactive oxygen species and oxidative DNA damage) at 6 months of age, when the mice showed very mild Abeta deposition. More pronounced mitochondrial abnormalities were present in 24 month-old TgAPParc mice with more extensive Abeta pathology. This study demonstrates for the first time mitochondrial dysfunction in transgenic mice with a mutation within the Abeta peptide (the Arctic APP mutation), and confirms previous studies suggesting that mitochondrial dysfunction and oxidative stress is an early event in the pathogenesis of Alzheimer disease. This study demonstrates mitochondrial dysfunction in transgenic mice with a mutation within the amyloid beta (Abeta) peptide (the Arctic amyloid precursor protein (APP) mutation). We found evidence of mitochondrial dysfunction (i.e. decreased mitochondrial membrane potential (MMP), increased production of reactive oxygen species (ROS) and oxidative DNA damage) at 6 months of age, when very mild Abeta deposition is present in the mice. Also, the cytochrome c (COX) activity was significantly decreased in mitochondria from transgenic mice at 24 months of age. PMID- 26500159 TI - Psychological predictors for health-related quality of life and disability in persons with chronic obstructive pulmonary disease (COPD). AB - OBJECTIVE: Individuals with chronic obstructive pulmonary disease (COPD) exhibit low physical and mental health-related quality of life (HRQL) and high susceptibility to disability. We investigated the influence of psychological factors on HRQL and disability in COPD individuals recruited from the general population. In line with Leventhal's common sense model, we expected psychological factors to be associated with HRQL and disability even after controlling for medical status. METHODS: Individuals with COPD (n = 502; 59.7 years old; GOLD grades were I: 3%, II: 17%, III: 34%, IV: 46%) were assessed through an online survey administered via COPD patient organisations in Germany. Individuals filled in the Short Form Health Survey (SF-12), COPD Assessment Test, Patient Health Questionnaire (modules: GAD-2, PHQ-15, PHQ-9), Brief Illness Perception Questionnaire, a questionnaire that assesses causal illness attributions, and the internal illness-related locus of control scale of the 'KKG questionnaire for the assessment of control beliefs about illness and health'. Multiple linear regressions were calculated. RESULTS: The investigated factors explained high variances (disability = 56%, physical HRQL = 28%, mental HRQL = 63%, p <= .001). Better mental health, more optimistic illness perceptions, attribution to psychological causes, and stronger internal locus of control were associated with lower disability and better HRQL. Comorbid somatic symptoms contributed to high disability and low quality of life. CONCLUSION: Psychological factors, such as illness perception, attribution and internal locus of control, were associated with disability and HRQL. These factors should be considered when designing treatments for individuals with COPD, and adequate interventions should be provided to enhance illness understanding and self-management skills. PMID- 26500160 TI - In Situ Tuning of Switching Window in a Gate-Controlled Bilayer Graphene Electrode Resistive Memory Device. AB - A resistive random access memory (RRAM) device with a tunable switching window is demonstrated for the first time. The SET voltage can be continuously tuned from 0.27 to 4.5 V by electrical gating from -10 to +35 V. The gate-controlled bilayer graphene-electrode RRAM can function as 1D1R and potentially increase the RRAM density. PMID- 26500161 TI - How would case managers' practice change in a consumer-directed care environment in Australia? AB - The aim of this study was to explore case managers' perceived changes in their practice in the future when consumer-directed care (CDC) is widely implemented in Australia's community aged care system. Purposeful sampling was used and semi structured individual and group interviews were conducted between September 2012 and March 2013. Participants were drawn from a list of all case managers who administered publicly funded community aged care packages in Victoria, Australia. Empowerment theory was used to guide the analysis and interpretation of the data. The thematic analysis revealed that case managers had mixed views about CDC. They also perceived changes in case managers' practice in the future when CDC is widely implemented. These might specifically include: first, case managers would not directly manage clients' budgets. While some case managers were concerned about losing power for this change, others believed that they would still have important financial roles to perform, such as setting rules, providing financial support and monitoring clients' use of budgets. Second, case managers would focus on performing roles in providing information, and empowering, facilitating and educating clients. These would help to strengthen clients' capacities and assist them to self-manage their care. Third, case managers would work in partnership with clients through frequent or skilful communication, mutual goal setting and goal facilitation. Fourth, case managers would manage more clients. In addition, they would provide less support to each individual client and perform less care co-ordination role. The findings suggest case managers paying attention to power balance regarding budget management in a CDC environment. Furthermore, they might frequently or skilfully communicate with, empower, facilitate and educate clients; work together with them to set up goals; and facilitate them to achieve goals. New research using empowerment theory to examine the actual practice of case managers in a well-established CDC system is warranted. PMID- 26500162 TI - The importance of accurately modelling human interactions: Comment on "Coupled disease-behavior dynamics on complex networks: A review" by Z. Wang et al. PMID- 26500164 TI - Micromorphological characterization of zinc/silver particle composite coatings. AB - The aim of this study was to evaluate the three-dimensional (3D) surface micromorphology of zinc/silver particles (Zn/AgPs) composite coatings with antibacterial activity prepared using an electrodeposition technique. These 3D nanostructures were investigated over square areas of 5 MUm * 5 MUm by atomic force microscopy (AFM), fractal, and wavelet analysis. The fractal analysis of 3D surface roughness revealed that (Zn/AgPs) composite coatings have fractal geometry. Triangulation method, based on the linear interpolation type, applied for AFM data was employed in order to characterise the surfaces topographically (in amplitude, spatial distribution and pattern of surface characteristics). The surface fractal dimension Df , as well as height values distribution have been determined for the 3D nanostructure surfaces. PMID- 26500165 TI - Melanopsin and the Non-visual Photochemistry in the Inner Retina of Vertebrates. AB - Melanopsin (Opn4), a member of the G-protein-coupled receptor family, is a vitamin A-based opsin in the vertebrate retina that has been shown to be involved in the synchronization of circadian rhythms, pupillary light reflexes, melatonin suppression and other light-regulated tasks. In nonmammalian vertebrates there are two Opn4 genes, Opn4m and Opn4x, the mammalian and Xenopus orthologs respectively. Opn4x is only expressed in nonmammalian vertebrates including reptiles, fish and birds, while Opn4m is found in a subset of retinal ganglion cells (RGCs), the intrinsically photosensitive (ip) RGCs of the inner retina of both mammals and nonmammalian vertebrates. All opsins described utilize retinaldehyde as chromophore, photoisomerized from 11-cis- to all-trans-retinal upon light exposure. Visual retinal photoreceptor cones and rods, responsible for day and night vision respectively, recycle retinoids through a process called the visual cycle that involves the retinal pigment epithelium or glial Muller cells. Although Opn4 has been characterized as a bistable photopigment, little is known about the mechanism/s involved in its chromophore regeneration. In this review, we will attempt to shed light on the visual cycle taking place in the inner retina and discuss the state of the art in the nonvisual photochemistry of vertebrates. PMID- 26500166 TI - Addressing the stimulant treatment gap: A call to investigate the therapeutic benefits potential of cannabinoids for crack-cocaine use. AB - Crack-cocaine use is prevalent in numerous countries, yet concentrated primarily largely within urban contexts - in the Northern and Southern regions of the Americas. It is associated with a variety of behavioral, physical and mental health and social problems which gravely affect users and their environments. Few evidence-based treatments for crack-cocaine use exist and are available to users in the reality of street drug use. Numerous pharmacological treatments have been investigated but with largely disappointing results. An important therapeutic potential for crack-cocaine use may rest in cannabinoids, which have recently seen a general resurgence for varied possible therapeutic usages for different neurological diseases. Distinct potential therapeutic benefits for crack-cocaine use and common related adverse symptoms may come specifically from cannabidiol (CBD) - one of the numerous cannabinoid components found in cannabis - with its demonstrated anxiolytic, anti-psychotic, anti-convulsant effects and potential benefits for sleep and appetite problems. The possible therapeutic prospects of cannabinoids are corroborated by observational studies from different contexts documenting crack-cocaine users' 'self-medication' efforts towards coping with crack-cocaine-related problems, including withdrawal and craving, impulsivity and paranoia. Cannabinoid therapeutics offer further benefits of being available in multiple formulations, are low in adverse risk potential, and may easily be offered in community-based settings which may add to their feasibility as interventions for - predominantly marginalized - crack-cocaine user populations. Supported by the dearth of current therapeutic options for crack-cocaine use, we are advocating for the implementation of a rigorous research program investigating the potential therapeutic benefits of cannabinoids for crack cocaine use. Given the high prevalence of this grave substance use problem in the Americas, opportunities for such research should urgently be created and facilitated there. PMID- 26500167 TI - Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy. AB - BACKGROUND: An association between inflammatory/immunonutritional status and patient prognosis has been reported in various types of cancer. The aim of this study was to evaluate the utility of inflammatory/immunonutritional factors as therapeutic predictors for patients with locally advanced pancreatic cancer treated with chemoradiotherapy (CRT). METHODS: Ninety-six patients with histologically proven locally advanced pancreatic adenocarcinoma who underwent CRT were enrolled in this study. We evaluated significance of inflammation-based factors as predictors of therapeutic effect and prognosis. RESULTS: The median progression free survival (PFS) and overall survival (OS) of all patients was 10 and 18 months, respectively. A Glasgow prognostic score (GPS) of 2 and plasma fibrinogen levels >= 400 mg/dL were independent predictors of poor PFS and OS. A prognostic nutritional index (PNI) >= 45 was a predictor of a significantly better reduction rate of the primary tumor. The prognosis between patients with GPS 0/1 and fibrinogen <400 mg/dL, GPS 2 or fibrinogen >=400 mg/dL, and GPS 2 and fibrinogen >=400 mg/dL were significantly different. Patients with GPS 2 and/or plasma fibrinogen >= 400 mg/dL had significantly higher incidence of metastasis within 6 months after CRT. CONCLUSIONS: GPS, fibrinogen, PNI are useful therapeutic and prognostic predictors in patients with locally advanced pancreatic cancer treated with CRT. PMID- 26500168 TI - The Clinical and Serological Effect of a Gluten-Free Diet in Border Terriers with Epileptoid Cramping Syndrome. AB - BACKGROUND: Canine epileptoid cramping syndrome (CECS) is a paroxysmal movement disorder of Border Terriers (BTs). These dogs might respond to a gluten-free diet. OBJECTIVES: The objective of this study was to examine the clinical and serological effect of a gluten-free diet in BTs with CECS. ANIMALS: Six client owned BTs with clinically confirmed CECS. METHODS: Dogs were prospectively recruited that had at least a 6-month history of CECS based on the observed phenomenology (using video) and had exhibited at least 2 separate episodes on different days. Dogs were tested for anti-transglutaminase 2 (TG2 IgA) and anti gliadin (AGA IgG) antibodies in the serum at presentation, and 3, 6, and 9 months after the introduction of a gluten-free diet. Duodenal biopsies were performed in 1 dog. RESULTS: Serum TG2 IgA titers were increased in 6/6 BTs (P = .006) and AGA IgG titers were increased in 5/6 BTs at presentation compared to those of controls (P = .018). After 9 months, there was clinical and serological improvement in all BTs with CECS strictly adhering to a gluten-free diet (5/5). One dog had persistently increased antibody titers. This dog scavenged horse manure. On the strict introduction of a gluten-free diet this dog also had an improved clinical and serological response. The diet-associated improvement was reversible in 2 dogs on completion of the study, both of which suffered a relapse of CECS on the re-introduction of gluten. CONCLUSIONS: Canine epileptoid cramping syndrome in BTs is a gluten-sensitive movement disorder triggered and perpetuated by gluten and thus responsive to a gluten-free diet. PMID- 26500169 TI - Evaluation of a hybrid treatment for Veterans with comorbid traumatic brain injury and posttraumatic stress disorder: Study protocol for a randomized controlled trial. AB - Comorbidity of posttraumatic stress disorder (PTSD) and history of traumatic brain injury (TBI) is high among Veterans of Operation Iraqi Freedom/Enduring Freedom/New Dawn (OIF/OEF/OND). Cognitive processing therapy (CPT) is empirically supported for the treatment of PTSD, but it is not specifically designed to accommodate the memory, attention, or problem solving deficits that are experienced by many Veterans with comorbid PTSD and TBI. Compensatory cognitive rehabilitation, including cognitive symptom management and rehabilitation therapy (CogSMART), is effective for cognitive deficits stemming from a variety of etiologies, including TBI. We have integrated components of CogSMART into CPT in order to address the unique challenges faced by Veterans with ongoing cognitive complaints related to PTSD and a history of mild TBI. Here we describe an ongoing randomized controlled trial investigating the efficacy of our novel hybrid treatment, SMART-CPT, as compared to standard CPT, for OIF/OEF/OND Veterans with PTSD and a history of mild to moderate TBI. We describe the development of this hybrid treatment as well as implementation of the randomized controlled trial. PMID- 26500170 TI - Family Access to a Dentist Study (FADS): A multi-center randomized controlled trial. AB - INTRODUCTION: Many low-income parent/caregivers do not understand the importance of cavity-free primary (baby) teeth and the chronic nature of dental caries (tooth decay). As a consequence, dental preventive and treatment utilization is low even when children are screened in schools and referred for care. This study aims to test a referral letter and Dental Information Guide (DIG) designed using the Common-Sense Model of Self-Regulation (CSM) framework to improve caregivers' illness perception of dental caries and increase utilization of care by children with restorative dental needs. METHODS: A multi-site randomized controlled trial with caregivers of Kindergarten to 4th grade children in urban Ohio and rural Washington State will compare five arms: (1) CSM referral letter alone; (2) CSM referral letter+DIG; (3) reduced CSM referral letter alone; (4) reduced CSM referral letter+DIG; and (5) standard (control) referral. At baseline, children will be screened at school to determine restorative dental needs. If in need of treatment, caregivers will be randomized to study arms and an intervention packet will be sent home. The primary outcome will be dental care based on a change in oral health status by clinical examination 7 months post-screening (ICDAS sealant codes 1 and 2; restoration codes 3-8; extraction). Enrollment commenced summer 2015 with results in summer 2016. CONCLUSION: This study uses the CSM framework to develop and test behavioral interventions to increase dental utilization among low-income caregivers. If effective this simple intervention has broad applicability in clinical and community-based settings. PMID- 26500171 TI - Neutrophil-to-Lymphocyte Ratio and 30-Day Mortality in Patients with Acute Intracerebral Hemorrhage. AB - BACKGROUND: Although a highly significant association has been described between neutrophil-to-lymphocyte ratio (NLR) and mortality in patients with various types of stroke, the association between NLR and mortality in intracerebral hemorrhage (ICH) patients remains unclear. METHODS: In this observational study, we enrolled 224 ICH patients. They were divided into 2 groups based on their 30-day outcomes. Multivariate logistic regression was performed to identify independent risk factors of 30-day mortality. An optimal cutoff value for the continuous NLR was calculated by applying a receiver operating curve analysis to discriminate between the survival and death groups. RESULTS: Among 224 patients, 26 died. No significant difference in NLR at admission was observed between the 2 groups (surviving: 2.39 +/- 1.75 versus nonsurviving: 3.09 +/- 2.16, P= .065), whereas NLR on the next morning following admission was significantly higher in the patients who died (12.53 +/- 9.33) than in those who survived (5.53 +/- 4.68) (P <.001). On multivariate logistic analysis, Glasgow Coma Scale score (odds ratio [OR] .805, 95% confidence interval [CI] .661-.979, P = .030), age (>=80 years; OR .203, CI .055-.750, P = .017), ICH volume (>=30 cm(3); OR .112, CI .108-.699, P = .019), and NLR on the next morning (OR 1.091, CI 1.002-1.188, P = .044) were independent risk factors of 30-day mortality. An NLR of 7.35 was identified as the optimal cutoff value. The area under the curve of NLR for 30-day mortality was .762 (P < .001). The mortality was significantly higher in patients with an NLR of 7.35 or higher than in those with an NLR less than 7.35 (31.6% versus 4.8%, P <.001). CONCLUSIONS: Higher NLR exhibited an increased mortality in ICH patients. NLR could be used to predict 30-day outcome in ICH patients. PMID- 26500172 TI - Methodological Quality of Motor Intervention Randomized Controlled Trials in Stroke Rehabilitation. AB - PURPOSE: The objective of the study was to evaluate the methodological quality of motor intervention randomized controlled trials (RCTs) published in the stroke rehabilitation literature and to examine trends in quality over time. METHODS: A systematic literature search was conducted for all English articles (published up to December 2013) examining rehabilitation for motor recovery poststroke. All RCTs with a human sample, of which at least 50% had a stroke, were included in the analysis. A Physiotherapy Evidence Database (PEDro) score was assigned to assess methodological quality. A one-way analysis of variance was conducted to examine adherence to quality items overall and over time, with post hoc t-tests performed where appropriate. RESULTS: Six hundred seventy-six RCTs met inclusion criteria, of which 32.0% had excellent, 42.0% good, 23.1% fair, and 3.0% poor methodological qualities. The overall mean PEDro score was 6.6 +/- 1.6; with scores improving significantly between 1979-1983 and 2009-2013 (5.0 +/- 1.4 versus 7.0 +/- 1.5; P = .0003); however, no significant improvements in individual items were found (P > .05). CONCLUSIONS: This study showed improvements in the total methodological quality of motor intervention RCTs in stroke rehabilitation over time. However, no relationship was found between individual quality items and improvement over time. PMID- 26500173 TI - Correlation between Carotid Intima-Media Thickness and Early-Stage Chronic Kidney Disease: Results from Asymptomatic Polyvascular Abnormalities in Community Study. AB - OBJECTIVE: Chronic kidney disease (CKD) might be a potential independent risk factor for increased carotid intima-media thickness (IMT). Our aim is to determine whether mild to moderate kidney dysfunction is associated with increased carotid IMT. METHODS: We employed 3629 subjects free from clinical cardiovascular diseases at the baseline visit of the Asymptomatic Polyvascular Abnormalities in Community Study. Kidney function was evaluated in terms of estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease Epidemiology Collaboration China equation. The mean of the maximal internal and common carotid IMT was measured by means of high-resolution B-mode ultrasound. Univariable linear regressions and multivariate logistic regressions were used to evaluate the independent association between kidney function and carotid IMT. RESULTS: In the unadjusted linear analysis, carotid IMT showed a significant negative correlation with eGFR in both male (r = -.346, P < .001) and female (r = -.253, P < .001) subjects. After adjustment for age, traditional vascular risk factors (smoking, diabetes, systolic blood pressure, diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, and antihypertensive drug use), and nontraditional risk factors (C-reactive protein and homocysteine), the association remained significant. The odds ratio for increased IMT was 1.299 (95% confidence interval [CI], 1.062-1.588) in the group with an eGFR of 60-89 mL/minute/1.73 m(2) and 1.789 (95% CI, 1.203-2.660) in the group with an eGFR of 30-59 mL/minute/1.73 m(2). CONCLUSIONS: Increased IMT is associated with early stage CKD. This association is independent of traditional and nontraditional cardiovascular risk factors. Early detection of kidney dysfunction is important to improve risk stratification of atherosclerotic disease. PMID- 26500174 TI - Outcomes after Stroke in Patients with Previous Pressure Ulcer: A Nationwide Matched Retrospective Cohort Study. AB - BACKGROUND: Factors associated with poststroke adverse events were not completely understood. The purpose of this study was to investigate whether stroke patients with previous pressure ulcers had more adverse events after stroke. METHODS: Using the claims data from Taiwan's National Health Insurance Research Database, we conducted a retrospective cohort study matched by propensity score. Three thousand two first-ever stroke patients with previous pressure ulcer and 3002 first-ever stroke patients without pressure ulcer were investigated between 2002 and 2009. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of complications and 30-day mortality after stroke associated with previous pressure ulcer were calculated in the multivariate logistic regressions. RESULTS: Patients with pressure ulcer had significantly higher risk than control for poststroke urinary tract infection (OR: 1.56, 95% CI: 1.38-1.78), pneumonia (OR: 1.35, 95% CI: 1.16-1.58), gastrointestinal bleeding (OR: 1.31, 95% CI: 1.04-1.66), and epilepsy (OR: 1.84, 95% CI: 1.83-1.85). Stroke patients with pressure ulcer had increased 30-day poststroke mortality (OR: 2.01, 95% CI: 1.55-2.61), particularly in those treated with debridement (OR: 2.87, 95% CI: 1.85-4.44) or high quantity of antibiotics (OR: 4.01, 95% CI: 2.10-7.66). Pressure ulcer was associated with poststroke mortality in both genders and patients aged 60 years or older. CONCLUSIONS: This study showed increased poststroke complications and mortality in patients with previous pressure ulcer, which suggests the urgent need for monitoring stroke patients for pressure ulcer history. PMID- 26500175 TI - Impact of kidney ischemic lesions on renal function after fenestrated endovascular repair. AB - OBJECTIVE: Fenestrated endovascular aortic repair (fEVAR) is being used increasingly in the treatment of complex aortic aneurysms; however, this procedure can be associated with visceral and renal complications. Because the causes of possible renal function (RF) impairment have not been fully examined yet, we conducted a study to investigate whether there are risk factors associate with renal ischemic lesions (RILs) and if they influence RF in patients treated for complex aortic aneurysm with fEVAR. METHODS: We evaluated the clinical, anatomic, and technical characteristics of consecutive patients treated with fEVAR from 2008 to 2014. RIL were identified by postoperative computed tomography angiography and the volume of renal parenchyma involved quantified. A decrease in RF (>30% glomerular filtration rate reduction) was evaluated at discharge, and at the 6- and 12-month follow-ups. RESULTS: Among 53 patients, we analyzed 38 (72%) juxta/pararenal and 15 (28%) thoracoabdominal aortic aneurysms (33 [64%] with >=3 fenestrations) and 102 renal arteries. Fifteen patients (30%) showed RIL, which was caused by accessory renal artery (ARA) coverage in 6 cases (38%), distal embolism in 6 (38%), renal artery thrombosis in 2 (18%), and iatrogenic embolization for intraoperative bleeding during fEVAR in 1 (6%). The volume of renal parenchyma involved was less than 25% in 10 (67%) and 25% to 50% in 5 (33%) cases. In no cases was more than 50% renal volume affected. On multivariate analysis, RIL predictors were the presence of ARA (odds ratio [OR], 8.00; 95% confidence interval [CI], 1.16-54.89; P = .03) and extensive thrombosis of the pararenal aorta (OR, 39.93; 95% CI, 3.36-474.23; P = .003). At discharge, chronic renal failure (CRF; OR, 4.80; 95% CI, 1.27-18.09; P = .01), diabetes (OR, 8.44; 95% CI, 1.33-53.51; P = .01), and extensive thrombosis of the pararenal aorta (OR, 5.50; 95% CI, 1.32-29.92; P = .01) were significantly associated with worsening RF. RIL, independent from volume, did not influence the postoperative RF. At 6 months and 1-year, preoperative CRF and perioperative declines in RF were identified as the only risk factors for worsening RF. CONCLUSIONS: RIL is a common fEVAR complication and is primarily owing to ARA coverage and aortic thrombus embolization. However, RIL does not influence RF, which is predicted by preoperative CRF, diabetes, and extensive aortic thrombus. PMID- 26500176 TI - pH responsive graft copolymers of chitosan. AB - Grafting suitable polymers onto chitosan can produce cationic or polyampholyte polymers or hydrogels that are potential smart biomedical materials. Chitosan graft-[poly(diethylamino)ethyl methacrylate] has been prepared in three different physical forms as linear free chains in solution, chemical gels crosslinked with glutaraldehyde, and poly(diethylamino)ethyl methacrylate] grafted onto chitosan tripolyphosphate gel beads. In addition to chemical structure, the graft copolymers were characterized with respect to their dissolution and swelling behavior in aqueous solution. It has been established that solubility of the products is controlled by the grafting yield. While pH sensitive polymers, which collapse at a given pH value are obtained at lower grafting yields, hydrogels form at higher grafting yields with pH responsive swelling behavior. Glutaraldehyde crosslinked chitosan-graft-[poly(diethylamino)ethyl methacrylate] gels and chitosan tripolyphosphate gel beads grafted with poly[(diethylamino)ethyl methacrylate] exhibit pH sensitive swelling with highest equilibrium swelling capacity at pH=1.2. PMID- 26500177 TI - Effect of CaCO3/HCl pretreatment on the surface modification of chitin gel beads via graft copolymerization of 2-hydroxy ethyl methacrylate and 4-vinylpyridine. AB - Although chitin, poly(N-acetylglucosamine), possesses considerable potential as a biomaterial, it has not been as thoroughly studied as its derivative chitosan. In this study, the potential of chitin gel beads has been evaluated for surface modification via vinyl polymer grafting. Grafting behavior of two well established vinyl monomers, namely 2-hydroxyethylmethacrylate (HEMA) and 4 vinylpyridine (4-VP) were investigated using cerium (IV) ammonium nitrate as the redox initiator with the aim of obtaining chemically functionalized more hydrophilic chitin surfaces. The intractable nature of chitin, which is one of its primary drawbacks as a grafting substrate was overcome by applying a CaCO3 treatment during bead preparation. The maximum grafting percentage of poly(HEMA) onto chitin bead without CaCO3 treatment was found to be 65%, while the value for CaCO3 treated chitin beads was 515%. The maximum grafting yield of poly(4-VP) on to CaCO3 treated chitin powder was 380% at optimum conditions. The grafting system was extensively characterized before and after grafting by FT-IR, SEM, C 13 NMR and XRD analyses. Significant improvement on the swelling capacities of chitin based gel beads in aqueous acidic, basic and neutral media was obtained. An account of the pros and cons of the system has been presented. PMID- 26500178 TI - Pathogenesis of Hepatorenal Syndrome: Implications for Therapy. AB - Patients with cirrhosis are prone to develop acute kidney injury (AKI) due to a number of causes, including bacterial infections with or without septic shock, hypovolemia, administration of nephrotoxic drugs, and intrinsic kidney diseases, among others. Most importantly, patients with advanced cirrhosis develop a distinctive cause of AKI, characterized by rapidly progressive glomerular filtration rate loss associated with marked disturbances in circulatory function in the absence of obvious pathologic abnormalities in the kidneys, known as hepatorenal syndrome (HRS). Decreased kidney function results from intense renal vasoconstriction secondary to the complex circulatory changes of cirrhosis with splanchnic vasodilatation and effective hypovolemia. Beyond activation of vasoactive systems, factors including impaired renal blood flow autoregulation and systemic inflammation may play a role in the development of HRS. Most patients improve with albumin and vasopressors; however, the prognosis of HRS remains very poor. Novel biomarkers may be helpful in distinguishing HRS from other causes of AKI in patients with cirrhosis. PMID- 26500179 TI - Future Avenues to Decrease Uremic Toxin Concentration. AB - In this article, we review approaches for decreasing uremic solute concentrations in chronic kidney disease and in particular, in end-stage renal disease (ESRD). The rationale to do so is the straightforward relation between concentration and biological (toxic) effect for most toxins. The first section is devoted to extracorporeal strategies (kidney replacement therapy). In the context of high flux hemodialysis and hemodiafiltration, we discuss increasing dialyzer blood and dialysate flows, frequent and/or extended dialysis, adsorption, bioartificial kidney, and changing physical conditions within the dialyzer (especially for protein-bound toxins). The next section focuses on the intestinal generation of uremic toxins, which in return is stimulated by uremic conditions. Therapeutic options are probiotics, prebiotics, synbiotics, and intestinal sorbents. Current data are conflicting, and these issues need further study before useful therapeutic concepts are developed. The following section is devoted to preservation of (residual) kidney function. Although many therapeutic options may overlap with therapies provided before ESRD, we focus on specific aspects of ESRD treatment, such as the risks of too-strict blood pressure and glycemic regulation and hemodynamic changes during dialysis. Finally, some recommendations are given on how research might be organized with regard to uremic toxins and their effects, removal, and impact on outcomes of uremic patients. PMID- 26500180 TI - TGF-beta superfamily signaling in testis formation and early male germline development. AB - The TGF-beta ligand superfamily contains at least 40 members, many of which are produced and act within the mammalian testis to facilitate formation of sperm. Their progressive expression at key stages and in specific cell types determines the fertility of adult males, influencing testis development and controlling germline differentiation. BMPs are essential for the interactive instructions between multiple cell types in the early embryo that drive initial specification of gamete precursors. In the nascent foetal testis, several ligands including Nodal, TGF-betas, Activins and BMPs, serve as key masculinizing switches by regulating male germline pluripotency, somatic and germline proliferation, and testicular vascularization and architecture. In postnatal life, local production of these factors determine adult testis size by regulating Sertoli cell multiplication and differentiation, in addition to specifying germline differentiation and multiplication. Because TGF-beta superfamily signaling is integral to testis formation, it affects processes that underlie testicular pathologies, including testicular cancer, and its potential to contribute to subfertility is beginning to be understood. PMID- 26500181 TI - Adenosine receptor targets for pain. AB - The main focus for the development of adenosine targets as analgesics to date has been A1Rs due to its antinociceptive profile in various preclinical pain models. The usefulness of systemic A1R agonists may be limited by other effects (cardiovascular, motor), but enhanced selectivity for pain might occur with partial agonists, potent and highly selective agonists, or allosteric modulators. A2AR agonists exhibit some peripheral pronociceptive effects, but also act on immune cells to suppress inflammation and on spinal glia to suppress pain signaling and may be useful for inflammatory and neuropathic pain. A2BR agonists exhibit peripheral proinflammatory effects on immune cells, but also spinal antinociceptive effects similar to A2AR agonists. A3Rs are now demonstrated to produce antinociception in several preclinical neuropathic pain models, with mechanistic actions on glial cells, and may be useful for neuropathic pain. Endogenous adenosine levels can be augmented by inhibition of metabolism (via adenosine kinase) or increased generation (via nucleotidases), and these approaches have implications for pain. Endogenous adenosine contributes to antinociception by several pharmacological agents, herbal remedies, acupuncture, transcutaneous electrical nerve stimulation, exercise, joint mobilization, and water immersion via spinal and/or peripheral effects, such that this system appears to constitute a major pain regulatory system. Finally, caffeine inhibits A1-, A2A- and A3Rs with similar potency, and dietary caffeine intake will need attention in trials of: (a) agonists and/or modulators acting at these receptors, (b) some pharmacological and herbal analgesics, and (c) manipulations that enhance endogenous adenosine levels, all of which are inhibited by caffeine and/or A1R antagonists in preclinical studies. All adenosine receptors have effects on spinal glial cells in regulating nociception, and gender differences in the involvement of such cells in chronic neuropathic pain indicate gender may also need attention in preclinical and human trials evaluating the efficacy of adenosine-based analgesics. PMID- 26500182 TI - Activation of inositol 1,4,5-trisphosphate receptors during preconditioning low frequency stimulation suppresses subsequent induction of long-term potentiation in hippocampal CA1 neurons. AB - We investigated the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) activated during preconditioning low-frequency stimulation (LFS) in the subsequent high-frequency stimulation (HFS)-induced induction of long-term potentiation (LTP) in CA1 neurons in hippocampal slices from mature guinea pigs. Induction of LTP in the field excitatory postsynaptic potential (EPSP) or the population spike (PS) by delivery of HFS (a tetanus of 100 pulses at 100 Hz) to the Schaffer collateral-commissural pathway to CA1 neuron synapses was suppressed when the CA1 synapses were preconditioned by LFS of 1000 pulses at 1 Hz. This effect was inhibited when the preconditioning LFS was applied in the presence of an N-methyl-D-aspartate receptors (NMDARs) antagonist, a metabotropic glutamate receptor (mGluR) antagonist, IP3R antagonist, a calmodulin-dependent kinase II inhibitor or a calcineurin inhibitor. Furthermore, blockade of group I mGluRs immediately before the delivery of HFS blocked the inhibitory effect of the preconditioning LFS on subsequent induction of LTP by HFS. These results suggest that, in hippocampal CA1 neuron synapses, co-activation of NMDARs and IP3Rs during a preconditioning LFS results in both phosphorylation and dephosphorylation events that lead to prolonged activation of group I mGluRs that is responsible for the failure of LTP induction. PMID- 26500183 TI - From GFP to beta-lactamase: advancing intact cell imaging for toxins and effectors. AB - Canonical reporters such as green fluorescent protein (GFP) and luciferase have assisted researchers in probing cellular pathways and processes. Prior research in pathogenesis depended on sensitivity of biochemical and biophysical techniques to identify effectors and elucidate entry mechanisms. Recently, the beta lactamase (betalac) reporter system has advanced toxin and effector reporting by permitting measurement of betalac delivery into the cytosol or host betalac expression in intact cells. betalac measurement in cells was facilitated by the development of the fluorogenic substrate, CCF2-AM, to identify novel effectors, target cells, and domains involved in bacterial pathogenesis. The assay is also adaptable for high-throughput screening of small molecule inhibitors against toxins, providing information on mechanism and potential therapeutic agents. The versatility and limitations of the betalac reporter system as applied to toxins and effectors are discussed in this review. PMID- 26500184 TI - Folic acid supplementation in early pregnancy and the risk of preeclampsia, small for gestational age offspring and preterm delivery. AB - OBJECTIVE: To assess whether folic acid intake during the first trimester of pregnancy is related to pregnancy outcomes preeclampsia, low birth weight or preterm birth. STUDY DESIGN: Prospective cohort study of 3647 women who were followed from the first trimester of pregnancy. Detailed information on quantity of folic acid intake before and during the first three months of pregnancy was recorded. Pregnancy outcome data were abstracted from obstetric records. RESULTS: Lean mothers who used folic acid supplementation the month before pregnancy had a 40% reduced risk of developing preeclampsia. The adjusted odds ratio (OR) with 95% confidence intervals (95%CI) for preeclampsia in lean mothers (BMI<25) who used folic acid supplements the month before pregnancy was 0.6 (95% CI 0.4-1.0). Obese mothers who used folic acid supplementation in the first trimester had an increased, but not statistically significant risk for preterm birth (adjusted OR 1.9 with 95% CI 0.9-4.0). There were no significant associations between folic acid supplementation and low birth weight. CONCLUSION: Our study supports a possible protective effect of folate intake in early pregnancy on preeclampsia in lean mothers. There was no support for any beneficial effect of folic acid use on preterm birth or low birth weight, and we found no evidence of any harmful effects of folate use for the outcomes included in our study. PMID- 26500185 TI - An optimized procedure for stained bloodless anatomic hepatectomy in canines. AB - BACKGROUND: Poloxamer 407 (P407) is a thermosensitive polymer that can gelatinize at body temperature and dissolve below critical temperature. The aim of this study was to evaluate an optimized procedure for hepatectomy, in which the target liver section was stained with methylene blue, and the blood inflow was occluded with P407. METHODS: Twelve dogs were randomized into two equal groups. The conventional group (CG) underwent unstained liver resection with the hemi-Pringle maneuver for blood control. After angiography, the optimized group (OG) was cannulated to the target lobar hepatic artery via the femoral artery and to the target segmental portal vein via a branch of the splenic vein. The artery was then occluded with P407, whereas the vein was administered methylene blue and P407 sequentially before excision along the stained border. Blood specimens and necropsy were acquired periodically. RESULTS: The stained resection margins were clearly visualized and were accompanied by negligible blood loss. The occlusion duration was significantly reduced from 24.5 +/- 2.3 min in the conventional group to 18.5 +/- 4.9 min in the OG (P < 0.05). The aspartate aminotransferase and alanine aminotransferase levels were less elevated in the OG postoperatively. No significant evidence of pathology was detected in either group. CONCLUSIONS: This optimized procedure represents an easy, time-saving and effective approach for stained anatomic hepatectomy with temporary intravascular blood occlusion. PMID- 26500186 TI - Twitter-Delivered Behavioral Weight-Loss Interventions: A Pilot Series. AB - BACKGROUND: Lifestyle interventions are efficacious at reducing risk for diabetes and cardiovascular disease but have not had a significant public health impact given high cost and patient and provider burden. OBJECTIVE: Online social networks may reduce the burden of lifestyle interventions to the extent that they displace in-person visits and may enhance opportunities for social support for weight loss. METHODS: We conducted an iterative series of pilot studies to evaluate the feasibility and acceptability of using online social networks to deliver a lifestyle intervention. RESULTS: In Study 1 (n=10), obese participants with depression received lifestyle counseling via 12 weekly group visits and a private group formed using the online social network, Twitter. Mean weight loss was 2.3 pounds (SD 7.7; range -19.2 to 8.2) or 1.2% (SD 3.6) of baseline weight. A total of 67% (6/9) of participants completing exit interviews found the support of the Twitter group at least somewhat useful. In Study 2 (n=11), participants were not depressed and were required to be regular users of social media. Participants lost, on average, 5.6 pounds (SD 6.3; range -15 to 0) or 3.0% (SD 3.4) of baseline weight, and 100% (9/9) completing exit interviews found the support of the Twitter group at least somewhat useful. To explore the feasibility of eliminating in-person visits, in Study 3 (n=12), we delivered a 12-week lifestyle intervention almost entirely via Twitter by limiting the number of group visits to one, while using the same inclusion criteria as that used in Study 2. Participants lost, on average, 5.4 pounds (SD 6.4; range -14.2 to 3.9) or 3.0% (SD 3.1) of baseline weight, and 90% (9/10) completing exit interviews found the support of the Twitter group at least somewhat useful. Findings revealed that a private Twitter weight-loss group was both feasible and acceptable for many patients, particularly among regular users of social media. CONCLUSIONS: Future research should evaluate the efficacy and cost-effectiveness of online social network-delivered lifestyle interventions relative to traditional modalities. PMID- 26500187 TI - Protective efficacy of a peptide derived from a potential adhesin of Pseudomonas aeruginosa against corneal infection. AB - Dissecting the interactions between Pseudomonas aeruginosa and corneal cells is important to identify a novel target for prevention and treatment of Pseudomonas keratitis. The current study began with a peptide identified by phage display, and was to investigate the protective efficacy against P. aeruginosa infection in cornea. The original peptide Pc-E, with high homology to a hypothetical membrane protein (HmpA) in P. aeruginosa, and the derived peptide Pc-EP, with the same sequence as a region in HmpA, were synthesized. Peptide Pc-EP could directly bind to HCEC, stronger than Pc-E, and specifically activate toll-like receptor 5, and thereby significantly induce the production of pro-inflammatory factors, such as IL-1beta, IL-6, IFN-gamma and IL-17. Moreover, Pc-EP could act as an antagonist to inhibit the adhesion of wild-type P. aeruginosa to HCEC and mouse corneas. No inhibitory effect was observed on the adhesion of the strain loss of HmpA. When compared to the wild-type strain, the adhesion of the hmpA mutant to corneal cells was significantly decreased. Treatment of infected mouse corneas with Pc-EP before infection significantly decreased the bacterial load in the cornea and attenuated the corneal pathology. These results indicate that Pc-EP can be a useful prophylactic agent for P. aeruginosa keratitis. PMID- 26500188 TI - The SPAIC-11 and SPAICP-11: Two brief child- and parent-rated measures of social anxiety. AB - The Social Phobia and Anxiety Inventory for Children-11 (SPAIC-11) and Social Phobia and Anxiety Inventory for Children's Parents-11 (SPAICP-11) were developed as brief versions of the Social Phobia and Anxiety Inventory--Child and Parent Versions via item response theory (IRT) using child and parent reports of social anxiety. A sample of 496 children was analyzed using IRT analyses, revealing 11 items that exhibit measurement equivalence across parent and child reports. Descriptive and psychometric data are provided for the child, parent, and combined total scores. Discriminant validity was demonstrated using logistic regression and receiver operating characteristic curve analyses. The SPAIC-11 and SPAICP-11 are psychometrically sound measures that are able to measure social anxiety invariantly across children and their parents. These brief measures which include combined parent and child perception of the child's social anxiety may provide notable benefits to clinical research. PMID- 26500189 TI - Prospects for the gliding mechanism of Mycoplasma mobile. AB - Mycoplasma mobile forms gliding machinery at a cell pole and glides continuously in the direction of the cell pole at up to 4.5MUm per second on solid surfaces such as animal cells. This motility system is not related to those of any other bacteria or eukaryotes. M. mobile uses ATP energy to repeatedly catch, pull, and release sialylated oligosaccharides on host cells with its approximately 50-nm long legs. The gliding machinery is a large structure composed of huge surface proteins and internal jellyfish-like structure. This system may have developed from an accidental combination between an adhesin and a rotary ATPase, both of which are essential for the adhesive parasitic life of Mycoplasmas. PMID- 26500190 TI - Organization principles in visual working memory: Evidence from sequential stimulus display. AB - Although the mechanisms of visual working memory (VWM) have been studied extensively in recent years, the active property of VWM has received less attention. In the current study, we examined how VWM integrates sequentially presented stimuli by focusing on the role of Gestalt principles, which are important organizing principles in perceptual integration. We manipulated the level of Gestalt cues among three or four sequentially presented objects that were memorized. The Gestalt principle could not emerge unless all the objects appeared together. We distinguished two hypotheses: a perception-alike hypothesis and an encoding-specificity hypothesis. The former predicts that the Gestalt cue will play a role in information integration within VWM; the latter predicts that the Gestalt cue will not operate within VWM. In four experiments, we demonstrated that collinearity (Experiment 1) and closure (Experiment 2) cues significantly improved VWM performance, and this facilitation was not affected by the testing manner (Experiment 3) or by adding extra colors to the memorized objects (Experiment 4). Finally, we re-established the Gestalt cue benefit with similarity cues (Experiment 5). These findings together suggest that VWM realizes and uses potential Gestalt principles within the stored representations, supporting a perception-alike hypothesis. PMID- 26500191 TI - The Alternative Omen Effect: Illusory negative correlation between the outcomes of choice options. AB - In situations of choice between uncertain options, one might get feedback on both the outcome of the chosen option and the outcome of the unchosen option ("the alternative"). Extensive research has shown that when both outcomes are eventually revealed, the alternative's outcome influences the way people evaluate their own outcome. In a series of experiments, we examined whether the outcome of the alternative plays an additional role in the decision-making process by creating expectations regarding the outcome of the chosen option. Specifically, we hypothesized that people see a good (bad) alternative's outcome as a bad (good) sign regarding their own outcome when the two outcomes are in fact uncorrelated, a phenomenon we call the "Alternative Omen Effect" (ALOE). Subjects had to repeatedly choose between two boxes, the outcomes of which were then sequentially revealed. In Experiments 1 and 2 the alternative's outcome was presented first, and we assessed the individual's prediction of their own outcome. In Experiment 3, subjects had to predict the alternative's outcome after seeing their own. We find that even though the two outcomes were in fact uncorrelated, people tended to see a good (bad) alternative outcome as a bad (good) sign regarding their own outcome. Importantly, this illusory negative correlation affected subsequent behavior and led to irrational choices. Furthermore, the order of presentation was critical: when the outcome of the chosen option was presented first, the effect disappeared, suggesting that this illusory negative correlation is influenced by self-relevance. We discuss the possible sources of this illusory correlation as well as its implications for research on counterfactual thinking. PMID- 26500192 TI - Comparison of inducible versus constitutive expression of plectasin on yields and antimicrobial activities in Pichia pastoris. AB - BACKGROUND: Plectasin might serve as a substitute for traditional antibiotics, but its yields and antimicrobial activities warrant further investigation. OBJECTIVE: To identify the influence of inducible versus constitutive expression of plectasin on yields and antimicrobial activities. METHODS: Through SOE-PCR, a recombinant plectasin gene was generated and inserted into inducible (pPICZalphaA) and constitutive (pGAPZalphaA) vectors in order to create Pichia pastoris GS115 strains. After 120 h of fermentation, supernatants were purified by an AKTA purifier using nickel columns. Minimal inhibitory concentration (MIC) and inhibition zone assays were performed after Tricine-SDS-PAGE. RESULTS: After 120 h of fermentation, the yield of constitutive plectasin (370 MUg/ml) was much lower than that from inducible vector (880 MUg/ml) (P < 0.05). However, constitutive strain reached its plateau phase faster and keep more consistent yield (P < 0.05). The MICs of inducible plectasin against Methicillin-resistant Staphylococcus aureus (MRSA) 15471118, vancomycin-resistant Enterococcus feces (VREF), and penicillin-resistant Streptococcus pneumonia (PRSP) 31355 were 64, 32, and 64 MUg/ml, respectively, while those of constitutive plectasin were 4, 4, and 16 MUg/ml. No significant differences were observed in antimicrobial activities between inducible and constitutive plectasin for MRSA 15471118, VREF and PRSP 31355 (all P > 0.05). However, constitutive plectasin had a larger inhibition zone than inducible plectasin with the same mass. CONCLUSIONS: Although P. pastoris GS115 (pGAPZalphaA-Plectasin-GS115) had lower expression than P. pastoris GS115 (pPICZalphaA-plectasin-GS115), it reached the plateau phase faster, had steadier yields and showed superiority in antimicrobial activities. Therefore, pGAPZalphaA might be more suitable for expression of plectasin in GS115 compared with pPICZalphaA. PMID- 26500193 TI - Short-term treatment with VEGF receptor inhibitors induces retinopathy of prematurity-like abnormal vascular growth in neonatal rats. AB - Retinal arterial tortuosity and venous dilation are hallmarks of plus disease, which is a severe form of retinopathy of prematurity (ROP). In this study, we examined whether short-term interruption of vascular endothelial growth factor (VEGF) signals leads to the formation of severe ROP-like abnormal retinal blood vessels. Neonatal rats were treated subcutaneously with the VEGF receptor (VEGFR) tyrosine kinase inhibitors, KRN633 (1, 5, or 10 mg/kg) or axitinib (10 mg/kg), on postnatal day (P) 7 and P8. The retinal vasculatures were examined on P9, P14, or P21 in retinal whole-mounts stained with an endothelial cell marker. Prevention of vascular growth and regression of some preformed capillaries were observed on P9 in retinas of rats treated with KRN633. However, on P14 and P21, density of capillaries, tortuosity index of arterioles, and diameter of veins significantly increased in KRN633-treated rats, compared to vehicle (0.5% methylcellulose) treated animals. Similar observations were made with axitinib-treated rats. Expressions of VEGF and VEGFR-2 were enhanced on P14 in KRN633-treated rat retinas. The second round of KRN633 treatment on P11 and P12 completely blocked abnormal retinal vascular growth on P14, but thereafter induced ROP-like abnormal retinal blood vessels by P21. These results suggest that an interruption of normal retinal vascular development in neonatal rats as a result of short-term VEGFR inhibition causes severe ROP-like abnormal retinal vascular growth in a VEGF-dependent manner. Rats treated postnatally with VEGFR inhibitors could serve as an animal model for studying the mechanisms underlying the development of plus disease. PMID- 26500194 TI - Neuropilin-2 contributes to LPS-induced corneal inflammatory lymphangiogenesis. AB - Neuropilin-2 (NP2), a high-affinity kinase-deficient co-receptor for vascular endothelial growth factor (VEGF)-C, is involved in embryonic vessel development, tumor growth, tumor lymphangiogenesis and metastasis. However, the pathological role of NP2 in other disorders, particularly under inflammatory lymphangiogenic conditions, remains largely unknown. In this study, we investigated the role of NP2 in inflammation-induced lymphangiogenesis in vivo using a lipopolysaccharide (LPS)-induced corneal neovascularization mouse model and in vitro using a macrophage-mouse lymphatic endothelial cell (mLEC) co-culture system. In the mouse model of LPS-induced inflammatory corneal neovascularization, NP2 and VEGFR 3 expression were rapidly up-regulated after LPS stimulation, and microRNA mediated knockdown of NP2 significantly inhibited the up-regulation of VEGFR-3. Moreover, NP2 knockdown specifically inhibited the increase in the number of corneal lymphatic vessels but did not influence the increase in the number of blood vessels or macrophage recruitment induced by LPS. In a macrophage-LEC co culture system, LPS up-regulated VEGFR-3 expression and induced mLEC migration and proliferation, and NP2 knockdown inhibited the up-regulation of VEGFR-3 expression and mLEC migration but not proliferation. Taken together, these results suggested that NP2 might be involved in the regulation of lymphangiogenesis via the regulation of VEGFR-3 expression during corneal inflammation. Therefore, NP2-targeted therapy might be a promising strategy for selective inhibition of inflammatory lymphangiogenesis in corneal inflammatory diseases, transplant immunology and oncology. PMID- 26500196 TI - Spatial distribution of metabolites in the human lens. AB - Spatial distribution of 34 metabolites along the optical and equatorial axes of the human lens has been determined. For the majority of metabolites, the homogeneous distribution has been observed. That suggests that the rate of the metabolite transformation in the lens is low due to the general metabolic passivity of the lens fiber cells. However, the redox processes are active in the lens; as a result, some metabolites, including antioxidants, demonstrate the "nucleus-depleted" type of distribution, whereas secondary UV filters show the "nucleus-enriched" type. The metabolite concentrations at the lens poles and equator are similar for all metabolites under study. The concentric pattern of the "nucleus-depleted" and "nucleus-enriched" distributions testifies that the metabolite distribution inside the lens is mostly governed by a passive diffusion, relatively free along the fiber cells and retarded in the radial direction across the cells. No significant difference in the metabolite distribution between the normal and cataractous human lenses was found. PMID- 26500197 TI - Postoperative antiviral therapy with nucleos(t)ide analogs for patients with hepatitis B virus-related hepatocellular carcinoma. PMID- 26500195 TI - Expansions of the neurovascular scleral canal and contained optic nerve occur early in the hypertonic saline rat experimental glaucoma model. AB - PURPOSE: To characterize early optic nerve head (ONH) structural change in rat experimental glaucoma (EG). METHODS: Unilateral intraocular pressure (IOP) elevation was induced in Brown Norway rats by hypertonic saline injection into the episcleral veins and animals were sacrificed 4 weeks later by perfusion fixation. Optic nerve cross-sections were graded from 1 (normal) to 5 (extensive injury) by 5 masked observers. ONHs with peripapillary retina and sclera were embedded, serial sectioned, 3-D reconstructed, delineated, and quantified. Overall and animal-specific EG versus Control eye ONH parameter differences were assessed globally and regionally by linear mixed effect models with significance criteria adjusted for multiple comparisons. RESULTS: Expansions of the optic nerve and surrounding anterior scleral canal opening achieved statistical significance overall (p < 0.0022), and in 7 of 8 EG eyes (p < 0.005). In at least 5 EG eyes, significant expansions (p < 0.005) in Bruch's membrane opening (BMO) (range 3-10%), the anterior and posterior scleral canal openings (8-21% and 5 21%, respectively), and the optic nerve at the anterior and posterior scleral canal openings (11-30% and 8-41%, respectively) were detected. Optic nerve expansion was greatest within the superior and inferior quadrants. Optic nerve expansion at the posterior scleral canal opening was significantly correlated to optic nerve damage (R = 0.768, p = 0.042). CONCLUSION: In the rat ONH, the optic nerve and surrounding BMO and neurovascular scleral canal expand early in their response to chronic experimental IOP elevation. These findings provide phenotypic landmarks and imaging targets for detecting the development of experimental glaucomatous optic neuropathy in the rat eye. PMID- 26500198 TI - Liver transplantation in adults with portal vein thrombosis: Data from the China Liver Transplant Registry. AB - OBJECTIVES: Portal vein thrombosis (PVT) is a common complication in patients with liver cirrhosis. During liver transplantation (LT), PVT may complicate the procedure and lead to a poor prognosis. The aim of this study is to evaluate patients enrolled in the China Liver Transplant Registry, to understand the influence of PVT to the LT recipients. METHODS: We collected data from patients who underwent LT and were entered into the China Liver Transplant Registry. All data of medical records and follow-up were retrospectively reviewed. The preoperative condition, duration of surgery, intraoperative blood loss, postoperative early and late PVT, and survival rates were compared between patients with PVT and those without PVT. Multivariate Cox analysis and survival analysis were used to determine the influence of PVT. RESULTS: A total of 20,524 cases were recruited into the study. In all, 1810 (8.82%) patients were diagnosed with preoperative PVT of various severities. All patients were followed up for an average of 30.25+/-33.25months (up to a maximum of 171.68months). Patients with PVT had a significantly longer operating time, more intraoperative blood loss and a higher rate of post-LT PVT (P<0.001). Multivariate Cox analysis showed that PVT did not reduce the recipients' survival rate (HR=0.89, 95% CI: 0.774-1.024, P=0.103). There was no significant difference in cumulative survival rate (P=0.059) between patients without PVT, and patients with PVT. CONCLUSIONS: PVT increases the difficulty of LT, but doesn't reduce the survival rate. Therefore, PVT is not an absolute contraindication for LT in experienced transplantation centers. PMID- 26500199 TI - Intrahepatic cholestasis of pregnancy: A risk factor for cancer, autoimmune and cardiovascular diseases? AB - The authors show, in an elegant population-based study, a significant association between intrahepatic cholestasis of pregnancy and liver and biliary cancer. This association is most probably related to the high frequency of hepatitis C and gallstone disease in women with intrahepatic cholestasis of pregnancy, both being risk factors for liver and biliary cancer. In addition, the study clearly shows an increased risk of diabetes mellitus and autoimmune diseases, such as thyroid diseases, psoriasis, autoimmune arthropathies and Crohn's disease, and a small increase in cardiovascular diseases. In practice, a follow-up of liver function tests 6-12 weeks after delivery is strongly recommended to detect a possible associated liver disease. PMID- 26500200 TI - Safety and efficacy of palliative systemic chemotherapy combined with colorectal self-expandable metallic stents in advanced colorectal cancer: A multicenter study. AB - PURPOSE: Self-expandable metallic stent (SEMS) placement is an accepted palliative therapy for management of acute malignant bowel obstruction in advanced colorectal cancer. Nevertheless, data are lacking on the effects of systemic chemotherapy combined with colorectal SEMS. The aim of this study was to investigate the safety and efficacy of palliative chemotherapy for advanced colorectal cancer combined with colorectal SEMS placement. PATIENTS AND METHODS: This multicentre retrospective study included all consecutive advanced colorectal cancer patients who received first-line palliative chemotherapy combined with endoscopic stenting for colorectal cancer with obstruction. We analyzed the number of cycles and the type of combination used. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, response rate, grade 3-4 toxicity and the outcomes of SEMS for malignant colorectal obstruction. RESULTS: A total of 38 patients were included. Among them, 25 patients received oxaliplatin and 5-fluorouracil combination chemotherapy. Objective response and stabilization occurred in 38 and 24% of patients, respectively. The median overall survival and progression-free survival from the start of chemotherapy were 18 and 5months, respectively. The objective response rate and overall disease control rate were 38 and 62%, respectively. Toxicity was generally acceptable. Major complications related to stenting included perforation (8%), stent migration (5%), and reobstruction secondary to tumor ingrowths (13%). CONCLUSIONS: Chemotherapy combined with colonic stenting as a first-line treatment seems to be a valid option in advanced colorectal cancer patients with malignant colorectal obstruction. PMID- 26500201 TI - Association study of PNPLA2 gene with histological parameters of NAFLD in an obese population. AB - INTRODUCTION: The prevalence of non-alcoholic fatty liver disease (NAFLD) and the closely associated metabolic syndrome is high and is related to risk factors such as obesity and type 2 diabetes. A genetic basis for NAFLD has been suggested, but only few causal genes have been identified. The most significant association reported to date is the robust association of the PNPLA3 I148M variant with susceptibility to NAFLD. We therefore hypothesized that the PNPLA2 gene might also be involved in NAFLD pathogenesis, because of its close sequence similarity with PNPLA3 and its possible involvement in ectopic fat accumulation. METHODS: In this study, we investigated the association of PNPLA2 polymorphisms with the development of non-alcoholic fatty liver disease in a prospectively recruited Belgian obese population comprising 633 individuals with varying degrees of fatty liver disease. We selected 3 PNPLA2 SNPs for genotyping, including 2 tagSNPs that cover most information on common genetic variation in the selected region. RESULTS: After performing linear regression analysis, we found that 2 of the analyzed PNPLA2 SNPs were associated with anthropometric and metabolic parameters. In our subcohort of patients that underwent liver biopsy (n=372/633 or 58.7%), we assessed the influence of the PNPLA2 variants on the severity of histologically determined liver damage, but we did not find convincing evidence for association. CONCLUSION: Although we found evidence for moderate association between PNPLA2 tagSNPs and anthropometric and metabolic parameters in our cohort, no evidence for association between polymorphisms in the PNPLA2 gene and the presence and severity of NAFLD was identified. PMID- 26500202 TI - Restrained eating predicts effortful self-control as indicated by heart rate variability during food exposure. AB - When confronted with food, restrained eaters have to inhibit the pursuit of the short-term goal of enjoying their food for the sake of the long-term goal of controlling their weight. Thus, restrained eating creates a self-control situation. In the present study we investigated the initiation of effortful self control by food cues in accordance with the level of restrained eating. We expected that a preceding act of self-control would moderate the association between restrained eating and effortful self-control initiated by food cues. Participants (N=111) were randomly assigned to a task requiring self-control or a task not requiring self-control. Subsequently, participants were exposed to palatable food, and effortful self-control was measured via heart rate variability (HRV). Restrained eating was associated with enhanced HRV during food exposure after exercising self-control but not after not exercising self-control. The results indicate that maintaining dieting goals results in food cues initiating effortful self-control after a preceding act of self-control. We suggest considering the effect of acts of self-control when modeling the initial steps on the path from food cues to unsuccessful restrained eating. PMID- 26500203 TI - Characterization of maize spermine synthase 1 (ZmSPMS1): Evidence for dimerization and intracellular location. AB - Polyamines are ubiquitous positively charged metabolites that play an important role in wide fundamental cellular processes; because of their importance, the homeostasis of these amines is tightly regulated. Spermine synthase catalyzes the formation of polyamine spermine, which is necessary for growth and development in higher eukaryotes. Previously, we reported a stress inducible spermine synthase 1 (ZmSPMS1) gene from maize. The ZmSPMS1 enzyme differs from their dicot orthologous by a C-terminal extension, which contains a degradation PEST sequence involved in its turnover. Herein, we demonstrate that ZmSPMS1 protein interacts with itself in split yeast two-hybrid (Y2H) assays. A Bimolecular Fluorescence Complementation (BiFC) assay revealed that ZmSPMS1 homodimer has a cytoplasmic localization. In order to gain a better understanding about ZmSPMS1 interaction, two deletion constructs of ZmSPMS1 protein were obtained. The DeltaN-ZmSPMS1 version, where the first 74 N-terminal amino acids were eliminated, showed reduced capability of dimer formation, whereas the DeltaC-ZmSPMS1 version, lacking the last 40 C-terminal residues, dramatically abated the ZmSPMS1-ZmSPMS1 protein interaction. Recombinant protein expression in Escherichia coli of ZmSPMS1 derived versions revealed that deletion of its N-terminal domain affected the spermine biosynthesis, whereas C-terminal ZmSPMS1 truncated version fail to generate this polyamine. These data suggest that N- and C-terminal domains of ZmSPMS1 play a role in a functional homodimer. PMID- 26500204 TI - Futility of Imaging Atherosclerotic Renal Artery Stenosis? PMID- 26500205 TI - The Reply. PMID- 26500206 TI - Fever-induced Brugada Pattern. PMID- 26500207 TI - The Reply. PMID- 26500208 TI - Brugada Phenocopy Is an Important Differential Diagnosis in Patients with Type 1 Brugada ECG Patterns. PMID- 26500209 TI - The Reply. PMID- 26500210 TI - Cocaine-related Aortic Dissection: Questions yet to Be Resolved. PMID- 26500211 TI - The Reply. PMID- 26500212 TI - Changes in Internal Medicine Fellowship Timeline Are Not Favorable for Applicants on J1 Visa. PMID- 26500213 TI - The Reply. PMID- 26500214 TI - Autonomic Dysfunction and Takotsubo Cardiomyopathy. PMID- 26500215 TI - The Reply. PMID- 26500216 TI - Hypertensives May Safely Consume Ethanol and Coffee in Moderation. PMID- 26500217 TI - Dr Alpert Is on the Money! PMID- 26500218 TI - From pay-per-bag to pay-per-kg: The case of Flanders revisited. AB - Weight-based pricing systems for municipal solid waste collection and processing are increasingly popular in many European countries and regions. However, the impact on waste generation of such pricing schedules remains debated and depends strongly on the practical details of the system used. This article assesses the impact of a voluntary transition by Flemish municipalities from the default price per-bag pricing systems to a more sophisticated weight-based pricing schedule. By (1) exploiting alternative statistical techniques, (2) using more recent data and (3) focusing on the introduction effect of the new pricing schedule, we are able to complement and refine prior research on this topic. Our results indicate that introducing weight-based pricing has initially a significant and substantial downward impact on the amount of residual municipal solid waste per capita. This result is robust under different methodologies that control for selection bias. There are however, indications that this initial effect does not persist in the years after introduction. PMID- 26500219 TI - Ethanol attenuates vasorelaxation via inhibition of inducible nitric oxide synthase in rat artery exposed to interleukin-1beta. AB - Nitric oxide produced by inducible nitric oxide synthase (iNOS) regulates sepsis induced hypotension. During septic shock, interleukin (IL)-1beta is synthesized in endothelial cells and smooth muscle cells by endotoxin. Ethanol (EtOH) suppresses endotoxin-induced hypotension. The present study aimed to elucidate the effect of EtOH on gradual relaxation and iNOS expression induced by IL-1beta in isolated rat superior mesenteric arteries (SMAs). Exposure to IL-1beta-induced contraction in SMA rings, followed by a gradual relaxation of phenylephrine precontracted tone. Contraction was abolished by indomethacin (IM), cycloheximide (Chx), and endothelium denudation. In contrast, the gradual relaxation was abolished by NOS inhibitors, Chx, endothelium denudation, and inhibited by EtOH (50 and 100 mM). However, IM had no effect on relaxation. Western blot analysis demonstrated that iNOS expression was induced by IL-1beta and was inhibited by EtOH and endothelium denudation. Furthermore, messenger RNA expression of iNOS, but not endothelial NOS, was inhibited by EtOH. These data suggest that IL-1beta induced contraction is mediated by thromboxane A2, whereas IL-1beta-induced relaxation occurs via NO derived from iNOS. The endothelium plays an important role in vasorelaxation. Taken together, EtOH inhibits IL-1beta-mediated vasorelaxation by suppressing endothelium iNOS expression. This study provides the first evidence of EtOH -induced inhibition of IL-1beta-mediated vasorelaxation. PMID- 26500220 TI - Genotoxic and mutagenic effects of vigabatrin, a gamma-aminobutyric acid transaminase inhibitor, in Wistar rats submitted to rotarod task. AB - Vigabatrin (VGB) is an antiepileptic drug thatincreases brain gamma-aminobutyric acid (GABA) levels through irreversible inhibition of GABA transaminase. The aim of this study was to evaluate neurotoxicological effects of VGB measuring motor activity and genotoxic and mutagenic effects after a single and repeated administration. Male Wistar rats received saline, VGB 50, 100, or 250 mg/kg by gavage for acute and subchronic (14 days) treatments and evaluated in the rotarod task. Genotoxicity was evaluated using the alkaline version of the comet assay in samples of blood, liver, hippocampus, and brain cortex after both treatments. Mutagenicity was evaluated using the micronucleus test in bone marrow of the same animals that received subchronic treatment. The groups treated with VGB showed similar performance in rotarod compared with the saline group. Regarding the acute treatment, it was observed that only higher VGB doses induced DNA damage in blood and hippocampus. After the subchronic treatment, VGB did not show genotoxic or mutagenic effects. In brief, VGB did not impair motor activities in rats after acute and subchronic treatments. It showed a repairable genotoxic potential in the central nervous system since genotoxicity was observed in the acute treatment group. PMID- 26500221 TI - Effects of silver nanoparticles on human dermal fibroblasts and epidermal keratinocytes. AB - Biomedical application of silver nanoparticles (AgNPs) has been rapidly increasing. Owing to their strong antimicrobial activity, AgNPs are used in dermatology in the treatment of wounds and burns. However, recent evidence for their cytotoxicity gives rise to safety concerns. This study was undertaken as a part of an ongoing programme in our laboratory to develop a topical agent for wound healing. Here, we investigated the potential toxicity of AgNPs using normal human dermal fibroblasts (NHDF) and normal human epidermal keratinocytes (NHEK) with the aim of comparing the effects of AgNPs and ionic silver (Ag-I). Besides the effect of AgNPs and Ag-I on cell viability, the inflammatory response and DNA damage in AgNPs and Ag-I-treated cells were examined. The results showed that Ag I were significantly more toxic than AgNPs both on NHDF and NHEK. Non-cytotoxic concentrations of AgNPs and Ag-I did not induce DNA strand breaks and did not affect inflammatory markers, except for a transient increase in interleukin 6 levels in Ag-I-treated NHDF. The results showed that AgNPs are more suitable for the intended application as a topical agent for wound healing up to the concentration 25 ug/mL. PMID- 26500222 TI - Association of ADAM33 gene polymorphism and arginase activity with susceptibility to ventilatory impairment in wood dust-exposed workers. AB - ADAM33 represents an important gene of susceptibility for lung function impairment. This work aimed to evaluate the association between genetic polymorphism of ADAM33 at four single nucleotide polymorphisms (T1, T2, S1, and Q1) and arginase activity with respiratory functions impairment in wood workers. The study was done to compare ventilatory functions and arginase activity of 82 wood workers and 81 controls. Genotyping was determined by using the polymerase chain restriction fragment length polymorphism method. Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and peak expiratory flow rate (PEF) of the workers were significantly reduced compared with the controls. T1 single nucleotide polymorphism (SNP) was associated with obvious decline in the FEV1, FVC, and PEF in wood workers, while T2 SNP was associated with decline in FEV1 and PEF. A significant increase in arginase activity was found in T2 and S1 SNPs of the exposed workers. Increase in duration of exposure was correlated with the decline in ventilatory functions. This inverse correlation was significant for pulmonary function indices in AA and GG genotypes of T1 and T2, respectively. Moreover, significance was detected for FVC and FEV1 in AA and GA genotypes of S1 and Q1. A positive correlation between arginase activity and duration of exposure was found to be significant in GG genotype of S1 SNP. An association between ADAM33 gene polymorphism and impaired lung functions was detected in wood dust-exposed workers. Arginase activity may play an associated important role in increasing this impairment in wood workers. PMID- 26500223 TI - Do phages impact microbial dynamics, prokaryotic community structure and nutrient dynamics in Lake Bourget? AB - Phages are the most abundant and diversified biological entities in aquatic ecosystems. Understanding their functional role requires laboratory experiments on a short time-scale. Using samples of surface waters of Lake Bourget, we studied whether viruses impact (i) the abundance patterns of the bacterial and phytoplankton communities, (ii) a part of the prokaryotic community composition (both for Eubacteria and Archaea), and (iii) the recycling of nutrients and/or organic matter. Three experiments were performed (one each in February, March and April) at the transition between winter and spring in 2013. The experiment reduced or increased the abundance of virus-like particles in samples containing only the picoplanktonic fraction. Viral and cellular abundances, bacterial and archaeal community structures as well as nutrient concentrations were analysed every 24 h for 3 days. Some of the results reveal that increasing the phage abundance increased the diversity of the eubacterial community. Consistent with the 'killing the winner' concept, viruses are thus likely to significantly change the composition of the bacterial community. This suggests a positive association between viral abundance and bacterial diversity. In contrast, the composition of the archaeal community did not seem to be affected by phage abundance, suggesting the absence of viral control on this community or the inability to observe it at this period of year, either based on the time scale of the investigation or because the archaeal virus titre was too low to induce a significant and visible effect. Lastly, we were unable to demonstrate viruses driving the cycling of nutrients or the response of plankton to nutrient concentration changes in a significant way, suggesting that the role of viruses may be subtle or difficult to assess through the use of such experimental procedures. PMID- 26500224 TI - Hox11 genes regulate postnatal longitudinal bone growth and growth plate proliferation. AB - Hox genes are critical regulators of skeletal development and Hox9-13 paralogs, specifically, are necessary for appendicular development along the proximal to distal axis. Loss of function of both Hoxa11 and Hoxd11 results in severe malformation of the forelimb zeugopod. In the radius and ulna of these mutants, chondrocyte development is perturbed, growth plates are not established, and skeletal growth and maturation fails. In compound mutants in which one of the four Hox11 alleles remains wild-type, establishment of a growth plate is preserved and embryos develop normally through newborn stages, however, skeletal phenotypes become evident postnatally. During postnatal development, the radial and ulnar growth rate slows compared to wild-type controls and terminal bone length is reduced. Growth plate height is decreased in mutants and premature growth plate senescence occurs along with abnormally high levels of chondrocyte proliferation in the reserve and proliferative zones. Compound mutants additionally develop an abnormal curvature of the radius, which causes significant distortion of the carpal elements. The progressive bowing of the radius appears to result from physical constraint caused by the disproportionately slower growth of the ulna than the radius. Collectively, these data are consistent with premature depletion of forelimb zeugopod progenitor cells in the growth plate of Hox11 compound mutants, and demonstrate a continued function for Hox genes in postnatal bone growth and patterning. PMID- 26500225 TI - Donor platelet plasma components inactivate sensitive and multidrug resistant Acinetobacter baumannii isolates. AB - Acinetobacter baumannii is an environmentally resilient healthcare-associated opportunistic pathogen responsible for infections at many body sites. In the last 10 years, clinical strains resistant to many or all commonly used antibiotics have emerged globally. With few antimicrobial agents in the pharmaceutical pipeline, new and alternative agents are essential. Platelets secrete a large number of proteins, including proteins with antimicrobial activity. In a previous study, we demonstrated that donor platelet supernatants and plasma significantly inhibited the growth of a reference strain of A. baumannii in broth and on skin. This inhibition appeared to be unrelated to the platelet activation state. In this study, we demonstrate that this growth inhibition extends to clinical multidrug resistant isolates. We also demonstrate that there is no relationship between this activity and selected platelet-derived antimicrobial proteins. Instead, the donor plasma components complement and alpha-2 macroglobulin are implicated. PMID- 26500226 TI - Microbiota-mitochondria inter-talk: consequence for microbiota-host interaction. AB - New discoveries in metagenomics and clinical research have highlighted the importance of the gut microbiota for human health through the regulation of the host immune response and energetic metabolism. The microbiota interacts with host cells in particular by intermingling with the mitochondrial activities. This mitochondria-microbiota cross-talk is intriguing because mitochondria share many common structural and functional features with the prokaryotic world. Several studies reported a correlation between microbiota quality and diversity and mitochondrial function. The mitochondrial production of reactive oxygen species (ROS) plays an important role during the innate immune response and inflammation, and is often targeted by pathogenic bacteria. Data suggest that excessive mitochondrial ROS production may affect ROS signaling induced by the microbiota to regulate the gut epithelial barrier. Finally, the microbiota releases metabolites that can directly interfere with the mitochondrial respiratory chain and ATP production. Short chain fatty acids have beneficial effects on mitochondrial activity. All these data suggest that the microbiota targets mitochondria to regulate its interaction with the host. Imbalance of this targeting may result in a pathogenic state as observed in numerous studies. The challenge to find new treatments will be to find strategies to modulate the quality and diversity of the microbiota rather than acting on microbiota metabolites and microbiota-related factors. PMID- 26500227 TI - State Fall Prevention Coalitions as Systems Change Agents: An Emphasis on Policy. AB - BACKGROUND: Falls among older adults are an escalating public health issue, which requires a multidisciplinary and multilevel approach to affect systems change to effectively address this problem. The National Council on Aging established the Falls Free(r) Initiative, enfolding and facilitating statewide Fall Prevention Coalitions. Fall Free(r) activities included developing the State Policy Toolkit for Advancing Falls Prevention to promote sustainable change by supporting the dissemination and adoption of evidence-based strategies. PURPOSE: To (1) determine if the policies being implemented were recommended and supported by the Toolkit, (2) identify the perceived barriers and facilitators to implementing policies, and (3) identify Coalitions' current and future fall prevention policy activities. METHODS: A 63-item online survey was distributed to State Coalition Leads. Descriptive statistics (frequencies and counts) were used to describe Coalition characteristics and activities. RESULTS: Coalitions had several similarities, and varied greatly in their number of member organizations and members as well as meeting frequencies. Key activities included building partnerships, disseminating programs, and pursuing at least one of the eight National Council on Aging-recommended policy goals. The most commonly reported facilitator was active support from the Coalition Leads, whereas the lack of funding was the most cited barrier. CONCLUSION: This study serves as the first national census of empirical evidence regarding Falls Coalitions' composition, goals, and activities. Results indicate that Coalitions are actively pursuing evidence-based policies but could benefit from additional technical assistance and resources. Findings support the value of Toolkit recommendations by documenting what is feasible and being implemented. Knowledge about facilitators and barriers will inform future efforts to foster sustainable systems change in states with active Coalitions and encourage Coalitions in other states. PMID- 26500228 TI - Identifying the Rehabilitative Potential of Electronically Monitored Release Preparation: A Randomized Controlled Study in Germany. AB - As one of many fields of application, electronic monitoring (EM) of offenders can be used-in conjunction with other measures-for release preparation. Using such measures, policymakers expect an alleviation of the negative effects of imprisonment and the promotion of positive rehabilitative effects by adding structure and social support. At the same time, policymakers are willing to maintain community safety through the close supervision provided by EM. The present study examines participants' psychological and psychosocial changes during two measures of electronically monitored release preparation, namely, home detention and early work release. These findings are compared with a randomized group of participants who remained in custody. In sum, we found no distinctive positive effects of the tested measures. Because most participants already displayed functional psychological characteristics at pretest, there was only a small margin for improvement through electronically monitored release preparation. We conclude that if rehabilitation is sought by the use of such measures, it is important to select a target group that is actually in need of rehabilitative support and equally important to conduct further research on the rehabilitative potential of EM measures. PMID- 26500230 TI - Continued EGFR Inhibition With Postprogression Chemotherapy: Where Do We Stand? PMID- 26500229 TI - Brentuximab Vedotin in Transplant-Naive Relapsed/Refractory Hodgkin Lymphoma: Experience in 30 Patients. AB - BACKGROUND: Hodgkin lymphoma (HL) is characterized by the presence of CD30 positive Hodgkin Reed-Sternberg cells. Approximately 30%-40% of patients with advanced disease are refractory to frontline therapy or will relapse after first line treatment. The standard management of these patients is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT). The best prognostic factor is the status of disease before ASCT; in particular, the normalization of positron emission tomography (PET) scan. Brentuximab vedotin (BV) has shown a high overall response rate in refractory/relapsed HL after ASCT, whereas few data are available regarding its role before ASCT. PATIENTS AND METHODS: A multicenter, retrospective, observational study was conducted. The primary endpoint of the study was the effectiveness of BV as single agent in patients with relapsed/refractory, ASCT-naive HL, determined by the conversion of PET status from positive to negative; secondary endpoints were safety, capacity to proceed to ASCT, survival, and progression-free status. RESULTS: Thirty patients with relapsed/refractory HL- and PET-positive disease after conventional chemotherapy salvage treatments were treated with a median of 4 cycles of BV. Normalization of PET findings (Deauville score <=2) occurred in 9 of 30 patients (30%). Those nine patients proceeded to ASCT. CONCLUSION: These data suggest that BV can normalize PET status in a subset of HL patients refractory to conventional chemotherapy salvage treatments, such as ifosfamide-containing regimens, cytarabine- and platinum-containing regimens, prior to ASCT. PMID- 26500231 TI - On Rounds: The King. PMID- 26500232 TI - Delayed aneurysm rupture due to residual blood flow at the inflow zone of the intracranial paraclinoid internal carotid aneurysm treated with the Pipeline embolization device: Histopathological investigation. AB - Cerebral aneurysm rupture is a serious complication that can occur after flow diverter (FD) placement, but the underlying mechanisms remain unclear. We encountered a case in which direct stress on the aneurysm wall caused by residual blood flow at the inflow zone near the neck during the process of thrombosis after FD placement appeared associated with aneurysm rupture. The patient was a 67-year-old woman with progressive optic nerve compression symptoms caused by a large intracranial paraclinoid internal carotid aneurysm. The patient had undergone treatment with a Pipeline embolization device (PED) with satisfactory adherence between the PED and vessel wall. Surgery was completed without complications, and optic nerve compression symptoms improved immediately after treatment. Postoperative clinical course was satisfactory, but the patient suddenly died 34 days postoperatively. Autopsy confirmed the presence of subarachnoid hemorrhage caused by rupture of the internal carotid aneurysm that had been treated with PED. Although the majority of the aneurysm lumen including the outflow zone was thrombosed, a non-thrombosed area was observed at the inflow zone. Perforation was evident in the aneurysm wall at the inflow zone near the neck, and this particular area of aneurysm wall was not covered in thrombus. Macrophage infiltration was not seen on immunohistochemical studies of the aneurysm wall near the perforation. A hemodynamically unstable period during the process of complete thrombosis of the aneurysm lumen after FD placement may be suggested, and blood pressure management and appropriate management with antiplatelet therapy may be important. PMID- 26500233 TI - Delayed vertebral body collapse after stereotactic radiosurgery and radiofrequency ablation: Case report with histopathologic-MRI correlation. AB - Stereotactic radiosurgery and percutaneous radiofrequency ablation are emerging therapies for pain palliation and local control of spinal metastases. However, the post-treatment imaging findings are not well characterized and the risk of long-term complications is unknown. We present the case of a 46-year-old woman with delayed vertebral body collapse after stereotactic radiosurgery and radiofrequency ablation of a painful lumbar metastasis. Histopathologic-MRI correlation confirmed osteonecrosis as the underlying etiology and demonstrated that treatment-induced vascular fibrosis and tumor progression can have identical imaging appearances. PMID- 26500234 TI - The Debaryomyces hansenii carboxylate transporters Jen1 homologues are functional in Saccharomyces cerevisiae. AB - We have functionally characterized the four Saccharomyces cerevisiae (Sc) Jen1 homologues of Debaryomyces hansenii (Dh) by heterologous expression in S. cerevisiae. Debaryomyces hansenii cells display mediated transport for the uptake of lactate, acetate, succinate and malate. DHJEN genes expression was detected by RT-PCR in all carbon sources assayed, namely lactate, succinate, citrate, glycerol and glucose. The heterologous expression in the S. cerevisiae W303-1A jen1Delta ady2Delta strain demonstrated that the D. hansenii JEN genes encode four carboxylate transporters. DH27 gene encodes an acetate transporter (Km 0.94 +/- 0.17 mM; Vmax 0.43 +/- 0.03 nmol s(-1) mg(-1)), DH17 encodes a malate transporter (Km 0.27 +/- 0.04 mM; Vmax 0.11 +/- 0.01 nmol s(-1) mg(-1)) and both DH18 and DH24 encode succinate transporters with the following kinetic parameters, respectively, Km 0.31 +/- 0.06 mM; Vmax 0.83 +/- 0.04 nmol s(-1) mg( 1)and Km 0.16 +/- 0.02 mM; Vmax 0.19 +/- 0.02 nmol s(-1) mg(-1). Surprisingly, no lactate transporter was found, although D. hansenii presents a mediated transport for this acid. This work advanced the current knowledge on yeast carboxylate transporters by characterizing four new plasma membrane transporters in D. hansenii. PMID- 26500235 TI - Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T Cell Responses in Metastatic Melanoma Patients--Report of a Phase I/IIa Clinical Trial. AB - PURPOSE: Cancer vaccines aim to generate and maintain antitumor immune responses. We designed a phase I/IIa clinical trial to test a vaccine formulation composed of Montanide ISA-51 (Incomplete Freund's Adjuvant), LAG-3Ig (IMP321, a non-Toll like Receptor agonist with adjuvant properties), and five synthetic peptides derived from tumor-associated antigens (four short 9/10-mers targeting CD8 T cells, and one longer 15-mer targeting CD4 T-cells). Primary endpoints were safety and T-cell responses. EXPERIMENTAL DESIGN: Sixteen metastatic melanoma patients received serial vaccinations. Up to nine injections were subcutaneously administered in three cycles, each with three vaccinations every 3 weeks, with 6 to 14 weeks interval between cycles. Blood samples were collected at baseline, 1 week after the third, sixth and ninth vaccination, and 6 months after the last vaccination. Circulating T-cells were monitored by tetramer staining directly ex vivo, and by combinatorial tetramer and cytokine staining on in vitro stimulated cells. RESULTS: Side effects were mild to moderate, comparable to vaccines with Montanide alone. Specific CD8 T-cell responses to at least one peptide formulated in the vaccine preparation were found in 13 of 16 patients. However, two of the four short peptides of the vaccine formulation did not elicit CD8 T-cell responses. Specific CD4 T-cell responses were found in all 16 patients. CONCLUSIONS: We conclude that vaccination with IMP321 is a promising and safe strategy for inducing sustained immune responses, encouraging further development for cancer vaccines as components of combination therapies. PMID- 26500236 TI - Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma. AB - PURPOSE: To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: This multicenter, open-label, phase I, dose-escalation study included patients aged 20 to 80 years, refractory to standard therapy, and stratified by hepatic function measured using Child-Pugh (CP) scores: CP-A (score, 5-6) and CP-B (score, 7-8). Lenvatinib was administered continually once daily for 4-week cycles. MTD was defined as the maximum dose associated with <= 1 dose-limiting toxicity (DLT) occurring in cycle 1 among 6 patients. RESULTS: In total, 20 patients (9 in CP-A and 11 in CP-B) were enrolled. The MTD was 12 and 8 mg once daily in CP-A and CP-B, respectively; DLTs included proteinuria, hepatic encephalopathy, and hyperbilirubinemia. The most common grade 3 toxicities included hypertension in CP-A and hyperbilirubinemia in CP-B. Lenvatinib plasma concentration at 24 hours after administration (C24 h) for 12 mg once daily was higher in patients with HCC than in patients with other solid tumors shown in a previous phase I study, but C24 h for 25 mg once daily lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit(+) cells decreased and the levels of interleukin (IL)-6, IL10, granulocyte-colony stimulating factor, and vascular endothelial growth factor increased (P < 0.05). Partial responses were observed in 3 patients and tumor shrinkage occurred in 14 patients. CONCLUSIONS: Lenvatinib (12 mg once daily) demonstrated preliminary efficacy with manageable toxicity and is the recommended dose for phase II studies in patients with HCC and CP-A. PMID- 26500237 TI - Sensitive Detection of Mono- and Polyclonal ESR1 Mutations in Primary Tumors, Metastatic Lesions, and Cell-Free DNA of Breast Cancer Patients. AB - PURPOSE: Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell-free DNA (cfDNA). EXPERIMENTAL DESIGN: Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n = 43), bone (n = 12) and brain metastases (n = 38), and cfDNA (n = 29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. RESULTS: ESR1 mutations were detected for D538G (n = 13), Y537S (n = 3), and Y537C (n = 1), and not for K303R, S463P, or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3% to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n = 5), mutations were detected in both (n = 3) or in cfDNA only (n = 2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. CONCLUSIONS: ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1-mutant clones are enriched by endocrine therapy. Further studies should address whether sensitive detection of ESR1 mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease. See related commentary by Gu and Fuqua, p. 1034. PMID- 26500239 TI - Neonatal randomised point-of-care trials are feasible and acceptable in the UK: results from two national surveys. PMID- 26500238 TI - IL1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NF-kappaB Activation. AB - PURPOSE: Constitutive NF-kappaB activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required for oncogenic KRAS induced PDAC development in mouse models. We sought to determine whether targeting IL-1alpha pathway would inhibit NF-kappaB activity and thus suppress PDAC cell growth. EXPERIMENTAL DESIGN: We determined whether anakinra, a human IL 1 receptor (rhIL-1R) antagonist, inhibited NF-kappaB activation. Assays for cell proliferation, migration, and invasion were performed with rhIL-1R antagonist using the human PDAC cell lines AsPc1, Colo357, MiaPaCa-2, and HPNE/K ras(G12V)/p16sh. In vivo NF-kappaB activation-dependent tumorigenesis was assayed using an orthotopic nude mouse model (n = 20, 5 per group) treated with a combination of gemcitabine and rhIL-1RA. RESULTS: rhIL-1R antagonist treatment led to a significant decrease in NF-kappaB activity. PDAC cells treated with rhIL 1R antagonist plus gemcitabine reduced proliferation, migration, and invasion as compared with single gemcitabine treatment. In nude mice, rhIL-1R antagonist plus gemcitabine significantly reduced the tumor burden (gemcitabine plus rhIL-1RA vs. control, P = 0.014). CONCLUSIONS: We found that anakinra, an FDA-approved drug that inhibits IL-1 receptor (IL-1R), when given with or without gemcitabine, can reduce tumor growth by inhibiting IL1alpha-induced NF-kappaB activity; this result suggests that it is a useful therapeutic approach for PDAC. PMID- 26500240 TI - Religion, reason, controversies and perspectives in clinical and research ethics. PMID- 26500242 TI - The Role of Prematurity in Patients With Hemiplegic Cerebral Palsy. AB - A multicenter retrospective study was conducted to investigate the perinatal factors, imaging findings and clinical characteristics of hemiplegic cerebral palsy with a particular focus on children born prematurely. Our cohort included 135 patients of whom 42% were born prematurely; 16% were extreme premature infants who were born at 30 weeks or earlier. Nineteen (14%) were twins. Right hemiplegia was slightly more common and accounted for 59% of the patients. Imaging findings of intraventricular hemorrhage and periventricular leukomalacia were more prevalent in premature children whereas stroke, porencephaly, cerebral hemorrhage and cerebral atrophy were more evenly distributed in both term-born and prematurely-born children (p< 0.01). The overall prevalence of epilepsy in the cohort was 26% with no differences in full-term compared to prematurely-born children. Regardless of the gestational birth age, intellectual deficits were more common in the presence of comorbidity of both hemiplegia and epilepsy (p< 0.05). PMID- 26500243 TI - Neurodevelopmental and Behavioral Outcomes in Children With Sepsis-Associated Encephalopathy Admitted to Pediatric Intensive Care Unit: A Prospective Case Control Study. AB - The authors prospectively compared the neurodevelopmental and behavioral outcomes in 50 consecutive children with sepsis-associated encephalopathy admitted to intensive care unit with healthy controls. Children with sepsis-associated encephalopathy had significantly worse mean verbal IQ, full-scale IQ, General Development Score, and its physical, adaptive, social-emotional, cognitive, and communication subscales. Significant proportion of cases (52% vs 32% in controls) had low intelligence. Decline in school performance (44%), disobedience (28%), and stubbornness/irritable behavior (26%) were the most common behavior changes. Children with Glasgow Coma Scale score <=10 and <=8 had impairments in full-scale IQ even though overall Glasgow Coma Scale score did not show significant correlation with developmental outcomes. In conclusion, children with sepsis associated encephalopathy have delayed neurodevelopment, low verbal IQ, decline in school performance and low intelligence at short-term follow-up. Irritability, shock and duration of sedation are associated with poor behavioral outcomes, especially scholastic performance. PMID- 26500244 TI - Association of Interleukin-1 Gene Cluster and Interleukin-1 Receptor Polymorphisms With Febrile Seizures. AB - Interleukin-1 (IL-1) plays a key role in inflammation, has an effect on a wide variety of cells, and often leads to tissue destruction. While the ratio between IL-1 and IL-1Ra could influence the development of different diseases of the central nervous system, its gene polymorphisms were investigated in a group of patients with febrile seizures. Ninety patients with febrile seizures were enrolled and compared with 140 controls. The allele and genotype frequency of single nucleotide polymorphisms within the IL-1alpha, beta, IL-1 R and IL-1Ra gene were determined. The frequency of the IL-1Ra/C allele at position Mspa-I 11100 was decreased significantly (P= .002) and the IL-1Ra/T frequency was significantly increased in patients (P= .002). In addition, the CT genotype frequency at the same position was significantly overrepresented in controls compared to patients (P= .001). Certain alleles and genotypes in the IL-1 gene were overrepresented in patients with febrile seizures, which possibly could predispose individuals to this disease. PMID- 26500245 TI - Partial and intermediate atrioventricular septal defects without major associated cardiac anomalies. AB - Partial and intermediate atrioventricular septal defects (p-i AVSDs) constitute approximately 20-40% of all AVSDs. Children with p-i AVSDs are usually asymptomatic and typically undergo surgery at the preschool age or earlier if the signs of heart failure have developed. Surgical treatment for repair of p-i AVSDs has been successful for more than 60 years and is mainly directed towards closing septal defects, and maintaining or creating competent, non-stenotic left and/or right atrioventricular valves. By most measures, the outcomes of surgical management of p-i AVSDs have improved over the last 5 decades. In spite of significantly reduced mortality, the need for reoperation and long-term morbidity remains an issue in some patients from this population. The purpose of this article is to review current options and outcomes concerning the surgical management of the p-AVSD and i-AVSD variants without major associated cardiac malformations. PMID- 26500246 TI - Association between Serum Potassium and Outcomes in Patients with Reduced Kidney Function. AB - BACKGROUND AND OBJECTIVES: Patients with CKD are more likely than others to have abnormalities in serum potassium (K(+)). Aside from severe hyperkalemia, the clinical significance of K(+) abnormalities is not known. We sought to examine the association of serum K(+) with mortality and hospitalization rates within narrow eGFR strata to understand how the burden of hyperkalemia varies by CKD severity. Associations were examined between serum K(+) and discontinuation of medications that block the renin-angiotensin-aldosterone system (RAAS), which are known to increase serum K(+). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cohort of patients with CKD (eGFR<60 ml/min per 1.73 m(2)) with serum K(+) data were studied (n=55,266) between January 1, 2009, and June 30, 2013 (study end). Serum K(+), eGFR, and covariates were considered on a time-updated basis. Mortality, major adverse cardiovascular events (MACE), hospitalization, and discontinuation of RAAS blockers were considered per time at risk. RESULTS: During the study, serum K(+) levels of 5.5-5.9 and >=6.0 mEq/L were most prevalent at lower eGFR: they were present, respectively, in 1.7% and 0.2% of patient-time for eGFR of 50-59 ml/min per 1.73 m(2) versus 7.6% and 1.8% of patient-time for eGFR<30 ml/min per 1.73 m(2). Serum K(+) level <3.5 mEq/L was present in 1.2%-1.4% of patient-time across eGFR strata. The median follow-up time was 2.76 years. There was a U-shaped association between serum K(+) and mortality; pooled adjusted incidence rate ratios were 3.05 (95% confidence interval, 2.53 to 3.68) and 3.31 (95% confidence interval, 2.52 to 4.34) for K(+) levels <3.5 mEq/L and >=6.0 mEq/L, respectively. Within eGFR strata, there were U shaped associations of serum K(+) with rates of MACE, hospitalization, and discontinuation of RAAS blockers. CONCLUSIONS: Both hyperkalemia and hypokalemia were independently associated with higher rates of death, MACE, hospitalization, and discontinuation of RAAS blockers in patients with CKD who were not undergoing dialysis. Future studies are needed to determine whether interventions targeted at maintaining normal serum K(+) improve outcomes in this population. PMID- 26500247 TI - Evaluation of Neurocognition in Youth with CKD Using a Novel Computerized Neurocognitive Battery. AB - BACKGROUND AND OBJECTIVES: Neurocognitive problems in CKD are well documented; time-efficient methods are needed to assess neurocognition in this population. We performed the first study of the efficient 1-hour Penn Computerized Neurocognitive Battery (CNB) in children and young adults with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We administered the Penn CNB cross sectionally to individuals aged 8-25 years with stage 2-5 CKD (n=92, enrolled from three academic nephrology practices from 2011 to 2014) and matched healthy controls (n=69). We analyzed results from 12 tests in four domains: executive control, episodic memory, complex cognition, and social cognition. All tests measure accuracy and speed; we converted raw scores to age-specific z-scores on the basis of Philadelphia Neurodevelopmental Cohort (n=1790) norms. We analyzed each test in a linear regression with accuracy and speed z-scores as dependent variables and with (1) CKD versus control or (2) eGFR as explanatory variables, adjusted for race, sex, and maternal education. RESULTS: Patients with CKD (mean+/-SD eGFR, 48+/-25 ml/min per 1.73 m(2); mean age, 16.3+/-3.9 years) and controls (mean eGFR, 98+/-20 ml/min per 1.73 m(2); mean age, 16.0+/-4.0 years) were similar demographically. CKD participants had lower accuracy than controls in tests of complex cognition, with moderate to large effect sizes: -0.53 (95% confidence interval [95% CI], -0.87 to -0.19) for verbal reasoning, -0.52 (95% CI, -0.83 to -0.22) for nonverbal reasoning, and -0.64 (95% CI, -0.99 to -0.29) for spatial processing. For attention, patients with CKD had lower accuracy (effect size, -0.35 [95% CI, -0.67 to -0.03]) but faster response times (effect size, 0.44 [95% CI, 0.04 to 0.83]) than controls, perhaps reflecting greater impulsivity. Lower eGFR was associated with lower accuracy for complex cognition, facial and visual memory, and emotion identification tests. CONCLUSIONS: CKD is associated with lower accuracy in tests of complex cognition, attention, memory, and emotion identification, which related to eGFR. These findings are consistent with traditional neurocognitive testing in previous studies. PMID- 26500248 TI - Factors Associated with Recovery of Renal Function following Radical Nephrectomy for Kidney Neoplasms. AB - BACKGROUND AND OBJECTIVES: Partial nephrectomy or radical nephrectomy is the standard of care for patients with kidney neoplasms, but surgery may result in loss of renal function. We sought to identify patient characteristics associated with renal functional recovery following radical nephrectomy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective study among 572 patients with kidney neoplasms who underwent RN between 2006 and 2013. The primary endpoint was recovery of postoperative eGFR to the preoperative level. We plotted the trajectory of each patient's eGFR from their first postoperative visit up to 3 years after surgery. Cumulative incidence and competing risks regression estimated associations between patient and clinical characteristics and eGFR recovery, stratified by preoperative eGFR. RESULTS: Median age was 61.5 years; 68% of patients were male, and 89% were white. Overall, eGFR increased over time following an initial postoperative decrease. Median postoperative follow-up among survivors was 10.8 (minimum, 0.03; maximum, 36.0) months; during follow-up, 263 patients achieved eGFR recovery. Median time to eGFR recovery was 25.3 months. Two-year cumulative incidence of eGFR recovery was 49% overall and 44% and 58% among those with preoperative eGFR>=60 and <60 ml/min per 1.73 m(2), respectively (P<0.001). On multivariable analysis, younger age at surgery and female sex were significantly associated with a higher chance of eGFR recovery among patients with preoperative eGFR<60 ml/min per 1.73 m(2). Among patients with preoperative eGFR>=60 ml/min per 1.73 m(2), hypertension was significantly associated with a lower chance of eGFR recovery, whereas increased tumor size was significantly associated with a higher chance of eGFR recovery. CONCLUSIONS: Overall, almost half of the patients in this study recovered to their preoperative eGFR by 2 years following surgery. Distributions of preoperative risk factors differed by preoperative eGFR, leading to distinct factors that were significantly associated with chance of eGFR recovery. PMID- 26500249 TI - Developing the eHistology Atlas. AB - The eMouseAtlas project has undertaken to generate a new resource providing access to high-resolution colour images of the slides used in the renowned textbook 'The Atlas of Mouse Development' by Matthew H. Kaufman. The original histology slides were digitized, and the associated anatomy annotations captured for display in the new resource. These annotations were assigned to objects in the standard reference anatomy ontology, allowing the eHistology resource to be linked to other data resources including the Edinburgh Mouse Atlas Gene Expression database (EMAGE) an the Mouse Genome Informatics (MGI) gene-expression database (GXD). The provision of the eHistology Atlas resource was assisted greatly by the expertise of the eMouseAtlas project in delivering large image datasets within a web environment, using IIP3D technology. This technology also permits future extensions to the resource through the addition of further layers of data and annotations to the resource. Database URL: www.emouseatlas.org/emap/eHistology/index.php. PMID- 26500250 TI - First-Step Mutations during Adaptation Restore the Expression of Hundreds of Genes. AB - The temporal change of phenotypes during the adaptive process remains largely unexplored, as do the genetic changes that affect these phenotypic changes. Here we focused on three mutations that rose to high frequency in the early stages of adaptation within 12 Escherichia coli populations subjected to thermal stress (42 degrees C). All the mutations were in the rpoB gene, which encodes the RNA polymerase beta subunit. For each mutation, we measured the growth curves and gene expression (mRNAseq) of clones at 42 degrees C. We also compared growth and gene expression with their ancestor under unstressed (37 degrees C) and stressed conditions (42 degrees C). Each of the three mutations changed the expression of hundreds of genes and conferred large fitness advantages, apparently through the restoration of global gene expression from the stressed toward the prestressed state. These three mutations had a similar effect on gene expression as another single mutation in a distinct domain of the rpoB protein. Finally, we compared the phenotypic characteristics of one mutant, I572L, with two high-temperature adapted clones that have this mutation plus additional background mutations. The background mutations increased fitness, but they did not substantially change gene expression. We conclude that early mutations in a global transcriptional regulator cause extensive changes in gene expression, many of which are likely under positive selection for their effect in restoring the prestress physiology. PMID- 26500252 TI - Disentangling Sources of Selection on Exonic Transcriptional Enhancers. AB - In addition to coding for proteins, exons can also impact transcription by encoding regulatory elements such as enhancers. It has been debated whether such features confer heightened selective constraint, or evolve neutrally. We have addressed this question by developing a new approach to disentangle the sources of selection acting on exonic enhancers, in which we model the evolutionary rates of every possible substitution as a function of their effects on both protein sequence and enhancer activity. In three exonic enhancers, we found no significant association between evolutionary rates and effects on enhancer activity. This suggests that despite having biochemical activity, these exonic enhancers have no detectable selective constraint, and thus are unlikely to play a major role in protein evolution. PMID- 26500253 TI - Identification and Validation of Larixyl Acetate as a Potent TRPC6 Inhibitor. AB - Classical or canonical transient receptor potential 6 (TRPC6), a nonselective and Ca(2+)-permeable cation channel, mediates pathophysiological responses within pulmonary and renal diseases that are still poorly controlled by current medication. Thus, controlling TRPC6 activity may provide a promising and challenging pharmacological approach. Recently identified chemical entities have demonstrated that TRPC6 is pharmacologically targetable. However, isotype selectivity with regard to its closest relative, TRPC3, is difficult to achieve. Reasoning that balsams, essential oils, or incense materials that are traditionally used for inhalation may contain biologic activities to block TRPC6 activity, we embarked on a natural compound strategy to identify new TRPC6 blocking chemical entities. Within several preparations of plant extracts, a strong TRPC6-inhibitory activity was found in conifer balsams. The biologic activity was associated with nonvolatile resins, but not with essential oils. Of various conifers, the larch balsam was unique in displaying a marked TRPC6 prevalent mode of action. By testing the main constituents of larch resin, we identified larixol and larixyl acetate as blockers of Ca(2+) entry and ionic currents through diacylglycerol- or receptor-activated recombinant TRPC6 channels, exhibiting approximately 12- and 5-fold selectivity compared with its closest relatives TRPC3 and TRPC7, respectively. No significant inhibition of more distantly related TRPV or TRPM channels was seen. The potent inhibition of recombinant TRPC6 by larixyl acetate (IC50 = 0.1-0.6 uM) was confirmed for native TRPC6-like [Ca(2+)]i signals in diacylglycerol-stimulated rat pulmonary artery smooth muscle cells. In isolated mouse lungs, larix-6-yl monoacetate (CAS 4608-49 5; larixyl acetate; 5 uM) prevented acute hypoxia-induced vasoconstriction. We conclude that larch-derived labdane-type diterpenes are TRPC6-selective inhibitors and may represent a starting point for pharmacological TRPC6 modulation within experimental therapies. PMID- 26500254 TI - Rapid Short-Read Sequencing and Aneuploidy Detection Using MinION Nanopore Technology. AB - MinION is a memory stick-sized nanopore-based sequencer designed primarily for single-molecule sequencing of long DNA fragments (>6 kb). We developed a library preparation and data-analysis method to enable rapid real-time sequencing of short DNA fragments (<1 kb) that resulted in the sequencing of 500 reads in 3 min and 40,000-80,000 reads in 2-4 hr at a rate of 30 nt/sec. We then demonstrated the clinical applicability of this approach by performing successful aneuploidy detection in prenatal and miscarriage samples with sequencing in <4 hr. This method broadens the application of nanopore-based single-molecule sequencing and makes it a promising and versatile tool for rapid clinical and research applications. PMID- 26500251 TI - Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes. AB - Phenotypes resulting from mutations in genetic model organisms can help reveal candidate genes for evolutionarily important phenotypic changes in related taxa. Although testing candidate gene hypotheses experimentally in nonmodel organisms is typically difficult, ontology-driven information systems can help generate testable hypotheses about developmental processes in experimentally tractable organisms. Here, we tested candidate gene hypotheses suggested by expert use of the Phenoscape Knowledgebase, specifically looking for genes that are candidates responsible for evolutionarily interesting phenotypes in the ostariophysan fishes that bear resemblance to mutant phenotypes in zebrafish. For this, we searched ZFIN for genetic perturbations that result in either loss of basihyal element or loss of scales phenotypes, because these are the ancestral phenotypes observed in catfishes (Siluriformes). We tested the identified candidate genes by examining their endogenous expression patterns in the channel catfish, Ictalurus punctatus. The experimental results were consistent with the hypotheses that these features evolved through disruption in developmental pathways at, or upstream of, brpf1 and eda/edar for the ancestral losses of basihyal element and scales, respectively. These results demonstrate that ontological annotations of the phenotypic effects of genetic alterations in model organisms, when aggregated within a knowledgebase, can be used effectively to generate testable, and useful, hypotheses about evolutionary changes in morphology. PMID- 26500255 TI - Targeted Integration of Single-Copy Transgenes in Drosophila melanogaster Tissue Culture Cells Using Recombination-Mediated Cassette Exchange. AB - Transfection of transgenes into Drosophila cultured cells is a standard approach for studying gene function. However, the number of transgenes present in the cell following transient transfection or stable random integration varies, and the resulting differences in expression level affect interpretation. Here we developed a system for Drosophila cell lines that allows selection of cells with a single-copy transgene inserted at a specific genomic site using recombination mediated cassette exchange (RMCE). We used the phiC31 integrase and its target sites attP and attB for RMCE. Cell lines with an attP-flanked genomic cassette were transfected with donor plasmids containing a transgene of interest (UAS-x), a dihydrofolate reductase (UAS-DHFR) gene flanked by attB sequences, and a thymidine kinase (UAS-TK) gene in the plasmid backbone outside the attB sequences. In cells undergoing RMCE, UAS-x and UAS-DHFR were exchanged for the attP-flanked genomic cassette, and UAS-TK was excluded. These cells were selected using methotrexate, which requires DHFR expression, and ganciclovir, which causes death in cells expressing TK. Pure populations of cells with one copy of a stably integrated transgene were efficiently selected by cloning or mass culture in ~6 weeks. Our results show that RMCE avoids the problems associated with current methods, where transgene number is not controlled, and facilitates the rapid generation of Drosophila cell lines in which expression from a single transgene can be studied. PMID- 26500256 TI - A gamma-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans. AB - Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) occur in most early onset familial Alzheimer's Disease. Despite the identification of the involvement of PSEN in Alzheimer's Disease (AD) ~20 years ago, the underlying role of PSEN in AD is not fully understood. To gain insight into the biological function of PSEN, we investigated the role of the PSEN homolog SEL-12 in Caenorhabditis elegans. Using genetic, cell biological, and pharmacological approaches, we demonstrate that mutations in sel-12 result in defects in calcium homeostasis, leading to mitochondrial dysfunction. Moreover, consistent with mammalian PSEN, we provide evidence that SEL-12 has a critical role in mediating endoplasmic reticulum (ER) calcium release. Furthermore, we found that in SEL-12 deficient animals, calcium transfer from the ER to the mitochondria leads to fragmentation of the mitochondria and mitochondrial dysfunction. Additionally, we show that the impact that SEL-12 has on mitochondrial function is independent of its role in Notch signaling, gamma-secretase proteolytic activity, and amyloid plaques. Our results reveal a critical role for PSEN in mediating mitochondrial function by regulating calcium transfer from the ER to the mitochondria. PMID- 26500257 TI - Deep History of East Asian Populations Revealed Through Genetic Analysis of the Ainu. AB - Despite recent advances in population genomics, much remains to be elucidated with regard to East Asian population history. The Ainu, a hunter-gatherer population of northern Japan and Sakhalin island of Russia, are thought to be key to elucidating the prehistory of Japan and the peopling of East Asia. Here, we study the genetic relationship of the Ainu with other East Asian and Siberian populations outside the Japanese archipelago using genome-wide genotyping data. We find that the Ainu represent a deep branch of East Asian diversity more basal than all present-day East Asian farmers. However, we did not find a genetic connection between the Ainu and populations of the Tibetan plateau, rejecting their long-held hypothetical connection based on Y chromosome data. Unlike all other East Asian populations investigated, the Ainu have a closer genetic relationship with northeast Siberians than with central Siberians, suggesting ancient connections among populations around the Sea of Okhotsk. We also detect a recent genetic contribution of the Ainu to nearby populations, but no evidence for reciprocal recent gene flow is observed. Whole genome sequencing of contemporary and ancient Ainu individuals will be helpful to understand the details of the deep history of East Asians. PMID- 26500258 TI - Roles of Nucleoid-Associated Proteins in Stress-Induced Mutagenic Break Repair in Starving Escherichia coli. AB - The mutagenicity of DNA double-strand break repair in Escherichia coli is controlled by DNA-damage (SOS) and general (RpoS) stress responses, which let error-prone DNA polymerases participate, potentially accelerating evolution during stress. Either base substitutions and indels or genome rearrangements result. Here we discovered that most small basic proteins that compact the genome, nucleoid-associated proteins (NAPs), promote or inhibit mutagenic break repair (MBR) via different routes. Of 15 NAPs, H-NS, Fis, CspE, and CbpA were required for MBR; Dps inhibited MBR; StpA and Hha did neither; and five others were characterized previously. Three essential genes were not tested. Using multiple tests, we found the following: First, Dps, which reduces reactive oxygen species (ROS), inhibited MBR, implicating ROS in MBR. Second, CbpA promoted F' plasmid maintenance, allowing MBR to be measured in an F'-based assay. Third, Fis was required for activation of the SOS DNA-damage response and could be substituted in MBR by SOS-induced levels of DinB error-prone DNA polymerase. Thus, Fis promoted MBR by allowing SOS activation. Fourth, H-NS represses ROS detoxifier sodB and was substituted in MBR by deletion of sodB, which was not otherwise mutagenic. We conclude that normal ROS levels promote MBR and that H-NS promotes MBR by maintaining ROS. CspE positively regulates RpoS, which is required for MBR. Four of five previously characterized NAPs promoted stress responses that enhance MBR. Hence, most NAPs affect MBR, the majority via regulatory functions. The data show that a total of six NAPs promote MBR by regulating stress responses, indicating the importance of nucleoid structure and function to the regulation of MBR and of coupling mutagenesis to stress, creating genetic diversity responsively. PMID- 26500259 TI - Estimating Relatedness in the Presence of Null Alleles. AB - Studies of genetics and ecology often require estimates of relatedness coefficients based on genetic marker data. However, with the presence of null alleles, an observed genotype can represent one of several possible true genotypes. This results in biased estimates of relatedness. As the numbers of marker loci are often limited, loci with null alleles cannot be abandoned without substantial loss of statistical power. Here, we show how loci with null alleles can be incorporated into six estimators of relatedness (two novel). We evaluate the performance of various estimators before and after correction for null alleles. If the frequency of a null allele is <0.1, some estimators can be used directly without adjustment; if it is >0.5, the potency of estimation is too low and such a locus should be excluded. We make available a software package entitled PolyRelatedness v1.6, which enables researchers to optimize these estimators to best fit a particular data set. PMID- 26500260 TI - Selective Strolls: Fixation and Extinction in Diploids Are Slower for Weakly Selected Mutations Than for Neutral Ones. AB - In finite populations, an allele disappears or reaches fixation due to two main forces, selection and drift. Selection is generally thought to accelerate the process: a selected mutation will reach fixation faster than a neutral one, and a disadvantageous one will quickly disappear from the population. We show that even in simple diploid populations, this is often not true. Dominance and recessivity unexpectedly slow down the evolutionary process for weakly selected alleles. In particular, slightly advantageous dominant and mildly deleterious recessive mutations reach fixation slightly more slowly than neutral ones (at most 5%). This phenomenon determines genetic signatures opposite to those expected under strong selection, such as increased instead of decreased genetic diversity around the selected site. Furthermore, we characterize a new phenomenon: mildly deleterious recessive alleles, thought to represent a wide fraction of newly arising mutations, on average survive in a population slightly longer than neutral ones, before getting lost. Consequently, these mutations are on average slightly older than neutral ones, in contrast with previous expectations. Furthermore, they slightly increase the amount of weakly deleterious polymorphisms, as a consequence of the longer unconditional sojourn times compared to neutral mutations. PMID- 26500261 TI - The Differences Between Cis- and Trans-Gene Inactivation Caused by Heterochromatin in Drosophila. AB - Position-effect variegation (PEV) is the epigenetic disruption of gene expression near the de novo-formed euchromatin-heterochromatin border. Heterochromatic cis inactivation may be accompanied by the trans-inactivation of genes on a normal homologous chromosome in trans-heterozygous combination with a PEV-inducing rearrangement. We characterize a new genetic system, inversion In(2)A4, demonstrating cis-acting PEV as well as trans-inactivation of the reporter transgenes on the homologous nonrearranged chromosome. The cis-effect of heterochromatin in the inversion results not only in repression but also in activation of genes, and it varies at different developmental stages. While cis actions affect only a few juxtaposed genes, trans-inactivation is observed in a 500-kb region and demonstrates a nonuniform pattern of repression with intermingled regions where no transgene repression occurs. There is no repression around the histone gene cluster and in some other euchromatic sites. trans Inactivation is accompanied by dragging of euchromatic regions into the heterochromatic compartment, but the histone gene cluster, located in the middle of the trans-inactivated region, was shown to be evicted from the heterochromatin. We demonstrate that trans-inactivation is followed by de novo HP1a accumulation in the affected transgene; trans-inactivation is specifically favored by the chromatin remodeler SAYP and prevented by Argonaute AGO2. PMID- 26500262 TI - Dual Role of Jun N-Terminal Kinase Activity in Bone Morphogenetic Protein Mediated Drosophila Ventral Head Development. AB - The Drosophila bone morphogenetic protein encoded by decapentaplegic (dpp) controls ventral head morphogenesis by expression in the head primordia, eye antennal imaginal discs. These are epithelial sacs made of two layers: columnar disc proper cells and squamous cells of the peripodial epithelium. dpp expression related to head formation occurs in the peripodial epithelium; cis-regulatory mutations disrupting this expression display defects in sensory vibrissae, rostral membrane, gena, and maxillary palps. Here we document that disruption of this dpp expression causes apoptosis in peripodial cells and underlying disc proper cells. We further show that peripodial Dpp acts directly on the disc proper, indicating that Dpp must cross the disc lumen to act. We demonstrate that palp defects are mechanistically separable from the other mutant phenotypes; both are affected by the c-Jun N-terminal kinase pathway but in opposite ways. Slight reduction of both Jun N-terminal kinase and Dpp activity in peripodial cells causes stronger vibrissae, rostral membrane, and gena defects than Dpp alone; additionally, strong reduction of Jun N-terminal kinase activity alone causes identical defects. A more severe reduction of dpp results in similar vibrissae, rostral membrane, and gena defects, but also causes mutant maxillary palps. This latter defect is correlated with increased peripodial Jun N-terminal kinase activity and can be caused solely by ectopic activation of Jun N-terminal kinase. We conclude that formation of sensory vibrissae, rostral membrane, and gena tissue in head morphogenesis requires the action of Jun N-terminal kinase in peripodial cells, while excessive Jun N-terminal kinase signaling in these same cells inhibits the formation of maxillary palps. PMID- 26500264 TI - Persistence of the tissue culture origin vaccine for infectious laryngotracheitis virus in commercial chicken flocks in Brazil. AB - Infectious laryngotracheitis (ILT) is a respiratory disease of great importance that causes serious economic losses in the poultry industry. Its control is based on biosecurity procedures and vaccination programs that use live attenuated vaccines such as tissue culture origin (TCO), chicken embryo origin (CEO), and vectored vaccines. However, problems have been reported, such as the reversion of virulence, virus latency, and field virus outbreaks. Several molecular techniques have been developed to differentiate between the field and vaccine strains. This study was conducted to determine the presence of infectious laryngotracheitis virus (ILTV) in Brazil from 2012 to 2014. PCR-RFLP (restriction fragment length polymorphism) was used to detect and differentiate ILTV strains; DNA sequencing and predictive RFLP analysis were also used for this purpose. Molecular analysis detected the presence of ILTV in 15 samples that were characterized as strains of TCO vaccine origin. This study showed that the ILTV TCO vaccine strain has been circulating in commercial chicken flocks in Brazil since its introduction during the 2002 outbreak. PMID- 26500263 TI - Manipulation of Karyotype in Caenorhabditis elegans Reveals Multiple Inputs Driving Pairwise Chromosome Synapsis During Meiosis. AB - Meiotic chromosome segregation requires pairwise association between homologs, stabilized by the synaptonemal complex (SC). Here, we investigate factors contributing to pairwise synapsis by investigating meiosis in polyploid worms. We devised a strategy, based on transient inhibition of cohesin function, to generate polyploid derivatives of virtually any Caenorhabditis elegans strain. We exploited this strategy to investigate the contribution of recombination to pairwise synapsis in tetraploid and triploid worms. In otherwise wild-type polyploids, chromosomes first sort into homolog groups, then multipartner interactions mature into exclusive pairwise associations. Pairwise synapsis associations still form in recombination-deficient tetraploids, confirming a propensity for synapsis to occur in a strictly pairwise manner. However, the transition from multipartner to pairwise association was perturbed in recombination-deficient triploids, implying a role for recombination in promoting this transition when three partners compete for synapsis. To evaluate the basis of synapsis partner preference, we generated polyploid worms heterozygous for normal sequence and rearranged chromosomes sharing the same pairing center (PC). Tetraploid worms had no detectable preference for identical partners, indicating that PC-adjacent homology drives partner choice in this context. In contrast, triploid worms exhibited a clear preference for identical partners, indicating that homology outside the PC region can influence partner choice. Together, our findings, suggest a two-phase model for C. elegans synapsis: an early phase, in which initial synapsis interactions are driven primarily by recombination independent assessment of homology near PCs and by a propensity for pairwise SC assembly, and a later phase in which mature synaptic interactions are promoted by recombination. PMID- 26500265 TI - Chicken gga-miR-181a targets MYBL1 and shows an inhibitory effect on proliferation of Marek's disease virus-transformed lymphoid cell line. AB - Marek's disease (MD), caused by Marek's disease virus (MDV), is a lymphoproliferative neoplastic disease of chickens and is characterized by MD lymphoma in multiple visceral organs of chicken. It causes great damage to poultry health. Recently, miRNA has been reported to be involved in Marek's disease lymphomagenesis. Our previous study showed that gga-miR-181a was downregulated in MDV-induced lymphoma, and its target gene, v-myb myeloblastosis viral oncogene homolog-like 1 (MYBL1), was predicted. In this study, the interaction between gga-miR-181a and MYBL1 was further verified by detecting protein expression levels of MYBL1 after transfecting miR-181a mimic into MD lymphoma cell line, MSB1. The result showed that protein level of MYBL1 was lower in gga-miR-181a mimic transfecting group than that in the negative control group at 96 h post transfection, which indicated that MYBL1 was a target gene of gga miR-181a. Additionally, we found that the expression of MYBL1 was higher in MDV infected samples than that in non-infected controls, which agreed with the proposition that miRNA showed a negatively correlated expression pattern with its target gene. We observed the inhibitory effect of gga-miR-181a on MSB1 cell proliferation. Collectively, the aberrant expression of gga-miR-181a and MYBL1 in MD lymphoma suggested that they might be involved in MD tumor transformation and played important roles. PMID- 26500266 TI - A comparison of post-mortem findings in broilers dead-on-farm and broilers dead on-arrival at the abattoir. AB - Broiler mortality during transport to abattoirs (dead-on-arrival/DOA) evokes concern due to compromised animal welfare and associated economic losses. The general aim of this study was to characterize pathological lesions associated with mortality in broilers close to slaughter. The specific aim was to investigate whether disease at the end of the growth period may be a predisposing factor for DOA by describing and comparing the pathological findings in broilers dead-on-farm (DOF) in the final days of the production cycle and in broilers DOA from the same flocks. Gross post-mortem examinations were performed on 607 broilers from 32 flocks, either DOF (371) or DOA (236). In DOF broilers, the most common pathological lesions were lung congestion (37.7%), endocarditis (29.4%), and ascites (24.0%), whereas the most common findings in broilers DOA were lung congestion (57.2%) and trauma (24.6%). Lung congestion was more prevalent among DOA broilers compared to DOF broilers (P-value of > 0.001). A possible cause behind the pathological finding lung congestion is sudden death syndrome (SDS). The study indicates that steps in the transportation process per se cause the majority of pathological lesions such as lung congestion and trauma that may have led to the mortalities registered. Pre-existing diseases such as ascites and osteomyelitis may also predispose for DOA. Thus, factors relating to on-farm health, catching, and transportation are all areas of future investigation in order to reduce transport mortalities and to enhance welfare in broilers. PMID- 26500267 TI - Comparison of 3 phytases on energy utilization of a nutritionally marginal wheat soybean meal broiler diet. AB - The net energy (NE) value may be a better measure than apparent metabolizable energy (ME) of the effect of supplemental phytase on energy utilization in broilers. The present study was conducted to assess the impact of 3 microbial phytases supplemented at an unconventionally high level (1,000 FTU/kg feed) on performance and NE of broilers using the indirect calorimetric method (IC). Four treatments included: 1) Control, formulated to be deficient in ME (12.35 MJ/kg in the starter diet; 12.56 MJ/kg in the grower diet), calcium (0.72% in the starter diet; 0.60% in the grower diet), and available phosphorus (0.25% in the starter diet; 0.20% in the grower diet); 2) control + intrinsically thermostable phytase A; 3) control + intrinsically thermostable phytase B; and 4) control + coated phytase C. A completely randomized design was employed. A total of 384 male broiler chicks were used, and each treatment had 6 replicates with 16 birds per replicate. The birds were reared until d 21 in floor pens with hardwood shavings. Thirty-two birds (8 birds per treatment) were randomly selected to determine heat production and NE (from 25-28 d) following a 3-d acclimatization in the respiratory chambers. Performance results at d 21 showed that supplementation with either of the 3 phytases improved body weight (P < 0.001) and feed intake (P < 0.05), and increased the relative weights of tibia ash (P < 0.05) and toe ash (P < 0.01). Phytases A and B increased the NE value of the diet (P < 0.05). It may be concluded that the negative effects imposed by calcium and available phosphorus down-specification can be compensated by phytase supplementation in general, and intrinsically thermostable phytases improve the ME and NE value. However, phytase did not reduce heat production, heat increment, or increase NE:ME in birds. PMID- 26500269 TI - In ovo feeding with minerals and vitamin D3 improves bone properties in hatchlings and mature broilers. AB - The objective of this study was to examine the effect of in ovo feeding (IOF) with inorganic minerals or organic minerals and vitamin D3 on bone properties and mineral consumption. Eggs were incubated and divided into 4 groups: IOF with organic minerals, phosphate, and vitamin D3 (IOF-OMD); IOF with inorganic minerals and phosphate (IOF-IM); sham; and non-treated controls (NTC). IOF was performed on embryonic day (E) 17; tibiae and yolk samples were taken on E19 and E21. Post-hatch, only chicks from the IOF-OMD, sham, and NTC were raised, and tibiae were taken on d 10 and 38. Yolk mineral content was examined by inductively coupled plasma spectroscopy. Tibiae were tested for their whole-bone mechanical properties, and mid-diaphysis bone sections were indented in a micro indenter to determine bone material stiffness (Young's modulus). Micro-computed tomography (MUCT) was used to examine cortical and trabecular bone structure. Ash content analysis was used to examine bone mineralization. A latency-to-lie (LTL) test was used to measure standing ability of the d 38 broilers. The results showed that embryos from both IOF-OMD and IOF-IM treatments had elevated Cu, Mn, and Zn amounts in the yolk on E19 and E21 and consumed more of these minerals (between E19 and E21) in comparison to the sham and NTC. On E21, these hatchlings had higher whole-bone stiffness in comparison to the NTC. On d 38, the IOF-OMD had higher ash content, elevated whole-bone stiffness, and elevated Young's modulus (in males) in comparison to the sham and NTC; however, no differences in standing ability were found. Very few structural differences were seen during the whole experiment. This study demonstrates that mineral supplementation by in ovo feeding is sufficient to induce higher mineral consumption from the yolk, regardless of its chemical form or the presence of vitamin D3. Additionally, IOF with organic minerals and vitamin D3 can increase bone ash content, as well as stiffness of the whole bone and bone material in the mature broiler, but does not lead to longer LTL. PMID- 26500268 TI - Effects of supplemental zinc source and level on antioxidant ability and fat metabolism-related enzymes of broilers. AB - The objective of the present study was to investigate the effects of dietary supplemental Zinc (Zn) source and level on antioxidant ability and fat metabolism related enzymes of broilers. Dietary treatments included the Zn-unsupplemented corn-soybean meal basal diet (control) and basal diets supplemented with 60, 120, or 180 mg Zn/kg as Zn sulfate, Zn amino acid chelate with a weak chelation strength of 6.5 quotient of formation (Qf) (11.93% Zn) (Zn-AA W), Zn proteinate with a moderate chelation strength of 30.7 Qf (13.27% Zn) (Zn-Pro M), or Zn proteinate with an extremely strong chelation strength of 944.0 Qf (18.61% Zn) (Zn-Pro S). The results showed that dietary supplemental Zn increased (P < 0.01) Zn contents in the liver, breast, and thigh muscles of broilers, and up-regulated mRNA expressions of copper and Zn containing superoxide dismutase (CuZnSOD) and metallothioneins (MT) in the liver (P < 0.01) and thigh muscle (P < 0.05), and also enhanced (P < 0.05) CuZnSOD activities in the breast and thigh muscles, which exerted antioxidant ability and a decreased malondialdehyde (MDA) level in the liver (P < 0.01) and breast and thigh muscles (P < 0.05) of broilers. Furthermore, supplemental Zn increased activities of malate dehydrogenase (MDH) and lipoprotein lipase (LPL) in the abdominal fat (P < 0.05), and fatty acid synthetase (FAS) and LPL in the liver (P < 0.01), which were accompanied with up regulation (P < 0.01) of the mRNA expressions levels of these enzymes in the abdominal fat and liver of broilers. Dietary Zn source, and an interaction between Zn source and level, had no effects on any measurements. It is concluded that dietary Zn supplementation improved Zn status and resulted in promoting antioxidant ability and activities and gene expressions of fat metabolism-related enzymes of broilers regardless of Zn source and level, and the addition of 60 mg Zn/kg to the corn-soybean meal basal diet (a total dietary Zn of approximately 90 mg/kg) was appropriate for improving the above aspects of broilers. PMID- 26500270 TI - Selenium deposition kinetics of different selenium sources in muscle and feathers of broilers. AB - The objective of this study was to determine selenium (Se) deposition kinetics in muscles and feathers of broilers in order to develop a rapid method to compare bioavailability of selenium sources. Different Se sources such as 2-hydroxy-4 methylselenobutanoic acid (HMSeBA, SO), sodium selenite (SS) and seleno-yeast (SY) were compared for their kinetics on Se deposition in muscles and feathers in broiler chicks from 0 to 21 d of age. A total of 576 day-old broilers were divided into four treatments with 8 replicates of 18 birds per pen. The diets used in the experiment were a negative control (NC) not supplemented with Se and 3 diets supplemented with 0.2 mg Se/kg as SS, SY or SO. Total Se content in breast muscle and feathers were assessed on days 0, 7, 14 and 21. At 7 d of age, SO increased muscle Se content compared to D0 (P < 0.05), whereas with the other treatments, muscle Se concentration decreased (P < 0.05). After 21 days, organic Se sources maintained (SY) or increased (SO) (P < 0.05) breast muscle Se concentration compared to hatch value whereas inorganic source (SS) or non supplemented group (NC) showed a significant decrease in tissue Se concentration (P < 0.05). At D21, Se contents of muscle and feathers were highly correlated (R(2) = 0.927; P < 0.0001). To conclude, these results indicate that efficiency of different Se sources can be discriminated through a 7 d using muscle Se content in broiler chickens. Muscle and feathers Se contents were highly correlated after 21 days. Also feather sampling at 21 days of age represents a reliable and non-invasive procedure for Se bioefficacy comparison. PMID- 26500271 TI - Lysine, methionine, phenylalanine, arginine, valine, isoleucine, leucine, and threonine maintenance requirements of broiler breeders. AB - Five hundred and sixty Cobb-Vantress broiler breeders were used to determine the maintenance requirement of dietary Arg, His, Ile, Leu, Lys, Met, Phe, Thr, and Val in 10 21-d assays using the comparative slaughter technique. Fifty sexually immature broiler breeder pullets per assay were given crystalline amino acid diets containing graded levels of Arg, His, Ile, Leu, Lys, Met, Phe, Thr, or Val, respectively, representing 0, 10, 20, 30, 40% of their suggested requirement level (NRC, 1994) with all other amino acids maintained at 40% of their suggested requirement level. Sixty hens were slaughtered prior to the beginning of the study to assess initial body composition at 3 weight groups. Linear regression lines (protein accretion vs. amino acid intake) were determined and the maintenance requirements were calculated based on zero protein accretion. The maintenance requirements expressed on a metabolic weight basis were determined to be 174, 94, 52, 81, 60, 126, 133, and 155 mg/kg(0.75)/d for Arg, Ile, Leu, Lys, Met, Phe, Thr, and Val, respectively. Additionally, the maintenance requirements, expressed on metabolic protein weight basis, were determined to be 651, 329, 172, 295, 223, 523, 478, and 546 mg/kgCP/d for Arg, Ile, Leu, Lys, Met, Phe, Thr, and Val, respectively. The requirement for His could not be established as the results obtained were outside of assay range. PMID- 26500272 TI - Inclusion of fiber in diets for brown-egg laying pullets: Effects on growth performance and digestive tract traits from hatching to 17 weeks of age. AB - We investigated the effects of fiber inclusion in the diet on growth performance and digestive traits in pullets from hatching to 17 wk of age. The control diets of the 3 feeding periods (0 to 5 wk, 5 to 10 wk, and 10 to 17 wk) were based on corn and soybean meal and did not include any additional fiber source. The experimental diets included 2 or 4% of cereal straw or sugar beet pulp (SBP) at the expense (wt:wt) of the control diet. From 0 to 5 wk of age, fiber inclusion did not affect pullet performance. From hatch to 17 wk of age, the inclusion of straw had little effect on pullet performance but the inclusion of 4% SBP reduced (ADG) (P < 0.05) and reduced feed conversion ratio (FCR; P < 0.001). Pullets fed straw had greater ADG (P < 0.05) and better energy conversion ratio (P < 0.01) than pullets fed SBP. An increase in fiber from 2 to 4% reduced FCR (P < 0.05). Body weight uniformity was not affected by diet. Fiber inclusion increased the relative weight (% BW) of the gizzard at 5 wk (P = 0.056) and 10 wk (P < 0.01) of age, but no differences were detected between fiber sources. At same ages, the relative length (cm/kg BW) of the pullets (P = 0.058 and P < 0.01, respectively) and tarsus (P = 0.079 and P < 0.05, respectively) was higher in pullets fed SBP than in pullets fed straw. Fiber inclusion, however, did not affect any of these traits at 17 wk of age. In summary, the inclusion of 2% straw at the expense (wt:wt) of the whole diet did not affect pullet performance at 17 wk of age. An increase in the level of straw from 2 to 4% reduced FCR but did not affect ADG. The inclusion of SBP, however, reduced pullet growth, with effects being more pronounced at the higher level. PMID- 26500273 TI - Effect of various fiber types and choice feeding of fiber on performance, gut development, humoral immunity, and fiber preference in broiler chicks. AB - Two experiments were conducted to investigate the effect of fibrous materials with one single diet or by choice feeding on performance, intestinal morphology, immunity, and fiber preference in broiler chicks. In experiment 1, 240-day-old chicks (Ross 308) were assigned to one of 4 treatments, comprising 5 replicates per treatment in a completely randomized design. Dietary treatments included: a basal diet (control) or 30 g/kg sugar beet pulp (SBP), 30 g/kg rice hull (RH), or 30 g/kg equal combination of them (SBP/RH) added to the basal diet. Results showed SBP and SBP/RH impaired daily weight gain (DWG) in the growing period compared with control (P < 0.05). Additionally, chickens that received SBP had deteriorated FCR across the entire rearing period (P < 0.05). In comparison to control and SBP, supplementing SBP/RH significantly increased antibody titer against Newcastle disease virus (NDV; P < 0.05) at 23 d of age. Furthermore, SBP reduced duodenal and ileal villus height compared with control at 21 d of age. In experiment 2, a total of 240 chicks were allotted to 4 experimental treatments of feeding: 1) control; or choice feeding between 2) control and SBP (C-SBP); 3) control and RH (C-RH); 4) control and SBP/RH (C- SBP/RH). Results indicated that chicks had a tendency to use separate sources of fiber. RH was consumed lower than C-SBP/RH and C-SBP in starter and growing periods, respectively (P < 0.05). Chickens choice fed RH and SBP/RH had greater daily feed intake than control across 14 to 28 d of age (P < 0.05). However, DWG reduced in all fiber fed birds (P < 0.05) and resulted in impaired FCR in broilers of the C-SBP group (P < 0.05). In addition, choice feeding of SBP/RH increased antibody titer against NDV as compared with control and SBP (P < 0.05). In conclusion, fiber inclusion in both experiments impaired growth performance but an equal combination of fiber improved immunity. In addition, broilers had a tendency to use separate sources of fiber. PMID- 26500274 TI - Rice and soy protein isolate in pre-starter diets for broilers. AB - Although most industries use a specific diet for the pre-starter phase, ingredients are used in the later phases, primarily corn and soybean meal, which at this stage do not have high digestibility. Three experiments : Exp : were carried out to evaluate the substitution of corn by white or parboiled rice : WR, PR : and the inclusion of 6% soy protein isolate : SPI : in pre-starter diets (1 to 7 d). In Exp 1 (1 to 21 d), WR, PR, and SPI were added to the diets until the birds were 21-day-old, whereas in Exps 2 and 3 (1 to 33 d), only until birds were 7-day-old. Birds were fed a basal diet based on corn and soybean meal until the end of the experimental period. In Exp 1, the coefficients of total tract apparent retention : CTTAR : of the pre-starter and the starter diets, ileal and jejunal digestibility of starch in the starter diets, and broiler performance were measured. Subsequently, the same pre-starter diets Exp 1 were evaluated in pellet (Exp 2) or mash (Exp 3) form and different oil percentage (Exp 2) or not (Exp 3). We hypothesized that the ingredients particle size (Exp 2) and fat content (Exp 3) could influence feed intake. There was no interaction among the evaluated factors (P > 0.05). Rice (WR or PR) promoted better results than corn in terms of CTTAR of dietary components, jejunal and ileal starch digestibility, and broiler performance (P < 0.01). In Exp 1, diets with 6% SPI presented better CTTAR, except Nitrogen ( N: ), but lower feed intake, which negatively affected broiler performance (P < 0.01). In Exps 1, 2, and 3, the inclusion of SPI did not improve broiler performance (P > 0.05), so that SPI may not be the best choice for pre-starter diets. The study also suggests that better growth performance and nutrient digestibility can be obtained in broiler chickens if corn is replaced by rice in pre-starter diets. PMID- 26500275 TI - A meta-analysis of the effects of nonphytate phosphorus on broiler performance and tibia ash concentration. AB - Decreasing feed costs while maintaining broiler performance at a high level with minimal environmental pollution has become a major challenge for poultry nutritionists in recent years. In this regard, phosphorus (P) is a nutrient that is problematic. To overcome this, a comprehensive knowledge of the responses of broilers to P is needed and the factors that affect its utilization need better understanding. For this purpose, a meta-analysis was conducted using results published in the literature on the responses of broilers to different levels of nonphytate P (NPP), calcium (Ca), microbial phytase (MP), and vitamin D3 or its metabolites (VD). The effects of Ca, MP, and VD on NPP requirements were investigated. Results showed significant (P <= 0.0001) linear and quadratic effects of NPP on all the responses, viz. average daily gain (ADG), feed intake (FI), feed efficiency (FE), and tibia ash concentration (TA). Results showed the negative effect of high Ca levels on all investigated responses, although these deleterious effects were alleviated when levels of NPP were increased or MP and/or VD added. Synergistic effects of MP and VD on FI and TA were observed. Best performance for all responses was found when MP and VD were added to low or moderate levels of Ca and NPP. Optimization showed higher levels of NPP are required to maximize TA compared to ADG, FI, and FE. Based on our analysis, requirements for NPP were affected mostly by Ca (increased) and MP (decreased), and, to a lesser extent, VD (inconsistent). PMID- 26500276 TI - Influence of soy oil source and dietary supplementation of vitamins E and C on the oxidation status of serum and egg yolk, and the lipid profile of egg yolk. AB - An experiment was conducted to determine the effects of adding vitamins E and C to diets containing 3.5% refined soy oil (SO), recycled soy oil (RSO), or acidulated soy oil soapstocks (ASS) on 1) fatty acid (FA) profile, and cholesterol, triglyceride (TG) and alpha-tocopherol (alpha-T) concentrations of yolk, and 2) the oxidation status of serum and yolk. Twelve dietary treatments, using 3 oil sources, 2 levels of vitamin E (0 vs. 250 mg/kg), and 2 levels of vitamin C (0 vs. 250 mg/kg), were prepared. A total of 300 W36 Hy-line laying hens, from 44 to 56 weeks of age, were placed in 60 cages (5 birds/cage) and 5 cages were randomly assigned to one of the 12 diets. Blood samples and eggs were collected after 84 d on trial. No interactions among main effects were found for any of the traits studied. Oil sources had little effects on the FA profile of the yolk, except for C18:3 that was higher (P-value of < 0.01) in the hens fed SO than those fed RSO or ASS. Vitamin E supplementation significantly (P-value of < 0.05) increased the concentration of C16:0, C18:0, and C16:1 but decreased that of C18:2 and C22:6n3 in the yolk. Vitamin C supplementation significantly (P value of < 0.05) increased C18:0 and C18:3 concentrations in the yolk but decreased the n6 to n3 FA ratio. The concentrations of cholesterol and triglyceride in serum and yolk were not affected by dietary treatment but alpha tocopherol concentration increased (P-value of < 0.01) by the dietary vitamin E. Compared with the hens fed the SO diets, malondialdehyde (MDA) concentration in serum was higher with RSO diet but lower with ASS diet. Vitamin E and vitamin C supplementation decreased (P-value of < 0.05) serum MDA. Yolk FA profile was affected not only by the FA profile of the oil source used in diet, but also by the supplementation of vitamin E and C. The results showed that triglyceride profile, but not cholesterol content, of egg was affected by fatty acid profile of the supplemental oil and the vitamin C and E supplementations. PMID- 26500278 TI - Method for the determination of chromium in feed matrix by HPLC. AB - An improved method for the chromatographic separation and determination of chromium (III) and (VI) [ CRIII AND CRVI: ] in mineral mixtures and feed samples has been developed. The method uses precolumn derivatization using ammonium pyrrolidinedithiocarbamate ( APD: ) followed by reversed-phase liquid chromatography to separate the chromium ions. Both Cr(III) and Cr(VI) species are chelated with ammonium pyrrolidinedithiocarbamate prior to separation by mixing with acetonitrile and 0.5 mmol acetate buffer (pH 4.5). Optimum chromatographic separations were obtained with a polymer-based reversed-phase column (Kinetex, 5 MU, 250 * 4.5 mm, Phenomenex, Torrance, CA) and a mobile phase containing acetonitrile and water (7:3). Both Cr(III) and Cr(VI) ion concentrations were directly determined from the corresponding areas in the chromatogram. The effect of analytical parameters, including pH, concentration of ligand, incubation temperature, and mobile phase, was optimized for both chromium complexes. The range of the procedure was found to be linear for Cr(III) and Cr(VI) concentrations between 0.125 and 4 MUg/mL (r2 = 0.9926) and 0.1 and 3.0 MUg/mL (r2 = 0.9983), respectively. Precision was evaluated by replicate analysis in which the percentage relative standard deviation values for chromium complex were found to be below 4.0. The recoveries obtained (85-115%) for both Cr(III) and Cr(VI) complexes indicated the accuracy of the developed method. The degradation products, as well as the excipients, were well resolved from the chromium complex peak in the chromatogram. Finally, the new method proved to be suitable for routine analysis of Cr(III) and Cr(VI) species in raw materials, mineral mixtures, and feed samples. PMID- 26500279 TI - A method of production of boneless chicken wings (drumettes and winglets) by separation of periosteum from bone without cutting skin and muscles. AB - The deboning of broiler chicken wings, including drumettes and winglets, is not common in the poultry processing industry. However, consumers who like convenient foods may be interested in boneless products. Samples of broiler wings were deboned by articular cartilage dislocation and periosteum stripping without cutting skin and muscles to obtain boneless drumettes and winglets, with each having inner space formed by bone removal. The average weight of bone-in winglets (30.7 g) was less (P < 0.05) than that of bone-in drumettes (39.9 g), whereas the average percentage of boneless product was less (P < 0.05) in the drumettes (74.9) than in the winglets (80.1). There was a smaller number of muscles in the drumettes than in the winglets, but major muscles in the drumettes were larger than any muscles in the winglets. The average weight of muscle was greater (P < 0.05) and that of skin was less (P < 0.05) in the drumettes than in the winglets, and thus the muscle/skin ratio was approximately twice as high (P < 0.05) in the drumettes. The size and shape were different between the bone-in and boneless products, as expected. When a cooked product was examined, no appreciable inner space (resulting from bone removal) was seen on its transverse section. The advantages of boneless wing products over bone-in wing products were discussed. It was concluded that the method described in the present study is useful for the production of high-quality boneless wing products. PMID- 26500277 TI - Super pharmacological levels of calcitriol (1,25-(OH)2D3) inhibits mineral deposition and decreases cell proliferation in a strain dependent manner in chicken mesenchymal stem cells undergoing osteogenic differentiation in vitro. AB - The biologically active form of vitamin D3, calcitriol (1,25-(OH)2D3), plays a key role in mineral homeostasis and bone formation and dietary vitamin D3deficiency is a major cause of bone disorders in poultry. Supplementary dietary cholecalciferol (25-hydroxyvitamin D, 25-OH), the precursor of calcitriol, is commonly employed to combat this problem; however, dosage must be carefully determined as excess dietary vitamin D can cause toxicity resulting in a decrease in bone calcification, hypercalcinemia and renal failure. Despite much research on the therapeutic administration of dietary vitamin D in humans, the relative sensitivity of avian species to exogenous vitamin D has not been well defined. In order to determine the effects of exogenous 1,25-(OH)2D3during avian osteogenesis, chicken bone marrow-derived mesenchymal stem cells (BM-MSCs) were exposed to varying doses of 1,25-(OH)2D3during in vitro osteogenic differentiation and examined for markers of early proliferation and osteogenic induction. Similar to humans and other mammals, poultry BM-MSCs were found to be highly sensitive to exogenous 1,25-(OH)2D3with super pharmacological levels exerting significant inhibition of mineralization and loss of cell proliferation in vitro. Strain related differences were apparent, with BM-MCSs derived from layers strains showing a higher level of sensitivity to 1,25-(OH)2D3than those from broilers. These data suggest that understanding species and strain specific sensitivities to 1,25-(OH)2D3is important for optimizing bone health in the poultry industry and that use of avian BM-MSCs are a useful tool for examining underlying effects of genetic variation in poultry. PMID- 26500280 TI - Glycosomal bromodomain factor 1 from Trypanosoma cruzi enhances trypomastigote cell infection and intracellular amastigote growth. AB - Acetylation is a ubiquitous protein modification present in prokaryotic and eukaryotic cells that participates in the regulation of many cellular processes. The bromodomain is the only domain known to bind acetylated lysine residues. In the last few years, many bromodomain inhibitors have been developed in order to treat diseases caused by aberrant acetylation of lysine residues and have been tested as anti-parasitic drugs. In the present paper, we report the first characterization of Trypanosoma cruzi bromodomain factor 1 (TcBDF1). TcBDF1 is expressed in all life cycle stages, but it is developmentally regulated. It localizes in the glycosomes directed by a PTS2 (peroxisome-targeting signal 2) sequence. The overexpression of wild-type TcBDF1 is detrimental for epimastigotes, but it enhances the infectivity rate of trypomastigotes and the replication of amastigotes. On the other hand, the overexpression of a mutated version of TcBDF1 has no effect on epimastigotes, but it does negatively affect trypomastigotes' infection and amastigotes' replication. PMID- 26500281 TI - Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2 overexpressing BT-474 breast cancer cells. AB - Phytoestrogen intake is known to be beneficial to decrease breast cancer incidence and progression. But its molecular mechanisms of action are still unknown. The present study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of BT-474 cells in a dose- and time-dependent manner. Apigenin also inhibited clonogenic survival (anchorage dependent and -independent) of BT-474 cells in a dose-dependent manner. These growth inhibitions were accompanied with an increase in sub-G0/G1 apoptotic populations. Apigenin-induced extrinsic a caspase-dependent apoptosis up regulating the levels of cleaved caspase-8 and cleaved caspase-3, and inducing the cleavage of poly (ADP-ribose) polymerase (PARP). Whereas, apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential without affecting the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Apigenin reduced the expression of phospho-JAK1, phospho-JAK2 and phospho-STAT3 and decreased signal transducer and activator of transcription 3 (STAT3) dependent luciferase reporter gene activity in BT-474 cells. Apigenin inhibited CoCl2-induced VEGF secretion and decreased the nuclear translocation of STAT3. Our study indicates that apigenin induces apoptosis through inhibition of STAT3 signalling and could serve as a useful compound to prevent or treat HER2 overexpressing breast cancer. PMID- 26500283 TI - Releasing prophase arrest in zebrafish oocyte: synergism between maturational steroid and Igf1. AB - Binding of 17beta-estradiol (E2) to novel G-protein coupled receptor, Gper1, promotes intra-oocyte adenylyl cyclase activity and transactivates epidermal growth factor receptor to ensure prophase-I arrest. Although involvement of either membrane progestin receptor (mPR) or Igf system has been implicated in regulation of meiosis resumption, possibility of concurrent activation and potential synergism between 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP)- and Igf-mediated signalling cascades in alleviating E2 inhibition of oocyte maturation (OM) has not been investigated. Here using zebrafish (Danio rerio) defolliculated oocytes, we examined the effect of DHP and Igf1, either alone or in combination, in presence or absence of E2, on OM in vitro. While priming of denuded oocytes with E2 blocked spontaneous maturation, co-treatment with DHP (3 nM) and Igf1 (10 nM), but not alone, reversed E2 inhibition and promoted a robust increase in germinal vesicle breakdown (GVBD). Although stimulation with either Igf1 or DHP promoted Akt phosphorylation, pharmacological inhibition of PI3K/Akt signalling prevented Igf1-induced GVBD but delayed DHP action till 4-5 h of incubation. Moreover, high intra-oocyte cAMP attenuates both DHP and Igf1 mediated OM and co-stimulation with DHP and Igf1 could effectively reverse E2 action on PKA phosphorylation. Interestingly, data from in vivo studies reveal that heightened expression of igf1, igf3 transcripts in intact follicles corresponded well with elevated phosphorylation of Igf1r and Akt, mPRa immunoreactivity, PKA inhibition and accelerated GVBD response just prior to ovulation. This indicates potential synergism between maturational steroid and Igf1 which might have physiological relevance in overcoming E2 inhibition of meiosis resumption in zebrafish oocytes. PMID- 26500282 TI - Control of Pim2 kinase stability and expression in transformed human haematopoietic cells. AB - The oncogenic Pim2 kinase is overexpressed in several haematological malignancies, such as multiple myeloma and acute myeloid leukaemia (AML), and constitutes a strong therapeutic target candidate. Like other Pim kinases, Pim2 is constitutively active and is believed to be essentially regulated through its accumulation. We show that in leukaemic cells, the three Pim2 isoforms have dramatically short half-lives although the longer isoform is significantly more stable than the shorter isoforms. All isoforms present a cytoplasmic localization and their degradation was neither modified by broad-spectrum kinase or phosphatase inhibitors such as staurosporine or okadaic acid nor by specific inhibition of several intracellular signalling pathways including Erk, Akt and mTORC1. Pim2 degradation was inhibited by proteasome inhibitors but Pim2 ubiquitination was not detected even by blocking both proteasome activity and protein de-ubiquitinases (DUBs). Moreover, Pyr41, an ubiquitin-activating enzyme (E1) inhibitor, did not stabilize Pim2, strongly suggesting that Pim2 was degraded by the proteasome without ubiquitination. In agreement, we observed that purified 20S proteasome particles could degrade Pim2 molecule in vitro. Pim2 mRNA accumulation in UT7 cells was controlled by erythropoietin (Epo) through STAT5 transcription factors. In contrast, the translation of Pim2 mRNA was not regulated by mTORC1. Overall, our results suggest that Pim2 is only controlled by its mRNA accumulation level. Catalytically active Pim2 accumulated in proteasome inhibitor-treated myeloma cells. We show that Pim2 inhibitors and proteasome inhibitors, such as bortezomib, have additive effects to inhibit the growth of myeloma cells, suggesting that Pim2 could be an interesting target for the treatment of multiple myeloma. PMID- 26500284 TI - In juvenile dermatomyositis, heart rate variability is reduced, and associated with both cardiac dysfunction and markers of inflammation: a cross-sectional study median 13.5 years after symptom onset. AB - OBJECTIVES: Low heart rate variability (HRV) is a well-established predictor of cardiac death. The aim of this study was to investigate arrhythmias and HRV in patients with JDM, and associations between HRV and inflammatory markers, echocardiographic measurements and disease parameters. METHODS: Fifty-five patients with JDM were examined 2-34 years (median 13.5 years) after disease onset, and compared with 55 age and sex matched controls. Holter ECG monitoring and echocardiography were analysed blinded to patient information. Arrhythmia and HRV (six parameters) were analysed by standard software, finally adjudicated by an experienced cardiologist. Markers of inflammation (ESR, high sensitivity (hs)CRP and cytokines) were analysed. Disease activity and organ damage were assessed by clinical examination at follow-up and retrospectively by chart review. RESULTS: In two out of six HRV parameters, JDM patients had lower values than controls. No difference in arrhythmias was found between the groups. In patients, but not in controls, there were significant negative correlations between five out of six HRV parameters, and ESR and hsCRP (Spearman correlation coefficient, -0.306 to -0.470; P, 0.023 to <0.001). Also, in patients, negative correlations were found between three out of six HRV parameters and systolic and diastolic function. Active disease and low HRV were associated. Patients with hsCRP in the highest quartile (Q4) had lower HRV in all parameters compared with those in pooled Q1-3 (P < 0.001). CONCLUSION: JDM patients had reduced HRV, which was associated with elevated inflammatory markers, active disease and reduced myocardial function. This suggests reduced vagal control of the heart; further studies are needed to determine whether this is also associated with cardiac morbidity or mortality. PMID- 26500285 TI - CALIBRATION OF THERMOLUMINESCENCE AND FILM DOSEMETERS FOR SKIN DOSES FROM HIGH ACTIVITY MICROPARTICLES. AB - The use of EXT-RADTM extremity TLDs and radiochromic film to measure doses from primarily beta-emitting microparticles is discussed. Specific calibration techniques have been developed, using both Monte Carlo modelling and experiments. Results for a (90)Sr/(90)Y microparticle are presented to illustrate the general techniques and to demonstrate reasonable agreement between the dosimetry methods. PMID- 26500287 TI - Key Genetic and Epigenetic Mechanisms in Chemical Carcinogenesis. AB - DNA sequence and genetic factors alone cannot fully explain the many processes implicated in diseases initiation and development. It is now well understood that additional factors are involved in a final resulting phenotype. Epigenetic modifications, heritable changes not affecting the DNA sequence, are a key phenomenon at the basis of normal growth and differentiation. However, these can be defective leading to diseases, such as cancer. An increasing body of literature reports the environmental and occupational exposure to a mixture of natural and man-produced substances leading to epigenetic alterations. The identification of key genetic and/or epigenetic events involved in chemical carcinogenesis is an important step towards the discovery of biomarkers that can be used to evaluate the exposure, predict biological effects, and prevent adverse health consequences. Here, we focus on epidemiological studies to review the most recent advances in understanding genetic and epigenetic factors in relation to particulate matter, benzene and polycyclic aromatic hydrocarbons exposure. PMID- 26500288 TI - Adverse Outcome Pathways for Regulatory Applications: Examination of Four Case Studies With Different Degrees of Completeness and Scientific Confidence. AB - Adverse outcome pathways (AOPs) offer a pathway-based toxicological framework to support hazard assessment and regulatory decision-making. However, little has been discussed about the scientific confidence needed, or how complete a pathway should be, before use in a specific regulatory application. Here we review four case studies to explore the degree of scientific confidence and extent of completeness (in terms of causal events) that is required for an AOP to be useful for a specific purpose in a regulatory application: (i) Membrane disruption (Narcosis) leading to respiratory failure (low confidence), (ii) Hepatocellular proliferation leading to cancer (partial pathway, moderate confidence), (iii) Covalent binding to proteins leading to skin sensitization (high confidence), and (iv) Aromatase inhibition leading to reproductive dysfunction in fish (high confidence). Partially complete AOPs with unknown molecular initiating events, such as 'Hepatocellular proliferation leading to cancer', were found to be valuable. We demonstrate that scientific confidence in these pathways can be increased though the use of unconventional information (eg, computational identification of potential initiators). AOPs at all levels of confidence can contribute to specific uses. A significant statistical or quantitative relationship between events and/or the adverse outcome relationships is a common characteristic of AOPs, both incomplete and complete, that have specific regulatory uses. For AOPs to be useful in a regulatory context they must be at least as useful as the tools that regulators currently possess, or the techniques currently employed by regulators. PMID- 26500289 TI - Resting-state functional connectivity of the default mode network associated with happiness. AB - Happiness refers to people's cognitive and affective evaluation of their life. Why are some people happier than others? One reason might be that unhappy people are prone to ruminate more than happy people. The default mode network (DMN) is normally active during rest and is implicated in rumination. We hypothesized that unhappiness may be associated with increased default-mode functional connectivity during rest, including the medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC) and inferior parietal lobule (IPL). The hyperconnectivity of these areas may be associated with higher levels of rumination. One hundred forty-eight healthy participants underwent a resting-state fMRI scan. A group-independent component analysis identified the DMNs. Results indicated increased functional connectivity in the DMN was associated with lower levels of happiness. Specifically, relative to happy people, unhappy people exhibited greater functional connectivity in the anterior medial cortex (bilateral MPFC), posterior medial cortex regions (bilateral PCC) and posterior parietal cortex (left IPL). Moreover, the increased functional connectivity of the MPFC, PCC and IPL, correlated positively with the inclination to ruminate. These results highlight the important role of the DMN in the neural correlates of happiness, and suggest that rumination may play an important role in people's perceived happiness. PMID- 26500291 TI - Retraction: MDA-9/Syntenin is essential for factor VIIa-induced signaling, migration, and metastasis in melanoma cells. PMID- 26500290 TI - Coordinated activation of premotor and ventromedial prefrontal cortices during vicarious reward. AB - The vicarious reward we receive from watching likable others obtaining a positive outcome is a pervasive phenomenon, yet its neural correlates are poorly understood. Here, we conducted a series of functional magnetic resonance imaging experiments to test the hypothesis that the brain areas responsible for action observation and reward processing work in a coordinated fashion during vicarious reward. In the first experiment (manipulation phase), the participant was instructed to cheer for a particular player in a two-player competitive game (Rock-Paper-Scissors). This manipulation made participants feel more unity with that player and resulted in unity-related activation in the premotor area during action observation. In the following main experiment, the participant witnessed the previously cheered-for or non-cheered-for player succeed in a new solitary game (a stopwatch game). The ventromedial prefrontal cortex (vmPFC) was activated when the cheered-for player succeeded in the game but not when the other player did. Interestingly, this vmPFC activation was functionally connected with premotor activation only during the cheered-for player's success. These results suggest that vicarious reward is processed in the vmPFC-premotor network, which is activated specifically by the success of the other person with whom the individual feels unity and closeness. PMID- 26500292 TI - Tocopherol transfer protein sensitizes prostate cancer cells to vitamin E. PMID- 26500293 TI - Retraction: G protein-coupled receptor kinase-2 is a novel regulator of collagen synthesis in adult human cardiac fibroblasts. PMID- 26500294 TI - Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer. PMID- 26500295 TI - Altered Monoaminergic Systems and Depressive-like Behavior in Congenic Prion Protein Knock-out Mice. PMID- 26500296 TI - Reply to Altered Monoaminergic Systems and Depressive-like Behavior in Congenic Prion Protein Knock-out Mice. PMID- 26500297 TI - Politically Incorrect. PMID- 26500298 TI - Caring for older people: is home care always best? PMID- 26500299 TI - Promoting modifiable risk factors for dementia: is there a role for general practice? PMID- 26500300 TI - Statins for all: should patients who have migraine with aura be on a statin? PMID- 26500302 TI - Is general practice engaged with physical activity promotion? PMID- 26500303 TI - The 10-minute appointment. PMID- 26500304 TI - Why do 'high risk' women book late or not at all for antenatal care? PMID- 26500305 TI - Patient consent and opting-out. PMID- 26500306 TI - Practice with a difference! PMID- 26500307 TI - RCGP Research Paper of the Year 2014: partnership with patients is an important theme in primary care research. PMID- 26500308 TI - Yonder: Fatigue, role models, MDT meetings, and GP signatures. PMID- 26500309 TI - Law note: giving evidence in court. PMID- 26500314 TI - Is there an anthropologist in the house? PMID- 26500315 TI - Access to general practice in England: time for a policy rethink. PMID- 26500316 TI - Creatinine point-of-care testing for detection and monitoring of chronic kidney disease: primary care diagnostic technology update. PMID- 26500317 TI - Elbow pain: a guide to assessment and management in primary care. PMID- 26500318 TI - Determinants of health-related quality of life in older primary care patients: results of the longitudinal observational AgeCoDe Study. AB - BACKGROUND: In older patients with chronic diseases, focusing on subjective, patient-relevant outcomes, such as health-related quality of life (HRQoL), is more pertinent than pursuing clinical or laboratory target values. AIM: To investigate factors influencing the course of HRQoL in older (aged >=78 years) primary care patients and to derive non-pharmacological recommendations for improving their quality of life. DESIGN AND SETTING: A population-based prospective longitudinal observational study featuring data analysis from waves 2 to 5 of the AgeCoDe study, which was conducted in six cities in Germany. METHOD: The HRQoL of 1968 patients over the course of 4.5 years was observed. Patients were, on average, aged 82.6 (+/-3.4) years and their HRQoL was measured using the EQ-5D visual analogue scale in a face-to-face assessment. Fixed-effects regression models were calculated to examine impact of change in potential influencing factors. This method allows unobserved heterogeneity to be controlled. RESULTS: The course of the participants' HRQoL declined with increasing age, walking and incident hearing impairment. Increasing the number of physical activities improved the HRQoL. These findings were modified by sex, education level, and depression. Especially in females and patients with rather low education levels, increased physical activity improved the subjects' HRQoL, while hearing impairment decreased it. Moving to an institution only improved the HRQoL in patients without depression or those with a low level of education (primary education). CONCLUSION: Motivating patients to increase their weekly physical activity and to focus on preserving their ability to walk are promising approaches to improving HRQoL in older age. Less-educated patients and those without depression can also benefit from moving into an institution (for example, a care or retirement home). PMID- 26500319 TI - Comparison of end-of-life care for older people living at home and in residential homes: a mortality follow-back study among GPs in the Netherlands. AB - BACKGROUND: The proportion of older people is increasing, therefore their place of residence and place of care at the end of life are becoming increasingly important. AIM: To compare aspects of end-of-life care among older people in residential homes and home settings in the Netherlands. DESIGN AND SETTING: Nationwide representative mortality follow-back study among GPs in the Netherlands. METHOD: The study included patients aged >=65 years who died non suddenly, whose longest place of residence in their last year of life was at home or in a residential home (n = 498). Differences were analysed using Pearson's chi(2) test, Mann-Whitney U tests, and multivariate logistic regression. RESULTS: Controlling for the differences between the populations in home settings and residential homes, no differences were found in treatment goals, communication about end-of-life care, or use of specialised palliative care between the two settings. However, people living in a residential home were more likely to have received palliative care from a GP than people living at home (OR 2.84, 95% confidence interval [CI] = 1.41 to 5.07). In residential homes, people more often experienced no transfer between care settings (OR 2.76, 95% CI = 1.35 to 5.63) and no hospitalisations (OR 2.2, 95% CI = 1.04 to 4.67) in the last 3 months of life, and died in hospital less often (OR 0.78, 95% CI = 0.63 to 0.97) than those people living at home. CONCLUSION: Despite similar treatment goals, care in residential homes seems more successful in avoiding transfers and hospitalisation at the end of life. Especially since older people are encouraged to stay at home longer, measures should be taken to ensure they are not at higher risk of transfers and hospitalisations in this setting. PMID- 26500320 TI - Promoting physical activity in older people in general practice: ProAct65+ cluster randomised controlled trial. AB - BACKGROUND: Regular physical activity reduces falls, hip fractures, and all-cause mortality, but physical activity levels are low in older age groups. AIM: To evaluate two exercise programmes promoting physical activity among older people. DESIGN AND SETTING: Pragmatic three-arm, parallel-design cluster randomised controlled trial involving 1256 people aged >=65 years (of 20 507 invited) recruited from 43 general practices in London, Nottingham, and Derby. METHOD: Practices were randomised to the class-based Falls Management Exercise programme (FaME), the home-based Otago Exercise Program (OEP), or usual care. The primary outcome was the proportion reaching the recommended physical activity target 12 months post-intervention. Secondary outcomes included falls, quality of life, balance confidence, and costs. RESULTS: In total, 49% of FaME participants reached the physical activity target compared with 38% for usual care (adjusted odds ratio 1.78, 95% confidence interval [CI] =1.11 to 2.87, P = 0.02). Differences between FaME and usual care persisted 24 months after intervention. There was no significant difference comparing those in the OEP (43% reaching target at 12 months) and usual-care arms. Participants in the FaME arm added around 15 minutes of moderate-to-vigorous physical activity per day to their baseline level; this group also had a significantly lower rate of falls (incident rate ratio 0.74, 95% CI = 0.55 to 0.99, P = 0.042). Balance confidence was significantly improved in both intervention arms. The mean cost per extra person achieving the physical activity target was L1740. Attrition and rates of adverse reactions were similar. CONCLUSION: The FaME programme increases self-reported physical activity for at least 12 months post-intervention and reduces falls in people aged >=65 years, but uptake is low. There was no statistically significant difference in reaching the target, or in falls, between the OEP and usual-care arms. PMID- 26500321 TI - GPs' perspectives on secondary cardiovascular prevention in older age: a focus group study in the Netherlands. AB - BACKGROUND: Although guidelines recommend secondary cardiovascular prevention irrespective of age, in older age the uptake of treatment is lower than in younger age groups. AIM: To explore the dilemmas GPs in the Netherlands encounter when implementing guidelines for secondary cardiovascular prevention in older age. DESIGN AND SETTING: Qualitative study in four focus groups consisting of GPs (n = 23, from the northern part of the province South Holland) and a fifth focus group consisting of GP trainees (n = 4, from the Leiden University Medical Center). METHOD: Focus group discussions were organised to elicit perspectives on the implementation of secondary cardiovascular prevention for older people. The 14 theoretical domains of the refined Theoretical Domains Framework (TDF) were used for (deductive) coding of the focus group discussions. The coded texts were analysed, content was discussed, and barriers and facilitators were identified for each domain of the TDF. RESULTS: The main theme that emerged was 'uncertainty'. Identified barriers were guideline-related, patient-related, and organisation-related. Identified facilitators were doctor-related, patient related, and organisation-related. The main aim of secondary preventive treatment was improvement in quality of life. CONCLUSION: GPs in the Netherlands are uncertain about many aspects of secondary cardiovascular prevention in older age; the guidelines themselves, their own role, patient factors, and the organisation of care. In view of this uncertainty, GPs consciously weigh all aspects of the situation in close dialogue with the individual patient, with the ultimate aim of improving quality of life. This highly-individualised care may largely explain the reduced prescription rates. PMID- 26500322 TI - Chest pain for coronary heart disease in general practice: clinical judgement and a clinical decision rule. AB - BACKGROUND: The Marburg Heart Score (MHS) is a simple, valid, and robust clinical decision rule assisting GPs in ruling out coronary heart disease (CHD) in patients presenting with chest pain. AIM: To investigate whether using the rule adds to the GP's clinical judgement. DESIGN AND SETTING: A comparative diagnostic accuracy study was conducted using data from 832 consecutive patients with chest pain in general practice. METHOD: Three diagnostic strategies were defined using the MHS: diagnosis based solely on the MHS; using the MHS as a triage test; and GP's clinical judgement aided by the MHS. Their accuracy was compared with the GPs' unaided clinical judgement. RESULTS: Sensitivity and specificity of the GPs' unaided clinical judgement was 82.9% (95% confidence interval [CI] = 72.4 to 89.9) and 61.0% (95% CI = 56.7 to 65.2), respectively. In comparison, the sensitivity of the MHS was higher (difference 8.5%, 95% CI = -2.4 to 19.6) and the specificity was similar (difference -0.4%, 95% CI = -5.3 to 4.5); the sensitivity of the triage was similar (difference -1.5%, 95% CI = -9.8 to 7.0) and the specificity was higher (difference 11.6%, 95% CI = 7.8 to 15.4); and both the sensitivity and specificity of the aided clinical judgement were higher (difference 8.0%, 95% CI = -6.9 to 23.0 and 5.8%, 95% CI = -1.6 to 13.2, respectively). CONCLUSION: Using the Marburg Heart Score for initial triage can improve the clinical diagnosis of CHD in general practice. PMID- 26500323 TI - Utilising out-of-hours primary care for assistance with cancer pain: a semi structured interview study of patient and caregiver experiences. AB - BACKGROUND: Pain is the most frequent complication of cancer and an important reason for out-of-hours (OOH) primary care contacts by patients with established cancer. Existing quantitative data give little insight into the reason for these contacts. Exploring such encounters of care could highlight ways to improve anticipatory cancer care and communication between daytime and OOH primary care services. AIM: To explore the experiences, views, and opinions of patients and their caregivers who have used OOH primary care for help with managing cancer pain. DESIGN AND SETTING: A semi-structured interview study with patients and caregivers who have utilised an OOH primary care service in Grampian, Scotland, because of pain related to cancer. METHOD: Semi-structured interviews with 11 patients and four caregivers (n = 15), transcribed verbatim and analysed using framework analysis and, to a lesser extent, inductive thematic analysis. RESULTS: Six key themes emerged: making sense of pain and predicting its likely course; beliefs about analgesics; priority daytime access; the importance of continuity of care and communication between all involved; barriers and facilitators to seeking help in the OOH period; and satisfaction/dissatisfaction with OOH care. Three prominent sub-themes were: patient knowledge; the influence of a caregiver on decision-making; and the benefits of having a palliative care summary. CONCLUSION: Effective daytime and anticipatory care can positively influence OOH care. Interventions that aid patients in understanding cancer pain, communicating about pain, utilising analgesics effectively, and seeking appropriate and timely help may improve cancer pain management. PMID- 26500324 TI - Caring for people living with, and beyond, cancer: an online survey of GPs in England. AB - BACKGROUND: Increasing numbers of people are living with, and beyond, cancer. They are at risk of long-term morbidity and premature mortality due to the consequences of their disease and its treatment. Primary care can contribute to providing ongoing care. AIM: To determine the current practice and views of GPs in England regarding cancer survivorship care. DESIGN AND SETTING: Online survey of a sample of 500 GPs, stratified by NHS region in England. METHOD: The survey included questions adapted from prior surveys assessing physician knowledge and attitudes regarding care of patients with cancer. RESULTS: In total, 500 GPs responded; approximately half reported often providing care to people living beyond cancer for treatment-related side effects (51%), psychological symptoms (65%), and lifestyle advice (55%). Only 29% felt very confident managing treatment-related side effects compared with 46% and 65% for psychological symptoms and lifestyle advice respectively. Half reported usually receiving cancer treatment summaries and survivorship care plans but most of the sample felt these would improve their ability to provide care (76%). Only 53% were convinced of the usefulness of cancer care reviews. Although most felt that primary and specialist care should share responsibility for managing bone (81%) and cardiovascular (77%) health consequences, fewer than half reported often taking previous history of cancer or cancer treatment into consideration when assessing bone health; only one-fifth did this in relation to cardiovascular health. Most responders were interested in receiving education to improve their knowledge and expertise. CONCLUSION: GPs have a potentially important role to play in caring for people following cancer treatment. This study has highlighted areas where further support and education are needed to enable GPs to optimise their role in cancer survivorship care. PMID- 26500325 TI - The association between symptoms and bladder or renal tract cancer in primary care: a systematic review. AB - BACKGROUND: Appropriate selection for further investigation of patients presenting in primary care with symptoms that may indicate cancer is key to early diagnosis. AIM: To quantify the risk of urinary tract cancer in patients presenting in primary care with symptoms that may indicate bladder or renal cancer. DESIGN AND SETTING: Systematic review of studies relating to bladder or renal cancer in primary care. METHOD: Databases searched were MEDLINE, PreMEDLINE, Embase, the Cochrane Library, Web of Science (SCI and SSCI), and ISI Proceedings from 1980 to August 2014, and PsycINFO (1980-2012) and BioMed Central (inception to 2012) for retrospective, prospective, or case-control diagnostic accuracy studies of symptomatic patients presenting to primary care with one or more symptoms for whom follow-up data were available. The target conditions were bladder or renal cancer. The studies were appraised using the QUADAS-2 tool. RESULTS: Eleven studies with 3 451 675 patients were included. The positive predictive value (PPV) from meta-analysis of visible haematuria was 5.1% in adult patients. It increased with age and was higher in males. The PPVs of other single symptoms were very low, with the highest non-haematuria PPV being 1.4% for anaemia in males. Fewer data were available on the PPVs of symptom combinations. Generally, these data showed that, with the exception of symptom combinations including haematuria, these were very low. CONCLUSION: The only high-risk feature of bladder/renal cancer in primary care was visible haematuria, and this clearly warrants investigation. However, not all patients with one of these cancers experience haematuria, so a policy restricting investigation to patients with haematuria will inevitably delay the diagnosis in some patients. PMID- 26500326 TI - Improving management and effectiveness of home blood pressure monitoring: a qualitative UK primary care study. AB - BACKGROUND: Self-monitoring blood pressure (SMBP) is becoming an increasingly prevalent practice in UK primary care, yet there remains little conceptual understanding of why patients with hypertension engage in self-monitoring. AIM: To identify psychological factors or processes prompting the decision to self monitor blood pressure. DESIGN AND SETTING: A qualitative study of patients previously participating in a survey study about SMBP from four general practices in the West Midlands. METHOD: Taped and transcribed in-depth interviews with 16 patients (6 currently monitoring, 2 used to self-monitor, and 8 had never self monitored). Thematic analysis was undertaken. RESULTS: Three main themes emerged: 'self' and 'living with hypertension' described the emotional element of living with an asymptomatic condition; 'self-monitoring behaviour and medication' described overall views about self-monitoring, current practice, reasons for monitoring, and the impact on medication adherence; and 'the GP-patient transaction' described the power relations affecting decisions to self-monitor. Self-monitoring was performed by some as a protective tool against the fears of a silent but serious condition, whereas others self-monitor simply out of curiosity. People who self-monitored tended not to discuss this with their nurse or GP, partly due to perceiving minimal or no interest from their clinician about home monitoring, and partly due to fear of being prescribed additional medication. CONCLUSION: The decision to self-monitor appeared often to be an individual choice with no schedule or systems to integrate it with other medical care. Better recognition by clinicians that patients are self-monitoring, perhaps utilising the results in shared decision-making, might help integrate it into daily practice. PMID- 26500327 TI - Can we trust studies using audit software? A case study of atrial fibrillation audit. PMID- 26500328 TI - Academic general practice: a viewpoint on achievements and challenges. PMID- 26500329 TI - Adherence to medication in stroke survivors dependent on caregivers. PMID- 26500330 TI - Ocular surface disease in patients with diabetic peripheral neuropathy. AB - PURPOSE: To analyse clinical signs and symptoms of ocular surface disease in patients with diabetes mellitus (DM), based on severity of diabetic peripheral neuropathy (DPN). METHODS: This cross-sectional study included participants who were carefully phenotyped by a multidisciplinary team and categorised into groups based on severity of DPN. All study participants underwent ophthalmic evaluation and completed the Ocular Surface Disease Index (OSDI) and Visual Function Questionnaire (VFQ-25). RESULTS: The 34 study participants were healthy controls (n=9), patients with DM and mild or no DPN (n=16) and patients with DM and severe DPN (n=9). Tear osmolarity was increased, and corneal nerve fibre length was decreased, with increasing severity of DPN. In addition, patients with DM were found to have decreased Schirmer's test values when compared with healthy controls. No statistically significant differences were found between groups in OSDI, tear breakup time or corneal sensitivity. No statistically significant correlations were noted between the OSDI or VFQ-25 scores and clinical signs of dry eyes. CONCLUSION: This study demonstrates some increased clinical signs of ocular surface disease but not an increase in subjective symptoms of dry eyes, with increasing severity of DPN. Furthermore, no significant correlation was found between OSDI scores and clinical signs of dry eye. A periodic evaluation of the ocular surface is important for patients with DM, in addition to retinopathy screening, as they may be asymptomatic but have severe dry eye disease, which can lead to further ocular surface complications such as corneal ulceration. TRIAL REGISTRATION NUMBER: NCT01695629. PMID- 26500331 TI - Frequent BRAF mutation in early-onset colorectal cancer in Taiwan: association with distinct clinicopathological and molecular features and poor clinical outcome. AB - BACKGROUND: Occurrence of early-onset colorectal cancer (EOCRC) under the age of 30 is very rare and the molecular characteristics are poorly understood. A low BRAF mutation rate has been noted in several studies of EOCRC from Western countries. AIMS: To determine the clinicopathological and molecular features of EOCRCs in Taiwan. METHODS: KRAS/BRAF gene mutation, mismatch repair protein immunohistochemistry, microsatellite instability and CpG island methylation phenotype analyses were examined to determine the molecular characteristics of EOCRC. RESULTS: Sixty-six patients with EOCRC at our hospital between 2000 and 2012 were studied. BRAF mutation was detected in 11 of the 59 tumours analysed (19%) and the rate was significantly higher than the overall BRAF mutation rate of colorectal cancer in patients older than 30 years (p<0.001). Clinically, 9 of 11 patients with BRAF-mutated tumours presented with advanced-stage diseases and they presented significantly more frequently with stage IV disease than those with BRAF wild-type tumours (p=0.042). Histologically, BRAF mutation was associated with a poorly differentiated histology, a serrated precursor polyp and focal signet ring cell differentiation (p=0.042, 0.008 and 0.008, respectively). None of the BRAF-mutated tumours was mismatch repair protein-deficient and/or microsatellite instability-high. Overall survival of patients with BRAF-mutated tumours was significantly worse than that of patients with BRAF wild-type tumours, despite adjustment for the disease stages and tumour differentiation. CONCLUSIONS: BRAF mutation was frequent in EOCRCs in Taiwan and was associated with distinct clinicopathological and molecular features. PMID- 26500332 TI - Serine-arginine protein kinase 1 (SRPK1), a determinant of angiogenesis, is upregulated in prostate cancer and correlates with disease stage and invasion. AB - Vascular endothelial growth factor (VEGF) undergoes alternative splicing to produce both proangiogenic and antiangiogenic isoforms. Preferential splicing of proangiogenic VEGF is determined by serine-arginine protein kinase 1 (SRPK1), which is upregulated in a number of cancers. In the present study, we aimed to investigate SRPK1 expression in prostate cancer (PCa) and its association with cancer progression. SRPK1 expression was assessed using immunohistochemistry of PCa tissue extracted from radical prostatectomy specimens of 110 patients. SRPK1 expression was significantly higher in tumour compared with benign tissue (p<0.00001) and correlated with higher pT stage (p=0.004), extracapsular extension (p=0.003) and extracapsular perineural invasion (p=0.008). Interestingly, the expression did not correlate with Gleason grade (p=0.21), suggesting that SRPK1 facilitates the development of a tumour microenvironment that favours growth and invasion (possibly through stimulating angiogenesis) while having little bearing on the morphology or function of the tumour cells themselves. PMID- 26500333 TI - Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets. AB - AIM: We queried whether extrahepatic cholangiocarcinoma featured clinically relevant genomic alterations that could lead to targeted therapy. METHODS: Comprehensive genomic profiling by hybridisation capture of up to 315 genes was performed on 99 clinically advanced extrahepatic cholangiocarcinoma. RESULTS: There were 60 male and 39 female patients with a median age of 60.5 years. A total of 400 alterations were identified (mean 4.0; range 0-13) in 84 genes. Eighty-two (83%) of extrahepatic cholangiocarcinoma patients featured at least one clinically relevant genomic alterations including KRAS (43%); ERBB2 (9%), PTEN (7%); ATM and NF1 (6%) and CCND1, FBXW7, GNAS, MDM2 and NRAS (all at 5%). BRAF, BRCA2, CDK4, CDK6, FGFR1, FGFR3, PTCH1, RAF1 and STK11 were each altered in a single patient. No IDH1/2 mutations or FGFR2 gene fusions were identified. CONCLUSIONS: Comprehensive genomic profiling of extrahepatic cholangiocarcinoma differs significantly from intrahepatic cholangiocarcinoma and pancreatic adenocarcinoma, and reveals diverse opportunities for the use of targeted therapies. PMID- 26500334 TI - Immunophenotyping of ampullary carcinomata allows for stratification of treatment specific subgroups. AB - BACKGROUND: Ampullary carcinomata (AC) can be separated into intestinal (IT) or pancreatobiliary (PB) subtypes. Although morphological, immunohistochemical and molecular differentiation of IT and PB have been well documented; the prognostic significance of histological subtype and whether patients with either subtype benefit from differential chemotherapeutic regimens remains unclear. METHODS: As part of a larger cohort study, patients who underwent resection for AC or pancreatic ductal adenocarcinoma (PDAC) were retrospectively identified. Clinicopathological covariates and outcome were obtained and MUC1, MUC2, CDX2 and CK20 were assessed with immunohistochemistry. RESULTS: Of 99 ACs, the resultant immunophenotypes indicated 48% and 22% were IT and PB, respectively. Thirty (30%) cases were quadruple negative (QN). Within the PDAC cohort (N = 257), the most prevalent immunophenotype was QN (53%). Subsequently, all QN ACs were classified as PB immunohistochemically yielding 47.5% and 52.5% classified as IT and PB, respectively. Involved regional lymph nodes and elevated T-stage were significantly associated with PB compared with IT AC (p = 0.0032 and 0.0396, respectively). Progression-free survival revealed inferior survival for PB versus IT AC (p = 0.0156). CONCLUSIONS: AC can be classified into prognostic groups with unique clinicopathological characteristics using immunohistochemistry. Immunophenotypical similarity of PB and PDAC suggests that treatment regimens similar to those used in PDAC should be explored. PMID- 26500335 TI - Immunohistochemical detection of cytoplasmic nucleophosmin in formalin-fixed paraffin-embedded marrow trephine biopsies in acute myeloid leukaemia. AB - AIMS: Nucleophosmin (NPM1) gene mutations resulting in cytoplasmic delocalisation of nucleophosmin (NPMc+) are the most common genetic abnormality in acute myeloid leukaemia (AML). In this study, we tested whether immunohistochemical (IHC) detection of cytoplasmic NPM1 (cNPM1) in formalin-fixed bone marrow trephine biopsies correlated with NPM1 mutations and the prognostic impact of NPM1 and fms related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) gene mutations was also assessed. METHODS: A total of 71 Chinese adult de novo AML cases were evaluated for cNPM1 by IHC where the bone marrow trephines were fixed in 10% buffered formalin and decalcified by 5% EDTA. NPM1 and FLT3-ITD gene mutations were also investigated using PCR, fragment analysis and direct DNA sequencing. RESULTS: IHC analysis of cNPM1 had a very good sensitivity (86.7%) and excellent specificity (96.4%) for NPM1 mutation. The positive predictive value was 86.7% and the negative predictive value was 96.4%. NPM1 mutations and FLT3-ITD were closely associated (p = 0.003). Patients with mutated NPM1 and without FLT3-ITD mutation have a longer overall survival (p = 0.042) than patients with both NPM1 and FLT3-ITD mutations. CONCLUSIONS: Our results showed that IHC detection of cNPM1 in formalin-fixed trephine biopsies correlated well but not entirely with NPM1 mutation. Furthermore, NPM1 mutations were significantly more frequent in FLT3-ITD than FLT3-wild-type cases. PMID- 26500336 TI - Leisure time physical activity and cancer risk: evaluation of the WHO's recommendation based on 126 high-quality epidemiological studies. AB - BACKGROUND: The WHO has concluded that physical activity reduces the risk of numerous diseases. However, few systemic reviews have been performed to assess the role of leisure time physical activity (LTPA) in lowering the risk of cancer in a dose-dependent manner and furthermore the suitability of recommendation of physical activity by the WHO. METHODS: A systematic review and meta-analysis was designed to estimate cancer risk by LTPA in binary comparison and in a dose dependent manner. MEDLINE and Web of Science were searched up to 30 December 2014 without language restrictions. Reference lists were reviewed for potential articles. RESULTS: A total of 126 studies were recruited into the meta-analysis. Overall, the total cancer risk was reduced by 10% in people who undertook the most LTPA as compared with those who did the least. Dose-response meta-analysis indicated that the current WHO recommendation (equal to an average of 10 metabolic equivalents of energy hours per week) induced a 7% (95% CI 5% to 9%) cancer reduction. Moreover, the protective role of LTPA against cancer becomes saturated at 20 metabolic equivalents of energy hours per week, with a relative risk of 0.91 (95% CI 0.88 to 0.93). Subanalyses results based on cancer types showed that LTPA only exhibited significant protection against breast cancer and colorectal cancer. CONCLUSIONS: Our meta-analysis indicates that the current WHO recommendation of physical activity can result in a 7% reduction in cancer risk, which is mainly attributed to its protective role against breast cancer and colorectal cancer. Furthermore, two-fold of current recommendation level is considered to give its saturated protection against cancer. PMID- 26500337 TI - Examining the link between women's exposure to stressful life events prior to conception and infant and toddler health: the role of birth weight. AB - BACKGROUND: The life course perspective suggests a pathway may exist among maternal exposure to stressful life events prior to conception (PSLEs), infant birth weight and subsequent offspring health, whereby PSLEs are part of a 'chains of-risk' that set children on a certain health pathway. No prior study has examined the link between PSLEs and offspring health in a nationally representative sample of US mothers and their children. We used longitudinal, nationally representative data to evaluate the relation between maternal exposure to PSLEs and subsequent measures of infant and toddler health, taking both maternal and obstetric characteristics into account. METHODS: We examined 6900 mother-child dyads participating in 2 waves of the nationally representative Early Childhood Longitudinal Study-Birth Cohort (n=6900). Infant and toddler health outcomes assessed at 9 and 24 months included overall health status, special healthcare needs and severe health conditions. Adjusted path analyses examined associations between PSLEs, birth weight and child health outcomes. RESULTS: In adjusted analyses, PSLEs increased the risk for very low birth weight (VLBW, <1500 g), which, in turn, predicted poor health at both 9 and 24 months of age. Path analyses demonstrated that PSLEs had small indirect effects on children's subsequent health that operated through VLBW. CONCLUSIONS: Our analysis suggests a chains-of-risk model in which women's exposure to PSLEs increases the risk for giving birth to a VLBW infant, which, in turn, adversely affects infant and toddler health. Addressing women's preconception health may have important downstream benefits for their children, although more research is needed to replicate these findings. PMID- 26500338 TI - Effects of Interplanting Flowering Plants on the Biological Control of Corn Earworm (Lepidoptera: Noctuidae) and Thrips (Thysanoptera: Thripidae) in Sweet Corn. AB - Natural enemy exploitation of food resources and alternative hosts in noncrop vegetation has been shown to be an effective means of enhancing natural enemy populations in diversified agro-ecosystem. Field trials were conducted in Hawaii to examine effects of interplanting flowering plants on 1) parasitism of corn earworm, Helicoverpa zea (Boddie) eggs by Trichogramma spp., and 2) abundance of Orius spp. in relation to prey (H. zea eggs and thrips [primarily, Frankliniella occidentalis (Pergande) and Frankliniella williamsi Hood]). Sweet corn (maize), Zea mays L., was interplanted with three flowering plants, buckwheat, Fagopyrum esculentum Moench, cowpea, Vigna unguiculata (L.), and sunn hemp, Crotolaria juncea L., at 2:1 and 4:1 (corn: flowering plant) ratios in 2009 and 2010, respectively. In 2009, the abundance of Orius spp. was significantly greater in the buckwheat-interplanted treatment compared to the monocrop control at similar levels of prey availability, indicating buckwheat flowers might have provided both prey and nectar resources. In 2010, cowpea and sunn hemp flowering plants provided a source of an alternate host insect's eggs for Trichogramma spp. oviposition, resulting in significantly higher parasitism of H. zea eggs in the cowpea- and sunn hemp-interplanted treatments compared to the monocrop control. Despite of differences in pest and natural enemy interactions in two field trials, our findings suggested that provisioning of an alternate host insect's eggs through flowering plants is an effective means for enhancing Trichogramma spp. and provisioning of both nectar and prey resources through flowering plants is important for enhancing predation by Orius spp. PMID- 26500340 TI - Monovalent Fc receptor blockade by an anti-Fcgamma receptor/albumin fusion protein ameliorates murine ITP with abrogated toxicity. AB - Patients with immune thrombocytopenia (ITP) commonly have antiplatelet antibodies that cause thrombocytopenia through Fcgamma receptors (FcgammaRs). Antibodies specific for FcgammaRs, designed to inhibit antibody-FcgammaR interaction, had been shown to improve ITP in refractory human patients. However, the development of such FcgammaR-specific antibodies has stalled because of adverse events, a phenomenon recapitulated in mouse models. One hypothesis behind these adverse events involved the function of the Fc region of the antibody, which engages FcgammaRs, leading to inflammatory responses. Unfortunately, inhibition of Fc function by deglycosylation failed to prevent this inflammatory response. In this work, we hypothesize that the bivalent antigen-binding fragment regions of immunoglobulin G are sufficient to trigger adverse events and have reasoned that designing a monovalent targeting strategy could circumvent the inflammatory response. To this end, we generated a fusion protein comprising a monovalent human FcgammaRIIIA-specific antibody linked in tandem to human serum albumin, which retained FcgammaR-binding activity in vitro. To evaluate clinically relevant in vivo FcgammaR-blocking function and inflammatory effects, we generated a murine version targeting the murine FcgammaRIII linked to murine albumin in a passive murine ITP model. Monovalent blocking of FcgammaR function dramatically inhibited antibody-dependent murine ITP and successfully circumvented the inflammatory response as assessed by changes in body temperature, basophil activation, and basophil depletion. Consistent with our hypothesis, in vivo cross-linking of the fusion protein induced these inflammatory effects, recapitulating the adverse events of the parent antibody. Thus, monovalent blocking of FcgammaR function demonstrates a proof of concept to successfully treat FcgammaR-mediated autoimmune diseases. PMID- 26500339 TI - Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. AB - Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) are 2 standards of care for elderly untreated multiple myeloma (MM) patients. We planned to use VMP and Rd for 18 cycles in a sequential or alternating scheme. Patients (233) with untreated MM, >65 years, were randomized to receive 9 cycles of VMP followed by 9 cycles of Rd (sequential scheme; n = 118) vs 1 cycle of VMP followed by 1 cycle of Rd, and so on, up to 18 cycles (alternating scheme; n = 115). VMP consisted of one 6-week cycle of bortezomib using a biweekly schedule, followed by eight 5-week cycles of once-weekly VMP. Rd included nine 4-week cycles of Rd. The primary end points were 18-month progression free survival (PFS) and safety profile of both schemes. The 18-month PFS was 74% and 80% in the sequential and alternating arms, respectively (P = .21). The sequential and alternating groups exhibited similar hematologic and nonhematologic toxicity. Both arms yielded similar complete response rate (42% and 40%), median PFS (32 months vs 34 months, P = .65), and 3-year overall survival (72% vs 74%, P = .63). The benefit of both schemes was remarkable in patients aged 65 to 75 years. In addition, achieving complete and immunophenotypic response was associated with better outcome. The present approach, based on VMP and Rd, is associated with high efficacy and acceptable toxicity profile with no differences between the sequential and alternating regimens. This trial was registered at www.clinicaltrials.gov as #NCT00443235. PMID- 26500341 TI - Improving evidence on anticoagulant therapies for venous thromboembolism in children: key challenges and opportunities. AB - Venous thromboembolism (VTE) is increasingly diagnosed in pediatric patients, and anticoagulant use in this population has become common, despite the absence of US Food and Drug Administration (FDA) approval for this indication. Guidelines for the use of anticoagulants in pediatrics are largely extrapolated from large randomized controlled trials (RCTs) in adults, smaller dose-finding and observational studies in children, and expert opinion. The recently FDA-approved direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and edoxaban, provide potential advantages over oral vitamin K antagonists and subcutaneous low-molecular-weight heparins (LMWHs). However, key questions arise regarding their potential off-label clinical application in pediatric thromboembolic disease. In this Perspective, we provide background on the use of LMWHs such as enoxaparin as the mainstay of treatment of pediatric provoked VTE; identify key questions and challenges with regard to DOAC trials and future DOAC therapy in pediatric VTE; and discuss applicable lessons learned from the recent pilot/feasibility phase of a large multicenter RCT of anticoagulant duration in pediatric VTE. The challenges and lessons learned present opportunities to improve evidence for anticoagulant therapies in pediatric VTE through future clinical trials. PMID- 26500342 TI - KIR2DL5B genotype predicts outcomes in CML patients treated with response directed sequential imatinib/nilotinib strategy. AB - Killer immunoglobulin-like receptors (KIRs) on natural killer (NK) cells have been shown to predict for response in chronic phase-chronic myeloid leukemia (CP CML) patients treated with tyrosine kinase inhibitors. We performed KIR genotyping in 148 newly diagnosed CP-CML patients treated with a novel sequential imatinib/nilotinib strategy aimed at achievement of optimal molecular responses at defined time points. We found the presence of KIR2DL5B to be associated with inferior transformation-free survival and event-free survival and an independent predictor of inferior major molecular response (BCR-ABL1 <=0.1%) and molecular response 4.5 (BCR-ABL1 <=0.0032%). This suggests a critical early role for NK cells in facilitating response to imatinib that cannot be overcome by subsequent intensification of therapy. KIR genotyping may add valuable prognostic information to future baseline predictive scoring systems in CP-CML patients and facilitate optimal frontline treatment selection. PMID- 26500343 TI - Total knee replacement is linked to reduced pain but with serious side effects, trial finds. PMID- 26500344 TI - Many cancer drugs recently approved in US do not improve overall survival, study finds. PMID- 26500345 TI - The scientific report guiding the US dietary guidelines: is it scientific? PMID- 26500346 TI - Green Turtles (Chelonia mydas) Have Novel Asymmetrical Antibodies. AB - Igs in vertebrates comprise equally sized H and L chains, with exceptions such as H chain-only Abs in camels or natural Ag receptors in sharks. In Reptilia, Igs are known as IgYs. Using immunoassays with isotype-specific mAbs, in this study we show that green turtles (Chelonia mydas) have a 5.7S 120-kDa IgY comprising two equally sized H/L chains with truncated Fc and a 7S 200-kDa IgY comprised of two differently sized H chains bound to L chains and apparently often noncovalently associated with an antigenically related 90-kDa moiety. Both the 200- and 90-kDa 7S molecules are made in response to specific Ag, although the 90 kDa molecule appears more prominent after chronic Ag stimulation. Despite no molecular evidence of a hinge, electron microscopy reveals marked flexibility of Fab arms of 7S and 5.7S IgY. Both IgY can be captured with protein G or melon gel, but less so with protein A. Thus, turtle IgY share some characteristics with mammalian IgG. However, the asymmetrical structure of some turtle Ig and the discovery of an Ig class indicative of chronic antigenic stimulation represent striking advances in our understanding of immunology. PMID- 26500347 TI - Costimulation of IL-2 Production through CD28 Is Dependent on the Size of Its Ligand. AB - Optimal T cell activation typically requires engagement of both the TCR and costimulatory receptors, such as CD28. Engagement of CD28 leads to tyrosine phosphorylation of its cytoplasmic region and recruitment of cytoplasmic signaling proteins. Although the exact mechanism of CD28 signal transduction is unknown, CD28 triggering has similarities to the TCR, which was proposed to use the kinetic-segregation (KS) mechanism. The KS model postulates that, when small receptors engage their ligands within areas of close (~15 nm) contact in the T cell/APC interface, this facilitates phosphorylation by segregating the engaged receptor/ligand complex from receptor protein tyrosine phosphatases with large ectodomains, such as CD45. To test this hypothesis, we examined the effect of elongating the extracellular region of the CD28 ligand, CD80, on its ability to costimulate IL-2 production by primary T cells. CD80 elongation reduced its costimulatory effect without abrogating CD28 binding. Confocal microscopy revealed that elongated CD80 molecules were less well segregated from CD45 at the T cell/APC interface. T cells expressing CD28 harboring a key tyrosine-170 mutation were less sensitive to CD80 elongation. In summary, the effectiveness of CD28 costimulation is inversely proportional to the dimensions of the CD28-CD80 complex. Small CD28-CD80 complex dimensions are required for optimal costimulation by segregation from large inhibitory tyrosine phosphatases. These results demonstrate the importance of ligand dimensions for optimal costimulation of IL-2 production by T cells and suggest that the KS mechanism contributes to CD28 signaling. PMID- 26500349 TI - CD8 T Cells Enter the Splenic T Cell Zones Independently of CCR7, but the Subsequent Expansion and Trafficking Patterns of Effector T Cells after Infection Are Dysregulated in the Absence of CCR7 Migratory Cues. AB - CCR7 is an important chemokine receptor that regulates T cell trafficking and compartmentalization within secondary lymphoid organs. However, the T cell intrinsic role of CCR7 during infection in the spleen is not well understood. This study was designed to understand how CCR7-dependent localization and migration of CD8(+) T cells in different compartments of the spleen affected the primary and recall responses after infection. To this end, we used adoptive transfer of naive Ag-specific CD8 T cells (OT-I) that either lacked CCR7 or constitutively expressed CCR7 (CD2-CCR7) in mice that were subsequently infected i.v. with Listeria monocytogenes. We show that naive CCR7(-/-)CD8(+) T cells failed to enter the T cell zone, whereas CD2-CCR7 OT-I cells were exclusively confined to the T cell zones of the spleen. Surprisingly, however, CCR7(-/-) OT-I cells entered the T cell zones after infection, but the entry and egress migratory pattern of these cells was dysregulated and very distinct compared with wild-type OT-I cells. Moreover, CCR7-deficient OT-I cells failed to expand robustly when compared with wild-type OT-I cells and were preferentially skewed toward a short-lived effector cell differentiation pattern. Interestingly, CCR7( /-), CD2-CCR7, and wild-type OT-I memory cells responded equally well to rechallenge infection. These results highlight a novel role of CCR7 in regulating effector CD8 T cell migration in the spleen and demonstrate differential requirement of CCR7 for primary and secondary CD8 T cell responses to infection. PMID- 26500348 TI - IgM-Dependent Phagocytosis in Microglia Is Mediated by Complement Receptor 3, Not Fcalpha/MU Receptor. AB - Microglia play an important role in receptor-mediated phagocytosis in the CNS. In brain abscess and other CNS infections, invading bacteria undergo opsonization with Igs or complement. Microglia recognize these opsonized pathogens by Fc or complement receptors triggering phagocytosis. In this study, we investigated the role of Fcalpha/MUR, the less-studied receptor for IgM and IgA, in microglial phagocytosis. We showed that primary microglia, as well as N9 microglial cells, express Fcalpha/MUR. We also showed that anti-Staphylococcus aureus IgM markedly increased the rate of microglial S. aureus phagocytosis. To unequivocally test the role of Fcalpha/MUR in IgM-mediated phagocytosis, we performed experiments in microglia from Fcalpha/MUR(-/-) mice. Surprisingly, we found that IgM-dependent phagocytosis of S. aureus was similar in microglia derived from wild-type or Fcalpha/MUR(-/-) mice. We hypothesized that IgM-dependent activation of complement receptors might contribute to the IgM-mediated increase in phagocytosis. To test this, we used immunologic and genetic inactivation of complement receptor 3 components (CD11b and CD18) as well as C3. IgM-, but not IgG-mediated phagocytosis of S. aureus was reduced in wild-type microglia and macrophages following preincubation with an anti-CD11b blocking Ab. IgM-dependent phagocytosis of S. aureus was also reduced in microglia derived from CD18(-/-) and C3(-/-) mice. Taken together, our findings implicate complement receptor 3 and C3, but not Fcalpha/MUR, in IgM-mediated phagocytosis of S. aureus by microglia. PMID- 26500350 TI - Imbalanced PTEN and PI3K Signaling Impairs Class Switch Recombination. AB - Class switch recombination (CSR) generates isotype-switched Abs with distinct effector functions. B cells express phosphatase and tensin homolog (PTEN) and multiple isoforms of class IA PI3K catalytic subunits, including p110alpha and p110delta, whose roles in CSR remain unknown or controversial. In this article, we demonstrate a direct effect of PTEN on CSR signaling by acute deletion of Pten specifically in mature B cells, thereby excluding the developmental impact of Pten deletion. We show that mature B cell-specific PTEN overexpression enhances CSR. More importantly, we establish a critical role for p110alpha in CSR. Furthermore, we identify a cooperative role for p110alpha and p110delta in suppressing CSR. Mechanistically, dysregulation of p110alpha or PTEN inversely affects activation-induced deaminase expression via modulating AKT activity. Thus, our study reveals that a signaling balance between PTEN and PI3K isoforms is essential to maintain normal CSR. PMID- 26500351 TI - Estimation of the Antirelapse Efficacy of Tafenoquine, Using Plasmodium vivax Genotyping. AB - Prevention of relapse of Plasmodium vivax infection is a key treatment goal in malaria. Use of P. vivax genotyping in a multicenter, double-blind, randomized, placebo-controlled phase 2b study in Peru, India, Thailand, and Brazil allowed determination of genetically heterologous or homologous P. vivax infection recurrence following receipt of chloroquine plus one of 4 doses of tafenoquine (50, 100, 300, or 600 mg) or chloroquine plus primaquine, compared with receipt of chloroquine alone. The antihypnozoite efficacy of tafenoquine was evident as a reduction in homologous recurrences of P. vivax infection as drug doses were increased. No clear dose-response pattern was evident for heterologous recurrences of P. vivax infection. Rates of homologous recurrence of P. vivax infection appear to be clinically useful for comparing drug efficacy for the prevention of P. vivax infection relapse. CLINICAL TRIALS REGISTRATION: NCT01376167. PMID- 26500353 TI - Inheriting the Journal. PMID- 26500352 TI - Mimicking Biological Delivery Through Feedback-Controlled Drug Release Systems Based on Molecular Imprinting. AB - Intelligent drug delivery systems (DDS) are able to rapidly detect a biological event and respond appropriately by releasing a therapeutic agent; thus, they are advantageous over their conventional counterparts. Molecular imprinting is a promising area that generates a polymeric network which can selectively recognize a desired analyte. This field has been studied for a variety of applications over a long period of time, but only recently has it been investigated for biomedical and pharmaceutical applications. Recent work in the area of molecularly imprinted polymers in drug delivery highlights the potential of these recognitive networks as environmentally responsive DDS that can ultimately lead to feedback controlled recognitive release systems. PMID- 26500354 TI - Chiropractors' characteristics associated with their number of workers' compensation patients. AB - STUDY DESIGN: A cross-sectional survey. OBJECTIVE: The purpose of this study was to identify characteristics of Canadian doctors of chiropractic (DCs) associated with their number of workers' compensation patients. SUMMARY OF BACKGROUND DATA: It has been previously hypothesized that DCs that treat a relatively high volume of workers' compensation cases may have different characteristics than the general chiropractic community. METHODS: Secondary data analyses were performed on data collected in the 2011 survey of the Canadian Chiropractic Resources Databank (CCRD). The CCRD survey included 81 questions concerning the practice and concerns of DCs. Of the 6,533 mailed questionnaires, 2,529 (38.7%) were returned. Of these, 652 respondents did not meet our inclusion criteria, and our final study sample included 1,877 respondents. Bivariate analyses were conducted between predetermined independent variables and the annual number of workers' compensation patients. A negative binomial multivariate regression was performed to identify significant factors associated with the number of workers' compensation patients. RESULTS: On average, DCs received 10.3 (standard deviation (SD) = 17.6) workers' compensation cases and nearly one-third did not receive any such cases. The type of clinic (other than sole provider), practice area population (smaller than 500,000), practice province (other than Quebec), number of practice hours per week, number of treatments per week, main sector of activity (occupational/ industrial), care provided to patients (electrotherapy, soft-tissue therapy), percentage of patients with neuromusculoskeletal conditions, and percentage of patients referred by their employer or a physician were associated with a higher annual number of workers' compensation cases. CONCLUSION: Canadian DCs who reported a higher volume of workers' compensation patients had practices oriented towards the treatment of injured workers, collaborated with other health care providers, and facilitated workers' access to care. PMID- 26500355 TI - Collaborative care for a patient with complex low back pain and long-term tobacco use: a case report. AB - Few examples of interprofessional collaboration by chiropractors and other healthcare professionals are available. This case report describes an older adult with complex low back pain and longstanding tobacco use who received collaborative healthcare while enrolled in a clinical trial. This 65 year-old female retired office worker presented with chronic back pain. Imaging findings included disc extrusion and spinal stenosis. Multiple co-morbidities and the complex nature of this case substantiated the need for multidisciplinary collaboration. A doctor of chiropractic and a doctor of osteopathy provided collaborative care based on patient goal setting and supported by structured interdisciplinary communication, including record sharing and telephone consultations. Chiropractic and medical interventions included spinal manipulation, exercise, tobacco reduction counseling, analgesic use, nicotine replacement, dietary and ergonomic recommendations, and stress reduction strategies. Collaborative care facilitated active involvement of the patient and resulted in decreased radicular symptoms, improvements in activities of daily living, and tobacco use reduction. PMID- 26500357 TI - Conservative treatment of a rock climber with a SLAP lesion: a case report. AB - This case report describes the clinical presentation and conservative treatment of a patient who suffered from a superior labrum anteroposterior (SLAP) tear of the shoulder after a rock climbing session. The 26 year old man had injured his right shoulder while trying to reach a distant socket with his shoulder 90 degrees abducted and in extreme external rotation. After initial treatment failure in chiropractic, the patient sought an orthopaedist and physiotherapy care. A contrast magnetic resonance examination revealed a SLAP lesion. Awaiting orthopaedic consultation and in the absence of clinical improvement the patient sought care from a second chiropractor. Clinical examination revealed a mild winging of the right scapula and the presence of trigger points in the rotator cuff muscles, biceps, rhomboids and serratus anterior. The chiropractic treatment then included soft tissue mobilization and the prescription of strengthening exercises of the serratus anterior and rotator cuff muscles. After 4 sessions, the patient did not feel any pain and gradually resumed all his recreational activities. Clinicians should be aware that SLAP lesions are difficult to identify clinically and that manual therapy might be an important component of conservative treatment of SLAP lesions. PMID- 26500356 TI - Leg length discrepancy and osteoarthritis in the knee, hip and lumbar spine. AB - Osteoarthritis (OA) is an extremely common condition that creates substantial personal and health care costs. An important recognised risk factor for OA is excessive or abnormal mechanical joint loading. Leg length discrepancy (LLD) is a common condition that results in uneven and excessive loading of not only knee joints but also hip joints and lumbar motion segments. Accurate imaging methods of LLD have made it possible to study the biomechanical effects of mild LLD (LLD of 20mm or less). This review examines the accuracy of these methods compared to clinical LLD measurements. It then examines the association between LLD and OA of the joints of the lower extremity. More importantly, it addresses the largely neglected association between LLD and degeneration of lumbar motion segments and the patterns of biomechanical changes that accompany LLD. We propose that mild LLD may be an important instigator or contributor to OA of the hip and lumbar spine, and that it deserves to be rigorously studied in order to decrease OA's burden of disease. PMID- 26500358 TI - Whole body vibration and cerebral palsy: a systematic review. AB - PURPOSE: The goal of this review is to evaluate the effects of whole body vibration on outcomes in patients with cerebral palsy. The findings in this review may help clinicians make evidence informed decisions on the use of whole body vibration for cerebral palsy. METHODS: A systematic search was conducted on April 29, 2014.The following search terms were used to search of several databases: (whole body vibration OR whole-body vibration OR whole body-vibration OR WBV) AND (cerebral palsy). Articles that met the inclusion criteria were assessed using the Scottish intercollegiate guidelines network (SIGN) rating system to assess the methodology and bias of the articles for randomized control trials. RESULTS: The search produced 25 articles, of which 12 duplicates were identified and removed. Another seven articles were not considered since they did not fit the inclusion criteria, leaving a total of five studies for review. Four of the articles analyzed the effects of WBV in children while the other study focused on adults with cerebral palsy. There was one low quality article, four acceptable quality articles and one high quality article when assessed using the SIGN criteria. CONCLUSIONS: It appears that whole body vibration has the potential to provide symptomatic relief for patients with cerebral palsy. Whole body vibration may improve spasticity, muscle strength and coordination. There is a lack of research to conclusively determine whether it does alter bone mineral density. PMID- 26500359 TI - A rare case of unilateral variations of forearm arteries: anatomy, embryology and clinical implications. AB - This study documents the existence and topographic anatomy of a rare case of variant forearm arteries found in the left upper limb of a 68-year-old male cadaver. The arteries of the arm followed typical courses, but both the radial and ulnar arteries in the forearm followed a superficial course. The common interosseous artery and recurrent ulnar arteries branched from the radial, not the ulnar, artery. The radial artery was larger than the ulnar artery and was the major source of blood supply to the forearm. Clinical implications for single superficial forearm arteries are reviewed. A person with both superficial radial and superficial ulnar arteries would be at a substantially increased risk of injury or iatrogenic effects that could compromise blood supply to the hand. This study will enhance clinician's awareness of potential arterial variations, so they can provide adequate assessment, diagnosis and treatment of upper limb lesions. PMID- 26500360 TI - Intra- and inter-observer reliability of the Cobb measurement by chiropractic interns using digital evaluation methods. AB - INTRODUCTION: It is important to create a body of evidence surrounding the reliability of certain diagnostic criteria. While the reliability of the Cobb measurement is well established with various licensed health care professionals, this study aims to determine the inter- and intra-observer reliability of the Cobb Measurement among chiropractic interns. METHODS: Fourteen chiropractic interns analyzed 10 pre-selected digital spinal radiographs on a Picture Archiving and Communication System (PACS) in two separate rounds of observation. The participants indicated their choice of end vertebra and Cobb Measurement in each round of observation. Agreement on vertebral levels selected was estimated using percentage agreement. Intra-observer reliability was estimated using the Pearson r correlation coefficient, and inter-observer correlation was estimated using the Inter-Class Coefficient (ICC). RESULTS: The range of percentage agreement on vertebral level selection was 0.36 - 0.79. The Pearson r correlation coefficient for round 1 and round 2 was 0.79. The ICC (3,1) was 0.79 (round 1), and 0.70 (round 2). CONCLUSION: Less than optimal agreement on end vertebrae selection was found between observers. Intra- and inter-observer reliability of the Cobb Measurement was 'excellent' (round 1) and 'good' (round 2). PMID- 26500361 TI - Chiropractic management of a patient with breast cancer metastases to the brain and spine: a case report. AB - Cancers of the breast, kidney, lungs, prostate and thyroid metastasize to the musculoskeletal system in the majority of patients with malignancy. This report chronicles the case of a 65-year-old female with a known history of breast cancer who presented to a chiropractic clinic. Once metastasis was ruled out as the cause of her complaint, the patient was treated with manual therapies and exercises. As the patient's treatments progressed and her pain improved, she presented with a new complaint of 'pressure' in her head. Advanced imaging revealed metastasis to the brain and subsequently to the spine. The aim of this case is to heighten awareness of the presentation of metastasis to the brain and the spine in a chiropractic patient, and to demonstrate the benefit of chiropractic care in the management of such patients. PMID- 26500362 TI - Diagnostic and treatment methods used by chiropractors: A random sample survey of Canada's English-speaking provinces. AB - OBJECTIVE: It is important to understand how chiropractors practice beyond their formal education. The objective of this analysis was to assess the diagnostic and treatment methods used by chiropractors in English-speaking Canadian provinces. METHODS: A questionnaire was created that examined practice patterns amongst chiropractors. This was sent by mail to 749 chiropractors, randomly selected and stratified proportionally across the nine English-speaking Canadian provinces. Participation was voluntary and anonymous. Data were entered into an Excel spreadsheet, and descriptive statistics were calculated. RESULTS: The response rate was 68.0%. Almost all (95.1%) of respondents reported performing differential diagnosis procedures with their new patients; most commonly orthopaedic testing, palpation, history taking, range of motion testing and neurological examination. Palpation and painful joint findings were the most commonly used methods to determine the appropriate joint to apply manipulation. The most common treatment methods were manual joint manipulation/mobilization, stretching and exercise, posture/ergonomic advice and soft-tissue therapies. CONCLUSIONS: Differential diagnosis is a standard part of the assessment of new chiropractic patients in English-speaking Canadian provinces and the most common methods used to determine the site to apply manipulation are consistent with current scientific literature. Patients are treated with a combination of manual and/or manipulative interventions directed towards the joints and/or soft tissues, as well as exercise instruction and postural/ergonomic advice. PMID- 26500363 TI - Is "fear of passive movement" a distinctive component of the Fear-Avoidance Model in whiplash? AB - OBJECTIVES: Modify the Tampa Scale for Kinesiophobia (TSK) for 'fear of passive motion' beliefs. METHODS: With permission, a 14-item modification, the TSK-PM (passive movement), was created. Test-retest reliability was tested first. Construct validity was tested in chronic whiplash patients by comparing the TSK PM with the TSK, the Neck Disability Index (NDI) and cervical ranges of motion. RESULTS: The TSK-PM showed high test-retest reliability (r = 0.83) and high correlation with the original TSK (r = 0.84). Low, non-significant correlations were found with other variables. NDI scores were strongly correlated with ranges of motion. CONCLUSIONS: While having high test-retest reliability and a single factor structure, the TSK-PM failed to demonstrate distinctive construct validity vs the original TSK. The original TSK is likely to be sufficient to assess fear of being moved in neck pain patients in a clinical setting. Modifications to the current version of the TSK-PM might improve its construct validity in future studies. PMID- 26500364 TI - Missed appendicitis diagnosis: A case report. AB - OBJECTIVE: The purpose of this case report is to highlight and emphasize the need for an appropriate and thorough list of differential diagnoses when managing patients, as it is insufficient to assume cases are mechanical, until proven non mechanical. There are over 250,000 cases of appendicitis annually in the United States. Of these cases, <50% present with classic signs and symptoms of pain in the right lower quadrant, mild fever and nausea. It is standard for patients who present with appendicitis to be managed operatively with a laparoscopic appendectomy within 24 hours, otherwise the risk of complications such as rupture, infection, and even death increases dramatically. CLINICAL FEATURES: This is a retrospective case report following a 27-year-old male with missed appendicitis, who presented to a chiropractor two-weeks after self-diagnosed food poisoning. On assessment, he was tender with resisted lumbar rotation. Psoas Sign, McBurney's Point, vascular exam, hip exam, were negative. A diagnosis of an abdominal strain was provided. Two weeks later, he returned to the chiropractor without an improvement of symptoms. INTERVENTION & OUTCOME: The patient was sent to the hospital, where he was provided a diagnosis of missed appendicitis. He required a hemicolonectomy due to the associated phlegmonous mass. SUMMARY: When a patient presents to a chiropractic clinic with symptoms of abdominal pain, having a comprehensive list of non-mechanical differential diagnoses as well as mechanical differentials is crucial. Appropriate assessment and management of abdominal cases decreases the risk to patients, as missed diagnoses often require more invasive interventions. PMID- 26500366 TI - Robert M. Wingfield, dc: A conscientious chiropractor. AB - "I slept and dreamed that life was beauty. I woke - and found that life was duty." This quote from the poet Ellen Sturgis Hooper, could be attributed to Robert Wingfield, who has persevered in his quest for personal and professional excellence. This historical biography begins with his genealogy, going back to the 11(th) century in Merry England and ends in 2015, with his relatively quiet existence still centred in Ontario. The essay scrutinizes Dr. Wingfield's accomplishments for the Ontario Chiropractic Association (OCA), Canadian Chiropractic Association (CCA) and Ontario Board of Directors of Chiropractic (BDC). Moreover, it attempts to give the reader a glimpse into his personal endeavours, to help us fathom how he tackles (as William Shakespeare would say) "the thousand natural shocks that flesh is heir to." PMID- 26500365 TI - What is the pain source? A case report of a patient with low back pain and bilateral hip osteonecrosis. AB - BACKGROUND: Low back pain is a common symptom arising from many possible sources and includes the possibility of the contribution of remote pathology. This report describes a patient with bilateral osteonecrosis of the femoral heads presenting with a primary symptom of low back pain. CASE PRESENTATION: A 37-year-old male presented for evaluation of dominant pain that existed for approximately 6-12 months and was located in the right low back. Milder pain was also reported in the right hip. Low back and hip pain were both aggravated by weight-bearing activities. An evidence-based diagnostic evaluation revealed little indication for a primary pain source originating from low back structures. Radiographs revealed bilateral osteonecrosis with evidence of left femoral head collapse. CONCLUSION: Hip osteonecrosis may have contributed to an atypical presentation of low back pain due to aberrant localization of pain and/or combined with altered biomechanical loading of musculoskeletal structures. PMID- 26500367 TI - Postpartum Contraception: a Comparative Study of Berlin Women with and without Immigration Background. AB - Research Questions: Are there differences in postpartum contraceptive use between women with and without immigration background? Do women more commonly use contraception following a high-risk pregnancy or caesarean section? What role does current breastfeeding play and, amongst immigrants, what is the effect of acculturation level on the frequency of contraceptive use? Study Population and Methods: Data collection was carried out as part of a larger study in three Berlin delivery units using standardised interviews (questionnaires covering e.g. sociodemographics, immigration history/acculturation and use of antenatal care); telephone interviews comprising 6 questions on postpartum contraception, breastfeeding and postpartum complications were conducted on a sample of the study population six months after delivery. Results: 247 women with, and 358 women without a background of immigration were included in the study (total study population n = 605, response rate 81.1 %). 68 % of 1st generation immigrants, 87 % of 2nd/3rd generation women and 73 % of women without immigration background (non-immigrants) used contraception. In the logistical regression analysis 1st generation immigrants were less likely than non-immigrants to be using contraception six months postpartum, and 1st generation immigrants with low acculturation level were significantly less likely to use contraception than 2nd/3rd generation women with low acculturation level. Conclusion: In the extended postpartum period there was no major difference in contraceptive use between immigrants in general and non-immigrants. It remains unclear whether the differing contraceptive behaviour of 1st generation immigrants is the result of less access to information, sociocultural factors or differing contraceptive requirements and further targeted, qualitative study is required. PMID- 26500368 TI - Prevalence and Associated Risk Factors for Obesity During Pregnancy Over Time. AB - Objective: The increasing prevalence of obesity is having an impact on morbidity worldwide. Since young mature women are equally affected by the general increase in weight, the aim of the study was to evaluate the prevalence of obesity together with associated maternal risk factors, complications during pregnancy, and fetal outcomes in a local cohort for the years 2006 and 2011. Study Design: Maternal and fetal records of women who delivered at the University of Wurzburg, with a 5-year interval (2006 and 2011) between investigations, were retrospectively analyzed. Descriptive statistics included prevalence of obesity, maternal weight gain, as well as several complications during pregnancy and fetal characteristics. The association between maternal or fetal complications and extent of maternal obesity was analyzed. Results: Our analysis included 2838 mothers with singleton pregnancies who delivered in 2006 (n = 1293) or 2011 (n = 1545) in our department. We found that neither pre-pregnancy body mass index (23.77 +/- 4.85 vs. 24.09 +/- 5.10 kg/m2, p = 0.25) nor weight gain (14.41 +/- 5.77 vs. 14.78 +/- 5.65 kg; p = 0.09) increased significantly over time. But the majority of all overweight (71 %) or obese (60.4 %) mothers gained more weight than generally recommended. The prevalence of gestational diabetes, gestational hypertension, and preeclampsia increased significantly and was associated with high pre-pregnancy body mass index, as was delivery by cesarean section. However, obesity was not associated with prolonged pregnancy and did not seem to negatively affect fetal outcome. Conclusion: There is a trend to increasing weight gain during pregnancy, and the majority of mothers, especially those with a high pre-pregnancy body mass index, exceeded the weight gain recommendations. Associated risk factors such as gestational diabetes, hypertension, and delivery by cesarean section are increasing. PMID- 26500369 TI - Treatment of Giant Fibroadenoma in Young Women: Results after Tumor Excision without Reconstructive Surgery. AB - Introduction: Giant fibroadenoma (GFA) of the breast is defined as fibroadenoma larger than 5 cm, usually presenting unilaterally and manifesting as breast asymmetry or deformity of the breast. Material and Methods: A retrospective database search was done of all patients with giant fibroadenoma who underwent surgery for GFA in the breast center of Hanover Medical School between 2007 and 2014; all patients with GFA were followed up. Data were analyzed with regard to tumor and patient characteristics and esthetic outcome. Results: A total of 13 patients with symptomatic GFA underwent surgery between 2007 and 2014. Mean patient age was 21.2 years (range 14-31 years). In 8 of 13 patients the tumor had resulted in breast deformity and/or breast asymmetry. Average size of the mass was 10.2 cm (range 8.5-12 cm) and average weight was 203.6 g (range 151.2-323.5 g). Initial clinical suspicion of GFA was confirmed by ultrasound examination. Preoperative core biopsy revealed fibroadenoma in 8/13 cases, cellular fibroepithelial lesions with a differential diagnosis of benign phyllodes tumor in 3 cases and unspecific histological findings in the remaining 2 cases. Conclusion: Excision was done using an inframammary or periareolar approach without reconstructive plasty. The cosmetic results were good, as were the outcomes on follow-up. We therefore favor this surgical technique to treat giant fibroadenoma of similar size to those described above. PMID- 26500370 TI - ICG Fluorescence Technique for the Detection of Sentinel Lymph Nodes in Breast Cancer: Results of a Prospective Open-label Clinical Trial. AB - Introduction: Detection of sentinel lymph nodes (SLN) is the standard procedure to evaluate axillary lymph node status in breast cancer. In addition to known and established procedures such as the blue dye method and scintigraphy, this study investigated the efficacy of a method based on use of the fluorescent dye indocyanine green (ICG). Patients and Method: A total of 126 women with breast cancer histologically verified by punch biopsy were studied during surgical removal of SLN. In addition to SLN marking with technetium and scintigraphy, intra-individual comparison was done using indocyanine green (ICG) for marking instead of the standard blue dye. Results: Scintigraphy had a detection rate of 96 %; the detection rate with ICG was just under 89 %. A body mass index (BMI) > 40 was found to be a limiting factor for the fluorescent method. Investigation into potential toxicities associated with the use of the fluorescent dye ICG revealed no systemic or even local side effects. The fluorescent method was found to be significantly less expensive than the scintigraphy method. Conclusion: The ICG fluorescence technique for the detection of SLN was found to be a valid and feasible method in clinical practice when compared directly with the blue dye method and scintigraphy. PMID- 26500371 TI - High Estradiol Levels During Postmenopause - Pitfalls in Laboratory Analysis. AB - A 54-year-old woman was admitted with a result of high serum estradiol levels (> 4300 pg/ml) and typical postmenopausal symptoms. She had a history of an adnexectomy (normal histopathology) due to the elevated estradiol levels. After surgery, estradiol levels were as high as before. Analyzing the anti-mullerian hormone (AMH), inhibin B, DHEA-S and estrone, typical postmenopausal levels were found. Serum estradiol levels were controlled several times with rabbit-derived polyclonal as well as monoclonal antibodies to optimize the selectivity of the test system. Secondary, a radioimmunoassay was performed to exclude interferences of the detection system where lower, but still elevated estradiol levels (186 pg/ml) were found. Hypothesizing that our patient underwent a cross reaction with irregular antibodies, a control was done using sheep-derived antibodies, which proved a postmenopausal hormone level (estradiol level < 5 pg/ml). This result was confirmed using a fluorescence enzyme immunoassay (FEIA) revealing high levels of irregular antibodies (> 200 mg/l; reference < 30 mg/l). This case depicts the pitfalls of estradiol measurement detecting false elevated estradiol levels in a postmenopausal woman. PMID- 26500372 TI - Traumatic Vulvar Epithelial Inclusion Cysts Following Female Genital Mutilation (FGM). AB - Background: Female genital mutilation (FGM) occurs mainly in Africa, parts of the Arabian Peninsula and parts of Asia. It is commonly associated with acute complications as well as diverse late/delayed complications. One of the most common of these late complications is progressively enlarging painless cysts of the vulva. Case Report: An 8-year-old girl from Eritrea presented to our paediatric emergency department with a progressively enlarging mass of the vulva. She had undergone a clitoridectomy and partial removal of the labia minora as an infant in Eritrea. We performed surgical excision of the cyst and reconstruction of the labia. Histology showed a traumatic squamous epithelial inclusion cyst of the vulva. Conclusion: Epithelial or dermoid cysts of the vulva following FGM are extremely rare. Symptoms often require surgical intervention. Through increasing migration, more girls and female youths with FGM are likely to present to practices and hospitals in Germany. Thus increased knowledge and awareness of the medical complications of FGM and their treatment will be necessary in years to come. PMID- 26500373 TI - Emissions of nitrous oxide and ammonia from a sandy soil following surface application and incorporation of cauliflower leaf residues. AB - Vegetable production systems are often characterized by excessive nitrogen (N) fertilization and the incorporation of large amounts of post-harvest crop residues. This makes them particularly prone to ammonia (NH3) and nitrous oxide (N2O) emissions. Yet, urgently needed management strategies that can reduce these harmful emissions are missing, because underlying processes are not fully understood. The present study therefore focuses on the effects of residue placement on NH3 and N2O emissions. For this, cauliflower leaf residues (286 kg N/ha) were either applied as surface mulch (mulch) or mixed with the topsoil (mix) and in situ NH3 and N2O emissions were investigated. The experiment took place on a sandy soil in Northeastern Germany during summer 2012. Residue application created a high peak in N2O emissions during the first 2 weeks, irrespective of residue placement. There was no significant difference in the emission sums over the experimental period (65 days) between the mix (5.8 +/- 0.68 kg N2O-N/ha) and the mulch (9.7 +/- 1.53 kg N2O-N/ha) treatment. This was also the case for NH3 emissions, which exhibited a lower initial peak followed by a prolonged decline. Measured emission sums were 4.1 +/- 0.33 (mix) and 5.1 +/- 0.73 (mulch) kg NH3-N/ha. It was concluded that substantial NH3 and N2O emissions can occur after high input of available organic carbon and N even in a coarse textured soil with low water-holding capacity. Other than expected, surface application does not enhance NH3 emissions at the expense of N2O emissions compared with residue mixing into the soil, at least under the conditions of the present study. PMID- 26500374 TI - The effects of treading by two breeds of dairy cow with different live weights on soil physical properties, poaching damage and herbage production on a poorly drained clay-loam soil. AB - There is little empirical evidence to indicate that dairy cow live weight affects the extent of soil damage at the hoof-soil interface during grazing on poorly drained permanent grassland. In the present study the impact of Holstein-Friesian (HF) dairy cows with a mean (+/-standard deviation) live weight of 570 (+/-61) kg were compared with Jersey * Holstein-Friesian (JX) with a mean live weight of 499 (+/-52) kg each at two stocking densities: mean 2.42 +/- (0.062) and 2.66 (+/ 0.079) cows/ha. Soil physical properties (bulk density, macroporosity, gravimetric water content, air-filled porosity, penetration resistance and shear strength), poaching damage (post-grazing soil surface deformation and hoof-print depth), herbage yield and milk production were measured throughout 2011 and 2012. Soil physical properties, post-grazing soil surface deformation and herbage production were not affected by dairy cow breed or by interactions between breed and stocking density. Hoof-print depth was higher in the HF treatments (39 v. 37 mm, s.e. 0.5 mm). Loading pressure imposed at the soil surface was the same for both breeds due to a direct correlation between live weight and hoof size. Poaching damage was greater at higher stocking density. Using the lighter JX cow offered little advantage in terms of lowering the negative impact of treading on soil physical properties or reducing poaching damage and no advantage in terms of herbage or milk production compared with the heavier HF cow. PMID- 26500375 TI - Maize yield response to a phosphorus-solubilizing microbial inoculant in field trials. AB - Findings from multi-year, multi-site field trial experiments measuring maize yield response to inoculation with the phosphorus-solubilizing fungus, Penicillium bilaiae Chalabuda are presented. The main objective was to evaluate representative data on crop response to the inoculant across a broad set of different soil, agronomic management and climate conditions. A statistical analysis of crop yield response and its variability was conducted to guide further implementation of a stratified trial and sampling plan. Field trials, analysed in the present study, were conducted across the major maize producing agricultural cropland of the United States (2005-11) comprising 92 small (with sampling replication) and 369 large (without replication) trials. The multi-plot design enabled both a determination of how sampling area affects the estimation of maize yield and yield variance and an estimation of the ability of inoculation with P. bilaiae to increase maize yield. Inoculation increased maize yield in 66 of the 92 small and 295 of the 369 large field trials (within the small plots, yield increased significantly at the 95% confidence level, by 0.17 +/- 0.044 t/ha or 1.8%, while in the larger plots, yield increases were higher and less variable (i.e., 0.33 +/- 0.026 t/ha or 3.5%). There was considerable inter-annual variability in maize yield response attributed to inoculation compared to the un inoculated control, with yield increases varying from 0.7 +/- 0.75 up to 3.7 +/- 0.73%. No significant correlation between yield response and soil acidity (i.e., pH) was detected, and it appears that pH reduction (through organic acid or proton efflux) was unlikely to be the primary pathway for better phosphorus availability measured as increased yield. Seed treatment and granular or dribble band formulations of the inoculant were found to be equally effective. Inoculation was most effective at increasing maize yield in fields that had low or very low soil phosphorus status for both small and large plots. At higher levels of soil phosphorus, yield in the large plots increased more with inoculation than in the small plots, which could be explained by phosphorus fertilization histories for the different field locations, as well as transient (e.g., rainfall) and topographic effects. PMID- 26500376 TI - Extraction and pre-concentration of platinum and palladium from microwave digested road dust via ion exchanging mesoporous silica microparticles prior to their quantification by quadrupole ICP-MS. AB - We report on the use of mesoporous silica microparticles (MUPs) functionalized with quarternary amino groups for the isolation of platinum and palladium tetrachloro complexes from aqueous road dust digests. The MUPs have a size ranging from 450 to 850 nm and are suspended directly in the aqueous digests, upon which the anionic Pt and Pd complexes are retained on the cationic surface. Subsequently, the MUPs are separated by centrifugation. Elements that cause spectral interferences in ICP-MS determination of Pt and Pd can be quantitatively removed by adding fresh 0.240 mol L-1 HCl to the MUPs and by repeating the centrifugation step. The analyte-loaded MUPs are then dissolved in 0.1 mL of 2 mol L-1 HF, diluted to 2 mL, and the solutions thus obtained are analyzed by quadrupole ICP-MS. This method avoids analyte elution from the sorbent. This "dispersed particle extraction" approach yielded a run-to-run relative standard deviation <= 5 % for Pt and <= 4 % for Pd (at 0.1 ng mL-1, n = 4 road dust digests). Method detection limits (expressed as concentrations in the dust samples) are 2 and 1 ng g-1 for Pt and Pd, respectively. The method was validated by analysis of a reference material (BCR CRM 723) and applied to the analysis of road dust samples collected in downtown Vienna. Pt and Pd concentrations in samples collected in summer and in winter were compared, with concentrations ranging from 205 to 1445 ng g-1 for Pt and from 201 to 1230 ng g-1 for Pd. Graphical AbstractMesoporous silica microparticles (MUPs) functionalized with quarternary amino groups were used for isolating platinum and palladium from aqueous road dust digests. The MUPs were suspended directly in the aqueous digests, and the analyte-loaded MUPs were analyzed using "dispersed particle extraction". PMID- 26500377 TI - Mesoscale simulations of curvature-inducing protein partitioning on lipid bilayer membranes in the presence of mean curvature fields. AB - The membrane-surface migration of curvature-inducing proteins in response to membrane curvature gradients has been investigated using Monte Carlo simulations of a curvilinear membrane model based on the Helfrich Hamiltonian. Consistent with theoretical and experimental data, we find the proteins that generate curvature can also sense the background membrane curvature, wherein they preferentially partition to the high curvature regions. The partitioning strength depends linearly on local membrane curvature and the slope (or the coupling constant) of the partitioning probability versus mean curvature depends on the membrane bending rigidity and instantaneous curvature field caused by different proteins. Our simulation study allows us to quantitatively characterize and identify the important factors affecting the coupling constant (slope), which may be difficult to determine in experiments. Furthermore, the membrane model is used to study budding of vesicles where it is found that in order to stabilize a mature vesicle with a stable 'neck-region' (or stable membrane overhangs), the area (extent) of the intrinsic curvature region needs to exceed a threshold critical value. The migration and partitioning of curvature-inducing proteins in a budding vesicle with a stable neck (with a characteristic negative value of the Gaussian curvature) is investigated. PMID- 26500378 TI - LEARNING WORDS FOR LIFE: Promoting Vocabulary in Dual Language Learners. AB - Teaching vocabulary to young dual language learners is critical for their learning in school. This article presents recommendations for promoting vocabulary during reading aloud and conversations in early childhood. PMID- 26500379 TI - Long Term Physical Health Consequences of Adverse Childhood Experiences. AB - This study examined associations between adverse childhood family experiences and adult physical health using data from 52,250 US adults aged 18-64 from the 2009 2012 Behavioral Risk Factor Surveillance System (BRFSS). We found that experiencing childhood physical, verbal, or sexual abuse, witnessing parental domestic violence, experiencing parental divorce, and living with someone who was depressed, abused drugs or alcohol, or who had been incarcerated were associated with one or more of the following health outcomes: self-rated health, functional limitations, diabetes, and heart attack. Adult socioeconomic status and poor mental health and health behaviors significantly mediated several of these associations. The results of this study highlight the importance of family-based adverse childhood experiences on adult health outcomes and suggest that adult SES and stress-related coping behaviors may be crucial links between trauma in the childhood home and adult health. PMID- 26500380 TI - Inference for High-dimensional Differential Correlation Matrices. AB - Motivated by differential co-expression analysis in genomics, we consider in this paper estimation and testing of high-dimensional differential correlation matrices. An adaptive thresholding procedure is introduced and theoretical guarantees are given. Minimax rate of convergence is established and the proposed estimator is shown to be adaptively rate-optimal over collections of paired correlation matrices with approximately sparse differences. Simulation results show that the procedure significantly outperforms two other natural methods that are based on separate estimation of the individual correlation matrices. The procedure is also illustrated through an analysis of a breast cancer dataset, which provides evidence at the gene co-expression level that several genes, of which a subset has been previously verified, are associated with the breast cancer. Hypothesis testing on the differential correlation matrices is also considered. A test, which is particularly well suited for testing against sparse alternatives, is introduced. In addition, other related problems, including estimation of a single sparse correlation matrix, estimation of the differential covariance matrices, and estimation of the differential cross-correlation matrices, are also discussed. PMID- 26500381 TI - Interventions to Improve Late Life. PMID- 26500382 TI - Why crying does and sometimes does not seem to alleviate mood: a quasi experimental study. AB - Whereas retrospective studies suggest that crying can be beneficial in terms of mood enhancement, results of quasi-experimental laboratory studies consistently demonstrate its negative effects on mood. The present study was specifically designed to evaluate a parsimonious explanation for this paradox by assessing mood after crying in a laboratory, both immediately and at follow up. Mood ratings of 28 objectively established criers and 32 non-criers were compared before and immediately after the exposure to an emotional movie, as well as 20 and 90 min later. As expected, immediately after the film, negative mood significantly increased in criers, while it did not change in non-criers. This mood deterioration was followed by a recovery that resulted in return to the baseline mood levels at the third measurement. Criers subsequently reported mood enhancements at the final measurement compared to the pre-film measurement. Crying frequency did not predict mood changes above those predicted by the presence of crying. The observed relation between crying and more long-term mood recovery reconciles seemingly contrasting earlier results and provides a simple and obvious explanation. After the initial deterioration of mood following crying that was observed in laboratory studies, it apparently takes some time for the mood, not just to recover, but also to become even less negative than before the emotional event, which corresponds to the results of retrospective studies. PMID- 26500383 TI - Religious Affiliation and Fertility in a Sub-Saharan Context: Dynamic and Lifetime Perspectives. AB - We use uniquely detailed data from a predominantly Christian high-fertility area in Mozambique to examine denominational differentials in fertility from two complementary perspectives-dynamic and cumulative. First, we use event-history analysis to predict yearly risks of birth from denominational affiliation. Then, we employ Poisson regression to model the association between the number of children ever born and share of reproductive life spent in particular denominations or outside organized religion. Both approaches detect a significant increase in fertility associated with membership in a particular type of African initiated churches which is characterized by strong organizational identity, rigid hierarchy, and insular corporate culture. Membership in the Catholic Church is also associated with elevated completed fertility. We relate these results to extant theoretical perspectives on the relationship between religion and fertility by stressing the interplay between ideological, social, and organizational characteristics of different types of churches and situate our findings within the context of fertility transition and religious demographics in Mozambique and elsewhere in sub-Saharan Africa. PMID- 26500384 TI - Sources of variation in emotional awareness: Age, gender, and socioeconomic status. AB - The present study examined associations between emotional awareness facets (type clarity, source clarity, negative emotion differentiation, voluntary attention, involuntary attention) and sociodemographic characteristics (age, gender, and socioeconomic status (SES)) in a large US sample (N = 919). Path analyses controlling for variance shared between sociodemographic variables and allowing emotional awareness facets to correlate-demonstrated that (a) age was positively associated with type clarity and source clarity, and inversely associated with involuntary attention; (b) gender was associated with all facets but type clarity, with higher source clarity, negative emotion differentiation, voluntary attention, and involuntary attention reported by women then men; and (c) SES was positively associated with type clarity with a very small effect. These findings extend our understanding of emotional awareness and identify future directions for research to elucidate the causes and consequences of individual differences in emotional awareness. PMID- 26500385 TI - Computational Characterization of Mutations in Cardiac Troponin T Known to Cause Familial Hypertrophic Cardiomyopathy. AB - Cardiac Troponin T (cTnT) is a central modulator of thin filament regulation of myofilament activation. The lack of structural data for the TNT1 tail domain, a proposed alpha-helical region, makes the functional implications of the FHC mutations difficult to determine. Studies have suggested that flexibility of TNT1 is important in normal protein-protein interactions within the thin filament. Our groups have previously shown through Molecular Dynamics (MD) simulations that some FHC mutations, Arg92Leu(R92L) and Arg92Trp(R92W), result in increased flexibility at a critical hinge region 12 residues distant from the mutation. To explain this distant effect and its implications for FHC mutations, we characterized the dynamics of wild type and mutational segments of cTnT using MD. Our data shows an opening of the helix between residues 105-110 in mutants. Consequently, the dihedral angles of these residues correspond to non-alpha helical regions on Ramachandran plots. We hypothesize the removal of a charged residue decreases electrostatic repulsion between the point mutation and surrounding residues resulting in local helical compaction. Constrained ends of the helix and localized compaction results in expansion within the nearest non polar helical turn from the mutation site, residues 105-109. PMID- 26500386 TI - Uncertainty analysis of a model of wind-blown volcanic plumes. AB - Mathematical models of natural processes can be used as inversion tools to predict unobserved properties from measured quantities. Uncertainty in observations and model formulation impact on the efficacy of inverse modelling. We present a general methodology, history matching, that can be used to investigate the effect of observational and model uncertainty on inverse modelling studies. We demonstrate history matching on an integral model of volcanic plumes that is used to estimate source conditions from observations of the rise height of plumes during the eruptions of Eyjafjallajokull, Iceland, in 2010 and Grimsvotn, Iceland, in 2011. Sources of uncertainty are identified and quantified, and propagated through the integral plume model. A preliminary sensitivity analysis is performed to identify the uncertain model parameters that strongly influence model predictions. Model predictions are assessed against observations through an implausibility measure that rules out model inputs that are considered implausible given the quantified uncertainty. We demonstrate that the source mass flux at the volcano can be estimated from plume height observations, but the magmatic temperature, exit velocity and exsolved gas mass fraction cannot be accurately determined. Uncertainty in plume height observations and entrainment coefficients results in a large range of plausible values of the source mass flux. Our analysis shows that better constraints on entrainment coefficients for volcanic plumes and more precise observations of plume height are required to obtain tightly constrained estimates of the source mass flux. PMID- 26500388 TI - A Bayesian Nonparametric Approach for the Analysis of Multiple Categorical Item Responses. AB - We develop a modeling framework for joint factor and cluster analysis of datasets where multiple categorical response items are collected on a heterogeneous population of individuals. We introduce a latent factor multinomial probit model and employ prior constructions that allow inference on the number of factors as well as clustering of the subjects into homogenous groups according to their relevant factors. Clustering, in particular, allows us to borrow strength across subjects, therefore helping in the estimation of the model parameters, particularly when the number of observations is small. We employ Markov chain Monte Carlo techniques and obtain tractable posterior inference for our objectives, including sampling of missing data. We demonstrate the effectiveness of our method on simulated data. We also analyze two real-world educational datasets and show that our method outperforms state-of-the-art methods. In the analysis of the real-world data, we uncover hidden relationships between the questions and the underlying educational concepts, while simultaneously partitioning the students into groups of similar educational mastery. PMID- 26500387 TI - A Cough Aerosol Simulator for the Study of Disease Transmission by Human Cough Generated Aerosols. AB - Aerosol particles expelled during human coughs are a potential pathway for infectious disease transmission. However, the importance of airborne transmission is unclear for many diseases. To better understand the role of cough aerosol particles in the spread of disease and the efficacy of different types of protective measures, we constructed a cough aerosol simulator that produces a humanlike cough in a controlled environment. The simulated cough has a 4.2 l volume and is based on coughs recorded from influenza patients. In one configuration, the simulator produces a cough aerosol containing particles from 0.1 to 100 um in diameter with a volume median diameter (VMD) of 8.5 um and a geometric standard deviation (GSD) of 2.9. In a second configuration, the cough aerosol has a size range of 0.1-30 um, a VMD of 3.4 um, and a GSD of 2.3. The total aerosol volume expelled during each cough is 68 ul. By generating a controlled and reproducible artificial cough, the simulator allows us to test different ventilation, disinfection, and personal protection scenarios. The system can be used with live pathogens, including influenza virus, which allows isolation precautions used in the healthcare field to be tested without risk of exposure for workers or patients. The information gained from tests with the simulator will help to better understand the transmission of infectious diseases, develop improved techniques for infection control, and improve safety for healthcare workers and patients. PMID- 26500389 TI - College Students' Perceptions of Depressed Mood: Exploring Accuracy and Associations. AB - College is a time of high risk for depressed mood. Theories about depression (i.e. Cognitive Theory and Depressive Realism theory) are well researched, but suggest different venues of understanding the cognitive underpinnings of mood. In addition, much research is available about normative perceptions around substance use and how those perceptions relate to behaviors. However, there are no studies examining normative perceptions around depressed mood nor how these perceptions may relate to students' own well-being. Undergraduates (N=1577) ages 18-24 responded to an online survey as part of a larger study on drinking and depressed mood. The survey assessed symptoms of depression and feelings of sadness, depression and suicidal ideation experienced in the past 2 weeks, as well as students' perceptions of the prevalence of these feelings among other students. Rates of sadness and depression reported in the sample were relatively high; whereas rates of reported suicidal ideation were low. Most students under estimated the prevalence of sadness and depression experienced by other students; a finding that was especially true for male students. Conversely, most students over-estimated the prevalence of suicidal ideation. Students who reported experiencing a given feeling in the past two weeks perceived greater rates of the feeling among other students. Depression symptoms were associated with both greater perceived prevalence of sadness, depression and suicidal ideation, as well as correct and over-estimates of the prevalence of sadness and depression. Implications for future directions in prevention and interventions efforts are discussed. PMID- 26500390 TI - THE EFFECTS OF PAST SEXUAL ASSAULT PERPETRATION AND ALCOHOL CONSUMPTION ON MEN'S REACTIONS TO WOMEN'S MIXED SIGNALS. AB - Theories about misperception of sexual intent, cognitive distortions among rapists, and alcohol's effects on cognition describe processes that may contribute to acquaintance sexual assault. Drawing on these literatures, an experiment was conducted to examine hypotheses about the effects of past sexual assault perpetration and alcohol consumption on 153 college men's reactions to a female confederate. As compared to nonperpetrators, self-acknowledged rapists and verbal coercers reported being more sexually attracted to the confederate. Trained coders were least certain that rapists noticed specific positive and negative cues that the confederate used and most certain that verbal coercers did. Intoxicated participants perceived themselves and their partner as acting more sexually than did sober or placebo participants. Suggestions are discussed for research and treatment programs with college sexual assault perpetrators. PMID- 26500391 TI - Is long-term structural priming affected by patterns of experience with individual verbs? AB - Several recent papers have reported long-term structural priming effects in experiments where previous patterns of experience with the double object and prepositional object constructions are shown to affect later patterns of language production for those constructions. The experiments reported in this paper address the extent to which these long-term priming effects are modulated by the participants' patterns of experience with particular verbs within the double object and prepositional object constructions. The results of three experiments show that patterns of experience with particular verbs using the double object or prepositional object constructions do not have much effect on the shape of the longterm structural priming effects reported elsewhere in the literature. These findings lend support to the claim that structural priming is the result of adaptations to the language production system that occur on an abstract, structural level of representation that is separate from representations regarding the behavior of particular lexical items in particular constructions [e.g., Chang, F., Dell, G. S., & Bock, K. (2006). Becoming syntactic. Psychological Review, 113, 234-272]. 2007 Elsevier Inc. All rights reserved. PMID- 26500392 TI - MS2 Coliphage as a Surrogate for 2009 Pandemic Influenza A (H1N1) Virus (pH1N1) in Surface Survival Studies on N95 Filtering Facepiece Respirators. AB - Research on influenza viruses regarding transmission and survival has surged in the recent years due to infectious emerging strains and outbreaks such as the 2009 Influenza A (H1N1) pandemic. MS2 coliphage has been applied as a surrogate for pathogenic respiratory viruses, such as influenza, as it's safe for personnel to handle and requires less time and labor to measure virus infectivity. However, direct comparisons to determine the effectiveness of coliphage as a surrogate for influenza virus regarding droplet persistence on personal protective equipment such as N95 filtering facepiece respirators (FFRs) are lacking. Persistence of viral droplets deposited on FFRs in healthcare settings is important to discern due to the potential risk of infection via indirect fomite transmission. The objective of this study was to determine if MS2 coliphage could be applied as a surrogate for influenza A viruses for studying persistence when applied to the FFRs as a droplet. The persistence of MS2 coliphage and 2009 Pandemic Influenza A (H1N1) Virus on FFR coupons in different matrices (viral media, 2% fetal bovine serum, and 5 mg ml-1 mucin) were compared over time (4, 12, 24, 48, 72, and 144 hours) in typical absolute humidity conditions (4.1 * 105 mPa [18 degrees C/20% relative humidity (RH)]). Data revealed significant differences in viral infectivity over the 6-day period (H1N1- P <0.0001; MS2 - P <0.005), although a significant correlation of viral log10 reduction in 2% FBS (P <0.01) was illustrated. Overall, MS2 coliphage was not determined to be a sufficient surrogate for influenza A virus with respect to droplet persistence when applied to the N95 FFR as a droplet. PMID- 26500393 TI - Am I looking at a cat or a dog? Gaze in the semantic variant of primary progressive aphasia is subject to excessive taxonomic capture. AB - Object naming impairments or anomias are the most frequent symptom in aphasia, and can be caused by a variety of underlying neurocognitive mechanisms. Anomia in neurodegenerative or primary progressive aphasias (PPA) often appears to be based on taxonomic blurring of word meaning: words such as "dog" and "cat" are still recognized generically as referring to animals, but are no longer conceptually differentiated from each other, leading to coordinate errors in word-object matching. This blurring is the hallmark symptom of the "semantic variant" of PPA, who invariably show focal atrophy in the left anterior temporal lobe. In this study we used eye tracking to characterize information processing online (in real time) as non-aphasic controls, semantic and non-semantic PPA participants completed a word-to-object matching task. All participants (including controls) showed taxonomic capture of gaze, spending more time viewing foils that were from the same category as the target compared to unrelated foils, but capture was more extreme in the semantic PPA group. The semantic group showed heightened capture even on trials where they ultimately pointed to the correct target, demonstrating the superiority of eye movements over traditional testing methods in detecting subtle processing impairments. Heightened capture was primarily driven by a tendency to direct gaze back and forth, repeatedly, between a set of related foils on each trial, a behavior almost never shown by controls or non-semantic participants. This suggests semantic PPA participants were accumulating and weighing evidence for a probabilistic rather than definitive mapping between the noun and several candidate objects. Neurodegeneration in PPA thus appears to distort lexical concepts prior to extinguishing them altogether, causing uncertainty in recognition and word-object matching. PMID- 26500394 TI - A ratiometric two-photon fluorescent probe for hydrazine and its applications. AB - A ratiometric two-photon fluorescent probe TNQ was developed based on quinoline platform to detect hydrazine (N2H4) with high selectivity. TNQ exhibited large two-photon absorption cross sections at 710 nm (250 GM) and excellent ratiometric two-photon fluorescent detection signal for hydrazine. TNQ was also successfully applied to selectively detect hydrazine vapor even at a concentration down to 0.05%. Cell cytotoxicity and bio-imaging studies revealed that probe TNQ was cell permeable and could be used to detect hydrazine in living cells with low cytotoxicity under two-photon excitation. PMID- 26500395 TI - Evidence that rodent control strategies ought to be improved to enhance food security and reduce the risk of rodent-borne illnesses within subsistence farming villages in the plague-endemic West Nile region, Uganda. AB - Rodents pose serious threats to human health and economics, particularly in developing countries where the animals play a dual role as pests: they are reservoirs of human pathogens, and they inflict damage levels to stored products sufficient to cause food shortages. To assess the magnitude of the damage caused by rodents to crops, their level of contact with humans, and to better understand current food storage and rodent control practices, we conducted a survey of 37 households from 17 subsistence farming villages within the West Nile region of Uganda. Our survey revealed that rodents cause both pre- and post-harvest damage to crops. Evidence of rodent access to stored foods was reported in conjunction with each of the reported storage practices. Approximately half of the respondents reported that at least one family member had been bitten by a rat within the previous three months. Approximately two-thirds of respondents practiced some form of rodent control in their homes. The abundance of rodents was similar within homes that practiced or did not practice rodent control. Together, our results show that current efforts are inadequate for effectively reducing rodent abundance in homes. PMID- 26500396 TI - Demand and supply of medical physicists: Issues of quantity, quality, and competency in India. PMID- 26500397 TI - Performance characteristics of mobile MOSFET dosimeter for kilovoltage X-rays used in image guided radiotherapy. AB - The main objective of this study was to investigate the characteristics of metal oxide semiconductor field effect transistor (MOSFET) dosimeter for kilovoltage (kV) X-ray beams in order to perform the in vivo dosimetry during image guidance in radiotherapy. The performance characteristics of high sensitivity MOSFET dosimeters were investigated for 80, 90, 100, 110, 120, and 125 kV X-ray beams used for imaging in radiotherapy. This study was performed using Clinac 2100 C/D medical electron linear accelerator with on-board imaging and kV cone beam computed tomography system. The characteristics studied in this work include energy dependence, angular dependence, and linearity. The X-ray beam outputs were measured as per American Association of Physicists in Medicine (AAPM) TG 61 recommendations using PTW parallel plate (PP) ionization chamber, which was calibrated in terms of air kerma (Nk) by the National Standard Laboratory. The MOSFET dosimeters were calibrated against the PP ionization chamber for all the kV X-ray beams and the calibration coefficient was found to be 0.11 cGy/mV with a standard deviation of about +/-1%. The response of MOSFET was found to be energy independent for the kV X-ray energies used in this study. The response of the MOSFET dosimeter was also found independent of angle of incidence for the gantry angles in the range of 0 degrees to 360 degrees in-air as well as at 3 cm depth in tissue equivalent phantom. PMID- 26500398 TI - Determination of dosimetric leaf gap using amorphous silicon electronic portal imaging device and its influence on intensity modulated radiotherapy dose delivery. AB - As complex treatment techniques such as intensity modulated radiotherapy (IMRT) entail the modeling of rounded leaf-end transmission in the treatment planning system, it is important to accurately determine the dosimetric leaf gap (DLG) value for a precise calculation of dose. The advancements in the application of the electronic portal imaging device (EPID) in quality assurance (QA) and dosimetry have facilitated the determination of DLG in this study. The DLG measurements were performed using both the ionization chamber (DLGion) and EPID (DLGEPID) for sweeping gap fields of different widths. The DLGion values were found to be 1.133 mm and 1.120 mm for perpendicular and parallel orientations of the 0.125 cm(3) ionization chamber, while the corresponding DLGEPID values were 0.843 mm and 0.819 mm, respectively. It was found that the DLG was independent of volume and orientation of the ionization chamber, depth, source to surface distance (SSD), and the rate of dose delivery. Since the patient-specific QA tests showed comparable results between the IMRT plans based on the DLGEPID and DLGion, it is concluded that the EPID can be a suitable alternative in the determination of DLG. PMID- 26500399 TI - Simulation of the 6 MV Elekta Synergy Platform linac photon beam using Geant4 Application for Tomographic Emission. AB - The present work validates the Geant4 Application for Tomographic Emission Monte Carlo software for the simulation of a 6 MV photon beam given by Elekta Synergy Platform medical linear accelerator treatment head. The simulation includes the major components of the linear accelerator (LINAC) with multi-leaf collimator and a homogeneous water phantom. Calculations were performed for the photon beam with several treatment field sizes ranging from 5 cm * 5 cm to 30 cm * 30 cm at 100 cm distance from the source. The simulation was successfully validated by comparison with experimental distributions. Good agreement between simulations and measurements was observed, with dose differences of about 0.02% and 2.5% for depth doses and lateral dose profiles, respectively. This agreement was also emphasized by the Kolmogorov-Smirnov goodness-of-fit test and by the gamma-index comparisons where more than 99% of the points for all simulations fulfill the quality assurance criteria of 2 mm/2%. PMID- 26500400 TI - A phantom study on the behavior of Acuros XB algorithm in flattening filter free photon beams. AB - To study the behavior of Acuros XB algorithm for flattening filter free (FFF) photon beams in comparison with the anisotropic analytical algorithm (AAA) when applied to homogeneous and heterogeneous phantoms in conventional and RapidArc techniques. Acuros XB (Eclipse version 10.0, Varian Medical Systems, CA, USA) and AAA algorithms were used to calculate dose distributions for both 6X FFF and 10X FFF energies. RapidArc plans were created on Catphan phantom 504 and conventional plans on virtual homogeneous water phantom 30 * 30 * 30 cm(3), virtual heterogeneous phantom with various inserts and on solid water phantom with air cavity. Dose at various inserts with different densities were measured in both AAA and Acuros algorithms. The maximum % variation in dose was observed in (-944 HU) air insert and minimum in (85 HU) acrylic insert in both 6X FFF and 10X FFF photons. Less than 1% variation observed between -149 HU and 282 HU for both energies. At -40 HU and 765 HU Acuros behaved quite contrarily with 10X FFF. Maximum % variation in dose was observed in less HU values and minimum variation in higher HU values for both FFF energies. Global maximum dose observed at higher depths for Acuros for both energies compared with AAA. Increase in dose was observed with Acuros algorithm in almost all densities and decrease at few densities ranging from 282 to 643 HU values. Field size, depth, beam energy, and material density influenced the dose difference between two algorithms. PMID- 26500401 TI - Monte Carlo dose calculation in dental amalgam phantom. AB - It has become a great challenge in the modern radiation treatment to ensure the accuracy of treatment delivery in electron beam therapy. Tissue inhomogeneity has become one of the factors for accurate dose calculation, and this requires complex algorithm calculation like Monte Carlo (MC). On the other hand, computed tomography (CT) images used in treatment planning system need to be trustful as they are the input in radiotherapy treatment. However, with the presence of metal amalgam in treatment volume, the CT images input showed prominent streak artefact, thus, contributed sources of error. Hence, metal amalgam phantom often creates streak artifacts, which cause an error in the dose calculation. Thus, a streak artifact reduction technique was applied to correct the images, and as a result, better images were observed in terms of structure delineation and density assigning. Furthermore, the amalgam density data were corrected to provide amalgam voxel with accurate density value. As for the errors of dose uncertainties due to metal amalgam, they were reduced from 46% to as low as 2% at d80 (depth of the 80% dose beyond Zmax) using the presented strategies. Considering the number of vital and radiosensitive organs in the head and the neck regions, this correction strategy is suggested in reducing calculation uncertainties through MC calculation. PMID- 26500402 TI - Production, biodistribution, and dosimetry of (47)Sc-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid as a bone-seeking radiopharmaceutical. AB - In this study 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) was used as the polyaminophosphonic acid carrier ligand and the therapeutic potential of the bone seeking radiopharmaceutical (47)Sc-DOTMP was assessed by measuring its dosage-dependent skeletal uptake and then the absorbed radiation dose of human organs was estimated. Because of limited availability of (47)Sc we performed some preliminary studies using (46)Sc. (46)Sc was produced with a specific activity of 116.58 MBq/mg (3.15 mCi/mg) and radionuclide purity of 98%. (46)Sc-DOTMP was prepared and an activity of 1.258 MBq (34 MUCi) at a chelant-to-metal ratio of 60:1 was administered to five groups of mice with each group containing 3 mice that were euthanized at 4, 24, 48, 96 and 192 h post administration. The heart, lungs, liver, spleen, kidneys, intestine, skin, muscle, and a femur were excised, weighed, and counted. The data were analyzed to determine skeletal uptake and source organ residence times and cumulated activities for (47)Sc-DOTMP. (46)Sc-DOTMP complex was prepared in radiochemical purity about 93%. In vitro stability of complex was evaluated at room temperature for 48 h. Biodistribution studies of complex in mice were studied for 7 days. The data were analyzed to estimate skeletal uptake and absorbed radiation dose of human organs using biodistribution data from mice. By considering the results, (47)Sc-DOTMP is a possible therapeutic agent for using in palliation of bone pain due to metastatic skeletal lesions from several types of primary cancers in prostate, breast, etc. PMID- 26500403 TI - Radiobiological evaluation of intensity modulated radiation therapy treatments of patients with head and neck cancer: A dual-institutional study. AB - In clinical practice, evaluation of clinical efficacy of treatment planning stems from the radiation oncologist's experience in accurately targeting tumors, while keeping minimal toxicity to various organs at risk (OAR) involved. A more objective, quantitative method may be raised by using radiobiological models. The purpose of this work is to evaluate the potential correlation of OAR-related toxicities to its radiobiologically estimated parameters in simultaneously integrated boost (SIB) intensity modulated radiation therapy (IMRT) plans of patients with head and neck tumors at two institutions. Lyman model for normal tissue complication probability (NTCP) and the Poisson model for tumor control probability (TCP) models were used in the Histogram Analysis in Radiation Therapy (HART) analysis. In this study, 33 patients with oropharyngeal primaries in the head and neck region were used to establish the correlation between NTCP values of (a) bilateral parotids with clinically observed rates of xerostomia, (b) esophagus with dysphagia, and (c) larynx with dysphagia. The results of the study indicated a strong correlation between the severity of xerostomia and dysphagia with Lyman NTCP of bilateral parotids and esophagus, respectively, but not with the larynx. In patients without complications, NTCP values of these organs were negligible. Using appropriate radiobiological models, the presence of a moderate to strong correlation between the severities of complications with NTCP of selected OARs suggested that the clinical outcome could be estimated prior to treatment. PMID- 26500404 TI - Cost-effective pediatric head and body phantoms for computed tomography dosimetry and its evaluation using pencil ion chamber and CT dose profiler. AB - In the present work, a pediatric head and body phantom was fabricated using polymethyl methacrylate (PMMA) at a low cost when compared to commercially available phantoms for the purpose of computed tomography (CT) dosimetry. The dimensions of head and body phantoms were 10 cm diameter, 15 cm length and 16 cm diameter, 15 cm length, respectively. The dose from a 128-slice CT machine received by the head and body phantom at the center and periphery were measured using a 100 mm pencil ion chamber and 150 mm CT dose profiler (CTDP). Using these values, the weighted computed tomography dose index (CTDIw) and in turn the volumetric CTDI (CTDIv) were calculated for various combinations of tube voltage and current-time product. A similar study was carried out using standard calibrated phantom and the results have been compared with the fabricated ones to ascertain that the performance of the latter is equivalent to that of the former. Finally, CTDIv measured using fabricated and standard phantoms were compared with respective values displayed on the console. The difference between the values was well within the limits specified by Atomic Energy Regulatory Board (AERB), India. These results indicate that the cost-effective pediatric phantom can be employed for CT dosimetry. PMID- 26500406 TI - Need for travel health services in India. PMID- 26500405 TI - Three-dimensional polymer gel dosimetry using an onboard 0.35 T magnetic resonance imaging scanner: A simulation study. PMID- 26500407 TI - Social determinants of health and oral health: An Indian perspective. AB - Several conventional approaches have been tried in the past to resolve health inequities in India. However, achieving Universal Health Coverage (UHC) is yet to be fully realized as the benefits have been meager. The recent concept of targeting social determinants of general and oral health in order to achieve health for all has shown positive results in the developed as well as the developing nations. Based on the framework recommended by the Commission on Social Determinants of Health, several policies have been introduced and suitably backed up with the intention of providing health care even to people living in remote sections of the society. This paper intends to highlight the rationale for social determinants approach in Indian context, its application and future recommendations for the same. It is considered as a radical approach, and adequate measures have been implemented by health systems to achieve the desired targets without delay. However, in order to achieve UHC, redistribution of the available resources and converting the "normative" needs into "felt" needs of the people is going to be an uphill task to accomplish. PMID- 26500408 TI - Metabolic syndrome in different sub occupations among mine workers. AB - INTRODUCTION: Metabolic syndrome (MS) is a condition described by the group of risk factors associated with obesity that raise the risk of cardiovascular disease and type 2 diabetes. MS has an increasing trend in developing countries with change of diet and lifestyle. Many studies in India have reported high prevalence of MS among general population however there is little information available about the same in working population. MATERIAL AND METHODS: The present study was conducted among 281 mine employees from an organized mining company from Southern India. The workers were classified into different sub occupational groups according to ISCO-88. WHO Criteria was used for the diagnosis of MS. RESULTS: The overall prevalence of MS in mine employees was about 17%. Among different sub occupations, the highest was observed in professional group of 52.9% and lowest in elementary occupations of 9.4%. In other sub occupational groups it was 23.3% in clerical, 18.9% in trade workers, 17.5% in technicians and 15.5% in machine operators. Occurrence of MS when compared in different sub occupations was statistically significant (P = <0.001). Further MS was found to be 6.4% in the 18-30 years of age group which significantly increased to 40.3% in the 51-60 years age group suggesting direct relation of MS with increase in age. DISCUSSION: Mining being physical demanding occupation prevalence of MS is assumed to be lower than the general population; however it was observed that the prevalence is in similar line to that of general population with the prevalence ranging from 9.4% to 52.9% among different sub occupations. Hence it is concluded that there is need of health education and promotion among the mine workers. PMID- 26500409 TI - Occupation-related psychological distress among police constables of Udupi taluk, Karnataka: A cross-sectional study. AB - BACKGROUND: Police occupational stress is an extensive issue due to number of negative consequences on an individual as well as the police department which is often neglected. This study is the first of its kind in Udupi district. AIM: The present study intended to find out the prevalence of psychological distress among police constable, assess stressors, and the factors influencing it. SETTINGS AND DESIGN: A cross-sectional study was conducted among police constables in police stations of Udupi taluk. SUBJECTS AND METHODS: A total of 76 constables participated in the study, who were taken up from seven randomly selected police stations. General health questionnaire and organizational and operational police stress questionnaire were used to assess psychological distress and stressors, respectively. STATISTICAL ANALYSIS USED: Data were analyzed using SPSS version 15. Results were tabulated using frequency distribution and proportions for dichotomous variables and mean with a standard deviation for continuous variables. Chi-square test was performed to find the association between psychological distress and other variables. RESULTS: One-fourth (95% confidence interval: 0.153, 0.347) of the participants reported as having high levels of psychological distress. Years of service and 28 stressful activities were significantly associated with psychological distress. CONCLUSION: Psychological distress among the police constables is of concern; hence some modifications such as sharing work, fixed duty hours, etc., should be done in the police department in order to avoid stress and its adverse effects. Stress management training can be given at regular intervals to improve competitiveness and enhance coping skills. PMID- 26500410 TI - Empirical estimation of the grades of hearing impairment among industrial workers based on new artificial neural networks and classical regression methods. AB - BACKGROUND: Prediction models are used in a variety of medical domains, and they are frequently built from experience which constitutes data acquired from actual cases. This study aimed to analyze the potential of artificial neural networks and logistic regression techniques for estimation of hearing impairment among industrial workers. MATERIALS AND METHODS: A total of 210 workers employed in a steel factory (in West of Iran) were selected, and their occupational exposure histories were analyzed. The hearing loss thresholds of the studied workers were determined using a calibrated audiometer. The personal noise exposures were also measured using a noise dosimeter in the workstations. Data obtained from five variables, which can influence the hearing loss, were used as input features, and the hearing loss thresholds were considered as target feature of the prediction methods. Multilayer feedforward neural networks and logistic regression were developed using MATLAB R2011a software. RESULTS: Based on the World Health Organization classification for the grades of hearing loss, 74.2% of the studied workers have normal hearing thresholds, 23.4% have slight hearing loss, and 2.4% have moderate hearing loss. The accuracy and kappa coefficient of the best developed neural networks for prediction of the grades of hearing loss were 88.6 and 66.30, respectively. The accuracy and kappa coefficient of the logistic regression were also 84.28 and 51.30, respectively. CONCLUSION: Neural networks could provide more accurate predictions of the hearing loss than logistic regression. The prediction method can provide reliable and comprehensible information for occupational health and medicine experts. PMID- 26500411 TI - Situational analysis of industrial hygienists in India. AB - BACKGROUND: Industrial growth in India has resulted in increased employment opportunities thereby inflating the size of the workforce engaged in both organized and unorganized sectors. This workforce is exposed to various occupational factors at workplace and hence is susceptible to occupational diseases, the control of which requires trained occupational health manpower. METHODS: The present study was undertaken to map the institutions offering courses to develop industrial hygienist in India, estimate the requirement of such occupational health manpower and to design competencies and curriculum for such a course. RESULTS: Though there are no norms for the industrial hygienist in the Indian Factories Act, on assumption on the basis of norms provided for Safety Officer, it is estimated that for 26.92 million workforce engaged in organized sector, a total of 5407 Industrial hygienists will be required. Thus there is an estimated deficit of 51% for Industrial hygienist based on current ratio of employment. However on supply side there are only three institutes offering specialized courses on industrial hygiene out of which only one is full time residential course while rest two are offered through distance learning mode. CONCLUSIONS: Therefore, there is a vital need for the development of industrial hygienist not only in quantity but also in quality so that the workers in industries and communities lead socially and environmentally productive lives. PMID- 26500412 TI - Chronic pesticide exposure: Health effects among pesticide sprayers in Southern India. AB - BACKGROUND: Occupational health has never been a priority for policy makers in India, despite 63% of the Indian population being in the economically productive age group. OBJECTIVES: The study was designed to find out the morbidity as a result of long-term exposure to pesticides among professional pesticide sprayers in a rural block in Tamil Nadu. SUBJECTS AND METHODS: A cross-sectional study was done in Kaniyambadi block of Vellore district, Tamil Nadu, during July to October 2013. A total of 70 professional pesticide sprayers and 66 people engaged in other occupations were enrolled into the study. The participants were administered a standardized questionnaire apart from measuring pulmonary function and peripheral sensations. Venous blood samples were collected for measuring serum cholinesterase. RESULTS: The pesticide sprayers had higher prevalence of breathlessness on activities of daily living (odds ratio [OR]: 3.14, 95% confidence interval [CI]: 1.22-8.07), chronic cough/phlegm (OR: 3.53, 95% CI: 1.09-11.46), symptoms of peripheral sensory neuropathy (OR: 6.66, 95% CI: 2.53 17.51) and recurrent abdominal pain (OR: 3.05, 95% CI: 1.03-9.01), when compared to people engaged in other occupations. Pesticide sprayers also had significantly lower mean peak expiratory low rates and poor peripheral sensations. The serum cholinesterase levels were not statistically different between the groups. CONCLUSION: The pesticide sprayers had a higher morbidity when compared to people engaged in other occupations, and further research is needed to find out methods to prevent the same. Serum cholinesterase may not be a good marker for quantifying exposure to pesticide among sprayers, during a spraying season. PMID- 26500413 TI - Neopterin: A candidate biomarker for the early assessment of toxicity of aluminum among bauxite dust exposed mine workers. AB - INTRODUCTION: Bauxite ore is a major source of aluminum (Al) which contains approximately 35-60% Al by weight. Occupational and environmental bauxite dust exposure may cause toxicity by interaction with human biological systems resulting in oxidative stress (OS) and cell death. A neopterin derivative as an antioxidant is able to modulate cytotoxicity by the induction of OS. MATERIALS AND METHODS: A total of 273 subjects were selected for blood collection from three different major Al producing bauxite mines and were categorized into three groups as experimental (Exp) (n = 150), experimental controls (ExC) (n = 73) and control (Con) (n = 50). Whole blood and serum samples were used for measurement of Al, neopterin, urea and creatinine values. Statistical analysis was performed using R-2.15.1 programming language. RESULTS AND DISCUSSION: The result showed that age, body mass index and the behavioral habits, that is, smoking, tobacco and alcohol consumption have possible effects on neopterin level. Serum neopterin levels were found to be significantly higher (P <0.0001) in the experimental group as compared to other groups. Significantly positive correlation (P < 0.0001) was observed between neopterin and creatinine. It was also observed that neopterin level increases as the duration of exposure increases. CONCLUSION: On the basis of findings it was concluded that exposure to bauxite dust (even at low levels of Al) changes biochemical profile leading to high levels of serum neopterin. Levels of serum neopterin in workers exposed to bauxite dust were probably examined for the 1(st) time in India. The outcome of this study suggested that serum neopterin may be used as potential biomarker for early detection of health risks associated with bauxite dust exposed population. PMID- 26500414 TI - Evaluation of occupational exposure of carpet weavers in northern province of Madhya Pradesh (India) during different seasons. AB - OBJECTIVES: We investigated general working conditions in the carpet manufacturing industry and assessed the health risk factors of weavers working in this industry. MATERIALS AND METHODS: Noise level, light intensity, temperature and humidity were measured with the help of sound level meter, lux meter and thermohygrometer, respectively at the workplace and the result were subjected to One Way Analysis of Variance. A pretested questionnaire was used to evaluate the health problems among different weavers working in the carpet industry. RESULTS: Results indicated that the weavers in these units were exposed to extreme environmental conditions. The majority of these weavers were suffering from eye irritation, back pain, allergies, general weakness, hearing loss, with most workers having three to five of these health problems. Our study reported higher incidence of musculoskeletal and respiratory diseases among weavers, during different season. CONCLUSION: A large variation during different seasons is an indication that environmental conditions play an important role in determining the health of weavers at the workplace. Results clearly demonstrate that working conditions were not suitable for the type of work carried out by the weavers. PMID- 26500415 TI - Ascertaining the standard of journal using quality indices. AB - In the modern era, most of the researchers want to share their work on a global platform so that they not only receive the due recognition but even their findings can be utilized by other professionals working in the same arena. In order to achieve this, the most common approach is to publish the research findings in an appropriate journal. However, the indicators which eventually determine the overall quality of a journal are variable and there is a great need that the contributors should understand the meaning and scope of each of these indicators. In conclusion, in order to establish the journal's quality, the researchers should obtain the information about the various indices from the journals' website or editorial board and then only submit their research work for publishing. PMID- 26500416 TI - Successful treatment of frostbite with hyperbaric oxygen treatment. PMID- 26500417 TI - Identification and Classification of Rhizobia by Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry. AB - Mass spectrometry (MS) has been widely used for specific, sensitive and rapid analysis of proteins and has shown a high potential for bacterial identification and characterization. Type strains of four species of rhizobia and Escherichia coli DH5alpha were employed as reference bacteria to optimize various parameters for identification and classification of species of rhizobia by matrix-assisted laser desorption/ionization time-of-flight MS (MALDI TOF MS). The parameters optimized included culture medium states (liquid or solid), bacterial growth phases, colony storage temperature and duration, and protein data processing to enhance the bacterial identification resolution, accuracy and reliability. The medium state had little effects on the mass spectra of protein profiles. A suitable sampling time was between the exponential phase and the stationary phase. Consistent protein mass spectral profiles were observed for E. coli colonies pre-grown for 14 days and rhizobia for 21 days at 4 degrees C or 21 degrees C. A dendrogram of 75 rhizobial strains of 4 genera was constructed based on MALDI TOF mass spectra and the topological patterns agreed well with those in the 16S rDNA phylogenetic tree. The potential of developing a mass spectral database for all rhizobia species was assessed with blind samples. The entire process from sample preparation to accurate identification and classification of species required approximately one hour. PMID- 26500418 TI - Insight into the Protein Composition of Immunoglobulin Light Chain Deposits of Eyelid, Orbital and Conjunctival Amyloidosis. AB - Amyloidosis is a disease characterized by the formation of extracellular amyloid deposits. Immunoglobulin light-chain amyloidosis can appear as a local disorder presenting with mild symptoms or as a life threatening systemic disease. The systemic form of immunoglobulin light-chain amyloidosis is the most common type of amyloidosis in western countries although it is a rare disease. Identification of the proteins forming amyloid fibrils is essential for the diagnosis of the disease and knowledge about the overall protein composition of the deposits may lead to a larger understanding of the deposition events thereby facilitating a more detailed picture of the molecular pathology. In this pilot study, we investigated the protein composition of amyloid deposits isolated from human specimens of the eyelid, conjunctiva, and orbit. Deposits and internal control tissue (patient tissue without apparent deposits) were procured by laser capture microdissection. Proteins in the captured amyloid and control samples were quantified by liquid chromatography tandem mass spectrometry using the label-free exponential modified Protein Abundance Index (emPAI) method. Immunoglobulin light chain kappa or lambda was found to be the most predominant protein in the amyloid deposits from the eyelid, conjunctiva, and orbit. Five proteins, apolipoprotein A I, carboxypeptidase B2 (TAFI), complement component C9, fibulin-1 and plasminogen were found solely across all amyloid but not in the control tissue. In addition, the protein profiles identified apolipoprotein E and serum amyloid P component to be associated with the immunoglobulin light chain deposits across all three tissues analyzed. The method used in this study provided high sensitivity and specificity for the type of amyloid and may provide additional information on the pathology of the amyloid deposits in the ocular tissues studied. PMID- 26500419 TI - Prenatal Iron Deficiency and Auditory Brainstem Responses at 3 and 10 Months: A Pilot Study. AB - PURPOSE: To examine whether prenatal iron deficiency delays auditory brainstem response (ABR) maturation in infancy. METHODS: One hundred and fifteen full-term healthy Chinese infants with maternal and cord blood haemoglobin and serum ferritin determinations were recruited into this study. Forty-eight infants received ABR testing at 3 months, and 45 infants were tested at 10 months. Comparison of the ABR variables were made between infants with and those without evidence of prenatal iron deficiency (maternal 3rd trimester haemoglobin <110 g/L, cord blood ferritin <75 MUg/L); or anaemia at 10 months (haemoglobin <110 g/L). RESULTS: Latencies for wave V and wave III-V and I-V intervals were prolonged at 3 months in infants of anaemic mothers (effect sizes 1.02-1.19 SD). At 10 months, infants with low cord blood serum ferritin (indicating low iron stores at birth) showed longer wave I latency and possibly wave V latency also, besides demonstrating a smaller wave V amplitude (effect sizes 0.58-0.62 SD). Infants with low ferritin at birth and anemia at 10 months had longer wave III-V latency than other groups. CONCLUSION: In full-term healthy infants, prenatal iron deficiency appears to have adverse effects on the developing central nervous system and auditory system as assessed by ABRs at 3 and/or 10 months. PMID- 26500420 TI - Comprehension Tools for Teachers: Reading for Understanding from Prekindergarten through Fourth Grade. AB - This paper describes the theoretical framework, as well as the development and testing of the intervention, Comprehension Tools for Teachers (CTT), which is composed of eight component interventions targeting malleable language and reading comprehension skills that emerging research indicates contribute to proficient reading for understanding for prekindergarteners through fourth graders. Component interventions target processes considered largely automatic as well as more reflective processes, with interacting and reciprocal effects. Specifically, we present component interventions targeting cognitive, linguistic, and text-specific processes, including morphological awareness, syntax, mental state verbs, comprehension monitoring, narrative and expository text structure, enacted comprehension, academic knowledge, and reading to learn from informational text. Our aim was to develop a tool set composed of intensive meaningful individualized small group interventions. We improved feasibility in regular classrooms through the use of design-based iterative research methods including careful lesson planning, targeted scripting, pre- and postintervention proximal assessments, and technology. In addition to the overall framework, we discuss seven of the component interventions and general results of design and efficacy studies. PMID- 26500421 TI - Preventing Drug Abuse Among Hispanic Adolescents: Developing a Responsive Intervention Approach. AB - Intervention research is essential to help Hispanic American adolescents avoid drug use. This article describes an intervention research program aimed at preventing drug use among these youths. Grounded in salient epidemiological data, the program is informed by bicultural competence, social learning, and motivational interviewing theories. The program, called Vamos, is aimed at the risk and protective factors as well as the cultural prerogatives that demark the adolescent years of Hispanic American youths. Innovative in its approach, the program is delivered through a smartphone application (app). By interacting with engaging content presented via the app, youths can acquire the cognitive behavioral skills necessary to avoid risky situations, urges, and pressures associated with early drug use. The intervention development process is presented in detail, and an evaluation plan to determine the program's efficacy is outlined. Lessons for practice and intervention programming are discussed. PMID- 26500422 TI - Highway Healthcare: How Naturalistic Driving Data Index Adherence to CPAP Therapy in Obstructive Sleep Apnea. AB - Drowsy driving is a major factor in many vehicle crashes around the world. Sleep disorders, such as obstructive sleep apnea (OSA), underpin many of these crashes. Continuous positive airway pressure (CPAP) therapy is an effective treatment for sleep apnea but it requires consistent use and is often rejected by OSA patients. Rejection of CPAP treatment creates a dangerous on-road environment for both OSA sufferers and the general public. Algorithms capable of detecting CPAP use and its effects on driving are integral to identifying and mitigating this danger. This work uses naturalistic kinematic driving data to develop an algorithm which can detect nightly CPAP abstinence and adequate CPAP use. Speed and lateral acceleration data were collected using a data recorder in participant's primary vehicle and CPAP data were collected by downloading adherence data from participant CPAP machines. The speed and acceleration data were reduced to a set of symbols using Symbolic Aggregate approximation (SAX) time-series analysis. The symbols were converted into a sequence frequency dataset using sliding windows of size 1 to 10 s with a 1 Hz sampling rate. A Random Forest classifier was trained on the data to create a classification algorithm. On a held aside testing set, the Random Forest algorithm correctly identified 71% of the instances and had an area under the receiver operating characteristic curve of 0.76. The variable importance of the algorithm suggested that kinematic patterns associated with common drowsy driver crash types were key features in the algorithm's prediction performance. PMID- 26500423 TI - Holistic Processing in the Composite Task Depends on Face Size. AB - Holistic processing is a hallmark of face processing. There is evidence that holistic processing is strongest for faces at identification distance, 2 - 10 meters from the observer. However, this evidence is based on tasks that have been little used in the literature and that are indirect measures of holistic processing. We use the composite task- a well validated and frequently used paradigm - to measure the effect of viewing distance on holistic processing. In line with previous work, we find a congruency x alignment effect that is strongest for faces that are close (2m equivalent distance) than for faces that are further away (24m equivalent distance). In contrast, the alignment effect for same trials, used by several authors to measure holistic processing, produced results that are difficult to interpret. We conclude that our results converge with previous findings providing more direct evidence for an effect of size on holistic processing. PMID- 26500424 TI - Sexual assault and alcohol consumption: what do we know about their relationship and what types of research are still needed? AB - Approximately half of all sexual assaults are associated with either the perpetrator's alcohol consumption, the victim's alcohol consumption, or both. Although the emphasis of this review is on alcohol-involved sexual assaults, their unique aspects can only be evaluated by comparing them to other types of sexual assault. Theoretical perspectives on sexual assault that focus on characteristics of the perpetrator, the victim, and the situation are described. A number of personality traits, attitudes, and past experiences have been systematically linked to sexual assault perpetration, including beliefs about alcohol and heavy drinking. In contrast, only a few experiences have been significantly related to sexual assault victimization, including childhood sexual abuse and heavy drinking. There is support for both psychological and pharmacological mechanisms linking alcohol and sexual assault. Beliefs about alcohol's effects reinforce stereotypes about gender roles and can exacerbate their influence on perpetrators' actions. Alcohol's effects on cognitive and motor skills also contribute to sexual assault through their effects on perpetrators' and victims' ability to process and react to each other's verbal and nonverbal behavior. Limitations with existing research and methodological challenges associated with conducting research on this topic are described. Suggestions are made for future research which can inform prevention and treatment programs. PMID- 26500425 TI - Spirituality and religious coping in African American youth with depressive illness. AB - The research team completed a secondary data analysis of primary data from a 2 phase depression treatment engagement behavioral trial to assess African American adolescents reported experiences of spiritual and religious coping when dealing with depression. The team utilized data collected from twenty-eight youth who participated in focus groups or individual interviews. Qualitative data were analyzed using thematic techniques for transcript-based analysis to identify the key patterns and elements of the study participants' accounts and to extract 6 primary themes. The main themes are reported in this manuscript and include; "Religion as Treatment Incentive", "Prayer & Agency", "Mixed Emotions", "Doesn't Hurt, Might Help", "Finding Support in the Church", and "Prayer and Church: Barriers to Treatment?" Overall, the data suggested that religion and spirituality play a key role in African American adolescents' experiences of depression. As well, it is surmised that these factors may be important for improving treatment seeking behaviors and reducing racial mental health disparities in this population of youth. PMID- 26500426 TI - A joint effort of the Brazilian Evo-Devo community. PMID- 26500427 TI - Evolution of flatworm central nervous systems: Insights from polyclads. AB - The nervous systems of flatworms have diversified extensively as a consequence of the broad range of adaptations in the group. Here we examined the central nervous system (CNS) of 12 species of polyclad flatworms belonging to 11 different families by morphological and histological studies. These comparisons revealed that the overall organization and architecture of polyclad central nervous systems can be classified into three categories (I, II, and III) based on the presence of globuli cell masses -ganglion cells of granular appearance-, the cross-sectional shape of the main nerve cords, and the tissue type surrounding the nerve cords. In addition, four different cell types were identified in polyclad brains based on location and size. We also characterize the serotonergic and FMRFamidergic nervous systems in the cotylean Boninia divae by immunocytochemistry. Although both neurotransmitters were broadly expressed, expression of serotonin was particularly strong in the sucker, whereas FMRFamide was particularly strong in the pharynx. Finally, we test some of the major hypothesized trends during the evolution of the CNS in the phylum by a character state reconstruction based on current understanding of the nervous system across different species of Platyhelminthes and on up-to-date molecular phylogenies. PMID- 26500428 TI - A putative RA-like region in the brain of the scale-backed antbird, Willisornis poecilinotus (Furnariides, Suboscines, Passeriformes, Thamnophilidae). AB - The memorization and production of song in songbirds share important parallels with the process of speech acquisition in humans. In songbirds, these processes are dependent on a group of specialized telencephalic nuclei known as the song system: HVC (used as a proper name), RA (robust nucleus of arcopallium), LMAN (lateral magnocellular nucleus of the nidopallium) and striatal Area X. A recent study suggested that the arcopallium of the Sayornis phoebe, a non vocal learner suboscine species, contains a nucleus with some properties similar to those of songbird RA, suggesting that the song system may have been present in the last common ancestor of these groups. Here we report morphological and gene expression evidence that a region with some properties similar to RA is present in another suboscine, the Amazonian endemic Willisornis poecilinotus. Specifically, a discrete domain with a distinct Nissl staining pattern and that expresses the RA marker RGS4 was found in the arcopallium where the oscine RA is localized. Our findings, combined with the previous report on the S. phoebe, suggest that an arcopallial region with some RA-like properties was present in the ancestor of both Suboscines infraorders Tyranni and Furnarii, and is possibly an ancestral feature of Passeriformes. PMID- 26500429 TI - Molecular evolution of HoxA13 and the multiple origins of limbless morphologies in amphibians and reptiles. AB - Developmental processes and their results, morphological characters, are inherited through transmission of genes regulating development. While there is ample evidence that cis-regulatory elements tend to be modular, with sequence segments dedicated to different roles, the situation for proteins is less clear, being particularly complex for transcription factors with multiple functions. Some motifs mediating protein-protein interactions may be exclusive to particular developmental roles, but it is also possible that motifs are mostly shared among different processes. Here we focus on HoxA13, a protein essential for limb development. We asked whether the HoxA13 amino acid sequence evolved similarly in three limbless clades: Gymnophiona, Amphisbaenia and Serpentes. We explored variation in omega (dN/dS) using a maximum-likelihood framework and HoxA13sequences from 47 species. Comparisons of evolutionary models provided low omega global values and no evidence that HoxA13 experienced relaxed selection in limbless clades. Branch-site models failed to detect evidence for positive selection acting on any site along branches of Amphisbaena and Gymnophiona, while three sites were identified in Serpentes. Examination of alignments did not reveal consistent sequence differences between limbed and limbless species. We conclude that HoxA13 has no modules exclusive to limb development, which may be explained by its involvement in multiple developmental processes. PMID- 26500430 TI - Insights into the dynamics of hind leg development in honey bee (Apis mellifera L.) queen and worker larvae - A morphology/differential gene expression analysis. AB - Phenotypic plasticity is a hallmark of the caste systems of social insects, expressed in their life history and morphological traits. These are best studied in bees. In their co-evolution with angiosperm plants, the females of corbiculate bees have acquired a specialized structure on their hind legs for collecting pollen. In the highly eusocial bees (Apini and Meliponini), this structure is however only present in workers and absent in queens. By means of histological sections and cell proliferation analysis we followed the developmental dynamics of the hind legs of queens and workers in the fourth and fifth larval instars. In parallel, we generated subtractive cDNA libraries for hind leg discs of queen and worker larvae by means of a Representational Difference Analysis (RDA). From the total of 135 unique sequences we selected 19 for RT-qPCR analysis, where six of these were confirmed as differing significantly in their expression between the two castes in the larval spinning stage. The development of complex structures such as the bees' hind legs, requires diverse patterning mechanisms and signaling modules, as indicated by the set of differentially expressed genes related with cell adhesion and signaling pathways. PMID- 26500431 TI - small ORFs: A new class of essential genes for development. AB - Genes that contain small open reading frames (smORFs) constitute a new group of eukaryotic genes and are expected to represent 5% of the Drosophila melanogaster transcribed genes. In this review we provide a historical perspective of their recent discovery, describe their general mechanism and discuss the importance of smORFs for future genomic and transcriptomic studies. Finally, we discuss the biological role of the most studied smORF so far, the Mlpt/Pri/Tal gene in arthropods. The pleiotropic action of Mlpt/Pri/Tal in D. melanogaster suggests a complex evolutionary scenario that can be used to understand the origins, evolution and integration of smORFs into complex gene regulatory networks. PMID- 26500433 TI - Exploring the role of auxin in the androgynophore movement in Passiflora. AB - The flowers of the species belonging to the genus Passiflorashow a range of features that are thought to have arisen as adaptations to different pollinators. Some Passiflora species belonging to the subgenus Decaloba sect. Xerogona, show touch-sensitive motile androgynophores. We tested the role of auxin polar transport in the modulation of the androgynophore movement by applying auxin (IAA) or an inhibitor of auxin polar transport (NPA) in the flowers. We recorded the movement of the androgynophore during mechano-stimulation and analyzed the duration, speed, and the angle formed by the androgynophore before and after the movement, and found that both IAA and NPA increase the amplitude of the movement in P. sanguinolenta. We hypothesize that auxin might have a role in modulating the fitness of these Decaloba species to different pollination syndromes and demonstrate that an interspecific hybrid between insect- and hummingbird pollinated Xerogona species present a heterosis effect on the speed of the androgynophore movement. PMID- 26500434 TI - Occupational exposure of workers to pesticides: Toxicogenetics and susceptibility gene polymorphisms. AB - Farm workers are often exposed to pesticides, which are products belonging to a specific chemical group that affects the health of agricultural workers and is mostly recognized as genotoxic and carcinogenic. The exposure of workers from Piaui, Brazil, to these hazardous chemicals was assessed and cytogenetic alterations were evaluated using the buccal micronucleus assay, hematological and lipid parameters, butyrylcholinesterase (BChE) activity and genetic polymorphisms of enzymes involved in the metabolism of pesticides, such as PON1, as well as of the DNA repair system (OGG1, XRCC1 and XRCC4). Two groups of farm workers exposed to different types of pesticides were evaluated and compared to matched non exposed control groups. A significant increase was observed in the frequencies of micronuclei, kariorrhexis, karyolysis and binucleated cells in the exposed groups (n = 100) compared to controls (n = 100). No differences were detected regarding the hematological parameters, lipid profile and BChE activity. No significant difference was observed either regarding DNA damage or nuclear fragmentation when specific metabolizing and DNA repair genotypes were investigated in the exposed groups. PMID- 26500432 TI - Evo-devo of non-bilaterian animals. AB - The non-bilaterian animals comprise organisms in the phyla Porifera, Cnidaria, Ctenophora and Placozoa. These early-diverging phyla are pivotal to understanding the evolution of bilaterian animals. After the exponential increase in research in evolutionary development (evo-devo) in the last two decades, these organisms are again in the spotlight of evolutionary biology. In this work, I briefly review some aspects of the developmental biology of nonbilaterians that contribute to understanding the evolution of development and of the metazoans. The evolution of the developmental genetic toolkit, embryonic polarization, the origin of gastrulation and mesodermal cells, and the origin of neural cells are discussed. The possibility that germline and stem cell lineages have the same origin is also examined. Although a considerable number of non-bilaterian species are already being investigated, the use of species belonging to different branches of non-bilaterian lineages and functional experimentation with gene manipulation in the majority of the non-bilaterian lineages will be necessary for further progress in this field. PMID- 26500435 TI - Prevalence of beta(S)-globin gene haplotypes, alpha-thalassemia (3.7 kb deletion) and redox status in patients with sickle cell anemia in the state of Parana, Brazil. AB - The aim of this study was to determine the frequency of beta S-globin gene (beta(S) globin) haplotypes and alpha thalassemia with 3.7 kb deletion ( alpha(3.7kb) thalassemia) in the northwest region of Parana state, and to investigate the oxidative and clinical-hematological profile of beta(S) globin carriers in this population. Of the 77 samples analyzed, 17 were Hb SS, 30 were Hb AS and 30 were Hb AA. The beta(S)globin haplotypes and -alpha(3.7kb) thalassemia were identified using polymerase chain reaction.Trolox equivalent antioxidant capacity (TEAC) and lipid peroxidation (LPO) were assessed spectophotometrically. Serum melatonin levels were determined using high performance liquid chromatography coupled to coulometric electrochemical detection. The haplotype frequencies in the SS individuals were as follows: Bantu 21 (62%), Benin - 11 (32%) and Atypical- 2 (6%). Bantu/Benin was the most frequent genotype. Of the 47 SS and AS individuals assessed, 17% (n = 8) had the alpha(3.7kb) mutation. Clinical manifestations, as well as serum melatonin, TEAC and LPO levels did not differ between Bantu/Bantu and Bantu/Benin individuals (p > 0.05). Both genotypes were associated with high LPO and TEAC levels and decreased melatonin concentration. These data suggest that the level of oxidative stress in patients with Bantu/Bantu and Bantu/Benin genotypes may overload the antioxidant capacity. PMID- 26500436 TI - High interpopulation homogeneity in Central Argentina as assessed by Ancestry Informative Markers (AIMs). AB - The population of Argentina has already been studied with regard to several genetic markers, but much more data are needed for the appropriate definition of its genetic profile. This study aimed at investigating the admixture patterns and genetic structure in Central Argentina, using biparental markers and comparing the results with those previously obtained by us with mitochondrial DNA (mtDNA) in the same samples. A total of 521 healthy unrelated individuals living in 13 villages of the Cordoba and San Luis provinces were tested. The individuals were genotyped for ten autosomal ancestry informative markers (AIMs). Allele frequencies were compared with those of African, European and Native American populations, chosen to represent parental contributions. The AIM estimates indicated a greater influence of the Native American ancestry as compared to previous studies in the same or other Argentinean regions, but smaller than that observed with the mtDNA tests. These differences can be explained, respectively, by different genetic contributions between rural and urban areas, and asymmetric gene flow occurred in the past. But a most unexpected finding was the marked interpopulation genetic homogeneity found in villages located in diverse geographic environments across a wide territory, suggesting considerable gene flow. PMID- 26500437 TI - Costs of genetic testing: Supporting Brazilian Public Policies for the incorporating of molecular diagnostic technologies. AB - This study identifies and describes the operating costs associated with the molecular diagnosis of diseases, such as hereditary cancer. To approximate the costs associated with these tests, data informed by Standard Operating Procedures for various techniques was collected from hospital software and a survey of market prices. Costs were established for four scenarios of capacity utilization to represent the possibility of suboptimal use in research laboratories. Cost description was based on a single site. The results show that only one technique was not impacted by rising costs due to underutilized capacity. Several common techniques were considerably more expensive at 30% capacity, including polymerase chain reaction (180%), microsatellite instability analysis (181%), gene rearrangement analysis by multiplex ligation probe amplification (412%), non labeled sequencing (173%), and quantitation of nucleic acids (169%). These findings should be relevant for the definition of public policies and suggest that investment of public funds in the establishment of centralized diagnostic research centers would reduce costs to the Public Health System. PMID- 26500438 TI - Characterization of the complete mitochondrial genome and a set of polymorphic microsatellite markers through next-generation sequencing for the brown brocket deer Mazama gouazoubira. AB - The complete mitochondrial genome of the brown brocket deer Mazama gouazoubira and a set of polymorphic microsatellite markers were identified by 454 pyrosequencing. De novo genome assembly recovered 98% of the mitochondrial genome with a mean coverage of 9-fold. The mitogenome consisted of 16,356 base pairs that included 13 protein-coding genes, two ribosomal subunit genes, 22 transfer RNAs and the control region, as found in other deer. The genetic divergence between the mitogenome described here and a previously published report was ~0.5%, with the control region and ND5 gene showing the highest intraspecific variation. Seven polymorphic loci were characterized using 15 unrelated individuals; there was moderate genetic variation across most loci (mean of 5.6 alleles/locus, mean expected heterozygosity = 0.70), with only one locus deviating significantly from Hardy-Weinberg equilibrium, probably because of null alleles. Marker independence was confirmed with tests for linkage disequilibrium. The genetic variation of the mitogenome and characterization of microsatellite markers will provide useful tools for assessing the phylogeography and population genetic patterns in M. gouazoubira, particularly in the context of habitat fragmentation in South America. PMID- 26500439 TI - Green turtle (Chelonia mydas) genetic diversity at Paranagua Estuarine Complex feeding grounds in Brazil. AB - Sea turtles are marine reptiles that undertake long migrations through their life, with limited information regarding juvenile stages. Feeding grounds (FGs), where they spend most of their lives, are composed by individuals from different natal origins, known as mixed stock populations. The aim of this study was to assess genetic composition, natal origins and demographic history of juvenile green turtles (Chelonia mydas) at the Paranagua Estuarine Complex (PEC), Brazil, considered a Natural World Heritage site. Tissue samples of stranded animals were collected (n = 60), and 700 bp mitochondrial DNA sequences were generated and compared to shorter sequences from previously published studies. Global exact tests of differentiation revealed significant differences among PEC and the other FGs, except those at the South Atlantic Ocean. Green turtles at PEC present genetic signatures similar to those of nesting females from Ascension Island, Guinea Bissau and Aves Island/Surinam. Population expansion was evidenced to have occurred 20-25 kYA, reinforcing the hypothesis of recovery from Southern Atlantic refugia after the last Glacial Maximum. These results contribute to a better understanding of the dynamics of green turtle populations at a protected area by providing knowledge on the dispersion patterns and reinforcing the importance of the interconnectivity between nesting and foraging populations. PMID- 26500440 TI - Successful crosses between fungal-resistant wild species of Arachis (section Arachis) and Arachis hypogaea. AB - Peanut (Arachis hypogaea) is the fifth most produced oil crop worldwide. Besides lack of water, fungal diseases are the most limiting factors for the crop. Several species of Arachis are resistant to certain pests and diseases. This study aimed to successfully cross the A-genome with B-K-A genome wild species previously selected for fungal disease resistance, but that are still untested. We also aimed to polyplodize the amphihaploid chromosomes; cross the synthetic amphidiploids and A. hypogaea to introgress disease resistance genes into the cultivated peanut; and analyze pollen viability and morphological descriptors for all progenies and their parents. We selected 12 A-genome accessions as male parents and three B-genome species, one K-genome species, and one A-genome species as female parents. Of the 26 distinct cross combinations, 13 different interspecific AB-genome and three AA-genome hybrids were obtained. These sterile hybrids were polyploidized and five combinations produced tetraploid flowers. Next, 16 combinations were crossed between A. hypogaea and the synthetic amphidiploids, resulting in 11 different hybrid combinations. Our results confirm that it is possible to introgress resistance genes from wild species into the peanut using artificial hybridization, and that more species than previously reported can be used, thus enhancing the genetic variability in peanut genetic improvement programs. PMID- 26500441 TI - The chitinase C gene PsChiC from Pseudomonas sp. and its synergistic effects on larvicidal activity. AB - Pseudomonas sp. strain TXG6-1, a chitinolytic gram-negative bacterium, was isolated from a vegetable field in Taixing city, Jiangsu Province, China. In this study, a Pseudomonas chitinase C gene (PsChiC) was isolated from the chromosomal DNA of this bacterium using a pair of specific primers. The PsChiC gene consisted of an open reading frame of 1443 nucleotides and encoded 480 amino acid residues with a calculated molecular mass of 51.66 kDa. The deduced PsChiC amino acid sequence lacked a signal sequence and consisted of a glycoside hydrolase family 18 catalytic domain responsible for chitinase activity, a fibronectin type III like domain (FLD) and a C-terminal chitin-binding domain (ChBD). The amino acid sequence of PsChiCshowed high sequence homology (> 95%) with chitinase C from Serratia marcescens. SDS-PAGE showed that the molecular mass of chitinase PsChiC was 52 kDa. Chitinase assays revealed that the chitobiosidase and endochitinase activities of PsChiCwere 51.6- and 84.1-fold higher than those of pET30a, respectively. Although PsChiC showed little insecticidal activity towards Spodoptera litura larvae, an insecticidal assay indicated that PsChiC increased the insecticidal toxicity of SpltNPV by 1.78-fold at 192 h and hastened death. These results suggest that PsChiC from Pseudomonas sp. could be useful in improving the pathogenicity of baculoviruses. PMID- 26500442 TI - High-throughput nucleotide sequence analysis of diverse bacterial communities in leachates of decomposing pig carcasses. AB - The leachate generated by the decomposition of animal carcass has been implicated as an environmental contaminant surrounding the burial site. High-throughput nucleotide sequencing was conducted to investigate the bacterial communities in leachates from the decomposition of pig carcasses. We acquired 51,230 reads from six different samples (1, 2, 3, 4, 6 and 14 week-old carcasses) and found that sequences representing the phylum Firmicutes predominated. The diversity of bacterial 16S rRNA gene sequences in the leachate was the highest at 6 weeks, in contrast to those at 2 and 14 weeks. The relative abundance of Firmicutes was reduced, while the proportion of Bacteroidetes and Proteobacteria increased from 3-6 weeks. The representation of phyla was restored after 14 weeks. However, the community structures between the samples taken at 1-2 and 14 weeks differed at the bacterial classification level. The trend in pH was similar to the changes seen in bacterial communities, indicating that the pH of the leachate could be related to the shift in the microbial community. The results indicate that the composition of bacterial communities in leachates of decomposing pig carcasses shifted continuously during the study period and might be influenced by the burial site. PMID- 26500443 TI - Cloning and expression analysis of the chitinase gene Ifu-chit2 from Isaria fumosorosea. AB - Entomopathogenic fungi can produce a series of chitinases, some of which function synergistically with proteases and other hydrolytic enzymes to degrade the insect cuticle. In the present study, the chitinase gene Ifu-chit2 from Isaria fumosorosea was investigated. The Ifu-chit2 gene is 1,435-bp long, interrupted by three short introns, and encodes a predicted protein of 423 amino acids with a 22 residue signal peptide. The predicted Ifu-Chit2 protein is highly homologous to Beauveria bassiana chitinase Bbchit2 and belongs to the glycohydrolase family 18. Ifu-Chit2 was expressed in Escherichia coli to verify chitinase activity, and the recombinant enzyme exhibited activity with a colloidal chitin substrate. Furthermore, the expression profiles of Ifu-chit2 were analyzed at different induction times under in vivo conditions. Quantitative real-time PCR analysis revealed that Ifu-chit2 expression peaked at two days post-induction. The expression of chitinase Ifu-chit2 in vivo suggests that the chitinase may play a role in the early stage of pathogenesis. PMID- 26500445 TI - The best of both worlds: Phylogenetic eigenvector regression and mapping. AB - Eigenfunction analyses have been widely used to model patterns of autocorrelation in time, space and phylogeny. In a phylogenetic context, Diniz-Filho et al. (1998) proposed what they called Phylogenetic Eigenvector Regression (PVR), in which pairwise phylogenetic distances among species are submitted to a Principal Coordinate Analysis, and eigenvectors are then used as explanatory variables in regression, correlation or ANOVAs. More recently, a new approach called Phylogenetic Eigenvector Mapping (PEM) was proposed, with the main advantage of explicitly incorporating a model-based warping in phylogenetic distance in which an Ornstein-Uhlenbeck (O-U) process is fitted to data before eigenvector extraction. Here we compared PVR and PEM in respect to estimated phylogenetic signal, correlated evolution under alternative evolutionary models and phylogenetic imputation, using simulated data. Despite similarity between the two approaches, PEM has a slightly higher prediction ability and is more general than the original PVR. Even so, in a conceptual sense, PEM may provide a technique in the best of both worlds, combining the flexibility of data-driven and empirical eigenfunction analyses and the sounding insights provided by evolutionary models well known in comparative analyses. PMID- 26500444 TI - Phylogenetic incongruence inferred with two mitochondrial genes in Mepraia spp. and Triatoma eratyrusiformis(Hemiptera, Reduviidae). AB - Mitochondrial DNA (mtDNA) is widely used to clarify phylogenetic relationships among and within species, and to determine population structure. Due to the linked nature of mtDNA genes it is expected that different genes will show similar results. Phylogenetic incongruence using mtDNA genes may result from processes such as heteroplasmy, nuclear integration of mitochondrial genes, polymerase errors, contamination, and recombination. In this study we used sequences from two mitochondrial genes (cytochrome b and cytochrome oxidase subunit I) from the wild vectors of Chagas disease, Triatoma eratyrusiformis and Mepraia species to test for topological congruence. The results showed some cases of phylogenetic incongruence due to misplacement of four haplotypes of four individuals. We discuss the possible causes of such incongruence and suggest that the explanation is an intra-individual variation likely due to heteroplasmy. This phenomenon is an independent evidence of common ancestry between these taxa. PMID- 26500446 TI - Form factors of the isovector scalar current and the [Formula: see text] scattering phase shifts. AB - A model for S-wave [Formula: see text] scattering is proposed which could be realistic in an energy range from threshold up to above 1 GeV, where inelasticity is dominated by the [Formula: see text] channel. The T-matrix, satisfying two channel unitarity, is given in a form which matches the chiral expansion results at order [Formula: see text] exactly for the [Formula: see text], [Formula: see text] amplitudes and approximately for [Formula: see text]. It contains six phenomenological parameters. Asymptotic conditions are imposed which ensure a minimal solution of the Muskhelishvili-Omnes problem, thus allowing one to compute the [Formula: see text] and [Formula: see text] form factor matrix elements of the [Formula: see text] scalar current from the T-matrix. The phenomenological parameters are determined such as to reproduce the experimental properties of the [Formula: see text], [Formula: see text] resonances, as well as the chiral results of the [Formula: see text] and [Formula: see text] scalar radii, which are predicted to be remarkably small at [Formula: see text]. This T matrix model could be used for a unified treatment of the [Formula: see text] final-state interaction problem in processes such as [Formula: see text], [Formula: see text], or the [Formula: see text] initial-state interaction in [Formula: see text]. PMID- 26500447 TI - Discriminant validity and test re-test reproducibility of a gait assessment in patients with vestibular dysfunction. AB - BACKGROUND: Gait function may be impaired in patients with vestibular disorders, making gait assessment in the clinical setting relevant for this patient population. The purpose of this study was to evaluate the discriminant validity of a gait assessment protocol between patients with vestibular disorders and healthy participants. Furthermore, test re-test reproducibility and the measurement error of gait performance measures in patients with vestibular lesions was performed under different walking conditions. METHODS: Gait parameters of thirty-five patients with vestibular disorders and twenty-seven healthy controls were assessed twice with the GAITRite(r) system. Discriminant validity, reproducibility (intra class correlation [ICC]) and the measurement error (standard error of measurement [SEM], smallest detectable change [SDC]) were determined for gait speed, cadence and step length. Bland-Altman plots were made to assess systematic bias between tests. RESULTS: A significant effect of grouping on gait performance indicates discriminant validity of gait assessment. All tests revealed differences between patients and healthy controls (p < 0.01). The ICCs for test re-test reproducibility were excellent (0.70-0.96) and measurement error showed acceptable SDC values for gait parameters derived from three walking conditions (9-19 %). Bland-Altman plots indicated no systematic bias. CONCLUSIONS: Good validity and reproducibility of GAITRite(r) system measurements suggest that this system could facilitate the study of gait in patients with vestibular disorders in clinical settings. The SDC values for gait are generally small enough to detect changes after a rehabilitation program for patients with vestibular disorders. PMID- 26500448 TI - Treading the clinical pathway: a qualitative study of advanced practice nurses in a local health district in Australia. AB - BACKGROUND: Career planning in nursing is often haphazard, with many studies showing that nurses need personal motivation, education, and the support of workplaces, which are often dominated by political and fiscal agendas. Nurses often need institutional and personal support to plan their careers and make decisions regarding their career aspirations. METHOD: A descriptive qualitative design was used. Data were gathered using semi-structured digitally recorded interviews and analysed for common categories. Twenty seven (n = 27) participants were interviewed. RESULTS: There were four categories revealed by the participants who described their career progression experiences: moving up the ladder, changing jobs for career progression, self-driven and the effects of institutional environments. CONCLUSION: Many of the participants' careers had been shaped serendipitously. Similar to other studies, these nurses felt political, institutional and financial factors impacted on their career opportunities. There are implications for nursing managers with more support required for nurses to plan their career trajectories. In addition to an organisation centred approach to career planning, nurse leaders and managers must take into account the personal and professional requirements of their nurses. Nurses themselves also need to take personal responsibility for career development. Greater support for nurses' career planning and personal drive will help organisations to plan their future workforce needs. PMID- 26500449 TI - Medication administration error: magnitude and associated factors among nurses in Ethiopia. AB - BACKGROUND: The significant impact of medication administration errors affect patients in terms of morbidity, mortality, adverse drug events, and increased length of hospital stay. It also increases costs for clinicians and healthcare systems. Due to this, assessing the magnitude and associated factors of medication administration error has a significant contribution for improving the quality of patient care. The aim of this study was to assess the magnitude and associated factors of medication administration errors among nurses at the Felege Hiwot Referral Hospital inpatient department. METHODS: A prospective, observation based, cross-sectional study was conducted from March 24-April 7, 2014 at the Felege Hiwot Referral Hospital inpatient department. A total of 82 nurses were interviewed using a pre-tested structured questionnaire, and observed while administering 360 medications by using a checklist supplemented with a review of medication charts. Data were analyzed by using SPSS version 20 software package and logistic regression was done to identify possible factors associated with medication administration error. RESULT: The incidence of medication administration error was 199 (56.4 %). The majority (87.5 %) of the medications have documentation error, followed by technique error 263 (73.1 %) and time error 193 (53.6 %). Variables which were significantly associated with medication administration error include nurses between the ages of 18-25 years [Adjusted Odds Ratio (AOR) = 2.9, 95 % CI (1.65,6.38)], 26-30 years [AOR = 2.3, 95 % CI (1.55, 7.26)] and 31-40 years [AOR = 2.1, 95 % CI (1.07, 4.12)], work experience of less than or equal to 10 years [AOR = 1.7, 95 % CI (1.33, 4.99)], nurse to patient ratio of 7-10 [AOR = 1.6, 95 % CI (1.44, 3.19)] and greater than 10 [AOR = 1.5, 95 % CI (1.38, 3.89)], interruption of the respondent at the time of medication administration [AOR = 1.5, 95 % CI (1.14, 3.21)], night shift of medication administration [AOR = 3.1, 95 % CI (1.38, 9.66)] and age of the patients with less than 18 years [AOR = 2.3, 95 % CI (1.17, 4.62)]. CONCLUSION: In general, medication errors at the administration phase were highly prevalent in Felege Hiwot Referral Hospital. Documentation error is the most dominant type of error observed during the study. Increasing nurses' staffing levels, minimizing distraction and interruptions during medication administration by using no interruptions zones and "No-Talk" signage are recommended to overcome medication administration errors. Retaining experienced nurses from leaving to train and supervise inexperienced nurses with the focus on medication safety, in addition providing convenient sleep hours for nurses would be helpful in ensuring that medication errors don't occur as frequently as observed in this study. PMID- 26500451 TI - Annuity choices and income drawdown: evidence from the decumulation phase of defined contribution pensions in England. AB - We provide new empirical evidence on the importance of defined contribution pension wealth in England, and the nature of annuitization decisions taken by older adults who retire with such sources of wealth. Other things equal, financial literacy, and numeracy in particular, are important factors governing individuals' choices over whether to shop around for an annuity as opposed to taking the 'path of least resistance' option and purchasing from their original pension fund provider. This has important policy and welfare implications given that buying an annuity on the open market has significant financial benefits for most people. In the context of the increasing reliance on private provision for retirement, the importance of individuals having the financial literacy to successfully navigate complex financial decisions late in life should not be underestimated. PMID- 26500450 TI - Caregiver perceptions regarding the measurement of level and quality of care in Alzheimer's disease. AB - BACKGROUND: Primary informal caregivers play a critical role in the care and support of persons with Alzheimer's disease (AD). A recent systematic review found little existing research into whether caregiver quality-of-life affects the level or quality of care that caregivers provide to their loved ones with AD. The dearth of research could be due to the absence of research questionnaires designed specifically to measure level or quality of care in AD. In the present study, we interviewed primary informal caregivers to obtain their views on the type of questionnaire that would be most suitable to assess level or quality of care in AD. METHODS: A qualitative descriptive design was used. Purposive sampling was used to select participants. Participants were primary informal caregivers who were 18 years of age and older and were directly involved in the day-to-day care of community-dwelling (residing in private homes) persons with AD. A total of 21 caregivers were interviewed using focus groups or one-on-one interviews. Data were analyzed using qualitative content analysis. RESULTS: Informal caregivers identified a number of factors that researchers should consider when developing an instrument to measure level or quality of care that informal caregivers provide to their loved ones with AD. Overall, caregivers preferred a questionnaire that would employ a case management approach that recognizes the increase in care demands as patient health deteriorates, that acknowledges the importance of social support for caregivers, and that considers the role of hired help. CONCLUSIONS: The information generated from this study can help in developing an instrument for measuring the level or quality of care provided. Such an instrument could guide nursing practice in supporting caregivers as they care for persons with AD. PMID- 26500452 TI - Xanthorrhizol: a review of its pharmacological activities and anticancer properties. AB - Xanthorrhizol (XNT) is a bisabolane-type sesquiterpenoid compound extracted from Curcuma xanthorrhiza Roxb. It has been well established to possess a variety of biological activities such as anticancer, antimicrobial, anti-inflammatory, antioxidant, antihyperglycemic, antihypertensive, antiplatelet, nephroprotective, hepatoprotective, estrogenic and anti-estrogenic effects. Since many synthetic drugs possess toxic side effects and are unable to support the increasing prevalence of disease, there is significant interest in developing natural product as new therapeutics. XNT is a very potent natural bioactive compound that could fulfil the current need for new drug discovery. Despite its importance, a comprehensive review of XNT's pharmacological activities has not been published in the scientific literature to date. Here, the present review aims to summarize the available information in this area, focus on its anticancer properties and indicate the current status of the research. This helps to facilitate the understanding of XNT's pharmacological role in drug discovery, thus suggesting areas where further research is required. PMID- 26500453 TI - Celastrol induces cell cycle arrest by MicroRNA-21-mTOR-mediated inhibition p27 protein degradation in gastric cancer. AB - OBJECTIVE: Celastrol has anti-cancer effects by increase of apoptosis of gastric cancer cells. However, its role in gastric cancer cell cycle is still unclear. The aim of this study was to investigate the effect and mechanism of celastrol on gastric cancer cell cycle. METHODS: The effects of celastrol on cell cycle in BGC 823 and MGC-803 cells were assayed via flow cytometry analysis. The expression of p27 and mTOR was detected by real-time PCR and western blot. The activity of mTOR and mTORC2 was measured by mTOR and mTORC2 kinase assays. miR-21 mimic was used to up-regulate miR-21 expression and mTOR expression plasmid was used to increase mTOR level in gastric cancer cells. RESULTS: Celastrol caused G2/M cell-cycle arrest that was accompanied by the down-regulation of miR-21 expression. In particular, miR-21 overexpression reversed cell cycle arrest effects of celastrol. Further study showed that celastrol increased levels of the p27 protein by inhibiting its degradation. miR-21 and mTOR signaling pathway was involved in the increase of p27 protein expression in BGC-823 and MGC-803 cells treated with celastrol. Significantly, miR-21 overexpression restored the decrease of mTOR activity in cells exposed celastrol. CONCLUSIONS: The effect of celastrol on cell cycle arrest of gastric cancer cells was due to an increase of p27 protein level via inhibiting miR-21-mTOR signaling pathway. PMID- 26500454 TI - The choroid plexus may be an underestimated site of tumor invasion to the brain: an in vitro study using neuroblastoma cell lines. AB - BACKGROUND: The central nervous system (CNS) is protected by several barriers, including the blood-brain (BBB) and blood-cerebrospinal fluid (BCSFB) barriers. Understanding how cancer cells circumvent these protective barriers to invade the CNS is of crucial interest, since brain metastasis during cancer is often a fatal event in both children and adults. However, whereas much effort has been invested in elucidating the process of tumor cell transmigration across the BBB, the role of the BCSFB might still be underestimated considering the significant number of meningeal cancer involvement. Our work aimed to investigate the transmigration of neuroblastoma cells across the BCSFB in vitro. METHODS: We used an inverted model of the human BCSFB presenting proper restrictive features including adequate expression of tight-junction proteins, low permeability to integrity markers, and high trans-epithelial electrical resistance. Two different human neuroblastoma cell lines (SH-SY5Y and IMR-32) were used to study the transmigration process by fluorescent microscopy analysis. RESULTS: The results show that neuroblastoma cells are able to actively cross the tight human in vitro BCSFB model within 24 h. The presence and transmigration of neuroblastoma cancer cells did not affect the barrier integrity within the duration of the experiment. CONCLUSIONS: In conclusion, we presume that the choroid plexus might be an underestimated site of CNS invasion, since neuroblastoma cell lines are able to actively cross a choroid plexus epithelial cell layer. Further studies are warranted to elucidate the molecular mechanisms of tumor cell transmigration in vitro and in vivo. PMID- 26500455 TI - Nitric oxide secretion in human conjunctival fibroblasts is inhibited by alpha linolenic acid. AB - PURPOSE: It is known that both human conjunctival fibroblasts (HCF) and corneal epithelial (HCE) cells contribute to the inflammatory process in the ocular surface by releasing inflammatory cytokines. In addition, nitric oxide (NO) has an important role in inflammatory responses in the ocular surface. In the present study, we aimed to characterize the capacity of these cells to release nitric oxide in response to cytokines and Lipopolysaccharide (LPS), and show that Alpha linoleic acid (ALA) inhibits these responses. METHODS: HCF, HCE cells, peripheral blood mononuclear cells (PBMCs) and co-culture of HCF and PBMC were treated with different combinations of inflammatory inducers, including interleukin)IL- (6, tumor necrosis factors (TNF)-alpha, interferon (IFN)- gamma and IL-1beta and LPS. Nitrite levels were measured in cell supernatants with and without ALA by the Griess reaction test at 24, 48 and 72 h respectively. Expression of nitric oxide synthase 2 (NOS-2) was evaluated by real-time PCR. RESULTS: All cytokine combinations had an inducible effect on nitrite secretion in HCF, PBMC and co cultured PBMC and HCF, but not in HCE cells. Treatment with a combination of IL 6, LPS, TNF-alpha, IFN- gamma and IL-1beta induced the highest nitrite secretion (2.91 fold, P < 0.01) as compared to cells incubated in medium alone. nitrite secretion was reduced by 38.9 % (P < 0.05) after treatment with ALA alone. Co culturing PBMC with HCF with and without ALA treatment demonstrated similar results in nitrite level as,compared to PBMC alone. In addition, ALA significantly decreased NOS-2 expression in HCF by 48.9 % (P < 0. 001) after 72 h. CONCLUSIONS: The decrease in nitrite release and inhibition of NOS-2 expression indicate that ALA may have an anti-inflammatory effect both on HCF and on peripheral immune cells. This indicates that ALA may serve as a potent anti inflammatory agent in ocular surface inflammation. PMID- 26500456 TI - Should lifelong anticoagulation for unprovoked venous thromboembolism be revisited? AB - Venous thromboembolism [VTE] is a common medical condition that has significant morbidity and mortality. Although stringent guidelines recommend lifelong anticoagulation for patients with unprovoked VTE, the optimal management strategy for their long term treatment remains controversial. Whereas in cancer-associated VTE and second unprovoked VTE lifelong anticoagulation is universally accepted, a careful analysis of the benefit vs. risk of long-term anticoagulation following a first unprovoked VTE should be considered as case fatality rates [CFR] from VTE appear more pronounced in the first few months. The CFR from major bleeding remains constant throughout therapy. Therefore, the risk of bleeding may be underestimated over longer treatment periods relative to the morbidity of recurrent VTE which appears to peak in the first year. The current review highlights the balance between the recurrence risk and bleeding risks in the era of direct oral anticoagulants. Vitamin K antagonists have been the standard of care for over 50 years bearing significant bleeding risks. The new oral anticoagulants [NOACs] have shown similar efficacy and perhaps a questionable improved safety profile when compared to warfarin. Aspirin has historically not been a useful agent in the management of VTE. However, two recent trials [WARFASA and ASPIRE] showed a likely 20-30 % risk reduction when compared to placebo for recurrent VTE after initial anticoagulation. The risk of major hemorrhage was low in both trials. With the emergence of NOACs and the increased utility of aspirin, there are multiple therapeutic options for long term management for VTE. Given comparable efficacy and improved safety of NOACs and aspirin, the risk benefit of anticoagulation is improving. A risk stratification model may help identifying patients at high risk for recurrence necessitating a lifelong anticoagulation. This cohort should be separated from a low risk group that may benefit from clinical observation, aspirin or NOACs. Prospective clinical trials are needed to support these clinical observations. PMID- 26500457 TI - Family history of venous thromboembolism is a risk factor for venous thromboembolism in combined oral contraceptive users: a nationwide case-control study. AB - BACKGROUND: The aim was to assess the risk of venous thromboembolism (VTE) associated with use of combined oral contraceptives (COCs) in women with a family history of VTE. METHODS: The study is a Swedish nationwide case-control study based on the Multigeneration register, the Swedish Hospital Discharge Register, the Outpatient Care Register, and the Swedish Prescribed Drug Register. Cases (n = 2,311) were non-pregnant Swedish women aged 15-49 with first VTE diagnoses between January 2006 and December 2010. Five controls without VTE were matched to each case on age and education level. Conditional logistic regression examined the associations with VTE with determination of odds ratio (OR) for first VTE diagnosis. Effect modification was assessed by interaction testing. RESULTS: Both among controls (14.6 % vs. 4.5 %; p < 0.0001) and cases (27.2 % vs. 8.8 %; p < 0.0001) COC use was more common in women without a family history of VTE compared with women with a family history of VTE. In a multivariate conditional logistic regression model the OR for VTE was 2.53 (95 % CI 2.23-2.87) for COC users and 2.38 (2.09-2.71) for individuals with a family history of VTE. The OR for VTE for COC users with a family history of VTE was 6.02 (5.02-7.22). There was no significant interaction between family history of VTE and COC use (OR 0.92, 0.57 1.46). CONCLUSIONS: Family history of VTE is a risk factor for VTE in women using COCs. The low prevalence of COC use among women with a family history of VTE suggests that family history of VTE is considered when COCs are prescribed in Sweden. The present study may therefore even underestimate the importance of family history of VTE. The lack of interaction indicates that the risk of COC use in women with family history of VTE is determined by the product of the ORs for family history and COC use. PMID- 26500458 TI - The management of acute venous thromboembolism in clinical practice - study rationale and protocol of the European PREFER in VTE Registry. AB - BACKGROUND: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. METHODS/DESIGN: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. RESULTS: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. CONCLUSION: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. TRIAL REGISTRATION: Registered in DRKS register, ID number: DRKS00004795. PMID- 26500459 TI - The Potential Clinical Utility of Transdermal Alcohol Monitoring Data to Estimate the Number of Alcoholic Drinks Consumed. AB - OBJECTIVES: Transdermal alcohol monitoring is used extensively in forensic settings to identify whether individuals have violated court-ordered mandates to abstain from drinking. Despite widespread use in that setting, comparatively few studies have explored the clinical utility of transdermal alcohol monitoring. Furthermore, of the few studies conducted, most have relied on the forensically established conservative criteria to identify whether or not a drinking episode has occurred. Here, we explore how transdermal alcohol monitoring data can be used to estimate more clinically meaningful parameters relevant to clinical treatment programs. METHODS: We developed a procedure to use transdermal data to objectively estimate the number of standardized drinks an individual has consumed. Participants included 46 men and women who consumed 1 to 5 beers within 2 hours in the laboratory on separate days while wearing devices to monitor transdermal alcohol concentrations (TAC). RESULTS: A mathematical model was derived to estimate the number of standardized alcohol drinks consumed, which included a number of variables (time-to-peak TAC, area under the TAC curve, and sex). The model was then validated by applying it to data from a separate study. Our results indicate that transdermal alcohol devices can be used to estimate the number of standard drinks consumed. CONCLUSIONS: Objective methods characterizing both the level of intoxication achieved and the number of drinks consumed, such as transdermal alcohol monitoring, could be useful in both research and treatment settings. PMID- 26500460 TI - How close are the Slater and Becke-Roussel potentials in solids? AB - The Becke-Roussel (BR) potential [Phys. Rev. A 1989, 39, 3761] was proposed as an approximation to the Slater potential, which is the Coulomb potential generated by the exact exchange hole. In the present work, a detailed comparison between the Slater and BR potentials in solids is presented. It is shown that the two potentials usually lead to very similar results for the electronic structure; however, in a few cases, e.g., Si, Ge, or strongly correlated systems like NiO, the fundamental band gap or magnetic properties can differ markedly. Such differences should not be neglected when the computationally expensive Slater potential is replaced by the cheap semilocal BR potential in approximations to the exact-exchange Kohn-Sham potential, such as the one proposed by Becke and Johnson [J. Chem. Phys. 2006, 124, 221101]. PMID- 26500461 TI - Computational investigation of RNA CUG repeats responsible for myotonic dystrophy 1. AB - Despite the importance of the knowledge of molecular hydration entropy (DeltaShyd) in chemical and biological processes, the exact calculation of DeltaShyd is very difficult, because of the complexity in solute-water interactions. Although free-energy perturbation (FEP) methods have been employed quite widely in the literature, the poor convergent behavior of the van der Waals interaction term in the potential function limited the accuracy and robustness. In this study, we propose a new method for estimating DeltaShyd by means of combining the FEP approach and the scaled particle theory (or information theory) to separately calculate the electrostatic solute-water interaction term (DeltaSelec) and the hydrophobic contribution approximated by the cavity formation entropy (DeltaScav), respectively. Decomposition of DeltaShyd into DeltaScav and DeltaSelec terms is found to be very effective with a substantial accuracy enhancement in DeltaShyd estimation, when compared to the conventional full FEP calculations. DeltaScav appears to dominate over DeltaSelec in magnitude, even in the case of polar solutes, implying that the major contribution to the entropic cost for hydration comes from the formation of a solvent-excluded volume. Our hybrid scaled particle theory and FEP method is thus found to enhance the accuracy of DeltaShyd prediction by effectively complementing the conventional full FEP method. PMID- 26500462 TI - A high protein diet (3.4 g/kg/d) combined with a heavy resistance training program improves body composition in healthy trained men and women--a follow-up investigation. AB - BACKGROUND: The consumption of a high protein diet (>4 g/kg/d) in trained men and women who did not alter their exercise program has been previously shown to have no significant effect on body composition. Thus, the purpose of this investigation was to determine if a high protein diet in conjunction with a periodized heavy resistance training program would affect indices of body composition, performance and health. METHODS: Forty-eight healthy resistance trained men and women completed this study (mean +/- SD; Normal Protein group [NP n = 17, four female and 13 male]: 24.8 +/- 6.9 yr; 174.0 +/- 9.5 cm height; 74.7 +/- 9.6 kg body weight; 2.4 +/- 1.7 yr of training; High Protein group [HP n = 31, seven female and 24 male]: 22.9 +/- 3.1 yr; 172.3 +/- 7.7 cm; 74.3 +/- 12.4 kg; 4.9 +/- 4.1 yr of training). Moreover, all subjects participated in a split routine, periodized heavy resistance-training program. Training and daily diet logs were kept by each subject. Subjects in the NP and HP groups were instructed to consume their baseline (~2 g/kg/d) and >3 g/kg/d of dietary protein, respectively. RESULTS: Subjects in the NP and HP groups consumed 2.3 and 3.4 g/kg/day of dietary protein during the treatment period. The NP group consumed significantly (p < 0.05) more protein during the treatment period compared to their baseline intake. The HP group consumed more (p < 0.05) total energy and protein during the treatment period compared to their baseline intake. Furthermore, the HP group consumed significantly more (p < 0.05) total calories and protein compared to the NP group. There were significant time by group (p <= 0.05) changes in body weight (change: +1.3 +/- 1.3 kg NP, -0.1 +/- 2.5 HP), fat mass (change: -0.3 +/- 2.2 kg NP, -1.7 +/- 2.3 HP), and % body fat (change: -0.7 +/- 2.8 NP, -2.4 +/- 2.9 HP). The NP group gained significantly more body weight than the HP group; however, the HP group experienced a greater decrease in fat mass and % body fat. There was a significant time effect for FFM; however, there was a non-significant time by group effect for FFM (change: +1.5 +/- 1.8 NP, +1.5 +/- 2.2 HP). Furthermore, a significant time effect (p <= 0.05) was seen in both groups vis a vis improvements in maximal strength (i.e., 1-RM squat and bench) vertical jump and pull-ups; however, there were no significant time by group effects (p >= 0.05) for all exercise performance measures. Additionally, there were no changes in any of the blood parameters (i.e., basic metabolic panel). CONCLUSION: Consuming a high protein diet (3.4 g/kg/d) in conjunction with a heavy resistance-training program may confer benefits with regards to body composition. Furthermore, there is no evidence that consuming a high protein diet has any deleterious effects. PMID- 26500463 TI - Effects of zeolite supplementation on parameters of intestinal barrier integrity, inflammation, redoxbiology and performance in aerobically trained subjects. AB - BACKGROUND: Zeolites are crystalline compounds with microporous structures of Si tetrahedrons. In the gut, these silicates could act as adsorbents, ion exchangers, catalysts, detergents or anti-diarrheic agents. This study evaluated whether zeolite supplementation affects biomarkers of intestinal wall permeability and parameters of oxidation and inflammation in aerobically trained individuals, and whether it could improve their performance. METHODS: In a randomized, double-blinded, placebo controlled trial, 52 endurance trained men and women, similar in body fat, non-smokers, 20-50 years, received 1.85 g of zeolite per day for 12 weeks. Stool samples for determination of intestinal wall integrity biomarkers were collected. From blood, markers of redox biology, inflammation, and DNA damage were determined at the beginning and the end of the study. In addition, VO2max and maximum performance were evaluated at baseline and after 12 weeks of treatment. For statistical analyses a 2-factor ANOVA was used. RESULTS: At baseline both groups showed slightly increased stool zonulin concentrations above normal. After 12 weeks with zeolite zonulin was significantly (p < 0.05) decreased in the supplemented group. IL-10 increased tendentially (p < 0.1) in the zeolite group. There were no significant changes observed in the other measured parameters. CONCLUSIONS: Twelve weeks of zeolite supplementation exerted beneficial effects on intestinal wall integrity as indicated via decreased concentrations of the tight junction modulator zonulin. This was accompanied by mild anti-inflammatory effects in this cohort of aerobically trained subjects. Further research is needed to explore mechanistic explanations for the observations in this study. PMID- 26500464 TI - Small-angle neutron scattering correlation functions of bulk magnetic materials. AB - On the basis of the continuum theory of micromagnetics, the correlation function of the spin-misalignment small-angle neutron scattering cross section of bulk ferromagnets (e.g. elemental polycrystalline ferromagnets, soft and hard magnetic nanocomposites, nanoporous ferromagnets, or magnetic steels) is computed. For such materials, the spin disorder which is related to spatial variations in the saturation magnetization and magnetic anisotropy field results in strong spin misalignment scattering dSigmaM/dOmega along the forward direction. When the applied magnetic field is perpendicular to the incoming neutron beam, the characteristics of dSigmaM/dOmega (e.g. the angular anisotropy on a two dimensional detector or the asymptotic power-law exponent) are determined by the ratio of magnetic anisotropy field strength Hp to the jump DeltaM in the saturation magnetization at internal interfaces. Here, the corresponding one- and two-dimensional real-space correlations are analyzed as a function of applied magnetic field, the ratio Hp/DeltaM, the single-particle form factor and the particle volume fraction. Finally, the theoretical results for the correlation function are compared with experimental data on nanocrystalline cobalt and nickel. PMID- 26500465 TI - Representational analysis of extended disorder in atomistic ensembles derived from total scattering data. AB - With the increased availability of high-intensity time-of-flight neutron and synchrotron X-ray scattering sources that can access wide ranges of momentum transfer, the pair distribution function method has become a standard analysis technique for studying disorder of local coordination spheres and at intermediate atomic separations. In some cases, rational modeling of the total scattering data (Bragg and diffuse) becomes intractable with least-squares approaches, necessitating reverse Monte Carlo simulations using large atomistic ensembles. However, the extraction of meaningful information from the resulting atomistic ensembles is challenging, especially at intermediate length scales. Representational analysis is used here to describe the displacements of atoms in reverse Monte Carlo ensembles from an ideal crystallographic structure in an approach analogous to tight-binding methods. Rewriting the displacements in terms of a local basis that is descriptive of the ideal crystallographic symmetry provides a robust approach to characterizing medium-range order (and disorder) and symmetry breaking in complex and disordered crystalline materials. This method enables the extraction of statistically relevant displacement modes (orientation, amplitude and distribution) of the crystalline disorder and provides directly meaningful information in a locally symmetry-adapted basis set that is most descriptive of the crystal chemistry and physics. PMID- 26500466 TI - Profex: a graphical user interface for the Rietveld refinement program BGMN. AB - Profex is a graphical user interface for the Rietveld refinement program BGMN. Its interface focuses on preserving BGMN's powerful and flexible scripting features by giving direct access to BGMN input files. Very efficient workflows for single or batch refinements are achieved by managing refinement control files and structure files, by providing dialogues and shortcuts for many operations, by performing operations in the background, and by providing import filters for CIF and XML crystal structure files. Refinement results can be easily exported for further processing. State-of-the-art graphical export of diffraction patterns to pixel and vector graphics formats allows the creation of publication-quality graphs with minimum effort. Profex reads and converts a variety of proprietary raw data formats and is thus largely instrument independent. Profex and BGMN are available under an open-source license for Windows, Linux and OS X operating systems. PMID- 26500467 TI - SASfit: a tool for small-angle scattering data analysis using a library of analytical expressions. AB - SASfit is one of the mature programs for small-angle scattering data analysis and has been available for many years. This article describes the basic data processing and analysis workflow along with recent developments in the SASfit program package (version 0.94.6). They include (i) advanced algorithms for reduction of oversampled data sets, (ii) improved confidence assessment in the optimized model parameters and (iii) a flexible plug-in system for custom user provided models. A scattering function of a mass fractal model of branched polymers in solution is provided as an example for implementing a plug-in. The new SASfit release is available for major platforms such as Windows, Linux and MacOS. To facilitate usage, it includes comprehensive indexed documentation as well as a web-based wiki for peer collaboration and online videos demonstrating basic usage. The use of SASfit is illustrated by interpretation of the small angle X-ray scattering curves of monomodal gold nanoparticles (NIST reference material 8011) and bimodal silica nanoparticles (EU reference material ERM-FD 102). PMID- 26500468 TI - Molecular weight-gyration radius relation of globular proteins: a comparison of light scattering, small-angle X-ray scattering and structure-based data. AB - The molecular weight-gyration radius relation for a number of globular proteins based on experimental light scattering data is compared with small-angle X-ray scattering data recently published by Mylonas & Svergun [J. Appl. Cryst. (2007 ?), 40, s245-s249]. In addition, other recent experimental data and theoretical calculations are reviewed. It is found that the MW-Rg relation for the globular proteins is well represented by a power law with an exponent of 0.37 (2). PMID- 26500469 TI - Novel Methods for Pulse Wave Velocity Measurement. AB - The great incidence of cardiovascular (CV) diseases in the world spurs the search for new solutions to enable an early detection of pathological processes and provides more precise diagnosis based in multi-parameters assessment. The pulse wave velocity (PWV) is considered one of the most important clinical parameters for evaluate the CV risk, vascular adaptation, and therapeutic efficacy. Several studies were dedicated to find the relationship between PWV measurement and pathological status in different diseases, and proved the relevance of this parameter. The commercial devices dedicate to PWV estimation make a regional assessment (measured between two vessels), however a local measurement is more precise evaluation of artery condition, taking into account the differences in the structure of arteries. Moreover, the current devices present some limitations due to the contact nature. Emerging trends in CV monitoring are moving away from more invasive technologies to non-invasive and non-contact solutions. The great challenge is to explore the new instrumental solutions that allow the PWV assessment with fewer approximations for an accurately evaluation and relatively inexpensive techniques in order to be used in the clinical routine. PMID- 26500470 TI - Comparison of Three Fixation Methods for Femoral Neck Fracture in Young Adults: Experimental and Numerical Investigations. AB - Femoral neck fractures in young patients are usually caused by a high-energy trauma, which results in a perpendicular fracture. Although efforts are focused on preserving the femoral head in young patients, vertical femoral neck fracture is a problematic orthopedic injury due to the domination of shear forces. Due to controversy regarding which fixation method is the best choice, the purpose of this study was to find the most stable fixation method for this kind of fracture. This study includes experimental testing on cadaveric bone samples and finite element analysis (FEA) for three fracture fixation techniques, namely cannulated screws (CSs), dynamic hip screw with derotational screw (DHS + DS), and proximal femoral locking plate (PFLP). Experimental results of bone-implant stiffness, average femoral head displacement, failure load, failure energy, and relative position of the fractured fragments indicate that DHS + DS offers the strongest structure for stabilizing a vertical femoral neck fracture. Experimental data and FEA results both indicate that under static loading, the DHS + DS method of fixation produces the lowest femoral head displacement and interfragmentary movement, followed by PFLP and then CSs. The results of this research suggest that, based on the clinical assumption that a restricted weight-bearing regimen is recommended in the postoperative rehabilitation protocol, the DHS + DS method of fixation is a better choice compared to CSs and PFLP for a vertical femoral neck fracture fixation in young adults. PMID- 26500471 TI - Overview of state policies requiring smoking cessation therapy in psychiatric hospitals and drug abuse treatment centers. AB - BACKGROUND: Research demonstrates that individuals in substance abuse treatment are more likely to die from tobacco addiction than from their primary addiction, yet historically substance abuse treatment has not included treatment for tobacco addiction. The purpose of our study was to (1) review the diffusion of state policies mandating the provision of tobacco cessation treatment as a condition of state licensure in substance abuse treatment facilities and psychiatric treatment centers and (2) describe the current landscape of policies relating to tobacco cessation in state-licensed substance abuse treatment facilities and psychiatric treatment centers. FINDINGS: We conducted a nationwide assessment of all 50 states from May 2013 - October 2014 to determine the progress each has made with developing a statewide tobacco cessation policy. We reviewed state government websites, conducted phone interviews with state regulatory agencies, and emailed state employees. Overall, 13 of 50 states (26 %) require tobacco cessation provision in alcohol, drug rehabilitation, and or mental health treatment centers, 6 states (12 %) are currently working towards a state policy, and 31 states (62 %) do not require tobacco cessation nor are working towards a state policy, though many of them have smoke free policies in both substance abuse centers and mental health wards. CONCLUSIONS: Our updated review of statewide smoking cessation policies in alcoholic, drug abuse, and mental health populations reveals that while clinical findings that affect population health may be well-publicized in the research community, these findings are not necessarily translated into policy. Further research on policy diffusion is needed. PMID- 26500472 TI - Use of snus, its association with smoking and alcohol consumption, and related attitudes among adolescents: the Finnish National School Health Promotion Study. AB - BACKGROUND: The relationship between the use of snus and lifestyle-related habits - especially in adolescence, when these behaviours begin and become established - is not widely studied. Our aim was to analyse associations between snus use and habits of and attitudes towards smoking and alcohol consumption among Finnish adolescents. METHODS: The study is a part of the National School Health Promotion Study in Finland. The study population consisted of a representative sample of Finnish adolescents (n = 183 226). A questionnaire enquired about pupils' use of snus, habits of and attitudes towards smoking and alcohol consumption, as well as their (age, gender, school type) and their parents' (education and smoking) background factors. Chi-square tests and logistic regression models served in the statistical analyses. RESULTS: Of the adolescents, 18 % had used snus (2 % daily, 16 % experimented) while 82 % never had. Snus use was more common among boys than girls (p < 0.05). Concerning smoking, 19 % were daily and 15 % occasional smokers. Regarding alcohol, 11 % consumed it weekly and 57 % monthly or less frequently. More than two thirds of the adolescents held positive attitudes towards smoking (71 %), and alcohol (67 %). Male gender (OR = 9.9; 95 % CI 9.4 10.4), current (OR = 32.8; 95 % CI 26.1-41.1) or former (OR = 10.1; 95 % CI 8.0 12.9) smoking, weekly consumption of alcohol (OR = 27.4; 95 % CI 21.0-35.8), positive attitude towards smoking (OR = 1.4; 95 % CI 1.3-1.6), and higher parental education (OR = 1.4; 95 % CI 1.3-1.4) associated significantly with adolescents' current snus use, whereas parental smoking did not. CONCLUSION: Current snus use among adolescents may signal an accumulation of other lifestyle related risky behaviours such as current or past smoking and alcohol consumption as well as a positive attitude towards smoking. In addition to these possible co existing health-related risk factors, health promotion activities should take into account gender and school differences in order to target preventive messages to youth more effectively. PMID- 26500473 TI - Distributed encoding of spatial and object categories in primate hippocampal microcircuits. AB - The primate hippocampus plays critical roles in the encoding, representation, categorization and retrieval of cognitive information. Such cognitive abilities may use the transformational input-output properties of hippocampal laminar microcircuitry to generate spatial representations and to categorize features of objects, images, and their numeric characteristics. Four nonhuman primates were trained in a delayed-match-to-sample (DMS) task while multi-neuron activity was simultaneously recorded from the CA1 and CA3 hippocampal cell fields. The results show differential encoding of spatial location and categorization of images presented as relevant stimuli in the task. Individual hippocampal cells encoded visual stimuli only on specific types of trials in which retention of either, the Sample image, or the spatial position of the Sample image indicated at the beginning of the trial, was required. Consistent with such encoding, it was shown that patterned microstimulation applied during Sample image presentation facilitated selection of either Sample image spatial locations or types of images, during the Match phase of the task. These findings support the existence of specific codes for spatial and numeric object representations in primate hippocampus which can be applied on differentially signaled trials. Moreover, the transformational properties of hippocampal microcircuitry, together with the patterned microstimulation are supporting the practical importance of this approach for cognitive enhancement and rehabilitation, needed for memory neuroprosthetics. PMID- 26500474 TI - Avoidance and contextual learning induced by a kairomone, a pheromone and a common odorant in female CD1 mice. AB - Chemosignals mediate both intra- and inter-specific communication in most mammals. Pheromones elicit stereotyped reactions in conspecifics, whereas kairomones provoke a reaction in an allospecific animal. For instance, predator kairomones elicit anticipated defensive responses in preys. The aim of this work was to test the behavioral responses of female mice to two chemosignals: 2 heptanone (2-HP), a putative alarm pheromone, and 2,4,5-trimethylthiazoline (TMT), a fox-derived putative kairomone, widely used to investigate fear and anxiety in rodents. The banana-like odorant isoamyl acetate (IA), unlikely to act as a chemosignal, served as a control odorant. We first presented increasing amounts of these odorants in consecutive days, in a test box in which mice could explore or avoid them. Female mice avoided the highest amounts of all three compounds, with TMT and IA eliciting avoidance at lower amounts (3.8 pmol and 0.35 MUmol, respectively) than 2-HP (35 MUmol). All three compounds induced minimal effects in global locomotion and immobility in this set up. Further, mice detected 3.5 pmol of TMT and IA in a habituation-dishabituation test, so avoidance of IA started well beyond the detection threshold. Finally, both TMT and IA, but not 2-HP, induced conditioned place avoidance and increased immobility in the neutral compartment during a contextual memory test. These data suggest that intense odors can induce contextual learning irrespective of their putative biological significance. Our results support that synthetic predator related compounds (like TMT) or other intense odorants are useful to investigate the neurobiological basis of emotional behaviors in rodents. Since intense odorants unlikely to act as chemosignals can elicit similar behavioral reactions than chemosignals, we stress the importance of using behavioral measures in combination with other physiological (e.g., hormonal levels) or neural measures (e.g., immediate early gene expression) to establish the ethological significance of odorants. PMID- 26500475 TI - Astrocyte matricellular proteins that control excitatory synaptogenesis are regulated by inflammatory cytokines and correlate with paralysis severity during experimental autoimmune encephalomyelitis. AB - The matricellular proteins, secreted protein acidic and rich in cysteine (SPARC) and SPARC-like 1 (SPARCL1), are produced by astrocytes and control excitatory synaptogenesis in the central nervous system. While SPARCL1 directly promotes excitatory synapse formation in vitro and in the developing nervous system in vivo, SPARC specifically antagonizes the synaptogenic actions of SPARCL1. We hypothesized these proteins also help maintain existing excitatory synapses in adult hosts, and that local inflammation in the spinal cord alters their production in a way that dynamically modulates motor synapses and impacts the severity of paralysis during experimental autoimmune encephalomyelitis (EAE) in mice. Using a spontaneously remitting EAE model, paralysis severity correlated inversely with both expression of synaptic proteins and the number of synapses in direct contact with the perikarya of motor neurons in spinal gray matter. In both remitting and non-remitting EAE models, paralysis severity also correlated inversely with sparcl1:sparc transcript and SPARCL1:SPARC protein ratios directly in lumbar spinal cord tissue. In vitro, astrocyte production of both SPARCL1 and SPARC was regulated by T cell-derived cytokines, causing dynamic modulation of the SPARCL1:SPARC expression ratio. Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal gray matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE. Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation. This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis. PMID- 26500476 TI - The WIN-speller: a new intuitive auditory brain-computer interface spelling application. AB - The objective of this study was to test the usability of a new auditory Brain Computer Interface (BCI) application for communication. We introduce a word based, intuitive auditory spelling paradigm the WIN-speller. In the WIN-speller letters are grouped by words, such as the word KLANG representing the letters A, G, K, L, and N. Thereby, the decoding step between perceiving a code and translating it to the stimuli it represents becomes superfluous. We tested 11 healthy volunteers and four end-users with motor impairment in the copy spelling mode. Spelling was successful with an average accuracy of 84% in the healthy sample. Three of the end-users communicated with average accuracies of 80% or higher while one user was not able to communicate reliably. Even though further evaluation is required, the WIN-speller represents a potential alternative for BCI based communication in end-users. PMID- 26500477 TI - Commentary: "Compensatory plasticity: time matters". PMID- 26500479 TI - Sleep deprivation alters choice strategy without altering uncertainty or loss aversion preferences. AB - Sleep deprivation alters decision making; however, it is unclear what specific cognitive processes are modified to drive altered choices. In this manuscript, we examined how one night of total sleep deprivation (TSD) alters economic decision making. We specifically examined changes in uncertainty preferences dissociably from changes in the strategy with which participants engage with presented choice information. With high test-retest reliability, we show that TSD does not alter uncertainty preferences or loss aversion. Rather, TSD alters the information the participants rely upon to make their choices. Utilizing a choice strategy metric which contrasts the influence of maximizing and satisficing information on choice behavior, we find that TSD alters the relative reliance on maximizing information and satisficing information, in the gains domain. This alteration is the result of participants both decreasing their reliance on cognitively-complex maximizing information and a concomitant increase in the use of readily-available satisficing information. TSD did not result in a decrease in overall information use in either domain. These results show that sleep deprivation alters decision making by altering the informational strategies that participants employ, without altering their preferences. PMID- 26500480 TI - An fMRI comparison of neural activity associated with recognition of familiar melodies in younger and older adults. AB - Several studies of semantic memory in non-musical domains involving recognition of items from long-term memory have shown an age-related shift from the medial temporal lobe structures to the frontal lobe. However, the effects of aging on musical semantic memory remain unexamined. We compared activation associated with recognition of familiar melodies in younger and older adults. Recognition follows successful retrieval from the musical lexicon that comprises a lifetime of learned musical phrases. We used the sparse-sampling technique in fMRI to determine the neural correlates of melody recognition by comparing activation when listening to familiar vs. unfamiliar melodies, and to identify age differences. Recognition-related cortical activation was detected in the right superior temporal, bilateral inferior and superior frontal, left middle orbitofrontal, bilateral precentral, and left supramarginal gyri. Region-of interest analysis showed greater activation for younger adults in the left superior temporal gyrus and for older adults in the left superior frontal, left angular, and bilateral superior parietal regions. Our study provides powerful evidence for these musical memory networks due to a large sample (N = 40) that includes older adults. This study is the first to investigate the neural basis of melody recognition in older adults and to compare the findings to younger adults. PMID- 26500478 TI - Transcranial direct current stimulation (tDCS) in behavioral and food addiction: a systematic review of efficacy, technical, and methodological issues. AB - OBJECTIVES: Behavioral addictions (BA) are complex disorders for which pharmacological and psychotherapeutic treatments have shown their limits. Non invasive brain stimulation, among which transcranial direct current stimulation (tDCS), has opened up new perspectives in addiction treatment. The purpose of this work is to conduct a critical and systematic review of tDCS efficacy, and of technical and methodological considerations in the field of BA. METHODS: A bibliographic search has been conducted on the Medline and ScienceDirect databases until December 2014, based on the following selection criteria: clinical studies on tDCS and BA (namely eating disorders, compulsive buying, Internet addiction, pathological gambling, sexual addiction, sports addiction, video games addiction). Study selection, data analysis, and reporting were conducted according to the PRISMA guidelines. RESULTS: Out of 402 potential articles, seven studies were selected. So far focusing essentially on abnormal eating, these studies suggest that tDCS (right prefrontal anode/left prefrontal cathode) reduces food craving induced by visual stimuli. CONCLUSIONS: Despite methodological and technical differences between studies, the results are promising. So far, only few studies of tDCS in BA have been conducted. New research is recommended on the use of tDCS in BA, other than eating disorders. PMID- 26500481 TI - Diversifying the secretory routes in neurons. AB - Nervous system homeostasis and synaptic function need dedicated mechanisms to locally regulate the molecular composition of the neuronal plasma membrane and allow the development, maintenance and plastic modification of the neuronal morphology. The cytoskeleton and intracellular trafficking lies at the core of all these processes. In most mammalian cells, the Golgi apparatus (GA) is at the center of the biosynthetic pathway, located in the proximity of the microtubule organizing center. In addition to this central localization, the somatic GA in neurons is complemented by satellite Golgi outposts (GOPs) in dendrites, which are essential for dendritic morphogenesis and are emerging like local stations of membranes trafficking to synapses. Largely, GOPs participation in post-ER trafficking has been determined by imaging the transport of the exogenous protein VSVG. Here we review the diversity of neuronal cargoes that traffic through GOPs and the assortment of different biosynthetic routes to synapses. We also analyze the recent advances in understanding the role of cytoskeleton and Golgi matrix proteins in the biogenesis of GOPs and how the diversity of secretory routes can be generated. PMID- 26500482 TI - Prediction of individual differences in risky behavior in young adults via variations in local brain structure. AB - In recent years the problem of how inter-individual differences play a role in risk-taking behavior has become a much debated issue. We investigated this problem based on the well-known balloon analog risk task (BART) in 48 healthy subjects in which participants inflate a virtual balloon opting for a higher score in the face of a riskier chance of the balloon explosion. In this study, based on a structural Voxel Based Morphometry (VBM) technique we demonstrate a significant positive correlation between BART score and size of the gray matter volume in the anterior insula in riskier subjects. Although the anterior insula is among the candidate brain areas that were involved in the risk taking behavior in fMRI studies, here based on our structural data it is the only area that was significantly related to structural variation among different subjects. PMID- 26500483 TI - Identification of dopamine receptors across the extant avian family tree and analysis with other clades uncovers a polyploid expansion among vertebrates. AB - Dopamine is an important central nervous system transmitter that functions through two classes of receptors (D1 and D2) to influence a diverse range of biological processes in vertebrates. With roles in regulating neural activity, behavior, and gene expression, there has been great interest in understanding the function and evolution dopamine and its receptors. In this study, we use a combination of sequence analyses, microsynteny analyses, and phylogenetic relationships to identify and characterize both the D1 (DRD1A, DRD1B, DRD1C, and DRD1E) and D2 (DRD2, DRD3, and DRD4) dopamine receptor gene families in 43 recently sequenced bird genomes representing the major ordinal lineages across the avian family tree. We show that the common ancestor of all birds possessed at least seven D1 and D2 receptors, followed by subsequent independent losses in some lineages of modern birds. Through comparisons with other vertebrate and invertebrate species we show that two of the D1 receptors, DRD1A and DRD1B, and two of the D2 receptors, DRD2 and DRD3, originated from a whole genome duplication event early in the vertebrate lineage, providing the first conclusive evidence of the origin of these highly conserved receptors. Our findings provide insight into the evolutionary development of an important modulatory component of the central nervous system in vertebrates, and will help further unravel the complex evolutionary and functional relationships among dopamine receptors. PMID- 26500484 TI - The GOLPH3 pathway regulates Golgi shape and function and is activated by DNA damage. AB - The Golgi protein GOLPH3 binds to PtdIns(4)P and MYO18A, linking the Golgi to the actin cytoskeleton. The GOLPH3 pathway is essential for vesicular trafficking from the Golgi to the plasma membrane. A side effect of GOLPH3-dependent trafficking is to generate the extended ribbon shape of the Golgi. Perturbation of the pathway results in changes to both Golgi morphology and secretion, with functional consequences for the cell. The cellular response to DNA damage provides an example of GOLPH3-mediated regulation of the Golgi. Upon DNA damage, DNA-PK phosphorylation of GOLPH3 increases binding to MYO18A, activating the GOLPH3 pathway, which consequently results in Golgi fragmentation, reduced trafficking, and enhanced cell survival. The PtdIns(4)P/GOLPH3/MYO18A/F-actin pathway provides new insight into the relationship between Golgi morphology and function, and their regulation. PMID- 26500485 TI - The scent of wolves: pyrazine analogs induce avoidance and vigilance behaviors in prey. AB - The common gray wolf (Canis lupus) is an apex predator located at the top of the food chain in the Northern Hemisphere. It preys on rodents, rabbits, ungulates, and many other kinds of mammal. However, the behavioral evidence for, and the chemical basis of, the fear-inducing impact of wolf urine on prey are unclear. Recently, the pyrazine analogs 2, 6-dimethylpyrazine, 2, 3, 5-trimethylpyrazine and 3-ethyl-2, 5-dimethyl pyrazine were identified as kairomones in the urine of wolves. When mice were confronted with a mixture of purified pyrazine analogs, vigilance behaviors, including freezing and excitation of neurons at the accessory olfactory bulb, were markedly increased. Additionally, the odor of the pyrazine cocktail effectively suppressed the approach of deer to a feeding area, and for those close to the feeding area elicited fear-related behaviors such as the "tail-flag," "flight," and "jump" actions. In this review, we discuss the transfer of chemical information from wolf to prey through the novel kairomones identified in wolf urine and also compare the characteristics of wolf kairomones with other predator-produced kairomones that affect rodents. PMID- 26500486 TI - How the risky features of previous selection affect subsequent decision-making: evidence from behavioral and fMRI measures. AB - Human decision making is rarely conducted in temporal isolation. It is often biased and affected by environmental variables, particularly prior selections. In this study, we used a task that simulates a real gambling process to explore the effect of the risky features of a previous selection on subsequent decision making. Compared with decision making after an advantageous risk-taking situation (Risk_Adv), that after a disadvantageous risk-taking situation (Risk_Disadv) is associated with a longer response time (RT, the time spent in making decisions) and higher brain activations in the caudate and the dorsolateral prefrontal cortex (DLPFC). Compared with decisions after Risk_Adv, those after Risk_Disadv in loss trials are associated with higher brain activations in the left superior temporal gyrus (STG) and the precuneus. Brain activity and relevant RTs significantly correlated. Overall, people who experience disadvantageous risk taking selections tend to focus on current decision making and engage cognitive endeavors in value evaluation and in the regulation of their risk-taking behaviors during decision making. PMID- 26500487 TI - Injury in aged animals robustly activates quiescent olfactory neural stem cells. AB - While the capacity of the olfactory epithelium (OE) to generate sensory neurons continues into middle age in mice, it is presumed that this regenerative potential is present throughout all developmental stages. However, little experimental evidence exists to support the idea that this regenerative capacity remains in late adulthood, and questions about the functionality of neurons born at these late stages remain unanswered. Here, we extend our previous work in the VNO to investigate basal rates of proliferation in the OE, as well as after olfactory bulbectomy (OBX), a commonly used surgical lesion. In addition, we show that the neural stem cell retains its capacity to generate mature olfactory sensory neurons in aged animals. Finally, we demonstrate that regardless of age, a stem cell in the OE, the horizontal basal cell (HBC), exhibits a morphological switch from a flattened, quiescent phenotype to a pyramidal, proliferative phenotype following chemical lesion in aged animals. These findings provide new insights into determining whether an HBC is active or quiescent based on a structural feature as opposed to a biochemical one. More importantly, it suggests that neural stem cells in aged mice are responsive to the same signals triggering proliferation as those observed in young mice. PMID- 26500488 TI - Misidentifications of specific forms of cross-frequency coupling: three warnings. AB - Cross-frequency coupling (CFC) between neural oscillations has received increased attention over the last decade, as it is believed to underlie a number of cognitive operations in different brain systems. Coupling can take different forms as it associates the phase, frequency, and/or amplitude of coupled oscillations. These specific forms of coupling are a signature for the underlying network physiology and probably relate to distinct cognitive functions. Here I discuss three caveats in data analysis that can lead to mistake one specific form of CFC for another: (1) bicoherence assesses the level of phase-amplitude and not of phase-phase coupling (PPC) as commonly accepted; (2) a test for phase amplitude coupling (PAC) can indeed signal phase-frequency coupling (PFC) when the higher frequency signal is extracted using a too narrow band; (3) an oscillation whose frequency fluctuates may induce spurious amplitude anticorrelations between neighboring frequency bands. I indicate practical rules to avoid such misidentifications and correctly identify the specific nature of cross-frequency coupled signals. PMID- 26500489 TI - Resveratrol: brain effects on SIRT1, GPR50 and photoperiodic signaling. AB - Silent information regulator-1 (SIRT1) deacetylase, a sensor of intermittent energy restriction, is inextricably intertwined with circadian regulation of central and peripheral clock genes. The purpose of this study was to identify SIRT1-specific target genes that are expressed in a circadian rhythm pattern and driven, in part, by specific components of foodstuffs. Using human cells and rats fed with a resveratrol diet we show that SIRT1 binds to, and transcriptionally regulates, a gene locus encoding the G protein-coupled receptor (GPR), GPR50 in the brain. GPR50 is the mammalian orthologue of the melatonin1c membrane-bound receptor which has been identified as a genetic risk factor for bipolar disorder and major depression in women. In general, our findings support and expand the notion that circadian clock signaling components and dietary interventions are adaptively linked, and suggest that the brain may be particularly sensitive to metabolic events in response to light-dark cycles. PMID- 26500490 TI - Dendritic morphology, synaptic transmission, and activity of mature granule cells born following pilocarpine-induced status epilepticus in the rat. AB - To understand the potential role of enhanced hippocampal neurogenesis after pilocarpine-induced status epilepticus (SE) in the development of epilepsy, we quantitatively analyzed the geometry of apical dendrites, synaptic transmission, and activation levels of normotopically distributed mature newborn granule cells in the rat. SE in male Sprague-Dawley rats (between 6 and 7 weeks old) lasting for more than 2 h was induced by an intraperitoneal injection of pilocarpine. The complexity, spine density, miniature post-synaptic currents, and activity regulated cytoskeleton-associated protein (Arc) expression of granule cells born 5 days after SE were studied between 10 and 17 weeks after CAG-GFP retroviral vector-mediated labeling. Mature granule cells born after SE had dendritic complexity similar to that of granule cells born naturally, but with denser mushroom-like spines in dendritic segments located in the outer molecular layer. Miniature inhibitory post-synaptic currents (mIPSCs) were similar between the controls and rats subjected to SE; however, smaller miniature excitatory post synaptic current (mEPSC) amplitude with a trend toward less frequent was found in mature granule cells born after SE. After maturation, granule cells born after SE did not show denser Arc expression in the resting condition or 2 h after being activated by pentylenetetrazol-induced transient seizure activity than vicinal GFP-unlabeled granule cells. Thus our results suggest that normotopic granule cells born after pilocarpine-induced SE are no more active when mature than age matched, naturally born granule cells. PMID- 26500491 TI - Imatinib treatment reduces brain injury in a murine model of traumatic brain injury. AB - Current therapies for Traumatic brain injury (TBI) focus on stabilizing individuals and on preventing further damage from the secondary consequences of TBI. A major complication of TBI is cerebral edema, which can be caused by the loss of blood brain barrier (BBB) integrity. Recent studies in several CNS pathologies have shown that activation of latent platelet derived growth factor CC (PDGF-CC) within the brain can promote BBB permeability through PDGF receptor alpha (PDGFRalpha) signaling, and that blocking this pathway improves outcomes. In this study we examine the efficacy for the treatment of TBI of an FDA approved antagonist of the PDGFRalpha, Imatinib. Using a murine model we show that Imatinib treatment, begun 45 min after TBI and given twice daily for 5 days, significantly reduces BBB dysfunction. This is associated with significantly reduced lesion size 24 h, 7 days, and 21 days after TBI, reduced cerebral edema, determined from apparent diffusion co-efficient (ADC) measurements, and with the preservation of cognitive function. Finally, analysis of cerebrospinal fluid (CSF) from human TBI patients suggests a possible correlation between high PDGF CC levels and increased injury severity. Thus, our data suggests a novel strategy for the treatment of TBI with an existing FDA approved antagonist of the PDGFRalpha. PMID- 26500492 TI - NDRG2 phosphorylation provides negative feedback for SGK1-dependent regulation of a kainate receptor in astrocytes. AB - Glutamate receptors play an important role in the function of astrocytes. Among their tasks is the regulation of gliotransmission, gene expression and exocytosis of the tissue-type plasminogen activator (tPA), which has an enhancing effect on N-methyl-D-aspartate (NMDA) receptors and thus prevent over-excitation of neighboring neurons. The kainate receptor GluK2, which is expressed in neurons and astrocytes, is under tight regulation of the PI3-kinase SGK pathway as shown in neurons. SGK1 targets include N-myc downstream-regulated genes (NDRGs) 1 and 2 (NDRG1, NDRG2), proteins with elusive function. In the present study, we analyzed the effects of SGK1, NDRG1, and NDRG2 on GluK2 current amplitude and plasma membrane localization in astrocytes and heterologous expression. We demonstrate that NDRG1 and NDRG2 themselves have no effect on GluK2 current amplitudes in heterologous expressed ion channels. However, when NDRG2 is coexpressed with GluK2 and SGK1, the stimulating effect of SGK1 on GluK2 is suppressed both in heterologous expression and in astrocytes. Here, we reveal a new negative feedback mechanism, whereby GluK2 stimulation by SGK1 is regulated by parallel phosphorylation of NDRG2. This regulation of GluK2 by SGK1 and NDRG2 in astrocytes may play an important role in gliotransmission, modulation of gene expression and regulation of exocytosis of tPA. PMID- 26500493 TI - Decrease of gene expression of astrocytic 5-HT2B receptors parallels development of depressive phenotype in a mouse model of Parkinson's disease. AB - Astrocytes contribute to pathogenesis of neuropsychiatric disorders, including major depression. Stimulation of astroglial 5-HT2B receptors transactivates epidermal growth factor receptors (EGFRs) and regulates gene expression. Previously we reported that expression of 5-HT2B receptors in cortical astrocytes is down-regulated in animals, which developed anhedonia in response to chronic stress; moreover this down-regulation as well as anhedonia, are reversed by chronic treatment with fluoxetine. In this study we have investigated whether astrocytic 5-HT2B receptor is involved in anhedonia in C57BL/6 mice model of Parkinson' disease (PD) induced by intraperitoneal injection of 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) for 7 days. The MPTP treatment induced anhendonia in 66.7% of animals. The appearance of depressive behavior was accompanied with motor deficiency and decrease of tyrosine hydroxylase (TH) expression. Expression of mRNA and protein of 5-HT2B receptor in animals that became anhedonic decreased to 77.3 and 79.3% of control groups, respectively; in animals that received MPTP but did not develop anhedonia the expression of 5-HT2B receptor did not change. Experiments with FACS-sorted isolated cells demonstrated that decrease in 5-HT2B receptor expression was confined to astrocytes, and did not occur in neurons. Fluoxetine corrected MPTP-induced decrease of 5-HT2B receptor expression and depressive behavior. Our findings indicate that regulation of gene expression of 5-HT2B receptors in astroglia may be associated with pathophysiological evolution of PD-induced depression. PMID- 26500494 TI - Vesicular expression and release of ATP from dopaminergic neurons of the mouse retina and midbrain. AB - Vesicular nucleotide transporter (VNUT) is required for active accumulation of adenosine tri-phosphate (ATP) into vesicles for purinergic neurotransmission, however, the cell types that express VNUT in the central nervous system remain unknown. This study characterized VNUT expression within the mammalian retina and brain and assessed a possible functional role in purinergic signaling. Two native isoforms of VNUT were detected in mouse retina and brain based on RNA transcript and protein analysis. Using immunohistochemistry, VNUT was found to co-localize with tyrosine hydroxylase (TH) positive, dopaminergic (DA) neurons of the substantia nigra and ventral tegmental area, however, VNUT expression in extranigral non-DA neurons was also observed. In the retina, VNUT labeling was found to co-localize solely with TH-positive DA-cells. In the outer retina, VNUT positive interplexiform cell processes were in close contact with horizontal cells and cone photoreceptor terminals, which are known to express P2 purinergic receptors. In order to assess function, dissociated retinal neurons were loaded with fluorescent ATP markers (Quinacrine or Mant-ATP) and the DA marker FFN102, co-labeled with a VNUT antibody and imaged in real time. Fluorescent ATP markers and FFN102 puncta were found to co-localize in VNUT positive neurons and upon stimulation with high potassium, ATP marker fluorescence at the cell membrane was reduced. This response was blocked in the presence of cadmium. These data suggest DA neurons co-release ATP via calcium dependent exocytosis and in the retina this may modulate the visual response by activating purine receptors on closely associated neurons. PMID- 26500495 TI - Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia. AB - Homocysteine (HCY) is a pro-inflammatory sulphur-containing redox active endogenous amino acid, which concentration increases in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). A widely held view suggests that HCY could contribute to neurodegeneration via promotion of oxidative stress. However, the action of HCY on motor nerve terminals has not been investigated so far. We previously reported that oxidative stress inhibited synaptic transmission at the neuromuscular junction, targeting primarily the motor nerve terminals. In the current study, we investigated the effect of HCY on oxidative stress-induced impairment of transmitter release at the mouse diaphragm muscle. The mild oxidant H2O2 decreased the intensity of spontaneous quantum release from nerve terminals (measured as the frequency of miniature endplate potentials, MEPPs) without changes in the amplitude of MEPPs, indicating a presynaptic effect. Pre-treatment with HCY for 2 h only slightly affected both amplitude and frequency of MEPPs but increased the inhibitory potency of H2O2 almost two fold. As HCY can activate certain subtypes of glutamate N-methyl D aspartate (NMDA) receptors we tested the role of NMDA receptors in the sensitizing action of HCY. Remarkably, the selective blocker of NMDA receptors, AP-5 completely removed the sensitizing effect of HCY on the H2O2-induced presynaptic depressant effect. Thus, at the mammalian neuromuscular junction HCY largely increases the inhibitory effect of oxidative stress on transmitter release, via NMDA receptors activation. This combined effect of HCY and local oxidative stress can specifically contribute to the damage of presynaptic terminals in neurodegenerative motoneuron diseases, including ALS. PMID- 26500496 TI - Cellullar insights into cerebral cortical development: focusing on the locomotion mode of neuronal migration. AB - The mammalian brain consists of numerous compartments that are closely connected with each other via neural networks, comprising the basis of higher order brain functions. The highly specialized structure originates from simple pseudostratified neuroepithelium-derived neural progenitors located near the ventricle. A long journey by neurons from the ventricular side is essential for the formation of a sophisticated brain structure, including a mammalian-specific six-layered cerebral cortex. Neuronal migration consists of several contiguous steps, but the locomotion mode comprises a large part of the migration. The locomoting neurons exhibit unique features; a radial glial fiber-dependent migration requiring the endocytic recycling of N-cadherin and a neuron-specific migration mode with dilation/swelling formation that requires the actin and microtubule organization possibly regulated by cyclin-dependent kinase 5 (Cdk5), Dcx, p27(kip1), Rac1, and POSH. Here I will introduce the roles of various cellular events, such as cytoskeletal organization, cell adhesion, and membrane trafficking, in the regulation of the neuronal migration, with particular focus on the locomotion mode. PMID- 26500497 TI - Synaptic remodeling of neuronal circuits in early retinal degeneration. AB - Photoreceptor degenerations are a major cause of blindness and among the most common forms of neurodegeneration in humans. Studies of mouse models revealed that synaptic dysfunction often precedes photoreceptor degeneration, and that abnormal synaptic input from photoreceptors to bipolar cells causes circuits in the inner retina to become hyperactive. Here, we provide a brief overview of frequently used mouse models of photoreceptor degenerations. We then discuss insights into circuit remodeling triggered by early synaptic dysfunction in the outer and hyperactivity in the inner retina. We discuss these insights in the context of other experimental manipulations of synaptic function and activity. Knowledge of the plasticity and early remodeling of retinal circuits will be critical for the design of successful vision rescue strategies. PMID- 26500498 TI - Dendritic spine density of prefrontal layer 6 pyramidal neurons in relation to apical dendrite sculpting by nicotinic acetylcholine receptors. AB - Prefrontal layer 6 (L6) pyramidal neurons play an important role in the adult control of attention, facilitated by their strong activation by nicotinic acetylcholine receptors. These neurons in mouse association cortex are distinctive morphologically when compared to L6 neurons in primary cortical regions. Roughly equal proportions of the prefrontal L6 neurons have apical dendrites that are "long" (reaching to the pial surface) vs. "short" (terminating in the deep layers, as in primary cortical regions). This distinct prefrontal morphological pattern is established in the post-juvenile period and appears dependent on nicotinic receptors. Here, we examine dendritic spine densities in these two subgroups of prefrontal L6 pyramidal neurons under control conditions as well as after perturbation of nicotinic acetylcholine receptors. In control mice, the long neurons have significantly greater apical and basal dendritic spine density compared to the short neurons. Furthermore, manipulations of nicotinic receptors (chrna5 deletion or chronic developmental nicotine exposure) have distinct effects on these two subgroups of L6 neurons: apical spine density is significantly reduced in long neurons, and basal spine density is significantly increased in short neurons. These changes appear dependent on the alpha5 nicotinic subunit encoded by chrna5. Overall, the two subgroups of prefrontal L6 neurons appear positioned to integrate information either across cortex (long neurons) or within the deep layers (short neurons), and nicotinic perturbations differently alter spine density within each subgroup. PMID- 26500500 TI - Commentary: "Nitric oxide releases Cl(-) from acidic organelles in retinal amacrine cells". PMID- 26500499 TI - Stimulating somatosensory psychophysics: a double-blind, sham-controlled study of the neurobiological mechanisms of tDCS. AB - The neuromodulation technique transcranial direct current stimulation (tDCS) is thought to produce its effects on behavior by altering cortical excitability. Although the mechanisms underlying the observed effects are thought to rely on the balance of excitatory and inhibitory neurotransmission, the physiological principles of the technique are not completely understood. In this study, we examine the influence of tDCS on vibrotactile adaptation, using a simple amplitude discrimination paradigm that has been shown to exhibit modifications in performance due to changes in inhibitory neurotransmission. Double-blind tDCS (Anodal/Sham) of 1 mA was delivered for 600 s to electrodes positioned in a somatosensory/contralateral orbit montage. Stimulation was applied as part of a pre/post design, between blocks of the behavioral tasks. In accordance with previous work, results obtained before the application of tDCS indicated that amplitude discrimination thresholds were significantly worsened during adaptation trials, compared to those achieved at baseline. However, tDCS failed to modify amplitude discrimination performance. Using a Bayesian approach, this finding was revealed to constitute substantial evidence for the null hypothesis. The failure of DC stimulation to alter vibrotactile adaptation thresholds is discussed in the context of several factors that may have confounded the induction of changes in cortical plasticity. PMID- 26500501 TI - Tissue plasminogen activator inhibits NMDA-receptor-mediated increases in calcium levels in cultured hippocampal neurons. AB - NMDA receptors (NMDARs) play a critical role in neurotransmission, acting as essential mediators of many forms of synaptic plasticity, and also modulating aspects of development, synaptic transmission and cell death. NMDAR-induced responses are dependent on a range of factors including subunit composition and receptor location. Tissue-type plasminogen activator (tPA) is a serine protease that has been reported to interact with NMDARs and modulate NMDAR activity. In this study we report that tPA inhibits NMDAR-mediated changes in intracellular calcium levels in cultures of primary hippocampal neurons stimulated by low (5 MUM) but not high (50 MUM) concentrations of NMDA. tPA also inhibited changes in calcium levels stimulated by presynaptic release of glutamate following treatment with bicucculine/4-aminopyridine (4-AP). Inhibition was dependent on the proteolytic activity of tPA but was unaffected by alpha2-antiplasmin, an inhibitor of the tPA substrate plasmin, and receptor-associated protein (RAP), a pan-ligand blocker of the low-density lipoprotein receptor, two proteins previously reported to modulate NMDAR activity. These findings suggest that tPA can modulate changes in intracellular calcium levels in a subset of NMDARs expressed in cultured embryonic hippocampal neurons through a mechanism that involves the proteolytic activity of tPA and synaptic NMDARs. PMID- 26500502 TI - First evidence for glial pathology in late life minor depression: S100B is increased in males with minor depression. AB - Minor depression is diagnosed when a patient suffers from 2 to 4 depressive symptoms for at least 2 weeks. Though minor depression is a widespread phenomenon, its pathophysiology has hardly been studied. To get a first insight into the pathophysiological mechanisms underlying this disorder we assessed serum levels of biomarkers for plasticity, glial and neuronal function: brain-derived neurotrophic factor (BDNF), S100B and neuron specific enolase (NSE). 27 subjects with minor depressive episode and 82 healthy subjects over 60 years of age were selected from the database of the Leipzig population-based study of civilization diseases (LIFE). Serum levels of BDNF, S100B and NSE were compared between groups, and correlated with age, body-mass index (BMI), and degree of white matter hyperintensities (score on Fazekas scale). S100B was significantly increased in males with minor depression in comparison to healthy males, whereas other biomarkers did not differ between groups (p = 0.10-0.66). NSE correlated with Fazekas score in patients with minor depression (rs = 0.436, p = 0.048) and in the whole sample (rs = 0.252, p = 0.019). S100B correlated with BMI (rs = 0.246, p = 0.031) and with age in healthy subjects (rs = 0.345, p = 0.002). Increased S100B in males with minor depression, without alterations in BDNF and NSE, supports the glial hypothesis of depression. Correlation between white matter hyperintensities and NSE underscores the vascular hypothesis of late life depression. PMID- 26500503 TI - The neocortical microcircuit collaboration portal: a resource for rat somatosensory cortex. PMID- 26500504 TI - A computational relationship between thalamic sensory neural responses and contrast perception. AB - Uncovering the relationship between sensory neural responses and perceptual decisions remains a fundamental problem in neuroscience. Decades of experimental and modeling work in the sensory cortex have demonstrated that a perceptual decision pool is usually composed of tens to hundreds of neurons, the responses of which are significantly correlated not only with each other, but also with the behavioral choices of an animal. Few studies, however, have measured neural activity in the sensory thalamus of awake, behaving animals. Therefore, it remains unclear how many thalamic neurons are recruited and how the information from these neurons is pooled at subsequent cortical stages to form a perceptual decision. In a previous study we measured neural activity in the macaque lateral geniculate nucleus (LGN) during a two alternative forced choice (2AFC) contrast detection task, and found that single LGN neurons were significantly correlated with the monkeys' behavioral choices, despite their relatively poor contrast sensitivity and a lack of overall interneuronal correlations. We have now computationally tested a number of specific hypotheses relating these measured LGN neural responses to the contrast detection behavior of the animals. We modeled the perceptual decisions with different numbers of neurons and using a variety of pooling/readout strategies, and found that the most successful model consisted of about 50-200 LGN neurons, with individual neurons weighted differentially according to their signal-to-noise ratios (quantified as d primes). These results supported the hypothesis that in contrast detection the perceptual decision pool consists of multiple thalamic neurons, and that the response fluctuations in these neurons can influence contrast perception, with the more sensitive thalamic neurons likely to exert a greater influence. PMID- 26500505 TI - Functional connectivity in in vitro neuronal assemblies. AB - Complex network topologies represent the necessary substrate to support complex brain functions. In this work, we reviewed in vitro neuronal networks coupled to Micro-Electrode Arrays (MEAs) as biological substrate. Networks of dissociated neurons developing in vitro and coupled to MEAs, represent a valid experimental model for studying the mechanisms governing the formation, organization and conservation of neuronal cell assemblies. In this review, we present some examples of the use of statistical Cluster Coefficients and Small World indices to infer topological rules underlying the dynamics exhibited by homogeneous and engineered neuronal networks. PMID- 26500506 TI - Editorial: Neuromodulation of executive circuits. PMID- 26500507 TI - OFF bipolar cells in macaque retina: type-specific connectivity in the outer and inner synaptic layers. AB - OFF bipolar cells in the macaque retina were recently classified into five types: flat midget bipolar (FMB) and diffuse bipolar (DB) 1, 2, 3a, and 3b. We examined all parallel pathways from cone photoreceptors via OFF bipolar cells to parasol and midget ganglion cells by serial section transmission electron microscopy. Basal contacts of OFF bipolar cells to cone pedicles were previously categorized as triad-associated (TA) and non-TA (NTA). The latter was further divided into two groups located in the middle and marginal areas of the pedicle at the present eccentricity of 15 degrees . We then mapped the distributions of all three basal contacts of the five OFF bipolar cell types in the same area of cone pedicles. TA contacts were more numerous than NTA contacts in FMB (93%), DB1 (67%), and DB3a (81%) cells, but less in DB2 (30%) and DB3b (21%) cells. Cluster analysis of these contact parameters reconfirmed five distinct OFF bipolar cell types and showed these positional configurations of basal synapses to be cell type specific. This architecture is thought to provide a spatial framework for the interstitial diffusion and local uptake of the neurotransmitter (glutamate) that spills over from ribbon synapses. All five OFF bipolar cell types formed ribbon synaptic contacts to both parasol and midget ganglion cells. DB2 and 3a, DB1 and 3b, and FMB predominantly, moderately, and negligibly contacted parasol ganglion cells, respectively. FMB almost exclusively contacted midget ganglion cells, to which DB1 provided dominant output (58%), and DB2, 3a, and 3b provided between 3% and 10% of their output. Consequently, the cone signal sampling routes of a midget ganglion cell consisted of two substructures: the narrow (mainly 2-3 cones) FMB pathway and the wide (mainly 10 cones) DB pathway, where connection strength was four-fold greater in the FMB than DB pathway. The narrow and strong FMB pathway may confer the highest spatial resolution and sporadically may include blue cone signals. PMID- 26500508 TI - Genetic variations in the serotonergic system contribute to amygdala volume in humans. AB - The amygdala plays a critical role in emotion processing and psychiatric disorders associated with emotion dysfunction. Accumulating evidence suggests that amygdala structure is modulated by serotonin-related genes. However, there is a gap between the small contributions of single loci (less than 1%) and the reported 63-65% heritability of amygdala structure. To understand the "missing heritability," we systematically explored the contribution of serotonin genes on amygdala structure at the gene set level. The present study of 417 healthy Chinese volunteers examined 129 representative polymorphisms in genes from multiple biological mechanisms in the regulation of serotonin neurotransmission. A system-level approach using multiple regression analyses identified that nine SNPs collectively accounted for approximately 8% of the variance in amygdala volume. Permutation analyses showed that the probability of obtaining these findings by chance was low (p = 0.043, permuted for 1000 times). Findings showed that serotonin genes contribute moderately to individual differences in amygdala volume in a healthy Chinese sample. These results indicate that the system-level approach can help us to understand the genetic basis of a complex trait such as amygdala structure. PMID- 26500509 TI - Extra-neurohypophyseal axonal projections from individual vasopressin-containing magnocellular neurons in rat hypothalamus. AB - Conventional neuroanatomical, immunohistochemical techniques, and electrophysiological recording, as well as in vitro labeling methods may fail to detect long range extra-neurohypophyseal-projecting axons from vasopressin (AVP) containing magnocellular neurons (magnocells) in the hypothalamic paraventricular nucleus (PVN). Here, we used in vivo extracellular recording, juxtacellular labeling, post-hoc anatomo-immunohistochemical analysis and camera lucida reconstruction to address this question. We demonstrate that all well-labeled AVP immunopositive neurons inside the PVN possess main axons joining the tract of Greving and multi-axon-like processes, as well as axonal collaterals branching very near to the somata, which project to extra-neurohypophyseal regions. The detected regions in this study include the medial and lateral preoptical area, suprachiasmatic nucleus (SCN), lateral habenula (LHb), medial and central amygdala and the conducting systems, such as stria medullaris, the fornix and the internal capsule. Expression of vesicular glutamate transporter 2 was observed in axon-collaterals. These results, in congruency with several previous reports in the literature, provided unequivocal evidence that AVP magnocells have an uncommon feature of possessing multiple axon-like processes emanating from somata or proximal dendrites. Furthermore, the long-range non-neurohypophyseal projections are more common than an "occasional" phenomenon as previously thought. PMID- 26500510 TI - Peri-saccadic compression to two locations in a two-target choice saccade task. AB - When visual stimuli are presented at the onset of a saccadic eye movement they are seen compressed onto the target location of the saccade. This peri-saccadic compression is believed to result from internal feedback pathways between oculomotor and visual areas of the brain. This feedback enhances vision around the saccade target at the expense of localization ability in other regions of the visual field. Although saccades can be targeted at only one object at a time, often multiple potential targets are available in a visual scene, and the oculomotor system has to choose which target to look at. If two targets are available, preparatory activity builds-up at both target locations in oculomotor maps. Here we show that, in this situation, two foci of compression develop, independent of which of the two targets is eventually chosen for the saccade. Our results suggest that theories that use oculomotor feedback as efference copy signals for upcoming eye movements should take the possibility into account that multiple feedback signals from potential targets may occur in parallel before the execution of a saccade. PMID- 26500511 TI - Neurogenesis paradoxically decreases both pattern separation and memory interference. AB - The hippocampus has been the focus of memory research for decades. While the functional role of this structure is not fully understood, it is widely recognized as being vital for rapid yet accurate encoding and retrieval of associative memories. Since the discovery of adult hippocampal neurogenesis in the dentate gyrus by Altman and Das in the 1960's, many theories and models have been put forward to explain the functional role it plays in learning and memory. These models postulate different ways in which new neurons are introduced into the dentate gyrus and their functional importance for learning and memory. Few if any previous models have incorporated the unique properties of young adult-born dentate granule cells and the developmental trajectory. In this paper, we propose a novel computational model of the dentate gyrus that incorporates the developmental trajectory of the adult-born dentate granule cells, including changes in synaptic plasticity, connectivity, excitability and lateral inhibition, using a modified version of the Restricted Boltzmann machine. Our results show superior performance on memory reconstruction tasks for both recent and distally learned items, when the unique characteristics of young dentate granule cells are taken into account. Even though the hyperexcitability of the young neurons generates more overlapping neural codes, reducing pattern separation, the unique properties of the young neurons nonetheless contribute to reducing retroactive and proactive interference, at both short and long time scales. The sparse connectivity is particularly important for generating distinct memory traces for highly overlapping patterns that are learned within the same context. PMID- 26500514 TI - Augmenting brain function with meditation: can detachment coincide with empathy? PMID- 26500512 TI - Neuroimaging studies of striatum in cognition part II: Parkinson's disease. AB - In recent years a gradual shift in the definition of Parkinson's disease (PD) has been established, from a classical akinetic-rigid movement disorder to a multi system neurodegenerative disease. While the pathophysiology of PD is complex and goes much beyond the nigro-striatal degeneration, the striatum has been shown to be responsible for many cognitive functions. Patients with PD develop impairments in multiple cognitive domains and the PD model is probably the most extensively studied regarding striatum dysfunction and its influence on cognition. Up to 40% of PD patients present cognitive impairment even in the early stages of disease development. Thus, understanding the key patterns of striatum and connecting regions' influence on cognition will help develop more specific approaches to alleviate cognitive impairment and slow down its decline. This review focuses on the contribution of neuroimaging studies in understanding how striatum impairment affects cognition in PD. PMID- 26500513 TI - Neuroimaging studies of the striatum in cognition Part I: healthy individuals. AB - The striatum has traditionally mainly been associated with playing a key role in the modulation of motor functions. Indeed, lesion studies in animals and studies of some neurological conditions in humans have brought further evidence to this idea. However, better methods of investigation have raised concerns about this notion, and it was proposed that the striatum could also be involved in different types of functions including cognitive ones. Although the notion was originally a matter of debate, it is now well-accepted that the caudate nucleus contributes to cognition, while the putamen could be involved in motor functions, and to some extent in cognitive functions as well. With the arrival of modern neuroimaging techniques in the early 1990, knowledge supporting the cognitive aspect of the striatum has greatly increased, and a substantial number of scientific papers were published studying the role of the striatum in healthy individuals. For the first time, it was possible to assess the contribution of specific areas of the brain during the execution of a cognitive task. Neuroanatomical studies have described functional loops involving the striatum and the prefrontal cortex suggesting a specific interaction between these two structures. This review examines the data up to date and provides strong evidence for a specific contribution of the fronto-striatal regions in different cognitive processes, such as set-shifting, self-initiated responses, rule learning, action contingency, and planning. Finally, a new two-level functional model involving the prefrontal cortex and the dorsal striatum is proposed suggesting an essential role of the dorsal striatum in selecting between competing potential responses or actions, and in resolving a high level of ambiguity. PMID- 26500515 TI - Timing of therapies for Down syndrome: the sooner, the better. AB - Intellectual disability (ID) is the unavoidable hallmark of Down syndrome (DS), with a heavy impact on public health. Accumulating evidence shows that DS is characterized by numerous neurodevelopmental alterations among which the reduction of neurogenesis, dendritic hypotrophy and connectivity alterations appear to play a particularly prominent role. Although the mechanisms whereby gene triplication impairs brain development in DS have not been fully clarified, it is theoretically possible to correct trisomy-dependent defects with targeted pharmacotherapies. This review summarizes what we know about the effects of pharmacotherapies during different life stages in mouse models of DS. Since brain alterations in DS start to be present prenatally, the prenatal period represents an optimum window of opportunity for therapeutic interventions. Importantly, recent studies clearly show that treatment during the prenatal period can rescue overall brain development and behavior and that this effect outlasts treatment cessation. Although late therapies are unlikely to exert drastic changes in the brain, they may have an impact on the hippocampus, a brain region where neurogenesis continues throughout life. Indeed, treatment at adult life stages improves or even rescues hippocampal neurogenesis and connectivity and hippocampal-dependent learning and memory, although the duration of these effects still remains, in the majority of cases, a matter of investigation. The exciting discovery that trisomy-linked brain abnormalities can be prevented with early interventions gives us reason to believe that treatments during pregnancy may rescue brain development in fetuses with DS. For this reason we deem it extremely important to expedite the discovery of additional therapies practicable in humans in order to identify the best treatment/s in terms of efficacy and paucity of side effects. Prompt achievement of this goal is the big challenge for the scientific community of researchers interested in DS. PMID- 26500516 TI - Neural correlates of rules and conflict in medial prefrontal cortex during decision and feedback epochs. AB - The ability to properly adjust behavioral responses to cues in a changing environment is crucial for survival. Activity in the medial Prefrontal Cortex (mPFC) is thought to both represent rules to guide behavior as well as detect and resolve conflicts between rules in changing contingencies. However, while lesion and pharmacological studies have supported a crucial role for mPFC in this type of set-shifting, an understanding of how mPFC represents current rules or detects and resolves conflict between different rules is unclear. Here, we directly address the role of rat mPFC in shifting rule based behavioral strategies using a novel behavioral task designed to tease apart neural signatures of rules, conflict and direction. We demonstrate that activity of single neurons in rat mPFC represent distinct rules. Further, we show increased firing on high conflict trials in a separate population of mPFC neurons. Reduced firing in both populations of neurons was associated with poor performance. Moreover, activity in both populations increased and decreased firing during the outcome epoch when reward was and was not delivered on correct and incorrect trials, respectively. In addition, outcome firing was modulated by the current rule and the degree of conflict associated with the previous decision. These results promote a greater understanding of the role that mPFC plays in switching between rules, signaling both rule and conflict to promote improved behavioral performance. PMID- 26500517 TI - Distinct neural correlates for attention lapses in patients with schizophrenia and healthy participants. AB - Momentary lapses in attention are common in healthy populations. This phenomenon has recently received increased investigation, particularly in relationship to the default mode network (DMN). Previous research has suggested that these lapses may be due to intrusive task-irrelevant thoughts. The study of this phenomenon in schizophrenia, which is characterized by a wide variety of cognitive deficits including deficits in attention, has not previously been explored. We used the AX Continuous Performance Task to investigate attention lapses in healthy participants as well as patients with schizophrenia. We found distinct patterns of network activation between these two groups. Lapses in healthy participants were associated with DMN activation, while in patients, the same behavioral phenomenon was associated with deactivations in frontal-parietal control network (FPCN) regions. When considered in contrast to the results observed in healthy participants, these results suggest an additional origin of attention lapses in patients derived from a loss of task-related context, rather than intrusive task irrelevant thoughts. PMID- 26500518 TI - The effects of impulsivity and proactive inhibition on reactive inhibition and the go process: insights from vocal and manual stop signal tasks. AB - This study measured proactive and reactive response inhibition and their relationships with self-reported impulsivity. We examined the domains of both vocal and manual responding using a stop signal task (SST) with two stop probabilities: high and low probability stop (1/3 and 1/6 stops respectively). Our aim was to evaluate the effect stop probability would have on reactive and proactive inhibition. We tested 44 subjects and found that for the high compared to low probability stop signal condition, more proactive inhibition was evident and this was correlated with a reduction in the stop signal reaction time (SSRT). We found that reactive inhibition had a positive relationship with dysfunctional but not functional impulsivity in both vocal and manual domains of responding. These findings support the hypothesis that proactive inhibition may pre-activate the network for reactive inhibition. PMID- 26500520 TI - Bimanual non-congruent actions in motor neglect syndrome: a combined behavioral/fMRI study. AB - In Motor Neglect (MN) syndrome, a specific impairment in non-congruent bimanual movements has been described. In the present case-control study, we investigated the neuro-functional correlates of this behavioral deficit. Two right-brain damaged (RBD) patients, one with (MN+) and one without (MN-) MN, were evaluated by means of functional Magnetic Resonance Imaging (fMRI) in a bimanual Circles Lines (CL) paradigm. Patients were requested to perform right-hand movements (lines-drawing) and, simultaneously, congruent (lines-drawing) or non-congruent (circles-drawing) left-hand movements. In the behavioral task, MN- patient showed a bimanual-coupling-effect, while MN+ patient did not. The fMRI study showed that in MN-, a fronto-parietal network, mainly involving the pre-supplementary motor area (pre-SMA) and the posterior parietal cortex (PPC), was significantly more active in non-congruent than in congruent conditions, as previously shown in healthy subjects. On the contrary, MN+ patient showed an opposite pattern of activation both in pre-SMA and in PPC. Within this fronto-parietal network, the pre-SMA is supposed to exert an inhibitory influence on the default coupling of homologous muscles, thus allowing the execution of non-congruent movements. In MN syndrome, the described abnormal pre-SMA activity supports the hypothesis that a failure to inhibit ipsilesional motor programs might determine a specific impairment of non-congruent movements. PMID- 26500519 TI - Auditory cortical deactivation during speech production and following speech perception: an EEG investigation of the temporal dynamics of the auditory alpha rhythm. AB - Sensorimotor integration (SMI) across the dorsal stream enables online monitoring of speech. Jenson et al. (2014) used independent component analysis (ICA) and event related spectral perturbation (ERSP) analysis of electroencephalography (EEG) data to describe anterior sensorimotor (e.g., premotor cortex, PMC) activity during speech perception and production. The purpose of the current study was to identify and temporally map neural activity from posterior (i.e., auditory) regions of the dorsal stream in the same tasks. Perception tasks required "active" discrimination of syllable pairs (/ba/ and /da/) in quiet and noisy conditions. Production conditions required overt production of syllable pairs and nouns. ICA performed on concatenated raw 68 channel EEG data from all tasks identified bilateral "auditory" alpha (alpha) components in 15 of 29 participants localized to pSTG (left) and pMTG (right). ERSP analyses were performed to reveal fluctuations in the spectral power of the alpha rhythm clusters across time. Production conditions were characterized by significant alpha event related synchronization (ERS; pFDR < 0.05) concurrent with EMG activity from speech production, consistent with speech-induced auditory inhibition. Discrimination conditions were also characterized by alpha ERS following stimulus offset. Auditory alpha ERS in all conditions temporally aligned with PMC activity reported in Jenson et al. (2014). These findings are indicative of speech-induced suppression of auditory regions, possibly via efference copy. The presence of the same pattern following stimulus offset in discrimination conditions suggests that sensorimotor contributions following speech perception reflect covert replay, and that covert replay provides one source of the motor activity previously observed in some speech perception tasks. To our knowledge, this is the first time that inhibition of auditory regions by speech has been observed in real-time with the ICA/ERSP technique. PMID- 26500521 TI - Training Efficiency and Transfer Success in an Extended Real-Time Functional MRI Neurofeedback Training of the Somatomotor Cortex of Healthy Subjects. AB - This study investigated the level of self-regulation of the somatomotor cortices (SMCs) attained by an extended functional magnetic resonance imaging (fMRI) neurofeedback training. Sixteen healthy subjects performed 12 real-time functional magnetic resonance imaging neurofeedback training sessions within 4 weeks, involving motor imagery of the dominant right as well as the non-dominant left hand. Target regions of interests in the SMC were individually localized prior to the training by overt finger movements. The feedback signal (FS) was defined as the difference between fMRI activation in the contra- and ipsilateral SMC and visually presented to the subjects. Training efficiency was determined by an off-line general linear model analysis determining the fMRI percent signal changes in the SMC target areas accomplished during the neurofeedback training. Transfer success was assessed by comparing the pre- and post-training transfer task, i.e., the neurofeedback paradigm without the presentation of the FS. Group results show a distinct increase in feedback performance (FP) in the transfer task for the trained group compared to a matched untrained control group, as well as an increase in the time course of the training, indicating an efficient training and a successful transfer. Individual analysis revealed that the training efficiency was not only highly correlated to the transfer success but also predictive. Trainings with at least 12 efficient training runs were associated with a successful transfer outcome. A group analysis of the hemispheric contributions to the FP showed that it is mainly driven by increased fMRI activation in the contralateral SMC, although some individuals relied on ipsilateral deactivation. Training and transfer results showed no difference between left- and right-hand imagery, with a slight indication of more ipsilateral deactivation in the early right-hand trainings. PMID- 26500522 TI - Neural Mechanisms Underlying Perilesional Transcranial Direct Current Stimulation in Aphasia: A Feasibility Study. AB - Little is known about the neural mechanisms by which transcranial direct current stimulation (tDCS) impacts on language processing in post-stroke aphasia. This was addressed in a proof-of-principle study that explored the effects of tDCS application in aphasia during simultaneous functional magnetic resonance imaging (fMRI). We employed a single subject, cross-over, sham-tDCS controlled design, and the stimulation was administered to an individualized perilesional stimulation site that was identified by a baseline fMRI scan and a picture naming task. Peak activity during the baseline scan was located in the spared left inferior frontal gyrus and this area was stimulated during a subsequent cross over phase. tDCS was successfully administered to the target region and anodal- vs. sham-tDCS resulted in selectively increased activity at the stimulation site. Our results thus demonstrate that it is feasible to precisely target an individualized stimulation site in aphasia patients during simultaneous fMRI, which allows assessing the neural mechanisms underlying tDCS application. The functional imaging results of this case report highlight one possible mechanism that may have contributed to beneficial behavioral stimulation effects in previous clinical tDCS trials in aphasia. In the future, this approach will allow identifying distinct patterns of stimulation effects on neural processing in larger cohorts of patients. This may ultimately yield information about the variability of tDCS effects on brain functions in aphasia. PMID- 26500523 TI - A task-independent neural representation of subjective certainty in visual perception. AB - Am I really sure? This is a question not only scientists ask themselves but practically everybody every day. A recent study provides behavioral evidence supporting the view that one's subjective confidence in a decision (i.e., feeling sure that a decision is correct) is represented in a task-independent format. Previous neuroimaging studies identified neural correlates of decision confidence but whether or not these are task-dependent remains unclear. Here, combining two perceptual decision tasks with functional magnetic resonance imaging (fMRI), we provide neural evidence for a task-independent representation of degrees of subjective certainty (i.e., a neural representation of subjective certainty that remains constant across two visual tasks). Importantly, due to the constant stimulus-intensity used this result is independent of task-difficulty and stimulus properties. Our data provide strong evidence for a generic mechanism underlying the computation of subjective perceptual certainty in vision. PMID- 26500524 TI - Psychopathic traits are associated with reduced attention to the eyes of emotional faces among adult male non-offenders. AB - Psychopathic traits are linked with impairments in emotional facial expression recognition. These impairments may, in part, reflect reduced attention to the eyes of emotional faces. Although reduced attention to the eyes has been noted among children with conduct problems and callous-unemotional traits, similar findings are yet to be found in relation to psychopathic traits among adult male participants. Here we investigated the relationship of primary (selfish, uncaring) and secondary (impulsive, antisocial) psychopathic traits with attention to the eyes among adult male non-offenders during an emotion recognition task. We measured the number of fixations, and overall dwell time, on the eyes, and the mouth of male and female faces showing the six basic emotions at varying levels of intensity. We found no relationship of primary or secondary psychopathic traits with recognition accuracy. However, primary psychopathic traits were associated with a reduced number of fixations, and lower overall dwell time, on the eyes relative to the mouth across expressions, intensity, and sex. Furthermore, the relationship of primary psychopathic traits with attention to the eyes of angry and fearful faces was influenced by the sex and intensity of the expression. We also showed that a greater number of fixations on the eyes, relative to the mouth, were associated with increased accuracy for angry and fearful expression recognition. These results are the first to show effects of psychopathic traits on attention to the eyes of emotional faces in an adult male sample, and may support amygdala based accounts of psychopathy. These findings may also have methodological implications for clinical studies of emotion recognition. PMID- 26500525 TI - Differential effects of socioeconomic status on working and procedural memory systems. AB - While prior research has shown a strong relationship between socioeconomic status (SES) and working memory performance, the relation between SES and procedural (implicit) memory remains unknown. Convergent research in both animals and humans has revealed a fundamental dissociation, both behaviorally and neurally, between a working memory system that depends on medial temporal-lobe structures and the dorsal lateral prefrontal cortex (DLPFC) vs. a procedural memory system that depends on the basal ganglia. Here, we measured performance in adolescents from lower- and higher-SES backgrounds on tests of working memory capacity (complex working memory span) and procedural memory (probabilistic classification) and their hippocampal, DLPFC, and caudate volumes. Lower-SES adolescents had worse working memory performance and smaller hippocampal and DLPFC volumes than their higher-SES peers, but there was no significant difference between the lower- and higher-SES groups on the procedural memory task or in caudate volumes. These findings suggest that SES may have a selective influence on hippocampal prefrontal-dependent working memory and little influence on striatal-dependent procedural memory. PMID- 26500526 TI - Neural bases of accented speech perception. AB - The recognition of unfamiliar regional and foreign accents represents a challenging task for the speech perception system (Floccia et al., 2006; Adank et al., 2009). Despite the frequency with which we encounter such accents, the neural mechanisms supporting successful perception of accented speech are poorly understood. Nonetheless, candidate neural substrates involved in processing speech in challenging listening conditions, including accented speech, are beginning to be identified. This review will outline neural bases associated with perception of accented speech in the light of current models of speech perception, and compare these data to brain areas associated with processing other speech distortions. We will subsequently evaluate competing models of speech processing with regards to neural processing of accented speech. See Cristia et al. (2012) for an in-depth overview of behavioral aspects of accent processing. PMID- 26500527 TI - Children's belief- and desire-reasoning in the temporoparietal junction: evidence for specialization from functional near-infrared spectroscopy. AB - Behaviorally, children's explicit theory of mind (ToM) proceeds in a progression of mental-state understandings: developmentally, children demonstrate accurate explicit desire-reasoning before accurate explicit belief-reasoning. Given its robust and cross-cultural nature, we hypothesize this progression may be paced in part by maturation/specialization of the brain. Neuroimaging research demonstrates that the right temporoparietal junction (TPJ) becomes increasingly selective for ToM reasoning as children age, and as their ToM improves. But this research has narrowly focused on beliefs or on undifferentiated mental-states. A recent ERP study in children included a critical contrast to desire-reasoning, and demonstrated that right posterior potentials differentiated belief-reasoning from desire-reasoning. Taken together, the literature suggests that children's desire-belief progression may be paced by specialization of the right TPJ for belief-reasoning specifically, beyond desire-reasoning. In the present study, we tested this hypothesis directly by examining children's belief- and desire reasoning using functional near-infrared spectroscopy in conjunction with structural magnetic resonance imaging to pinpoint brain activation in the right TPJ. Results showed greatest activation in the right TPJ for belief-reasoning, beyond desire-reasoning, and beyond non-mental reasoning (control). Findings replicate and critically extend prior ERP results, and provide clear evidence for a specific neural mechanism underlying children's progression from understanding desires to understanding beliefs. PMID- 26500528 TI - Unsupervised invariance learning of transformation sequences in a model of object recognition yields selectivity for non-accidental properties. AB - Non-accidental properties (NAPs) correspond to image properties that are invariant to changes in viewpoint (e.g., straight vs. curved contours) and are distinguished from metric properties (MPs) that can change continuously with in depth object rotation (e.g., aspect ratio, degree of curvature, etc.). Behavioral and electrophysiological studies of shape processing have demonstrated greater sensitivity to differences in NAPs than in MPs. However, previous work has shown that such sensitivity is lacking in multiple-views models of object recognition such as Hmax. These models typically assume that object processing is based on populations of view-tuned neurons with distributed symmetrical bell-shaped tuning that are modulated at least as much by differences in MPs as in NAPs. Here, we test the hypothesis that unsupervised learning of invariances to object transformations may increase the sensitivity to differences in NAPs vs. MPs in Hmax. We collected a database of video sequences with objects slowly rotating in depth in an attempt to mimic sequences viewed during object manipulation by young children during early developmental stages. We show that unsupervised learning yields shape-tuning in higher stages with greater sensitivity to differences in NAPs vs. MPs in agreement with monkey IT data. Together, these results suggest that greater NAP sensitivity may arise from experiencing different in-depth rotations of objects. PMID- 26500529 TI - An algorithm to predict the connectome of neural microcircuits. AB - Experimentally mapping synaptic connections, in terms of the numbers and locations of their synapses and estimating connection probabilities, is still not a tractable task, even for small volumes of tissue. In fact, the six layers of the neocortex contain thousands of unique types of synaptic connections between the many different types of neurons, of which only a handful have been characterized experimentally. Here we present a theoretical framework and a data driven algorithmic strategy to digitally reconstruct the complete synaptic connectivity between the different types of neurons in a small well-defined volume of tissue-the micro-scale connectome of a neural microcircuit. By enforcing a set of established principles of synaptic connectivity, and leveraging interdependencies between fundamental properties of neural microcircuits to constrain the reconstructed connectivity, the algorithm yields three parameters per connection type that predict the anatomy of all types of biologically viable synaptic connections. The predictions reproduce a spectrum of experimental data on synaptic connectivity not used by the algorithm. We conclude that an algorithmic approach to the connectome can serve as a tool to accelerate experimental mapping, indicating the minimal dataset required to make useful predictions, identifying the datasets required to improve their accuracy, testing the feasibility of experimental measurements, and making it possible to test hypotheses of synaptic connectivity. PMID- 26500530 TI - A model-based approach to predict muscle synergies using optimization: application to feedback control. AB - This paper presents a new model-based method to define muscle synergies. Unlike the conventional factorization approach, which extracts synergies from electromyographic data, the proposed method employs a biomechanical model and formally defines the synergies as the solution of an optimal control problem. As a result, the number of required synergies is directly related to the dimensions of the operational space. The estimated synergies are posture-dependent, which correlate well with the results of standard factorization methods. Two examples are used to showcase this method: a two-dimensional forearm model, and a three dimensional driver arm model. It has been shown here that the synergies need to be task-specific (i.e., they are defined for the specific operational spaces: the elbow angle and the steering wheel angle in the two systems). This functional definition of synergies results in a low-dimensional control space, in which every force in the operational space is accurately created by a unique combination of synergies. As such, there is no need for extra criteria (e.g., minimizing effort) in the process of motion control. This approach is motivated by the need for fast and bio-plausible feedback control of musculoskeletal systems, and can have important implications in engineering, motor control, and biomechanics. PMID- 26500532 TI - Enhanced HMAX model with feedforward feature learning for multiclass categorization. AB - In recent years, the interdisciplinary research between neuroscience and computer vision has promoted the development in both fields. Many biologically inspired visual models are proposed, and among them, the Hierarchical Max-pooling model (HMAX) is a feedforward model mimicking the structures and functions of V1 to posterior inferotemporal (PIT) layer of the primate visual cortex, which could generate a series of position- and scale- invariant features. However, it could be improved with attention modulation and memory processing, which are two important properties of the primate visual cortex. Thus, in this paper, based on recent biological research on the primate visual cortex, we still mimic the first 100-150 ms of visual cognition to enhance the HMAX model, which mainly focuses on the unsupervised feedforward feature learning process. The main modifications are as follows: (1) To mimic the attention modulation mechanism of V1 layer, a bottom up saliency map is computed in the S1 layer of the HMAX model, which can support the initial feature extraction for memory processing; (2) To mimic the learning, clustering and short-term memory to long-term memory conversion abilities of V2 and IT, an unsupervised iterative clustering method is used to learn clusters with multiscale middle level patches, which are taken as long-term memory; (3) Inspired by the multiple feature encoding mode of the primate visual cortex, information including color, orientation, and spatial position are encoded in different layers of the HMAX model progressively. By adding a softmax layer at the top of the model, multiclass categorization experiments can be conducted, and the results on Caltech101 show that the enhanced model with a smaller memory size exhibits higher accuracy than the original HMAX model, and could also achieve better accuracy than other unsupervised feature learning methods in multiclass categorization task. PMID- 26500531 TI - Coordinated alpha and gamma control of muscles and spindles in movement and posture. AB - Mounting evidence suggests that both alpha and gamma motoneurons are active during movement and posture, but how does the central motor system coordinate the alpha-gamma controls in these tasks remains sketchy due to lack of in vivo data. Here a computational model of alpha-gamma control of muscles and spindles was used to investigate alpha-gamma integration and coordination for movement and posture. The model comprised physiologically realistic spinal circuitry, muscles, proprioceptors, and skeletal biomechanics. In the model, we divided the cortical descending commands into static and dynamic sets, where static commands (alpha s and gamma s ) were for posture maintenance and dynamic commands (alpha d and gamma d ) were responsible for movement. We matched our model to human reaching movement data by straightforward adjustments of descending commands derived from either minimal-jerk trajectories or human EMGs. The matched movement showed smooth reach-to-hold trajectories qualitatively close to human behaviors, and the reproduced EMGs showed the classic tri-phasic patterns. In particular, the function of gamma d was to gate the alpha d command at the propriospinal neurons (PN) such that antagonistic muscles can accelerate or decelerate the limb with proper timing. Independent control of joint position and stiffness could be achieved by adjusting static commands. Deefferentation in the model indicated that accurate static commands of alpha s and gamma s are essential to achieve stable terminal posture precisely, and that the gamma d command is as important as the alpha d command in controlling antagonistic muscles for desired movements. Deafferentation in the model showed that losing proprioceptive afferents mainly affected the terminal position of movement, similar to the abnormal behaviors observed in human and animals. Our results illustrated that tuning the simple forms of alpha-gamma commands can reproduce a range of human reach-to-hold movements, and it is necessary to coordinate the set of alpha-gamma descending commands for accurate and stable control of movement and posture. PMID- 26500533 TI - Editorial: Modularity in motor control: from muscle synergies to cognitive action representation. PMID- 26500534 TI - Eccrine Angiomatous Hamartoma in an Adolescent. AB - Eccrine angiomatous hamartoma is a rare hamartoma that usually affects childhood and adolescence. In this report we describe a typical onset and clinical presentation of eccrine angiomatous hamartoma. Histopathological analysis and immunohistochemical staining of the sections were done to confirm the diagnosis. PMID- 26500535 TI - Adult Onset of BRAF(V600E)-Mutated Langerhans Cell Histiocytosis with Cutaneous Involvement Successfully Diagnosed by Immunohistochemical Staining. AB - Langerhans cell histiocytosis (LCH) is characterized by the clonal proliferation of Langerhans cells; it is categorized as a single-system disease with single or multifocal lesions, and as a multi-system disease with or without the risk of organ involvement. Although the skin is not categorized as a risk organ, the precise diagnosis of skin lesions is necessary to determine the protocol for the treatment of LCH. In this report, we describe a 28-year-old Japanese man with adult onset of BRAF(V600E)-mutated LCH with cutaneous involvement successfully diagnosed by immunohistochemical staining. Our report suggests that immunohistochemical staining for the BRAF(V600E) gene could be a diagnostic tool to determine the clinical type of LCH. PMID- 26500536 TI - Giant Hidroacanthoma Simplex Mimicking Bowen's Disease. AB - Hidroacanthoma simplex is a benign tumor of the skin, macroscopically resembling seborrheic keratosis or Bowen's disease and histologically mimicking clonal-type seborrheic keratosis. We observed a plaque of 70 * 50 mm on the right flank part. From clinical appearance, we suspected Bowen's disease; however, based on immunohistochemical findings, we made a diagnosis of hidroacanthoma simplex. PMID- 26500537 TI - A Case of Leser-Trelat Syndrome Associated with a Renal Cell Carcinoma. AB - Seborrheic keratoses can often be found in elderly people. In general, they appear gradually. In cases of a sudden eruption with itching it might be paraneoplastic. Although some authors doubt the existence of the paraneoplastic Leser-Trelat syndrome, we present a case of sudden eruption of seborrheic keratoses connected with a newly diagnosed renal cell carcinoma. As far as we know, this is the first case report of a Leser-Trelat syndrome with a malignancy of the kidney. PMID- 26500538 TI - Cutaneous Eruption due to Telaprevir. AB - Hepatitis C virus (HCV) chronically infects 0.5-3% of the world population. A large group of patients develop cirrhosis and its complications. Since 2011, telaprevir and boceprevir are used, improving the disease evolution. One of the main side effects of these drugs is skin eruption. We report a 53-year-old patient with cirrhosis due to HCV who started the classic treatment associated with telaprevir. In the ninth week, he presented a severe rash that required the interruption of this drug. We emphasize the importance of early recognition and appropriate management of adverse skin reaction. PMID- 26500539 TI - Successful Treatment with Pazopanib for Multiple Lung Metastases of Inguinal Epithelioid Sarcoma: A Case Report. AB - Epithelioid sarcoma is a rare soft tissue sarcoma and usually resistant to chemotherapy. It has high rates of local recurrence and distant metastasis, and the prognosis after metastasis is poor. We report a case of multiple lung metastases of an epithelioid sarcoma originating in the inguinal area that we treated with the multikinase inhibitor pazopanib. The patient was a 38-year-old male who began to experience discomfort in his left inguinal area. Magnetic resonance imaging showed a tumor extended from the medial aspect of the wing of the left ilium along the iliopsoas muscle to its site of insertion on the femur. The histopathological diagnosis with a biopsy was proximal-type epithelioid sarcoma. Although a positron emission tomography examination showed fluorodeoxyglucose accumulation in the left inguinal tumor, there was no distant metastasis. Wide resection by a combined iliac resection procedure was performed. Twelve months after surgery, computed tomography revealed multiple nodules and a diagnosis of bilateral multiple lung metastases was made. Treatment with pazopanib 800 mg was started. After 2.5 months of treatment, a clear reduction in the size of the pulmonary metastases was shown. Thirty months after the start of pazopanib treatment, most of the metastases have disappeared, and no development of new lesions has been seen. Therefore, it appeared that pazopanib was capable of serving as one of the choices of therapeutic agents that should be taken into consideration for the treatment of advanced epithelioid sarcoma. PMID- 26500540 TI - Adipsia in a Diabetes Insipidus Patient. AB - Central diabetes insipidus is a very common disorder after brain surgery or/trauma or even in the presence of brain inflammatory diseases. Polyuria and polydipsia are the clinical markers, but sometimes clinical situations are presenting with no thirst. These are not frequent but are life-treating conditions. Diagnosis is not easy, and for this reason some cases are treated late. We describe here a very infrequent oncological case of dangerous adipsic diabetes insipidus in a young girl who survived. PMID- 26500541 TI - Hypercalcemia-Induced Hypokalemic Metabolic Alkalosis in a Multiple Myeloma Patient: The Risk of Furosemide Use. AB - Hypercalcemia is often seen in patients with malignancies, and in the past treatment for this has traditionally included loop diuretics. Clinically, patients with hypercalcemia frequently present with polyuria and volume contraction which may be further exacerbated by diuretic therapy. In the lab, hypercalcemia has been shown to activate the calcium-sensing receptor in the thick ascending limb of Henle and inactivate the 2 chloride sodium potassium co transporter and induce a hypokalemic metabolic alkalosis, an effect similar to that of the loop diuretic furosemide. We now report what may well be the first clinical correlate of this laboratory finding in a patient who developed a hypokalemic metabolic alkalosis as a consequence of severe hypercalcemia due to multiple myeloma and whose metabolic derangement was corrected without the use of a loop diuretic which may have exacerbated the electrolyte abnormalities. PMID- 26500542 TI - Hemiparetic Primary Lateral Sclerosis: Revisiting Mills Syndrome. AB - A slowly progressive hemiparesis beginning in a single limb with evolution to the ipsilateral limb was originally described in 8 patients in 1906 by Mills. We present 5 cases of progressive hemiparetic corticospinal tract degeneration, identified by the clinical presentation and the exclusion of other etiologies using serological, imaging, and electrodiagnostic studies. PMID- 26500543 TI - A Case of Recurrent Hemorrhages due to a Chronic Expanding Encapsulated Intracranial Hematoma. AB - Few case reports of encapsulated intracranial hematoma (EIH) exist, and the mechanisms underlying the onset and enlargement of EIH remain unclear. Here, we report on a 39-year-old woman with an EIH that repeatedly hemorrhaged and swelled and was ultimately surgically removed. In June 2012, the patient visited her local doctor, complaining of headaches. A magnetic resonance imaging (MRI) scan identified a small hemorrhage of approximately 7 mm in her right basal ganglia, and a wait-and-see approach was adopted. Six months later, her headaches recurred. She was admitted to our department after MRI showed tumor lesions accompanying the intermittent hemorrhaging in the right basal ganglia. After admission, hemorrhaging was again observed, with symptoms progressing to left sided hemiplegia and fluctuating consciousness; thus, a craniotomy was performed. No obvious abnormal blood vessels were observed on the preoperative cerebral angiography. We accessed the lesion using a transcortical approach via a right frontotemporal craniotomy and removed the subacute hematoma by extracting the encapsulated tumor as a single mass. Subsequent pathological examinations showed that the hematoma exhibited abnormal internal vascularization and was covered with a capsule formed from growing capillaries and accumulating collagen fibers, suggesting that it was an EIH. No lingering neurological symptoms were noted upon postoperative follow-up. This type of hematoma expands slowly and is asymptomatic, with reported cases consisting of patients that already have neurological deficits due to progressive hematoma growth. Our report is one of a few to provide a clinical picture of the initial stages that occur prior to hematoma encapsulation. PMID- 26500544 TI - Pharmacokinetics of Levodopa before and after Gastrointestinal Resection in Parkinson's Disease. AB - INTRODUCTION: Levodopa (LD) is important in the clinical treatment of Parkinson's disease (PD), and the changes of its pharmacokinetics may affect the clinical outcome. LD is mainly absorbed in the upper intestine; thus, the pharmacokinetics of LD may change after gastrointestinal operation. Here, we present the case of a patient who underwent resection of the intestine and compared his LD pharmacokinetics before and after resection. CASE PRESENTATION: A 72-year-old Japanese male PD patient developed jaundice and was diagnosed with cholangiocarcinoma. Pancreaticoduodenectomy was performed and part of the stomach, total duodenum, and part of the jejunum were resected. The patient had been treated with LD, and his pharmacokinetics was checked twice at the age of 68 years. Because LD is absorbed in the duodenum and jejunum, we checked his pharmacokinetics again after the operation. The results before the operation were almost similar; however, in comparison, the area under the curve and peak drug concentration was reduced, and the time-to-peak drug concentration and elimination halftime were elongated after the operation. CONCLUSION: Physicians must pay attention to the change of LD pharmacokinetics after gastrointestinal operation. PMID- 26500545 TI - Wallenberg Syndrome with Associated Motor Weakness in a Two-Week-Postpartum Female. AB - A 30-year-old, right-handed female presented 2 weeks postpartum with acute-onset severe headache, vertigo, and vomiting. Initial neurologic examination illustrated lingual dysarthria, horizontal nystagmus, right dysmetria on finger to-nose testing, and weakness of the extremities. Magnetic resonance imaging showed a large, left lateral medullary infarction (Wallenberg syndrome) with cephalad extension into the ipsilateral pons as well as involvement of the left middle cerebellar peduncle. The patient was discharged 3 weeks later to an inpatient rehabilitation facility with gradual improvement of her symptoms. PMID- 26500546 TI - Computational reconstitution of spine calcium transients from individual proteins. AB - We have built a stochastic model in the program MCell that simulates Ca(2+) transients in spines from the principal molecular components believed to control Ca(2+) entry and exit. Proteins, with their kinetic models, are located within two segments of dendrites containing 88 intact spines, centered in a fully reconstructed 6 * 6 * 5 MUm(3) cube of hippocampal neuropil. Protein components include AMPA- and NMDA-type glutamate receptors, L- and R-type voltage-dependent Ca(2+) channels, Na(+)/Ca(2+) exchangers, plasma membrane Ca(2+) ATPases, smooth endoplasmic reticulum Ca(2+) ATPases, immobile Ca(2+) buffers, and calbindin. Kinetic models for each protein were taken from published studies of the isolated proteins in vitro. For simulation of electrical stimuli, the time course of voltage changes in the dendritic spine was generated with the desired stimulus in the program NEURON. Voltage-dependent parameters were then continuously re adjusted during simulations in MCell to reproduce the effects of the stimulus. Nine parameters of the model were optimized within realistic experimental limits by a process that compared results of simulations to published data. We find that simulations in the optimized model reproduce the timing and amplitude of Ca(2+) transients measured experimentally in intact neurons. Thus, we demonstrate that the characteristics of individual isolated proteins determined in vitro can accurately reproduce the dynamics of experimentally measured Ca(2+) transients in spines. The model will provide a test bed for exploring the roles of additional proteins that regulate Ca(2+) influx into spines and for studying the behavior of protein targets in the spine that are regulated by Ca(2+) influx. PMID- 26500548 TI - Association of Statins with Sensory and Autonomic Ganglionopathy. AB - OBJECTIVE: To examine if statins have an effect on small nerve fibers. METHODS: This retrospective study evaluated the effect of statins in pure small-fiber neuropathy (SFN). Outcome measures were symptom scales (numbness, tingling, and autonomic symptoms), skin biopsies assessing epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD), and quantitative autonomic testing. RESULTS: One hundred and sixty participants with pure SFN were identified. Eighty participants (women/men, age +/- SD 33/47, 68.1 +/- 11.6 years old) were on statins for 53.5 +/- 28.7 months to treat dyslipidemia and they were age and gender matched with 80 participants (33/47, 68.1 +/- 9.5) that were off statins. ANOVA showed reduced ENFD/SGNFD at the proximal leg in the statin group [(count/mm) 8.3 +/- 3.6/51.3 +/- 14.2] compared to the off statin group (10.4 +/- 3.8, p = 0.0008/56.4 +/- 12.7, p = 0.018). There was no difference in ENFD/SGNFD at the distal leg in the statin group (4.9 +/- 3.2/39.8 +/- 15.7) compared to the off statin group (5.9 +/- 3.4, p = 0.067/41.8 +/- 15.9, p = 0.426). Statins did not affect symptom scales and the outcome of autonomic testing. CONCLUSION: Statin use is associated with degeneration of sensory and autonomic fibers. The pattern of abnormalities, e.g., degeneration of proximal while sparing of distal fibers, is consistent with a non-length-dependent process with lesions in the dorsal root and the autonomic ganglia. The statin-associated sensory and autonomic ganglionopathy is mild. PMID- 26500549 TI - White matter microstructure contributes to age-related declines in task-induced deactivation of the default mode network. AB - Task-induced deactivations within the brain's default mode network (DMN) are thought to reflect suppression of endogenous thought processes to support exogenous goal-directed task processes. Older adults are known to show reductions in deactivation of the DMN compared to younger adults. However, little is understood about the mechanisms contributing to functional dysregulation of the DMN in aging. Here, we explored the relationships between functional modulation of the DMN and age, task performance and white matter (WM) microstructure. Participants were 117 adults ranging from 25 to 83 years old who completed an fMRI task switching paradigm, including easy (single) and difficult (mixed) conditions, and underwent diffusion tensor imaging (DTI). The fMRI results revealed an age by condition interaction (beta = -0.13, t = -3.16, p = 0.002) such that increasing age affected deactivation magnitude during the mixed condition (beta = -0.29, t = -3.24 p = 0.002) but not the single condition (p = 0.58). Additionally, there was a WM by condition interaction (beta = 0.10, t = 2.33, p = 0.02) such that decreasing WM microstructure affected deactivation magnitude during the mixed condition (beta = 0.30, t = 3.42 p = 0.001) but not the single condition (p = 0.17). Critically, mediation analyses indicated that age-related reductions in WM microstructure accounted for the relationship between age and DMN deactivation in the more difficult mixed condition. These findings suggest that age-related declines in anatomical connectivity between DMN regions contribute to functional dysregulation within the DMN in older adults. PMID- 26500550 TI - Organic anion transporter 2 transcript variant 1 shows broad ligand selectivity when expressed in multiple cell lines. AB - Organic anion transporter 2 (OAT2) is likely important for renal and hepatic drug elimination. Three variants of the OAT2 peptide sequence have been described - OAT2 transcript variant 1 (OAT2-tv1), OAT2 transcript variant 2 (OAT2-tv2), and OAT2 transcript variant 3 (OAT2-tv3). Early studies helping to define the ligand selectivity of OAT2 failed to identify the variant used, and the studies used several heterologous expression systems. In preliminary studies using OAT2-tv1, we failed to observe transport of several previously identified substrates, leading us to speculate that ligand selectivity of OAT2 differs with variant and/or heterologous expression system. The purpose was to further investigate the ligand selectivity of the OAT2 variants expressed in multiple cell types. We cloned OAT2-tv1 and OAT2-tv2, but were unsuccessful at amplifying mRNA for OAT2 tv3 from human kidney. OAT2-tv1 and OAT2-tv2 were individually expressed in human embryonic kidney (HEK), Madin-Darby canine kidney (MDCK), or Chinese hamster ovary (CHO) cells. mRNA for OAT2-tv1 and OAT2-tv2 was demonstrated in each cell type transfected with the respective construct, indicating their expression. OAT2 tv1 trafficked to the plasma membrane of all three cell types, but OAT2-tv2 did not. OAT2-tv1 transported penciclovir in all three cell types, but failed to transport para-aminohippurate, succinate, glutarate, estrone-3-sulfate, paclitaxel or dehydroepiandrosterone sulfate - previously identified substrates of OAT2-tv2. Not surprising given its lack of plasma membrane expression, OAT2 tv2 failed to transport any of the organic solutes examined, including penciclovir. Penciclovir transport by OAT2-tv1 was sensitive to large (e.g., cyclosporine A) and small (e.g., allopurinol) organic compounds, as well as organic anions, cations and neutral compounds, highlighting the multiselectivity of OAT2-tv1. The potencies with which indomethacin, furosemide, cyclosporine A and cimetidine inhibited OAT2-tv1 are in good agreement with previous studies using this variant, but inconsistent with studies using OAT2 with an unidentified sequence. This study shows that organic molecules with diverse physicochemical properties interact with OAT2-tv1, making it a likely site of drug interactions. Many previously identified substrates of OAT2 are not transported by OAT2-tv1, suggesting that variant and/or expression system may contribute. Future work should establish the expression pattern and ligand selectivity of OAT2-tv3. PMID- 26500547 TI - A muscle stem cell for every muscle: variability of satellite cell biology among different muscle groups. AB - The human body contains approximately 640 individual skeletal muscles. Despite the fact that all of these muscles are composed of striated muscle tissue, the biology of these muscles and their associated muscle stem cell populations are quite diverse. Skeletal muscles are affected differentially by various muscular dystrophies (MDs), such that certain genetic mutations specifically alter muscle function in only a subset of muscles. Additionally, defective muscle stem cells have been implicated in the pathology of some MDs. The biology of muscle stem cells varies depending on the muscles with which they are associated. Here we review the biology of skeletal muscle stem cell populations of eight different muscle groups. Understanding the biological variation of skeletal muscles and their resident stem cells could provide valuable insight into mechanisms underlying the susceptibility of certain muscles to myopathic disease. PMID- 26500551 TI - HDL particle number and size as predictors of cardiovascular disease. AB - Previous studies indicate that reduced concentrations of circulating high-density lipoprotein (HDL) particles can be superior to HDL-cholesterol (HDL-C) levels as a predictor of cardiovascular disease. Measurements of HDL particle numbers, therefore, bear a potential for the improved assessment of cardiovascular risk. Furthermore, such measurement can be relevant for the evaluation of novel therapeutic approaches targeting HDL. Modern in-depth analyses of HDL particle profile may further improve evaluation of cardiovascular risk. Although clinical relevance of circulating concentrations of HDL subpopulations to cardiovascular disease remains controversial, the negative relationship between the number of large HDL particles and cardiovascular disease suggests that assessment of HDL particle profile can be clinically useful. Reduced mean HDL size is equally associated with cardiovascular disease in large-scale clinical studies. Since HDL C is primarily carried in the circulation by large, lipid-rich HDL particles, the inverse relationship between HDL size and cardiovascular risk can be secondary to those established for plasma levels of HDL particles, HDL-C, and large HDL. The epidemiological data thereby suggest that HDL particle number may represent a more relevant therapeutic target as compared to HDL-C. PMID- 26500552 TI - Non-clinical development of CER-001. AB - Cardiovascular disease remains the most pressing healthcare issue for the developed world and is becoming so for developing countries. There are no currently approved therapies that can rapidly reduce the burden of unstable, inflamed plaque in the overall coronary vascular bed. High-density lipoprotein (HDL) has multiple actions that could lead to plaque stabilization, such as rapid removal of large quantities of cholesterol from the vasculature through the process of reverse lipid transport, improvement in endothelial function, protection against oxidative damage, and reduction in inflammation. Short-term infusion of HDL-mimetics in animal models as well as in humans has shown promising effects on the plaque size and morphology. Cerenis Therapeutics has developed CER-001, a negatively charged lipoprotein complex consisting of phospholipid and recombinant human apoA-I that mimics the structure and function of natural HDL. Three clinical trials using CER-001 infusions have demonstrated improvements in the carotid wall thickness of patients with familial hypercholesterolaemia and in patients with hypo-alphalipoproteinaemia, as well as an impact on coronary plaque burden measured by intravascular ultrasonography at the lowest tested dose (3 mg/kg) in post-ACS patients. Here, we reviewed the non clinical data leading to the demonstration that CER-001 is a full HDL mimetic. PMID- 26500554 TI - Influence of aerobic exercise training on post-exercise responses of aortic pulse pressure and augmentation pressure in postmenopausal women. AB - Central arterial blood pressure (BP) is more predictive of future cardiovascular events than is brachial BP because it reflects the BP load imposed on the left ventricle with greater accuracy. However, little is known about the effects of exercise training on central hemodynamic response to acute exercise. The purpose of the present study was to determine the influence of an aerobic exercise regimen on the response of aortic BP after a single aerobic exercise in postmenopausal women. Nine healthy postmenopausal women (age: 61 +/- 2 years) participated in a 12-week aerobic exercise training regimen. Before and after the training, each subjects performed a single bout of cycling at ventilatory thresholds for 30 min. We evaluated the post-exercise aortic BP response, which was estimated via the general transfer function from applanation tonometry. After the initial pre-training aerobic exercise session, aortic BP did not change significantly: however, aortic pulse pressure and augmentation pressure were significantly attenuated after the single aerobic exercise session following the 12-week training regimen. The present study demonstrated that a regular aerobic exercise training regimen induced the post-exercise reduction of aortic pulse pressure and augmentation pressure. Regular aerobic exercise training may enhance post-exercise reduction in aortic BP. PMID- 26500555 TI - Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and restoring NO/GC signaling. AB - Type 2 diabetes (DM2) increases the risk of cardiovascular disease. Aldosterone, which has pro-oxidative and pro-inflammatory effects in the cardiovascular system, is positively regulated in DM2. We assessed whether blockade of mineralocorticoid receptors (MR) with spironolactone decreases reactive oxygen species (ROS)-associated vascular dysfunction and improves vascular nitric oxide (NO) signaling in diabetes. Leptin receptor knockout [LepR(db)/LepR(db) (db/db)] mice, a model of DM2, and their counterpart controls [LepR(db)/LepR(+), (db/+) mice] received spironolactone (50 mg/kg body weight/day) or vehicle (ethanol 1%) via oral per gavage for 6 weeks. Spironolactone treatment abolished endothelial dysfunction and increased endothelial nitric oxide synthase (eNOS) phosphorylation (Ser(1177)) in arteries from db/db mice, determined by acetylcholine-induced relaxation and Western Blot analysis, respectively. MR antagonist therapy also abrogated augmented ROS-generation in aorta from diabetic mice, determined by lucigenin luminescence assay. Spironolactone treatment increased superoxide dismutase-1 and catalase expression, improved sodium nitroprusside and BAY 41-2272-induced relaxation, and increased soluble guanylyl cyclase (sGC) beta subunit expression in arteries from db/db mice. Our results demonstrate that spironolactone decreases diabetes-associated vascular oxidative stress and prevents vascular dysfunction through processes involving increased expression of antioxidant enzymes and sGC. These findings further elucidate redox sensitive mechanisms whereby spironolactone protects against vascular injury in diabetes. PMID- 26500553 TI - The role of serotonin 5-HT2A receptors in memory and cognition. AB - Serotonin 5-HT2A receptors (5-HT2ARs) are widely distributed in the central nervous system, especially in brain region essential for learning and cognition. In addition to endogenous 5-HT, several hallucinogens, antipsychotics, and antidepressants function by targeting 5-HT2ARs. Preclinical studies show that 5 HT2AR antagonists have antipsychotic and antidepressant properties, whereas agonist ligands possess cognition-enhancing and hallucinogenic properties. Abnormal 5-HT2AR activity is associated with a number of psychiatric disorders and conditions, including depression, schizophrenia, and drug addiction. In addition to its traditional activity as a G protein-coupled receptor (GPCR), recent studies have defined novel operations of 5-HT2ARs. Here we review progress in the (1) receptor anatomy and biology: distribution, signaling, polymerization and allosteric modulation; and (2) receptor functions: learning and memory, hallucination and spatial cognition, and mental disorders. Based on the recent progress in basic research on the 5-HT2AR, it appears that post-training 5-HT2AR activation enhances non-spatial memory consolidation, while pre-training 5-HT2AR activation facilitates fear extinction. Further, the potential influence that 5 HT2AR-elicited visual hallucinations may have on visual cue (i.e., landmark) guided spatial cognition is discussed. We conclude that the development of selective 5-HT2AR modulators to target distinct signaling pathways and neural circuits represents a new possibility for treating emotional, neuropsychiatric, and neurodegenerative disorders. PMID- 26500556 TI - Evolution from electrophysiologic to hemodynamic monitoring: the story of left atrial and pulmonary artery pressure monitors. AB - Heart failure (HF) is a costly, challenging and highly prevalent medical condition. Hospitalization for acute decompensation is associated with high morbidity and mortality. Despite application of evidence-based medical therapies and technologies, HF remains a formidable challenge for virtually all healthcare systems. Repeat hospitalizations for acute decompensated HF (ADHF) can have major financial impact on institutions and resources. Early and accurate identification of impending ADHF is of paramount importance yet there is limited high quality evidence or infrastructure to guide management in the outpatient setting. Historically, ADHF was identified by physical exam findings or invasive hemodynamic monitoring during a hospital admission; however, advances in medical microelectronics and the advent of device-based diagnostics have enabled long term ambulatory monitoring of HF patients in the outpatient setting. These monitors have evolved from piggybacking on cardiac implantable electrophysiologic devices to standalone implantable hemodynamic monitors that transduce left atrial or pulmonary artery pressures as surrogate measures of left ventricular filling pressure. As technology evolves, devices will likely continue to miniaturize while their capabilities grow. An important, persistent challenge that remains is developing systems to translate the large volumes of real-time data, particularly data trends, into actionable information that leads to appropriate, safe and timely interventions without overwhelming outpatient cardiology and general medical practices. Future directions for implantable hemodynamic monitors beyond their utility in heart failure may include management of other major chronic diseases such as pulmonary hypertension, end stage renal disease and portal hypertension. PMID- 26500557 TI - Commentary: Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure. PMID- 26500558 TI - Extracting extensor digitorum communis activation patterns using high-density surface electromyography. AB - The extensor digitorum communis muscle plays an important role in hand dexterity during object manipulations. This multi-tendinous muscle is believed to be controlled through separate motoneuron pools, thereby forming different compartments that control individual digits. However, due to the complex anatomical variations across individuals and the flexibility of neural control strategies, the spatial activation patterns of the extensor digitorum communis compartments during individual finger extension have not been fully tracked under different task conditions. The objective of this study was to quantify the global spatial activation patterns of the extensor digitorum communis using high-density (7 * 9) surface electromyogram (EMG) recordings. The muscle activation map (based on the root mean square of the EMG) was constructed when subjects performed individual four finger extensions at the metacarpophalangeal joint, at different effort levels and under different finger constraints (static and dynamic). Our results revealed distinct activation patterns during individual finger extensions, especially between index and middle finger extensions, although the activation between ring and little finger extensions showed strong covariance. The activation map was relatively consistent at different muscle contraction levels and for different finger constraint conditions. We also found that distinct activation patterns were more discernible in the proximal-distal direction than in the radial-ulnar direction. The global spatial activation map utilizing surface grid EMG of the extensor digitorum communis muscle provides information for localizing individual compartments of the extensor muscle during finger extensions. This is of potential value for identifying more selective control input for assistive devices. Such information can also provide a basis for understanding hand impairment in individuals with neural disorders. PMID- 26500559 TI - Computational implementation of a tunable multicellular memory circuit for engineered eukaryotic consortia. AB - Cells are complex machines capable of processing information by means of an entangled network of molecular interactions. A crucial component of these decision-making systems is the presence of memory and this is also a specially relevant target of engineered synthetic systems. A classic example of memory devices is a 1-bit memory element known as the flip-flop. Such system can be in principle designed using a single-cell implementation, but a direct mapping between standard circuit design and a living circuit can be cumbersome. Here we present a novel computational implementation of a 1-bit memory device using a reliable multicellular design able to behave as a set-reset flip-flop that could be implemented in yeast cells. The dynamics of the proposed synthetic circuit is investigated with a mathematical model using biologically-meaningful parameters. The circuit is shown to behave as a flip-flop in a wide range of parameter values. The repression strength for the NOT logics is shown to be crucial to obtain a good flip-flop signal. Our model also shows that the circuit can be externally tuned to achieve different memory states and dynamics, such as persistent and transient memory. We have characterized the parameter domains for robust memory storage and retrieval as well as the corresponding time response dynamics. PMID- 26500560 TI - Respiratory kinematic and airflow differences between reflex and voluntary cough in healthy young adults. AB - BACKGROUND: Cough is a defensive behavior that can be initiated in response to a stimulus in the airway (reflexively), or on command (voluntarily). There is evidence to suggest that physiological differences exist between reflex and voluntary cough; however, the output (mechanistic and airflow) differences between the cough types are not fully understood. Therefore, the aims of this study were to determine the lung volume, respiratory kinematic, and airflow differences between reflex and voluntary cough in healthy young adults. METHODS: Twenty-five participants (14 female; 18-29 years) were recruited for this study. Participants were evaluated using respiratory inductance plethysmography calibrated with spirometry. Experimental procedures included: (1) respiratory calibration, (2) three voluntary sequential cough trials, and (3) three reflex cough trials induced with 200 MUM capsaicin. RESULTS: Lung volume initiation (LVI; p = 0.003) and lung volume excursion (LVE; p < 0.001) were significantly greater for voluntary cough compared to reflex cough. The rib cage and abdomen significantly influenced LVI for voluntary cough (p < 0.001); however, only the rib cage significantly impacted LVI for reflex cough (p < 0.001). LVI significantly influenced peak expiratory flow rate (PEFR) for voluntary cough (p = 0.029), but not reflex cough (p = 0.610). DISCUSSION: Production of a reflex cough results in significant mechanistic and airflow differences compared to voluntary cough. These findings suggest that detection of a tussigenic stimulus modifies motor aspects of the reflex cough behavior. Further understanding of the differences between reflex and voluntary cough in older adults and in persons with dystussia (cough dysfunction) will be essential to facilitate the development of successful cough treatment paradigms. PMID- 26500561 TI - Alexithymic Trait, Painful Heat Stimulation, and Everyday Pain Experience. AB - BACKGROUND: Alexithymia was found to be associated with a variety of somatic complaints, including somatoform pain symptoms. This study addressed the question of whether the different facets of alexithymia are related to responses in heat pain stimulation and its interrelations with levels of everyday pain as assessed by self-report. METHODS: In the study, sensitivity to heat pain was assessed in 50 healthy female participants. Alexithymia facets were assessed by the Toronto Alexithymia Scale. Pain threshold and tolerance were determined using a testing the limits procedure. Participants, furthermore, rated subjective intensities and unpleasantness of tonic heat stimuli (45.5-47.5 degrees C) on visual analog scales and on a questionnaire. Possible confounding with temperature sensitivity and mood was controlled. Everyday pain was assessed by self-report addressing everyday pain frequency, intensity, and impairment experienced over the last 2 months. RESULTS: Main results were that the facets of alexithymia were differentially associated with pain perception. The affective scale "difficulties in describing feelings" was associated with hyposensitivity to pain as indicated by higher pain tolerance scores. Furthermore, everyday pain frequency was related to increased alexithymia values on the affective scale "difficulties in identifying feelings," whereas higher values on the cognitive alexithymia scale "externally oriented thinking" were related to lower pain impairment and intensity. CONCLUSION: We conclude that the different facets of alexithymia are related to alternations in pain processing. Further research on clinical samples is necessary to elucidate whether different aspects of alexithymia act as a vulnerability factor for the development of pain symptoms. PMID- 26500562 TI - Differential Intrinsic Coupling Modes in Psychological and Physical Trauma. PMID- 26500563 TI - Impulsivity is Associated with Early Sensory Inhibition in Neurophysiological Processing of Affective Sounds. AB - Impulsivity is widely related to socially problematic behaviors and psychiatric illness. Previous studies have investigated the relationship between response inhibition and impulsivity. However, no study has intensively examined how impulsivity correlates with automatic sensory processing before the drive for response inhibition to sensory inputs. Sensory gating (SG) is an automatic inhibitory function that attenuates the neural response to redundant sensory information and protects higher cognitive functions from the burst of information processing. Although SG functions abnormally in several clinical populations, there is very little evidence supporting SG changes in conjunction with impulsivity traits in non-clinical populations. The present study recruited healthy adults (n = 23) to conduct a neurophysiological experiment using a paired click paradigm and self-report scales assessing impulsive behavioral traits. Auditory stimuli included not only a pure tone but also white noise to explore the differences in auditory-evoked potential (AEP) responses between the two stimuli. White noise is more affective than pure tones; therefore, we predicted that the SG of AEPs (P50, N100, and P200) for white noise would correlate more with self-reported impulsivity than with those for pure tones. Our main findings showed that SG of the P50 and P200 amplitudes significantly correlated with self reported reward responsiveness and fun-seeking, respectively, only for white noise stimuli, demonstrating that higher-scoring impulsivity subcomponents were related to greater SG. Frequency-domain analyses also revealed that greater desynchronization of the beta band for the second white noise stimulus was associated with higher motor impulsivity scores, suggesting that an impulsivity related change of SG was associated with attentional modulation. These findings indicate that the measurement of SG of white noise may be an efficient tool to evaluate impulsivity in non-clinical populations, and should also be applied to clinical populations. PMID- 26500565 TI - Commentary: The Impact of Neuroimmune Alterations in Autism Spectrum Disorder. PMID- 26500564 TI - Eyeblink Conditioning and Novel Object Recognition in the Rabbit: Behavioral Paradigms for Assaying Psychiatric Diseases. AB - Analysis of data collected from behavioral paradigms has provided important information for understanding the etiology and progression of diseases that involve neural regions mediating abnormal behavior. The trace eyeblink conditioning (EBC) paradigm is particularly suited to examine cerebro-cerebellar interactions since the paradigm requires the cerebellum, forebrain, and awareness of the stimulus contingencies. Impairments in acquiring EBC have been noted in several neuropsychiatric conditions, including schizophrenia, Alzheimer's disease (AD), progressive supranuclear palsy, and post-traumatic stress disorder. Although several species have been used to examine EBC, the rabbit is unique in its tolerance for restraint, which facilitates imaging, its relatively large skull that facilitates chronic neuronal recordings, a genetic sequence for amyloid that is identical to humans which makes it a valuable model to study AD, and in contrast to rodents, it has a striatum that is differentiated into a caudate and a putamen that facilitates analysis of diseases involving the striatum. This review focuses on EBC during schizophrenia and AD since impairments in cerebro-cerebellar connections have been hypothesized to lead to a cognitive dysmetria. We also relate EBC to conditioned avoidance responses that are more often examined for effects of antipsychotic medications, and we propose that an analysis of novel object recognition (NOR) may add to our understanding of how the underlying neural circuitry has changed during disease states. We propose that the EBC and NOR paradigms will help to determine which therapeutics are effective for treating the cognitive aspects of schizophrenia and AD, and that neuroimaging may reveal biomarkers of the diseases and help to evaluate potential therapeutics. The rabbit, thus, provides an important translational system for studying neural mechanisms mediating maladaptive behaviors that underlie some psychiatric diseases, especially cognitive impairments associated with schizophrenia and AD, and object recognition provides a simple test of memory that can corroborate the results of EBC. PMID- 26500567 TI - Implicit beliefs about ideal body image predict body image dissatisfaction. AB - We examined whether implicit measures of actual and ideal body image can be used to predict body dissatisfaction in young female adults. Participants completed two Implicit Relational Assessment Procedures (IRAPs) to examine their implicit beliefs concerning actual (e.g., I am thin) and desired ideal body image (e.g., I want to be thin). Body dissatisfaction was examined via self-report questionnaires and rating scales. As expected, differences in body dissatisfaction exerted a differential influence on the two IRAP scores. Specifically, the implicit belief that one is thin was lower in participants who exhibited a high degree of body dissatisfaction than in participants who exhibited a low degree of body dissatisfaction. In contrast, the implicit desire to be thin (i.e., thin ideal body image) was stronger in participants who exhibited a high level of body dissatisfaction than in participants who were less dissatisfied with their body. Adding further weight to the idea that both IRAP measures captured different underlying constructs, we also observed that they correlated differently with body mass index, explicit body dissatisfaction, and explicit measures of actual and ideal body image. More generally, these findings underscore the advantage of using implicit measures that incorporate relational information relative to implicit measures that allow for an assessment of associative relations only. PMID- 26500568 TI - Perceived legitimacy of normative expectations motivates compliance with social norms when nobody is watching. AB - Three main motivations can explain compliance with social norms: fear of peer punishment, the desire for others' esteem and the desire to meet others' expectations. Though all play a role, only the desire to meet others' expectations can sustain compliance when neither public nor private monitoring is possible. Theoretical models have shown that such desire can indeed sustain social norms, but empirical evidence is lacking. Moreover it is unclear whether this desire ranges over others' "empirical" or "normative" expectations. We propose a new experimental design to isolate this motivation and to investigate what kind of expectations people are inclined to meet. Results indicate that, when nobody can assign either material or immaterial sanctions, the perceived legitimacy of others' normative expectations can motivate a significant number of people to comply with costly social norms. PMID- 26500566 TI - Opening the gender diversity black box: causality of perceived gender equity and locus of control and mediation of work engagement in employee well-being. AB - The study is aimed at assessing the role of perceived gender equity and locus of control in employee well-being at the workplace and ascertaining if work engagement mediates between perceived gender equity, locus of control, and employee well-being (measured through optimism, general satisfaction with life and work, and executive burnout). Adopting a personal survey method data was collected from 373 managers (both males and females) from the public and private sectors representing manufacturing and service industry in India. The study bridges the knowledge gap by operationalizing the construct of perceived gender equity and studying its role in the work engagement and employee well-being. Conceptualization of the well-being in an unconventional way covering both the positive and the negative aspects extends the understanding of the emerging concept of well-being. It has practical implications for talent management and work engagement besides promoting gender equity at the workplace for employee well-being. It opens vistas for the gender based theory and cross cultural research on gender equity. PMID- 26500569 TI - Children's understanding of Aesop's fables: relations to reading comprehension and theory of mind. AB - Two studies examined children's developing understanding of Aesop's fables in relation to reading comprehension and to theory of mind. Study 1 included 172 children from Junior Kindergarten through Grade 6 in a school-wide examination of the relation between reading comprehension skills and understanding of Aesop's fables told orally. Study 2 examined the relation between theory of mind and fables understanding among 186 Junior (4-year-old) and Senior (5-year-old) Kindergarten children. Study 1 results showed a developmental progression in fables understanding with children's responses becoming increasingly decontextualized as they were able to extract the life lesson. After general vocabulary, passage comprehension predicted fables understanding. Study 2 results showed a relation between young children's theory of mind development and their understanding of fables. After general vocabulary, second-order theory of mind predicted children's fables understanding. Findings point to the importance of developing mental state awareness in children's ability to judge characters' intentions and to understand the deeper message embedded in fables. PMID- 26500570 TI - Does Cognitive Behavior Therapy for psychosis (CBTp) show a sustainable effect on delusions? A meta-analysis. AB - Cognitive Behavior Therapy for psychosis (CBTp) is an effective treatment resulting in small to medium effect sizes with regard to changes in positive symptoms and psychopathology. As a consequence, CBTp is recommended by national guidelines for all patients with schizophrenia. However, although CBTp was originally developed as a means to improve delusions, meta-analyses have generally integrated effects for positive symptoms rather than for delusions. Thus, it is still an open question whether CBTp is more effective with regard to change in delusions compared to treatment as usual (TAU) and to other interventions, and whether this effect remains stable over a follow-up period. Moreover, it would be interesting to explore whether newer studies that focus on specific factors involved in the formation and maintenance of delusions (causal interventionist approach) are more effective than the first generation of CBTp studies. A systematic search of the trial literature identified 19 RCTs that compared CBTp with TAU and/or other interventions and reported delusions as an outcome measure. Meta-analytic integration resulted in a significant small to medium effect size for CBTp in comparison to TAU at end-of-therapy (k = 13; [Formula: see text] 0.27) and after an average follow-up period of 47 weeks (k = 12; [Formula: see text] 0.25). When compared with other interventions, there was no significant effect of CBTp at end-of-therapy (k = 8; [Formula: see text] 0.16) and after a follow-up period (k = 5; [Formula: see text]). Comparison between newer studies taking a causal-interventionist approach (k = 4) and first generation studies showed a difference of 0.33 in mean effect sizes in favor of newer studies at end-of-therapy. The findings suggest that CBTp is superior to TAU, but is not superior to other interventions, in bringing about a change in delusions, and that this superiority is maintained over the follow-up period. Moreover, interventions that focus on causal factors of delusions seem to be a promising approach to improving interventions for delusions. PMID- 26500573 TI - Learning psychological research and statistical concepts using retrieval-based practice. AB - Research methods and statistics are an indispensable subject in the undergraduate psychology curriculum, but there are challenges associated with engaging students in it, such as making learning durable. Here we hypothesized that retrieval-based learning promotes long-term retention of statistical knowledge in psychology. Participants either studied the educational material in four consecutive periods, or studied it just once and practiced retrieving the information in the subsequent three periods, and then took a final test through which their learning was assessed. Whereas repeated studying yielded better test performance when the final test was immediately administered, repeated practice yielded better performance when the test was administered a week after. The data suggest that retrieval practice enhanced the learning-produced better long-term retention-of statistical knowledge in psychology than did repeated studying. PMID- 26500574 TI - Variability in social reasoning: the influence of attachment security on the attribution of goals. AB - Over the last half decade there has been a growing move to apply the methods and theory of cognitive development to questions regarding infants' social understanding. Though this combination has afforded exciting opportunities to better understand our species' unique social cognitive abilities, the resulting findings do not always lead to the same conclusions. For example, a growing body of research has found support for both universal similarity and individual differences in infants' social reasoning about others' responses to incomplete goals. The present research examines this apparent contradiction by assessing the influence of attachment security on the ability of university undergraduates to represent instrumental needs versus social-emotional distress. When the two varieties of goals were clearly differentiated, we observed a universally similar pattern of results (Experiments 1A/B). However, when the goals were combined, and both instrumental need and social-emotional distress were presented together, individual differences emerged (Experiments 2 and 3). Taken together, these results demonstrate that by integrating the two perspectives of shared universals and individual differences, important points of contact can be revealed supporting a deeper, more nuanced understanding of the nature of human social reasoning. PMID- 26500571 TI - The neurosciences and the search for a unified psychology: the science and esthetics of a single framework. AB - The search for a so-called unified or integrated theory has long served as a goal for some psychologists, even if the search is often implicit. But if the established sciences do not have an explicitly unified set of theories, then why should psychology? After examining this question again I argue that psychology is in fact reasonably unified around its methods and its commitment to functional explanations, an indeterminate functionalism. The question of the place of the neurosciences in this framework is complex. On the one hand, the neuroscientific project will not likely renew and synthesize the disparate arms of psychology. On the other hand, their reformulation of what it means to be human will exert an influence in multiple ways. One way to capture that influence is to conceptualize the brain in terms of a technology that we interact with in a manner that we do not yet fully understand. In this way we maintain both a distance from neuro reductionism and refrain from committing to an unfettered subjectivity. PMID- 26500576 TI - Bridging the gap between DeafBlind minds: interactional and social foundations of intention attribution in the Seattle DeafBlind community. AB - This article is concerned with social and interactional processes that simplify pragmatic acts of intention attribution. The empirical focus is a series of interactions among DeafBlind people in Seattle, Washington, where pointing signs are used to individuate objects of reference in the immediate environment. Most members of this community are born deaf and slowly become blind. They come to Seattle using Visual American Sign Language, which has emerged and developed in a field organized around visual modes of access. As vision deteriorates, however, links between deictic signs (such as pointing) and the present, remembered, or imagined environment erode in idiosyncratic ways across the community of language users, and as a result, it becomes increasingly difficult for participants to converge on objects of reference. In the past, DeafBlind people addressed this problem by relying on sighted interpreters. Under the influence of the recent "pro-tactile" movement, they have turned instead to one another to find new solutions to these referential problems. Drawing on analyses of 120 h of videorecorded interaction and language-use, detailed fieldnotes collected during 12 months of sustained anthropological fieldwork, and more than 15 years of involvement in this community in a range of capacities, I argue that DeafBlind people are generating new and reciprocal modes of access to their environment, and this process is aligning language with context in novel ways. I discuss two mechanisms that can account for this process: embedding in the social field and deictic integration. I argue that together, these social and interactional processes yield a deictic system set to retrieve a restricted range of values from the extra-linguistic context, thereby attenuating the cognitive demands of intention attribution and narrowing the gap between DeafBlind minds. PMID- 26500579 TI - Wh-filler-gap dependency formation guides reflexive antecedent search. AB - Prior studies on online sentence processing have shown that the parser can resolve non-local dependencies rapidly and accurately. This study investigates the interaction between the processing of two such non-local dependencies: wh filler-gap dependencies (WhFGD) and reflexive-antecedent dependencies. We show that reflexive-antecedent dependency resolution is sensitive to the presence of a WhFGD, and argue that the filler-gap dependency established by WhFGD resolution is selected online as the antecedent of a reflexive dependency. We investigate the processing of constructions like (1), where two NPs might be possible antecedents for the reflexive, namely which cowgirl and Mary. Even though Mary is linearly closer to the reflexive, the only grammatically licit antecedent for the reflexive is the more distant wh-NP, which cowgirl. (1). Which cowgirl did Mary expect to have injured herself due to negligence? Four eye-tracking text-reading experiments were conducted on examples like (1), differing in whether the embedded clause was non-finite (1 and 3) or finite (2 and 4), and in whether the tail of the wh-dependency intervened between the reflexive and its closest overt antecedent (1 and 2) or the wh-dependency was associated with a position earlier in the sentence (3 and 4). The results of Experiments 1 and 2 indicate the parser accesses the result of WhFGD formation during reflexive antecedent search. The resolution of a wh-dependency alters the representation that reflexive antecedent search operates over, allowing the grammatical but linearly distant antecedent to be accessed rapidly. In the absence of a long-distance WhFGD (Experiments 3 and 4), wh-NPs were not found to impact reading times of the reflexive, indicating that the parser's ability to select distant wh-NPs as reflexive antecedents crucially involves syntactic structure. PMID- 26500580 TI - Commentary: Cultural recycling of neural substrates during language evolution and development. PMID- 26500578 TI - A psychometric analysis of the reading the mind in the eyes test: toward a brief form for research and applied settings. AB - The Reading the Mind in the Eyes Test is a popular measure of individual differences in Theory of Mind that is often applied in the assessment of particular clinical populations (primarily, individuals on the autism spectrum). However, little is known about the test's psychometric properties, including factor structure, internal consistency, and convergent validity evidence. We present a psychometric analysis of the test followed by an evaluation of other empirically proposed and statistically identified structures. We identified, and cross-validated in a second sample, an adequate short-form solution that is homogeneous with adequate internal consistency, and is moderately related to Cognitive Empathy, Emotion Perception, and strongly related to Vocabulary. We recommend the use of this short-form solution in normal adults as a more precise measure over the original version. Future revisions of the test should seek to reduce the test's reliance on one's vocabulary and evaluate the short-form structure in clinical populations. PMID- 26500577 TI - Flow theory - goal orientation theory: positive experience is related to athlete's goal orientation. AB - The main purpose of this study was to examine the relationship between flow experience and goal orientation theory, as well as, the differences in flow experience based on the orthogonal model of goal orientation theory. Two hundred and seventy eight athletes completed the Task and Ego Orientation Sport Questionnaire based on how they usually feel. The challenge and skills ratings were completed 1 h before the competition, based on how they felt at the exact time of answering. In the following, the Flow State Scale-2 was completed up to 30 min after the competition they just participated, along with the challenge skill ratings, based on how athletes felt during the competition. The results indicated that the athletes' task orientation may be an important factor for attaining flow in competitive sport, feeling more skillful and estimating the upcoming competition as challenging, while low ego and low task oriented athletes lack these elements, which are important for them to get into flow. Additionally, not the level of task and ego orientation per se, but the balance between athletes' goal orientation preferences seems important for the formation of flow experience, indicating that high task - high ego and high task - low ego athletes are experiencing the most positive mental state. PMID- 26500572 TI - Chemosensory anxiety cues moderate the experience of social exclusion - an fMRI investigation with Cyberball. AB - Recent evidence suggests that the experience of stress can be communicated between individuals via chemosensory cues. Little is known, however, about the impact of these cues on neurophysiological responses during a socially threatening situation. In the current investigation we implemented a widely used paradigm to study social exclusion-Cyberball-to examine whether chemosensory cues signaling anxiety modulate the neuronal effects of ostracism. In a double-blind, within-subjects design, 24 healthy, normosmic participants were presented with chemosensory cues of anxiety (or control samples) and completed the Cyberball task while in a 3T fMRI scanner. Axillary sweat collected from male students awaiting an oral examination served as the anxiety cues while the chemosensory control stimuli consisted of sweat collected from the same individuals participating in an ergometer training session. The neuroimaging data revealed that under the control chemosensory condition, exclusion from Cyberball was associated with significantly higher orbitofrontal cortex and anterior cingulate cortex activity, which is consistent with previous studies in the field. However, when participants were primed with the anxiety sweat, the activity in these regions was not observed. Further, under exposure to anxiety cues during ostracism the participants showed deactivations in brain regions involved in memory (hippocampus), social cognition (middle temporal gyrus, superior temporal gyrus) and processing of salience (inferior frontal gyrus). These results suggest that successful communication of anxiety via the chemosensory domain may moderate the experience of social exclusion. It is possible that the anxiety signals make it easier for the individuals to detach from the group, pointing to the communicative role of chemosensory anxiety cues in enhancing adjustment mechanisms in light of a distressing situation. PMID- 26500586 TI - The hows and whys of face memory: level of construal influences the recognition of human faces. AB - Three experiments investigated the influence of level of construal (i.e., the interpretation of actions in terms of their meaning or their details) on different stages of face memory. We employed a standard multiple-face recognition paradigm, with half of the faces inverted at test. Construal level was manipulated prior to recognition (Experiment 1), during study (Experiment 2) or both (Experiment 3). The results support a general advantage for high-level construal over low-level construal at both study and at test, and suggest that matching processing style between study and recognition has no advantage. These experiments provide additional evidence in support of a link between semantic processing (i.e., construal) and visual (i.e., face) processing. We conclude with a discussion of implications for current theories relating to both construal and face processing. PMID- 26500575 TI - Internalizing and externalizing traits predict changes in sleep efficiency in emerging adulthood: an actigraphy study. AB - Research on psychopathology and experimental studies of sleep restriction support a relationship between sleep disruption and both internalizing and externalizing disorders. The objective of the current study was to extend this research by examining sleep, impulsivity, antisocial personality traits, and internalizing traits in a university sample. Three hundred and eighty six individuals (161 males) between the ages of 18 and 27 years (M = 18.59, SD = 0.98) wore actigraphs for 7 days and completed established measures of disorder-linked personality traits and sleep quality (i.e., Personality Assessment Inventory (PAI), Triarchic Psychopathy Measure, Barratt Impulsiveness Scale-11, and the Pittsburgh Sleep Quality Index). As expected, sleep measures and questionnaire scores fell within the normal range of values and sex differences in sleep and personality were consistent with previous research results. Similar to findings in predominantly male forensic psychiatric settings, higher levels of impulsivity predicted poorer subjective sleep quality in both women and men. Consistent with well-established associations between depression and sleep, higher levels of depression in both sexes predicted poorer subjective sleep quality. Bidirectional analyses showed that better sleep efficiency decreases depression. Finally, moderation analyses showed that gender does have a primary role in sleep efficiency and marginal effects were found. The observed relations between sleep and personality traits in a typical university sample add to converging evidence of the relationship between sleep and psychopathology and may inform our understanding of the development of psychopathology in young adulthood. PMID- 26500581 TI - Improving reading skills in students with dyslexia: the efficacy of a sublexical training with rhythmic background. AB - The core deficit underlying developmental dyslexia (DD) has been identified in difficulties in dynamic and rapidly changing auditory information processing, which contribute to the development of impaired phonological representations for words. It has been argued that enhancing basic musical rhythm perception skills in children with DD may have a positive effect on reading abilities because music and language share common mechanisms and thus transfer effects from the former to the latter are expected to occur. A computer-assisted training, called Rhythmic Reading Training (RRT), was designed in which reading exercises are combined with rhythm background. Fourteen junior high school students with DD took part to 9 biweekly individual sessions of 30 min in which RRT was implemented. Reading improvements after the intervention period were compared with ones of a matched control group of 14 students with DD who received no intervention. Results indicated that RRT had a positive effect on both reading speed and accuracy and significant effects were found on short pseudo-words reading speed, long pseudo words reading speed, high frequency long words reading accuracy, and text reading accuracy. No difference in rhythm perception between the intervention and control group were found. Findings suggest that rhythm facilitates the development of reading skill because of the temporal structure it imposes to word decoding. PMID- 26500589 TI - Working alliance inventory applied to virtual and augmented reality (WAI-VAR): psychometrics and therapeutic outcomes. AB - This study examines the psychometric properties of the Working Alliance Inventory Short (WAI-S) adaptation to Virtual Reality (VR) and Augmented Reality (AR) therapies (WAI-VAR). The relationship between the therapeutic alliance (TA) with VR and AR and clinically significant change (CSC) is also explored. Seventy-five patients took part in this study (74.7% women, M age = 34.41). Fear of flying and adjustment disorder patients received VR therapy, and cockroach phobia patients received AR therapy. Psychometric properties, CSC, one-way ANOVA, Spearman's Correlations and Multiple Regression were calculated. The WAI-VAR showed a unidimensional structure, high internal consistency and adequate convergent validity. "Not changed" patients scored lower on the WAI-VAR than "improved" and "recovered" patients. Correlation between the WAI-VAR and CSC was moderate. The best fitting model for predicting CSC was a linear combination of the TA with therapist (WAI-S) and the TA with VR and AR (WAI-VAR), due to the latter variable slightly increased the percentage of variability accounted for in CSC. The WAI VAR is the first validated instrument to measure the TA with VR and AR in research and clinical practice. This study reveals the importance of the quality of the TA with technologies in achieving positive outcomes in the therapy. PMID- 26500583 TI - Can vocal conditioning trigger a semiotic ratchet in marmosets? AB - The complexity of human communication has often been taken as evidence that our language reflects a true evolutionary leap, bearing little resemblance to any other animal communication system. The putative uniqueness of the human language poses serious evolutionary and ethological challenges to a rational explanation of human communication. Here we review ethological, anatomical, molecular, and computational results across several species to set boundaries for these challenges. Results from animal behavior, cognitive psychology, neurobiology, and semiotics indicate that human language shares multiple features with other primate communication systems, such as specialized brain circuits for sensorimotor processing, the capability for indexical (pointing) and symbolic (referential) signaling, the importance of shared intentionality for associative learning, affective conditioning and parental scaffolding of vocal production. The most substantial differences lie in the higher human capacity for symbolic compositionality, fast vertical transmission of new symbols across generations, and irreversible accumulation of novel adaptive behaviors (cultural ratchet). We hypothesize that increasingly-complex vocal conditioning of an appropriate animal model may be sufficient to trigger a semiotic ratchet, evidenced by progressive sign complexification, as spontaneous contact calls become indexes, then symbols and finally arguments (strings of symbols). To test this hypothesis, we outline a series of conditioning experiments in the common marmoset (Callithrix jacchus). The experiments are designed to probe the limits of vocal communication in a prosocial, highly vocal primate 35 million years far from the human lineage, so as to shed light on the mechanisms of semiotic complexification and cultural transmission, and serve as a naturalistic behavioral setting for the investigation of language disorders. PMID- 26500585 TI - Distinct effects of contrast and color on subjective rating of fearfulness. AB - Natural scenes provide important affective cues for observers to avoid danger. From an adaptationist perspective, such cues affect the behavior of the observer and shape the evolution of the observer's response. It is evolutionarily significant for individuals to extract affective information from the environment as quickly and as efficiently as possible. However, the nearly endless variations in physical appearance of natural scenes present a fundamental challenge for perceiving significant visual information. How image-level properties, such as contrast and color, influence the extraction of affective information leading to subjective emotional perception is unclear. On the one hand, studies have shown that visual perception and emotional perception seem to interact with each other at the earliest stages in cortical processing. On the other hand, it is important for high-level subjective ratings to be invariant to low-level visual properties. Using a psychophysical approach and signal detection theory (SDT), we tested how contrast and color influenced fearfulness ratings of a set of natural scene pictures that varied in contents and in levels of fearfulness. Image contrast influenced perceptual sensitivity but not the decision criterion of fearfulness rating, whereas color affected the decision criterion but not perceptual sensitivity. These results show that different low-level visual features contribute independently to sensitivity or decision criterion in affective perception, suggesting distinct interactions between visual cognition and affective processing. Specifically, our naturalistic approach using a novel stimulus set, combined with SDT, has demonstrated two dissociable types of cognitive mechanisms underlying how image-level properties leverage the extraction of affective information in natural vision. PMID- 26500587 TI - The effect of magnocellular-based visual-motor intervention on Chinese children with developmental dyslexia. AB - Magnocellular (M) deficit theory points out that the core deficit of developmental dyslexia (DD) is the impairment in M pathway, which has been evidenced in many previous studies. Based on the M deficit, some researchers found that visual intervention focusing on M deficit improved dyslexics' M function as well as reading abilities. However, the number and reliability of these training studies were limited. Therefore, the present study conducted an M based visual-motor intervention on Chinese children with DD to investigate the relationship between M deficit and Chinese DD. Intervention programs included coherent motion detection, visual search, visual tracking, and juggling, which were related to M function. The results showed that M function and phonological awareness of training dyslexic group were improved to a normal level as age matched normal children after intervention, while non-training dyslexics did not. It supported M deficit theory, and suggested M deficit might be the core deficit of Chinese DD. PMID- 26500584 TI - Neurotransmitters as food supplements: the effects of GABA on brain and behavior. AB - Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex. The food supplement version of GABA is widely available online. Although many consumers claim that they experience benefits from the use of these products, it is unclear whether these supplements confer benefits beyond a placebo effect. Currently, the mechanism of action behind these products is unknown. It has long been thought that GABA is unable to cross the blood-brain barrier (BBB), but the studies that have assessed this issue are often contradictory and range widely in their employed methods. Accordingly, future research needs to establish the effects of oral GABA administration on GABA levels in the human brain, for example using magnetic resonance spectroscopy. There is some evidence in favor of a calming effect of GABA food supplements, but most of this evidence was reported by researchers with a potential conflict of interest. We suggest that any veridical effects of GABA food supplements on brain and cognition might be exerted through BBB passage or, more indirectly, via an effect on the enteric nervous system. We conclude that the mechanism of action of GABA food supplements is far from clear, and that further work is needed to establish the behavioral effects of GABA. PMID- 26500582 TI - Dopaminergic modulation of positive expectations for goal-directed action: evidence from Parkinson's disease. AB - Parkinson's disease (PD) impairs the control of movement and cognition, including the planning of action and its consequences. This provides the opportunity to study the dopaminergic influences on the perception and awareness of action. Here we examined the perception of the outcome of a goal-directed action made by medicated patients with PD. A visuomotor task probed the integration of sensorimotor signals with the positive expectations of outcomes (Self priors), which in healthy adults bias perception toward success in proportion to trait optimism. We tested the hypotheses that (i) the priors on the perception of the consequences of one's own actions differ between patients and age- and sex matched controls, and (ii) that these priors are modulated by the levodopa dose equivalent (LDEs) in patients. There was no overall difference between patients and controls in the perceptual priors used. However, the precision of patient priors was inversely related to their LDE. Patients with high LDE showed more accurate priors, representing predictions that were closer to the true distribution of performance. Such accuracy has previously been demonstrated when observing the actions of others, suggesting abnormal awareness of action in these patients. These results confirm a link between dopamine and the positive expectation of the outcome of one's own actions, and may have implications for the management of PD. PMID- 26500588 TI - Discrete versus multiple word displays: a re-analysis of studies comparing dyslexic and typically developing children. AB - The study examines whether impairments in reading a text can be explained by a deficit in word decoding or an additional deficit in the processes governing the integration of reading subcomponents (including eye movement programming and pronunciation) should also be postulated. We report a re-analysis of data from eleven previous experiments conducted in our lab where the reading performance on single, discrete word displays as well multiple displays (texts, and in few cases also word lists) was investigated in groups of dyslexic children and typically developing readers. The analysis focuses on measures of time and not accuracy. Across experiments, dyslexic children are slower and more variable than typically developing readers in reading texts as well as vocal reaction time (RTs) to singly presented words; the dis-homogeneity in variability between groups points to the inappropriateness of standard measures of size effect (such as Cohen's d), and suggests the use of the ratio between groups' performance. The mean ratio for text reading is 1.95 across experiments. Mean ratio for vocal RTs for singly presented words is considerably smaller (1.52). Furthermore, this latter value is probably an overestimation as considering total reading times (i.e., a measure including also the pronunciation component) considerably reduces the group difference in vocal RTs (1.19 according to Martelli et al., 2014). The ratio difference between single and multiple displays does not depend upon the presence of a semantic context in the case of texts as large ratios are also observed with lists of unrelated words (though studies testing this aspect were few). We conclude that, if care is taken in using appropriate comparisons, the deficit in reading texts or lists of words is appreciably greater than that revealed with discrete word presentations. Thus, reading multiple stimuli present a specific, additional challenge to dyslexic children indicating that models of reading should incorporate this aspect. PMID- 26500590 TI - What goes on in the resting-state? A qualitative glimpse into resting-state experience in the scanner. AB - The brain's resting-state has attracted considerable interest in recent years, but currently little is known either about typical experience during the resting state or about whether there are inter-individual differences in resting-state phenomenology. We used descriptive experience sampling (DES) in an attempt to apprehend high fidelity glimpses of the inner experience of five participants in an extended fMRI study. Results showed that the inner experiences and the neural activation patterns (as quantified by amplitude of low frequency fluctuations analysis) of the five participants were largely consistent across time, suggesting that our extended-duration scanner sessions were broadly similar to typical resting-state sessions. However, there were very large individual differences in inner phenomena, suggesting that the resting-state itself may differ substantially from one participant to the next. We describe these individual differences in experiential characteristics and display some typical moments of resting-state experience. We also show that retrospective characterizations of phenomena can often be very different from moment-by-moment reports. We discuss implications for the assessment of inner experience in neuroimaging studies more generally, concluding that it may be possible to use fMRI to investigate neural correlates of phenomena apprehended in high fidelity. PMID- 26500593 TI - Square bananas, blue horses: the relative weight of shape and color in concept recognition and representation. AB - The present study investigates the role that shape and color play in the representation of animate (i.e., animals) and inanimate manipulable entities (i.e., fruits), and how the importance of these features is modulated by different tasks. Across three experiments participants were shown either images of entities (e.g., a sheep or a pineapple) or images of the same entities modified in color (e.g., a blue pineapple) or in shape (e.g., an elongated pineapple). In Experiment 1 we asked participants to categorize the entities as fruit or animal. Results showed that with animals color does not matter, while shape modifications determined a deterioration of the performance - stronger for fruit than for animals. To better understand our findings, in Experiments 2 we asked participants to judge if entities were graspable (manipulation evaluation task). Participants were faster with manipulable entities (fruit) than with animals; moreover alterations in shape affected the response latencies more for animals than for fruit. In Experiment 3 (motion evaluation task), we replicated the disadvantage for shape-altered animals, while with fruits shape and color modifications produced no effect. By contrasting shape- and color- alterations the present findings provide information on shape/color relative weight, suggesting that the action based property of shape is more crucial than color for fruit categorization, while with animals it is critical for both manipulation and motion tasks. This contextual dependency is further revealed by explicit judgments on similarity - between the altered entities and the prototypical ones provided after the different tasks. These results extend current literature on affordances and biofunctionally embodied understanding, revealing the relative robustness of biofunctional activity compared to intellectual one. PMID- 26500596 TI - Music stimulates muscles, mind, and feelings in one go. PMID- 26500594 TI - Normative data on the n-back task for children and young adolescents. AB - The n-back task is a frequently used measure of working memory (WM) in cognitive neuroscience research contexts, and it has become widely adopted in other areas over the last decade. This study aimed to obtain normative data for the n-back task from a large sample of children and adolescents. To this end, a computerized verbal n-back task with three levels of WM load (1-back, 2-back, and 3-back) was administered to 3722 Spanish school children aged 7-13 years. Results showed an overall age-related increase in performance for the different levels of difficulty. This trend was less pronounced at 1-back than at 2-back when hits were considered. Gender differences were also observed, with girls outperforming boys although taking more time to respond. The theoretical implications of these results are discussed. Normative data stratified by age and gender for the three WM load levels are provided. PMID- 26500592 TI - Preference reversal in quantum decision theory. AB - We consider the psychological effect of preference reversal and show that it finds a natural explanation in the frame of quantum decision theory. When people choose between lotteries with non-negative payoffs, they prefer a more certain lottery because of uncertainty aversion. But when people evaluate lottery prices, e.g., for selling to others the right to play them, they do this more rationally, being less subject to behavioral biases. This difference can be explained by the presence of the attraction factors entering the expression of quantum probabilities. Only the existence of attraction factors can explain why, considering two lotteries with close utility factors, a decision maker prefers one of them when choosing, but evaluates higher the other one when pricing. We derive a general quantitative criterion for the preference reversal to occur that relates the utilities of the two lotteries to the attraction factors under choosing vs. pricing and test successfully its application on experiments by Tversky et al. We also show that the planning paradox can be treated as a kind of preference reversal. PMID- 26500602 TI - Erratum: Observing the restriction of another person: vicarious reactance and the role of self-construal and culture. AB - [This corrects the article on p. 1052 in vol. 6, PMID: 26300795.]. PMID- 26500597 TI - Just let them play? Deliberate preparation as the most appropriate foundation for lifelong physical activity. PMID- 26500595 TI - Heritage language and linguistic theory. AB - This paper discusses a common reality in many cases of multilingualism: heritage speakers, or unbalanced bilinguals, simultaneous or sequential, who shifted early in childhood from one language (their heritage language) to their dominant language (the language of their speech community). To demonstrate the relevance of heritage linguistics to the study of linguistic competence more broadly defined, we present a series of case studies on heritage linguistics, documenting some of the deficits and abilities typical of heritage speakers, together with the broader theoretical questions they inform. We consider the reorganization of morphosyntactic feature systems, the reanalysis of atypical argument structure, the attrition of the syntax of relativization, and the simplification of scope interpretations; these phenomena implicate diverging trajectories and outcomes in the development of heritage speakers. The case studies also have practical and methodological implications for the study of multilingualism. We conclude by discussing more general concepts central to linguistic inquiry, in particular, complexity and native speaker competence. PMID- 26500599 TI - Student assessment of teaching as a source of information about aspects of teaching quality in multiple subject domains: an application of multilevel bifactor structural equation modeling. AB - Research on educational effectiveness most often uses student assessments of classroom instruction for measuring aspects of teaching quality. Given that crucial inferences on the success of education are based on these assessments, it is essential to ensure that they provide valid indicators. In this study, we illustrate the application of an innovative application of a multilevel bifactor structural equation model (ML-BFSEM) to examine the validity of student assessments. Analyzing a large-scale data set of 12,077 fourth-grade students in three countries (Finland, Norway, and Sweden), we find that (i) three aspects of teaching quality and subject domain factors can be established; (ii) metric and scalar invariance could be established for the ML-BFSEM approach across countries; and (iii) significant relations between students' assessments of how easy the teacher is to understand and achievement in all subjects exist. In support of substantive research, we demonstrate a methodological approach for representing the complex nature of student assessments of teaching quality. We finally encourage substantive and methodological researchers to advance the ML BFSEM. PMID- 26500600 TI - Investigating expectation effects using multiple physiological measures. AB - The study aimed at experimentally investigating whether the human body can anticipate future events under improved methodological conditions. Previous studies have reported contradictory results for the phenomenon typically called presentiment. If the positive findings are accurate, they call into doubt our views about human perception, and if they are inaccurate, a plausible conventional explanation might be based on the experimental design of the previous studies, in which expectation due to item sequences was misinterpreted as presentiment. To address these points, we opted to collect several physiological variables, to test different randomization types and to manipulate subjective significance individually. For the latter, we combined a mock crime scenario, in which participants had to steal specific items, with a concealed information test (CIT), in which the participants had to conceal their knowledge when interrogated about items they had stolen or not stolen. We measured electrodermal activity, respiration, finger pulse, heart rate (HR), and reaction times. The participants (n = 154) were assigned randomly to four different groups. Items presented in the CIT were either drawn with replacement (full) or without replacement (pseudo) and were either presented category-wise (cat) or regardless of categories (nocat). To understand how these item sequences influence expectation and modulate physiological reactions, we compared the groups with respect to effect sizes for stolen vs. not stolen items. Group pseudo_cat yielded the highest effect sizes, and pseudo_nocat yielded the lowest. We could not find any evidence of presentiment but did find evidence of physiological correlates of expectation. Due to the design differing fundamentally from previous studies, these findings do not allow for conclusions on the question whether the expectation bias is being confounded with presentiment. PMID- 26500598 TI - From pre-registration to publication: a non-technical primer for conducting a meta-analysis to synthesize correlational data. AB - Meta-analysis synthesizes a body of research investigating a common research question. Outcomes from meta-analyses provide a more objective and transparent summary of a research area than traditional narrative reviews. Moreover, they are often used to support research grant applications, guide clinical practice, and direct health policy. The aim of this article is to provide a practical and non technical guide for psychological scientists that outlines the steps involved in planning and performing a meta-analysis of correlational datasets. I provide a supplementary R script to demonstrate each analytical step described in the paper, which is readily adaptable for researchers to use for their analyses. While the worked example is the analysis of a correlational dataset, the general meta-analytic process described in this paper is applicable for all types of effect sizes. I also emphasize the importance of meta-analysis protocols and pre registration to improve transparency and help avoid unintended duplication. An improved understanding this tool will not only help scientists to conduct their own meta-analyses but also improve their evaluation of published meta-analyses. PMID- 26500591 TI - Visual duration aftereffect is position invariant. AB - Adaptation to relatively long or short sensory events leads to a negative aftereffect, such that the durations of the subsequent events within a certain range appear to be contracted or expanded. The distortion in perceived duration is presumed to arise from the adaptation of duration detectors. Here, we focus on the positional sensitivity of those visual duration detectors by exploring whether the duration aftereffect may be constrained by the visual location of stimuli. We adopted two different paradigms, one that tests for transfer across visual hemifields, and the other that tests for simultaneous selectivity between visual hemifields. By employing these experimental designs, we show that the duration aftereffect strongly transfers across visual hemifields and is not contingent on them. The lack of position specificity suggests that duration detectors in the visual system may operate at a relatively later stage of sensory processing. PMID- 26500603 TI - Suggesting a Way to Understand the Actual Potential of Anti-Alzheimer's Disease Drugs That Show Promise in Transgenic Mouse Models. PMID- 26500606 TI - Determinants of Concurrent Motor and Language Recovery during Intensive Therapy in Chronic Stroke Patients: Four Single-Case Studies. AB - Despite intensive research on mechanisms of recovery of function after stroke, surprisingly little is known about determinants of concurrent recovery of language and motor functions in single patients. The alternative hypotheses are that the two functions might either "fight for resources" or use the same mechanisms in the recovery process. Here, we present follow-up data of four exemplary patients with different base levels of motor and language abilities. We assessed functional scales and performed exact lesion analysis to examine the connection between lesion parameters and recovery potential in each domain. Results confirm that preservation of the corticospinal tracts (CSTs) is a neural predictor for good motor recovery while preservation of the arcuate fasciculus (AF) is important for a good language recovery. However, results further indicate that even patients with large lesions in CST, AF, and superior longitudinal fasciculus, respectively, are able to recover their motor/language abilities during intensive therapy. We further found some indicators of a facilitating interaction between motor and language recovery. Patients with positive improvement of motor skills after therapy also improved in language skills, while the patients with no motor improvements were not able to gain any language recovery. PMID- 26500605 TI - Training in Compensatory Strategies Enhances Rapport in Interactions Involving People with Mobius Syndrome. AB - In the exploratory study reported here, we tested the efficacy of an intervention designed to train teenagers with Mobius syndrome (MS) to increase the use of alternative communication strategies (e.g., gestures) to compensate for their lack of facial expressivity. Specifically, we expected the intervention to increase the level of rapport experienced in social interactions by our participants. In addition, we aimed to identify the mechanisms responsible for any such increase in rapport. In the study, five teenagers with MS interacted with three naive participants without MS before the intervention, and with three different naive participants without MS after the intervention. Rapport was assessed by self-report and by behavioral coders who rated videos of the interactions. Individual non-verbal behavior was assessed via behavioral coders, whereas verbal behavior was automatically extracted from the sound files. Alignment was assessed using cross recurrence quantification analysis and mixed effects models. The results showed that observer-coded rapport was greater after the intervention, whereas self-reported rapport did not change significantly. Observer-coded gesture and expressivity increased in participants with and without MS, whereas overall linguistic alignment decreased. Fidgeting and repetitiveness of verbal behavior also decreased in both groups. In sum, the intervention may impact non-verbal and verbal behavior in participants with and without MS, increasing rapport as well as overall gesturing, while decreasing alignment. PMID- 26500604 TI - Transplanted Neural Progenitor Cells from Distinct Sources Migrate Differentially in an Organotypic Model of Brain Injury. AB - Brain injury is a major cause of long-term disability. The possibility exists for exogenously derived neural progenitor cells to repair damage resulting from brain injury, although more information is needed to successfully implement this promising therapy. To test the ability of neural progenitor cells (NPCs) obtained from rats to repair damaged neocortex, we transplanted neural progenitor cell suspensions into normal and injured slice cultures of the neocortex acquired from rats on postnatal day 0-3. Donor cells from E16 embryos were obtained from either the neocortex, including the ventricular zone (VZ) for excitatory cells, ganglionic eminence (GE) for inhibitory cells or a mixed population of the two. Cells were injected into the ventricular/subventricular zone (VZ/SVZ) or directly into the wounded region. Transplanted cells migrated throughout the cortical plate with GE and mixed population donor cells predominately targeting the upper cortical layers, while neocortically derived NPCs from the VZ/SVZ migrated less extensively. In the injured neocortex, transplanted cells moved predominantly into the wounded area. NPCs derived from the GE tended to be immunoreactive for GABAergic markers while those derived from the neocortex were more strongly immunoreactive for other neuronal markers such as MAP2, TUJ1, or Milli-Mark. Cells transplanted in vitro acquired the electrophysiological characteristics of neurons, including action potential generation and reception of spontaneous synaptic activity. This suggests that transplanted cells differentiate into neurons capable of functionally integrating with the host tissue. Together, our data suggest that transplantation of neural progenitor cells holds great potential as an emerging therapeutic intervention for restoring function lost to brain damage. PMID- 26500608 TI - The Emerging Regulation of VEGFR-2 in Triple-Negative Breast Cancer. AB - Vascular endothelial growth factor-A (VEGF) signals vascular development and angiogenesis mainly by binding to VEGF receptor family member 2 (VEGFR-2). Adaptor proteins mediate many VEGFR-2's functions in the development of blood vessels. Cancer cells secrete VEGF to activate VEGFR-2 pathway in their neighboring endothelial cells in the process of cancer-related angiogenesis. Interestingly, activation of VEGFR-2 signaling is found in breast cancer cells, but its role and regulation are not clear. We highlighted research advances of VEGFR-2, with a focus on VEGFR-2's regulation by mutant p53 in breast cancer. In addition, we reviewed recent Food and Drug Administration-approved tyrosine kinase inhibitor drugs that can inhibit the function of VEGFR-2. Ongoing preclinical and clinical studies might prove that pharmaceutically targeting VEGFR-2 could be an effective therapeutic strategy in treating triple-negative breast cancer. PMID- 26500609 TI - From chemolithoautotrophs to electrolithoautotrophs: CO2 fixation by Fe(II) oxidizing bacteria coupled with direct uptake of electrons from solid electron sources. AB - At deep-sea vent systems, hydrothermal emissions rich in reductive chemicals replace solar energy as fuels to support microbial carbon assimilation. Until recently, all the microbial components at vent systems have been assumed to be fostered by the primary production of chemolithoautotrophs; however, both the laboratory and on-site studies demonstrated electrical current generation at vent systems and have suggested that a portion of microbial carbon assimilation is stimulated by the direct uptake of electrons from electrically conductive minerals. Here we show that chemolithoautotrophic Fe(II)-oxidizing bacterium, Acidithiobacillus ferrooxidans, switches the electron source for carbon assimilation from diffusible Fe(2+) ions to an electrode under the condition that electrical current is the only source of energy and electrons. Site-specific marking of a cytochrome aa3 complex (aa3 complex) and a cytochrome bc1 complex (bc1 complex) in viable cells demonstrated that the electrons taken directly from an electrode are used for O2 reduction via a down-hill pathway, which generates proton motive force that is used for pushing the electrons to NAD(+) through a bc1 complex. Activation of carbon dioxide fixation by a direct electron uptake was also confirmed by the clear potential dependency of cell growth. These results reveal a previously unknown bioenergetic versatility of Fe(II)-oxidizing bacteria to use solid electron sources and will help with understanding carbon assimilation of microbial components living in electronically conductive chimney habitats. PMID- 26500601 TI - Me, myself, and I: self-referent word use as an indicator of self-focused attention in relation to depression and anxiety. AB - Self-focused attention (SFA) is considered a cognitive bias that is closely related to depression. However, it is not yet well understood whether it represents a disorder-specific or a trans-diagnostic phenomenon and which role the valence of a given context is playing in this regard. Computerized quantitative text-analysis offers an integrative psycho-linguistic approach that may help to provide new insights into these complex relationships. The relative frequency of first-person singular pronouns in natural language is regarded as an objective, linguistic marker of SFA. Here we present two studies that examined the associations between SFA and symptoms of depression and anxiety in two different contexts (positive vs. negative valence), as well as the convergence between pronoun-use and self-reported aspects of SFA. In the first study, we found that the use of first-person singular pronouns during negative but not during positive memory recall was positively related to symptoms of depression and anxiety in patients with anorexia nervosa with varying levels of co-morbid depression and anxiety. In the second study, we found the same pattern of results in non-depressed individuals. In addition, use of first-person singular pronouns during negative memory recall was positively related to brooding (i.e., the assumed maladaptive sub-component of rumination) but not to reflection. These findings could not be replicated in two samples of depressed patients. However, non-chronically depressed patients used more first-person singular pronouns than healthy controls, irrespective of context. Taken together, the findings lend partial support to theoretical models that emphasize the effects of context on self-focus and consider SFA as a relevant trans-diagnostic phenomenon. In addition, the present findings point to the construct validity of pronoun-use as a linguistic marker of maladaptive self-focus. PMID- 26500612 TI - In situ metabolism in halite endolithic microbial communities of the hyperarid Atacama Desert. AB - The Atacama Desert of northern Chile is one of the driest regions on Earth, with areas that exclude plants and where soils have extremely low microbial biomass. However, in the driest parts of the desert there are microorganisms that colonize the interior of halite nodules in fossil continental evaporites, where they are sustained by condensation of atmospheric water triggered by the salt substrate. Using a combination of in situ observations of variable chlorophyll fluorescence and controlled laboratory experiments, we show that this endolithic community is capable of carbon fixation both through oxygenic photosynthesis and potentially ammonia oxidation. We also present evidence that photosynthetic activity is finely tuned to moisture availability and solar insolation and can be sustained for days, and perhaps longer, after a wetting event. This is the first demonstration of in situ active metabolism in the hyperarid core of the Atacama Desert, and it provides the basis for proposing a self-contained, endolithic community that relies exclusively on non-rainfall sources of water. Our results contribute to an increasing body of evidence that even in hyperarid environments active metabolism, adaptation, and growth can occur in highly specialized microhabitats. PMID- 26500617 TI - Biocide effects of volatile organic compounds produced by potential biocontrol rhizobacteria on Sclerotinia sclerotiorum. AB - Six rhizobacteria isolated from common bean and able to protect bean plants from the common bacterial blight (CBB) causal agent, were in vitro evaluated for their potential antifungal effects toward different plant pathogenic fungi, mostly soil borne. By dual culture assays, the above bacteria resulted producing diffusible and volatile metabolites which inhibited the growth of the majority of the pathogens under study. In particular, the latter substances highly affected the mycelium growth of Sclerotinia sclerotiorum strains, one of which was selected for further studies either on mycelium or sclerotia. Gas chromatographic analysis of the bacterial volatiles led to the identification of an array of volatile organic compounds (VOCs). Time course studies showed the modification of the VOCs profile along a period of 5 days. In order to evaluate the single detected VOC effects on fungal growth, some of the pure compounds were tested on S. sclerotiorum mycelium and their minimal inhibitory quantities were determined. Similarly, the minimal inhibitory quantities on sclerotia germination were also defined. Moreover, observations by light and transmission electron microscopes highlighted hyphae cytoplasm granulation and ultrastructural alterations at cell organelles, mostly membranes, mitochondria, and endoplasmic reticulum. The membranes appeared one of the primary targets of bacterial volatiles, as confirmed by hemolytic activity observed for the majority of pure VOCs. However, of interest is the alteration observed on mitochondria as well. PMID- 26500610 TI - Proteomics identifies Bacillus cereus EntD as a pivotal protein for the production of numerous virulence factors. AB - Bacillus cereus is a Gram-positive pathogen that causes a wide variety of diseases in humans. It secretes into the extracellular milieu proteins that may contribute directly or indirectly to its virulence. EntD is a novel exoprotein identified by proteogenomics of B. cereus ATCC 14579. We constructed a DeltaentD mutant and analyzed the impact of entD disruption on the cellular proteome and exoproteome isolated from early, late, and stationary-phase cultures. We identified 308 and 79 proteins regulated by EntD in the cellular proteome and the exoproteome, respectively. The contribution of these proteins to important virulence-associated functions, including central metabolism, cell structure, antioxidative ability, cell motility, and toxin production, are presented. The proteomic data were correlated with the growth defect, cell morphology change, reduced motility, and reduced cytotoxicity of the DeltaentD mutant strain. We conclude that EntD is an important player in B. cereus virulence. The function of EntD and the putative EntD-dependent regulatory network are discussed. To our knowledge, this study is the first characterization of an Ent family protein in a species of the B. cereus group. PMID- 26500619 TI - Genetic manipulation of a metabolic enzyme and a transcriptional regulator increasing succinate excretion from unicellular cyanobacterium. AB - Succinate is a building block compound that the U.S. Department of Energy (DOE) has declared as important in biorefineries, and it is widely used as a commodity chemical. Here, we identified the two genes increasing succinate production of the unicellular cyanobacterium Synechocystis sp. PCC 6803. Succinate was excreted under dark, anaerobic conditions, and its production level increased by knocking out ackA, which encodes an acetate kinase, and by overexpressing sigE, which encodes an RNA polymerase sigma factor. Glycogen catabolism and organic acid biosynthesis were enhanced in the mutant lacking ackA and overexpressing sigE, leading to an increase in succinate production reaching five times of the wild type levels. Our genetic and metabolomic analyses thus demonstrated the effect of genetic manipulation of a metabolic enzyme and a transcriptional regulator on succinate excretion from this cyanobacterium with the data based on metabolomic technique. PMID- 26500615 TI - Optimization of cellulase production by Enhydrobacter sp. ACCA2 and its application in biomass saccharification. AB - Cellulase finds use in saccharification of lignocellulosic agroresidues to fermentable sugars which can be used for production of commercially important metabolites. This study reports endoglucanase (CMCase) production by Enhydrobacter sp. ACCA2. The CMCase activity of the strain ACCA2 was successively improved by optimization of range of physical and nutritional parameter in a set of non-statistical and statistical experiments. Initial non-statistical selection of carbon source, incubation time, temperature and pH resulted in 1.07 fold increase of CMCase activity. In a subsequent statistical method, response surface methodology, optimization of medium components such as carboxymethylcellulose, peptone, NaCl, MgSO4, K2HPO4, and (NH4)2SO4 yielded further increase up to 2.39 fold CMCase activity. The cellulolytic potential was evaluated in biomass saccharification with different plant materials and the results revealed that the enzyme produced by strain may have significant commercial values for industrial saccharification process. Moreover, this is the first report of cellulase production by an Enhydrobacter spp. PMID- 26500611 TI - Cell scale host-pathogen modeling: another branch in the evolution of constraint based methods. AB - Constraint-based models have become popular methods for systems biology as they enable the integration of complex, disparate datasets in a biologically cohesive framework that also supports the description of biological processes in terms of basic physicochemical constraints and relationships. The scope, scale, and application of genome scale models have grown from single cell bacteria to multi cellular interaction modeling; host-pathogen modeling represents one of these examples at the current horizon of constraint-based methods. There are now a small number of examples of host-pathogen constraint-based models in the literature, however there has not yet been a definitive description of the methodology required for the functional integration of genome scale models in order to generate simulation capable host-pathogen models. Herein we outline a systematic procedure to produce functional host-pathogen models, highlighting steps which require debugging and iterative revisions in order to successfully build a functional model. The construction of such models will enable the exploration of host-pathogen interactions by leveraging the growing wealth of omic data in order to better understand mechanism of infection and identify novel therapeutic strategies. PMID- 26500613 TI - Molecular tools in understanding the evolution of Vibrio cholerae. AB - Vibrio cholerae, the etiological agent of cholera, has been a scourge for centuries. Cholera remains a serious health threat for developing countries and has been responsible for millions of deaths globally over the past 200 years. Identification of V. cholerae has been accomplished using a variety of methods, ranging from phenotypic strategies to DNA based molecular typing and currently whole genomic approaches. This array of methods has been adopted in epidemiological investigations, either singly or in the aggregate, and more recently for evolutionary analyses of V. cholerae. Because the new technologies have been developed at an ever increasing pace, this review of the range of fingerprinting strategies, their relative advantages and limitations, and cholera case studies was undertaken. The task was challenging, considering the vast amount of the information available. To assist the study, key references representative of several areas of research are provided with the intent to provide readers with a comprehensive view of recent advances in the molecular epidemiology of V. cholerae. Suggestions for ways to obviate many of the current limitations of typing techniques are also provided. In summary, a comparative report has been prepared that includes the range from traditional typing to whole genomic strategies. PMID- 26500618 TI - Specific microbial gene abundances and soil parameters contribute to C, N, and greenhouse gas process rates after land use change in Southern Amazonian Soils. AB - Ecological processes regulating soil carbon (C) and nitrogen (N) cycles are still poorly understood, especially in the world's largest agricultural frontier in Southern Amazonia. We analyzed soil parameters in samples from pristine rainforest and after land use change to pasture and crop fields, and correlated them with abundance of functional and phylogenetic marker genes (amoA, nirK, nirS, norB, nosZ, nifH, mcrA, pmoA, and 16S/18S rRNA). Additionally, we integrated these parameters using path analysis and multiple regressions. Following forest removal, concentrations of soil C and N declined, and pH and nutrient levels increased, which influenced microbial abundances and biogeochemical processes. A seasonal trend was observed, suggesting that abundances of microbial groups were restored to near native levels after the dry winter fallow. Integration of the marker gene abundances with soil parameters using path analysis and multiple regressions provided good predictions of biogeochemical processes, such as the fluxes of NO3, N2O, CO2, and CH4. In the wet season, agricultural soil showed the highest abundance of nitrifiers (amoA) and Archaea, however, forest soils showed the highest abundances of denitrifiers (nirK, nosZ) and high N, which correlated with increased N2O emissions. Methanogens (mcrA) and methanotrophs (pmoA) were more abundant in forest soil, but methane flux was highest in pasture sites, which was related to soil compaction. Rather than analyzing direct correlations, the data integration using multivariate tools provided a better overview of biogeochemical processes. Overall, in the wet season, land use change from forest to agriculture reduced the abundance of different functional microbial groups related to the soil C and N cycles; integrating the gene abundance data and soil parameters provided a comprehensive overview of these interactions. Path analysis and multiple regressions addressed the need for more comprehensive approaches to improve our mechanistic understanding of biogeochemical cycles. PMID- 26500614 TI - Transcriptional and metabolic effects of glucose on Streptococcus pneumoniae sugar metabolism. AB - Streptococcus pneumoniae is a strictly fermentative human pathogen that relies on carbohydrate metabolism to generate energy for growth. The nasopharynx colonized by the bacterium is poor in free sugars, but mucosa lining glycans can provide a source of sugar. In blood and inflamed tissues glucose is the prevailing sugar. As a result during progression from colonization to disease S. pneumoniae has to cope with a pronounced shift in carbohydrate nature and availability. Thus, we set out to assess the pneumococcal response to sugars found in glycans and the influence of glucose (Glc) on this response at the transcriptional, physiological, and metabolic levels. Galactose (Gal), N-acetylglucosamine (GlcNAc), and mannose (Man) affected the expression of 8 to 14% of the genes covering cellular functions including central carbon metabolism and virulence. The pattern of end-products as monitored by in vivo (13)C-NMR is in good agreement with the fermentation profiles during growth, while the pools of phosphorylated metabolites are consistent with the type of fermentation observed (homolactic vs. mixed) and regulation at the metabolic level. Furthermore, the accumulation of alpha-Gal6P and Man6P indicate metabolic bottlenecks in the metabolism of Gal and Man, respectively. Glc added to cells actively metabolizing other sugar(s) was readily consumed and elicited a metabolic shift toward a homolactic profile. The transcriptional response to Glc was large (over 5% of the genome). In central carbon metabolism (most represented category), Glc exerted mostly negative regulation. The smallest response to Glc was observed on a sugar mix, suggesting that exposure to varied sugars improves the fitness of S. pneumoniae. The expression of virulence factors was negatively controlled by Glc in a sugar-dependent manner. Overall, our results shed new light on the link between carbohydrate metabolism, adaptation to host niches and virulence. PMID- 26500616 TI - Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches. AB - The human body is the residence of a large number of commensal (non-pathogenic) and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system, and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics) as well as phages engineered with CRISPR/Cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community) and common diseases (e.g., diabetes and obesity). The designing and production of pharmaceuticals based on our own body's microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies. PMID- 26500622 TI - Diverse electron sources support denitrification under hypoxia in the obligate methanotroph Methylomicrobium album strain BG8. AB - Aerobic methane-oxidizing bacteria (MOB) are a diverse group of microorganisms that are ubiquitous in natural environments. Along with anaerobic MOB and archaea, aerobic methanotrophs are critical for attenuating emission of methane to the atmosphere. Clearly, nitrogen availability in the form of ammonium and nitrite have strong effects on methanotrophic activity and their natural community structures. Previous findings show that nitrite amendment inhibits the activity of some cultivated methanotrophs; however, the physiological pathways that allow some strains to transform nitrite, expression of gene inventories, as well as the electron sources that support this activity remain largely uncharacterized. Here we show that Methylomicrobium album strain BG8 utilizes methane, methanol, formaldehyde, formate, ethane, ethanol, and ammonia to support denitrification activity under hypoxia only in the presence of nitrite. We also demonstrate that transcript abundance of putative denitrification genes, nirS and one of two norB genes, increased in response to nitrite. Furthermore, we found that transcript abundance of pxmA, encoding the alpha subunit of a putative copper-containing monooxygenase, increased in response to both nitrite and hypoxia. Our results suggest that expression of denitrification genes, found widely within genomes of aerobic methanotrophs, allow the coupling of substrate oxidation to the reduction of nitrogen oxide terminal electron acceptors under oxygen limitation. The present study expands current knowledge of the metabolic flexibility of methanotrophs by revealing that a diverse array of electron donors support nitrite reduction to nitrous oxide under hypoxia. PMID- 26500621 TI - Incorporating the soil environment and microbial community into plant competition theory. AB - Plants affect microbial communities and abiotic properties of nearby soils, which in turn influence plant growth and interspecific interaction, forming a plant soil feedback (PSF). PSF is a key determinant influencing plant population dynamics, community structure, and ecosystem functions. Despite accumulating evidence for the importance of PSF and development of specific PSF models, different models are not yet fully integrated. Here, we review the theoretical progress in understanding PSF. When first proposed, PSF was integrated with various mathematical frameworks to discuss its influence on plant competition. Recent theoretical models have advanced PSF research at different levels of ecological organizations by considering multiple species, applying spatially explicit simulations to examine how local-scale predictions apply to larger scales, and assessing the effect of PSF on plant temporal dynamics over the course of succession. We then review two foundational models for microbial- and litter-mediated PSF. We present a theoretical framework to illustrate that although the two models are typically presented separately, their behavior can be understood together by invasibility analysis. We conclude with suggestions for future directions in PSF theoretical studies, which include specifically addressing microbial diversity to integrate litter- and microbial-mediated PSF, and apply PSF to general coexistence theory through a trait-based approach. PMID- 26500607 TI - A New Role for Browning as a Redox and Stress Adaptive Mechanism? AB - The worldwide epidemic of obesity and metabolic disorders is focusing the attention of the scientific community on white adipose tissue (WAT) and its biology. This tissue is characterized not only by its capability to change in size and shape but also by its heterogeneity and versatility. WAT can be converted into brown fat-like tissue according to different physiological and pathophysiological situations. The expression of uncoupling protein-1 in brown like adipocytes changes their function from energy storage to energy dissipation. This plasticity, named browning, was recently rediscovered and convergent recent accounts, including in humans, have revived the idea of using these oxidative cells to fight against metabolic diseases. Furthermore, recent reports suggest that, beside the increased energy dissipation and thermogenesis that may have adverse effects in situations such as cancer-associated cachexia and massive burns, browning could be also considered as an adaptive stress response to high redox pressure and to major stress that could help to maintain tissue homeostasis and integrity. The aim of this review is to summarize the current knowledge concerning brown adipocytes and the browning process and also to explore unexpected putative role(s) for these cells. While it is important to find new browning inducers to limit energy stores and metabolic diseases, it also appears crucial to develop new browning inhibitors to limit adverse energy dissipation in wasting-associated syndromes. PMID- 26500624 TI - Temperature and pressure adaptation of a sulfate reducer from the deep subsurface. AB - Microbial life in deep marine subsurface faces increasing temperatures and hydrostatic pressure with depth. In this study, we have examined growth characteristics and temperature-related adaptation of the Desulfovibrio indonesiensis strain P23 to the in situ pressure of 30 MPa. The strain originates from the deep subsurface of the eastern flank of the Juan de Fuca Ridge (IODP Site U1301). The organism was isolated at 20 degrees C and atmospheric pressure from ~61 degrees C-warm sediments approximately 5 m above the sediment-basement interface. In comparison to standard laboratory conditions (20 degrees C and 0.1 MPa), faster growth was recorded when incubated at in situ pressure and high temperature (45 degrees C), while cell filamentation was induced by further compression. The maximum growth temperature shifted from 48 degrees C at atmospheric pressure to 50 degrees C under high-pressure conditions. Complementary cellular lipid analyses revealed a two-step response of membrane viscosity to increasing temperature with an exchange of unsaturated by saturated fatty acids and subsequent change from branched to unbranched alkyl moieties. While temperature had a stronger effect on the degree of fatty acid saturation and restructuring of main phospholipids, pressure mainly affected branching and length of side chains. The simultaneous decrease of temperature and pressure to ambient laboratory conditions allowed the cultivation of our moderately thermophilic strain. This may in turn be one key to a successful isolation of microorganisms from the deep subsurface adapted to high temperature and pressure. PMID- 26500627 TI - Bioactivity of volatile organic compounds produced by Pseudomonas tolaasii. AB - Pseudomonas tolaasii is the main bacterial pathogen of several mushroom species. In this paper we report that strains of P. tolaasii produce volatile substances inducing in vitro mycelia growth inhibition of Pleurotus ostreatus and P. eryngii, and Agaricus bisporus and P. ostreatus basidiome tissue blocks brown discoloration. P. tolaasii strains produced the volatile ammonia but not hydrogen cyanide. Among the volatiles detected by GC-MS, methanethiol, dimethyl disulfide (DMDS), and 1-undecene were identified. The latter, when assayed individually as pure compounds, led to similar effects noticed when P. tolaasii volatiles natural blend was used on mushrooms mycelia and basidiome tissue blocks. Furthermore, the natural volatile mixture resulted toxic toward lettuce and broccoli seedling growth. In contrast, pure volatiles showed different activity according to their nature and/or doses applied. Indeed, methanethiol resulted toxic at all the doses used, while DMDS toxicity was assessed till a quantity of 1.25 MUg, below which it caused, together with 1-undecene (>=10 MUg), broccoli growth increase. PMID- 26500620 TI - Functional and evolutionary analyses of Helicobacter pylori HP0231 (DsbK) protein with strong oxidative and chaperone activity characterized by a highly diverged dimerization domain. AB - Helicobacter pylori does not encode the classical DsbA/DsbB oxidoreductases that are crucial for oxidative folding of extracytoplasmic proteins. Instead, this microorganism encodes an untypical two proteins playing a role in disulfide bond formation - periplasmic HP0231, which structure resembles that of EcDsbC/DsbG, and its redox partner, a membrane protein HpDsbI (HP0595) with a beta-propeller structure. The aim of presented work was to assess relations between HP0231 structure and function. We showed that HP0231 is most closely related evolutionarily to the catalytic domain of DsbG, even though it possesses a catalytic motif typical for canonical DsbA proteins. Similarly, the highly diverged N-terminal dimerization domain is homologous to the dimerization domain of DsbG. To better understand the functioning of this atypical oxidoreductase, we examined its activity using in vivo and in vitro experiments. We found that HP0231 exhibits oxidizing and chaperone activities but no isomerizing activity, even though H. pylori does not contain a classical DsbC. We also show that HP0231 is not involved in the introduction of disulfide bonds into HcpC (Helicobacter cysteine-rich protein C), a protein involved in the modulation of the H. pylori interaction with its host. Additionally, we also constructed a truncated version of HP0231 lacking the dimerization domain, denoted HP0231m, and showed that it acts in Escherichia coli cells in a DsbB-dependent manner. In contrast, HP0231m and classical monomeric EcDsbA (E. coli DsbA protein) were both unable to complement the lack of HP0231 in H. pylori cells, though they exist in oxidized forms. HP0231m is inactive in the insulin reduction assay and possesses high chaperone activity, in contrast to EcDsbA. In conclusion, HP0231 combines oxidative functions characteristic of DsbA proteins and chaperone activity characteristic of DsbC/DsbG, and it lacks isomerization activity. PMID- 26500625 TI - Genome sequencing reveals a new lineage associated with lablab bean and genetic exchange between Xanthomonas axonopodis pv. phaseoli and Xanthomonas fuscans subsp. fuscans. AB - Common bacterial blight is a devastating seed-borne disease of common beans that also occurs on other legume species including lablab and Lima beans. We sequenced and analyzed the genomes of 26 strains of Xanthomonas axonopodis pv. phaseoli and X. fuscans subsp. fuscans, the causative agents of this disease, collected over four decades and six continents. This revealed considerable genetic variation within both taxa, encompassing both single-nucleotide variants and differences in gene content, that could be exploited for tracking pathogen spread. The bacterial strain from Lima bean fell within the previously described Genetic Lineage 1, along with the pathovar type strain (NCPPB 3035). The strains from lablab represent a new, previously unknown genetic lineage closely related to strains of X. axonopodis pv. glycines. Finally, we identified more than 100 genes that appear to have been recently acquired by Xanthomonas axonopodis pv. phaseoli from X. fuscans subsp. fuscans. PMID- 26500623 TI - New strategic insights into managing fungal biofilms. AB - Fungal infections have dramatically increased in the last decades in parallel with an increase of populations with impaired immunity, resulting from medical conditions such as cancer, transplantation, or other chronic diseases. Such opportunistic infections result from a complex relationship between fungi and host, and can range from self-limiting to chronic or life-threatening infections. Modern medicine, characterized by a wide use of biomedical devices, offers new niches for fungi to colonize and form biofilm communities. The capability of fungi to form biofilms is well documented and associated with increased drug tolerance and resistance. In addition, biofilm formation facilitates persistence in the host promoting a persistent inflammatory condition. With a limited availability of antifungals within our arsenal, new therapeutic approaches able to address both host and pathogenic factors that promote fungal disease progression, i.e., chronic inflammation and biofilm formation, could represent an advantage in the clinical setting. In this paper we discuss the antifungal properties of myriocin, fulvic acid, and acetylcholine in light of their already known anti-inflammatory activity and as candidate dual action therapeutics to treat opportunistic fungal infections. PMID- 26500628 TI - Beauveria bassiana Lipase A expressed in Komagataella (Pichia) pastoris with potential for biodiesel catalysis. AB - Lipases (EC 3.1.1.3) comprise a biotechnologically important group of enzymes because they are able to catalyze both hydrolysis and synthesis reactions, depending on the amount of water in the system. One of the most interesting applications of lipase is in the biofuel industry for biodiesel production by oil and ethanol (or methanol) transesterification. Entomopathogenic fungi, which are potential source of lipases, are still poorly explored in biotechnological processes. The present work reports the heterologous expression and biochemical characterization of a novel Beauveria bassiana lipase with potential for biodiesel production. The His-tagged B. bassiana lipase A (BbLA) was produced in Komagataella pastoris in buffered methanol medium (BMM) induced with 1% methanol at 30 degrees C. Purified BbLA was activated with 0.05% Triton X-100 and presented optimum activity at pH 6.0 and 50 degrees C. N-glycosylation of the recombinant BbLA accounts for 31.5% of its molecular weight. Circular dichroism and molecular modeling confirmed a structure composed of alpha-helix and beta sheet, similar to alpha/beta hydrolases. Immobilized BbLA was able to promote transesterification reactions in fish oil, demonstrating potential for biodiesel production. BbLA was successfully produced in K. pastoris and shows potential use for biodiesel production by the ethanolysis reaction. PMID- 26500626 TI - Diversity and functions of volatile organic compounds produced by Streptomyces from a disease-suppressive soil. AB - In disease-suppressive soils, plants are protected from infections by specific root pathogens due to the antagonistic activities of soil and rhizosphere microorganisms. For most disease-suppressive soils, however, the microorganisms and mechanisms involved in pathogen control are largely unknown. Our recent studies identified Actinobacteria as the most dynamic phylum in a soil suppressive to the fungal root pathogen Rhizoctonia solani. Here we isolated and characterized 300 isolates of rhizospheric Actinobacteria from the Rhizoctonia suppressive soil. Streptomyces species were the most abundant, representing approximately 70% of the isolates. Streptomyces are renowned for the production of an exceptionally large number of secondary metabolites, including volatile organic compounds (VOCs). VOC profiling of 12 representative Streptomyces isolates by SPME-GC-MS allowed a more refined phylogenetic delineation of the Streptomyces isolates than the sequencing of 16S rRNA and the house-keeping genes atpD and recA only. VOCs of several Streptomyces isolates inhibited hyphal growth of R. solani and significantly enhanced plant shoot and root biomass. Coupling of Streptomyces VOC profiles with their effects on fungal growth, pointed to VOCs potentially involved in antifungal activity. Subsequent assays with five synthetic analogs of the identified VOCs showed that methyl 2-methylpentanoate, 1,3,5-trichloro-2-methoxy benzene and the VOCs mixture have antifungal activity. In conclusion, our results point to a potential role of VOC-producing Streptomyces in disease suppressive soils and show that VOC profiling of rhizospheric Streptomyces can be used as a complementary identification tool to construct strain-specific metabolic signatures. PMID- 26500631 TI - The Shewanella algae strain YM8 produces volatiles with strong inhibition activity against Aspergillus pathogens and aflatoxins. AB - Aflatoxigenic Aspergillus fungi and associated aflatoxins are ubiquitous in the production and storage of food/feed commodities. Controlling these microbes is a challenge. In this study, the Shewanella algae strain YM8 was found to produce volatiles that have strong antifungal activity against Aspergillus pathogens. Gas chromatography-mass spectrometry profiling revealed 15 volatile organic compounds (VOCs) emitted from YM8, of which dimethyl trisulfide was the most abundant. We obtained authentic reference standards for six of the VOCs; these all significantly reduced mycelial growth and conidial germination in Aspergillus; dimethyl trisulfide and 2,4-bis(1,1-dimethylethyl)-phenol showed the strongest inhibitory activity. YM8 completely inhibited Aspergillus growth and aflatoxin biosynthesis in maize and peanut samples stored at different water activity levels, and scanning electron microscopy revealed severely damaged conidia and a complete lack of mycelium development and conidiogenesis. YM8 also completely inhibited the growth of eight other agronomically important species of phytopathogenic fungi: A. parasiticus, A. niger, Alternaria alternate, Botrytis cinerea, Fusarium graminearum, Fusarium oxysporum, Monilinia fructicola, and Sclerotinia sclerotiorum. This study demonstrates the susceptibility of Aspergillus and other fungi to VOCs from marine bacteria and indicates a new strategy for effectively controlling these pathogens and the associated mycotoxin production during storage and possibly in the field. PMID- 26500633 TI - Potential probiotic yeasts isolated from the fish gut protect zebrafish (Danio rerio) from a Vibrio anguillarum challenge. AB - Due to the negative consequences associated with the use of antibiotics, researchers, and food producers have studied alternatives, such as probiotics, for the control of fish diseases. The probiotic properties of yeasts in aquaculture have been scarcely considered. The present study investigated the probiotic properties of local yeast strains for aquaculture application in the protection of bacterial diseases. Yeast strains (n = 15), previously isolated from the intestinal gut of healthy salmonids, yellowtail, and croaker, were evaluated for their protection of zebrafish larvae following a Vibrio anguillarum challenge. We developed an infection model on zebrafish larvae with V. anguillarum, observing rapid mortality (>=50%) 5 days post-immersion challenge. Infection of Tg(Lyz:DsRed)(nz50) larvae with fluorescent-marked V. anguillarum showed the oro-intestinal as the natural route of infection concomitant with an inflammatory response of the larvae reflected by neutrophil migration outside the hematopoietic tissue. Thirteen of 15 strains increased the percentage of larvae survival after the V. anguillarum challenge, although no yeast showed in vitro anti-V. anguillarum activity. In a subset of yeasts, we explored yeast-larvae interactions using fluorescent yeast and evaluated larvae colonization by culture analysis. All fluorescent yeasts were located in the gastrointestinal tract until 5 days post-inoculation (dpi). Yeasts reached 10(3) CFU/larvae at 0 dpi, although the persistence until 5 dpi of the viable yeast in the gut was different among the strains. These results reveal that some yeasts isolated from the gut of fish could be potential probiotics, reducing the mortality associated to V. anguillarum challenge, and suggest that gut colonization could be involved in the protective effect. Future studies should elucidate other mechanisms involved in yeast protection and verify the beneficial effects of probiotic use in commercial fish species. PMID- 26500634 TI - Escherichia coli lipoprotein binds human plasminogen via an intramolecular domain. AB - Escherichia coli lipoprotein (Lpp) is a major cellular component that exists in two distinct states, bound-form and free-form. Bound-form Lpp is known to interact with the periplasmic bacterial cell wall, while free-form Lpp is localized to the bacterial cell surface. A function for surface-exposed Lpp has yet to be determined. We hypothesized that the presence of C-terminal lysinses in the surface-exposed region of Lpp would facilitate binding to the host zymogen plasminogen (Plg), a protease commandeered by a number of clinically important bacteria. Recombinant Lpp was synthesized and the binding of Lpp to Plg, the effect of various inhibitors on this binding, and the effects of various mutations of Lpp on Lpp-Plg interactions were examined. Additionally, the ability of Lpp-bound Plg to be converted to active plasmin was analyzed. We determined that Lpp binds Plg via an atypical domain located near the center of mature Lpp that may not be exposed on the surface of intact E. coli according to the current localization model. Finally, we found that Plg bound by Lpp can be converted to active plasmin. While the consequences of Lpp binding Plg are unclear, these results prompt further investigation of the ability of surface exposed Lpp to interact with host molecules such as extracellular matrix components and complement regulators, and the role of these interactions in infections caused by E. coli and other bacteria. PMID- 26500630 TI - Isolation of new Brazilian giant viruses from environmental samples using a panel of protozoa. AB - The Megavirales are a newly described order capable of infecting different types of eukaryotic hosts. For the most part, the natural host is unknown. Several methods have been used to detect these viruses, with large discrepancies between molecular methods and co-cultures. To isolate giant viruses, we propose the use of different species of amoeba as a cellular support. The aim of this work was to isolate new Brazilian giant viruses by comparing the protozoa Acanthamoeba castellanii, A. polyphaga, A. griffini, and Vermamoeba vermiformis (VV) as a platform for cellular isolation using environmental samples. One hundred samples were collected from 3 different areas in September 2014 in the Pampulha lagoon of Belo Horizonte city, Minas Gerais, Brazil. PCR was used to identify the isolated viruses, along with hemacolor staining, labelling fluorescence and electron microscopy. A total of 69 viruses were isolated. The highest ratio of isolation was found in A. polyphaga (46.38%) and the lowest in VV (0%). Mimiviruses were the most frequently isolated. One Marseillevirus and one Pandoravirus were also isolated. With Brazilian environmental samples, we demonstrated the high rate of lineage A mimiviruses. This work demonstrates how these viruses survive and circulate in nature as well the differences between protozoa as a platform for cellular isolation. PMID- 26500629 TI - Regulation of lung immunity and host defense by the intestinal microbiota. AB - Every year in the United States approximately 200,000 people die from pulmonary infections, such as influenza and pneumonia, or from lung disease that is exacerbated by pulmonary infection. In addition, respiratory diseases such as, asthma, affect 300 million people worldwide. Therefore, understanding the mechanistic basis for host defense against infection and regulation of immune processes involved in asthma are crucial for the development of novel therapeutic strategies. The identification, characterization, and manipulation of immune regulatory networks in the lung represents one of the biggest challenges in treatment of lung associated disease. Recent evidence suggests that the gastrointestinal (GI) microbiota plays a key role in immune adaptation and initiation in the GI tract as well as at other distal mucosal sites, such as the lung. This review explores the current research describing the role of the GI microbiota in the regulation of pulmonary immune responses. Specific focus is given to understanding how intestinal "dysbiosis" affects lung health. PMID- 26500632 TI - The effect of diet and host genotype on ceca microbiota of Japanese quail fed a cholesterol enriched diet. AB - Two Japanese quail strains, respectively atherosclerosis-susceptible (SUS) and resistant (RES), have been shown to be good models to study cholesterol metabolism and transportation associated with atherosclerosis. Our objective was to examine possible difference in cecal microbiota between these strains when fed a control diet and a cholesterol enriched diet, to determine how host genotype and diet could affect the cecal microbiome that may play a part in cholesterol metabolism. A factorial study with both strains and two diets (control, cholesterol) was carried out. Cecal content was collected from 12 week old quail that have been on their respective diets for 6 weeks. DNA was extracted from the samples and the variable region 3-5 of the bacterial 16S rRNA gene was amplified. The amplicon libraries were subjected to pyrosequencing. Principal Component Analysis (PCA) of beta-diversity showed four distinct microbiota communities that can be assigned to the 4 treatment groups (RES/control, RES/cholesterol, SUS/control, SUS/cholesterol). At the Phylum level, the 4 treatment groups has distinct Firmicutes community characteristics but no significant difference in Bacteroidetes. Eubacterium dolichum was rare in RES/control but became overabundant in RES/cholesterol. An unclassified species of Lactobacillaceae was found in abundance in SUS/control but the same species was rare in RES/cholesterol. On the other hand, two Lactobacillus species were only found in RES/control and an unclassified Lachnospiraceae species was abundant in RES/cholesterol but rare in SUS/control. The abundance of four species of Lachnospiraceae, three species of Ruminococcaceae and one species of Coprobacillaceae was positively correlated with plasma Total Cholesterol, plasma LDL, and LDL/HDL ratio. Our study of cecal microbiota in these quail has demonstrated that selection for susceptibility/resistance to diet induced atherosclerosis has also affected the quail's cecal environment to host distinctly different cecal microbiome. PMID- 26500636 TI - Nutrient-cycling microbes in coastal Douglas-fir forests: regional-scale correlation between communities, in situ climate, and other factors. AB - Microbes such as fungi and bacteria play fundamental roles in litter-decay and nutrient-cycling; however, their communities may respond differently than plants to climate change. The structure (diversity, richness, and evenness) and composition of microbial communities in climate transects of mature Douglas-fir stands of coastal British Columbia rainshadow forests was analyzed, in order to assess in situ variability due to different temperature and moisture regimes. We compared denaturing gradient gel electrophoresis profiles of fungi (18S FF390/FR1), nitrogen-fixing bacteria (NifH-universal) and ammonia-oxidizing bacteria (AmoA) polymerase chain reaction amplicons in forest floor and mineral soil samples from three transects located at different latitudes, each transect spanning the Coastal Western Hemlock and Douglas-fir biogeoclimatic zones. Composition of microbial communities in both soil layers was related to degree days above 0 degrees C (2725-3489), while pH (3.8-5.5) best explained shifts in community structure. At this spatial scale, climatic conditions were likely to directly or indirectly select for different microbial species while local site heterogeneity influenced community structure. Significant changes in microbial community composition and structure were related to differences as small as 2.47% and 2.55 degrees C in mean annual moisture and temperature variables, respectively. The climatic variables best describing microbial composition changed from one functional group to the next; in general they did not alter community structure. Spatial distance, especially associated with latitude, was also important in accounting for community variability (4-23%); but to a lesser extent than the combined influence of climate and soil characteristics (14-25%). Results suggest that in situ climate can independently account for some patterns of microbial biogeography in coastal Douglas-fir forests. The distribution of up to 43% of nutrient-cycling microorganisms detected in forest soils responded to smaller abiotic gradients than host trees. PMID- 26500635 TI - FvBck1, a component of cell wall integrity MAP kinase pathway, is required for virulence and oxidative stress response in sugarcane Pokkah Boeng pathogen. AB - Fusarium verticillioides (formerly F. moniliforme) is suggested as one of the causal agents of Pokkah Boeng, a serious disease of sugarcane worldwide. Currently, detailed molecular and physiological mechanism of pathogenesis is unknown. In this study, we focused on cell wall integrity MAPK pathway as one of the potential signaling mechanisms associated with Pokkah Boeng pathogenesis. We identified FvBCK1 gene that encodes a MAP kinase kinase kinase homolog and determined that it is not only required for growth, micro- and macro-conidia production, and cell wall integrity but also for response to osmotic and oxidative stresses. The deletion of FvBCK1 caused a significant reduction in virulence and FB1 production, a possibly carcinogenic mycotoxin produced by the fungus. Moreover, we found the expression levels of three genes, which are known to be involved in superoxide scavenging, were down regulated in the mutant. We hypothesized that the loss of superoxide scavenging capacity was one of the reasons for reduced virulence, but overexpression of catalase or peroxidase gene failed to restore the virulence defect in the deletion mutant. When we introduced Magnaporthe oryzae MCK1 into the FvBck1 deletion mutant, while certain phenotypes were restored, the complemented strain failed to gain full virulence. In summary, FvBck1 plays a diverse role in F. verticillioides, and detailed investigation of downstream signaling pathways will lead to a better understanding of how this MAPK pathway regulates Pokkah Boeng on sugarcane. PMID- 26500637 TI - Deterioration to extinction of wastewater bacteria by non-thermal atmospheric pressure air plasma as assessed by 16S rDNA-DGGE fingerprinting. AB - The use of cold plasma jets for inactivation of a variety of microorganisms has recently been evaluated via culture-based methods. Accordingly, elucidation of the role of cold plasma in decontamination would be inaccurate because most microbial populations within a system remain unexplored owing to the high amount of yet uncultured bacteria. The impact of cold atmospheric plasma on the bacterial community structure of wastewater from two different industries was investigated by metagenomic-based polymerase chain reaction-denaturing gradient gel electrophoresis (DGGE) utilizing 16S rRNA genes. Three doses of atmospheric pressure dielectric barrier discharge plasma were applied to wastewater samples on different time scales. DGGE revealed that the bacterial community gradually changed and overall abundance decreased to extinction upon plasma treatment. The bacterial community in food processing wastewater contained 11 key operational taxonomic units that remained almost completely unchanged when exposed to plasma irradiation at 75.5 mA for 30 or 60 s. However, when exposure time was extended to 90 s, only Escherichia coli, Coliforms, Aeromonas sp., Vibrio sp., and Pseudomonas putida survived. Only E. coli, Aeromonas sp., Vibrio sp., and P. putida survived treatment at 81.94 mA for 90 s. Conversely, all bacterial groups were completely eliminated by treatment at 85.34 mA for either 60 or 90 s. Dominant bacterial groups in leather processing wastewater also changed greatly upon exposure to plasma at 75.5 mA for 30 or 60 s, with Enterobacter aerogenes, Klebsiella sp., Pseudomonas stutzeri, and Acidithiobacillus ferrooxidans being sensitive to and eliminated from the community. At 90 s of exposure, all groups were affected except for Pseudomonas sp. and Citrobacter freundii. The same trend was observed for treatment at 81.94 mA. The variability in bacterial community response to different plasma treatment protocols revealed that plasma had a selective impact on bacterial community structure at lower doses and potential bactericidal effects at higher doses. PMID- 26500638 TI - Functional bacterial amyloid increases Pseudomonas biofilm hydrophobicity and stiffness. AB - The success of Pseudomonas species as opportunistic pathogens derives in great part from their ability to form stable biofilms that offer protection against chemical and mechanical attack. The extracellular matrix of biofilms contains numerous biomolecules, and it has recently been discovered that in Pseudomonas one of the components includes beta-sheet rich amyloid fibrils (functional amyloid) produced by the fap operon. However, the role of the functional amyloid within the biofilm has not yet been investigated in detail. Here we investigate how the fap-based amyloid produced by Pseudomonas affects biofilm hydrophobicity and mechanical properties. Using atomic force microscopy imaging and force spectroscopy, we show that the amyloid renders individual cells more resistant to drying and alters their interactions with hydrophobic probes. Importantly, amyloid makes Pseudomonas more hydrophobic and increases biofilm stiffness 20 fold. Deletion of any one of the individual members of in the fap operon (except the putative chaperone FapA) abolishes this ability to increase biofilm stiffness and correlates with the loss of amyloid. We conclude that amyloid makes major contributions to biofilm mechanical robustness. PMID- 26500639 TI - Rapid detection of Pseudomonas aeruginosa targeting the toxA gene in intensive care unit patients from Beijing, China. AB - Pseudomonas aeruginosa is a major opportunistic pathogen in hospital-acquired infections and exhibits increasing antibiotic resistance. A rapid and sensitive molecular method for its detection in clinical samples is needed to guide therapeutic treatment and to control P. aeruginosa outbreaks. In this study, we established a polymerase spiral reaction (PSR) method for rapid detection of P. aeruginosa by targeting the toxA gene, which regulates exotoxin A synthesis. Real time turbidity monitoring and a chromogenic visualization using hydroxynaphthol blue were used to assess the reaction. All 17 non- P. aeruginosa strains tested negative, indicating the high specificity of the PSR primers. The detection limit was 2.3 pg/MUl within 60 min at isothermal temperature (65 degrees C), 10-fold more sensitive than conventional PCR. Then, the PSR assay was applied to a clinical surveillance of P. aeruginosa in three top hospitals in Beijing, China. Of the 130 sputum samples collected from ICU patients with suspected multi resistant infections, 37 P. aeruginosa isolates were identified from the positive samples. All clinical strains belonged to 10 different P. aeruginosa multilocus sequence typing groups and exhibited high resistance to carbapenems, cephalosporins, and aminoglycosides. Interestingly, of the 33 imipenem-resistant isolates, 30 (90.9%) had lost the outer membrane porin oprD gene. Moreover, isolate SY-95, containing multiple antibiotic resistance genes, possessed the ability to hydrolyze all antibiotics used in clinic and was susceptible only to polymyxin B. Our study showed the high level of antibiotic resistance and co occurrence of resistance genes in the clinical strains, indicating a rapid and continuing evolution of P. aeruginosa. In conclusion, we developed a P. aeruginosa PSR assay, which could be a useful tool for clinical screening, especially in case of poor resources, or for point-of-care testing. PMID- 26500640 TI - Prevalence and characteristics of extended-spectrum beta-lactamase genes in Escherichia coli isolated from piglets with post-weaning diarrhea in Heilongjiang province, China. AB - OBJECTIVES: The purpose of this study was to investigate the prevalence of extended spectrum beta-lactamase (ESBL) genes in Escherichia coli isolated from post-weaning diarrhea (PWD) piglets in Heilongjiang province, China. METHODS: Of 458 E. coli isolated from 589 fecal samples from PWD piglets, a total of 198 isolates were confirmed as ESBL producers by the double-disk synergy test (DDST). Polymerase chain reaction (PCR) and sequencing were performed to identify genes for ESBL, plasmid-mediated quinolone resistance (PMQR), and integrons. RESULTS: Of the 198 isolates, bla CTX-M and bla TEM were detected in 191 and 149 isolates, respectively. Sequencing revealed that 10 bla CTX-M subtypes were detected, and bla CTX-M-14 was the most prevalent, followed by bla CTX-M-55 and bla CTX-M-65. Of the 149 TEM-positive strains, four were bla TEM-52 and the rest were bla TEM 1. Among the 198 ESBL-positive isolates, 173 isolates were found to harbor at least one PMQR gene, with oqxAB, qnrS, qnrB, qepA, and aac(6')-Ib-cr being detected alone or in combination in 125, 114, 26, 24, and 45 strains, respectively. One hundred and fifty-five ESBL-positive isolates were also positive for class I integron (int1), and eight different gene cassette arrays were confirmed in 110 isolates by restriction fragment length polymorphism (RFLP) and DNA sequencing analyses, with predominance of dfrA17-aadA5, dfrA12-orfF aadA2, and dfrA1-aadA1 arrays. CONCLUSION: To the best of our knowledge, this is the first report of the bla TEM-52 gene in pig E. coli isolates in China and this is also the first description of the coexistence of the qnrB, qnrS, aac(6')-Ib cr, qepA, and oqxAB genes in one E. coli strain. PMID- 26500641 TI - A tail of two phages: genomic and functional analysis of Listeria monocytogenes phages vB_LmoS_188 and vB_LmoS_293 reveal the receptor-binding proteins involved in host specificity. AB - The physical characteristics of bacteriophages establish them as viable candidates for downstream development of pathogen detection assays and biocontrol measures. To utilize phages for such purposes, a detailed knowledge of their host interaction mechanisms is a prerequisite. There is currently a wealth of knowledge available concerning Gram-negative phage-host interaction, but little by comparison for Gram-positive phages and Listeria phages in particular. In this research, the lytic spectrum of two recently isolated Listeria monocytogenes phages (vB_LmoS_188 and vB_LmoS_293) was determined, and the genomic basis for their observed serotype 4b/4e host-specificity was investigated using comparative genomics. The late tail genes of these phages were identified to be highly conserved when compared to other serovar 4-specific Listeria phages. Spontaneous mutants of each of these phages with broadened host specificities were generated. Their late tail gene sequences were compared with their wild-type counterparts resulting in the putative identification of the products of ORF 19 of vB_LmoS_188 and ORF 20 of vB_LmoS_293 as the receptor binding proteins of these phages. The research findings also indicate that conserved baseplate architectures and host interaction mechanisms exist for Listeria siphoviruses with differing host specificities, and further contribute to the current knowledge of phage-host interactions with regard to Listeria phages. PMID- 26500642 TI - Food safety concerns deriving from the use of silver based food packaging materials. AB - The formulation of innovative packaging solutions, exerting a functional antimicrobial role in slowing down food spoilage, is expected to have a significant impact on the food industry, allowing both the maintenance of food safety criteria for longer periods and the reduction of food waste. Different materials are considered able to exert the required antimicrobial activity, among which are materials containing silver. However, challenges exist in the application of silver to food contact materials due to knowledge gaps in the production of ingredients, stability of delivery systems in food matrices and health risks caused by the same properties which also offer the benefits. Aims of the present study were to test the effectiveness and suitability of two packaging systems, one of which contained silver, for packaging and storing Stracchino cheese, a typical Italian fresh cheese, and to investigate if there was any potential for consumers to be exposed to silver, via migration from the packaging to the cheese. Results did not show any significant difference in the effectiveness of the packaging systems on packaged Stracchino cheese, excluding that the active packaging systems exerted an inhibitory effect on the growth of spoilage microorganisms. Moreover, silver migrated into the cheese matrix throughout the storage time (24 days). Silver levels in cheese finally exceeded the maximum established level for the migration of a non-authorised substance through a functional barrier (Commission of the European Communities, 2009). This result poses safety concerns and strongly suggests the need for more research aimed at better characterizing the new packaging materials in terms of their potential impacts on human health and the environment. PMID- 26500643 TI - Commentary: Role of Sterylglucosidase 1 (Sgl1) on the pathogenicity of Cryptococcus neoformans: potential applications for vaccine development. PMID- 26500644 TI - Large-scale analysis of macromolecular crowding effects on protein aggregation using a reconstituted cell-free translation system. AB - Proteins must fold into their native structures in the crowded cellular environment, to perform their functions. Although such macromolecular crowding has been considered to affect the folding properties of proteins, large-scale experimental data have so far been lacking. Here, we individually translated 142 Escherichia coli cytoplasmic proteins using a reconstituted cell-free translation system in the presence of macromolecular crowding reagents (MCRs), Ficoll 70 or dextran 70, and evaluated the aggregation propensities of 142 proteins. The results showed that the MCR effects varied depending on the proteins, although the degree of these effects was modest. Statistical analyses suggested that structural parameters were involved in the effects of the MCRs. Our dataset provides a valuable resource to understand protein folding and aggregation inside cells. PMID- 26500645 TI - Crossing of the epithelial barriers by Bacillus anthracis: the Known and the Unknown. AB - Anthrax, caused by Bacillus anthracis, a Gram-positive spore-forming bacterium, is initiated by the entry of spores into the host body. There are three types of human infection: cutaneous, inhalational, and gastrointestinal. For each form, B. anthracis spores need to cross the cutaneous, respiratory or digestive epithelial barriers, respectively, as a first obligate step to establish infection. Anthrax is a toxi-infection: an association of toxemia and rapidly spreading infection progressing to septicemia. The pathogenicity of Bacillus anthracis mainly depends on two toxins and a capsule. The capsule protects bacilli from the immune system, thus promoting systemic dissemination. The toxins alter host cell signaling, thereby paralyzing the immune response of the host and perturbing the endocrine and endothelial systems. In this review, we will mainly focus on the events and mechanisms leading to crossing of the respiratory epithelial barrier, as the majority of studies have addressed inhalational infection. We will discuss the critical gaps of knowledge that need to be addressed to gain a comprehensive view of the initial steps of inhalational anthrax. We will then discuss the few data available on B. anthracis crossing the cutaneous and digestive epithelia. PMID- 26500647 TI - Polyclonal Expansion of NKG2C(+) NK Cells in TAP-Deficient Patients. AB - Adaptive natural killer (NK) cell responses to human cytomegalovirus infection are characterized by the expansion of NKG2C(+) NK cells expressing self-specific inhibitory killer-cell immunoglobulin-like receptors (KIRs). Here, we set out to study the HLA class I dependency of such NKG2C(+) NK cell expansions. We demonstrate the expansion of NKG2C(+) NK cells in patients with transporter associated with antigen presentation (TAP) deficiency, who express less than 10% of normal HLA class I levels. In contrast to normal individuals, expanded NKG2C(+) NK cell populations in TAP-deficient patients display a polyclonal KIR profile and remain hyporesponsive to HLA class I-negative target cells. Nonetheless, agonistic stimulation of NKG2C on NK cells from TAP-deficient patients yielded significant responses in terms of degranulation and cytokine production. Thus, while interactions with self-HLA class I molecules likely shape the KIR repertoire of expanding NKG2C(+) NK cells during adaptive NK cell responses in normal individuals, they are not a prerequisite for NKG2C(+) NK cell expansions to occur. The emergence of NKG2C-responsive adaptive NK cells in TAP deficient patients may contribute to antiviral immunity and potentially explain these patients' low incidence of severe viral infections. PMID- 26500649 TI - The Role of Crk Adaptor Proteins in T-Cell Adhesion and Migration. AB - Crk adaptor proteins are key players in signal transduction from a variety of cell surface receptors. They are involved in early steps of lymphocyte activation through their SH2-mediated transient interaction with signal transducing effector molecules, such as Cbl, ZAP-70, CasL, and STAT5. In addition, they constitutively associate, via their SH3 domain, with effector molecules, such as C3G, that mediate cell adhesion and regulate lymphocyte extravasation and recruitment to sites of inflammation. Recent studies demonstrated that the conformation and function of CrkII is subjected to a regulation by immunophilins, which also affect CrkII-dependent T-cell adhesion to fibronectin and migration toward chemokines. This article addresses mechanisms that regulate CrkII conformation and function, in general, and emphasizes the role of Crk proteins in receptor coupled signaling pathways that control T-lymphocyte adhesion and migration to inflammatory sites. PMID- 26500648 TI - Mechanisms of Control of Mycobacterium tuberculosis by NK Cells: Role of Glutathione. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), continues to be one of the most prevalent infectious diseases in the world. There is an upward trend in occurrence due to emerging multidrug resistant strains and an increasingly larger proportion of immunocompromised patient populations as a result of the acquired immunodeficiency syndrome pandemic. The complex and often deadly combination of multidrug resistant M. tb (MDR-M. tb) along with human immunodeficiency virus (HIV) puts a significant number of people at high risk for pulmonary and extra-pulmonary TB without sufficient therapeutic options available. Natural killer (NK) cells and macrophages are major components of the body's innate immune system, contributing significantly to the body's ability to synergistically inhibit the growth of M. tb in immune compromised individuals lacking a sufficient T cell response. Direct mechanisms of control are largely through the secretory products perforin, granulysin, and granzymes, as well as multiple membrane-bound death receptors that facilitate target directed lysis. NK cells also have a role in indirectly stimulating an immune response through activation of macrophages and monocytes with multiple signaling pathways, including both reactive oxygen species and reactive nitrogen species. Glutathione (GSH) has been shown to play a part in inhibiting the growth of intracellular M. tb through bacteriostatic mechanisms. Enhancing cellular GSH through several cytokines and N-acetyl cysteine has been shown to increase these effects, at least in part, through their action on NK cells. Taken together, there is substantial evidence for a mechanistic correlation between NK cell activity and functionality in combating M. tb in HIV infection mediated through adequate GSH production and use. PMID- 26500646 TI - Radio-Immunotherapy-Induced Immunogenic Cancer Cells as Basis for Induction of Systemic Anti-Tumor Immune Responses - Pre-Clinical Evidence and Ongoing Clinical Applications. AB - Radiotherapy (RT) primarily aims to locally destroy the tumor via the induction of DNA damage in the tumor cells. However, the so-called abscopal, namely systemic and immune-mediated, effects of RT move over more and more in the focus of scientists and clinicians since combinations of local irradiation with immune therapy have been demonstrated to induce anti-tumor immunity. We here summarize changes of the phenotype and microenvironment of tumor cells after exposure to irradiation, chemotherapeutic agents, and immune modulating agents rendering the tumor more immunogenic. The impact of therapy-modified tumor cells and damage associated molecular patterns on local and systemic control of the primary tumor, recurrent tumors, and metastases will be outlined. Finally, clinical studies affirming the bench-side findings of interactions and synergies of radiation therapy and immunotherapy will be discussed. Focus is set on combination of radio(chemo)therapy (RCT) with immune checkpoint inhibitors, growth factor inhibitors, and chimeric antigen receptor T-cell therapy. Well-deliberated combination of RCT with selected immune therapies and growth factor inhibitors bear the great potential to further improve anti-cancer therapies. PMID- 26500651 TI - HIV-1 Infection of T Lymphocytes and Macrophages Affects Their Migration via Nef. AB - The human immunodeficiency virus (HIV-1) disseminates in the body and is found in several organs and tissues. Although HIV-1 mainly targets both CD4(+) T lymphocytes and macrophages, it has contrasting effects between these cell populations. HIV-1 infection namely reduces the viability of CD4(+) T cells, whereas infected macrophages are long-lived. In addition, the migration of T cells is reduced by the infection, whereas HIV-1 differentially modulates the migration modes of macrophages. In 2-dimensions (2D) assays, infected macrophages are less motile compared to the control counterparts. In 3D environments, macrophages use two migration modes that are dependent on the matrix architecture: amoeboid and mesenchymal migration. HIV-1-infected macrophages exhibit a reduced amoeboid migration but an enhanced mesenchymal migration, via the viral protein Nef. Indeed, the mesenchymal migration involves podosomes, and Nef stabilizes these cell structures through the activation of the tyrosine kinase Hck, which in turn phosphorylates the Wiskott-Aldrich syndrome protein (WASP). WASP is a key player in actin remodeling and cell migration. The reprogramed motility of infected macrophages observed in vitro correlates in vivo with enhanced macrophage infiltration in experimental tumors in Nef-transgenic mice compared to control mice. In conclusion, HIV infection of host target cells modifies their migration capacity; we infer that HIV-1 enhances virus spreading in confined environments by reducing T cells migration, and facilitates virus dissemination into different organs and tissues of the human body by enhancing macrophage mesenchymal migration. PMID- 26500652 TI - Leukotriene B4 as a Potential Therapeutic Target for the Treatment of Metabolic Disorders. PMID- 26500650 TI - Selective Manipulation of the Gut Microbiota Improves Immune Status in Vertebrates. AB - All animals develop in association with complex microbial communities. It is now well established that commensal microbiota is essential for the correct functionality of each organ in the host. Particularly, the commensal gastro intestinal microbiota (CGIM) is a key factor for development, immunity and nutrient conversion, rendering them bio-available for various uses. Thus, nutritional inputs generate a positive loop in maintaining host health and are essential in shaping the composition of the CGIM communities. Probiotics, which are live exogenous microorganisms, selectively provided to the host, are a promising concept for manipulating the microbiota and thus for increasing the host health status. Nevertheless, most mechanisms induced by probiotics to fortify the immune system are still a matter of debate. Alternatively, prebiotics, which are non-digestible food ingredients, can favor the growth of specific target groups of CGIM. Several metabolites are produced by the CGIM, one of the most important are the short-chain fatty acids (SCFAs), which emerge from the fermentation of complex carbohydrates. SCFAs have been recognized as key players in triggering beneficial effects elicited by simple diffusion and by specific receptors present, thus, far only in epithelial cells of higher vertebrates at different gastro-intestinal locations. However, both strategies have shown to provide resistance against pathogens during periods of high stress. In fish, knowledge about the action of pro- and prebiotics and SCFAs is still limited. Thus, in this review, we briefly summarize the mechanisms described on this topic for higher vertebrates and discuss why many of them may operate in the fish gut representing a model for different mucosal tissues. PMID- 26500653 TI - Exploiting the Immunomodulatory Properties of Chemotherapeutic Drugs to Improve the Success of Cancer Immunotherapy. AB - Cancer immunotherapy is gaining momentum in the clinic. The current challenge is to understand why a proportion of cancer patients do not respond to cancer immunotherapy, and how this can be translated into the rational design of combinatorial cancer immunotherapy strategies aimed at maximizing success of immunotherapy. Here, we discuss how tumors orchestrate an immunosuppressive microenvironment, which contributes to their escape from immune attack. Relieving the immunosuppressive networks in cancer patients is an attractive strategy to extend the clinical success of cancer immunotherapy. Since the clinical availability of drugs specifically targeting immunosuppressive cells or mediators is still limited, an alternative strategy is to use conventional chemotherapy drugs with immunomodulatory properties to improve cancer immunotherapy. We summarize the preclinical and clinical studies that illustrate how the anti-tumor T cell response can be enhanced by chemotherapy-induced relief of immunosuppressive networks. Treatment strategies aimed at combining chemotherapy induced relief of immunosuppression and T cell-boosting checkpoint inhibitors provide an attractive and clinically feasible approach to overcome intrinsic and acquired resistance to cancer immunotherapy, and to extend the clinical success of cancer immunotherapy. PMID- 26500656 TI - Dysfunctional Crohn's Disease-Associated NOD2 Polymorphisms Cannot be Reliably Predicted on the Basis of RIPK2 Binding or Membrane Association. AB - Polymorphisms in NOD2 represent the single greatest genetic risk factor for the development of Crohn's disease. Three different non-synonomous NOD2 polymorphisms - R702W, G908R, and L1007fsincC - account for roughly 80% of all NOD2-associated cases of Crohn's disease and are reported to result in a loss of receptor function in response to muramyl dipeptide (MDP) stimulation. Loss of NOD2 signaling can result from a failure to detect ligand; alterations in cellular localization; and changes in protein interactions, such as an inability to interact with the downstream adaptor protein RIPK2. Using an overexpression system, we analyzed ~50 NOD2 polymorphisms reportedly connected to Crohn's disease to determine if they also displayed loss of function and if this could be related to alterations in protein localization and/or association with RIPK2. Just under half the polymorphisms displayed a significant reduction in signaling capacity following ligand stimulation, with nine of them showing near complete ablation. Only two polymorphisms, R38M and R138Q, lost the ability to interact with RIPK2. However, both these polymorphisms still associated with cellular membranes. In contrast, L248R, W355stop, L550V, N825K, L1007fsinC, L1007P, and R1019stop still bound RIPK2, but showed impaired membrane association and were unable to signal in response to MDP. This highlights the complex contributions of NOD2 polymorphisms to Crohn's disease and reiterates the importance of both RIPK2 binding and membrane association in NOD2 signaling. Simply ascertaining whether or not NOD2 polymorphisms bind RIPK2 or associate with cellular membranes is not sufficient for determining their signaling competency. PMID- 26500655 TI - Inflammasome/IL-1beta Responses to Streptococcal Pathogens. AB - Inflammation mediated by the inflammasome and the cytokine IL-1beta are some of the earliest and most important alarms to infection. These pathways are responsive to the virulence factors that pathogens use to subvert immune processes, and thus are typically activated only by microbes with potential to cause severe disease. Among the most serious human infections are those caused by the pathogenic streptococci, in part because these species numerous strategies for immune evasion. Since the virulence factor armament of each pathogen is unique, the role of IL-1beta and the pathways leading to its activation varies for each infection. This review summarizes the role of IL-1beta during infections caused by streptococcal pathogens, with emphasis on emergent mechanisms and concepts countering paradigms determined for other organisms. PMID- 26500657 TI - Microbiota-Specific CD4CD8alphaalpha Tregs: Role in Intestinal Immune Homeostasis and Implications for IBD. AB - In studies in murine models, active suppression by IL-10-secreting Foxp3 regulatory T cells (Tregs) has emerged as an essential mechanism in colon homeostasis. However, the role of the equivalent subset in humans remains unclear, leading to suggestions that other subsets and/or mechanisms may substitute for Foxp3 Tregs in the maintenance of colon homeostasis. We recently described a new subset of CD4CD8alphaalpha T cells reactive to the gut bacterium Faecalibacterium prausnitzii and endowed with regulatory/suppressive functions. This subset is abundant in the healthy colonic mucosa, but less common in that of patients with inflammatory bowel disease (IBD). We discuss here the physiological significance and potential role of these Tregs in preventing inflammation of the gut mucosa and the potential applications of these discoveries for IBD management. PMID- 26500654 TI - Hypersensitivity Responses in the Central Nervous System. AB - Immune-mediated tissue damage or hypersensitivity can be mediated by autospecific IgG antibodies. Pathology results from activation of complement, and antibody dependent cellular cytotoxicity, mediated by inflammatory effector leukocytes include macrophages, natural killer cells, and granulocytes. Antibodies and complement have been associated to demyelinating pathology in multiple sclerosis (MS) lesions, where macrophages predominate among infiltrating myeloid cells. Serum-derived autoantibodies with predominant specificity for the astrocyte water channel aquaporin-4 (AQP4) are implicated as inducers of pathology in neuromyelitis optica (NMO), a central nervous system (CNS) demyelinating disease where activated neutrophils infiltrate, unlike in MS. The most widely used model for MS, experimental autoimmune encephalomyelitis, is an autoantigen-immunized disease that can be transferred to naive animals with CD4(+) T cells, but not with antibodies. By contrast, NMO-like astrocyte and myelin pathology can be transferred to mice with AQP4-IgG from NMO patients. This is dependent on complement, and does not require T cells. Consistent with clinical observations that interferon-beta is ineffective as a therapy for NMO, NMO-like pathology is significantly reduced in mice lacking the Type I IFN receptor. In MS, there is evidence for intrathecal synthesis of antibodies as well as blood-brain barrier (BBB) breakdown, whereas in NMO, IgG accesses the CNS from blood. Transfer models involve either direct injection of antibody and complement to the CNS, or experimental manipulations to induce BBB breakdown. We here review studies in MS and NMO that elucidate roles for IgG and complement in the induction of BBB breakdown, astrocytopathy, and demyelinating pathology. These studies point to significance of T-independent effector mechanisms in neuroinflammation. PMID- 26500658 TI - A current perspective on the role of AGCVIII kinases in PIN-mediated apical hook development. AB - Despite their sessile lifestyle, seed plants are able to utilize differential growth rates to move their organs in response to their environment. Asymmetrical growth is the cause for the formation and maintenance of the apical hook-a structure of dicotyledonous plants shaped by the bended hypocotyl that eases the penetration through the covering soil. As predicted by the Cholodny-Went theory, the cause for differential growth is the unequal distribution of the phytohormone auxin. The PIN-FORMED proteins transport auxin from cell-to-cell and control the distribution of auxin in the plant. Their localization and activity are regulated by two subfamilies of AGCVIII protein kinases: the D6 PROTEIN KINASEs as well as PINOID and its two closely related WAG kinases. This mini-review focuses on the regulatory mechanism of these AGCVIII kinases as well as their role in apical hook development of Arabidopsis thaliana. PMID- 26500660 TI - Bacterial endophytes from wild maize suppress Fusarium graminearum in modern maize and inhibit mycotoxin accumulation. AB - Wild maize (teosinte) has been reported to be less susceptible to pests than their modern maize (corn) relatives. Endophytes, defined as microbes that inhabit plants without causing disease, are known for their ability to antagonize plant pests and pathogens. We hypothesized that the wild relatives of modern maize may host endophytes that combat pathogens. Fusarium graminearum is the fungus that causes Gibberella Ear Rot (GER) in modern maize and produces the mycotoxin, deoxynivalenol (DON). In this study, 215 bacterial endophytes, previously isolated from diverse maize genotypes including wild teosintes, traditional landraces and modern varieties, were tested for their ability to antagonize F. graminearum in vitro. Candidate endophytes were then tested for their ability to suppress GER in modern maize in independent greenhouse trials. The results revealed that three candidate endophytes derived from wild teosintes were most potent in suppressing F. graminearum in vitro and GER in a modern maize hybrid. These wild teosinte endophytes could suppress a broad spectrum of fungal pathogens of modern crops in vitro. The teosinte endophytes also suppressed DON mycotoxin during storage to below acceptable safety threshold levels. A fourth, less robust anti-fungal strain was isolated from a modern maize hybrid. Three of the anti-fungal endophytes were predicted to be Paenibacillus polymyxa, along with one strain of Citrobacter. Microscopy studies suggested a fungicidal mode of action by all four strains. Molecular and biochemical studies showed that the P. polymyxa strains produced the previously characterized anti-Fusarium compound, fusaricidin. Our results suggest that the wild relatives of modern crops may serve as a valuable reservoir for endophytes in the ongoing fight against serious threats to modern agriculture. We discuss the possible impact of crop evolution and domestication on endophytes in the context of plant defense. PMID- 26500661 TI - Corrigendum: De novo assembly of the Japanese lawngrass (Zoysia japonica Steud.) root transcriptome and identification of candidate unigenes related to early responses under salt stress. AB - [This corrects the article on p. 610 in vol. 6, PMID: 26347751.]. PMID- 26500662 TI - Ion and lipid signaling in apical growth-a dynamic machinery responding to extracellular cues. AB - Apical cell growth seems to have independently evolved throughout the major lineages of life. To a certain extent, so does our body of knowledge on the mechanisms regulating this morphogenetic process. Studies on pollen tubes, root hairs, rhizoids, fungal hyphae, even nerve cells, have highlighted tissue and cell specificities but also common regulatory characteristics (e.g., ions, proteins, phospholipids) that our focused research sometimes failed to grasp. The working hypothesis to test how apical cell growth is established and maintained have thus been shaped by the model organism under study and the type of methods used to study them. The current picture is one of a dynamic and adaptative process, based on a spatial segregation of components that network to achieve growth and respond to environmental (extracellular) cues. Here, we explore some examples of our live imaging research, namely on cyclic nucleotide gated ion channels, lipid kinases and syntaxins involved in exocytosis. We discuss how their spatial distribution, activity and concentration suggest that the players regulating apical cell growth may display more mobility than previously thought. Furthermore, we speculate on the implications of such perspective in our understanding of the mechanisms regulating apical cell growth and their responses to extracellular cues. PMID- 26500663 TI - Transcriptome analysis of Ginkgo biloba kernels. AB - Ginkgo biloba is a dioecious species native to China with medicinally and phylogenetically important characteristics; however, genomic resources for this species are limited. In this study, we performed the first transcriptome sequencing for Ginkgo kernels at five time points using Illumina paired-end sequencing. Approximately 25.08-Gb clean reads were obtained, and 68,547 unigenes with an average length of 870 bp were generated by de novo assembly. Of these unigenes, 29,987 (43.74%) were annotated in publicly available plant protein database. A total of 3,869 genes were identified as significantly differentially expressed, and enrichment analysis was conducted at different time points. Furthermore, metabolic pathway analysis revealed that 66 unigenes were responsible for terpenoid backbone biosynthesis, with up to 12 up-regulated unigenes involved in the biosynthesis of ginkgolide and bilobalide. Differential gene expression analysis together with real-time PCR experiments indicated that the synthesis of bilobalide may have interfered with the ginkgolide synthesis process in the kernel. These data can remarkably expand the existing transcriptome resources of Ginkgo, and provide a valuable platform to reveal more on developmental and metabolic mechanisms of this species. PMID- 26500664 TI - Impact of high temperature stress on floret fertility and individual grain weight of grain sorghum: sensitive stages and thresholds for temperature and duration. AB - Sorghum [Sorghum bicolor (L.) Moench] yield formation is severely affected by high temperature stress during reproductive stages. This study pursues to (i) identify the growth stage(s) most sensitive to high temperature stress during reproductive development, (ii) determine threshold temperature and duration of high temperature stress that decreases floret fertility and individual grain weight, and (iii) quantify impact of high daytime temperature during floret development, flowering and grain filling on reproductive traits and grain yield under field conditions. Periods between 10 and 5 d before anthesis; and between 5 d before- and 5 d after-anthesis were most sensitive to high temperatures causing maximum decreases in floret fertility. Mean daily temperatures >25 degrees C quadratically decreased floret fertility (reaching 0% at 37 degrees C) when imposed at the start of panicle emergence. Temperatures ranging from 25 to 37 degrees C quadratically decreased individual grain weight when imposed at the start of grain filling. Both floret fertility and individual grain weights decreased quadratically with increasing duration (0-35 d or 49 d during floret development or grain filling stage, respectively) of high temperature stress. In field conditions, imposition of temperature stress (using heat tents) during floret development or grain filling stage also decreased floret fertility, individual grain weight, and grain weight per panicle. PMID- 26500659 TI - Chloroplast signaling within, between and beyond cells. AB - The most conspicuous function of plastids is the oxygenic photosynthesis of chloroplasts, yet plastids are super-factories that produce a plethora of compounds that are indispensable for proper plant physiology and development. Given their origins as free-living prokaryotes, it is not surprising that plastids possess their own genomes whose expression is essential to plastid function. This semi-autonomous character of plastids requires the existence of sophisticated regulatory mechanisms that provide reliable communication between them and other cellular compartments. Such intracellular signaling is necessary for coordinating whole-cell responses to constantly varying environmental cues and cellular metabolic needs. This is achieved by plastids acting as receivers and transmitters of specific signals that coordinate expression of the nuclear and plastid genomes according to particular needs. In this review we will consider the so-called retrograde signaling occurring between plastids and nuclei, and between plastids and other organelles. Another important role of the plastid we will discuss is the involvement of plastid signaling in biotic and abiotic stress that, in addition to influencing retrograde signaling, has direct effects on several cellular compartments including the cell wall. We will also review recent evidence pointing to an intriguing function of chloroplasts in regulating intercellular symplasmic transport. Finally, we consider an intriguing yet less widely known aspect of plant biology, chloroplast signaling from the perspective of the entire plant. Thus, accumulating evidence highlights that chloroplasts, with their complex signaling pathways, provide a mechanism for exquisite regulation of plant development, metabolism and responses to the environment. As chloroplast processes are targeted for engineering for improved productivity the effect of such modifications on chloroplast signaling will have to be carefully considered in order to avoid unintended consequences on plant growth and development. PMID- 26500665 TI - Gaseous 3-pentanol primes plant immunity against a bacterial speck pathogen, Pseudomonas syringae pv. tomato via salicylic acid and jasmonic acid-dependent signaling pathways in Arabidopsis. AB - 3-Pentanol is an active organic compound produced by plants and is a component of emitted insect sex pheromones. A previous study reported that drench application of 3-pentanol elicited plant immunity against microbial pathogens and an insect pest in crop plants. Here, we evaluated whether 3-pentanol and the derivatives 1 pentanol and 2-pentanol induced plant systemic resistance using the in vitro I plate system. Exposure of Arabidopsis seedlings to 10 MUM and 100 nM 3-pentanol evaporate elicited an immune response to Pseudomonas syringae pv. tomato DC3000. We performed quantitative real-time PCR to investigate the 3-pentanol-mediated Arabidopsis immune responses by determining Pathogenesis-Related (PR) gene expression levels associated with defense signaling through salicylic acid (SA), jasmonic acid (JA), and ethylene signaling pathways. The results show that exposure to 3-pentanol and subsequent pathogen challenge upregulated PDF1.2 and PR1 expression. Selected Arabidopsis mutants confirmed that the 3-pentanol mediated immune response involved SA and JA signaling pathways and the NPR1 gene. Taken together, this study indicates that gaseous 3-pentanol triggers induced resistance in Arabidopsis by priming SA and JA signaling pathways. To our knowledge, this is the first report that a volatile compound of an insect sex pheromone triggers plant systemic resistance against a bacterial pathogen. PMID- 26500667 TI - The Arabidopsis minE mutation causes new plastid and FtsZ1 localization phenotypes in the leaf epidermis. AB - Plastids in the leaf epidermal cells of plants are regarded as immature chloroplasts that, like mesophyll chloroplasts, undergo binary fission. While mesophyll chloroplasts have generally been used to study plastid division, recent studies have suggested the presence of tissue- or plastid type-dependent regulation of plastid division. Here, we report the detailed morphology of plastids and their stromules, and the intraplastidic localization of the chloroplast division-related protein AtFtsZ1-1, in the leaf epidermis of an Arabidopsis mutant that harbors a mutation in the chloroplast division site determinant gene AtMinE1. In atminE1, the size and shape of epidermal plastids varied widely, which contrasts with the plastid phenotype observed in atminE1 mesophyll cells. In particular, atminE1 epidermal plastids occasionally displayed grape-like morphology, a novel phenotype induced by a plastid division mutation. Observation of an atminE1 transgenic line harboring an AtMinE1 promoter::AtMinE1 yellow fluorescent protein fusion gene confirmed the expression and plastidic localization of AtMinE1 in the leaf epidermis. Further examination revealed that constriction of plastids and stromules mediated by the FtsZ1 ring contributed to the plastid pleomorphism in the atminE1 epidermis. These results illustrate that a single plastid division mutation can have dramatic consequences for epidermal plastid morphology, thereby implying that plastid division and morphogenesis are differentially regulated in epidermal and mesophyll plastids. PMID- 26500666 TI - Plant-derived SAC domain of PAR-4 (Prostate Apoptosis Response 4) exhibits growth inhibitory effects in prostate cancer cells. AB - The gene Par-4 (Prostate Apoptosis Response 4) was originally identified in prostate cancer cells undergoing apoptosis and its product Par-4 showed cancer specific pro-apoptotic activity. Particularly, the SAC domain of Par-4 (SAC-Par 4) selectively kills cancer cells leaving normal cells unaffected. The therapeutic significance of bioactive SAC-Par-4 is enormous in cancer biology; however, its large scale production is still a matter of concern. Here we report the production of SAC-Par-4-GFP fusion protein coupled to translational enhancer sequence (5' AMV) and apoplast signal peptide (aTP) in transgenic Nicotiana tabacum cv. Samsun NN plants under the control of a unique recombinant promoter M24. Transgene integration was confirmed by genomic DNA PCR, Southern and Northern blotting, Real-time PCR, and Nuclear run-on assays. Results of Western blot analysis and ELISA confirmed expression of recombinant SAC-Par-4-GFP protein and it was as high as 0.15% of total soluble protein. In addition, we found that targeting of plant recombinant SAC-Par-4-GFP to the apoplast and endoplasmic reticulum (ER) was essential for the stability of plant recombinant protein in comparison to the bacterial derived SAC-Par-4. Deglycosylation analysis demonstrated that ER-targeted SAC-Par-4-GFP-SEKDEL undergoes O-linked glycosylation unlike apoplast-targeted SAC-Par-4-GFP. Furthermore, various in vitro studies like mammalian cells proliferation assay (MTT), apoptosis induction assays, and NF-kappaB suppression suggested the cytotoxic and apoptotic properties of plant-derived SAC-Par-4-GFP against multiple prostate cancer cell lines. Additionally, pre-treatment of MAT-LyLu prostate cancer cells with purified SAC-Par-4-GFP significantly delayed the onset of tumor in a syngeneic rat prostate cancer model. Taken altogether, we proclaim that plant made SAC-Par 4 may become a useful alternate therapy for effectively alleviating cancer in the new era. PMID- 26500668 TI - Transition from somatic embryo to friable embryogenic callus in cassava: dynamic changes in cellular structure, physiological status, and gene expression profiles. AB - Friable embryogenic callus (FEC) is considered as the most suitable material for efficient genetic transformation of cassava. Heavy genotype dependence of FEC induction and amenability to somaclonal variation limits the production and maintenance of reliable FEC. Identifying key elements involved in biological processes from somatic embryos (SEs) to FEC at different stages provides critical insights for FEC improvement. Cytological observation showed a dramatic change of subcellular structures among SEs, fresh FEC (FFEC), and old FEC (OFEC). Decrease of sucrose and increase of fructose and glucose were detected in OFEC. A total of 6871 differentially expressed genes (DEGs) were identified from SEs, FFEC, and OFEC by RNA-seq. Analysis of the DEGs showed that FEC induction was accompanied by the process of dedifferentiation, whereas the epigenetics modification occurred during the continuous subculturing process. The cell structure was reconstructed, mainly including the GO terms of "cell periphery" and "external encapsulating structure"; in parallel, the internal mechanisms changed correspondingly, including the biological process of glycolysis and metabolisms of alanine, aspartate, and glutamate. The significant reduction of genomic DNA methylation in OFEC indicated altered gene expression via chromatin modification. These results indicate that the induction and long-term subculture of FEC is a complicated biological process involving changes of genome modification, gene expression, and subcellular reconstruction. The findings will be useful for improving FEC induction and maintenance from farmer-preferred cassava cultivars recalcitrant to genetic transformation, hence improving cassava through genetic engineering. PMID- 26500669 TI - Myrosinase-dependent and -independent formation and control of isothiocyanate products of glucosinolate hydrolysis. AB - Brassicales contain a myrosinase enzyme that hydrolyzes glucosinolates to form toxic isothiocyanates (ITC), as a defense against bacteria, fungi, insects and herbivores including man. Low levels of ITC trigger a host defense system in mammals that protects them against chronic diseases. Because humans typically cook their brassica vegetables, destroying myrosinase, there is a great interest in determining how human microbiota can hydrolyze glucosinolates and release them, to provide the health benefits of ITC. ITC are highly reactive electrophiles, binding reversibly to thiols, but accumulating and causing damage when free thiols are not available. We found that addition of excess thiols released protein-thiol-bound ITC, but that the microbiome supports only poor hydrolysis unless exposed to dietary glucosinolates for a period of days. These findings explain why 3-5 servings a week of brassica vegetables may provide health effects, even if they are cooked. PMID- 26500670 TI - Overexpression of OsDof12 affects plant architecture in rice (Oryza sativa L.). AB - Dof (DNA binding with one finger) proteins, a class of plant-specific transcription factors, are involved in plant growth and developmental processes and stress responses. However, their biological functions remain to be elucidated, especially in rice (Oryza sativa L.). Previously, we have reported that OsDof12 can promote rice flowering under long-day conditions. Here, we further investigated the other important agronomical traits of the transgenic plants overexpressing OsDof12 and found that overexpressing OsDof12 could lead to reduced plant height, erected leaf, shortened leaf blade, and smaller panicle resulted from decreased primary and secondary branches number. These results implied that OsDof12 is involved in rice plant architecture formation. Furthermore, we performed a series of Brassinosteroid (BR)-responsive tests and found that overexpression of OsDof12 could also result in BR hyposensitivity. Of note, in WT plants the expression of OsDof12 was found up-regulated by BR treatment while in OsDof12 overexpression plants two positive BR signaling regulators, OsBRI1 and OsBZR1, were significantly down-regulated, indicating that OsDof12 may act as a negative BR regulator in rice. Taken together, our results suggested that overexpression of OsDof12 could lead to altered plant architecture by suppressing BR signaling. Thus, OsDof12 might be used as a new potential genetic regulator for future rice molecular breeding. PMID- 26500671 TI - Making better maize plants for sustainable grain production in a changing climate. AB - Achieving grain supply security with limited arable land is a major challenge in the twenty-first century, owing to the changing climate and increasing global population. Maize plays an increasingly vital role in global grain production. As a C4 plant, maize has a high yield potential. Maize is predicted to become the number one cereal in the world by 2020. However, maize production has plateaued in many countries, and hybrid and production technologies have been fully exploited. Thus, there is an urgent need to shape maize traits and architectures for increased stress tolerance and higher yield in a changing climate. Recent achievements in genomics, proteomics, and metabolomics have provided an unprecedented opportunity to make better maize. In this paper, we discuss the current challenges and potential of maize production, particularly in China. We also highlight the need for enhancing maize tolerance to drought and heat waves, summarize the elite shoot and root traits and phenotypes, and propose an ideotype for sustainable maize production in a changing climate. This will facilitate targeted maize improvement through a conventional breeding program combined with molecular techniques. PMID- 26500673 TI - Unraveling the in vitro secretome of the phytopathogen Botrytis cinerea to understand the interaction with its hosts. AB - Botrytis cinerea is a necrotrophic fungus with high adaptability to different environments and hosts. It secretes a large number of extracellular proteins, which favor plant tissue penetration and colonization, thus contributing to virulence. Secretomics is a proteomics sub-discipline which study the secreted proteins and their secretion mechanisms, so-called secretome. By using proteomics as experimental approach, many secreted proteins by B. cinerea have been identified from in vitro experiments, and belonging to different functional categories: (i) cell wall-degrading enzymes such as pectinesterases and endo polygalacturonases; (ii) proteases involved in host protein degradation such as an aspartic protease; (iii) proteins related to the oxidative burst such as glyoxal oxidase; (iv) proteins which may induce the plant hypersensitive response such as a cerato-platanin domain-containing protein; and (v) proteins related to production and secretion of toxins such as malate dehydrogenase. In this mini review, we made an overview of the proteomics contribution to the study and knowledge of the B. cinerea extracellular secreted proteins based on our current work carried out from in vitro experiments, and recent published papers both in vitro and in planta studies on this fungi. We hypothesize on the putative functions of these secreted proteins, and their connection to the biology of the B. cinerea interaction with its hosts. PMID- 26500672 TI - Genome-wide DNA methylation profiling by modified reduced representation bisulfite sequencing in Brassica rapa suggests that epigenetic modifications play a key role in polyploid genome evolution. AB - Brassica rapa includes some of the most important vegetables worldwide as well as oilseed crops. The complete annotated genome sequence confirmed its paleohexaploid origins and provides opportunities for exploring the detailed process of polyploid genome evolution. We generated a genome-wide DNA methylation profile for B. rapa using a modified reduced representation bisulfite sequencing (RRBS) method. This sampling represented 2.24% of all CG loci (2.5 * 10(5)), 2.16% CHG (2.7 * 10(5)), and 1.68% CHH loci (1.05 * 10(5)) (where H = A, T, or C). Our sampling of DNA methylation in B. rapa indicated that 52.4% of CG sites were present as (5m)CG, with 31.8% of CHG and 8.3% of CHH. It was found that genic regions of single copy genes had significantly higher methylation compared to those of two or three copy genes. Differences in degree of genic DNA methylation were observed in a hierarchical relationship corresponding to the relative age of the three ancestral subgenomes, primarily accounted by single copy genes. RNA-seq analysis revealed that overall the level of transcription was negatively correlated with mean gene methylation content and depended on copy number or was associated with the different subgenomes. These results provide new insights into the role epigenetic variation plays in polyploid genome evolution, and suggest an alternative mechanism for duplicate gene loss. PMID- 26500674 TI - Internal transcribed spacer 2 barcode: a good tool for identifying Acanthopanacis cortex. AB - Acanthopanacis cortex has been used in clinical applications for a long time. Considering some historical and geographical factors, Acanthopanacis cortex is easily confused with other herbs in medicine markets, thereby causing potential safety issues. In this study, we used the internal transcribed spacer 2 (ITS2) barcode to identify 69 samples belonging to six species, including Acanthopanacis cortex and its adulterants. The nearest distance, single-nucleotide polymorphisms (SNPs), and neighbor-joining (NJ) tree methods were used to evaluate the identification ability of the ITS2 barcode. According to the kimura-2-parameter model, the intraspecific distance of Eleutherococcus nodiflorus ITS2 sequences ranged from 0 to 0.0132. The minimum interspecific distance between E. nodiflorus and E. giraldii was 0.0221, which was larger than the maximum intraspecific distance of E. nodiflorus. Three stable SNPs in ITS2 can be used to distinguish Acanthopanacis cortex and its closely related species. The NJ tree indicated that the Acanthopanacis cortex samples clustered into one clade, which can be distinguished clearly from the adulterants of this herb. A secondary structure of ITS2 provided another dimensionality to identify species. In conclusion, the ITS2 barcode effectively identifies Acanthopanacis cortex, and DNA barcoding is a convenient tool for medicine market supervision. PMID- 26500675 TI - Ecogeography and utility to plant breeding of the crop wild relatives of sunflower (Helianthus annuus L.). AB - Crop wild relatives (CWR) are a rich source of genetic diversity for crop improvement. Combining ecogeographic and phylogenetic techniques can inform both conservation and breeding. Geographic occurrence, bioclimatic, and biophysical data were used to predict species distributions, range overlap and niche occupancy in 36 taxa closely related to sunflower (Helianthus annuus L.). Taxa lacking comprehensive ex situ conservation were identified. The predicted distributions for 36 Helianthus taxa identified substantial range overlap, range asymmetry and niche conservatism. Specific taxa (e.g., Helianthus deblis Nutt., Helianthus anomalus Blake, and Helianthus divaricatus L.) were identified as targets for traits of interest, particularly for abiotic stress tolerance, and adaptation to extreme soil properties. The combination of techniques demonstrates the potential for publicly available ecogeographic and phylogenetic data to facilitate the identification of possible sources of abiotic stress traits for plant breeding programs. Much of the primary genepool (wild H. annuus) occurs in extreme environments indicating that introgression of targeted traits may be relatively straightforward. Sister taxa in Helianthus have greater range overlap than more distantly related taxa within the genus. This adds to a growing body of literature suggesting that in plants (unlike some animal groups), geographic isolation may not be necessary for speciation. PMID- 26500676 TI - A possible mechanism of biological silicification in plants. AB - Plants are significant exponents of biological silicification. While not all plants are generally considered as biosilicifiers the extent to which all plants deposit biogenic silica is largely unknown. There are plants which are known as silica accumulators though even in these plants the extent and degree to which their tissues are silicified is neither appreciated nor understood. An elucidation of the mechanism of silicification in biota is complicated by a lack of known bio-organic chemistry of silicic acid, the starting point in this process. Herein I argue the case that biological silicification is an entirely passive process. It is passive from the point of view that its underlying mechanisms and processes do not require us to invoke any as yet undiscovered silicon biochemistry. It is also passive in that although silicification confers clear biological/ecological advantages under certain conditions, it is actually non-essential in all plants and potentially, at least, toxic in some. PMID- 26500677 TI - Simultaneous inference of haplotypes and alleles at a causal gene. AB - We present a methodology which jointly infers haplotypes and the causal alleles at a gene influencing a given trait. Often in human genetic studies, the available data consists of genotypes (series of genetic markers along the chromosomes) and a phenotype. However, for many genetic analyses, one needs haplotypes instead of genotypes. Our methodology is not only able to estimate haplotypes conditionally on the disease status, but is also able to infer the alleles at the unknown disease locus. Some applications of our methodology are in genetic mapping and in genetic counseling. PMID- 26500678 TI - Moving from capstones toward cornerstones: successes and challenges in applying systems biology to identify mechanisms of autism spectrum disorders. AB - The substantial progress in the last few years toward uncovering genetic causes and risk factors for autism spectrum disorders (ASDs) has opened new experimental avenues for identifying the underlying neurobiological mechanism of the condition. The bounty of genetic findings has led to a variety of data-driven exploratory analyses aimed at deriving new insights about the shared features of these genes. These approaches leverage data from a variety of different sources such as co-expression in transcriptomic studies, protein-protein interaction networks, gene ontologies (GOs) annotations, or multi-level combinations of all of these. Here, we review the recurrent themes emerging from these analyses and highlight some of the challenges going forward. Themes include findings that ASD associated genes discovered by a variety of methods have been shown to contain disproportionate amounts of neurite outgrowth/cytoskeletal, synaptic, and more recently Wnt-related and chromatin modifying genes. Expression studies have highlighted a disproportionate expression of ASD gene sets during mid fetal cortical development, particularly for rare variants, with multiple analyses highlighting the striatum and cortical projection and interneurons as well. While these explorations have highlighted potentially interesting relationships among these ASD-related genes, there are challenges in how to best transition these insights into empirically testable hypotheses. Nonetheless, defining shared molecular or cellular pathology downstream of the diverse genes associated with ASDs could provide the cornerstones needed to build toward broadly applicable therapeutic approaches. PMID- 26500679 TI - Arthropod venom Hyaluronidases: biochemical properties and potential applications in medicine and biotechnology. AB - Hyaluronidases are enzymes that mainly degrade hyaluronan, the major glycosaminoglycan of the interstitial matrix. They are involved in several pathological and physiological activities including fertilization, wound healing, embryogenesis, angiogenesis, diffusion of toxins and drugs, metastasis, pneumonia, sepsis, bacteremia, meningitis, inflammation and allergy, among others. Hyaluronidases are widely distributed in nature and the enzymes from mammalian spermatozoa, lysosomes and animal venoms belong to the subclass EC 3.2.1.35. To date, only five three-dimensional structures for arthropod venom hyaluronidases (Apis mellifera and Vespula vulgaris) were determined. Additionally, there are four molecular models for hyaluronidases from Mesobuthus martensii, Polybia paulista and Tityus serrulatus venoms. These enzymes are employed as adjuvants to increase the absorption and dispersion of other drugs and have been used in various off-label clinical conditions to reduce tissue edema. Moreover, a PEGylated form of a recombinant human hyaluronidase is currently under clinical trials for the treatment of metastatic pancreatic cancer. This review focuses on the arthropod venom hyaluronidases and provides an overview of their biochemical properties, role in the envenoming, structure/activity relationship, and potential medical and biotechnological applications. PMID- 26500680 TI - Peak cortisol response to corticotropin-releasing hormone is associated with age and body size in children referred for clinical testing: a retrospective review. AB - BACKGROUND: Corticotropin-Releasing Hormone (CRH) testing is used to evaluate suspected adrenocorticotropic hormone (ACTH) deficiency, but the clinical characteristics that affect response in young children are incompletely understood. Our objective was to determine the effect of age and body size on cortisol response to CRH in children at risk for ACTH deficiency referred for clinical testing. METHODS: Retrospective, observational study of 297 children, ages 30 days - 18 years, undergoing initial, clinically indicated outpatient CRH stimulation testing at a tertiary referral center. All subjects received 1mcg/kg corticorelin per institutional protocol. Serial, timed ACTH and cortisol measurements were obtained. Patient demographic and clinical factors were abstracted from the medical record. Patients without full recorded anthropometric data, pubertal assessment, ACTH measurements, or clear indication for testing were excluded (number remaining = 222). Outcomes of interest were maximum cortisol after stimulation (peak) and cortisol rise from baseline (delta). Bivariable and multivariable linear regression analyses were used to assess the effects of age and size (weight, height, body mass index (BMI), body surface area (BSA), BMI z-score, and height z-score) on cortisol response while accounting for clinical covariates including sex, race/ethnicity, pubertal status, indication for testing, and time of testing. RESULTS: Subjects were 27 % female, with mean age of 8.9 years (SD 4.5); 75 % were pre-pubertal. Mean peak cortisol was 609.2 nmol/L (SD 213.0); mean delta cortisol was 404.2 nmol/L (SD 200.2). In separate multivariable models, weight, height, BSA and height z-score each remained independently negatively associated (p < 0.05) with peak and delta cortisol, controlling for indication of testing, baseline cortisol, and peak or delta ACTH, respectively. Age was negatively associated with peak but not delta cortisol in multivariable analysis. CONCLUSIONS: Despite the use of a weight-based dosing protocol, both peak and delta cortisol response to CRH are negatively associated with several measures of body size in children referred for clinical testing, raising the question of whether alternate CRH dosing strategies or age- or size based thresholds for adequate cortisol response should be considered in pediatric patients, or, alternatively, whether this finding reflects practice patterns followed when referring children for clinical testing. PMID- 26500681 TI - Anti-Hepatitis E Antibody in Hemodialysis Patients in Isfahan, Iran: Prevalence and Risk Factors. AB - BACKGROUND: Many studies have been performed regarding the prevalence of hepatitis E in the general population, but there is controversial evidence for an increased risk of the infection in patients on maintenance hemodialysis (HD). OBJECTIVES: The primary end point of the present study was to determine if the prevalence of anti-hepatitis E virus IgG (anti-HEV IgG) is higher in patients on maintenance HD than in the normal population in Isfahan. PATIENTS AND METHODS: In a case-control study performed in Isfahan in June 2012, we compared the seroprevalence of HEV among 274 patients on maintenance HD and 275 otherwise healthy individuals. The patients were recruited from 3 HD centers in Isfahan. Anti-HEV IgG was detected using a Dia Pro Diagnostic HEV enzyme immunoassay (ELISA) kit. Demographic and clinical data (sex, age, blood transfusion history, HD duration, age at HD initiation, and evidence of hepatitis B and hepatitis C infections) were obtained from the medical records of the HD patients. RESULTS: Anti-HEV IgG was detected in 27 (9.9%) controls and 78 (28.3%) patients, with the difference being statistically significant (P < 0.05). Furthermore, there was a significant association between positive anti-HEV antibody, HD duration, and blood transfusion history in the HD patients. CONCLUSIONS: Considering the results, it seems necessary to conduct prospective studies in order to identify factors responsible for the high seroprevalence of HEV in Isfahan HD units. PMID- 26500682 TI - Five Years Survival of Patients After Liver Transplantation and Its Effective Factors by Neural Network and Cox Poroportional Hazard Regression Models. AB - BACKGROUND: Transplantation is the only treatment for patients with liver failure. Since the therapy imposes high expenses to the patients and community, identification of effective factors on survival of such patients after transplantation is valuable. OBJECTIVES: The current study attempted to model the survival of patients (two years old and above) after liver transplantation using neural network and Cox Proportional Hazards (Cox PH) regression models. The event is defined as death due to complications of liver transplantation. PATIENTS AND METHODS: In a historical cohort study, the clinical findings of 1168 patients who underwent liver transplant surgery (from March 2008 to march 2013) at Shiraz Namazee Hospital Organ Transplantation Center, Shiraz, Southern Iran, were used. To model the one to five years survival of such patients, Cox PH regression model accompanied by three layers feed forward artificial neural network (ANN) method were applied on data separately and their prediction accuracy was compared using the area under the receiver operating characteristic curve (ROC). Furthermore, Kaplan-Meier method was used to estimate the survival probabilities in different years. RESULTS: The estimated survival probability of one to five years for the patients were 91%, 89%, 85%, 84%, and 83%, respectively. The areas under the ROC were 86.4% and 80.7% for ANN and Cox PH models, respectively. In addition, the accuracy of prediction rate for ANN and Cox PH methods was equally 92.73%. CONCLUSIONS: The present study detected more accurate results for ANN method compared to those of Cox PH model to analyze the survival of patients with liver transplantation. Furthermore, the order of effective factors in patients' survival after transplantation was clinically more acceptable. The large dataset with a few missing data was the advantage of this study, the fact which makes the results more reliable. PMID- 26500683 TI - Increased Ribavirin Bioavailability Associated With Telaprevir Use in Hepatitis C Patients Treated With PEGylated -Interferon/Ribavirin/Telaprevir Triple Therapy. AB - BACKGROUND: Anemia is more frequent in patients receiving telaprevir with PEGylated interferon/ribavirin (PEG-IFN/RBV) than in those receiving PEG-IFN/RBV alone. OBJECTIVES: The objective was to measure the impact of telaprevir on RBV bioavailability and to assess the concomitant renal function. MATERIALS AND METHODS: Thirty-seven hepatitis C virus (HCV) patients non-responders to a previous course of PEG-IFN/RBV therapy and re-treated with triple therapy combining PEG-IFN/RBV and telaprevir were analyzed. RBV bioavailability was measured before the triple therapy initiation, during telaprevir treatment at week (W) 4 and W8, and after telaprevir cessation (post W16). The renal function was assessed by estimating the glomerular filtration rate (eGFR). RESULTS: At W4, RBV bioavailability, expressed as mg/L/daily dose/kg body weight, was significantly increased (median increase = 0.06 mg/L/dose/kg; P < 0.001). In parallel, the renal function was impaired with a mean eGFR decrease of -6.8 mL/minutes/1.73 m2 (P = 0.109). Between W4 and W8, RBV bioavailability continued to increase (P < 0.001) but subsequently decreased slightly after telaprevir discontinuation with a concomitant restoration of the renal function (eGFR increase of 6.34 mL/minutes/1.73 m2). CONCLUSIONS: Our results indicated a reversible increase in RBV bioavailability after telaprevir exposure, which might be linked to the impairment of the GFR. This also suggests a RBV-telaprevir pharmacological interaction, a possible source of severe anemia observed under triple therapy. These results suggest that RBV pharmacological monitoring may be clinically relevant, especially in the context of first-generation HCV protease inhibitor-based therapy. PMID- 26500684 TI - Plasma Osteopontin Level in Chronic Liver Disease and Hepatocellular Carcinoma. AB - BACKGROUND: Osteopontin (OPN) is a secreted glycoprotein and is frequently associated with various tumors. OBJECTIVES: We sought to investigate the clinical usefulness of the level of plasma OPN, compared to alpha-fetoprotein (AFP), as a biomarker for hepatocellular carcinoma (HCC) and to evaluate its diagnostic value in nonalcoholic fatty liver disease (NAFLD) and its relationship with clinical and laboratory features of HCC and NAFLD. PATIENTS AND METHODS: The study was performed on 120 subjects classified into 5 groups: Group I included 25 chronic non-cirrhotic hepatitis C virus (HCV)-infected patients; Group II encompassed 25 patients with chronic HCV infection with liver cirrhosis; Group III comprised 25 patients with chronic HCV with liver cirrhosis and HCC; Group IV was comprised of 25 patients with NAFLD; and Group V consisted of 20 healthy age- and sex-matched controls. All the participants were subjected to history taking and clinical and abdominal ultrasonographic examinations as well as the following laboratory investigations: liver function tests, complete blood count, blood sugar, hepatitis B surface antigen, hepatitis C virus antibodies, HCV-RNA by qualitative polymerase chain reaction (for Groups I, II, and III) and serum AFP and plasma OPN levels. RESULTS: There were statistically significant differences in plasma OPN levels between the HCC group (401 +/- 72 ng/mL) and the other groups, between the cirrhotic group (258.3 +/- 35 ng/mL) and the non-cirrhotic group (HCV group, 168.7 +/- 41 ng/mL; fatty liver group, 106.7 +/- 35 ng/mL), and between the chronic non-cirrhotic HCV group and the fatty liver group (I and IV) and the controls (35.1 +/- 6 ng/mL). In the HCC group, the diagnostic value of OPN was comparable to that of AFP at a cutoff value of 280 ng/mL, achieving sensitivity, specificity, and overall accuracy of 100%, 98%, and 96%, respectively. Regarding the validity of plasma OPN as a predictor of fatty change, our results revealed a diagnostic accuracy of 50% with 70% sensitivity, 45% specificity, 50% positive predictive value, and 75% negative predictive value at a cutoff value of 134 ng/mL. CONCLUSIONS: Plasma OPN is comparable to AFP as a diagnostic marker and is related to the severity of liver involvement in HCC patients. Plasma OPN is of diagnostic potential value in NAFLD. PMID- 26500685 TI - Neurons of self-defence: neuronal innervation of the exocrine defence glands in stick insects. AB - BACKGROUND: Stick insects (Phasmatodea) use repellent chemical substances (allomones) for defence which are released from so-called defence glands in the prothorax. These glands differ in size between species, and are under neuronal control from the CNS. The detailed neural innervation and possible differences between species are not studied so far. Using axonal tracing, the neuronal innervation is investigated comparing four species. The aim is to document the complexity of defence gland innervation in peripheral nerves and central motoneurons in stick insects. RESULTS: In the species studied here, the defence gland is innervated by the intersegmental nerve complex (ISN) which is formed by three nerves from the prothoracic (T1) and suboesophageal ganglion (SOG), as well as a distinct suboesophageal nerve (Nervus anterior of the suboesophageal ganglion). In Carausius morosus and Sipyloidea sipylus, axonal tracing confirmed an innervation of the defence glands by this N. anterior SOG as well as N. anterior T1 and N. posterior SOG from the intersegmental nerve complex. In Peruphasma schultei, which has rather large defence glands, only the innervation by the N. anterior SOG was documented by axonal tracing. In the central nervous system of all species, 3-4 neuron types are identified by axonal tracing which send axons in the N. anterior SOG likely innervating the defence gland as well as adjacent muscles. These neurons are mainly suboesophageal neurons with one intersegmental neuron located in the prothoracic ganglion. The neuron types are conserved in the species studied, but the combination of neuron types is not identical. In addition, the central nervous system in S. sipylus contains one suboesophageal and one prothoracic neuron type with axons in the intersegmental nerve complex contacting the defence gland. CONCLUSIONS: Axonal tracing shows a very complex innervation pattern of the defence glands of Phasmatodea which contains different neurons in different nerves from two adjacent body segments. The gland size correlates to the size of a neuron soma in the suboesophageal ganglion, which likely controls gland contraction. In P. schultei, the innervation pattern appears simplified to the anterior suboesophageal nerve. Hence, some evolutionary changes are notable in a conserved neuronal network. PMID- 26500688 TI - Telemedicine - a scientometric and density equalizing analysis. AB - BACKGROUND: As a result of the various telemedicine projects in the past years a large number of studies were recently published in this field. However, a precise bibliometric analysis of telemedicine publications does not exist so far. METHODS: The present study was conducted to establish a data base of the existing approaches. Density-equalizing algorithms were used and data was retrieved from the Thomson Reuters database Web of Science. RESULTS: During the period from 1900 to 2006 a number of 3290 filed items were connected to telemedicine, with the first being published in 1964. The studies originate from 101 countries, with the USA, Great Britain and Canada being the most productive suppliers participating in 56.08 % of all published items. Analyzing the average citation per item for countries with more than 10 publications, Ireland ranked first (10.19/item), New Zealand ranked second (9.5/item) followed by Finland (9.04/item). The citation rate can be assumed as an indicator for research quality. The ten most productive journals include three journals with the main focus telemedicine and another five with the main focus "Information/Informatics". In all subject categories examined for published items related to telemedicine, "Health Care Sciences & Services" ranked first by far. More than 36 % of all publications are assigned to this category, followed by "Medical Informatics" with 9.72 % and "Medicine, General & Internal" with 8.84 % of all publications. CONCLUSION: In summary it can be concluded that the data shows clearly a strong increase in research productivity. Using science citation analysis it can be assumed that there is a large rise in the interest in telemedicine studies. PMID- 26500686 TI - A randomized controlled trial: the effect of inulin on weight management and ectopic fat in subjects with prediabetes. AB - BACKGROUND: Fat infiltration of the liver, muscle and pancreas is associated with insulin resistance and risk of diabetes. Weight loss reduces ectopic fat deposition and risk of diabetes, but is difficult to sustain to due to compensatory increases in appetite. Fermentable carbohydrates have been shown to decrease appetite and food intake, and promote weight loss in overweight subjects. In animal studies, fermentable carbohydrate reduces ectopic fat independent of weight loss. We aimed to investigate the effect of the fermentable carbohydrate inulin on weight maintenance, appetite and ectopic fat in subjects with prediabetes. METHODS: Forty-four subjects with prediabetes were randomized to 18 weeks' inulin or cellulose supplementation. During weeks 1-9 (weight loss phase) all subjects had four visits with a dietitian to guide them towards a 5 % weight loss. During weeks 10-18 (weight maintenance phase) subjects continued taking their assigned supplementation and were asked to maintain the weight they had lost but were offered no further support. All subjects attended study sessions at baseline, 9 and 18 weeks for measurement of weight; assessment of adipose tissue and ectopic fat content by magnetic resonance imaging and magnetic resonance spectroscopy; glucose, insulin and GLP-1 levels following a meal tolerance test; and appetite by ad libitum meal test and visual analogue scales. RESULTS: Both groups lost approximately 5 % of their body weight by week nine ( 5.3 +/- 0.1 % vs -4.3 +/- 0.4 %, p = 0.13, but the inulin group lost significantly more weight between 9 and 18 weeks (-2.3 +/- 0.5 % vs -0.6 +/- 0.4 %, p = 0.012). Subjects taking inulin had lower hepatic (p = 0.02) and soleus muscle (p < 0.05) fat content at 18 weeks compared to control even after controlling for weight loss and consumed less at the ad libitum meal test (p = 0.027). Fasting glucose significantly decreased at week nine only (p = 0.005), insulin concentrations did not change, and there was a significant increase in GLP-1 in the cellulose group at 9 and 18 weeks (p < 0.03, p < 0.00001). CONCLUSION: Inulin may have a two-pronged effect on the risk of diabetes by 1) promoting weight loss 2) reducing intrahepatocellular and intramyocellular lipid in people with prediabetes independent of weight loss. TRIAL REGISTRATION: CLINICAL TRIAL NUMBER: NCT01841073. PMID- 26500687 TI - Weight loss-induced changes in adipose tissue proteins associated with fatty acid and glucose metabolism correlate with adaptations in energy expenditure. AB - BACKGROUND: Energy restriction causes adaptations in energy expenditure (total ,TEE; resting-,REE; activity induced-,AEE). OBJECTIVE: To determine if changes in the levels of proteins involved in adipocyte glucose and fatty acid metabolism as indicators for energy deficiency are related to adaptations in energy expenditure during weight loss. METHODS: Forty-eight healthy subjects (18 men, 30 women), mean +/- SD age 42 +/- 8 y and BMI 31.4 +/- 2.8 kg/m(2), followed a very low energy diet for 8 wk. Protein levels of fatty acid binding protein 4 (FABP4), fructose-bisphosphate aldolase C (AldoC) and short chain 3-hydroxyacyl-CoA dehydrogenase (HADHsc) (adipose tissue biopsy, western blot), TEE (doubly labeled water), REE (ventilated hood), and AEE were assessed before and after the 8-wk diet. RESULTS: There was a positive correlation between the decrease in AldoC and the decrease in TEE (R = 0.438, P < 0.01) and the decrease change in AEE (R = 0.439, P < 0.01). Furthermore, there was a negative correlation between the increases in HADHsc and the decrease in REE (R = 0.343, P < 0.05). CONCLUSION: The decrease in AldoC correlated with the decrease in AEE, which may be explained by a decreased glycolytic flux. Additionally, the change in HADHsc, a crucial enzyme for a step in beta-oxidation, correlated with the adaptation in REE. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION NUMBER: NCT01015508 at clinicaltrials.gov. PMID- 26500689 TI - The isolation of early nuclear endosperm of Oryza sativa to facilitate gene expression analysis and screening imprinted genes. AB - BACKGROUND: Since the quality and yield of rice production depends on endosperm development, previous studies have focused on the molecular mechanism that regulates this developmental process. Recently, how this process is epigenetically regulated has become an important topic. However, the gene expression analysis and screening imprinted genes during early endosperm development remain challenging since the isolation of early endosperm has not been possible. Here, we report a procedure for the isolation of endosperm at 24 or 48 HAP (hours after pollination) during the free nuclear stage of endosperm development. RESULTS: This technique allows for rapid and convenient collection of pure free nuclear endosperm. Early endosperm RNA can then be extracted from the isolated endosperm cells using dynabeads. Our results showed that the quality of RNA is satisfactory for gene expression analysis and screening the parental-of origin specific genes in early endosperm. CONCLUSIONS: Thus, we offer a reliable method to overcome one of the major obstacles in the investigation of the molecular mechanisms of early endosperm development. Our approach can be used for accurate gene expression analysis and screening of imprinted genes, and facilitates the confirmation of endosperm-specific gene expression at the very early stages of endosperm development. This method could also be used in other species to collect early free nuclear endosperm. PMID- 26500691 TI - Carbon accretion in unthinned and thinned young-growth forest stands of the Alaskan perhumid coastal temperate rainforest. AB - BACKGROUND: Accounting for carbon gains and losses in young-growth forests is a key part of carbon assessments. A common silvicultural practice in young forests is thinning to increase the growth rate of residual trees. However, the effect of thinning on total stand carbon stock in these stands is uncertain. In this study we used data from 284 long-term growth and yield plots to quantify the carbon stock in unthinned and thinned young growth conifer stands in the Alaskan coastal temperate rainforest. We estimated carbon stocks and carbon accretion rates for three thinning treatments (basal area removal of 47, 60, and 73 %) and a no-thin treatment across a range of productivity classes and ages. We also accounted for the carbon content in dead trees to quantify the influence of both thinning and natural mortality in unthinned stands. RESULTS: The total tree carbon stock in naturally-regenerating unthinned young-growth forests estimated as the asymptote of the accretion curve was 484 (+/-26) Mg C ha-1 for live and dead trees and 398 (+/-20) Mg C ha-1 for live trees only. The total tree carbon stock was reduced by 16, 26, and 39 % at stand age 40 y across the increasing range of basal area removal. Modeled linear carbon accretion rates of stands 40 years after treatment were not markedly different with increasing intensity of basal area removal from reference stand values of 4.45 Mg C ha-1 year-1to treatment stand values of 5.01, 4.83, and 4.68 Mg C ha-1 year-1 respectively. However, the carbon stock reduction in thinned stands compared to the stock of carbon in the unthinned plots was maintained over the entire 100 year period of observation. CONCLUSIONS: Thinning treatments in regenerating forest stands reduce forest carbon stocks, while carbon accretion rates recovered and were similar to unthinned stands. However, that the reduction of carbon stocks in thinned stands persisted for a century indicate that the unthinned treatment option is the optimal choice for short-term carbon sequestration. Other ecologically beneficial results of thinning may override the loss of carbon due to treatment. Our model estimates can be used to calculate regional carbon losses, alleviating uncertainty in calculating the carbon cost of the treatments. PMID- 26500692 TI - Preparing Early Childhood Teachers to Work With Young Dual Language Learners. AB - Teacher preparation is clearly linked to the quality of early childhood programs. In order for young dual language learners (DLLs) to be academically successful, teacher preparation should focus on those skills and abilities relevant to students' particular needs. This article reviews the content of professional preparation for early educators working with young DLLs and briefly discusses the importance of developing the cultural and linguistic diversity of the early childhood workforce. It identifies 6 content areas: (a) understanding language development, (b) understanding the relationship between language and culture, PMID- 26500690 TI - WSES position paper on vascular emergency surgery. AB - Trauma, both blunt and penetrating, is extremely common worldwide, as trauma to major vessels. The management of these patients requires specialized surgical skills and techniques of the trauma surgeon. Furthermore few other surgical emergencies require immediate diagnosis and treatment like a ruptured abdominal aortic aneurysm (rAAA). Mortality of patients with a rAAA reaches 85 %, with more than half dying before reaching the hospital. These are acute events demanding immediate intervention to save life and limb and precluding any attempt at transfer or referral. It is the purpose of this position paper to discuss neck, chest, extremities and abdominal trauma, bringing to light recent evidence based data as well as expert opinions; besides, in this paper we present a review of the recent literature on rAAA and we discuss the rationale for transfer to referral center, the role of preoperative imaging and the pros and cons of Endoluminal repair of rAAA (REVAR) versus Open Repair (OR). PMID- 26500693 TI - Towards automatic image analysis and assessment of the multicellular apoptosis process. AB - Apoptotic programmed cell death (PCD) is a fundamental aspect of developmental maturation. However, the authors' understanding of apoptosis, especially in the multi-cell regime, is incomplete because of the difficulty of identifying dying cells by conventional strategies. Real-time in vivo microscopy of Drosophila, an excellent model system for studying the PCD during development, has been used to uncover plausible collective apoptosis at the tissue level, although the dynamic regulation of the process remains to be deciphered. In this work, the authors have developed an image-analysis program that can quantitatively analyse time lapse microscopy of live tissues undergoing apoptosis with a fluorescent nuclear marker, and subsequently extract the spatiotemporal patterns of multicellular response. The program can process a large number of cells (>103) automatically tracked across sets of image frames. It is applied to characterise the apoptosis of Drosophila wing epithelium at eclosion. Using the natural anatomic structures as reference, the authors identify dynamic patterns in the progression of PCD within the Drosophila tissues. The results not only confirm the previously observed collective multi-cell behaviour from a quantitative perspective, but also reveal a plausible role played by the anatomic structures, such as the wing veins, in the PCD propagation across the Drosophila wing. PMID- 26500694 TI - Dual functional nisin-multi-walled carbon nanotubes coated filters for bacterial capture and inactivation. AB - BACKGROUND: Removal of pathogens from water is one way to prevent waterborne illness. In this paper, we developed dual functional carbon nanotube (CNT) modified filters for bacterial capture and inactivation, utilizing multi-walled CNTs (MWCNTs) to coat on commercially available filters and making use of the exceptional adsorption property of CNTs to adsorb a natural antimicrobial peptide nisin on it. Two types of MWCNTs with different outer layer diameters were used (MWCNTs1: <8 nm in diameter; MWCNTs2: 10-20 nm in diameter). RESULTS: The thickness of MWCNT layers, surface morphology, and surface hydrophobicity of both types of MWCNT coated filters were characterized. The MWCNT coating on filters significantly increased the surface hydrophobicity. The absorption of nisin and the capture of bacterial pathogens were correlated with increased surface hydrophobicity. The MWCNTs1 and MWCNTs2 filters with 1.5 mg MWCNTs loading captured 2.44 and 3.88 log of cells, respectively, from aqueous solutions containing a total of ~10(6) CFU/mL cells. Nisin deposit at the amount of 0.5 mg on the surfaces of MWCNT filters significantly reduced the viability of captured B. anthracis cells by 95.71-97.19 %, and inhibited the metabolic activities of the captured cells by approximately 98.3 %. CONCLUSIONS: The results demonstrated that the MWCNT-nisin filters achieved dual functions in bacterial pathogen capture and inhibition in one single filtration step, which is potentially applicable in removing undesired microorganisms from water sources and inhibiting captured Gram positive bacteria activities. PMID- 26500695 TI - Inducible gene expression system by 3-hydroxypropionic acid. AB - BACKGROUND: 3-Hydroxypropionic acid (3-HP) is an important platform chemical that boasts a variety of industrial applications. Gene expression systems inducible by 3-HP, if available, are of great utility for optimization of the pathways of 3-HP production and excretion. RESULTS: Here we report the presence of unique inducible gene expression systems in Pseudomonas denitrificans and other microorganisms. In P. denitrificans, transcription of three genes (hpdH, mmsA and hbdH-4) involved in 3-HP degradation was upregulated by 3-HP by the action of a transcriptional regulator protein, LysR, and a cis-acting regulatory site for LysR binding. Similar inducible systems having an LysR transcriptional regulator were identified in other microorganisms that also could degrade 3-HP. A docking study showed that the 3-HP binding pocket is located between the N-terminal helix turn-helix motif and the C-terminal cofactor-binding domain. CONCLUSIONS: This LysR-regulated 3-HP-inducible system should prove useful for control of the level of gene expression in response to 3-HP. PMID- 26500696 TI - Bioflocculant production from untreated corn stover using Cellulosimicrobium cellulans L804 isolate and its application to harvesting microalgae. AB - BACKGROUND: Microalgae are widely studied for biofuel production. Nevertheless, harvesting step of biomass is still a critical challenge. Bioflocculants have been applied in numerous applications including the low-cost harvest of microalgae. A major bottleneck for commercial application of bioflocculant is its high production cost. Lignocellulosic substrates are abundantly available. Hence, the hydrolyzates of rice stover and corn stover have been used as carbon source to produce the bioflocculant in previous studies. However, the hydrolyzates of biomass required the neutralization of pH before the downstream fermentation processes, and the toxic by-products produced during hydrolysis process inhibited the microbial activities in the subsequent fermentation processes and contaminated the bioflocculant product. Therefore, strains that can secrete plant cell-wall-degrading enzymes and simultaneously produce bioflocculants through directly degrading the lignocellulosic biomasses are of academic and practical interests. RESULTS: A lignocellulose-degrading strain Cellulosimicrobium cellulans L804 was isolated in this study, which can produce the bioflocculant MBF-L804 using untreated biomasses, such as corn stover, corn cob, potato residues, and peanut shell. The effects of culture conditions including initial pH, carbon source, and nitrogen source on MBF-L804 production were analyzed. The results showed that over 80 % flocculating activity was achieved when the corn stover, corn cob, potato residues, and peanut shell were used as carbon sources and 4.75 g/L of MBF-L804 was achieved under the optimized condition: 20 g/L dry corn stover as carbon source, 3 g/L yeast extract as nitrogen source, pH 8.2. The bioflocculant MBF-L804 contained 68.6 % polysaccharides and 28.0 % proteins. The Gel permeation chromatography analysis indicated that the approximate molecular weight (MW) of MBF-L804 was 229 kDa. The feasibility of harvesting microalgae Chlamydomonas reinhardtii and Chlorella minutissima using MBF-L804 was evaluated. The highest flocculating efficiencies for C. reinhardtii and C. minutissima were 99.04 and 93.83 %, respectively. CONCLUSIONS: This study shows for the first time that C. cellulans L804 can directly convert corn stover, corn cob, potato residues and peanut shell into the bioflocculants, which can be used to effectively harvest microalgae. PMID- 26500697 TI - Microbial population dynamics during long-term sludge adaptation of thermophilic and mesophilic sequencing batch digesters treating sewage fine sieved fraction at varying organic loading rates. AB - BACKGROUND: In this research, the feasibility of, and population dynamics in, one step anaerobic sequencing batch reactor systems treating the fine sieved fraction (FSF) from raw municipal wastewater was studied under thermophilic (55 degrees C) and mesophilic (35 degrees C) conditions. FSF was sequestered from raw municipal wastewater, in the Netherlands, using a rotating belt filter (mesh size 350 micron). FSF is a heterogeneous substrate that mainly consists of fibres originating from toilet paper and thus contains a high cellulosic fraction (60-80 % of total solids content), regarded as an energy-rich material. RESULTS: Results of the 656-day fed-batch operation clearly showed that thermophilic digestion was more stable, applying high organic loading rates (OLR) up to 22 kg COD/(m(3) day). In contrast, the mesophilic digester already failed applying an OLR of 5.5 kg COD/(m(3) day), indicated by a drop in pH and increase in volatile fatty acids (VFAs). The observed viscosity values of the mesophilic sludge were more than tenfold higher than the thermophilic sludge. 454-pyrosequencing of eight mesophilic and eight thermophilic biomass samples revealed that Bacteroides and aceticlastic methanogen Methanosaeta were the dominant genera in the mesophilic digester, whereas OP9 lineages, Clostridium and the hydrogenotrophic methanogen Methanothermobacter dominated the thermophilic one. CONCLUSIONS: Our study suggests that applying thermophilic conditions for FSF digestion would result in a higher biogas production rate and/or a smaller required reactor volume, comparing to mesophilic conditions. PMID- 26500698 TI - Phylogeny-structured carbohydrate metabolism across microbiomes collected from different units in wastewater treatment process. AB - BACKGROUND: With respect to global priority for bioenergy production from plant biomass, understanding the fundamental genetic associations underlying carbohydrate metabolisms is crucial for the development of effective biorefinery process. Compared with gut microbiome of ruminal animals and wood-feed insects, knowledge on carbohydrate metabolisms of engineered biosystems is limited. RESULTS: In this study, comparative metagenomics coupled with metabolic network analysis was carried out to study the inter-species cooperation and competition among carbohydrate-active microbes in typical units of wastewater treatment process including activated sludge and anaerobic digestion. For the first time, sludge metagenomes demonstrated rather diverse pool of carbohydrate-active genes (CAGs) comparable to that of rumen microbiota. Overall, the CAG composition correlated strongly with the microbial phylogenetic structure across sludge types. Gene-centric clustering analysis showed the carbohydrate pathways of sludge systems were shaped by different environmental factors, including dissolved oxygen and salinity, and the latter showed more determinative influence of phylogenetic composition. Eventually, the highly clustered co-occurrence network of CAGs and saccharolytic phenotypes, revealed three metabolic modules in which the prevalent populations of Actinomycetales, Clostridiales and Thermotogales, respectively, play significant roles as interaction hubs, while broad negative co-exclusion correlations observed between anaerobic and aerobic microbes, probably implicated roles of niche separation by dissolved oxygen in determining the microbial assembly. CONCLUSIONS: Sludge microbiomes encoding diverse pool of CAGs was another potential source for effective lignocellulosic biomass breakdown. But unlike gut microbiomes in which Clostridiales, Lactobacillales and Bacteroidales play a vital role, the carbohydrate metabolism of sludge systems is built on the inter-species cooperation and competition among Actinomycetales, Clostridiales and Thermotogales. PMID- 26500699 TI - Karyotype alteration generates the neoplastic phenotypes of SV40-infected human and rodent cells. AB - BACKGROUND: Despite over 50 years of research, it remains unclear how the DNA tumor viruses SV40 and Polyoma cause cancers. Prevailing theories hold that virus coded Tumor (T)-antigens cause cancer by inactivating cellular tumor suppressor genes. But these theories don't explain four characteristics of viral carcinogenesis: (1) less than one in 10,000 infected cells become cancer cells, (2) cancers have complex individual phenotypes and transcriptomes, (3) recurrent tumors without viral DNA and proteins, (4) preneoplastic aneuploidies and immortal neoplastic clones with individual karyotypes. RESULTS: As an alternative theory we propose that viral carcinogenesis is a form of speciation, initiated by virus-induced aneuploidy. Since aneuploidy destabilizes the karyotype by unbalancing thousands of genes it catalyzes chain reactions of karyotypic and transcriptomic evolutions. Eventually rare karyotypes evolve that encode cancer specific autonomy of growth. The low probability of forming new autonomous cancer species by random karyotypic and transcriptomic variations predicts individual and clonal cancers. Although cancer karyotypes are congenitally aneuploid and thus variable, they are stabilized or immortalized by selections for variants with cancer-specific autonomy. Owing to these inherent variations cancer karyotypes are heterogeneous within clonal margins. To test this theory we analyzed karyotypes and phenotypes of SV40-infected human, rat and mouse cells developing into neoplastic clones. In all three systems we found (1) preneoplastic aneuploidies, (2) neoplastic clones with individual clonal but flexible karyotypes and phenotypes, which arose from less than one in 10,000 infected cells, survived over 200 generations, but were either T-antigen positive or negative, (3) spontaneous and drug-induced variations of neoplastic phenotypes correlating 1-to-1 with karyotypic variations. CONCLUSIONS: Since all 14 virus induced neoplastic clones tested contained individual clonal karyotypes and phenotypes, we conclude that these karyotypes have generated and since maintained these neoplastic clones. Thus SV40 causes cancer indirectly, like carcinogens, by inducing aneuploidy from which new cancer-specific karyotypes evolve automatically at low rates. This theory explains the (1) low probability of carcinogenesis per virus-infected cell, (2) the individuality and clonal flexibility of cancer karyotypes, (3) recurrence of neoplasias without viral T antigens, and (4) the individual clonal karyotypes, transcriptomes and immortality of virus-induced neoplasias - all unexplained by current viral theories. PMID- 26500700 TI - A modified method for preparing meiotic chromosomes based on digesting pollen mother cells in suspension. AB - BACKGROUND: Meiotic chromosome preparation is a key step in plant meiotic research. Pollen mother cell (PMC) wall elimination is beneficial to cytogenetic experimental procedures. Without wall interference, these procedures are easier and more successful. In existing methods it is difficult to eliminate PMC walls completely and uniformly. In this paper, we present an improved method for digesting PMC walls, and one for providing massive chromosomal spreads on a slide for other cytogenetic experimental procedures. RESULTS: Three plants were selected to exhibit the modified meiotic chromosome preparation method. PMCs were dispersed as single cells and incubated in a mixed enzyme solution (3 % cellulose + 0.3 % pectinase + 1 % snailase) for 1.5-2.5 h. In total, 28.28 % cells were lost during this process. There were 800-1900 spreads on every slide and no PMC wall interference was found on any of the slides. The spreads were also evenly distributed on the slides. More spreads were obtained when PMC and protoplast densities in the suspension were increased. All three plants' spreads were successfully used to locate a 5 s rDNA conserved sequence. The Nicotiana hybrid's spreads were successfully used to identify the hybrid's parental genome. CONCLUSION: This is an alternative method for meiotic chromosome preparation. Through this method, PMC walls can be completely and uniformly eliminated, and hundreds of spreads on every slide can be obtained. These spreads can be successfully used for DNA in situ hybridization. PMID- 26500701 TI - Characterization of whole-genome autosomal differences of DNA methylation between men and women. AB - BACKGROUND: Disease risk and incidence between males and females reveal differences, and sex is an important component of any investigation of the determinants of phenotypes or disease etiology. Further striking differences between men and women are known, for instance, at the metabolic level. The extent to which men and women vary at the level of the epigenome, however, is not well documented. DNA methylation is the best known epigenetic mechanism to date. RESULTS: In order to shed light on epigenetic differences, we compared autosomal DNA methylation levels between men and women in blood in a large prospective European cohort of 1799 subjects, and replicated our findings in three independent European cohorts. We identified and validated 1184 CpG sites to be differentially methylated between men and women and observed that these CpG sites were distributed across all autosomes. We showed that some of the differentially methylated loci also exhibit differential gene expression between men and women. Finally, we found that the differentially methylated loci are enriched among imprinted genes, and that their genomic location in the genome is concentrated in CpG island shores. CONCLUSION: Our epigenome-wide association study indicates that differences between men and women are so substantial that they should be considered in design and analyses of future studies. PMID- 26500702 TI - The histone chaperone DAXX maintains the structural organization of heterochromatin domains. AB - BACKGROUND: The death domain-associated protein (DAXX) collaborates with accessory proteins to deposit the histone variant H3.3 into mouse telomeric and pericentromeric repeat DNA. Pericentromeric repeats are the main genetic contributor to spatially discrete, compact, constitutive heterochromatic structures called chromocentres. Chromocentres are enriched in the H3K9me3 histone modification and serve as integral, functionally important components of nuclear organization. To date, the role of DAXX as an H3.3-specific histone chaperone has been investigated primarily using biochemical approaches which provide genome-wide views on cell populations and information on changes in local chromatin structures. However, the global chromatin and subnuclear reorganization events that coincide with these changes remain to be investigated. RESULTS: Using electron spectroscopic imagine (ESI), a specialized form of energy-filtered transmission electron microscopy that allows us to visualize chromatin domains in situ with high contrast and spatial resolution, we show that in the absence of DAXX, H3K9me3-enriched domains are structurally altered and become uncoupled from major satellite DNA. In addition, the structural integrity of nucleoli and the organization of ribosomal DNA (rDNA) are disrupted. Moreover, the absence of DAXX leads to chromatin that is more sensitive, on a global level, to micrococcal nuclease digestion. CONCLUSIONS: We identify a novel role of DAXX as a major regulator of subnuclear organization through the maintenance of the global heterochromatin structural landscape. As well, we show, for the first time, that the loss of a histone chaperone can have severe consequences for global nuclear organization. PMID- 26500703 TI - Effectiveness and safety of prolotherapy injections for management of lower limb tendinopathy and fasciopathy: a systematic review. AB - INTRODUCTION: The aim of this review was to identify and evaluate existing research to determine the clinical effectiveness and safety of prolotherapy injections for treatment of lower limb tendinopathy and fasciopathy. REVIEW: Nine databases were searched (Medline, Science Direct, AMED, Australian Medical Index, APAIS-Health, ATSIhealth, EMBASE, Web of Science, OneSearch) without language, publication or data restrictions for all relevant articles between January 1960 and September 2014. All prospective randomised and non-randomised trials, cohort studies, case-series, cross-sectional studies and controlled trials assessing the effectiveness of one or more prolotherapy injections for tendinopathy or fasciopathy at or below the superior aspect of the tibia/fibula were included. Methodological quality of studies was determined using a modified evaluation tool developed by the Cochrane Musculoskeletal Injuries Group. Data analysis was carried out to determine the mean change of outcome measure scores from baseline to final follow-up for trials with no comparative group, and for randomised controlled trials, standardised mean differences between intervention groups were calculated. Pooled SMD data were calculated where possible to determine the statistical heterogeneity and overall effect for short-, intermediate- and long term data. Adverse events were also reported. Two hundred and three studies were identified, eight of which met the inclusion criteria. These were then grouped according to tendinopathy or fasciopathy being treated with prolotherapy injections: Achilles tendinopathy, plantar fasciopathy and Osgood-Schlatter disease. The methodological quality of the eight included studies was generally poor, particularly in regards to allocation concealment, intention to treat analysis and blinding procedures. Results of the analysis provide limited support for the hypothesis that prolotherapy is effective in both reducing pain and improving function for lower limb tendinopathy and fasciopathy, with no study reporting a mean negative or non-significant outcome following prolotherapy injection. The analysis also suggests prolotherapy injections provide equal or superior short-, intermediate- and long-term results to alternative treatment modalities, including eccentric loading exercises forAchilles tendinopathy, platelet-rich plasma for plantar fasciopathy and usual care or lignocaine injections for Osgood-Schlatter disease. No adverse events following prolotherapy injections were reported in any study in this review. CONCLUSIONS: The conclusions of this review were derived from the best available scientific evidence. It is intended that the results of this study will assist clinical decision-making by practitioners. The results of this review found limited evidence that prolotherapy injections are a safe and effective treatment for Achilles tendinopathy, plantar fasciopathy and Osgood-Schlatter disease, however more robust research using large, methodologically-sound randomised controlled trials is required to substantiate these findings. PMID- 26500704 TI - AtomicChargeCalculator: interactive web-based calculation of atomic charges in large biomolecular complexes and drug-like molecules. AB - BACKGROUND: Partial atomic charges are a well-established concept, useful in understanding and modeling the chemical behavior of molecules, from simple compounds, to large biomolecular complexes with many reactive sites. RESULTS: This paper introduces AtomicChargeCalculator (ACC), a web-based application for the calculation and analysis of atomic charges which respond to changes in molecular conformation and chemical environment. ACC relies on an empirical method to rapidly compute atomic charges with accuracy comparable to quantum mechanical approaches. Due to its efficient implementation, ACC can handle any type of molecular system, regardless of size and chemical complexity, from drug like molecules to biomacromolecular complexes with hundreds of thousands of atoms. ACC writes out atomic charges into common molecular structure files, and offers interactive facilities for statistical analysis and comparison of the results, in both tabular and graphical form. CONCLUSIONS: Due to high customizability and speed, easy streamlining and the unified platform for calculation and analysis, ACC caters to all fields of life sciences, from drug design to nanocarriers. ACC is freely available via the Internet at http://ncbr.muni.cz/ACC. PMID- 26500714 TI - Thinking Outside the Stroke: Treating Primary Progressive Aphasia (PPA). AB - In this article, we explore the symptoms, cause, treatment potential, and supportive services for individuals diagnosed with Primary Progressive Aphasia (PPA). Although it is possible to regain certain cognitive abilities with stroke or brain injury, in PPA, language abilities worsen and other symptoms emerge with time, shortening the lifespan. The goal of speech therapy for PPA is not to regain lost language, but rather to maximize communication for as long as possible. In this article, we offer information and tools for speech-language pathologists to help people living with PPA achieve these goals and improve overall quality of life. PMID- 26500708 TI - Implementation of Mindfulness Training for Mental Health Staff: Organizational Context and Stakeholder Perspectives. AB - Occupational stress and burnout adversely impacts mental health care staff well being and patient outcomes. Mindfulness training reduces staff stress and may improve patient care. However, few studies explore mental health setting implementation. This qualitative study used focus groups to evaluate stakeholders' perceptions of organizational factors affecting implementation of an adapted version of Mindfulness-Based Stress Reduction (MBSR) for staff on adolescent mental health units. Common facilitators included leadership securing buy-in with staff, allocating staff time to participate, and quiet space for training and practice. Other facilitators were past staff knowledge of mindfulness, local champions, and acculturating staff with mindfulness through a non-mandatory training attendance policy. Common barriers were limited staff time to attend training sessions and insufficient training coverage for some staff. Staff also reported improved focus when interacting with adolescents and improved social cohesion on the units. We conclude that a mindfulness-based program for reducing occupational stress can be successfully implemented on adolescent mental health units. Implementation appeared to change the social context of the units, including staff and patient interactions. More broadly, our findings highlight the importance of environmental factors in shaping attitudes, diffusion of innovation, and acculturation of wellness program implementations. PMID- 26500706 TI - Efficacy and safety of vildagliptin, sitagliptin, and linagliptin as add-on therapy in Chinese patients with T2DM inadequately controlled with dual combination of insulin and traditional oral hypoglycemic agent. AB - OBJECTIVE: We aimed to evaluate the efficacy and safety of the three dipeptidyl peptidase 4 (DPP-4) inhibitors (vildagliptin, sitagliptin, and linagliptin) as add-on therapy in Chinese patients with type 2 diabetes mellitus (T2DM)inadequately controlled on dual combination of insulin and metformin or acarbose. METHODS: A total of 535 T2DM patients who failed to achieve glycemic control with insulin and a traditional oral hypoglycemic agent were randomized to receive vildagliptin, sitagliptin, or linagliptin. Body mass index, glycosylated hemoglobin (HbA1c), fasting and postprandial plasma glucose (FPG and PPG), insulin dose, and adverse events were evaluated during the study. RESULTS: The baseline HbA1c was 9.59 +/- 1.84 % (vildagliptin group), 9.22 +/- 1.60 % (sitagliptin group), and 9.58 +/- 1.80 % (linagliptin group). At week 12 it was 8.16 +/- 1.29 % (vildagliptin), 8.56 +/- 1.96 % (linagliptin), and 8.26 +/- 1.10 % (sitagliptin). The changes in HbA1c from baseline were -1.33 +/- 0.11 % (vildagliptin), -0.84 +/- 0.08 % (sitagliptin) and -0.81 +/- 0.08 % (linagliptin), the vildagliptin group had the greatest reduction in HbA1c (P < 0.05). The proportions of patients that reached target HbA1c were 66.27 % (vildagliptin), 52.73 % (sitagliptin), and 55.49 % (linagliptin), the vildagliptin group had the highest one (P < 0.05). The baseline FPG and PPG values in the three groups were at the same level. At week 12, mean FPG levels in the vildagliptin (7.31 +/- 1.50 mmol/L) and linagliptin (6.90 +/- 1.55 mmol/L) groups were significantly lower than in the sitagliptin group (8.02 +/- 4.48 mmol/L; P < 0.05); the linagliptin group had the lowest mean PPG followed by the vildagliptin group which was also significant lower (P = 0.000) than the sitagliptin group. Additionally, the required insulin dosage in the vildagliptin group was the lowest among the groups at weeks 6 and 12. Only mild AEs were reported during the study. CONCLUSION: The three DPP-4 inhibitors appear to be effective and safe as add-on therapy for T2DM patients on dual combination of insulin and a traditional OHA. Vildagliptin was more effective in decreasing insulin requirement and achieving glycemic control when compared to the other two. PMID- 26500705 TI - Target prediction utilising negative bioactivity data covering large chemical space. AB - BACKGROUND: In silico analyses are increasingly being used to support mode-of action investigations; however many such approaches do not utilise the large amounts of inactive data held in chemogenomic repositories. The objective of this work is concerned with the integration of such bioactivity data in the target prediction of orphan compounds to produce the probability of activity and inactivity for a range of targets. To this end, a novel human bioactivity data set was constructed through the assimilation of over 195 million bioactivity data points deposited in the ChEMBL and PubChem repositories, and the subsequent application of a sphere-exclusion selection algorithm to oversample presumed inactive compounds. RESULTS: A Bernoulli Naive Bayes algorithm was trained using the data and evaluated using fivefold cross-validation, achieving a mean recall and precision of 67.7 and 63.8 % for active compounds and 99.6 and 99.7 % for inactive compounds, respectively. We show the performances of the models are considerably influenced by the underlying intraclass training similarity, the size of a given class of compounds, and the degree of additional oversampling. The method was also validated using compounds extracted from WOMBAT producing average precision-recall AUC and BEDROC scores of 0.56 and 0.85, respectively. Inactive data points used for this test are based on presumed inactivity, producing an approximated indication of the true extrapolative ability of the models. A distance-based applicability domain analysis was also conducted; indicating an average Tanimoto Coefficient distance of 0.3 or greater between a test and training set can be used to give a global measure of confidence in model predictions. A final comparison to a method trained solely on active data from ChEMBL performed with precision-recall AUC and BEDROC scores of 0.45 and 0.76. CONCLUSIONS: The inclusion of inactive data for model training produces models with superior AUC and improved early recognition capabilities, although the results from internal and external validation of the models show differing performance between the breadth of models. The realised target prediction protocol is available at https://github.com/lhm30/PIDGIN.Graphical abstractThe inclusion of large scale negative training data for in silico target prediction improves the precision and recall AUC and BEDROC scores for target models. PMID- 26500713 TI - Effect of musical training on static and dynamic measures of spectral-pattern discrimination. AB - Both behavioral and physiological studies have demonstrated enhanced processing of speech in challenging listening environments attributable to musical training. The relationship, however, of this benefit to auditory abilities as assessed by psychoacoustic measures remains unclear. Using tasks previously shown to relate to speech-in-noise perception, the present study evaluated discrimination ability for static and dynamic spectral patterns by 49 listeners grouped as either musicians or nonmusicians. The two static conditions measured the ability to detect a change in the phase of a logarithmic sinusoidal spectral ripple of wideband noise with ripple densities of 1.5 and 3.0 cycles per octave chosen to emphasize either timbre or pitch distinctions, respectively. The dynamic conditions assessed temporal-pattern discrimination of 1-kHz pure tones frequency modulated by different lowpass noise samples with thresholds estimated in terms of either stimulus duration or signal-to-noise ratio. Musicians performed significantly better than nonmusicians on all four tasks. Discriminant analysis showed that group membership was correctly predicted for 88% of the listeners with the structure coefficient of each measure greater than 0.51. Results suggest that enhanced processing of static and dynamic spectral patterns defined by low rate modulation may contribute to the relationship between musical training and speech-in-noise perception. [Supported by NIH.]. PMID- 26500712 TI - Absorption Enhancement in Organic-Inorganic Halide Perovskite Films with Embedded Plasmonic Gold Nanoparticles. AB - We report on the numerical analysis of solar absorption enhancement in organic inorganic halide perovskite films embedding plasmonic gold nanoparticles. The effect of particle size and concentration is analyzed in realistic systems in which random particle location within the perovskite film and the eventual formation of dimers are also taken into account. We find a maximum integrated solar absorption enhancement of ~10% in perovskite films of 200 nm thickness and ~6% in 300 nm films, with spheres of radii 60 and 90 nm, respectively, in volume concentrations of around 10% in both cases. We show that the presence of dimers boosts the absorption enhancement up to ~12% in the thinnest films considered. Absorption reinforcement arises from a double contribution of plasmonic near field and scattering effects, whose respective weight can be discriminated and evaluated from the simulations. PMID- 26500707 TI - Association of JAZF1 and TSPAN8/LGR5 variants in relation to type 2 diabetes mellitus in a Saudi population. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic and multifactorial disease with a rapidly rising incidence in Saudi Arabia. Various genes including zinc finger protein 1 (JAZF1) and tetraspanin 8/leucine-rich repeat-containing G protein-coupled receptor (TSPAN8/LGR5) have been previously described to be associated with T2DM. This study investigated the association of JAZF1 (rs864745) and TSPAN8 (rs7961581) with T2DM in a Saudi population. METHODS: Genomic DNA samples from 400 Saudi T2DM patients and 400 healthy controls were genotyped and analyzed using a polymerase chain reaction-restriction fragment length polymorphism method. The difference between the genotype frequencies were carried out with Chi-square test. Odds ratio, 95 % confidence intervals and p values were calculated using multinomial logistic regression. Dominant and recessive models were implemented to show the statistical significances. Analysis of variance was used to compare differences between genotypes for the various parameters. RESULTS: Distribution frequencies of the AA, AG, and GG genotypes of JAZF1 (rs864745) differed significantly among T2DM patients and healthy controls (p < 0.05). The AG and GG genotypes were independently and significantly associated with a T2DM risk after adjusting for factors such as age, sex, and body mass index [odds ratio (OR) 2.1 (95 % confidence interval (CI) 1.3-3.4); p = 0.002] and [OR 1.9 (95 % CI 1.2-3.1); p = 0.005], respectively. A genotype-based stratification of anthropometric and biochemical data revealed that the AG + GG genotype is associated with waist circumference (p = 0.04) and fasting blood glucose (p = 0.01) and high-density lipoprotein cholesterol levels (p = 0.02). None of the allele or genotype showed the significant association between the T2DM cases and control subjects in rs7961581 polymorphism in TSPAN8/LGR5 gene. CONCLUSION: The rs864745 variant in JAZF1 gene may act as genetic risk factors for the development of T2DM in a Saudi population. PMID- 26500710 TI - Sources of cigarettes among adolescent smokers: Free or purchased? AB - BACKGROUND: Few studies have described youth cigarette sources in terms of whether the cigarettes were free or purchased. Understanding the different ways youth obtain tobacco can guide development of interventions to more effectively reduce youth smoking. PURPOSE: To determine the propensity for youth to purchase cigarettes versus obtain cigarettes for free, and the factors associated with each obtainment method. METHODS: Our sample included 812 youth ages 12-17 who reported ever smoking a whole cigarette. Our outcome was the source of the last cigarette smoked (purchased vs. free) and independent variables included demographics, smoking behaviors, and smoking status of parents/siblings/friends. We conducted logistic regression to assess relationships between outcome and independent variables. RESULTS: Eighty-four percent of youth obtained their last cigarette for free and 16% purchased their last cigarette. Youth who smoked less and had less weekly spending money were more likely to have obtained their last cigarette for free. DISCUSSION: Youth smokers appear to have a high propensity to obtain their cigarette for free, particularly those who smoke relatively infrequently. TRANSLATION TO HEALTH EDUCATION PRACTICE: Interventions that target sources of free cigarettes have the potential to reduce the progression of youth smoking at a critical stage in its development. PMID- 26500709 TI - Molecular and immunologic markers of kidney cancer-potential applications in predictive, preventive and personalized medicine. AB - Kidney cancer is one of the deadliest malignancies due to frequent late diagnosis (33 % or renal cell carcinoma are metastatic at diagnosis) and poor treatment options. There are two major subtypes of kidney cancer: renal cell carcinoma (RCC) and renal pelvis carcinoma. The risk factors for RCC, accounting for more than 90 % of all kidney cancers, are smoking, obesity, hypertension, misuse of pain medication, and some genetic diseases. The most common molecular markers of kidney cancer include mutations and epigenetic inactivation of von Hippel-Lindau (VHL) gene, genes of vascular endothelial growth factor (VEGF) pathway, and carbonic anhydrase IX (CIAX). The role of epigenetic pathways, including DNA methylation and chromatin structure remodeling, was also demonstrated. Immunologic properties of RCC enable this type of tumor to escape immune response effectively. An important role in this process is played by tumor-associated macrophages that demonstrate mixed M1/M2 phenotype. In this review, we discuss molecular and cellular aspects for RCC development and current state of knowledge allowing personalized approaches for diagnostics and prognostic prediction of this disease. A set of macrophage markers is suggested for the analysis of the association of macrophage phenotype and disease prognosis. PMID- 26500715 TI - Teaching reading to youth with fragile X syndrome: Should phonemic awareness and phonics instruction be used? AB - CLINICAL QUESTION: Would a child with fragile X syndrome benefit more from phonemic awareness and phonics instruction or whole-word training to increase reading skills? METHOD: Systematic review. STUDY SOURCES: PsycINFO. SEARCH TERMS: Fragile X or Down Syndrome or Cognitive Impairment or Cognitive Deficit or Cognitive Disability or Intellectual Disorder or Intellectual Delay or Intellectual Disability or Mental Retardation AND Whole Word or Sight Word or Phonological Awareness or Phonics. NUMBER OF STUDIES INCLUDED: FXS = 0; DS = 6; ID = 17. PRIMARY RESULTS: There are currently no published peer-reviewed treatment studies testing reading interventions for children with fragile X syndrome.Phonological awareness and reading outcomes are correlated in children with fragile X syndrome, similar to the pattern seen in typical development.There is converging empirical evidence that phonologically-based approaches, often included as part of a comprehensive program, can be beneficial with children and adolescents with other developmental disabilities, including Down syndrome, intellectual disabilities, and autism spectrum disorder. CONCLUSIONS: There is a need for more research to determine what types of reading interventions are beneficial when working with children with fragile X syndrome. Given the lack of published empirical research in this area, clinicians should rely on existing evidence-based treatment data and professional judgment when determining which course of treatment to implement. PMID- 26500711 TI - SEX, LIES AND SELF-REPORTED COUNTS: BAYESIAN MIXTURE MODELS FOR HEAPING IN LONGITUDINAL COUNT DATA VIA BIRTH-DEATH PROCESSES. AB - Surveys often ask respondents to report non-negative counts, but respondents may misremember or round to a nearby multiple of 5 or 10. This phenomenon is called heaping, and the error inherent in heaped self-reported numbers can bias estimation. Heaped data may be collected cross-sectionally or longitudinally and there may be covariates that complicate the inferential task. Heaping is a well known issue in many survey settings, and inference for heaped data is an important statistical problem. We propose a novel reporting distribution whose underlying parameters are readily interpretable as rates of misremembering and rounding. The process accommodates a variety of heaping grids and allows for quasi-heaping to values nearly but not equal to heaping multiples. We present a Bayesian hierarchical model for longitudinal samples with covariates to infer both the unobserved true distribution of counts and the parameters that control the heaping process. Finally, we apply our methods to longitudinal self-reported counts of sex partners in a study of high-risk behavior in HIV-positive youth. PMID- 26500718 TI - Complete genome sequences of bacteriophages P12002L and P12002S, two lytic phages that infect a marine Polaribacter strain. AB - The bacterial genus Polaribacter is distributed widely in marine environments; however, there have been no reports of phages infecting Polaribacter strains. Here, we describe the isolation and genome sequencing of two lytic siphophages, P12002L and P12002S, that infect Polaribacter sp. strain IMCC12002. The two phages and host strain were isolated from coastal seawater of Korea. Complete genome sequences of the two phages were similar to each other and about 50 kb in length, with a G + C content of 28.9 %. The two genomes showed typical characteristics of phage genomes: a modular structure and high proportion of hypothetical proteins. The genome sequences have been deposited in GenBank under accession numbers KR136259 (P12002L) and KR136260 (P12002S). PMID- 26500720 TI - Structural Elucidation of a Small Molecule Inhibitor of Protein Disulfide Isomerase. AB - Compound libraries provide a starting point for multiple biological investigations, but the structural integrity of compounds is rarely assessed experimentally until a late stage in the research process. Here, we describe the discovery of a neuroprotective small molecule that was originally incorrectly annotated with a chemical structure. We elucidated the correct structure of the active compound using analytical chemistry, revealing it to be the natural product securinine. We show that securinine is protective in a cell model of Huntington disease and identify the binding site of securinine to its target, protein disulfide isomerase using NMR chemical shift perturbation studies. We show that securinine displays favorable pharmaceutical properties, making it a promising compound for in vivo studies in neurodegenerative disease models. In addition to finding this unexpected activity of securinine, this study provides a systematic roadmap to those who encounter compounds with incorrect structural annotation in the course of screening campaigns. PMID- 26500717 TI - Complete genome sequences of Geobacillus sp. Y412MC52, a xylan-degrading strain isolated from obsidian hot spring in Yellowstone National Park. AB - Geobacillus sp. Y412MC52 was isolated from Obsidian Hot Spring, Yellowstone National Park, Montana, USA under permit from the National Park Service. The genome was sequenced, assembled, and annotated by the DOE Joint Genome Institute and deposited at the NCBI in December 2011 (CP002835). Based on 16S rRNA genes and average nucleotide identity, Geobacillus sp. Y412MC52 and the related Geobacillus sp. Y412MC61 appear to be members of a new species of Geobacillus. The genome of Geobacillus sp. Y412MC52 consists of one circular chromosome of 3,628,883 bp, an average G + C content of 52 % and one circular plasmid of 45,057 bp and an average G + C content of 45 %. Y412MC52 possesses arabinan, arabinoglucuronoxylan, and aromatic acid degradation clusters for degradation of hemicellulose from biomass. Transport and utilization clusters are also present for other carbohydrates including starch, cellobiose, and alpha- and beta galactooligosaccharides. PMID- 26500719 TI - Complete genome sequence of Propionibacterium freudenreichii DSM 20271(T). AB - Propionibacterium freudenreichii subsp. freudenreichii DSM 20271(T) is the type strain of species Propionibacterium freudenreichii that has a long history of safe use in the production dairy products and B12 vitamin. P. freudenreichii is the type species of the genus Propionibacterium which contains Gram-positive, non motile and non-sporeforming bacteria with a high G + C content. We describe the genome of P. freudenreichii subsp. freudenreichii DSM 20271(T) consisting of a 2,649,166 bp chromosome containing 2320 protein-coding genes and 50 RNA-only encoding genes. PMID- 26500716 TI - Cardiac CT vs. Stress Testing in Patients with Suspected Coronary Artery Disease: Review and Expert Recommendations. AB - Diagnosis and management of coronary artery disease represent a major challenge to our health care systems affecting millions of patients each year. Until recently, the diagnosis of coronary artery disease could be conclusively determined only by invasive coronary angiography. To avoid risks from cardiac catheterization, many healthcare systems relied on stress testing as gatekeeper for coronary angiography. Advancements in cardiac computed tomography angiography technology now allows to noninvasively visualize coronary artery disease, challenging the role of stress testing as the default noninvasive imaging tool for evaluating patients with chest pain. In this review, we summarize current data on the clinical utility of cardiac computed tomography and stress testing in stable patients with suspected coronary artery disease. PMID- 26500722 TI - Moderated mediation analysis: An illustration using the association of gender with delinquency and mental health. AB - PURPOSE: When researchers find an association between two variables, it is useful to evaluate the role of other constructs in this association. While assessing these mediation effects, it is important to determine if results are equal for different groups. It is possible that the strength of a mediation effect may differ for males and females, for example - such an effect is known as moderated mediation. DESIGN: Participants were 2532 adolescents from diverse ethnic/racial backgrounds and equally distributed across gender. The goal of this study was to investigate parental respect as a potential mediator of the relationship between gender and delinquency and mental health, and to determine whether observed mediation is moderated by gender. FINDINGS: Parental respect mediated the association between gender and both delinquency and mental health. Specifically, parental respect was a protective factor against delinquency and mental health problems for both females and males. PRACTICAL IMPLICATIONS: Demonstrated the process of estimating models in Lavaan, using two approaches (i.e. single group regression and multiple group regression model), and including covariates in both models. PMID- 26500721 TI - Glyconanomaterials: Emerging applications in biomedical research. AB - Carbohydrates constitute the most abundant organic matter in nature, serving as structural components and energy sources, and mediating a wide range of cellular activities. The emergence of nanomaterials with distinct optical, magnetic, and electronic properties has witnessed a rapid adoption of these materials for biomedical research and applications. Nanomaterials of various shapes and sizes having large specific surface areas can be used as multivalent scaffolds to present carbohydrate ligands. The resulting glyconanomaterials effectively amplify the glycan-mediated interactions, making it possible to use these materials for sensing, imaging, diagnosis, and therapy. In this review, we summarize the synthetic strategies for the preparation of various glyconanomaterials. Examples are given where these glyconanomaterials have been used in sensing and differentiation of proteins and cells, as well as in imaging glycan-medicated cellular responses. PMID- 26500723 TI - Two Paraneoplastic Autoimmune Syndromes: Limbic Encephalitis and Palmar Fasciitis in a Patient with Small Cell Lung Cancer. AB - Small cell lung cancer (SCLC) is characterized by a relatively high rate of autoimmune phenomena. Paraneoplastic limbic encephalitis (PLE) is an autoimmune syndrome in which a non-neural tumor containing an antigen normally present in the nervous system precipitates an antibody attack on neural tissues. Patients with PLE usually present with rapidly progressive short-term memory deficits, confusion or even dementia. Palmar fasciitis and polyarthritis syndrome (PFPAS) is another autoimmune syndrome characterized by rheumatologic manifestations, especially involving the palms of the hands. We report a case of a 59-year old woman who presented with worsening neurological symptoms of two-week duration, and later coma. The combined clinical, serological, and imaging studies suggested a diagnosis of PLE. A chest computed tomographic scan showed a 1.2 cm-diameter mass in the upper lobe of the left lung that was surgically removed and showed SCLC. Following surgery, neurological symptoms rapidly improved, allowing the patient to receive adjuvant chemotherapy. While in remission for both SCLC and PLE, the patient developed pain, soft-tissue swelling, and stiffness in both palms, suggesting the diagnosis of PFPAS. Five months following the diagnosis of palmar fasciitis, SCLC relapsed with mediastinal and cervical lymphadenopathy. This case report underlines the continuous interaction of SCLC with the immune system, expressed by coexistence of two rare paraneoplastic diseases, PLE, and PFPAS, in a patient with SCLC. While symptoms related to PLE preceded the initial diagnosis of SCLC, other symptoms related to PFPAS preceded relapse. PMID- 26500724 TI - Carcinosarcoma with Choriocarcinomatous and Osteosarcomatous Differentiation in a Patient with Juvenile Polyposis Syndrome. AB - Juvenile polyposis syndrome (JPS) is an infrequent autosomal dominant hereditary predisposition to the occurrence of hamartomatous polyps in the colon and rectum. We describe the case of a 12-year-old boy with JPS associated with an abdominal tumor. Histological sections of the abdominal tumor showed components of adenocarcinoma, osteosarcoma, and choriocarcinoma. Immunohistochemistry was AE1/AE3, CK7, HCG and SALL4 positive. Juvenile polyposis syndrome patients are at increased risk of colorectal adenocarcinoma. However, we present a case of an adenocarcinoma associated with other unusual components. This association has not been reported before. PMID- 26500725 TI - Metastatic Ghost Cell Odontogenic Carcinoma: Description of a Case and Search for Actionable Targets. AB - Ghost cell odontogenic carcinoma (GCOC) is an exceedingly rare malignant tumor on the spectrum of already uncommon odontogenic or dentinogenic tumors. We describe here the case of metastatic GCOC in a patient with a history of recurrent dentinogenic ghost cell tumor of the mandible, now presenting with bilateral pleural effusions. We will discuss typical histopathologic and histochemical features of GCOC, along with results of genomic testing and their role in directing therapy. PMID- 26500726 TI - Paratesticular Spindle Cell Rhabdomyosarcoma. AB - Spindle cell rhabdomyosarcoma is a rare variant of embryonal rhabdomyosarcoma that affects young males and most commonly involves the paratesticular region. We report a case of paratesticular spindle cell rhabdomyosarcoma in a 14-year-old boy, who presented with a painless scrotal mass. Left inguinal orchidectomy was performed. Histopathological and immunohistochemical examination of the mass revealed spindle cell rhabdomyosarcoma of the paratesticular region. PMID- 26500727 TI - Metastatic Renal Cell Carcinoma Masquerading as a Primary Ovarian Mass in a Post Operative Case of Meningioma and Renal Cell Carcinoma. AB - The clinical presentation of metastatic renal cell carcinoma to ovary is extremely rare as well as confusing due to its close resemblance to primary ovarian tumors, especially clear cell carcinoma. We present a case of metastatic renal cell carcinoma diagnosed in a 48-year-old female, who had renal cell carcinoma of the right kidney and right sphenoid wing meningioma of transitional type. PMID- 26500728 TI - Palliative Radiation for Leukemic Arthropathy from Human T-Cell Lymphoma Virus associated Adult T-Cell Leukemia Lymphoma. AB - Human T-cell lymphoma virus (HTLV)-associated adult T-cell leukemia lymphoma is a rare cancer in the United States, but there are several areas around the world where the virus is endemic. HTLV-associated adult T-cell leukemia lymphoma has been associated with leukemic arthropathy. We present a patient with HTLV associated adult T-cell leukemia lymphoma with leukemic arthropathy. Although non steroidal anti-inflammatory drugs and chemotherapy are often used for treatment, we describe the successful use of radiation therapy in the palliative relief of symptoms from leukemic arthropathy. PMID- 26500730 TI - Cavernous Hemangioma of the Left Forearm. AB - Cavernous hemangiomas are benign hamartomatous proliferation of endothelial tissues. They can arise virtually anywhere in the body and do not contain tissues native to the organ or structure in which they are located. Contrary to what is seen in capillary hemangiomas and the cavernous cutaneous variety, intramuscular hemangiomas almost always never regress. We report a case of intramuscular cavernous hemangioma in an 18-year-old male Nigerian with swelling in the left forearm of 9 years duration. The swelling progressively increased in size and nearly involved the entire forearm with occasional pain and no preceding history of trauma. Pre-operative plain radiographs showed an ill-defined soft tissue swelling with multiple calcifications or phleboliths. Surgical excision with ligation of feeding vessels was done and histology confirmed the diagnosis with free margin of excision. Post-operative clinical improvement was marked. PMID- 26500729 TI - A Rare Metastatic Myositis Ossificans of Obturator Muscle Secondary to Urothelial Carcinoma. AB - The most frequent metastatic sites of the urothelial bladder cancers (UBCs) are bones, lungs, lymph nodes, liver, pleura, and brain. In the literature, skeletal muscle metastases from UBC have been rarely reported. We report a case of a 65 year-old male with metastatic myositis ossificans to obturator muscle 14 months after radical cystectomy performed for a muscle invasive transitional cell carcinoma. An abdomen computed tomography scan showed a lesion of about 8 cm in diameter in the left obturator muscle with myositis ossificans aspect. Ultrasound guided biopsy specimen of the left obturator muscle revealed poorly differentiated metastatic urothelial carcinoma with malignant myositis ossificans aspects. The patient refused additional surgery and received systemic chemotherapy and radiotherapy at the site of the lesion. The patient more than 6 months after treatment has a good performance status with a partial reduction of the mass and negative imaging for metastases in the follow-up. PMID- 26500731 TI - Locally Advanced Spiroadenocarcinoma in the Regional Axilla of a Breast Cancer Patient: Hallmarks of Definitive Diagnosis and Management. AB - Eccrine spiroadenocarcinoma is an extremely rare malignant eccrine gland tumor which may masquerade as other more common malignancies such as poorly differentiated squamous carcinoma or metastatic breast cancer. We report a case of an ulcerated axillary skin lesion with bulky adenopathy in a 77 year-old female with a prior history of ipsilateral triple negative breast carcinoma. The clear transition of benign spiradenoma to malignant carcinoma was essential to establishing a definitive diagnosis and treatment plan. PMID- 26500732 TI - Synchronous Pulmonary Malignancies: Atypical Presentation of Mantle Cell Lymphoma Masking a Lung Malignancy. AB - We present a case of a pleural space malignancy masked by an atypical presentation of mantle cell lymphoma. Our patient presented with a large pleural effusion and right sided pleural studding, initially attributed to a new diagnosis of mantle cell lymphoma. Rare atypical epithelial cells were also seen amongst the clonal population of lymphocytes. The patient lacked systemic manifestations of mantle cell lymphoma and did not improve with chemotherapy. A pleural biopsy ultimately revealed the presence of an undifferentiated carcinoma, favoring a lung primary. A discussion of synchronous pleural space malignancies involving lymphomas is given. PMID- 26500733 TI - A Case of Endometrioid Adenocarcinoma Originating from the Serous Surface of the Small Intestine. AB - Malignant transformation of endometriosis has been extensively described in the literature. However, extragonadal endometrioid adenocarcinoma, either de novo or arising from malignant transformation of endometriosis, is rare. The present case report describes a patient with endometrioid adenocarcinoma on the serous surface of the small intestine. A 25-year-old female with no history of endometriosis was referred to our hospital with an intrapelvic tumor. An internal examination, ultrasound, and magnetic resonance imaging revealed a round mass approximately 80 mm in diameter; however, identification of the affected organ was difficult. Because we could not rule out malignancy based on the non-specific radiologic findings, laparotomy was performed. A mass with ileal adhesions was detected intraoperatively. In addition, the uterus and bilateral adnexa appeared normal. The tumor was resected with part of the ileum. Histopathology confirmed a diagnosis of endometrioid adenocarcinoma originating from the serous surface of the small intestine. PMID- 26500734 TI - Peritoneal Malignant Mesothelioma with Epithelioid Type, Demonstrating High Serum and Ascitic KL-6 Levels: Immunohistochemical Analyses. AB - We report a case of KL-6 producing peritoneal malignant mesothelioma. A 56-year old woman was referred to our hospital on November 2005 with severe abdominal distention. Peritoneal malignant mesothelioma with epithelioid type was diagnosed by clinical symptoms, laboratory investigations, imaging studies, and immunohistochemical examination of known tumor markers. In addition, high serum and ascitic KL-6 levels were observed and the immunostaining of the tumor for KL 6 was evident. We thus consider KL-6 to be a potential novel marker for peritoneal malignant mesothelioma with epithelioid type. PMID- 26500735 TI - The Present and Future Opportunities of the Rare Cancer Network: An International Consortium for Advancement of Oncologic Care. AB - To date, the Rare Cancer Network (RCN) has initiated more than 90 studies and 54 peer-reviewed publications were produced as a result. The Second International Symposium of the Rare Cancer Network recently took place in Istanbul, Turkey on April 17-18, 2015, and update was given on multiple currently ongoing projects, while also giving room for new proposals which will shape the direction of future studies for the group. This companion issue of the RCN Proceedings summarized the findings of this meeting, while also serving as a call for fresh projects and papers which will continue to energize the group and advance the oncologic science. A brief introduction to the principles, history, and vision of the RCN was also included. To review, the academic year of 2014-15 marked an enormous success for the international members of the RCN, with the generation of 8 fully published papers and more than 12 newly proposed topics. By the collective efforts of all RCN members, in the future, we look forward to the upcoming opportunities in continuing to advance the standard of chemo- and radiotherapeutic oncologic care for selected rare tumor topics. The studies of these rare cancers often do not allow the design and execution of prospectively enrolled trials; however, these uncommon malignancies do impact the humankind and add to its suffering globally in significant ways. PMID- 26500737 TI - Corynebacterium CDC Group G Native and Prosthetic Valve Endocarditis. AB - We report the first case of native and recurrent prosthetic valve endocarditis with Corynebacterium CDC group G, a rarely reported cause of infective endocarditis (IE). Previously, there have been only two cases reported for prosthetic valve IE caused by these organisms. A 69-year-old female with a known history of mitral valve regurgitation presented with a 3-day history of high grade fever, pleuritic chest pain and cough. Echocardiography confirmed findings of mitral valve thickening consistent with endocarditis, which subsequently progressed to become large and mobile vegetations. Both sets of blood cultures taken on admission were positive for Corynebacterium CDC group G. Despite removal of a long-term venous access port, the patient's presumed source of line associated bacteremia, mitral valve replacement, and aggressive antibiotic therapy, the patient had recurrence of vegetations on the prosthetic valve. She underwent replacement of her prosthetic mitral valve in the subsequent 2 weeks, before she progressed to disseminated intravascular coagulation and expired. Although they are typically considered contaminants, corynebacteria, in the appropriate clinical setting, should be recognized, identified, and treated as potentially life-threatening infections, particularly in the case of line associated bacteremias, and native and prosthetic valve endocarditis. PMID- 26500736 TI - Management of Metastatic Apocrine Hidradenocarcinoma with Chemotherapy and Radiation. AB - Hidradenocarcinoma is a rare aggressive form of cutaneous adnexal skin carcinoma originating from the sweat gland. Due to its low incidence, prognostic and treatment strategies are still being explored both for primary and advanced disease. This tumor most often presents as either solid or cystic appearing subcutaneous nodules, which may be associated with pruritus or ulceration. To date the mainstay of treatment for local disease has been surgical excision; however, the paucity of historical data available has shown that these tumors often behave aggressively with high rates of local recurrence, metastasis, and poor overall outcomes. There are few case reports describing the utility of radiation therapy in the treatment of hidradenocarcinoma. Herein, we present a case of metastatic apocrine hidradenocarcinoma in a 32-year-old Caucasian male. The patient initially underwent excisional biopsy which confirmed the diagnosis of poorly differentiated, highly infiltrative, apocrine hidradenocarcinoma. He received systemic chemotherapy for metastatic disease, followed by radiation therapy to areas of grossly palpable adenopathy. Prior to radiation therapy the patient had an enlarged hypermetabolic conglomerate of lymph nodes in the right axilla, and borderline enlarged low activity nodes within the left axilla. He received 3 cycles of chemotherapy followed by tamoxifen and radiation therapy (50.4 Gy in 28 fractions) to areas of progressive disease in the bilateral axilla, lower neck, and axillary skin. Following treatment, the patient had complete resolution of skin nodules and improvement of his pruritus. While the role of radiation therapy in the treatment of hidradenocarcinoma has not been well established, this case report demonstrated the potential benefit of external beam radiotherapy in the management of this rare disease. PMID- 26500738 TI - Vibrio Vulnificus Necrotizing Fasciitis Associated with Acupuncture. AB - Necrotizing fasciitis is a severe life-threatening infection of the deep subcutaneous tissues and fascia. Infection with Vibrio vulnificus, a halophilic Gram-negative bacillus found worldwide in warm coastal waters, can lead to severe complications, particularly among patients with chronic liver diseases. We herein present an unusual case of necrotizing fasciitis caused by V. vulnificus triggered by acupuncture needle insertion. The patient, who suffered from diabetes mellitus and nonalcoholic fatty liver disease and worked at a fish hatchery, denied any injury prior to acupuncture. This is the first ever reported case of V. vulnificus infection triggered by acupuncture needle insertion, clearly emphasizing the potential hazards of the prolonged survival of V. vulnificus on the skin. The potential infectious complications of acupuncture needle insertion are discussed. PMID- 26500739 TI - Trends and Predictors of Mortality Among HIV Positive Patients in the Era of Highly Active Antiretroviral Therapy in Uganda. AB - Knowledge of mortality trends and predictors among HIV-positive patients in the era of highly active antiretroviral therapy (HAART) in resource poor settings is still limited. The aim of this study was to describe trends and predictors of mortality among HIV-positive patients in the era of HAART in Uganda. Data from 2004 to 2013 for adult HIV-positive patients (>=15 years) obtaining care and treatment from the AIDS Support Organization in Uganda were reviewed for mortality. Descriptive statistics were analyzed by frequencies and cross tabulations. Calendar period was used as a proxy measure for HAART exposure and a time plot of the proportion of HIV-positive patients reporting dead per year was used to describe the trends. Logistic regression was used to determine the predictors of mortality at bivariate and multivariate levels, respectively. We included in the analysis 95,857 HIV positive patients; 64% were female with median age of 33 years (interquartile range 27-40). Of these 36,133 (38%) were initiated on ART and a total of 4279 (4.5%) died; 19.5% (835/4279) of those who died had an opportunistic infection. Overall, mortality first increased between 2004 and 2006 and thereafter substantially declined (X(2) trend=211.9, P<0.001). Mortality was relatively higher in Eastern Uganda compared to other geographical areas. Male gender, older age (>45 years), being from Eastern or Northern Uganda, having none or primary education, being unemployed, advanced immunodeficiency (CD4 count <100 cell/uL or WHO stage III or IV) and underweight (<45 kg weight) at HAART initiation and calendar period 2004-2008 were significant predictors of mortality (P<0.001). Overall, the expanding coverage of HAART is associated with a declining trend in mortality among HIV positive patients in Uganda. However, mortality trends differed significantly by geographical area and men remain potentially at higher risk of death probably because of delayed initiation on ART. There is urgent need for men targeted interventions for improved ART performance. PMID- 26500740 TI - Serum 25-Hydroxyvitamin D Levels are not Associated with Adverse Outcomes in Clostridium Difficile Infection. AB - Clostridium difficile infection (CDI) is a significant source of healthcare associated morbidity and mortality. This study investigated whether serum 25 hydroxyvitamin D is associated with adverse outcomes from CDI. Patients with CDI were prospectively enrolled. Charts were reviewed and serum 25-hydroxyvitamin D was measured. The primary outcome was a composite definition of severe disease: fever (temperature >38 degrees C), acute organ dysfunction, or serum white blood cell count >15,000 cells/uL within 24-48 hours of diagnosis; lack of response to therapy by day 5; and intensive care unit admission; colectomy; or death within 30 days. Sixty-seven patients were included in the final analysis. Mean (+/-SD) serum 25-hydroxyvitamin D was 26.1 (+/-18.54) ng/mL. Severe disease, which occurred in 26 (39%) participants, was not associated with serum 25 hydroxyvitamin D [odds ratio (OR) 1.00; 95% confidence interval (CI) 0.96-1.04]. In the adjusted model for severe disease only serum albumin (OR 0.12; 95%CI 0.02 0.64) and diagnosis by detection of stool toxin (OR 5.87; 95%CI 1.09-31.7) remained independent predictors. We conclude that serum 25-hydroxyvitamin D is not associated with the development of severe disease in patients with CDI. PMID- 26500742 TI - Importance of Coryneform Bacteria in Infective Endocarditis. PMID- 26500741 TI - Gastrointestinal Mucormycosis Resulting in a Catastrophic Outcome in an Immunocompetent Patient. AB - We present a case of a middle-aged female who was admitted to the hospital with a respiratory infection and subsequently developed an acute surgical abdomen secondary to a perforated viscous. She was found to have mucormycosis of the intestinal tract and eventually succumbed to the sequelae of the infection. PMID- 26500743 TI - Spontaneous Bacterial Peritonitis Due to Methicillin-Resistant Staphylococcus Aureus in a Patient with Cirrhosis: The Potential Role for Daptomycin and Review of the Literature. AB - Gram-positive cocci are emerging causes of spontaneous bacterial peritonitis (SBP), especially in patients with healthcare-associated infections. We report the case of a 68-year-old man with hepatitis C virus and alcohol-related cirrhosis who developed SBP due to methicillin-resistant Staphylococcus aureus treated with daptomycin. We discuss the potential role of daptomycin in this setting with a review of the literature about the use of daptomycin in primary or secondary bacterial peritonitis. PMID- 26500744 TI - Acute Myositis Associated with Concurrent Infection of Rotavirus and Norovirus in a 2-Year-Old Girl. AB - Rotavirus and norovirus are common pathogens associated with gastroenteritis in children. Although rotavirus occasionally induces central nervous system disease, only 3 cases with rotavirus-induced acute myositis have been reported in the English literature. We recently treated a female patient with acute myositis associated with gastroenteritis induced by concurrent infection with rotavirus and norovirus. Having suffered from gastroenteritis for 3 days, she suddenly developed myositis affecting her lower extremities with concomitant creatine kinase elevation. Herein, we present our patient and review the previous cases including those reported in the Japanese literature. PMID- 26500745 TI - A Rare Case of Painful Goiter Secondary to Pediatric Hashimoto's Thyroiditis Requiring Thyroidectomy for Pain Control. AB - Hashimoto's thyroiditis (HT) usually presents as painless thyroid swelling. Painful pediatric HT is a rare condition with limited literature on pain management. We report a 15-year-old female who presented with 4 weeks history of fatigue, malaise and progressive, painful midline thyroid swelling. There was no difficulty in swallowing, no fever or recent upper respiratory infection symptoms. Exam was remarkable for diffusely enlarged, very tender, and non nodular thyroid. Thyroid function tests, C-reactive protein, and complete blood count were normal. Ultrasound revealed diffusely enlarged non-nodular, non-cystic gland with mild increased vascularity. Diagnosis of HT was confirmed by biopsy and thyroid antibodies. Over a 6 week period, pain management with ibuprofen, levothyroxine, corticosteroid, gabapentin and amitriptyline was unsuccessful. Ultimately, total thyroidectomy resulted in complete resolution of thyroid pain. We can conclude that thyroidectomy may be considered for the rare case of painful HT in children. PMID- 26500746 TI - Rare but Lethal Disease of Childhood: Metastatic, Muscle Invasive Bladder Cancer. AB - Bladder cancer is the most common malignancy of urinary tract and the seventh most common cancer in men with the peak incidence in the sixth decade of life. Our knowledge about bladder tumors in pediatric age group mainly relies on case series. The reported cases are mostly low grade and non-muscle invasive. We herein present a case of a 17-year-old male with metastatic high-grade muscle invasive bladder cancer who was presented with macroscopic hematuria and flank pain. PMID- 26500747 TI - Adrenal Hypoplasia Congenita: A Rare Cause of Primary Adrenal Insufficiency and Hypogonadotropic Hypogonadism. AB - Primary adrenal insufficiency is defined by the impaired synthesis of adrenocortical hormones due to an intrinsic disease of the adrenal cortex. Determining its etiology is crucial to allow adequate long-term management and genetic counseling. We report the case of a male adolescent that presented in the neonatal period with adrenal crisis and received replacement therapy for primary adrenal insufficiency. During follow-up, adrenal hypoplasia congenita (AHC) was suspected given his persistently raised adrenocorticotropic hormone levels, with markedly low 17-OH progesterone and androstenedione levels. DNA sequence analysis revealed a mutation in NR0B1 gene (c.1292delG), confirming the diagnosis. Delayed puberty and persistent low levels of gonadotropins led to testosterone replacement therapy. X-linked AHC is a rare cause of primary adrenal insufficiency and hypogonadotropic hypogonadism, related to mutations in NR0B1 gene. Despite its rarity, AHC should be considered in patients who present with primary adrenal failure, low levels of 17-OH progesterone and hypogonadotropic hypogonadism. PMID- 26500748 TI - Recurrent Rhino-Ocular-Cerebral Mucormycosis in a Leukemic Child: A Case Report and Review of Pediatric Literature. AB - Mucormycosis is an uncommon but severe fungal infection, typically observed in immunocompromized patients. We report a case of acute lymphoblastic leukemia complicated by rhino-oculo-cerebral mucormycosis in a pediatric patient. Combination lipid polyene-echinocandin therapy, along with surgical debridement appeared to be effective. Nevertheless, a severe relapse occurred during posaconazole prophylaxis; antifungal therapy, hemimaxillectomy and suspension of chemotherapy were performed. Although mucormycosis is a frequently lethal infection, prompt diagnosis and aggressive treatment can be successful even in cases of relapse. PMID- 26500749 TI - Fecal Impaction Causing Pelvic Venous Compression and Edema. AB - Chronic constipation is a common condition which may result in fecal impaction. A 13-year-old male with chronic constipation and encopresis presented with fecal impaction for three weeks. The impaction caused abdominal pain, distension, encopresis, and decreased oral intake. He was found in severe distress with non pitting edema of his feet and ankles along with perineal edema. The pedal edema worsened after receiving a fluid bolus, so concern arose for venous compression or a thrombus. A Duplex Ultrasound demonstrated changes in the venous waveforms of the bilateral external iliac and common femoral veins without thrombosis. Manual disimpaction and polyethylene glycol 3350 with electrolytes resolved the pedal and perineal edema. Four months later, he had soft bowel movements without recurrence of the edema. A repeat Duplex Ultrasound was normal. We present a child in whom severe fecal impaction caused pelvic venous compression resulting in bilateral pedal and perineal edema. PMID- 26500750 TI - Lessons from Prenatal Care Provider-Based Recruitment into the National Children's Study. AB - In response to recruitment difficulties experienced by the National Children's Study, alternatives to the door-to-door recruitment method were pilot tested. This report describes outcomes, successes, and challenges of recruiting women through prenatal care providers in Benton County, Arkansas, USA. Eligible women residing in 14 randomly selected geographic segments were recruited. Data were collected during pregnancy, at birth, and at 3, 6, 9, 12, 18, and 24 months postpartum. Participants were compared to non-enrolled eligible women through birth records. Of 6402 attempts to screen for address eligibility, 468 patients were potentially eligible. Of 221 eligible women approached to participate, 151 (68%) enrolled in the 21-year study. Enrolled women were similar to non-enrolled women in age, marital status, number of prenatal care visits, and gestational age and birth weight of the newborn. Women enrolled from public clinics were more likely to be Hispanic, lower educated, younger and unmarried than those enrolled from private clinics. Sampling geographic areas from historical birth records failed to produce expected equivalent number of births across segments. Enrollment of pregnant women from prenatal care providers was successful. PMID- 26500751 TI - Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex. AB - BACKGROUND: RBFOX1 (also known as FOX1 or A2BP1) regulates alternative splicing of a variety of transcripts crucial for neuronal functions. Physiological significance of RBFOX1 during brain development is seemingly essential since abnormalities in the gene cause autism spectrum disorder (ASD) and other neurodevelopmental and neuropsychiatric disorders such as intellectual disability, epilepsy, attention deficit hyperactivity disorder, and schizophrenia. RBFOX1 was also shown to serve as a "hub" in ASD gene transcriptome network. However, the pathophysiological significance of RBFOX1 gene abnormalities remains to be clarified. METHODS: To elucidate the pathophysiological relevance of Rbfox1, we performed a battery of in vivo and in vitro analyses of the brain-specific cytoplasmic isoform, Rbfox1-iso2, during mouse corticogenesis. In vivo analyses were based on in utero electroporation, and the role of Rbfox1-iso2 in cortical neuron migration, neurogenesis, and morphology was investigated by morphological methods including confocal laser microscope-assisted time-lapse imaging. In vitro analyses were carried out to examine the morphology of primary cultured mouse hippocampal neurons. RESULTS: Silencing of Rbfox1-iso2 in utero caused defects in the radial migration and terminal translocation of cortical neurons during corticogenesis. Time-lapse imaging revealed that radial migration was apparently impaired by dysregulated nucleokinesis. Rbfox1-iso2 also regulated neuronal network formation in vivo since axon extension to the opposite hemisphere and dendritic arborization were hampered by the knockdown. In in vitro analyses, spine density and mature spine number were reduced in Rbfox1-iso2-deficient hippocampal neurons. CONCLUSIONS: Impaired Rbfox1-iso2 function was found to cause abnormal corticogenesis during brain development. The abnormal process may underlie the basic pathophysiology of ASD and other neurodevelopmental disorders and may contribute to the emergence of the clinical symptoms of the patients with RBFOX1 gene abnormalities. PMID- 26500753 TI - Colil: a database and search service for citation contexts in the life sciences domain. AB - BACKGROUND: To promote research activities in a particular research area, it is important to efficiently identify current research trends, advances, and issues in that area. Although review papers in the research area can suffice for this purpose in general, researchers are not necessarily able to obtain these papers from research aspects of their interests at the time they are required. Therefore, the utilization of the citation contexts of papers in a research area has been considered as another approach. However, there are few search services to retrieve citation contexts in the life sciences domain; furthermore, efficiently obtaining citation contexts is becoming difficult due to the large volume and rapid growth of life sciences papers. RESULTS: Here, we introduce the Colil (Comments on Literature in Literature) database to store citation contexts in the life sciences domain. By using the Resource Description Framework (RDF) and a newly compiled vocabulary, we built the Colil database and made it available through the SPARQL endpoint. In addition, we developed a web-based search service called Colil that searches for a cited paper in the Colil database and then returns a list of citation contexts for it along with papers relevant to it based on co-citations. The citation contexts in the Colil database were extracted from full-text papers of the PubMed Central Open Access Subset (PMC OAS), which includes 545,147 papers indexed in PubMed. These papers are distributed across 3,171 journals and cite 5,136,741 unique papers that correspond to approximately 25 % of total PubMed entries. CONCLUSIONS: By utilizing Colil, researchers can easily refer to a set of citation contexts and relevant papers based on co-citations for a target paper. Colil helps researchers to comprehend life sciences papers in a research area more efficiently and makes their biological research more efficient. PMID- 26500752 TI - Platelet studies in autism spectrum disorder patients and first-degree relatives. AB - BACKGROUND: Platelets have been proven to be a useful cellular model to study some neuropathologies, due to the overlapping biological features between neurons and platelets as granule secreting cells. Altered platelet dense granule morphology was previously reported in three autism spectrum disorder (ASD) patients with chromosomal translocations that disrupted ASD candidate genes NBEA, SCAMP5, and AMYSIN, but a systematic analysis of platelet function in ASD is lacking in contrast to numerous reports of elevated serotonin levels in platelets and blood as potential biomarker for ASD. METHODS: We explored platelet count, size, epinephrine-induced activation, and dense granule ATP secretion in a cohort of 159 ASD patients, their 289 first-degree relatives (103 unaffected siblings, 99 mothers, and 87 fathers), 45 adult controls, and 65 pediatric controls. For each of the responses separately, a linear mixed model with gender as a covariate was used to compare the level between groups. We next investigated the correlation between platelet function outcomes and severity of impairments in social behavior (social responsiveness score (SRS)). RESULTS: The average platelet count was increased in ASD patients and siblings vs. controls (ASD 320.3 * 10(9)/L, p = 0.003; siblings 332.0 * 10(9)/L, p < 0.001; controls 283.0 * 10(9)/L). The maximal platelet secretion-dependent aggregation response to epinephrine was not significantly lower for ASD patients. However, secondary wave responses following stimulation with epinephrine were more frequently delayed or absent compared to controls (ASD 52 %, siblings 45 %, parents 53 %, controls 22 %, p = 0.002). In addition, stimulated release of ATP from dense granules was reduced in ASD patients, siblings, and parents vs. controls following activation of platelets with either collagen (ASD 1.54 MUM, p = 0.001; siblings 1.51 MUM, p < 0.001; parents 1.67 MUM, p = 0.021; controls 2.03 MUM) or ADP (ASD 0.96 MUM, p = 0.003; siblings 1.00 MUM, p = 0.012; parents 1.17 MUM, p = 0.21; controls 1.40 MUM). Plasma serotonin levels were increased for ASD patients (n = 20, p = 0.005) and siblings (n = 20, p = 0.0001) vs. controls (n = 16). No significant correlations were found in the different groups between SRS scores and count, size, epinephrine aggregation, or ATP release. CONCLUSIONS: We report increased platelet counts, decreased platelet ATP dense granule secretion, and increased serotonin plasma levels not only in ASD patients but also in their first-degree relatives. This suggests that potential genetic factors associated with platelet counts and granule secretion can be associated with, but are not fully penetrant for ASD. PMID- 26500754 TI - RDF2Graph a tool to recover, understand and validate the ontology of an RDF resource. AB - BACKGROUND: Semantic web technologies have a tremendous potential for the integration of heterogeneous data sets. Therefore, an increasing number of widely used biological resources are becoming available in the RDF data model. There are however, no tools available that provide structural overviews of these resources. Such structural overviews are essential to efficiently query these resources and to assess their structural integrity and design, thereby strengthening their use and potential. RESULTS: Here we present RDF2Graph, a tool that automatically recovers the structure of an RDF resource. The generated overview allows to create complex queries on these resources and to structurally validate newly created resources. CONCLUSION: RDF2Graph facilitates the creation of complex queries thereby enabling access to knowledge stored across multiple RDF resources. RDF2Graph facilitates creation of high quality resources and resource descriptions, which in turn increases usability of the semantic web technologies. PMID- 26500755 TI - Risk factors for endoscopic sedation reversal events: a five-year retrospective study. AB - OBJECTIVE: Conscious sedation is widely used in endoscopic practice but is not without risk. We aimed to determine the frequency of sedation complications requiring reversal, and to identify potential patient and procedural risk factors. DESIGN: A retrospective study of all gastrointestinal endoscopic procedures performed under conscious sedation, in a large three-campus tertiary referral endoscopic centre, between 12 October 2007 and 31 December 2012 (n=52 553). Flumazenil or naloxone administration was used as a marker of sedation complications requiring reversal. Reversal cases were analysed for associations with sedation dose, patient American Society of Anesthesiologists (ASA) grade, age and type of procedure undertaken. RESULTS: In total, 149 sedation reversals occurred, representing 0.28% of all sedated endoscopic procedures carried out. Endoscopic Retrograde Cholangiopancreatography (ERCP) and increasing patient ASA grade were positively associated with sedation reversal (p<0.05). Mean midazolam dose was highest for ERCP (4.9+/-2.9 mg) and lowest for flexible sigmoidoscopy (1.7+/-0.6 mg; p<0.01). Mean opioid dose (calculated as pethidine equivalent) was highest for ERCP (62.9+/-38.7 mg) and lowest for gastroscopy (6.9+/-13.5 mg; p<0.01). Maximum doses of midazolam or opioid recommended by the British Society of Gastroenterology were exceeded in 7.4% and 14.1% of reversals, respectively. CONCLUSIONS: ERCP procedures and higher patient ASA grade were associated with an increased risk of conscious sedation-related complications requiring reversal. In these high-risk groups, alternative sedation strategies should be considered and tested. Prospective studies are needed to further explore risk factors that may help predict adverse sedation outcomes. PMID- 26500756 TI - Clinical trial: free fatty acid suppositories compared with enema as bowel preparation for flexible sigmoidoscopy. AB - OBJECTIVES: The purpose of this trial was to evaluate the efficacy and safety of recently developed suppositories containing free fatty acids as a bowel-cleansing agent prior to flexible sigmoidoscopy and compare them with Klyx (docusate sodium/sorbitol). DESIGN: A controlled, non-inferiority, single-blind, randomised study on outpatients undergoing flexible sigmoidoscopy. SETTING: Department of Gastroenterology, Landspitali-University Hospital and endoscopic clinic. PATIENTS: 53 outpatients undergoing flexible sigmoidoscopy. INTERVENTION: Participants were randomised to receive either free fatty acid suppositories (28) or a standard bowel preparation with Klyx enema (25). In the study group, two suppositories were administered the evening before as well as 2 h prior to the sigmoidoscopy. In the control group, Klyx enema (120 mL) was administered the evening before and repeated 2 h prior to the procedure. MAIN OUTCOME MEASUREMENTS: Quality of the bowel cleansing, height of scope insertion and safety. RESULTS: The mean height of scope insertion and bowel cleansing was 43 cm (SD=13.4) in the study group and 48 cm (SD=10.4) in the control group (NS). The investigating physicians were less satisfied with the bowel preparation in the study group compared with the control group with a difference of 20% (p<0.016). The amount of faeces noted in the rectum was similar in both groups with no significant difference (p<0.56). No serious side effects, toxic reaction or irritation were observed. CONCLUSIONS: The suppositories are well tolerated with no significant side effects. The suppositories had distinct bowel emptying effect and as effective as Klyx in rectal cleansing. Although physician's satisfaction was slightly lower, the height of scope insertion was similar. TRIAL REGISTRATION NUMBER: EudraCT nr.: 2010-018761-35. PMID- 26500757 TI - Gastrulation occurs in multiple phases at two distinct sites in Latrodectus and Cheiracanthium spiders. AB - BACKGROUND: The longstanding canonical model of spider gastrulation posits that cell internalization occurs only at a unitary central blastopore; and that the cumulus (dorsal organizer) arises from within the early deep layer by cell-cell interaction. Recent work has begun to challenge the canonical model by demonstrating cell internalization at extra-blastoporal sites in two species (Parasteatoda tepidariorum and Zygiella x-notata); and showing in Zygiella that the prospective cumulus internalizes first, before other cells are present in the deep layer. The cell behaviors making up spider gastrulation thus appear to show considerable variation, and a wider sampling of taxa is indicated. RESULTS: We evaluated the model in three species from two families by direct observation of living embryos. Movements of individual cells were traced from timelapse recordings and the origin and fate of the cumulus determined by CM-DiI labeling. We show that there are two distinct regions of internalization: most cells enter the deep layer via the central blastopore but many additional cells ingress via an extra-blastoporal ring, either at the periphery of the germ disc (Latrodectus spp.) or nearer the central field (Cheiracanthium mildei). In all species, the cumulus cells internalize first; this is shown by tracing cells in timelapse, histology, and by CM-DiI injection into the deep layer. Injection very early in gastrulation labels only cumulus mesenchyme cells whereas injections at later stages label non-cumulus mesoderm and endoderm. CONCLUSIONS: We propose a revised model to accommodate the new data. Our working model has the prospective cumulus cells internalizing first, at the central blastopore. The cumulus cells begin migration before other cells enter the deep layer. This is consistent with early specification of the cumulus and suggests that cell-cell interaction with other deep layer cells is not required for its function. As the cumulus migrates, additional mesendoderm internalizes at two distinct locations: through the central blastopore and at an extra-blastoporal ring. Our work thus demonstrates early, cell-autonomous behavior of the cumulus and variation in subsequent location and timing of cell internalization during gastrulation in spiders. PMID- 26500758 TI - Cytotoxic and targeted therapy for treatment of pseudomyogenic hemangioendothelioma. AB - Pseudomyogenic hemangioendothelioma (PMH) is a recently described, indolent vascular tumor that usually presents in the distal extremities. PMH typically has a multi-focal presentation and can involve several tissue planes including the dermis, subcutis, muscle, and bone. This soft tissue tumor predominantly affects men between 20 and 50 years of age. PMH tumors typically are resected but frequently recur locally; thus, more efficacious treatment options are needed. Herein, we report two cases of patients with PMH who were treated with systemic therapy. To the best of our knowledge, our report is the first to describe a response of PMH either to gemcitabine/taxane cytotoxic chemotherapy or to a mammalian target of rapamycin inhibitor. In the first case, a 45-year-old man with PMH of the right ilium was treated with gemcitabine plus docetaxel. Although chemotherapy was ultimately halted owing to gemcitabine-induced pulmonary toxicity, positron emission tomography-computer tomography scans taken after three cycles of gemcitabine plus docetaxel illustrated a noticeable response to the regimen. In the second case, a 22-year-old man with PMH of the right distal femur and metastases in the left ilium showed no response to gemcitabine plus docetaxel therapy, but underwent surgical resection after cisplatin and doxorubicin resulted in stable disease. DNA sequencing of his tumor revealed the presence of a tuberous sclerosis 1 (TSC1) mutation, so daily everolimus, which inhibits mammalian target of rapamycin, was started. Two months after beginning everolimus, the patient underwent magnetic resonance imaging of the pelvis, which revealed mild shrinkage of PMH metastases in the left iliac bone. Despite the apparent heterogeneity of response to gemcitabine/taxane chemotherapy in our two patients, these two cases indicate that gemcitabine/taxane and mammalian target of rapamycin inhibitor may serve as systemic treatment options for PMH and warrant further investigation. PMID- 26500759 TI - Unveiling the hidden function of long non-coding RNA by identifying its major partner-protein. AB - Tens of thousands of long non-coding RNAs (lncRNAs) have been discovered in eukarya, but their functions are largely unknown. Fortunately, lncRNA-protein interactions may offer details of how lncRNAs play important roles in various biological processes, thus identifying proteins associated with lncRNA is critical. Here we review progress of molecular archetypes that lncRNAs execute as guides, scaffolds, or decoys for protein, focusing on advantages, shortcomings and applications of various conventional and emerging technologies to probe lncRNAs and protein interactions, including protein-centric biochemistry approaches such as nRIP and CLIP, and RNA-centric biochemistry approaches such as ChIRP, CHART and RAP. Overall, this review provides strategies for probing interactions between lncRNAs and protein. PMID- 26500760 TI - Human in vitro induced T regulatory cells and memory T cells share common demethylation of specific FOXP3 promoter region. AB - BACKGROUND: The FOXP3 gene is the master regulator for T regulatory cells and is under tight DNA methylation control at the Treg specific demethylated region (TSDR) in its first intron. This said, methylation of its promoter region, the significance of which is unknown, has also been associated with various immune related disease states such as asthma, food allergy, auto-immunity and cancer. Here, we used induced T regulatory cells (iTreg) as a target cell population to identify candidate hypomethylated CpG sites in the FOXP3 gene promoter to design a DNA methylation quantitative assay for this region. FINDINGS: Three CpG sites at the promoter region showed clear demethylation pattern associated with high FOXP3 expression after activation in presence of TGFbeta and were selected as primary targets to design methylation-dependent RT-PCR primers and probes. We then examined the methylation of this 'inducible-promoter-demethylated-region' (IPDR) in various FOXP3+ T cell subsets. Both naive and memory thymic-derived Treg cells were found to be fully demethylated at both the IPDR and TSDR. Interestingly, in addition to iTregs, both CD25- and CD25(lo) conventional memory CD4+CD45RA- T cells displayed a high fraction of IPDR demethylated cells in absence of TSDR demethylation. CONCLUSION: This implies that the fraction of memory T cells should be taken in account when interpreting FOXP3 promoter methylation results from clinical studies. This approach, which is available for testing in clinical samples could have diagnostic and prognostic value in patients with immune or auto-inflammatory diseases. PMID- 26500761 TI - Vascularization mediated by mesenchymal stem cells from bone marrow and adipose tissue: a comparison. AB - Tissue-engineered constructs are promising to overcome shortage of organ donors and to reconstruct at least parts of injured or diseased tissues or organs. However, oxygen and nutrient supply are limiting factors in many tissues, especially after implantation into the host. Therefore, the development of a vascular system prior to implantation appears crucial. To develop a functional vascular system, different cell types that interact with each other need to be co cultured to simulate a physiological environment in vitro. This review provides an overview and a comparison of the current knowledge of co-cultures of human endothelial cells (ECs) with human adipose tissue-derived stem/stromal cells (ASCs) or bone marrow-mesenchymal stem cells (BMSCs) in three dimensional (3D) hydrogel matrices. Mesenchymal stem cells (MSCs), BMSCs or ASCs, have been shown to enhance vascular tube formation of ECs and to provide a stabilizing function in addition to growth factor delivery and permeability control for ECs. Although phenotypically similar, MSCs from different tissues promote tubulogenesis through distinct mechanisms. In this report, we describe differences and similarities regarding molecular interactions in order to investigate which of these two cell types displays more favorable characteristics to be used in clinical applications. Our comparative study shows that ASCs as well as BMSCs are both promising cell types to induce vascularization with ECs in vitro and consequently are promising candidates to support in vivo vascularization. PMID- 26500764 TI - Important considerations for microRNA extraction methods from whole blood and peripheral blood mononuclear cells. AB - MicroRNAs are non-coding RNAs that negatively regulate mRNA expression and play significant roles in both health and disease. Differential microRNA expression has been used to aid diagnosis and discriminate disease stages. The accuracy and reliability of microRNA expression measurement is of utmost importance. For diagnostic investigations, microRNA expression in human peripheral blood is commonly detected using total RNA extracted using different methods. To date, no convincing data have been available showing whether microRNA expression levels are comparable when total RNA has been extracted from whole blood or peripheral blood mononuclear cells (PBMCs). The present study examined miR-146a-5p and miR 155-5p expression using total RNA extracted in parallel from whole blood and PBMCs of 14 healthy volunteers. MicroRNA expression levels were significantly different between whole blood and PBMCs. No significant difference was observed in microRNA expression between fresh and cryopreserved PBMCs (p=0.125 for both). Further observations revealed that gender differences did not influence miR-146a 5p or miR-155-5p expression regardless of using whole blood (p = 0.797 and 1.00 respectively) or PBMC (p = 0.190 and 0.898 respectively). Our results demonstrate that microRNA expression could be subjective to the methods used for total RNA extraction which highlights the importance of using uniform extraction methods. PMID- 26500763 TI - Evaluation of three therapeutic alternatives for the early treatment of ovine pregnancy toxaemia. AB - BACKGROUND: Ovine pregnancy toxaemia is a common metabolic disorder of ewes due to increased foetal energy requirements in late pregnancy. This pathology is a metabolic condition characterized by hypoglycaemia and hyperketonaemia resulting in the inability of the animal to maintain an adequate energy balance. The response to treatment is effective, if it is started in the early stages of the disease, when irreversible neurological injuries have not yet been established. The aim was to evaluate three therapeutic alternatives to effectively reverse the disease process in its early stages. For this, thirty adult Corriedale ewes, pregnant with a single lamb, were randomly separated in three groups of ten animals each, at day 130 of gestation. From that day onwards, ewes were locked up for forage fasting until glycaemia reached clinical values defining sub-clinical pregnancy toxaemia (1.59 +/- 0.24 mmol/L). After fasting, ewes grazed and received a treatment for 4 days: 50 ml i.v. infusions of hypertonic glucose and 20 UI insulin/ewe/day s.c. or 100 ml/sheep/12 h of glycerol together with propylene glycol oral solution or fed with pasture supplemented with two daily intakes 300 g/sheep of cracked corn. Glycaemia and beta-hydroxybutyrate were determined in all the animals from the beginning of fasting until the completion of the treatment. RESULTS: Fasting caused a decline in blood glucose in the 3 groups. This decline continued until fasting was withdrawn and treatment began. Thereafter blood glucose increased in all three groups, although in the group supplemented with glycerol and propylene glycol it started to increase significantly after 12 h. The values of beta-hydroxybutyrate decreased in the 3 groups at the start of treatment, and this decline was more pronounced earlier on and in the group supplemented with glycerol and propylene glycol. We found no significant differences between all experimental groups. No animal showed clinical signs of pregnancy toxaemia throughout the research. CONCLUSIONS: The three treatments administered to sheep affected by sub-clinical pregnancy toxaemia were able to restore normal concentration of glucose and beta hydroxybutyrate in blood, although per os administration of 100 ml/sheep/12 h of glycerol with propylene glycol, was the most successful treatment, normalizing the aforementioned biochemical parameters in a shorter time. PMID- 26500762 TI - Arrhythmogenic right ventricular cardiomyopathy secondary to adipose infiltration as a cause of episodic collapse in a horse. AB - A 15-year-old Clydesdale cross gelding was investigated and managed over a 2-year period for intermittent collapse. The horse presented initially after an observed episode of collapse at rest, and had a resting tachycardia, elevated Cardiac Troponin I and polycythaemia. Multiple dysrhythmias were detected on telemetric electrocardiography. Vital parameters, cardiac rhythm and red cell count returned to reference range with prolonged rest but further resting syncopal episodes were observed, and due to safety concerns and limited treatment options the horse was euthanased. Post mortem evaluation identified extensive infiltration and replacement of right and left ventricular myocardial fibres with adipose and fibrous tissue, consistent with arrhythmogenic right ventricular cardiomyopathy. This report provides further information regarding the clinical and pathological features of this rarely reported condition. PMID- 26500765 TI - The increase in hydric volume is associated to contractile impairment in the calf after the world's most extreme mountain ultra-marathon. AB - BACKGROUND: Studies have recently focused on the effect of running a mountain ultra-marathon (MUM) and their results show muscular inflammation, damage and force loss. However, the link between peripheral oedema and muscle force loss is not really established. We tested the hypothesis that, after a MUM, lower leg muscles' swelling could be associated with muscle force loss. The knee extensor (KE) and the plantar flexor (PF) muscles' contractile function was measured by supramaximal electrical stimulations, potentiated low- and high-frequency doublets (PS10 and PS100) of the KE and the PF were measured by transcutaneous electrical nerve stimulation and bioimpedance was used to assess body composition in the runners (n = 11) before (Pre) and after (Post) the MUM and compared with the controls (n = 8). RESULTS: The maximal voluntary contraction of the KE and the PF significantly decreased by 20 % Post-MUM in the runners. Hydration of the non-fat mass (NF-Hyd) and extracellular water volume (Ve) were increased by 12 % Post-MUM (p < 0.001) in the runners. Calf circumference (+2 %, p < 0.05) was also increased. Significant relationships were found for percentage increases in Ve and NF-Hyd with percentage decrease in PS10 of the PF (r = -0.68 and r = -0.70, p < 0.05) and with percentage increase of calf circumference (r = 0.72 and r = 0.73, p < 0.05) in the runners. CONCLUSIONS: The present study suggests that increases in circumference and in hydric volume are associated to contractile impairment in the calf in ultra-marathon runners. PMID- 26500767 TI - Rcorrector: efficient and accurate error correction for Illumina RNA-seq reads. AB - BACKGROUND: Next-generation sequencing of cellular RNA (RNA-seq) is rapidly becoming the cornerstone of transcriptomic analysis. However, sequencing errors in the already short RNA-seq reads complicate bioinformatics analyses, in particular alignment and assembly. Error correction methods have been highly effective for whole-genome sequencing (WGS) reads, but are unsuitable for RNA-seq reads, owing to the variation in gene expression levels and alternative splicing. FINDINGS: We developed a k-mer based method, Rcorrector, to correct random sequencing errors in Illumina RNA-seq reads. Rcorrector uses a De Bruijn graph to compactly represent all trusted k-mers in the input reads. Unlike WGS read correctors, which use a global threshold to determine trusted k-mers, Rcorrector computes a local threshold at every position in a read. CONCLUSIONS: Rcorrector has an accuracy higher than or comparable to existing methods, including the only other method (SEECER) designed for RNA-seq reads, and is more time and memory efficient. With a 5 GB memory footprint for 100 million reads, it can be run on virtually any desktop or server. The software is available free of charge under the GNU General Public License from https://github.com/mourisl/Rcorrector/. PMID- 26500766 TI - Potential return on investment for implementation of perioperative goal-directed fluid therapy in major surgery: a nationwide database study. AB - BACKGROUND: Preventable postsurgical complications are increasingly recognized as a major clinical and economic burden. A recent meta-analysis showed a 17-29 % decrease in postoperative morbidity with goal-directed fluid therapy. Our objective was to estimate the potential economic impact of perioperative goal directed fluid therapy. METHODS: We studied 204,680 adult patients from 541 US hospitals who had a major non-cardiac surgical procedure between January 2011 and June 2013. Hospital costs (including 30-day readmission costs) in patients with and without complications were extracted from the Premier Inc. research database, and potential cost-savings associated with a 17-29 % decrease in postoperative morbidity were estimated. RESULTS: A total of 76,807 patients developed one or more postsurgical complications (morbidity rate 37.5 %). In patients with and without complications, hospital costs were US$27,607 +/- 32,788 and US$15,783 +/- 12,282 (p < 0.0001), respectively. Morbidity rate was anticipated to decrease to 26.6-31.1 % with goal-directed fluid therapy, yielding potential gross cost savings of US$153-263 million for the study period, US$61-105 million per year, or US$754-1286 per patient. Potential savings per patient were highly variable from one surgical procedure to the other, ranging from US$354-604 for femur and hip-fracture repair to US$3515-5996 for esophagectomies. When taking into account the volume of procedures, the total potential savings per year were the most significant (US$32-55 million) for colectomies. CONCLUSIONS: Postsurgical complications occurred in more than one third of our study population and had a dramatic impact on hospital costs. With goal-directed fluid therapy, potential cost-savings per patient were US$754-1286. The highest cost-savings per year were observed for colectomies. These projections should help hospitals estimate the return on investment when considering the implementation of goal-directed fluid therapy. PMID- 26500768 TI - Optimized production of transgenic buffalo embryos and offspring by cytoplasmic zygote injection. AB - BACKGROUND: Cytoplasmic injection of exogenous DNA into zygotes is a promising technique to generate transgenic livestock. However, it is still relatively inefficient and has not yet been demonstrated to work in buffalo. We sought to improve two key technical parameters of the procedure, namely i) how much linear DNA to inject and ii) when to inject it. For this, we introduced a constitutively expressed enhanced green fluorescent protein (EGFP) plasmid into buffalo zygotes. RESULTS: First, we found that the proportion of EGFP-expressing blastocysts derived from zygotes injected with 20 or 50 ng/MUL DNA was significantly higher than from those injected with 5 MUg/mL. However, 50 ng/MUL exogenous DNA compromised blastocyst development compared to non-injected IVF controls. Therefore the highest net yield of EGFP-positive blastocysts was achieved at 20 ng/MUL DNA. Second, zygotes injected early (7-8 h post-insemination [hpi]) developed better than those injected at mid (12-13 hpi) or late (18-19 hpi) time points. Blastocysts derived from early injections were also more frequently EGFP positive. As a consequence, the net yield of EGFP-expressing blastocysts was more than doubled using early vs late injections (16.4 % vs 7.7 %). With respect to blastocyst quality, we found no significant difference in cell numbers of EGFP positive blastocysts vs non-injected blastocysts. Following embryo transfer of six EGFP-positive blastocysts into four recipient animals, two viable buffalo calves were born. Biopsied ear tissues from both buffalo calves were analyzed for transgene presence and expression by Southern blot, PCR and confocal laser scanning microscopy, respectively. This confirmed that both calves were transgenic. CONCLUSIONS: Our cytoplasmic injection protocol improved generation of transgenic embryos and resulted in the first transgenic buffalo calves produced by this method. PMID- 26500769 TI - A review of the effects of dietary organic acids fed to swine. AB - Animal production depends on nutrient utilization and if done there is an accelerated momentum towards growth with a low cost to feed ratio Public concern over the consumption of pork with antibiotic residues of the animals fed with antibiotic growth promoters (AGP) has paved the way to use other additives like herbs and their products, probiotics, prebiotics etc. Numerous feed additives are in vogue for achieving this target and one such classical example is the usage of organic acids and their salts. Usage of organic acids was in progress for over four decades. Early weaned piglets are (3-4 weeks age) exposed to stress with a reduced feed intake, little or no weight gain. This post weaning lag period is due to a limited digestive and absorptive capacity due to insufficient production of hydrochloric acid, pancreatic enzymes and sudden changes in feed consistency and intake. Lowering dietary pH by weak organic acids was found to overcome these problems. The main activity of organic acids is associated with a reduction in gastric pH converting the inactive pepsinogen to active pepsin for effective protein hydrolysis. Organic acids are both bacteriostatic and bactericidal. Lactic acid has been reported to reduce gastric pH and delay the multiplication of an enterotoxigenic E. coli. These acids are the intermediary products in Kreb's cycle and thus act as an energy source preventing the tissue breakdown resulting from gluconeogenesis and lipolysis. Excretion of supplemental minerals and nitrogen are minimized with organic acids as these form complexes with minerals and aids for their bio-availability. Short chain fatty cids like acetic, propionic and n-butyric acid produced by microbial fermentation of dietary fibre in the large intestines may increase the proliferation of epithelial cells and have stimulatory effects on both endocrine and exocrine pancreatic secretions in pigs. Organic acids also enhances apparent total tract digestibility and improves growth performance. It is concluded that organic acids and their salts increase the protein utilization especially in weaner pigs and improves production indices. PMID- 26500771 TI - Erratum to: Review of the nutritional benefits and risks related to intense sweeteners. AB - [This corrects the article DOI: 10.1186/s13690-015-0092-x.]. PMID- 26500770 TI - Targeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth. AB - BACKGROUND: Numerous studies have demonstrated that functional mitochondria are required for tumorigenesis, suggesting that mitochondrial oxidative phosphorylation (OXPHOS) might be a potential target for cancer therapy. In this study, we investigated the effects of BAY 87-2243, a small molecule that inhibits the first OXPHOS enzyme (complex I), in melanoma in vitro and in vivo. RESULTS: BAY 87-2243 decreased mitochondrial oxygen consumption and induced partial depolarization of the mitochondrial membrane potential. This was associated with increased reactive oxygen species (ROS) levels, lowering of total cellular ATP levels, activation of AMP-activated protein kinase (AMPK), and reduced cell viability. The latter was rescued by the antioxidant vitamin E and high extracellular glucose levels (25 mM), indicating the involvement of ROS-induced cell death and a dependence on glycolysis for cell survival upon BAY 87-2243 treatment. BAY 87-2243 significantly reduced tumor growth in various BRAF mutant melanoma mouse xenografts and patient-derived melanoma mouse models. Furthermore, we provide evidence that inhibition of mutated BRAF using the specific small molecule inhibitor vemurafenib increased the OXPHOS dependency of BRAF mutant melanoma cells. As a consequence, the combination of both inhibitors augmented the anti-tumor effect of BAY 87-2243 in a BRAF mutant melanoma mouse xenograft model. CONCLUSIONS: Taken together, our results suggest that complex I inhibition has potential clinical applications as a single agent in melanoma and also might be efficacious in combination with BRAF inhibitors in the treatment of patients with BRAF mutant melanoma. PMID- 26500772 TI - Networks' Characteristics Matter for Systems Biology. AB - A fundamental goal of systems biology is to create models that describe relationships between biological components. Networks are an increasingly popular approach to this problem. However, a scientist interested in modeling biological (e.g., gene expression) data as a network is quickly confounded by the fundamental problem: how to construct the network? It is fairly easy to construct a network, but is it the network for the problem being considered? This is an important problem with three fundamental issues: How to weight edges in the network in order to capture actual biological interactions? What is the effect of the type of biological experiment used to collect the data from which the network is constructed? How to prune the weighted edges (or what cut-off to apply)? Differences in the construction of networks could lead to different biological interpretations. Indeed, we find that there are statistically significant dissimilarities in the functional content and topology between gene co-expression networks constructed using different edge weighting methods, data types, and edge cut-offs. We show that different types of known interactions, such as those found through Affinity Capture-Luminescence or Synthetic Lethality experiments, appear in significantly varying amounts in networks constructed in different ways. Hence, we demonstrate that different biological questions may be answered by the different networks. Consequently, we posit that the approach taken to build a network can be matched to biological questions to get targeted answers. More study is required to understand the implications of different network inference approaches and to draw reliable conclusions from networks used in the field of systems biology. PMID- 26500773 TI - Characterization of the human T cell response to in vitro CD27 costimulation with varlilumab. AB - BACKGROUND: Clinical targeting of TNFR family of receptors (CD40, CD134 and CD137) with immunostimulatory monoclonal antibodies has been successful in cancer immunotherapy. However, targeting of CD27 with a mAb is a relatively new approach to provide costimulation of immune cells undergoing activation. Thus, activation of human CD27 (TNFRSF7) with a monoclonal antibody (varlilumab) has previously been demonstrated to result in T cell activation and anti-tumor activity in preclinical models, and is currently in early phase clinical trials in patients with advanced malignancies. In this study we used an in vitro system using human peripheral blood T cells to characterize the varlilumab-mediated costimulatory effects in combination with TCR stimulation in terms of phenotypic, transcriptional and functionality changes. METHODS: T cells were isolated from normal volunteer PBMCs using magnetic bead isolation kits and stimulated in vitro with plate bound anti-CD3 Ab (OKT3) and varlilumab or control Ab for 72 h. Activation profiles were monitored by ELISA or Luminex-based testing cytokine/chemokine releases, cell surface phenotyping for costimulatory and coinhibitory markers and CFSE dye dilution by proliferating T cells and Tregs. Changes in gene expression and transcriptome analysis of varlilumab-stimulated T cells was carried on Agilent Human whole genome microarray datasets using a suite of statistical and bioinformatic software tools. RESULTS: Costimulation of T cells with varlilumab required continuous TCR signaling as pre-activated T cells were unable to produce cytokines with CD27 signaling alone. Analysis of T cell subsets further revealed that memory CD4+ and CD8+ T cells were specifically activated with a bias toward CD8+ T lymphocyte proliferation. Activation was accompanied by upregulated cell surface expression of costimulatory [4-1BB, OX40, GITR and ICOS] and coinhibitory [PD-1] molecules. Importantly, varlilumab costimulation did not activate purified Tregs as measured by cytokine production, proliferation and suppression of dividing non-Treg T cells. Analysis of changes in gene expression during varlilumab stimulation of T cells revealed modulation of pro-inflammatory signatures consistent with cellular activation and proliferation, with the IL-2 pathway showing the highest frequency of gene modulation. CONCLUSIONS: Altogether, the data reveal the requirements and T cell subtype-specific effects of CD27 costimulation, and helps select relevant biomarkers for studying the effects of varlilumab in patients. PMID- 26500774 TI - Immune monitoring technology primer. AB - BACKGROUND: Recent biotechnological developments have resulted in increasing interest in immunology biomarkers. These biomarkers have potential clinical utility in the near future as predictors of treatment response. Hence, clinical validation of these predictive markers is critical. FINDINGS: The process of clinically validating a predictive biomarker is reviewed. Validation of a predictive biomarker requires quantifying the strength of a statistical interaction between marker and a treatment. Different study designs are considered. CONCLUSIONS: Clinical validation of immunology biomarkers can be demanding both in terms of time and resources, and careful planning and study design are critical. PMID- 26500775 TI - Prognostic impact of circulating Her-2-reactive T-cells producing pro- and/or anti-inflammatory cytokines in elderly breast cancer patients. AB - BACKGROUND: Treating elderly breast cancer patients remains a challenge but the increasing availability of immunotherapeutic approaches instills optimism that these tumours may also be susceptible to immune control. Because aging leads to a number of alterations in the immune system ("immunosenescence") reflecting potential exhaustion which could compromise immunomodulatory antibody therapy, here we have assessed the immunocompetence of elderly breast cancer patients compared with a group of younger patients, and related this to the 5-year survival of the former. METHODS: T-cell responses to Her-2 peptide pools in vitro were assessed by analyzing pro- and anti-inflammatory cytokine production by CD4+ and CD8+ T-cells in 40 elderly and 35 younger breast cancer patients. RESULTS: The proportions of older and younger patients whose peripheral T-cells responded to Her-2 peptides in vitro were found to be similar, although a significantly higher fraction of younger patients possessed IL-2-producing CD4+ Her-2-reactive T-cells than in the elderly (p = 0.03). However, IL-2 production did not impart a survival benefit to the latter. In contrast, there was a survival benefit of possessing Her-2-reactive CD8+ T-cells, but this was abrogated in patients if they also had CD4+ Her-2-responsive T-cells that producedIL-5 and/or IL-17 (p = 0.01). This resulted in a 5-yr survival rate of only 29 % compared to 76 % for patients whose her-2-reactive CD4+ T-cells did not produceIL-5 and/or IL-17. Additionally, patients whose CD8+ T-cells produced TNF had a significantly better survival than those that did not (93 % compared to 52 %, p = 0.01), whereas no survival benefit was attributable to possessing IFN-gamma-producing cells. CONCLUSIONS: Elderly breast cancer patients appear perfectly immunocompetent to respond to Her-2 peptide pools in vitro, with response patterns very similar to younger patients. The nature of this response is associated with 5-year survival of these elderly patients, suggesting that boosting anti-tumor responses and modulating the nature of the T-cell response is likely to be effective even in potentially immunosenescent elderly breast cancer patients, and might be useful for predicting which patients are most likely to benefit from such treatments. PMID- 26500777 TI - Introducing the clinical trials monitor: a new section of the journal for immunotherapy of cancer. PMID- 26500776 TI - Multispectral imaging of formalin-fixed tissue predicts ability to generate tumor infiltrating lymphocytes from melanoma. AB - BACKGROUND: Adoptive T cell therapy (ACT) has shown great promise in melanoma, with over 50 % response rate in patients where autologous tumor-reactive tumor infiltrating lymphocytes (TIL) can be cultured and expanded. A major limitation of ACT is the inability to generate or expand autologous tumor-reactive TIL in 25 45 % of patients tested. Methods that successfully identify tumors that are not suitable for TIL generation by standard methods would eliminate the costs of fruitless expansion and enable these patients to receive alternate therapy immediately. METHODS: Multispectral fluorescent immunohistochemistry with a panel including CD3, CD8, FoxP3, CD163, PD-L1 was used to analyze the tumor microenvironment in 17 patients with melanoma among our 36-patient cohort to predict successful TIL generation. Additionally, we compared tumor fragments and enzymatic digestion of tumor samples for efficiency in generating tumor-reactive TIL. RESULTS: Tumor-reactive TIL were generated from 21/36 (58 %) of melanomas and for 12/13 (92 %) tumors where both enzymatic and fragment methods were compared. TIL generation was successful in 10/13 enzymatic preparations and in 10/13 fragment cultures; combination of both methods resulted in successful generation of autologous tumor-reactive TIL in 12/13 patients. In 17 patients for whom tissue blocks were available, IHC analysis identified that while the presence of CD8(+) T cells alone was insufficient to predict successful TIL generation, the CD8(+) to FoxP3(+) ratio was predictive with a positive predictive value (PPV) of 91 % and negative-predictive value (NPV) of 86 %. Incorporation of CD163+ macrophage numbers and CD8:PD-L1 ratio did not improve the PPV. However, the NPV could be improved to 100 % by including the ratio of CD8(+):PD-L1(+) expressing cells. CONCLUSION: This is the first study to apply 7 color multispectral immunohistochemistry to analyze the immune environment of tumors from patients with melanoma. Assessment of the data using unsupervised hierarchical clustering identified tumors from which we were unable to generate TIL. If substantiated, this immune profile could be applied to select patients for TIL generation. Additionally, this biomarker profile may also indicate a pre existing immune response, and serve as a predictive biomarker of patients who will respond to checkpoint blockade. We postulate that expanding the spectrum of inhibitory cells and molecules assessed using this technique could guide combination immunotherapy treatments and improve response rates. PMID- 26500778 TI - Wintering North Pacific black-legged kittiwakes balance spatial flexibility and consistency. AB - BACKGROUND: Marine environments are inherently dynamic, yet marine predators are often long-lived and employ strategies where consistency, individual specialization, routine migrations, and spatial memory are key components to their foraging and life-history strategies. Intrinsic determinates of animal movements are linked to physiological and life-history traits (e.g. sex, colony, experience), while extrinsic influences occur as the result of an animal's interactions with either other animals or the environment (e.g. prey availability, weather, competition). Knowledge of the factors affecting animal movements is critical to understand energetic bottlenecks and population dynamics. Here, we attempt to understand the interaction of some of these factors on the winter distributions of a surface-feeding seabird in the North Pacific. Between 2008 and 2011, we tracked 99 black-legged kittiwakes breeding at St. Paul and St. George in the Pribilof Islands, Alaska using geolocation loggers. We tested for colony and sex differences in winter distributions, and individual spatial fidelity over two consecutive winters of 17 individuals. Then we linked tracking data to associated environmental conditions as proxies of prey availability (e.g. sea surface temperature, mesoscale eddies, chlorophyll a, and wind) to understand their influence on kittiwake space use at an ocean basin scale. RESULTS: Black-legged kittiwakes from both Pribilof Islands primarily wintered in pelagic sub-arctic waters, however, distributions spanned seven ecoregions of the North Pacific. There was a high degree of similarity in area use of birds from the two closely situated colonies and between sexes. Birds tracked for two consecutive years showed higher fidelity to wintering areas than occurred at random. Annual changes were apparent, as distributions were further north in 2009/10 than 2008/09 or 2010/11. This occurred because 70 % of birds remained in the Bering Sea in the fall of 2009, which corresponded with lower October sea surface temperatures than the other two years. CONCLUSIONS: Although individuals returned to wintering areas in consecutive years, our results suggest that under current conditions individual black-legged kittiwakes have a high capacity to alter winter distributions. PMID- 26500779 TI - Post-operative cardiac arrest induced by co-administration of amiodarone and dexmedetomidine: a case report. AB - We firstly report a postoperative hemodialysis patient who was co-administered with amiodarone and dexmedetomidine and developed severe bradycardia followed by cardiac arrest. A 79-year-old male patient underwent an amputation of the right lower extremity. The electrocardiogram of the patient showed a complete right bundle branch block with left anterior fascicular block before the anesthesia, and paroxysmal atrial tachycardia over 200 beats/min lasting 15 min was observed during surgery. After admission to the intensive care unit, the intensivist and the consultant cardiologist decided to treat tachycardia using amiodarone. The initial dosing of amiodarone and the maintenance infusion succeeded to decrease the heart rate. Approximately 2 h and a half after the start of dexmedetomidine infusion for sedation, the heart rate gradually declined and severe bradycardia suddenly followed by cardiac arrest was observed. Resuscitation was promptly initiated and the patient regained sinus rhythm without delay. In retrospective analysis, the monitoring record of the electrocardiogram revealed the marked atrioventricular conduction abnormalities. This is the first case report concerning a cardiac arrest induced by amiodarone and dexmedetomidine. PMID- 26500780 TI - Numerical analysis of in vivo platelet consumption data from ITP patients. AB - BACKGROUND: Numerical methods have recently allowed quantitative interpretation of in vivo murine platelet consumption data in terms of values for the random destruction rate constant (RD), intrinsic lifespan (LS), and the standard deviation of ln LS (SD), as well as the platelet production rate (PR) and age distribution (AD). But application of these methods to data obtained in thrombocytopenic patients is problematic for two reasons. First, such data has in all cases been obtained with radiolabeled platelets, and uptake of the radio isotope by long lived cells complicates the analysis. Second, inferred values of the platelet production rate (PR) and random destruction rate (RD) are difficult to interpret, since increased RD can occur either as a cause or a consequence of thrombocytopenia. METHODS: We used a numerical method to analyze in vivo platelet consumption data from a series of 41 patients with immune thrombocytopenic purpura (ITP). An additional parameter, the fraction of labeled long-lived cells (LL), was evaluated concurrently with RD, LS, and SD. To provide a basis for interpreting these values, we used an iterative interpolation process to predict their response to different pathophysiologic mechanisms. The process also generates predicted effects on the widely used immature platelet fraction (IPF). RESULTS: Optimal parameter value sets were identified in 76 % (31 of 41) of the data sets. 27 of 31 ITP patients showed no substantial homeostatic increase in platelet production, with the remaining 4 showing both augmented platelet consumption and a compensatory increase in PR. Up to 1/3 of the patients showed the degree of increased RD expected to result from reduced thrombopoiesis only. "Jacknife" resampling yielded CV values of <0.5 in over 75 % of the evaluable data sets. Predicted platelet age distributions indicate that interpretation of the IPF and absolute IPF (aIPF) is a complex function of platelet count. We found, counter-intuitively, that reduced PR can increase the IPF, and increased RD can reduce the aIPF. CONCLUSIONS: Our findings support the feasibility of using numerical analysis to quantitatively interpret in vivo platelet consumption data, to identify likely etiologies of thrombocytopenias, and to assess the utility of IPF measurements in that context. PMID- 26500781 TI - Anemia in prospective blood donors deferred by the copper sulphate technique of hemoglobin estimation. AB - BACKGROUND: Patients who require transfusion as part of their clinical management have the right to expect sufficient blood to be available to meet their needs and to receive the safest blood possible. Donor deferrals (disqualification) lead to loss of precious blood donors and blood units available for transfusion purposes. It is believed that a large majority of donor deferrals are due to temporal and correctable causes such as anemia in developing countries. It is therefore important to determine anemia among donor population to inform decision-making on the type of measures to be taken to reduce deferrals due to anemia. The aim of the study was to determine anemia in prospective blood donors deferred by the copper sulphate technique of hemoglobin estimation. This, to provide information that would help plan a future strategy for donor recruitment and management. METHODS: Three (3) ml of venous blood samples were collected from the study subjects into EDTA anticoagulant tubes. The hemoglobin levels and red cell indices were measured using Sysmex hematology analyser. A thin blood film was prepared and stained using Leishman stain and then observed under the light microscope. RESULTS: The prevalence of anemia among the total deferred patients (538) was 17.1 %. Four different types of anemia were found among the subjects. These were normocytic normochromic (46.74 %), microcytic hypochromic (42.39 %) normocytic hypochromic (8.70 %), and microcytic normochromic anemia (2.17 %). CONCLUSION: The study showed that a significant number of the prospective blood donors deferred for having low hemoglobin by the copper sulphate method turned out to have anemia by the standard method of diagnosis. Prevalence of anemia among apparently healthy blood donors was therefore higher than expected. Measures must therefore be taken to address this in order not to lose potential blood donors due to a correctable and preventable cause such as anemia. PMID- 26500782 TI - The study of CaO and MgO heterogenic nano-catalyst coupling on transesterification reaction efficacy in the production of biodiesel from recycled cooking oil. AB - BACKGROUND: Fossil fuels' pollution and their non-renewability have motivated the search for alternative fuels. Some common example of seed oils are sunflower oil, date seed oil, soy bean oil. For instance, soy methyl and soy-based biodiesel are the main biodiesel. Biodiesel is a clean diesel fuel that can be produced through transesterification reaction. Recycled cooking oil, on the other hand, is one of the inexpensive, easily available sources for producing biodiesel. RESULTS: This article is aimed at production of biodiesel via trans-esterification method, Nano CaO synthesis using sol-gel method, and Nano MgO synthesis using sol-gel self combustion. Two catalysts' combination affecting the reaction's efficacy was also discussed. Optimum conditions for the reaction in the presence of Nano CaO are 1.5 % weight fracture, 1:7 alcohol to oil proportion and 6 h in which biodiesel and glycerin (the byproduct) are produced. Moreover, the optimum conditions for this reaction in the presence of Nano CaO and Nano MgO mixture are 3 % weight fracture (0.7 g of Nano CaO and 0.5 g of Nano MgO), 1:7 alcohols to oil proportion and 6 h. CONCLUSIONS: Nano MgO is not capable of catalyzing the transesterification by itself, because it has a much weaker basic affinity but when used with Nano CaO due to its surface structure, the basic properties increase and it becomes a proper base for the catalyst so that CaO contact surface increases and transesterification reaction yield significantly increases as well. This study investigates the repeatability of transesterification reaction in the presence of these Nano catalysts as well. PMID- 26500783 TI - Initial experience of SPECT/CT in the diagnosis of occult scaphoid fracture. AB - BACKGROUND: *Equal contributors.Planar bone scintigraphy (PBS) is often advocated for diagnosing occult scaphoid fractures. PBS is a sensitive diagnostic modality, but lacks specificity, which may result in over-diagnosis. PURPOSE: To examine, in a pilot study, the potential additional value of single photon emission computed tomography (SPECT) combined with low dose computed tomography (CT) for the diagnosis of an occult scaphoid fracture. MATERIAL AND METHODS: Ten patients that underwent combined PBS and SPECT/CT for a clinically suspected scaphoid fracture, where radiographs could not detect a fracture, were included in this pilot study. The PBS and SPECT/CT results were independently and separately evaluated by a nuclear physician for scaphoid fractures and other injuries. RESULTS: PBS was positive for a scaphoid fracture in four patients and diagnosed three other fractures. SPECT/CT showed five scaphoid fractures and one other fracture. SPECT/CT - PBS had discrepant results in three patients. In two patients PBS diagnosed a trapezoid fracture where SPECT/CT showed a scaphoid fracture. The other patient was diagnosed with a scaphoid fracture on PBS, whereas SPECT/CT showed bone bruise of other carpal bones. CONCLUSION: SPECT/CT has the potential to be more accurate than PBS as it uses anatomical information of the CT to discriminate between the scaphoid, other carpal bones, and bone bruises. Larger studies with an independent reference standard are needed for confirmation of these preliminary data. PMID- 26500784 TI - Image rejects in general direct digital radiography. AB - BACKGROUND: The number of rejected images is an indicator of image quality and unnecessary imaging at a radiology department. Image reject analysis was frequent in the film era, but comparably few and small studies have been published after converting to digital radiography. One reason may be a belief that rejects have been eliminated with digitalization. PURPOSE: To measure the extension of deleted images in direct digital radiography (DR), in order to assess the rates of rejects and unnecessary imaging and to analyze reasons for deletions, in order to improve the radiological services. MATERIAL AND METHODS: All exposed images at two direct digital laboratories at a hospital in Norway were reviewed in January 2014. Type of examination, number of exposed images, and number of deleted images were registered. Each deleted image was analyzed separately and the reason for deleting the image was recorded. RESULTS: Out of 5417 exposed images, 596 were deleted, giving a deletion rate of 11%. A total of 51.3% were deleted due to positioning errors and 31.0% due to error in centering. The examinations with the highest percentage of deleted images were the knee, hip, and ankle, 20.6%, 18.5%, and 13.8% respectively. CONCLUSION: The reject rate is at least as high as the deletion rate and is comparable with previous film-based imaging systems. The reasons for rejection are quite different in digital systems. This falsifies the hypothesis that digitalization would eliminates rejects. A deleted image does not contribute to diagnostics, and therefore is an unnecessary image. Hence, the high rates of deleted images have implications for management, training, education, as well as for quality. PMID- 26500785 TI - Pulmonary gas conducting interstitial pathway. AB - In spite of the growing efforts oriented towards revealing different aspects of emphysema, the persistence of the emphysematous or emphysema-like changes (ELCs) is not explored yet in the open literature. In this study we demonstrate the persistence of an ELC for 22 years in a spontaneous pneumothorax (SP) patient which indicates a hitherto unknown gas supply to the ELC. For this purpose we used high resolution computed tomography (HRCT) images processed into three dimensional (3D) geometry. By the same token, not only a long persistence but also the volume increase of this ELC between 2002 and 2010 was demonstrated. The 3D geometry visualized an aerated interstitial structure between the sites of supposed gas leakage at the wall of the third generation airways and the ELC. This potential gas conducting interstitial pathway is not a continuation and has neither the form nor the structure of a bronchus. The finding suggests that in this patient the intrabronchial gas passes through the bronchial wall and via a gas conducting interstitial pathway reaches the ELC. Despite the availability of the presently employed techniques for at least 15 years, such case and phenomenon have not been described previously. The retrieval of the patient suggests that the findings could be relevant for a considerable proportion of the population. PMID- 26500786 TI - NRG1 and KITL Signal Downstream of Retinoic Acid in the Germline to Support Soma Free Syncytial Growth of Differentiating Spermatogonia. AB - Defined culture systems supporting spermatogonial differentiation will provide experimental platforms to study spermatogenesis. However, germline-intrinsic signaling mechanisms sufficient to support spermatogonial differentiation without somatic cells remain largely undefined. Here, we analyzed EGF superfamily receptor and ligand diversity in rat testis cells, and delineated germline intrinsic signaling via an ERBB3 co-transducer, ERBB2, as essential for retinoic acid-induced syncytial growth by differentiating spermatogonia. Like the ERBB2/3 agonist NRG1, we found KIT Ligand (KITL) robustly supported spermatogonial differentiation without serum or somatic cells. ERBB2 inhibitors failed to disrupt KITL-dependent spermatogonial development, and, KITL prevented ERBB3 deficient spermatogonial degeneration upon differentiation. Thus, we report NRG1 and KITL activate alternative pathways downstream of retinoic acid signaling in the germline that are essential for stem cells to undergo pre-meiotic steps of spermatogenesis in culture. Robust serum/soma-free spermatogonial differentiation opens new doors to study mammalian germ cell biology in culture, which will facilitate the discovery of spermatogenic factors that can drive meiotic progression in vitro. PMID- 26500788 TI - Blended Learning: The Student Viewpoint. AB - BACKGROUND: Blended learning (BL) is defined as "a way of meeting the challenges of tailoring learning and development to the needs of individuals by integrating the innovative and technological advances offered by online learning with the interaction and participation offered in the best of traditional learning." The Gulf Medical University (GMU), Ajman, UAE, offers a number of courses which incorporate BL with contact classes and online component on an E-learning platform. Insufficient learning satisfaction has been stated as an obstacle to its implementation and efficacy. AIM: To determine the students' perceptions toward BL which in turn will determine their satisfaction and the efficacy of the courses offered. SUBJECTS AND METHODS: This was a cross-sectional study conducted at the GMU, Ajman between January and December 2013. Perceptions of BL process, content, and ease of use were collected from 75 students enrolled in the certificate courses offered by the university using a questionnaire. Student perceptions were assessed using Mann-Whitney U-test and Kruskal-Wallis test on the basis of gender, age, and course enrollment. RESULTS: The median scores of all the questions in the three domains were above three suggesting positive perceptions on BL. The distribution of perceptions was similar between gender and age. However, significant differences were observed in the course enrollment (P = 0.02). CONCLUSION: Students hold a positive perception of the BL courses being offered in this university. The difference in perceptions among students of different courses suggest that the BL format offered needs modification according to course content to improve its perception. PMID- 26500787 TI - Putting a bit into the polo-box domain of polo-like kinase 1. AB - Polo-like kinase 1 (Plk1) plays key roles in regulating various mitotic processes that are critical for cellular proliferation. A growing body of evidence suggests that Plk1 overexpression is tightly associated with the development of human cancers. Interestingly, various types of cancer cells are shown to be addicted to a high level of Plk1, and the reversal of Plk1 addiction appears to be an effective strategy for selectively killing cancer cells, but not normal cells. Therefore, Plk1 is considered an attractive anticancer drug target. Over the years, a large number of inhibitors that target the catalytic activity of Plk1 have been developed. However, these inhibitors exhibit significant levels of cross-reactivity with related kinases, including Plk2 and Plk3. Consequently, as an alternative approach for developing anti-Plk1 therapeutics, substantial effort is under way to develop inhibitors that target the C-terminal protein-protein interaction domain of Plk1, called the polo-box domain (PBD). In this communication, I will discuss the pros and cons of targeting the PBD in comparison to those of targeting the ATP-binding site within the kinase domain. PMID- 26500789 TI - To Assess Sleep Quality among Pakistani Junior Physicians (House Officers): A Cross-sectional Study. AB - BACKGROUND: Sleep deprivation among junior physicians (house officers) is of growing concern. In developed countries, duty hours are now mandated, but in developing countries, junior physicians are highly susceptible to develop sleep impairment due to long working hours, on-call duties and shift work schedule. AIM: We undertook the study to assess sleep quality among Pakistani junior physicians. SUBJECTS AND METHODS: A cross-sectional study was conducted at private and public hospitals in Karachi, Pakistan, from June 2012 to January 2013. The study population comprised of junior doctors (house physicians and house surgeons). A consecutive sample of 350 physicians was drawn from the above mentioned study setting. The subject underwent two validated self-administered questionnaires, that is, Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). RESULTS: A total of 334 physicians completely filled out the questionnaire with a response rate of 95.4% (334/350). Of 334 physicians, 36.8% (123/334) were classified as "poor sleepers" (global PSQI score > 5). Poor sleep quality was associated with female gender (P = 0.01), excessive daytime sleepiness (P < 0.01), lower total sleep time (P < 0.001), increased sleep onset latency (P < 0.001), and increased frequency of sleep disturbances (P < 0.001). Abnormal ESS scores (ESS > 10) were more prevalent among poor sleepers (P < 0.01) signifying increased level of daytime hypersomnolence. CONCLUSION: Sleep quality among Pakistani junior physicians is significantly poor. Efforts must be directed towards proper sleep hygiene education. Regulations regarding duty hour limitations need to be considered. PMID- 26500790 TI - Molecular Epidemiology of Mycobacterium Tuberculosis Strains in the North-West and West of Iran. AB - BACKGROUND: Identifying Mycobacterium tuberculosis (MTB) transmission type is a key step in the control of this disease. AIM: This study aimed to determine the path and transmission type of MTB and the insertion sequence IS6110 band number and verify their relationship to demographic and clinical risk factors. SUBJECTS AND METHODS: In this cross-sectional study, 64 MTB patients from three border provinces of Iran were selected after full clinical history and physical evaluation design. The drug susceptibility testing was carried out using the standard proportion technique on sputum samples. Isolates tested with restriction fragment length polymorphism technique used IS6110. RESULTS: Recent transmission of disease was 33/50 (66%) based on clustering rate. The IS6110 band number had a significant relationship with drug resistance detected in proportion method tested by univariate linear regression (P < 0.01). Furthermore, the IS6110 band number had association with Bacillus Calmette-Guerin vaccination history (P = 0.02), sex (P < 0.01), and purified protein derivative (PPD) reaction size (P < 0.01) tested by multiple analysis. The risk of recent transmission inferred from the clustering rate was significantly higher in patients from Western provinces compared to those from the North-West province (P = 0.048). However, age (P = 0.39), gender (P = 0.16), vaccination history (P = 0.57), drug susceptibility, and PPD (P < 0.6) were independent of clustering. The largest cluster of up to six subjects was found in the Western provinces. CONCLUSION: Recent MTB transmission was much more common in the West compared to the North-West of Iran. Large MTB clusters with strong epidemiological links may be reflective of a disease outbreak. Correlation noted between the IS6110 band number and vaccination history; PPD size and female gender necessitates further studies. PMID- 26500791 TI - Periodontal Disease Awareness and Knowledge among Nigerian Primary School Teachers. AB - BACKGROUND: Teacher-led oral health education is equally effective in improving the oral health knowledge and oral hygiene status of adolescents as dentist-led and peer-led strategies. AIM: The aim was to determine periodontal disease awareness and knowledge among Nigerian primary school teachers. SUBJECTS AND METHODS: This cross-sectional study was conducted among primary school teachers in Edo State, Nigeria. A self-administered questionnaire which elicited information on demography, awareness of the periodontal disease and source of information, knowledge of etiology, and symptoms of the periodontal disease, was the data collection tool.. The test of association was done using either Chi square or Fisher's exact statistics. P value was set at 0.05 for significance level. RESULTS: Out of 180 teachers recruited from seven public primary schools in Benin City, Edo State, Nigeria, 151 of them fully participated by filling the study questionnaires giving a 83.9% (151/180) response rate. The majority 74.2% (112/151) of the participants reported having heard of the periodontal disease and the leading source of information was television. A total of 29.8% (45/151) of participants considered periodontal disease as the main cause of tooth loss among adult Nigerian. Only 12.6% (19/151) of the participants knew dental plaque as soft debris on teeth and 29.1% (44/151) attested that plaque can cause periodontal disease. The majority of the participants were not aware of age 81.5% (123/151) and gender 96.7% (146/151) predisposition to periodontal disease. The perceived manifestations of the periodontal disease reported by were mainly gum bleeding 35.1% (53/151) and swollen gum 20.5% (31/151). A total of 70.2% (106/151) of the participants considered periodontal disease as a preventable disease and about half 49.0% (74/151) of the participants considered daily mouth cleaning as the best preventive method. The majority 95.4% (144/151) of the participants expressed interest in learning about the periodontal disease and the most preferred methods were workshops and lectures. CONCLUSION: A significant proportion of the participants heard about periodontal disease from nondental clinic sources. There existed a poor awareness of etiology, age and gender predispositions, manifestation, complications, and the preventable nature of periodontal disease among the participants. However, the majority of them indicated interest in learning about periodontal disease which should be utilized in optimizing their knowledge. PMID- 26500792 TI - The Effectiveness of Prenatal Intervention on Pain and Anxiety during the Process of Childbirth-Northern Iran: Clinical Trial Study. AB - BACKGROUND: Due to the painful nature of childbirth and its maternal and neonatal complications, the woman needs support in this phase of their life. Increased knowledge and skills during pregnancy prepares pregnant mothers for labor and leads to promoted health. AIM: This study was designed to evaluate the effectiveness of "prenatal education" on the process of childbirth. SUBJECTS AND METHODS: This clinical trial was conducted on 195 pregnant women, that is, control group (N = 132) and case group (N = 63) attending health centers in Amol Iran from 20 weeks of gestation age during 2012. Case group members attended in "prenatal education" class and the control group only received routine care. Data were collected through demographic questionnaire, standard hospital anxiety questionnaire, and a checklist related to childbirth information, and intensity of pain based on visual analogue scale and McGill scales. The data were analyzed by Statistical Package for the Social Sciences software using t-test and Chi square test. RESULTS: The result of this study showed that the parent with a high level of education was more interested to participant in prenatal classes. The anxiety level in case group (who received education) was 14.47 (4.69) and in control group it was 16 (4.86), (P < 0.001) the pain intensity in case group was 85.68 (1.85) and in control group was 90.99 (14.72) (P = 0.03), intervention on labor such episiotomy was 39 %66.1 (39/63) in case group and 80 %72.8 (80/132) in control group (P = 0.01) and cesarean section was 13 %17.1 (13/63) in case group and 58 %32.2 (58/132) in control group (P = 0.01). CONCLUSIONS: According to findings of this study, the prenatal education and psychological support are beneficial for mothers during pregnancy and labor. Therefore, it is recommended for educating all the pregnant women. PMID- 26500793 TI - Influence of Sociodemographic and Stroke-related Factors on Availability of Social Support among Nigerian Stroke Survivors. AB - BACKGROUND: Availability of social support has been identified as an important prerequisite for positive outcomes after stroke. There is however, little information on variables that influence the availability of social support after stroke. AIM: This study explored the influence of selected sociodemographic and clinical variables on social support of stroke survivors in Nigeria. SUBJECTS AND METHODS: One hundred stroke survivors undergoing rehabilitation at two tertiary care hospitals in Northern Nigeria participated in the study. Data on age, gender, living arrangement, marital, education and prestroke employment status, and time after stroke were obtained through interview, while poststroke disability was evaluated with the modified Rankin Scale. Social support was assessed with the multidimensional scale of perceived social support (MSPSS). Univariate and multiple linear regression analyses were conducted. A P value of less than 0.05 is considered as significant. RESULTS: Univariate analysis showed that gender, education, and prestroke employment status were significantly associated with the availability of social support. In a regression model that accounted for 11 % of the variance in social support, prestroke employment was the only variable that independently influenced availability of social support (beta = -0.33, P < 0.01) with previously employed stroke survivors having higher MSPSS score (5.28 [0.98]) compared to the unemployed (4.57 [0.82]). CONCLUSION: Employment is a known significant contributor to social network and was also found to influence significantly, the availability of poststroke social support in this study. Further studies are required to identify factors that more substantially influence the availability of social support after stroke. PMID- 26500795 TI - Concurrent Occurrence of Uterovaginal and Rectal Prolapse: An Uncommon Presentation. AB - Concomitant uterovaginal and rectal prolapse is an uncommon occurrence. Where laparoscopic equipment and skills are lacking, sacrohysteropexy with synthetic mesh and rectopexy can be accomplished by laparotomy, especially in women who desire to retain their uterus for either biological or psychological reasons. A 40-year-old primipara with a history of concomitant mass protruding from both her vagina and anus following a spontaneous unsupervised delivery at home. Following pelvic examination, a diagnosis of uterovaginal and rectal prolapse was made. In view of her parity and desire to retain her reproductive function, she was offered abdominal sacrohysteropexy with synthetic mesh and rectopexy with satisfactory postoperative recovery. In resource-limited settings with concomitant uterine and rectal prolapse, open abdominal sacrohysteropexy with synthetic mesh and rectopexy is an effective and safe alternative to Manchester operation in the absence of laparoscopic equipment and skills. PMID- 26500794 TI - Body Size Perceptions and Weight Status of Adults in a Nigerian Rural Community. AB - BACKGROUND: Overweight and obesity are now recognized worldwide as increasing public health problems throughout the life course and wrong perception of one's body size may reduce the motivation for an overweight person to lose weight. AIM: This study was conducted to investigate how Nigerian rural dwellers perceive their body size and how their perception agrees with their body mass index (BMI). SUBJECTS AND METHODS: A cross-sectional sample of 183 adults living in a rural community, South-West Nigeria was randomly recruited into the study. Their verbal and visual body size perceptions were assessed through structured questions and body images. Descriptive and inferential statistics were used to analyze the data. RESULTS: Thirty-five percent (64/183) of participants were classified as either overweight or obese by BMI. More than half of the participants perceived themselves as normal weight. More women perceived themselves to be obese than men in both verbal and visual perceptions. Based on BMI classification, 43% (79/183) and 54% (98/183) of participants misperceived themselves in verbal and visual perception, respectively. Underestimation of body size was higher in men (38.3%, 36/94) while overestimation was higher in women (9.0%, 8/89). Men had consistently higher values of kappa coefficient which indicate greater agreement than women in both types of perception. CONCLUSION: We found considerable gender differences in body weight perception of adults in the Nigerian rural community. A large proportion of these rural dwellers could not appropriately classify their weight status; and over 30% (64/183) and nearly 50% (92/183) of them underestimated their own body weight in verbal and visual perceptions respectively. PMID- 26500797 TI - Case series of choroid plexus papilloma in children at uncommon locations and review of the literature. AB - BACKGROUND: Choroid plexus papillomas (CPPs) comprise around 1% of intracranial neoplasms. The most common location is atrium of the lateral ventricle in children and fourth ventricle in adults. Other rare locations include third ventricle, cerebellopontine (CP) angle and cerebral parenchyma, with only a few cases reported. Authors report three cases of CPP at uncommon locations in pediatric patients. The rarity of these locations, diagnostic dilemma and management aspects are discussed along with an extensive review of the literature. METHODS: Retrospective institutional data analysis of histopathologically confirmed pediatric CPPs from 2010 to 2014. RESULTS: Authors noted three cases of CPP in children in uncommon locations-one each in the posterior third ventricle, fourth ventricle, and CP angle. All were males in the first decade. Two cases presented with features of obstructive hydrocephalus while the latter presented with compressive effects. Complete excision was achieved in two cases while subtotal removal was performed in one case (fourth ventricular) because of excess blood loss. Mean follow-up duration was 24.6 months (range 20-30 months). One case (of subtotal removal) had fair recovery while other two had excellent outcomes. CONCLUSIONS: Posterior third ventricle, fourth ventricle, and CP angle are uncommon locations for these tumors in children. Complete surgical removal is the treatment of choice and approach needs to be tailored according to the site and size of the lesion. Blood loss is a major concern in young children as they are highly vascular tumors. Complete removal leads to excellent long-term survival rates. Adjuvant treatment is not required. PMID- 26500796 TI - Multiple Intussusceptions Associated with Polycythemia in an Anabolic Steroid Abuser, A Case Report and Literature Review. AB - Intussusceptions are generally associated with mechanical lead points or localized inflammation that function as foci for intestinal telescoping. We present the case of a patient whose abuse of anabolic steroids resulted in the development of multiple simultaneous intussusceptions. Our patient had no additional identifiable risk factors for intussusception. Consistent with previous reports, corticosteroid induced polycythemia and its consequent hyperviscosity led to intravascular sludging and mesenteric ischemia with associated bowel wall thickening. The localized intestinal induration then served as mechanical foci for intussusception. Due to the illicit nature of anabolic androgenic steroid (AAS) abuse, the physiologic effects of supraphysiologic doses are sparsely reported and poorly understood. The scope of AAS abuse and its consequences are likely under-reported and under-recognized within the medical community. Our case presented a unique diagnostic and therapeutic challenge with which we aim to increasing awareness and clinical suspicion for AAS among healthcare personnel. PMID- 26500798 TI - Penetrating intracranial nail-gun injury to the middle cerebral artery: A successful primary repair. AB - BACKGROUND: Penetrating nail-gun injuries to the head are rare, however, the incidence has been gradually rising over the last decade. While there is a large volume of case reports in the literature, there are only a few incidences of cerebrovascular injury. We present a case of a patient with a nail-gun injury to the brain, which compromised the cerebral vasculature. In this article, we present the case, incidence, pathology, and a brief literature review of penetrating nail-gun injuries to highlight the principles of management pertaining to penetration of cerebrovascular structures. CASE DESCRIPTION: A 26 year-old male presented with a penetrating nail-gun injury to his head. There were no neurological deficits. Initial imaging revealed that the nail had penetrated the cranium and suggested the vasculature to be intact. However, due to the proximity of the nail to the circle of Willis the operative approach was tailored in anticipation of a vascular injury. Intraoperatively removal of the foreign body demonstrated a laceration to the M1 branch of the middle cerebral artery (MCA), which was successfully repaired. CONCLUSION: To our knowledge, this is the first reported case of a vascular arterial injury to the MCA from a nail gun injury. It is imperative to have a high clinical suspicion for cerebrovascular compromise in penetrating nail-gun injuries even when conventional imaging suggests otherwise. PMID- 26500799 TI - Repeat Gamma Knife surgery for vestibular schwannomas. AB - BACKGROUND: Gamma Knife (GK) surgery is a recognized treatment option for the management of small to medium-sized vestibular schwannoma (VS) associated with high-tumor control and low morbidity. When a radiosurgical treatment fails to stop tumor growth, repeat GK surgery can be proposed in selected cases. METHODS: A series of 27 GK retreatments was performed in 25 patients with VS; 2 patients underwent three procedures. The median time interval between GK treatments was 45 months. The median margin dose used for the first, second, and third GK treatments was 12 Gy, 12 Gy, and 14 Gy, respectively. Six patients (4 patients for the second irradiation and 2 patients for the third irradiation) with partial tumor regrowth were treated only on the growing part of the tumor using a median margin dose of 13 Gy. The median tumor volume was 0.9, 2.3, and 0.7 cc for the first, second, and third treatments, respectively. Stereotactic positron emission tomography (PET) guidance was used for dose planning in 6 cases. RESULTS: Mean follow-up duration was 46 months (range 24-110). At the last follow-up, 85% of schwannomas were controlled. The tumor volume decreased, remained unchanged, or increased after retreatment in 15, 8, and 4 cases, respectively. Four patients had PET during follow-up, and all showed a significant metabolic decrease of the tumor. Hearing was not preserved after retreatment in any patients. New facial or trigeminal palsy did not occur after retreatment. CONCLUSIONS: Our results support the long-term efficacy and low morbidity of repeat GK treatment for selected patients with tumor growth after initial treatment. PMID- 26500800 TI - The incidence and risk factors for surgical site infection after clean spinal operations: A prospective cohort study and review of the literature. AB - BACKGROUND: Postoperative infection is one of the most common complications after spine surgeries. In our study, surgical site infection (SSI) is described as; superficial (i.e., skin and subcutaneous tissues) and deep (i.e., fascia and muscles) infections occurring in the short term (i.e., 1-month) after spine surgeries (Centers for Disease Control and Prevention definition 81.00-81.08). To detect the risk factors for the occurrence of such a complication, studies require a large number of patients, a high quality of data and adequate analysis. In this study, we prospectively enrolled 987 patients undergoing spinal surgery over a 3 years period. METHODS: From November 2010 to November 2013, 987 patients had a variety of spinal operations that included; disc herniation, spinal stenosis, spondylolisthesis, fracture-dislocations, spine and spinal cord tumors, and syringomyelia. Patients under the age of 10, those with a recent history of infection and antibiotherapy, and patients with immunodeficiency disorders were excluded. RESULTS: Of the 987 spine procedures performed, 27 (2.73%) developed postoperative infections. Multi-variant data analysis indicated that multiple factors correlated with an increased risk of SSI in descending order; trauma, a past history of diabetes, smoking, being confined to bed, in the perioperative period, mean blood sugar levels above 120 mg/dl, longer lengths of incisions, and longer hospital stay. CONCLUSION: Considering the preventable nature of most of the factors contributing to SSI, it should be possible to reduce these complications. PMID- 26500801 TI - Review of the management of pneumocephalus. AB - BACKGROUND: Pneumocephalus (PNC) is the presence of air in the intracranial cavity. The most frequent cause is trauma, but there are many other etiological factors, such as surgical procedures. PNC with compression of frontal lobes and the widening of the interhemispheric space between the tips of the frontal lobes is a characteristic radiological finding of the "Mount Fuji sign." In addition to presenting our own case, we reviewed the most relevant clinical features, diagnostic methods, and conservative management for this condition. CASE DESCRIPTION: A 74-year-old male was diagnosed with meningioma of olfactory groove several years ago. After no improvement, surgery of the left frontal craniotomy keyhole type was conducted. A computed tomography (CT) scan of the skull performed 24 h later showed a neuroimaging that it is described as the silhouette of Mount Fuji. The treatment was conservative and used continuous oxygen for 5 days. Control CT scan demonstrated reduction of the intracranial air with normal brain parenchyma. CONCLUSION: The review of the literature, we did not find any cases of tension pneumocephalus documented previously through a supraorbital keyhole approach. There are a few cases reported of patients with Mount Fuji signs that do not require surgical procedures. The conservative treatment in our report leads to clinical and radiological improvement as well as a reduction in hospitalization time. PMID- 26500802 TI - Imaging the spontaneous obliteration of a cerebral arteriovenous malformation using c-arm cone beam computed tomography: A case report. AB - BACKGROUND: Spontaneous occlusion of a cerebral arteriovenous malformation (AVM) without treatment is a rare occurrence. CASE DESCRIPTION: We report the case of a 56-year-old male who presented with aphasia and right hemiparesis secondary to intracerebral and intraventricular hemorrhage. Diagnostic digital subtraction angiography (DSA) and c-arm cone beam computed tomography (CBCT) demonstrated a 5 mm Spetzler-Martin Grade III left thalamic AVM drained by the internal cerebral vein. Subsequent DSA and CBCT studies confirmed the spontaneous obliteration of the AVM. CONCLUSIONS: In this case, CBCT provided high resolution imaging of the AVM. Future clinical use of CBCT as an adjunct to DSA may enhance the diagnostic and therapeutic imaging of vascular lesions. PMID- 26500803 TI - Is there room for stereotactic radiosurgery as an option for third ventricular colloid cysts in patients refusing surgery? A case report and some therapeutic considerations. AB - BACKGROUND: Colloid cysts of the third ventricle are epithelium-lined mucus filled cysts usually occurring in the anterosuperior third ventricle. They are benign, slow-growing lesions but with the risk of sudden death. Treatment alternatives for symptomatic cysts include stereotactic aspiration, microsurgical or endoscopic approaches, and shunts for hydrocephalus. CASE DESCRIPTION: The current case describes a patient presenting with hydrocephalus and a colloid cyst. A ventriculoperitoneal shunt was placed as the patient refused a definitive surgical procedure for the removal of the cyst, and stereotactic radiosurgery was then performed. CONCLUSIONS: Stereotactic radiosurgery may be a reasonable alternative with minimal risks in those patients harboring a third ventricle colloid cyst refusing a definitive surgical procedure for resection of the cyst. PMID- 26500804 TI - mBLAST: Keeping up with the sequencing explosion for (meta)genome analysis. AB - Recent advances in next-generation sequencing technologies require alignment algorithms and software that can keep pace with the heightened data production. Standard algorithms, especially protein similarity searches, represent significant bottlenecks in analysis pipelines. For metagenomic approaches in particular, it is now often necessary to search hundreds of millions of sequence reads against large databases. Here we describe mBLAST, an accelerated search algorithm for translated and/or protein alignments to large datasets based on the Basic Local Alignment Search Tool (BLAST) and retaining the high sensitivity of BLAST. The mBLAST algorithms achieve substantial speed up over the National Center for Biotechnology Information (NCBI) programs BLASTX, TBLASTX and BLASTP for large datasets, allowing analysis within reasonable timeframes on standard computer architectures. In this article, the impact of mBLAST is demonstrated with sequences originating from the microbiota of healthy humans from the Human Microbiome Project. mBLAST is designed as a plug-in replacement for BLAST for any study that involves short-read sequences and includes high-throughput analysis. The mBLAST software is freely available to academic users at www.multicorewareinc.com. PMID- 26500806 TI - Curriculum Development of a Research Laboratory Methodology Course for Complementary and Integrative Medicine Students. AB - Training in fundamental laboratory methodologies is valuable to medical students because it enables them to understand the published literature, critically evaluate clinical studies, and make informed decisions regarding patient care. It also prepares them for research opportunities that may complement their medical practice. The National College of Natural Medicine's (NCNM) Master of Science in Integrative Medicine Research (MSiMR) program has developed an Introduction to Laboratory Methods course. The objective of the course it to train clinical students how to perform basic laboratory skills, analyze and manage data, and judiciously assess biomedical studies. Here we describe the course development and implementation as it applies to complementary and integrative medicine students. PMID- 26500805 TI - Macrophage Polarization in AIDS: Dynamic Interface between Anti-Viral and Anti Inflammatory Macrophages during Acute and Chronic Infection. AB - Monocyte and macrophage inflammation in parenchymal tissues during acute and chronic HIV and SIV infection plays a role in early anti-viral immune responses and later in restorative responses. Macrophage polarization is observed in such responses in the central nervous system (CNS) and the heart and cardiac vessels that suggest early responses are M1 type antiviral responses, and later responses favor M2 restorative responses. Macrophage polarization is unique to different tissues and is likely dictated as much by the local microenvironment as well as other inflammatory cells involved in the viral responses. Such polarization is found in HIV infected humans, and the SIV infected animal model of AIDS, and occurs even with effective anti-retroviral therapy. Therapies that directly target macrophage polarization in HIV infection have recently been implemented, as have therapies to directly block traffic and accumulation of macrophages in tissues. PMID- 26500807 TI - Role of Male Factor Testing in Recurrent Pregnancy Loss or In Vitro Fertilization Failure. PMID- 26500808 TI - Future Prospects for Periodontal Bioengineering Using Growth Factors. AB - Polypeptide growth factors have demonstrated strong potential to repair defects associated with teeth and dental implants. Over the past two decades, intense research efforts have led to the clinical development of several growth factors or biologic agents, including bone morphogenetic proteins, platelet-derived growth factor, fibroblast growth factors, and enamel matrix proteins. Several of these growth factors are now being used clinically for a variety of applications, such as the promotion of periodontal regeneration, sinus floor augmentation, and root coverage procedures. Although clinical results have been promising and growth factors add another dimension to clinical care, optimization of growth factor targeting approaches to periodontal wounds remains a challenge. Enhancement of growth factor local application to improve bioavailability, bioactivity, and allowance of three-dimensional reconstruction of complex anatomic defects is a goal. This article will highlight developments for growth factor delivery to better stimulate the wound healing response for periodontal and bone regeneration in the maxillofacial region. PMID- 26500809 TI - Competition from native hydrophytes reduces establishment and growth of invasive dense-flowered cordgrass (Spartina densiflora). AB - Experimental studies to determine the nature of ecological interactions between invasive and native species are necessary for conserving and restoring native species in impacted habitats. Theory predicts that species boundaries along environmental gradients are determined by physical factors in stressful environments and by competitive ability in benign environments, but little is known about the mechanisms by which hydrophytes exclude halophytes and the life history stage at which these mechanisms are able to operate. The ongoing invasion of the South American Spartina densiflora in European marshes is causing concern about potential impacts to native plants along the marsh salinity gradient, offering an opportunity to evaluate the mechanisms by which native hydrophytes may limit, or even prevent, the expansion of invasive halophytes. Our study compared S. densiflora seedling establishment with and without competition with Phragmites australis and Typha domingensis, two hydrophytes differing in clonal architecture. We hypothesized that seedlings of the stress tolerant S. densiflora would be out-competed by stands of P. australis and T. domingensis. Growth, survivorship, biomass patterns and foliar nutrient content were recorded in a common garden experiment to determine the effect of mature P. australis and T. domingensis on the growth and colonization of S. densiflora under fresh water conditions where invasion events are likely to occur. Mature P. australis stands prevented establishment of S. densiflora seedlings and T. domingensis reduced S. densiflora establishment by 38%. Seedlings grown with P. australis produced fewer than five short shoots and all plants died after ca. 2 yrs. Our results showed that direct competition, most likely for subterranean resources, was responsible for decreased growth rate and survivorship of S. densiflora. The presence of healthy stands of P. australis, and to some extent T. domingensis, along river channels and in brackish marshes may prevent the invasion of S. densiflora by stopping the establishment of its seedlings. PMID- 26500810 TI - Comments and corrections on 3D modeling studies of locomotor muscle moment arms in archosaurs. AB - In a number of recent studies we used computer modeling to investigate the evolution of muscle leverage (moment arms) and function in extant and extinct archosaur lineages (crocodilians, dinosaurs including birds and pterosaurs). These studies sought to quantify the level of disparity and convergence in muscle moment arms during the evolution of bipedal and quadrupedal posture in various independent archosaur lineages, and in doing so further our understanding of changes in anatomy, locomotion and ecology during the group's >250 million year evolutionary history. Subsequent work by others has led us to re-evaluate our models, which revealed a methodological error that impacted on the results obtained from the abduction-adduction and long-axis rotation moment arms in our published studies. In this paper we present corrected abduction-adduction and long axis rotation moment arms for all our models, and evaluate the impact of this new data on the conclusions of our previous studies. We find that, in general, our newly corrected data differed only slightly from that previously published, with very few qualitative changes in muscle moments (e.g., muscles originally identified as abductors remained abductors). As a result the majority of our previous conclusions regarding the functional evolution of key muscles in these archosaur groups are upheld. PMID- 26500811 TI - Multifaceted interventions to decrease mortality in patients with severe sepsis/septic shock-a quality improvement project. AB - Despite knowledge that EGDT improves outcomes in septic patients, staff education on EGDT and compliance with the CPOE order set has been variable. Based on results of a resident survey to identify barriers to decrease severe sepsis/septic shock mortality in the medical intensive care unit (MICU), multifaceted interventions such as educational interventions to improve awareness to the importance of early goal-directed therapy (EGDT), and the use of the Computerized Physician Order Entry (CPOE) order set, were implemented in July 2013. CPOE order set was established to improve compliance with the EGDT resuscitation bundle elements. Orders were reviewed and compared for patients admitted to the MICU with severe sepsis/septic shock in July and August 2013 (controls) and 2014 (following the intervention). Similarly, educational slide sets were used as interventions for residents before the start of their ICU rotations in July and August 2013. While CPOE order set compliance did not significantly improve (78% vs. 76%, p = 0.74), overall EGDT adherence improved from 43% to 68% (p = 0.0295). Although there was a trend toward improved mortality, this did not reach statistical significance. This study shows that education interventions can be used to increase awareness of severe sepsis/septic shock and improve overall EGDT adherence. PMID- 26500812 TI - Short-term fertilizer application alters phenotypic traits of symbiotic nitrogen fixing bacteria. AB - Fertilizer application is a common anthropogenic alteration to terrestrial systems. Increased nutrient input can impact soil microbial diversity or function directly through altered soil environments, or indirectly through plant-microbe feedbacks, with potentially important effects on ecologically-important plant associated mutualists. We investigated the impacts of plant fertilizer, containing all common macro and micronutrients on symbiotic nitrogen-fixing bacteria (rhizobia), a group of bacteria that are important for plant productivity and ecosystem function. We collected rhizobia nodule isolates from natural field soil that was treated with slow-release plant fertilizer over a single growing season and compared phenotypic traits related to free-living growth and host partner quality in these isolates to those of rhizobia from unfertilized soils. Through a series of single inoculation assays in controlled glasshouse conditions, we found that isolates from fertilized field soil provided legume hosts with higher mutualistic benefits. Through growth assays on media containing variable plant fertilizer concentrations, we found that plant fertilizer was generally beneficial for rhizobia growth. Rhizobia isolated from fertilized field soil had higher growth rates in the presence of plant fertilizer compared to isolates from unfertilized field soil, indicating that plant fertilizer application favoured rhizobia isolates with higher abilities to utilize fertilizer for free-living growth. We found a positive correlation between growth responses to fertilizer and mutualism benefits among isolates from fertilized field soil, demonstrating that variable plant fertilizer induces context-dependent genetic correlations, potentially changing the evolutionary trajectory of either trait through increased trait dependencies. Our study shows that short-term application is sufficient to alter the composition of rhizobia isolates in the population or community, either directly though changes in the soil chemistry or indirectly through altered host legume feedbacks, and is potentially a strong selective agent acting on natural rhizobia populations. PMID- 26500813 TI - Validation experiments on finite element models of an ostrich (Struthio camelus) cranium. AB - The first finite element (FE) validation of a complete avian cranium was performed on an extant palaeognath, the ostrich (Struthio camelus). Ex-vivo strains were collected from the cranial bone and rhamphotheca. These experimental strains were then compared to convergence tested, specimen-specific finite element (FE) models. The FE models contained segmented cortical and trabecular bone, sutures and the keratinous rhamphotheca as identified from micro-CT scan data. Each of these individual materials was assigned isotropic material properties either from the literature or from nanoindentation, and the FE models compared to the ex-vivo results. The FE models generally replicate the location of peak strains and reflect the correct mode of deformation in the rostral region. The models are too stiff in regions of experimentally recorded high strain and too elastic in regions of low experimentally recorded low strain. The mode of deformation in the low strain neurocranial region is not replicated by the FE models, and although the models replicate strain orientations to within 10 degrees in some regions, in most regions the correlation is not strong. Cranial sutures, as has previously been found in other taxa, are important for modifying both strain magnitude and strain patterns across the entire skull, but especially between opposing the sutural junctions. Experimentally, we find that the strains on the surface of the rhamphotheca are much lower than those found on nearby bone. The FE models produce much higher principal strains despite similar strain ratios across the entirety of the rhamphotheca. This study emphasises the importance of attempting to validate FE models, modelling sutures and rhamphothecae in birds, and shows that whilst location of peak strain and patterns of deformation can be modelled, replicating experimental data in digital models of avian crania remains problematic. PMID- 26500814 TI - Under which conditions can introverts achieve happiness? Mediation and moderation effects of the quality of social relationships and emotion regulation ability on happiness. AB - Personality traits have been directly associated with happiness. One consistent finding is a strong link between extraversion and happiness: extraverts are happier than introverts. Although happy introverts exist, it is currently unclear under what conditions they can achieve happiness. The present study analyzes, generally, how the quality of social relationships and emotion regulation ability influence happiness and, specifically, how these factors can lead introverts to be happy. In the present study, 1,006 participants aged 18-80 (42% males) completed measures of extraversion, neuroticism, quality of social relationships, emotion regulation ability, and happiness. We found that extraverts had significantly higher happiness, quality of social relationships and emotion regulation ability scores than introverts. In addition, people with high quality social relationships or high emotion regulation ability were happier. Serial mediation analyses indicated that greater levels of extraversion were associated with greater happiness, with small effect size, via two indirect mechanisms: (a) higher quality of social relationships, and (b) higher quality of social relationships followed serially by higher emotion regulation ability. We also found a moderating effect due to the three-way interaction of extraversion, quality of social relationships, and emotion regulation ability: introverts were happier when they had high scores for these two variables, though the effect size was small. These results suggest that the quality of social relationships and emotion regulation ability are relevant to our understanding of complex associations between extraversion and happiness. PMID- 26500815 TI - Antityrosinase activity of Euphorbia characias extracts. AB - Tyrosinase is a well-known key enzyme in melanin biosynthesis and its inhibitors have become increasingly important because of their potential use as hypopigmenting agents. In the present study, the anti-melanogenic effect of aqueous and ethanolic extracts from Euphorbia characias leaves, stems, and flowers in cell-free and cellular systems was examined. All the extracts showed inhibitory effects against mushroom tyrosinase with leaf extracts exhibiting the lowest IC50 values of 24 and 97 ug/mL for aqueous and ethanolic extracts respectively. Enzyme kinetic analysis indicated that leaf aqueous extract acts as a mixed type inhibitor, while ethanolic extract shows a competitive inhibition effect on mushroom tyrosinase using L-DOPA as substrate. In addition, the inhibitory effect of leaf extracts on tyrosinase activity and melanin production was examined in murine melanoma B16F10 cells. Cellular tyrosinase activity as well as levels of melanin synthesis are reduced in a dose-dependent manner by extracts in cells treated with alpha-melanocyte stimulating hormone (alpha-MSH). The effects are comparable, and sometimes even better, than that of kojic acid, a well known tyrosinase inhibitor used for reference. All these results suggest that E. characias could be a great source of the natural inhibitors from tyrosinase and has the potential to be used as a whitening agent in therapeutic fields. PMID- 26500816 TI - Intraspecific variation of phragmocone chamber volumes throughout ontogeny in the modern nautilid Nautilus and the Jurassic ammonite Normannites. AB - Nautilus remains of great interest to palaeontologists after a long history of actualistic comparisons and speculations on aspects of the palaeoecology of fossil cephalopods, which are otherwise impossible to assess. Although a large amount of work has been dedicated to Nautilus ecology, conch geometry and volumes of shell parts and chambers have been studied less frequently. In addition, although the focus on volumetric analyses for ammonites has been increasing recently with the development of computed tomographic technology, the intraspecific variation of volumetric parameters has never been examined. To investigate the intraspecific variation of the phragmocone chamber volumes throughout ontogeny, 30 specimens of Recent Nautilus pompilius and two Middle Jurassic ammonites (Normannites mitis) were reconstructed using computed tomography and grinding tomography, respectively. Both of the ontogenetic growth trajectories from the two Normannites demonstrate logistic increase. However, a considerable difference in Normannites has been observed between their entire phragmocone volumes (cumulative chamber volumes), in spite of their similar morphology and size. Ontogenetic growth trajectories from Nautilus also show a high variation. Sexual dimorphism appears to contribute significantly to this variation. Finally, covariation between chamber widths and volumes was examined. The results illustrate the strategic difference in chamber construction between Nautilus and Normannites. The former genus persists to construct a certain conch shape, whereas the conch of the latter genus can change its shape flexibly under some constraints. PMID- 26500817 TI - A taste for exotic food: Neotropical land planarians feeding on an invasive flatworm. AB - Invasive species establish successfully in new habitats especially due to their ability to include new species in their diet and due to the freedom from natural enemies. However, native species may also adapt to the use of new elements in their ecosystem. The planarian Endeavouria septemlineata, first recorded in Hawaii, was later found in Brazil. Recently, we found it in human-disturbed areas in southern Brazil and here we investigate its interactions with other invertebrates both in the field and in the laboratory. We observed the species in the field during collecting activities and hence maintained some specimens alive in small terraria in the laboratory, where we offered different invertebrate species as potential prey and also put them in contact with native land planarians in order to examine their interaction. Both in the field and in the laboratory, E. septemlineata showed a gregarious behavior and was found feeding on woodlice, millipedes, earwigs and gastropods. In the laboratory, specimens often did not attack live prey, but immediately approached dead specimens, indicating a scavenging behavior. In an experiment using the slug Deroceras laeve and the woodlouse Atlantoscia floridana, there was a higher consumption of dead specimens of woodlice and slugs compared to live specimens, as well as a higher consumption of dead woodlice over dead slugs. Four native land planarians of the genus Obama and one of the genus Paraba attacked and consumed E. septemlineata, which, after the beginning of the attack, tried to escape by tumbling or using autotomy. As a scavenger, E. septemlineata would have no impact on the populations of species used as food, but could possibly exclude native scavengers by competition. On the other hand, its consumption by native land planarians may control its spread and thus reduce its impact on the ecosystem. PMID- 26500818 TI - Variations in leopard cat (Prionailurus bengalensis) skull morphology and body size: sexual and geographic influences. AB - The leopard cat, Prionailurus bengalensis (Kerr, 1792), is one of the most widespread Asian cats, occurring in continental eastern and southeastern Asia. Since 1929, several studies have focused on the morphology, ecology, and taxonomy of leopard cats. Nevertheless, hitherto there has been no agreement on basic aspects of leopard cat biology, such as the presence or absence of sexual dimorphism, morphological skull and body differences between the eleven recognized subspecies, and the biogeography of the different morphotypes. Twenty measurements on 25 adult leopard cat skulls from different Asian localities were analyzed through univariate and multivariate statistical approaches. Skull and external body measurements from studies over the last 77 years were assembled and organized in two categories: full data and summary data. Most of this database comprises small samples, which have never been statistically tested and compared with each other. Full data sets were tested with univariate and multivariate statistical analyses; summary data sets (i.e., means, SDs, and ranges) were analyzed through suitable univariate approaches. The independent analyses of the data from these works confirmed our original results and improved the overview of sexual dimorphism and geographical morphological variation among subspecies. Continental leopard cats have larger skulls and body dimensions. Skulls of Indochinese morphotypes have broader and higher features than those of continental morphotypes, while individuals from the Sunda Islands have skulls with comparatively narrow and low profiles. Cranial sexual dimorphism is present in different degrees among subspecies. Most display subtle sex-related variations in a few skull features. However, in some cases, sexual dimorphism in skull morphology is absent, such as in P. b. sumatranus and P. b. borneoensis. External body measurement comparisons also indicate the low degree of sexual dimorphism. Apart from the gonads, the longer hind foot of male leopard cats is the main feature of sexual dimorphism among P. b. bengalensis (and probably among P. b. horsfieldii too). External body measurements also indicated the absence of sexual dimorphism among individuals of P. b. borneoensis. Inter-subspecific skull comparisons provided a morphometric basis for differentiating some subspecies. Prionailurus b. horsfieldii and P. b. bengalensis were distinguished only by a subtle difference in PM(4) size, indicating that overall skull morphology does not appear to support their separate taxonomical status, in spite of the marked differences reported in their coat patterns. Geological events affecting the Sunda Shelf connection between the Sunda Islands and the mainland during the Last Glacial Maximum seem to have influenced directly the morphological pattern shown by leopard cat subspecies nowadays. PMID- 26500819 TI - Expression of temperature-sensitive ion channel TRPM8 in sperm cells correlates with vertebrate evolution. AB - Transient Receptor Potential cation channel, subfamily Melastatin, member 8 (TRPM8) is involved in detection of cold temperature, different noxious compounds and in execution of thermo- as well as chemo-sensitive responses at cellular levels. Here we explored the molecular evolution of TRPM8 by analyzing sequences from various species. We elucidate that several regions of TRPM8 had different levels of selection pressure but the 4th-5th transmembrane regions remain highly conserved. Analysis of synteny suggests that since vertebrate origin, TRPM8 gene is linked with SPP2, a bone morphogen. TRPM8, especially the N-terminal region of it, seems to be highly variable in human population. We found 16,656 TRPM8 variants in 1092 human genomes with top variations being SNPs, insertions and deletions. A total of 692 missense mutations are also mapped to human TRPM8 protein of which 509 seem to be delateroiours in nature as supported by Polyphen V2, SIFT and Grantham deviation score. Using a highly specific antibody, we demonstrate that TRPM8 is expressed endogenously in the testis of rat and sperm cells of different vertebrates ranging from fish to higher mammals. We hypothesize that TRPM8 had emerged during vertebrate evolution (ca 450 MYA). We propose that expression of TRPM8 in sperm cell and its role in regulating sperm function are important factors that have guided its molecular evolution, and that these understandings may have medical importance. PMID- 26500820 TI - Metacarpal torsion in apes, humans, and early Australopithecus: implications for manipulatory abilities. AB - Human hands, when compared to that of apes, have a series of adaptations to facilitate manipulation. Numerous studies have shown that Australopithecus afarensis and Au. africanus display some of these adaptations, such as a longer thumb relative to the other fingers, asymmetric heads on the second and fifth metacarpals, and orientation of the second metacarpal joints with the trapezium and capitate away from the sagittal plane, while lacking others such as a very mobile fifth metacarpal, a styloid process on the third, and a flatter metacarpo trapezium articulation, suggesting some adaptation to manipulation but more limited than in humans. This paper explores variation in metacarpal torsion, a trait said to enhance manipulation, in humans, apes, early australopithecines and specimens from Swartkrans. This study shows that humans are different from large apes in torsion of the third and fourth metacarpals. Humans are also characterized by wedge-shaped bases of the third and fourth metacarpals, making the metacarpal-base row very arched mediolaterally and placing the ulnar-most metacarpals in a position that facilitate opposition to the thumb in power or cradle grips. The third and fourth metacarpals of Au. afarensis are very human like, suggesting that the medial palm was already well adapted for these kinds of grips in that taxon. Au. africanus present a less clear human-like morphology, suggesting, perhaps, that the medial palm was less suited to human-like manipulation in that taxa than in Au. afarensis. Overall, this study supports previous studies on Au. afarensis and Au. africanus that these taxa had derived hand morphology with some adaptation to human-like power and precision grips and support the hypothesis that dexterous hands largely predated Homo. PMID- 26500821 TI - The development of Negative Self-Beliefs Inventory (NSBI): cultural adaptation and psychometric validation. AB - Social anxiety is an emotional disorder common to various populations around the world. The newly developed Self-Beliefs Related to Social Anxiety Scale (SBSA) aims to assess three kinds of self-beliefs through 15 items that include self related cognitive factors that evidently result in social anxiety. This study explored the psychometric characteristics of SBSA among 978 Chinese. An eight item Negative Self-beliefs Inventory (NSBI) was developed through qualitative and quantitative analyses. Exploratory factor analysis, confirmatory factor analysis, and multi-group confirmatory factor analysis suggested that NSBI contained clear, meaningful, stable, and invariant three-factor structure consistent with the original SBSA. Further analyses showed that the three subscales and the entire scale exhibited high internal consistency (0.779-0.837), good criterion validity, and good convergent and divergent validity (i.e., negative associations with flourishing and positive associations with anxiety, depression, and stress). These findings indicated that NSBI is reliable and valid for measuring negative self-beliefs in the Chinese population. A higher total score of NSBI indicates the more serious negative self-beliefs. Limitations of the present study and implications for research and practice were also discussed. Further studies are needed to evaluate the predictive ability, incremental validity, and potential role of NSBI in clinical and large-scale populations. PMID- 26500822 TI - Growing coral larger and faster: micro-colony-fusion as a strategy for accelerating coral cover. AB - Fusion is an important life history strategy for clonal organisms to increase access to shared resources, to compete for space, and to recover from disturbance. For reef building corals, fragmentation and colony fusion are key components of resilience to disturbance. Observations of small fragments spreading tissue and fusing over artificial substrates prompted experiments aimed at further characterizing Atlantic and Pacific corals under various conditions. Small (~1-3 cm(2)) fragments from the same colony spaced regularly over ceramic tiles resulted in spreading at rapid rates (e.g., tens of square centimeters per month) followed by isogenic fusion. Using this strategy, we demonstrate growth, in terms of area encrusted and covered by living tissue, of Orbicella faveolata, Pseudodiploria clivosa, and Porites lobata as high as 63, 48, and 23 cm(2) per month respectively. We found a relationship between starting and ending size of fragments, with larger fragments growing at a faster rate. Porites lobata showed significant tank effects on rates of tissue spreading indicating sensitivity to biotic and abiotic factors. The tendency of small coral fragments to encrust and fuse over a variety of surfaces can be exploited for a variety of applications such as coral cultivation, assays for coral growth, and reef restoration. PMID- 26500823 TI - Autophagic flux inhibition and lysosomogenesis ensuing cellular capture and retention of the cationic drug quinacrine in murine models. AB - The proton pump vacuolar (V)-ATPase is the driving force that mediates the concentration of cationic drugs (weak bases) in the late endosome-lysosome continuum; secondary cell reactions include the protracted transformation of enlarged vacuoles into autophagosomes. We used the inherently fluorescent tertiary amine quinacrine in murine models to further assess the accumulation and signaling associated with cation trapping. Primary fibroblasts concentrate quinacrine ~5,000-fold from their culture medium (KM 9.8 uM; transport studies). The drug is present in perinuclear granules that are mostly positive for Rab7 and LAMP1 (microscopy). Both drug uptake and retention are extensively inhibited by treatments with the V-ATPase inhibitor bafilomycin A1. The H(+) ionophore monensin also prevented quinacrine concentration by fibroblasts. However, inhibition of plasma membrane transporters or of the autophagic process with spautin-1 did not alter quinacrine transport parameters. Ancillary experiments did not support that low micromolar concentrations of quinacrine are substrates for organic cation transporters-1 to -3 or P-glycoprotein. The secondary autophagy induced by quinacrine in cells may derive from the accumulation of incompetent autophagolysosomes, as judged from the accumulation of p62/SQSTM1 and LC3 II (immunoblots). Accordingly, protracted lysosomogenesis is evidenced by increased expression of LAMP1 and LAMP2 in quinacrine-treated fibroblasts (48 h, immunoblots), a response that follows the nuclear translocation of the lysosomal genesis transcription factor TFEB and upregulation of LAMP1 and -2 mRNAs (24 h). Quinacrine administration to live mice evidenced variable distribution to various organs and heterogeneous accumulation within the lung (stereo-microscopy, extraction). Dose-dependent in vivo autophagic and lysosomal accumulation was observed in the lung (immunoblots). No evidence has been found for transport or extrusion mechanisms modulating the cellular uptake of micromolar quinacrine at the plasma membrane level. As shown in vitro and in vivo, V-ATPase-mediated cation sequestration is associated, above a certain threshold, to autophagic flux inhibition and feed-back lysosomogenesis. PMID- 26500824 TI - Six simple questions to detect malnutrition or malnutrition risk in elderly women. AB - Of the numerous instruments available to detect nutritional risk, the most widely used is the Mini Nutritional Assessment (MNA), but it takes 15-20 min to complete and its systematic administration in primary care units is not feasible in practice. We developed a tool to evaluate malnutrition risk that can be completed more rapidly using just clinical variables. Between 2008 and 2013, we conducted a cross-sectional study of 418 women aged >=60 years from Mexico. Our outcome was positive MNA and our secondary variables included were: physical activity, diabetes mellitus, hypertension, educational level, dentition, psychological problems, living arrangements, history of falls, age and the number of tablets taken daily. The sample was divided randomly into two groups: construction and validation. Construction: a risk table was constructed to estimate the likelihood of the outcome, and risk groups were formed. VALIDATION: the area under the ROC curve (AUC) was calculated and we compared the expected and the observed outcomes. The following risk factors were identified: physical activity, hypertension, diabetes, dentition, psychological problems and living with the family. The AUC was 0.77 (95% CI [0.68-0.86], p < 0.001). No differences were found between the expected and the observed outcomes (p = 0.902). This study presents a new malnutrition screening test for use in elderly women. The test is based on six very simple, quick and easy-to-evaluate questions, enabling the MNA to be reserved for confirmation. However, it should be used with caution until validation studies have been performed in other geographical areas. PMID- 26500825 TI - Assessing shoreline exposure and oyster habitat suitability maximizes potential success for sustainable shoreline protection using restored oyster reefs. AB - Oyster reefs provide valuable ecosystem services that contribute to coastal resilience. Unfortunately, many reefs have been degraded or removed completely, and there are increased efforts to restore oysters in many coastal areas. In particular, much attention has recently been given to the restoration of shellfish reefs along eroding shorelines to reduce erosion. Such fringing reef approaches, however, often lack empirical data to identify locations where reefs are most effective in reducing marsh erosion, or fully take into account habitat suitability. Using monitoring data from 5 separate fringing reef projects across coastal Louisiana, we quantify shoreline exposure (fetch + wind direction + wind speed) and reef impacts on shoreline retreat. Our results indicate that fringing oyster reefs have a higher impact on shoreline retreat at higher exposure shorelines. At higher exposures, fringing reefs reduced marsh edge erosion an average of 1.0 m y(-1). Using these data, we identify ranges of shoreline exposure values where oyster reefs are most effective at reducing marsh edge erosion and apply this knowledge to a case study within one Louisiana estuary. In Breton Sound estuary, we calculate shoreline exposure at 500 random points and then overlay a habitat suitability index for oysters. This method and the resulting visualization show areas most likely to support sustainable oyster populations as well as significantly reduce shoreline erosion. Our results demonstrate how site selection criteria, which include shoreline exposure and habitat suitability, are critical to ensuring greater positive impacts and longevity of oyster reef restoration projects. PMID- 26500826 TI - Anvi'o: an advanced analysis and visualization platform for 'omics data. AB - Advances in high-throughput sequencing and 'omics technologies are revolutionizing studies of naturally occurring microbial communities. Comprehensive investigations of microbial lifestyles require the ability to interactively organize and visualize genetic information and to incorporate subtle differences that enable greater resolution of complex data. Here we introduce anvi'o, an advanced analysis and visualization platform that offers automated and human-guided characterization of microbial genomes in metagenomic assemblies, with interactive interfaces that can link 'omics data from multiple sources into a single, intuitive display. Its extensible visualization approach distills multiple dimensions of information about each contig, offering a dynamic and unified work environment for data exploration, manipulation, and reporting. Using anvi'o, we re-analyzed publicly available datasets and explored temporal genomic changes within naturally occurring microbial populations through de novo characterization of single nucleotide variations, and linked cultivar and single cell genomes with metagenomic and metatranscriptomic data. Anvi'o is an open source platform that empowers researchers without extensive bioinformatics skills to perform and communicate in-depth analyses on large 'omics datasets. PMID- 26500828 TI - Promoting an active form of learning out-of-class via answering online "study questions" leads to higher than expected exam scores in General Biology. AB - A rising need for workers in science, technology, engineering and mathematics (STEM) fields has fueled interest in improving teaching within STEM disciplines. Numerous studies have demonstrated the benefits of active learning approaches on student learning outcomes. However, many of these studies have been conducted in experimental, rather than real-life class, settings. In addition, most of these studies have focused on in-class active learning exercises. This study tested the effects of answering questions outside of class on exam performance for General Biology students at the University of Minnesota. An online database of 1,020 multiple-choice questions covering material from the first half of the course was generated. Students in seven course sections (with an average of ~265 students per section) were given unlimited access to the online study questions. These students made extensive use of the online questions, with students answering an average of 1,323 questions covering material from the half of the semester for which the questions were available. After students answered a set of questions, they were shown the correct answers for those questions. More specific feedback describing how to arrive at the correct answer was provided for the 73% of the questions for which the correct answers were not deemed to be self-explanatory. The extent to which access to the online study questions improved student learning outcomes was assessed by comparing the performance on exam questions of students in the seven course sections with access to the online study questions with the performance of students in course sections without access to the online study questions. Student performance was analyzed for a total of 89 different exams questions that were not included in the study questions, but that covered the same material covered by the study questions. Each of these 89 questions was used on one to five exams given to students in course sections that had access to the online study questions and on three to 77 exams given to students in sections that lacked such access. Data from over 1,800 students in sections with access to the online study questions show that those students scored a statistically significant average of 6.6% points higher on the exam questions analyzed than students in sections without access to the study questions. This difference was greater than the average amount necessary to raise students' exam grades by one grade (e.g., from a "B-" to a "B"). In addition, there was a higher correlation between number of questions answered and success on exam questions on material related to the study questions than between number of questions answered and success on exam questions on material unrelated to the study questions. The online study question system required substantial effort to set up, but required minimal effort to maintain and was effective in significantly raising average exam scores for even very large course sections. PMID- 26500827 TI - Interdisciplinary, interinstitutional and international collaboration of family medicine researchers in Taiwan. AB - The family medicine researches flourished worldwide in the past decade. However, the collaborative patterns of family medicine publications had not been reported. Our study analyzed the collaborative activity of family medicine researchers in Taiwan. We focused on the types of collaboration among disciplines, institutions and countries. We searched "family medicine" AND "Taiwan" in address field from Web of Science and documented the disciplines, institutions and countries of all authors. We analyzed the collaborative patterns of family medicine researchers in Taiwan from 2010 to 2014. The journal's impact factor of each article in the same publication year was also retrieved. Among 1,217 articles from 2010 to 2014, interdisciplinary collaboration existed in 1,185 (97.3%) articles, interinstitutional in 1,012 (83.2%) and international in 142 (11.7%). Public health was the most common collaborative discipline. All international researches were also interdisciplinary and interinstitutional. The United States (75 articles), the United Kingdom (21) and the People's Republic of China (20) were the top three countries with which family medicine researchers in Taiwan had collaborated. We found a high degree of interdisciplinary and interinstitutional collaboration of family medicine researches in Taiwan. However, the collaboration of family medicine researchers in Taiwan with family medicine colleagues of other domestic or foreign institutions was insufficient. The future direction of family medicine studies could focus on the promotion of communication among family medicine researchers. PMID- 26500830 TI - Stable isotope analyses of web-spinning spider assemblages along a headwater stream in Puerto Rico. AB - Web-spinning spiders that inhabit stream channels are considered specialists of aquatic ecosystems and are major consumers of emerging aquatic insects, while other spider taxa are more commonly found in riparian forests and as a result may consume more terrestrial insects. To determine if there was a difference in spider taxa abundance between riverine web-spinning spider assemblages within the stream channel and the assemblages 10 m into the riparian forest, we compared abundances for all web-spinning spiders along a headwater stream in El Yunque National Forest in northeast Puerto Rico. By using a nonmetric dimensional scaling (NMDS) abundance analysis we were able to see a clear separation of the two spider assemblages. The second objective of the study was to determine if aquatic insects contributed more to the diet of the spider assemblages closest to the stream channel and therefore stable isotope analyses of delta (15)N and delta (13)C for web-spinning spiders along with their possible prey were utilized. The results of the Bayesian mixing model (SIAR) however showed little difference in the diets of riverine (0 m), riparian (10 m) and upland (25 m) spiders. We found that aquatic insects made up ~50% of the diet for web-spinning spiders collected at 0 m, 10 m, and 25 m from the stream. This study highlights the importance of aquatic insects as a food source for web-spinning spiders despite the taxonomic differences in assemblages at different distances from the stream. PMID- 26500829 TI - A reappraisal of the morphology and systematic position of the theropod dinosaur Sigilmassasaurus from the "middle" Cretaceous of Morocco. AB - Sigilmassasaurus brevicollis is an enigmatic theropod dinosaur from the early Late Cretaceous (Cenomanian) of Morocco, originally based on a few isolated cervical vertebrae. Ever since its original description, both its taxonomic validity and systematic affinities were contentious. Originally considered to represent its own family, Sigilmassasauridae, the genus has variously been suggested to represent a carcharodontosaurid, an ornithischian, and, more recently, a spinosaurid. Here we describe new remains referrable to this taxon and re-evaluate its taxonomic status and systematic affinities. Based on the new remains, a re-evaluation of the original materials, and comparisons with other spinosaurids, the holotype of Sigilmassasaurus brevicollis is identified as an anterior dorsal, rather than a cervical vertebra, and differences between elements referred to this taxon can be explained by different positions of the elements in question within the vertebral column. Many characters used previously to diagnose the genus and species are found to be more widespread among basal tetanurans, and specifically spinosaurids. However, the taxon shows several autapomorphies that support its validity, including the presence of a strongly rugose, ventrally offset triangular platform that is confluent with a ventral keel anteriorly in the mid-cervical vertebral centra and a strongly reduced lateral neural arch lamination, with no or an incomplete distinction between anterior and posterior centrodiapophyseal laminae in the posterior cervical and anterior dorsal vertebrae. We argue furthermore that Spinosaurus maroccanus, also described on the basis of isolated cervical vertebrae from the same stratigraphic unit and in the same paper as Sigilmassasaurus brevicollis, is a subjective synonym of the latter. Both a detailed comparison of this taxon with other theropods and a formal phylogenetic analysis support spinosaurid affintities for Sigilmassasaurus. However, we reject the recently proposed synonymy of both Spinosaurus maroccanus and Sigilmassasurus brevicollis with Spinosaurus aegyptiacus from the Cenomanian of Egypt, as there are clear differences between the vertebrae of these taxa, and they do not share any derived character that is not found in other spinosaurids. Together with a comparison with other spinosaurid vertebral material from the Kem Kem, this suggests that more than one taxon of spinosaurid was present in the Kem Kem assemblage of Morocco, so the referral of non-overlapping material from this unit to a single taxon should be regarded with caution. PMID- 26500831 TI - Clustering symptoms of non-severe malaria in semi-immune Amazonian patients. AB - Malaria is a disease that generates a broad spectrum of clinical features. The purpose of this study was to evaluate the clinical spectrum of malaria in semi immune populations. Patients were recruited in Mancio Lima, a city situated in the Brazilian Amazon region. The study included 171 malaria cases, which were diagnosed via the use of a thick blood smear and confirmed by molecular methods. A questionnaire addressing 19 common symptoms was administered to all patients. Multiple correspondence analysis and hierarchical cluster analysis were performed to identify clusters of symptoms, and logistic regression was used to identify factors associated with the occurrence of symptoms. The cluster analysis revealed five groups of symptoms: the first cluster, which included algic- and fever related symptoms, occurred in up to 95.3% of the cases. The second cluster, which comprised gastric symptoms (nausea, abdominal pain, inappetence, and bitter mouth), occurred in frequencies that ranged between 35.1% and 42.7%, and at least one of these symptoms was observed in 71.9% of the subjects. All respiratory symptoms were clustered and occurred in 42.7% of the malaria cases, and diarrhea occurred in 9.9% of the cases. Symptoms constituting the fifth cluster were vomiting and pallor, with a 14.6% and 11.7% of prevalence, respectively. A higher parasitemia count (more than 300 parasites/mm(3)) was associated with the presence of fever, vomiting, dizziness, and weakness (P < 0.05). Arthralgia and myalgia were associated with patients over the age of 14 years (P < 0.001). Having experienced at least eight malaria episodes prior to the study was associated with a decreased risk of chills and fever and an increased risk of sore throat (P < 0.05). None of the symptoms showed an association with gender or with species of Plasmodium. The clinical spectrum of malaria in semi-immune individuals can have a broad range of symptoms, the frequency and intensity of which are associated with age, past exposure to malaria, and parasitemia. Understanding the full spectrum of nonsevere malaria is important in endemic areas to guide both passive and active case detection, for the diagnosis of malaria in travelers returning to non-endemic areas, and for the development of vaccines aimed to decrease symptom severity. PMID- 26500832 TI - Allocation trade-off under climate warming in experimental amphibian populations. AB - Climate change could either directly or indirectly cause population declines via altered temperature, rainfall regimes, food availability or phenological responses. However few studies have focused on allocation trade-offs between growth and reproduction under marginal resources, such as food scarce that may be caused by climate warming. Such critical changes may have an unpredicted impact on amphibian life-history parameters and even population dynamics. Here, we report an allocation strategy of adult anuran individuals involving a reproductive stage under experimental warming. Using outdoor mesocosm experiments we simulated a warming scenario likely to occur at the end of this century. We examined the effects of temperature (ambient vs. pre-/post-hibernation warming) and food availability (normal vs. low) on reproduction and growth parameters of pond frogs (Pelophylax nigromaculatus). We found that temperature was the major factor influencing reproductive time of female pond frogs, which showed a significant advancing under post-hibernation warming treatment. While feeding rate was the major factor influencing reproductive status of females, clutch size, and variation of body size for females, showed significant positive correlations between feeding rate and reproductive status, clutch size, or variation of body size. Our results suggested that reproduction and body size of amphibians might be modulated by climate warming or food availability variation. We believe this study provides some new evidence on allocation strategies suggesting that amphibians could adjust their reproductive output to cope with climate warming. PMID- 26500833 TI - Non-invasive Testing for NASH and NASH with Advanced Fibrosis: Are We There Yet? AB - Nonalcoholic fatty liver disease (NAFLD) is the most prevalent etiology of chronic liver disease in America. NAFLD can be broadly classified in two subtypes: nonalcoholic fatty liver (NAFL), which is generally considered a benign condition with negligible risk of progression to cirrhosis, and nonalcoholic steatohepatitis (NASH), which is generally considered to be progressive with substantial risk of progression to cirrhosis. Additionally, recent studies suggest the odds of liver mortality increases amongst NASH patients with advanced fibrosis (bridging fibrosis +/- cirrhosis). Liver biopsy examination is the current gold standard to accurately discriminate between NAFL vs. NASH as well as diagnose advanced fibrosis. However, due to its invasive nature, risk of bleeding (and even rarely death), prohibitive cost, and sampling error, liver biopsies are imperfect for diagnosis and monitoring of NAFLD. As a result, noninvasive biomarkers that can accurately detect NASH and advanced fibrosis without biopsy are needed. This article will discuss the most novel noninvasive biomarkers in diagnosing NASH and advanced fibrosis. PMID- 26500834 TI - Online Gambling Addiction: the Relationship Between Internet Gambling and Disordered Gambling. AB - One of the most significant changes to the gambling environment in the past 15 years has been the increased availability of Internet gambling, including mobile; Internet gambling is the fastest growing mode of gambling and is changing the way that gamblers engage with this activity. Due to the high level of accessibility, immersive interface and ease at which money can be spent, concerns have been expressed that Internet gambling may increase rates of disordered gambling. The current paper aimed to provide an overview of the research to date as well as highlight new and interesting findings relevant to Internet gambling addiction. A comprehensive review of the existing literature was conducted to provide an overview of significant trends and developments in research that relates to disordered Internet gambling. This paper presents research to inform a greater understanding of adult participation in Internet gambling, features of this interface that may impact problem severity, the relationship between Internet gambling and related problems, as well as considering the role of the wider spectrum of gambling behaviour and relevant individual factors that moderate this relationship. PMID- 26500835 TI - Cognitive Behavioral Therapy for Insomnia in the Context of Cardiovascular Conditions. AB - Cardiovascular disease (CVD) is the leading cause of death worldwide and is associated with high levels of morbidity, disability and poor quality of life. The prevalence of insomnia symptoms and diagnosis of insomnia are high among those with CVD. Although insomnia appears to be important to CVD, less is known about the effects of insomnia treatment on important biological, sleep, symptom, quality of life, functional and morbidity or mortality outcomes in people with or at-risk for CVD. The purposes of this paper are to review the literature on the effects of CBT-I on insomnia, sleep, daytime symptoms, function, and biological outcomes in the context of CVD and to suggest implications for future research and practice. Limited available evidence suggests that CBT-I improves biomarkers that may contribute to CVD risk. CBT-I shows promise as a way to improve cardiovascular morbidity associated with the negative biological consequences of chronic insomnia, as well as symptom burden, functional performance and quality of life in the large population of people who are living with chronic CVD and insomnia. Additional research is needed to answer basic questions about short and long term outcomes, the role of biomarkers, and optimal delivery methods of CBT-I in cardiac conditions. PMID- 26500836 TI - Progenitor Cells of the Mandibular Condylar Cartilage. AB - The secondary cartilage of the mandibular condyle is unique as it undergoes endochondral ossification during growth and robustly remodels in response to changes in its mechanical loading environment. This cartilage is derived from mesenchymal progenitor cells that express markers of early osteoblast differentiation, namely alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2). Interestingly, these progenitor cells then differentiate into cartilage with appropriate mechanical loading. Our laboratory has determined that these cells can be labeled by osteoblast progenitor cell markers, including the 3.6 fragment of the rat collagen type 1. However, the role these mesenchymal progenitor cells play in adult mandibular condylar cartilage maintenance and adaptation, as well as the existence of a more potent progenitor cell population within the mandibular condylar cartilage, remain in question. Further characterization of these cells is necessary to determine their potency and regenerative capacity to elucidate their potential for regenerative therapy. PMID- 26500837 TI - Analysis by a highly sensitive split luciferase assay of the regions involved in APP dimerization and its impact on processing. AB - Alzheimer's disease (AD) is a neurodegenerative disease that causes progressive loss of cognitive functions, leading to dementia. Two types of lesions are found in AD brains: neurofibrillary tangles and senile plaques. The latter are composed mainly of the beta-amyloid peptide (Abeta) generated by amyloidogenic processing of the amyloid precursor protein (APP). Several studies have suggested that dimerization of APP is closely linked to Abeta production. Nevertheless, the mechanisms controlling APP dimerization and their role in APP function are not known. Here we used a new luciferase complementation assay to analyze APP dimerization and unravel the involvement of its three major domains: the ectodomain, the transmembrane domain and the intracellular domain. Our results indicate that within cells full-length APP dimerizes more than its alpha and beta C-terminal fragments, confirming the pivotal role of the ectodomain in this process. Dimerization of the APP transmembrane (TM) domain has been reported to regulate processing at the gamma-cleavage site. We show that both non-familial and familial AD mutations in the TM GXXXG motifs strongly modulate Abeta production, but do not consistently change dimerization of the C-terminal fragments. Finally, we found for the first time that removal of intracellular domain strongly increases APP dimerization. Increased APP dimerization is linked to increased non-amyloidogenic processing. PMID- 26500838 TI - Generation of an alpaca-derived nanobody recognizing gamma-H2AX. AB - Post-translational modifications are difficult to visualize in living cells and are conveniently analyzed using antibodies. Single-chain antibody fragments derived from alpacas and called nanobodies can be expressed and bind to the target antigenic sites in living cells. As a proof of concept, we generated and characterized nanobodies against the commonly used biomarker for DNA double strand breaks gamma-H2AX. In vitro and in vivo characterization showed the specificity of the gamma-H2AX nanobody. Mammalian cells were transfected with fluorescent fusions called chromobodies and DNA breaks induced by laser microirradiation. We found that alternative epitope recognition and masking of the epitope in living cells compromised the chromobody function. These pitfalls should be considered in the future development and screening of intracellular antibody biomarkers. PMID- 26500839 TI - E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte. AB - BACKGROUND/PURPOSE: Type 2 diabetes remains a worldwide epidemic with major pathophysiological changes as a result of chronic insulin resistance. Insulin regulates numerous biochemical pathways related to carbohydrate and lipid metabolism. METHODS: We have generated a novel mouse model that allows us to constitutively activate, in an inducible fashion, the distal branch of the insulin signaling transduction pathway specifically in adipocytes. RESULTS: Using the adenoviral 36 E4orf1 protein, we chronically stimulate locally the Ras-ERK MAPK signaling pathway. At the whole body level, this leads to reduced body weight gain under a high fat diet challenge. Despite overlapping glucose tolerance curves, there is a reduced requirement for insulin action under these conditions. The mice further exhibit reduced circulating adiponectin levels that ultimately lead to impaired lipid clearance, and inflamed and fibrotic white adipose tissues. Nevertheless, they are protected from diet-induced hepatic steatosis. As we observe constitutively elevated p-Akt levels in the adipocytes, even under conditions of low insulin levels, this pinpoints enhanced Ras-ERK-MAPK signaling in transgenic adipocytes as a potential alternative route to bypass proximal insulin signaling events. CONCLUSION: We conclude that E4orf1 expression in the adipocyte leads to enhanced baseline activation of the distal insulin signaling node, yet impaired insulin receptor stimulation in the presence of insulin, with important implications for the regulation of adiponectin secretion. The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte. PMID- 26500840 TI - The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis. AB - OBJECTIVE: Hypothalamic agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) expressing neurons play critical roles in control of energy balance. Glutamatergic input via n-methyl-d-aspartate receptors (NMDARs) is pivotal for regulation of neuronal activity and is required in AgRP neurons for normal body weight homeostasis. NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function. Currently, the role of specific GluN2 subunits in AgRP and POMC neurons on whole body energy and glucose balance is unknown. METHODS: We used the cre-lox system to genetically delete GluN2A or GluN2B only from AgRP or POMC neurons in mice. Mice were then subjected to metabolic analyses and assessment of AgRP and POMC neuronal function through morphological studies. RESULTS: We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control. GluN2A subunits in either AgRP or POMC neurons are not required for regulation of body weight. Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length. In addition, loss of GluN2B in AgRP neurons of the morbidly obese and severely diabetic leptin-deficient Lep (ob/ob) mice does not affect body weight and food intake but, remarkably, leads to full correction of hyperglycemia. Lep (ob/ob) mice lacking GluN2B in AgRP neurons are also more sensitive to leptin's anti obesity actions. CONCLUSIONS: GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action. PMID- 26500841 TI - Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation. AB - OBJECTIVE: Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome. METHODS: Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4r (K314X) (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTB (Mc4r) mice, wild-type mice body weight-matched to loxTB (Mc4r) mice, and wild type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats. RESULTS: Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased DeltaFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners. CONCLUSIONS: Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R haploinsufficient individuals despite reduced positive reinforcement during exercise training. PMID- 26500842 TI - Leptin modulates nutrient reward via inhibitory galanin action on orexin neurons. AB - OBJECTIVE: Leptin modulates food reward via central leptin receptor (LepRb) expressing neurons. Food reward requires stimulation of midbrain dopamine neurons and is modulated by central leptin action, but the exact central mechanisms remain unclear. Stimulatory and inhibitory leptin actions on dopamine neurons have been reported, e.g. by indirect actions on orexin neurons or via direct innervation of dopamine neurons in the ventral tegmental area. METHODS: We showed earlier that LepRb neurons in the lateral hypothalamus (LHA) co-express the inhibitory acting neuropeptide galanin (GAL-LepRb neurons). We studied the involvement of GAL-LepRb neurons to regulate nutrient reward in mice with selective LepRb deletion from galanin neurons (GAL-LepRb(KO) mice). RESULTS: We found that the rewarding value and preference for sucrose over fat was increased in GAL-LepRb(KO) mice compared to controls. LHA GAL-LepRb neurons innervate orexin neurons, but not the VTA. Further, expression of galanin and its receptor GalR1 are decreased in the LHA of GAL-LepRb(KO) mice, resulting in increased activation of orexin neurons. CONCLUSION: We suggest galanin as an important mediator of leptin action to modulate nutrient reward by inhibiting orexin neurons. PMID- 26500843 TI - Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. AB - OBJECTIVE: Although Glucagon-like peptide 1 is a key regulator of energy metabolism and food intake, the precise location of GLP-1 receptors and the physiological relevance of certain populations is debatable. This study investigated the novel GLP-1R-Cre mouse as a functional tool to address this question. METHODS: Mice expressing Cre-recombinase under the Glp1r promoter were crossed with either a ROSA26 eYFP or tdRFP reporter strain to identify GLP-1R expressing cells. Patch-clamp recordings were performed on tdRFP-positive neurons in acute coronal brain slices from adult mice and selective targeting of GLP-1R cells in vivo was achieved using viral gene delivery. RESULTS: Large numbers of eYFP or tdRFP immunoreactive cells were found in the circumventricular organs, amygdala, hypothalamic nuclei and the ventrolateral medulla. Smaller numbers were observed in the nucleus of the solitary tract and the thalamic paraventricular nucleus. However, tdRFP positive neurons were also found in areas without preproglucagon-neuronal projections like hippocampus and cortex. GLP-1R cells were not immunoreactive for GFAP or parvalbumin although some were catecholaminergic. GLP-1R expression was confirmed in whole-cell recordings from BNST, hippocampus and PVN, where 100 nM GLP-1 elicited a reversible inward current or depolarisation. Additionally, a unilateral stereotaxic injection of a cre-dependent AAV into the PVN demonstrated that tdRFP-positive cells express cre recombinase facilitating virally-mediated eYFP expression. CONCLUSIONS: This study is a comprehensive description and phenotypic analysis of GLP-1R expression in the mouse CNS. We demonstrate the power of combining the GLP-1R-CRE mouse with a virus to generate a selective molecular handle enabling future in vivo investigation as to their physiological importance. PMID- 26500844 TI - Molecular regulation of urea cycle function by the liver glucocorticoid receptor. AB - OBJECTIVE: One of the major side effects of glucocorticoid (GC) treatment is lean tissue wasting, indicating a prominent role in systemic amino acid metabolism. In order to uncover a novel aspect of GCs and their intracellular-receptor, the glucocorticoid receptor (GR), on metabolic control, we conducted amino acid and acylcarnitine profiling in human and mouse models of GC/GR gain- and loss-of function. METHODS: Blood serum and tissue metabolite levels were determined in Human Addison's disease (AD) patients as well as in mouse models of systemic and liver-specific GR loss-of-function (AAV-miR-GR) with or without dexamethasone (DEX) treatments. Body composition and neuromuscular and metabolic function tests were conducted in vivo and ex vivo, the latter using precision cut liver slices. RESULTS: A serum metabolite signature of impaired urea cycle function (i.e. higher [ARG]:[ORN + CIT]) was observed in human (CTRL: 0.45 +/- 0.03, AD: 1.29 +/ 0.04; p < 0.001) and mouse (AAV-miR-NC: 0.97 +/- 0.13, AAV-miR-GR: 2.20 +/- 0.19; p < 0.001) GC/GR loss-of-function, with similar patterns also observed in liver. Serum urea levels were consistently affected by GC/GR gain- (~+32%) and loss (~-30%) -of-function. Combined liver-specific GR loss-of-function with DEX treatment revealed a tissue-autonomous role for the GR to coordinate an upregulation of liver urea production rate in vivo and ex vivo, and prevent hyperammonaemia and associated neuromuscular dysfunction in vivo. Liver mRNA expression profiling and GR-cistrome mining identified Arginase I (ARG1) a urea cycle gene targeted by the liver GR. CONCLUSIONS: The liver GR controls systemic and liver urea cycle function by transcriptional regulation of ARG1 expression. PMID- 26500846 TI - Corrigendum to "Obesity in a model of gpx4 haploinsufficiency uncovers a causal role for lipid-derived aldehydes in human metabolic disease and cardiomyopathy" [Mol Metab 4 (6) (2015) 493-506]. AB - [This corrects the article DOI: 10.1016/j.molmet.2015.04.001.]. PMID- 26500845 TI - TIMP3 interplays with apelin to regulate cardiovascular metabolism in hypercholesterolemic mice. AB - OBJECTIVE: Tissue inhibitor of metalloproteinase 3 (TIMP3) is an extracellular matrix (ECM) bound protein, which has been shown to be downregulated in human subjects and experimental models with cardiometabolic disorders, including type 2 diabetes mellitus, hypertension and atherosclerosis. The aim of this study was to investigate the effects of TIMP3 on cardiac energy homeostasis during increased metabolic stress conditions. METHODS: ApoE(-/-)TIMP3(-/-) and ApoE(-/-) mice on a C57BL/6 background were subjected to telemetric ECG analysis and experimental myocardial infarction as models of cardiac stress induction. We used Western blot, qRT-PCR, histology, metabolomics, RNA-sequencing and in vivo phenotypical analysis to investigate the molecular mechanisms of altered cardiac energy metabolism. RESULTS: ApoE(-/-)TIMP3(-/-) revealed decreased lifespan. Telemetric ECG analysis showed increased arrhythmic episodes, and experimental myocardial infarction by left anterior descending artery (LAD) ligation resulted in increased peri-operative mortality together with increased scar formation, ventricular dilatation and a reduction of cardiac function after 4 weeks in the few survivors. Hearts of ApoE(-/-)TIMP3(-/-) exhibited accumulation of neutral lipids when fed a chow diet, which was exacerbated by a high fat, high cholesterol diet. Metabolomics analysis revealed an increase in circulating markers of oxidative stress with a reduction in long chain fatty acids. Using whole heart mRNA sequencing, we identified apelin as a putative modulator of these metabolic defects. Apelin is a regulator of fatty acid oxidation, and we found a reduction in the levels of enzymes involved in fatty acid oxidation in the left ventricle of ApoE(-/-)TIMP3(-/-) mice. Injection of apelin restored the hitherto identified metabolic defects of lipid oxidation. CONCLUSION: TIMP3 regulates lipid metabolism as well as oxidative stress response via apelin. These findings therefore suggest that TIMP3 maintains metabolic flexibility in the heart, particularly during episodes of increased cardiac stress. PMID- 26500848 TI - A radiolabeled antibody targeting CD123(+) leukemia stem cells - initial radioimmunotherapy studies in NOD/SCID mice engrafted with primary human AML. AB - Radioimmunotherapy (RIT) with anti-CD123 monoclonal antibody CSL360 modified with nuclear translocation sequence (NLS) peptides and labeled with the Auger electron emitter, (111)In ((111)In-NLS-CSL360) was studied in the prevalent NOD/SCID mouse AML engraftment assay. Significant decreases in CD123(+) leukemic cells and impairment of leukemic stem cell self-renewal were achieved with high doses of RIT. However, NOD/SCID mice were very radiosensitive to these doses. At low non toxic treatment doses, (111)In-NLS-CSL360 demonstrated a trend towards improved survival associated with decreased spleen/body weight ratio, an indicator of leukemia burden, and almost complete eradication of leukemia from the bone marrow in some mice. PMID- 26500847 TI - Synchrotron infrared imaging of advanced glycation endproducts (AGEs) in cardiac tissue from mice fed high glycemic diets. AB - Recent research findings correlate an increased risk for dieases such as diabetes, macular degeneration and cardiovascular disease (CVD) with diets that rapidly raise the blood sugar levels; these diets are known as high glycemic index (GI) diets which include white breads, sodas and sweet deserts. Lower glycemia diets are usually rich in fruits, non-starchy vegetables and whole grain products. The goal of our study was to compare and contrast the effects of a low vs. high glycemic diet using the biochemical composition and microstructure of the heart. The improved spatial resolution and signal-to-noise for SR-FTIR obtained through the coupling of the bright synchrotron infrared photon source to an infrared spectral microscope enabled the molecular-level observation of diet related changes within unfixed fresh frozen histologic sections of mouse cardiac tissue. High and low glycemic index (GI) diets were started at the age of five months and continued for one year, with the diets only differing in their starch distribution (high GI diet = 100% amylopectin versus low GI diet = 30% amylopectin/70% amylose). Serial cryosections of cardiac tissue for SR-FTIR imaging alternated with adjacent hematoxylin and eosin (H&E) stained sections allowed not only fine-scale chemical analyses of glycogen and glycolipid accumulation along a vein as well as protein glycation hotspots co-localizing with collagen cold spots but also the tracking of morphological differences occurring in tandem with these chemical changes. As a result of the bright synchrotron infrared photon source coupling, we were able to provide significant molecular evidence for a positive correlation between protein glycation and collagen degradation in our mouse model. Our results bring a new insight not only to the effects of long-term GI dietary practices of the public but also to the molecular and chemical foundation behind the cardiovascular disease pathogenesis commonly seen in diabetic patients. PMID- 26500849 TI - Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia. AB - PI3Kdelta inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (alpha, beta, delta, and gamma) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms. PMID- 26500850 TI - Patterns of relapse and outcome of elderly multiple myeloma patients treated as front-line therapy with novel agents combinations. AB - We report the characteristics of relapse, treatment response, and outcomes of 145 elderly patients with multiple myeloma in first relapse after front-line treatment with VMP or VTP. Reappearance of CRAB symptoms (113 patients) and more aggressive forms of disease (32 patients) were the most common patterns of relapse. After second-line therapy, 75 (51.7%) patients achieved at partial response and 16 (11%) complete response (CR). Overall survival was longer among patients receiving VMP as front-line induction (21.4 vs. 14.4 months, P=0.037), in patients achieving CR (28.3 vs. 14.8 months; P=0.04), and in patients without aggressive relapse (28.6 vs. 7.6 months; P=0.0007). PMID- 26500851 TI - Surgical Neonatal Sepsis in Developing Countries. PMID- 26500852 TI - Feeding Intolerance and Poor Growth in Infants with Gastroschisis: Longitudinal Experience with Consecutive Patients over Thirteen Years. AB - OBJECTIVES: 1) To investigate in-hospital factors associated with delayed tolerance of full volume enteral nutrition and 2) To assess longitudinal growth in a contemporary population of infants with gastroschisis. DESIGN: Retrospective single-center study of all infants with gastroschisis Setting: Level III neonatal intensive care unit in a free-standing Children's Hospital Duration: 13.5 years MATERIALS & METHODS: Detailed data regarding demographics, nutritional support, growth, and infant outcomes was collected for all infants with gastroschisis. Linear regression was used to investigate in-hospital factors associated with feeding intolerance and poor growth. RESULTS: For 52 infants, the median gestational age at birth was 36 weeks, the median postnatal age to achieve full feeds was 22 days, and median in-hospital weight gain was 18 gm/day. With linear regression, there was a positive association between time to full feeds and both hospital length of stay (adjusted R2=0.503, p < 0.0001) and (unexpectedly) in hospital weight gain (adjusted R2=0.125, p=0.0248). There was a negative association between in-hospital weight gain and preterm birth (adjusted R2=0.125, p=0.0356). For infants with longitudinal growth data, 35% had a weight < 5th percentile (of whom 67% were preterm). CONCLUSIONS: Many infants with gastroschisis have poor growth before and after hospital discharge. Aggressive feeding advancement may be a contributing factor to this finding and preterm infants may be at greater risk for poor growth than term infants. PMID- 26500853 TI - Urinary Claudin-2 Measurements as a Predictor of Necrotizing Enterocolitis: A Pilot Study. AB - BACKGROUND: Necrotizing Enterocolitis (NEC) affects 5-10% of NICU patients where initially patients may have only nonspecific clinical findings. A noninvasive tool for detection would aid in diagnosis. Increased urinary claudins have been associated with active adult inflammatory bowel disease. METHODS: Institutional Review Board approval was obtained. Neonatal intestinal tissue samples were obtained from patients with and without NEC. Immunofluorescence analysis of claudin-2 was performed on the intestinal tissue. Thirty two urine samples were collected from 6 NICU patients. Proteins were extracted and urinary claudin-2 expression was measured using Western Blot Analysis. All sample concentrations were normalized to urinary creatinine. Differences were analyzed with ANOVA or Student's T-test. Findings were correlated to the patient's clinical status. RESULTS: Neonatal intestinal immunofluorescence analysis revealed that claudin-2 is present in healthy intestinal epithelium and is decreased in NEC intestinal tissue (p=0.0001). Of the six patients evaluated, three patients had NEC. All 3 patients with NEC had spikes in urinary claudin-2 levels (p<0.001, p<0.001, p 0.0598 respectively). Spikes did not appear to correlate with other etiologies of neonatal sepsis, medication use or need for mechanical ventilation. Levels during active NEC were almost twice that of NEC-free periods (p<0.0001). CONCLUSION: A tool for early detection would facilitate early intervention and potential prevention of severe NEC. Preliminary findings indicate that urinary claudin-2 may represent a potential biomarker for NEC worth further investigation. PMID- 26500855 TI - Upper Airway Obstruction in a Newborn with Vallecular Cyst. AB - Vallecular cyst is a rare cause of stridor in neonates, which may present as a life threatening airway obstruction. Here, we report a preterm infant with a congenital vallecular cyst who presented with stridor and respiratory distress that developed immediately after birth. She was successfully treated with endoscopic marsupialization. PMID- 26500854 TI - Coexistence of Anal Atresia, Anophthalmia and Intestinal Neuronal Dysplasia Type A in a Newborn. AB - We report a patient with anal atresia, anophthalmia and intestinal neuronal dysplasia type A. PMID- 26500856 TI - Meckel's Diverticulum causing Intussusception in a Newborn. AB - A neonate presenting with intussusception probably caused by Meckel's diverticulum is reported here. PMID- 26500857 TI - Epidermolysis Bullosa with Hypertrophic Pyloric Stenosis in a Newborn. AB - Epidermolysis bullosa (EB) is an inherited blistering disorder characterized by the fragility of the skin and mucous membranes. Extracutaneous manifestations can be associated. We report a unique concomitant occurrence of EB and hypertrophic pyloric stenosis in a newborn. PMID- 26500858 TI - Intestinal Obstruction due to Ileal Duplication Cyst and Malrotation in a Preterm Neonate. PMID- 26500859 TI - Hernia of Umbilical Cord associated with Cleft Lip and Palate, and Congenital Glaucoma. PMID- 26500860 TI - Livedo reticularis: A review of the literature. AB - Livedo reticularis (LR) is a cutaneous physical sign characterized by transient or persistent, blotchy, reddish-blue to purple, net-like cyanotic pattern. LR is a benign disorder affecting mainly middle-aged females, whereas livedo racemosa (LRC) is pathologic, commonly associated with antiphospholipid antibody syndrome. This article aims to review the causes of LR and LRC along with the evaluation and management. PMID- 26500861 TI - Role of C-reactive protein as a marker of disease severity and cardiovascular risk in patients with psoriasis. AB - BACKGROUND: There is a paucity of studies addressing the elevation of C-reactive protein (CRP) among psoriatic patients and the role of this marker in assessment of disease severity and association with cardiovascular diseases (CVDs). OBJECTIVE: To assess the difference in CRP levels between psoriatic patients and healthy population and to determine their role in disease severity. Also to compare CRP levels in psoriatic patients with and without the metabolic syndrome. MATERIALS AND METHODS: A total of hundred patients with chronic plaque psoriasis and an equal number of age- and gender-matched healthy controls were enrolled in the study over a period of one year. Serum CRP levels of both cases and controls were estimated. Metabolic syndrome was identified among psoriasis patients using National Cholesterol Education Program's Adult Panel III (ATP III) guidelines. Clinical activity of psoriasis was evaluated using Psoriasis Area and Severity Index Score. RESULTS: Patients with psoriasis reported significantly higher levels of CRP than healthy controls (P value 0.001). Patients with severe disease had significantly higher levels of CRP (P value < 0.003). Elevated level of CRP was observed among psoriatic patients with the metabolic syndrome than patients without the metabolic syndrome and the difference was statistically significant (P value = 0.001). CONCLUSION: CRP may be considered as a useful marker of psoriasis severity that could be used to monitor psoriasis and its treatment. Elevated levels of CRP may be an independent risk factor for CVD in patients with psoriasis. PMID- 26500863 TI - Kindler syndrome with palmoplantar hyperhidrosis and blonde hair. AB - Kindler syndrome (KS) is a very rare genodermatosis characterized by acral blistering starting in infancy along with photosensitivity, progressive poikiloderma, cutaneous atrophy, and a variable degree of mucosal involvement. A large number of other cutaneous and extracutaneous features have been described, which aid in diagnosing it. Generally KS has been found to be associated with hypohidrosis/anhidrosis. We herein present a rare case of KS with unique features. PMID- 26500862 TI - Narrowband UVB phototherapy in pityriasis rosea. AB - OBJECTIVE: Pityriasis rosea (PR) is an acute self-limiting disease. Despite vigorous efforts by generations of researchers since nearly 150 years, present treatment modalities for PR are not very gratifying. Ultraviolet radiation has been recommended in PR, although only a few studies validate this proposal. This study was conducted to explore the therapeutic effect of NBUVB on the symptoms, course, and severity of PR. MATERIALS AND METHODS: This study involved a hundred patients who were randomly divided into two groups, using computer-generated randomization chart. Group A underwent treatment with fixed dose NBUVB of 250 mJ/cm(2) three times (nonconsecutive) a week for 4 weeks. Group B formed the placebo group who did not receive any treatment. The two groups were compared with each other for the intensity of pruritis, course and duration of disease, and PR severity score (PRSS). RESULTS: The t values of improvement in PRSS score in Group A (t = 12.796) were higher as compared with that in Group B (t = 10.066). Similarly, the t value of the pruritus scale in Group A (t = 7.758) was higher than Group B (t = 5.754) indicating the symptomatic improvement in itching. CONCLUSION: Fixed-dose NBUVB phototherapy resulted in marked improvement in the severity and symptoms of the disease as quantitatively assessed by PRSS. PMID- 26500864 TI - Lichen striatus with onychodystrophy in an infant. AB - Lichen striatus with nail involvement is rare and is often unnoticed. Nail changes are often nonspecific but they are usually localized to one portion of the nail. Also single nail involvement and presence of skin lesions near the nail are often noticed. We report the case of an infant with lichen striatus and nail involvement. PMID- 26500865 TI - Ecthyma gangrenosum in a previously healthy patient. AB - Ecthyma gangrenosum is a rare skin infection caused by Pseudomonas aeruginosa. It is usually seen in immunocompromised and critically ill patients. We report one such case in a previously healthy 20-year old male. Ecthyma gangrenosum can occur in healthy patients without bacteremia. PMID- 26500866 TI - Penoscrotal porokeratosis: A distinct entity. AB - A 26-year-old man presented with five months history of redness associated with itching and burning over the scrotum and shaft of the penis with a persistent rash on those sites. There had been no response to topical steroid and antifungal creams. Clinical examination revealed a large well-circumscribed erythematous plaque with a thready raised border with a tiny groove at its summit that involved almost two-thirds of the ventral part of the shaft of the penis. Ill defined erythema with a granular surface was seen over the anterior scrotal skin. A 4 mm punch biopsy of the plaque on the penile shaft revealed multiple cornoid lamellae located adjacent to one another. The patient was treated with topical emollients. Follow up after four months revealed almost complete resolution of the plaque on the penile shaft. Penoscrotal porokeratosis appears to be a distinct entity in the family of porokeratotic diseases, described only in young males in their twenties with involvement of the penile shaft and anterior scrotum with severe burning and itching and histologically associated with multiple cornoid lamellae. It may represent an unusual epidermal porokeratotic reaction pattern and may be a self-resolving condition. PMID- 26500867 TI - Extragenital lichen sclerosus et atrophicus along the lines of Blaschko. AB - Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory dermatosis of unknown etiology. Extragenital involvement is uncommon and commonly affects the neck, shoulders, and upper portion of the trunk. It is predominant in women with a male-to-female ratio of 1:6 and occurs at any age. Linear pattern along the lines of Blaschko are seen. There is no cure for LSA. Topical corticosteroids and calcineurin inhibitors, such as tacrolimus, pimecrolimus, PUVA antimalarial agents, and topical retinoids have been tried with varying results. A case of a 33-year-old man with LSA over right lower limb along the lines of Blasckho is reported here. PMID- 26500868 TI - Linear Darier's disease: A case with bilateral presentation. AB - Darier's disease is an autosomal dominant genodermatosis characterized by a persistent eruption of hyperkeratotic greasy papules mainly over the seborrheic sites of the body, usually associated with nail abnormalities and sometimes with mucous membrane lesions. The lesions typically occur in the younger age group and are associated with pruritus. We report here an atypical case of Linear Darier's disease with bilateral presentation in a middle-aged adult that could be confused with conditions such as lichen planus, inflammatory linear verrucous epidermal nevus, and wart. PMID- 26500869 TI - Unilateral hypertrophic skin lesions, hemimegalencephaly, and meningioma: The many faces of Proteus syndrome. AB - Proteus syndrome is a rare condition with a wide spectrum of abnormalities. It is characterized by hamartomatous malformations involving multiple organs. Serious complications may ensue, such as pulmonary embolism, cystic lung disease, and various neoplasms such as parotid adenomas, ovarian cystadenomas, and meningiomas. We report here a case of Proteus syndrome in a 21-year-old woman who had facial hemihypertrophy, cerebriform plantar hyperplasia, hemimegalencephaly, and meningioma for the rarity of the entity. PMID- 26500870 TI - Atrichia congenita. AB - Atrichia congenita is a rare genodermatoses is characterized by a mutation of the human hairless (HR) gene on chromosome 8p22. There is loss of scalp hair between one to six months of age, after which no growth occurs. Eyebrow, eyelash, and body hair may also be sparse or absent; patients may have a few pubic and axillary hairs. The condition may present in isolation or along with other defects. PMID- 26500871 TI - A rubbery dermal nodule. PMID- 26500872 TI - An indurated plantar plaque with surface nodularity. PMID- 26500873 TI - Nevus depigmentosus with unilateral bluish sclera, a rare entity. PMID- 26500874 TI - Phaeohyphomycosis presenting as a solitary nodulocystic lesion in a renal transplant patient. PMID- 26500875 TI - Neutrophilic dermatosis of the dorsal hands: A rare unilateral presentation. PMID- 26500876 TI - Pronounced skin folds with finger clubbing. PMID- 26500877 TI - Kaposi varicelliform eruption. PMID- 26500878 TI - Liposomal doxorubicin-induced palmoplantar erythrodysthesia syndrome. PMID- 26500879 TI - SkIndia Quiz 20: A case of multiple nodules on forearm. PMID- 26500880 TI - Vulval elephantiasis. PMID- 26500881 TI - Sister Mary Joseph's nodule. PMID- 26500882 TI - Soft pink nodules on the scalp. PMID- 26500883 TI - Crab louse. PMID- 26500884 TI - Axillary syringomas mimicking Fox-Fordyce disease. PMID- 26500885 TI - Misfolded N-CoR is Linked to the Ectopic Reactivation of CD34/Flt3-Based Stem Cell Phenotype in Promyelocytic and Monocytic Acute Myeloid Leukemia. AB - Nuclear receptor co-repressor (N-CoR) is the key component of generic co repressor complex essential for the transcriptional control of genes involved in cellular hemostasis. We have recently reported that N-CoR actively represses Flt3, a key factor of hematopoietic stem cells (HSC) self-renewal and growth, and that de-repression of Flt3 by the misfolded N-CoR plays an important role in the pathogenesis of promyelocytic and monocytic acute myeloid leukemia (AML). The leukemic cells derived from the promyelocytic and monocytic AML are distinctly characterized by the ectopic reactivation of stem cell phenotypes in relatively committed myeloid compartment. However, the molecular mechanism underlying this phenomenon is not known. Here, we report that N-CoR function is essential for the commitment of primitive hematopoietic cells to the cells of myeloid lineage and that loss of N-CoR function due to misfolding is linked to the ectopic reactivation of generic stem cell phenotypes in promyelocytic and monocytic AML. Analysis of N-CoR and Flt3 transcripts in mouse hematopoietic cells revealed a positive correlation between N-CoR level and the commitment of myeloid cells and an inverse correlation between N-CoR and Flt3 levels in primitive as well as committed myeloid cells. Enforced N-CoR expression in mouse HSCs inhibited their growth and self-renewal potentials and promoted maturation toward cells of myeloid lineage, suggesting a role of N-CoR in the commitment of cells of myeloid lineage. In contrast to AML cells with natively folded N-CoR, primary and secondary promyelocytic and monocytic AML cells harboring the misfolded N-CoR were highly positive for Flt3 and myeloid antigen-based HSC marker CD34. Genetic and therapeutic restoration of N-CoR conformation significantly down-regulated the CD34 levels in monocytic AML cells, suggesting an important role of N-CoR in the suppression of CD34-based HSC phenotypes. These findings collectively suggest that N-CoR is crucial for the commitment of primitive hematopoietic cells to cells of myeloid lineage and that misfolded N-CoR may contribute to transformation of committed myeloid cells through the ectopic reactivation of Flt3/CD34-based stem cell phenotypes in promyelocytic and monocytic AML. Moreover, these findings provide novel mechanistic insights into the formation of leukemic stem cells in subsets of AML and identify the misfolded N-CoR as a subtype-specific biomarker of AML. PMID- 26500886 TI - Beyond Bevacizumab: An Outlook to New Anti-Angiogenics for the Treatment of Ovarian Cancer. AB - In addition to the monoclonal vascular endothelial growth factor (VEGF) antibody bevacizumab, several alternative anti-angiogenic treatment strategies for ovarian cancer patients have been evaluated in clinical trials. Apart from targeting extracellular receptors by the antibody aflibercept or the peptibody trebananib, the multikinase inhibitors pazopanib, nintedanib, cediranib, sunitinib, and sorafenib were developed to interfere with VEGF receptors and multiple additional intracellular pathways. Nintedanib and pazopanib significantly improved progression-free survival in two positive phase III trials for first-line therapy. A reliable effect on overall survival could, however, not be observed for any anti-angiogenic first-line therapies so far. In terms of recurrent disease, two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication. Patient selection and biomarker guided prediction of response seems to be a central aspect for future studies. Combining anti-angiogenics with other targeted therapies to possibly spare chemotherapy in certain constellations represents another very interesting future perspective for clinical trials. This short review gives an overview of current clinical trials for anti-angiogenic treatment strategies beyond bevacizumab. In this context, possible future perspectives combining anti angiogenics with other targeted therapies and the need for specific biomarkers predicting response are elucidated. PMID- 26500887 TI - Plastic and Reconstructive Surgery in the Treatment of Oncological Perineal and Genital Defects. AB - Defects of the perineum may result from ablative procedures of different malignancies. The evolution of more radical excisional surgery techniques resulted in an increase in large defects of the perineum. The perineogenital region per se has many different functions for urination, bowel evacuation, sexuality, and reproduction. Up-to-date individual and interdisciplinary surgical treatment concepts are necessary to provide optimum oncological as well as quality of life outcome. Not only the reconstructive method but also the timing of the reconstruction is crucial. In cases of postresectional exposition of e.g., pelvic or femoral vessels or intrapelvic and intra-abdominal organs, simultaneous flap procedure is mandatory. In particular, the reconstructive armamentarium of the plastic surgeon should include not only pedicled flaps but also free microsurgical flaps so that no compromise in terms of the extent of the oncological resection has to be accepted. For intra-abdominally and/or pelvic tumors of the rectum, the anus, or the female reproductive system, which were resected through an abdominally and a sacrally surgical access, simultaneous vertical rectus abdominis myocutaneous (VRAM) flap reconstruction is recommendable. In terms of soft tissue sarcoma of the pelvic/caudal abdomen/proximal thigh region, two-stage reconstructions are possible. This review focuses on the treatment of perineum, genitals, and pelvic floor defects after resection of malignant tumors, giving a distinct overview of the different types of defects faced in this region and describing a number of reconstructive techniques, especially VRAM flap and pedicled flaps like antero-lateral thigh flap or free flaps. Finally, this review outlines some considerations concerning timing of the different operative steps. PMID- 26500888 TI - Treatment Plan Technique and Quality for Single-Isocenter Stereotactic Ablative Radiotherapy of Multiple Lung Lesions with Volumetric-Modulated Arc Therapy or Intensity-Modulated Radiosurgery. AB - The aim of this study is to provide a practical approach to the planning technique and evaluation of plan quality for the multi-lesion, single-isocenter stereotactic ablative radiotherapy (SABR) of the lung. Eleven patients with two or more lung lesions underwent single-isocenter volumetric-modulated arc therapy (VMAT) radiosurgery or IMRS. All plans were normalized to the target maximum dose. For each plan, all targets were treated to the same dose. Plan conformity and dose gradient were maximized with dose-control tuning structures surrounding targets. For comparison, multi-isocenter plans were retrospectively created for four patients. Conformity index (CI), homogeneity index (HI), gradient index (GI), and gradient distance (GD) were calculated for each plan. V5, V10, and V20 of the lung and organs at risk (OARs) were collected. Treatment time and total monitor units (MUs) were also recorded. One patient had four lesions and the remainder had two lesions. Six patients received VMAT and five patients received intensity-modulated radiosurgery (IMRS). For those treated with VMAT, two patients received 3-arc VMAT and four received 2-arc VMAT. For those treated with IMRS, two patients were treated with 10 and 11 beams, respectively, and the rest received 12 beams. Prescription doses ranged from 30 to 54 Gy in three to five fractions. The median prescribed isodose line was 84% (range: 80-86%). The median maximum dose was 57.1 Gy (range: 35.7-65.1 Gy). The mean combined PTV was 49.57 cm(3) (range: 14.90-87.38 cm(3)). For single-isocenter plans, the median CI was 1.15 (range: 0.97-1.53). The median HI was 1.19 (range: 1.16-1.28). The median GI was 4.60 (range: 4.16-7.37). The median maximum radiation dose (Dmax) to total lung was 55.6 Gy (range: 35.7-62.0 Gy). The median mean radiation dose to the lung (Dmean) was 4.2 Gy (range: 1.1-9.3 Gy). The median lung V5 was 18.7% (range: 3.8-41.3%). There was no significant difference in CI, HI, GI, GD, V5, V10, and V20 (lung, heart, trachea, esophagus, and spinal cord) between single-isocenter and multi-isocenter plans. This multi-lesion, single-isocenter lung SABR planning technique demonstrated excellent plan quality and clinical efficiency and is recommended for radiosurgical treatment of two or more lung targets for well suited patients. PMID- 26500889 TI - Editorial: Radioembolization in the Treatment of Liver Cancer: A Multidisciplinary Approach for Individualized Therapy. PMID- 26500890 TI - Structural Characterization of Mucin O-Glycosylation May Provide Important Information to Help Prevent Colorectal Tumor Recurrence. AB - Although colorectal cancer is a preventable and curable disease if early stage tumors are removed, it still represents the second cause of cancer-related death worldwide. Surgical resection is the only curative treatment but once operated the patient is either subjected to adjuvant chemotherapy or not, depending on the invasiveness of the cancer and risks of recurrence. In this context, we investigated, by mass spectrometry (MS), alterations in the repertoire of glycosylation of mucins from colorectal tumors of various stages, grades, and recurrence status. Tumors were also compared with their counterparts in resection margins from the same patients and with healthy controls. The obtained data showed an important decrease in the level of expression of sialylated core 3 based O-glycans in tumors correlated with an increase in sialylated core 1 structures. No correlation was established between stages of the tumor samples and mucin O-glycosylation. However, with the notable exception of sialyl Tn antigens, tumors with recurrence presented a milder alteration of glycosylation profile than tumors without recurrence. These results suggest that mucin O glycans from tumors with recurrence might mimic a healthier physiological situation, hence deceiving the immune defense system. PMID- 26500891 TI - Decreased RXRalpha is Associated with Increased beta-Catenin/TCF4 in (56)Fe Induced Intestinal Tumors. AB - Although it is known that accumulation of oncogenic beta-catenin is critical for intestinal tumorigenesis, the underlying mechanisms have not yet been fully explored. Post-translational beta-catenin level is regulated via the adenomatous polyposis coli (APC)-dependent as well as the APC-independent ubiquitin proteasome pathway (UPP). Employing an APC-mutant mouse model (APC(Min/+)) the present study aimed to investigate the status of RXRalpha, an APC-independent factor involved in targeting beta-catenin to UPP for degradation, in tumor bearing and tumor-free areas of intestine after exposure to energetic (56)Fe ions. APC(Min/+) mice were exposed to energetic (56)Fe ions (4 or 1.6 Gy) and intestinal tumor samples and tumor-free normal intestinal samples were collected 100-110 days after exposure. The status of TCF4, beta-catenin, cyclin D1, and RXRalpha was examined using immunohistochemistry and immunoblots. We observed increased accumulation of the transcription factor TCF4 and its co-activator beta catenin as well as their downstream oncogenic target protein cyclin-D1 in (56)Fe ion-induced intestinal tumors. Further, decreased expression of RXRalpha in tumors as well as in adjacent normal epithelium was indicative of perturbations in beta-catenin proteasomal-targeting machinery. This indicates that decreased UPP targeting of beta-catenin due to downregulation of RXRalpha can contribute to further accumulation of beta-catenin and to (56)Fe-induced tumorigenesis. PMID- 26500892 TI - MicroRNA-17-5p induces drug resistance and invasion of ovarian carcinoma cells by targeting PTEN signaling. AB - BACKGROUND: The miR-17-5p was overexpressed in ovarian cancer cells, and those cells were treated with paclitaxel. The proliferation of ovarian cancer cells was assessed by MTT assay. The Caspase-Glo3/7 and TUNEL assay were used to examine the effect of miR-17-5p on paclitaxel-induced apoptosis in ovarian cancer cells. The migration and invasion of ovarian cancer cells were analyzed by BD matrigel assays. Western blot was performed to evaluate the expression of apoptotic proteins and epithelial-mesenchymal transition markers in ovarian cancer cells. RESULTS: The survival rate of ovarian cancer cells was increased after overexpression of miR-17-5p. The apoptosis decreased in miR-17-5p overexpressed ovarian cancer cells. Altered miR-17-5p expression affected migration and invasion of ovarian cancer cells. The overexpression of miR-17-5p altered the expression of EMT markers. miR-17-5p activates AKT by downregulation of PTEN in ovarian cancer cells. CONCLUSION: Our results indicate that miR-17-5p might serve as potential molecular therapeutic target. PMID- 26500893 TI - Study of Normal Branching Pattern of the Coeliac Trunk and its Variations Using CT Angiography. AB - INTRODUCTION: Blood vessel anomalies are always interesting from embryological view and of considerable significance from a clinical or a surgical standpoint. Vascular anomalies are usually asymptomatic; they may cause problems in patients undergoing diagnostic angiography or any operative procedure. The length and course of the coeliac artery are variable and its branches frequently arise separately from the main trunk. Several other branches may additionally arise from the coeliac trunk, for example, inferior phrenic arteries, the dorsal pancreatic artery, and the middle colic artery. AIM: The present study was undertaken to analyse the vertebral level of origin of coeliac artery, its branching pattern and the associated variations using computed tomographic angiography in 75 subjects. RESULTS: The results obtained were analysed and classified based on Adachi's and Lipshutz's classification method. The results were also compared with various other studies cited in the literature. The level of origin was found to be at the inter-vertebral disc between T12 and L1 in a majority of the cases (70.6%). It was also found that the coeliac trunk trifurcates in majority of the cases i.e. 90.6%. Trifurcation was of two types, classical and non-classical, the classical trunk being the commonest type. Variations included bifurcation of the trunk (8%) with Left gastric artery arising directly from the aorta, in a few cases (1.3%) Common hepatic artery arose as a separate trunk from the aorta. CONCLUSION: A comprehensive knowledge of this arterial anatomy and variations will be very useful when planning abdominal surgeries and image-guided interventions. The success of procedures such as liver transplantation, intestinal anastomosis, intra-arterial chemotherapy, chemo-embolization, and radio-embolization requires a detailed knowledge of the coeliac artery and its anatomical variants, which are extremely common, to avoid iatrogenic injuries and to prevent complications. PMID- 26500894 TI - Junctura Tendinae in the First Intermetacarpal Space: A Case Report. AB - The anatomy of extensor tendons and juncturae tendinum (JT) is of interest to both anatomists and surgeons. Understanding the structure of the JTs and the interactions between the tendons of the fingers is of utmost importance in hand assessment, especially during the reconstructive procedures such as tendon transfers. During routine dissection of extensor tendons of dorsum of hand there was a filamentous band between the tendon of extensor pollicis longus and extensor indices in the first intermetacarpal space. This band was identified as Juncturae tendinae of Type 1. It was attached to the extensor tendons on either side of the first intermetacarpal space in a transverse direction. The presence of Juncturae tendinae in the first intermetacarpal space is a rare variation. This variation is important as it interferes with independent motion of thumb and index finger and also in tendon repairs. PMID- 26500895 TI - Effect of Ubiquinol Therapy on Sperm Parameters and Serum Testosterone Levels in Oligoasthenozoospermic Infertile Men. AB - INTRODUCTION: The male sperm counts decline due to environmental factors, such as pesticides, heavy metals and exogenous estrogens causing negative impact on spermatogenesis. The low testosterone levels are associated with lower levels of antioxidants that protect against free radical damage to glands that produce testosterone. The earlier studies showed that the supplementation of vitamins and antioxidants including 10mg Ubiquinol per-day increases in sperm count and motility. MATERIALS AND METHODS: The Ubiquinol is strong antioxidant, hence in view of the above study 150 mg/day Ubiquinol was supplemented to 60 men with age group of 20-40 years. The patients were supplemented for six months, the testosterone level and sperm parameters were analysed before and after supplementation of Ubiquinol every month up to six months. The total sperm count increased by 53% (p<0.05). RESULTS: The total sperm motility was observed 26% (p<0.05) high after supplementations. Out of total motility, the quantity of rapidly motile sperm increased 41% (p<0.05). The number of sluggish motile sperm was decreased approximate 29% (p<0.05). The non motile sperm count was also decreased up to 55% (p<0.05). CONCLUSION: The testosterone level is maintained during the study and morphology of flagella of sperm has improved. The finding suggests that the supplementation of Ubiquinol may be beneficial for oligospermic patients. PMID- 26500896 TI - A Study on the Level of Oxidative Stress and Inflammatory Markers in Type 2 Diabetes Mellitus Patients with Different Treatment Modalities. AB - INTRODUCTION: The prevalence of type 2 diabetes mellitus is increasing worldwide in all the age group. UKPDS study had shown that good glycaemic control is maintained by the administration of insulin in addition to hypoglycaemic drugs. But, hyperinsulinemia might cause vascular complications in T2DM. Oxidative stress and inflammation are common in diabetes and plays an important role in vascular complications. AIM: The study has been designed to estimate and compare the level of oxidative stress and inflammation in type 2 diabetic patients under different treatment modalities. MATERIALS AND METHODS: Sixty Type 2 diabetic subjects undergoing treatment were selected from Government Hospital and VMKV Medical College & Hospital at Salem. The subjects were divided into two groups based on treatment modalities, hypoglycaemic drugs subjects as Group-I (30) and hypoglycaemic drugs & Insulin subjects in Group-II (30). BMI was calculated by standard formula and Fasting blood sugar (FBS), postprandial blood sugar (PPBS), glycated haemoglobin (HbA1c), Lipid profile, oxidative stress (MDA) and inflammatory markers were measured by well established methods. SPSS 16.0 version was used for statistical analysis. RESULT: In our study we have found significantly high levels of BMI, MDA and hsCRP (25.5+/-2.79, 2.73+/-1.65, 1.98+/ 0.85) in Group II subjects when compared to Group I subjects (23.4+/-3.09, 2.23+/ 1.76, 1.168+/-1.124). CONCLUSION: Since risk factors like BMI, MDA and hsCRP were high in Diabetes mellitus patients on both oral hypoglycaemic drugs and insulin, they are more susceptible to cardiovascular diseases. Evaluation of these markers at regular interval can reduce the incidence of vascular complications in Type 2 DM patients. PMID- 26500897 TI - Serum Adenosine Deaminase as Inflammatory Marker in Rheumatoid Arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a prototypical inflammatory joint disease. The degree of inflammation is reflected in the extent of joint damage, which further has influence on the quality of life of patients with RA, including risk of atherosclerosis. Hence, besides clinical indices, estimation of degree of inflammation using biochemical markers helps in effecting optimum treatment strategies. C-reactive protein (CRP) is established as an inflammatory marker in patients with RA. Adenosine deaminase (ADA), an enzyme of purine metabolism is considered as a marker of cell mediated immunity and has also been suggested as a marker of inflammatory process in RA. The present study attempts to study the efficacy of serum ADA activity as an inflammatory marker in RA. MATERIALS AND METHODS: Forty six RA patients and forty six age and sex matched healthy controls were included in the study. ADA activity and high sensitivity C-reactive protein (hsCRP) levels in serum were measured in all the subjects. Statistical analyses were done using Medcalc statistical software version 12.2.2. RESULTS: ADA activity and hsCRP levels were increased in RA patients compared to controls (p<0.0001 and 0.0001 respectively). Significant positive correlation was obtained between hsCRP and ADA in patients (r=0.316, p=0.033). Receiver operating characteristic (ROC) curve analysis revealed statistically significant area under curve (AUC) for ADA that is comparable to that obtained for hsCRP (0.776, p<0.0001 for ADA, 0.726, p<0.0001 for hsCRP). Similar diagnostic utility was obtained with ROC generated cut-off value of 25.3 IU/L (82.6% sensitivity and 65.2% specificity) and with control mean value of 23.48 IU/L (86.96% sensitivity and 54.35% specificity) for ADA. CONCLUSION: Findings of the present study indicate the importance of ADA as a marker of inflammation. Considering the higher sensitivity obtained, we propose control mean (23.48 IU/L) as a cut-off for serum ADA activity as an inflammatory marker. Owing to the simplicity and also the cost effectiveness of ADA assay, ADA may be recommended as a marker of inflammation in patients with RA. However, further larger and well controlled studies are needed to establish its role as inflammatory marker. PMID- 26500898 TI - Association of Serum Ferritin Levels with Metabolic Syndrome and Insulin Resistance. AB - INTRODUCTION: The impact of CVDs and Type II DM is increasing over the last decade. It has been estimated that by 2025 their incidence will double. Ferritin is one of the key proteins regulating iron homeostasis and is a widely available clinical biomarker of iron status. Some studies suggest that prevalence of atherosclerosis and insulin resistance increases significantly with increasing serum ferritin. Metabolic syndrome is known to be associated with increased risk of atherosclerosis as well as insulin resistance. AIM: The present study was designed to explore the association of serum ferritin levels with metabolic syndrome and insulin resistance. MATERIALS AND METHODS: The present study was prospective, cross sectional. The study protocol was approved by IEC. The study group consisted of 90 participants (50 cases of metabolic syndrome and 40 age and sex matched controls). Diagnosis of metabolic syndrome was done as per NCEP ATP III criteria. Estimation of serum Ferritin and Insulin was done by Chemiluminescence Immunoassay (CLIA) while Glucose by Glucose Oxidase and Peroxidase (GOD-POD) method. Insulin Resistance was calculated by HOMA IR score. STATISTICAL ANALYSIS: Data obtained was statistically analysed by using student t test. RESULTS: We found statistically significant rise in the levels of serum ferritin (p=<0.001), glucose (p=<0.001), insulin (p=<0.001) and HOMA IR score (p=<0.0001) in cases of metabolic syndrome as compared with controls. CONCLUSION: High serum ferritin levels though within normal range are significantly associated with both metabolic syndrome and insulin resistance. PMID- 26500899 TI - Bisalbuminemia in a Hypothyroid Patient with Diabetes: A Case Report. AB - Bisalbuminemia is a rarely encountered anomaly characterized by presence of bifid albumin bands or a single widened albumin band in electrophoretogram. Inherited bisalbuminemia is quite rare and inherited as an autosomal dominant form. The acquired form of bisalbuminemia is usually transient and may be observed during long term beta lactam antibiotic therapy, acute pancreatitis, myeloma and nephrotic syndrome. This is a case of bisalbuminemia in 61-year-old diabetic female with hypothyroidism came with acute exacerbation of bronchial asthma. PMID- 26500900 TI - Carotid Artery Intima-Media Thickness in Young Adults with Family History of Coronary Artery Disease. AB - BACKGROUND: It is well established that accelerated athero-sclerosis occurs in middle-aged and elderly adults with family history of coronary artery disease (CAD). However similar data on younger population with genetic predisposition is lacking. As identifying and treating this target group at an early stage will help in postponing the disease progression and delay the onset of clinical events later in life. AIM: We undertook the present study to investigate whether structural vascular changes related to atherosclerosis are detectable in healthy young adults with family history of CAD by non-invasive high resolution scan of the carotid artery intima media thickness (CIMT). MATERIALS AND METHODS: Fifty healthy young adults of both sexes, aged 18-25 years with family history of CAD were taken as cases and fifty age, sex, body mass index (BMI) and blood pressure matched subjects without family history of CAD served as control. All participants completed a standardized cardiovascular disease risk assessment questionnaire and resting blood pressure, pulse rate and BMI were recorded. None of the subjects were smoker or alcoholic. Both cases and controls were subjected to high resolution B-mode ultrasonographic evaluation of CIMT. Fasting blood samples were drawn for baseline investigations and lipid profile estimation. RESULTS: Compared to control subjects, cases had increased CIMT (mean of combined sites 0.57 +/- 0.08 mm vs 0.46 +/- 0.05 mm in controls, p<0.001). Offspring with family history of CAD exhibited an unfavourable lipid profile. We observed a direct association between carotid intima media thickness and triglyceride concentration (Correlation coefficient=0.32). Multiple logistic regression analysis showed family history of CAD to be independent risk factor for CIMT (Odds ratio=5.36, confidence interval 1.84 - 10.53, p=0.003). CONCLUSION: Arterial wall abnormalities are present at an early age in offspring with family history of CAD. Identifying such high risk individuals is feasible with an easy, non-invasive and reproducible technique like CIMT measurement and hence is recommended. PMID- 26500901 TI - Effect of Age on Response to Experimental Pain in Normal Indian Males. AB - BACKGROUND AND OBJECTIVES: Response to experimental pain depends on the nature of the pain stimulus, as well as on gender, racial, cultural and socioeconomic factors. This study investigates the effect of age on pain sensitivity and cardiovascular reactivity produced by experimental pain. We have also compared the values of body mass index (BMI) and resting blood pressure of volunteers with the normal values. MATERIALS AND METHODS: The study was conducted on 83 Indian males of different age groups. The volunteers were divided into 4 groups: Children, Young Adults, Middle-Aged Adults and Old Adults; and their basal parameters (BMI, resting pulse and blood pressure) were recorded. Selected volunteers were subjected to cold pressor task (CPT). Pain sensitivity (PS) (pain threshold, tolerance and pain rating on a visual analog scale) and cardiovascular reactivity (CVR) (increase in pulse and blood pressure) were recorded. RESULTS: Many volunteers had abnormal values of BMI and resting blood pressure and had to be excluded from the study. PS and CVR between different groups were compared by one-way ANOVA. Significant differences in PS were observed, with highest pain sensitivity in Children and lowest in Old Adults. No significant differences were observed in the CVR. CONCLUSION: The high numbers of volunteers with abnormal basal parameters (BMI and resting blood pressure) show an urgent need to educate the general public about the dangers and risk factors of obesity and hypertension. Less exposure of children to painful encounters may be responsible for their high pain sensitivity while higher values of resting blood pressure and decreased sensitivity of the sensory systems with advancing age may be responsible for the hypoalgesia observed in old adults. PMID- 26500902 TI - Evaluation of Multidrug Resistant Staphylococcus aureus and their Association with Biofilm Production in a Tertiary Care Hospital, Tripura, Northeast India. AB - BACKGROUND: High morbidity and mortality rates are associated with Methicillin resistant Staphylococcus aureus (MRSA) because of development of multidrug resistance. Staphylococcus aureus (S. aureus) has the ability to colonize and form biofilms on biomaterials which is causing resistance towards antimicrobials and thus making them difficult to eradicate from the infected hosts. MATERIALS AND METHODS: Culture isolation, identification was done following standard protocol and antibiogram of the isolates were done. The detection of MRSA, Macrolide-Lincosamide-Streptogramin B resistance (MLSB), vancomycin resistance phenotypes were done by using cefoxitin disc diffusion test, D zone test and vancomycin E test. Biofilm was detected by Congo red agar method. RESULTS: A total of 100 (31.7%) S. aureus strains were isolated from 315 clinical specimens. The prevalence of MRSA was 47% (47/100) with 85.1% were homogeneous MRSA and 14.9% were heterogeneous. Out of 47 MRSA strains, 63.8% were Hospital acquired MRSA (HA-MRSA) infections whereas rests 36.2% were caused by Community acquired MRSA (CA-MRSA) strains. Maximum number of MRSA isolates belonged to group A biotype (34%). A 14.9% isolates were of nontypeable group. Out of 100 S. aureus isolates, the prevalence of Vancomycin resistant S. aureus (VRSA) was found to be 3%. The MLSB phenotypes showed that the rates of inducible MLSB (iMLSB), constitutive MLSB (cMLSB) and Macrolide-Streptogramin B (MSB) in case of MRSA to be 19.1%, 31.9% and 12.8%. Prevalence of low-level (MUP(L)) and high-level mupirocin resistance (MUP(H)) among MRSA was 19.1% and 6.4%. Biofilm production was found in 55% strains of S. aureus. Out of 47 MRSA strains 76.6%were producing biofilm in comparison to 38.8% in methicillin-sensitive S. aureus (MSSA). Higher degree of antibiotic resistance in biofilm producers was seen especially in case of ciprofloxacin, co-trimoxazole, rifampicin, kanamycin, erythromycin and clindamycin whereas gentamycin, tetracycline and penicillin resistance was more in non-biofilm producers. CONCLUSION: This study shows high rate of circulating MRSA with a majority of these isolates are multi-drug resistant of which mostly are biofilm producers in our hospital setup. Development of antimicrobial stewardship program based on the local epidemiological data and national guidelines is the need of the hour. PMID- 26500903 TI - Comparison of Enzyme-Linked Immunosorbent Assay and Immunochromatography for Rotavirus Detection in Children Below Five Years with Acute Gastroenteritis. AB - BACKGROUND: Group-A rotaviruses are responsible for 30 to 60% of severe watery diarrhea cases in young children. Timely diagnosis of rotavirus infection helps to determine appropriate treatment and prevents unnecessary use of antibiotics. AIM: To compare Immunochromatography (ICG) with standard ELISA test for diagnosis of and to determine incidence, clinical socio-epidemiological profile and possible risk factors associated with rotavirus infection in children below five years with acute gastroenteritis. SETTINGS AND DESIGN: A prospective study performed from February 2013 to April 2014 in Microbiology and Paediatrics Departments, Government Medical College, Amritsar, Punjab, India. MATERIALS AND METHODS: Hundred stool samples from children below five years diagnosed with acute gastroenteritis were taken and tested by ICG and standard ELISA test. STATISTICAL ANALYSIS: Performed using the SPSS software for Windows, version 17.0. P-values calculated using chi(2) test for categorical variables. A p < 0.05 was considered significant. RESULTS: Maximum cases with ICG showed a sensitivity of 95.24% and specificity of 97.47% when compared to ELISA. Incidence of rotavirus diarrhea was 21% using ELISA and 23% using ICG. With ELISA rotavirus infection was highest in age group 6 months to 24 months (83.3%) and in male (90.47%). The infection was maximum during November to April and presented with triad of diarrhea, vomiting, fever (76.2%). Majority of cases had watery diarrhea in high percentage (90.47%). Severe dehydration (76.19%), respiratory symptoms (38.09%), bottle feeding (52.38%), malnourished children (47.61%), children playing with toys (47.6%) and submersible water pump (61.95%) as a source of drinking water associated with rotavirus infection were found to statistically significant. CONCLUSION: ICG shows a good agreement with ELISA and has the advantage of being a quicker, cost-effective and useful for testing single specimen, convenient, not requiring additional equipment, readily available, simple to perform and easy-to-read results. PMID- 26500904 TI - Correlation of Single Nucleotide Polymorphism 35-Kb Upstream of HLA-C and Clinical Profile of Multidrug-Resistant Tuberculosis. AB - INTRODUCTION: The SNP HLA-C-35 kb (rs9264942) may contribute to the host immune defense mechanism by affecting the cell surface expression pattern of HLA-C and antigen presentation to CD8+ cytotoxic cells. Thus, this SNP may contribute to intracellular multidrug-resistant (MDR)-tuberculosis (TB) infection. AIM: To examine the association between the SNP HLA-C-35 kb (rs9264942) and the clinical profile of MDR-TB infection. SETTINGS AND DESIGN: MDR-TB-positive patients were followed from May 2012 to December 2013 to observe the progression of MDR-TB infection. Non-TB individuals and non-MDR-TB individuals were also recruited as controls. MATERIALS AND METHODS: The patients' HLA-C-35 kb (rs9264942) status was determined by PCR. RESULTS: The C allele was slightly more frequent in the MDR-TB patients than in the non-MDR TB patients (OR= 1.28; 95% CI: 0.701 - 2.328). The C allele was found to be more frequent in the MDR-TB patients exhibiting pulmonary fibrosis (OR= 2.13; 95% CI: 0.606 - 7.480) or pulmonary infiltrates (OR= 3.17; 95% CI: 0.690 - 14.598) and among the MDR-TB patients who were classified as underweight (OR= 8.00; 95% CI: 1.261 - 50.770). The CC genotype was associated with the treatment after failure of category II group (OR= 4.17; 95% CI: 1.301 - 13.346). CONCLUSION: The C allele SNP HLA-C-35 kb (rs9264942) may contribute to the clinical profile in MDR-TB infection. PMID- 26500905 TI - Multi Drug Resistant Klebsiella Isolates in Burn Patients: A Comparative Study. AB - INTRODUCTION: Infections are the most common complications in the burn patients admitted to the hospitals leading to high morbidity and mortality. Klebsiella is one of the most frequently isolated bacteria from burn wounds. MATERIALS AND METHODS: We studied antimicrobial susceptibility patterns of Klebsiella isolates from burn patients. In this cross- sectional study wound swabs from 1294 patients hospitalized in burnward were collected for bacteriological examination. Antibiotic sensitivity testing of Klebsiella isolates was done by modified Stokes disc diffusion method. RESULTS: Out of 883 isolates from 1294 patients 195 were found to be Klebsiella spp. Based on the biochemical properties 153 isolates were Klebsiella pneumoniae, 37 were Klebsiella oxytoca and 5 were others species. In our study we found that 54% of the Klebsiella isolates were multidrug resistant as they were resistant to at least one antibiotic of three or more different groups of antibiotics. [Table: see text]. CONCLUSION: Rate of isolation of Klebsiella as well as its resistance for commonly used antibiotics is increasing over the time. PMID- 26500906 TI - Pulmonary Infection by Blastoschizomyces capitatus in An old Tuberculosis Patient. AB - Blastoschizomyces capitatus is an arthrospore filamentous fungus. Lung infection by Blastoschizomyces can develop as an opportunistic infection in patients with underlying conditions especially when there is immunosuppression including neutropenia. However, it can occur in non-neutropenic patients with solid organ transplant and patients whose local pulmonary defenses are altered by chronic underlying lung pathology. We report here a case of pulmonary infection by B. capitatus in an old tuberculosis patient. PMID- 26500907 TI - Breast Abscess by Salmonella Paratyphi A: Case Report and Literature Review. AB - A case of suspicious breast mass due to Salmonella enterica serotype Paratyphi A in a non-lactating, diabetic female is being described. The infection was successfully treated with a combination of surgical drainage and antibiotic treatment. This case highlights the fact that a focal Salmonella infection involving the breast should be considered as a rare differential diagnosis for breast malignancy and submission of specimens for microbiological analysis may be helpful in establishment of an accurate diagnosis and management. PMID- 26500908 TI - Human Microbiome Engineering: The Future and Beyond. AB - Microbial flora of skin and mucosal surface are vital component of human biology. Current research indicates that this microbial constellation, rather than being inert commensals, has greater implications in health and disease. They play essential role in metabolism, immunity, inflammation, neuro-endocrine regulation and even moderate host response to cancer. Genetic engineering was a major breakthrough in medical research in 1970's and it opened up newer dimensions in vaccinology, large-scale synthesis of bio-molecule and drug development. Engineering human microbiome is a novel concept. Recombinant DNA technology can be employed to modify the genome of critical components of resident microflora to achieve unprecedented goals. PMID- 26500909 TI - Rapid Screening for Carbapenem Resistant Organisms: Current Results and Future Approaches. AB - Carbapenem producing Enterobacteriaceae (CPE) is a major public health threat. A total of 120 carbapenem resistant E.coli (n=32) and K.pneumoniae (n=88) from blood stream infections were screened for the presence of carbapenem resistant genes KPC, NDM, IMP, VIM, and OXA-48 like using both conventional multiplex PCR and Xpert((r)) Carba-R test. Additionally 26 faeces samples were directly screened with Xpert((r)) Carba-R test. Of the tested isolates, 40% (n=48) of NDM and 39.2% (n=47/) of OXA-48-like were identified. Co-production of OXA-48 and NDM was seen in 15 (12.5%) isolates. In Xpert((r)) Carba-R test, only NDM was identified in 55% (n=66) of tested isolates. Of the tested faeces samples, 12 were identified as carbapenemase producers: nine with NDM, two with the co production of NDM and VIM and in Klebsiella spp (n=1), NDM and KPC co-production was seen. However, Xpert((r)) Carba-R test fails to detect OXA-48 like as compared with multiplex PCR. The sensitivity, specificity, PPV, NPV of Xpert((r)) Carba-R test was 100%, 77%, 96% and 100% respectively. Incorporation of OXA-48 like specific sequence in the panel of Xpert((r)) Carba-R test may improve its sensitivity and maximize the coverage of assay. PMID- 26500910 TI - Spectrum of Typical and Atypical Clinico-Histopathological and Radiological Presentation of Soft Tissue and Muscular Cysticercosis in Mid-Western and Far Western Region of Nepal. AB - INTRODUCTION: Soft tissue and muscular involvement in cysticercosis is a relatively rarer presentation. MATERIALS AND METHODS: Twenty seven histopathologically confirmed cases of soft tissue and muscular cysticercosis were collected and the clinical, radiological data was reviewed. RESULTS: There was female predominance for the lesions (19 cases among 27 cases). The most common location for the lesion was in the arm (9 cases), thigh (4 cases), forearm (7 cases), abdominal wall (4 cases) followed by nape of the neck (2 cases). Lesion ranged from 8 mm to 5 cm in size. Ultrasound was diagnostic in 24 cases and inconclusive in three cases. Histopathologically, intact cyst wall was noted in 12 cases, scolex in 5 cases. Seven cases showed degenerating cyst wall surrounded by inflammatory cells, granulation tissue and fibrosis. CONCLUSION: Fine needle aspiration cytology and histopathological assessment is prudent in the diagnosis of soft tissue and muscular cysticercosis in cases posing clinical diagnostic dilemma. PMID- 26500912 TI - Otocephaly: Agnathia- Microstomia-Synotia Syndrome- A Rare Congenital Anomaly. AB - Otocephaly is a rare malformation characterized by the association of agnathia (agenesis of mandible) or mandibular hypoplasia, melotia (anteromedial malposition of ears), microstomia (small mouth), aglossia or microglossia (absent or rudimentary tongue). This rare anomaly of the ventral portion of first brachial arch is a consequence of failure of migration of neural crest cells from hind brain. It leads to the development of maxillary and mandibular prominences and starts to develop at the fourth and fifth week of gestation. We hereby present the autopsy findings of a fetus of 28 weeks gestation abortus having otocephaly without holoprosencephaly. PMID- 26500911 TI - Serous Microcystic Adenocarcinoma of Pancreas Infiltrating Into Spleen: A Case Report. AB - Cystic tumours of pancreas account for 5-10% of all pancreatic neoplasms and serous tumours represent 1% among those tumours. Most of the serous tumours are benign and very rarely they infiltrate adjacent organs like liver and spleen. Herewith we present a rare case report of serous cystadenocarcinoma of pancreas in a 65-year-old woman. The tumour involved the body and tail of pancreas and contiguously invaded the spleen. The histopathology of tumour was similar to serous cystadenoma with mild nuclear hyperchromasia and atypia. The spleen showed tumour infiltration as microcysts diffusely infitrating the red pulp. PMID- 26500914 TI - An Unusual Presacral Cyst in An Infant. AB - The neurenteric cyst is a rare developmental lesion arising as a result of persistence of the neurenteric canal. It usually presents in the second and third decade. Lesions occurring in children are rare. Majority of the cases presented with signs of spinal cord involvement. This is a rare case of neurenteric cyst in an infant who presented with a presacral mass. A nine-month-old female had an antenatally diagnosed sacrococcygeal lesion. Radiology suggested a diagnosis of sacrococcygeal teratoma. Histology was typical of a neurenteric cyst. We report this case to create awareness about this rare cystic lesion and inclusion of this entity in the differential diagnosis of cystic masses in children at this location. PMID- 26500913 TI - Primary Bladder Neurofibroma: A Rare Case with Clinical Implications and Diagnostic Challenges. AB - Neurofibroma of the genito-urinary tract is rare. Urinary bladder is the commonest organ involved in cases of urinary tract involvement. Patients present early in life and there is male preponderance. We discuss here a case of primary neurofibroma of the urinary bladder in a 52-year-male presenting with haematuria, irritative bladder symptoms and pelvic mass. Cystoscopy showed a swelling in the left lateral wall. A transurethral biopsy revealed neurofibroma of the urinary bladder. Immunohistochemical studies confirmed the diagnosis. PMID- 26500915 TI - Retroperitoneal Malignant Peripheral Nerve Sheath Tumour: A Rare Case Report. AB - Malignant nerve sheath tumours (MPNST) are rare neoplasias and retroperitoneal cases are fairly rare and clinically difficult to be detected, but they are very agressive neoplasias. MPNST are frequently seen in head, neck and upper extremities. In patients with NF1; MPNST, a poor-prognostic lesion, may result from a malignant degeneration of a former plexiform neurofibroma. It is necessary to be aware of a potential malignancy in patients diagnosed with plexiform neurofibroma. We present a 21-year-old female with a diagnosis of MPNST. The patient was admited to the hospital because of a tumour in the subcutaneous region on her left buttock. The surgeon's clinical diagnosis was lipoma. After the pathological examination of biopsy specimen, the lesion was identified as "plexiform neurofibroma" and then the patient was diagnosed with Neurofibromatosis Type 1 (NF1). Simultaneously, another mass on the retroperitoneal region was identified as malignant peripheral nerve sheath tumour (MPNST). PMID- 26500916 TI - Cytologic Interpretation of Melanotic Neuroectodermal Tumour of Infancy Involving Cranial Bones: Clue to Diagnosis. AB - Melanotic neuroectodermal tumour of infancy (MNTI) is a rare, benign but locally aggressive neoplasm of infants commonly affecting the maxilla. It can also involve other areas like skull, mandible, brain and epididymis. The tumour comprise of dual populations of cells like small, basophilic neuroblast like cells and large pigment laden epithelial cells arranged in tubular and pseudoglandular pattern. The proportion of two components varies and therefore the diagnosis can be difficult in absence of the large cells. We describe the cytologic, histologic and immunohistochemical findings in a case of MNTI involving left side orbit with frontal, temporal and parietal bones. The cytologic interpretation could be made due to the suggestive clinical and radiologic findings and detection of large epithelial pigmented cells on thorough searching. The neuroblast like cells was positive for Neuron specific enolase, large cells for HMB-45 and Pan CK. Both the cellular components were negative for desmin. This case report is presented due to its rarity and also to aid the surgical pathologists in diagnosis where the findings are not too straight forward. PMID- 26500917 TI - Metastatic Renal Cell Carcinoma: An Unusual Cause of Bleeding Pancreatic Mass. AB - Renal Cell Carcinoma metastasizing to pancreas is uncommon, occurring in 1-2% of cases; lung being the most common site. It is usually asymptomatic, or may present as abdominal pain, weight loss, pancreatitis or gastrointestinal bleeding. Herein, we present a case of 75-year-old male presented as intraabdominal bleeding to the Emergency Department. Contrast enhanced computed tomography with angiography of abdomen showed lobulated soft tissue mass in the uncinate process region, infiltrating into the distal third and proximal fourth part of duodenum. A clinico-radiological diagnosis of carcinoma head of pancreas infiltrating into duodenum was made and the patient underwent Whipple's operation. With past history of nephrectomy 3 years back, microscopy and the immunoprofile; a final diagnosis of clear cell renal cell carcinoma metastasizing to pancreas was given on histopathology. A high index of suspicion is required for patients with a history of RCC and they should be monitored lifelong for early detection of metastases and to improve survival. PMID- 26500918 TI - An Extemly Rare Case of Left Atrium and Right Pulmonary Vein Leiomyosarcoma. AB - We report a case of a 43-year-old female, presented with complaints of breathlessness for 1 month and had three episodes of syncopal attacks in the past two months. On clinical evaluation, bilateral pedal oedema was noticed. Echo cardiogram revealed large left atrial blood clot measuring 5.7x4.3x4.3 cm. Ultrasound whole abdomen was normal. We received an excised mass with right pulmonary vein end arterectomy speciemen. Histopathology of the mass revealed characteristic features of leiomyosarcoma with grade III, according to FNCCS grading system. The tumour was consistent with substantial amount of poorly differentiated fasicles of pleomorphic spindle cells and brisk atypical mitosis, with marked necrosis. Immunohistochemistry revealed the tumour cells in strong diffuse cytoplasmic positive for smooth muscle actin and Ki-67 showed 15-20% of tumour cells postivity. The prognosis depends on the individual tumour origin for individual site, size of tumour and depth of tumour than histological features. Pulmonary venous leiomyosarcomas were assumed to be misinterpretation of left atrial leiomyosarcomas with growth of the tumour into pulmonary vein lumen. We report this case in view of its extreme rarity. PMID- 26500919 TI - Co-Existence of Acinic Cell Carcinoma - Papillary Cystic Variant and Extrapulmonary Tuberculosis - Report of A Case with Brief Review. AB - Tuberculosis (TB) and cancer are two lethal diseases causing significant morbidity and mortality in developing countries like India. Co-existence of these two disease lead to diagnostic dielemma among the clinicians. Overlapping clinical manifestations lead to delay in diagnosis. We report a case of acinic cell carcinoma -papillary cystic variant of the salivary gland and extra pulmonary tuberculosis in a young female. We emphasize the importance of the awareness of the co-existence of these two diseases and the role of fine needle aspiration cytology in the initial diagnosis. PMID- 26500920 TI - Information Education and Communication can Improve Adherence to Artemether Lumefantrine Combination in Patients of Uncomplicated Falciparum Malaria. AB - BACKGROUND: Early diagnosis and prompt treatment with Artemisinin combination therapy (ACT) is vital to improve mortality in Falciparum Malaria. Information education and communication (IEC) is a strong tool that can improve drug adherence. AIM: To explore if IEC in the form of designed drug bags with verbal communication can improve ACT adherence in Falciparum Malaria patients. MATERIALS AND METHODS: A prospective, interventional, controlled study was conducted in OPD patients of both SCB Medical college, Cuttack and district headquarter hospital Cuttack district of Odisha. IEC material in the form of well designed drug bag and verbal communication was used for intervention. Control group received ACT combinations but were not given IEC. RESULTS: Adherence to IEC was significantly higher (81%) in patients receiving IEC compared to controlled patients not receiving IEC. Educational status and the geographical area of the patient were found out to affect adherence to IEC to a significant extent. CONCLUSION: IEC in the form of designed drug bags, supplemented by verbal communication can improve ACT adherence in Falciparum Malaria. PMID- 26500921 TI - Prevalence of Y Chromosome Microdeletions in Idiopathic Azoospermia Cases in Central Indian Men. AB - BACKGROUND: Genetic factor is important determinant of human male fertility, it is involved in 10-15% infertile males. Chromosome abnormalities and Y chromosome microdeletions are the main genetic causative factors for infertility. The frequency of male infertility & microdeletions in Y chromosome are also related to ethnic, geographical variations. In this study, we evaluated the prevalence of chromosomal abnormalities and microdeletions of Y chromosome in infertile azoospermia cases in central India to assess the geographical or population based variations. MATERIALS AND METHODS: We have studied 160 non-obstructive azoospermia cases to find out frequency of chromosomal abnormalities and Y chromosome microdeletions of AZF locus. G-banding method was used for exclusion of chromosomal abnormalities. One hundred and forty eight azoospermic infertile men were screened using 12 sequence-tagged-sites (STS) primers of AZFa, AZFb, AZFc region and SRY gene (Yp) region by polymerase chain reactions. RESULTS: Out of 160 azoospermic infertile males, 12 (7.5%) confirmed chromosomal abnormalities and Klinefelter's syndrome was predominantly cause of azoospermia. Of the 148 infertile males, 19 (12.8%) were shown microdeletions in different AZF regions. Deletions in AZFa region were 2.02% and 3.37% was in AZFb whereas high frequencies of deletions (6.08%) in AZFc were recorded in azoospermic males. In two azoospermic males were shown microdeletions in AZFb+c loci. CONCLUSION: The prevalence of Y chromosome microdeletions in azoospermic men was 12.8% in this geographical region. Klinefelter's syndrome is important cause in male infertility. So, the screening of Y microdeletions is essential. PMID- 26500922 TI - Prevalence of Atherosclerotic Coronary Stenosis in Asymptomatic North Indian Population: A Post-mortem Coronary Angiography Study. AB - AIM: A preliminary study of coronaries using post-mortem angiography was undertaken to see the prevalence of atherosclerotic coronary stenosis in non cardiac unnatural deaths. MATERIALS AND METHODS: This study was conducted in a tertiary care centre located in Chandigarh. A total of 128 medico-legal cases were studied comprising 88 males and 40 females. Post-mortem examinations of these MLC cases were conducted in the Department of Forensic Medicine, PGIMER, Chandigarh. All hearts were visually screened by post-mortem coronary angiography first and then grossly examined using serial transverse incision technique in positive screening cases to find the degree of narrowing. RESULTS: Of the study group, 34% males and 20% females showed evidence of narrowing on angiography. Of the males showing coronary stenosis, 83% had single vessel disease and 13% had double vessel disease, while only one individual had triple vessel disease. In cases of female, all the cases of coronary stenosis were single vessel disease. Left anterior descending coronary artery (LAD) was the most common vessel involved, followed by right coronary artery (RCA) & Left circumflex artery (LCX) and in cases of double vessel disease, LAD in combination with LCX was responsible for 75% of the cases. Remarkably 23.6% of study population in the age group of less than 40 years showed appreciable narrowing in at least one of the coronaries. CONCLUSION: In general, the prevalence of CAD is on the rise, particularly in younger population owing to the changes in their lifestyle and food habits. This preliminary study revealed evidence of narrowing of at least one coronary in 34% male and 20% female population and 23.6% subjects were less than 40 years old. Further detailed studies are needed especially in younger age group and to support the need for preventive cardiology in the early years of life. PMID- 26500923 TI - Is the Time Right to Start Using Flipped Classrooms in Indian Medical Colleges? PMID- 26500924 TI - Screening Depression Among Elderly in a City of Southeast Asia. AB - INTRODUCTION: Changing family structure (Joint to Nuclear), increased life expectancy above 60 years of age, generation and communication gap, financial dependency on children leads to conflict among family members. This may sometime lead to old age home settlement of elderly people. All these condition leads to isolation and insecurity among elderly people and this condition affect the mental status of elderly people which may sometime lead to depression among Old Age Homes residents and family living elderly people. OBJECTIVE: To study the prevalence of depression and diagnosed systemic morbidities among elderly people. To study the predictors of depression among study subjects. MATERIALS AND METHODS: A descriptive cross-sectional study was conducted among elderly people (age >=60 years) residing in old age homes (OAHs) and in community/families in Lucknow, India. Multistage sampling technique was used to include required sample of subjects from the community and for OAHs all the elderly people living in OAHs were included. Geriatric depression scale was used to screen depression. RESULTS: Depression was 27.7% among elderly people residing in OAHs while it was 15.6% those residing at their own homes. In community most frequent morbidity was hypertension (17.7%) while 41.1% elderly people had no diagnosed morbidity. In OAHs out of total the musculoskeletal morbidity (33.7%) was most frequent and 18.8% had no diagnosed morbidity. On multivariate analysis financial dependency and education were found to be statistically significant. CONCLUSION: Depression was more common among elderly living in Old Age Homes as compare to those living in community. Hypertension, musculoskeletal morbidities and eye related morbidities were most frequent diagnosed morbidities. Financial Dependency & Education were found to be primary predictors of depression. PMID- 26500925 TI - Menstrual Disorders and Its Determinants Among Married Women of Rural Haryana. AB - INTRODUCTION: Disorders of menstruation are common problems among women. They have several psychological effects on women's health. AIM: This study aimed to estimate prevalence of menstrual disorders, usage of sanitary pads and their determinants among married women in selected villages of rural Haryana. MATERIALS AND METHODS: A cross-sectional study was conducted during September 2011 in 10 villages of PHC (Primary Health Centre) Mandi, Haryana, using a systematic random sampling technique. Currently married women in the age group of 18-45 years living in study area for more than 1 year were included in the study while those who were pregnant and unable to understand questions were excluded. Informed verbal consent was obtained from all participants. RESULTS: A total of 344 women were interviewed. The mean (SD) age of participants was 28.0 (5.4) years. Majority of women were housewives (78.8%) and most had education up to middle school (22.7%). Mean (SD) age at menarche was 14.3 (1.2) years. Nearly one-tenth of women had married before 18 years of age. Prevalence of all menstrual disorders was 20.3% and most common disorder was excessive pain. About one fifth reported irregularity of menstrual cycles. Almost half were not using sanitary pads during menses. Menstrual disorders were more common among non-users of contraception (OR=1.7, p = 0.04) and housewives (OR = 2.4, p= 0.03). CONCLUSION: Disorders of menstruation were fairly common among women surveyed. Usage of sanitary pads was quiet low. Awareness generation among women regarding menstrual problems and Behaviour Change Communication to promote usage of sanitary pads are important measures to reduce related morbidity. PMID- 26500926 TI - Burden of Diabetes Related Complications Among Hypertensive and Non Hypertensive Diabetics: A Comparative Study. AB - BACKGROUND: Diabetes and hypertension are the conditions with overlapping risk factors and complications. Objective of present study was to compare the burden of complications of diabetes among hypertensive and non hypertensive diabetes individuals. MATERIALS AND METHODS: This cross-sectional study was conducted at Saveetha medical college and hospital, Chennai, India. A total of 100 diabetics having hypertension and 50 non-hypertensive diabetic patients were enrolled on the basis of purposive sampling. Information about sociodemograpic characteristics, general health, health distress, diabetes symptoms, communication with physician, healthcare utilization and lifetime occurrence of diabetes related complications. Mean, standard deviation and median of continuous variables and proportion of categorical variables were recorded. RESULTS: Average age of the hypertensive diabetes patients (M=57; SD=11) was higher than non hypertensive diabetes patients (M=52; SD=11) which was statistically significant (p=.009). Diabetic neuropathy was reported by 45% of the hypertensive and 38% of the non-hypertensive diabetics. Mean self reported general health score was higher among hypertensive diabetic participants (M=3.4; SD=1) in comparison to non hypertensive diabetic participants (M=3; SD=1) and it was found statistically significant (p=.03) indicating towards poor self health perception among hypertensive's. Results of the study have shown that the proportion of participants who have prepared any list of questions before visiting doctor's clinic (fairly often to always) was significantly higher among hypertensive diabetics (30%) in comparison to non-hypertensive diabetics (14%). CONCLUSION: The proportion of participants reporting diabetes neuropathy and retinopathy was higher among hypertensive diabetics in comparison to non hypertensive diabetics. PMID- 26500927 TI - Role of Behavioural Risk Factors in Symptoms Related to UTI Among Nursing Students. AB - INTRODUCTION: UTI is a well known entity amongst young girls, and the majority of girls have recurrent infections within one year. Anything that disturbs the usual vaginal environment would result in conditions favouring the production of unwanted microorganisms leading to infections of this very sensitive area. Studies have shown that, there is an evident relation of UTI's among students and practices of personal hygiene. AIM: To determine association between the behavioural risk factors and UTI among nursing girls. MATERIALS AND METHODS: The present study was undertaken amongst unmarried nursing students of a Medical College Hospital. A predesigned pretested questionnaire was used to know the personal hygiene of students and to find out its association with UTI in the last three months. Chi-square test was used to analyse the data. RESULTS: A significant association was observed between perineal hygiene and UTI. The major risk factors of UTI identified were incorrect perineal washing technique, use of synthetic/silk innerwears, not sundrying the innerwears, improper menstrual hygiene. CONCLUSION: There are still major gaps in the knowledge regarding causation of UTI among the nursing students. This calls for an urgent need for educational talks periodically addressing these gaps. PMID- 26500928 TI - Attitude Towards Alzheimer's Disease Among Undergraduate Students of University of the West Indies, Trinidad and Tobago. AB - BACKGROUND: Alzheimer's disease is most common among the dementias and is characterized by gradual declines in functional and cognitive abilities. Caregivers including family members play a key role in providing critically needed care for these patients. OBJECTIVE: This study compared the knowledge and attitudes of pre-healthcare and non-medical undergraduate students towards patients with Alzheimer's disease. MATERIALS AND METHODS: A cross-sectional study was conducted involving quota sampling of 691 undergraduate students (369 pre healthcare and 322 non-medical). A 28-item questionnaire was utilised comprising of closed-ended questions and some based on a scale rating. The students' knowledge of Alzheimer's disease was arranged into categories such as: 0 for no knowledge about Alzheimer's disease, 1 for very little knowledge about Alzheimer's disease, 2 for fair knowledge about Alzheimer's disease and 3 for great knowledge about Alzheimer's disease. STATISTICAL ANALYSIS: The data was analysed using the computer software SPSS and the Chi squared test of independence was also used to determine which knowledge variables were independent of student's status. RESULTS: Overall, 40.01% of the students have great or fair knowledge of Alzheimer's disease, with that of pre-healthcare students being satisfactory (54.47%). Pre-healthcare students have a more positive attitude towards Alzheimer's disease and 82.2% of students wished to take advantage of predictive test for Alzheimer's disease. Age and genetics were identified as risk factors of the disease. CONCLUSION: Pre-healthcare students had greater understanding of Alzheimer's disease and depicted a more empathetic and caring attitude towards patients. This can be attributed mainly to their knowledge and exposure toward the disease. PMID- 26500929 TI - Prevalence and Current Approaches of Ebola Virus Disease in ASEAN Countries. AB - As indicated by the World Health Organization as of year 2014, around 10,000 people have been influenced with Ebola infection. The episode of Ebola in African locale is courged with a high death rate. Notwithstanding, in the United States, people influenced by Ebola have been given brilliant wellbeing offices, as the U.S. is one of the highest nations that have taken sterner wellbeing measures and principles against Ebola. Aside from the U.S., individuals in Asia, where billions live in indigence and general wellbeing frameworks are frequently extremely powerless, are under more serious danger of the Ebola infection. Despite the fact that nations like Singapore, Malaysia, South Korea and Japan can take stretched out measures to battle against the infection, nations like Philippines and Indonesia have unfathomable quantities of poor who may be incredibly influenced by a conceivable episode. At this moment, the chances that Asia will take a critical hit from the Ebola infection appear to be genuinely little. Yet, while it is far-fetched that Asia will encounter a real flare-up, genuine concerns stay about the infection coming to urban communities like Hong Kong, Beijing, Shanghai and Singapore through their worldwide airplane terminals. Wellbeing priests from the Association of Southeast Asian Nations (ASEAN) reported key measures not long ago to keep the Ebola plague from coming to the locale and to backing influenced nations. This article accordingly will concentrate on the prevalence and current approaches of Ebola Virus Disease in ASEAN nations which is the need of the hour. PMID- 26500930 TI - Treatment of Acute Painful Thyroiditis with Low Dose Prednisolone: A Study on Patients from Western Nepal. AB - INTRODUCTION: Thyroiditis is a disorder that involves inflammation of the thyroid gland. Subacute thyroiditis is the most common cause of acute painful thyroiditis. It is thought to be a viral inflammatory disorder. Subacute thyroiditis has been treated with either nonsteroidal anti-inflammatory drugs (NSAIDs) or high dose corticosteroids. The response to steroids is more dramatic and quicker than the NSAIDs. Prednisolone is the most commonly used corticosteroid to treat subacute thyroiditis. The usual dose is one mg/kg/day tapered over six weeks although the basis for this dose has not been established yet by prospective studies. AIM: The current research was carried out to study if prednisolone in lower initial dose (20 mg/day tapered over four weeks) is effective in patients with acute painful thyroiditis. MATERIALS AND METHODS: This study was a prospective, cross sectional, observational study carried out at Pokhara, Nepal. All the patients presenting with anterior neck pain of less than 1 week with tender thyroid on palpation and ESR more than 30mm/h were included in the study. The patients were administered prednisolone in a starting dose of 20 mg/day tapered over four weeks. Data were collected, analysed and the results were interpreted. RESULTS: One hundred and twenty two patients of acute painful thyroiditis were included in our study. Age of the patients ranged from 19 years to 69 years with the mean age of 36.58 years. Female to Male ratio was 10:1. Mean ESR was 57.03 at the time of presentation. ESR decreased to 29.63 at two weeks and 17.03 mm per hour (normal) at 4 weeks after continuation of the drug. All the patients reported with severe pain in the anterior neck at the time of presentation. Pain was completely relieved in 115 patients (94%) at 2 weeks after starting the treatment and it was better than previous in seven patients. CONCLUSION: Twenty mg of prednisolone daily tapered over 4 weeks is an adequate treatment of subacute thyroiditis. However, dose can be drastically tapered after 2 weeks. PMID- 26500931 TI - Effect of Refractive Status and Axial Length on Peripapillary Retinal Nerve Fibre Layer Thickness: An Analysis Using 3D OCT. AB - BACKGROUND: Accurate measurement of retinal nerve fiber layer (RNFL) is now possible with the high resolution optical coherence tomography (OCT). Effect of refractive status of the eye on RNFL thickness may be relevant in the diagnosis of glaucoma and other optic nerve diseases. AIM: To assess the RNFL thickness and compare its correlation with refractive status and axial length of the eye. MATERIAL AND METHODS: Three hundred eyes of 150 patients were included in this study, who underwent RNFL analysis using TOPCON 3D OCT 2000. Analysis of variance has been used to find the significance of study parameters between the study groups. RESULTS: The study showed that refractive status/axial length affected the peripapillary RNFL thickness significantly. CONCLUSION: The study suggests that the diagnostic accuracy of OCT may be improved by considering refractive status and axial length of the eye when RNFL is measured. PMID- 26500932 TI - Post Surgical Giant Epidermal Inclusion Cyst of the Lid and Orbit- A Rare Case. AB - Epidermoid cyst within the lid and orbit is extremely rare. Epidermoid tumours are inclusion of ectodermal elements in the site not normally containing these structures. It is of two types; primary type related to implantation of ectoderm at the time of closure of the neural groove and secondary type caused by post traumatic inclusion of the surface epithelium. A 45-year-old male had complaint of swelling on the right upper lid and orbital region. It first appeared two years back. It was painless progressively increased in size and shape. There was difficulty in opening of eye lid due to large swelling, feeling of heaviness in the right upper lid and occasional headache. There was history of right eye ocular infection following vegetative matter injury three years back. Evisceration of right eye was done for aforementioned reason. USG report shows cystic encapsulated mass with calcification foci in right upper lid-orbital region with fat component. MRI right orbit shows fairly large hyperintense cystic lesion seen involving right orbit with posterior extension up to optic canal. No intracranial extension. FNAC confirmed epidermal inclusion cyst. We did upper lid reconstruction with removal of mass. We have successfully removed the mass without any complication and with one year follow-up there is no recurrence. PMID- 26500933 TI - The Prevalence, Risk Factors and Changes in Symptoms of Self Reported Asthma, Rhinitis and Eczema Among Pregnant Women in Ogbomoso, Nigeria. AB - BACKGROUND: Allergic disorders have become a major public health concern worldwide. No Nigerian study has examined the epidemiology of allergic diseases among women. AIM: To document the prevalence, risk factors and the changes in the symptoms of allergic disorders during pregnancy. SETTINGS AND DESIGN: Cross sectional study conducted at the booking and antenatal clinics of LAUTECH Teaching Hospital and Millennium Development Goals (MDG) Clinic of the Comprehensive Health Center, Oja Igbo, Ogbomoso, Nigeria. MATERIALS AND METHODS: Study enrolled 432 women from two public hospitals. Sociodemographic and clinical history were obtained and allergic disorders were diagnosed using ISAAC questionnaires. RESULTS: The prevalence of wheezing, eczema and rhinitis in pregnancy are 7.5%, 4.0% and 5.8% respectively. The prevalence of wheezing and eczema was slightly higher among the pregnant in past 12 months. Wheeze worsened in 70% (18/26), improved in 15% (2/26), and stable in 15% (2/26). Eczema worsened in 50% (7/14), improved in 7.1% (1/14) and stable in 42.9% (6/14), while allergic rhinitis worsened in 50% (11/22), improved in 22.7% (5/22) and stabilized in 27.3 % (6/22). In multivariate analysis, the risk of allergic diseases in pregnancy was increase 2 times by low income earning (CI: 1.2 - 2.1, p = 0.002), low level education (OR = 0.6, CI: 0.3 - 0.9, p = 0.011) and by family history of asthma, OR-4.3, CI - 1.3 - 13.9, p = 0.015. Family history of asthma increase the chances of asthma by 18.7 times, CI-2.3 - 152.2, p = 0.006, while the odd of eczema was increased 9.1 times (CI-2.7 - 30.6, p<0.001) and 2.4 times (CI: 1.2 - 4.7, p = 0.008) by second hand home smoking and low-family income respectively. The risk of allergic rhinitis were raised 1.8 times by low family income (CI 1.1 - 2.8, p = 0.013) and 3.9 times by family history of rhinitis (OR = 3.9, CI 1.2 - 12.7, p = 0.024). CONCLUSION: Prevalence of wheezing and eczema are higher in pregnancy probably due to exacerbation induced by pregnancy. Social and genetic factors are important risk factors for allergic disorders in pregnancy. PMID- 26500934 TI - Decreased Bone Mineral Density at the Femoral Neck and Lumbar Spine in South Indian Patients with Type 2 Diabetes. AB - BACKGROUND: With prevalence of diabetes in India reaching epidemic proportions and increase in the population of geriatric age group and risks of falls, it is important to understand the effect that diabetes has on bone health. AIM: The objective was to assess bone mineral density (BMD) of patients with type 2 diabetes mellitus (T2DM) and to study factors contributing to BMD in patients with T2DM. MATERIALS AND METHODS: This was a prospective cross-sectional study on 150 patients with T2DM (diagnosed at age > 30 years) and an equal number (n=150) of age and sex matched healthy controls from September 2012 to July 2014 at a tertiary care center located in Southern India. BMD was measured at the femoral neck and lumbar spine (L2-L4) by dual energy absorptiometry (DXA) in cases and controls. Serum total calcium, phosphorus and alkaline phosphatase (ALP) and 25 OH- vitamin D3 was measured in patient group. RESULTS: Mean age (SD) was 51.29 (+/-8.05) and 51 (+/-8.3) years in cases and controls, respectively. The femoral neck and lumbar spine BMD was significantly lower in T2DM cases compared to controls. Also the femoral neck and lumbar spine T-score was significantly lower in T2DM cases compared to controls. Femoral neck BMD among male patients with T2DM was significantly lower compared to controls (men). Among women, BMD at femoral neck as well as lumbar spine was significantly lower in cases when compared to controls. Ninety six out of 150 (64%) T2DM cases had Vitamin D values <20 ng/mL. There was weak negative correlation between age of patient, duration of diabetes and HbA1C with femoral neck BMD. There was weak negative correlation between HbA1C and lumbar spine BMD. CONCLUSION: Indian subjects with type 2 diabetes have significantly lower BMD at both femoral neck and lumbar spine compared to age and sex matched healthy controls. We conclude that osteopenia and osteoporosis are overlooked complications of diabetes. Longitudinal studies are needed to see for actual incidence of fractures among this high risk group. PMID- 26500935 TI - Anti-perinuclear Factor as Diagnostic Marker in Rheumatoid Arthritis. AB - INTRODUCTION: Rheumatoid Arthritis (RA) is a systemic autoimmune disease. It is associated with several auto antibodies which can serve as diagnostic and prognostic markers. AIM: In this study, Anti perinuclear Factor (APF) was evaluated as a biomarker in comparison with Rheumatoid Factor (RF) in Rheumatoid Arthritis. MATERIALS AND METHODS: Fifty two sera of patients with RA (mean age 48+/-15.8), 23 sera of Patient control group (mean age 32.5 +/- 16.9) and 30 sera of Healthy control group (mean age 32.1+/- 16.9) were analysed. The method is based on the binding of APF to perinuclear keratohyalin granules of buccal mucosal cell and its detection using a fluorescently labeled anti human total antiserum. RESULTS: APF were found in 71.2 %(37/52) of patients with RA. The sensitivity and specificity for APF from 1/5 serum dilution was 71.2% and 94.3% respectively. RF test had higher sensitivity (88.5%) compare to the APF test (71.2%), but its specificity was (86.8%) less than APF (94.3%). There was no significant relationship between the onset of APF and severity of disease but there was significant relationship between the APF titer and severity of disease (p<0.05). CONCLUSION: It is concluded that APF test is a valuable serological tool for the diagnosis of the disease and a useful serological marker to differentiate from the other inflammatory rheumatoid diseases. PMID- 26500936 TI - Hypokalaemic Periodic Paralysis- A Prospective Study of the Underlying Etiologies. AB - BACKGROUND: Hypokalaemic periodic paralysis (HPP) is a rare muscular disorder characterised by episodic weakness associated with hypokalaemia. The disease can either be inherited or acquired and misdiagnosis of the disease is quite common. Most of the data available on the disease is from the western world. Studies reporting aetiological, clinical and metabolic profiles of Indian population are sparse. Hence we tried to provide insights of the disease among the Indian population. AIM: To study the aetiological, clinical and metabolic profile of patients diagnosed with Hypokalaemic Periodic Paralysis (HPP). MATERIALS AND METHODS: This is an observational and analytical study on HPP diagnosed patients, during September 2011 to September 2014 in Kasturba Hospital, Manipal. A total of 23 patients were studied. Detailed history, clinical evaluation and metabolic workup for secondary causes of HPP were analysed. RESULTS: Of the 23 patients, 57% had primary HPP while 43% had secondary HPP. The group of patients with primary HPP comprised of 92% males and 8% females with mean age of 28 years and the mean duration of symptoms of 18 hours. The group with secondary HPP comprised of 70% males and 30% females with mean age of 38.7 years and the mean duration of symptoms of 60 hours. The secondary causes of HPP were thyrotoxicosis (50%), infective diarrhea (20%), Crohn's disease (10%), renal tubular acidosis (RTA) Type I (10%) and Conn's syndrome (10%). CONCLUSION: In our study primary HPP was found to be more common than secondary HPP. Males were predominantly affected in both groups. HPP should be ruled out before starting therapy for Guillain-Barre Syndrome (GBS). PMID- 26500937 TI - Therapeutic Hypothermia after Prolonged Cardiac Arrest: Case Report with Review of Literature. AB - Patients who survive cardiac arrest often develop severe neurological dysfunction due to the hypoxic brain injury and reperfusion induced cell death. Therapeutic hypothermia (TH) has become a standard therapy of cerebral protection following the successful return of spontaneous circulation in patients of out-of-hospital cardiac arrest, according to American heart association guidelines. This is a case report of a 30-year-old patient who developed in-hospital cardiac arrest and was revived after prolonged cardiopulmonary resuscitation (CPR) and also required primary angioplasty. TH was then established with local measures for 24 hours for cerebral protection. The patient was gradually and successfully weaned off from ventilator with no neurological impairment. There is an increasing evidence of TH and its protective mechanisms in patients with non-shockable arrest rhythms with particular emphasis on neurological outcomes. This article emphasizes the role of TH in every successful CPR irrespective of the cardiac rhythm. PMID- 26500938 TI - Immunologic Cerebral Vasculitis and Extrapulmonary Tuberculosis: An Uncommon Association. AB - Infection can cause cerebral vasculitis not only by direct invasion of the vessel wall, but by immune complex deposition, or through secondary cryoglobulineamia. There are also two types of cerebral vasculitis associated with tuberculosis (TB). In TB treatment, cerebral vasculitis caused by immunologic injury received little attention than vasculitis due to direct invasion of TB infection. We report a case in a young woman who presented with fever, generalized lymphadenopathy, stroke-like events, movement disorder and coma, which was found to be active, lymph node TB with immunologic cerebral vacuities without tuberculosis meningitis. PMID- 26500939 TI - Gerbode Defect-A Rare Defect of Atrioventricular Septum and Tricuspid Valve. AB - Left ventricular to right atrial communications (the Gerbode defect) are rare types of ventricular septal defect and present as direct or an indirect type. We hereby, report two cases, one direct and another indirect type. Cardiopulmonary bypass surgery was done and a successful suture closure of ventricularseptal defect using pericardial patch was performed. PMID- 26500940 TI - Inheritance of Hereditary Persistence of Fetal Haemoglobin (HPFH) in a Family of Western Odisha, India. AB - Hereditary persistence of foetal haemoglobin (HPFH) is a rare inherited haemoglobin disorders in India. We encountered five cases of HPFH-3 in heterozygous condition in a single family of western Odisha, India. All the cases had raised % HbF (26.1+/-3.23%) with pancellular distribution of HbF in erythrocytes. There were no abnormalities found in the red cell indices. All the cases were asymptomatic till date with normal growth and development. Molecular confirmation of this haemoglobin disorders is important for control and prevention of haemoglobinopathies in this region. PMID- 26500942 TI - Pseudo-ballooning of Radial Artery-An Artifact. PMID- 26500941 TI - Follicular Bronchiolitis: A Literature Review. AB - Follicular bronchiolitis (FB) also known as hyperplasia of the bronchial associated lymphoid tissue (BALT), or bronchiolar nodular lymphoid hyperplasia, is an entity characterized by the development of lymphoid follicles with germinal centers in the walls of small airways. FB is thought to be caused by antigenic stimulation of BALT, followed by a polyclonal lymphoid hyperplasia. It is currently classified as one of the reactive pulmonary lymphoid disorders in a group known as the lymphoproliferative pulmonary diseases (LPDs). FB is a pathological diagnosis that can be seen in several clinical settings, including connective tissue diseases, immunodeficiency states, autoimmune diseases, infections, obstructive airway diseases, as well as several types of interstitial lung diseases (ILDs). Its characteristics need to be carefully identified and differentiated from other closely related diseases in the group of LPDs due to significant differences in treatment and prognosis. PMID- 26500943 TI - Atrial Fibrillation Due to Acute Myocarditis During Dengue Haemorrhagic Fever. PMID- 26500944 TI - A Comparison of Clinical Features, Pathology and Outcomes in Various Subtypes of Breast Cancer in Indian Women. AB - BACKGROUND: Breast cancer is often classified into subtypes using immunohistochemical markers. These subtypes have distinct biological behaviour. This study was conducted with the aim of estimating the distribution of various subtypes of breast cancer in Indian population based on immunohistochemistry markers and to determine the clinical features, pathology and outcomes of these subtypes of breast cancer. MATERIALS AND METHODS: A retrospective study was undertaken and all patients of breast cancer over a 5 year period were included. These patients were divided into 4 subgroups depending on the presence or absence of immunohistochemical markers: i) Luminal A (ER/PR+, Her 2 neu-); ii) Luminal B (ER/PR+, Her 2 neu+); iii) Her 2 enriched (ER-/PR-, Her 2 neu+) and; iv) Triple negative (ER-, PR-, Her2 neu-). Clinical and pathological features and survival were compared between patients in the 4 subgroups. RESULTS: Luminal A subgroup had majority of patients (43.8%). Patients in Luminal B, Her 2 enriched, and Triple negative subgroups were 14.8%, 16.1% and 25.3%. Median follow-up of patients was for 34 months. Luminal A subgroup patients were more likely to be postmenopausal and have smaller and lower grade (I/II) tumours with better survival (OS-91.06%). Patients in the Triple negative subgroup were more likely to be premenopausal (p-value 0.036, odds ratio 0.611, CI 0.394-0.949), have larger and higher grade (III) tumours with worse overall survival (OS-88.46%, odds ratio 1.32, 95%CI 0.602-2.39). Her 2 enriched group patients had bad prognostic features like larger size of tumour and higher grade of tumour and worst survival among all the subgroups (OS-85.07%, odds ratio 1.78, 95% CI 0.767 4.163). However, these outcomes were not statistically significant for the subgroups. CONCLUSION: A retrospective study was undertaken of breast cancer patients in India, according to subtypes based on immunohistochemistry. Luminal A had prognostic features and survival which was better as compared to other subgroups (Luminal B, Her 2 enriched and Triple negative). Incidence of patients with Triple negative breast cancer was higher in the premenopausal period. Patients with Her 2 enriched breast cancer had the worst survival among all the subgroups. PMID- 26500945 TI - Paraganglioma of Urinary Bladder Presenting as An Early Preeclampsia with Successful Perinatal Outcome After Surgery: A Case Report and Review of Literature. AB - Paraganglioma in urinary bladder associated with pregnancy is extremely rare with a prevalence of less than 1%. We report a case of 25-year-old pregnant female who presented with gross haematuria and clot retention during first trimester. MRI pelvis showed a mass antero- inferior to bladder. Transurethral resection biopsy revealed paraganglioma of the urinary bladder. Her workup showed neither raised plasma free normetanephrine levels. Patient underwent partial cystectomy during second trimester. Postoperatively, she is normotensive with normal serum free normetanephrine levels. At term, she delivered a healthy female child. This case highlights a successful perinatal outcome with timely intervention, adequate preoperative control of hypertension and counselling. We report a case of paraganglioma of urinary bladder presenting as an early preeclampsia with successful perinatal outcome after surgery. PMID- 26500946 TI - Penile Metastases From Prostate Adenocarcinoma: A Rare Presentation. AB - Penile metastases are rare in occurrence and are usually secondary to other genitourinary primary tumours. It is a debilitating near terminal condition at presentation with a dismal prognosis and poor survival rates. Supportive and palliative care is generally recommended to improve the quality of life of patients. We present a case of penile metastases in a 74-year-old male patient with prostatic adenocarcinoma in association with multiple skeletal metastases. PMID- 26500947 TI - A Case Series & Review of Literature of Angiomyolipoma with Medical & Surgical Perspective. AB - The angiomyolipoma of renal origin is a rare benign tumour composed of fat cells, smooth muscle cells, and thick-wall blood vessels. Mostly these are sporadic origin, asymptomatic and benign in nature. Here we present two cases of Renal angiomyolipoma (AML) presenting as fever, pain, perirenal haematoma & frank haematuria. After initial stabilization, evaluated by contrast enhanced computer tomography (CECT) & diagnosed as renal angiomyolipoma because of low Hounsfield areas (10-20HU) suggestive for fat. Patient later underwent angiography with selective angioembolisation. Post intervention period was uneventful and was treated by an oral Everolimus 10 mg daily for a period of one year in first case & partial resection was done in second case. On two year follow-up both patients were doing well & had normal renal function without any recurrence. Embolisation is the emergency treatment of choice for bleeding angiomyolipoma. When preventive treatment is considered a nephron sparing approach by either transarterial embolisation or partial nephrectomy is clearly important. While angiomyolipoma in both kidneys or in solitary functioning kidneys, renal preservation is mandatory in order to avoid need for renal replacement therapy. Also, recently approved drug Everolimus may be considered for patients not suitable for surgery particularly in tumour seen with tuberous sclerosis. PMID- 26500948 TI - An Unusual Transorbital Penetrating Injury by House-key (lock): A Case Report with a Small Review of Literature. AB - Penetrating injuries of the brain are quite uncommon, comprising approximately 0.4% of all head injuries. In our case, a four-year-old boy who fell forward on a house-key (lock) accidentally while playing with some other children sustained a left sided penetrating transorbital brain injury. After hospital admission, the patient had a Glasgow Coma Scale (GCS) score of 15/15, no visual loss but restriction of upward gaze (left eye) and profuse bleeding from the wound site. Firstly, the metallic key was removed in emergency operation theatre and haemostasis secured. Next day we did a combined surgical approach with neurosurgeons, Eye-surgeons and general surgeons after having CT scan report. We report this case because penetrating head injury is rare and transorbital penetrating head injury is even rarer and a predicament in emergency surgical practice with controversial management. PMID- 26500949 TI - Ectopic Ureter Accompanied by Duplicated Ureter: Three Cases. AB - We report cases of ectopic ureter accompanied by three types of ureteral duplication that had been diagnosed previously and treated for enuresis. Data from three female patients ranging in age from 1 to 10 years were evaluated. The ectopic ureter was observed on the left in one case, on the right in another and bilateral in the third case. Complete duplication was found in two cases, while the third had incomplete duplication. Ureteroneocystostomy was performed in one case and subtotal nephrectomy was carried out in the other two cases. Ureteroneocystostomy was performed for the ectopic ureter found in the opposite urinary system in one of the cases. Ectopic duplicated ureter should be considered in treatment-resistant enuresis and urinary tract infections and after a careful physical examination, imaging as well as function tests should be performed. PMID- 26500950 TI - A Rare Case of Emphysematous Cholecystitis. AB - Emphysematous cholecystitis is an acute infection of the gallbladder wall caused by gas-forming organisms. It is infrequent with insidious onset and diagnosed by the use of radiographs detecting presence of air within the gallbladder wall or lumen. The report describes the case of a 42-year-old alcoholic male who presented with sudden onset of pain in the right upper quadrant of abdomen, fever and bilious vomiting of two days duration. The patient did not have symptoms of jaundice. Emergency partial cholecystectomy was done and the culture directed antibiotics were given. The patient was followed up for 4 years and he remained asymptomatic. PMID- 26500951 TI - Perigraft Seroma Presenting as Discharging Sinus and Spontaneous Exteriorization of Vascular Graft - A Rare Entity Following Vascular Repair with PTFE Graft. AB - Perigraft seroma presenting as discharging sinus and spontaneous exteriorization of vascular graft are rare complication of vascular injury repair with polytetrafluoroethylene (PTFE) grafts. We hereby report a case of young boy who presented with discharging sinuses and vascular graft coming out from one of the sinuses following vascular repair of femoral artery with PTFE graft after a follow-up of six months but the limb was salvaged. On evaluation PTFE graft was found to be thrombosed and collaterals were formed for distal perfusion. Because of persistent discharging sinuses, PTFE graft was removed and femoral artery was ligated proximal and distal to the graft. This case highlights an unusual complication of PTFE grafts that is commonly used in vascular surgery and also highlights the fact that these graft buy time for gradual collaterals formation for distal perfusion and hence when thrombosed and complicated can be safely removed. PMID- 26500952 TI - De novo Choledocholithiasis in Retained Common Bile Duct Stent. AB - De novo choledocholithiasis means formation of stone in the common bile duct (CBD). It can present as biliary colic, jaundice, cholangitis, pancreatitis or it may be asymptomatic. There are various indications for biliary stenting like CBD stone, CBD stricture, biliary leak, peri ampullary carcinoma, CBD malignancy, etc. Foreign bodies like silk sutures, endo-clips, fish bone, retained T- tubes, plastic or metallic stents, etc. lead to biliary stasis leading to eventual stone formation. Here, we discuss a case of choledocholithiasis post-cholecystectomy with CBD stenting done 15 years back which had migrated and acted as a nidus for stone formation in the CBD and hepatic duct. PMID- 26500953 TI - Intramuscular Ossified Haemangioma: A Rare Case Report. AB - Haemangiomas are benign vascular neoplasm and intra muscular haemangioma constitutes 0.8% of all. Of these intramuscular ossified haemangioma is very rare. Here we are reporting a 30-year-old female admitted in our institute with complaints of pain and swelling in the medial aspect of right thigh for duration of one year. On evaluation CT showed well defined soft tissue lesion with calcification in vastus medialis which on guided aspiration showed numerous RBCs along with clusters of histiocytes with occasional calcified specs seen without presence of granulomas. The swelling was excised and histopathology confirmed intra muscular haemangioma with ossification. We hereby reporting a rare case of calcified intra muscular cavernous haemangioma which should be considered as differential diagnosis in any case of deep seated swelling with unexplained pain. PMID- 26500954 TI - Pacinian Neuroma Presenting as Congenital Macrodactyly: A Rare Case Report. AB - Pacinian neuromas are rare benign tumours of pacinian corpuscles of the digits. They generally occur on the volar aspect of the fingertips. Pacinian corpuscles are specialised nerve endings with a lamellated structure and are regarded as pressure and vibration receptors. Here, we report a case of pacinian neuroma presenting as congenital macrodactyly of the right little finger with pain for which the lesion was surgically excised. PMID- 26500955 TI - Pleomorphic Adenoma in Subcutaneous Plane of the Neck: A Rare Entity. AB - Heterotopic Salivary Gland Tissue (HSGT) is salivary tissue found in locations not normally host to it. Neoplasms occurring in these heterotopic tissues are very rare. Review of literature has revealed the neck to be host to HSGT and rarely, tumourigenic changes in these inclusions have been observed. We present a clinically unsuspected case of an ectopic pleomorphic adenoma of lower neck in which the ectopic salivary tissue was found in subcutaneous plane, which to the best of our knowledge has not been reported and was proved only on cytology and histopathology. There is a probability of this tumour undergoing malignant transformation. Therefore, these tumours need to be promptly diagnosed, adequately treated and should be included in the differential diagnosis of neck masses. PMID- 26500956 TI - Ectopic Spleen Presenting as Lump Abdomen: A Rare Case Report and Review of Literature. AB - Ectopic spleen is due to failure of fusion of the mesogastrium and the lining body wall epithelium, resulting in lax or absent supporting ligaments of spleen, making it abnormally mobile. This case presented as lump abdomen with history of recurrent attacks of abdominal pain. Clinical diagnosis was unidentified abdominal mass. The radiological imaging was suggestive of the diagnosis, and the exploration of abdomen has clinched the diagnosis. PMID- 26500957 TI - CT Guided Removal of Iatrogenic Foreign Body: A Broken Intravenous Cannula. AB - Foreign bodies are encountered on day to day basis by a surgeon. Usually foreign bodies are lodged in narrow cavities of the body and the common age group is in children. They may range from foreign bodies in ear, nose, cricopharynx and even in rectum. Iatrogenic foreign bodies are not uncommon. Unknowingly, surgeons have been known to leave sponges, artery forceps in the abdomen which lead to hazardous sequelae. Intravascular foreign bodies occurrence has increased from a decade or so. PMID- 26500958 TI - A Rare Case of Jejunal Atresia Due to Intrauterine Intussusception. AB - Intestinal atresia is generally caused by intrauterine vascular obstructions involving mesenteric vessels. Intrauterine intussusceptions (IUI) are one of these disruptive events. Intestinal intussusceptions affects children commonly between 3 months and 3 years of age, but it rarely affects in intrauterine life. The relationship between intrauterine intussusception and intestinal atresia has been demonstrated by few cases in literature, suggesting intrauterine intussusception as a rare cause of intestinal atresia. We report a 7-day-old full term neonate presenting with intrauterine intussusceptions (jejuno-jejunal) resulting in jejunal atresia. PMID- 26500959 TI - Indwelling Catheterization in Caesarean Section: Time To Retire It! AB - BACKGROUND: Routine placement of indwelling catheter preoperatively in Caesarean Section is being practiced without justified scientific evidence. AIM: To evaluate the effect of routine indwelling catheterization on the postoperative ambulation, morbidity and hospital stay in women undergoing Caesarean section. SETTINGS AND DESIGN: Case-Control study carried in a tertiary teaching hospital. MATERIALS AND METHODS: This study was carried over 150 women undergoing primary Caesarean section without any medical complication or pre-existing Urinary Tract Infections (UTI). The subjects were randomly allocated to 2 groups i.e. Group 1(Non-Catheterized; NC) and Group 2 (Catheterized for 24 hours postoperatively; C). Parameters noted were; duration of surgery, time of ambulation, postoperative voiding discomfort {graded as - no, mild, moderate-severe, by Visual Analog Scoring (VAS)}, incidence of UTI, postoperative urinary retention, need of postoperative antibiotics and duration of hospital stay. STATISTICAL ANALYSIS: Results were analysed using unpaired t-test. RESULTS: There was no significant difference in duration of surgery and postoperative urinary retention in both groups. However, it was seen that non-catheterized patients had significantly earlier ambulation, shorter hospital stay, took less time for first voiding, lesser voiding discomfort, less incidence of UTI and lesser use of postoperative antibiotics. CONCLUSION: The routine use of indwelling catheter in Caesarean section is unscientific and unnecessary. There should be selective rather than routine catheterization. PMID- 26500960 TI - A Case Control Study to Evaluate the Association between Primary Cesarean Section for Dystocia and Vitamin D Deficiency. AB - BACKGROUND: Milder forms of vitamin D deficiency could be responsible for poor muscular performance causing dysfunctional labor. The aim of our research was to study the association between vitamin D deficiency and primary cesarean section. MATERIALS AND METHODS: This was a case control study. Forty six women who delivered by primary cesarean section with dystocia as primary or secondary indication after 37 weeks of gestation were taken as cases and a similar number of women who delivered vaginally were taken as controls. Vitamin D deficiency was diagnosed when the serum 25(OH)D level was <=20 ng/ml and this was compared between cases and controls. RESULTS: Median serum (OH) vitamin D levels was 23.3ng/ml among women who delivered by cesarean section and 26.2ng/ml among controls (p=0.196). Baseline characteristics were similar in both groups except for a strong association between Body Mass Index (BMI) and cesarean section, (29.7kg/m(2) in cases and 25.9kg/m(2) in controls p=0.001) seen in multivariate analysis. Vitamin D deficiency was seen in 34.8% of cases and 21.7% of controls (p=0.165). CONCLUSION: This small case control study did not show a significant association between vitamin D deficiency and primary cesarean section. PMID- 26500961 TI - Pregnancy with Irreducible Utero-Vaginal Prolapse. AB - Pregnancy with uterine prolapse is a relatively rare condition. Irreducible prolapse occurring during pregnancy is even rarer. There is still a need for obstetricians to be aware about the management of uterine prolapse which allows for an uneventful pregnancy, labour and delivery. Here we present a case of a woman who developed irreducible uterine prolapse during pregnancy and the issues surrounding its management. We had to abort her pregnancy to reduce her prolapse which could otherwise have been life threatening. PMID- 26500962 TI - A Huge Mature Cystic Teratoma in a Nulliparous Patient. AB - Here we report a case of a giant mature cystic teratoma of the ovary in a 38-year old nullipaous woman. The patient presented with abdominal distension and abdominal pain. Laparotomy and cystectomy yielded satisfactory results. Histologic evaluation confirmed a benign cystic teratoma of the ovary. The patient underwent surgery for rupture of corpus luteum six years ago and no gross lesion was seen at the operation. This case demonstrates that dermoid cysts can grow to enormous sizes within a short duration. PMID- 26500963 TI - Virilizing Ovarian Steroid Cell Tumor: A Rare Case. AB - Ovarian steroid cell tumours are fewer than 5 percent of sex-cord stromal tumours and 0.1% of all ovarian tumours. The average age at diagnosis is the mid-20s, but patients can present at virtually any age. We present a case of 38-year-old multipara with history of secondary amenorrhea, clinical signs & symptoms of virilization developed over the past 5 years. With elevated (115ng/dL) serum testosterone level and radiological findings of a left adnexal solid mass; the patient was suspected to have a virilizing tumour of left ovary. Laparoscopic left salpingo-oophorectomy was performed. Histopathology revealed tumour cells in small nests with vacuolated to eosinophilic cytoplasm with nuclear atypia completely replacing the ovarian tissue suggestive of steroid cell tumour (NOS) of ovary. The patient was discharged and advised for follow up with serum testosterone levels after 3 weeks. PMID- 26500964 TI - Takayasu Arteritis with Bilateral Renal Artery Stenosis and Left Subclavian Artery Stenosis in Pregnancy. AB - Takayasu arteritis (TA) is a rare, systemic, chronic inflammatory, progressive, idiopathic disease of aorta and its main branches. It causes narrowing, occlusion and aneurysm of arteries. It affects mainly young females in about 80-90% of cases (young female arteritis). TA has adverse effect on pregnancy in the form of abortion, superimposed preeclampsia, IUGR (Intrauterine growth restriction), IUFD (intrauterine fetal death), abruption and CCF (congestive cardiac failure). Careful assessment, treatment of TA complication, regular antenatal followup and multidisciplinary approach involving obstetrician, cardiologist, rheumatologist and anaesthetist improve maternal and fetal outcome. We described here a case of pregnancy with TA with bilateral renal artery stenosis and left subclavian artery stenosis. PMID- 26500965 TI - Post-Partum Diastasis of the Pubic Symphysis: Report of a Rare Case. AB - Post-partum pubic symphysis diastasis refers to an abnormally wide gap between the two pubic bones following delivery. It is an uncommon and under diagnosed condition resulting in acute pelvic pain. A case of pelvic diastasis in a 24-year old G2A1 following normal vaginal delivery is reported. Management consisted of simple conservative treatment with binders and analgesics, which were sufficient in achieving a complete reversal of the condition. The low incidence of 1 in 3700 normal vaginal deliveries over a 5 year period at Public Health Centre, Chennai, coupled with the rarity of the condition renders it as a salient presentation in the practice of our profession. PMID- 26500966 TI - Middle Interhemispheric Variant of Holoprosencephaly - Presenting as Non Visualized Cavum Septum Pellucidum and An Interhemispheric Cyst in A 19-Weeks Fetus. AB - Middle Interhemispheric variant (MIH) is a rare subtype of holoprosencephaly (HPE), also known as syntelencephaly. We present a case of MIH, which was diagnosed as an interhemispheric cyst on antenatal sonography at 19 weeks, but later diagnosed as MIH variant of holoprosencephaly after a postabortal MRI and perinatal autopsy. PMID- 26500967 TI - An Abdominal Wall Desmoid Tumour Mimicking Cesarean Scar Endometriomas: A Case Report and Review of the Literature. AB - Abdominal wall desmoid tumours (DT) are rare, slow-growing benign muscular aponeurotic fibrous tumours with the tendency to locally invade and recur. They constitute 0.03% of all neoplasms and high infiltration and recurrence rate, but there is no metastatic potential. Although surgery is the primary treatment modality, the optimal treatment remains unclear. Abdominal wall endometriosis is also an unusual disease, and preoperative clinical diagnosis is not always easy. The preoperative radiologic imaging modalities may not aid all the time. Herein, we report an abdominal mass presenting as cyclic pain. Forty-two years old woman who gave birth by cesarean section admitted the complaints of painful abdominal mass (78x45 mm in size) under her cesarean incision scar. She had severe pain, particularly during menstruation. The clinical and radiological imaging findings mimicking endometrioma. We performed wide surgical excision of mass with a 1 cm tumor-free margin with the diagnosis of a benign mesenchymal tumor in the frozen section. The postoperative course was uneventful and recovered without any complication and recurrence three years after surgery. This report presents a case of abdominal wall desmoid tumor mimicking endometrioma. In this paper, shortcomings in diagnosis, abdominal wall endometriomas, and DTs were discussed in the view of literature. PMID- 26500968 TI - Primary Tubal Choriocarcinoma Presented as Ruptured Ectopic Pregnancy. AB - The primary tubal choriocarcinoma associated with ectopic pregnancy is very rare. A 31-year-old woman was admitted to the emergency room due to amenorrhea, left lower abdominal pain and fatigue. Her beta-Hcg level was 29251.4 mIU/ml and transvaginal ultrasund revealed a 24x21 mm of left tubal ectopic pregancy mass with large amount of free fluid in pelvic cavity. The patient was diagnosed with ruptured tubal ectopic pregnancy and thus, she underwent laparotomy with left total salpingectomy. The pathological assessment was reported as primary tubal choriocarcinoma with the involvement of whole tubal layer. The patient was defined to have stage I choriocarcinoma with good prognostic factors and methotrexate monotherapy was administered. Serum beta- Hcg levels of the patient gradually declined and eventually became negative at the first month of the treatment. With this case report we aimed to implicate that when diagnosing the ectopic pregnancy, even very rare, the tubal choriocarcinoma should be kept in mind. PMID- 26500969 TI - Management of Proximal Tibia Fractures Using Wire Based Circular External Fixator. AB - INTRODUCTION: Management of high grade proximal tibia or tibial plateau fractures is often associated with complications. The use of wire fixators for the definitive treatment of such fractures entails a minimally invasive technique of insertion that gives good fracture reduction and stability combined with minimal postoperative complications. AIM: To assess the outcome of treatment of such fractures by the use of Joshi's external stabilization system (JESS), which is a wire based, circular external fixator system. MATERIALS AND METHODS: A prospective, uncontrolled study was done using JESS on 20 consecutive patients of high energy fractures of the tibial plateau, classified according to the Schatzker's classification as type VI. RESULTS: In this series, road traffic accidents accounted for most of the injuries (n=12), while pedestrian accidents (n=4), injury due to fall from height (n=3) and injury due to fall while playing (n=1) were the other modes of injury. The mean patient age was 39.4 years. The mean follow up period was 24 weeks. In this study, using Knee society score evaluation, excellent results were seen in 12 patients (60%), good results were seen in 5 patients (25%), fair in 2 patients (10%) and bad in 1 patient (5%). Complications seen were, pin tract infections in two cases (10%) which resolved with dressings and oral antibiotics and one case of non-union (5%), in which the tibial plateau fracture extended into proximal 1/3 of the tibial shaft with severe comminution. No other complication was encountered. CONCLUSION: JESS is a simple, inexpensive and useful technique in the management of high grade tibial plateau fractures. PMID- 26500970 TI - Measurement of Ulnar Variance in a Regional Subset of Indian Population-A Pilot Study of 30 Subjects. AB - BACKGROUND: The variation of level of distal articulating surface of ulna with respect to distal articulating surface of radius is known as ulnar variance (UV). Positive and negative UV has been implicated in various wrist and hand pathologies. AIM: To measure ulnar variance in a regional subset of Indian population and to compare two techniques of measurement of ulnar variance viz. method of perpendiculars and modification of the concentric circles method. MATERIALS AND METHODS: UV was measured in a regional subset of Indian population comprising of 30 subjects. The mean age of patients was 35.9 years. There were 16 males and 14 females in the study group. Antero-posterior (AP) X-rays of wrist in neutral position were taken and UV was measured using method of perpendiculars and the modified circle method. RESULTS: The mean UV using method of perpendiculars (UVA) was 0.387 mm and using modified circle method (UVB) was 0.507mm. A higher predominance of positive UV in this regional subset of Indian population was observed. There was no correlation between UV with respect to age and sex. No statistically significant difference was observed between the two methods of measurement utilized in the study. CONCLUSION: The documentation of a negative and positive ulnar variance will help in prophylactic and timely intervention for various wrist pathologies, if required. However, a larger sample size with a longer follow up is required to suggest a correlation of ulnar variance with clinically symptomatic disease. PMID- 26500971 TI - A Rare Combination of Avulsion Fractures Around the Knee -A Case Report. AB - Patella fractures, tibial spine avulsion and Segond fractures are mainly due to trauma to the knee which may be direct or indirect injuries. While each entity is well documented when occurring in isolation, but bilateral inferior pole patella fracture, tibial spine avulsion in the right knee and bilateral segond fracture in a same patient is a rare occurrence. We report a case of 24-year-old male with such an injury. The diagnosis was confirmed by X-ray, CT scan and MRI imaging of right knee. Then the patient was treated with arthroscopic anterior cruciate ligament (ACL) avulsion fixation with pull through technique and suture disc; bilateral inferior pole patella was treated conservatively with knee brace, segond fracture was treated conservatively similarly. To the best of our knowledge, this is the rare case in the medical literature with all these injuries occurring simultaneously. PMID- 26500972 TI - Determinants of Capillary Refill Time in Healthy Neonates. AB - OBJECTIVES: Traditionally Capillary refilling time (CRT) has been used as a widely accepted method to assess cardiac output and peripheral circulation in neonates. There are only few studies describing normal values and the correct method of recording CRT. The value of CRT is affected by various factors like ambient or skin temperature, age, site of measurement, duration as well as amount of pressure and inter observer variation. However, none of these have been standardized. Hence, we conducted this study to establish the normal value and factors affecting Capillary Refilling Time (CRT) in healthy neonates in Varanasi. DESIGN: Prospective observational study done over a period of 2 years. SETTING: Maternity wards and Neonatal intensive care unit of Sir Sunderlal Hospital, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. PARTICIPANTS: Healthy neonates between 35-42 weeks of gestation staying with their mothers and admitted in neonatal intensive care unit. MATERIALS AND METHODS: CRT was measured by standard technique four times during first week of life on day 1, 3, 5 and 7. STATISTICS ANALYSIS: Student t-test was used for analysis. A p-value less than 0.05 was taken as statistically significant. RESULTS: The mean capillary refilling time (CRT) was 2.23 +/- 0.37 seconds in healthy neonates during first week of life. We studied each neonate four times in first week of life. Significantly lower values of CRT were noted in low birth weight babies throughout first week in healthy neonates. Babies under phototherapy and radiant warmer had also shorter CRT values. Values were not affected by age, sex and gestation. CONCLUSION: The normal value of capillary refilling time (CRT) in healthy neonate is less than three seconds. The major determinants of CRT in healthy neonate are birth weight, radiant warmer and phototherapy. CRT alone in neonatal age is less informative haemodynamic parameter; it should be evaluated along with either blood pressure or oxygen saturation with pulse oxymeter. Further studies are needed to assess the reliability and validity of CRT as a clinical tool to measure perfusion in neonates. PMID- 26500973 TI - Evaluation of Cord Blood - Haematological Scoring System as an Early Predictive Screening Method for the Detection of Early Onset Neonatal Sepsis. AB - BACKGROUND: Sepsis is one of the major causes of neonatal morbidity and mortality. Early recognition and diagnosis of neonatal sepsis are difficult because of the variable and non-specific clinical presentation of this condition. Hence, there is a need for early predictive screening method for neonatal sepsis. OBJECTIVES: To evaluate the role of Cord blood Haematological Scoring System as an early predictive screening method for detection of early onset neonatal sepsis and also to identify the neonates who are at risk of developing neonatal sepsis using cord blood. SETTINGS AND DESIGN: The present prospective cross-sectional study was conducted by taking 153 cord blood samples of full term newborns immediately after delivery in the hospital. Pre-term, still birth and emergency deliveries were excluded from the study. MATERIALS AND METHODS: The cord blood was collected and analysed for various Haematological parameters like Total leucocyte count, Absolute Neutrophil count, Immature to mature Neutrophil ratio, immature to mature ratio, Neutrophil morphology, nucleated erythrocytes, platelet count, micro erythrocyte sedimentation rate. Blood cultures were performed as gold standard for diagnosing neonatal sepsis. STATISTICAL ANALYSIS: Chi-square test, Risk ratio, risks in exposed and risk in unexposed were performed. RESULTS: Of 153 newborns for analysis, 59 (38.56%) developed sepsis. The haematological scoring system found that an abnormal immature to total neutrophil ratio, Neutropenia, micro erythrocyte sedimentation rate followed by an abnormal immature to mature neutrophil ratio were the most sensitive indicators in identifying infants with sepsis. The study also found that higher the score, the greater the certainty of sepsis being present. CONCLUSION: The haematological scoring system using cord blood can be considered as an early predictive screening method for detection of early onset neonatal sepsis. Identifying the risk of developing sepsis early can prevent morbidity and mortality of the neonates. PMID- 26500974 TI - Study of Asymptomatic Hypoglycemia in Full Term Exclusively Breastfed Neonates in First 48 Hours of Life. AB - INTRODUCTION: Hypoglycemia is a common metabolic problem in the neonatal period especially in the presence of settings like prematurity, small for gestational age babies and sepsis. Episodes of asymptomatic hypoglycemia may occur in term neonates without apparent risk factors. AIM: This study was conducted to estimate the incidence of hypoglycemia in healthy, intramural, singleton full term neonates and to correlate the above incidence with maternal factors like parity, mode of delivery and time of initiation of breast feeding after birth. MATERIALS AND METHODS: A hospital based, prospective longitudinal study involving healthy, term, asymptomatic neonates. Blood glucose values were measured at 1, 6, 24 and 48 hours of life. RESULTS: The overall incidence of hypoglycemia was 10 % in asymptomatic, healthy term newborns. All the hypoglycemic episodes occurred in the first 24 hours of life. 23.07% of neonates born to primiparous mothers had hypoglycemia, against 5.4% neonates born to multiparous mothers (p<0.05). There was a higher recording of hypoglycemia when breast feeding was initiated > 1 hour after delivery (16.67%) than when breast feeding was initiated within one hour of delivery (7.89%). CONCLUSION: Asymptomatic hypoglycemia occurred in about 10% of healthy, full term neonates; primiparity and delayed initiation of breast feeding > 1 hour are noted as additional risk factors. PMID- 26500975 TI - Incontinence in Intellectual Disability: An Under Recognized Cause. AB - Many children with Down syndrome may develop urinary incontinence during adolescence or nearing adulthood. Most often low mental ability, behavioural issues, urinary tract infection, hypothyroidism, atlanto-axial subluxation or sexual abuse may be suspected to be the reason. We report a case of Down syndrome with tethered cord syndrome (TCS) and Lipoma of Filum terminale with Cauda equina in normal position, as a cause of bowel and bladder incontinence. The need for operating with Cauda Equina in normal position is debated. But a conscious decision was taken to operate and the incontinence improved markedly which was documented by using a standardized questionnaire (King's questionnaire) and thereby making a difference in the child's life. A literature search did not result in any case of Down syndrome with tethered cord syndrome and secondary incontinence as presentation. Considering the possibility of TCS as a cause of incontinence, often neglected even in normal children, careful evaluation and correction of such problems will make a difference in the life of many intellectually disabled children. Incontinence should not be casually attributed to intellectual disability without ruling out other causes. PMID- 26500976 TI - Mesenchymal Hamartoma of Chest Wall in an Infant: Mimicking Persistent Pneumonia. AB - Mesenchymal Hamartoma of the chest wall (MHCW) is a very rare benign tumour. They are usually discovered in infancy. Spontaneous regression is known to occur in this benign condition. Management is surgical removal of mass if respiratory compromise is present. Conservative management is preferred modality in asymptomatic children as malignant transformation is not reported. Herein, we present a case of MHCW in a 5 month old infant presenting with acute respiratory distress with history of respiratory problem at 3 months of age. Child was suspected to have persistent pneumonia in view of radiological findings. Child's respiratory distress improved with antibiotics and bronchodilators. Respiratory symptoms in MHCW are due to extrinsic compression of lung parenchyma. Present case had respiratory symptoms with persistent radiological findings leading to suspicion of persistent pneumonia. His respiratory symptoms and exacerbation on follow up was attributed to hyper reactive airway disease and MHCW was managed conservatively. The non-neoplastic nature, characteristic presentation, histopathology, imaging modality and management options of MHCW are discussed. PMID- 26500977 TI - Efficacy of High Frequency Ultrasound in Localization and Characterization of Orbital Lesions. AB - BACKGROUND: The complicated anatomy of orbit and the wide spectrum of pathological conditions present a formidable challenge for early diagnosis, which is critical for management. Ultrasonography provides a detailed cross sectional anatomy of the entire globe with excellent topographic visualization and real time display of the moving organ. OBJECTIVES OF THE STUDY: To evaluate the efficacy of high frequency Ultrasound in localization of orbital diseases and to characterize various orbital pathologies sonologically. MATERIALS AND METHODS: Hundred eyes of 85 patients were examined with ultrasound using linear high frequency probe (5 to 17 MHz) of PHILPS IU22 ultrasound system. Sonological diagnosis was made based on location, acoustic characteristics, kinetic properties and Doppler flow dynamics. Final diagnosis was made based on clinical & laboratory findings/higher cross-sectional imaging/surgery & histopathology (as applicable). Diagnostic accuracy of ultrasonography was evaluated and compared with final diagnosis. RESULTS: The distinction between ocular and extraocular pathologies was made in 100% of cases. The overall sensitivity, specificity, NPV and accuracy of ultrasonography were 94.2%, 98.8%, 92.2% & 94.9% respectively for diagnosis of ocular pathologies and 94.2%, 99.2%, 95.9% & 95.2% respectively for extra ocular pathologies. CONCLUSION: Ultrasonography is a readily available, simple, cost effective, non ionizing and non invasive modality with overall high diagnostic accuracy in localising and characterising orbital pathologies. It has higher spatial and temporal resolution compared to CT/MRI. However, CT/MRI may be indicated in certain cases for the evaluation of calcifications, bony involvement, extension to adjacent structures and intracranial extension. PMID- 26500978 TI - Role of High Resolution Computed Tomography in Evaluation of Pathologies of Temporal Bone. AB - BACKGROUND: High Resolution Computed Tomography (HRCT), a modification of routine CT, provides a direct visual window in the temporal bone providing minute structural details. Purpose of the present study was to evaluate the normal variations, pathological processes (infections and congenital anomalies) and their extent involving the temporal bone along with their complications on HRCT and to correlate these imaging findings surgically, wherever available. MATERIALS AND METHODS: The prospective study included 50 patients who were referred to the radiology department with clinically suspected temporal bone or ear pathologies. After detailed clinical examination, the patients were subjected to high resolution computed tomography (HRCT) examination. The imaging findings were correlated with the surgical findings wherever available. The surgical findings were considered as final. RESULTS: From a total of 50 cases, 83.33% had cholesteatoma. The surgical and radiological findings showed a high level of sensitivity (89.29%) in the identification of cholesteatoma. HRCT provides a good sensitivity of 80.65% in the identification of changes to the ossicular chain despite the presence of surrounding soft tissue. HRCT was highly informative in identification of erosion of lateral semicircular canal. In diagnosis of facial canal dehiscence HRCT had a low sensitivity of 33.33%. In the evaluation of any congenital abnormality of the ear HRCT proved to be beneficial in depicting the anatomical details. CONCLUSION: The clinical and radiological findings showed a high level sensitivity with intraoperative findings as regards to the presence of cholesteatoma, changes of the ossicular chain and erosion of the lateral semicircular canal. HRCT findings, in the treatment of any congenital abnormality of the ear were a good guide to the surgeon for planning and management. PMID- 26500979 TI - Lhermitte-Duclos Disease: Diagnosis on MRI, MR Spectroscopy, CT and Positron Emission Tomography. PMID- 26500980 TI - Efficacy of Caudal Clonidine and Fentanyl on Analgesia, Neuroendocrine Stress Response and Emergence Agitation in Children Undergoing Lower Abdominal Surgeries Under General Anaesthesia with Sevoflurane. AB - INTRODUCTION: Clonidine has proved to be effective drug for postoperative analgesia but it's efficacy to alter neuroendocrine stress response and emergence agitation is unknown. This study was conducted to assess and compare the efficacy of caudal fentanyl vs. clonidine for analgesia, blunting of neuroendocrine stress responses (NESR) and emergence agitation (EA) following sevoflurane anaesthesia. MATERIALS AND METHODS: This prospective, randomized, double blind study enrolled 60 children undergoing infraumbilical surgery. Three groups of 20 each were assigned to receive caudal block with either bupivacaine 0.25% 1 ml/kg with normal saline (group I) or bupivacaine 0.25% 1 ml/kg and 1 microgram*kg-1fentanyl (group II), or bupivacaine 0.25% 1 ml/kg and 3 MUg/kg clonidine [group III]. Postoperative analgesia, sedation, NESR, emergence agitation and side effects were observed. RESULTS: VAS score at two hours was significantly less in group III (0.60+/- 0.60) than in group I (1.80+/- 0.41) and group II (1.25+/- 0.44), the time to rescue analgesia was also significantly greater in group III (8.03+0.41hours) than groups I and II (4.15+/- 0.54 hours) and (6.18+/- 0.5hours) respectively. The EA scores were significantly better in Group III but patients were significantly more sedated postoperatively. Intraoperatively, NESR was blunted in all the groups and the markers of NESR were lowest in group III. CONCLUSION: Caudal clonidine in a dose of 3 MUg/kg prolongs analgesia and decreases emergence agitation as compared to bupivacaine alone or with fentanyl 1MUg/kg. Modulation of the neuroendocrine stress response was observed in all the investigated groups though the indicators were lowest in clonidine group. PMID- 26500981 TI - Comparative Evaluation of Bolus Administration of Dexmedetomidine and Fentanyl for Stress Attenuation During Laryngoscopy and Endotracheal Intubation. AB - BACKGROUND: Laryngoscopy and endotracheal intubation can cause hypertension and tachycardia which can result in myocardial ischemia or stroke in vulnerable people. The objective of our study was to compare the efficacy of bolus dose of dexmedetomidine and fentanyl in attenuating haemodynamic stress responses following laryngoscopy and intubation. MATERIALS AND METHODS: Sixty patients who were fixed to undergo elective surgeries under general anaesthesia were randomly divided into 2 groups. Group 1 received 1 mcg/kg of dexmedetomidine over 10 minutes and group 2 received fentanyl 2mcg/kg before induction. Anaesthesia was standardized in both the groups and vital parameters were recorded for up to 10 minutes after intubation. RESULTS: Dexmedetomidine in a dose of 1mcg/kg prevented an increase in heart rate following laryngoscopy when compared to fentanyl group. This effect lasted for 10 minutes after intubation is performed. Though dexmedetomidine prevented an increase in blood pressure, this effect was statistically significant only for 2 minutes after intubation when compared to fentanyl group. CONCLUSION: Attenuation of rise in heart rate and blood pressure following laryngoscopy and endotracheal intubation was better with 1mcg/kg of dexmedetomidine when compared to fentanyl. PMID- 26500982 TI - Comparison of Effects of Different Doses Dexmedetomidine on Inhibiting Tracheal Intubation-Evoked Haemodynamic Response in the Elderly Patients. AB - BACKGROUND: Dexmedetomidine (DEX) is a selective alpha2-adrenergic receptor agonist with anxiolytic and analgesic properties. In the present study, we aimed primarily to assess the effects of DEX on sedation, cognitive function and cardiovascular reflex responses before, during and after the tracheal intubation in the elderly patients. MATERIALS AND METHODS: Eighty patients undergoing elective abdominal surgery were randomly assigned to four Groups: Group A(saline, n=20), Group B (0.25MUg/kg DEX, n=20), Group C (0.50MUg/kg DEX, n=20) and Group D (1.00MUg/kg DEX, n=20). With the constant speed infusion of saline and a loading different doses of DEX (diluted with saline to 50ml) for 10min respectively before induction of anaesthesia, the values of arterial pressure {systolic blood pressure (SBP), diastolic blood pressure (DBP)}, heart rate (HR) and bispectral index (BIS) at the time point of before pump DEX (T0), at the end of infusing DEX (T1), before tracheal intubation (T2), at the moment of tracheal intubation (T3) and 5min after trachea intubation (T4) were observed, oxygen saturation (SPO2) and the Modified Observers Assessment of Alertness/Sedation Scale (OAA/S) score were observed at the time of T1 and T0. RESULTS: Comparison among Groups, compared with Group A, SBP and DBP values in Group C at T2 showed significant differences (p<0.05), SBP and DBP values in Group D at T1, T2 and T4 indicated significant differences (p<0.05), HR values in Group D at T1, T2, T3 and T4 showed significant differences (p<0.05); Compared with Group A, BIS values in Group C at T2 and T3 indicated significant differences (p<0.05), BIS values in Group D at T1, T2, T3 and T4 showed significant differences (p<0.05); Comparison between T3 andT2, means of SBP, DBP and HR in Group A and in Group B showed significant differences (p<0.05); Group D showed significant differences in SPO2 and (OAA/S) betweenT1 and T0 (p<0.05). CONCLUSION: Comparison within Groups and between Groups in different doses DEX, the present result showed that 0.5MUg/kg DEX had an effective inhibition, without respiratory depression, on tracheal intubation evoked cardiovascular response in the elderly patients. PMID- 26500983 TI - Evaluation of Efficacy of Epidural Clonidine with 0.5% Bupivacaine for Postoperative Analgesia for Orthopaedic Lower Limb Surgeries. AB - OBJECTIVE: The objective of this study is to evaluate the efficacy of epidural clonidine in intra and postoperative analgesia, the level of sedation caused by clonidine and monitor its side effects. MATERIALS AND METHODS: Forty patients of ASA1 & ASA2 scheduled for lower limb orthopaediac surgeries were chosen for the study. Study group received 50MUg of clonidine diluted to 1ml along with first dose of epidural injection and Control group received 1ml of normal saline along with first dose of epidural. Intra and postoperative vitals, verbal pain rating scale (VRS), sedation score and number of rescue anlgesics required postoperatively were noted. Patients received rescue analgesic when VRS was 1. RESULTS: Addition of clonidine to bupivacaine definitely improves the quality of analgesia by reducing the overall pain score, prolonging the duration of the time of first rescue analgesia and causing reduction of total analgesic consumption in the postoperative period without any hemodynamic instability. Sedation may be beneficial during the intraoperative period. CONCLUSION: Epidural clonidine produces long lasting, good quality analgesia with good level of sedation and with minimal side effects. PMID- 26500984 TI - A Randomized Double Blinded Comparison of Epidural Infusion of Bupivacaine, Ropivacaine, Bupivacaine-Fentanyl, Ropivacaine-Fentanyl for Postoperative Pain Relief in Lower Limb Surgeries. AB - BACKGROUND: Continuous epidural infusion of Bupivacaine and Ropivacaine with or without the addition of Fentanyl has been evaluated by various researchers for effective postoperative pain relief. Studies however, depict significant variability in their results with regard to analgesic efficacy and adverse effects like hypotension, motor blockade etc. AIM: To comparatively evaluate postoperative analgesic efficacy, motor sparing effect, postoperative haemodynamic variations and total postoperative analgesic consumption in first 24 hours. MATERIALS AND METHODS: A randomised double blind study was conducted on 100 adult, ASA grade I and II patients, of either sex who had undergone elective lower limb surgery under spinal anaesthesia. According to the group allocated, patients were started on epidural infusion after completion of surgery. Group I (0.2% Ropivacaine), Group II (0.1% Ropivacaine + 2MUg/ml Fentanyl), Group III (0.2% Bupivacaine), Group IV (0.1% Bupivacaine + 2MUg/ml Fentanyl) at the rate of 6 ml/hour. VAS scores, epidural consumption, supplemental epidural boluses, rescue analgesics, haemodynamics, motor block, sensory block regression, sedation, nausea and pruritis were recorded by a blinded observer for 24 hours. RESULTS: The haemodynamic parameters were stable in all the groups. Side effects including the motor block were negligible and comparable in all groups. Group I patients had significantly lower VAS scores, mean total epidural consumption, supplemental epidural bolus requirement and rescue analgesic requirement among all groups. CONCLUSION: It can be concluded that epidural analgesia using Ropivacaine 0.2% infusion is more effective than other study groups when used for postoperative pain relief in lower limb surgeries. PMID- 26500985 TI - Intubating Conditions of two Different Doses of Rocuronium At 60 Seconds; by Clinical Assessment; and with T.O.F Response of Adductor Pollicis Muscle. AB - BACKGROUND: At 60 seconds, 2xED95 dose (0.6mg/kg) of rocuronium is frequently used for intubation. Some studies suggest 3XED95 (0.9mg/kg body weight) dose in achieving excellent intubating conditions. In this context, present study aimed at comparing intubating conditions with these two doses of rocuronium, using clinical criteria by cooper's score; assisted with adductor pollicis T.O.F response. MATERIALS AND METHODS: Present prospective randomized comparative clinical study was conducted on 60 patients subjected for general anaesthesia. Induction was done with fentanyl (1mcg/kg body weight) and propofol (2mg/kg body weight) and relaxation achieved with Rocuronium 0.6 mg/kg (Group A-30 cases); 0.9mg/kg (Group B- 30 cases). (n=30) intubation was done at 60 seconds. Intubating conditions were assessed clinically by cooper's score.T.O.F responses of AP by visual and tactile means. RESULTS: Intubating conditions clinically were excellent in 16 cases (53%), good in 12 cases (40%), and fair in 2 cases (7%) respectively in Group-A. In group-B excellent in 29 cases (97%) and good in 1case (3%). In group A in no case TOF-0 achieved. TOF 1, 2, 3, and 4 were observed in 1 case (3%), 7 cases (23%) 16 cases (54%) and 6 cases (20%) respectively. Whereas in group B, TOF 0, 1, 2, 3 were observed in 18 cases (61%), 4 cases (13%), 7 cases (23%) and 1 case (3%). In no case TOF-4 observed. Chi square test (p<0.0001) confirmed a highly significant statistical difference with respect to elicited TOFcounts, and intubating conditions achieved. CONCLUSION: 3xED95 dose of Rocuronium achieves more intense NMB and better conditions for intubation at 60 seconds than 2ED 95 dose. PMID- 26500986 TI - Sports Induced Cardiac Arrest: A Case of Missed Rhabdomyolysis. AB - Exercise induced rhabdomyolysis although uncommon, is well known in strenuous and exhaustive sports like marathons, cycling and wrestlers. But it is not known in Kabaddi players. We report a case of nearly fatal rhabdomyolysis which was missed during early resuscitation in emergency room and lead to cardiac arrest due to catastrophic metabolic acidosis and severe -hyperkalemia. After high quality cardiopulmonary resuscitation and return of spontaneous rhythm, emergency resuscitative exploratory laparotomy was performed for suspected bladder injury which was negative. He had remarkable recovery over 24 h following diagnosis and aggressive supportive management including peritoneal dialysis. Heat stroke and rhabdomyolysis should be suspected early in players playing strenuous sports in tropical countries even during winter. High degree of suspicion and early aggressive general support is the key to success for unusual clinical presentation of any such clinical entity. PMID- 26500987 TI - A Simple Technique to Prevent Reverse Flow of Blood From Intravenous Line in Ipsilateral Arm with Noninvasive Blood Pressure Cuff. PMID- 26500988 TI - Psychiatric Morbidity in Infertility Patients in a Tertiary Care Setup. AB - CONTEXT: Infertility is regarded as a trigger for psychological morbidity. Infertile couples often suffer from anxiety, depression and lack of self confidence. AIMS: To study the demographic factors associated with infertility in a tertiary care setup and to determine the level of anxiety and depression associated with it by using standardized scales. The study protocol also included studying the various coping strategies employed by these patient groups. SETTINGS AND DESIGN: Case control study. MATERIALS AND METHODS: A prestructured questionnaire based study conducted for a span of 6 months. The study population included the patients attending the infertility and the family planning outpatient department. We applied the Hospital Anxiety and Depression scale (HADS) and the Becks Depression Inventory (BDI). Brief COPE Inventory was applied to look for the various coping measures that are employed by the anxious and depressed patients. STATISTICAL ANALYSIS: Data analysis was done using SPSS ver20. RESULTS: A total of 280 study subjects were included in the study; which included 140 women from the infertility clinic and 140 from the family planning OPD. A total of 56.4% (79/140) of the females were found to be suffering from depression and 68.9% (96/140) of the females were found to be suffering from anxiety and depression both. Seven risk factors were found to be significant for depression based on the Beck Depression Inventory (BDI) scale and 6 risk factors were found to be significant based on the Hospital Anxiety and Depression Scale (HADS). The most common coping method employed by depressed women was venting 72.2% (57/79) followed by behavioural disengagement 70.9% (56/79); whereas the most important coping method employed by the anxious and depressed women was behavioural disengagement 71.9% (69/96). CONCLUSION: Anxiety and depression is common among patients suffering from infertility and measures should be taken to alleviate it. PMID- 26500989 TI - Development of Screening Questionnaire for Detection of Alcohol Dependence. AB - INTRODUCTION: Alcohol dependence (AD) is a major reason for morbidity and visits to emergency medical settings. However, the detection of AD is often difficult or overlooked. This study aimed to develop a brief screening questionnaire in Hindi language for detection of AD in an emergency medical setting. MATERIALS AND METHODS: The authors in consultation devised a set of questions related to AD in the Hindi language requiring binary yes/no type of response. These questions were guided by clinical experience, nosological criteria and previously published screening questionnaires. After initial piloting, these questions were administered by the treating doctors to 100 consenting adult patients presenting with possible AD in the emergency medical services of a tertiary care hospital in North India. A diagnosis of AD was arrived at by administering Mini-International Neuropsychiatric Interview separately. Identification of the most discriminant combinations of items for the detection of AD were based on the chi-square test and binary logistic regression analyses. The final version of the questionnaire was then externally validated on another cohort of patients. RESULTS: Based on the analyses, we retained 5 items in the final version of the questionnaire. Sensitivity and specificity values for cut-off scores were calculated. Subsequent external validation revealed satisfactory psychometric properties of the questionnaire. CONCLUSION: The questionnaire represents a simple and brief clinician-administered instrument for screening of AD in an emergency medical setting. PMID- 26500990 TI - Obsessive Compulsive Disorder with Intellectual Disability: A Diagnostic and Therapeutic Challenge. AB - Obsessive compulsive disorder (OCD) are known to occur in patients with intellectual disability and at rates least proportional to the general population but often the developmental disabilities and lack of communication in these patients make it difficult to diagnose and assess the disorder and hence go undetected and untreated. Once diagnosed, treating OCD is another challenge faced by therapist in patients with intellectual disabilities. We report a case of intellectual disability with OCD highlighting the diagnostic and therapeutic challenges. PMID- 26500992 TI - Telogen Effluvium: A Review. AB - Telogen effluvium was first described by Kligman in 1961. It is a most common cause of diffuse hair loss. Women with telogen effluvium more frequently present to dermatologist. A wide variety of potential triggers have been implicated in the pathogenesis of telogen effluvium. Diffuse shedding of telogen hair are seen after 3-4 months of triggering event. The observation of increased telogen hair shedding does not infer a cause. Establishing aetiology of telogen effluvium requires elicitation of relevant history and appropriate laboratory investigations to exclude endocrine, nutritional and autoimmune disorders. PMID- 26500993 TI - Leprosy Mimicking Psoriasis. PMID- 26500991 TI - Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond. AB - Alcohol dependence is an increasing and pervasive problem. Alcohol withdrawal symptoms are a part of alcohol dependence syndrome and are commonly encountered in general hospital settings, in most of the departments. Alcohol withdrawal syndrome ranges from mild to severe. The severe complicated alcohol withdrawal may present with hallucinations, seizures or delirium tremens. Benzodiazepines have the largest and the best evidence base in the treatment of alcohol withdrawal, and are considered the gold standard. Others, such as anticonvulsants, barbiturates, adrenergic drugs, and GABA agonists have been tried and have evidence. Supportive care and use of vitamins is essential in the management. Symptom triggered regime is favoured over fixed tapering dose regime, although monitoring through scales is cumbersome. This article aims to review the evidence base for appropriate clinical management of the alcohol withdrawal syndrome. We searched Pubmed for articles published in English on 'Alcohol withdrawal syndrome' in humans during the last 10 years. A total of 1182 articles came up. Articles not relevant to clinical utility and management were excluded based on the titles and abstract available. Full text articles, meta-analyses, systematic reviews and randomized controlled trials were obtained from this list and were considered for review. PMID- 26500994 TI - Impact of Adjuvant Therapy on Survival in Curatively Resected Gallbladder Carcinoma. AB - BACKGROUND: Gallbladder carcinoma (GBC) has the propensity to fail at loco regional (LR) and distant sites despite aggressive radical surgery. Adjuvant therapy in the form of radiotherapy (RT), systemic chemotherapy (CT) and chemoradiation (CRT) is the usual practice. Due to rarity of this disease, there is limited evidence to suggest the type of adjuvant treatment which should be offered to the patients. AIM: The study was conducted to evaluate the impact of adjuvant treatment on curatively resected GBC patients. SETTINGS AND DESIGN: Histological proven patients of GBC registered between June, 2008 and July, 2014 were identified from our hospital database and retrospective analysis was done. MATERIALS AND METHODS: Patients of GBC who had curative resection followed by adjuvant treatment as RT alone, CT alone or CRT were included in the study. STATISTICAL ANALYSIS: Adverse prognostic factors and the effect of adjuvant treatment on overall survival (OS) and disease free survival (DFS) were evaluated using Cox Regression Method and Kaplan Meier plot. RESULTS: We identified 33 patients of which 23 were Stage I or II disease (Early disease) and the remaining 10 were Stage III or IV disease (Advanced disease). All except one patient had adenocarcinoma. A total of 5 patients were treated with RT alone while 16 patients received CT alone. The remaining 12 patients were treated with CRT. Median follow-up period was 8.5 months. At analysis 4 were alive while the remaining 29 were dead due to disease. With regard to "Early disease" patients who had RT alone, CT alone and CRT, the median OS was 22.3, 10.3 and 15.2 months respectively (p = .440). Cohort of patients with "Advanced disease" who were treated with CT alone and CRT the median OS was 7.5 and 7.0 months respectively (p = .643). On multivariate analysis none of the prognostic factors had an adverse impact on survival. CONCLUSION: The impact of adjuvant treatment in the form of RT, CT or CRT after curative resection in GBC patients was seen in terms of improved survival but was not statistically significant. PMID- 26500995 TI - Synchronous Bilateral Breast Cancers. AB - BACKGROUND: Bilateral breast cancer (BBC) is not an uncommon entity in contemporary breast clinics. Improved life expectancy after breast cancer treatment and routine use of contra-lateral breast mammography has led to increased incidence of BBC. Our study objective was to define the epidemiological and tumour characteristics of BBC in India. MATERIALS AND METHODS: A total of 1251 breast cancer patients were treated during the period January 2007 to March 2015 and 30 patients were found to have BBC who constituted the study population (60 tumour samples). Synchronous bilateral breast cancers (SBC) was defined as two tumours diagnosed within an interval of 6 months and a second cancer diagnosed after 6 months was labelled as metachronous breast cancer (MBC). Analyses of patient and tumour characteristics were done in this prospective data base of BBC patients. RESULTS: Median patient age was 66 years (range 39-85). Majority of the patients had SBC (n=28) and in 12 patients the second tumour was clinically occult and detected only by mammography of the contra-lateral breast. The second tumour was found at lower tumour size compared to the first in 73% of cases and was negative for axillary metastasis in 80% of cases (24/30). Infiltrating ductal carcinoma was the commonest histological type (n=51) and majority of the tumours were ER/PR positive (50/60). Her2 was overexpressed in 13 tumours (21%). Over 70% (22/30) of patients had similar histology in both breasts and amongst them grade concordance was present in about 69% (15/22) of patients. Concordance rates of ER, PR and Her2 statuses were 83%, 80% and 90% respectively. Bilateral mastectomy was the commonest surgery performed in 80% of the patients followed by bilateral breast conservation in 13%. At the end of study period, 26 patients were alive and disease free. Median survival was 29 months (range 3-86 months). CONCLUSION: In most patients with BBC, the second tumour is identified at an early stage than index tumours supporting the importance of contralateral breast cancer screening at the time of primary diagnosis and during follow-up. BBC occurs more frequently in old age group and majority of these tumours are estrogen dependent. There is good pathological concordance between the index tumour and the contralateral breast cancer. PMID- 26500996 TI - Identifying the Factors Causing Delayed Presentation of Cancer Patients to a Government Medical College of Central India. AB - BACKGROUND: The incidence of cancer is increasing throughout the world. One of the prime aims of its management is early diagnosis and therapeutic intervention. Factors causing delay to either of these goals should be identified and rectified. AIM: To identify the factors causing delayed initial diagnosis and subsequent management in patients presenting to the Oncology department. MATERIALS AND METHODS: Three hundred proven cancer patients were prospectively evaluated for the pattern of presentation to the outpatient Department of Radiation Oncology of a Government Medical College (MC) in Central India. RESULTS: The mean age of presentation was 51.05 years (range 7 months-77 years). The number of male patients was 168 while females were 132. The duration of symptoms ranged from 20 days to 3 years. The number of patients with little/no education presented mainly in advanced stages as compared to their educated counterpart and this difference was statistically significant (p<0.001). The number of patients presenting directly to the department was 108, those diagnosed outside and referred to us was 84 while those diagnosed and received some form of oncologic treatment outside and referred thereafter was 108. The difference in the primary delay between patients presenting directly to the MC versus those diagnosed outside was significant (p=0.0126). The mean duration of starting definitive treatment after presentation to the outpatient was 4.68 days (range 0 22 days) and was very significantly (p< 0.001) less than the secondary delays caused to the other two subsets of patients. CONCLUSION: Factors causing delayed presentation are both patient and system related. It is imperative to educate the common people regarding the early signs and symptoms of cancer. At the same time, the system needs to overhaul its efficiency to avoid secondary delays that adversely affect the treatment outcome. An upgradation of the existing oncology facilities in the public sector can achieve this target efficiently. PMID- 26500997 TI - Isolated Langerhans Histiocytosis in Thyroid: Thyroidectomy or Chemotherapy? AB - Langerhans cell histiocytosis (LCH) is a rare disorder of mononuclear phagocytic system whose clinical presentation varies from the localised involvement of a single bone to a widely disseminated disease. Langerhans cell histiocytosis rarely involves the thyroid gland and isolated involvement of thyroid is even rarer. We report a case of an eight-year-old male child diagnosed with Langerhans cell histiocytosis limited to thyroid gland with review of literature. Should thyroidectomy be done or proceed with chemotherapy? Our case report raises this question with a note on the role of 18 fluoro deoxy glucose positron emission tomography-computed tomography in the management of the same. PMID- 26500998 TI - Oncologic Concerns in An Exstrophied Urinary Bladder - An Indian Scenario. AB - Exstrophy of the urinary bladder is a rare congenital anomaly which if untreated causes bladder carcinoma and intestinal tumours noted if urinary diversion is performed. It is seen that 50% of all persons afflicted with exstrophy are dead by their tenth year and 66-67% are dead by their twentieth year. It is thus a great rarity to see a case of ectopia vesicae in adulthood. Still more uncommon is to see a case of exstrophy complicated by carcinoma. Here, we report a case of papillary adenocarcinoma of ectopic urinary bladder in a 42-year-old male patient. In view of locally advanced disease, patient was given neoadjuvant chemotherapy. The case is being reported on account of its rarity to sensitise clinicians about rising incidence of carcinoma if mismanaged due to lack of protocol in oncological screening. PMID- 26500999 TI - Diode Laser in Management of Tracheobronchial Typical Carcinoid: A Case Report with Review of Literature. AB - Tracheobronchial carcinoids are relatively uncommon neoplasms with malignant (though indolent) potential and variable behavior. Clinical presentation is usually similar to any obstructive tracheobronchial lesions or rarely with presentation of carcinoid syndrome. Management varies from Pneumonectomy to use of lung sparing bronchoscoplastic techniques. We report the case of a 32-year-old male patient diagnosed with carcinoid of left main bronchus. Patient was successfully treated with trans-bronchoscopic diode laser. At 24 months of follow up patient remains asymptomatic and recurrence-free. PMID- 26501000 TI - Post Esophagectomy Hiatal Hernia; Expect the Unexpected. PMID- 26501001 TI - Comparison of Plaque Inhibiting Efficacies of Aloe Vera and Propolis Tooth Gels: A Randomized PCR Study. AB - BACKGOUND AND AIM: Allopathic medications used for periodontal disease are known to be associated with various side effects. Hence a search for naturotherapies are on the rise. Among the natural pharmacons available aloevera and propolis are considered to be effective and free from adverse effects. Taking this into account, the present study was done to compare the plaque inhibiting efficacies of Aloe vera and Propolis tooth gels in patients with chronic periodontitis. MATERIALS AND METHODS: Forty patients diagnosed with chronic periodontitis were randomly allocated to groups A and B containing 20 patients each. Patients in group A were advised to use Aloe vera tooth gel while those in group B were advised to use Propolis tooth gel. Clinical and microbiologic parameters using Polymerase chain reaction (PCR) were recorded at baseline and after 3 months. RESULTS: Student t-test was performed for all the obtained results. In the Aloe vera group, comparison of baseline PCR and after 3 month results showed reduction only in P. gingivalis (p=0.001), where as statistically significant reduction in all the three red complex microorganisms was seen in propolis group. All the clinical parameters (Plaque Index, Gingival Index, Bleeding on Probing, Probing pocket Depth, and Clinical Attachment Level) in both the groups showed statistically significant reductions after 3 months. CONCLUSION: Propolis showed a statistically significant reduction in plaque, microbiologic and clinical parameters. However, clinical trials of longer durations with larger sample sizes are required to evaluate the efficacy. PMID- 26501002 TI - SBS vs Inhouse Recycling Methods-An Invitro Evaluation. AB - INTRODUCTION: In today's world of economic crisis it is not feasible for an orthodontist to replace each and every debonded bracket with a new bracket- quest for an alternative thrives Orthodontist. The concept of recycling bracket for its reuse has evolved over a period of time. Orthodontist can send the brackets to various commercial recycling companies for recycling, but it's impractical as these are complex procedures and require time and usage of a new bracket would seem more feasible. Thereby, in-house methods have been developed. The aim of the study was to determine the SBS (Shear Bond Strength) and to compare, evaluate the efficiency of in house recycling methods with that of the SBS of new brackets. MATERIALS AND METHODS: Five in-house-recycling procedures-Adhesive Grinding Method, Sandblasting Method, Thermal Flaming Method, Buchman method and Acid Bath Method were used in the present study. Initial part of the study included the use of UV/Vis spectrophotometer where in the absorption level of base of new stainless steel bracket is compared with the base of a recycled bracket. The difference seen in the UV absorbance can be attributed to the presence of adhesive remnant. For each recycling procedure the difference in UV absorption is calculated. New stainless steel brackets and recycled brackets were tested for its shear bond strength with Instron testing machine. Comparisons were made between shear bond strength of new brackets with that of recycled brackets. The last part of the study involved correlating the findings of UV/Vis spectrophotometer with the shear bond strength for each recycling procedure. RESULTS: Among the recycled brackets the Sandblasting technique showed the highest shear bond strength (19.789MPa) and the least was shown by the Adhesive Grinding method (13.809MPa). CONCLUSION: The study concludes that sand blasting can be an effective choice among the 5 in house methods of recycling methods. PMID- 26501003 TI - Prevalence of Zygomatic Air Cell Defect using Orthopantomogram. AB - AIM: To determine the prevalence, radiographic appearance, variations, characteristics and establishing dominant location and type of zygomatic air cell defect (ZACD) among the North Indian population. MATERIALS AND METHODS: The panoramic radiographs of 2500 dental clinic outpatients were examined for the presence of ZACD for estimating the prevalence and characteristics of the ZACD. RESULTS: ZACD was found in 63 patients with a prevalence of 2.5% with male predominance. Unilateral (70%) and unilocular appearance (78%) of ZACD were the dominant patterns. Patients with ZACD had a mean age of 37.4 years and a range of 19-78 years. CONCLUSION: The prevalence of ZACD among the Indian population is in accordance with the other studies carried out in other populations of the world. So it is important for surgeons to assess location of ZACD before planning any surgical procedure in order to avoid intraoperative complications. PMID- 26501004 TI - Influence of Full Veneer Restoration on Fracture Resistance of Three Different Core Materials: An Invitro Study. AB - AIMS AND OBJECTIVES: One of the factor which affects the strength of the tooth restored with core material is the property of the material. In clinical situation all such restored teeth are protected by crowns. This study evaluated the strength of different core materials on a compromised tooth structure after restoration with a crown. MATERIALS AND METHODS: Seventy extracted intact human premolars were collected and mounted within a mould using auto-polymerizing resin. The teeth were divided in-to four groups - A, B, C and D. Each group contained 20 teeth except group A with 10 teeth. All the teeth were prepared for full veneer cast crown. Except for the teeth in group: A) extensive class-I cavities were prepared in the teeth of all the groups and restored with; B) composite resin, 3M EPSE Filtek P60; C) Silver reinforced glass ionomer, SHOFU Hi Dense XP and; (D) Resin reinforced glass ionomer, GC Gold Label light cure GIC. All the teeth were restored with cast-metal alloy and exposed to 1.2 million cycles of cyclic loading in a chewing simulator. Subsequently, the teeth that survived were loaded till fracture in the universal testing machine. Fracture loads and type of fractures were recorded. RESULTS: All the specimens survived cyclic loading. The mean fracture strength of the silver reinforced glass ionomer was greater with and without crown (p<0.001). Statistical analysis for the mean fracture load of each specimen showed significant difference between the groups. CONCLUSION: Under the condition of this study, core materials when restored with artificial crown had a significant increase in fracture resistance. PMID- 26501005 TI - Influence of Surface Modifications of Acrylic Resin Teeth on Shear Bond Strength with Denture Base Resin-An Invitro Study. AB - BACKGROUND: Debonding of artificial teeth from the denture base is an important issue for edentulous patients rehabilitated with conventional or implant supported complete dentures. AIM: The purpose of this study was to evaluate shear bond strength between denture base resin and acrylic resin denture teeth subjected to three different surface modifications on the ridge lap area as compared to unmodified denture teeth. MATERIALS AND METHODS: Forty acrylic resin central incisor denture teeth were selected and randomly divided into four test groups. The teeth in each group were subjected to one of the three different surface modifications, namely, chemical treatment, sandblasting and placement of retentive grooves on the ridge lap area respectively, prior to packing of the denture base resin. The group with unmodified teeth served as control. Forty acrylic resin test blocks thus obtained were tested for shear bond strength between acrylic resin teeth and denture base resin in Universal Testing Machine. Data obtained was statistically analysed using one-way ANOVA and Student- Newman- Keul's test (p< 0.05). RESULTS: Analysis of shear bond strength revealed that retentive grooves on the ridge lap area showed highest bond strength values followed by sandblasting and both were statistically significant compared to the control and chemically treated groups. Unmodified surface of the resin teeth showed the least bond strength. CONCLUSION: Within the limitations of this invitro study the placement of retentive grooves or sandblasting of the ridge lap area showed highly significant improvement in shear bond strength compared to the unmodified surface. Chemical treatment did not result in any significant improvement in the shear bond strength compared to the unmodified surface. PMID- 26501006 TI - Have Smartphones Contributed in the Clinical Progress of Oral and Maxillofacial Surgery? AB - BACKGROUND: Dental surgeons who encounter complex situations, such as those in unscheduled care, often have limited resources to provide a structured and specialty care. Therefore, there is always a need for cost-effective, easy to handle, easy to carry "Smartphones". OBJECTIVE: The purpose of this paper was to undertake a review of literature on "Smartphone in Oral and Maxillofacial Surgery" online data-base and discuss the case series with emphasis on the role of attending dental surgeon and the maxillofacial surgeon. MATERIALS AND METHODS: The available literature relevant to oral and maxillofacial surgery in online data-base of the United States National Library of Medicine: PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) was searched. The inclusion criterion was to review the published clinical papers, abstracts and evidence based reviews on 'Uses of Smartphone in Oral and Maxillofacial Surgery'. RESULTS: Six articles were found with the search term "Smartphone in Oral and Maxillofacial Surgery" in the literature searched. Five articles met the inclusion criteria for the study. The relevant data was extracted, tabulated, and reviewed to draw evidence-based conclusions for uses of smartphone in oral and maxillofacial surgery. CONCLUSION: Utilization of smartphones in oral and maxillofacial surgery facilitate in differential diagnosis, treatment, follow up, prevention of the disease further and thereby improve the quality of patient care without requiring the presence of the maxillofacial surgeon in remote areas. PMID- 26501007 TI - The Efficacy of Tranexamic Acid in the Reduction of Incidence of Dry Socket: An Institutional Double Blind Study. AB - BACKGROUND: Alveolar osteitis (AO) is an important postoperative problem with an incidence of 20% to 35% especially prevalent after the removal of mandibular molars. Fibrinolysis with subsequent loss of blood clotting is believed to be the general cause of AO. OBJECTIVES: This study aims to evaluate the efficacy of tranexamic acid, an antifibrinolytic agent in comparison with a placebo with respect to the reduction of incidence of AO after the extraction of mandibular molars by using following parameters: Pain, disintegration of Clot, halitosis. MATERIALS AND METHODS: A double blind study consisted of 60 patients, who underwent routine dental extractions of mandibular molar teeth. Group A (30 patients) requiring routine dental extractions of mandibular teeth was randomly selected and was administered a dose of tranexamic acid orally (Pause 500mg) one hour prior to extraction of teeth. Gel foam soaked in tranexamic acid (160mg) was placed into the extraction socket postoperatively. A figure of eight silk suture was placed over the socket to secure the gelfoam. Group B (30 patients); a placebo (crocin) was given orally one hour prior to the extraction and gel foam soaked in saline was placed into the extraction socket postoperatively. A figure of eight silk suture was placed over the socket. Pain was rated individually by each patient at 3(rd), 7(th), 14(th) day after extraction and the results was statistically analysed. RESULTS: This study supports that the use of tranexamic acid both locally and systemically following the removal of the teeth reduces the incidence of AO associated with the extraction of mandibular molars. CONCLUSION: Tranexamic acid has several advantages also when used for simple dental extractions, namely: low cost and ready availability and therefore we recommend this treatment modality. PMID- 26501008 TI - Clinical Evaluation of Efficacy of CIA and CNA Intrusion Arches. AB - BACKGROUND AND OBJECTIVES: Excessive overbite is one of the most common problems that confront the orthodontist. Deep bite can be due to infraocclusion of posterior teeth, supraocclusion of anterior teeth or a combination of the two. Correction of same can be carried out by extrusion of molars, intrusion of incisors or by a combination of both respectively. Various intrusion arches are recommended for correcting deep bite by true intrusion of anterior teeth, Utility arches, Segmental arch, Connecticut Intrusion Arch (CIA) and Connecticut New Arch (CNA). The purpose of this study was to evaluate clinical efficacy of CIA and CNA intrusion arches. MATERIALS AND METHODS: Tracings recorded from pre and post treatment lateral cephalograms of 25 patients treated by CIA (Group I) and another 25 patients treated by CNA (Group II) intrusion arches in deep bite cases after four months of treatment were analysed and findings were recorded. STATISTICAL ANALYSIS: Paired t-test was used to compare pre and post-treatment changes within Groups I and II and unpaired t-test was used to compare treatment changes between Group I and Group II. A P-value of < 0.05 was set for statistical significance. RESULTS: Findings of this study demonstrate that an average of 1mm of intrusion takes place with CIA intrusion arch and 1.3mm with CNA intrusion arch in a period of 4 months. Both intrusion arches do not affect the position of molar in vertical or anteroposterior plane. INTERPRETATION & CONCLUSION: Both CIA and CNA intrusion arches are effective in bringing about intrusion of lower incisors. PMID- 26501010 TI - Effect of Cigarette Smoke on Surface Roughness of Different Denture Base Materials. AB - BACKGROUND: Surface roughness is an important property of denture bases since denture bases are in contact with oral tissues and a rough surface may affect tissues health due to microorganism accumulation. Therefore, the effect of cigarette smoke on the surface roughness of two commercially available denture base materials was evaluated to emphasize which type has superior properties for clinical use. MATERIALS AND METHODS: A total numbers of 40 specimens were constructed from two commercially available denture base materials; heat-cured PMMA and visible light cured UDMA resins (20 for each). The specimens for each type were randomly divided into: Group I: Heat cured resin control group; Group II: Heat cured acrylic resin specimens exposed to cigarette smoking; Group III: Light cured resin control group; Group IV: Light cured resin specimens exposed to cigarette smoking. The control groups used for immersion in distilled water and the smoke test groups used for exposure to cigarette smoking. The smoke test groups specimens were exposed to smoking in a custom made smoking chamber by using 20 cigarettes for each specimen. The surface roughness was measured by using Pocket SurfPS1 profilometer and the measurements considered as the difference between the initial and final roughness measured before and after smoking. RESULTS: The t-test for paired observation of test specimens after exposure to smoking was indicated significant change in surface roughness for Group II (p< 0.05) but has no significance with Group IV. Otherwise, there were no significant differences with control groups (Group I and III). CONCLUSION: The surface roughness of the dentures constructed from heat cured acrylic resin had been increased after exposure to cigarette smoke but had no impact on the dentures constructed from visible light cured resin. PMID- 26501009 TI - Cross-Cultural Adaptation of Kannada Version of Modified Dental Anxiety Scale Among an Adult Indian Population. AB - BACKGROUND: Dental anxiety is one of the most common barriers in seeking dental care. In order to overcome this barrier dentist need to screen patients to successfully help in treatment. A scale is thus needed to measure dental anxiety which is socially & culturally acceptable. AIM: This study aimed to assess the Cross cultural adaptation and validity of the Kannada translation of the Modified Dental Anxiety Scale (MDAS-K). MATERIALS AND METHODS: A test-retest was conducted on 30 patients visiting a dental institution to assess the reliability of MDAS- K. A cross-sectional survey of 301 patients was conducted in different departments at a dental institution to test the psychometric properties of MDAS K. The assessment tool consisted of a proforma containing socio-demographic, non socio- demographic variables, MDAS-K and Visual analogue scale (VAS). STATISTICAL ANALYSIS: Reliability was assessed using Cronbach's alpha, inter-item Spearman's correlation. Independent t-test, ANOVA and post hoc Bonferroni were used to analyse dental anxiety in the psychometric constructs. RESULTS: The internal consistency of MDAS-K was good with Cronbach's alpha of 0.83. The test-retest reliability for MDAS K had a good correlation of 0.901. The psychometric variables established the construct validity of MDAS-K.MDAS-K also showed good convergent validity with VAS score. The anxiety levels differed in patients visiting different dental departments. CONCLUSION: The high reliability and validity of the MDAS-K supports its cross cultural adaptation and indicates that it can be a valuable tool for dental practioners in quantifying anxiety among patients and provide quality dental care. PMID- 26501011 TI - Impact of Bariatric Surgery and Diet Modification on Periodontal Status: A Six Month Cohort Study. AB - BACKGROUND: Nutrition is an essential component of oral health and improper nutrition is an important aetiological factor in the development of obesity as well. AIMS AND OBJECTIVES: This study aimed to evaluate effect of diet modification and oral hygiene maintenance after bariatric surgery on the periodontal status of Class III and IV obese patients. MATERIALS AND METHODS: Two hundred and twenty four patients between the age ranges of 18 -64 years, from both sexes, were subjected to complete periodontal examination prior to bariatric surgery and 6 months post surgery. Patients were advised diet modification which included more fibrous food intake & decreased intake of soft and sugary food along with supragingival scaling & oral health care regime after bariatric surgery with a 6 month follow up. No periodontal surgical intervention was performed. RESULTS: The patients showed a mean differences in the bleeding score, plaque and gingival index which was found to be statistically significant (p<0.001). The improvement in clinical attachment level and probing pocket depth before and after surgery were found to be statistically insignificant (p>0.05). CONCLUSION: Thus we conclude that fibrous diet along with good periodontal care can help to improve the oral hygiene status of patients undergoing bariatric surgery, even if periodontal surgical intervention is not performed resulting in freedom from periodontitis, thus improving quality of life of the patient. PMID- 26501012 TI - Desensitizing Agent Reduces Dentin Hypersensitivity During Ultrasonic Scaling: A Pilot Study. AB - BACKGROUND: Dentin hypersensitivity can interfere with optimal periodontal care by dentists and patients. The pain associated with dentin hypersensitivity during ultrasonic scaling is intolerable for patient and interferes with the procedure, particularly during supportive periodontal therapy (SPT) for patients with gingival recession. AIM: This study proposed to evaluate the desensitizing effect of the oxalic acid agent on pain caused by dentin hypersensitivity during ultrasonic scaling. MATERIALS AND METHODS: This study involved 12 patients who were incorporated in SPT program and complained of dentin hypersensitivity during ultrasonic scaling. We examined the availability of the oxalic acid agent to compare the degree of pain during ultrasonic scaling with or without the application of the dentin hypersensitivity agent. Evaluation of effects on dentin hypersensitivity was determined by a questionnaire and visual analog scale (VAS) pain scores after ultrasonic scaling. The statistical analysis was performed using the paired Student t-test and Spearman rank correlation coefficient. RESULTS: The desensitizing agent reduced the mean VAS pain score from 69.33 +/- 16.02 at baseline to 26.08 +/- 27.99 after application. The questionnaire revealed that >80% patients were satisfied and requested the application of the desensitizing agent for future ultrasonic scaling sessions. CONCLUSION: This study shows that the application of the oxalic acid agent considerably reduces pain associated with dentin hypersensitivity experienced during ultrasonic scaling. This pain control treatment may improve patient participation and treatment efficiency. PMID- 26501013 TI - Evaluation of Salivary Levels of Pyridinoline Cross Linked Carboxyterminal Telopeptide of Type I Collagen (ICTP) in Periodontal Health and Disease. AB - BACKGROUND: Traditional parameters (Pocket depth, bleeding on probing, clinical attachment loss, radiographic findings) have been used for a long time for the assessment of periodontal disease conditions. However, these parameters only indicate towards the periodontal damage that has already taken place but do not give any idea regarding the current status of the periodontal health or disease. Hence, the present study is aimed at evaluating the concentration of the bone biomarker ICTP in saliva, which can give a better real time assessment of periodontal health and disease. MATERIALS AND METHODS: Forty three patients were selected and divided into three groups based on the recorded clinical parameters of probing pocket depth, attachment loss and bleeding on probing. Group I (Healthy, n = 11), Group II (Gingivitis, n = 17), Group III (Periodontitis. n = 15). Salivary samples were collected before scaling and root planning to avoid contamination by blood. ICTP levels were evaluated in the salivary samples by using enzyme linked immunosorbent assay (ELISA). STATISTICAL ANALYSIS USED: Kruskal Wallis test was used to compare the mean ICTP level of the three groups. RESULTS: ICTP was detected in all the samples. Highest mean ICTP concentrations in saliva were obtained for group III (periodontitis group) and the lowest mean ICTP concentrations were seen in group I (healthy group). This suggests that the level of ICTP in saliva increases proportionally from periodontal health to diseased conditions (gingivitis & periodontitis). CONCLUSION: There is a substantial increase in the salivary concentration of ICTP in chronic periodontitis patients than in gingivitis and healthy patients. Salivary ICTP levels were the maximum in chronic periodontitis patients followed by gingivitis patients and the least in healthy individuals. ICTP may be considered as a biomarker in periodontal disease progression. PMID- 26501014 TI - Spectrophotometric Study of the Effect of Luting Agents on the Resultant Shade of Ceramic Veneers: An Invitro Study. AB - INTRODUCTION: Dentistry has found practically the best available aesthetic answer, is ceramic restoration. There are various factors that contribute to the success of ceramic veneers, like colour of underlying tooth, thickness if ceramics and the type of underlying luting cement. Shade selection and matching remains still challenge, however the shade of luting agent used for cementation of veneers produces a change in resultant shade of veneers. AIM: To compare and analyze the spectrophotometric effect of opaque and transparent luting agent on resultant shade of ceramic veneers made of 2L1.5 shade (Vitapan 3D-Masters) and B2 shade (Vitapan Classic). MATERIALS AND METHODS: Out of 15 ceramic veneers of 2L1.5 shade (VITAPAN 3D- Master), seven teeth cemented with opaque cement and eight teeth with transparent cement shade of dual cure resin cement (Variolink II(TM)). Out of 10 ceramic veneers of B2 shade (VITAPAN Classic), five teeth were cemented with opaque cement and other five teeth with transparent cement shade of dual cure resin cement (Variolink II(TM)). Spectrophotometric (Macbeth U.S.A.) analysis of all ceramic veneer crowns done with optiview software and readings were recorded in Commission Internationale de I' Eclairge {CIELAB} system and dE value was calculated. STATISTICAL ANALYSIS: Statistical analysis was done by using Paired t-test. RESULTS: Spectrophotometric analysis of all the veneers cemented with opaque luting agent were lighter in shade due to significant change in dL value. Veneers cemented with transparent luting agent were darker in shade due to significant change in the dL value. CONCLUSION: Opaque luting agent gives lighter shade and transparent luting agent gives darker shade to ceramic veneers fabricated with 2L1.5 and B2 shades. PMID- 26501015 TI - Evaluation of Microleakage of Dental Composites Using Bonding Agents with Different Placement Techniques: An Invitro Study. AB - BACKGROUND: The rapid progress of adhesive dentistry over the past decade has been attributed to the significant advances in dentin bonding technology. Requirements of an ideal bonding agent are quite similar to those indicated by Buonocore despite of many improvements. As we enter the new millennium, it is important for us to examine the past. OBJECTIVE: To evaluate the microleakage of three bonding agents namely Single Bond, Prime & Bond NT and Excite using different composite materials namely Z100, Spectrum TPH, Tetric with three different placement techniques. MATERIALS AND METHODS: Fifty four extracted human premolars were taken & divided into 9 groups depending upon application of bonding agents followed by composite restorations. Specimens were subjected to thermal cycling at 6(0)C, 37(0)C, 54(0)C and again at 37(0)C & then placed in 10 ml each of freshly prepared 50% silver nitrate solution for 2 hour in darkness, washed & placed under sun light for 24 hours. The sectioned specimens were then observed under stereomicroscope to detect microleakage. RESULTS: On comparing the mean microleakage scores among the three groups, maximum microleakage scores have been obtained when no bonding agent was used, while least microleakage scores were obtained with double coat of bonding agent. CONCLUSION: The present study suggests that the placement of bonding agent technique before composite restoration can be effective to limit the microleakage at the tooth restoration interface. PMID- 26501016 TI - Prevalence and Difficulty Index Associated with the 3(rd) Mandibular Molar Impaction among Malaysian Ethnicities: A Clinico-Radiographic Study. AB - BACKGROUND: The mandibular third molars (3Mms) are the most common impacted teeth in the human dentition and their prevalence ranges from 27-68.8% in various parts of the world. The assessment of surgical difficulty of 3Mms extraction helps in better formulation of treatment plan by minimizing postoperative complications. OBJECTIVES: The aim of this retrospective study was to investigate the prevalence and pattern of 3Mm impaction in patients between 20-44-year-old among Malaysian's ethnicities attending Oral Health Center/ SEGi University, Faculty of dentistry. MATERIALS AND METHODS: This study reviewed 1249 orthopantomograms (OPGs) of subjects aged 20 to 44 years of three Malaysian ethnic groups. Of the study population 918 OPGs were considered for the study. Patient's details include age, gender and ethnicity were extracted from the patient's clinical record and all details related to impaction were obtained from patient's panoramic radiograph that was individually examined by two investigators. The data collected was statistically analysed using SPSS 16. RESULTS: This study found that Chinese female recorded the highest number of patients with "very difficult" category of impacted mandibular third molars. The most common age group involved was 20-24 years, mesioangular impaction, deep occlusal level and no ramus space for impacted mandibular third molars (3ms) were the most common findings observed. CONCLUSION: The present study suggests that predicting the level of difficulty preoperatively for impacted 3m surgery will help in formulating the better treatment plan, thereby minimizing the postoperative complication for the ultimate benefit of the patient. PMID- 26501017 TI - Inhibition of Tongue Coat and Dental Plaque Formation by Stabilized Chlorine Dioxide Vs Chlorhexidine Mouthrinse: A Randomized, Triple Blinded Study. AB - BACKGROUND: Chlorine dioxide (ClO2) is an oxidizing agent with known bactericidal, viricidal and fungicidal properties. Its efficacy in reducing the halitosis has been established by previous literature. However, data evaluating its antiplaque property is scarce. Chlorhexidine (CHX) is considered as the gold standard and an effective adjunctive to mechanical plaque removal. However, it is associated with few reversible side effects. Therefore a study was conducted to assess the antiplaque property of ClO2 containing mouthrinse against CHX mouthrinse. AIMS AND OBJECTIVES: To evaluate the efficacy of stabilized chlorine dioxide containing mouthrinse and CHX containing mouthrinse in inhibition of tongue coat accumulation and dental plaque formation using a four day plaque regrowth model clinically and microbiologically in a healthy dental cohort. MATERIALS AND METHODS: A Single Center, Randomized, Triple blinded, Microbiological clinical trial was conducted involving 25 healthy dental students volunteers (11 males, 14 females). Two commercially available mouthrinse: Mouthrinse A - Aqueous based ClO2 mouthrinse Freshchlor((r)) and Mouthrinse B - Aqueous based 0.2% CHX mouthrinse Hexidine((r)) were selected as the test products. Subjects were asked to rinse and gargle for 1 minute with the allocated mouthrinse under supervision after supragingival scaling, polishing and tongue coat removal. After four hours, smears were taken from the buccal mucosa and tooth surface. On the fifth day from baseline of four day non brushing plaque regrowth model the samples were again taken from buccal mucosa and tooth surface followed by recording of plaque scores by Rastogi Modification of Navy Plaque index, extent of tongue coat by Winkel's tongue coating index and measuring tongue coat wet weight in grams. The samples collected were subjected to microbial analysis and the results were expressed as colony forming units (CFUs) per sample. STATISTICAL ANALYSIS: The Data was analysed using SPSS 16.00 and presented using descriptive statistics. Independent t-test was used for the comparison between mouthrinse A groups & mouthrinse B group. RESULTS: The plaque scores and Winkels tongue coat scores, wet tongue coat weight recorded on the fifth day after the use of the two mouthrinse didn't show a statistically significant difference. The CFU per sample from tooth and mucosa after four hours revealed low bacteria count with respect to mouthrinse B however the CFU obtained on the fifth day did not show a statistically significant difference between the two mouthrinse. CONCLUSION: The clinical antiplaque efficacy of CHX and ClO2 mouthwash is comparable and so is the efficacy in reducing the oral bacterial load. PMID- 26501018 TI - Estimation of Release of Nickel and Chromium by Indian Made Orthodontic Appliance in Saliva. AB - INTRODUCTION: With increasing use of Indian made orthodontic materials, need was felt to know nickel and chromium release from these material. MATERIALS AND METHODS: This study was conducted on simulated appliances consisting of brackets (022"Roth, Modern orthodontics, Ludhiana, India), from second premolar to central incisor, buccal tube and 0.019*0.025- inch SS arch wires secured with SS ligatures. Immersion was done in artificial saliva. Samples were analysed to using Atomic Absorption Photospectrometer (GVC ScientificEquipment Pvt. Ltd Australia) at AES Laboratories (P) Ltd., Noida India on 1(st), 7(th), 14(th) and 28(th) day. RESULTS: SPSS (ver 17, Inc., Chicago, Illinois, USA) was used toperform the statistical analysis. Descriptive statistics i.e. median and 25 and75 percentiles were used. Peak nickel release was on 7(th) day and subsequently declined over 14(th) and 28(th) day. The peak level of chromium concentration was on 14(th) day, which declined thereafter. CONCLUSION: Average daily release of nickel and chromium over a period of one month was 97.368 MUg/day and 47.664 MUg/day respectively. The estimated release rates were approximately 32% and 16% of the reported average daily dietary. PMID- 26501019 TI - Evaluation of Relationship Between Demographics and Dental Status in a Defined Group of Iranian Paediatric Patients Undergoing Cancer Therapy. AB - CONTEXT: Cancer is a major cause of death in children under 15 years of age. AIMS: This study aimed to evaluate relationship between demographics and dental status in a defined group of Iranian paediatric patients undergoing cancer therapy. SETTINGS AND DESIGN: This cross-sectional study was accomplished on 161 subjects age ranging 8-12 years. There were 76 cancerous patients hospitalized at Mahak Hospital (one of the major children's cancer centers in Tehran) as the study group and 85 healthy children attending at Dental School, International Branch of Shahid Beheshti University of Medical Sciences, Tehran, Iran from 2012 to 2013. MATERIALS AND METHODS: Demographics were gathered by using data-form. Oral examination and DMFT Index were used to describe teeth status in all teeth and in the first permanent molars. According to Becker's definition, "D" stands for untreated decayed teeth, "M" indicates missing teeth, and "F" shows Filled teeth. It is noteworthy that full coverage crowns are considered as "F" in this Index. STATISTICAL ANALYSIS: Chi-square, Mann-Whitney U, Student's t-tests and Logistic Regression were used for data analysis. RESULTS: The most frequent type of cancer was acute lymphoblastic/lymphocytic leukemia (33.3%). Patients were significantly shorter than controls (p=0.03), and their fathers and mothers were of lower educational achievement (p=0.01, p= 0.001). Although DMFT of all dentition showed significantly higher score in cancerous children (p=0.001), DMFT of four first permanent molars (left, right, upper, and lower) was borderline significantly higher in patients (p= 0.06). Moreover, frequency of cancer was borderline significantly higher in children with lower birth order (p= 0.05). According to Logistic Regression, in as much as patients grew elder 1 year, DMFT index increased 1.5 units. CONCLUSION: Patients under cancer therapy were shorter than healthy ones, and their parents were of lower educational levels. In addition, their teeth status was poorer than controls. PMID- 26501020 TI - Spontaneous Bone Regeneration After Enucleation of Large Jaw Cysts: A Digital Radiographic Analysis of 44 Consecutive Cases. AB - PURPOSE: This study evaluated the healing in cystic defect of the jaw to substantiate our understanding of spontaneous bone healing after enucleation of jaw cysts subjectively and with analysis of digital postoperative panoramic radiographs. MATERIALS AND METHODS: Fourty four consecutive patients reporting to the Department of Dental and Oral Surgery, during the period between 2008-2012 having maxillary and mandibular cysts treated by either surgical enucleation or by marsupialization followed by enucleation were evaluated for subsequent bone formation at the site of cystectomy defect by subjective clinical examination along with digital radiographic examination. Postoperative clinical and radiographic examinations were performed at 6,9,12, and 24 months. Bone regeneration was evaluated by reduction of the size of residual cavities at the cystectomy defect using digital orthopantomogram. RESULTS: Out of 44 patients 15 patients completed two years of follow-up with all the patients having 6 months follow-up. The maximum size of the cystic pathology was 150.40mm and minimum of 14.73mm at the time of presentation (average size of 58.16mm). Twenty patients were diagnosed with odontogenic keratocyst, with one patient having multiple OKC associated with Gorlin Goltz Syndrome, 17 patients had dentigerous cyst, 5 had Radicular cyst; solitary bone cyst and globulomaxillary cyst formed one each. Uneventful healing and spontaneous filling of the residual cavities were obtained in all cases. The digital analysis of the postoperative radiographs showed mean values of reduction in size of the residual cavity of 25.85% after 6 months, 57.13% after 9 months, 81.03% after one year and 100% after two year. CONCLUSION: Spontaneous bone regeneration can occur after surgical removal of jaw cysts without the aid of any graft materials even in large cystic cavity sufficiently surrounded by enough bony walls. This simplifies the surgical procedure, decreases the overall cost of surgery, and reduces the risk of postoperative complications associated with grafting. PMID- 26501021 TI - Prevalence of Elongated Styloid Process in a Central Brazilian Population. AB - BACKGROUND: Eagle's syndrome comprises a rare disorder caused by compression of an elongated or deformed styloid process or ossified/calcified stylohyoid ligament on neural and vascular structures. It is characterized by facial and neck pain and can be confused with a wide variety of facial neuralgias, oral and dental diseases and temporomandibular disorders. An imaging evaluation associated with a careful clinical examination, are mandatory in structuring a correct differential diagnosis and in the establishment of a proper therapeutic protocol. AIM: To investigate the prevalence of the elongated styloid process in a Central Brazilian population and its relation to gender, age and side. MATERIALS AND METHODS: Digital panoramic radiographs of 736 patients (412 female and 324 male, with a mean age of 35.03 years) were consecutively selected from a private radiology clinic's secondary database. The apparent length of the styloid process was measured from the point where the styloid left the tympanic plate to the tip of the process by two specialists in dental radiology, with the help of the measuring tools on the accompanying software. Styloid process measuring more than 30 mm was considered elongated. The statistical analysis included frequency distribution and cross tabulation. The data were analysed by using Chi-squared tests. The level of significance was set at 5% for all analyses. RESULTS: A total of 323 (43.89%) radiographic images were suggestive of elongated styloid process. No statistically significant difference was found between the genders, although a higher prevalence was noticed in female participants. Approximately, 31% of the elongated styloid process was observed in 18-53-year-old participants (p < 0.05). Two hundred and sixty seven styloid processes (36.28%) were elongated on both right and left sides. CONCLUSION: The prevalence of elongated styloid process was high and no statistically significant correlation was found between the presence of elongated styloid process and the studied variables with the exception of the age. PMID- 26501022 TI - Driving the Mineral out Faster: Simple Modifications of the Decalcification Technique. AB - INTRODUCTION: Quicker decalcification is essential for faster diagnosis of hard tissue pathology. Heat and mechanical agitation are known to hasten decalcification. AIM: To compare the rate of decalcification, cellular and staining characteristics of decalcified specimens of bone and teeth by using the conventional method (10% formal formic acid), heating to 45(o)C and by physical agitation with magnetic stirrer. MATERIALS AND METHODS: Weight-matched samples of caprine-origin bone (n=15) and teeth (n=15) were decalcified using three methods namely: a) Gooding and Stewart's fluid; b) Gooding and Stewart's fluid heated to 45(o)C for 6 hours daily; and c) Gooding and Stewart's fluid agitated using a magnetic stirrer for 6 hours daily. Non-lesional skin tissue samples were placed along with each specimen. End point of decalcification (chemical test) was noted; 4 micron sections were taken and stained with H&E. STATISTICAL ANALYSIS: Differences in rate of decalcification and staining characteristics were assessed by Kruskal Wallis test and chi-square test respectively. RESULTS: Hard tissues decalcified faster with stirring and heating methods. The amount of osteocyte retraction noted in bone was significantly reduced in the stirring method. In tooth specimens, modified techniques resulted in poorer nuclear-cytoplasmic contrast of pulp cells. Heating affected the odontoblast layer. Soft tissues exhibited higher eosinophilia in stirring and conventional methods, whereas nuclear-cytoplasmic contrast and chromatin staining was poorest in heating and conventional methods. CONCLUSION: Physical agitation of decalcifying fluid may be recommended while maintaining satisfactory quality of tissue morphology and staining. PMID- 26501023 TI - Amnion and Chorion Allografts in Combination with Coronally Advanced Flap in the Treatment of Gingival Recession: A Clinical Study. AB - BACKGROUND: Guided tissue regeneration (GTR) based root coverage using different allograft membranes has been utilized to correct gingival recession defects with promising results. Amnion and chorion allograft membranes of alternative origin derived from human placental tissue has been advocated in the treatment of gingival recession. However, chorion membrane has been used in combination with amnion membrane no study has compared these allograft membranes in the treatment of gingival recession. Therefore, the purpose of this study was to clinically evaluate and compare the efficacy of amnion membrane and chorion membrane in combination with coronally advanced flap in the treatment of gingival recessions. MATERIALS AND METHODS: Twelve systemically healthy patients having at least 2 bilateral Miller's Class I or Class II gingival recession were recruited and coronally advanced flap was performed with amnion membrane or chorion membrane. Clinical parameters such as gingival Index, plaque index, length of the recession, width of the recession, width of keratinized gingiva, relative attachment level were evaluated at baseline, 3 and 6 months post-surgery. RESULTS: The mean decrease in length of recession (LR) for Chorion site was 2.00+/-1.54mm and amnion site was 1.58+/-1.14mm. The gain in attachment level for amnion site was 2.17+/-1.53mm and for chorion site was 1.58+/-1.22mm. The total mean percentage of root coverage was 34% for chorion site and 22% for amnion site. CONCLUSION: Both amnion membrane and chorion membrane has shown to be versatile allograft material to be used in the treatment of root coverage. PMID- 26501024 TI - Modified Occlusal Table - An Aid to Enhance Function of Hemimandibulectomy Patient: A Case Report. AB - Completely edentulous patients who have undergone hemimandibulectomy suffer severe anatomic and functional loss. Functions like mastication, speech and deglutition are severely compromised. The mandibular deviation towards the resected side leads to inefficient mastication. In order to alleviate the difficulties encountered by the patient, construction of a modified occlusal table into conventional complete denture has been described in this article. This simple modification enables the patient to articulate teeth on a broader surface area. The inclines of the cusps also help in mandibular guidance. Thus, prosthetic rehabilitation of hemimandibulectomy patients with two rows of teeth on the unresected side serves to restore function and aaesthetics providing them with an added psychological comfort. PMID- 26501025 TI - A Case of Dentinogenesis Imperfecta Treated with Submerged Root Technique. AB - Dentinogenesis imperfecta (DGI), an autosomal dominant trait, is one of the most common hereditary disorders affecting both the formation and mineralization of dentin. Either or both primary and permanent dentition is affected by it. Here, we present a case report of a 13-year-old female patient affected with DGI who had undergone prosthetic rehabilitation with submerged root technique. PMID- 26501026 TI - Reconstruction and Intentional Replantation of a Maxillary Central Incisor with a Complete Vertical Root Fracture: A Rare Case Report with Three Years Follow up. AB - Vertical root fractures in teeth present with challenges not only with diagnosis but also with management. The prognosis in such teeth is generally questionable with extraction of the tooth being the most common treatment option. However, conservative treatment options such as reconstruction of the fractured fragments with adhesive resin followed by intentional replantation have been recently suggested. There are only a few case reports that describe management of complete vertical root fracture by reconstruction of fragments. The present case report describes successful management of an unusual complete vertical root fracture of a maxillary right central incisor in a 23-year-old male by reconstructing the fragments with a dual cure resin followed by intentional replantation. At the three year follow up, the tooth was asymptomatic, radiographically sound with probing depth and mobility within normal physiological limits. PMID- 26501027 TI - Heterogeneity of Nasolabial Flap- Role in Prevention of Morbidity Associated with Reconstruction of Orofacial Defects. AB - Reconstructive technique after surgical excision of malignancy in orofacial region should be planned in preoperative period itself. Surgery is the preferred modality of treatment if the tumour is small and located in an accessible area. Nasolabial flap is a versatile flap which is well suited to cover small defects in maxillofacial region. Nasolabial flap can be used as an alternative to other distant pedicled flaps in selected cases. A retrospective analysis of 12 cases of oral cancer treated with primary excision and reconstruction using nasolabial flap was done. Patients who underwent resection of tumour and reconstruction with nasolabial flap in selected cases reduced the morbidity associated with Distant pedicled flaps. Two selected cases are described in detail. PMID- 26501028 TI - Magnet and Semi Precision Attachment in an Implant Retained Partial Denture for the Rehabilitation of an Irradiated Marginal Mandibulectomy Patient: A Case Report. AB - Surgical treatment of malignancies in the oral cavity (mandible, tongue, floor of the mouth, alveolus, buccal sulcus) often results in an unfavourable anatomic condition for prosthodontic rehabilitation. Hence, maxillofacial prosthetic rehabilitation becomes a mightier task when resection is accompanied by radiation therapy. In selected cases, implant therapy comes to rescue. The following report throws light on the case of prosthetic rehabilitation of a patient who underwent right marginal mandibulectomy and right partial glossectomy, with the aid of a single implant, semi precision attachment and magnet supported partial denture. PMID- 26501029 TI - Deceptive Lesions of Periodontium: A Case Series. AB - Basic pathology of the common appearing diseases of the periodontium are not always common inflammatory reactions. The root cause may be malignant and metastatic lesions. Here, we present unusual causes of these common periodontal lesions. This article also stress upon the importance of histopathological examination of the surgically excised localized gingival swellings which fail to regress after conservative therapy. PMID- 26501030 TI - Proposed Clinico-Pathological Classification for Oral Exophytic Lesions. AB - Oral exophytic lesions often have proven to be diagnostically challenging due to the varied clinical presentation. The exophytic growth of the oral lesions is due to the type of pathology and histological changes. Careful clinical interpretation with a better histological understanding of exophytic lesions may ease the diagnosis from the differential diagnosis panel. The purpose of proposing classification system is to categorize the exophytic lesions of interest under specific clinical and/or histological explanation; and this will eventually lead to better understanding of the pathological condition that is described. To the best of our knowledge, there is no such classification system available for oral exophytic lesions and hence proposal of classification system is attempted in this study. Further, proposing a new classification system is not just to influence the academic contribution, but also to assist at greatest extent for diagnosis during clinical practice. PMID- 26501031 TI - A Review on Perforation Repair Materials. AB - Perforation is an artificial communication between the root canal system and supporting tissues of the teeth. Root perforation complicates the treatment and deprives the prognosis if not properly managed. A wide variety of materials to seal the perforations have been suggested in literature. There are many comparative studies showing the efficacy of one material over the other. Literature shows many reviews on diagnosis, treatment plan and factors affecting prognosis of perforation repair; but none of these articles elaborated upon various materials available to seal the perforation. The present article aims at describing all the materials used for perforation repair from the past till date; it also offers a literature review of all the articles published over last four decades referred to the treatment of perforation with various root repair materials. PMID- 26501032 TI - Toll-Like Receptors: A Key Marker for Periodontal Disease and Preterm Birth - A Contemporary Review. AB - The receptors of the innate immune system have evolved to recognize pathogenic bacteria in a complex manner. Out of these immune receptors, the pattern recognition receptors (PRRs) such as Toll like receptors have gained importance off late to play a key role in the activation of cascade of inflammatory cytokines in pathogenesis of preterm birth. Preterm birth has become leading cause of neonatal deaths globally. The concept of oral infection influencing the occurrence of preterm delivery has gained importance. Translocation of periodontal pathogens and inflammatory mediators play role in the pathogenesis of preterm labour. The transmembrane toll like receptors of innate immunity have been recently implicated in the association of periodontal infection and preterm labour. The TLRs are considered as a key marker and TLR blockade can be a critical method for treating women who are exposed to periodontal pathogens. This review is aimed at discussing the role of TLR in periodontal disease and its relationship with preterm birth. PMID- 26501033 TI - Osseoperception: An Implant Mediated Sensory Motor Control- A Review. AB - Osseointegration of dental implants has been researched extensively, covering various aspects such as bone apposition, biomechanics and microbiology etc however, physiologic integration of implants and the associated prosthesis in the body has received very little attention. This integration is due to the development of a special sensory ability, which is able to restore peripheral sensory feedback mechanism. The underlying mechanism of this so-called 'osseoperception' phenomenon remains a matter of debate. The following article reveals the histological, neurophysiologic and psychophysical aspects of osseoperception. A comprehensive research to provide scientific evidence of osseoperception was carried out using various online resources such as Pubmed, Google scholar etc to retrieve studies published between 1985 to 2014 using the following keywords: "osseoperception", "mechanoreceptors", "tactile sensibility". Published data suggests that a peripheral feedback pathway can be restored with osseointegrated implants. This implant-mediated sensory-motor control may have important clinical implications in the normal functioning of the implant supported prosthesis. PMID- 26501034 TI - Biomedical Biopolymers, their Origin and Evolution in Biomedical Sciences: A Systematic Review. AB - Biopolymers provide a plethora of applications in the pharmaceutical and medical applications. A material that can be used for biomedical applications like wound healing, drug delivery and tissue engineering should possess certain properties like biocompatibility, biodegradation to non-toxic products, low antigenicity, high bio-activity, processability to complicated shapes with appropriate porosity, ability to support cell growth and proliferation and appropriate mechanical properties, as well as maintaining mechanical strength. This paper reviews biodegradable biopolymers focusing on their potential in biomedical applications. Biopolymers most commonly used and most abundantly available have been described with focus on the properties relevant to biomedical importance. PMID- 26501035 TI - Forensic Facial Reconstruction: The Final Frontier. AB - Forensic facial reconstruction can be used to identify unknown human remains when other techniques fail. Through this article, we attempt to review the different methods of facial reconstruction reported in literature. There are several techniques of doing facial reconstruction, which vary from two dimensional drawings to three dimensional clay models. With the advancement in 3D technology, a rapid, efficient and cost effective computerized 3D forensic facial reconstruction method has been developed which has brought down the degree of error previously encountered. There are several methods of manual facial reconstruction but the combination Manchester method has been reported to be the best and most accurate method for the positive recognition of an individual. Recognition allows the involved government agencies to make a list of suspected victims'. This list can then be narrowed down and a positive identification may be given by the more conventional method of forensic medicine. Facial reconstruction allows visual identification by the individual's family and associates to become easy and more definite. PMID- 26501036 TI - Oral Squamous Cell Carcinoma: Hematoxylin and Eosin Staining. PMID- 26501037 TI - The Use of Hyperbaric Oxygen Therapy in Dentistry. PMID- 26501038 TI - Letter to the Editor Regarding Prevalence of Periodontal Disease and Characterization of its Extent and Severity in An Adult Population: An Observational Study. PMID- 26501039 TI - A Contemporary Approach to Classify Ghost Cells Comprising Oral Lesions. AB - Ghost cells are swollen eosinophilic epithelial cells that have lost their nuclei but retain the cellular and nuclear outline. Pathologic ghost cell formation could be the process of aberrant keratinization or the result of coagulative necrosis. Ghost cells have been described in several odontogenic lesions, which include calcifying epithelial odontogenic cysts or tumours like odontomas, ameloblastic fibro-odontomas, and ameloblastomas. This article present a view on the formation of ghost cells with proposal/introduction of a classification for ghost cell lesions of the oral cavity in an attempt to organize these lesions for the better understanding and academic purpose. PMID- 26501040 TI - Erratum to: Combined effect of hydrogen sulphide donor and losartan in experimental diabetic nephropathy in rats. AB - [This corrects the article DOI: 10.1186/s40200-015-0185-7.]. PMID- 26501041 TI - Hyperglycaemia and its related risk factors in Ilam province, west of Iran- a population-based study. AB - BACKGROUND: Impaired fasting glycaemia (IFG) has been defined as the fasting plasma glucose level between 6.1 (110 mgl/dl) and 6.9 mmol/l (125 mgl/dl). Control of hyperglycaemia during acute illness among diabetic and non-diabetic patients has been associated with improved outcome. The aim of this study was to investigate the prevalence of and factors related to hyperglycaemia, IFG and diabetes in west of Iran. METHODS: This project was performed by a cross sectional method in Ilam province including 2158 people >= 25 years old. From the list of all rural and urban health centers of each county, several were randomly selected. For each selected health centre, families numbered 1-20 completed questionnaire forms for all the members aging >= 25 years. FBS was measured for all the participants by standard method. All the demographic and laboratory results were analysed using SPSS 16. Descriptive and regression analysis were used for statistical analysis appropriately. RESULTS: A total of 2158 people were evaluated in this study, among which 72 % were female with a mean age of 45.5 +/- 14 years. 40 % of participants were from urban regions and the mean height, weight, FBS and waist size of the participants were respectively as follows: 164 +/- 8.9 cm, 68.4 +/- 12.3 kg, 5.7 +/- 2.8 mmol/l (102.6 +/- 49.9 mg/dl) and 82.3 +/- 14.3 cm. The prevalence of IFG, diabetes and hyperglycaemia among participants were 7.8 %, 11.8 % and 19.6 %, respectively and participants from urban area showed a significantly higher prevalence of hyperglycaemia compared to rural regions (P < 0.0001). CONCLUSION: The most effective factors associated with IFG and diabetes were family history of diabetes, age, hypertension, marital status, place of life and smoking, respectively. The prevalence of IFG, diabetes and hyperglycemia among the population living in Ilam province, west of Iran, were 7.8, 11.8 and 19.6 % respectively which were directly increased with age. PMID- 26501042 TI - Condylar positioning changes following unilateral sagittal split ramus osteotomy in patients with mandibular prognathism. AB - BACKGROUND: This study was performed to evaluate three-dimensional positional change of the condyle using three-dimensional computed tomography (3D-CT) following unilateral sagittal split ramus osteotomy (USSRO) in patients with mandibular prognathism. METHODS: This study examined two patients exhibiting skeletal class III malocclusion with facial asymmetry who underwent USSRO for a mandibular setback. 3D-CT was performed before surgery, immediately after surgery, and 6 months postoperatively. After creating 3D-CT images by using the In-vivo 5TM program, the axial plane, coronal plane, and sagittal plane were configured. Three-dimensional positional changes from each plane to the condyle, axial condylar head axis angle (AHA), axial condylar head position (AHP), frontal condylar head axis angle (FHA), frontal condylar head position (FHP), sagittal condylar head axis angle (SHA), and sagittal condylar head position (SHP) of the two patients were measured before surgery, immediately after surgery, and 6 months postoperatively. RESULTS: In the first patient, medial rotation of the operated condyle in AHA and anterior rotation in SHA were observed. There were no significant changes after surgery in AHP, FHP, and SHP after surgery. In the second patient, medial rotation of the operated condyle in AHA and lateral rotation of the operated condyle in FHA were observed. There were no significant changes in AHP, FHP, and SHP postoperatively. This indicates that in USSRO, postoperative movement of the condylar head is insignificant; however, medial rotation of the condylar head is possible. Although three-dimensional changes were observed, these were not clinically significant. CONCLUSIONS: The results of this study suggest that although three-dimensional changes in condylar head position are observed in patients post SSRO, there are no significant changes that would clinically affect the patient. PMID- 26501043 TI - Reconstruction of extensive jaw defects induced by keratocystic odontogenic tumor via patient-customized devices. AB - Keratocystic odontogenic tumors can occur in any area of the maxilla or mandible. According to their size, location, and relations with surrounding structures, they are treated by cyst enucleation or enucleation after either marsupialization or decompression. Enucleation is performed when cysts are not large and when only minor damage to adjacent anatomical structures is expected. Although marsupialization and decompression follow the same basic bone-regeneration principle, which is to say, by reducing the pressure within the cyst, the former leaves a large defect after healing due to the large fistula necessary to induce the conversion of the cyst-lining epithelia to oral epithelia; the latter leaves only a relatively small defect, because of the continuous washing carried out by means of a tube inserted into a small hole in the cyst. In the latter case too, a decompressor appropriate for the focal position is required, owing to the importance of maintaining the device and controlling for oral hygiene. We report herein decompression treatment with a patient-customized device for an extensive cyst in the anterior region of the mandible. PMID- 26501044 TI - A Case of New Familiar Genetic Variant of Autosomal Dominant Polycystic Kidney Disease-2: A Case Study. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal cyst formation due to mutations in genes coding for polycystin-1 [PKD1 (85-90% of cases), on ch 16p13.3] and polycystin-2 [PKD2 (10-15% of cases), on ch 4q13-23] and PKD3 gene (gene unmapped). It is also associated with TSC2/PKD1 contiguous gene syndrome. ADPKD is usually inherited, but new mutations without a family history occur in approximately 10% of the cases. CASE PRESENTATION: A 17 year-old boy was followed up for bilateral cystic kidney disease, hypertension, and obesity since he was 13 years old. The diagnosis was an accidental finding during abdominal CT at age 13 to rule out appendicitis. A renal ultrasonogram also demonstrated a multiple bilateral cysts. Because of parental history of bilateral renal cysts, PKD1 and PKD2, genetic testing was ordered. Results showed, PKD2 variant 1:3 bp deletion of TGT; nucleotide position: 1602-1604; codon position: 512-513; mRNA reading frame maintained. The same mutation was later identified in his father. CONCLUSION: A smaller number of patients have a defect in the PKD2 locus on chromosome 4 (resulting in PKD2 disease). There are no known published cases on this familiar genetic variant of ADPKD-2 cystic kidney disease. In this case, the disease is present unusually early in life. PMID- 26501045 TI - Altered Fetal Head Growth in Preeclampsia: A Retrospective Cohort Proof-Of Concept Study. AB - BACKGROUND: Preeclampsia is associated with fetal growth restriction and low birth weights. Neurotrophins, which mediate neuronal growth and development, are also increased in the placenta and cord blood in preeclampsia. Hence, the aim of this study was to determine whether fetal head growth is altered in preeclampsia, adjusting for growth restriction and other confounding variables. METHODS: This research included a retrospective cohort study, looking at fetal head circumference at birth, plus a case-control study examining fetal head circumference at mid-gestation. The head circumference at birth analysis consisted of 14,607 pregnancies (preeclampsia = 382, control = 14,225), delivered between July 2006 and June 2012 at Nepean Hospital, Australia. Head circumference at birth, in addition to other maternal and fetal variables, was sourced from the Nepean Obstetric Database. The head circumference at mid-gestation study consisted of 756 pregnancies (preeclampsia = 248, control = 508), delivered within the same data collection period at Nepean Hospital. Head circumference at mid-gestation was retrieved from an earlier ultrasound scan. Exclusion criteria included >1 fetus, illegal drug use, alcohol consumption, and chronic or gestational hypertension. Generalized linear models were used to analyze fetal head circumference in preeclampsia versus controls, adjusting for confounding variables. RESULTS: Head circumference increased at a greater rate in preeclampsia versus controls, adjusted for gestation, fetal gender, birth weight and length, smoking, maternal BMI, and growth restriction. At mid-gestation, there was no difference in head circumference between preeclampsia and controls. CONCLUSION: For the first time, this research has suggested increased fetal head growth in preeclampsia, adjusted for confounders. This finding may be explained by altered fetal exposure to neurotrophins in preeclampsia. The long-term neurodevelopmental consequences of preeclampsia remain unclear. PMID- 26501046 TI - Building Interdisciplinary Leadership Skills among Health Practitioners in the Twenty-First Century: An Innovative Training Model. AB - Transformational learning is the focus of twenty-first century global educational reforms. In India, there is a need to amalgamate the skills and knowledge of medical, nursing, and public health practitioners and to develop robust leadership competencies among them. This initiative proposed to identify interdisciplinary leadership competencies among Indian health practitioners and to develop a training program for interdisciplinary leadership skills through an Innovation Collaborative. Medical, nursing, and public health institutions partnered in this endeavor. An exhaustive literature search was undertaken to identify leadership competencies in these three professions. Published evidence was utilized in searching for the need for interdisciplinary training of health practitioners, including current scenarios in interprofessional health education and the key competencies required. The interdisciplinary leadership competencies identified were self-awareness, vision, self-regulation, motivation, decisiveness, integrity, interpersonal communication skills, strategic planning, team building, innovation, and being an effective change agent. Subsequently, a training program was developed, and three training sessions were piloted with 66 participants. Each cohort comprised a mix of participants from different disciplines. The pilot training guided the development of a training model for building interdisciplinary leadership skills and organizing interdisciplinary leadership workshops. The need for interdisciplinary leadership competencies is recognized. The long-term objective of the training model is integration into the regular medical, nursing, and public health curricula, with the aim of developing interdisciplinary leadership skills among them. Although challenging, formal incorporation of leadership skills into health professional education is possible within the interdisciplinary classroom setting using principles of transformative learning. PMID- 26501048 TI - How Target and Perceiver Gender Affect Impressions of HIV Risk. AB - BACKGROUND: People do not use condoms consistently but instead rely on intuition to identify sexual partners high at risk for human immunodeficiency virus (HIV) infection. The present study examined gender differences of intuitive impressions about HIV risk. METHODS: Male and female perceivers evaluated portraits of unacquainted male and female targets regarding their risk for HIV, trait characteristics (trust, responsibility, attractiveness, valence, arousal, and health), and willingness for interaction. RESULTS: Male targets were perceived as more risky than female targets for both perceiver genders. Furthermore, male perceivers reported higher HIV risk perception for both male and female targets than female perceivers. Multiple regression indicated gender differences in the association between person characteristics and HIV risk. In male targets, only trustworthiness predicts HIV risk. In female targets, however, HIV risk is related to trustworthiness, attractiveness, health, valence (for male perceivers), and arousal (for female perceivers). CONCLUSION: The present findings characterize intuitive impressions of HIV risk and reveal differences according to both target and perceiver gender. Considering gender differences in intuitive judgments of HIV risk may help devise effective strategies by shifting the balance from feelings of risk toward a more rational mode of risk perception and the adoption of effective precautionary behaviors. PMID- 26501047 TI - Concordance between Self-Reports and Medicare Claims among Participants in a National Study of Chronic Disease Self-Management Program. AB - OBJECTIVES: To evaluate the concordance between self-reported data and variables obtained from Medicare administrative data in terms of chronic conditions and health care utilization. DESIGN: Retrospective observational study. PARTICIPANTS: We analyzed data from a sample of Medicare beneficiaries who were part of the National Study of Chronic Disease Self-Management Program (CDSMP) and were eligible for the Centers for Medicare and Medicaid Services (CMS) pilot evaluation of CDSMP (n = 119). METHODS: Self-reported and Medicare claims-based chronic conditions and health care utilization were examined. Percent of consistent numbers, kappa statistic (kappa), and Pearson's correlation coefficient were used to evaluate concordance. RESULTS: The two data sources had substantial agreement for diabetes and chronic obstructive pulmonary disease (COPD) (kappa = 0.75 and kappa = 0.60, respectively), moderate agreement for cancer and heart disease (kappa = 0.50 and kappa = 0.47, respectively), and fair agreement for depression (kappa = 0.26). With respect to health care utilization, the two data sources had almost perfect or substantial concordance for number of hospitalizations (kappa = 0.69-0.79), moderate concordance for ED care utilization (kappa = 0.45-0.61), and generally low agreement for number of physician visits (kappa <= 0.31). CONCLUSION: Either self-reports or claim-based administrative data for diabetes, COPD, and hospitalizations can be used to analyze Medicare beneficiaries in the US. Yet, caution must be taken when only one data source is available for other types of chronic conditions and health care utilization. PMID- 26501049 TI - A Selected Review of the Mortality Rates of Neonatal Intensive Care Units. AB - INTRODUCTION: Newborn babies in need of critical medical attention are normally admitted to the neonatal intensive care unit (NICU). These infants tend to be preterm, have low birth weight, and/or have serious medical conditions. Neonatal survival varies, but progress in perinatal and neonatal care has notably diminished mortality rates. In this selected review, we examine and compare the NICU mortality rates and etiologies of death in different countries. METHODS: A literature search was conducted in Ovid MEDLINE, OLDMEDLINE, EMBASE Classic, and EMBASE. The primary endpoint was the mortality rates in NICUs. Secondary endpoints included the reasons for death and the correlation between infant age and mortality outcome. For the main analysis, we examined all infants admitted to NICUs. Subgroup analyses included extremely low birth weight infants (based on the authors' own definition), very low birth weight infants, very preterm infants, preterm infants, preterm infants with a birth weight of <=1,500 g, and by developed and developing countries. RESULTS: The literature search yielded 1,865 articles, of which 20 were included. The total mortality rates greatly varied among countries. Infants in developed and developing countries had similar ages at death, ranging from 4 to 20 days and 1 to 28.9 days, respectively. The mortality rates ranged from 4 to 46% in developed countries and 0.2 to 64.4% in developing countries. CONCLUSION: The mortality rates of NICUs vary between nations but remain high in both developing and developed countries. PMID- 26501050 TI - Pediatric Nephrology in Primary Care: The Forest for the Trees. PMID- 26501051 TI - Implementation and evaluation of a training program as part of the Cooperative Biological Engagement Program in Azerbaijan. AB - A training program for animal and human health professionals has been implemented in Azerbaijan through a joint agreement between the United States Defense Threat Reduction Agency and the Government of Azerbaijan. The training program is administered as part of the Cooperative Biological Engagement Program, and targets key employees in Azerbaijan's disease surveillance system including physicians, veterinarians, epidemiologists, and laboratory personnel. Training is aimed at improving detection, diagnosis, and response to especially dangerous pathogens (EDPs), although the techniques and methodologies can be applied to other pathogens and diseases of concern. Biosafety and biosecurity training is provided to all trainees within the program. Prior to 2014, a variety of international agencies and organizations provided training, which resulted in gaps related to lack of coordination of training materials and content. In 2014 a new training program was implemented in order to address those gaps. This paper provides an overview of the Cooperative Biological Engagement Program training program in Azerbaijan, a description of how the program fits into existing national training infrastructure, and an evaluation of the new program's effectiveness to date. Long-term sustainability of the program is also discussed. PMID- 26501052 TI - The Association between Medicare Advantage Market Penetration and Diabetes in the United States. AB - The objective of this study is to explore the extent to which managed care market penetration in the United States is associated with the presence of chronic disease. Diabetes was selected as the chronic disease of interest due to its increasing prevalence as well as the disease management protocols that can lessen disease complications. We hypothesized that greater managed care market penetration would be associated with (1) lower prevalence of diabetes and (2) lower prevalence of diabetes-related comorbidities (DRCs) among diabetics. Data for this analysis came from two sources. We merged Medicare Advantage (MA) market penetration data from the Centers for Medicare and Medicaid Services (CMS) with data from the Medical Expenditure Panel Survey (MEPS) (2004-2008). Results suggest that county-level MA market penetration is not significantly associated with prevalence of diabetes or DRCs. That finding is quite interesting in that managed care market penetration has been shown to have an effect on utilization of inpatient services. It may be that managed care protocols do not offer the same benefits beyond the inpatient setting. PMID- 26501053 TI - Structure-odor relationships of linalool, linalyl acetate and their corresponding oxygenated derivatives. AB - Linalool 1 is an odorant that is commonly perceived as having a pleasant odor, but is also known to elicit physiological effects such as inducing calmness and enhancing sleep. However, no comprehensive studies are at hand to show which structural features are responsible for these prominent effects. Therefore, a total of six oxygenated derivatives were synthesized from both 1 and linalyl acetate 2, and were tested for their odor qualities and relative odor thresholds (OTs) in air. Linalool was found to be the most potent odorant among the investigated compounds, with an average OT of 3.2 ng/L, while the 8 hydroxylinalool derivative was the least odorous compound with an OT of 160 ng/L; 8-carboxylinalool was found to be odorless. The odorant 8-oxolinalyl acetate, which has very similar odor properties to linalool, was the most potent odorant besides linalool, exhibiting an OT of 5.9 ng/L. By comparison, 8-carboxylinalyl acetate had a similar OT (6.1 ng/L) as its corresponding 8-oxo derivative but exhibited divergent odor properties (fatty, greasy, musty). Overall, oxygenation on carbon 8 had a substantial effect on the aroma profiles of structural derivatives of linalool and linalyl acetate. PMID- 26501054 TI - An imidazole functionalized pentameric thiophene displays different staining patterns in normal and malignant cells. AB - Molecular tools for fluorescent imaging of cells and their components are vital for understanding the function and activity of cells. Here, we report an imidazole functionalized pentameric oligothiophene, p-HTIm, that can be utilized for fluorescent imaging of cells. p-HTIm fluorescence in normal cells appeared in a peripheral punctate pattern partially co-localized with lysosomes, whereas a one-sided perinuclear Golgi associated localization of the dye was observed in malignant cells. The uptake of p-HTIm was temperature dependent and the intracellular target was reached within 1 h after staining. The ability of p-HTIm to stain cells was reduced when the imidazole side chain was chemically altered, verifying that specific imidazole side-chain functionalities are necessary for achieving the observed cellular staining. Our findings confirm that properly functionalized oligothiophenes can be utilized as fluorescent tools for vital staining of cells and that the selectivity toward distinct intracellular targets are highly dependent on the side-chain functionalities along the conjugated thiophene backbone. PMID- 26501055 TI - Relevance of Crop Biology for Environmental Risk Assessment of Genetically Modified Crops in Africa. AB - Knowledge about the crop biology of economic crops in Africa is needed for regulators to accurately review dossiers and conduct comprehensive environmental risk assessments (ERAs). This information allows regulators to decide whether biotech crops present a risk to biodiversity, since crossing between domesticated crops and their wild relatives could affect the adaptations of the wild species. The criteria that should be used in the evaluation of African crops for ERA include growth habit, center of origin, center of genetic diversity, proximity of wild relatives, inter-fertility, mode of pollen dispersal, length of pollen viability, mating system, invasiveness, weediness, mode of propagation, mode of seed dispersal, and length of seed dormancy. In this paper, we discuss the crops being genetic engineered in Africa and describe the crop biology of those with native relatives. PMID- 26501056 TI - Effect of Ceramic Scaffold Architectural Parameters on Biological Response. AB - Numerous studies have focused on the optimization of ceramic architectures to fulfill a variety of scaffold functional requirements and improve biological response. Conventional fabrication techniques, however, do not allow for the production of geometrically controlled, reproducible structures and often fail to allow the independent variation of individual geometric parameters. Current developments in additive manufacturing technologies suggest that 3D printing will allow a more controlled and systematic exploration of scaffold architectures. This more direct translation of design into structure requires a pipeline for design-driven optimization. A theoretical framework for systematic design and evaluation of architectural parameters on biological response is presented. Four levels of architecture are considered, namely (1) surface topography, (2) pore size and geometry, (3) porous networks, and (4) macroscopic pore arrangement, including the potential for spatially varied architectures. Studies exploring the effect of various parameters within these levels are reviewed. This framework will hopefully allow uncovering of new relationships between architecture and biological response in a more systematic way as well as inform future refinement of fabrication techniques to fulfill architectural necessities with a consideration of biological implications. PMID- 26501057 TI - Public Submissions on the Uganda National Biotechnology and Biosafety Bill, 2012 Reveal Potential Way Forward for Uganda Legislators to Pass the Bill. AB - The Cartagena Protocol on Biosafety to the Convention on Biological Diversity is an internationally binding instrument addressing issues of biosafety. Biosafety refers to the need to protect human health and the environment from the possible adverse effects of the products of modern biotechnology. Accordingly, all countries to the convention are required to put in place regulatory mechanisms to enhance the safety of biotechnology in the context of the Convention's overall goal of reducing all potential threats to biological diversity, while taking into account the risks to human health. Therefore, each country party to the convention has its own procedures to enact laws to guide the safe use of biotechnology. In Uganda, the process involves the drafting of the bill by the first parliamentary counsel, approval by cabinet, first reading at the parliament, committal to the responsible parliamentary sessional committee, tabling of the bill for public hearing, consultations, and final approval. In Uganda, the Committee on Science and Technology is responsible for the Biosafety Bill. In March 2013, the Committee tabled the bill for public hearing and submissions from public institutions. There were comments supporting the passage of the Bill and comments in objection. The reasons for objection are mainly due to precaution, speculation, lack of knowledge about biotechnology and biosafety, and alleged influence from biosafety entrepreneurs. This article reviews these public views, revealing controversy and possible consensus to pass the bill. PMID- 26501058 TI - Modeling the Contribution of Allosteric Regulation for Flux Control in the Central Carbon Metabolism of E. coli. AB - Modeling cellular metabolism is fundamental for many biotechnological applications, including drug discovery and rational cell factory design. Central carbon metabolism (CCM) is particularly important as it provides the energy and precursors for other biological processes. However, the complex regulation of CCM pathways has still not been fully unraveled and recent studies have shown that CCM is mostly regulated at post-transcriptional levels. In order to better understand the role of allosteric regulation in controlling the metabolic phenotype, we expand the reconstruction of CCM in Escherichia coli with allosteric interactions obtained from relevant databases. This model is used to integrate multi-omics datasets and analyze the coordinated changes in enzyme, metabolite, and flux levels between multiple experimental conditions. We observe cases where allosteric interactions have a major contribution to the metabolic flux changes. Inspired by these results, we develop a constraint-based method (arFBA) for simulation of metabolic flux distributions that accounts for allosteric interactions. This method can be used for systematic prediction of potential allosteric regulation under the given experimental conditions based on experimental data. We show that arFBA allows predicting coordinated flux changes that would not be predicted without considering allosteric regulation. The results reveal the importance of key regulatory metabolites, such as fructose-1,6 bisphosphate, in controlling the metabolic flux. Accounting for allosteric interactions in metabolic reconstructions reveals a hidden topology in metabolic networks, improving our understanding of cellular metabolism and fostering the development of novel simulation methods that account for this type of regulation. PMID- 26501059 TI - Editorial: Bioinformatics of Non-Coding RNAs with Applications to Biomedicine: Recent Advances and Open Challenges. PMID- 26501060 TI - Effect of Infliximab Dose Increase in Rheumatoid Arthritis at Different Trough Concentrations: A Cohort Study in Clinical Practice Conditions. AB - BACKGROUND: Evidence supporting treatment intensification in rheumatoid arthritis (RA) is limited and controversial. We explored outcomes of infliximab dose increases and accounted for pre-existing trough levels in patients with active RA. METHODS: This study was a retrospective study of 42 RA patients who received increased infliximab following an insufficient response (DAS28 >3.2). Serum concentrations of infliximab and antibodies to infliximab (ATI) and DAS28 and EULAR clinical response parameters were recorded for 1 year. Analyses were performed in three patient groups that were defined by infliximab serum concentration prior to treatment enhancement: no detectable, low (<1.1 MUg/mL) or high (>=1.1 MUg/mL) drug levels. RESULTS: No circulating infliximab was detected in 20 patients (47.6%), but 13 (31%) and 9 (21.4%) patients exhibited low and high levels, respectively. ATI was only detected in patients with no detectable drug levels because the drug interferes with ELISA. DAS28 disease activity globally showed a modest improvement after dose escalation, but this improvement did not persist after 6 and 12 months. Infliximab serum levels increased significantly in the high group (p = 0.016), but no increase was achieved in the low and no detectable groups. The three study groups exhibited similar disease activity over time, and no improvement was observed in the non-responder EULAR rates. CONCLUSION: These results suggest that the efficacy of an infliximab dose increase is limited, and the response is independent of the infliximab trough serum concentration that is achieved prior to escalation. PMID- 26501061 TI - Targeted Therapies in Liver Fibrosis: Combining the Best Parts of Platelet Derived Growth Factor BB and Interferon Gamma. AB - Cytokines, growth factors, and other locally produced mediators play key roles in the regulation of disease progression. During liver fibrosis, these mediators orchestrate the balance between pro- and antifibrotic activities as exerted by the hepatic cells. Two important players in this respect are the profibrotic mediator platelet-derived growth factor BB (PDGF-BB) and the antifibrotic cytokine interferon gamma (IFNgamma). PDGF-BB, produced by many resident and infiltrating cells, causes extensive proliferation, migration, and contraction of hepatic stellate cells (HSCs) and myofibroblasts. These cells are the extracellular matrix-producing hepatic cells and they highly express the PDGFbeta receptor. On the other hand, IFNgamma is produced by natural killer cells in fibrotic livers and is endowed with proinflammatory, antiviral, and antifibrotic activities. This cytokine attracted much attention as a possible therapeutic compound in fibrosis. However, clinical trials yielded disappointing results because of low efficacy and adverse effects, most likely related to the dual role of IFNgamma in fibrosis. In our studies, we targeted the antifibrotic IFNgamma to the liver myofibroblasts. For that, we altered the cell binding properties of IFNgamma, by delivery of the IFNgamma-nuclear localization sequence to the highly expressed PDGFbeta receptor using a PDGFbeta receptor recognizing peptide, thereby creating a construct referred to as "Fibroferon" (i.e., fibroblast targeted interferon gamma). In recent years, we demonstrated that HSC-specific delivery of IFNgamma increased its antifibrotic potency and improved its general safety profile in vivo, making Fibroferon highly suitable for the treatment of (fibrotic) diseases associated with elevated PDGFbeta receptor expression. The present review summarizes the knowledge on these two key mediators, PDGF-BB and IFNgamma, and outlines how we used this knowledge to create the cell-specific antifibrotic compound Fibroferon containing parts of both of these mediators. PMID- 26501063 TI - Students' Consumption of Beverages and Snacks at School and Away from School: A Case Study in the North East of Italy. AB - In North-East Italy (the Veneto region), several public school nutrition policies have been developed to reduce the consumption of high-caloric snacks and beverages. However, little is known about whether the policies actually influence students' dietary behaviors. In order to address this point, a multi-center cross sectional survey of 691 Italian students was conducted. Students completed the Beverage and Snack Questionnaire, which assesses the consumption of beverages and snacks at school and out of school. Three-level Poisson Models with random intercept with students (level 1 units) nested into classroom (level 2 units), and nested into schools (level 3 units), were used to examine the influence of the school setting vs. the out of school environment (independent variable) on students' consumption of sweet beverages, snacks, milk-based beverages, low carbohydrate drinks, fruit, and vegetables (dependent variable) (p <= 0.05). The results showed a significantly higher consumption of sweet beverages, snacks, milk-based beverages, low-carbohydrate drinks, fruit, and vegetables out-of-the school, suggesting a school-protective association Thus, the policies aimed to limit or deny access to unhealthy foods in the school environment may play an important role in promoting more healthful dietary patterns for school children. Additional studies should be conducted to compare students' dietary behaviors between schools with nutrition policies to those without nutrition policies. PMID- 26501062 TI - Psychosocial Risk Factors, Interventions, and Comorbidity in Patients with Non Specific Low Back Pain in Primary Care: Need for Comprehensive and Patient Centered Care. AB - Non-specific low back pain (LBP) affects many people and has major socio-economic consequences. Traditional therapeutic strategies, mainly focused on biomechanical factors, have had moderate and short-term impact. Certain psychosocial factors have been linked to poor prognosis of LBP and they are increasingly considered as promising targets for management of LBP. Primary health care providers (HCPs) are involved in most of the management of people with LBP and they are skilled in providing comprehensive care, including consideration of psychosocial dimensions. This review aims to discuss three pieces of recent research focusing on psychosocial issues in LBP patients in primary care. In the first systematic review, the patients' or HCPs' overall judgment about the likely evolution of LBP was the factor most strongly linked to poor outcome, with predictive validity similar to that of multidimensional scales. This result may be explained by the implicit aggregation of many prognostic factors underlying this judgment and suggests the relevance of considering the patients from biopsychosocial and longitudinal points of view. The second review showed that most of the interventions targeting psychosocial factors in LBP in primary care have to date focused on the cognitive-behavioral factors, resulting in little impact. It is unlikely that any intervention focusing on a single factor would ever fit the needs of most patients; interventions targeting determinants from several fields (mainly psychosocial, biomechanical, and occupational) may be more relevant. Should multiple stakeholders be involved in such interventions, enhanced interprofessional collaboration would be critical to ensure the delivery of coordinated care. Finally, in the third study, the prevalence of psychosocial comorbidity in chronic LBP patients was not found to be significantly higher than in other patients consulting in primary care. Rather than specifically screening for psychosocial conditions, this suggests taking into account any potential comorbidity in patients with chronic LBP, as in other patients. All these results support the adoption of a more comprehensive and patient-centered approach when dealing with patients with LBP in primary care. As this condition is illustrative of many situations encountered in primary care, the strategies proposed here may benefit most patients consulting in this setting. PMID- 26501064 TI - Superficial Temporal Artery Pseudoaneurysm: A Case Report. AB - Pseudoaneurysms of the superficial temporal artery are an uncommon vascular lesion of the external carotid system and most often the result of blunt head trauma. The frequency of pseudoaneurysms of the superficial temporal artery developing after craniotomy is exceedingly low and only a few cases have been reported. We present a case of pseudoaneurysm of this type in a 45-year-old male who underwent craniotomy for excision of meningioma. One month postoperatively, the craniotomy flap exhibited an enormous diffuse pulsate swelling. The suspected diagnosis of pseudoaneurysm arising from superficial temporal artery was confirmed on angiography. Surgical excision was done and no recurrences of the tumor or aneurysm were noted on subsequent follow up. PMID- 26501065 TI - Metazoan Hsp70-based protein disaggregases: emergence and mechanisms. AB - Proteotoxic stresses and aging cause breakdown of cellular protein homeostasis, allowing misfolded proteins to form aggregates, which dedicated molecular machines have evolved to solubilize. In bacteria, fungi, protozoa and plants protein disaggregation involves an Hsp70*J-protein chaperone system, which loads and activates a powerful AAA+ ATPase (Hsp100) disaggregase onto protein aggregate substrates. Metazoans lack cytosolic and nuclear Hsp100 disaggregases but still eliminate protein aggregates. This longstanding puzzle of protein quality control is now resolved. Robust protein disaggregation activity recently shown for the metazoan Hsp70-based disaggregases relies instead on a crucial cooperation between two J-protein classes and interaction with the Hsp110 co-chaperone. An expanding multiplicity of Hsp70 and J-protein family members in metazoan cells facilitates different configurations of this Hsp70-based disaggregase allowing unprecedented versatility and specificity in protein disaggregation. Here we review the architecture, operation, and adaptability of the emerging metazoan disaggregation system and discuss how this evolved. PMID- 26501066 TI - Mood Disorders and BDNF Relationship with Alcohol Drinking Trajectories among PLWH Receiving Care. AB - BACKGROUND: Despite the excessive rates of Hazardous Alcohol Use (HAU) among people living with HIV (PLWH), although largely speculated, psychological and physiological components associated with HAU, has not been actively measured. Therefore, the present study was geared toward determining: 1) the rates of mood disorders and its relationship with HAU, and 2) to assess the impact of Brain Derived Neurotrophic Factor (BDNF), a well-known regulator of alcohol and mood disorders. METHODS: For this study, participants of the longitudinal PADS Study n=400, were followed over time. Alcohol use (Alcohol Use Disorders Identification Test -AUDIT- and the Alcohol Dependence Scale -ADS) and moods (depression, anxiety, and stress) were assessed repeatedly. RESULTS: A cluster analyses shows three distinctive trajectories. The first one, revealed a group with increased drinking (Cluster 1: n=140), constant alcohol intake (Cluster 2: n = 60), and one with decreased consumption (Cluster 3: n =120). Analyses discovered higher AUDIT scores across the clusters with Cluster 1 being followed by Clusters 2 and 3 (1: 14.5 +/- 8 vs. 2=8.7 +/- 7.5 vs. 3= 6.6 +/- 4.2, p = 0.001). Women in Clusters 1 and 2 had higher levels of stress (1:21 +/- 7.5; 2:19.3 +/- 7) and lower BDNF levels (7904 +/- 1248 pg/ml and 10405 +/- 909 pg/mL) than their counterparts in Cluster 3 (PSS: 3: 16.6 +/-5, p = 0.02 BDNF: 10828 +/- 1127 pg/mL, p = 0.08). Men in Cluster 1 differed in terms of stress (19.8 +/- 7 vs. 21 +/- 7.5 score) and BDNF levels (Cluster 1: 5204 +/- 818 vs. Cluster 2: 7656 +/- 843 pg/ml, p = 0.002) but not in the number of years living with HIV. The proportion of subjects with multiple mood comorbidities was disturbingly higher (26%), and all were members of Cluster 1. Multiple logistic regression analyses indicated that participants reporting high relative to low levels of perceived stress, dual mood comorbidity, altered BDNF levels and low income increased the likelihood of being a member of Cluster 1. CONCLUSION: This study found that stress and overlaying psychiatric comorbidities are linked with persistent alcohol use. Findings suggest that BDNF and social support seems to be a logical target as it seems to be the bridge linking mood disorders and alcohol consumption. PMID- 26501067 TI - Platelets Contribute to BBB Disruption Induced by HIV and Alcohol. AB - The role of platelets in the neurological diseases that underlie cognitive impairment has attracted increasing attention in recent years. Multiple pathways in platelets contribute to host defenses, as well as to CNS function. In the current study, we hypothesize that the Blood Brain Barrier (BBB) is disrupted when exposed to platelets from patients with triple Co-morbidity (hazardous alcohol users+ HIV+ thrombocytopenia), compared to those with dual, single or no morbidity (HIV only, alcohol only or healthy controls). PMID- 26501068 TI - Lysosomal acid lipase in cancer. PMID- 26501069 TI - BCL-2 proteins: melanoma lives on the edge. PMID- 26501070 TI - Translation, Pdcd4 and eIF4A. PMID- 26501071 TI - "MetasTAZation" and beyond. PMID- 26501072 TI - Checkmate to CHK1 in T-cell ALL? PMID- 26501073 TI - JAK-STAT in lymphoproliferative disorders. PMID- 26501074 TI - Tumorigenicity of RTK/RAS in urothelium. PMID- 26501075 TI - Transport and senescence. PMID- 26501076 TI - Targeting the tumor-stromal-immune cell axis. PMID- 26501077 TI - Regulation of microRNA-200c in cancer stem cells. PMID- 26501078 TI - Circumventing HSP90 inhibitors via apoptosis block. PMID- 26501079 TI - Pten in mouse vagina. PMID- 26501080 TI - Viruses, stemness, embryogenesis, and cancer: a miracle leap toward molecular definition of novel oncotargets for therapy-resistant malignant tumors? AB - Recent breakthrough studies documented consistent activation of specific endogenous retroviruses in human embryonic stem cells and preimplantation human embryos and demonstrated the essential role of the sustained retroviral activities for maintenance of pluripotency and embryonic stem cell identity. Present analysis has led to the hypothesis that activation of the human stem cell associated retroviruses (SCARs), namely LTR7/HERVH and LTR5_Hs/HERVK, is likely associated with the emergence of clinically lethal therapy resistant death-from cancer phenotypes in a sub-set of cancer patients diagnosed with different types of malignant tumors. PMID- 26501081 TI - The PI3K regulatory subunit gene PIK3R1 is under direct control of androgens and repressed in prostate cancer cells. AB - Androgen receptor (AR) signalling and the PI3K pathway mediate survival signals in prostate cancer, and have been shown to regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Understanding the reciprocal regulation of these pathways is important for disease management as tumour cells can adapt and survive when either single pathway is inhibited pharmacologically. We recently carried out genome-wide exon-specific profiling of prostate cancer cells to identify novel androgen-regulated transcriptional events. Here we interrogated this dataset for novel androgen-regulated genes associated with the PI3K pathway. We find that the PI3K regulatory subunits PIK3R1 (p85alpha) and PIK3R3 (p55gamma) are direct targets of the AR which are rapidly repressed by androgens in LNCaP cells. Further characterisation revealed that the PIK3CA p110alpha catalytic subunit is also indirectly regulated by androgens at the protein level. We show that PIK3R1 mRNA is significantly under expressed in prostate cancer (PCa) tissue, and provide data to suggest a context dependent regulatory mechanism whereby repression of the p85alpha protein by the AR results in destabilisation of the PI3K p110alpha catalytic subunit and downstream PI3K pathway inhibition that functionally affects the properties of prostate cancer cells. PMID- 26501083 TI - Smart tools and orthogonal click-like reactions onto small unilamellar vesicles: Additional molecular data. AB - We present here the synthetic routes and the experimental data (NMR and MS spectra) for model reactions for copper-free Huisgen 1,4-cycloaddition, Staudinger ligation and for addition of a dithiol on a dibromomaleimide ring. Starting materials were synthesized from the commercially available 4 chlorophenethylamine, previously described 2-(cyclooct-2-yn-1-yloxy)acetic acid, 1-fluorocyclooct-2-ynecarboxylic acid, commercial 2 (diphenylphosphino)terephthalic acid 1-methyl 4-pentafluorophenyl diester and dibromomaleimide. In all cases, the expected compounds were obtained with good yield (50% to quantitative). A novel synthesis of the lipid anchor DOGP3NH2 is also described. These data were used as basis for the study reported in the article "Smart Tools and Orthogonal Click-like Reactions onto Small Unilamellar Vesicles" in Chemistry and Physics of Lipids [1]. PMID- 26501082 TI - Combination of heat shock protein 90 and focal adhesion kinase inhibitors synergistically inhibits the growth of non-small cell lung cancer cells. AB - Discovery of effective drug combinations is a promising strategy to improve patient survival. This study explores the impact of heat shock protein 90 (Hsp90) inhibition in combination with focal adhesion kinase (FAK) inhibitor on the growth of non-small cell lung cancer cells (NSCLC cells). Our data show that 17-N Allylamino-17-demethoxygeldanamycin (17-AAG), a well-studied Hsp90 inhibitor, synergized with FAK inhibitor, PF-573228, on the growth inhibition of NSCLC cells. This combination effect was confirmed using additional chemically distinct Hsp90 inhibitor, STA-9090, which is currently undergoing phase 3 clinical evaluation. Co-treatment of NSCLC cells with Hsp90 and FAK inhibitors significantly enhanced the inhibition on long-term colony formation compared to that with single agent. Inhibition of FAK exacerbated the G2 cell cycle arrest and annexin-V apoptotic staining induced by 17-AAG. Further mechanistic studies revealed that the combination of Hsp90 and FAK inhibitors reduced the activity of canonical proliferative and survival Akt-mTOR signaling, and increased pro apoptotic caspase activation. Interestingly, FAK inhibition alone induced feedback activation of pro-survival Erk signaling, which was abrogated by co treatment with Hsp90 inhibitors. Both Hsp90 and FAK inhibitors are undergoing clinical evaluation. Our studies suggest the tandem of Hsp90 and FAK inhibitors may provide an effective treatment option for NSCLC patients. PMID- 26501084 TI - Data in support of quantitative proteomics to identify potential virulence regulators in Paracoccidioides brasiliensis isolates. AB - Paracoccidioides genus are the etiologic agents of paracoccidioidomycosis (PCM), a systemic mycosis endemic in Latin America. Few virulence factors have been identified in these fungi. This paper describes support data from the quantitative proteomics of Paracoccidioides brasiliensis attenuated and virulent isolates [1]. The protein compositions of two isolates of the Pb18 strain showing distinct infection profiles were quantitatively assessed by stable isotopic dimethyl labeling and proteomic analysis. The mass spectrometry and the analysis dataset have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with identifier PXD000804. PMID- 26501085 TI - Supporting data for characterization of the busulfan metabolite EdAG and the Glutaredoxins that it adducts. AB - This article describes data related to a research article titled "The Busulfan Metabolite EdAG Irreversibly Glutathionylates Glutaredoxins" [1]. EdAG is an electrophilic GSH analog formed in vivo from busulfan, which is used in hematopoietic stem cell transplants. EdAG glutathionylates Glutaredoxins (Grx's) but not glutathione transferase A1-1 (GSTA1-1) in vitro. This article includes a complete NMR characterization of synthetic EdAG including homonuclear and heteronuclear correlation spectra. Also included are mass spectra of peptides from Grx's or GSTA1-1 that have cys residues that do not react with EdAG. PMID- 26501086 TI - Electrochemical and passivation behavior investigation of ferritic stainless steel in simulated concrete pore media. AB - The applications of stainless steel are one of the most reliable solutions in concrete structures to reduce chloride-induced corrosion problems and increase the structures service life, however, due to high prices of nickel, especially in many civil engineering projects, the austenitic stainless steel is replaced by the ferritic stainless steels. Compared with austenite stainless steel, the ferritic stainless steel is known to be extremely resistant of stress corrosion cracking and other properties. The good corrosion resistance of the stainless steel is due to the formation of passive film. While, there is little literature about the electrochemical and passive behavior of ferritic stainless steel in the concrete environments. So, here, we present the several corrosion testing methods, such as the potentiodynamic measurements, EIS and Mott-Schottky approach, and the surface analysis methods like XPS and AES to display the passivation behavior of 430 ferritic stainless steel in alkaline solution with the presence of chloride ions. These research results illustrated a simple and facile approach for studying the electrochemical and passivation behavior of stainless steel in the concrete pore environments. PMID- 26501087 TI - Treating the Inflammatory Core of Metabolic Syndromes. PMID- 26501088 TI - Surgical Approaches to the Lumbar Hidden Zone: Current Strategies and Future Directions. PMID- 26501089 TI - The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Trial: Where to Now? PMID- 26501090 TI - Understanding Hidden Antigens and Targeting Parasitic Nematodes. PMID- 26501091 TI - High Dose Meclizine Prevents Renal Ischemia-Reperfusion Injury in Healthy Male Mice. PMID- 26501092 TI - Intracranial Glioblastomas: New Hope for an Effective Treatment. PMID- 26501093 TI - Tenofovir Activating Kinases May Impact the Outcome of HIV Treatment and Prevention. PMID- 26501094 TI - HIV-1 Reservoir Association with Immune Activation. AB - In this issue of EBioMedicine, Ruggiero and colleagues describe immune activation biomarkers associated with the size of the HIV reservoir in a carefully designed cross-sectional study. The cohort consists of a homogeneous sample of HIV-1 infected patients with long-term plasma HIV-1 RNA suppression under antiretroviral treatment (ART). It is crucial to explore the potential utility of biomarkers that are easier (less labor intensive, less expensive) to measure than integrated HIV DNA load, in order to quickly and accurately quantify cellular reservoirs of HIV. PMID- 26501095 TI - Emergence of Microbial Resistance During Hospitalization. PMID- 26501096 TI - Plasmodium malariae Malaria: From Monkey to Man? PMID- 26501097 TI - Who is Funding What in the Fight Against Pneumonia? PMID- 26501098 TI - Prevention of Maternal-Fetal Transmission of Cytomegalovirus. PMID- 26501099 TI - Another Important Lesson from Military Surgery? PMID- 26501100 TI - A Breath of Fresh Air for Clinical Diagnoses. PMID- 26501101 TI - Cost Efficiencies in the Healthcare Setting: Telephone Versus Face-to-Face. PMID- 26501102 TI - Muscleblind-Like 1 and Muscleblind-Like 3 Depletion Synergistically Enhances Myotonia by Altering Clc-1 RNA Translation. AB - Loss of Muscleblind-like 1 (Mbnl1) is known to alter Clc-1 splicing to result in myotonia. Mbnl1(DeltaE3/DeltaE3)/Mbnl3(DeltaE2) mice, depleted of Mbnl1 and Mbnl3, demonstrate a profound enhancement of myotonia and an increase in the number of muscle fibers with very low Clc-1 currents, where gClmax values approach ~ 1 mS/cm(2), with the absence of a further enhancement in Clc-1 splice errors, alterations in polyA site selection or Clc-1 localization. Significantly, Mbnl1(DeltaE3/DeltaE3)/Mbnl3(DeltaE2) muscles demonstrate an aberrant accumulation of Clc-1 RNA on monosomes and on the first polysomes. Mbnl1 and Mbnl3 bind Clc-1 RNA and both proteins bind Hsp70 and eEF1A, with these associations being reduced in the presence of RNA. Thus binding of Mbnl1 and Mbnl3 to Clc-1 mRNA engaged with ribosomes can facilitate an increase in the local concentration of Hsp70 and eEF1A to assist Clc-1 translation. Dual depletion of Mbnl1 and Mbnl3 therefore initiates both Clc-1 splice errors and translation defects to synergistically enhance myotonia. As the HSA(LR) model for myotonic dystrophy (DM1) shows similar Clc-1 defects, this study demonstrates that both splice errors and translation defects are required for DM1 pathology to manifest. RESEARCH IN CONTEXT: Research in context: Myotonic Dystrophy type 1 (DM1) is a dominant disorder resulting from the expression of expanded CUG repeat RNA, which aberrantly sequesters and inactivates the muscleblind-like (MBNL) family of proteins. In mice, inactivation of Mbnl1 is known to alter Clc-1 splicing to result in myotonia. We demonstrate that concurrent depletion of Mbnl1 and Mbnl3 results in a synergistic enhancement of myotonia, with an increase in muscle fibers showing low chloride currents. The observed synergism results from the aberrant accumulation of Clc-1 mRNA on monosomes and the first polysomes. This translation error reflects the ability of Mbnl1 and Mbnl3 to act as adaptors that recruit Hsp70 and eEF1A to the Clc-1 mRNA engaged with ribosomes, to facilitate translation. Thus our study demonstrates that Clc-1 RNA translation defects work coordinately with Clc-1 splice errors to synergistically enhance myotonia in mice lacking Mbnl1 and Mbnl3. PMID- 26501103 TI - Involvement of Potassium and Cation Channels in Hippocampal Abnormalities of Embryonic Ts65Dn and Tc1 Trisomic Mice. AB - Down syndrome (DS) mouse models exhibit cognitive deficits, and are used for studying the neuronal basis of DS pathology. To understand the differences in the physiology of DS model neurons, we used dissociated neuronal cultures from the hippocampi of Ts65Dn and Tc1 DS mice. Imaging of [Ca(2+)]i and whole cell patch clamp recordings were used to analyze network activity and single neuron properties, respectively. We found a decrease of ~ 30% in both fast (A-type) and slow (delayed rectifier) outward potassium currents. Depolarization of Ts65Dn and Tc1 cells produced fewer spikes than diploid cells. Their network bursts were smaller and slower than diploids, displaying a 40% reduction in Deltaf / f0 of the calcium signals, and a 30% reduction in propagation velocity. Additionally, Ts65Dn and Tc1 neurons exhibited changes in the action potential shape compared to diploid neurons, with an increase in the amplitude of the action potential, a lower threshold for spiking, and a sharp decrease of about 65% in the after hyperpolarization amplitude. Numerical simulations reproduced the DS measured phenotype by variations in the conductance of the delayed rectifier and A-type, but necessitated also changes in inward rectifying and M-type potassium channels and in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. We therefore conducted whole cell patch clamp measurements of M-type potassium currents, which showed a ~ 90% decrease in Ts65Dn neurons, while HCN measurements displayed an increase of ~ 65% in Ts65Dn cells. Quantitative real-time PCR analysis indicates overexpression of 40% of KCNJ15, an inward rectifying potassium channel, contributing to the increased inhibition. We thus find that changes in several types of potassium channels dominate the observed DS model phenotype. PMID- 26501104 TI - Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy. AB - Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 * 10(- 3)) and non-epilepsy disease controls (P = 1.2 * 10(- 3)). The polygenic burden was driven both by the number of variants per individual, and over representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP. PMID- 26501106 TI - Pan-Nematoda Transcriptomic Elucidation of Essential Intestinal Functions and Therapeutic Targets With Broad Potential. AB - The nematode intestine is continuous with the outside environment, making it easily accessible to anthelmintics for parasite control, but the development of new therapeutics is impeded by limited knowledge of nematode intestinal cell biology. We established the most comprehensive nematode intestinal functional database to date by generating transcriptional data from the dissected intestines of three parasitic nematodes spanning the phylum, and integrating the results with the whole proteomes of 10 nematodes (including 9 pathogens of humans or animals) and 3 host species and 2 outgroup species. We resolved 10,772 predicted nematode intestinal protein families (IntFams), and studied their presence and absence within the different lineages (births and deaths) among nematodes. Conserved intestinal cell functions representing ancestral functions of evolutionary importance were delineated, and molecular features useful for selective therapeutic targeting were identified. Molecular patterns conserved among IntFam proteins demonstrated large potential as therapeutic targets to inhibit intestinal cell functions with broad applications towards treatment and control of parasitic nematodes. PMID- 26501107 TI - Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury. AB - Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a 'nutrient-sensitized' chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 +/- 0.06 mg/dl (sham, n = 3), 1.59 +/- 0.10 mg/dl (vehicle, n = 8) and 0.89 +/- 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo. PMID- 26501108 TI - Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma. AB - Infection with HIV ultimately leads to advanced immunodeficiency resulting in an increased incidence of cancer. For example primary effusion lymphoma (PEL) is an aggressive non-Hodgkin lymphoma with very poor prognosis that typically affects HIV infected individuals in advanced stages of immunodeficiency. Here we report on the dual anti-HIV and anti-PEL effect of targeting a single process common in both diseases. Inhibition of the exportin-1 (XPO1) mediated nuclear transport by clinical stage orally bioavailable small molecule inhibitors (SINE) prevented the nuclear export of the late intron-containing HIV RNA species and consequently potently suppressed viral replication. In contrast, in CRISPR-Cas9 genome edited cells expressing mutant C528S XPO1, viral replication was unaffected upon treatment, clearly demonstrating the anti-XPO1 mechanism of action. At the same time, SINE caused the nuclear accumulation of p53 tumor suppressor protein as well as inhibition of NF-kappaB activity in PEL cells resulting in cell cycle arrest and effective apoptosis induction. In vivo, oral administration arrested PEL tumor growth in engrafted mice. Our findings provide strong rationale for inhibiting XPO1 as an innovative strategy for the combined anti-retroviral and anti-neoplastic treatment of HIV and PEL and offer perspectives for the treatment of other AIDS-associated cancers and potentially other virus-related malignancies. PMID- 26501109 TI - Investigating Reports of Complex Regional Pain Syndrome: An Analysis of HPV-16/18 Adjuvanted Vaccine Post-Licensure Data. AB - Complex regional pain syndrome (CRPS) is a chronic pain disorder that typically follows trauma or surgery. Suspected CRPS reported after vaccination with human papillomavirus (HPV) vaccines led to temporary suspension of proactive recommendation of HPV vaccination in Japan. We investigated the potential CRPS signal in relation to HPV-16/18-adjuvanted vaccine (Cervarix(r)) by database review of CRPS cases with independent expert confirmation; a disproportionality analysis and analyses of temporality; an observed versus expected analysis using published background incidence rates; systematic reviews of aggregate safety data, and a literature review. The analysis included 17 case reports of CRPS: 10 from Japan (0.14/100,000 doses distributed) and seven from the United Kingdom (0.08/100,000). Five cases were considered by independent experts to be confirmed CRPS. Quantitative analyses did not suggest an association between CRPS and HPV 16/18-adjuvanted vaccine. Observed CRPS incidence after HPV-16/18 vaccination was statistically significantly below expected rates. Systematic database reviews using search terms varying in specificity and sensitivity did not identify new cases. No CRPS was reported during clinical development and no unexpected results found in the literature. There is not sufficient evidence to suggest an increased risk of developing CRPS following vaccination with HPV-16/18-adjuvanted vaccine. Post-licensure safety surveillance confirms the acceptable benefit-risk of HPV 16/18 vaccination. PMID- 26501110 TI - Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug. AB - The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models. PMID- 26501112 TI - Discovery of Genetic Variants of the Kinases That Activate Tenofovir in a Compartment-specific Manner. AB - Tenofovir (TFV) is used in combination with other antiretroviral drugs for human immunodeficiency virus (HIV) treatment and prevention. TFV requires two phosphorylation steps to become pharmacologically active; however, the kinases that activate TFV in cells and tissues susceptible to HIV infection have yet to be identified. Peripheral blood mononuclear cells (PBMC), vaginal, and colorectal tissues were transfected with siRNA targeting nucleotide kinases, incubated with TFV, and TFV-monophosphate (TFV-MP) and TFV-diphosphate (TFV-DP) were measured using mass spectrometry-liquid chromatography. Adenylate kinase 2 (AK2) performed the first TFV phosphorylation step in PBMC, vaginal, and colorectal tissues. Interestingly, both pyruvate kinase isozymes, muscle (PKM) or liver and red blood cell (PKLR), were able to phosphorylate TFV-MP to TFV-DP in PBMC and vaginal tissue, while creatine kinase, muscle (CKM) catalyzed this conversion in colorectal tissue. In addition, next-generation sequencing of the Microbicide Trials Network MTN-001 clinical samples detected 71 previously unreported genetic variants in the genes encoding these kinases. In conclusion, our results demonstrate that TFV is activated in a compartment-specific manner. Further, genetic variants have been identified that could negatively impact TFV activation, thereby compromising TFV efficacy in HIV treatment and prevention. PMID- 26501111 TI - Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study. AB - BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome. METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone. FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions. INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts. PMID- 26501113 TI - Host Protein Biomarkers Identify Active Tuberculosis in HIV Uninfected and Co infected Individuals. AB - Biomarkers for active tuberculosis (TB) are urgently needed to improve rapid TB diagnosis. The objective of this study was to identify serum protein expression changes associated with TB but not latent Mycobacterium tuberculosis infection (LTBI), uninfected states, or respiratory diseases other than TB (ORD). Serum samples from 209 HIV uninfected (HIV(-)) and co-infected (HIV(+)) individuals were studied. In the discovery phase samples were analyzed via liquid chromatography and mass spectrometry, and in the verification phase biologically independent samples were analyzed via a multiplex multiple reaction monitoring mass spectrometry (MRM-MS) assay. Compared to LTBI and ORD, host proteins were significantly differentially expressed in TB, and involved in the immune response, tissue repair, and lipid metabolism. Biomarker panels whose composition differed according to HIV status, and consisted of 8 host proteins in HIV(-) individuals (CD14, SEPP1, SELL, TNXB, LUM, PEPD, QSOX1, COMP, APOC1), or 10 host proteins in HIV(+) individuals (CD14, SEPP1, PGLYRP2, PFN1, VASN, CPN2, TAGLN2, IGFBP6), respectively, distinguished TB from ORD with excellent accuracy (AUC = 0.96 for HIV(-) TB, 0.95 for HIV(+) TB). These results warrant validation in larger studies but provide promise that host protein biomarkers could be the basis for a rapid, blood-based test for TB. PMID- 26501114 TI - Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure. AB - Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host-pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mechanism that promotes antibiotic resistance in vivo at concentrations of drug that far exceed dosages determined by standardized antimicrobial testing. This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells. Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance. This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies. PMID- 26501115 TI - Hidden Selection of Bacterial Resistance to Fluoroquinolones In Vivo: The Case of Legionella pneumophila and Humans. AB - BACKGROUND: Infectious diseases are the leading cause of human morbidity and mortality worldwide. One dramatic issue is the emergence of microbial resistance to antibiotics which is a major public health concern. Surprisingly however, such in vivo adaptive ability has not been reported yet for many intracellular human bacterial pathogens such as Legionella pneumophila. METHODS: We examined 82 unrelated patients with Legionnaire's disease from which 139 respiratory specimens were sampled during hospitalization and antibiotic therapy. We both developed a real time PCR assay and used deep-sequencing approaches to detect antibiotic resistance mutations in L. pneumophila and follow their selection and fate in these samples. FINDINGS: We identified the in vivo selection of fluoroquinolone resistance mutations in L. pneumophila in two infected patients treated with these antibiotics. By investigating the mutational dynamics in patients, we showed that antibiotic resistance occurred during hospitalization most likely after fluoroquinolone treatment. INTERPRETATION: In vivo selection of antibiotic resistances in L. pneumophila may be associated with treatment failures and poor prognosis. This hidden resistance must be carefully considered in the therapeutic management of legionellosis patients and in the control of the gradual loss of effectiveness of antibiotics. PMID- 26501116 TI - Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon. AB - BACKGROUND: The quartan malaria parasite Plasmodium malariae is the widest spread and best adapted human malaria parasite. The simian Plasmodium brasilianum causes quartan fever in New World monkeys and resembles P. malariae morphologically. Since the genetics of the two parasites are nearly identical, differing only in a range of mutations expected within a species, it has long been speculated that the two are the same. However, no naturally acquired infection with parasites termed as P. brasilianum has been found in humans until now. METHODS: We investigated malaria cases from remote Yanomami indigenous communities of the Venezuelan Amazon and analyzed the genes coding for the circumsporozoite protein (CSP) and the small subunit of ribosomes (18S) by species-specific PCR and capillary based-DNA sequencing. FINDINGS: Based on 18S rRNA gene sequencing, we identified 12 patients harboring malaria parasites which were 100% identical with P. brasilianum isolated from the monkey, Alouatta seniculus. Translated amino acid sequences of the CS protein gene showed identical immunodominant repeat units between quartan malaria parasites isolated from both humans and monkeys. INTERPRETATION: This study reports, for the first time, naturally acquired infections in humans with parasites termed as P. brasilianum. We conclude that quartan malaria parasites are easily exchanged between humans and monkeys in Latin America. We hypothesize a lack of host specificity in mammalian hosts and consider quartan malaria to be a true anthropozoonosis. Since the name P. brasilianum suggests a malaria species distinct from P. malariae, we propose that P. brasilianum should have a nomenclatorial revision in case further research confirms our findings. The expansive reservoir of mammalian hosts discriminates quartan malaria from other Plasmodium spp. and requires particular research efforts. PMID- 26501117 TI - Mapping pneumonia research: A systematic analysis of UK investments and published outputs 1997-2013. AB - BACKGROUND: The burden of pneumonia continues to be substantial, particularly among the poorest in global society. We describe here the trends for UK pneumonia R&D investment and published outputs, and correlate with 2013 global mortality. METHODS: Data related to awards to UK institutions for pneumonia research from 1997 to 2013 were systematically sourced and categorised by disease area and type of science. Investment was compared to mortality figures in 2010 and 2013 for pneumonia, tuberculosis and influenza. Investment was also compared to publication data. RESULTS: Of all infectious disease research between 2011 and 2013 (L917.0 million), L28.8 million (3.1%) was for pneumonia. This was an absolute and proportionate increase from previous time periods. Translational pneumonia research (33.3%) received increased funding compared with 1997-2010 where funding was almost entirely preclinical (87.5%, here 30.9%), but high burden areas such as paediatrics, elderly care and antimicrobial resistance received little investment. Annual investment remains volatile; publication temporal trends show a consistent increase. When comparing investment to global burden with a novel 'investment by mortality observed' metric, tuberculosis (L48.36) and influenza (L484.21) receive relatively more funding than pneumonia (L43.08), despite investment for pneumonia greatly increasing in 2013 compared to 2010 (L7.39). Limitations include a lack of private sector data and the need for careful interpretation of the comparisons with burden, plus categorisation is subjective. CONCLUSIONS: There has been a welcome increase for pneumonia funding awarded to UK institutions in 2011-2013 compared with 1997-2010, along with increases for more translational research. Published outputs relating to pneumonia rose steadily from 1997 to 2013. Investment relative to mortality for pneumonia has increased, but it remains low compared to other respiratory infections and clear inequities remain. Analyses that measure investments in pneumonia can provide an insight into funding trends and research gaps. RESEARCH IN CONTEXT: Pneumonia continues to be a high-burden illness around the globe. This paper shows that although research funding is increasing in the UK (between 1997 and 2013), it remains poorly funded compared to other important respiratory infectious diseases such as tuberculosis and influenza. Publications about pneumonia have been steadily increasing over time, indicating continuing academic and clinical interest in the topic. Though global mortality of pneumonia is declining, it should still be an area of high priority for funders, policymakers and researchers. PMID- 26501119 TI - Prevention of Primary Cytomegalovirus Infection in Pregnancy. AB - BACKGROUND: Cytomegalovirus (CMV) is the leading infectious agent causing congenital sensorineural hearing loss and psychomotor retardation. CMV vaccine is currently unavailable and treatment options in pregnancy are limited. Susceptible pregnant women caring for children are at high risk for primary infection. CMV educational and hygienic measures have the potential to prevent primary maternal infection. METHODS: A mixed interventional and observational controlled study was conducted to investigate the effectiveness of hygiene information among pregnant women at risk for primary CMV infection for personal/occupational reasons. In the intervention arm, CMV-seronegative women, identified at the time of maternal serum screening for fetal aneuploidy at 11-12 weeks of gestation, were given hygiene information and prospectively tested for CMV until delivery. The comparison arm consisted of women enrolled at delivery who were neither tested for nor informed about CMV during pregnancy, and who had a serum sample stored at the screening for fetal aneuploidy. By design, groups were homogeneous for age, parity, education, and exposure to at least one risk factor. The primary outcome was CMV seroconversion. Acceptance of hygiene recommendations was a secondary objective and was measured by a self-report. FINDINGS: Four out of 331 (1.2%) women seroconverted in the intervention group compared to 24/315 (7.6%) in the comparison group (delta = 6.4%; 95% CI 3.2-9.6; P < 0.001). There were 3 newborns with congenital infection in the intervention group and 8 in the comparison group (1 with cerebral ultrasound abnormalities at birth). Ninety-three percent of women felt hygiene recommendations were worth suggesting to all pregnant women at risk for infection. INTERPRETATION: This controlled study provides evidence that an intervention based on the identification and hygiene counseling of CMV seronegative pregnant women significantly prevents maternal infection. While waiting for CMV vaccine to become available, the intervention described may represent a responsible and acceptable primary prevention strategy to reduce congenital CMV. PMID- 26501105 TI - The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study. AB - BACKGROUND: Although statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients. METHODS: This is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints. FINDING: Although 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 +/- 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events. INTERPRETATION: Although whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis. FUNDING: This study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation. PMID- 26501120 TI - Reporting of Cardiovascular Medical Device Adverse Events to Pharmaceuticals and Medical Devices Agency, Japan. AB - BACKGROUND: Marketing authorization holders (MAHs) are obligated to report adverse events (AEs) within 15 days (some cases 30 days) to the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan. METHODS: To analyze the timeliness of AE reporting to the PMDA, 6610 reports for five categories of cardiovascular devices were retrieved. Two durations were calculated: (1) time from the date the AE occurred to that when the MAH captured it (DOC: days); and (2) time from the date of MAH capture to that of MAH report (DCR: days). Number of DOC > 15 days (DOC15) and delayed reports (DCR > 15 or 30 days) were also calculated. RESULTS: AEs included 9.2% deaths and 7.5% non-recoveries. DOC15 and delayed reports were 51.0% and 10.9%, respectively. By multivariate analysis, DOC15 was associated with foreign AE, device category, MAH, patient outcome, event category, and AE that had to be reported within 15 or 30 days (AE15/30). Delayed report was associated with device category, MAH, patient outcome, event category, and AE15/30. COMMENTS: Although Japanese MAHs complied with the obligation to report AEs, they often failed to share AEs with healthcare providers. Registry may be a potential solution, although the cooperation of healthcare providers to input data is essential. PMID- 26501118 TI - The Helicobacter Eradication Aspirin Trial (HEAT): A Large Simple Randomised Controlled Trial Using Novel Methodology in Primary Care. AB - BACKGROUND: Clinical trials measuring the effect of an intervention on clinical outcomes are more influential than those investigating surrogate measures but are costly. We developed methods to reduce costs substantially by using existing data in primary care systems, to ask whether Helicobacter pylori eradication would reduce the incidence of hospitalisation for ulcer bleeding in aspirin users. METHODS: The Helicobacter Eradication Aspirin Trial (HEAT) is a National Institute of Health Research-funded, double-blind placebo controlled randomised trial of the effects of H. pylori eradication on subsequent ulcer bleeding in infected individuals taking aspirin daily, conducted in practices across the whole of England, Wales and Northern Ireland. A bespoke web-based trial management system developed for the trial (and housed within the secure NHS Data Network) communicates directly with the HEAT Toolkit software downloaded at participating practices, which issues queries searching entry criteria (>= 60 years, on chronic aspirin <= 325 mg daily, not on anti-ulcer therapy or non steroidal anti-inflammatory drugs) for GP review of eligibility. Trial participation is invited using a highly secure automated online mail management system. Interested patients are seen once for consent and breath testing. Those with a positive test are randomised to eradication treatment (lansoprazole, clarithromycin, metronidazole) or placebo, with drug sent by post. Events are tracked by upload of accumulating information in the GP database, patient contact, review of National Hospital Episode Statistics and Office of National Statistics data. RESULTS: HEAT is the largest Clinical Research Network-supported drug trial, with 115,660 invitation letters sent from 850 practices, 22,922 volunteers, and 3038 H. pylori positive patients randomised to active or placebo treatment after 2.5 years of recruitment. 178 practices have performed their first follow-up data search to identify 21 potential endpoints to date. DISCUSSION: HEAT is important medically, because aspirin is so widely used, and methodologically, as a successful trial would show that large-scale studies of important clinical outcomes can be conducted at a fraction of the cost of those conducted by industry, which in turn will help to ensure that trials of primarily medical rather than commercial interest can be conducted successfully in the UK. PMID- 26501121 TI - Continuous Postoperative Pericardial Flushing: A Pilot Study on Safety, Feasibility, and Effect on Blood Loss. AB - BACKGROUND: Prolonged or excessive blood loss is a common complication after cardiac surgery. Blood remnants and clots, remaining in the pericardial space in spite of chest tube drainage, induce high fibrinolytic activity that may contribute to bleeding complications. Continuous postoperative pericardial flushing (CPPF) with an irrigation solution may reduce blood loss by preventing the accumulation of clots. In this pilot study, the safety and feasibility of CPPF were evaluated and the effect on blood loss and other related complications was investigated. METHODS: Between November 2011 and April 2012 twenty-one adult patients undergoing surgery for congenital heart disease (CHD) received CPPF from sternal closure up to 12 h postoperative. With an inflow Redivac drain that was inserted through one of the chest tube incision holes, an irrigation solution (NaCl 0.9% at 38 degrees C) was delivered to the pericardial cavity using a volume controlled flushing system. Safety aspects, feasibility issues and complications were registered. The mean actual blood loss in the CPPF group was compared to the mean of a retrospective group (n = 126). RESULTS: CPPF was successfully completed in 20 (95.2%) patients, and no method related complications were observed. Feasibility was good in this experimental setting. Patients receiving CPPF showed a 30% (P = 0.038) decrease in mean actual blood loss 12 h postoperatively. CONCLUSIONS: CPPF after cardiac surgery was found to be safe and feasible in this experimental setting. The clinically relevant effect on blood loss needs to be confirmed in a randomized clinical trial. PMID- 26501122 TI - Do We Know Why We Make Errors in Morphological Diagnosis? An Analysis of Approach and Decision-Making in Haematological Morphology. AB - BACKGROUND: The laboratory interpretation of blood film morphology is frequently a rapid, accurate, and cost-effective final-stage of blood count analysis. However, the interpretation of findings often rests with a single individual, and errors can carry significant impact. Cell identification and classification skills are well supported by existing resources, but the contribution and importance of other skills are less well understood. METHODS: The UK external quality assurance group in haematology (UK NEQAS(H)) runs a Continued Professional Development scheme where large digital-images of abnormal blood smears are presented using a web-based virtual microscope. Each case is answered by more than 800 individuals. Morphological feature selection and prioritisation, as well as diagnosis and proposed action, are recorded. We analysed the responses of participants, aiming to identify successful strategies as well as sources of error. FINDINGS: The approach to assessment by participants depended on the affected cell type, case complexity or skills of the morphologist. For cases with few morphological abnormalities, we found that accurate cell identification and classification were the principle requirements for success. For more complex films however, feature recognition and prioritisation had primary importance. Additionally however, we found that participants employed a range of heuristic techniques to support their assessment, leading to associated bias and error. INTERPRETATION: A wide range of skills together allow successful morphological assessment and the complexity of this process is not always understood or recognised. Heuristic techniques are widely employed to support or reinforce primary observations and to simplify complex findings. These approaches are effective and are integral to assessment; however they may also be a source of bias or error. Improving outcomes and supporting diagnosis require the development of decision-support mechanisms that identify and support the benefits of heuristic strategies while identifying or avoiding associated biases. FUNDING: The CPD scheme is funded by participant subscription. PMID- 26501123 TI - Lessons of War: Turning Data Into Decisions. AB - BACKGROUND: Recent conflicts in Afghanistan and Iraq produced a substantial number of critically wounded service-members. We collected biomarker and clinical information from 73 patients who sustained 116 life-threatening combat wounds, and sought to determine if the data could be used to predict the likelihood of wound failure. METHODS: From each patient, we collected clinical information, serum, wound effluent, and tissue prior to and at each surgical debridement. Inflammatory cytokines were quantified in both the serum and effluent, as were gene expression targets. The primary outcome was successful wound healing. Computer intensive methods were used to derive prognostic models that were internally validated using target shuffling and cross-validation methods. A second cohort of eighteen critically injured civilian patients was evaluated to determine if similar inflammatory responses were observed. FINDINGS: The best performing models enhanced clinical observation with biomarker data from the serum and wound effluent, an indicator that systemic inflammatory conditions contribute to local wound failure. A Random Forest model containing ten variables demonstrated the highest accuracy (AUC 0.79). Decision Curve Analysis indicated that the use of this model would improve clinical outcomes and reduce unnecessary surgical procedures. Civilian trauma patients demonstrated similar inflammatory responses and an equivalent wound failure rate, indicating that the model may be generalizable to civilian settings. INTERPRETATION: Using advanced analytics, we successfully codified clinical and biomarker data from combat patients into a potentially generalizable decision support tool. Analysis of inflammatory data from critically ill patients with acute injury may inform decision-making to improve clinical outcomes and reduce healthcare costs. FUNDING: United States Department of Defense Health Programs. PMID- 26501125 TI - Telephone Consultation as a Substitute for Routine Out-patient Face-to-face Consultation for Children With Inflammatory Bowel Disease: Randomised Controlled Trial and Economic Evaluation. AB - BACKGROUND: Evidence for the use of telephone consultation in childhood inflammatory bowel disease (IBD) is lacking. We aimed to assess the effectiveness and cost consequences of telephone consultation compared with the usual out patient face-to-face consultation for young people with IBD. METHODS: We conducted a randomised-controlled trial in Manchester, UK, between July 12, 2010 and June 30, 2013. Young people (aged 8-16 years) with IBD were randomized to receive telephone consultation or face-to-face consultation for 24 months. The primary outcome measure was the paediatric IBD-specific IMPACT quality of life (QOL) score at 12 months. Secondary outcome measures included patient satisfaction with consultations, disease course, anthropometric measures, proportion of consultations attended, duration of consultations, and costs to the UK National Health Service (NHS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02319798. FINDINGS: Eighty six patients were randomised to receive either telephone consultation (n = 44) or face-to-face consultation (n = 42). Baseline characteristics of the two groups were well balanced. At 12 months, there was no evidence of difference in QOL scores (estimated treatment effect in favour of the telephone consultation group was 5.7 points, 95% CI - 2.9 to 14.3; p = 0.19). Mean consultation times were 9.8 min (IQR 8 to 12.3) for telephone consultation, and 14.3 min (11.6 to 17.0) for face-to-face consultation with an estimated reduction (95% CI) of 4.3 (2.8 to 5.7) min in consultation times (p < 0.001). Telephone consultation had a mean cost of UKL35.41 per patient consultation compared with L51.12 for face-face consultation, difference L15.71 (95% CI 11.8-19.6; P < 0.001). INTERPRETATION: We found no suggestion of inferiority of telephone consultation compared with face to-face consultation with regard to improvements in QOL scores, and telephone consultation reduced consultation time and NHS costs. Telephone consultation is a cost-effective alternative to face-to-face consultation for the routine outpatient follow-up of children and adolescents with IBD. FUNDING: Research for Patient Benefit Programme, UK National Institute for Health Research. PMID- 26501124 TI - Volatile Biomarkers in Breath Associated With Liver Cirrhosis - Comparisons of Pre- and Post-liver Transplant Breath Samples. AB - BACKGROUND: The burden of liver disease in the UK has risen dramatically and there is a need for improved diagnostics. AIMS: To determine which breath volatiles are associated with the cirrhotic liver and hence diagnostically useful. METHODS: A two-stage biomarker discovery procedure was used. Alveolar breath samples of 31 patients with cirrhosis and 30 healthy controls were mass spectrometrically analysed and compared (stage 1). 12 of these patients had their breath analysed after liver transplant (stage 2). Five patients were followed longitudinally as in-patients in the post-transplant period. RESULTS: Seven volatiles were elevated in the breath of patients versus controls. Of these, five showed statistically significant decrease post-transplant: limonene, methanol, 2 pentanone, 2-butanone and carbon disulfide. On an individual basis limonene has the best diagnostic capability (the area under a receiver operating characteristic curve (AUROC) is 0.91), but this is improved by combining methanol, 2-pentanone and limonene (AUROC curve 0.95). Following transplant, limonene shows wash-out characteristics. CONCLUSIONS: Limonene, methanol and 2 pentanone are breath markers for a cirrhotic liver. This study raises the potential to investigate these volatiles as markers for early-stage liver disease. By monitoring the wash-out of limonene following transplant, graft liver function can be non-invasively assessed. PMID- 26501126 TI - Nanoporous Superhydrophobic Coatings that Promote the Extended Release of Water Labile Quorum Sensing Inhibitors and Enable Long-Term Modulation of Quorum Sensing in Staphylococcus aureus. AB - Materials and coatings that inhibit bacterial colonization are of interest in a broad range of biomedical, environmental, and industrial applications. In view of the rapid increase in bacterial resistance to conventional antibiotics, the development of new strategies that target nonessential pathways in bacterial pathogens-and that thereby limit growth and reduce virulence through nonbiocidal means-has attracted considerable attention. Bacterial quorum sensing (QS) represents one such target, and is intimately connected to virulence in many human pathogens. Here, we demonstrate that the properties of nanoporous, polymer based superhydrophobic coatings can be exploited to host and subsequently sustain the extended release of potent and water-labile peptide-based inhibitors of QS (QSIs) in Staphylococcus aureus. Our results demonstrate that these peptidic QSIs can be released into surrounding media for periods of at least 8 months, and that they strongly inhibit agr-based QS in S. aureus for at least 40 days. These results also suggest that these extremely nonwetting coatings can confer protection against the rapid hydrolysis of these water-labile peptides, thereby extending their useful lifetimes. Finally, we demonstrate that these peptide loaded superhydrophobic coatings can strongly modulate the QS-controlled formation of biofilm in wild-type S. aureus. These nanoporous superhydrophobic films provide a new, useful, and nonbiocidal approach to the design of coatings that attenuate bacterial virulence. This approach has the potential to be general, and could prove suitable for the encapsulation, protection, and release of other classes of water-sensitive agents. We anticipate that the materials, strategies, and concepts reported here will enable new approaches to the long term attenuation of QS and associated bacterial phenotypes in a range of basic research and applied contexts. PMID- 26501127 TI - Functionalizing Soft Matter for Molecular Communication. AB - The information age was enabled by advances in microfabrication and communication theory that allowed information to be processed by electrons and transmitted by electromagnetic radiation. Despite immense capabilities, microelectronics has limited abilities to access and participate in the molecular-based communication that characterizes our biological world. Here, we use biological materials and methods to create components and fabricate devices to perform simple molecular communication functions based on bacterial quorum sensing (QS). Components were created by protein engineering to generate a multidomain fusion protein capable of sending a molecular QS signal, and by synthetic biology to engineer E. coli to receive and report this QS signal. The device matrix was formed using stimuli responsive hydrogel-forming biopolymers (alginate and gelatin). Assembly of the components within the device matrix was achieved by physically entrapping the cell-based components, and covalently conjugating the protein-based components using the enzyme microbial transglutaminase. We demonstrate simple devices that can send or receive a molecular QS signal to/from the surrounding medium, and a two-component device in which one component generates the signal (i.e., issues a command) that is acted upon by the second component. These studies illustrate the broad potential of biofabrication to generate molecular communication devices. PMID- 26501128 TI - Robotic Surgery: Applications. PMID- 26501129 TI - An Adaptive Difference Distribution-based Coding with Hierarchical Tree Structure for DNA Sequence Compression. AB - Previous reference-based compression on DNA sequences do not fully exploit the intrinsic statistics by merely concerning the approximate matches. In this paper, an adaptive difference distribution-based coding framework is proposed by the fragments of nucleotides with a hierarchical tree structure. To keep the distribution of difference sequence from the reference and target sequences concentrated, the sub-fragment size and matching offset for predicting are flexible to the stepped size structure. The matching with approximate repeats in reference will be imposed with the Hamming-like weighted distance measure function in a local region closed to the current fragment, such that the accuracy of matching and the overhead of describing matching offset can be balanced. A well-designed coding scheme will make compact both the difference sequence and the additional parameters, e.g. sub-fragment size and matching offset. Experimental results show that the proposed scheme achieves 150% compression improvement in comparison with the best reference-based compressor GReEn. PMID- 26501131 TI - Inflammation as a Mediator of the Association Between Race and Atrial Fibrillation: Results from the Health, Aging, and Body Composition Study. AB - BACKGROUND: Despite a lower prevalence of established atrial fibrillation (AF) risk factors, Whites exhibit substantially higher rates of this arrhythmia compared to Blacks. The mechanism underlying this observation is not known. Both inflammation and obesity are risk factors for AF, and adipose tissue is a known contributor to systemic inflammation. OBJECTIVES: We sought to determine the degree to which racial differences in AF risk are explained by differences in inflammation and adiposity. METHODS: Baseline serum inflammatory biomarker concentrations and abdominal adiposity (assessed by computed tomography) were quantified in a subset of Black and White participants without prevalent AF in the Health, Aging, and Body Composition (Health ABC) Study. Participants were prospectively followed for the diagnosis of AF using study ECGs and Medicare claims data. Cox proportional hazards models were used to determine the adjusted relative hazard of incident AF between races before and after biomarker adjustment. RESULTS: Among 2,768 participants (43% Black), 721 developed incident AF over a median follow up of 10.9 years. White race was associated with a heightened adjusted risk of incident AF (HR 1.55, 95% CI 1.30 to 1.84, p < 0.001). Abdominal adiposity was not associated with AF when added to the adjusted model. Among the studied biomarkers, adiponectin, TNF-alpha, TNF-alpha SR I, and TNF-alpha SR II concentrations were each higher among Whites and independently associated with a greater risk of incident AF. Together, these inflammatory cytokines mediated 42% (95% CI 15 to 119%, p = 0.004) of the adjusted race-AF association. CONCLUSIONS: Systemic inflammatory pathways significantly mediate the heightened risk of AF among Whites. The higher level of systemic inflammation and concomitant increased AF risk in Whites is not explained by racial differences in abdominal adiposity or the presence of other pro-inflammatory cardiovascular comorbidities. PMID- 26501130 TI - Mini-ISES identifies promising carbafructopyranose-based salens for asymmetric catalysis: Tuning ligand shape via the anomeric effect. AB - This study introduces new methods of screening for and tuning chiral space and in so doing identifies a promising set of chiral ligands for asymmetric synthesis. The carbafructopyranosyl-1,2-diamine(s) and salens constructed therefrom are particularly compelling. It is shown that by removing the native anomeric effect in this ligand family, one can tune chiral ligand shape and improve chiral bias. This concept is demonstrated by a combination of (i) x-ray crystallographic structure determination, (ii) assessment of catalytic performance, and (iii) consideration of the anomeric effect and its underlying dipolar basis. The title ligands were identified by a new mini version of the in situ enzymatic screening (ISES) procedure through which catalyst-ligand combinations are screened in parallel, and information on relative rate and enantioselectivity is obtained in real time, without the need to quench reactions or draw aliquots. Mini-ISES brings the technique into the nanomole regime (200 to 350 nmol catalyst/20 MUml organic volume) commensurate with emerging trends in reaction development/process chemistry. The best-performing beta-d-carbafructopyranosyl-1,2-diamine-derived salen ligand discovered here outperforms the best known organometallic and enzymatic catalysts for the hydrolytic kinetic resolution of 3-phenylpropylene oxide, one of several substrates examined for which the ligand is "matched." This ligand scaffold defines a new swath of chiral space, and anomeric effect tunability defines a new concept in shaping that chiral space. Both this ligand set and the anomeric shape-tuning concept are expected to find broad application, given the value of chiral 1,2-diamines and salens constructed from these in asymmetric catalysis. PMID- 26501132 TI - Using Machine Learning to Identify Benign Cases with Non-Definitive Biopsy. AB - When mammography reveals a suspicious finding, a core needle biopsy is usually recommended. In 5% to 15% of these cases, the biopsy diagnosis is non-definitive and a more invasive surgical excisional biopsy is recommended to confirm a diagnosis. The majority of these cases will ultimately be proven benign. The use of excisional biopsy for diagnosis negatively impacts patient quality of life and increases costs to the healthcare system. In this work, we employ a multi relational machine learning approach to predict when a patient with a non definitive core needle biopsy diagnosis need not undergo an excisional biopsy procedure because the risk of malignancy is low. PMID- 26501133 TI - Multi-scale and Multimodal Fusion of Tract-tracing, Myelin Stain and DTI-derived Fibers in Macaque Brains. AB - Assessment of structural connectivity patterns of brains can be an important avenue for better understanding mechanisms of structural and functional brain architectures. Therefore, many efforts have been made to estimate and validate axonal pathways via a number of techniques, such as myelin stain, tract-tracing and diffusion MRI (dMRI). The three modalities have their own advantages and are complimentary to each other. From myelin stain data, we can infer rich in-plane information of axonal orientation at micro-scale. Tract-tracing data is considered as 'gold standard' to estimate trustworthy meso-scale pathways. dMRI currently is the only way to estimate global macro-scale pathways given further validation. We propose a framework to take advantage of these three modalities. Information of the three modalities is integrated to determine the optimal tractography parameters for dMRI fibers and identify cross-validated fiber bundles that are finally used to construct atlas. We demonstrate the effectiveness of the framework by a collection of experimental results. PMID- 26501134 TI - Common airborne fungi induce species-specific effects on upper airway inflammatory and remodelling responses. AB - OBJECTIVE: Whilst the exact cause of chronic rhinosinusitis (CRS) remains elusive, it is clear that both inflammation and remodelling are key disease processes. Environmental fungi have been linked to airway inflammation in CRS; however, their role in the pathogenesis of this condition remains controversial. The current consensus suggests that whilst fungi may not be directly causative, it is likely that CRS patients have deficits in their innate and potentially acquired immunity, which in turn may modify their ability to react to fungi. This study used a nasal polyp explant tissue stimulation model to study the inflammatory and remodelling responses related to challenge with common airborne fungal species. METHODS: Ex vivo nasal polyp tissue from six well phenotyped CRSwNP patients undergoing functional endoscopic sinus surgery was stimulated with 1, 10 and 100 MUg/ml of Alternaria alternata, Aspergillus niger, Cladosporium sphaerospermum and Penicillium notatum and compared with unchallenged polyp tissue as control. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of pro-inflammatory cytokines interleukin-6 (IL 6), granulocyte macrophage colony stimulating factor (GM-CSF) and tumour necrosis factor-alpha (TNF-alpha); and pro-remodelling cytokines transforming growth factor-b1 (TGF-b1), and basic fibroblast growth factor (bFGF) in the polyp supernatant. RESULTS: Aspergillus niger stimulation increased pro-inflammatory cytokines TNF-alpha, GM-CSF and IL-6 whilst having little effect on the remodelling cytokines bFGF and TGF-b1. In contrast, stimulation with Cladosporium sphaerospermum, Alternaria alternata and Penicillium notatum reduced pro inflammatory cytokines TNF-alpha and IL-6, but induced a dose-dependent increase in remodelling cytokines TGF-b1 and bFGF. CONCLUSIONS: This study shows that common airborne fungi induce species-specific effects on the upper airway inflammatory and remodelling responses. These findings provide further immunological evidence of a disease-modifying role for fungi in CRS. PMID- 26501135 TI - The microbiome of the maxillary sinus and middle nasal meatus in chronic rhinosinusitis. AB - AIM: This multicenter study was focused on the identification of the microorganisms inhabiting the maxillary sinus and middle nasal meatus in chronic rhinosinusitis. METHODOLOGY: 112 middle meatus swabs and 112 maxillary sinus aspirates from 103 patients were available for culture. RESULTS: A total of 244 strains of microorganisms representing more than 50 families were identified in the maxillary sinus and middle nasal meatus (164 and 80, respectively). These included 154 (63.0%) strains of aerobic bacteria from 32 species and 90 (37.0%) strains of anaerobic bacteria from 23 species. Aerobes were more common than anaerobes in both the nasal cavity (78.7% vs. 21.3%) and in the maxillary sinus (55.2% vs. 44.8%). Species of Streptococci (28.8%) and Prevotella (17.8%) were the most common findings in the maxillary sinus aspirates. S. pneumonia, H. influenza, and S. aureus were relatively rare, and found in only 6.7%, 5.4%, and 8.9% of the samples, respectively. CONCLUSIONS: The results obtained suggest that common upper airway pathogens do not play a major role in the pathogenesis of chronic rhinosinusitis. The microbiome of inflamed sinonasal mucosa is extremely diverse and involves exotic species of bacteria that, to date, have not been considered as potential inhabitants of the paranasal sinuses. PMID- 26501136 TI - Can mid-infrared biomedical spectroscopy of cells, fluids and tissue aid improvements in cancer survival? A patient paradigm. AB - This review will take a fresh approach from the patient perspective; offering insight into the applications of mid-infrared biomedical spectroscopy in a scenario whereby the patient presents with non-specific symptoms and via an extensive diagnostic process multiple lesions are discovered but no clear sign of the primary tumour; a condition known as cancer of unknown primary (CUP). With very limited options to diagnose the cancer origin, treatment options are likely to be ineffective and prognosis is consequentially very poor. CUP has not yet been targeted by infrared biospectroscopy, however, this timely, concise dissemination will focus on a series of research highlights and breakthroughs from the field for the management of a variety of cancer-related diseases - many examples of which have occurred within this year alone. The case for integration of mid-infrared (MIR) technology into clinical practice will be demonstrated largely via diagnostic, but also therapeutic and prognostic avenues by means of including cytological, bio-fluid and tissue analysis. The review is structured around CUP but is relevant for all cancer diagnoses. Infrared spectroscopy is fast developing a reputation as a valid and powerful tool for the detection and diagnosis of cancer using a variety of sample formats. The technology will produce data and tools that are designed to complement routine clinical practice; enhancing the ability of the clinician to make a reliable and non-subjective decision and enabling decreased levels of mortality and morbidity and gains in patient quality of life. PMID- 26501137 TI - Sensitive electrochemical detection of copper ions based on the copper(II) ion assisted etching of Au@Ag nanoparticles. AB - A new sensitive electrochemical sensor for the detection of copper ions based on the copper ion assisted etching of Au@Ag nanoparticles was developed in this work. Since copper ions could greatly catalyze the etching process of the silver shell of Au@Ag nanoparticles in the presence of thiosulfate solutions, leading to an obvious decrease of the linear sweep voltammetry (LSV) signals of silver, the concentration of the copper ions, therefore, can be measured. Under the optimized conditions, the electrochemical sensor exhibited excellent sensitivity and selectivity for Cu(2+), with wide linear ranges of 1 nM to 100 MUM, and the detection limit of 0.3 nM. In addition, this method was successfully applied for the analysis of Cu(2+) in river water and exhibited good analytical performance. PMID- 26501138 TI - Electronic vs. structural ordering in a manganese(III) spin crossover complex. AB - A symmetry breaking spin transition in a Mn(III) complex is reported with three structural phases, a high symmetry high temperature S = 2 phase, an intermediate S = 1/S = 2 ordered phase and an aperiodic low temperature phase with S = 1 cations. The aperiodicity is interpreted as resulting from long-range ordering of the NTf2(-) anions. PMID- 26501139 TI - miR-221 Promotes Epithelial-Mesenchymal Transition through Targeting PTEN and Forms a Positive Feedback Loop with beta-catenin/c-Jun Signaling Pathway in Extra Hepatic Cholangiocarcinoma. AB - Extrahepatic cholangiocarcinoma (EHCC) is a refractory malignancy with poor prognosis due to its early invasion, metastasis and recurrence after operation. Therefore, understanding the mechanisms of invasion and metastasis is the key to the development of new and effective therapeutic strategies for EHCC. In the present study we demonstrated that miR-221 promoted EHCC invasion and metastasis through targeting PTEN and formed a positive feedback loop with beta-catenin/c Jun signaling pathway. We found miR-221 was upregulated in EHCC specimens and CC cell lines. Moreover, miR-221 was found strongly associated with the metastasis and prognosis of EHCC patients. The expression of PTEN was downregulated in EHCC patients and CC cell lines, and was further demonstrated as one of the downstream targets of miR-221. In addition, our data indicated that beta-catenin activated miR-221 through c-jun, while miR-221 enhanced beta-catenin signaling induced epithelial-mesenchymal transition (EMT) by targeting PTEN, hence forming a positive feedback loop in EHCC cell lines. In conclusion, our results suggested that miR-221 promotes EMT through targeting PTEN and forms a positive feedback loop with beta-catenin/c-Jun signaling pathway in EHCC. PMID- 26501140 TI - [Approval procedures for clinical trials in the field of radiation oncology]. AB - BACKGROUND AND PURPOSE: Application of ionizing radiation for the purpose of medical research in Germany needs to be approved by the national authority for radiation protection (Bundesamt fur Strahlenschutz, BfS). For studies in the field of radiation oncology, differentiation between use of radiation for "medical care (Heilkunde)" versus "medical research" frequently leads to contradictions. The aim of this article is to provide principle investigators, individuals, and institutions involved in the process, as well as institutional review or ethics committees, with the necessary information for this assessment. Information on the legal frame and the approval procedures are also provided. METHODS: A workshop was co-organized by the German Society for Radiation Oncology (DEGRO), the Working Party for Radiation Oncology (ARO) of the German Cancer Society (DKG), the German Society for Medical Physics (DGMP), and the German Cancer Consortium (DKTK) in October 2013. This paper summarizes the results of the workshop and the follow-up discussions between the organizers and the BfS. RESULTS: Differentiating between "Heilkunde" which does not need to be approved by the BfS and "medical research" is whether the specific application of radiation (beam quality, dose, schedule, target volume, etc.) is a clinically established and recognized procedure. This must be answered by the qualified physician(s) ("fachkundiger Arzt" according to German radiation protection law) in charge of the study and the treatments of the patients within the study, taking into consideration of the best available evidence from clinical studies, guidelines and consensus papers. Among the important parameters for assessment are indication, total dose, and fractionation. Radiation treatments applied outside clinical trials do not require approval by the BfS, even if they are applied within a randomized or nonrandomized clinical trial. The decision-making by the "fachkundigem Arzt" may be supported on request by an opinion given by the DEGRO Expert Committee for clinical trials. CONCLUSION: An important aim for promoting clinical research and patient care in radiation oncology is to further professionalize planning and implementation of clinical trials in this field. Correct assessment, at an early stage, whether a trial needs to be approved by the BfS may reduce unnecessary costs and reduce the time needed for the approval procedure for those trials which need to be assessed by the BfS. PMID- 26501141 TI - Temporal changes in tumor oxygenation and perfusion upon normo- and hyperbaric inspiratory hyperoxia. AB - BACKGROUND: Inspiratory hyperoxia under hyperbaric conditions has been shown to effectively reduce tumor hypoxia and to improve radiosensitivity. However, applying irradiation (RT) under hyperbaric conditions is technically difficult in the clinical setting since RT after decompression may be effective only if tumor pO2 remains elevated for a certain period of time. The aim of the present study was to analyze the time course of tumor oxygenation and perfusion during and after hyperbaric hyperoxia. MATERIALS AND METHODS: Tumor oxygenation, red blood cell (RBC) flux for perfusion monitoring, and vascular resistance were assessed continuously in experimental rat DS-sarcomas by polarographic catheter electrodes and laser Doppler flowmetry at 1 and 2 atm (bar) of environmental pressure during breathing of pure O2 or carbogen (95 % O2 + 5 % CO2). RESULTS: During room air breathing, the tumor pO2 followed very rapidly within a few minutes the change of the ambient pressure during compression or decompression. With O2 breathing under hyperbaric conditions, the tumor pO2 increased more than expected based on the rise of the environmental pressure, although the time course was comparably rapid. Breathing carbogen, the tumor pO2 followed with a slight delay of the pressure change, and within 10 min after decompression the baseline values were reached again. RBC flux increased during carbogen breathing but remained almost constant with pure O2, indicating a vasodilation (decrease in vascular resistance) with carbogen but a vasoconstriction (increase in vascular resistance) with O2 during hyperbaric conditions. CONCLUSION: Since the tumor pO2 directly followed the environmental pressure, teletherapy after hyperbaric conditions does not seem to be promising as the pO2 reaches baseline values again within 5-10 min after decompression. PMID- 26501142 TI - Neuroprotection and Retinal Diseases. AB - Neuronal death is the primary cause of vision loss in most retinal diseases. Neuroprotection is the modification of neurons, and/or their surrounding environment, to promote the survival and function of the neurons, especially in environments that would normally be deleterious to their health. Through advances in antioxidative therapy, neurotrophic support and anti-apoptotic therapy, the field of neuroprotection is advancing with the therapeutic hope of improving vision and clinical outcomes for patients. PMID- 26501143 TI - Docetaxel Induced Sclerosing Cholangitis. PMID- 26501144 TI - META-GSA: Combining Findings from Gene-Set Analyses across Several Genome-Wide Association Studies. AB - INTRODUCTION: Gene-set analysis (GSA) methods are used as complementary approaches to genome-wide association studies (GWASs). The single marker association estimates of a predefined set of genes are either contrasted with those of all remaining genes or with a null non-associated background. To pool the p-values from several GSAs, it is important to take into account the concordance of the observed patterns resulting from single marker association point estimates across any given gene set. Here we propose an enhanced version of Fisher's inverse chi2-method META-GSA, however weighting each study to account for imperfect correlation between association patterns. SIMULATION AND POWER: We investigated the performance of META-GSA by simulating GWASs with 500 cases and 500 controls at 100 diallelic markers in 20 different scenarios, simulating different relative risks between 1 and 1.5 in gene sets of 10 genes. Wilcoxon's rank sum test was applied as GSA for each study. We found that META-GSA has greater power to discover truly associated gene sets than simple pooling of the p values, by e.g. 59% versus 37%, when the true relative risk for 5 of 10 genes was assume to be 1.5. Under the null hypothesis of no difference in the true association pattern between the gene set of interest and the set of remaining genes, the results of both approaches are almost uncorrelated. We recommend not relying on p-values alone when combining the results of independent GSAs. APPLICATION: We applied META-GSA to pool the results of four case-control GWASs of lung cancer risk (Central European Study and Toronto/Lunenfeld-Tanenbaum Research Institute Study; German Lung Cancer Study and MD Anderson Cancer Center Study), which had already been analyzed separately with four different GSA methods (EASE; SLAT, mSUMSTAT and GenGen). This application revealed the pathway GO0015291 "transmembrane transporter activity" as significantly enriched with associated genes (GSA-method: EASE, p = 0.0315 corrected for multiple testing). Similar results were found for GO0015464 "acetylcholine receptor activity" but only when not corrected for multiple testing (all GSA-methods applied; p ~ 0.02). PMID- 26501146 TI - Neovascular Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of severe vision loss in individuals over the age of 50 years. Choroidal neovascularization (CNV) is the hallmark of 'wet' or 'exudative' AMD, and is responsible for approximately 90% of cases of severe vision loss due to AMD. Vascular endothelial growth factor (VEGF) is a key component in the development and progression of wet AMD. Since the approval of ranibizumab in 2006, VEGF inhibitors have rapidly altered the treatment and standard of care for wet AMD. Ranibizumab, bevacizumab, and aflibercept are now the most widely used anti-VEGF agents for the treatment of wet AMD. This chapter discusses the pharmacologic properties, pharmacokinetics, safety, and efficacy of these medications, as well as revisits landmark clinical trials that establish these drugs as gold standards in care. While these medications have greatly and positively altered the way we treat AMD, there are still many economic and therapeutic limitations with our current therapy regimens. There continue to be advancements and innovations in exploring alternative and new treatment modalities, as well as combining existing treatment options to improve efficacy, and reduce cost and patient burden. PMID- 26501145 TI - Prediction of Post-Operative Liver Dysfunction by Serum Markers of Liver Fibrosis in Hepatocellular Carcinoma. AB - AIM: To investigate the role of biomarkers in predicting postoperative liver dysfunction in patients with hepatocellular carcinoma (HCC). METHODS: A total of 200 patients operated from July 2009 to June 2010 at Zhongshan Hospital, Fudan University for pathologically confirmed HCC were retrospectively analyzed for clinical data, HBD DNA level and serum biochemical markers for liver fibrosis. The patients were followed up to observersation end point. Correlation of the monitored parameters with postoperative liver dysfunction and patient survival was statistically analyzed. RESULTS: Preoperative hepatitis B virus (HBV) DNA level, serum prealbumin (PA) hyaluronic acid (HA), and laminin (LN) levels correlated with postoperative liver dysfunction, and preoperative LN level also was associated with the patients' survival. A predictive model was generated using these 4 parameters and validated in 89 HCC patients with sensitivity and specificity of 0.625 and 0.912, respectively [corrected]. However, no correlation was identified between postoperative liver function and overall survival. CONCLUSION: Liver fibrosis markers could be preoperatively used in predicting postoperative liver dysfunction in HCC patients. PMID- 26501147 TI - Comparative Effect of a Renin Inhibitor and a Thiazide Diuretic on Renal Tissue Oxygenation in Hypertensive Patients. AB - BACKGROUND/AIMS: The purpose of the present study was to compare the direct renin inhibitor aliskiren to the diuretic hydrochlorothiazide (HCTZ) in their ability to modulate renal tissue oxygenation in hypertensive patients. METHODS: 24 patients were enrolled in this randomized prospective study and 20 completed the protocol. Patients were randomly assigned to receive either aliskiren 150-300 mg/d or HCTZ 12.5 - 25 mg/d for 8 weeks. Renal oxygenation was measured by BOLD MRI at weeks 0 and 8. BOLD-MRI was also performed before and after an i.v. injection of 20 mg furosemide at week 0 and at week 8. BOLD-MRI data were analyzed by measuring the oxygenation in 12 computed layers of the kidney enabling to asses renal oxygenation according to the depth within the kidney and by the classical method of regions of interest (ROI). RESULTS: The classical ROI analysis of the data showed no difference between the groups at week 8. The analysis of renal oxygenation according to the 12 layers method shows no significant difference between aliskiren and HCTZ at week 8 before administration of furosemide. However, within group analyses show that aliskiren slightly but not significantly increased oxygenation in the cortex and decreased medullary oxygenation whereas HCTZ induced a significant overall decrease in renal tissue oxygenation. With the same method of analysis we observed that the response to furosemide was unchanged in the HCTZ group at week 8 but was characterized by an increase in both cortical and medullary oxygenation in aliskiren-treated patients. Patients responding to aliskiren and HCTZ by a fall in systolic blood pressure of >10 mmHg improved their renal tissue oxygenation when compared to non responders. CONCLUSION: With the classical method of evaluation using regions no difference were found between aliskiren and HCTZ on renal tissue oxygenation after 8 weeks. In contrast, with our new method that takes into account the entire kidney, within group analyses show that aliskiren slightly increases cortical and medullary renal tissue oxygenation in hypertensive patients whereas HCTZ decreases significantly renal oxygenation at trough. PMID- 26501148 TI - Ocular Immunity and Inflammation. AB - Complex immunologic mechanisms are involved in multiple intraocular diseases. The field of immunology has aided greatly in better understanding and treating inflammation in the posterior segment. While traditional therapy has relied on drugs such as corticosteroids and antimetabolites that exert there effects by multiple mechanisms, the more recently developed biologic immune modulators involve specific mechanisms of action with the potential to significantly reduce side effects relative to more traditional agents. Better understanding of diseases such as age-related macular degeneration or diabetic retinopathy has led to the appreciation of immune mechanisms involved in these diseases and has suggested potential targets for therapy. PMID- 26501149 TI - Therapeutic Monoclonal Antibodies and Fragments: Ranibizumab. AB - Ranibizumab is a recombinant, humanized, affinity-matured, monoclonal antibody Fab fragment against all isoforms of vascular endothelial growth factor-A, which was developed specifically for intraocular use. Ranibizumab has been extensively investigated in clinical trials on choroidal neovascularization from wet age related macular degeneration and pathologic myopia, as well as macular edema due to diabetic retinopathy and retinal vein occlusion. Numerous randomized, controlled clinical trials have shown this medication to be effective in improving both vision as well as anatomical outcomes, and the medication has repeatedly shown to have an acceptable safety profile. PMID- 26501151 TI - Investigation of Model Sunscreen Formulations Comparing the Sun Protection Factor, the Universal Sun Protection Factor and the Radical Formation Ratio. AB - In view of globally rising skin cancer rates and harmful effects exerted by sunlight throughout the ultraviolet, visible and infrared ranges, an objective, safe and comprehensive method for determining sunscreen efficacy is required in order to warrant safe sun exposure. In this study, the influence of characteristic active ingredients (chemical filters, physical filters and antioxidants) on different sunscreen indicators, including the universal sun protection factor and the radical formation ratio, was determined and compared to their influence on sun protection factor values. Spectroscopic universal sun protection factor measurements were conducted ex vivo by analyzing tape strips taken from human skin, and radical formation ratio determination was performed via electron paramagnetic resonance spectroscopy using porcine ear skin ex vivo. The sun protection factor determination was conducted according to ISO standards (ISO 24444:2010). It was shown that chemical filters provide a protective effect which was measurable by all methods examined (spectroscopy, electron paramagnetic resonance spectroscopy and erythema formation). Physical filters, when used as single active ingredients, increased protective values in universal sun protection factor and sun protection factor measurements but exhibited no significant effect on universal sun protection factor measurements when used in combination with chemical filters or antioxidants. Antioxidants were shown to increase sun protection factor values. Radical formation ratio values were shown to be influenced merely by chemical filters, leading to the conclusion that the universal sun protection factor is the most suitable efficacy indicator for the ultraviolet range. PMID- 26501150 TI - Role of BioResponse 3,3'-Diindolylmethane in the Treatment of Human Prostate Cancer: Clinical Experience. AB - Castration-resistant prostate cancer (CRPC) progression after androgen deprivation therapy shows upregulated expression of androgen receptor (AR) splice variants, induced epithelial-to-mesenchymal transition phenotypes and enhanced stem cell characteristics, all of which are associated with resistance to enzalutamide. Since there is no curative treatment for CRPC, innovative treatments are urgently needed. In our recent study, we found that resistance to enzalutamide was partly due to deregulated expression of microRNAs such as miR 34a, miR-124, miR-27b, miR-320 and let-7, which play important roles in regulating AR and stem cell marker gene expression that appears to be linked with resistance to enzalutamide. Importantly, we found that BioResponse 3,3' diindolylmethane (BR-DIM) treatment in vitro and in vivo caused downregulation in the expression of wild-type AR. The AR splice variants, Lin28B and EZH2, appear to be deregulated through the re-expression of let-7, miR-27b, miR-320 and miR 34a in human prostate cancer (PCa). BR-DIM administered in clinical trials was well tolerated, and 93% of patients had detectable prostatic DIM levels. The inhibitory effects of BR-DIM on AR and AR target gene such as prostate-specific antigen were also observed in the clinical trial. Our preclinical and clinical studies provide the scientific basis for a 'proof-of-concept' clinical trial in CRPC patients treated with enzalutamide in combination with BR-DIM. This strategy could be expanded in future clinical trials in patients with PCa to determine whether or not they could achieve a better treatment outcome which could be partly mediated by delaying or preventing the development of CRPC. PMID- 26501152 TI - Diabetic Retinopathy and Diabetic Macular Edema. AB - Diabetic retinopathy and diabetic macular edema result from chronic damage to the neurovascular structures of the retina. The pathophysiology of retinal damage remains uncertain but includes metabolic and neuroinflammatory insults. These mechanisms are addressed by intensive metabolic control of the systemic disease and by the use of ocular anti-inflammatory agents, including vascular endothelial growth factor inhibitors and corticosteroids. Improved understanding of the ocular and systemic mechanisms that underlie diabetic retinopathy will lead to improved means to diagnose and treat retinopathy and better maintain vision. PMID- 26501153 TI - Purchases of Prescription Antidepressants in the Swedish Population in Relation to Major Workplace Downsizing. AB - Organizational downsizing may be a risk factor for morbidity among both the displaced and those who remain in work. However, the knowledge is limited regarding its impact on clinically relevant mental health problems. Our objective was to investigate purchases of prescription antidepressants across 5 years in relation to workplace downsizing. We studied all Swedish residents 2004 throughout 2010, 22-54 years old in 2006, gainfully employed, and with a stable labor market position up to 2006. People primarily employed at a workplace with >=18% staff reduction were considered exposed to major downsizing (in 2006-2007, 2007-2008, or 2008-2009). We applied repeated measures regression analyses through generalized estimating equations, calculating odds of any purchase of prescription antidepressants (inferred from the prescribed drug register) within five 12-month periods from 2 years before to 2 years after the period of major downsizing and compared the trends for newly exposed (n = 632,500) and unexposed (n = 1,021,759) to major downsizing. The odds of purchasing prescription antidepressants for exposed increased more than for nonexposed, mainly peridownsizing (1 year before to 1 year after), and postdownsizing (1 year after to 2 years after) for survivors (odds ratio 1.24 vs. 1.14 peridownsizing and 1.12 vs. 1.00 postdownsizing) and those changing workplace (odds ratio 1.22 vs. 1.14 peridownsizing and 1.10 vs. 1.00 postdownsizing) with no previous sickness absence or disability pension (>=7% more than unexposed peri- and postdownsizing). This large-scale study indicates that downsizing is associated with a slight increase in the odds of purchasing prescription antidepressants among people without previous sickness absence or disability pension. PMID- 26501154 TI - Halo and Pseudohalo Cu(I)-Pyridinato Double Chains with Tunable Physical Properties. AB - The properties recently reported on the Cu(I)-iodide pyrimidine nonporous 1D coordination polymer [CuI(ANP)]n (ANP = 2-amino-5-nitropyridine) showing reversible physically and chemically driven electrical response have prompted us to carry a comparative study with the series of [CuX(ANP)]n (X = Cl (1), X = Br (2), X = CN (4), and X = SCN (5)) in order to understand the potential influence of the halide and pseudohalide bridging ligands on the physical properties and their electrical response to vapors of these materials. The structural characterization of the series shows a common feature, the presence of -X-Cu(ANP) X- (X = Cl, Br, I, SCN) double chain structure. Complex [Cu(ANP)(CN)]n (4) presents a helical single chain. Additionally, the chains show supramolecular interlinked interactions via hydrogen bonding giving rise to the formation of extended networks. Their luminescent and electrical properties have been studied. The results obtained have been correlated with structural changes. Furthermore, the experimental and theoretical results have been compared using the density functional theory (DFT). The electrical response of the materials has been evaluated in the presence of vapors of diethyl ether, dimethyl methylphosphonate (DMMP), CH2Cl2, HAcO, MeOH, and EtOH, to build up simple prototype devices for gas detectors. Selectivity toward gases consisting of molecules with H-bonding donor or acceptor groups is clearly observed. This selective molecular recognition is likely due to the 2-amino-5-nitropyridine terminal ligand. PMID- 26501155 TI - 3D automatic liver segmentation using feature-constrained Mahalanobis distance in CT images. AB - Automatic 3D liver segmentation is a fundamental step in the liver disease diagnosis and surgery planning. This paper presents a novel fully automatic algorithm for 3D liver segmentation in clinical 3D computed tomography (CT) images. Based on image features, we propose a new Mahalanobis distance cost function using an active shape model (ASM). We call our method MD-ASM. Unlike the standard active shape model (ST-ASM), the proposed method introduces a new feature-constrained Mahalanobis distance cost function to measure the distance between the generated shape during the iterative step and the mean shape model. The proposed Mahalanobis distance function is learned from a public database of liver segmentation challenge (MICCAI-SLiver07). As a refinement step, we propose the use of a 3D graph-cut segmentation. Foreground and background labels are automatically selected using texture features of the learned Mahalanobis distance. Quantitatively, the proposed method is evaluated using two clinical 3D CT scan databases (MICCAI-SLiver07 and MIDAS). The evaluation of the MICCAI SLiver07 database is obtained by the challenge organizers using five different metric scores. The experimental results demonstrate the availability of the proposed method by achieving an accurate liver segmentation compared to the state of-the-art methods. PMID- 26501156 TI - Perinatal outcome of dichorionic-triamniotic as compared to trichorionic triplets. AB - OBJECTIVE: To evaluate if the perinatal outcomes of dichorionic-triamniotic (DC) triplets are significantly different than that of trichorionic (TC) triplets. STUDY DESIGN: Comparison of maternal and neonatal data of 44 DC to 46 TC triplets, using univariate analysis. RESULTS: DC triplets were significantly more common after spontaneous conception but all other maternal characteristics as well complications and cesarean section rates were similar. Both groups had similar incidence of birth at <32 and <28 weeks as well as similar incidence of very low and extremely low birth weight. There was similar incidence of neonatal morbidity except for twin-twin transfusion syndrome (13.6%) in the DC group. The stillbirth rate was 45/1000 and 29/1000, the early neonatal mortality rates were 63/1000 and 45/1000, and the perinatal mortality rate was 106/1000 and 72/1000 for DC and TC triplets, respectively (all not significantly different). CONCLUSIONS: Our data indicate that DC twins are not significantly disadvantaged compared to TC triplets and the similar outcomes might be reassuring for those who consider continuing their DC triplet pregnancy. PMID- 26501157 TI - Idiopathic infantile hypercalcemia: case report and review of the literature. AB - The widespread use of supplemental vitamin D has dramatically reduced the incidence of rickets. While generally considered a safe practice, there is potential for toxicity in patients with idiopathic infantile hypercalcemia (IIH). Inadequate 24-hydroxylase-enzyme activity renders these individuals unable to degrade active vitamin D, resulting in hypercalcemia due to increased intestinal calcium absorption, decreased renal calcium excretion, and increased osteoclastic bone activity. Clinicians should be aware that even therapeutic doses of vitamin D can prove harmful for patients with CYP24A1 mutations. Studies have also demonstrated a link between inadequate 24-hydroxylase activity and nephrocalcinosis, renal insufficiency, and calcium containing kidney stones, further emphasizing the importance of early recognition of this disease and judicious use of vitamin D. We present a case with an interesting diagnostic algorithm used to diagnose IIH when given an incomplete history and subsequently review the existing literature on the subject. PMID- 26501158 TI - Decrease of small dense LDL and lipoprotein-associated phospholipase A2 due to human growth hormone treatment in short children with growth hormone deficiency and small for gestational age status. AB - BACKGROUND: Growth hormone deficiency (GHD) and small for gestational age (SGA) status are associated with cardiovascular risks. We therefore, investigated antiatherogenic effects of growth hormone (GH). METHODS: Subfractions of low density lipoprotein (LDL) and high-density lipoprotein (HDL), lipoprotein associated phospholipase A2 (Lp-PLA2), and high-sensitivity C-reactive protein (hsCRP) were measured at baseline, after 8 and 52 weeks of GH treatment in 51 short children born SGA (n=33) or with GHD (n=18). RESULTS: The overall group showed post-treatment reductions of LDL cholesterol (LDL-C) (p=0.016), small dense LDL cholesterol (sdLDL-C, p<0.001), Lp-PLA2 (p<0.001), and hsCRP (p=0.005), but increase of HDL2a cholesterol (HDL2a-C, p=0.025). SGA children revealed significant correlations between Lp-PLA2 and LDL-C and sdLDL-C both before and after GH, significant reductions of sdLDL-C, Lp-PLA2, hsCRP, and an increase of HDL2a-C. GHD children showed the same lipid responses, though not significantly. CONCLUSIONS: Children with GHD or born SGA may benefit from GH by growth acceleration and reduction of cardiovascular long-term risks. PMID- 26501159 TI - Phytochemical, sub-acute toxicity, and antibacterial evaluation of Cordia sebestena leaf extracts. AB - BACKGROUND: In Nigeria, Cordia sebestena (Boraginaceae), an understudied medicinal plant, is used in traditional medicine for the treatment of gastrointestinal disorders. In this study, we investigated the chemical composition, antibacterial potential, and sub-acute toxicity of C. sebestena leaves. METHODS: Ethyl acetate extracts were analyzed using thin layer chromatography (TLC) and Fourier transform infrared (FTIR) spectrophotometry. The antibacterial potential of the extracts was tested against five standard bacteria, namely Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Clinical observations and blood parameters were used to evaluate the possible toxicity of C. sebestena. RESULTS: The TLC profile yielded 39 fractions, which were pooled to nine combined sub fractions (A-I). The FTIR spectrum of sub-fraction H indicated the presence of aliphatic C-H stretching vibration at 2922 and 2850 cm-1, C=O stretch at 1734 and 1708 cm-1, and C=C stretch of aromatics and aliphatics at 1464 and (shoulder) 1618 cm-1, respectively. The fractions of the C. sebestena ethyl acetate leaf extract showed antibacterial potential across board, but fraction H had the highest antibacterial activity against B. cereus and S. aureus. The study also indicated the relatively low toxicity profile of the ethyl acetate leaf extract of C. sebestena in the liver of rats. CONCLUSIONS: The study showed that C. sebestena leaves have strong antibacterial potential and low toxicity, thereby underlying the scientific basis for their folkloric use in the management of microbial infections and its associated complications. PMID- 26501160 TI - Preventive effect of total glycosides from Ligustri Lucidi Fructus against nonalcoholic fatty liver in mice. AB - The protective effects of the total glycosides from Ligustri Lucidi Fructus against nonalcoholic fatty liver (NAFL) in mice were investigated. Liver injury was induced by the administration of high fat diet for 60 days. During this period, the model group received high fat diet only; the treatment groups received various drugs plus high fat diet. Compared with the model group, the total glycosides significantly decreased the contents of triglyceride (TG) and cholesterol (TC), as well as the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum. Moreover, the contents of TG and TC in liver tissue and the liver index were reduced. Histological findings also confirmed antisteatosis. Compared with the model group, total glycosides significantly reduced the levels of the sterol regulatory element binding protein 1c (SREBP-1c) and liver X receptor-a (LXR-alpha) protein, and down-regulated the expression of SREBP-1c, LXR-alpha and interleukin-6 (IL-6) mRNA in the liver. These results suggest that the total glycosides are effective in the treatment of NAFL of mice. Their mode of action is associated with inhibiting SREBP-1c, LXR alpha and IL-6 mRNA, reducing lipid synthesis factor SREBP-1c and LXR-alpha protein and gene expression, suppressing inflammatory responses, then decreasing serum lipid and hepatic lipid. PMID- 26501161 TI - Synthesis of platinum(II) complexes of 2-cycloalkyl-substituted benzimidazoles and their cytotoxic effects. AB - Five novel Pt(II) complexes with some 2-cycloalkyl-substituted benzimidazole carrier-ligands were synthesized and evaluated for their in vitro cytotoxic activities against HeLa and OVCAR-3 cell lines. A cell viability test revealed that [dichloro-bis(2-cycloheptylbenzimidazole) platinum(II)] is less cytotoxic than cisplatin, and its cytotoxic effect can be compared with that of carboplatin. Flow cytometric analysis revealed that this complex at 117 MUM concentration causes apoptosis in approx. 72 % of the OVCAR-3 cell population. In addition, the complex was found to cause an increase in the SubG1 population of both OVCAR-3 and HeLa cells and to cause less apoptosis in HeLa cells than cisplatin. PMID- 26501162 TI - Evaluation of the water soluble extractive of astragali radix with different growth patterns using 1H-NMR spectroscopy. AB - Astragali radix (AR), known in China as huangqi, is commonly used in traditional Chinese medicine. Water soluble extractive (WSE) values play an important role in the quality evaluation of herbal drugs. In this study, WSE of wild and cultivated AR were compared systematically. The WSE value of cultivated AR was significantly higher than that of the wild AR, and their UV-absorbance in the range of 250-400 nm was also different. The chemical compositions of different WSE were further compared by 1H NMR spectroscopy combined with multivariate analysis. Results from the principal component analysis and the hierarchical cluster analysis showed a clear separation between the WSEs of wild and cultivated AR. The differential metabolites responsible for the separation were identified by orthogonal projections to latent structures discriminant analysis and recursive support vector machine. The WSE of wild AR contained more arginine, valine, threonine, asparagine, succinate, and glutamine, while the cultivated AR contained more sucrose. Thus, the WSE can be used as a simple and reliable method for discrimination of wild and cultivated ARs, and the results obtained in this study extend the potential use of WSE in the quality evaluation of herbal drugs. PMID- 26501163 TI - De novo ceramide synthesis is involved in acute inflammation during labor. AB - Gestation is regulated by an inflammatory process that allows implantation and parturition. The comprehension of such inflammatory switches is important for the identification of therapeutic targets in pregnancy defects. Sphingolipids are a class of structural membrane components with important signaling functions. Among sphingolipids, ceramide is a well-known mediator of stress signals and pro inflammatory responses. In this paper, we evaluated the association between ceramide increase and the inflammatory process of labor, comparing placentas from vaginal deliveries, including both spontaneous and induced labor, versus elective cesarean. We demonstrated that: (i) the inflammatory marker IL-6 is upregulated in labored placentas; (ii) IL-6 content inversely correlates with labor duration; (iii) ceramide content and expression of serine palmitoyl transferase (SPT, rate limiting enzyme for de novo ceramide synthesis) are increased in labored placentas; (iv) the expression of SPT directly correlates with inflammation and inversely with labor duration. These observations suggest that ceramide metabolism and signaling may be implicated in controlling important inflammatory mechanisms driving gestation: we hypothesize that ceramide can be a therapeutic target in inflammatory complications of parturition. PMID- 26501164 TI - Diagnostic values of CD64, C-reactive protein and procalcitonin in ventilator associated pneumonia in adult trauma patients: a pilot study. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is one of the most common nosocomial infections; however, its diagnosis remains difficult to establish in the critical care setting. We investigated the potential role of neutrophil CD64 (nCD64) expression as an early marker for the diagnosis of VAP. METHODS: Forty nine consecutive patients with clinically suspected VAP were prospectively included in a single-center study. The levels of nCD64, C-reactive protein (CRP), and serum procalcitonin (PCT) were analyzed for diagnostic evaluation at the time of intubation (baseline), at day 0 (time of diagnosis), and at day 3. The receiver operating characteristic curves were analyzed to identify the ideal cutoff values. RESULTS: VAP was confirmed in 36 of 49 cases. In patients with and without VAP, the median levels (interquartile range, IQR) of nCD64 did not differ either at baseline [2.4 (IQR, 1.8-3.1) and 2.6 (IQR, 2.3-3.2), respectively; p=0.3] or at day 0 [2 (IQR, 2.5-3.0) and 2.6 (IQR, 2.4-2.9), respectively; p=0.8]. CRP showed the largest area under the curve (AUC) at day 3. The optimum cutoff value for CRP according to the maximum Youden index was 133 mg/dL. This cutoff value had 69% sensitivity and 76% specificity for predicting VAP; the AUC was 0.73 (95% CI, 0.59-0.85). The nCD64 and PCT values could not discriminate between the VAP and non-VAP groups either at day 0 or day 3. CONCLUSIONS: The results of this pilot study suggest that neutrophil CD64 measurement has a poor role in facilitating the diagnosis of VAP and thus may not be practically recommended to guide the administration of antibiotics when VAP is suspected. PMID- 26501165 TI - Pharmacogenetics of healthy volunteers in Puerto Rico. AB - Puerto Ricans are a unique Hispanic population with European, Native American (Taino), and higher West African ancestral contributions than other non-Caribbean Hispanics. In admixed populations, such as Puerto Ricans, genetic variants can be found at different frequencies when compared to parental populations and uniquely combined and distributed. Therefore, in this review, we aimed to collect data from studies conducted in healthy Puerto Ricans and to report the frequencies of genetic polymorphisms with major relevance in drug response. Filtering for healthy volunteers or individuals, we performed a search of pharmacogenetic studies in academic literature databases without limiting the period of the results. The search was limited to Puerto Ricans living in the island, excluding those studies performed in mainland (United States). We found that the genetic markers impacting pharmacological therapy in the areas of cardiovascular, oncology, and neurology are the most frequently investigated. Coincidently, the top causes of mortality in the island are cardiovascular diseases, cancer, diabetes, Alzheimer's disease, and stroke. In addition, polymorphisms in genes that encode for members of the CYP450 family (CYP2C9, CYP2C19, and CYP2D6) are also available due to their relevance in the metabolism of drugs. The complex genetic background of Puerto Ricans is responsible for the divergence in the reported allele frequencies when compared to parental populations (Africans, East Asians, and Europeans). The importance of reporting the findings of pharmacogenetic studies conducted in Puerto Ricans is to identify genetic variants with potential utility among this genetically complex population and eventually move forward the adoption of personalized medicine in the island. PMID- 26501167 TI - Photosensitizers and Photodynamic Therapy: Verteporfin. AB - Photodynamic therapy (PDT) is a phototherapy in which a photosensitive dye is injected into a peripheral vein and activated by light in order to occlude choroidal vessels or change their permeability. PDT has been largely applied in the treatment of choroidal neovascularization (CNV), especially CNV related to age-related macular degeneration, but was also of benefit in other diseases, including central serous chorioretinopathy and choroidal hemangioma. PMID- 26501166 TI - Dermal Patch with Integrated Flexible Heater for on Demand Drug Delivery. AB - Topical administration of drugs and growth factors in a controlled fashion can improve the healing process during skin disorders and chronic wounds. To achieve this goal, a dermal patch is engineered that utilizes thermoresponsive drug microcarriers encapsulated within a hydrogel layer attached to a flexible heater with integrated electronic heater control circuitry. The engineered patch conformally covers the wound area and enables controlled drug delivery by electronically adjusting the temperature of the hydrogel layer. The drugs are encapsulated inside microparticles in order to control their release rates. These monodisperse thermoresponsive microparticles containing active molecules are fabricated using a microfluidic device. The system is used to release two different active molecules with molecular weights similar to drugs and growth factors and their release profiles are characterized. This platform is a key step towards engineering smart and closed loop systems for topical applications. PMID- 26501169 TI - From honeybees to robots and back: division of labour based on partitioning social inhibition. AB - In this paper, a distributed adaptive partitioning algorithm inspired by division of labor in honeybees is investigated for its applicability in a swarm of underwater robots in one hand and is qualitatively compared with the behavior of honeybee colonies on the other hand. The algorithm, partitioning social inhibition (PSI), is based on local interactions and uses a simple logic inspired from age-polyethism and task allocation in honeybee colonies. The algorithm is analyzed in simulation and is successfully applied here to partition a swarm of underwater robots into groups demonstrating its adaptivity to changes and applicability in real world systems. In a turn towards the inspiration origins of the algorithm, three honeybee colonies are then studied for age-polyethism behaviors and the results are contrasted with a simulated swarm running the PSI algorithm. Similar effects are detected in both the biological and simulated swarms suggesting biological plausibility of the mechanisms employed by the artificial system. PMID- 26501171 TI - Kappa-opioid antagonism impairs forebrain-dependent associative learning: A trace eyeblink conditioning study. AB - The opioid receptor system is well known for its relationship to painful stimuli but has also been discovered to have a role in acquisition and consolidation of associative memories. Most opioid receptor specific studies have focused on, and attributed these findings to, modulation of the mu-opioid receptor (MOR); however, some studies have suggested that the kappa-opioid receptor (KOR) also plays in role in memory modulation. The following study set out to determine KOR involvement in acquisition for forebrain-dependent associations. Using the forebrain-dependent associative task whisker-trace eyeblink conditioning (WTEB), the current study demonstrated that KOR inhibition via NorBNI (10 mg/kg) significantly delayed acquisition. To explore the brain region mediating these NorBNI-induced learning impairments, subsequent experiments focused on primary somatosensory cortex (S1). S1 plays a pivotal role in the acquisition of WTEB with lesions either before or after conditioning inhibiting acquisition or retrieval respectively. NorBNI (10 MUg or 20 MUg) in S1 was found to significantly delay acquisition, similar to that observed following systemic injections. In support of these findings, studies have suggested a role for dynorphin (KOR's endogenous ligand) expressing GABAergic interneurons in cortical processing of whisker information. Although, additional studies will be required to determine the specific mechanism for KOR and these GABAergic interneurons; these findings strongly support previous studies suggesting KOR involvement in learning mechanisms, while elucidating an unexplored neocortical learning mechanism. PMID- 26501170 TI - Cross-modal savings in the contralateral eyelid conditioned response. AB - The present experiment monitored bilateral eyelid responses during eyeblink conditioning in rats trained with a unilateral unconditioned stimulus (US). Three groups of rats were used to determine if cross-modal savings occurs when the location of the US is switched from one eye to the other. Rats in each group first received paired or unpaired eyeblink conditioning with a conditioned stimulus (tone or light; conditional stimulus [CS]) and a unilateral periorbital electrical stimulation US. All rats were subsequently given paired training, but with the US location (Group 1), CS modality (Group 2), or US location and CS modality (Group 3) changed. Changing the location of the US alone resulted in an immediate transfer of responding in both eyelids (Group 1) in rats that received paired training before the transfer session. Rats in Groups 2 and 3 that initially received paired training showed facilitated learning to the new CS modality during the transfer sessions, indicating that cross-modal savings occurs whether or not the location of the US is changed. All rats that were initially given unpaired training acquired conditioned eyeblink responses similar to de novo acquisition rate during the transfer sessions. Savings of CR incidence was more robust than savings of CR amplitude when the US switched sides, a finding that has implications for elucidating the neural mechanisms of cross-modal savings. PMID- 26501172 TI - Sexual receptivity facilitated by unesterified estradiol: Dependence on estrogen and progestin receptors and priming dose of estradiol benzoate. AB - In some conditions, female sexual behavior in ovariectomized rats can be induced by continuous exposure of estradiol (E2) alone or by a single injection of a high dose of the long-lasting, esterified estradiol benzoate (EB). However, there are inconsistencies in the literature on the role of estrogens during priming or in the facilitation on female sexual behavior in EB-primed rats, as well as the cellular mechanisms involved. Either subcutaneous (sc) or intracerebral (icv) administration of some doses of free unesterified E2, induced lordosis in EB primed rats. Either sc or icv injection of E2, immediately prior to testing, induced high levels of sexual receptivity when the female rats were primed with an EB sc injection of 2 MUg EB. The roles of progesterone receptor (PR) and estrogen receptor on lordosis induced by sc or icv administration of E2 were explored. Tamoxifen or RU486 administrated sc or icv; each reduced lordosis induced by E2. Similarly, antisense oligonucleotides directed at PR-B or total PR (PR-A + PR-B) administrated icv immediately before EB injection inhibited lordosis induced by daily injections of EB. These results suggest that lordosis facilitated by free E2 is dependent on priming dose of EB. Furthermore both ERs and PRs are involved in this action of E2. PMID- 26501173 TI - Structural plasticity in hippocampal cells related to the facilitative effect of intracranial self-stimulation on a spatial memory task. AB - Posttraining intracranial self-stimulation (SS) in the lateral hypothalamus facilitates the acquisition and retention of several implicit and explicit memory tasks. Here, intracellular injections of Lucifer yellow were used to assess morphological changes in hippocampal neurons that might be specifically related to the facilitative posttraining SS effect upon the acquisition and retention of a distributed spatial task in the Morris water maze. We examined the structure, size and branching complexity of cornus ammonis 1 (CA1) cells, and the spine density of CA1 pyramidal neurons and granular cells of the dentate gyrus (DG). Animals that received SS after each acquisition session performed faster and better than Sham ones--an improvement that was also evident in a probe trial 3 days after the last training session. The neuromorphological analysis revealed an increment in the size and branching complexity in apical CA1 dendritic arborization in SS-treated subjects as compared with Sham animals. Furthermore, increased spine density was observed in the CA1 field in SS animals, whereas no effects were observed in DG cells. Our results support the hypothesis that the facilitating effect of SS on the acquisition and retention of a spatial memory task could be related to structural plasticity in CA1 hippocampal cells. PMID- 26501174 TI - Auditory processing and morphological anomalies in medial geniculate nucleus of Cntnap2 mutant mice. AB - Genetic epidemiological studies support a role for CNTNAP2 in developmental language disorders such as autism spectrum disorder, specific language impairment, and dyslexia. Atypical language development and function represent a core symptom of autism spectrum disorder (ASD), with evidence suggesting that aberrant auditory processing-including impaired spectrotemporal processing and enhanced pitch perception-may both contribute to an anomalous language phenotype. Investigation of gene-brain-behavior relationships in social and repetitive ASD symptomatology have benefited from experimentation on the Cntnap2 knockout (KO) mouse. However, auditory-processing behavior and effects on neural structures within the central auditory pathway have not been assessed in this model. Thus, this study examined whether auditory-processing abnormalities were associated with mutation of the Cntnap2 gene in mice. Cntnap2 KO mice were assessed on auditory-processing tasks including silent gap detection, embedded tone detection, and pitch discrimination. Cntnap2 knockout mice showed deficits in silent gap detection but a surprising superiority in pitch-related discrimination as compared with controls. Stereological analysis revealed a reduction in the number and density of neurons, as well as a shift in neuronal size distribution toward smaller neurons, in the medial geniculate nucleus of mutant mice. These findings are consistent with a central role for CNTNAP2 in the ontogeny and function of neural systems subserving auditory processing and suggest that developmental disruption of these neural systems could contribute to the atypical language phenotype seen in autism spectrum disorder. PMID- 26501175 TI - Neural activation patterns underlying basolateral amygdala influence on intra accumbens opioid-driven consummatory versus appetitive high-fat feeding behaviors in the rat. AB - The present study explored the role of the amygdala in mediating a unique pattern of feeding behavior driven by intra-accumbens (intra-Acb) opioid activation in the rat. Temporary inactivation of the basolateral amygdala (BLA), via GABAA agonist muscimol administration prevents increased consumption following intra Acb opioid administration of the selective MU-opioid agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), yet leaves food approach behaviors intact, particularly after consumption has ended. One interpretation is that inactivation of the BLA selectively blocks neural activity underlying DAMGO-driven consummatory (consumption) but not appetitive (approach) behaviors. The present experiments take advantage of this temporal dissociation of consumption and approach behaviors to investigate their associated neural activity. Following either intra-Acb saline or DAMGO administration, with or without BLA muscimol administration, rats were given 2-hr access to a limited amount of high-fat diet. Immediately following the feeding session, rats were sacrificed and brains assayed for neural activity patterns across critical brain regions known to regulate both appetitive and consummatory feeding behaviors. The results show that intra-Acb DAMGO administration increased c-Fos activation in orexin neurons within the perifornical area of the hypothalamus and that this increase in activation is blocked by BLA muscimol inactivation. Intra-Acb DAMGO administration significantly increased c-Fos activation within dopaminergic neurons of the ventral tegmental area, compared to saline controls, and BLA inactivation had no effect on this increase. Overall, these data provide underlying circuitry that may mediate the selective influence of the BLA on driving consummatory, but not appetitive, feeding behaviors in a model of hedonically driven feeding behavior. PMID- 26501176 TI - The head direction cell system and behavior: The effects of lesions to the lateral mammillary bodies on spatial memory in a novel landmark task and in the water maze. AB - The head direction system is composed of neurons found in a number of connected brain areas that fire in a sharply tuned, directional way. The function of this system, however, has not been fully established. To assess this, we devised a novel spatial landmark task, comparable to the paradigms in which stimulus control has been assessed for spatially tuned neurons. The task took place in a large cylinder and required rats to dig in a specific sand cup, from among 16 alternatives, to obtain a food reward. The reinforced cup was in a fixed location relative to a salient landmark, and probe sessions confirmed that the landmark exerted stimulus control over the rats' cup choices. To assess the contribution of the head direction cell system to this memory task, half of the animals received ibotenic acid infusions into the lateral mammillary nuclei (LMN), an essential node in the head direction network, while the other received sham lesions. No differences were observed in performance of this task between the 2 groups. Animals with LMN lesions were impaired, however, in reversal learning on a water maze task. These results suggest that the LMN, and potentially the head direction cell system, are not essential for the use of visual landmarks to guide spatial behavior. PMID- 26501178 TI - On the genetics of loss aversion: An interaction effect of BDNF Val66Met and DRD2/ANKK1 Taq1a. AB - Loss aversion is the tendency to overweight losses compared with gains in decision situations. Several studies have investigated the neurobiological background of this phenomenon and it was found that activation in the mesolimbic mesocortical dopamine system during a gambling decision correlates with loss aversion. In a behavioral experiment with N = 143 subjects, the present study investigates the influence of 2 functional single-nucleotide polymorphisms on the BDNF gene (BDNF Val66Met polymorphism) and ANKK1 gene (DRD2 Taq1a/ANKK1 polymorphism), that are known to affect the dopamine system, on loss aversion. Additionally, associations of alexithymia, a personality construct describing the disability to consciously experience emotions in the self, with loss aversion and with the mentioned polymorphisms were assessed using the TAS-20 questionnaire, to replicate associations that have been reported before. Results revealed a significant interaction effect of the 2 polymorphisms on loss aversion. Carriers of the genetic constellation 66Met+/A1+ had the lowest loss aversion scores, compared with all other allelic groups. According to the literature this allelic configuration is characterized by a relatively low D2/3 receptor binding in the striatum and an impaired activity-dependent secretion of BDNF. This is the first study showing that loss aversion is related to naturally occurring differences in dopamine function. PMID- 26501177 TI - Low expression of D2R and Wntless correlates with high motivation for heroin. AB - Drug overdose now exceeds car accidents as the leading cause of accidental death in the United States. Of those drug overdoses, a large percentage of the deaths are due to heroin and/or pharmaceutical overdose, specifically misuse of prescription opioid analgesics. It is imperative, then, that we understand the mechanisms that lead to opioid abuse and addiction. The rewarding actions of opioids are mediated largely by the mu-opioid receptor (MOR), and signaling by this receptor is modulated by various interacting proteins. The neurotransmitter dopamine also contributes to opioid reward, and opioid addiction has been linked to reduced expression of dopamine D2 receptors (D2R) in the brain. That said, it is not known if alterations in the expression of these proteins relate to drug exposure and/or to the "addiction-like" behavior exhibited for the drug. Here, we held total drug self-administration constant across acquisition and showed that reduced expression of the D2R and the MOR interacting protein, Wntless, in the medial prefrontal cortex was associated with greater addiction-like behavior for heroin in general and with a greater willingness to work for the drug in particular. In contrast, reduced expression of the D2R in the nucleus accumbens and hippocampus was correlated with greater seeking during signaled nonavailability of the drug. Taken together, these data link reduced expression of both the D2R and Wntless to the explicit motivation for the drug rather than to differences in total drug intake per se. PMID- 26501179 TI - Antidepressant drugs specifically inhibiting noradrenaline reuptake enhance recognition memory in rats. AB - Patients suffering from major depression often experience memory deficits even after the remission of mood symptoms, and many antidepressant drugs do not affect, or impair, memory in animals and humans. However, some antidepressant drugs, after a single dose, enhance cognition in humans (Harmer et al., 2009). To compare different classes of antidepressant drugs for their potential as memory enhancers, we used a version of the novel object recognition task in which rats spontaneously forget objects 24 hr after their presentation. Antidepressant drugs were injected systemically 30 min before or directly after the training phase (Session 1 [S1]). Post-S1 injections were used to test for specific memory consolidation effects. The noradrenaline reuptake inhibitors reboxetine and atomoxetine, as well as the serotonin noradrenaline reuptake inhibitor duloxetine, injected prior to S1 significantly enhanced recognition memory. In contrast, the serotonin reuptake inhibitors citalopram and paroxetine and the cyclic antidepressant drugs desipramine and mianserin did not enhance recognition memory. Post-S1 injection of either reboxetine or citalopram significantly enhanced recognition memory, indicating an effect on memory consolidation. The fact that citalopram had an effect only when injected after S1 suggests that it may counteract its own consolidation-enhancing effect by interfering with memory acquisition. However, pretreatment with citalopram did not attenuate reboxetine's memory-enhancing effect. The D1/5-receptor antagonist SCH23390 blunted reboxetine's memory-enhancing effect, indicating a role of dopaminergic transmission in reboxetine-induced recognition memory enhancement. Our results suggest that antidepressant drugs specifically inhibiting noradrenaline reuptake enhance cognition and may be beneficial in the treatment of cognitive symptoms of depression. PMID- 26501180 TI - Perinatal stress effects on later anxiety and hormone secretion in male mandarin voles. AB - The estradiol (E2), estrogen receptor-alpha (ERalpha), testosterone (T), and androgen receptor (AR) can contribute to anxiety, but whether they are associated with the reversion of prenatal adverse outcomes remains unclear. Here, we tested the interactive effects of prenatal maternal restraint stress and early postnatal short-term maternal separation on adult male mandarin vole (Microtus mandarinus) behavior and changes in E2, T, and their receptors. The results showed that PS adult males (PS/NH) exhibited an increase in anxiety-like behavior in open-field and elevated plus-maze tests than the other 3 groups, including adult male offspring controls (PC/NH), adult male offspring controls with short-term maternal separation (PC/H), and PS adult males with short-term maternal separation (PS/H). The increase in anxiety-like behavior was associated with significantly lower E2 and T serum levels, had significantly more ERalpha immunoreactive neurons (ERalpha-IRs) in some brain regions, as well as significantly fewer AR immunoreactive neurons (AR-IRs) in some brain regions than the other 3 groups. We found it interesting that the PC/H and PS/H were similar to the PC/NH in that they did not produce anxiety-like behavior. However, early postnatal short-term maternal separation reversed prenatally induced changes in E2 and T serum levels and altered ERalpha-IRs and AR-IRs in the brain. These data suggest that changes in anxious adults may be governed by early environmental factors and their interactions because changes in E2 and T serum levels and the distribution of ERalpha and AR in the brain result in behavioral changes related to less anxiety into adulthood. PMID- 26501182 TI - Spectroscopic Analysis of Binary Mixed-Solvent-Polyimide Precursor Systems with the Preferential Solvation Model for Determining Solute-Centric Kamlet-Taft Solvatochromic Parameters. AB - Hydrogen bond donor/acceptor mixed-solvent systems for solutes that exhibit strong specific interactions are not readily characterized with methods that depend on solvatochromic parameters. In this work, the reaction of two monomers, 4,4'-oxidianiline (ODA) and pyromellitic dianhydride (PMDA), to form the common engineering plastic precursor, poly(amic acid) (PAA), are studied for the tetrahydrofuran (THF) mixed-solvent systems (THF-methanol, THF-ethanol, THF water) with spectroscopy. Solute-centric (SC) Kamlet-Taft solvatochromic (K-T) parameters for the solvent environment around the monomer are determined using a proposed model that incorporates spectroscopically determined local composition (X(L)) around the ODA monomer and the preferential solvation model. For the example reaction to occur under homogeneous conditions, mixed-solvent conditions need have HBA-rich local compositions (0.30 < X(HBA)(L) < 0.83), high solute centric basicity (beta(SC) > 0.60), high solute-centric polarity, (pi(SC)* > 0.63), and low solute-centric acidity (alpha(SC) < 0.63). The method developed allows characterization of mixed-solvent effects and can be readily extended to other systems that have strong specific interactions. PMID- 26501183 TI - Selective modification of the 3''-amino group of kanamycin prevents significant loss of activity in resistant bacterial strains. AB - Aminoglycosides are highly potent, wide-spectrum bactericidals. N-1 modification of aminoglycosides has thus far been the best approach to regain bactericidal efficiency of this class of antibiotics against resistant bacterial strains. In the present study we have evaluated the effect that both, the number of modifications and their distribution on the aminoglycoside amino groups (N-1, N 3, N-6' and N-3''), have on the antibiotic activity. The modification of N-3'' in the antibiotic kanamycin A is the key towards the design of new aminoglycoside antibiotics. This derivative maintains the antibiotic activity against aminoglycoside acetyl-transferase- and nucleotidyl-transferase-expressing strains, which are two of the most prevalent modifying enzymes found in aminoglycoside resistant bacteria. PMID- 26501181 TI - Characterization of cognitive deficits in mice with an alternating hemiplegia linked mutation. AB - Cognitive impairment is a prominent feature in a range of different movement disorders. Children with Alternating Hemiplegia of Childhood are prone to developmental delay, with deficits in cognitive functioning becoming progressively more evident as they grow older. Heterozygous mutations of the ATP1A3 gene, encoding the Na+,K+-ATPase alpha3 subunit, have been identified as the primary cause of Alternating Hemiplegia. Heterozygous Myshkin mice have an amino acid change (I810N) in Na+,K+-ATPase alpha3 that is also found in Alternating Hemiplegia. To investigate whether Myshkin mice exhibit learning and memory deficits resembling the cognitive impairments of patients with Alternating Hemiplegia, we subjected them to a range of behavioral tests that interrogate various cognitive domains. Myshkin mice showed impairments in spatial memory, spatial habituation, locomotor habituation, object recognition, social recognition, and trace fear conditioning, as well as in the visible platform version of the Morris water maze. Increasing the duration of training ameliorated the deficit in social recognition but not in spatial habituation. The deficits of Myshkin mice in all of the learning and memory tests used are consistent with the cognitive impairment of the vast majority of AHC patients. These mice could thus help advance our understanding of the underlying neural mechanisms influencing cognitive impairment in patients with ATP1A3-related disorders. PMID- 26501184 TI - Templateless Infrared Heating Process for Fabricating Carbon Nitride Nanorods with Efficient Photocatalytic H2 Evolution. AB - The bottom-up fabrication of carbon nitride nanorods is realized through the direct infrared heating of dicyandiamide. The approach requires no templates or extra organics. The controlled infrared heating has a major influence on the morphology of the obtained carbon nitrides. The precursors assemble into carbon nitride nanorods at low power levels, and they grow into nanoplates at high power levels. The formation mechanism of the carbon nitride nanorods is proposed to be a kinetically driven process, and the photocatalytic activity of the carbon nitride nanorods prepared at 50% power for hydrogen evolution is about 2.9 times that of carbon nitride nanoplates at 100% power. Structural, optical, and electronic analysis demonstrates that the enhancement is primarily attributed to the elimination of structural defects and the improved charge-carrier separation in highly condensed and oriented carbon nitride nanorods. PMID- 26501185 TI - Light-driven carboxylation of o-alkylphenyl ketones with CO2. AB - o-Alkylphenyl ketones undergo a C-C bond forming carboxylation reaction with CO2 simply upon irradiation with UV light or even solar light. The reaction presents a clean process exploiting light energy as the driving force for carboxylation of organic molecules with CO2. PMID- 26501186 TI - WITHDRAWN: Dengue Human Infection Models to Advance Dengue Vaccine Development. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.vaccine.2015.09.052. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26501187 TI - Sexual arousal and masculinity-femininity of women. AB - Studies with volunteers in sexual arousal experiments suggest that women are, on average, physiologically sexually aroused to both male and female sexual stimuli. Lesbians are the exception because they tend to be more aroused to their preferred sex than the other sex, a pattern typically seen in men. A separate research line suggests that lesbians are, on average, more masculine than straight women in their nonsexual behaviors and characteristics. Hence, a common influence could affect the expression of male-typical sexual and nonsexual traits in some women. By integrating these research programs, we tested the hypothesis that male-typical sexual arousal of lesbians relates to their nonsexual masculinity. Moreover, the most masculine-behaving lesbians, in particular, could show the most male-typical sexual responses. Across combined data, Study 1 examined these patterns in women's genital arousal and self-reports of masculine and feminine behaviors. Study 2 examined these patterns with another measure of sexual arousal, pupil dilation to sexual stimuli, and with observer-rated masculinity-femininity in addition to self-reported masculinity-femininity. Although both studies confirmed that lesbians were more male-typical in their sexual arousal and nonsexual characteristics, on average, there were no indications that these 2 patterns were in any way connected. Thus, women's sexual responses and nonsexual traits might be masculinized by independent factors. (PsycINFO Database Record PMID- 26501188 TI - Metamorphic GaAs/GaAsBi Heterostructured Nanowires. AB - GaAs/GaAsBi coaxial multishell nanowires were grown by molecular beam epitaxy. Introducing Bi results in a characteristic nanowire surface morphology with strong roughening. Elemental mappings clearly show the formation of the GaAsBi shell with inhomogeneous Bi distributions within the layer surrounded by the outermost GaAs, having a strong structural disorder at the wire surface. The nanowire exhibits a predominantly ZB structure from the bottom to the middle part. The polytipic WZ structure creates denser twin defects in the upper part than in the bottom and middle parts of the nanowire. We observe room temperature cathodoluminescence from the GaAsBi nanowires with a broad spectral line shape between 1.1 and 1.5 eV, accompanied by multiple peaks. A distinct energy peak at 1.24 eV agrees well with the energy of the reduced GaAsBi alloy band gap by the introduction of 2% Bi. The existence of localized states energetically and spatially dispersed throughout the NW are indicated from the low temperature cathodoluminescence spectra and images, resulting in the observed luminescence spectra characterized by large line widths at low temperatures as well as by the appearance of multiple peaks at high temperatures and for high excitation powers. PMID- 26501190 TI - HLADR: a database system for enhancing the discovery of biomarkers for predicting human leukocyte antigen-mediated idiosyncratic adverse drug reactions. AB - AIM: To establish a database for the associations between idiosyncratic drug reactions (IDRs) and human leukocyte antigens (HLAs) and to systematically assess the characteristics of the drug-HLA associations. MATERIALS & METHODS: Electronic databases were searched to extensively identify drug-HLA association studies from 1966 to present. RESULTS: A drug-HLA-IDR database, HLADR, was created. The drug HLA relationship network clearly reflected an ethnicity dependency of the associations. The positive predictive values and the negative predictive values demonstrated that other potential factors may also regulate the occurrence of HLA specific IDRs. CONCLUSIONS: Constructing studies with samples from homogeneous ethnic groups and identifying cofactors that affect negative predictive values and positive predictive values will become necessary to enhance the predictability of HLA biomarkers for future research on IDRs. PMID- 26501189 TI - Biomechanical Comparison of Glutaraldehyde-Crosslinked Gelatin Fibrinogen Electrospun Scaffolds to Porcine Coronary Arteries. AB - Cardiovascular disease (CVD) is the leading cause of death for Americans. As coronary artery bypass graft surgery (CABG) remains a mainstay of therapy for CVD and native vein grafts are limited by issues of supply and lifespan, an effective readily available tissue-engineered vascular graft (TEVG) for use in CABG would provide drastic improvements in patient care. Biomechanical mismatch between vascular grafts and native vasculature has been shown to be the major cause of graft failure, and therefore, there is need for compliance-matched biocompatible TEVGs for clinical implantation. The current study investigates the biaxial mechanical characterization of acellular electrospun glutaraldehyde (GLUT) vapor crosslinked gelatin/fibrinogen cylindrical constructs, using a custom-made microbiaxial optomechanical device (MOD). Constructs crosslinked for 2, 8, and 24 hrs are compared to mechanically characterized porcine left anterior descending coronary (LADC) artery. The mechanical response data were used for constitutive modeling using a modified Fung strain energy equation. The results showed that constructs crosslinked for 2 and 8 hrs exhibited circumferential and axial tangential moduli (ATM) similar to that of the LADC. Furthermore, the 8-hrs experimental group was the only one to compliance-match the LADC, with compliance values of 0.0006+/-0.00018 mm Hg-1 and 0.00071+/-0.00027 mm Hg-1, respectively. The results of this study show the feasibility of meeting mechanical specifications expected of native arteries through manipulating GLUT vapor crosslinking time. The comprehensive mechanical characterization of cylindrical biopolymer constructs in this study is an important first step to successfully develop a biopolymer compliance-matched TEVG. PMID- 26501193 TI - Facile Synthesis of DendriMac Polymers via the Combination of Living Anionic Polymerization and Highly Efficient Coupling Reactions. AB - Two DendriMac polymers (Dendri-hydr and Dendri-click) are efficiently and conveniently synthesized via the combination of living anionic polymerization (LAP) and hydrosilylation/click chemistry. Based on the end-capping of DPE derivatives (DPE-SiH and DPE-DA) toward polymeric anions, the polymeric core and arms are effectively synthesized, and the base polymers can be regarded as polymeric bricks. Hydrosilylation and click chemistry are used as coupling reactions to construct the DendriMac polymers with high efficiency and convenience. The numbers of branched arms are calculated by SEC as 5.84 and 6.08 for Dendri-hydr and Dendri-click, respectively, which indicate that the DendriMac architectures exhibit high structural integrity. Because of its independence, high efficiency, and convenience, the whole construction can be regarded as the "building of polymeric bricks." PMID- 26501191 TI - Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. AB - There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies. PMID- 26501194 TI - Seizures From Solving Sudoku Puzzles. PMID- 26501192 TI - Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. AB - Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders. PMID- 26501195 TI - Mass spectrometry of modified RNAs: recent developments. AB - A common feature of ribonucleic acids (RNAs) is that they can undergo a variety of chemical modifications. As nearly all of these chemical modifications result in an increase in the mass of the canonical nucleoside, mass spectrometry has long been a powerful approach for identifying and characterizing modified RNAs. Over the past several years, significant advances have been made in method development and software for interpreting tandem mass spectra resulting in approaches that can yield qualitative and quantitative information on RNA modifications, often at the level of sequence specificity. We discuss these advances along with instrumentation developments that have increased our ability to extract such information from relatively complex biological samples. With the increasing interest in how these modifications impact the epitranscriptome, mass spectrometry will continue to play an important role in bioanalytical investigations revolving around RNA. PMID- 26501196 TI - Combat application tourniquet (CAT) eradicates popliteal pulses effectively by correcting the windlass turn degrees: a trial on 145 participants. AB - INTRODUCTION: We aimed to define an ideal range of windlass turn degrees for 100 % success rates within the study population. METHODS: CAT was applied at mid thigh level. Data included age, lower extremity circumference (LEC), body mass index (BMI), and mean arterial pressure (MAP). Windlass turn degrees were measured in failed and successful participants. The failed participants' windlass mechanisms were twisted until the popliteal artery was occluded. Failure to success and additional turn degrees to secure the windlass mechanism of CAT was determined. Doppler ultrasound was used to examine the popliteal artery blood flow. RESULTS: 145 servicemen have participated in the study. Initially, 70 % successfully applied CAT. There was no statistically significant difference in BMI and MAP values between successful and failed participants. The mean LEC for failed and successful applications were 57.5 +/- 4 and 56.8 +/- 4, respectively. The required turn degrees for success ranged between 45 degrees and 270 degrees . After correction, the cumulative success rate of 93 and 100 % was reached at 990 degrees and 1170 degrees overall turn degrees. DISCUSSION: In order to adequately stop limb hemorrhage, soldiers should be taught their optimal turn degrees. PMID- 26501197 TI - Persistent lymphopenia is an independent predictor of mortality in critically ill emergency general surgical patients. AB - INTRODUCTION: Lymphopenia has been associated with poor outcome following sepsis, burns and trauma. This study was designed to establish whether lymphocyte count was associated with mortality in emergency general surgery (EGS) patients, and whether persistent lymphopenia was an independent predictor of mortality. METHODS: A retrospective review of a prospectively compiled database of adult patients requiring ICU admission between 2002 and 2013 was performed. EGS patients with acute intra-abdominal pathology and organ dysfunction were included. Lymphocyte counts obtained from the day of ICU admission through to day 7 were examined. Multivariate logistic regression models were used to determine the relationship between persistent lymphopenia and outcome. The primary outcome measure was in-hospital mortality. RESULTS: The study included 173 patients, of whom 135 (78 %) had a low lymphocyte count at admission to ICU and 91 % (158/173) developed lymphopenia on at least one occasion. Lymphocyte counts were lower among non-survivors compared with survivors on each day from day 2 (0.62 vs 0.81, p = 0.03) through to day 7 (0.87 vs 1.15, p < 0.01). Patients with a persistently low lymphocyte count during the study period had significantly higher mortality when compared to patients with other lymphocyte patterns (64 vs 29 %, p < 0.01). On multivariate regression analysis, persistent lymphopenia was independently associated with increased in-hospital mortality [odds ratio 3.5 (95 % CI 1.7 7.3), p < 0.01]. CONCLUSION: Lymphopenia is commonly observed in critically ill EGS patients. Patients with persistent lymphopenia are 3.5 times more likely to die and lymphopenia is an independent predictor of increased mortality in this patient group. PMID- 26501198 TI - Intramuscular Immunisation with Chlamydial Proteins Induces Chlamydia trachomatis Specific Ocular Antibodies. AB - BACKGROUND: Ocular infection with Chlamydia trachomatis can cause trachoma, which is the leading cause of blindness due to infection worldwide. Despite the large scale implementation of trachoma control programmes in the majority of countries where trachoma is endemic, there remains a need for a vaccine. Since C. trachomatis infects the conjunctival epithelium and stimulates an immune response in the associated lymphoid tissue, vaccine regimens that enhance local antibody responses could be advantageous. In experimental infections of non-human primates (NHPs), antibody specificity to C. trachomatis antigens was found to change over the course of ocular infection. The appearance of major outer membrane protein (MOMP) specific antibodies correlated with a reduction in ocular chlamydial burden, while subsequent generation of antibodies specific for PmpD and Pgp3 correlated with C. trachomatis eradication. METHODS: We used a range of heterologous prime-boost vaccinations with DNA, Adenovirus, modified vaccinia Ankara (MVA) and protein vaccines based on the major outer membrane protein (MOMP) as an antigen, and investigated the effect of vaccine route, antigen and regimen on the induction of anti-chlamydial antibodies detectable in the ocular lavage fluid of mice. RESULTS: Three intramuscular vaccinations with recombinant protein adjuvanted with MF59 induced significantly greater levels of anti-MOMP ocular antibodies than the other regimens tested. Intranasal delivery of vaccines induced less IgG antibody in the eye than intramuscular delivery. The inclusion of the antigens PmpD and Pgp3, singly or in combination, induced ocular antigen specific IgG antibodies, although the anti-PmpD antibody response was consistently lower and attenuated by combination with other antigens. CONCLUSIONS: If translatable to NHPs and/or humans, this investigation of the murine C. trachomatis specific ocular antibody response following vaccination provides a potential mouse model for the rapid and high throughput evaluation of future trachoma vaccines. PMID- 26501199 TI - Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in Sao Miguel Island Population (Azores, Portugal). AB - Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the Sao Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations- c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family's HH pseudodominant pattern is due to consanguineous marriage of HFE c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the alpha1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40-2.94, p<0.001). Therefore, homozygous for this complex allele are at risk of having iron overload because they will produce two altered proteins--the p.63Asp [c.187G], and the protein lacking 88 amino acids encoded by exon 2. In summary, we provide evidence that the complex allele HFE-c.[187C>G;340+4T>C] has a role, as genetic predisposition factor, on iron overload in the Sao Miguel population. Independent replication studies in other populations are needed to confirm this association. PMID- 26501200 TI - Characterization, Genome Sequence, and Analysis of Escherichia Phage CICC 80001, a Bacteriophage Infecting an Efficient L-Aspartic Acid Producing Escherichia coli. AB - Escherichia phage CICC 80001 was isolated from the bacteriophage contaminated medium of an Escherichia coli strain HY-05C (CICC 11022S) which could produce L aspartic acid. The phage had a head diameter of 45-50 nm and a tail of about 10 nm. The one-step growth curve showed a latent period of 10 min and a rise period of about 20 min. The average burst size was about 198 phage particles per infected cell. Tests were conducted on the plaques, multiplicity of infection, and host range. The genome of CICC 80001 was sequenced with a length of 38,810 bp, and annotated. The key proteins leading to host-cell lysis were phylogenetically analyzed. One protein belonged to class II holin, and the other two belonged to the endopeptidase family and N-acetylmuramoyl-L-alanine amidase family, respectively. The genome showed the sequence identity of 82.7% with that of Enterobacteria phage T7, and carried ten unique open reading frames. The bacteriophage resistant E. coli strain designated CICC 11021S was breeding and its L-aspartase activity was 84.4% of that of CICC 11022S. PMID- 26501202 TI - Tracing potential soil contamination in the historical Solvay soda ash plant area, Jaworzno, Southern Poland. AB - This study of soil conditions was carried out on 30 meadow soil (podzol) samples from the vicinity of the soda ash heap in Jaworzno, supplemented by analyses of 18 samples of waste deposited on the heap. In all samples, the total content of macroelements (Ca and Na) and heavy metals (Cd, Cr, Ni, Pb and Zn) as well as pH were analysed. The element concentrations were measured using inductively coupled plasma optical emission spectrometry (ICP-OES). The materials examined were neutral to ultra-alkaline. Total accumulations (mg kg(-1)) of chemical elements in the soil vary from 130.24 to 14076.67 for Ca, 41.40-926.23 for Na, 0.03-3.34 for Cd, 0.94-103.62 for Cr, 0.94-35.89 for Ni, 3.51-76.47 for Pb and 12.05-279.13 for Zn, whereas quantities of the same elements in the waste samples vary from 171705.13 to 360487.94 for Ca, 517.64-3152.82 for Na, 0.2-9.89 for Cd, 1.16-20.40 for Cr, 1.08-9.79 for Ni, 0.1-146.05 for Pb and 10.26-552.35 for Zn. The vertical distribution of the metals was determined in each soil profile. Despite enrichment of heavy metals in the uppermost horizon on the top of the heap, the results lead to the conclusion that the relation of historical production of soda ash in Jaworzno to current contamination of the local soil environment is insignificant. PMID- 26501201 TI - Perinatal Asphyxia May Influence the Level of Beta-Amyloid (1-42) in Cerebrospinal Fluid: An Experimental Study on Newborn Pigs. AB - OBJECTIVE: Total tau (T-tau), phosphorylated tau (p-Tau) and Beta-Amyloid 1-42 (AB42) in Cerebrospinal Fluid (CSF) are useful biomarkers in neurodegenerative diseases. The aim of the study was to investigate the role of these and other CSF biomarkers (T-tau, p-Tau, AB42, S100B and NSE), during hypoxia-reoxygenation in a newborn pig model. DESIGN: Thirty newborn pigs were included in a study of moderate or severe hypoxia. The moderate hypoxia group (n = 12) was exposed to global hypoxia (8% O2) until Base excess (BE) reached -15 mmol/l. The pigs in the group exposed to severe hypoxia (n = 12) received 8% O2 until BE reached -20 mmol/l or mean Blood Pressure fell below 20 mm Hg, The control group (n = 6) was kept at room air. For all treatments, the CSF was collected at 9.5 hours after the intervention. RESULTS: The level of AB42 in CSF was significantly lower in the pigs exposed to severe hypoxia compared with the control group, 922(SD +/ 445)pg/ml versus. 1290(SD +/-143) pg/ml (p<0.05), respectively. Further, a non significant reduction of AB42 was observed in the group exposed to moderate hypoxia T-tau and p-Tau revealed no significant differences between the intervention groups and the control group, however a significantly higher level of S100B was seen in the CSF of pigs receiving hypoxia in comparison to the level in the control group. Further on, there was a moderate negative correlation between the levels of AB42 and S100B in CSF, as well as a moderate negative correlation between Lactate in blood at end of hypoxia and AB42 in CSF. INTERPRETATION: This is the first study to our knowledge that demonstrated a significant drop in AB42 in CSF after neonatal hypoxia. Whether or not this has an etiological basis for adult neurodegenerative disorders needs to be studied with additional experiments and epidemiological studies. AB42 and S100B are significantly changed in neonatal pigs subjected to hypoxia compared to controls and thus may be valuable biomarkers of perinatal asphyxia. PMID- 26501203 TI - A Young Woman With Blurred Vision and Distal Paresthesias. AB - A 29-year-old woman presented with blurred vision and distal paresthesias. Her initial evaluation revealed severe bilateral optic disc edema with distal lower extremity sensory and motor deficits and electrodiagnostic evidence of a length dependent mixed demyelinating and axonal polyneuropathy. The results of routine diagnostic testing, including laboratory tests, magnetic resonance imaging, and lumbar puncture, were nondiagnostic. A targeted biopsy was ultimately required for diagnosis. In this article, we discuss the differential diagnosis and outline the clinical evaluation indicated for a patient presenting with demyelinating polyneuropathy and concurrent papilledema. PMID- 26501205 TI - THE IOM FRAMEWORK FOR DEVELOPING EVIDENCE-BASED STANDARDS IN THE FIELD OF PSYCHOSOCIAL INTERVENTIONS FOR MENTAL ILLNESS AND SUBSTANCE ABUSE: A DYNAMIC RESEARCHER'S PERSPECTIVE. CAUSE FOR CONCERN. PMID- 26501204 TI - A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers. AB - OBJECTIVE: This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710). METHODS: Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart+oral placebo, two doses of inhaled placebo+oral placebo, or two doses of inhaled placebo+oral moxifloxacin (400 mg; positive control), with >=3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (DeltaDeltaTcIs) at 12 time points throughout 24 hours after dosing. A DeltaDeltaTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazett-corrected QT duration and QTcI outliers. Pharmacokinetics and adverse events (AEs) were also assessed. RESULTS: Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no DeltaDeltaTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by DeltaDeltaTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE. CONCLUSIONS: Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study. PMID- 26501206 TI - Invisible Sensors: Simultaneous Sensing and Camouflaging in Multiphysical Fields. AB - The first multiphysical invisible sensor is theoretically and experimentally presented. An ultrathin, homogeneous, and isotropic shell is designed to simultaneously manipulate heat flux and DC current and eliminate the multiphysical perturbation, while maintaining the receiving and transmitting properties of the sensor. PMID- 26501207 TI - Synergistic effect of wire bending and salivary pH on surface properties and mechanical properties of orthodontic stainless steel archwires. AB - BACKGROUND: The aim of this study was to investigate the corrosive behaviour of stainless steel archwires in a more clinically relevant way by bending and exposing to various pH. METHODS: One hundred and twenty pieces of rectangular stainless steel wires (0.43 * 0.64 mm) were randomly assigned into four groups. In each group, there were 15 pieces of bent wires and 15 straight ones. Prior to measurements of the wires, as individual experimental groups (group 1, 2, and 3), the wires were exposed to artificial saliva for 4 weeks at pH 5.6, 6.6, and 7.6, respectively. A control group of wires (group 4) remained in air for the same period of time before sent for measurements. Surface roughness (Ra-value) was measured by a profilometer. Young's modulus and maximum force were determined by a four-point flexural test apparatus. Scanning electron microscopy was used to observe the surface morphology of straight wire. Differences between groups were examined using a two-way analysis of variance (ANOVA). RESULTS: Mean surface roughness values, flexural Young's moduli, and maximum force values of bent wires are significantly different from those of the straight wires, which was the main effect of wire bending, ignoring the influence of pH. A significant effect was found between Ra-values regarding the main effect of pH, ignoring the influence of shape. There was a significant interaction effect of bending and pH on flexural Young's moduli of stainless steel archwires, while pH did not show much impact on the maximum force values of those stainless steel wires. Bigger surface irregularities were seen on SEM images of straight wires immersed in artificial saliva at pH 5.6 compared to artificial saliva at other pH values. Surface depth (Rz) was more sensitive than Ra in revealing surface roughness, both measured from 3D reconstructed SEM images. Ra showed a comparable result of surface roughness to Ra-value measured by the profilometer. CONCLUSIONS: Bending has a significant influence on surface roughness and mechanical properties of rectangular SS archwires. pH plays a synergistic effect on the change of mechanical properties of stainless steel (SS) wires along with wire bending. PMID- 26501208 TI - Ratiometric Fluorescence Azide-Alkyne Cycloaddition for Live Mammalian Cell Imaging. AB - Click chemistry with metabolic labeling has been widely used for selectively imaging biomacromolecules in cells. The first example of azide-alkyne cycloaddition for ratiometric fluorescent imaging of live cells is reported. The precursor of the azido fluorophore (cresyl violet) has a fluorescence emission peak at 620 nm. The electron-rich nitrogen of the azido group blue-shifts the emission peak to 566 nm. When the click reaction occurs, an emission peak appears at 620 nm due to the lower electronic density of the newly formed triazole ring, which allows us to ratiometrically record fluorescence signals. This emission shift was applied to ratiometric imaging of propargylcholine- and dibenzocyclooctyne-labeled human breast cancer cells MCF-7 under laser confocal microscopy. Two typical triazole compounds were isolated for photophysical parameter measurements. The emission spectra presented a fluorescence emission peak around 620 nm for both click products. The results further confirmed the emission wavelength change was the result of azide-alkyne cycloaddition reaction. Since nearly all biomolecules can be metabolically labeled by reported alkyne functionalized derivatives of native metabolites, our method can be readily applied to image these biomacromolecules. PMID- 26501209 TI - Complement Activation and Inhibition in Retinal Diseases. AB - Within the past several decades, a brigade of dedicated researchers from around the world has provided essential insights into the critical niche of immune mediated inflammation in the pathogenesis of age-related macular degeneration (AMD). Yet, the question has lingered as to whether disease-initiating events are more or less dependent on isolated immune-related responses, unimpeded inflammation, endogenous pathways of age-related cell senescence and oxidative stress, or any of the other numerous molecular derangements that have been identified in the natural history of AMD. There is now an abundant cache of data signifying immune system activation as an impetus in the pathogenesis of this devastating condition. Furthermore, recent rigorous investigations have revealed multiple inciting factors, including several important complement-activating components, thus creating a new array of disease-modulating targets for the research and development of molecular therapeutic interventions. While the precise in vivo effects of complement activation and inhibition in the progression and treatment of AMD remain to be determined, ongoing clinical trials of the first generation of complement-targeted therapeutics are hoped to yield critical data on the contribution of this pathway to the disease process. PMID- 26501210 TI - Pharmacological effects of primaquine ureas and semicarbazides on the central nervous system in mice and antimalarial activity in vitro. AB - New primaquine (PQ) urea and semicarbazide derivatives 1-4 were screened for the first time for central nervous system (CNS) and antimalarial activity. Behavioural tests were performed on mice. In vitro cytotoxicity on L-6 cells and activity against erythrocytic stages of Plasmodium falciparum was determined. Compound 4 inhibited 'head-twitch' responses and decreased body temperature of mice, which suggests some involvement of the serotonergic system. Compound 4 protected mice against clonic seizures and was superior in the antimalarial test. A hybrid of two PQ urea 2 showed a strong antimalarial activity, confirming the previous findings of the high activity of bis(8-aminoquinolines) and other bisantimalarial drugs. All the compounds decreased the locomotor activity of mice, what suggests their weak depressive effects on the CNS, while PQ derivatives 1 and 2 increased amphetamine-induced hyperactivity. None of the compounds impaired coordination, what suggests a lack of their neurotoxicity. All the tested compounds presented an antinociceptive activity in the 'writhing' test. Compounds 3 and 4 were active in nociceptive tests, and those effects were reversed by naloxone. Compound 4 could be a useful lead compound in the development of CNS active agents and antimalarials, whereas compound 3 may be considered as the most promising lead for new antinociceptive agents. PMID- 26501212 TI - Generalized Intermolecular Interaction Tensor Applied to Long-Range Interactions in Hydrogen and Coinage Metal (Cu, Ag, and Au) Clusters. AB - We present a novel formulation for the intermolecular interaction tensor, which is used to describe the long-range electrostatic, induction, and dispersion interactions. Our formulation is based on concepts drawn from combinatorial analysis and Clifford calculus and enables us to present the interaction tensor in a form that is simple to use and suitable for both numerical and symbolic analyses. We apply the derived formulas to calculate the long-range interaction coefficients in hydrogen and coinage metal (Cu, Ag, and Au) clusters. The electronic structure calculations are performed at the CCSD(T) level, with triple zeta and quadruple-zeta basis sets. The multipole moments and dispersion coefficients are obtained as fits to the derived interaction formulas. The most important interaction parameters are obtained accurately and are in good agreement with other results. PMID- 26501211 TI - Epidemiology of Sarcoidosis in a Prospective Cohort Study of U.S. Women. AB - RATIONALE: Sarcoidosis is a systemic granulomatous and inflammatory disorder that most often involves the lungs but also affects many other organs. Data on sarcoidosis from large epidemiological studies remain scarce. OBJECTIVES: To evaluate the baseline prevalence and 22-year incidence of sarcoidosis and their associations with demographic and geographic characteristics in a large cohort of U.S. women. METHODS: The Nurses' Health Study II is a prospective cohort study of U.S. female nurses enrolled in 1989 (aged 25-44 yr, n = 116,430). Data on major illnesses were collected through biennial questionnaires (1989-2011). Cases were identified by the nurses' self-report of physician-diagnosed sarcoidosis. Associations of demographic and geographic characteristics with sarcoidosis were evaluated by logistic regression and Cox models. MEASUREMENTS AND MAIN RESULTS: A total of 377 sarcoidosis cases were identified. The baseline prevalence was 100/100,000 women. The average annual incidence rate was 11/100,000 during 2,275,028 person-years of follow up. Incidence rate increased with age (P = 0.003), from 9 to 15/100,000 in women aged less than 35 to 55 or more years, respectively. Black women had a higher prevalence (odds ratio, 5.24; 95% confidence interval, 2.87-9.55) and incidence (hazard ratio, 3.80; 95% confidence interval, 2.31-6.24) than white women. Across U.S. regions, more than twofold differences were observed in sarcoidosis prevalence and incidence, with consistently higher rates in the Northeast. CONCLUSIONS: We provide recent national data on the epidemiology of sarcoidosis among U.S. women. Important differences in prevalence and incidence were observed across U.S. regions. Large epidemiological studies are needed to better understand the causes of the observed demographic and geographic differences in sarcoidosis. PMID- 26501213 TI - A Simple Derived Prediction Score for the Identification of an Elevated Pulmonary Artery Wedge Pressure Using Precatheterization Clinical Data in Patients Referred to a Pulmonary Hypertension Center. AB - BACKGROUND: One of the foremost diagnostic challenges in clinical pulmonary hypertension is discriminating between pulmonary arterial hypertension (group 1) and heart failure with preserved ejection fraction (group 2.2). Group 2.2 is defined as a normal left ventricular ejection fraction (> 50%) and a pulmonary arterial wedge pressure (PAWP) > 15 mm Hg. We aimed to determine whether patient history, demographics, and noninvasive measures could predict PAWP before to right heart catheterization. METHODS: Data were prospectively collected on 350 consecutive patients at a single tertiary care medical center; of these patients, 151 met criteria for entry into our study (88 in group 1 and 63 in group 2.2). Data included historical features, demographics, and results of a transthoracic echocardiogram. A multivariate regression model was developed to predict PAWP > 15 mm Hg. RESULTS: Univariate predictors of PAWP > 15 mm Hg included older age, higher BMI and weight, systemic systolic BP and pulse pressure, more features of the metabolic syndrome, presence of hypertension and left atrial enlargement, absence of right ventricular enlargement, and lower glomerular filtration rate and 6-min walk distance. The optimal model for predicting PAWP > 15 mm Hg was composed of age (> 68 years), BMI (> 30 kg/m(2)), absence of right ventricular enlargement, and presence of left atrial enlargement (area under the curve, 0.779). CONCLUSIONS: Clinical characteristics obtained before diagnostic right heart catheterization accurately predict the probability of elevation of PAWP > 15 mm Hg in patients with preserved ejection fraction. These combined clinical characteristics can be used a priori to predict the likelihood of group 2.2 pulmonary hypertension. PMID- 26501214 TI - Optimizing Vowel Formant Measurements in Four Acoustic Analysis Systems for Diverse Speaker Groups. AB - PURPOSE: This study systematically assessed the effects of select linear predictive coding (LPC) analysis parameter manipulations on vowel formant measurements for diverse speaker groups using 4 trademarked Speech Acoustic Analysis Software Packages (SAASPs): CSL, Praat, TF32, and WaveSurfer. METHOD: Productions of 4 words containing the corner vowels were recorded from 4 speaker groups with typical development (male and female adults and male and female children) and 4 speaker groups with Down syndrome (male and female adults and male and female children). Formant frequencies were determined from manual measurements using a consensus analysis procedure to establish formant reference values, and from the 4 SAASPs (using both the default analysis parameters and with adjustments or manipulations to select parameters). Smaller differences between values obtained from the SAASPs and the consensus analysis implied more optimal analysis parameter settings. RESULTS: Manipulations of default analysis parameters in CSL, Praat, and TF32 yielded more accurate formant measurements, though the benefit was not uniform across speaker groups and formants. In WaveSurfer, manipulations did not improve formant measurements. CONCLUSIONS: The effects of analysis parameter manipulations on accuracy of formant-frequency measurements varied by SAASP, speaker group, and formant. The information from this study helps to guide clinical and research applications of SAASPs. PMID- 26501215 TI - Pinhal Virus, a New Arenavirus Isolated from Calomys tener in Brazil. AB - Arenavirus Sabia was originally isolated from a fatal human infection in Brazil, and after the occurrence of the second fatal human case in Sao Paulo state, epidemiologic and virologic studies were performed in the area where the patient lived, aiming at the identification of the Sabia natural rodent reservoir. A broadly cross-reactive enzyme-linked immunosorbent assay (ELISA) was used to screen for antibody-positive samples. Antibodies to arenavirus were detected in two of the 55 samples of Calomys tener, and from these results, samples of rodents were analyzed by a broad RT-PCR assay. RT-PCR amplification detected arenavirus sequences in five of the 55 C. tener samples, and sequencing showed that this virus is a distinct form of Sabia virus. Thus, we describe here the evidence for the circulation of a new arenavirus in Brazil (proposed name Pinhal virus) and its genetic characterization compared to other arenaviruses. This study also suggests C. tener as a probable rodent reservoir for this virus and associates this new virus with the lineage C of New World arenaviruses. Although we have defined some characteristics of this virus, so far, there is no evidence of its involvement in human disease. PMID- 26501216 TI - Biologic Therapies: Anti-Tumor Necrosis Factor-alpha, Anti-Interleukins, Rituximab and Others. AB - Biologic agents are a group of therapeutic agents targeting mediators of inflammation, including soluble factors (e.g. cytokines and chemokines), cytokine/chemokine receptors and immune cell surface markers. The purpose of this chapter is to introduce the use of biologic therapies for the treatment of ocular inflammatory diseases. Anti-tumor necrosis factor agents, particularly infliximab and adalimumab, are well studied. We will review these, as well as newer options in the development of more targeted therapy, including anti-interleukins, anti cell surface molecule biologics and interferon-2alpha. Biologic treatment of ocular inflammatory disease has advanced rapidly over the past 10 years and continues to be an exciting field of study. PMID- 26501217 TI - Association of Financial Integration Between Physicians and Hospitals With Commercial Health Care Prices. AB - IMPORTANCE: Financial integration between physicians and hospitals may help health care provider organizations meet the challenges of new payment models but also may enhance the bargaining power of provider organizations, leading to higher prices and spending in commercial health care markets. OBJECTIVE: To assess the association between recent increases in physician-hospital integration and changes in spending and prices for outpatient and inpatient services. DESIGN, SETTING, AND PARTICIPANTS: Using regression analysis, we estimated the relationship between changes in physician-hospital integration from January 1, 2008, through December 31, 2012, in 240 metropolitan statistical areas (MSAs) and concurrent changes in spending. Adjustments were made for patient, plan, and market characteristics, including physician, hospital, and insurer market concentration. The study population included a cohort of 7,391,335 nonelderly enrollees in preferred-provider organizations or point-of-service plans included in the Truven Health MarketScan Commercial Database during the study period. Data were analyzed from December 1, 2013, through July 13, 2015. EXPOSURE: Physician hospital integration, measured using Medicare claims data as the share of physicians in an MSA who bill for outpatient services with a place-of-service code indicating employment or practice ownership by a hospital. MAIN OUTCOMES AND MEASURES: Annual inpatient and outpatient spending per enrollee and associated use of health care services, with utilization measured by price-standardized spending (the sum of annual service counts multiplied by the national mean of allowed charges for the service). RESULTS: Among the 240 MSAs, physician-hospital integration increased from 2008 to 2012 by a mean of 3.3 percentage points, with considerable variation in increases across MSAs (interquartile range, 0.8-5.2 percentage points). For our study sample of 7,391,335 nonelderly enrollees, an increase in physician-hospital integration equivalent to the 75th percentile of changes experienced by MSAs was associated with a mean increase of $75 (95% CI, $38-$113) per enrollee in annual outpatient spending (P < .001) from 2008 to 2012, a 3.1% increase relative to mean outpatient spending in 2012 ($2407 [95% CI, $2400-$2414] per enrollee). This increase in outpatient spending was driven almost entirely by price increases because associated changes in utilization were minimal (corresponding change in price-standardized spending, $14 [95% CI, -$13 to $41] per enrollee; P = .32). Changes in physician-hospital integration were not associated with significant changes in inpatient spending ($22 [95% CI, -$1 to $46] per enrollee; P = .06) or utilization ($10 [95% CI, -$12 to $31] per enrollee; P = .37). CONCLUSIONS AND RELEVANCE: Financial integration between physicians and hospitals has been associated with higher commercial prices and spending for outpatient care. PMID- 26501219 TI - Retinal Vein Occlusion. AB - The primary treatment against macular edema with retinal vein occlusion (RVO) has changed from observation in central RVO (CRVO) and laser photocoagulation in branch RVO (BRVO) to administration of intravitreal agents based on anti-vascular endothelial growth factor (VEGF) or anti-inflammatory strategies. Anti-VEGF treatment such as ranibizumab, bevacizumab, or aflibercept improved vision by 13.9-16.2 letters (best-corrected visual acuity) after 12 months versus baseline in patients with macular edema secondary to CRVO. A long-term study showed that reduced follow-up and fewer retreatments resulted in worsening visual acuity. Intravitreal therapy with anti-inflammatory agents stabilized visual acuity in CRVO. However, increased intraocular pressure and cataract progression were frequently observed. Anti-VEGF agents such as ranibizumab or bevacizumab improved visual acuity by 15.5-18.3 letters in patients with macular edema secondary to BRVO after 12 months. The improved vision remained during the long-term follow up. There was no significant difference between standard care and intravitreal triamcinolone groups in BRVO, and increased intraocular pressure and cataract progression occurred frequently in the triamcinolone group. Anti-VEGF intravitreal administration resulted in good vision in CRVO and BRVO patients and is employed as a primary therapy. Anti-VEGF therapy requires frequent observations and intravitreal injections to maintain good vision. PMID- 26501218 TI - Clinical Evaluation of the Use of Tibial Bone Grafting in Dentoalveolar Reconstructive Surgery. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of tibial autogenous bone grafting in the treatment of patients with alveolar bone defects. MATERIALS AND METHODS: The study subjects consisted of 12 patients (10 male, 2 female, age: 19-51 years) who underwent reconstructive autogenous bone-grafting procedures. The medial approach to the tibial bone was used to harvest autogenous cancellous bone grafts in all the patients. Clinical parameters (complications at the donor and recipient sites, resorption and volume of the grafts) were evaluated retrospectively. RESULTS: The mean age of the patients was 36.25 +/- 0.9 years. Of the 12 patients, 5 (41.7%) received bone grafts for sinus augmentation, 3 (25%) for cyst cavity reconstruction and 4 (33.3%) for alveolar cleft reconstruction procedures. The average follow-up period was 28.4 months (range: 21-40 months). An average of 5.2 cm3 of cancellous bone was harvested for grafting procedures. All the grafting procedures were successful, and there were no surgical complications during the harvesting protocol. In all cases, pain and gait disturbance lasted less than 2 weeks. CONCLUSION: The results of this study suggest that the use of tibial autogenous bone graft harvested using a medial approach was a safe, simple and effective method for grafting various alveolar bone defects where high amounts of cancellous bone grafts were needed with low morbidity. PMID- 26501220 TI - Right Atrial Flap Repair for Left Superior Vena Cava Draining into Left Atrium. AB - There are different surgical methods for the repair of persistent left superior vena cava that connects directly to the left atrium. We describe an extracardiac surgical technique that includes direct anastomosis of persistent left superior vena cava to the right atrium with right atrial flap and autologous pericardium. We have performed this procedure in four cases and there is no obstruction at postoperative control studies. Right atrial flap repair is a feasible extracardiac technique that offers growth potential. PMID- 26501221 TI - Dynamic Cerebral Autoregulation after Cardiopulmonary Bypass. AB - Background Cerebral hemodynamic disturbances in the peri- or postoperative period may contribute to postoperative cognitive dysfunction (POCD) in patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). We therefore examined dynamic cerebral autoregulation (dCA) post-CPB and changes in neurocognitive function in patients that had undergone CABG. Materials and Methods We assessed dCA by transfer function analysis of spontaneous oscillations between arterial blood pressure and middle cerebral artery blood flow velocity measured by transcranial Doppler ultrasound in eight patients 6 hours after the cessation of CPB; 10 healthy volunteers served as controls. Neurocognitive function was assessed by four specific tests 1 day prior to and 3 days after CPB. Results Even though patients exhibited systemic inflammation and anemic hypoxemia, dCA was similar to healthy volunteers (gain: 1.24 [0.94-1.49] vs. 1.22 [1.06-1.34] cm mm Hg-1 s-1, p = 0.97; phase: 0.33 [0.15-0.56] vs. 0.69 [0.50-0.77] rad, p = 0.09). Neurocognitive testing showed a perioperative decline in the Letter Digit Coding Score (p = 0.04), while weaker dCA was associated with a lower Stroop Color Word Test (rho = - 0.90; p = 0.01). Discussion and Conclusion We found no changes in dCA 6 hours after CPB. However, based on the data at hand, it cannot be ruled out that changes in dCA predispose to POCD, which calls for larger studies that assess the potential impact of dCA in the early postoperative period on POCD. PMID- 26501222 TI - Predictive Value of EuroSCORE II in Patients Undergoing Left Ventricular Assist Device Therapy. AB - Background Left ventricular assist devices (LVADs) are nowadays a widespread option for the effective treatment of heart failure. We hypothesized that the European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) might be a superior tool in clinical decision making compared with other established score systems. Methods In this retrospective, single-center analysis, between 2008 and 2014, 40 consecutive patients were followed for up to 36 months after LVAD (Thoratec HeartMate II) implantation. Postoperative survival was correlated to the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) levels, Destination Therapy Risk Score (DTRS), HeartMate II Risk Score (HMRS), and EuroSCORE II. Results Overall, a positive outcome (survival, transplantation, or weaning) was reached in 87.5% (30 days), 70% (1 year), and 60% (2 and 3 years) of cases. Patients were categorized as high, medium, and low risk by use of the different scores. Within the created subgroups, the following 1-year positive outcomes were achieved-INTERMACS: high risk 58% versus low risk 68%; EuroSCORE II: high risk 17% versus low risk 89%; DTRS: high risk 44% versus low risk 75%; and HMRS: high risk 60% versus low risk 100%. After 1 year, the EuroSCORE II classification's area under the receiver operating characteristic curve (AUC) was superior (AUC = 0.78) and Fisher exact test revealed a significant predictive value for this classification (p = 0.0037) but not for INTERMACS levels, DTRS, or HMRS classifications. Conclusion These results support the assumption that EuroSCORE II risk classification may be useful to predict survival in LVAD patients. In our observation, it proved to be superior to INTERMACS, DTRS, and HMRS after 1 year. PMID- 26501223 TI - Tricuspid Valve Surgery in Patients with Isolated Tricuspid Valve Endocarditis: Analysis of Perioperative Parameters and Long-Term Outcomes. AB - Background The aim of this study was to evaluate the perioperative characteristics and the short- and mid-term outcomes in patients undergoing tricuspid valve (TV) surgery for isolated TV endocarditis. Patients and Methods A total of 56 patients with isolated TV endocarditis underwent TV surgery at a single center between June 1995 and February 2012. Mean age of patients was 53.8 +/- 17.1 years, 39 (69.6%) being male. The mean left ventricular ejection fraction was 60.4 +/- 13.6% and 13 (23.2%) patients had diabetes mellitus. Average logistic EuroSCORE was 19.4 +/- 17.0%. Mean follow-up was 4.7 +/- 3.8 years. Results Microbiological investigations revealed positive blood cultures in 89.1% of patients and positive intraoperative swabs in 51.9%. The most common pathogen (42.9%) isolated was Staphylococcus aureus, followed by coagulase negative staphylococcus (17.9%). Discussion A history of intravenous drug abuse (IVDA) was recorded in 11 patients (19.6%), of which 8 patients additionally had hepatitis C. A total of 15 patients (26.8%) had a permanent pacemaker/implantable cardioverter-defibrillator in situ. TV replacement was performed in 22 patients (39.3%) and TV repair was performed in 34 patients (60.7%). Overall 30-day mortality was 12.5%. Five-year survival was 63.9 +/- 7.2% (95% confidence interval [CI]: 64.0-137.5 months). Freedom from reoperation for recurrent TV endocarditis was 91.7 +/- 4.0% (95% CI: 152.3-179.3 months) at 5 years. Conclusion Blood culture is the most important tool to detect the causative pathogen causing IE of TV. The high risk of hepatitis C in patients with IVDA and IE of the TV should be mentioned. PMID- 26501224 TI - Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab. AB - IMPORTANCE: Vitiligo is an autoimmune skin disorder that reacts against melanocytes. The association of vitiligo with tumor response in patients with melanoma who undergo immunotherapy has been reported but is still controversial. OBJECTIVE: To prospectively evaluate the appearance of vitiligo in patients receiving pembrolizumab, a monoclonal antibody directed against the programmed death cell receptor. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational study was conducted from January 1, 2012, through September 24, 2013, in a single tertiary care hospital with a unit dedicated to patients with melanoma. Sixty-seven patients with metastatic melanoma who received pembrolizumab treatment in the context of a phase 1 study were included and screened for the emergence of vitiligo. Data were collected from January 1, 2012, to February 28, 2014, and analyzed from February through December 2014. MAIN OUTCOMES AND MEASURES: Objective tumor response with regard to the occurrence of vitiligo in patients receiving pembrolizumab therapy. Correlation between vitiligo occurrence and overall survival was also estimated using the Kaplan Meier product-limit method and compared with a log-rank test. To prevent guarantee- or lead-time bias, a landmark analysis approach after 12, 16, and 20 weeks of treatment was retained. RESULTS: Of the 67 patients included in the study, 17 (25%) developed vitiligo during pembrolizumab treatment and 50 (75%) did not. An objective (complete or partial) response to treatment was associated with a higher occurrence of vitiligo (12 of 17 [71%] vs 14 of 50 [28%]; P = .002). The time to onset of vitiligo ranged from 52 to 453 (median, 126) days from the start of treatment. Of the 17 patients with vitiligo, 3 (18%) had a complete response, 9 (53%) had a partial response, 3 (18%) had stable disease, and 2 (12%) had progressive disease at the final follow-up. All the patients treated with pembrolizumab who developed vitiligo were alive at the time of analysis, with a median follow-up of 441 days. CONCLUSIONS AND RELEVANCE: Vitiligo, a clinically visible immune-related adverse event could be associated with clinical benefit in the context of pembrolizumab treatment. PMID- 26501225 TI - Effect of High Temperature- and High Pressure-Treated Red Ginseng on Lipolysis and Lipid Oxidation in C2C12 Myotubes. AB - Korean red ginseng (KRG), a highly valuable medicinal herb in oriental societies, has biological activity similar to that of Panax ginseng. Recently, it has been discovered that the biological activities of red ginseng can vary according to heating and steaming processes under different conditions that change the principal components of KRG and result in changes in biological activity. This study evaluated and compared the effects of high temperature- and high pressure treated red ginseng (HRG) and commercial red ginseng (RG) on beta-oxidation in C2C12 myotubes. HRG enhanced the phosphorylation levels of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), but RG did not affect the phosphorylation of AMPK in C2C12 myotubes. HRG also promoted the nuclear translocation of forkhead box protein O1 (FoxO1), and the translocation exerted an increase in the protein expression of adipose triglyceride lipase (ATGL). As a consequence, HRG increased the mRNA expression level of carnitine palmitoyltransferase 1 (CPT-1) compared to the control. Taken together, our results indicated that HRG promotes the lipolysis of triglycerides and mitochondrial beta-oxidation of fatty acids in C2C12 myotubes, suggesting that alterations to the principal components by high temperature and pressure may positively influence the nutraceutical functions of HRG. PMID- 26501226 TI - A Molecular Study of Pediatric Spindle and Sclerosing Rhabdomyosarcoma: Identification of Novel and Recurrent VGLL2-related Fusions in Infantile Cases. AB - Sclerosing rhabdomyosarcoma (ScRMS) and spindle cell rhabdomyosarcoma (SRMS) have been recently reclassified as a stand-alone pathologic entity, separate from embryonal RMS. Genetically, a subset of the congenital cases display NCOA2 gene rearrangements, whereas tumors occurring in older children or adults harbor MYOD1 gene mutations with or without coexisting PIK3CA mutations. Despite these recent advances, a significant number of tumors lack known genetic alterations. In this study we sought to investigate a large group of pediatric SRMS/ScRMS, spanning a diverse clinical and pathologic spectrum, by using a combined fluorescence in situ hybridization, targeted DNA, and whole-transcriptome sequencing methodology for a more definitive molecular classification. A total of 26 SRMS and ScRMS cases were selected from the 2 participating institutions for the molecular analysis. Ten of the 11 congenital/infantile SRMS showed recurrent fusion genes: with novel VGLL2 rearrangements seen in 7 (63%), including VGLL2-CITED2 fusion in 4 and VGLL2-NCOA2 in 2 cases. Three (27%) cases harbored the previously described NCOA2 gene fusions, including TEAD1-NCOA2 in 2 and SRF-NCOA2 in 1. All fusion positive congenital/infantile SRMS patients with available long-term follow-up were alive and well, none developing distant metastases. Among the remaining 15 SRMS patients older than 1 year, 10 (67%) showed MYOD1 L122R mutations, most of them following a fatal outcome despite an aggressive multimodality treatment. All 4 cases harboring coexisting MYOD1/PIK3CA mutations shared sclerosing morphology. All 5 fusion/mutation-negative SRMS cases presented as intra-abdominal or paratesticular lesions. PMID- 26501229 TI - Sirolimus for Retinal and Uveitic Diseases. AB - Chronic inflammation plays an important role in the pathogenesis of ocular diseases such as diabetic retinopathy, uveitis and age-related macular degeneration. Activation and proliferation of naive T cells may result in pathological changes responsible for significant visual morbidity. Sirolimus (earlier termed rapamycin) is a novel drug that inhibits cellular kinases and, thereby, inhibits T-cell proliferation. Preclinical studies in experimental models have shown promising results with the use of this pharmacological agent in various ocular conditions. Subsequently, early phase I/II studies have provided encouraging safety and efficacy data. This chapter focuses on the mechanisms of action, preclinical study results and data from human clinical trials of sirolimus in human eye diseases. Key highlights from ongoing phase III clinical trials are also provided. Sirolimus, thus, appears to be an important addition to the armamentarium of steroid-sparing therapeutic agents that act on various steps in the inflammatory pathway. PMID- 26501227 TI - Action-specific influences on perception and postperceptual processes: Present controversies and future directions. AB - The action-specific perception account holds that people perceive the environment in terms of their ability to act in it. In this view, for example, decreased ability to climb a hill because of fatigue makes the hill visually appear to be steeper. Though influential, this account has not been universally accepted, and in fact a heated controversy has emerged. The opposing view holds that action capability has little or no influence on perception. Heretofore, the debate has been quite polarized, with efforts largely being focused on supporting one view and dismantling the other. We argue here that polarized debate can impede scientific progress and that the search for similarities between 2 sides of a debate can sharpen the theoretical focus of both sides and illuminate important avenues for future research. In this article, we present a synthetic review of this debate, drawing from the literatures of both approaches, to clarify both the surprising similarities and the core differences between them. We critically evaluate existing evidence, discuss possible mechanisms of action-specific effects, and make recommendations for future research. A primary focus of future work will involve not only the development of methods that guard against action specific postperceptual effects but also development of concrete, well constrained underlying mechanisms. The criteria for what constitutes acceptable control of postperceptual effects and what constitutes an appropriately specific mechanism vary between approaches, and bridging this gap is a central challenge for future research. PMID- 26501230 TI - Adaptive estimation of hand movement trajectory in an EEG based brain-computer interface system. AB - OBJECTIVE: The various parameters that define a hand movement such as its trajectory, speed, etc, are encoded in distinct brain activities. Decoding this information from neurophysiological recordings is a less explored area of brain computer interface (BCI) research. Applying non-invasive recordings such as electroencephalography (EEG) for decoding makes the problem more challenging, as the encoding is assumed to be deep within the brain and not easily accessible by scalp recordings. APPROACH: EEG based BCI systems can be developed to identify the neural features underlying movement parameters that can be further utilized to provide a detailed and well defined control command set to a BCI output device. A real-time continuous control is better suited for practical BCI systems, and can be achieved by continuous adaptive reconstruction of movement trajectory than discrete brain activity classifications. In this work, we adaptively reconstruct/estimate the parameters of two-dimensional hand movement trajectory, namely movement speed and position, from multi-channel EEG recordings. The data for analysis is collected by performing an experiment that involved center-out right-hand movement tasks in four different directions at two different speeds in random order. We estimate movement trajectory using a Kalman filter that models the relation between brain activity and recorded parameters based on a set of defined predictors. We propose a method to define these predictor variables that includes spatial, spectral and temporally localized neural information and to select optimally informative variables. MAIN RESULTS: The proposed method yielded correlation of (0.60 +/- 0.07) between recorded and estimated data. Further, incorporating the proposed predictor subset selection, the correlation achieved is (0.57 +/- 0.07, p < 0.004) with significant gain in stability of the system, as well as dramatic reduction in number of predictors (76%) for the savings of computational time. SIGNIFICANCE: The proposed system provides a real time movement control system using EEG-BCI with control over movement speed and position. These results are higher and statistically significant compared to existing techniques in EEG based systems and thus promise the applicability of the proposed method for efficient estimation of movement parameters and for continuous motor control. PMID- 26501228 TI - Appealing to fear: A meta-analysis of fear appeal effectiveness and theories. AB - Fear appeals are a polarizing issue, with proponents confident in their efficacy and opponents confident that they backfire. We present the results of a comprehensive meta-analysis investigating fear appeals' effectiveness for influencing attitudes, intentions, and behaviors. We tested predictions from a large number of theories, the majority of which have never been tested meta analytically until now. Studies were included if they contained a treatment group exposed to a fear appeal, a valid comparison group, a manipulation of depicted fear, a measure of attitudes, intentions, or behaviors concerning the targeted risk or recommended solution, and adequate statistics to calculate effect sizes. The meta-analysis included 127 articles (9% unpublished) yielding 248 independent samples (NTotal = 27,372) collected from diverse populations. Results showed a positive effect of fear appeals on attitudes, intentions, and behaviors, with the average effect on a composite index being random-effects d = 0.29. Moderation analyses based on prominent fear appeal theories showed that the effectiveness of fear appeals increased when the message included efficacy statements, depicted high susceptibility and severity, recommended one-time only (vs. repeated) behaviors, and targeted audiences that included a larger percentage of female message recipients. Overall, we conclude that (a) fear appeals are effective at positively influencing attitude, intentions, and behaviors; (b) there are very few circumstances under which they are not effective; and (c) there are no identified circumstances under which they backfire and lead to undesirable outcomes. PMID- 26501231 TI - Physical Activity, Television Viewing Time, and 12-Year Changes in Waist Circumference. AB - PURPOSE: Both moderate-to-vigorous physical activity (MVPA) and sedentary behavior can be associated with adult adiposity. Much of the relevant evidence is from cross-sectional studies or from prospective studies with relevant exposure measures at a single time point before weight gain or incident obesity. This study examined whether changes in MVPA and television (TV) viewing time are associated with subsequent changes in waist circumference, using data from three separate observation points in a large population-based prospective study of Australian adults. METHODS: Data were obtained from the Australian Diabetes, Obesity, and Lifestyle study collected in 1999-2000 (baseline), 2004-2005 (wave 2), and 2011-2012 (wave 3). The study sample consisted of adults age 25 to 74 yr at baseline who also attended site measurement at three time points (n = 3261). Multilevel linear regression analysis examined associations of initial 5-yr changes in MVPA and TV viewing time (from baseline to wave 2) with 12-yr change in waist circumference (from baseline to wave 3), adjusting for well-known confounders. RESULTS: As categorical predictors, increases in MVPA significantly attenuated increases in waist circumference (P for trend < 0.001). TV viewing time change was not significantly associated with changes in waist circumference (P for trend = 0.06). Combined categories of MVPA and TV viewing time changes were predictive of waist circumference increases; compared with those who increased MVPA and reduced TV viewing time, those who reduced MVPA and increased TV viewing time had a 2-cm greater increase in waist circumference (P = 0.001). CONCLUSION: Decreasing MVPA emerged as a significant predictor of increases in waist circumference. Increasing TV viewing time was also influential, but its impact was much weaker than MVPA. PMID- 26501232 TI - Objective Sedentary Time, Moderate-to-Vigorous Physical Activity, and Physical Capability in a British Cohort. AB - PURPOSE: Sedentariness has been proposed as an independent risk factor for poor health. However, few studies have considered associations of sedentary time (ST) with physical functional health independent of time spent in moderate-to-vigorous physical activity (MVPA). METHODS: Community-based men and women (n = 8623, 48-92 yr old) in the European Prospective Investigation of Cancer-Norfolk study attended a health examination for objective measurement of physical capability, including grip strength (Smedley dynamometer (kg)), usual walking speed (UWS (cm.s(-1))), and timed chair stand speed (TCSS (stands per minute)). Of these, 4051 participants wore an accelerometer (GT1M ActiGraph) for 7 d to estimate time spent in MVPA (MVPA, >=1952 counts per minute) and ST (ST, <100 counts per minute). Relations between physical capability outcomes and both MVPA and ST were explored using linear regression. The mutual independence of associations was also tested, and ST-MVPA interactions were explored using fractional polynomial models to account for nonlinear associations. RESULTS: Men in the highest compared with those in the lowest sex-specific quartile of MVPA were stronger (1.84 kg; 95% confidence interval (CI), 0.79-2.89), had faster UWS (11.7 cm.s( 1); 95% CI, 8.4-15.1) and faster TCSS (2.35 stands per minute; 95% CI, 1.11-3.59) after multivariable adjustment. Similarly, women in the highest quartile of MVPA were stronger (2.47 kg; 95% CI, 1.79-3.14) and had faster UWS (15.5 cm.s(-1); 95% CI, 12.4-18.6) and faster TCSS (3.27 stands per minute; 95% CI, 2.19-4.25). Associations persisted after further adjustment for ST. Associations between higher ST and lower physical capability were also observed, but these were attenuated after accounting for MVPA. Furthermore, no MVPA-ST interactions were observed (Pinteractions > 0.05). CONCLUSIONS: More time spent in MVPA was associated with higher physical capability, but there were no independent ST associations. PMID- 26501234 TI - Total nucleated cell and leukocyte differential counts in canine pleural and peritoneal fluid and equine synovial fluid samples: comparison of automated and manual methods. AB - BACKGROUND: Rapid and precise measurement of total and differential nucleated cell counts is a crucial diagnostic component of cavitary and synovial fluid analyses. OBJECTIVES: The objectives of this study included (1) evaluation of reliability and precision of canine and equine fluid total nucleated cell count (TNCC) determined by the benchtop Abaxis VetScan HM5, in comparison with the automated reference instruments ADVIA 120 and the scil Vet abc, respectively, and (2) comparison of automated with manual canine differential nucleated cell counts. METHODS: The TNCC and differential counts in canine pleural and peritoneal, and equine synovial fluids were determined on the Abaxis VetScan HM5 and compared with the ADVIA 120 and Vet abc analyzer, respectively. Statistical analyses included correlation, least squares fit linear regression, Passing Bablok regression, and Bland-Altman difference plots. In addition, precision of the total cell count generated by the VetScan HM5 was determined. RESULTS: Agreement was excellent without significant constant or proportional bias for canine cavitary fluid TNCC. Automated and manual differential counts had R(2) < .5 for individual cell types (least squares fit linear regression). Equine synovial fluid TNCC agreed but with some bias due to the VetScan HM5 overestimating TNCC compared to the Vet abc. Intra-assay precision of the VetScan HM5 in 3 fluid samples was 2-31%. CONCLUSIONS: The Abaxis VetScan HM5 provided rapid, reliable TNCC for canine and equine fluid samples. The differential nucleated cell count should be verified microscopically as counts from the VetScan HM5 and also from the ADVIA 120 were often incorrect in canine fluid samples. PMID- 26501235 TI - Hypoxia-Inducible Factor-1alpha Is Associated With Sprouting Angiogenesis in the Murine Laser-Induced Choroidal Neovascularization Model. AB - PURPOSE: To investigate the expression and distribution of neoangiogenic molecules and the role of hypoxia during the development of experimental choroidal neovascularization (CNV). METHODS: Lesions were induced on C57Bl6 mice using laser photocoagulation. Animals were euthanized in a timely manner and eyecups were dissected from enucleated eyes. Choroids were immunostained for pericytes, sprouting endothelial cells (EC), or vascular EC. Choroidal neovascularization lesions where analyzed for tissue hypoxia, hypoxia-inducible factors (HIF), and heat-shock proteins (HSP). RESULTS: Choroidal neovascularization lesions showed a trend of increased cellular recruitment throughout the time-course and the lesions displayed positive staining for angiogenic markers. Both pericytes and sprouting EC displayed a radial progression, while vascular EC displayed a more uniform distribution across the CNV lesions. Furthermore, positive tissue hypoxia staining was observed and associated with expression of HIF-1alpha and vascular endothelial growth factor (VEGF). CONCLUSIONS: Our data delimitate specific temporal windows during CNV initiation, propagation, maturation, and even recovery in experimental CNV. We show that murine CNV undergoes hypoxia-associated sprouting angiogenesis, and demonstrate involvement of pericytes. Moreover, we have shown expression of HIF 1alpha to the retinal pigment epithelium surrounding the CNV lesions, together with VEGF upregulation, independently of the HSP response induced by the laser thermal insult. PMID- 26501233 TI - A four-component model of age-related memory change. AB - We develop a novel, computationally explicit, theory of age-related memory change within the framework of the context maintenance and retrieval (CMR2) model of memory search. We introduce a set of benchmark findings from the free recall and recognition tasks that include aspects of memory performance that show both age related stability and decline. We test aging theories by lesioning the corresponding mechanisms in a model fit to younger adult free recall data. When effects are considered in isolation, many theories provide an adequate account, but when all effects are considered simultaneously, the existing theories fail. We develop a novel theory by fitting the full model (i.e., allowing all parameters to vary) to individual participants and comparing the distributions of parameter values for older and younger adults. This theory implicates 4 components: (a) the ability to sustain attention across an encoding episode, (b) the ability to retrieve contextual representations for use as retrieval cues, (c) the ability to monitor retrievals and reject intrusions, and (d) the level of noise in retrieval competitions. We extend CMR2 to simulate a recognition memory task using the same mechanisms the free recall model uses to reject intrusions. Without fitting any additional parameters, the 4-component theory that accounts for age differences in free recall predicts the magnitude of age differences in recognition memory accuracy. Confirming a prediction of the model, free recall intrusion rates correlate positively with recognition false alarm rates. Thus, we provide a 4-component theory of a complex pattern of age differences across 2 key laboratory tasks. PMID- 26501236 TI - Outcome Preferences in Patients With Noninfectious Uveitis: Results of a Best Worst Scaling Study. AB - PURPOSE: To estimate patient preferences regarding potential adverse outcomes of local versus systemic corticosteroid therapies for noninfectious uveitis by using a best-worst scaling (BWS) approach. METHODS: Local and systemic therapies are alternatives for noninfectious uveitis that have different potential adverse outcomes. Patients participating in the Multicenter Uveitis Steroid Treatment Trial Follow-up Study (MUST FS) and additional patients with a history of noninfectious uveitis treated at two academic medical centers (Johns Hopkins University and University of Pennsylvania) were surveyed about their preferences regarding six adverse outcomes deemed important to patients. Using "case 1" BWS, patients were asked to repeatedly select the most and least worrying from a list of outcomes (in the survey three outcomes per task). RESULTS: Eighty-two patients in the MUST FS and 100 patients treated at the academic medical centers completed the survey. According to BWS, patients were more likely to select vision not meeting the requirement for driving (individual BWS score: median = 3, interquartile range, 0-5), development of glaucoma (2, 1-4), and needing eye surgery (1, 0-3) as the most worrying outcomes as compared to needing medicine for high blood pressure/cholesterol (-2, -4 to 0), development of cataracts (-2, 3 to -1), or infection (sinusitis) (-3, -5 to 0). Larger BWS scores indicated the outcomes were more worrying to patients. CONCLUSIONS: Patients with noninfectious uveitis considered impaired vision, development of glaucoma, and need for eye surgery worrying adverse outcomes, which suggests that it is especially desirable to avoid these outcomes if possible. (ClinicalTrials.gov number, NCT00132691.) PMID- 26501237 TI - Successful use of a bivalirudin treatment protocol to prevent extracorporeal thrombosis in ambulatory hemodialysis patients with heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) is an uncommon problem in hemodialysis (HD) patients. There have been a few reports on the use of lepirudin, argatroban, or danaparoid in the management of extracorporeal thrombosis (ECT) during dialysis in these patients, because heparin is contraindicated. Here, we report the first long-term use of bivalirudin to prevent ECT. Our study was conducted at Fahd Bin Jassim Kidney Center in Doha, Qatar. All patients diagnosed with HIT were included. A bivalirudin treatment protocol was developed with the initial dosage and dosage adjustments based on the value of activated partial thromboplastin time (aPTT), the risk of bleeding, and the recurrence of ECT. Eight patients were positive for HIT AB. Among them, three were excluded: two due to the use of warfarin for atrial fibrillation and one due to a negative repeat HIT AB test with no ECT. Five patients who were positive for HIT AB and experienced recurrent ECT events during dialysis were included. These patients were monitored while on bivalirudin protocol for a mean of 4.6 +/- 2 months, during which they received a mean number of HD treatments of 66 +/- 24. There were no bleeding events or adverse reactions related to bivalirudin during the study. Here, we report the first long-term successful use of a bivalirudin protocol to prevent ECT in ambulatory HD patients with HIT. This protocol allowed for a simple dosing initiation with easy adjustment based on weight, aPTT, and recurrence of ECT events. The protocol provided excellent safety. PMID- 26501238 TI - Long-term prognosis of early repolarization with J-wave and QRS slur patterns on the resting electrocardiogram: a cohort study. AB - BACKGROUND: The prognostic value of early repolarization with J waves and QRS slurs remains controversial. Although these findings are more prevalent in patients with idiopathic ventricular fibrillation, their ability to predict cardiovascular death has varied across studies. OBJECTIVE: To test the hypothesis that J waves and QRS slurs on electrocardiograms (ECGs) are associated with increased risk for cardiovascular death. DESIGN: Retrospective cohort. SETTING: Veterans Affairs Palo Alto Health Care System. PATIENTS: Veterans younger than 56 years who had resting 12-lead electrocardiography, 90.5% of whom were men. MEASUREMENTS: Electrocardiograms were manually measured and visually coded using criteria of 0.1 mV or greater in at least 2 contiguous leads. J waves were measured at the peak of an upward deflection or notch at the end of QRS, and QRS slurs were measured at the top of conduction delay on the QRS downstroke. Absolute risk differences at 10 years were calculated to study the associations between J waves or QRS slurs and the primary outcome of cardiovascular death. RESULTS: Over a median follow-up of 17.5 years, 859 cardiovascular deaths occurred. Of 20 661 ECGs, 4219 (20%) had J waves or QRS slurs in the inferior and/or lateral territories; of these, 3318 (78.6%) had J waves or QRS slurs in inferior leads and 1701 (40.3%) in lateral leads. The upper bound of differences in risk for cardiovascular death from any of the J-wave or QRS slur patterns suggests that an increased risk can be safely ruled out (inferior, -0.77% [95% CI, -1.27% to -0.27%]; lateral, -1.07% [CI, -1.72% to -0.43%]). LIMITATION: The study consisted of predominantly men, and deaths could be classified as cardiovascular but not arrhythmic. CONCLUSION: J waves and QRS slurs did not exhibit a clinically meaningful increased risk for cardiovascular death in long term follow-up. PRIMARY FUNDING SOURCE: None. PMID- 26501239 TI - Evaluation and Management of Chronic Aspiration in Children With Normal Upper Airway Anatomy. AB - IMPORTANCE: Chronic airway aspiration is a challenging problem for physicians and caregivers and can cause significant pulmonary morbidity in pediatric patients. Our knowledge regarding the causes and optimal management of these patients is in its infancy. OBJECTIVE: To review our experience with the evaluation and management of pediatric patients with documented aspiration and normal upper airway anatomy. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective medical record review, we studied pediatric patients for airway disorders at a pediatric tertiary referral center who were diagnosed as having aspiration on modified barium swallow study during a 10-year period (June 1, 2002, through September 31, 2012). INTERVENTIONS: Direct laryngoscopy and bronchoscopy performed with the patient under general anesthesia. MAIN OUTCOMES AND MEASURES: Demographics, comorbidities, management, and swallowing outcomes were analyzed. RESULTS: Forty six patients met the inclusion criteria. The mean age at presentation was 1.56 years, and there was a male to female ratio of approximately 2:1. Eight patients (17%) were syndromic, 16 (35%) had developmental delay, and 12 (26%) had congenital heart disease. Fifteen patients (33%) underwent brain magnetic resonance imaging, and none had a brainstem or posterior fossa lesion that accounted for their aspiration. Patients were subdivided according to the consistency of the fluids that they aspirated: 25 (54%) aspirated thin liquids, 15 (33%) aspirated thickened liquids, and 6 (13%) aspirated purees. Of these patients, 21 (84%), 12 (80%), and 3 (50%) had resolution of their swallowing dysfunction with feeding and swallowing therapy, respectively. A total of 3 patients (7%) required a tracheostomy for their refractory aspiration. CONCLUSIONS AND RELEVANCE: We recommend feeding and swallowing therapy for children with normal upper airway anatomy. Brain magnetic resonance imaging should be considered for patients with suspected brainstem or posterior fossa lesion based on neurologic examination findings. Most patients who aspirate thin and thickened liquids will have resolution of their swallowing dysfunction within 1 year of beginning therapy. PMID- 26501240 TI - In situ electronic probing of semiconducting nanowires in an electron microscope. AB - For the development of electronic nanoscale structures, feedback on its electronic properties is crucial, but challenging. Here, we present a comparison of various in situ methods for electronically probing single, p-doped GaAs nanowires inside a scanning electron microscope. The methods used include (i) directly probing individual as-grown nanowires with a sharp nano-manipulator, (ii) contacting dispersed nanowires with two metal contacts and (iii) contacting dispersed nanowires with four metal contacts. For the last two cases, we compare the results obtained using conventional ex situ litho-graphy contacting techniques and by in situ, direct-write electron beam induced deposition of a metal (Pt). The comparison shows that 2-probe measurements gives consistent results also with contacts made by electron beam induced deposition, but that for 4-probe, stray deposition can be a problem for shorter nanowires. This comparative study demonstrates that the preferred in situ method depends on the required throughput and reliability. PMID- 26501241 TI - Study of the Biotransformation of Tongmai Formula by Human Intestinal Flora and Its Intestinal Permeability across the Caco-2 Cell Monolayer. AB - Tongmai formula (TMF) is a well-known Chinese medicinal preparation that contains isoflavones as its major bioactive constituents. As traditional Chinese medicines (TCMs) are usually used by oral administration, their fate inside the intestinal lumen, including their biotransformation by human intestinal flora (HIF) and intestinal absorption deserves study. In this work TMF extract was incubated with human intestinal bacteria under anaerobic conditions and the changes in the twelve main constituents of TMF were then investigated. Their intestinal permeabilities, i.e., the transport capability across the intestinal brush border were investigated with a human colon carcinoma cell line (Caco-2) cell monolayer model to predict the absorption mechanism. Meanwhile, rapid HPLC-DAD methods were established for the assay. According to the biotransformation curves of the twelve constituents and the permeability coefficients, the intestinal absorption capacity of the typical compounds was elevated from the levels of 10(-7) cm/s to 10(-5) cm/s from those of the original compounds in TMF. Among them the main isoflavone glycosides puerarin (4), mirificin (6) and daidzin (7) were transformed into the same aglycone, daidzein (10). Therefore it was predicted that the aglycone compounds might be the real active ingredients in TMF. The models used can represent a novel path for the TCM studies. PMID- 26501242 TI - Enzymatic Hydrolysis and Simultaneous Extraction for Preparation of Genipin from Bark of Eucommia ulmoides after Ultrasound, Microwave Pretreatment. AB - A continuous process based on the combination of ultrasounds and/or microwaves pretreatments followed by enzymatic hydrolysis and simultaneous extraction (EHSE) has been proposed to recover genipin from Eucommia ulmoides bark. At first, in the pretreatment step, the mixture of 1.0 g dried bark powder and 10 mL deionized water were irradiated by microwave under 500 W for 10 min. Then, in hydrolysis step, the optimal conditions were as follows: 0.5 mg/mL of cellulase concentration, 4.0 pH of enzyme solution, 24 h of incubation time and 40 degrees C of incubation temperature. After incubation, 10 mL ethanol was added to extract genipin for 30 min by ultrasound. After EHSE treatment, the yield of genipin could reach 1.71 MUmol/g. Moreover, scanning electron micrographs illustrated that severe structural disruption of plant was obtained by EHSE. The results indicated that the EHSE method provided a good alternative for the preparation of genipin from Eucommia ulmoides bark as well as other herbs. PMID- 26501244 TI - Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs. AB - Drugs with low water solubility are predisposed to poor and variable oral bioavailability and, therefore, to variability in clinical response, that might be overcome through an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate forms) may resolve these bioavailability problems, but they can be a challenge to ensure physicochemical stability for the entire shelf life of the drug product. Since clinical failures of polymorph drugs have not been uncommon, and some of them have been entirely unexpected, the Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) has required preliminary and exhaustive screening studies to identify and characterize all the polymorph crystal forms for each drug. In the past, the polymorphism of many drugs was detected fortuitously or through manual time consuming methods; today, drug crystal engineering, in particular, combinatorial chemistry and high-throughput screening, makes it possible to easily and exhaustively identify stable polymorphic and/or hydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related problems or clinical failures. This review describes the concepts involved, provides examples of drugs characterized by poor solubility for which polymorphism has proven important, outlines the state-of-the-art technologies and discusses the pertinent regulations. PMID- 26501245 TI - In Vitro Cytoprotective Effects and Antioxidant Capacity of Phenolic Compounds from the Leaves of Swietenia macrophylla. AB - Swietenia macrophylla (mahogany) is a highly valued timber species, whereas the leaves are considered to be waste product. A total of 27 phenolic compounds were identified in aqueous extracts from mahogany leaves by comparing retention times and mass spectra data with those of authentic standards using LC-ESI-MS/MS. Polyphenols play an important role in plants as defense mechanisms against pests and pathogens and have potent antioxidant properties. In terms of health applications, interest has increased considerably in naturally occurring antioxidant sources, since they can retard the progress of many important neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The antioxidant capacities of two aqueous extracts, M1 (decoction) and M2 (infusion), were measured using TEAC and Folin-Ciocalteau methods. Additionally, M1 was used in order to investigate its potential cytoprotective effects on an in vitro model of neurodegeneration, by using primary cerebellar cultures exposed to methyl mercury (MeHg). Under experimental sub-chronic conditions (72 h), concomitant exposure of the same cultures to MeHg and M1 extract resulted in a statistically significant increase in cell viability in all three concentrations tested (10, 50 and 100 MUg/mL), strongly suggesting that due to its high content of antioxidant compounds, the M1 extract provides significant cytoprotection against the MeHg induced in vitro neurotoxicity. PMID- 26501246 TI - Phosphonylated Acyclic Guanosine Analogues with the 1,2,3-Triazole Linker. AB - A novel series of {4-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1 yl}alkylphosphonates and {4-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-1H 1,2,3-triazol-1-yl}alkylphosphonates as acyclic analogues of guanosine were synthesized and assessed for antiviral activity against a broad range of DNA and RNA viruses and for their cytostatic activity toward three cancerous cell lines (HeLa, L1210 and CEM). They were devoid of antiviral activity; however, several phosphonates were found slightly cytostatic against HeLa cells at an IC50 in the 80-210 uM range. Compounds (1R,2S)-17k and (1S,2S)-17k showed the highest inhibitory effects (IC50=15-30 uM) against the proliferation of murine leukemia (L1210) and human T-lymphocyte (CEM) cell lines. PMID- 26501243 TI - Charting a Path to Success in Virtual Screening. AB - Docking is commonly applied to drug design efforts, especially high-throughput virtual screenings of small molecules, to identify new compounds that bind to a given target. Despite great advances and successful applications in recent years, a number of issues remain unsolved. Most of the challenges and problems faced when running docking experiments are independent of the specific software used, and can be ascribed to either improper input preparation or to the simplified approaches applied to achieve high-throughput speed. Being aware of approximations and limitations of such methods is essential to prevent errors, deal with misleading results, and increase the success rate of virtual screening campaigns. In this review, best practices and most common issues of docking and virtual screening will be discussed, covering the journey from the design of the virtual experiment to the hit identification. PMID- 26501247 TI - Synthesis, Hydrolysis, and Protonation-Promoted Intramolecular Reductive Breakdown of Potential NRTIs: Stavudine alpha-P-Borano-gamma-P-N-L tryptophanyltriphosphates. AB - Phosphorus-modified prodrugs of dideoxynucleoside triphosphates (ddNTPs) have shown promise as pronucleotide strategies for improving antiviral activity compared to their parent dideoxynucleosides. Borane modified NTPs offer a promising choice as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). However, the availability of alpha-P-borano-gamma-P-substituted NTP analogs remains limited due to challenges with synthesis and purification. Here, we report the chemical synthesis and stability of a new potential class of NRTI prodrugs: stavudine (d4T) 5'-alpha-P-borano-gamma-P-N-L tryptophanyltriphosphates. One-pot synthesis of these compounds was achieved via a modified cyclic trimetaphosphate approach. Pure Rp and Sp diastereomers were obtained after HPLC separation. Based on LC-MS analysis, we report degradation pathways, half-lives (5-36 days) and mechanisms arising from structural differences to generate the corresponding borano tri- and di-phosphates, and H phosphonate, via several parallel routes in buffer at physiologically relevant pH and temperature. Here, the major hydrolysis products, d4T alpha-P boranotriphosphate Rp and Sp isomers, were isolated by HPLC and identified with spectral data. We first propose that one of the major degradation products, d4T H phosphonate, was generated from the d4T pronucleotides via a protonation-promoted intramolecular reduction followed by a second step nucleophilic attack. This report could provide valuable information for pronucleotide-based drug design in terms of selective release of target nucleotides. PMID- 26501248 TI - Synthesis and Crystallographic Insight into the Structural Aspects of Some Novel Adamantane-Based Ester Derivatives. AB - Adamantyl-based compounds are commercially important in the treatments for neurological conditions and type-2 diabetes, aside from their anti-viral abilities. Their values in drug design are chronicled as multi-dimensional. In the present study, a series of 2-(adamantan-1-yl)-2-oxoethyl benzoates, 2(a-q), and 2-(adamantan-1-yl)-2-oxoethyl 2-pyridinecarboxylate, 2r, were synthesized by reacting 1-adamantyl bromomethyl ketone with various carboxylic acids using potassium carbonate in dimethylformamide medium at room temperature. Three dimensional structures studied using X-ray diffraction suggest that the adamantyl moiety can serve as an efficient building block to synthesize 2-oxopropyl benzoate derivatives with synclinal conformation with a looser-packed crystal packing system. Compounds 2a, 2b, 2f, 2g, 2i, 2j, 2m, 2n, 2o, 2q and 2r exhibit strong antioxidant activities in the hydrogen peroxide radical scavenging test. Furthermore, three compounds, 2p, 2q and 2r, show good anti-inflammatory activities in the evaluation of albumin denaturation. PMID- 26501249 TI - Amine-Functionalized ZnO Nanosheets for Efficient CO2 Capture and Photoreduction. AB - Amine-functionalized ZnO nanosheets were prepared through a one-step hydrothermal method by using monoethanolamine, which has a hydroxyl group, for covalent attachment on ZnO and a primary amine group to supply the amine functionalization. We demonstrate that the terminal amine groups on ZnO surfaces substantially increase the capability of CO2 capture via chemisorption, resulting in effective CO2 activation. As a result, the photogenerated electrons from excited ZnO can more readily reduce the surface-activated CO2, which thereby enhances the activity for photocatalytic CO2 reduction. PMID- 26501250 TI - Maleimides Designed for Self-Assembly and Reactivity on Graphene. AB - Two new maleimide derivatives have been synthesized, prone to self-assemble and react with graphene as dienophiles. Both compounds bear a long alkyl chain on the carbon-carbon double bond position 3. The maleimide 1 bears a second alkyl chain at the nitrogen, while in compound 2, three maleimide functionalities are linked to a triethynylbenzene core. PMID- 26501252 TI - Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism. AB - Melatonin is a tryptophan-derived molecule with pleiotropic activities. It is present in almost all or all organisms. Its synthetic pathway depends on the species in which it is measured. For example, the tryptophan to melatonin pathway differs in plants and animals. It is speculated that the melatonin synthetic machinery in eukaryotes was inherited from bacteria as a result of endosymbiosis. However, melatonin's synthetic mechanisms in microorganisms are currently unknown. Melatonin metabolism is highly complex with these enzymatic processes having evolved from cytochrome C. In addition to its enzymatic degradation, melatonin is metabolized via pseudoenzymatic and free radical interactive processes. The metabolic products of these processes overlap and it is often difficult to determine which process is dominant. However, under oxidative stress, the free radical interactive pathway may be featured over the others. Because of the complexity of the melatonin degradative processes, it is expected that additional novel melatonin metabolites will be identified in future investigations. The original and primary function of melatonin in early life forms such as in unicellular organisms was as a free radical scavenger and antioxidant. During evolution, melatonin was selected as a signaling molecule to transduce the environmental photoperiodic information into an endocrine message in multicellular organisms and for other purposes as well. As an antioxidant, melatonin exhibits several unique features which differ from the classic antioxidants. These include its cascade reaction with free radicals and its capacity to be induced under moderate oxidative stress. These features make melatonin a potent endogenously-occurring antioxidant that protects organisms from catastrophic oxidative stress. PMID- 26501251 TI - Structure-Activity Relationship of Oligomeric Flavan-3-ols: Importance of the Upper-Unit B-ring Hydroxyl Groups in the Dimeric Structure for Strong Activities. AB - Proanthocyanidins, which are composed of oligomeric flavan-3-ol units, are contained in various foodstuffs (e.g., fruits, vegetables, and drinks) and are strongly biologically active compounds. We investigated which element of the proanthocyanidin structure is primarily responsible for this functionality. In this study, we elucidate the importance of the upper-unit of 4-8 condensed dimeric flavan-3-ols for antimicrobial activity against Saccharomyces cerevisiae (S. cerevisiae) and cervical epithelioid carcinoma cell line HeLa S3 proliferation inhibitory activity. To clarify the important constituent unit of proanthocyanidin, we synthesized four dimeric compounds, (-)-epigallocatechin [4,8]-(+)-catechin, (-)-epigallocatechin-[4,8]-(-)-epigallocatechin, (-) epigallocatechin-[4,8]-(-)-epigallocatechin-3-O-gallate, and (+)-catechin-[4,8]-( )-epigallocatechin and performed structure-activity relationship (SAR) studies. In addition to antimicrobial activity against S. cerevisiae and proliferation inhibitory activity on HeLa S3 cells, the correlation of 2,2-diphenyl-l picrylhydrazyl radical scavenging activity with the number of phenolic hydroxyl groups was low. On the basis of the results of our SAR studies, we concluded that B-ring hydroxyl groups of the upper-unit of the dimer are crucially important for strong and effective activity. PMID- 26501253 TI - Phytochemicals from Ruta graveolens Activate TAS2R Bitter Taste Receptors and TRP Channels Involved in Gustation and Nociception. AB - Ruta graveolens (rue) is a spontaneous plant in the Mediterranean area with a strong aroma and a very intense bitter taste, used in gastronomy and in folk medicine. From the leaves, stems and fruits of rue, we isolated rutin, rutamarin, three furanocoumarins, two quinolinic alkaloids, a dicoumarin and two long chain ketones. Bitter taste and chemesthetic properties have been evaluated by in vitro assays with twenty receptors of the TAS2R family and four TRP ion channels involved in gustation and nociception. Among the alkaloids, skimmianine was active as a specific agonist of T2R14, whereas kokusaginin did not activate any of the tested receptors. The furanocoumarins activates TAS2R10, 14, and 49 with different degrees of selectivity, as well as the TRPA1 somatosensory ion channel. Rutamarin is an agonist of TRPM5 and TRPV1 and a strong antagonist of TRPM8 ion channels. PMID- 26501254 TI - Membrane Interactions of Phytochemicals as Their Molecular Mechanism Applicable to the Discovery of Drug Leads from Plants. AB - In addition to interacting with functional proteins such as receptors, ion channels, and enzymes, a variety of drugs mechanistically act on membrane lipids to change the physicochemical properties of biomembranes as reported for anesthetic, adrenergic, cholinergic, non-steroidal anti-inflammatory, analgesic, antitumor, antiplatelet, antimicrobial, and antioxidant drugs. As well as these membrane-acting drugs, bioactive plant components, phytochemicals, with amphiphilic or hydrophobic structures, are presumed to interact with biological membranes and biomimetic membranes prepared with phospholipids and cholesterol, resulting in the modification of membrane fluidity, microviscosity, order, elasticity, and permeability with the potencies being consistent with their pharmacological effects. A novel mechanistic point of view of phytochemicals would lead to a better understanding of their bioactivities, an insight into their medicinal benefits, and a strategic implication for discovering drug leads from plants. This article reviews the membrane interactions of different classes of phytochemicals by highlighting their induced changes in membrane property. The phytochemicals to be reviewed include membrane-interactive flavonoids, terpenoids, stilbenoids, capsaicinoids, phloroglucinols, naphthodianthrones, organosulfur compounds, alkaloids, anthraquinonoids, ginsenosides, pentacyclic triterpene acids, and curcuminoids. The membrane interaction's applicability to the discovery of phytochemical drug leads is also discussed while referring to previous screening and isolating studies. PMID- 26501255 TI - Expression of Vitamin D Receptor (VDR) Positively Correlates with Survival of Urothelial Bladder Cancer Patients. AB - Vitamin D3 shows tumoristatic and anticancer effects by acting through the vitamin D receptor (VDR), while hydroxylation of 25-hydroxyvitamin D3 at position 1alpha by CYP27B1 is an essential step in its activation. The expression of both the VDR and CYP27B1 has been found in many normal and cancer tissues, but there is a lack of information about its expression in human bladder cancers. The aim of the present research was to examine whether the expression of the VDR and CYP27B1 in bladder cancer was related to the prognostic markers and disease outcome. We analyzed VDR and CYP27B1 in samples of tumor and normal tissues obtained from 71 urinary bladder cancer patients. The highest VDR immunostaining was found in normal epithelium and was significantly lower in bladder cancer cells (p<0.001 with Mann-Whitney U test). VDR expression was lowest in more advanced (pT2b-pT4) (p=0.005 with Mann-Whitney U test) and metastasizing cancers (p<0.05 and p=0.004 with Mann-Whitney U test for nuclear and cytoplasmic VDR immunostaining, respectively). The lack of cytoplasmic and nuclear VDR was also related to shorter overall survival (for cytoplasmic VDR immunolocalization 13.3 vs. 55.3 months of survival, HR=1.92, p=0.04 and for nuclear VDR immunostaining 13.5 vs. 55.3 months of survival, HR=2.47, p=0.002 with Mantel-Cox test). In cases with the lack of high cytoplasmic VDR staining the non-classic differentiations (NDs) was observed in higher percentage of tumor area. CYP27B1 expression was lower in cancer cells than in normal epithelial cells (p=0.03 with Mann-Whitney U test), but its expression did not correlate with tumor stage (pT), metastasizing, grade, mitotic activity or overall survival. In conclusion, expression of the VDR and CYP27B1 are deregulated in urothelial bladder cancers. Although our results showing a relationship between the decreased VDR expression and prognostic markers and survival time indicate potential usefulness of VDR as a new indicator of a poorer prognosis, further studies are needed in different patient cohorts by independent groups to validate this hypothesis. We also suggest that vitamin D-based therapies may represent an adjuvant strategy in treatment for bladder cancers expressing VDR. PMID- 26501256 TI - Comparison of Metabolite Concentrations in the Left Dorsolateral Prefrontal Cortex, the Left Frontal White Matter, and the Left Hippocampus in Patients in Stable Schizophrenia Treated with Antipsychotics with or without Antidepressants. 1H-NMR Spectroscopy Study. AB - Managing affective, negative, and cognitive symptoms remains the most difficult therapeutic problem in stable phase of schizophrenia. Efforts include administration of antidepressants. Drugs effects on brain metabolic parameters can be evaluated by means of proton nuclear magnetic resonance (1H-NMR) spectroscopy. We compared spectroscopic parameters in the left prefrontal cortex (DLPFC), the left frontal white matter (WM) and the left hippocampus and assessed the relationship between treatment and the spectroscopic parameters in both groups. We recruited 25 patients diagnosed with schizophrenia (DSM-IV-TR), with dominant negative symptoms and in stable clinical condition, who were treated with antipsychotic and antidepressive medication for minimum of three months. A group of 25 patients with schizophrenia, who were taking antipsychotic drugs but not antidepressants, was matched. We compared metabolic parameters (N acetylaspartate (NAA), myo-inositol (mI), glutamatergic parameters (Glx), choline (Cho), and creatine (Cr)) between the two groups. All patients were also assessed with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS). In patients receiving antidepressants we observed significantly higher NAA/Cr and NAA/Cho ratios within the DLPFC, as well as significantly higher mI/Cr within the frontal WM. Moreover, we noted significantly lower values of parameters associated with the glutamatergic transmission--Glx/Cr and Glx/Cho in the hippocampus. Doses of antipsychotic drugs in the group treated with antidepressants were also significantly lower in the patients showing similar severity of psychopathology. PMID- 26501257 TI - Microanalysis, Pharmacokinetics and Tissue Distribution of Polysaccharide-Protein Complexes from Longan Pulp in Mice. AB - A high performance size exclusion-fluorescence detection (HPSEC-FD) method combined with fluorescein isothiocyanate (FITC) prelabeling was established for the microanalysis of polysaccharide-protein complexes from longan pulp (LPP). FITC-labeled LPP (LPPF) was fractionated by gel filtration chromatography. The weight-average molecular weight and FITC substitution degree of LPPF were 39.01 kDa and 0.20%, respectively. The HPSEC-FD calibration curves linear over the range of 1-200 ug/mL in mouse plasma, spleen and lung samples with correlation coefficients greater than 0.995. The inter-day and intra-day precisions of the method were not more than 6.9%, and the relative recovery ranged from 93.7% to 106.4%. The concentration-time curve of LPPF in plasma following intravenous (i.v.) administration at 40 mg/kg body weight well fitted to a two-compartment model. LPPF rapidly eliminated from plasma according to the short half-lives (t1/2alpha=2.23 min, t1/2beta=39.11 min) and mean retention times (MRT0-t=1.15 h, MRT0-infinity=1.39 h). After administration over 5 to 360 min, the concentration of LPPF in spleen homogenate decreased from 7.41 to 3.68 ug/mL; the concentration in lung homogenate decreased from 9.08 to 3.40 ug/mL. On the other hand, the increasing concentration of LPPF fraction with low molecular weight in heart homogenate was observed. PMID- 26501259 TI - Studies on [5,6]-Fused Bicyclic Scaffolds Derivatives as Potent Dual B RafV600E/KDR Inhibitors Using Docking and 3D-QSAR Approaches. AB - Research and development of multi-target inhibitors has attracted increasing attention as anticancer therapeutics. B-RafV600E synergistically works with vascular endothelial growth factor receptor 2 (KDR) to promote the occurrence and progression of cancers, and the development of dual-target drugs simultaneously against these two kinds of kinase may offer a better treatment advantage. In this paper, docking and three-dimensional quantitative structure activity relationship (3D-QSAR) studies were performed on a series of dual B-Raf/KDR inhibitors with a novel hinge-binding group, [5,6]-fused bicyclic scaffold. Docking studies revealed optimal binding conformations of these compounds interacting with both B Raf and KDR. Based on these conformations, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were constructed, and the best CoMFA (q2=0.542, r2=0.989 for B-Raf; q2=0.768, r2=0.991 for KDR) and CoMSIA models (q2=0.519, r2=0.992 for B-Raf; q2=0.849, r2=0.993 for KDR) were generated. Further external validations confirmed their predictability, yielding satisfactory correlation coefficients (r2pred=0.764 (CoMFA), r2pred=0.841 (CoMSIA) for B-Raf, r2pred=0.912 (CoMFA), r2pred=0.846 (CoMSIA) for KDR, respectively). Through graphical analysis and comparison on docking results and 3D-QSAR contour maps, key amino acids that affect the ligand-receptor interactions were identified and structural features influencing the activities were discussed. New potent derivatives were designed, and subjected to preliminary pharmacological evaluation. The study may offer useful references for the modification and development of novel dual B-Raf/KDR inhibitors. PMID- 26501258 TI - In Vitro/In Vivo Toxicity Evaluation and Quantification of Iron Oxide Nanoparticles. AB - Increasing biomedical applications of iron oxide nanoparticles (IONPs) in academic and commercial settings have alarmed the scientific community about the safety and assessment of toxicity profiles of IONPs. The great amount of diversity found in the cytotoxic measurements of IONPs points toward the necessity of careful characterization and quantification of IONPs. The present document discusses the major developments related to in vitro and in vivo toxicity assessment of IONPs and its relationship with the physicochemical parameters of IONPs. Major discussion is included on the current spectrophotometric and imaging based techniques used for quantifying, and studying the clearance and biodistribution of IONPs. Several invasive and non invasive quantification techniques along with the pitfalls are discussed in detail. Finally, critical guidelines are provided to optimize the design of IONPs to minimize the toxicity. PMID- 26501260 TI - Adding Sarcosine to Antipsychotic Treatment in Patients with Stable Schizophrenia Changes the Concentrations of Neuronal and Glial Metabolites in the Left Dorsolateral Prefrontal Cortex. AB - The glutamatergic system is a key point in pathogenesis of schizophrenia. Sarcosine (N-methylglycine) is an exogenous amino acid that acts as a glycine transporter inhibitor. It modulates glutamatergic transmission by increasing glycine concentration around NMDA (N-methyl-d-aspartate) receptors. In patients with schizophrenia, the function of the glutamatergic system in the prefrontal cortex is impaired, which may promote negative and cognitive symptoms. Proton nuclear magnetic resonance (1H-NMR) spectroscopy is a non-invasive imaging method enabling the evaluation of brain metabolite concentration, which can be applied to assess pharmacologically induced changes. The aim of the study was to evaluate the influence of a six-month course of sarcosine therapy on the concentration of metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine and gamma-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left dorso-lateral prefrontal cortex (DLPFC) in patients with stable schizophrenia. Fifty patients with schizophrenia, treated with constant antipsychotics doses, in stable clinical condition were randomly assigned to administration of sarcosine (25 patients) or placebo (25 patients) for six months. Metabolite concentrations in DLPFC were assessed with 1.5 Tesla 1H-NMR spectroscopy. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). The first spectroscopy revealed no differences in metabolite concentrations between groups. After six months, NAA/Cho, mI/Cr and mI/Cho ratios in the left DLPFC were significantly higher in the sarcosine than the placebo group. In the sarcosine group, NAA/Cr, NAA/Cho, mI/Cr, mI/Cho ratios also significantly increased compared to baseline values. In the placebo group, only the NAA/Cr ratio increased. The addition of sarcosine to antipsychotic therapy for six months increased markers of neurons viability (NAA) and neurogilal activity (mI) with simultaneous improvement of clinical symptoms. Sarcosine, two grams administered daily, seems to be an effective adjuvant in the pharmacotherapy of schizophrenia. PMID- 26501261 TI - Enhanced Bio-Ethanol Production from Industrial Potato Waste by Statistical Medium Optimization. AB - Industrial wastes are of great interest as a substrate in production of value added products to reduce cost, while managing the waste economically and environmentally. Bio-ethanol production from industrial wastes has gained attention because of its abundance, availability, and rich carbon and nitrogen content. In this study, industrial potato waste was used as a carbon source and a medium was optimized for ethanol production by using statistical designs. The effect of various medium components on ethanol production was evaluated. Yeast extract, malt extract, and MgSO4.7H2O showed significantly positive effects, whereas KH2PO4 and CaCl2.2H2O had a significantly negative effect (p-value<0.05). Using response surface methodology, a medium consisting of 40.4 g/L (dry basis) industrial waste potato, 50 g/L malt extract, and 4.84 g/L MgSO4.7H2O was found optimal and yielded 24.6 g/L ethanol at 30 degrees C, 150 rpm, and 48 h of fermentation. In conclusion, this study demonstrated that industrial potato waste can be used effectively to enhance bioethanol production. PMID- 26501262 TI - May the Best Molecule Win: Competition ESI Mass Spectrometry. AB - Electrospray ionization mass spectrometry has become invaluable in the characterization of macromolecular biological systems such as nucleic acids and proteins. Recent advances in the field of mass spectrometry and the soft conditions characteristic of electrospray ionization allow for the investigation of non-covalent interactions among large biomolecules and ligands. Modulation of genetic processes through the use of small molecule inhibitors with the DNA minor groove is gaining attention as a potential therapeutic approach. In this review, we discuss the development of a competition method using electrospray ionization mass spectrometry to probe the interactions of multiple DNA sequences with libraries of minor groove binding molecules. Such an approach acts as a high throughput screening method to determine important information including the stoichiometry, binding mode, cooperativity, and relative binding affinity. In addition to small molecule-DNA complexes, we highlight other applications in which competition mass spectrometry has been used. A competitive approach to simultaneously investigate complex interactions promises to be a powerful tool in the discovery of small molecule inhibitors with high specificity and for specific, important DNA sequences. PMID- 26501263 TI - Small RNAs in Plant Responses to Abiotic Stresses: Regulatory Roles and Study Methods. AB - To survive under abiotic stresses in the environment, plants trigger a reprogramming of gene expression, by transcriptional regulation or translational regulation, to turn on protective mechanisms. The current focus of research on how plants cope with abiotic stresses has transitioned from transcriptomic analyses to small RNA investigations. In this review, we have summarized and evaluated the current methodologies used in the identification and validation of small RNAs and their targets, in the context of plant responses to abiotic stresses. PMID- 26501264 TI - The Mixture of Salvianolic Acids from Salvia miltiorrhiza and Total Flavonoids from Anemarrhena asphodeloides Attenuate Sulfur Mustard-Induced Injury. AB - Sulfur mustard (SM) is a vesicating chemical warfare agent used in numerous military conflicts and remains a potential chemical threat to the present day. Exposure to SM causes the depletion of cellular antioxidant thiols, mainly glutathione (GSH), which may lead to a series of SM-associated toxic responses. MSTF is the mixture of salvianolic acids (SA) of Salvia miltiorrhiza and total flavonoids (TFA) of Anemarrhena asphodeloides. SA is the main water-soluble phenolic compound in Salvia miltiorrhiza. TFA mainly includes mangiferin, isomangiferin and neomangiferin. SA and TFA possess diverse activities, including antioxidant and anti-inflammation activities. In this study, we mainly investigated the therapeutic effects of MSTF on SM toxicity in Sprague Dawley rats. Treatment with MSTF 1 h after subcutaneous injection with 3.5 mg/kg (equivalent to 0.7 LD50) SM significantly increased the survival levels of rats and attenuated the SM-induced morphological changes in the testis, small intestine and liver tissues. Treatment with MSTF at doses of 60 and 120 mg/kg caused a significant (p<0.05) reversal in SM-induced GSH depletion. Gene expression profiles revealed that treatment with MSTF had a dramatic effect on gene expression changes caused by SM. Treatment with MSTF prevented SM-induced differential expression of 93.8% (973 genes) of 1037 genes. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 36 pathways, such as the MAPK signaling pathway, pathways in cancer, antigen processing and presentation. These data suggest that MSTF attenuates SM-induced injury by increasing GSH and targeting multiple pathways, including the MAPK signaling pathway, as well as antigen processing and presentation. These results suggest that MSTF has the potential to be used as a potential therapeutic agent against SM injuries. PMID- 26501266 TI - Poly-gamma-glutamate-based Materials for Multiple Infection Prophylaxis Possessing Versatile Coating Performance. AB - Poly-gamma-glutamate (PGA) possesses a nylon-like backbone and polyacrylate-like carboxyl groups, and shows an extraordinary solubility in water. In this study, the effective synthesis and structural analysis of some water-insoluble PGA ion complexes (PGAICs) using cationic surfactants, hexadecylpyridinium (HDP), dodecylpyridinium, benzalkonium and benzetonium, were examined. We demonstrated their spontaneous coating performance to the surfaces of different materials (i.e., plastics, metals, and ceramics) as potent anti-staphylococcal and anti Candida agents. The tests against Staphylococcus aureus revealed that, regardless of a variety of materials, PGAICs maintained surface antimicrobial activity, even after the water-soaking treatment, whereas those against Candida albicans indicated that, among PGAICs, PGA/HDP complex is most useful as an anti-fungal agent because of its coating stability. Moreover, the log reduction values against Influenza A and B viruses of PGA/HDP-coated surfaces were estimated to be 5.4 and 3.2, respectively, suggesting that it can be dramatically suppressed the infection of influenza. This is to our knowledge the first observation of PGA based antiviral coatings. PMID- 26501265 TI - Knockdown of PKM2 Suppresses Tumor Growth and Invasion in Lung Adenocarcinoma. AB - Accumulating evidence shows that activity of the pyruvate kinase M2 (PKM2) isoform is closely related to tumorigenesis. In this study, we investigated the relationship between PKM2 expression, tumor invasion, and the prognosis of patients with lung adenocarcinoma. We retrospectively analyzed 65 cases of patients with lung adenocarcinoma who were divided into low and a high expression groups based on PKM2 immunohistochemical staining. High PKM2 expression was significantly associated with reduced patient survival. We used small interfering RNA (siRNA) technology to investigate the effect of targeted PKM2-knockout on tumor growth at the cellular level. In vitro, siRNA-mediated PKM2-knockdown significantly inhibited the proliferation, glucose uptake (25%), ATP generation (20%) and fatty acid synthesis of A549 cells, while the mitochondrial respiratory capacity of the cells increased (13%).Western blotting analysis showed that PKM2 knockout significantly inhibited the expression of the glucose transporter GLUT1 and ATP citrate lyase, which is critical for fatty acid synthesis. Further Western blotting analysis showed that PKM2-knockdown inhibited the expression of matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor (VEGF), which are important in degradation of the extracellular matrix and angiogenesis, respectively. These observations show that PKM2 activates both glycolysis and lipid synthesis, thereby regulating cell proliferation and invasion. This information is important in elucidating the mechanisms by which PKM2 influences the growth and metastasis of lung adenocarcinoma at the cellular and molecular level, thereby providing the basic data required for the development of PKM2 targeted gene therapy. PMID- 26501267 TI - No Effect of Omega-3 Fatty Acid Supplementation on Cognition and Mood in Individuals with Cognitive Impairment and Probable Alzheimer's Disease: A Randomised Controlled Trial. AB - Findings from epidemiological and observational studies have indicated that diets high in omega-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may reduce the risk of cognitive decline and Alzheimer's disease (AD). To determine if increasing intake of DHA and EPA through supplementation is beneficial to cognition and mood in individuals with cognitive impairment no dementia (CIND) or Alzheimer's disease (AD) a four month, randomised, double-blind, placebo controlled study was conducted. Fifty-seven participants with CIND and nineteen with AD were randomised to receive either omega-3 PUFAs (600 mg EPA and 625 mg DHA per day) or placebo (olive oil) over a four month period. Elevating depleted levels of EPA and DHA through supplementation in individuals with CIND or AD was found to have negligible beneficial effect on their cognition or mood. These findings confirm an overall negligible benefit of omega-3 PUFA supplementation for those with cognitive impairment and dementia. More intervention studies need to be undertaken with longer study durations and larger sample sizes. It may prove fruitful to examine effects of different doses as well as effects in other dementia subtypes. PMID- 26501268 TI - Structural Analysis of Crystalline R(+)-alpha-Lipoic Acid-alpha-cyclodextrin Complex Based on Microscopic and Spectroscopic Studies. AB - R(+)-alpha-lipoic acid (RALA) is a naturally-occurring substance, and its protein bound form plays significant role in the energy metabolism in the mitochondria. RALA is vulnerable to a variety of physical stimuli, including heat and UV light, which prompted us to study the stability of its complexes with cyclodextrins (CDs). In this study, we have prepared and purified a crystalline RALA-alphaCD complex and evaluated its properties in the solid state. The results of 1H NMR and PXRD analyses indicated that the crystalline RALA-alphaCD complex is a channel type complex with a molar ratio of 2:3 (RALA:alpha-CD). Attenuated total reflection/Fourier transform infrared analysis of the complex showed the shift of the C=O stretching vibration of RALA due to the formation of the RALA-alphaCD complex. Raman spectroscopic analysis revealed the significant weakness of the S S and C-S stretching vibrations of RALA in the RALA-alphaCD complex implying that the dithiolane ring of RALA is almost enclosed in glucose ring of alpha-CD. Extent of this effect was dependent on the direction of the excitation laser to the hexagonal morphology of the crystal. Solid-state NMR analysis allowed for the chemical shift of the C=O peak to be precisely determined. These results suggested that RALA was positioned in the alpha-CD cavity with its 1,2-dithiolane ring orientated perpendicular to the plane of the alpha-CD ring. PMID- 26501270 TI - Staphylococcus aureus and MRSA Growth and Biofilm Formation after Treatment with Antibiotics and SeNPs. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a dangerous pathogen resistant to beta-lactam antibiotics. Due to its resistance, it is difficult to manage the infections caused by this strain. We examined this issue in terms of observation of the growth properties and ability to form biofilms in sensitive S. aureus and MRSA after the application of antibiotics (ATBs)-ampicillin, oxacillin and penicillin-and complexes of selenium nanoparticles (SeNPs) with these ATBs. The results suggest the strong inhibition effect of SeNPs in complexes with conventional ATBs. Using the impedance method, a higher disruption of biofilms was observed after the application of ATB complexes with SeNPs compared to the group exposed to ATBs without SeNPs. The biofilm formation was intensely inhibited (up to 99%+/-7% for S. aureus and up to 94%+/-4% for MRSA) after application of SeNPs in comparison with bacteria without antibacterial compounds whereas ATBs without SeNPs inhibited S. aureus up to 79%+/-5% and MRSA up to 16%+/-2% only. The obtained results provide a basis for the use of SeNPs as a tool for the treatment of bacterial infections, which can be complicated because of increasing resistance of bacteria to conventional ATB drugs. PMID- 26501269 TI - Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders. AB - Atypical parkinsonism syndromes, such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, are neurodegenerative diseases with complex clinical and pathological features. Heterogeneity in clinical presentations, possible secondary determinants as well as mimic syndromes pose a major challenge to accurately diagnose patients suffering from these devastating conditions. Over the last two decades, significant advancements in genomic technologies have provided us with increasing insights into the molecular pathogenesis of atypical parkinsonism and their intriguing relationships to related neurodegenerative diseases, fueling new hopes to incorporate molecular knowledge into our diagnostic, prognostic and therapeutic approaches towards managing these conditions. In this review article, we summarize the current understanding of genetic mechanisms implicated in atypical parkinsonism syndromes. We further highlight mimic syndromes relevant to differential considerations and possible future directions. PMID- 26501272 TI - Surface-Deacetylated Chitin Nano-Fiber/Hyaluronic Acid Composites as Potential Antioxidative Compounds for Use in Extended-Release Matrix Tablets. AB - In this study, we examined a possible use of a surface-deacetylated chitin nano fiber (SDCH-NF) and hyaluronic acid (HA) interpolymer complex (IPC) tablet as a potential antioxidative compound in extended-release matrix tablets. The antioxidant properties of untreated chitin (UCH), SDCH-NF, and HA were examined using N-centered radicals derived from 1,1'-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). SDCH-NF and HA had acceptable scavenging abilities and were relatively efficient radical scavengers, but UCH was much less effective. The results suggest that SDCH-NF and HA could serve as scavengers of compounds related to the development of oxidative stress. An SDCH-NF/HA IPC tablet was prepared and evaluated as an extended-release tablet matrix using famotidine (FMT) as a model drug. The release of FMT from the IPC tablet (DCF-NF:HA=1:1) was slower than that from a SDCH-NF only tablet. Turbidity measurements and X-ray diffraction (XRD) data also indicated that the optimum complexation ratio for IPC between SDCH-NF/HA is 1/1, resulting in a good relationship between turbidity or XRD of the complex and the release ratio of FMT. These results suggest that an SDCH-NF/HA tablet has the potential for use in an extended-release IPC tablet with a high antioxidant activity. PMID- 26501271 TI - Bioactive Compounds and Antioxidant Activity in Different Types of Berries. AB - Berries, especially members of several families, such as Rosaceae (strawberry, raspberry, blackberry), and Ericaceae (blueberry, cranberry), belong to the best dietary sources of bioactive compounds (BAC). They have delicious taste and flavor, have economic importance, and because of the antioxidant properties of BAC, they are of great interest also for nutritionists and food technologists due to the opportunity to use BAC as functional foods ingredients. The bioactive compounds in berries contain mainly phenolic compounds (phenolic acids, flavonoids, such as anthocyanins and flavonols, and tannins) and ascorbic acid. These compounds, either individually or combined, are responsible for various health benefits of berries, such as prevention of inflammation disorders, cardiovascular diseases, or protective effects to lower the risk of various cancers. In this review bioactive compounds of commonly consumed berries are described, as well as the factors influencing their antioxidant capacity and their health benefits. PMID- 26501273 TI - Biological Screening of Newly Synthesized BIAN N-Heterocyclic Gold Carbene Complexes in Zebrafish Embryos. AB - N-Heterocyclic carbene (NHC) metal complexes possess diverse biological activities but have yet to be extensively explored as potential chemotherapeutic agents. We have previously reported the synthesis of a new class of NHC metal complexes N-heterocyclic with acetate [IPr(BIAN)AuOAc] and chloride [IPr(BIAN)AuCl] ligands. In the experiments reported herein, the zebrafish embryos were exposed to serial dilutions of each of these complexes for 10-12 h. One hundred percent mortality was observed at concentrations>=50 uM. At sub lethal concentrations (10-30 uM), both compounds influenced zebrafish embryonic development. However, quite diverse categories of abnormalities were found in exposed embryos with each compound. Severe brain deformation and notochord degeneration were evident in the case of [IPr(BIAN)AuOAc]. The zebrafish embryos treated with [IPr(BIAN)AuCl] exhibited stunted growth and consequently had smaller body sizes. A depletion of 30%-40% glutathione was detected in the treated embryos, which could account for one of the possible mechanism of neurotoxicity. The fact that these compounds are capable of both affecting the growth and also compromising antioxidant systems by elevating intracellular ROS production implies that they could play an important role as a new breed of therapeutic molecules. PMID- 26501274 TI - CRISPR/Cas9-Mediated Rapid Generation of Multiple Mouse Lines Identified Ccdc63 as Essential for Spermiogenesis. AB - Spermatozoa are flagellated cells whose role in fertilization is dependent on their ability to move towards an oocyte. The structure of the sperm flagella is highly conserved across species, and much of what is known about this structure is derived from studies utilizing animal models. One group of proteins essential for the movement of the flagella are the dyneins. Using the advanced technology of CRISPR/Cas9 we have targeted three dynein group members; Dnaic1, Wdr63 and Ccdc63 in mice. All three of these genes are expressed strongly in the testis. We generated mice with amino acid substitutions in Dnaic1 to analyze two specific phosphorylation events at S124 and S127, and generated simple knockouts of Wdr63 and Ccdc63. We found that the targeted phosphorylation sites in Dnaic1 were not essential for male fertility. Similarly, Wdr63 was not essential for male fertility; however, Ccdc63 removal resulted in sterile male mice due to shortened flagella. This study demonstrates the versatility of the CRISPR/Cas9 system to generate animal models of a highly complex system by introducing point mutations and simple knockouts in a fast and efficient manner. PMID- 26501275 TI - Minimizing off-Target Mutagenesis Risks Caused by Programmable Nucleases. AB - Programmable nucleases, such as zinc finger nucleases (ZFNs), transcription activator like effector nucleases (TALENs), and clustered regularly interspersed short palindromic repeats associated protein-9 (CRISPR-Cas9), hold tremendous potential for applications in the clinical setting to treat genetic diseases or prevent infectious diseases. However, because the accuracy of DNA recognition by these nucleases is not always perfect, off-target mutagenesis may result in undesirable adverse events in treated patients such as cellular toxicity or tumorigenesis. Therefore, designing nucleases and analyzing their activity must be carefully evaluated to minimize off-target mutagenesis. Furthermore, rigorous genomic testing will be important to ensure the integrity of nuclease modified cells. In this review, we provide an overview of available nuclease designing platforms, nuclease engineering approaches to minimize off-target activity, and methods to evaluate both on- and off-target cleavage of CRISPR-Cas9. PMID- 26501276 TI - Elevated STAT3 Signaling-Mediated Upregulation of MMP-2/9 Confers Enhanced Invasion Ability in Multidrug-Resistant Breast Cancer Cells. AB - The development of multidrug resistance greatly impedes effective cancer therapy. Recent advances in cancer research have demonstrated that acquisition of multidrug resistance by cancer cells is usually accompanied by enhanced cell invasiveness. Several lines of evidence indicated that cross activation of other signaling pathways during development of drug resistance may increase invasive potential of multidrug-resistant (MDR) cancer cells. However, the accurate mechanism of this process is largely undefined. In this study, to better understand the associated molecular pathways responsible for cancer progression induced by drug resistance, a MDR human breast cancer cell line SK-BR-3/EPR with P-glycoprotein overexpression was established using stepwise long-term exposure to increasing concentration of epirubicin. The SK-BR-3/EPR cell line exhibited decreased cell proliferative activity, but enhanced cell invasive capacity. We showed that the expression of metastasis-related matrix metalloproteinase (MMP) 2/9 was elevated in SK-BR-3/EPR cells. Moreover, SK-BR-3/EPR cells showed elevated activation of STAT3. Activation of STAT3 signaling is responsible for enhanced invasiveness of SK-BR-3/EPR cells through upregulation of MMP-2/9. STAT3 is a well-known oncogene and is frequently implicated in tumorigenesis and chemotherapeutic resistance. Our findings augment insight into the mechanism underlying the functional association between MDR and cancer invasiveness. PMID- 26501277 TI - Analytical modelling of a refractive index sensor based on an intrinsic micro Fabry-Perot interferometer. AB - In this work a refractive index sensor based on a combination of the non dispersive sensing (NDS) and the Tunable Laser Spectroscopy (TLS) principles is presented. Here, in order to have one reference and one measurement channel a single-beam dual-path configuration is used for implementing the NDS principle. These channels are monitored with a couple of identical optical detectors which are correlated to calculate the overall sensor response, called here the depth of modulation. It is shown that this is useful to minimize drifting errors due to source power variations. Furthermore, a comprehensive analysis of a refractive index sensing setup, based on an intrinsic micro Fabry-Perot Interferometer (FPI) is described. Here, the changes over the FPI pattern as the exit refractive index is varied are analytically modelled by using the characteristic matrix method. Additionally, our simulated results are supported by experimental measurements which are also provided. Finally it is shown that by using this principle a simple refractive index sensor with a resolution in the order of 2.15 * 10(-4) RIU can be implemented by using a couple of standard and low cost photodetectors. PMID- 26501278 TI - A wireless sensor network for urban traffic characterization and trend monitoring. AB - Sustainable mobility requires a better management of the available infrastructure resources. To achieve this goal, it is necessary to obtain accurate data about road usage, in particular in urban areas. Although a variety of sensor alternates for urban traffic exist, they usually require extensive investments in the form of construction works for installation, processing means, etc. Wireless Sensor Networks (WSN) are an alternative to acquire urban traffic data, allowing for flexible, easy deployment. Together with the use of the appropriate sensors, like Bluetooth identification, and associate processing, WSN can provide the means to obtain in real time data like the origin-destination matrix, a key tool for trend monitoring which previously required weeks or months to be completed. This paper presents a system based on WSN designed to characterize urban traffic, particularly traffic trend monitoring through the calculation of the origin destination matrix in real time by using Bluetooth identification. Additional sensors are also available integrated in different types of nodes. Experiments in real conditions have been performed, both for separate sensors (Bluetooth, ultrasound and laser), and for the whole system, showing the feasibility of this approach. PMID- 26501279 TI - A new model based on adaptation of the external loop to compensate the hysteresis of tactile sensors. AB - This paper presents a novel method to compensate for hysteresis nonlinearities observed in the response of a tactile sensor. The External Loop Adaptation Method (ELAM) performs a piecewise linear mapping of the experimentally measured external curves of the hysteresis loop to obtain all possible internal cycles. The optimal division of the input interval where the curve is approximated is provided by the error minimization algorithm. This process is carried out off line and provides parameters to compute the split point in real time. A different linear transformation is then performed at the left and right of this point and a more precise fitting is achieved. The models obtained with the ELAM method are compared with those obtained from three other approaches. The results show that the ELAM method achieves a more accurate fitting. Moreover, the involved mathematical operations are simpler and therefore easier to implement in devices such as Field Programmable Gate Array (FPGAs) for real time applications. Furthermore, the method needs to identify fewer parameters and requires no previous selection process of operators or functions. Finally, the method can be applied to other sensors or actuators with complex hysteresis loop shapes. PMID- 26501280 TI - Modified particle filtering algorithm for single acoustic vector sensor DOA tracking. AB - The conventional direction of arrival (DOA) estimation algorithm with static sources assumption usually estimates the source angles of two adjacent moments independently and the correlation of the moments is not considered. In this article, we focus on the DOA estimation of moving sources and a modified particle filtering (MPF) algorithm is proposed with state space model of single acoustic vector sensor. Although the particle filtering (PF) algorithm has been introduced for acoustic vector sensor applications, it is not suitable for the case that one dimension angle of source is estimated with large deviation, the two dimension angles (pitch angle and azimuth angle) cannot be simultaneously employed to update the state through resampling processing of PF algorithm. To solve the problems mentioned above, the MPF algorithm is proposed in which the state estimation of previous moment is introduced to the particle sampling of present moment to improve the importance function. Moreover, the independent relationship of pitch angle and azimuth angle is considered and the two dimension angles are sampled and evaluated, respectively. Then, the MUSIC spectrum function is used as the "likehood" function of the MPF algorithm, and the modified PF-MUSIC (MPF MUSIC) algorithm is proposed to improve the root mean square error (RMSE) and the probability of convergence. The theoretical analysis and the simulation results validate the effectiveness and feasibility of the two proposed algorithms. PMID- 26501281 TI - Real-time single-frequency GPS/MEMS-IMU attitude determination of lightweight UAVs. AB - In this paper, a newly-developed direct georeferencing system for the guidance, navigation and control of lightweight unmanned aerial vehicles (UAVs), having a weight limit of 5 kg and a size limit of 1.5 m, and for UAV-based surveying and remote sensing applications is presented. The system is intended to provide highly accurate positions and attitudes (better than 5 cm and 0.5 degrees ) in real time, using lightweight components. The main focus of this paper is on the attitude determination with the system. This attitude determination is based on an onboard single-frequency GPS baseline, MEMS (micro-electro-mechanical systems) inertial sensor readings, magnetic field observations and a 3D position measurement. All of this information is integrated in a sixteen-state error space Kalman filter. Special attention in the algorithm development is paid to the carrier phase ambiguity resolution of the single-frequency GPS baseline observations. We aim at a reliable and instantaneous ambiguity resolution, since the system is used in urban areas, where frequent losses of the GPS signal lock occur and the GPS measurement conditions are challenging. Flight tests and a comparison to a navigation-grade inertial navigation system illustrate the performance of the developed system in dynamic situations. Evaluations show that the accuracies of the system are 0.05 degrees for the roll and the pitch angle and 0.2 degrees for the yaw angle. The ambiguities of the single-frequency GPS baseline can be resolved instantaneously in more than 90% of the cases. PMID- 26501282 TI - Protein adsorption in microengraving immunoassays. AB - Microengraving is a novel immunoassay for characterizing multiple protein secretions from single cells. During the immunoassay, characteristic diffusion and kinetic time scales and determine the time for molecular diffusion of proteins secreted from the activated single lymphocytes and subsequent binding onto the glass slide surface respectively. Our results demonstrate that molecular diffusion plays important roles in the early stage of protein adsorption dynamics which shifts to a kinetic controlled mechanism in the later stage. Similar dynamic pathways are observed for protein adsorption with significantly fast rates and rapid shifts in transport mechanisms when is increased a hundred times from 0.313 to 31.3. Theoretical adsorption isotherms follow the trend of experimentally obtained data. Adsorption isotherms indicate that amount of proteins secreted from individual cells and subsequently captured on a clean glass slide surface increases monotonically with time. Our study directly validates that protein secretion rates can be quantified by the microengraving immunoassay. This will enable us to apply microengraving immunoassays to quantify secretion rates from 104-105 single cells in parallel, screen antigen-specific cells with the highest secretion rate for clonal expansion and quantitatively reveal cellular heterogeneity within a small cell sample. PMID- 26501283 TI - PUFKEY: a high-security and high-throughput hardware true random number generator for sensor networks. AB - Random number generators (RNG) play an important role in many sensor network systems and applications, such as those requiring secure and robust communications. In this paper, we develop a high-security and high-throughput hardware true random number generator, called PUFKEY, which consists of two kinds of physical unclonable function (PUF) elements. Combined with a conditioning algorithm, true random seeds are extracted from the noise on the start-up pattern of SRAM memories. These true random seeds contain full entropy. Then, the true random seeds are used as the input for a non-deterministic hardware RNG to generate a stream of true random bits with a throughput as high as 803 Mbps. The experimental results show that the bitstream generated by the proposed PUFKEY can pass all standard national institute of standards and technology (NIST) randomness tests and is resilient to a wide range of security attacks. PMID- 26501284 TI - Sparse Bayesian learning for DOA estimation with mutual coupling. AB - Sparse Bayesian learning (SBL) has given renewed interest to the problem of direction-of-arrival (DOA) estimation. It is generally assumed that the measurement matrix in SBL is precisely known. Unfortunately, this assumption may be invalid in practice due to the imperfect manifold caused by unknown or misspecified mutual coupling. This paper describes a modified SBL method for joint estimation of DOAs and mutual coupling coefficients with uniform linear arrays (ULAs). Unlike the existing method that only uses stationary priors, our new approach utilizes a hierarchical form of the Student t prior to enforce the sparsity of the unknown signal more heavily. We also provide a distinct Bayesian inference for the expectation-maximization (EM) algorithm, which can update the mutual coupling coefficients more efficiently. Another difference is that our method uses an additional singular value decomposition (SVD) to reduce the computational complexity of the signal reconstruction process and the sensitivity to the measurement noise. PMID- 26501286 TI - Experimental validation of normalized uniform load surface curvature method for damage localization. AB - In this study, we experimentally validated the normalized uniform load surface (NULS) curvature method, which has been developed recently to assess damage localization in beam-type structures. The normalization technique allows for the accurate assessment of damage localization with greater sensitivity irrespective of the damage location. In this study, damage to a simply supported beam was numerically and experimentally investigated on the basis of the changes in the NULS curvatures, which were estimated from the modal flexibility matrices obtained from the acceleration responses under an ambient excitation. Two damage scenarios were considered for the single damage case as well as the multiple damages case by reducing the bending stiffness (EI) of the affected element(s). Numerical simulations were performed using MATLAB as a preliminary step. During the validation experiments, a series of tests were performed. It was found that the damage locations could be identified successfully without any false-positive or false-negative detections using the proposed method. For comparison, the damage detection performances were compared with those of two other well-known methods based on the modal flexibility matrix, namely, the uniform load surface (ULS) method and the ULS curvature method. It was confirmed that the proposed method is more effective for investigating the damage locations of simply supported beams than the two conventional methods in terms of sensitivity to damage under measurement noise. PMID- 26501287 TI - Using polynomials to simplify fixed pattern noise and photometric correction of logarithmic CMOS image sensors. AB - An important class of complementary metal-oxide-semiconductor (CMOS) image sensors are those where pixel responses are monotonic nonlinear functions of light stimuli. This class includes various logarithmic architectures, which are easily capable of wide dynamic range imaging, at video rates, but which are vulnerable to image quality issues. To minimize fixed pattern noise (FPN) and maximize photometric accuracy, pixel responses must be calibrated and corrected due to mismatch and process variation during fabrication. Unlike literature approaches, which employ circuit-based models of varying complexity, this paper introduces a novel approach based on low-degree polynomials. Although each pixel may have a highly nonlinear response, an approximately-linear FPN calibration is possible by exploiting the monotonic nature of imaging. Moreover, FPN correction requires only arithmetic, and an optimal fixed-point implementation is readily derived, subject to a user-specified number of bits per pixel. Using a monotonic spline, involving cubic polynomials, photometric calibration is also possible without a circuit-based model, and fixed-point photometric correction requires only a look-up table. The approach is experimentally validated with a logarithmic CMOS image sensor and is compared to a leading approach from the literature. The novel approach proves effective and efficient. PMID- 26501288 TI - Two-dimensional automatic measurement for nozzle flow distribution using improved ultrasonic sensor. AB - Spray deposition and distribution are affected by many factors, one of which is nozzle flow distribution. A two-dimensional automatic measurement system, which consisted of a conveying unit, a system control unit, an ultrasonic sensor, and a deposition collecting dish, was designed and developed. The system could precisely move an ultrasonic sensor above a pesticide deposition collecting dish to measure the nozzle flow distribution. A sensor sleeve with a PVC tube was designed for the ultrasonic sensor to limit its beam angle in order to measure the liquid level in the small troughs. System performance tests were conducted to verify the designed functions and measurement accuracy. A commercial spray nozzle was also used to measure its flow distribution. The test results showed that the relative error on volume measurement was less than 7.27% when the liquid volume was 2 mL in trough, while the error was less than 4.52% when the liquid volume was 4 mL or more. The developed system was also used to evaluate the flow distribution of a commercial nozzle. It was able to provide the shape and the spraying width of the flow distribution accurately. PMID- 26501285 TI - Fluorescent proteins as genetically encoded FRET biosensors in life sciences. AB - Fluorescence- or Forster resonance energy transfer (FRET) is a measurable physical energy transfer phenomenon between appropriate chromophores, when they are in sufficient proximity, usually within 10 nm. This feature has made them incredibly useful tools for many biomedical studies on molecular interactions. Furthermore, this principle is increasingly exploited for the design of biosensors, where two chromophores are linked with a sensory domain controlling their distance and thus the degree of FRET. The versatility of these FRET biosensors made it possible to assess a vast amount of biological variables in a fast and standardized manner, allowing not only high-throughput studies but also sub-cellular measurements of biological processes. In this review, we aim at giving an overview over the recent advances in genetically encoded, fluorescent protein based FRET-biosensors, as these represent the largest and most vividly growing group of FRET-based sensors. For easy understanding, we are grouping them into four categories, depending on their molecular mechanism. These are based on: (a) cleavage; (b) conformational-change; (c) mechanical force and (d) changes in the micro-environment. We also address the many issues and considerations that come with the development of FRET-based biosensors, as well as the possibilities that are available to measure them. PMID- 26501289 TI - Position estimation and local mapping using omnidirectional images and global appearance descriptors. AB - This work presents some methods to create local maps and to estimate the position of a mobile robot, using the global appearance of omnidirectional images. We use a robot that carries an omnidirectional vision system on it. Every omnidirectional image acquired by the robot is described only with one global appearance descriptor, based on the Radon transform. In the work presented in this paper, two different possibilities have been considered. In the first one, we assume the existence of a map previously built composed of omnidirectional images that have been captured from previously-known positions. The purpose in this case consists of estimating the nearest position of the map to the current position of the robot, making use of the visual information acquired by the robot from its current (unknown) position. In the second one, we assume that we have a model of the environment composed of omnidirectional images, but with no information about the location of where the images were acquired. The purpose in this case consists of building a local map and estimating the position of the robot within this map. Both methods are tested with different databases (including virtual and real images) taking into consideration the changes of the position of different objects in the environment, different lighting conditions and occlusions. The results show the effectiveness and the robustness of both methods. PMID- 26501290 TI - Hardware design and implementation of a wavelet de-noising procedure for medical signal preprocessing. AB - In this paper, a discrete wavelet transform (DWT) based de-noising with its applications into the noise reduction for medical signal preprocessing is introduced. This work focuses on the hardware realization of a real-time wavelet de-noising procedure. The proposed de-noising circuit mainly consists of three modules: a DWT, a thresholding, and an inverse DWT (IDWT) modular circuits. We also proposed a novel adaptive thresholding scheme and incorporated it into our wavelet de-noising procedure. Performance was then evaluated on both the architectural designs of the software and. In addition, the de-noising circuit was also implemented by downloading the Verilog codes to a field programmable gate array (FPGA) based platform so that its ability in noise reduction may be further validated in actual practice. Simulation experiment results produced by applying a set of simulated noise-contaminated electrocardiogram (ECG) signals into the de-noising circuit showed that the circuit could not only desirably meet the requirement of real-time processing, but also achieve satisfactory performance for noise reduction, while the sharp features of the ECG signals can be well preserved. The proposed de-noising circuit was further synthesized using the Synopsys Design Compiler with an Artisan Taiwan Semiconductor Manufacturing Company (TSMC, Hsinchu, Taiwan) 40 nm standard cell library. The integrated circuit (IC) synthesis simulation results showed that the proposed design can achieve a clock frequency of 200 MHz and the power consumption was only 17.4 mW, when operated at 200 MHz. PMID- 26501291 TI - Ammonia gas sensing behavior of tanninsulfonic acid doped polyaniline-TiO2 composite. AB - A highly active tannin doped polyaniline-TiO2 composite ammonia gas sensor was developed and the mechanism behind the gas sensing activity was reported for the first time. A tanninsulfonic acid doped polyaniline (TANIPANI)-titanium dioxide nanocomposite was synthesized by an in situ polymerization of aniline in the presence of tanninsulfonic acid and titanium dioxide nanoparticles. X-ray diffraction and thermogravimetric analysis were utilized to determine the incorporation of TiO2 in TANIPANI matrix. UV-Visible and infrared spectroscopy studies provided information about the electronic interactions among tannin, polyaniline, and TiO2. Scanning electron microscopy (SEM) along with energy dispersive X-ray spectroscopy (EDS) and atomic force microscopy (AFM) surface analysis techniques were used to investigate the metal oxide dispersions inside polyaniline matrix. Gas sensors were prepared by spin coating solutions of TANIPANI-TiO2 and TANIPANI composites onto glass slides. Sensors were tested at three different concentrations (20 ppm, 40 ppm, and 60 ppm) of ammonia gas at ambient temperature conditions by measuring the changes in surface resistivity of the films with respect to time. Ammonia gas sensing plots are presented showing the response values, response times and recovery times. The TANIPANI-TiO2 composite exhibited better response and shorter recovery times when compared to TANIPANI control and other polyaniline composites that have been reported in the literature. For the first time a proposed mechanism of gas sensing basing on the polaron band localization and its effects on the gas sensing behavior of polyaniline are reported. PMID- 26501292 TI - Development of kinematic 3D laser scanning system for indoor mapping and as-built BIM using constrained SLAM. AB - The growing interest and use of indoor mapping is driving a demand for improved data-acquisition facility, efficiency and productivity in the era of the Building Information Model (BIM). The conventional static laser scanning method suffers from some limitations on its operability in complex indoor environments, due to the presence of occlusions. Full scanning of indoor spaces without loss of information requires that surveyors change the scanner position many times, which incurs extra work for registration of each scanned point cloud. Alternatively, a kinematic 3D laser scanning system, proposed herein, uses line-feature-based Simultaneous Localization and Mapping (SLAM) technique for continuous mapping. Moreover, to reduce the uncertainty of line-feature extraction, we incorporated constrained adjustment based on an assumption made with respect to typical indoor environments: that the main structures are formed of parallel or orthogonal line features. The superiority of the proposed constrained adjustment is its reduction for uncertainties of the adjusted lines, leading to successful data association process. In the present study, kinematic scanning with and without constrained adjustment were comparatively evaluated in two test sites, and the results confirmed the effectiveness of the proposed system. The accuracy of the 3D mapping result was additionally evaluated by comparison with the reference points acquired by a total station: the Euclidean average distance error was 0.034 m for the seminar room and 0.043 m for the corridor, which satisfied the error tolerance for point cloud acquisition (0.051 m) according to the guidelines of the General Services Administration for BIM accuracy. PMID- 26501293 TI - Sensor and methodology for dielectric analysis of vegetal oils submitted to thermal stress. AB - Vegetable oils used in frying food represent a social problem as its destination. The residual oil can be recycled and returned to the production line, as biodiesel, as soap, or as putty. The state of the residual oil is determined according to their physicochemical characteristics whose values define its economically viable destination. However, the physicochemical analysis requires high costs, time and general cost of transporting. This study presents the use of a capacitive sensor and a quick and inexpensive method to correlate the physicochemical variables to the dielectric constant of the material undergoing oil samples to thermal cycling. The proposed method allows reducing costs in the characterization of residual oil and the reduction in analysis time. In addition, the method allows an assessment of the quality of the vegetable oil during use. The experimental results show the increasing of the dielectric constant with the temperature, which facilitates measurement and classification of the dielectric constant at considerably higher temperatures. The results also confirm a definitive degradation in used oil and a correlation between the dielectric constant of the sample with the results of the physicochemical analysis (iodine value, acid value, viscosity and refractive index). PMID- 26501294 TI - Tunable micro- and nanomechanical resonators. AB - Advances in micro- and nanofabrication technologies have enabled the development of novel micro- and nanomechanical resonators which have attracted significant attention due to their fascinating physical properties and growing potential applications. In this review, we have presented a brief overview of the resonance behavior and frequency tuning principles by varying either the mass or the stiffness of resonators. The progress in micro- and nanomechanical resonators using the tuning electrode, tuning fork, and suspended channel structures and made of graphene have been reviewed. We have also highlighted some major influencing factors such as large-amplitude effect, surface effect and fluid effect on the performances of resonators. More specifically, we have addressed the effects of axial stress/strain, residual surface stress and adsorption induced surface stress on the sensing and detection applications and discussed the current challenges. We have significantly focused on the active and passive frequency tuning methods and techniques for micro- and nanomechanical resonator applications. On one hand, we have comprehensively evaluated the advantages and disadvantages of each strategy, including active methods such as electrothermal, electrostatic, piezoelectrical, dielectric, magnetomotive, photothermal, mode coupling as well as tension-based tuning mechanisms, and passive techniques such as post-fabrication and post-packaging tuning processes. On the other hand, the tuning capability and challenges to integrate reliable and customizable frequency tuning methods have been addressed. We have additionally concluded with a discussion of important future directions for further tunable micro- and nanomechanical resonators. PMID- 26501296 TI - Household Air Pollution and Under-Five Mortality in Bangladesh (2004-2011). AB - Household air pollution (HAP) is one of the leading causes of respiratory illness and deaths among children under five years in Bangladesh. This study investigates the association between HAP from cooking fuel and under-five mortality using Bangladesh Demographic and Health Survey (BDHS) datasets over the period 2004 2011 (n = 18,308 children), and the extent to which this association differed by environmental and behavioral factors affecting level of exposure. The association between HAP and neonatal (age between 0-28 days), infant (age between 0 and 11 months) and under-five (age between 0 and 59 months) mortality was examined using multilevel logistic regression models. HAP was not strongly associated with overall neonatal (OR = 1.49, 95% CI = 1.01-2.22, p = 0.043), infant (OR = 1.27, 95% CI = 0.91-1.77, p = 0.157) or under-five mortality (OR = 1.14, 95% CI = 0.83 1.55, p = 0.422) in the context of overall decreasing trends in under-five mortality. The association was stronger for households with an indoor kitchen using polluting fuels, and in women who had never breastfed. Reductions in exposure to pollution from cooking fuel, given it is a ubiquitous and modifiable risk factor, can result in further declines in under-five mortality with household design and behavioural interventions. PMID- 26501295 TI - Quantifying and Adjusting for Disease Misclassification Due to Loss to Follow-Up in Historical Cohort Mortality Studies. AB - The purpose of this analysis was to quantify and adjust for disease misclassification from loss to follow-up in a historical cohort mortality study of workers where exposure was categorized as a multi-level variable. Disease classification parameters were defined using 2008 mortality data for the New Zealand population and the proportions of known deaths observed for the cohort. The probability distributions for each classification parameter were constructed to account for potential differences in mortality due to exposure status, gender, and ethnicity. Probabilistic uncertainty analysis (bias analysis), which uses Monte Carlo techniques, was then used to sample each parameter distribution 50,000 times, calculating adjusted odds ratios (ORDM-LTF) that compared the mortality of workers with the highest cumulative exposure to those that were considered never-exposed. The geometric mean ORDM-LTF ranged between 1.65 (certainty interval (CI): 0.50-3.88) and 3.33 (CI: 1.21-10.48), and the geometric mean of the disease-misclassification error factor (epsilonDM-LTF), which is the ratio of the observed odds ratio to the adjusted odds ratio, had a range of 0.91 (CI: 0.29-2.52) to 1.85 (CI: 0.78-6.07). Only when workers in the highest exposure category were more likely than those never-exposed to be misclassified as non-cases did the ORDM-LTF frequency distributions shift further away from the null. The application of uncertainty analysis to historical cohort mortality studies with multi-level exposures can provide valuable insight into the magnitude and direction of study error resulting from losses to follow-up. PMID- 26501297 TI - Evidence for Public Health Risks of Wastewater and Excreta Management Practices in Southeast Asia: A Scoping Review. AB - The use of wastewater and excreta in agriculture is a common practice in Southeast Asia; however, concerns remain about the potential public health risks of this practice. We undertook a scoping review to examine the extent, range, and nature of literature, as well as synthesize the evidence for associations between wastewater and excreta management practices and public health risks in Southeast Asia. Three electronic databases (PubMed, CAB Direct, and Web of Science) were searched and a total of 27 relevant studies were included and evaluated. The available evidence suggested that possible occupational health risks of wastewater and excreta management practices include diarrhea, skin infection, parasitic infection, bacterial infection, and epilepsy. Community members can be at risk for adverse health outcomes through consuming contaminated fish, vegetables, or fruits. Results suggested that practices including handling, treatment, and use of waste may be harmful to human health, particularly farmer's health. Many studies in this review, however, had limitations including lack of gender analyses, exposure assessment, and longitudinal study designs. These findings suggest that more studies on identifying, quantitatively assessing, and mitigating health risks are needed if sustainable benefits are to be obtained from wastewater and excreta reuse in agriculture in Southeast Asia. PMID- 26501298 TI - Planning of Green Space Ecological Network in Urban Areas: An Example of Nanchang, China. AB - Green space plays an important role in sustainable urban development and ecology by virtue of multiple environmental, recreational, and economic benefits. Constructing an effective and harmonious urban ecological network and maintaining a sustainable living environment in response to rapid urbanization are the key issues required to be resolved by landscape planners. In this paper, Nanchang City, China was selected as a study area. Based on a series of landscape metrics, the landscape pattern analysis of the current (in 2005) and planned (in 2020) green space system were, respectively, conducted by using FRAGSTATS 3.3 software. Considering the actual situation of the Nanchang urban area, a "one river and two banks, north and south twin cities" ecological network was constructed by using network analysis. Moreover, the ecological network was assessed by using corridor structure analysis, and the improvement of an ecological network on the urban landscape was quantitatively assessed through a comparison between the ecological network and green space system planning. The results indicated that: (1) compared to the green space system in 2005, the planned green space system in 2020 of the Nanchang urban area will decline in both districts (Changnan and Changbei districts). Meanwhile, an increase in patch density and a decrease in mean patch size of green space patches at the landscape level implies the fragmentation of the urban green space landscape. In other words, the planned green space system does not necessarily improve the present green space system; (2) the ecological network of two districts has high corridor density, while Changnan's ecological network has higher connectivity, but Changbei's ecological network is more viable from an economic point of view, since it has relatively higher cost efficiency; (3) decrease in patch density, Euclidean nearest neighbor distance, and an increase in mean patch size and connectivity implied that the ecological network could improve landscape connectivity greatly, as compared with the planned green space system. That is to say, the planned ecological network would reduce landscape fragmentation, and increase the shape complexity of green space patches and landscape connectivity. As a result, the quality of the urban ecological environment would be improved. PMID- 26501299 TI - A Case Study Perspective on Working with ProUCL and a State Environmental Agency in Determining Background Threshold Values. AB - ProUCL is a software package made available by the Environmental Protection Agency (EPA) to provide environmental scientists with better tools with which to conduct statistical analyses. ProUCL has been in production for over ten years and is in its fifth major version. In time, it has included more sophisticated and appropriate analysis tools. However, there is still substantial criticism of it among statisticians for its various omissions and even its philosophical approach. Due to limited resources, some state agencies have set ProUCL as a standard by which all state-mandated environmental analyses are compared, despite the EPA's more open acceptance of other software products and methodologies. As such, it can be difficult for state-supervised sites to convince the state to allow the use of more appropriate methodologies or different software. In the current case study, several such instances arose and substantial resources were invested to demonstrate the appropriateness of alternative methodologies, sometimes without acquiring acceptance by the state despite sound statistical demonstration. In particular, efforts were made to address: inappropriate outlier detection, upper tolerance limit (UTL) calculations based on gamma distributions when non-detects were present, and inappropriate use of nonparametric UTL formulas. PMID- 26501300 TI - Association of Exposure to particular matter and Carotid Intima-Media Thickness: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Long time exposure to particular matter has been linked to myocardial infarction, stroke and blood pressure, but its association with atherosclerosis is not clear. This meta-analysis was aimed at assessing whether PM2.5 and PM10 have an effect on subclinical atherosclerosis measured by carotid intima-media thickness (CIMT). METHODS: Pubmed, Ovid Medline, Embase and NICK between 1948 and 31 March 2015 were searched by combining the keywords about exposure to the outcome related words. The random-effects model was applied in computing the change of CIMT and their corresponding 95% confidence interval (95% CI). The effect of potential confounding factors was assessed by stratified analysis and the impact of traffic proximity was also estimated. RESULTS: Among 56 identified studies, 11 articles satisfied the inclusion criteria. In overall analysis increments of 10 MUg/m3 in PM2.5 and PM10 were associated with an increase of CIMT (16.79 MUm; 95% CI, 4.95-28.63 MUm and 4.13 MUm; 95% CI, -5.79-14.04 MUm, respectively). RESULTS shown in subgroup analysis had reference value for comparing with those of the overall analysis. The impact of traffic proximity on CIMT was uncertain. CONCLUSIONS: Exposure to PM2.5 had a significant association with CIMT and for women the effect may be more obvious. PMID- 26501301 TI - Research Priorities for NCD Prevention and Climate Change: An International Delphi Survey. AB - Climate change and non-communicable diseases (NCDs) are arguably the greatest global challenges of the 21st Century. However, the confluence between them remains under-examined and there is little evidence of a comprehensive, systematic approach to identifying research priorities to mitigate their joint impact. Consequently, we: (i) convened a workshop of academics (n = 25) from the Worldwide Universities Network to identify priority areas at the interface between NCDs and climate change; (ii) conducted a Delphi survey of international opinion leaders in public health and relevant other disciplines; and (iii) convened an expert panel to review and advise on final priorities. Three research areas (water security; transport; conceptualising NCD harms to support policy formation) were listed among the top 10 priorities by >90% of Delphi respondents, and ranked among the top 12 priorities by >60% of respondents who ranked the order of priority. A fourth area (reducing the carbon footprint of cities) was ranked highest by the same >60% of respondents. Our results are consistent with existing frameworks on health and climate change, and extends them by focusing specifically on NCDs. Researching these priorities could progress understanding of climate change and NCDs, and inform global and national policy decisions for mitigating associated harms. PMID- 26501302 TI - The Effects of Targeted Deliveries of Lovastatin and Tocotrienol on Ossification Related Gene Expressions in Fracture Healing in an Osteoporosis Rat Model. AB - Osteoporotic drugs are used to prevent fragility fractures, but their role in fracture healing still remains unknown. Thus, alternative agents with suitable mode of delivery are needed to promote fracture healing. This study was performed to investigate the effects of direct deliveries of lovastatin and tocotrienol to fracture sites on ossification-related gene expression in fracture healing in a postmenopausal osteoporosis model. Forty-eight Sprague Dawley female rats were divided into six groups. Group I comprised the sham-operated rats, while Groups II-VI were ovariectomized rats. After 8 weeks, the right tibiae of all rats were fractured and stabilized. Group I and Group II were given two single injections of lovastatin and tocotrienol carriers. Group III was given an estrogen preparation at 64.5 ug/kg daily via oral gavages. Group IV was injected with lovastatin particles (750 ug/kg), while Group V was injected with tocotrienol particles (60 mg/kg). Group VI received two single injections of 750 ug/kg lovastatin particles and 60 mg/kg tocotrienol particles. After 4 weeks, the gene expressions were measured. Group VI showed significantly higher gene expressions of osteocalcin, BMP-2, VEGF-alpha, and RUNX-2 compared to Group II. In conclusion, combined treatment of lovastatin and tocotrienol upregulated the expression of genes related to fracture healing. PMID- 26501303 TI - Occupational Exposure to Urban Air Pollution and Allergic Diseases. AB - Exposure to air pollution is associated with increased morbidity from cardiovascular diseases, lung cancer, respiratory and allergic diseases. The aim of this study was to investigate allergic diseases in 111 traffic wardens compared to a control group of 101 administrative employees. All participating subjects underwent a physical examination, in which a complete medical history was taken and a dedicated allergological questionnaire administered. Spirometry, Specific IgE dosage (RAST) and skin prick tests (SPT) were done. Diagnostic investigations such as the nasal cytology, a specific nasal provocation test and rhinomanometry were also performed. Statistical analyses were performed using STATA version 11. The percentage of subjects with a diagnosis of allergy was higher in the exposed workers than in the controls. As regards the clinical tests, the positivity was higher for the group of exposed subjects. Among the exposed workers, those who worked on foot or motorcycle had a higher positivity in clinical trials compared to the traffic wardens who used the car. Our study showed a higher percentage of allergic subjects in the group of workers exposed to outdoor pollutants than in the controls. These results suggest that allergological tests should be included in the health surveillance protocols for workers exposed to outdoor pollutants. PMID- 26501304 TI - Changes in Active Commuting to School in Czech Adolescents in Different Types of Built Environment across a 10-Year Period. AB - Active commuting (AC) to school represents a great opportunity to incorporate walking or cycling into adolescents' everyday routine. The objective of the study was to describe changes in AC in Czech adolescents across a 10-year period in different built environments. Data from the 2001 and 2011 Czech Census of Population and Housing were used to examine the mode of transportation taken to school in 6236 adolescents. Changes in AC over time were analyzed for low and high walkable areas separately in two Czech regional cities, Olomouc and Hradec Kralove. Between 2001 and 2011, the proportion of adolescents actively commuting to school decreased by 47%, from an absolute rate of 49.1% to 26%. The proportion of active commuters fell in low walkable areas by 61% and in high walkable areas by 39%. The results indicated that adolescents in 2011 were 2.7 times less (OR = 0.365, p < 0.001) likely to actively commute than in 2001. The AC behavior in Czech adolescents has a negative tendency to replicate travel-to-school patterns in adolescents previously described in more developed countries. The findings might serve as a recommendation for municipal policy. PMID- 26501305 TI - Relationships between Sleep Behaviors and Unintentional Injury in Southern Chinese School-Aged Children: A Population-Based Study. AB - The purpose of this study is to explore the relationships between sleep behaviors and injury occurrence among Chinese school-aged children. Data were collected with self-administered questionnaires of a cross-sectional survey which covered the school-aged children from southeastern Chinese urban and rural areas in April 2010. Information was collected on unintentional injury in the past year, sleep duration, napping and daytime fatigue, sleeping pill use, and social-demographic variables. Multivariable logistic regression analyses, controlling for confounding factors, were conducted to assess sleep-related variables that were associated with injuries. Students who slept for less than 8 h had a 30% increased risk of injury (OR: 1.30; 95%CI: 1.01-1.69) compared with those who slept for 8-9 h. Lack of napping, snoring and use of sleeping pills were significantly associated with injury. Among different genders, the slight difference in sleep behaviors predicted the occurrence of injury. Rural children displayed more sleep behaviors associated with injury than urban children. The sleep behaviors of primary school students were more negatively correlated with injury occurrence than junior/senior high school children. Consideration should be given to the prevention of problematic sleep behaviors as a potential risk factor in order to decrease injury rates and promote the health of school-aged children. PMID- 26501306 TI - Help Received for Perceived Needs Related to Mental Health in a Montreal (Canada) Epidemiological Catchment Area. AB - This study sought to identify variables associated with help received in terms of information, medication, counselling and total help received (including other needs) among 571 individuals needing health care services for mental health problems. Study participants were randomly selected from an epidemiological survey. Data on help received were collected using the Canadian version of the Perceived Need for Care Questionnaire (PNCQ), and were analyzed using a multinomial logistic regression model. Most help received was in the form of counselling, followed by medication and information. Compared with individuals who received no help, those who reported receiving help for all their needs were more likely to have psychological distress, to be non-verbally aggressive, to consult more healthcare professionals, to be men and to be somewhat older. Compared with individuals who received no help, those who received partial help were more likely to be not addicted to drugs or alcohol, to consult more healthcare professionals, and to be older. Healthcare services should prioritize strategies (e.g., early detection, outreach, public education on mental and addiction disorders) that address barriers to help seeking among youth, as well as individuals addicted to drugs and alcohol or those presenting with aggressive behavior. PMID- 26501307 TI - Association of Sand Dust Particles with Pulmonary Function and Respiratory Symptoms in Adult Patients with Asthma in Western Japan Using Light Detection and Ranging: A Panel Study. AB - Light detection and ranging (LIDAR) can estimate daily volumes of sand dust particles from the East Asian desert to Japan. The objective of this study was to investigate the relationship between sand dust particles and pulmonary function, and respiratory symptoms in adult patients with asthma. One hundred thirty-seven patients were included in the study. From March 2013 to May 2013, the patients measured their morning peak expiratory flow (PEF) and kept daily lower respiratory symptom diaries. A linear mixed model was used to estimate the correlation of the median daily levels of sand dust particles, symptoms scores, and PEF. A heavy sand dust day was defined as an hourly concentration of sand dust particles of >0.1 km(-1). By this criterion, there were 8 heavy sand dust days during the study period. Elevated sand dust particles levels were significantly associated with the symptom score (0.04; 95% confidence interval (CI); 0.03, 0.05), and this increase persisted for 5 days. There was no significant association between PEF and heavy dust exposure (0.01 L/min; 95% CI, 0.62, 0.11). The present study found that sand dust particles were significantly associated with worsened lower respiratory tract symptoms in adult patients with asthma, but not with pulmonary function. PMID- 26501308 TI - Coarse Particulate Air Pollution Associated with Increased Risk of Hospital Admissions for Respiratory Diseases in a Tropical City, Kaohsiung, Taiwan. AB - This study was undertaken to determine whether there was an association between coarse particles (PM2.5-10) levels and frequency of hospital admissions for respiratory diseases (RD) in Kaohsiung, Taiwan. Hospital admissions for RD including chronic obstructive pulmonary disease (COPD), asthma, and pneumonia, and ambient air pollution data levels for Kaohsiung were obtained for the period from 2006 to 2010. The relative risk of hospital admissions for RD was estimated using a case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. For the single pollutant model (without adjustment for other pollutants), increased rate of admissions for RD were significantly associated with higher coarse PM levels only on cool days (<25 degrees C), with a 10 ug/m3 elevation in PM2.5-10 concentrations associated with a 3% (95% CI = 1%-5%) rise in COPD admissions, 4% (95% CI = 1%-7%) increase in asthma admissions, and 3% (95% CI = 2%-4%) rise in pneumonia admissions. No significant associations were found between coarse particle levels and the number of hospital admissions for RD on warm days. In the two-pollutant models, PM2.5-10 levels remained significantly correlated with higher rate of RD admissions even controlling for sulfur dioxide, nitrogen dioxide, carbon monoxide, or ozone on cool days. This study provides evidence that higher levels of PM2.5-10 enhance the risk of hospital admissions for RD on cool days. PMID- 26501309 TI - Thyroid Disruption in Zebrafish Larvae by Short-Term Exposure to Bisphenol AF. AB - Bisphenol AF (BPAF) is extensively used as a raw material in industry, resulting in its widespread distribution in the aqueous environment. However, the effect of BPAF on the hypothalamic-pituitary-thyroidal (HPT) axis remains unknown. For elucidating the disruptive effects of BPAF on thyroid function and expression of the representative genes along the HPT axis in zebrafish (Danio rerio) embryos, whole-body total 3,3',5-triiodothyronine (TT3), total 3,5,3',5' tetraiodothyronine (TT4), free 3,3',5-triiodothyronine (FT3) and free 3,5,3',5' tetraiodothyronine (FT4) levels were examined following 168 h post-fertilization exposure to different BPAF concentrations (0, 5, 50 and 500 MUg/L). The results showed that whole-body TT3, TT4, FT3 and FT4 contents decreased significantly with the BPAF treatment, indicating an endocrine disruption of thyroid. The expression of thyroid-stimulating hormone-beta and thyroglobulin genes increased after exposing to 50 MUg/L BPAF in seven-day-old larvae. The expressions of thyronine deiodinases type 1, type 2 and transthyretin mRNAs were also significantly up-regulated, which were possibly associated with a deterioration of thyroid function. However, slc5a5 gene transcription was significantly down regulated at 50 MUg/L and 500 MUg/L BPAF exposure. Furthermore, tralpha and trbeta genes were down-regulated transcriptionally after BPAF exposure. It demonstrates that BPAF exposure triggered thyroid endocrine toxicity by altering the whole-body contents of thyroid hormones and changing the transcription of the genes involved in the HPT axis in zebrafish larvae. PMID- 26501310 TI - Trace Elements Speciation of Submicron Particulate Matter (PM1) Collected in the Surroundings of Power Plants. AB - This study reports the concentrations of PM1 trace elements (As, Cd, Co, Cr, Hg, Mn, Ni, Pb, Sb and Se) content in highly mobile (F1), mobile (F2), less mobile (F3) and not mobile (F4) fractions in samples that were collected in the surroundings of power plants in southern Poland. It also reports source identification by enrichment factors (EF) and a principal component analysis (PCA). There is limited availability of scientific data concerning the chemical composition of dust, including fractionation analyses of trace elements, in the surroundings of power plants. The present study offers important results in order to fill this data gap. The data collected in this study can be utilized to validate air quality models in this rapidly developing area. They are also crucial for comparisons with datasets from similar areas all over the world. Moreover, the identification of the bioavailability of selected carcinogenic and toxic elements in the future might be used as output data for potential biological and population research on risk assessment. This is important in the context of air pollution being hazardous to human health. PMID- 26501311 TI - A 2,5-Dihydroxybenzoic Acid-Gelatin Conjugate: The Synthesis, Antiviral Activity and Mechanism of Antiviral Action Against Two Alphaherpesviruses. AB - Various natural and synthetic polyanionic polymers with different chemical structures are known to exhibit potent antiviral activity in vitro toward a variety of enveloped viruses and may be considered as promising therapeutic agents. A water-soluble conjugate of 2,5-dihydroxybezoic acid (2,5-DHBA) with gelatin was synthesized by laccase-catalyzed oxidation of 2,5-DHBA in the presence of gelatin, and its antiviral activity against pseudorabies virus (PRV) and bovine herpesvirus type 1 (BoHV-1), two members of the Alphaherpesvirinae subfamily, was studied. The conjugate produced no direct cytotoxic effect on cells, and did not inhibit cell growth at concentrations up to 1000 ug/mL. It exhibited potent antiviral activity against PRV (IC50, 1.5-15 ug/mL for different virus strains) and BoHV-1 (IC50, 0.5-0.7 ug/mL). When present during virus adsorption, the conjugate strongly inhibited the attachment of PRV and BoHV-1 to cells. The 2,5-DHBA-gelatin conjugate had no direct virucidal effect on the viruses and did not influence their penetration into cells, cell-to-cell spread, production of infectious virus particles in cells, and expression of PRV glycoproteins E and B. The results indicated that the 2,5-DHBA-gelatin conjugate strongly inhibits the adsorption of alphaherpesviruses to cells and can be a promising synthetic polymer for the development of antiviral formulations against alphaherpesvirus infections. PMID- 26501312 TI - Respiratory Syncytial Virus Persistence in Murine Macrophages Impairs IFN-beta Response but Not Synthesis. AB - Type-I interferon (IFN-I) production is an early response to viral infection and pathogenic viruses have evolved multiple strategies to evade this cellular defense. Some viruses can establish and maintain persistent infections by altering the IFN-I signaling pathway. Here, we studied IFN-I synthesis and response in an in vitro model of persistent infection by respiratory syncytial virus (RSV) in a murine macrophage-like cell line. In this model, interferon regulatory factor 3 was constitutively active and located at nuclei of persistently infected cells, inducing expression of IFN-beta mRNA and protein. However, persistently infected macrophages did not respond in an autocrine manner to the secreted-IFN-beta or to recombinant-IFN-beta, since phosphorylated-STAT1 was not detected by western blot and transcription of the interferon-stimulated genes (ISGs) Mx1 and ISG56 was not induced. Treatment of non-infected macrophages with supernatants from persistently infected cells induced STAT1 phosphorylation and ISGs expression, mediated by the IFN-I present in the supernatants, because blocking the IFN-I receptor inhibited STAT1 phosphorylation. Results suggest that the lack of autocrine response to IFN-I by the host cell may be one mechanism for maintenance of RSV persistence. Furthermore, STAT1 phosphorylation and ISGs expression induced in non-infected cells by supernatants from persistently infected macrophages suggest that RSV persistence may trigger a proinflammatory phenotype in non-infected cells as part of the pathogenesis of RSV infection. PMID- 26501313 TI - Emerging Roles of Viroporins Encoded by DNA Viruses: Novel Targets for Antivirals? AB - Studies have highlighted the essential nature of a group of small, highly hydrophobic, membrane embedded, channel-forming proteins in the life cycles of a growing number of RNA viruses. These viroporins mediate the flow of ions and a range of solutes across cellular membranes and are necessary for manipulating a myriad of host processes. As such they contribute to all stages of the virus life cycle. Recent discoveries have identified proteins encoded by the small DNA tumor viruses that display a number of viroporin like properties. This review article summarizes the recent developments in our understanding of these novel viroporins; describes their roles in the virus life cycles and in pathogenesis and speculates on their potential as targets for anti-viral therapeutic intervention. PMID- 26501314 TI - Effects of Rhodomyrtus tomentosa Leaf Extract on Staphylococcal Adhesion and Invasion in Bovine Udder Epidermal Tissue Model. AB - Bovine mastitis is one of the most important infectious diseases in dairy herds, and staphylococci are the most important etiologic agents of this disease. Antibiotics and chemical agents used in livestock for prevention and cure of the disease can accumulate in milk and give rise to food safety concerns. Rhodomyrtus tomentosa leaf extract was studied as an alternative approach to reduce the bacterial infections. The ethanolic extract of this plant demonstrated antibacterial activity with minimum inhibitory concentration (MIC) values as low as 16-64 MUg/mL against staphylococcal isolates. In addition, the extract had an effect on the bacterial cell surface properties by increasing its hydrophobicity in a concentration dependent manner. To further extend the antibacterial efficacy, silver nanoparticles synthesized with the extract, a pure rhodomyrtone, and liposomal encapsulated rhodomyrtone were applied and their inhibitory effects on bacterial adhesion and invasion were determined by ex vivo study in a bovine udder epidermal tissue model. These agents exerted remarkable antibacterial activity against staphylococci and decreased the adhesion of the bacterial cells to the tissues. These results supported that R. tomentosa ethanolic extract could be applied as an alternative agent for bovine udder care in dairy farms. PMID- 26501315 TI - Effects of Dietary Plant Sterols and Stanol Esters with Low- and High-Fat Diets in Chronic and Acute Models for Experimental Colitis. AB - In this study, we evaluated the effects of dietary plant sterols and stanols as their fatty acid esters on the development of experimental colitis. The effects were studied both in high- and low-fat diet conditions in two models, one acute and another chronic model of experimental colitis that resembles gene expression in human inflammatory bowel disease (IBD). In the first experiments in the high fat diet (HFD), we did not observe a beneficial effect of the addition of plant sterols and stanols on the development of acute dextran sulphate sodium (DSS) colitis. In the chronic CD4CD45RB T cell transfer colitis model, we mainly observed an effect of the presence of high fat on the development of colitis. In this HFD condition, the presence of plant sterol or stanol did not result in any additional effect. In the second experiments with low fat, we could clearly observe a beneficial effect of the addition of plant sterols on colitis parameters in the T cell transfer model, but not in the DSS model. This positive effect was related to the gender of the mice and on Treg presence in the colon. This suggests that especially dietary plant sterol esters may improve intestinal inflammation in a T cell dependent manner. PMID- 26501316 TI - Antidiabetic Effects of Yam (Dioscorea batatas) and Its Active Constituent, Allantoin, in a Rat Model of Streptozotocin-Induced Diabetes. AB - The objective of this study was to investigate the therapeutic efficacies of crude yam (Dioscorea batatas) powder (PY), water extract of yam (EY), and allantoin (the active constituent of yam) in streptozotocin (STZ)-induced diabetic rats with respect to glucose, insulin, glucagon-like peptide-1 (GLP-1), C-peptide, glycated hemoglobin (HbAlc), lipid metabolism, and oxidative stress. For this purpose, 50 rats were divided into five groups: normal control (NC), diabetic control (STZ), and STZ plus treatment groups (STZ + PY, STZ + EY, and STZ + allantoin). After treatment for one-month, there was a decrease in blood glucose: 385 +/- 7 in STZ, 231 +/- 3 in STZ + PY, 214 +/- 11 in STZ + EY, and 243 +/- 6 mg/dL in STZ + allantoin, respectively. There were significant statistical differences (p < 0.001) compared to STZ (100%): 60% in STZ + PY, 55% in STZ + EY, and 63% in STZ + allantoin. With groups in the same order, there were significant decreases (p < 0.001) in HbAlc (100% as 24.4 +/- 0.6 ng/mL, 78%, 75%, and 77%), total cholesterol (100% as 122 +/- 3 mg/dL, 70%, 67%, and 69%), and low-density lipoprotein (100% as 29 +/- 1 mg/dL, 45%, 48%, and 38%). There were also significant increases (p < 0.001) in insulin (100% as 0.22 +/- 0.00 ng/mL, 173%, 209%, and 177%), GLP-1 (100% as 18.4 +/- 0.7 pmol/mL, 160%, 166%, and 162%), and C-peptide (100% as 2.56 +/- 0.10 ng/mL, 129%, 132%, and 130%). The treatment effectively ameliorated antioxidant stress as shown by a significant decrease (p < 0.001) in malondialdehyde (100% as 7.25 +/- 0.11 nmol/mL, 87%, 86%, and 85%) together with increases (p < 0.01) in superoxide dismutase (100% as 167 +/- 6 IU/mL, 147%, 159%, and 145%) and reduced glutathione (100% as 167 +/- 6 nmol/mL, 123%, 141%, and 140%). The results indicate that yam and allantoin have antidiabetic effects by modulating antioxidant activities, lipid profiles and by promoting the release of GLP-1, thereby improving the function of beta-cells maintaining normal insulin and glucose levels. PMID- 26501317 TI - Prevalence and Predictors of Functional Vitamin K Insufficiency in Mothers and Newborns in Uganda. AB - Vitamin K deficiency bleeding (VKDB) in infancy is a serious but preventable cause of mortality or permanent disability. Lack of epidemiologic data for VKDB in sub-Saharan Africa hinders development and implementation of effective prevention strategies. We used convenience sampling to consecutively enroll mothers delivering in a southwestern Uganda Hospital. We collected socio demographic and dietary information, and paired samples of maternal venous and neonatal cord blood for the immunoassay of undercarboxylated prothrombin (PIVKA II), a sensitive marker of functional vitamin K (VK) insufficiency. We used univariable and multivariable logistic regression models to identify predictors of VK insufficiency. We detected PIVKA-II of >=0.2 AU (Arbitrary Units per mL)/mL (indicative of VK insufficiency) in 33.3% (47/141) of mothers and 66% (93/141) of newborns. Importantly, 22% of babies had PIVKA-II concentrations >=5.0 AU/mL, likely to be associated with abnormal coagulation indices. We found no significant predictors of newborn VK insufficiency, including infant weight (AOR (adjusted odds ratio) 1.85, 95% CI (confidence interval) 0.15-22.49), gender (AOR 0.54, 95% CI 0.26-1.11), term birth (AOR 0.72, 95% CI 0.20-2.62), maternal VK rich diet (AOR 1.13, 95% CI 0.55-2.35) or maternal VK insufficiency (AOR 0.99, 95% CI 0.47-2.10). VK insufficiency is common among mothers and newborn babies in southwestern Uganda, which in one fifth of babies nears overt deficiency. Lack of identifiable predictors of newborn VK insufficiency support strategies for universal VK prophylaxis to newborns to prevent VKDB. PMID- 26501319 TI - Beyond Food Promotion: A Systematic Review on the Influence of the Food Industry on Obesity-Related Dietary Behaviour among Children. AB - An increased consumption of energy-dense, nutrient-poor food and beverages as a result of a changing obesogenic environment contributes substantially to the increasing prevalence of childhood overweight and obesity. This paper reviews the nature and extent of food industry influences which expose children to commercial influences and thus might affect unhealthy dietary behaviour and finally contributes to obesity. A systematic search of nine electronic databases (including PubMed, PsycINFO, EconLit) and reference lists of original studies and reviews using key search terms identified 1900 articles. Of these only thirty-six articles met the inclusion and quality criteria. A narrative synthesis of the reviewed studies revealed six key obesogenic environments by which the food industry possibly influences obesity-related dietary behaviours in young children. These were schools, retailers, mass media "television", mass media "internet", home and promotional campaigns. Identifying these obesogenic environments is critical for monitoring and controlling the food industry, the development of effective environmental-level interventions to prevent childhood overweight and obesity and to identify knowledge gaps to be addressed in future research to support informed decisions of policy makers. PMID- 26501318 TI - The Association of a Mediterranean-Style Diet Pattern with Polycystic Ovary Syndrome Status in a Community Cohort Study. AB - Polycystic ovary syndrome (PCOS) is a common condition in reproductive-aged women. While lifestyle management is first-line treatment in PCOS, the dietary intake of women with PCOS is unclear and there is no research assessing dietary patterns of women with and without PCOS. The aim of this study was to examine dietary patterns in a large cohort of women with and without PCOS. Data were from 7569 participants in the 1973-1978 cohort of the Australian Longitudinal Study on Women's Health population assessed at 2009 (Survey 5) (n = 414 PCOS, n = 7155 non PCOS). Dietary patterns were evaluated using factor analysis and multiple logistic regressions assessed their associations with PCOS status. Three dietary patterns were identified that explained 27% of the variance in food intake between women with and without PCOS: Non-core foods; Meats and take-away and Mediterranean-style. The Mediterranean-style dietary pattern was independently associated with PCOS status. On adjusted analysis for each 1 SD increase in the Mediterranean-style dietary pattern, there was a 26% greater likelihood that women had PCOS. This may indicate an improvement in the quality of dietary intake following a diagnosis of PCOS. Future research should examine the contribution of dietary patterns to the incidence and severity of PCOS and the potential for modification of dietary patterns in the lifestyle management of PCOS. PMID- 26501320 TI - EDIN-B Promotes the Translocation of Staphylococcus aureus to the Bloodstream in the Course of Pneumonia. AB - It is crucial to define risk factors that contribute to host invasion by Staphylococcus aureus. Here, we demonstrate that the chromosomally encoded EDIN-B isoform from S. aureus contributes to the onset of bacteremia during the course of pneumonia. Deletion of edinB in a European lineage community-acquired methicillin resistant S. aureus (CA-MRSA) strain (ST80-MRSA-IV) dramatically decreased the frequency and magnitude of bacteremia in mice suffering from pneumonia. This deletion had no effect on the bacterial burden in both blood circulation and lung tissues. Re-expression of wild-type EDIN-B, unlike the catalytically inactive mutant EDIN-R185E, restored the invasive characteristics of ST80-MRSA-IV. PMID- 26501321 TI - The Inhibitory Effect of Botulinum Toxin Type A on Rat Pyloric Smooth Muscle Contractile Response to Substance P In Vitro. AB - A decrease in pyloric myoelectrical activity and pyloric substance P (SP) content following intrasphincteric injection of botulinum toxin type A (BTX-A) in free move rats have been demonstrated in our previous studies. The aim of the present study was to investigate the inhibitory effect of BTX-A on rat pyloric muscle contractile response to SP in vitro and the distributions of SP and neurokinin 1 receptor (NK1R) immunoreactive (IR) cells and fibers within pylorus. After treatment with atropine, BTX-A (10 U/mL), similar to [D-Arg1, D-Phe5, D-Trp(7,9), Leu(11)]-SP (APTL-SP, 1 MUmol/L) which is an NK1R antagonist, decreased electric field stimulation (EFS)-induced contractile tension and frequency, whereas, subsequent administration of APTL-SP did not act on contractility. Incubation with BTX-A at 4 and 10 U/mL for 4 h respectively decreased SP (1 MUmol/L)-induced contractions by 26.64% +/- 5.12% and 74.92% +/- 3.62%. SP-IR fibers and NK1R-IR cells both located within pylorus including mucosa and circular muscle layer. However, fewer SP-fibers were observed in pylorus treated with BTX-A (10 U/mL). In conclusion, BTX-A inhibits SP release from enteric terminals in pylorus and EFS-induced contractile responses when muscarinic cholinergic receptors are blocked by atropine. In addition, BTX-A concentration- and time-dependently directly inhibits SP-induced pyloric smooth muscle contractility. PMID- 26501322 TI - Risk Assessment on Dietary Exposure to Aflatoxin B1 in Post-Harvest Peanuts in the Yangtze River Ecological Region. AB - Based on the 2983 peanut samples from 122 counties in six provinces of China's Yangtze River ecological region collected between 2009-2014, along with the dietary consumption data in Chinese resident nutrition and health survey reports from 2002 and 2004, dietary aflatoxin exposure and percentiles in the corresponding statistics were calculated by non-parametric probability assessment, Monte Carlo simulation and bootstrap sampling methods. Average climatic conditions in the Yangtze River ecological region were calculated based on the data from 118 weather stations via the Thiessen polygon method. The survey results found that the aflatoxin contamination of peanuts was significantly high in 2013. The determination coefficient (R2) of multiple regression reflected by the aflatoxin B1 content with average precipitation and mean temperature in different periods showed that climatic conditions one month before harvest had the strongest impact on aflatoxin B1 contamination, and that Hunan and Jiangxi provinces were greatly influenced. The simulated mean aflatoxin B1 intake from peanuts at the mean peanut consumption level was 0.777-0.790 and 0.343-0.349 ng/(kg.d) for children aged 2-6 and standard adults respectively. Moreover, the evaluated cancer risks were 0.024 and 0.011/(100,000 persons.year) respectively, generally less than China's current liver cancer incidence of 24.6 cases/(100,000 persons.year). In general, the dietary risk caused by peanut production and harvest was low. Further studies would focus on the impacts of peanut circulation and storage on aflatoxin B1 contamination risk assessment in order to protect peanut consumers' safety and boost international trade. PMID- 26501323 TI - Bioactive Mimetics of Conotoxins and other Venom Peptides. AB - Ziconotide (Prialt(r)), a synthetic version of the peptide omega-conotoxin MVIIA found in the venom of a fish-hunting marine cone snail Conus magnus, is one of very few drugs effective in the treatment of intractable chronic pain. However, its intrathecal mode of delivery and narrow therapeutic window cause complications for patients. This review will summarize progress in the development of small molecule, non-peptidic mimics of Conotoxins and a small number of other venom peptides. This will include a description of how some of the initially designed mimics have been modified to improve their drug-like properties. PMID- 26501325 TI - Photoreceptor Sensory Cilium: Traversing the Ciliary Gate. AB - Cilia are antenna-like extensions of the plasma membrane found in nearly all cell types. In the retina of the eye, photoreceptors develop unique sensory cilia. Not much was known about the mechanisms underlying the formation and function of photoreceptor cilia, largely because of technical limitations and the specific structural and functional modifications that cannot be modeled in vitro. With recent advances in microscopy techniques and molecular and biochemical approaches, we are now beginning to understand the molecular basis of photoreceptor ciliary architecture, ciliary function and its involvement in human diseases. Here, I will discuss the studies that have revealed new knowledge of how photoreceptor cilia regulate their identity and function while coping with high metabolic and trafficking demands associated with processing light signal. PMID- 26501324 TI - Development, Maintenance, and Reversal of Multiple Drug Resistance: At the Crossroads of TFPI1, ABC Transporters, and HIF1. AB - Early detection and improved therapies for many cancers are enhancing survival rates. Although many cytotoxic therapies are approved for aggressive or metastatic cancer; response rates are low and acquisition of de novo resistance is virtually universal. For decades; chemotherapeutic treatments for cancer have included anthracyclines such as Doxorubicin (DOX); and its use in aggressive tumors appears to remain a viable option; but drug resistance arises against DOX; as for all other classes of compounds. Our recent work suggests the anticoagulant protein Tissue Factor Pathway Inhibitor 1alpha (TFPI1alpha) plays a role in driving the development of multiple drug resistance (MDR); but not maintenance; of the MDR state. Other factors; such as the ABC transporter drug efflux pumps MDR-1/P-gp (ABCB1) and BCRP (ABCG2); are required for MDR maintenance; as well as development. The patient population struggling with therapeutic resistance specifically requires novel treatment options to resensitize these tumor cells to therapy. In this review we discuss the development, maintenance, and reversal of MDR as three distinct phases of cancer biology. Possible means to exploit these stages to reverse MDR will be explored. Early molecular detection of MDRcancers before clinical failure has the potential to offer new approaches to fightingMDRcancer. PMID- 26501327 TI - A Synthetic Virus-Like Particle Streptococcal Vaccine Candidate Using B-Cell Epitopes from the Proline-Rich Region of Pneumococcal Surface Protein A. AB - Alternatives to the well-established capsular polysaccharide-based vaccines against Streptococcus pneumoniae that circumvent limitations arising from limited serotype coverage and the emergence of resistance due to capsule switching (serotype replacement) are being widely pursued. Much attention is now focused on the development of recombinant subunit vaccines based on highly conserved pneumococcal surface proteins and virulence factors. A further step might involve focusing the host humoral immune response onto protective protein epitopes using as immunogens structurally optimized epitope mimetics. One approach to deliver such epitope mimetics to the immune system is through the use of synthetic virus like particles (SVLPs). SVLPs are made from synthetic coiled-coil lipopeptides that are designed to spontaneously self-assemble into 20-30 nm diameter nanoparticles in aqueous buffer. Multivalent display of epitope mimetics on the surface of SVLPs generates highly immunogenic nanoparticles that elicit strong epitope-specific humoral immune responses without the need for external adjuvants. Here, we set out to demonstrate that this approach can yield vaccine candidates able to elicit a protective immune response, using epitopes derived from the proline-rich region of pneumococcal surface protein A (PspA). These streptococcal SVLP-based vaccine candidates are shown to elicit strong humoral immune responses in mice. Following active immunization and challenge with lethal doses of streptococcus, SVLP-based immunogens are able to elicit significant protection in mice. Furthermore, a mimetic-specific monoclonal antibody is shown to mediate partial protection upon passive immunization. The results show that SVLPs combined with synthetic epitope mimetics may have potential for the development of an effective vaccine against Streptococcus pneumoniae. PMID- 26501326 TI - Caffeine Consuming Children and Adolescents Show Altered Sleep Behavior and Deep Sleep. AB - Caffeine is the most commonly ingested psychoactive drug worldwide with increasing consumption rates among young individuals. While caffeine leads to decreased sleep quality in adults, studies investigating how caffeine consumption affects children's and adolescents' sleep remain scarce. We explored the effects of regular caffeine consumption on sleep behavior and the sleep electroencephalogram (EEG) in children and adolescents (10-16 years). While later habitual bedtimes (Caffeine 23:14 +/- 11.4, Controls 22:17 +/- 15.4) and less time in bed were found in caffeine consumers compared to the control group (Caffeine 08:10 +/- 13.3, Controls 09:03 +/- 16.1), morning tiredness was unaffected. Furthermore, caffeine consumers exhibited reduced sleep EEG slow-wave activity (SWA, 1-4.5 Hz) at the beginning of the night compared to controls (20% +/- 9% average reduction across all electrodes and subjects). Comparable reductions were found for alpha activity (8.25-9.75 Hz). These effects, however, disappeared in the morning hours. Our findings suggest that caffeine consumption in adolescents may lead to later bedtimes and reduced SWA, a well-established marker of sleep depth. Because deep sleep is involved in recovery processes during sleep, further research is needed to understand whether a caffeine-induced loss of sleep depth interacts with neuronal network refinement processes that occur during the sensitive period of adolescent development. PMID- 26501329 TI - Enhanced Fermentative Hydrogen and Methane Production from an Inhibitory Fruit Flavored Medium with Membrane-Encapsulated Cells. AB - This study focused on the possibility of improving fermentative hydrogen and methane production from an inhibitory fruit-flavored medium using polyvinylidene fluoride (PVDF) membrane-encapsulated cells. Hexanal, myrcene, and octanol, which are naturally produced in fruits such as apple, grape, mango, orange, strawberry, and plum, were investigated. Batch and semi-continuous fermentation processes at 55 degrees C were carried out. Presence of 5 g/L of myrcene, octanol, and hexanal resulted in no methane formation by fermenting bacteria, while encapsulated cells in the membranes resulted in successful fermentation with 182, 111, and 150 mL/g COD of methane, respectively. The flavor inhibitions were not serious on hydrogen-producing bacteria. With free cells in the presence of 5 g/L (final concentration) of hexanal-, myrcene-, and octanol-flavored media, average daily yields of 68, 133, and 88 mL/g COD of hydrogen, respectively, were obtained. However, cell encapsulation further improved these hydrogen yields to 189, 179, and 198 mL/g COD. The results from this study indicate that the yields of fermentative hydrogen and methane productions from an inhibitory medium could be improved using encapsulated cells. PMID- 26501330 TI - Bio-Environment-Induced Degradation and Failure of Internal Fixation Implants. AB - Internal fixations provide fast healing but their failure remains problematic to patients. Here, we report an experimental study in failure of three typical cases of metals: a bent intramedullary stainless steel nail, a broken exterior pure Ti plate, and a broken intramedullary stainless steel nail. Characterization of the bent nail indicates that those metals are vulnerable to corrosion with the evidence of increased surface roughness and embrittlement. Depredated surface of the Ti plate resulted debris particles in the surrounding tissue of 15.2 +/- 6.5 MUm in size. Nanoparticles were observed in transmission electron microscope. The electron diffraction pattern of the debris indicates a combination of nanocrystalline and amorphous phases. The failure mode of the broken nail made of stainless steel was found to be fatigue initiated from the surface. This study clearly shows the biological-attack induced surface degradation resulting in debris and fatigue. Future design and selection of implant materials should consider such factors for improvement. PMID- 26501328 TI - Membrane Binding and Modulation of the PDZ Domain of PICK1. AB - Scaffolding proteins serve to assemble protein complexes in dynamic processes by means of specific protein-protein and protein-lipid binding domains. Many of these domains bind either proteins or lipids exclusively; however, it has become increasingly evident that certain domains are capable of binding both. Especially, many PDZ domains, which are highly abundant protein-protein binding domains, bind lipids and membranes. Here we provide an overview of recent large scale studies trying to generalize and rationalize the binding patterns as well as specificity of PDZ domains towards membrane lipids. Moreover, we review how these PDZ-membrane interactions are regulated in the case of the synaptic scaffolding protein PICK1 and how this might affect cellular localization and function. PMID- 26501331 TI - The Tribology of Explanted Hip Resurfacings Following Early Fracture of the Femur. AB - A recognized issue related to metal-on-metal hip resurfacings is early fracture of the femur. Most theories regarding the cause of fracture relate to clinical factors but an engineering analysis of failed hip resurfacings has not previously been reported. The objective of this work was to determine the wear volumes and surface roughness values of a cohort of retrieved hip resurfacings which were removed due to early femoral fracture, infection and avascular necrosis (AVN). Nine resurfacing femoral heads were obtained following early fracture of the femur, a further five were retrieved due to infection and AVN. All fourteen were measured for volumetric wear using a co-ordinate measuring machine. Wear rates were then calculated and regions of the articulating surface were divided into "worn" and "unworn". Roughness values in these regions were measured using a non contacting profilometer. The mean time to fracture was 3.7 months compared with 44.4 months for retrieval due to infection and AVN. Average wear rates in the early fracture heads were 64 times greater than those in the infection and AVN retrievals. Given the high wear rates of the early fracture components, such wear may be linked to an increased risk of femoral neck fracture. PMID- 26501332 TI - Design Principles as a Guide for Constraint Based and Dynamic Modeling: Towards an Integrative Workflow. AB - During the last 10 years, systems biology has matured from a fuzzy concept combining omics, mathematical modeling and computers into a scientific field on its own right. In spite of its incredible potential, the multilevel complexity of its objects of study makes it very difficult to establish a reliable connection between data and models. The great number of degrees of freedom often results in situations, where many different models can explain/fit all available datasets. This has resulted in a shift of paradigm from the initially dominant, maybe naive, idea of inferring the system out of a number of datasets to the application of different techniques that reduce the degrees of freedom before any data set is analyzed. There is a wide variety of techniques available, each of them can contribute a piece of the puzzle and include different kinds of experimental information. But the challenge that remains is their meaningful integration. Here we show some theoretical results that enable some of the main modeling approaches to be applied sequentially in a complementary manner, and how this workflow can benefit from evolutionary reasoning to keep the complexity of the problem in check. As a proof of concept, we show how the synergies between these modeling techniques can provide insight into some well studied problems: Ammonia assimilation in bacteria and an unbranched linear pathway with end product inhibition. PMID- 26501333 TI - Two-Dimensional N-Glycan Distribution Mapping of Hepatocellular Carcinoma Tissues by MALDI-Imaging Mass Spectrometry. AB - A new mass spectrometry imaging approach to simultaneously map the two dimensional distribution of N-glycans in tissues has been recently developed. The method uses Matrix Assisted Laser Desorption Ionization Imaging Mass Spectrometry (MALDI-IMS) to spatially profile the location and distribution of multiple N linked glycan species released by peptide N-glycosidase F in frozen or formalin fixed tissues. Multiple formalin-fixed human hepatocellular carcinoma tissues were evaluated with this method, resulting in a panel of over 30 N-glycans detected. An ethylation reaction of extracted N-glycans released from adjacent slides was done to stabilize sialic acid containing glycans, and these structures were compared to N-glycans detected directly from tissue profiling. In addition, the distribution of singly fucosylated N-glycans detected in tumor tissue microarray cores were compared to the histochemistry staining pattern of a core fucose binding lectin. As this MALDI-IMS workflow has the potential to be applied to any formalin-fixed tissue block or tissue microarray, the advantages and limitations of the technique in context with other glycomic methods are also summarized. PMID- 26501334 TI - Alcohol and the Intestine. AB - Alcohol abuse is a significant contributor to the global burden of disease and can lead to tissue damage and organ dysfunction in a subset of alcoholics. However, a subset of alcoholics without any of these predisposing factors can develop alcohol-mediated organ injury. The gastrointestinal tract (GI) could be an important source of inflammation in alcohol-mediated organ damage. The purpose of review was to evaluate mechanisms of alcohol-induced endotoxemia (including dysbiosis and gut leakiness), and highlight the predisposing factors for alcohol induced dysbiosis and gut leakiness to endotoxins. Barriers, including immunologic, physical, and biochemical can regulate the passage of toxins into the portal and systemic circulation. In addition, a host of environmental interactions including those influenced by circadian rhythms can impact alcohol induced organ pathology. There appears to be a role for therapeutic measures to mitigate alcohol-induced organ damage by normalizing intestinal dysbiosis and/or improving intestinal barrier integrity. Ultimately, the inflammatory process that drives progression into organ damage from alcohol appears to be multifactorial. Understanding the role of the intestine in the pathogenesis of alcoholic liver disease can pose further avenues for pathogenic and treatment approaches. PMID- 26501335 TI - Hsp90: A New Player in DNA Repair? AB - Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and DNA repair. Cells respond to DNA damage by activating complex DNA damage response (DDR) pathways that include: (i) cell cycle arrest; (ii) transcriptional and post-translational activation of a subset of genes, including those associated with DNA repair; and (iii) triggering of programmed cell death. The efficacy of the DDR pathways is influenced by the nuclear levels of DNA repair proteins, which are regulated by balancing between protein synthesis and degradation as well as by nuclear import and export. The inability to respond properly to either DNA damage or to DNA repair leads to genetic instability, which in turn may enhance the rate of cancer development. Multiple components of the DNA double strand breaks repair machinery, including BRCA1, BRCA2, CHK1, DNA PKcs, FANCA, and the MRE11/RAD50/NBN complex, have been described to be client proteins of Hsp90, which acts as a regulator of the diverse DDR pathways. Inhibition of Hsp90 actions leads to the altered localization and stabilization of DDR proteins after DNA damage and may represent a cell-specific and tumor selective radiosensibilizer. Here, the role of Hsp90-dependent molecular mechanisms involved in cancer onset and in the maintenance of the genome integrity is discussed and highlighted. PMID- 26501337 TI - Modulation of Intestinal Barrier and Bacterial Endotoxin Production Contributes to the Beneficial Effect of Nicotinic Acid on Alcohol-Induced Endotoxemia and Hepatic Inflammation in Rats. AB - Alcohol consumption causes nicotinic acid deficiency. The present study was undertaken to determine whether dietary nicotinic acid supplementation provides beneficial effects on alcohol-induced endotoxin signaling and the possible mechanisms at the gut-liver axis. Male Sprague-Dawley rats were pair-fed the Lieber-DeCarli liquid diets containing ethanol or isocaloric maltose dextrin for eight weeks, with or without dietary supplementation with 750 mg/liter nicotinic acid. Chronic alcohol feeding elevated the plasma endotoxin level and activated hepatic endotoxin signaling cascade, which were attenuated by nicotinic acid supplementation. Alcohol consumption remarkably decreased the mRNA levels of claudin-1, claudin-5, and ZO-1 in the distal intestine, whereas nicotinic acid significantly up-regulated these genes. The concentrations of endotoxin, ethanol, and acetaldehyde in the intestinal contents were increased by alcohol exposure, and niacin supplementation reduced the intestinal endotoxin and acetaldehyde levels. Nicotinic acid supplementation upregulated the intestinal genes involved in aldehyde detoxification via transcriptional regulation. These results demonstrate that modulation of the intestinal barrier function and bacterial endotoxin production accounts for the inhibitory effects of nicotinic acid on alcohol-induced endotoxemia and hepatic inflammation. PMID- 26501336 TI - A Mechanistic Review of Mitophagy and Its Role in Protection against Alcoholic Liver Disease. AB - Alcoholic liver disease (ALD) is a major health problem worldwide, and alcohol is well-known to cause mitochondrial damage, which exacerbates alcohol-induced liver injury and steatosis. No successful treatments are currently available for treating ALD. Therefore, a better understanding of mechanisms involved in regulation of mitochondrial homeostasis in the liver and how these mechanisms may protect against alcohol-induced liver disease is needed for future development of better therapeutic options for ALD. Mitophagy is a key mechanism for maintaining mitochondrial homeostasis by removing damaged mitochondria, and mitophagy protects against alcohol-induced liver injury. Parkin, an E3 ubiquitin ligase, is well-known to induce mitophagy in in vitro models although Parkin-independent mechanisms for mitophagy induction also exist. In this review, we discuss the roles of Parkin and mitophagy in protection against alcohol-induced liver injury and steatosis. We also discuss Parkin-independent mechanisms for mitophagy induction, which have not yet been evaluated in the liver but may also potentially have a protective role against ALD. In addition to mitophagy, mitochondrial spheroid formation may also provide a novel mechanism of protection against ALD, but the role of mitochondrial spheroids in protection against ALD progression needs to be further explored. Targeting removal of damaged mitochondria by mitophagy or inducing formation of mitochondrial spheroids may be promising therapeutic options for treatment of ALD. PMID- 26501338 TI - Autophagy Protects against CYP2E1/Chronic Ethanol-Induced Hepatotoxicity. AB - Autophagy is an intracellular pathway by which lysosomes degrade and recycle long lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to also be protective against CYP2E1-dependent toxicity in vitro in HepG2 cells which express CYP2E1 and in vivo in an acute alcohol/CYPE1-dependent liver injury model. The goal of the current report was to extend the previous in vitro and acute in vivo experiments to a chronic ethanol model to evaluate whether autophagy is also protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. Wild type (WT), CYP2E1 knockout (KO) or CYP2E1 humanized transgenic knockin (KI), mice were fed an ethanol liquid diet or control dextrose diet for four weeks. In the last week, some mice received either saline or 3-methyladenine (3-MA), an inhibitor of autophagy, or rapamycin, which stimulates autophagy. Inhibition of autophagy by 3-MA potentiated the ethanol-induced increases in serum transaminase and triglyceride levels in the WT and KI mice but not KO mice, while rapamycin prevented the ethanol liver injury. Treatment with 3-MA enhanced the ethanol-induced fat accumulation in WT mice and caused necrosis in the KI mice; little or no effect was found in the ethanol-fed KO mice or any of the dextrose-fed mice. 3-MA treatment further lowered the ethanol-decrease in hepatic GSH levels and further increased formation of TBARS in WT and KI mice, whereas rapamycin blunted these effects of ethanol. Neither 3-MA nor rapamycin treatment affected CYP2E1 catalytic activity or content or the induction CYP2E1 by ethanol. The 3-MA treatment decreased levels of Beclin-1 and Atg 7 but increased levels of p62 in the ethanol-fed WT and KI mice whereas rapamycin had the opposite effects, validating inhibition and stimulation of autophagy, respectively. These results suggest that autophagy is protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. We speculate that autophagy-dependent processes such as mitophagy and lipophagy help to minimize ethanol-induced CYP2E1-dependent oxidative stress and therefore the subsequent liver injury and steatosis. Attempts to stimulate autophagy may be helpful in lowering ethanol and CYP2E1 dependent liver toxicity. PMID- 26501339 TI - Alphalpha-Synuclein as a Mediator in the Interplay between Aging and Parkinson's Disease. AB - Accumulation and misfolding of the alpha-synuclein protein are core mechanisms in the pathogenesis of Parkinson's disease. While the normal function of alpha synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial activity, as well as proteasome and autophagic degradation of proteins. Remarkably, these functions are also affected when the renewal of macromolecules and organelles becomes impaired during the normal aging process. As aging is considered a major risk factor for Parkinson's disease, it is critical to explore its molecular and cellular implications in the context of the alpha-synuclein pathology. Here, we discuss similarities and differences between normal brain aging and Parkinson's disease, with a particular emphasis on the nigral dopaminergic neurons, which appear to be selectively vulnerable to the combined effects of alpha-synuclein and aging. PMID- 26501340 TI - The La-Related Proteins, a Family with Connections to Cancer. AB - The evolutionarily-conserved La-related protein (LARP) family currently comprises Genuine La, LARP1, LARP1b, LARP4, LARP4b, LARP6 and LARP7. Emerging evidence suggests each LARP has a distinct role in transcription and/or mRNA translation that is attributable to subtle sequence variations within their La modules and specific C-terminal domains. As emerging research uncovers the function of each LARP, it is evident that La, LARP1, LARP6, LARP7 and possibly LARP4a and 4b are dysregulated in cancer. Of these, LARP1 is the first to be demonstrated to drive oncogenesis. Here, we review the role of each LARP and the evidence linking it to malignancy. We discuss a future strategy of targeting members of this protein family as cancer therapy. PMID- 26501342 TI - Global N-linked Glycosylation is Not Significantly Impaired in Myoblasts in Congenital Myasthenic Syndromes Caused by Defective Glutamine-Fructose-6 Phosphate Transaminase 1 (GFPT1). AB - Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the first enzyme of the hexosamine biosynthetic pathway. It transfers an amino group from glutamine to fructose-6-phosphate to yield glucosamine-6-phosphate, thus providing the precursor for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis. UDP GlcNAc is an essential substrate for all mammalian glycosylation biosynthetic pathways and N-glycan branching is especially sensitive to alterations in the concentration of this sugar nucleotide. It has been reported that GFPT1 mutations lead to a distinct sub-class of congenital myasthenic syndromes (CMS) termed "limb-girdle CMS with tubular aggregates". CMS are hereditary neuromuscular transmission disorders in which neuromuscular junctions are impaired. To investigate whether alterations in protein glycosylation at the neuromuscular junction might be involved in this impairment, we have employed mass spectrometric strategies to study the N-glycomes of myoblasts and myotubes derived from two healthy controls, three GFPT1 patients, and four patients with other muscular diseases, namely CMS caused by mutations in DOK7, myopathy caused by mutations in MTND5, limb girdle muscular dystrophy type 2A (LGMD2A), and Pompe disease. A comparison of the relative abundances of bi-, tri-, and tetra antennary N-glycans in each of the cell preparations revealed that all samples exhibited broadly similar levels of branching. Moreover, although some differences were observed in the relative abundances of some of the N-glycan constituents, these variations were modest and were not confined to the GFPT1 samples. Therefore, GFPT1 mutations in CMS patients do not appear to compromise global N-glycosylation in muscle cells. PMID- 26501344 TI - Delays in Surgery for Patients With Coronary Stents Placed After Diagnosis of Colorectal Cancer. PMID- 26501341 TI - The Role of the Transcriptional Regulation of Stromal Cells in Chronic Inflammation. AB - Chronic inflammation is a common process connecting pathologies that vary in their etiology and pathogenesis such as cancer, autoimmune diseases, and infections. The response of the immune system to tissue damage involves a carefully choreographed series of cellular interactions between immune and non immune cells. In recent years, it has become clear that stromal resident cells have an essential role perpetuating the inflammatory environment and dictating in many cases the outcome of inflammatory based pathologies. Signal transduction pathways remain the main focus of study to understand how stimuli contribute to perpetuating the inflammatory response, mainly due to their potential role as therapeutic targets. However, molecular events orchestrated in the nucleus by transcription factors add additional levels of complexity and may be equally important for understanding the phenotypic differences of activated stromal components during the chronic inflammatory process. In this review, we focus on the contribution of transcription factors to the selective regulation of inducible proinflammatory genes, with special attention given to the regulation of the stromal fibroblastic cell function and response. PMID- 26501343 TI - Molecular Mechanisms of Transcription Initiation at gal Promoters and their Multi Level Regulation by GalR, CRP and DNA Loop. AB - Studying the regulation of transcription of the gal operon that encodes the amphibolic pathway of d-galactose metabolism in Escherichia coli discerned a plethora of principles that operate in prokaryotic gene regulatory processes. In this chapter, we have reviewed some of the more recent findings in gal that continues to reveal unexpected but important mechanistic details. Since the operon is transcribed from two overlapping promoters, P1 and P2, regulated by common regulatory factors, each genetic or biochemical experiment allowed simultaneous discernment of two promoters. Recent studies range from genetic, biochemical through biophysical experiments providing explanations at physiological, mechanistic and single molecule levels. The salient observations highlighted here are: the axiom of determining transcription start points, discovery of a new promoter element different from the known ones that influences promoter strength, occurrence of an intrinsic DNA sequence element that overrides the transcription elongation pause created by a DNA-bound protein roadblock, first observation of a DNA loop and determination its trajectory, and piggybacking proteins and delivering to their DNA target. PMID- 26501345 TI - The effect of post-resistance exercise alcohol ingestion on lipopolysaccharide stimulated cytokines. AB - PURPOSE: To examine the effect of post-resistance exercise alcohol ingestion on lipopolysaccharide (LPS)-stimulated production of IFNgamma, TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10. METHODS: Recreationally resistance-trained men (n = 10, 25 +/- 3 year, 177 +/- 7 cm, 83.8 +/- 15.7 kg, 14.8 +/- 8.5% body fat) and women (n = 8, 23 +/- 2 year, 161 +/- 3 cm, 59.5 +/- 6.0 kg, 26.5 +/- 3.0% body fat) completed two identical heavy back squat sessions (6 * 10 at 80% 1 repetition maximum) followed by ingestion of either an alcohol (ALC; 1.09 g ethanol . kg fat free mass(-1)) or water (PLA) drink. Blood samples were collected before exercise (PRE), and at 3 h (3 h), and 5 h (5 h) after exercise, stimulated with LPS, and analyzed for IFNgamma, TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10 concentrations. RESULTS: There were no drink conditions by time effects for IFNgamma, TNF-alpha, IL-1beta, or IL-10. Regardless of condition, resistance exercise induce an increase in IFNgamma, TNF-alpha, and IL-1beta at 5 h compared to PRE but a decrease in IL-10 at 3 and 5 h compared to PRE. For ALC, IL-8 was reduced at 5 h compared to PLA. From PRE to 3 h, IL-6 was reduced for ALC but increased for PLA; resistance exercise induced an increase in IL-6 for both conditions at 5 h. CONCLUSIONS: Heavy resistance exercise increased production of IFNgamma, TNF alpha, IL-1beta, and Il-6 and decreased production of IL-10. Alcohol ingestion after resistance exercise affected aspects of inflammatory capacity (IL-6 and IL 8 production). It appears that some of the effects previously observed for alcohol ingestion alone on the LPS-stimulated cytokine production were overwhelmed by the response to resistance exercise. PMID- 26501346 TI - Pilot Enhancement of the Arthritis Foundation Exercise Program with a Healthy Aging Program. AB - Older adults with arthritis or joint pain were targeted for a pilot program enhancing the Arthritis Foundation Exercise Program with the 10 KeysTM to Healthy Aging Program. Using a one-group, pre-post design, feasibility was examined and improvements in preventive behaviors, arthritis outcomes, and cardiometabolic outcomes were explored. A 10-week program was developed, instructors were recruited and trained, and four sites and 51 participants were recruited. Measures included attendance, adherence, satisfaction, preventive behaviors, Western Ontario and McMaster Universities Osteoarthritis Index (pain and stiffness), glucose, and cholesterol. Three fourths of participants attended >50% of the sessions. At 6 and 12 months, more than one half performed the exercises 1 to 2 days per week, whereas 28% and 14% exercised 3 to 7 days per week, respectively. Participants (92%) rated the program as excellent/very good. Nonsignificant changes were observed in expected directions. Effect sizes were small for arthritis and cardiometabolic outcomes. This program engaged community partners, demonstrated feasibility, and showed improvements in some preventive behaviors and health risk profiles. [Res Gerontol Nurs. 2016; 9(3):123-132.]. PMID- 26501347 TI - Achieving a National Sample of Nursing Homes: Balancing Probability Techniques and Practicalities. AB - Sampling design is critical to the quality of quantitative research, yet it does not always receive appropriate attention in nursing research. The current article details how balancing probability techniques with practical considerations produced a representative sample of Australian nursing homes (NHs). Budgetary, logistical, and statistical constraints were managed by excluding some NHs (e.g., those too difficult to access) from the sampling frame; a stratified, random sampling methodology yielded a final sample of 53 NHs from a population of 2,774. In testing the adequacy of representation of the study population, chi-square tests for goodness of fit generated nonsignificant results for distribution by distance from major city and type of organization. A significant result for state/territory was expected and easily corrected for by the application of weights. The current article provides recommendations for conducting high quality, probability-based samples and stresses the importance of testing the representativeness of achieved samples. PMID- 26501348 TI - Toward Assessment of Dementia Caregiver Activation for Health Care: An Integrative Review of Related Constructs and Measures. AB - The purpose of this integrative literature review was to establish the rationale for a new measure of dementia caregiver activation for health care. Little is known about how caregivers form working partnerships with clinicians to manage the health of individuals who, because of cognitive impairment and functional limitations, can no longer actively manage their own health. Building on three sources-the construct of patient activation, an empirical health care framework for individuals living with dementia, and a set of dementia care quality indicators-the construct of dementia caregiver activation for health care was defined and initial relevant domains were specified. An integrative literature review was performed to identify related constructs and assess currently available measures with respect to their inclusion of these key health care domains. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 647 citations were reviewed and reduced to 17 studies, which were included in the analysis and qualitative synthesis. No existing measure was found that captures all of the domains required for caregiver-clinician partnership, establishing the need for a novel measure of caregiver activation focused on the health care of individuals living with dementia. [Res Gerontol Nurs. 2016; 9(3):145-155.]. PMID- 26501349 TI - [Not Available]. PMID- 26501350 TI - Health Behavior Change after Blood Pressure Feedback. AB - Better understanding is needed for antihypertensive medication initiation and lifestyle modification among younger populations with elevated blood pressure. This study aimed to assess health behavior change after receiving a report of elevated blood pressure among African Americans and Caucasians younger than 50 years old. We used the Coronary Artery Risk Development in Young Adults (CARDIA) repository dataset. By examination year twenty, 424 out of 2,478 Caucasian and 2,637 African American participants had received feedback from the CARDIA study due to elevated blood pressure readings. Blood pressure was measured by trained CARDIA researchers at the participant's home and was repeatedly recorded at seven examinations over twenty years. A feedback/referral letter was sent to participants with an elevated blood pressure reading. On average, participants first had an elevated blood pressure reading at the age of 34. After receiving the feedback letter, 44% of the previously undiagnosed participants received a formal diagnosis. In addition, 23% initiated the use of antihypertensive medication if they had not received medication treatment before. Among the participants with at-risk lifestyle behaviors, 40% reduced alcohol consumption, 14% increased exercise level, 11% stopped smoking, and 8% reached normal weight. While none of the studied patient factors were associated with lifestyle modification, age had a positive impact on antihypertensive medication initiation (p<0.05). We found no evidence of differences in health behavior change between African American and Caucasian participants after receiving the feedback letter. This research is one of the first to study what followed after receiving a feedback letter about elevated blood pressure outside of healthcare settings. Although additional referral care and behavior interventions are needed to facilitate medication initiation and lifestyle modification, our observations suggest that providing blood pressure feedback may have promise as part of a multi-method approach involving blood pressure screening and follow up. PMID- 26501351 TI - Do Predictors of Career Success Differ between Swedish Women and Men? Data from the Swedish Longitudinal Occupational Survey of Health (SLOSH). AB - The aim of this prospective study was to explore predictors of objective career success among Swedish women and men, focussing on gender differences. Data were drawn from the 2008 and 2010 waves of the Swedish Longitudinal Occupational Survey of Health (SLOSH) with a total of 3670 female and 2773 male participants. Odds ratios and 95% confidence intervals for job promotion and an above-average salary increase between 2008 and 2010 were obtained through binary logistic regression analyses. Individual and organisational factors measured in 2008 were used as predictors in analyses stratified by sex. Mutual adjustment was performed for these variables, as well as for labour market sector and staff category at baseline. In both sexes, younger age predicted both job promotion and an above average salary increase. Job promotion was also in both sexes predicted by being part of decision-making processes, having conflicts with superiors, and being eager to advance. Furthermore, promotion was predicted by, among men, being educated to post-graduate level and having an open coping strategy and, among women, working >60 hours/week. An above-average salary increase was predicted in both sexes by having a university education. Postgraduate education, having children living at home, and being very motivated to advance predicted an above average salary increase among women, as did working 51-60 hours/week and being part of decision-making processes in men. Gender differences were seen in several predictors. In conclusion, the results support previous findings of gender differences in predictors of career success. A high level of education, motivation to advance, and procedural justice appear to be more important predictors of career success among women, while open coping was a more important predictor among men. PMID- 26501352 TI - Effect of Some Psychoactive Drugs Used as 'Legal Highs' on Brain Neurotransmitters. AB - New psychoactive "designer drugs" are synthetic compounds developed to provide similar effects to illicit drugs of abuse, but not subjected to legal control. The rapidly changing legal status of novel psychoactive drugs triggers the development of new compounds, analogs of well-known amphetamine or mescaline. New designer drugs used as substitutes in ecstasy pills are the least investigated and can cause life-threatening effects on users. The aim of our research was to examine the effects of acute administration of 4-methoxyamphetamine (PMA, 5 and 10 mg/kg), 4-methoxy-N-methylamphetamine (PMMA, 5 and 10 mg/kg), and mephedrone (MEPH, 5, 10 and 20 mg/kg) on extracellular and tissue level of dopamine (DA), 5 hydroxytryptamine (5-HT) and their metabolites in rat brain, by microdialysis method in freely moving animals and HPLC. Similarly to 3,4 methylenedioxymethamphetamine (MDMA, 5 and 10 mg/kg) PMA, PMMA and MEPH enhanced the release of DA and 5-HT in rat striatum, nucleus accumbens, and frontal cortex. DA tissue content was increased by MEPH and PMMA in striatum, by MEPH, PMA, and PMMA in nucleus accumbens, and by PMA in frontal cortex. Instead, cortical DA level was decreased by MEPH and PMMA. MEPH did not influence 5-HT tissue level in striatum and nucleus accumbens, but decreased its level in frontal cortex. PMMA increased 5-HT content in striatum, while PMA enhanced it in nucleus accumbens and frontal cortex. Observed changes in brain monoamines and their metabolites by new psychoactive drugs suggest that these drugs may be capable of development of dependence. Further experiments are needed to fully investigate the neurotoxic and abuse potential of those drugs. PMID- 26501353 TI - Loss of Nek11 Prevents G2/M Arrest and Promotes Cell Death in HCT116 Colorectal Cancer Cells Exposed to Therapeutic DNA Damaging Agents. AB - The Nek11 kinase is a potential mediator of the DNA damage response whose expression is upregulated in early stage colorectal cancers (CRCs). Here, using RNAi-mediated depletion, we examined the role of Nek11 in HCT116 WT and p53-null CRC cells exposed to ionizing radiation (IR) or the chemotherapeutic drug, irinotecan. We demonstrate that depletion of Nek11 prevents the G2/M arrest induced by these genotoxic agents and promotes p53-dependent apoptosis both in the presence and absence of DNA damage. Interestingly, Nek11 depletion also led to long-term loss of cell viability that was independent of p53 and exacerbated following IR exposure. CRC cells express four splice variants of Nek11 (L/S/C/D). These are predominantly cytoplasmic, but undergo nucleocytoplasmic shuttling mediated through adjacent nuclear import and export signals in the C-terminal non catalytic domain. In HCT116 cells, Nek11S in particular has an important role in the DNA damage response. These data provide strong evidence that Nek11 contributes to the response of CRC cells to genotoxic agents and is essential for survival either with or without exposure to DNA damage. PMID- 26501355 TI - Dependence of the Rate of LiF Ion-Pairing on the Description of Molecular Interaction. AB - We present an analysis of the dynamics of ion-pairing of lithium fluoride (LiF) in aqueous solvent using both detailed molecular simulation as well as reduced models within a generalized Langevin equation (GLE) framework. We explored the sensitivity of the ion-pairing phenomena to the details of descriptions of molecular interaction, comparing two empirical potentials to explicit quantum based density functional theory. We find quantitative differences in the potentials of mean force for ion-pairing as well as time dependent frictions that lead to variations in the rate constant and reactive flux correlation functions. These details reflect differences in solvent response to ion-pairing between different representations of molecular interaction and influence anharmonicity of the dynamic response. We find that the short-time anharmonic response is recovered with a GLE parametrization. Recovery of the details of long time response may require extensions to the reduced model. We show that the utility of using a reduced model leads to a straightforward application of variational transition state theory concepts to the condensed phase system. The significance of this is reflected in the analysis of committor distributions and the variation of planar hypersurfaces, leading to an improved understanding of factors that determine the rate of LiF ion-pairing. PMID- 26501354 TI - A Copper-Mediated Disulfiram-Loaded pH-Triggered PEG-Shedding TAT Peptide Modified Lipid Nanocapsules for Use in Tumor Therapy. AB - Disulfiram, which exhibits marked tumor inhibition mediated by copper, was encapsulated in lipid nanocapsules modified with TAT peptide (TATp) and pH triggered sheddable PEG to target cancer cells on the basis of tumor environmental specificity. PEG-shedding lipid nanocapsules (S-LNCs) were fabricated from LNCs by decorating short PEG chains with TATp (HS-PEG(1k)-TATp) to form TATp-LNCs and then covered by pH-sensitive graft copolymers of long PEG chains (PGA-g-PEG(2k)). The DSF-S-LNCs had sizes in the range of 60-90 nm and were stable in the presence of 50% plasma. DSF-S-LNCs exhibited higher intracellular uptake and antitumor activity at pH 6.5 than at pH 7.4. The preincubation of Cu showed that the DSF cytotoxicity was based on the accumulation of Cu in Hep G2 cells. Pharmacokinetic studies showed the markedly improved pharmacokinetic profiles of DSF-S-LNCs (AUC= 3921.391 MUg/L.h, t(1/2z) = 1.294 h) compared with free DSF (AUC = 907.724 MUg/L.h, t(1/2z) = 0.252 h). The in vivo distribution of S-LNCs was investigated using Cy5.5 as a fluorescent probe. In tumor-bearing mice, the delivery efficiency of S-LNCs was found to be 496.5% higher than that of free Cy5.5 and 74.5% higher than that of LNCs in tumors. In conclusion, DSF-S-LNCs increased both the stability and tumor internalization and further increased the cytotoxicity because of the higher copper content. PMID- 26501356 TI - Highly Sensitive, Encapsulated MoS2 Photodetector with Gate Controllable Gain and Speed. AB - Semiconducting, two-dimensional molybdenum disulfide (MoS2) is considered a promising new material for highly sensitive photodetection, because of its atomically thin profile and favorable bandgap. However, reported photodetectors to date show strong variation in performance due to the detrimental and uncontrollable effects of environmental adsorbates on devices due to large surface to volume ratio. Here, we report on highly stable and high-performance monolayer and bilayer MoS2 photodetectors encapsulated with atomic layer deposited hafnium oxide. The protected devices show enhanced electronic properties by isolating them from the ambience as strong n-type doping, vanishing hysteresis, and reduced device resistance. By controlling the gate voltage the responsivity and temporal response can be tuned by several orders of magnitude with R ~ 10-10(4) A/W and t ~ 10 ms to 10 s. At strong negative gate voltage, the detector is operated at higher speed and simultaneously exhibits a low-bound, record sensitivity of D* >= 7.7 * 10(11) Jones. Our results lead the way for future application of ultrathin, flexible, and high-performance MoS2 detectors and prompt for further investigation in encapsulated transition metal dichalcogenide optoelectronics. PMID- 26501357 TI - Lithium Aluminate Complexes and Alumoles from 1,4-Dilithio-1,3-Butadienes and AlEt2Cl. AB - A series of lithium aluminate complexes and alumoles were synthesized from 1,4 dilithio-1,3-butadienes 1 and AlEt2Cl. Their structures were characterized using single-crystal X-ray structural analysis and NMR spectroscopy. The structure of the lithium aluminate complex 2-TMEDA showed that the Al atom adopted a tetra coordinated mode bonded with two butadienyl Csp2 atoms and two ethyl Csp3 atoms. The lithium cation was located above the alumole ring. The structure of 3a revealed a dimeric 1-ethylalumole in the solid state. Diffusion ordered spectroscopy NMR spectra showed that 3a was also a dimer in C6D6 solvent. However, in tetrahydrofuran (THF) solution, the dimeric 3a dissociated into the 1 ethylalumole-THF adduct. The lithium aluminate complex 2 transformed into 3a-THF when treated with 1.0 equiv of AlEt2Cl. Preliminary reaction chemistry and synthetic applications of the lithium aluminate complex were also investigated. PMID- 26501358 TI - Evaluation of Controlled-Release Property and Phytotoxicity Effect of Insect Pheromone Zinc-Layered Hydroxide Nanohybrid Intercalated with Hexenoic Acid. AB - A controlled release formulation for the insect pheromone hexenoic acid (HE) was successfully developed using zinc-layered hydroxide (ZLH) as host material through a simple coprecipitation technique, resulting in the formation of inorganic-organic nanolayered material with sustained release properties. The release of HE from its nanohybrid was found to occur in a controlled manner, governed by a pseudo-second order kinetics model. The maximum amount of HE released from the nanocomposite into solutions at pH 4, 6.5, and 8 was found to be 84, 73, and 83% for 1100 min, respectively. The hexenoate zinc-layered hydroxide nanomaterial (HEN) was found to be nontoxic for plants when green beans and wheat seeds were successfully germinated in all HEN concentrations tested in the experiment, with higher percentage of seed germination and higher radical seed growth as compared to its counter anion, HE. ZLH can be a promising carrier for insect pheromone toward a new generation of environmentally safe pesticide nanomaterial for crop protection. PMID- 26501359 TI - gem-Difluoroolefination of Diazo Compounds with TMSCF3 or TMSCF2Br: Transition Metal-Free Cross-Coupling of Two Carbene Precursors. AB - A new olefination protocol for transition-metal-free cross-coupling of two carbene fragments arising from two different sources, namely, a nonfluorinated carbene fragment resulting from a diazo compound and a difluorocarbene fragment derived from Ruppert-Prakash reagent (TMSCF3) or TMSCF2Br, has been developed. This gem-difluoroolefination proceeds through the direct nucleophilic addition of diazo compounds to difluorocarbene followed by elimination of N2. Compared to previously reported Cu-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3, which possesses a narrow substrate scope due to a demanding requirement on the reactivity of diazo compounds and in-situ-generated CuCF3, this transition metal-free protocol affords a general and efficient approach to various disubstituted 1,1-difluoroalkenes, including difluoroacrylates, diaryldifluoroolefins, as well as arylalkyldifluoroolefins. In view of the ready availability of diazo compounds and difluorocarbene reagents and versatile transformations of 1,1-difluoroalkenes, this new gem-difluoroolefination method is expected to find wide applications in organic synthesis. PMID- 26501360 TI - Novel iterative reconstruction method with optimal dose usage for partially redundant CT-acquisition. AB - In CT imaging, a variety of applications exist which are strongly SNR limited. However, in some cases redundant data of the same body region provide additional quanta. Examples in dual energy CT, the spatial resolution has to be compromised to provide good SNR for material decomposition. However, the respective spectral dataset of the same body region provides additional quanta which might be utilized to improve SNR of each spectral component. Perfusion CT is a high dose application, and dose reduction is highly desirable. However, a meaningful evaluation of perfusion parameters might be impaired by noisy time frames. On the other hand, the SNR of the average of all time frames is extremely high.In redundant CT acquisitions, multiple image datasets can be reconstructed and averaged to composite image data. These composite image data, however, might be compromised with respect to contrast resolution and/or spatial resolution and/or temporal resolution. These observations bring us to the idea of transferring high SNR of composite image data to low SNR 'source' image data, while maintaining their resolution.It has been shown that the noise characteristics of CT image data can be improved by iterative reconstruction (Popescu et al 2012 Book of Abstracts, 2nd CT Meeting (Salt Lake City, UT) p 148). In case of data dependent Gaussian noise it can be modelled with image-based iterative reconstruction at least in an approximate manner (Bruder et al 2011 Proc. SPIE 7961 79610J). We present a generalized update equation in image space, consisting of a linear combination of the previous update, a correction term which is constrained by the source image data, and a regularization prior, which is initialized by the composite image data. This iterative reconstruction approach we call bimodal reconstruction (BMR). Based on simulation data it is shown that BMR can improve low contrast detectability, substantially reduces the noise power and has the potential to recover spatial resolution of the source image data.For different CT applications: dual energy imaging, liver imaging, spiral imaging, cardiac imaging, we show that SNR can efficiently be transferred from the composite image to the source image data at constant patient dose, while maintaining resolution properties of the source data. PMID- 26501361 TI - Toxicological and hematological effect of Terminalia arjuna bark extract on a freshwater catfish, Heteropneustes fossilis. AB - Increasing demand for eco-friendly botanical piscicides and pesticides as replacements for harmful synthetic chemicals has led to investigation of new sources of plant materials. Stem bark of Terminalia arjuna, which has been used as a popular folk medicine since ancient time, was examined for its piscicidal activity. This study aims to determine toxicity of ethanol extract of T. arjuna bark on fresh water stinging catfish (Heteropneustes fossilis), along with evaluation of changes in hematological parameters of the fishes exposed to a lethal concentration. The percent mortality of fishes varied significantly in response to concentrations of the extract and exposure times (between exposure time F = 36.57, p < 0.001; between concentrations F = 39.93, p < 0.001). The lethal concentrations (LC50) of ethanol extract were found to be 12.7, 8.94, 5.63 and 4.71 mg/l for 24, 48, 72 and 96 h, respectively. During acute toxicity test, blood samples of treatment fishes showed significant decreases in the red blood cells count, hematocrit content, hemoglobin concentration, mean corpuscular hemoglobin concentration and plasma protein level when compared to those of the control group, while there were significant increases in the mean corpuscular volume, mean corpuscular hemoglobin, white blood cells count and plasma glucose concentration. These results suggest that T. arjuna bark extract could be considered as a potent piscicide due to its toxic effect on fish, particularly fish hematology. PMID- 26501362 TI - Development and Validation of a High-Throughput Ultrahigh-Performance Liquid Chromatography-Mass Spectrometry Approach for Screening of Oxylipins and Their Precursors. AB - Lipid mediators, highly bioactive compounds synthesized from polyunsaturated fatty acids (PUFAs), have a fundamental role in the initiation and signaling of the inflammatory response. Although extensively studied in isolation, only a limited number of analytical methods offer a comprehensive coverage of the oxylipin synthetic cascade applicable to a wide range of human biofluids. We report the development of an ultrahigh-performance liquid chromatography electrospray ionization triple quadrupole mass spectrometry (UHPLC-MS) assay to quantify oxylipins and their PUFA precursors in 100 MUL of human serum, plasma, urine, and cell culture supernatant. A single 15 min UHPLC run enables the quantification of 43 oxylipins and 5 PUFAs, covering pro and anti-inflammatory lipid mediators synthesized across the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) pathways. The method was validated in multiple biofluid matrixes (serum, plasma, urine, and cell supernatant) and suppliers, ensuring its suitability for large scale metabonomic studies. The approach is accurate, precise, and reproducible (RSD < 15%) over multiple days and concentrations. Very high sensitivity is achieved with limits of quantification inferior to picograms for the majority of analytes (0.05-125 pg) and linear range spanning up to 5 orders of magnitude. This enabled the quantification of the great majority of these analytes at their low endogenous level in human biofluids. We successfully applied the procedure to individuals undergoing a fasting intervention; oxylipin profiles highlighted significantly altered PUFA and inflammatory profiles in accordance with previously published studies as well as offered new insight on the modulation of the biosynthetic cascade responsible for the regulation of oxylipins. PMID- 26501364 TI - Models for Copper Dynamic Behavior in Doped Cadmium dl-Histidine Crystals: Electron Paramagnetic Resonance and Crystallographic Analysis. AB - Electron paramagnetic resonance and crystallographic studies of copper-doped cadmium dl-histidine, abbreviated as CdDLHis, were undertaken to gain further understanding on the relationship between site structure and dynamic behavior in biological model complexes. X-ray diffraction measurements determined the crystal structure of CdDLHis at 100 and 298 K. CdDLHis crystallizes in the monoclinic space group P21/c with two cadmium complexes per asymmetric unit. In each complex, the Cd is hexacoordinated to two histidine molecules. Both histidines are l in one complex and d in the other. Additionally, each complex contains multiple waters of varying disorder. Single crystal EPR spectroscopic splitting (g) and copper hyperfine (A(Cu)) tensors at room temperature (principal values: g = 2.249, 2.089, 2.050; A(Cu) = -453, -30.5, -0.08 MHz) were determined from rotational experiments. Alignments of the tensor directions with the host structure were used to position the copper unpaired dx(2)-y(2) orbital in an approximate plane made by four proposed ligand atoms: the N-imidazole and N-amino of one histidine, and the N-amino and O-carboxyl of the other. Each complex has two such planes related by noncrystallographic symmetry, which make an angle of 65 degrees and have a 1.56 A distance between their midpoints. These findings are consistent with three interpretations that can adequately explain previous temperature-dependent EPR powder spectra of this system: (1) a local structural distortion (static strain) at the copper site has a temperature dependence significant enough to affect the EPR pattern, (2) the copper can hop between the two sites in each complex at high temperature, and (3) there exists a dynamic Jahn-Teller effect involving the copper ligands. PMID- 26501363 TI - Visceral adiposity is a predictor of parathyroid hormone levels in healthy adults. AB - PURPOSE: Parathyroid hormone (PTH) has been shown to correlate positively with fat mass, however there are no studies that have investigated whether this association is a result of, or is modified by, body fat distribution. The aim of this study was to investigate the association of PTH with several body composition indices, namely visceral (VAT) and subcutaneous adiposity (SCAT) as well as with lean mass and with serum leptin, which has been reported to increase PTH. METHODS: This was a cross-sectional study in which PTH was measured by chemiluminescent assay; body fat and lean mass by dual-energy X-ray absorptiometry (DXA) and abdominal fat by ultrasonography in 714 healthy adults aged 18-65 years. Serum leptin was measured by ELISA. RESULTS: In a multivariate linear regression model that included height, age, gender, ethnicity, serum 25 hydroxyvitamin D, leptin levels, calcium, magnesium and phosphate concentrations, glomerular filtration rate, smoking status, and calcium and vitamin D supplementation as independent variables and PTH as the dependent variable, VAT (beta = 0.094, p = 0.035) correlated significantly with PTH levels but SCAT (beta = -0.045, p = 0.386) and body fat mass (beta = 0.098, p = 0.126) did not. Leptin did not correlate with PTH (beta = 0.013, p = 0.832) in this regression model. CONCLUSIONS: Plasma PTH is significantly associated with VAT in healthy adults. In view of the association of PTH with increased cardiovascular mortality, it is important to investigate this association further. PMID- 26501365 TI - Genetics in Retinal Diseases. AB - The phenotypic presentation of retinal diseases is typically underpinned by the presence of genetic variation represented by either polymorphic changes, mutations, copy number variations or epigenetic changes. Retinal dystrophies can broadly be divided into two forms, either monogenic (single-gene) or complex (multifactorial) diseases. Recent advances in molecular techniques such as genome wide association studies and next-generation sequencing have revolutionized the discovery of genetic variants associated with different retinal disorders, including retinitis pigmentosa and age-related macular degeneration. Understanding the genetic profile of the disease not only helps in diagnostics but also in gene therapy, as recently shown for Leber's congenital amaurosis. Following the elucidation of many genetic features of retinal diseases, the task is now to make sense of this large amount of data to better understand as well as experimentally prove the physiological process of the retinal disease genes and the mechanisms behind the diseases. This in turn will lead to improved gene-based therapies and personalize treatments for patients. PMID- 26501366 TI - Sensitive electrochemical immunoassay with signal enhancement based on nanogold encapsulated poly(amidoamine) dendrimer-stimulated hydrogen evolution reaction. AB - A new electrochemical immunosensor with signal enhancement was designed for sensitive detection of disease-related protein (human carbohydrate antigen 19-9, CA 19-9 used in this case). The assay was carried out on a capture antibody modified screen-printed carbon electrode with a sandwich-type mode by using detection antibody-functionalized nanogold-encapsulated poly(amidoamine) dendrimer (AuNP-PAAD). The AuNP-PAAD was first synthesized through the in situ reduction method and functionalized with the polyclonal rabbit anti-human CA 19-9 antibody. Upon target CA 19-9 introduction, a sandwiched immunocomplex could be formed between the capture antibody and detection antibody. Accompanying the AuNP PAAD, the electrocatalytic activity of the carried gold nanoparticles toward the hydrogen evolution reaction (HER) allowed the rapid quantification of the target analyte on the electrode. The amplified electrochemical signal mainly derived from AuNP-catalyzed HER in an acidic medium. Under optimal conditions, the immuno HER assay displayed a wide dynamic concentration range from 0.01 to 300 U mL(-1) toward target CA 19-9 with a detection limit (LOD) of 6.3 mU mL(-1). The reproducibility, precision, specificity and stability of our strategy were acceptable. Additionally, the system was further validated by assaying 13 human serum specimens, giving well matched results obtained from the commercialized enzyme-linked immunosorbent assay (ELISA) method. PMID- 26501367 TI - Selective synthesis of functionalized pyrroles from 3-aza-1,5-enynes. AB - 2-Trifluoromethyl-5-(arylsulfonyl)methyl pyrroles and 2-trifluoromethyl-4 (arylsulfonyl)methyl pyrroles were selectively synthesized from trifluoromethyl substituted 3-aza-1,5-enynes via a cyclization/sulfonyl group migration cascade catalyzed by AgOOCCF3 and CsOPiv, respectively. Alkylvinyl-substituted pyrroles were generated from seven-atom skeleton 3-aza-1,5-enynes via aryl sulfinic acid elimination in the presence of Cs2CO3. Two ion-pair intermediates were proposed and a key intermediate, aza-diene-yne, was successfully isolated in the mechanistic studies. PMID- 26501368 TI - Immunomodulatory Therapy in Uveitis. AB - Corticosteroids are the cornerstone of treating intraocular inflammation, but may be inadequate in controlling the disease, or related side effects preclude long term treatment. Additional immunosuppressive drugs are used in these cases to augment the effect of corticosteroids and allow for their reduction to safe levels while maintaining control of the ocular inflammation. Here we review the different classes of immunosuppressive drugs and discuss their effect on ocular inflammation. PMID- 26501369 TI - Trypanosoma cruzi and Leishmania infantum chagasi Infection in Wild Mammals from Maranhao State, Brazil. AB - Trypanosoma and Leishmania are obligate parasites that cause important diseases in human and domestic animals. Wild mammals are the natural reservoirs of these parasites, which are transmitted by hematophagous arthropods. The present study aimed to detect the natural occurrence of trypanosomatids through serological diagnosis, PCR of whole blood and blood culture (hemoculture), and phylogenetic relationships using small subunit ribosomal DNA (SSU rDNA), cytochrome b, and glycosomal glyceraldehyde 3-phosphate dehydrogenase (gGAPDH) genes. Samples from 131 wild animals, including rodents, marsupials, and bats, were sampled in six areas in the state of Maranhao, in a transition zone of semiarid climates northeast of the equatorial humid Amazon. Serological analysis for Leishmania (Leishmania) infantum chagasi was performed in opossums by indirect fluorescent antibody test (IFAT), and all animals were serologically negative. Nine positive hemocultures (6.77%) were isolated and cryopreserved and from mammals of the Didelphimorphia and Chiroptera orders and positioned in phylogenies on the basis of sequences from different genes with reference strains of Trypanosoma cruzi marinkellei and T. cruzi. From primary samples (blood and tissues) only one bat, Pteronotus parnellii, was positive to SSU rDNA and gGAPDH genes and grouped with the L. infantum chagasi branch. The studies conducted in Maranhao State provide knowledge of parasite diversity. It is important to determine the presence of trypanosomatids in wild mammals with synanthropic habits. PMID- 26501370 TI - Emotional Intelligence: A Novel Outcome Associated with Wellbeing and Self Management in Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Individuals with chronic obstructive pulmonary disease (COPD) often struggle with diminished autonomy and quality of life. Emotional factors play a crucial role in the well-being of patients with COPD; they are independently associated with critical outcomes such as dyspnea, quality of life, and health care use. Emotional intelligence is the capacity to understand and manage personal thoughts and feelings, as well as to positively influence interpersonal communication and social well-being. Emotional intelligence is a trainable skill that is extensively used in corporate business to improve well-being and performance, and it may also be significant in the self-management of emotions in patients with chronic disease. Importantly, research supports the proposition that emotional intelligence may be developed and learned at any time or any age, and training programs have been associated with increased well-being and better emotional regulation in patients with chronic disease. However, to date, no research has been done to investigate its value in patients with COPD. OBJECTIVES: We aimed to investigate the association between emotional intelligence and two meaningful outcomes in COPD: quality of life and self management abilities. METHODS: Participants with moderate to severe COPD completed a disease-specific quality of life tool (Chronic Respiratory Questionnaire), the Trait Emotional Intelligence Questionnaire, the Self Management Abilities Scale, the modified Medical Research Council Dyspnea Scale, and pulmonary function tests, and also provided information about living conditions and self-reported health care use. MEASUREMENTS AND MAIN RESULTS: A total of 310 patients with COPD (mean age, 69 +/- 9 yr; 40% female; mean FEV1%, 42.4 +/- 15.8) participated in the study. Emotional intelligence was significantly and independently associated with self-management abilities (P < 0.0001) and all domains of quality of life assessed (dyspnea, fatigue, emotions, and mastery; P < 0.0001) after adjusting for age, degree of bronchial obstruction, breathlessness, and other significant confounders. CONCLUSIONS: Emotional intelligence may represent an important attribute in COPD, as it is associated with self-management abilities and all domains of quality of life, regardless of age or disease severity. Emotional intelligence can be learned and may complement existing rehabilitation efforts. Attention to it may address the current gap that exists in the treatment of emotional components of COPD responsible for decreased quality of life and increased health care use. PMID- 26501371 TI - Gap Analysis between Perceptions and Expectations of Medical-Surgical Patients in a Public Hospital in Saudi Arabia. AB - OBJECTIVES: To investigate patients' satisfaction with nursing care by measuring the gap between patients' expectations of care and perceptions of the actual care provided and to identify the areas of nursing care that need improvement. SUBJECTS AND METHODS: A cross-sectional survey was conducted among patients who were admitted to the Departments of Medicine and Surgery at King Saud Medical City, Riyadh, Saudi Arabia. A modified Service Quality (SERVQUAL) instrument was adapted to collect information from a convenience sample of 432 patients from November 25, 2012, to February 3, 2013. The instrument comprised 22 pairs of questions assessing 5 dimensions of the nursing care provided to patients during hospitalizations. The mean patient expectations and perceptions as well as the gap score values for each dimension of nursing service were tested for differences between the mean scores of the sample at a level of significance of 0.05 using a t test. RESULTS: The gap score for all of the 5 dimensions of nursing services were: responsiveness, -1.71; reliability, -1.48; tangibles, 1.36; assurance, -1.26, and empathy, -0.96. Service quality across the dimensions of responsiveness and reliability was statistically significant (p < 0.05). This result indicated that patients were not satisfied with the nursing service quality in relation to all dimensions. CONCLUSION: Our study showed negative gaps for the 5 nursing service quality dimensions evaluated. This could provide nurses with information about the aspects of nursing care that promote more positive patient outcomes and satisfaction. PMID- 26501372 TI - Pilot study on the efficacy of combined intraoral and extraoral low-level laser therapy for prevention of oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation. AB - OBJECTIVE AND BACKGROUND DATA: Studies suggest that intraoral low-level laser therapy (LLLT) can ameliorate oral mucositis in adult patients receiving high dose chemotherapy. The objective of this study was to evaluate the use of a combined protocol of intraoral and extraoral LLLT in children undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Twelve children undergoing HSCT were treated four times a week with a combined protocol of intraoral and extraoral LLLT, for a mean duration of 22 days. Clinical and functional mucositis scores were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). These scores were compared with a matched retrospective control group of 12 children who did not receive LLLT during HSCT. RESULTS: Clinical mucositis scores were significantly lower in the LLLT group than in the control group (p = 0.004). Incidence of ulcerative oral mucositis was also significantly lower in the LLLT group (p = 0.027). Functional limitation associated with diet/swallowing was less severe in the LLLT group; however, this was not statistically significant. CONCLUSIONS: This study indicates that a combined protocol of intraoral and extraoral application of LLLT can reduce the severity of oral mucositis in pediatric patients undergoing HSCT. Randomized double-blind clinical trials with a larger number of subjects are needed to further test such combined protocols. PMID- 26501373 TI - A facile synthesis of 2,5-disubstituted oxazoles via a copper-catalyzed cascade reaction of alkenes with azides. AB - A novel and efficient approach to the synthesis of 2,5-disubstituted oxazoles is developed via a 1,3-dipolar cycloaddition/ring cleavage/1,2-H migration/denitrogenation/copper-catalyzed aerobic oxidative dehydrogenative cyclization cascade. The desired products can be obtained from readily available aromatic terminal alkenes and azides employing air as the oxidant under mild conditions, and it offers an attractive alternative method for the synthesis of oxazole derivatives. PMID- 26501374 TI - Comparative analysis of oncogenes identified by microarray and RNA-sequencing as biomarkers for clinical prognosis. AB - AIMS: Although RNA-sequencing has been widely used to identify the differentially expressed genes (DEGs) as biomarkers to guide the therapeutic treatment, it is necessary to investigate the concordance of DEGs identified by microarray and RNA sequencing for the clinical prognosis. MATERIAL & METHODS: By using The Cancer Genome Atlas data sets, we thoroughly investigated the concordance of DEGs identified from microarray and RNA-sequencing data and their molecular functions. RESULTS: The DEGs identified by both technologies averaged ~98.6% overlap. The cancer-related gene sets were significantly enriched with the DEGs and consistent between two technologies. CONCLUSIONS: The highly consistency of DEGs in their regulation directionality and molecular functions indicated the good reproducibility between microarray and RNA-sequencing in identifying potential oncogenes for clinical prognosis. PMID- 26501375 TI - Retinal Detachment and Proliferative Vitreoretinopathy. AB - In normal eyes, retinal detachment (RD) occurs at a rate of approximately 5 per 100,000 people per year and the frequency of proliferative vitreoretinopathy (PVR) remains largely unchanged in primary RD, with the incidence ranging from 5.1 to 11.7%. PVR is the most common cause of failed repair of rhegmatogenous RD, and risk factors for PVR are related to several well-known pre-, intra-, and postoperative clinical situations. Current methods of surgical management of RD and PVR are pneumatic retinopexy, scleral buckling, and pars plana vitrectomy (PPV). Surgical success rates for PVR have improved as techniques and instruments of vitrectomy evolved. However, despite these advances, more than one fourth of initially successful cases results in redetachment due to recurrent vitreoretinal traction. Retinal pigment epithelial cells are the key factor in triggering PVR development. In addition, soluble mediators and the extracellular matrix components play a critical role in cellular events, including proliferation and tissue contraction which occur in PVR. Although PPV remains a critical component of the treatment in RD and PVR, ongoing efforts seek to identify adjuvant therapies that might inhibit PVR development. Recent studies have therefore been directed toward pharmacologic inhibition of cellular proliferation and membrane contraction with drugs such as daunorubicin, 5-fluorouracil, and heparin. More detailed understanding of the pathophysiology underlying PVR may lead to the development of effective prophylactic and/or adjunctive therapies. Further work is necessary to identify optimal adjunctive therapies for the management of RD and PVR. PMID- 26501376 TI - Temporal and spatial expression of Drosophila Neurexin during the life cycle visualized using a DNRX-Gal4/UAS-reporter. AB - Drosophila neurexin (DNRX) plays a critical role in proper architecture development and synaptic function in vivo. However, the temporal and spatial expression pattern of DNRX still remains unclear. For this study, we generated a novel Drosophila transgenic strain termed the DNRX-Gal4 transgenic line, with characteristic features in agreement with the endogenous DNRX expression pattern. DNRX expression was examined by driving the expression of a GFP reporter (nuclear localized and membrane- localized GFP) using the DNRX-Gal4 promoter. We found that DNRX was expressed preferentially in central and motor neurons in embryos, larvae and adults, but not in glial cells. DNRX was expressed in pre- and post synaptic areas in third instar larvae neuromuscular junctions (NMJs). Reporter expression was also observed in the salivary glands, guts, wings and legs of adult flies. In the adult brain, reporter expression was observed throughout several brain regions, including the mushroom body (MBs), antennal lobe (AL) and optic lobe neurons, which is consistent with endogenous DNRX expression via antibody staining. Interestingly, DNRX was also expressed in clock neurons. Meanwhile, we found that DNRX expression in the MBs was required for olfactory learning and memory. PMID- 26501377 TI - Artemisinin (Qinghaosu): a mesmerizing drug that still puzzles. PMID- 26501378 TI - A significant carbon sink in temperate forests in Beijing: based on 20-year field measurements in three stands. AB - Numerous efforts have been made to characterize forest carbon (C) cycles and stocks in various ecosystems. However, long-term observation on each component of the forest C cycle is still lacking. We measured C stocks and fluxes in three permanent temperate forest plots (birch, oak and pine forest) during 2011-2014, and calculated the changes of the components of the C cycle related to the measurements during 1992-1994 at Mt. Dongling, Beijing, China. Forest net primary production in birch, oak, and pine plots was 5.32, 4.53, and 6.73 Mg C ha-1 a-1, respectively. Corresponding net ecosystem production was 0.12, 0.43, and 3.53 Mg C ha-1 a-1. The C stocks and fluxes in 2011-2014 were significantly larger than those in 1992-1994 in which the biomass C densities in birch, oak, and pine plots increased from 50.0, 37.7, and 54.0 Mg C ha-1 in 1994 to 101.5, 77.3, and 110.9 Mg C ha-1 in 2014; soil organic C densities increased from 207.0, 239.1, and 231.7 Mg C ha-1 to 214.8, 241.7, and 238.4 Mg C ha-1; and soil heterotrophic respiration increased from 2.78, 3.49, and 1.81 Mg C ha-1 a-1 to 5.20, 4.10, and 3.20 Mg C ha-1 a-1. These results suggest that the mountainous temperate forest ecosystems in Beijing have served as a carbon sink in the last two decades. These observations of C stocks and fluxes provided field-based data for a long-term study of C cycling in temperate forest ecosystems. PMID- 26501379 TI - The role of apoptosis in Caenorhabditis elegans neuronal differentiation. PMID- 26501380 TI - Interventions for smokeless tobacco use cessation. AB - BACKGROUND: Use of smokeless tobacco (ST) can lead to tobacco dependence and long term use can lead to health problems including periodontal disease, cancer, and cerebrovascular and cardiovascular disease. OBJECTIVES: To assess the effects of behavioural and pharmacologic interventions for the treatment of ST use. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group specialised register in June 2015. SELECTION CRITERIA: Randomized trials of behavioural or pharmacological interventions to help users of ST to quit with follow-up of at least six months. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by the Cochrane Collaboration. We summarised outcomes as risk ratios (RRs). For subgroups of trials with similar types of intervention and without substantial statistical heterogeneity, we estimated pooled effects using a Mantel-Haenszel fixed-effect method. MAIN RESULTS: We identified 34 trials that met the inclusion criteria, of which nine were new for this update, representing over 16,000 participants. There was moderate quality evidence from two studies suggesting that varenicline increases ST abstinence rates (risk ratio [RR] 1.34, 95% confidence interval (CI) 1.08 to 1.68, 507 participants). Pooled results from two trials of bupropion did not detect a benefit of treatment at six months or longer (RR 0.89, 95% CI 0.54 to 1.44, 293 participants) but the confidence interval was wide. Neither nicotine patch (five trials, RR 1.13, 95% CI 0.93 to 1.37, 1083 participants) nor nicotine gum (two trials, RR 0.99, 95% CI 0.68 to 1.43, 310 participants) increased abstinence. Pooling five studies of nicotine lozenges did increase tobacco abstinence (RR 1.36, 95% CI 1.17 to 1.59, 1529 participants) but confidence in this estimate is low as the result is sensitive to the exclusion of three trials which did not use a placebo control.Statistical heterogeneity was evident among the 17 trials of behavioural interventions: eight of them reported statistically and clinically significant benefits; six suggested benefit but with wide CIs and no statistical significance; and three had similar intervention and control quit rates and relatively narrow CIs. Heterogeneity was not explained by study design (individual or cluster randomization), whether participants were selected for interest in quitting, or specific intervention components. In a post hoc subgroup analysis, trials of behavioural interventions incorporating telephone support, with or without oral examination and feedback, were associated with larger effect sizes, but oral examination and feedback alone were not associated with benefit.In one trial an interactive website increased abstinence more than a static website. One trial comparing immediate cessation using nicotine patch versus a reduction approach using either nicotine lozenge or brand switching showed greater success for the abrupt cessation group. AUTHORS' CONCLUSIONS: Varenicline, nicotine lozenges and behavioural interventions may help ST users to quit. Confidence in results for nicotine lozenges is limited. Confidence in the size of effect from behavioural interventions is limited because the components of behavioural interventions that contribute to their impact are not clear. PMID- 26501381 TI - Galangin Prevents Acute Hepatorenal Toxicity in Novel Propacetamol-Induced Acetaminophen-Overdosed Mice. AB - Acetaminophen (APAP) overdose causes severe liver and kidney damage. APAP-induced liver injury (AILI) represents the most frequent cause of drug-induced liver failure. APAP is relatively insoluble and can only be taken orally; however, its prodrug, propacetamol, is water soluble and usually injected directly. In this study, we examined the time-dependent effects of AILI after propacetamol injection in mice. After analyses of alanine aminotransferase and aspartate aminotransferase activities and liver histopathology, we demonstrated that a novel AILI mouse model can be established by single propacetamol injection. Furthermore, we compared the protective and therapeutic effects of galangin with a known liver protective extract, silymarin, and the only clinical agent for treating APAP toxicity, N-acetylcysteine (NAC), at the same dose in the model mice. We observed that galangin and silymarin were more effective than NAC for protecting against AILI. However, only NAC greatly improved both the survival time and rate consequent to a lethal dose of propacetamol. To decipher the hepatic protective mechanism(s) of galangin, galangin pretreatment significantly decreased the hepatic oxidative stress, increased hepatic glutathione level, and decreased hepatic microsomal CYP2E1 levels induced by propacetamol injection. In addition, propacetamol injection also reproduced the probability of APAP-induced kidney injury (AIKI), appearing similar to a clinical APAP overdose. Only galangin pretreatment showed the protective effect of AIKI. Thus, we have established a novel mouse model for AILI and AIKI using a single propacetamol injection. We also demonstrated that galangin provides significant protection against AILI and AIKI in this mouse model. PMID- 26501382 TI - A Standardized Extract of Rhus verniciflua Stokes Protects Wistar Rats Against Lipopolysaccharide-Induced Acute Inflammation. AB - Rhus verniciflua stokes (RVS) (Anacardiaceae) has been traditionally used as a folk remedy for gastritis, several cancers, and various metabolic diseases. The present study evaluated the anti-inflammatory effect of RVS extract standardized to fustin content using lipopolysaccharide (LPS)-stimulated rats. The rats were randomly divided into six groups and intragastrically administered 0, 100, 250, or 500 mg/kg body weight (bw) of RVS or 15 mg/kg bw of fustin for 14 days. LPS was intraperitoneally injected 18 h before sacrifice. The nitric oxide levels of RVS extract in either the serum or liver were significantly decreased compared to the LPS-treated rats (P<.05). The treatment with the RVS extract also blunted the rise of malondialdehyde levels in the liver (P<.05). The administration of RVS extract and fustin significantly prevented the elevation of interleukin 6 cytokine, iNOS, and COX-2 mRNA expression in the liver. Inflammatory cell infiltration was also significantly attenuated by the RVS extract or fustin supplementation. These results suggest that our standardized RVS extract has preventive effects on inflammatory reactions. PMID- 26501383 TI - Milk Collected at Night Induces Sedative and Anxiolytic-Like Effects and Augments Pentobarbital-Induced Sleeping Behavior in Mice. AB - Milk has long been known and used to promote sleep. The sleep-promoting effect of milk has been attributed to its psychological associations (i.e., the memory of a mother giving milk at bedtime) and its rich store of sleep-promoting constituents (e.g., tryptophan). Studies have shown that milk harvested at night (Night milk) contains exceptionally high amounts of tryptophan and melatonin. In the present study, we evaluated the psychopharmacological properties of Night milk, particularly its probable sleep-promoting/enhancing, and anxiolytic effects. Night milk was orally administered to ICR mice at various concentrations (100, 200, or 300 mg/kg). An hour after administration, assessment of its sedative (open-field and rotarod tests) and sedative sleep-potentiating effects (pentobarbital-induced sleeping test) was conducted. For comparison, the effects of Day milk (daytime milking) were also assessed. In addition, the effects of Night milk on anxiety behavior (elevated plus maze [EPM] test) and electroencephalographic (EEG) waves were evaluated. Night milk-treated animals exhibited decreased spontaneous locomotion (open-field test) and impaired motor balance and coordination (rotarod test). Furthermore, Night milk shortened the sleep onset and prolonged the sleep duration induced by pentobarbital sodium. These effects were comparable to that of diazepam. In addition, Night milk significantly increased the percentage of time spent and entries into the open arms of the EPM, indicating that it also has anxiolytic effects. No significant changes in EEG waves were observed. Altogether, these findings suggest that Night milk is a promising natural aid for sleep- and anxiety-related disturbances. PMID- 26501384 TI - Investigation of the Viability, Adhesion, and Migration of Human Fibroblasts in a Hyaluronic Acid/Gelatin Microgel-Reinforced Composite Hydrogel for Vocal Fold Tissue Regeneration. AB - The potential use of a novel scaffold biomaterial consisting of cross-linked hyaluronic acid (HA)-gelatin (Ge) composite microgels is investigated for use in treating vocal fold injury and scarring. Cell adhesion integrins and kinematics of cell motion are investigated in 2D and 3D culture conditions, respectively. Human vocal fold fibroblast (hVFF) cells are seeded on HA-Ge microgels attached to a HA hydrogel thin film. The results show that hVFF cells establish effective adhesion to HA-Ge microgels through the ubiquitous expression of beta1 integrin in the cell membrane. The microgels are then encapsulated in a 3D HA hydrogel for the study of cell migration. The cells within the HA-Ge microgel-reinforced composite hydrogel (MRCH) scaffold have an average motility speed of 0.24 +/- 0.08 MUm min(-1) . The recorded microscopic images reveal features that are presumably associated with lobopodial and lamellipodial cell migration modes within the MRCH scaffold. Average cell speed during lobopodial migration is greater than that during lamellipodial migration. The cells move faster in the MRCH than in the HA-Ge gel without microgels. These findings support the hypothesis that HA-Ge MRCH promotes cell adhesion and migration; thereby they constitute a promising biomaterial for vocal fold repair. PMID- 26501385 TI - Evaluation of Perioperative Medication Errors and Adverse Drug Events. AB - BACKGROUND: The purpose of this study is to assess the rates of perioperative medication errors (MEs) and adverse drug events (ADEs) as percentages of medication administrations, to evaluate their root causes, and to formulate targeted solutions to prevent them. METHODS: In this prospective observational study, anesthesia-trained study staff (anesthesiologists/nurse anesthetists) observed randomly selected operations at a 1,046-bed tertiary care academic medical center to identify MEs and ADEs over 8 months. Retrospective chart abstraction was performed to flag events that were missed by observation. All events subsequently underwent review by two independent reviewers. Primary outcomes were the incidence of MEs and ADEs. RESULTS: A total of 277 operations were observed with 3,671 medication administrations of which 193 (5.3%; 95% CI, 4.5 to 6.0) involved a ME and/or ADE. Of these, 153 (79.3%) were preventable and 40 (20.7%) were nonpreventable. The events included 153 (79.3%) errors and 91 (47.2%) ADEs. Although 32 (20.9%) of the errors had little potential for harm, 51 (33.3%) led to an observed ADE and an additional 70 (45.8%) had the potential for patient harm. Of the 153 errors, 99 (64.7%) were serious, 51 (33.3%) were significant, and 3 (2.0%) were life-threatening. CONCLUSIONS: One in 20 perioperative medication administrations included an ME and/or ADE. More than one third of the MEs led to observed ADEs, and the remaining two thirds had the potential for harm. These rates are markedly higher than those reported by retrospective surveys. Specific solutions exist that have the potential to decrease the incidence of perioperative MEs. PMID- 26501386 TI - Methylprednisolone Does Not Reduce Persistent Pain after Cardiac Surgery. AB - BACKGROUND: Persistent incisional pain is common after cardiac surgery and is believed to be in part related to inflammation and poorly controlled acute pain. Methylprednisolone is a corticosteroid with substantial antiinflammatory and analgesic properties and is thus likely to ameliorate persistent surgical pain. Therefore, the authors tested the primary hypothesis that patients randomized to methylprednisolone have less persistent incisional pain than those given placebo. METHODS: One thousand forty-three patients having cardiopulmonary bypass for cardiac surgery via a median sternotomy were included in this substudy of Steroids in Cardiac Surgery (SIRS) trial. Patients were randomized to 500 mg intraoperative methylprednisolone or placebo. Incisional pain was assessed at 30 days and 6 months after surgery, and the potential risk factors were also evaluated. RESULTS: Methylprednisolone administration did not reduce pain at 30 days or persistent incisional pain at 6 months, which occurred in 78 of 520 patients (15.7%) in the methylprednisolone group and in 88 of 523 patients (17.8%) in the placebo group. The odds ratio for methylprednisolone was 0.93 (95% CI, 0.79 to 1.09, P = 0.37). Furthermore, there was no difference in worst pain and average pain in the last 24 h, pain interference with daily life, or use of pain medicine at 6 months. Younger age, female sex, and surgical infections were associated with the development of persistent incisional pain. CONCLUSIONS: Intraoperative methylprednisolone administration does not reduce persistent incisional pain at 6 months in patients recovering from cardiac surgery. PMID- 26501387 TI - Nitrous Oxide and Serious Long-term Morbidity and Mortality in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II Trial. AB - BACKGROUND: The Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II trial randomly assigned 7,112 noncardiac surgery patients at risk of perioperative cardiovascular events to 70% N2O or 70% N2 groups. The aim of this follow-up study was to determine the effect of nitrous oxide on a composite primary outcome of death and major cardiovascular events at 1 yr after surgery. METHODS: One-year follow-up was conducted via a medical record review and telephone interview. Disability was defined as a Katz index of independence in activities of daily living score less than 8. Adjusted odds ratios and hazard ratios were calculated as appropriate for primary and secondary outcomes. RESULTS: Among 5,844 patients evaluated at 1 yr, 435 (7.4%) had died, 206 (3.5%) had disability, 514 (8.8%) had a fatal or nonfatal myocardial infarction, and 111 (1.9%) had a fatal or nonfatal stroke during the 1-yr follow-up period. Exposure to nitrous oxide did not increase the risk of the primary outcome (odds ratio, 1.08; 95% CI, 0.94 to 1.25; P = 0.27), disability or death (odds ratio, 1.07; 95% CI, 0.90 to 1.27; P = 0.44), death (hazard ratio, 1.17; 95% CI, 0.97 to 1.43; P = 0.10), myocardial infarction (odds ratio, 0.97; 95% CI, 0.81 to 1.17; P = 0.78), or stroke (odds ratio, 1.08; 95% CI, 0.74 to 1.58; P = 0.70). CONCLUSION: These results support the long-term safety of nitrous oxide administration in noncardiac surgical patients with known or suspected cardiovascular disease. PMID- 26501388 TI - Perioperative Medication Errors: Building Safer Systems. PMID- 26501389 TI - Value of Sequels: Is It Safe to Include Nitrous Oxide in Your Anesthetic? PMID- 26501390 TI - Multifunctional Hybrid Porous Micro-/Nanocomposite Materials. AB - Multifunctional hybrid porous micro-/nanocomposite materials with hierarchical structures of soft silicone nanofilaments on hard porous glass microbeads are designed and synthesized. Such materials display selective super antiwetting/superwetting properties with unique mechanical, chemical, and thermal stabilities, as well as excellent antifouling properties. They are ideal materials for highly efficient separation of oil/water mixtures and emulsions, and display great advantages as carriers for organocatalysts. PMID- 26501391 TI - TRANSLATING RESEARCH TO PRACTICE: TOO MUCH RESEARCH, NOT ENOUGH PRACTICE? PMID- 26501392 TI - Involvement of cytokines in the modulation and progression of renal fibrosis induced by unilateral ureteral obstruction in C57BL/6 mice: effects of thalidomide and dexamethasone. AB - This study investigated the kinetics of cytokines that are involved in the development of interstitial fibrosis in mice that were subjected to UUO, the interstitial type I and III collagen deposition, and the effects of Thalido and Dexa treatment on these parameters. Inbred C57BL/6 mice were divided into the groups: Normal (not submitted surgery), Sham (sham surgery), Control (UUO treated with 0.5% carboxymethyl cellulose), Thalido (UUO treated with 5 mg/kg thalidomide), and Dexa (UUO treated with 1 mg/kg dexamethasone). The treatments began the day before surgery and were administered once daily by gavage for 1, 7, or 14 days. At the end of each treatment period, blood samples were collected for the determination of creatinine, urea, cytokines. The Control group exhibited a increase in creatinine concentration compared with the Normal and Sham groups within the first 24 h after UUO, which remained high until days 7 and 14. The urea concentration was higher on days 7 and 14 in the Control group compared with the Sham group. In the Thalido and Dexa groups, a reduction of serum creatinine concentration was seen on day 14. Treatment with Dexa reduced the serum concentration of urea on day 7. The serum concentrations of cytokines (TNF-alpha, IL-1beta, IL-6, IL-10 and IL-17) and chemokines (KC, MIG, bFGF) increased in UUO mice at all of the sampling times. The Dexa and Thalido groups exhibited alterations in the concentrations of these cytokines, suggesting the involvement of anti-inflammatory and immunomodulatory mechanisms that may have modified the fibrosis framework. PMID- 26501393 TI - Scanning for oscillations. AB - OBJECTIVE: Oscillations are an important aspect of brain activity, but they often have a low signal-to-noise ratio (SNR) due to source-to-electrode mixing with competing brain activity and noise. Filtering can improve the SNR of narrowband signals, but it introduces ringing effects that may masquerade as genuine oscillations, leading to uncertainty as to the true oscillatory nature of the phenomena. Likewise, time-frequency analysis kernels have a temporal extent that blurs the time course of narrowband activity, introducing uncertainty as to timing and causal relations between events and/or frequency bands. APPROACH: Here, we propose a methodology that reveals narrowband activity within multichannel data such as electroencephalography, magnetoencephalography, electrocorticography or local field potential. The method exploits the between channel correlation structure of the data to suppress competing sources by joint diagonalization of the covariance matrices of narrowband filtered and unfiltered data. MAIN RESULTS: Applied to synthetic and real data, the method effectively extracts narrowband components at unfavorable SNR. SIGNIFICANCE: Oscillatory components of brain activity, including weak sources that are hard or impossible to observe using standard methods, can be detected and their time course plotted accurately. The method avoids the temporal artifacts of standard filtering and time-frequency analysis methods with which it remains complementary. PMID- 26501395 TI - Health Professions Education Research and the Institutional Review Board. AB - The growth in health professions education (HPE) and a desire on the part of nurse and medical educators to disseminate their work have raised important questions about the ethical conduct of education research. At the center of the debate is the institutional review board (IRB) and its proper role in the oversight of HPE research. This article examines the IRB process and types of reviews for education research and presents an Education Project Summary Template to use for IRB reviews. PMID- 26501396 TI - Reliability and agreement in student ratings of the class environment. AB - The current study estimated the reliability and agreement of student ratings of the classroom environment obtained using the Responsive Environmental Assessment for Classroom Teaching (REACT; Christ, Nelson, & Demers, 2012; Nelson, Demers, & Christ, 2014). Coefficient alpha, class-level reliability, and class agreement indices were evaluated as each index provides important information for different interpretations and uses of student rating scale data. Data for 84 classes across 29 teachers in a suburban middle school were sampled to derive reliability and agreement indices for the REACT subscales across 4 class sizes: 25, 20, 15, and 10. All participating teachers were White and a larger number of 6th-grade classes were included (42%) relative to 7th- (33%) or 8th- (23%) grade classes. Teachers were responsible for a variety of content areas, including language arts (26%), science (26%), math (20%), social studies (19%), communications (6%), and Spanish (3%). Coefficient alpha estimates were generally high across all subscales and class sizes (alpha = .70-.95); class-mean estimates were greatly impacted by the number of students sampled from each class, with class-level reliability values generally falling below .70 when class size was reduced from 25 to 20. Further, within-class student agreement varied widely across the REACT subscales (mean agreement = .41-.80). Although coefficient alpha and test-retest reliability are commonly reported in research with student rating scales, class level reliability and agreement are not. The observed differences across coefficient alpha, class-level reliability, and agreement indices provide evidence for evaluating students' ratings of the class environment according to their intended use (e.g., differentiating between classes, class-level instructional decisions). (PsycINFO Database Record PMID- 26501394 TI - Gene-diet interaction of a common FADS1 variant with marine polyunsaturated fatty acids for fatty acid composition in plasma and erythrocytes among men. AB - SCOPE: Limited information exists on how the relationship between dietary intake of fat and fatty acids in erythrocytes and plasma is modulated by polymorphisms in the FADS gene cluster. We examined gene-diet interaction of total marine PUFA intake with a known gene encoding Delta-5 desaturase enzyme (FADS1) variant (rs174550) for fatty acids in erythrocyte membranes and plasma phospholipids (PL), cholesteryl esters (CE), and triglycerides (TG). METHODS AND RESULTS: In this cross-sectional study, fatty acid compositions were measured using GC, and total intake of polyunsaturated fat from fish and fish oil was estimated using a food frequency questionnaire in a subsample (n = 962) of the Metabolic Syndrome in Men Study. We found nominally significant gene-diet interactions for eicosapentaenoic acid (EPA, 20:5n-3) in erythrocytes (pinteraction = 0.032) and for EPA in plasma PL (pinteraction = 0.062), CE (pinteraction = 0.035), and TG (pinteraction = 0.035), as well as for docosapentaenoic acid (22:5n-3) in PL (pinteraction = 0.007). After excluding omega-3 supplement users, we found a significant gene-diet interaction for EPA in erythrocytes (pinteraction < 0.003). In a separate cohort of the Kuopio Obesity Surgery Study, the same locus was strongly associated with hepatic mRNA expression of FADS1 (p = 1.5 * 10(-10) ). CONCLUSION: FADS1 variants may modulate the relationship between marine fatty acid intake and circulating levels of long-chain omega-3 fatty acids. PMID- 26501397 TI - Platelet-Derived Growth Factor Inhibitors: A Potential Therapeutic Approach for Ocular Neovascularization. AB - Retinochoroidal vascular diseases are the leading causes of blindness in the developed world. They include diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, age-related macular degeneration (AMD), and pathological myopia, among many others. Several different therapies are currently under consideration for the aforementioned disorders. In the following section, agents targeting platelet-derived growth factors (PDGF) are discussed as a potential therapeutic option for retinochoroidal vascular diseases. PDGF play an important role in the angiogenesis cascade that is activated in retinochoroidal vascular diseases. The mechanism of action, side effects, efficacy, and the potential synergistic role of these agents in combination with other treatment options is discussed. The future of treatment of retinochoroidal vascular diseases, particularly neovascular AMD, has become more exciting due to agents like PDGF antagonists. PMID- 26501398 TI - Differences in Morphology and Traction Generation of Cell Lines Representing Different Stages of Osteogenesis. AB - Osteogenesis is the process by which mesenchymal stem cells differentiate to osteoblasts and form bone. The morphology and root mean squared (RMS) traction of four cell types representing different stages of osteogenesis were quantified. Undifferentiated D1, differentiated D1, MC3T3-E1, and MLO-A5 cell types were evaluated using both automated image analysis of cells stained for F-actin and by traction force microscopy (TFM). Undifferentiated mesenchymal stem cell lines were small, spindly, and exerted low traction, while differentiated osteoblasts were large, had multiple processes, and exerted higher traction. Size, shape, and traction all correlated with the differentiation stage. Thus, cell morphology evolved and RMS traction increased with differentiation. The results provide a foundation for further work with these cell lines to study the mechanobiology of bone formation. PMID- 26501399 TI - A Thalamocortical Mechanism for the Absence of Overt Motor Behavior in Covertly Aware Patients. AB - IMPORTANCE: It is well accepted that a significant number of patients in a vegetative state are covertly aware and capable of following commands by modulating their neural responses in motor imagery tasks despite remaining nonresponsive behaviorally. To date, there have been few attempts to explain this dissociation between preserved covert motor behavior and absent overt motor behavior. OBJECTIVES: To investigate the differential neural substrates of overt and covert motor behavior and assess the structural integrity of the underlying networks in behaviorally nonresponsive patients. DESIGN, SETTING, AND PARTICIPANTS: A case-control study was conducted at an academic center between February 7, 2012, and November 6, 2014. Data analysis was performed between March 2014 and June 2015. Participants included a convenience sample of 2 patients with severe brain injury: a paradigmatic patient who fulfilled all clinical criteria for the vegetative state but produced repeated evidence of covert awareness (patient 1) and, as a control case, a patient with similar clinical variables but capable of behavioral command following (patient 2). Fifteen volunteers participated in the study as a healthy control group. MAIN OUTCOMES AND MEASURES: We used dynamic causal modeling of functional magnetic resonance imaging to compare voluntary motor imagery and motor execution. We then used fiber tractography to assess the structural integrity of the fibers that our functional magnetic resonance imaging study revealed as essential for successful motor execution. RESULTS: The functional magnetic resonance imaging study revealed that, in contrast to mental imagery, motor execution was associated with an excitatory coupling between the thalamus and primary motor cortex (Bayesian model selection; winning model Bayes factors >17). Moreover, we detected a selective structural disruption in the fibers connecting these 2 regions in patient 1 (fractional anisotropy, 0.294; P = .047) but not in patient 2 (fractional anisotropy, 0.413; P = .35). CONCLUSIONS AND RELEVANCE: These results suggest a possible biomarker for the absence of intentional movement in covertly aware patients (ie, specific damage to motor thalamocortical fibers), highlight the importance of the thalamus for the execution of intentional movements, and may provide a target for restorative therapies in behaviorally nonresponsive patients. PMID- 26501400 TI - Detection Accuracy of Collective Intelligence Assessments for Skin Cancer Diagnosis. AB - Importance: Incidence rates of skin cancer are increasing globally, and the correct classification of skin lesions (SLs) into benign and malignant tissue remains a continuous challenge. A collective intelligence approach to skin cancer detection may improve accuracy. Objective: To evaluate the performance of 2 well known collective intelligence rules (majority rule and quorum rule) that combine the independent conclusions of multiple decision makers into a single decision. Design, Setting, and Participants: Evaluations were obtained from 2 large and independent data sets. The first data set consisted of 40 experienced dermoscopists, each of whom independently evaluated 108 images of SLs during the Consensus Net Meeting of 2000. The second data set consisted of 82 medical professionals with varying degrees of dermatology experience, each of whom evaluated a minimum of 110 SLs. All SLs were evaluated via the Internet. Image selection of SLs was based on high image quality and the presence of histopathologic information. Data were collected from July through October 2000 for study 1 and from February 2003 through January 2004 for study 2 and evaluated from January 5 through August 7, 2015. Main Outcomes and Measures: For both collective intelligence rules, we determined the true-positive rate (ie, the hit rate or specificity) and the false-positive rate (ie, the false-alarm rate or 1 - sensitivity) and compared these rates with the performance of single decision makers. Furthermore, we evaluated the effect of group size on true- and false positive rates. Results: One hundred twenty-two medical professionals performed 16 029 evaluations. Use of either collective intelligence rule consistently outperformed single decision makers. The groups achieved an increased true positive rate and a decreased false-positive rate. For example, individual decision makers in study 1, using the pattern analysis as diagnostic algorithm, achieved a true-positive rate of 0.83 and a false-positive rate of 0.17. Groups of 3 individuals achieved a true-positive rate of 0.91 and a false-positive rate of 0.14. These improvements increased with increasing group size. Conclusions and Relevance: Collective intelligence might be a viable approach to increase diagnostic accuracy in skin cancer and reduce skin cancer-related mortality. PMID- 26501401 TI - Thrombolysis-Related Hemorrhage: Can We Make Thrombolysis Safer? PMID- 26501402 TI - The Value of the History and Physical Examination--Sailing Through Medicine With Modern Tools: A Teachable Moment. PMID- 26501403 TI - Aortic root volume is associated with contained rupture of the aortic annulus in balloon-expandable transcatheter aortic valve replacement. AB - BACKGROUND: Aortic annulus rupture is a rare, but potentially fatal complication of transcatheter aortic valve replacement (TAVR), especially when it occurs by balloon-expandable devices. In order to improve the predictability of procedures and avoid ruptures we investigated whether or not the aortic root volume measures is a useful indicator of risk, and if it could be useful for the prosthesis size selection. METHODS AND RESULTS: From a retrospective series of 172 TAVR patients, seven experienced contained aortic annulus ruptures. The receiver operating curves were used to illustrate sensitivity and specificity of the different aortic annulus size and aortic root volume measures. The annulus area oversizing of >=20% resulted in a sensitivity of 100%, specificity of 55.76%, and positive predictive value (PPV) of 8.75%. In patients receiving 26 mm prostheses, the aortic root volume (ARV <13600 mm(3)) provided a better specificity and PPV (79.63 and 18.52%, respectively). A two-step testing procedure considering the area derived average annulus diameter (Darea <23 mm) as a first separating parameter and then the ARV (<13,600 mm(3)) as a further indicator showed the most promising results with the PPV of 31.25%. Regardless of the procedure steps no false negative results were predicted. CONCLUSIONS: Our data show that the ARV provides a better predictive value for correct prosthesis sizing than established annulus measurements, especially in 'borderline' annuli. We suggest a two-step testing procedure for prostheses size selection, considering Darea and ARV to minimize the risk of annulus rupture. Prospective studies and examination of larger datasets are warranted to confirm these findings. PMID- 26501405 TI - Linking perceptual learning with identical stimuli to imagery perceptual learning. AB - Perceptual learning is usually thought to be exclusively driven by the stimuli presented during training (and the underlying synaptic learning rules). In some way, we are slaves of our visual experiences. However, learning can occur even when no stimuli are presented at all. For example, Gabor contrast detection improves when only a blank screen is presented and observers are asked to imagine Gabor patches. Likewise, performance improves when observers are asked to imagine the nonexisting central line of a bisection stimulus to be offset either to the right or left. Hence, performance can improve without stimulus presentation. As shown in the auditory domain, performance can also improve when the very same stimulus is presented in all learning trials and observers were asked to discriminate differences which do not exist (observers were not told about the set up). Classic models of perceptual learning cannot handle these situations since they need proper stimulus presentation, i.e., variance in the stimuli, such as a left versus right offset in the bisection stimulus. Here, we show that perceptual learning with identical stimuli occurs in the visual domain, too. Second, we linked the two paradigms by telling observers that only the very same bisection stimulus was presented in all trials and asked them to imagine the central line to be offset either to the left or right. As in imagery learning, performance improved. PMID- 26501404 TI - Perceptual learning improves neural processing in myopic vision. AB - Visual performance is jointly determined by the quality of optical transmission of the eye and neural processing in the visual system. An open question is: Can effects of optical defects be compensated by perceptual learning in neural processing? To address this question, we conducted a perceptual learning study on 23 observers with myopic vision, targeting high frequency deficits by training them in a monocular grating detection task in the non-dominant eye near their individual cutoff spatial frequencies. The contrast sensitivity function and visual acuity in both eyes (without optical correction) were assessed for all the observers in the training group before and after training, and for all the observers in the control group twice with a 10-day interval between the tests. In addition, the threshold versus external noise contrast function was measured for five observers in the training group before and after training. We found that (a) training significantly improved contrast sensitivity at the trained spatial frequency, visual acuity, and contrast sensitivity over a wide range of spatial frequencies in both eyes; (b) training did not lead to any significant refractive changes; (c) the mechanism of improvements was a combination of internal additive noise reduction and external noise exclusion; and (d) the improvements in visual acuity and contrast sensitivity were almost fully retained for at least four months in the three observers tested. These results suggest that perceptual learning may provide a potential noninvasive procedure to compensate for optical defects in mild to modest myopia. PMID- 26501406 TI - Markers, Models, and Measurement Error: Exploring the Links Between Attention Deficits and Language Impairments. AB - PURPOSE: The empirical record regarding the expected co-occurrence of attention deficit/hyperactivity disorder (ADHD) and specific language impairment is confusing and contradictory. A research plan is presented that has the potential to untangle links between these 2 common neurodevelopmental disorders. METHOD: Data from completed and ongoing research projects examining the relative value of different clinical markers for separating cases of specific language impairment from ADHD are presented. RESULTS: The best option for measuring core language impairments in a manner that does not potentially penalize individuals with ADHD is to focus assessment on key grammatical and verbal memory skills. Likewise, assessment of ADHD symptoms through standardized informant rating scales is optimized when they are adjusted for overlapping language and academic symptoms. CONCLUSION: As a collection, these clinical metrics set the stage for further examination of potential linkages between attention deficits and language impairments. PMID- 26501407 TI - Synergy temporal sequences and topography in the spinal cord: evidence for a traveling wave in frog locomotion. AB - Locomotion is produced by a central pattern generator. Its spinal cord organization is generally considered to be distributed, with more rhythmogenic rostral lumbar segments. While this produces a rostrocaudally traveling wave in undulating species, this is not thought to occur in limbed vertebrates, with the exception of the interneuronal traveling wave demonstrated in fictive cat scratching (Cuellar et al. J Neurosci 29:798-810, 2009). Here, we reexamine this hypothesis in the frog, using the seven muscle synergies A to G previously identified with intraspinal NMDA (Saltiel et al. J Neurophysiol 85:605-619, 2001). We find that locomotion consists of a sequence of synergy activations (A-B G-A-F-E-G). The same sequence is observed when focal NMDA iontophoresis in the spinal cord elicits a caudal extension-lateral force-flexion cycle (flexion onset without the C synergy). Examining the early NMDA-evoked motor output at 110 sites reveals a rostrocaudal topographic organization of synergy encoding by the lumbar cord. Each synergy is preferentially activated from distinct regions, which may be multiple, and partially overlap between different synergies. Comparing the sequence of synergy activation in locomotion with their spinal cord topography suggests that the locomotor output is achieved by a rostrocaudally traveling wave of activation in the swing-stance cycle. A two-layer circuitry model, based on this topography and a traveling wave reproduces this output and explores its possible modifications under different afferent inputs. Our results and simulations suggest that a rostrocaudally traveling wave of excitation takes advantage of the topography of interneuronal regions encoding synergies, to activate them in the proper sequence for locomotion. PMID- 26501409 TI - Quantification of structural changes in acute inflammation by fractal dimension, angular second moment and correlation. AB - The aim of the study was to examine alteration and possible application of fractal dimension, angular second moment, and correlation for quantification of structural changes in acutely inflamed tissue. Acute inflammation was induced by injection of turpentine oil into the right and left hind limb muscles of mice, whereas control animals received intramuscular saline injection. After 12 h, animals were anesthetised and treated muscles collected. The tissue was stained by hematoxylin and eosin, digital micrographs produced, enabling determination of fractal dimension of the cells, angular second moment and correlation of studied tissue. Histopathological analysis showed presence of inflammatory infiltrate and tissue damage in inflammatory group, whereas tissue structure in control group was preserved, devoid of inflammatory infiltrate. Fractal dimension of the cells, angular second moment and correlation of treated tissue in inflammatory group decreased in comparison to the control group. In this study, we were first to observe and report that fractal dimension of the cells, angular second moment, and correlation were reduced in acutely inflamed tissue, indicating loss of overall complexity of the cells in the tissue, the tissue uniformity and structure regularity. Fractal dimension, angular second moment and correlation could be useful methods for quantification of structural changes in acute inflammation. PMID- 26501410 TI - The predicament of comparative effectiveness research using observational data. PMID- 26501408 TI - Expression and distribution of peroxiredoxins in the retina and optic nerve. AB - Oxidative stress is implicated in various pathological conditions of the retina and optic nerve. Peroxiredoxins (Prdxs) comprise a recently characterized family of antioxidant enzymes. To date, little information exists regarding the distribution of Prdxs in the eye. Herein, we employed a combination of qRT-PCR, immunohistochemistry and Western blotting to determine the level of expression and distribution of the six Prdx isoforms in the retina and optic nerve of the rat. In addition, we performed some parallel analyses on the common marmoset (Callithrix Jacchus). In the rat, all of the Prdx transcripts were expressed in relatively high amounts in both retina and optic nerve, with abundances ranging from approximately 3-50 % of the level of the housekeeping gene cyclophilin. With regard to protein expression, each isoform was detected in the retina and optic nerve by either Western blotting and/or immunohistochemistry. Excepting Prdx4, there was a good correspondence between the rodent and primate results. In the retina, Prdx1 and Prdx2 were principally localized to neurons in the inner nuclear layer and cone photoreceptors, Prdx3 and Prdx5 displayed characteristic mitochondrial immunolabeling, while Prdx6 was associated with astrocytes and Muller cells. In the optic nerve, Prdx1 was robustly expressed by oligodendrocytes, Prdx3 and Prdx5 were observed in axons, and Prdx6 was restricted to astrocytes. The present findings augment our understanding of the distribution and expression of the Prdxs in the retina and optic nerve of rodents and primates and lay the foundation for subsequent analysis of their involvement in relevant blinding diseases. PMID- 26501411 TI - Hemodynamic Thresholds for Precapillary Pulmonary Hypertension. AB - BACKGROUND: Hemodynamic differentiation between pulmonary arterial hypertension (PAH) and postcapillary pulmonary hypertension (PH) is important because treatment options are strikingly different for the two disease subsets. Whereas patients with PAH can be treated effectively with targeted therapies, their use in postcapillary PH is currently not recommended. Our aim was to establish an algorithm to identify patients who are likely to experience a significant hemodynamic treatment response. METHODS: We determined hemodynamic cutoffs to discriminate between idiopathic PAH and postcapillary PH in a large database of 4,363 stable patients undergoing first diagnostic right and left heart catheterizations. In a second step, we performed a patient-level pooled analysis of four randomized, placebo-controlled trials including 541 patients with PAH who received treprostinil or placebo, to validate hemodynamic cutoffs with regard to treatment response. RESULTS: Receiver operating characteristic analysis identified mean pulmonary arterial wedge pressure (mPAWP) < 12 mm Hg and diastolic pulmonary vascular pressure gradient (DPG) >= 7 mm Hg as the best hemodynamic discriminators between idiopathic PAH and postcapillary PH. In our treatment study, only patients with mPAWP < 12 mm Hg, DPG > 20 mm Hg or a combination of both had a significant placebo-corrected improvement in hemodynamics. CONCLUSIONS: mPAWP < 12 mm Hg and DPG > 20 mm Hg identify patients with PAH who are likely to have significant hemodynamic improvement with prostacyclin treatment. PMID- 26501412 TI - Towards a calcium-based rechargeable battery. AB - The development of a rechargeable battery technology using light electropositive metal anodes would result in a breakthrough in energy density. For multivalent charge carriers (M(n+)), the number of ions that must react to achieve a certain electrochemical capacity is diminished by two (n = 2) or three (n = 3) when compared with Li(+) (ref. ). Whereas proof of concept has been achieved for magnesium, the electrodeposition of calcium has so far been thought to be impossible and research has been restricted to non-rechargeable systems. Here we demonstrate the feasibility of calcium plating at moderate temperatures using conventional organic electrolytes, such as those used for the Li-ion technology. The reversibility of the process on cycling has been ascertained and thus the results presented here constitute the first step towards the development of a new rechargeable battery technology using calcium anodes. PMID- 26501413 TI - Mechanics of fire ant aggregations. AB - Fire ants link their bodies to form aggregations; these can adopt a variety of structures, they can drip and spread, or withstand applied loads. Here, by using oscillatory rheology, we show that fire ant aggregations are viscoelastic. We find that, at the lowest ant densities probed and in the linear regime, the elastic and viscous moduli are essentially identical over the spanned frequency range, which highlights the absence of a dominant mode of structural relaxation. As ant density increases, the elastic modulus rises, which we interpret by alluding to ant crowding and subsequent jamming. When deformed beyond the linear regime, the aggregation flows, exhibiting shear-thinning behaviour with a stress load that is comparable to the maximum load the aggregation can withstand before individual ants are torn apart. Our findings illustrate the rich, collective mechanical behaviour that can arise in aggregations of active, interacting building blocks. PMID- 26501414 TI - Reducing Language Barriers in Health Care: Is Technology the Answer? PMID- 26501415 TI - Rare Variants in the Functional Domains of Complement Factor H Are Associated With Age-Related Macular Degeneration. AB - PURPOSE: Age-related macular degeneration (AMD) has a substantial genetic risk component, as evidenced by the risk from common genetic variants uncovered in the first genome-wide association studies. More recently, it has become apparent that rare genetic variants also play an independent role in AMD risk. We sought to determine if rare variants in complement factor H (CFH) played a role in AMD risk. METHODS: We had previously collected DNA from a large population of patients with advanced age-related macular degeneration (A-AMD) and controls for targeted deep sequencing of candidate AMD risk genes. In this analysis, we tested for an increased burden of rare variants in CFH in 1665 cases and 752 controls from this cohort. RESULTS: We identified 65 missense, nonsense, or splice-site mutations with a minor allele frequency <= 1%. Rare variants with minor allele frequency <= 1% (odds ratio [OR] = 1.5, P = 4.4 * 10-2), 0.5% (OR = 1.6, P = 2.6 * 10-2), and all singletons (OR = 2.3, P = 3.3 * 10-2) were enriched in A-AMD cases. Moreover, we observed loss-of-function rare variants (nonsense, splice site, and loss of a conserved cysteine) in 10 cases and serum levels of FH were decreased in all 5 with an available sample (haploinsufficiency). Further, rare variants in the major functional domains of CFH were increased in cases (OR = 3.2; P = 1.4 * 10-3) and the magnitude of the effect correlated with the disruptive nature of the variant, location in an active site, and inversely with minor allele frequency. CONCLUSIONS: In this large A-AMD cohort, rare variants in the CFH gene were enriched and tended to be located in functional sites or led to low serum levels. These data, combined with those indicating a similar, but even more striking, increase in rare variants found in CFI, strongly implicate complement activation in A-AMD etiopathogenesis as CFH and CFI interact to inhibit the alternative pathway. PMID- 26501416 TI - Structural Measurements for Monitoring Change in Glaucoma: Comparing Retinal Nerve Fiber Layer Thickness With Minimum Rim Width and Area. AB - PURPOSE: Minimum rim width (MRW) and area (MRA) have been introduced as anatomically defensible measures of neuroretinal rim tissue observable using spectral-domain optical coherence tomography (SDOCT). They have been reported to change earlier than retinal nerve fiber layer thickness (RNFLT) in glaucoma. This study sought to determine which is better to distinguish subsequent change from variability, using the previously described longitudinal signal-to-noise ratio (LSNR). METHODS: Data from 157 eyes of 157 participants with high-risk ocular hypertension or non-end-stage glaucoma (mean deviation [MD] from -22 to +3 dB) were used. Participants were tested approximately every 6 months for at least six visits. For each eye, MRW, MRA, and RNFLT were regressed linearly against time. Longitudinal signal-to-noise ratio for each eye was defined as the rate of change over time (signal) divided by the standard deviation of residuals from this trend (noise). These were compared between parameters using a Wilcoxon signed rank test. RESULTS: The median LSNRs were -0.58y-1 for RNFLT (bootstrapped 95% confidence interval -0.69 to -0.48y-1); -0.44y-1 (-0.59 to -0.32y-1) for MRW; and -0.23y-1 (-0.32 to -0.08y-1) for MRA. Longitudinal signal-to-noise ratios were significantly more negative for RNFLT than for MRW (P = 0.025) or for MRA (P < 0.001). CONCLUSIONS: Retinal nerve fiber layer thickness measured by SDOCT had a better LSNR than MRW or MRA. Although MRW and MRA may be more sensitive for early detection of glaucomatous damage, these data suggest that RNFLT may be preferable for monitoring change. PMID- 26501418 TI - A new chapter. PMID- 26501417 TI - Helmet Use and Injury Patterns in Motorcycle-Related Trauma. PMID- 26501419 TI - Gate-Bias Stability Behavior Tailored by Dielectric Polymer Stereostructure in Organic Transistors. AB - Understanding charge trapping in a polymer dielectric is critical to the design of high-performance organic field-effect transistors (OFETs). We investigated the OFET stability as a function of the dielectric polymer stereostructure under a gate bias stress and during long-term operation. To this end, iso-, syn-, and atactic poly(methyl methacrylate) (PMMA) polymers with identical molecular weights and polydispersity indices were selected. The PMMA stereostructure was found to significantly influence the charge trapping behavior and trap formation in the polymer dielectrics. This influence was especially strong in the bulk region rather than in the surface region. The regular configurational arrangements (isotactic > syntactic > atactic) of the pendant groups on the PMMA backbone chain facilitated closer packing between the polymer interchains and led to a higher crystallinity of the polymer dielectric, which caused a reduction in the free volumes that act as sites for charge trapping and air molecule absorption. The PMMA dielectrics with regular stereostructures (iso- and syn stereoisomers) exhibited more stable OFET operation under bias stress compared to devices prepared using irregular a-PMMA in both vacuum and air. PMID- 26501420 TI - The Relationship between Native American Ancestry, Body Mass Index and Diabetes Risk among Mexican-Americans. AB - Higher body mass index (BMI) is a well-established risk factor for type 2 diabetes, and rates of obesity and type 2 diabetes are substantially higher among Mexican-Americans relative to non-Hispanic European Americans. Mexican-Americans are genetically diverse, with a highly variable distribution of Native American, European, and African ancestries. Here, we evaluate the role of Native American ancestry on BMI and diabetes risk in a well-defined Mexican-American population. Participants were randomly selected among individuals residing in the Houston area who are enrolled in the Mexican-American Cohort study. Using a custom Illumina GoldenGate Panel, we genotyped DNA from 4,662 cohort participants for 87 Ancestry-Informative Markers. On average, the participants were of 50.2% Native American ancestry, 42.7% European ancestry and 7.1% African ancestry. Using multivariate linear regression, we found BMI and Native American ancestry were inversely correlated; individuals with <20% Native American ancestry were 2.5 times more likely to be severely obese compared to those with >80% Native American ancestry. Furthermore, we demonstrated an interaction between BMI and Native American ancestry in diabetes risk among women; Native American ancestry was a strong risk factor for diabetes only among overweight and obese women (OR = 1.190 for each 10% increase in Native American ancestry). This study offers new insight into the complex relationship between obesity, genetic ancestry, and their respective effects on diabetes risk. Findings from this study may improve the diabetes risk prediction among Mexican-American individuals thereby facilitating targeted prevention strategies. PMID- 26501421 TI - Combined Treatments Reduce Chilling Injury and Maintain Fruit Quality in Avocado Fruit during Cold Quarantine. AB - Quarantine treatment enables export of avocado fruit (Persea americana) to parts of the world that enforce quarantine against fruit fly. The recommended cold based quarantine treatment (storage at 1.1 degrees C for 14 days) was studied with two commercial avocado cultivars 'Hass' and 'Ettinger' for 2 years. Chilling injuries (CIs) are prevalent in the avocado fruit after cold-quarantine treatment. Hence, we examined the effect of integrating several treatments: modified atmosphere (MA; fruit covered with perforated polyethylene bags), methyl jasmonate (MJ; fruit dipped in 2.5 MUM MJ for Hass or 10 MUM MJ for Ettinger for 30 s), 1-methylcyclopropene (1-MCP; fruit treated with 300 ppb 1-MCP for 18 h) and low-temperature conditioning (LTC; a gradual decrease in temperature over 3 days) on CI reduction during cold quarantine. Avocado fruit stored at 1 degrees C suffered from severe CI, lipid peroxidation, and increased expression of chilling responsive genes of fruit peel. The combined therapeutic treatments alleviated CI in cold-quarantined fruit to the level in fruit stored at commercial temperature (5 degrees C). A successful therapeutic treatment was developed to protect 'Hass' and 'Ettinger' avocado fruit during cold quarantine against fruit fly, while maintaining fruit quality. Subsequently, treated fruit stored at 1 degrees C had a longer shelf life and less decay than the fruit stored at 5 degrees C. This therapeutic treatment could potentially enable the export of avocado fruit to all quarantine-enforcing countries. Similar methods might be applicable to other types of fruit that require cold quarantine. PMID- 26501422 TI - NFATC1 promotes cell growth and tumorigenesis in ovarian cancer up-regulating c Myc through ERK1/2/p38 MAPK signal pathway. AB - It has been reported that nuclear factor of activated T cells (NFATC1) was up regulated in cancers mediating malignant behaviors. However, the role of NFATC1 in ovarian cancer has not been elucidated. In the present study, we undertook to explore the clinicopathological significance of NFATC1 expression and the mechanism by which NFATC1 works in ovarian cancer. Expression status of NFATC1 was examined using immunohistochemistry. Both knockdown and re-expression of NFATC1 on ovarian cancer cells were employed to observe the effect overgrowth. It was found that NFATC1 was significantly overexpressed in ovarian cancer tissues in comparison with paired normal control tissues and that overexpression of NFATC1 was significantly associated with metastasis and poor prognosis on clinical tissue level. In in vitro ovarian cancer cell lines, we found that NFATC1 can promote proliferation up-regulating c-myc through activation of ERK1/2/p38/MAPK signal pathway. Together, the results we obtained demonstrated that NFATC1 played oncogenic role in ovarian cancer. Mechanistically, NFATC1 promoted growth of ovarian cancer cells up-regulating c-myc through activation of ERK1/2/p38/MAPK signal pathway, suggesting that NFATC1 might be used as a therapeutic target for ovarian cancer. PMID- 26501423 TI - CCL15/CCR1 axis is involved in hepatocellular carcinoma cells migration and invasion. AB - The identification of new biomarkers for the early detection of hepatocellular carcinoma is critical in the development of tumor-targeted therapy, which is possibly advantageous on the prognosis of this disease. Results from our previous study indicated that CCL15 can be a specific proteomic biomarker of hepatocellular carcinoma, which plays an important role in tumorigenesis and tumor invasion. In this study, we found that CCL15 can induce hepatocellular carcinoma cell migration and invasion. Furthermore, CCR1, the receptor of CCL15, was demonstrated to play a critical role in metastatic hepatocellular carcinoma. CCR1 short hairpin RNA significantly inhibited CCL15-induced chemotaxis and invasion of HepG2 cells. Moreover, CCR1 knockdown significantly limited the activity and expression of matrix metalloproteinase-2 (MMP-2) and MMP-9. These findings suggest that CCR1 plays critical roles in hepatocellular carcinoma metastasis, which indicates that CCR1 may be a potential molecular target in hepatocellular carcinoma therapy. PMID- 26501426 TI - A Review of Hard Palate Fracture Repair Techniques. AB - PURPOSE: Hard palate trauma is a relatively infrequent occurrence compared with other craniofacial injuries. Several techniques of hard palate fracture repair have been described. To date, there is no consensus on the optimal management of this type of fracture. The purpose of this study was to compile and analyze studies describing hard palate fracture repair techniques with outcomes data. MATERIALS AND METHODS: A systematic review of the Medline, Scopus, and Web of Science databases was performed for articles describing hard palate fracture repair techniques. RESULTS: Eight articles were ultimately included in the review. Of the collective 310 fractures reported, postoperative malocclusion occurred in 21 of 235 cases (8.9%) and other complications occurred in 13 of 299 cases (4.3%). The most important variability in technique was the method of palatal vault stabilization. Three studies described wiring techniques, 3 described internal fixation techniques, and 2 described external fixation techniques. Studies describing internal fixation techniques reported higher rates of wound complications. Proponents of rigid internal fixation believe that this technique provides better fracture reduction. External fixation techniques appear to impart low rates of wound complications, but their overall effectiveness remains in question. CONCLUSIONS: Hard palate fractures are associated with high rates of malocclusion and wound complications. The most established methods of palatal vault stabilization are closed reduction with wiring and internal plate fixation. Depending on the fracture type, patient comorbidities, and associated injuries, either technique might be preferable in a given circumstance. PMID- 26501425 TI - Effects of Antiseptic Solutions Commonly Used in Dentistry on Bone Viability, Bone Morphology, and Release of Growth Factors. AB - PURPOSE: Antiseptic solutions are commonly used in dentistry for a number of sterilization procedures, including harvesting of bone chips, irrigation of extraction sockets, and sterilization of osteonecrotic bone. Despite its widespread use, little information is available regarding the effects of various antiseptic solutions on bone cell viability, morphology, and the release of growth factors. MATERIALS AND METHODS: The antiseptic solutions included 1) 0.5% povidone iodine (PI), 2) 0.2% chlorhexidine diguluconate (CHX), 3) 1% hydrogen peroxide (H2O2), and 4) 0.25% sodium hypochlorite (HYP). Bone samples collected from porcine mandibular cortical bone were rinsed in the antiseptic solutions for 10 minutes and assessed for cell viability using an MTS assay and protein release of transforming growth factor (TGF-beta1), bone morphogenetic protein 2 (BMP2), vascular endothelial growth factor (VEGF), interleukin (IL)-1beta, and receptor activator of nuclear factor kappaB ligand (RANKL) using an enzyme-linked immunosorbent assay at 15 minutes and 4 hours after rinsing. RESULTS: After antiseptic rinsing, changes to the surface protein content showed marked alterations, with an abundant protein layer remaining on CHX-rinsed bone samples. The amount of surface protein content gradually decreased in the following order: CHX, H2O2, PI, and HYP. A similar trend was also observed for the relative cell viability from within bone samples after rinsing, with up to 6 times more viable cells found in the CHX-rinsed bone samples than in the HYP- and PI-rinsed samples. An analysis of the growth factors found that both HYP and PI had significantly lower VEGF and TGF-beta1 protein release from bone samples at 15 minutes and 4 hours after rinsing compared with CHX and H2O2. A similar trend was observed for RANKL and IL-1beta protein release, although no change was observed for BMP2. CONCLUSIONS: The results from the present study have demonstrated that antiseptic solutions present with very different effects on bone samples after 10 minutes of rinsing. Rinsing with CHX maintained significantly higher cell viability and protein release of growth factors potent to the bone remodeling cycle. PMID- 26501427 TI - Telemedicine Consultations in Oral and Maxillofacial Surgery: A Follow-Up Study. AB - PURPOSE: The purpose of this study was to follow up on the previous study in evaluating the efficiency and reliability of telemedicine consultations for preoperative assessment of patients. MATERIALS AND METHODS: A retrospective study of 335 patients over a 6-year period was performed to evaluate success rates of telemedicine consultations in adequately assessing patients for surgical treatment under anesthesia. Success or failure of the telemedicine consultation was measured by the ability to triage patients appropriately for the hospital operating room versus the clinic, to provide an accurate diagnosis and treatment plan, and to provide a sufficient medical and physical assessment for planned anesthesia. Data gathered from the average distance traveled and data from a previous telemedicine study performed by the National Institute of Justice were used to estimate the cost savings of using telemedicine consultations over the 6 year period. RESULTS: Practitioners performing the consultation were successful 92.2% of the time in using the data collected to make a diagnosis and treatment plan. Patients were triaged correctly 99.6% of the time for the clinic or hospital operating room. Most patients (98.0%) were given sufficient medical and physical assessment and were able to undergo surgery with anesthesia as planned at the clinic appointment immediately after telemedicine consultation. Most patients (95.9%) were given an accurate diagnosis and treatment plan. The estimated amount saved by providing consultation by telemedicine and eliminating in-office consultation was substantial at $134,640. CONCLUSION: This study confirms the findings from previous studies that telemedicine consultations are as reliable as those performed by traditional methods. PMID- 26501424 TI - HIV-Infected Spleens Present Altered Follicular Helper T Cell (Tfh) Subsets and Skewed B Cell Maturation. AB - Follicular helper T (Tfh) cells within secondary lymphoid organs control multiple steps of B cell maturation and antibody (Ab) production. HIV-1 infection is associated with an altered B cell differentiation and Tfh isolated from lymph nodes of HIV-infected (HIV+) individuals provide inadequate B cell help in vitro. However, the mechanisms underlying this impairment of Tfh function are not fully defined. Using a unique collection of splenocytes, we compared the frequency, phenotype and transcriptome of Tfh subsets in spleens from HIV negative (HIV-) and HIV+ subjects. We observed an increase of CXCR5+PD-1highCD57-Tfh and germinal center (GC) CD57+ Tfh in HIV+ spleens. Both subsets showed a reduced mRNA expression of the transcription factor STAT-3, co-stimulatory, regulatory and signal transduction molecules as compared to HIV- spleens. Similarly, Foxp3 expressing follicular regulatory T (Tfr) cells were increased, suggesting sustained GC reactions in chronically HIV+ spleens. As a consequence, GC B cell populations were expanded, however, complete maturation into memory B cells was reduced in HIV+ spleens where we evidenced a compromised production of B cell activating cytokines such as IL-4 and IL-10. Collectively our data indicate that, although Tfh proliferation and GC reactions seem to be ongoing in HIV-infected spleens, Tfh "differentiation" and expression of costimulatory molecules is skewed with a profound effect on B cell maturation. PMID- 26501429 TI - Mechanically Self-Assembled, Three-Dimensional Graphene-Gold Hybrid Nanostructures for Advanced Nanoplasmonic Sensors. AB - Hybrid structures of graphene and metal nanoparticles (NPs) have been actively investigated as higher quality surface enhanced Raman spectroscopy (SERS) substrates. Compared with SERS substrates, which only contain metal NPs, the additional graphene layer provides structural, chemical, and optical advantages. However, the two-dimensional (2D) nature of graphene limits the fabrication of the hybrid structure of graphene and NPs to 2D. Introducing three-dimensionality to the hybrid structure would allow higher detection sensitivity of target analytes by utilizing the three-dimensional (3D) focal volume. Here, we report a mechanical self-assembly strategy to enable a new class of 3D crumpled graphene gold (Au) NPs hybrid nanoplasmonic structures for SERS applications. We achieve a 3D crumpled graphene-Au NPs hybrid structure by the delamination and buckling of graphene on a thermally activated, shrinking polymer substrate. We also show the precise control and optimization of the size and spacing of integrated Au NPs on crumpled graphene and demonstrate the optimized NPs' size and spacing for higher SERS enhancement. The 3D crumpled graphene-Au NPs exhibits at least 1 order of magnitude higher SERS detection sensitivity than that of conventional, flat graphene-Au NPs. The hybrid structure is further adapted to arbitrary curvilinear structures for advanced, in situ, nonconventional, nanoplasmonic sensing applications. We believe that our approach shows a promising material platform for universally adaptable SERS substrate with high sensitivity. PMID- 26501430 TI - Spatiotemporal Characterization of Ambient PM2.5 Concentrations in Shandong Province (China). AB - China experiences severe particulate matter (PM) pollution problems closely linked to its rapid economic growth. Advancing the understanding and characterization of spatiotemporal air pollution distribution is an area where improved quantitative methods are of great benefit to risk assessment and environmental policy. This work uses the Bayesian maximum entropy (BME) method to assess the space-time variability of PM2.5 concentrations and predict their distribution in the Shandong province, China. Daily PM2.5 concentrations obtained at air quality monitoring sites during 2014 were used. On the basis of the space time PM2.5 distributions generated by BME, we performed three kinds of querying analysis to reveal the main distribution features. The results showed that the entire region of interest is seriously polluted (BME maps identified heavy pollution clusters during 2014). Quantitative characterization of pollution severity included both pollution level and duration. The number of days during which regional PM2.5 exceeded 75, 115, 150, and 250 MUg m(-3) varied: 43-253, 13 128, 4-66, and 0-15 days, respectively. The PM2.5 pattern exhibited an increasing trend from east to west, with the western part of Shandong being a heavily polluted area (PM2.5 exceeded 150 MUg m(-3) during long time periods). Pollution was much more serious during winter than during other seasons. Site indicators of PM2.5 pollution intensity and space-time variation were used to assess regional uncertainties and risks with their interpretation depending on the pollutant threshold. The observed PM2.5 concentrations exceeding a specified threshold increased almost linearly with increasing threshold value, whereas the relative probability of excess pollution decreased sharply with increasing threshold. PMID- 26501431 TI - An Ab Initio QM/MM-Based Approach to Efficiently Evaluate Vertical Excitation Energies in Condensed Phases Including the Nonequilibrium Solvation Effect. AB - An efficient quantum mechanical/molecular mechanics-based approach is presented to calculate a vertical excitation energy of a chromophore in condensed phases including the nonequilibrium solvation effect. The electronic polarization of a medium and the related nonequilibrium solvation effect associated with the vertical excitation are described using a polarizable solvent model. By virtue of the mean-field approximation, the target energy can be completely separated into classical and quantum mechanical parts, which enables us to efficiently evaluate the vertical excitation energy with a high-level quantum mechanical method. The method is applied to N,N-dimethyl-4-nitroaniline in a variety of solutions at the MRMP2/CASSCF level, showing quantitative agreement with the experimental reports. The observed large bathochromic shifts are analyzed by focusing on the induction effects of the solvents. PMID- 26501432 TI - Correction to Magnetic Mn and Co Complexes with a Large Polycyclic Aromatic Substituted Nitronylnitroxide. PMID- 26501428 TI - Serum Markers of Bone Turnover and Angiogenesis in Patients With Bisphosphonate Related Osteonecrosis of the Jaw After Discontinuation of Long-Term Intravenous Bisphosphonate Therapy. AB - PURPOSE: To analyze serum markers of bone turnover, angiogenesis, endocrine function, and inflammation in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) who discontinued long-term intravenous bisphosphonate (BP) therapy. PATIENTS AND METHODS: Serum samples were obtained from 25 BRONJ patients who had discontinued long-term intravenous BP therapy for an average of 11.4 +/- 8.7 months and 48 non-BRONJ controls who continued receiving intravenous BP therapy. Samples were analyzed for total alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, C-telopeptide, vascular endothelial growth factor, triiodothyronine, thyroxine, thyroid-stimulating hormone, 25 hydroxyvitamin D, and C-reactive protein. RESULTS: The mean number of BP infusions was significantly higher in BRONJ patients compared with controls (38.4 +/- 26.3 infusions vs 18.8 +/- 7.2 infusions, P < .0001); however, the duration of BP therapy was not significantly different between the groups (P = .23). Overall, there were no significant differences in any of the markers between BRONJ patients and controls (all P values >= .16). In a subgroup analysis that matched BRONJ patients and controls according to mean age and number of BP infusions (10 BRONJ patients and 48 controls), log10 vascular endothelial growth factor (2.9 +/- 0.4 pg/mL vs 2.4 +/- 0.4 pg/mL, P < .001) and C-reactive protein (34 +/- 26 mg/L vs 13 +/- 8 mg/L, P < .01) levels were significantly higher in BRONJ patients compared with controls. Within BRONJ patients, none of the serum markers were correlated with duration of BP discontinuation. CONCLUSIONS: Levels of bone turnover and endocrine markers in BRONJ patients who discontinue long term intravenous BP therapy are similar to those in non-BRONJ controls receiving intravenous BP therapy. However, levels of angiogenesis and inflammation markers are higher in BRONJ patients who discontinue long-term intravenous BP therapy. The prolonged skeletal half-life of BPs may suppress bone turnover markers in BRONJ patients for several years after discontinuation of intravenous BP therapy, suggesting an extended effect on bone homeostasis. PMID- 26501433 TI - Determination of five folate monoglutamates in rodent diets. AB - A method for the quantitative determination of folates in rodent diets is very important for correct interpretation of folate intake during feeding trials, given the possible discrepancy between the actual folate concentration in the diet and that mentioned on the product sheet. Liquid chromatography tandem-mass spectrometry is the method of choice to differentiate and quantify the individual folate species present. This discrepancy may be accounted for by, e.g., inaccurate folic acid supplementation and/or the presence of endogenous reduced and substituted folates. We developed a method, validated based on FDA guidelines, that allows the measurement of added and endogenous folates by quantitative determination of 5 folate monoglutamates with linear ranges from 8 MUg to 2 mg/kg feed. This information, combined with feed intake data, allows insight into the actual folate intake in animal feeding studies. The relevance of this method was illustrated by the analysis of several feed samples of varying composition, by the investigation of the effect of casein incorporation, and by evaluating the variability of the folate content between pellets and production batches. PMID- 26501434 TI - Influence of the geometrical detail in the description of DNA and the scoring method of ionization clustering on nanodosimetric parameters of track structure: a Monte Carlo study using Geant4-DNA. AB - The aim of this study was to evaluate the influence of the geometrical detail of the DNA on nanodosimetric parameters of track structure induced by protons and alpha particles of different energies (LET values ranging from 1 to 162.5 keV um 1) as calculated by Geant4-DNA Monte Carlo simulations.The first geometry considered consisted of a well-structured placement of a realistic description of the DNA double helix wrapped around cylindrical histones (GeomHist) forming a 18 kbp-long chromatin fiber. In the second geometry considered, the DNA was modeled as a total of 1800 ten bp-long homogeneous cylinders (2.3 nm diameter and 3.4 nm height) placed in random positions and orientations (GeomCyl). As for GeomHist, GeomCyl contained a DNA material equivalent to 18 kbp. Geant4-DNA track structure simulations were performed and ionizations were counted in the scoring volumes. For GeomCyl, clusters were defined as the number of ionizations (nu) scored in each 10 bp-long cylinder. For GeomHist, clusters of ionizations scored in the sugar-phosphate groups of the double-helix were revealed by the DBSCAN clustering algorithm according to a proximity criteria among ionizations separated by less than 10 bp. The topology of the ionization clusters formed using GeomHist and GeomCyl geometries were compared in terms of biologically relevant nanodosimetric quantities.The discontinuous modeling of the DNA for GeomCyl led to smaller cluster sizes than for GeomHist. The continuous modeling of the DNA molecule for GeomHist allowed the merging of ionization points by the DBSCAN algorithm giving rise to larger clusters, which were not detectable within the GeomCyl geometry. Mean cluster size (m1) was found to be of the order of 10% higher for GeomHist compared to GeomCyl for LET < 15 keV um-1. For higher LETs, the difference increased with LET similarly for protons and alpha particles. Both geometries showed the same relationship between m1 and the cumulative relative frequency of clusters with v>=3 (f3) within statistical variations, independently of particle type. In order to obtain ionization cluster size distributions relevant for biological DNA lesions, the complex DNA geometry and a scoring method without fixed boundaries should be preferred to the simple cylindrical geometry with a fixed scoring volume. PMID- 26501435 TI - miR-30d Blocked Transforming Growth Factor beta1-Induced Epithelial-Mesenchymal Transition by Targeting Snail in Ovarian Cancer Cells. AB - OBJECTIVE: MicroRNAs (miRs) are essential regulators of gene expression by suppressing translation or causing degradation of target mRNA. Growing evidence sheds light on the crucial roles of miR dysregulation in cancer development and progression. In this study, we focused on the role of miR-30d in transforming growth factor beta1 (TGF-beta1)-initiated epithelial-mesenchymal transition (EMT) in ovarian cancer cells. METHODS: Transforming growth factor beta1 (10 ng/mL) was used to initiate EMT in SKOV3 and 3AO cells. The expression of miR-30 family members was determined by quantitative real-time polymerase chain reaction. Messenger RNA and protein levels of E-cadherin, N-cadherin, vimentin, and Snail were detected by quantitative real-time polymerase chain reaction and Western blot, respectively. Cell migration and invasion capacities were evaluated by Transwell chamber assay. Luciferase activity assay was performed to verify the direct inhibition of Snail by miR-30d. RESULTS: MiR-30b, MiR-30c, and MiR-30d were down-regulated during TGF-beta1-induced EMT in SKOV3 and 3AO ovarian cancer cells. Restoration of miR-30d by miR-30d mimic reversed TGF-beta1-induced EMT phenotypes including the morphological changes, expression pattern of molecular markers (E-cadherin, N-cadherin), and migratory and invasive capabilities in ovarian cancer cells. Furthermore, Snail was identified as the direct target of miR-30d. CONCLUSIONS: Our results revealed that miR-30d functioned as a suppressor of ovarian cancer progression by decreasing Snail expression and thus blocking TGF-beta1-induced EMT process, suggesting the potentiality of miR-30d analogs to be used as therapeutics for ovarian cancer. PMID- 26501436 TI - HE4 as an Early Detection Biomarker of Epithelial Ovarian Cancer: Investigations in Prediagnostic Specimens From the Janus Serumbank. AB - OBJECTIVES: Epithelial ovarian cancer is characterized by nonspecific signs and clinical symptoms arising at late stages. Early detection is therefore important and may significantly improve the survival rate. Cancer antigen 125 (CA125) has been the most extensively studied serum biomarker in epithelial ovarian cancer, but low specificity limits its usefulness. A relatively novel biomarker, human epididymis protein 4 (HE4), has shown promise in early detection of the disease. The aim of this study was to investigate how early the tumor marker increases before diagnosis. METHODS/MATERIALS: A nested case-control design was used to evaluate the performance of HE4 and CA125 in prediagnostic serum samples from the Janus Serumbank. Serial specimens from 120 women with invasive epithelial ovarian cancer were compared with healthy controls. Serum level of CA125, HE4, and cotinine was measured. Spearman correlation and multiple linear regression analyses were used to investigate impact of smoking, age, storage time, and lag time (time from sampling until date of diagnosis). RESULTS: Spearman correlation showed a strong positive correlation between HE4 and smoking in both cases and controls. Multiple linear regression analyses for pairwise differences between case and control showed that serum level of HE4 and CA125 was significantly increased (P = 0.002 and P < 0.001, respectively) 2 years before diagnosis and that CA125 also was significantly increased up to 4 years before diagnosis (P = 0.002). CONCLUSIONS: The present study showed that a difference between cases and controls in serum concentration of HE4 seemed to be increased 2 years before diagnosis and that CA125 was increased until 4 years before diagnosis. PMID- 26501437 TI - Oncologists' Perceptions of Recurrent Ovarian Cancer Patients' Preference for Participation in Treatment Decision Making and Strategies for When and How to Involve Patients in This Process. AB - OBJECTIVES: The treatment decision-making (TDM) process in the medical encounter in ovarian cancer (OC) is directed by oncologists. There is little information on oncologists' perceptions of this process. Our objectives were to explore oncologists' perceptions concerning (1) patients' preference for involvement in TDM, (2) factors that affect when to introduce this discussion, and (3) strategies used for engaging women in TDM. METHODS: We adopted a qualitative descriptive approach. Individual in-person interviews were used to collect data; themes were identified. RESULTS: Fifteen gynecologic and 5 medical oncologists from Ontario, Canada, participated. We found that oncologists made the assumption that women with recurrent OC were interested in being involved in TDM but rarely reported attempting to validate this assumption. The oncologists timed the initiation of the TDM discussion based on their degree of certainty of recurrent OC and their perception of the patient's readiness to be involved in TDM. Oncologists reported using strategies to engage women such as getting the women to take ownership of the decision, verbalize their priorities, lead the discussions, and giving the opportunity to gather information. CONCLUSIONS: Oncologists need to listen to each patient rather than make assumptions about the person based on her disease. PMID- 26501439 TI - Engineering a Polyketide Synthase for In Vitro Production of Adipic Acid. AB - Polyketides have enormous structural diversity, yet polyketide synthases (PKSs) have thus far been engineered to produce only drug candidates or derivatives thereof. Thousands of other molecules, including commodity and specialty chemicals, could be synthesized using PKSs if composing hybrid PKSs from well characterized parts derived from natural PKSs was more efficient. Here, using modern mass spectrometry techniques as an essential part of the design-build-test cycle, we engineered a chimeric PKS to enable production one of the most widely used commodity chemicals, adipic acid. To accomplish this, we introduced heterologous reductive domains from various PKS clusters into the borrelidin PKS' first extension module, which we previously showed produces a 3-hydroxy-adipoyl intermediate when coincubated with the loading module and a succinyl-CoA starter unit. Acyl-ACP intermediate analysis revealed an unexpected bottleneck at the dehydration step, which was overcome by introduction of a carboxyacyl-processing dehydratase domain. Appending a thioesterase to the hybrid PKS enabled the production of free adipic acid. Using acyl-intermediate based techniques to "debug" PKSs as described here, it should one day be possible to engineer chimeric PKSs to produce a variety of existing commodity and specialty chemicals, as well as thousands of chemicals that are difficult to produce from petroleum feedstocks using traditional synthetic chemistry. PMID- 26501438 TI - Clinical Neuropathology mini-review 6-2015: PD-L1: emerging biomarker in glioblastoma? AB - Programmed death 1 (PD-1, CD279) and programmed death ligand 1 (PD-L1, CD274) are involved in generating tumor-associated immunosuppression by suppression of T cell proliferation and interleukin 2 (IL-2) production and immune checkpoint inhibitors targeting these molecules are showing compelling activity against a variety of human cancers. PD-L1 expression has shown a positive association with response to PD-1 inhibition in noncentral nervous system (CNS) tumors, e.g., melanoma or non-small cell lung cancer, and is discussed as a potential predictive biomarker for patient selection in these tumor types. This review summarizes current knowledge and potential clinical implications of PD-L1 expression in glioblastoma. At present, the following conclusions are drawn: (a) functional data support a role for PD-1/PD-L1 in tumor-associated immunosuppression in glioblastoma; (b) the incidence of PD-L1-expressing glioblastomas seems to be relatively high in comparison to other tumor types, however, the reported rates of glioblastomas with PD-L1 protein expression vary and range from 61 to 88%; (c) there is considerable variability in the methodology of PD-L1 assessment in glioblastoma across studies with heterogeneity in utilized antibodies, tissue sampling strategies, immunohistochemical staining protocols, cut-off definitions, and evaluated staining patterns; (d) there are conflicting data on the prognostic role and so far no data on the predictive role of PD-L1 gene and protein expression in glioblastoma. In summary, the ongoing clinical studies evaluating the activity of PD-1/PD-L1 inhibitors in glioblastoma need to be complemented with well designed and stringently executed studies to understand the influence of PD-1/PD-L1 expression on therapy response or failure and to develop robust means of PD-L1 assessment for meaningful biomarker development. PMID- 26501440 TI - Noble Gas Inserted Protonated Silicon Monoxide Cations: HNgOSi(+) (Ng = He, Ne, Ar, Kr, and Xe). AB - The existence of noble gas containing protonated silicon monoxide complexes have been predicted theoretically through ab initio quantum chemical methods. The predicted HNgOSi(+) ions are obtained by insertion of a noble gas atom (Ng = He, Ne, Ar, Kr, and Xe) between the H and O atoms in SiOH(+) ion. The structural parameters, energetics, harmonic vibrational frequencies, and charge distributions have been analyzed by optimizing the minima and the transition state structures using second-order Moller-Plesset perturbation theory (MP2), density functional theory (DFT), and coupled-cluster theory (CCSD(T)) based techniques. The predicted HNgOSi(+) ions are found to be stable with respect to all possible 2-body and 3-body dissociation channels, except the dissociation path leading to the respective global minimum products. However, these ions are found to be kinetically stable with respect to the global minimum dissociation process as revealed from the finite barrier heights, which in turn can prevent the transformation of these metastable species to the global minimum products. Furthermore, the computed bond lengths, vibrational frequencies, and force constant values suggest that a strong covalent bond exists between the H and Ng atoms in HNgOSi(+) ions while the Ng and O atoms share a strong van der Waals kind of interaction. Charge distributions and bonding analysis indicate that HNgOSi(+) ions can be best represented as strong complexes between the [HNg](+) ions and OSi molecule. All the computational results suggest that the predicted species, HNgOSi(+), may be prepared and characterized by suitable experimental technique at cryogenic temperature. PMID- 26501442 TI - DNA bases ring-expanded with a cyclopentadiene free radical: a theoretical investigation of building blocks with diradical character. AB - In this work, we computationally design radical nucleobases which possess improved electronic properties, especially diradical properties through introducing a cyclopentadiene radical. We predict that the detailed electromagnetic features of base assemblies are based on the orientation of the extra five-membered cyclopentadiene ring. Broken symmetry DFT calculations take into account the relevant structures and properties. Our results reveal that both the radicalized DNA bases and the base pairs formed when they combine with their counterparts remain stable and display larger spin delocalization. The mode of embedding the cyclopentadiene free radical in the structures has some influence on the degree of pi-conjugation, which results in various diradical characteristics. Single-layered radical base pairs all have an open-shell singlet ground state, but the energy difference between singlet and triplet is not significant. For two-layered radical base pairs, the situation is more complex. All of them have an open-shell state as their ground state, including an open shell singlet state and an open-shell triplet state. That is, the majority of radical base pairs possess anti-ferromagnetic or ferromagnetic characteristics. We present here a more in-depth discussion and analyses to study the magnetic characteristics of radical bases and base pairs. As an important factor, two layered radical base pairs also have been carefully analyzed. We hope that all the measurements and results presented here will stimulate further detailed insights into the related mechanisms in modified DNA bases and the design of better ring-expanded DNA magnetic materials. PMID- 26501443 TI - EJNMMI Physics - an editor's perspective. PMID- 26501444 TI - The contribution of Medical Physics to Nuclear Medicine: looking back - a physicist's perspective. AB - BACKGROUND: This paper is the first in a series of invited perspectives by four pioneers of Nuclear Medicine imaging and physics. A medical physicist and a Nuclear Medicine clinical specialist each take a backward look and a forward look at the contributions of Medical Physics to Nuclear Medicine. DISCUSSION: Contributions of Medical Physics are presented from the early discovery of radioactivity, development of first imaging devices, computers and emission tomography to recent development of hybrid imaging. There is evidence of significant contribution of Medical Physics throughout the development of Nuclear Medicine. PMID- 26501445 TI - The contribution of medical physics to nuclear medicine: a physician's perspective. AB - This paper is the second in a series of invited perspectives by four pioneers of nuclear medicine imaging and physics. A medical physicist and a nuclear medicine clinical specialist each take a backward look and a forward look at the contributions of physics to nuclear medicine. Here is a backward look from a nuclear medicine physician's perspective. PMID- 26501446 TI - Thirty years from now: future physics contributions in nuclear medicine. AB - BACKGROUND: This paper is the first in a series of invited perspectives by pioneers of nuclear medicine imaging and physics. A medical physicist and a nuclear medicine physician each take a backward and a forward look at the contributions of physics to nuclear medicine. Here, we provide a forward look from the medical physicist's perspective. DISCUSSION: The author examines a number of developments in nuclear medicine and discusses the ways in which physics has contributed to these. Future developments are postulated in the context of an increasingly personalised approach to medical diagnostics and therapies. CONCLUSIONS: A skill set for the next generation of medical physicists in nuclear medicine is proposed in the context of the increasing complexity of 'Molecular Imaging' in the next three decades. The author sees a shift away from 'traditional' roles in instrumentation QA to more innovative approaches in understanding radiobiology and human disease. PMID- 26501447 TI - The contribution of physics to Nuclear Medicine: physicians' perspective on future directions. AB - BACKGROUND: Advances in Nuclear Medicine physics enabled the specialty of Nuclear Medicine and directed research in other aspects of radiotracer imaging, ultimately leading to Nuclear Medicine's emergence as an important component of current medical practice. DISCUSSION: Nuclear Medicine's unique ability to characterize in vivo biology without perturbing it will assure its ongoing role in a practice of medicine increasingly driven by molecular biology. However, in the future, it is likely that advances in molecular biology and radiopharmaceutical chemistry will increasingly direct future developments in Nuclear Medicine physics, rather than relying on physics as the primary driver of advances in Nuclear Medicine. Working hand-in-hand with clinicians, chemists, and biologists, Nuclear Medicine physicists can greatly enhance the specialty by creating more sensitive and robust imaging devices, by enabling more facile and sophisticated image analysis to yield quantitative measures of regional in vivo biology, and by combining the strengths of radiotracer imaging with other imaging modalities in hybrid devices, with the overall goal to enhance Nuclear Medicine's ability to characterize regional in vivo biology. PMID- 26501448 TI - The dynamics of physics in PET. AB - From a technical perspective, there are fundamentally two forces driving the evolution of instrumentation in positron emission tomography (PET) and nuclear medicine generally: clinical needs and technical innovation. This essay considers some of the dynamics of these forces as they act on physics-related developments in PET and suggests that progress will be greatest if these differing motivations are kept in balance as the field evolves. PMID- 26501449 TI - Cluster-based segmentation of dual-echo ultra-short echo time images for PET/MR bone localization. AB - BACKGROUND: Magnetic resonance (MR)-based attenuation correction is a critical component of integrated positron emission tomography (PET)/MR scanners. It is generally achieved by segmenting MR images into tissue classes with known attenuation properties (e.g., bone, fat, soft tissue, lung, air). Ultra-short echo time (UTE) have been proposed in the past to locate bone tissue. In this study, tri-modality computed tomography data was used to develop an improved algorithm for the localization of bone in the head and neck. METHODS: Twenty patients were scanned using a tri-modality setup. A UTE acquisition with 22-cm transaxial and 24-cm axial field of view was acquired, with a resolution of 1.5 * 1.5 * 2.0 mm(3). The sequence consisted of two echoes (30 MUs, 1.7 ms) with a flip angle of 10 degrees and 125-kHz bandwidth. The CT images of all patients were classified by thresholding and used to compute maps of the posterior probability of each tissue class, given a pair of UTE echo values. The Jaccard distance was used to compare with CT the bone masks obtained when using this information to segment the UTE datasets. RESULTS: The results show the desired bony structures as a cluster pattern in the space of dual-echo measurements. The clusters obtained for the tissue classes are strongly overlapped, indicating that the MR data will not, regardless of the chosen space partition, be able to completely differentiate the bony and soft structures. The classification obtained by maximizing the posterior probability compared well to previously published methods, providing a more intuitive and robust choice of the final classification threshold. The distance between MR- and CT-based bone masks was 59% on average (0% being a perfect match), compared to 76% and 69% for two previously published methods. CONCLUSIONS: The study of tri-modality datasets shows that improved bone tissue classification can be achieved by estimating maps of the posterior probability of voxels belonging to a particular tissue class, given a measured pair of UTE echoes. PMID- 26501450 TI - On transcending the impasse of respiratory motion correction applications in routine clinical imaging - a consideration of a fully automated data driven motion control framework. AB - Positron emission tomography (PET) is increasingly used for the detection, characterization, and follow-up of tumors located in the thorax. However, patient respiratory motion presents a unique limitation that hinders the application of high-resolution PET technology for this type of imaging. Efforts to transcend this limitation have been underway for more than a decade, yet PET remains for practical considerations a modality vulnerable to motion-induced image degradation. Respiratory motion control is not employed in routine clinical operations. In this article, we take an opportunity to highlight some of the recent advancements in data-driven motion control strategies and how they may form an underpinning for what we are presenting as a fully automated data-driven motion control framework. This framework represents an alternative direction for future endeavors in motion control and can conceptually connect individual focused studies with a strategy for addressing big picture challenges and goals. PMID- 26501451 TI - Effective dose to adult patients from 338 radiopharmaceuticals estimated using ICRP biokinetic data, ICRP/ICRU computational reference phantoms and ICRP 2007 tissue weighting factors. AB - BACKGROUND: Effective dose represents the potential risk to a population of stochastic effects of ionizing radiation (mainly lethal cancer). In recent years, there have been a number of revisions and updates influencing the way to estimate the effective dose. The aim of this work was to recalculate the effective dose values for the 338 different radiopharmaceuticals previously published by the International Commission on Radiological Protection (ICRP). METHOD: The new estimations are based on information on the cumulated activities per unit administered activity in various organs and tissues and for the various radiopharmaceuticals obtained from the ICRP publications 53, 80 and 106. The effective dose for adults was calculated using the new ICRP/International Commission on Radiation Units (ICRU) reference voxel phantoms and decay data from the ICRP publication 107. The ICRP human alimentary tract model has also been applied at the recalculations. The effective dose was calculated using the new tissue weighting factors from ICRP publications 103 and the prior factors from ICRP publication 60. The results of the new calculations were compared with the effective dose values published by the ICRP, which were generated with the Medical Internal Radiation Dose (MIRD) adult phantom and the tissue weighting factors from ICRP publication 60. RESULTS: For 79% of the radiopharmaceuticals, the new calculations gave a lower effective dose per unit administered activity than earlier estimated. As a mean for all radiopharmaceuticals, the effective dose was 25% lower. The use of the new adult computational voxel phantoms has a larger impact on the change of effective doses than the change to new tissue weighting factors. CONCLUSION: The use of the new computational voxel phantoms and the new weighting factors has generated new effective dose estimations. These are supposed to result in more realistic estimations of the radiation risk to a population undergoing nuclear medicine investigations than hitherto available values. PMID- 26501452 TI - Missing head and color banding in low-count SPECT reconstructions. AB - Due to low counts in an (111)In single photon emission computed tomography (SPECT) scan, a large part of the head was missing in the reconstructed images on Philips Extended Brilliance Workspace (EBW) and IntelliSpace Portal (ISP) workstations. This problem occurred for the ordered subsets expectation maximization (OSEM) algorithm with and without resolution recovery (Astonish), but not for filtered backprojection (FBP) or maximum likelihood expectation maximization (MLEM). There were also underflow problems because the images are stored as integers resulting in a loss of intensity resolution and color banding.Philips EBW2.0 and ISP5.02 workstations upscale low-count images, but the result is not always optimal, for example, in the case of low counts in one part and more counts in another part of an image. On these workstations, the missing head artefact problem could be resolved by applying a Hann pre-filter (with a cutoff at the Nyquist frequency, which only influences the filtering) in the reconstruction process. Upscaling of the projection data prior to reconstruction did not recover the head in the images, neither did limiting the reconstructed volume to the low-count part of interest.Underflow problems were partially solved by the new version 2.0 of the Philips EBW and ISP stations, although situations could arise where underflow still poses a problem. A solution for the underflow problems is to upscale the raw projection data before reconstruction. While this results in a pure upscaling of the FBP reconstruction, the effect in iterative statistical reconstruction is not only upscaling of the intensities because the assumption of Poisson statistics of the data is violated. However, the influence of this last matter seems limited.Reconstruction of studies with low counts in relevant areas should be performed with care. Reconstruction artefacts and scaling issues can easily arise. PMID- 26501453 TI - New prospects for PET in prostate cancer imaging: a physicist's viewpoint. AB - Prostate cancer is one of the most common forms of cancer among men. Early diagnosis, correct staging, accurate detection of metastasis, and monitoring of the therapy are the key tasks that could greatly benefit from medical imaging. After a review of the main developments in the field of positron emission tomography (PET) tracers for prostate cancer, the impact of improved PET instrumentation with good spatial resolution and high sensitivity is discussed, together with the latest development in PET technology: lutetium oxy-ortho silicate (LSO) and lutetium-yttrium oxy-ortho-silicate (LYSO) scintillators, resolution recovery, and time-of-flight reconstruction. New directions and multiple approaches in PET instrumentation for prostate cancer are presented and discussed. In particular, improved hardware and noise suppressing reconstruction algorithms allow for higher detectability of small lesions and better spatial resolution in PET/computerized tomography (CT) and PET/magnetic resonance (MR). This can be beneficial for guiding biopsy and surgery and for accurate therapy monitoring. PMID- 26501454 TI - The influence of different signal-to-background ratios on spatial resolution and F18-FDG-PET quantification using point spread function and time-of-flight reconstruction. AB - BACKGROUND: F18-fluorodeoxyglucose positron-emission tomography (FDG-PET) reconstruction algorithms can have substantial influence on quantitative image data used, e.g., for therapy planning or monitoring in oncology. We analyzed radial activity concentration profiles of differently reconstructed FDG-PET images to determine the influence of varying signal-to-background ratios (SBRs) on the respective spatial resolution, activity concentration distribution, and quantification (standardized uptake value [SUV], metabolic tumor volume [MTV]). METHODS: Measurements were performed on a Siemens Biograph mCT 64 using a cylindrical phantom containing four spheres (diameter, 30 to 70 mm) filled with F18-FDG applying three SBRs (SBR1, 16:1; SBR2, 6:1; SBR3, 2:1). Images were reconstructed employing six algorithms (filtered backprojection [FBP], FBP + time of-flight analysis [FBP + TOF], 3D-ordered subset expectation maximization [3D OSEM], 3D-OSEM + TOF, point spread function [PSF], PSF + TOF). Spatial resolution was determined by fitting the convolution of the object geometry with a Gaussian point spread function to radial activity concentration profiles. MTV delineation was performed using fixed thresholds and semiautomatic background-adapted thresholding (ROVER, ABX, Radeberg, Germany). RESULTS: The pairwise Wilcoxon test revealed significantly higher spatial resolutions for PSF + TOF (up to 4.0 mm) compared to PSF, FBP, FBP + TOF, 3D-OSEM, and 3D-OSEM + TOF at all SBRs (each P < 0.05) with the highest differences for SBR1 decreasing to the lowest for SBR3. Edge elevations in radial activity profiles (Gibbs artifacts) were highest for PSF and PSF + TOF declining with decreasing SBR (PSF + TOF largest sphere; SBR1, 6.3%; SBR3, 2.7%). These artifacts induce substantial SUVmax overestimation compared to the reference SUV for PSF algorithms at SBR1 and SBR2 leading to substantial MTV underestimation in threshold-based segmentation. In contrast, both PSF algorithms provided the lowest deviation of SUVmean from reference SUV at SBR1 and SBR2. CONCLUSIONS: At high contrast, the PSF algorithms provided the highest spatial resolution and lowest SUVmean deviation from the reference SUV. In contrast, both algorithms showed the highest deviations in SUVmax and threshold-based MTV definition. At low contrast, all investigated reconstruction algorithms performed approximately equally. The use of PSF algorithms for quantitative PET data, e.g., for target volume definition or in serial PET studies, should be performed with caution - especially if comparing SUV of lesions with high and low contrasts. PMID- 26501455 TI - The effect of object size on the sensitivity of single photon emission computed tomography: comparison of two CZT cardiac cameras and an Anger scintillation camera. AB - BACKGROUND: Heart sizes vary greatly across the spectrum of patients referred for myocardial perfusion imaging. We therefore performed a phantom study to explore under controlled circumstances how count rates change when different volumes containing the same amount of activity are scanned. Two dedicated cadmium-zinc telluride cameras, the D-SPECT (Spectrum Dynamics, Caesarea, Israel) and Discovery 530c (D530c, GE Healthcare, Haifa, Israel), and the conventional SPECT Anger (A-SPECT, GE Healthcare, Haifa, Israel) camera are included in the study. METHODS: Different heart sizes were represented by syringes of various column heights mimicking a range of cardiac diameters. Syringes with fixed activity were scanned at five different volumes by successively adding non-radioactive water to the syringes. This procedure was repeated five times on each of the three cameras. Raw count rates were recorded for each scan to determine whether count rates changed with syringe column height. RESULTS: Using mixed-effect regression modeling, a linear relationship was found between count rate and water column height. For the D-SPECT, D530c, and A-SPECT, the changes in count rate for each centimeter increase in water column height were -1.75, +0.28, and -0.022 kilocounts per min per MBq, respectively (95% confidence intervals -1.89 to 1.61, 0.19 to 0.36, and -0.035 to -0.009); all effects are significantly different from each other and significantly different from zero. Average coefficients of variation were 0.080, 0.028, and 0.009. CONCLUSIONS: The D-SPECT demonstrated a significant progressive increase in count rate related to decreasing size of the imaged object. D530c count rate increased slightly with increasing column height. The Anger SPECT showed minimally increased count rates with decreasing column height, an order of magnitude smaller than the D-SPECT based on their relative coefficients of variation. PMID- 26501456 TI - Unconstrained image reconstruction with resolution modelling does not have a unique solution. AB - Positron emission tomography systems have a finite spatial resolution. When the system point spread function (PSF) is taken into account, the unconstrained reconstruction problem does not have a unique solution. As a result, the solution obtained with the maximum likelihood reconstruction algorithm typically suffers from Gibbs artefacts, which can have an adverse effect on tracer uptake quantification in small lesions. To deal with this problem, some assumptions about the undetected image features have to be introduced, either implicitly or explicitly. If one is willing to sacrifice resolution, the improvement of the PSF model can be used to suppress noise and at the same time impose a predefined (suboptimal) spatial resolution, facilitating pooled analysis of multicentre data. PMID- 26501457 TI - Impact of point spread function modelling and time of flight on FDG uptake measurements in lung lesions using alternative filtering strategies. AB - BACKGROUND: The use of maximum standardised uptake value (SUVmax) is commonplace in oncology positron emission tomography (PET). Point spread function (PSF) modelling and time-of-flight (TOF) reconstructions have a significant impact on SUVmax, presenting a challenge for centres with defined protocols for lesion classification based on SUVmax thresholds. This has perhaps led to the slow adoption of these reconstructions. This work evaluated the impact of PSF and/or TOF reconstructions on SUVmax, SUVpeak and total lesion glycolysis (TLG) under two different schemes of post-filtering. METHODS: Post-filters to match voxel variance or SUVmax were determined using a NEMA NU-2 phantom. Images from 68 consecutive lung cancer patients were reconstructed with the standard iterative algorithm along with TOF; PSF modelling - Siemens HD.PET (HD); and combined PSF modelling and TOF - Siemens ultraHD.PET (UHD) with the two post-filter sets. SUVmax, SUVpeak, TLG and signal-to-noise ratio of tumour relative to liver (SNR(T L)) were measured in 74 lesions for each reconstruction. Relative differences in uptake measures were calculated, and the clinical impact of any changes was assessed using published guidelines and local practice. RESULTS: When matching voxel variance, SUVmax increased substantially (mean increase +32% and +49% for HD and UHD, respectively), potentially impacting outcome in the majority of patients. Increases in SUVpeak were less notable (mean increase +17% and +23% for HD and UHD, respectively). Increases with TOF alone were far less for both measures. Mean changes to TLG were <10% for all algorithms for either set of post filters. SNR(T-L) were greater than ordered subset expectation maximisation (OSEM) in all reconstructions using both post-filtering sets. CONCLUSIONS: Matching image voxel variance with PSF and/or TOF reconstructions, particularly with PSF modelling and in small lesions, resulted in considerable increases in SUVmax, inhibiting the use of defined protocols for lesion classification based on SUVmax. However, reduced partial volume effects may increase lesion detectability. Matching SUVmax in phantoms translated well to patient studies for PSF reconstruction but less well with TOF, where a small positive bias was observed in patient images. Matching SUVmax significantly reduced voxel variance and potential variability of uptake measures. Finally, TLG may be less sensitive to reconstruction methods compared with either SUVmax or SUVpeak. PMID- 26501458 TI - Chewing-gum stimulation did not reduce the absorbed dose to salivary glands during radioiodine treatment of thyroid cancer as inferred from pre-therapy (124)I PET/CT imaging. AB - BACKGROUND: The goal of this prospective study was to estimate the absorbed (radiation) doses to salivary glands in radioiodine therapy of thyroid cancer under chewing-gum stimulation using (124)I positron emission tomography (PET)/computed tomography (CT) imaging. METHODS: Duplex ultrasonography was conducted in three test persons for visual comparison of the glandular blood flow with three different stimulation types (no stimulation, chewing tasteless gum base, sucking on lemon slices). Ten patients with newly diagnosed differentiated thyroid cancer received (124)I PET/CT dosimetry after thyroidectomy and prior to radioiodine therapy. Patients underwent a series of three (124)I PET/CT scans (4, 24, and >=96 h after administration of 23 MBq (124)I). They were instructed to chew gum base (tasteless) approximately 20 min after ingesting the (124)I containing capsule in the course of the first day. Absorbed doses per administered (131)I activity to the salivary glands were calculated and compared with the previously published results of the lemon-juice stimulation and non stimulation groups. RESULTS: The sonograms in the three test persons showed that glandular blood perfusion by lemon-juice stimulation was clearly increased compared with non-stimulation or chewing of gum base. The sonogram comparison between the chewing-gum stimulation and non-stimulation demonstrated a minor increase of blood flow for the gum base-stimulated salivary glands. The mean +/- standard deviation of the absorbed dose per activity under chewing-gum stimulation for the submandibular and parotid glands (within parentheses) was 0.22 +/- 0.09 Gy/GBq (0.22 +/- 0.08 Gy/GBq). Compared with the absorbed doses of the non-stimulation group, 0.24 +/- 0.08 Gy/GBq (0.21 +/- 0.05 Gy/GBq), those of the chewing-gum stimulation group showed no significant change (P > 0.60), but the absorbed doses of the lemon-juice stimulation group, 0.35 +/- 0.14 Gy/GBq (0.33 +/- 0.09 Gy/GBq), were significantly higher (P < 0.04) than those of the chewing-gum stimulation group. CONCLUSIONS: The results suggest that salivary flow induced by chewing gum base does not cause a significant reduction of the salivary gland absorbed dose compared with that in the non-stimulation group. The increased blood flow appears to be a decisive factor causing the increased (131)I absorbed doses in the lemon-juice stimulation group. PMID- 26501459 TI - Impact of incorrect tissue classification in Dixon-based MR-AC: fat-water tissue inversion. AB - BACKGROUND: The current MR-based attenuation correction (AC) used in combined PET/MR systems computes a Dixon attenuation map (MR-ACDixon) based on fat and water images derived from in- and opposed-phase MRI. We observed an occasional fat/water inversion in MR-ACDixon. The aim of our study was to estimate the prevalence of this phenomenon in a large patient cohort and assess the possible bias on PET data. METHODS: PET/MRI was performed on a Siemens Biograph mMR (Siemens AG, Erlangen, Germany). We visually inspected attenuation maps of 283 brain or head/neck (H/N) patients, classified them as non-inverted or inverted, and calculated the fat/water tissue fraction. We selected ten FDG-PET brain patients with non-inverted attenuation maps for further analysis. Tissue inversion was simulated, and PET images were reconstructed using both original and inverted attenuation maps. The FDG-PET images of the ten brain patients were analyzed using 11 concentric annulus regions of 5 mm width placed over a central transaxial image plane traversing PETDixon. RESULTS: Out of the 283 patients, a fat/water inversion in 23 patients (8.1%) was observed. The average fraction of fat in the correct MR-ACDixon was 13% for brain and 17% for H/N patients. In the inverted cases, we found an average fat fraction of 56% for the brain patients and 41% for the H/N patients. The effect of the simulated tissue inversion in the brain studies was clearly seen on AC-PET images. The percent-difference image revealed a radial error where the largest difference was at the ventricles (30% +/- 3%) and smallest at the cortical region (10% +/- 2%). CONCLUSIONS: Tissue inversion in Dixon MRI is well known and can occur when there is an error in the off-resonance correction method. Tissue inversion needs to be considered if, based on Dixon-AC, the construction of normal PET databases is performed or any quantitative physiological parameters are fitted. Visual inspection is needed if Dixon-AC is to be used in clinical routine. PMID- 26501460 TI - Metal artifact reduction in patients with dental implants using multispectral three-dimensional data acquisition for hybrid PET/MRI. AB - BACKGROUND: Hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) shows high potential for patients with oropharyngeal cancer. Dental implants can cause substantial artifacts in the oral cavity impairing diagnostic accuracy. Therefore, we evaluated new MRI sequences with multi-acquisition variable-resonance image combination (MAVRIC SL) in comparison to conventional high-bandwidth techniques and in a second step showed the effect of artifact size on MRI-based attenuation correction (AC) with a simulation study. METHODS: Twenty five patients with dental implants prospectively underwent a trimodality PET/CT/MRI examination after informed consent was obtained under the approval of the local ethics committee. A conventional 3D gradient-echo sequence (LAVA-Flex) commonly used for MRI-based AC of PET (acquisition time of 14 s), a T1w fast spin echo sequence with high bandwidth (acquisition time of 3.2 min), as well as MAVRIC SL sequence without and with increased phase acceleration (MAVRIC, acquisition time of 6 min; MAVRIC-fast, acquisition time of 3.5 min) were applied. The absolute and relative reduction of the signal void artifact was calculated for each implant and tested for statistical significance using the Wilcoxon signed-rank test. The effect of artifact size on PET AC was simulated in one case with a large tumor in the oral cavity. The relative difference of the maximum standardized uptake value (SUVmax) in the tumor was calculated for increasing artifact sizes centered over the second molar. RESULTS: The absolute reduction of signal void from LAVA-Flex sequences to the T1-weighted fast spin echo (FSE) sequences was 416 mm(2) (range 4 to 2,010 mm(2)) to MAVRIC 481 mm(2) (range 12 to 2,288 mm(2)) and to MAVRIC-fast 486 mm(2) (range 39 to 2,209 mm(2)). The relative reduction in signal void was significantly improved for both MAVRIC and MAVRIC-fast compared to T1 FSE (-75%/-78% vs. -62%, p < 0.001 for both). The relative error for SUVmax was negligible for artifacts of 0.5-cm diameter ( 0.1%), but substantial for artifacts of 5.2-cm diameter (-33%). CONCLUSIONS: MAVRIC-fast could become useful for artifact reduction in PET/MR for patients with dental implants. This might improve diagnostic accuracy especially for patients with tumors in the oropharynx and substantially improve accuracy of PET quantification. PMID- 26501461 TI - Clinical image quality perception and its relation to NECR measurements in PET. AB - BACKGROUND: The purpose of this study is to describe a clinical relation of noise equivalent count rate (NECR) - an objective measurement of positron emission tomography (PET) systems - measured in a large number of patients, to clinical image quality of PET and their relation to 18F-fluoro-2-deoxyglucose (FDG) activity and patient's weight. METHODS: A total of 71 consecutive patients were evaluated in this retrospective study. All data was automatically analysed using Matlab to estimate the noise equivalent count rate. Then, image quality was evaluated according to two subjective scores: the IQ local score was a 3-point scale assigned to each bed position in all patients and the IQ global score was a 10-point scale assigned after evaluating the coronal whole-body PET. Patient data was also analysed concerning weight, body mass index, FDG dose at the start of acquisition (D Acq), presence of bowel uptake and presence of FDG-positive pathologic lesions. Two additional parameters were defined for each patient: the ratio between D Acq and patient weight (R DW) and the ratio between D Acq and patient BMI (R DBMI). RESULTS: Clinically perceived image quality in PET has a significant positive correlation with NECR measured in patients, R DW, R DBMI and presence of pathologic lesions. Clinical image quality furthermore has significant negative correlation with weight, body mass index (BMI) and presence of bowel uptake. Thresholds of R DW and R DBMI in which clinical IQ is good to excellent in more than 90% of the patients were 2.6 and 8.0, respectively. CONCLUSIONS: Clinically perceived image quality in PET systems is positively and significantly related to NECR measured in patients. An optimal threshold for the R DW and R DBMI was defined in which clinical IQ is good to excellent in more than 90% of patients. With this data, it is possible to extrapolate technical as well as clinical image quality to other PET system and to predict clinical image perception. PMID- 26501462 TI - Routes for Drug Delivery to the Eye and Retina: Intravitreal Injections. AB - The advantage of intravitreal injections is an immediate and increased therapeutic effect in the intended retinal tissue. The accuracy, precision and reproducibility of the delivered volume depend on the size of the syringe and the physician's manual experience. The eyelids and eyelashes are usually disinfected using a povidone-iodine solution (10%); a sterile speculum is placed and drops of povidone-iodine (5%) are applied. The use of adequate anesthetic topical lidocaine 2% is required. The injection site should be located 3.5-4 mm posterior to the limbus. The angle of the incision through the sclera may be directed in an oblique fashion of 30 degrees . The diameter of the needle should be smaller than 25 G, and the injected volume should be limited to 0.15 ml without a routine paracentesis. The incidence of lens injury is 0.006% (2/32,318) and 0.013% (5/35,942) for rhegmatogenous retinal detachments. The rate of suspected endophthalmitis is 0.018% after bevacizumab and 0.027% after ranibizumab injections. Sterile inflammations have been observed after Avastin injections. The concentrations of vascular endothelial growth factor inhibitors decline in a monoexponential fashion. The half-life of unbound bevacizumab is 9.82 days and that of ranibizumab 7.19 days. PMID- 26501463 TI - Molecular Detection of Candidatus Bartonella hemsundetiensis in Bats. AB - Although bats have been implicated as reservoir hosts for a number of zoonotic and life-threatening viruses, the bat bacterial flora and its zoonotic threat remain elusive. However, members of the vector-borne bacterial genera Bartonella causing various human as well as animal diseases have recently been isolated or detected from bats and their ectoparasites. In this study, we sampled 124 insectivorous microbats (Daubenton's bat, Myotis daubentonii) for peripheral blood in southwestern Finland in 2010. A Bartonella-specific PCR targeting rpoB (RNA polymerase beta-subunit) was positive with blood samples from 46 bats (prevalence 37%). Scaled mass indexes of the infected and noninfected bats did not differ (p = 0.057). One rpoB sequence was identical with the rpoB sequence of B. naantaliensis strain 2574/1, previously isolated from bats in Finland. The rest of the sequences were highly similar to each other with nucleotide identity scores of 96% or higher. Nucleotide identity scores to the previously described type strain sequences of Bartonella or other database entries were no higher than 87%. Sequence analyses of another gene, gltA (citrate synthase), gave no higher than 90% nucleotide identity scores. On the basis of the conventional 95% sequence similarity cutoff in bacterial species delineation, a novel species of Bartonella was detected. We propose a species name Candidatus B. hemsundetiensis. Phylogenetic analyses based on rpoB and gltA sequences indicate that Candidatus B. hemsundetiensis clusters in a deep-branching position close to the ancestral species B. tamiae and B. bacilliformis. Our study reinforces the importance of bats as reservoirs of Bartonella. PMID- 26501465 TI - Synthesis of Au@UiO-66(NH2) structures by small molecule-assisted nucleation for plasmon-enhanced photocatalytic activity. AB - We have provided a small molecule-assisted heterogeneous nucleation of MOF route to successfully synthesize Au@UiO-66(NH2) heterostructures. UiO-66(NH2) with a localized electronic state that was characterized by C-AFM exhibited higher photocatalytic activity in the heterostructures via a plasmonic sensitization process. PMID- 26501466 TI - Ethanol Lock Therapy for the Treatment of Intravenous Catheter Infections That Have Failed Standard Treatment. AB - This study used ethanol lock therapy (ELT) to treat intravenous catheter infections that had failed standard intravenous antimicrobial treatment. Of 15 patients enrolled, 13 were successfully treated with ELT. Twenty-one organisms were identified: 12 bacteria, 9 fungi. Eight of the 9 fungi were eradicated, and no patient became hemodynamically unstable on treatment. PMID- 26501467 TI - Pediatric Neglected Tropical Diseases in a Major Metropolitan Children's Hospital in the United States, 2004-2013. AB - We conducted a retrospective study of neglected tropical diseases (NTDs) diagnosed at Texas Children's Hospital between 2004 and 2013. Forty-three patients with an NTD were identified; 47% had never traveled outside of the United States. The results of this study highlight the importance of physician awareness of NTDs in children in the United States. PMID- 26501464 TI - Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is a rare progressive disease of the pulmonary vasculature that is characterized by endothelial dysfunction, inflammation, and right ventricular dysfunction. OBJECTIVES: The main objective was to determine whether endothelial, inflammatory, and cardiac biomarkers would be associated with the World Health Organization functional assessment and survival in patients with PAH. METHODS: We performed a retrospective cohort study of patients with PAH enrolled in the Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension (ASA-STAT). Biomarkers (N terminal fragment of pro-BNP [NT-pro-BNP], von Willebrand factor [vWF], soluble P selectin, C-reactive protein, total and high-density lipoprotein cholesterol, triglycerides, tumor necrosis factor, IL-6, beta-thromboglobulin, and thromboxane B2) were measured at baseline. Patients from the study were followed until lung transplantation, death, or August 1, 2013. Ordinal logistic regression and Cox regression analyses were performed. MEASUREMENTS AND MAIN RESULTS: Sixty-five patients with PAH were enrolled. The mean age was 51 years, and 86% were women. Higher vWF activity, lower high-density lipoprotein cholesterol, and higher thromboxane B2 levels were associated with worse World Health Organization functional class after adjustment for age, sex, and etiology of PAH. Higher NT pro-BNP levels, lower vWF activity, and lower total cholesterol were associated with an increased risk of death or lung transplant after adjustment for age, sex, etiology of PAH, and 6-minute-walk distance. CONCLUSIONS: In patients with PAH, lower vWF activity and cholesterol levels and higher NT-pro-BNP levels at baseline were associated with an increased risk of death or transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT00384865). PMID- 26501468 TI - Type 19 Pneumococcal Meningitis: A Patient With 75-Year Clinical and Serologic Follow Up, With a Review of the Evolution of Therapy From Antiserum to Sulfonamides to Penicillin. PMID- 26501469 TI - Boiling Over: The Antimicrobial Stewardship Stew May Finally Be Ready. PMID- 26501470 TI - The Health Burden of Invasive Meningococcal Disease: A Systematic Review. AB - OF KEY POINTS: Although relatively rare, invasive meningococcal disease continues to be a health concern, especially in young children. This systematic review clearly delineates both the near- and long-term morbidities that can occur after, and persist beyond, the period of acute illness. BACKGROUND: Although rare, invasive meningococcal disease (IMD) continues to be a health concern in high income countries because of its severe morbidity and relatively high case fatality rate, especially in young children. However, studies measuring sequelae of IMD across the spectrum of invasive syndromes have not been systematically reviewed. We conducted a systematic review of sequelae attributable to IMD and quality of life (QoL) in IMD survivors in high-income countries. METHODS: We searched Medline, Embase, and HealthSTAR for primary studies that assessed sequelae or QoL in individuals of any age with and without IMD. Two independent reviewers screened articles, abstracted data, and performed quality appraisal. The findings were summarized qualitatively. RESULTS: Of 1884 citations screened, 17 studies were included. The most commonly assessed sequelae were hearing impairment, cognitive impairment, and psychological problems. In general, children with IMD had a greater incidence of hearing loss and psychological disorders, including attention-deficit/hyperactivity disorder. However, its effects on intelligence in children remain unclear. No statistical differences in overall cognitive function in adults were reported. The odds of death were significantly increased with IMD at hospital discharge and up to 30 years after disease. Lower overall QoL was observed in those who had IMD versus controls. CONCLUSIONS: The results of this systematic review delineate both the short- and long-term morbidities that can occur after, and persist beyond, the period of acute illness. A better understanding of the full spectrum of IMD sequelae is critical for assessing the burden of IMD and supporting healthcare planning and decision making in light of new vaccines. PMID- 26501471 TI - A Blinded Comparison of Injection Pain With Quadrivalent Human Papilloma Virus Vaccine Versus Other Vaccines. PMID- 26501472 TI - Risk Factors for Late-Onset Group B Streptococcal Disease Before and After Implementation of Universal Screening and Intrapartum Antibiotic Prophylaxis. AB - BACKGROUND: It is unclear whether risk factors for late-onset Group B Streptococcus disease (LOD) have changed since the introduction of universal screening and treatment in 2002. METHODS: We conducted a case-control study using linked birth certificates and hospital discharge records. All infants born in Washington State from 1992 to 2011 and hospitalized between 7 and 89 days of life with a Group B Streptococcus (GBS)-related International Classification of Diseases (ICD)-9 code were included. Controls were matched 4:1 by birth year. Multivariate logistic regression was used to evaluate the association between clinical characteristics and LOD. We compared differences in the effect of risk factors on LOD between infants born before and after 2002 using likelihood ratio tests. RESULTS: We identified 138 cases of LOD. In multivariate analyses, prematurity and young maternal age were significantly associated with risk of LOD throughout the study period; positive GBS screen was associated with LOD from 2003 to 2011. Each week of decreasing gestation was associated with a 1.24 (95% confidence interval: 1.15-1.35) times greater likelihood of LOD. We did not detect differences in the association between prematurity or young maternal age and LOD comparing infants born before and after 2002. Compared with infants of non-Hispanic white mothers, risk of LOD among infants of non-Hispanic black mothers decreased after 2002 (adjusted odds ratio [aOR] = 2.74 vs 0.64; pinteraction = 0.02), whereas risk of LOD among infants of Hispanic mothers increased (aOR = 0.80 vs 2.23; pinteraction <= 0.001). CONCLUSIONS: Our results confirm studies conducted before 2002, which found that prematurity and young maternal age were associated with increased risk of LOD. Ethnicity-associated LOD risk differed before and after 2002, which may be related to healthcare access. PMID- 26501474 TI - Linezolid-Resistant Staphylococcus aureus in Children With Cystic Fibrosis. PMID- 26501473 TI - Outcomes Among Children Who Received a Kidney Transplant in the United States From a Hepatitis B Core Antibody-Positive Donor, 1995-2010. AB - BACKGROUND: Accepting kidneys for transplant from donors with a history of hepatitis B virus infection may increase the availability of organs for those with end-stage kidney disease. In adult recipients, kidney transplants from hepatitis B virus core antibody-positive donors have resulted in favorable graft and patient survival rates. However, pediatric organ transplant recipients have developing immune systems and a higher risk of infectious complications than adults. Accordingly, little is known about the outcomes of children who have received a kidney transplant from a hepatitis B virus core antibody-positive donor. METHODS: We included 11 898 children <=18 years of age who received a first kidney transplant in the United States between January 1, 1995, and December 31, 2010, and who were recorded in the Scientific Registry of Transplant Recipients. We examined differences in graft and patient survival rates among children who received a kidney transplant from a hepatitis B virus core antibody positive donor. RESULTS: There were 199 children (1.7%) who received a kidney transplant from a hepatitis B virus core antibody-positive donor. More than 80% of these transplants occurred in recipients who were hepatitis B virus core antibody and surface antigen negative. After a median follow-up of 7.9 years, there were no significant differences in the adjusted graft (hazard ratio [HR], 1.03 [95% confidence interval (CI), 0.80-1.31]) or patient (HR, 1.12 [95% CI, 0.73-1.73]) survival rates according to donor core antibody status. CONCLUSIONS: It may be acceptable, on a case-by-case basis, to consider hepatitis B virus core antibody-positive donors for kidney transplants to seroprotected children with end-stage kidney disease. PMID- 26501475 TI - Manifestation of West Nile Encephalitis in Infancy. PMID- 26501476 TI - The Protein Kinase C Inhibitor: Ruboxistaurin. AB - The isozyme protein kinase C (PKC) beta is involved in several processes that are deregulated in different retinal cell types by hyperglycemia. This family of serine/threonine-specific protein kinases comprises several different members, which differ in their structure, cofactor requirement and substrate specificity. Therefore, PKCbeta was considered a valuable target for therapeutic intervention. However, there is now evidence that even inhibition of different PKC isozymes is not sufficient to normalize vascular endothelial growth factor (VEGF)-induced barrier damage of retinal endothelial cells. On the other hand, PKCbeta inhibition prevents hyperglycemia-induced VEGF expression in retinal pericytes, suggesting that PKC inhibitors should be administered before increased VEGF expression is established in the diabetic retina. Although initial studies have indicated that the treatment of diabetic patients with ruboxistaurin, a specific inhibitor of PKCbeta, may reduce visual loss in patients with diabetic retinopathy, the overall benefit seems to be small. PMID- 26501477 TI - NETBAGs: a network-based clustering approach with gene signatures for cancer subtyping analysis. AB - AIM: To evaluate gene signature and network-based approach for cancer subtyping and classification. MATERIALS & METHODS: Here we introduced NETwork Based clustering Approach with Gene signatures (NETBAGs) algorithm, which clustered samples based on gene signatures and identified molecular markers based on their significantly expressed gene network profiles. RESULTS: Applying NETBAGs to multiple independent breast cancer datasets, we demonstrated that the clustering results were highly associated with the clinical subtypes and clearly revealed the genomic diversity of breast cancer samples. CONCLUSION: NETBAGs algorithm is able to classify samples by their genomic signatures into clinically significant phenotypes so that potential biomarkers can be identified. The approach may contribute to cancer research and clinical study of complex diseases. PMID- 26501478 TI - Epilepsy in Punjab (India): A Population-Based Epidemiologic Study. AB - AIMS: To assess the prevalence of epilepsy in a rural area adjoining a city. METHODS: A door-to-door, cross-sectional epidemiological survey was carried out covering an entire rural population of 103,693 people. RESULTS: Crude period and point prevalence rates for active epilepsy were 7.67 and 7.44 per 1,000 respectively. Crude incidence rate was 60.76 per 100,000 during the year 2007. Mean, SD, median and variance were 17.2, 16, 13 and 257.6 years respectively for age at onset of active epilepsy patients. The overall prevalence patterns among males and females were not significantly different. Active epilepsy cases (n = 795) included electro-clinical syndromes and constellations (n = 117, 14.7%), symptomatic epilepsy (n = 153, 19.2%), epilepsy due to unknown cause (n = 513, 64.5%) and dual diagnosis (n = 12, 1.5%). CONCLUSIONS: The present study showed that the prevalence rate, in the rural area adjoining a city, was comparable to that of the urban area and significantly less than that of the remote rural area as described by another study. Age- and sex-specific prevalence and incidence rates were similar to the rates reported by other studies. The reason for a lower number of symptomatic cases to be reported, per this study, may be due to lack of neuroimaging. PMID- 26501479 TI - Molecular marker development and genetic diversity exploration by RNA-seq in Platycodon grandiflorum. AB - Platycodon grandiflorum, generally known as the bellflower or balloon flower, is the only species in the genus Platycodon of the family Campanulaceae. Platycodon plants have been traditionally used as a medicinal crop in East Asia for their antiphlogistic, antitussive, and expectorant properties. Despite these practical uses, marker-assisted selection and molecular breeding in platycodons have lagged due to the lack of genetic information on this genus. In this study, we performed RNA-seq analysis of three platycodon accessions to develop molecular markers and explore genetic diversity. First, genic simple sequence repeats (SSRs) were retrieved and compared; dinucleotide motifs were the most abundant repeats (39% 40%) followed by trinucleotide (25%-31%), tetranucleotide (1.5%-1.9%), and pentanucleotide (0.3%-1.0%) repeats. The result of in silico SSR analysis, three SSR markers were detected and showed possibility to distinguish three platycodon accessions. After several filtering procedures, 180 single nucleotide polymorphisms (SNPs) were used to design 40 cleaved amplified polymorphic sequence (CAPS) markers. Twelve of these PCR-based markers were validated as highly polymorphic and utilized to investigate genetic diversity in 21 platycodon accessions collected from various regions of South Korea. Collectively, the 12 markers yielded 35 alleles, with an average of 3 alleles per locus. Polymorphism information content (PIC) values ranged from 0.087 to 0.693, averaging 0.373 per locus. Since platycodon genetics have not been actively studied, the sequence information and the DNA markers generated from our research have the potential to contribute to further genetic improvements, genomic studies, and gene discovery in this genus. PMID- 26501480 TI - Semiparametric methods to contrast gap time survival functions: Application to repeat kidney transplantation. AB - Times between successive events (i.e., gap times) are of great importance in survival analysis. Although many methods exist for estimating covariate effects on gap times, very few existing methods allow for comparisons between gap times themselves. Motivated by the comparison of primary and repeat transplantation, our interest is specifically in contrasting the gap time survival functions and their integration (restricted mean gap time). Two major challenges in gap time analysis are non-identifiability of the marginal distributions and the existence of dependent censoring (for all but the first gap time). We use Cox regression to estimate the (conditional) survival distributions of each gap time (given the previous gap times). Combining fitted survival functions based on those models, along with multiple imputation applied to censored gap times, we then contrast the first and second gap times with respect to average survival and restricted mean lifetime. Large-sample properties are derived, with simulation studies carried out to evaluate finite-sample performance. We apply the proposed methods to kidney transplant data obtained from a national organ transplant registry. Mean 10-year graft survival of the primary transplant is significantly greater than that of the repeat transplant, by 3.9 months (p=0.023), a result that may lack clinical importance. PMID- 26501481 TI - Fusion Proteins: Aflibercept (VEGF Trap-Eye). AB - Vascular endothelial growth factor (VEGF) inhibitors currently used to treat eye diseases have included monoclonal antibodies, antibody fragments, and an aptamer. A different method of achieving VEGF blockade in retinal diseases includes the concept of a cytokine trap. Cytokine traps are being evaluated for the treatment of various diseases that are driven by excessive cytokine levels. Traps, such as VEGF Trap, consist of two extracellular cytokine receptor domains fused together to form a human IgG. Aflibercept (VEGF Trap-Eye) is a soluble fusion protein which combines ligand-binding elements taken from the extracellular components of VEGF receptor (VEGFR)-1 and VEGFR-2 fused to the Fc portion of IgG. This protein contains all human amino-acid sequences, which minimizes the potential for immunogenicity in human patients. The chapter will summarize the chemical properties of aflibercept and the various studies that have demonstrated a role of aflibercept in the management of retinal vascular diseases such as neovascular age-related macular degeneration, diabetic retinopathy, macular edema, and retinal vein occlusion. PMID- 26501482 TI - Successful Right Hemihepatectomy for a Patient with Right-Sided Round Ligament. AB - Right-sided round ligament (RSRL) is a rare congenital anomaly that is strongly associated with a number of intrahepatic vascular anomalies. Here, we report a 77 year-old male case of hepatolithiasis associated with RSRL for which resection was performed using right hemi-hepatectomy (RHH). Intraoperative ultrasonography revealed that the portal branch of segment 4 ramified from the right anterior portal branch, and the patient was diagnosed as having RSRL. To decide the resection line, the portal branch of segment 4 was punctured and stained with indigo carmine under ultrasonographic guidance, clearly demonstrating the demarcation line between the right and left hemiliver. RHH was then carried out successfully without injuring the portal branch of segment 4. PMID- 26501483 TI - Self-Expanding Metallic Stents for the Management of Emergency Malignant Large Bowel Obstruction: a Systematic Review. AB - OBJECTIVES: This paper evaluates the safety and effectiveness of self-expanding metallic stents (SEMS) for the management of emergency malignant colorectal obstruction in patients otherwise requiring multi-stage surgery. No systematic review has been conducted comparing SEMS to only multi-stage surgery. METHODS: Bibliographic databases, including Cochrane, PubMed, EMBASE, and CINAHL, were searched in September 2011 and repeated in November 2013. A pre-determined protocol outlined the study inclusion and appraisal. RESULTS: Forty articles were included, seven compared SEMS to multi-stage surgery. Included studies were of low to moderate quality. Bowel perforation was the most severe stent-related complication, while tumor- and stent-related events occurred most frequently. No significant differences in rates of obstruction relief were reported between treatments, and results regarding relative quality of life were inconclusive. SEMS recipients progressed to elective surgery sooner and required shorter post procedural hospital stays, but commonly required re-intervention. SEMS provided enduring palliative relief of obstruction, with comparable survival longevity between treatments. Conclusion: SEMS placement is a viable alternative to multi stage surgery, providing patients with benefits as a bridge-to-surgery and relief of obstruction in a palliative context, with minimal differences in clinical success and safety compared to multi-stage surgery. PMID- 26501484 TI - An Independent Evaluation of a Novel Peptide Mimetic, Brilacidin (PMX30063), for Ocular Anti-infective. AB - OBJECTIVE: Brilacidin (BRI), a novel defensin mimetic, was evaluated as an ocular anti-infective. METHODS: In vitro: Potency based on MIC90s was compared for 50 Staphylococcus aureus (SA), 50 Staphylococcus epidermidis (SE), and 25 each of Streptococcus pneumonia (SP), Streptococcus viridans (SV), Moraxella (MS), Haemophilus influenzae (HI), Pseudomonas aeruginosa (PA), and Serratia marcescens (SM). In vivo: Using established methods, ocular toxicity was graded with Draize testing. For efficacy testing, both corneas of 24 rabbits were infected with methicillin-resistant S. aureus (MRSA), whereas the corneal epithelium was removed in the left eye. After 4 h, 21 topical drops over 5 h were administered to 4 groups: BRI 0.5%, vancomycin (VAN) 5%, saline, and no treatment. The eyes were clinically graded and the corneas were harvested for colony counts. RESULTS: In vitro: Both SA and SE had the lowest minimum inhibitory concentrations among the bacterial groups. The MIC90s to BRI for SP, SV, MS, HI, PA, and SM were 4, 32, 256, 32, 16, and 128-fold higher, respectively, than SA and SE. In vivo: Draize testing determined BRI 0.5% to be minimally irritating. For abraded corneas, BRI was not statistically different from VAN for reducing MRSA. BRI was bactericidal. For intact corneas, VAN reduced more CFU than BRI. BRI reduced CFU in abraded corneas more than intact corneas suggesting poor corneal penetration. CONCLUSIONS: BRI has Gram-positive in vitro activity; topical BRI 0.5% was minimally irritating; and BRI 0.5% was equally efficacious as VAN in a MRSA keratitis model when the corneal epithelium was removed. PMID- 26501485 TI - The Role of Follicular Helper T Cell Molecules and Environmental Influences in Autoantibody Production and Progression to Inflammatory Arthritis in Mice. AB - OBJECTIVE: Antibody-mediated autoimmunity involves cognate interactions between self-reactive T cells and B cells during germinal center (GC) reactions. The aim of this study was to determine the role of essential follicular helper T (Tfh) cell molecules (CXCR5, signaling lymphocytic activation molecule-associated protein) on autoreactive CD4+ cells and the role of certain environmental influences that may determine GC-driven autoantibody production and arthritis development. METHODS: We transferred self-reactive CD4+ cells from KRN-Tg mice into recipient mice, which induced autoantibodies and autoinflammatory arthritis. This model allowed manipulation of environmental effects, such as inflammation, and use of transferred cells that were genetically deficient in important Tfh cell-associated molecules. RESULTS: A deficiency of signaling lymphocytic activation molecule-associated protein (SAP) in CD4+ cells from KRN-Tg mice completely protected against arthritis, indicating that stable T cell-B cell interactions are required for GC formation, autoantibody production, and arthritis induction. In contrast, a CXCR5 deficiency in CD4+ cells from KRN-Tg mice still induced disease when these cells were transferred into wild-type mice, suggesting that T cell help for B cells could rely on other migration mechanisms. However, various manipulations influenced this system, including elimination of bystander effects through use of CD28(-/-) recipient mice (reduced disease) or use of inflammation-inducing Freund's complete adjuvant (progression to arthritis). We also examined the capacity of preexisting GCs with a nonautoimmune specificity to co-opt autoimmune T cells and observed no evidence for any influence. CONCLUSION: In addition to the quality and quantity of cognate CD4+ cell help, external factors such as inflammation and noncognate CD4+ cell bystander activation trigger autoimmunity by shaping events within autoimmune GC responses. SAP is an essential molecule for autoimmune antibody production, whereas the importance of CXCR5 varies depending on the circumstances. PMID- 26501486 TI - Ivabradine in Combination with Metoprolol Improves Symptoms and Quality of Life in Patients with Stable Angina Pectoris: A post hoc Analysis from the ADDITIONS Trial. AB - OBJECTIVES: Elevated heart rate can increase myocardial oxygen demand and reduce myocardial perfusion, provoking myocardial ischemia and angina symptoms. We evaluated adding ivabradine to the therapy of patients on metoprolol. METHODS: ADDITIONS (prActical Daily efficacy anD safety of Procoralan(r) In combinaTION with betablockerS) was a multicenter, 4-month, noninterventional, prospective, open-label trial that involved stable-angina patients. Along with metoprolol, patients received ivabradine (5 or 7.5 mg, b.i.d.). We investigated the effect of ivabradine on heart rate, angina attacks, nitrate consumption, quality of life (QoL) and tolerability as well as the influence of baseline heart rate. RESULTS: Heart rate fell by 19.7 +/- 11.2 bpm, with an 8-fold decrease in weekly angina attacks (1.7 +/- 2.2 to 0.2 +/- 0.7) and nitrate consumption (2.4 +/- 3.4 to 0.3 +/- 0.9). Patient numbers in Canadian Cardiovascular Society class I more than doubled (i.e. from 29 to 65%) and QoL improved (the EQ-5D index and visual analog scale scores rose from 0.68 +/- 0.27 to 0.84 +/- 0.20 and 58.1 +/- 18.4 to 72.2 +/- 15.5 mm, respectively). The effect of ivabradine was greater in patients with a baseline heart rate >=70 bpm (mean reduction in heart rate -21.2 +/- 10.4 bpm, with a relative reduction in angina attacks and short-acting nitrate consumption of 87.1 and 87.2%, respectively). CONCLUSIONS: Ivabradine combined with metoprolol safely and effectively reduces heart rate, angina attacks and nitrate use, and improves QoL in stable-angina patients. PMID- 26501487 TI - Role of EFNB2/EPHB4 signaling in spiral artery development during pregnancy: An appraisal. AB - EFNB2 and EPHB4, which belong to a large tyrosine kinase receptor superfamily, are molecular markers of arterial and venous blood vessels, respectively. EFNB2/EPHB4 signaling plays an important role in physiological and pathological angiogenesis, and its role in tumor vessel development has been extensively studied. Pregnancy and tumors share similar features, including continuous cell proliferation and increased demand for a blood supply. Our previous studies showed that Efnb2 and Ephb4 were expressed dynamically in the spiral arteries, uterine natural killer cells, and trophoblasts during mouse gestation Days 6.5 12.5. Moreover, uterine natural killer cells and trophoblasts are required for the modification of spiral arteries. Oxygen tension within the pregnant uterus, which contributes to the vascular development, also affects EFNB2 and EPHB4 expression. Considering the role of EFNB2/EPHB4 signaling in embryonic and tumor vascular development, and its dynamic expression in the decidua and placenta, we hypothesize that EFNB2 and EPHB4 are involved in the regulation of spiral artery remodeling. Investigating this hypothesis will help clarify the mechanisms of pathological pregnancy that may underlie abnormal spiral artery development. PMID- 26501488 TI - Inconsistent Data Resources Weaken the Quality of Research Results. PMID- 26501489 TI - New 3-Tiered Circumferential Resection Margin Criteria in Esophageal Squamous Cell Carcinoma. AB - OBJECTIVE: We aimed to investigate the optimal cutoff value of circumferential resection margin (CRM) of esophageal squamous cell carcinoma (ESCC) in patients who underwent radical esophagectomy. BACKGROUND: Tumor involvement of a CRM in ESCC has not been clearly defined. METHODS: We reviewed 479 pT3 ESCC patients to find the optimal cutoff point of distance from CRM in addition to 0 MUm for discriminating survival time. RESULTS: The partitions at and near the 500 MUm distance from CRM generated the largest log-rank statistics (P = 0.0086). Therefore, we added 500 MUm as an additional cutoff value for a positive CRM. Compared to patients with CRM greater than 500 MUm, patients with CRM 0 MUm showed worse overall survival (P < 0.001) and progression-free survival (P < 0.001), followed by patients with 0 to 500 MUm (P = 0.008 and 0.066, respectively). In multivariable analyses, overall survival differences remained significant [0 < CRM <= 500 MUm vs CRM > 500 MUm, hazards ratio (HR) = 1.875, 97.5% CI: 1.243-2.829, P = 0.002; CRM = 0 MUm vs CRM > 500 MUm, HR = 2.666, 97.5% CI: 1.745-4.076, P < 0.001]. In comparison of criteria from the College of American Pathologists, the Royal College of Pathologists, and this study, HRs of positive CRM (95% CI, P-value) were 1.969 (1.501-2.584, P < 0.001), 1.384 (1.039 1.844, P = 0.027), and 1.696 (1.342-2.143, P < 0.001), respectively. CONCLUSIONS: In patients with ESCC, we developed new, 3-tiered CRM criteria providing more detailed prognostic information than the 2-tiered criteria. PMID- 26501490 TI - Racial/Ethnic Disparities in Perioperative Outcomes of Major Procedures: Results From the National Surgical Quality Improvement Program. AB - OBJECTIVE: To determine the association between race/ethnicity and perioperative outcomes in individuals undergoing major oncologic and nononcologic surgical procedures in the United States. BACKGROUND: Prior work has shown that there are significant racial/ethnic disparities in perioperative outcomes after several types of major cardiac, general, vascular, orthopedic, and cancer surgical procedures. However, recent evidence suggests attenuation of these racial/ethnic differences, particularly at academic institutions. METHODS: We utilized the American College of Surgeons National Surgical Quality Improvement Program database to identify 142,344 patients undergoing one of the 16 major cancer and noncancer surgical procedures between 2005 and 2011. RESULTS: Eighty-five percent of the cohort was white, with black and Hispanic individuals comprising 8% and 4%, respectively. In multivariable analyses, black patients had greater odds of experiencing prolonged length of stay after 10 of the 16 procedures studied (all P < 0.05), though there was no disparity in odds of 30-day mortality after any surgery. Hispanics were more likely to experience prolonged length of stay after 5 surgical procedures (all P < 0.04), and were at greater odds of dying within 30 days after colectomy, heart valve repair/replacement, or abdominal aortic aneurysm repair (all P < 0.03). Fewer disparities were observed for Hispanics, than for black patients, and also for cancer, than for noncancer surgical procedures. CONCLUSIONS: Important racial/ethnic disparities in perioperative outcomes were observed among patients undergoing major cancer and noncancer surgical procedures at American College of Surgeons National Surgical Quality Improvement Program institutions. There were fewer disparities among individuals undergoing cancer surgery, though black patients, in particular, were more likely to experience prolonged length of stay. PMID- 26501491 TI - A Cofacially Stacked Electron-Deficient Small Molecule with a High Electron Mobility of over 10 cm(2) V(-1) s(-1) in Air. AB - A strong, electron-deficient small molecule, F4 -BDOPV, has a lowest unoccupied molecular orbital (LUMO) level down to -4.44 eV and exhibits cofacial packing in single crystals. These features provide F4 -BDOPV with good ambient stability and large charge-transfer integrals for electrons, leading to a high electron mobility of up to 12.6 cm(2) V(-1) s(-1) in air. PMID- 26501492 TI - THE INSTITUTE OF MEDICINE (IOM) SETS A FRAMEWORK FOR EVIDENCE-BASED STANDARDS FOR PSYCHOTHERAPY. PMID- 26501493 TI - Immunohistochemical determination of the extracellular matrix modulation in a rat model of choline-deprived myocardium: the effects of carnitine. AB - Choline has been identified as an essential nutrient with crucial role in many vital biological functions. Recent studies have demonstrated that heart dysfunction can develop in the setting of choline deprivation even in the absence of underlying heart disease. Matrix metalloproteinases (MMPs) are responsible for extracellular matrix degradation, and the dysregulation of MMP-2 and MMP-9 has been involved in the pathogenesis of various cardiovascular disorders. The aim of the study was to investigate the role of MMPs and their inhibitors (TIMPs), in the pathogenesis of choline deficiency-induced cardiomyopathy, and the way they are affected by carnitine supplementation. Male Wistar Albino adult rats were divided into four groups and received standard or choline-deficient diet with or without L-carnitine in drinking water (0.15% w/v) for 1 month. Heart tissue immunohistochemistry for MMP-2, MMP-9, TIMP-1, and TIMP-2 was performed. Choline deficiency was associated with suppressed immunohistochemical expression of MMP-2 and an increased expression of TIMP-2 compared to control, while it had no impact on TIMP-1. MMP-9 expression was decreased without, however, reaching statistical significance. Carnitine did not affect MMP-2, MMP-9, TIMP-1 or TIMP-2 expression. The pattern of TIMP and MMP modulation observed in a choline deficiency setting appears to promote fibrosis. Carnitine, although shown to suppress fibrosis, does not seem to affect MMP-2, MMP-9, TIMP-1 or TIMP-2 expression. Further studies will be required to identify the mechanism underlying the beneficial effects of carnitine. PMID- 26501495 TI - Can model Hamiltonians describe the electron-electron interaction in pi conjugated systems? PAH and graphene. AB - Model Hamiltonians have been, and still are, a valuable tool for investigating the electronic structure of systems for which mean field theories work poorly. This review will concentrate on the application of Pariser-Parr-Pople (PPP) and Hubbard Hamiltonians to investigate some relevant properties of polycyclic aromatic hydrocarbons (PAH) and graphene. When presenting these two Hamiltonians we will resort to second quantisation which, although not the way chosen in its original proposal of the former, is much clearer. We will not attempt to be comprehensive, but rather our objective will be to try to provide the reader with information on what kinds of problems they will encounter and what tools they will need to solve them. One of the key issues concerning model Hamiltonians that will be treated in detail is the choice of model parameters. Although model Hamiltonians reduce the complexity of the original Hamiltonian, they cannot be solved in most cases exactly. So, we shall first consider the Hartree-Fock approximation, still the only tool for handling large systems, besides density functional theory (DFT) approaches. We proceed by discussing to what extent one may exactly solve model Hamiltonians and the Lanczos approach. We shall describe the configuration interaction (CI) method, a common technology in quantum chemistry but one rarely used to solve model Hamiltonians. In particular, we propose a variant of the Lanczos method, inspired by CI, that has the novelty of using as the seed of the Lanczos process a mean field (Hartree-Fock) determinant (the method will be named LCI). Two questions of interest related to model Hamiltonians will be discussed: (i) when including long-range interactions, how crucial is including in the Hamiltonian the electronic charge that compensates ion charges? (ii) Is it possible to reduce a Hamiltonian incorporating Coulomb interactions (PPP) to an 'effective' Hamiltonian including only on-site interactions (Hubbard)? The performance of CI will be checked on small molecules. The electronic structure of azulene and fused azulene will be used to illustrate several aspects of the method. As regards graphene, several questions will be considered: (i) paramagnetic versus antiferromagnetic solutions, (ii) forbidden gap versus dot size, (iii) graphene nano-ribbons, and (iv) optical properties. PMID- 26501494 TI - Employment and income losses among cancer survivors: Estimates from a national longitudinal survey of American families. AB - BACKGROUND: Cancer presents a substantial hardship for patients and their families in multiple domains beyond health and survival. Relatively little is known about the economic impact of cancer. The authors present estimates of the aggregate effects of a cancer diagnosis on employment and income in a prospective, nationally representative sample of US adults. METHODS: The authors used data from the 1990 through 2009 waves of the Panel Study of Income Dynamics, a nationally representative, prospective, population-based observational study with high-quality individual and family-level economic information. Age-adjusted, sex-stratified, individual fixed-effects regression models were used to derive estimates of the impact of cancer on employment, hours worked, individual income, and total family income. RESULTS: Significant effects of cancer on all 4 outcomes were observed. The probability of a cancer patient being employed dropped by almost 10 percentage points, and hours worked declined by up to 200 hours in the first year after diagnosis. Annual labor-market earnings dropped almost 40% within 2 years after diagnosis and remained low, whereas total family income declined by 20%, although it recovered within 4 years after the diagnosis. These economic impacts on survivors were driven by effects among men; the effects among women largely were not statistically significant. CONCLUSIONS: A cancer diagnosis has substantial effects on the economic well-being of affected adults and their families. With the increasing number of cancer survivors in the US population, there is a growing need for examining the long-term implications for economic well-being and ways to mitigate the economic hardship associated with cancer. PMID- 26501496 TI - Evaluation of a school-based treatment program for young adolescents with ADHD. AB - OBJECTIVE: This study compared 2 school-based training interventions for adolescents with attention deficit-hyperactivity disorder (ADHD): the Challenging Horizons Program-after school version (CHP-AS) and Challenging Horizons Program mentoring version (CHP-M) with each other and with a community care (CC) condition. METHOD: Participants were 326 students (sixth through eighth grade) diagnosed with ADHD. Interventions were conducted for 1 academic year. CHP-AS occurred twice weekly and included organization, social functioning, and academic study skills interventions. In CHP-M, students were paired with a mentor (e.g., teacher) who was trained by a consultant and delivered a subset of the CHP-AS interventions during school. No direct intervention was provided in CC. Participants were assessed at pretreatment, 4 occasions during the intervention year, posttreatment, and at a 6-month follow-up. RESULTS: Intent-to-treatment analyses using hierarchical linear modeling to compare outcomes between the 3 conditions indicate participation in the CHP-AS intervention is associated with moderate effect size improvements in parent-rated organization and time management skills, homework problems, and ADHD symptoms of inattention, and with small improvements in overall academic functioning and grade point average (GPA). These improvements were in comparison to CC and to CHP-M. Gains were sustained into the next school year and even increased in magnitude for several of the measures. CONCLUSIONS: The CHP-AS program leads to significant benefits for adolescents with ADHD compared with the services provided in the CHP-M and CC. The persistence of improvements over time supports the use of training interventions that teach skills for adolescents. PMID- 26501497 TI - Effects of relationship education on couple communication and satisfaction: A randomized controlled trial with low-income couples. AB - OBJECTIVE: Although preventive educational interventions for couples have been examined in more than 100 experimental studies, the value of this work is limited by reliance on economically advantaged populations and by an absence of data on proposed mediators and moderators. Data from the Supporting Healthy Marriage Project-a randomized, controlled trial of relationship education for couples living with low incomes-were therefore analyzed to test whether intervention effects on relationship satisfaction would be mediated by observational assessments of relationship communication and whether any such effects would be moderated by couples' pretreatment risk. METHOD: Within the larger sample of Supporting Healthy Marriage Project couples randomized to a relationship education or no-treatment control condition, the present analyses focus on the 1,034 couples who provided (a) data on sociodemographic risk at baseline, (b) observational data on couple communication 12 months after randomization, and (c) reports of relationship satisfaction 30 months after randomization. RESULTS: Intervention couples reported higher satisfaction at 30 months than control couples, regardless of their level of pretreatment risk. Among higher risk couples, the intervention improved observed communication as well. Contrary to prediction, treatment effects on satisfaction were not mediated by improvements in communication, and improvements in communication did not translate into greater satisfaction. CONCLUSIONS: Relationship education programs produce small improvements in relationship satisfaction and communication, particularly for couples at elevated sociodemographic risk. The absence of behavioral effects on satisfaction indicates, however, that the mechanisms by which couples may benefit from relationship education are not yet well understood. PMID- 26501498 TI - Partner accommodation moderates treatment outcomes for couple therapy for posttraumatic stress disorder. AB - OBJECTIVE: Partner accommodation of posttraumatic stress disorder (PTSD) symptoms (i.e., altering one's own behaviors to minimize patient distress and/or relationship conflict due to patients' PTSD symptoms) has been shown to be positively associated with patient and partner psychopathology and negatively associated with patient and partner relationship satisfaction cross-sectionally. However, the prognostic value of partner accommodation in treatment outcomes is unknown. The goals of the present study were to determine if partner accommodation decreases as a function of couple therapy for PTSD and if pretreatment partner accommodation moderates the efficacy of couple therapy for PTSD. METHOD: Thirty-nine patients with PTSD and their intimate partners (n = 39) were enrolled in a randomized controlled trial of cognitive-behavioral conjoint therapy (CBCT) for PTSD (Monson & Fredman, 2012) and received CBCT for PTSD immediately or after 3 months of waiting. Blinded assessors determined clinician rated PTSD symptoms and patient-rated PTSD and depressive symptoms and relationship satisfaction at baseline, midtreatment/4 weeks of waiting, and posttreatment/12 weeks of waiting. RESULTS: Contrary to expectation, partner accommodation levels did not change over time for either treatment condition. However, baseline partner accommodation significantly moderated treatment outcomes. Higher levels of partner accommodation were associated with greater improvements in PTSD, depressive symptoms, and relationship satisfaction among patients receiving CBCT for PTSD compared with waiting list. At lower levels of partner accommodation, patients in both groups improved or remained at low levels of these outcomes. CONCLUSIONS: Individuals with PTSD who have more accommodating partners may be particularly well-suited for couple therapy for PTSD. PMID- 26501502 TI - When does the test-study-test sequence optimize learning and retention? AB - In educational learning contexts, unlike typical contemporary laboratory paradigms, students have repeated opportunities to study and learn target material, thereby potentially allowing different sequences of testing and studying. We investigated learning and retention after several plausible sequences that were patterned on a classic memory paradigm. After initially reading a research methods text, 2 days later in 1 condition participants repeatedly restudied the material 3 times (SSS), in another condition they engaged in a test-restudy-test sequence (TST), and in a third condition participants repeatedly tested on the studied material (3 times: TTT). Participants received a final test 5 days later. In Experiment 1, both TST and TTT produced better final performance than did SSS; however, TST was not better than TTT. In Experiment 2 the TST condition was altered so that after the first test, correct/incorrect feedback was provided and the test and feedback were available during the study phase. With this protocol, TST produced better learning and retention than did TTT or SSS. These findings suggest possible critical aspects regarding test feedback and the availability of previous tests for helping students to optimize their restudy efforts after low- or no-stakes quizzes. PMID- 26501499 TI - A brief manualized treatment for problematic caffeine use: A randomized control trial. AB - OBJECTIVE: The goal of the present investigation was to develop and test a brief therapist-guided manualized treatment for problematic caffeine use, including cognitive-behavioral strategies and 5 weeks of progressively decreased consumption. METHOD: Individuals seeking treatment for problematic caffeine use (mean daily caffeine consumption of 666 mg at baseline) were randomized using a waitlist-control design to receive immediate treatment (N = 33) or delayed treatment (~6 weeks later; N = 34). A 1-hr treatment session designed to help individuals quit or reduce caffeine consumption was provided by a trained counselor along with a take-home booklet. After the treatment session, participants completed daily diaries of caffeine consumption for 5 weeks. They returned for follow-up assessments at 6, 12, and 26 weeks and had a telephone interview at 52-weeks posttreatment. RESULTS: Treatment resulted in a significant reduction in self-reported caffeine use and salivary caffeine levels. No significant posttreatment increases in caffeine use were observed for up to 1 year follow-up. Comparisons to the waitlist-control condition revealed that reductions in caffeine consumption were due to treatment and not the passing of time, with a treatment effect size of R2 = .35 for the model. CONCLUSION: A brief 1-session manualized intervention with follow-up was efficacious at reducing caffeine consumption. Future researchers should replicate and extend these findings, as well as consider factors affecting dissemination of treatment for problematic caffeine use to those in need. PMID- 26501503 TI - The effects of timing of exposure to principles and procedural instruction specificity on learning an electrical troubleshooting skill. AB - Domain principles provided in task instructions are assumed to help performance as learners can later apply this knowledge when faced with new tasks. The goal of the research was to investigate whether the timing of the exposure to principles studying the principles before or while completing training tasks-and the specificity in the accompanying step-by-step procedural instructions would influence learning to troubleshoot a simulated electrical circuit. The results of a pilot study suggested that timing of principle exposure and specificity might interact. This was investigated by comparing the performance of 4 groups of participants (n = 24) who received either general or detailed procedural instructions and were either exposed to the principles before or during the training. The results showed that studying the principles before training benefited test task performance when the procedural instructions were detailed but not when they were general. The results also showed that using general procedural instructions benefited test task performance while using detailed procedural instructions benefited training task performance. Overall the results reveal how the learning situation as a whole must be considered when determining the efficacy of instructional materials, and how conditions can be created where principles enhance learning. PMID- 26501505 TI - Cartilage Strain Distributions Are Different Under the Same Load in the Central and Peripheral Tibial Plateau Regions. AB - There is increasing evidence that the regional spatial variations in the biological and mechanical properties of articular cartilage are an important consideration in the pathogenesis of knee osteoarthritis (OA) following kinematic changes at the knee due to joint destabilizing events (such as an anterior cruciate ligament (ACL) injury). Thus, given the sensitivity of chondrocytes to the mechanical environment, understanding the internal mechanical strains in knee articular cartilage under macroscopic loads is an important element in understanding knee OA. The purpose of this study was to test the hypothesis that cartilage from the central and peripheral regions of the tibial plateau has different internal strain distributions under the same applied load. The internal matrix strain distribution for each specimen was measured on osteochondral blocks from the tibial plateau of mature ovine stifle joints. Each specimen was loaded cyclically for 20 min, after which the specimen was cryofixed in its deformed position and freeze fractured. The internal matrix was viewed in a scanning electron microscope (SEM) and internal strains were measured by quantifying the deformation of the collagen fiber network. The peak surface tensile strain, maximum principal strain, and maximum shear strain were compared between the regions. The results demonstrated significantly different internal mechanical strain distributions between the central and peripheral regions of tibial plateau articular cartilage under both the same applied load and same applied nominal strain. These differences in the above strain measures were due to differences in the deformation patterns of the collagen network between the central and peripheral regions. Taken together with previous studies demonstrating differences in the biochemical response of chondrocytes from the central and peripheral regions of the tibial plateau to mechanical load, the differences in collagen network deformation observed in this study help to provide a fundamental basis for understanding the association between altered knee joint kinematics and premature knee OA. PMID- 26501507 TI - Cognitive Biases in Clinical Decision Making: A Primer for the Practicing Dermatologist. PMID- 26501506 TI - Attitudes of Research Participants and the General Public Regarding Disclosure of Alzheimer Disease Research Results. AB - IMPORTANCE: Results of Alzheimer disease (AD) research assessments typically are not disclosed to participants. Recent research has suggested interest in disclosure, but, to our knowledge, few studies have accounted for awareness of potential benefits and limitations of disclosure. OBJECTIVE: To determine the attitudes of cognitively normal research participants and members of the general public regarding disclosure of AD research results. DESIGN, SETTING, AND PARTICIPANTS: Participants in a longitudinal aging study (Alzheimer Disease Research Center [ADRC]) were given preintervention and postintervention surveys about disclosure attitudes. In a general public sample (The American Panel Survey), participants responded to a similar survey about disclosure attitudes. INTERVENTIONS: Participants in the ADRC sample were randomly assigned to a group (n = 119) that read an education intervention about the usefulness of AD biomarkers or to a placebo group (n = 100) that read as its intervention general information about the ADRC. Participants in the general public sample read a brief vignette describing participation in a longitudinal AD study. MAIN OUTCOME AND MEASURE: Interest in disclosure of AD research results. RESULTS: Cognitively normal ADRC participants (n = 219) were 60.7% (n = 133) female, 83.6% (n = 183) of white race, and reported a mean of 15.91 years of education. Twenty-nine individuals refused participation. The American Panel Survey participants (n = 1418) indicated they did not have AD and were 50.5% (n = 716) female, 76.7% (n = 1087) of white race, and reported a mean of 13.85 years of education. Overall, 77.6% of eligible participants (1583 of 2041) completed the survey in July 2014. Interest in disclosure was high among the ADRC participants (55.1% [119 of 216] were "extremely interested"). Viewing the education intervention predicted lower interest in disclosure (odds ratio, 2.01; 95% CI, 1.15-3.53; P = .02). High subjective risk of AD, a family history of AD, and minimal attendance at research meetings were associated with high interest after the intervention. In the general public, interest was lower overall (12.5% [174 of 1389] were "extremely interested"), but the subset of participants most likely to join an AD research study reported higher interest (43.5% [40 of 92] were extremely interested). CONCLUSIONS AND RELEVANCE: Experience with AD appears to increase interest in disclosure of AD research results. Learning about potential limitations of disclosure somewhat tempered interest. These findings should inform the development of disclosure policies for asymptomatic individuals in AD studies. PMID- 26501508 TI - Cerebral Straight Sinus Thrombosis: An Unusual Cause of Confusion. PMID- 26501509 TI - Treating Influenza With Neuraminidase Inhibitors: What Is the Evidence? PMID- 26501510 TI - Emixustat and Lampalizumab: Potential Therapeutic Options for Geographic Atrophy. AB - Two novel classes of medications are currently under extensive investigation for the treatment of dry age-related macular degeneration (AMD). Emixustat, an orally administered visual cycle inhibitor, and lampalizumab, an intravitreally administered monoclonal body directed against complement factor D, have shown promise in phase 2 clinical trials in the treatment of nonneovascular (dry) AMD. Lampalizumab is currently being evaluated in a large, multicenter, phase 3 clinical trial for dry AMD - geographic atrophy. PMID- 26501511 TI - Voice Disorder Management Competencies: A Survey of School-Based Speech-Language Pathologists in Nebraska. AB - PURPOSE: The purpose of this survey was to determine the self-perceived competence levels in voice disorders of practicing school-based speech-language pathologists (SLPs) and identify correlated variables. METHOD: Participants were 153 master's level, school-based SLPs with a Nebraska teaching certificate and/or licensure who completed a survey, including demographic information and a 25-item voice disorders competency checklist. RESULTS: Findings indicated school-based SLPs did not feel particularly competent in their ability to assess and treat students with voice disorders. Only 1 response mean was higher than a "moderately competent" level. All other item means were at or below this level. Four correlations indicated positive associations with SLPs' overall self-perceived competence levels: number of continuing education activities related to voice disorders, number of clients with voice disorders in the last 3 months, percentage of time spent with clients who have voice disorders, and feelings of preparation in the area of voice disorders immediately after academic program completion. Informal comparisons to medically based SLP respondents (n = 22) were included. CONCLUSION: School-based SLPs' competence perceptions with voice disorders are consistent with the minimal levels of competence reported for other underserved or low-incidence populations. Pursuing continuing education in voice disorders is recommended at the same time as access to the population becomes available. PMID- 26501512 TI - Diabetes screening by telecentric digital holographic microscopy. AB - Diabetes is currently the world's fastest growing chronic disease and it is caused by deficient production of insulin by the endocrine pancreas or by abnormal insulin action in peripheral tissues. This results in persistent hyperglycaemia that over time may produce chronic diabetic complications. Determination of glycated haemoglobin level is currently the gold standard method to evaluate and control sustained hyperglycaemia in diabetic people. This measurement is currently made by high-performance liquid chromatography, which is a complex chemical process that requires the extraction of blood from the antecubital vein. To reduce the complexity of that measurement, we propose a fully-optical technique that is based in the fact that there are changes in the optical properties of erythrocytes due to the presence of glucose-derived adducts in the haemoglobin molecule. To evaluate these changes, we propose to perform quantitative phase maps of erythrocytes by using telecentric digital holographic microscopy. Our experiments show that telecentric digital holographic microscopy allows detecting, almost in real time and from a single drop of blood, significant differences between erythrocytes of diabetic patients and healthy patients. Besides, our phase measurements are well correlated with the values of glycated haemoglobin and the blood glucose values. PMID- 26501513 TI - Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus: U.S. Preventive Services Task Force Recommendation Statement. AB - DESCRIPTION: Update of the 2008 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for diabetes in asymptomatic adults. METHODS: The USPSTF reviewed the evidence on screening for impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes in asymptomatic, nonpregnant adults who are at average or high risk for diabetes and its complications. POPULATION: This recommendation applies to adults aged 40 to 70 years seen in primary care settings who do not have symptoms of diabetes and are overweight or obese. RECOMMENDATION: The USPSTF recommends screening for abnormal blood glucose as part of cardiovascular risk assessment in adults aged 40 to 70 years who are overweight or obese. Clinicians should offer or refer patients with abnormal blood glucose to intensive behavioral counseling interventions to promote a healthful diet and physical activity. (B recommendation). PMID- 26501514 TI - Associations Between Different Sedatives and Ventilator-Associated Events, Length of Stay, and Mortality in Patients Who Were Mechanically Ventilated. AB - BACKGROUND: Current sedation guidelines recommend avoiding benzodiazepines but express no preference for propofol vs dexmedetomidine. In addition, few data exist on whether randomized controlled trials of sedatives can be successfully generalized to routine practice, in which conditions tend to be more varied and complex. METHODS: Data regarding daily sedative exposure were gathered from all patients undergoing mechanical ventilation for >= 3 days over a 7-year period in a large academic medical center. Hazard ratios (HRs) were compared for ventilator associated events (VAEs), extubation, hospital discharge, and hospital death among patients receiving benzodiazepines, propofol, and dexmedetomidine. Proportional subdistribution hazard models with competing risks were used for analysis. All analyses were adjusted for ICU type, demographic characteristics, comorbidities, procedures, severity of illness, hypotension, oxygenation, renal function, opioids, neuroleptic agents, neuromuscular blockers, awakening and breathing trials, and calendar year. RESULTS: A total of 9,603 consecutive episodes of mechanical ventilation were evaluated. Benzodiazepines and propofol were associated with increased VAE risk, whereas dexmedetomidine was not. Propofol was associated with less time to extubation compared with benzodiazepines (HR, 1.4; 95% CI, 1.3-1.5). Dexmedetomidine was associated with less time to extubation compared with benzodiazepines (HR, 2.3; 95% CI, 2.0-2.7) and propofol (HR, 1.7; 95% CI, 1.4-2.0), but relatively few dexmedetomidine exposures were available for analysis. There were no differences between any two agents in HRs for hospital discharge or mortality. CONCLUSIONS: In this large, real-world cohort, propofol and dexmedetomidine were associated with less time to extubation compared with benzodiazepines, but dexmedetomidine was also associated with less time to extubation vs propofol. These possible differences merit further study. PMID- 26501515 TI - Whole-animal functional and developmental imaging with isotropic spatial resolution. AB - Imaging fast cellular dynamics across large specimens requires high resolution in all dimensions, high imaging speeds, good physical coverage and low photo-damage. To meet these requirements, we developed isotropic multiview (IsoView) light sheet microscopy, which rapidly images large specimens via simultaneous light sheet illumination and fluorescence detection along four orthogonal directions. Combining these four views by means of high-throughput multiview deconvolution yields images with high resolution in all three dimensions. We demonstrate whole animal functional imaging of Drosophila larvae at a spatial resolution of 1.1-2.5 MUm and temporal resolution of 2 Hz for several hours. We also present spatially isotropic whole-brain functional imaging in Danio rerio larvae and spatially isotropic multicolor imaging of fast cellular dynamics across gastrulating Drosophila embryos. Compared with conventional light-sheet microscopy, IsoView microscopy improves spatial resolution at least sevenfold and decreases resolution anisotropy at least threefold. Compared with existing high-resolution light-sheet techniques, IsoView microscopy effectively doubles the penetration depth and provides subsecond temporal resolution for specimens 400-fold larger than could previously be imaged. PMID- 26501516 TI - xTract: software for characterizing conformational changes of protein complexes by quantitative cross-linking mass spectrometry. AB - Chemical cross-linking in combination with mass spectrometry generates distance restraints of amino acid pairs in close proximity on the surface of native proteins and protein complexes. In this study we used quantitative mass spectrometry and chemical cross-linking to quantify differences in cross-linked peptides obtained from complexes in spatially discrete states. We describe a generic computational pipeline for quantitative cross-linking mass spectrometry consisting of modules for quantitative data extraction and statistical assessment of the obtained results. We used the method to detect conformational changes in two model systems: firefly luciferase and the bovine TRiC complex. Our method discovers and explains the structural heterogeneity of protein complexes using only sparse structural information. PMID- 26501518 TI - Challenges in Prevention of Abusive Head Trauma. PMID- 26501521 TI - Aurora Borealis: Frederic Edwin Church. PMID- 26501517 TI - Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. AB - Epigenome editing with the CRISPR (clustered, regularly interspaced, short palindromic repeats)-Cas9 platform is a promising technology for modulating gene expression to direct cell phenotype and to dissect the causal epigenetic mechanisms of gene regulation. Fusions of nuclease-inactive dCas9 to the Kruppel associated box (KRAB) repressor (dCas9-KRAB) can silence target gene expression, but the genome-wide specificity and the extent of heterochromatin formation catalyzed by dCas9-KRAB are not known. We targeted dCas9-KRAB to the HS2 enhancer, a distal regulatory element that orchestrates the expression of multiple globin genes, and observed highly specific induction of H3K9 trimethylation (H3K9me3) at the enhancer and decreased chromatin accessibility of both the enhancer and its promoter targets. Targeted epigenetic modification of HS2 silenced the expression of multiple globin genes, with minimal off-target changes in global gene expression. These results demonstrate that repression mediated by dCas9-KRAB is sufficiently specific to disrupt the activity of individual enhancers via local modification of the epigenome. PMID- 26501530 TI - Pilot Studies: A Critical but Potentially Misused Component of Interventional Research. PMID- 26501531 TI - A PIECE OF MY MIND. When Accommodation Gets Complicated. PMID- 26501532 TI - New Guidelines for Breast Cancer Screening in US Women. PMID- 26501533 TI - Naproxen With Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for Treating Acute Low Back Pain: A Randomized Clinical Trial. AB - IMPORTANCE: Low back pain (LBP) is responsible for more than 2.5 million visits to US emergency departments (EDs) annually. These patients are usually treated with nonsteroidal anti-inflammatory drugs, acetaminophen, opioids, or skeletal muscle relaxants, often in combination. OBJECTIVE: To compare functional outcomes and pain at 1 week and 3 months after an ED visit for acute LBP among patients randomized to a 10-day course of (1) naproxen + placebo; (2) naproxen + cyclobenzaprine; or (3) naproxen + oxycodone/acetaminophen. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, 3-group study was conducted at one urban ED in the Bronx, New York City. Patients who presented with nontraumatic, nonradicular LBP of 2 weeks' duration or less were eligible for enrollment upon ED discharge if they had a score greater than 5 on the Roland-Morris Disability Questionnaire (RMDQ). The RMDQ is a 24-item questionnaire commonly used to measure LBP and related functional impairment on which 0 indicates no functional impairment and 24 indicates maximum impairment. Beginning in April 2012, a total of 2588 patients were approached for enrollment. Of the 323 deemed eligible for participation, 107 were randomized to receive placebo and 108 each to cyclobenzaprine and to oxycodone/acetaminophen. Follow-up was completed in December 2014. INTERVENTIONS: All participants were given 20 tablets of naproxen, 500 mg, to be taken twice a day. They were randomized to receive either 60 tablets of placebo; cyclobenzaprine, 5 mg; or oxycodone, 5 mg/acetaminophen, 325 mg. Participants were instructed to take 1 or 2 of these tablets every 8 hours, as needed for LBP. They also received a standardized 10-minute LBP educational session prior to discharge. MAIN OUTCOMES AND MEASURES: The primary outcome was improvement in RMDQ between ED discharge and 1 week later. RESULTS: Demographic characteristics were comparable among the 3 groups. At baseline, median RMDQ score in the placebo group was 20 (interquartile range [IQR],17-21), in the cyclobenzaprine group 19 (IQR,17-21), and in the oxycodone/acetaminophen group 20 (IQR,17-22). At 1-week follow-up, the mean RMDQ improvement was 9.8 in the placebo group, 10.1 in the cyclobenzaprine group, and 11.1 in the oxycodone/acetaminophen group. Between-group difference in mean RMDQ improvement for cyclobenzaprine vs placebo was 0.3 (98.3% CI, -2.6 to 3.2; P = .77), for oxycodone/acetaminophen vs placebo, 1.3 (98.3% CI, -1.5 to 4.1; P = .28), and for oxycodone/acetaminophen vs cyclobenzaprine, 0.9 (98.3% CI, -2.1 to 3.9; P = .45). CONCLUSIONS AND RELEVANCE: Among patients with acute, nontraumatic, nonradicular LBP presenting to the ED, adding cyclobenzaprine or oxycodone/acetaminophen to naproxen alone did not improve functional outcomes or pain at 1-week follow-up. These findings do not support use of these additional medications in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01587274. PMID- 26501534 TI - Association of Tdap Vaccination With Acute Events and Adverse Birth Outcomes Among Pregnant Women With Prior Tetanus-Containing Immunizations. AB - IMPORTANCE: The Advisory Committee on Immunization Practices (ACIP) recommends the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine for pregnant women during each pregnancy, regardless of prior immunization status. However, safety data on repeated Tdap vaccination in pregnancy is lacking. OBJECTIVE: To determine whether receipt of Tdap vaccine during pregnancy administered in close intervals from prior tetanus-containing vaccinations is associated with acute adverse events in mothers and adverse birth outcomes in neonates. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study in 29,155 pregnant women aged 14 through 49 years from January 1, 2007, through November 15, 2013, using data from 7 Vaccine Safety Datalink sites in California, Colorado, Minnesota, Oregon, Washington, and Wisconsin. EXPOSURES: Women who received Tdap in pregnancy following a prior tetanus-containing vaccine less than 2 years before, 2 to 5 years before, and more than 5 years before. MAIN OUTCOMES AND MEASURES: Acute adverse events (fever, allergy, and local reactions) and adverse birth outcomes (small for gestational age, preterm delivery, and low birth weight) were evaluated. Women who were vaccinated with Tdap in pregnancy and had a prior tetanus-containing vaccine more than 5 years before served as controls. RESULTS: There were no statistically significant differences in rates of medically attended acute adverse events or adverse birth outcomes related to timing since prior tetanus-containing vaccination. [table: see text]. CONCLUSIONS AND RELEVANCE: Among women who received Tdap vaccination during pregnancy, there was no increased risk of acute adverse events or adverse birth outcomes for those who had been previously vaccinated less than 2 years before or 2 to 5 years before compared with those who had been vaccinated more than 5 years before. These findings suggest that relatively recent receipt of a prior tetanus-containing vaccination does not increase risk after Tdap vaccination in pregnancy. PMID- 26501535 TI - Association Between Preeclampsia and Congenital Heart Defects. AB - IMPORTANCE: The risk of congenital heart defects in infants of women who had preeclampsia during pregnancy is poorly understood, despite shared angiogenic pathways in both conditions. OBJECTIVE: To determine the prevalence of congenital heart defects in offspring of women with preeclampsia. DESIGN, SETTING, AND PARTICIPANTS: Population-level analysis of live births before discharge, 1989 2012, was conducted for the entire province of Quebec, comprising a quarter of Canada's population. All women who delivered an infant with or without heart defects in any Quebec hospital were included (N = 1,942,072 neonates). EXPOSURES: Preeclampsia or eclampsia with onset before or after 34 weeks of gestation. MAIN OUTCOMES AND MEASURES: Presence of any critical or noncritical congenital heart defect detected in infants at birth, comparing prevalence in those exposed and not exposed to preeclampsia. RESULTS: The absolute prevalence of congenital heart defects was higher for infants of women with preeclampsia than those without it. Infants of women with preeclampsia had no increased prevalence of critical heart defects but did have an increased prevalence of noncritical heart defects compared with infants of nonpreeclamptic women. [table: see text]. Among specific defects, prevalence was greatest for septal defects. Compared with infants of women with late-onset preeclampsia, those with early onset (<34 weeks) had greater prevalence of critical heart defects (364.4/100,000 [20/5488]; prevalence ratio, 2.78; 95% CI, 1.71-4.50; prevalence difference, 249.6/100,000; 95%CI, 89.7 409.6) and noncritical heart defects (7306.9/100,000 [401/5488]; prevalence ratio, 5.55; 95%CI, 4.98-6.19; prevalence difference, 6089.2/100,000; 95%CI, 5350.0-6828.3). CONCLUSIONS AND RELEVANCE: In this population-based study, preeclampsia was significantly associated with noncritical heart defects in offspring, and preeclampsia before 34 weeks was associated with critical heart defects. However, the absolute risk of congenital heart defects was low. PMID- 26501537 TI - Benefits and Harms of Breast Cancer Screening: A Systematic Review. AB - IMPORTANCE: Patients need to consider both benefits and harms of breast cancer screening. OBJECTIVE: To systematically synthesize available evidence on the association of mammographic screening and clinical breast examination (CBE) at different ages and intervals with breast cancer mortality, overdiagnosis, false positive biopsy findings, life expectancy, and quality-adjusted life expectancy. EVIDENCE REVIEW: We searched PubMed (to March 6, 2014), CINAHL (to September 10, 2013), and PsycINFO (to September 10, 2013) for systematic reviews, randomized clinical trials (RCTs) (with no limit to publication date), and observational and modeling studies published after January 1, 2000, as well as systematic reviews of all study designs. Included studies (7 reviews, 10 RCTs, 72 observational, 1 modeling) provided evidence on the association between screening with mammography, CBE, or both and prespecified critical outcomes among women at average risk of breast cancer (no known genetic susceptibility, family history, previous breast neoplasia, or chest irradiation). We used summary estimates from existing reviews, supplemented by qualitative synthesis of studies not included in those reviews. FINDINGS: Across all ages of women at average risk, pooled estimates of association between mammography screening and mortality reduction after 13 years of follow-up were similar for 3 meta-analyses of clinical trials (UK Independent Panel: relative risk [RR], 0.80 [95% CI, 0.73-0.89]; Canadian Task Force: RR, 0.82 [95% CI, 0.74-0.94]; Cochrane: RR, 0.81 [95% CI, 0.74 0.87]); were greater in a meta-analysis of cohort studies (RR, 0.75 [95% CI, 0.69 to 0.81]); and were comparable in a modeling study (CISNET; median RR equivalent among 7 models, 0.85 [range, 0.77-0.93]). Uncertainty remains about the magnitude of associated mortality reduction in the entire US population, among women 40 to 49 years, and with annual screening compared with biennial screening. There is uncertainty about the magnitude of overdiagnosis associated with different screening strategies, attributable in part to lack of consensus on methods of estimation and the importance of ductal carcinoma in situ in overdiagnosis. For women with a first mammography screening at age 40 years, estimated 10-year cumulative risk of a false-positive biopsy result was higher (7.0% [95% CI, 6.1% 7.8%]) for annual compared with biennial (4.8% [95% CI, 4.4%-5.2%]) screening. Although 10-year probabilities of false-positive biopsy results were similar for women beginning screening at age 50 years, indirect estimates of lifetime probability of false-positive results were lower. Evidence for the relationship between screening and life expectancy and quality-adjusted life expectancy was low in quality. There was no direct evidence for any additional mortality benefit associated with the addition of CBE to mammography, but observational evidence from the United States and Canada suggested an increase in false-positive findings compared with mammography alone, with both studies finding an estimated 55 additional false-positive findings per extra breast cancer detected with the addition of CBE. CONCLUSIONS AND RELEVANCE: For women of all ages at average risk, screening was associated with a reduction in breast cancer mortality of approximately 20%, although there was uncertainty about quantitative estimates of outcomes for different breast cancer screening strategies in the United States. These findings and the related uncertainty should be considered when making recommendations based on judgments about the balance of benefits and harms of breast cancer screening. PMID- 26501538 TI - Optimizing Mammography Screening Intervals. PMID- 26501536 TI - Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society. AB - IMPORTANCE: Breast cancer is a leading cause of premature mortality among US women. Early detection has been shown to be associated with reduced breast cancer morbidity and mortality. OBJECTIVE: To update the American Cancer Society (ACS) 2003 breast cancer screening guideline for women at average risk for breast cancer. PROCESS: The ACS commissioned a systematic evidence review of the breast cancer screening literature to inform the update and a supplemental analysis of mammography registry data to address questions related to the screening interval. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. EVIDENCE SYNTHESIS: Screening mammography in women aged 40 to 69 years is associated with a reduction in breast cancer deaths across a range of study designs, and inferential evidence supports breast cancer screening for women 70 years and older who are in good health. Estimates of the cumulative lifetime risk of false-positive examination results are greater if screening begins at younger ages because of the greater number of mammograms, as well as the higher recall rate in younger women. The quality of the evidence for overdiagnosis is not sufficient to estimate a lifetime risk with confidence. Analysis examining the screening interval demonstrates more favorable tumor characteristics when premenopausal women are screened annually vs biennially. Evidence does not support routine clinical breast examination as a screening method for women at average risk. RECOMMENDATIONS: The ACS recommends that women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years (strong recommendation). Women aged 45 to 54 years should be screened annually (qualified recommendation). Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation). Women should have the opportunity to begin annual screening between the ages of 40 and 44 years (qualified recommendation). Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation). The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age (qualified recommendation). CONCLUSIONS AND RELEVANCE: These updated ACS guidelines provide evidence-based recommendations for breast cancer screening for women at average risk of breast cancer. These recommendations should be considered by physicians and women in discussions about breast cancer screening. PMID- 26501539 TI - The Propensity Score. PMID- 26501540 TI - Red Blood Cell Concentrate Storage and Survival After Cardiac Surgery. PMID- 26501541 TI - Trends in Traumatic Spinal Cord Injury. PMID- 26501542 TI - Trends in Traumatic Spinal Cord Injury--Reply. PMID- 26501543 TI - High-Flow Nasal Oxygen Therapy for Postextubation Acute Hypoxemic Respiratory Failure. PMID- 26501544 TI - High-Flow Nasal Oxygen Therapy for Postextubation Acute Hypoxemic Respiratory Failure--Reply. PMID- 26501545 TI - Organ Donation After Circulatory Death. PMID- 26501546 TI - Organ Donation After Circulatory Death. PMID- 26501547 TI - Organ Donation After Circulatory Death--Reply. PMID- 26501548 TI - Incorrect Data in the Abstract and Conclusion. PMID- 26501550 TI - Transfusion of Blood. PMID- 26501551 TI - JAMA PATIENT PAGE. Breast Cancer Screening Guidelines in the United States. PMID- 26501553 TI - Misclassification of Acceptable Venous Thromboembolism Prophylaxis Leading to Flawed Inferences and Recommendations Regarding Prevention Efforts. PMID- 26501552 TI - Hypermethylation of p15 gene associated with an inferior poor long-term outcome in childhood acute lymphoblastic leukemia. AB - PURPOSE: To quantitate methylation of the CpG island of the promoter region of the p15 gene in childhood acute lymphoblastic leukemia (ALL) and explore its effect on prognosis. METHODS: We assessed methylation of the CpG island on the p15 gene in bone marrow mononuclear cells in 93 ALL cases and in a control group of 20 children with idiopathic thrombocytopenia (ITP) by restriction enzyme Eco52I digestion combined with polymerase chain reaction techniques. We explored the effect of varying levels of methylation on event-free survival (EFS). RESULTS: The mean methylation level was 25 % in de novo ALL and significantly higher than the control group 2 %, P < 0.01). Forty-two percent of cases (39/93) had hypermethylation (level over 10 %). Fifty-seven percent (12/21) and 38 % (27/72) T- and precursor-B ALL patients had hypermethylation (not significant). For all patients, the 8-year EFS was (83 +/- 4) %, standard risk (91 +/- 4) %, intermediate risk (IR) (82 +/- 5) %, and high risk (HR) (43 +/- 19) % (chi(2) = 11.58, P < 0.01). Hypermethylation was associated with a lower 8-year EFS (71 +/- 7 vs. 91 +/- 4 %, P = 0.02) in univariate analyses. CONCLUSIONS: Children with ALL have higher levels of p15 CpG island methylation than a control group of children with ITP. Among children with ALL, hypermethylation was associated with inferior EFS. Higher levels of p15 CpG island methylation may be a poor prognostic marker in childhood ALL. PMID- 26501554 TI - Nanotextured Polymer Substrate for Flexible and Mechanically Robust Metal Electrodes by Nanoimprint Lithography. AB - Metal thin film electrodes on flexible polymer substrates are inherently unstable against humidity and mechanical stresses because of their poor adhesion properties. We introduce a novel approach for improving the adhesion characteristics of metal-polymer interface based on the nanostructuring of the polymer substrate by using nanoimprint lithography. The adhesion characteristics of metal-polymer interface were measured by accelerated test, cyclic bending test and double cantilever beam (DCB) test. The interface of Au/Ti dual layer thin film and nanoimprinted PMMA substrate shows over 2.03 and 1.95 times higher adhesion energy (G(c)) than that of Au/Ti dual layer thin film and plane PMMA substrate in air and wet environments, respectively. The adhesion energy between metal thin film and polymer substrate was dramatically improved by the increased surface roughness and mechanical interlocking effect of numerous nanoscale anchors at the edges of nanoimprinted surface, which was verified by both experiment and numerical analysis. PMID- 26501555 TI - Serum VEGF Predicts Worse Clinical Outcome of Patients with Coronary Heart Disease After Percutaneous Coronary Intervention Therapy. AB - BACKGROUND: Percutaneous coronary intervention (PCI) is an effective treatment for coronary heart disease (CHD) patients. However, patients after PCI treatment often have ischemic events that result in poor prognosis. Our study aimed to investigate the effects of vascular endothelial growth factor (VEGF) level on the prognosis of CHD patients. MATERIAL AND METHODS: We enrolled 114 CHD patients in the study. Serum VEGF level was measured by enzyme-linked immunosorbent assay (ELISA). Total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and Hs-CRP were also tested in patients. The patients were divided into 2 groups according to the level of VEGF. Kaplan-Meier curve was used to observe the differences in survival situation of patients of the 2 groups. Cox regression analysis was conducted to judge whether VEGF was an independent biomarker for prognosis in CHD. RESULTS: We included 104 patients for survival analysis. VEGF level in CHD patients was significantly lower than that of healthy individuals (P<0.05). In the analysis of basic information, we found differences in sex distribution and hypertension between groups (P<0.05 for both). Kaplan-Meier curve indicated that patients with low expression of VEGF presented with poor prognosis. The mortality rate of the low-expression group was 37.71%, higher than that of the high-expression group (14.3%). Cox analysis suggested that VEGF could serve as a biomarker for prognosis in CHD (HR: 3.014, P: 0.019). CONCLUSIONS: Low level of VEGF may predict poor clinical outcome of CHD patients after PCI treatment. PMID- 26501556 TI - Simultaneous bilateral atypical femoral fracture in a patient receiving denosumab: case report and literature review. AB - Osteoporosis remains a chronic and common disease associated with high medical costs. Pharmacological therapy has shown to be a good strategy to significantly reduce fracture risk. While literary evidence for bone protection in the short and medium term is strongly in it's favor, there are concerns about long-term treatment with antiresorptive drugs. Increased risk of atypical femoral fractures (AFFs) have been demonstrated in several studies following the long-term use of bisphosphonate. Denosumab offers an alternative approach to the treatment of osteoporosis, however, it is also an antiresorptive drug. We present a case of simultaneous bilateral atypical femoral fractures in a patient with denosumab treatment. These findings highlight the need to reevaluate the optimal antiresorptive therapy duration, as well as the safety of transition from bisphosphonates to denosumab and the need for continued monitoring in the prevention of AFFs. PMID- 26501557 TI - Meta-analysis of diabetes mellitus and risk of hip fractures: small-study effect. PMID- 26501559 TI - Sacroiliitis or insufficiency fracture? AB - Sacral stress fracture and sacroiliitis are two conditions that present with pain. Sacral stress fractures are a rare cause of lumbar and hip pain. Sacral insufficiency fractures are a type of sacral stress fractures. Sacroiliitis represents inflammation of the sacroiliac joints. Coexistence of sacroiliitis and sacral insufficiency fracture (SIF) has not been reported before. Case 1: A 39 year-old woman reporting inflammatory back pain. Imaging revealed bilateral chronic sacroiliitis and bilateral SIF. Case 2: A 31-year-old woman presenting with left hip and inguinal pain. Imaging revealed left sacroiliitis and ipsilateral SIF. Calcium and vitamin D supplementation together with nonsteroidal anti-inflammatory drug (NSAID) treatment were given. Sulfasalazine was added to the treatment of the second patient who developed peripheral arthritis during follow-ups. Early diagnosis is best made with magnetic resonance imaging (MRI) since roentgenograms may be negative initially. Furthermore, MRI findings of both entities share common features leading to a diagnostic dilemma. Interpretation of radiological findings assisted by detailed history and clinical findings is crucial for diagnosis and treatment. PMID- 26501560 TI - Palladium-Catalyzed Intermolecular Carbene Insertion Prior to Intramolecular Heck Cyclization: Synthesis of 2-Arylidene-3-aryl-1-indanones. AB - A domino process that converges the migratory insertion of carbene with a Heck reaction has been established as a versatile tool for the synthesis of 2 arylidene-3-aryl-1-indanones from very stable and easily accessible N tosylhydrazones and 2'-iodochalcones. The reaction selectively proceeds through 5 exo-trig cyclization and delivers the products selectively with the E configuration of the double bond in excellent yields. The one-pot synthesis of 2 arylidene-3-aryl-1-indanones involving in situ synthesis of both 2'-iodochalcones and N-tosylhydrazones has also been demonstrated. PMID- 26501558 TI - Impaired skeletal health and neuromuscular function among amphetamine users in clinical treatment. AB - SUMMARY: This study examined musculoskeletal health in amphetamine users, compared with healthy age-matched controls. We show that amphetamine users have reduced bone mass at several skeletal sites and attenuated maximal muscle strength and force development capacity in the lower extremities. INTRODUCTION: Amphetamine use may cause poor bone quality and elevated risk of osteoporosis. The purpose of this study was to investigate whether amphetamine users exhibit reduced regional and whole body bone mineral density (BMD), altered bone metabolism, and how muscle function may relate to the patient groups' skeletal health. METHODS: We assessed hip, lumbar spine and whole body BMD, and trabecular bone score (TBS) by dual x-ray absorptiometry (DXA), and bone metabolism markers in serum and maximal strength and force development capacity in 36 amphetamine users (25 men, 30 +/- 7 years; 11 women 35 +/- 10 years) and in 37 healthy controls (23 men, 31 +/- 9 years; 14 women, 35 +/- 7 years). RESULTS: Whole body BMD was lower in amphetamine users (8% in males and 7% females, p < 0.01), as were BMD at the total hip and sub-regions of the hip (9-11% in men and 10-11 % in women, p < 0.05). Male users had 4% lower TBS (p < 0.05) and higher serum level of type 1 collagen amino-terminal propeptide (p < 0.01). This coincided with reduced lower extremity maximal strength of 30% (males, p < 0.001) and 25% (females, p < 0.05) and 27% slower muscular force development in males compared to controls (p < 0.01). CONCLUSIONS: These findings demonstrate that amphetamine users suffer from a generalized reduction in bone mass, which was associated with attenuated maximal muscle strength and force development capacity in the lower extremities. PMID- 26501561 TI - Abolishing Fees at Health Centers in the Context of Community Case Management of Malaria: What Effects on Treatment-Seeking Practices for Febrile Children in Rural Burkina Faso? AB - INTRODUCTION: Burkina Faso started nationwide community case management of malaria (CCMm) in 2010. In 2011, health center user fees for children under five were abolished in some districts. OBJECTIVE: To assess the effects of concurrent implementation of CCMm and user fees abolition on treatment-seeking practices for febrile children. METHODS: This is a natural experiment conducted in the districts of Kaya (CCMm plus user fees abolition) and Zorgho (CCMm only). Registry data from 2005 to 2014 on visits for malaria were collected from all eight rural health centers in the study area. Annual household surveys were administered during malaria transmission season in 2011 and 2012 in 1,035 randomly selected rural households. Interrupted time series models were fitted for registry data and Fine and Gray's competing risks models for survey data. RESULTS: User fees abolition in Kaya significantly increased health center use by eligible children with malaria (incidence rate ratio for intercept change = 2.1, p <0.001). In 2011, in Kaya, likelihood of health center use for febrile children was three times higher and CHW use three times lower when caregivers knew services were free. Among the 421 children with fever in 2012, the delay before visiting a health center was significantly shorter in Kaya than in Zorgho (1.46 versus 1.79 days, p <0.05). Likelihood of visiting a health center on the first day of fever among households <2.5 km or <5 km from a health center was two and three times higher in Kaya than in Zorgho, respectively (p <0.001). CONCLUSIONS: User fees abolition reduced visit delay for febrile children living close to health centers. It also increased demand for and use of health center for children with malaria. Concurrently, demand for CHWs' services diminished. User fees abolition and CCMm should be coordinated to maximize prompt access to treatment in rural areas. PMID- 26501563 TI - MafG, A Novel Target of FXR that Regulates Bile Acid Homeostasis. PMID- 26501562 TI - Resistance versus Balance Training to Improve Postural Control in Parkinson's Disease: A Randomized Rater Blinded Controlled Study. AB - BACKGROUND: Reduced muscle strength is an independent risk factor for falls and related to postural instability in individuals with Parkinson's disease. The ability of resistance training to improve postural control still remains unclear. OBJECTIVE: To compare resistance training with balance training to improve postural control in people with Parkinson's disease. METHODS: 40 patients with idiopathic Parkinson's disease (Hoehn&Yahr: 2.5-3.0) were randomly assigned into resistance or balance training (2x/week for 7 weeks). Assessments were performed at baseline, 8- and 12-weeks follow-up: primary outcome: Fullerton Advanced Balance (FAB) scale; secondary outcomes: center of mass analysis during surface perturbations, Timed-up-and-go-test, Unified Parkinson's Disease Rating Scale, Clinical Global Impression, gait analysis, maximal isometric leg strength, PDQ 39, Beck Depression Inventory. Clinical tests were videotaped and analysed by a second rater, blind to group allocation and assessment time. RESULTS: 32 participants (resistance training: n = 17, balance training: n = 15; 8 drop-outs) were analyzed at 8-weeks follow-up. No significant difference was found in the FAB scale when comparing the effects of the two training types (p = 0.14; effect size (Cohen's d) = -0.59). Participants from the resistance training group, but not from the balance training group significantly improved on the FAB scale (resistance training: +2.4 points, Cohen's d = -0.46; balance training: +0.3 points, Cohen's d = -0.08). Within the resistance training group, improvements of the FAB scale were significantly correlated with improvements of rate of force development and stride time variability. No significant differences were found in the secondary outcome measures when comparing the training effects of both training types. CONCLUSIONS: The difference between resistance and balance training to improve postural control in people with Parkinson's disease was small and not significant with this sample size. There was weak evidence that freely coordinated resistance training might be more effective than balance training. Our results indicate a relationship between the enhancement of rate of force development and the improvement of postural control. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02253563. PMID- 26501564 TI - Direct Energy Consumption Associated Emissions by Rural-to-Urban Migrants in Beijing. AB - Hundreds of millions of rural residents have migrated to cities in China in recent years. Different lifestyles and living conditions lead to substantial changes in their household energy. Here, we present the result of a survey on direct household energy use of low-skilled rural-to-urban migrants in Beijing. The migrants moved up the energy ladder immediately after arriving in the city by replacing biomass fuels with coal, electricity, and liquefied petroleum gas. After the original shift, pattern of household energy use by the migrants has not changed much over decades, likely due to the long-existing household registration system (Hukou). As a result, the mix of energy types used by the rural-to-urban migrants were different from those by long-term urban residents, although total quantities were similar. Shifting from biomass fuels to coal, the migrants emitted 2.4 times more non-neutral CO2 than rural residents and 14% more than urban residents. The migration also resulted in significant increase in emissions of SO2 and mercury but dramatic decreases in some incomplete combustion products including particulate matter. All these changes have significant implication on air quality, health, and climate considering the scale of urbanization in China. PMID- 26501566 TI - Extension of Hopfield's Electron Transfer Model To Accommodate Site-Site Correlation. AB - Extension of the Forster analogue for the ET rate constant (based on virtual intermediate electron detachment or attachment states) with inclusion of site site correlation due to coulomb terms associated with solvent reorganization energy and the driving force, has been developed and illustrated for a simple three-state, two-mode model. The model is applicable to charge separation (CS), recombination (CR), and shift (CSh) ET processes, with or without an intervening bridge. The model provides a unified perspective on the role of virtual intermediate states in accounting for the thermal Franck-Condon weighted density of states (FCWD), the gaps controlling superexchange coupling, and mean absolute redox potentials, with full accommodation of site-site coulomb interactions. Two types of correlation have been analyzed: aside from the site-site correlation due to coulomb interactions, we have emphasized the intrinsic "nonorthogonality" which generally pertains to reaction coordinates (RCs) for different ET processes involving multiple electronic states, as may be expressed by suitably defined direction cosines (cos(theta)). A pair of RCs may be nonorthogonal even when the site-site coulomb correlations are absent. While different RCs are linearly independent in the mathematical sense for all theta ? 0 degrees , they are independent in the sense of being "uncorrelated" only in the limit of orthogonality (theta = 90 degrees ). Application to more than two coordinates is straightforward and may include both discrete and continuum contributions. PMID- 26501567 TI - Nonradiative Deactivation of Lanthanoid Excited States by Inner-Sphere Carboxylates. AB - The vibrational deactivation of metal-centered excited states is one of the fundamental processes that governs the luminescence of inorganic luminophores. In molecular lanthanoid luminescence, the most reliable way to modulate and systematically investigate these processes is deuteration of X-H stretching modes (X = O, N, C). Apart from the effect of these high-energy vibrational motifs, very little is known about the impact of other oscillator fragments present in lanthanoid complexes. We have developed a synthetic protocol to efficiently and selectively label the popular chelator motif "pyridine-2-carboxylic acid" with stable (13)C/(18)O isotope at the carboxylate group. The corresponding isotopologic lanthanoid complexes (Ln = Sm, Eu, Ho) show a decrease of the local mode carbonyl stretching frequency of up to 5% after isotopic substitution. While this does not seems to have any effect on the luminescence of lanthanoids with medium- to high-energy gaps (Sm and Eu), we have found the first example of a quantifiable luminescence isotope effect for one of the near-IR transitions of holmium ((3)K8 -> (5)I5) that only involves the isotopic editing of the vibrational environment at the four carbonyl oscillators. PMID- 26501565 TI - High Lysyl Oxidase (LOX) in the Non-Malignant Prostate Epithelium Predicts a Poor Outcome in Prostate Cancer Patient Managed by Watchful Waiting. AB - Lysyl oxidase (LOX) has been shown to both promote and suppress tumor progression, but its role in prostate cancer is largely unknown. LOX immunoreactivity was scored in prostate tumor epithelium, tumor stroma and in the tumor-adjacent non-malignant prostate epithelium and stroma. LOX scores in tumor and non-malignant prostate tissues were then examined for possible associations with clinical characteristics and survival in a historical cohort of men that were diagnosed with prostate cancer at transurethral resection and followed by watchful waiting. Men with a low LOX score in the non-malignant prostate epithelium had significantly longer cancer specific survival than men with a high score. Furthermore, LOX score in non-malignant prostate epithelium remained prognostic in a multivariable analysis including Gleason score. LOX score in prostate tumor epithelium positively correlated to Gleason score and metastases but was not associated with cancer survival. LOX score in tumor and non-malignant prostate stroma appeared unrelated to these tumor characteristics. In radical prostatectomy specimens, LOX immune-staining corresponded to LOX in-situ hybridization and LOX mRNA levels were found to be similar between tumor and adjacent non-malignant areas, but significantly increased in bone metastases samples. LOX levels both in tumors and in the surrounding tumor-bearing organ are apparently related to prostate cancer aggressiveness. PMID- 26501568 TI - Discovery of 2-Acylaminothiophene-3-Carboxamides as Multitarget Inhibitors for BCR-ABL Kinase and Microtubules. AB - The emergence of drug resistance of the BCR-ABL kinase inhibitor imatinib, especially toward the T315I gatekeeper mutation, poses a great challenge to targeted therapy in treating chronic myeloid leukemia (CML) patients. To discover novel inhibitors against drug-resistant CML bearing T315I mutation, we applied a physics-based hierarchical virtual screening approach to dock a large chemical library against ATP binding pockets of both wild-type (WT) and T315I mutant ABL kinases in a combinatorial fashion. This strategy automatically resulted in 87 compounds satisfying structural and energetic criteria of both WT and T315I mutant kinases. Among them, nine compounds, which share a common thiophene-based scaffold and adopt similar binding poses, were chosen for experimental testing and one of them was shown to have low micromolar inhibition activities against both WT and mutant ABL kinases. Structure-activity relationship analysis with a series of structural modifications based on 2-acylaminothiophene-3-carboxamide scaffold supports our predicted binding mode. Interestingly, the same chemical scaffold was also enriched in our previous virtual screening campaign against colchicine site of microtubules using the same computational protocol, which suggests our virtual screening strategy is capable of discovering small-molecule ligands targeting distinct protein binding sites without sharing any sequential and structural similarity. Furthermore, the multitarget inhibition activity of this class of compounds was assessed in cellular experiments. We expect that the 2-acylaminothiophene-3-carboxamide scaffold may serve as a promising starting point for developing multitarget inhibitors in cancer treatment by targeting both kinases and microtubules. PMID- 26501569 TI - Characterization and validation of a Monte Carlo code for independent dose calculation in proton therapy treatments with pencil beam scanning. AB - We propose a method of creating and validating a Monte Carlo (MC) model of a proton Pencil Beam Scanning (PBS) machine using only commissioning measurements and avoiding the nozzle modeling. Measurements with a scintillating screen coupled with a CCD camera, ionization chamber and a Faraday Cup were used to model the beam in TOPAS without using any machine parameter information but the virtual source distance from the isocenter. Then the model was validated on simple Spread Out Bragg Peaks (SOBP) delivered in water phantom and with six realistic clinical plans (many involving 3 or more fields) on an anthropomorphic phantom. In particular the behavior of the moveable Range Shifter (RS) feature was investigated and its modeling has been proposed. The gamma analysis (3%,3 mm) was used to compare MC, TPS (XiO-ELEKTA) and measured 2D dose distributions (using radiochromic film). The MC modeling proposed here shows good results in the validation phase, both for simple irradiation geometry (SOBP in water) and for modulated treatment fields (on anthropomorphic phantoms). In particular head lesions were investigated and both MC and TPS data were compared with measurements. Treatment plans with no RS always showed a very good agreement with both of them (gamma-Passing Rate (PR) > 95%). Treatment plans in which the RS was needed were also tested and validated. For these treatment plans MC results showed better agreement with measurements (gamma-PR > 93%) than the one coming from TPS (gamma-PR < 88%). This work shows how to simplify the MC modeling of a PBS machine for proton therapy treatments without accounting for any hardware components and proposes a more reliable RS modeling than the one implemented in our TPS. The validation process has shown how this code is a valid candidate for a completely independent treatment plan dose calculation algorithm. This makes the code an important future tool for the patient specific QA verification process. PMID- 26501571 TI - Intangible successes. PMID- 26501572 TI - Handcuffs. PMID- 26501573 TI - Mirabegron: A new option in treating overactive bladder. AB - Antimuscarinic medications have long been the mainstay of drug treatment for overactive bladder. This article describes mirabegron, one of a new class of agents that relaxes the detrusor muscle directly via a beta3 adrenoceptor agonist. Mirabegron's efficacy on frequency, urgency, and urge incontinence was tested in several trials before its wide clinical introduction. However, caution is still needed as data are lacking on the drug's efficacy and safety in frail older adults and for long-term therapy. PMID- 26501574 TI - A hyperpigmented periorbital patch. PMID- 26501576 TI - A fast-growing, painless, solid scrotal mass. AB - The history and physical examination of an adolescent male are critical to early detection of scrotal abnormalities. Although rare, paratesticular rhabdomyosarcoma grows quickly and can be life-threatening. This article focuses on the importance of prompt recognition, diagnosis, and appropriate management of paratesticular rhabdomyosarcoma in an adolescent. PMID- 26501575 TI - New oral anticoagulants for patients with nonvalvular atrial fibrillation. AB - Four new oral anticoagulants have been approved for reducing stroke risk in patients with nonvalvular atrial fibrillation. Compared with warfarin, these agents offer a more predictable dose response with fewer food and drug interactions and no regular blood monitoring, although some of the drugs have an increased risk of major gastrointestinal bleeding. This article reviews the new drugs. PMID- 26501577 TI - Recognizing and treating Raynaud phenomenon. AB - Raynaud phenomenon is an episodic ischemia caused by cold, emotional stimuli, or rheumatologic disorders, and is more common in women than men. This article describes the clinical presentation of Raynaud phenomenon and how to diagnose and appropriately treat patients and prevent complications. Research on the use of different pharmacologic interventions for Raynaud phenomenon is ongoing and treatment options are expanding. PMID- 26501578 TI - Veterans as physician assistants. AB - The physician assistant (PA) profession emerged nearly 50 years ago to leverage the healthcare experience of Vietnam-era military trained medics and corpsmen to fill workforce shortages in medical care. In 2009, the American Recovery and Reinvestment Act Primary Care Training and Enhancement program was established to improve access to primary care. Training military veterans as PAs was again identified as a strategy to meet provider access shortages. However, fewer than 4% of veterans with military healthcare training are likely to apply to PA school and little is known regarding the factors that predict acceptance to training. In 2012, we surveyed all veteran applicants and a stratified random sample of nonveterans applying to PA training. We compare the similarities and differences between veteran and nonveteran applicants, application barriers, and the factors predicting acceptance. We conclude with a discussion of the link between modern veterans and the PA profession. PMID- 26501579 TI - Slipped capital femoral epiphysis. PMID- 26501580 TI - Bedside ultrasound to evaluate abdominal pain. PMID- 26501581 TI - Inhaled technosphere regular insulin powder. AB - The lungs are an effective way to deliver insulin for patients with diabetes, but an initial inhaled insulin product was withdrawn from the market because of high cost and inconsistent dosing. This article describes a recently approved inhaled insulin that appears to control blood glucose as well as rapid-acting injectable insulin. PMID- 26501583 TI - A painful, hard mass on the ankle. PMID- 26501584 TI - On the brink. PMID- 26501585 TI - Carbocation Stability in H-ZSM5 at High Temperature. AB - Zeolites are common catalysts for multiple industrial applications, including alcohol dehydration to produce olefins, and given their commercial importance, reaction mechanisms in zeolites have long been proposed and studied. Some proposed reaction mechanisms for alcohol dehydration exhibit noncyclic carbocation intermediates or transition states that resemble carbocations, and several previous studies suggest that the tert-butyl cation is the only noncyclic cation more stable than the corresponding chemisorbed species with the hydrocarbon bound to the framework oxygen (i.e., an alkoxide). To determine if carbocations can exist at high temperatures in zeolites, where these catalysts are finding new applications for biomass vapor-phase upgrading (~500 degrees C), the stability of carbocations and the corresponding alkoxides were calculated with two ONIOM embedding methods (M06-2X/6-311G(d,p):M06-2X/3-21G) and (PBE-D3/6 311G(d,p):PBE-D3/3-21G) and plane-wave density functional theory (DFT) using the PBE functional corrected with entropic and Tkatchenko-Scheffler van der Waals corrections. The embedding methods tested are unreliable at finding minima for primary carbocations, and only secondary or higher carbocations can be described with embedding methods consistent with the periodic DFT results. The relative energy between the carbocations and alkoxides differs significantly between the embedding and the periodic DFT methods. The difference is between ~0.23 and 14.30 kcal/mol depending on the molecule, the model, and the functional chosen for the embedding method. At high temperatures, the pw-DFT calculations predict that the allyl, isopropyl, and sec-butyl cations exhibit negligible populations while acetyl and tert-butyl cations exhibit significant populations (>10%). Moreover, the periodic DFT results indicate that mechanisms including secondary and tertiary carbocations intermediates or carbocations stabilized by adjacent oxygen or double bonds are possible at high temperatures relevant to some industrial uses of zeolite catalysts, although as the minority species in most cases. PMID- 26501586 TI - Label-free microfluidic free-flow isoelectric focusing, pH gradient sensing and near real-time isoelectric point determination of biomolecules and blood plasma fractions. AB - We demonstrate the fabrication, characterization and application of microfluidic chips capable of continuous electrophoretic separation via free flow isoelectric focussing (FFIEF). By integration of a near-infrared (NIR) fluorescent pH sensor layer under the whole separation bed, on-line observation of the pH gradient and determination of biomolecular isoelectric points (pI) was achieved within a few seconds. Using an optical setup for imaging of the intrinsic fluorescence of biomolecules at 266 nm excitation, labelling steps could be avoided and the native biomolecules could be separated, collected and analysed for their pI. The fabricated microchip was successfully used for the monitoring of the separation and simultaneous observation of the pH gradient during the isoelectric focussing of the proteins alpha-lactalbumin and beta-lactoglobulin, blood plasma proteins and the antibiotics ampicillin and ofloxacin. The obtained pIs are in good agreement with literature data, demonstrating the applicability of the system. Mass spectra from the separated antibiotics taken after 15 minutes of continuous separation from different fractions at the end of the microchip validated the separation via microfluidic isoelectric focussing and indicate the possibility of further on- or off-chip processing steps. PMID- 26501587 TI - Intellectually disabled and impaired people serving sentences in conventional correctional facilities: some considerations. PMID- 26501588 TI - Influence of burnout on the health of prison workers. AB - OBJECTIVE: This study investigates differences in health (Somatic Symptoms, Anxiety / Insomnia, Social Dysfunction and Severe Depression) relating to professional burnout (emotional exhaustion, depersonalization and personal fulfillment) suffered by prison staff, taking into account the workplace where they perform their activities (therapeutic vs. non therapeutic modules). METHODS: The participants consisted of 222 workers of both sexes, with ages ranging from 18 to 60 years, working in different prisons in Spain (Educational and Therapeutic Modules, N = 1001; Non Educational and Therapeutic Modules = 121). The tools used were the General Health Questionnaire (GHQ-28) of Goldberg and Hillier (1979) and the burnout Inventory of Maslach and Jackson (1981). A mean comparison was performed using Student?s t test along with a linear regression analysis, differentiating between Educational and Therapeutic Modules and Non Educational and Therapeutic Modules. RESULTS: Significant differences were found between both clusters and predictive values of burnout factors for the different health levels in both prison models were identified. Possible explanations for the findings and the implications for intervention are discussed. PMID- 26501589 TI - [Health care in the prisons of the Kingdom. General Royal Ordinance of prisons of 1834]. AB - In the 19th century, the concept of "prison health" began to make an appearance in Spanish legislation as an integral part of prison management. Thanks to a series of ideological and progressive principles in the same century, laws were decreed and regulated to address the need for adequate medical care for prisoners in Africa, Spain and the overseas territories. The most important of these was the Royal Ordinance of Prisoners of the Kingdom of 1834, and subsequent Regulation of 1844. PMID- 26501590 TI - A review of the regulatory and functional aspects of prison health care and nursing staff. AB - The aim of this study of prison health care staff in Prison Health Care and Nursing Units is twofold. The first one is to consider those aspects of the legal system applicable to them as government employees of the General State Administration at the service of Prisons, highlighting the peculiarities of the legal regulations that can be applied as a result of providing said service. The second, based on the general regulations on prison health contained in Organic Law 1/1979, of 26 September, General Penitentiary Law and the implementing regulations thereof, approved by Royal Decree 190/1966, of 9 February, sets out to provide a critical analysis of the obligatory and functional framework for health care and nursing staff established in the old Penitentiary Regulations of 1981, to determine from a legal perspective if it is possible to impede or brake so that the Prison Administration may develop or carry out the functions for which it is responsible in terms of planning, organization and management of activities geared towards maintaining and improving hygiene and health in the prison environment. PMID- 26501591 TI - Subcultural manifestations of self-injury in correctional settings. PMID- 26501592 TI - 3-Trimethylsilylcycloalkylidenes. gamma-Silyl vs gamma-Hydrogen Migration to Carbene Centers. AB - A series of gamma-trimethylsilyl-substituted carbenes have been studied experimentally and by computational methods. In an acyclic system, 1,3 trimethylsilyl migration successfully competes with 1,3-hydrogen migration to the carbene center. The behavior of cyclic 3-trimethylsilyl-substituted carbenes contrasts with that of the acyclic system. Only 1,2-hydrogen migration processes are observed in the five-membered ring due to the high barrier to 1,3-hydrogen migration. In the cyclohexyl system, a small amount of a cyclopropane derived from 1,3-hydrogen migration occurs, as shown by a labeling study. In the cycloheptyl carbene system, a labeling study again showed that 1,3-hydrogen migration to the carbene center leads to the major product. Computational studies suggest that the cyclic carbenes all have lower energy conformations where the trimethylsilyl group is in a pseudo equatorial conformation where it cannot migrate to the carbene center. Computational studies also suggest that cyclohexyl and cycloheptyl carbene systems are slightly stabilized by a rear lobe interaction of the Si-C bond with the carbene center. PMID- 26501593 TI - Prevalence of Chlamydia psittaci and Other Chlamydia Species in Wild Birds in Poland. AB - Avian chlamydiosis is a zoonotic disease occurring in humans, poultry, and exotic birds. It has been suggested that some wild bird species play an important role as reservoirs for Chlamydia, especially Chlamydia psittaci. Whereas C. psittaci is the predominant chlamydial agent in birds, in the present study we have determined the prevalence of different species of Chlamydia among selected wild bird species in Poland using a rapid and sensitive real-time PCR method. In total, 369 free-living birds from 35 bird species and 15 orders were examined. Samples from 27 birds (7.3%) were positive for chlamydial DNA in the PCR; 22 positive samples (81.5%) belonged to C. psittaci, three to Chlamydia trachomatis (11.1%), and two (7.4%) classified only to the genus Chlamydia. Most of C. psittaci-positive samples belonged to five orders: Anseriformes, Columbiformes, Gruiformes, Phasianiformes, and Passeriformes. All C. trachomatis samples were obtained from Eurasian coots (Gruiformes). Two Chlamydia-positive samples not classified to any Chlamydia species were obtained from a common wood pigeon (Columbiformes) and a common buzzard (Accipitriformes). Detection of C. psittaci and C. trachomatis in free-living bird populations force to think on significance of birds as reservoir of varied Chlamydia species and their epidemiological importance. PMID- 26501594 TI - Proceedings of the 3rd PSMR Conference on PET/MR and SPECT/MR. PMID- 26501595 TI - Scintillation properties of Ca co-doped L(Y)SO:Ce between 193 K and 373 K for TOF PET/MRI. PMID- 26501596 TI - Updates from the SPADnet project (fully digital, scalable and networked photonic component for Time-of-Flight PET applications). PMID- 26501597 TI - Analog electro-optical readout of SiPMs for compact, low power ToF PET/MRI. PMID- 26501598 TI - Preliminary evaluation of a brain PET insertable to MRI. PMID- 26501599 TI - Characterization of linearly graded position-sensitive silicon photomultipliers. PMID- 26501600 TI - Hybrid PET/MRI insert: B0 field optimization by applying active and passive shimming on PET detector level. PMID- 26501601 TI - Track-based detector alignment for PET scanners. PMID- 26501602 TI - MRI compatible detector design: experience from the development of a digital SiPM based detector stack for simultaneous PET/MRI. PMID- 26501603 TI - Effects of multiple photon scattering on maximum likelihood positioning in PET. PMID- 26501604 TI - Minimization of border effects in monolithic scintillators using neural networks, based on MR-compatible SiPM arrays. PMID- 26501605 TI - MR-compatibility study of a preclinical digital PET/MRI insert. PMID- 26501606 TI - ToF performance evaluation of a PET insert with Digital Silicon Photomultiplier technology during MR operation. PMID- 26501607 TI - Collimator design for a clinical brain SPECT/MRI insert. PMID- 26501608 TI - Temporal analysis of Z-Gradient coil eddy currents in tungsten collimator with different resistivities for SPECT/MRI. PMID- 26501609 TI - Influence of temperature on digital photon counter performance for SPECT. PMID- 26501610 TI - Development of a high-resolution detection module for the INSERT SPECT/MRI system. PMID- 26501611 TI - Susceptibility phantom for compatibility testing of SPECT components for a SPECT/MR hybrid system. PMID- 26501612 TI - Joint reconstruction of simultaneously acquired MR-PET data with multi sensor compressed sensing based on a joint sparsity constraint. PMID- 26501613 TI - 4-D PET joint image reconstruction/non-rigid motion estimation with limited MRI prior information. PMID- 26501614 TI - Blind source separation analysis of PET dynamic data: a simple method with exciting MR-PET applications. PMID- 26501615 TI - New SPM8-based MRAC method for simultaneous PET/MR brain images: comparison with state-of-the-art non-rigid registration methods. PMID- 26501616 TI - PET performance evaluation of a preclinical digital PET/MRI insert. PMID- 26501617 TI - Image derived input function applied in CBF Studies with [15O]water PET in an integrated MR-PET. PMID- 26501618 TI - Optimization of transmission-scan time for the FixER method: a MR-based PET attenuation correction with a weak fixed-position external radiation source. PMID- 26501619 TI - GPU-accelerated Monte Carlo based scatter correction in brain PET/MR. PMID- 26501621 TI - Towards using scattered PET emission data for reconstruction of attenuation map in PET/MRI. PMID- 26501620 TI - Preliminary evaluation of the MLAA algorithm with the Philips Ingenuity PET/MR. PMID- 26501622 TI - MR-based attenuation correction in brain PET based on UTE sequences. PMID- 26501623 TI - Sparsely sampled MR navigators as a practical tool for quality control and correction of head motion in simultaneous PET/MR. PMID- 26501624 TI - A 3D MR-acquisition scheme for non-rigid bulk motion correction in simultaneous PET-MR. PMID- 26501625 TI - Combined MR-assisted motion and partial volume effects corrections - impact on PET data quantification. PMID- 26501626 TI - Motion estimation in PET-MRI based on dual registration: preliminary results for human data. PMID- 26501627 TI - PET/MR synchronization by detection of switching gradients. PMID- 26501628 TI - Initial evaluation of a practical PET respiratory motion correction method in clinical simultaneous PET/MRI. PMID- 26501629 TI - Preliminary evaluation of image quality in a new clinical ToF-PET/MR scanner. PMID- 26501630 TI - Iterative reconstruction incorporating positron range correction within STIR framework. PMID- 26501631 TI - Incorporation of MRI-AIF information for improved kinetic modelling of dynamic PET data. PMID- 26501632 TI - Image reconstruction of mMR PET data using the open source software STIR. PMID- 26501633 TI - Highly accelerated Point-Spread Function mapping based on Finite Rate of Innovation for EPI distortion correction. PMID- 26501634 TI - Effects of regularisation priors on dynamic PET Data. PMID- 26501635 TI - Comparison template-based with CT-based attenuation correction for hybrid MR/PET scanners. PMID- 26501636 TI - A fully automated and reproducible level-set segmentation approach for generation of MR-based attenuation correction map of PET images in the brain employing single STE-MR imaging modality. PMID- 26501637 TI - A robust MR-based attenuation map generation in short-TE MR images of the head employing hybrid spatial fuzzy C-means clustering and intensity inhomogeneity correction. PMID- 26501638 TI - RF-Penetrable PET insert for simultaneous PET/MR imaging. PMID- 26501639 TI - Effect of the magnetic field on positron range using GATE for PET-MR. PMID- 26501640 TI - High-resolution, quantitative 3D PET image reconstruction for the Siemens hybrid 3T MR/BrainPET scanner using the PET reconstruction software toolkit (PRESTO). PMID- 26501641 TI - Attenuation correction synthesis for hybrid PET-MR scanners: validation for brain study applications. PMID- 26501642 TI - PET motion correction using MR-derived motion parameters. PMID- 26501643 TI - Modelling the impact of injection time on the bolus shapes in PET-MRI AIF Conversion. PMID- 26501644 TI - MR constrained simultaneous reconstruction of activity and attenuation maps in brain TOF-PET/MR imaging. PMID- 26501645 TI - Dynamic analysis of MR-PET data on brain tumors. PMID- 26501646 TI - Masamune: a tool for automatic dynamic PET data processing, image reconstruction and integrated PET/MRI data analysis. PMID- 26501647 TI - Fast 2D MRI acquisitions for motion correction in PET-MRI. PMID- 26501648 TI - PET motion correction using PRESTO with ITK motion estimation. PMID- 26501649 TI - Combined (1)H MRI, PET and Multinuclear MRS hybrid imaging system. PMID- 26501650 TI - Optimisation of PET framing sequences. PMID- 26501651 TI - Multimodal imaging brain connectivity analysis (MIBCA) toolbox: preliminary application to Alzheimer's disease. PMID- 26501652 TI - Quantitative evaluation of PET respiratory motion correction using real- time PET/MR simulated data. PMID- 26501653 TI - Numerical modeling of MR angiography for validation of image-driven quantitative diagnosis of intracranial aneurysm and carotid stenosis. PMID- 26501654 TI - Adapting MR-BrainPET scans for comparison with conventional PET: experiences with dynamic FET-PET in brain tumours. PMID- 26501655 TI - Effect of inherent misalignment and head motion in neurological PET/MR with the Philips Ingenuity TF - phantom and patient study. PMID- 26501656 TI - Progress report on the MindView brain PET detector module based on large area SiPMs arrays. PMID- 26501657 TI - PET/MR imaging of sarcomas: effect of PET quantification by classification of tissue. PMID- 26501658 TI - Identification and characterization of human brown adipose tissue (BAT) content and metabolism in adults using [(18)F]-FDG PET/MR - a pilot study. PMID- 26501659 TI - Quantification and accuracy of clinical [11C]-PiB PET/MRI: the effect of MR-based attenuation correction. PMID- 26501660 TI - In-line high resolution PET and 3T MRI hybrid device for preclinical multimodal imaging. PMID- 26501661 TI - Quantitative carotid MR/PET imaging: comprehensive comparison of MRAC and CTAC attenuation maps in MR/PET emission data and PET/CT. PMID- 26501662 TI - Wavelet-based partial volume effect correction for simultaneous MR/PET of the carotid arteries. PMID- 26501663 TI - Performance of a high sensitivity time-of-flight PET ring operating simultaneously within a 3T MR system. PMID- 26501664 TI - Non rigid respiratory motion correction in whole body PET/MR imaging. PMID- 26501665 TI - Generation of pseudo-CT from a single MRI for PET/MR attenuation correction purposes. PMID- 26501666 TI - Dynamic comparison of PET imaging performance between state-of-the-art ToF-PET/CT and ToF-PET/MR scanners. PMID- 26501667 TI - Geometric distortions of diffusion weighted imaging of the head/neck in combined PET/MR: optimization of image acquisition and post-processing correction for oncology applications. PMID- 26501668 TI - A hybrid method for generation of attenuation map for MR-based attenuation correction of PET data in prostate PET/MR imaging. PMID- 26501669 TI - Whole body MR-PET: a new internal dosimetry method for radiation transport calculation from biokinetic model data. PMID- 26501670 TI - Towards authentically labelled bi-modal PET (SPECT)/MR-probes. PMID- 26501671 TI - Development of PET insert for simultaneous PET/MR imaging of human brain. PMID- 26501672 TI - Innovative multimodal DOTA/NODA nanoparticles for MRI and PET imaging for tumor detection. PMID- 26501673 TI - New imaging agents targeting chemokine receptor CXCR4 for PET/SPECT and MRI. PMID- 26501674 TI - Preliminary in vitro and in vivo evaluation of liposomal nanoparticles for passive and active tumour targeting by scintigraphic and MRI imaging. PMID- 26501675 TI - Characterization of sensitivity encoded silicon photomultiplier (SeSP) with 1 dimensional and 2-dimensional encoding for high resolution PET/MR. PMID- 26501676 TI - Combining MRI with PET for partial volume correction improves image-derived input functions in mice. PMID- 26501678 TI - Automated body-lung-air material map segmentation from pre-clinical MRI images for PET attenuation correction in Tera-Tomo 3D PET reconstruction engine of nanoScan PET/MRI system. PMID- 26501677 TI - Direct evaluation of MR-derived attenuation correction maps for PET/MR of the mouse myocardium. PMID- 26501679 TI - RESCUE - reduction of MR-SNR-degradation by using an MR-synchronous low interfering PET acquisition technique. PMID- 26501680 TI - Use of a clinical PET/MR scanner for preclinical research with first results. PMID- 26501681 TI - Distortion correction of MR data in whole-body small animal PET-MR using 3D thin plate splines. PMID- 26501682 TI - A fully digital approach for MR compatible Time-of-Flight PET techniques. PMID- 26501684 TI - Correction: The invertible electrochemical properties and thermal response of a series of gel-type ionic liquids based on polyoxometalates. AB - Correction for 'The invertible electrochemical properties and thermal response of a series of gel-type ionic liquids based on polyoxometalates' by Xuefei Wu et al., Phys. Chem. Chem. Phys., 2014, 16, 24598-24603. PMID- 26501685 TI - Routes for Drug Delivery to the Retina: Topical, Transscleral, Suprachoroidal and Intravitreal Gas Phase Delivery. AB - Local drug delivery to the posterior segment, particularly the macula, represents a significant challenge. In this chapter, we review current challenges, barriers and limitations. Due to the local drug delivery to the retina and macula, systemic side effects are limited. In this chapter, we also discuss the historical approaches, key aspects of ideal drug delivery systems, the use of animal models to study pharmacokinetics, and the principles of transscleral, suprachoroidal and gas phase drug delivery. PMID- 26501683 TI - Physiological and perceptual responses to incremental exercise testing in healthy men: effect of exercise test modality. AB - In a randomized cross-over study of 15 healthy men aged 20-30 years, we compared physiological and perceptual responses during treadmill and cycle exercise test protocols matched for increments in work rate - the source of increased locomotor muscle metabolic and contractile demands. The rates of O2 consumption and CO2 production were higher at the peak of treadmill versus cycle testing (p <= 0.05). Nevertheless, work rate, minute ventilation, tidal volume (VT), breathing frequency (fR), inspiratory capacity (IC), inspiratory reserve volume (IRV), tidal esophageal (Pes,tidal) and transdiaphragmatic pressure swings (Pdi,tidal), peak expiratory gastric pressures (Pga,peak), the root mean square of the diaphragm electromyogram (EMGdi,rms) expressed as a percentage of maximum EMGdi,rms (EMGdi,rms%max), and dyspnea ratings were similar at the peak of treadmill versus cycle testing (p > 0.05). Ratings of leg discomfort were higher at the peak of cycle versus treadmill exercise (p <= 0.05), even though peak O2 consumption was lower during cycling. Oxygen consumption, CO2 production, minute ventilation, fR, Pes,tidal, Pdi,tidal and Pga,peak were higher (p <= 0.05), while VT, IC, IRV, EMGdi,rms%max, and ratings of dyspnea and leg discomfort were similar (p > 0.05) at all or most submaximal work rates during treadmill versus cycle exercise. Our findings highlight important differences (and similarities) in physiological and perceptual responses at maximal and submaximal work rates during incremental treadmill and cycle exercise testing protocols. The lack of effect of exercise test modality on peak work rate advocates for the use of this readily available parameter to optimize training intensity determination, regardless of exercise training mode. PMID- 26501686 TI - Transcriptomics: a sword to cut the Gordian knot of traditional Chinese medicine. AB - The systemic effects of traditional Chinese medicine (TCM) seem to be a Gordian knot, impossible to untie for decades. With the advent of transcriptomics, a useful sword is provided to cut the knot and shed some light on complex bioprocesses and intrinsic connections among them. Here, we revisit studies on TCM ZHENGs using this approach, highlight its applications on elucidating the potential scientific basis of ZHENG and investigating mechanisms of action for the TCM formula, and demonstrating its unique role in novel TCM drug design and discovery through active ingredient detection from TCM and compatibility theory study of TCM. The limitations and future perspectives of transcriptomics approaches to TCM study are also discussed. PMID- 26501688 TI - Value-Based Medicine and Pharmacoeconomics. AB - Pharmacoeconomics is assuming increasing importance in the pharmaceutical field since it is entering the public policy arena in many countries. Among the variants of pharmacoeconomic analysis are cost-minimization, cost-benefit, cost effectiveness and cost-utility analyses. The latter is the most versatile and sophisticated in that it integrates the patient benefit (patient value) conferred by a drug in terms of improvement in length and/or quality of life. It also incorporates the costs expended for that benefit, as well as the dollars returned to patients and society from the use of a drug (financial value). Unfortunately, one cost-utility analysis in the literature is generally not comparable to another because of the lack of standardized formats and standardized input variables (costs, cost perspective, quality-of-life measurement instruments, quality-of-life respondents, discounting and so forth). Thus, millions of variants can be used. Value-based medicine(r) (VBM) cost-utility analysis standardizes these variants so that one VBM analysis is comparable to another. This system provides a highly rational methodology that allows providers and patients to quantify and compare the patient value and financial value gains associated with the use of pharmaceutical agents for example. PMID- 26501687 TI - A Bayesian hierarchical framework for modeling brain connectivity for neuroimaging data. AB - We propose a novel Bayesian hierarchical model for brain imaging data that unifies voxel-level (the most localized unit of measure) and region-level brain connectivity analyses, and yields population-level inferences. Functional connectivity generally refers to associations in brain activity between distinct locations. The first level of our model summarizes brain connectivity for cross region voxel pairs using a two-component mixture model consisting of connected and nonconnected voxels. We use the proportion of connected voxel pairs to define a new measure of connectivity strength, which reflects the breadth of between region connectivity. Furthermore, we evaluate the impact of clinical covariates on connectivity between region-pairs at a population level. We perform parameter estimation using Markov chain Monte Carlo (MCMC) techniques, which can be executed quickly relative to the number of model parameters. We apply our method to resting-state functional magnetic resonance imaging (fMRI) data from 32 subjects with major depression and simulated data to demonstrate the properties of our method. PMID- 26501689 TI - Atypical mitochondrial inheritance patterns in eukaryotes. AB - Mitochondrial DNA (mtDNA) is predominantly maternally inherited in eukaryotes. Diverse molecular mechanisms underlying the phenomenon of strict maternal inheritance (SMI) of mtDNA have been described, but the evolutionary forces responsible for its predominance in eukaryotes remain to be elucidated. Exceptions to SMI have been reported in diverse eukaryotic taxa, leading to the prediction that several distinct molecular mechanisms controlling mtDNA transmission are present among the eukaryotes. We propose that these mechanisms will be better understood by studying the deviations from the predominating pattern of SMI. This minireview summarizes studies on eukaryote species with unusual or rare mitochondrial inheritance patterns, i.e., other than the predominant SMI pattern, such as maternal inheritance of stable heteroplasmy, paternal leakage of mtDNA, biparental and strictly paternal inheritance, and doubly uniparental inheritance of mtDNA. The potential genes and mechanisms involved in controlling mitochondrial inheritance in these organisms are discussed. The linkage between mitochondrial inheritance and sex determination is also discussed, given that the atypical systems of mtDNA inheritance examined in this minireview are frequently found in organisms with uncommon sexual systems such as gynodioecy, monoecy, or andromonoecy. The potential of deviations from SMI for facilitating a better understanding of a number of fundamental questions in biology, such as the evolution of mtDNA inheritance, the coevolution of nuclear and mitochondrial genomes, and, perhaps, the role of mitochondria in sex determination, is considerable. PMID- 26501690 TI - U.S. Women's Intended Sources for Reproductive Health Care. AB - INTRODUCTION: The current sociopolitical climate and context of the Affordable Care Act have led some to question the future role of family planning clinics in reproductive health care. We explored where women plan to get their future contraception, pelvic exam/pap smears, and sexually transmitted infection testing, with a focus on the role of family planning clinics. METHODS: Data were drawn from a study of United States adults conducted in January 2013 from a national online panel. We focused on English-literate women aged 18-45 years who answered items on intended sources of care (private office/health maintenance organization [HMO], family planning clinic, other, would not get care) for reproductive health services. We used Rao-Scott F tests to compare intended sources across sociodemographic groups, and logistic regression to model odds of intending to use family planning clinics. Probability weights were used to adjust for the complex sampling design. RESULTS: The response rate was 61% (n = 2,182). Of the 723 respondents who met the inclusion criteria, approximately half intended to use private offices/HMOs. Among some subgroups, including less educated (less than high school), lower annual incomes (<$25,000) and uninsured women, the proportion intending to use family planning clinics was higher than the proportion intending to use private office/HMO in unadjusted analyses. Across all service types, unmarried and uninsured status were associated with intention to use family planning clinics in multivariable models. CONCLUSIONS: While many women intend to use private offices/HMOs for their reproductive health care, family planning clinics continue to play an important role, particularly for socially disadvantaged women. PMID- 26501691 TI - Early Life Epidemiology of Alzheimer's Disease--A Critical Review. AB - BACKGROUND: As adult brain structure is primarily established in early life, genetic and environmental exposures in infancy and childhood influence the risk for Alzheimer disease (AD). In this systematic review, we identified several early life risk factors and discussed the evidence and underlying mechanism for each. SUMMARY: Early risk factors for AD may alter brain anatomy, causing vulnerability to AD-related dementia later in life. In the perinatal period, both genes and learning disabilities have been associated with the development of distinct AD phenotypes. During early childhood, education and intellect, as well as body growth, may predispose to AD through alterations in cognitive and brain reserve, though the specific mediators of neural injury are disputed. Childhood socioeconomic status (SES) may predispose to AD by influencing adult SES and cognition. Association of these risk factors with underlying AD pathology (rather than just clinical diagnosis) has not been sufficiently examined. KEY MESSAGES: Factors that impede or alter brain growth during early life could render certain brain regions or networks selectively vulnerable to the onset, accumulation or spread of AD-related pathology during later life. Careful life-course epidemiology could provide clues as to why the brain systematically degenerates during AD. PMID- 26501692 TI - Clinical presentation and treatment strategies for ulcerative colitis: A retrospective study of 247 inpatients. AB - OBJECTIVE: Complementary and alternative medicine, particularly herbal therapy, is widely used by patients with ulcerative colitis (UC), but controlled data are limited. To describe the clinical presentation and treatment strategies for UC in inpatients from Shanghai, China and to improve the therapeutic outcomes for patients with UC. METHODS: Medical records from 247 patients with UC who were admitted to Longhua Hospital Affifiliated to Shanghai University of Traditional Chinese Medicine between January 2008 and June 2013 were analyzed for gender, age, course of the disease, clinical type, extent and severity of the disease, treatment strategies, and therapeutic outcomes. RESULTS: Gender ratios and disease onset of inpatients with UC in the Shanghai area were consistent with other reports in the literature. In contrast to previous studies, most patients exhibited disease of the left colon, over half of the patients had problems of the rectum or sigmoid colon, and most patients had either mild or moderate UC. Comparison of Sutherland Disease Actirity Index scores for patients treated with Chinese medicine (CM) and those treated with integrated CM and Western medicine revealed signifificant reductions in scores for both groups after treatment (P<0.01), with no signifificant difference in therapeutic effects between groups (P=0.938). CONCLUSIONS: Herbal medicine has been widely used in patients with mild to moderate disease and as adjunct therapy in patients with moderate to severe disease. Therefore, the strategy was proposed for the treatment of UC with CM therapy based on 2 steps according to the stage of the disease, even in the clinical setting. PMID- 26501693 TI - Integrative treatment for low back pain: An exploratory systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: Low back pain (LBP) is a common musculoskeletal condition often treated using integrative medicine (IM). Most reviews have focused on a single complementary and alternative medicine (CAM) therapy for LBP rather than evaluating wider integrative approaches. This exploratory systematic review aimed to identify randomized controlled trials (RCTs) and provide evidence on the effectiveness, cost effectiveness and adverse effects of integrative treatment for LBP. METHODS: A literature search was conducted in 12 English and Chinese databases. RCTs evaluating an integrative treatment for musculoskeletal related LBP were included. Reporting, methodological quality and relevant clinical characteristics were assessed and appraised. Metaanalyses were performed for outcomes where trials were sufficiently homogenous. RESULTS: Fifty-six RCTs were identified evaluating integrative treatment for LBP. Although reporting and methodological qualities were poor, meta-analysis showed a favourable effect for integrative treatment over conventional and CAM treatment for back pain and function at 3 months or less follow-up. Two trials investigated costs, reporting L 5332 per quality adjusted life years with 6 Alexander technique lessons plus exercise at 12 months follow-up; and an increased total costs of $244 when giving an additional up to 15 sessions of CAM package of care at 12 weeks. Sixteen trials mentioned safety; no severe adverse effects were reported. CONCLUSION: Integrative treatment that combines CAM with conventional therapies appeared to have beneficial effects on pain and function. However, evidence is limited due to heterogeneity, the relatively small numbers available for subgroup analyses and the low methodological quality of the included trials. Identification of studies of true IM was not possible due to lack of reporting of the intervention details (registration No. CRD42013003916). PMID- 26501694 TI - Future Perspectives: Agents on the Horizon. AB - As demonstrated in the previous chapters of this textbook, retinal pharmacotherapeutics is a rapidly developing area. The enormous burden of disease in an aging population will hopefully be met by significant improvements in our understanding and treatment of disease processes such as age-related macular degeneration (AMD) and diabetic retinopathy. This chapter will provide perspectives on select anti-angiogenic drugs currently in development, as well as therapies directed against the complement cascade for the treatment of AMD, and an anti-inflammatory monoclonal antibody for the treatment of diabetic macular edema, among others, that have not been discussed elsewhere in this book. The mechanism of action of a number of drugs under discussion differs enough to have the potential to control neovascularization in several different ways, potentially allowing for more effective management of this process with fewer treatments. PMID- 26501696 TI - Isolated Pulmonary Valve Endocarditis. AB - Endocarditis of only the pulmonary valve is a very rare finding and is often missed during echocardiographic evaluation due to limited views of the pulmonary valve and a low index of suspicion. We report 2 cases of pulmonary valve endocarditis (PVE), highlighting the importance of echocardiography in the assessment of the infected pulmonary valve. In addition, we review the published case reports of isolated PVE from 1979 to 2013 in order to study the role of echocardiography in the diagnosis of pulmonary valve masses. PMID- 26501695 TI - Effect of ICD Therapies on Mortality in the OMNI Trial. AB - BACKGROUND: Analyses from primary prevention trials on implantable cardioverter defibrillator (ICD) therapy have shown an association between shocks and increased mortality. Recent data suggest a similar association with antitachycardia pacing (ATP). OBJECTIVE: The OMNI study is an observational study of pacemaker and ICD use. We aim to examine associations between ICD therapies and mortality in this setting. METHODS: A total of 2,255 OMNI patients with ICDs were included. Treated episodes were classified as appropriate or inappropriate. Patients were assigned into 1 of 3 groups depending on whether the episode required ATP only, single shock, or multiple shocks, and then followed for all cause mortality. Additionally, we aimed to determine the frequency with which inappropriate ATP precipitated ventricular arrhythmias that led to shock, since this has been suggested as a mechanism of harm. RESULTS: Over a mean follow-up of 39 +/- 19 months, there were a total of 470 deaths (21%). Compared to patients with no treated episodes, patients with appropriate therapy had greater risk of death. Hazard ratios were 1.46 (95% confidence interval [CI] 1.05-2.02; P = 0.023) for the ATP-only group, 2.11 (95% CI 1.51-2.96; P < 0.001) for the single shock group, and 2.55 (95% CI 1.43-4.57; P = 0.002) for the multishock group. There was no significant association between any type of inappropriate therapy and increased mortality. We identified only 7 instances of inappropriate ATP precipitating ventricular arrhythmia resulting in shock. CONCLUSIONS: Patients receiving appropriate therapy of all types had increased mortality compared to those with no episodes. Furthermore, inappropriate ATP rarely precipitates ventricular arrhythmias. PMID- 26501697 TI - Alvimopan Provides Additional Improvement in Outcomes and Cost Savings in Enhanced Recovery Colorectal Surgery. AB - OBJECTIVE: To examine the impact of alvimopan on outcomes and costs in a rigorous enhanced recovery colorectal surgery protocol. BACKGROUND: Postoperative ileus remains a major source of morbidity and costs in colorectal surgery. Alvimopan has been shown to reduce incidence of postoperative ileus in enhanced recovery colorectal surgery; however, data are equivocal regarding its benefit in reducing length of stay and costs. METHODS: Patients undergoing major elective enhanced recovery colorectal surgery were identified from a prospectively-collected database (2010-2013). Multivariable analyses were employed to compare outcomes and hospital costs among patients who had alvimopan versus no alvimopan by adjusting for demographic, clinical, and treatment characteristics. RESULTS: A total of 660 patients were included; 197 patients received alvimopan and 463 patients had no alvimopan. In unadjusted analysis, the alvimopan group had a faster return of bowel function, shorter length of stay, and lower rates of ileus, Foley re-insertion, and urinary tract infection (all P < 0.01). After adjustment, alvimopan was associated with a faster return of bowel function by 0.6 day (P = 0.0006), and lower incidence of postoperative ileus (odds ratio 0.23, P = 0.0002). With adjustment, alvimopan was associated with a shorter length of stay by 1.6 days (P = 0.002), and a hospital cost savings of $1492 per patient (P = 0.01). CONCLUSIONS: Alvimopan administration as an element of enhanced recovery colorectal surgery is associated with faster return of bowel function, lower incidence of postoperative ileus, shorter hospitalization, and a significant cost savings. These results suggest that alvimopan is cost-effective in the setting of enhanced recovery colorectal surgery protocols, and should therefore be considered in these programs. PMID- 26501698 TI - Increased Patient Enrollment to a Randomized Surgical Trial Through Equipoise Polling of an Expert Surgeon Panel. AB - OBJECTIVE: To determine whether patients who learned the views of an expert surgeons' panel's assessment of equipoise between 2 alternative operative treatments had increased likelihood of consenting to randomization. BACKGROUND: Difficulty obtaining patient consent to randomization is an important barrier to conducting surgical randomized clinical trials, the gold standard for generating clinical evidence. METHODS: Observational study of the rate of patient acceptance of randomization within a 5-center randomized clinical trial comparing lumbar spinal decompression versus lumbar spinal decompression plus instrumented fusion for patients with symptomatic grade I degenerative lumbar spondylolisthesis with spinal stenosis. Eligible patients were enrolled in the trial and then asked to accept randomization. A panel of 10 expert spine surgeons was formed to review clinical information and images for individual patients to provide an assessment of suitability for randomization. The expert panel vote was disclosed to the patient by the patient's surgeon before the patient decided whether to accept randomization or not. RESULTS: Randomization acceptance among eligible patients without expert panel review was 40% (19/48) compared with 81% (47/58) among patients undergoing expert panel review (P < 0.001). Among expert-reviewed patients, randomization acceptance was 95% when all experts or all except 1 voted for randomization, 75% when 2 experts voted against randomization, and 20% with 3 or 4 votes against (P < 0.001 for trend). CONCLUSIONS: Patients provided with an expert panel's assessment of their own suitability for randomization were twice as likely to agree to randomization compared with patients receiving only their own surgeon's recommendation. PMID- 26501699 TI - Long-term Quality of Life After Distal Subtotal and Total Gastrectomy: Symptom- and Behavior-oriented Consequences. AB - OBJECTIVE: This study assessed long-term quality of life (QoL) after subtotal gastrectomy (STG) and total gastrectomy (TG) by comparing groups matched by a set of patient factors at and beyond postoperative 5 years. The cause of QoL gaps based on symptomatic and behavioral consequences of surgery were investigated. BACKGROUND: Survivors after STG and TG were matched by a set of patient factors (age, sex, stage, chemotherapy, and postoperative period). QoL data were obtained from 53 and 36 pairs of survivors at and beyond postoperative 5 years, respectively. METHODS: The European Organization for Research and Treatment of Cancer QoL Questionnaire (QLQ)-C30 and QLQ-STO22 were used to assess QoL. QoL comparisons between STG and TG groups were made for 5-year survivors and long term survivors. RESULTS: Five-year survivors after TG showed significantly worse QoL in social functioning, nausea and vomiting, eating restrictions, and taste. For long-term survivors, QoL inferiority of the TG group was observed only in eating restrictions. Among 4 items constituting eating restrictions, the TG group tended to exhibit worse QoL in 2 items (enjoyable meals and social meals). CONCLUSIONS: Although 5-year survivors after TG still suffer from QoL inferiority from symptomatic and behavioral consequences of surgery, inferiority from behavioral consequences will persist even after symptomatic inferiority to STG survivors is no longer valid. Efforts to ameliorate persistent QoL inferiority in TG survivors should be directed toward restoring dietary behaviors, where TG survivors are prevented from enjoyable meals and social meals. PMID- 26501701 TI - Surgeon Volume and Cancer Esophagectomy, Gastrectomy, and Pancreatectomy: A Population-based Study in England. AB - OBJECTIVE: The aim of the study was to assess whether there is a proficiency curve-like relationship between surgeon volume and operative mortality and determine the minimum surgeon volume for optimum operative mortality. BACKGROUND: The inverse relationship between hospital volume and operative mortality is well established for esophageal, gastric, and pancreatic cancer. The recommended minimum surgeon volumes are however uncertain. METHODS: We retrieved data on esophagectomies, gastrectomies, and pancreatectomies for cancer from the NHS Hospital Episodes Statistics database from April 2000 to March 2010. We defined mortality as in-hospital death within 30 days of surgery. We determined whether there was a proficiency curve relationship by inspecting surgeon volume-mortality graphs after adjusting for patient age, sex, socioeconomic, and comorbidity indices. We then statistically determined the minimum surgeon volume that produced a mortality rate insignificantly different from the optimum of the curve. RESULTS: Sixteen thousand five hundred seventy-two esophagectomies, 12,622 gastrectomies, and 9116 pancreatectomies were examined. Surgeon volume ranged from 2 to 29 esophagectomies, from 1 to 14 gastrectomies, and from 2 to 31 pancreatectomies per surgeon per year. We demonstrated a proficiency relationship between surgeon volume and mortality in esophageal, gastric, and pancreatic cancer surgery. Each additional case of esophagectomy, gastrectomy, and pancreatectomy would reduce 30-day mortality odds by 3.4%, 7.2%, and 4.1%, respectively. However, as surgeon volume increased, mortality rate continued to improve. Therefore, we were unable to recommend minimum surgeon volume. CONCLUSIONS: Mortality after resections for esophageal, gastric, and pancreatic cancer falls as surgeon volume rises up to 30 cases. Within this range, we did not demonstrate any statistical threshold that could be recommended as a minimum volume target. PMID- 26501702 TI - Minimally Invasive Versus Open Low Anterior Resection: Equivalent Survival in a National Analysis of 14,033 Patients With Rectal Cancer. AB - OBJECTIVE: To examine survival of patients who underwent minimally invasive versus open low anterior resection (LAR) for rectal cancer. BACKGROUND: Utilization of laparoscopic and robotic LAR for rectal cancer has steadily increased. Short-term outcomes between these techniques and open surgery have shown equivalent results; however, survival outcomes are unknown. METHODS: Adults from the National Cancer Data Base undergoing LAR for rectal adenocarcinoma were identified. Patients were stratified by intent-to-treat into open (OLAR) or minimally invasive LAR (MI-LAR). Multivariable modeling was used to compare short term outcomes and survival between MI-LAR and OLAR and between laparoscopic (LLAR) and robotic LAR (RLAR). RESULTS: Among 14,033 patients included, 57.8% underwent OLAR and 42.2% MI-LAR. After adjustment, MI-LAR was associated with shorter length of stay (P < 0.001), but similar rates of positive margins, 30-day readmission, 30-day mortality, and use of adjuvant therapies (all P > 0.05). At 36 months, there was no difference in adjusted risk of mortality between MI-LAR and OLAR (hazard ratio [HR] 0.88, P = 0.089). In a subgroup analysis of LLAR versus RLAR, there were no differences in lymph node harvest, margin positivity, length of stay, readmission rate, 30-day mortality, or overall survival after adjustment (all P > 0.05). CONCLUSIONS: Minimally invasive LAR for rectal cancer is associated with similar overall survival with the benefit of shorter hospitalization. Although the conversion rate is lower, robotic LAR is not associated with superior oncologic outcomes compared to laparoscopic LAR. Our findings support the ongoing adoption of minimally invasive techniques for rectal adenocarcinoma. PMID- 26501700 TI - Efficacy and Safety of Glutamine-supplemented Parenteral Nutrition in Surgical ICU Patients: An American Multicenter Randomized Controlled Trial. AB - OBJECTIVE: To determine whether glutamine (GLN)-supplemented parenteral nutrition (PN) improves clinical outcomes in surgical intensive care unit (SICU) patients. SUMMARY BACKGROUND DATA: GLN requirements may increase with critical illness. GLN supplemented PN may improve clinical outcomes in SICU patients. METHODS: A parallel-group, multicenter, double-blind, randomized, controlled clinical trial in 150 adults after gastrointestinal, vascular, or cardiac surgery requiring PN and SICU care. Patients were without significant renal or hepatic failure or shock at entry. All received isonitrogenous, isocaloric PN [1.5 g/kg/d amino acids (AAs) and energy at 1.3* estimated basal energy expenditure]. Controls (n = 75) received standard GLN-free PN (STD-PN); the GLN group (n = 75) received PN containing alanyl-GLN dipeptide (0.5 g/kg/d), proportionally replacing AA in PN (GLN-PN). Enteral nutrition (EN) was advanced and PN weaned as indicated. Hospital mortality and infections were primary endpoints. RESULTS: Baseline characteristics, days on study PN and daily macronutrient intakes via PN and EN, were similar between groups. There were 11 hospital deaths (14.7%) in the GLN-PN group and 13 deaths in the STD-PN group (17.3%; difference, -2.6%; 95% confidence interval, -14.6% to 9.3%; P = 0.66). The 6-month cumulative mortality was 31.4% in the GLN-PN group and 29.7% in the STD-PN group (P = 0.88). Incident bloodstream infection rate was 9.6 and 8.4 per 1000 hospital days in the GLN-PN and STD-PN groups, respectively (P = 0.73). Other clinical outcomes and adverse events were similar. CONCLUSIONS: PN supplemented with GLN dipeptide was safe, but did not alter clinical outcomes among SICU patients. PMID- 26501704 TI - The Conflicting Evidence of Three-dimensional Displays in Laparoscopy: A Review of Systems Old and New. AB - OBJECTIVE: To describe studies evaluating 3 generations of three-dimensional (3D) displays over the course of 20 years. SUMMARY BACKGROUND DATA: Most previous studies have analyzed performance differences during 3D and two-dimensional (2D) laparoscopy without using appropriate controls that equated conditions in all respects except for 3D or 2D viewing. METHODS: Databases search consisted of MEDLINE and PubMed. The reference lists for all relevant articles were also reviewed for additional articles. The search strategy employed the use of keywords "3D," "Laparoscopic," "Laparoscopy," "Performance," "Education," "Learning," and "Surgery" in appropriate combinations. RESULTS: Our current understanding of the performance metrics between 3D and 2D laparoscopy is mostly from the research with flawed study designs. This review has been written in a qualitative style to explain in detail how prior research has underestimated the potential benefit of 3D displays and the improvements that must be made in future experiments comparing 3D and 2D displays to better determine any advantage of using one display or the other. CONCLUSIONS: Individual laparoscopic performance in 3D may be affected by a multitude of factors. It is crucial for studies to measure participant stereoscopic ability, control for system crosstalk, and use validated measures of performance. PMID- 26501703 TI - Development and Validation of the Air Medical Prehospital Triage Score for Helicopter Transport of Trauma Patients. AB - OBJECTIVE: The aim of this study was to develop and internally validate a triage score that can identify trauma patients at the scene who would potentially benefit from helicopter emergency medical services (HEMS). SUMMARY BACKGROUND DATA: Although survival benefits have been shown at the population level, identification of patients most likely to benefit from HEMS transport is imperative to justify the risks and cost of this intervention. METHODS: Retrospective cohort study of subjects undergoing scene HEMS or ground emergency medical services (GEMS) in the National Trauma Databank (2007-2012). Data were split into training and validation sets. Subjects were grouped by triage criteria in the training set and regression used to determine which criteria had a survival benefit associated with HEMS. Points were assigned to these criteria to develop the Air Medical Prehospital Triage (AMPT) score. The score was applied in the validation set to determine whether subjects triaged to HEMS had a survival benefit when actually transported by helicopter. RESULTS: There were 2,086,137 subjects included. Criteria identified for inclusion in the AMPT score included GCS <14, respiratory rate <10 or >29, flail chest, hemo/pneumothorax, paralysis, and multisystem trauma. The optimal cutoff for triage to HEMS was >=2 points. In subjects triaged to HEMS, actual transport by HEMS was associated with an increased odds of survival (AOR 1.28; 95% confidence interval [CI] 1.21-1.36, P < 0.01). In subjects triaged to GEMS, actual transport mode was not associated with survival (AOR 1.04; 95% CI 0.97-1.11, P = 0.20). CONCLUSIONS: The AMPT score identifies patients with improved survival following HEMS transport and should be considered in air medical triage protocols. PMID- 26501705 TI - Rethinking Priorities: Cost of Complications After Elective Colectomy. AB - OBJECTIVE: To compare incremental costs associated with complications of elective colectomy using nationally representative data among patients undergoing laparoscopic/open resections for the 4 most frequent diagnoses. SUMMARY BACKGROUND DATA: Rising healthcare costs have led to increasing focus on the need to achieve a better understanding of the association between costs and quality. Among elective colectomies, a focus of surgical quality-improvement initiatives, interpretable evidence to support existing approaches is lacking. METHODS: The 2009 to 2011 Nationwide Inpatient Sample (NIS) data were queried for adult (>=18 years) patients undergoing elective colectomy. Patients with primary diagnoses for colon cancer, diverticular disease, benign colonic neoplasm, and ulcerative colitis/regional enteritis were included. Based on system-based complications considered relevant to long-term treatment of elective colectomy, stratified differences in risk-adjusted incremental hospital costs and complications probabilities were compared. RESULTS: A total of 68,462 patients were included, weighted to represent 337,887 patients nationwide. A total of 16.4% experienced complications. Annual risk-adjusted incremental costs amounted to >$150 million. Magnitudes of complication prevalences/costs varied by primary diagnosis, operative technique, and complication group. Infectious complications contributed the most ($55 million), followed by gastrointestinal ($53 million), pulmonary ($22 million), and cardiovascular ($11 million) complications. Total annual costs for elective colectomies amounted to >$1.7 billion: 11.3% was due to complications [1.9% due to current Centers for Medicare and Medicaid Services (CMS) complications]. CONCLUSIONS: The results highlight a need to consider the varied/broad impact of complications, offering a stratified paradigm for priority setting in surgery. As we move forward in the development of novel/adaptation of existing interventions, it will be essential to weigh the cost of complications in an evidence-based way. PMID- 26501707 TI - Factors Associated With Treatment Failure of Infected Pressure Sores. AB - OBJECTIVE: In this study, we assess interdisciplinary surgical and medical parameters associated to recurrences of infected pressure ulcers. BACKGROUND: There is a little in the published literature regarding factors associated with the outcome of treatment of infected pressure ulcers. METHODS: We undertook a single-center review of spinal injured adults hospitalized for an infected pressure ulcer or implant-free osteomyelitis and reviewed the literature on this topic from 1990-2015. RESULTS: We found 70 lesions in 31 patients (52 with osteomyelitis) who had a median follow-up of 2.7 years (range, 4 months to 19 years). The median duration of antibiotic therapy was 6 weeks, of which 1 week was parenteral. Clinical recurrence after treatment was noted in 44 infected ulcers (63%), after a median interval of 1 year. In 86% of these recurrences, cultures yielded a different organism than the preceding episode. By multivariate analyses, the following factors were not significantly related to recurrence: number of surgical interventions (hazard ratio 0.9, 95% confidence interval 0.5 1.5); osteomyelitis (hazard ratio 1.5; 0.7-3.1); immune suppression; prior sacral infections, and duration of total (or just parenteral) antibiotic sue. Patients with antibiotic treatment for <6 weeks had the same failure rate as those with as >12 weeks (chi test; P = 0.90). CONCLUSIONS: In patients with infected pressure ulcers, clinical recurrence occurs in almost two-thirds of lesions, but in only 14% with the same pathogen(s). The number of surgical debridements, flap use, or duration of antibiotic therapy was not associated with recurrence, suggesting recurrences are caused by reinfections caused by other extrahospital factors. PMID- 26501706 TI - Impact of Hospital Characteristics on Failure to Rescue Following Major Surgery. AB - OBJECTIVE: To determine the effect of hospital characteristics on failure to rescue after high-risk surgery in Medicare beneficiaries. SUMMARY BACKGROUND DATA: Reducing failure to rescue events is a common quality target for US hospitals. Little is known about which hospital characteristics influence this phenomenon and more importantly by how much. METHODS: We identified 1,945,802 Medicare beneficiaries undergoing 1 of six high-risk general or vascular operations between 2007 and 2010. Using multilevel mixed-effects logistic regression modeling, we evaluated how failure to rescue rates were influenced by specific hospital characteristics previously associated with postsurgical outcomes. We used variance partitioning to determine the relative influence of patient and hospital characteristics on the between-hospital variability in failure to rescue rates. RESULTS: Failure to rescue rates varied up to 11-fold between very high and very low mortality hospitals. Comparing the highest and lowest mortality hospitals, we observed that teaching status (range: odds ratio [OR] 1.08-1.54), high hospital technology (range: OR 1.08-1.58), increasing nurse to-patient ratio (range: OR 1.02-1.14), and presence of >20 intensive care unit (ICU) beds (range: OR 1.09-1.62) significantly influenced failure to rescue rates for all procedures. When taken together, hospital and patient characteristics accounted for 12% (lower extremity revascularization) to 57% (esophagectomy) of the observed variation in failure to rescue rates across hospitals. CONCLUSIONS: Although several hospital characteristics are associated with lower failure to rescue rates, these macrosystem factors explain a small proportion of the variability between hospitals. This suggests that microsystem characteristics, such as hospital culture and safety climate, may play a larger role in improving a hospital's ability to manage postoperative complications. PMID- 26501708 TI - A Nightlight for Adults? A Commentary on "Identifying Ureters In Situ Under Fluorescence During Laparoscopic and Open Colorectal Surgery". PMID- 26501709 TI - Metastatic Spread Emerging From Liver Metastases of Colorectal Cancer: Does the Seed Leave the Soil Again? AB - OBJECTIVE: To investigate whether liver metastases contribute to metastatic spread of colorectal cancer (CRC) by shedding intact tumor cells. BACKGROUND: Metastases represent the primary cause of death in CRC. Understanding the metastatic activity of metastases and which patients are at high risk for tumor cell dissemination may, therefore, have significant influence on cancer care in the future. METHODS: Circulating tumor cells (CTCs) were detected in the hepatic inflow (portal venous blood [PVB]) and outflow compartment (hepatic venous blood [HVB]) of a training (n = 55) and validation (n = 50) set using the CellSearch system. Isolated CTC from the HVB were subjected to gene expression analyses by quantitative polymerase chain reaction. RESULTS: CTC detection rate (37.2% vs 19.6%; P = 0.04) and count (mean: 12.7, SEM: +/- 5.9 vs 1.9; +/- 1.2; P = 0.01) were significantly higher in HVB compared to PVB. The increased CTC detection rate (54% vs 11.4%; P < 0.001) and CTC count (14.7 +/- 5.1 vs 1.1 +/- 0.6; P < 0.001) in the HVB compared to the PVB compartment was confirmed in the validation cohort. Expression of epithelial markers and genes involved in cell-to-cell and cell-to-matrix adhesion was reduced in CTC compared to tumor cells in liver metastases. Metastasis size greater than 5 cm was associated with CTC shedding from established liver metastases in the training and validation cohorts. CONCLUSIONS: Colorectal liver metastases shed intact tumor cells with an invasive phenotype. Metastasis size serves as a surrogate marker for metastatic activity of colorectal liver metastases. PMID- 26501711 TI - Body Mass Index and Perioperative Complications After Esophagectomy for Cancer. AB - BACKGROUND: Given the increasing rate of obesity, the effects of excessive body weight on surgical outcomes constitute a relevant quality of care concern. Our aim was to determine the relationship between preoperative body mass index (BMI) on perioperative complications after esophagectomy for cancer. METHODS: From our comprehensive esophageal cancer database consisting of 510 patients, we identified 166 obese (BMI >=30), 176 overweight (BMI 25-29), and 148 normal weight (BMI 20-24) patients. Malnourished patients (BMI of <20) were excluded. Incidence of preoperative risk factors and perioperative complications in each group were analyzed. RESULTS: The patient group consists of 420 men and 70 women with a mean age at time of surgery were 64 years (range 28-86 years). The categories of patients (obese, overweight, and normal-weight) were similar in terms of demographics and comorbidities, with the exception of a younger age (62.5 years vs 66.2 years vs 65.3 years, P = 0.002), and a higher incidence of diabetes (23.5% vs 11.4% vs 10.1%, P = 0.001) and hiatal hernia (28.3% vs 14.8% vs 20.3%, P = 0.01) for obese patients. More patients with BMI >24 were found with adenocarcinoma, compared with the normal-weight group (90.8% vs 90.9% vs 82.5%, P = 0.03). Despite similar preoperative stage, obese patients were less likely to receive neoadjuvant treatment (47.6% vs 54.5% vs 66.2%, P = 0.004). The type of surgery performed, overall blood loss, extent of lymphadenectomy, rate of resections with negative margins, and postoperative complications were not influenced by BMI on univariate and multivariate analysis. CONCLUSIONS: In our experience, BMI did not affect number of harvested lymph-nodes, rates of negative margins, and morbidity and mortality after esophagectomy for cancer. In our experience, esophagectomy could be performed safely and efficiently in mildly obese patients. PMID- 26501712 TI - Systematic Review and Meta-analysis of Current Experience in Treating IPNB: Clinical and Pathological Correlates. AB - OBJECTIVE: To systematically review studies reporting clinicopathological features of intraductal papillary neoplasm of the bile duct (IPNB) to provide evidence-based guidance for management. BACKGROUND: IPNB is a rare tumor type. Management decisions are currently based upon anecdotal evidence and small case series. To data, there has been no systematic review of IPNB literature. METHODS: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched and data were extracted from relevant studies. Meta-analysis was used to pool study estimates. Evidence of association was determined by comparing pooled crude odds ratios (OR) derived from abstracted data. RESULTS: Fifty-seven retrospective case series were included. At least 43% of 476 specimens contained invasive disease. Invasive tumors were found at significantly higher frequency in pancreaticobiliary than intestinal, gastric or oncocytic-type IPNB [pooled OR 2.5, 95% confidence interval (CI) 1.5-4.2, P < 0.001]. A significantly higher proportion of pancreaticobiliary tumors compared with intestinal tumors expressed MUC-1 [86.4% (95% CI 75.1%-94.7%) vs 13.2% (95% CI 4.6%-25.2%), respectively P < 0.001]. IPNB identified in centers from Asia were more likely to be intrahepatic and were less frequently invasive compared with those from Western centers. Pooled estimates of absolute survival after IPNB resection were 96% (95% CI 93% 99%) at 1 year, 79% (95% CI 69%-88%) at 3 years, and 65% (95% CI 46%-76%) at 5 years. CONCLUSIONS: Early surgery is advisable for radiologically suspected IPNB as it is frequently invasive. The pathobiology of IPNB demonstrates geographic variation. Pancreaticobiliary IPNB expresses MUC1 and is more frequently associated with invasive disease than other IPNB subtypes. PMID- 26501713 TI - Outcomes From Minimal Access Retroperitoneal and Open Pancreatic Necrosectomy in 394 Patients With Necrotizing Pancreatitis. AB - OBJECTIVE: To examine the outcomes from minimal access retroperitoneal pancreatic necrosectomy (MARPN) and open pancreatic necrosectomy (OPN) for severe necrotizing pancreatitis in a single center. BACKGROUND: The optimal management of severe pancreatic necrosis is evolving with a few large center single series. METHODS: Between 1997 and 2013, patients with necrotizing pancreatitis at the Liverpool Pancreas Center were reviewed. Outcome measures were retrospectively analyzed by intention to treat. RESULTS: There were 394 patients who had either MARPN (274, 69.5%) or OPN (120, 30.5%). Complications occurred in 174 MARPN patients (63.5%) and 98 (81.7%) OPN patients (P < 0.001). OPN was associated with increased postoperative multiorgan failure [42 (35%) vs 56 (20.4%), P = 0.001] and median (inter-quartile range) Acute Physiology and Chronic Health Evaluation II score 9 (6-11.5) vs 8 (5-11), P < 0.001] with intensive care required less frequently in MARPN patients [40.9% (112) vs 75% (90), P < 0.001]. The mortality rate was 42 (15.3%) in MARPNs and 28 (23.3%) in OPNs (P = 0.064). Both the mortality and the overall complication rates decreased between 1997-2008 and 2008 2013 [49 (23.8%) vs 21 (11.2%) P = 0.001, respectively; and 151 (73.3%) vs 121 (64.4%), P = 0.080, respectively). Increased mortality was independently associated with age (P < 0.001), preoperative intensive care stay (P = 0.014), and multiple organ failure (P < 0.001); operation before 2008 (P < 0.001) and conversion to OPN (P = 0.035). MARPN independently reduced mortality odds risk (odds ratio = 0.27; 95% confidence interval = 0.12-0.57; P < 0.001). CONCLUSIONS: Increasing experience and advances in perioperative care have led to improvement in outcomes. The role of MARPN in reducing complications and deaths within a multimodality approach remains substantial and should be used initially if feasible. PMID- 26501714 TI - Antireflux Surgery and Risk of Esophageal Adenocarcinoma: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To investigate the preventive effect of antireflux surgery against esophageal adenocarcinoma (EAC) compared with medical treatment of gastroesophageal reflux disease (GERD) and to the background population. BACKGROUND: GERD is causally associated with EAC. Effective symptomatic treatment can be achieved with medication and antireflux surgery; however the possible preventive effect on EAC development remains unclear. METHODS: This systematic review identified 10 studies comparing EAC risk after antireflux surgery with nonoperated GERD patients, including 7 studies of patients with Barrett's esophagus, and 2 studies comparing EAC risk after antireflux surgery to the background population. A fixed-effects Poisson meta-analysis was conducted to calculate pooled incidence rate ratios (IRR) and 95% confidence intervals (CIs). RESULTS: The pooled IRR in patients after antireflux surgery was 0.76 (95% CI 0.42-1.39) compared with medically treated GERD patients. In patients with Barrett's esophagus, the corresponding IRR was 0.46 (95% CI 0.20-1.08), and 0.26 (95% CI 0.09-0.79) when restricted to publications after 2000. There was no difference in EAC risk between antireflux surgery and medical treatment in GERD patients without known Barrett's esophagus (IRR 0.98, 95% CI 0.72-1.33). The EAC risk remained elevated in patients after antireflux surgery compared with the background population (IRR 10.78, 95% CI 8.48-13.71). Although the clinical heterogeneity of the included studies was high, the statistical heterogeneity was low. CONCLUSIONS: Antireflux surgery may prevent EAC better than medical therapy in patients with Barrett's esophagus. The EAC risk after antireflux surgery does not seem to revert to that of the background population. PMID- 26501715 TI - Safety of the Use of Blood Salvage and Autotransfusion During Liver Transplantation for Hepatocellular Carcinoma. AB - OBJECTIVE: To determine whether autotransfusion of red blood cells (RBCs) salvaged during liver transplantation is associated with the recurrence of hepatocellular carcinoma (HCC). BACKGROUND: Blood salvage is widely used during liver transplantation to reinfuse salvaged autologous RBCs and reduce allogeneic transfusion. However, the reintroduction of cancer cells via autotransfusion is a major concern in HCC patients. METHODS: Among 397 patients who underwent living donor liver transplantation for HCC, 97 of 114 recipients without intraoperative autotransfusion were matched with 222 of 283 recipients with intraoperative autotransfusion with unfixed matching ratio using the propensity score based on age, sex, allogeneic transfusion, immunosuppression, tumor biology, and others. Competing risks Cox regression was used to compare HCC recurrence risk of the 2 paired groups. RESULTS: Recipients in autotransfusion group received 1177 +/- 1318 mL of salvaged RBCs during surgery. A leukocyte depletion filter was used for all autotransfused RBCs. Cumulative HCC recurrence rate at 1, 2, and 5 years after transplantation were 10.4% (5.3%-17.6%), 19.1% (11.6%-28.0%), and 24.1% (15.2%-34.0%) for nonautotransfusion group and 10.8% (7.2%-15.4%), 14.9% (10.5% 20.0%), and 20.3% (14.9%-26.4%) for autotransfusion group, respectively. Autotransfusion versus nonautotransfusion group was not significantly different in overall recurrence [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.47 1.53, P = 0.579] and intrahepatic recurrence (HR 0.75, 95% CI 0.36-1.56) or extrahepatic recurrence (HR 1.00, 95% CI 0.49-2.04). CONCLUSIONS: We found no evidence of a significant impact of autotransfusion on posttransplant HCC recurrence. Thus, salvaged and filtered RBCs could be used in HCC patients undergoing liver transplantation with potential benefits from avoiding allogeneic RBCs transfusion and its complications. PMID- 26501718 TI - Design of a Metal Oxide-Organic Framework (MoOF) Foam Microreactor: Solar-Induced Direct Pollutant Degradation and Hydrogen Generation. AB - A macroporous carbon network combined with mesoporous catalyst immobilization by a template method gives a metal-oxide-organic framework (MoOF) foam microreactor that readily soaks up pollutants and localizes solar energy in itself, leading to effective degradation of water pollutants (e.g., methyl orange (MO) and also hydrogen generation. The cleaned-up water can be removed from the microreactor simply by compression, and the microreactor used repeatedly. PMID- 26501719 TI - IOM REPORT ON PSYCHOSOCIAL TREATMENTS: CBT PERSPECTIVE. PMID- 26501720 TI - EDUCATION AND IMAGING. Gastrointestinal: Not just a simple pneumothorax. PMID- 26501721 TI - Economic recovery: A measure of the quality of cancer treatment and survivorship? PMID- 26501722 TI - Vortex domain wall propagation in periodically modulated diameter FeCoCu nanowire as determined by the magneto-optical Kerr effect. AB - Control over the magnetization reversal process of nanowires is essential to current advances in modern spintronic media and magnetic data storage. Much effort has been devoted to permalloy nanostrips with rectangular cross section and vanishing crystalline anisotropy. Our aim was to unveil and control the reversal process in FeCoCu nanowires with significant anisotropy and circular cross section with tailored periodical modulations in diameter. Magneto-optical Kerr effect measurements and their angular dependence performed on individual nanowires together with their analysis allow us to conclude that the demagnetization process takes place due to the propagation of a single vortex domain wall which is eventually pinned at given modulations with slightly higher energy barrier. In addition these results create new expectations for further controlling of the propagation of single and multiple domain walls. PMID- 26501723 TI - Developing concepts of ordinary and extraordinary communication. AB - We examine how understandings of ordinary and extraordinary communication develop. Three- to 10-year-old children and adults (N = 183) were given scenarios in which a protagonist wanted help from a human (their parent) or from God. Scenarios varied in whether protagonists expressed their desires aloud (by asking) or silently (by hoping), whether (for human scenarios) parents were nearby or far away, and whether (for God scenarios) protagonists expressed desires through ordinary means (asking or hoping) or more extraordinary means (praying). Following each scenario, participants were asked whether the recipient (either the parent or God) was aware of the protagonist's desire. Children as young as 3 to 4 years old understood that both loudness and distance limit the effectiveness of human communication, reporting that humans would most likely be aware of desires when they were expressed both aloud and nearby. As well, by this age children reported that God would more often be aware of desires than would humans, but children of all ages often reported that God (like humans) would be more aware of desires expressed aloud (rather than silently). These concepts of ordinary and extraordinary communication continued to be refined through middle childhood. Children's performance on standard theory-of-mind tasks and participants' religious background predicted whether they attributed awareness to God. (PsycINFO Database Record PMID- 26501724 TI - Is greater improvement in early self-regulation associated with fewer behavioral problems later in childhood? AB - The aim of this study was to determine whether the extent of improvement in self regulation achieved between ages 4 and 6 years is associated with the level of behavioral problems later in childhood. Participants were 4-year-old children (n = 510) attending preschools in South Australia. Children's level of self regulation was assessed using the parent-completed Devereux Early Childhood Assessment when children were aged 4, 5, and 6. Children's level of behavioral problems was assessed using total, internalizing, and externalizing scores on parent- and teacher-rated Strengths and Difficulties Questionnaires (SDQs) when children were 6 years old. Random effects regression was used to describe the changes to children's self-regulation between 4 and 6 years. Linear regression models were then used to determine the strength of the association between the extent of self-regulation improvement and level of behavioral problems. Greater improvement in self-regulation, adjusted for family characteristics and baseline self-regulation scores, was associated with lower levels of parent- (B = -3.57, 95% confidence interval [CI] [-4.49, -2.65]) and teacher-rated SDQ total difficulties scores at 6 years (B = -2.42, 95% CI [-3.50, -1.34]). These effects remained after adjustment for level of parent-rated behavioral problems at 4 years. Similar effects were found for internalizing and externalizing scores at age 6 years. The results highlight the importance of improvements in self regulation from 4-6 years for childhood behavioral problems during the early school years. Children with lower levels of improvement in self-regulation early in life are at risk for higher levels of behavioral problems both at home and at school. PMID- 26501725 TI - Who mothers mommy? Factors that contribute to mothers' well-being. AB - Developmental science is replete with studies on the impact of mothers on their children, but little is known about what might best help caregivers to function well themselves. In an initial effort to address this gap, we conducted an Internet-based study of over 2,000 mostly well-educated mothers, seeking to illuminate salient risk and protective processes associated with their personal well-being. When women's feelings in the parenting role were considered along with dimensions of personal support as predictors, the latter set explained at least as much variance-and often much more-across dimensions of mothers' personal well-being. Within the latter set of personal support predictors, findings showed that 4 had particularly robust links with mothers' personal adjustment: their feeling unconditionally loved, feeling comforted when in distress, authenticity in relationships, and satisfaction with friendships. Partner satisfaction had some associations with personal adjustment outcomes, but being married in itself had negligible effects. Findings are discussed in terms of implications for future research, and for interventions aimed at fostering resilience among mothers facing high level of stress in their role as parents. (PsycINFO Database Record PMID- 26501726 TI - A longitudinal study of coordination in mother-infant vocal interaction from age 4 to 10 months. AB - This is a longitudinal study of development in coordinated mother-infant vocal interaction from 4 to 10 months (N = 41) focusing on the development of turn taking patterns and time spent in coordinated vocal interaction. Data analyses were carried out using multistate analysis. Both mothers and infants were found to coordinate their own vocalizations with their partners' vocalizations. The infants had a predominant pattern of covocalizing, whereas the mothers had a predominant turn-taking pattern at all ages (4, 7, and 10 months). However, a significant reduction in the duration of covocalization was found between 4 and 7 months, due to less covocalizing compared to turn-taking from the infants. In addition, time spent in coordinated vocal interaction increased significantly between 4 and 7 months and a development for the infants was found from repeated vocalizations toward single vocalizations between maternal turns. Taken together, these findings indicate a developmental process of fine-tuning and increasing the turn-taking format for vocal communication, characterizing adult communication, before the development of speech. In addition, our results indicate that this development starts earlier and is more prolonged than has been hypothesized from previous research. (PsycINFO Database Record PMID- 26501727 TI - What it feels like to be a mother: Variations by children's developmental stages. AB - The central question we addressed was whether mothers' adjustment might vary systematically by the developmental stages of their children. In an Internet based study of over 2,200 mostly well-educated mothers with children ranging from infants to adults, we examined multiple aspects of mothers' personal well-being, parenting, and perceptions of their children. Uniformly, adjustment indices showed curvilinear patterns across children's developmental stages, with mothers of middle-schoolers faring the most poorly, and mothers of adult children and infants faring the best. Findings based on children in mutually exclusive age groups-for example, mothers with only (1 or more) infants, preschoolers, and so forth-had larger effect sizes than those based on the age of the mothers' oldest child. In contrast to the recurrent findings based on children's developmental stages, mothers' adjustment dimensions showed few variations by their children's gender. Collectively, results of this study suggest that there is value in preventive interventions involving mothers not just in their children's infancy and preschool years, but also as their children traverse the developmentally challenging years surrounding puberty. (PsycINFO Database Record PMID- 26501728 TI - Older adults have difficulty in decoding sarcasm. AB - Younger and older adults differ in performance on a range of social-cognitive skills, with older adults having difficulties in decoding nonverbal cues to emotion and intentions. Such skills are likely to be important when deciding whether someone is being sarcastic. In the current study we investigated in a life span sample whether there are age-related differences in the interpretation of sarcastic statements. Using both video and verbal materials, 116 participants aged between 18 and 86 completed judgments about whether statements should be interpreted literally or sarcastically. For the verbal stories task, older adults were poorer at understanding sarcastic intent compared with younger and middle aged participants, but there was no age difference in interpreting control stories. For the video task, older adults showed poorer understanding of sarcastic exchanges compared with younger and middle-aged counterparts, but there was no age difference in understanding the meaning of sincere interactions. For the videos task, the age differences were mediated by the ability to perceive facial expressions of emotion. Age effects could not be explained in terms of variance in working memory. These results indicate that increased age is associated with specific difficulties in using nonverbal and contextual cues to understand sarcastic intent. (PsycINFO Database Record PMID- 26501729 TI - Perceived discrimination and personality development in adulthood. AB - Perceived discrimination is common and a significant source of stress that may have implications for personality development across adulthood. In this study, we examined whether experiences with discrimination were associated with maladaptive changes in the 5 major dimensions of personality using 2 longitudinal samples that differed in age and follow-up interval. In the Health and Retirement Study, participants who perceived discrimination increased in their tendency to experience negative emotions (neuroticism), decreased in their tendency to be trusting (agreeableness), and decreased in their tendency to be organized and disciplined (conscientiousness). These associations replicated using participants from the Midlife in the United States study. The findings indicate that social pathways, in addition to biological and developmental tasks, are important for adult personality development. (PsycINFO Database Record PMID- 26501730 TI - Romance, risk, and replication: Can consumer choices and risk-taking be primed by mating motives? AB - Interventions aimed at influencing spending behavior and risk-taking have considerable practical importance. A number of studies motivated by the costly signaling theory within evolutionary psychology have reported that priming inductions (such as looking at pictures of attractive opposite sex members) designed to trigger mating motives increase males' stated willingness to purchase conspicuous consumption items and to engage in risk-taking behaviors, and reduce loss aversion. However, a meta-analysis of this literature reveals strong evidence of either publication bias or p-hacking (or both). We then report 8 studies with a total sample of over 1,600 participants which sought to reproduce these effects. None of the studies, including one that was fully preregistered, was successful. The results question the claim that romantic primes can influence risk-taking and other potentially harmful behaviors. PMID- 26501731 TI - Bedside to Bench Well Illustrated in Myopia. PMID- 26501733 TI - Driving with Glaucoma: Task Performance and Gaze Movements. AB - PURPOSE: The aim of this pilot study was to assess the driving performance and the visual search behavior, that is, eye and head movements, of patients with glaucoma in comparison to healthy-sighted subjects during a simulated driving test. METHODS: Driving performance and gaze behavior of six glaucoma patients and eight healthy-sighted age- and sex-matched control subjects were compared in an advanced driving simulator. All subjects underwent a 40-minute driving test including nine hazardous situations on city and rural roads. Fitness to drive was assessed by a masked driving instructor according to the requirements of the official German driving test. Several driving performance measures were investigated: lane position, time to line crossing, and speed. Additionally, eye and head movements were tracked and analyzed. RESULTS: Three out of six glaucoma patients passed the driving test and their driving performance was indistinguishable from that of the control group. Patients who passed the test showed an increased visual exploration in comparison to patients who failed; that is, they showed increased number of head and gaze movements toward eccentric regions. Furthermore, patients who failed the test showed a rightward bias in average lane position, probably in an attempt to maximize the safety margin to oncoming traffic. CONCLUSIONS: Our study suggests that a considerable subgroup of subjects with binocular glaucomatous visual field loss shows a safe driving behavior in a virtual reality environment, because they adapt their viewing behavior by increasing their visual scanning. Hence, binocular visual field loss does not necessarily influence driving safety. We recommend that more individualized driving assessments, which will take into account the patient's ability to compensate, are required. PMID- 26501735 TI - Who Says There's Nothing New under the Sun? AB - The time since our first publication in 2007 describing time spent outdoors as protective for juvenile myopia onset to clinical trials incorporating outdoor light interventions has been short. The time outdoors/myopia example highlights the incorporation of clinical or epidemiologic evidence to translational research that may eventually change clinical practice and/or behavior. PMID- 26501737 TI - A 2-year multicentre, open-label, randomized, controlled study of growth hormone (Genotropin(r)) treatment in very young children born small for gestational age: Early Growth and Neurodevelopment (EGN) Study. AB - OBJECTIVE: In Europe, growth hormone (GH) treatment for children born small for gestational age (SGA) can only be initiated after 4 years of age. However, younger age at treatment initiation is a predictor of favourable response. To assess the effect of GH treatment on early growth and cognitive functioning in very young (<30 months), short-stature children born SGA. DESIGN: A 2-year, randomized controlled, multicentre study (NCT00627523; EGN study), in which patients received either GH treatment or no treatment for 24 months. PATIENTS: Children aged 19-29 months diagnosed as SGA at birth, and for whom sufficient early growth data were available, were eligible. Patients were randomized (1:1) to GH treatment (Genotropin(r), Pfizer Inc.) at a dose of 0.035 mg/kg/day by subcutaneous injection, or no treatment. MEASUREMENTS: The primary objective was to assess the change from baseline in height standard deviation score (SDS) after 24 months of GH treatment. RESULTS: Change from baseline in height SDS was significantly greater in the GH treatment vs control group at both month 12 (1.03 vs 0.14) and month 24 (1.63 vs 0.43; both P < 0.001). Growth velocity SDS was significantly higher in the GH treatment vs control group at 12 months (P < 0.001), but not at 24 months. There was no significant difference in mental or psychomotor development indices between the two groups. CONCLUSIONS: GH treatment for 24 months in very young short-stature children born SGA resulted in a significant increase in height SDS compared with no treatment. PMID- 26501738 TI - Improving Accuracy in Arrhenius Models of Cell Death: Adding a Temperature Dependent Time Delay. AB - The Arrhenius formulation for single-step irreversible unimolecular reactions has been used for many decades to describe the thermal damage and cell death processes. Arrhenius predictions are acceptably accurate for structural proteins, for some cell death assays, and for cell death at higher temperatures in most cell lines, above about 55 degrees C. However, in many cases--and particularly at hyperthermic temperatures, between about 43 and 55 degrees C--the particular intrinsic cell death or damage process under study exhibits a significant "shoulder" region that constant-rate Arrhenius models are unable to represent with acceptable accuracy. The primary limitation is that Arrhenius calculations always overestimate the cell death fraction, which leads to severely overoptimistic predictions of heating effectiveness in tumor treatment. Several more sophisticated mathematical model approaches have been suggested and show much-improved performance. But simpler models that have adequate accuracy would provide useful and practical alternatives to intricate biochemical analyses. Typical transient intrinsic cell death processes at hyperthermic temperatures consist of a slowly developing shoulder region followed by an essentially constant-rate region. The shoulder regions have been demonstrated to arise chiefly from complex functional protein signaling cascades that generate delays in the onset of the constant-rate region, but may involve heat shock protein activity as well. This paper shows that acceptably accurate and much-improved predictions in the simpler Arrhenius models can be obtained by adding a temperature-dependent time delay. Kinetic coefficients and the appropriate time delay are obtained from the constant-rate regions of the measured survival curves. The resulting predictions are seen to provide acceptably accurate results while not overestimating cell death. The method can be relatively easily incorporated into numerical models. Additionally, evidence is presented to support the application of compensation law behavior to the cell death processes- that is, the strong correlation between the kinetic coefficients, ln{A} and E(a), is confirmed. PMID- 26501739 TI - Measuring the Effectiveness of Mammography. PMID- 26501740 TI - Persistent Language Delay Versus Late Language Emergence in Children With Early Cochlear Implantation. AB - PURPOSE: The purpose of the present investigation is to differentiate children using cochlear implants (CIs) who did or did not achieve age-appropriate language scores by midelementary grades and to identify risk factors for persistent language delay following early cochlear implantation. MATERIALS AND METHOD: Children receiving unilateral CIs at young ages (12-38 months) were tested longitudinally and classified with normal language emergence (n = 19), late language emergence (n = 22), or persistent language delay (n = 19) on the basis of their test scores at 4.5 and 10.5 years of age. Relative effects of demographic, audiological, linguistic, and academic characteristics on language emergence were determined. RESULTS: Age at CI was associated with normal language emergence but did not differentiate late emergence from persistent delay. Children with persistent delay were more likely to use left-ear implants and older speech processor technology. They experienced higher aided thresholds and lower speech perception scores. Persistent delay was foreshadowed by low morphosyntactic and phonological diversity in preschool. Logistic regression analysis predicted normal language emergence with 84% accuracy and persistent language delay with 74% accuracy. CONCLUSION: CI characteristics had a strong effect on persistent versus resolving language delay, suggesting that right-ear (or bilateral) devices, technology upgrades, and improved audibility may positively influence long-term language outcomes. PMID- 26501742 TI - Development of new ecological long-lasting dispensers of semiochemicals for the control of Bactrocera oleae (Rossi). PMID- 26501741 TI - Treatment and Outcome of Thrombolysis-Related Hemorrhage: A Multicenter Retrospective Study. AB - IMPORTANCE: Treatments for symptomatic intracerebral hemorrhage (sICH) are based on expert opinion, with limited data available on efficacy. OBJECTIVE: To better understand the natural history of thrombolysis-related sICH, with a focus on the efficacy of various treatments used. DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective study between January 1, 2009, and April 30, 2014, at 10 primary and comprehensive stroke centers across the United States. Participants were all patients with sICH, using the definition by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), which included a parenchymal hematoma type 2 and at least a 4-point increase in the National Institutes of Health Stroke Scale score. MAIN OUTCOMES AND MEASURES: The primary outcome was in-hospital mortality, and the secondary outcome was hematoma expansion, defined as a 33% increase in the hematoma volume on follow-up imaging. RESULTS: Of 3894 patients treated with intravenous recombinant tissue plasminogen activator (rtPA) within 41/2 hours after symptom onset of ischemic stroke, 128 (3.3%) had sICH. The median time from initiation of rtPA therapy to sICH diagnosis was 470 minutes (range, 30-2572 minutes), and the median time from diagnosis to treatment of sICH was 112 minutes (range, 12-628 minutes). The in hospital mortality rate was 52.3% (67 of 128), and 26.8% (22 of 82) had hematoma expansion. In the multivariable models, code status change to comfort measures after sICH diagnosis was the sole factor associated with increased in-hospital mortality (odds ratio, 3.6; 95% CI, 1.2-10.6). Severe hypofibrinogenemia (fibrinogen level, <150 mg/dL) was associated with hematoma expansion, occurring in 36.3% (8 of 22) of patients without hematoma expansion vs in 25.0% (15 of 60) of patients with hematoma expansion (P = .01), highlighting a role for cryoprecipitate in reversing rtPA coagulopathy. CONCLUSIONS AND RELEVANCE: In this study, treatment of postthrombolysis sICH did not significantly reduce the likelihood of in-hospital mortality or hematoma expansion. Shortening the time to diagnosis and treatment may be a key variable in improving outcomes of patients with sICH. PMID- 26501743 TI - Cancer Hallmark-Based Gene Sets and Personalized Medicine for Patients With Stage II Colon Cancer. PMID- 26501744 TI - Strain mapping accuracy improvement using super-resolution techniques. AB - Super-resolution (SR) software-based techniques aim at generating a final image by combining several noisy frames with lower resolution from the same scene. A comparative study on high-resolution high-angle annular dark field images of InAs/GaAs QDs has been carried out in order to evaluate the performance of the SR technique. The obtained SR images present enhanced resolution and higher signal to-noise (SNR) ratio and sharpness regarding the experimental images. In addition, SR is also applied in the field of strain analysis using digital image processing applications such as geometrical phase analysis and peak pairs analysis. The precision of the strain mappings can be improved when SR methodologies are applied to experimental images. PMID- 26501745 TI - Potentially inappropriate anticholinergic medication use in older adults with dementia. AB - OBJECTIVE: To examine the prevalence and predictors of potentially inappropriate anticholinergic medication use in older adults with dementia. DESIGN: A cross sectional study. SETTING: United States, 2009-2010. PARTICIPANTS: Medical Expenditure Panel Survey household component participants aged 65 years or older identified as having dementia and using potentially inappropriate anticholinergic medication. MAIN OUTCOME MEASURES: Prevalence and predictors of potentially inappropriate anticholinergic medication use as per the updated 2012 American Geriatrics Society Beers criteria. RESULTS: A total of 3.78 million older adult patients (95% confidence interval [CI] 3.17 million to 4.38 million) were identified as having dementia, for an overall prevalence of 4.81%. Of those patients, an estimated 1.02 million (95% CI 0.70 million to 1.30 million) were reported to use potentially inappropriate anticholinergic medications, for an overall prevalence of 26.95% (95% CI 20.10% to 33.79%). The most frequently prescribed drugs were oxybutynin, solifenacin, paroxetine, tolterodine, promethazine, and cyclobenzaprine. Multivariable logistic analysis revealed that those patients with the need characteristics of self-reported anxiety, mood disorders, and "fair/poor" general health status had increased odds of potentially inappropriate anticholinergic use, while patients with the predisposing characteristic of being aged 75-84 years had decreased odds of potentially inappropriate anticholinergic use. CONCLUSION: More than one in four older adults with dementia were found to use potentially inappropriate anticholinergics. Given the adverse cognitive effects of these medications, there is a strong need to monitor and optimize their use in older adult patients with dementia. PMID- 26501746 TI - Summaries for Patients. Screening for Abnormal Blood Glucose and Type 2 Diabetes: U.S. Preventive Services Task Force Recommendation. PMID- 26501748 TI - Chemotherapy for Malignant Intraocular Tumors. AB - Chemotherapeutic approaches, including chemoreduction (CRD), chemothermotherapy, as well as periocular, intravitreal, and intra-arterial chemotherapy, are effective tools in managing different types of ocular tumors. Treatments are often individualized to patient and tumor types to yield best possible outcomes. Due to space limitations, this chapter will focus on CRD and intra-arterial chemotherapy for retinoblastoma. PMID- 26501747 TI - Pulmonary Artery Enlargement Is Associated With Cardiac Injury During Severe Exacerbations of COPD. AB - BACKGROUND: Relative pulmonary arterial enlargement, defined by a pulmonary artery to aorta (PA/A) ratio > 1 on CT scanning, predicts hospitalization for acute exacerbations of COPD (AECOPD). However, it is unclear how AECOPD affect the PA/A ratio. We hypothesized that the PA/A ratio would increase at the time of AECOPD and that a ratio > 1 would be associated with worse clinical outcomes. METHODS: Patients discharged with an International Classification of Diseases, Ninth Revision, diagnosis of AECOPD from a single center over a 5-year period were identified. Patients were included who had a CT scan performed during the stable period prior to the index AECOPD episode as well as a CT scan at the time of hospitalization. A subset of patients also underwent postexacerbation CT scans. The pulmonary arterial diameter, ascending aortic diameter, and the PA/A ratio were measured on CT scans. Demographic data, comorbidities, troponin level, and hospital outcome data were analyzed. RESULTS: A total of 134 patients were included in the study. They had a mean age of 65 +/- 10 years, 47% were male, and 69% were white; overall, patients had a mean FEV1 of 47% +/- 19%. The PA/A ratio increased from baseline at the time of exacerbation (0.97 +/- 0.15 from 0.91 +/- 0.17; P < .001). Younger age and known pulmonary hypertension were independently associated with an exacerbation PA/A ratio > 1. Patients with PA/A ratio > 1 had higher troponin values. Those with a PA/A ratio > 1 and troponin levels > 0.01 ng/mL had increased acute respiratory failure, ICU admission, or inpatient mortality compared with those without both factors (P = .0028). The PA/A ratio returned to baseline values following AECOPD. CONCLUSIONS: The PA/A ratio increased at the time of severe AECOPD and a ratio > 1 predicted cardiac injury and a more severe hospital course. PMID- 26501749 TI - 2D materials: Single photons at room temperature. PMID- 26501750 TI - Macromolecular crowding creates heterogeneous environments of gene expression in picolitre droplets. AB - Understanding the dynamics of complex enzymatic reactions in highly crowded small volumes is crucial for the development of synthetic minimal cells. Compartmentalized biochemical reactions in cell-sized containers exhibit a degree of randomness due to the small number of molecules involved. However, it is unknown how the physical environment contributes to the stochastic nature of multistep enzymatic processes. Here, we present a robust method to quantify gene expression noise in vitro using droplet microfluidics. We study the changes in stochasticity in the cell-free gene expression of two genes compartmentalized within droplets as a function of DNA copy number and macromolecular crowding. We find that decreased diffusion caused by a crowded environment leads to the spontaneous formation of heterogeneous microenvironments of mRNA as local production rates exceed the diffusion rates of macromolecules. This heterogeneity leads to a higher probability of the molecular machinery staying in the same microenvironment, directly increasing the system's stochasticity. PMID- 26501751 TI - Quantum emission from hexagonal boron nitride monolayers. AB - Artificial atomic systems in solids are widely considered the leading physical system for a variety of quantum technologies, including quantum communications, computing and metrology. To date, however, room-temperature quantum emitters have only been observed in wide-bandgap semiconductors such as diamond and silicon carbide, nanocrystal quantum dots, and most recently in carbon nanotubes. Single photon emission from two-dimensional materials has been reported, but only at cryogenic temperatures. Here, we demonstrate room-temperature, polarized and ultrabright single-photon emission from a colour centre in two-dimensional hexagonal boron nitride. Density functional theory calculations indicate that vacancy-related defects are a probable source of the emission. Our results demonstrate the unprecedented potential of van der Waals crystals for large-scale nanophotonics and quantum information processing. PMID- 26501752 TI - Non-Boolean computing with nanomagnets for computer vision applications. AB - The field of nanomagnetism has recently attracted tremendous attention as it can potentially deliver low-power, high-speed and dense non-volatile memories. It is now possible to engineer the size, shape, spacing, orientation and composition of sub-100 nm magnetic structures. This has spurred the exploration of nanomagnets for unconventional computing paradigms. Here, we harness the energy-minimization nature of nanomagnetic systems to solve the quadratic optimization problems that arise in computer vision applications, which are computationally expensive. By exploiting the magnetization states of nanomagnetic disks as state representations of a vortex and single domain, we develop a magnetic Hamiltonian and implement it in a magnetic system that can identify the salient features of a given image with more than 85% true positive rate. These results show the potential of this alternative computing method to develop a magnetic coprocessor that might solve complex problems in fewer clock cycles than traditional processors. PMID- 26501753 TI - Intern and Resident Workflow Patterns on Pediatric Inpatient Units: A Multicenter Time-Motion Study. PMID- 26501754 TI - Utility of Evidence-Based Medicine in the Medical Profession. PMID- 26501755 TI - Landmark Article Supports Osteopathic Medicine. PMID- 26501756 TI - Correction. PMID- 26501757 TI - Feasibility of Using Ultrasonography to Establish Relationships Among Sacral Base Position, Sacral Sulcus Depth, Body Mass Index, and Sex. AB - CONTEXT: Identifying relationships among anatomical structures is key in diagnosing somatic dysfunction. Ultrasonography can be used to visualize anatomical structures, identify sacroiliac landmarks, and validate anatomical findings and measurements in relation to somatic dysfunction. As part of the osteopathic manipulative medicine course at A.T. Still University-Kirksville College of Osteopathic Medicine, first-year students are trained to use ultrasonography to establish relationships among musculoskeletal structures. OBJECTIVES: To determine the ability of first-year osteopathic medical students to establish sacral base position (SBP) and sacral sulcus depth (SSD) using ultrasonography and to identify the relationship of SBP and SSD to body mass index (BMI) and sex. METHODS: Students used ultrasonography to obtain the distance between the skin and the sacral base (the SBP) and the distance between the skin and the tip of the posterior superior iliac spine bilaterally. Next, students calculated the SSD (the distance between the tip of the posterior superior iliac spine and the SBP). Data were analyzed with respect to side of the body, BMI, sex, and age. The BMI data were subdivided into normal (18-25 mg/kg) and overweight (25-30 mg/kg) groups. RESULTS: Ultrasound images of 211 students were included in the study. The SBP was not significantly different between the left and right sides (36.5 mm vs 36.5 mm; P=.95) but was significantly different between normal and overweight BMI categories (33.0 mm vs 40.0 mm; P<.001) and between men and women (34.1 mm vs 39.0 mm; P<.001). The SSD was not significantly different between left and right sides (18.9 mm vs 19.8 mm; P=.08), normal and overweight BMI categories (18.9 mm vs 19.7 mm, P=.21), or men and women (19.7 mm vs 19.0 mm; P=.24). No significant relationship was identified between age and SBP (P=.46) or SSD (P=.39); however, the age range was narrow (21-33 years). CONCLUSION: The study yielded repeatable and reproducible results when establishing SBP and SSD using ultrasonography. The statistically significant relationship between SBP and higher BMI and between SBP and female sex may point to more soft tissue overlaying the sacrum in these groups. Further research is needed on the use of ultrasonography to establish criteria for somatic dysfunction. PMID- 26501758 TI - Incidence of Somatic Dysfunction in Healthy Newborns. AB - CONTEXT: Recent evidence suggests that osteopathic manipulative treatment of somatic dysfunction in newborns may decrease complications and hospital length of stay. Such dysfunction may result from external forces related to the birth process, but its incidence is unknown. OBJECTIVE: To identify the incidence and patterns of somatic dysfunction in healthy newborns at least 6 hours after birth and to correlate those findings with maternal and labor history, gestational age, and findings of the initial newborn assessment performed immediately after birth. METHODS: Healthy newborns aged 6 to 72 hours were physically examined and assessed for somatic dysfunction, including asymmetry and motion restriction of the cranial, cervical, lumbar, and sacral regions. The total somatic dysfunction identified was summarized in a somatic dysfunction severity score (SDSS), calculated by assigning 1 point for each identified finding; the SDSS could range from 0 (no somatic dysfunction) to 34 (all somatic dysfunctions assessed present). Findings were correlated with maternal and newborn characteristics and labor history. Descriptive analyses were performed, and findings were compared between the initial newborn assessment and the research examination. RESULTS: One hundred newborns were examined (mean gestational age, 38.5 weeks). In 99 newborns (99%), at least 1 sphenobasilar synchondrosis strain pattern was present, with sidebending rotations being the most common (present in 63 newborns [63%]). Condylar compression was found in 95 newborns (95%), temporal bone restrictions in 85 (85%), motion restriction of at least 1 cervical vertebral segment in 91 (91%) and at least 1 lumbar vertebral segment in 94 (94%), and a posterior sacral base in 80 (80%). The SDSS was not associated with mode of delivery or labor augmentation (P=.49 and P=.54, respectively), but it was positively associated with the duration of labor; each 1-hour increase in labor increased the predicted SDSS by 0.12 points (P=.04). CONCLUSION: Somatic dysfunction of the cranial, cervical, lumbar, and sacral regions was common in healthy newborns, and the total somatic dysfunction (SDSS) was related to the length of labor. (ClinicalTrials.gov number NCT01496872). PMID- 26501759 TI - Pigmented Skin Lesion Biopsies After Computer-Aided Multispectral Digital Skin Lesion Analysis. AB - BACKGROUND: The incidence of melanoma has been rising over the past century. With 37% of patients presenting to their primary care physician with at least 1 skin problem, primary care physicians and other nondermatologist practitioners have substantial opportunity to make an impact at the forefront of the disease process. New diagnostic aids have been developed to augment physician analysis of suspicious pigmented skin lesions (PSLs). OBJECTIVE: To determine the effects of computer-aided multispectral digital skin lesion analysis (MSDSLA) on dermatologists' and nondermatologist clinicians' decisions to biopsy suspicious PSLs after clinical and dermatoscopic evaluation. METHODS: Participants were shown 6 images of PSLs. For each PSL, participants were asked 3 times if they would biopsy the lesion: first after reviewing a clinical image of the PSL, again after reviewing a high-resolution dermatoscopic image, and again after reviewing MSDSLA probability findings. An answer was right if a melanoma or high-risk lesion was selected for biopsy or a low-risk lesion was not selected for biopsy. An answer was wrong if a melanoma or high-risk lesion was not selected for biopsy or a low-risk lesion was selected for biopsy. Clinicians' decisions to biopsy were evaluated using chi2 analysis for proportions. RESULTS: Data were analyzed from a total of 212 participants, 177 of whom were dermatologists. Overall, sensitivity of clinical image review was 63%; dermatoscopic image review, 5%; and MSDSLA, 83%. Specificity of clinical image review was 59%; dermatoscopic image review, 40%; and MSDSLA, 76%. Biopsy decision accuracy was 61% after review of clinical images, 52% after review of dermatoscopic images, and 80% after review of MSDSLA findings. The number of lesions participants indicated that they would biopsy increased significantly, from 52% after reviewing clinical images to 63% after reviewing dermatoscopic images (P<.001). However, the overall number of specimens that participants indicated they would biopsy did not change significantly after they reviewed MSDSLA findings (53%). CONCLUSION: Sensitivity, specificity, and biopsy decision accuracy increased after clinicians reviewed MSDSLA findings. The use of objective, computer-based diagnostic aids such as MSDSLA during clinical evaluations of ambiguous PSLs could aid clinicians' decisions to biopsy such lesions. PMID- 26501760 TI - Achilles Tendon Disorders. AB - Disorders of the Achilles tendon, the largest tendon in the human body, are common and occur in both active and sedentary persons. A thorough history and physical examination allow primary care physicians to make an accurate diagnosis and to initiate appropriate management. Mismanaged or neglected injuries markedly decrease a patient's quality of life. A growing body of related literature is the basis for current therapeutic regimens, which use a multimodal conservative approach, including osteopathic manipulative treatment. Although primary care physicians can manage most cases of Achilles tendon disorders, specialty care may be needed in certain instances. Procedural intervention should consider any comorbid conditions in addition to patients' lifestyle to help guide decision making. When appropriately managed, Achilles tendon disorders generally carry a favorable prognosis. PMID- 26501761 TI - Learning With Reflection: Practices in an Osteopathic Surgery Clinical Clerkship Through an Online Module. AB - CONTEXT: The value of reflective practices has gained momentum in osteopathic medical education. However, the use of reflective pedagogies has not been explored in the larger context of medical course delivery and design, to the authors' knowledge. OBJECTIVE: To determine the types of reflection demonstrated by osteopathic medical students on an online discussion board and to explore differences in discussion engagement caused by the use of a reflective learning self-assessment tool. METHODS: Using a mixed-method approach, reflection processes in an osteopathic surgery clinical clerkship online module were investigated in third-year osteopathic medical students. Discussion board messages were captured and coded. Both manual coding techniques and automated interrogation using NVivo9 (a computer program) for qualitative data were applied. Correlations of scores across 4 case-based discussion tasks and scores for self-reflection were computed as quantitative data. RESULTS: Twenty-eight students were included. Four main types of reflection (ie, content, contextual, dialogic, and personal) along with corresponding differentiated subthemes for each type of case-based discussion board group message were identified. Group collaboration revealed insights about the reflection process itself and also about the evidence of collective efforts, group engagements, and intragroup support among students. Student preparation revealed that students' metacognition was triggered when they judged their own contributions to group work. Challenges in completing readings and meeting deadlines were related to the students' long work hours. CONCLUSION: Reflective practices are essential to the practice of osteopathic medicine and medical education. Curricula can promote the development of reflective skills by integrating these deliberate practices in educational activities. PMID- 26501762 TI - Killian-Jamieson Diverticulum. PMID- 26501763 TI - Development of Peer Tutoring Services to Support Osteopathic Medical Students' Academic Success. AB - CONTEXT: Peer tutoring can benefit both tutors and tutored students, but information is lacking regarding establishing and measuring outcomes of such a program at new medical schools. OBJECTIVE: To examine the outcomes of a pilot peer tutoring initiative and explore the implications for long-term program development. METHODS: Fifty-one osteopathic medical students who participated in a pilot peer tutoring program during the 2013-2014 academic year were surveyed regarding satisfaction with the program. Course grade means for the tutors (all courses) and tutored students (specific courses) were analyzed before and after participating in the tutoring experience. Data analyses were performed using frequency distributions, t tests, and qualitative assessment of emergent themes. RESULTS: The survey had a 76% response rate (39 of 51 students). Both tutored students and tutors were satisfied with the tutoring program. Statistically significant changes in course grades for the tutored courses were noted at 3 to 4 and 8 to 9 months among the tutored students who were most at risk for failure (P=.001). Tutor course grades showed no significant changes for any of the courses in which they were enrolled (P=.445). CONCLUSION: Learning gains were realized by the students at greatest academic risk. Additional research is needed to evaluate long-term outcomes. PMID- 26501764 TI - Misclassification of Acceptable Venous Thromboembolism Prophylaxis Leading to Flawed Inferences and Recommendations Regarding Prevention Efforts--Reply. PMID- 26501765 TI - Template Synthesis of Shape-Tailorable NiS2 Hollow Prisms as High-Performance Supercapacitor Materials. AB - Uniform NiS2 hollow nanoprisms have been controllably synthesized by a facial sacrificial template method including two-step refluxed reactions. The morphology of the hollow NiS2 prisms can be easily tailored by the low cost nickel complex template. With unique hollow structure, efficient electron, and ion transport pathway as well as single crystal structure, the NiS2 hollow prisms electrode exhibits excellent pseudocapacitive performance in LiOH electrolyte. It can deliver a specific capacitance of 1725 F g(-1) at a current density of 5 A g(-1) and 1193 F g(-1) even at a current density of 40 A g(-1). Furthermore, the materials also present an amazing cycling stability, that is, the specific capacitance can increase from 1367 F g(-1) to 1680 F g(-1) after 10,000 cycles of charge-discharge at the current density of 20 A g(-1). PMID- 26501767 TI - Control of hepatitis B virus infection in hematopoietic stem cell recipients after receiving grafts from vaccinated donors. PMID- 26501766 TI - Minor histocompatibility Ags: identification strategies, clinical results and translational perspectives. AB - Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion are effective treatment modalities for various hematological malignancies. Their therapeutic effect, the graft-versus-tumor (GvT) effect, is based mainly on an alloimmune response of donor T cells directed at tumor cells, in which differences in the expression of minor histocompatibility Ags (mHags) on the cells of the patient and donor have a crucial role. However, these differences are also responsible for induction of sometimes detrimental GvHD. As relapse and development of GvHD pose major threats for a large proportion of allotransplanted patients, additional therapeutic strategies are required. To augment the GvT response without increasing the risk of GvHD, specific mHag-directed immunotherapeutic strategies have been developed. Over the past years, much effort has been put into the identification of therapeutically relevant mHags to enable these strategies for a substantial proportion of patients. Currently, the concept of mHag-directed immunotherapy is tested in clinical trials on feasibility, safety and efficacy. In this review, we will summarize the recent developments in mHag identification and the clinical data on mHag-specific immune responses and mHag-directed therapies in patients with hematological malignancies. Finally, we will outline the current challenges and future prospectives in the field. PMID- 26501768 TI - Unmanipulated haploidentical hematopoietic cell transplantation with post transplant cyclophosphamide in a patient with paroxysmal nocturnal hemoglobinuria and secondary aplastic anemia. PMID- 26501769 TI - Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties. AB - Historically, invasive aspergillosis (IA) has been a major barrier for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The influence of invasive IA on long-term survival and on transplant-related complications has not been investigated in a larger patient cohort under current conditions. Our aim was to analyze the long-term outcome of patients undergoing allo-HSCT with a history of prior IA. We used European Society for Blood and Marrow Transplantation database data of first allo-HSCTs performed between 2005 and 2010 in patients with acute leukemia. One thousand one hundred and fifty patients with data on IA before allo HSCT were included in the analysis. The median follow-up time was 52.1 months. We found no significant impact of IA on major transplant outcome variables such as overall survival, relapse-free survival, non-relapse mortality, cumulative incidence of acute GvHD grade II-IV, chronic GvHD, pulmonary complications and leukemia relapse. However, we found a trend toward lower overall survival (P=0.078, hazard ratio (HR) (95% confidence interval (CI)): 1.16 (0.98, 1.36)) and higher non-relapse mortality (P=0.150, HR (95% CI): 1.19 (0.94, 1.50)) in allo-HSCT recipients with pre-existing IA. Our data suggest that a history of IA should not generally be a contraindication when considering the performance of allo-HSCT in patients with acute leukemia. PMID- 26501770 TI - Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones. AB - The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF3)3-t-BuPHOX ligand, alpha-quaternary cyclopentanones were isolated in yields up to >99% with ee's up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee. PMID- 26501771 TI - In silico and wet-lab study revealed cadmium is the potent inhibitor of HupL in Anabaena sp. PC C 7120. AB - The hupL of Anabaena sp. PCC 7120 encodes the large subunit of uptake hydrogenase found in all diazotrophic cyanobacteria and boosts up the nitrogen-fixing potential by catalyzing the removal of the molecular hydrogen produced as a by product of dinitrogen fixation. Bioinformatics analysis revealed that HupL from Anabaena sp. PCC7120 is a 60.2 kDa, thermostable, glycine-rich protein having highest structural similarity with NiFeSe hydrogenase of Desulfomicrobium baculatumis. Toxicity of selected abiotic stresses like arsenic, cadmium, copper, and salt with HupL was further reconciled by wet-lab approaches like qRT-PCR, hydrogenase and nitrogenase activity assay as hydrogenases unintendedly affect the nitrogenase activity in Anabaena. Down-regulated transcript along with highly inhibited hydrogenase and nitrogenase activities under cadmium stress revealed that cadmium is a potent inhibitor of hydrogenases in Anabaena which indirectly affects its nitrogen-fixing capabilities PMID- 26501772 TI - Top predators affect the composition of naive protist communities, but only in their early-successional stage. AB - Introduced top predators have the potential to disrupt community dynamics when prey species are naive to predation. The impact of introduced predators may also vary depending on the stage of community development. Early-succession communities are likely to have small-bodied and fast-growing species, but are not necessarily good at defending against predators. In contrast, late-succession communities are typically composed of larger-bodied species that are more predator resistant relative to small-bodied species. Yet, these aspects are greatly neglected in invasion studies. We therefore tested the effect of top predator presence on early- and late-succession communities that were either naive or non-naive to top predators. We used the aquatic community held within the leaves of Sarracenia purpurea. In North America, communities have experienced the S. purpurea top predator and are therefore non-naive. In Europe, this predator is not present and its niche has not been filled, making these communities top-predator naive. We collected early- and late-succession communities from two non-naive and two naive sites, which are climatically similar. We then conducted a common-garden experiment, with and without the presence of the top predator, in which we recorded changes in community composition, body size spectra, bacterial density, and respiration. We found that the top predator had no statistical effect on global measures of community structure and functioning. However, it significantly altered protist composition, but only in naive, early-succession communities, highlighting that the state of community development is important for understanding the impact of invasion. PMID- 26501773 TI - Neighborhood-Scale Spatial Models of Diesel Exhaust Concentration Profile Using 1 Nitropyrene and Other Nitroarenes. AB - With emerging evidence that diesel exhaust exposure poses distinct risks to human health, the need for fine-scale models of diesel exhaust pollutants is growing. We modeled the spatial distribution of several nitrated polycyclic aromatic hydrocarbons (NPAHs) to identify fine-scale gradients in diesel exhaust pollution in two Seattle, WA neighborhoods. Our modeling approach fused land-use regression, meteorological dispersion modeling, and pollutant monitoring from both fixed and mobile platforms. We applied these modeling techniques to concentrations of 1-nitropyrene (1-NP), a highly specific diesel exhaust marker, at the neighborhood scale. We developed models of two additional nitroarenes present in secondary organic aerosol: 2-nitropyrene and 2-nitrofluoranthene. Summer predictors of 1-NP, including distance to railroad, truck emissions, and mobile black carbon measurements, showed a greater specificity to diesel sources than predictors of other NPAHs. Winter sampling results did not yield stable models, likely due to regional mixing of pollutants in turbulent weather conditions. The model of summer 1-NP had an R(2) of 0.87 and cross-validated R(2) of 0.73. The synthesis of high-density sampling and hybrid modeling was successful in predicting diesel exhaust pollution at a very fine scale and identifying clear gradients in NPAH concentrations within urban neighborhoods. PMID- 26501774 TI - 23Na Magnetic Resonance Imaging of the Lower Leg of Acute Heart Failure Patients during Diuretic Treatment. AB - OBJECTIVE: Na+ can be stored in muscle and skin without commensurate water accumulation. The aim of this study was to assess Na+ and H2O in muscle and skin with MRI in acute heart failure patients before and after diuretic treatment and in a healthy cohort. METHODS: Nine patients (mean age 78 years; range 58-87) and nine age and gender-matched controls were studied. They underwent 23Na/1H-MRI at the calf with a custom-made knee coil. Patients were studied before and after diuretic therapy. 23Na-MRI gray-scale measurements of Na+-phantoms served to quantify Na+-concentrations. A fat-suppressed inversion recovery sequence was used to quantify H2O content. RESULTS: Plasma Na+-levels did not change during therapy. Mean Na+-concentrations in muscle and skin decreased after furosemide therapy (before therapy: 30.7+/-6.4 and 43.5+/-14.5 mmol/L; after therapy: 24.2+/ 6.1 and 32.2+/-12.0 mmol/L; p?0.05 and p?0.01). Water content measurements did not differ significantly before and after furosemide therapy in muscle (p = 0.17) and only tended to be reduced in skin (p = 0.06). Na+-concentrations in calf muscle and skin of patients before and after diuretic therapy were significantly higher than in healthy subjects (18.3+/-2.5 and 21.1+/-2.3 mmol/L). CONCLUSIONS: 23Na-MRI shows accumulation of Na+ in muscle and skin in patients with acute heart failure. Diuretic treatment can mobilize this Na+-deposition; however, contrary to expectations, water and Na+-mobilization are poorly correlated. PMID- 26501775 TI - A Modified BFGS Formula Using a Trust Region Model for Nonsmooth Convex Minimizations. AB - This paper proposes a modified BFGS formula using a trust region model for solving nonsmooth convex minimizations by using the Moreau-Yosida regularization (smoothing) approach and a new secant equation with a BFGS update formula. Our algorithm uses the function value information and gradient value information to compute the Hessian. The Hessian matrix is updated by the BFGS formula rather than using second-order information of the function, thus decreasing the workload and time involved in the computation. Under suitable conditions, the algorithm converges globally to an optimal solution. Numerical results show that this algorithm can successfully solve nonsmooth unconstrained convex problems. PMID- 26501776 TI - Photoinduced Bimolecular Electron Transfer from Cyano Anions in Ionic Liquids. AB - Ionic liquids with electron-donating anions are used to investigate rates and mechanisms of photoinduced bimolecular electron transfer to the photoexcited acceptor 9,10-dicyanoanthracene (9,10-DCNA). The set of five cyano anion ILs studied comprises the 1-ethyl-3-methylimidazolium cation paired with each of these five anions: selenocyanate, thiocyanate, dicyanamide, tricyanomethanide, and tetracyanoborate. Measurements with these anions dilute in acetonitrile and 1 ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide show that the selenocyanate and tricyanomethanide anions are strong quenchers of the 9,10-DCNA fluorescence, thiocyanate is a moderately strong quencher, dicyanamide is a weak quencher, and no quenching is observed for tetracyanoborate. Quenching rates are obtained from both time-resolved fluorescence transients and time-integrated spectra. Application of a Smoluchowski diffusion-and-reaction model showed that the complex kinetics observed can be fit using only two adjustable parameters, D and V0, where D is the relative diffusion coefficient between donor and acceptor and V0 is the value of the electronic coupling at donor-acceptor contact. PMID- 26501777 TI - Nonlinear Fano-Resonant Dielectric Metasurfaces. AB - Strong nonlinear light-matter interaction is highly sought-after for a variety of applications including lasing and all-optical light modulation. Recently, resonant plasmonic structures have been considered promising candidates for enhancing nonlinear optical processes due to their ability to greatly enhance the optical near-field; however, their small mode volumes prevent the inherently large nonlinear susceptibility of the metal from being efficiently exploited. Here, we present an alternative approach that utilizes a Fano-resonant silicon metasurface. The metasurface results in strong near-field enhancement within the volume of the silicon resonator while minimizing two photon absorption. We measure a third harmonic generation enhancement factor of 1.5 * 10(5) with respect to an unpatterned silicon film and an absolute conversion efficiency of 1.2 * 10(-6) with a peak pump intensity of 3.2 GW cm(-2). The enhanced nonlinearity, combined with a sharp linear transmittance spectrum, results in transmission modulation with a modulation depth of 36%. The modulation mechanism is studied by pump-probe experiments. PMID- 26501778 TI - 2nd International Conference on Progressive Multifocal Leukoencephalopathy (PML) 2015: JCV virology, progressive multifocal leukoencephalopathy pathogenesis, diagnosis and risk stratification, and new approaches to prevention and treatment. PMID- 26501779 TI - Reactivation of HSV-1 following explant of tree shrew brain. AB - Herpes Simplex Virus type I (HSV-1) latently infects peripheral nervous system (PNS) sensory neurons, and its reactivation leads to recurring cold sores. The reactivated HSV-1 can travel retrograde from the PNS into the central nervous system (CNS) and is known to be causative of Herpes Simplex viral encephalitis. HSV-1 infection in the PNS is well documented, but little is known on the fate of HSV-1 once it enters the CNS. In the murine model, HSV-1 genome persists in the CNS once infected through an ocular route. To gain more details of HSV-1 infection in the CNS, we characterized HSV-1 infection of the tree shrew (Tupaia belangeri chinensis) brain following ocular inoculation. Here, we report that HSV 1 enters the tree shrew brain following ocular inoculation and HSV-1 transcripts, ICP0, ICP4, and LAT can be detected at 5 days post-infection (p.i.), peaking at 10 days p.i. After 2 weeks, ICP4 and ICP0 transcripts are reduced to a basal level, but the LAT intron region continues to be expressed. Live virus could be recovered from the olfactory bulb and brain stem tissue. Viral proteins could be detected using anti-HSV-1 antibodies and anti-ICP4 antibody, during the acute stage but not beyond. In situ hybridization could detect LAT during acute infection in most brain regions and in olfactory bulb and brain stem tissue well beyond the acute stage. Using a homogenate from these tissues' post-acute infection, we did not recover live HSV-1 virus, supporting a latent infection, but using a modified explant cocultivation technique, we were able to recover reactivated virus from these tissues, suggesting that the HSV-1 virus latently infects the tree shrew CNS. Compared to mouse, the CNS acute infection of the tree shrew is delayed and the olfactory bulb contains most latent virus. During the acute stage, a portion of the infected tree shrews exhibit symptoms similar to human viral encephalitis. These findings, together with the fact that tree shrews are closely related to primates, provided a valuable alternative model to study HSV-1 infection and pathogenesis in the CNS. PMID- 26501781 TI - Matched Peptides: Tuning Matched Molecular Pair Analysis for Biopharmaceutical Applications. AB - Biopharmaceuticals hold great promise for the future of drug discovery. Nevertheless, rational drug design strategies are mainly focused on the discovery of small synthetic molecules. Herein we present matched peptides, an innovative analysis technique for biological data related to peptide and protein sequences. It represents an extension of matched molecular pair analysis toward macromolecular sequence data and allows quantitative predictions of the effect of single amino acid substitutions on the basis of statistical data on known transformations. We demonstrate the application of matched peptides to a data set of major histocompatibility complex class II peptide ligands and discuss the trends captured with respect to classical quantitative structure-activity relationship approaches as well as structural aspects of the investigated protein peptide interface. We expect our novel readily interpretable tool at the interface of cheminformatics and bioinformatics to support the rational design of biopharmaceuticals and give directions for further development of the presented methodology. PMID- 26501780 TI - HIV-1 transgenic rats display an increase in [(3)H]dopamine uptake in the prefrontal cortex and striatum. AB - HIV viral proteins within the central nervous system are associated with the development of neurocognitive impairments in HIV-infected individuals. Dopamine transporter (DAT)-mediated dopamine transport is critical for normal dopamine homeostasis. Abnormal dopaminergic transmission has been implicated as a risk determinant of HIV-induced neurocognitive impairments. Our published work has demonstrated that transactivator of transcription (Tat)-induced inhibition of DAT is mediated by allosteric binding site(s) on DAT, not the interaction with the dopamine uptake site. The present study investigated whether impaired DAT function induced by Tat exposure in vitro can be documented in HIV-1 transgenic (HIV-1Tg) rats. We assessed kinetic analyses of [(3)H]dopamine uptake into prefrontal and striatal synaptosomes of HIV-1Tg and Fisher 344 rats. Compared with Fisher 344 rats, the capacity of dopamine transport in the prefrontal cortex (PFC) and striatum of HIV-1Tg rats was increased by 34 and 32 %, respectively. Assessment of surface biotinylation indicated that DAT expression in the plasma membrane was reduced in PFC and enhanced in striatum, respectively, of HIV-1Tg rats. While the maximal binding sites (B max) of [(3)H]WIN 35,428 was decreased in striatum of HIV-1Tg rats, an increase in DAT turnover proportion was found, relative to Fisher 344 rats. Together, these findings suggest that neuroadaptive changes in DAT function are evidenced in the HIV-1Tg rats, perhaps compensating for viral-protein-induced abnormal dopaminergic transmission. Thus, our study provides novel insights into understanding mechanism underlying neurocognitive impairment evident in neuroAIDS. PMID- 26501783 TI - Photothermally Induced Optical Property Changes of Poly(N-isopropylacrylamide) Microgel-Based Etalons. AB - Poly(N-isopropylacrylamide) microgel-based optical devices were designed such that they can be stimulated to change their optical properties in response to light produced by a light-emitting diode (LED). The devices were fabricated by sandwiching the synthesized microgels between two Cr/Au layers all supported on a glass coverslip with gold nanoparticles (AuNPs) deposited. Here, we found that these devices can be stimulated to change their optical properties when exposed to green LED light, which excites the AuNPs and increases the local temperature, causing the thermoresponsive microgels to decrease in diameter, resulting in a change in the devices' optical properties. We also found that the sensitivity of the devices to light was more pronounced as the environmental temperature approached the lower critical solution temperature (LCST) for the microgels, although the sensitivity of the devices to light exposure dropped off dramatically as the environmental temperature was increased above the LCST. This was a direct result of the microgels already being in their collapsed state and therefore unable to decrease in diameter any further due to light exposure. Finally, we found that the sensitivity of the devices to light exposure increased with increasing number of AuNP layers in the devices. We anticipate that these devices could be used for drug delivery applications; by using light to stimulate microgel collapse, the microgel-based devices can be stimulated to release small molecules on demand. PMID- 26501782 TI - Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Newly Diagnosed Pulmonary TB Patients in Tanzania. AB - Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients. PMID- 26501784 TI - Comment on 'Monte Carlo calculated microdosimetric spread for cell nucleus-sized targets exposed to brachytherapy (125)I and (192)Ir sources and (60)Co cell irradiation'. AB - The relative standard deviation, sigmar,D, of calculated multi-event distributions of specific energy for (60)Co Upsilon rays was reported by the authors F Villegas, N Tilly and A Ahnesjo (Phys. Med. Biol. 58 6149-62). The calculations were made with an upgraded version of the Monte Carlo code PENELOPE. When the results were compared to results derived from experiments with the variance method and simulated tissue equivalent volumes in the micrometre range a difference of about 50% was found. Villegas et al suggest wall-effects as the likely explanation for the difference. In this comment we review some publications on wall-effects and conclude that wall-effects are not a likely explanation. PMID- 26501785 TI - Comparison of 2 Measures of HIV Sexual Risk Behavior in Women in Outpatient Drug Treatment Programs. AB - OBJECTIVES: HIV/STD sexual risk behavior is common among women who use drugs. To effectively implement interventions in busy drug treatment programs, it is important to have a rapid and accurate measure of sexual risk. This study compared 2 dichotomous ratings of unprotected sex among women in substance abuse treatment who participated in a HIV sexual risk reduction clinical trial: (1) any unprotected vaginal/anal sex occasions in the last 3 months, versus (2) unprotected vaginal/anal sex at last sexual occasion (LSO). METHODS: Sexually active women from 12 methadone maintenance or psychosocial outpatient programs who had a main (n = 363) or other male partner(s) (n = 117) were assessed at baseline for unprotected sex in the last 3 months and at LSO. These 2 measures were compared for congruence. RESULTS: Participants who reported unprotected sex at LSO consistently reported at least 1 unprotected sex occasion in the last 3 months: 99.1% for main male partner sex and 93.8% for other male partner sex. Participants who reported using a condom at LSO were less consistent of those reporting condom use at LSO; only 30.3% reported protected sex at all sex occasions in the last 3 months with main male partner and only 67.6% for other male partner(s). CONCLUSIONS: Use of one question about condom protected sex at LSO appears to be a partially useful tool. It can be useful for detecting sexual risk in clinical or research settings wherein the central focus is not on sexual behavior or when time is limited. PMID- 26501787 TI - A Simplified Protocol for the Treatment of Alcohol Withdrawal. AB - OBJECTIVES: The aim of the study was to evaluate a novel simplified tool for symptom-triggered treatment of alcohol withdrawal. METHODS: This retrospective cohort study involved inpatients in a county hospital with an International Classification of Diseases, Ninth Revision, Clinical Modification discharge diagnosis of alcohol withdrawal syndrome (AWS) or delirium tremens between January 1, 2007 and December 31, 2008. The study used the Highland Alcohol Withdrawal Protocol (HAWP)-a simplified derivative of the Revised Clinical Institute Withdrawal Assessment for Alcohol. Multivariable regression analysis was performed to compare severity of withdrawal to hospital length of stay, total dose of sedative given, and risk of complications. RESULTS: The study identified 442 patients with a primary diagnosis of AWS or delirium tremens, and those with another primary medical diagnosis complicated by alcohol withdrawal. After adjusting for demographic variables, each one-point increase in the initial and maximum HAWP scores correlated with an increase in the hospital length of stay of 0.3 days [95% confidence interval (95% CI), 0.17 to 0.43 days] and 0.45 days (95% CI, 0.32-0.57 days), and a 15.8 mg (95% CI, 6.6-25.1 mg) and 19.8 mg (95% CI, 11.1-28.5 mg) increase in the total dose of lorazepam given, respectively. The complication rate of seizures, intubations, pneumonia, and death was 13.1%, 12.9%, 6.1% and 0.9%, respectively; a composite endpoint of these outcomes also correlated with initial and maximum HAWP scores (odds ratio 1.09, 95% CI, 1.03% 1.14%). CONCLUSIONS: The HAWP correlates with medication received and complications, and as such appears to give an indication of AWS severity. It is feasible and shorter than prior scales, and merits further study to confirm its effectiveness as part of symptom-triggered protocols to manage alcohol withdrawal in the hospital. PMID- 26501786 TI - Substance Use, Depression and Sociodemographic Determinants of HIV Sexual Risk Behavior in Outpatient Substance Abuse Treatment Patients. AB - OBJECTIVES: The NIDA Clinical Trials Network trial of rapid HIV testing/counseling in 1281 patients was a unique opportunity to examine relationships among substance use, depressive symptoms, and sex risk behavior. METHODS: Past 6-month substance use; substance use severity (Drug Abuse Screening Test - 10); depressive symptoms (Quick Inventory of Depressive Symptomatology); and three types of sex risk behavior (unprotected sex occasions [USOs] with primary partners; USOs with nonprimary partners; and USOs while high/drunk) were assessed. Zero-inflated negative binomial analyses provided: probability and rate of sex risk behavior (in risk behavior subsample). RESULTS: Levels of sexual risk behavior were high, while variable across the three types of sex risk behaviors. Among the patients, 50.4% had engaged in USOs with primary partners, 42% in sex while drunk or high, and 23.8% in USOs with nonprimary partners. Similar factors were significantly associated with all three types of sex risk behaviors. For all types, problem drinking, cocaine use, and substance use severity had an exacerbating effect. Older age was associated with lower risk behavior; other relationship categories (eg, married, separated/divorced, cohabitating) were associated with greater risk behavior than was single status. Depressive symptoms were associated with decreased likelihood of USOs with a primary partner. CONCLUSIONS: Sexual risk behavior is common among individuals in outpatient substance abuse treatment. Results highlight problem drinking (eg, up to three fold) and cocaine (eg, up to twice) in increasing sex risk behavior. They demonstrate the utility of distinguishing between partner types and presence/absence of alcohol/drugs during sex. Findings argue for the need to integrate sex risk reduction into drug treatment. PMID- 26501789 TI - A Simple Kinetic Model for Description of the Iodate-Arsenous Acid Reaction: Experimental Evidence of the Direct Reaction. AB - The autocatalytic iodate-arsenous acid reaction was investigated by a stopped flow instrument under strongly acidic medium (pH <= 1) by monitoring the absorbance-time profiles at 468 nm. The kinetic traces were found to exhibit a perfect sigmoidal shape in stoichiometric excess of iodate with a well-defined and reproducible induction period that depends on the initial concentration of the reactants as well as on the pH. All the experimental curves can be globally fitted by a simple kinetic model involving the direct reaction between the reactants to produce iodide ion, the Dushman and the Roebuck reactions, and two rapid equilibria. Our measurements along with simultaneous evaluation of the kinetic traces clearly support that indeed the initiation reaction exists at strongly acidic conditions and contributes to the overall kinetics. The measured traces cannot be described adequately by the iodide ion impurity-driven Dushman and Roebuck reactions with assuming no direct reaction at all. PMID- 26501788 TI - Effects of Prereactivation Propranolol on Cocaine Craving Elicited by Imagery Script/Cue Sets in Opioid-dependent Polydrug Users: A Randomized Study. AB - OBJECTIVES: Relapse to drug misuse may follow exposure to drug cues that elicit craving. The learned associations, or "emotional memories," that underlie responses to cues may be attenuated or erased by the beta-adrenergic antagonist propranolol during a "reconsolidation window" shortly after the memories are reactivated by cues. METHODS: We evaluated the effects of propranolol on cue induced drug cravings in healthy opioid-dependent individuals who used cocaine while receiving methadone maintenance (n = 33). Participants were asked to recall specific cocaine use and neutral events in an interview; these events were used to develop personalized auditory script/cue sets. Approximately 1 week later, propranolol (40 mg) or placebo (random assignment, double blind) was administered orally before presentation of the script/cue sets; the presentation of the script/cue sets were tested 1 week and 5 weeks after the propranolol/placebo session. Ongoing drug use was monitored via urine screens and self-report in twice-weekly visits. RESULTS: Cue reactivity, as assessed by craving scales and physiological responses, was unexpectedly greater in the propranolol group than in the placebo group. This counterhypothesized group difference was present acutely during propranolol administration and seemed to persist (without reaching statistical significance) during the subsequent test sessions. CONCLUSIONS: Our results do not support the use of propranolol for cue-induced cocaine craving in opioid-maintained patients. PMID- 26501790 TI - Inconsistency in Missing Cases in Derivation Data and Validation Data. PMID- 26501791 TI - Modular Preparation of 5-Halomethyl-2-oxazolines via PhI(OAc)2-Promoted Intramolecular Halooxygenation of N-Allylcarboxamides. AB - A new method for the construction of oxazoline moiety was detailed. Using (diacetoxyiodo)benzene (PIDA) as the reaction promoter and halotrimethylsilane as the halogen source, intramolecular halooxygenation and halothionation of N allylcarboxamides/N-allylcarbothioamides proceeded readily, leading to the corresponding 5-halomethyloxazolines/5-halomethylthiazolines in good to excellent isolated yields. The 5-halomethyl products could be converted to different derivatives via conventional nucleophilic substitution methods. The reactions were carried out using easily available starting materials, and did not need harsh reaction conditions. All these features made this reaction a viable method for the construction of different oxazoline and thiazoline structures. PMID- 26501792 TI - Regulatory T Cells Are Critical for Clearing Influenza A Virus in Neonatal Mice. AB - We previously reported that neonatal mice infected with influenza A virus (IAV) develop interstitial pneumonia characterized by reduced lung cytokine and chemokine responses. The failure of T cells to infiltrate the airways of neonates correlated with delayed clearance of sublethal IAV infections compared to adults. We hypothesized that negative regulators in the neonatal lungs such as cytokines or T regulatory (Treg) cells are responsible for these differences. Neonates either deficient in interleukin-10 (IL-10) or with T cells unresponsive to transforming growth factor-beta signaling due to absence of SMAD family member 4 (Smad4) had similar IAV clearance kinetics to wild-type pups and no difference in T-cell responses. In contrast, functional depletion of Treg cells with anti-CD25 monoclonal antibody resulted in increased proportions of activated CD4(+) T cells in the lungs, but failure to clear IAV. Similarly, scurfy pups (mutation in forkhead box P3 [Foxp3] rendering them deficient in Treg cells) had increased proportions of activated T cells in the lungs compared to littermate controls. Scurfy pups also had increased proportions of IL-13-producing CD4(+) T cells. Interestingly, like anti-CD25-treated pups, scurfy pups had significantly elevated viral loads compared to controls. Based on these data, we conclude that Tregs are critical for clearance of IAV in neonatal mice. PMID- 26501793 TI - A combined experimental and computational study of novel nanocage-based metal organic frameworks for drug delivery. AB - Three new metal organic frameworks (MOFs) with chemical formulae [(CH3)2NH2] [Sm3(L1)2(HCOO)2(DMF)2(H2O)].2DMF.18H2O (1), [Cu2(L2)(H2O)2].2.22DMA (2) and [Zn2(L1)(DMA)].1.75DMA were synthesized and structurally characterized. 1 and 2 show a classical NbO-like topology and have two types of interconnected cages. 3 exhibits an uncommon zzz topology and has two types of interconnected cages. These MOFs can adsorb large amounts of the drug 5-fluorouracil (5-FU) and release it in a progressive way. 5-FU was incorporated into desolvated 1, 2 and 3 with loadings of 0.40, 0.42, and 0.45 g g(-1), respectively. The drug release rates were 72%, 96% and 79% of the drug after 96 hours in 1, 120 hours in 2 and 96 hours in 3, respectively. Grand Canonical Monte Carlo (GCMC) simulations were performed to investigate the molecular interactions during 5-FU adsorption to the three novel materials. The GCMC simulations reproduced the experimental trend with respect to the drug loading capacity of each material. They also provided a structural description of drug packing within the frameworks, helping to explain the load capacity and controlled release characteristics of the materials. 5-FU binding preferences to 1, 2 and 3 reflect the diversity in pore types, chemistry and sizes. The calculated drug load is more related to the molecular properties of accessible volume Vacc than to the pore size. PMID- 26501794 TI - Antibiotic Use after Free Tissue Reconstruction of Head and Neck Defects: Short Course vs. Long Course. AB - BACKGROUND: Free tissue reconstruction has become the standard of care for most major defects in the head and neck. Surgical site infection (SSI) can lead to vessel thrombosis and eventual flap loss. The use of antibiotics after free tissue reconstruction has not been studied in the current environment of heightened bacterial antibiotic resistance. We compared the use of short-term and longer-term antibiotics in a series of patients receiving free tissue reconstructions. METHODS: A retrospective review was performed of 147 patients receiving 149 free flaps who were treated with either short-course (<=2 d; n = 149 [43%]) or long-course (>2 d; n = 85 [57%])) post-operative antibiotics from 2009 to 2014. The outcomes examined were infection, return to the operating room, length of hospital stay, and patient death up to six weeks post-surgery. In addition, risk factors associated with SSI were explored. RESULTS: Surgical site infection, flap dehiscence, flap loss, and length of stay were not different in the two groups. However, those receiving long-course antibiotics had a significantly higher rate of pneumonia (24.7% vs. 10.9%; p = 0.03), although they had a lower rate of urinary tract infection (0.0% vs 9.4%, respectively; p = 0.01). Body mass index remained a statistically significant risk factor in the multivariable analysis (p = 0.005). CONCLUSION: Prolonged antibiotic use after free flap reconstruction of head and neck defects does not appear to prevent SSI better than short-course treatment in this population. Moreover, long-course antibiotic use was associated with a higher risk of pneumonia. PMID- 26501799 TI - Opening doors to participation of youth with physical disabilities: An intervention study. AB - BACKGROUND: While participation in leisure activities is beneficial to youth's health, little is known about effective intervention strategies to promote participation. PURPOSE: The aim of this study was to examine the effectiveness of environment-based interventions on participation of youth with physical disabilities. METHOD: Six adolescents ages 14 to 17 years participated in a 12 week intervention aimed at removing environmental barriers and coaching parents. An interrupted time series design was employed and a systematic replication of the intervention effect was examined across three individualized participation goals and across participants (17 goals overall). Goal performance was measured repeatedly using the Canadian Occupational Performance Measure and analyzed using visual inspection and a celeration line approach. FINDINGS: A clinically significant improvement in performance scores (M = 4.5, SD = 1.77) was observed across all 17 goals, and a statistically significant treatment effect was replicated in 13 goals (76%). IMPLICATIONS: Findings support the effectiveness of environment-based interventions in promoting youth participation, but larger studies are required. PMID- 26501800 TI - Morphology and aggregation of RADA-16-I peptide Studied by AFM, NMR and molecular dynamics simulations. AB - RADA-16-I is a self-assembling peptide which forms biocompatible fibrils and hydrogels. We used molecular dynamics simulations, atomic-force microscopy, NMR spectroscopy, and thioflavin T binding assay to examine size, structure, and morphology of RADA-16-I aggregates. We used the native form of RADA-16-I (H (ArgAlaAspAla)4 -OH) rather than the acetylated one commonly used in the previous studies. At neutral pH, RADA-16-I is mainly in the fibrillar form, the fibrils consist of an even number of stacked beta-sheets. At acidic pH, RADA-16-I fibrils disassemble into monomers, which form an amorphous monolayer on graphite and monolayer lamellae on mica. RADA-16-I fibrils were compared with the fibrils of a similar peptide RLDL-16-I. Thickness of beta-sheets measured by AFM was in excellent agreement with the molecular dynamics simulations. A pair of RLDL-16-I beta-sheets was thicker (2.3 +/- 0.4 nm) than a pair of RADA-16-I beta-sheets (1.9 +/- 0.1 nm) due to the volume difference between alanine and leucine residues. PMID- 26501801 TI - Insight into human protease activated receptor-1 as anticancer target by molecular modelling. AB - Protease-activated receptor 1 (PAR1) has been established as a promising target in many diseases, including various cancers. Strong evidence also suggests its role in metastasis. It is proved experimentally that PAR1 can induce numerous cell phenotypes, i.e. proliferation and differentiation. A strong link between PAR1 gene overexpression and high levels of beta-catenin was suggested by a study of the PAR1-Galpha(13)-DVL axis in beta-catenin stabilization in cancers. An in vitro study was carried out to analyze PAR1 expression by flow cytometry on CD38+138+ plasma cells obtained from patients either at diagnosis (n: 46) (newly diagnosed multiple myeloma (NDMM)) or at relapse (n: 45) (relapsed/refractory multiple myeloma (RRMM)) and compared with the controls. Our previously synthesized benzoxazole (XT2B) and benzamide (XT5) derivatives were tested with in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, which revealed significant inhibitory activity on PAR1. We provide docking studies using Autodock Vina of these newly tested compounds to compare with the known PAR1 inhibitors in order to examine the binding mechanisms. In addition, the docking results are validated using HYDE binding assessment and a neural network (NN) scoring function. PMID- 26501802 TI - Choroidal Neovascularization Secondary to Myopia, Infection and Inflammation. AB - Choroidal neovascularization (CNV) is a significant cause of vision loss in all age groups. The most common cause of CNV is age-related macular degeneration (AMD). However, CNV can also occur as a secondary manifestation of various inherited and acquired conditions, including pathologic myopia, presumed ocular histoplasmosis syndrome, angioid streaks, and various hereditary, traumatic or inflammatory disorders. Fluorescein angiography and optical coherence tomography are useful tools in the diagnosis and evaluation of CNV. Treatment options are similar to those for CNV secondary to AMD, specifically anti-angiogenic therapy, but including laser photocoagulation, photodynamic therapy and surgery. Anti angiogenic therapy has been associated with better visual outcomes than other treatment modalities and is now advocated as the first-line therapy for CNV secondary to myopia, infection and inflammation. PMID- 26501795 TI - microRNAs as pharmacogenomic biomarkers for drug efficacy and drug safety assessment. AB - Much evidence has documented that microRNAs (miRNAs) play an important role in the modulation of interindividual variability in the production of drug metabolizing enzymes and transporters (DMETs) and nuclear receptors (NRs) through multidirectional interactions involving environmental stimuli/stressors, the expression of miRNA molecules and genetic polymorphisms. MiRNA expression has been reported to be affected by drugs and miRNAs themselves may affect drug metabolism and toxicity. In cancer research, miRNA biomarkers have been identified to mediate intrinsic and acquired resistance to cancer therapies. In drug safety assessment, miRNAs have been found associated with cardiotoxicity, hepatotoxicity and nephrotoxicity. This review article summarizes published studies to show that miRNAs can serve as early biomarkers for the evaluation of drug efficacy and drug safety. PMID- 26501803 TI - Development and performance test of an online blood sampling system for determination of the arterial input function in rats. AB - BACKGROUND: For positron emission tomography (PET) kinetic modelling, an accurate determination of the arterial input function is required. In this study, a blood sampling system was developed and tested using different radiotracers in rats. METHODS: The detector consists of pairs of lutetium yttrium oxyorthosilicate (LYSO) detectors, photomultiplier tubes and lead shield assembled within a steel casing working in coincidence mode. Rats were cannulated with microtubes in the femoral artery and vein for arterial blood sampling as well as administration of the PET tracers. Connected PTFE microtubes were centred between the LYSO crystals using a special holder. To enhance sensitivity, three layers with two coils were used. A flexible tube pump was used to ensure a constant blood flow. Performance of the detector was assessed with [(18)F]fludeoxyglucose (FDG), [(18)F]ciprofloxacin, (R)-[(11)C]verapamil, [(11)C]tariquidar, [(11)C]mephobarbital and [(11)C]MC113. Obtained input function curves were compared with manual samples drawn every 5 s during the first 3 min and further on at 5, 10, 20, 30, 40, 50 and 60 min after radiotracer injection. After manual sampling, an arterio/venous shunt was established. Shape and area-under-the-curve (AUC; Bq/MUl*h) of the input functions were evaluated. RESULTS: The developed detector system provided an absolute sensitivity of 6.5%. Maximum peak values agreed well between manual samples and the detector with a mean difference of 0.4% +/- 7.0% (max 12.0%, min -9.9%). AUC values also exhibited an excellent correlation (R = 0.996) between manual sampling and detector measurements with a mean difference of 9.3% +/- 9.7% (max 24.1%, min -3.2%). The system was able to measure peak blood activity concentration levels of 110 to 2,000 Bq/MUl which corresponds to injected activities from 5.5 to 100 MBq depending on the used radiotracer, applied volume and weight of the animal. CONCLUSIONS: This study demonstrates that the developed blood sampling system can be used for in vivo small animal PET studies in rats in a reliable way. The usage of the systems enhances the accuracy of the input curve as handling of small blood samples especially with low activity (as for C-11) is prone to measurement errors. Additionally, the radiation dose of the experimenters can be reduced, as it is not required anymore to continuously draw samples where the personal is in close contact to the radioactive animals and blood. PMID- 26501804 TI - Evaluation of inter-departmental variability of ejection fraction and cardiac volumes in myocardial perfusion scintigraphy using simulated data. AB - BACKGROUND: Myocardial perfusion scintigraphy (MPS) is a clinically useful noninvasive imaging modality for diagnosing patients with suspected coronary artery disease. By utilizing gated MPS, the end diastolic volume (EDV) and end systolic volume (ESV) can be measured and the ejection fraction (EF) calculated, which gives incremental prognostic value compared with assessment of perfusion only. The aim of this study was to evaluate the inter-departmental variability of EF, ESV, and EDV during gated MPS in Sweden. METHODS: Seventeen departments were included in the study. The SIMIND Monte Carlo (MC) program together with the XCAT phantom was used to simulate three patient cases with different EDV, ESV, and EF. Individual simulations were performed for each department, corresponding to their specific method of performing MPS. Images were then sent to each department and were evaluated according to clinical routine. EDV, ESV, and EF were reported back. RESULTS: There was a large underestimation of EDV and ESV for all three cases. Mean underestimation for EDV varied between 26% and 52% and for ESV between 15% and 60%. EF was more accurately measured, but mean bias still varied between an underestimation of 24% to an overestimation of 14%. In general, the intra-departmental variability for EDV, ESV, and EF was small, whereas inter departmental variability was larger. CONCLUSIONS: Left ventricular volumes were generally underestimated, whereas EF was more accurately estimated. There was, however, large inter-departmental variability. PMID- 26501805 TI - Intravenous contrast-enhanced CT can be used for CT-based attenuation correction in clinical (111)In-octreotide SPECT/CT. AB - BACKGROUND: CT-based attenuation correction (CT-AC) using contrast-enhancement CT impacts (111)In-SPECT image quality and quantification. In this study we assessed and evaluated the effect. METHODS: A phantom (5.15 L) was filled with an aqueous solution of In-111. Three SPECT/CT scans were performed: (A) no IV contrast, (B) with 100-mL IV contrast, and (C) with 200-mL IV contrast added. Scan protocol included a localization CT, a low-dose CT (LD), and a full-dose CT (FD). Phantom, LD and FD scan series were performed at 90, 120, and 140 kVp. Phantom data were evaluated looking at mean counts in a central volume. Ten patients referred for (111)In-octreotide scintigraphy were scanned according to our clinical (111)In SPECT/CT protocol including a topogram, a LD (140 kVp), and a FD (120 kVp). The FD/contrast-enhanced CT was acquired in both arterial (FDAP) and venous phase (FDVP) following a mono-phasic IV injection of 125-mL Optiray (4.5 mL/s). For patient data, we report image quality, Krenning scores, and mean/max values for liver and tumor regions. RESULTS: Phantoms: in uncorrected emission data, mean counts (average +/- SD) decreased with increasing IV concentration: (A) 119 +/- 9, (B) 113 +/- 8, and (C) 110 +/- 9. For all attenuation correction (AC) scans, the mean values increased with increasing iodine concentration. PATIENTS: there were no visible artifacts in single photon emission computed tomography (SPECT) following CT-AC with contrast-enhanced CT. The average score of image quality was 4.1 +/- 0.3, 3.8 +/- 0.4, and 4.2 +/- 0.4 for LD, arterial phase, and venous phase, respectively. A total of 16 lesions were detected. The Krenning scores of 13/16 lesions were identical across all scan series. The max pixel values for the 16 lesions showed generally lower values for LD than for contrast-enhanced CT. CONCLUSIONS: In (111)In-SPECT/CT imaging of phantoms and patients, the use of IV CT contrast did neither degrade the SPECT image quality nor affect the clinical Krenning score. Reconstructed counts in healthy liver tissues were unaffected, and there was a generally lower count value in lesions following CT-AC based on the LD non-enhanced images. Overall, for clinical interpretation, no separate low dose CT is required for CT-AC in (111)In-SPECT/CT. PMID- 26501806 TI - Clinical evaluation of respiration-induced attenuation uncertainties in pulmonary 3D PET/CT. AB - BACKGROUND: In contemporary positron emission tomography (PET)/computed tomography (CT) scanners, PET attenuation correction is performed by means of a CT-based attenuation map. Respiratory motion can however induce offsets between the PET and CT data. Studies have demonstrated that these offsets can cause errors in quantitative PET measures. The purpose of this study is to quantify the effects of respiration-induced CT differences on the attenuation correction of pulmonary 18-fluordeoxyglucose (FDG) 3D PET/CT in a patient population and to investigate contributing factors. METHODS: For 32 lung cancer patients, 3D-CT, 4D PET and 4D-CT data were acquired. The 4D FDG PET data were attenuation corrected (AC) using a free-breathing 3D-CT (3D-AC), the end-inspiration CT (EI-AC), the end-expiration CT (EE-AC) or phase-by-phase (P-AC). After reconstruction and AC, the 4D-PET data were averaged. In the 4Davg data, we measured maximum tumour standardised uptake value (SUV)max in the tumour, SUVmean in a lung volume of interest (VOI) and average SUV (SUVmean) in a muscle VOI. On the 4D-CT, we measured the lung volume differences and CT number changes between inhale and exhale in the lung VOI. RESULTS: Compared to P-AC, we found -2.3% (range -9.7% to 1.2%) lower tumour SUVmax in EI-AC and 2.0% (range -0.9% to 9.5%) higher SUVmax in EE-AC. No differences in the muscle SUV were found. The use of 3D-AC led to respiration-induced SUVmax differences up to 20% compared to the use of P-AC. SUVmean differences in the lung VOI between EI-AC and EE-AC correlated to average CT differences in this region (rho = 0.83). SUVmax differences in the tumour correlated to the volume changes of the lungs (rho = -0.55) and the motion amplitude of the tumour (rho = 0.53), both as measured on the 4D-CT. CONCLUSIONS: Respiration-induced CT variations in clinical data can in extreme cases lead to SUV effects larger than 10% on PET attenuation correction. These differences were case specific and correlated to differences in CT number in the lungs. PMID- 26501807 TI - Tumor and red bone marrow dosimetry: comparison of methods for prospective treatment planning in pretargeted radioimmunotherapy. AB - BACKGROUND: Red bone marrow (RBM) toxicity is dose-limiting in (pretargeted) radioimmunotherapy (RIT). Previous blood-based and two-dimensional (2D) image based methods have failed to show a clear dose-response relationship. We developed a three-dimensional (3D) image-based RBM dosimetry approach using the Monte Carlo-based 3D radiobiological dosimetry (3D-RD) software and determined its additional value for predicting RBM toxicity. METHODS: RBM doses were calculated for 13 colorectal cancer patients after pretargeted RIT with the two step administration of an anti-CEA * anti-HSG bispecific monoclonal antibody and a (177)Lu-labeled di-HSG-peptide. 3D-RD RBM dosimetry was based on the lumbar vertebrae, delineated on single photon emission computed tomography (SPECT) scans acquired directly, 3, 24, and 72 h after (177)Lu administration. RBM doses were correlated to hematologic effects, according to NCI-CTC v3 and compared with conventional 2D cranium-based and blood-based dosimetry results. Tumor doses were calculated with 3D-RD, which has not been possible with 2D dosimetry. Tumor-to RBM dose ratios were calculated and compared for (177)Lu-based pretargeted RIT and simulated pretargeted RIT with (90)Y. RESULTS: 3D-RD RBM doses of all seven patients who developed thrombocytopenia were higher (range 0.43 to 0.97 Gy) than that of the six patients without thrombocytopenia (range 0.12 to 0.39 Gy), except in one patient (0.47 Gy) without thrombocytopenia but with grade 2 leucopenia. Blood and 2D image-based RBM doses for patients with grade 1 to 2 thrombocytopenia were in the same range as in patients without thrombocytopenia (0.14 to 0.29 and 0.11 to 0.26 Gy, respectively). Blood-based RBM doses for two grade 3 to 4 patients were higher (0.66 and 0.51 Gy, respectively) than the others, and the cranium-based dose of only the grade 4 patient was higher (0.34 Gy). Tumor-to-RBM dose ratios would increase by 25% on average when treating with (90)Y instead of (177)Lu. CONCLUSIONS: 3D dosimetry identifies patients at risk of developing any grade of RBM toxicity more accurately than blood- or 2D image based methods. It has the added value to enable calculation of tumor-to-RBM dose ratios. PMID- 26501808 TI - Effects of ferumoxytol on quantitative PET measurements in simultaneous PET/MR whole-body imaging: a pilot study in a baboon model. AB - BACKGROUND: Simultaneous PET/MR imaging depends on MR-derived attenuation maps (mu-maps) for accurate attenuation correction of PET data. Currently, these maps are derived from gradient-echo-based MR sequences, which are sensitive to susceptibility changes. Iron oxide magnetic nanoparticles have been used in the measurement of blood volume, tumor microvasculature, tumor-associated macrophages, and characterizing lymph nodes. Our aim in this study was to assess whether the susceptibility effects associated with iron oxide nanoparticles can potentially affect measured (18)F-FDG PET standardized uptake values (SUV) through effects on MR-derived attenuation maps. METHODS: The study protocol was approved by the Institutional Animal Care and Use Committee. Using a Siemens Biograph mMR PET/MR scanner, we evaluated the effects of increasing concentrations of ferumoxytol and ferumoxytol aggregates on MR-derived mu-maps using an agarose phantom. In addition, we performed a baboon experiment evaluating the effects of a single i.v. ferumoxytol dose (10 mg/kg) on the liver, spleen, and pancreas (18)F-FDG SUV at baseline (ferumoxytol-naive), within the first hour and at 1, 3, 5, and 11 weeks. RESULTS: Phantom experiments showed mu map artifacts starting at ferumoxytol aggregate concentrations of 10 to 20 mg/kg. The in vivo baboon data demonstrated a 53% decrease of observed (18)F-FDG SUV compared to baseline within the first hour in the liver, persisting at least 11 weeks. CONCLUSIONS: A single ferumoxytol dose can affect measured SUV for at least 3 months, which should be taken into account when administrating ferumoxytol in patients needing sequential PET/MR scans. Advances in knowledge 1. Ferumoxytol aggregates, but not ferumoxytol alone, produce significant artifacts in MR-derived attenuation correction maps at approximate clinical dose levels of 10 mg/kg. 2. When performing simultaneous whole-body (18)F-FDG PET/MR, a single dose of ferumoxytol can result in observed SUV decreases up to 53%, depending on the amount of ferumoxytol aggregates in the studied tissue. Implications for patient care Administration of a single, clinically relevant, dose of ferumoxytol can potentially result in changes in observed SUV for a prolonged period of time in the setting of simultaneous PET/MR. These potential changes should be considered in particular when administering ferumoxytol to patients with expected future PET/MR studies, as ferumoxytol-induced SUV changes might interfere with therapy assessment. PMID- 26501809 TI - Impact of injection dose, post-reconstruction filtering, and collimator choice on image quality of myocardial perfusion SPECT using cadmium-zinc telluride detectors in the rat. AB - BACKGROUND: The aims of this study were (1) to evaluate the impact of injection dose, post-reconstruction filtering, and collimator choice on image quality of myocardial perfusion single-photon emission computed tomography (SPECT) using cadmium-zinc telluride (CZT) detectors and (2) to determine how these factors affect measured infarct size in the in vivo rat. METHODS: Twenty-four healthy and eight myocardial infarct (MI) rats underwent myocardial perfusion SPECT imaging after injection of various doses (25 to 200 MBq) of (99m)Tc-tetrofosmin using a standard (STD) five-pinhole collimator and high-sensitivity (HS) five-pinhole collimator. Image quality score, contrast-to-noise ratio, sharpness index, coefficient of variation (CV), and measured defect size were assessed as measures of image quality. RESULTS: The image quality score increased and CV decreased as a function of injection dose. The contrast-to-noise ratio increased and sharpness index decreased as a function of Gaussian kernel size. When STD and HS were compared, HS tended to show higher image quality score and lower CV than STD. The use of post-reconstruction filter significantly improved image quality score and lessened CV. The reproducibility of defect size measurements, as assessed by intraclass correlation coefficients (ICC), between the collimators was poor-to moderate (ICC = -0.31~0.57) with low (25 MBq) injection dose and with no or light (1.5-mm kernel size) filtering, whereas it was good-to-excellent (ICC = 0.75~0.97) with high (200 MBq) dose or low dose with heavy (2.5-mm kernel size) filtering. The filtering-related reproducibility was poor (ICC = -0.18~0.17) for STD with low injection dose, whereas it was good-to-excellent (ICC = 0.79~0.89) for HS. Furthermore, there was a filtering-related underestimation of defect size particularly with the use of heavy smoothing. CONCLUSIONS: Appropriate imaging setting is important to obtain high quality images and thereby reliable measurements using a preclinical myocardial SPECT in the rat. When only a low injection dose (25 MBq) is allowed, we would recommend to use HS with light (1.5 mm kernel size) filtering. PMID- 26501810 TI - Dental artifacts in the head and neck region: implications for Dixon-based attenuation correction in PET/MR. AB - BACKGROUND: In the absence of CT or traditional transmission sources in combined clinical positron emission tomography/magnetic resonance (PET/MR) systems, MR images are used for MR-based attenuation correction (MR-AC). The susceptibility effects due to metal implants challenge MR-AC in the neck region of patients with dental implants. The purpose of this study was to assess the frequency and magnitude of subsequent PET image distortions following MR-AC. METHODS: A total of 148 PET/MR patients with clear visual signal voids on the attenuation map in the dental region were included in this study. Patients were injected with [(18)F]-FDG, [(11)C]-PiB, [(18)F]-FET, or [(64)Cu]-DOTATATE. The PET/MR data were acquired over a single-bed position of 25.8 cm covering the head and neck. MR-AC was based on either standard MR-ACDIXON or MR-ACINPAINTED where the susceptibility-induced signal voids were substituted with soft tissue information. Our inpainting algorithm delineates the outer contour of signal voids breaching the anatomical volume using the non-attenuation-corrected PET image and classifies the inner air regions based on an aligned template of likely dental artifact areas. The reconstructed PET images were evaluated visually and quantitatively using regions of interests in reference regions. The volume of the artifacts and the computed relative differences in mean and max standardized uptake value (SUV) between the two PET images are reported. RESULTS: The MR-based volume of the susceptibility-induced signal voids on the MR-AC attenuation maps was between 1.6 and 520.8 mL. The corresponding/resulting bias of the reconstructed tracer distribution was localized mainly in the area of the signal void. The mean and maximum SUVs averaged across all patients increased after inpainting by 52% (+/- 11%) and 28% (+/- 11%), respectively, in the corrected region. SUV underestimation decreased with the distance to the signal void and correlated with the volume of the susceptibility artifact on the MR-AC attenuation map. CONCLUSIONS: Metallic dental work may cause severe MR signal voids. The resulting PET/MR artifacts may exceed the actual volume of the dental fillings. The subsequent bias in PET is severe in regions in and near the signal voids and may affect the conspicuity of lesions in the mandibular region. PMID- 26501811 TI - PET image segmentation using a Gaussian mixture model and Markov random fields. AB - BACKGROUND: Classification algorithms for positron emission tomography (PET) images support computational treatment planning in radiotherapy. Common clinical practice is based on manual delineation and fixed or iterative threshold methods, the latter of which requires regression curves dependent on many parameters. METHODS: An improved statistical approach using a Gaussian mixture model (GMM) is proposed to obtain initial estimates of a target volume, followed by a correction step based on a Markov random field (MRF) and a Gibbs distribution to account for dependencies among neighboring voxels. In order to evaluate the proposed algorithm, phantom measurements of spherical and non-spherical objects with the smallest diameter being 8 mm were performed at signal-to-background ratios (SBRs) between 2.06 and 9.39. Additionally (68)Ga-PET data from patients with lesions in the liver and lymph nodes were evaluated. RESULTS: The proposed algorithm produces stable results for different reconstruction algorithms and different lesion shapes. Furthermore, it outperforms all threshold methods regarding detection rate, determines the spheres' volumes more accurately than fixed threshold methods, and produces similar values as iterative thresholding. In a comparison with other statistical approaches, the algorithm performs equally well for larger volumes and even shows improvements for small volumes and SBRs. The comparison with experts' manual delineations on the clinical data shows the same qualitative behavior as for the phantom measurements. CONCLUSIONS: In conclusion, a generic probabilistic approach that does not require data measured beforehand is presented whose performance, robustness, and swiftness make it a feasible choice for PET segmentation. PMID- 26501812 TI - Increased absorbed liver dose in Selective Internal Radiation Therapy (SIRT) correlates with increased sphere-cluster frequency and absorbed dose inhomogeneity. AB - BACKGROUND: The higher tolerated mean absorbed dose for selective internal radiation therapy (SIRT) with intra-arterially infused (90)Y microspheres compared to external beam therapy is speculated to be caused by absorbed dose inhomogeneity, which allows for liver regeneration. However, the complex liver microanatomy and rheology makes modelling less valuable if the tolerance doses are not based on the actual microsphere distribution. The present study demonstrates the sphere distribution and small-scale absorbed dose inhomogeneity and its correlation with the mean absorbed dose in liver tissue resected after SIRT. METHODS: A patient with marginally resectable cholangiocarcinoma underwent SIRT 9 days prior to resection including adjacent normal liver tissue. The resected specimen was formalin-fixed and sliced into 1 to 2-mm sections. Forty one normal liver biopsies 6-8 mm in diameter were punched from these sections and the radioactivity measured. Sixteen biopsies were further processed for detailed analyses by consecutive serial sectioning of 15 30-MUm sections per biopsy, mounted and stained with haematoxylin-eosin. All sections were scrutinised for isolated or conglomerate spheres. Small-scale dose distributions were obtained by applying a (90)Y-dose point kernel to the microsphere distributions. RESULTS: A total of 3888 spheres were found in the 240 sections. Clusters were frequently found as strings in the arterioles and as conglomerates in small arteries, with the largest cluster comprising 453 spheres. An increased mean absorbed dose in the punch biopsies correlated with large clusters and a greater coefficient of variation. In simulations the absorbed dose was 5-1240 Gy; 90% were 10-97 Gy and 45% were <30 Gy, the assumed tolerance in external beam therapy. CONCLUSIONS: Sphere clusters were located in both arterioles and small arteries and increased in size with increasing sphere concentration, resulting in increased absorbed dose inhomogeneity, which contradicts earlier modelling studies. PMID- 26501813 TI - Applicability of emission-based attenuation map for rapid CBF, OEF, and CMRO2 measurements using gaseous (15)O-labeled compounds. AB - BACKGROUND: Cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) images have facilitated understanding of the pathophysiological basis of cerebrovascular disorders. Such parametric images can be rapidly, measured within around 15 min, using positron emission tomography (PET) with sequentially administered (15)O-labeled oxygen and water. For further shortening, one option is to eliminate the transmission scan by applying an emission-based attenuation correction. METHODS: The validity of the present method was tested by comparing parametric values with emission-based attenuation correction to those with transmission-based correction. This was applied to 27 subjects who were diagnosed with or without cerebrovascular disorders. All subjects received the rapid CBF/OEF/CMRO2 PET measurements. An emission-based attenuation map was generated by estimating the edge of the brain tissue contour on an obtained sinogram and by assuming the uniform tissue coefficient to be 0.1 cm(-1). Then images were reconstructed, and parametric images were computed. RESULTS: No difference was apparent between the emission- and transmission-based methods. Paired t-test showed no significant differences in CBF, OEF, or CMRO2 values between the emission- and transmission-based methods, except in the parietal and occipital and cerebellum and occipital regions, and the differences were less than 10%. The regression analysis showed a close correlation of r = 0.89 to 0.99. CONCLUSIONS: The present study revealed that the attenuation correction can be performed by the emission-based estimation method and clinical PET duration can be shortened for the CBF, OEF, and CMRO2 gas study. PMID- 26501814 TI - A novel phantom technique for evaluating the performance of PET auto-segmentation methods in delineating heterogeneous and irregular lesions. AB - BACKGROUND: Positron Emission Tomography (PET)-based automatic segmentation (PET AS) methods can improve tumour delineation for radiotherapy treatment planning, particularly for Head and Neck (H&N) cancer. Thorough validation of PET-AS on relevant data is currently needed. Printed subresolution sandwich (SS) phantoms allow modelling heterogeneous and irregular tracer uptake, while providing reference uptake data. This work aimed to demonstrate the usefulness of the printed SS phantom technique in recreating complex realistic H&N radiotracer uptake for evaluating several PET-AS methods. METHODS: Ten SS phantoms were built from printouts representing 2mm-spaced slices of modelled H&N uptake, printed using black ink mixed with 18F-fluorodeoxyglucose, and stacked between 2mm thick plastic sheets. Spherical lesions were modelled for two contrasted uptake levels, and irregular and spheroidal tumours were modelled for homogeneous, and heterogeneous uptake including necrotic patterns. The PET scans acquired were segmented with ten custom PET-AS methods: adaptive iterative thresholding (AT), region growing, clustering applied to 2 to 8 clusters, and watershed transform based segmentation. The difference between the resulting contours and the ground truth from the image template was evaluated using the Dice Similarity Coefficient (DSC), Sensitivity and Positive Predictive value. RESULTS: Realistic H&N images were obtained within 90 min of preparation. The sensitivity of binary PET-AS and clustering using small numbers of clusters dropped for highly heterogeneous spheres. The accuracy of PET-AS methods dropped between 4% and 68% for irregular lesions compared to spheres of the same volume. For each geometry and uptake modelled with the SS phantoms, we report the number of clusters resulting in optimal segmentation. Radioisotope distributions representing necrotic uptakes proved most challenging for most methods. Two PET-AS methods did not include the necrotic region in the segmented volume. CONCLUSIONS: Printed SS phantoms allowed identifying advantages and drawbacks of the different methods, determining the most robust PET-AS for the segmentation of heterogeneities and complex geometries, and quantifying differences across methods in the delineation of necrotic lesions. The printed SS phantom technique provides key advantages in the development and evaluation of PET segmentation methods and has a future in the field of radioisotope imaging. PMID- 26501815 TI - Motion correction in simultaneous PET/MR brain imaging using sparsely sampled MR navigators: a clinically feasible tool. AB - BACKGROUND: We present a study performing motion correction (MC) of PET using MR navigators sampled between other protocolled MR sequences during simultaneous PET/MR brain scanning with the purpose of evaluating its clinical feasibility and the potential improvement of image quality. FINDINGS: Twenty-nine human subjects had a 30-min [(11)C]-PiB PET scan with simultaneous MR including 3D navigators sampled at six time points, which were used to correct the PET image for rigid head motion. Five subjects with motion greater than 4 mm were reconstructed into six frames (one for each navigator) which were averaged to one image after MC. The average maximum motion magnitude observed was 3.9 +/- 2.4 mm (1 to 11 mm). Visual evaluation by a nuclear medicine physician of the five subjects' motion corrected rated three of the five images blurred before motion correction, while no images were rated blurred after. The image quality was scored on a scale of 1 5, 5 being best. The score changed from an average of 3.4 before motion correction to 4.0 after. There was no correlation between maximum motion magnitude and rating. Quantitative SUVr scoring did not change markedly with motion correction. CONCLUSIONS: Sparsely sampled navigators can be used for characterization and correction of head motion. A slight, overall decrease in blurring and an increase in image quality with MC was found, but without impact on clinical interpretation. In future studies with noteworthy motion artifacts, our method is an important and simple-to-use tool to have available for motion correction. PMID- 26501816 TI - Impact of image-based motion correction on dopamine D3/D2 receptor occupancy comparison of groupwise and frame-by-frame registration approaches. AB - BACKGROUND: Image registration algorithms are frequently used to align the reconstructed brain PET frames to remove subject head motion. However, in occupancy studies, this is a challenging task where competitive binding of a drug can further reduce the available signal for registration. The purpose of this study is to evaluate two kinds of algorithms-a conventional frame-by-frame (FBF) registration and a recently introduced groupwise image registration (GIR), for motion correction of a dopamine D3/D2 receptor occupancy study. METHODS: The FBF method co-registers all the PET frames to a common reference based on normalised mutual information as the spatial similarity. The GIR method incorporates a pharmacokinetic model and conducts motion correction by maximising a likelihood function iteratively on tracer kinetics and subject motion. Data from eight healthy volunteers scanned with [11C]-(+)-PHNO pre- and post-administration of a range of doses of the D3 antagonist GSK618334 were used to compare the motion correction performance. RESULTS: The groupwise registration achieved improved motion correction results, both by visual inspection of the dynamic PET data and by the reduction of the variability in the outcome measures, and required no additional steps to exclude unsuccessfully realigned PET data for occupancy modelling as compared to frame-by-frame registration. Furthermore, for the groupwise method, the resultant binding potential estimates had reduced variation and bias for individual scans and improved half maximal effective concentration (EC50) estimates were obtained for the study as a whole. CONCLUSIONS: These results indicate that the groupwise registration approach can provide improved motion correction of dynamic brain PET data as compared to frame-by-frame registration approaches for receptor occupancy studies. PMID- 26501817 TI - Comparing voxel-based absorbed dosimetry methods in tumors, liver, lung, and at the liver-lung interface for (90)Y microsphere selective internal radiation therapy. AB - BACKGROUND: To assess differences between four different voxel-based dosimetry methods (VBDM) for tumor, liver, and lung absorbed doses following (90)Y microsphere selective internal radiation therapy (SIRT) based on (90)Y bremsstrahlung SPECT/CT, a secondary objective was to estimate the sensitivity of liver and lung absorbed doses due to differences in organ segmentation near the liver-lung interface. METHODS: Investigated VBDM were Monte Carlo (MC), soft tissue kernel with density correction (SKD), soft-tissue kernel (SK), and local deposition (LD). Seventeen SIRT cases were analyzed. Mean absorbed doses ([Formula: see text]) were calculated for tumor, non-tumoral liver (NL), and right lung (RL). Simulations with various SPECT spatial resolutions (FHWMs) and multiple lung shunt fractions (LSs) estimated the accuracy of VBDM at the liver lung interface. Sensitivity of patient RL and NL [Formula: see text] on segmentation near the interface was assessed by excluding portions near the interface. RESULTS: SKD, SK, and LD were within 5 % of MC for tumor and NL [Formula: see text]. LD and SKD overestimated RL [Formula: see text] compared to MC on average by 17 and 20 %, respectively; SK underestimated RL [Formula: see text] on average by -60 %. Simulations (20 mm FWHM, 20 % LS) showed that SKD, LD, and MC were within 10 % of the truth deep (>39 mm) in the lung; SK significantly underestimated the absorbed dose deep in the lung by approximately -70 %. All VBDM were within 10 % of truth deep (>12 mm) in the liver. Excluding 1, 2, and 3 cm of RL near the interface changed the resulting RL [Formula: see text] by -22, 38, and -48 %, respectively, for all VBDM. An average change of -7 % in the NL [Formula: see text] was realized when excluding 3 cm of NL from the interface. [Formula: see text] was realized when excluding 3 cm of NL from the interface. CONCLUSIONS: SKD, SK, and LD are equivalent to MC for tumor and NL [Formula: see text]. SK underestimates RL [Formula: see text] relative to MC whereas LD and SKD overestimate. RL [Formula: see text] is strongly influenced by the liver-lung interface. PMID- 26501818 TI - Reliability and advantages of using non-uniform Chang's attenuation correction method using a CT-based attenuation coefficient map in (99m)Tc-GSA SPECT/CT hepatic imaging. AB - BACKGROUND: Generally, attenuation correction is made by incorporating a linear attenuation coefficient, which is based on the attenuation coefficient map (mu map) created from a computed tomography scan, into the ordered subsets expectation maximization reconstruction method in non-uniform domains. A non uniform Chang's attenuation correction method that uses the mu-map created from a computed tomography image that was made after reconstruction has been performed is currently available. The purpose of this study was to determine the usefulness of the non-uniform Chang's attenuation correction method in (99m)Tc-galactosyl human serum albumin diethylenetriamine pentaacetic acid single photon emission computed tomography/computed tomography imaging. METHODS: Single photon emission computed tomography/computed tomography imaging was performed in phantoms with (99m)Tc water solutions and in a clinical study of 20 donors in living liver tissue transplantation. Attenuation correction was then performed in the reconstructed single photon emission computed tomography images with the non uniform Chang's method and ordered subsets-expectation maximization attenuation correction methods with triple energy window scatter correction. Root mean square error values were used for assessment of the image uniformity, and we evaluated the absolute radioactivity in liver parts in the phantoms and those in the donors who had a normal liver function. RESULTS: The values of root mean square error on the non-uniform Chang's attenuation correction images were lower than those on ordered subsets-expectation maximization attenuation correction images for both the phantoms and the 20 donors. The difference between the true and estimated radioactivity in the non-uniform Chang's attenuation correction method was smaller than that in the ordered subsets-expectation maximization attenuation correction methods in the phantom study. CONCLUSIONS: The non-uniform Chang's attenuation correction is considered to be superior to the ordered subsets expectation maximization attenuation correction in the assessment of absolute liver radioactivity and liver image uniformity on (99m)Tc-galactosyl human serum albumin diethylenetriamine pentaacetic acid single photon emission computed tomography/computed tomography imaging. PMID- 26501819 TI - NEMA image quality phantom measurements and attenuation correction in integrated PET/MR hybrid imaging. AB - BACKGROUND: In integrated PET/MR hybrid imaging the evaluation of PET performance characteristics according to the NEMA standard NU 2-2007 is challenging because of incomplete MR-based attenuation correction (AC) for phantom imaging. In this study, a strategy for CT-based AC of the NEMA image quality (IQ) phantom is assessed. The method is systematically evaluated in NEMA IQ phantom measurements on an integrated PET/MR system. METHODS: NEMA IQ measurements were performed on the integrated 3.0 Tesla PET/MR hybrid system (Biograph mMR, Siemens Healthcare). AC of the NEMA IQ phantom was realized by an MR-based and by a CT-based method. The suggested CT-based AC uses a template MU-map of the NEMA IQ phantom and a phantom holder for exact repositioning of the phantom on the systems patient table. The PET image quality parameters contrast recovery, background variability, and signal-to-noise ratio (SNR) were determined and compared for both phantom AC methods. Reconstruction parameters of an iterative 3D OP-OSEM reconstruction were optimized for highest lesion SNR in NEMA IQ phantom imaging. RESULTS: Using a CT-based NEMA IQ phantom MU-map on the PET/MR system is straightforward and allowed performing accurate NEMA IQ measurements on the hybrid system. MR-based AC was determined to be insufficient for PET quantification in the tested NEMA IQ phantom because only photon attenuation caused by the MR-visible phantom filling but not the phantom housing is considered. Using the suggested CT-based AC, the highest SNR in this phantom experiment for small lesions (<= 13 mm) was obtained with 3 iterations, 21 subsets and 4 mm Gaussian filtering. CONCLUSION: This study suggests CT-based AC for the NEMA IQ phantom when performing PET NEMA IQ measurements on an integrated PET/MR hybrid system. The superiority of CT-based AC for this phantom is demonstrated by comparison to measurements using MR-based AC. Furthermore, optimized PET image reconstruction parameters are provided for the highest lesion SNR in NEMA IQ phantom measurements. PMID- 26501820 TI - A method for comparing intra-tumoural radioactivity uptake heterogeneity in preclinical positron emission tomography studies. AB - BACKGROUND: Non-uniformity influences the interpretation of nuclear medicine based images and consequently their use in treatment planning and monitoring. However, no standardised method for evaluating and ranking heterogeneity exists. Here, we have developed a general algorithm that provides a ranking and a visualisation of the heterogeneity in small animal positron emission tomography (PET) images. METHODS: The code of the algorithm was written using the Matrix Laboratory software (MATLAB). Parameters known to influence the heterogeneity (distances between deviating peaks, gradients and size compensations) were incorporated into the algorithm. All data matrices were mathematically constructed in the same format with the aim of maintaining overview and control. Histograms visualising the spread and frequency of contributions to the heterogeneity were also generated. The construction of the algorithm was tested using mathematically generated matrices and by varying post-processing parameters. It was subsequently applied in comparisons of radiotracer uptake in preclinical images in human head and neck carcinoma and endothelial and ovarian carcinoma xenografts. RESULTS: Using the developed algorithm, entire tissue volumes could be assessed and gradients could be handled in an indirect manner. Similar-sized volumes could be compared without modifying the algorithm. Analyses of the distribution of different tracers gave results that were generally in accordance with single plane preclinical images, indicating that it could appropriately handle comparisons of targeting vs. non-targeting tracers and also for different target levels. Altering the reconstruction algorithm, pixel size, tumour ROI volumes and lower cut-off limits affected the calculated heterogeneity factors in expected directions but did not reverse conclusions about which tumour was more or less heterogeneous. CONCLUSIONS: The algorithm constructed is an objective and potentially user-friendly tool for one-to-one comparisons of heterogeneity in whole similar-sized tumour volumes in PET imaging. PMID- 26501821 TI - In vivo quantification of (177)Lu with planar whole-body and SPECT/CT gamma camera imaging. AB - BACKGROUND: Advances in gamma camera technology and the emergence of a number of new theranostic radiopharmaceutical pairings have re-awakened interest in in vivo quantification with single-photon-emitting radionuclides. We have implemented and validated methodology to provide quantitative imaging of (177)Lu for 2D whole body planar studies and for 3D tomographic imaging with single-photon emission computed tomography (SPECT)/CT. METHODS: Whole-body planar scans were performed on subjects to whom a known amount of [(177)Lu]-DOTA-octreotate had been administered for therapy. The total radioactivity estimated from the images was compared with the known amount of the radionuclide therapy administered. In separate studies, venous blood samples were withdrawn from subjects after administration of [(177)Lu]-DOTA-octreotate while a SPECT acquisition was in progress and the concentration of the radionuclide in the venous blood sample compared with that estimated from large blood pool structures in the SPECT reconstruction. The total radioactivity contained within an internal SPECT calibration standard was also assessed. RESULTS: In the whole-body planar scans (n = 28), the estimated total body radioactivity was accurate to within +4.6 +/- 5.9 % (range -17.1 to +11.2 %) of the correct value. In the SPECT reconstructions (n = 12), the radioactivity concentration in the cardiac blood pool was accurate to within -4.0 +/- 7.8 % (range -16.1 to +7.5 %) of the true value and the internal standard measurements (n = 89) were within 2.0 +/- 8.5 % (range -16.3 to +24.2 %) of the known amount of radioactivity contained. CONCLUSIONS: In our hands, state-of-the-art hybrid SPECT/CT gamma cameras were able to provide accurate estimates of in vivo radioactivity to better than, on average, +/-10 % for use in biodistribution and radionuclide dosimetry calculations. PMID- 26501822 TI - Correcting for respiratory motion in liver PET/MRI: preliminary evaluation of the utility of bellows and navigated hepatobiliary phase imaging. AB - BACKGROUND: The purpose of this study was to evaluate the utility of bellows based respiratory compensation and navigated hepatobiliary phase imaging to correct for respiratory motion in the setting of dedicated liver PET/MRI. METHODS: Institutional review board approval and informed consent were obtained. Six patients with metastatic neuroendocrine tumor were imaged using Ga-68 DOTA TOC PET/MRI. Whole body imaging and a dedicated 15-min liver PET acquisition was performed, in addition to navigated and breath-held hepatobiliary phase (HBP) MRI. Liver PET data was reconstructed three ways: the entire data set (liver PET), gated using respiratory bellows (RC-liver PET), and a non-gated data set reconstructed using the same amount of data used in the RC-liver PET (shortened liver PET). Liver lesions were evaluated using SUVmax, SUVpeak, SUVmean, and Volisocontour. Additionally, the displacement of each lesion between the RC-liver PET images and the navigated and breath-held HBP images was calculated. RESULTS: Respiratory compensation resulted in a 43 % increase in SUVs compared to ungated data (liver vs RC-liver PET SUVmax 26.0 vs 37.3, p < 0.001) and a 25 % increase compared to a non-gated reconstruction using the same amount of data (RC-liver vs shortened liver PET SUVmax 26.0 vs 32.6, p < 0.001). Lesion displacement was minimized using navigated HBP MRI (1.3 +/- 1.0 mm) compared to breath-held HBP MRI (23.3 +/- 1.0 mm). CONCLUSIONS: Respiratory bellows can provide accurate respiratory compensation when imaging liver lesions using PET/MRI, and results in increased SUVs due to a combination of increased image noise and reduced respiratory blurring. Additionally, navigated HBP MRI accurately aligns with respiratory compensated PET data. PMID- 26501823 TI - Erratum to: Effective dose to adult patients from 338 radiopharmaceuticals estimated using ICRP biokinetic data, ICRP/ICRU computational reference phantoms and ICRP 2007 tissue weighting factors. PMID- 26501824 TI - Erratum to: Motion correction in simultaneous PET/MR brain imaging using sparsely sampled MR navigators: a clinically feasible tool. PMID- 26501825 TI - Method dependence, observer variability and kidney volumes in radiation dosimetry of (177)Lu-DOTATATE therapy in patients with neuroendocrine tumours. AB - BACKGROUND: Radionuclide therapy can be individualized by performing dosimetry. To determine absorbed organ doses in (177)Lu-DOTATATE therapy, three methods based on activity concentrations are currently in use: the small volume of interest (sVOI) method, and two methods based on large VOIs either on anatomical CT (aVOI) or on thresholds on functional images (tVOI). The main aim of the present work was to validate the sVOI in comparison to the other two methods regarding agreement and time efficiency. Secondary aims were to investigate inter observer variability for the sVOI and the change of functional organ volumes following therapy. METHODS: Thirty patients diagnosed with neuroendocrine tumours undergoing therapy with (177)Lu-DOTATATE were included. Each patient underwent three SPECT/CT scans at 1, 4 and 7 days after the treatment. Three independent observers calculated absorbed doses to the right and left kidney and the spleen using sVOI and one observer used aVOI. For tVOI, the absorbed doses were calculated based on automatically drawn isocontours around the organs at different thresholds (42, 50, 60 and 70 %). The inter-observer difference between the calculated absorbed doses for sVOI was calculated, and the differences between the three methods were computed. Ratios of organ volumes acquired at days 1, 4 and 7 versus the volume at day 1 were calculated for the tVOI method. RESULTS: The differences in results of the absorbed dose calculations using all the sVOI and tVOI were small (<5 %). Absorbed dose calculations using aVOI differed slightly more from these results but were still below 10 %. The differences between the three dose calculation methods varied between <5 and 10 %. The organ volumes derived from the tVOI were independent of time for the spleen while they decreased with time for the kidneys. The fastest analysis was performed with the sVOI method. CONCLUSIONS: All three dose calculation methods rendered comparable results with small inter-observer differences for sVOI. Unlike the spleen, the functional volume of the kidneys decreased over time during therapy, which suggests that the absorbed dose calculation for the kidneys on activity concentrations should be performed for each time point. The sVOI is the preferred method for calculating absorbed doses in solid organs. PMID- 26501826 TI - Automatic extraction of forward stroke volume using dynamic PET/CT: a dual-tracer and dual-scanner validation in patients with heart valve disease. AB - BACKGROUND: The aim of this study was to develop and validate an automated method for extracting forward stroke volume (FSV) using indicator dilution theory directly from dynamic positron emission tomography (PET) studies for two different tracers and scanners. METHODS: 35 subjects underwent a dynamic (11)C acetate PET scan on a Siemens Biograph TruePoint-64 PET/CT (scanner I). In addition, 10 subjects underwent both dynamic (15)O-water PET and (11)C-acetate PET scans on a GE Discovery-ST PET/CT (scanner II). The left ventricular (LV) aortic time-activity curve (TAC) was extracted automatically from PET data using cluster analysis. The first-pass peak was isolated by automatic extrapolation of the downslope of the TAC. FSV was calculated as the injected dose divided by the product of heart rate and the area under the curve of the first-pass peak. Gold standard FSV was measured using phase-contrast cardiovascular magnetic resonance (CMR). RESULTS: FSVPET correlated highly with FSVCMR (r = 0.87, slope = 0.90 for scanner I, r = 0.87, slope = 1.65, and r = 0.85, slope = 1.69 for scanner II for (15)O-water and (11)C-acetate, respectively) although a systematic bias was observed for both scanners (p < 0.001 for all). FSV based on (11)C-acetate and (15)O-water correlated highly (r = 0.99, slope = 1.03) with no significant difference between FSV estimates (p = 0.14). CONCLUSIONS: FSV can be obtained automatically using dynamic PET/CT and cluster analysis. Results are almost identical for (11)C-acetate and (15)O-water. A scanner-dependent bias was observed, and a scanner calibration factor is required for multi-scanner studies. Generalization of the method to other tracers and scanners requires further validation. PMID- 26501827 TI - Performance evaluation of the Biograph mCT Flow PET/CT system according to the NEMA NU2-2012 standard. AB - BACKGROUND: The purpose of the study is to evaluate the physical performance of a Biograph mCT Flow 64-4R PET/CT system (Siemens Healthcare, Germany) and to compare clinical image quality in step-and-shoot (SS) and continuous table motion (CTM) acquisitions. METHODS: The spatial resolution, sensitivity, count rate curves, and Image Quality (IQ) parameters following the National Electrical Manufactures Association (NEMA) NU2-2012 standard were evaluated. For resolution measurements, an (18)F point source inside a glass capillary tube was used. Sensitivity measurements were based on a 70-cm-long polyethylene tube, filled with 4.5 MBq of FDG. Scatter fraction and count rates were measured using a 70-cm long polyethylene cylinder with a diameter of 20 cm and a line source (1.04 GBq of FDG) inserted axially into the cylinder 4.5 cm off-centered. A NEMA IQ phantom containing six spheres (10- to 37-mm diameter) was used for the evaluation of the image quality. First, a single-bed scan was acquired (NEMA standard), followed by a two-bed scan (4 min each) of the IQ phantom with the image plane containing the spheres centered in the overlap region of the two bed positions. In addition, a scan of the same region in CTM mode was performed with a table speed of 0.6 mm/s. Furthermore, two patient scans were performed in CTM and SS mode. Image contrasts and patient images were compared between SS and CTM acquisitions. RESULTS: Full Width Half Maximum (FWHM) of the spatial resolution ranged from 4.3 to 7.8 mm (radial distance 1 to 20 cm). The measured sensitivity was 9.6 kcps/MBq, both at the center of the FOV and 10 cm off-center. The measured noise equivalent count rate (NECR) peak was 185 kcps at 29.0 kBq/ml. The scatter fraction was 33.5 %. Image contrast recovery values (sphere-to-background of 8:1) were between 42 % (10-mm sphere) to 79 % (37-mm sphere). The background variability was between 2.1 and 5.3 % (SS) and between 2.4 and 6.9 % (CTM). No significant difference in image quality was observed between SS and CTM mode. CONCLUSIONS: The spatial resolution, sensitivity, scatter fraction, and count rates were in concordance with the published values for the predecessor system, the Biograph mCT. Contrast recovery values as well as image quality obtained in SS and CTM acquisition modes were similar. PMID- 26501828 TI - Treatment for Macular Telangiectasia Type 2. AB - Macular telangiectasia (MacTel) type 2 is a bilateral disease of unknown cause with localized retinal degeneration and characteristic changes of the retinal vasculature. Funduscopic findings include reduced retinal transparency, crystalline deposits, ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy and neovascular complexes. Leakage of telangiectatic macular capillaries is a characteristic finding on fluorescein angiography, and neurosensory atrophy may be present on optical coherence tomography images. Furthermore, there is a specific depletion of macular pigment in the central retina. Depending on the development of neovascular membranes, a nonproliferative and a proliferative (neovascular) disease stage may be distinguished. To date, there is no evidence for an effective treatment of nonproliferative MacTel type 2. Patients with proliferative MacTel type 2 and hence decreasing visual function may benefit from intravitreal application of vascular endothelial growth factor inhibitors. Early treatment and a small size of the neovascular membrane might be predictive factors for visual function outcome. PMID- 26501829 TI - The medial prefrontal cortex-lateral entorhinal cortex circuit is essential for episodic-like memory and associative object-recognition. AB - The prefrontal cortex directly projects to the lateral entorhinal cortex (LEC), an important substrate for engaging item-associated information and relaying the information to the hippocampus. Here we ask to what extent the communication between the prefrontal cortex and LEC is critically involved in the processing of episodic-like memory. We applied a disconnection procedure to test whether the interaction between the medial prefrontal cortex (mPFC) and LEC is essential for the expression of recognition memory. It was found that male rats that received unilateral NMDA lesions of the mPFC and LEC in the same hemisphere, exhibited intact episodic-like (what-where-when) and object-recognition memories. When these lesions were placed in the opposite hemispheres (disconnection), episodic like and associative memories for object identity, location and context were impaired. However, the disconnection did not impair the components of episodic memory, namely memory for novel object (what), object place (where) and temporal order (when), per se. Thus, the present findings suggest that the mPFC and LEC are a critical part of a neural circuit that underlies episodic-like and associative object-recognition memory. PMID- 26501830 TI - Short Sitting Height and Low Relative Sitting Height Are Associated with Severe Cognitive Impairment among Older Women in an Urban Community in China. AB - BACKGROUND: Anthropometric indexes are powerful indicators of the environment and the plasticity of the human body. This study aimed at exploring the anthropometric indexes that are associated with late-life cognition impairment among the elderly Chinese in the Shanghai Aging Study. METHODS: The height, weight, and sitting height of 3,741 participants were measured. Participants were diagnosed with 'dementia', 'mild cognitive impairment', or 'cognitive normal' by neurologists using DSM-IV and Petersen criteria. Logistic regression was used to evaluate the association between height, sitting height, leg length or relative sitting height and cognitive function. RESULTS: Participants with dementia had the shortest body height (mean 157.2 cm, SD 9.1), the shortest sitting height (mean 81.8 cm, SD 5.6), and the lowest relative sitting height (mean 52.0 cm, SD 1.9). After adjustment for age, gender, education, lifestyles, medical history, apolipoprotein genotype and weight, shorter sitting height (OR 1.08, 95% CI 1.01 1.16 per cm), longer leg length (OR 0.93, 95% CI 0.88-0.99 per cm), and lower relative sitting height (OR 1.17, 95% CI 1.04-1.31 per 1%) were found to be significantly associated with dementia in older women. CONCLUSIONS: The potential risks for late-life severe cognitive impairment may be related to health problems in childhood and slow growth during puberty in women. PMID- 26501831 TI - The Effect of Systemic Magnesium on Postsurgical Pain in Children Undergoing Tonsillectomies: A Double-Blinded, Randomized, Placebo-Controlled Trial. AB - BACKGROUND: Tonsillectomy is a frequently performed surgical procedure in children; however, few multimodal analgesic strategies have been shown to improve postsurgical pain in this patient population. Systemic magnesium infusions have been shown to reliably improve postoperative pain in adults, but their effects in pediatric surgical patients remain to be determined. In the current investigation, our main objective was to evaluate the use of systemic magnesium to improve postoperative pain in pediatric patients undergoing tonsillectomy. We hypothesized that children who received systemic magnesium infusions would have less post-tonsillectomy pain than the children who received saline infusions. METHODS: The study was a prospective, randomized, double-blinded, clinical trial. Subjects were randomly assigned using a computer-generated table of random numbers to 1 of the 2 intervention groups: systemic magnesium infusion (initial loading dose 30 mg/kg given over 15 minutes followed by a continuous magnesium infusion 10 mg/kg/h) and the same volume of saline. The primary outcome was pain scores in the postanesthesia care unit (PACU) measured by FLACC (Face, Legs, Activity, Cry, Consolability) pain scores. Pain reduction was measured by the decrement in the area under the pain scale versus 90-minute postoperative time curve using the trapezoidal method. Secondary outcomes included opioid consumption in the PACU, emergence delirium scores (measured by the pediatric anesthesia emergence delirium scale), and parent satisfaction. RESULTS: Sixty subjects were randomly assigned and 60 completed the study. The area under pain scores (up to 90 minutes) was not different between the study groups, median (interquartile range [IQR]) of 30 (0-120) score * min and 45 (0-135) score * min for the magnesium and control groups, respectively (P = 0.74). Similarly, there was no clinically significant difference in the morphine consumption in the PACU between the magnesium group, median (IQR) of 2.0 (0-4.44) mg IV morphine, compared with the control, median (IQR) of 2.5 (0-4.99) mg IV morphine (P = 0.25). The serum level of magnesium was significantly lower in the control group than in the treatment group at the end of the surgery (P < 0.001). CONCLUSIONS: Despite a large number of studies demonstrating the efficacy of systemic magnesium for preventing postsurgical pain in adults, we could not find evidence for a significant clinical benefit of systemic magnesium infusion in children undergoing tonsillectomies. Our findings reiterate the importance of validating multimodal analgesic strategies in children that have been demonstrated to be effective in the adult population. PMID- 26501832 TI - Conductance Quantization in Resistive Random Access Memory. AB - The intrinsic scaling-down ability, simple metal-insulator-metal (MIM) sandwich structure, excellent performances, and complementary metal-oxide-semiconductor (CMOS) technology-compatible fabrication processes make resistive random access memory (RRAM) one of the most promising candidates for the next-generation memory. The RRAM device also exhibits rich electrical, thermal, magnetic, and optical effects, in close correlation with the abundant resistive switching (RS) materials, metal-oxide interface, and multiple RS mechanisms including the formation/rupture of nanoscale to atomic-sized conductive filament (CF) incorporated in RS layer. Conductance quantization effect has been observed in the atomic-sized CF in RRAM, which provides a good opportunity to deeply investigate the RS mechanism in mesoscopic dimension. In this review paper, the operating principles of RRAM are introduced first, followed by the summarization of the basic conductance quantization phenomenon in RRAM and the related RS mechanisms, device structures, and material system. Then, we discuss the theory and modeling of quantum transport in RRAM. Finally, we present the opportunities and challenges in quantized RRAM devices and our views on the future prospects. PMID- 26501833 TI - In Situ SR-XPS Observation of Ni-Assisted Low-Temperature Formation of Epitaxial Graphene on 3C-SiC/Si. AB - Low-temperature (~1073 K) formation of graphene was performed on Si substrates by using an ultrathin (2 nm) Ni layer deposited on a 3C-SiC thin film heteroepitaxially grown on a Si substrate. Angle-resolved, synchrotron-radiation X-ray photoemission spectroscopy (SR-XPS) results show that the stacking order is, from the surface to the bulk, Ni carbides(Ni3C/NiCx)/graphene/Ni/Ni silicides (Ni2Si/NiSi)/3C-SiC/Si. In situ SR-XPS during the graphitization annealing clarified that graphene is formed during the cooling stage. We conclude that Ni silicide and Ni carbide formation play an essential role in the formation of graphene. PMID- 26501834 TI - Effect of Intrinsic Ripples on Elasticity of the Graphene Monolayer. AB - The effect of intrinsic ripples on the mechanical response of the graphene monolayer is investigated under uniaxial loading using molecular dynamics (MD) simulations with a focus on nonlinear behavior at a small strain. The calculated stress-strain response shows a nonlinear relation through the entire range without constant slopes as a result of the competition between ripple softening and bond stretching hardening. For a small strain, entropic contribution is dominant due to intrinsic ripples, leading to elasticity softening. As the ripples flatten at increasing strain, the energetic term due to C-C bonds stretching competes with the entropic contribution, followed by energetic dominant deformation. Elasticity softening is enhanced at increased temperature as the ripple amplitude increases. The study shows that the intrinsic ripple of graphene affects elasticity. This result suggests that a change of ripple amplitudes due to various environmental conditions such as temperature, and substrate interactions can lead to a change of the mechanical properties of graphene. The understanding of the rippling effect on the mechanical behavior of 2D materials is useful for strain-based ripple manipulation for their engineering applications. PMID- 26501835 TI - Ontogenetic Change in the Regional Distribution of Dehydroepiandrosterone Synthesizing Enzyme and the Glucocorticoid Receptor in the Brain of the Spiny Mouse (Acomys cahirinus). AB - The androgen dehydroepiandrosterone (DHEA) has trophic and anti-glucocorticoid actions on brain growth. The adrenal gland of the spiny mouse (Acomys cahirinus) synthesizes DHEA. The aim of this study was to determine whether the brain of this precocial species is also able to produce DHEA de novo during fetal, neonatal and adult life. The expression of P450c17 and cytochrome b5 (Cytb5), the enzyme and accessory protein responsible for the synthesis of DHEA, was determined in fetal, neonatal and adult brains by immunocytochemistry, and P450c17 bioactivity was determined by the conversion of pregnenolone to DHEA. Homogenates of fetal brain produced significantly more DHEA after 48 h in culture (22.46 +/- 2.0 ng/mg tissue) than adult brain homogenates (5.04 +/- 2.0 ng/mg tissue; p < 0.0001). P450c17 and Cytb5 were co-expressed in fetal neurons but predominantly in oligodendrocytes and white matter tracts in the adult brain. Because DHEA modulates glucocorticoids actions, the expression of the glucocorticoid receptor (GR) was also determined. In the brainstem, medulla, midbrain, and cerebellum, the predominant GR localization changed from neurons in the fetal brain to oligodendrocytes and white matter tracts in the adult brain. The change of expression of P450c17, Cytb5 and GR proteins with cell type, brain region and developmental age indicates that DHEA is an endogenous neurosteroid in this species that may have important trophic and stress-modifying actions during both prenatal and postnatal life. PMID- 26501836 TI - Adsorption Behavior of Cellulose and Its Derivatives toward Ag(I) in Aqueous Medium: An AFM, Spectroscopic, and DFT Study. AB - The aim of this study was to develop a fundamental understanding of the adsorption behavior of metal ions on cellulose surfaces using experimental techniques supported by computational modeling, taking Ag(I) as an example. Force interactions among three types of cellulose microspheres (native cellulose and its derivatives with sulfate and phosphate groups) and the silica surface in AgNO3 solution were studied with atomic force microscopy (AFM) using the colloidal probe technique. The adhesion force between phosphate cellulose microspheres (PCM) and the silica surface in the aqueous AgNO3 medium increased significantly with increasing pH while the adhesion force slightly decreased for sulfate cellulose microspheres (SCM), and no clear adhesion force was observed for native cellulose microspheres (CM). The stronger adhesion enhancement for the PCM system is mainly attributed to the electrostatic attraction between Ag(I) and the negative silica surface. The observed force trends were in good agreement with the measured zeta potentials. The scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) analyses confirmed the presence of silver on the surface of cellulose microspheres after adsorption. This study showed that PCM with a high content of phosphate groups exhibited a larger amount of adsorbed Ag(I) than CM and SCM and possible clustering of Ag(I) to nanoparticles. The presence of the phosphate group and a wavenumber shift of the P-OH vibration caused by the adsorption of silver ions on the phosphate groups were further confirmed with computational studies using density functional theory (DFT), which gives support to the above findings regarding the adsorption and clustering of Ag(I) on the cellulose surface decorated with phosphate groups as well as IR spectra. PMID- 26501837 TI - IOM REPORT ON PSYCHOSOCIAL INTERVENTIONS: COMMENTARY FROM A DBT PERSPECTIVE. PMID- 26501839 TI - The impact of word prevalence on lexical decision times: Evidence from the Dutch Lexicon Project 2. AB - Keuleers, Stevens, Mandera, and Brysbaert (2015) presented a new variable, word prevalence, defined as word knowledge in the population. Some words are known to more people than other. This is particularly true for low-frequency words (e.g., screenshot vs. scourage). In the present study, we examined the impact of the measure by collecting lexical decision times for 30,000 Dutch word lemmas of various lengths (the Dutch Lexicon Project 2). Word prevalence had the second highest correlation with lexical decision times (after word frequency): Words known by everyone in the population were responded to 100 ms faster than words known to only half of the population, even after controlling for word frequency, word length, age of acquisition, similarity to other words, and concreteness. Because word prevalence has rather low correlations with the existing measures (including word frequency), the unique variance it contributes to lexical decision times is higher than that of the other variables. We consider the reasons why word prevalence has an impact on word processing times and we argue that it is likely to be the most important new variable protecting researchers against experimenter bias in selecting stimulus materials. PMID- 26501838 TI - Regulatory T-cell neutralization in mice during filariasis helps in parasite clearance by enhancing T helper type 17-mediated pro-inflammatory response. AB - Lymphatic filariasis leads to profound impairment of parasite-specific T helper type 1 (Th1) and Th2 immune responses and significantly increases the expression of regulatory networks and regulatory effectors like transforming growth factor beta, CD25, cytotoxic T-lymphocyte antigen 4, glucocorticoid-induced tumour necrosis factor receptor (GITR) and regulatory T (Treg) cells, which together play an important role in immunosuppression. While Treg cells suppress the activity of effector cells, monocyte dysfunction, characterized by an alternatively activated immunoregulatory phenotype, is one hypothesis that explains the lack of an antigen-specific T-cell response in infected individuals. In the present study, we administered neutralizing antibodies against the Treg cell-associated markers CD25 and GITR and observed its effects on filaria-induced immunosuppression. Our results show that administration of anti-CD25 and anti GITR in infected animals not only arrested the accumulation of Treg cells and reduced arginase activity, but also led to an increase in the percentages of Th17 cells in the secondary lymphoid organs of mice. Elevated levels of interferon gamma and decreased levels of interleukin-10 were also noted in the culture supernatants of mouse splenocytes that were treated with neutralizing antibodies. Furthermore, treatment with neutralizing antibodies enhanced the expression of inducible nitric oxide synthase on host macrophages and CD40 on host dendritic cells with concomitant decreased expression of alternative activation markers Arg1, Ym1 and Fizz1, which together lead to reduced parasite burden in treated animals. In summary, administration of neutralizing antibodies helps in breaking the regulatory network in mice and limits parasite-induced immunosuppression at the earliest host-parasite interface. PMID- 26501840 TI - The structure of distractor-response bindings: Conditions for configural and elemental integration. AB - Human action control is influenced by bindings between perceived stimuli and responses carried out in their presence. Notably, responses given to a target stimulus can also be integrated with additional response-irrelevant distractor stimuli that accompany the target (distractor-response binding). Subsequently reencountering such a distractor then retrieves the associated response. Although a large body of evidence supports the existence of this effect, the specific structure of distractor-response bindings is still unclear. Here, we test the predictions derived from 2 possible assumptions about the structure of bindings between distractors and responses. According to a configural approach, the entire distractor object is integrated with a response, and only upon repetition of the entire distractor object the associated response would be retrieved. According to an elemental approach, one would predict integration of individual distractor features with the response and retrieval due to the repetition of an individual distractor feature. Four experiments indicate that both, configural and elemental bindings exist and specify boundary conditions for each type of binding. These findings provide detailed insights into the architecture of bindings between response-irrelevant stimuli and actions and thus allow for specifying how distractor stimuli influence human behavior. (PsycINFO Database Record PMID- 26501841 TI - Conductive polycrystalline diamond probes for local anodic oxidation lithography. AB - This is the first report characterizing local anodic oxidation (LAO) lithography performed using conductive monolithic polycrystalline diamond (MD) and conductive polycrystalline diamond-coated (DC) tips and comparing it to the diamond-like carbon-coated and metal-coated silicon tips. The range and the rate of increase in the lithographic linewidth and height with tip bias (dw/dV and dh/dV) differed based on the tip material. The DC tips resulted in wider and taller lines and a higher dw/dV and dh/dV compared to metal-coated tips with a similar force constant (k(Avg)). The metal-coated and the DC tips with comparable k(Avg) showed comparable threshold voltages, whereas the MD tips with similar k(Avg) showed a higher threshold voltage. The MD tips exhibited less than half the height and nearly half the dw/dV and dh/dV obtained with the metal-coated tips with similar k Avg, thus also resulting in a smaller width at -10 V. The linewidths were found to be proportional to the inverse of the log of write speed(v) for all the tips; however, the proportionality constant varied with tip material; the DC tips had larger values, and the MD and the metal-coated tips had comparable values. When varying the speed, the height was found to be a sigmoidal function of width, with the MD probes achieving lower height compared to the metal-coated and the DC tips with comparable k(Avg). This study expands the application of monolithic conductive polycrystalline diamond (PCD) probes with outstanding wear resistance to fine LAO lithography. PMID- 26501842 TI - Pupil Diameter Changes in High Myopes after Collamer Lens Implantation. AB - PURPOSE: To observe the changes in pupil size under photopic and scotopic conditions after Implantable Collamer Lens (ICL) implantations in eyes with high myopia. METHODS: The ICL was implanted in 90 eyes belonging to 45 patients with high myopia. Photopic pupil diameters, scotopic pupil diameters, anterior chamber depths, and ICL vaults were examined at the preoperative, postoperative 1-month, and postoperative 3-month stages. The preoperative and postoperative photopic pupil diameters and scotopic pupil diameters were also compared with each other to note the differences between them. The correlations between preoperative and postoperative pupil diameter changes under different light conditions and presurgical refractive error were analyzed alongside patient's age and ICL vault. RESULTS: Pupil diameters at both postoperative 1-month and postoperative 3-month stages were smaller than those before operation in distinct light environments, as well as pupil constriction amplitude. Correlation analysis showed that there was a statistically significant correlation between pupil diameter changes under different light conditions and presurgical refractive error at 1 month and 3 months after ICL implantation; pupil diameter decreased more when presurgical refractive error powers were less myopic. Statistically significant correlations were not found, however, with patient's age and ICL vault. Postoperative 1-month and mean postoperative 3-month anterior chamber depths were decreased when compared with preoperative anterior chamber depths. Statistically significant correlations were found in change in preoperative and postoperative anterior chamber depth and ICL vault. No statistically significant difference was found between ICL vault at the postoperative 1-month and postoperative 3-month stages. CONCLUSIONS: Pupil diameter may decrease at the 1- and 3-month stages after ICL implantation under both photopic and scotopic conditions. This indicates that reduction of pupil diameter may be caused by mechanical contact between the ICL and the posterior iris surface. PMID- 26501843 TI - Pituitary dysfunction following cranial radiotherapy for adult-onset nonpituitary brain tumours. AB - OBJECTIVE: There are limited data concerning the evolution of radiation-induced hypopituitarism in adult-onset brain tumour (AO-BT) survivors, in part the consequence of the limited survival of many of these individuals. We aim to characterize the pituitary-related outcomes following cranial radiotherapy (cXRT) for adult-onset primary nonpituitary brain tumours. DESIGN: We retrospectively analysed longitudinal data of patients with AO-BT who received cXRT within a tertiary cancer referral centre. PATIENTS: A total of 107 adults (age 40.0 +/- 13.1 years) followed for a median duration of 8 years following cXRT. MEASUREMENTS: Prevalence of radiotherapy-induced hypopituitarism. RESULTS: 94.4% received fractionated photon radiotherapy (median dose 54 Gy), while the remaining patients received proton beam or stereotactic radiotherapy. 88.8% of patients developed hypopituitarism during follow-up. The frequency of GH, gonadotrophin, ACTH and TSH deficiencies was 86.9% (severe GHD 64.5%, partial GHD 22.4%), 34.6%, 23.4% and 11.2%, respectively. ACTH deficiency was clinically significant, necessitating glucocorticoid replacement, in only 10.3% of cases. Hyperprolactinaemia developed in 15% of patients, which was persistent in only 50% of cases. Multiple pituitary hormone deficiencies were present in 47.7% of patients, encountered more frequently in patients with tumours in proximity to the sella. Longitudinal data analysis revealed accumulation of hormone deficits throughout the follow-up period, with incidence of all pituitary hormone deficiencies almost doubling between years 2 and 7 of follow-up. CONCLUSIONS: Pituitary dysfunction in AO-BT survivors following cXRT is a common, evolving, time-dependent phenomenon. It is important that deficits are identified early and replacement therapies introduced to optimize quality of life in these individuals, where prognosis is often guarded. PMID- 26501845 TI - The Development of English as a Second Language With and Without Specific Language Impairment: Clinical Implications. AB - PURPOSE: The purpose of this research forum article is to provide an overview of typical and atypical development of English as a second language (L2) and to present strategies for clinical assessment with English language learners (ELLs). METHOD: A review of studies examining the lexical, morphological, narrative, and verbal memory abilities of ELLs is organized around 3 topics: timeframe and characteristics of typical English L2 development, comparison of the English L2 development of children with and without specific language impairment (SLI), and strategies for more effective assessment with ELLs. RESULTS: ELLs take longer than 3 years to converge on monolingual norms and approach monolingual norms asynchronously across linguistic subdomains. Individual variation is predicted by age, first language, language learning aptitude, length of exposure to English in school, maternal education, and richness of the English environment outside school. ELLs with SLI acquire English more slowly than ELLs with typical development; their morphological and nonword repetition abilities differentiate them the most. Use of strategies such as parent questionnaires on first language development and ELL norm referencing can result in accurate discrimination of ELLs with SLI. CONCLUSIONS: Variability in the language abilities of ELLs presents challenges for clinical practice. Increased knowledge of English language learning development with and without SLI together with evidence-based alternative assessment strategies can assist in overcoming these challenges. PMID- 26501846 TI - Progression in Behavioral Variant Frontotemporal Dementia: A Longitudinal Study. AB - IMPORTANCE: A gap in the literature exists regarding progression in behavioral variant frontotemporal dementia (BVFTD). Guidance is needed concerning markers that will enable clinicians to discriminate FTD more effectively from phenocopies and to identify factors that determine progression and thereby prognosis. OBJECTIVES: To observe longitudinal outcomes and progression in probable and possible BVFTD in accordance with international diagnostic criteria and to identify features that may aid clinicians to prognosticate better in cases of possible BVFTD. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal cohort study performed in a specialist tertiary FTD research clinic. Fifty-eight consecutive patients were followed up longitudinally from January 1, 2008, through December 31, 2013, and classified as having possible, probable, or definite BVFTD at presentation and latest review. Final follow-up was completed on December 31, 2013, and data were analyzed from January 1 to August 1, 2014. MAIN OUTCOMES AND MEASURES: Clinical, pathological, genetic, neuropsychological, and neuroimaging data were analyzed to categorize patients, to compare differences between groups with changed and unchanged diagnoses, to determine rates of progression in BVFTD, and to identify prognostic features in possible BVFTD. RESULTS: At presentation, 38 of the 58 patients fulfilled criteria for probable BVFTD; of these, 36 continued to satisfy probable criteria or underwent conversion to definite criteria over time. The remaining 20 patients satisfied possible criteria only, and 11 of these patients changed categories over time to probable or definite BVFTD and showed progression on cognitive and functional measures (termed changed status). Of these 11 patients, 8 (73%) carried the C9orf72 expansion. A positive family history, memory impairment, and clinical abnormalities at presentation were key features of progression (P < .05). A continuum of neuropsychological scores, progression rates, and atrophy severity emerged across patients in probable, possible, changed status, and nonchanged status groups; patients with probable BVFTD exhibited the most severe abnormalities. CONCLUSIONS AND RELEVANCE: Behavioral variant FTD shows variable progression over time. Clinicians can use a detailed neurologic and cognitive assessment to identify key predictive features of progression when faced with possible BVFTD, whereas a diagnosis of probable BVFTD is accurate in a clinical setting. PMID- 26501844 TI - Breast Tumor Prognostic Characteristics and Biennial vs Annual Mammography, Age, and Menopausal Status. AB - IMPORTANCE: Screening mammography intervals remain under debate in the United States. OBJECTIVE: To compare the proportion of breast cancers with less vs more favorable prognostic characteristics in women screening annually vs biennially by age, menopausal status, and postmenopausal hormone therapy (HT) use. DESIGN, SETTING, AND PARTICIPANTS: This was a study of a prospective cohort from 1996 to 2012 at Breast Cancer Surveillance Consortium facilities. A total of 15,440 women ages 40 to 85 years with breast cancer diagnosed within 1 year of an annual or within 2 years of a biennial screening mammogram. EXPOSURES: We updated previous analyses by using narrower intervals for defining annual (11-14 months) and biennial (23-26 months) screening. MAIN OUTCOMES AND MEASURES: We defined less favorable prognostic characteristics as tumors that were stage IIB or higher, size greater than 15 mm, positive nodes, and any 1 or more of these characteristics. We used log-binomial regression to model the proportion of breast cancers with less favorable characteristics following a biennial vs annual screen by 10-year age groups and by menopausal status and current postmenopausal HT use. RESULTS: Among 15,440 women with breast cancer, most were 50 years or older (13,182 [85.4%]), white (12,063 [78.1%]), and postmenopausal (9823 [63.6%]). Among 2027 premenopausal women (13.1%), biennial screeners had higher proportions of tumors that were stage IIB or higher (relative risk [RR], 1.28 [95% CI, 1.01-1.63]; P=.04), size greater than 15 mm (RR, 1.21 [95% CI, 1.07 1.37]; P=.002), and with any less favorable prognostic characteristic (RR, 1.11 [95% CI, 1.00-1.22]; P=.047) compared with annual screeners. Among women currently taking postmenopausal HT, biennial screeners tended to have tumors with less favorable prognostic characteristics compared with annual screeners; however, 95% CIs were wide, and differences were not statistically significant (for stage 2B+, RR, 1.14 [95% CI, 0.89-1.47], P=.29; size>15 mm, RR, 1.13 [95% CI, 0.98-1.31], P=.09; node positive, RR, 1.18 [95% CI, 0.98-1.42], P=.09; any less favorable characteristic, RR, 1.12 [95% CI, 1.00-1.25], P=.053). The proportions of tumors with less favorable prognostic characteristics were not significantly larger for biennial vs annual screeners among postmenopausal women not taking HT (eg, any characteristic: RR, 1.03 [95% CI, 0.95-1.12]; P=.45), postmenopausal HT users after subdividing by type of hormone use (eg, any characteristic: estrogen+progestogen users, RR, 1.16 [95% CI, 0.91-1.47]; P=.22; estrogen-only users, RR, 1.14 [95% CI, 0.94-1.37]; P=.18), or any 10-year age group (eg, any characteristic: ages 40-49 years, RR, .1.04 [95% CI, 0.94-1.14]; P=.48; ages 50-59 years, RR, 1.03 [95% CI, 0.94-1.12]; P=.58; ages 60-69 years, RR, 1.07 [95% CI, 0.97-1.19]; P=.18; ages 70-85 years, RR, 1.05 [95% CI, 0.94 1.18]; P=.35). CONCLUSIONS AND RELEVANCE: Premenopausal women diagnosed as having breast cancer following biennial vs annual screening mammography are more likely to have tumors with less favorable prognostic characteristics. Postmenopausal women not using HT who are diagnosed as having breast cancer following a biennial or annual screen have similar proportions of tumors with less favorable prognostic characteristics. PMID- 26501847 TI - Forced Migration: The Human Face of a Health Crisis. PMID- 26501848 TI - Perspectives on Cost and Value in Cancer Care. PMID- 26501849 TI - Evaluation of In-Use Stability of Anticoagulant Drug Products: Warfarin Sodium. AB - The objective of the study was to evaluate the stability of warfarin products during use by patients or caregivers. For evaluation, three commercial products manufactured by different processes were selected and placed at 30 degrees C/75%RH to simulate in use condition. Samples were withdrawn up to 12 weeks and analyzed for the physicochemical changes. Scanning electron microscopy demonstrated increasing holes and craters in the tablets over the timeframe. Near infrared chemical imaging and powder X-ray powder diffraction corroborated the change arising from conversion of crystalline to amorphous forms of the drug. Hardness and disintegration time of the tablets were found to increase progressively. With increasing time, moisture contents of the products were found to increase and consequent decrease in isopropyl alcohol content of the product. Dissolution of the tablets in media at pH 4.5 demonstrated discrimination between crystalline and amorphous drug products. Overall, percent drug dissolved in each product at 30 min was found to decrease with increasing exposure time. Dissolution of drug decreased from 54% to 38% and 82% to 54% for the two products while the third product maintained consistently high level of dissolution. These results suggest that the drug product quality attributes can change during use. PMID- 26501850 TI - Pilot study of patient perception of pharmacists as care providers based on health screening encounters with student pharmacists. AB - OBJECTIVES: To assess how patient perceptions of the clinical role of pharmacists may be affected by use of the AIDET communication tool during student-led health fairs, as well as how such events can help promote pharmacy practice. SETTING: 12 community health fair screenings throughout northeastern Minnesota and northwestern Wisconsin, from February to November 2012. PRACTICE DESCRIPTION: University of Minnesota-College of Pharmacy students trained in the use of AIDET employed the tool's techniques in their communication with health fair patient attendees. Project participants were those patients aged 18 years and older who successfully completed a health fair survey. PRACTICE INNOVATION: The AIDET communication tool is designed to provide consistency in patient encounters through the use of key words at key times. AIDET is a mnemonic acronym that stands for acknowledge, introduce, duration, explanation, and thank you. University of Minnesota-College of Pharmacy students are taught how to use the AIDET framework in classroom and laboratory settings prior to their interactions with patients at area health fairs. INTERVENTION: Health fair attendees were asked to complete a survey to determine their satisfaction level with student pharmacist-delivered pharmacy services. EVALUATION: 87 patients were surveyed, with a response rate of 22.5% and a completion rate of 91.6%. The average age of the patient population for the study cohort was 52 years, with greater than 50% being 65 years or older. Patient ages ranged from 24 to 89 years. RESULTS: When AIDET techniques were employed in a health fair setting, patients reported high levels of satisfaction with pharmacy services and said they felt "happy, comfortable, and trusting." CONCLUSION: The AIDET framework provides a consistent process for patient-centered care delivery because it places emphasis on patient needs and expectations. Use of the technique is capable of enhancing student and pharmacist engagement with patients. PMID- 26501851 TI - Urinary Biomarkers for Diagnosis of Bladder Cancer: A Systematic Review and Meta analysis. AB - BACKGROUND: Urinary biomarkers may be a useful alternative or adjunct to cystoscopy for diagnosis of bladder cancer. PURPOSE: To systematically review the evidence on the accuracy of urinary biomarkers for diagnosis of bladder cancer in adults who have signs or symptoms of the disease or are undergoing surveillance for recurrent disease. DATA SOURCES: Ovid MEDLINE (January 1990 through June 2015), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists. STUDY SELECTION: 57 studies that evaluated the diagnostic accuracy of quantitative or qualitative nuclear matrix protein 22 (NMP22), qualitative or quantitative bladder tumor antigen (BTA), fluorescence in situ hybridization (FISH), fluorescent immunohistochemistry (ImmunoCyt [Scimedx]), and Cxbladder (Pacific Edge Diagnostics USA) using cystoscopy and histopathology as the reference standard met inclusion criteria. Case-control studies were excluded. DATA EXTRACTION: Dual extraction and quality assessment of individual studies. Overall strength of evidence (SOE) was also assessed. DATA SYNTHESIS: Across biomarkers, sensitivities ranged from 0.57 to 0.82 and specificities ranged from 0.74 to 0.88. Positive likelihood ratios ranged from 2.52 to 5.53, and negative likelihood ratios ranged from 0.21 to 0.48 (moderate SOE for quantitative NMP22, qualitative BTA, FISH, and ImmunoCyt; low SOE for others). For some biomarkers, sensitivity was higher for initial diagnosis of bladder cancer than for diagnosis of recurrence. Sensitivity increased with higher tumor stage or grade. Studies that directly compared the accuracy of quantitative NMP22 and qualitative BTA found no differences in diagnostic accuracy (moderate SOE); head-to-head studies of other biomarkers were limited. Urinary biomarkers plus cytologic evaluation were more sensitive than biomarkers alone but missed about 10% of bladder cancer cases. LIMITATION: Restricted to English-language studies; no search for studies published only as abstracts; statistical heterogeneity present in most analyses; few studies for qualitative NMP22, quantitative BTA, and Cxbladder; and methodological shortcomings in almost all studies. CONCLUSION: Urinary biomarkers miss a substantial proportion of patients with bladder cancer and are subject to false positive results in others. Accuracy is poor for low-stage and low-grade tumors. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO registration number: CRD42014013284). PMID- 26501852 TI - Efficacy and Safety of Corticosteroids for Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Corticosteroids are an option in the treatment of community-acquired pneumonia (CAP). However, the benefits and adverse effects of corticosteroids, especially in severe CAP, have not been well assessed. METHODS: PubMed, Embase, and Cochrane library databases from inception to May 2015 were searched. Randomized controlled trials (RCTs) and cohort studies that evaluated use of corticosteroids in adult patients with CAP were included. The quality of outcomes was evaluated using Grading of Recommendations Assessment, Development and Evaluation methodology. The Mantel-Haenszel method with random-effects modeling was used to calculate pooled relative risks (RRs) and 95% CIs. RESULTS: Nine eligible RCTs (1,667 patients) and six cohort studies (4,095 patients) were identified. The mean corticosteroid dose and treatment duration were 30 mg/day methylprednisolone for 7 days. Corticosteroids did not have a statistically significant effect on mortality (RR, 0.72; 95% CI, 0.43-1.21; evidence rank, low) in patients with CAP and patients with severe CAP (RCTs: RR, 0.72; 95% CI, 0.43 1.21; evidence rank, low; cohort studies: RR, 1.00; 95% CI, 0.86-1.17 ). Corticosteroids treatment was associated with a decreased risk of ARDS (RR, 0.21; 95% CI, 0.08-0.59) and may reduce lengths of hospital and ICU stay, duration of IV antibiotic treatment, and time to clinical stability. Corticosteroids were not associated with increased rates of adverse events. CONCLUSIONS: Short-term treatment with corticosteroids is safe and may reduce the risk of ARDS, shortening the length of the disease in patients with CAP. PMID- 26501855 TI - TIFA, an inflammatory signaling adaptor, is tumor suppressive for liver cancer. AB - TIFA (TNF receptor associated factor (TRAF)-interacting protein with a Forkhead associated (FHA) domain), also called T2BP, was first identified using a yeast two-hybrid screening. TIFA contains a FHA domain, which directly binds phosphothreonine and phosphoserine, and a consensus TRAF6-binding motif. TIFA mediated oligomerization and poly-ubiquitinylation of TRAF6 mediates signaling downstream of the Tumor necrosis factor alpha receptor 1 (TNFaR-I) and interleukin-1/Toll-like receptor 4 (TLR4) pathways. Examining TIFA expression in hepatocellular carcinoma (HCC) tissues microarrays, we noted marked decreases TIFA reactivity in tumor versus control samples. In agreement, we found that HCC cell lines show reduced TIFA expression levels versus normal liver controls. Reconstituting TIFA expression in HCC cell lines promoted two independent apoptosis signaling pathways: the induction of p53 and cell cycle arrest, and the activation of caspase-8 and caspase-3. In contrast, the expression of a non oligomerizing mutant of TIFA impacted cells minimally, and suppression of TIFA expression protected cells from apoptosis. Mice bearing TIFA overexpression hepatocellular xenografts develop smaller tumors versus TIFA mutant tumors; terminal deoxynucleotidyl transferase dUTP nick end labeling staining demonstrates increased cell apoptosis, and decreased proliferation, reflecting cell cycle arrest. Interestingly, p53 has a greater role in decreased proliferation than cell death, as it appeared dispensable for TIFA-induced cell killing. The findings demonstrate a novel suppressive role of TIFA in HCC progression via promotion of cell death independent of p53. PMID- 26501863 TI - Systemic Inflammatory Disease and Its Association With Type II Endoleak and Late Interventions After Endovascular Aneurysm Repair. AB - IMPORTANCE: Abdominal aortic aneurysms are associated with chronic inflammation within the aortic wall, and previous studies have suggested that chronic inflammation may be a consequence of a dysregulated and persistent autoimmune response. Persistent aortic remodeling after aneurysm repair could place the patient at risk for endoleak or sac rupture. OBJECTIVE: To determine whether patients with systemic inflammatory disease and large aneurysms have persistent aortic remodeling after endovascular aneurysm repair (EVAR). DESIGN, SETTING, AND PARTICIPANTS: The records of all patients who underwent EVAR between July 2002 and June 2011 at the Veterans Affairs Connecticut Healthcare System were included in this retrospective review. Patients were considered to have a systemic inflammatory disease when confirmed by a referring specialist. Post-EVAR surveillance was performed by yearly imaging. INTERVENTION: Endovascular aneurysm repair. MAIN OUTCOMES AND MEASURES: Significant endoleak, defined as endoleak and sac diameter increase of 0.5 cm or greater. RESULTS: A total of 51 of 79 patients (65%) had a systemic inflammatory disease. These patients had similar comorbid conditions compared with patients without inflammation but significantly greater numbers of major postoperative complications after EVAR (23.5% vs 3.6%; P = .02) and overall postoperative complications after EVAR (27.5% vs 7.1%; P = .03). Patients with a history of systemic inflammatory disease developed more endoleaks (45.1% vs 17.9%; P = .02) and late sac expansion (51.0% vs 21.4%; P = .01) and required more interventions (21.6% vs 3.6%; P = .03) during long-term follow-up. Systemic inflammatory disease was significantly associated with significant endoleak (odds ratio, 5.18; 95% CI, 1.56-17.16; P = .007). CONCLUSIONS AND RELEVANCE: Patients with systemic inflammatory disease are at high risk for postoperative complications, type II endoleak, sac expansion, and additional interventions after EVAR. Additional strategies for improving the efficacy of EVAR in these patients may be warranted. PMID- 26501862 TI - Effect of Telephone vs Video Interpretation on Parent Comprehension, Communication, and Utilization in the Pediatric Emergency Department: A Randomized Clinical Trial. AB - IMPORTANCE: Consistent professional interpretation improves communication with patients who have limited English proficiency. Remote modalities (telephone and video) have the potential for wide dissemination. OBJECTIVE: To test the effect of telephone vs. video interpretation on communication during pediatric emergency care. DESIGN, SETTING, AND PARTICIPANTS: Randomized trial of telephone vs. video interpretation at a free-standing, university-affiliated pediatric emergency department (ED). A convenience sample of 290 Spanish-speaking parents of pediatric ED patients with limited English proficiency were approached from February 24 through August 16, 2014, of whom 249 (85.9%) enrolled; of these, 208 (83.5%) completed the follow-up survey (91 parents in the telephone arm and 117 in the video arm). Groups did not differ significantly by consent or survey completion rate, ED factors (eg, ED crowding), child factors (eg, triage level, medical complexity), or parent factors (eg, birth country, income). Investigators were blinded to the interpretation modality during outcome ascertainment. Intention-to-treat data were analyzed August 25 to October 20, 2014. INTERVENTIONS: Telephone or video interpretation for the ED visit, randomized by day. MAIN OUTCOMES AND MEASURES: Parents were surveyed 1 to 7 days after the ED visit to assess communication and interpretation quality, frequency of lapses in interpreter use, and ability to name the child's diagnosis. Two blinded reviewers compared parent-reported and medical record-abstracted diagnoses and classified parent-reported diagnoses as correct, incorrect, or vague. RESULTS: Among 208 parents who completed the survey, those in the video arm were more likely to name the child's diagnosis correctly than those in the telephone arm (85 of 114 [74.6%] vs. 52 of 87 [59.8%]; P = .03) and less likely to report frequent lapses in interpreter use (2 of 117 [1.7%] vs. 7 of 91 [7.7%]; P = .04). No differences were found between the video and telephone arms in parent-reported quality of communication (101 of 116 [87.1%] vs. 74 of 89 [83.1%]; P = .43) or interpretation (58 of 116 [50.0%] vs. 42 of 89 [47.2%]; P = .69). Video interpretation was more costly (per-patient mean [SD] cost, $61 [$36] vs. $31 [$20]; P < .001). Parent-reported adherence to the assigned modality was higher for the video arm (106 of 114 [93.0%] vs .68 of 86 [79.1%]; P = .004). CONCLUSIONS AND RELEVANCE: Families with limited English proficiency who received video interpretation were more likely to correctly name the child's diagnosis and had fewer lapses in interpreter use. Use of video interpretation shows promise for improving communication and patient care in this population. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01986179. PMID- 26501864 TI - Air-Stable Black Phosphorus Devices for Ion Sensing. AB - Black phosphorus (BP) is one of the most attractive graphene analogues, and its properties make it a promising nanomaterial for chemical sensing. However, mono- and few-layer BP flakes are reported to chemically degrade rapidly upon exposure to ambient conditions. Therefore, little is known about the performance and sensing mechanism of intrinsic BP, and chemical sensing of intrinsic BP with acceptable air stability remains only theoretically explored. Here, we experimentally demonstrated the first air-stable high-performance BP sensor using ionophore coating. Ionophore-encapsulated BP demonstrated significantly improved air stability. Its performance and sensing mechanism for trace ion detection were systematically investigated. The BP sensors were able to realize multiplex ion detection with superb selectivity, and sensitive to Pb(2+) down to 1 ppb. Additionally, the time constant for ion adsorption extracted was only 5 s. The detection limit and response rate of BP were both superior to those of graphene based sensors. Moreover, heavy metal ions can be effectively detected over a wide range of concentration with BP conductance change following the Langmuir isotherm for molecules adsorption on surface. The simplicity of this ionophore-encapsulate approach provides a route for achieving air-stable intrinsic black phosphorus sensors that may stimulate further fundamental research and potential applications. PMID- 26501865 TI - Antibiotics. AB - The Endophthalmitis Vitrectomy Study (EVS) provided ophthalmologists with evidence-based management strategies to deal with endophthalmitis for the first time. However, since the completion of the EVS, numerous unresolved issues remain. The use of oral antibiotics has important implications for the ophthalmologist, particularly in the prophylaxis and/or management of postoperative, posttraumatic, or bleb-associated bacterial endophthalmitis. One can reasonably conclude that significant intraocular penetration of an antibiotic after oral administration may be a property unique to the newer-generation fluoroquinolones. Prophylactic use of mupirocin nasal ointment resulted in significant reduction of conjunctival flora with or without preoperative topical 5% povidone-iodine preparation. Ocular fungal infections have traditionally been very difficult to treat due to limited therapeutic options both systemically and intravitreally. Because of its broad spectrum of coverage, low MIC90 levels for the organisms of concern, good tolerability, and excellent bioavailability, voriconazole through various routes of administration may be useful to the ophthalmologist in the primary treatment of or as an adjunct to the current management of ocular fungal infections. PMID- 26501866 TI - Transcription factors related to chondrogenesis in pleomorphic adenoma of the salivary gland: a mechanism of mesenchymal tissue formation. AB - In salivary gland pleomorphic adenoma, expression of extracellular matrix (ECM) substances indicates that tumor epithelial cells are becoming chondrogenic and will produce cartilage-like mesenchymal tissues. Sox9, the master transcription factor of chondrogenesis, is expressed in mouse salivary gland cells. To clarify the mechanism behind chondrogenesis in tumor epithelial cells, we examined the expression of transcription factors related to chondrogenesis in tumors and salivary glands. Reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR, and immunostaining were performed on pleomorphic adenoma tissues, salivary gland tissues, and human submandibular gland (HSG) cells. The mRNAs of essential transcription factors for chondrogenesis-Sox9, Sox6, and Sox5-were detected in both tumor and salivary gland tissues. The mRNAs of aggrecan and type II collagen-cartilage-specific ECM substances-were detected only in tumors. Sox9 and Sox6 proteins were colocalized in many epithelial cells in tumors and salivary glands. Tumor epithelial cells also possessed aggrecan protein and occasionally type II collagen protein. Moreover, mRNAs for transcription repressors of chondrogenesis deltaEF1 and AP-2alpha were detected in both tumors and salivary glands, whereas Twist1 mRNA was detected only in salivary glands and was at significantly low-to-undetectable levels in tumors. Twist1 protein was localized in the Sox9-expressing salivary gland cells. HSG cells expressed Sox9, Sox6, and Twist1, but not aggrecan or type II collagen, and thus were similar to salivary gland cells. Twist1 depletion by Twist1 siRNA led to the upregulation of aggrecan and type II collagen mRNA expression in HSG cells. In contrast, forced expression of Twist1, using Twist1 cDNA, resulted in the downregulation of both these genes. Taken together, these results indicate that salivary gland cells have a potential for chondrogenesis, and Twist1 depletion concomitant with neoplastic transformation, which would permit tumor epithelial cells to produce cartilage-like mesenchymal tissues in salivary gland pleomorphic adenoma. PMID- 26501867 TI - IL-12 immunotherapy of Braf(V600E)-induced papillary thyroid cancer in a mouse model. AB - Papillary thyroid carcinoma (PTC) accounts for >80% thyroid malignancies, and BRAF(V600E) mutation is frequently found in >40% PTC. Interleukin-12 (IL-12) is a proinflammatory heterodimeric cytokine with strong antitumor activity. It is not known whether IL-12 immunotherapy is effective against Braf(V600E)-induced PTC. In the present study, we investigated the effectiveness of IL-12 immunotherapy against Braf(V600E)-induced PTC in LSL-Braf(V600E)/TPO-Cre mice. LSL Braf(V600E)/TPO-Cre mice were created for thyroid-specific expression of Braf(V600E) under the endogenous Braf promoter, and spontaneous PTC developed at about 5 weeks of age. The mice were subjected to two treatment regimens: (1) weekly intramuscular injection of 50 MUg plasmid DNA expressing a single-chain IL 12 fusion protein (scIL-12/CMVpDNA), (2) daily intraperitoneal injection of mouse recombinant IL-12 protein (mrIL-12, 100 ng per day). The role of T cells, natural killer (NK) cells, and transforming growth factor-beta (TGF-beta) in IL-12 mediated antitumor effects was determined by a (51)Cr-release cytotoxicity assay. Tumor size and weight were significantly reduced by either weekly intramuscular injection of scIL-12/CMVpDNA or daily intraperitoneal injection of mrIL-12, and tumor became more localized. Survival was significantly increased when treatment started at 1 week of age as compared with that at the 6 weeks of age. Both NK and CD8(+) T cells were involved in the cytotoxicity against tumor cells and their antitumor activity was significantly reduced in tumor-bearing mice. TGF-beta also inhibited the antitumor activity of NK and CD8(+) T cells. The immune suppression was completely reversed by IL-12 treatment and partially recovered by anti-TGF beta antibody. We conclude that both IL-12 gene therapy and recombinant protein therapy are effective against PTC. Given that the immune response is significantly suppressed in tumor-bearing mice and can be restored by IL-12, the current study raises a possibility of the application of IL-12 as an adjuvant therapy for thyroid cancer. PMID- 26501869 TI - Synthesis of the Carbocyclic Core of Massadine. AB - The carbocyclic core of massadine has been synthesized relying on a stereoselective formal [3 + 2] cycloaddition of lithiumtrimethylsilyldiazomethane with alpha,beta-unsaturated esters to form a Delta(2)-pyrazoline moiety followed by facile N-N bond cleavage. A unique feature of the current approach is the direct installation of the tertiary alpha-amino center and a beta-cyano group in a cis arrangement on the resulting cyclopentane framework via a previously developed formal aminocyanation protocol. PMID- 26501868 TI - Selective IL-1alpha exposure to the fetal gut, lung, and chorioamnion/skin causes intestinal inflammatory and developmental changes in fetal sheep. AB - Chorioamnionitis, caused by intra-amniotic exposure to bacteria and their toxic components, is associated with fetal gut inflammation and mucosal injury. In a translational ovine model, we have shown that these adverse intestinal outcomes to chorioamnionitis were the combined result of local gut and pulmonary-driven systemic immune responses. Chorioamnionitis-induced gut inflammation and injury was largely prevented by inhibiting interleukin-1 (IL-1) signaling. Therefore, we investigated whether local (gut-derived) IL-1alpha signaling or systemic IL 1alpha-driven immune responses (lung or chorioamnion/skin-derived) were sufficient for intestinal inflammation and mucosal injury in the course of chorioamnionitis. Fetal surgery was performed in sheep to isolate the lung, gastrointestinal tract, and chorioamnion/skin, and IL-1alpha or saline was given into the trachea, stomach, or amniotic cavity 1 or 6 days before preterm delivery. Selective IL-1alpha exposure to the lung, gut, or chorioamnion/skin increased the CD3+ cell numbers in the fetal gut. Direct IL-1alpha exposure to the gut impaired intestinal zonula occludens protein-1 expression, induced villus atrophy, changed the expression pattern of intestinal fatty acid-binding protein along the villus, and increased the CD68, IL-1, and TNF-alpha mRNA levels in the fetal ileum. With lung or chorioamnion/skin exposure to IL-1alpha, intestinal inflammation was associated with increased numbers of blood leukocytes without induction of intestinal injury or immaturity. We concluded that local IL-1alpha signaling was required for intestinal inflammation, disturbed gut maturation, and mucosal injury in the context of chorioamnionitis. PMID- 26501870 TI - Dose-Dependent Early Life Stage Toxicities in Xenopus laevis Exposed In Ovo to Selenium. AB - Selenium (Se) is a developmental toxicant in oviparous vertebrates. The adverse reproductive effects of Se toxicity have been predominantly investigated in fishes and birds with only a few studies focusing on amphibians. The objective of this study was to determine tissue-based toxicity thresholds for early life stage Se toxicities in Xenopus laevis as a consequence of in ovo exposure through maternal transfer of dietary Se. Following a 68-day dietary exposure to food augmented with l-selenomethionine (SeMet) at measured concentrations of 0.7 (control), 10.9, 30.4, or 94.2 MUg Se/g dry mass (d.m.), adult female X. laevis were bred with untreated males, and resulting embryos were incubated until 5 days postfertilization (dpf). The measured Se concentrations in eggs were 1.6, 10.8, 28.1, and 81.7 MUg Se/g d.m., respectively. No biologically significant effects were observed on fertilization success, hatchability, or mortality in offspring. Frequency and severity of morphological abnormalities were significantly greater in 5 dpf tadpoles from the highest exposure group when compared to the control, with eye lens abnormalities being the most prominent of all abnormalities. The estimated EC10 value for frequency of total early life stage abnormalities was 44.9 MUg Se/g egg d.m., which suggests that this amphibian species is less sensitive to in ovo Se exposure than most of the fish species studied to date. PMID- 26501871 TI - Activation of ETA Receptor by Endothelin-1 Induces Hepatocellular Carcinoma Cell Migration and Invasion via ERK1/2 and AKT Signaling Pathways. AB - Endothelin-1 (ET-1), a member of endothelins family, binds to ETA receptor (ETAR) and ETB receptor to exert its role in multiple cellular processes. Although ET-1 and its receptors has been reported to be overexpressed in many cancers, and overexpression of ET-1 is able to trigger hepatocarcinogenesis in zebrafish, the functions of ET-1 and its receptors in hepatocellular carcinoma (HCC) cell migration and invasion remain unclear. In the present study, we found that ETAR was greatly expressed in HCC cells and HCC tissues. ETAR expression as well as ET 1 expression was associated with vascular invasion and tumor stage in HCC. Activation of ETAR by ET-1 dose-dependently promoted cell migration and invasion of HCC cells, while silencing of ETAR by siRNA or blocking of ETAR by specific inhibitor resulted in significant reduction in ET-1-mediated migration and invasion. Furthermore, ET-1 induced activation of ERK1/2 and AKT and increased MMP-3 production via ETAR. In addition, using inhibitors of ERK1/2 and AKT, we found that ERK1/2 and AKT pathways were both involved in ETAR-mediated migration, invasion, and MMP-3 production. Taken together, our findings suggest that activation of ETAR by ET-1 promotes HCC cell migration and invasion via activating ERK1/2 and AKT signaling pathways and upregulating MMP-3 expression. Thus, ETAR may play an important role in the progress of HCC. PMID- 26501872 TI - Controlling Nanowire Growth by Light. AB - Individual Au catalyst nanoparticles are used for selective laser-induced chemical vapor deposition of single germanium nanowires. Dark-field scattering reveals in real time the optical signatures of all key constituent growth processes. Growth is initially triggered by plasmonic absorption in the Au catalyst, while once nucleated the growing Ge nanowire supports magnetic and electric resonances that then dominate the laser interactions. This spectroscopic understanding allows real-time laser feedback that is crucial toward realizing the full potential of controlling nanomaterial growth by light. PMID- 26501873 TI - Temporal Considerations for Stimulating Spiral Ganglion Neurons with Cochlear Implants. AB - A wealth of knowledge about different types of neural responses to electrical stimulation has been developed over the past 100 years. However, the exact forms of neural response properties can vary across different types of neurons. In this review, we survey four stimulus-response phenomena that in recent years are thought to be relevant for cochlear implant stimulation of spiral ganglion neurons (SGNs): refractoriness, facilitation, accommodation, and spike rate adaptation. Of these four, refractoriness is the most widely known, and many perceptual and physiological studies interpret their data in terms of refractoriness without incorporating facilitation, accommodation, or spike rate adaptation. In reality, several or all of these behaviors are likely involved in shaping neural responses, particularly at higher stimulation rates. A better understanding of the individual and combined effects of these phenomena could assist in developing improved cochlear implant stimulation strategies. We review the published physiological data for electrical stimulation of SGNs that explores these four different phenomena, as well as some of the recent studies that might reveal the biophysical bases of these stimulus-response phenomena. PMID- 26501874 TI - Micro Regional Heterogeneity of 64Cu-ATSM and 18F-FDG Uptake in Canine Soft Tissue Sarcomas: Relation to Cell Proliferation, Hypoxia and Glycolysis. AB - OBJECTIVES: Tumour microenvironment heterogeneity is believed to play a key role in cancer progression and therapy resistance. However, little is known about micro regional distribution of hypoxia, glycolysis and proliferation in spontaneous solid tumours. The overall aim was simultaneous investigation of micro regional heterogeneity of 64Cu-ATSM (hypoxia) and 18F-FDG (glycolysis) uptake and correlation to endogenous markers of hypoxia, glycolysis, proliferation and angiogenesis to better therapeutically target aggressive tumour regions and prognosticate outcome. METHODS: Exploiting the different half-lives of 64Cu-ATSM (13 h) and 18F-FDG (2 h) enabled simultaneous investigation of micro regional distribution of hypoxia and glycolysis in 145 tumour pieces from four spontaneous canine soft tissue sarcomas. Pairwise measurements of radioactivity and gene expression of endogenous markers of hypoxia (HIF-1alpha, CAIX), glycolysis (HK2, GLUT1 and GLUT3), proliferation (Ki-67) and angiogenesis (VEGFA and TF) were performed. Dual tracer autoradiography was compared with Ki-67 immunohistochemistry. RESULTS: Micro regional heterogeneity in hypoxia and glycolysis within and between tumour sections of each tumour piece was observed. The spatial distribution of 64Cu-ATSM and 18F-FDG was rather similar within each tumour section as reflected in moderate positive significant correlations between the two tracers (rho = 0.3920-0.7807; p = 0.0180 -<0.0001) based on pixel-to pixel comparisons of autoradiographies and gamma counting of tumour pieces. 64Cu ATSM and 18F-FDG correlated positively with gene expression of GLUT1 and GLUT3, but negatively with HIF-1alpha and CAIX. Significant positive correlations were seen between Ki-67 gene expression and 64Cu-ATSM (rho = 0.5578, p = 0.0004) and 18F-FDG (rho = 0.4629-0.7001, p = 0.0001-0.0151). Ki-67 gene expression more consistently correlated with 18F-FDG than with 64Cu-ATSM. CONCLUSIONS: Micro regional heterogeneity of hypoxia and glycolysis was documented in spontaneous canine soft tissue sarcomas. 64Cu-ATSM and 18F-FDG uptakes and distributions showed significant moderate correlations at the micro regional level indicating overlapping, yet different information from the tracers.18F-FDG better reflected cell proliferation as measured by Ki-67 gene expression than 64Cu-ATSM. PMID- 26501875 TI - The Humanistic and Economic Burden of Restless Legs Syndrome. AB - RLSOBJECTIVES: To evaluate the humanistic and economic burden of a restless legs syndrome (RLS) diagnosis with regard to health-related quality of life, work productivity loss, healthcare resource use, and direct and indirect costs. STUDY DESIGN: Self-reported data came from the 2012 National Health and Wellness Survey (NHWS), a large, annual, nationally representative cross-sectional general health survey of US adults. METHODS: RLS patients (n = 2,392) were matched on demographic and health characteristics to Non-RLS respondents via propensity score matching differences between groups were tested with Bivariate and multivariable analyses. RESULTS: RLS patients had significantly lower health related quality of life scores: Mental Component Summary (44.60 vs. 48.92, p<.001), Physical Component Summary (40.57 vs. 46.78, p<.001), Health Utilities (.63 vs. .71, p<.001) and higher levels of work productivity loss in the past seven days including absenteeism (8.1% vs. 3.9%, p<.001), presenteeism (26.5% vs. 15.8%, p<.001), and overall productivity loss (30.1% vs. 18.1%, p<.001) as well as general activity impairment (46.1% vs. 29.7%, p<.001) [corrected]. RLS patients had significantly higher healthcare resource use in the past 6 months than non-RLS patients: healthcare provider visits (7.46 vs. 4.42%, p<.001), ER visits (0.45 vs. 0.24, p<.001), and hospitalizations (0.24 vs. 0.15, p<.001). RLS patients also had higher estimated direct and indirect costs than non-RLS patients. Finally, it was found that across outcomes increasing severity is associated with increased economic and humanistic burden for RLS patients. CONCLUSIONS: RLS patients suffer a greater humanistic and economic burden than those without RLS. Moreover as severity increases so does the burden of RLS. PMID- 26501876 TI - Controlled Au-Polymer Nanostructures for Multiphoton Imaging, Prodrug Delivery, and Chemo-Photothermal Therapy Platforms. AB - We have successfully introduced a proton-induced controlled reaction of HAuCl4 and poly(styrene-alt-maleic acid) (PSMA) sodium salt to prepare triangular and multicore Au@polymer nanoparticles (NPs). The interparticle interactions in the core gave rise to an absorption band at the near-infrared wavelength. The near infrared optical properties of the resulting Au-polymer nanostructures are highly stable in a physiological environment, which offered strong photo-to-thermal conversion by a moderate continuous-wave 808 nm laser and exhibited multiphoton fluorescence for imaging using a 1230 nm light excitation (femtosecond laser). Exposure of the carboxylate groups at the polymer shell made the surface structure of the Au multicore @polymer NPs directly conjugate Pt(II)-/Pt(IV) based drugs, which possessed the elimination of the immediate toxicity over the short time and resulted in an anticancer effect after 3 days. A synergistic effect of the chemo-photothermal therapy showed a moderate hyperthermia assistance (<1 W/cm(2)) and better anticancer performance over time compared with the individual treatments. We demonstrated that such PSMA-based methodology not only enables a broad range of chemical material synthesis in the kinetic control to form Au nano-octahedrons and nanotriangles using Br(-)/I(-) ions additives but also could be extended to form Au/Fe3O4@polymer nanocomposites via proton assisted PSMA self-assembly. PMID- 26501878 TI - The Impact of Smoking on Inflammatory Bowel Disease. PMID- 26501877 TI - Quality of Life in Screen-detected Celiac Disease Patients in the United States. AB - BACKGROUND AND AIMS: Celiac disease (CD) is increasingly diagnosed through screening of at-risk groups (relatives of individuals and associated autoimmune disorders). The impact of diagnosis and treatment on screen-detected CD patients is poorly studied, particularly in the United States. We therefore compared the quality of life (QOL) between screen-detected and symptom-detected CD patients. METHODS: Patients with a known diagnosis of CD were invited to complete 3 validated survey instruments: the CD Quality of Life (CDQOL), the CD Adherence Test for dietary adherence and the general Psychological General Well-Being index. In addition, demographic details, mode of presentation, and compliance with gluten-free diet (GFD) were assessed. RESULTS: The overall response rate was high at 69%. Of 226 responses received, 211 were eligible for inclusion; the median age was 47, and the median duration of GFD was 4 years. One third of the sample (71, 34%) was screen detected. Of these, 57 (80%) had a relative diagnosed with CD, whereas 14 (20%) had an associated condition. Despite being screen detected, 49 (69%) reported symptoms before diagnosis. GFD adherence was excellent and did not differ between groups. Overall, there were no significant differences between screen-detected and symptom-detected patients with regard to CDQOL, CD Adherence Test, and Psychological General Well-Being scores. CONCLUSIONS: Screen-detected and symptom-detected CD patients do not differ with regard to QOL or disease adherence as measured by validated disease-specific instruments. A high proportion of screen-detected patients reported symptoms before diagnosis, which often improve with GFD. PMID- 26501879 TI - The Clinical Utility of Evaluating the Luminal Upper Gastrointestinal Tract During Linear Endoscopic Ultrasonography. AB - BACKGROUND: The clinical utility of performing esophagogastroduodenoscopy (EGD) before linear endoscopic ultrasonography (L-EUS) to evaluate the luminal upper gastrointestinal (GI) tract is not well established. GOALS: The study was aimed to determine the prevalence of clinically meaningful luminal abnormalities (any luminal finding requiring further evaluation with mucosal biopsy or initiation of treatment) in patients undergoing L-EUS. The study also sought to compare the ability of the gastroscope and the linear echoendoscope in identifying these lesions. STUDY: A prospective, multicenter cohort study enrolled patients undergoing L-EUS for nonluminal indications. All patients underwent EGD followed by L-EUS by 2 different endoscopists. The second endoscopist was blinded to the results of the initial EGD. The identification of clinically meaningful luminal lesions and quality of endoscopic visualization of the upper GI tract were measured. RESULTS: In the cohort of 175 patients, 52 (29.7%) patients had clinically meaningful luminal findings seen in the upper GI tract. There was no significant difference in the number of clinically meaningful lesions identified on EGD and L-EUS (25.1% vs. 22.9%, P=0.39). No significant difference was found in the miss rate of clinically meaningful lesions between the 2 modalities (EGD: 4.5% vs. EUS: 6.9%, P=0.39). CONCLUSIONS: A substantial minority of patients undergoing L-EUS for nonluminal indications will have clinically meaningful luminal findings. The endoscopic evaluation of the luminal upper GI tract can be adequately achieved using the linear echoendoscope. PMID- 26501880 TI - Importance of Patients' Knowledge of Their Prescribed Medication in Improving Treatment Adherence in Inflammatory Bowel Disease. AB - GOALS: To investigate the association between treatment nonadherence and patients' knowledge of the prescribed medication among individuals with inflammatory bowel disease (IBD), and evaluate the impact of nonadherence on relapse. BACKGROUND: The patient's knowledge of the prescribed medication has been identified as an important predictor of treatment adherence in chronic diseases. However, this association has not been examined in IBD. STUDY: In this prospective study, at baseline, 138 patients with IBD completed a self-reported survey on demographic data, knowledge of the prescribed medication, and candidate factors related to the degree of treatment adherence. To investigate the impact of nonadherence among patients in remission, relapse was analyzed for 18 months after enrollment. RESULTS: Nonadherence was observed in 50 (36.2%) of the 138 subjects. In multivariate analysis, nonadherence was significantly associated with younger age (less than 30 y) at participation [odds ratio (OR), 5.88; 95% confidence interval (CI), 1.51-22.94; P=0.011], longer intervals between outpatient clinic visits (>=3 mo) (OR, 30.31; 95% CI, 3.06-300.17; P=0.004), and limited knowledge of the prescribed medication (OR, 5.61; 95% CI, 1.60-19.67; P=0.038). Nonadherent patients had a significantly greater risk of relapse of IBD than adherent patients (relative risk, 2.9; 95% CI, 2.25-3.79; P=0.045). CONCLUSION: Younger age, longer intervals between outpatient clinic visits, and limited knowledge of the prescribed medication tended to be associated with nonadherence to treatment, which consequently also affects the risk of relapse. PMID- 26501881 TI - Obscure Gastrointestinal Bleeding in the Setting of Portal Hypertension. PMID- 26501882 TI - Does Better Specimen Orientation and a Simplified Grading System Promote More Reliable Histologic Interpretation of Serrated Colon Polyps in the Community Practice Setting? Results of a Nationwide Study. AB - INTRODUCTION: Colonoscopic surveillance guidelines for serrated polyps (SPs) are predicated upon the histologic characteristics of the index polyp. However, discrimination between SP subtypes [hyperplastic polyps vs. sessile serrated adenoma/polyps (SSA/P)] is often unreliable. MATERIALS AND METHODS: We studied the impact of (1) a novel tissue orientation method, performed in the endoscopy laboratory, whereby polyps are flattened in a small paper envelope immediately after resection (modified protocol); and (2) 2012 consensus-modified criteria (CM 2012). These interventions were compared with conventional tissue-handling protocol (CP) and traditional 2008 World Health Organization criteria (WHO). Twenty blinded community pathologists from around the United States scored 100, independent, 0.5 to 2.0 cm, proximal colonic SPs randomly selected from a 2-site tissue section archive. We compared interobserver agreement and diagnostic grading. RESULTS: Interobserver agreement was higher using CM-2012 than WHO criteria (absolute agreement: 13% vs. 4%, P<0.01; 75% agreement: 54% vs. 38%, P<0.01). Interobserver agreement was higher with the modified protocol than with CP (WHO absolute agreement: 6% vs. 2%, P>0.05; WHO 75% agreement: 46% vs. 30%, P>0.05, and CM-2012 absolute agreement: 20% vs. 6%, P=0.07; CM-2012 75% agreement: 66% vs. 42%, P=0.03). Compared with WHO, use of CM-2012 criteria resulted in fewer diagnoses of "indeterminate"; more diagnoses of SSA/P (P<0.01); and "upgraded" the diagnosis from hyperplastic polyps to SSA/P in approximately 7% of cases. These observations were independent of polyp size, patient gender, and study site. CONCLUSIONS: Simple enhancements to postresection SP handling and diagnostic criteria markedly improve interobserver agreement of SP diagnosis among nongastrointestinal community pathologists. This finding, if confirmed, has important implications for SP colonoscopy surveillance guidelines. PMID- 26501883 TI - Aggregation of a Crown Ether Decorated Zinc-Phthalocyanine by Collision-Induced Desolvation of Electrospray Droplets. AB - The aggregation of phthalocyanines is well-known in solution but has never before been studied in the gas phase. We investigated the tetra-[18]crown-6 ether functionalized zinc-phthalocyanine (ZnPcTetCr, M) with electrospray ionization mass spectrometry (ESI-MS) in the absence of coordinating metal cations. Apart from the molecular ion M(+*), singly and multiply charged aggregates Mn(z(+*)) were observed, bound together by electrostatic interactions, without alkali metal cations inside the crown ethers. Collision-induced dissociation (CID) experiments indicate that these clusters consist of stacked neutral M and radical cations M(+*). After the oxidation of individual molecules at the electrospray needle, the aggregation occurs during desolvation of the charged droplets created in the source. Complete evaporation of the solvent and detection of the aggregates was found to require an additional acceleration of the droplets in the transfer region of the instrument, the resulting collisions with neutral gas assisting the desolvation process. PMID- 26501884 TI - Leaf Fluctuating Asymmetry and Herbivory of Tibouchina heteromalla in Restored and Natural Environments. AB - Fluctuating asymmetry (FA) is a parameter to measure developmental stability in plants, which can be altered by disturbances, pollution, and biotic factors such as herbivory. We evaluated the effects of environmental stress and herbivory on the FA levels in individuals of Tibouchina heteromalla (Melastomataceae) that occur in natural and undergoing restoration areas in rupestrian grasslands at Serra do Cipo, Brasil. Individuals were collected and measured in seven restored and five natural areas, totalizing 240 individuals. We found that individuals in restored areas had greater leaf area, higher levels of insect herbivory and FA compared to individuals that occurred in natural areas. In both environments, the proportion of individuals with leaf damage caused by herbivory was higher than the proportion of undamaged individuals. In addition, FA was positively correlated with herbivory and total leaf area in both restored and natural areas. These results suggest that more favorable conditions in the restored areas enhanced leaf growth, resulting in higher FA. PMID- 26501886 TI - Spreading the Benefits of Infection Prevention in the Neonatal Intensive Care Unit. PMID- 26501885 TI - The Knowledge of the Role of Papillomavirus-Related Head and Neck Pathologies among General Practitioners, Otolaryngologists and Trainees. A Survey-Based Study. AB - OBJECTIVES: The aim of the survey was to introduce knowledge of HPV's role in head and neck pathologies to general physicians (GPs), otorhinolaryngologists (ENTs) and newly graduated doctors, as well as to promote HPV-related diseases prevention. STUDY DESIGN: Cross-sectional study. METHODS: Self-designed questionnaire was sent to 2100 doctors. A total of 404 doctors, including 144 ENTs, 192 GPs and 68 trainees, responded. RESULTS: The majority of ENTs (86.8%) had contact with recurrent respiratory papillomatosis (RRP) and oropharyngeal cancers (OPCs) patients; in contrast, the majority of GPs (55.7%) did not (p = 0.00). The knowledge of HPV aetiology of cervical cancer versus OPCs and RRP was statistically higher. 7% of ENTs, 20% of GPs and 10% of trainees had not heard about HPV in oropharyngeal diseases. Women had greater knowledge than men. Both in the group of GPs and ENTs, 100% of respondents had heard about the impact of vaccination on the reduction of cervical cancer incidence. Only 39.11% of respondents had heard about the possibility of using vaccination against HPV in RRP-ENT doctors significantly more often than GPs and trainees (p = 0.00). Only 28.96% of physicians had heard about the potential value of HPV vaccination in preventing OPCs, including 44.44% of ENT doctors, 23.44% of GPs and 11.76% of trainees (p = 0.00). The doctors from district hospitals showed lower level of knowledge compared with clinicians (p = 0.04). CONCLUSIONS: The different levels of knowledge and awareness of HPV issues highlight the need for targeted awareness strategies in Poland with implementation of HPV testing and vaccination. The information should be accessible especially to those with lower education levels: ENTs from small, provincial wards, GPs from cities of < 200,000 inhabitants and older physicians. The incorporation of HPV issues into the studies curriculum would be fruitful in terms of improving the knowledge of trainees. PMID- 26501887 TI - Real-time reaction monitoring by ultrafast 2D NMR on a benchtop spectrometer. AB - Reaction monitoring is widely used to follow chemical processes in a broad range of application fields. Recently, the development of robust benchtop NMR spectrometers has brought NMR under the fume hood, making it possible to monitor chemical reactions in a safe and accessible environment. However, these low-field NMR approaches suffer from limited resolution leading to strong peak overlaps, which can limit their application range. Here, we propose an approach capable of recording ultrafast 2D NMR spectra on a compact spectrometer and of following in real time reactions in the synthetic chemistry laboratory. This approach--whose potential is shown here on a Heck-Matsuda reaction--is highly versatile; the duration of the measurement can be optimized to follow reactions whose time scale ranges from between a few tens of seconds to a few hours. It makes it possible to monitor complex reactions in non-deuterated solvents, and to confirm in real time the molecular structure of the compounds involved in the reaction while giving access to relevant kinetic parameters. PMID- 26501888 TI - A Newly Identified Natural Splice Variant ASN Enhances Hepatitis B Virus Amplification. AB - Chronic hepatitis B virus (HBV) infection causes approximately one-third of all the cases of liver cirrhosis and more than three-quarters of hepatocellular carcinoma (HCC) worldwide. There are eight different genotypes (A-H) of HBV, among which B and C are the major types of HBV in China. There is a positive correlation between viral load and level of viral splicing variants and the high risk of HCC. The aim of this study was to investigate the splicing variants of HBV circulating in HCC patients. Twenty-four carcinoma and adjacent liver tissues collected from HCC patients were studied. Using reverse transcription-polymerase chain reaction (RT-PCR) and sequencing, we identified a new type of natural splice variant with nucleotides 2448-489 and 910-2120 deleted, and we named it ASN. We also found that a higher viral load and splicing variant level existed in liver carcinoma tissues compared to paracarcinoma tissues. In the investigation of our splicing variant, we found its enhancing effect on HBV replication in vitro. Although splicing variants are not essential for the replication of HBV, they may have an important influence. PMID- 26501890 TI - Novel synthesis of dispersed molybdenum and nickel phosphides from thermal carbonization of metal- and phosphorus-containing resins. AB - Dispersed pure phases of MoP and Ni2P nanoparticles supported by carbon were synthesized by carbonization of metal- and phosphorus-containing resins under an inert atmosphere. The solid products and the evolution of gases during the carbonization process were investigated by various techniques, including X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), inductively coupled plasma-atomic emission spectroscopy (ICP-AES), N2 adsorption-desorption analysis, and mass spectrometry (MS). The resins underwent two carbonization stages: the low-temperature carbonization stage (<650 degrees C) and the high-temperature carbonization stage (>=650 degrees C). There was an initial reduction of Mo and Ni precursors in the low-temperature region. However, the formation of phosphides was observed in the high-temperature carbonization stage, in which Mo(Ni) and POx species were further reacted with the carbonization products (C, H2 and CH4) to yield Mo(Ni) phosphide. Note that compared with the traditional H2-temperature programmed reduction (H2-TPR) method, this novel synthesis route produced a large amount of CO(x) besides H2O, leading to a lower water vapor pressure. In addition, the residual carbon produced from resin can play a role in bonding of nanoparticle aggregation. Therefore, the better dispersions and higher surface areas of the as-prepared phosphide nanoparticles were attributed to the mitigation of hydrothermal sintering and the intimate contact between phosphide nanoparticles and carbon species. PMID- 26501891 TI - Breastfeeding: The Basis for Normal Infant Development and Societal Well-Being. PMID- 26501892 TI - The Sharjah Baby-Friendly Campaign: A Community-Based Model for Breastfeeding Promotion, Protection, and Support. AB - INTRODUCTION: Breastfeeding promotion, protection, and support are one of the most cost-effective public health interventions to advance maternal and child health. The World Health Organization, the United Nations International Children's Emergency Fund, and numerous health organizations have recommended exclusive breastfeeding for the first 6 months of life, which is a key indicator of breastfeeding promotion programs worldwide. Despite the recommendations and various initiatives to promote breastfeeding, most women do not reach the exclusive breastfeeding target in both developed and developing countries. Such has been the case in the United Arab Emirates (UAE). MATERIALS AND METHODS: Therefore, based on the decree for breastfeeding promotion, protection, and support by the ruler of the Emirate of Sharjah, UAE, H.H. Sheikh Doctor Sultan Al Qasimi, a multisectorial, multidirectional breastfeeding campaign--the Sharjah Baby-Friendly Campaign--was launched in March 2012 by H.E. Sheikha Bodour Al Qasimi, under her patronage. It consisted of four initiatives-namely, Baby Friendly Health Facility, Mother-Friendly Workplace, Breastfeeding-Friendly Nursery, and Mother-Baby Friendly Public Place. Once an organization met the criteria for any of these initiatives, it was awarded the designation or accreditation of that initiative. RESULTS: The campaign initiatives worked through capacity building of healthcare workers, provided professional support and facilitation for the accreditation process, developed breastfeeding education content and resources, and organized and conducted breastfeeding promotion seminars in health facilities and community, as well as community outreach through social media and an innovative mobile mother' room. CONCLUSIONS: The positive impact of the campaign on breastfeeding promotion, protection, and support is evident by the increased exclusive breastfeeding rate at 6 months and decreased bottle feeding rates at both 4 and 6 months. PMID- 26501889 TI - Proteoglycans: Potential Agents in Mammographic Density and the Associated Breast Cancer Risk. AB - Although increased mammographic density (MD) has been well established as a marker for increased breast cancer (BC) risk, its pathobiology is far from understood. Altered proteoglycan (PG) composition may underpin the physical properties of MD, and may contribute to the associated increase in BC risk. Numerous studies have investigated PGs, which are a major stromal matrix component, in relation to MD and BC and reported results that are sometimes discordant. Our review summarises these results and highlights discrepancies between PG associations with BC and MD, thus serving as a guide for identifying PGs that warrant further research towards developing chemo-preventive or therapeutic agents targeting preinvasive or invasive breast lesions, respectively. PMID- 26501893 TI - Gatekeeping and its impact on father involvement among Black South Africans in rural KwaZulu-Natal. AB - Involved and caring fatherhood contributes to the health and wellbeing of children, women and men. The corollary is also true - men, women and children are affected when fathers are not involved or supportive of their children. Many factors affect fathers' involvement, including women's attitudes, the history and nature of the relationship between mother and father, and the cultural context. This study explores gatekeeping and its impact on father involvement among Black South Africans in rural KwaZulu-Natal. Among married couples, gatekeeping occurs with respect to childcare and housework through women's attempts to validate their maternal identity according to socially and culturally constructed gender roles. Among unmarried, non-resident parents, women control father-child contact and involvement, with mothers and/or their families either facilitating or inhibiting father involvement. In this context, we found that cultural gatekeeping had a huge impact on father involvement, with the non-payment of inhlawulo or lobola regulating father-child involvement. In a country like South Africa, where there is high non-marital fertility and father-child non-residence, future research, parenting and family programmes should focus on strategies that encourage positive paternal involvement as well as maternal and cultural support for father involvement, regardless of parental relationship and residence status. PMID- 26501894 TI - Biomarker identification from next-generation sequencing data for pathogen bacteria characterization and surveillance. AB - AIM: The purpose was to develop an analytical pipeline for specific gene analysis and biomarker discovery from next generation sequencing (NGS) data. MATERIALS & METHODS: As a test case, the fliC gene reference sequences of 24 Salmonella enterica strains of 13 serotypes and NGS reads of 32 serovar Newport, 48 Montevideo and 115 Enteritidis outbreak isolates were retrieved from the National Center for Biotechnology Information database. RESULTS: Establishment of an analytical pipeline consisting of four steps: reference sequences retrieval and template sequence determination; NGS sequence reads retrieval; multiple sequence alignments and phylogenetic analysis; data mining and biomarker discovery. CONCLUSION: The pipeline developed provides an effective bioinformatics tool for genetic diversity clarification and marker sequences discovery for pathogen characterization and surveillance. PMID- 26501895 TI - Cell differentiation on disk- and string-shaped hydrogels fabricated from Ca(2+) responsive self-assembling peptides. AB - We recently developed a self-assembling peptide, E1Y9, that self-assembles into nanofibers and forms a hydrogel in the presence of Ca(2+) . E1Y9 derivatives conjugated with functional peptide sequences derived from extracellular matrices (ECMs) reportedly self-assemble into peptide nanofibers that enhance cell adhesion and differentiation. In this study, E1Y9/E1Y9-IKVAV-mixed hydrogels were constructed to serve as artificial ECMs that promote cell differentiation. E1Y9 and E1Y9-IKVAV co-assembled into networked nanofibers, and hydrogels with disk and string shapes were formed in response to Ca(2+) treatment. The neuronal differentiation of PC12 cells was facilitated on hydrogels of both shapes that contained the IKVAV motifs. Moreover, long neurites extended along the long axis of the string-shaped gel, suggesting that the structure of hydrogels of this shape can affect cellular orientation. Thus, E1Y9 hydrogels can potentially be used as artificial ECMs with desirable bioactivities and shapes that could be useful in tissue engineering applications. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 476-483, 2016. PMID- 26501896 TI - Marked and sustained improvement on nerve conduction study of anti-myelin associated glycoprotein neuropathy following rituximab therapy. PMID- 26501898 TI - HTRF Kinase Assay Development and Methods in Inhibitor Characterization. AB - Due to their important roles in cellular signaling and their dysfunctions being linked to diseases, kinases have become a class of proteins being actively pursued as potential drug targets. Biochemical assays for kinases have been developed in various formats to facilitate inhibitor screening and selectivity profiling. Here, we focus on one such technology: homogeneous time-resolved fluorescence (HTRF). In this chapter, we describe the methods of developing an HTRF kinase assay using mutant EGFR enzyme as an example. We show how to determine the kinetic parameter of the enzyme (ATP K m), as well as how to study the inhibitor mechanism of action (MoA) exemplified by inhibitors of different MoAs. All methods described here can be readily applied to other kinases with minor modifications. PMID- 26501899 TI - Application of Eukaryotic Elongation Factor-2 Kinase (eEF-2K) for Cancer Therapy: Expression, Purification, and High-Throughput Inhibitor Screening. AB - Protein kinases have emerged as an important class of therapeutic targets, as they are known to be involved in pathological pathways linked to numerous human disorders. Major efforts to discover kinase inhibitors in both academia and pharmaceutical companies have centered on the development of robust assays and cost-effective approaches to isolate them. Drug discovery procedures often start with hit identification for lead development, by screening a library of chemicals using an appropriate assay in a high-throughput manner. Considering limitations unique to each assay technique and screening capability, intelligent integration of various assay schemes and level of throughput, in addition to the choice of chemical libraries, is the key to success of this initial step. Here, we describe the purification of the protein kinase, eEF-2K, and the utilization of three biochemical assays in the course of identifying small molecules that block its enzymatic reaction. PMID- 26501900 TI - Recombinant Kinase Production and Fragment Screening by NMR Spectroscopy. AB - During the past decade fragment-based drug discovery (FBDD) has rapidly evolved and several drugs or drug candidates developed by FBDD approach are clinically in use or in clinical trials. For example, vemurafenib, a V600E mutated BRAF inhibitor, was developed by utilizing FBDD approach and approved by FDA in 2011. In FBDD, screening of fragments is the starting step for identification of hits and lead generation. Fragment screening usually relies on biophysical techniques by which the protein-bound small molecules can be detected. NMR spectroscopy has been extensively used to study the molecular interaction between the protein and the ligand, and has many advantages in fragment screening over other biophysical techniques. This chapter describes the practical aspects of fragment screening by saturation transfer difference NMR. PMID- 26501897 TI - Ocular Infection: Endophthalmitis. AB - Endophthalmitis is characterized by marked inflammation of intraocular fluids and tissues. Infective endophthalmitis may be categorized by the cause of the infection, which helps predict the underlying etiology and most likely causative organisms. The major category remains acute-onset postoperative endophthalmitis. Infective endophthalmitis is a clinical diagnosis but is confirmed by evaluation of intraocular fluid specimens. The Endophthalmitis Vitrectomy Study offered important guidelines for the initial management of endophthalmitis, and these guidelines remain relevant to this day. Prompt initiation of empiric broad spectrum antimicrobial therapy is important in achieving best outcomes. PMID- 26501902 TI - Using Bioluminescent Kinase Profiling Strips to Identify Kinase Inhibitor Selectivity and Promiscuity. AB - The advancement of a kinase inhibitor throughout drug discovery and development is predicated upon its selectivity towards the target of interest. Thus, profiling the compound against a broad panel of kinases is important for providing a better understanding of its activity and for obviating any off-target activities that can result in undesirable consequences. To assess the selectivity and potency of an inhibitor against multiple kinases, it is desirable to use a universal assay that can monitor the activity of all classes of kinases regardless of the nature of their substrates. The luminescent ADP-Glo kinase assay is a universal platform that measures kinase activity by quantifying the amount of the common kinase reaction product ADP. Here we present a method using standardized kinase profiling systems for inhibitor profiling studies based on ADP detection by luminescence. The kinase profiling systems are sets of kinases organized by family, presented in multi-tube strips containing eight enzymes, each with corresponding substrate strips, and standardized for optimal kinase activity. We show that using the kinase profiling strips we could quickly and easily generate multiple selectivity profiles using small or large kinase panels, and identify compound promiscuity within the kinome. PMID- 26501901 TI - Bioluminescence Methods for Assaying Kinases in Quantitative High-Throughput Screening (qHTS) Format Applied to Yes1 Tyrosine Kinase, Glucokinase, and PI5P4Kalpha Lipid Kinase. AB - Assays in which the detection of a biological phenomenon is coupled to the production of bioluminescence by luciferase have gained widespread use. As firefly luciferases (FLuc) and kinases share a common substrate (ATP), coupling of a kinase to FLuc allows for the amount of ATP remaining following a kinase reaction to be assessed by quantitating the amount of luminescence produced. Alternatively, the amount of ADP produced by the kinase reaction can be coupled to FLuc through a two-step process. This chapter describes the bioluminescent assays that were developed for three classes of kinases (lipid, protein, and metabolic kinases) and miniaturized to 1536-well format, enabling their use for quantitative high-throughput (qHTS) of small-molecule libraries. PMID- 26501903 TI - Measuring Activity of Phosphoinositide Lipid Kinases Using a Bioluminescent ADP Detecting Assay. AB - Phosphatidylinositol (PI) and its phosphorylated derivatives, collectively called phosphoinositides, are important second messengers involved in a variety of cellular processes, including cell proliferation, apoptosis, metabolism, and migration. These derivatives are generated by a family of kinases called phosphoinositide lipid kinases (PIKs). Due to the central role of these kinases in signaling pathways, assays for measuring their activity are often used for drug development. Lipid kinase substrates are present in unique membrane environments in vivo and are insoluble in aqueous solutions. Therefore the most important consideration in developing successful lipid kinase assays is the physical state of lipid kinase substrates. Here we describe the preparation of lipid substrates for two major classes of lipid kinases, phosphatidylinositol 3 kinases (PI3Ks) and phosphatidylinositol 4-kinases (PI4Ks). Using PI4Ks as an example, we also provide a detailed protocol for small-scale kinase expression and affinity purification from transiently transfected mammalian cells. For measuring lipid kinase activity we apply a universal bioluminescent ADP detection approach. The approach is compatible with diverse lipid substrates and can be used as a single integrated platform for measuring all classes of lipid and protein kinases. PMID- 26501904 TI - A High-Throughput Radiometric Kinase Assay. AB - Aberrant kinase signaling has been implicated in a number of diseases. While kinases have become attractive drug targets, only a small fraction of human protein kinases have validated inhibitors. Screening of libraries of compounds against a kinase or kinases of interest is routinely performed during kinase inhibitor development to identify promising scaffolds for a particular target and to identify kinase targets for compounds of interest. Screening of more focused compound libraries may also be conducted in the later stages of inhibitor development to improve potency and optimize selectivity. The dot blot kinase assay is a robust, high-throughput kinase assay that can be used to screen a number of small-molecule compounds against one kinase of interest or several kinases. Here, a protocol for a dot blot kinase assay used for measuring insulin receptor kinase activity is presented. This protocol can be readily adapted for use with other protein kinases. PMID- 26501905 TI - A High-Content Assay to Screen for Modulators of EGFR Function. AB - Cell-based assays have the potential and advantage to identify cell-permeable modulators of kinase function, and hence provide an alternative to the conventional enzymatic activity-driven discovery approaches that rely on purified recombinant kinase catalytic domains. Here, we describe a domain-based high content biosensor approach to study endogenous EGFR activity whereby EGF-induced receptor activation, subsequent trafficking, and internalization are imaged and quantified using time-dependent granule formation in cells. This method can readily be used to search for EGFR modulators in both chemical and RNAi screening; with potential applicability to other receptor tyrosine kinases. PMID- 26501906 TI - Monitoring Protein Kinase Expression and Phosphorylation in Cell Lysates with Antibody Microarrays. AB - Fuelled by advances in our understanding of the human kinome and phosphoproteome and the increasing availability of pan- and phosphosite-specific antibodies, antibody microarrays have emerged as powerful tools for interrogating protein phosphorylation-mediated signaling systems in ex vivo studies. This economical platform permits ultra-sensitive, semiquantitative measurements of the levels of hundreds of protein kinases and their substrates along with their phosphorylation status simultaneously with minute amounts of specimens. Recent technological innovations in the design and fabrication of antibody microarrays and sample preparation have permitted further refinements of the technology to yield improvements in data quality. In this chapter, we describe a detailed protocol that we have developed for tracking the expression and phosphorylation of protein kinases and their substrates in crude cell lysate samples using a high-content antibody microarray. PMID- 26501907 TI - From Enzyme to Whole Blood: Sequential Screening Procedure for Identification and Evaluation of p38 MAPK Inhibitors. AB - p38 mitogen-activated protein kinase (MAPK) is a pivotal enzyme in the biosynthesis of pro-inflammatory cytokines like IL-1 and TNF. Therefore, the success of anti-cytokine therapy for treatment of inflammatory processes qualified p38-MAPK as a solid target in drug research concerning chronic inflammatory diseases including infectious vascular, neurobiological, and autoimmune disorders. However, the discovery of new kinase inhibitors is limited by the need for a high biological activity combined with restricted activity to the target enzyme or pathway interaction. As a consequence, no p38 MAPK inhibitor has been introduced to the market so far, although several p38 inhibitors have proceeded into clinical trials. The development of novel inhibitor types and optimization of already known structural classes of MAPK inhibitors require appropriate testing systems reaching across these crucial parameters. As a new approach, we describe the sequential arrangement of three testing systems custom tailored to the requirements of drug discovery programs with focus on p38 inhibition. Integrated analysis of the obtained results enables a concerted step by-step selection of tested molecules in order to screen a compound library for the most suitable inhibitor. First, evaluation of the inhibitor's activity on the isolated p38 MAPK enzyme via an ELISA assay gives a first idea about the inhibitory potency of the molecule. Moreover, structure-activity relationships can be elucidated when comparing molecules within inhibitor series. Second, screening in living cells via a p38 substrate-specific MK2-EGFP translocation assay supplies further information about efficacy, but provides also a first notion concerning selectivity and toxicity. Third, efficacy is evaluated more specifically in vivo in LPS-stimulated human whole blood with regard to in vivo parameters, e.g., pharmacokinetic characteristics like plasma protein binding and cellular permeability. These three testing systems complement one another synergistically by providing a high overlap and predictability. Clear advantages of all presented systems are their realizability in an academic environment as well as their applicability for high-throughput screenings on a larger scale. PMID- 26501908 TI - Genetically Encoded Fluorescent Indicators to Visualize Protein Phosphorylation in Living Cells. AB - Protein phosphorylation by intracellular kinases plays one of the most pivotal roles in signaling pathways within cells. To reveal the biological processes related to the kinase proteins, electrophoresis, immunocytochemistry, and in vitro kinase assay have been used. However, these conventional methods do not provide enough information about spatial and temporal dynamics of the signal transduction based on protein phosphorylation and dephosphorylation in living cells. To overcome the limitation for investigating the kinase signaling, we developed genetically encoded fluorescent indicators for visualizing the protein phosphorylation in living cells. Using these indicators, we visualized under a fluorescence microscope when, where, and how the protein kinases are activated in single living cells. PMID- 26501909 TI - Characterization of an Engineered Src Kinase to Study Src Signaling and Biology. AB - Pharmacologic inhibitors of protein kinases comprise the vast majority of approved signal transduction inhibitors for cancer treatment. An important facet of their clinical development is the identification of the key substrates critical for their driver role in cancer. One approach for substrate identification involves evaluating the phosphorylation events associated with stable expression of an activated protein kinase. Another involves genetic or pharmacologic inhibition of protein kinase expression or activity. However, both approaches are limited by the dynamic nature of signaling, complicating whether phosphorylation changes are primary or secondary activities of kinase function. We have developed rapamycin-regulated (RapR) protein kinases as molecular tools that allow for the study of spatiotemporal regulation of signaling. Here we describe the application of this technology to the Src tyrosine kinase and oncoprotein (RapR-Src). We describe how to achieve stable expression of this tool in cell lines and how to subsequently activate the tool and determine its function in signaling and morphology. PMID- 26501910 TI - Screening One-Bead-One-Compound Peptide Libraries for Optimal Kinase Substrates. AB - Protein kinases phosphorylate specific serine, threonine, and/or tyrosine residues in their target proteins, resulting in functional changes of the target proteins such as enzymatic activity, cellular location, or association with other proteins. For many kinases, their in vivo substrate specificity is at least partially defined by the amino acid sequence surrounding the phosphorylatable residue (or sequence specificity). We report here a robust, high-throughput method for profiling the sequence specificity of protein kinases. Up to 10(7) different peptides are rapidly synthesized on PEGA beads in the one-bead-one compound format and subjected to kinase reaction in the presence of [gamma-S]ATP. Positive beads displaying the optimal kinase substrates are identified by covalently labeling the thiophosphorylated peptides with a fluorescent dye via a disulfide exchange reaction. Finally, the most active hit(s) is identified by the partial Edman degradation-mass spectrometry (PED-MS) method. The ability of this method to provide individual sequences of the preferred substrates permits the identification of sequence contextual effects and non-permissive residues. This method is applicable to protein serine, threonine, and tyrosine kinases. PMID- 26501911 TI - Determination of the Substrate Specificity of Protein Kinases with Peptide Micro- and Macroarrays. AB - Elucidation of the key determinants for the phosphorylation site specificities of protein kinases facilitates identification of their physiological substrates, and serves to better define their critical roles in the signaling networks that underlie a multitude of cellular activities. Albeit with some apparent limitations, such as the lack of contextual information for secondary substrate binding sites, the synthetic peptide-based approach has been adopted widely for the kinase specificity profiling studies, especially when they are used in an array format, which permits the screening of large numbers of potential peptide substrates in parallel. In this chapter, we present detailed protocols for determining protein kinase substrate specificity using an approach that involves both peptide microarrays and macroarrays. In particular, SPOT synthesis on macroarrays can be used to follow up on in silico predictions of protein kinase substrate specificity with predictive algorithms. PMID- 26501912 TI - Rapid Identification of Protein Kinase Phosphorylation Site Motifs Using Combinatorial Peptide Libraries. AB - Eukaryotic protein kinases phosphorylate substrates at serine, threonine, and tyrosine residues that fall within the context of short sequence motifs. Knowing the phosphorylation site motif for a protein kinase facilitates designing substrates for kinase assays and mapping phosphorylation sites in protein substrates. Here, we describe an arrayed peptide library protocol for rapidly determining kinase phosphorylation consensus sequences. This method uses a set of peptide mixtures in which each of the 20 amino acid residues is systematically substituted at nine positions surrounding a central site of phosphorylation. Peptide mixtures are arrayed in multiwell plates and analyzed by radiolabel assay with the kinase of interest. The preferred sequence is determined from the relative rate of phosphorylation of each peptide in the array. Consensus peptides based on these sequences typically serve as efficient and specific kinase substrates for high-throughput screening or incorporation into biosensors. PMID- 26501913 TI - Routes for Drug Delivery: Sustained-Release Devices. AB - Several different technologies exist for sustained-release drug delivery devices, including: (1) nonbiodegradable implants; (2) biodegradable implants; (3) micro- and nanoparticles; (4) liposomes, and (5) encapsulated cell technology (ECT). Currently, the only sustained-release devices approved by the Food and Drug Administration are the ganciclovir implant for the treatment of cytomegalovirus retinitis, the fluocinolone acetonide implant for the treatment of noninfectious posterior uveitis and the dexamethasone implant for the treatment of diabetic macular edema or noninfectious posterior uveitis. The first two implants are nonbiodegradable and require surgical placement, whereas the dexamethasone implant is biodegradable, and can be shaped and injected using a small-gauge needle or applicator into the vitreous. ECT, currently in a phase II clinical trial, utilizes modified retinal pigment epithelium cells to produce protein drug molecules in the vitreous. The microparticle, nanoparticle and liposome technology currently in development may offer the most flexibility for prolonged drug release and combination therapy for retinal diseases. PMID- 26501914 TI - Employing Mesenchymal Stem Cells in Wound Care: Are We There Yet? PMID- 26501915 TI - Cardiorespiratory Mechanical Simulator for In Vitro Testing of Impedance Minute Ventilation Sensors in Cardiac Pacemakers. AB - We developed a cardiorespiratory mechanical simulator (CRMS), a system able to reproduce both the cardiac and respiratory movements, intended to be used for in vitro testing of impedance minute ventilation (iMV) sensors in cardiac pacemakers. The simulator consists of two actuators anchored to a human thorax model and a software interface to control the actuators and to acquire/process impedance signals. The actuators can be driven separately or simultaneously to reproduce the cardiac longitudinal shortening at a programmable heart rate and the diaphragm displacement at a programmable respiratory rate (RR). A standard bipolar pacing lead moving with the actuators and a pacemaker case fixed to the thorax model have been used to measure impedance (Z) variations during the simulated cardiorespiratory movements. The software is able to discriminate the low-frequency component because of respiration (Z(R)) from the high-frequency ripple because of cardiac effect (Z(C)). Impedance minute ventilation is continuously calculated from Z(R) and RR. From preliminary tests, the CRMS proved to be a reliable simulator for in vitro evaluation of iMV sensors. Respiration impedance recordings collected during cardiorespiratory movements reproduced by the CRMS were comparable in morphology and amplitude with in vivo assessments of transthoracic impedance variations. PMID- 26501917 TI - Demikhov's "Mechanical Heart": The Circumstances Surrounding Creation of the World's First Implantable Total Artificial Heart in 1937. AB - The world's first implantable total artificial heart was designed by Vladimir Demikhov as a fourth year biology student in Voronezh, Soviet Union, in 1937. As a prototype of his device, Demikhov must have used an apparatus for extracorporeal blood circulation invented by Sergei Bryukhonenko of Moscow. The device was the size of a dog's native heart and consisted of two diaphragm pumps brought into motion by an electric motor. A dog with an implanted device lived for 2.5 hours. In addition to having the prototype, the preconditions for Demikhov's artificial heart creation were his manual dexterity, expertise in animal physiology, and his mechanistic worldview. PMID- 26501918 TI - Early Implementation of Video Capsule Enteroscopy in Patients with Left Ventricular Assist Devices and Obscure Gastrointestinal Bleeding. AB - Gastrointestinal bleeding (GIB) is a frequent challenge encountered in patients implanted with a left ventricular assist device (LVAD), affecting approximately 25% of this population. Many patients have no identifiable source of bleeding after routine esophagogastroduodenoscopy and colonoscopy and are labeled as obscure GIB (OGIB). Significant costs and invasive procedures are required to investigate and stop the source of bleeding in these patients. We performed a retrospective analysis at a single tertiary referral center to investigate the diagnostic yield and overall effectiveness of video capsule enteroscopy (VCE) in this population. Eight patients with LVADs underwent nine VCE studies for OGIB. The diagnostic yield was 100%, with intraluminal blood the most common finding. The jejunum was the most common location for pathology detected on VCE. Sixty seven percent of the studies directly guided further endoscopy with successful cessation of bleeding in 100% of these patients. Finally, after an average follow up of 46 weeks, the total number of endoscopic procedures and total units of transfused packed red blood cells (pRBC) were significantly less after the patient underwent the VCE study compared with before. Video capsule enteroscopy is a safe and high-yield investigative procedure in this population and should be implemented earlier to improve patient outcomes and reduce costs of care. PMID- 26501916 TI - Hemodialysis Catheter Heat Transfer for Biofilm Prevention and Treatment. AB - Central line-associated bloodstream infections (CLABSIs) are not easily treated, and many catheters (e.g., hemodialysis catheters) are not easily replaced. Biofilms (the source of infection) on catheter surfaces are notoriously difficult to eradicate. We have recently demonstrated that modest elevations of temperature lead to increased staphylococcal susceptibility to vancomycin and significantly soften the biofilm matrix. In this study, using a combination of microbiological, computational, and experimental studies, we demonstrate the efficacy, feasibility, and safety of using heat as an adjuvant treatment for infected hemodialysis catheters. Specifically, we show that treating with heat in the presence of antibiotics led to additive killing of Staphylococcus epidermidis with similar trends seen for Staphylococcus aureus and Klebsiella pneumoniae. The magnitude of temperature elevation required is relatively modest (45-50 degrees C) and similar to that used as an adjuvant to traditional cancer therapy. Using a custom-designed benchtop model of a hemodialysis catheter, positioned with tip in the human vena cava as well as computational fluid dynamic simulations, we demonstrate that these temperature elevations are likely achievable in situ with minimal increased in overall blood temperature. PMID- 26501919 TI - Evaluation of a Self-Administered Computerized Cognitive Battery in an Older Population. AB - OBJECTIVE: The aim of this study is to assess the utility of the Cogstate self administered computerized neuropsychological battery in a large population of older men. METHODS: We invited 7,167 men (mean age of 75 years) from the Health Professionals Follow-up Study, a prospective cohort of male health professionals. We considered individual Cogstate scores and composite scores measuring psychomotor speed and attention, learning and working memory and overall cognition. Multivariate linear regression was used to assess the association between risk factors measured 4 and 28 years prior to cognitive testing and each outcome. RESULTS: The 1,866 men who agreed to complete Cogstate testing were similar to the 5,301 non-responders. Many expected risk factors were associated with Cogstate scores in multivariate adjusted models. Increasing age was significantly associated with worse performance on all outcomes (p < 0.001). For risk factors measured 4 years prior to testing and overall cognition, a history of hypertension was significantly associated with worse performance (mean difference of -0.08 standard units (95% CI -0.16, 0.00)) and higher consumption of nuts was significantly associated with better performance (>2 servings/week vs. <1 serving/month: 0.15 (0.03, 0.27)). CONCLUSIONS: The self-administered Cogstate battery showed significant associations with several risk factors known to be associated with cognitive function. Future studies of cognitive aging may benefit from the numerous advantages of self-administered computerized testing. PMID- 26501920 TI - Stereoselective Behavior of the Chiral Herbicides Diclofop-Methyl and Diclofop During the Soy Sauce Brewing Process. AB - Chiral pesticides are now receiving more and more attention in the food-making process. This experiment studied the enantioselective behavior of diclofop-methyl (DM) and its main metabolite, diclofop (DC), during the soy sauce brewing process. Two kinds of commonly used strains, Aspergillus oryzae and Saccharomyces rouxii, were investigated. However, they showed a different degradation ability to the enantiomers of DM and DC. It was observed that (-)-(S)-DM was degraded much faster than (+)-(R)-DM by Saccharomyces rouxii, while no stereoselective degradation was found by Aspergillus oryzae. DC represented a relatively long residue period in this fermentation process and both strains showed a weak degradation ability to DC, especially Saccharomyces rouxii. There was little DC detected in the final product, while most of the DC residues persisted in the lees, which were usually used as animal feeds or discarded into the environment directly as waste. Therefore, more attention should be paid to the soy sauce brewing process concerning pesticide residues both in the final product and byproducts. PMID- 26501924 TI - Slow Relaxation of Shape and Orientational Texture in Membrane Gel Domains. AB - Gel domains in lipid bilayers are structurally more complex than fluid domains. Growth dynamics can lead to noncircular domains with a heterogeneous orientational texture. Most model membrane studies involving gel domain morphology and lateral organization assume the domains to be static. Here we show that rosette shaped gel domains, with heterogeneous orientational texture and a central topological defect, after early stage growth, undergo slow relaxation. On a time scale of days to weeks domains converge to circular shapes and approach uniform texture. 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) enriched gel domains are grown by cooling 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC):DPPC bilayers into the solid-liquid phase coexistence region and are visualized with fluorescence microscopy. The relaxation of individual domains is quantified through image analysis of time-lapse image series. We find a shape relaxation mechanism which is inconsistent with Ostwald ripening and coalescence as observed in membrane systems with coexisting liquid phases. Moreover, domain texture changes in parallel with the changes in domain shape, and selective melting and growth of particular subdomains cause the texture to become more uniform. We propose a relaxation mechanism based on relocation of lipids from high-energy lattice positions, through evaporation-condensation and edge diffusion, to low energy positions. The relaxation process is modified significantly by binding Shiga toxin, a bacterial toxin from Shigella dysenteriae, to the membrane surface. Binding alters the equilibrium shape of the gel domains from circular to eroded rosettes with disjointed subdomains. This observation may be explained by edge diffusion while evaporation-condensation is restricted, and it provides further support for the proposed overall relaxation mechanism. PMID- 26501922 TI - Uranium from German Nuclear Power Projects of the 1940s--A Nuclear Forensic Investigation. AB - Here we present a nuclear forensic study of uranium from German nuclear projects which used different geometries of metallic uranium fuel. Through measurement of the (230)Th/(234)U ratio, we could determine that the material had been produced in the period from 1940 to 1943. To determine the geographical origin of the uranium, the rare-earth-element content and the (87)Sr/(86)Sr ratio were measured. The results provide evidence that the uranium was mined in the Czech Republic. Trace amounts of (236)U and (239)Pu were detected at the level of their natural abundance, which indicates that the uranium fuel was not exposed to any major neutron fluence. PMID- 26501926 TI - Erratum to: Adherence to Psychiatric Follow-up Predicts 1-Year BMI Loss in Gastric Bypass Surgery Patients. PMID- 26501925 TI - DrugTargetInspector: An assistance tool for patient treatment stratification. AB - Cancer is a large class of diseases that are characterized by a common set of features, known as the Hallmarks of cancer. One of these hallmarks is the acquisition of genome instability and mutations. This, combined with high proliferation rates and failure of repair mechanisms, leads to clonal evolution as well as a high genotypic and phenotypic diversity within the tumor. As a consequence, treatment and therapy of malignant tumors is still a grand challenge. Moreover, under selective pressure, e.g., caused by chemotherapy, resistant subpopulations can emerge that then may lead to relapse. In order to minimize the risk of developing multidrug-resistant tumor cell populations, optimal (combination) therapies have to be determined on the basis of an in-depth characterization of the tumor's genetic and phenotypic makeup, a process that is an important aspect of stratified medicine and precision medicine. We present DrugTargetInspector (DTI), an interactive assistance tool for treatment stratification. DTI analyzes genomic, transcriptomic, and proteomic datasets and provides information on deregulated drug targets, enriched biological pathways, and deregulated subnetworks, as well as mutations and their potential effects on putative drug targets and genes of interest. To demonstrate DTI's broad scope of applicability, we present case studies on several cancer types and different types of input -omics data. DTI's integrative approach allows users to characterize the tumor under investigation based on various -omics datasets and to elucidate putative treatment options based on clinical decision guidelines, but also proposing additional points of intervention that might be neglected otherwise. DTI can be freely accessed at http://dti.bioinf.uni-sb.de. PMID- 26501927 TI - Evolving Knowledge in Pharmacologic Treatments of Age-Related Macular Degeneration. AB - Modern retinal drug therapy is a result of the recent challenges and breakthroughs in chemistry, physics, genetics, cell biology and biotechnologies. Specific pharmaceutical and pharmacokinetic characteristics of a drug are of major importance and contribute to its ability to penetrate targeted ocular tissues in order to result in effective therapeutic concentrations. In addition, the drugs should maintain a prolonged time of activity and be safe with minimal local and systemic toxicity. The transporter vehicle or drug delivery system is crucial in order to enhance ocular tissue penetration and establish controlled drug release. Administration methods should be local, thereby reducing systemic side effects, and, ideally, treatment should be noninvasive. Within the group of so-called classic therapies, the use of pharmacologic treatments has become widespread for most severe retinal diseases. Thereby, ocular therapy of diseases like exudative age-related macular degeneration has improved markedly. Moreover, new metabolic pathways have been identified, new molecules have emerged, new synthesis technologies have been discovered, and new formulae conceived. These developments have opened new avenues for limiting disease progression. PMID- 26501928 TI - Head movements encode emotions during speech and song. AB - When speaking or singing, vocalists often move their heads in an expressive fashion, yet the influence of emotion on vocalists' head motion is unknown. Using a comparative speech/song task, we examined whether vocalists' intended emotions influence head movements and whether those movements influence the perceived emotion. In Experiment 1, vocalists were recorded with motion capture while speaking and singing each statement with different emotional intentions (very happy, happy, neutral, sad, very sad). Functional data analyses showed that head movements differed in translational and rotational displacement across emotional intentions, yet were similar across speech and song, transcending differences in F0 (varied freely in speech, fixed in song) and lexical variability. Head motion specific to emotional state occurred before and after vocalizations, as well as during sound production, confirming that some aspects of movement were not simply a by-product of sound production. In Experiment 2, observers accurately identified vocalists' intended emotion on the basis of silent, face-occluded videos of head movements during speech and song. These results provide the first evidence that head movements encode a vocalist's emotional intent and that observers decode emotional information from these movements. We discuss implications for models of head motion during vocalizations and applied outcomes in social robotics and automated emotion recognition. PMID- 26501929 TI - Forgetting feelings: Opposite biases in reports of the intensity of past emotion and mood. AB - Memory for feelings is subject to fading and bias over time. In 2 studies, the authors examined whether the magnitude and direction of bias depend on the type of feeling being recalled: emotion or mood. A few days after the U.S. Presidential elections in 2008 and 2012, participants reported how they felt about the election outcome (emotion) and how they felt in general (mood). A month after the elections, participants recalled their feelings. The intensity of past emotion was recalled more accurately than the intensity of past mood. Participants underestimated the intensity of emotion but overestimated the intensity of mood. Participants' appraisals of the importance of the election, which diminished over time, contributed to underestimating the intensity of emotion. In contrast, participants' strong emotional response to the election contributed to overestimating the intensity of mood. These opposing biases have important implications for decision making and clinical assessment. PMID- 26501930 TI - The relation between navigation strategy and associative memory: An individual differences approach. AB - Although the hippocampus is implicated in both spatial navigation and associative memory, very little is known about whether individual differences in the 2 domains covary. People who prefer to navigate using a hippocampal-dependent place strategy may show better performance on associative memory tasks than those who prefer a caudate-dependent response strategy (Bohbot, Gupta, Banner, & Dahmani, 2011), but not all studies suggest such an effect (Woollett & Maguire, 2009, 2012). Here we tested nonexpert young adults and found that preference for a place strategy positively correlated with spatial (object-location) associative memory performance but did not correlate with nonspatial (face-name) associative memory performance. Importantly, these correlations differed from each other, indicating that the relation between navigation strategy and associative memory is specific to the spatial domain. In addition, the 2 associative memory tasks significantly correlated, suggesting that object-location memory taps into processes relevant to both hippocampal-dependent navigation and nonspatial associative memory. Our findings also suggest that individual differences in spatial associative memory may account for some of the variance in navigation strategies. PMID- 26501931 TI - Permanent reduction of dissipation in nanomechanical Si resonators by chemical surface protection. AB - We report on mechanical dissipation measurements carried out on thin (~100 nm), single-crystal silicon cantilevers with varying chemical surface termination. We find that the 1-2 nm-thick native oxide layer of silicon contributes about 85% to the friction of the mechanical resonance. We show that the mechanical friction is proportional to the thickness of the oxide layer and that it crucially depends on oxide formation conditions. We further demonstrate that chemical surface protection by nitridation, liquid-phase hydrosilylation, or gas-phase hydrosilylation can inhibit rapid oxide formation in air and results in a permanent improvement of the mechanical quality factor between three- and five fold. This improvement extends to cryogenic temperatures. Presented recipes can be directly integrated with standard cleanroom processes and may be especially beneficial for ultrasensitive nanomechanical force- and mass sensors, including silicon cantilevers, membranes, or nanowires. PMID- 26501932 TI - The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments. AB - AIMS: Neurofibrillary tangles (NFTs), a cardinal pathological feature of neurodegenerative disorders, such as Alzheimer's disease (AD) are primarily composed of hyper-phosphorylated tau protein. Recently, several other molecules, including flotillin-1, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] and cyclin-dependent kinase 5 (CDK5), have also been revealed as constituents of NFTs. Flotillin-1 and PtdIns(4,5)P2 are considered markers of raft microdomains, whereas CDK5 is a tau kinase. Therefore, we hypothesized that NFTs have a relationship with raft domains and the tau phosphorylation that occurs within NFTs. METHODS: We investigated six cases of AD, six cases of other neurodegenerative diseases with NFTs and three control cases. We analysed the PtdIns(4,5)P2-immunopositive material in detail, using super-resolution microscopy and electron microscopy to elucidate its pattern of expression. We also investigated the spatial relationship between the PtdIns(4,5)P2 immunopositive material and tau kinases through double immunofluorescence analysis. RESULTS: Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 MUm in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons. These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase-3beta and spleen tyrosine kinase. CONCLUSIONS: These observations suggest that clusters of raft-derived vesicles that resemble GVD bodies are substructures of pretangles other than PHFs. These tau kinase-bearing vesicles are likely involved in the modification of tau protein and in NFT formation. PMID- 26501933 TI - Man With Blurry Vision and Eye Pain. PMID- 26501934 TI - Sentence Recall by Children With SLI Across Two Nonmainstream Dialects of English. AB - PURPOSE: The inability to accurately recall sentences has proven to be a clinical marker of specific language impairment (SLI); this task yields moderate-to-high levels of sensitivity and specificity. However, it is not yet known if these results hold for speakers of dialects whose nonmainstream grammatical productions overlap with those that are produced at high rates by children with SLI. METHOD: Using matched groups of 70 African American English speakers and 36 Southern White English speakers and dialect-strategic scoring, we examined children's sentence recall abilities as a function of their dialect and clinical status (SLI vs. typically developing [TD]). RESULTS: For both dialects, the SLI group earned lower sentence recall scores than the TD group with sensitivity and specificity values ranging from .80 to .94, depending on the analysis. Children with SLI, as compared with TD controls, manifested lower levels of verbatim recall, more ungrammatical recalls when the recall was not exact, and higher levels of error on targeted functional categories, especially those marking tense. CONCLUSION: When matched groups are examined and dialect-strategic scoring is used, sentence recall yields moderate-to-high levels of diagnostic accuracy to identify SLI within speakers of nonmainstream dialects of English. PMID- 26501935 TI - "Graft to" Synthesis and Ibuprofen-Loading Performance of pH-Sensitive PMAA Silica Hybrid Nanoparticles with Controlled Bimodal Mesopores. AB - Bimodal mesoporous silicas (BMMs) have been proved to be a good drug-loaded carrier. However, it did not provide stimuli sensitivity or controlled release performance yet. In the present work, a "smart" mesoporous silica-based pH dependent [poly(methacrylic acid)]-silica hybrid nanoparticles (P/NN-BMMs) drug delivery system was developed and evaluated with ibuprofen (IBU) as a model drug. P/NN-BMMs were prepared by coating poly(methacrylic acid) (PMAA) onto amino modified surface of BMMs via the "graft to" strategy. The structure and texture of resultant hybrid nanoparticles were determined with X-ray diffraction, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared, thermogravimetric analysis, N2 sorption isotherms, and elemental analysis. The PMAA acts as a molecular switch to achieve controlled drug release and the amount of grafted-PMAA can remarkably affect its performance. The drug loading rate is decreased markedly with the increasing of the amount of grafted PMAA, meanwhile, the drug-loading kinetics on P/NN-BMMs fits Korsmeyer-Peppas model. In addition, the drug-release amount from drug-loaded P/NN-BMMs is pH dependent, showing an increasing tendency with the increase of pH value. PMID- 26501936 TI - Risk-Based Therapy for Localized Osteosarcoma. AB - BACKGROUND: The outcome of localized osteosarcoma has remained constant over the past 30 years. Histological response to preoperative chemotherapy is the best predictor of outcome. Strategies to alter treatment based on histological response have not resulted in increased survival. PROCEDURE: Patients with localized osteosarcoma received preoperative chemotherapy with cisplatin, doxorubicin, and methotrexate. Patients whose tumors had a good histological response (>=90% necrosis) continued with the same treatment postoperatively. Patients with poor histological response (<90% necrosis) received three courses of melphalan 100 mg/m(2) on day -4, cyclophosphamide 2,000 mg/m(2) on days -3, and -2 followed by stem cell infusion. RESULTS: Fifty-two patients were enrolled. Median age was 14 years, and 56% of patients were male. The femur was the most common site. Forty patients underwent limb salvage surgery and amputation was performed in six patients. Forty-eight percent of tumors showed good histological response. Forty patients were evaluable for outcome; 18 patients with poor histologic response received high-dose chemotherapy. The 5-year event-free survival (EFS) and overall survival (OS) for patients treated on the high-dose chemotherapy arm were 28% (95% confidence interval [CI], 10-49) and 48% (95% CI, 23-69), respectively. The 5-year EFS and OS for patients treated on the standard chemotherapy arm were 62% (95% CI, 36-80) and 74% (95% CI, 44-90), respectively. All patients who received high-dose chemotherapy developed grade 3 or higher hematological toxicity. There were no treatment-related deaths. CONCLUSIONS: Postoperative alkylator intensification with high-dose cyclophosphamide and melphalan in patients with localized osteosarcoma with poor histological response failed to improve survival. PMID- 26501937 TI - Polydioxanone Absorbable Plate for Cartilaginous Grafting in Endonasal Rhinoplasty: A Randomized Clinical Trial. AB - IMPORTANCE: The caudal septal extension (CSE) graft maneuver commonly is used to adjust the nasal tip projection. It can, however, be difficult to stabilize and straighten the CSE graft, especially when the procedure is performed through an endonasal approach. Because the stabilization and correct positioning of the CSE graft are vital for achievement of the desired outcome, new approaches must be found that facilitate the technical ease of this procedure. OBJECTIVE: To assess the safety and efficacy of the polydioxanone (PDS) absorbable plate in CSE graft procedures performed via an endonasal approach. DESIGN, SETTING, AND PARTICIPANTS: In an open-label, 2-arm parallel trial, 30 patients who requested a surgical nasal correction and required a CSE graft performed via an endonasal approach were randomized into 2 groups of 15 patients each. All patients underwent endonasal rhinoplasty at a single center from February 17, 2011, to December 26, 2013. Depending on their treatment group, patients received a CSE graft with or without a PDS plate. Data were collected and evaluated from November 24, 2010, to January 19, 2015, when final follow-up occurred. Data were analyzed based on an evaluable population. INTERVENTIONS: Endonasal rhinoplasty with or without the use of a PDS plate. MAIN OUTCOMES AND MEASURES: Technical difficulty assessed using a visual analog scale (range, 0-100; higher scores indicate increased difficulty of use), surgeon and blinded evaluator satisfaction with the graft assessed using a 4-point categorical scale (1 indicates highly satisfied; 4, unsatisfied), change in nasal tip projection, and complications at 30, 60, 180, and 365 days after surgery. RESULTS: Twenty-seven patients (13 in the PDS group and 14 in the non-PDS group) completed their 6-month postoperative visit, and 19 patients (10 in the PDS group and 9 in the non-PDS group) completed the entire study (12 months). The mean (SD; range) surgeon-assessed visual analog scale score for ease of use was 46 (13; 25-64) mm for the 15 patients in the non PDS treatment group and 17 (10; 7-48) mm for the 15 patients in the PDS group (P < .001). The surgeon's satisfaction with the graft did not differ significantly between the PDS and the non-PDS groups (P = .34), and the nontreating blinded evaluator's assessment of standardized photographs taken at the time of the graft placement and at postoperative days 30, 60, 180, and 365 did not establish any significant differences between the 2 groups (P > .99). Postoperative change in the nasal tip projection at 365 postoperative days compared with 30 postoperative days was significantly lower in the PDS group compared with the non-PDS group ( 0.31% vs -6.5%; P = .04), thus increasing the long-term stability of the graft in the PDS group. A single incident of infection was observed in each group along with no episodes of rejection or extrusion. CONCLUSIONS AND RELEVANCE: In this study, use of a PDS plate in CSE graft procedures was associated with less technical difficulty than CSE graft procedures without use of a PDS plate and with reduced long-term variations in the nasal tip projection after the graft placement. LEVEL OF EVIDENCE: 1. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01225250. PMID- 26501938 TI - Brugada Syndrome Presenting as Polymorphic Ventricular Tachycardia-Ventricular Fibrillation Lasting 94 Seconds Recorded on an Ambulatory Monitor. AB - IMPORTANCE: Cardiac arrhythmias are common causes of syncope. Brugada syndrome is an uncommon but serious genetic arrhythmia disorder that can be unmasked by medicines causing sodium channel blockade. OBSERVATIONS: This report documents a case of Brugada syndrome and polymorphic ventricular tachycardia-ventricular fibrillation not initially recognized in a patient taking nortriptyline and experiencing syncope. It also illustrates one of the longest episodes of ventricular fibrillation recorded on an ambulatory monitor (94 seconds). Although the baseline electrocardiogram did not demonstrate a typical appearance for Brugada syndrome, provocative testing with flecainide in this patient with documented polymorphic ventricular tachycardia revealed a Brugada electrocardiogram pattern. CONCLUSIONS AND RELEVANCE: Vigilance should be maintained for arrhythmia substrates such as Brugada syndrome in patients with typical symptoms when they are prescribed membrane-active medicines. Long-term ambulatory rhythm monitors can provide useful information in these cases, especially when symptoms are infrequent. PMID- 26501939 TI - Mammography Screening and Overdiagnosis. PMID- 26501940 TI - Nanoporous Silicon Combustion: Observation of Shock Wave and Flame Synthesis of Nanoparticle Silica. AB - The persistent hydrogen termination present in nanoporous silicon (nPS) is unique compared to other forms of nanoscale silicon (Si) which typically readily form a silicon dioxide passivation layer. The hydrogen terminated surface combined with the extremely high surface area of nPS yields a material capable of powerful exothermic reactions when combined with strong oxidizers. Here, a galvanic etching mechanism is used to produce nPS both in bulk Si wafers as well as in patterned regions of Si wafers with microfabricated ignition wires. An explosive composite is generated by filling the pores with sodium perchlorate (NaClO4). Using high-speed video including Schlieren photography, a shock wave is observed to propagate through air at 1127 +/- 116 m/s. Additionally, a fireball is observed above the region of nPS combustion which persists for nearly 3* as long when reacted in air compared to N2, indicating that highly reactive species are generated that can further combust with excess oxygen. Finally, reaction products from either nPS-NaClO4 composites or nPS alone combusted with only high pressure O2 (400 psig) gas as an oxidizer are captured in a calorimeter bomb. The products in both cases are similar and verified by transmission electron microscopy (TEM) to include nano- to micrometer scale SiOx particles. This work highlights the complex oxidation mechanism of nPS composites and demonstrates the ability to use a solid state reaction to create a secondary gas phase combustion. PMID- 26501941 TI - Practice-Based Research: Another Pathway for Closing the Research-Practice Gap. AB - PURPOSE: Practice-based research is proposed as an additional way to bridge the divide between research and practice. METHOD: The article compares the traditional, laboratory-based research with research that is generated from practice: practice-based research. The defining features of each are described, with an emphasis on contrasting internal and external validity. Retrospective and prospective practice-based studies are described. Guidelines for designing a retrospective study are provided along with a specific example from practice focusing on social communication learning. Last, the authors discuss the value of information generated from practice-based research for contributing to the knowledge base of not only a practice, but also a discipline. CONCLUSION: The argument is made that approaching research from more than one perspective is necessary for ultimately improving the quality of client and patient care. Practice-based research acknowledges the value of understanding clinical decision making in everyday contexts as an important complement to evidence generated in laboratories. This article is intended to invigorate interest in the uniqueness of practice-based research as a way of encouraging the talents of researchers and practitioners as they work together to gather evidence for improving the lives of individuals with communication disorders. PMID- 26501942 TI - Measuring the Efficacy and Value of Urothelial Cancer Urinary Biomarkers. PMID- 26501943 TI - Evaluation of Occupational and Environmental Factors in the Assessment of Chronic Cough in Adults: A Systematic Review. AB - BACKGROUND: Several recent cough guidelines have advised consideration of occupational or environmental causes for chronic cough, but it is unclear how frequently this recommendation has been routinely applied. Therefore, we undertook a systematic review to address this aspect. METHODS: Cough guidelines and protocols were reviewed to identify recommendations for assessment of occupational and environmental aspects of chronic cough. The systematic search previously used to identify intervention fidelity to the use of protocols for diagnosis and management of chronic cough in adults was used for this review after extension to June 2015. PubMed, Scopus, and the Cochrane Library were searched using the same search terms and inclusion criteria as previously. Papers that met our criteria were then reviewed to identify methods used to assess occupational and environmental aspects of chronic cough and the outcomes of these assessments. RESULTS: Among the 10 general chronic cough guidelines and protocols identified, only the three published since 2006 included details advising detailed occupational and environmental assessments. One additional cough statement focused entirely on occupational cough. Of the 28 cohort studies of patients with chronic cough that specifically noted that they followed guidelines or protocols, none provided details of occupational and environmental assessments. CONCLUSIONS: Despite published recommendations, it is not apparent that occupational and environmental causes for chronic cough are addressed in detail during assessments of patients with chronic cough. This leaves open to speculation whether lack of recognition of an occupational cause may delay important preventive measures, put additional workers at risk, and/or be the reason why a chronic cough may remain unexplained. PMID- 26501944 TI - Use of Protamine for Anticoagulation During Carotid Endarterectomy: A Meta analysis. AB - IMPORTANCE: Protamine sulfate can be administered at the conclusion of carotid endarterectomy (CEA) to reverse the anticoagulant effects of heparin and to limit the risk for postoperative bleeding. Protamine use remains controversial owing to concern for increased thrombotic complications with its use. OBJECTIVE: To review the evidence for and against protamine use, both in its association with increased thrombotic complications and with decreased bleeding. DATA SOURCES: We searched Medline (1946-2014), EMBASE (1966-2014), Cochrane Library (1972-2014), clinical trial registries (World Health Organization International Clinical Trials Registry and clinicaltrials.gov), and abstracts from conferences of the Society of Vascular Surgery (2002-2014) and American Heart Association Scientific Sessions (1980-2014) in November 2014. No language restrictions were applied. STUDY SELECTION: We included clinical trials and observational studies comparing reversal of heparin with protamine sulfate vs no reversal in patients undergoing carotid revascularization and reporting stroke during hospitalization. Of 360 records screened, 12 studies (3%) of CEA were eligible for data pooling. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted data and assessed quality. Random-effects models were used to summarize relative risks (RRs). MAIN OUTCOME AND MEASURE: Stroke after CEA. RESULTS: We included 12 observational studies involving 10,621 patients in the meta-analysis. Event rates did not differ significantly between patients who received protamine vs those who did not for the following outcomes: stroke (RR, 0.84; 95% CI, 0.55-1.29; I(2) = 15%; 9 studies), myocardial infarction (RR, 0.89; 95% CI, 0.53-1.51; I(2) = 0%; 3 studies), or mortality (RR, 0.9, 95% CI, 0.62-1.29; I(2) = 0%; 7 studies). The use of protamine was associated with a significant decrease in major bleeding complications requiring reoperation (RR, 0.57; 95% CI, 0.39-0.84; I(2) = 32%; 10 studies). CONCLUSIONS AND RELEVANCE: Based on available evidence, the use of protamine following CEA is associated with a reduction in bleeding complications, without increasing major thrombotic outcomes, including stroke, myocardial infarction, or death. PMID- 26501945 TI - Effectiveness of a Statewide Abusive Head Trauma Prevention Program in North Carolina. AB - IMPORTANCE: Abusive head trauma (AHT) is a serious condition, with an incidence of approximately 30 cases per 100,000 person-years in the first year of life. OBJECTIVE: To assess the effectiveness of a statewide universal AHT prevention program. DESIGN, SETTING, AND PARTICIPANTS: In total, 88.29% of parents of newborns (n = 405 060) in North Carolina received the intervention (June 1, 2009, to September 30, 2012). A comparison of preintervention and postintervention was performed using nurse advice line telephone calls regarding infant crying (January 1, 2005, to December 31, 2010). A difference-in-difference analysis compared AHT rates in the prevention program state with those of other states before and after the implementation of the program (January 1, 2000, to December 31, 2011). INTERVENTION: The Period of PURPLE Crying intervention, developed by the National Center on Shaken Baby Syndrome, was delivered by nurse-provided education, a DVD, and a booklet, with reinforcement by primary care practices and a media campaign. MAIN OUTCOMES AND MEASURES: Changes in proportions of telephone calls for crying concerns to a nurse advice line and in AHT rates per 100,000 infants after the intervention (June 1, 2009, to September 30, 2011) in the first year of life using hospital discharge data for January 1, 2000, to December 31, 2011. RESULTS: In the 2 years after implementation of the intervention, parental telephone calls to the nurse advice line for crying declined by 20% for children younger than 3 months (rate ratio, 0.80; 95% CI, 0.73-0.87; P < .001) and by 12% for children 3 to 12 months old (rate ratio, 0.88; 95% CI, 0.78-0.99; P = .03). No reduction in state-level AHT rates was observed, with mean rates of 34.01 person-years before the intervention and 36.04 person-years after the intervention. A difference-in-difference analysis from January 1, 2000, to December 31, 2011, controlling for economic indicators, indicated that the intervention did not have a statistically significant effect on AHT rates (beta coefficient, -1.42; 95% CI, -13.31 to 10.45). CONCLUSIONS AND RELEVANCE: The Period of PURPLE Crying intervention was associated with a reduction in telephone calls to a nurse advice line. The study found no reduction in AHT rates over time in North Carolina relative to other states. Consequently, while this observational study was feasible and supported the program effectiveness in part, further programmatic efforts and evaluation are needed to demonstrate an effect on AHT rates. PMID- 26501951 TI - A comparison of genetically matched cell lines reveals the equivalence of human iPSCs and ESCs. AB - The equivalence of human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) remains controversial. Here we use genetically matched hESC and hiPSC lines to assess the contribution of cellular origin (hESC vs. hiPSC), the Sendai virus (SeV) reprogramming method and genetic background to transcriptional and DNA methylation patterns while controlling for cell line clonality and sex. We find that transcriptional and epigenetic variation originating from genetic background dominates over variation due to cellular origin or SeV infection. Moreover, the 49 differentially expressed genes we detect between genetically matched hESCs and hiPSCs neither predict functional outcome nor distinguish an independently derived, larger set of unmatched hESC and hiPSC lines. We conclude that hESCs and hiPSCs are molecularly and functionally equivalent and cannot be distinguished by a consistent gene expression signature. Our data further imply that genetic background variation is a major confounding factor for transcriptional and epigenetic comparisons of pluripotent cell lines, explaining some of the previously observed differences between genetically unmatched hESCs and hiPSCs. PMID- 26501952 TI - A qPCR ScoreCard quantifies the differentiation potential of human pluripotent stem cells. AB - Research on human pluripotent stem cells has been hampered by the lack of a standardized, quantitative, scalable assay of pluripotency. We previously described an assay called ScoreCard that used gene expression signatures to quantify differentiation efficiency. Here we report an improved version of the assay based on qPCR that enables faster, more quantitative assessment of functional pluripotency. We provide an in-depth characterization of the revised signature panel (commercially available as the TaqMan hPSC Scorecard Assay) through embryoid body and directed differentiation experiments as well as a detailed comparison to the teratoma assay. We further show that the improved ScoreCard enables a wider range of applications, such as screening of small molecules, genetic perturbations and assessment of culture conditions. Our approach can be extended beyond stem cell applications to characterize and assess the utility of other cell types and lineages. PMID- 26501953 TI - Long-term culture and expansion of primary human hepatocytes. AB - Hepatocytes have a critical role in metabolism, but their study is limited by the inability to expand primary hepatocytes in vitro while maintaining proliferative capacity and metabolic function. Here we describe the oncostatin M (OSM) dependent expansion of primary human hepatocytes by low expression of the human papilloma virus (HPV) genes E6 and E7 coupled with inhibition of epithelial-to mesenchymal transition. We show that E6 and E7 expression upregulates the OSM receptor gp130 and that OSM stimulation induces hepatocytes to expand for up to 40 population doublings, producing 1013 to 1016 cells from a single human hepatocyte isolate. OSM removal induces differentiation into metabolically functional, polarized hepatocytes with functional bile canaliculi. Differentiated hepatocytes show transcriptional and toxicity profiles and cytochrome P450 induction similar to those of primary human hepatocytes. Replication and infectivity of hepatitis C virus (HCV) in differentiated hepatocytes are similar to those of Huh7.5.1 human hepatoma cells. These results offer a means of expanding human hepatocytes of different genetic backgrounds for research, clinical applications and pharmaceutical development. PMID- 26501956 TI - Lewis Acid Catalyzed Tandem Polycyclization of Internal Alkynols and Vinyl Azides. AB - A novel Lewis acid catalyzed tandem cyclization reaction of internal alkynols and vinyl azides has been achieved to afford a series of products containing a pyran based indeno[1,2-c]isochromene scaffold in moderate to high yields. This tandem polycyclization protocol provides a straightforward entry to construct the complex polycyclic skeleton through cycloisomerization, formal [4 + 2] cycloaddition, and an elimination process. PMID- 26501954 TI - In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity. AB - The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer-TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer-TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer-TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens. PMID- 26501955 TI - Comprehensive characterization of the Published Kinase Inhibitor Set. AB - Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome. PMID- 26501957 TI - Impact of Heavy Metals on Transcriptional and Physiological Activity of Nitrifying Bacteria. AB - Heavy metals can inhibit nitrification, a key process for nitrogen removal in wastewater treatment. The transcriptional responses of amoA, hao, nirK, and norB were measured in conjunction with specific oxygen uptake rate (sOUR) for nitrifying enrichment cultures exposed to different metals (Ni(II), Zn(II), Cd(II), and Pb(II)). There was significant decrease in sOUR with increasing concentrations for Ni(II) (0.03-3 mg/L), Zn(II) (0.1-10 mg/L), and Cd(II) (0.03-1 mg/L) (p < 0.05). However, no considerable changes in sOUR were observed with Pb(II) (1-100 mg/L), except at a dosage of 1000 mg/L causing 84% inhibition. Based on RT-qPCR data, the transcript levels of amoA and hao decreased when exposed to Ni(II) dosages. Slight up-regulation of amoA, hao, and nirK (0.5-1.5 fold) occurred after exposure to 0.3-3 mg/L Zn(II), although their expression decreased for 10 mg/L Zn(II). With the exception of 1000 mg/L Pb(II), stimulation of all genes occurred on Cd(II) and Pb(II) exposure. While overall the results show that RNA-based function-specific assays can be used as potential surrogates for measuring nitrification activity, the degree of inhibition inferred from sOUR and gene transcription is different. We suggest that variations in transcription of functional genes may supplement sOUR based assays as early warning indicators of upsets in nitrification. PMID- 26501959 TI - Enzymatic Vitrectomy and Pharmacologic Vitreodynamics. AB - The field of vitreoretinal surgery has evolved substantially over the last several decades. Scientific advances have improved our understanding of disease pathophysiology, and new surgical adjuncts and techniques have decreased surgical time and improved patient outcomes. Pharmacologic agents have recently been developed for intraocular use in order to enhance vitreous removal and even as a nonsurgical treatment for pathology due to an abnormal vitreoretinal interface. Plasmin can successfully cause vitreous liquefaction and induce a posterior vitreous detachment. Additionally, ocriplasmin has been approved for symptomatic vitreomacular adhesion and others appear to be promising for pharmacologic manipulation of the vitreous. The ability to induce vitreous liquefaction and a complete posterior vitreous detachment (PVD) with a single intravitreal injection has potential implications for the management of multiple vitreoretinopathies. Enzymatic vitrectomy may help to reduce vitreous viscosity, thereby facilitating removal during vitrectomy and reducing surgical time, especially when using smaller-gauge vitrectomy instruments. The induction of a PVD also has the potential to reduce intraoperative complications. As we improve our understanding of the molecular flux in the vitreous cavity, pharmacologic vitreodynamics will likely become more important as it may allow for improved manipulation of intravitreal molecules. PMID- 26501958 TI - Live Fast, Die Young: Experimental Evidence of Population Extinction Risk due to Climate Change. AB - Evidence has accumulated in recent decades on the drastic impact of climate change on biodiversity. Warming temperatures have induced changes in species physiology, phenology, and have decreased body size. Such modifications can impact population dynamics and could lead to changes in life cycle and demography. More specifically, conceptual frameworks predict that global warming will severely threaten tropical ectotherms while temperate ectotherms should resist or even benefit from higher temperatures. However, experimental studies measuring the impacts of future warming trends on temperate ectotherms' life cycle and population persistence are lacking. Here we investigate the impacts of future climates on a model vertebrate ectotherm species using a large-scale warming experiment. We manipulated climatic conditions in 18 seminatural populations over two years to obtain a present climate treatment and a warm climate treatment matching IPCC predictions for future climate. Warmer temperatures caused a faster body growth, an earlier reproductive onset, and an increased voltinism, leading to a highly accelerated life cycle but also to a decrease in adult survival. A matrix population model predicts that warm climate populations in our experiment should go extinct in around 20 y. Comparing our experimental climatic conditions to conditions encountered by populations across Europe, we suggest that warming climates should threaten a significant number of populations at the southern range of the distribution. Our findings stress the importance of experimental approaches on the entire life cycle to more accurately predict population and species persistence in future climates. PMID- 26501960 TI - Wedding Cake Growth Mechanism in One-Dimensional and Two-Dimensional Nanostructure Evolution. AB - The kinetic processes and atomistic mechanisms in nanostructure growth are of fundamental interest to nanomaterial syntheses with precisely controlled morphology and functionality. By programming deposition conditions at time domain, we observed the wedding cake growth mechanism in the formation of 1D and 2D ZnO nanostructures. Within a narrow growth window, the surfaces of the 1D and 2D structures were covered with a unique concentric terrace feature. This mechanism was further validated by comparing the characteristic growth rates to the screw dislocation-driven model. An interesting 1D to 2D morphology transition was also found during the wedding cake growth, when the adatoms overcome the Ehrlich-Schwoebel (ES) barrier along the edge of the top crystal facet triggered by lowering the supersaturation. The wedding cake model might be a general growth mechanism for flat-tipped nanowires that do not possess any dislocations. This study enriches our understanding on the fundamental kinetics of nanostructured crystal growth and provides a transformative strategy to achieve rational design and control of nanoscale geometry. PMID- 26501961 TI - An unusual variant of the abducens nerve duplication with two nerve trunks merging within the orbit: a case report with comments on developmental background. AB - This study reports the first case of abducens nerve duplication along its entire intracranial course, ending within the orbit. A distinct abducens nerve duplication reaching the common tendinous ring (annulus of Zinn), as well as another split within the intraconal segment of the nerve have been revealed. Additionally, two groups (superior and inferior) of abducens nerve sub-branches to the lateral rectus muscle were visualised using Sihler's stain. The analysed anatomical variation has never been reported before and it seems to be in the middle of the spectrum between the cases of duplication occurring only within the intracranial segments of the abducens nerve found in the literature and those continuing throughout the whole course of the nerve. Abducens nerve duplication may be treated as a relic of early stages of ontogenesis. Such a variant might result from alternative developmental pathways in which axons of the abducens nerve, specific for a given segment of the lateral rectus muscle, run separately at some stage, instead of forming a single stem. PMID- 26501963 TI - Enhancing the High-Voltage Cycling Performance of LiNi(0.5)Mn(0.3)Co(0.2)O2 by Retarding Its Interfacial Reaction with an Electrolyte by Atomic-Layer-Deposited Al2O3. AB - High-voltage (>4.3 V) operation of LiNi(x)Mn(y)Co(z)O2 (NMC; 0 <= x, y, z < 1) for high capacity has become a new challenge for next-generation lithium-ion batteries because of the rapid capacity degradation over cycling. In this work, we investigate the performance of LiNi(0.5)Mn(0.3)Co(0.2)O2 (NMC532) electrodes with and without an atomic-layer-deposited (ALD) Al2O3 layer for charging/discharging in the range from 3.0 to 4.5 V (high voltage). The results of the electrochemical measurements show that the cells with ALD Al2O3-coated NMC532 electrodes have much enhanced cycling stability. The mechanism was investigated by using X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, and electrochemical methods. We find that the ultrathin ALD Al2O3 film can reduce the interface resistance of lithium-ion diffusion and enhance the surface stability of NMC532 by retarding the reactions at NMC532/electrolyte interfaces for preventing the formation of a new microstructure rock-salt phase NiO around the NMC532 surfaces. PMID- 26501962 TI - DNA methylation of RAMP1 gene in migraine: an exploratory analysis. AB - BACKGROUND: Receptor activity modifying protein 1(RAMP1) is a key receptor subunit of calcitonin gene related peptide (CGRP) playing a critical role in migraine. But variations in RAMP1 gene have not been found to link with migraine. Still it is elusive that DNA methylation at RAMP1 promoter is associated with migraine. METHODS: A total of 51 blood DNA samples from 26 patients with migraine and 25 matched healthy controls were collected, extracted and treated with bisulfate. Subsequently DNA methylation levels at RAMP1 promoter region were measured using Sequenom Mass ARRAY systems. RESULTS: Among 13 detected CpG sites or units at RAMP1 promoter region, there were no significant differences between the migraine and control groups, but indicating a low methylation trend overall in migraine group (total average methylation level: 8.41 % +/-1.92 % vs. 9.90 % +/- 3.88 %, p = 0.197). Stratification analysis showed that methylation level at (+25, +27, +31, related to the transcription start site) CpG unit was higher in migraineurs with migraine family history compared to those without (13.92 % +/- 5.97 % vs. 8.77 % +/- 6.61 %, p = 0.034), and methylation level at (+89, +94, +96) CpG unit was lower in migraine female than that in healthy female (2.18 % +/ 1.91 % vs. 5.85 % +/- 5.41 %, p = 0.02). For female with methylation level at (+89, +94, +96) CpG unit below 3.50 %, the probability of being a migraine patient was significantly higher than those with methylation level above the threshold (OR: 7.313; 95%CI: 1.439-37.164). CONCLUSIONS: This study provides the first evidence that DNA methylation at RAMP1 promoter might play a role in migraine. A low methylation trend overall was presented in migraine subjects, and two CpG units were observed to link with positive migraine family history and female migraine, respectively. Lower methlytion level at (+89, +94, +96) CpG unit may be a risk of migraine in females. PMID- 26501964 TI - Estimating the Counterfactual Impact of Conservation Programs on Land Cover Outcomes: The Role of Matching and Panel Regression Techniques. AB - Deforestation and conversion of native habitats continues to be the leading driver of biodiversity and ecosystem service loss. A number of conservation policies and programs are implemented--from protected areas to payments for ecosystem services (PES)--to deter these losses. Currently, empirical evidence on whether these approaches stop or slow land cover change is lacking, but there is increasing interest in conducting rigorous, counterfactual impact evaluations, especially for many new conservation approaches, such as PES and REDD, which emphasize additionality. In addition, several new, globally available and free high-resolution remote sensing datasets have increased the ease of carrying out an impact evaluation on land cover change outcomes. While the number of conservation evaluations utilizing 'matching' to construct a valid control group is increasing, the majority of these studies use simple differences in means or linear cross-sectional regression to estimate the impact of the conservation program using this matched sample, with relatively few utilizing fixed effects panel methods--an alternative estimation method that relies on temporal variation in the data. In this paper we compare the advantages and limitations of (1) matching to construct the control group combined with differences in means and cross-sectional regression, which control for observable forms of bias in program evaluation, to (2) fixed effects panel methods, which control for observable and time-invariant unobservable forms of bias, with and without matching to create the control group. We then use these four approaches to estimate forest cover outcomes for two conservation programs: a PES program in Northeastern Ecuador and strict protected areas in European Russia. In the Russia case we find statistically significant differences across estimators--due to the presence of unobservable bias--that lead to differences in conclusions about effectiveness. The Ecuador case illustrates that if time-invariant unobservables are not present, matching combined with differences in means or cross-sectional regression leads to similar estimates of program effectiveness as matching combined with fixed effects panel regression. These results highlight the importance of considering observable and unobservable forms of bias and the methodological assumptions across estimators when designing an impact evaluation of conservation programs. PMID- 26501965 TI - Hidden Markov modelling of intra-snore episode behavior of acoustic characteristics of obstructive sleep apnea patients. AB - Obstructive sleep apnea (OSA) is a breathing disorder that can cause serious medical consequences. It is caused by full (apnea) or partial (hypopnea) obstructions of the upper airway during sleep. The gold standard for diagnosis of OSA is the polysomnography (PSG). The main measure for OSA diagnosis is the apnea hypopnea index (AHI). However, the AHI is a time averaged summary measure of vast amounts of information gathered in an overnight PSG study. It cannot capture the dynamic characteristics associated with apnea/hypopnea events and their overnight distribution. The dynamic characteristics of apnea/hypopnea events are affected by the structural and functional characteristics of the upper airway. The upper airway characteristics also affect the upper airway collapsibility. These effects are manifested in snoring sounds generated from the vibrations of upper airway structures which are then modified by the upper airway geometric and physical characteristics. Hence, it is highly likely that the acoustical behavior of snoring is affected by the upper airway structural and functional characteristics. In the current work, we propose a novel method to model the intra-snore episode behavior of the acoustic characteristics of snoring sounds which can indirectly describe the instantaneous and temporal dynamics of the upper airway. We model the intra-snore episode acoustical behavior by using hidden Markov models (HMMs) with Mel frequency cepstral coefficients. Assuming significant differences in the anatomical and physiological upper airway configurations between low-AHI and high-AHI subjects, we defined different snorer groups with respect to AHI thresholds 15 and 30 and also developed HMM-based classifiers to classify snore episodes into those groups. We also define a measure called instantaneous apneaness score (IAS) in terms of the log likelihoods produced by respective HMMs. IAS indicates the degree of class membership of each episode to one of the predefined groups as well as the instantaneous OSA severity. We then assigned each patient to an overall AHI band based on the majority vote of each episode of snoring. The proposed method has a diagnostic sensitivity and specificity between 87-91%. PMID- 26501967 TI - Assessing Patient-Reported Outcomes Following Orthognathic Surgery and Osseous Genioplasty. AB - Primary outcomes for orthognathic surgery and genioplasty patients include satisfaction with appearance, improved motor function, and enhanced quality of life. The goal of this study was to assess outcomes among patients undergoing these procedures, and to highlight the potential use of FACE-Q instrument for use in patients with dentofacial deformities. A total of 56 patients presenting for orthognathic surgery and/or osseous genioplasty completed the FACE-Q during preoperative and/or at postoperative visits. FACE-Q scores increased following surgery in satisfaction with facial appearance overall (+24.5, P < 0.01), satisfaction with lower face and jawline (+40.7, P < 0.01), and in all satisfaction with chin items (profile, prominence, shape, and overall). Patients also demonstrated increased social confidence (+8.9, P = 0.29). There was no improvement in psychologic well-being (-0.8, P = 0.92). All 3 surgical groups of patients experienced gains in satisfaction with appearance following surgery. Patients who underwent orthognathic surgery either alone or in combination with genioplasty demonstrated statistically significant improvements in satisfaction with facial appearance overall (P < 0.01 for both groups), whereas patients who underwent genioplasty alone did not (P = 0.13). In addition, patients who underwent orthognathic surgery combined with genioplasty demonstrated greater improvement in satisfaction with chin than patients who underwent genioplasty alone. In conclusion, patients who underwent orthognathic surgery and/or genioplasty demonstrated improvement in appearance and social confidence. The use of this model supports the successful outcomes possible for patients undergoing these procedures. PMID- 26501966 TI - Genomics Virtual Laboratory: A Practical Bioinformatics Workbench for the Cloud. AB - BACKGROUND: Analyzing high throughput genomics data is a complex and compute intensive task, generally requiring numerous software tools and large reference data sets, tied together in successive stages of data transformation and visualisation. A computational platform enabling best practice genomics analysis ideally meets a number of requirements, including: a wide range of analysis and visualisation tools, closely linked to large user and reference data sets; workflow platform(s) enabling accessible, reproducible, portable analyses, through a flexible set of interfaces; highly available, scalable computational resources; and flexibility and versatility in the use of these resources to meet demands and expertise of a variety of users. Access to an appropriate computational platform can be a significant barrier to researchers, as establishing such a platform requires a large upfront investment in hardware, experience, and expertise. RESULTS: We designed and implemented the Genomics Virtual Laboratory (GVL) as a middleware layer of machine images, cloud management tools, and online services that enable researchers to build arbitrarily sized compute clusters on demand, pre-populated with fully configured bioinformatics tools, reference datasets and workflow and visualisation options. The platform is flexible in that users can conduct analyses through web-based (Galaxy, RStudio, IPython Notebook) or command-line interfaces, and add/remove compute nodes and data resources as required. Best-practice tutorials and protocols provide a path from introductory training to practice. The GVL is available on the OpenStack-based Australian Research Cloud (http://nectar.org.au) and the Amazon Web Services cloud. The principles, implementation and build process are designed to be cloud-agnostic. CONCLUSIONS: This paper provides a blueprint for the design and implementation of a cloud-based Genomics Virtual Laboratory. We discuss scope, design considerations and technical and logistical constraints, and explore the value added to the research community through the suite of services and resources provided by our implementation. PMID- 26501968 TI - A Study of the Association Between Sleep Bruxism, Low Quality of Sleep, and Degenerative Changes of the Temporomandibular Joint. AB - The aim of this study was to evaluate the presence of degenerative bone changes of the temporomandibular joint (TMJ) in individuals suffering from sleep bruxism (SB), associating these characteristics with the quality of sleep. For this, we followed the International Classification of Sleep Disorders for the diagnosis of SB, in addition to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) for the classification of TMD and cone beam computed tomography. It was found that 97.7% of the individuals with bruxism had at least 1 RDC/TMD group III diagnosis, 75.6% of the subjects considered their sleep quality as poor, and the largest group (23%) had centric bruxism. There was no significant association between the pattern of sleep quality (P = 0.36), the type of SB (P = 0.277), and the presence of degenerative changes of the TMJ. Regardless of the quality of sleep and the type of bruxism presented, the prevalence of degenerative bone disorders was high (67%) among women with a mean age of 46 years and a clinical diagnosis of SB. PMID- 26501969 TI - The Affordable Care Act: Opportunities and Challenges for Physicians. AB - The Affordable Care Act (ACA) will affect many aspects of health care across the nation, presenting both opportunities and challenges. Physicians who have a solid understanding of the recent industry trends and the role they will be playing in the post-ACA world will be able to better adapt to the new environment. This article analyzes the implications of the health care reform for physicians and offers recommendations on how to turn challenges into opportunities. PMID- 26501970 TI - Residents' Perceptions of Plastic Surgeons as Craniofacial Surgery Specialists. AB - OBJECTIVE: To assess residents' perceptions of plastic surgeons as craniofacial surgery specialists in Brazil. METHODS: Brazilian residents were asked to choose 1 or 2 specialists that they perceived to be an expert for 14 craniofacial surgery-related scenarios. Both an overall analysis (all 14 scenarios) and subanalysis (each scenario separately) were performed. Response patterns were distributed as "plastic surgeons alone," "plastic surgeons combined with other specialists," or "without plastic surgeons." RESULTS: Overall, plastic surgeons were chosen more (all P < 0.05) as experts than all other specialists. The subanalysis showed that plastic surgeons were chosen more (all P < 0.05) as experts than other specialists in 50% of craniofacial surgery-related scenarios and also demonstrated that "plastic surgeons alone" and "without plastic surgeons" were selected more (all P < 0.05) than other response patterns in 31.71% and 42.86% of scenarios, respectively. General surgery residents and male residents chose more (all P < 0.05) plastic surgeons as experts than their peers. CONCLUSION: Residents' perceptions of plastic surgeons as craniofacial surgery specialists are limited in Brazil. PMID- 26501971 TI - Effects of Obstructive Sleep Apnea in Children as a Result of Adenoid and/or Adenotonsillar Hypertrophy on Maternal Psychologic Status. AB - The authors aimed to evaluate the effects of obstructive sleep apnea in children as a result of adenoid and/or adenotonsillar hypertrophy on maternal psychologic status. The study sample comprised the mothers of 66 children aged 3 to 15 years (mean age: 7.55 +/- 2.94 years) who were scheduled to undergo curette adenoidectomy or adenotonsillectomy because of airway obstruction. The mothers completed the 14-item Hospital Anxiety and Depression Scale (HADS), 20-item State Trait Anxiety Inventory-1 (STAI-1), and 20-item State-Trait Anxiety Inventory-2 (STAI-2) questionnaires before the operation and 10 days afterwards. Mothers who were under psychiatric treatment or declined to fill the questionnaires were excluded from the study. The results obtained postoperatively by day 10, when all the children had considerable improvement in their breathing, were analyzed as control data. The mean postoperative HAD-A and HAD-D scores of the mothers were significantly lower than the mean preoperative scores (P < 0.001). Mothers' mean STAI-1 and STAI-2 scores were also significantly lower postoperatively (P < 0.001). Pediatric adenoidectomy or adenotonsillectomy to relieve airway obstruction has a beneficial effect not only on the health of pediatric patients but also on the psychologic status of their mothers. PMID- 26501972 TI - Evaluation of Relationship Between Body Dysmorphic Disorder and Self-Esteem in Rhinoplasty Candidates. AB - AIM: To investigate the relationship between body dysmorphic syndrome and self esteem in rhinoplasty candidates. RESULTS: A negative statistical correlation was evident between Rosenberg Self-Esteem Scale (RSES) and Body Dysmorphic Disorder Examination-Self Report (BDDE-SR) scores. In terms of responses to the first Body Dysmorphic Disorder Questionnaire (BDDQ) question, which focuses on general attitude toward body dysmorphic syndrome, the average RSES "YES" score was significantly less than the "NO" score. No significant differences appeared between RSES scores and scores for the 4th subgroup of BDDQ questions (subgroups A, B, and C; these questions explore how much time is spent daily on maintenance of bodily appearance). However, significant differences appeared between scores for the 4th subgroup of BDDQ questions and BDDE-SR scores. The average BDD-SR score of subgroup A (less than 1 hour spent on bodily maintenance) was significantly lower than those of group B (1-3 hours) and group C (more than 3 hours). However, no significant differences appeared in average BDD-SR scores between subgroups B and C. MATERIALS AND METHODS: In this prospective study, 56 patients (31 females and 25 males) were evaluated preoperatively using the BDDQ, the BDDE-SR, and the RSES. Patients younger than 15 years and those with deformities caused by trauma were excluded. CONCLUSIONS: Rhinoplasty candidates had higher levels of body dysmorphic disorder (BDD). Although patients with low RSES scores were more likely to have BDD, rhinoplasty candidates were not notably deficient in self-esteem. However, in rhinoplasty candidates with low RSES scores, the frequency of BDD was elevated. Therefore, the authors suggest that rhinoplasty candidates with low RSES scores should be investigated carefully in terms of BDD. PMID- 26501973 TI - Microvascular Decompression for Trigeminal Neuralgia: Zone Exploration and Decompression Techniques. AB - OBJECTIVE: The aim of this study is to introduce zone exploration of the trigeminal nerve and decompression techniques for different types of vasculars. METHODS: The trigeminal nerve was sectioned into 5 zones. Zone 1, 2, 3, 4 was located at the rostral, caudal, ventral, and dorsal part of the nerve root entry zone (REZ) respectively, and zone 5 was located at the distal of the nerve root. This study contained 86 patients with trigeminal neuralgia underwent microvascular decompression. Every zone was exposed through preoperative imaging. During the operation, offending vessels were explored from zone 1 to zone 5, and different decompression techniques were used for different types of vessels. RESULTS: Through zone exploration, the sensitivity of preoperative imaging was 96.5% and specificity was 100%. Location of the neurovascular conflict was in the zone 1 in 53.5% of the patients, zone 2 in 32.6%, zone 3 in 45.3%, zone 4 in 29.1%, and zone 5 in 34.9%. In total, 2 zones were both involved in 59.3%, and 3 zones were involved in 18.6%. All offending arteries were moved away and interposed with Teflon sponge. Offending veins of 11 patients were too small to interpose, and coagulated and cut was adopted. The other offending veins were interposed with wet gelatin and Teflon sponge, respectively. CONCLUSIONS: Zone exploration is helpful in finding offending vessels and adequate decompression can be achieved by choosing different methods according to different types of offending vessels. PMID- 26501974 TI - Development of Technical Skills: Education, Simulation, and Maintenance of Certification. AB - The goal of this article is to provide a focused overview of technical skills education inside the operating room (OR), opportunities for learning outside of the OR (with a focus on simulation), and methods for measuring technical skills. In addition, the authors review the role of maintenance of certification in continuing education and quality improvement and consider the role that simulation plays in this process. The perspectives on teaching in the OR of both residents and faculty going into the case affect the learning environment, and preoperative interactions between attendings and residents to establish learning needs and goals are important. Furthermore, in regards to attending surgeons improving their skills, interaction with more experienced peers and feedback during and after a procedure can be beneficial. Simulation is increasingly being utilized as an education tool outside of the OR. Training in plastic surgery is poised to exploit simulation in multiple technical areas. There is potential to utilize these simulation environments to collect real-time data, such as motion, visual focus, and pressure. How to incorporate technical skill evaluation results in ways that are most beneficial for learning should be the focus of future research and curriculum development. Finally, simulation could be better utilized as a mechanism for both self and peer evaluation and assessment for continuing education and quality improvement. Professional development for faculty and surgery trainees on how to engage with simulation for teaching and learning and how to translate these experiences into improving patient care will be required. PMID- 26501975 TI - Reconstruction of Rare Skull Metastases Using Free Latissimus Dorsi Flap and the Role of Preoperative Embolization in Hypervascular Skull Tumors. AB - Metastatic tumors are the most common cranial neoplasms in adults. Skull metastases from rare primary tumors, such as cholangiocarcinoma or pancreatic neuroendocrine tumor, are extremely uncommon and rarely reported. Given the scarcity and variation of these rare skull metastases, treatments and outcomes of such patients are of interest to treating surgeons. The authors describe the treatment algorithm, course, and outcomes of 2 patients with rare gastrointestinal skull metastases. The first patient had intrahepatic cholangiocarcinoma metastatic to the skull, while the second patient developed a solitary skull metastasis secondary to a pancreatic neuroendocrine tumor. As part of this report, the authors include a literature review of rare skull metastases as well as the treatment of these 2 patients. Both the patients ultimately underwent successful resection of the tumor for relief of their clinical symptoms. Wide resections in both patients necessitated reconstruction using a free latissimus dorsi muscle flap in both the patients. Preoperative embolization of the hypervascular cholangiocarcinoma skull metastasis was performed prior to resection in the first patient. To date, there have been only 4 such reports of skull metastases from intrahepatic cholangiocarcinoma and limited reported cases of isolated skull metastases from a pancreatic neuroendocrine tumor.In patients with large or numerous skull metastasis from rare primary tumors, surgical resection should be considered for symptomatic improvement. In cases of hypervascular lesions, preoperative embolization can be considered to decrease the intraoperative bleeding. Free tissue transfers using myocutaneous flaps such as latissimus dorsi help in obliterating dead space, and creating a healthy soft tissue envelope to withstand postoperative radiation treatment. In addition, a chimeric flap can be designed to include additional muscle or soft tissue to obliterate and exclude the sinus cavities. PMID- 26501976 TI - Feedback in Plastic and Reconstructive Surgery Education: Past, Present, and Future. AB - Education is to be provided efficiently and effectively according to guidelines in the United States by the Accreditation Council for Graduate Medical Education as core competencies and in Canada by the Royal College according to the CanMEDS framework. This article defines formative feedback, reviews the currently available validated feedback tools, and describes the future use of technology to enhance feedback in plastic surgery education. PMID- 26501977 TI - Errors in Derivation Data and Validation Data. PMID- 26501978 TI - Management of Thrombocytopenia in Chronic Liver Disease: Focus on Pharmacotherapeutic Strategies. AB - Thrombocytopenia (platelet count <150 * 10(9)/L) often complicates chronic liver disease, impeding optimal management of these patients. The prevalence of this manifestation ranges from 6% among non-cirrhotic patients with chronic liver disease to 70% among patients with liver cirrhosis. It has also been shown that the severity of liver disease is associated with both prevalence and level of thrombocytopenia. Its development is often multifactorial, although thrombopoietin is thought to be a major factor. The discovery of and ability to clone thrombopoietin led to new treatment opportunities for this clinical manifestation. This review discusses data on the three most important thrombopoietin receptor agonists: eltrombopag, avatrombopag, and romiplostim. Currently, only eltrombopag is approved for usage among patients with thrombocytopenia and chronic hepatitis C virus infection in order to initiate and maintain interferon-based antiviral treatment. Nevertheless, the optimal management of hematologic abnormalities among patients with chronic liver disease, and its risk for bleeding complications, is still a matter of discussion. Thrombocytopenia definitely contributes to hemostatic defects but is often counterbalanced by the enhanced presence of procoagulant factors. Therefore, a thorough assessment of the patient's risk for thrombotic events is essential when the use of thrombopoietin receptor agonists is considered among patients with chronic liver disease and thrombocytopenia. PMID- 26501979 TI - Intrathecal Analgesia for Chronic Refractory Pain: Current and Future Prospects. AB - The intrathecal drug-delivery system (IDDS) is one mode of infusing analgesic medications directly into the cerebrospinal fluid in close proximity to their site of action. This modality has been employed in patients with refractory pain either due to malignant or non-malignant causes for over 30 years. Unfortunately, and despite the number of years it has been in use, there is still a scarcity of rigorous evidence to guide its integration into clinical practice. Current best evidence is inconclusive as to the comparative effectiveness and harms of the IDDS relative to routine medical care of patients. There are far more systematic reviews than high-quality primary comparative studies of the IDDS vs. conventional pain treatment. Existing clinical practice recommendations are best viewed as expert opinion with competing interests. This article will review the existing literature for indications, contraindications, consensus statements, different technologies, and complications of the IDDS. Although approved analgesics for IDDS delivery are limited to morphine and ziconotide, many other analgesics, alone or in combination, are routinely used in this setting. This review will also focus on the pharmacology, clinical efficacy, and safety of intrathecal medications extensively used in clinical practice; including agents approved, unapproved, and under development. PMID- 26501982 TI - Controlled Therapy Interruption Improves Host Immune Control of Chronic Hepatitis B Virus Infection in HBeAg-Positive Patients. AB - Prolonged viral suppression with oral antiviral drugs allows partial immune reconstitution. Controlled therapy interruption (CTI), by leveraging secondary immune response, proposes further augmentation in chronic hepatitis B virus (HBV) infection. Transient treatment interruptions (TIs) at months 0, 1, and 3 during otherwise continuous oral antiviral therapy allow viremic bursts, simulating autovaccination. Four weekly injections of Hepatitis B Immunoglobulin are given before the second and third TI to simulate prime boosting, which specifically amplifies the immune response. Fourteen patients (10 males; four controls, four HBeAg positive, and six anti-HBe positive) aged 28-46 years were studied. The period between TI and reappearance of viremia, time to relapse (TTR) (weeks) estimated immune control. The other endpoints included reduction in serum HBsAg IU/mL and loss of HBeAg. TTR after the first TI was significantly shorter in HBeAg-positive patients, indicating low baseline immunity. TTR increased significantly after the second and subsequent TI in all four HBeAg-positive patients. One patient persistently lost HBeAg. Mean HBsAg levels fell significantly in three of four patients after the second TI. In contrast, in the anti-HBe-positive group, TTR was unchanged after all three TI. Furthermore, no significant changes in HBsAg levels were detected after the second or subsequent TIs. No significant differences in adverse events were noted between groups. HBeAg-positive patients have low baseline levels of host immune control against HBV. CTI consistently boosts this immunity. CTI did not influence immunity in anti-HBe-positive patients. PMID- 26501981 TI - Calreticulin Mutations in Myeloproliferative Neoplasms: Comparison of Three Diagnostic Methods. AB - Calreticulin (CALR) mutations have recently been reported in 70-84% of JAK2V617F negative myeloproliferative neoplasms (MPN), and this detection has become necessary to improve the diagnosis of MPN. In a large single-centre cohort of 298 patients suffering from Essential Thrombocythemia (ET), the JAK2V617F, CALR and MPL mutations were noted in 179 (60%), 56 (18.5%) and 13 (4.5%) respectively. For the detection of the CALR mutations, three methods were compared in parallel: high-resolution melting-curve analysis (HRM), product-sizing analysis and Sanger sequencing. The sensitivity for the HRM, product-sizing analysis and Sanger sequencing was 96.4%, 98.2% and 89.3% respectively, whereas the specificity was 96.3%, 100% and 100%. In our cohort, the product-sizing analysis was the most sensitive method and was the easiest to interpret, while the HRM was sometimes difficult to interpret. In contrast, when large series of samples were tested, HRM provided results more quickly than did the other methods, which required more time. Finally, the sequencing method, which is the reference method, had the lowest sensitivity but can be used to describe the type of mutation precisely. Altogether, our results suggest that in routine laboratory practice, product sizing analysis is globally similar to HRM for the detection of CALR mutations, and that both may be used as first-line screening tests. If the results are positive, Sanger sequencing can be used to confirm the mutation and to determine its type. Product-sizing analysis provides sensitive and specific results, moreover, with the quantitative measurement of CALR, which might be useful to monitor specific treatments. PMID- 26501983 TI - Formulation and characterization of nanoencapsulated curcumin using sodium caseinate and its incorporation in ice cream. AB - In the present investigation, the preparation and characterization of a curcumin nanoemulsion with milk protein (sodium caseinate) and its incorporation into ice cream were undertaken. Among the different combinations, the most stable formulation was observed using milk fat (8%), medium chain triglycerides (2%), curcumin (0.24%) and sodium caseinate (6%) with a mean particle size of 333.8 +/- 7.18 nm, a zeta potential of -44.1 +/- 0.72 mV and an encapsulation efficiency of 96.9 +/- 0.28%. The effect of different processing conditions (heating, pH and ionic strength) on the particle size distribution and zeta potential of the nanoemulsion was evaluated. During heat treatment, the particle size of the nanoemulsion was increased from 333.8 +/- 7.18 to 351.1 +/- 4.04 nm. The nanoemulsion was destabilized at pH 4.6 and the particle size increased above and below pH 5.0. However, there was a slight increase in the particle size with a change in the ionic concentration. The release kinetics data suggested that in simulated gastro-intestinal digestion, the nanoemulsion was stable against pepsin digestion (a 5.25% release of curcumin), while pancreatic action led to a 16.12% release of curcumin from the nanoemulsion. Finally, our formulation was successfully incorporated into ice cream and the sensory attributes were evaluated. No significant difference was observed in the scores of the sensory attributes between the control and ice cream prepared with a curcumin nanoemulsion. Moreover, the encapsulation efficiency of the curcumin incorporated into the ice cream was 93.7%, which indicates that it can withstand the processing conditions. The findings suggest that ice cream is a suitable dairy product for the delivery of lipophilic bioactive components (curcumin) which can be used for therapeutic purposes. PMID- 26501984 TI - Translating extracellular microRNA into clinical biomarkers for drug-induced toxicity: from high-throughput profiling to validation. AB - Over the past 5 years, extracellular microRNAs (miRNAs) are being vigorously explored as injury biomarkers, including drug-induced cardiotoxicity, hepatotoxicity and nephrotoxicity. Currently, the development of miRNAs as clinical biomarkers has been hindered by the lack of standardization. Therefore, extracellular miRNA-based biomarkers have not been embraced as diagnostic tools. Each platform has its strengths and weaknesses when working with low-input-amount RNA samples from body fluids; the selection of a miRNA quantification approach should be based on the study design. The following review provides a summary of the extracellular miRNA release and stability in body fluids, performances of different miRNA quantification platforms, existing clinical gold standards for drug-induced tissue damage and translation of the miRNA biomarkers from the nonclinical to clinical setting. PMID- 26501985 TI - Preparation of peptide thioesters from naturally occurring sequences using reaction sequence consisting of regioselective S-cyanylation and hydrazinolysis. AB - The vital roles of peptide/protein thioesters in protein chemistry, including chemical or semi-synthesis of proteins, have encouraged studies on the development of methods for the preparation of such chemical units. Biochemical protocols using intein or sortase have proved to be useful in protein chemistry as methods suitable for naturally occurring sequences, including recombinant proteins. Although chemical protocols are potential options for thioester preparation, only a few are applicable to naturally occurring sequences, because standard chemical protocols require an artificial chemical device for producing thioesters. In this context, the chemical preparation of thioesters based on a reaction sequence consisting of regioselective S-cyanylation and hydrazinolysis was investigated. Regioselective S-cyanylation, which is required for cysteine containing thioesters, was achieved with the aid of a zinc-complex formation of a CCHH-type zinc-finger sequence. Free cysteine residues that are not involved in complex formation were selectively protected with a 6-nitroveratryl group followed by S-cyanylation of the zinc-binding cysteine. Hydrazinolysis of the resulting S-cyanopeptide and subsequent photo-removal of the 6-nitroveratryl group yielded the desired peptide hydrazide, which was then converted to the corresponding thioester. The generated thioester was successfully used in N-to-C directed one-pot/sequential native chemical ligation using an N sulfanylethylanilide peptide to give a 64-residue peptide toxin. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 531-546, 2016. PMID- 26501986 TI - Telomerase Reverse Transcriptase (TERT) Gene Variations and Susceptibility of Colorectal Cancer. AB - AIM: Colorectal cancer is the third most common cause of cancer-related mortality. Previous studies demonstrated increased telomerase activity in colorectal cancer tissue and suggested a prognostic value for patients with colorectal carcinoma. Telomerase reverse transcriptase (TERT), one of the main functional subunits of the telomerase, is an important factor in modulating telomerase activity, telomere length, and genomic stability. However, there are few studies that have addressed the association between genetic variation at TERT and the risk of colorectal cancer. METHOD: We evaluated the influence of three common single-nucleotide polymorphisms (SNPs) of the TERT gene (rs2853669, rs2736100, rs2736098) on susceptibility to colorectal cancer in 104 patients and 135 controls in a Turkish population. RESULTS: We observed that rs2736098 was significantly associated with increased risk of colorectal cancer (OR = 2.53; 95% CI = 1.26-5.10; p = 0.008). On the other hand, rs2736100 and rs2853669 showed no association with colorectal cancer (p >= 0.128). CONCLUSION: These findings are the first results of TERT allele distributions in the Turkish population and also provide increased understanding with respect to colorectal cancer etiology. PMID- 26501980 TI - Recent Advances in the Development of Antineoplastic Agents Derived from Natural Products. AB - Through years of evolutionary selection pressures, organisms have developed potent toxins that coincidentally have marked antineoplastic activity. These natural products have been vital for the development of multiagent treatment regimens currently employed in cancer chemotherapy, and are used in the treatment of a variety of malignancies. Therefore, this review catalogs recent advances in natural product-based drug discovery via the examination of mechanisms of action and available clinical data to highlight the utility of these novel compounds in the burgeoning age of precision medicine. The review also highlights the recent development of antibody-drug conjugates and other immunotoxins, which are capable of delivering highly cytotoxic agents previously deemed too toxic to elicit therapeutic benefit preferentially to neoplastic cells. Finally, the review examines natural products not currently used in the clinic that have novel mechanisms of action, and may serve to supplement current chemotherapeutic protocols. PMID- 26501987 TI - Diagnostic markers of axonal degeneration and demyelination in sensory nerve conduction. AB - INTRODUCTION: The aim of this study was to formulate diagnostic hallmarks of axonal degeneration and demyelination in sensory nerve conduction studies (NCS). METHODS: We compared nerve conduction data obtained with surface electrode (SE) NCS and on-nerve needle (ONN) NCS in 50 cases of demyelination and 22 cases of axonal degeneration as assessed by sural nerve biopsy. RESULTS: The overall diagnostic sensitivities of sensory nerve conduction were 26% by SE-NCS and 69% by ONN-NCS. The most helpful marker for demyelination was negative-peak nerve conduction velocity (NP-NCV), using a 36% decrease from the means in both techniques. Dispersion was also helpful in identifying demyelination. Low amplitude and absence of compound nerve action potential were indicative of general pathology in SE-NCS but of axonal degeneration in ONN-NCS. CONCLUSION: Although diagnostic sensitivity is low, NP-NCV and dispersion can be used for diagnosis of demyelination in sensory NCS. Muscle Nerve 53: 866-871, 2016. PMID- 26501988 TI - I International Congress on Mindfulness, Zaragoza (Spain), 11-14 June 2014. PMID- 26501990 TI - Role of Antiplatelet Therapy and Anticoagulation in Nonischemic Cardiomyopathy. AB - Heart failure continues to be a leading cause of morbidity and mortality throughout the United States. The pathophysiology of heart failure involves the activation of complex neurohormonal pathways, many of which mediate not only hypertrophy and fibrosis within ventricular myocardium and interstitium, but also activation of platelets and alteration of vascular endothelium. Platelet activation and vascular endothelial dysfunction may contribute to the observed increased risk of thromboembolic events in patients with chronic heart failure. However, current data from clinical trials do not support the routine use of chronic antiplatelet or oral anticoagulation therapy for ambulatory heart failure patients without other indications (atrial fibrillation and/or coronary artery disease) as the risk of bleeding seems to outweigh the potential benefit related to reduction in thromboembolic events. In this review, we consider the potential clinical utility of targeting specific pathophysiological mechanisms of platelet and vascular endothelial activation to guide clinical decision making in heart failure patients. PMID- 26501989 TI - Neovascular Glaucoma. AB - Neovascular glaucoma (NVG) is a secondary ocular pathological condition resulting from a myriad of ocular and systemic conditions with retinal ischemia as a mediator in over 95% of cases. NVG is caused by the growth of a fibrovascular membrane secondary to a local angiogenic stimulus over the trabecular meshwork obstructing aqueous outflow. This results in an initial secondary open-angle glaucoma stage that may be amenable to intraocular pressure (IOP)-lowering medications and modulation of the underlying ischemic process, often in combination with panretinal photocoagulation and adjunctive use of vascular endothelial growth factor inhibitors. In the more advanced stages of neovascularization, connective tissue myofibroblasts associated with new vessel growth contract causing progressive synechial closure of the anterior-chamber angle. Elevation of IOP, once significant secondary angle closure is established, tends to be refractory to topical and oral IOP-lowering medications and often requires glaucoma surgical interventions. PMID- 26501991 TI - Right-Sided Infective Endocarditis and Pulmonary Infiltrates: An Update. AB - Sixty years after its initial description, right-sided infective endocarditis (RSIE) still poses a challenge to all medical practitioners. Epidemiological data reveal a rising incidence attributable to the global surge in the number of intravenous drug users and the increased use of central vascular catheters and implantable cardiac devices. RSIE differs from left-sided infective endocarditis in more than just the location of the involved cardiac valve. They have different clinical presentations, diagnostic findings, and prognoses; hence, they require different management strategies. Cardiac murmurs and systemic emboli are usually absent in RSIE, whereas pulmonary embolism and its related complications dominate the clinical picture. Diagnostic delay of RSIE is secondary to the similarity in its initial presentation to other entities. Complications may ensue as a result of this delay. Diagnosis can be initially confirmed by using transthoracic echocardiography, except in patients with implanted cardioverter defibrillator, where a transesophageal echocardiogram is necessary. Various factors may increase mortality and morbidity in RSIE such as tricuspid valve vegetation size, fungal etiology, and low CD4 cell count in HIV patients. Oxacillin and vancomycin had been the traditionally used agents for the treatment of methicillin-susceptible and methicillin-resistant Staphylococcus aureus, respectively. More recently, daptomycin has shown promising results, which has led to its Food and Drug Administration (FDA) approval for the treatment of S. aureus bacteremia and associated RSIE. The aim of this article is to provide a comprehensive update on RSIE including epidemiology, pathogenesis, microbiology, diagnosis, management, and prognosis. PMID- 26501992 TI - Impact of aging and comorbidity on the efficacy of low-intensity shock wave therapy for erectile dysfunction. AB - OBJECTIVES: To evaluate the efficacy of low-intensity shock wave therapy and to identify the predictive factors of its efficacy in Japanese patients with erectile dysfunction. METHODS: The present study included 57 patients with erectile dysfunction who satisfied all the following conditions: more than 6 months history of erectile dysfunction, sexual health inventory for men score of <= 12 without phosphodiesterase type-5 inhibitor, erection hardness score grade 1 or 2, mean penile circumferential change by erectometer assessing sleep related erection of < 25 mm and non-neurological pathology. Patients were treated by a low-energy shock waves generator (ED1000; Medispec, Gaithersburg, MD, USA). A total of 12 shock wave treatments were applied. Sexual health inventory for men score, erection hardness score with or without phosphodiesterase type-5 inhibitor, and mean penile circumferential change were assessed at baseline, 1, 3 and 6 months after the termination of low-intensity shock wave therapy. RESULTS: Of 57 patients who were assigned for the low-intensity shock wave therapy trial, 56 patients were analyzed. Patients had a median age of 64 years. The sexual health inventory for men and erection hardness score (with and without phosphodiesterase type-5 inhibitor) were significantly increased (P < 0.001) at each time-point. The mean penile circumferential change was also increased from 13.1 to 20.2 mm after low-intensity shock wave therapy (P < 0.001). In the multivariate analysis, age and the number of concomitant comorbidities were statistically significant predictors for the efficacy. CONCLUSIONS: Low-intensity shock wave therapy seems to be an effective physical therapy for erectile dysfunction. Age and comorbidities are negative predictive factors of therapeutic response. PMID- 26501994 TI - Microspheres and Nanotechnology for Drug Delivery. AB - Ocular drug delivery to the posterior segment of the eye can be accomplished by invasive drug injections into different tissues of the eye and noninvasive topical treatment. Invasive treatment involves the risks of surgical trauma and infection, and conventional topical treatments are ineffective in delivering drugs to the posterior segment of the eye. In recent years, nanotechnology has become an ever-increasing part of ocular drug delivery. In the following, we briefly review microspheres and nanotechnology for drug delivery to the eye, including different forms of nanotechnology such as nanoparticles, microparticles, liposomes, microemulsions and micromachines. The permeation barriers and anatomical considerations linked to ocular drug delivery are discussed and a theoretical overview on drug delivery through biological membranes is given. Finally, in vitro, in vivo and human studies of x03B3; cyclodextrin nanoparticle eyedrop suspensions are discussed as an example of nanotechnology used for drug delivery to the eye. PMID- 26501993 TI - Protease receptor antagonism to target blood platelet therapies. AB - Platelet activation and thrombus formation play a central role in ischemic vascular disease. Thrombin, an especially potent physiologic agonist mediating in vivo activation of platelets, acts via a unique family of G-protein-coupled receptors called protease-activated receptors (PARs) with a broad tissue expression. This review focuses on current antiplatelet therapies as well as innovative approaches to targeting PARs in patients with atherothrombotic vascular disease. PMID- 26501995 TI - Double pylorus from a chronic gastric ulcer: an interesting and rare case. PMID- 26501996 TI - Effect of Ionic Strength and Surface Charge on Convective Deposition. AB - Particle-particle and particle-substrate interactions play a crucial role in capillary driven convective self-assembly for continuous deposition of particles. This systematic study demonstrates the nontrivial effects of varying surface charge and ionic strength of monosized silica microspheres in water on the quality of the deposited monolayer. Increase in particle surface charge results a broader range of parameters that result in monolayer deposition which can be explained considering the particle-substrate electrostatic repulsion in solution. Resulting changes in the coating morphology and microstructure at different solution conditions were observed using confocal microscopy enabling correlation of order to disorder transitions with relative particle stability. These results, in part, may explain similar results seen by Muangnapoh et al., 2013 in vibration assisted convective deposition. PMID- 26501998 TI - Insights on the Early-Life Origins of Alzheimer's Disease: Relevance for Primary Prevention? PMID- 26501997 TI - A concurrent ultra-fractionated radiation therapy and temozolomide treatment: A promising therapy for newly diagnosed, inoperable glioblastoma. AB - We report on a phase II clinical trial to determine the effect of a concurrent ultra-fractionated radiotherapy and temozolomide treatment in inoperable glioblastoma patients. A phase II study opened; patients over 18 years of age who were able to give informed consent and had histologically proven, newly diagnosed inoperable diagnosed and supratentorial glioblastoma were eligible. Three doses of 0.75 Gy spaced apart by at least 4 hr were delivered daily, 5 days a week for six consecutive weeks for a total of 67.5 Gy. Chemotherapy was administered during the same period, which consisted of temozolomide given at a dose of 75 mg/m(2) for 7 days a week. After a 4-week break, chemotherapy was resumed for up to six cycles of adjuvant temozolomide treatment, given every 28 days, according to the standard 5-day regimen. Tolerance and toxicity were the primary endpoints; survival and progression-free survival were the secondary endpoints. In total, 40 patients were enrolled in this study, 29 men and 11 women. The median age was 58 years, and the median Karnofsky performance status was 80. The concomitant ultra fractionated radiotherapy and temozolomide treatment was well tolerated. Complete responses were seen in four patients, and partial responses were reported in seven patients. The median survival from the initial diagnosis was 16 months. Several long-term survivors were noted. Concurrent ultra-fractionated radiation therapy and temozolomide treatment are well accepted by the patients. The results showed encouraging survival rates for these unfavorable patients. PMID- 26501999 TI - EVIDENCE-BASED PSYCHOSOCIAL INTERVENTIONS: NOVEL CHALLENGES FOR TRAINING AND IMPLEMENTATION. PMID- 26502000 TI - The Association between Smoking Abstinence and Mortality in the National Lung Screening Trial. AB - RATIONALE: Smoking is the largest contributor to lung cancer risk, and those who continue to smoke after diagnosis have a worse survival. Screening for lung cancer with low-dose computed tomography (LDCT) reduces mortality in high-risk individuals. Smoking cessation is an essential component of a high-quality screening program. OBJECTIVES: To quantify the effects of smoking history and abstinence on mortality in high-risk individuals who participated in the NLST (National Lung Screening Trial). METHODS: This is a secondary analysis of a randomized controlled trial (NLST). MEASUREMENTS AND MAIN RESULTS: Measurements included self-reported demographics, medical and smoking history, and lung cancer specific and all-cause mortality. Cox regression was used to study the association of mortality with smoking status and pack-years. Kaplan-Meier survival curves were examined for differences in survival based on trial arm and smoking status. Current smokers had an increased lung cancer-specific (hazard ratio [HR], 2.14-2.29) and all-cause mortality (HR, 1.79-1.85) compared with former smokers irrespective of screening arm. Former smokers in the control arm abstinent for 7 years had a 20% mortality reduction comparable with the benefit reported with LDCT screening in the NLST. The maximum benefit was seen with the combination of smoking abstinence at 15 years and LDCT screening, which resulted in a 38% reduction in lung cancer-specific mortality (HR, 0.62; 95% confidence interval, 0.51-0.76). CONCLUSIONS: Seven years of smoking abstinence reduced lung cancer-specific mortality at a magnitude comparable with LDCT screening. This reduction was greater when abstinence was combined with screening, highlighting the importance of smoking cessation efforts in screening programs. PMID- 26502001 TI - The psychology of corporate rights: Perception of corporate versus individual rights to religious liberty, privacy, and free speech. AB - The U.S. Supreme Court has increasingly expanded the scope of constitutional rights granted to corporations and other collective entities. Although this tendency receives widespread public and media attention, little empirical research examines how people ascribe rights, commonly thought to belong to natural persons, to corporations. This article explores this issue in 3 studies focusing on different rights (religious liberty, privacy, and free speech). We examined participants' willingness to grant a given right while manipulating the type of entity at stake (from small businesses, to larger corporations, to for profit and nonprofit companies), and the identity of the right holder (from employees, to owners, to the company itself as a separate entity). We further examined the role of political ideology in perceptions of rights. Results indicated a significant decline in the degree of recognition of entities' rights (the company itself) in comparison to natural persons' rights (owners and employees). Results also demonstrated an effect of the type of entity at stake: Larger, for-profit businesses were less likely to be viewed as rights holders compared with nonprofit entities. Although both tendencies persisted across the ideological spectrum, ideological differences emerged in the relations between corporate and individual rights: these were positively related among conservatives but negatively related among liberals. Finally, we found that the desire to protect citizens (compared with businesses) underlies individuals' willingness to grant rights to companies. These findings show that people (rather than corporations) are more appropriate recipients of rights, and can explain public backlash to judicial expansions of corporate rights. PMID- 26502003 TI - Back Cover: Macromol. Biosci. 11/2015. AB - Back Cover: The micellar prodrugs of desmethyl anethole dithiolethione (ADT-OH) with different hydrolysis rates prepared from block copolymers having ADT-OH linked via an ester bond using glycine and isoleucine linkers are presented. Micelles having a glycine linker inhibit proliferation of cancer cells. Further details can be found in the article by U. Hasegawa, N. Tateishi, H. Uyama, A. J. van der Vlies on page 1512. PMID- 26502004 TI - Nano-morphology induced additional surface plasmon resonance enhancement of SERS sensitivity in Ag/GaN nanowall network. AB - The GaN nanowall network, formed by opening the screw dislocations by kinetically controlled MBE growth, possesses a large surface and high conductivity. Sharp apexed nanowalls show higher surface electron concentration in the band-tail states, in comparison to blunt apexed nanowalls. Uncapped silver nanoparticles are vapor deposited on the blunt and sharp GaN nanowall networks to study the morphological dependence of band-edge plasmon-coupling. Surface enhanced Raman spectroscopy studies performed with a rhodamine 6G analyte on these two configurations clearly show that the sharp nanowall morphology with smaller Ag nanoparticles shows higher enhancement of the Raman signal. A very large enhancement factor of 2.8 * 10(7) and a very low limit of detection of 10(-10) M is observed, which is attributed to the surface plasmon resonance owing to the high surface electron concentration on the GaN nanowall in addition to that of the Ag nanoparticles. The significantly higher sensitivity with same-sized Ag nanoparticles confirms the unconventional role of morphology-dependent surface charge carrier concentration of GaN nanowalls in the enhancement of Raman signals. PMID- 26502005 TI - Retinal Biochemistry, Physiology and Cell Biology. AB - The vitreous, the vasculature of the retina, macular pigments, phototransduction, retinal pigment epithelium, Bruch's membrane and the extracellular matrix, all play an important role in the normal function of the retina as well as in diseases. Understanding the pathophysiology allows us to target treatment. As ocular angiogenesis, immunity and inflammation are covered elsewhere, those subjects will not be discussed in this chapter. PMID- 26502006 TI - Optical Coherence Tomography Angiography. PMID- 26502007 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF TYPE 3 NEOVASCULARIZATION SECONDARY TO AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To characterize the vascular structure of Type 3 neovascularization secondary to age-related macular degeneration using optical coherence tomography angiography. METHODS: Optical coherence tomography angiography cube scans (3 mm * 3 mm) were acquired in 29 eyes of 24 patients with Type 3 lesions secondary to age-related macular degeneration using the RTVue XR Avanti with AngioVue, Split spectrum amplitude-decorrelation, and motion correction technology. Automated layer segmentation boundaries were adjusted to best visualize the neovascular complex on en face projection images. RESULTS: A distinct neovascular complex could be identified in 10 (34%) eyes, all of which were active on optical coherence tomography imaging. In all 10 eyes, the neovascular complex appeared as a small tuft of bright, high-flow tiny vessels with curvilinear morphology located in the outer retinal layers with a feeder vessel communicating with the inner retinal circulation (i.e., deep retinal capillary plexus). The mean (SD) size of the neovascular complex measured 0.07 (+/- 0.07) mm. CONCLUSION: With optical coherence tomography angiography, it is possible to identify small intraretinal neovascular complexes communicating with the deep retinal capillary plexus in eyes with Type 3 neovascularization secondary to age-related macular degeneration. Qualitative and quantitative analyses of Type 3 neovascular complexes can be performed using optical coherence tomography angiography. PMID- 26502008 TI - CAPILLARY NETWORK ANOMALIES IN BRANCH RETINAL VEIN OCCLUSION ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To analyze the foveal microvasculature features in eyes with branch retinal vein occlusion (BRVO) using optical coherence tomography angiography based on split spectrum amplitude decorrelation angiography technology. METHODS: A total of 10 BRVO eyes (mean age 64.2 +/- 8.02 range between 52 years and 76 years) were evaluated by optical coherence tomography angiography (XR-Avanti; Optovue). The macular angiography scan protocol covered a 3 mm * 3 mm area. The focus of angiography analysis were two retinal layers: superficial vascular network and deep vascular network. The following vascular morphological congestion parameters were assessed in the vein occlusion area in both the superficial and deep networks: foveal avascular zone enlargement, capillary non perfusion occurrence, microvascular abnormalities appearance, and vascular congestion signs. Image analyses were performed by 2 masked observers and interobserver agreement of image analyses was 0.90 (kappa = 0.225, P < 0.01). RESULTS: In both superficial and deep network of BRVO, a decrease in capillary density with foveal avascular zone enlargement, capillary non-perfusion occurrence, and microvascular abnormalities appearance was observed (P < 0.01). The deep network showed the main vascular congestion at the boundary between healthy and nonperfused retina. CONCLUSION: Optical coherence tomography angiography in BRVO allows to detect foveal avascular zone enlargement, capillary nonperfusion, microvascular abnormalities, and vascular congestion signs both in the superficial and deep capillary network in all eyes. Optical coherence tomography angiography technology is a potential clinical tool for BRVO diagnosis and follow-up, providing stratigraphic vascular details that have not been previously observed by standard fluorescein angiography. The normal retinal vascular nets and areas of nonperfusion and congestion can be identified at various retinal levels. Optical coherence tomography angiography provides noninvasive images of the retinal capillaries and vascular networks. PMID- 26502009 TI - NONINVASIVE GRADING OF RADIATION RETINOPATHY: The Use of Optical Coherence Tomography Angiography. AB - PURPOSE: Previous studies have shown that spectral domain optical coherence tomography can diagnose radiation retinopathy (RR) before ophthalmoscopic findings. Recently, optical coherence tomography angiography (OCT-A) has been helpful in seeing vascular findings undetected by spectral domain optical coherence tomography. The authors wish to demonstrate the OCT-A grading at varying levels of RR. METHODS: The OCT-A, spectral domain optical coherence tomography, and ophthalmoscopic findings on 7 patients from December 2014 to March 2015 with varying levels of RR are demonstrated. RESULTS: Findings on OCT-A could be demonstrated before spectral domain optical coherence tomography findings. Patients can be graded on a scale of increasing severity from 0 to 5, based on positive or negative clinical findings of RR between OCT-A. Optical coherence tomography increased central macular thickness, optical coherence tomography evident cysts, and ophthalmoscopy (Grade 0: -,-,-,-; Grade 1: +,-,-,-; Grade 2: +,+,-,-; Grade 3: +,+,+,-; Grade 4: ++,+,+,+; Grade 5: unreadable,++,++,+). CONCLUSION: The use of OCT-A allows for earlier detection of RR; thus, existing grading systems should be modified to include OCT-A. PMID- 26502010 TI - Correspondence. PMID- 26502011 TI - Reply: To PMID 25768249. PMID- 26502012 TI - Assessing potential risks of treatment with long-term azithromycin in COPD patients: long-term oxygen users beware? AB - INTRODUCTION: Long-term daily azithromycin therapy reduces the frequency of exacerbations in chronic obstructive pulmonary disease (COPD) in a randomized controlled clinical trial setting. Concerns exist regarding arrhythmic and auditory toxicities from chronic use in the real-world setting. We hypothesized that risk factors for adverse drug reactions to azithromycin would be more frequent than previously reported, that certain specific subgroups would have different frequencies of these risk factors and that the whispered voice test would be a useful test with which to test for hearing deficits. METHODS: Following ethical approval, 47 consecutive hospital-based patients with a mean age 69 years +/- 8.2, and with physician-diagnosed COPD (mean FEV1 45.1 +/- 18 % predicted), were screened for subjective hearing impairment (screening questions and whispered voice test) and by electrocardiogram for prolonged QTc. Other potential risk factors and contraindications to long-term daily azithromycin were sought. RESULTS: In total, 38 patients (80.9 %) had at least one risk factor or contraindication to azithromycin treatment. 19 patients (40.4 % of total) had subjective hearing impairment. 17 (36.1 %) had prolonged QTc intervals. 4 patients (8.51 %) had contraindicating co-morbidities. Those on long-term oxygen therapy were significantly more likely to have at least one risk factors or contraindications to azithromycin (p = 0.0025). CONCLUSION: In a COPD population who would otherwise potentially be candidates for long-term daily azithromycin therapy, over 80 % had risk factors for complications from long-term daily azithromycin. Preventative treatment with long-term daily azithromycin may be appropriate for fewer COPD patients than previously thought, especially in those on long-term oxygen therapy. PMID- 26502014 TI - Explicating our core competency: A call for global research on occupational enablement. PMID- 26502013 TI - Lenalidomide in the treatment of Rosai Dorfman disease--a first in use report. PMID- 26502015 TI - [Expliciter notre competence premiere et fondamentale: Un appel a une recherche mondiale sur l'habilitation a l'occupation]. PMID- 26502016 TI - Transforming values into action: Advocacy as a professional imperative. AB - BACKGROUND: The goal of enabling meaningful occupation for all requires occupational therapy to become a more socially and politically responsible discipline. PURPOSE: This paper argues that occupational therapy's dominant individualist perspective is too narrow to meet this goal. It presents an argument for integrating advocacy into occupational therapy identity and discusses why we should advocate at political and public levels. KEY ISSUES: Although the dominant paradigm and political climate pose challenges, there must be a realignment of the balance between helping individuals who are facing disruptions in their occupational lives and addressing systems and structures that prevent them from moving forward. Adopting a broader sociopolitical approach involves engaging in advocacy as a key strategy. Indeed, advocacy is a professional imperative for occupational therapy. IMPLICATIONS: Advocacy must become part of the process of professional socialization. A new set of competencies is needed in our educational programs and in our professional development, accompanied by a sense of self-confident idealism. PMID- 26502017 TI - Investigating visual attention during scene perception of safe and unsafe occupational performance. AB - BACKGROUND: Occupational therapists routinely use observation for evaluation, intervention planning, and prediction of a client's occupational performance and/or safety within the environment. Perception of safety contributes to the decision-making process for discharge or placement recommendations. PURPOSE: The purpose of this study was to determine if differences exist in safety ratings and eye movements between occupational therapists and nontrained matched individuals while viewing domain-specific versus non-domain-specific images. METHOD: Ten licensed occupational therapists and 10 age-, gender-, and education level matched participants completed this eye-tracking study. FINDINGS: For all image exposure durations, occupational therapists had more polarized safety ratings for stroke-related image content but little evidence of differences in eye movements between groups. Eye movement group differences did not emerge in the regions of interest identified by an independent expert panel. IMPLICATIONS: The results point to a complex relationship between decision making and observational behaviour in occupational assessment and highlight the need to look beyond image features. PMID- 26502019 TI - User-perceived utility of the Daily Experiences of Pleasure, Productivity, and Restoration Profile. AB - BACKGROUND: Awareness of the relationship between everyday occupations and subjective experience could help clients make changes that promote health. PURPOSE: This study evaluated user-perceived utility of the Daily Experiences of Pleasure, Productivity, and Restoration Profile (PPR Profile), a time-use survey designed to uncover users' experiences of pleasure, productivity, and restoration and to promote awareness of how these experiences are related to daily occupations. METHOD: Eighteen participants completed the PPR Profile on 2 days within I week and were subsequently interviewed. Content analysis was used to uncover themes. FINDINGS: Analysis revealed that completion of the PPR Profile requires time and energy, completion more than once is useful, and the PPR Profile contributes to awareness. Four subthemes of awareness were identified: awareness of the here and now, insights into one's occupations, context matters, and what is and what might be. IMPLICATIONS: Results support the utility of the PPR Profile to promote users' awareness of their occupations and related subjective experiences. This awareness may encourage positive change. Further research is recommended to continue to evaluate the PPR Profile's clinical utility. PMID- 26502020 TI - Sharpening our critical edge: Occupational therapy in the context of marginalized populations. AB - BACKGROUND: An emerging and important area of occupational therapy practice involves engaging with various individuals and population groups who live in marginalizing conditions that result in health inequities. PURPOSE: This paper calls for more critical and intersectional analyses of occupational therapy in the context of marginalized populations. KEY ISSUES: Intersectionality has the potential to reveal important and complex interactions among social systems that create and sustain marginalization and to inform more nuanced, contextualized, and socially responsive forms of occupational therapy. Central to this process is the co-construction of knowledge with people who experience marginalization. Engaging in this work requires occupational therapists to undertake ongoing critical reflexivity to attend to our sociohistorical positioning of power and privilege in relation to marginalized populations. IMPLICATION: Complicating our discourse on marginalized populations is imperative to enacting our critical potential in working toward social justice and health equity. PMID- 26502022 TI - [The personal digital assistant: A tool for supporting mental health rehabilitation]. AB - BACKGROUND: People living with mental illness may manifest cognitive and social emotional difficulties leading to several challenges in their daily lives. Using technological aids may help to compensate for some of these difficulties. PURPOSE: The objective of this study was to document the effects and issues of the use of mobile technology applications (apps) with people with mental illness during the rehabilitation process. METHOD: Using an exploratory qualitative evaluative approach, 12 participants were engaged in ongoing brief interviews in which they discussed their use of a variety of apps that met their rehabilitation needs. A thematic analysis (descriptive interpretive) was used to uncover the effects and issues of the integration of apps in participants' daily life. FINDINGS: The apps helped participants to overcome their cognitive difficulties, facilitated the management of their daily tasks and socialization, and prevented boredom. However, several issues related to the context, the technology, and the person need to be considered. IMPLICATIONS: The findings prompt one to consider the therapist's role in the integration of personal digital assistants in psychosocial rehabilitation. PMID- 26502024 TI - Transformer les valeurs en action: La defense des interets en tant qu'imperatif professionnel. PMID- 26502025 TI - Stereoscopic Surgical Recording Using GoPro Cameras: A Low-Cost Means for Capturing External Eye Surgery. PMID- 26502027 TI - Displacement of Drugs From Cyclodextrin Complexes by Bile Salts: A Suggestion of an Intestinal Drug-Solubilizing Capacity From an In Vitro Model. AB - The dosing of drugs in an aqueous cyclodextrin formulation requires sufficient amount of cyclodextrins to fully solubilize the drug, as described by Stella's cyclodextrin utility number (UCD). However, this framework does not take biopharmaceutical elements into account, such as the displacement of drug from the cyclodextrin cavity by bile salts present in the small intestine. As bile salts in the intestine are present at concentrations above the critical micelle concentration, an understanding of the interaction between cyclodextrins and bile salts at such supramicellar concentrations (SMC) is required for a better biopharmaceutical understanding of the release mechanism from orally dosed cyclodextrin complexes. To address this, experiments were conducted by isothermal titration calorimetry to determine how various beta-cyclodextrins and bile salt interacts at SMC. Combined analysis of the current results and earlier data demonstrated that direct interactions between bile salt micelles and cyclodextrin were negligible. From this knowledge, an extended form of the UCD was suggested to describe the concentration of cyclodextrins to achieve full drug solubilization in the intestine where bile salts are present. Dosing cyclodextrins above this limit will diminish the free drug concentration, potentially decreasing the amount of drug absorbed. PMID- 26502026 TI - Language Impairment in the Attention-Deficit/Hyperactivity Disorder Context. AB - PURPOSE: Attention-deficit/hyperactivity disorder (ADHD) is a ubiquitous designation that affects the identification, assessment, treatment, and study of pediatric language impairments (LIs). METHOD: Current literature is reviewed in 4 areas: (a) the capacity of psycholinguistic, neuropsychological, and socioemotional behavioral indices to differentiate cases of LI from ADHD; (b) the impact of co-occurring ADHD on children's LI; (c) cross-etiology comparisons of the nonlinguistic abilities of children with ADHD and specific LI (SLI); and (d) the extent to which ADHD contributes to educational and health disparities among individuals with LI. RESULTS: Evidence is presented demonstrating the value of using adjusted parent ratings of ADHD symptoms and targeted assessments of children's tense marking, nonword repetition, and sentence recall for differential diagnosis and the identification of comorbidity. Reports suggest that the presence of ADHD does not aggravate children's LI. The potential value of cross-etiology comparisons testing the necessity and sufficiency of proposed nonlinguistic contributors to the etiology of SLI is demonstrated through key studies. Reports suggest that children with comorbid ADHD+LI receive speech language services at a higher rate than children with SLI. CONCLUSION: The ADHD context is multifaceted and provides the management and study of LI with both opportunities and obstacles. PMID- 26502028 TI - Common skin and bleeding disorders that can potentially masquerade as child abuse. AB - Child abuse and neglect remains a major cause of morbidity and mortality among children worldwide. Over the last few decades, there has been growing research in the field of Child Abuse Pediatrics with greater recognition and research into potential diagnostic mimics of inflicted injury. This paper reviews some common skin findings and bleeding disorders that have features in common with child abuse. PMID- 26502029 TI - Association Between Alzheimer Dementia Mortality Rate and Altitude in California Counties. PMID- 26502030 TI - Targeting Vascular Risk Factors in Older Adults: From Polypill to Personalized Prevention. PMID- 26502031 TI - Engineering the Electrochemical Capacitive Properties of Microsupercapacitors Based on Graphene Quantum Dots/MnO2 Using Ionic Liquid Gel Electrolytes. AB - All-solid-state microsupercapacitors (MSCs) have been receiving intense interest due to their potential as micro/nanoscale energy storage devices, but their low energy density has limited practical applications. It has been reported that gel electrolytes based on ionic liquids (ionogels) with large potential windows can be used as solid electrolytes to enhance the energy density of MSCs, but a systematic study on how to select and evaluate such ionogels for MSCs is rare. In this study, we construct a series of all-solid-state asymmetric MSCs on the interdigital finger electrodes, using graphene quantum dots (GQDs) as the negative electrode, MnO2 nanosheets as the positive electrode, and different ionogels as the solid electrolytes. Among them, the MSC using 1-ethyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][NTF2]) with 4 wt % fumed SiO2 ionogel exhibited the best electrochemical performance, having excellent rate capability with the scan rate up to 2000 V s(-1), ultrafast frequency response (tau0 = 206.9 MUs) and high energy density. The outstanding performance of this device mainly results from fast ion diffusion, high ion conductivity of the ionogel, and ionic liquid-matrix interactions. The results presented here provide guidance for picking out appropriate ionogels for use in high-performance all-solid-state MSCs to meet the growing requirement of micronanoscale energy storage devices. Additionally, the ultrafast frequency response of our MSCs suggests potential applications in ac line-filters. PMID- 26502032 TI - The Meaning of Race in Prostate Cancer Treatment. PMID- 26502033 TI - Implementation Science: Buzzword or Game Changer? AB - PURPOSE: The purpose of this supplement article is to provide a resource of pertinent information concerning implementation science for immediate research application in communication sciences and disorders. METHOD: Key terminology related to implementation science is reviewed. Practical suggestions for the application of implementation science theories and methodologies are provided, including an overview of hybrid research designs that simultaneously investigate clinical effectiveness and implementation as well as an introduction to approaches for engaging stakeholders in the research process. A detailed example from education is shared to show how implementation science was utilized to move an intervention program for autism into routine practice in the public school system. In particular, the example highlights the value of strong partnership among researchers, policy makers, and frontline practitioners in implementing and sustaining new evidence-based practices. CONCLUSIONS: Implementation science is not just a buzzword. This is a new field of study that can make a substantive contribution in communication sciences and disorders by informing research agendas, reducing health and education disparities, improving accountability and quality control, increasing clinician satisfaction and competence, and improving client outcomes. PMID- 26502034 TI - New Orleans Rises Anew: Community Health After Katrina. PMID- 26502035 TI - Antimicrobial Peptides and Innate Lung Defenses: Role in Infectious and Noninfectious Lung Diseases and Therapeutic Applications. AB - Respiratory infections are a major clinical problem, and treatment is increasingly complicated by the emergence of microbial antibiotic resistance. Development of new antibiotics is notoriously costly and slow; therefore, alternative strategies are needed. Antimicrobial peptides, central effector molecules of the immune system, are being considered as alternatives to conventional antibiotics. These peptides display a range of activities, including not only direct antimicrobial activity, but also immunomodulation and wound repair. In the lung, airway epithelial cells and neutrophils in particular contribute to their synthesis. The relevance of antimicrobial peptides for host defense against infection has been demonstrated in animal models and is supported by observations in patient studies, showing altered expression and/or unfavorable circumstances for their action in a variety of lung diseases. Importantly, antimicrobial peptides are active against microorganisms that are resistant against conventional antibiotics, including multidrug-resistant bacteria. Several strategies have been proposed to use these peptides in the treatment of infections, including direct administration of antimicrobial peptides, enhancement of their local production, and creation of more favorable circumstances for their action. In this review, recent developments in antimicrobial peptides research in the lung and clinical applications for novel therapies of lung diseases are discussed. PMID- 26502036 TI - Serial Assessment of Trauma Care Capacity in Ghana in 2004 and 2014. AB - IMPORTANCE: Trauma care capacity assessments in developing countries have generated evidence to support advocacy, detailed baseline capabilities, and informed targeted interventions. However, serial assessments to determine the effect of capacity improvements or changes over time have rarely been performed. OBJECTIVE: To compare the availability of trauma care resources in Ghana between 2004 and 2014 to assess the effects of a decade of change in the trauma care landscape and derive recommendations for improvements. DESIGN, SETTING, AND PARTICIPANTS: Capacity assessments were performed using direct inspection and structured interviews derived from the World Health Organization's Guidelines for Essential Trauma Care. In Ghana, 10 hospitals in 2004 and 32 hospitals in 2014 were purposively sampled to represent those most likely to care for injuries. Clinical staff, administrators, logistic/procurement officers, and technicians/biomedical engineers who interacted, directly or indirectly, with trauma care resources were interviewed at each hospital. MAIN OUTCOMES AND MEASURES: Availability of items for trauma care was rated from 0 (complete absence) to 3 (fully available). Factors contributing to deficiency in 2014 were determined for items rated lower than 3. Each item rated lower than 3 at a specific hospital was defined as a hospital-item deficiency. Scores for total number of hospital-item deficiencies were derived for each contributing factor. RESULTS: There were significant improvements in mean ratings for trauma care resources: district-level (smaller) hospitals had a mean rating of 0.8 for all items in 2004 vs 1.3 in 2014 (P = .002); regional (larger) hospitals had a mean rating of 1.1 in 2004 vs 1.4 in 2014 (P = .01). However, a number of critical deficiencies remain (eg, chest tubes, diagnostics, and orthopedic and neurosurgical care; mean ratings <= 2). Leading contributing factors were item absence (503 hospital-item deficiencies), lack of training (335 hospital-item deficiencies), and stockout of consumables (137 hospital-item deficiencies). CONCLUSIONS AND RELEVANCE: There has been significant improvement in trauma care capacity during the past decade in Ghana; however, critical deficiencies remain and require urgent redress to avert preventable death and disability. Serial capacity assessment is a valuable tool for monitoring efforts to strengthen trauma care systems, identifying what has been successful, and highlighting needs. PMID- 26502037 TI - Influence of Ossicular Chain Damage on Hearing After Chronic Otitis Media and Cholesteatoma Surgery: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Physicians should ideally be able to provide patients with chronic otitis media and/or cholesteatoma specific information about postoperative hearing outcome, based on their level of preoperative ossicular chain damage (OCD). OBJECTIVE: To identify the influence of preoperative OCD on hearing outcomes in patients after chronic otitis media and/or cholesteatoma surgery. DATA SOURCES: PubMed, EMBASE, and the Cochrane Library databases were systematically searched for available evidence, without any constraints, on December 13, 2014, for articles published between January 1, 1975, and December 13, 2014. STUDY SELECTION: We reviewed the literature for articles assessing the prognostic value of OCD on postoperative hearing outcome (air-bone gap [ABG] in decibels), using Austin-Kartush criteria or independent OCD classification systems. We assessed relevance and validity using a self-designed critical appraisal tool based on the Cochrane Collaboration's risk of bias tool. DATA EXTRACTION: Characteristics of study populations and postoperative ABGs in decibels were extracted from all included studies by 4 authors (E.F.B., M.N.G., N.J.K., A.S.H.J.L.). RESULTS: The tested hypothesis was formulated before data collection. Primary study outcome was defined as postoperative adult hearing outcomes after COM and/or cholesteatoma surgery defined as mean postoperative ABG. Our search yielded 5661 articles. Nine articles with high relevance were included. Pooled results of studies using the Austin-Kartush criteria showed a significant (P < .001) difference in mean ABG in favor of group B, when comparing group B (patients with malleus present, stapes absent; 11.1 [95% CI, 10.3-11.8] dB) to group C (patients with malleus absent, stapes present; 15.7 [95% CI, 14.6 16.7] dB) and group B to group D (patients with malleus absent, stapes absent; 16.5 [95% CI, 15.2-17.9] dB). Three studies using independent OCD classification criteria found no influence of stapes structure (intact stapes suprastructure, 13.5 [95% CI, 10.3-16.7], 15.1 [95% CI, 11.8-18.3], and 21.9 [95% CI, 15.0-28.8] dB vs absent stapes structure, 12.8 [95% CI, 9.5-16.1], 19.5 [95% CI, 14.9-24.1], and 30.2 [95% CI, 24.7-35.8] dB) on postoperative ABG. One study reported a significant (P = .04) difference in mean ABG between patients with present (18.9 [95% CI, 15.7-22.1] dB) and absent (24.4 [95% CI, 20.2-28.6] dB) malleus. CONCLUSIONS AND RELEVANCE: Pooled results of Austin-Kartush studies showed that in patients with COM, with or without cholesteatoma, the malleus status is a significant predictor of postoperative hearing outcome, independent of the stapes condition. Studies reporting on individual ossicle status supported this finding by showing that only malleus condition influenced postoperative hearing outcome. These findings are based on level IV evidence, which indicates the need for future high-level evidence studies. PMID- 26502054 TI - Atg5-independent autophagy regulates mitochondrial clearance and is essential for iPSC reprogramming. AB - Successful generation of induced pluripotent stem cells entails a major metabolic switch from mitochondrial oxidative phosphorylation to glycolysis during the reprogramming process. The mechanism of this metabolic reprogramming, however, remains elusive. Here, our results suggest that an Atg5-independent autophagic process mediates mitochondrial clearance, a characteristic event involved in the metabolic switch. We found that blocking such autophagy, but not canonical autophagy, inhibits mitochondrial clearance, in turn, preventing iPSC induction. Furthermore, AMPK seems to be upstream of this autophagic pathway and can be targeted by small molecules to modulate mitochondrial clearance during metabolic reprogramming. Our work not only reveals that the Atg5-independent autophagy is crucial for establishing pluripotency, but it also suggests that iPSC generation and tumorigenesis share a similar metabolic switch. PMID- 26502058 TI - tert-Butyl Sulfoxide as a Starting Point for the Synthesis of Sulfinyl Containing Compounds. AB - Sulfoxides bearing a tert-butyl group can be activated using N-bromosuccinimide (NBS) under acidic conditions and then subsequently treated with a variety of nitrogen, carbon, or oxygen nucleophiles to afford a wide range of the corresponding sulfinic acid amides, new sulfoxides, and sulfinic acid esters. PMID- 26502055 TI - The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice. AB - DNA double-strand breaks (DSBs) are repaired mainly by non-homologous end joining or homologous recombination (HR). Cell cycle stage and DNA end resection are believed to regulate the commitment to HR repair. Here we identify RNF138 as a ubiquitin E3 ligase that regulates the HR pathway. RNF138 is recruited to DNA damage sites through zinc fingers that have a strong preference for DNA with 5'- or 3'-single-stranded overhangs. RNF138 stimulates DNA end resection and promotes ATR-dependent signalling and DSB repair by HR, thereby contributing to cell survival on exposure to DSB-inducing agents. Finally, we establish that RNF138 dependent Ku removal from DNA breaks is one mechanism whereby RNF138 can promote HR. These results establish RNF138 as an important regulator of DSB repair pathway choice. PMID- 26502056 TI - Heterochromatic breaks move to the nuclear periphery to continue recombinational repair. AB - Heterochromatin mostly comprises repeated sequences prone to harmful ectopic recombination during double-strand break (DSB) repair. In Drosophila cells, 'safe' homologous recombination (HR) repair of heterochromatic breaks relies on a specialized pathway that relocalizes damaged sequences away from the heterochromatin domain before strand invasion. Here we show that heterochromatic DSBs move to the nuclear periphery to continue HR repair. Relocalization depends on nuclear pores and inner nuclear membrane proteins (INMPs) that anchor repair sites to the nuclear periphery through the Smc5/6-interacting proteins STUbL/RENi. Both the initial block to HR progression inside the heterochromatin domain, and the targeting of repair sites to the nuclear periphery, rely on SUMO and SUMO E3 ligases. This study reveals a critical role for SUMOylation in the spatial and temporal regulation of HR repair in heterochromatin, and identifies the nuclear periphery as a specialized site for heterochromatin repair in a multicellular eukaryote. PMID- 26502057 TI - Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair. AB - Ubiquitylation is crucial for proper cellular responses to DNA double-strand breaks (DSBs). If unrepaired, these highly cytotoxic lesions cause genome instability, tumorigenesis, neurodegeneration or premature ageing. Here, we conduct a comprehensive, multilayered screen to systematically profile all human ubiquitin E2 enzymes for impacts on cellular DSB responses. With a widely applicable approach, we use an exemplary E2 family, UBE2Ds, to identify ubiquitylation-cascade components downstream of E2s. Thus, we uncover the nuclear E3 ligase RNF138 as a key homologous recombination (HR)-promoting factor that functions with UBE2Ds in cells. Mechanistically, UBE2Ds and RNF138 accumulate at DNA-damage sites and act at early resection stages by promoting CtIP ubiquitylation and accrual. This work supplies insights into regulation of DSB repair by HR. Moreover, it provides a rich information resource on E2s that can be exploited by follow-on studies. PMID- 26502059 TI - Occurrence of Legacy and New Persistent Organic Pollutants in Avian Tissues from King George Island, Antarctica. AB - Legacy and new persistent organic pollutants (POPs), including polychlorinated naphthalenes (PCNs), Dechlorane Plus (DPs) and related compounds (Dechloranes), hexabromocyclododecanes (HBCDs), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs), were analyzed in avian tissue samples from King George Island, Antarctica. The avian species consisted of the Gentoo penguin (Pygoscelis papua), the Adelie penguin (Pygoscelis adeliae), the South polar skua (Stercorarius maccormicki), and the Brown skua (Stercorarius antarcticus). HBCDs were detected in all samples and ranged from 1.67-713 pg/g-lipid. In the penguin samples, the concentrations of PCNs ranged from 0.69-2.07 ng/g-lipid, whereas those in the skua samples ranged from 7.41-175 ng/g-lipid. The levels of Dechloranes ranged from 0.60-1.30 ng/g-lipid in the penguin samples and from 6.57 47.4 ng/g-lipid in the skua samples. The concentrations and congener distributions of OCPs and PCBs were similar to the results of previous reports. The three new POPs were detected in all samples, and this study was one of the first reports on the occurrence of these pollutants in the Antarctic biota. Because Antarctica is one of the most pristine places on Earth, the detection of new POPs in the Antarctic birds, especially penguins, is direct evidence of the long-range transport of pollutants. Furthermore, the concentration ratios of the penguin to the skua samples (BMFs-p) were greater than 1 in most legacy and new POPs, and the BMFs-p values of the new POPs were comparable to those of some OCPs, suggesting a possibility of biomagnification. Despite the small sample size, the results of this study identified POP contamination of the Antarctic avian species and long-range transport and biomagnification of HBCDs, Dechloranes, and PCNs. PMID- 26502060 TI - Tandem Solar Cells Using GaAs Nanowires on Si: Design, Fabrication, and Observation of Voltage Addition. AB - Multijunction solar cells provide us a viable approach to achieve efficiencies higher than the Shockley-Queisser limit. Due to their unique optical, electrical, and crystallographic features, semiconductor nanowires are good candidates to achieve monolithic integration of solar cell materials that are not lattice matched. Here, we report the first realization of nanowire-on-Si tandem cells with the observation of voltage addition of the GaAs nanowire top cell and the Si bottom cell with an open circuit voltage of 0.956 V and an efficiency of 11.4%. Our simulation showed that the current-matching condition plays an important role in the overall efficiency. Furthermore, we characterized GaAs nanowire arrays grown on lattice-mismatched Si substrates and estimated the carrier density using photoluminescence. A low-resistance connecting junction was obtained using n(+) GaAs/p(+)-Si heterojunction. Finally, we demonstrated tandem solar cells based on top GaAs nanowire array solar cells grown on bottom planar Si solar cells. The reported nanowire-on-Si tandem cell opens up great opportunities for high efficiency, low-cost multijunction solar cells. PMID- 26502062 TI - The Use of Vital Dyes during Vitreoretinal Surgery - Chromovitrectomy. AB - The aim of this article is to present the current data with regard to the application of vital dyes during vitreoretinal surgery, 'chromovitrectomy', as well as to overview the current literature regarding the properties of dyes, techniques of application, indications and complications in chromovitrectomy. It is well known that indocyanine green is toxic to the retina and consequently not the ideal dye for chromovitrectomy. Different vital dyes has been tested for chromovitrectomy including trypan blue, patent blue, triamcinolone acetonide, infracyanine green, sodium fluorescein and brilliant blue. Brilliant blue seems to be the ideal dye for internal limiting membrane due to its afinity, lower toxic profile and to reduce the appearance of apoptosis. Besides the dye itself, the injection technique is crucial to avoid additional toxicity, slow injection, far from the retina and protection of the macular hole are some tips. More recently the use of dyes has been applied to stain perfluorcarbon liquids that may enhance its visualization during vitrectomy. PMID- 26502061 TI - Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials. AB - The p38/MAPK-activated kinase 2 (MK2) pathway is involved in a series of pathological conditions (inflammation diseases and metastasis) and in the resistance mechanism to antitumor agents. None of the p38 inhibitors entered advanced clinical trials because of their unwanted systemic side effects. For this reason, MK2 was identified as an alternative target to block the pathway but avoiding the side effects of p38 inhibition. However, ATP-competitive MK2 inhibitors suffered from low solubility, poor cell permeability, and scarce kinase selectivity. Fortunately, non-ATP-competitive inhibitors of MK2 have been already discovered that allowed circumventing the selectivity issue. These compounds showed the additional advantage to be effective at lower concentrations in comparison to the ATP-competitive inhibitors. Therefore, although the significant difficulties encountered during the development of these inhibitors, MK2 is still considered as an attractive target to treat inflammation and related diseases to prevent tumor metastasis and to increase tumor sensitivity to chemotherapeutics. PMID- 26502064 TI - High Power Efficiency Solution-Processed Blue Phosphorescent Organic Light Emitting Diodes Using Exciplex-Type Host with a Turn-on Voltage Approaching the Theoretical Limit. AB - Three solution-processable exciplex-type host materials were successfully designed and characterized by equal molar blending hole transporting molecules with a newly synthesized electron transporting material, which possesses high thermal stability and good film-forming ability through a spin-coating technique. The excited-state dynamics and the structure-property relationships were systematically investigated. By gradually deepening the highest occupied molecular orbital (HOMO) level of electron-donating components, the triplet energy of exciplex hosts were increased from 2.64 to 3.10 eV. Low temperature phosphorescence spectra demonstrated that the excessively high triplet energy of exciplex would induce a serious energy leakage from the complex state to the constituting molecule. Furthermore, the low energy electromer state, which only exists under the electroexcitation, was found as another possible channel for energy loss in exciplex-based phosphorescent organic light-emitting diodes (OLEDs). In particular, as quenching of the exciplex-state and the triplet exciton were largely eliminated, solution-processed blue phosphorescence OLEDs using the exciplex-type host achieved an extremely low turn-on voltage of 2.7 eV and record-high power efficiency of 22.5 lm W(-1), which were among the highest values in the devices with identical structure. PMID- 26502063 TI - Sensorimotor Model of Obstacle Avoidance in Echolocating Bats. AB - Bat echolocation is an ability consisting of many subtasks such as navigation, prey detection and object recognition. Understanding the echolocation capabilities of bats comes down to isolating the minimal set of acoustic cues needed to complete each task. For some tasks, the minimal cues have already been identified. However, while a number of possible cues have been suggested, little is known about the minimal cues supporting obstacle avoidance in echolocating bats. In this paper, we propose that the Interaural Intensity Difference (IID) and travel time of the first millisecond of the echo train are sufficient cues for obstacle avoidance. We describe a simple control algorithm based on the use of these cues in combination with alternating ear positions modeled after the constant frequency bat Rhinolophus rouxii. Using spatial simulations (2D and 3D), we show that simple phonotaxis can steer a bat clear from obstacles without performing a reconstruction of the 3D layout of the scene. As such, this paper presents the first computationally explicit explanation for obstacle avoidance validated in complex simulated environments. Based on additional simulations modelling the FM bat Phyllostomus discolor, we conjecture that the proposed cues can be exploited by constant frequency (CF) bats and frequency modulated (FM) bats alike. We hypothesize that using a low level yet robust cue for obstacle avoidance allows bats to comply with the hard real-time constraints of this basic behaviour. PMID- 26502066 TI - [Not Available]. PMID- 26502065 TI - Developing new predictive alarms based on ECG metrics for bradyasystolic cardiac arrest. AB - We investigated 17 metrics derived from four leads of electrocardiographic (ECG) signals from hospital patient monitors to develop new ECG alarms for predicting adult bradyasystolic cardiac arrest events.A retrospective case-control study was designed to analyze 17 ECG metrics from 27 adult bradyasystolic and 304 control patients. The 17 metrics consisted of PR interval (PR), P-wave duration (Pdur), QRS duration (QRSdur), RR interval (RR), QT interval (QT), estimate of serum K + using only frontal leads (SerumK2), T-wave complexity (T Complex), ST segment levels for leads I, II, V (ST I, ST II, ST V), and 7 heart rate variability (HRV) metrics. These 7 HRV metrics were standard deviation of normal to normal intervals (SDNN), total power, very low frequency power, low frequency power, high frequency power, normalized low frequency power, and normalized high frequency power. Controls were matched by gender, age (+/-5 years), admission to the same hospital unit within the same month, and the same major diagnostic category. A research ECG analysis software program developed by co-author D M was used to automatically extract the metrics. The absolute value for each ECG metric, and the duration, terminal value, and slope of the dominant trend for each ECG metric, were derived and tested as the alarm conditions. The maximal true positive rate (TPR) of detecting cardiac arrest at a prescribed maximal false positive rate (FPR) based on the trending conditions was reported. Lead time was also recorded as the time between the first time alarm condition was triggered and the event of cardiac arrest.While conditions based on the absolute values of ECG metrics do not provide discriminative information to predict bradyasystolic cardiac arrest, the trending conditions can be useful. For example, with a max FPR = 5.0%, some derived alarms conditions are: trend duration of PR > 2.8 h (TPR = 48.2%, lead time = 10.0 +/- 6.6 h), trend duration of QRSdur > 2.7 h (TPR = 40.7%, lead time = 8.8 +/- 6.2 h), trend duration of RR > 3.5 h (TPR = 51.9%, lead time = 6.4 +/- 5.5 h), trend duration of T Complex > 2.9 h (TPR = 40.7%, lead time = 6.8 +/- 5.5 h), trend duration of ST I > 3.0 h (TPR of 51.9%, lead time = 8.4 +/- 8.0 h), trend duration of SDNN > 3.6 h (TPR of 40.7%, lead time = 11.0 +/- 8.6 h), trend duration of HRV total power > 3.0 h (TPR of 25.9%, lead time = 7.5 +/- 8.1 h), terminal value of ST I < -56 uV (TPR = 22.2%, lead time = 12.8 +/- 8.3 h), and slope of QR > 19.4 ms h(-1) (TPR = 25.9%, lead time = 6.7 +/- 6.9 h). Eleven trend duration alarms, eight terminal value alarms, and ten slope alarms, achieved a positive TPR with zero FPR. Furthermore, these alarms conditions with zero PFR can be combined by the 'OR'logic could further improve the TPR without increasing the FPR.The trend duration, terminal value, and slope of the dominant trend of the ECG metrics considered in this study are able to predict a subset of patients with bradyasystolic cardiac arrests with low or even zero FPR, which can be used for developing new ECG alarms. PMID- 26502067 TI - Erratum to: Postural change in volunteers: sympathetic tone determines microvascular response to cardiac preload and output increases. PMID- 26502068 TI - A Model for Hospital Discharge Preparation: From Case Management to Care Transition. AB - There has been a proliferation of initiatives to improve discharge processes and outcomes for the transition from hospital to home and community-based care. Operationalization of these processes has varied widely as hospitals have customized discharge care into innovative roles and functions. This article presents a model for conceptualizing the components of hospital discharge preparation to ensure attention to the full range of processes needed for a comprehensive strategy for hospital discharge. PMID- 26502069 TI - Evaluation of Authentic Human Caring Professional Practices. AB - OBJECTIVE: The aim of this study was to present an instrument and comparative database designed to evaluate patients' perceptions of caring behaviors of caregivers. BACKGROUND: Acute care leaders are under pressure to improve publicly reported patient satisfaction scores. Some nurse leaders have implemented professional practice environments based on human caring theory, whereas others have used scripting to standardize communication between staff and patients. METHODS: The Watson Caritas Patient Score (WCPS) is collected quarterly from a random sample of patients who are admitted to acute care hospital units. RESULTS: The WCPS was able to discriminate across unit types and hospitals. Items were related to publicly reported nursing communication scores. CONCLUSIONS: Participation in research based on human caring theory has given nurse leaders the opportunity to evaluate effectiveness of professional practice environments. It may provide the opportunity to focus staff communication with patients more authentically and in a way that enriches the experience for both. PMID- 26502070 TI - CAB-Align: A Flexible Protein Structure Alignment Method Based on the Residue Residue Contact Area. AB - Proteins are flexible, and this flexibility has an essential functional role. Flexibility can be observed in loop regions, rearrangements between secondary structure elements, and conformational changes between entire domains. However, most protein structure alignment methods treat protein structures as rigid bodies. Thus, these methods fail to identify the equivalences of residue pairs in regions with flexibility. In this study, we considered that the evolutionary relationship between proteins corresponds directly to the residue-residue physical contacts rather than the three-dimensional (3D) coordinates of proteins. Thus, we developed a new protein structure alignment method, contact area-based alignment (CAB-align), which uses the residue-residue contact area to identify regions of similarity. The main purpose of CAB-align is to identify homologous relationships at the residue level between related protein structures. The CAB align procedure comprises two main steps: First, a rigid-body alignment method based on local and global 3D structure superposition is employed to generate a sufficient number of initial alignments. Then, iterative dynamic programming is executed to find the optimal alignment. We evaluated the performance and advantages of CAB-align based on four main points: (1) agreement with the gold standard alignment, (2) alignment quality based on an evolutionary relationship without 3D coordinate superposition, (3) consistency of the multiple alignments, and (4) classification agreement with the gold standard classification. Comparisons of CAB-align with other state-of-the-art protein structure alignment methods (TM-align, FATCAT, and DaliLite) using our benchmark dataset showed that CAB-align performed robustly in obtaining high-quality alignments and generating consistent multiple alignments with high coverage and accuracy rates, and it performed extremely well when discriminating between homologous and nonhomologous pairs of proteins in both single and multi-domain comparisons. The CAB-align software is freely available to academic users as stand-alone software at http://www.pharm.kitasato-u.ac.jp/bmd/bmd/Publications.html. PMID- 26502071 TI - Influence of quasi-specific sites on kinetics of target DNA search by a sequence specific DNA-binding protein. AB - Functions of transcription factors require formation of specific complexes at particular sites in cis-regulatory elements of genes. However, chromosomal DNA contains numerous sites that are similar to the target sequences recognized by transcription factors. The influence of such "quasi-specific" sites on functions of the transcription factors is not well understood at present by experimental means. In this work, using fluorescence methods, we have investigated the influence of quasi-specific DNA sites on the efficiency of target location by the zinc finger DNA-binding domain of the inducible transcription factor Egr-1, which recognizes a 9 bp sequence. By stopped-flow assays, we measured the kinetics of Egr-1's association with a target site on 143 bp DNA in the presence of various competitor DNAs, including nonspecific and quasi-specific sites. The presence of quasi-specific sites on competitor DNA significantly decelerated the target association by the Egr-1 protein. The impact of the quasi-specific sites depended strongly on their affinity, their concentration, and the degree of their binding to the protein. To quantitatively describe the kinetic impact of the quasi specific sites, we derived an analytical form of the apparent kinetic rate constant for the target association and used it for fitting to the experimental data. Our kinetic data with calf thymus DNA as a competitor suggested that there are millions of high-affinity quasi-specific sites for Egr-1 among the 3 billion bp of genomic DNA. This study quantitatively demonstrates that naturally abundant quasi-specific sites on DNA can considerably impede the target search processes of sequence-specific DNA-binding proteins. PMID- 26502075 TI - Retraction of: Hosseinkhani H, et al.; DOI: 10.1089/ten.2006.0120. PMID- 26502072 TI - A Method for Recording Urethral Pressure Profiles in Female Rats. AB - AIMS: Urethral pressure profile (UPP) and leak-point pressure (LPP) measurements as well as external urethral sphincter (EUS) electromyography (EMG) and videourodynamic analyses are the primary methods for evaluating urethral function in humans. However, UPP recording in female rats, a widely used animal model, is challenging due to their small body sizes. This study reports a novel method for recording UPP in female rats. MATERIALS AND METHODS: Seventeen anesthetized female rats were studied. LPP data for 14 rats were included. The other 3 rats were excluded because of death or abnormal urogenital organs. UPP curves were recorded using a modified water-perfusion catheter system, with the lateral hole facing the 3-, 6-, 9-, and 12-o'clock positions in a randomized sequence. LPP, functional urethral length (FUL) and maximum urethral closure pressure (MUCP) were analyzed. RESULTS: The mean LPP was 64.39 +/- 20.29 cm H2O. The mean FUL and MUCP values at the 3-, 6-, 9-, and 12-o'clock positions were 12.90 +/- 1.20, 16.70 +/- 1.95, 13.90 +/- 2.42, and 11.60 +/- 0.97 mm, respectively, and 38.70 +/ 11.85, 33.90 +/- 11.82, 37.40 +/- 11.95, and 71.90 +/- 23.01 cm H2O, respectively. The FUL at the 6-o'clock position and MUCP at the 12-o'clock position were significantly greater than those at the other 3 positions. The FUL and MUCP of repeated UPP recordings were not significantly different than those of the first recordings. CONCLUSIONS: UPP recording using a modified method based on a water-perfusion catheter system is feasible and replicable in female rats. It produces UPP curves that sensitively and appreciably reflect detailed pressure changes at different points within the urethra and thus provides opportunity to evaluate urethral structures, especially the urethral sphincter, in detail. These results may enhance the utility of female rat models in research of urinary sphincter mechanisms. PMID- 26502076 TI - Haemoglobin content modulated deformation dynamics of red blood cells on a compact disc. AB - We investigate the deformation characteristics of red blood cells (RBCs) on a rotating compact disc platform. Our study brings out the interplay between haemoglobin content and RBC deformability in a centrifugally actuated microfluidic environment. We reveal that RBC deformations follow the similar trend of principal stress distributed throughout the radial direction, rendering an insight into the mechano-physical processes involved. This study can be used as a diagnostic marker to determine haematological disorders in diseased blood samples tested on compact disc based microfluidic platforms. PMID- 26502073 TI - Burden of Invasive Staphylococcus aureus Infections in Hospitalized Infants. AB - IMPORTANCE: Staphylococcus aureus is a frequent cause of infection in hospitalized infants. These infections are associated with increased mortality and morbidity and longer hospital stays, but data on the burden of S aureus disease in hospitalized infants are limited. OBJECTIVES: To compare demographics and mortality of infants with invasive methicillin-resistant S aureus (MRSA) and methicillin-susceptible S aureus (MSSA), to determine the annual proportion of S aureus infections that were MRSA, and to contrast the risk of death after an invasive MRSA infection with the risk after an invasive MSSA infection. DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective study of a large, nationally representative cohort at 348 neonatal intensive care units managed by the Pediatrix Medical Group. Participants were 3888 infants with an invasive S aureus infection who were discharged from calendar year 1997 through calendar year 2012. EXPOSURE: Invasive S aureus infection. MAIN OUTCOMES AND MEASURES: The incidence of invasive S aureus infections, as well as infant characteristics and mortality after MRSA or MSSA infection. RESULTS: The 3888 infants had 3978 invasive S aureus infections (2868 MSSA and 1110 MRSA). The incidence of invasive S aureus infection was 44.8 infections per 10,000 infants. The yearly proportion of invasive infections caused by MRSA increased from calendar year 1997 through calendar year 2006 and has moderately decreased since then. Infants with invasive MRSA or MSSA infections had similar gestational ages and birth weights. Invasive MRSA infections occurred more often at a younger postnatal age. For infants with available mortality data, more infants with invasive MSSA infections (n = 237) died before hospital discharge than infants with invasive MRSA infections (n = 110). The proportions of infants who died after invasive MSSA and MRSA infections were similar at 237 of 2474 (9.6%) and 110 of 926 (11.9%), respectively (P = .05). The adjusted risk of death before hospital discharge was similar after invasive MSSA and MRSA infections (risk ratio, 1.19; 95% CI, 0.96-1.49). The risks of death at 7 and 30 days after invasive infection were similar between infants with invasive MSSA infection and infants with invasive MRSA infection. CONCLUSIONS AND RELEVANCE: Infant mortality after invasive MRSA and MSSA infections is similar, but MSSA causes more infections and more deaths in infants than MRSA. Measures to prevent S aureus infection should include MSSA in addition to MRSA. PMID- 26502077 TI - Hodgkin's lymphoma (relapsed or refractory): autologous stem cell therapy. AB - INTRODUCTION: People with Hodgkin's lymphoma usually present with a lump in the neck or upper chest, but a quarter of people also have fever, sweating, weight loss, fatigue, and itch. Almost all people with localised disease can be cured and, even among people with relapsed advanced disease, almost 50% to 60% survive event-free for 4 years or more. However, a proportion of patients with early Hodgkin's lymphoma with poor prognostic factors (up to 15%) or with advanced disease (40%-50%) still relapses or has refractory disease. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of high-dose chemotherapy plus autologous stem cell therapy for relapsed or refractory Hodgkin's lymphoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: Searching of electronic databases retrieved 298 studies. Appraisal of titles and abstracts led to the exclusion of 245 studies and the further review of 53 full publications. Of the 53 full articles evaluated, one systematic review was added. We performed a GRADE evaluation for three PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for one intervention, based on information relating to the effectiveness and safety of high-dose chemotherapy plus autologous stem cell therapy (versus conventional chemotherapy). PMID- 26502078 TI - A Novel Ribonuclease from Rana Chensinensis and Its Potential for the Treatment of Human Breast Cancer. AB - Onconase, a member of the pancreatic RNAase A superfamily of ribonucleases, is a chemotherapeutic agent, which has demonstrated selective antitumor activity in a variety of human malignancies. However, little is known about the mechanisms of it's action on human breast cancer cells. To investigate a novel Onconase from the frog of Rana chensinensis changbaishanensis on human breast cancer cells and the underlying mechanisms, a novel Onconase named Rdchonc from Rana chensinensis changbaishanensis was cloned by polymerase chain reaction. SDS-PAGE revealed that the Rdchonc had a high heterologous expression in Escherichia coli BL21(DE3). The MTT assay indicated that purified Rdchonc was cytotoxic to human breast cancer MCF-7 and MD-MB-231 cells. Treatment with 20 MUg/mL Rdchonc protein significantly reduced the invasive capacities of MCF-7 and MD-MB-231 cells. Interestingly, the authors found that such inhibitory effort on tumor cell growth induced by Rdchonc treatment may be explained by the regulation of proapoptotic Bcl-2 family proteins and inhibition of MEK/ERK phosphorylation. PMID- 26502079 TI - Relationship between Blood Myostatin Levels and Kidney Function:Shimane CoHRE Study. AB - OBJECTIVES: Myostatin (MSTN), a member of TGF-beta superfamily, is produced in the skeletal muscle to inhibit myocyte differentiation. MSTN expression is increased in the skeletal muscle in patients with chronic kidney disease (CKD), which may play a role in the pathogenesis of sarcopenia or in the protein energy wasting (PEW). This observation implies that the plasma MSTN level may be correlated with kidney function. Thus, we conducted a cross-sectional study to evaluate the association between the plasma MSTN concentration and the estimated glomerular filtration rate (eGFR). SUBJECTS AND METHODS: Subjects were 781 participants of a health examination performed in a rural area in Japan. Among them, 124 subjects were selected by stratified random sampling according to eGFR. Creatinine clearance (ClCr) by the Cockcroft-Gault equation was used as a measure of kidney function. Plasma concentration of MSTN was determined by ELISA. RESULTS: The plasma MSTN level was not different between men (3.42+/-1.61 ng/mL) and women (3.27+/-1.43 ng/mL). In a simple regression analysis, the MSTN level was significantly correlated with eGFR (r = -0.25, p<0.01) and ClCr (r = -0.20, p<0.05) but not with age and BMI. In a multiple linear regression analysis, the MSTN level showed a negative correlation with eGFR (standardized beta = -0.31, p<0.01) and ClCr (standardized beta = -0.35, p<0.01) under the adjustment with age, sex, BMI and LDL-C. Weak correlation was observed between the MSTN level and BMI / the serum LDL-C level. When the subjects were stratified into 4 groups according to eGFR, MSTN was significantly greater in the groups with the lowest and the 2nd lowest eGFR (3.55+/-1.79 and 3.76+/-1.75 ng/mL, respectively) than the level in the group with the highest eGFR (2.77+/-0.85 ng/mL). CONCLUSION: Plasma MSTN level was elevated in an early stage of CKD, which could be involved in the progression of sarcopenia. PMID- 26502080 TI - NIST RM 8398: Standardizing Discoveries. PMID- 26502081 TI - Distal acquired demyelinating symmetric neuropathy associated with colorectal adenocarcinoma: Should it be termed paraneoplastic? PMID- 26502082 TI - Evaluation of Different Thickness, Die Color, and Resin Cement Shade for Veneers of Multilayered CAD/CAM Blocks. AB - PURPOSE: To investigate the effect of resin cement color on the post-cementation shade of thin laminate veneers milled from multilayered glass ceramic blocks for each layer. MATERIALS AND METHODS: Thin slices (N = 180) with two thicknesses (A: 8 * 8*0.55 mm and B: 8*8*0.8 mm; n = 90/group) were obtained from multilayered glass ceramic blocks using a diamond saw. Resin die specimens were prepared (8 * 8 * 4 mm) (n = 180) and divided into two resin cement colors (D: -3. L: +3) and one control group (C: translucent). Each slice was luted to the composite specimens using a dual-curing resin cement under a constant load of 250 g and light-polymerized for 120 seconds. Specimens were placed on a white background and CIELab values for each layer of the blank slices (incisal [In], body [Bo], and cervical [Ce]) were recorded using a dental contact spectrophotometer. The values were calculated as DeltaE, and the data were statistically analyzed (one way ANOVA, Shapiro-Wilk). RESULTS: Mean DeltaE values for A and B were significant (p < 0.05) for In (A: 6.2 +/- 1.1; B: 6.6 +/- 1.2), Bo (A: 5.1 +/- 2.6; B: 3.9 +/- 1), and Ce (A: 5.3 +/- 2.7; B: 3.8 +/- 1.2). Mean DeltaE values for In for D and L for A and B groups were significantly higher (6.3 +/- 1.2; 6.6 +/- 1.2) than Bo and Ce for D (4.4 +/- 2.4; 4.6 +/- 2.6) and L (4.6 +/- 1.4; 4.5 +/- 1.7) groups (p < 0.05), respectively. Mean differences between Bo and Ce for A and B groups were insignificant (p >= 0.05), while for In the differences were significant. Mean differences between Bo and Ce for A (5.1 +/- 2.6; 5.3 +/- 2.7) and for B (3.9 +/- 1; 3.5 +/- 1.2) groups were insignificant (p >= 0.05), while for In the differences were significant (6.2 +/- 1.1 for A and 6.6 +/- 1.2 for B). CONCLUSION: The color changes for body and cervical regions of multilayered ceramic veneers were not affected by resin color or ceramic thickness, but the incisal area was affected. The translucency of each layer in ceramic veneer fabricated with multilayered blanks should be considered for clinical situations. PMID- 26502083 TI - Regenerative Peripheral Nerve Interface for Prostheses Control: Electrode Comparison. AB - BACKGROUND: This study compared epimysial patch electrodes with intramuscular hook electrodes using monopolar and bipolar recording configurations. The purpose was to determine which strategy transduced muscle signals with better fidelity for control of myoelectric prostheses. METHODS: One of the two electrode styles, patch (n = 4) or hook (n = 6) was applied to the left extensor digitorum longus muscle in rats. Electrodes were evaluated at the time of placement and at monthly intervals for 4 months. Evaluations consisted of evoked electromyography signals from stimulation pulses applied to the peroneal and tibial nerves in both monopolar and bipolar recording configurations. RESULTS: Compared with hook electrodes, patch electrodes recorded larger signals of interest and minimized muscle tissue injury. A bipolar electrode configuration significantly reduced signal noise when compared with a monopolar configuration. CONCLUSION: Epimysial patch electrodes outperform intramuscular hook electrodes during chronic skeletal muscle implantation. PMID- 26502085 TI - Universal Prevention for Anxiety and Depressive Symptoms in Children: A Meta analysis of Randomized and Cluster-Randomized Trials. AB - Although under-diagnosed, anxiety and depression are among the most prevalent psychiatric disorders in children and adolescents, leading to severe impairment, increased risk of future psychiatric problems, and a high economic burden to society. Universal prevention may be a potent way to address these widespread problems. There are several benefits to universal relative to targeted interventions because there is limited knowledge as to how to screen for anxiety and depression in the general population. Earlier meta-analyses of the prevention of depression and anxiety symptoms among children suffer from methodological inadequacies such as combining universal, selective, and indicated interventions in the same analyses, and comparing cluster-randomized trials with randomized trials without any correction for clustering effects. The present meta-analysis attempted to determine the effectiveness of universal interventions to prevent anxiety and depressive symptoms after correcting for clustering effects. A systematic search of randomized studies in PsychINFO, Cochrane Library, and Google Scholar resulted in 30 eligible studies meeting inclusion criteria, namely peer-reviewed, randomized or cluster-randomized trials of universal interventions for anxiety and depressive symptoms in school-aged children. Sixty-three percent of the studies reported outcome data regarding anxiety and 87 % reported outcome data regarding depression. Seventy percent of the studies used randomization at the cluster level. There were small but significant effects regarding anxiety (.13) and depressive (.11) symptoms as measured at immediate posttest. At follow up, which ranged from 3 to 48 months, effects were significantly larger than zero regarding depressive (.07) but not anxiety (.11) symptoms. There was no significant moderation effect of the following pre-selected variables: the primary aim of the intervention (anxiety or depression), deliverer of the intervention, gender distribution, children's age, and length of the intervention. Despite small effects, we argue for the possible clinical and practical significance of these programs. Future evaluations should carefully investigate the moderators and mediators of program effects to identify active program components. PMID- 26502086 TI - Prognostic factors after salvage radiotherapy alone in patients with biochemical recurrence after radical prostatectomy. AB - OBJECTIVES: To evaluate the oncological outcome and to assess prognostic factors of salvage radiotherapy alone in patients with biochemical recurrence after radical prostatectomy. METHODS: We reviewed our single institution, prospectively maintained database of 2043 patients who underwent radical prostatectomy between September 1995 and December 2011. In this cohort, 149 patients who developed biochemical recurrence after radical prostatectomy and received salvage radiotherapy alone after pelvic magnetic resonance imaging were included. Three dimensional conformal radiotherapy or intensity-modulated radiotherapy was delivered with a median dose of 70.0 Gy (66.0-78.0 Gy) or 67.2 Gy (64.8-70.0 Gy). Kaplan-Meier and Cox regression analyses were carried out. RESULTS: With a median follow up of 82 months (range 20-153 months), 55 patients (36.9%) failed salvage radiotherapy. The 5-year salvage radiotherapy failure-free probability was 53.6%. On multivariate analysis, pre-salvage radiotherapy prostate-specific- antigen >= 1.0 ng/mL (P = 0.003, hazard ratio 3.592, 95% confidence interval 1.522-8.579), pathological stage >= T3a (P = 0.004, hazard ratio 2.261, 95% confidence interval 1.290-3.833), pathological Gleason score >= 7 (P = 0.018, hazard ratio 5.501, 95% confidence interval 1.577-21.221), prostate-specific antigen doubling time < 12 months (P = 0.014, hazard ratio 2.243, 95% confidence interval 1.177-4.275) and no visible lesion on pelvic magnetic resonance imaging (P = 0.016, hazard ratio 2.068, 95% confidence interval 1.268-3.501) were independent prognostic factors of salvage radiotherapy failure after radical prostatectomy. CONCLUSIONS: Pre salvage radiotherapy prostate-specific antigen >= 1.0 ng/mL, pathological stage >= T3a, pathological Gleason score >= 7, prostate-specific antigen doubling time < 12 months and no visible lesion on pelvic magnetic resonance imaging are prognostic factors of salvage radiotherapy failure after radical prostatectomy. We should consider additional treatment in patients with these factors for favorable outcomes. PMID- 26502087 TI - Therapeutic advances in idiopathic pulmonary fibrosis. PMID- 26502088 TI - Nonsteroidal Anti-Inflammatory Drugs in the Treatment of Retinal Diseases. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of drugs in medicine and ophthalmology. Several NSAIDs have been commercially available for many years: diclofenac, flurbiprofen, indomethacin, ketorolac and suprofen. The purpose of this chapter is to review the clinical use of earlier and newer pharmacologic agents of the NSAID class. NSAIDs may have a modulating effect on ocular inflammation and pain through the prevention of prostaglandin synthesis via cyclooxygenase inhibition. Newer-generation NSAIDs have emerged in recent years for the treatment of ocular pain and inflammation. Nepafenac ophthalmic suspension 0.1% is a new topical NSAID prodrug that has been approved by the Food and Drug Administration for the treatment of pain and inflammation after cataract surgery. Preliminary data suggest nepafenac may also provide unique efficacy in the posterior segment, since its corneal permeability characteristics are superior to those of other NSAIDs. Nevanac, diclofenac, ketorolac and bromfenac are some notable NSAID candidates which should be investigated intravitreally or topically for retinal pharmacotherapy. In addition, for intraocular surgery, NSAIDs can help to prevent intraoperative miosis, reduce ocular pain, decrease postoperative inflammation and prevent cystoid macular edema. Retinal, choroidal and vitreous diseases may be the target of future nepafenac studies, either as monotherapy or as combination treatments. PMID- 26502089 TI - Electrodeposition and Screening of Photoelectrochemical Activity in Conjugated Polymers Using Scanning Electrochemical Cell Microscopy. AB - A number of renewable energy systems require an understanding and correlation of material properties and photoelectrochemical activity on the micro to nanoscale. Among these, conducting polymer electrodes continue to be important materials. In this contribution, an ultrasensitive scanning electrochemical cell microscopy (SECCM) platform is used to electrodeposit microscale thin films of poly(3 hexylthiophene) (P3HT) on an optically transparent gold electrode and to correlate the morphology (film thickness and structural order) with photoactivity. The electrochemical growth of P3HT begins with a thin ordered film up to 10 nm thick, after which a second more disordered film is deposited, as revealed by micro-Raman spectroscopy. A decrease in photoactivity for the thicker films, measured in situ immediately following film deposition, is attributed to an increase in bulk film disorder that limits charge transport. Higher resolution ex situ SECCM phototransient measurements, using a smaller diameter probe, show local variations in photoactivity within a given deposit. Even after aging, thinner, more ordered regions within a deposit exhibit sustained enhanced photocurrent densities compared to areas where the film is thicker and more disordered. The platform opens up new possibilities for high-throughput combinatorial correlation studies, by allowing materials fabrication and high spatial resolution probing of processes in photoelectrochemical materials. PMID- 26502090 TI - Rab11-FIP2 promotes the metastasis of gastric cancer cells. AB - Rab11-FIP2 can interact with MYO5B and plays an important role in regulating plasma membrane recycling. Our previous study has shown that MYO5B is epigenetically silenced and associated with c-Met signaling in human gastric cancer. However, little is known of the function of Rab11-FIP2 in gastric cancer. In this study, we investigated Rab11-FIP2 expression by immunohistochemistry in 86 patients with gastric cancer. We found that the expression level of Rab11-FIP2 was significantly increased in gastric cancer tissues and high expression of Rab11-FIP2 was closely correlated with nodal metastasis in gastric cancer patients. Rab11-FIP2 overexpression promoted epithelial-mesenchymal transition (EMT) in a manner associated with gastric cancer metastasis in vitro and in vivo. We also found that hypoxia could enhance the expression of Rab11-FIP2 through HIF 1alpha. Inactivation of Rab11-FIP2 dramatically decreased hypoxia-induced migration of gastric cancer cells. Suppression of the internalization of EGFR, at least in part, plays an important role in EMT induced by overexpression of Rab11 FIP2 in gastric cancer cells. Finally, we demonstrated that Rab11-FIP2 could regulate actin cytoskeleton dynamics. In conclusion, our findings reveal a novel mechanism underlying the role of Rab11-FIP2 in gastric cancer dissemination, suggesting that Rab11-FIP2 may be a promising candidate target for gastric cancer treatment. PMID- 26502091 TI - Thermo-Responsive Hydrogels for Ocular Drug Delivery. AB - Hydrogel as an ocular drug delivery platform holds great potential. Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of absorbing large amounts of water or biological fluids. They have the ability to swell in an aqueous solvent system, holding solvents within a cross-linked gel system for potential sustained delivery. Through manipulation of permeation and diffusion characteristics, they can retain hydrophobic and hydrophilic agents, small molecules and macromolecules. In addition, hydrogel can be combined with nano- or microspheres to enhance delivery capacity. The aqueous environment of hydrogels can also protect cells and pharmacological agents. Depending on the specific structure, they can be nondegradable or degradable in their application. PMID- 26502093 TI - Trajectories of depressive symptoms in old age: Integrating age-, pathology-, and mortality-related changes. AB - Late life involves a variety of different challenges to well-being. This study extends and qualifies propositions drawn from the paradox of well-being in aging using 15-year longitudinal data on depressive symptoms from old and very old participants in the Australian Longitudinal Study of Ageing (Baseline N = 2,087; Mage = 78.69 years; range: 65-103 years; 49.40% women). We first examined age related trajectories in depressive symptoms from young-old to oldest-old, taking into account (changes in) relevant correlates, pathology, and mortality; and, second, we investigated gender differences in these trajectories. Results revealed that age-related trajectories of depressive symptoms were predictive of mortality hazards. The unique predictive effects of both level of, and change in, depressive symptoms were independent of one another and held after taking into account education as well as changes in marital status, living arrangements, cognitive function, and illness burden. In addition, results indicated that depressive symptoms were elevated among participants suffering from arthritis, and increased with age more markedly in men than in women. In particular, the significant Age * Gender interaction indicated that the gender gap in depressive symptoms reduced from young-old to old-old and reversed in very old age when men showed more depressive symptoms than women. Qualifying the paradox of well-being in aging, findings demonstrated that depressive symptoms increased from young-old to oldest-old and suggest that age-, pathology-, and mortality-related changes should be examined in concert to advance our understanding of individual differences in depressive symptom trajectories in late life. PMID- 26502084 TI - Speciation with gene flow in whiptail lizards from a Neotropical xeric biome. AB - Two main hypotheses have been proposed to explain the diversification of the Caatinga biota. The riverine barrier hypothesis (RBH) claims that the Sao Francisco River (SFR) is a major biogeographic barrier to gene flow. The Pleistocene climatic fluctuation hypothesis (PCH) states that gene flow, geographic genetic structure and demographic signatures on endemic Caatinga taxa were influenced by Quaternary climate fluctuation cycles. Herein, we analyse genetic diversity and structure, phylogeographic history, and diversification of a widespread Caatinga lizard (Cnemidophorus ocellifer) based on large geographical sampling for multiple loci to test the predictions derived from the RBH and PCH. We inferred two well-delimited lineages (Northeast and Southwest) that have diverged along the Cerrado-Caatinga border during the Mid-Late Miocene (6-14 Ma) despite the presence of gene flow. We reject both major hypotheses proposed to explain diversification in the Caatinga. Surprisingly, our results revealed a striking complex diversification pattern where the Northeast lineage originated as a founder effect from a few individuals located along the edge of the Southwest lineage that eventually expanded throughout the Caatinga. The Southwest lineage is more diverse, older and associated with the Cerrado-Caatinga boundaries. Finally, we suggest that C. ocellifer from the Caatinga is composed of two distinct species. Our data support speciation in the presence of gene flow and highlight the role of environmental gradients in the diversification process. PMID- 26502095 TI - Immobilization of silver nanoparticles on exfoliated mica nanosheets to form highly conductive nanohybrid films. AB - Highly electrically conductive films were prepared by coating organic/inorganic nanohybrid solutions with a polymeric dispersant and exfoliated mica nanosheets (Mica) on which silver nanoparticles (AgNPs) had been dispersed in various components. Transmission electronic microscopy showed that the synthesized AgNPs had a narrow size distribution and a diameter of approximately 20 nm. Furthermore, a 60 MUm thick film with a sheet resistance as low as 4.5 * 10(-2) Omega/sq could be prepared by controlling the heating temperature and by using AgNPs/POE-imide/Mica in a weight ratio of 20:20:1. During the heating process, the surface color of the hybrid film changed from dark golden to white, suggesting the accumulation of the AgNPs through surface migration and their melting to form an interconnected network. These nanohybrid films have potential for use in various electrically conductive devices. PMID- 26502094 TI - Complement Stimulates Retinal Pigment Epithelial Cells to Undergo Pro Inflammatory Changes. AB - BACKGROUND/AIMS: We examined the effect of human complement sera (HCS) on retinal pigment epithelial (RPE) cells with respect to pro-inflammatory mediators relevant in early age-related macular degeneration (AMD). METHODS: RPE cells were treated with complement-containing HCS or with heat-inactivated (HI) HCS or C7 deficient HCS as controls. Cells were analysed for C5b-9 using immunocytochemistry and flow cytometry. Interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) were quantified by ELISA and RT-PCR. Tumour necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), were analysed by Western blotting. The intracellular distribution of nuclear factor (NF)-x03BA;B was investigated by immunofluorescence. RESULTS: A concentration-dependent increased staining for C5b 9 but no influence on cell viability was observed after HCS treatment. ELISA and RT-PCR analysis revealed elevated secretion and expression of IL-6, IL-8, and MCP 1. Western blot analysis showed a concentration-dependent increase in ICAM-1, VCAM-1, and TNF-alpha in response to HCS, and immunofluorescence staining revealed nuclear translocation of NF-x03BA;B. CONCLUSION: This study suggests that complement stimulates NF-x03BA;B activation in RPE cells that might further create a pro-inflammatory environment. All these factors together may support early AMD development. PMID- 26502096 TI - Physical constraints, fundamental limits, and optimal locus of operating points for an inverted pendulum based actuated dynamic walker. AB - The inverted pendulum is a popular model for describing bipedal dynamic walking. The operating point of the walker can be specified by the combination of initial mid-stance velocity (v0) and step angle (phim) chosen for a given walk. In this paper, using basic mechanics, a framework of physical constraints that limit the choice of operating points is proposed. The constraint lines thus obtained delimit the allowable region of operation of the walker in the v0-phim plane. A given average forward velocity vx,avg can be achieved by several combinations of v0 and phim. Only one of these combinations results in the minimum mechanical power consumption and can be considered the optimum operating point for the given vx,avg. This paper proposes a method for obtaining this optimal operating point based on tangency of the power and velocity contours. Putting together all such operating points for various vx,avg, a family of optimum operating points, called the optimal locus, is obtained. For the energy loss and internal energy models chosen, the optimal locus obtained has a largely constant step angle with increasing speed but tapers off at non-dimensional speeds close to unity. PMID- 26502092 TI - Sleep-disordered Breathing and Incident Heart Failure in Older Men. AB - RATIONALE: The directionality of the relationship between sleep-disordered breathing and heart failure is controversial. OBJECTIVES: We assessed whether elevations in the obstructive or central sleep apnea index or the presence of Cheyne-Stokes breathing are associated with decompensated and/or incident heart failure. METHODS: We conducted a prospective, longitudinal study of 2,865 participants derived from the Osteoporotic Fractures in Men Study, a prospective multicenter observational study of community-dwelling older men. Participants underwent baseline polysomnography and were followed for a mean 7.3 years for development of incident or decompensated heart failure. Our main exposures were the obstructive apnea-hypopnea index (AHI), central apnea index (CAI >= 5), and Cheyne-Stokes breathing. Covariates included age, race, clinic site, comorbidities, physical activity, and alcohol and tobacco use. MEASUREMENTS AND MAIN RESULTS: CAI greater than or equal to five and presence of Cheyne-Stokes breathing but not obstructive AHI were significant predictors of incident heart failure (adjusted hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.16 2.77 for CAI >= 5) (HR, 2.23; 95% CI, 1.45-3.43 for Cheyne-Stokes breathing). After excluding those with baseline heart failure, the incident risk of heart failure was attenuated for those with CAI greater than or equal to five (HR, 1.57; 95% CI, 0.92-2.66) but remained significantly elevated for those with Cheyne-Stokes breathing (HR, 1.90; 95% CI, 1.10-3.30). CONCLUSIONS: An elevated CAI/Cheyne-Stokes breathing, but not an elevated obstructive AHI, is significantly associated with increased risk of decompensated heart failure and/or development of clinical heart failure in a community-based cohort of older men. PMID- 26502097 TI - The Minimum Clinically Important Difference of the Modified Japanese Orthopaedic Association Scale in Patients with Degenerative Cervical Myelopathy. AB - STUDY DESIGN: Analysis of the prospective AOSpine CSM-International and North America datasets and survey of AO Spine International. OBJECTIVE: This study aims to define the minimum clinically important difference (MCID) of the modified Japanese Orthopaedic Association (mJOA) in patients with degenerative cervical myelopathy (DCM). SUMMARY OF BACKGROUND DATA: The mJOA is the most frequently used clinician-administered tool to assess functional status in patients with DCM. By defining its MCID, clinicians can better evaluate treatment outcomes for this condition. METHODS: Three methods were used to determine the MCID of the mJOA: (1) distribution-based, (2) anchor-based and receiver operating characteristic (ROC) analysis, and (3) professional opinion. Distribution-based methods were used to estimate the MCID by computing the half standard deviation and standard error of measurement. Using anchor-based methods, mJOA at 12 months after surgery was compared between patients who were "slightly improved" on the Neck Disability Index (NDI) and those who were "unchanged." ROC analysis was performed to compute a discrete integer value for the MCID that yielded the smallest difference between sensitivity and specificity. We repeated anchor-based methods for patients with mild (mJOA: 15-17), moderate (mJOA: 12-14), and severe disease (mJOA <12). RESULTS: The half standard deviation of the baseline mJOA was 1.36 and the standard error of measurement was 1.21. The difference in mJOA between patients who "slightly improved" on the NDI and "unchanged" patients was 1.11. ROC analysis yielded a value of 2 for the MCID. The survey of 416 spine professionals confirmed these estimates: the mean response was 1.65 +/- 0.66. The MCID significantly varied depending on myelopathy severity: ROC analysis yielded a threshold of 1 for mild, 2 for moderate, and 3 for severe patients. CONCLUSION: The MCID of the mJOA is estimated to be between 1 and 2 points and varies with myelopathy severity. This knowledge will enable clinicians to identify meaningful functional improvements in DCM patients. LEVEL OF EVIDENCE: N/A. PMID- 26502098 TI - Effect of Lumbar Disc Degeneration and Low-Back Pain on the Lumbar Lordosis in Supine and Standing: A Cross-Sectional MRI Study. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To examine the influence of low back pain (LBP) and lumbar disc degeneration (LDD) on the lumbar lordosis in weight-bearing positional magnetic resonance imaging (pMRI). SUMMARY OF BACKGROUND DATA: The lumbar lordosis increases with a change of position from supine to standing and is known as an essential contributor to dynamic changes. However, the lordosis may be affected by disc degeneration and pain. METHODS: Patients with LBP >40 on a 0 to 100 mm Visual Analog Scale (VAS) both during activity and rest and a sex and age-decade matching control group without LBP were scanned in the supine and standing position in a 0.25-T open MRI unit. LDD was graded using Pfirrmann's grading-scale. Subsequently, the L2-to-S1 lumbar lordosis angle (LA) was measured. RESULTS: Thirty-eight patients with an average VAS of 58 (+/-13.8) mm during rest and 75 (+/-5.0) mm during activities, and 38 healthy controls were included. MRI findings were common in both groups, whereas, the summation of the Pfirrmann's grades (LDD-score) was significantly higher in the patients [(MD 1.44; 95% confidence intervals (CI) 0.80 to 2.10; P < 0.001]. The patients were less lordotic than the controls in both the supine (MD -6.4 degrees ; 95% CI -11.4 to -1.3), and standing position (MD -5.6 degrees ; 95% CI 10.7 to -0.7); however, the changes between the positions (DeltaLA) were the same (MD 0.8 degrees ; 95% CI -1.8 to 3.3). Using generalized linear model the LDD score was associated with age (P < 0.001) for both groups. The LDD-score and DeltaLA were negatively associated in the control group (P < 0.001), also after adjustments for gender and age (beta-coefficient: -2.66; 95% CI -4.3 to -1.0; P = 0.002). CONCLUSION: Patients may be less lordotic in both the supine and standing position, whereas, change in the lordosis between the positions may be independent of pain. Decreasing lordosis change seems to be associated with age related increasing disc degeneration in healthy individuals. LEVEL OF EVIDENCE: 2. PMID- 26502099 TI - Retraction. PMID- 26502100 TI - Prevalence, Comorbidities, and Risk of Perioperative Complications in Human Immunodeficiency Virus-Positive Patients Undergoing Cervical Spine Surgery. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVE: To evaluate outcomes of human immunodeficiency virus (HIV) positive patients after cervical spine surgery. SUMMARY OF BACKGROUND DATA: Highly active antiretroviral medications have qualitatively altered the natural history of HIV, thus increasing the number of HIV-positive patients seeking treatment for chronic degenerative conditions. Minimal data exist on HIV patients undergoing degenerative cervical spine surgery. METHODS: The Nationwide Inpatient Sample was examined from 2002 to 2011. Hospitalizations were identified using International Classification of Diseases Ninth Revision, Clinical Modification (ICD-9-CM) procedural codes for cervical spine surgery and diagnoses codes for degenerative conditions of the cervical spine, and HIV. Statistical analysis was conducted to evaluate associations between HIV status and perioperative complications. RESULTS: A total of 1,602,129 patients underwent degenerative cervical spine surgery, of which 3700 patients (0.23%) had HIV. The prevalence of HIV increased over the study period from 0.19% to 0.33% (P < 0.001). Patients with HIV were younger (48.6 yrs vs. 53.4 yrs, P < 0.001) and more likely to be male (P < 0.001). HIV patients had significantly greater odds of having chronic pulmonary disease, liver disease, and drug abuse. Unadjusted analysis did not reveal increased rate of acute complications among HIV-positive patients compared with negative controls (3.8% vs. 3.7%, P = 0.62). Multivariate analysis did not identify HIV as a significant predictor of complication (odds ratio = 1.04, P = 0.84). HIV was associated with a 1.5 day increased length of stay AND 1.29 fold increase in median costs compared with controls ($14,551 vs. 18,846, P < 0.001). CONCLUSION: The prevalence of HIV patients undergoing degenerative cervical spine surgery is increasing. A diagnosis of HIV was not associated with an increased risk of perioperative complication among patients undergoing degenerative cervical spine surgery. Further clinical studies are needed to evaluate predictors of complications among HIV patients and long-term outcomes. LEVEL OF EVIDENCE: 4. PMID- 26502101 TI - Efficacy of Erythropoietin-Beta Injections During Autologous Blood Donation Before Spinal Deformity Surgery in Children and Teenagers. AB - STUDY DESIGN: Retrospective observational study OBJECTIVE.: To clarify the efficacy of recombinant human erythropoietin-beta (EPO-beta) injections during autologous blood donation (ABD) before spinal deformity surgery in children and teenagers. SUMMARY OF BACKGROUND DATA: ABD is preferred for spinal deformity surgery. A few studies have assessed the usefulness of preoperative ABD with EPO beta in anemic patients. METHODS: Fifty-six spinal deformity surgery patients (41 females, 15 males; median age: 15 yrs; range, 5-19 yrs) underwent preoperative ABD. ABD was performed weekly according to the patient's body weight with a subcutaneous EPO-beta injection (24,000 U). The collected blood volumes were compared among the low hemoglobin (low-Hb) (<13 g/dL), mid-Hb (13-13.9 g/dL), and high-Hb (>=14 g/dL) groups using the Kruskal-Wallis test. The effects of EPO-beta injection on the Hb levels were estimated using a linear mixed model. RESULTS: The patients underwent a median of four ABD collections (range, two to six). The median collected volume per ABD was 200 mL (range, 40-400 mL). The median total blood collection was 700 mL (range, 160-1,350 mL); the corresponding values were 700 mL, 700 mL, and 800 mL in the low-Hb, mid-Hb, and high-Hb groups, respectively (P = 0.964). The median blood loss was 500 mL (range, 10-2,940 mL); 53 out of 55 patients (96%) did not require unplanned allogeneic transfusion, including 11 out of 12 (92%) cases with blood loss >1,000 mL. The additional recovery of Hb levels with one EPO-beta injection was 0.29 +/- 0.14 g/dL (P = 0.039) after adjusting for confounding factors. CONCLUSION: ABD with an EPO-beta injection is useful for avoiding allogeneic transfusion during spinal deformity surgery in children and teenagers, and patients in the low-Hb group achieved ABD volumes equivalent to those in the high-Hb group. Thus, an additional recovery of Hb levels of 0.29 g/dL per injection can be expected after 1 week. LEVEL OF EVIDENCE: 4. PMID- 26502102 TI - Validation of the Simplified Chinese Version of the Body Image Disturbance Questionnaire-Scoliosis. AB - STUDY DESIGN: Cross-cultural adaptation and validation of the Body Image Disturbance Questionnaire-Scoliosis (BIDQ-S). OBJECTIVE: The aim of this study was to validate the Chinese version of BIDQ-S (C-BIDQ-S) in adolescent idiopathic scoliosis (AIS) patients in Mainland China. SUMMARY OF BACKGROUND DATA: A modified version of the Body Image Disturbance Questionnaire instrument has been validated in AIS patients (BIDQ-S) to assess the perception of spinal appearance and psychological disturbance. However, there is no culturally adapted, reliable, and validated BIDQ-S for the Chinese population. METHOD: The BIDQ-S was translated into simplified Chinese, and the cross-cultural adaptation of the original BIDQ-S was performed according to international guidelines. A total of 100 AIS patients were recruited into this study. Validation including reliability, internal consistency, and convergent validity was evaluated by comparing the C-BIDQ-S with Scoliosis Research Society (SRS)-22 and Spinal Appearance Questionnaire (SAQ) instruments. The relationship between C-BIDQ-S score and patient characteristics was also assessed. RESULTS: Internal consistency for the C-BIDQ-S was satisfactory with a Cronbach alpha value of 0.877. The construct validity test demonstrated significant correlations between the C-BIDQ-S score and all SRS-22 domains as well as between the C-BIDQ-S score and most of SAQ domains. Although the C-BIDQ-S score was not correlated with age or BMI, patients with Cobb angle >40 degrees presented a significantly higher (poorer) C-BIDQ-S score. CONCLUSION: The Simplified Chinese version of BIDQ-S showed good internal consistency, strong psychometric properties, and satisfactory reliability. This concise questionnaire is suitable for widespread use in Mainland China. PMID- 26502103 TI - Should Dynamic Cervical Plates be Used With Interbody Cages? PMID- 26502104 TI - Water depth modifies back kinematics of horses during water treadmill exercise. AB - REASONS FOR PERFORMING STUDY: Water treadmill exercise can be incorporated into the rehabilitation programmes of horses recovering from back pathology, yet little is known about the effect of this type of exercise on thoracolumbar movement ranges. OBJECTIVES: To measure the flexion-extension range of motion (FE ROM) of the thoracolumbar spine and pelvic vertical displacement during water treadmill walking at 3 water depths and compare these with the control condition. STUDY DESIGN: Within-subject trial using a crossover design in healthy horses. METHODS: A total of 14 horses walked at 0.8 m/s on a water treadmill for 3 min at each of the following depths; hoof (control), metatarsophalangeal joint (low), tarsal joint (medium) and femoropatellar joint (high). Skin surface markers on T6, T10, T13, T18, L3, L5 and S3 were used to obtain FE ROM and the minimum and maximum angular motion pattern values (AMPmin and AMPmax) for T10, T13, T18, L3 and L5. Markers placed on left and right tuber coxae were used to obtain pelvic vertical displacement. Friedman's tests and post hoc Wilcoxon's signed ranks tests were used to determine the effects of water depth on measured variables. RESULTS: The FE ROM of T10 (8.4 degrees ), T13 (8.1 degrees ), T18 (6.9 degrees ) and L3 (6.4 degrees ) when walking at high depth was significantly greater than control (5.5, 5.7, 5.1 and 5.1 degrees , respectively; P<0.008); T13 AMPmin was significantly lower in high water (-3.0 degrees ) than control (0.1 degrees , P = 0.001) and L3 AMPmax significantly greater in high water (-1.9 degrees ) than control (-4.8 degrees , P = 0.001). There was no significant association between pelvic vertical displacement and water depth. CONCLUSIONS: Walking in high water causes cranial thoracic extension and thoracolumbar flexion when compared with walking in water at hoof depth. This postural change should be considered when designing rehabilitation programmes for horses with back and/or hindlimb pathology. PMID- 26502105 TI - Retinal Hereditary and Degenerative/Dystrophic Diseases (Non-Age-Related Macular Degeneration). AB - The definition of hereditary retinal diseases includes heterogeneous conditions leading to significant visual impairment. Great strides are being made in the management of many of these dystrophies, with many ongoing trials aiming to ascertain if a pharmacological therapy can reverse or at least stop the natural course of these disorders. In addition, good results have also been achieved in the treatment of typical complications of inherited dystrophies such as cystoid macular edema and choroidal neovascularization. PMID- 26502106 TI - What Are the 30-day Readmission Rates Across Orthopaedic Subspecialties? AB - BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) now include hip and knee replacements in the Hospital Readmission Reduction Program. The 30-day readmission rate is an important quality metric; however, the incidence has not yet been defined across the numerous orthopaedic subspecialties. Elucidating the readmission rate for each subspecialty may indicate that certain services are being disincentivized by the CMS reimbursement program. Furthermore, the "planned" and "unplanned" definitions of readmission have not been well examined to determine their clinical relevance and representation of safe patient care. Therefore, reducing the 30-day readmission rate has become a top priority in orthopaedic quality assurance. QUESTIONS/PURPOSES: (1) What are the 30-day readmission rates for the different orthopaedic subspecialties? (2) What are the risk factors associated with readmission within 30 days? (3) What are the causes of 30-day readmissions? (4) What is the interrater agreement among CMS, hospital, and clinician definitions of planned and unplanned readmissions? METHODS: We retrospectively examined one tertiary care academic hospital's quality improvement database and identified 4792 discharges from the department of orthopaedics during a continuous 24-month period. Discharges were divided and analyzed according to the subspecialty of orthopaedic care. Demographics and comorbidities were extracted from the database and subjected to univariate and multivariate analysis to determine risk factors for 30-day readmission. Further chart review was conducted on all cases of 30-day readmission to identify causes. The authors' determination of planned versus unplanned was compared with two other definitions (hospital and CMS) and analyzed for agreement by using Fleiss' kappa for multiple rater. RESULTS: The all-cause 30-day readmission rate was 4% (95% confidence interval [CI], 3.8-4.8). The unplanned readmission rate was 3% (95% CI, 2.8-3.8). After controlling for relevant confounding variables, we found that length of stay (odds ratio [OR], 1.10 per day; p < 0.001), American Society of Anesthesiologists score (OR, 1.89 per point; p < 0.001), and care under trauma (OR, 2.55; p < 0.001) or "other" (OR, 1.65; p = 0.009) as compared with joint subspecialty were associated with increased risk of readmission. Of the 160 unplanned readmissions, 93 (58%) were surgical and 67 (42%) were medical. The most common surgical cause was surgical site infection (38% of surgical readmissions) and the most common medical causes were gastrointestinal bleed, pulmonary embolus, and unrelated trauma (each 9% of medical readmissions). There was poor agreement (Fleiss' kappa = 0.120) among the three definitions of planned readmission. CONCLUSIONS: There are important differences in the risk of readmission by subspecialty across orthopaedics and the CMS-driven disincentives may be applied unequally across these subspecialties. This could result in hospitals deemphasizing those service lines and could potentially limit access to care for the patients most in need. Avenues of readmission reduction should be further studied including telephone followup programs and outpatient management of threatened wounds. Clinical, hospital, and CMS definitions of planned readmission have poor agreement, suggesting that hospitals are being unnecessarily penalized. The CMS should develop a more clinically relevant definition of 30-day readmission to more accurately evaluate the rate of readmissions. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26502108 TI - Stereoscopic Surgical Recording Using GoPro Cameras--Reply. PMID- 26502107 TI - Objective Structured Assessments of Technical Skills (OSATS) Does Not Assess the Quality of the Surgical Result Effectively. AB - BACKGROUND: Performance assessment in skills training is ideally based on objective, reliable, and clinically relevant indicators of success. The Objective Structured Assessment of Technical Skill (OSATS) is a reliable and valid tool that has been increasingly used in orthopaedic skills training. It uses a global rating approach to structure expert evaluation of technical skills with the experts working from a list of operative competencies that are each rated on a 5 point Likert scale anchored by behavioral descriptors. Given the observational nature of its scoring, the OSATS might not effectively assess the quality of surgical results. QUESTIONS/PURPOSES: (1) Does OSATS scoring in an intraarticular fracture reduction training exercise correlate with the quality of the reduction? (2) Does OSATS scoring in a cadaveric extraarticular fracture fixation exercise correlate with the mechanical integrity of the fixation? METHODS: Orthopaedic residents at the University of Iowa (six postgraduate year [PGY]-1s) and at the University of Minnesota (seven PGY-1s and eight PGY-2s) undertook a skills training exercise that involved reducing a simulated intraarticular fracture under fluoroscopic guidance. Iowa residents participated three times during 1 month, and Minnesota residents participated twice with 1 month between their two sessions. A fellowship-trained orthopaedic traumatologist rated each performance using a modified OSATS scoring scheme. The quality of the articular reduction obtained was then directly measured. Regression analysis was performed between OSATS scores and two metrics of articular reduction quality: articular surface deviation and estimated contact stress. Another skills training exercise involved fixing a simulated distal radius fracture in a cadaveric specimen. Thirty residents, distributed across four PGY classes (PGY-2 and PGY-3, n = 8 each; PGY 4 and PGY-5, n = 7 each), simultaneously completed the exercise at individual stations. One of three faculty hand surgeons independently scored each performance using a validated OSATS scoring system. The mechanical integrity of each fixation construct was then assessed in a materials testing machine. Regression analysis was performed between OSATS scores and two metrics of fixation integrity: stiffness and failure load. RESULTS: In the intraarticular fracture model, OSATS scores did not correlate with articular reduction quality (maximum surface deviations: R = 0.17, p = 0.25; maximum contact stress: R = 0.22, p = 0.13). Similarly in the cadaveric extraarticular fracture model, OSATS scores did not correlate with the integrity of the mechanical fixation (stiffness: R = 0.10, p = 0.60; failure load: R = 0.30, p = 0.10). CONCLUSIONS: OSATS scoring methods do not effectively assess the quality of the surgical result. Efforts must be made to incorporate assessment metrics that reflect the quality of the surgical result. CLINICAL RELEVANCE: New objective, reliable, and clinically relevant measures of the quality of the surgical result obtained by a trainee are urgently needed. For intraarticular fracture reduction and extraarticular fracture fixation, direct physical measurement of reduction quality and of mechanical integrity of fixation, respectively, meet this need. PMID- 26502109 TI - Rheological Analysis of Polymer Interactions and Ageing of Poly(Methylvinylether Co-Maleic Anhydride)/Poly(Vinyl Alcohol) Binary Networks and Their Effects on Mucoadhesion. AB - Polymer blends of poly(vinylalcohol, PVA) and poly(methylvinylether-co-maleic anhydride, PMVE/MA) were formulated and their viscoelastic and mucoadhesive properties characterised. The viscoelastic and mucoadhesive properties were dependent on polymer concentration, molecular weight of PVA and PVA:PMVE/MA ratio. Alteration of these properties allowed platforms to be designed to offer defined rheological and mucoadhesive properties, properties that could not be achieved using monopolymeric platforms. A strong correlation was noted between the modulus of the polymeric blends and mucoadhesion. After storage, the polymeric blends underwent rheological structuring (ageing) with an attendant enhancement of mucoadhesion. In certain blends containing the highest molecular weight of PVA (146-186 kDa), storage ultimately resulted in an increase and then a significant decrease in the rheological and mucoadhesive properties, the latter phenomenon being accredited to polymer recrystallisation. Ageing of the rheological and mucoadhesive properties was modelled using an exponential growth model, allowing predictions of the storage period associated with the maxima in viscoelastic and mucoadhesive properties. These observations highlight the possible implications whenever interactive polymeric blends are employed in drug delivery. Caution is therefore urged whenever a formulation strategy based on interactive polymer blends is employed to ensure that ageing is fully understood and mathematically characterised. PMID- 26502110 TI - Risk Factors Associated With Language in Autism Spectrum Disorder: Clues to Underlying Mechanisms. AB - PURPOSE: Identifying risk factors associated with neurodevelopmental disorders is an important line of research, as it will lead to earlier identification of children who could benefit from interventions that support optimal developmental outcomes. The primary goal of this review was to summarize research on risk factors associated with autism spectrum disorder (ASD). METHOD: The review focused on studies of infants who have older siblings with ASD, with particular emphasis on risk factors associated with language impairment that affects the majority of children with ASD. Findings from this body of work were compared to the literature on specific language impairment. RESULTS: A wide range of risk factors has been found for ASD, including demographic (e.g., male, family history), behavioral (e.g., gesture, motor) and neural risk markers (e.g., atypical lateralization for speech and reduced functional connectivity). Environmental factors, such as caregiver interaction, have not been found to predict language outcomes. Many of the risk markers for ASD are also found in studies of risk for specific language impairment, including demographic, behavioral, and neural factors. CONCLUSIONS: There are significant gaps in the literature and limitations in the current research that preclude direct cross syndrome comparisons. Future research directions are outlined that could address these limitations. PMID- 26502111 TI - Epigenetics and child abuse: Modern-day Darwinism--The miraculous ability of the human genome to adapt, and then adapt again. AB - It has long been recognized that early adversity can have life-long consequences, and the extent to which this is true is gaining increasing attention. A growing body of literature implicates Adverse Childhood Experiences, including physical, sexual, and emotional abuse, in a broad range of negative health consequences including adult psychopathology, cardiovascular, and immune disease. Increasing evidence from animal, clinical, and epidemiological studies highlight the critical role of epigenetic programing, such as DNA methylation and histone modification, in altering gene expression, brain structure and function, and ultimately life-course trajectories. This review outlines our developing insight into the interplay between our human biology and our changing environment, and explores the growing evidence base for how interventions may prevent and ameliorate damage inflicted by toxic stress in early life. PMID- 26502113 TI - Appropriate Prescribing for Patients With Diabetes at High Risk for Hypoglycemia: National Survey of Veterans Affairs Health Care Professionals. PMID- 26502112 TI - Prevalence of Marijuana Use Disorders in the United States Between 2001-2002 and 2012-2013. AB - IMPORTANCE: Laws and attitudes toward marijuana in the United States are becoming more permissive but little is known about whether the prevalence rates of marijuana use and marijuana use disorders have changed in the 21st century. OBJECTIVE: To present nationally representative information on the past-year prevalence rates of marijuana use, marijuana use disorder, and marijuana use disorder among marijuana users in the US adult general population and whether this has changed between 2001-2002 and 2012-2013. DESIGN, SETTING, AND PARTICIPANTS: Face-to-face interviews conducted in surveys of 2 nationally representative samples of US adults: the National Epidemiologic Survey on Alcohol and Related Conditions (data collected April 2001-April 2002; N = 43,093) and the National Epidemiologic Survey on Alcohol and Related Conditions-III (data collected April 2012-June 2013; N = 36,309). Data were analyzed March through May 2015. MAIN OUTCOMES AND MEASURES: Past-year marijuana use and DSM-IV marijuana use disorder (abuse or dependence). RESULTS: The past-year prevalence of marijuana use was 4.1% (SE, 0.15) in 2001-2002 and 9.5% (SE, 0.27) in 2012-2013, a significant increase (P < .05). Significant increases were also found across demographic subgroups (sex, age, race/ethnicity, education, marital status, income, urban/rural, and region). The past-year prevalence of DSM-IV marijuana use disorder was 1.5% (0.08) in 2001-2002 and 2.9% (SE, 0.13) in 2012-2013 (P < .05). With few exceptions, increases in the prevalence of marijuana use disorder between 2001-2002 and 2012-2013 were also statistically significant (P < .05) across demographic subgroups. However, the prevalence of marijuana use disorder among marijuana users decreased significantly from 2001-2002 (35.6%; SE, 1.37) to 2012-2013 (30.6%; SE, 1.04). CONCLUSIONS AND RELEVANCE: The prevalence of marijuana use more than doubled between 2001-2002 and 2012-2013, and there was a large increase in marijuana use disorders during that time. While not all marijuana users experience problems, nearly 3 of 10 marijuana users manifested a marijuana use disorder in 2012-2013. Because the risk for marijuana use disorder did not increase among users, the increase in prevalence of marijuana use disorder is owing to an increase in prevalence of users in the US adult population. Given changing laws and attitudes toward marijuana, a balanced presentation of the likelihood of adverse consequences of marijuana use to policy makers, professionals, and the public is needed. PMID- 26502114 TI - Transportable, Chemical Genetic Methodology for the Small Molecule-Mediated Inhibition of Heat Shock Factor 1. AB - Proteostasis in the cytosol is governed by the heat shock response. The master regulator of the heat shock response, heat shock factor 1 (HSF1), and key chaperones whose levels are HSF1-regulated have emerged as high-profile targets for therapeutic applications ranging from protein misfolding-related disorders to cancer. Nonetheless, a generally applicable methodology to selectively and potently inhibit endogenous HSF1 in a small molecule-dependent manner in disease model systems remains elusive. Also problematic, the administration of even highly selective chaperone inhibitors often has the side effect of activating HSF1 and thereby inducing a compensatory heat shock response. Herein, we report a ligand-regulatable, dominant negative version of HSF1 that addresses these issues. Our approach, which required engineering a new dominant negative HSF1 variant, permits dosable inhibition of endogenous HSF1 with a selective small molecule in cell-based model systems of interest. The methodology allows us to uncouple the pleiotropic effects of chaperone inhibitors and environmental toxins from the concomitantly induced compensatory heat shock response. Integration of our method with techniques to activate HSF1 enables the creation of cell lines in which the cytosolic proteostasis network can be up- or down-regulated by orthogonal small molecules. Selective, small molecule-mediated inhibition of HSF1 has distinctive implications for the proteostasis of both chaperone-dependent globular proteins and aggregation-prone intrinsically disordered proteins. Altogether, this work provides critical methods for continued exploration of the biological roles of HSF1 and the therapeutic potential of heat shock response modulation. PMID- 26502116 TI - Comparison of Pedicle Screw Loosening Mechanisms and the Effect on Fixation Strength. AB - Screw loosening is a common complication in spinal fixation using pedicle screws which may lead to loss of correction and revision surgery. The mechanisms of pedicle screw loosening are not well understood. The purpose of this study was to compare the pedicle screw pullout force and stiffness subsequent or not to multidirectional cyclic bending load (toggling). Pedicle screws inserted into porcine lumbar vertebrae underwent toggling in craniocaudal (CC), mediolateral (ML) directions, and no toggling (NT) before pullout. This study suggests that toggling and in particular CC toggling should be included in biomechanical evaluation of pedicle screw fixation strength. PMID- 26502115 TI - Racial Differences in the Surgical Care of Medicare Beneficiaries With Localized Prostate Cancer. AB - IMPORTANCE: There is extensive evidence suggesting that black men with localized prostate cancer (PCa) have worse cancer-specific mortality compared with their non-Hispanic white counterparts. OBJECTIVE: To evaluate racial disparities in the use, quality of care, and outcomes of radical prostatectomy (RP) in elderly men (>= 65 years) with nonmetastatic PCa. DESIGN, SETTING, AND PARTICIPANTS: This retrospective analysis of outcomes stratified according to race (black vs non Hispanic white) included 2020 elderly black patients (7.6%) and 24,462 elderly non-Hispanic white patients (92.4%) with localized PCa who underwent RP within the first year of PCa diagnosis in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database between 1992 and 2009. The study was performed in 2014. MAIN OUTCOMES AND MEASURES: Process of care (ie, time to treatment, lymph node dissection), as well as outcome measures (ie, complications, emergency department visits, readmissions, PCa-specific and all-cause mortality, costs) were evaluated using Cox proportional hazards regression. Multivariable conditional logistic regression and quantile regression were used to study the association of racial disparities with process of care and outcome measures. RESULTS: The proportion of black patients with localized prostate cancer who underwent RP within 90 days was 59.4% vs 69.5% of non-Hispanic white patients (P < 001). In quantile regression of the top 50% of patients, blacks had a 7-day treatment delay compared with non-Hispanic whites. (P < 001). Black patients were less likely to undergo lymph node dissection (odds ratio [OR], 0.76 [95% CI, 0.66-0.80]; P < .001) but had higher odds of postoperative visits to the emergency department (within 30 days: OR, 1.48 [95% CI, 1.18-1.86]); after 30 days or more (OR, 1.45 [95% CI, 1.19-1.76]) and readmissions (within 30 days: OR, 1.28 [95% CI, 1.02-1.61]); >= 30 days (OR, 1.27 [95% CI, 1.07-1.51]) compared with non-Hispanic whites. The surgical treatment of black patients was associated with a higher incremental annual cost (the top 50% of blacks spent $1185.50 (95% CI , $804.85-1 $1566.10; P < .001) more than the top 50% of non-Hispanic whites). There was no difference in PCa-specific mortality (P = .16) or all-cause mortality (P = .64) between black and non-Hispanic white men. CONCLUSIONS AND RELEVANCE: Blacks treated with RP for localized PCa are more likely to experience adverse events and incur higher costs compared with non-Hispanic white men; however, this does not translate into a difference in PCa-specific or all-cause mortality. PMID- 26502119 TI - Celebrating the ACP Centennial: From the Annals Archive-Alcohol and Diabetes. PMID- 26502120 TI - A Meeting at Autopsy. PMID- 26502122 TI - Risk Assessment and Prevention of Pressure Ulcers. PMID- 26502117 TI - Impact of Tobacco Smoke and Nicotine Exposure on Lung Development. AB - Tobacco smoke and nicotine exposure during prenatal and postnatal life can impair lung development, alter the immune response to viral infections, and increase the prevalence of wheezing during childhood. The following review examines recent discoveries in the fields of lung development and tobacco and nicotine exposure, emphasizing studies published within the last 5 years. In utero tobacco and nicotine exposure remains common, occurring in approximately 10% of pregnancies within the United States. Exposed neonates are at increased risk for diminished lung function, altered central and peripheral respiratory chemoreception, and increased asthma symptoms throughout childhood. Recently, genomic and epigenetic risk factors, such as alterations in DNA methylation, have been identified that may influence the risk for long-term disease. This review examines the impact of prenatal tobacco and nicotine exposure on lung development with a particular focus on nicotinic acetylcholine receptors. In addition, this review examines the role of prenatal and postnatal tobacco smoke and nicotine exposure and its association with augmenting infection risk, skewing the immune response toward a T-helper type 2 bias and increasing risk for developing an allergic phenotype and asthmalike symptoms during childhood. Finally, this review outlines the respiratory morbidities associated with childhood secondhand smoke and nicotine exposure and examines genetic and epigenetic modifiers that may influence respiratory health in infants and children exposed to in utero or postnatal tobacco smoke. PMID- 26502123 TI - Risk Assessment and Prevention of Pressure Ulcers. PMID- 26502124 TI - Risk Assessment and Prevention of Pressure Ulcers. PMID- 26502125 TI - Treatment of Pressure Ulcers. PMID- 26502126 TI - Treatment of Pressure Ulcers. PMID- 26502127 TI - Treatment of Pressure Ulcers. PMID- 26502128 TI - Treatment of Pressure Ulcers. PMID- 26502129 TI - Treatment of Pressure Ulcers. PMID- 26502130 TI - Differences Between Early and Late Readmissions Among Patients. PMID- 26502131 TI - Differences Between Early and Late Readmissions Among Patients. PMID- 26502132 TI - The Roles of Providers and Patients in the Overuse of Prostate-Specific Antigen Screening in the United States. PMID- 26502134 TI - Web Exclusives. The Consult Guys - Strokes and Surgery: What and When Are the Risks? PMID- 26502135 TI - ACP Journal Club. Review: Brief screening tests for dementia have pooled sensitivity of 76% to 92% and specificity of 81% to 91. PMID- 26502136 TI - ACP Journal Club. In atrial fibrillation treated with warfarin, intracranial hemorrhage was associated with ischemic events. PMID- 26502137 TI - ACP Journal Club. Oral contraceptives or NSAIDs before surgery for a fracture distal to the knee were linked to postdischarge VTE. PMID- 26502138 TI - ACP Journal Club. A risk calculator based on self-reported information predicted 5-year mortality in adults in the UK. PMID- 26502139 TI - ACP Journal Club. Review: In AF or VTE, direct oral anticoagulants reduce fatal bleeding compared with vitamin K antagonists. PMID- 26502140 TI - ACP Journal Club. Review: DOACs do not differ from standard anticoagulants for recurrent VTE; factor Xa inhibitors reduce bleeding. PMID- 26502141 TI - ACP Journal Club. Review: In acute ischemic stroke, adding endovascular therapy to t-PA improves functional independence at 90 days. PMID- 26502142 TI - ACP Journal Club. Review: In RA, standard- and high-dose biologic drugs increase serious infection compared with traditional DMARDs. PMID- 26502143 TI - ACP Journal Club. After source control in intraabdominal infections, 4-day and longer-duration antibiotics did not differ at 30-days. PMID- 26502144 TI - ACP Journal Club. Review: Dutasteride, fesoterodine, and finasteride are beneficial for lower urinary tract symptoms in older patients. PMID- 26502145 TI - ACP Journal Club. Review: In patients with type 2 diabetes who fast, sitagliptin reduces hypoglycemia more than sulfonylurea. PMID- 26502146 TI - ACP Journal Club. In adult smokers in the ED, a multicomponent intervention increased smoking cessation at 3 months. PMID- 26502147 TI - A Surgeon's Guide to Bundled Payment Models for Episodes of Care. PMID- 26502148 TI - Algorithm for the Measure of Vitreous Hyperreflective Foci in Optical Coherence Tomographic Scans of Patients With Diabetic Macular Edema. AB - IMPORTANCE: Developing a noninvasive measure of diabetic retinopathy disease progression may provide physicians with information needed for patient-specific intervention. OBJECTIVE: To develop an algorithm to measure vitreous hyperreflective foci (VHRF) from standard, 3-dimensional optical coherence tomographic (OCT) images in an unbiased manner. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed OCT scans from 97 patients who were evaluated at the Kellogg Eye Center, University of Michigan. Patients with diabetes mellitus without signs of retinopathy (n = 9) and patients with diabetic macular edema (DME) (n = 31) were compared with healthy control participants (n = 37). The algorithm was used to determine whether the VHRF score is associated with DME and may serve as a noninvasive measure of inflammation. The study was conducted from November 14, 2011, to August 5, 2015. Data analysis was performed from May 15, 2014, to August 13, 2015. MAIN OUTCOMES AND MEASURES: An algorithm was developed to enhance the vitreous imaging from OCT to allow automated quantification of VHRF and calculation of a VHRF score. This score was compared between the healthy control, diabetes without retinopathy, and DME groups. RESULTS: In the 97 scans evaluated, VHRF scores, reported as mean (SD), were increased in patients with DME by 2.95-fold (5.60 [8.65]) compared with healthy controls (1.90 [3.42]; 95% CI, 0.75-7.45; P = .012) and by 6.83-fold compared with patients with diabetes without retinopathy (0.82 [1.26]; 95% CI, 1.46-8.82; P = .005). CONCLUSIONS AND RELEVANCE: Scores obtained using the VHRF algorithm may be obtained from OCT images that include the vitreous and could provide a rapid, noninvasive clinical correlate for ocular inflammation. Higher VHRF scores in patients with DME compared with controls and diabetic patients without retinopathy warrant further population-based and longitudinal studies to help determine the value of the VHRF score in selecting therapeutic intervention. PMID- 26502156 TI - Crystal structure of group II intron domain 1 reveals a template for RNA assembly. AB - Although the importance of large noncoding RNAs is increasingly appreciated, our understanding of their structures and architectural dynamics remains limited. In particular, we know little about RNA folding intermediates and how they facilitate the productive assembly of RNA tertiary structures. Here, we report the crystal structure of an obligate intermediate that is required during the earliest stages of group II intron folding. Composed of domain 1 from the Oceanobacillus iheyensis group II intron (266 nucleotides), this intermediate retains native-like features but adopts a compact conformation in which the active site cleft is closed. Transition between this closed and the open (native) conformation is achieved through discrete rotations of hinge motifs in two regions of the molecule. The open state is then stabilized by sequential docking of downstream intron domains, suggesting a 'first come, first folded' strategy that may represent a generalizable pathway for assembly of large RNA and ribonucleoprotein structures. PMID- 26502155 TI - A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. AB - There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors. PMID- 26502157 TI - Highly Diastereoselective Michael Reactions Using beta-Nitrocarbonyl Nucleophiles. AB - We have discovered a highly diastereoselective Michael reaction of alpha substituted, beta-nitrocarbonyl compounds to deliver highly functionalized stereodiads containing fully substituted nitrogen-bearing centers. Good to excellent yields and diastereoselectivities are observed. This transformation is tolerant of various types of carbonyl groups on the nucleophilic partner, as well as a range of unsaturated electrophiles. Mechanistic investigations are consistent with internal hydrogen bonding in the nitroalkane tautomer as the major factor in the control of diastereoselectivity in these transformations. PMID- 26502158 TI - Cr-Cr Quintuple Bonds: Ligand Topology and Interplay Between Metal-Metal and Metal-Ligand Bonding. AB - Chromium-chromium quintuple bonds seem to be approaching the lower limit for their bond distances, and this computational density functional theory study tries to explore the geometrical and electronic factors that determine that distance and to find ways to fine-tune it via the ligand choice. While for monodentate ligands the Cr-Cr distance is predicted to shorten as the Cr-Cr-L bond angle increases, with bridging bidentate ligands the trend is the opposite, since those ligands with a larger number of spacers between the donor atoms favor larger bond angles and longer bond distances. Compared to Cr-Cr quadruple bonds, the quintuple bonding in Cr2L2 compounds (with L a bridging bidentate N-donor ligand) involves a sophisticated mechanism that comprises a positive pyramidality effect for the sigma and one pi bond, but a negative effect for one of the delta bonds. Moreover, the shorter Cr-Cr distances produce a mismatch of the bridging ligand lone pairs and the metal acceptor orbitals, which results in a negative correlation of the Cr-Cr and Cr-N bond distances in both experimental and calculated structures. PMID- 26502159 TI - Nanoparticles at Grain Boundaries Inhibit the Phase Transformation of Perovskite Membrane. AB - The high-energy nature of grain boundaries makes them a common source of undesirable phase transformations in polycrystalline materials. In both metals and ceramics, such grain-boundary-induced phase transformation can be a frequent cause of performance degradation. Here, we identify a new stabilization mechanism that involves inhibiting phase transformations of perovskite materials by deliberately introducing nanoparticles at the grain boundaries. The nanoparticles act as "roadblocks" that limit the diffusion of metal ions along the grain boundaries and inhibit heterogeneous nucleation and new phase formation. Ba0.5Sr0.5Co0.8Fe0.2O3-delta, a high-performance oxygen permeation and fuel cell cathode material whose commercial application has so far been impeded by phase instability, is used as an example to illustrate the inhibition action of nanoparticles toward the phase transformation. We obtain stable oxygen permeation flux at 600 degrees C with an unprecedented 10-1000 times increase in performance compared to previous investigations. This grain boundary stabilization method could potentially be extended to other systems that suffer from performance degradation due to a grain-boundary-initiated heterogeneous nucleation phase transformations. PMID- 26502161 TI - In Situ AFM Imaging of Solid Electrolyte Interfaces on HOPG with Ethylene Carbonate and Fluoroethylene Carbonate-Based Electrolytes. AB - Chemical and morphological structure of solid electrolyte interphase (SEI) plays a vital role in lithium-ion battery (LIB), especially for its cyclability and safety. To date, research on SEI is quite limited because of the complexity of SEI and lack of effective in situ characterization techniques. Here, we present real-time views of SEI morphological evolution using electrochemical atomic force microscopy (EC-AFM). Complemented by an ex situ XPS analysis, fundamental differences of SEI formation from ethylene carbonate (EC) and fluoroethylene carbonate (FEC)-based electrolytes during first lithiation/delithiation cycle on HOPG electrode surface were revealed. PMID- 26502160 TI - A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum-Infected Mouse Models from Structure-Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines. AB - Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics profiles. The lead compounds also proved to be very potent in the parasite liver and gametocyte stages, which makes them of high interest. PMID- 26502162 TI - Correcting electrode modelling errors in EIT on realistic 3D head models. AB - Electrical impedance tomography (EIT) is a promising medical imaging technique which could aid differentiation of haemorrhagic from ischaemic stroke in an ambulance. One challenge in EIT is the ill-posed nature of the image reconstruction, i.e., that small measurement or modelling errors can result in large image artefacts. It is therefore important that reconstruction algorithms are improved with regard to stability to modelling errors. We identify that wrongly modelled electrode positions constitute one of the biggest sources of image artefacts in head EIT. Therefore, the use of the Frechet derivative on the electrode boundaries in a realistic three-dimensional head model is investigated, in order to reconstruct electrode movements simultaneously to conductivity changes. We show a fast implementation and analyse the performance of electrode position reconstructions in time-difference and absolute imaging for simulated and experimental voltages. Reconstructing the electrode positions and conductivities simultaneously increased the image quality significantly in the presence of electrode movement. PMID- 26502163 TI - Plummer-Vinson Syndrome in Children. AB - OBJECTIVES: Plummer-Vinson syndrome (PVS), also called Kelly-Paterson syndrome, is a rare cause of dysphagia in children. This syndrome associates single or multiple webs in the upper esophagus with frequent iron deficiency. METHODS: We reported 3 pediatric cases of PVS before analyzing all of the cases of PVS in children reported in the PubMed and EMBASE databases. RESULTS: Among 17 reported PVS cases in children, all of the patients experienced iron-deficiency anemia, and no immunological disease was reported. The male/female ratio was 1/1.9, and most cases were observed in adolescents. Conversely to adults, endoscopic dilation was often necessary because dysphagia resisted iron supplementation. A single dilation was usually sufficient. One case of pediatric PVS experienced esophageal cancer in adulthood. CONCLUSIONS: In the case of dysphagia in children, a swallow barium exploration with lateral incidence should look for PVS. Conversely to adults, an endoscopic dilation is frequently necessary to control dysphagia in children. PMID- 26502164 TI - A Spectroscopic Study of the Aggregation State of the Human Antimicrobial Peptide LL-37 in Bacterial versus Host Cell Model Membranes. AB - The LL-37 antimicrobial peptide is the only cathelicidin peptide found in humans that has antimicrobial and immunomodulatory properties. Because it exerts also chemotactic and angiogenetic activity, LL-37 is involved in promoting wound healing, reducing inflammation, and strengthening the host immune response. The key to the effectiveness of antimicrobial peptides (AMPs) lies in the different compositions of bacterial versus host cell membranes. In this context, antimicrobial peptide LL-37 and two variants were studied in the presence of model membranes with different lipid compositions and charges. The investigation was performed using an experimental strategy that combines the site-directed spin labeling-electron paramagnetic resonance technique with circular dichroism and fluorescence emission spectroscopies. LL-37 interacts with negatively charged membranes forming a stable aggregate, which can likely produce toroidal pores until the amount of bound peptide exceeds a critical concentration. At the same time, we have clearly detected an aggregate with a higher oligomeric degree for interaction of LL-37 with neutral membranes. These data confirm the absence of cell selectivity of the peptide and a more complex role in stimulating host cells. PMID- 26502165 TI - Regulatory and Economic Considerations of Retinal Drugs. AB - The advent of anti-VEGF therapy for neovascular age-related macular degeneration and macular edema secondary to retinal vein occlusion and diabetes mellitus has prevented blindness in tens of thousands of people. However, the costs of these drugs are without precedent in ophthalmic drug therapeutics. An analysis of the financial implications of retinal drugs and the impact of the Food and Drug Administration on treatment of retinal disease must include not only an evaluation of the direct costs of the drugs and the costs associated with their administration, but also the cost savings which accrue from their clinical benefit. This chapter will discuss the financial and regulatory issues associated with retinal drugs. PMID- 26502166 TI - Mechanisms of Dihydroartemisinin and Dihydroartemisinin/Holotransferrin Cytotoxicity in T-Cell Lymphoma Cells. AB - The validated therapeutic effects of dihydroartemisinin (DHA) in solid tumors have encouraged us to explore its potential in treating T-cell lymphoma. We found that Jurkat cells (a T-cell lyphoma cell line) were sensitive to DHA treatment with a IC50 of dihydroartemisinin. The cytotoxic effect of DHA in Jurkat cells showed a dose- and time- dependent manner. Interestingly, the cytotoxic effect of DHA was further enhanced by holotransferrin (HTF) due to the high expression of transferrin receptors in T-cell lymphoma. Mechanistically, DHA significantly increased the production of intracellular reactive oxygen species, which led to cell cycle arrest and apoptosis. The DHA treatment also inhibited the expression of protumorgenic factors including VEGF and telomerase catalytic subunit. Our results have proved the therapeutic effect of DHA in T-cell lymphoma. Especially in combination with HTF, DHA may provide a novel efficient approach in combating the deadly disease. PMID- 26502168 TI - [Palsy of CVI caused by ecchordosis physaliphora]. AB - We report a case of symptomatic ecchordosis physaliphora (EP) in a 34-year-old woman who presented with progressive diplopia due to palsy of the left sixth cranial nerve. Repeated magnetic resonance imaging (MRI) disclosed typical characteristics of a congenital EP lesion with compression of the left abducens nerve presumably because of a secondary herniation of the arachnoid mater. We performed an augmenting combined recess resect procedure on the left eye. No progression of the lesion was observed over a period of 5 years. For differential diagnostics an EP has to be distinguished from skull base tumors, such as chordoma and chondrosarcoma. PMID- 26502167 TI - [Adjuvant therapy and interdisciplinary follow-up care of conjunctival melanoma]. AB - BACKGROUND: Despite microscopically controlled tumor excision, malignant melanomas of the conjunctiva have a propensity for local recurrence, lymphatic spread and distant metastases. OBJECTIVES: This review outlines the options of adjuvant therapy as well as the structure of interdisciplinary follow-up care for patients with conjunctival melanoma. METHODS: The study provides a PubMed literature review and own clinical results. RESULTS: In conjunctival melanoma complete tumor excision using a minimal touch technique should always be combined with adjuvant therapy, such as cryotherapy, radiotherapy, topical chemotherapy and/or immunotherapy. For locally circumscribed lesions of the bulbar conjunctiva adjuvant brachytherapy can be supplemented and for non-bulbar, extensive, diffuse or multilocular tumor growth, complementary adjuvant topical mitomycin C therapy or proton radiotherapy can be used. Novel adjuvant approaches include topical interferon alpha-2b immunotherapy, topical vascular endothelial growth factor (VEGF) inhibitors or in cases of BRAF mutations personalized therapy using selective BRAF inhibitors or in combination with mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK), MAPK/ERK (MEK) inhibitors. All patients should be integrated into an interdisciplinary follow-up care program including quarter yearly checkups in the first 5 years and psycho oncological healthcare. CONCLUSION: Following microscopically controlled tumor excision, adjuvant treatment using cryotherapy, radiotherapy, topical chemotherapy and/or immunotherapy as well as interdisciplinary follow-up care are mandatory for the modern management of patients with conjunctival melanoma. PMID- 26502169 TI - Effect of Diet and Age on Arterial Stiffening Due to Atherosclerosis in ApoE(-/-) Mice. AB - This work analyzes the progressive stiffening of the aorta due to atherosclerosis development of both ApoE(-/-) and C57BL/6J mice fed on a Western (n = 5) and a normal (n = 5) chow diet for the ApoE(-/-) group and on a normal chow diet (n = 5) for the C57BL/6J group. Sets of 5 animals from the three groups were killed after 10, 20, 30 and 40 weeks on their respective diets (corresponding to 17, 27, 37 and 47 weeks of age). Mechanical properties (inflation test and axial residual stress measurements) and histological properties were compared for both strains, ApoE(-/-) on the hyper-lipidic diet and both ApoE(-/-) and C57BL/6J on the normal diet, after the same period and after different periods of diet. The results indicated that the aorta stiffness in the ApoE(-/-) and C57BL/6J mice under normal diet remained approximately constant irrespective of their age. However, the arterial stiffness in the ApoE(-/-) on the hyper-lipidic diet increased over time. Statistical differences were found between the group after 10 weeks and the groups after 30 and 40 weeks of a hyper-lipidic diet. Comparing the hyper-lipidic and normal diet mice, statistical differences were also found between both diets in all cases after 40 weeks of diet, frequently after 30 weeks, and in some cases after 20 weeks. The early stages of lesion corresponded to the first 2 weeks of diet. Advanced lesions were found at 30 weeks and, finally, the aorta was completely damaged after 40 weeks of diet. In conclusion, we found substantial changes in the mechanical properties of the aorta walls of the ApoE(-/-) mice fed with the hyper-lipidic diet compared to the normal chow diet groups for both the ApoE(-/-) and C57BL/6J groups. These findings could serve as a reference for the study of changes in the arterial wall properties in cases of atherosclerosis. PMID- 26502170 TI - Tracking of Drug Release and Material Fate for Naturally Derived Omega-3 Fatty Acid Biomaterials. AB - In vitro and in vivo studies were conducted on omega-3 fatty acid-derived biomaterials to determine their utility as an implantable material for adhesion prevention following soft tissue hernia repair and as a means to allow for the local delivery of antimicrobial or antibiofilm agents. Naturally derived biomaterials offer several advantages over synthetic materials in the field of medical device development. These advantages include enhanced biocompatibility, elimination of risks posed by the presence of toxic catalysts and chemical crosslinking agents, and derivation from renewable resources. Omega-3 fatty acids are readily available from fish and plant sources and can be used to create implantable biomaterials either as a stand-alone device or as a device coating that can be utilized in local drug delivery applications. In-depth characterization of material erosion degradation over time using non-destructive imaging and chemical characterization techniques provided mechanistic insight into material structure: function relationship. This in turn guided rational tailoring of the material based on varying fatty acid composition to control material residence time and hence drug release. These studies demonstrate the utility of omega-3 fatty acid derived biomaterials as an absorbable material for soft tissue hernia repair and drug delivery applications. PMID- 26502171 TI - Properties and Mechanobiological Behavior of Bovine Nasal Septum Cartilage. AB - Bovine nasal septum (BNS) is a source of non-load bearing hyaline cartilage. Little information is available on its mechanical and biological properties. The aim of this work was to assess the characteristics of BNS cartilage and investigate its behavior in in vitro mechanobiological experiments. Mechanical tests, biochemical assays, and microscopic assessment were performed for tissue characterization. Compressions tests showed that the tissue is viscoelastic, although values of elastic moduli differ from the ones of other cartilaginous tissues. Water content was 78 +/- 1.4%; glycosaminoglycans and collagen contents measured by spectrophotometric assay and hydroxyproline assay-were 39 +/- 5% and 25 +/- 2.5% of dry weight, respectively. Goldner's Trichrome staining and transmission electron microscopy proved isotropic cells distribution and results of earlier cell division. Furthermore, gene expression was measured after uniaxial compression, showing variations depending on compression time as well as trends depending on equilibration time. In conclusion, BNS has been characterized at several levels, revealing that bovine nasal tissue is regionally homogeneous. Results suggest that, under certain conditions, BNS could be used to perform in vitro cartilage loading experiments. PMID- 26502172 TI - Association of a Guardian's Report of a Child Acting Abnormally With Traumatic Brain Injury After Minor Blunt Head Trauma. AB - IMPORTANCE: Increased use of computed tomography (CT) in children is concerning owing to the cancer risk from ionizing radiation, particularly in children younger than 2 years. A guardian report that a child is acting abnormally is a risk factor for clinically important traumatic brain injury (ciTBI) and may be a driving factor for CT use in the emergency department. OBJECTIVE: To determine the prevalence of ciTBIs and TBIs in children younger than 2 years with minor blunt head trauma and a guardian report of acting abnormally with (1) no other findings or (2) other concerning findings for TBI. DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of a large, prospective, multicenter cohort study that included 43 399 children younger than 18 years with minor blunt head trauma evaluated in 25 emergency departments. The study was conducted on data obtained between June 2004 and September 2006. Data analysis was performed between August 21, 2014, and March 9, 2015. EXPOSURES: A guardian report that the child was acting abnormally after minor blunt head trauma. MAIN OUTCOMES AND MEASURES: The prevalence of ciTBI (defined as death, neurosurgery, intubation for >24 hours, or hospitalization for >=2 nights in association with TBI on CT imaging) and TBI on CT imaging in children with a guardian report of acting abnormally with (1) no other findings and (2) other concerning findings for TBI. RESULTS: Of 43 399 children in the cohort study, a total of 1297 children had reports of acting abnormally, of whom 411 (31.7%) had this report as their only finding. Reported as percentage (95% CI), 1 of 411 (0.2% [0-1.3%]) had a ciTBI, and 4 TBIs were noted on the CT scans in 185 children who underwent imaging (2.2% [0.6%-5.4%]). In children with reports of acting abnormally and other concerning findings for TBI, 29 of 886 (3.3% [2.2%-4.7%]) had ciTBIs and 66 of 674 (9.8% [7.7%-12.3%]) had TBIs on CT. CONCLUSIONS AND RELEVANCE: Clinically important TBIs are very uncommon, and TBIs noted on CT are uncommon in children younger than 2 years with minor blunt head trauma and guardian reports of the child acting abnormally with no other clinical findings suspicious for TBI. Computed tomographic scans are generally not indicated in these children although observation in the emergency department may be warranted. PMID- 26502173 TI - Extending Protein Domain Boundary Predictors to Detect Discontinuous Domains. AB - A variety of protein domain predictors were developed to predict protein domain boundaries in recent years, but most of them cannot predict discontinuous domains. Considering nearly 40% of multidomain proteins contain one or more discontinuous domains, we have developed DomEx to enable domain boundary predictors to detect discontinuous domains by assembling the continuous domain segments. Discontinuous domains are predicted by matching the sequence profile of concatenated continuous domain segments with the profiles from a single-domain library derived from SCOP and CATH, and Pfam. Then the matches are filtered by similarity to library templates, a symmetric index score and a profile-profile alignment score. DomEx recalled 32.3% discontinuous domains with 86.5% precision when tested on 97 non-homologous protein chains containing 58 continuous and 99 discontinuous domains, in which the predicted domain segments are within +/-20 residues of the boundary definitions in CATH 3.5. Compared with our recently developed predictor, ThreaDom, which is the state-of-the-art tool to detect discontinuous-domains, DomEx recalled 26.7% discontinuous domains with 72.7% precision in a benchmark with 29 discontinuous-domain chains, where ThreaDom failed to predict any discontinuous domains. Furthermore, combined with ThreaDom, the method ranked number one among 10 predictors. The source code and datasets are available at https://github.com/xuezhidong/DomEx. PMID- 26502176 TI - Erratum. PMID- 26502175 TI - Seroprevalence of the Hepatitis B, Hepatitis C, and Human Immunodeficiency Viruses and Treponema pallidum at the Beijing General Hospital from 2010 to 2014: A Cross-Sectional Study. AB - BACKGROUND: The hepatitis B, hepatitis C, human immunodeficiency viruses and Treponema pallidum are important causes of infectious diseases concern to public health. METHODS: Between 2010 and 2014, we used an automated chemiluminescence microparticle immunoassay to detect the hepatitis B, hepatitis C, and human immunodeficiency viruses as well as Treponema pallidum (the rapid plasma regain test was used in 2010-2011). Positive human immunodeficiency virus tests were confirmed via western blotting. RESULTS: Among 416,130 subjects, the seroprevalences for hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and Treponema pallidum were 5.72%, 1.23%, 0.196%, and 0.76%, respectively. Among 671 patients with positive human immunodeficiency virus results, 392 cases were confirmed via western blotting. Hepatitis B and human immunodeficiency virus infections were more frequent in men (7.78% and 0.26%, respectively) than in women (4.45% and 0.021%, respectively). The hepatitis B and C virus seroprevalences decreased from 6.21% and 1.58%, respectively, in 2010, to 5.37% and 0.988%, respectively, in 2014. The human immunodeficiency virus seroprevalence increased from 0.04% in 2010 to 0.17% in 2014, and was elevated in the Infectious Disease (2.65%), Emergency (1.71%), and Dermatology and Sexually Transmitted Diseases (1.12%) departments. The specificity of the human immunodeficiency virus screening was 71.4%. The false positive rates for the Treponema pallidum screening tests increased in patients who were 60-70 years old. The co-infection rates for the hepatitis C and human immunodeficiency viruses were 0.47% in hepatitis C virus-positive patients and 7.33% in human immunodeficiency virus-positive patients. CONCLUSIONS: During 2010-2014, hepatitis B virus and human immunodeficiency virus infections were more frequent among men at our institution. Although the seroprevalences of hepatitis B and C viruses decreased, the seroprevalence of human immunodeficiency virus infection increased (with higher seroprevalences in high-risk departments). Older patients were more likely to exhibit false positive findings for syphilis. PMID- 26502177 TI - Correction: An integrated slidable and valveless microdevice with solid phase extraction, polymerase chain reaction, and immunochromatographic strip parts for multiplex colorimetric pathogen detection. AB - Correction for 'An integrated slidable and valveless microdevice with solid phase extraction, polymerase chain reaction, and immunochromatographic strip parts for multiplex colorimetric pathogen detection' by Yong Tae Kim et al., Lab Chip, 2015, 15, 4148-4155. PMID- 26502178 TI - Cellular properties of extensor carpi radialis brevis and trapezius muscles in healthy males and females. AB - In this study, we sought to determine whether differences in cellular properties associated with energy homeostasis could explain the higher incidence of work related myalgia in trapezius (TRAP) compared with extensor carpi radialis brevis (ECRB). Tissue samples were obtained from the ECRB (n = 19) and TRAP (n = 17) of healthy males and females (age 27.9 +/- 2.2 and 28.1 +/- 1.5 years, respectively; mean +/- SE) and analyzed for properties involved in both ATP supply and utilization. The concentration of ATP and the maximal activities of creatine phosphokinase, phosphorylase, and phosphofructokinase were higher (P < 0.05) in ECRB than TRAP. Succinic dehydrogenase, citrate synthase, and cytochrome c oxidase were not different between muscles. The ECRB also displayed a higher concentration of Na(+)-K(+)-ATPase and greater sarcoplasmic reticulum Ca(2+) release and uptake. No differences existed between muscles for either monocarboxylate transporters or glucose transporters. It is concluded that the potentials for high-energy phosphate transfer, glycogenolysis, glycolysis, and excitation-contraction coupling are higher in ECRB than TRAP. Histochemical measurements indicated that the muscle differences are, in part, related to differing amounts of type II tissue. Depending on the task demands, the TRAP may experience a greater metabolic and excitation-contraction coupling strain than the ECRB given the differences observed. PMID- 26502179 TI - An ethical approach to health promotion in physiotherapy practice. AB - ISSUE ADDRESSED: With increased emphasis on reducing the global burden of non communicable disease, health professionals who traditionally focused on the individual are being encouraged to address population-level health problems. While physiotherapists are broadening their clinical role to include health promotion strategies in their clinical practice, the ethical foundations of this practice focus have received less attention. METHODS: We use a physiotherapy clinical scenario to highlight different physiotherapeutic approaches and to analyse underpinning ethical values and implications for practice. RESULTS: We suggest there are potential harms of incorporating health promotion into physiotherapy management of individuals if the population-based research does not resonate with an individual's particular circumstances, capacity to change or view of what counts as important and meaningful. We propose that critical reasoning and ethical judgment by the physiotherapist is required to determine how health promotion messages applied in primary care settings might work to benefit and enhance a client's well being rather than impose burdens or cause harm. CONCLUSION: We suggest four ethical reasoning strategies designed to assist physiotherapists to frame and understand fundamental ethical principles of beneficence, harm, autonomy and justice when implementing health promotion and self-management approaches in clinical practice. PMID- 26502180 TI - Postoperative nodal irradiation in breast cancer patients with 1 to 3 axillary lymph nodes involved: the debate continues.... AB - Regional lymph node irradiation is usually indicated in patients with positive node breast cancer. However, there are some controversies regarding the clinical benefits of adding regional nodal irradiation to whole-breast or thoracic-wall irradiation after breast surgery especially for patients with 1 to 3 positive axillary lymph nodes. More recently, two important studies (NCIC MA.20 and EORTC 22,922-10925) were published to address this significant issue and some further points need to be discussed. PMID- 26502181 TI - Reply: Distal acquired demyelinating symmetric neuropathy associated with colorectal adenocarcinoma: should it be termed paraneoplastic? PMID- 26502182 TI - Can Impression Procedures Affect Certain Vital Functions of Edentulous Patients? A Clinical Study. AB - PURPOSE: The most suitable treatment conditions and timing for medically unstable patients with severe systemic diseases about to undergo invasive dental treatment are well documented in the literature; however, no medical guides or recommendations identify these conditions for noninvasive dental treatments in such patients. The aim of this clinical study was to determine the effect of impression procedures on arterial oxygen saturation (AOS) and pulse rates (PRs) of edentulous subjects. MATERIALS AND METHODS: A total of 28 Caucasian edentulous participants (15 females, 13 males) were included in the study. Pulse oximetry recordings (150 seconds) were performed for each participant at three stages; recording at rest (CON), during mandibular impressions (MANIs), and maxillary impressions (MAXIs). The mean values of PR, AOS, and event scores (ESs) indicating desaturation were obtained from the records. The comparisons of mean PR and AOS values were performed with the Bonferroni-corrected Wilcoxon-signed ranks test. The ESs were analyzed with the McNemar Test. RESULTS: The mean AOS values of MANI and MAXI did not display significant changes when compared with CON; however, the ESs obtained in both MANI and MAXI were significantly higher than those of CON (p = 0.008, p = 0.004). In addition, mean PR values obtained in MAXI were significantly higher than CON (p = 0.009). CONCLUSIONS: According to the results of this clinical study, the impression procedures may affect the PR values and lead to desaturation events in edentulous patients; however, further studies evaluating blood gas levels, which indicate precise AOS values, are necessary to support the results of this study. PMID- 26502184 TI - Frequency of Oral Mucositis and Local Virus Reactivation in Herpes Simplex Virus Seropositive Children with Myelosuppressive Therapy. AB - BACKGROUND: Oral mucositis (OM) is a common chemo- and radiotherapy adverse effect in oncological pediatric patients. Herpes simplex virus (HSV) infection can cause a severe clinical course. We hypothesize, that HSV seropositivity is a risk factor for local HSV-1 reactivation and increased frequency of OM in patients with myelosuppressive therapies. PATIENTS AND METHOD: We evaluated the prevalence of seropositivity of HSV-1 between June 2011 and April 2014 in patients with potential oncological disease and correlated it to the frequency of OM and local viral reactivation in OM under myelosuppressive therapy. RESULTS: The overall rate of HSV-seropositivity in our cohort was 22%. 48 patients underwent myelosuppressive therapy. Of these, 7 were HSV-1 IgG positive and 41 negative. All patients with OM under myelosuppressive therapy and positive local swab for viral HSV (l-PCR) were HSV-1 IgG positive before the start of therapy (100%). The absolute risk for OM in HSV-1 IgG positive patients was increased by 58.5% (95%CI: 20.0 - 72.2%) corresponding to a relative risk (RR) of 2.4 (95%CI: 1.7-3.5, P=0.009). The multivariable adjusted OR to suffer 2 or more OM episodes in HSV-1 IgG positivity was 8.8 (95%CI: 1.5-95.8, P=0.014). DISCUSSION AND CONCLUSION: In HSV-1 IgG positive patients half of the OM episode showed HSV reactivation, and the risk for multiple OM episodes was increased. These patients should be investigated for HSV-infection in every OM episode. Prophylactic and preemptive therapeutic measures should be discussed early, but prospective data on HSV prophylaxis and preemptive treatment is required. PMID- 26502183 TI - Family-Based Cluster Randomized Controlled Trial Enhancing Physical Activity and Motor Competence in 4-7-Year-Old Children. AB - Little is known of how to involve families in physical activity (PA) interventions for children. In this cluster randomized controlled trial, we recruited families with four- to seven-year-old children to participate in a year long study where parents in the intervention group families (n = 46) received tailored counseling to increase children's PA. Structured PA was not served. Control group families (n = 45) did not receive any counseling. PA in all children (n = 91; mean age 6.16 +/- 1.13 years at the baseline) was measured by accelerometers at the baseline and after three, six, nine and 12 months. Motor competence (MC) (n = 89) was measured at the baseline and after six and 12 months by a KTK (KorperkoordinationsTest fur Kinder) and throwing and catching a ball (TCB) protocols. The effect of parental counseling on study outcomes was analyzed by a linear mixed-effects model fit by REML and by a Mann-Whitney U test in the case of the TCB. As season was hypothesized to affect counseling effect, an interaction of season on the study outcomes was examined. The results show significant decrease of MVPA in the intervention group when compared to the control group (p < .05). The TCB showed a nearly significant improvement at six months in the intervention group compared to the controls (p = .051), but not at 12 months. The intervention group had a steadier development of the KTK when the interaction of season was taken into account. In conclusion, more knowledge of family constructs associating with the effectiveness of counseling is needed for understanding how to enhance PA in children by parents. However, a hypothesis may be put forward that family-based counseling during an inactive season rather than an active season may provide a more lasting effect on the development of KTK in children. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN28668090. PMID- 26502185 TI - Outcomes After Lumbar Disc Herniation in the National Basketball Association. AB - BACKGROUND: Professional basketball players are at risk for lumbar disc herniation (LDH), yet the evidence guiding treatment after operative or nonoperative management of this condition in the National Basketball Association (NBA) is limited. HYPOTHESIS: NBA players with LDH will have different performance outcomes based on treatment type. STUDY DESIGN: Case-control study. LEVEL OF EVIDENCE: Level 4. METHODS: Athletes in the NBA with an LDH were identified through team injury reports, transaction records, and public sports archives. A 1:2 case-control study was performed in which LDH players and players without LDH were matched for player variables. Statistical analysis was employed to compare pre- and postindex season performance (games played and player efficiency rating [PER]) and career longevity between test subjects and controls in the operatively treated (OT) and nonoperatively treated (NOT) cohorts. RESULTS: A total of 61 NBA players with LDH were included, of whom 34 underwent discectomy and 27 were managed nonoperatively. Return-to-play (RTP) rates did not differ between NOT and OT players (77.8% vs. 79.4%). When compared with controls, OT players played significantly fewer games and had a lower PER than controls during the first postoperative season, but no difference was seen 2 and 3 years after surgery, with no difference in postoperative career length. In contrast, no difference in games played or PER was seen between NOT players and controls, although NOT players played significantly fewer postindex seasons. CONCLUSION: NBA players have a high RTP rate regardless of type of treatment for LDH; however, postindex performance differs between surgically and nonoperatively managed patients when compared with players without an LDH. However, further studies with a larger sample size are required for more definitive recommendations. CLINICAL RELEVANCE: There is a high RTP rate after LDH in the NBA, although postindex performance may differ based on operative versus nonoperative treatment. PMID- 26502186 TI - Traumatic Carpal Axial Instability in a Professional Football Player: A Case Report. AB - This is a case of traumatic carpal axial instability in a professional football player. Traumatic carpal axial instability characteristically involves longitudinal separation of the ulnar or radial distal carpal row along with intermetacarpal injury. Rarely, pancarpal ligament disruption occurs, as in this case. Early diagnosis and treatment of unstable wrist injuries is important in achieving a satisfactory outcome. PMID- 26502188 TI - Knee Articular Cartilage Repair and Restoration Techniques: A Review of the Literature. AB - CONTEXT: Isolated chondral and osteochondral defects of the knee are a difficult clinical challenge, particularly in younger patients for whom alternatives such as partial or total knee arthroplasty are rarely advised. Numerous surgical techniques have been developed to address focal cartilage defects. Cartilage treatment strategies are characterized as palliation (eg, chondroplasty and debridement), repair (eg, drilling and microfracture [MF]), or restoration (eg, autologous chondrocyte implantation [ACI], osteochondral autograft [OAT], and osteochondral allograft [OCA]). EVIDENCE ACQUISITION: PubMed was searched for treatment articles using the keywords knee, articular cartilage, and osteochondral defect, with a focus on articles published in the past 5 years. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: In general, smaller lesions (<2 cm(2)) are best treated with MF or OAT. Furthermore, OAT shows trends toward greater longevity and durability as well as improved outcomes in high-demand patients. Intermediate-size lesions (2-4 cm(2)) have shown fairly equivalent treatment results using either OAT or ACI options. For larger lesions (>4 cm(2)), ACI or OCA have shown the best results, with OCA being an option for large osteochondritis dissecans lesions and posttraumatic defects. CONCLUSION: These techniques may improve patient outcomes, though no single technique can reproduce normal hyaline cartilage. PMID- 26502187 TI - Return-to-Play Recommendations After Cervical, Thoracic, and Lumbar Spine Injuries: A Comprehensive Review. AB - CONTEXT: Currently, there is a national focus on establishing and disseminating standardized guidelines for return to play for athletes at all levels of competition. As more data become available, protocols and guidelines are being refined and implemented to assist physicians, coaches, trainers, players, and parents in making decisions about return to play. To date, no standardized criteria for returning to play exist for injuries to the spine. EVIDENCE ACQUISITION: Electronic databases including PubMed and MEDLINE and professional orthopaedic, neurosurgical, and spine organizational websites were reviewed between 1980 and 2015. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Although clinical guidelines have been published for return to play after spine injury, they are almost exclusively derived from expert opinion and clinical experience rather than from well-designed studies. Furthermore, recommendations differ and vary depending on anatomic location, type of sport, and surgery performed. CONCLUSION: Despite a lack of consensus and specific recommendations, there is universal agreement that athletes should be pain free, completely neurologically intact, and have full strength and range of motion before returning to play after spinal injury. PMID- 26502189 TI - Evaluation, Treatment, and Rehabilitation Implications of the Infrapatellar Fat Pad. AB - CONTEXT: The infrapatellar fat pad (IFP) is in the anterior knee compartment and may be a major pain generator. EVIDENCE ACQUISITION: A PubMed database search using the terms Hoffas fat pad, anterior interval, and infrapatellar fat pad was performed from the years 1970 to 2015. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 5. RESULTS: Limited research exists examining the role of the IFP in relation to potential treatment and rehabilitation implications. CONCLUSIONS: Alterations in IFP mobility, whether the result of postsurgical scarring or faulty movement patterns, result in pain and disability in a variety of patient populations. The majority of treatment approaches are driven by the surgical technique. PMID- 26502190 TI - Ex vivo construction of a novel model of bioengineered bladder mucosa: A preliminary study. AB - OBJECTIVE: To generate and to evaluate ex vivo a novel model of bioengineered human bladder mucosa based on fibrin-agarose biomaterials. METHODS: We first established primary cultures of stromal and epithelial cells from small biopsies of the human bladder using enzymatic digestion and selective cell culture media. Then, a bioengineered substitute of the bladder lamina propria was generated using cultured stromal cells and fibrin-agarose scaffolds, and the epithelial cells were then subcultured on top to generate a complete bladder mucosa substitute. Evaluation of this substitute was carried out by cell viability and histological analyses, immunohistochemistry for key epithelial markers and transmission electron microscopy. RESULTS: The results show a well-configured stroma substitute with a single-layer epithelium on top. This substitute was equivalent to the control bladder mucosa. After 7 days of ex vivo development, the epithelial layer expressed pancytokeratin, and cytokeratins CK7, CK8 and CK13, as well as filaggrin and ZO-2, with negative expression of CK4 and uroplakin III. A reduction of the expression of CK8, filaggrin and ZO-2 was found at day 14 of development. An immature basement membrane was detected at the transition between the epithelium and the lamina propria, with the presence of epithelial hemidesmosomes, interdigitations and immature desmosomes. CONCLUSIONS: The present results suggest that this model of bioengineered human bladder mucosa shared structural and functional similarities with the native bladder mucosa, although the epithelial cells were not fully differentiated ex vivo. We hypothesize that this bladder mucosa substitute could have potential clinical usefulness after in vivo implantation. PMID- 26502192 TI - The Effect of Increasing Intracranial Pressure on Ocular Vestibular-Evoked Myogenic Potential Frequency Tuning. AB - OBJECTIVE: Ocular vestibular-evoked myogenic potentials (oVEMPs) represent extraocular muscle activity in response to vestibular stimulation. The authors sought to investigate whether posture-induced increase of the intracranial pressure (ICP) modulated oVEMP frequency tuning, that is, the amplitude ratio between 500-Hz and 1000-Hz stimuli. DESIGN: Ten healthy subjects were enrolled in this study. The subjects were positioned in the horizontal plane (0 degree) and in a 30-degree head-downwards position to elevate the ICP. In both positions, oVEMPs were recorded using 500-Hz and 1000-Hz air-conducted tone bursts. RESULTS: When tilting the subject from the horizontal plane to the 30-degree head-down position, oVEMP amplitudes in response to 500-Hz tone bursts distinctly decreased (3.40 MUV versus 2.06 MUV; p < 0.001), whereas amplitudes to 1000 Hz were only slightly diminished (2.74 MUV versus 2.48 MUV; p = 0.251). Correspondingly, the 500/1000-Hz amplitude ratio significantly decreased when tilting the subjects from 0- to 30-degree inclination (1.59 versus 1.05; p = 0.029). Latencies were not modulated by head-down position. CONCLUSIONS: Increasing ICP systematically alters oVEMPs in terms of absolute amplitudes and frequency tuning characteristics. oVEMPs are therefore in principle suited for noninvasive ICP monitoring. PMID- 26502191 TI - Electrophysiology and Perception of Speech in Noise in Older Listeners: Effects of Hearing Impairment and Age. AB - OBJECTIVES: Speech perception in background noise is difficult for many individuals, and there is considerable performance variability across listeners. The combination of physiological and behavioral measures may help to understand sources of this variability for individuals and groups and prove useful clinically with hard-to-test populations. The purpose of this study was threefold: (1) determine the effect of signal-to-noise ratio (SNR) and signal level on cortical auditory evoked potentials (CAEPs) and sentence-level perception in older normal-hearing (ONH) and older hearing-impaired (OHI) individuals, (2) determine the effects of hearing impairment and age on CAEPs and perception, and (3) explore how well CAEPs correlate with and predict speech perception in noise. DESIGN: Two groups of older participants (15 ONH and 15 OHI) were tested using speech-in-noise stimuli to measure CAEPs and sentence-level perception of speech. The syllable /ba/, used to evoke CAEPs, and sentences were presented in speech-spectrum background noise at four signal levels (50, 60, 70, and 80 dB SPL) and up to seven SNRs (-10, -5, 0, 5, 15, 25, and 35 dB). These data were compared between groups to reveal the hearing impairment effect and then combined with previously published data for 15 young normal-hearing individuals to determine the aging effect. RESULTS: Robust effects of SNR were found for perception and CAEPs. Small but significant effects of signal level were found for perception, primarily at poor SNRs and high signal levels, and in some limited instances for CAEPs. Significant effects of age were seen for both CAEPs and perception, while hearing impairment effects were only found with perception measures. CAEPs correlate well with perception and can predict SNR50s to within 2 dB for ONH. However, prediction error is much larger for OHI and varies widely (from 6 to 12 dB) depending on the model that was used for prediction. CONCLUSIONS: When background noise is present, SNR dominates both perception-in-noise testing and cortical electrophysiological testing, with smaller and sometimes significant contributions from signal level. A mismatch between behavioral and electrophysiological results was found (hearing impairment effects were primarily only seen for behavioral data), illustrating the possible contributions of higher order cognitive processes on behavior. It is interesting that the hearing impairment effect size was more than five times larger than the aging effect size for CAEPs and perception. Sentence-level perception can be predicted well in normal-hearing individuals; however, additional research is needed to explore improved prediction methods for older individuals with hearing impairment. PMID- 26502193 TI - Emerging monoclonal antibodies as targeted innovative therapeutic approaches to asthma. AB - Asthma is characterized by discordant responses among cells of the adaptive and innate immune systems. This interplay involves a complex pattern of cytokine driven processes resulting in cell migration and recruitment, inflammation, and proliferative states. The significant majority of asthmatic patients respond well to conventional inhaled treatments. However, about 5% of asthmatics have severe refractory asthma and account for 50% of the health expenditure on asthma. Human(ized) monoclonal antibodies (hMabs) targeting inflammatory pathways are promising therapeutic agents in asthma management. The anti-IgE hMab omalizumab was the first biologic treatment approved for the treatment of allergic asthma. Potential future strategies and targets include interleukin (IL)-5, IL-4, and IL 13, anti-TSLP, IL-25, and IL-33. hMabs targeting IL-5 have shown great promise in severe refractory asthma with a persisting eosinophilia, and clinical trials with hMabs against IL-13 and IL4Ralpha have also shown clinical benefit. Studies of hMabs against other cytokines in severe asthma are under way. PMID- 26502194 TI - The Relationship Between Immigrant School Composition, Classmate Support and Involvement in Physical Fighting and Bullying among Adolescent Immigrants and Non immigrants in 11 Countries. AB - Increasing numbers of migrant youth around the world mean growing numbers of heterogeneous school environments in many countries. Contradictory findings regarding the relationship between immigrant school composition (the percentage of immigrant versus non-immigrant students in a school) and adolescent peer violence necessitate further consideration. The current study examined the relationship between immigrant school composition and peer violence, considering classmate support as a potential moderator among 51,636 adolescents (50.1% female) from 11 countries. The findings showed that a higher percentage of immigrant adolescents in a school was related to higher levels of physical fighting and bullying perpetration for both immigrant and non-immigrant adolescents and lower levels of victimization for immigrants. In environments of low classmate support, the positive relationship between immigrant school composition and fighting was stronger for non-immigrants than in environments with high classmate support. In environments of low classmate support, the negative relationship between immigrant school composition and fighting and bullying victimization was stronger for immigrant adolescents than in environments with high classmate support. In general, the contribution of immigrant school composition was modest in comparison to the contribution of classmate support. The findings emphasize that it is not just the number of immigrants in a class per se, but rather the environment in the classroom which influences levels of peer violence. The results highlight a need for school intervention programs encouraging positive relations in schools with immigrant populations. PMID- 26502196 TI - Binding of Capsaicin to the TRPV1 Ion Channel. AB - Transient receptor potential (TRP) ion channels constitute a notable family of cation channels involved in the ability of an organisms to detect noxious mechanical, thermal, and chemical stimuli that give rise to the perception of pain, taste, and changes in temperature. One of the most experimentally studied agonist of TRP channels is capsaicin, which is responsible for the burning sensation produced when chili pepper is in contact with organic tissues. Thus, understanding how this molecule interacts and regulates TRP channels is essential to high impact pharmacological applications, particularly those related to pain treatment. The recent publication of a three-dimensional structure of the vanilloid receptor 1 (TRPV1) in the absence and presence of capsaicin from single particle electron cryomicroscopy experiments provides the opportunity to explore these questions at the atomic level. In the present work, molecular docking and unbiased and biased molecular dynamics simulations were employed to generate a structural model of the capsaicin-channel complex. In addition, the standard free energy of binding was estimated using alchemical transformations coupled with conformational, translational, and orientational restraints on the ligand. Key binding modes consistent with previous experimental data are identified, and subtle but essential dynamical features of the binding site are characterized. These observations shed some light into how TRPV1 interacts with capsaicin, and may help to refine design parameters for new TRPV1 antagonists, and potentially guide further developments of TRP channel modulators. PMID- 26502195 TI - Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology. AB - Neuromuscular junctions are primary pathological targets in the lethal motor neuron diseases spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Synaptic pathology and denervation of target muscle fibers has been reported prior to the appearance of clinical symptoms in mouse models of both diseases, suggesting that neuromuscular junctions are highly vulnerable from the very early stages, and are a key target for therapeutic intervention. Here we examined neuromuscular pathology longitudinally in three clinically relevant muscle groups in mouse models of ALS and SMA in order to assess their relative vulnerabilities. We show for the first time that neuromuscular junctions of the extraocular muscles (responsible for the control of eye movement) were resistant to degeneration in endstage SMA mice, as well as in late symptomatic ALS mice. Tongue muscle neuromuscular junctions were also spared in both animal models. Conversely, neuromuscular junctions of the lumbrical muscles of the hind-paw were vulnerable in both SMA and ALS, with a loss of neuronal innervation and shrinkage of motor endplates in both diseases. Thus, the pattern of selective vulnerability was conserved across these two models of motor neuron disease. However, the first evidence of neuromuscular pathology occurred at different timepoints of disease progression, with much earlier evidence of presynaptic involvement in ALS, progressing to changes on the postsynaptic side. Conversely, in SMA changes appeared concomitantly at the neuromuscular junction, suggesting that mechanisms of neuromuscular disruption are distinct in these diseases. J. Comp. Neurol. 524:1424-1442, 2016. (c) 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID- 26502197 TI - REALIZING MISSED OPPORTUNITIES FOR IMPROVING MENTAL HEALTH CARE QUALITY: BRIDGING THE GREAT DIVIDE IN THE DELIVERY OF PSYCHOSOCIAL TREATMENTS. PMID- 26502198 TI - Pulmonary Hypertension. PMID- 26502199 TI - Reliability and validity of the Brief Resilience Scale (BRS) Spanish Version. AB - Resilience is defined as the ability to recover from stress. However, all resilience measures with exception of the Brief Resilience Scale (BRS) assess resources that make resilience possible instead of recovery. The purpose of this study was to translate the BRS to Spanish and to analyze the reliability and validity of its scores. The psychometric properties of its scores were examined in a heterogeneous sample of 620 Spanish adults. Confirmatory factor analyses were carried out to study its scores' evidence of structural validity. Besides, to study its scores' evidence of convergent, discriminant, and predictive validity in relation to other resilience questionnaires (Connor Davidson Resilience Scale 10-item version, Situated Subjective Resilience Questionnaire for Adults and Resiliency Questionnaire for Adults) and to variables such as emotions (Modified Differential Emotions Scale), coping (Person-situation Coping Questionnaire for Adults), anxiety and depression (Hospital Anxiety and Depression Scale), posttraumatic growth (Posttraumatic Growth Inventory), perceived stress (Perceived Stress Scale) and posttraumatic stress (Davidson Trauma Scale), correlation and regression analyses were conducted. To study its sensitivity, we assessed the effect of sociodemographics and the ability of the scale to identify high-risk populations by conducting analyses of variance and Pearson correlations. The BRS scores showed adequate reliability (alpha = .83; intraclass coefficient = .69). Confirmatory factor analyses showed that the Spanish version of the BRS is mono-factorial (chi2/df = 2.36; standardized root mean square residual = .036; goodness-of-fit index = .980; comparative fit index = .984; incremental fit index = .984; root mean square error of approximation = .067). They also showed adequate evidence of the scores' convergent, concurrent and predictive validity. The Spanish version of the BRS is a reliable and valid means to assess resilience as the ability to bounce back. (PsycINFO Database Record PMID- 26502200 TI - Measuring ability to enhance and suppress emotional expression: The Flexible Regulation of Emotional Expression (FREE) Scale. AB - Flexibility in self-regulatory behaviors has proved to be an important quality for adjusting to stressful life events and requires individuals to have a diverse repertoire of emotion regulation abilities. However, the most commonly used emotion regulation questionnaires assess frequency of behavior rather than ability, with little evidence linking these measures to observable capacity to enact a behavior. The aim of the current investigation was to develop and validate a Flexible Regulation of Emotional Expression (FREE) Scale that measures a person's ability to enhance and suppress displayed emotion across an array of hypothetical contexts. In Studies 1 and 2, a series of confirmatory factor analyses revealed that the FREE Scale consists of 4 first-order factors divided by regulation and emotional valence type that can contribute to 2 higher order factors: expressive enhancement ability and suppression ability. In Study 1, we also compared the FREE Scale to other commonly used emotion regulation measures, which revealed that suppression ability is conceptually distinct from suppression frequency. In Study 3, we compared the FREE Scale with a composite of traditional frequency-based indices of expressive regulation to predict performance in a previously validated emotional modulation paradigm. Participants' enhancement and suppression ability scores on the FREE Scale predicted their corresponding performance on the laboratory task, even when controlling for baseline expressiveness. These studies suggest that the FREE Scale is a valid and flexible measure of expressive regulation ability. (PsycINFO Database Record PMID- 26502201 TI - "The Intolerance of Uncertainty Index: Replication and Extension With an English Sample": Correction to Carleton, Gosselin, and Asmundson (2010). AB - Reports an error in "The Intolerance of Uncertainty Index: Replication and extension with an English sample" by R. Nicholas Carleton, Patrick Gosselin and Gordon J. G. Asmundson (Psychological Assessment, 2010[Jun], Vol 22[2], 396-406). In the article, the Factor loading of the First sample in Table 2 should have begun with Item 2 and the final value in that table should not exist. Factor 1 should be associated with Items 2, 5, 6, 7, 9, 11, 13, 17, 21, and 30; Factor 2 should be associated with Items 3, 14, 19, 23, and 29; and Factor 3 should be associated with Items 4, 10, 18, 24, and 27. (The following abstract of the original article appeared in record 2010-10892-019.) Intolerance of uncertainty (IU) is related to anxiety, depression, worry, and anxiety sensitivity. Precedent IU measures were criticized for psychometric instability and redundancy; alternative measures include the novel 45-item measure (Intolerance of Uncertainty Index; IUI). The IUI was developed in French with 2 parts, assessing general unacceptability of uncertainty (15 items, Part A) and manifestations of uncertainty approximating more common anxiety disorder symptoms (30 items, Part B). The psychometric stability of the back-translated English items of the IUI as well as the incremental variance of Parts A and B remain to be assessed. The current study involved 2 samples of English-speaking community participants (n = 437 and n = 309; 73% women and 27% men) who completed the IUI and several related measures. Exploratory and confirmatory factor analyses suggested a refinement of IUI items as well as a unitary structure for Part A and a 3-factor structure for Part B. Regression results suggested Parts A and B each provide incremental validity in measures of worry, generalized anxiety disorder symptoms, negative problem orientation, and depression. Comprehensive results, implications, and future research directions are discussed. (PsycINFO Database Record PMID- 26502202 TI - Limitations of a single-item assessment of suicide attempt history: Implications for standardized suicide risk assessment. AB - Although a suicide attempt history is among the single best predictors of risk for eventual death by suicide, little is known about the extent to which reporting of suicide attempts may vary by assessment type. The current study aimed to investigate the correspondence between suicide attempt history information obtained via a single-item self-report survey, multi-item self-report survey, and face-to-face clinical interview. Data were collected among a high risk sample of undergraduates (N = 100) who endorsed a past attempt on a single item prescreening survey. Participants subsequently completed a multi-item self report survey, which was followed by a face-to-face clinical interview, both of which included additional questions regarding the timing and nature of previous attempts. Even though 100% of participants (n = 100) endorsed a suicide attempt history on the single-item prescreening survey, only 67% (n = 67) reported having made a suicide attempt on the multi-item follow-up survey. After incorporating ancillary information from the in-person interview, 60% of participants qualified for a Centers for Disease Control and Prevention (CDC)-defined suicide attempt. Of the 40% who did not qualify for a CDC-defined suicide attempt, 30% instead qualified for no attempt, 7% an aborted attempt, and 3% an interrupted attempt. These findings suggest that single-item assessments of suicide attempt history may result in the misclassification of prior suicidal behaviors. Given that such assessments are commonly used in research and clinical practice, these results emphasize the importance of utilizing follow-up questions and assessments to improve precision in the characterization and assessment of suicide risk. (PsycINFO Database Record PMID- 26502203 TI - Do the Kaufman tests of cognitive ability and academic achievement display construct bias across a representative sample of Black, Hispanic, and Caucasian school-age children in grades 1 through 12? AB - As the demographic profile in the United States continues to change and becomes ethnically more diverse, the need for culturally appropriate test instruments has become a national concern among educators, clinicians, and researchers. The Kaufman Assessment Battery for Children-2nd Edition (KABC-II) and the Kaufman Test of Educational Achievement-2nd Edition (KTEA-II) are 2 popular tests of intelligence and achievement, known to appeal to an ethnically diverse client population. The present study investigated test bias in terms of the test scores' construct validity across a nationally representative sample of Caucasian, Black, and Hispanic (N = 2,001) children in Grades 1-12. Confirmatory factor analysis was used to assess whether increasing sets of equality constraints fit the test scores' underlying theoretical model equally well for all 3 ethnic groups. Results showed that factorial invariance of the factor structure, based on 7 Cattell-Horn-Carroll (CHC) model broad abilities, was met for all 3 groups. Outcomes contribute to a scarce body of literature on ethnic test bias that goes beyond the simple comparison of mean score differences. Results of this study provide the evidence needed to justify continuous use of the KABC-II and KTEA-II in the assessment of minority group children and adolescents. Furthermore, findings are generalizable beyond the Kaufman tests to other popular tests of intelligence and achievement; this is because this study is based on the CHC factor structure, a universal theory of cognition that is used as the theoretical underpinning by many well-known tests of intelligence and achievement, including the most recent versions of the Wechsler scales. (PsycINFO Database Record PMID- 26502204 TI - Assessing trauma and posttraumatic stress disorder: Single, open-ended question versus list-based inventory. AB - Trauma exposure is a precursor to a diagnosis of posttraumatic stress disorder (PTSD). A dearth of empirical evidence exists on the impact of different measurement practices on estimates of trauma exposure and PTSD within representative epidemiological samples. In the present study, we examined differences in reported trauma exposure and rates of PTSD using single, open ended question versus list-based trauma assessments in a general community sample. Using data from the third wave of the Montreal epidemiological catchment area study (N = 1029), participants were interviewed in person by a lay interviewer about lifetime history of trauma exposure and PTSD. Prevalence rates of trauma exposure and PTSD diagnosis using single, open-ended question and list based assessment were compared using a within-subject design. A single, open ended question versus list-based trauma assessment yielded trauma-exposure rates of 61%, 95% CI [57.8, 63.8] and 78%, 95% CI [75.2, 80.3], respectively. Conditional rates of lifetime PTSD decreased from 6.7%, 95% CI [5.8, 9.4] to 6%, 95% CI [4.4, 7.7], respectively. Increases in trauma exposure were more pronounced in women (33.7%) than men (21.5%), as well as in the younger stratum of study participants (15-24 years old; 36.1%). Underestimation of PTSD using a single, open-ended question assessment was minimal, although all missing cases were women. Our results lend support to the importance of using comprehensive assessments of exposure to potentially traumatic events when conducting epidemiological research, especially when reporting conditional rates of PTSD. Previous research may have underestimated the prevalence of trauma exposure, particularly among young women. (PsycINFO Database Record PMID- 26502205 TI - Bifactor latent structure of attention-deficit/hyperactivity disorder (ADHD)/oppositional defiant disorder (ODD) symptoms and first-order latent structure of sluggish cognitive tempo symptoms. AB - The objective was to determine if the latent structure of attention deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) symptoms is best explained by a general disruptive behavior factor along with specific inattention (IN), hyperactivity/impulsivity (HI), and ODD factors (a bifactor model) whereas the latent structure of sluggish cognitive tempo (SCT) symptoms is best explained by a first-order factor independent of the bifactor model of ADHD/ODD. Parents' (n = 703) and teachers' (n = 366) ratings of SCT, ADHD-IN, ADHD-HI, and ODD symptoms on the Child and Adolescent Disruptive Behavior Inventory (CADBI) in a community sample of children (ages 5-13; 55% girls) were used to evaluate 4 models of symptom organization. Results indicated that a bifactor model of ADHD/ODD symptoms, in conjunction with a separate first order SCT factor, was the best model for both parent and teacher ratings. The first-order SCT factor showed discriminant validity with the general disruptive behavior and specific IN factors in the bifactor model. In addition, higher scores on the SCT factor predicted greater academic and social impairment, even after controlling for the general disruptive behavior and 3 specific factors. Consistent with predictions from the trait-impulsivity etiological model of externalizing liability, a single, general disruptive behavior factor accounted for nearly all common variance in ADHD/ODD symptoms, whereas SCT symptoms represented a factor different from the general disruptive behavior and specific IN factor. These results provide additional support for distinguishing between SCT and ADHD-IN. The study also demonstrates how etiological models can be used to predict specific latent structures of symptom organization. (PsycINFO Database Record PMID- 26502206 TI - Association of multiple genetic variants with chronic obstructive pulmonary disease susceptibility in Hainan region. AB - BACKGROUND AND AIMS: Recent genome-wide association studies have shown associations between variants in loci (4q28.1, 6p21.32, 6p21.1, 6q16.1, 10q22.1 and 10q22.3) and chronic obstructive pulmonary disease (COPD) or smoking behaviors. The objective of this study was to look for associations between 16 single nucleotide polymorphisms (SNP) at these six loci and COPD susceptibility in Hainan region. METHODS: A case-control cohort was composed of 200 COPD cases and 401 controls that were genotyped and analyzed statistically. Odds ratios (OR) and 95% confidence intervals (CIs) were computed by chi-square (chi2 ) test and genetic models by unconditional logistic regression. RESULTS: After Hardy Weinberg equilibrium (HWE) P value screening, we excluded the SNP rs12220777 with P < 0.001. By chi2 test only rs9296092 which located on 6p21.32 was provided the strongest evidence of an increasing risk of COPD with an OR of 3.28 (95% CI = 1.03 - 2.32; P = 0.003) between cases and controls. By genetic models analysis, we not only found rs9296092 increased COPD risk, but also found in the over dominant model the genotype 'C/T' (OR = 0.55; 95% CI = 0.33 - 0.93; P = 0.023) of rs950063 was proved to be associated with decreased COPD risk. CONCLUSIONS: This study is the first to provide evidence of importance of rs9296092 and rs950063 for risk of COPD in Hainan Province. Further studies are needed to characterize the functional sequences that cause COPD. PMID- 26502207 TI - Corticosteroids: Triamcinolone, Dexamethasone and Fluocinolone. AB - Steroids have been extensively used to treat macular edema due to diabetic retinopathy, venous occlusive disease, ocular inflammation and, to a lesser extent, also in some cases of choroidal neovascularization. The various intraocular steroids that have been employed include dexamethasone, triamcinolone and fluocinolone. During the past few years, new drug delivery methods for corticosteroids have been developed and are now part of our therapeutic armamentarium. This chapter provides a brief description of the pharmacology, efficacy and adverse effects associated with the use of steroids in various retinal diseases. PMID- 26502208 TI - PbS nanosculptured thin film for phase retarder, anti-reflective, excellent absorber, polarizer and sensor applications. AB - Lead-sulphide (PbS) nanosculptured thin film (nSTF) is prepared using a glancing angle deposition (GLAD) technique and the physical vapour deposition (PVD) process. The morphology of the GLAD films clearly shows that an anisotropic structure is obtained and is composed of micro-sheets with sharp top edges (a few tens of nanometres tip width). Due to this anisotropy, optical birefringence is induced in the nSTF as well as linear dichroism. The structural and optical properties of the PbS nSTF have been characterized by scanning electron microscopy, atomic force microscopy, Raman spectroscopy and transmission measurements. The Raman spectra of PbS nSTF exhibit sharp peaks representative of vibrations in nano-crystalline PbS. Due to the absorption of PbS the nSTF is found to act as a linear polarizer with good extinction and contrast in the near infra-red range. Due to its porosity this nSTF also has the ability to sense fluids, which we demonstrate using ethanol-water solution at different concentrations. The combination of these effects in PbS nSTF is believed to constitute a prime candidate for many desirable device applications in different aspects with the low cost of production in large areas. PMID- 26502209 TI - Nonneovascular Age-Related Macular Degeneration. AB - The discovery of several genetic variants associated with an increased risk for age-related macular degeneration (AMD) has led to a completely new understanding of AMD. In addition to the known modifiable risk factors, genetic risk factors may also help to assess the risk to progress to nonneovascular AMD. Recently published primary studies have indicated that genetic risk analysis may be valuable in the selection of the currently available antioxidant therapy. So far, the best evidence for preventing progression to nonneovascular AMD comes from the Age-Related Eye Disease Studies (AREDS) I and II. These studies indicate that high doses of antioxidants can reduce the risk of progression to the advanced form of the disease. However, the recent evaluation of the addition of either lutein and zeaxanthin, or omega-3 long-chain polyunsaturated fatty acids, or both, to the established AREDS I formulation did not significantly reduce the risk of developing advanced AMD. There is clearly a large unmet medical need for new therapeutic options for nonneovascular AMD. The modulation of the complement cascade is - despite initially disappointing outcomes obtained with blocking complement factor 5 - currently the most promising approach to the treatment of nonneovascular AMD. PMID- 26502210 TI - Analytical model and stability analysis of the leading edge spar of a passively morphing ornithopter wing. AB - This paper presents the stability analysis of the leading edge spar of a flapping wing unmanned air vehicle with a compliant spine inserted in it. The compliant spine is a mechanism that was designed to be flexible during the upstroke and stiff during the downstroke. Inserting a variable stiffness mechanism into the leading edge spar affects its structural stability. The model for the spar-spine system was formulated in terms of the well-known Mathieu's equation, in which the compliant spine was modeled as a torsional spring with a sinusoidal stiffness function. Experimental data was used to validate the model and results show agreement within 11%. The structural stability of the leading edge spar-spine system was determined analytically and graphically using a phase plane plot and Strutt diagrams. Lastly, a torsional viscous damper was added to the leading edge spar-spine model to investigate the effect of damping on stability. Results show that for the un-damped case, the leading edge spar-spine response was stable and bounded; however, there were areas of instability that appear for a range of spine upstroke and downstroke stiffnesses. Results also show that there exist a damping ratio between 0.2 and 0.5, for which the leading edge spar-spine system was stable for all values of spine upstroke and downstroke stiffnesses. PMID- 26502211 TI - Surgical wound assessment by sonography in the prediction of surgical wound infections. AB - BACKGROUND: Surgical site infections (SSIs) are important sources of morbidity, prolonged hospital stays, and readmissions, so they have become a major economic burden. We hypothesized that surgical wound assessment by sonography (SWATS) used at the bedside would detect wound fluid collections and that the presence of such collections would predict SSI better than standard clinical examination. If so, SWATS might be used to indicate early intervention that could prevent SSI morbidity. METHODS: A prospective, single-institution observational study was conducted on adult inpatients following open abdominal surgery for trauma, gastrointestinal pathology, or biliary pathology at high risk (>5%) for SSI using traditional wound classifications. After informed consent was obtained, SWATS was performed using a smartphone-based ultrasound system on postoperative Day 2 to 4 and again before discharge or at postoperative Day 30, whichever came first. Primary treating physicians delivered standard wound care and were blinded to SWATS. SSI was diagnosed if treatment was implemented for suspected or documented wound infection by the treating physician. Results were analyzed by chi test and two-sample pooled variance t test where appropriate, with significance set at p < 0.05. RESULTS: Forty-nine patients were studied. Nineteen patients had peri incisional fluid collections found by SWATS. Eight of these patients went on to develop an SSI. SSI was significantly associated with the presence of fluid collections on SWATS (p = 0.009). SWATS had a sensitivity of 72.7% (0.43-0.92), a specificity of 71.1% (0.62-0.77), a positive predictive value of 42.1% (0.25 0.53), and a negative predictive value of 90.0% (0.79-0.97). CONCLUSION: SWATS has a high negative predictive value that may allow it be an effective screening tool for developing SSI in high-risk surgical wounds. SWATS has the potential to be a useful and cost-effective adjunct to the clinician by objectively suggesting need for early therapy. Further study with larger sample sizes and randomized, SWATS-based interventions are required to validate this small study and determine its place in clinical care. LEVEL OF EVIDENCE: Diagnostic study, level IV. PMID- 26502212 TI - Military Acute Concussion Evaluation screen in a civilian population. PMID- 26502213 TI - Re: Military Acute Concussion Evaluation screen in a civilian population. PMID- 26502214 TI - Cost of specific emergency general surgery diseases and factors associated with high-cost patients. AB - BACKGROUND: We have previously shown that overall cost of hospitalization for emergency general surgery (EGS) diseases is more than $28 billion annually and rising. The purposes of this study were to estimate the costs associated with specific EGS diseases and to identify factors associated with high-cost hospitalizations. METHODS: The American Association for the Surgery of Trauma definition was used to identify hospitalizations of adult EGS patients in the 2010 National Inpatient Sample data. Cost of each hospitalization was obtained using cost-to-charge ratio in National Inpatient Sample. Regression analysis was used to estimate the cost for each EGS disease adjusted for patient and hospital characteristics. Hospitalizations with cost exceeding 75th percentile for each EGS disease were compared with lower-cost hospitalizations to identify factors associated with high cost. RESULTS: Thirty-one EGS diseases resulted in 2,602,074 hospitalizations nationwide in 2010 at an average adjusted cost of $10,110 (95% confidence interval, $10,086-$10,134) per hospitalization. Of these, only nine diseases constituted 80% of the total volume and 74% of the total cost. Empyema chest, colorectal cancer, and small intestine cancer were the most expensive EGS diseases with adjusted mean cost per hospitalization exceeding $20,000, while breast infection, abdominal pain, and soft tissue infection were the least expensive, with mean adjusted costs of less than $7,000 per hospitalization. The most important factors associated with high-cost hospitalizations were the number and type of procedures performed (76.2% of variance), but a region in Western United States (11.3%), Medicare and Medicaid payors (2.6%), and hospital ownership by public or not-for-profit entities (5.6%) were also associated with high-cost hospitalizations. CONCLUSION: A small number of diseases constitute a vast majority of EGS hospitalizations and their cost. Attempts at reducing the cost of EGS hospitalization will require controlling the cost of procedures. LEVEL OF EVIDENCE: Economic analysis, level IV. PMID- 26502215 TI - Clinical features and management of equine post operative ileus (POI): Survey of Diplomates of the American Colleges of Veterinary Internal Medicine (ACVIM), Veterinary Surgeons (ACVS) and Veterinary Emergency and Critical Care (ACVECC). AB - REASONS FOR PERFORMING STUDY: A recent survey of European Colleges (European College of Equine Internal Medicine [ECEIM] and European College of Veterinary Surgeons [ECVS]) revealed the different strategies implemented by, and some of the challenges facing, European clinicians presented with cases of post operative ileus (POI). It was concluded that further comparative analysis of opinions, canvassed from additional colleges of equine veterinary specialism worldwide, would provide valuable additional insight into current POI knowledge on a more global scale. OBJECTIVES: To report and compare the current strategies favoured by American veterinary specialists when managing POI in horses that underwent emergency colic surgery. STUDY DESIGN: Cross-sectional survey. METHODS: Electronic invitations were sent to 814 Large Animal specialists, including 3 colleges: the American College of Veterinary Internal Medicine (ACVIM), American College of Veterinary Surgeons (ACVS) and the American College of Veterinary Emergency and Critical Care (ACVECC). RESULTS: The response rate was 14% (115/814). The majority of respondents (68%) reported an estimated prevalence range of POI of 0-20%. The presence of reflux on nasogastric intubation was the main criterion used to define POI. A lesion involving the small intestine was considered the main risk factor for POI. Anti-inflammatory drugs, intravenous (i.v.) fluids and antimicrobial drugs were the primary strategies used when managing POI. Flunixin meglumine and i.v. lidocaine were the drugs most commonly used in the treatment of horses with POI. Supplementary management strategies targeted mainly the prevention of post operative adhesions, infection and inflammation. CONCLUSIONS: There is a lack of consensus on the clinical definition of POI. Prospective and objective clinical assessment of the effectiveness of the different strategies contained within this and the European survey is necessary in order to identify a standardised approach to the management of equine POI. PMID- 26502216 TI - A Region-of-Interest Approach for Detecting Progression of Glaucomatous Damage With Optical Coherence Tomography. AB - IMPORTANCE: Detecting progression of glaucomatous damage is often challenging. OBJECTIVE: To test the feasibility of using frequency-domain optical coherence tomography (FD-OCT) and a region-of-interest (ROI) approach to measure progressive changes in glaucomatous damage. DESIGN, SETTING, AND PARTICIPANTS: Among a group of patients in an institutional glaucoma practice who were likely to show glaucoma progression, eyes with a history of an optic disc hemorrhage (DH) confirmed by stereophotography were followed up with FD-OCT cube scans of the optic disc. All patients underwent FD-OCT scans on at least 2 occasions separated by at least 1 year (mean, 3.45 years; range, 1.42-6.39 years). Because we were not studying the effects of an optic DH, no constraint was placed on the time between the documentation of an optic DH and the first scan used in the analysis. MAIN OUTCOMES AND MEASURES: After en face images of the FD-OCT scan were aligned based on the blood vessels, circumpapillary images were derived for an annulus 100 um in width, and the retinal nerve fiber layer (RNFL) thickness profiles were plotted for the first and last visits. The ROI width associated with the optic DH was defined as the region of the RNFL profile below the 1% CI based on healthy norms. The change in the ROI width was compared with the change in the global RNFL thickness, which was obtained by averaging the circumpapillary RNFL thickness. RESULTS: The change in the ROI width (mean [SD], 8.0 degrees [6.4 degrees ]; 95% CI, 4.9 degrees to 11.1 degrees ; range, -0.7 degrees to 19.3 degrees ) was significant (P < .001, 2-tailed t test) while the change in the global thickness (mean [SD], 2.40 [5.87] MUm; 95% CI, -0.48 to 5.28 MUm) was not significant (P > .12, 2-tailed t test). Although 15 of the 16 ROIs increased in width between visits, only 11 showed a decrease in the global RNFL thickness. CONCLUSIONS AND RELEVANCE: For detecting progression of local RNFL damage in patients with glaucoma, an OCT ROI approach appears superior to the OCT global RNFL thickness measure typically used. PMID- 26502217 TI - Neuroprotective Effects of 17beta-Estradiol against Thrombin-Induced Apoptosis in Primary Cultured Cortical Neurons. AB - AIMS: 17beta-estradiol (E2) is a powerful neuroprotective agent in the central nervous system; however, little is known about its effects on intracerebral hemorrhage. This study examined the effects of E2 on thrombin-induced apoptosis in vitro and investigated the potential mechanisms. METHODS: Primary cultured cortical neurons were treated with E2 or vehicle and then the cells were exposed to thrombin. Neuronal apoptosis was assessed by flow cytometry. The phosphorylated c-Jun-N-terminal kinase (p-JNK), phosphorylated extracellular signal-regulated kinases 1/2 (p-ERK1/2), B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax) and caspase-3 were assayed by western blot. RESULTS: Consequently, we found that E2 has significantly reduced the apoptosis in thrombin-treated neurons. E2 also exhibited a downregulation in the ratio of Bax/Bcl-2, caspase-3 and p-JNK. However, E2 had little effect on p-ERK1/2 proteins activation. CONCLUSION: Taken together, E2 has shown neuroprotective effects on thrombin-induced neuronal apoptosis, and the molecular mechanisms may correlate with the inhibition of the JNK signaling pathway. PMID- 26502218 TI - Specific Language Impairment, Nonverbal IQ, Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Cochlear Implants, Bilingualism, and Dialectal Variants: Defining the Boundaries, Clarifying Clinical Conditions, and Sorting Out Causes. AB - PURPOSE: The purpose of this research forum article is to provide an overview of a collection of invited articles on the topic "specific language impairment (SLI) in children with concomitant health conditions or nonmainstream language backgrounds." Topics include SLI, attention-deficit/hyperactivity disorder, autism spectrum disorder, cochlear implants, bilingualism, and dialectal language learning contexts. METHOD: The topic is timely due to current debates about the diagnosis of SLI. An overarching comparative conceptual framework is provided for comparisons of SLI with other clinical conditions. Comparisons of SLI in children with low-normal or normal nonverbal IQ illustrate the unexpected outcomes of 2 * 2 comparison designs. RESULTS: Comparative studies reveal unexpected relationships among speech, language, cognitive, and social dimensions of children's development as well as precise ways to identify children with SLI who are bilingual or dialect speakers. CONCLUSIONS: The diagnosis of SLI is essential for elucidating possible causal pathways of language impairments, risks for language impairments, assessments for identification of language impairments, linguistic dimensions of language impairments, and long-term outcomes. Although children's language acquisition is robust under high levels of risk, unexplained individual variations in language acquisition lead to persistent language impairments. PMID- 26502219 TI - Flavored Tobacco Product Use Among US Youth Aged 12-17 Years, 2013-2014. PMID- 26502221 TI - Investigation of Specific Binding Proteins to Photoaffinity Linkers for Efficient Deconvolution of Target Protein. AB - Photoaffinity-based target identification has received recent attention as an efficient research tool for chemical biology and drug discovery. The major obstacle of photoaffinity-based target identification is the nonspecific interaction between target identification probes and nontarget proteins. Consequently, the rational design of photoaffinity linkers has been spotlighted for successful target identification. These nonspecific interactions have been considered as random events, and therefore no systematic investigation has been conducted regarding nonspecific interactions between proteins and photoaffinity linkers. Herein, we report the protein-labeling analysis of photoaffinity linkers containing three photoactivatable moieties: benzophenone, diazirine, and arylazide. Each photoaffinity linker binds to a different set of proteins in a structure-dependent manner, in contrast to the previous conception. The list of proteins labeled by each photoaffinity linker was successfully used to eliminate the nonspecific binding proteins from target candidates, thereby increasing the success rate of target identification. PMID- 26502220 TI - Rates of Deintensification of Blood Pressure and Glycemic Medication Treatment Based on Levels of Control and Life Expectancy in Older Patients With Diabetes Mellitus. AB - IMPORTANCE: Older patients with diabetes mellitus receiving medical treatment whose blood pressure (BP) or blood glucose level are potentially dangerously low are rarely deintensified. Given the established risks of low blood pressure and blood glucose, this is a major opportunity to decrease medication harm. OBJECTIVE: To examine the rate of BP- and blood glucose-lowering medicine deintensification among older patients with type 1 or 2 diabetes mellitus who potentially receive overtreatment. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study conducted using data from the US Veterans Health Administration. Participants included 211 667 patients older than 70 years with diabetes mellitus who were receiving active treatment (defined as BP-lowering medications other than angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or glucose-lowering medications other than metformin hydrochloride) from January 1 to December 31, 2012. Data analysis was performed December 10, 2013, to July 20, 2015. EXPOSURES: Participants were eligible for deintensification of treatment if they had low BP or a low hemoglobin A1c (HbA1c) level in their last measurement in 2012. We defined very low BP as less than 120/65 mm Hg, moderately low as systolic BP of 120 to 129 mm Hg or diastolic BP (DBP) less than 65 mm Hg, very low HbA1c as less than 6.0%, and moderately low HbA1c as 6.0% to 6.4%. All other values were not considered low. MAIN OUTCOMES AND MEASURES: Medication deintensification, defined as discontinuation or dosage decrease within 6 months after the index measurement. RESULTS: The actively treated BP cohort included 211,667 participants, more than half of whom had moderately or very low BP levels. Of 104,486 patients with BP levels that were not low, treatment in 15.1% was deintensified. Of 25,955 patients with moderately low BP levels, treatment in 16.0% was deintensified. Among 81,226 patients with very low BP levels, 18.8% underwent BP medication deintensification. Of patients with very low BP levels whose treatment was not deintensified, only 0.2% had a follow-up BP measurement that was elevated (BP >=140/90 mm Hg). The actively treated HbA1c cohort included 179,991 participants. Of 143,305 patients with HbA1c levels that were not low, treatment in 17.5% was deintensified. Of 23,769 patients with moderately low HbA1c levels, treatment in 20.9% was deintensified. Among 12,917 patients with very low HbA1c levels, 27.0% underwent medication deintensification. Of patients with very low HbA1c levels whose treatment was not deintensified, fewer than 0.8% had a follow-up HbA1c measurement that was elevated (>=7.5%). CONCLUSIONS AND RELEVANCE: Among older patients whose treatment resulted in very low levels of HbA1c or BP, 27% or fewer underwent deintensification, representing a lost opportunity to reduce overtreatment. Low HbA1c or BP values or low life expectancy had little association with deintensification events. Practice guidelines and performance measures should place more focus on reducing overtreatment through deintensification. PMID- 26502222 TI - Identification and Construction of Combinatory Cancer Hallmark-Based Gene Signature Sets to Predict Recurrence and Chemotherapy Benefit in Stage II Colorectal Cancer. AB - IMPORTANCE: Decisions regarding adjuvant therapy in patients with stage II colorectal cancer (CRC) have been among the most challenging and controversial in oncology over the past 20 years. OBJECTIVE: To develop robust combinatory cancer hallmark-based gene signature sets (CSS sets) that more accurately predict prognosis and identify a subset of patients with stage II CRC who could gain survival benefits from adjuvant chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: Thirteen retrospective studies of patients with stage II CRC who had clinical follow-up and adjuvant chemotherapy were analyzed. Respective totals of 162 and 843 patients from 2 and 11 independent cohorts were used as the discovery and validation cohorts, respectively. A total of 1005 patients with stage II CRC were included in the 13 cohorts. Among them, 84 of 416 patients in 3 independent cohorts received fluorouracil-based adjuvant chemotherapy. MAIN OUTCOMES AND MEASURES: Identification of CSS sets to predict relapse-free survival and identify a subset of patients with stage II CRC who could gain substantial survival benefits from fluorouracil-based adjuvant chemotherapy. RESULTS: Eight cancer hallmark-based gene signatures (30 genes each) were identified and used to construct CSS sets for determining prognosis. The CSS sets were validated in 11 independent cohorts of 767 patients with stage II CRC who did not receive adjuvant chemotherapy. The CSS sets accurately stratified patients into low-, intermediate-, and high-risk groups. Five-year relapse-free survival rates were 94%, 78%, and 45%, respectively, representing 60%, 28%, and 12% of patients with stage II disease. The 416 patients with CSS set-defined high-risk stage II CRC who received fluorouracil-based adjuvant chemotherapy showed a substantial gain in survival benefits from the treatment (ie, recurrence reduced by 30%-40% in 5 years). CONCLUSIONS AND RELEVANCE: The CSS sets substantially outperformed other prognostic predictors of stage 2 CRC. They are more accurate and robust for prognostic predictions and facilitate the identification of patients with stage II disease who could gain survival benefit from fluorouracil-based adjuvant chemotherapy. PMID- 26502223 TI - Effectiveness of an early versus a conservative invasive treatment strategy in acute coronary syndromes: a nationwide cohort study. AB - BACKGROUND: Randomized clinical trials have found that early invasive strategies reduce mortality, myocardial infarction (MI), and rehospitalization compared with a conservative invasive approach in acute coronary syndromes (ACSs), but the effectiveness of such strategies in real-world settings is unknown. OBJECTIVE: To investigate adverse cardiovascular outcomes of an early versus a conservative invasive strategy in a national cohort of patients with ACSs. DESIGN: Retrospective cohort study. SETTING: Administrative health care data on hospitalizations, procedures, and outcomes abstracted from the Danish national registries and covering all acute invasive procedures in patients presenting with an ACS. PATIENTS: 19 704 propensity score-matched patients hospitalized with a first ACS between 1 January 2005 and 31 December 2011. MEASUREMENTS: Risk for cardiac death or rehospitalization for MI within 60 days of hospitalization. RESULTS: Compared with a conservative approach, early invasive strategies were associated with a lower risk for cardiac death (cumulative incidence, 5.9% vs. 7.6%; adjusted hazard ratio [HR], 0.75 [95% CI, 0.66 to 0.84]; P < 0.001). Similar results were found for rehospitalization for MI (cumulative incidence, 3.4% vs. 5.0%; adjusted odds ratio, 0.67 [CI, 0.58 to 0.77]; P < 0.001) and all cause death (cumulative incidence, 7.3% vs. 10.6%; adjusted HR, 0.65 [CI, 0.59 to 0.72]; P < 0.001). LIMITATION: Potential residual confounding due to lack of core clinical variables. CONCLUSION: In this real-world cohort of patients with a first hospitalization for an ACS, the use of an early invasive treatment strategy was associated with a lower risk for cardiac death and rehospitalization for MI compared with a conservative invasive approach. PRIMARY FUNDING SOURCE: Department of Cardiology, University Hospital Gentofte. PMID- 26502225 TI - Retinal Anatomy and Pathology. AB - Normal retina contains neuroretina and retinal pigment epithelium. The neuroretina consists of outer and inner segments of photoreceptors (rods and cones), external limiting membrane, outer nuclear layer, outer plexiform layer, inner nuclear layer, inner plexiform layer, ganglion cell layer, nerve fiber layer and internal limiting membrane. There is a broad spectrum of retinal pathology including congenital abnormalities, dystrophies, degenerations (notably age-related macular degeneration), retinal vascular diseases, toxicities, inflammatory diseases, neoplasms, retinal detachment, trauma and retinal involvement of systemic diseases. This chapter presents a few major pathological processes in retinal diseases, especially processes that are amenable to pharmacotherapeutics. PMID- 26502227 TI - Quantitatively differentiating microstructures of tissues by frequency distributions of Mueller matrix images. AB - We present a new way to extract characteristic features of the Mueller matrix images based on their frequency distributions and the central moments. We take the backscattering Mueller matrices of tissues with distinctive microstructures, and then analyze the frequency distribution histograms (FDHs) of all the matrix elements. For anisotropic skeletal muscle and isotropic liver tissues, we find that the shapes of the FDHs and their central moment parameters, i.e., variance, skewness, and kurtosis, are not sensitive to the sample orientation. Comparisons among different tissues further indicate that the frequency distributions of Mueller matrix elements and their corresponding central moments can be used as indicators for the characteristic microstructural features of tissues. A preliminary application to human cervical cancerous tissues shows that the distribution curves and central moment parameters may have the potential to give quantitative criteria for cancerous tissues detections. PMID- 26502228 TI - All-plastic miniature fluorescence microscope for point-of-care readout of bead based bioassays. AB - A number of new platforms have been developed for multiplexed bioassays that rely on imaging targeted fluorescent beads labeled with different fluorescent dyes. We developed a compact, low-cost three-dimensional printed fluorescence microscope that can be used as a detector for mutiplexed, bead-based assays to support point of-care applications. Images obtained with the microscope were analyzed to differentiate multiple analytes in a single sample with a comparable limit of detection to commercially available macroscopic assay platforms. PMID- 26502226 TI - Update on Diffuse Lung Disease in Children. AB - Diffuse lung diseases in children, also called children's interstitial lung disease, are a diverse group of rare disorders that cause disturbances of gas exchange in the lungs. Although individually rare, there are many different forms of diffuse lung disease in children, and collectively these disorders are associated with significant morbidity and mortality, as well as health-care resource utilization. Over the past several years, there have been many significant advances in the field, including genetic discoveries and the development of clinical practice guidelines. This review summarizes recent advances in the understanding, diagnosis, and treatment of diffuse lung diseases in children. PMID- 26502224 TI - Genetic, Epigenetic, and Environmental Factors Influencing Neurovisceral Integration of Cardiovascular Modulation: Focus on Multiple Sclerosis. AB - Thought to be an autoimmune inflammatory CNS disease, multiple sclerosis (MS) involves multiple pathologies with heterogeneous clinical presentations. An impaired neurovisceral integration of cardiovascular modulation, indicated by sympathetic and parasympathetic autonomic nervous system (ANS) dysfunction, is among common MS clinical presentations. ANS dysfunction could not only enhance MS inflammatory and neurodegenerative processes, but can also lead to clinical symptoms such as depression, fatigue, sleep disorder, migraine, osteoporosis, and cerebral hemodynamic impairments. Therefore, factors influencing ANS functional activities, in one way or another, will have a significant impact on MS disease course. This review describes the genetic and epigenetic factors, and their interactions with a number of environmental factors contributing to the neurovisceral integration of cardiovascular modulation, with a focus on MS. Future studies should investigate the improvement in cardiovascular ANS function, as a strategy for preventing and minimizing MS-related morbidities, and improving patients' quality of life. PMID- 26502229 TI - Phase matching of backward second harmonic generation assisted by lattice structure in collagen tissues. AB - Phase matching of backward second harmonic generation (SHG) in a periodic structure of collagen fibrils is investigated through theoretical modeling, simulation, and experiments. The lattice structure of collagen fibrils is considered to provide a virtual momentum for assisting the phase matching of backward SHG. Phase matching over a relatively wide excitation wavelength range is achieved by tilting the angle of the fundamental excitation and SHG wave vectors. The SHG intensity in the periodic structure is simulated to quantify the phase matching effect. The effect of the fundamental excitation and the SHG emission angles on the peak excitation wavelength of the SHG excitation spectrum is further validated in experiments, where the excitation and emission angles are controlled by spatial filtering. It is found that an optimized excitation wavelength exists for a certain collagen fibril structure, which shifts toward a shorter wavelength when the excitation and emission angles are increased. Our results show that the lattice structure of collagen fibrils can assist the phase matching, providing a mechanism for generating backward SHG in multiphoton microscopy. PMID- 26502230 TI - Surgical lighting with contrast enhancement based on spectral reflectance comparison and entropy analysis. AB - Surgical light is important for helping the surgeon easily identify specific tissues during an operation. We propose a spectral reflectance comparison model to optimize the light-emitting diode light spectrum in the operating room. An entropy evaluation method, meant specifically for surgical situations, was developed to evaluate images of biological samples. White light was mixed to achieve an optimal spectrum, and images of different tissues under the light were captured and analyzed. Results showed that images obtained with light with an optimal spectrum had a higher contrast than those obtained with a commercial white light of different color temperatures. Optimized surgical light obtained using this simple and effective method could replace the traditional surgical illumination systems. PMID- 26502231 TI - Validating tyrosinase homologue melA as a photoacoustic reporter gene for imaging Escherichia coli. AB - To understand the pathogenic processes for infectious bacteria, appropriate research tools are required for replicating and characterizing infections. Fluorescence and bioluminescence imaging have primarily been used to image infections in animal models, but optical scattering in tissue significantly limits imaging depth and resolution. Photoacoustic imaging, which has improved depth-to-resolution ratio compared to conventional optical imaging, could be useful for visualizing melA-expressing bacteria since melA is a bacterial tyrosinase homologue which produces melanin. Escherichia coli-expressing melA was visibly dark in liquid culture. When melA-expressing bacteria in tubes were imaged with a VisualSonics Vevo LAZR system, the signal-to-noise ratio of a 9*dilution sample was 55, suggesting that ~20 bacteria cells could be detected with our system. Multispectral (680, 700, 750, 800, 850, and 900 nm) analysis of the photoacoustic signal allowed unmixing of melA-expressing bacteria from blood. To compare photoacoustic reporter gene melA (using Vevo system) with luminescent and fluorescent reporter gene Nano-lantern (using Bruker Xtreme In-Vivo system), tubes of bacteria expressing melA or Nano-lantern were submerged 10 mm in 1% Intralipid, spaced between <1 and 20 mm apart from each other, and imaged with the appropriate imaging modality. Photoacoustic imaging could resolve the two tubes of melA-expressing bacteria even when the tubes were less than 1 mm from each other, while bioluminescence and fluorescence imaging could not resolve the two tubes of Nano-lantern-expressing bacteria even when the tubes were spaced 10 mm from each other. After injecting 100-MUL of melA-expressing bacteria in the back flank of a chicken embryo, photoacoustic imaging allowed visualization of melA-expressing bacteria up to 10-mm deep into the embryo. Photoacoustic signal from melA could also be separated from deoxy- and oxy-hemoglobin signal observed within the embryo and chorioallantoic membrane. Our results suggest that melA is a useful photoacoustic reporter gene for visualizing bacteria, and further work incorporating photoacoustic reporters into infectious bacterial strains is warranted. PMID- 26502232 TI - Dual-wavelength laser speckle imaging for monitoring brain metabolic and hemodynamic response to closed head traumatic brain injury in mice. AB - Abstract. The measurement of dynamic changes in brain hemodynamic and metabolism events following head trauma could be valuable for injury prognosis and for planning of optimal medical treatment. Specifically, variations in blood flow and oxygenation levels serve as important biomarkers of numerous pathophysiological processes. We employed the dual-wavelength laser speckle imaging (DW-LSI) technique for simultaneous monitoring of changes in brain hemodynamics and cerebral blood flow (CBF) at early stages of head trauma in a mouse model of intact head injury (n=10). For induction of head injury, we used a weight-drop device involving a metal mass (~50 g ) striking the mouse's head in a regulated manner from a height of ~90 cm. In comparison to baseline measurements, noticeable dynamic variations were revealed immediately and up to 1 h postinjury, which indicate the severity of brain damage and highlight the ability of the DW LSI arrangement to track brain pathophysiology induced by injury. To validate the monitoring of CBF by DW-LSI, measurements with laser Doppler flowmetry (LDF) were also performed (n=5), which confirmed reduction in CBF following injury. A secondary focus of the study was to investigate the effectiveness of hypertonic saline as a neuroprotective agent, inhibiting the development of complications after brain injury in a subgroup of injured mice (n=5), further demonstrating the ability of DW-LSI to monitor the effects upon brain dynamics of drug treatment. Overall, our findings further support the use of DW-LSI as a noninvasive, cost effective tool to assess changes in hemodynamics under a variety of pathological conditions, suggesting its potential contribution to the biomedical field. To the best of our knowledge, this work is the first to make use of the DW-LSI modality in a small animal model to (1) investigate brain function during the critical first hour of closed head injury trauma, (2) correlate between injury parameters of LDF measurements, and (3) monitor brain hemodynamic and metabolic response to neuroprotective drug treatment. PMID- 26502233 TI - Investigating the influence of chromatic aberration and optical illumination bandwidth on fundus imaging in rats. AB - Abstract. Rodent models are indispensable in studying various retinal diseases. Noninvasive, high-resolution retinal imaging of rodent models is highly desired for longitudinally investigating the pathogenesis and therapeutic strategies. However, due to severe aberrations, the retinal image quality in rodents can be much worse than that in humans. We numerically and experimentally investigated the influence of chromatic aberration and optical illumination bandwidth on retinal imaging. We confirmed that the rat retinal image quality decreased with increasing illumination bandwidth. We achieved the retinal image resolution of 10 MUm using a 19 nm illumination bandwidth centered at 580 nm in a home-built fundus camera. Furthermore, we observed higher chromatic aberration in albino rat eyes than in pigmented rat eyes. This study provides a design guide for high resolution fundus camera for rodents. Our method is also beneficial to dispersion compensation in multiwavelength retinal imaging applications. PMID- 26502234 TI - Effect of low-level laser therapy on irradiated parotid glands--study in mice. AB - The objective of this study was to evaluate the effect of low-level laser therapy (LLLT) on radiotherapy-induced morphological changes and caspase-3 immunodetection in parotids of mice. Forty-one Swiss mice were divided into control, radiotherapy, 2- and 4-J laser groups. The experimental groups were exposed to ionizing radiation in a single session of 10 Gy. In the laser groups, a GaAlAs laser (830 nm, 100 mW, 0.028 cm2, 3.57 W/cm2) was used on the region corresponding to the parotid glands, with 2-J energy (20 s, 71 J/cm2) or 4 J (40 s, 135 J/cm2) per point. LLLT was performed immediately before and 24 h after radiotherapy. One point was applied in each parotid gland. The animals were euthanized 48 h or 7 days after radiotherapy and parotid glands were dissected for morphological analysis and immunodetection of caspase-3. There was no significant difference between groups in the immunodetection of caspase-3, but the laser groups had a lower percentage compared to the radiotherapy group. LLLT promoted the preservation of acinar structure, reduced the occurrence of vacuolation, and stimulated parotid gland vascularization. Of the two LLLT protocols, the one using 4 J of energy showed better results. PMID- 26502235 TI - Randomized in vivo evaluation of photodynamic antimicrobial chemotherapy on deciduous carious dentin. AB - The aim of this randomized in vivo study was to compare antimicrobial chemotherapies in primary carious dentin. Thirty-two participants ages 5 to 7 years underwent partial caries removal from deep carious dentin lesions in primary molars and were subsequently divided into three groups: control [chlorhexidine and resin-modified glass ionomer cement (RMGIC)], LEDTB [photodynamic antimicrobial chemotherapy (PACT) with light-emitting diode associated with toluidine blue solution and RMGIC], and LMB [PACT with laser associated with methylene blue solution and RMGIC]. The participants were submitted to initial clinical and radiographic examinations. Demographic features and biofilm, gingival, and DMFT/DMFS indexes were evaluated, in addition to clinical and radiographic followups at 6 and 12 months after treatments. Carious dentin was collected before and after each treatment, and the number of Streptococcus mutans, Streptococcus sobrinus, Lactobacillus casei, Fusobacterium nucleatum, Atopobium rimae, and total bacteria was established by quantitative polymerase chain reaction. No signs of pain or restoration failure were observed. All therapies were effective in reducing the number of microorganisms, except for S. sobrinus. No statistical differences were observed among the protocols used. All therapies may be considered as effective modern approaches to minimal intervention for the management of deep primary caries treatment. PMID- 26502236 TI - Inflammation, Endoleaks, and Aortic Remodeling--The Chicken or the Egg. PMID- 26502259 TI - Hospital Acquisition of Physician Groups: On the Road to Value-Based or Higher Priced Care? PMID- 26502260 TI - Trajectory events across hippocampal place cells require previous experience. AB - Replay of hippocampal place cell sequences has been proposed as a fundamental mechanism of learning and memory. However, the standard interpretation of replay has been challenged by reports that similar activity is observed before experience ('preplay'). By the preplay account, pre-existing temporal sequences are mapped onto new experiences without learning sequential structure. Here we employed high density recording methods to monitor hundreds of place cells simultaneously while rats explored multiple novel environments. While we observed large numbers of synchronous spiking events before experience, they were not temporally correlated with subsequent experience. Multiple measures differentiated pre-experience and postexperience events that, taken together, defined the latter but not the former as trajectory-depicting. The formation of events with these properties was prevented by administration of an NMDA-receptor antagonist during experience. These results suggest that the sequential structure of behavioral episodes is encoded during experience and reexpressed as trajectory events. PMID- 26502261 TI - GDF10 is a signal for axonal sprouting and functional recovery after stroke. AB - Stroke produces a limited process of neural repair. Axonal sprouting in cortex adjacent to the infarct is part of this recovery process, but the signal that initiates axonal sprouting is not known. Growth and differentiation factor 10 (GDF10) is induced in peri-infarct neurons in mice, non-human primates and humans. GDF10 promotes axonal outgrowth in vitro in mouse, rat and human neurons through TGFbetaRI and TGFbetaRII signaling. Using pharmacogenetic gain- and loss of-function studies, we found that GDF10 produced axonal sprouting and enhanced functional recovery after stroke; knocking down GDF10 blocked axonal sprouting and reduced recovery. RNA sequencing from peri-infarct cortical neurons revealed that GDF10 downregulated PTEN, upregulated PI3 kinase signaling and induced specific axonal guidance molecules. Using unsupervised genome-wide association analysis of the GDF10 transcriptome, we found that it was not related to neurodevelopment, but may partially overlap with other CNS injury patterns. Thus, GDF10 is a stroke-induced signal for axonal sprouting and functional recovery. PMID- 26502262 TI - Sensory uncertainty decoded from visual cortex predicts behavior. AB - Bayesian theories of neural coding propose that sensory uncertainty is represented by a probability distribution encoded in neural population activity, but direct neural evidence supporting this hypothesis is currently lacking. Using fMRI in combination with a generative model-based analysis, we found that probability distributions reflecting sensory uncertainty could reliably be estimated from human visual cortex and, moreover, that observers appeared to use knowledge of this uncertainty in their perceptual decisions. PMID- 26502264 TI - Palladium-Catalyzed Difluoroalkylation of Isocyanides: Access to Difluoroalkylated Phenanthridine Derivatives. AB - An efficient and general method for the synthesis of difluoroalkylated phenanthridine derivatives through palladium-catalyzed reaction of difluoroalkyl bromides with isocyanides is described. The reaction can also be extended to perfluoroalkyl iodides. Mechanistic studies reveal that a difluoroalkyl radical via a single-electron-transfer pathway is involved in the reaction. PMID- 26502263 TI - Distinct recurrent versus afferent dynamics in cortical visual processing. AB - How intracortical recurrent circuits in mammalian sensory cortex influence dynamics of sensory representation is not understood. Previous methods could not distinguish the relative contributions of recurrent circuits and thalamic afferents to cortical dynamics. We accomplish this by optogenetically manipulating thalamus and cortex. Over the initial 40 ms of visual stimulation, excitation from recurrent circuits in visual cortex progressively increased to exceed direct thalamocortical excitation. Even when recurrent excitation exceeded thalamic excitation, upon silencing thalamus, sensory-evoked activity in cortex decayed rapidly, with a time constant of 10 ms, which is similar to a neuron's integration time window. In awake mice, this cortical decay function predicted the time-locking of cortical activity to thalamic input at frequencies <15 Hz and attenuation of the cortical response to higher frequencies. Under anesthesia, depression at thalamocortical synapses disrupted the fidelity of sensory transmission. Thus, we determine dynamics intrinsic to cortical recurrent circuits that transform afferent input in time. PMID- 26502265 TI - Chemical Cleavage of Layered Carbon Nitride with Enhanced Photoluminescent Performances and Photoconduction. AB - Graphene quantum dots (GQDs) and carbon dots (C-dots) have various alluring properties and potential applications, but they are often limited by unsatisfied optical performance such as low quantum yield, ambiguous fluorescence emission mechanism, and narrow emission wavelength. Herein, we report that bulk polymeric carbon nitride could be utilized as a layered precursor to prepare carbon nitride nanostructures such as nanorods, nanoleaves and quantum dots by chemical tailoring. As doped carbon materials, these carbon nitride nanostructures not only intrinsically emitted UV lights but also well inherited the explicit photoluminescence mechanism of the bulk pristine precursor, both of which were rarely reported for GQDs and C-dots. Especially, carbon nitride quantum dots (CNQDs) had a photoluminescence quantum yield (QY) up to 46%, among the highest QY for metal-free quantum dots so far. As examples, the CNQDs were utilized as a photoluminescence probe for rapid detection of Fe(3+) with a detection limit of 1 MUM in 2 min and a photoconductor in an all-solid-state device. This work would open up an avenue for doped nanocarbon in developing photoelectrical devices and sensors. PMID- 26502266 TI - A Highly Stable Nanotubular MOF Rotator for Selective Adsorption of Benzene and Separation of Xylene Isomers. AB - A remarkably stable tubular 3D Zn-MOF with hexagonal channels and a rare ptr topology was prepared under solvothermal conditions for liquid and vapor phase adsorption and separation of the C6-8 aromatic compounds. The material showed preferential affinity for benzene and can effectively separate benzene from its organic analogues under ambient conditions in both vapor and liquid phases. Furthermore, it exhibited preferable uptake of p-xylene over other C8 xylenes. PMID- 26502268 TI - Systematic Effect for an Ultralong Cycle Lithium-Sulfur Battery. AB - Rechargeable lithium-sulfur (Li-S) batteries are attractive candidates for energy storage devices because they have five times the theoretical energy storage of state-of-the-art Li-ion batteries. The main problems plaguing Li-S batteries are poor cycle life and limited rate capability, caused by the insulating nature of S and the shuttle effect associated with the dissolution of intermediate lithium polysulfides. Here, we report the use of biocell-inspired polydopamine (PD) as a coating agent on both the cathode and separator to address these problems (the "systematic effects"). The PD-modified cathode and separator play key roles in facilitating ion diffusion and keeping the cathode structure stable, leading to uniform lithium deposition and a solid electrolyte interphase. As a result, an ultralong cycle performance of more than 3000 cycles, with a capacity fade of only 0.018% per cycle, was achieved at 2 C. It is believed that the systematic modification of the cathode and separator for Li-S batteries is a new strategy for practical applications. PMID- 26502267 TI - Gelation Landscape Engineering Using a Multi-Reaction Supramolecular Hydrogelator System. AB - Simultaneous control of the kinetics and thermodynamics of two different types of covalent chemistry allows pathway selectivity in the formation of hydrogelating molecules from a complex reaction network. This can lead to a range of hydrogel materials with vastly different properties, starting from a set of simple starting compounds and reaction conditions. Chemical reaction between a trialdehyde and the tuberculosis drug isoniazid can form one, two, or three hydrazone connectivity products, meaning kinetic gelation pathways can be addressed. Simultaneously, thermodynamics control the formation of either a keto or an enol tautomer of the products, again resulting in vastly different materials. Overall, this shows that careful navigation of a reaction landscape using both kinetic and thermodynamic selectivity can be used to control material selection from a complex reaction network. PMID- 26502269 TI - Capacitive Sensing of Intercalated H2O Molecules Using Graphene. AB - Understanding the interactions of ambient molecules with graphene and adjacent dielectrics is of fundamental importance for a range of graphene-based devices, particularly sensors, where such interactions could influence the operation of the device. It is well-known that water can be trapped underneath graphene and its host substrate; however, the electrical effect of water beneath graphene and the dynamics of how the interfacial water changes with different ambient conditions has not been quantified. Here, using a metal-oxide-graphene variable capacitor (varactor) structure, we show that graphene can be used to capacitively sense the intercalation of water between graphene and HfO2 and that this process is reversible on a fast time scale. Atomic force microscopy is used to confirm the intercalation and quantify the displacement of graphene as a function of humidity. Density functional theory simulations are used to quantify the displacement of graphene induced by intercalated water and also explain the observed Dirac point shifts as being due to the combined effect of water and oxygen on the carrier concentration in the graphene. Finally, molecular dynamics simulations indicate that a likely mechanism for the intercalation involves adsorption and lateral diffusion of water molecules beneath the graphene. PMID- 26502270 TI - Identification of oxygen-19 during in vivo neutron activation analysis of water phantoms. AB - Hand bone equivalent phantoms (250 ml) carrying selenium in various amounts were irradiated and counted for in vivo neutron activation analysis (IVNAA) by employing a 4pi NaI(TI) based detection system. During the analysis of counting data, a feature at a higher energy than the gamma ray peak from (77m)Se (0.162 MeV) was observed at 0.197 MeV. Further investigations were made by preparing water phantoms containing only de-ionized water in 250 ml and 1034 ml quantities. Neutrons were produced by the (7)Li(p,n)(7)Be reaction using the high beam current Tandetron accelerator. Phantoms were irradiated at a fixed proton energy of 2.3 MeV and proton currents of 400 MUA and 550 MUA for 30 s and 22 s respectively. The counting data saved using the 4pi NaI(TI) detection system for 10 s intervals in anticoincidence, coincidence and singles modes of detection were analyzed. Areas under gamma peaks at energies 0.197 MeV and 1.357 MeV were computed and half-lives from the number of counts for the two peaks were established. It was concluded that during neutron activation of water phantoms, oxygen-18 is activated, producing short-lived radioactive 19O having T(1/2) = 26.9 s. Induced activity from 19O may contribute spectral interference in the gamma ray spectrum. This effect may need to be taken into account by researchers while carrying out IVNAA of biological subjects. PMID- 26502271 TI - FMS Scores Change With Performers' Knowledge of the Grading Criteria-Are General Whole-Body Movement Screens Capturing "Dysfunction"? AB - Deficits in joint mobility and stability could certainly impact individuals' Functional Movement Screen (FMS) scores; however, it is also plausible that the movement patterns observed are influenced by the performers' knowledge of the grading criteria. Twenty-one firefighters volunteered to participate, and their FMS scores were graded before and immediately after receiving knowledge of the movement patterns required to achieve a perfect score on the FMS. Standardized verbal instructions were used to administer both screens, and the participants were not provided with any coaching or feedback. Time-synchronized sagittal and frontal plane videos were used to grade the FMS. The firefighters significantly (p < 0.001) improved their FMS scores from 14.1 (1.8) to 16.7 (1.9) when provided with knowledge pertaining to the specific grading criteria. Significant improvements (p < 0.05) were also noted in the deep squat (1.4 [0.7]-2.0 [0.6]), hurdle step (2.1 [0.4]-2.4 [0.5]), in-line lunge (2.1 [0.4]-2.7 [0.5]), and shoulder mobility (1.8 [0.8]-2.4 [0.7]) tests. Because a knowledge of a task's grading criteria can alter a general whole-body movement screen score, FMS or otherwise, observed changes may not solely reflect "dysfunction." The instant that individuals are provided with coaching and feedback regarding their performance on a particular task, the task may lose its utility to evaluate the transfer of training or predict musculoskeletal injury risk. PMID- 26502272 TI - Cold Vs. Heat After Exercise-Is There a Clear Winner for Muscle Soreness. AB - Because of the differences in the exercise type, temperature, and timing of the use of cold and heat after exercise in different studies, there is no clear conclusion as to the efficacy of either modality on reducing delayed onset muscle soreness. One hundred subjects at similar fitness levels were examined. They accomplished leg squats for 15 minutes and heat and cold were applied after or 24 hours after exercise using ThermaCare heat or cold wraps. Measurements obtained were strength, the force to passively move the knee, analog visual pain scales, and blood myoglobin. Control subjects lost 24% strength after exercise. Subjects with heat or cold just after exercise only lost 4% strength (p < 0.01). For strength recovery, cold applied after 24 hours was better than heat at 24 hours. Heat or cold applied after exercise was significantly better to prevent elastic tissue damage (p < 0.01), whereas heat and cold immediately after exercise caused no loss in muscle myoglobin and heat or cold after 24 hours showed no less muscle damage from myoglobin than in control subjects. Myoglobin in the control and heat and cold 24-hour groups averaged 135.1% of the baseline data but averaged 106.1% of baseline in the immediate heat and cold groups. For reducing pain, control subjects showed a significant amount of pain the days after exercise. But cold immediately after exercise or 24 hours later was superior to heat in reducing pain. In conclusion, both cold and heat appear to be efficacious in reducing muscle damage after exercise. PMID- 26502273 TI - The Molecular Influence of Graphene and Graphene Oxide on the Immune System Under In Vitro and In Vivo Conditions. AB - Graphene and graphene oxide (GO), due to their physicochemical properties and biocompatibility, can be used as an innovative biomedical material in biodetection, drug distribution in the body, treating neoplasms, regenerative medicine, and in implant surgery. Research on the biomedical use of graphene and GO that has been carried out until now is very promising and shows that carbon nanomaterials present high biocompatibility. However, the intolerance of the immune system to graphene nanomaterials, however low, may in consequence make it impossible to use them in medicine. This paper shows the specific mechanism of the molecular influence of graphene and GO on macrophages and lymphocytes under in vitro and in vivo conditions and their practical application in medicine. Under in vitro conditions graphene and GO cause an increased production of pro inflammatory cytokines, mainly IL-1, IL-6, IL-10 and TNF-alpha, as a result of the activation of Toll-like receptors in macrophages. Graphene activates apoptosis in macrophages through the TGFbr/Smad/Bcl-2 pathway and also through JNK kinases that are stimulated by an increase of ROS in the cell or through a signal received by Smad proteins. Under in vivo conditions, graphene nanomaterials induce the development of the local inflammatory reaction and the development of granulomas in parenchymal organs. However, there is a huge discrepancy between the results obtained by different research groups, which requires a detailed analysis. In this work we decided to collect and analyze existing research and tried to explain the discrepancies. Understanding the precise mechanism of how this nanomaterial influences immune system cells allows estimating the potential influence of grapheme and GO on the human body. PMID- 26502274 TI - Preparation of Silicon-Carbon-Based Dots@Dopamine and Its Application in Intracellular Ag(+) Detection and Cell Imaging. AB - A novel nanocomposite, silicon-carbon-based dots@dopamine (Si-CDs@DA) was prepared using (3-aminopropyl) triethoxysilane, glycerol, and dopamine as raw materials via a rapid microwave-assisted irradiation. This type of Si-CDs@DA exhibited ultrabright fluorescence emission (quantum yield of 12.4%) and could response to Ag(+) selectively and sensitively. Moreover, the obtained Si-CDs@DA can be further applied in sensing intracellular Ag(+) and cell imaging, because of its photostability, salt stability, and low cytotoxicity. This study provides a simple and efficient approach for preparing novel Ag(+) fluorescent probes, which could expand the application of carbon nanomaterials in designing related biosensors. PMID- 26502276 TI - Posterior Uveitis. AB - Posterior uveitis is a major cause of ocular morbidity worldwide. Systemic corticosteroids (CS) remain the primary method of treatment for noninfectious posterior uveitis; however, CS are associated with many side effects. Immunomodulatory therapy (IMT) is recommended when inflammatory control is not attained with a tolerable level of systemic CS (<10 mg/day of prednisone). IMT agents are associated with several toxicities and limited benefits in some patients. Locally administered therapies (e.g. intravitreal CS implants) offer the promise of providing therapeutic levels of anti-inflammatory agents while avoiding systemic complications. This chapter will briefly discuss common posterior uveitis entities that are amenable to retinal pharmacotherapy. PMID- 26502275 TI - Annotation of the Staphylococcus aureus Metabolome Using Liquid Chromatography Coupled to High-Resolution Mass Spectrometry and Application to the Study of Methicillin Resistance. AB - Staphylococcus aureus can cause a variety of severe disease patterns and can readily acquire antibiotic resistance; however, the mechanisms by which this commensal becomes a pathogen or develops antibiotic resistance are still poorly understood. Here we asked whether metabolomics can be used to distinguish bacterial strains with different antibiotic susceptibilities. Thus, an efficient and robust method was first thoroughly implemented to measure the intracellular metabolites of S. aureus in an unbiased and reproducible manner. We also placed special emphasis on metabolome coverage and annotation and used both hydrophilic interaction liquid chromatography and pentafluorophenyl-propyl columns coupled to high-resolution mass spectrometry in conjunction with our spectral database developed in-house to identify with high confidence as many meaningful S. aureus metabolites as possible. Overall, we were able to characterize up to 210 metabolites in S. aureus, which represents a substantial ~50% improvement over previously published data. We then preliminarily compared the metabolic profiles of 10 clinically relevant methicillin-resistant and susceptible strains harvested at different time points during the exponential growth phase (without any antibiotic exposure). Interestingly, the resulting data revealed a distinct behavior of "slow-growing" resistant strains, which show modified levels of several precursors of peptidoglycan and capsular polysaccharide biosynthesis. PMID- 26502277 TI - Doing More vs. Doing Good: Aligning Our Ethical Principles From the Personal to the Societal. PMID- 26502278 TI - Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation. AB - A novel class of phthalimides functionalized with privileged scaffolds was designed, synthesized and evaluated as potential inhibitors of plasmepsin 2 (Ki: 0.99 +/- 0.1 MUM for 6u) and plasmepsin 4 (Ki: 3.3 +/- 0.3 MUM for 6t), enzymes found in the digestive vacuole of the plasmodium parasite and considered as crucial drug targets. Three compounds were identified as potential candidates for further development. The listed compounds were also assayed for their antimalarial efficacy against chloroquine (CQ) sensitive strain (3D7) of Plasmodium falciparum. Assay of twenty seven hydroxyethylamine derivatives revealed four (5e, 6j, 6o and 6s) as strongly active, which were further evaluated against CQ resistant strain (7GB) of P. falciparum. Compound 5e possessing the piperidinopiperidine moiety exhibited promising antimalarial activity with an IC50 of 1.16 +/- 0.04 MUM. Further, compounds 5e, 6j, 6o and 6s exhibited low cytotoxic effect on MCF-7 cell line. Compound 6s possessing C2 symmetry was identified as the least cytotoxic with significant antimalarial activity (IC50: 1.30 +/- 0.03 MUM). The combined presence of hydroxyethylamine and cyclic amines (piperazines and piperidines) was observed as crucial for the activity. The current studies suggest that hydroxyethylamine based molecules act as potent antimalarial agent and may be helpful in drug development. PMID- 26502280 TI - Micronutrient status and intake in omnivores, vegetarians and vegans in Switzerland. AB - PURPOSE: Vegetarian and vegan diets have gained popularity in Switzerland. The nutritional status of individuals who have adopted such diets, however, has not been investigated. The aim of this study was to assess the intake and status of selected vitamins and minerals among vegetarian and vegan adults living in Switzerland. METHODS: Healthy adults [omnivores (OVs), n OV = 100; vegetarians (VGs), n VG = 53; vegans (VNs), n VN = 53] aged 18-50 years were recruited, and their weight and height were measured. Plasma concentrations of the vitamins A, C, E, B1, B2, B6, B12, folic acid, pantothenic acid, niacin, biotin and beta carotene and of the minerals Fe, Mg and Zn and urinary iodine concentration were determined. Dietary intake was assessed using a three-day weighed food record, and questionnaires were issued in order to assess the physical activity and lifestyle of the subjects. RESULTS: Omnivores had the lowest intake of Mg, vitamin C, vitamin E, niacin and folic acid. Vegans reported low intakes of Ca and a marginal consumption of the vitamins D and B12. The highest prevalence for vitamin and mineral deficiencies in each group was as follows: in the omnivorous group, for folic acid (58 %); in the vegetarian group, for vitamin B6 and niacin (58 and 34 %, respectively); and in the vegan group, for Zn (47 %). Despite negligible dietary vitamin B12 intake in the vegan group, deficiency of this particular vitamin was low in all groups thanks to widespread use of supplements. Prevalence of Fe deficiency was comparable across all diet groups. CONCLUSIONS: Despite substantial differences in intake and deficiency between groups, our results indicate that by consuming a well-balanced diet including supplements or fortified products, all three types of diet can potentially fulfill requirements for vitamin and mineral consumption. PMID- 26502281 TI - Development and regulatory application of microRNA biomarkers. AB - MicroRNAs, a class of regulatory small non-coding RNAs, are emerging as promising biomarkers for different health outcomes. Due to their tissue specificity, stability in extracellular space and high conservation between preclinical test species, applications of novel miRNA-based biomarkers for drug safety testing regarding hepatotoxicity and cardiotoxicity are investigated. Furthermore, miRNA expression is altered by environmental exposure such as cigarette smoke or polychlorinated biphenyls. As a consequence, miRNAs potentially influence tumor suppressor genes and oncogenes and may influence carcinogenesis. This has raised the interest in the use of miRNA profiles for health risk assessment. This review summarizes the recent developments in miRNA research with focus on biomarkers for drug safety testing and biomarkers for health outcomes related to environmental exposures. PMID- 26502282 TI - Penile Strangulation Caused by a Seal Ring. PMID- 26502283 TI - An Online Assessment of Personality, Psychological, and Sexuality Trait Variables Associated with Self-Reported Hypersexual Behavior. AB - "Hypersexual" behavior represents a perceived inability to control one's sexual behavior. To investigate hypersexual behavior, an international sample of 510 self-identified heterosexual, bisexual, and homosexual men and women completed an anonymous online self-report questionnaire battery. In addition to age and sex (male), hypersexual behavior was related to higher scores on measures of sexual excitation, sexual inhibition due to the threat of performance failure, trait impulsivity, and both depressed mood and anxiety. In contrast, hypersexual behavior was related to lower scores on sexual inhibition due to the threat of performance consequences. Higher neuroticism and extraversion, as well as lower agreeableness and conscientiousness, also predicted hypersexual behavior. Interestingly, interactions among the variables assessed did not significantly predict hypersexual behavior, suggesting the possible existence of multiple and predominantly independent taxa for various persons reporting hypersexual behavior. Core personality features may also be present in persons with hypersexual behavior. Clinical implications and future research directions are discussed. PMID- 26502284 TI - E-Cigarette Awareness, Perceptions and Use among Community-Recruited Smokers in Hong Kong. AB - BACKGROUND: Electronic cigarettes (e-cigarettes) are being increasingly used. We examined the correlates associated with e-cigarette awareness, use and perceived effectiveness in smoking cessation among Chinese daily smokers in Hong Kong. METHODS: Daily smokers (N = 1,307) were recruited to a community-based randomised controlled trial ('Quit to Win') in 2014. Socio-demographic characteristics, conventional cigarette smoking status, nicotine addiction level, quit attempts, quit intention, e-cigarette awareness, use and perceived effectiveness on quitting were reported at baseline and 1-week follow-up. Multivariate logistic regression was used to identify factors associated with e-cigarette awareness, use and perceived effectiveness in quitting. RESULTS: Most smokers (82.6%, 95% CI 80.2%-84.9%) had heard about e-cigarettes, and 13.3% (11.3%-15.5%) ever used e cigarettes. Most users (74.1%) and non-users (91.2%) did not perceive e cigarettes as effective in quitting. Being younger and having a larger family income were associated with e-cigarette awareness. Being younger, a tertiary education and a stronger addiction to nicotine were associated with e-cigarette use, which was itself associated with lower levels of intention to quit and had no association with attempts to quit (P for trend 0.45). E-cigarette use, the last quit attempt being a month earlier, having made a quit attempt lasting 24 hours or longer and perceiving quitting as important were all associated with the perceived effectiveness of e-cigarettes in quitting (all P <0.05). CONCLUSIONS: Among community-recruited smokers who intended to quit, awareness of e-cigarettes was high, but most did not perceive e-cigarettes as effective in quitting. Correlates concerning e-cigarette perceptions and use will help to inform prospective studies, public education and policy on controlling e-cigarettes. PMID- 26502285 TI - Polyethylenimine-interlayered core-shell-satellite 3D magnetic microspheres as versatile SERS substrates. AB - Precise fabrication of subtle nanogaps amid individual nanoparticles or between adjacent ones to obtain the highest SERS enhancement is still a challenge. Here, we reported a novel approach for fabricating core-shell-satellite 3D magnetic microspheres (CSSM), that easily form a porous 1.5 nm PEI interlayer to accommodate molecules and create sufficient hotspots between the inner Fe3O4@Ag core and outer assembled Au@Ag satellites. Experiments and finite-difference time domain (FDTD) simulation demonstrated that the enhancement factor (EF) was about 2.03 * 10(8) and 6.25 * 10(6), respectively. In addition, the micro-scale magnetic core endowed the CSSM with a superior magnetic nature, which enabled easy separation and further enhanced Raman signals due to enrichment of targeted analytes and abundant interparticle hotspots created by magnetism-induced aggregation. Our results further demonstrated that the CSSM is expected to be a versatile SERS substrate, which has been verified by the detection of the adsorbed pesticide thiram and the non-adsorbed pesticide paraquat with a detection limit as low as 5 * 10(-12) M and 1 * 10(-10) M, respectively. The novel CSSM can overcome the long-standing limitations of SERS for the trace characterization of various analytes in different solutions and promises to transform SERS into a practical analytical technique. PMID- 26502287 TI - Continuous Subcutaneous Insulin Infusion During Pregnancy in Women with Complicated Type 1 Diabetes Is Associated with Better Glycemic Control but Not with Improvement in Pregnancy Outcomes. AB - BACKGROUND: The aim of this study was to evaluate maternal and fetal pregnancy outcomes of women with type 1 diabetes managed on continuous subcutaneous insulin infusion (CSII) compared with multiple daily insulin injections (MDI). SUBJECTS AND METHODS: Pregnancy outcomes were assessed retrospectively in women with type 1 diabetes who were patients of the Diabetes Clinic of North Karelia Hospital (Joensuu, Finland) between 2000 and 2012. The medical records of 72 women experiencing 135 pregnancies and data of their infants were retrospectively reviewed. RESULTS: In total, 48 pregnancies were treated with CSII and 87 with MDI. Women on CSII treatment were older and had more diabetes complications compared with women on MDI. No significant differences in glycated hemoglobin (HbA1c) levels were observed between the CSII and MDI groups before or during pregnancy. Maternal or fetal outcomes did not differ between the treatment groups. However, among women with complicated diabetes, HbA1c levels were significantly lower in the CSII group until the second trimester (prepregnancy, 7.22% vs. 8.14%, respectively [P = 0.034]; first trimester, 6.85% vs. 7.87% [P < 0.001]; second trimester, 6.41% vs. 7.03% [P = 0.029]) without an increased rate of maternal hypoglycemia. CONCLUSIONS: Pregnancy outcomes were similar regardless of insulin treatment modality. Although using an insulin pump did not result in improvement of pregnancy outcomes, it allowed for better glycemic control in pregnancies of women with complicated diabetes. Therefore, it is worth considering in high-risk T1DM pregnancies, especially if good glycemic control is not achieved otherwise. PMID- 26502286 TI - Interactions between Hepatitis C Virus and the Human Apolipoprotein H Acute Phase Protein: A Tool for a Sensitive Detection of the Virus. AB - The Hepatitis C virus (HCV) infection exhibits a high global prevalence frequently associated with hepatocellular carcinoma, taking years to develop. Despite the standardization of highly sensitive HCV quantitative RT-PCR (qRT-PCR) detection methods, false-negative diagnoses may be generated with current methods, mainly due to the presence of PCR inhibitors and/or low viral loads in the patient's sample. These false-negative diagnoses impact both public health systems, in developing countries, and an in lesser extent, in developed countries, including both the risk of virus transmission during organ transplantation and/or blood transfusion and the quality of the antiviral treatment monitoring. To adopt an appropriate therapeutic strategy to improve the patient's prognosis, it is urgent to increase the HCV detection sensitivity. Based upon previous studies on HBV, we worked on the capacity of the scavenger acute phase protein, Apolipoprotein H (ApoH) to interact with HCV. Using different approaches, including immunoassays, antibody-inhibition, oxidation, ultracentrifugation, electron microscopy and RT-PCR analyses, we demonstrated specific interactions between HCV particles and ApoH. Moreover, when using a two step HCV detection process, including capture of HCV by ApoH-coated nanomagnetic beads and a home-made real-time HCV-RT-PCR, we confirmed the presence of HCV for all samples from a clinical collection of HCV-seropositive patients exhibiting an RT-PCR COBAS(r) TaqMan(r) HCV Test, v2.0 (COBAS)-positive result. In contrast, for HCV-seropositive patients with either low HCV-load as determined with COBAS or exhibiting HCV-negative COBAS results, the addition of the two-step ApoH-HCV capture and HCV-detection process was able to increase the sensitivity of HCV detection or more interestingly, detect in a genotype sequence-independent manner, a high-proportion (44%) of HCV/RNA-positive among the COBAS HCV-negative patients. Thus, the immune interaction between ApoH and HCV could be used as a sample preparation tool to enrich and/or cleanse HCV patient's samples to enhance the detection sensitivity of HCV and therefore significantly reduce the numbers of false-negative HCV diagnosis results. PMID- 26502288 TI - Visceral adiposity index as a predictor of clinical severity and therapeutic outcome of PCOS. AB - Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disease which often accompany with abnormal fat distribution. Visceral adiposity has association with abnormal lipid metabolic, pro-inflammatory activity, insulin resistance (IR) and hyperandrogenism. Increased visceral adiposity raises the risk of metabolic syndrome, type 2 diabetes and cardiovascular (CV) events, and aggravates ovulatory dysfunction and hyperandrogenism in PCOS women. Visceral adiposity index (VAI), a simple surrogate maker of visceral adipose dysfunction and visceral adiposity, is a predictor of IR, and link hyperinsulinemia, hyperandrogenism and anovulation. This review aims to discuss the visceral adiposity situation in PCOS women, and suggests that VAI may be a useful predictor of clinical severity and therapeutic outcome of PCOS. PMID- 26502289 TI - Previous and future use of HIV self-testing: a survey of Australian gay and bisexual men. AB - Background The awareness and previous and intended use of HIV self-testing (HST), and the associated factors, among Australian gay and bisexual men (GBM) was investigated. METHODS: An online cross-sectional survey was conducted in Australia during 2012. Of 1410 respondents, 559 non-HIV-positive men answered questions about HST. RESULTS: Men reported reasons for having avoided or delayed HIV testing, most of which could be broadly categorised as: the inconvenience of current testing procedures; concerns about privacy; and a belief that they had not done anything risky. Over one-third of men (39.7%) were aware that HST was available internationally, with 1.6% having accessed HST through online purchase. The majority of men in the study indicated that they would be 'likely' (36.5%) or 'very likely' (34.3%) to use HST if it was available in Australia. Also, 36.7% indicated they would test partners they met at sex-on-site venues, and 73.2% would test partners with whom they were already acquainted. Nearly half (47.6%) indicated that having the capacity to test themselves at home would likely increase their testing frequency. Men who had engaged in unprotected anal intercourse, who were not gay-identified, and who indicated inconvenience issues with using clinic-based HIV testing were more likely to indicate a willingness to use HST. Many men indicated they would be likely to offer HST to at least some of their sex partners. CONCLUSION: Many GBM who engage in HIV risk behaviours would appreciate HST, and may be encouraged to test more often, as it may alleviate their concerns about testing. PMID- 26502290 TI - IOM REPORT ON PSYCHOSOCIAL INTERVENTIONS FOR MENTAL AND SUBSTANCE USE DISORDERS: THE INTERPERSONAL PSYCHOTHERAPY PERSPECTIVE. PMID- 26502291 TI - [Functional and Somatoform Disorders in the Mirror of ICD-10 Routine Data]. AB - The ICD-10 offers the possibility of double coding of diagnoses in functional disorders on the one hand, somatoform disorders on the other side. The current S3 guideline for "dealing with patients with non-specific, functional and somatoform physical complaints" states that "[...] in most cases, the specialty of the (initial) examiner and not the clinical constellation seems to define how a diagnosis is made". Based on selective routine data of the Daimler BKK for the years 2008-2010 frequencies of specific functional diagnoses were compared with those of somatoform disorders, additional diagnoses analyzed and compared with epidemiological data from the Federal Health Monitoring System. The incidence found in epidemiological studies of somatoform disorders cannot be found in present routine data. Functional disorders were more frequently diagnosed than somatoform disorders. Certain additional diagnoses that may provide clues to etiological relations are rarely used. As the validity, reliability and purpose of ICD-10 invoicing diagnoses is debatable, there seems to be an imbalance relevant for the health care system. Non-adherence to the guidelines may prevent adequate quality and quantity of patient care. PMID- 26502292 TI - Asymmetric Hearing Loss in Chinese Workers Exposed to Complex Noise. AB - OBJECTIVES: Evaluate the audiometric asymmetry in Chinese industrial workers and investigate the effects of noise exposure, sex, and binaural average thresholds on audiometric asymmetry. DESIGN: Data collected from Chinese industrial workers during a cross-sectional study were reanalyzed. Of the 1388 workers, 266 met the inclusion criteria for this study. Each subject underwent a physical examination and an otologic examination and completed a health-related questionnaire. chi and t tests were used to examine the differences between the asymmetric and symmetric hearing loss groups. RESULTS: One hundred thirty-one subjects (49.2%) had a binaural hearing threshold difference of 15 dB or more for at least one frequency, and there was no statistically significant difference between the left and right ears. The asymmetric hearing loss group was not exposed to higher cumulative noise levels (t = 0.522, p = 0.602), and there was no dose-response relation between asymmetry and cumulative noise levels (chi = 6.502, p = 0.165). Men were 1.849 times more likely to have asymmetry than women were (95% confidence interval, 1.051 to 3.253). Among the workers with higher high frequency hearing thresholds, audiometric asymmetry was 1.024 times more prevalent than that among those with lower high-frequency hearing thresholds (95% confidence interval, 1.004 to 1.044). CONCLUSIONS: The results indicated that occupational noise exposure contributed minimally to asymmetry, whereas sex and binaural average thresholds significantly affected audiometric asymmetry. There was no evidence that the left ears were worse than the right ears. PMID- 26502293 TI - Validation of an educational program balancing surgeon training and surgical quality control during robot-assisted radical prostatectomy. AB - OBJECTIVES: To establish a mentoring program that allows novice surgeons to use robotics while maintaining surgical quality during robot-assisted radical prostatectomy. METHODS: A total of 242 cases of robot-assisted radical prostatectomy for patients with localized prostate cancer were considered for this study. Each novice surgeon carried out a step-by-step robot-assisted radical prostatectomy procedure by following technical checkpoints and time limits that were established on the basis of previous surgical performance by a mentor. If technical checkpoints could not be accomplished, or the times were being exceeded, a mentor replaced the novice surgeon to finish the operative step or the surgery. Furthermore, if total blood loss exceeded 500 mL, a mentor completed the surgery. The primary end-point was the number of cases required for a new surgeon to successfully complete the entire robot-assisted radical prostatectomy procedure. Clinicopathological outcomes and any cases that deviated more than the standard deviation were also analyzed. RESULTS: Median patient age, serum prostate-specific antigen level (ng/mL), and Gleason score at diagnosis were 68 years, 7.6 and 7, respectively. Mean console and total operative times were 184 and 237 min, respectively. Mean perioperative blood loss was 300 mL. Seven out of eight new surgeons finished the total procedure after 10.7 cases (range 8-12). Four cases (1.7%) exceeded perioperative total blood loss and operative time. Positive surgical margin rates for total, T2, and T3 were 22, 9.3 and 47%, respectively. Positive surgical margin localized at bladder neck 19%, lateral lobe 39%, apex 32% and peripheral fat 9.4%. CONCLUSIONS: Herein we demonstrate an institutional mentoring program that effectively balances surgeon robot-assisted radical prostatectomy training and surgical quality control. PMID- 26502295 TI - Pretransplant renal function according to CKD-EPI cystatin C equation is a prognostic factor of death after liver transplantation. AB - BACKGROUND & AIMS: In patients with cirrhosis, cystatin C (CystC) based equations may be more accurate indicators of glomerular filtration rate (GFR) than creatinine (Pcr) based equations. Renal function before liver transplantation (LT) is thought to impact survival after LT. We aimed at assessing pretransplant creatinine and CystC based equations with respect to their predictive value on long-term survival after LT. METHODS: From 2001 to 2011, CystC was determined at pre-LT evaluation in 682 patients together with GFR assessed using MDRD-4, MDRD 6, CKD-EPI-cystatin C, CKD-EPI-creatinine and CKD-EPI-creatinine-cystatin C equations. Patients were classified according to the Kidney Disease Outcomes Quality Initiative classification (KDOQI). RESULTS: Median age at LT was 55 [49 60] years with a median MELD score of 13.5 [8.3-19.2] and a median post transplant follow-up of 60 [26-89] months. Using CKD-EPI Cystatin C and the KDOQI classification, 21.1% of patients were stage 1, 43.1% stage 2, 29.1% stage 3 and 6.5% stage 4. Kaplan-Meier survival estimates were significantly different between KDOQI stages when determined using the CKD-EPI-CystatinC equation. This was not the case when using the other equations. At multivariate analysis, GFR and KDOQI estimated using the CKD-EPI-CystatinC equation were significantly associated with death (HR: 0.992; CI95%: 0.986-0.999 and 1.24; CI95%: 1.02-1.50 respectively). When assessed using the MDRD-4, MDRD-6, CKD-EPI-Creatinine CystatinC and CKD-EPI-Creatinine equations GFR was not significantly associated with death. CONCLUSIONS: Estimated pre-LT renal function is predictive of post-LT survival only when assessed using the CKD-EPI cystatin C equation. This supports the use of Cystatine C and of its related equation for the assessment of renal function before liver transplantation. PMID- 26502294 TI - Neurobehavioral development of common marmoset monkeys. AB - Common marmoset (Callithrix jacchus) monkeys are a resource for biomedical research and their use is predicted to increase due to the suitability of this species for transgenic approaches. Identification of abnormal neurodevelopment due to genetic modification relies upon the comparison with validated patterns of normal behavior defined by unbiased methods. As scientists unfamiliar with nonhuman primate development are interested to apply genomic editing techniques in marmosets, it would be beneficial to the field that the investigators use validated methods of postnatal evaluation that are age and species appropriate. This review aims to analyze current available data on marmoset physical and behavioral postnatal development, describe the methods used and discuss next steps to better understand and evaluate marmoset normal and abnormal postnatal neurodevelopment. PMID- 26502296 TI - Direct detection of illicit drugs from biological fluids by desorption/ionization mass spectrometry with nanoporous silicon microparticles. AB - Surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS) is a high throughput analytical technique capable of detecting low molecular weight analytes, including illicit drugs, and with potential applications in forensic toxicology as well as athlete and workplace testing, particularly for biological fluids (oral fluids, urine and blood). However, successful detection of illicit drugs using SALDI-MS often requires extraction steps to reduce the inherent complexity of biological fluids. Here, we demonstrate an all-in-one extraction and analytical system consisting of hydrophobically functionalized porous silicon microparticles (pSi-MPs) for affinity SALDI-MS of prescription and illicit drugs. This novel approach allows for the analysis of drugs from multiple biological fluids without sample preparation protocols. The effect of pSi-MP size, pore diameter, pore depth and functionalization on analytical performance is investigated. pSi-MPs were optimized for the rapid and high sensitivity detection of methadone, cocaine and 3,4-methylenedioxymethamphetamine (MDMA). This optimized system allowed extraction and detection of methadone from spiked saliva and clinical urine samples. Furthermore, by detecting oxycodone in additional clinical saliva and plasma samples, we were able to demonstrate the versatility of the pSi-MP SALDI-MS technique. PMID- 26502297 TI - Early [18F]FET-PET in Gliomas after Surgical Resection: Comparison with MRI and Histopathology. AB - BACKGROUND: The precise definition of the post-operative resection status in high grade gliomas (HGG) is crucial for further management. We aimed to assess the feasibility of assessment of the resection status with early post-operative positron emission tomography (PET) using [18F]O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET). METHODS: 25 patients with the suspicion of primary HGG were enrolled. All patients underwent pre-operative [18F]FET-PET and magnetic resonance imaging (MRI). Intra-operatively, resection status was assessed using 5-aminolevulinic acid (5-ALA). Imaging was repeated within 72 h after neurosurgery. Post-operative [18F]FET-PET was compared with MRI, intra-operative assessment and clinical follow-up. RESULTS: [18F]FET-PET, MRI and intra-operative assessment consistently revealed complete resection in 12/25 (48%) patients and incomplete resection in 6/25 cases (24%). In 7 patients, PET revealed discordant findings. One patient was re-resected. 3/7 experienced tumor recurrence, 3/7 died shortly after brain surgery. CONCLUSION: Early assessment of the resection status in HGG with [18F]FET-PET seems to be feasible. PMID- 26502298 TI - Neomycin damage and regeneration of hair cells in both mechanoreceptor and electroreceptor lateral line organs of the larval Siberian sturgeon (Acipenser baerii). AB - The lateral line found in some amphibians and fishes has two distinctive classes of sensory organs: mechanoreceptors (neuromasts) and electroreceptors (ampullary organs). Hair cells in neuromasts can be damaged by aminoglycoside antibiotics and they will regenerate rapidly afterward. Aminoglycoside sensitivity and the capacity for regeneration have not been investigated in ampullary organs. We treated Siberian sturgeon (Acipenser baerii) larvae with neomycin and observed loss and regeneration of sensory hair cells in both organs by labeling with DASPEI and scanning electron microscopy (SEM). The numbers of sensory hair cells in both organs were reduced to the lowest levels at 6 hours posttreatment (hpt). New sensory hair cells began to appear at 12 hpt and were regenerated completely in 7 days. To reveal the possible mechanism for ampullary hair cell regeneration, we analyzed cell proliferation and the expression of neural placodal gene eya1 during regeneration. Both cell proliferation and eya1 expression were concentrated in peripheral mantle cells and both increased to the highest level at 12 hpt, which is consistent with the time course for regeneration of the ampullary hair cells. Furthermore, we used Texas Red-conjugated gentamicin in an uptake assay following pretreatment with a cation channel blocker (amiloride) and found that entry of the antibiotic was suppressed in both organs. Together, our results indicate that ampullary hair cells in Siberian sturgeon larvae can be damaged by neomycin exposure and they can regenerate rapidly. We suggest that the mechanisms for aminoglycoside uptake and hair cell regeneration are conserved for mechanoreceptors and electroreceptors. J. Comp. Neurol. 524:1443-1456, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26502299 TI - Combined orthodontic-surgical management of a transmigrated mandibular canine. AB - The presence of an impacted mandibular canine is one of the most difficult challenges that an orthodontist will meet. Orthodontic treatment is planned on an individual basis after thoroughly considering the patient's overall facial and dentoskeletal characteristics; the duration, risks, and costs of treatment; patient preferences; and the orthodontist's experience. This article reports an orthodontic treatment of a boy, age 12.9 years, with an impacted mandibular canine in the permanent dentition that was successfully managed. Radiographic analysis indicated a transmigration of the mandibular right canine. The orthodontic treatment plan included extraction of the deciduous right canine followed by surgical exposure and ligation of the permanent canine. Eruption was properly guided, and the correct position of the tooth was achieved. This challenging treatment approach is described in detail, including the mechanics used to align the impacted canine. PMID- 26502300 TI - A behavioral economic analysis of the nonmedical use of prescription drugs among young adults. AB - The nonmedical use of prescription drugs is a widely recognized public health issue, and young adults are particularly vulnerable to their use. Behavioral economic drug purchase tasks capture an individual's strength of desire and motivation for a particular drug. We examined young adult prescription drug purchase and consumption patterns using hypothetical behavioral economic purchase tasks for prescription sedatives/tranquilizers, stimulants, and opiate pain relievers. We also examined relations between demand, use frequency, and Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) substance use disorder (SUD) symptoms, and sex differences in these relations. Undergraduate students who endorsed past-year prescription drug use (N = 393) completed an online questionnaire for course credit. Measures assessed substance use frequency and DSM-5 SUD symptoms. Hypothetical purchase tasks for sedatives, stimulants, and pain relievers assessed participants' consumption and expenditure patterns for these substances across 25 prices. Past-year prescription sedative, stimulant, and pain reliever use was endorsed by 138, 258, and 189 participants, respectively. Among these users, consumption for their respective substance decreased as a function of ascending price, as expected. Demand indices for a prescription drug were associated with each other and with use frequency and SUD symptoms, with variability across substances but largely not by sex. In addition, demand for prescription pain relievers differentially predicted symptoms independent of use, with differences for females and males. In conclusion, hypothetical consumption and expenditure patterns for prescription drugs were generally well described by behavioral economic demand curves, and the observed associations with use and SUD symptoms provide support for the utility of prescription drug purchase tasks. PMID- 26502301 TI - Cardiac Abnormalities in Adult Patients With Polymyositis or Dermatomyositis as Assessed by Noninvasive Modalities. AB - OBJECTIVE: Cardiac events are a major cause of death in patients with idiopathic inflammatory myopathies. The study objective was in a controlled setting to describe cardiac abnormalities by noninvasive methods in a cohort of patients with polymyositis (PM) or dermatomyositis (DM) and to identify predictors for cardiac dysfunction. METHODS: In a cross-sectional study, 76 patients with PM/DM and 48 matched healthy controls (HCs) were assessed by serum levels of cardiac troponin I, electrocardiography, Holter monitoring, echocardiography with tissue Doppler imaging, and quantitative cardiac (99m) Tc-pyrophosphate ((99m) Tc-PYP) scintigraphy. RESULTS: Compared to HCs, patients with PM/DM more frequently had left ventricular diastolic dysfunction (LVDD) (12% versus 0%; P = 0.02) and longer QRS and QT intervals (P = 0.007 and P < 0.0001, respectively). In multivariate analysis, factors associated with LVDD were age (P = 0.001), disease duration (P = 0.004), presence of myositis-specific or -associated autoantibodies (P = 0.05), and high cardiac (99m) Tc-PYP uptake (P = 0.006). In multivariate analysis of the pooled data for patients and HCs, a diagnosis of PM/DM (P < 0.0001) was associated with LVDD. CONCLUSION: Patients with PM or DM had an increased prevalence of cardiac abnormalities compared to HCs. LVDD was a common occurrence in PM/DM patients and correlated to disease duration. In addition, the association of LVDD with myositis-specific or -associated autoantibodies and high cardiac (99m) Tc-PYP uptake supports the notion of underlying autoimmunity and myocardial inflammation in patients with PM/DM. PMID- 26502302 TI - Direct analytical method of contact position effects on the energy-level alignments at organic semiconductor/electrode interfaces using photoemission spectroscopy combined with Ar gas cluster ion beam sputtering. AB - Poly(3, 4-ethylenedioxythiophene) (PEDOT) polymerized with poly(4 styrenesulfonate) (PSS) is one of the most widely used conducting organic electrodes owing to its outstanding optical/electrical properties and high work function. Because its work function depends significantly on the molecular arrangements between PEDOT and PSS molecules on the surface, the contact position of PEDOT: PSS films on organic semiconductors (OSCs) must also be an essential consideration. However, existing analysis methods based on in situ deposition/analysis are limited in their ability to accurately investigate the electronic structures of the buried interface regions under the solution processed electrode or OSC layer in organic devices. Therefore, to overcome such limitations, we propose a top-down method based on photoemission spectroscopy analysis combined with Ar gas cluster ion beam (GCIB) sputtering. Through this method, both energy-level alignments and molecular distributions at various OSC/electrode interfaces can be successfully characterized without reference to any deposition process. PMID- 26502303 TI - Rapid area change in pitch-up manoeuvres of small perching birds. AB - Rapid pitch-up has been highlighted as a mechanism to generate large lift and drag during landing manoeuvres. However, pitching rates had not been measured previously in perching birds, and so the direct applicability of computations and experiments to observed behaviour was not known. We measure pitch rates in a small, wild bird (the black-capped chickadee; Poecile atricapillus), and show that these rates are within the parameter range used in experiments. Pitching rates were characterized by the shape change number, a metric comparing the rate of frontal area increase to acceleration. Black-capped chickadees increase the shape change number during perching in direct proportion to their total kinetic and potential energy at the start of the manoeuvre. The linear relationship between dissipated energy and shape change number is in accordance with a simple analytical model developed for two-dimensional pitching and decelerating airfoils. Black-capped chickadees use a wing pitch-up manoeuvre during perching to dissipate energy quickly while maintaining lift and drag through rapid area change. It is suggested that similar pitch-and-decelerate manoeuvres could be used to aid in the controlled, precise landings of small manoeuvrable air vehicles. PMID- 26502304 TI - Making the Invisible Visible: Imaging of Traumatic Brain Injury. PMID- 26502305 TI - Brain Magnetic Resonance Imaging for Traumatic Brain Injury: Why, When, and How? AB - Conventional magnetic resonance imaging (MRI) and angiography (MRA) provide invaluable information in the evaluation of patients with all stages and grades of traumatic brain injury (TBI). The information obtained with MRI provides a more complete assessment of the patient's brain injury and possible long-term sequelae. PMID- 26502306 TI - Diffusion Tensor Imaging of TBI: Potentials and Challenges. AB - Neuroimaging plays a critical role in the setting in traumatic brain injury (TBI). Diffusion tensor imaging (DTI) is an advanced magnetic resonance imaging technique that is capable of providing rich information on the brain's neuroanatomic connectome. The purpose of this article is to systematically review the role of DTI and advanced diffusion techniques in the setting of TBI, including diffusion kurtosis imaging (DKI), neurite orientation dispersion and density imaging, diffusion spectrum imaging, and q-ball imaging. We discuss clinical applications of DTI and review the DTI literature as it pertains to TBI. Despite the continued advancements in DTI and related diffusion techniques over the past 20 years, DTI techniques are sensitive for TBI at the group level only and there is insufficient evidence that DTI plays a role at the individual level. We conclude by discussing future directions in DTI research in TBI including the role of machine learning in the pattern classification of TBI. PMID- 26502307 TI - Evaluating the Role of Reduced Oxygen Saturation and Vascular Damage in Traumatic Brain Injury Using Magnetic Resonance Perfusion-Weighted Imaging and Susceptibility-Weighted Imaging and Mapping. AB - The cerebral vasculature, along with neurons and axons, is vulnerable to biomechanical insult during traumatic brain injury (TBI). Trauma-induced vascular injury is still an underinvestigated area in TBI research. Cerebral blood flow and metabolism could be important future treatment targets in neural critical care. Magnetic resonance imaging offers a number of key methods to probe vascular injury and its relationship with traumatic hemorrhage, perfusion deficits, venous blood oxygen saturation changes, and resultant tissue damage. They make it possible to image the hemodynamics of the brain, monitor regional damage, and potentially show changes induced in the brain's function not only acutely but also longitudinally following treatment. These methods have recently been used to show that even mild TBI (mTBI) subjects can have vascular abnormalities, and thus they provide a major step forward in better diagnosing mTBI patients. PMID- 26502308 TI - Magnetic Resonance Spectroscopy for Traumatic Brain Injury. AB - Magnetic resonance spectroscopy (MRS) provides a noninvasive tool to assess metabolic change in the brain following head injury. Observable metabolites reflect neuronal density and viability, glial density, membrane injury, and hypoxia or ischemia. MRS has been used in traumatic brain injury (TBI) research for nearly 20 years and this article reviews the MRS findings in the adult TBI population.Although MRS observations are heterogeneous, there are consistent patterns in TBI with the neuronal metabolite N-acetyl-aspartate (NAA) significantly reduced in the vast majority of studies, while the membrane related choline signal (Cho) is almost equally found to be elevated. The glial metabolites myo-inositol is often observed to be increased postinjury and this elevation persists into the chronic phase, which is interpreted as revealing gliosis. Observation of elevated lactate levels are sporadic and mainly in acute studies in severely injured subjects. In general, these spectral changes show a dependency on injury severity and acute changes relate to both neuropsychological deficits and to long-term outcome. PMID- 26502309 TI - Arterial Spin Labeling Magnetic Resonance Perfusion for Traumatic Brain Injury: Technical Challenges and Potentials. AB - Traumatic brain injury (TBI), including concussion, is a public health concern, as it affects over 1.7 million persons in the United States per year. Yet, the diagnosis of TBI, particularly mild TBI (mTBI), can be controversial, as neuroimaging findings can be sparse on conventional magnetic resonance and computed tomography examinations, and when present, often poorly correlate with clinical signs and symptoms. Furthermore, the discussion of TBI, concussion, and head impact exposure is immediately complicated by the many differing opinions of what constitutes each, their respective severities, and how the underlying biomechanics of the inciting head impact might alter the distribution, severity, and prognosis of the underlying brain injury. Advanced imaging methodologies hold promise in improving the sensitivity and detectability of associated imaging biomarkers that might better correlate with patient outcome and prognostication, allowing for improved triage and therapeutic guidance in the setting of TBI, particularly in mTBI. This work will examine the defining symptom complex associated with mTBI and explore changes in cerebral blood flow measured by arterial spin labeling, as a potential imaging biomarker for TBI, and briefly correlate these observations with findings identified by single photon emission computed tomography and positron emission tomography imaging. PMID- 26502311 TI - Therapeutic Monoclonal Antibodies and Fragments: Bevacizumab. AB - Bevacizumab (Avastin) is a recombinant humanized monoclonal immunoglobulin antibody that has two antigen-binding domains and blocks all active forms of vascular endothelial growth factor-A. It was originally designed and is still in use as antitumor agent (for colorectal and non-small cell lung cancers). Besides inhibiting vessel growth and neovascularization, the drug promotes the regression of existing microvessels and induces 'normalization' of surviving mature vasculature, stabilizes vessels and prevents leakage. Its molecular weight is 149 kDa and its estimated terminal half-life is approximately 20 days for both men and women. The effectiveness and safety of bevacizumab was proven in retrospective and prospective controlled clinical trials for the treatment of neovascular age-related macular degeneration, neovascularization in proliferative diabetic retinopathy, diabetic macular edema, retinal vein occlusion and retinopathy of prematurity, especially for zone I. Uncontrolled trials have shown its effectiveness in various other conditions as myopic and uveitic choroidal neovascularization and neovascular glaucoma. There are no absolute contraindications to intravitreal injection though it is recommended to withhold treatment in patients who have recently suffered from a cardiovascular or cerebrovascular event and during pregnancy. Ocular complications from intravitreal use are usually mild and transient (corneal abrasion, chemosis, subconjunctival hemorrhage and vitreous hemorrhage). Bacterial endophthalmitis is rare (about 0.1%). New or progressive subretinal hemorrhages, tears of the retinal pigment epithelium and an increased incidence of geographic atrophy have also been reported. PMID- 26502310 TI - A flexible nested sodium and proton coil array with wideband matching for knee cartilage MRI at 3T. AB - PURPOSE: We describe a 2 * 6 channel sodium/proton array for knee MRI at 3T. Multielement coil arrays are desirable because of well-known signal-to-noise ratio advantages over volume and single-element coils. However, low tissue-coil coupling that is characteristic of coils operating at low frequency can make the potential gains from a phased array difficult to realize. METHODS: The issue of low tissue-coil coupling in the developed six-channel sodium receive array was addressed by implementing 1) a mechanically flexible former to minimize the coil to-tissue distance and reduce the overall diameter of the array and 2) a wideband matching scheme that counteracts preamplifier noise degradation caused by coil coupling and a high-quality factor. The sodium array was complemented with a nested proton array to enable standard MRI. RESULTS: The wideband matching scheme and tight-fitting mechanical design contributed to >30% central signal-to-noise ratio gain on the sodium module over a mononuclear sodium birdcage coil, and the performance of the proton module was sufficient for clinical imaging. CONCLUSION: We expect the strategies presented in this study to be generally relevant in high density receive arrays, particularly in x-nuclei or small animal applications. Magn Reson Med 76:1325-1334, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26502312 TI - Antibiotic Resistance Among Ocular Pathogens in the United States: Five-Year Results From the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) Surveillance Study. AB - IMPORTANCE: The Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) study is the only ongoing nationwide antibiotic resistance surveillance program specific to ocular pathogens. OBJECTIVE: To report resistance rates and trends among common ocular isolates collected during the first 5 years of the ARMOR study. DESIGN, SETTING, AND PARTICIPANTS: This antibiotic resistance surveillance study was performed at an independent central laboratory. Clinical centers across the United States were invited to submit ocular isolates of Staphylococcus aureus, coagulase-negative staphylococci (CoNS), Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa. Isolates were collected from January 1, 2009, through December 31, 2013, and analyzed from January 16 to May 15, 2015. MAIN OUTCOMES AND MEASURES: Minimum inhibitory concentrations for various antibiotic classes were determined by broth microdilution according to the guidelines of the Clinical and Laboratory Standards Institute. Minimum inhibitory concentrations were interpreted as susceptible, intermediate, or resistant based on established break points. RESULTS: A total of 3237 ocular isolates (1169 S aureus, 992 CoNS, 330 S pneumoniae, 357 H influenzae, and 389 P aeruginosa) were collected from 72 centers. Methicillin resistance was found among 493 S aureus isolates (42.2%; 95% CI, 39.3%-45.1%) and 493 CoNS isolates (49.7%; 95% CI, 46.5%-52.9%), and methicillin-resistant (MR) isolates had a high probability of concurrent resistance to fluoroquinolones, aminoglycosides, or macrolides (P < .001). Multidrug resistance to at least 3 additional antibiotic classes was found in 428 MR S aureus isolates (86.8%) and 381 MRCoNS isolates (77.3%). All staphylococcal isolates were susceptible to vancomycin. Resistance among S pneumoniae isolates was highest for azithromycin (113 isolates [34.2%]) whereas resistance among P aeruginosa and H influenzae was low against the antibiotics tested. Staphylococcal isolates from elderly patients were more likely to be MR, as were S aureus isolates obtained from the southern United States (P < .001). Methicillin resistance among staphylococci did not increase during the 5-year study period (P <= .22), and small decreases in resistance to ciprofloxacin among CoNS and MRCoNS and to tobramycin among CoNS (P <= .03) were found. CONCLUSIONS AND RELEVANCE: Methicillin resistance was prevalent among staphylococcal isolates from ocular infections, with many strains demonstrating multidrug resistance. These findings are consistent with resistance trends reported for nonocular staphylococcal isolates. Overall ocular resistance did not increase during the 5-year study period. Continued surveillance of ocular isolates provides critical information to guide selection of topical antibacterials used for empirical management of ocular infections. PMID- 26502313 TI - Ocular Gene Therapy. AB - Ocular gene therapy involves the introduction of an exogenous gene product to a host's cellular and genetic machinery for endogenous production of a desired gene product. The eye represents an ideal target organ due to its easy visibility and accessibility, and several trials have demonstrated proof-of-principle safety and efficacy in a subtype of Leber's congenital amaurosis. There are numerous ongoing clinical trials exploring gene therapy in other retinal diseases. In autosomal recessively inherited retinal degenerations, the introduced gene product replaces a known genetically deficient gene product and provides restoration of function. In other disease states, such as neovascular age-related macular degeneration, the delivered gene product modulates existing proteins within a cell, such as vascular endothelial growth factor, for a desired therapeutic effect. This latter approach may have broader applications in other diseases such as diabetes and other retinal vascular diseases that are as yet unrealized. This review summarizes the current state of clinical research in ocular gene therapy focusing on those diseases in which the technology has reached clinical trials. PMID- 26502314 TI - Fracture Characterization of Human Cortical Bone Under Mode I Loading. AB - A miniaturized version of the double cantilever beam (DCB) test is used to determine the fracture energy in human cortical bone under pure mode I loading. An equivalent crack length based data-reduction scheme is used with remarkable advantages relative to classical methods. Digital image correlation (DIC) technique is employed to determine crack opening displacement at the crack tip being correlated with the evolution of fracture energy. A method is presented to obtain the cohesive law (trapezoidal bilinear softening) mimicking the mechanical behavior observed in bone. Cohesive zone modeling (CZM) (finite-element method) was performed to validate the procedure showing excellent agreement. PMID- 26502316 TI - Factors Influencing Applicants' Ranking of Dermatology Residency Programs in the National Resident Matching Program. PMID- 26502315 TI - Chemopreventive effect of oleuropein in colitis-associated colorectal cancer in c57bl/6 mice. AB - SCOPE: The main phenolic secoiridoid oleuropein and active constituent from olive tree (Olea europaea, Oleaceae), has demonstrated anti-inflammatory properties in intestinal inflammation and anti-tumoral effects in different cancer cells. In this study, we evaluated the chemoprevention of oleuropein in a model of azoxymethane (AOM)/Dextran sulfate sodium (DSS)-induced colorectal cancer (CRC) in C57BL/6 mice and the modulatory effect on the Th17 response in DSS acute colitis. METHODS AND RESULTS: Oleuropein protected from AOM/DSS-induced CRC by improving clinical symptoms, disease activity index score as well as suppressed the growth and multiplicity of colonic tumors. Treatment with oleuropein reduced intestinal IL-6, IFN-gamma, TNF-alpha, and IL-17A concentration, and decreased cyclooxygenase-2, Bax and proliferating cell nuclear antigen protein expression. Western blot analysis also showed a markedly downregulation of CRC-related pathways as nuclear factor-kappaB (NF-kappaB), Wnt/beta-catenin, phosphatidylinositol-3-kinase (P3IK)/Akt, and signal transducer and activators of transcription (STAT)3. In DSS acute model, oleuropein inhibited Th17 response, by decreasing CD4(+) Rorgammat(+) IL-17(+) IFN-gamma(+) T-cell subsets in the lamina propria, as well as IL-17A and IFN-gamma expression. CONCLUSION: Oleuropein as a dietary supplementation could be a promising protective agent against colitis associated CRC. PMID- 26502317 TI - Reconsidering Guidelines on the Use of Pneumococcal Vaccines in Adults 65 Years or Older. PMID- 26502318 TI - Wall teichoic acids prevent antibody binding to epitopes within the cell wall of Staphylococcus aureus. AB - Staphylococcus aureus is a Gram-positive bacterial pathogen that produces a range of infections including cellulitis, pneumonia, and septicemia. The principle mechanism in antistaphylococcal host defense is opsonization with antibodies and complement proteins, followed by phagocytic clearance. Here we use a previously developed technique for installing chemical epitopes in the peptidoglycan cell wall to show that surface glycopolymers known as wall teichoic acids conceal cell wall epitopes, preventing their recognition and opsonization by antibodies. Thus, our results reveal a previously unrecognized immunoevasive role for wall teichoic acids in S. aureus: repulsion of peptidoglycan-targeted antibodies. PMID- 26502319 TI - Progress Toward Consensus on Breast Cancer Screening Guidelines and Reducing Screening Harms. PMID- 26502320 TI - The burden of health care costs for patients with dementia in the last 5 years of life. AB - BACKGROUND: Common diseases, particularly dementia, have large social costs for the U.S. population. However, less is known about the end-of-life costs of specific diseases and the associated financial risk for individual households. OBJECTIVE: To examine social costs and financial risks faced by Medicare beneficiaries 5 years before death. DESIGN: Retrospective cohort. SETTING: The HRS (Health and Retirement Study). PARTICIPANTS: Medicare fee-for-service beneficiaries, aged 70 years or older, who died between 2005 and 2010 (n = 1702), stratified into 4 groups: persons with a high probability of dementia or those who died because of heart disease, cancer, or other causes. MEASUREMENTS: Total social costs and their components, including Medicare, Medicaid, private insurance, out-of-pocket spending, and informal care, measured over the last 5 years of life; and out-of-pocket spending as a proportion of household wealth. RESULTS: Average total cost per decedent with dementia ($287 038) was significantly greater than that of those who died of heart disease ($175 136), cancer ($173 383), or other causes ($197 286) (P < 0.001). Although Medicare expenditures were similar across groups, average out-of-pocket spending for patients with dementia ($61 522) was 81% higher than that for patients without dementia ($34 068); a similar pattern held for informal care. Out-of-pocket spending for the dementia group (median, $36 919) represented 32% of wealth measured 5 years before death compared with 11% for the nondementia group (P < 0.001). This proportion was greater for black persons (84%), persons with less than a high school education (48%), and unmarried or widowed women (58%). LIMITATION: Imputed Medicaid, private insurance, and informal care costs. CONCLUSION: Health care expenditures among persons with dementia were substantially larger than those for other diseases, and many of the expenses were uncovered (uninsured). This places a large financial burden on families, and these burdens are particularly pronounced among the demographic groups that are least prepared for financial risk. PRIMARY FUNDING SOURCE: National Institute on Aging. PMID- 26502321 TI - Navigating Ethical Conflicts Between Advance Directives and Surrogate Decision Makers' Interpretations of Patient Wishes. AB - There is little guidance on what clinicians should do when advance directives (or living wills, specifically) are challenged, particularly when surrogate decision makers' interpretations of patients' wishes conflict with the living will. In our commentary, we make a controversial argument suggesting that overriding living wills can be ethically preferable to the alternative of strictly adhering to them. We propose four ethical considerations for determining whether it is ethically supportable to override living wills. PMID- 26502330 TI - The Benefit of Heparin Reversal With Protamine During Carotid Endarterectomy. PMID- 26502322 TI - Quantitative investigation of red blood cell three-dimensional geometric and chemical changes in the storage lesion using digital holographic microscopy. AB - Quantitative phase information obtained by digital holographic microscopy (DHM) can provide new insight into the functions and morphology of single red blood cells (RBCs). Since the functionality of a RBC is related to its three dimensional (3-D) shape, quantitative 3-D geometric changes induced by storage time can help hematologists realize its optimal functionality period. We quantitatively investigate RBC 3-D geometric changes in the storage lesion using DHM. Our experimental results show that the substantial geometric transformation of the biconcave-shaped RBCs to the spherocyte occurs due to RBC storage lesion. This transformation leads to progressive loss of cell surface area, surface-to volume ratio, and functionality of RBCs. Furthermore, our quantitative analysis shows that there are significant correlations between chemical and morphological properties of RBCs. PMID- 26502331 TI - Subjective, Objective, and Observed Long-term Survival: A Longitudinal Cohort Study. PMID- 26502332 TI - Acute onset anterior uveitis after darbepoetin alfa infusion. AB - A 79-year-old female with a 2-month history of newly diagnosed myelodysplastic syndrome for which she received blood transfusion with darbepoetin alfa presented with bilateral anterior uveitis 1 day after her fourth transfusion. On exam, visual acuity was 20/20 in both eyes with biomicroscopy notable for conjunctival injection and anterior chamber cell and flare consistent with anterior uveitis. She had no systemic symptoms, no history of eye trauma, and no known infections. This case, along with prior reports in the literature, suggests that anterior uveitis may be an idiosyncratic complication of darbepoetin alfa therapy. PMID- 26502333 TI - Ocular Angiogenesis: Vascular Endothelial Growth Factor and Other Factors. AB - Systematic study of the mechanisms underlying pathological ocular neovascularization has yielded a wealth of knowledge about pro- and anti angiogenic factors that modulate diseases such as neovascular age-related macular degeneration. The evidence implicating vascular endothelial growth factor (VEGF) in particular has led to the development of a number of approved anti-VEGF therapies. Additional proangiogenic targets that have emerged as potential mediators of ocular neovascularization include hypoxia-inducible factor-1, angiopoietin-2, platelet-derived growth factor-B and components of the alternative complement pathway. As for VEGF, knowledge of these factors has led to a product pipeline of many more novel agents that are in various stages of clinical development in the setting of ocular neovascularization. These agents are represented by a range of drug classes and, in addition to novel small- and large-molecule VEGF inhibitors, include gene therapies, small interfering RNA agents and tyrosine kinase inhibitors. In addition, combination therapy is beginning to emerge as a strategy to improve the efficacy of individual therapies. Thus, a variety of agents, whether administered alone or as adjunctive therapy with agents targeting VEGF, offer the promise of expanding the range of treatments for ocular neovascular diseases. PMID- 26502335 TI - Booze cues and attentional narrowing: Neural correlates of virtual alcohol myopia. AB - Exposure to alcohol cues reduces the breadth of attentional scope, called "virtual myopia." Past researchers have suggested approach motivation as a possible mechanism that underlies this myopia in response to alcohol cues. We expanded on these findings in the current study by identifying the neural underpinnings of the relationship between attentional narrowing, approach motivation, and exposure to alcohol cues. Participants completed 64 trials that consisted of neutral or alcohol-related stimuli followed by a measure of attentional narrowing (i.e., Navons letter task). Electroencephalography (EEG) was recorded during the experiment to assess greater left frontal hemispheric asymmetry, a measure of approach motivation. Results revealed that alcohol cues led to greater "virtual myopia" as measured by narrowed attentional scope. Greater left frontal activation to alcohol cues related to greater myopia, suggesting that approach motivation is associated with virtual myopia. Left frontal activation appears to be a neural correlate of cognitive narrowing related to approach motivation. (PsycINFO Database Record PMID- 26502334 TI - Does drinking to cope explain links between emotion-driven impulse control difficulties and hazardous drinking? A longitudinal test. AB - Difficulty controlling impulsive behaviors when experiencing negative emotions is a prominent risk factor for hazardous alcohol use, and prior research suggests that drinking to cope may mediate this association. The present study examines this possibility prospectively in a sample of 490 young adult women between the ages of 18 and 25. Participants completed measures of emotion-driven impulse control difficulties, drinking to cope, and hazardous alcohol use at 6 time points over the course of approximately 20 months (i.e., 1 assessment every 4 months). Multilevel structural equation modeling revealed that drinking to cope fully mediated the relationship between emotion-driven impulse control difficulties and hazardous alcohol use when examining these relationships between individuals and partially mediated this relation when examining these relationships within individuals. These findings suggest that drinking to cope is a key mechanism in the relationship between emotion-driven impulse control difficulties and hazardous drinking. Results highlight the importance of targeting both emotion dysregulation and drinking to cope when treating young women for alcohol use problems. PMID- 26502336 TI - Correlates of engaging in drug distribution in a national sample. AB - In this study, we examined self-reported behaviors and characteristics of individuals involved in drug distribution to identify correlates of engaging in drug-distribution behaviors. Correlates of interest included demographic characteristics, substance-use patterns, psychological impairment, and criminal involvement. Data from the 2012 National Survey on Drug Use and Health (U.S. Department of Health and Human Services, Substance Abuse & Mental Health Services Administration, 2013) were used for analyses (N = 55,108). A logistic regression analysis distinguished those who have sold drugs from those who have not sold drugs to identify correlates of engaging in drug distribution. Results showed that recency of substance use, severity of substance use, criminal activity, mental health diagnoses, substance-use treatment, and arrest history were all significantly associated with distribution behaviors. Findings indicate the importance of accounting for the heterogeneous characteristics of individuals involved in distribution behaviors when considering treatment options or criminal proceedings. PMID- 26502337 TI - Recurrent inactivating RASA2 mutations in melanoma. AB - Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in >=30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer. PMID- 26502340 TI - Spontaneous Pattern Formation of Surface Nanodroplets from Competitive Growth. AB - Nanoscale droplets on a substrate are of great interest because of their relevance for droplet-based technologies for light manipulation, lab-on-chip devices, miniaturized reactors, encapsulation, and many others. In this work, we establish a basic principle for symmetrical arrangements of surface nanodroplets during their growth out of oversaturated solution established through solvent exchange, which takes place under simple and controlled flow conditions. In our model system, nanodroplets nucleate at the rim of spherical cap microstructures on a substrate, due to a pulse of oversaturation supplied by a solvent exchange process. We find that, while growing at the rim of the microcap, the nanodroplets self-organize into highly symmetric arrangements, with respect to position, size, and mutual distance. The angle between the neighboring droplets is 4 times the ratio between the base radii of the droplets and the spherical caps. We show and explain how the nanodroplets acquire the symmetrical spatial arrangement during their competitive growth and why and how the competition enhances the overall growth rate of the nucleated nanodroplets. This mechanism behind the nanodroplet self-organization promises a simple approach to control the location of droplets with a volume down to attoliters. PMID- 26502341 TI - Interlayer Communication in Aurivillius Vanadate to Enable Defect Structures and Charge Ordering. AB - The fluorite-like [Bi2O2](2+) layer is a fundamental building unit in a great variety of layered compounds. Here in this contribution, we presented a comprehensive study on an unusual Aurivillius phase Bi3.6V2O10 with respect to its defect chemistry and polymorphism control as well as implications for fast oxide ion transport at lower temperatures. The bismuth oxide layer in Bi4V2O11 is found to tolerate a large number of Bi vacancies without breaking the high temperature prototype I4/mmm structure (gamma-phase). On cooling, an orthorhombic distortion occurs to the gamma-phase, giving rise to a different type of phase (B phase) in the intermediate temperature region. Cooling to room temperature causes a further transition to an oxygen-vacancy ordered A-phase, which is accompanied by the charge ordering of V(4+) and V(5+) cations, providing magnetic (d(1)) and nonmagnetic (d(0)) chains along the a axis. This is a novel charge ordering transition in terms of the concomitant change of oxygen coordination. Interestingly, upon quenching, both the gamma- and B-phase can be kinetically trapped, enabling the structural probing of the two phases at ambient temperature. Driven by the thermodynamic forces, the oxide anion in the gamma phase undergoes an interlayer diffusion process to reshuffle the compositions of both Bi-O and V-O layers. PMID- 26502338 TI - Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis acting eQTL effects in a range of ex vivo immune cells. We found an over representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE. PMID- 26502339 TI - Large-scale identification of sequence variants influencing human transcription factor occupancy in vivo. AB - The function of human regulatory regions depends exquisitely on their local genomic environment and on cellular context, complicating experimental analysis of common disease- and trait-associated variants that localize within regulatory DNA. We use allelically resolved genomic DNase I footprinting data encompassing 166 individuals and 114 cell types to identify >60,000 common variants that directly influence transcription factor occupancy and regulatory DNA accessibility in vivo. The unprecedented scale of these data enables systematic analysis of the impact of sequence variation on transcription factor occupancy in vivo. We leverage this analysis to develop accurate models of variation affecting the recognition sites for diverse transcription factors and apply these models to discriminate nearly 500,000 common regulatory variants likely to affect transcription factor occupancy across the human genome. The approach and results provide a new foundation for the analysis and interpretation of noncoding variation in complete human genomes and for systems-level investigation of disease-associated variants. PMID- 26502342 TI - Determination of Effective Stability Constants of Ion-Carrier Complexes in Ion Selective Nanospheres with Charged Solvatochromic Dyes. AB - Ionophores are widely used ion carriers in ion selective sensors. The effective stability constant (beta) is a key physical parameter providing valuable guidelines to the design of ionophores and carrier-based ion selective sensors. The beta value of ion-carrier complex in plasticized poly(vinyl chloride) (PVC) membranes and solutions have been determined in the past by various techniques, but most of them are difficult to implement at the nanoscale owing to the ultrasmall sample volume. A new methodology based on charged solvatochromic dyes is introduced here for the first time to determine beta values directly within ion selective nanospheres. Four ionophores with different selectivities toward Na(+), K(+), Ca(2+), and H(+), respectively, are successfully characterized in nanospheres composed of triblock copolymer Pluronic F-127 and bis(2-ethylhexyl) sebacate. The values determined in the nanospheres are smaller compared with those in plasticized PVC membranes, indicating a more polar nanosphere microenvironment and possible uneven distribution of the sensing components in the interfacial region. PMID- 26502343 TI - Chemomimetic biocatalysis: exploiting the synthetic potential of cofactor dependent enzymes to create new catalysts. AB - Despite the astonishing breadth of enzymes in nature, no enzymes are known for many of the valuable catalytic transformations discovered by chemists. Recent work in enzyme design and evolution, however, gives us good reason to think that this will change. We describe a chemomimetic biocatalysis approach that draws from small-molecule catalysis and synthetic chemistry, enzymology, and molecular evolution to discover or create enzymes with non-natural reactivities. We illustrate how cofactor-dependent enzymes can be exploited to promote reactions first established with related chemical catalysts. The cofactors can be biological, or they can be non-biological to further expand catalytic possibilities. The ability of enzymes to amplify and precisely control the reactivity of their cofactors together with the ability to optimize non-natural reactivity by directed evolution promises to yield exceptional catalysts for challenging transformations that have no biological counterparts. PMID- 26502344 TI - Graphene Dynamic Synapse with Modulatable Plasticity. AB - The synaptic activities in the nervous system is the basis of memory and learning behaviors, and the concept of biological synapse has also spurred the development of neuromorphic engineering. In recent years, the hardware implementation of the biological synapse has been achieved based on CMOS circuits, resistive switching memory, and field effect transistors with ionic dielectrics. However, the artificial synapse with regulatable plasticity has never been realized of the device level. Here, an artificial dynamic synapse based on twisted bilayer graphene is demonstrated with tunable plasticity. Due to the ambipolar conductance of graphene, both behaviors of the excitatory synapse and the inhibitory synapse could be realized in a single device. Moreover, the synaptic plasticity could also be modulated by tuning the carrier density of graphene. Because the artificial synapse here could be regulated and inverted via changing the bottom gate voltage, the whole process of synapse development could be imitated. Hence, this work would offer a broad new vista for the 2D material electronics and guide the innovation of neuro-electronics fundamentally. PMID- 26502345 TI - Constructing Highly Graphitized Carbon-Wrapped Li3VO4 Nanoparticles with Hierarchically Porous Structure as a Long Life and High Capacity Anode for Lithium-Ion Batteries. AB - Li3VO4 nanoparticles (NPs) embedded in a continuous, highly graphitized carbon network with an interconnected hierarchically porous structure (HP-Li3VO4/C) were prepared using a facile, green freeze-drying method followed by in situ carbonizing. Because of its unique microstructure, the resultant HP-Li3VO4/C exhibits excellent lithium storage performance in terms of specific capacity, cycling stability, and rate capability when used as an anode material in lithium ion batteries (LIBs). Specifically, it delivers an extremely high capacity of 381 mAh g(-1) for up to 300 cycles at 0.2 A g(-1), and even at a rate as high as 4 A g(-1), a high reversible capacity of 275 mAh g(-1) can be retained after testing for 500 cycles. This excellent electrochemical performance can be attributed to Li3VO4 NPs wrapped with highly graphitized carbon conductive framework and hierarchically porous structure. This work may offer a new methodology for the preparation of other electrode materials for LIBs. PMID- 26502346 TI - Diffusion-weighted Magnetic Resonance Imaging in the Differential Diagnosis of Benign and Metastatic Malignant Pleural Thickening. AB - PURPOSE: Imaging plays a critical role not only in detection but also in characterization of pleural thickening as benign or malignant. The aim of the study was to investigate the value of diffusion-weighted (DW) imaging in the differential diagnosis of benign and metastatic malignant pleural thickening. MATERIALS AND METHODS: Thirty-four patients with 64 pleural foci of nodular thickening (47 metastatic malignant and 17 benign) were included in this prospective study. DW imaging was performed using a breath-hold single-shot spin echo echo-planar sequence. Two different apparent diffusion coefficient (ADC1,2) maps were obtained with different b factors (ADC1 reconstructed from b factors of 0 and 650 mm/s and ADC2 reconstructed from b factors of 0 and 1000 mm/s), and ADCs were calculated. Quantitatively, ADCs were compared between the groups, and the optimal cutoff value was found by using receiver operating characteristic curve analysis. RESULTS: Quantitatively, differences in signal intensities on DW trace images with b factors of 650 and 1000 mm/s were not statistically significant. The ADC1 and ADC2 of the metastatic malignant thickening were significantly lower than those of benign ones [mean ADC1 was 1.37+/-0.65*10 mm/s for metastatic malignant thickening and 2.11+/-0.69*10 mm/s for benign thickening (P=0.045); ADC2 was 1.06+/-0.56*10 mm/s for metastatic malignant thickening and 1.56+/-0.71*10 mm/s for benign thickening (P=0.038)]. However, because of the ADC overlap between malignant and benign disease, a sufficiently discriminative cutoff value could not be defined by the receiver operating characteristic curve analysis. CONCLUSION: Despite fair sensitivity and specificity, DW imaging may serve as a complementary tool that improves the differential diagnosis of pleural thickening. PMID- 26502347 TI - Safety and Efficacy of Modified Preoperative Lung Nodule Microcoil Localization Without Pleural Marking: A Pilot Study. AB - PURPOSE: The purpose of this pilot study was to evaluate the safety and efficacy of preoperative computed tomography (CT)-guided percutaneous microcoil lung nodule localization without pleural marking compared with the established technique with pleural marking. MATERIALS AND METHODS: Sixty-three consecutive patients (66.7% female, mean age 61.6+/-11.4 y) with 64 lung nodules resected between October 2008 and January 2014 were retrospectively evaluated. Of the nodules, 29.7% (n=19) had microcoil deployment with pleural marking (control group) and 70.3% (n=45) had microcoil deployment without pleural marking (pilot group). Clinical, pathologic, and imaging characteristics, radiation dose, CT procedure and operating room time, and complete resection and complication rates were compared between the pilot and control groups. RESULTS: There was no significant difference in nodule size (P=0.552) or distance from the pleural surface (P=0.222) between the pilot and control groups. However, mean procedure duration (53.6+/-18.3 vs. 72.8+/-25.3 min, P=0.001) and total effective radiation dose (5.1+/-2.6 vs. 7.1+/-4.9 mSv, P=0.039) were significantly lower in the pilot group compared with the control group. CT procedure-related complications (P=0.483) [including pneumothoraces (P=0.769) and pulmonary hemorrhage (P=1.000)], operating room time (P=0.926), complete resection rates (P=0.520), intraoperative complications (P=0.549), and postoperative complications (P=1.000) were similar between the pilot and control groups. CONCLUSIONS: Preoperative CT guided lung nodule microcoil localization performed without visceral pleural marking appears to decrease the CT procedure time and radiation dose while maintaining equivalent complete resection rates and procedural and surgical complications, when compared with microcoil localization performed with pleural marking. PMID- 26502348 TI - Cognitive Motor Dissociation Following Severe Brain Injuries. PMID- 26502350 TI - Ultrafast Dynamics of Long Homologues of Carotenoid Zeaxanthin. AB - Three zeaxanthin homologues with conjugation lengths N of 15, 19, and 23 denoted as Z15, Z19, and Z23 were studied by femtosecond transient absorption spectroscopy, and the results were compared to those obtained for zeaxanthin (Z11). The energies of S2 decrease from 20 450 cm(-1) (Z11) to 18 280 cm(-1) (Z15), 17 095 cm(-1) (Z19), and 16 560 cm(-1) (Z23). Fitting the N dependence of the S2 energies allowed the estimation of [Formula: see text], the S2 energy of a hypothetical infinite zeaxanthin, to be ~14 000 cm(-1). Exciting the 0-0 band of the S2 state produces characteristic S1-Sn spectral profiles in transient absorption spectra with maxima at 556 nm (Z11), 630 nm (Z15), 690 nm (Z19), and 740 nm (Z23). The red shift of the S1-Sn transition with increasing conjugation length is caused by a decrease in the S1 state energy, resulting in S1 lifetimes of 9 ps (Z11), 0.9 ps (Z15), 0.35 ps (Z19), and 0.19 ps (Z23). Essentially the same lifetimes were obtained after excess energy excitation at 400 nm, but S1-Sn becomes broader, indicating a larger conformation disorder in the S1 state after 400 nm excitation compared to excitation into the 0-0 band of the S2 state. An S* signal was observed in all samples, but only for Z15, Z19, and Z23 does the S* signal decay with a lifetime different from that of the S1 state. The S* lifetimes are 2.9 and 1.6 ps for Z15 and Z19, respectively. In Z23 the S* signal needs two decay components yielding lifetimes of 0.24 and 2.3 ps. The S* signal is more pronounced after 400 nm excitation. PMID- 26502352 TI - Trans-Endplate Pedicle Pillar System in Unstable Spinal Burst Fractures: Design, Technique, and Mechanical Evaluation. AB - BACKGROUND: Short-segment pedicle screw instrumentation (SSPI) is used for unstable burst fractures to correct deformity and stabilize the spine for fusion. However, pedicle screw loosening, pullout, or breakage often occurs due to the large moment applied during spine motion, leading to poor outcomes. The purpose of this study was to test the ability of a newly designed device, the Trans Endplate Pedicle Pillar System (TEPPS), to enhance SSPI rigidity and decrease the screw bending moment with a simple posterior approach. METHODS: Six human cadaveric spines (T11-L3) were harvested. A burst fracture was created at L1, and the SSPI (Moss Miami System) was used for SSPI fixation. Strain gauge sensors were mounted on upper pedicle screws to measure screw load bearing. Segmental motion (T12-L2) was measured under pure moment of 7.5 Nm. The spine was tested sequentially under 4 conditions: intact; first SSPI alone (SSPI-1); SSPI+TEPPS; and second SSPI alone (SSPI-2). RESULTS: SSPI+TEPPS increased fixation rigidity by 41% in flexion/extension, 28% in lateral bending, and 37% in axial rotation compared with SSPI-1 (P<0.001), and it performed even better compared to SSPI-2 (P<0.001 for all). Importantly, the bending moment on the pedicle screws for SSPI+TEPPS was significantly decreased 63% during spine flexion and 47% in lateral bending (p<0.001). CONCLUSION: TEPPS provided strong anterior support, enhanced SSPI fixation rigidity, and dramatically decreased the load on the pedicle screws. Its biomechanical benefits could potentially improve fusion rates and decrease SSPI instrumentation failure. PMID- 26502353 TI - Standardization efforts enabling next-generation sequencing and microarray based biomarkers for precision medicine. AB - Microarrays and next-generation sequencing technologies have been increasingly employed in biomedical research. However, before they can be reliably used as clinical biomarker tests, standardization and quality control measures need to be developed to ensure their analytical validity. This review summarizes community wide efforts such as the MicroArray and Sequencing Quality Control (MAQC/SEQC) project which have identified factors influencing the performance of these technologies. Consequently, consensus-based standards and well-documented best practices have been developed to improve the quality of scientific research, and reference materials and reference datasets have been made available for evaluating the technical proficiency in future studies. These efforts have built the foundation on which the translational application of genomics based technologies can help realize precision medicine. PMID- 26502354 TI - Surveillance for Borrelia burgdorferi in Ixodes Ticks and Small Rodents in British Columbia. AB - To determine the prevalence of Borrelia burgdorferi in British Columbian ticks, fieldwork was conducted over a 2-year period. In all, 893 ticks (Ixodes pacificus, I. angustus, I. soricis, Ixodes spp., and Dermacentor andersoni) of different life stages were retrieved from 483 small rodents (Peromyscus maniculatus, Perognathus parvus, and Reithrodontomys megalotis). B. burgdorferi DNA was detected in 5 out of 359 tick pools, and 41 out of 483 mice were serologically confirmed to have antibodies against B. burgdorferi. These results were consistent with previous studies, data from passive surveillance in British Columbia, and data from neighboring states in the Pacific Northwest, suggesting a continually low prevalence of B. burgdorferi in British Columbia ticks. PMID- 26502355 TI - The alloying effect and AgCl-directing growth for synthesizing a trimetallic nanoring with improved SERS. AB - We report the synthesis of high quality trimetallic Au/Ag/Pt nanorings (TAAPNs) by using Au/Ag alloy decahedra (AAAD) as templates. The alloying effect and AgCl directing growth have been investigated in detail during the formation of TAAPN. It was found that the doping of Ag in AAAD changes the surrounding environment of Au atoms and decreases the oxidization reduction potential (ORP) of [AuCl(2)]( )/Au because of the alloying effect, resulting in the dissolved O(2) molecules that serve as an effective etchant for oxidizing Au to Au(I). Ascorbic acid (AA) and chloroplatinic acid (H(2)PtCl(6)) are weak acids which can accelerate the etching by increasing the concentration of H(+). The AgCl selectively absorbs on {100} of the decahedra and induces the preferential deposition of H(2)PtCl(6) here via their complexing interaction. AA reduces Pt(IV) and Ag(I) to atoms which grow on {100} facets. The formed Pt/Ag layer changes the etching direction from along [100] to [111] and generates the TAAPN. Besides, it has been noted that the TAAPNs exhibit good Surface Enhanced Raman Scattering (SERS) performance. PMID- 26502349 TI - Autophagy in stem and progenitor cells. AB - Autophagy is a highly conserved cellular process, responsible for the degradation and recycling of damaged and/or outlived proteins and organelles. This is the major cellular pathway, acting throughout the formation of cytosolic vesicles, called autophagosomes, for the delivering to lysosome. Recycling of cellular components through autophagy is a crucial step for cell homeostasis as well as for tissue remodelling during development. Impairment of this process has been related to the pathogenesis of various diseases, such as cancer and neurodegeneration, to the response to bacterial and viral infections, and to ageing. The ability of stem cells to self-renew and differentiate into the mature cells of the body renders this unique type of cell highly crucial to development and tissue renewal, not least in various diseases. During the last two decades, extensive knowledge about autophagy roles and regulation in somatic cells has been acquired; however, the picture about the role and the regulation of autophagy in the different types of stem cells is still largely unknown. Autophagy is a major player in the quality control and maintenance of cellular homeostasis, both crucial factors for stem cells during an organism's life. In this review, we have highlighted the most significant advances in the comprehension of autophagy regulation in embryonic and tissue stem cells, as well as in cancer stem cells and induced pluripotent cells. PMID- 26502356 TI - Piperazine derivatives as iron chelators: a potential application in neurobiology. AB - Polysubstituted piperazine derivatives, designed as new iron chelators, were synthesized and fully characterized by nuclear magnetic resonance and mass spectroscopy. Their potential to prevent iron-induced neurotoxicity was assessed using a cellular model of Parkinson disease. We demonstrated their ability to provide sustained neuroprotection to dopaminergic neurons that are vulnerable in this pathology. The iron chelating properties of the new compounds were determined by spectrophotometric titration illustrating that high affinity for iron is not associated with important neuroprotective effects. PMID- 26502357 TI - Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males. AB - CONTEXT: TAK-385 is a highly selective, oral, nonpeptide GnRH antagonist being investigated as a possible prostate cancer treatment. OBJECTIVE: The objectives were to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-385 on LH and testosterone. DESIGN, SETTING, AND PARTICIPANTS: This was a three-part, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study in 176 healthy male UK volunteers. INTERVENTIONS: Part 1, single doses of TAK-385 (0 [placebo], 80, 120, 180, or 360 mg). Part 2, 14-day TAK-385 (0, 20, 40, 80, or 180 mg) daily. Part 3, 28-day TAK-385 (40 [with loading dose], 60, 80, or 160 mg) or placebo daily. Parts 2 and 3 included men aged 40-75 years. MAIN OUTCOME MEASURES: Main outcome measures included plasma concentrations of TAK 385, LH, and testosterone. RESULTS: Oral TAK-385 was readily absorbed, and steady state was reached in <= 14 days. Food reduced TAK-385 systemic exposure by 47 52%. Mean serum testosterone levels declined <= 6 hours after TAK-385 administration. Loading doses up to 360 mg on day 1 or 360 mg on day 1 followed by 240 mg on day 2 reduced the time to achieve castrate testosterone levels from >= 7 to <3 days. TAK-385 doses >= 80 mg/d achieved sustained medical castration and trough TAK-385 concentrations >4 ng/mL. After discontinuation of TAK-385 on day 28, testosterone levels normalized in most subjects in <= 28 days. Common adverse events included bradycardia, headache, and hot flush (all grade <= 2). CONCLUSIONS: Oral TAK-385 (40-180 mg/d) was well tolerated and effectively lowered testosterone in healthy men. Planned phase 2 doses in men with hormone sensitive prostate cancer are 80 and 120 mg/d. PMID- 26502358 TI - Reversal of Pathological Features of Graves' Orbitopathy by Activation of Forkhead Transcription Factors, FOXOs. AB - CONTEXT: Graves' orbitopathy (GO) is a disfiguring/distressing, inflammatory autoimmune condition. This intractable problem is caused by expansion of the orbital contents around the eye by excessive fat generation (adipogenesis) and overproduction of extracellular matrix components, especially hyaluronan (HA) from preadipocytes/fibroblasts (PFs). Current immunosuppressive/antiinflammatory treatments are largely ineffective and have unpleasant side effects, and a better therapeutic strategy through understanding GO-associated pathological features is needed. OBJECTIVE: Previously we identified depot-specific HA synthase 2 regulation (HAS2; major source of HA), which facilitates orbit-specific HA accumulation during adipogenesis, and targeting phosphatidylinositol-3 kinase/mechanistic target of rapamycin-complex-1 pathways blocked both pathological features. The current study revealed low expression levels of Forkhead box O (FOXOs; critical downstream effectors of phosphatidylinositol-3 kinase) in orbital PFs through adipogenesis compared with sc levels. We aimed to dissect the role of FOXOs in GO pathogenesis to identify nonimmunosuppressive targets for GO treatment. DESIGN/SETTING/PARTICIPANTS: Human orbital and sc primary PFs were treated with small interfering RNA/chemical inhibitor (AS1842856) of FOXOs or FOXO enhancer trifluoperazine hydrochloride (TFP; Food and Drug Administration approved drug), in serum-free medium for 24 hours, or TFP treatment in adipogenic medium for 15 days. MAIN OUTCOME MEASURES: Quantitative PCR was used to measure HAS2 transcripts and the terminal adipogenesis differentiation marker lipoprotein lipase. HA accumulation in the medium was measured by an ELISA. RESULTS: Substantially increased or decreased HAS2/HA production was observed by inhibiting (small interfering RNA or chemical inhibitor) or enhancing (TFP) FOXO expression, respectively. TFP treatment is also sufficient to counteract thyrotropin receptor-activated HAS2/HA production and block adipogenesis in orbital PFs. CONCLUSIONS: FOXOs play a crucial repressor role in the regulation of HAS2/HA production and adipogenesis in orbital PFs. Our data reveal for the first time that resetting GO-associated pathological features through drug-targeted activation of FOXOs could provide a feasible nonimmunosuppressive therapeutic strategy for GO. PMID- 26502359 TI - Role of the Entero-Insular Axis in the Pathogenesis of Idiopathic Reactive Hypoglycemia: A Pilot Study. AB - CONTEXT: Idiopathic reactive hypoglycemia (IRH) is characterized by recurrent episodes of symptomatic hypoglycemia occurring within 4 hours after meals. The underlying mechanisms remain obscure. OBJECTIVE: This study aimed to investigate the response of the glucoregulatory and gastrointestinal hormones to an oral glucose load (OGTT) in individuals with documented IRH. DESIGN AND SETTING: This was a cross-sectional study composed of outpatients referred to "Federico II" University of Naples. PATIENTS: We enrolled subjects with IRH documented by a mixed meal under ordinary life conditions and healthy subjects as controls. MAIN OUTCOME MEASURE: We measured plasma glucose, insulin, glucagon-like peptide 1 (GLP-1), GIP, and glucagon response to a 75-g OGTT in cases and controls. RESULTS: Ten IRH and eight control subjects were enrolled. During the OGTT, mean plasma glucose tended to be lower in IRH than in control subjects, reaching a statistically significant difference at 240 minutes (T240) (43 +/- 1.6 vs 72 +/- 0.3 mg/dL; P = .001). Accordingly, the insulin response was higher in IRH than in control subjects (P < .019) with a statistically significant difference (46%) at T90 (P = .045) and was associated with significantly lower glucagon levels in the late phase of the OGTT: at T120 (P = .031) and T180 (P = .048) in IRH than in control subjects. A greater GLP-1 response was found among IRH compared with control subjects (P = .005); GLP-1 peak was 2-fold higher in IRH individuals (9.77 +/- 2.52 pmol/L) than in the control group (4.19 +/- 0.53 pmol/L; P = .041). In the IRH group, GLP-1 peak inversely correlated with the nadir of plasma glucose (r = -0.66; P = .039). A multivariate analysis confirmed that GLP-1 peak independently predicted the plasma glucose nadir (beta = -0.593; P = .026). CONCLUSIONS: GLP-1 may play a significant role in the pathogenesis of idiopathic IRH. PMID- 26502360 TI - Liver capsule: Entry and entry inhibition of hepatitis B virus and hepatitis delta virus into hepatocytes. PMID- 26502361 TI - Photoinduced Cross-Linking of Dynamic Poly(disulfide) Films via Thiol Oxidative Coupling. AB - Initially developed as an elastomer with an excellent record of barrier and chemical resistance properties, poly(disulfide) has experienced a revival linked to the dynamic nature of the S-S covalent bond. A novel photobase-catalyzed oxidative polymerization of multifunctional thiols to poly(disulfide) network is reported. Based solely on air oxidation, the single-step process is triggered by the photodecarboxylation of a xanthone acetic acid liberating a strong bicyclic guanidine base. Starting with a 1 MUm thick film based on trithiol poly(ethylene oxide) oligomer, the UV-mediated oxidation of thiols to disulfides occurs in a matter of minutes both selectively, i.e., without overoxidation, and quantitatively as assessed by a range of spectroscopic techniques. Thiolate formation and film thickness determine the reaction rates and yield. Spatial control of the photopolymerization serves to generate robust micropatterns, while the reductive cleavage of S-S bridges allows the recycling of 40% of the initial thiol groups. PMID- 26502362 TI - Editorial Comment to Validation of active surveillance criteria for pathologically insignificant prostate cancer in Asian men. PMID- 26502363 TI - Copeptin is an independent prognostic factor for transplant-free survival in cirrhosis. AB - BACKGROUND & AIMS: Copeptin is a stable cleavage product of the arginine vasopressin (AVP) precursor and is equimolarly secreted with AVP. Copeptin is currently considered a reliable prognostic marker in a wide variety of diseases other than cirrhosis. We aimed to investigate the association between severity of cirrhosis and copeptin concentrations and to confirm whether copeptin is of prognostic significance in cirrhosis. METHODS: One hundred and eighty-four cirrhotic patients hospitalized in two tertiary referral centres were studied. Serum copeptin was measured in samples obtained at hospital admission. Differences in serum copeptin between Child-Pugh classes were evaluated using the Kruskal-Wallis test. Cox proportional hazard regression and Kaplan-Meier analyses were performed to evaluate associations of copeptin and other possible prognostic factors with 6- and 12-month mortality. RESULTS: Median serum copeptin (interquartile range) increased significantly through Child-Pugh classes A [5.4 (3.1-10.7) pmol/L], B [9.6 (6.0-17.3) pmol/L] and C [13.8 (5.8-34.1) pmol/L, P < 0.01]. Patients with serum copeptin >12.3 pmol/L displayed significantly higher mortality rates at 6 and 12 months as compared to those with serum copeptin <=12.3 pmol/L (Log-rank test: P < 0.01). Serum copeptin >12.3 pmol/L was significantly associated with mortality, particularly at 6 months, independently of age, clinical parameters and Model for End stage Liver Disease (MELD), MELD sodium and Child-Pugh score. CONCLUSIONS: Serum copeptin concentration increases significantly along with the severity of cirrhosis as defined by the Child-Pugh classification. A high serum copeptin concentration predicts survival, particularly at 6 months, independently of liver-specific scoring systems in a heterogeneous population of hospitalized cirrhotic patients. PMID- 26502364 TI - Nicking endonuclease-assisted signal amplification of a split molecular aptamer beacon for biomolecule detection using graphene oxide as a sensing platform. AB - Sensitive and selective detection of ultralow concentrations of specific biomolecules is important in early clinical diagnoses and biomedical applications. Many types of aptasensors have been developed for the detection of various biomolecules, but usually suffer from false positive signals and high background signals. In this work, we have developed an amplified fluorescence aptasensor platform for ultrasensitive biomolecule detection based on enzyme assisted target-recycling signal amplification and graphene oxide. By using a split molecular aptamer beacon and a nicking enzyme, the typical problem of false positive signals can be effectively resolved. Only in the presence of a target biomolecule, the sensor system is able to generate a positive signal, which significantly improves the selectivity of the aptasensor. Moreover, using graphene oxide as a super-quencher can effectively reduce the high background signal of a sensing platform. We select vascular endothelial growth factor (VEGF) and adenosine triphosphate (ATP) as model analytes in the current proof-of concept experiments. It is shown that under optimized conditions, our strategy exhibits high sensitivity and selectivity for the quantification of VEGF and ATP with a low detection limit (1 pM and 4 nM, respectively). In addition, this biosensor has been successfully utilized in the analysis of real biological samples. PMID- 26502366 TI - INCREASING SUPPLY OF AND DEMAND FOR EVIDENCE-BASED PSYCHOTHERAPY: NEAR-TERM OPTIONS FOR PAYERS AND POLICYMAKERS. PMID- 26502365 TI - Heat Transfer during Blanching and Hydrocooling of Broccoli Florets. AB - The objective of this work was to simulate heat transfer during blanching (90 degrees C) and hydrocooling (5 degrees C) of broccoli florets (Brassica oleracea L. Italica) and to evaluate the impact of these processes on the physicochemical and nutrimental quality properties. Thermophysical properties (thermal conductivity [line heat source], specific heat capacity [differential scanning calorimetry], and bulk density [volume displacement]) of stem and inflorescence were measured as a function of temperature (5, 10, 20, 40, 60, and 80 degrees C). The activation energy and the frequency factor (Arrhenius model) of these thermophysical properties were calculated. A 3-dimensional finite element model was developed to predict the temperature history at different points inside the product. Comparison of the theoretical and experimental temperature histories was carried out. Quality parameters (firmness, total color difference, and vitamin C content) and peroxidase activity were measured. The satisfactory validation of the finite element model allows the prediction of temperature histories and profiles under different process conditions, which could lead to an eventual optimization aimed to minimize the nutritional and sensorial losses in broccoli florets. PMID- 26502367 TI - Walking Speed As a Potential Indicator of Cartilage Breakdown Following Anterior Cruciate Ligament Reconstruction. AB - OBJECTIVE: To determine whether or not self-selected walking speed associates with serum biomarkers of cartilage (collagen and proteoglycan) breakdown in anterior cruciate ligament reconstructed (ACLR) individuals. METHODS: Twenty individuals with a history of a primary unilateral ACLR participated in this cross-sectional study. Resting blood was collected from each participant prior to completing 5 walking gait trials at a self-selected comfortable speed. Walking speed was evaluated in a 3-dimensional motion capture laboratory and determined from the velocity of the pelvic center of mass. Sera were assessed for collagen type II cleavage product (C2C) and proteoglycan (aggrecan) concentrations using commercially available specific enzyme-linked immunosorbent assays. Pearson's product-moment (r) and Spearman's (rho) correlations were used to evaluate associations between walking speed and biomarkers of cartilage breakdown metabolism. Partial correlations were used to determine whether covariates influenced associations between walking speed and biomarkers of cartilage breakdown. RESULTS: ACLR individuals with a slower walking speed demonstrated higher concentrations of serum C2C (r = -0.52, P = 0.02), while there was no significant association between walking speed and aggrecan concentrations (rho = 0.29, P = 0.31). After accounting for the variance associated with stance phase duration, ACLR individuals with a slower walking speed still demonstrated greater serum C2C concentrations (partial r = -0.53, P = 0.02). CONCLUSION: ACLR individuals who habitually walk slower may experience a greater degree of collagen breakdown, suggesting that walking speed may be a future useful clinical indicator for identifying individuals with higher levels of cartilage breakdown and preradiographic osteoarthritic joint changes. PMID- 26502368 TI - Acute Kidney Disease After Liver and Heart Transplantation. AB - After transplantation of nonrenal solid organs, an acute decline in kidney function develops in the majority of patients. In addition, a significant number of nonrenal solid organ transplant recipients develop chronic kidney disease, and some develop end-stage renal disease, requiring renal replacement therapy. The incidence varies depending on the transplanted organ. Acute kidney injury after nonrenal solid organ transplantation is associated with prolonged length of stay, cost, increased risk of death, de novo chronic kidney disease, and end-stage renal disease. This overview focuses on the risk factors for posttransplant acute kidney injury after liver and heart transplantation, integrating discussion of proteinuria and chronic kidney disease with emphasis on pathogenesis, histopathology, and management including the use of mechanistic target of rapamycin inhibition and costimulatory blockade. PMID- 26502370 TI - Decrease in 1-year Kidney Graft Size Predicts Inferior Outcomes After Deceased Donor Kidney Transplantation. AB - BACKGROUND: Longest bipolar length of the kidney graft is routinely measured for ultrasonographic assessment of graft size (GS), although the value of the graft length remains unclear. METHODS: In a single-center, observational study involving 319 deceased-donor kidney transplant recipients, we assessed variations in absolute and adjusted GS (corrected for body surface area) between 1 and 12 months after transplantation ([INCREMENT]GS1m->12m). We tested whether variations in GS during the first year were predictive of the composite outcome of a reduction of 50% or more in the estimated glomerular filtration rate or end-stage graft failure. RESULTS: At 1 year after transplantation, 121 patients (38%) had a decrease in GS ([INCREMENT]GS1m->12m <0), and 198 patients (62%) had an increase in GS ([INCREMENT]GS1m->12m >=0). After a median follow-up of 53 months, 41 patients with a decrease in GS reached the composite outcome as compared with 12 patients with an increase in GS (34% and 6%, respectively; P < 0.001). Areas under the receiver operating characteristics curves of absolute and adjusted [INCREMENT]GS1m->12m for composite outcome were 0.81 (95% confidence interval [95% CI], 0.74-0.88) and 0.78 (95% CI, 0.70-0.86), respectively. In multivariate analysis, the risk of the composite outcome was significantly higher among patients with a decrease in GS during the first year after transplantation (hazard ratio, 4.55; 95% CI, 2.35-8.81; P < 0.001). CONCLUSIONS: A decrease in kidney GS during the first year after transplantation, as compared with an increase in GS, is a powerful predictor of subsequent graft dysfunction or end stage graft failure. PMID- 26502369 TI - Calcineurin-inhibition Results in Upregulation of Local Renin and Subsequent Vascular Endothelial Growth Factor Production in Renal Collecting Ducts. AB - BACKGROUND: Tacrolimus (Tac) and Cyclosporine A (CyA) calcineurin inhibitors (CNIs) are 2 effective immunosuppressants which are essential to prevent allograft rejection. Calcineurin inhibitors are known to be nephrotoxic. However, the precise mechanism of nephrotoxicity is not fully understood. In this study, we investigated the in vivo effects of CNIs on the local renal renin-angiotensin system in the collecting duct (CD). METHODS: Three-week-old mice were treated with either vehicle, CyA (2 mg/kg per day), Tac (0.075 mg/kg per day), CyA + Aliskiren (25 mg/kg per day), or Tac + Aliskiren for 3 weeks. Serum creatinine was measured. Renin and vascular endothelial growth factor (VEGF) contents in CD were evaluated with flow cytometry and multiphoton microscopy. The diameter of vessels was assessed with multiphoton microscopy, and the amount of renal collagen was determined by real-time polymerase chain reaction and Masson staining. RESULTS: The elevated level of serum creatinine in CNI groups was abolished by Aliskiren. Flow cytometric analysis found elevated renin content in principal cells, which was prevented by Aliskiren. This result was further confirmed with multiphoton microscopy. The VEGF content in CD correlated with reduced capillary diameter and with the formation of fibrotic islands. CONCLUSIONS: Calcineurin inhibitors induce production of renin in the CD that may contribute to decreased renal blood flow. In turn, CD responds with increased VEGF production, resulting in disproportional vessel growth, further worsening the local hypoxia and striped fibrosis surrounding the CDs. Aliskiren, a direct renin inhibitor blocks these effects and improves CNI-induced nephropathy by decreasing renin production in the CDs. Our data suggest that Aliskiren may be used for the prevention of CNI nephrotoxicity. PMID- 26502372 TI - Simultaneous Nephrectomy and Ipsilateral Dual Kidney Transplantation in Patients With Autosomal Polycystic Kidney Disease. PMID- 26502371 TI - alpha-Lipoic Acid Protects Against Ischemia-Reperfusion Injury in Simultaneous Kidney-Pancreas Transplantation. AB - BACKGROUND: Multiple factors have been implicated in the process of ischemia reperfusion injury (IRI) in organ transplantation. Among these factors, oxidative damage seems to initiate the injury. alpha-lipoic acid (ALA) is a potent antioxidant that is used in patients with diabetic polyneuropathy. The aim of the present study was to determine the effect of ALA in patients undergoing simultaneous kidney-pancreas transplant by evaluating the functional recovery of the graft and biochemical markers of IRI. METHODS: Twenty-six patients were included in the following groups: (i) untreated control; (ii) donor and recipient (DR) ALA-treated, in which ALA was administered both to the deceased donor and to the recipients; and (iii) recipient ALA-treated group. The expression of inflammatory genes, as observed in biopsies taken at the end of surgery, as well as the serum cytokines, secretory leukocyte protease inhibitor, regenerating islet-derived protein 3beta/pancreatitis-associated protein, amylase, lipase, glucose, and creatinine levels were quantified as markers of organ function. RESULTS: The DR group showed high levels of TGFbeta and low levels of C3 and TNFalpha in the kidneys, whereas high levels of C3 and heme oxygenase were identified in pancreas biopsies. Decreases in serum IL-8, IL-6, secretory leukocyte protease inhibitor, and regenerating islet-derived protein 3 beta/pancreatitis-associated protein were observed after surgery in the DR group. Serum lipase and amylase were lower in the DR group than in the control and recipient groups. Early kidney dysfunction and clinical pancreatitis were higher in the control group than in either treatment group. CONCLUSIONS: These results show that ALA preconditioning is capable of reducing inflammatory markers while decreasing early kidney dysfunction and clinical posttransplant pancreatitis. PMID- 26502373 TI - Test-retest reproducibility of neurochemical profiles with short-echo, single voxel MR spectroscopy at 3T and 7T. AB - PURPOSE: To determine the test-retest reproducibility of neurochemical concentrations obtained with a highly optimized, short-echo, single-voxel proton MR spectroscopy (MRS) pulse sequence at 3T and 7T using state-of-the-art hardware. METHODS: A semi-LASER sequence (echo time = 26-28 ms) was used to acquire spectra from the posterior cingulate and cerebellum at 3T and 7T from six healthy volunteers who were scanned four times weekly on both scanners. Spectra were quantified with LCModel. RESULTS: More neurochemicals were quantified with mean Cramer-Rao lower bounds (CRLBs) <=20% at 7T than at 3T despite comparable frequency-domain signal-to-noise ratio. Whereas CRLBs were lower at 7T (P < 0.05), between-session coefficients of variance (CVs) were comparable at the two fields with 64 transients. Five metabolites were quantified with between-session CVs <=5% at both fields. Analysis of subspectra showed that a minimum achievable CV was reached with a lower number of transients at 7T for multiple metabolites and that between-session CVs were lower at 7T than at 3T with fewer than 64 transients. CONCLUSION: State-of-the-art MRS methodology allows excellent reproducibility for many metabolites with 5-min data averaging on clinical 3T hardware. Sensitivity and resolution advantages at 7T are important for weakly represented metabolites, short acquisitions, and small volumes of interest. Magn Reson Med 76:1083-1091, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26502374 TI - Hyponatremia and Right Maxillary Sinus Mass. PMID- 26502375 TI - Graded specialization within and between the anterior temporal lobes. AB - Considerable evidence from different methodologies has identified the anterior temporal lobes (ATLs) as key regions for the representation of semantic knowledge. Research interest is now shifting to investigate the roles of different ATL subregions in semantic representation, with particular emphasis on the functions of the left versus right ATLs. In this review, we provide evidence for graded specializations both between and within the ATLs. We argue (1) that multimodal, pan-category semantic representations are supported jointly by both left and right ATLs, yet (2) that the ATLs are not homogeneous in their function. Instead, subtle functional gradations both between and within the ATLs emerge as a consequence of differential connectivity with primary sensory/motor/limbic regions. This graded specialization account of semantic representation provides a compromise between theories that posit no differences between the functions of the left and right ATLs and those that posit that the left and right ATLs are entirely segregated in function. Evidence for this graded account comes from converging sources, and its benefits have been exemplified in formal computational models. We propose that this graded principle is not only a defining feature of the ATLs but is also a more general neurocomputational principle found throughout the temporal lobes. PMID- 26502377 TI - Fish protein increases circulating levels of trimethylamine-N-oxide and accelerates aortic lesion formation in apoE null mice. AB - SCOPE: The protective effect of fish consumption on the cardiovascular system has primarily been ascribed to n-3 fatty acids, but data investigating the vascular effects of fish protein consumption are scarce. This study aimed to investigate the vascular impact of fish protein in a mouse model of atherosclerosis. METHODS AND RESULTS: Male apoE null mice were fed a Western diet containing 20% fish (turbot) protein, casein, or soy protein, for 16 wk. Morphometric analysis of the aorta revealed that the atherosclerotic plaque area of fish protein fed mice was twofold larger than that in casein- or soy protein-fed mice. The percentage area of calcification deposits in plaques of fish protein fed mice was higher (7.57%) than that in casein-fed (2.86%) or soy protein-fed (3.46%) mice, and fish protein fed mice exhibited higher plaque expression of CD68, CD36, and IL-6 than the other two groups. Fish protein intake was accompanied by increased serum concentrations of trimethylamine-N-oxide (7.03 +/- 2.83 MUmol/L), as compared with casein (0.92 +/- 0.46 MUmol/L) and soy protein (1.32 +/- 0.54 MUmol/L) intake. CONCLUSION: The present data indicate adverse effects of fish protein on the vascular system, which could be attributable to the high serum trimethylamine N-oxide concentrations in these mice. PMID- 26502376 TI - Role of Mitral Annulus Diastolic Geometry on Intraventricular Filling Dynamics. AB - The mitral valve (MV) is a bileaflet valve positioned between the left atrium and ventricle of the heart. The annulus of the MV has been observed to undergo geometric changes during the cardiac cycle, transforming from a saddle D-shape during systole to a flat (and less eccentric) D-shape during diastole. Prosthetic MV devices, including heart valves and annuloplasty rings, are designed based on these two configurations, with the circular design of some prosthetic heart valves (PHVs) being an approximation of the less eccentric, flat D-shape. Characterizing the effects of these geometrical variations on the filling efficiency of the left ventricle (LV) is required to understand why the flat D shaped annulus is observed in the native MV during diastole in addition to optimizing the design of prosthetic devices. We hypothesize that the D-shaped annulus reduces energy loss during ventricular filling. An experimental left heart simulator (LHS) consisting of a flexible-walled LV physical model was used to characterize the filling efficiency of the two mitral annular geometries. The strength of the dominant vortical structure formed and the energy dissipation rate (EDR) of the measured fields, during the diastolic period of the cardiac cycle, were used as metrics to quantify the filling efficiency. Our results indicated that the O-shaped annulus generates a stronger (25% relative to the D shaped annulus) vortical structure than that of the D-shaped annulus. It was also found that the O-shaped annulus resulted in higher EDR values throughout the diastolic period of the cardiac cycle. The results support the hypothesis that a D-shaped mitral annulus reduces dissipative energy losses in ventricular filling during diastole and in turn suggests that a symmetric stent design does not provide lower filling efficiency than an equivalent asymmetric design. PMID- 26502378 TI - BRAF Inhibition in a Lung Transplant Recipient With Metastatic Melanoma. PMID- 26502380 TI - Medicare, Medicaid, and Mental Health Care: Historical Perspectives on Reforms Before the US Congress. PMID- 26502379 TI - Pneumococcal Prevention Gets Older and Wiser. PMID- 26502381 TI - Health care costs for patients with dementia at the end of life. PMID- 26502382 TI - Early Language Intervention Using Distance Video-Teleconferencing: A Pilot Study of Young Boys With Fragile X Syndrome and Their Mothers. AB - PURPOSE: This study examined the effects of a naturalistic parent-implemented language intervention on the use of verbally responsive language by mothers of 6 young boys with fragile X syndrome. The intervention included parent education sessions and clinician coaching delivered onsite and by distance video teleconferencing. METHOD: A single-case multiple baseline across participants was used to examine intervention effects on maternal use of language support strategies. A nonparametric analysis was used to evaluate the relative effectiveness of onsite compared with distance coaching sessions. RESULTS: Mothers increased their use of utterances that followed into their child's focus of attention and prompted child communication acts. Intervention effects were not observed for maternal contingent responses to child communication, possibly due to the limited number of spontaneous communication acts children produced. Children showed moderate increases in the use of prompted communication acts, whereas intervention effects on spontaneous communication acts were more modest and variable. Comparable increases in maternal strategy use were observed during onsite and distance sessions. CONCLUSIONS: No previous study has examined a distance-delivered parent-implemented language intervention for young boys with fragile X syndrome. Mothers were able to increase their use of verbally responsive language. Intervention efficacy might be enhanced by incorporating an augmentative and alternative communication device for some children and a more concerted focus on increasing the frequency of child communication acts. Findings provide preliminary support for the efficacy of the distance delivery format. PMID- 26502383 TI - Digital phantoms generated by spectral and spatial light modulators. AB - A hyperspectral image projector (HIP) based on liquid crystal on silicon spatial light modulators is explained and demonstrated to generate data cubes. The HIP constructed data cubes are three-dimensional images of the spatial distribution of spectrally resolved abundances of intracellular light-absorbing oxyhemoglobin molecules in single erythrocytes. Spectrally and spatially resolved image data indistinguishable from the real scene may be used as standard data cubes, so called digital phantoms, to calibrate image sensors and validate image analysis algorithms for their measurement quality, performance consistency, and interlaboratory comparisons for quantitative biomedical imaging applications. PMID- 26502402 TI - Surveillance and Data Capture to Assess Trauma Care Capacity in Low- and Middle Income Countries. PMID- 26502403 TI - Cancer Drugs Approved on the Basis of a Surrogate End Point and Subsequent Overall Survival: An Analysis of 5 Years of US Food and Drug Administration Approvals. PMID- 26502404 TI - A map of the distribution of sphingosine 1-phosphate in the spleen. AB - Despite the importance of signaling lipids, many questions remain about their function because few tools are available for charting lipid gradients in vivo. Here we generated a sphingosine 1-phosphate (S1P) reporter mouse and used this mouse to define the distribution of S1P in the spleen. Unexpectedly, the presence of blood did not serve as a predictor of the concentration of signaling-available S1P. Large areas of the red pulp had low concentrations of S1P, while S1P was sensed by cells inside the white pulp near the marginal sinus. The lipid phosphate phosphatase LPP3 maintained low S1P concentrations in the spleen and enabled efficient shuttling of marginal zone B cells. The exquisitely tight regulation of S1P availability might explain how a single lipid can simultaneously orchestrate the movements of many cells of the immune system. PMID- 26502405 TI - Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. AB - Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-kappaB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy. PMID- 26502406 TI - Long non-coding RNA profiling of human lymphoid progenitor cells reveals transcriptional divergence of B cell and T cell lineages. AB - To elucidate the transcriptional 'landscape' that regulates human lymphoid commitment during postnatal life, we used RNA sequencing to assemble the long non coding transcriptome across human bone marrow and thymic progenitor cells spanning the earliest stages of B lymphoid and T lymphoid specification. Over 3,000 genes encoding previously unknown long non-coding RNAs (lncRNAs) were revealed through the analysis of these rare populations. Lymphoid commitment was characterized by lncRNA expression patterns that were highly stage specific and were more lineage specific than those of protein-coding genes. Protein-coding genes co-expressed with neighboring lncRNA genes showed enrichment for ontologies related to lymphoid differentiation. The exquisite cell-type specificity of global lncRNA expression patterns independently revealed new developmental relationships among the earliest progenitor cells in the human bone marrow and thymus. PMID- 26502407 TI - [In Process Citation]. PMID- 26502408 TI - [Acute coronary syndrome in acute stroke]. AB - BACKGROUND: Elevated troponin levels are commonly found in patients with acute stroke and approximately 60 % of stroke patients suffer from an accompanying coronary artery disease. Troponin release can be caused either by an acute thrombotic myocardial infarction or by insufficient coronary perfusion due to neurocardiogenic causes like blood pressure or heart rate variability without thrombotic coronary occlusion. Due to the often unclear pathological cause of troponin release and the risk of secondary hemorrhage during dual antiplatelet therapy, the determination of the best time point for coronary diagnostics and therapy in stroke patients is a common challenge in clinical daily routine. MATERIALS AND METHODS: Based on the current literature, we describe a potential diagnostic and therapeutic approach in stroke patients with increased troponin levels. RESULTS: First, the probability of an acute thrombotic myocardial infarction should be evaluated based on clinical, laboratory, and electrocardiographic parameters. In case of suspected myocardial infarction, a diagnostic coronary angiography/CT angiography should be performed and dual antiplatelet therapy should be given depending on the intracranial bleeding risk. In patients with high risk of intracranial bleeding, thrombus aspiration and balloon dilatation should be considered. CONCLUSION: In patients with acute stroke and elevated troponin levels, a thorough diagnostic workup is necessary to estimate the probability for a thrombotic myocardial infarction and to prevent cardiac and neurologic complications. PMID- 26502409 TI - Two New PRP Conjugate Gradient Algorithms for Minimization Optimization Models. AB - Two new PRP conjugate Algorithms are proposed in this paper based on two modified PRP conjugate gradient methods: the first algorithm is proposed for solving unconstrained optimization problems, and the second algorithm is proposed for solving nonlinear equations. The first method contains two aspects of information: function value and gradient value. The two methods both possess some good properties, as follows: 1) betak >= 0 2) the search direction has the trust region property without the use of any line search method 3) the search direction has sufficient descent property without the use of any line search method. Under some suitable conditions, we establish the global convergence of the two algorithms. We conduct numerical experiments to evaluate our algorithms. The numerical results indicate that the first algorithm is effective and competitive for solving unconstrained optimization problems and that the second algorithm is effective for solving large-scale nonlinear equations. PMID- 26502411 TI - Hoops News. PMID- 26502410 TI - Photodynamic therapy as an effective therapeutic approach in MAME models of inflammatory breast cancer. AB - Photodynamic therapy (PDT) is a minimally invasive, FDA-approved therapy for treatment of endobronchial and esophageal cancers that are accessible to light. Inflammatory breast cancer (IBC) is an aggressive and highly metastatic form of breast cancer that spreads to dermal lymphatics, a site that would be accessible to light. IBC patients have a relatively poor survival rate due to lack of targeted therapies. The use of PDT is underexplored for breast cancers but has been proposed for treatment of subtypes for which a targeted therapy is unavailable. We optimized and used a 3D mammary architecture and microenvironment engineering (MAME) model of IBC to examine the effects of PDT using two treatment protocols. The first protocol used benzoporphyrin derivative monoacid A (BPD) activated at doses ranging from 45 to 540 mJ/cm(2). The second PDT protocol used two photosensitizers: mono-L-aspartyl chlorin e6 (NPe6) and BPD that were sequentially activated. Photokilling by PDT was assessed by live-dead assays. Using a MAME model of IBC, we have shown a significant dose-response in photokilling by BPD-PDT. Sequential activation of NPe6 followed by BPD is more effective in photokilling of tumor cells than BPD alone. Sequential activation at light doses of 45 mJ/cm(2) for each agent resulted in >90 % cell death, a response only achieved by BPD-PDT at a dose of 360 mJ/cm(2). Our data also show that effects of PDT on a volumetric measurement of 3D MAME structures reflect efficacy of PDT treatment. Our study is the first to demonstrate the potential of PDT for treating IBC. PMID- 26502412 TI - Prevention of Lower Extremity Injuries in Basketball: A Systematic Review and Meta-Analysis. AB - CONTEXT: Lower extremity injuries are common in basketball, yet it is unclear how prophylactic interventions affect lower extremity injury incidence rates. OBJECTIVE: To analyze the effectiveness of current lower extremity injury prevention programs in basketball athletes, focusing on injury rates of (1) general lower extremity injuries, (2) ankle sprains, and (3) anterior cruciate ligament (ACL) tears. DATA SOURCES: PubMed, MEDLINE, CINAHL, SPORTDiscus, and the Cochrane Register of Controlled Trials were searched in January 2015. STUDY SELECTION: Studies were included if they were randomized controlled or prospective cohort trials, contained a population of competitive basketball athletes, and reported lower extremity injury incidence rates specific to basketball players. In total, 426 individual studies were identified. Of these, 9 met the inclusion criteria. One other study was found during a hand search of the literature, resulting in 10 total studies included in this meta-analysis. STUDY DESIGN: Systematic review and meta-analysis. LEVEL OF EVIDENCE: Level 2. DATA EXTRACTION: Details of the intervention (eg, neuromuscular vs external support), size of control and intervention groups, and number of injuries in each group were extracted from each study. Injury data were classified into 3 groups based on the anatomic diagnosis reported (general lower extremity injury, ankle sprain, ACL rupture). RESULTS: Meta-analyses were performed independently for each injury classification. Results indicate that prophylactic programs significantly reduced the incidence of general lower extremity injuries (odds ratio [OR], 0.69; 95% CI, 0.57-0.85; P < 0.001) and ankle sprains (OR, 0.45; 95% CI, 0.29-0.69; P < 0.001), yet not ACL ruptures (OR, 1.09; 95% CI, 0.36-3.29; P = 0.87) in basketball athletes. CONCLUSION: In basketball players, prophylactic programs may be effective in reducing the risk of general lower extremity injuries and ankle sprains, yet not ACL injuries. PMID- 26502413 TI - Weightbearing Versus Nonweightbearing After Meniscus Repair. AB - CONTEXT: Optimal rehabilitation after meniscal repair remains controversial. OBJECTIVE: To review the current literature on weightbearing status after meniscal repairs and to provide evidence-based recommendations for postoperative rehabilitation. DATA SOURCES: MEDLINE (January 1, 1993 to July 1, 2014) and Embase (January 1, 1993 to July 1, 2014) were queried with use of the terms meniscus OR/AND repair AND rehabilitation. STUDY SELECTION: Included studies were those with levels of evidence 1 through 4, with minimum 2 years follow-up and in an English publication. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 4. DATA EXTRACTION: Demographics and clinical and radiographic outcomes of meniscus repair at a minimum of 2 years follow-up were extracted. RESULTS: Successful clinical outcomes ranged from 70% to 94% with conservative rehabilitation. More recent studies using an accelerated rehabilitation protocol with full weightbearing and early range of motion reported 64% to 96% good results. CONCLUSION: Outcomes after both conservative (restricted weightbearing) protocols and accelerated rehabilitation (immediate weightbearing) yielded similar good to excellent results; however, lack of similar objective criteria and consistency among surgical techniques and existing studies makes direct comparison difficult. PMID- 26502414 TI - Reference Values for the Marx Activity Rating Scale in a Young Athletic Population: History of Knee Ligament Injury Is Associated With Higher Scores. AB - BACKGROUND: Activity-related patient-reported outcome measures are an important component of assessment after knee ligament injury in young and physically active patients; however, normative data for most activity scales are limited. OBJECTIVE: To present reference values by sex for the Marx Activity Rating Scale (MARS) within a young and physically active population while accounting for knee ligament injury history and sex. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 2. METHODS: All incoming freshman entering a US Service Academy in June of 2011 were recruited to participate in this study. MARS was administered to 1169 incoming freshmen (203 women) who consented to participate within the first week of matriculation. All subjects were deemed healthy and medically fit for military service on admission. Subjects also completed a baseline questionnaire that asked for basic demographic information and injury history. We calculated means with standard deviations, medians with interquartile ranges, and percentiles for ordinal and continuous variables, and frequencies and proportions for dichotomous variables. We also compared median scores by sex and history of knee ligament injury using the Kruskal-Wallis test. MARS was the primary outcome of interest. RESULTS: The median MARS score was significantly higher for men when compared with women (chi(2) = 13.22, df = 1, P < 0.001) with no prior history of knee ligament injury. In contrast, there was no significant difference in median MARS scores between men and women (chi(2) = 0.47, df = 1, P = 0.493) who reported a history of injury. Overall, median MARS scores were significantly higher among those who reported a history of knee ligament injury when compared with those who did not (chi(2) = 9.06, df = 1, P = 0.003). CONCLUSION: Assessing activity as a patient-reported outcome after knee ligament injury is important, and reference values for these instruments need to account for the influence of prior injury and sex. PMID- 26502415 TI - Treatment of Popliteal (Baker) Cysts With Ultrasound-Guided Aspiration, Fenestration, and Injection: Long-term Follow-up. AB - BACKGROUND: The purpose of this study was to determine the efficacy of ultrasound guided aspiration, fenestration, and injection as a treatment in patients with symptomatic popliteal cysts. HYPOTHESIS: Ultrasound-guided aspiration, fenestration, and injection (UGAFI) is an effective and safe treatment option for symptomatic popliteal cysts. STUDY DESIGN: Retrospective cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: Patients who received a UGAFI of popliteal cysts from 2008 to 2011 were identified. Preaspiration (PA) and follow-up Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, cyst recurrence, complications, cyst complexity, and size were obtained and compared for statistical significance. UGAFI involved aspiration of fluid through a spinal needle, fenestration of the cyst walls and septations, and injection of 1 mL (40 mg) triamcinolone (Kenalog) and 2 mL 0.5% bupivacaine (Sensorcaine) into the decompressed remnant. RESULTS: The mean PA WOMAC score (48.55) improved significantly at final follow-up (FFU) to 17.15 (P < 0.0001) for 47 patients. Within the WOMAC subcategories, there was also a significant difference in pain (PA, 10.68; FFU, 3.94; P < 0.0001), stiffness (PA, 4.51; FFU, 1.77; P < 0.0001), and physical function (PA, 31.34; FFU, 12.17; P < 0.0001). There were 6 reaspirations for recurrence (12.7%), and 1 patient underwent unicompartmental knee arthroplasty. There were no infections or other complications. CONCLUSION: Significant clinical improvement in patients with symptomatic popliteal cysts can be achieved via UGAFI as the sole treatment. CLINICAL RELEVANCE: UGAFI is a safe and effective option as the sole treatment modality for symptomatic popliteal cysts. PMID- 26502417 TI - A Unique Incidental Finding in Two Young Dancers: A Case Series. AB - Dancers frequently present to the sports medicine clinic with a variety of lower extremity complaints ranging from acute and traumatic injuries to more chronic, overuse injuries. This case series depicts a similar and unique incidental radiographic finding found in 2 young dancers seen at the same sports medicine clinic. While the findings are likely benign and unrelated to both patients' initial presentation, the finding of acroosteolysis can be found in more serious systemic and genetic processes as well an early finding in repetitive trauma. PMID- 26502416 TI - Patellar Tendinopathy. AB - CONTEXT: Patellar tendinopathy is a common condition. There are a wide variety of treatment options available, the majority of which are nonoperative. No consensus exists on the optimal method of treatment. EVIDENCE ACQUISITION: PubMed spanning 1962-2014. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: The majority of cases resolve with nonoperative therapy: rest, physical therapy with eccentric exercises, cryotherapy, anti-inflammatories, corticosteroid injections, extracorporeal shockwave therapy, glyceryl trinitrate, platelet-rich plasma injections, and ultrasound-guided sclerosis. Refractory cases may require either open or arthroscopic debridement of the patellar tendon. Corticosteroid injections provide short-term pain relief but increase risk of tendon rupture. Anti-inflammatories and injectable agents have shown mixed results. Surgical treatment is effective in many refractory cases unresponsive to nonoperative modalities. CONCLUSION: Physical therapy with an eccentric exercise program is the mainstay of treatment for patellar tendinopathy. Platelet-rich plasma has demonstrated mixed results; evidence-based recommendations on its efficacy cannot be made. In the event that nonoperative treatment fails, surgical intervention has produced good to excellent outcomes in the majority of patients. PMID- 26502418 TI - Pattern of Fascicular Involvement in Midportion Achilles Tendinopathy at Ultrasound. AB - BACKGROUND: The Achilles tendon is composed of fascicles from the soleus and gastrocnemius muscles, which are identifiable as discrete components at anatomical dissection. HYPOTHESIS: The pattern of fascicular involvement in Achilles tendinopathy may be characterized at ultrasound, and this characterization is reliable between different observers. STUDY DESIGN: Cross sectional diagnostic study. LEVEL OF EVIDENCE: Level 3. METHODS: One hundred cases of Achilles tendinopathy were retrospectively evaluated by 2 blinded musculoskeletal radiologists. Using a short-axis anatomical map, each case was categorized as involving the fascicular territories of the medial head of gastrocnemius, lateral head of gastrocnemius, soleus, or combinations of these, or as indeterminate. RESULTS: Both radiologists agreed on the fascicular involvement pattern in 93 of 100 cases; 20 involved only medial gastrocnemius territories, 8 lateral gastrocnemius, 15 soleus, 3 medial and lateral gastrocnemius, 21 medial gastrocnemius and soleus, 9 soleus and lateral gastrocnemius, and 16 the entire tendon, and 1 case was classified as indeterminate. In 7 cases, the interpretations were discordant. The kappa value was calculated as 0.92 (95% CI, 0.86-0.98) in keeping with a high level of interobserver agreement. CONCLUSION: As assessed at ultrasound, most cases of Achilles tendinopathy involve the medial head of gastrocnemius and/or soleus fascicles. CLINICAL RELEVANCE: The provided observational data will increase understanding of patterns of Achilles tendinopathy. PMID- 26502419 TI - Impact of Femoroacetabular Impingement Morphology on Gait Assessment in Symptomatic Patients. AB - BACKGROUND: Gait is abnormal in patients with femoroacetabular impingement (FAI). To date, studies have not correlated radiographic FAI morphology with gait abnormalities. HYPOTHESIS: Gait abnormalities in FAI patients will be associated with radiographic FAI morphology. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 4. METHODS: Patients with symptomatic FAI (n = 20) underwent radiographic and gait analysis. Exclusion criteria included previous injuries or surgeries to the lower extremities or lumbar spine as well as bilateral symptomatic FAI. The alpha angle (AA) and center-edge angle (CEA) were measured on anteroposterior (AP) pelvis, Dunn lateral, and false-profile radiographs, and inter- and intraobserver variability was determined. Motion analysis techniques were used to obtain gait data including 3-dimensional kinematic and kinetic data. Descriptive analysis was performed using Spearman correlations for morphologic measurements. A stepwise regression model was used to examine the association of gait measures with AA and CEA. RESULTS: Intraobserver agreement for the AA and CEA was 0.92 (CI, 0.80-0.97) and 0.90 (CI, 0.76-0.96), while interobserver agreement for the angles was 0.96 (CI, 0.89-0.98) and 0.96 (CI, 0.90-0.98), respectively. Descriptive analysis suggested correlations between AA and peak external hip and knee external rotation moments, maximum ankle flexion angle, and ankle range of motion (range, -0.51 to 0.42; P < 0.0001). The CEA correlated with stride, peak external ankle eversion and inversion moments, peak external knee extension moment, and peak external hip flexion moment (range, -0.44 to 0.51; P < 0.0001). We found that gait variables accounted for a large amount of variation in AA (8 variables accounted for 87% variation) and in CEA (7 variables accounted for 82% variation). CONCLUSION: Lower extremity gait parameters correlate highly with radiographic FAI morphology in symptomatic FAI patients. CLINICAL RELEVANCE: Gait abnormalities are present in FAI patients and may be a useful measure in outcome studies. PMID- 26502420 TI - Sport Specialization, Part I: Does Early Sports Specialization Increase Negative Outcomes and Reduce the Opportunity for Success in Young Athletes? AB - CONTEXT: There is increased growth in sports participation across the globe. Sports specialization patterns, which include year-round training, participation on multiple teams of the same sport, and focused participation in a single sport at a young age, are at high levels. The need for this type of early specialized training in young athletes is currently under debate. EVIDENCE ACQUISITION: Nonsystematic review. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. CONCLUSION: Sports specialization is defined as year-round training (greater than 8 months per year), choosing a single main sport, and/or quitting all other sports to focus on 1 sport. Specialized training in young athletes has risks of injury and burnout, while the degree of specialization is positively correlated with increased serious overuse injury risk. Risk factors for injury in young athletes who specialize in a single sport include year-round single-sport training, participation in more competition, decreased age-appropriate play, and involvement in individual sports that require the early development of technical skills. Adults involved in instruction of youth sports may also put young athletes at risk for injury by encouraging increased intensity in organized practices and competition rather than self-directed unstructured free play. STRENGTH-OF-RECOMMENDATION TAXONOMY SORT: C. PMID- 26502421 TI - Test-Retest Reliability of a Computerized Concussion Test: CNS Vital Signs. AB - BACKGROUND: Neurocognitive testing is an important concussion evaluation tool, but for neurocognitive tests to be useful, their psychometric properties must be well established. Test-retest reliability of computerized neurocognitive tests can influence their clinical utility. The reliability for a commonly used computerized neurocognitive test, CNS Vital Signs, is not well established. The purpose of this study was to examine test-retest reliability and reliable change indices for CNS Vital Signs in a healthy, physically active college population. HYPOTHESIS: CNS Vital Signs yields acceptable test-retest reliability, with greater reliability between the second and third test administration compared with between the first and second administration. STUDY DESIGN: Cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: Forty healthy, active volunteers (16 men, 24 women; mean age, 21.05 +/- 2.17 years) reported to a clinical laboratory for 3 sessions, 1 week apart. At each session, participants were administered CNS Vital Signs. Outcomes included standard scores for the following CNS Vital Signs domains: verbal memory, visual memory, psychomotor speed, cognitive flexibility, complex attention, processing speed, reaction time, executive functioning, and reasoning. RESULTS: Participants performed significantly better on the second session and/or third session than they did on the first testing session on 6 of 9 neurocognitive domains. Pearson r test-retest correlations between sessions ranged from 0.11 to 0.87. Intraclass correlation coefficients ranged from 0.10 to 0.86. CONCLUSION: Clinicians should consider using reliable change indices to account for practice effects, identify meaningful score changes due to pathology, and inform clinical decisions. CLINICAL RELEVANCE: This study highlights the importance of clinicians understanding the psychometric properties of computerized neurocognitive tests when using them in the management of sport related concussion. If CNS Vital Signs is administered twice within a small time frame (such as 1 week), athletes should be expected to improve between the first and second administration. PMID- 26502422 TI - Review of Lacrosse-Related Musculoskeletal Injuries in High School and Collegiate Players. AB - CONTEXT: Participation in lacrosse has dramatically increased since 2001. Changes in the game rules, sport equipment, and athlete characteristics have all contributed to the injury patterns in lacrosse over time. OBJECTIVE: A summary of lacrosse-related musculoskeletal injuries. DATA SOURCES: Medline, CINAHL, Scopus, and Web of Science were searched for articles relating to the epidemiology and mechanisms of lacrosse injuries in high school and collegiate lacrosse players. STUDY SELECTION: The search strategy used the following keywords: lacrosse, injury, musculoskeletal, high school, intercollegiate, knee, shoulder, fracture, ankle, foot, concussion, and surveillance. Studies were included if they reported injury risk, injury type, or injury mechanism in high school or collegiate lacrosse players. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 4. DATA EXTRACTION: Injury type, frequency, and mechanism as well as population were extracted. RESULTS: Thirteen cohort studies and an additional 15 case series and reports were included. For all lacrosse players, ankle, knee, and hand/wrist were key sites for acute injury. Among collegiate players, preseasonal play elicits more injuries than seasonal play. Female players incur more noncontact and overuse injuries than male players. Boys have 3 to 5 times the risk for sustaining a fracture compared with girls in competition and practice. Women experienced fewer concussions but more facial fractures than men. Injuries to the foot/ankle, head, face, and wrist/hand more often required surgery in girls than in boys. CONCLUSION: Male players incur more injuries than female players. However, because of the collisional nature of play, more shoulder, arm, and upper leg injuries occur in male players. Fractures to the head and hand occur relatively more frequently in female players. Injury risk can be modified with appropriate training regimens and by respecting the game rules. PMID- 26502423 TI - Suicide in National Collegiate Athletic Association (NCAA) Athletes: A 9-Year Analysis of the NCAA Resolutions Database. AB - BACKGROUND: The National Collegiate Athletic Association (NCAA) has recently highlighted mental health concerns in student athletes, though the incidence of suicide among NCAA athletes is unclear. The purpose of this study was to determine the rate of suicide among NCAA athletes. HYPOTHESIS: The incidence of suicide in NCAA athletes differs by sex, race, sport, and division. STUDY DESIGN: Retrospective cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: NCAA Memorial Resolutions list and published NCAA demographic data were used to identify student-athlete deaths and total participant seasons from 2003-2004 through 2011 2012. Deaths were analyzed by age, sex, race, division, and sport. RESULTS: Over the 9-year study period, 35 cases of suicide were identified from a review of 477 student-athlete deaths during 3,773,309 individual participant seasons. The overall suicide rate was 0.93/100,000 per year. Suicide represented 7.3% (35/477) of all-cause mortality among NCAA student athletes. The annual incidence of suicide in male athletes was 1.35/100,000 and in female athletes was 0.37/100,000 (relative risk [RR], 3.7; P < 0.01). The incidence in African American athletes was 1.22/100,000 and in white athletes was 0.87/100,000 (RR, 1.4; P = 0.45). The highest rate of suicide occurred in men's football (2.25/100,000), and football athletes had a relative risk of 2.2 (P = 0.03) of committing suicide compared with other male, nonfootball athletes. CONCLUSION: The suicide rate in NCAA athletes appears to be lower than that of the general and collegiate population of similar age. NCAA male athletes have a significantly higher rate of suicide compared with female athletes, and football athletes appear to be at greatest risk. CLINICAL RELEVANCE: Suicide represents a preventable cause of death, and development of effective prevention programs is recommended. PMID- 26502426 TI - Combating Negative Transfer From Predictive Distribution Differences. AB - Domain adaptation (DA), which leverages labeled data from related source domains, comes in handy when the label information of the target domain is scarce or unavailable. However, as the source data do not come from the same origin as that of the target domain, the predictive distributions of the source and target domains are likely to differ in reality. At the extreme, the predictive distributions of the source domains can differ completely from that of the target domain. In such case, using the learned source classifier to assist in the prediction of target data can result in prediction performance that is poorer than that with the omission of the source data. This phenomenon is established as negative transfer with impact known to be more severe in the multiclass context. To combat negative transfer due to differing predictive distributions across domains, we first introduce the notion of positive transferability for the assessment of synergy between the source and target domains in their prediction models, and we also propose a criterion to measure the positive transferability between sample pairs of different domains in terms of their prediction distributions. With the new measure, a predictive distribution matching (PDM) regularizer and a PDM framework learn the target classifier by favoring source data with large positive transferability while inferring the labels of target unlabeled data. Extensive experiments are conducted to validate the performance efficacy of the proposed PDM framework using several commonly used multidomain benchmark data sets, including Sentiment, Reuters, and Newsgroup, in the context of both binary-class and multiclass domains. Subsequently, the PDM framework is put to work on a real-world scenario pertaining to water cluster molecule identification. The experimental results illustrate the adverse impact of negative transfer on several state-of-the-art DA methods, whereas the proposed framework exhibits excellent and robust predictive performances. PMID- 26502424 TI - Omohyoid Muscle Syndrome in a Mixed Martial Arts Athlete: A Case Report. AB - Omohyoid muscle syndrome is a rare cause of an X-shaped bulging lateral neck mass that occurs on swallowing. This is a diagnostic case report of a 22-year-old mixed martial arts athlete who acquired this condition. PMID- 26502427 TI - Fuzzy-Rough Simultaneous Attribute Selection and Feature Extraction Algorithm. AB - Among the huge number of attributes or features present in real-life data sets, only a small fraction of them are effective to represent the data set accurately. Prior to analysis of the data set, selecting or extracting relevant and significant features is an important preprocessing step used for pattern recognition, data mining, and machine learning. In this regard, a novel dimensionality reduction method, based on fuzzy-rough sets, that simultaneously selects attributes and extracts features using the concept of feature significance is presented. The method is based on maximizing both the relevance and significance of the reduced feature set, whereby redundancy therein is removed. This paper also presents classical and neighborhood rough sets for computing the relevance and significance of the feature set and compares their performances with that of fuzzy-rough sets based on the predictive accuracy of nearest neighbor rule, support vector machine, and decision tree. An important finding is that the proposed dimensionality reduction method based on fuzzy-rough sets is shown to be more effective for generating a relevant and significant feature subset. The effectiveness of the proposed fuzzy-rough-set-based dimensionality reduction method, along with a comparison with existing attribute selection and feature extraction methods, is demonstrated on real-life data sets. PMID- 26502429 TI - Target Localization Using Ensemble Support Vector Regression in Wireless Sensor Networks. AB - Target localization, whose goal is to estimate the location of an unknown target, is one of the key issues in applications of wireless sensor networks (WSNs). With recent advances in fabrication technology, deployments of large-scale WSNs have become economically feasible. However, there exist issues such as limited communication and the curse of dimensionality in applying machine-learning algorithms such as support vector regression (SVR) on large-scale WSNs. Here, in order to overcome such issues, we propose an ensemble implementation of SVR for the problem of target localization. The convergence property of the localization algorithm using the ensemble SVR is verified, and the robustness of the proposed scheme against measurement noise is analyzed. Furthermore, experimental results confirm that the estimation performance of the proposed method is more accurate and robust to measurement noise than the conventional SVR predictor. PMID- 26502428 TI - Unbounded Motion Optimization by Developmental Learning. AB - An algorithm is presented for autonomous motion development with unbounded waveform resolution. Rather than a single optimization in a very large space, memory is built to support incremental improvements; therefore, complexity is balanced by experience. Analogously, human development manages complexity by limiting it during initial learning stages. Motions are represented by cubic spline interpolation; therefore, the development technique applies broadly to function optimization. Adding a node to the splines allows all previous memory samples to transfer to the higher dimension space exactly. The memory-based model, which is a locally weighted regression (LWR), predicts the expected outcome for a motion and provides gradient information for optimizing the motion. Results are compared against bootstrapping a direct optimization (DO) on a mathematical problem. Additionally, the method has been implemented to learn voltage profiles with the lowest peak current for starting a motor. This method shows practical accuracy and scalability. PMID- 26502430 TI - Sound Source Localization for HRI Using FOC-Based Time Difference Feature and Spatial Grid Matching. AB - In human-robot interaction (HRI), speech sound source localization (SSL) is a convenient and efficient way to obtain the relative position between a speaker and a robot. However, implementing a SSL system based on TDOA method encounters many problems, such as noise of real environments, the solution of nonlinear equations, switch between far field and near field. In this paper, fourth-order cumulant spectrum is derived, based on which a time delay estimation (TDE) algorithm that is available for speech signal and immune to spatially correlated Gaussian noise is proposed. Furthermore, time difference feature of sound source and its spatial distribution are analyzed, and a spatial grid matching (SGM) algorithm is proposed for localization step, which handles some problems that geometric positioning method faces effectively. Valid feature detection algorithm and a decision tree method are also suggested to improve localization performance and reduce computational complexity. Experiments are carried out in real environments on a mobile robot platform, in which thousands of sets of speech data with noise collected by four microphones are tested in 3D space. The effectiveness of our TDE method and SGM algorithm is verified. PMID- 26502431 TI - Direct Adaptive Neural Control for a Class of Uncertain Nonaffine Nonlinear Systems Based on Disturbance Observer. AB - In this paper, the direct adaptive neural control is proposed for a class of uncertain nonaffine nonlinear systems with unknown nonsymmetric input saturation. Based on the implicit function theorem and mean value theorem, both state feedback and output feedback direct adaptive controls are developed using neural networks (NNs) and a disturbance observer. A compounded disturbance is defined to take into account of the effect of the unknown external disturbance, the unknown nonsymmetric input saturation, and the approximation error of NN. Then, a disturbance observer is developed to estimate the unknown compounded disturbance, and it is established that the estimate error converges to a compact set if appropriate observer design parameters are chosen. Both state feedback and output feedback direct adaptive controls can guarantee semiglobal uniform boundedness of the closed-loop system signals as rigorously proved by Lyapunov analysis. Numerical simulation results are presented to illustrate the effectiveness of the proposed direct adaptive neural control techniques. PMID- 26502432 TI - Inverse Dynamics for Action Recognition. AB - Pose-based approaches for human action recognition are attractive owing to their accurate use of human motion information. Traditionally, such approaches used kinematic features for classification. However, in addition to having high dimensions and a small interclass variation, kinematic features do not consider the interaction of the environment on human motion. In this paper, we propose a method for action recognition using dynamic features, derived by applying inverse dynamics to a physics-based representation of the human body. The physics-based model is articulated and actuated with muscles and consists of joints with variable stiffness. Dynamic features under consideration include the torques from the knee and hip joints of both legs and, implicitly, gravity, ground reaction forces, and the pose of the remaining body parts. These features are more discriminative than kinematic features, resulting in a low-dimensional representation for human actions, which preserves much of the information of the original high-dimensional pose. This low-dimensional feature achieves good classification performance even with a relatively small training data set in a simple classification framework such as a hidden Markov model. The effectiveness of the proposed method is demonstrated through experiments on the Carnegie Mellon University motion capture data set and Osaka University Kinect action data set with various actions. PMID- 26502433 TI - Tracking Control of Mobile Robots Localized via Chained Fusion of Discrete and Continuous Epipolar Geometry, IMU and Odometry. AB - This paper presents a novel navigation and control system for autonomous mobile robots that includes path planning, localization, and control. A unique vision based pose and velocity estimation scheme utilizing both the continuous and discrete forms of the Euclidean homography matrix is fused with inertial and optical encoder measurements to estimate the pose, orientation, and velocity of the robot and ensure accurate localization and control signals. A depth estimation system is integrated in order to overcome the loss of scale inherent in vision-based estimation. A path following control system is introduced that is capable of guiding the robot along a designated curve. Stability analysis is provided for the control system and experimental results are presented that prove the combined localization and control system performs with high accuracy. PMID- 26502434 TI - Induced l2 filtering of fuzzy stochastic systems with time-varying delays. AB - This paper is concerned with the problem of induced l2 filter design for a class of discrete-time Takagi-Sugeno fuzzy Ito stochastic systems with time-varying delays. Attention is focused on the design of the desired filter to guarantee an induced l2 performance for the filtering error system. A new comparison model is proposed by employing a new approximation for the time-varying delay state, and then, sufficient conditions for the obtained filtering error system are derived by this comparison model. A desired filter is constructed by solving a convex optimization problem, which can be efficiently solved by standard numerical algorithms. Finally, simulation examples are provided to illustrate the effectiveness of the proposed approaches. PMID- 26502435 TI - Efficient Semisupervised MEDLINE Document Clustering With MeSH-Semantic and Global-Content Constraints. AB - For clustering biomedical documents, we can consider three different types of information: the local-content (LC) information from documents, the global content (GC) information from the whole MEDLINE collections, and the medical subject heading (MeSH)-semantic (MS) information. Previous methods for clustering biomedical documents are not necessarily effective for integrating different types of information, by which only one or two types of information have been used. Recently, the performance of MEDLINE document clustering has been enhanced by linearly combining both the LC and MS information. However, the simple linear combination could be ineffective because of the limitation of the representation space for combining different types of information (similarities) with different reliability. To overcome the limitation, we propose a new semisupervised spectral clustering method, i.e., SSNCut, for clustering over the LC similarities, with two types of constraints: must-link (ML) constraints on document pairs with high MS (or GC) similarities and cannot-link (CL) constraints on those with low similarities. We empirically demonstrate the performance of SSNCut on MEDLINE document clustering, by using 100 data sets of MEDLINE records. Experimental results show that SSNCut outperformed a linear combination method and several well-known semisupervised clustering methods, being statistically significant. Furthermore, the performance of SSNCut with constraints from both MS and GC similarities outperformed that from only one type of similarities. Another interesting finding was that ML constraints more effectively worked than CL constraints, since CL constraints include around 10% incorrect ones, whereas this number was only 1% for ML constraints. PMID- 26502436 TI - An Uncertainty Measure for Incomplete Decision Tables and Its Applications. AB - Uncertainty measures can supply new viewpoints for analyzing data. They can help us in disclosing the substantive characteristics of data. The uncertainty measurement issue is also a key topic in the rough-set theory. Although there are some measures to evaluate the uncertainty for complete decision systems (also called decision tables), they cannot be trivially transplanted into incomplete decision systems. There are relatively few studies on uncertainty measurement in incomplete decision systems. In this paper, we propose a new form of conditional entropy, which can be used to measure the uncertainty in incomplete decision systems. Some important properties of the conditional entropy are obtained. In particular, two validity theorems guarantee that the proposed conditional entropy can be used as a reasonable uncertainty measure for incomplete decision systems. Experiments on some real-life data sets are conducted to test and verify the validity of the proposed measure. Applications of the proposed uncertainty measure in ranking attributes and feature selection are also studied with experiments. PMID- 26502437 TI - Robotic Emotional Expression Generation Based on Mood Transition and Personality Model. AB - This paper presents a method of mood transition design of a robot for autonomous emotional interaction with humans. A 2-D emotional model is proposed to combine robot emotion, mood, and personality in order to generate emotional expressions. In this design, the robot personality is programmed by adjusting the factors of the five factor model proposed by psychologists. From Big Five personality traits, the influence factors of robot mood transition are determined. Furthermore, a method to fuse basic robotic emotional behaviors is proposed in order to manifest robotic emotional states via continuous facial expressions. An artificial face on a screen is a way to provide a robot with a humanlike appearance, which might be useful for human-robot interaction. An artificial face simulator has been implemented to show the effectiveness of the proposed methods. Questionnaire surveys have been carried out to evaluate the effectiveness of the proposed method by observing robotic responses to a user's emotional expressions. Preliminary experimental results on a robotic head show that the proposed mood state transition scheme appropriately responds to a user's emotional changes in a continuous manner. PMID- 26502438 TI - Autofocus of Iris Patterns Using a Triangle Aperture. AB - This paper shows that, by simply adding a triangle aperture (TA) in front of a camera lens, iris autofocus can be easily achieved. Through the TA, the corneal reflection of a light source forms a triangle glint on the image plane. The size and orientation of the glint can be used to infer the amount and the direction of the focus adjustment. A gradient-descent autofocus control law is proposed for uncalibrated lenses. Results from theoretical analysis and real experiments show that the proposed method is more efficient and accurate than the conventional circular aperture approach. PMID- 26502439 TI - Many Thanks! PMID- 26502440 TI - Ulnar Collateral Ligament and Elbow Adaptations in High School Baseball Pitchers. AB - BACKGROUND: Baseball pitchers have adaptive changes in the soft tissues of the throwing elbow. HYPOTHESIS: High school baseball pitchers would show adaptive changes in the ulnar collateral ligament (UCL), such as calcifications and hypoechoic foci, thickening, and increased ulnohumeral joint laxity, on dynamic ultrasound (DUS). STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: Twenty-two asymptomatic high school pitchers, designated as their primary position by their coach, underwent DUS and physical examination of the throwing and nonthrowing elbows prior to the start of the season. UCL substance consistency and thickness, ulnohumeral joint space widening, and soft tissue elbow structures were evaluated. RESULTS: The mean age of the cohort was 16.9 years. Calcifications of the UCL were similar, being present in 7 of 22 (32%) throwing elbows versus 8 of 22 (36%) nonthrowing elbows (P = 0.11). UCL hypoechoic foci also were similar between elbows: 2 of 22 (9%) throwing elbows versus 0 of 22 nonthrowing elbows (P = 0.11). UCL thickness was also found to be similar in both elbows (throwing arm, 6.54 mm vs nonthrowing, 6.71 mm; P = 0.48). Ulnohumeral joint laxity unloaded (throwing arm, 3.13 mm vs nonthrowing, 3.17 mm; P = 0.835) and loaded (throwing arm, 3.87 mm vs nonthrowing arm, 4.11 mm; P = 0.30) was similar between elbows. Throwing elbows showed posteromedial olecranon spurring in 36%, effusions in 27%, and synovitis in 9%. CONCLUSION: High school pitchers show limited adaptive changes in the elbow, including UCL calcifications, hypoechoic foci, posteromedial olecranon spurring, and effusions. However, these changes are similar to those seen in the nonthrowing elbow, and these younger athletes lack findings seen in professional and collegiate pitchers such as UCL thickening and increased ulnohumeral joint space laxity. CLINICAL RELEVANCE: Preseason ultrasound examination of the high school pitching elbow lacks the adaptive changes to the elbow as seen in professional pitchers. These changes likely occur later in a pitcher's career. PMID- 26502441 TI - The Development of Humeral Retrotorsion and Its Relationship to Throwing Sports. AB - CONTEXT: Several investigations have noted that throwing athletes exhibit a more posteriorly oriented humeral head (humeral retrotorsion) in the dominant arm. This asymmetry is believed to represent an adaptive response to the stress of throwing that occurs during childhood. The significance of this alteration and factors that affect its development are currently not clear. EVIDENCE ACQUISITION: Basic science, research studies, and review articles were searched through PubMed with search terms including humeral torsion, humeral retrotorsion, and with 1 of the following: pediatric, adult, baseball, pitching, shoulder, and range of motion. The references from each article were reviewed for further inclusion. This review included articles through March 2015. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: The throwing motion creates stressors that result in bony adaptations that occur while skeletally immature. These osseous changes likely contribute to the observed shift in the arc of rotational range of motion noted in throwing athletes and may play a protective role against injury. However, too much or too little retrotorsion may predispose the shoulder to injury. The degree of "optimal" humeral retrotorsion and factors that influence its development are not fully understood. CONCLUSION: Evidence supports the assertion that the throwing motion creates stressors that alter bony anatomy while young. It is important to determine what specific factors affect this adaptation and its relationship to injury. PMID- 26502442 TI - Prospective Player-Reported Injuries in Female Youth Fast-Pitch Softball Players. AB - BACKGROUND: There is a scarcity of literature evaluating injuries in youth fast pitch softball players. PURPOSE: To perform a descriptive analysis of player reported injuries in youth fast-pitch softball position players and pitchers during a single select-level season. STUDY DESIGN: Prospective observation cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: Ninety-eight athletes (48 pitchers, 50 position players) were followed for a single select fast-pitch softball season. Study participants completed web-based surveys every 3 weeks reporting injuries related to participation in fast-pitch softball. Injury was defined as pain causing cessation of participation in the current game or practice that prevents the player's return to that session or any pain that causes cessation of a player's customary participation on the day after the day of onset. RESULTS: The median age of the study participants was 14 years (range, 9-18 years). There were 49 reported injuries in 98 athletes. The average age was 13 years for those not injured and 14 years for those who were injured (P < 0.02). There were 31 injuries that were not related to pitching: 19 occurred in position players and 12 occurred in pitchers; 70% of these injuries were to the lower extremity. The proportion of injuries not related to pitching was significantly greater than the proportion of injuries related to pitching (P < 0.02). Eighteen injuries among the 48 pitchers (38%) were directly attributed to pitching. Among the 18 pitching injuries, 11 (61%) involved the shoulder. The majority (78%) of injuries related to pitching occurred in the first 6 weeks of the season. CONCLUSION: There was a high incidence of injury in this prospective cohort of youth select-level fast pitch softball players. Better off-season and preseason conditioning may be a key factor for reducing pitching injuries. CLINICAL RELEVANCE: Recognition of injury patterns in fast-pitch softball players is critical to developing strategies to keep these athletes competing safely. PMID- 26502443 TI - A Comparison of Women's Collegiate and Girls' High School Volleyball Injury Data Collected Prospectively Over a 4-Year Period. AB - BACKGROUND: There is a relative paucity of research examining the sport-specific injury epidemiology of high school and collegiate volleyball athletes. Moreover, differences in study methodology frequently limit our ability to compare and contrast injury data collected from selected populations. HYPOTHESIS: There are differences between the injury patterns characteristic of high school and collegiate female volleyball athletes. STUDY DESIGN: Retrospective clinical review. LEVEL OF EVIDENCE: Level 3. METHODS: We statistically analyzed injury incidence and outcome data collected over a 4-year interval (2005-2006 to 2008 2009) by 2 similar injury surveillance systems, the National Collegiate Athletic Association's Injury Surveillance System (NCAA ISS) and the High School Reporting Injuries Online (HS RIO). We compared diagnoses, anatomic distribution of injuries, mechanisms of injury, and time lost from training or competition between high school and collegiate volleyball athletes. RESULTS: The overall volleyball-related injury rate was significantly greater among collegiate athletes than among high school athletes during both competition (injury rate ratio, 2.9; 95% CI, 2.5-3.4) and practice (injury rate ratio, 3.5; 95% CI, 3.1 3.9). Collegiate athletes had a higher rate of ankle sprain, knee injury, and shoulder injury. Concussions represented a relatively high percentage of injuries in both populations (5.0% of total NCAA ISS injuries vs 4.8% of total HS RIO injuries, respectively). CONCLUSION: The data suggest that although similar, there were distinct differences between the injury patterns of the 2 populations. Compared with high school volleyball players, collegiate athletes have a higher rate of acute time loss injury as well as overuse time loss injury (particularly patellar tendinosis). Concussions represented a significant and worrisome component of the injury pattern for both study populations. CLINICAL RELEVANCE: The injury data suggest that important differences exist in the injury patterns of female high school compared with collegiate volleyball athletes. Consideration of the specific injury patterns may be helpful in future prevention efforts. PMID- 26502444 TI - Ulnar Collateral Ligament Reconstruction: Anatomy, Indications, Techniques, and Outcomes. AB - CONTEXT: Ulnar collateral ligament (UCL) injuries lead to pain and loss of performance in the thrower's elbow. Ulnar collateral ligament reconstruction (UCLR) is a reliable treatment option for the symptomatic, deficient UCL. Injury to the UCL usually occurs because of chronic accumulation of microtrauma, although acute ruptures occur and an acute-on-chronic presentation is also common. EVIDENCE ACQUISITION: Computerized databases, references from pertinent articles, and research institutions were searched for all studies using the search terms ulnar collateral ligament from 1970 until 2015. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 5. RESULTS: All studies reporting outcomes for UCLR are level 4. Most modern fixation methodologies appear to be biomechanically and clinically equivalent. Viable graft choices include ipsilateral palmaris longus tendon autograft, gracilis or semitendinosus autograft, and allograft. Clinical studies report excellent outcomes of UCLR for both recreational and elite level athletes with regard to return to sport and postoperative performance. Complications, although rare, include graft rerupture or attenuation, ulnar nerve symptoms, stiffness, pain, and/or weakness leading to decreased performance. CONCLUSION: Injuries to the UCL have become commonplace among pitchers. Nonoperative treatment should be attempted, but the limited studies have not shown promising results. Operative treatment can be performed with several techniques, with retrospective studies showing promising results. Complications include ulnar neuropathy as well as failure to return to sport. Detailed preoperative planning, meticulous surgical technique, and a comprehensive rehabilitation program are essential components to achieving a satisfactory result. PMID- 26502445 TI - Current Concepts in Hip Preservation Surgery: Part I. AB - CONTEXT: An evolution in conceptual understanding, coupled with technical innovations, has enabled hip preservation surgeons to address complex pathomorphologies about the hip joint to reduce pain, optimize function, and potentially increase the longevity of the native hip joint. Technical aspects of hip preservation surgeries are diverse and range from isolated arthroscopic or open procedures to hybrid procedures that combine the advantages of arthroscopy with open surgical dislocation, pelvic and/or proximal femoral osteotomy, and biologic treatments for cartilage restoration. EVIDENCE ACQUISITION: PubMed and CINAHL databases were searched to identify relevant scientific and review articles from January 1920 to January 2015 using the search terms hip preservation, labrum, surgical dislocation, femoroacetabular impingement, peri acetabular osteotomy, and rotational osteotomy. Reference lists of included articles were reviewed to locate additional references of interest. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Thoughtful individualized surgical procedures are available to optimize the femoroacetabular joint in the presence of hip dysfunction. CONCLUSION: A comprehensive understanding of the relationship between femoral and pelvic orientation, morphology, and the development of intra-articular abnormalities is necessary to formulate a patient specific approach to treatment with potential for a successful long-term result. PMID- 26502446 TI - Exercise in Pregnancy: A Clinical Review. AB - CONTEXT: Health professionals who care for pregnant women should discuss potential health benefits and harms of exercise. Although most pregnant women do not meet minimal exercise recommendations, there are a growing number of physically active women who wish to continue training throughout pregnancy. EVIDENCE ACQUISITION: A search of the Web of Science database of articles and reviews available in English through 2014. The search terms exercise pregnancy, strenuous exercise pregnancy, and vigorous exercise pregnancy were used. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: With proper attention to risk stratification and surveillance, exercise is safe for the mother and fetus. Benefits of exercise in pregnancy include reduction in Cesarean section rates, appropriate maternal and fetal weight gain, and managing gestational diabetes. Exercise as a means of preventing gestational diabetes, preeclampsia, or perinatal depression cannot be reliably supported. Overall, the current evidence suffers from a lack of rigorous study design and compliance with physical activity interventions. CONCLUSION: Research thus far has been unable to consistently demonstrate proposed benefits of exercise in pregnancy, such as preventing gestational diabetes, preeclampsia, or perinatal depression. However, moderate- and high-intensity exercise in normal pregnancies is safe for the developing fetus and clearly has several important benefits. Thus, exercise should be encouraged according to the woman's preconception physical activity level. PMID- 26502447 TI - Evaluation of the Functional Movement Screen as an Injury Prediction Tool Among Active Adult Populations: A Systematic Review and Meta-analysis. AB - CONTEXT: The Functional Movement Screen (FMS) is an assessment tool for quality of human movement. Research reports a significant difference between FMS scores of subjects who later experienced injury and those who remain uninjured. OBJECTIVE: To systematically review literature related to predictive validity of the FMS. From the aggregated data, a meta-analysis was conducted to determine the prognostic accuracy of the FMS. DATA SOURCES: PubMed, Ebscohost, Google Scholar, and the Cochrane Review databases were searched between 1998 and February 20, 2014. STUDY SELECTION: Identified studies were reviewed in full detail to validate inclusion criteria. Seven of the 11 identified studies were included. Articles were reviewed for inclusion criteria, then bias assessment and critical analysis were conducted. STUDY DESIGN: Systematic review and meta-analysis. LEVEL OF EVIDENCE: Level 3. DATA EXTRACTION: Extracted data included the following: study type, methodology, study subjects, number of subjects, injury classification definition, FMS cut score, sensitivity, specificity, odds ratios, likelihood ratios (LR), predictive values, receiver operator characteristic (ROC) analysis, and area under the curve (AUC). RESULTS: Overall bias for the included 7 studies was low with respect to patient selection. Quality assessment scored 1 study 5 of a possible 7, 2 studies were scored 3 of 7, and 4 studies were scored 2 of 7. The meta-analysis indicated the FMS was more specific (85.7%) than sensitive (24.7%), with a positive predictive value of 42.8% and a negative predictive value of 72.5%. The area under the curve was 0.587 (LR+, 1.7; LR-, 0.87; 95% CI, 0.6-6.1) and the effect size was 0.68. CONCLUSION: Based on analysis of the current literature, findings do not support the predictive validity of the FMS. Methodological and statistical limitations identified threaten the ability of the research to determine the predictive validity of FMS. PMID- 26502448 TI - Rehabilitation Charges Associated With Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Pre- and postoperative rehabilitation are important to the management of patients with anterior cruciate ligament (ACL) reconstruction, but little attention has been given to the costs. This study evaluated the pre- and postoperative rehabilitation charges in patients with ACL reconstruction in the United States. HYPOTHESIS: Patients receive preoperative rehabilitation less commonly than postoperative rehabilitation. STUDY DESIGN: Retrospective database study. LEVEL OF EVIDENCE: Level 4. METHODS: Using the PearlDiver database, we identified patients undergoing ACL reconstruction from 2007 through 2011 using Current Procedural Terminology codes. The associated rehabilitation charges billed to insurance providers for 90 days preoperatively and 6 months postoperatively were categorized as physical therapy or as durable medical equipment (DME). The charges were examined by year and geographic region and represented as per-patient average charges (PPACs). RESULTS: A total of 92,179 patients were identified in the study period. The PPAC for rehabilitation was $241 during the 90-day preoperative period and $1876 for the 6-month postoperative period. Patients averaged 2 preoperative sessions for physical therapy, with 44% of patients receiving preoperative rehabilitation in contrast with an average of 17 postoperative sessions per patient in 93% of patients. Rehabilitation charges were greater postoperatively than preoperatively (P < 0.05). Preoperatively, 24% of patients received a DME, while 35% received a DME postoperatively. Preoperative rehabilitation PPACs were highest in the Northeast, followed by Midwest, South, and West (P < 0.05). There were no significant differences in postoperative rehabilitation PPACs for geographic region (P = 0.43). CONCLUSION: Preoperative rehabilitation charges were lower than postoperative charges. A patient undergoing ACL reconstruction typically received 9 times more sessions of postoperative physical therapy than preoperative. CLINICAL RELEVANCE: This study found that preoperative supervised rehabilitation for patients with ACL reconstruction was infrequent across the United States. PMID- 26502449 TI - On-Ice Functional Assessment of an Elite Ice Hockey Goaltender After Treatment for Femoroacetabular Impingement. AB - BACKGROUND: Femoroacetabular impingement (FAI) is a major cause of performance inhibition in elite-level athletes. The condition is characterized by pain, osseous abnormalities such as an increased alpha angle, and decreased range of motion at the affected hip joint. Arthroscopic surgical decompression is useful in reshaping the joint to alleviate symptoms. Functional kinematic outcomes of sport-specific movements after surgery, however, are presently unknown. HYPOTHESIS: The ability of an ice hockey goaltender to execute sport-specific movements would improve after arthroscopic surgery. STUDY DESIGN: Clinical research. LEVEL OF EVIDENCE: Level 5. METHODS: An ice hockey goaltender was evaluated after arthroscopic correction of FAI on the symptomatic hip. Passive range of motion and radiographic parameters were assessed from a computed tomography-derived 3-dimensional model. An on-ice motion capture system was also used to determine peak femoral shock and concurrent hip joint postures during the butterfly and braking movements. RESULTS: Maximum alpha angles were 47 degrees in the surgical and 61 degrees in the nonsurgical hip. Internal rotation range of motion was, on average, 23 degrees greater in the surgically corrected hip compared with contralateral. Peak shock was lower in the surgical hip by 1.39 g and 0.86 g during butterfly and braking, respectively. At peak shock, the surgical hip demonstrated increased flexion, adduction, and internal rotation for both tasks (butterfly, 6.1 degrees , 12.3 degrees , and 30.8 degrees ; braking, 14.8 degrees , 19.2 degrees , and 41.4 degrees ). CONCLUSION: On-ice motion capture revealed performance differences between hips after arthroscopic surgery in a hockey goaltender. Range of motion and the patient's subjective assessment of hip function were improved in the surgical hip. While presenting as asymptomatic, it was discovered that the contralateral hip displayed measurements consistent with FAI. Therefore, consideration of preemptive treatment in a presently painless hip may be deemed beneficial for young athletes seeking a long career in sport, and future work is needed to determine the costs and benefits of such an approach. CLINICAL RELEVANCE: Surgical treatment of symptomatic FAI can achieve pain relief and improved kinematics of the hip joint with athletic activities. Additional studies are necessary to determine whether improved kinematics enhance the longevity of the native hip and alter the progression of osteoarthritic changes in those with asymptomatic FAI deformity. PMID- 26502450 TI - Traumatic Tear of the Latissimus Dorsi Myotendinous Junction: Case Report of a CrossFit-Related Injury. AB - A case of a latissimus dorsi myotendinous junction strain in an avid CrossFit athlete is presented. The patient developed acute onset right axillary burning and swelling and subsequent palpable pop with weakness while performing a "muscle up." Magnetic resonance imaging examination demonstrated a high-grade tear of the right latissimus dorsi myotendinous junction approximately 9 cm proximal to its intact humeral insertion. There were no other injuries to the adjacent shoulder girdle structures. Isolated strain of the latissimus dorsi myotendinous junction is a very rare injury with a scarcity of information available regarding its imaging appearance and preferred treatment. This patient was treated conservatively and was able to resume active CrossFit training within 3 months. At 6 months postinjury, he had only a mild residual functional deficit compared with his preinjury level. PMID- 26502453 TI - Corrigendum. PMID- 26502454 TI - Comparison of Estimated and Measured Muscle Activity During Inclined Walking. AB - While inclined walking is a frequent daily activity, muscle forces during this activity have rarely been examined. Musculoskeletal models are commonly used to estimate internal forces in healthy populations, but these require a priori validation. The aim of this study was to compare estimated muscle activity using a musculoskeletal model with measured EMG data during inclined walking. Ten healthy male participants walked at different inclinations of 0 degrees , +/- 6 degrees , +/- 12 degrees , and +/- 18 degrees on a ramp equipped with 2 force plates. Kinematics, kinetics, and muscle activity of the musculus (m.) biceps femoris, m. rectus femoris, m. vastus lateralis, m. tibialis anterior, and m. gastrocnemius lateralis were recorded. Agreement between estimated and measured muscle activity was determined via correlation coefficients, mean absolute errors, and trend analysis. Correlation coefficients between estimated and measured muscle activity for approximately 69% of the conditions were above 0.7. Mean absolute errors were rather high with only approximately 38% being <= 30%. Trend analysis revealed similar estimated and measured muscle activities for all muscles and tasks (uphill and downhill walking), except m. tibialis anterior during uphill walking. This model can be used for further analysis in similar groups of participants. PMID- 26502455 TI - A Global Gait Asymmetry Index. AB - High levels of gait asymmetry are associated with many pathologies. Our long-term goal is to improve gait symmetry through real-time biofeedback of a symmetry index. Symmetry is often reported as a single metric or a collective signature of multiple discrete measures. While this is useful for assessment, incorporating multiple feedback metrics presents too much information for most subjects to use as visual feedback for gait retraining. The aim of this article was to develop a global gait asymmetry (GGA) score that could be used as a biofeedback metric for gait retraining and to test the effectiveness of the GGA for classifying artificially-induced asymmetry. Eighteen participants (11 males; age 26.9 y [SD = 7.7]; height 1.8 m [SD = 0.1]; body mass 72.7 kg [SD = 8.9]) walked on a treadmill in 3 symmetry conditions, induced by wearing custom-made sandals: a symmetric condition (identical sandals) and 2 asymmetric conditions (different sandals). The GGA score was calculated, based on several joint angles, and compared between conditions. Significant differences were found among all conditions (P < .001), meaning that the GGA score is sensitive to different levels of asymmetry, and may be useful for rehabilitation and assessment. PMID- 26502456 TI - Orthotic Heel Wedges Do Not Alter Hindfoot Kinematics and Achilles Tendon Force During Level and Inclined Walking in Healthy Individuals. AB - Conservative treatments such as in-shoe orthotic heel wedges to treat musculoskeletal injuries are not new. However, weak evidence supporting their use in the management of Achilles tendonitis suggests the mechanism by which these heel wedges works remains poorly understood. It was the aim of this study to test the underlying hypothesis that heel wedges can reduce Achilles tendon load. A musculoskeletal modeling approach was used to quantify changes in lower limb mechanics when walking due to the introduction of 12-mm orthotic heel wedges. Nineteen healthy volunteers walked on an inclinable walkway while optical motion, force plate, and plantar pressure data were recorded. Walking with heel wedges increased ankle dorsiflexion moments and reduced plantar flexion moments; this resulted in increased peak ankle dorsiflexor muscle forces during early stance and reduced tibialis posterior and toe flexor muscle forces during late stance. Heel wedges did not reduce overall Achilles tendon force during any walking condition, but did redistribute load from the medial to lateral triceps surae during inclined walking. These results add to the body of clinical evidence confirming that heel wedges do not reduce Achilles tendon load and our findings provide an explanation as to why this may be the case. PMID- 26502457 TI - The Role of Physical Activity and Physical Function on the Risk of Falls in Older Mexican Americans. AB - We investigated the relationship between physical activity and physical function on the risk of falls over time in a cohort of Mexican-American adults aged 75 and older from the Hispanic Established Population for the Epidemiologic Study of the Elderly (H-EPESE). Participants were divided into four groups according to their level of physical activity and physical function: low physical activity and low physical function (n = 453); low physical activity and high physical function (n = 54); high physical activity and low physical function (n = 307); and high physical activity and high physical function (n = 197). Using generalized linear equation estimation, we showed that participants with high physical activity and low physical function had a greater fall risk over time, followed by the high physical activity and high physical function group. Participants seldom took part in activities that improve physical function. To prevent falls, modifications to physical activity should be made for older Mexican Americans. PMID- 26502458 TI - Acute Physical Exercise Affects Cognitive Functioning in Children With Cerebral Palsy. AB - Little is known about the effects of acute exercise on the cognitive functioning of children with cerebral palsy (CP). Selected cognitive functions were thus measured using a pediatric version of the Stroop test before and after maximal, locomotor based aerobic exercise in 16 independently ambulatory children (8 children with CP), 6-15 years old. Intense exercise had: 1) a significant, large, positive effect on reaction time (RT) for the CP group (preexercise: 892 +/- 56.5 ms vs. postexercise: 798 +/- 45.6 ms, p < .002, d = 1.87) with a trend for a similar but smaller response for the typically developing (TD) group (preexercise: 855 +/- 56.5 ms vs. postexercise: 822 +/- 45.6 ms, p < .08, d = 0.59), and 2) a significant, medium, negative effect on the interference effect for the CP group (preexercise: 4.5 +/- 2.5%RT vs. postexercise: 13 +/- 2.9%RT, p < .04, d = 0.77) with no significant effect for the TD group (preexercise: 7.2 +/ 2.5%RT vs. postexercise: 6.9 +/- 2.9%RT, p > .4, d = 0.03). Response accuracy was high in both groups pre- and postexercise (>96%). In conclusion, intense exercise impacts cognitive functioning in children with CP, both by increasing processing speed and decreasing executive function. PMID- 26502459 TI - Associations of Cognitive Function Scores with Carbon Dioxide, Ventilation, and Volatile Organic Compound Exposures in Office Workers: A Controlled Exposure Study of Green and Conventional Office Environments. AB - BACKGROUND: The indoor built environment plays a critical role in our overall well-being because of both the amount of time we spend indoors (~90%) and the ability of buildings to positively or negatively influence our health. The advent of sustainable design or green building strategies reinvigorated questions regarding the specific factors in buildings that lead to optimized conditions for health and productivity. OBJECTIVE: We simulated indoor environmental quality (IEQ) conditions in "Green" and "Conventional" buildings and evaluated the impacts on an objective measure of human performance: higher-order cognitive function. METHODS: Twenty-four participants spent 6 full work days (0900-1700 hours) in an environmentally controlled office space, blinded to test conditions. On different days, they were exposed to IEQ conditions representative of Conventional [high concentrations of volatile organic compounds (VOCs)] and Green (low concentrations of VOCs) office buildings in the United States. Additional conditions simulated a Green building with a high outdoor air ventilation rate (labeled Green+) and artificially elevated carbon dioxide (CO2) levels independent of ventilation. RESULTS: On average, cognitive scores were 61% higher on the Green building day and 101% higher on the two Green+ building days than on the Conventional building day (p < 0.0001). VOCs and CO2 were independently associated with cognitive scores. CONCLUSIONS: Cognitive function scores were significantly better under Green+ building conditions than in the Conventional building conditions for all nine functional domains. These findings have wide ranging implications because this study was designed to reflect conditions that are commonly encountered every day in many indoor environments. CITATION: Allen JG, MacNaughton P, Satish U, Santanam S, Vallarino J, Spengler JD. 2016. Associations of cognitive function scores with carbon dioxide, ventilation, and volatile organic compound exposures in office workers: a controlled exposure study of green and conventional office environments. Environ Health Perspect 124:805-812; http://dx.doi.org/10.1289/ehp.1510037. PMID- 26502460 TI - Epidemiology of angioedema without wheals in an allergy and immunology center. AB - We describe the diagnostic epidemiology, the clinical course, the family history and the response to treatment of patients with angioedema without wheals (AWW) at an Allergy and Immunology Clinical Center. We reviewed the case records of all patients at our office from January 1997 to April 2013. We recorded sex, age, age at onset of symptoms, family history of angioedema, number of visits to the office, type of angioedema, and response to treatment from those patients with angioedema without wheals. We classified angioedema according to its pathophysiology. We also describe those patients with angioedema mimics. From a total of 17,823 new patients, 303 had a presumptive diagnosis of angioedema without wheals. Twenty-three patients had an angioedema mimic. Forty percent were male and 60% were female. Average age at first visit was 40.6. Average number of visits was 2.4. Fifty-seven patients referred a family history. We attributed idiopathic angioedema to 55.7% of patients, 24.3% were drug related, 15.7% were due to C1 inhibitor deficiency, 2.1% were drug related+idiopathic angioedema, 1.4% were type III and 0.7% had exercise-induced angioedema. Ninety six percent of 53 evaluable idiopathic angioedema patients referred a benefit with anti histamine therapy. AWW was a rare cause of consultation. Most of our patients had anti H1 responsive idiopathic angioedema and none had allergic angioedema. Women cases prevailed over men's. Family history and average age of onset of symptoms were different among the different types of angioedema. PMID- 26502461 TI - Medium-term glycemic control in diabetics before coronary bypass surgery. AB - The aim of this study was to determine the association between preoperative medium-term (60-90 days) glycemic control, as reflected by glycosylated hemoglobin levels (HbA1c), and the incidence of major complications (mediastinitis, perioperative infarction, heart failure, stroke and kidney failure dialysis) and mortality in diabetic patients undergoing elective coronary artery by-pass graft surgery (CABG). This study suggests that aggressive glycemic control three months before surgery, achieving HbA1c=7% improvement results with less postoperative morbidity and mortality. PMID- 26502462 TI - [A survey on biomarkers and early diagnosis in Alzheimer's disease]. AB - Given the potential use of biomarkers in the diagnosis of Alzheimer's disease (AD) in early stages, new ethical and communication dilemmas appear in everyday clinical practice. The aim of this study was to know the opinion of health professionals (HP) and general public (GP) on the implementation of early diagnostic techniques in AD and the use of biomarkers for this purpose. A survey with multiple choice answers was elaborated in two versions: one for HP and the other for GP. Respondents were invited to participate through a system of mass mailing e-mail; e-mail addresses were collected from CEMIC database. A total of 1503 answers were analyzed: 807 HP and 696 GP. Most respondents, 84.7%, preferred the option of early diagnosis of AD even knowing the lack of curative treatment. Forty five percent of GP and 26.8% of HP replied that there is no ethical dilemma in the use of biomarkers and that no communication or ethical dilemma is generated to physicians when informing the diagnosis of the disease. The HP group showed more divergence in the views than the GP group. These results may indicate a change in the physician-patient relationship, showing the GP group with an active and supportive position towards the use of biomarkers for early diagnosis of AD. PMID- 26502463 TI - [Using descriptors during the implementation of Mini-CEX at pediatric residency]. AB - The Mini Clinical Evaluation Exercise (Mini-CEX) is an assessment tool, which emphasizes the educational value and is based on direct performance observation. The objective was to evaluate the reliability and feasibility of Mini-CEX using pediatric descriptors during its implementation in two pediatric residency programs. The design was observational, exploratory and feasibility in the use of this evaluation tool. Based on the original format, descriptors related to the pediatric consult for each Mini-CEX dimension's were agreed. Operators were trained in the use of this tool by means of descriptors as well as in debriefing strategies. Finally, there were two simultaneous and independent evaluations for each observation. ANALYSIS: a) Mini-CEX global and dimension score; b) Concordance between operators scores (mean differences and 95% CI); c) Non evaluable descriptors frequency; d) Duration and satisfaction in use. There were 80 observations in 40 pediatric consults. Overall score 7.5+/-0.9 (6.4+/-2 to 8.3+/-1.1 depending on dimension), with no significant differences between the two institutions. There was high agreement between observers (Mean, difference between 0.1 and 0.3, 95% CI -0.8 to 0.3). The frequency of non evaluable descriptors ranged 5-28 (9% to 51%) and it was not associated with the implementation stage. The average implementation time was 20 minutes, and satisfaction in use was high among both operators and residents. Mini-CEX tool using pediatric descriptors showed high reliability. The joint experience was satisfactory and simultaneously confirmed the value of debriefing. PMID- 26502464 TI - [Sensory neuronopathy. Its recognition and early treatment]. AB - Sensory neuronopathies or ganglionopathies, or dorsal root ganglion disorders, represent a subgroup of peripheral nervous system diseases, frequently associated with dysinmune or neoplastic disorders and with toxic agents. A degeneration of both central and peripheral sensory proyections is present. Patients typically show early ataxia, loss of deep tendon reflexes and positive sensory symptoms present both in proximal and distal sites of the body. We retrospectively studied 10 cases with a final diagnosis of sensory neuronopathy. Sensory neuropathy was the presenting symptom and the course was subacute in all cases. Paresthesias in upper limbs were a predominant manifestation (100%). Other manifestations included: hypoesthesia (10/10), gait ataxia (8/10), autonomic symptoms (3/10) and perioral paresthesias (3/10). Electrophysiology showed sensory axonal neuronal pattern, with normal motor responses. Final diagnosis was acquired sensory neuronopathy in all patients, associated with Sjogren's syndrome in 2, with lupus erythematosus in 1, with rheumatoid arthritis in 1, with a cancer in 2 (paraneoplastic) and idiopathic in 4. In paraneoplastic cases, the tumor was small cell lung cancer in 1 (with positive anti-Hu antibodies), and epidermoid lung cancer in the other. Eight patients were treated with immunotherapy, high dose intravenous methylprednisolone and/or intravenous immunoglobulin; with poor response in 4 cases, neurologic improvement in 5, and without any change in 1 patient. The present work shows the typical clinical and electrophysiological pattern of subacute sensory neuronopathy, and the relevance of early treatment. PMID- 26502465 TI - [Low grade parosteal osteosarcoma. Clinical and oncological outcomes]. AB - The objective of the study was to analyze a group of patients with low grade parosteal osteosarcoma treated with limb salvage surgery and reconstructed with bone allograft. A retrospective review from our oncologic data base between 1980 and 2010 was done and all patients with diagnosis of low grade parosteal osteosarcoma, treated with limb salvage surgery and reconstructed with allograft were included. Twenty-two patients were included for the analysis. The mean age was 32+/-11 years (10-59) y the mean follow-up 93+/-69 months (8-237). Ten year overall survival of the series was 91% (95% CI: 79-100). Four patients developed local recurrence, 2 of them histological classified after the resection dedifferentiated parosteal osteosarcoma. Two patients developed distant recurrence, being the lung the only site of metastasis. Ten year limb salvage reconstruction survival was 65% (95% CI: 44-86). Long term survival rate in low grade parosteal osteosarcoma is over 90%. Surgical resection wide margin should be the elective treatment and biological limb salvage reconstruction is a good alternative. PMID- 26502466 TI - [Successful treatment with fondaparinux in heparin-induced thrombocytopenia and thrombosis]. AB - Heparin induced thrombocytopenia (HIT) is an immune-mediated adverse reaction characterized by thrombocytopenia and paradoxical arterial or venous thrombosis, due to the formation IgG antibodies directed to a multimolecular complex of heparin-platelet factor 4 (PF4). Fondaparinux is a selective factor Xa inhibitor with little affinity for PF4 and thus less likely to induce an immune response, making fondaparinux a potentially useful drug for the treatment of HIT. Herein we report the case of a 73 years old woman with HIT associated with arterial and venous thrombosis that was successfully treated with fondaparinux, with normalization of the platelet countand without progression of thrombosis. PMID- 26502467 TI - [Endoscopic ultrasound-guided choledocho-duodenostomy in advanced pancreatic cancer with duodenal obstruction]. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is considered the first approach for biliary drainage. In cases of ERCP failure, patients are usually referred for percutaneous transhepatic biliary drainage or surgical biliary bypass. In the last decade, the indications of endoscopic ultrasound (EUS) in the management of patients with pancreatic cancer have increased, and numerous cases of EUS-guided biliary drainage have been reported in patients with failures during the ERCP. Our goal is to report a patient with locally advanced pancreatic cancer who presented with painless jaundice and cholestasis with biliary and duodenal obstruction. A EUS-guided choledochoduodenostomy was performed by placement of a self-expanding metal stent. PMID- 26502468 TI - [Thymic neuroendocrine carcinoma with Pompe's disease of the adult]. AB - Pompe disease (glycogenosis type II) is an inherited autosomal recessive lysosomal storage disease caused by a deficiency of acid alpha-glucosidase. Thymic neuroendocrine tumors, are primary thymic neoplasms with neuroendocrine differentiation that generally present as a mass within the anterior mediastinum. Both diseases are considered rare. To our knowledge the co-existence of Pompe disease and thymic neuroendocrine tumor in the same patient has not been previously reported. We could not find biological plausibility between both diseases. Further studies are needed to confirm the finding and to further increase our understanding of this association. Clinical data from epidemiological studies, case reports, case series and small formal open or controlled clinical trials may define both clinical plausibility and causality between the two conditions. PMID- 26502469 TI - [Rituximab and hypogammaglobulinemia]. AB - Rituximab, a chimeric monoclonal antibody against CD20, induces the depletion of B lymphocytes. It is used for the treatment of lymphoproliferative and autoimmune diseases. Antibody immunodeficiency associated to RTX treatment is a new motif for consultation to our service. We decided to study those patients that having been treated with RTX, consulted for hypogammaglobulinemia or recurrent infections between November 2010 and December 2014. We evaluated eight patients, seven female and one male. The average follow up time was 19.3+/-18.8 months, range 1 to 54, median 13. Three had a normal electrophoretic proteinogram before receiving RTX, three had hypogammaglobulinemia and in two data was not available. None of them had a quantitative determination of immunoglobulins before receiving RTX. Four received RTX as a treatment of non Hodking lymphoma, two as a treatment of chronic lymphocytic leukemia, one for immune thrombocytopenic purpura and other for microscopic polyangiitis. Six were diagnosed with hypogammaglobulinemia and one with combined IgM, IgA and IgG2 deficiency. Five presented infections, four of them with good response to intravenous immunoglobulin. RTX related antibody deficiency consultations are increasing. It is important to determine the immunoglobulin levels previously to RTX use in order to establish an etiologic relationship with RTX and a quick diagnosis of antibody deficiency. The substitutive treatment with gammaglobulin seems to be useful in patients with severe or recurrent infections. PMID- 26502470 TI - [POEMS syndrome. A report of four cases]. AB - Four cases of a rare paraneoplastic syndrome associated to a plasmatic cell disorder with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin lesions (POEMS) are here reported. The purpose of the communication is to warn of different forms of presentation of POEMS syndrome to decrease the time of diagnosis, because early treatment reduces sequels and improves quality of life in the long term, also to remark the importance of classifying the hematological disease for specific treatment. PMID- 26502472 TI - [Dyspnea in an old woman with multiple hepatic nodule images]. PMID- 26502471 TI - [Accidents with caterpillar Lonomia obliqua (Walker, 1855). An emerging problem]. AB - Lonomia obliqua (Walker, 1855) is a moth from the family Saturniidae, widely distributed in tropical rainforests of South America. In its larval stage (caterpillar) it is characterized by bristles that cover the animal's body. These structures are hard and branched spiny evaginations of the cuticle, underneath which a complex mixture of toxic molecules is stored. When spicules are brought into contact with the skin of people, toxins enter passively through the injury, causing not only local but also systemic poisoning (primarily hemorrhagic manifestations). When the whole animal is accidentally crushed, the insect's chitinous bristles are broken and the venomous secretions penetrate the human skin, reaching the blood circulation. Due to the numerous registered cases of erucism in Southern Brazil, the Butantan Institute has produced an antivenom able to neutralize the deleterious effects produced by contact with L. obliqua caterpillar bristles. In Argentina, these kinds of accidents are rare and restricted to the province of Misiones. Taking into account that to date there is no report in this country about clinical cases submitted to a specific treatment (antivenom), our aim is to communicate here six cases of Lonomia caterpillar induced bleeding syndrome that were treated in the Hospital SAMIC of Puerto Iguazu (Misiones, Argentina) during 2014 with the antilonomic serum produced in Brazil. It is worthy to note that all patients evolved favorably within the first few hours, and for this reason, the use of this antivenom is recommended to treat the cases of Lonomia erucism in Argentina. PMID- 26502473 TI - [Giant bladder stone]. PMID- 26502474 TI - [Hyperdense middle cerebral artery sign]. PMID- 26502475 TI - [Butterflies, quebracho fever and a naturalist]. PMID- 26502476 TI - [Faraday and "The Chemical History of a Candle". Six historical lectures (and without projector)]. PMID- 26502477 TI - [Symposium's syndrome (Iatrolalic's s., Iatrophonic's s.)]. PMID- 26502479 TI - Alternative temporal control systems for hypodermal cell differentiation in Caenorhabditis elegans. PMID- 26502478 TI - The pathophysiology of pulmonary hypertension in left heart disease. AB - Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure leading to right-sided heart failure and can arise from a wide range of etiologies. The most common cause of PH, termed Group 2 PH, is left-sided heart failure and is commonly known as pulmonary hypertension with left heart disease (PH-LHD). Importantly, while sharing many clinical features with pulmonary arterial hypertension (PAH), PH-LHD differs significantly at the cellular and physiological levels. These fundamental pathophysiological differences largely account for the poor response to PAH therapies experienced by PH-LHD patients. The relatively high prevalence of this disease, coupled with its unique features compared with PAH, signal the importance of an in-depth understanding of the mechanistic details of PH-LHD. The present review will focus on the current state of knowledge regarding the pathomechanisms of PH-LHD, highlighting work carried out both in human trials and in preclinical animal models. Adaptive processes at the alveolocapillary barrier and in the pulmonary circulation, including alterations in alveolar fluid transport, endothelial junctional integrity, and vasoactive mediator secretion will be discussed in detail, highlighting the aspects that impact the response to, and development of, novel therapeutics. PMID- 26502480 TI - Organ Donation and Transplantation in the Kingdom of Saudi Arabia 2014. PMID- 26502482 TI - Facing up to hospital-acquired infections. PMID- 26502481 TI - Buttonhole Cannulation: Current Prospects and Challenges. Preface. PMID- 26502483 TI - National infection prevention and control programmes: Endorsing quality of care. AB - Core components Health care-associated infections (HAIs) are a major cause of morbidity and mortality. In addition to pain and suffering, HAIs increase the cost of health care and generates indirect costs from loss of productivity for patients and society as a whole. Since 2005, the Pan American Health Organization has provided support to countries for the assessment of their capacities in infection prevention and control (IPC). More than 130 hospitals in 18 countries were found to have poor IPC programmes. However, in the midst of many competing health priorities, IPC programmes are not high on the agenda of ministries of health, and the sustainability of national programmes is not viewed as a key point in making health care systems more consistent and trustworthy. Comprehensive IPC programmes will enable countries to reduce the mobility, mortality and cost of HAIs and improve quality of care. This paper addresses the relevance of national infection prevention and control (NIPC) programmes in promoting, supporting and reinforcing IPC interventions at the level of hospitals. A strong commitment from national health authorities in support of national IPC programmes is crucial to obtaining a steady decrease of HAIs, lowering health costs due to HAIs and ensuring safer care. PMID- 26502484 TI - Provoking "Eureka" moments for effective infection control strategies. AB - Safety is now a fundamental principle of patient care and a critical component of quality management. Health care-associated infection prevention strategies need to be constantly revisited and updated to be effective. The "Geneva hand hygiene model" is a typical example of a breakthrough innovatory campaign that caught fire and went viral worldwide, thanks to its adoption by the World Health Organization (WHO) as the First Global Patient Safety Challenge. The campaign remains an inspiration for further innovation. To encourage new and disruptive technologies with the potential to improve patient safety through the successful implementation of the WHO multimodal strategy, the University of Geneva Hospitals/WHO Collaborating Centre on Patient Safety, together with the Aesculap Academy, have created a series of "Hand Hygiene Excellence Awards" and "Hand Hygiene Innovation Awards" worldwide. PMID- 26502485 TI - Planning strategies for nosocomial infection control. AB - According to the American Centers for Disease Control and Prevention, 99,000 deaths per year in the United States are caused or impacted on by multiple hospital-acquired infections (HAIs), which are roughly estimated to be around 1.7 million cases. In Europe, there are 25,000 deaths per year from the same cause, 17.000 of which are linked to nosocomial infections. Patient safety is a core issue in today's health care settings. There is a growing consensus, supported by scientific investigation, that the role of the built environment is central towards minimizing and controlling the level of such infections. The contribution of architectural solutions and planning choices becomes crucial at this stage. This paper outlines the most common measures to adopt at the architectural and planning level, to combat HAI, focusing on the most critical areas of the hospital: wards, intensive care units and operating theatres. PMID- 26502486 TI - How can emerging disinfection technologies gain a foothold in the current culture of hospitals? AB - In the United States, more than 90% of hospitals still use only the traditional "spray and wipe" disinfection methods initiated over a century ago to protect patients from their environment; international adoption of new methods is even lower. Innovative approaches like whole room disinfection find an inhospitable reception in spite of clearly superior reductions in health care-acquired infections. Much of the resistance is due to a lack of true accountability for patient safety in hospital organizations and to perverse incentive structures in historical reimbursement policies. But all of that may change in the coming years as hospitals and doctors become more responsible for the health outcomes of their patients. PMID- 26502487 TI - Nosocomial infections: Aligning strategy and action from mission to outcomes. AB - Outstanding health care institutions around the world lead, in effect, by setting an example and keeping hospital-acquired infections to a minimum. Behind the apparent simplicity of an indicator hides an enormous complexity. We believe that the difficulty in achieving seemingly simple benchmarks stems from the necessity to perform optimally at different levels of the organization consistently. This challenge can be summarized in a word: alignment. Institutional alignment starts with the mission and must be ubiquitous. Achieving the benchmark illustrates the elusive trait of institutional coherence. We will describe the dimensions and levels at our institution that influence our ability to strive for better indicators in the prevention of nosocomial infections, examine some of the difficulties and provide a few examples of success. PMID- 26502488 TI - The urgent need for infection control programmes in Indian health care. AB - The emergence of "superbugs" like carbapenem resistant Enterobactericiae with a NDM1 resistance pattern is a serious situation in clinical facilities in present times. The risk of health care-associated infections (HCAI) in emerging countries is two to 20 times higher than in developed countries; in some countries, the proportion can exceed 25% (1). Hospital infection prevention and control is fundamental to improving care, reducing the emergence of multidrug-resistant organisms and ensuring safety. In India constant efforts are taking place in this direction. The Clinical Infectious Diseases Society of India, along with other clinical societies, has come up with the Chennai Declaration in 2012. This has been adopted by Indian Government Health Departments and necessary steps for curtailing indiscriminate antibiotic use have also been taken. Also, it is extending the concept of antimicrobial stewardship to the community. Some novel ideas tried at Columbia Asia Hospitals in India to improve hospital infection control programmes are shared in this article. PMID- 26502489 TI - Integrating electronic medical records to improve antimicrobial stewardship at the Montpellier Hospital in France. AB - Improvements in the optimal use of antibiotics is the cornerstone of the French national point-of-care alert for antibiotics (2011-2016). Integrated electronic medical records for antibiotic prescriptions have been deployed in the Montpellier University Hospital (2,800 beds) since 2012. The present paper proposes an overview of integrated electronic medical records for antibiotic prescriptions and how telecounselling at the Montpellier Hospital fits with the global anti-infection ICT strategy. This management change is fully traceable. A review of the results of the project has lead to an improvement in patient care via a collaboration between IDS and other hospital members. This project is part of the Region Reference site of the European Innovation Partnership on Active and Healthy Ageing (MACVIA-LR). PMID- 26502490 TI - Business process re-engineering a cardiology department. AB - The health care sector is the world's third largest industry and is facing several problems such as excessive waiting times for patients, lack of access to information, high costs of delivery and medical errors. Health care managers seek the help of process re-engineering methods to discover the best processes and to re-engineer existing processes to optimize productivity without compromising on quality. Business process re-engineering refers to the fundamental rethinking and radical redesign of business processes to achieve dramatic improvements in critical, contemporary measures of performance, such as cost, quality and speed. The present study is carried out at a tertiary care corporate hospital with 1000 plus-bed facility. A descriptive study and case study method is used with intensive, careful and complete observation of patient flow, delays, short comings in patient movement and workflow. Data is collected through observations, informal interviews and analyzed by matrix analysis. Flowcharts were drawn for the various work activities of the cardiology department including workflow of the admission process, workflow in the ward and ICCU, workflow of the patient for catheterization laboratory procedure, and in the billing and discharge process. The problems of the existing system were studied and necessary suggestions were recommended to cardiology department module with an illustrated flowchart. PMID- 26502491 TI - [Diagnostic Reference Levels and Their Effects]. PMID- 26502492 TI - [A Survey Towards Standardization of Dosimetric Verification in Intensity modulated Radiation Therapy]. AB - PURPOSE: The purpose of this study was to investigate the status of the implementation of quality assurance (QA) for intensity-modulated radiation therapy (IMRT) in Japan using a questionnaire survey. METHODS: The questionnaire consisted of seven sections: (1) clinical uses of IMRT, (2) treatment planning systems, treatment machines, phantoms for verification and CT scanning, (3) absorbed dose verification, (4) dose distribution verification, (5) fluence map verification, (6) acceptance criteria for each verification, and (7) comments. RESULTS: The questionnaire was completed by 129 institutions (response rate: 76.8%). IMRT was performed for prostate cancer in 125 institutions (96.9%), followed by head and neck cancer in 83 (64.3%), and brain tumors in 69 (53.5%). Although at least three individuals were engaged in IMRT QA in 77.5% of the institutions, the number of full-time persons involved in IMRT QA was one or less in 94 institutions (72.9%). This indicated that most institutions in Japan have a staff shortage. More than 90% of the institutions verified both the absorbed dose and dose distribution. The acceptance criterion for the absorbed dose verification was set to +/-3% in at least 80% of the institutions. Gafchromic film was used for the majority of dose distribution verifications. The acceptance criteria for dose distribution verification mainly involved gamma analysis and a comparison of dose profiles; however, the judgment of acceptance did not depend on the results of the gamma analysis. CONCLUSION: This survey increases our understanding of how institutions currently perform IMRT QA analysis. This understanding will help to move institutions toward more standardization of IMRT QA in Japan. PMID- 26502493 TI - [An Easy-to-Understand Risk Communication]. AB - A new definition of risk is that risk is the product of a measure of the size of the hazard and its probability of occurrence. We have some mechanisms that would be make too perception of risk in our mind. These mechanisms are including information processing of risk, binary judgment, and risk perception of low probability area. We are required to have bidirectional communication with other person. So, in order to do good risk communication, we have to establish a trust relationship with other person. PMID- 26502494 TI - [Series: Utilization of Differential Equations and Methods for Solving Them in Medical Physics (1)]. AB - Utilization of differential equations and methods for solving them in medical physics are presented. First, the basic concept and the kinds of differential equations were overviewed. Second, separable differential equations and well known first-order and second-order differential equations were introduced, and the methods for solving them were described together with several examples. In the next issue, the symbolic and series expansion methods for solving differential equations will be mainly introduced. PMID- 26502495 TI - [Series: Fundamental Electromagnetics for Beginners (1)]. PMID- 26502496 TI - [Quality of Life of Patients With Ischemic Heart Disease and Pronounced Dysfunction of Left Ventricular Myocardium With Medical and Surgical Treatments]. AB - We assessed quality of life in 80 patients with ischemic heart disease and pronounced dysfunction of left ventricular myocardium. Forty patients underwent coronary bypass surgery and 40 patients received only medical therapy. Duration of follow-up was 7 years. Baseline quality of life was low in both groups. Degree of its lowering was positively related to functional class of angina and heart failure and negatively - to exercise tolerance. Incessant drug treatment was associated with moderate improvement of quality of life both in groups of patients subjected and not subjected to surgery. PMID- 26502497 TI - [Influence of Endothelial Dysfunction on Prognosis of Patients With Non ST Segment Elevation Acute Coronary Syndrome]. AB - We studied relationship between markers of endothelial dysfunction and multifocal atherosclerosis and adverse coronary events in 82 patients with non-ST segment elevation acute coronary syndrome (NSTEACS). Eighteen patients (21.9%) had adverse events during one year of observation. Patients with adverse coronary events had impaired vasodilatory, vasoconstrictive, and adhesive endothelial function. Predictors of unfavorable prognosis in NSTEACS were signs of impaired endothelium-dependent vasodilation during test with reactive hyperemia, high soluble platelet selectin and endothelin-1 levels on day 10 of the disease. Endothelin-1 and soluble platelet-endothelial cell adhesion molecule-1 had greatest predictive power relative to development of non-fatal myocardial infarction. PMID- 26502498 TI - [Stiffness of the Arterial Wall and Central Hemodynamics During Long-Term Combination Antihypertensive Therapy]. AB - Aim of the METR study - to assess effect of antihypertensive therapy with fixed combination of angiotensin converting enzyme inhibitor lisinopril (10 mg) and calcium antagonist amlodipine (5 mg) on parameters of arterial wall stiffness and central hemodynamics in patients with stage I-II essential hypertension (EH) and functional class II-III ischemic heart disease. Combination therapy was associated with persistent lowering of central arterial pressure, decrease of augmentation index and other parameters of arterial wall stiffness, and reduction of left ventricular myocardial mass. These changes have a potential to lower risk of cardiovascular complications and improve prognosis of patients with EH. PMID- 26502499 TI - [Pharmacoeconomic Efficacy of a Fixed Combination of Bisoprolol and Amlodipine]. PMID- 26502500 TI - [The Use of Dabigatran for Prevention of Thromboembolic Complications in Patients Underwent Atrial Fibrillation Catheter Ablation]. AB - The aim of the study was to estimate the efficacy and safety of dabigatran in comparison with warfarin after atrial fibrillation (AF) catheter ablation (CA). METHODS: 228 consecutive patients, having undergone AF CA, were enrolled in retrospective trial. In group I (n=170) warfarin was administered by modified interrupted scheme, in group II (n=58) dabigatran was administered by 150 mg twice a day. The main clinical efficacy and safety indicators were evaluated during the procedure and within 12 months after the procedure. RESULTS: There was no statistically significant difference between patients taking warfarin and dabigatran (p>0,1) in all of the investigated parameters, including the amount of bleeding and thromboembolic events. Side effects of mild dyspepsia were observed in the dabigatran group in 2.7% of the observations and in the warfarin group in 2.4% (p = 0,589). None of them required discontinuation of the therapy. CONCLUSION: Dabigatran can be considered as an alternative to warfarin for anticoagulation in patients undergoing AF CA. PMID- 26502501 TI - [The Use of Rivaroxaban in Perioperative Period of Pulmonary Vein Antrum Isolation in Patients With Paroxysmal Atrial Fibrillation]. AB - Results of an observational study. devoted to prevention of thromboembolic complications in patients with atrial fibrillation undergoing catheter pulmonary vein atrium isolation are discussed. Patients (n= 199) were divided into two comparable groups depending on the anticoagulant (rivaroxaban or warfarin) used. Clinical thromboembolic and/or hemorrhagic complications as well as rate of development of asymptomatic cerebral thromboembolisms in various periods after procedure were assessed. Main conclusion: rivaroxaban was not inferior to warfarin for thromboprophylaxis in patients with atrial fibrillation undergoing catheter pulmonary vein antrum isolation. PMID- 26502502 TI - [Results of Surgical Treatment of Infective Valvular Endocarditis]. AB - Immediate and long-term results of surgical treatment of infective valvular endocarditis (IVE) in 438 patients during the period from 1978 to 2013 are presented. Overall hospital mortality was 9.1% (11.2 and 6.7% among patients operated in the active stage of IVE and in remission, respectively) Depending on the site of infection mortality was: aortic valve (AV) - 7.9, mitral valve (MV) 10.1, MV and AV 10.7, tricuspid valve (TV) 6 7%. Overall 5 and 10 year survival after surgery was 78.6 4.7 and 66.2 3.9%, respectively. The lowest 5 and 10 year survival was observed in patients with MV and AV defects (66.3 and 52.7%, respectively). Long-term follow-up, the most consistent results are indicated in patients undergoing surgery with primary IE: to 1 year after surgery 94.5% survived to 5 year - 87%, to 10 - 85.5% of patients. In the group of patients with secondary IE to the first, fifth and tenth year observation survived 86.3%, 77.4%, 70.6%, respectively. The main reason for poor results was increasing heart failure, and recurrent infection. PMID- 26502503 TI - [Effect of Statins on Development of Early Cognitive Dysfunction After Coronary Artery Bypass Grafting]. AB - We studied the effect of rosuvastatin on the development of early postoperative cognitive dysfunction (POCD) in patients after coronary artery bypass grafting (CABG). One hundred nine men aged 45-70 year was divided into two groups. Group 1 comprised 69 patients (mean age 56.8 +/- 5.2 years) who were given 20 mg of rosuvastatin for 10-14 days before CABG and until discharge. Patients of group 2 (n=40, mean age 55.9 +/- 5.3 years) did not take rosuvastatin. It was shown that patients of group 2 had better neuropsychological parameters after CABG in comparison with the patients of group 2. Patients of group 1 had lower concentrations of interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha, high sensitivity C reactive protein, and higher concentrations of IL-10. Group 2 patients had worse neuropsychological parameters which were associated with higher concentrations of proinflammatory cytokines. These results may indicate that preoperative therapy with rosuvastatin had decreased the severity of systemic inflammatory response and reduced the development of early POCD after CABG. PMID- 26502505 TI - [Application of Methods of Assessment of Vascular Wall Stiffness in Clinical Practice: Capabilities of Cardio-Ankle Vascular Index]. AB - This paper contains discussion of application of methods of assessment of vascular stiffness in clinical practice, comparison of such parameters as pulse wave velocity, ankle-brachial and cardio-ankle vascular index (CAVI), as well as analysis of advantages of cardio-ankle CAVI for diagnosis, evaluation of effectiveness of treatment, and prognosis in various cardiovascular diseases. PMID- 26502504 TI - [Comparison of Empiric and Pharmacogenetic Approaches in Assessment of Efficacy of Anticoagulant Therapy]. AB - We compared pharmacogenetic (PG) and standard approaches to selection of individual dose of warfarin on 2 groups of patients each comprising 17 persons. In the group with PG selection we took into consideration the result of preliminary genotyping of polymorphisms of VKORC1 and CYP2C9 genes known to be associated with individual warfarin dose. Control of warfarin therapy was carried out during 6 months, number of measurements of international normalized ratio (INR) exceeded 500. Dosing based on knowledge of genotype allowed to achieve therapeutic effect 5 days earlier than with traditional selection of individual dose (p=0.023). Number of INR values above 3.5 indicative of increased risk of bleeding was lower at PG compared with standard approach (3.1 and 7.7%, respectively, p=0.03). Carriers of *2 and/or *3 of CYP2C9 associated with lowering of activity of this cytochrome had greater lability of INR values during course of therapy with warfarin. PMID- 26502506 TI - [Effect of Combination Antihypertensive Therapy Central Blood Pressure]. PMID- 26502507 TI - [The Evolution of Views on Lipoprotein(a): From Biomarker to the Therapeutic Target]. AB - Series of experimental, epidemiological, and genetic studies have demonstrated that elevated lipoprotein(a) [Lp(a)] level is associated with cardiovascular disease independently from traditional risk factors of atherosclerosis. This review covers the basics of Lp(a) pathogenicity in atherothrombosis and scrutinizes the biology of proinflammatory activity of the particle. We describe the evidence base around Lp(a) as an independent cardiovascular risk factor by giving an update on the results of epidemiological studies and genetic findings. We have summarized present evidence of Lp(a) lowering strategies and their impact on clinical outcomes in patients with high Lp(a) levels. We highlight a rationale for increased investigational efforts to further assess whether targeting Lp(a) levels minimizes cardiovascular risk. PMID- 26502508 TI - [Congenital Cardiac Conduction Abnormalities]. AB - Abnormalities in cardiac conduction can occur due to a variety of factors. So called "idiopathic", conduction system degeneration develops without evident causes and may have hereditary basis. In the majority of cases it has no clinical manifestation, do not require treatment and have overall good prognosis. In this review we focus on congenital complete atrioventricular block and progressive cardiac conduction defect - rare but malignant and potentially lethal conditions that can be caused by genetic mutations and may be isolated or associated with structural heart disease. Cardiac involvement is relatively common in rare hereditary diseases - myodystrophies and mitochondrial cytopathies. Conduction abnormalities are among the most severe manifestations that may determine prognosis in these rare genetic disorders. These conditions deserve special consideration because of rapid progression of conduction defects and high prevalence of sudden cardiac death if no appropriate treatment applied. PMID- 26502509 TI - [What We Know About Acute Decompensation of Heart Failure?]. PMID- 26502510 TI - [Azilsartan: Whether it Will Expand Treatment Options for Arterial Hypertension?]. PMID- 26502511 TI - [Capabilities of Multidetector Computed Tomography in Assessment of Atherosclerosis of Coronary Arteries]. AB - The prevalence of ischemic heart disease (IHD) as well as high mortality from its exacerbations led to an active search and study of diagnostic methods to predict the possible development of acute coronary events. At the moment, it is proved that the morphological properties of atherosclerotic plaque largely determine the course of IHD. Contemporary multidetector computed tomography (MDCT) is the only non-invasive method which allows to study the state of coronary arteries. In this review we have analyzed capabilities of MDCT in assessing the severity of stenosis and calcification in the coronary arteries, as well as the structure of atherosclerotic plaques, including signs of "instability". PMID- 26502512 TI - [Pulmonary Embolism: Clinical Appearance and Diagnosis in the Light of the new Recommendations of the European Society of Cardiology]. PMID- 26502513 TI - [The Place of Perindopril in the Treatment of Ischemic Heart Disease From Positions of Evidence Based Medicine]. PMID- 26502514 TI - [Clinical evaluation for cervical spinal cord injury]. PMID- 26502515 TI - [Correlation among prevertebral hyperintensity signal, canal sagittal diameter on MRI and neurologic function of patients with cervical vertebral hyperextension injury]. AB - OBJECTIVE: To explore the correlation among prevertebral hyperintensity (PVH), sagittal canal diameter on MRI and neurologic function of patients after cervical vertebral hyperextension injury without fracture and dislocation. METHODS: The clinical data of 100 patients with cervical vertebral hyperextension injury without fracture and dislocation were retrospectively analyzed from September 2010 to December 2013. The patients were divided into PVH group and non-PVH group according to the presence of PVH on T2-weighted magnetic resonance imaging. There were 39 patients in PVH group, including 31 males and 8 females, aged from 21 to 83 years old with an average of (58.10 +/- 14.78) years; and the other 69 patients in non-PVH group, including 49 males and 12 females, aged from 32 to 77 years old with an average of (55.05 +/- 10.36) years. The sagittal disc level canal diameters of subaxial cervical spine were measured on mid-sagittal magnetic resonance imaging. The age, sex, cause of injury, and the segments of spinal stenosis were recorded. American Spinal Injury Association (ASIA) impairment scale and motor score were used to evaluate the neurological status. RESULTS: The ASIA motor score of the group with PVH was 52.56 +/- 31.97 while the ASIA motor score was 67.70 +/- 22.83 in non-PVH group (P = 0.013). More patients with intramedullary hyperintensity signal on MRI were observed in the PVH group than in non-PVH group (P = 0.006). There was a significant positive correlation between ASIA motor score and sagittal disc level canal diameter of injury segment (P = 0.003). The neurological status was worse in patients with multi-level sagittal canal diameters below 8 mm. CONCLUSION: The PVH and the disc-level canal sagittal diameter of the injury segment are associated with neurological status. The patients with multi-level sagittal canal stenosis are vulnerable to severe cervical spinal cord injury. PMID- 26502516 TI - [Strategy by stages for preventing respiratory complications of acute cervical spinal cord injury]. AB - OBJECTIVE: To investigate clinical effects of strategy by stages for preventing respiratory complications of patients with acute cervical spinal cord injury (ACSCI). METHODS: From September 2009 to May 2013,the clinical data of 91 patients with ACSCI underwent surgery were retrospectively analyzed. Among the patients, 42 patients were divided into in-stages group, including 30 males and 12 females with an average age of 50 years old (ranged 28 to 76) which were treated with strategy by stages for preventing respiratory complications; others 49 patients which were not treated with the strategy regarded as control group, including 38 males and 11 females with an average age of 47 years old (ranged 30 to 77). All of them had definite history of trauma, and were admitted to orthopaedics within 48 h after trauma. In in-stages group, respiratory muscle strength training, high-dose ambroxol using and other treatment were performed to prevent respiratory complilcations according to preoperative, intraoperative and postoperative stage. While in control group, there were no systematic and effective measures utilized. Chi-square test was used to evaluate the difference for respiratory complications rate, the rate of tracheostomy or intubation and mortality caused by the respiratory complications between two groups. RESULTS: Ten patients developed with respiratory complications in in-stages group (7 patients with pneumonia, 1 with atelectasis and 2 with respiratory failure), among which 3 patients underwent tracheostomy or intubation. In control group, 24 patients developed with respiratory complilcations (15 with pneumonia,3 with atelectasis and 6 with respiratory failure), among which 11 patients underwent tracheostomy or intubation. There was significant difference between two groups (chi2 = 6.12, 4.07; P = 0.013, 0.044). Five patients died because of respiratory complications, one case were in in-stages group and 4 in control group. There was significant difference between two groups (chi2 = l.39, P = 0.238). CONCLUSION: The strategy by stages is an effective method for preventing respiratory complications of ACSCI and can reduce the respiratory complications rate and improve the prognosis of respiratory complications. PMID- 26502517 TI - [Progress on the role of autophagy in spinal cord injury]. AB - In recent years, the study of autophagy in spinal cord injury (SCI) gradually becomes the hot spot. However, the function of autophagy in the injured spinal cord is still controversial. In order to further understand the role of autophagy after SCI, we summarized the activation of autophagy, autophagic cell death, the relationship between autophagy and apoptosis, the function of autophagy in promoting the molecular metabolism and the role of autophagy after spinal cord injury. We concluded that the role of autophagy after SCI is a double-edged sword. Upregulating the level of autophagy appropriately can promote damaged proteins metabolism and inhibit apoptosis. However, excessive activation of antophagy may induce autophagic cell dealth. So we consider that the proper regulation of autophagy will be a new target in the treatment of SCI. PMID- 26502518 TI - [Comparison of the prognosis of intertrochanteric fracture with different surgical methods in elderly: a retrospective survival analysis]. AB - OBJECTIVE: To determine the difference of post-operative mortality between ORIF (open reduction internal fixation) and hip replacement for the treatment of intertrochanteric fracture in elderly by using survival analysis. METHODS: The clinical data of 110 patients above 60 years old who underwent surgical treatment (ORIF or hip replacement) for the intertrochanteric fracture between April 2003 and May 2013 were retrospectively analyzed. Among the patients, 83 cases were treated with ORIF (ORIF group), there were 32 males and 51 females, aged from 61.44 to 98.75 years old with an average of (78.52 +/- 7.98) years old; and 27 cases were treated with hip replacement (arthroplasty group), there were 8 males and 19 females, aged from 71.82 to 96.54 years old with an average of (79.99 +/- 6.11) years old. A survival analysis was performed on the clinical data by using SPSS 110 software. The survival rate of 1-year,2-year, 5-year and the mean survival time for the total patients, the mortality rate of 1-year, 2-year in each group, the survival rate of 1-year, 2-year and mean survival time and survival curve in each group were included. RESULTS: All wounds achieved primary healing and no deaths were found in stay hospital. All patients were followed up from 1 to 125 months with an average of (46.93 +/- 29.53) months. Among all 110 cases, 31 were dead and 79 survived. The survival rate of 1-year, 2-year and 5 year was (90.7 +/- 2.8)%, (82.5 +/- 3.9)% and (57.6 +/- 6.5)%, respectively,while the ensemble mean survival time was (84.137 +/- 5.902) months. The mortality rate of 1-year, 2-year in ORIF group was 7.2% and 12.0%, respectively; and in arthroplasty group, there was 14.8% and 25.9%, respectively. There was no significant difference in mortality rate of 1-year and 2-year between two groups. According to the survival analysis of the ORIF group, the survival rate of 1 year, 2-year was (92.6 +/- 2.9)%, and (85.8 +/- 4.3)%, respectively, and the mean survival time was (87.508 +/- 6.063) months. In arthroplasty group, the survival rate of 1-year, 2-year was (85.2 +/- 6.8)% and (73.9 +/- 8.5)%,and the mean survival time was (67.294 +/- 11.180) months. There was significant difference in mean survival time between two groups (P < 0.05). CONCLUSION: ORIF can achieve a better postoperative survival compare with hip replacement in treating intertrochanteric fracture in elderly. PMID- 26502519 TI - [The relationship between angle of puncture and distribution of bone cement of unilateral percutaneous kyphoplasty for the treatment of thoracolumbar compression fractures]. AB - OBJECTIVE: To explore the relationship of bone cement distribution and the puncture angle in the treatment of thoracolumbar compression fractures with unilateral percutaneous kyphoplasty (PKP). METHODS: The clinical data of 37 patients with thoracolumbar osteoporotic compression fractures underwent PKP between January 2013 to March 2014 were retrospectively analyzed, all punctures were performed unilaterally. There were 6 males, aged from 65 to 78 years old with an average of (71.83 +/- 6.15) years; and 31 females, aged from 57 to 89 years old with an average of (71.06 +/- 7.89) years. Imaging data were analyzed and puncture angle and puncture point were measured before operation. According to the measured data, the puncture were performeds during the operation. Distribution area of bone cement were calculated by X-rays data after operation. The effect of bone cement distribution on suitable puncture angle was analyzed; VAS score was used to evaluate the clinical effects. RESULTS: The puncture angle of thoracic vertebrae in T8-T12 was from 28 degrees to 33 degrees with an average 30.4 degrees ; and the puncture angle of lumbar vertebrae in L1-L5 was from 28 degrees to 35 degrees with an average of 31.3 degrees . Postoperative X rays showed the area ratios of bilateral bone cement was 0.97 +/- 0.15. Bilateral diffuse area were basic equal. Postoperative VAS score decreased significantly (1.89 +/- 1.29 vs 7.03 +/- 1.42). CONCLUSION: Through measure imaging data before operation with PKP,the puncture point and entry point can be confirmed. According the measured data to puncture during operation, unilateral puncture can reach the distribution effect of the bilateral puncture in the treatment of thoracolumbar compression fractures. PMID- 26502520 TI - [Analysis of risk factors of the infection after operation of open tibiofibula fractures]. AB - OBJECTIVE: To analyze the related factors of the infection after operation of open tibiofibula fractures. METHODS: The clinical data of 141 patients with open tibiofibula fractures underwent surgical treatment from June 2009 to December 2012 were retrospectively analyzed. All the patients were male and aged from 18 to 61 years old with an average of 39.2 years; all the fractures were unilateral. According to Gustilo typing of fracure, 5 cases were type I, 44 cases were type II, 27 cases were type III a, 56 cases were type III b and 9 cases were type III c. These clinical data included patients' age, gender, body mass index (BMI), underlying diseases, time of operation, fracture site, fracture type, fixation method, postoperative drainage, debridement condition and so on. The postoperative infection conditions were recorded, and the correlation between above factors and infections were analyzed. Finally, the significant related variables were introduced into a Logistic regression model to evaluated their risk. RESULTS: Among the 141 patients, 22 cases developed with infection (15.6%). The significant relative factors with infection contained fixation method, debridement condition, underlying diseases and postoperative drainage (P < 0.05). The correlativities were stepped up in order, their odds ratios value was 2.451, 3.164, 3.414, 5.117, respectively. CONCLUSION: Active treatment for underlying diseases before operation, thorough debridement for open wound, suitable fixation method for fracture and thorough draining are effective measures in preventing postoperative infection. PMID- 26502521 TI - [Surgical revision of lumbar vertebrae using transforaminal endoscopic spine system]. AB - OBJECTIVE: To explore the clinical effects of transforaminal endoscopic spine system in surgical revision of lumbar vertebrae. METHODS: From January 2012 to October 2013,14 patients who needed reoperations of lumbar vertebrae were treated using transforaminal endoscopic spine system (TESSYS). There were 8 males and 6 males, aged from 27 to 84 years old with an average of (50.4 +/- 18.9) years. Visual analogue scale (VAS) and Japanese Orthopaedic Association Scores (JOA) were compared before and after surgical revision. Macnab standard was used to assess the clinical effect. RESULTS: All the patients were followed up from 6 to 27 months with the mean of 18 months. Preoperative VAS score was 6.79 +/- 1.31, and in a week,3 months and 6 months after operation were 2.50 +/- 1.29, 2.21 +/- 1.53, 1.64 +/- 1.08, respectively, which were all much lower (P < 0.01) than preoperative score. Preoperative JOA score was 12.43 +/- 1.95, and the above corresponding postoperative JOA scores were 21.50 +/- 3.78, 21.93 +/- 4.55, 23.36 +/- 4.33, respectively, which were all much higher than preoperative score (P < 0.01). According to the modified Macnab criteria, 5 patients got an excellent results, 7 good, 1 fair and 1 poor. The nerve root injury of L5 occurred in 1 case during paracentesis and no other complications were found. CONCLUSION: Selecting the appropriate indications using TESSYS in surgical revision of lumbar vertebrae can successfully avoid the operation scar, reduce the surgical complications and obtain satisfactory clinical outcomes. PMID- 26502522 TI - [Prevention of postoperative cerebrospinal fluid leakage with absorbable hemostatic fluid gelatin]. AB - OBJECTIVE: To explore the effectiveness of absorbable hemostatic fluid gelatin in preventing postoperative cerebrospinal fluid leakage. METHODS: The clinical data of 17 patients with dura mater tear were retrospectively analyzed from March to September in 2003. There were 16 males and 1 female, aged from 16 to 67 years old with an average of (39.6 +/- 15.4) years. The injury site was at cervical vertebrae in 1 case, thoracic vertebrae in 9 cases, thoracolumbar junction in 4 cases, lumbar vertebrae in 3 cases. There were burst fracture in 4 cases and fracture-dislocation in 13 cases. According to ASIA grade, 12 cases were grade A, 2 cases were grade B, 2 cases were grade D, 1 case were grade E. Two cases caused by traffic accident, 10 by high falling, 4 by heavy parts crash, 1 by stairs fell during the earthquake. Absorbable hemostatic fluid gelatins were used to plug the dura mater tear,in order to prevent postoperative cerebrospinal fluid leakage. Postoperative drainage were recorded every day. RESULTS: Of 17 patients, 15 cases did not develop with cerebrospinal fluid leakage. Two cases develop with cerebrospinal fluid leakage after operation and their drainage were removed at 6 to 7 days after operation. In all cases, no complications related with cerebrospinal fluid leakage occurred, such as headache, dizzy, fever,neck resistance, rash, incision disunion, incision infection, hematoma, neurologic symptoms aggravation. No abnormal phenomena was found on incision surrounding at follow-up of 9 months. CONCLUSION: Using absorbable hemostatic fluid gelatin to plug the dura mater tear during operation is an effective method in preventing postoperative cerebrospinal fluid leakage. PMID- 26502523 TI - [Study on the clinical effect of the massage method of micro-regulating with vertical cross pressing lying on one side in treating cervicogenic headache]. AB - OBJECTIVE: To evaluate the clinical effects of the massage method of micro regulating with vertical cross pressing lying on one side in treating cervicogenic headache (CEH). METHODS: Total 136 patients with CEH were collected in the study from August 2012 to April 2014. They were divided randomly into two groups according to random digits table. Sixty-nine patients accepted the treatment of micro-regulating with vertical cross pressing lying on one side (pressing micro-regulating group), including 29 males and 40 females with an average age of (50.55 +/- 11.38) years old; 67 patients received the treatment of traditional massage (traditional massage group), including 28 males and 39 females with an average age of (51.20 +/- 11.90) years old. Clinical effect was observed according to the standard of curative effect of State Administration of Traditional Chinese Medicine; the function of cervical vertebra and all body status were evaluated according to NDI score. VAS score, frequency and time of headache were recorded and compared before and after treatment. RESULTS: No adverse reactions were found after treatment, all patients were followed up from 1 to 6 months with an average of 3.1 months. In pressing micro-regulating group, 25 cases got fully recover, 26 excellence, 14 effectiveness and 4 inefficiency; and in traditional massage group, the results were 12,21,22, 12;clinical effect of pressing micro-regulating group was better than that of traditional massage group (P<0.01). NDI score in pressing micro-regulating group decreased from preoperative 13.48 +/- 4.83 to postoperative 6.23 +/- 3.76; in traditional massage group also decreased from preoperative 13.82 +/- 5.78 to postoperative 8.25 +/- 4.75; the improvement of the pressing micro-regulating group was obviously better than that of traditional massage group (P < 0.01). VAS score in pressing micro-regulating group decreased from preoperative 4.75 +/- 0.97 to postoperative 1.88 +/- 1.78; and in traditional massage group decreased from pre operative 4.78 +/- 0.98 to postoperative 2.84 +/- 1.94; pressing micro-regulating group was more notable than that of traditional massage group (P < 0.01). The frequency per week,the pain time in pressing micro-regulating group decreased from preoperative (5.38 +/- 1.96) times and (6.87 +/- 3.67) hours to postoperative (1.71 +/- 2.04) times and (0.97 +/- 1.74) hours,respectively,in traditional massage group the above parameters decreased from preoperative (5.22 +/- 1.81) times and (6.90 +/- 3.79) hours to postoperative (2.81 +/- 2.42) times and (1.83 +/- 2.21) hours;pressing micr-regulating group was more notable than that of traditional massage group (P < 0.01 or P < 0.05). CONCLUSION: Using the tuina method of micro-regulating with vertical cross pressing lying on one side to treat CEH can improve function of cervical vertebra and all body status, lessen the intensity, frequency, duration time of pain, and had advantage of higher security, simple operation, and evident effect. PMID- 26502524 TI - [Design of the reduction fixator and its clinical application in treating fracture of lesser trochanter of femur]. AB - OBJECTIVE: To discuss the clinical significance of the reduction and fixation for femoral lesser trochanteric fragment in treating the femoral comminuted intertrochanteric fractures. METHODS: From January 2012 to December 2013,32 patients with intertrochanteric fractures were treated by surgery, and self designed reduction fixators were used in the patients for the fixation of lesser trochanter of femur. There were 11 males and 21 females, ranging in age from 45 to 81 years old with an average of 64 years old. According to the Evans typing, 12 cases were type II, 13 cases were type III and 7 cases were type IV. Simple lag screw fixed in 19 cases and steel wire fixed in 13 cases. Hip joint function was evaluated according Harris score and the complications such as coxa adducta,cutting of femoral head and neck,implants breakage were observed. RESULTS: Thirty-two patients were followed up from 9 to 24 months with an average of 13 months. Coxa adducta occurred in 1 case,no cutting of femoral head and neck occurred and implants breakage were found. The mean Harris score was 91.80 +/- 3.05 in 32 patients. CONCLUSION: The reconstruction and fixation for the posterior medial bone cortex continuity is a key factor on affect the stability of femoral intertrochanteric fracture. Self-designed reduction fixators can effective reduce and fix the lesser trochanter of femur, it has advantage of fast reduction and fixation, and simple operation. PMID- 26502525 TI - [Treatment of sternoclavicular joint dislocation with sternoclavicular hook plate fixation]. AB - OBJECTIVE: To evaluate the technique and therapeutic effect of sternoclavicular hook plate fixation in treating sternoclavicular joint (SCJ) dislocation. METHODS: From January 2010 to March 2014,6 patients with SCJ dislocation were treated with sternoclavicular hook plate fixation in our hospital. Among the 6 patients, 5 patients were male and 1 patient was female, and the average age was 34 years, ranging from 26 to 48 years. The course of the disease ranged from 3 to 20 days. All the SCJ dislocations were caused by external injury and accompanied with the symptoms of swelling pain and obvious shoulder joint activity restricted in affected side. All SCJ dislocations were anterior dislocation by the diagnosis of X-ray and CT scan. The postoperative curative effect was evaluated according to Rockwood score. RESULTS: All the patients' operative incision were healed well and in good appearance. X-ray showed that the dislocated SCJ was well reduced and the plate was on right position. All the 6 patients were followed up for 4 to 18 months, with an average of 12 months. The results were evaluated according to Rockwood score, 4 got excellent results, 1 good and 1 fair. No fixation loosening, redislocation or side injury such as vessel, nerve or pleura injury were found. CONCLUSION: With sternoclavicular hook plate fixation, SCJ dislocation could be reduced while keeping its amphiarthrodial function and the completeness of the cartilage surface. Sternoclavicular hook plate fixation has advantages of safety and stabilization in fixation, and patients can begin function exercises earlier. PMID- 26502526 TI - [Effects of electro-acupuncture on neuronal apoptosis and associative function in rats with spinal cord injury]. AB - OBJECTIVE: To explore the effect of electro-acupuncture to improve the bladder function after acute spinal cord injury in rats and its possible mechanism. METHODS: Sixty healthy adult male SD rats of SPF grade, with body weight of 220 to 250 g, one week after feeding adaptation, were randomly divided into sham operation group, model group, electro-acupuncture group, electro-acupuncture control group with 15 rats in each group. Sham operation group underwent no stimulation, and the moderate damage model of spinal cord injury were made in other three groups according to modified Allens method. The model group were not treated, electro-acupuncture group were treated with electro-acupuncture on Zhibianxue and Shuidaoxue, and electro-acupuncture control group were treated with electro-acupuncture on 0.5 inch next to Zhibianxue and Shuidaoxue. The frequency of 2/100 Hz, current of 1 mA, stimulation time of 15 min, once a day, left and right alternately stimulate every time, for a total of 7 times. The changes of residual urine volume and urine output in rats at the 1st and the 7th days after operation were observed. And 7 d later, the rats were sacrificed and the injured spinal cord were taken out to observe the apoptosis, and to detect the changes of Bcl-2, Bax, Bad content. RESULTS: After modeling,the rats of three groups showed different bladder dysfunction. In electro-acupuncture group and electro-acupuncture control group, the residual urine volume of the 7th day after operation was significant lower than the 1st day after operation (P < 0.001), and there was statistically significant difference on the 7th day after operation between two groups (P < 0.001). Compared with model group, the urine output of electro-acupuncture group and electro-acupuncture control group was significantly increased on the 7th day after operation, and there was sig- nificant difference between electro-acupuncture group and electro-acupuncture control group (P < 0.001). Electro-acupuncture can inhibit apoptosis of spinal cord neurons by TUNEL detection. Postoperative at 7 d, the rate of nerve cell apoptosis in electro acupuncture group and electro-acupuncture control group was significant increased than model group (P < 0.01, P < 0.05), and there was significant difference between electro-acupuncture group and electro-acupuncture control group (P < 0.005). Compared with model group, the positive expression rate of Bax, Bad decreased (P < 0.01, P < 0.05), and Bcl-2 increased (P < 0.01) in electro acupuncture group and electro-acupuncture control group,there was significant difference between electro-acupuncture group and electro-acupuncture control group (P < 0.01). CONCLUSION: Electro-acupuncture can obviously promote the repair of acute spinal cord injury,its mechanism may be through increasing Bcl-2, inhibiting the expression of Bax, Bad, which inhibits the apoptosis of spinal cord neurons. PMID- 26502527 TI - [Application of oil red O staining in spinal cord injury of rats]. AB - OBJECTIVE: To explore the value of the application of oil red O staining in spinal cord injury (SCI) of rats. METHODS: With simple randomization, 24 Spargue Dawley male rats were divided into normal control group including 6, and SCI group including 18. Spinal cord was transected at spinal lever T10 to build SCI model. Six rats of SCI group were sacrificed randomly at 1, 2, 4 weeks after surgery. After the spinal cord tissue sections were made, oil red O staining methods were used to observe the changes at the end of transected spinal cord. Images were analyzed by Image-Pro Plus 6.0 and SPSS 20.0 software. RESULTS: The oil red O staining of normal control group showed that white matter surrounded by myelin sheath was clear and obviously distinctive from grey matter. Uneven and strengthened staining in oil O was observed in grey matter of SCI group at 1, 2, 4 weeks post-SCI. CONCLUSION: It is a good method to label the myelin sheath in spinal cord and distinct white matter from grey matter by oil red O staining. Analysis of the images showed that lipid may become another target for drugs, which needs more researches. PMID- 26502528 TI - [Treatment of humeral supracondylar fracture in children with external plaster fixation on extension position]. AB - OBJECTIVE: To explore the effective method of preventing cubitus varus deformity in nonoperative treatment of humeral supracondylar fracture in children. METHODS: From May 1992 to December 2013,319 patients with hemeral supracondylar fracture in children were treated with manual reduction and external plaster fixation in extension position. There were 253 males and 66 females, aged from 15 months to 13 years old with an average of 6.7 years. Among the patients with humeral supracondylar fracture, extension type was in 284 cases and inflexion type was in 35 cases; 167 cases on the left and 152 cases on the right. Injury to treatment time was 1 hour to 7 days with a mean of 1.8 days. No included nerve injury and operative case in the patients. RESULTS: All patients were followed up from 3 months to 14 years with an average of 37.3 months. All fractures obtained bone healing and healed time was 6 to 8 weeks with an average of 6.9 weeks. No complications of serious cubitus varus deformity,vascular nerve injury or volkmann contracture were found. In 183 cases, the carrying angle was consistent with itself contralateral,ranged from 5 degrees to 15 degrees ; in 105 cases, the carrying angle of uninjuryed side was decreased. During the reset, the carrying angle of 26 patients with ulnar deviation angle was for -5 degrees to 0 degrees ; and 5 patients with radial deviation angle was for 15 degrees to 18 degrees , basically does not affect the appearance. The activities of all elbow joint were normal. CONCLUSION: External plaster fixation in extension position has some value to preventing cubitus varus deformity in nonoperative treatment of humeral supracondylar fracture in children and hope that more scholars to do further study. PMID- 26502529 TI - [Osteochondroma of cervical lamellar bone: a case report]. PMID- 26502530 TI - [Posterior spinal transpedicular wedge osteotomy for kyphosis due to delayed osteoporotic vertebral fracture in elderly]. AB - OBJECTIVE: To evaluate the clinical effects of posterior spinal transpedicular wedge osteotomy for kyphosis due to delayed osteoporotic vertebral fracture in elderly. METHODS: From July 2009 to February 2014,26 patients with kyphosis caused by delayed osteoporotic vertebral fracture were treated with transpedicular wedge osteotomy. There were 10 males and 16 females,aged from 55 to 75 years old with an average of 67 years. There were 1 osteotomy in thoracic vertebra,21 osteotomies in thoracolumbar vertebrae and 4 in lumbar vertebrae. Total 29 vertebrae were involved, 23 cases with single vertebral fracture and 3 cases with double vertebral fractures. Preoperative Cobb angles were 32 degrees ~51 degrees with the mean of (42.00 +/- 4.75) degrees and VAS scores were 6 to 9 points with an average of (8.40 +/- 0.75) points. According to the Frankel grade of spinal cord function, 4 cases were grade D and 22 cases were grade E. Intraoperative bleeding, operation time and perioperative complications were recorded, and improvements of Cobb angle were evaluated by X-rays. VAS score and Frankel grade were respectively used to evaluate the pain and nerve function. RESULTS: The average operation time were 155 min (ranged, 120 to 175) and the mean intraoperative bleeding were 1 100 ml (ranged,800 to 1 500). Postoperative at 2 days, Cobb angle and VAS score were (9.60 +/- 2.50) degrees and (4.00 +/- 1.00) points, respectively, ranged from 5 degrees to 15 degrees and 1 to 5 points. VAS score and Cobb angle improved obviously compared with preoperative (P < 0.05), and the improvement rate of Cobb angle was 76%. Frankel grade of 1 case changed from grade E to C, and the others did not become worse. The follow-up period ranged from 3 to 24 months with an average of 16.4 months. At the final follow-up, Cobb angles and VAS score were (11.00 +/- 3.50) degrees and (4.40 +/- 1.25) points, respectively, ranged from 5 degrees to 19 degrees and 1 to 6 points. The patient whose Frankel grade E changed to C at 2 days after surgery and changed to grade D at the latest follow-up. Vertebral body fracture below the fusion level happened in 1 case at 3 months after surgery, vertebral body fracture above the fusion level happened in 1 case at 5 months after surgery, and their chest pain symptoms were relieved after symptomatic treatment and anti osteoporosis treatment. All osteotomy levels obtained fusion which confirmed by X ray and no internal fixation loosening and breakage were found. CONCLUSION: The clinical effect of posterior transpedicular wedge osteotomy for kyphosis due to delayed osteoporotic vertebral fracture was satisfactory, but manipulation during the operation should be cautious and prevent adjacent vertebral body fracture should be pay attention to prevent. PMID- 26502531 TI - [Application of internal fixation combined with external fixator for unstable pelvic fracture]. AB - OBJECTIVE: To invesitigate the clinical effects of percutaneous closed reduction and cannulated screw internal fixation combined with external fixation in the treatment of unstable pelvic fractures. METHODS: From April 2006 to May 2009,29 patients with pelvic fractures of rotatory instability were treated with closed reduction and screw internal fixation combined with external fixation. There were 19 males and 10 females with an average age of 31 years old (ranged from 19 to 53 years). Based on the Tile classification,17 cases were type CI and 12 case were type C2. Tornetta standard and Majeed score were used to evaluated the clinical effect after operation. RESULTS: All patients were followed up from 10 to 24 months with an average of 16 months. There were no nerve injuries and other organ injuries, only one case of infection was found and it was cured with wound dressing. Time of fracture union was from 14 to 18 weeks with the mean of 16.2 weeks. No loosening, slippage or breakage of the screw were found. According to the Tornetta standards,14 cases obtained excellent results, 10 good, 4 fair and 1 poor. The Majeed score was 87.2 +/- 11.3, 16 cases got excellent results, 9 good and 4 fair. CONCLUSION: Closed reduction and screw internal fixation combined with external fixation is an effective way to treat unstable pelvic fractures with Tile type C1 and Tile type C2. PMID- 26502532 TI - [Minimally invasive percutaneous plate osteosynthesis versus open reduction and internal fixation for distal tibial fractures in adults: a meta-analysis]. AB - OBJECTIVE: To perform a meta-analysis on clinical outcomes of minimally invasive percutaneous plate osteosynthesis (MIPPO) or open reduction and internal fixation (ORIF) for distal tibial fractures in adults. METHODS: Pubmed database (from 1968 to March 2014), Cochrane library and CNKI database (from 1998 to March 2014) were searched. Case-control study on minimally invasive percutaneous plate osteosynthesis (MIPPO) or open reduction and internal fixation (ORIF) for distal tibial fractures in adults were chosen,and postoperative infection, operative time, blood loss, fracture nonunion rate, delayed union,fracture malunion rate were seen as evaluation index for meta analysis. The system review was performed using the method recommended by the Cochrane Collaboration. RESULTS: Totally 5 studies (366 patients) were enrolled. Meta-analysis showed that there were significant meaning in postoperative infection between MIPPO and ORIF [OR = 0.23,95% CI (0.06,0.92), P = 0.04]; fracture nonunion rate in MIPPO was lower than in ORIF group [OR = 0.16, 95% CI (0.03,0.76), P = 0.02]; operative time in MIPPO was shorter than in ORIF group, and had significant difference [MD = 14.42, 95% CI (-27.79, -1.05), P < 0.05]; blood loss in MIPPO was less than in ORIF group [MD= -87.17,95%CI (-99.20, -75.15), P < 0.05]; there was no obviously meaning in delayed union between two groups. CONCLUSION: For distal tibial fractures in adults, MIPPO has, advantages of short operative time, less blood loss, lower incidence of infection and fracture non-uniom, but with high fracture malunion rate. MIPPO for distal tibial fractures in adults is better than ORIF, and the best treatment should choose according to patient's condition. PMID- 26502533 TI - [Complications of percutaneous kyphoplasty non-related with bone leakage in treating osteoporotic thoracolumbar vertebral compression fractures]. AB - OBJECTIVE: To analyze the complications of percutaneous kyphoplasty except bone leakge for the treatment of osteoporotic thoracolumbar vertebral compression fractures. METHODS: From October 2008 to October 2012,178 patients with 224 osteoporotic vertebral compression fractures were treated with percutaneous kyphoplasty under local anethsia. There were 72 males and 106 females,ranging in age from 58 to 92 years old,with an average of 75.3 years,including 93 thoracic vertebrae and 131 lumbar vertebrae. The complications except bone cement leakage were analyzed during operation and after operation. RESULTS: All operations were successful and all patients were followed up from 12 to 60 months with an average of 26.2 months. No death was found. Bone cement leakage occurred in 27 cases, about 15.1% in 178 cases; and complications except bone cement leakage occurred in 15 cases. There was 1 case with cardiac arrest,was completely recovery by cardiopulmonary resuscitation (CPR) immediately; and 1 case with temporary absence of breathing,was recovery after treatment. There were 3 cases with fall of blood pressure and slower of heart rate; 1 case with intestinal obstruction; 2 cases with local hematoma and 1 case with intercostal neuralgia. Vertebral body fractures of 2 cases were split by bone cement and the fractures of adjacent body occurred in 4 cases. CONCLUSION: It's uncommon complication except bone cement leakge in treatment of osteoporotic thoracolumbar vertebral compression fractures with percutaneous kyphoplasty. The complication of cardiopulmonary system is a high risk in surgery; and cytotoxicity of bone cement,nervous reflex,fat embolism and alteration of intravertebral pressure may be main reasons. PMID- 26502534 TI - [Percutaneous needle break end expanding new and autologous bone marrow transplantation for bone nonunion: a case report]. PMID- 26502535 TI - [Progress on cervical muscle strength and soft tissue stiffness testing]. AB - Biomechanical evaluation of neck muscles has important significance in the diagnosis and treatment for cervical spondylosis, the neck muscle strength and soft tissue stiffness test is two aspects of biomechanical testing. Isometric muscle testing operation is relatively simple, the cost is lower, which can evaluate the muscle force below grade 3. However, isokinetic muscle strength testing can assess the muscle strength of joint motion in any position. It is hard to distinguish stiffness difference in different soft tissues when the load displacement curve is used to evaluate the local soft tissue stiffness. Elasticity imaging technique can not only show the elastic differences of different tissues by images, but also quantify the elastic modulus of subcutaneous tissues and muscles respectively. Nevertheless, it is difficult to observe the flexibility of the cervical spine by means of the analysis of the whole neck stiffness. In a word, a variety of test method will conduce not only the biomechanical evaluation of neck muscles, but also making an effective biomechanics mathematical model of neck muscles. Besides, isokinetic muscle testing and the elasticity imaging technology still need further validation and optimization before they are better applied to neck muscles biomechanical testing. PMID- 26502536 TI - [Progress on preparation methods of animal model of deep venous thrombosis]. AB - Deep venous thrombosis is a common and serious complication after orthopedics operation, with the characteristics of high incidence rate and death rate, its formation mechanism and the treatment is becoming more and more attention of scholars. Establishment of animal model of deep venous thrombosis can further explore the pathological process of thrombosis or dissolution, is an important means to research of thrombosis mechanism and evaluation of therapeutic method. This review discussed the basic principle of deep venous thrombosis, the selection of experimental animals and making method of animal models. PMID- 26502538 TI - [Effects of Acupuncture Intervention on Levels of T Lymphocyte Subsets in Plasma and Thymus in Stress-induced Anxiety Rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) intervention on the levels of CD 4+ and CD 8+ lymphocytes in the plasma and thymus in anxiety disorder rats, so as to explore its mechanism underlying favorable regulation of immune function. METHODS: Thirty-four SD rats were randomly divided into control (n = 10) , model (n = 12) and EA (n = 12) groups. The anxiety model was established by using chronic unpredictable emotional stress stimulation (fasting, water-deprivation, shaking, tail-clamping, forced warm- and cool-water swimming, electrical shock stimulation, etc.) for 15 days. EA (15 Hz/ 25 Hz) was applied to "Neiguan" (PC 6) and "Shenmen" (HT 7) for 15 min, once every other day for 15 days. The anxiety-like behavior was measured by elevated plus maze test. Anxiety reduction in the plus-maze is indicated by an increase in the proportion of time spent in the open arms (time in open arms/total time in open or closed arms) , and an increase in the proportion of entries into the open arms (entries into open arms/total entries into open or closed arms). While the contents and expression of CD 4+ and CD 8+ in the plasma and thymus tissues were measured by ELISA and immunohistochemistry, respectively. RESULTS: The values of proportions of open-arm entries (OE%) and the content of plasma CD 4+ lymphocytes were obviously lower in the model group than in the control group (P < 0.05), and were significantly higher in the EA group than in the model group (P < 0.05). Whereas, the content of plasma CD 8+ lymphocytes was obviously higher in the model group than in the control group (P < 0.05) and markedly down-regulated in the EA group after the treatment (P < 0.05). The ratio of CD 4+/CD 8+ was decreased in the model group in comparison with the control group (P = 0.054), and was significantly up-regulated in the EA group after EA stimulation (P < 0.01). Compared with the control group, the expression levels (optical density, OD values) of CD 4+ and CD 8+ lymphocytes in the thymus tissue were obviously decreased in the model group (P < 0.01). After EA, the expression levels of thymus CD 4+ and CD 8+ were remarkably up-regulated in the EA group (P < 0.05). No significant changes were found in proportion of open-arm time (OT%, P > 0.05). CONCLUSION: EA can effectively relieve anxiety disorder in anxiety rats, which may be related to its effects in up-regulating plasma CD 4+ , thymus CD 4+ and CD 8' levels as well as CD 4+/CD 8+ ratio, and down-regulating plasma CD 8+ content. PMID- 26502537 TI - [Effect of Electroacupuncture on 26 S Proteasome and Nuclear Factor kappa B in Substantia Nigra of Rats with Rotenone-induced Parkinson's Disease]. AB - OBJECTIVE: To explore the role of 26 S proteasome and nuclear factor kappa B (NFkappaB) in substantia nigra in the management of Parkinson's disease (PD) by acupuncture. METHODS: Forty-eight male SD rats were randomly divided into normal, sham operation, model and electroacupuncture (EA) groups (12 rats/group).. The PD model was established by 40-day consecutive subcutaneous injection of rotenone (1 mg/kg dissolved in dimethyl sulfoxide and normal saline) at the back shoulder. The rats in the sham operation group were treated by subcutaneous injection of dose of saline. "Fengfu" (GV 16) and "Taichong" (LR 3) acupoints were stimulated with EA at 2 Hz, 1 mA, 20 min of duration in each treatment, and daily for 28 consecutive days. The behavioral changes of rats in each group were measured and scored at 40th day and 68th day, respectively. Immunohistochemistry was used to determine the expression of tyrosine hydroxylase (TH) used to detect the expression of 26 S proteasome and NFkappaB and TH were measured by Western blot. RESULTS: In comparison with the normal and sham operation groups, the behavioral scores of rats in the model group were elevated, which were significantly decreased by EA intervention (P < 0.05). The expression of TH and 26 S proteasome decreased whereas the NFkappaB increased in the rats of model group (P < 0.05); and EA intervention reversed these changes (all P < 0.05). CONCLUSION: EA intervention can improve PD rats' behavioral changes, which is pobably related to its effects in reducing loss of TH-positive neurons, down-regulating NFkappaB protein expression, and up- regulating 26 S proteasome protein expression in the substantia nigra. PMID- 26502539 TI - [Effect of "Kidney-reinforcing and Govenor Vessel-regulating" of Acupuncture plus Moxibustion on Mitochondrial Dynamics-related Proteins in Hippocampal Neurons of Rats with Alzheimer's Disease]. AB - OBJECTIVE: To observe the effect of acupuncture plus moxibustion on mitochondrial dynamics-related proteins (OPA 1, Fis 1) of hippocampal neurons in rat with Alzheimer's disease (AD) , and to explore the potential mechanism underlying acupuncture for the protection of hippocampal neuronal mitochondria. METHODS: Eighty male Wistar rats were randomly divided into normal, sham-operation, model and acu-moxibustion groups. AD model was made by injecting Abeta1-42 into the hippocampus. "Baihui" (GV 20) and "Shenshu" (BL 23) acupoints were stimulated by manual acupuncture (15 min) in combination with moxibustion (15 min) for two sessions of treatment, with seven consecutive treatments for one session and one day break between the two sessions. The expression of hippocampal OPA 1 and Fis 1 was assessed by means of Western blot and immunofluorescence technique. RESULTS: The expression level of OPA 1 and Fis 1 of rats in the model group was significantly lower and higher, respectively, than those of the normal and sham operation groups (P < 0.01). Acupuncture plus moxibustion intervention notably increased OPA 1 and decreased Fis 1 expression levels in the acu-moxibustion group compared to those of the model group (P < 0.01). CONCLUSION: Acupuncture combined with moxibustion produce benefit to hippocampal neurons in AD rats probably via the regulation of the mitochondrial dynamics (imbalance between fission and fusion proteins) and improvement of the mitochondrial damage of hippocampus. PMID- 26502540 TI - [Effect of Acupotome Relaxing on Expression of Type I and II Collagens of Degenerative Cervical Inter- vertebral Discs in Rats]. AB - OBJECTIVE: To observe the effect of acupotome relaxing at cervical acupoints on type I and II collagens of degenerated cervical intervertebral discs in rats, so as to explore its potential mechanism underlying anti-degeneration of intervertebral discs. METHODS: Rats were randomly divided into control, model, Jiaji acupoints, cervical acupoints and medication groups (n = 15 in each group). The rat model of cervical intervertebral disc degeneration due to static-dynamic imbalance was made as previously specified. The Jiaji acupoints were those located along the cervical vertebra 2-7. The cervical acupoints included bilateral "Naokong"(GB 19) , "Naohu" (GV 17) , "Dazhui"(GV 14) , bilateral "Quyuan" (SI 13) and bilateral "Tianzong" (SI 11). Acupoints were treated according to the procedures of acupotome for 3 times in ten days with five days' break between every two treatment sessions. Rats of the medication group were intragastrically administered with Jing Fu Kang Granules and ibuprofen daily for ten days. Twenty days after the end of treatment, all rats were sacrificed for further examination of morphological changes of the intervertebral disc tissue. Immunoactivity of protein and mRNA expression levels of collagen type I and II of the intervertebral discs were measured by means of immunohistochemistry and RT PCR, respectively. RESULTS: In comparison with the control group, the immunoactivity and mRNA expression levels of collagen type I and II of the intervertebral discs were significantly elevated or reduced in rats of the model group, respectively (P < 0.05). After acupotome intervention and medication, the increased and decreased expression levels of type I and II collagen proteins and genes were markedly reversed (P < 0.05). The effects of acupotome relaxing of both cervical and Jiaji acupoints were significantly superior to those of medication in down-regulating expression of type I collagen protein and mRNA, and in up-regulating that of type II collagen protein and mRNA (P < 0.05). No significant differences were found between the cervical acupoints and Jiaji acupoints groups in the above- mentioned outcomes (P > 0.05) . The degree of severity of the degenerated intervertebral discs was the worst in the model group, followed by the medication group, then the Jiaji acupoints group and cervical acupoints group, and the control group the least. CONCLUSION: Acupotome at neck acupoints can regulate the extracellular matrix of the intervertebral disc via inhibiting the transformation between type I and type II collagens, which may contribute to its effect in delaying the degenerative process of the cervical intervertebral discs. PMID- 26502541 TI - [Effect of Electroacupuncture Stimulation of "Baihui" (GV 20) , etc. on Changes of Behavior and Plasma Ghrelin Content in Depression Rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Baihui" (GV 20) + "Anmian" (EX-HN 16) and "Baihui" (GV 20) + "Zusanli" (ST 36) on behavior reactions and plasma ghrelin level in depression rats, so as to explore the correlation between its antidepressant effect and plasma ghrelin level. METHODS: A total of 45 SD rats were randomly divided into 5 groups: normal control, model, Baihui (GV 20) + Anmian (EX-HN 16), Baihui (GV 20) + Zusanli (ST 36) and medication (clomipramine) groups, with 9 rats in each group. The depression model (unpredictable chronic mild stresses, UC-MS) was established by giving the animals with higher temperature environment (45 degrees C, 5 min), forced ice-water swimming (0- 4 degrees C, 5 min) , day and night reversal environment (12 h), stroboflash stimulation (12 h), noisy stimulation (12 h), rocking-bed movement (30 min) and damp pad dwelling (6-24 h), etc. for 4 weeks. EA was applied to GV 20-EX-HN 16, and GV 20-ST 36 for 30 min once every other day for 4 weeks after modeling. For rats of the medication group, clomipramine (5 mg/kg) was given (i. p. ) once a day for 4 weeks after modeling. The forced swimming test, sucrose preference test and open field test were used to evaluate the rats depressive-like behavior. Plasma ghrelin content was assayed by ELISA. RESULTS: After exposure to UCMS for 4 weeks, the immobility time was significantly increased, and the struggling time was significantly decreased in the model group (P < 0.05, P < 0.01). In comparison with the model group, the immobility time levels were obviously decreased, while the struggling time and sucrose preference were markedly increased in the Baihui (GV 20) + Anmian (EX-HN 16) , Baihui (GV 20) + Zusanli (ST 36) and medication groups (P < 0.05, P < 0.01). No significant changes were found in the rearing times and total distance of open-field test (locomotor activity) and plasma ghrelin content among the 5 groups among all the groups (P > 0.05). No significant differences were found among the two EA and medication groups in the decreased immobility time and the increased struggling times and sucrose preference levels (P > 0.05). CONCLUSION: EA intervention can improve the depression rats' hopeless behavior of forced swimming test and anhedonia behavior (sucrose preference test) , which may be not correlated to plasma ghrelin level at the late-stages and the antidepressant effect of EA intervention. PMID- 26502542 TI - [Effect of Electroacupuncture at "Zusanli" (ST 36), etc. on Gastrointestinal Motility and Expression of Ghrelin mRNA and Growth Hormone Secretagogue Receptor mRNA in Diabetic Gastroparesis Rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Zusanli" (ST 36), "Liangmen" (ST 21) and "Sanyinjiao" (SP 6) on gastrointestinal motility and expression of ghrelin and growth hormone secretagogue receptor (GHSR) mRNA in diabetic gastroparesis (diabetic gastroparesis, DGP) rats, so as to explore its mechanism underlying improvement of diabetic gastroparesis. METHODS: Sixty SD rats were randomly and equally divided into normal control, model, EA acupoint, EA non-acupoint, medication (metoclopramide) groups (n = 12 rat/group). The DGP model was established by intraperitoneal injection of streptozotocin (STZ, 55 mg/kg, 2%) and raised by high-sugar and high-fat fodder irregularly for 8 weeks. EA was applied to "Zusanli" (ST 36), "Liangmen" (ST 21) and "Sanyinjiao" (SP 6), and non-acupoints (about 5 mm lateral to the 3 acupoints, respectively). Those rats of the medication group were given with metoclopramide (1 mL/100 g). The blood sugar level was measured by glucometer, and the urine sugar level measured by Tes-Tape [urine glucose test paper]. The intestinal propulsion rate (IPR) was identified as ratio of the phenolsulfonphthalein promoting distance and the total length of the small intestine, and the gastric emptying rate (GER) was assessed by gavage of a liquid test meal (1.5 mL) containing a nonabsorbable marker (0. 5 mg/mL of phenol red in 5% glucose solution) and identification after being sacrificed 72 h after modeling. The expression levels of ghrelin mRNA and GHSR mRNA of gastric antrum tissue were examined by Quantitative real-time PCR. RESULTS: In comparison with the normal control group, the blood sugar and urine sugar levels of the model group was significantly increased in the model group (P < 0.01), while the GER and IPR and the expression level of ghrelin mRNA and GHSR mRNA in the gastric antrum were significantly decreased in the model group (P < 0.01, P < 0.05). Following EA stimulation of acupoint, the blood sugar and urine sugar levels were obviously down-regulated (P < 0.05), both GER and IPR, and ghrelin mRNA and GHSR mRNA expression levels in the EA-acupoint group were significantly up-regulated (P < 0.05, P < 0.01). No significant changes were found in both blood sugar and urine sugar levels, in both GER and IPR, and ghrelin mRNA and GHSR mRNA expression levels of both EA non-acupoint and medication groups after the intervention (P > 0.05). The GER and IPR were significantly higher in the EA acupoint group than in the EA non-acupoint group (P < 0.05, P < 0.01). CONCLUSION: EA stimulation of ST 36, ST 21 and SP 6 can promote the gastrointestinal motility of DGP rats, which may be closely associated with its effects in up-regulating the expression level of ghrelin mRNA and GHSR mRNA in gastric antrum. PMID- 26502543 TI - [The Impact of Electroacupuncture Intervention on Expression of 5-HTR 1 B/2 C Genes in Mice under Radiation Stimulation from Mobile Phone]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Yifen" (TE 17), "Shenshu" (BL 23) on the expression of 5-hydroxytryptamine receptor 1 B (5-HTR 1 B) mRNA and 5-hydroxytryptamine receptor 2 C (5-HTR 2 C) mRNA in the cochlear nucleus tissue in mice experiencing radiation from mobile phone, so as to explore its mechanisms underlying improvement of tinnitus. METHODS: Thirty Kunming mice were randomly divided into control group (n = 6) and modeling group (n = 24). The tinnitus model was established by giving the mice with mobile phone-radiation for 1 h in the morning and 1 h in the afternoon, continuously for 40 days. EA stimulation was applied to "Yifeng" (TE 17) group (n = 6) and "Shenshu" (BL 23) group (n = 6) for 20 min, once a day for 7 days. The expression of 5-THR 1 B/2 C mRNA in the cochlear nucleus was assayed by fluorescence quantitative polymerase chain reaction (real time-PCR). RESULTS: The expression level of 5-HTR 1 B was significantly lower in the model group than in the control group (P < 0.05), while that of 5-HTR 2 C mRNA significantly increased (P < 0.01). TE 17 group received a significant acupoint intervention effect (P < 0.01). Compared with TE 17 group, BL 23 group received a weaker effect (P < 0.05). CONCLUSION: EA of TE 17 can up-regulate expression level of 5 HTR 1 B and down-regulate expression level of 5-HTR 2 C in the cochlear nucleus in mice experiencing mobile-phone radiation. PMID- 26502544 TI - [Effect of Acupuncture plus Different Frequency Shock-wave Interventions on Pain Reactions and Motor Function in Knee Osteoarthritis Patients]. AB - OBJECTIVE: To observe the clinical effect of acupuncture plus shock-wave (SW) intervention for osteoarthritis (WA), so as to explore its practicability in clinical practice. METHODS: A total of 120 cases of knee OA patients were randomly divided into 4 groups, namely acupuncture (acupunct) + LFSW, acupunct + MFSW, acupunct + HFSW and routine acupunct groups, with 30 cases in each group. Xuehai (SP 10) , Liangqiu (ST 34), Yanglingquan (GB 34), Xiyan (ST 35) and Ashi point were punctured with filiform needles which were manipulated with uniform reinforcing-reducing techniques for 15-20 min, once every other day for 7 times. In addition, these acupoints were also respectively stimulated with shock waves(10 Hz, 14 Hz and 18 Hz, pressure: 1-4 bar) delivered from a DolorClastEMS therapeutic apparatus for 600 times in 3 acupunct+ SW groups. The patients' pain response changes of the knee-joint were assessed by using visual analog scale (VAS) and the motility was evaluated by using a 0-3 grade scale. RESULTS After 7 times of treatment, the patients' VAS scores and motility scores were significantly decreased in the acupunct+ LFSW, acupunct+ MFSW, acupunct+ HFSW and routine acupunct groups compared with their own basic values before treatment (P < 0.01), and the therapeutic effect of the acupunct+ MFSW group was significantly superior to those of the other 3 groups in reducing both VAS and motility scores (P < 0.05). Correspondingly, the Deqi sensation score of the acupunct+ MFSW group was markedly higher than those of the other 3 groups (P < 0.05). CONCLUSION: Shock wave acu-puncture treatment is effective in relieving OA patients' knee joint pain and functional activity, and the therapeutic effect of acu- punct + 14 Hz-SW is better, which is closely with Deqi-sensation. PMID- 26502545 TI - [Clinical Observation on Therapeutic Effect of Red-hot Needle Therapy for Spastic Hemiplegia in Stroke Patients]. AB - OBJECTIVE: To observe the curative effect of fire needle treatment on spastic hemiplegia in patients with stroke. METHODS: A total of 80 stroke patients with spastic hemiplegia who met the inclusion criteria were randomly divided into routine acupuncture (control) group and red-hot needle group (n = 40 cases in each group). Patients of the red-hot needle group were treated by pricking unilateral Jianyu (LI 15), Binao (LI 14), Quchi (LI 11), Shousanli (LI 10), Yinlingquan (SP 9), Xuehai (SP 10) , etc. with a cauterized needle, once every other day for 30 days; while those of the control group were treated by acupuncture stimulation of unilateral Jianyu (LI 15), Quchi (LI 11), Shousanli (LI 10), Huantiao (GB 30), Fengshi (GB 31), Yanglingquan (GB 34), etc. with filiform needles, once daily for 30 days. The muscular tension was evaluated using modified Ashworth Scale (MAS) and, the limb motor function evaluated using Fugl-Meyer Assessment Scale (FMA). RESULTS: After the treatment, the muscular tension of both upper and lower limbs in the red-hot needle and routine acupuncture groups was significantly reduced (P < 0.05), exhibiting an appearance of the stroke patients with MAS grade 0 (upper and lower limbs: 7 and 6 cases, 15 and 12 cases in the control and red-hot needle groups). The FMA scores of both upper and lower limbs were remarkably increased in both control and red-hot needle groups after the treatment (P < 0.01, P < 0.05), suggesting an improvement of the patients' motor function. The improvement of the muscular tension and motor function of upper limbs in the red-hot needle group was superior to that in the routine acupuncture group (P < 0.05, P < 0.01). No significant differences were found between the two groups in both MAS grades and FMA scores of lower limbs after the treatment (P > 0.05). Of the two 40 cases in the control and red hot needle groups, 5 and 13 were basically cured, 11 and 8 had marked improvement, 10 and 14 were improved, 14 and 5 ineffective, with the effective rates being 65.0% and 87.5%, respectively. CONCLUSION: Red-hot needle therapy is effective in reducing muscular tension and improving motor function of the limbs in hemiplegia patients. PMID- 26502546 TI - [Effects of Electroacupuncture Stimulation of Zhongwan (CV 12) on Skin Microcirculatory Blood Perfusion Levels along the Conception Vessel in Yin deficiency Constitution Volunteers]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation at Zhongwan (CV 12) on the skin microcirculatory blood flow along the Conception Vessel (CV) in yin-deficiency constitution volunteers. METHODS: A total of 16 yin deficiency constitution volunteers (9 woman and 6 men) from 200 students of Fujian University of Traditional Chinese Medicine finished a body constitution questionnaire and showed a yin-deficiency constitution. Skin microcirculatory blood perfusion units (MBPU) at Danzhong (CV 17), Xiawan (CV 10) , and Qihai (CV 6) of the CV were measured by using a Laser Doppler Flowmetry (Peri Flux 5000) in normal constitution, before and after EA stimulation of Zhongwan (CV 12) for 20 min. RESULTS: Under normal condition, the cutaneous MBPU values were significantly lower in the Qihai (CV 6) than in both Danzhong (CV 17) and Xiawan (CV 10) (P < 0.01). After EA stimulation of CV 12 for 20 min, the MBPU values were significantly decreased in the CV 17 and CV 6 acupoint regions compared with pre-stimulation (P < 0.05). No significant changes of skin MBPU were found in Xiawan (CV 10) after EA stimulation of CV 12 (P > 0.05). CONCLUSION: EA at Zhongwan (CV 12) can reduce the skin MBPU values of CV 6 and CV 17 of the Conception Vessel in yin-deficiency constitution volunteers. PMID- 26502547 TI - [Development of Researches on Mechanisms of Acupoint Combination for Some Disorders in Nerve-humoral-immunological Modulation]. AB - Proper combination of acupoints is one of the core issues of acupuncturology, and is also one of the factors affecting clinical outcomes. In the present paper, the authors make a review on the development of researches on the underlying mechanisms of acupoint combination for some clinical disorders from nerve system, humoral factors and immunological regulation. The neural mechanism involves both the peripheral nervous system (mainly the segmental innervation) and central nervous system (spinal cord, brainstem, hypothalamus, cerebral cortex and cerebellum) , while the humoral factors chiefly contain neurotransmitters and hormones of the endocrine system. The immunological mechanisms involve immunocytes and cytokines. Generally speaking, following acupuncture stimulation of different combined-acupoints or acupoint groups, some synergistic effects may be produced. In fact, the relatively specific clinical effect may be easy to be obtained at the peripheral segmental innervations level. PMID- 26502548 TI - [A Meta-analysis on Acupuncture Treatment of Attention Deficit/Hyperactivity Disorder]. AB - OBJECTIVE: To assess the efficacy and safety of acupuncture in treating attention deficit/hyperactivity disorder (ADHD) children. METHODS: A literature search was conducted to retrieve randomized cotrolled clinical trials of acupuncture in treating ADHD covering the period of the years of establishment of the databases to January 2014 from database of CBM, CNKI, PubMed, Cochrane Library by using key words "attention deficit hyperactivity disorder" "hyperactivity""minimal brain dysfunction" "acupuncture". Two independent researchers extracted data from located articles in a pre-defined structured way, and consulted the third researcher if necessary. RESULTS: Thirteen original trials including 1 304 cases of children with ADHD were obtained in this study according to our included criteria and excluded criteria. In these trials, acupuncture intervention alone, or acupuncture plus pharmacotherapy (methylphenidate, haloperidol) or acupuncture plus behavioral therapy were compared with simple pharmacotherapy or behavioral therapy alone. Results of Meta-analysis indicated that the total effective rate and Conners' index of hyperactivity (CIH) score-reduction rate in the acupuncture group were significantly superior to those of the other treatment groups [OR = 2.22, 95% CI (1.65, 3.00), Z = 5.22, P < 0.00001] [SMD = -0.94, 95% CI (-1.41, 0.47), Z = 3.89, P < 0.0001]. Acupuncture treatment is more effective than haloperidol in reducing the score of Conners' Rating Scale for ADHD [SMD = -7.28, 95% CI (-8.32, -6.23), Z = 13.62, P < 0.00001]. Acupuncture is similarly effective as Methylphenidate (Ritalin) in improving the Chinese medicine syndrome (liver-kidney yin hypoactivity) of children with ADHD [SMD = -1.14, 95% CI ( 2.53, 0.25), Z = 1.60, P = 0.11]. Less severe adverse effects were reported with acupuncture therapy than the pharmacotherapy (poor appetite, dry mouth, nausea and constipation). These effects were not likely due to publication bias (approximately symmetry funnel plot, Egger's test P > 0.1). CONCLUSION: Acupuncture is an effective and safe therapy in treating ADHD, combined administration of acupuncture and pharmacotherapy or behavioral therapy is more effective than the pharmacotherapy or behavioral therapy alone. However, more rigorously designed and high-quality RCTs are needed to confirm the above conclusion. PMID- 26502549 TI - [Principles and Methods for Formulating National Standards of "Regulations of Acupuncture-nee- dle Manipulating techniques"]. AB - The national standard of "Regulations of Acupuncture-needle Manipulating Techniques" is one of the national Criteria of Acupuncturology for which a total of 22 items have been already established. In the process of formulation, a series of common and specific problems have been met. In the present paper, the authors expound these problems from 3 aspects, namely principles for formulation, methods for formulating criteria, and considerations about some problems. The formulating principles include selection and regulations of principles for technique classification and technique-related key factors. The main methods for formulating criteria are 1) taking the literature as the theoretical foundation, 2) taking the clinical practice as the supporting evidence, and 3) taking the expounded suggestions or conclusions through peer review. PMID- 26502550 TI - [Methods for Accurately Locating "Feishu" (BL 13) in Rats]. AB - "Feishu" (BL 13) is a commonly used acupoint in experimental study,'but its definite position has not been described in current books about acupoints. In the'present paper, the authors introduced three methods for determining the anatomical location of "Feishu" (BL 13) acupoint in rats. The Wistar rats (200 +/ 20) g were anesthetized with 10% chloral hydrate first, and then, fixed at the prone position. The highest point of the spinous process of the second thoracic vertebra was used as the marker for positioning the spinal vertebra. The point, 7 mm lateral to the site below the spinous process of the 3rd thoracic vertebra is just the "Feishu" (BL 13). In order to determine the 3rd thoracic vertebra, three methods are recommended to be adopted: 1) finding the 5th thoracic vertebra process parallel to the inferior angle of the scapula first, then going upwards to find the 3rd thoracic vertebra , 2) finding the 1st thoracic vertebra along the 1st rib, then going downward to find the 3rd thoracic vertebra, and 3) taking the 6th lumbar vertebra (parallel to the hip-joint) as the bone-marker and going upward to find the 3rd thoracic vertebra. When "Feishu" (BL 13) punctured, a filiform needle was straight inserted into the skin, then downward to the subcutaneous tissue, muscular layer (including the trunk cutaneous muscle, trapezius muscle, broadest muscle of back, serratus muscle of back, atalanto longest muscle, longest muscle of neck, longest muscle of thorax, lumbar longest muscle, the medial part of the longest muscle, cervico-spinal muscle of back-, semispinal muscle of neck, biventer cervicis, and multifidus muscles) about 6 mm in depth. PMID- 26502551 TI - [Potential Mechanisms Underlying Acupuncture Regulation on Hypertensive Myocardial Hypertrophy and Cardiac Function Damage]. AB - Long-lasting hypertension results in ventricular remodeling characteristic of myocardial hypertrophy including myocyte hypertrophy and myocardial fibrosis, a pathological process failed to be blocked by the current biomedical means and could eventually lead to heart failure. It has been shown that acupuncture can excite the parasympathetic nerve to counter the overtonic activity of sympathetic nerve, elicit antihypertensive effect and produce cardioprotection via the regulation of calcium signaling-related proteins in myocytes, suggesting its potential role in the management of these disorders. In this paper, the authors review relevant studies and propose, with respect to the autonomic nerve, endocrine system, cytokines and intracellular calcium signaling pathways, several novel ideas concerning the treatment of hypertensive myocardial hypertrophy and cardiac malfunction by acupuncture. PMID- 26502552 TI - [Professor MA Ji-xing and Acupuncture Scientification at the Primary Stage of Establishment of the People's Republic of China]. AB - In the initial stage (1950s) of the establishment of the People's Republic of China, the Pavlov's theory played an important influence on Chinese biology and medical science fields. At that time, many schools or colleges of traditional Chinese medicine were set up one after another, the first edition of teaching materials or textbook was complete, and a lot of advanced training courses and training classes were developed. In that specific period of "acupuncture scientification", Mr. MA Ji-xing, a professor from China Academy of Traditional Chinese Medicine, is a representative scholar who employed Pavlov's theory to make a scientific explanation about the underlying physiological mechanisms of acupuncture-moxibustion therapy. For example, he employed nerve network or nerve system to explain topical acupuncture stimulation and distal stimulation to induce local effect or distal curative effect, employed the cutaneous-visceral reflex to explain the therapeutic effect of acu-moxibustion for visceral disorders, used the viscera-cutaneous reflex to explain the tender point (sensitized region) or Ashi-point, used the "predominant factor mechanism" or excitation transfer of the stimulated non-sensitized cutaneous region close to the diseased locus to explain the pain-relief of acupuncture stimulation, used the stimulation strength, duration, frequency and distance (to the locus) to explain the needling reinforcing or reducing effect, and so on and so forth. He wrote many articles and books about acupuncturology, one of which was named Jianyao Zhenjiu Xue (Concise Acupuncturology), a well-known demonstration teaching material for advanced training courses, inducing a significant influence on the acu-moxibustion field in both academic field and clinical practice. Looking back this period of history may provide a helpful reference for current research on academic development of acupuncturology. PMID- 26502553 TI - Considering the Importance of Theories in Relation to Defined Populations. PMID- 26502554 TI - Testing a Theoretical Model of Immigration Transition and Physical Activity. AB - The purposes of the study were to develop a theoretical model to explain the relationships between immigration transition and midlife women's physical activity and test the relationships among the major variables of the model. A theoretical model, which was developed based on transitions theory and the midlife women's attitudes toward physical activity theory, consists of 4 major variables, including length of stay in the United States, country of birth, level of acculturation, and midlife women's physical activity. To test the theoretical model, a secondary analysis with data from 127 Hispanic women and 123 non Hispanic (NH) Asian women in a national Internet study was used. Among the major variables of the model, length of stay in the United States was negatively associated with physical activity in Hispanic women. Level of acculturation in NH Asian women was positively correlated with women's physical activity. Country of birth and level of acculturation were significant factors that influenced physical activity in both Hispanic and NH Asian women. The findings support the theoretical model that was developed to examine relationships between immigration transition and physical activity; it shows that immigration transition can play an essential role in influencing health behaviors of immigrant populations in the United States. The NH theoretical model can be widely used in nursing practice and research that focus on immigrant women and their health behaviors. Health care providers need to consider the influences of immigration transition to promote immigrant women's physical activity. PMID- 26502555 TI - Predictors of Breastfeeding Attitudes Among College-Educated African Americans. AB - Breastfeeding initiation among African American women has reached 60%; however, it is the lowest rate among all races. This racial disparity is a public health concern considering the impact of breastfeeding on infant morbidity and mortality. The purpose of this study was to explore breastfeeding exposure and determinants of breastfeeding attitudes among African Americans. The theory of planned behavior guided this study focusing on the impact of background factors on determinants of breastfeeding attitudes. This secondary analysis included 348 African American college students with a mean age of 22 years with no children. The Iowa Infant Feeding Attitude Scale and a demographic questionnaire were used to collect data. A significant association between knowing someone who breastfed her infant and being breastfed as an infant (p < .001) was observed. Although gender, education, and breastfeeding exposure explained 15% of the variance in breastfeeding attitudes, being breastfed as an infant had no significant (p = .611) contribution. Breastfeeding exposure to someone who has breastfed her infant is a modifiable factor that influenced positive breastfeeding attitudes. Therefore, it is essential to identify strategies in practice to increase breastfeeding exposure for vulnerable populations in efforts to improve breastfeeding attitudes, intentions, and initiation. PMID- 26502556 TI - Applying the Theory of Planned Behavior to Explain Women's Role in Prostate Cancer Screening. AB - OBJECTIVE: To test the suitability of the theory of planned behavior (TPB) for explaining Italian women's role in prostatic cancer screening promotion. DESIGN/METHODS: A descriptive, cross-sectional, online self-report survey was conducted with a convenience sample of 235 Italian women. Variables included attitudes women's role, perceived behavioral control, subjective norm, behavioral intention, and prostate cancer screening promotion behavior. A survey composed of the Eastland Prostate Cancer Survey subscales that were consistent with the TPB was distributed via e-mail to potential participants. The survey was live for 12 weeks (March 2013 to May 2013). Responses were collated with eSurv.org. Data were analyzed using latent path analysis and structural equation modeling. RESULTS: Behavioral intentions in promoting prostate cancer screening significantly predicted the likelihood of the Italian women to adopt self-reported prostate cancer screening promotion behaviors. In addition, the exclusive direct impact of the intentions explained 39% of the variance in self-reported behaviors. CONCLUSIONS: The TPB could represent a good framework to explain the role of Italian women in prevention behaviors related to the prostatic screening domain. Consistent with literature findings in social and nursing sciences, the intention to promote prostate cancer screening was a powerful "predictor" of the behavior itself. PMID- 26502557 TI - The Key Role of Nurse Researchers in the Evaluation of Nurse Practitioner Models of Practice. AB - The Nurse Practitioner-Aged Care Models of Practice Program involved diverse models of practice comprising multiple stakeholders located in more than 30 locations across Australia, in remote, rural, urban, and metropolitan settings. Funded by the Australian government, the aims of the program included supporting development of effective, economically viable, and sustainable aged care nurse practitioner models of practice; and enabling improvements in access to primary health care for people aged older than 65 years. This article describes the process by which a framework was developed to support the evaluation of this program. A particular challenge for the nurse researchers involved in the evaluation was to ensure the unique values of the nursing profession were upheld alongside economic, biomedical, and empirical imperatives in the diverse processes involved in collecting and interpreting data. The evaluation framework developed provides an important means of enabling research teams who undertake complex evaluations of diverse nursing models of practice to maintain a common goal--to unify the various stakeholders involved, while at the same time upholding what is most important to the profession of nursing. This article highlights how nurses can play an influential role when involved in the multidisciplinary evaluation of new andinnovative approaches to practice. PMID- 26502558 TI - Job Satisfaction of Nurses and Its Moderating Effects on the Relationship Between Organizational Commitment and Organizational Citizenship Behaviors. AB - Because nurses deliver care to patients on behalf of hospitals, hospitals should enhance the spontaneous organizational citizenship behaviors of front-line nurses to increase patient satisfaction and, hence, to increase the competitiveness of the hospital. However, a major gap in the literature is the lack of evidence based studies of the correlations among job satisfaction, organizational commitment, and organizational citizenship behaviors in nursing personnel. Therefore, this study performed a cross-sectional survey of nurses in 1 large hospital in Taiwan; out of 400 questionnaires distributed, 386 valid questionnaires were collected, which was a valid response rate of 96.50%. The survey results revealed that organizational commitment has a significant positive effect on organizational citizenship behaviors (gamma11 = 0.57, p < .01) and that job satisfaction has a significant positive moderating effect on the relationship between organizational commitment and organizational citizenship behaviors (Deltachi2 = 26.397, p < .01). Therefore, hospitals can improve the job satisfaction of their nursing staff by improving perceived working satisfaction, interpersonal satisfaction, and remunerative satisfaction, which would then improve organizational commitment and organizational citizenship behaviors. PMID- 26502559 TI - On the Shoulders of Giants. PMID- 26502560 TI - Characterization of "Hydrocarbon" Dry Cleaning in King County, Washington. AB - In King County, Washington, the most frequently used alternative solvent to perchloroethylene is a hydrotreated petroleum hydrocarbon. The objectives of the authors' study were to 1) determine the frequency of use of process chemicals used in "hydrocarbon" dry cleaning and gather other operational information; 2) chemically characterize the process chemicals; 3) characterize the still bottoms and separator water wastes according to dangerous waste and wastewater discharge regulations; 4) identify linkages between work practices, process chemicals, and the chemical composition of the waste streams; and 5) evaluate the aquatic toxicity of the hydrocarbon solvent and detergent. Many hydrocarbon dry cleaners are using process chemicals that contain hazardous substances, including trichloroethylene. One sample of separator water contained 13,000 ug/L trichloroethylene. This sample was determined to be federal hazardous waste, state-only dangerous waste (i.e., according to Washington state-specific regulations), and failed wastewater discharge thresholds. All still bottoms were determined to be state-only dangerous wastes. Efforts should be directed towards replacing hazardous spot cleaning chemicals with safer alternatives and ensuring that wastes are disposed of appropriately. PMID- 26502561 TI - Methyl Iodide Fumigation of Bacillus anthracis Spores. AB - Fumigation techniques such as chlorine dioxide, vaporous hydrogen peroxide, and paraformaldehyde previously used to decontaminate items, rooms, and buildings following contamination with Bacillus anthracis spores are often incompatible with materials (e.g., porous surfaces, organics, and metals), causing damage or residue. Alternative fumigation with methyl bromide is subject to U.S. and international restrictions due to its ozone-depleting properties. Methyl iodide, however, does not pose a risk to the ozone layer and has previously been demonstrated as a fumigant for fungi, insects, and nematodes. Until now, methyl iodide has not been evaluated against Bacillus anthracis. Sterne strain Bacillus anthracis spores were subjected to methyl iodide fumigation at room temperature and at 550C. Efficacy was measured on a log-scale with a 6-log reduction in CFUs being considered successful compared to the U.S. Environmental Protection Agency biocide standard. Such efficacies were obtained after just one hour at 55 degrees C and after 12 hours at room temperature. No detrimental effects were observed on glassware, PTFE O-rings, or stainless steel. This is the first reported efficacy of methyl iodide in the reduction of Bacillus anthracis spore contamination at ambient and elevated temperatures. PMID- 26502562 TI - Characteristics of Noncompliant Food Handling Establishments and Factors That Inhibit Compliance in a Regional Health Authority, Jamaica. AB - The Jamaican food safety regulatory framework is embodied in the Public Health Act of 1974 with public health inspectors/ environmental health officers (PHIs/EHOs) empowered with its enforcement. The North East Regional Health Authority (NERHA) has consistently faced challenges in achieving national certification targets for food-handling establishments (FHEs). The aim of the authors' study was to identify and describe noncompliant FHEs and to identify factors influencing their noncompliance. FHEs (N = 248) were randomly selected and each owner/operator targeted for interview. Substantially more FHEs were compliant and respondents from compliant FHEs were more likely to have a valid food handlers' permit. Urban FHEs were less likely to be compliant than rural. The major barriers to compliance were forgetting to apply for a license and lack of money to correct infractions. NERHA should encourage FHE owners/operators to assume greater responsibility for the certification of their premises and to hold PHIs more accountable. PMID- 26502563 TI - The 2014 Dallas, Texas, Ebola Incident: Global Implications to All-Hazards Preparedness and Health Care Worker Protection. PMID- 26502564 TI - Embracing a Unified Brand Builds Capacity for Health Departments. PMID- 26502565 TI - The Need for Environmental Public Health Professionals and the Role of EHAC Accredited Programs in Increasing the Pool. PMID- 26502566 TI - The Navajo Birth Cohort Study. PMID- 26502567 TI - Letter Grading and Transparency Promote Restaurant Food Safety in New York City. PMID- 26502568 TI - HUD's Healthy Homes Program: Progress and Future Directions. PMID- 26502569 TI - Industry-Foodborne Illness Investigation Training and Recall Response (I-FIIT RR): A Three-Year Project of Collaboration. PMID- 26502570 TI - Go Big or Go Home. PMID- 26502571 TI - [Effect of alcohol on vascular function]. AB - Vascular function is regulated by a balance of vasoconstriction and vasorelaxation. Disorder in this balance due to alcohol consumption causes various clinical conditions. In this review, we discuss the effects of acute and chronic ethanol consumption on vascular responses, including vasoconstriction, endothelium-dependent vasorelaxation, and nerve-mediated vasorelaxation. Acute ethanol administration induces vasoconstriction in ethanol-naive animals in vitro. Furthermore, ethanol can both potentiate and suppress agonist-induced Ca(2+)-dependent vasoconstriction. Moreover, ethanol augments Ca(2+)-independent vasoconstriction by increasing Ca2+ sensitivity. Endothelium-dependent relaxation is mediated by the nitric oxide (NO) pathway and the endothelium-derived hyperpolarizing factor (EDHF) pathway. Acute ethanol treatment inhibits both NO- and EDHF-mediated relaxation. Furthermore, acute ethanol ingestion can also potentiate and suppress calcitonin gene-related peptide (CGRP)-induced nerve mediated relaxation. These opposing effects may be due to differences in species or vascular beds. Thus, acute ethanol treatment decreases vasorelaxation, thereby shifting the contraction-relaxation balance towards contraction. Combined, these effects are one mechanism by which acute heavy alcohol consumption causes circulatory disturbances such as vasospasms or ischemic heart disease. In contrast, chronic low-dose ethanol has no effect on vasoconstriction, whereas chronic high-dose ethanol increases vasoconstriction. Additionally, chronic ethanol intake has diminished, unchanged, and even increased effects on nerve mediated relaxation; therefore, conclusions on these effects are not possible at present. Interestingly, chronic low-dose ethanol administration enhanced endothelium-dependent relaxation; however, higher doses inhibited these responses. Therefore, regular or light-to-moderate alcohol intake increases vasorelaxation and may suppress elevated blood pressure, whereas chronic heavy alcohol consumption may raise blood pressure, causing various clinical conditions. PMID- 26502572 TI - [Behavioral characteristics of nicotine seeking: a role of the nicotine conditioned effects and other mechanisms]. AB - Nicotine dependence and its neural mechanisms have been well documented by pharmacological, behavioral and neuroscience studies. In this review, we introduce recent new findings in this theme, particularly on the role of nicotine -associated stimuli as non-pharmacological factors affecting maintaining/reinstating nicotine seeking. By using the techniques of drug self administration and conditioned place preference, nicotine's specific property of forming seeking/taking behavior is well characterized, and the mechanisms of seeking/taking could be partly explained by discrete and/or contextual conditioned stimuli (dCS and cCS). After having the repeated Pavlovian conditioning in the training/conditioning sessions, CSs begin to play a key role for eliciting nicotine seeking behavior, with the activation of mesolimbic dopaminergic systems. In our study, intracranial self- stimulation (ICSS) was used to assess the mesolimbic dopamine activity. The nicotine-associated cCS also activated this neural system, which resulted in decreasing the ICSS threshold approximately 20% in the testing session under the cCS presentation. This finding would support the evidence of CS-induced incentive motivation for nicotine. According to the incentive salience hypothesis, the mesolimbic dopamine reflects the motivation elicited by incentives (CSs), and induces the drug seeking behavior, which is activated through amygdala--nucleus accumbens--medial prefrontal cortex circuit. Additionally, human brain imaging studies have revealed that tobacco- associated stimuli activate not only these regions, but also right temporo-parietal junction of human cortex, which is relevant to the visual attention. In summary, the above evidence shows that nicotine-conditioned stimuli might have powerful incentive salience and regulate nicotine seeking/taking behavior in animals and humans, though stress and nicotine withdrawal could also enhance nicotine taking in the same way as other dependence -producing mechanisms. PMID- 26502573 TI - The Influence of Drinking Based on Data from Health Check-up. AB - A survey of 21,493 patients who visited our Health Check-up Center during the 6 year period from 2005 to 2010 was conducted for the endpoints of drinking situation and various lifestyle-related diseases. Males accounted for 57.2% (mean age: 53.2 +/- 11.4) and females accounted for 42.8% (mean age: 52.5 +/- 11.4) of patients surveyed. Patients with no drinking habit accounted for 24.8% and 62.9% of males and females, respectively, and a large gender difference was seen in drinking frequency. When examined by age group, drinking frequency was found to increase with age in males, but gradually decreased with age in females. An examination of alcohol consumption in males revealed that 23.5% had an ethanol conversion rate of 10 g/day, 19.1% had a rate of < 20 g/day, and 18.2% had a rate of < 40 g/day. Meanwhile, in females, 22.7% had a rate of <= 10 g/day, 7.6% had a rate of <= 20 g/day and 4.6% had a rate of <= 40 g/day. The association between lifestyle-related disease endpoints and alcohol consumption was next examined by multivariate logistic analysis. The association between drinking and body mass index (BMI) revealed an odds ratio of around 0.8 in patients who consumed <= 40 g/day and a significantly reduced frequency of obesity. The odds ratio of hypertension increased in a dose-dependent manner from 1.3 to 1.6 in patients who consumed >= 40 g/day. The frequency of high low-density lipoprotein cholesterol (LDL-C) was reduced in light drinkers and the odds ratio decreased from 0.77 to about 0.6 as alcohol consumption increased: The frequency of low high-density lipoprotein cholesterol (HDL-C) was similarly reduced in light drinkers, and the odds ratio decreased remarkably in a dose-dependent manner from 0.73 to 0.22 as alcohol consumption increased. The risk of triglycerides was reduced in light drinkers and was conversely significantly enhanced in heavy drinkers. In patients who consumed >= 20 g/day, the risk of impaired glucose tolerance increased significantly in a dose-dependent manner. Increased risk of hyperuricemia was seen even in light drinkers. and the odds ratio increased from 1.2 to 1.8 as alcohol consumption increased. The results of this cross-sectional study suggested that light drinking has a positive effect on BMI, LDL-C, HDL-C and triglycerides. On the other hand, heavy drinking was found to have a positive effect on LDL-C and HDL-C, but a negative effect on systolic blood pressure, triglycerides, fasting blood glucose and uric acid. PMID- 26502574 TI - The Inhibitory Effect of Ethanol on Interleukin-1 beta-Induced Suppression of Contractile Response in the Rat Superior Mesenteric Artery. AB - Interleukin (IL)-1 beta is a cytokine that is upregulated by the pro-inflammatory bacterial endotoxin lipopolysaccharide. This study examined the effect of ethanol on IL-1 beta-mediated suppression of phenylephrine-induced contractility and inducible nitric oxide synthase (iNOS) expression in the rat superior mesenteric artery (SMA). IL-1 beta suppressed the phenylephrine-induced contractile response, and this effect was inhibited by ethanol. The IL-1 beta-mediated effects were also blocked by cycloheximide, an inhibitor of protein synthesis, as well as AMT and 1400W, which are iNOS inhibitors, and PTIO, an NO scavenger. However, indomethacin, a cyclooxygenase (COX) inhibitor that promotes NO independent vasodilation, did not affect IL-1 beta-mediated suppression of the contractile response. Western blot analysis revealed that iNOS levels in SMA were upregulated by IL-1 beta and inhibited by ethanol (50 and 100 mM). These results indicate that the suppression of the SMA contractile response by IL-1 beta requires iNOS activity, but not COX-2. Furthermore, these data suggest that ethanol inhibits the effects of IL-1 beta on the contractile response via inhibition of iNOS, rather than COX-2. PMID- 26502575 TI - [Alcohol withdrawal syndrome showing various progress: A case report]. AB - We experienced a case showing various psychotic symptoms following cessation of alcohol consumption. The symptoms included depressive state, delusion, confusion, psychomotor excitement and delirium, all of which disappeared in about two months. At first, we regarded all the symptoms as alcoholic hallucinosis, by a clinical standpoint, in spite of no auditory hallucination in this case. However, taking the overall clinical course into consideration, withdrawal syndrome could have been affected by some factors. One of the possibilities is that delusion might have been induced by aripiprazole. There still may be some other unknown influential factors on withdrawal, which are indicated by previous papers. PMID- 26502576 TI - [What about all those non-inferiority trials to demonstrate the cardiovascular safety of new antidiabetic drugs?]. PMID- 26502577 TI - [2015 updated position statement of the management of hyperglycaemia in type 2 diabetes]. AB - The strategy for the management ot type 2 diabetes, summarized by a group of European and American experts, has been updated early 2015. A patient-centered approach is recommended and the first drug choice is metformin combined with lifestyle improvement. After failure of metformin monotherapy, the selection of a second drug should be based on the efficacy, safety and cost of each pharmacological class. When compared to the position statement of 2012, the most important changes are the possible addition of a gliptin to a dual oral therapy or even to insulin, the commercialization of sodium-glucose cotransporters type 2 (SGLT2) inhibitors (gliflozins, to be used in dual or triple therapy, even in combination with insulin) and the possible combination of a glucagon-like peptide I receptor agonist together with a basal insulin. PMID- 26502578 TI - [Gliptins, cardiovascular safety and congestive heart failure: state of the art after TECOS]. AB - The cardiovascular safety of dipeptidyl peptidase-4 inhibitors (gliptins) has been well studied. Favourable effects of these oral antidiabetic agents have been reported in meta-analyses of phase II-III randomised controlled trials. Three large prospective trials, which were specifically designed to investigate cardiovascular safety, showed non-inferiority of saxagliptin (SAVOR-TIMI 53), alogliptin (EXA-MINE) and sitagliptin (TECOS) versus placebo as far as major cardiovascular events are concerned, including mortality. The suspected increase in the rate of hospitalisation due to congestive heart failure reported in SAVOR TIMI 53 was neither found in EXAMINE nor recently confirmed in TECOS. Direct comparative trials, evaluating not only safety but also efficacy, with other oral antidiabetic medications would be of major interest. PMID- 26502579 TI - [Diabetic kidney disease: current management and potential future options]. AB - The diabetic kidney disease is the most frequent cause of end stage renal disease in Western countries. Its detection is obtained by simultaneously measuring urinary albumin excretion and estimating glomerular filtration rate through serum creatinine dosage. Many type 1 and type 2 diabetic patients can present decreased glomerular filtration rate before the occurrence of increased urinary albumin. While waiting for promising new pharmacological approaches currently evaluated in clinical trials, the best approach to stop the epidemic of diabetic nephropathy remains an early and individual multifactorial approach controlling the glucose level (without inducing hypoglycaemia), blood pressure (using a renin-angiotensin blocker), dyslipidaemia and over-weight. PMID- 26502580 TI - [Evolution in the therapeutic strategy of localized resectable pancreatic ductal adenocarcinoma]. AB - Pancreatic ductal adenocarcinoma is characterized by a high rate of early metastatic relapse. Surgical resection is still recognized as the cornerstone upfront therapy. However, reported 5 years survival rates are inferior to 20-25% even when surgery is followed by chemotherapy. Margins involvement on the surgical specimen (50 to 85%) and lymph node involvement (around 70%) both strongly impact survival. Median survivals are close to those of locally advanced diseases treated by chemotherapy or chemoradiotherapy, 15 to 16 months. This review focuses on adverse prognostic factors, post-operative outcomes and their impact on multimodality therapy completion rates and survivals in patients undergoing upfront surgery. Current data and emerging results from neoadjuvant series could lead to a change in the therapeutic strategy. PMID- 26502581 TI - [Current management of marginal zone lymphomas]. AB - Marginal zone lymphomas (MZL) encompass three sub-types: MALT (Mucosae Associated Lymphoid Tissue) MZL, nodal MZL and splenic MZL. Immunophenotyping is essential for accurate diagnosis. Helicobacter Pylori is frequently associated with gastric localizations and its eradication can be sufficient for cure. Treatment of nodal MZL is similar to that of follicular lymphoma. Eradication of hepatitis C virus, frequently associated with splenic MZL development, can be sufficient. Without HCV infection, splenectomy constitutes first line therapy. As other indolent lymphomas, disseminated MZL are incurable and treatment should be started only in symptomatic patients. PMID- 26502582 TI - [The diagnostic scores for deep venous thrombosis]. AB - Seven diagnostic scores for the deep venous thrombosis (DVT) of lower limbs are analyzed and compared. Two features make this exer- cise difficult: the problem of distal DVT and of their proximal extension and the status of patients, whether out- or in-patients. The most popular score is the Wells score (1997), modi- fied in 2003. It includes one subjective ele- ment based on clinical judgment. The Primary Care score 12005), less known, has similar pro- perties, but uses only objective data. The pre- sent trend is to associate clinical scores with the dosage of D-Dimers to rule out with a good sensitivity the probability of TVP. For the upper limb DVT, the Constans score (2008) is available, which can also be coupled with D-Dimers testing (Kleinjan). PMID- 26502583 TI - [Male/female medical students conduct research in the community]. PMID- 26502584 TI - [Sudden death: are we ready to use defibrillators?]. PMID- 26502585 TI - [Paraplegic on wheelchair in Lausanne: how to make sure that everything goes well?]. PMID- 26502586 TI - [Living with intersexuals: a multidisciplinary approach]. PMID- 26502588 TI - [The first vaccines against dengue and malaria are advertised on the market]. PMID- 26502587 TI - [My breasts, my choice - Prophylactic mastectomy]. PMID- 26502589 TI - [Mus musculus sapiens]. PMID- 26502590 TI - [August 2015: miscellanea on malaria, alcoholism and road accidents]. PMID- 26502591 TI - [Infarction with ST segment elevation: room air versus oxygen?]. PMID- 26502592 TI - [Is the French hospital medicine solvable in foreign money?]. PMID- 26502593 TI - [The FOPH is launching a website comparing the activity of hospitals]. PMID- 26502594 TI - [More than two million chronically ill in Switzerland]. PMID- 26502595 TI - [Will technology make doctors nurses?]. PMID- 26502596 TI - SOCIAL ACCOUNTABILITY IN THE DENTAL PROFESSION. PMID- 26502597 TI - Keratocystic Odontogenic Tumour of the Mandible: a case report of decompression with a customised removable tube and review of literature. AB - Keratocystic odontogenic tumour (KOT or KCOT) is defined by the WHO to be 'a benign uni- or multicystic, intraosseous tumour of odontogenic origin'. In 2005, the World Health Organization renamed the lesion; previously known as an odontogenic keratocyst (OKC) as the KCOT. WHO recommends the term KCOT as it reflects its neoplastic nature. In this case report, a 21-year-old female with a histologically proven large parakeratinised KCOT of the right mandible underwent treatment that involved a 14-month period of decompression, followed by enucleation (with Carnoys application) of the residual cyst. During the period of decompression, a custom made removable mandibular chrome-cobalt appliance was used to hold the decompression tube in the oral cavity. PMID- 26502598 TI - Stress and coping in fourth-year medical and dental students. AB - Medicine and dentistry are stressful professions. Dental and medical students suffer high levels of stress and may experience adverse psychological symptoms and use dysfunctional coping mechanisms. AIM: To investigate levels and sources of stress, anger, anxiety and sadness, and associated coping mechanisms, in fourth-year dental and medical students. METHODS: A link to an online questionnaire was emailed to all fourth-year dental and medical students at the University of Otago, in Dunedin (New Zealand). RESULTS: The response rate was 60.2% (N = 100). The majority of students (58.6%) reported frequently feeling stressed. More dental than medical students reported always feeling stressed, but a greater proportion of medical students reported not coping well with stress, suffering abnormal anxiety, anger and sadness, and having these feelings for prolonged periods. Destructive coping mechanisms were more common among dental students, while positive coping mechanisms were also used by both groups. Few students (13.5%) reported using professional counselling services during their undergraduate years. CONCLUSIONS: Mental stability is indispensable for the compassionate, professional and competent delivery of care by health professionals. The high prevalence of detrimental emotions and adverse mental states reported by students before they enter the health workforce is alarming and needs to be addressed. PMID- 26502599 TI - Interprofessional Education, Dentistry, and the New Zealand experience: a commentary. PMID- 26502600 TI - Brown tumour of the mandible in primary hyperparathyroidism; a case report. AB - We present an uncommon diagnosis in a 34-year-old female with a non-healing extraction socket. Incisional biopsy revealed multi-nucleated giant cells suggestive of central giant cell granuloma (CGCG). The computed tomography (CT) report made incidental note of a parathyroid mass. The parathyroid hormone (PTH) level was checked and found to be abnormally high. A diagnosis of brown tumour of the mandible was made. The patient was referred to a head and neck surgeon and the parathyroid mass was removed. The mandibular lesion was managed conservatively and continues to regress post-normalisation of PTH levels. The inclusion of the parathyroid region on the CT scan in this case was fortuitous. There are a range of pathologies containing multinucleated giant cells that can arise from the maxillofacial region; PTH level should, nevertheless, be checked in all such jaw lesions. This allows the clinician to exclude brown tumour from the diagnostic sieve. PMID- 26502601 TI - The role of a bus network in access to primary health care in Metropolitan Auckland, New Zealand. AB - Background: This study examined the spatial accessibility of the population of metropolitan Auckland, New Zealand to the bus network, to connect them to primary health providers, in this case doctors (GP) and dentists. Analysis of accessibility by ethnic identity and socio-economic status were also carried out, because of existing health inequalities along these dimensions. The underlying hypothesis was that most people would live within easy reach of primary health providers, or easy bus transport to such providers. METHODS: An integrated geographic model of bus transport routes and stops, with population and primary health providers (medical. and dental practices) was developed and analysed. RESULTS: Although the network of buses in metropolitan Auckland is substantial and robust it was evident that many people live more than 150 metres from a stop. CONCLUSION: Improving the access to bus stops, particularly in areas of high primary health care need (doctors and dentists), would certainly be an opportunity to enhance spatial access in a growing metropolitan area. PMID- 26502604 TI - [Kallikrein-Kinin System. Long History and Present. (To 90th Anniversary of Discovery of the System)]. AB - The kallikrein-kinin system (KKS) is the key proteolytic system participating in control of a wide spectrum of physiological functions and the development of many pathological conditions. This explains great interest in structures, functions and molecular biology of separate components of the system, molecular mechanisms of their interaction and relationship with other regulatory systems. The information in this field for the last two decades clarifies the role of KKS in morphogenesis of cells, regulation of smooth muscular contractility of some organs, decrease of blood pressure, increase of vascular permeability, the development of inflammation, transformation of cells and the other functions of both physiological and pathological processes. Essential progress in understanding of functions KKS was made by the discovery and study of bradykinin receptors, cloning of kininogen and kallikrein encoding genes, revealing of domain structure of kininogen, prekallikrein and some kininases and decoding of mechanisms of contact phase of proteolytic system activation in blood plasma. PMID- 26502603 TI - [Genetically Encoded Fluorescent Redox Sensors]. AB - Redox processes play a key role in cells of all.organisms. These processes imply directed flows of electrons via so-called redox pairs: substances that exist in both reduced and oxidized states simultaneously within the cell. Examples of redox pairs are NAD+/NADH, NADP+/NADPH, GSSG/2GSH. Until recently, studies of redox processes in the living cells were challenged by the lack of suitable methods. Genetically encoded fluorescent biosensors provide a new way to study biological processes including redox ones. Biosensors allow real-time detection of messengers, metabolites and enzymatic activities in living systems of different complexity from cultured cells to transgenic animals. In this review, we describe the main types of known redox biosensors with examples of their use. PMID- 26502605 TI - [Influence of Different Type of Surfactant on Bacteriolytic Activity of Lysozyme]. AB - The influence ofvarious surfactants (anionic sodium dodecyl sulfate, SDS, cationic dodecyltrimethylarnmonium bromide, DTAB, and zwitterionic cocoamidopropylbetaine, CAPB) on the activity of the chicken egg lysozyme is investigated. Lysis of Gram-positive bacteria by the enzyme was carried out at pH 7.2 and ionic strength of 0.15 M. It was found that at low SDS and DTAB concentrations (less than 1 x 10(-5) M) the bacteriolytic activity increases by 30-140%. At higher concentrations (1 x 10(-5) - 1 x 10(4) M) the activity returns to the level observed in the absence of the surfactants. The elevated activity correlated with the formation of hydrophobic lysozyme-surfactant complexes. Introduction of CAPB at concentrations above 1 x 10(-5) M sig, nificantly diminished the bacteriolytic activity due to CAPB induced aggregation of lysozyme. PMID- 26502606 TI - [Infrared Fluorescent Protein iRFP as an Acceptor for Forster Resonance Energy Transfer]. AB - Bacteriophytochrome-based infrared fluorescent protein iRFP was tested as an acceptor for F6rster resonance energy transfer (FRET). Far-red GFP-like fluorescent proteins mKate2, eqFP650, and eqFP670 were used as donors; Bacterial expression vectors encoding donor and acceptor proteins fused by a 17-amino acid linker were.constructed. FRET for purified proteins in vitro was, estimated from increase of the donor emission after digestion of the linker. Among the three constructs tested, the most efficient FRET (approximately 30%) was detected for the eqFP650-iRFP pair. PMID- 26502607 TI - [Modulating Effect of Extracellular HSP70 on Generation of Reactive Oxigen Species in Populations of Phagocytes]. AB - Reactive oxygen species (ROS) produced by phagocytic cells of the innate immune system play an important role in the first line of defense protecting the host from pathogens. The NADPH oxidase multi-subunit complex is the main source of ROS in all types of the phagocytes. Formation of the membrane-associated enzyme complex and its activity are dependent on many different factors controlling both intensification and suppression of the ROS production rate. However, the evidences are emerging in recent years indicating existence of poorly studied mechanisms of restriction of ROS generation level in phagocytes directed at protection of host tissues in the sites of inflammation from destruction caused by the oxygen free radicals. Our previous data and results of other authors demonstrate that a mechanism of the limitation of ROS production by phagocytes may by connected with immunomodulating activity of extracellular pool. of HSP70. In the present work, we used inhibitors of NADPH oxidase and in vitro cultures of different phagocytes to study a possible relationship between down-regulating effect of exogenous HSP70 on ROS generation and the interaction of the protein with the enzyme subunits. Our results confirmed the literature data concerning the ability of extracellular HSP70 to modulate NADPH oxidase activity and demonstrated for the first time an inhibitory effect of the protein on intracellular ROS generation in phagocytes. PMID- 26502608 TI - [Neutralizing Monoclonal and Chimeric Antibodies to Human IFN-gamma]. AB - Autoiminune disorders are chronic diseases characterized by abnormal immune response directed against self-antigens that leads to tissue damage and violation of its normal functioning. Such diseases often result in disability or even death of patients. Nowadays a number of monoclonal antibodies to pro-inflammatory cytokines and their receptors are successfully used for the targeted treatment of autoimmune diseases. One of the perspective targets in autoimmune disease therapy is interferon gamma, a key cytokine in Th1 cells differentiation, activation of macrophages, and inflammation. In the present work, 5 monoclonal antibodies to human IFN-gamma were obtained. For the development of potential therapeutic agent, we have performed neutralizing activity and affinity analysis of the antibodies. Based on the data obtained, the monoclonal antibody F1 was selected. This antibody has a dissociation constant 1.7 x 10(-9) M and IC90 = 8.9 +/- 2.0 nM measured upon antibody inhibition of the IFN-gamma-induced HLA-DR expression on the surface of U937 cells. We have constructed a bicistronic vector for the production of recombinant chimeric Fab fragment F1 chim in E. coli cells. The recombinant chimeric Fab fragment Fl chim neutralizes IFN-gamma activity in vitro and has a dissociation constant 1.8 x 10(-9) M. PMID- 26502609 TI - [The Increase of Oligonucleotides--Gold Nanoparticles Conjugates Stability]. AB - For today the reagents based on oligonucleotides--gold nanoparticles conjugates and used for specific nucleic acids detection are actively being developed. Such molecular structures are stabilized through the bonds between thiol group in oligonucleotides and gold atoms in nanoparticle. The durability of oligonucleotides--gold nanoparticles binding affects directly on the stability of conjugates and on the possibility of further manipulations. In this paper, a method for the strengthening of oligonucleotides attachment on the gold nano particles surface by means of anchor groups with dithiolane residues is proposed. A comparative study of the anchors molecular structure influence on the conjugates stability at conditions that typical for oligonucleotide probes was carried out. PMID- 26502610 TI - [Search of (-)-Cytisine Derivatives as Potential Inhibitors of NF-kappaB and STAT1]. AB - Design and synthesis ofnew derivatives of (-)-cytisine with a wide spectrum of pharmacological activity, represents the potential therapeutic interest for development of drug candidates for neurodegenerative disorders, inflammatory diseases, and treatment of nicotine addiction. We used HEK293 cell line transiently transfected with N F-kappaB and STATI luciferase reporter constructs to screen the (-)-cytisine derivatives for their potency to modulate basal and induced NF-kappaB and STAT1 activity. Currently, NF-kappaB, STAT1 and components of their signaling pathways are considered as attractive targets for pharmacological intervention, primarily in chronic inflammation, cancer, autoimmune, neurodegenerative and infectious diseases. The library of compounds included the derivatives of (-)-cytisine with amino-, amide-, thio- and carboxamide groups at 3, 5 and 12 position of the starting molecule, as well as some bimolecular derivatives. Our experimental data revealed compounds with moderate activating as well as inhibitory effects for basal NF-kappaB and STATI activity (IC50 or EC50 values are mainly in the micromolar range). The structure activity relationship analysis demonstrated that the character of activity (activation or inhibition of NFkappa-B and STAT1) is determined by the topology of the substituents at the (-)-cytisine molecule, whereas the nature of the substituents mainly contributes to severity of the effect (introduction of aromatic and adamantyl substituents, as well as thionyl or keto groups are of the principal importance). When evaluating the effect of (-)-cytisine derivatives on activity of NF-kappaB and STATI, induced by specific agents (TNFalpha and IFNgamma, respectively) we observed that some compounds inhibited basal and stimulated activity of NF-kappaB and STAT1, another compounds showed the dual effect (an increase of basal- and a decrease of stimulated NF-kappaB activity) and several compounds increase both basal and induced activity of NF-kappaB and STAT1. Thus, obtained results suggest that one of the possible mechanisms of biological action of (-)-cytisine derivatives is their ability to influence the components of NF-kappaB and STAT1-dependent signaling pathways. PMID- 26502611 TI - [Synthesis and Anticancer Activity of Betulonic Acid Imidazolides]. AB - Synthesis of lupane C28-imidazolides, contained 3-oxo-, 3-oximino- and 2-cyano 2,3-seco-4(23)-en-frag ments in cycle A was carried out. The most antitumor activity at. in vitro testing showed 3-oximino-lup- 20(29)-en-28-yl-1H-imidazole 1-carboxylate; which inhibited the growth or induced apoptosis of non-small lung cancer, colon cancer, breast cancer, CNS cancer, ovarian cancer, prostate cancer, leucosis, melanoma cells. In experiments in mice its moderate antitumor activity against grafted breast adenocarcinoma Ca 755 and adenocarcinima of colon was observed. PMID- 26502613 TI - SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL COUMARIN DERIVATIVES AS ANTIOXIDANT AGENTS. AB - Coumarins have been isolated from plants and reported for antioxidant properties. In the present study, we report synthesis of new coumarin derivatives as prospective therapeutic agents and investigate their antioxidant properties. PMID- 26502612 TI - ONE-POT THREE-COMPONENT MICROWAVE-ASSISTED SYNTHESIS OF NOVEL THIAZOLIDINONE DERIVATIVES CONTAINING THIENO[d]PYRIMIDINE-4-ONE MOIETY AS POTENTIAL ANTIMICROBIAL AGENTS. AB - New 2-methyl-5-(4-oxo-2-(substituted phenyl)thiazolidin-3-yl)thieno[3,4-d] pyrimidin-4-one, 5-(2,7-diphenyl-5-thioxo-5,6,7,7a-tetrahydrothiazolo[4,5 d]pyrimidin-3(2H)-yl)-2-methylthieno[3,4-d]pyrimidin-4(3H)-one, and 2-methyl-5-(5 phenyl-thiazolo[5,4-d]soxazol-6(5H)-yl)thieno[3,4-d]pyrimidin-4(3H)-one have been prepared under microwave-assisted and conventional conditions. The new compounds were screened for their in vitro antimicrobial activity against two gram-positive bacteria (Bacillus subtilis NCI M-2063 and Staphylococcus aureus NCIM-2901), one gram-negative bacteria (Escherichia coli NCIM-2256), and.three fungal strains (Candida albicans NCIM-3471, Aspergillusfiavus NCIM-539, and Aspergillus niger NCIM-1196) and showed promising biological activity. PMID- 26502614 TI - [Protective Effects of Myelopeptides in Neuroblastoma C-1300 Cell Culture]. AB - The effects of bone marrow regulatory peptides--myelopeptides 1-6--in mouse neuroblastoma C-1300 were studied. Cultivation in presence of myelopeptides stimulated morphological differentiation of neuroblasts. Neuroprotective abilities of myelopeptides were shown on the models of morphine toxity and oxygen glucose deprivation in neuroblastoma cell culture. PMID- 26502616 TI - [Hepatitis C: 25 years of progress with still major challenges]. PMID- 26502615 TI - [Novel Water-Soluble Substrate for Silicateins]. AB - We suggested to use tetrakis(2-hydroxyethyl)orthosilicate (THEOS) as a substrate for silicateins--an enzyme family playing a key role in formation of skeleton in marine sponges. We compared THEOS with tetraethylorthosilicate (TEOS)--a commonly used substrate for silicateins. These substrates were tested in reaction of amorphous silica formation in vitro catalyzed by silicatein Al from sponge Latrunculia oparinae. It was found that reaction with THEOS occurs more efficiently than with TEOS, probably due to high water solubility and higher hydrolysis rate of THEOS. PMID- 26502617 TI - [Whipple's disease, when to think about it?]. AB - Whipple's disease is a chronic, systemic, bacterial infection caused by Tropheryma whipplei. Its cardinal symptoms include intermittent and recurrent arthralgia or arthritis together with chronic diarrhoea, abdominal pain and weight loss. It may mimick many chronic inflammatory diseases, and the diagnosis remains a challenge. Salivary and faecal quantitative PCR for T. whipplei should be ensued, if positive, by an upper endoscopy for duodenal biopsies. The treatment consists of a combination of oral doxycycline and hydroxychloroquine for 12 months followed by life-long doxycycline. Whipple's disease, although rare, is an entity that should be considered regularly, as its progression may be fatal if left untreated. PMID- 26502618 TI - [Achalasia: which treatment to choose in 2015?]. AB - Achalasia is a rare disorder, whose diagnostic Gold standard is high-resolution cesophageal manometry. The proposed treatment must take into account the patient's health condition and the type of achalasia determined by HRM. Heller's laparoscopic myotomy and pneumatic dilation are the first line treatments for most of the patients, whereas Botulinum toxin injections and pharmacologic therapy are only indicated for patients with a high surgical risk who cannot undergo first line treatments. Peroral endoscopic myotomy (POEM) is a recent and promising endoscopic technique reserved for expert endoscopy centers, whose exact role is still to be determined by randomized prospective studies. Oesophagectomy has only a marginal role in rare patients with extremely advanced achalasia or at risk of neoplastic degeneration. PMID- 26502619 TI - [Digestive foreign body management]. AB - Foreign body (FB) ingestion is a frequent reason for gastroenterology consulting. Eighty percent of these ingestions are accidental and observed among paediatric subjects. However, intentional repetitive ingestions are also observed, especially amongst prisoners or psychiatric patients. Most FBs pass throughout the digestive tract without any complication and without any need for surgical or endoscopic intervention. Nevertheless, around 10-20% of cases require an endoscopy examination and 1% will lead to a surgical intervention. Management approaches should favor inter-disciplinarity, balance benefits and risks of FB removal based on its location, and integrate psychiatric comorbidities into the decision process. PMID- 26502620 TI - [When should we give albumin in patients with cirrhosis?]. AB - The beneficial effects of the use of albumin, either alone or combines with other treat- ments, have been demonstrated in patients with various complications of cirrhosis. Therefore, albumin should be administred in patients with spontaneous bacterial peritonitis in association with antibiotics, and in association with terlipressin in patients with type 1 hepatorenal syndrome. Albumin use reduces the occurrence of paracentesis-related circulatory dysfunction, in patients with large ascites undergoing paracentesis. So far, the beneficial effect of albumin has not been demonstrated, neither for infections other than spontaneous bacterial peritonitis nor for hepatic encephalopathy. This article provides an overview of the data evaluating the effects of albumin in patients with cirrhosis. PMID- 26502621 TI - [Factors influencing development and progression of alcoholic liver disease]. AB - Only a minority ot excessive drinkers develop cirrhosis. The main cofactors implicated in the pathophysiology of alcoholic liver disease are obesity, diabetes or the metabolic syndrome. Several genetic polymorphisms have been associated with a higher risk of alcoholic cirrhosis. Recent data indicate that gut microbiota could play a role in the pathogenesis of alcoholic liver disease. The aim of this review is to summarize the factors that influence development and progression of alcoholic liver disease. PMID- 26502622 TI - [Rethinking the reimbursement policy of direct acting antivirals against chronic hepatitis C]. AB - New direct-acting antivirals (DAA) against hepatitis C virus (HCV) have led to a therapeutic revolution in HCV management and virological cure rates approaching 100% while potentially avoiding significant complications of HCV (first cause of liver transplantation). We estimated the price of sustained virological response (SVR) depending on treatment strategy and patient profile. Costs of treatment with recent DAAs being so high, the accessibility to those drugs for the majority of subjects is hitherto limited to advanced stages of hepatitis C. This current situation increases the inequity and strengthens the dominant position of insurers and pharmaceutical companies with a rationing of care. We suggest herein global approaches from a population-level and health-care perspective aiming to reduce the prevalence, morbidity, and mortality related to HCV. PMID- 26502623 TI - [Management of an infection associated with a prosthetic arthroplasty: the necessity of collaboration between surgeon and infectiologist]. AB - The total number of total knee and hip joint arthroplasties is constinuously rising, due to an increasing population of physically active elderly patients. For primary elective arthroplasties, the infection risk ranges between I and 2%, but equals to a high morbidity, costs and complications for the individual infected patient. Diagnosis and management of prosthetic joint infections are improving. We review the latest consensus on the diagnosis and management of these infections and reveal some insight in still debated issues. PMID- 26502624 TI - [Disease management, an old fashion idea?]. PMID- 26502625 TI - [Louis Pasteur, science and the return of "belief"]. PMID- 26502626 TI - [Noninvasive screening for trisomy 21]. PMID- 26502627 TI - [The amazing American go ahead for flibanserin against female sexual apathy]. PMID- 26502628 TI - [A diagnostic blood test for irritable bowel syndrome: a utopia?]. PMID- 26502629 TI - [Statins and aggressiveness: unequal effects by sex, age and molecule]. PMID- 26502630 TI - [Neutral package and electronic cigarette: British anti-smoking revolution]. PMID- 26502631 TI - [ TarMed: an increasingly confrontational reform]. PMID- 26502632 TI - [Geneva wants to eliminate the tax deduction of complementary premiums]. PMID- 26502633 TI - [The usefulness of the useless]. PMID- 26502634 TI - Metallic Nanomaterials for Bone Tissue Engineering. AB - Conventional grafting techniques for bone regeneration are currently being replaced by tissue engineering approaches of using 3D biomimetic materials. Of these biomaterials, metals have the highest mechanical strength; moreover, they play a major role in accelerating bone formation and promoting bone regeneration. They act as cofactors for enzymes, serving as a structural component of bone forming enzymes and proteins, stimulating angiogenesis, increasing extra-cellular matrix synthesis, promoting bone formation, and inhibiting bone resorption. Metals have the inherent ability to promote osseointegration and osteoconductivity and possess antimicrobial activity. The current developments in bone tissue engineering focus on metal surface modifications by physical and chemical treatments to improve their bioactivity. Based on the recent literature available, this review aims at discussing the biological role of metals, namely Zn, Ti, Zr, B, Sr, Mg, Ag, and Cu along with their surface modifications for significantly enhanced bone regeneration. PMID- 26502635 TI - Non-Biologic Nanodelivery Therapies for Rheumatoid Arthritis. AB - Rheumatoid arthritis is a common chronic inflammatory disease characterized by progressive bone and cartilage destruction causing severe functional limitations, increased morbidity and mortality rate, which results in a strong negative socioeconomic impact. Current therapies only slow the progression of the disease and try to enhance quality of life. Furthermore, such therapies present several drawbacks due to the adverse effects caused by the lack of selectively of the drugs and frequent and long-term dosing that lead to patient non-compliance. Drug delivery systems based on nanocarriers represent a promising approach to overcome the current therapeutic limitations because they can selectively carry drugs to inflamed synovium allowing for improved drug efficacy, thereby reducing the biodistribution of anti-rheumatic drugs. Additionally, controlled drug release can lead to the reduction of drug dosages. The increasing interest and confidence that nanocarriers can revolutionize the treatment of rheumatoid arthritis has led to an increased number of investigations in this field. In this context, the present review focuses on drug delivery system strategies for non-biological drugs developed for the treatment of rheumatoid arthritis. PMID- 26502637 TI - Development and Evaluation of Solid Lipid Nanoparticles of N-6-Furfuryl Adenine for Prevention of Photoaging. AB - N-6-furfuryl adenine (N6FA) also known as "kinetin" is a biologically active natural phytochemical. It belongs to the category of cytokinins, the natural plant growth hormones that promote cell division and play role in cell differentiation. Overall, N6FA aids in increasing the plant's life span. Human cells also contain.small quantities of N6FA. Scientists are trying to understand its function in humans. N6FA is being investigated for its properties such as antiplatelet, antioxidant, antiproliferative and anti-aging effects on human cells. The aim of the present investigation was to prepare solid lipid nanoparticle (SLN) based topical formulations of N6FA and to evaluate its efficacy against ultraviolet (UV) radiation induced skin photodamage. SLNs were prepared by hot microemulsion technique and optimized for the type and concentration of lipid and surfactant(s). The optimized SLN formulation was characterized in terms of particle size, drug entrapment efficiency, zeta potential and pH; evaluated for stability, spreadability, ex-vivo skin permeation and photoprotective effects against UV induced skin damage. The cumulative amount of drug permeated through mice skin using SLNs was 3 folds higher than from conventional cream base. The results of biochemical and histopathological investigations of skin treated with N6FA loaded SLNs clearly demonstrated the efficacy of optimized formulation in preventing photodamage (lesions, ulcers and changes in skin integrity) due to chronic UV exposure. The effects were comparable with widely used marketed formulation, Garnier wrinkle lift anti-aging cream. Results suggested that N6FA incorporated into SLNs may provide therapeutic as well as cosmeceutical benefits. PMID- 26502638 TI - Pluronic F-127 Stabilised Docetaxel Nanocrystals Improve Apoptosis by Mitochondrial Depolarization in Breast Cancer Cells: Pharmacokinetics and Toxicity Assessment. AB - Docetaxel (DTX) is favoured option for breast cancer treatment; however its marketed formulation (Taxotere) generates therapeutic response at the cost of undue toxicity. In order to circumvent such limitations, DTX nanocrystals (DTX NCs) were prepared through high pressure homogenization (HPH) technique using pluronic F-127 (PF-127) as a stabilizer. DTX-NCs presented higher efficacy against MCF-7 breast cancer cells with exposition of 1.75 and 2.13 fold lower inhibitory concentration (IC50) compared to free drug and Taxotere, respectively. DTX-NCs enhanced the DTX induce G2-M arrest by 1.24 and 1.79 fold compared to Taxotere and free DTX whereas highest apoptotic population (54.79%) of MCF-7 cells was also observed when cells were incubated with DTX-NCs for 24 h in comparison to free DTX (9.69%) and Taxotere (12.55%). The claims of improvement were substantiated by investigating the modulation in apoptotic mechanism induced by the subtle physical state variation of DTX in DTX-NCs. Results revealed that DTX-NCs induced apoptosis was linked to altered mitochondrial membrane potential. DTX-NCs caused highest (39.53%) depolarization of mitochondria compared to free DTX (9.34%) and Taxotere (18.72%). Further, safety of DTX-NCs was ascertained via haemolytic testing and in-vivo toxicity studies in mice. Developed formulation exhibited acceptable haemolytic potential which suggested its suitability towards parenteral administration. Moreover, in-vivo acute toxicity studies demonstrated that the developed NCs were safer than marketed Taxotere. These results elicit that DTX-NCs would be a viable alternative to commercial formulation for treatment of breast cancer. PMID- 26502639 TI - Bioreducible Micelles with Endosomal Buffering and Multidrug Resistance-Reversing Function Enhance Anti-Tumor Efficacy of Doxorubicin. AB - The clinical success of anthracyclines-containing chemotherapy for breast cancer is mainly restricted by cardiac damage and the development of multidrug resistance (MDR). For efficient reversal of drug resistance, doxorubicin (DOX) loaded multifunctional bioreducible micelles were constructed from a new amphiphilic copolymer consisting of polyethylene glycol and poly[bis(2 hydroxylethyl)-disulfide-diacrylate-beta-histamine and characterized. The introduction of imidazole group endowed the micelles with endosomal buffering capacity and improved the endosomal escape. The reduction-responsiveness of the micelles promoted DOX release. The activity of P-glycoprotein, one of the most well-described drug-efflux pumps, and glutathione S-transferase, an important detoxification enzyme, were also inhibited by the micelles. The accumulation of DOX in tumor after intravenous administration of the drug-loading micelles was increased in drug resistant tumor-bearing mice. These results indicated that the micelle was a promising drug delivery system for MDR cancer therapy. PMID- 26502636 TI - Therapeutical Neurotargeting via Magnetic Nanocarrier: Implications to Opiate Induced Neuropathogenesis and NeuroAIDS. AB - Magnetite (Fe3O4) is the most commonly and extensively explored magnetic nanoparticles (MNPs) for drug-targeting and imaging in the field of biomedicine. Nevertheless, its potential application as safe and effective drug-carrier for CNS (Central Nervous System) anomalies is very limited. Previous studies have shown an entangled epidemic of opioid use and HIV infection and increased neuropathogenesis. Opiate such as morphine, heroine, etc. are used frequently as recreational drugs. Existing treatments to alleviate the action of opioid are less effective at CNS level due to impermeability of therapeutic molecules across brain barriers. Thus, development of an advanced nanomedicine based approach may pave the way for better treatment strategies. We herein report magnetic nanoformulation of a highly selective and potent morphine antagonist, CTOP (D-Pen Cys-Tyr-DTrp-Orn-Thr-Pen-Thr-NH2), which is impenetrable to the brain. MNPs, synthesized in size range from 25 to 40 nm, were characterized by Transmission electron microscopy and assembly of MNPs-CTOP nanoformulations were confirmed by FTIR spectroscopy and fluorescent detection. Flow-cytometry analysis showed that biological efficacy of this nanoformulation in prevention of morphine induced apoptosis in peripheral blood mononuclear cells remains equivalent to that of free CTOP. Similarly, confocal microscopy reveals comparable efficacy of free and MNPs bound CTOP in protecting modulation of neuronal dendrite and spine morphology during morphine exposure and morphine-treated HIV infection. Further, typical transmigration assay showed increased translocation of MNPs across in vitro blood-brain barrier upon exposure of external magnetic force where barrier integrity remains unaltered. Thus, the developed nanoformulation could be effective in targeting brain by application of external magnetic force to treat morphine addiction in HIV patients. PMID- 26502640 TI - Delivery of PUMA Apoptosis Gene Using Polyethyleneimine-SMCC-TAT/DNA Nanoparticles: Biophysical Characterization and In Vitro Transfection Into Malignant Melanoma Cells. AB - A synthesized PEI-based gene delivery system, wherein PEI was crosslinked with sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (Sulfo-SMCC) conjugating trans-activating transcriptional activator (TAT), yielding PEI-SMCC TAT (PST), a novel non-viral vector for apoptosis-related gene PUMA (p53 up regulated modulator of apoptosis), was designed and evaluated. Sulfo-SMCC is a commonly used heterobifunctional crosslinker and is soluble in water, making the crosslinking easier without organic reagent like DMSO or chloroform. The PST/pDNA nanoparticles were 171.9 nm at the optimal N/P ratio (50:1). DNA complexes of all the PST conjugation had much lower toxicity and exhibited enhancement in transfection efficiency in comparison with single PEI vector. The results also showed that the transfection efficiency of PST/pEGFP nanoparticles into malignant melanoma A375 cell increased, and PST carrying PUMA gene induced the apoptosis of A375 cells. It was suggested that PST could be a promising melanoma tumor targeting nanovector, and have a good potential in clinical application. PMID- 26502641 TI - Anti-Human Immunodeficiency Virus Activity of Thiol-Ene Carbosilane Dendrimers and Their Potential Development as a Topical Microbicide. AB - The concept of a "microbicide" was born out of the lack of a vaccine against HIV and the difficulty of women in ensuring the use of preventive prophylaxis by their partners, especially in developing countries. Approaches using polyanionic carbosilane dendrimers have shown promise in the development of new microbicides. We have developed and evaluated two anionic carbosilane dendrimers with sulfonate and carboxylate terminal groups, G2-STE16 and G2-CTE16. Both dendrimers showed high biosafety in human epithelial cell lines derived from the vagina and in primary blood human cells (PBMCs). The dendrimers not only have a greater capacity to block the entry of different X4- and R5-HIV-1 isolates into epithelial cells but also prevent the HIV-1 infection of activated PBMCs. The treatment of epithelial cells with different carbosilane dendrimers did not produce changes in the activation or proliferation of PBMCs or in the expression of CD4, CCR5 or CXCR4. Computational modeling showed significantly higher affinities for the complexes G2-STE16/gp120 and G2-CTE16/gp120. Moreover, no irritation or vaginal lesions were detected in female BALB/c mice after vaginal administration of the dendrimers. Summing up, G2-STE16 and G2-CTE16 are easy to synthesize and compatible with functional groups, and the purification steps are easy and short. Our results have clearly demonstrated that these dendrimers have high potency as a topical microbicide against HIV-1 infection. PMID- 26502642 TI - Adventitial Cells and Perictyes Support Chondrogenesis Through Different Mechanisms in 3-Dimensional Cultures With or Without Nanoscaffolds. AB - In previous studies, mesenchymal stromal cells (MSCs) derived from bone marrow and fat tissues were shown to increase proliferation and matrix production of chondrocytes (CH) in co-culture. The aim of this study was to investigate the roles of pericytes (CD31(neg)CD45(neg)CD146+CD34(neg)) and adventitial cells (CD31(neg)CD45(neg)CD146(neg)CD34+) sub-populations of MSCs in supporting proliferation and matrix deposition of CH. The MSCs were derived from synovial membrane and attaching fat tissue. Then, the pericytes and adventitial cells were sorted from total MSCs and co-cultured with articular CH respectively. In pellet co-culture model, the pericytes showed more prominent effects on glycosaminoglycans (GAGs) production and Collagen II synthesis than the adventitial cells which had stronger effects on promoting CH proliferation. In addition, quantitative polymerase chain reaction (qPCR) was performed to examine the expression of a group of secreted growth factors and co-culture performed on electrospun scaffolds based on Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P3HB4HB), to verify the trophic effects of different MSC sub-populations in 3 Dimensional (3D) environment. In conclusion, it was found that the pericytes and adventitial cells support CH in different ways; the adventitial cells more supporting the proliferation of CH, while pericytes are better in stimulating GAGs and collagen production of CH. PMID- 26502643 TI - Pharmacological Improvement and Preclinical Evaluation of Methotrexate-Loaded Lipid-Core Nanocapsules in a Glioblastoma Model. AB - Glioblastoma multiforme is a devastating cerebral tumor with an exceedingly poor prognosis. Methotrexate (MTX) is a folic acid analogue that inhibits DNA synthesis by binding to dihydrofolate reductase. Biodegradable nanoparticles are emerging as a promising system for drug delivery to specific tissues. The aims of the current study were pharmacological improvement and preclinical evaluation of MTX-loaded lipid-core nanocapsules (MTX-LNCs) in a glioblastoma model. Cell viability was assessed using the MTT assay, and the cell cycle was characterized by flow cytometry analysis of propidium iodide staining. Apoptosis was measured using an AnnexinV kit and by examining active caspase-3 immunocontent. In vivo glioma implantation was performed in rats, followed by measurement of the tumor size and tumoral apoptosis, BCL-2 immunohistochemistry and analyses of toxicological parameters. MTX-LNCs with increased encapsulation efficiency were successfully prepared. Our in vitro results showed a decrease in glioma cell viability after MTX-LNC treatment that was preceded by cell cycle arrest, leading the cells to undergo apoptotic death, as indicated by AnnexinV staining and increased active caspase-3 protein levels. In the in vivo glioma model, we observed a decrease in the tumor size and an increase in apoptosis in the tumor microenvironment (based on the AnnexinV assay and BCL-2 measurement). MTX-LNC treatment decreased the leukocyte number but altered neither toxicological tissue marker expression nor metabolic parameters. The present results reveal that MTX LNCs represented an efficient formulation in a preclinical model of glioma and are a potential candidate for clinical trials. PMID- 26502644 TI - 6-Month Follow-Up of a Novel Biodegradable Drug-Eluting Stent Composed of Poly-L Lactic Acid and Amorphous Calcium Phosphate Nanoparticles in Porcine Coronary Artery. AB - RATIONALE: We reported previously, in porcine coronary arteries, that the novel biodegradable PowerStent Absorb paclitaxel-eluting stent had improved and sustained structural strength and functional performance at one month post implantation. OBJECTIVE: To report the stent performance at 6-month follow-up. METHODS AND RESULTS: Six PowerStent Absorb and six TAXUS stents were randomly implanted in the left anterior descending and right coronary arteries of six Tibet miniature pigs. Quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) images were obtained at the time of implantation (T0) and at 6 months (T6). Two animals were sacrificed at T6 for histopathological evaluation. At T6, QCA showed that the mean luminal vascular diameter (mLD) between the PowerStent and the TAXUS stents were similar (2.36 +/- 0.38 vs. 2.61 +/- 0.31, respectively). Based on the IVUS analysis, the mLD and the mean lumen cross sectional area (mCSA) in the PowerStent-treated arteries were similar between T0 and T6 (mLD: 2.74 +/- 0.13 vs. 2.70 +/- 0.20 and mCSA: 6.81 +/- 0.62 mm2 vs. 6.68 +/- 0.94 mm2). Histopathology showed that the PowerStent stents were well apposed to the vessel wall with no recoil, strut fracture and thrombus formation. The stents were fully covered with a layer of endothelial cells. CONCLUSIONS: At six month post-implantation, the PowerStent Absorb stents maintained their structural strength and functional performance. The development of restenosis was controlled, no stent thrombosis was observed and the stents were fully re endothelialized. These results suggest the PowerStent Absorb stent is safe and effective for up to 6 months when implanted in porcine coronary arteries. PMID- 26502645 TI - Regulation of Extracellular Matrix Remodeling Proteins by Osteoblasts in Titanium Nanoparticle-Induced Aseptic Loosening Model. AB - Titanium (Ti)-wear particles, formed at the bone-implant interface, are responsible for aseptic loosening, which is a main cause of total joint replacement failure. There have been many studies on Ti particle-induced function changes in mono-cultured osteoblasts and synovial cells. However, little is known on extracellular matrix remodeling displayed by osteoblasts when in coexistence with Synovial cells. To further mimic the bone-implant interface environment, we firstly established a nanoscaled-Ti particle-induced aseptic loosening system by co-culturing osteoblasts and Synovial cells. We then explored the impact of the Synovial cells on Ti particle-engulfed osteoblasts in the mimicked flamed niche. The matrix metalloproteinases and lysyl oxidases expression levels, two protein families which are critical in osseointegration, were examined under induction by tumor necrosis factor-alpha. It was found that the co-culture between the osteoblasts and Synovial cells markedly increased the migration and proliferation of the osteoblasts, even in the Ti-particle engulfed osteoblasts. Importantly, the Ti-particle engulfed osteoblasts, induced by TNF-alpha after the co-culture, enhanced the release of the matrix metalloproteinases and reduced the expressions of lysyl oxidases. The regulation of extracellular matrix remodeling at the protein level was further assessed by investigations on gene expression of the matrix metalloproteinases and lysyl oxidases, which also suggested that the regulation started at the genetic level. Our research work has therefore revealed the critical role of multi cell-type interactions in the extracellular matrix remodeling within the peri-prosthetic tissues, which provides new insights on aseptic loosening and brings new clues about incomplete osseointegration between the implantation materials and their surrounding bones. PMID- 26502646 TI - Biodistribution, Clearance, and Toxicology of Polymeric Micelles Loaded with 0.9 or 5 nm Gold Nanoparticles. AB - Long-circulating gold nanoparticles (AuNPs) have garnered a great deal of interest as both imaging and therapeutic agents. However, their protracted elimination and long-term persistence within many organ systems remains a concern for clinical translation. To improve the excretion of long-circulating nanoparticles, we prepared -80 nm biodegradable polymeric micelles with 0.9 nm or 5 nm AuNPs tightly packed within the hydrophobic core. These gold-loaded polymeric micelles (GPMs) were expected to allow for improved excretion of gold, compared with single large AuNPs, owing to the smaller size and larger surface-to volume ratio of the individual AuNPs within the micelle. Following intravenous administration of GPMs, organs were harvested and examined for gold content using inductively coupled plasma optical emission spectrometry (ICP-OES) for up to 3 months post-injection. While both GPM formulations showed significant clearance of gold over time, micelles containing 0.9 nm AuNPs showed a 72% and 67% reduction in gold content in the liver and spleen, respectively, between 1 day and 3 months post-injection, compared with a 38% and 35% reduction in mice receiving 5 nm GPMs. Furthermore, feces and urine analysis revealed approximately 7.5 and 100 times more gold, respectively, in mice that received 0.9 nm GPMs one day after injection. These findings suggest that the excretion profile of inorganic nanomaterials may be improved if clusters of small inorganic materials are used in favor of single solid particles. PMID- 26502647 TI - Co-Delivery of Docetaxel and Berbamine by Chitosan/Sulfobutylether-beta Cyclodextrin Nanoparticles for Enhancing Bioavailability and Anticancer Activities. AB - Novel dual-drug sulfobutylether-beta-cyclodextrin (CD)/chitosan (CS) nanoparticles (NPs) containing docetaxel (DTX) and berbamine were developed and evaluated in this study. These NPs were prepared using ionic gelation method and were characterised for their particle size, polydispersity, zeta potential, drug loading percentage and yield. Cytotoxicity was measured through 3-(4,5 dimethyltiazol-2-ly)-2,5-diphenyltetrazolium bromide assay, and the expression of survivin mRNA in MCF-7 cells was detected using qRT-PCR. Cellular uptake and apoptosis were also analysed. Compared with the other DTX formulations in this study, the dual-drug CD/CS NPs showed better release and intestinal transport profiles in vitro and had improved pharmacokinetics data. The dual-drug CD/CS NPs exhibited higher cytotoxicity, cellular uptake, apoptosis and inhibition with the survivin mRNA expression. The relatively improved oral bioavailability and better antitumour efficacy indicated that the dual-drug CD/CS NPs developed in our study possessed significant advantages and might be a promising strategy for the development of drug, delivery systems for cancer chemotherapy. PMID- 26502648 TI - [The beginning of the gender equality in the Japanese Society of Child Neurology]. PMID- 26502649 TI - [A 9-month-old boy manifesting generalized hypotonia and tented mouth]. PMID- 26502650 TI - [Relation between psychological development and respiratory management in patients with congenital central hypoventilation syndrome in Japan]. AB - OBJECTIVE: To evaluate the psychological development of patients with congenital central hypoventilation syndrome (CCHS). METHODS: We performed a questionnaire based survey of 17 patients with CCHS aged over 7 years and assessed their clinical course, respiratory management, and psychological development. RESULTS: CCHS was present at birth in 15 patients, of which eight presented with respiratory failure with a low Apgar score. Twelve patients required mechanical ventilation with intubation, and five received mask ventilation. All patients with intubation underwent tracheostomy between 1 and 12 months of age (median 5.5 months), and most of them had associated conditions such as Hirschsprung disease. Four of 12 patients with intubation were eventually switched to mask ventilation and one to diaphragm pacing and mask ventilation. The patients undergoing mask ventilation had relatively milder disease severity and had fewer complications than did the patients with intubation. The psychological development of patients who received tracheostomy ranged from normal to severe retardation. Retardation was more likely to be severe in patients who received tracheostomy in late infancy. All patients who received mask ventilation experienced borderline to moderate psychological retardation. This effect could be attributed to poor compliance with mask fitting. CONCLUSION: Our findings suggest that the psychological development of CCHS patients was influenced by hypoxia; tracheostomy and strict respiratory management since the neonatal period were needed for neurological protection. PMID- 26502651 TI - [Evaluation of quality of life in attention-deficit hyperactivity disorder children without comorbidity]. AB - OBJECT: Improving quality of life (QOL) is one of the most important therapeutic goals for children with attention-deficit hyperactiv- ity disorder (AD/HD). The aim of this study was to measure QOL in AD/HD children without comorbidity and to examine associations between QOL and clinical symptoms of AD/HD for targeting early intervention. METHODS: Twenty-two enrolled patients and their parents completed the Questionnaire for Measuring Health-Related Quality of Life in Children (KINDL-R). Patients and teachers completed AD/HD rating scale-IV. Associations between QOL and clinical symptoms were assessed using t tests and correlations. RESULTS: Mean total score of the self-reported KINDL-R was 70.8. No difference in total QOL score was seen between AD/HD children and controls; however, the self-esteem subscale rated by AD/HD children was significantly higher than that of controls (p < 0.001). Total KINDL-R score correlated negatively with AD/HD rating scale-IV rated by teachers (p < 0.05). A difference was observed between AD/HD children in a lower QOL group and their parents in a subscale regarding QOL at school. CONCLUSIONS: These findings suggest that evaluation of QOL in AD/HD children without comorbidity is useful for identifying AD/HD children who might benefit from early intervention. PMID- 26502652 TI - [Efficacy and tolerability of topiramate, lamotrigine, and levetiracetam in children with refractory epilepsy]. AB - OBJECTIVE: Topiramate (TPM), lamotrigine (LTG), and levetiracetam (LEV) are three new-generation antiepileptic drugs (AEDs) which have recently come into use in add-on therapy for refractory childhood epilepsy in Japan. The aim of this study was to evaluate their efficacy and tolerability, and to clarify the role of these three AEDs in childhood epilepsy therapy. METHODS: Three separate audits were conducted between July 2007 and July 2012. All patients studied had epilepsy refractory to other AEDs. Efficacy was confirmed if a patient became seizure-free or achieved > 50% reduction (50% responder rate: 50% RR) in seizure frequency for 12 months after starting add-on therapy. RESULTS: A total of 55 children received TPM, 44 LTG, and 38 LEV. The 50% RR of partial epilepsy was 31.8% for LTG, 41.8% for TPM, and 52.6% for LEV. The 50% RR of generalized epilepsy was 28.6% for LTG, 26.7% for TPM, and 44.4% for LEV. The incidence of adverse events was 9.1% for LTG, 43.6% for TPM, and 15.8% for LEV. CONCLUSION: LEV was the most effective of the three add-on therapies in refractory childhood epilepsy with partial and generalized onset. Regarding seizure-free, TPM was more effective than the other therapies, but it had many side effects. LTG tended to be more effective for generalized epilepsy, particularly idiopathic epilepsy, than partial epilepsy. We conclude that it is necessary to develop a treatment plan for pediatric epilepsies after considering the advantages and disadvantage of these new AEDs. PMID- 26502653 TI - [A clinical study of laryngotracheal separation in spinal muscular atrophy type I patients]. AB - Artificial respiration by tracheostomy is necessary for long-term survival in spinal muscular atrophy (SMA) Type I patients. There are two types of tracheostomy: i )simple tracheostomy and ii) tracheostomy plus aspiration prevention surgery, including laryngotracheal separation. We experienced three cases of SMA type I patients that had good outcomes after undergoing laryngotracheal separation. The patients' ages at onset were 14 days, two months and one and a half months. Laryngotracheal separation was performed at five months, seven months, and 15 years and five months respectively, and the times from diagnosis to surgery were a month, three months and 15 years. The aspiration pneumonia disappeared in all three cases. This study suggests that laryngotracheal separation is an effective surgery to prevent aspiration in SMA type I cases, and also contributes to the improved quality of life of patients and their families. PMID- 26502654 TI - [Cognitive and linguistic abilities of a boy with PVL showing relatively higher VIQ compared to PIQ]. AB - In this study, we investigated the cognitive processing and language abilities of a 13-year-old boy with moderate periventricular leukomalacia (PVL), spastic diplegia and exotropia who had discrepant scores in the verbal intelligence quotient (VIQ) and performance intelligence quotient (PIQ) in the Wechsler Intelligence Scale for Children, third edition (VIQ; 82 > PIQ; under 40). In the Kaufman Assessment Battery for Children and Das-Naglieri Cognitive Assessment System, his performance was poor at simultaneous processing compared to sequential processing. He could not copy three-dimensional figures, and he could place only two out of eight blocks correctly in the second level models of Benton three-dimensional block construction test, showing visuospatial impairment typical of patients with PVL. Despite the relatively high score in VIQ, there was a gap among the scores of the subtests in the Illinois Test of Psycholinguistic Abilities. He tended to get low scores in tests that required visual abilities. In addition, there was also an impairment in reading fluency tested by the Diagnostic Criteria and Medical Guideline for Specific Developmental Disorders. He was much less fluent in reading syllables, words or sentences (6.0 SD or more compared to 12-year-old boys). The relatively higher score in VIQ superficially suggests adequate language ability. However, in the present study, precise investigation revealed some discrepancies even within the field of language. Thus, defining stronger and weaker points of a patient is important in order to determine optimal medical or educational approaches. PMID- 26502655 TI - [Scintigraphic imaging in the diagnosis of failed intrathecal baclofen therapy: a case report of a 7-year-old boy with ventriculoperitoneal shunt]. AB - Intrathecal baclofen (ITB) therapy is popular for the management of intractable spasticity. In 2007, the indications of ITB therapy expanded to include spasticity of children in Japan. In this report, we assessed the utility of radioisotopic scintigraphy in the diagnosis of failed ITB therapy. A 7-year-old boy with schizencephaly, hydrocephalus, and spastic quadriplegia had an ITB pump implanted. In his infancy, he had undergone ventriculoperitoneal shunt implantation. One month after the ITB operation, the ITB therapeutic effect diminished. Several examinations confirmed that the pump function was normal and catheter failure had not occurred. However, radioisotopic scintigraphy revealed that the baclofen had been washed out to blood circulation more rapidly than is typically observed. We considered two possible causes for this; obstruction of the cerebrospinal space due to kyphosis and excessive washout of celebrospinal fluid through the ventriculoperitoneal shunt. The catheter was moved to a more caudal site surgically, and his spasticity improved. The use of radioisotopic scintigraphy to identify the distribution of baclofen is an effective technique for investigation of baclofen pump system malfunction. PMID- 26502657 TI - The mutual shaping of life insurance and medicine in Finland. AB - This article examines the mutual shaping of medicine and private life insurance in Finland before the Second World War. Based on historical texts and archival material, it shows the important effects that the involvement of medicine in client selection for life insurance companies had on medical knowledge and practice. The analysis focuses on the tensions between the main actors in life insurance underwriting--candidates, insurance agents, examining physicians and the central office--as well as the medical examination as the key site of these tensions. The article shows how the introduction of a set of procedural and technical innovations reshaped the medical examination and helped to stabilize the fraught network of life insurance underwriting. These innovations re-scripted medical work. They stressed objective measurable knowledge over the personal skill and clinical acumen of the examining physician, propagated the physical examination and the use of diagnostic technologies and vital standards, multiplied medicine's administrative tasks, and contributed to the introduction of a risk factor approach to medicine. Moreover, the social organization of life insurance promoted the spread of these objects, practices and tasks to other fields of medicine. The case displays how medical innovations are developed through the situated interplay of multiple actors that cuts across the science society boundary. PMID- 26502656 TI - Adjudicating non-knowledge in the Omnibus Autism Proceedings. AB - After 5600 families of children diagnosed with autism filed claims with the National Vaccine Injury Compensation Program in the United States, the court selected 'test' cases consolidated into the Omnibus Autism Proceedings, held from 2007 to 2008, to examine claims that vaccines caused the development of autism. The court found all of the causation theories presented to be untenable and did not award damages to any parents. We analyze the Omnibus Autism Proceedings as a struggle within the scientific field between the scientific orthodoxy of the respondents and the heterodox position taken by the plaintiffs, suggesting that the ruling in these cases helped to shore up hegemony on autism causation. Drawing on the literature on non-knowledge, we suggest that only the respondents had enough scientific capital to strategically direct non-knowledge toward genetic research, thereby foreclosing the possibility of environmental causation of autism. The plaintiffs, who promote a non-standard ontology of autism, suggest that the science on autism remains undone and should not be circumscribed. In analyzing the Omnibus Autism Proceedings with field theory, we highlight the way in which scientific consensus-building and the setting of research agendas are the result of struggle, and we show that the strategic deployment of non knowledge becomes a major stake in battles for scientific legitimacy and the settling of scientific controversies. PMID- 26502658 TI - Making up 'national trauma, in Israel: From collective identity to collective vulnerability. AB - We sketch a variety of institutional, discursive, professional, and personal 'vectors', dating back to the 1980s, in order to explain how 'national trauma' was able to go from a cultural into a professional category in Israeli mental health during the Al-Aqsa Intifada (2000-2005). Our genealogy follows Ian Hacking's approach to transient mental illnesses, both illustrating its fertility and expanding its horizon. Thus, we also explore the dynamics that developed in the Israeli mental health community with the advent of 'national trauma': while the vast majority of Israeli psychologists and psychiatrists did not adopt the category, they embraced much of its underlying logic, establishing a link between Israeli identity and the mental harm said to be caused by Palestinian terror. Remarkably, the nexus of national identity and collective psychic vulnerability also prompted the cooperation of Jewish and Palestinian-Israeli mental health scholars seeking to explore the psychological effect that the minority status of Israeli Palestinians had on them during the Al-Aqsa Intifada. PMID- 26502659 TI - A controversial idea as a cultural resource: The Lysenko controversy and discussions of genetics as a 'democratic' science in postwar Japan. AB - The Japanese discussion of the theory of Soviet agronomist Trofim D. Lysenko began in the postwar years under the American occupation. Leftists introduced Lysenko's theory immediately after the war as part of a postwar scientists' movement. Unlike many American geneticists, who sharply criticized the theory, Japanese geneticists initially participated in the discussion in an even-handed way; their scientific interests in the roles of cytoplasm and the environment in heredity shaped their initial sympathetic reaction. As the Cold War divide deepened, however, Japanese scientists began expressing sharp anti-Lysenko criticisms that resembled the American criticisms. Interestingly, throughout the period, Japanese geneticists' overall aim in the discussion remained largely unchanged: to effectively reconstruct their discipline and maintain its proper image and authority. However, the shift in their reaction occurred due to an evolving sociopolitical context, especially the shift in the meaning of 'democratic' science from a science that employed democratic processes to a science of a liberal-democratic state. Regarding Lysenko's idea as a cultural resource could help to explain how and why it was treated differently in different places, and why a controversy emerged in certain contexts but not in others. PMID- 26502660 TI - The Pasteurization of Marie Curie: A (meta)biographical experiment. AB - Biographies of scientists occupy a liminal space, highly popular with general readers but questioned in academia. Nonetheless, in recent years, historians of science have not only embraced the genre with more enthusiasm and less guilt, they have also turned to the metabiography in order to renew the study and story of scientists' roles. This essay focuses on Marie Curie, the world's most famous female scientist, in order to unpack some of the theoretical and methodological claims of the science biography, and especially to address the sexing mechanisms at play in the construction of the biographical subject. Pierre Curie (1923), Marie's biography of her husband Pierre, paid tribute to her dead husband and collaborator, but also allowed Curie a legitimate outlet to construct her own persona and legacy. Categories such as personhood, person, and persona are not only central to the biography genre but also are essential to the sense of self and self-fashioning of scientists. Looking at how Marie Curie negotiated these categories in Pierre Curie not only gives new insight into Curie's self fashioning strategies but may also shed some light on the more general analytical lacunae of the science biography. PMID- 26502661 TI - On conveying and not conveying expertise. AB - This article attends to the movement between disclosing and non-disclosing in accounts of expertise. While referencing discussions about tacit knowledge ('experts know more than they can say') and the politics of non-disclosure ('withholding can help as well as harm the credibility of experts'), in the main it considers how experts move between conveying and not conveying in order to make their proficiencies recognized and accessible to others. The article examines this movement through a form that partakes in it, thus drawing attention to conventions and tensions in how authors make themselves accountable, and their subject matter available, to audiences. It thereby proposes to explore the possibilities of careful, and generative, non-disclosure as part of expert writing practices. PMID- 26502662 TI - Exploration of Alternative Mechanism for MiR-596-mediated Down-regulation of LGALS3BP in Oral Squamous Cell Carcinoma. AB - MicroRNAs (miRNAs) are endogenous small non-coding RNAs that negatively regulate gene expression via binding to the 3' -untranslated region (UTR) of transcripts. However, recent evidence suggests that miRNA can also bind to the open reading frame (ORF) region within transcripts for its down-regulation. On the other hand, a previous report demonstrated that miR-596 has a tumor suppressor function by targeting LGALS3BP via directly binding to its 3' UTR in oral squamous cell carcinoma (OSCC) cells. However, it is not clear whether this miRNA can bind to the ORF region of LGALS3BP. In this study, although four putative binding sites of miR-596 were included within the ORF region of LGALS3BP, it was found that miR 596 could not bind to those sites. Instead, the results showed that the expression of LGALS3BP might be in part negatively regulated by the proteasome system at the protein level. Thus, these findings may help clarify the molecular mechanism of the tumor-suppressive effect through down-regulation of LGALS3BP by miR-596 in OSCC cells. PMID- 26502663 TI - [Outcomes of Infection Control Team Inspections at the Dental Hospital, Tokyo Medical and Dental University]. AB - In the Dental Hospital, Tokyo Medical and Dental University, an infection control team (ICT) has been formed to inspect each diagnosis department of clinics and wards in order to identify problems regarding nosocomial infection control. In this study, we analyzed the inspection reports and highlighted the following serious problems: 1) inadequate hygienic hand-washing for out- and in-patient treatment, 2) incomplete wearing of personal protective equipment (PPE) by dental health care workers, 3) necessity of environmental improvement in the clinics, and 4) cross-infection risk induced by. the continuous use of treatment devices without appropriate disinfection. The ICT provided feedback to the inspected departments, suggesting solutions to problems regarding nosocomial infection control. In order to enhance infection control in our hospital, dental healthcare practitioners must make further efforts on nosocomial infection control and prevention, and act according to their position by continuously educating students and enlightening hospital staff about the importance of infection control. PMID- 26502664 TI - Healing the Empire: Indian Hospitals in Britain and France during the First World War. AB - Desperate for soldiers to stem the German onrush in late 1914, the British deployed some 135,000 Indian riflemen--known as sepoys--to the trenches of France and Belgium. Between October 1914 and December 1915, these soldiers fought at the battles of Ypres, Festubert, Givenchy, Neuve Chapelle, Second Ypres, and Loos, suffering some 34,252 casualties. This article looks to the experiences of these men at segregated hospitals in France and England from 1914 to 1915. These hospitals served many of the same dual purposes facilitated by hospitals for English soldiers: namely, they sustained the war-making capacity of the Indian battalions. The Indian hospitals also functioned as sites of propaganda, reaffirming the ideologies and racial hierarchies of imperial rule for audiences at home, abroad, and within the hospital wards. But as this article demonstrates, wounded Indian sepoys were rarely, if ever, mere pawns on the imperial chessboard. Hospital authorities were committed to two policies: returning sepoys to the front and protecting White prestige. Sepoys successfully resisted both. In so doing, Indian hospitals became what British hospital administrators hoped they would not: spaces where imperial subjects contested and even reshaped some of the policies and ideologies of imperial rule. PMID- 26502665 TI - Duncan Tanner Essay Prize Winner 2014. Against the 'Sacred Cow': NHS Opposition and the Fellowship for Freedom in Medicine, 1948-72. AB - This essay recovers organized opposition to the National Health Service (NHS) by considering the Fellowship for Freedom in Medicine (FFM), a conservative organization of doctors who challenged the 'Sacred Cow' of nationalized healthcare in the 1950s and 1960s. While there has been little interest in anti NHS politics because of shortcomings in the institution's historiography, this study suggests ways a new history of the service can be written. Central to that project is taking the broader ideological and emotive quality of the NHS seriously, and appreciating the way, for all sides of the political spectrum, as well as the general public, the service has always been a contested symbol of post-war British identity. This essay argues that two NHS 'crises'--panics over costs, and disillusionment within general practice--were not merely disagreements over budgets and pay-packets but politically charged moments infused with conservative anxieties over Britain's post-war trajectory. The FFM imagined the NHS as an economically dangerous bureaucratic machine that crushed medical independence and risked pushing the country towards dictatorship. Allies within the Conservative Party, private health insurance industry, and free-market 'think tanks' worked with the FFM to challenge defences of both the service's operation and meaning. To appreciate why the NHS remains 'the closest thing the English have to a religion', one must consider the apostates as well as the faithful. PMID- 26502666 TI - Painful Times: The Emergence and Campaigning of Parents Against Injustice in 1980s Britain. AB - In July 1985 Steve and Susan Amphlett established Parents Against Injustice (PAIN) to support and represent parents falsely accused of child abuse. The Amphletts ran the organization from their own home, and struggled to gain funding, before closing PAIN in 1999. PAIN was to an extent a reflection of the 'new politics' of identity and lifestyle, concurrent with the rise of New Social Movements, as falsely accused parents utilized communication technologies to make their experiences public, and to contact and support one another. At the same time, PAIN also sought to exert political influence through relatively traditional channels--contributing to public inquiries, encouraging their membership to write letters to Members of Parliament, and shaping media critique. Despite its small size, PAIN was able to act as an intermediary between parents and politicians, social workers, solicitors and physicians. PAIN represented, but also collated and shaped, parents' experiences. The case study of PAIN suggests that small groups have been able to mediate between 'public' and 'experts', effectively working with both groups because of their ability to combine experience and professionalism. These groups have brought experiential knowledge into social policy, and more broadly shifted the roles and responsibilities accorded to children, families and parents. PMID- 26502667 TI - [Draft guideline regarding appropriate use of 131I-MIBG radiotherapy for neuroendocrine tumors Drafting Committee for Guideline of Radiotherapy with 131I MIBG, Committee for Nuclear Oncology and Immunology, The Japanese Society of Nuclear Medicine]. AB - 131I-MIBG radiotherapy has been used for unresectable nueroendocrine tumors including malignant pheochromocytomas and neuroblastomas in foreign countries since the '80s when clinical therapeutic trials were initiated. In Japan, 131I MIBG radiotherapy has not been approved by Ministry of Health, Labor and Welfare, however, personally imported 131I-MIBG is now available in limited institutions for therapeutic purpose. This updated guideline draft aims to provide useful information concerning 131I-MIBG radiotherapy, to prevent side effects, and to protect physicians, nurses, other health care professionals, patients and their families from radiation exposure. The committee also provides appendices including practical guidance for attending physicians, patient management and referring physicians for their conveniences. PMID- 26502668 TI - [The 36th Report on Survey of the Adverse Reaction to Radiopharmaceuticals (The 39th Survey in 2013)]. AB - This survey was performed in order to investigate the incidence of adverse reactions to radiopharmaceuticals in FY2013 in Japan. It was based on responses to questionnaires sent to nuclear medicine institutions. The reply was obtained from 997 institutions among 1,249 to which the questionnaire had been sent. Eight cases of adverse reactions were reported. A total of 1,056,876 radiopharmaceutical administrations was reported. The incidence of adverse reactions per 100,000 cases was 0.8. One case of defect products was reported, and the incidence of defect products per 100,000 cases was 0.1. PMID- 26502669 TI - [Management of mucopolysaccharidosis type VI in adults]. AB - Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome, MPS VI) is a progressive multisystemic lysosomal storage disease. Physical symptoms generally include growth retardation, and bone dysplasia. Enzyme replacement therapy is the treatment of choice and is done with recombinant version of enzyme N acetylgalactosamine 4-sulfatase (galsulfase) which is administered intravenously. The enzyme replacement therapy should be applied once a week as a life-long treatment. Division of metabolic diseases, Department of internal medicine, University Hospital Center Zagreb continues with the treatment of MPS VI patients after they turn 18 years of life and are not treated any more by the pediatricians. The aim of this document is to provide the guidelines for diagnosis and management of adult patients with MPS VI which consists not only of regular galsulfase adiministration, but also of regular follow up and treatment of numerous comorbidities. These guidelines were produced by experts from the Division of metabolic diseases, Department of internal medicine, University Hospital Center Zagreb which is the Referral center for rare and metabolic diseases of the Ministry of Health, Republic of Croatia. The guidelines are result of collaboration with pediatricians, radiologists and biochemists without whose experience and advices appropriate treatment of these patients would not be possible. The guidelines were endorsed by the Croatian society for rare diseases, Croatian Medical Association. PMID- 26502670 TI - [POMPE DISEASE - GUIDELINES FOR DIAGNOSIS AND MANAGEMENT OF ADULT PATIENTS]. AB - These guidelines provide a short summary of recommendations on Pompe disease, how to diagnose this disease, management of adult patients with this disease, follow up of the patients and recommendations on therapy and genetic testing. Early diagnosis and management of patients with Pompe disease requires a multidisciplinary approach of several different experts. These guidelines were produced by the Division of Metabolic Diseases, Department of Internal Medicine, University Hospital Center Zagreb which is a Referral expert center for rare and metabolic diseases of the Ministry of Health of the Republic of Croatia. They were endorsed by the Croatian Society for Rare Diseases, Croatian Medical Association.These are the first guidelines published in Croatia on diagnosis, treatment and follow-up of Pompe disease. PMID- 26502671 TI - [INFLUENCE OF NECK DISSECTION ON THE CORRESPONDING MOTOR AND SENSORY NERVES]. AB - OBJECTIVE: Radical neck dissection (RND), utilized for treatment of lymph node metastases in patients with head and neck cancers, can result in clinically significant functional disturbance secondary to the corresponding nerve damage. However, there is only limited data relative to post-operative analysis of impact of RND on the cranial and cervical nerves after neck dissection especially regarding the technique used such as electroknife or scalpel. STUDY DESIGN: 48 patients (42 men and 6 women) with intraoral cancer were enrolled. A total of 55 dissections were performed, including 7 patients who received bilateral dissections. Analysis of motor and sensory nerves was conducted seven days and three months later with regard whether electroknife or scalpel was used. RESULTS: The most frequent post-operative loss of motor function was seen in accessory and hypoglossal nerves; within sensory nerves the lingual nerve was most frequently dysfunctional. Permanent diaphragm dysfunction was seen in 15% of investigated patients. CONCLUSION: We might conclude that routine evaluation of sensoneural and motor nerve function of all potentially damaged nerves should be performed after RND, especially regarding diaphragm paralysis. There were no differences in postoperative nerve function of the examined nerves with regard to the technique used (electroknife/scalpel). PMID- 26502672 TI - [THE INCIDENCE OF PERIPARTUM HYSTERECTOMY IN FIVE CROATIAN HOSPITALS DURING A SIXTEEN-YEAR PERIOD]. AB - INTRODUCTION: Peripartal hysterectomy (PPH) is a life saving surgical procedure that is performed when conservative measures fail to control bleeding. According to literature data there is an increase in incidence among developed countries. AIM: To define the rate of PPH during two eight-year periods in five Croatian hospitals in respect to mode of delivery. METHODS: Patients data were collected retrospectively from the medical records of the five Croatian hospitals. We analyzed data from 1998 to 2013, and divided them in two eight-year periods. RESULTS: In 70 cases out of 153,302 deliveries urgent PPH was performed. PPH after vaginal deliveries was found in 0.21%o and 0.16%o and PPH after caesarean section was 1.91 %o and 2.04%o in the first and second period, respectively. DISCUSSION AND CONCLUSION: There is no increase of PPH rate in the two analyzed periods, although there is a statistically significant increase of caesarean section rate. Caesarean section presents higher risk for PPH. PMID- 26502673 TI - [AWAKE SURGERY FOR A PRIMARY BRAIN TUMOR]. AB - Awake brain surgery has been approved as a safe and efficaceous operative procedure with the goal of maximal tumor resection and preservation of neurological function. This case report presents the first full awake primary brain tumor surgical procedure performed in Croatia. PMID- 26502674 TI - [SUBUNGUAL EXOSTOSIS OF THE THUMB - CASE REPORT IN AN EIGHT YEAR OLD GIRL]. AB - Subungual exostosis (SE) is a benign osteocartilaginous tumor of the distal phalanx of the finger, particularly of the toes. It affects both sexes, the most frequently occurring in the second and third decades of life, and very rarely in children younger than eight years. We present subungual exostosis (SE) in a eith year old female child affecting the terminal phalanx of the right thumb. She presented to us with gradually enlarging, painless, subungual hard nodule on the right thumb, spherical appearance size of 12 mm in diameter. Roentogram of the foot showed bony outgrowth arising from the terminal phalanx of right thumb. Lesion was excised with prior ablation of the nail, and sent for histopathological examination. Histology showed evidence of SE. No recurrence at postoperated site was seen till ten months of follow-up. PMID- 26502675 TI - [CORRELATION BETWEEN OBESITY AND PANCREATIC CANCER]. AB - Pancreatic cancer is an aggressive tumor with a very poor prognosis, lack of early diagnostic symptoms and highly resistant to therapy. Its incidence is approximately equal to the mortality rate. Even though in recent years progress has been made in defining the morphological and key genetic changes, it is still unclear which factors trigger its occurrence. Some risk factors are age, gender and race, genetic susceptibility, dietary factors, fever, chronic pancreatitis, diabetes and physical inactivity. Studies have shown that an increase in BMI consequently leads to an increased risk of malignancies, including pancreatic cancer. Research based on adipokines and their role in obesity and the occurrence of pancreatic cancer are the potential for a possible future therapeutic interventions. PMID- 26502676 TI - [Which tuberculin skin test hyperreactive child should be treated with -our experience]. AB - Since persons with latent tuberculosis infection (LTBI) represent a huge reservoir of potential tuberculosis (TB) disease, accurate diagnosis and treatment of LTBI is essential for TB control and eradication. The aim was to assess the diagnostic value of determination of interferon-gamma release assay in school children with hyperreactive tuberculin skin test (TST) reaction. A total of 120 BCG-vaccinated children were investigated due to a hyperreactive TST results. The QuantiFERON-TB Gold In-Tube test (QFT-GIT) was performed. Fifteen children (12.5%) had positive QFT-GIT and 105 (87.5%) children had negative QFT GIT. There was no statistically significant difference in TST reaction (21.5 mm u QFT+ vs. 20.9 mm u QFT-group, p=0.458). The children with positive QFT-GIT had a statistically higher level of interferon-gamma (IFN-gamma) than children with negative QFT-GIT. There were no statistically significant differences in concentrations of IFN-y either basic or upon stimulation with mitogen phytohemagglutinin. After isoniazid prophylaxis QFT-GIT remained positive in two children (p=0.019). In a difficult procedure for diagnosing LTBI in BCG vaccinated children determination of IFN-gamma could be the key factor in making decision whether to use preventive therapy or not. PMID- 26502678 TI - [Urea cycle disorders - how to prevent severe consequences of late diagnosis]. PMID- 26502677 TI - [DR ALEKSANDAR DORSNER THE FIRST HOSPITAL OTORHINOLARYNGOLOGIST IN SPLIT AND DALMATIA]. AB - Dr Aleksandar Dorsner (Trebinje, 1892 - Lima, 1967) was the first hospital otorhinolaryngologist in Split and Dalmatia. He graduated from the Faculty of Medicine in Prague in 1919, and specialized otorhinolaryngology in Graz and Vienna. He led and organized otorhinolaryngological service in Split Hospital from 1923 to 1934, and he also had a private practice. Temporarily he also worked outside Split in Dalmatian hinterland and in Sibenik, Zadar and Dubrovnik. Most frequently he performed the following otorhinolaryngological operations: tonsillectomies and adenoidectomies and operations of purulent middle ear inflammations with mastoiditis, nasal polyps, deviated nasal septum, maxillary sinus empyema and otorhinolaryngological trauma. In 1928 he became a member of Otorhinolaryngological section of Croatian Medical Chamber. He participated in the work of the first otorhinolaryngological congress of the former Yugoslavia in 1931, taken place in Zagreb. From 1928 he was a member of Oto-Neuro Ophthalmological Society. From 1933 to 1937 he was a vice-president of the main board of Free Organization of Dalmatian Physicians in Split. In 1938 he left Split permanently and continued living with his family in Lima (Peru) where he died in 1967. He was an erudite. He lived for his profession which he liked very much and dedicated his life to. He is one of the most meritorious doctors in Split medical history, whom otorhinolaryngology service in Split Hospital started with. PMID- 26502679 TI - [Mediastinal tumors]. PMID- 26502680 TI - [Prof. dr. sc. LUKA KOVACIC (13. 10. 1940.-21. 4. 2015.)]. PMID- 26502681 TI - A Discussion about Life at the End. PMID- 26502682 TI - Risks Associated with Co-Prescribing Opioids and Benzodiazepines and Delaware's Prescription Drug Monitoring Program. PMID- 26502683 TI - Aggressive Measures to Decrease Door to Balloon Time May Increase the Incidence of Unnecessary Cardiac Catheterization and Delay Appropriate Care. AB - Door-to-balloon (DTB) time is an important quality measure for ST-segment myocardial elevation infarction (STEMI). Aggressive measures to reduce DTB time can increase the incidence of false positive-STEMI and may increase mortality in that group. Efforts to reduce DTB time should be monitored systematically to avoid unnecessary procedures especially in critically ill patients who don't have STEMI and may benefit from other appropriate therapies in timely manner. We report two cases where trying to achieve an aggressive DTB time may have led to unwarranted outcomes. PMID- 26502684 TI - Editor's Choice June 2015. PMID- 26502685 TI - Current knowledge on Mycobacterium leprae transmission: a systematic literature review. AB - Summary BACKGROUND: The transmission pathways of Mycobacterium leprae are not fully understood. Solid evidence exists for an increased risk for individuals living in close contact with leprosy patients but the existence of zoonotic leprosy, environmental reservoirs and trauma-related transmission has also been established. PURPOSE: To assess the current state of knowledge on M. leprae transmission, we conducted a systematic review of the peer-reviewed literature pertaining to this topic. METHOD: Major electronic bibliographic databases were searched for relevant peer-reviewed articles published up to January 2014. No restrictions on study types, participants and location were applied, and all outcomes demonstrated to contribute to the transmission of M. leprae were considered. Included studies were grouped by mode of transmission, namely (i) human-to-human via aerosols or direct contact; (ii) direct inoculation (e.g. injury); and (iii) transmission to humans from environmental or zoonotic reservoirs, and by insects. The importance of the different transmission pathways and the strength of the evidence were assessed considering the number of publications describing similar findings, the consistency of the findings and the methodological quality of the studies. RESULTS: A total of 79 relevant articles were retained out of 3,805 hits resulting from the application of the search strategy. Solid evidence for transmission among contacts exists, and for zoonotic leprosy in the southern States of the USA. Based on the extant evidence, skin-to skin contact, aerosols/droplets and shedding of bacteria into the environment and subsequent infection, e.g. through dust or small wounds, all remain possible options. CONCLUSION: No study has unequivocally demonstrated the mechanisms by which M. leprae bacteria travel from one case of leprosy to another. PMID- 26502686 TI - Symposium Report: Developing Strategies to Block the Transmission of Leprosy. PMID- 26502687 TI - Clinical features of relapse after multidrug therapy for leprosy in China. AB - BACKGROUND: Although the World Health Organization (WHO) has defined relapse in leprosy, it is often difficult to confirm a relapse, especially in paucibacillary (PB) patients. OBJECTIVE: To study features of relapse cases in order to determine the information needed to allow better management of relapses in the leprosy control programme. DESIGN: A retrospective survey by questionnaire was carried out at national level at the end of 2012. RESULTS: There were 40 relapsed patients on register. The clinical form of leprosy was TT5, BT4, BB5, BL13 and LL13. Twenty-eight patients had had a positive skin smear test at the start of MDT, with a BI ranging from 0.83 to 6.0. At the time of completing MDT, the skin smear test remained positive in seven patients. After completion of MDT, other family members of 13 patients were identified as new leprosy patients. All relapse cases showed one or more active skin lesions. There were 33 patients with a positive skin smear test at the time of relapse. A total of 23 patients had a biopsy at the time of relapse, including seven patients with a negative skin smear test. The histological features of relapsed BB-LL patients included granulomas containing macrophages or epithelioid cells with sparse lymphocytes and acid-fast bacilli. The histological features of seven patients with negative skin smears showed epithelioid cell granulomas with dense lymphocytes surrounding the granuloma, but without distinct edema in the dermis. The average interval from completion of MDT to the diagnosis of relapse was 168.5 +/- 92.6 months with a range of 21-322 months. During the study, nine patients were tested for rifampicin resistance, but none showed any mutation. CONCLUSIONS: Leprosy relapse after MDT usually occurred late and all relapse cases had new active skin lesions. Most patients relapsed with a positive skin smear after previously reaching negative BI status. Relapse with a negative skin smear test should be confirmed very cautiously. PMID- 26502688 TI - Family motivation card: An innovative tool for increasing case detection in a resource poor setting. AB - INTRODUCTION: Leprosy is a chronic infectious disease, causing various physical disabilities and deformities. Even today, stigma leads to late detection of new cases. Household contacts are considered a primary focus for the spread of infection. AIM AND OBJECTIVE: To find new cases among household contacts of leprosy patients by providing a family motivation card (FMC) to each leprosy patient, thereby enabling early diagnosis and treatment leading to a decrease in disease and disability burden in the community. MATERIALS AND METHODS: 100 patients diagnosed with leprosy (both new and old cases) were enrolled in the study. All patients were provided with a family motivation card. The purpose of giving the card was discussed in detail with each patient. New family contacts brought by old patients were examined thoroughly for the presence of leprosy. Digital color photographs were taken of all family contacts. Data analysis was done. RESULTS: 23 new cases of leprosy (15 (65%) MB and eight (35%) PB cases) were detected among family members of primary cases. Most cases belonged to the under 15 years (43.47%) and over 60 years (34.78%) age groups. CONCLUSION: Adoption of a simple, cheap yet effective strategy such as the FMC could act as a bridge between intensive case-finding approaches, such as the Modified Leprosy Elimination Campaign (MLEC) and voluntary reporting. PMID- 26502689 TI - A case of lepromatous leprosy with co-existing tuberculosis verrucosa cutis (TVC). AB - The association of leprosy and cutaneous tuberculosis has been reported rarely. Though cross-immunity may exist between these two mycobacterial infections, tuberculosis can occur throughout the spectrum of leprosy. We report a case of lepromatous leprosy with Type II reaction, with tuberculosis verrucosa cutis (TVC). The patient presented with multiple skin-coloured tender nodules of variable size, involving the upper and lower extremities, nodular enlargement of both ear lobes, erythematous plaques on the face and icthyotic patches over both lower legs and feet, for 6 months. There was also a slow-growing asymptomatic warty plaque over the right lateral malleolus, present for 1 year. Slit skin smear examination from ear lobes, forehead and nodules, and histopathology of the warty lesion, respectively confirmed the diagnoses of leprosy and tuberculosis. PMID- 26502690 TI - Disseminated cutaneous BCG infection following BCG immunotherapy in patients with lepromatous leprosy. AB - Cutaneous complications of Bacillus Calmette-Guerin (BCG) vaccine, especially in the form of generalised disease, are uncommon and mostly occur in immunocompromised individuals. There is a paucity of data on the cutaneous adverse reactions secondary to BCG immunotherapy in leprosy. We report two unique cases of disseminated cutaneous BCG infection following immunotherapy in patients with lepromatous leprosy. To our knowledge, cutaneous BCG infection presenting as widespread lesions after immunotherapy and confirmed by isolation of Mycobacterium bovis by polymerase chain reaction (PCR) has not been described. A high index of suspicion is required when leprosy patients who receive BCG immunotherapy develop new lesions that cannot be classified as either reaction or relapse, and diagnosis may be confirmed on histopathology and PCR. PMID- 26502692 TI - Persistent serpentine supravenous hyperpigmented eruption in lepromatous leprosy after minocycline. AB - Persistent serpentine supravenous hyperpigmented eruption (PSSHE) is a peculiar patterned eruption characterised by hyperpigmented streaks following the superficial venous network on the skin. Unlike the superficial thrombophlebitis, it is characterised by underlying vessels that are patent. It has been described most commonly after injection of chemotherapeutic drugs. We describe a 40 year old man with lepromatous leprosy who developed PSSHE subsequent to starting modified multidrug therapy--multibacillary regimen in the form of minocycline and ofloxacin. PMID- 26502691 TI - Dapsone hypersensitivity syndrome in a lepromatous leprosy patient--A Case Report. AB - Dapsone hypersensitivity syndrome (DHS) can be classified as a 'drug reaction with eosinophilia and systemic symptoms' (DRESS). It has a variable course, it is not dose dependent and may present with different clinical and laboratory abnormalities. In some cases it may be fatal. We describe a 31 year old man with lepromatous leprosy in whom DHS developed 4 weeks after initiation of World Health Organization multibacillary multidrug therapy (dapsone, clofazimine and rifampin). He had fever, dehydration, diffuse rash, pain on abdominal palpation and inguinal painless lymph nodes. Severe anaemia, abnormal liver function and hyperbilirubinaemia were also found. The patient was treated with prednisone 50 mg daily. There was gradual improvement in the clinical and laboratory signs. We encourage health professionals to be aware of the risk of DHS and to have in mind the development of investigative studies related to HLA and MHC in these patients. PMID- 26502693 TI - Leprosy and Lobomycosis: First report from the Amazon Region. AB - Leprosy is still a relevant health problem in Brazil with 31 044 new cases diagnosed in 2013, of which 781 new cases diagnosed in the State of Amazonas. Lobomycosis is a cutaneous-subcutaneous mycosis caused by Lacazia loboi, an in vitro uncultivable fungus. Lobomycosis has been mainly reported in the Amazon region of Brazil and Colombia affecting mainly male farmers and workers in extraction of rubber. Lobomycosis is clinically characterised by keloid-like lesions and chronic evolution. Even if lobomycosis does not represent a major public health problem, it remains a serious condition for patients due to unsatisfactory treatment. We report a case of an old man with lepromatous leprosy diagnosed in 1983, treated with multidrug therapy until 1989 and presenting a leprosy relapse 15 years after treatment. At this time a lobomycosis was also diagnosed in a keloid-like lesion evolving for more than 30 years. This co infection has been only rarely reported and this is the first detailed case report in the English literature. PMID- 26502694 TI - Type 1 reaction masquerading clinically as ENL: A Case Report. AB - Attention is drawn to a Type 1 reaction masquerading clinically as ENL. Histology showed no evidence of ENL but suggested heightened T-cell activity (CMI), a characteristic feature of Type 1 reaction. We present a case of a 29 year old man diagnosed as lepromatous leprosy with recurrent Type 2 reaction treated with thalidomide for 2 years. The patient was referred to our institute from a teaching hospital. Skin biopsies were carried out during two separate eruptive episodes 2 months apart. Histopathology showed heightened T-cell activity, but no evidence of ENL. PMID- 26502695 TI - [BIOLOGICAL AND IMMUNOCHEMICAL PROPERTIES OF POLYREACTIVE IMMUNOGLOBULINS]. AB - A previously unknown phenomenon of acquired polyreactivity for serum immunoglobulins, which were subjected either to solutions of KSCN (3.0-5.0 M), low/high pH (pH 2.2-3.0), or heating to 58-60 degrees C, was described by us in 1990 year. Much later, eleven years after that, similar data were published by others, which completely confirmed our results concerning the influence of either chaotropic ions or the drastic shift of pH on immunoglobulins polyreactive properties. Our further investigations of polyreactive serum immunoglobulins (PRIG) properties have shown that the mechanism of non-specific interaction between PRIG and antigens much differs from the mechanism of interaction between specific antibodies and corresponding antigens. Later we have shown that the increasing of PRIG reactivity could be induced in vivo, and PRIG are one of serum components for human or animal sera. Then, it could be suggested that PRIG can perform certain biological functions. Studying of PRIG's effect on the phagocytosis of microbes by peritoneal cells or the tumor growth have shown that PRIG can play a certain role in protecting the body from infections and probably can influence on the development of various pathological processes. Recently we have also found that PRIG IgG contents significantly increases in aged people. These data demonstrate that further investigations of PRIG's immunochemical properties and studying of their biological role in organism protection from various diseases is very intriguing and important. PMID- 26502696 TI - THERMAL STABILITY OF Cryptococcus albidus alpha-L-RHAMNOSIDASE. AB - Yeast as well as micromycetes alpha-L-rhamnosidases, currently, are the most promising group of enzymes. Improving of the thermal stability of the enzyme preparation are especially important studies. Increase in stability and efficiency of substrate hydrolysis by alpha-L-rhamnosidase will improve the production technology of juices and wines. The aim of our study was to investigate the rate of naringin hydrolysis by alpha-L-rhamnosidase from Cryptococcus albidus, and also some aspects of the thermal denaturation and stabilization of this enzyme. We investigated two forms of alpha-L-rhamnosidase from C. albidus, which were obtained by cultivation of the producer on two carbon sources--naringin and rhamnose. A comparative study of properties and the process of thermal inactivation of alpha-L-rhamnosidases showed that the inducer of synthesis had no effect on the efficiency of naringin hydrolysis by the enzyme, but modified thermal stability of the protein molecule. Hydrophobic interactions and the cysteine residues are involved in maintaining of active conformation of the alpha-L-rhamnosidase molecule. Yeast alpha-L-rhamnosidase is also stabilized by 0.5% bovine serum albumin and 0.25% glutaraldehyde. PMID- 26502697 TI - FURIN INHIBITORS BASED ON THE DERIVATIVES OF CALIX[4]ARENE CX3im. AB - The aim of this work was to study antifurin activity of some derivatives of calix[4]arenes modified on the upper rim of the macrocycle by positively charged or uncharged groups. It was found that calixarene CX3im derivatives containing positively charged N-methylimidazolium cycles were indeed able to inhibit furin (K(i) = 58.2 MUM). The magnitude of the effects depended also on the hydrophobicity of the substituents located on the lower rim of the macrocycle. The findings indicated the possibility of creating furin inhibitors of new generation based on the calix[4]arene platform. PMID- 26502698 TI - [PROPERTIES OF CHICKEN LIVER MEMBRANE-ASSOCIATED THIAMINE TRIPHOSPHATASE]. AB - The enzymes involved in thiamine triphosphate (ThTP) metabolism in birds are not characterized so far. The aim of the present work was to study some properties of ThTPase in chicken liver. In liver homogenate, ThTPase activity has been found to display a bell-like pH-profile with a maximum of 5.5-6.0. Low activity was observed without divalent metal ions, while the addition of Mg2+ or Ca2+, each at 5 mM concentration, enhanced the rate of ThTP hydrolysis by a factor of 17-20. In the presence of 5 mM Mg2+ an apparent K(m) of the enzyme for ThTP was estimated by the method of non-linear regression as well as from the Hanes plot to be 1.7 2.2 mM. Monovalent anions such as I-, SCN-, NO3-, Br-, Cl- (at 150 mM concentration) showed inhibitory effect decreasing the rate of ThTPase reaction by 20-60%. After the homogenate was centrifuged, more than 85% of ThTPase activity was revealed in the fraction of insoluble particles indicating a membrane localization of the enzyme. The precipitate treatment with 1% sodium deoxycholate caused about 53% solubilization of the activity. During Toyopeal HW 55 chromatography, ThTPase activity was eluted simultaneously with ATPase and ITPase peaks in the void volume of the column. Thus, a non-specific high molecular mass protein complex seems to be involved in ThTP hydrolysis in the chicken liver. The chicken liver phosphatase is clearly distinguishable from all membrane-bound ThTPases reported previously. PMID- 26502699 TI - CARBONIC ANHYDRASE ACTIVITY OF INTEGRAL-FUNCTIONAL COMPLEXES OF THYLAKOID MEMBRANES OF SPINACH CHLOROPLASTS. AB - Isolated thylakoid membranes were disrupted by treatment with nonionic detergents digitonin or dodecyl maltoside. Solubilized polypeptide complexes were separated by native gel charge shift electrophoresis. The position of ATP-synthase complex and its isolated catalytic part (CF1) within gel was determined using the color reaction for ATPase activity. Due to the presence of cytochromes, the red band in unstained gels corresponded to the cytochrome b6f complex. Localization of the cytochrome b6f complex, ATP synthase and coupling CF1 in the native gel was confirmed by their subunit composition determined after SDS-electrophoretic analysis. Carbonic anhydrase (CA) activity in polypeptide zones of PS II, cytochrome b6f complex, and ATP-synthase CF1 was identified in native gels using indicator bromothymol blue. CA activity of isolated CF1 in solution was determined by infrared gas analysis as the rate of bicarbonate dehydration. The water-soluble acetazolamide, an inhibitor of CA, unlike lipophilic ethoxyzolamide inhibited CA activity of CF1 Thus, it was shown for the first time that ATP synthase has a component which is capable of catalyzing the interconversion of forms of carbonic acid associated with proton exchange. The data obtained suggest the presence of multiple forms of carbonic anhydrase in the thylakoid membranes of spinach chloroplasts and confirm their involvement in the proton transfer to the ATP synthase. PMID- 26502700 TI - HISTONE DEACETYLASE ACTIVITY AND REACTIVE OXYGEN SPECIES CONTENT IN THE TISSUE CULTURE OF Arabidopsis thaliana UNDER NORMAL CONDITIONS AND DEVELOPMENT OF ACUTE OSMOTIC STRESS. AB - The possible involvement of histone deacetylase (HDAC) in regulation of ROS content in the tissue culture of Arabidopsis thaliana under normal conditions and under development of acute osmotic stress was studied by using inhibition assay with application of trichostatin A (TSA). It was found that in the tissue culture grown under normal conditions a decrease in HDAC activity by means of TSA led to increase of the ROS content. Similar but more pronounced alterations occurred under stress. At the same time an increase in histone acetyltransferase (HAT) activity was also observed. The possible mechanisms of HDAC and HAT participation in regulation of ROS content by changes in expression of genes that are responsible for ROS production and antioxidant activity are discussed. PMID- 26502701 TI - INHIBITOR OF THE TRANSCRIPTION FACTOR NF-kappaB, DHMEQ, ENHANCES THE EFFECT OF PACLITAXEL ON CELLS OF ANAPLASTIC THYROID CARCINOMA IN VITRO AND IN VIVO. AB - Anticancer drug paclitaxel (Ptx) effect on biochemical mechanisms, regulating apoptosis in anaplas- tic thyroid carcinoma cells, was studied. It was shown that in addition to apoptotic cell death, Ptx induces signaling cascades that ensure cell survival. Paclitaxel-induced activation of nuclear factor kappa B (NF kappaB) leads to an increase of some antiapoptotic proteins expression such as survivin, cIAP, XIAP. A novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), was found to enhance cytotoxic effect of Ptx in anaplastic thyroid carcinoma cells. An enhancement of caspase-3 and -9 activation and PARP cleavage as well as the decreased levels of proteins-inhibitors of apoptosis were observed when cells were treated with a combination of both drugs. Mitochondria transmembrane potential (Deltapsi (m)) loss was observed at higher concentrations of Ptx and DHMEQ. NF-kappaB inhibition also potentiates paclitaxel effect at tumors formed by xenotransplantation of FRO cells into mice. Tumor mass reduction, significantly different from the effects of each of the compounds alone, was observed in animals, treated with paclitaxel and NF-kappaB inhibitor. Thus, the combined use of paclitaxel and NF-kappaB inhibitor inhibits biochemical processes that contribute to the resistance of anaplastic thyroid carcinoma cells to paclitaxel action. PMID- 26502702 TI - VITAMIN D3 CONTRIBUTION TO THE REGULATION OF OXIDATIVE METABOLISM IN THE LIVER OF DIABETIC MICE. AB - This work is devoted to the study of the features of oxidative metabolism of hepatocytes in diabetic mice and those under the vitamin D3 action. We found out that a 2.5-fold decrease of 25OHD3 content in the serum was caused by chronic hyperglycemia in diabetes. Intensification of the reactive oxygen species (ROS) and nitrogen monoxide (NO) production, protein oxidative modifications (detected by the contents of carbonyl groups and 3-nitrotyrosine), accumulation of diene conjugates and TBA-reactive products of lipid peroxidation, and the decreased level of free SH-groups of low molecular weight compounds in the liver were accompanied by development of vitamin D3 deficient state. It was shown that there was a decrease in the key antioxidant enzymes activity (catalase, SOD), while the activity of prooxidant enzymes NAD(P)H: quinone oxidoreductase, xanthine oxidase and NAD(P)H oxidase was increased. The identified oxidative metabolism lesions caused the elevation of the hepatocytes necrotic death that was tested for the ability of their nuclei to accumulate propidium iodide. Prolonged vitamin D3 administration (during 2 months) at a dose of 20 IU to diabetic mice helps to reduce the ROS formation and biomacromolecules oxidative damage, normalizes the antioxidant system state in the liver and increases survival of hepatocytes. The results suggest that vitamin D3 is a key player in the regulation of the oxidative metabolism in diabetes. PMID- 26502703 TI - INDICATORS OF HUMORAL IMMUNITY UNDER CHEMICAL BURNS OF ESOPHAGUS IN RATS. AB - It is well known that the immune system has been actively involved in the regeneration and healing processes of post burn wounds. However, unanswered questions remain concerning the role of humoral immunity in the healing mechanisms and development of burn wound complications. We have developed an experimental model of chemical esophageal burn (CEB) which corresponds to esophageal burn in 1-8 years old children. We studied the features of humoral immunity upon CEB in rats. A decrease in IgG levels and an increase in levels of medium- and low- molecular circulating immune complexes (CIC) on the first day of esophageal burns were observed. On the 21st day of burn, we observed an increase in the IgG concentration and a tendency to accumulation of medium- and low molecular CIC. The studied indicators can be used to differentiate CEB development and create a timeline of burn wounds. PMID- 26502704 TI - [LEVELS OF SERUM ANTIBODIES TO ENTEROBACTERIAL LIPOPOLYSACCHARIDES AND THEIR RELATIONSHIP WITH CONCENTRATION OF C-REACTIVE PROTEIN IN DIABETES MELLITUS PATIENTS]. AB - We examined patients with type 1 (DM 1) and type 2 (DM 2) diabetes mellitus. The concentration of C-reactive protein (CRP) in the blood and levels of serum antibodies to different classes of enterobacterial lipopolysaccharides (LPS) were determined by ELISA. Using cluster analysis it was shown that in 40.8% DM-1 patients the increased concentration of CRP is associated with a decrease in the levels of serum anti-LPS-IgA, anti-LPS-IgM and anti-LPS-IgG. In 56.7% of DM-2 patients with increased concentration of CRP levels of serum anti-LPS-IgA and anti-LPS-IgM were not significantly different from the normal values, but the levels of serum anti-LPS-IgG were significantly increased. Activation of inflammation and increase of concentration of the CRP in the blood of DM-2 patients is accompanied by a significant increase in the levels of serum anti-LPS A and anti-LPS-G, as well as the tendency to reduce the levels of anti-LPS-IgM. The results of this study suggest an association between low intensity inflammation and immune response to enterobacterial LPS in type 1 and 2 diabetes mellitus. PMID- 26502705 TI - [DIFFERENTIATION OF NORM AND PATHOLOGY DURING SELECTIVE BIOCHEMICAL SKREENING OF LYSOSOMAL STORAGE DISEASES WITH INCREASED EXCRETION OF OLIGOSACCHARIDES]. AB - Oligosaccharides are a class of polymeric carbohydrates, which are constituents of a glycoside portion of glycoprotein and glycolipid molecules. The lysosomal hydrolase dysfunction due to lysosomal storage disorders results in partial or complete failure of degradation of some glycoproteins and glycolipids, causing the accumulation of specific undegraded substrates in the lysosomes of cells, the formation of the great number of oligosaccharide chains and their increased excretion with urine. Our work was aimed at detailed study of the specificities of interpreting the results of thin-layer chromatography (TLC) of urine oligosaccharides in healthy persons of different age groups with the purpose of further application of these data while differentiating the norm and pathology in the course of primary selective screening of lysosomal storage disorders. The results obtained demonstrated that TLC plates for the majority of healthy persons had insignificant excretion of a number of oligosaccharides (from monosaccharides to hexasaccharides) with R(lac) > 0.15, which can be characterized as physiological oligosacchariduria, conditioned by the metabolism specificities in lysosomes. Therefore while interpreting the urine samples of patients with the suspected lysosomal storage disorder it is diagnostically reasonable to examine the TLC plates for the presence of both oligosaccharide groups, absent in the samples of healthy persons, and all the fractions with R(lac) < 0.15. PMID- 26502706 TI - DISTRIBUTION OF GLIAL FIBRILLARY ACIDIC PROTEIN IN DIFFERENT PARTS OF THE RAT BRAIN UNDER CADMIUM EXPOSURE. AB - The chronic effects of low doses of cadmium on the distribution of soluble and filament forms of glial fibrillary acidic protein (GFAP) and their polypeptide fragments in different parts of the rat brain were investigated. Obtained results showed dose-dependent effect of cadmium on the soluble form of GFAP and more pronounced effect on the filament form and composition of the polypeptide fragments of the protein in the rat brain. Prolonged intoxication by cadmium ions in a dose of 1.0 MUg/kg of body weight induced a significant decrease in soluble GFAP and an increase in the filament form in the rat brain, pointing to the development of reactive astrogliosis and the risk of neurodegeneration. PMID- 26502707 TI - [Inventive activity of Maksym Fedotovych Guly, Academician of NAS of Ukraine]. PMID- 26502708 TI - [A Case of Anorexia Nervosa with Chewing and Spitting Improved by Treatment with Selective Serotonin Reuptake Inhibitors]. AB - Chewing and spitting (CHSP) is the symptom of chewing and spitting out food without swallowing. CHSP is fairy common among patients with eating disorders, but no report has been published on drug treatment for it. We report a patient with anorexia nervosa showing extreme weight loss due to CHSP. After admission, CHSP was improved by treatment with Selective Serotonin Reuptake Inhibitors, leading to marked recovery of the body weight CHSP may represent a marker for illness severity, so its early treatment is critical to prevent the increasing severity of eating disorders. PMID- 26502709 TI - [A Comprehensive Care System for Children with Anorexia Nervosa in Pediatric Practice]. AB - Against the backdrop of rapid industrialization and westernization after the World War II, there has been an ever increasing number of children with anorexia nervosa (AN) in pediatric practice, making it one of the most common diseases in children. With a severe lack of AN specialists in Japan, pediatricians need to face the daunting task of treating AN on their own. Malnutrition overlooked during periods of growth and development yields a risk of death, growth disturbance and an intractable conditions with secondary disorders of brain atrophy, osteoporosis, infertility, maltreatment and childrearing failures, mental disorders and others, which can last for life. Prevention is the best and a must for AN, and an early detection and treatment need to be in place to mitigate its progress and aggravation. It is crucial that an effective care is provided in early, treatable stage to assist the patient back to a healthy developmental trajectory. In 1993, the Department of Pediatrics, School of Medicine, Keio University (hereafter PKU) appointed a child psychiatrist as its fulltime staff and has included inpatient treatment of AN as a compulsory item of its postgraduate training program. Over the past twenty years, PKU has developed a comprehensive treatment system of AN (Scientific Report of Ministry of Welfare and Labor 2006). In the primary care of AN, a screening tool using simple physical measurement of weight on growth chart combined with pulse proves effective. When a weight on growth chart reveals an unhealthy weight loss and is combined with bradycardia, it detects AN at sensitivity of 83% and specificity of 93%. In the secondary care of AN, 40 pediatric institutions affiliated with PKU implemented early treatment of AN with the support of the Mental Health Division of PKU. In the tertiary care for severely emaciated AN patients, an around-the clock intensive treatment program, called Anorexia Nervosa Intensive Care Unit (ANICU) was instituted. The gist of ANICU is to enhance the patient's awareness of the danger of catabolism and her incentive to overcome AN through active commitment to the treatment. This treatment program harbors principles of integrity, structure and persistence; starting with a complete bed rest and regular small-step provision of nutrition and steady enhancement of daily activities, it steadily and systematically converts the body's metabolism from catabolism to anabolism. In this treatment program, more than one hundred patients' lives were saved without a single fatal case. Trainees in PKU were provided with firsthand experience of providing comprehensive care, including taking on a role of feeding the AN patients three times a day. Around three hundred trainees were trained at PKU over the past twenty years, many of whom now treat AN in their affiliated hospitals. This collaborative care, comprised of a pediatric team, family and school, supported by a specialist, will become the most reliable way of treating AN in the coming days. We hope to decrease the sufferings of children with AN through spreading this comprehensive care system for children with AN in Japan. PMID- 26502710 TI - [Limitations and Problems with Treatment of Eating Disorders in a Psychiatric Hospital]. AB - Treating patients who have eating disorders in psychiatric hospitals is difficult for several reasons. The first reason is that there is a shortage of qualified psychiatrists. For each psychiatrist, there are approximately thirty hospitalized patients. In addition to this limited number of psychiatrists, funding in psychiatric hospitals only provides for a limited number of other medical staff when compared with funding available for general hospitals. The second reason is that there is a problem with the national medical treatment fee system. Specifically, in the current system, patients are not permitted to stay in hospitals long-term; outpatient treatment is preferred. The third reason is that psychiatric hospitals are not equipped to deal with patients who have physical illnesses. The following two case studies highlight the problems and limitations associated with treating patients who have eating disorders. Ways in which psychiatric hospitals can collaborate with other organizations, including low enforcement officials, are also considered. Although it is clear that an integrated and collaborative approach is necessary, implementation of such a system is still a long way from being realized, and greater effort is needed to provide patients suffering from eating disorders with the best possible treatment. PMID- 26502711 TI - [Treatment of Anorexia Nervosa Patients in General Hospitals with Psychiatric Wards Current Situation and Establishment of a Treatment System]. AB - Patients with anorexia nervosa (AN) exhibit physical and psychiatric symptoms, in addition to their behavioral problems, and often require admission to a general hospital with a psychiatric ward. There are only a few general hospitals with psychiatric wards available, and patients with AN tend to be concentrated in a small number of such institutions. Thus, it is difficult to provide adequate support for the treatment of patients with AN. In Kyoto, the number of general hospitals with a psychiatric ward is small. Patients with AN tend to be treated at the two university hospitals. However, our University Hospital cannot accept all patients with AN, especially the emergency admissions. Therefore, with respect to the inpatient treatment of AN, we established a cooperation agreement with other psychiatric hospitals. We are planning to divide the inpatient treatment of AN between our university hospital and other psychiatric hospitals, depending on the stage of AN and the severity of the patients' physical condition. With respect to the treatment of AN, it is necessary to establish a treatment system with each hospital playing a role. PMID- 26502712 TI - [Democratizing the Privileges of Psychiatrists]. AB - Psychiatrists are endowed with many privileges in their clinical practices. These include privileges to engage with personally and socially important disorders, those stemming from the role of psychiatrists as medical professionals, and those given by their situation in the context of a social psychiatric system. These privileges allow psychiatrists to attain profound insight into the significance and value of life. Psychiatrists must inculcate a mission to be aware of and to make use of these privileges for advances in psychiatry and clinical practices. One of the most important privileges of psychiatrists is to share their feeling of self-respect obtained by devoting themselves to "the most important medicine for humans" with their patients, families, and colleagues. PMID- 26502713 TI - [One-carbon Metabolism and Schizophrenia]. AB - One-carbon metabolism is a process whereby folate transters one-carbon groups in a range of biological processes, including DNA methylation and homocysteine metabolism. We have focused on and examined the potential roles of this one carbon metabolism in the pathology of schizophrenia. Firstly, we revealed that aberrant DNA methylation in schizophrenia occurred across the whole genome in peripheral leukocytes by conducting genome-wide DNA methylation profiling. Secondly, we demonstrated that plasma total homocysteine was associated with DNA methylation in patients with schizophrenia at specific genes. Thirdly, we demonstrated that blood homocysteine levels were significantly higher in patients with schizophrenia than in non-psychiatric controls by conducting meta-analysis of previous observational studies. Fourthly, we demonstrated a causal relationship between blood homocysteine and schizophrenia by conducting Mendelian randomization analysis. Finally, we demonstrated that the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which causes reduced enzyme activity and higher homocysteine levels, was a risk factor for developing schizophrenia in a Japanese population by conducting meta-analysis of previous genetic association studies. These results will add new insights into the pathology and treatment of schizophrenia. PMID- 26502714 TI - Temporal changes in haematocrit following artemisinin-based combination treatments of uncomplicated falciparum malaria in children. AB - BACKGROUND: Artemisinin-based combination treatments (ACTs) or intravenous artesunate are used in over 100 countries for uncomplicated or severe falciparum malaria. Although intravenous artesunate may cause delayed haemolytic anaemia, there is little evaluation of the temporal changes in haematocrit following ACTs. METHODS: Clinical and parasitological parameters were measured before and following treatment of uncomplicated falciparum malaria in children with artesunate-amodiaquine (AA) or artemether-lumefantrine (AL) over 6-weeks. Changes in haematocrit were characterized in individual patients based on a haematocrit <30 % or >=30 % before and following treatment. Kinetics of the deficit in haematocrit from <30 % until attainment of >=30 % were estimated by a non compartment model. RESULTS: In 248 of 1180 children eligible for evaluation, common temporal patterns were: no change or increase in haematocrit from >= 30 % [50 % of patients], haematocrit >30 % at presentation declining to <30 % within 2 weeks (early monophasic fall) [19 % of patients], and haematocrit <30 % at presentation increasing to >= 30 % [23 % of patients]. Haematocrit >30 % at presentation declining to <30 %, 3-5 weeks later (late monophasic fall) occurred in 7 children (3 %). Fall in haematocrit >=5 units following treatment occurred in 57 children [23 %] between 14 and 28 days after treatment began. Baseline parasitaemia and proportion with > 100,000MUL(-1) asexual forms were significantly higher in children with >=5 units compared to <5 units fall in haematocrit 21 or 28 days after treatment began. Irrespective of pattern, declines in haematocrit deficit from <30 % were mono-exponential, with similar half-times for AA- and AL-treated children (1.32 d versus 1.14 d). Anaemia half time correlated significantly positively with anaemia recovery time in the same patients (r = 0.55, P < 0.0001). Bland-Altman analysis of 9 or 10 multiples of anaemia half-time and anaemia recovery times showed narrow limit of agreement with insignificant biases (P = 0.19 or 0.63, respectively). CONCLUSIONS: In uncomplicated falciparum malaria, increases or falls in haematocrit are common following ACTs. Falls in haematocrit >= 5 units are common and may or may not result in early or late anaemia. In children who recovered from acute falciparum malaria-associated anaemia following ACTs, decline in haematocrit deficit is mono exponential. TRIALS REGISTRATION: Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201508001191898 , 7 July 2015 http://www.pactr.org . PMID- 26502715 TI - Channel-assisted minimally invasive repair of acute Achilles tendon rupture. AB - BACKGROUND: Percutaneous (minimally invasive) suturing is a promising option for Achilles tendon (AT) repair with low rerupture and infection rates. Sural nerve lesions are the major problem to avoid with the technique. A new device was therefore designed for suturing the AT, resulting in channel-assisted minimally invasive repair (CAMIR). The purpose of this study was to compare the clinical and functional outcomes of CAMIR with traditional open techniques. METHOD: Eighty two patients with AT rupture were included: 41 for CAMIR, 41 for open repair. All patients followed a standardized rehabilitation protocol. Follow-ups were at 12 and 24 months after surgery. Functional evaluation was based on the clinical American Orthopaedic Foot & Ankle Society score associated with neurologic deficit (sural nerve), calf circumference, range of motion (ROM), and isometric testing. RESULTS: There was no difference between groups regarding plantar flexor strength, ankle ROM, or calf circumference. CAMIR significantly decreased the operative time compared to open repair (17 vs. 56 min, P < 0.0001). Mean scar length was greater in the open repair group (10 vs. 2 cm, P < 0.0001). There were no wound complications in the CAMIR group but four in the open repair group (P < 0.0001). No deep vein thrombosis, rerupture, or sural nerve injury occurred. CONCLUSION: CAMIR and open repair yielded essentially identical clinical and functional outcomes. Sural nerve injuries can be minimized using CAMIR by carefully placing the suture channel with a stab incision and special trocar based on a modified Bunnell suture technique. PMID- 26502716 TI - The clinical features of respiratory infections caused by the Streptococcus anginosus group. AB - BACKGROUND: The Streptococcus anginosus group (SAG) play important roles in respiratory infections. It is ordinarily difficult to distinguish them from contaminations as the causative pathogens of respiratory infections because they are often cultured in respiratory specimens. Therefore, it is important to understand the clinical characteristics and laboratory findings of respiratory infections caused by the SAG members. The aim of this study is to clarify the role of the SAG bacteria in respiratory infections. METHODS: A total of 30 patients who were diagnosed with respiratory infections which were caused by the SAG bacteria between January 2005 and February 2015 were retrospectively evaluated. RESULTS: Respiratory infections caused by the SAG were mostly seen in male patients with comorbid diseases and were typically complicated with pleural effusion. Pleural effusion was observed in 22 (73.3%) patients. Empyema was observed in half of the 22 patients with pleural effusion. S. intermedius, S. constellatus and S. anginosus were detected in 16 (53.3 %), 11 (36.7 %) and 3 (10.0 %) patients, respectively. Six patients had mixed-infections. The duration from the onset of symptoms to the hospital visit was significantly longer in "lung abscess" patients than in "pneumonia" patients among the 24 patients with single infections, but not among the six patients with mixed-infection. The peripheral white blood cell counts of the "pneumonia" patients were higher than those of the "lung abscess" patients and S. intermedius was identified significantly more frequently in patients with pulmonary and pleural infections (pneumonia and lung abscess) than in patients with bacterial pleurisy only. In addition, the patients in whom S. intermedius was cultured were significantly older than those in whom S. constellatus was cultured. CONCLUSIONS: Respiratory infections caused by the SAG bacteria tended to be observed more frequently in male patients with comorbid diseases and to more frequently involve purulent formation. In addition, S. intermedius was mainly identified in elderly patients with having pulmonary infection complicated with pleural effusion, and the aspiration of oral secretions may be a risk factor in the formation of empyema thoracis associated with pneumonia due to S. intermedius. PMID- 26502717 TI - An evaluation of harvest plots to display results of meta-analyses in overviews of reviews: a cross-sectional study. AB - BACKGROUND: Harvest plots are used to graphically display evidence from complex and diverse studies or results. Overviews of reviews bring together evidence from two or more systematic reviews. Our objective was to determine the feasibility of using harvest plots to depict complex results of overviews of reviews. METHODS: We conducted a survey of 279 members of Cochrane Child Health to determine their preferences for graphical display of data, and their understanding of data presented in the form of harvest plots. Preferences were rated on a scale of 0 100 (100 most preferred) and tabulated using descriptive statistics. Knowledge and accuracy were assessed by tabulating the number of correctly answered questions for harvest plots and traditional data summary tables; t-tests were used to compare responses between formats. RESULTS: 53 individuals from 7 countries completed the survey (19%): 60% were females; the majority had an MD (38%), PhD (47%), or equivalent. Respondents had published a median of 3 systematic reviews (inter-quartile range 1 to 8). There were few differences between harvest plots and tables in terms of being: well-suited to summarize and display results from meta-analysis (52 vs. 56); easy to understand (53 vs. 51); and, intuitive (49 vs. 44). Harvest plots were considered more aesthetically pleasing (56 vs. 44, p = 0.03). 40% felt the harvest plots could be used in conjunction with tables to display results from meta-analyses; additionally, 45% felt the harvest plots could be used with some improvement. There was no statistically significant difference in percentage of knowledge questions answered correctly for harvest plots compared with tables. When considering both types of data display, 21% of knowledge questions were answered incorrectly. CONCLUSIONS: Neither harvest plots nor standard summary tables were ranked highly in terms of being easy to understand or intuitive, reflecting that neither format is ideal to summarize the results of meta-analyses in overviews of reviews. Responses to knowledge questions showed some misinterpretation of results of meta analyses. Reviewers should ensure that messages are clearly articulated and summarized in the text to avoid misinterpretation. PMID- 26502718 TI - Hypoxia biomarkers in squamous cell carcinoma of the uterine cervix. AB - BACKGROUND: There is significant evidence that severe tumor hypoxia may cause resistance to chemoradiotherapy and promote metastatic spread in locally advanced carcinoma of the uterine cervix. Some clinical investigations have suggested that high expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and/or its target gene carbonic anhydrase IX (CAIX) may be useful biomarkers of tumor hypoxia and poor outcome in cervical cancer. Here, we challenged this view by investigating possible associations between HIF-1alpha expression, CAIX expression, fraction of hypoxic tissue, and lymph node metastasis in experimental human tumors. METHODS: Tumors of two cervical carcinoma xenograft lines (CK-160 and TS-415) were included in the study. Pimonidazole was used as a hypoxia marker, and tumor hypoxia, HIF-1alpha expression, and CAIX expression were detected by immunohistochemistry. Metastatic status was assessed by examining external lymph nodes in the inguinal, axillary, interscapular, and submandibular regions and internal lymph nodes in the abdomen and mediastinum. RESULTS: Tissue regions staining positive for pimonidazole, HIF-1alpha, or CAIX were poorly colocalized, both in CK-160 and TS-415 tumors. The expression of HIF-1alpha or CAIX did not correlate with the fraction of hypoxic tissue in any of the two tumor lines. Furthermore, clinically relevant associations between HIF-1alpha or CAIX expression and lymph node metastasis were not found. CONCLUSION: Because significant associations between HIF-1alpha expression, CAIX expression, fraction of hypoxic tissue, and incidence of lymph node metastases could not be detected in any of two preclinical models of human cervical cancer, it is not realistic to believe that high expression of HIF-1alpha or CAIX can be useful biomarkers of tumor hypoxia and poor outcome in a highly heterogeneous disease like cervical carcinoma. PMID- 26502719 TI - Deciphering the mode of action of a mutant Allium sativum Leaf Agglutinin (mASAL), a potent antifungal protein on Rhizoctonia solani. AB - BACKGROUND: Mutant Allium sativum leaf agglutinin (mASAL) is a potent, biosafe, antifungal protein that exhibits fungicidal activity against different phytopathogenic fungi, including Rhizoctonia solani. METHODS: The effect of mASAL on the morphology of R.solani was monitored primarily by scanning electron and light microscopic techniques. Besides different fluorescent probes were used for monitoring various intracellular changes associated with mASAL treatment like change in mitochondrial membrane potential (MMP), intracellular accumulation of reactive oxygen species (ROS) and induction of programmed cell death (PCD). In addition ligand blot followed by LC-MS/MS analyses were performed to detect the putative interactors of mASAL. RESULTS: Knowledge on the mode of function for any new protein is a prerequisite for its biotechnological application. Detailed morphological analysis of mASAL treated R. solani hyphae using different microscopic techniques revealed a detrimental effect of mASAL on both the cell wall and the plasma membrane. Moreover, exposure to mASAL caused the loss of mitochondrial membrane potential (MMP) and the subsequent intracellular accumulation of reactive oxygen species (ROS) in the target organism. In conjunction with this observation, evidence of the induction of programmed cell death (PCD) was also noted in the mASAL treated R. solani hyphae. Furthermore, we investigated its interacting partners from R. solani. Using ligand blots followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses, we identified different binding partners including Actin, HSP70, ATPase and 14-3-3 protein. CONCLUSIONS: Taken together, the present study provides insight into the probable mode of action of the antifungal protein, mASAL on R. solani which could be exploited in future biotechnological applications. PMID- 26502720 TI - Suppression of MAPK attenuates neuronal cell death induced by activated glia conditioned medium in alpha-synuclein overexpressing SH-SY5Y cells. AB - BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease with characteristics and symptoms that are well defined. Nevertheless, its aetiology remains unknown. PD is characterized by the presence of Lewy bodies inside neurons. alpha-Synuclein (alpha-syn) is a soluble protein present in the pre synaptic terminal of neurons. Evidence suggests that alpha-syn has a fundamental role in PD pathogenesis, given that it is an important component of Lewy bodies localized in the dopaminergic neurons of PD patients. METHODS: In the present study, we investigated the influence of wild type (WT) and A30P alpha-syn overexpression on neuroblastoma SH-SY5Y toxicity induced by the conditioned medium (CM) from primary cultures of glia challenged with lipopolysaccharide (LPS) from Escherichia coli. RESULTS: We observed that SH-SY5Y cells transduced with alpha-syn (WT or A30P) and treated with CM from LPS-activated glia cells show evidence of cell death, which is not reverted by NF-kappaB inhibition by sodium salicylate or by blockage of P50 (NF-kappaB subunit). Furthermore, the expression of A30P alpha-syn in neuroblastoma SH-SY5Y decreases the cell death triggered by the CM of activated glia versus WT alpha-syn or control group. This effect of A30P alpha-syn may be due to the low MAPK42/44 phosphorylation. This finding is substantiated by MEK1 inhibition by PD98059, decreasing LDH release by CM in SH-SY5Y cells. CONCLUSION: Our results suggest that SH-SY5Y cells transduced with alpha-syn (WT or A30P) and treated with CM from LPS-activated glia cells show cell death, which is not reverted by NF-kappaB blockage. Additionally, the expression of A30P alpha-syn on neuroblastoma SH-SY5Y leads to decreased cell death triggered by the CM of activated glia, when compared to WT alpha-syn or control group. The mechanism underlying this process remains to be completely elucidated, but the present data suggest that MAPK42/44 phosphorylation plays an important role in this process. TRIAL REGISTRATION: PROSPERO: CRD42015020829. PMID- 26502721 TI - Microbiomes of the dust particles collected from the International Space Station and Spacecraft Assembly Facilities. AB - BACKGROUND: The International Space Station (ISS) is a unique built environment due to the effects of microgravity, space radiation, elevated carbon dioxide levels, and especially continuous human habitation. Understanding the composition of the ISS microbial community will facilitate further development of safety and maintenance practices. The primary goal of this study was to characterize the viable microbiome of the ISS-built environment. A second objective was to determine if the built environments of Earth-based cleanrooms associated with space exploration are an appropriate model of the ISS environment. RESULTS: Samples collected from the ISS and two cleanrooms at the Jet Propulsion Laboratory (JPL, Pasadena, CA) were analyzed by traditional cultivation, adenosine triphosphate (ATP), and propidium monoazide-quantitative polymerase chain reaction (PMA-qPCR) assays to estimate viable microbial populations. The 16S rRNA gene Illumina iTag sequencing was used to elucidate microbial diversity and explore differences between ISS and cleanroom microbiomes. Statistical analyses showed that members of the phyla Actinobacteria, Firmicutes, and Proteobacteria were dominant in the samples examined but varied in abundance. Actinobacteria were predominant in the ISS samples whereas Proteobacteria, least abundant in the ISS, dominated in the cleanroom samples. The viable bacterial populations seen by PMA treatment were greatly decreased. However, the treatment did not appear to have an effect on the bacterial composition (diversity) associated with each sampling site. CONCLUSIONS: The results of this study provide strong evidence that specific human skin-associated microorganisms make a substantial contribution to the ISS microbiome, which is not the case in Earth based cleanrooms. For example, Corynebacterium and Propionibacterium (Actinobacteria) but not Staphylococcus (Firmicutes) species are dominant on the ISS in terms of viable and total bacterial community composition. The results obtained will facilitate future studies to determine how stable the ISS environment is over time. The present results also demonstrate the value of measuring viable cell diversity and population size at any sampling site. This information can be used to identify sites that can be targeted for more stringent cleaning. Finally, the results will allow comparisons with other built sites and facilitate future improvements on the ISS that will ensure astronaut health. PMID- 26502722 TI - Modified response evaluation criteria in solid tumors is superior to response evaluation criteria in solid tumors for assessment of responses to sorafenib in patients with advanced hepatocellular carcinoma. AB - BACKGROUND: Modified response evaluation criteria in solid tumors (mRECIST) and RECIST are used to assess the effect of treatment with targeted agents for hepatocellular carcinoma (HCC). The aim of this study was to determine which set of criteria is superior in patients with advanced HCC treated with sorafenib. METHODS: A multicenter retrospective study to assess the tumor response and patient prognosis of 191 patients with HCC who had been treated with sorafenib from May 2009 through December 2011. We analyzed tumor responses as shown by contrast-enhanced computed tomography scan images according to RECIST 1.1 and mRECIST and compared the findings. RESULTS: The median duration of follow-up was 9.7 months and median overall survival was 10.8 months. Twenty-five patients (13.1 %) were assessed as responders by mRECIST and 15 (7.8 %) by RECIST 1.1. There was a significant difference in overall survival (OS) between responders and non-responders according to mRECIST (P = 0.0117), but no significant difference in OS between responders and non-responders according to RECIST 1.1 (P = 0.0722). Sixteen patients (8.4 %) had no measurable enhanced target lesions that could be assessed as required by mRECIST; however, these patients could be assessed by RECIST 1.1. According to RECIST 1.1, eight of them had stable disease (SD) and eight had progressive disease (PD). There was a significant difference in OS between these SD and PD patients (P = 0.0312). CONCLUSIONS: Patients treated with sorafenib for HCC should be evaluated by mRECIST; RECIST 1.1 is preferable only for assessment of patients with lesions that are non-measurable according to mRESIST. PMID- 26502723 TI - Human papillomavirus prevalence in South African women and men according to age and human immunodeficiency virus status. AB - BACKGROUND: Both cervical cancer and human immunodeficiency virus (HIV) are major public health problems in Sub-Saharan Africa. The objectives of the study were to investigate human papillomavirus (HPV) prevalence according to age, HIV status and gender. METHODS: Participants were 208 HIV-negative women, 278 HIV-positive women, 325 HIV-negative men and 161 HIV-positive men between the ages of 18-66 years. HPV types were determined in cervical and penile cells by Roche Linear Array HPV genotyping assay. RESULTS: HPV prevalence was 36.7 % (76/207; 95 % confidence intervals (CI): 30.4-43.4 %) in HIV-negative women, with the highest prevalence of 61.0 % (25/41; 95 % CI: 45.7-74.4 %) in women aged 18-25 years. HPV prevalence was 74.0 % (205/277; 95 % CI: 68.5-78.8 %) in HIV-positive women, with the highest prevalence of 86.4 % (38/44; 95 % CI: 72.9-94.0 %) in women aged 18 25 years. HPV prevalence was found to decrease with increasing age in HIV negative women (P = 0.0007), but not in HIV-positive women (P = 0.898). HPV prevalence was 50.8 % (159/313; 95 % CI: 45.3-56.3 %) in HIV-negative men, with the highest prevalence of 77.0 % (27/35; 95 % CI: 60.7-88.2 %) in men aged 18-25 years. HPV prevalence was 76.6 % (121/158; 95 % CI: 69.2-82.9 %) in HIV-positive men, with the highest prevalence of 87.5 % (7/8; 95 % CI: 50.8-99.9 %) in men 18 25 years of age. HPV prevalence was found to decrease with increasing age in HIV negative men (P = 0.004), but not in HIV-positive men (P = 0.385). HIV-positive women had a significantly higher prevalence of one or more HPV type(s) in the bivalent (HPV-16/18: 20 % 55/277, 9 % 12/207; P <0.001), quadrivalent (HPV 6/11/16/18: 26 % 71/277, 12 % 24/207; P = 0.001) and nonavalent vaccine (HPV 6/11/16/18/31/33/52/56/58: 65 % 181/277, 24 % 50/207; P <0.001) compared to HIV negative women. Similar observation were observed in men for bivalent (20 % 32/158, 10 % 30/313; P = 0.001), quadrivalent (35 % 56/158, 13 % 41/313; P <0.001) and nonavalent vaccine (75 % 119/158, 28 % 87/313; P <0.001). CONCLUSIONS: This study demonstrated high HPV prevalence among HIV-positive women and men in all age groups. The high prevalence of HPV types found in bivalent, quadrivalent and nonavalent vaccines in South African HIV-positive and HIV negative women and men demonstrate that this population will greatly benefit from current HPV vaccines. PMID- 26502724 TI - Interprofessional training for final year healthcare students: a mixed methods evaluation of the impact on ward staff and students of a two-week placement and of factors affecting sustainability. AB - BACKGROUND: Multiple care failings in hospitals have led to calls for increased interprofessional training in medical education to improve multi-disciplinary teamwork. Providing practical interprofessional training has many challenges and remains uncommon in medical schools in the UK. Unlike most previous research, this evaluation of an interprofessional training placement takes a multi-faceted approach focusing not only on the impact on students, but also on clinical staff delivering the training and on outcomes for patients. METHODS: We used mixed methods to examine the impact of a two-week interprofessional training placement undertaken on a medical rehabilitation ward by three cohorts of final year medical, nursing and therapy students. We determined the effects on staff, ward functioning and participating students. Impact on staff was evaluated using the Questionnaire for Psychological and Social factors at work (QPSNordic) and focus groups. Ward functioning was inferred from standard measures of care including length of stay, complaints, and adverse events. Impact on students was evaluated using the Readiness for Interprofessional Learning Survey (RIPLS) among all students plus a placement survey among medical students. RESULTS: Between 2007 and 2010, 362 medical students and 26 nursing and therapy students completed placements working alongside the ward staff to deliver patient care. Staff identified benefits including skills recognition and expertise sharing. Ward functioning was stable. Students showed significant improvements in the RIPLS measures of Teamwork, Professional Identity and Patient-Centred Care. Despite small numbers of students from other professions, medical students' rated the placement highly. Increasing student numbers and budgetary constraints led to the cessation of the placement after three years. CONCLUSIONS: Interprofessional training placements can be delivered in a clinical setting without detriment to care and with benefits for all participants. While financial support is a necessity, it appears that having students from multiple professions is not critical for a valuable training experience; staff from different professions and students from a single profession can work successfully together. Difficulty in aligning the schedules of different student professions is commonly cited as a barrier to interprofessional training. Our experience challenges this and should encourage provision of authentic interprofessional training experience. PMID- 26502725 TI - A Mass Balance-Based Semiparametric Approach to Evaluate Neonatal Erythropoiesis. AB - Postnatal hemoglobin (Hb) production in anemic preterm infants is determined by several factors including the endogenous erythropoietin levels, allogeneic RBC transfusions administered to treat anemia, and developmental age. As a result, their postnatal Hb production rate can vary considerably. This work introduces a novel Hb mass balance-based semiparametric approach that utilizes infant blood concentrations of Hb from the first 30 postnatal days to estimate the amount of Hb produced and the erythropoiesis rate in newborn infants. The proposed method has the advantage of not relying on specific structural pharmacodynamic model assumptions to describe the Hb production, but instead utilizes simple mass balance principles and nonparametric regression analysis. The developed method was applied to the Hb data from 79 critically ill anemic very low birth weight preterm infants to evaluate the dynamic changes in erythropoiesis during the first month of life and to determine the inter-subject variability in Hb production. The estimated mean (+/-SD) cumulative amount of Hb produced by the infants over the first month of life was 6.6 +/- 3.4 g (mean body weight, 0.768 kg), and the mean estimated body weight-scaled Hb production rate over the same period was 0.23 +/- 0.12 g/day/kg. A significant positive correlation was observed between infant gestational age and the mean body weight-scaled Hb production rate over the first month of life (P < 0.05). We conclude that the proposed mathematical approach and its implementation provide a flexible framework to evaluate postnatal erythropoiesis in newborn infants. PMID- 26502726 TI - Variation in Populus euphratica foliar carbon isotope composition and osmotic solute for different groundwater depths in an arid region of China. AB - Water use efficiency (WUE) is an important trait associated with plant acclimation caused by water deficits, and delta13C is a good surrogate of WUE under conditions of water deficits. Water deficiency also enhances the accumulation of compatible solutes in the leaves. In this study, variations in foliar delta(13)C values and main osmotic solutes were investigated. Those included total soluble sugar (TSS), sucrose, free proline, glycine betaine (GB), and inorganic ionic (K+, Ca2+, and Cl-) content of Populus euphratica for different groundwater depths in a Ejina desert riparian forest, China. Results indicated that foliar delta13C values in the P. euphratica for different groundwater depths ranged from -29.14+/-0.06 to -25.84+/-0.04 0/00. Foliar delta13C signatures became richer as groundwater levels declined. TSS, sucrose, free proline, GB, and K+ were accumulated in P. euphratica foliage with developing plant growth and increasing groundwater depth. Ca2+ and Cl- content increased under stronger P. euphratica transpiration rates for shallower groundwater depths (1-2.5 m) and decreased for deeper groundwater depths (greater than 3.0 m). Moreover, correlations between delta13C, osmotic solutes, and groundwater depths showed that the primary osmotic solutes were TSS, sucrose, proline, GB, and K+. Correlations also showed that delta13C was not only a useful measure for P. euphratica-integrated WUE but also could be used as an indicator reflecting some physiological osmotic indexes. PMID- 26502727 TI - Residues, dissipation, and risk assessment of spinosad in cowpea under open field conditions. AB - The dissipation and residues of an eco-friendly bio-pesticide, spinosad, in cowpea under field conditions were studied using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MSMS) after Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) extraction. The method exhibited good linearity with respect to spinosyn A and spinosyn D in solvent or blank cowpea matrix with correlation coefficients>0.99. Additionally, matrix effects were not significant in the range 0.987-1.014, and the average recoveries at three concentration levels were 75.1-91.1 and 79.4-90.5% for spinosyn A and spinosyn D, respectively. The intra- and inter-day relative standard deviations were 2.5-9.3 and 7.8-9.8% for spinosyn A, respectively, and 4.1-7.9 and 6.6-8.3% for spinosyn D, respectively. The limits of detection (LODs) and limits of quantification (LOQs) were 0.005 and 0.01 mg kg(-1), respectively, for spinosyn A, and 0.002 and 0.005 mg kg(-1), respectively, for spinosyn D. The dissipation of spinosad (sum of spinosyn A and spinosyn D) fitted well to first-order kinetics with half-lives of 0.9-1.5 days. The highest residue (HR) at pre-harvest interval (PHI) of 12 h was 0.321 mg kg(-1). Compared with the maximum residue limit (MRL) set by Codex, a PHI of at least 24 h was recommended. The estimated daily chronic intake of spinosad from cowpea was less than 0.14% of the acceptable daily intake (ADI). Therefore, the risk of consuming cowpea sprayed with spinosad under recommended field conditions was considered acceptable for the Chinese population. PMID- 26502728 TI - Relative effects of nutrient emission from intensive cage aquaculture on the semiarid reservoir water quality. AB - The effects of cage aquaculture on freshwater ecosystems are determined by multiple farming and environmental variables, and thus, the assessment of a wide range of abiotic and biotic variables enables better understanding of the impacts generated by this nutrient source. This study was carried out at Castanhao reservoir located in the State of Ceara, which is the largest Brazilian producer of Nile tilapia in cage systems, wherein about 8000 reservoirs provide a vast area to expand not only this important socio-economic but also pollution-prone activity. Nutrient mass budget, water quality monitoring, hydrodynamic characterization, and elemental/stable isotopic composition of end-member products were measured in cage aquaculture and other reservoir areas in order to determine the relative effects on reservoir conditions. Nutrient budgets showed that 34% of the artificial feed was lost to the water column but water quality monitoring and isotopic composition analysis suggested that the cages were not extensively impacting the water quality probably because of the physiographic and hydrodynamic features of the cage site. PMID- 26502729 TI - Apathy: a practical guide for neurologists. AB - Apathy is an under-recognised and underestimated problem for people with chronic neurological disorders. Despite being common and disabling, it is seldom volunteered as a symptom by patients or even their caregivers. Yet apathy undoubtedly has an important impact on caregiver stress, functional disability and quality of life. A detailed clinical assessment can distinguish apathy from depression and allow clinicians to make practical suggestions to reduce the impact of symptoms on individual patients and their families. Pharmacological approaches to treatment include cholinesterase inhibitors, dopamine agonists and stimulants. CASE 1A 66-year-old man with progressive supranuclear palsy returned to clinic for review. His wife was upset and finding it difficult to cope. She described him as 'completely lazy', as he just sat in his chair all day watching television, even though he could still do things for himself. She felt that he could not be bothered to speak to her anymore because he was 'obsessed with TV'. He did not seem to engage with the visits to the grandchildren that she arranged. He said that he felt fine apart from the problems with his walking.The neurologist was confident that the patient was not depressed, and that the wife's concerns reflected the apathy that is often very pronounced in progressive supranuclear palsy. By explaining to the man's wife that these problems were due to his disease, their relationship improved and she felt more able to cope with caring for him. CASE 2A 75-year-old man attended clinic with his wife. She had worried about him for over a year, as he had become increasingly withdrawn. He used to enjoy going to the local pub but now stayed at home all day. He seemed less concerned about his personal appearance, about which he used to be meticulous. More recently, she had noticed that he had become forgetful. On examination, he had a mild episodic memory deficit but no impairments in other domains.He was diagnosed with mild cognitive impairment but the presence of apathy suggested a high risk of him developing Alzheimer's disease. He did not improve with a trial of antidepressant treatment but had useful input from an occupational therapist. His apathy improved after he started a cholinesterase inhibitor a year later, when his cognitive symptoms had progressed. PMID- 26502730 TI - Engineering an efficient and tight D-amino acid-inducible gene expression system in Rhodosporidium/Rhodotorula species. AB - BACKGROUND: Rhodosporidium and Rhodotorula are two genera of oleaginous red yeast with great potential for industrial biotechnology. To date, there is no effective method for inducible expression of proteins and RNAs in these hosts. RESULTS: We have developed a luciferase gene reporter assay based on a new codon-optimized LUC2 reporter gene (RtLUC2), which is flanked with CAR2 homology arms and can be integrated into the CAR2 locus in the nuclear genome at >90 % efficiency. We characterized the upstream DNA sequence of a D-amino acid oxidase gene (DAO1) from R. toruloides ATCC 10657 by nested deletions. By comparing the upstream DNA sequences of several putative DAO1 homologs of Basidiomycetous fungi, we identified a conserved DNA motif with a consensus sequence of AGGXXGXAGX11GAXGAXGG within a 0.2 kb region from the mRNA translation initiation site. Deletion of this motif led to strong mRNA transcription under non-inducing conditions. Interestingly, DAO1 promoter activity was enhanced about fivefold when the 108 bp intron 1 was included in the reporter construct. We identified a conserved CT-rich motif in the intron with a consensus sequence of TYTCCCYCTCCYCCCCACWYCCGA, deletion or point mutations of which drastically reduced promoter strength under both inducing and non-inducing conditions. Additionally, we created a selection marker-free DAO1-null mutant (?dao1e) which displayed greatly improved inducible gene expression, particularly when both glucose and nitrogen were present in high levels. To avoid adding unwanted peptide to proteins to be expressed, we converted the original translation initiation codon to ATC and re-created a translation initiation codon at the start of exon 2. This promoter, named P DAO1-in1m1 , showed very similar luciferase activity to the wild-type promoter upon induction with D-alanine. The inducible system was tunable by adjusting the levels of inducers, carbon source and nitrogen source. CONCLUSION: The intron 1-containing DAO1 promoters coupled with a DAO1 null mutant makes an efficient and tight D-amino acid-inducible gene expression system in Rhodosporidium and Rhodotorula genera. The system will be a valuable tool for metabolic engineering and enzyme expression in these yeast hosts. PMID- 26502731 TI - Integrated analysis of genome-wide DNA methylation, gene expression and protein expression profiles in molecular subtypes of WHO II-IV gliomas. AB - BACKGROUND: Glioma is the most common malignant primary brain tumor among adults, among which glioblastoma (GBM) exhibits the highest malignancy. Despite current standard chemoradiation, glioma is still invariably fatal. A further insight into the molecular background of glioma is required to improve patient outcomes. METHOD: Previous studies evaluated molecular genetic differences through comparing different grades of glioma. Here, we integrated DNA methylation, RNA sequencing and protein expression data sets of WHO grade II to IV gliomas, to screen for dysregulated genes in subtypes during malignant progression of glioma. RESULTS: We propose a list of universal genes (UG) as novel glioma biomarkers: 977 up-regulated genes and 114 down-regulated genes, who involved in cell cycle, Wnt receptor signaling pathway and fatty acid metabolic process. Poorer survival was associated significantly with the high expression of 977 up-regulated genes and low expression of 114 down-regulated in UG (P <0.001). CONCLUSION: To our knowledge, this was the first study that focused on subtypes to detect dysregulated genes that could contribute to malignant progression. Furthermore, the differentially expressed genes profile may lead to the identification of new therapeutic targets for glioma patients. PMID- 26502732 TI - Improvement of Natamycin Production by Cholesterol Oxidase Overexpression in Streptomyces gilvosporeus. AB - Natamycin is a widely used antifungal antibiotic. For natamycin biosynthesis, the gene pimE encodes cholesterol oxidase, which acts as a signalling protein. To confirm the positive effect of the gene pimE on natamycin biosynthesis, an additional copy of the gene pimE was inserted into the genome of Streptomyces gilvosporeus 712 under the control of the ermE* promoter (permE*) using intergeneric conjugation. Overexpression of the target protein engendered 72% and 81% increases in the natamycin production and cell productivity, respectively, compared with the control strain. Further improvement in the antibiotic production was achieved in a 1 L fermenter to 7.0 g/l, which was a 153% improvement after 120 h cultivation. Exconjugants highly expressing pimE and pimM were constructed to investigate the effects of both genes on the increase of natamycin production. However, the co-effect of pimE and pimM did not enhance the antibiotic production obviously, compared with the exconjugants highly expressing pimE only. These results suggest not only a new application of cholesterol oxidase but also a useful strategy to genetically engineer natamycin production. PMID- 26502733 TI - Improvement of FK506 Production in the High-Yielding Strain Streptomyces sp. RM7011 by Engineering the Supply of Allylmalonyl-CoA Through a Combination of Genetic and Chemical Approach. AB - FK506, a widely used immunosuppressant, is a 23-membered polyketide macrolide that is produced by several Streptomyces species. FK506 high-yielding strain Streptomyces sp. RM7011 was developed from the discovered Streptomyces sp. KCCM 11116P by random mutagenesis in our previous study. The results of transcript expression analysis showed that the transcription levels of tcsA, B, C, and D were increased in Streptomyces sp. RM7011 by 2.1-, 3.1-, 3.3-, and 4.1- fold, respectively, compared with Streptomyces sp. KCCM 11116P. The overexpression of tcsABCD genes in Streptomyces sp. RM7011 gave rise to approximately 2.5-fold (238.1 MUg/ml) increase in the level of FK506 production compared with that of Streptomyces sp. RM7011. When vinyl pentanoate was added into the culture broth of Streptomyces sp. RM7011, the level of FK506 production was approximately 2.2 fold (207.7 MUg/ml) higher than that of the unsupplemented fermentation. Furthermore, supplementing the culture broth of Streptomyces sp. RM7011 expressing tcsABCD genes with vinyl pentanoate resulted in an additional 1.7-fold improvement in the FK506 titer (498.1 MUg/ml) compared with that observed under nonsupplemented condition. Overall, the level of FK506 production was increased approximately 5.2-fold by engineering the supply of allylmalonyl-CoA in the high yielding strain Streptomyces sp. RM7011, using a combination of overexpressing tcsABCD genes and adding vinyl pentanoate, as compared with Streptomyces sp. RM7011 (95.3 MUg/ml). Moreover, among the three precursors analyzed, pentanoate was the most effective precursor, supporting the highest titer of FK506 in the FK506 high-yielding strain Streptomyces sp. RM7011. PMID- 26502734 TI - Development and Characterization of PCE-to-Ethene Dechlorinating Microcosms with Contaminated River Sediment. AB - An industrial complex in Wonju, contaminated with trichloroethene (TCE), was one of the most problematic sites in Korea. Despite repeated remedial trials for decades, chlorinated ethenes remained as sources of down-gradient groundwater contamination. Recent efforts were being made to remove the contaminants of the area, but knowledge of the indigenous microbial communities and their dechlorination abilities were unknown. Thus, the objectives of the present study were (i) to evaluate the dechlorination abilities of indigenous microbes at the contaminated site, (ii) to characterize which microbes and reductive dehalogenase genes were responsible for the dechlorination reactions, and (iii) to develop a PCE-to-ethene dechlorinating microbial consortium. An enrichment culture that dechlorinates PCE to ethene was obtained from Wonju stream, nearby a trichloroethene (TCE)-contaminated industrial complex. The community profiling revealed that known organohalide-respiring microbes, such as Geobacter, Desulfuromonas, and Dehalococcoides grew during the incubation with chlorinated ethenes. Although Chloroflexi populations (i.e., Longilinea and Bellilinea) were the most enriched in the sediment microcosms, those were not found in the transfer cultures. Based upon the results from pyrosequencing of 16S rRNA gene amplicons and qPCR using TaqMan chemistry, close relatives of Dehalococcoides mccartyi strains FL2 and GT seemed to be dominant and responsible for the complete detoxification of chlorinated ethenes in the transfer cultures. This study also demonstrated that the contaminated site harbors indigenous microbes that can convert PCE to ethene, and the developed consortium can be an important resource for future bioremediation efforts. PMID- 26502735 TI - CRISPR/Cas9-Mediated Re-Sensitization of Antibiotic-Resistant Escherichia coli Harboring Extended-Spectrum beta-Lactamases. AB - Recently, the clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (CRISPR/Cas9) system, a genome editing technology, was shown to be versatile in treating several antibiotic-resistant bacteria. In the present study, we applied the CRISPR/ Cas9 technology to kill extended-spectrum beta lactamase (ESBL)-producing Escherichia coli. ESBL bacteria are mostly multidrug resistant (MDR), and have plasmid-mediated antibiotic resistance genes that can be easily transferred to other members of the bacterial community by horizontal gene transfer. To restore sensitivity to antibiotics in these bacteria, we searched for a CRISPR/Cas9 target sequence that was conserved among >1,000 ESBL mutants. There was only one target sequence for each TEM- and SHV-type ESBL, with each of these sequences found in ~200 ESBL strains of each type. Furthermore, we showed that these target sequences can be exploited to re-sensitize MDR cells in which resistance is mediated by genes that are not the target of the CRISPR/Cas9 system, but by genes that are present on the same plasmid as target genes. We believe our Re-Sensitization to Antibiotics from Resistance (ReSAFR) technology, which enhances the practical value of the CRISPR/Cas9 system, will be an effective method of treatment against plasmid-carrying MDR bacteria. PMID- 26502736 TI - Characterization of a Novel Alkaline Family VIII Esterase with S-Enantiomer Preference from a Compost Metagenomic Library. AB - A novel esterase gene, est7K, was isolated from a compost metagenomic library. The gene encoded a protein of 411 amino acids and the molecular mass of the Est7K was estimated to be 44,969 Da with no signal peptide. Est7K showed the highest identity of 57% to EstA3, which is an esterase from a drinking water metagenome, when compared with the enzymes with reported properties. Est7K had three motifs, SMTK, YSV, and WGG, which correspond to the typical motifs of family VIII esterases, SxxK, Yxx, and WGG, respectively. Est7K did not have the GxSxG motif in most lipolytic enzymes. Three additional motifs, LxxxPGxxW, PLGMxDTxF, and GGxG, were found to be conserved in family VIII enzymes. The results of the phylogenetic analysis and the alignment study suggest that family VIII enzymes could be classified into two subfamilies, VIII.1 and VIII.2. The purified Est7K was optimally active at 40 degrees C and pH 10.0. It was activated to exhibit a 2.1-fold higher activity by the presence of 30% methanol. It preferred short length p-nitrophenyl esters, particularly p-nitrophenyl butyrate, and efficiently hydrolyzed glyceryl tributyrate. It did not hydrolyze beta-lactamase substrates, tertiary alcohol esters, glyceryl trioleate, fish oil, and olive oil. Est7K preferred an Senantiomer, such as (S)-methyl-3-hydroxy-2-methylpropionate, as the substrate. The tolerance to methanol and the substrate specificity may provide potential advantage in the use of the enzyme in pharmaceutical and other biotechnological processes. PMID- 26502737 TI - Investigation of the Properties of Sand Tubules, a Biomineralization Product, and their Microbial Community. AB - Sand tubules, made up of sand grains cemented by microbe-induced calcium carbonate precipitation, have been found in China's Ningxia Province. Sand tubules grow like a tree's roots about 40-60 cm below the surface. The properties of sand tubules and their bacterial community were examined. X-Ray diffraction analysis revealed that the sand tubules were associated with crystalline calcite. Scanning electron microscopy showed that the crystalline solid had a lamellar structure and lacked the presence of cells, suggesting that no bacteria acted as nucleation sites, nor that the crystalline solid was formed by the aggregation of bacteria. Denaturing gradient gel electrophoresis analysis showed 11 of the 12 detectable bands were uncultured bacteria by BLAST analysis in the GenBank database, and the rest were closely related to Paenibacillus sp. (100% identity). By cultivation techniques, the only strain isolated from the sand tubule was suggested to be related to Paenibacillus sp.; no archaea were found. Furthermore, Paenibacillus sp. was demonstrated to induce calcium carbonate precipitation in vitro. PMID- 26502738 TI - Structural Insight into Dihydrodipicolinate Reductase from Corybebacterium glutamicum for Lysine Biosynthesis. AB - Dihydrodipicolinate reductase is an enzyme that converts dihydrodipicolinate to tetrahydrodipicolinate using an NAD(P)H cofactor in L-lysine biosynthesis. To increase the understanding of the molecular mechanisms of lysine biosynthesis, we determined the crystal structure of dihydrodipicolinate reductase from Corynebacterium glutamicum (CgDapB). CgDapB functions as a tetramer, and each protomer is composed of two domains, an Nterminal domain and a C-terminal domain. The N-terminal domain mainly contributes to nucleotide binding, whereas the C terminal domain is involved in substrate binding. We elucidated the mode of cofactor binding to CgDapB by determining the crystal structure of the enzyme in complex with NADP(+) and found that CgDapB utilizes both NADH and NADPH as cofactors. Moreover, we determined the substrate binding mode of the enzyme based on the coordination mode of two sulfate ions in our structure. Compared with Mycobacterium tuberculosis DapB in complex with its cofactor and inhibitor, we propose that the domain movement for active site constitution occurs when both cofactor and substrate bind to the enzyme. PMID- 26502740 TI - The influence of genetic constitution on migraine drug responses. AB - OBJECTIVE: Specific acute treatments of migraine are 5HT1B/D receptor agonists; triptans and ergotamine, but only two-thirds of patients respond well without side effects. No migraine-prophylactic drugs are specific to migraine. Prophylactic drugs are selected by time-consuming "trial and error." Personalized treatment is therefore much needed. The objective of this study was to test the effect of 12 single nucleotide polymorphisms (SNPs) significantly associated with migraine on migraine drug responses. METHODS: Semi-structured migraine interviews including questions on drug responses, blood samples and genotyping were performed on 1806 unrelated migraine cases recruited from the Danish Headache Center. Association analyses were carried out using logistic regression, assuming an additive model for the genetic effect. The effect on drug responses was tested for a combined genetic score and for each of the 12 SNPs. Significant findings were subsequently tested in an independent replication sample of 392 unrelated Danish migraine cases. RESULTS: A single risk variant, rs2651899 in PRDM16, was significantly associated with efficacy of triptans with an odds ratio (OR) of treatment success of 1.3, and a higher combined genetic score was significantly associated with efficacy of triptans with an OR of success of up to 2.6. A number of SNPs showed nominal preferential association with the efficacy of triptans and others with prophylactic drugs. Analyses of triptans and ergotamine complemented each other and gave a stronger signal when analyzed together. The associations between response to triptans and genetic load and rs2651899 were partially confirmed in the independent sample. CONCLUSION: We show for the first time an association between genetic constitution and migraine drug response. This is a first step toward future individualized medicine. PMID- 26502741 TI - Treatment of Substance Use Disorders in Older Adults: Implications for Care Delivery. AB - OBJECTIVES: To compare substance use treatment differences of individuals aged 65 and older with that of those younger than 65 by analyzing smaller age groupings. DESIGN: A retrospective analysis using Kruskal-Wallis chi-square and chi-square tests of association. Covariates were entered into an adjusted logistic regression to predict successful treatment completion. SETTING: Iowa substance use disorder treatment centers. PARTICIPANTS: Individuals aged 30 to 96 admitted to substance use treatment in Iowa between 2010 and 2013 (N = 57,591). MEASUREMENTS: Successful treatment completion, program length of stay, primary problem substance, referral source, and client demographic characteristics were analyzed to explore differences between age groupings in those aged 65 and older and between those aged 65 and older and those younger than 65. RESULTS: Findings demonstrated that individuals aged 65 to 69 were more likely to complete treatment successfully than those aged 75 and older (2 log likelihood chi(2) = 102.06, degrees of freedom = 6, P < .001), and treatment referrals were increasingly more likely to occur from a primary care setting with increasing age. The eldest group reported significantly more hospitalizations because of their substance use (Wald z = 3.05, P < .002). Finally, referrals for driving under the influence were more likely in those aged 70 and older. CONCLUSION: Excluding the oldest group (7,596), older age was associated with greater successful treatment completion. Overall, greater screening and earlier detection may be a critically important means of enhancing safety for older persons with substance use disorders. PMID- 26502739 TI - Tobacco smoke exposure and respiratory morbidity in young children. AB - OBJECTIVE: Secondhand smoke exposure is a potentially preventable cause of significant respiratory morbidity in young children. Our study aimed to quantify respiratory morbidity in young children exposed to secondhand smoke to identify potentially modifiable factors. MATERIALS AND METHODS: This study was embedded in a prospective birth cohort study of pregnant women and their children from fetal life onwards in Singapore (Growing Up in Singapore Towards healthy Outcomes, or GUSTO). Data on prenatal, antenatal and postnatal active and secondhand tobacco smoke exposure were obtained by an investigator-administered questionnaire for the periods before pregnancy, at 26-28 weeks' gestation and 24 months after delivery. Data on respiratory morbidity (wheezing episodes, croupy cough, nebuliser use, snoring) and other morbidity (fever, hospitalisation, ear infection) of the child was collected at week 3 and at months 3, 6, 9, 12, 15, 18 and 24 after delivery. Information on parental atopy and potential confounders such as socioeconomic status and maternal educational level were also obtained. Statistical analysis of the data was performed to quantify any significant differences in incidence of respiratory morbidity in children exposed to tobacco smoke in utero and postdelivery, compared with those in smoke-free environments. RESULTS: Women who smoked regularly prior to pregnancy comprised 12.5% (n=155) of the study population; this number fell to 2.3% (n=29) during pregnancy. Mothers exposed to secondhand smoke in the household before pregnancy comprised 35.7% of the study population (n=441) and 31.5% (n=389) were exposed during pregnancy. Postnatally, the prevalence of secondhand tobacco smoke exposure from birth to 2 years of age was 29% (n=359). Participants of Malay ethnicity (p<0.001), mothers with no or primary level education (p<0.001) and mothers with low socioeconomic status (p<0.001) had the highest exposure to tobacco smoke. Offspring secondhand smoke exposure at home by 12 months and by 24 months of age was associated with an increase in hospital admissions due to respiratory disease (RR 1.89, 95% CI 1.02 to 3.50, p=0.04 by 12 months and RR 1.64, 95% CI 1.05 to 2.55, p=0.03 by 24 months) as well as all-cause hospitalisation (RR 1.57, 95% CI 1.14 to 2.17, p=0.01 by 12 months and RR 1.49, 95% CI 1.17 to 1.90, p=0.001 by 24 months), adjusting for parental atopy and child atopic dermatitis. Participants exposed to secondhand smoke by 12 months postdelivery had a significantly increased risk of having at least one wheezing episode (RR 1.71, 95% CI 1.38 to 2.11, p<0.001). CONCLUSIONS: Secondhand smoke exposure during the prenatal and postnatal periods is associated with increased respiratory morbidity in children. Opportunistic screening and targeted smoking cessation counselling for parents at child hospital admissions and well-child outpatient visits, as well as preconception smoking cessation counselling for future pregnancies, may be beneficial to protect the child from negative health impacts. PMID- 26502742 TI - Ray transfer for triplicate digit. PMID- 26502743 TI - Margaret McCartney: Flibanserin for low sexual desire is not feminism. PMID- 26502744 TI - Prescription opioids, abuse and public health in Canada: is fentanyl the new centre of the opioid crisis? PMID- 26502745 TI - Exogenous Attention Enables Perceptual Learning. AB - Practice can improve visual perception, and these improvements are considered to be a form of brain plasticity. Training-induced learning is time-consuming and requires hundreds of trials across multiple days. The process of learning acquisition is understudied. Can learning acquisition be potentiated by manipulating visual attentional cues? We developed a protocol in which we used task-irrelevant cues for between-groups manipulation of attention during training. We found that training with exogenous attention can enable the acquisition of learning. Remarkably, this learning was maintained even when observers were subsequently tested under neutral conditions, which indicates that a change in perception was involved. Our study is the first to isolate the effects of exogenous attention and to demonstrate its efficacy to enable learning. We propose that exogenous attention boosts perceptual learning by enhancing stimulus encoding. PMID- 26502746 TI - Infectious Cognition: Risk Perception Affects Socially Shared Retrieval-Induced Forgetting of Medical Information. AB - When speakers selectively retrieve previously learned information, listeners often concurrently, and covertly, retrieve their memories of that information. This concurrent retrieval typically enhances memory for mentioned information (the rehearsal effect) and impairs memory for unmentioned but related information (socially shared retrieval-induced forgetting, SSRIF), relative to memory for unmentioned and unrelated information. Building on research showing that anxiety leads to increased attention to threat-relevant information, we explored whether concurrent retrieval is facilitated in high-anxiety real-world contexts. Participants first learned category-exemplar facts about meningococcal disease. Following a manipulation of perceived risk of infection (low vs. high risk), they listened to a mock radio show in which some of the facts were selectively practiced. Final recall tests showed that the rehearsal effect was equivalent between the two risk conditions, but SSRIF was significantly larger in the high risk than in the low-risk condition. Thus, the tendency to exaggerate consequences of news events was found to have deleterious consequences. PMID- 26502747 TI - Nodular pulmonary light chain deposition disease: an entity associated with Sjogren syndrome or marginal zone lymphoma. AB - BACKGROUND: Light chain deposition disease (LCDD) is usually a systemic disorder characterised by non-amyloid monoclonal immunoglobulin light chain deposition in tissues. Localised nodular pulmonary (NP) LCDD is a rare and poorly characterised entity and, owing to the difficulties in diagnosis, limited data are available. METHODS: We investigated the clinical, radiological and pathological characteristics of a series of six confidently diagnosed cases of NPLCDD. RESULTS: There were three men and three women with ages ranging from 33 to 74 years. In all cases there were single or multiple pulmonary nodules, in one case associated with cysts. Two patients had no previous history of a lymphoproliferative or autoimmune disorder, two had Sjogren syndrome (SS) and two had extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Lung biopsies led to diagnoses of MALT lymphoma in four patients, including both of those with a previous history of lymphoma and one with SS. In five cases the diagnosis was confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and in one by electron microscopy. There was no evidence of systemic LCDD in any of the cases. Five patients had an indolent course in spite of limited therapeutic intervention while, in the patient who died, the cause of death was related to the spread of the lymphoma and was not due to the pulmonary lesions. CONCLUSIONS: NPLCDD is an indolent disease, in most cases associated with MALT lymphoma or autoimmune disease. PMID- 26502748 TI - miR-19a and SOCS-1 expression in the differential diagnosis of laryngeal (glottic) verrucous squamous cell carcinoma. AB - BACKGROUND: Laryngeal verrucous squamous cell carcinoma (VSCC) is a highly differentiated squamous cell carcinoma (SCC), the diagnosis of which can meet with many pitfalls: benign hyperplastic lesions and conventional SCC are the most important differential diagnoses. The microRNA miR-19a is overexpressed in many solid tumours and regulates the suppressor of cytokine signalling-1 (SOCS-1) expression. AIMS: The main endpoints were to assess miR-19a and SOCS-1 expression in glottic VSCC, and the former's potential role in differentiating between glottic VSCC, conventional SCC and hyperplastic lesions. METHODS: The expression of MiR-19a (by reverse transcription and quantitative real-time PCR) and SOCS-1 (by immunohistochemistry, rabbit polyclonal anti-SOCS-1 antibody) was assessed in 11 consecutive cases of glottic VSCC, 20 of papillary hyperplasia and 42 cases of conventional SCC. RESULTS: Mean miR-19a expression was significantly higher (p = 0.000) in malignant glottic lesions (conventional SCC/VSCC) than in benign conditions. Significant differences in mean miR-19a expression also emerged between conventional SCC and papillary hyperplasia (p = 0.000), and between conventional SCC and VSCC (p = 0.03). miR-19a expression was not statistically associated with SOCS-1 immunoreactivity or immunostaining intensity in VSCC, conventional SCC or papillary hyperplasia. CONCLUSIONS: Our preliminary outcomes suggest the utility of miR-19a in the challenging differential diagnosis of laryngeal VSCC. Although miR-19a has been found to regulate SOCS-1 expression, this evidence was not confirmed by this investigation. PMID- 26502749 TI - Radioluminescence and photoluminescence of Th:CaF2 crystals. AB - We study thorium-doped CaF2 crystals as a possible platform for optical spectroscopy of the (229)Th nuclear isomer transition. We anticipate two major sources of background signal that might cover the nuclear spectroscopy signal: VUV-photoluminescence, caused by the probe light, and radioluminescence, caused by the radioactive decay of (229)Th and its daughters. We find a rich photoluminescence spectrum at wavelengths above 260 nm, and radioluminescence emission above 220 nm. This is very promising, as fluorescence originating from the isomer transition, predicted at a wavelength shorter than 200 nm, could be filtered spectrally from the crystal luminescence. Furthermore, we investigate the temperature-dependent decay time of the luminescence, as well as thermoluminescence properties. Our findings allow for an immediate optimization of spectroscopy protocols for both the initial search for the nuclear transition using synchrotron radiation, as well as future optical clock operation with narrow-linewidth lasers. PMID- 26502750 TI - Sub-phonon-period compression of electron pulses for atomic diffraction. AB - Visualizing the rearrangement of atoms in a wide range of molecular and condensed matter systems requires resolving picometre displacements on a 10-fs timescale, which is achievable using pump-probe diffraction, given short enough pulses. Here we demonstrate the compression of single-electron pulses with a de Broglie wavelength of 0.08 angstrom to a full-width at half-maximum duration of 28 fs or equivalently 12-fs root-mean square, substantially shorter than most phonon periods and molecular normal modes. Atomic resolution diffraction from a complex organic molecule is obtained with good signal-to-noise ratio within a data acquisition period of minutes. The electron-laser timing is found to be stable within 5 fs (s.d.) over several hours, allowing pump-probe diffraction at repetitive excitation. These measurements show the feasibility of laser pump/electron-probe scans that can resolve the fastest atomic motions relevant in reversible condensed-matter transformations and organic chemistry. PMID- 26502751 TI - Isorhamnetin inhibits cell proliferation and induces apoptosis in breast cancer via Akt and mitogen-activated protein kinase kinase signaling pathways. AB - Breast cancer is the most common cause of female cancer-associated mortality. Although treatment options, including chemotherapy, radiotherapy and surgery have led to a decline in the mortality rates associated with breast cancer, drug resistance remains one of the predominant causes for poor prognosis and high recurrence rates. The present study investigated the potential effects of the natural product, isorhamnetin on breast cancer, and examined the effects of isorhamnetin on the Akt/mammalian target of rapamycin (mTOR) and the mitogen activated protein kinase (MAPK)/MAPK kinase (MEK) signaling cascades, which are two important signaling pathways for endocrine therapy resistance in breast cancer. The results of the present study indicate that isorhamnetin inhibits cell proliferation and induces cell apoptosis. In addition, isorhamnetin was observed to inhibit the Akt/mTOR and the MEK/extracellular signal-regulated kinase phosphorylation cascades. The inhibition of these two signaling pathways was attenuated by the two Akt and MEK1 inhibitors, but not by the nuclear factor kappaB inhibitor. Furthermore, epidermal growth factor inhibited the effects of isorhamnetin via activation of the Akt and MEK signaling pathways. These results indicate that isorhamnetin exhibits antitumor effects in breast cancer, which are mediated by the Akt and MEK signaling pathways. PMID- 26502752 TI - Orientation of Anopheles gambiae (Diptera: Culicidae) to Plant-Host Volatiles in a Novel Diffusion-Cage Olfactometer. AB - A novel diffusion-cage olfactometer tested the responses of Anopheles gambiae Giles to plant volatiles. Green-leaf volatiles are often released from cut or injured plant tissue and may alter the headspace of plants used in olfactometer assays. The diffusion-cage olfactometer is designed for use with whole, intact plants, hence giving a more realistic behavioral assay. Its simple plastic construction, ease of assembly, and accommodation to whole plants makes it a useful tool for measuring mosquito orientation to plant volatiles within large enclosures. We compared its performance to that of the more commonly used T-tube wind-tunnel olfactometer, by testing the orientation of mosquitoes to volatiles of a few prevalent plants of eastern Africa reportedly utilized by An. gambiae for sugar: Parthenium hysterophorus (Asteraceae), Ricinus communis (Euphorbiaceae), Lantana camara (Verbenaceae), and Senna occidentalis (Fabaceae). Results indicate that the diffusion-cage olfactometer is an effective alternative to conventional wind-tunnel olfactometers, to test mosquito orientation to plant volatiles under seminatural conditions. PMID- 26502753 TI - A Dynamic Population Model to Investigate Effects of Climate and Climate Independent Factors on the Lifecycle of Amblyomma americanum (Acari: Ixodidae). AB - The lone star tick, Amblyomma americanum, is a disease vector of significance for human and animal health throughout much of the eastern United States. To model the potential effects of climate change on this tick, a better understanding is needed of the relative roles of temperature-dependent and temperature-independent (day-length-dependent behavioral or morphogenetic diapause) processes acting on the tick lifecycle. In this study, we explored the roles of these processes by simulating seasonal activity patterns using models with site-specific temperature and day-length-dependent processes. We first modeled the transitions from engorged larvae to feeding nymphs, engorged nymphs to feeding adults, and engorged adult females to feeding larvae. The simulated seasonal patterns were compared against field observations at three locations in United States. Simulations suggested that 1) during the larva-to-nymph transition, some larvae undergo no diapause while others undergo morphogenetic diapause of engorged larvae; 2) molted adults undergo behavioral diapause during the transition from nymph-to-adult; and 3) there is no diapause during the adult-to-larva transition. A model constructed to simulate the full lifecycle of A. americanum successfully predicted observed tick activity at the three U.S. study locations. Some differences between observed and simulated seasonality patterns were observed, however, identifying the need for research to refine some model parameters. In simulations run using temperature data for Montreal, deterministic die-out of A. americanum populations did not occur, suggesting the possibility that current climate in parts of southern Canada is suitable for survival and reproduction of this tick. PMID- 26502755 TI - William S. David, MD, PhD, FAAN, and David A. Chad, MD, FAAN. PMID- 26502754 TI - The Siren's Song: Exploitation of Female Flight Tones to Passively Capture Male Aedes aegypti (Diptera: Culicidae). AB - The need to capture male mosquitoes has intensified recently as a result of a number of male-based sterile insect technique (SIT) and population-modification programs focused on Aedes aegypti (L.) having initiated field releases. Here, we report the results of the successful exploitation of the attraction of male Ae. aegypti to female flight tones to enhance male collections in nonmechanical passive (nonbattery powered) Gravid Aedes Traps (GAT). Prior to field studies, male attraction to female flight tones of 484 and 560 Hz, as well as to a male flight tone of 715 Hz, were assessed in a series of controlled release-recapture and semifield trials. These trials determined that a pure tone of 484 Hz was significantly more attractive to free-flying males than the other flight tones and enabled their collection in sound-baited GATs (ca. 95% capture rate after 2 h; 484 Hz at 65 dB). In contrast, gravid females were unresponsive to male or female flight tones and were evenly distributed among sound-baited and control GATs. Importantly, under normal field conditions sound-baited GATs (484 Hz at 70 dB) captured significantly more male Ae. aegypti per 24-h trap interval (1.3 +/- 0.37) than controls (0.2 +/- 0.13). Overall, sound-bated GATs captured approximately twice as many Ae. aegypti (male and female; 3.0 +/- 0.68 per interval, 30 total) than controls (1.5 +/- 0.56 per interval, 15 total). These results reveal that sound-baited GATs are a simple and effective surveillance tool for Ae. aegypti that would allow current male-based SIT and population modification programs to effectively monitor males in their target populations. PMID- 26502756 TI - Neuromuscular Disorders. PMID- 26502757 TI - Myasthenia Gravis. AB - Myasthenia gravis is an autoimmune neuromuscular disease caused by antibodies directed against the postsynaptic muscle membrane. The clinical hallmark of the disease is fluctuating and fatigable weakness that affects the ocular muscles (resulting in diplopia and ptosis), the bulbar muscles (causing dysphagia, dysarthria, and dyspnea), and extremity muscles. The diagnosis is most often made with serological testing that identifies either acetylcholine receptor antibodies or muscle-specific tyrosine kinase antibodies. Electrodiagnostic testing has a role in supporting the diagnosis. There are many available treatments that result in improvement of function and quality of life. Treatment should be individualized after consideration of many factors, including disease distribution and severity, patient comorbidities, age, serological status, and what is known about the efficacy and safety of the various treatments. PMID- 26502758 TI - Presynaptic Disorders: Lambert-Eaton Myasthenic Syndrome and Botulism. AB - Lambert-Eaton myasthenic syndrome (LEMS) and botulism are acquired presynaptic nerve terminal disorders of the neuromuscular junction. Lambert-Eaton myasthenic syndrome is an idiopathic or paraneoplastic autoimmune syndrome in which autoantibodies of the P/Q-type voltage-gated calcium channel play a role in decreasing the release of acetylcholine, resulting in clinical symptoms of skeletal muscle weakness, diminished reflexes, and autonomic symptoms. Paraneoplastic LEMS is most often associated with small cell lung cancer. Diagnosis is confirmed by positive serologic testing and electrophysiological studies, which display characteristic features of low compound muscle action potentials, a decrement at 3Hz repetitive nerve stimulation, and facilitation with exercise or high-frequency repetitive stimulation. Treatment involves cancer monitoring and treatment, 3,4-diaminopyridine, immunosuppressive medications, and acetylcholinesterase inhibitors. Botulism is another presynaptic disorder of neuromuscular transmission. Clinical features classically involve cranial and bulbar palsies followed by descending weakness of the limbs, respiratory failure, and autonomic dysfunction. Electrodiagnostic testing is important in the evaluation and diagnosis. Treatment is supportive, and administration of antitoxin is beneficial in selected cases. PMID- 26502759 TI - Clinical Evaluation and Management of Inflammatory Myopathies. AB - The idiopathic inflammatory myopathies are classified into four distinct subtypes: dermatomyositis, polymyositis, inclusion body myositis, and immunomediated necrotizing myopathy. These subtypes are clinically, histologically, and pathogenically distinct. Dermatomyositis, polymyositis, and necrotizing myopathy generally respond to immunotherapy, whereas inclusion body myositis does not. In this review, the authors focus on the clinical evaluation and management of idiopathic inflammatory myopathies and highlight recent therapeutic studies and the evolving role of myositis-specific antibodies. PMID- 26502760 TI - Myotonic Disorders and Channelopathies. AB - Myotonic dystrophies and channelopathies are rare but important causes of muscle diseases which may present with myotonia, episodic attacks of weakness, fixed muscle weakness, and atrophy or their combination. Here, the authors provide an overview of these disorders and describe their clinical and pathophysiological features, diagnostic methods, and management. PMID- 26502761 TI - Dystrophinopathies. AB - The dystrophinopathies fall along a spectrum of muscular dystrophy phenotypes, with variable involvement of skeletal and cardiac muscle. The diagnosis of dystrophinopathy should be suspected in any patient with a highly elevated creatine kinase level beyond the context of rhabdomyolysis secondary to toxic or metabolic myopathy. Genetic testing for dystrophinopathy is highly sensitive and specific, and identifying a proband will often lead to implications for several relatives at risk for cardiomyopathy, weakness, or anesthetic reactions. Management of the dystrophinopathies is focused primarily on supportive care, although steroid therapy has changed the natural history of Duchenne muscular dystrophy and it is now standard-of-care internationally. An exciting and ongoing area of investigation of the dystrophinopathies is focused on the potential for altering gene expression, as a way of improving muscle health and slowing the rate of muscle degeneration. PMID- 26502762 TI - Metabolic Myopathies. AB - Metabolic myopathies encompass a group of rare disorders arising from defects in glycogen breakdown (glycogenolysis), glucose utilization (glycolysis), fatty acid transport and oxidation, and energy production along the mitochondrial respiratory chain. The authors review the ancillary testing used in the workup of metabolic myopathies and provide a detailed discussion of these individual disorders and how to approach patients suspected to have such diagnoses. PMID- 26502763 TI - Acquired Immunologic Neuropathies. AB - The acquired immunologic neuropathies are a collection of neuropathic conditions that result from abnormal immune responses that target peripheral nerve myelin, Schwann cells, or axons. Although the clinical features and diagnostic data are sometimes overlapping, the specific disorders are heterogeneous in pathogenesis, treatment, and prognosis. Importantly, there is no consensus as to which neuropathies are distinct conditions and which are better considered as variants or subtypes. The authors discuss the clinical, electrophysiological, histopathological, and treatment features that define the acquired immunomediated neuropathies, calling attention to differences that are observed between the specific neuropathies as well as the differences in the presumed variants within each syndrome. PMID- 26502764 TI - Inherited Neuropathies. AB - Hereditary neuropathies (HNs) are among the most common inherited neurologic disorders and are diverse both clinically and genetically. Recent genetic advances have contributed to a rapid expansion of identifiable causes of HN and have broadened the phenotypic spectrum associated with many of the causative mutations. The underlying molecular pathways of disease have also been better delineated, leading to the promise for potential treatments. This chapter reviews the clinical and biological aspects of the common causes of HN and addresses the challenges of approaching the diagnostic workup of these conditions in a rapidly evolving genetic landscape. PMID- 26502765 TI - Diabetic Neuropathies. AB - Diabetes mellitus is a common condition and diabetics are prone to develop a spectrum of neuropathic complications ranging from symmetric and diffuse to asymmetric and focal neuropathies that may be associated with significant morbidity. Diabetic sensorimotor polyneuropathy is the most common of these complications, occurring in patients with type 1 and 2 diabetes mellitus, as well as in those with prediabetes and glucose intolerance. In this review, the authors discuss the wide variety of neuropathies that can present in the context of diabetes, including the clinical manifestations, diagnostic features, and approach to management. PMID- 26502766 TI - Neuropathies in Systemic Disease. AB - Most peripheral neuropathies result from systemic disease. In this review, the authors highlight the main clinical features, electrographic abnormalities, histopathological aspects and treatment, as well as the current, but still incomplete understanding of the pathophysiological mechanisms involved. The peripheral neuropathic manifestations of renal failure, gastrointestinal illness, bariatric surgery, thyroid dysfunction, connective tissue disease, certain viral and bacterial infections, and critical illness are emphasized. PMID- 26502767 TI - Toxic Neuropathies. AB - Toxic neuropathies are a rare, but important cause of acquired polyneuropathy. In this review article, the authors discuss the general principles of toxic neuropathies and provide a systematic review of neuropathies related to drugs, heavy metals, environmental and industrial agents, and alcoholic neuropathies. PMID- 26502768 TI - Autonomic Neuropathy. AB - Autonomic nerve fibers are affected in most generalized peripheral neuropathies. Although this involvement is often mild or subclinical, there are a group of peripheral neuropathies in which the small or unmyelinated fibers are selectively or prominently targeted. These include the autonomic neuropathies associated with diabetes and amyloid, immune-mediated autonomic neuropathies including those associated with a paraneoplastic syndrome, inherited autonomic neuropathies, autonomic neuropathies associated with infectious diseases, and toxic autonomic neuropathies. The presenting features include impairment of cardiovascular, gastrointestinal, urogenital, thermoregulatory, sudomotor, and pupillomotor function. The accurate diagnosis of the autonomic neuropathies has been enhanced by the availability of physiological tests that measure autonomic function, and more recently, structural studies of the autonomic cutaneous innervation. With the help of these investigations and the judicious use of laboratory testing, many autonomic neuropathies can be accurately diagnosed and their clinical progression monitored. PMID- 26502769 TI - Amyotrophic Lateral Sclerosis: Review. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting the upper and lower motor neurons. The lifetime risk of developing ALS is estimated at 1:350 for men and 1:500 for women, higher for those who have served in the military. The diagnosis remains clinical with electrodiagnostic support. Alternative diagnoses can usually be ruled out by the use of neuroimaging studies and laboratory evaluation. Perhaps because ALS is a diagnosis of exclusion, there is a substantial delay in diagnosis, upward of 12 months after the onset of symptoms, and most patients see three or more providers in the course of the diagnostic process. Once diagnosed, patients are best medically managed in a multidisciplinary care setting, an approach that has been shown to prolong survival and improve quality of life. Riluzole is the only disease-modifying therapy approved by the Food and Drug Administration, but numerous symptomatic therapies exist. In the past 20 years, ALS has become the focus of intense investigation by a worldwide community of basic scientists, and for clinical investigators the disease is an active area of research, with stem cell therapies, gene therapies, and a host of small molecule agents under investigation at various stages of clinical and preclinical development. PMID- 26502770 TI - Secrets of virtuoso: neuromuscular attributes of motor virtuosity in expert musicians. AB - Musical performance requires extremely fast and dexterous limb movements. The underlying biological mechanisms have been an object of interest among scientists and non-scientists for centuries. Numerous studies of musicians and non-musicians have demonstrated that neuroplastic adaptations through early and deliberate musical training endowed superior motor skill. However, little has been unveiled about what makes inter-individual differences in motor skills among musicians. Here we determined the attributes of inter-individual differences in the maximum rate of repetitive piano keystrokes in twenty-four pianists. Among various representative factors of neuromuscular functions, anatomical characteristics, and training history, a stepwise multiple regression analysis and generalized linear model identified two predominant predictors of the maximum rate of repetitive piano keystrokes; finger tapping rate and muscular strength of the elbow extensor. These results suggest a non-uniform role of individual limb muscles in the production of extremely fast repetitive multi-joint movements. Neither age of musical training initiation nor the amount of extensive musical training before age twenty was a predictor. Power grip strength was negatively related to the maximum rate of piano keystrokes only during the smallest tone production. These findings highlight the importance of innate biological nature and explicit training for motor virtuosity. PMID- 26502771 TI - Voriconazole-Induced Hepatitis via Simvastatin- and Lansoprazole-Mediated Drug Interactions: A Case Report and Review of the Literature. AB - Therapeutic voriconazole concentrations have a narrow window of effectiveness before causing cholestatic hepatitis. After undergoing 1 year of voriconazole therapy for pulmonary aspergillosis, a 44-year-old man began treatment with 30 mg lansoprazole for gastroesophageal reflux symptoms. Within 5 days of starting treatment with lansoprazole, the patient presented with fatigue, jaundice, and cholestatic hepatitis. The hepatitis promptly resolved after stopping lansoprazole treatment. Sixteen months later, the patient was given simvastatin therapy, as recommended by the American Diabetes Association to prevent cardiovascular disease for patients with diabetes who are aged >40 years and have one additional risk factor. Within 2 weeks of taking simvastatin, a 3-hydroxy-3 methylglutaryl CoA reductase (statin) therapy, the patient redeveloped fatigue, jaundice, and cholestatic hepatitis. He described both episodes of fatigue and jaundice similarly in terms of onset and intensity. Voriconazole is metabolized by both CYP2C19 and CYP3A4 isoenzymes. Lansoprazole is an inhibitor of the CYP2C19 isoenzyme. Competition between voriconazole and lansoprazole likely led to increased voriconazole serum concentration and acute cholestatic hepatitis in this patient. Simvastatin inhibits the CYP3A4 isoenzyme. After the patient took 10 mg simvastatin daily for 2 weeks, cholestatic hepatitis occurred. The voriconazole concentration remained elevated (4.1 MUg/ml) when measured 15 days after stopping simvastatin. The patient's Naranjo Adverse Drug Reaction Probability Scale score of 7 revealed that the cholestatic hepatitis was probably precipitated by lansoprazole. Likewise, the patient's Naranjo score of 9 also revealed that cholestatic hepatitis was attributable to a definite adverse drug reaction precipitated by the addition of simvastatin to the stable baseline regimen of voriconazole. In a single patient, two different inhibitors of the cytochrome P450 pathway stimulated voriconazole-induced cholestatic hepatitis. Although the major cytochrome P450 pathways for the metabolism and clearance of lansoprazole and simvastatin are different, they both likely contributed to the reduced hepatic clearance of voriconazole in this patient. PMID- 26502772 TI - Molecular Cloning, Tissue Distribution, and Functional Characterization of Marmoset Cytochrome P450 1A1, 1A2, and 1B1. AB - The common marmoset (Callithrix jacchus), a New World monkey, has potential to be an animal model for drug metabolism studies. In this study, we identified and characterized cytochrome P450 (P450) 1A1 and 1B1 in addition to the known P450 1A2 in marmosets. Marmoset P450 1A1 and 1B1 cDNA contained open reading frames encoding 512 and 543 amino acids, respectively, with high sequence identities (90%-93%) to other primate P450 1A1s and 1B1s. A phylogenetic tree based on amino acid sequences showed close evolutionary relationships among marmoset, macaque, and human P450 1A and 1B enzymes. By mRNA quantification and immunoblot analyses in five marmoset tissues, P450 1A1 was mainly expressed in lungs and small intestines, and P450 1A2 was expressed predominantly in livers. In contrast, P450 1B1 was expressed in all tissues tested. Marmoset P450 1A1, 1A2, and 1B1 heterologously expressed in Escherichia coli catalyzed 7-ethoxyresorufin O deethylation, 7-ethoxycoumarin O-deethylation, and phenacetin O-deethylation, similar to those of humans and cynomolgus monkeys. Notably, marmoset P450 1A1 and 1A2 more efficiently catalyzed 7-ethoxyresorufin O-deethylation than those of the human homologs, but were comparable to those of the cynomolgus monkey homologs. Additionally, marmoset P450 1B1 preferentially catalyzed estradiol 4 hydroxylation; however, rat P450 1B1 more favorably catalyzed estradiol 2 hydroxylation, indicating that the estradiol hydroxylation specificity of marmoset P450 1B1 was similar to those of human and cynomolgus monkey P450 1B1. These results indicated that marmoset P450 1A and 1B enzymes had functional characteristics similar to those of humans and cynomolgus monkeys, suggesting that P450 1A and 1B-dependent metabolism was similar among marmosets, cynomolgus monkeys, and humans. PMID- 26502773 TI - Analysis of the Metabolic Pathway of Bosentan and of the Cytotoxicity of Bosentan Metabolites Based on a Quantitative Modeling of Metabolism and Transport in Sandwich-Cultured Human Hepatocytes. AB - To quantitatively understand the events in the human liver, we modeled a hepatic disposition of bosentan and its three known metabolites (Ro 48-5033, Ro 47-8634, and Ro 64-1056) in sandwich-cultured human hepatocytes based on the known metabolic pathway. In addition, the hepatotoxicity of Ro 47-8634 and Ro 64-1056 was investigated because bosentan is well known as a hepatotoxic drug. A model illustrating the hepatic disposition of bosentan and its three metabolites suggested the presence of a novel metabolic pathway(s) from the three metabolites. By performing in vitro metabolism studies on human liver microsomes, a novel metabolite (M4) was identified in Ro 47-8634 metabolism, and its structure was determined. Moreover, by incorporating the metabolic pathway of Ro 47-8634 to M4 into the model, the hepatic disposition of bosentan and its three metabolites was successfully estimated. In hepatocyte toxicity studies, the cell viability of human hepatocytes decreased after exposure to Ro 47-8634, and the observed hepatotoxicity was diminished by pretreatment with tienilic acid (CYP2C9 specific inactivator). Pretreatment with 1-aminobenzotriazole (broad cytochrome P450 inactivator) also tended to maintain the cell viability. Furthermore, Ro 64 1056 showed hepatotoxicity in a concentration-dependent manner. These results suggest that Ro 64-1056 is directly involved in bosentan-induced liver injury partly because CYP2C9 specifically mediates hydroxylation of the t-butyl group of Ro 47-8634. Our findings demonstrate the usefulness of a quantitative modeling of hepatic disposition of drugs and metabolites in sandwich-cultured hepatocytes. In addition, the newly identified metabolic pathway may be an alternative route that can avoid Ro 64-1056-induced liver injury. PMID- 26502775 TI - Aromatic Sulfonium Polyoxomolybdates: Solid-State Photochromic Materials with Tunable Properties. AB - A new aromatic sulfonium counter-ion motif for polyoxometalate (POM) clusters with potential for structural and electronic fine-tuning has been designed. Its two derivatives 4-hydroxyphenyl dimethylsulfonium triflate (HPDST) and 4 (allyloxy)phenyl dimethylsulfonium triflate (APDST) exhibit ionic liquid behaviors under ambient conditions. HPDST and APDST are used to develop a series of aromatic sulfonium POM hybrids (HPDS/APDS)n[XMo12 O40] (HPDS and APDS are the cations of HPDST and APDST, respectively; X=P or Si; n=3 or 4), which are tested for photochromic behavior. On exposure to UV light, these POM hybrids undergo color change from yellow to green/blue. The coloration kinetics half lives (t1/2) are less for APDS-based hybrids than for HPDS-based hybrids, suggesting that alkyl substitution on the phenolic group helps to fine-tune the electron availability on the sulfonium moiety and hence to control the photochromic behavior of the POM hybrids. The t1/2 values of these hybrids are considerably lower than those of the reported aliphatic sulfonium POM hybrids. We have also demonstrated the application of photoreduced POM hybrids as catalysts for the reduction of 4-nitrophenol to 4-aminophenol. PMID- 26502774 TI - Stereochemical Assignment of Strigolactone Analogues Confirms Their Selective Biological Activity. AB - Strigolactones (SLs) are new plant hormones with various developmental functions. They are also soil signaling chemicals that are required for establishing beneficial mycorrhizal plant/fungus symbiosis. In addition, SLs play an essential role in inducing seed germination in root-parasitic weeds, which are one of the seven most serious biological threats to food security. There are around 20 natural SLs that are produced by plants in very low quantities. Therefore, most of the knowledge on SL signal transduction and associated molecular events is based on the application of synthetic analogues. Stereochemistry plays a crucial role in the structure-activity relationship of SLs, as compounds with an unnatural D-ring configuration may induce biological effects that are unrelated to SLs. We have synthesized a series of strigolactone analogues, whose absolute configuration has been elucidated and related with their biological activity, thus confirming the high specificity of the response. Analogues bearing the R configured butenolide moiety showed enhanced biological activity, which highlights the importance of this stereochemical motif. PMID- 26502776 TI - Absence of WASp Enhances Hematopoietic and Megakaryocytic Differentiation in a Human Embryonic Stem Cell Model. AB - The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene and characterized by severe thrombocytopenia. Although the role of WASp in terminally differentiated lymphocytes and myeloid cells is well characterized, its role in early hematopoietic differentiation and in platelets (Plts) biology is poorly understood. In the present manuscript, we have used zinc finger nucleases targeted to the WAS locus for the development of two isogenic WAS knockout (WASKO) human embryonic stem cell lines (hESCs). Upon hematopoietic differentiation, hESCs-WASKO generated increased ratios of CD34(+)CD45(+) progenitors with altered responses to stem cell factor compared to hESCs-WT. When differentiated toward the megakaryocytic linage, hESCs-WASKO produced increased numbers of CD34(+)CD41(+) progenitors, megakaryocytes (MKs), and Plts. hESCs-WASKO-derived MKs and Plts showed altered phenotype as well as defective responses to agonist, mimicking WAS patients MKs and Plts defects. Interestingly, the defects were more evident in WASp-deficient MKs than in WASp deficient Plts. Importantly, ectopic WAS expression using lentiviral vectors restored normal Plts development and MKs responses. These data validate the AND 1_WASKO cell lines as a human cellular model for basic research and for preclinical studies for WAS. PMID- 26502777 TI - Virus-mediated EpoR76E Therapy Slows Optic Nerve Axonopathy in Experimental Glaucoma. AB - Glaucoma, a common cause of blindness, is currently treated by intraocular pressure (IOP)-lowering interventions. However, this approach is insufficient to completely prevent vision loss. Here, we evaluate an IOP-independent gene therapy strategy using a modified erythropoietin, EPO-R76E, which has reduced erythropoietic function. We used two models of glaucoma, the murine microbead occlusion model and the DBA/2J mouse. Systemic recombinant adeno-associated virus mediated gene delivery of EpoR76E (rAAV.EpoR76E) was performed concurrent with elevation of IOP. Axon structure and active anterograde transport were preserved in both models. Vision, as determined by the flash visual evoked potential, was preserved in the DBA/2J. These results show that systemic EpoR76E gene therapy protects retinal ganglion cells from glaucomatous degeneration in two different models. This suggests that EPO targets a component of the neurodegenerative pathway that is common to both models. The efficacy of rAAV.EpoR76E delivered at onset of IOP elevation supports clinical relevance of this treatment. PMID- 26502780 TI - Bereavement After Suicide: Disentangling Clues to Better Help Bereaved Adolescents. PMID- 26502779 TI - Effects of conventional tobacco smoke and nicotine-free cigarette smoke on airway inflammation, airway remodelling and lung function in a triple allergen model of severe asthma. AB - BACKGROUND: Patients with asthma who smoke have reduced lung function, increased exacerbation rates and increased steroid resistance compared to non-smoking asthmatics. In mice, cigarette smoke has been reported to have both pro- and anti Th2 response effects. OBJECTIVE: We hypothesized that combining tobacco cigarette smoke (tCS) with allergen exposure increases inflammation, airway remodelling and lung function in mice. To test this hypothesis, we combined a severe triple allergen model with tCS exposure and investigated whether effects were due to Toll-like receptor 4 signalling and/or nicotine and also observed when nicotine free cigarettes were used. METHODS: Mice were sensitized with ovalbumin, cockroach and house dust mite allergen in alum followed by intratracheal challenges with allergen twice a week for 6 weeks or additionally exposed to tCS during the allergen challenge period. Nicotine or nicotine-free herbal cigarette smoke was also applied to allergen challenged mice. RESULTS: tCS significantly reduced eosinophil numbers, IL-4 and IL-5 concentrations in the lung, total and allergen-specific IgE in serum, improved lung function and reduced collagen I levels. With the exception of collagen I all parameters reduced by tobacco cigarette smoke were also reduced in Toll-like receptor 4-deficient mice. Nicotine-free cigarette smoke also had significant anti-inflammatory effects on eosinophils, IL-4 and IL-5 concentrations in the lung and reduced airway hyperreactivity, albeit weaker than tobacco smoke. Applying nicotine alone also reduced Th2 cytokine levels and eosinophil numbers in the airways. CONCLUSION: Our experiments show that tCS exposure reduces allergen-induced Th2 response in the lung and associated collagen I production and development of airway hyperreactivity. With the exception on collagen I formation, these effects were not dependent on Toll-like receptor 4. The observed anti-Th2 effects of both nicotine and nicotine-free herbal cigarette smoke together suggests that tCS reduces the Th2 responses through nicotine and other products released by burning tobacco. PMID- 26502778 TI - Evaluation of TCR Gene Editing Achieved by TALENs, CRISPR/Cas9, and megaTAL Nucleases. AB - Present adoptive immunotherapy strategies are based on the re-targeting of autologous T-cells to recognize tumor antigens. As T-cell properties may vary significantly between patients, this approach can result in significant variability in cell potency that may affect therapeutic outcome. More consistent results could be achieved by generating allogeneic cells from healthy donors. An impediment to such an approach is the endogenous T-cell receptors present on T cells, which have the potential to direct dangerous off-tumor antihost reactivity. To address these limitations, we assessed the ability of three different TCR-alpha-targeted nucleases to disrupt T-cell receptor expression in primary human T-cells. We optimized the conditions for the delivery of each reagent and assessed off-target cleavage. The megaTAL and CRISPR/Cas9 reagents exhibited the highest disruption efficiency combined with low levels of toxicity and off-target cleavage, and we used them for a translatable manufacturing process to produce safe cellular substrates for next-generation immunotherapies. PMID- 26502781 TI - Root Cause Analyses of Suicides of Mental Health Clients: Identifying Systematic Processes and Service-Level Prevention Strategies. AB - BACKGROUND: The ability to predict imminent risk of suicide is limited, particularly among mental health clients. Root cause analysis (RCA) can be used by health services to identify service-wide approaches to suicide prevention. AIMS: To (a) develop a standardized taxonomy for RCAs; (b) to quantitate service related factors associated with suicides; and (c) to identify service-related suicide prevention strategies. METHOD: The RCAs of all people who died by suicide within 1 week of contact with the mental health service over 5 years were thematically analyzed using a data collection tool. RESULTS: Data were derived from RCAs of all 64 people who died by suicide between 2008 and 2012. Major themes were categorized as individual, situational, and care-related factors. The most common factor was that clients had recently denied suicidality. Reliance on carers, recent changes in medication, communication problems, and problems in follow-through were also commonly identified. CONCLUSION: Given the difficulty in predicting suicide in people whose expressions of suicidal ideation change so rapidly, services may consider the use of strategies aimed at improving the individual, stressor, support, and care factors identified in this study. PMID- 26502782 TI - Searching for Suicide Methods: Accessibility of Information About Helium as a Method of Suicide on the Internet. AB - BACKGROUND: Helium gas suicides have increased in England and Wales; easy-to access descriptions of this method on the Internet may have contributed to this rise. AIMS: To investigate the availability of information on using helium as a method of suicide and trends in searching about this method on the Internet. METHOD: We analyzed trends in (a) Google searching (2004-2014) and (b) hits on a Wikipedia article describing helium as a method of suicide (2013-2014). We also investigated the extent to which helium was described as a method of suicide on web pages and discussion forums identified via Google. RESULTS: We found no evidence of rises in Internet searching about suicide using helium. News stories about helium suicides were associated with increased search activity. The Wikipedia article may have been temporarily altered to increase awareness of suicide using helium around the time of a celebrity suicide. Approximately one third of the links retrieved using Google searches for suicide methods mentioned helium. CONCLUSION: Information about helium as a suicide method is readily available on the Internet; the Wikipedia article describing its use was highly accessed following celebrity suicides. Availability of online information about this method may contribute to rises in helium suicides. PMID- 26502783 TI - Using the Theory of Planned Behavior to Predict College Students' Intention to Intervene With a Suicidal Individual. AB - BACKGROUND: Suicide among college students is an issue of serious concern. College peers may effectively intervene with at-risk persons due to their regular contact and close personal relationships with others in this population of significantly enhanced risk. AIMS: The current study was designed to investigate whether the theory of planned behavior constructs predicted intention to intervene when a college peer is suicidal. METHOD: Undergraduate students (n = 367) completed an on-line questionnaire; they answered questions about their attitudes, subjective norms, perceived behavioral control regarding suicide and suicide intervention, as well as their intention to intervene when someone is suicidal. The data were analyzed using multiple regression. RESULTS: The statistical significance of this cross-sectional study indicates that the theory of planned behavior constructs predicts self-reported intention to intervene with a suicidal individual. CONCLUSION: Theory of planned behavior is an effective framework for understanding peers' intention to intervene with a suicidal individual. PMID- 26502784 TI - Perceptions of the Functions of Nonsuicidal Self-Injury in a College Sample. AB - BACKGROUND: Rates of nonsuicidal self-injury (NSSI) are particularly high on college campuses. Commonly endorsed reasons for NSSI include interpersonal (e.g., seeking support) and intrapersonal (e.g., affect regulation) functions. AIMS: This study compared college students with and without a history of NSSI on their views of NSSI functions in order to inform gatekeeper intervention/prevention programs targeting NSSI. METHOD: The Inventory of Statements About Self-Injury, which assessed NSSI behavior and functions of NSSI, was completed by 367 college students (73% female, 95% white). RESULTS: Ninety-eight participants endorsed lifetime moderate/severe NSSI, 109 endorsed minor NSSI, and 160 denied any history of NSSI. Noninjuring participants' views of NSSI functions were compared with the views held by participants with histories of NSSI. The groups did not differ in their views of the relevance of intrapersonal functions, although noninjuring individuals appeared to stress some interpersonal factors (e.g., influence) slightly more than individuals with a history of NSSI did. CONCLUSION: These results suggest that college students generally hold similar perceptions of the functions of NSSI. Our findings suggest intervention/prevention efforts may consider broadening the selection of gatekeepers (e.g., peers with no history of NSSI) in schools and colleges to identify at-risk students and encourage help seeking behaviors. PMID- 26502785 TI - Telephone Management Program for Patients Discharged From an Emergency Department After a Suicide Attempt: A 5-Year Follow-Up Study in a Spanish Population. AB - AIM: In a previous controlled study, the authors reported on the significant beneficial effects of a telephone intervention program for prevention of suicide attempts by patients for up to 1 year. This study reports the 5-year follow-up data. Outcomes were number of recurrences and time to recurrence. METHOD: The intervention was carried out on patients discharged from the emergency room (ER) following attempted suicide (Sabadell). It consisted of a systematic, 1-year telephone follow-up program: after 1 week, and thereafter at 1-, 3-, 6-, 9-, and 12-month intervals to assess the risk of suicide and encourage adherence to treatment. The population in the control group (Terrassa) received treatment as usual after discharge, without additional telephone contact. RESULTS: The effect of reattempt prevention observed in the first year was not maintained over the long term. CONCLUSION: A telephone management program for patients discharged from an ER after attempted suicide could be considered a useful strategy in delaying further suicide attempts and reducing the rate of reattempts in the first year. However, results showed that the beneficial effects were not maintained at the 5-year follow-up. PMID- 26502786 TI - Clinical and Psychosocial Profiles of Asian Immigrants Who Repeatedly Attempt Suicide: A Mixed-Method Study of Risk and Protective Factors. AB - BACKGROUND: Persons who repeatedly attempt suicide comprise a highly distressed population that warrants the understanding of risk and protective factors in assessment and treatment. There is a dearth of literature on Asian immigrants' suicidal behavior. AIMS: The study aimed to capture the clinical and psychosocial profiles of Asian immigrants who made repeated suicide attempts. METHOD: We utilized retrospective chart reviews (n = 44) and in-person interviews (n = 12) in two urban public hospitals. RESULTS: The study samples shared major suicide risk factors identified in studies of other populations. Participants of the interview sample suffered from a pervasive sense of hopelessness stemming from social isolation, self-stigma, feelings of failure in their life roles, and perceptions of rejection by their families. Conversely, psychological well-being- feeling cared for and able to reciprocate care for others--appeared to be a protective factor for participants who improved in their functioning and recovery. CONCLUSION: The study lays the groundwork for further research on suicide risk and protective factors. PMID- 26502787 TI - Frontal Motor Cortex Activity During Reactive Control Is Associated With Past Suicidal Behavior in Recent-Onset Schizophrenia. AB - BACKGROUND: Suicide is prevalent in schizophrenia (SZ), yet the neural system functions that confer suicide risk remain obscure. Circuits operated by the prefrontal cortex (PFC) are altered in SZ, including those that support reactive control, and PFC changes are observed in postmortem studies of heterogeneous suicide victims. AIMS: We tested whether history of suicide attempt is associated with altered frontal motor cortex activity during reactive control processes. METHOD: We evaluated 17 patients with recent onset of DSM-IV-TR-defined SZ using the Columbia Suicide Severity Rating Scale and functional magnetic resonance imaging during Stroop task performance. Group-level regression models relating past suicidal behavior to frontal activation controlled for depression, psychosis, and impulsivity. RESULTS: Past suicidal behavior was associated with relatively higher activation in the left-hemisphere supplementary motor area (SMA), pre-SMA, premotor cortex, and dorsolateral PFC, all ipsilateral to the active primary motor cortex. CONCLUSION: This study provides unique evidence that suicidal behavior in patients with recent-onset SZ directly relates to frontal motor cortex activity during reactive control, in a pattern reciprocal to the relationship with proactive control found previously. Further work should address how frontal-based control functions change with risk over time, and their potential utility as a biomarker for interventions to mitigate suicide risk in SZ. PMID- 26502788 TI - Perspectives of Suicidal Veterans on Safety Planning: Findings From a Pilot Study. AB - AIMS: Individual interviews were conducted and analyzed to learn about the engagement of suicidal veterans in safety planning. METHOD: Twenty suicidal veterans who had recently constructed safety plans were recruited at two VA hospitals. In semistructured interviews, they discussed how they felt about constructing and using the plan and suggested changes in plan content and format that might increase engagement. RESULTS: The veterans' experiences varied widely, from reviewing plans often and noting symptom improvement to not using them at all and doubting that they would think of doing so when deeply depressed. CONCLUSION: The veterans suggested ways to enrich safety planning encounters and identified barriers to plan use. Their ideas were specific and practical. Safety planning was most meaningful and helpful to them when they experienced the clinician as a partner in exploring their concerns (e.g., fear of discussing and attending to warning signs) and collaborating with them to devise solutions. PMID- 26502790 TI - Evaluation of the protective effect of chemical additives in the oxidation of phenolic compounds catalysed by peroxidase. AB - The use of oxidoredutive enzymes in removing organic pollutants has been the subject of much research. The oxidation of phenolic compounds in the presence of chemical additives has been the focus of this study. In this investigation, the influence of the additives polyethylene glycol and Triton X-100 was evaluated in the phenol oxidation, caffeic acid, chlorogenic acid and total phenolic compounds present in coffee processing wastewater (CPW) at different pH values, performed by turnip peroxidase and peroxidase extracted from soybean seed hulls. The influence of these additives was observed only in the oxidation of phenol and caffeic acid. In the oxidation of other studied phenolic compounds, the percentage of oxidation remained unchanged in the presence of these chemical additives. In the oxidation of CPW in the presence of additives, no change in the oxidation of phenolic compounds was observed. Although several studies show the importance of evaluating the influence of additives on the behaviour of enzymes, this study found a positive response from the economic point of view for the treatment of real wastewater, since the addition of these substances showed no influence on the oxidation of phenolic compounds, which makes the process less costly. PMID- 26502791 TI - A water-stable metal-organic framework of a zwitterionic carboxylate with dysprosium: a sensing platform for Ebolavirus RNA sequences. AB - We herein report a water-stable 3D dysprosium-based metal-organic framework (MOF) that can non-covalently interact with probe ss-DNA. The formed system can serve as an effective fluorescence sensing platform for the detection of complementary Ebolavirus RNA sequences with the detection limit of 160 pM. PMID- 26502792 TI - Multiple Goals and Homework Involvement in Elementary School Students. AB - This work arises from the need to investigate the role of motivational variables in homework involvement and academic achievement of elementary school students. The aims of this study are twofold: identifying the different combinations of student academic goals and analyzing the differences in homework involvement and academic achievement. The sample was composed of 535 fourth-, fifth- and sixth grade elementary school students, between the ages of 9 and 13 years old. Findings showed three groups with different motivational profiles: a group of students with high multiple goals, another group with a learning goal orientation and a third group defined by a low multiple goals profile. Focusing on the differences between groups, it was observed that the amount of time doing homework was not associated with any motivational profile. Nevertheless, the differences were statistically significant between the motivational groups in the amount of homework (F(2, 530) = 42.59; p < .001; etap 2 = .138), in the management of time spent on homework (F(2, 530) = 33.08; p < .001; etap 2 = .111), and in academic achievement (F(2, 530) = 33.99; p < .001; etap 2 = .114). The effect size was large for the amount of homework performed and was also relatively large in the case of management of time and academic achievement. PMID- 26502794 TI - Thermal conductivity of a two-dimensional phosphorene sheet: a comparative study with graphene. AB - A recently discovered two-dimensional (2D) layered material phosphorene has attracted considerable interest as a promising p-type semiconducting material. In this work, thermal conductivity (kappa) of monolayer phosphorene is calculated using large-scale classical non-equilibrium molecular dynamics (NEMD) simulations. The predicted thermal conductivities for infinite length armchair and zigzag phosphorene sheets are 63.6 and 110.7 W m(-1) K(-1) respectively. The strong anisotropic thermal transport is attributed to the distinct atomic structures at altered chiral directions and direction-dependent group velocities. Thermal conductivities of 2D graphene sheets with the same dimensions are also computed for comparison. The extrapolated kappa of the 2D graphene sheet are 1008.5(+37.6)(-37.6) and 1086.9(+59.1)(-59.1) W m(-1) K(-1) in the armchair and zigzag directions, respectively, which are an order of magnitude higher than those of phosphorene. The overall and decomposed phonon density of states (PDOS) are calculated in both structures to elucidate their thermal conductivity differences. In comparison with graphene, the vibrational frequencies that can be excited in phosphorene are severely limited. The temperature effect on the thermal conductivity of phosphorene and graphene sheets is investigated, which reveals a monotonic decreasing trend for both structures. PMID- 26502795 TI - Diagnosis of vertebral artery dissection in childhood posterior circulation arterial ischaemic stroke. AB - AIM: Review a series of children with posterior circulation arterial ischaemic stroke (PCAIS) to identify diagnostic modality and associations in cases of vertebral artery dissection (VAD). METHOD: Retrospective analysis of 30 cases of childhood PCAIS identified from two tertiary centres over 11 years. Clinical and demographic details were recorded. Brain and cerebrovascular imaging were reviewed. Aetiology was classified using the Childhood Arterial Ischaemic Stroke Standardized Classification and Diagnostic Evaluation criteria. Outcome was evaluated using standardized paediatric stroke outcome scores. Logistic regression was used to explore variables associated with diagnosis. RESULTS: Twenty-three patients were male (77%) and 7 were female (23%). VAD was the most commonly identified aetiology, in 15 cases (50%). Aetiology was undetermined in 12 (40%), probable cardioembolism in two, and reversible cerebral vasoconstriction syndrome in one. In those with VAD, diagnosis was made on initial magnetic resonance angiography (MRA) in six (40%). Further cases of VAD were diagnosed with catheter angiography (n=6), computed tomographic angiography (n=1), or follow-up MRA (n=2). Presence of multiple infarcts was associated with a diagnosis of VAD. INTERPRETATION: Endoluminal cerebrovascular imaging increases the rate of diagnosis of VAD in childhood PCAIS and should especially be considered if there are multiple infarcts. PMID- 26502797 TI - Sexual violence, weight perception, and eating disorder indicators in college females. AB - OBJECTIVE: To examine the relationships between sexual violence experiences, inaccurate body weight perceptions, and the presence of eating disorder (ED) indicators in a sample of female US college students. PARTICIPANTS: Participants were 6,090 college females 25 years of age and younger. METHODS: A secondary analysis of National College Health Assessment data gathered annually at one institution from 2004 to 2013 was utilized. A model predicting ED indicators was tested using logistic regression analyses with multiple categorical variables representing severity of sexual violence, accuracy of body weight perception, and an interaction between the two. RESULTS: Sexual violence and inaccurate body weight perception significantly predicted ED indicators; sexual violence was the strongest predictor of purging behavior, whereas inaccurate body weight perception was best predicted by underweight status. CONCLUSIONS: Findings provide support to the relationship between purging behavior and severity of sexual violence and also to the link between inaccurate body weight perception and being underweight. PMID- 26502796 TI - Ataxia Telangiectasia Mutated Dysregulation Results in Diabetic Retinopathy. AB - Ataxia telangiectasia mutated (ATM) acts as a defense against a variety of bone marrow (BM) stressors. We hypothesized that ATM loss in BM-hematopoietic stem cells (HSCs) would be detrimental to both HSC function and microvascular repair while sustained ATM would be beneficial in disease models of diabetes. Chronic diabetes represents a condition associated with HSC depletion and inadequate vascular repair. Gender mismatched chimeras of ATM(-/-) on wild type background were generated and a cohort were made diabetic using streptozotocin (STZ). HSCs from the STZ-ATM(-/-) chimeras showed (a) reduced self-renewal; (b) decreased long-term repopulation; (c) depletion from the primitive endosteal niche; (d) myeloid bias; and (e) accelerated diabetic retinopathy (DR). To further test the significance of ATM in hematopoiesis and diabetes, we performed microarrays on circulating angiogenic cells, CD34(+) cells, obtained from a unique cohort of human subjects with long-standing (>40 years duration) poorly controlled diabetes that were free of DR. Pathway analysis of microarrays in these individuals revealed DNA repair and cell-cycle regulation as the top networks with marked upregulation of ATM mRNA compared with CD34(+) cells from diabetics with DR. In conclusion, our study highlights using rodent models and human subjects, the critical role of ATM in microvascular repair in DR. PMID- 26502798 TI - Connective tissue diseases: New low disease activity target defined in SLE. PMID- 26502800 TI - A template-free solvent-mediated synthesis of high surface area boron nitride nanosheets for aerobic oxidative desulfurization. AB - Hexagonal boron nitride nanosheets (h-BNNs) with rather high specific surface area (SSA) are important two-dimensional layer-structured materials. Here, a solvent-mediated synthesis of h-BNNs revealed a template-free lattice plane control strategy that induced high SSA nanoporous structured h-BNNs with outstanding aerobic oxidative desulfurization performance. PMID- 26502799 TI - Propiverine increases urethral wall catecholamine levels and bladder leak point pressure in rats. AB - OBJECTIVE: To investigate whether propiverine has a noradrenaline re-uptake inhibitor and whether it acts on the lumbosacral cord or the urethral wall. In addition, we aimed to examine the effect of propiverine on leak point pressure in rats. METHODS: A total of 72 female and 30 male rats were used to examine the following: (i) the change of leak point pressure caused by intravenous agents in rats with vaginal distention; (ii) the change of leak point pressure caused by intrathecal agents in rats with vaginal distention; (iii) the noradrenaline re uptake inhibitor action of propiverine; and (iv) catecholamine levels in the bladder wall, urethral wall, cerebrospinal fluid and plasma after oral administration of propiverine. RESULTS: Intravenous injection of propiverine, imipramine and duloxetine increased the leak point pressure in rats with vaginal distention. Intrathecal naftopidil decreased the leak point pressure, whereas subsequent intravenous propiverine restored the leak point pressure to the level before intrathecal naftopidil in rats with vaginal distention. Propiverine acted like a noradrenaline re-uptake inhibitor, increasing noradrenaline and/or dopamine levels in the plasma, cerebrospinal fluid, and urethral wall perfusion fluid. CONCLUSION: Propiverine inhibits noradrenaline re-uptake, as well as having antimuscarinic and Ca-antagonist actions. The inhibition of noradrenaline re-uptake by propiverine mainly occurs at the urethral level and partially in the central nervous system, and might stimulate the smooth muscle of the bladder neck and proximal urethra through alpha1-adrenergic receptors, as well as stimulating the striated muscle of the urethra and pelvic floor by activation of spinal motoneurons. Therefore, propiverine might be effective for both stress and urge incontinence. PMID- 26502801 TI - Incorporation of Jahn-Teller Cu(2+) Ions into Magnetoelectric Multiferroic MnWO4: Structural, Magnetic, and Dielectric Permittivity Properties of Mn1-xCuxWO4 (x <= 0.25). AB - Polycrystalline samples of Mn1-xCuxWO4 (x <= 0.5) have been prepared by a solid state synthesis as well as from a citrate synthesis at moderate temperature (850 degrees C). The goal is to study changes in the structural, magnetic, and dielectric properties of magnetoelectric type-II multiferroic MnWO4 caused by replacing Jahn-Teller-inactive Mn(2+) (d(5), S = 5/2) ions with Jahn-Teller active Cu(2+) (d(9), S = 1/2) ions. Combination of techniques including scanning electron microscopy, powder X-ray and neutron diffraction, and Raman spectroscopy demonstrates that the polycrystalline samples with low copper content 0 <= x <= 0.25 are solid solution that forms in the monoclinic P2/c space group. Rietveld analyses indicate that Cu atoms substitutes for Mn atoms at the Mn crystallographic site of the MnWO4 structure and suggest random distributions of Jahn-Teller-distorted CuO6 octahedra in the solid solution. Magnetic susceptibility reveals that only 5% of Cu substitution suppresses the nonpolar collinear AF1 antiferromagnetic structure observed in pure MnWO4. Type-II multiferroicity survives a weak Cu substitution rate (x < 0.15). Multiferroic transition temperature and Neel temperature increase as the amount of Cu increases. New trends in some of the magnetic properties and in dielectric behaviors are observed for x = 0.20 and 0.25. Careful analysis of the magnetic susceptibility reveals that the incorporation of Cu into MnWO4 strengthens the overall antiferromagnetic interaction and reduces the magnetic frustration. PMID- 26502802 TI - Towards the realization of clinical extracellular vesicle diagnostics: challenges and opportunities. AB - Extracellular vesicles (EVs) have been intensively researched in the last decade. As a result, many reports have revealed that disease-associated EVs can indeed be used as novel diagnostic tools to serve as a noninvasive 'liquid biopsy'. EVs are multi-molecular complexes and each molecule can be targeted for diagnostics. An increasing number of targetable molecules in EVs, such as miRNAs or proteins, have been identified and the accumulation of evidence will likely result in the identification of consensus EV markers. Also highlighted here are some advanced technologies that can be used as next generation assays. These technologies may overcome several challenges that continue to hinder the clinical use of EV diagnostics. A perspective is outlined for the potential contribution of EV research to develop diagnostic technologies for cancer and various other diseases. PMID- 26502803 TI - Induction of interferon-lambda contributes to TLR3 and RIG-I activation-mediated inhibition of herpes simplex virus type 2 replication in human cervical epithelial cells. AB - STUDY HYPOTHESIS: Is it possible to immunologically activate human cervical epithelial cells to produce antiviral factors that inhibit herpes simplex virus type 2 (HSV-2) replication? STUDY FINDING: Our results indicate that human cervical epithelial cells possess a functional TLR3/RIG-I signaling system, the activation of which can mount an Interferon-lambda (IFN-lambda)-mediated anti-HSV 2 response. WHAT IS KNOWN ALREADY: There is limited information about the role of cervical epithelial cells in genital innate immunity against HSV-2 infection. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: We examined the expression of toll-like receptors (TLRs) and retinoic acid-inducible I (RIG-I) in End1/E6E7 cells by real time PCR. The IFN-lambda induced by TLR3 and RIG-I activation of End1/E6E7 cells was also examined by real-time PCR and ELISA. HSV-2 infection of End1/E6E7 cells was evaluated by the real-time PCR detection of HSV-2 gD expression. The antibody to IL-10Rbeta was used to determine whether IFN-lambda contributes to TLR3/RIG-I mediated HSV-2 inhibition. Expression of interferon regulatory factor 3 (IRF3), IRF7, IFN-stimulated gene 56 (ISG56), 2'-5'-oligoadenylate synthetase I (OAS-1) and myxovirus resistance A (MxA) were determined by the real-time PCR and western blot. End1/E6E7 cells were transfected with shRNA to knockdown the IRF3, IRF7 or RIG-I expression. Student's t-test and post Newman-Keuls test were used to analyze stabilized differences in the immunological parameters above between TLR3/RIG-I-activated cells and control cells. MAIN RESULTS AND THE ROLE OF CHANCE: Human cervical epithelial cells expressed functional TLR3 and RIG-I, which could be activated by poly I:C and 5'ppp double-strand RNAs (5'ppp dsRNA), resulting in the induction of endogenous interferon lambda (IFN-lambda). The induced IFN-lambda contributed to TLR3/RIG-I-mediated inhibition of HSV-2 replication in human cervical epithelial cells, as an antibody to IL-10Rbeta, an IFN-lambda receptor subunit, could compromise TLR3/RIG-I-mediated inhibition of HSV-2. Further studies showed that TLR3/RIG-I signaling in the cervical epithelial cells by dsRNA induced the expression of the IFN-stimulated genes (ISGs), ISG56, 2'-5'-oligoadenylate synthetase I (OAS-1) and myxovirus resistance A (MxA), the key antiviral elements in the IFN signaling pathway. In addition, we observed that the topical treatment of genital mucosa with poly I:C could protect mice from genital HSV-2 infection. LIMITATIONS, REASONS FOR CAUTION: Future prospective studies with primary cells and suitable animal models are needed in order to confirm these outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The findings provide direct and compelling evidence that there is intracellular expression and regulation of IFN-lambda in human cervical epithelial cells, which may have a key role in the innate genital protection against viral infections. LARGE SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: This work was supported by the National Natural Science Foundation of China (81301428 to L.Z. and 81271334 to W.-Z.H.), the Fundamental Research Funds for the Central Universities (2042015kf0188 to L.Z.), the China Postdoctoral Science Foundation (2013M531745 to L.Z.), the Development Program of China ('973', 2012CB518900 to W.-Z.H.) from the Ministry of Science and Technology of the People's Republic of China, grants (DA12815 and DA022177 to W.-Z.H.) from the National Institute on Drug Abuse (NIDA) and the open project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research (WDCM005 to M.S.). The authors declare no competing financial interests. PMID- 26502804 TI - Trophoblast cells primed with vasoactive intestinal peptide enhance monocyte migration and apoptotic cell clearance through alphavbeta3 integrin portal formation in a model of maternal-placental interaction. AB - STUDY HYPOTHESIS: Is apoptotic cell phagocytosis by monocytes modulated by pathways elicited by vasoactive intestinal peptide (VIP) action on trophoblast? STUDY FINDING: Targeting trophoblast cells with VIP induces monocyte migration, polarization to anti-inflammatory phenotypes and apoptotic trophoblast cell clearance which involves increased alphavbeta3 integrin expression on phagocytic cells and binding to thrombospondin 1. WHAT IS KNOWN ALREADY: Monocytes recruited to the maternal-placental interface interact with trophoblast cells and differentiate to alternatively activated macrophages involved in the silent clearance of apoptotic cells. Vasoactive intestinal peptide (VIP) is an immunomodulatory polypeptide synthesized at the human placenta that can target both trophoblast cells and monocytes/macrophages. Integrin alphavbeta3 and thrombospondin 1 are involved in the formation of a phagocytic portal for the immunosuppressant clearance of apoptotic cells. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: This is a laboratory-based study studying monocytes isolated from peripheral blood of healthy women (n = 33) and their interaction in vitro with first trimester trophoblast cell lines. Peripheral blood monocytes were isolated from healthy volunteers by Percoll gradient and tested in co-culture settings with first trimester trophoblast cell lines (Swan 71 and HTR8) or with trophoblast cell conditioned media obtained in the presence or absence of 10 or 100 nM VIP. The effect of VIP-conditioned media on monocyte migration was assessed through transwell systems and monocyte/macrophage phenotype was determined by flow cytometry. Phagocytosis of apoptotic cells and the mechanisms involved in phagocytic portal formation were assessed by flow cytometry, confocal microscopy, immunological blockade and RT-PCR. MAIN RESULTS AND THE ROLE OF CHANCE: Exposing cells to 100 nM VIP increased the migration of monocytes toward trophoblast cell conditioned media (VIP conditioned medium) (P < 0.05 versus conditioned media from cells not exposed to VIP) and contributed to the monocytes acquiring an anti-inflammatory profile with increased CD39 and IL-10 expression (P < 0.05). Phagocytosis of apoptotic trophoblast cells by monocytes and monocyte differentiated macrophages was increased by VIP conditioned medium (P < 0.05 versus media conditioned in the absence of VIP or direct addition of 100 nM VIP). The boosting effect of VIP conditioned medium on phagocytosis involved increased expression and re-localization of alphavbeta3 integrin on phagocytic cells along with enhanced expression of thrombospondin 1 on trophoblast cells. LIMITATIONS, REASONS FOR CAUTION: The conclusions are based on in vitro experiments with monocytes drawn from peripheral blood of healthy individuals and trophoblast cell lines and we were unable to ascertain that these mechanisms operate similarly in vivo. We cannot rule out a differential behavior of either trophoblast cells targeted in vivo with VIP, or primary cultures of first trimester trophoblast cells assayed in vitro. WIDER IMPLICATIONS OF THE FINDINGS: The results presented provide new clues for immune and trophoblast cell pharmacological targeting in pregnancy complications of immunopathologic nature. STUDY FUNDING/COMPETING INTERESTS: This work was funded by the National Agency of Sciences and Technology ANPCyT (PICT 2011-0144), National Research Council CONICET (PIP 602/2012) and University of Buenos Aires (UBACyT 20020130100040BA) to C.P.L. The authors have no conflicts of interest to disclose. PMID- 26502806 TI - Mitochondrial dysfunction rather than mtDNA sequence mutation is responsible for the multi-drug resistance of small cell lung cancer. AB - Small cell lung cancer (SCLC) accounts for ~15% of all lung cancer cases, and chemotherapy has dramatically improved the survival rate of SCLC patients. Yet, the long-term survival rate of this cancer has not improved since multi-drug resistance (MDR) may emerge after chemotherapy. Mitochondrial DNA (mtDNA) mutation-related biological processes, such as energy metabolism and reactive oxygen species (ROS) production, have been considered to be associated with tumorigenesis and drug resistance. It was hypothesized and demonstrated, in the present study, that mitochondrial dysfunction is the reason for the occurrence and progression of SCLC. mtDNA from drug sensitive and drug insensitive cell lines (H446 and H446/CDDP) was sequenced and compared with the revised Cambridge reference sequence (rCRS). The results revealed that there was no difference in the mtDNA sequence from H446 and H446/CDDP cells, but several spot mutations were observed according to that of rCRs. Further evaluation on mitochondrial function revealed that H446 cells synthesized and secreted more lactic acid and ROS compared with that of H446/CDDP cells when challenged by the same dose of cisplatin (P>0.05). In addition, examination of the mitochondrial apoptotic pathway indicated that more Bax, cleaved caspase-3 and cleaved caspase-9 were expressed in H446 cells compared with that of H446/CDDP cells when stimulated by the same dose of cisplatin (P>0.05). In conclusion, the results of the present study revealed that mtDNA mutations were responsible for the tumorigenesis of SLCL, but not associated with the drug sensitivity of SCLC cell lines. On the other hand, varied mitochondrium content-related mitochondrial dysfunction participated in the MDR of SCLC possibly by affecting the ROS-mediated mitochondrial apoptotic pathway. PMID- 26502807 TI - Educational interventions to improve quality of life in people with chronic inflammatory skin diseases: systematic reviews of clinical effectiveness and cost effectiveness. AB - BACKGROUND: Inflammatory skin diseases include a broad range of disorders. For some people, these conditions lead to psychological comorbidities and reduced quality of life (QoL). Patient education is recommended in the management of these conditions and may improve QoL. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of educational interventions to improve health-related quality of life (HRQoL) in people with chronic inflammatory skin diseases. DATA SOURCES: Twelve electronic bibliographic databases, including The Cochrane Library, MEDLINE and EMBASE, were searched to July 2014. Bibliographies of retrieved papers were searched and an Advisory Group contacted. REVIEW METHODS: Systematic reviews were conducted following standard methodologies. Clinical effectiveness studies were included if they were undertaken in people with a chronic inflammatory skin condition. Educational interventions that aimed to, or could, improve HRQoL were eligible. Studies were required to measure HRQoL, and other outcomes such as disease severity were also included. Randomised controlled trials (RCTs) or controlled clinical trials were eligible. For the review of cost-effectiveness, studies were eligible if they were full economic evaluations, cost-consequence or cost analyses. RESULTS: Seven RCTs were included in the review of clinical effectiveness. Two RCTs focused on children with eczema and their carers. Five RCTs were in adults. Of these, two were of people with psoriasis, one was of people with acne and two were of people with a range of conditions. There were few similarities in the interventions (e.g. the delivery mode, the topics covered, the duration of the education), which precluded any quantitative synthesis. Follow-up ranged from 4 weeks to 12 months, samples sizes were generally small and, overall, the study quality was poor. There appeared to be positive effects on HRQoL in participants with psoriasis in one trial, but no difference between groups in another trial in which participants had less severe psoriasis. Carers of children in one RCT of eczema showed improvement in HRQoL; however, in a RCT evaluating a website intervention there were no demonstrable effects on HRQoL. Neither the RCT in those adults with acne nor the RCT in those adults with mixed skin conditions demonstrated an effect on HRQoL. One RCT reported subgroups with atopic dermatitis or psoriasis and education was effective for psoriasis only. Other outcomes also showed mixed results. It is unclear how clinically meaningful any of the observed improvements are. Three studies of cost-effectiveness were included. The interventions, comparators and populations varied across the studies and, overall, the studies provided limited information on cost-effectiveness. The studies did provide detailed information on resources and costs that could be useful to inform a future cost-effectiveness evaluation in this area. LIMITATIONS: The application of the inclusion criterion around whether the interventions were aimed at improving HRQoL or the inference that they could improve HRQoL was difficult as information was rarely reported. CONCLUSIONS: There is uncertainty regarding whether educational interventions addressing issues that could improve HRQoL in people with chronic skin conditions are effective. Tentative conclusions about the best approach to delivering these kinds of interventions are that face-to-face, group, sessions may be beneficial; however, text messages may also be effective. Delivery over a period of time and by a multidisciplinary team may also be associated with positive outcomes. There is uncertainty over whether or not educational interventions are cost-effective. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014007426. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26502805 TI - Polygenic inheritance of cryptorchidism susceptibility in the LE/orl rat. AB - STUDY HYPOTHESIS: Susceptibility to inherited cryptorchidism in the LE/orl rat may be associated with genetic loci that influence developmental patterning of the gubernaculum by the fetal testis. STUDY FINDING: Cryptorchidism in the LE/orl rat is associated with a unique combination of homozygous minor alleles at multiple loci, and the encoded proteins are co-localized with androgen receptor (AR) and Leydig cells in fetal gubernaculum and testis, respectively. WHAT IS KNOWN ALREADY: Prior studies have shown aberrant perinatal gubernacular migration, muscle patterning defects and reduced fetal testicular testosterone in the LE/orl strain. In addition, altered expression of androgen-responsive, cytoskeletal and muscle-related transcripts in the LE/orl fetal gubernaculum suggest a role for defective AR signaling in cryptorchidism susceptibility. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: The long-term LE/orl colony and short-term colonies of outbred Crl:LE and Crl:SD, and inbred WKY/Ncrl rats were maintained for studies. Animals were intercrossed (LE/orl X WKY/Ncrl), and obligate heterozygotes were reciprocally backcrossed to LE/orl rats to generate 54 F2 males used for genotyping and/or linkage analysis. At least five fetuses per gestational time point from two or more litters were used for quantitative real time RT-PCR (qRT-PCR) and freshly harvested embryonic (E) day 17 gubernaculum was used to generate conditionally immortalized cell lines. We completed genotyping and gene expression analyses using genome-wide microsatellite markers and single nucleotide polymorphism (SNP) arrays, PCR amplification, direct sequencing, restriction enzyme digest with fragment analysis, whole genome sequencing (WGS), and qRT-PCR. Linkage analysis was performed in Haploview with multiple testing correction, and qRT-PCR data were analyzed using ANOVA after log transformation. Imaging was performed using custom and commercial antibodies directed at candidate proteins in gubernaculum and testis tissues, and gubernaculum cell lines. MAIN RESULTS AND THE ROLE OF CHANCE: LE/orl rats showed reduced fertility and fecundity, and higher risk of perinatal death as compared with Crl:LE rats, but there were no differences in breeding outcomes between normal and unilaterally cryptorchid males. Linkage analysis identified multiple peaks, and with selective breeding of outbred Crl:LE and Crl:SD strains for alleles within two of the most significant (P < 0.003) peaks on chromosomes 6 and 16, we were able to generate a non-LE/orl cryptorchid rat. Associated loci contain potentially functional minor alleles (0.25-0.36 in tested rat strains) including an exonic deletion in Syne2, a large intronic insertion in Ncoa4 (an AR coactivator) and potentially deleterious variants in Solh/Capn15, Ankrd28, and Hsd17b2. Existing WGS data indicate that homozygosity for these combined alleles does not occur in any other sequenced rat strain. We observed a modifying effect of the Syne2(del) allele on expression of other candidate genes, particularly Ncoa4, and for muscle and hormone-responsive transcripts. The selected candidate genes/proteins are highly expressed, androgen-responsive and/or co-localized with developing muscle and AR in fetal gubernaculum, and co-localized with Leydig cells in fetal testis. LIMITATIONS, REASONS FOR CAUTION: The present study identified multiple cryptorchidism-associated linkage peaks in the LE/orl rat, containing potentially causal alleles. These are strong candidate susceptibility loci, but further studies are needed to demonstrate functional relevance to the phenotype. WIDER IMPLICATIONS OF THE FINDINGS: Association data from both human and rat models of spontaneous, nonsyndromic cryptorchidism support a polygenic etiology of the disease. Both the present study and a human genome-wide association study suggest that common variants with weak effects contribute to susceptibility, and may exist in genes encoding proteins that participate in AR signaling in the developing gubernaculum. These findings have potential implications for the gene-environment interaction in the etiology of cryptorchidism. LARGE SCALE DATA: Sequences were deposited in the Rat Genome Database (RGD, http://rgd.mcw.edu/). STUDY FUNDING AND COMPETING INTERESTS: This work was supported by: R01HD060769 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), 2P20GM103446 and P20GM103464 from the National Institute of General Medical Sciences (NIGMS), and Nemours Biomedical Research. The authors have no competing interests to declare. PMID- 26502808 TI - Acute S100B in serum is associated with cognitive symptoms and memory performance 4 months after paediatric mild traumatic brain injury. AB - OBJECTIVE: This study explored whether acute serum marker S100B is related with post-concussive symptoms (PCS) and neuropsychological performance 4 months after paediatric mild traumatic brain injury (mTBI). RESEARCH DESIGN AND METHODS: This prospective short-term longitudinal study investigated children (aged 6-16 years) with mTBI (n = 36, 16 males) and children with orthopaedic injuries (OI, n = 27, 18 males) as a control group. S100B in serum was measured during the acute phase and was correlated with parent-rated PCS and neuropsychological performance 4 months after the injury. MAIN OUTCOMES AND RESULTS: The results revealed no between-group difference regarding acute S100B serum concentration. In children after mTBI, group-specific significant Spearman correlations were found between S100B and post-acute cognitive PCS (r = 0.54, p = 0.001) as well as S100B and verbal memory performance (r = -0.47, p = 0.006). In children after OI, there were insignificant positive relations between S100B and post-acute somatic PCS. In addition, insignificant positive correlations were found between neuropsychological outcome and S100B in children after OI. CONCLUSIONS: S100B was not specific for mild brain injuries and may also be elevated after OI. The group specific association between S100B and ongoing cognitive PCS in children after mTBI should motivate to examine further the role of S100B as a diagnostic biomarker in paediatric mTBI. PMID- 26502809 TI - What do consumers want to know about antibiotics? Analysis of a medicines call centre database. AB - BACKGROUND: Australia is one of the highest users of antibiotics in the developed world. OBJECTIVE: This study aimed to identify consumer antibiotic information needs to improve targeting of medicines information. METHODS: We conducted a retrospective, mixed-method study of consumers' antibiotic-related calls to Australia's National Prescribing Service (NPS) Medicines Line from September 2002 to June 2010. Demographic and question data were analysed, and the most common enquiry type in each age group was explored for key narrative themes. Relative antibiotic call frequencies were determined by comparing number of calls to antibiotic utilization in Australian Statistics on Medicines (ASM) data. RESULTS: Between 2002 and 2010, consumers made 8696 antibiotic calls to Medicines Line. The most common reason was questions about the role of their medicine (22.4%). Patient age groups differed in enquiry pattern, with more questions about lactation in the 0- to 4-year age group (33.6%), administration (5-14 years: 32.4%), interactions (15-24 years: 33.4% and 25-54 years: 23.3%) and role of the medicine (55 years and over: 26.6%). Key themes were identified for each age group. Relative to use in the community, antibiotics most likely to attract consumer calls were ciprofloxacin (18.0 calls/100,000 ASM prescriptions) and metronidazole (12.9 calls/100,000 ASM prescriptions), with higher call rates than the most commonly prescribed antibiotic amoxicillin (3.9 calls/100,000 ASM prescriptions). CONCLUSIONS: Consumers' knowledge gaps and concerns about antibiotics vary with age, and certain antibiotics generate greater concern relative to their usage. Clinicians should target medicines information to proactively address consumer concerns. PMID- 26502810 TI - Medical engagement and organizational characteristics in general practice. AB - BACKGROUND: Medical engagement is a mutual concept of the active and positive contribution of doctors to maintaining and enhancing the performance of their health care organization, which itself recognizes this commitment in supporting and encouraging high quality care. A Medical Engagement Scale (MES) was developed by Applied Research Ltd (2008) on the basis of emerging evidence that medical engagement is critical for implementing radical improvements. OBJECTIVES: To study the importance of medical engagement in general practice and to analyse patterns of association with individual and organizational characteristics. DESIGN AND SETTING: A cross-sectional study using a sampled survey questionnaire and the official register from the Danish General Practitioners' Organization comprising all registered Danish GPs. METHOD: The Danish version of the MES Questionnaire was distributed and the survey results were analysed in conjunction with the GP register data. RESULTS: Statistically adjusted analyses revealed that the GPs' medical engagement varied substantially. GPs working in collaboration with colleagues were more engaged than GPs from single-handed practices, older GPs were less engaged than younger GPs and female GPs had higher medical engagement than their male colleagues. Furthermore, GPs participating in vocational training of junior doctors were more engaged than GPs not participating in vocational training. CONCLUSION: Medical engagement in general practice varies a great deal and this is determined by a complex interaction between both individual and organizational characteristics. Working in collaboration, having staff and being engaged in vocational training of junior doctors are all associated with enhanced levels of medical engagement among GPs. PMID- 26502811 TI - The evolution of pharmaceutical care for drug misusers. AB - BACKGROUND: In the last 20 years, pharmaceutical care has evolved as a modus operandi for community pharmacy. This article tracks the development of pharmaceutical care for drug misusers since 1995 and considers the implications for pharmacy engagement with the wider care team. OBJECTIVE: To survey current community pharmacy service provision for drug misusers, past training and future training needs and compare with data from previous years (1995, 2000 and 2006). METHOD: A cross-sectional postal questionnaire of pharmacy managers in Scotland (n = 1246), and telephone interviews with non-respondents. Results were compared with previous surveys. RESULTS: The response rate was 70% (873) including 13.2% (164) by telephone. More pharmacies dispensed methadone in 2014 (88.5%) than previously, a significant increase across all time points (1995, 2000 and 2006) (P < 0.001). Most pharmacies (88.1%) had some drug misusers registered for the minor ailment scheme. In 2014, 43.4% of pharmacists always reported a drug misuser's non-attendance for opiate replacement treatment (ORT) to the prescriber (36.6% in 2006). If patient intoxication was suspected, medication was always withheld by 47.9% (27.5% in 2006). Pharmacists undertaking training in drug misuse and blood-borne diseases increased significantly since 1995, to 78.6% and 48.7%, respectively, in 2014 (P < 0.001). The preferred topic for future training was communication/engagement with other services. CONCLUSION: Pharmaceutical care for drug misusers has evolved from ORT supply to a more clinical approach. Pharmacists actively monitored ORT patients, managed their minor ailments and increasingly engaged with the wider care team. PMID- 26502812 TI - Abeta1-40 and Abeta1-42 Plasmatic Levels In Stroke: Influence of Pre-Existing Cognitive Status and Stroke Characteristics. AB - Many stroke patients have pre-existing cognitive impairment. Plasma amyloid beta peptides (Abeta) - possible biomarkers of Alzheimer's pathology - induce vascular dysfunction. Our objective was to evaluate factors influencing plasma Abeta1-40 and Abeta1-42 peptides in a cohort of stroke patients. In the Biostroke study (ClinicalTrials.gov Identifier: NCT00763217), we collected vascular risk factors, neuroimaging features and biological tests including Abeta1-40 and Abeta1-42. We used the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) to systematically assess the pre-existing cognitive status. Of 403 patients (371 ischemia), 25 met criteria for pre-existing dementia, 142 for pre-existing cognitive decline-no-dementia, and 236 had no PCoI. Abeta1-42 was independently associated with PCoI (odds ratio 0.973; 95% confidence interval: 0.950-0.996; p=0.024). Factors associated with plasma Abeta1- 40 were age, smoking and diabetes mellitus. After exclusion of hemorrhagic strokes, the results remained unchanged, but blood samples taken less than 12 hours after onset were associated with lower plasma Abeta1-40. Our results support a dissociated response of the 2 plasma Abeta peptides in stroke patients, plasma Abeta1-40 being involved in vascular aspects whereas Abeta1-42 might be involved in neurodegenerative processes. PMID- 26502813 TI - Rhein-Huprine Derivatives Reduce Cognitive Impairment, Synaptic Failure and Amyloid Pathology in AbetaPPswe/PS-1 Mice of Different Ages. AB - Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid beta (Abeta) peptide plays a key role in synaptic impairment and memory decline associated with neuronal dysfunction and intra-neuronal accumulation of hyperphosphorylated tau protein. Two novel enantiopure rhein-huprine hybrids ((+) 1 and (-)-1) exhibit potent inhibitory effects against human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE-1 and both Abeta and tau antiaggregation activity in vitro and reduction on the amyloid precursor protein (APP) processing in vivo. Interestingly, in this work, we observed beneficial effects with both (+)- and (-)-1 in the reversion of the neuropathology presented in the AbetaPPswe/PS-1 Alzheimer's model, including a reduction in the Abeta levels, tau phosphorylation and memory impairment with both treatments. Also, in young transgenic mice that present early symptoms of synaptic failure and memory loss, we found a protection of cognitive functions, including long-term potentiation (LTP) and a reduction of the neuro-inflammation by both (+)- and (-) 1. Furthermore, animals with an advanced disease (11month-old) present an exacerbate neurodegeneration that is reversed only with the dextrorotatory enantiomer. These studies indicated that rhein-huprine derivatives with multiple properties might have interesting therapeutic potential for AD. PMID- 26502814 TI - Aberrant Neuronal Activity and Dysfunctional Connectivity in Abeta1-42- mediated Memory Deficits in Rats. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that gradually induces cognitive deficit. Working memory deficits have been previously reported in AD and Amyloid-beta peptide (Abeta) is regarded as a causative factor for the impairments. Accumulating evidence has identified that neuronal ensemble activity as well as functional connectivity among neurons encode and process information in normal brain. How Abeta contributes to the abnormal neuronal ensemble activity and corresponding functional connectivity which, in turn, leads to the cognitive deficits? To address the issue, we simultaneously recorded neuronal activity from medial prefrontal cortex of rats (control and Abeta injected group) when the rats performed a Y-maze working memory task, to investigate the properties of neuronal ensemble activity and functional connectivity. In the control group, a group of neurons were collectively activated and the connectivity among the neurons strengthened during the working memory task. However, in the Abeta group, the neuronal activity and connectivity never experience significant change. Our results indicate that the dysfunction of neuronal activity and connectivity may provide insight for the Abeta-induced working memory deficits. PMID- 26502815 TI - The Possible Involvement of HLA Class III Haplotype (RAGE, HSP70 and TNF Genes) in Alzheimer's Disease. AB - In the central nervous system Hsp70s seems to have a protective role in repair and removal of cellular proteins damaged by stress conditions. A protective role of Hsp70 was also shown in Alzheimer Disease. The HSP70-1 +190 G/C polymorphism is located in the gene 5'UTR region and it is implicated in alteration of the transcription binding factor; HSP70-2 +1267 A/G causes a silent mutation in the coding region and it seems to influence the mechanism of mRNA translation; HSP70 hom +2437 A/G causes a substitution Met -> The (M493T) in the coding region and it seems to influence the bond with the substrate and therefore on the chaperone activity of hsp70. The aim of our study will be to investigate Alzheimer susceptibility to Hsp70 polymorphisms, taking into account our previous findings on HLA class III region, and to hypothesize a role of HLA class III haplotype configuration based on the variants of three genes: RAGE, HSP70 and TNF. We studied these polymorphisms with PCR-RFLP and PCR-TSP. We investigated 173 AD patients and 211 control subjects. Our results have shown a statistically significant decrease of the C allele frequency of the HSP70-1 +190 G/C polymorphism in AD patients vs controls (P value = 0,018), as well as the G allele of HSP70-2 +1267 G/A (p value = 0,02). We focalized our attention on haplotype reconstruction. We have observed a significant statistically decrease of GGT haplotype frequency (empirical p-value=0.0133 ); GAT haplotype was statistically significant increase in AD patients compared with control (empirical p-value=0.007). The total HLA class III haplotype are reconstructed. The causative haplotypes are the following ones: TTGATGGG ( p value =0,005; empirical p =0,0042); TTGATAGG (p value =0,45; empirical p =0,034). Patients with these haplotypes may show an earlier onset of the disease than patients with TTGGTGGG (p value=0,0138; empirical p =0,0102); TTCGTGGG (p value=0,021; empirical p =0,017); TTCGTGGA (p value =0,058; empirical p =0,043) haplotypes. The overall variation of the haplotypes formed by the RAGE and TNF and HSP70 variants influenced the presence of the AD phenotype (omnibus association LR test p-value 0.00185), HSP701 and HSP702 showed independent effect on AD risk after adjusting for the effect of the entire haplotype (conditional LR test p value=0.0114 and p-value=0.0044 respectively). These data confirm the involvement of HLA class III in AD. PMID- 26502816 TI - Lipid-Based Diets Improve Muscarinic Neurotransmission in the Hippocampus of Transgenic APPswe/PS1dE9 Mice. AB - Transgenic APPswe/PS1dE9 mice modeling Alzheimer's disease demonstrate ongoing accumulation of beta-amyloid fragments resulting in formation of amyloid plaques that starts at the age of 4-5 months. Buildup of beta-amyloid fragments is accompanied by impairment of muscarinic transmission that becomes detectable at this age, well before the appearance of cognitive deficits that manifest around the age of 12 months. We have recently demonstrated that long-term feeding of trangenic mice with specific isocaloric fish oil-based diets improves specific behavioral parameters. Now we report on the influence of short-term feeding (3 weeks) of three isocaloric diets supplemented with Fortasyn (containing fish oil and ingredients supporting membrane renewal), the plant sterol stigmasterol together with fish oil, and stigmasterol alone on markers of cholinergic neurotransmission in the hippocampus of 5-month-old transgenic mice and their wild-type littermates. Transgenic mice fed normal diet demostrated increase in ChAT activity and attenuation of carbachol-stimulated GTP-gamma(35)S binding compared to wild-type mice. None of the tested diets compared to control diet influenced the activities of ChAT, AChE, BuChE, muscarinic receptor density or carbachol-stimulated GTP-gamma(35)S binding in wild-type mice. In contrast, all experimental diets increased the potency of carbachol in stimulating GTP gamma(35)S binding in trangenic mice to the level found in wild-type animals. Only the Fortasyn diet increased markers of cholinergic synapses in transgenic mice. Our data demonstrate that even short-term feeding of transgenic mice with chow containing specific lipid-based dietary supplements can influence markers of cholinergic synapses and rectify impaired muscarinic signal transduction that develops in transgenic mice. PMID- 26502817 TI - Hypertension Impairs Cerebral Blood Flow in a Mouse Model for Alzheimer's Disease. AB - AIMS: Hypertension, a risk factor for Alzheimer's disease (AD), is a treatable condition, which offers possibilities for prevention of AD. Elevated angiotensin II (AngII) is an important cause of essential hypertension. AngII has deleterious effects on endothelial function and cerebral blood flow (CBF), which may contribute to AD. AngII blocking agents can thus provide potential candidates to reduce AD risk factors in hypertensive patients. METHODS: We studied the effect of 2 months induced hypertension (AngII-infusion via osmotic micropumps) on systolic blood pressure (SBP) and CBF in 10 months-old wild-type (WT) C57bl/6j and AbetaPPswe/PS1DeltaE9 (AbetaPP/PS1) mice, and treatment with two different antihypertensives, 1) eprosartan mesylate (EM, 0.35mg/kg) or 2) hydrochlorotiazide (HCT, 7.5mg/kg), after 1 month of induced-hypertension. SBP was monitored twice each month via tail cuff plethysmography. CBF was measured with MR by flow-sensitive alternating inversion recovery. RESULTS: Chronic AngII infusion induced an increase in SBP in both AbetaPP/PS1 and WT mice accompanied by a decrease in hippocampal and thalamic CBF only in the AbetaPP/PS1 mice. An additional difference between the AbetaPP/PS1 mice and WT mice was that SBP was much higher in AbetaPP/PS1 mice in both hypertensive and normotensive conditions. Moreover, both antihypertensives were less effective in reducing AngII-induced hypertension to normal levels in AbetaPP/PS1 mice, while being effective in WT mice. CONCLUSIONS: It can be concluded that AngII-induced elevated SBP results in impaired CBF and a decreased response to blood pressure lowering treatment in a transgenic model of AD. Our findings suggest a relation between midlife hypertension and decreased CBF in an AD mouse model, similar to the relation which has been found in AD patients. This translational mouse model could be used to investigate possible prevention and treatment strategies for AD. PMID- 26502818 TI - Neurodegeneration in Amygdala Precedes Hippocampus in the APPswe/ PS1dE9 Mouse Model of Alzheimer's Disease. AB - Both the hippocampus and amygdala are early vulnerable brain regions in the development of Alzheimer's disease (AD). However, previous studies mainly focused on characterizing the hippocampus in the pathophysiology of AD, leaving the amygdala less explored. Here, we characterized the structures and functions of neurons in the hippocampus and amygdala of young (2, 3 and 4 months of age) APP/PS1 double transgenic (Tg) mice, a widely used AD mouse model. Compared to wild-type littermates (Wt ), Tg mice performed worse in amygdala-dominant memory at all three ages, while hippocampus-dominant memory remained intact until 4 month-old. Likewise, the dendritic arbors of neurons in the basolateral amygdala were reduced in Tg mice as early as 2-months-old, while the dendritic arbors of neurons in the hippocampal CA1 and CA3 regions were relatively intact. BDNF signaling pathways (e.g. AKT and PKC) were reduced in the amygdala, but not in the hippocampus, of young Tg mice. Furthermore, reduction of 5-HT and elevation of Abeta levels also occurred earlier in the amygdala and were more pronounced than those in the hippocampus. Negative correlations between the levels of 5-HT and Abeta were evident in the amygdala, but not in the hippocampus. Taken together, these results suggest that neurodegeneration occurs earlier in the amygdala than in the hippocampus. We suggest that amygdala function should be incorporated into the cognitive screening tool for the diagnosis of mild cognitive impairment due to AD. PMID- 26502819 TI - Alterations of the X Chromosome in Lymphocytes of Alzheimer's Disease Patients. AB - Chromosomal alterations as a sign of genetic instability are a feature of Alzheimer's disease (AD). Assessment of the genetic instability of non-neuronal cells of AD patients may provide a method to diagnose or monitor prognosis of the disease. Considering the importance of X chromosome alterations in the possible etiology of AD females, we used fluorescent in situ hybridization (FISH) for the centromere region of the X chromosome to determine aneuploidy, for a possible correlation with premature centromere division (PCD, X) in lymphocytes of AD females and age-matched controls. In AD patients, our results showed a marked and significant increase in the frequency of the X chromosome aneuploidy comparing with age matched controls (p<0.001). Also, a significant difference was detected in the PCD, X frequency between AD females when compared with age matched controls (p<0.001). In addition, a strong (R2=0.97, n=20) and significant (p<0.001) correlation was found between the frequency of aneuploidy and PCD, X in the AD group. Our results support the view that AD is a generalized systematic disease where PCD is to be considered as a stable sign of disease leading to aneuploidy. PMID- 26502821 TI - In Vivo Longitudinal Monitoring of Changes in the Corpus Callosum Integrity During Disease Progression in a Mouse Model of Alzheimer's Disease. AB - The corpus callosum is the largest commissural fiber connecting left and right hemisphere of the brain. Emerging evidence suggests that a variety of abnormalities detected in the microstructure of this white matter fiber can be an early event in Alzheimer's disease (AD) pathology. However, little is known about tissue characteristics of these abnormalities and how these abnormalities evolve during AD progression. In this study, we measured in vivo magnetic resonance transverse relaxation times (T2) to longitudinally monitor changes in tissue integrity and abnormalities related to myelination and demyelination processes in corpus callosum of AD mouse models. The most striking finding of our study was a significant elongation of T2 values in the corpus callosum at 10, 14, 16 and 18 months of age compared to age-matched wild-type mice. In contrast, the gray matter regions surrounding the corpus callosum, such as the cortex and hippocampus, showed a significant T2 decrease compared to wild-type mice. Histological analyses clearly revealed demyelination, gliosis and amyloid-plaque deposition in the corpus callosum. Our results suggest that demyelinating and inflammatory pathology may result in prolonged relaxation time during AD progression. To our knowledge, this is the first in vivo T2 study assessing the microstructural changes with age in the corpus callosum of the Tg2576 mouse model and it demonstrates the application of T2 measurement to noninvasively detect tissue integrity of the corpus callosum, which can be an early event in disease progression. PMID- 26502820 TI - Differential Expression of Ribosomal Genes in Brain and Blood of Alzheimer's Disease Patients. AB - Changes in rRNA and rDNA expression have been associated with cellular and organism aging and have been linked to Alzheimer's disease (AD) pathogenesis. In this study, we investigated the mRNA expression of ribosomal genes (28S/18S) and beta-amyloid precursor protein (APP) in different post mortem brain tissue regions (the entorhinal and auditory cortices and the hippocampus) of AD patients and elderly control subjects and also evaluated the extent of expression in peripheral blood from young, healthy, elderly, and Alzheimer's disease patients in order to investigate whether these individuals experienced the effects of aging. The comparative threshold cycle (CT) method via Real Time Polymerase Chain Reaction and the Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) were used to analyze gene expression and the Apolipoprotein E (APOE) genotype, respectively. When the brain areas were analyzed collectively, we observed a significant decrease in APP expression and a significant increase in levels of mRNA of 18S and 28S in Alzheimer's disease patients compared to healthy elderly individuals. Furthermore, there was a significant upregulation of 28SrRNA in the entorhinal cortex and hippocampus, but not in the auditory cortex of patients with AD. On the other hand, tests of blood samples verified a decreased expression of 28S rRNA in patients with AD. These results support the hypothesis that changes in rRNA are present in AD patients, are tissue-specific, and seem to occur independently and differently in each tissue. However, the next challenge is to discover the mechanisms responsible for the differences in expression observed in the blood and the brain in both healthy elderly individuals and Alzheimer's disease patients, as well as the impact of these genes on AD pathogenesis. PMID- 26502822 TI - Enhanced Hippocampal Neurogenesis in APP/Ps1 Mouse Model of Alzheimer's Disease After Implantation of VEGF-loaded PLGA Nanospheres. AB - During adult life, hippocampus is an important brain region involved in neurogenesis. The generation and cell death of newly generated neuronal cells in this region have critical roles in brain maintenance and alterations in these processes are seen in Alzheimer's disease (AD). For the purpose of carrying out a neuroregenerative strategy, we propose a novel approach based on the encapsulation of vascular endothelial growth factor (VEGF) in poly (lactic co glycolic acid) (PLGA) biodegradable nanospheres (NS) administered by craniotomy to stimulate the proliferation of neuronal precursors in a transgenic mouse model of AD. VEGF loaded nanospheres were prepared by double emulsion solvent evaporation technique, obtaining 200 nm nanospheres with a biphasic release profile. After demonstrating their efficacy in the proliferation and differentiation of neuronal cell cultures, in vivo studies were carried out. 3 months after VEGF-NS were implanted directly into the cerebral cortex of APP/Ps1 mice, the determination of BrdU(+) cells in the whole hippocampal region and specifically in the dentate gyrus, demonstrated a significantly enhanced cellular proliferation in VEGF-NS treated group. These results were also confirmed showing an increased number of DCX(+) and NeuN(+) cells. Hence, PLGA-VEGF nanospheres may be a potential strategy to modulate proliferative neuronal progenitors in the hippocampal region, and therefore, provide new insight for future therapeutic approaches in AD. PMID- 26502824 TI - Tellurium-Assisted Low-Temperature Synthesis of MoS2 and WS2 Monolayers. AB - Chemical vapor deposition (CVD) is a scalable method able to synthesize MoS2 and WS2 monolayers. In this work, we reduced the synthesis temperature by 200 degrees C only by introducing tellurium (Te) into the CVD process. The as synthesized MoS2 and WS2 monolayers show high phase purity and crystallinity. The optical and electrical performance of these materials is comparable to those synthesized at higher temperatures. We believe this work will accelerate the industrial synthesis of these semiconducting monolayers. PMID- 26502823 TI - Autophagy is upregulated during colorectal carcinogenesis, and in DNA microsatellite stable carcinomas. AB - Cancer cells are exposed to a wide range of stress sources, such as nutrient deprivation and hypoxia, as well as cytotoxic chemotherapy and radiotherapy. Certain forms of stress can also promote survival activating the metabolic autophagy pathway in cancer cells. Autophagy is dramatically increased in cancer cells. In these conditions, it is becoming evident that autophagy protects cells, by providing an alternative energy source and by eliminating dysfunctional organelles or proteins. Its role in tumorigenesis is more controversial and both the presence and the absence of autophagy have been implicated. Autophagy is known to be associated with the poor outcome of patients with various types of cancers, and its effectiveness as a prognostic marker in colorectal cancer was demonstrated by several studies. The inhibition of autophagy may be a potential therapeutic target in colorectal cancer. In vitro experiments have shown that the inhibition of autophagy increases 5-FU-induced apoptosis. There are two trials currently investigating the addition of chloroquine to 5-FU-based chemotherapy and bevacizumab. In the present study, we evaluated the expression of LC3B-II in samples of human colorectal microadenomas (i.e., dysplastic aberrant crypt foci) and carcinomas compared to normal mucosa. Furthermore, the expression pattern of LC3B-II was assessed in carcinomas classified as DNA microsatellite stable (MSS) and unstable (MSI). Thus, immunofluorescence techniques coupled with confocal microscopy and immunoblot experiments were performed. The results clearly showed a significant increase in expression of the autophagic key factor in microadenomas and carcinomas with respect to normal mucosa. In MSS carcinomas, the level of LC3B-II expression was higher than that in the MSI carcinomas. PMID- 26502825 TI - Impaired surface membrane insertion of homo- and heterodimeric human muscle chloride channels carrying amino-terminal myotonia-causing mutations. AB - Mutations in the muscle chloride channel gene (CLCN1) cause myotonia congenita, an inherited condition characterized by muscle stiffness upon sudden forceful movement. We here studied the functional consequences of four disease-causing mutations that predict amino acid substitutions Q43R, S70L, Y137D and Q160H. Wild type (WT) and mutant hClC-1 channels were heterologously expressed as YFP or CFP fusion protein in HEK293T cells and analyzed by whole-cell patch clamp and fluorescence recordings on individual cells. Q43R, Y137D and Q160H, but not S70L reduced macroscopic current amplitudes, but left channel gating and unitary current amplitudes unaffected. We developed a novel assay combining electrophysiological and fluorescence measurements at the single-cell level in order to measure the probability of ion channel surface membrane insertion. With the exception of S70L, all tested mutations significantly reduced the relative number of homodimeric hClC-1 channels in the surface membrane. The strongest effect was seen for Q43R that reduced the surface insertion probability by more than 99% in Q43R homodimeric channels and by 92 +/- 3% in heterodimeric WT/Q43R channels compared to homodimeric WT channels. The new method offers a sensitive approach to investigate mutations that were reported to cause channelopathies, but display only minor changes in ion channel function. PMID- 26502826 TI - Increases in both temperature means and extremes likely facilitate invasive herbivore outbreaks. AB - Although increases in mean temperature (MT) and extreme high temperature (EHT) can greatly affect population dynamics of insects under global warming, how concurrent changes in both MT and EHT affect invasive species is largely unknown. We used four thermal regimes to simulate the increases in summer temperature and compared their effects on the life-history traits of three geographical populations (Chongqing, Wuhan and Shanghai) of an invasive insect, Corythucha ciliata, in China. The four thermal regimes were control (i.e., natural or ambient), an increase in MT (IMT), an increase in EHT, and a combination of IMT + EHT. We found that the three warming regimes significantly increased the developmental rate but did not affect the survival, sex ratio, longevity, or fecundity of C. ciliata. Consequently, the intrinsic rate of natural increase (rm) was enhanced and the number of days required for population doubling (t) was reduced by the warming regimes. The demographic parameters did not significantly differ among the three populations. These results indicate that population size of C. ciliata may be enhanced by increases in both temperature means and extremes. The increases in summer temperature associated with climate change, therefore, would likely facilitate population outbreaks of some thermophilic invasive insects. PMID- 26502827 TI - Impact of Mixed beta-Cyclodextrin Ratios on Pluronic Rotaxanation Efficiency and Product Solubility. AB - Water-soluble polyrotaxanes have been prepared under heterogeneous conditions from mixtures of beta-cyclodextrin (beta-CD), 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), methyl-beta-cyclodextrin, or 6-monoazido-beta-cyclodextrin with 4 sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD) and Pluronic L81 copolymer modified with cholesterol end caps. Threading reactions gave polyrotaxane products in modest chemical yield that were reflective of the beta-CD feed ratios in the reaction. Polyrotaxanes containing mixtures of HP-beta-CD and SBE-beta-CD were screened and found to be biologically active in an in vitro model of Niemann Pick Type C disease where they mobilize aberrantly stored cholesterol similarly to monomeric cyclodextrin controls. PMID- 26502828 TI - Design, Synthesis, and Antimycobacterial Activity of Novel Theophylline-7-Acetic Acid Derivatives With Amino Acid Moieties. AB - The theophylline-7-acetic acid (7-TAA) scaffold is a promising novel lead compound for antimycobacterial activity. Here, we derive a model for antitubercular activity prediction based on 14 7-TAA derivatives with amino acid moieties and their methyl esters. The model is applied to a combinatorial library, consisting of 40 amino acid and methyl ester derivatives of 7-TAA. The best three predicted compounds are synthesized and tested against Mycobacterium tuberculosis H37Rv. All of them are stable, non-toxic against human cells and show antimycobacterial activity in the nanomolar range being 60 times more active than ethambutol. PMID- 26502829 TI - Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent. AB - We previously demonstrated that prodynorphin (PDYN) haplotypes and single nucleotide polymorphism (SNP) rs2281285 are associated with alcohol dependence and the propensity to drink in negative emotional states, and recent studies suggest that PDYN gene effects on substance dependence risk may be sex-related. We examined sex-dependent associations of PDYN variation with alcohol dependence and related phenotypes, including negative craving, time until relapse after treatment and the length of sobriety episodes before seeking treatment, in discovery and validation cohorts of European ancestry. We found a significant haplotype-by-sex interaction (p = 0.03), suggesting association with alcohol dependence in males (p = 1E-4) but not females. The rs2281285 G allele increased risk for alcohol dependence in males in the discovery cohort (OR = 1.49, p = 0.002), with a similar trend in the validation cohort (OR = 1.35, p = 0.086). However, rs2281285 showed a trend towards association with increased negative craving in females in both the discovery (beta = 10.16, p = 0.045) and validation samples (OR = 7.11, p = 0.066). In the discovery cohort, rs2281285 was associated with time until relapse after treatment in females (HR = 1.72, p = 0.037); in the validation cohort, it was associated with increased length of sobriety episodes before treatment in males (beta = 13.49, p = 0.001). Our findings suggest that sex-dependent effects of PDYN variants in alcohol dependence are phenotype specific. PMID- 26502830 TI - G-CSF administration attenuates brain injury in rats following carbon monoxide poisoning via different mechanisms. AB - Acute severe carbon monoxide (CO) poisoning induces hypoxia that leads to cardiovascular and nervous systems disturbances. Different complex mechanisms lead to CO neurotoxicity including lipid peroxidation, inflammatory and immune mediated reactions, myelin degeneration and finally neuronal apoptosis and necrosis. Granulocyte colony-stimulating factor (G-CSF) is considered to be a novel neuroprotective agent. In this study, we evaluated the efficacy of G-CSF therapy on CO neurotoxicity in rats with acute CO poisoning. Rats were exposed to 3000 ppm CO in air (0.3%) for 1 h, and then different doses (50,100, and 150 ug/kg) of G-CSF or normal saline were administrated intraperitoneally. Water content of brain as an indicator for total edema and blood brain barrier integrity (Evans blue extravasation) were evaluated. Malondialydehyde was determined in order to evaluate the effect of G-CSF on CO-induced lipid peroxidation in brain tissues. Also, the effect of G-CSF on myeloperoxidase activity in the brain tissue was evaluated. The effect of G-CSF administration on induced apoptosis in the brain was measured using TUNEL method. To evaluate the level of MBP, STAT3 and pSTAT3 and HO-1 proteins and the effect of G-CSF on these proteins Western blotting was carried out. G-CSF reduced water content of the edematous poisoned brains (100 ug/kg) and BBB permeability (100 and 150 ug/kg) (P < 0.05). G-CSF (150 ug/kg) reduced the MDA level in the brain tissues (P < 0.05 as compared to CO poisoned animals). G-CSF did not decrease the MPO activity after CO poisoning in any doses. G-CSF significantly reduced the number of apoptotic neurons and Caspase 3 protein levels in the brain. Western blotting results showed that G-CSF treatment enhanced expression of HO-1 and MBP, STAT3 and pSTAT3 proteins in the brain tissues. Based on our results, a single dose of G-CSF immediately after CO poisoning significantly attenuates CO neurotoxicity via different mechanisms. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 37 47, 2017. PMID- 26502831 TI - Evaluation of the Usefulness of Consensus Definitions of Sarcopenia in Older Men: Results from the Observational Osteoporotic Fractures in Men Cohort Study. AB - OBJECTIVE: To evaluate the associations between definitions of sarcopenia and clinical outcomes and the ability of the definitions to discriminate those with a high likelihood of having these outcomes from those with a low likelihood. DESIGN: Osteoporotic Fractures in Men Study. SETTING: Six clinical centers. PARTICIPANTS: Community-dwelling men aged 65 and older (N = 5,934). MEASUREMENTS: Sarcopenia definitions from the International Working Group, European Working Group on Sarcopenia in Older Persons, Foundation for the National Institutes of Health Sarcopenia Project, Baumgartner, and Newman were evaluated. Recurrent falls were defined as two or more self-reported falls in the year after baseline (n = 694, 11.9%). Incident hip fractures (n = 207, 3.5%) and deaths (n = 2,003, 34.1%) were confirmed according to central review of medical records over 9.8 years. Self-reported functional limitations were assessed at baseline and 4.6 years later. Logistic regression or proportional hazards models were used to estimate associations between sarcopenia and falls, hip fractures, and death. The discriminative ability of the sarcopenia definitions (vs reference models) for these outcomes was evaluated using area under the receiver operating characteristic curve or C-statistics. Referent models included age alone for falls, functional limitations and mortality, and age and bone mineral density for hip fractures. RESULTS: The association between sarcopenia according to the various definitions and risk of falls, functional limitations, and hip fractures was variable; all definitions were associated with greater risk of death, but none of the definitions materially changed discrimination based on the AUC and C statistic when compared with reference models (change <=1% in all models). CONCLUSION: Sarcopenia definitions as currently constructed did not consistently improve prediction of clinical outcomes in relatively healthy older men. PMID- 26502832 TI - Transcriptome-wide sequencing provides insights into geocarpy in peanut (Arachis hypogaea L.). AB - A characteristic feature of peanut is the subterranean fructification, geocarpy, in which the gynophore ('peg'), a specialized organ that transitions from upward growth habit to downward outgrowth upon fertilization, drives the developing pod into the soil for subsequent development underground. As a step towards understanding this phenomenon, we explore the developmental dynamics of the peanut pod transcriptome at 11 successive stages. We identified 110 217 transcripts across developmental stages and quantified their abundance along a pod developmental gradient in pod wall. We found that the majority of transcripts were differentially expressed along the developmental gradient as well as identified temporal programs of gene expression, including hundreds of transcription factors. Thought to be an adaptation to particularly harsh subterranean environments, both up- and down-regulated gene sets in pod wall were enriched for response to a broad array of stimuli, like gravity, light and subterranean environmental factors. We also identified hundreds of transcripts associated with gravitropism and photomorphogenesis, which may be involved in the geocarpy. Collectively, this study forms a transcriptional baseline for geocarpy in peanut as well as provides a considerable body of evidence that transcriptional regulation in peanut aerial and subterranean fruits is complex. PMID- 26502833 TI - Atomic-Level Mechanisms of Nucleation of Pure Liquid Metals during Rapid Cooling. AB - To obtain a material with the desired performance, the atomic-level mechanisms of nucleation from the liquid to solid phase must be understood. Although this transition has been investigated experimentally and theoretically, its atomic level mechanisms remain debatable. In this work, the nucleation mechanisms of pure Fe under rapid cooling conditions are investigated. The local atomic packing stability and liquid-to-solid transition-energy pathways of Fe are studied using molecular dynamics simulations and first-principle calculations. The results are expressed as functions of cluster size in units of amorphous clusters (ACs) and body-centered cubic crystalline clusters (BCC-CCs). We found the prototypes of ACs in supercooled liquids and successfully divided these ACs to three categories according to their transition-energy pathways. The information obtained in this study could contribute to our current understanding of the crystallization of metallic melts during rapid cooling. PMID- 26502834 TI - The spatial range of peripheral collinear facilitation. AB - Contrast detection thresholds for a central Gabor patch (target) can be modulated by the presence of co-oriented and collinear high contrast Gabors flankers. In foveal vision collinear facilitation can be observed for target-to-flankers relative distances beyond two times the wavelength (lambda) of the Gabor's carrier, while for shorter relative distances (<2lambda) there is suppression. These modulatory influences seem to disappear after 12lambda. In this study, we measured contrast detection thresholds for different spatial frequencies (1, 4 and 6 cpd) and target-to-flankers relative distances ranging from 6 to 16lambda, but with collinear configurations presented in near periphery at 4 degrees of eccentricity. Results showed that in near periphery collinear facilitation extends beyond 12lambda for the higher spatial frequencies tested (4 and 6 cpd), while it decays already at 10lambda for the lowest spatial frequency used (i.e., 1 cpd). In addition, we found that increasing the spatial frequency the peak of collinear facilitation shifts towards larger target-to-flankers relative distances (expressed as multiples of the stimulus wavelength), an effect never reported neither for near peripheral nor for central vision. The results suggest that the peak and the spatial extent of collinear facilitation in near periphery depend on the spatial frequency of the stimuli used. PMID- 26502835 TI - The Physical and Psychosocial Benefits of Upper-Limb Transplantation: A Case Series of 5 Polish Patients. AB - BACKGROUND: Although upper-limb transplantation is not a life-saving procedure, every year more and more patients are ready to undergo this surgery. Conventional methods of treatment performed earlier have not brought the expected functional and aesthetic results. Patients who have received upper-limb transplantation (HTx) enjoy, in addition to the physical benefits associated with good functional effect, numerous benefits of a psychological and social nature. Investigation of these benefits was the aim of this interdisciplinary research. CASE REPORT: The wide spectrum of physical, psychological, and social benefits derived by recipients of limb transplantation include: improved physical fitness, recovery of the complete body form, corporeal well-being, enhanced self-esteem, recovery of self-confidence, a stable feeling of personal and social identity, higher integration of the body with performed social roles, greater confidence in the ability to act and have control over life, a feeling of greater security, the ability to return to work, restoration of social position, and positive personality changes. CONCLUSIONS: Potential benefits which may be derived by future upper limb recipients are manifested in the good functional effect of the transplantation, enhanced life satisfaction, and better functioning in society. It does not mean, however, restoration of 100% of fitness or absolutely problem free functioning in everyday life, which is extremely important in the context of prevention of possible disappointment to future limb recipients. PMID- 26502836 TI - Ginsenoside Rh2 attenuates allergic airway inflammation by modulating nuclear factor-kappaB activation in a murine model of asthma. AB - Allergic asthma is a chronic inflammatory disease that is regulated by coordination of T-helper type 2 cell cytokines and inflammatory signaling molecules. Ginsenoside Rh2 (G-Rh2) is an active component of ginseng with anti inflammatory and anti-tumor effects. The aim of the present study was to determine the inhibitory effects of G-Rh2 on allergic airway inflammation in a murine model of asthma, in which mice develop the following pathophysiological features of asthma: Increased abundance of inflammatory cells; increased levels of interleukin-4 (IL-4), IL-5 and IL-13; decreased abundance of interferon gamma in the bronchoalveolar lavage fluid and lung tissue; increased total and ovalbumin (OVA)-specific immunoglobulin E (IgE) levels in the serum; increased airway hyperresponsiveness (AHR); and activation of nuclear factor kappa B (NF kappaB) in lung tissue. In the asthmatic mice, administration of G-Rh2 markedly reduced peribronchiolar inflammation, recruitment of airway inflammatory cells, cytokine production, total and OVA-specific IgE levels and AHR. G-Rh2 administration inhibited NF-kappaB activation and p38 mitogen-activated protein kinase (MAPK) phosphorylation induced by OVA inhalation. These results suggested that G-Rh2 attenuates allergic airway inflammation by regulating NF-kappaB activation and p38 MAPK phosphorylation. The present study identified the molecular mechanisms of action of G-Rh2, which supported the potential use of G Rh2 to prevent and/or treat asthma and other airway inflammatory disorders. PMID- 26502837 TI - Protein folds recognized by an intelligent predictor based-on evolutionary and structural information. AB - Protein fold recognition is an important and essential step in determining tertiary structure of a protein in biological science. In this study, a model termed NiRecor is developed for recognizing protein folds based on artificial neural networks incorporated in an adaptive heterogeneous particle swarm optimizer. The main contribution of NiRecor is that it is a data-driven and highly-performing predictor without manually tuning control parameters for different data sets. In biological science, since evolutionary- and structure based information of amino acid sequences is greatly important in determination of tertiary structure of a protein, accordingly, in NiRecor we employ two different feature sets, which involve position specific scoring matrix and secondary structure prediction matrix, to predict the structural classes of protein folds. The experimental results demonstrate the proposed method is powerful in predicting protein folds with higher precisions by improvements of 1.1 ~7.8 percentages on three benchmark datasets by comparing with several existing predictors. PMID- 26502838 TI - Elective egg freezing: can you really turn back the clock? PMID- 26502839 TI - Copeptin levels in OSAS patients: still an unresolved issue. PMID- 26502840 TI - Neurotoxicity of general anesthetics: anesthesia and Alzheimer's disease in Serbia. PMID- 26502841 TI - Benign paroxysmal positional vertigo (BPPV): it may occur after dental implantology. A mini topical review. AB - OBJECTIVE: Benign Paroxysmal Positional Vertigo (BPPV) is one of the most frequent vestibular disorders. BPPV as a complication of Osteotome Sinus Floor Elevation (OSFE) is a complication that rarely occurs. The aim of this paper is to better understand the mechanisms underlying the BPPV after SFE with the osteotomes. This could be important for all the dental and maxillofacial surgeons that should know and manage this clinical occurrence. DISCUSSION: The osteotome sinus floor elevation (OSFE), firstly described by Summers requires the use of a surgical mallet for striking the bone, until the optimal depth is reached. The surgical mallet develops a mechanical trauma, even if the striking is performed with a gentle percussion. The recent literature describes an average occurrence of OSFE-induced BPPV quite low, but the symptoms show to be unpleasant and severe, often able to alter the patient's daily life. CONCLUSIONS: A successful remission of BPPV following treatment with a particle repositioning maneuver will be necessary and relatively urgent for the surgeons who have experienced this clinical complication. The surgeons, therefore, must be aware of these complications and about the ways to manage them. PMID- 26502842 TI - A post-market surveillance analysis of the safety of hydroxyapatite-derived products as bone graft extenders or substitutes for spine fusion. AB - OBJECTIVE: Iliac crest bone graft (ICBG) is considered the gold standard for spine surgical procedures to achieve a successful fusion, because of its known osteoinductive and osteoconductive properties. Considering its autogenous origin, the use of ICBG has not been associated to an increase of intraoperative or postoperative complications directly related to the surgery. However, complications related to the harvesting procedure and to the donor site morbidity have been largely reported in the literature, favoring the development of a wide range of alternative products to be used as bone graft extenders or substitutes for spine fusion. The family of ceramic-based bone grafts has been widely used and studied during the last years for spine surgical procedures in order to reduce the need for iliac crest bone grafting and the consequent morbidity associated to the harvesting procedures. PATIENTS AND METHODS: We report here the results of a post-market surveillance analysis performed on four independent cohorts of patients (115 patients) to evaluate the safety of three different formulations of hydroxyapatite-derived products used as bone graft extenders/substitutes for lumbar arthrodesis. RESULTS: No intraoperative or post operative complications related to the use of hydroxyapatite-derived products were detected, during medium and long follow up period (minimum 12 months-maximum 5 years). CONCLUSIONS: This post-market surveillance analysis evidenced the safety of ceramic products as bone graft extenders or substitutes for spine fusion. Moreover, the evidence of the safety of hydroxyapatite-derived products allows to perform clinical studies aimed at evaluating the fusion rates and the clinical outcomes of these materials as bone graft extenders/substitutes, in order to support their use as an alternative to ICBG for spine fusion. PMID- 26502843 TI - Tear function alterations in patients with polycystic ovary syndrome. AB - OBJECTIVE: Complaints of dry eye are prevalent worldwide and are known to be associated with insulin resistance (IR) and hyperandrogenism. However, dry eye is often overlooked in the context of polycystic ovary syndrome (PCOS). The aim of the present study was to evaluate whether or not there is any relation between tear functions and PCOS, which is a multifaceted disorder associated with IR or hyperandrogenism. PATIENTS AND METHODS: A total of 35 women with polycystic ovary syndrome (PCOS) were enrolled in this study, along with 27 healthy controls. Body mass index (BMI), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and free testosterone levels on the third day of menstruation were recorded, as well as hirsutism score (using the Ferriman Gallwey scoring system), insulin resistance (homeostasis model assessment), neutrophil-to- lymphocyte ratios (NLR), platelet-to-lymphocyte ratios (PLR), and mean platelet volumes (MPV). A complete ocular examination was followed by administration of the ocular surface disease index (OSDI) questionnaire and Schirmer and tear break-up time (TBUT) tests. RESULTS: Schirmer and OSDI results were similar between groups, but TBUT was significantly lower in the PCOS group (p = 0.002). There were negative correlations between FG score and TBUT test (r = -0.406, p = 0.001) and between NLR and Schirmer test (r = -0.294, p = 0.025). CONCLUSIONS: Although subjective dry eye symptoms do not present in all patients, these results confirm that tear reduction, which can cause further complications in patients with PCOS, can be detected by careful examination and sensitive tests. PMID- 26502844 TI - Evaluation of a diagnostic flow chart applying medical thoracoscopy, adenosine deaminase and T-SPOT.TB in diagnosis of tuberculous pleural effusion. AB - OBJECTIVE: To evaluate a diagnostic flow chart applying medical thoracoscoy (MT), adenosine deaminase (ADA) and T-SPOT.TB in diagnosis of tuberculous pleural effusion (TPE) at a high TB burden country. PATIENTS AND METHODS: 136 patients with pleural effusion (PE) were enrolled and divided into TPE and Non-TPE group. MT (histology), PE ADA and T-SPOT.TB were conducted on all patients. ROC analysis was performed for the best cut-off value of PE ADA in detection of TPE. The diagnostic flow chart applying MT, ADA and T-SPOT.TB was evaluated for improving the limitations of each diagnostic method. RESULTS: ROC analysis showed that the best cut-off value of PE ADA was 30U/L. The sensitivity and specificity of these tests were calculated respectively to be: 71.4% (58.5%-81.6%) and 100% (95.4 100.0%) for MT, 92.9% (83.0-97.2%) and 68.8% (57.9-77.9%) for T-SPOT.TB, and 80.0% (69.6-88.1%) and 92.9% (82.7-98.0%) for PE ADA. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predictive value and negative predictive value of the diagnostic flow chart were 96.4% (87.9-99.0%), 96.3% (89.6-98.7%), 25.714, 0.037, 97.4 and 94.9, respectively. CONCLUSIONS: The diagnostic flow chart applying MT, ADA and T SPOT.TB is an accurate and rapid diagnostic method in detection of TPE. PMID- 26502845 TI - Expression of VEGF and its effect on cell proliferation in patients with chronic myeloid leukemia. AB - OBJECTIVE: The aim of this study is to investigate the expression of vascular endothelial growth factor (VEGF) in the serum of patients with chronic myeloid leukemia (CML) and the effect of VEGF on cell proliferation. PATIENTS AND METHODS: Serum VEGF levels in 12 CML patients (7 chronic phase, 5 blast crisis phase) were measured using enzyme linked immunosorbent assay (ELISA). VEGF expression was interfered by transfection of K562 cells. VEGF mRNA levels in transfected K562 cells were determined using RT-PCR and the effect of VEGF on the proliferation of transfected K562 cells was investigated. RESULTS: VEGF expression levels were significantly higher in CML patients than normal controls and significantly increased during blast crisis phase than during chronic phase. Compared to controls, the proliferation of the K562 cells was suppressed when VEGF expression was inhibited. However, the inhibited proliferation of K562 cells after gene silencing of VEGF was partially abolished after introducing exogenous VEGF into the cells. CONCLUSIONS: VEGF plays an important role in the initiation and development of CML and monitoring serum VEGF assists guiding the treatment and predicting the prognosis of CML. PMID- 26502846 TI - Diagnostic accuracy of three-dimensional CT reconstruction and cephalometry for lateral skull base tumors. AB - OBJECTIVE: To explore the diagnostic accuracy of three-dimensional CT reconstruction and cephalometry in lateral skull base tumors. PATIENTS AND METHODS: Fifty-eight patients with lateral skull base tumors were randomly divided into control group (n = 29, examined with conventional diagnostic technique) or study group (n = 29, examined with three-dimensional CT reconstruction and cephalometry). The diagnostic accuracy, tumor distribution and image characteristics were compared between both patient groups. RESULTS: In control group, preoperative tumor diagnosis was consistent with intraoperative diagnosis in 20 patients, similar in 7 patients and discrepant in 2 patients. In study group, there were 24 consistent, 4 similar, and 1 discrepant diagnoses (p < 0.05 vs. control group). Frequency of individual tumor types, as revealed by either diagnostic method, was comparable. The images obtained with three dimensional CT reconstruction were clearer, facilitating an accurate demonstration of the tumor, including tumor size and location. CONCLUSIONS: Three dimensional CT reconstruction and cephalometry provides accurate diagnosis of lateral skull base tumors, which is helpful for subsequent surgical treatment. PMID- 26502847 TI - Bioinformatics analysis of miRNA expression profile between primary and recurrent glioblastoma. AB - OBJECTIVE: Glioblastoma (GBM) is the most malignant brain tumor with rapid relapse. The goal of this study is to identify microRNAs (miRNAs) involved in recurrent GBM. MATERIALS AND METHODS: miRNA transcription profile data (GSE32466) were downloaded, including 12 primary GBM samples and 12 recurrent GBM samples. Then, limma package was utilized to identify differentially expressed miRNAs (DEMs) with the criteria of false discovery rate < 0.05 and |log2 fold change| >= 1. Thereafter, miTarget and TargetScan databases were used to predict the potential target genes of DEMs. Regulatory co-expression network was constructed based on co-expressed genes and potential miRNA-gene pairs, and then, pathway analysis was conducted. Furthermore, database miRWalk was used to screen out known GBM-associated miRNAs from the identified DEMs. RESULTS: A total of 71 DEMs were identified between primary and recurrent GBM samples, and 2684 potential target genes were found. Besides, regulatory co-expression network was constructed, including 12 DEMs and 81 potential target genes. These genes significantly enriched in ECM-receptor interaction, ribosome, and focal adhesion pathways, and DEMs like hsa-miR-320a, hsa-miR-139-5p, has-miR-128, hsa-miR-140 5p, and hsa-miR-146b-5p had high degree. Notably, 7 DEMs in network were known GBM-associated miRNAs recorded in database miRWalk. CONCLUSIONS: DEMs like hsa miR-320a, hsa-miR-139-5p, has-miR-128, hsa-miR-146b-5p, hsa-let-7c, hsa-miR-128, and hsa-let-7a might participate in recurrent GBM. These results would pave ways for further study of recurrent GBM mechanism, and for the prevention and treatment of recurrent GBM. However, more experimental verifications are required to prove these predictions. PMID- 26502848 TI - Induction effect of MicroRNA-449a on glioma cell proliferation and inhibition on glioma cell apoptosis by promoting PKCalpha. AB - OBJECTIVE: This study aimed to investigate the expression of microRNA-449a in brain tissue and plasma of patients with glioma and its mechanism of action on glioma cell proliferation and apoptosis. PATIENTS AND METHODS: 30 cases of gliomas patients were recruited in the study, 12 cases in which with brain tissues excision due to decompression or exposure during the brain surgery were selected as the control group. RT-PCR was used to detect the microRNA-449a expression in brain tissue and peripheral blood of the two groups. Cell proliferation and apoptosis level were further determined after high or low expression of microRNA-145 in human glioma cell line U-251. RT-PCR and Western blotting were used to detect PKCalphamRNA and protein level in U-251. RESULTS: The expression of microRNA-449a in brain tissue or peripheral blood of patients with brain glioma was significantly lower than that of normal people, and the differences were statistically significant (p < 0.05). Upon interfering with microRNA-449a, the glioma cell proliferation was significantly increased while apoptosis was significantly reduced, the PKCalpha protein levels were increased significantly and the differences were statistically significant (all p < 0.05); after overexpression of microRNA-449a, the glioma cell proliferation was significantly decreased while the cell apoptosis was significantly increased, the PKCalpha protein levels were decreased significantly and the differences were statistically significant (all p < 0.05). CONCLUSIONS: The expression of microRNA 449a is low in patients with glioma, which may inhibit the proliferation of glioma and promote its cell apoptosis via affecting the expression of PKCalpha. PMID- 26502849 TI - Overexpression of miR-98 inhibits cell invasion in glioma cell lines via downregulation of IKKepsilon. AB - OBJECTIVE: MicroRNAs (miRNAs) function as negative regulators for the expression of genes involved in cancer metastasis. The aim of this study was to investigate the potential role of miR-98 in gliomas and validate its regulatory mechanism. PATIENTS AND METHODS: Cell viability assays are used to measure proliferation of cell. mRNA expression is measured by qRT-PCR. Western blot analysis is used to measure protein expression. RESULTS: Functional studies showed that miR-98 overexpression inhibited glioma migration and invasion, but had no effect on the cell viability. An enhanced green fluorescent protein reporter assay, quantitative RT-PCR, and a western blot analysis confirmed that miR-98 suppressed the expression of IkappaB kinase (IKKepsilon) by directly targeting its 3' untranslated region, also, the NF-kappaB p65 nuclear translocation and matrix metalloproteinase (MMP)-9 expression were significantly arrested in glioma cells treated with miR-98 mimics. Accordingly, the overexpression of IKKepsilon or NF kappaB p65 can restore cell migration and invasion after being inhibited by miR 98, and can restore NF-kappaB p65 nuclear translocation as well as increase MMP-9 expression. CONCLUSIONS: These findings demonstrated that miR-98 functions as a tumor suppressor in gliomas. Furthermore, miR-98 may act as a potential therapeutic biomarker for glioma patients. PMID- 26502850 TI - Efficacy and safety of capecitabine as maintenance therapy after capecitabine based combination chemotherapy for patients with advanced esophagogastric junction adenocarcinoma. AB - OBJECTIVE: The aim of the present study was to investigate the efficacy and safety of single-agent capecitabine therapy after capecitabine-based combination chemotherapy for patients with advanced adenocarcinoma of the esophagogastric junction (EGJ). PATIENTS AND METHODS: Seventy-two patients with pathologically proven advanced EGJ adenocarcinoma underwent 2-6 cycles of capecitabine-based first-line combination chemotherapy between January 2010 and October 2014. When initial disease control had been achieved, 60 patients were randomly assigned to receive the capecitabine treatment (oral capecitabine 1,250 mg/m2 twice daily on days 1-14 every 3 weeks) to see whether it is involved in maintenance regimen or not, while 12 patients were excluded. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and major adverse events were monitored. RESULTS: The median PFS was 11.0 months (95% confidence interval [CI], 0-23.2 months) and OS was 17.0 months (95% CI, 2.1 31.9 months) for the maintenance group. In contrast, median PFS was 7.0 months (95% CI, 5.8-8.2 months) and OS was 11.0 months (95% CI, 2.07-31.9 months) for the control group. Compared to controls, patients who received capecitabine maintenance therapy showed significantly prolonged PFS and OS. The capecitabine related adverse events included leukopenia, anemia, and thrombocytopenia, hand foot syndrome, nausea/vomiting, neuropathy, and liver dysfunction. Treatment related adverse events were tolerable, and there were no significant differences in the prevalence of adverse events between patients who received maintenance therapy and controls. CONCLUSIONS: Our finding shows that single-agent capecitabine maintenance therapy was effective, well-tolerated and safe after first-line capecitabine-based combination chemotherapy in patients with advanced EGJ adenocarcinoma. PMID- 26502851 TI - Comparison of colorectal neoplastic polyps and adenocarcinoma with regard to NLR and PLR. AB - OBJECTIVE: Cancer-related inflammation affects many aspects of malignancy, including proliferation and survival of malignant cells, angiogenesis, and therapeutic response. Some biomarkers representing the degree of systemic inflammation, such as the Glasgow prognostic score, NLR and PLR, have been shown to have prognostic value in many kinds of cancer patients. Aim of this study to investigate to compare neutrophil/leukocyte (NLR) and platelet/lymphocyte (PLR) ratios of the patients with colorectal neoplastic polyps and colorectal cancer (CRC) and tried to determine whether this could be used as a biomarker in follow up of the patients with neoplastic polyps. PATIENTS AND METHODS: A total of 100 colorectal polyps, 113 colorectal cancers and 124 healthy controls were included in the study. Exculusion criteria were endocrinologic or metabolic diseases, acute or chronic diseases, hypertension and atherosclerotic heart diseases, renal diseases. Blood count parameters of the patients were measured. The NLR was calculated as a simple ratio between the absolute neutrophil and the absolute lymphocyte counts. The PLR was defined as the platelet counts to lymphocyte ratio. RESULTS: A statistically significant difference was not detected between Group A and C with regard to NLR and PLR. NLR and PLR were found statistically significantly high in Group B (CRC), Group A (colorectal polyp) and Group C (healthy individuals) (p < 0.001 and p < 0.001). Our study showed that the optimum NLR cut-off point for neoplastic polyps was 2.28 (sensitivity: 68.7%, specificity: 42.3%). When the sensitivity and specificity levels of the PLR were assessed, they were 68.7% and 46.5% for neoplastic polyps, 80% and 68.9% for colorectal cancer. CONCLUSIONS: NLR and PLR may be used for follow up conversion of colonic and rectal neoplastic polyps to invasive tumor. PMID- 26502852 TI - Clinical presentation and outcome of non-AIDS defining cancers, in HIV-infected patients in the ART-era: the Italian Cooperative Group on AIDS and tumors activity. AB - The advent of antiretroviral therapy (ART) has markedly extended the survival rates of patients with human immunodeficiency virus (HIV), leading to suppression even though not eradication of HIV. In HIV infected patients, cancer has become a growing problem, representing the first cause of death. A large number of worldwide studies have shown that HIV infection raises the risk of many non-AIDS defining cancers (NADCs), including squamous cell carcinoma of the anus (SCCA), testis cancer, lung cancer, cancer of the colon and rectum (CRC), skin (basal cell skin carcinoma and melanoma), Hodgkin disease (HD) and hepatocellular carcinoma (HCC). Generally in HIV positive patients NADCs are more aggressive and in advanced stage disease than in the general population. In the ART era, however, the outcome of HIV positive patients is more similar as in the general population. Only about lung cancer the outcome seems different between HIV positive and HIV negative patients. The aim of this article is to provide an up date on NADCs within the activity of the Italian Cooperative Group on AIDS and Tumors (GICAT) to identify clinical prognostic and predicting factors in patients with HIV infection included in the GICAT. PMID- 26502853 TI - Identifying the biomarkers of multiple sclerosis based on non-coding RNA signature. AB - OBJECTIVE: miRNAs are key regulators in multiple sclerosis. To gain a better understanding of the molecular mechanisms of multiple sclerosis, differentially expressed microRNAs (DE-miRNAs) and genes (DEGs) were analyzed. MATERIALS AND METHODS: The miRNA expression profile GSE43590 including 11 samples of peripheral blood T-cells from relapsing-remitting MS patients and 9 normal samples as well as gene expression profile GSE52139 including 8 periplaque samples and 8 normal samples were downloaded from Gene Expression Omnibus. Then, DE-miRNAs and DEGs were identified using limma. Moreover, the target genes of DE-miRNAs were screened. Additionally, the integrated regulatory network of DEGs, DE-miRNAs and targets was constructed using Cytoscape. What's more, the functional modules were also screened using MINE in Cytoscape. Lastly, the functional annotation of genes in modules was conducted using DAVID. RESULTS: A total of 2394 DEGs were screened in 8 periplaque samples. Additionally, 296 DE-miRNAs were identified in the 11 samples of peripheral blood T-cells from relapsing-remitting MS patients. Besides, 6 functional modules (A-F) were screened. Among them, has-miR-197 could target HNF4A. What's more, HNF4A could interact with CYP3A4. Additionally, has miR-125b could target ID1 and ID3. Besides, ID1 could interact with THBS1. Furthermore, functional enrichment showed that CYP3A4 was significantly related to vitamin metabolic process. For the pathway enrichment, ID1 and ID3 were significantly enriched in TGF-beta signaling pathway. CONCLUSIONS: Some important DE-miRNAs (such as has-miR-197and has-miR-125b) might be crucial for MS by regulating the expressions of their target genes. PMID- 26502854 TI - The role of eosinophils in stroke: a pilot study. AB - OBJECTIVE: To evaluate the factors that may have an impact on the prognosis of ischemic stroke. PATIENTS AND METHODS: The study included 973 patients who were diagnosed with an ischemic stroke. The patients were divided into 6 groups according their eosinophil counts' level and occurred times. All patients were supervised by NIHSS score in three months. RESULTS: Baseline characteristics of all study groups were comparable. Thirty-four patients in group 2 and group 5 had higher eosinophil counts. In addition, the patients experienced impaired function on the face, but no impairment of limbs. All patients in these groups recovered quicker than the other groups (p < 0.05). Furthermore, 169 patients in both group 3 and group 6 had lower eosinophil counts. These patients experienced functional impairment in limbs and difficulty recovering from the disease. The NIHSS score was lower in both group 2 and group 5, compared with group 3 and group 6 (p < 0.05). CONCLUSIONS: This study suggests that eosinophil counts may have a significant impact on outcomes in stroke patients. The data underscore the importance in further investigating eosinophil dysregulation as well as the potential relationship between eosinophil dysregulation and organ functions in stroke patients. PMID- 26502855 TI - The clinical efficacy of laparoscopy combined with choledochoscopy for cholelithiasis and choledocholithiasis. AB - OBJECTIVE: To compare and analyze the clinical efficacy of laparoscopy combined with choledochoscopy, and laparoscopy combined with duodenoscopy, for cholelithiasis and choledocholithiasis. PATIENTS AND METHODS: A total of 105 patients with cholelithiasis and choledocholithiasis from our hospital, from January 2014 to January 2015, were enrolled in this study. All patients weren given primary treatment. After obtaining consent from our hospital Ethics Committee and the patients, all 10529 cases were divided into two groups according to their time of admission. The observation group consisted of 59 cases and the control group consisted of 46 cases. The control group were treated by laparoscopy combined with duodenoscopy (cholecystectomy +ERCP+calculi extraction with an endoscope) and the observation group were treated by laparoscopy combined with choledochoscopy. We then compared the clinical efficacy between the two groups of patients. RESULTS: The success rate of the first surgery in the observation group, was higher than that in the control group. The time of surgery and intra-operative blood loss of the observation group were less than the control group. The differences had statistical significance p < 0.05). When compared the post-operative fasting and evacuation time, average hospital stay and hospitalization expenses for the observation group were less than those of the control group. The difference had statistical significance (p < 0.05). The prevalence of post-operative complications and recurrence rate in the observation group were statistically significantly (p < 0.05) less than the control group (p < 0.05). CONCLUSIONS: Laparoscopy combined with choledochoscopy was effective and safe for treating cholelithiasis and choledocholithiasis. Its treatment outcomes might be superior to laparoscopy combined with duodenoscopy. PMID- 26502856 TI - Diagnosis accuracy of serum Glypican-3 level in patients with hepatocellular carcinoma and liver cirrhosis: a meta-analysis. AB - OBJECTIVE: The diagnostic value of serum GPC3 levels in patients with hepatocellular carcinoma (HCC) and liver cirrhosis remains controversial. Therefore, we performed a meta-analysis to assess the diagnostic accuracy of serum GPC3 for HCC and liver cirrhosis (LC). MATERIALS AND METHODS: A systematic search was performed for the relevant studies. Sensitivity, specificity and other measures regarding the accuracy of serum GPC3 in the diagnosis of HCC were performed by random-effects models. Summary receiver operating characteristic curve (sROC) analysis was taken to summarize GPC3's performance. RESULTS: 17 studies were included in our meta-analysis. The pooled sensitivity and 95 % confidence intervals (95% CIs) for GPC3 were 56% (53%-59%) and 89% (87%-90%) in specificity. The pooled positive LR and 95% confidence intervals (95% CIs) for GPC3 were 7.82 (3.86-15.85) and 0.48 (0.39-0.59) respectively in negative LR. The summary diagnostic odds ratio (DOR) and 95% CIs for GPC3 were 26.73 (10.31 69.26), and the area under sROC (AUC) and 95% CIs for GPC3 were 0.8827 (0.8324 0.9330). CONCLUSIONS: GPC3 is acceptable as a serum marker for the diagnosis of HCC, which can elevate the accuracy of diagnosis. PMID- 26502857 TI - Application of clinical indexes in ulcerative colitis patients in regular follow up visit: correlation with endoscopic 'mucosal healing' and implication for management. Preliminary results. AB - OBJECTIVE: Ulcerative Colitis (UC) is a chronic inflammatory disease of the colon of unknown etiology. Several clinical indexes have been proposed for UC disease activity evaluation, but none have been properly validated. Moreover, the reference parameter for the scores and their prognostic value is not clear. Mucosal healing has been recently proposed as an important end-point. Aim of the present study was to evaluate the correlation of four clinical indexes with objective diagnostic tools for UC evaluation, the discriminative ability in identifying patients with endoscopic mucosal healing, and to analyze the possible prognostic indication for disease course in 1 year of follow-up. PATIENTS AND METHODS: We analyzed data of 75 patients recorded in regular follow-up visit in IBD clinic at S. Andrea Hospital, Rome, between 2007-2011. We recorded clinical data and lab tests at the time of the visit, and endoscopic/histological reports performed within 1 month. Clinical indexes (Seo' activity index, Simple Clinical Colitis Activity Index, partial Mayo score and Endoscopic-Clinical Correlation Index) were calculated and correlation to endoscopic and histologic activity, and to C-reactive protein increment, was assessed by mean of Spearman's rank correlation. Discriminative ability of the indexes for patients with and without endoscopic mucosal healing was tested by calculation of area under ROC curve (AUC). Patients with low and high clinical scores were compared for number of flares and increment of therapy during 1 year of follow-up. RESULTS: Clinical indexes had a good correlation with endoscopic activity (mean r = 0.73 +/- 0.06), a fair correlation with CRP-increment (mean r = 0.55 +/- 0.01) and a poor one with histologic activity (mean r = 0.35 +/- 0.01). The discriminatory ability of the indexes for endoscopic mucosal healing was good for all the indexes (mean AUC = 0.87 +/- 0.05). Patients with high clinical score had more flares and required more frequently increase of therapy at 1 year of follow up compared with patients with low score. CONCLUSIONS: Clinical indexes have a good correlation with endoscopic activity and can discriminate patients with and without mucosal healing. Patients with low and high score have different risk of disease flare and of need to increase therapy at 1 year. Clinical indexes may represent a useful tool for disease assessment in clinical practice in UC outpatients with mild-moderate disease. PMID- 26502858 TI - Study on the correlation between the changes in intra-abdominal pressure and renal functional in the patients with abdominal compartment syndrome. AB - OBJECTIVE: To observe the effect on renal function from increased intra-abdominal pressure. PATIENTS AND METHODS: Sixty patients with abdominal compartment syndrome (ACS) were included in this study. Intra-abdominal pressure, mean arterial pressure (MAP) and central venous pressure (CVP) were recorded three times per day at a fixed time. Meanwhile, blood samples were collected for serum creatinine measurement and urine volume per hour was recorded. RESULTS: The urine volume gradually decreased with the increasing intra-abdominal pressure, from 92. 6 +/- 20 ml/h to 27.9 +/- 20 ml/h (p < 0. 05), and the serum creatinine increased from 68.4 +/- 39.9 mol/L to 249.4 +/- 111.5 mol/L (p < 0. 05). The CVP increased from 0.98 +/- 0.19 kPa to 1.56 +/- 0.31 kPa with the increase or decrease of the MAP. The increase in intra-abdominal pressure was negatively related to the urine volume (r = -0.193, p < 0.05), and positively related to the serum creatinine (r = 0.162, p < 0.05), but not related to the MAP. CONCLUSIONS: The increase of intra-abdominal pressure, was closely related to oliguria and increasing serum creatinine. The use of fluid resuscitation and diuretics had few effects on the recovery of the renal function. When the intra-abdominal pressure had decreased, the urine volume increased, and the serum creatinine decreased. PMID- 26502859 TI - Conscious sedation with midazolam and dezocine for diagnostic flexible bronchoscopy. AB - OBJECTIVE: This study aimed to assess the benefits and risks of conscious sedation with midazolam and dezocine in diagnostic flexible bronchoscopy (FB). PATIENTS AND METHODS: This prospective case control study enrolled 40 non-sedated and 40 sedated subjects who underwent diagnostic FB. All received the standard upper airway preparation, while sedated subjects received midazolam and dezocine for conscious sedation. Subject discomforts during FB were assessed using the verbal analogue score (VAS, 0-10 scale). Willingness to return was assessed as five scales to monitor subject's satisfaction level. Safety profiles throughout the procedures were also assessed. RESULTS: Anterograde amnesia existed in 75.0% sedated subjects. Compared to non-sedated subjects, sedated ones expressed less discomfort, with lower VAS scores regarding scope insertion (4 [0-10] vs. 0 [0 4], p < 0.001), cough (5.5 [0-10] vs. 0 [0-4], p < 0.001), dyspnea (3.5 [0-10] vs. 0 [0-4], p<0.001), pain (3 [0-10] vs. 0 [0-5], p < 0.001), and global tolerance of the procedures (5.5 [1-10] vs. 0 [0-5], p < 0.001). More sedated subjects expressed willingness to return (90.0% vs. 30.0%, p < 0.001). Sedated subjects had no more hypoxemic episodes during the procedure (7.5% vs. 5.0%, p > 0.99), which were all transient and not life-threatening. CONCLUSIONS: Conscious sedation with midazolam and dezocine reduces discomforts, improves satisfaction level, and carries no significantly risks in subjects undergoing diagnostic FB. PMID- 26502860 TI - Risk factors for mortality in severe multiply injury patients with acute hypoxemic respiratory failure. AB - OBJECTIVE: To investigate the risk factors related to mortality in severe polytrauma patients with acute hypoxemic respiratory failure (AHRF). PATIENTS AND METHODS: From December 2011 to December 2014, we identified and intubated 524 traumatic AHRF patients in a level 1 trauma centers. Amongst those, we enrolled seventy-six severe traumatic AHRF patients with an injury severity score (ISS) over 16 and need for over 24 hour intra-tracheal mechanical ventilation for our study. Patients were followed daily to collect data about demographics, injury characteristic, diagnostic, treatment, respiratory parameters, major complications, duration of mechanical ventilation, length of stay, prevalence of major complications and 28-days mortality. RESULTS: Of the 76 patients in our study, 61 patients were male. Patients' ages were from 15 to 78 years old (43+/ 17) and the predominant source of trauma was road traffic accidents. Before ventilation, patients had a mean PaO2/FiO2 ratio of 108+/-63, pH of 7.1+/-0.3, PaCO2 of 54+/-24 mmHg, respectively. The PaO2/FiO22 ratios were significantly improved by ventilation and the average duration of ventilation was 9.63+/-8.74 days. There were two peak dying times and the 28-days ICU mortality rate was 28.9%. Logistic regression analysis revealed the mortality rate to be significantly higher in patients with higher APACHE II scores (odds ratio: 1.60, p=0.002), shorter intervals between injury and admission (odds ratio: -0.91, p=0.03) and between admission and ventilation (odds ratio: -1.85, p=0.012), and lower pH (odds ratio: -0.692, p=0.044). The receiver operating characteristic (ROC) curves showed that best cut off points for mortality predictors were APACHE II scores greater than 25, time interval between injury and admission less than 2h, time interval between admission and ventilation less than 0.5h, and pH <7.16. CONCLUSIONS: Traumatic AHRF patients requiring ventilation support show a high rate of early mortality. Greater vigilance for high APACHE II score, short time interval between injury and ventilation, low pH in traumatic AHRF patients is required. PMID- 26502861 TI - A novel association between IL1-Ra (receptor antagonist) gene polymorphism and T1DM in Al-Madina Al-Mounawra. AB - OBJECTIVE: The Interleukin-1 receptor antagonist (IL1-Ra) is initiated to terminate the acute pro-inflammatory event and prevent chronic inflammation from damaging healthy cells. We aim to draw the attention of IL1-Ra (VNTR) gene polymorphism and determine whether IL1-Ra confer susceptibility to type 1 diabetes mellitus (T1DM) and evaluate the genotype and allele distribution of IL1 Ra gene in a Saudi population. PATIENTS AND METHODS: Case control study included (100) T1DM Saudi children, plus 102 healthy unrelated individuals as control group. They were evaluated for variable number of tandem repeat (VNTR) of IL1-Ra gene polymorphism. Polymerase chain reaction amplification of VNTR of 86bp in intron 2 of IL1-Ra was performed. RESULTS: A1A1 and A1A2 genotypes with alleles A1 and A2 frequency were the most common both in cases and controls (healthy population); prevalence (28%, 56% & 57.8%, 39.2% respectively) and (58%, 38% and 77.5%, 22.5% respectively). In addition IL1-Ra gene polymorphism had higher risk significantly different between diabetic children and controls. (A1/A2) genotype had higher frequency statistically significant in DM patients than controls [56% vs. 39.2%, p < 0.02] and had twice time risk [OR = 1.97, 95% CI = 1.1-3.4, p < 0.02]. With further stratification, there was strong association between diabetic patients carriage IL1-Ra (A2) allele and controls [38% vs. 22.5%, p = 0.001] which had higher risk [OR = 2.11, 95% CI = 1.4-3.2, p = 0.001] for susceptibility of diabetes. CONCLUSIONS: This study emphasizes a positive association between IL1-Ra (VNTR) polymorphism and DM among Saudi children. This may suggest that (A2) allele may play important role in disease susceptibility. PMID- 26502862 TI - The anti-inflammatory effects of exercise in the syndromic thread of diabetes and autoimmunity. AB - A unifying thread over the wide spectrum of diabetes might be the triggering of innate immunological and inflammatory pathways leading to insulin resistance, beta-cell dysfunction and beta-cell destruction: the hybrid features of type 1 and type 2 diabetes. In fact, hyperglycemia can arise from a deficit in insulin action, insulin secretion, or both. Regularly exercising at moderate intensity has been shown to efficiently and positively impact upon physiological imbalances caused by several morbid conditions. Even in different immunological dysfunctions, physical exercise has been prescribed as a complementary therapeutic strategy. In fact, as suggested by our observations, there is a putative inverse relationship between autoimmunity markers (GAD, IA) and exercise derived energy expenditure in type 1 pre-diabetic subjects. Exercise also has been shown to maintain muscle mitochondrial function and thus ability to maintain fuel metabolism and islet cell function. An additional benefit is the enhancement of antioxidant defense system and thus reducing oxidative stress. Therefore, the purpose of this review is to address the importance of physical exercise in a broad range of metabolic disorders that set out a common milieu in which type 1 and type 2 diabetes could be identified as one extensive syndrome. PMID- 26502863 TI - Research on rat models of hypobaric hypoxia-induced pulmonary hypertension. AB - OBJECTIVE: Rat models of hypobaric hypoxia-induced pulmonary hypertension are commonly used in studies of chronic mountain sickness, while there are few researches specially focusing on these rats model. This study aims to exploring possible pathogenesis of hypobaric hypoxia-induced pulmonary hypertension by experimenting on hypobaric hypoxia-induced PH rat models at different simulate- altitudes. MATERIALS AND METHODS: 32 healthy male SD rats were randomly divided into six groups of different degree and time period of hypobaric hypoxia. The mean pulmonary arterial pressure (m PAP), right ventricular pressure (RVSP), the right ventricle (RV), left ventricular (LV), ventricular septal (S), the right ventricular hypertrophy index (RVHI) [calculated under the formula of RV / (LV + S)], hematoxylin-eosin staining, elastic fibers staining, the ratio of the thickness of vascular wall to its outer diameter (MT%), the ratio of the cross sectional area of the middle vascular wall to the total vascular cross-sectional area (MA%); the alpha-SMA, and the Ki6 expressions were detected to evaluated the pulmonary hypertension. RESULTS: There were significant differences of the mPAP, RVSP and RVHI value between the hypobaric hypoxia groups and the control group (p < 0.05). The mPAP, RVSP, RVHI, MT%, MA%, alpha-SMA, and Ki6 of rats in model groups at an altitude of 3KM were higher than those of the control group, which raised gradually with the number of weeks increasing. The mPAP, RVSP, RV / (LV + S) value, MT%, MA%, alpha-SMA, and Ki67 of the 5KM-4W group were significantly higher than those of the control group (p < 0.05). CONCLUSIONS: Rat models with pulmonary hypertension at different altitudes have been successfully established by automatic adjusting hypobaric hypoxia chamber. Exposure to a low oxygen environment at a simulate-altitude of 3 km for 8 weeks have caused the pathological remodeling of pulmonary vascular walls and pulmonary hypertension, and further led to a series of pathological changes, including right ventricular hypertrophy. This model is easy to be replicated with good reproducibility and provides evidence for clinical trial of drugs. PMID- 26502864 TI - Helicobacter pylori and cardiovascular disease. AB - Helicobacter pylori (H. pylori) is one of the most common infections in human. The association between H. pylori and gastrointestinal diseases including peptic ulcer, chronic gastritis, mucosa associated tissue lymphoma (MALT) and gastric cancer is well known. However it was also suggested that H. pylori was linked to various extra-gastrointestinal disorders such as diabetes mellitus and coronary artery disease. In this review we summarized the association between H. pylori and cardiovascular disease. PMID- 26502865 TI - Preparation of solid lipid nanoparticles loaded with garlic oil and evaluation of their in vitro and in vivo characteristics. AB - OBJECTIVE: Solid lipid nanoparticles (SLN) are colloidal drug carriers and may be suitable for delivery of garlic oil, a nutraceutical with medicinal properties, whose use has been limited by its poor solubility. We tested whether poor solubility of garlic oil would be overcome by complexing with SLN by high pressure homogenization and ultrasound techniques. The effects of lipid phase, surfactant mixture and loading concentration of garlic oil on particle size and distribution were also investigated. MATERIALS AND METHODS: High pressure homogenization technique was used to prepare SLN, using orthogonal experiment method to optimize entrapment efficiency, loading efficiency, and recovery of SLN. Pharmacokinetics of garlic oil loaded solid lipid nanoparticles after oral administration to rats was studied by using LC/MS/MS method. RESULTS: Mean particle size and zeta potential of SLN were, respectively, 106.5 +/- 40.3 nm and -30.2 mv. The majority of SLN had a less ordered arrangement of crystals at room temperature, which was beneficial for increasing the drug loading capacity. Drug entrapment efficiency was > 90 percent and showed a relatively long-term physical stability. It was feasible to prepare a lyophilized product with good long-term stability. When 10% trehalose and 5% sucrose were used as cryopreservants, SNL particle size increased from 106.5 nm prior to lyophilisation to 155.3 nm after reconstitution. The garlic oil content in SLN decreased to about 85% (respectively, 34.3 vs. 39.4 mg/mL prior to lyophilisation) due to volatility of garlic oil. Pharmacokinetic studies in rats demonstrated that distribution and elimination of diallyl trisulfide (DATS) and diallyl disulfide (DADS) in garlic oil were rapid. Additionally, elimination of garlic oil-SLN complex is faster than that of garlic oil alone, probably, due to phagocytosis. CONCLUSIONS: An SLN complex with garlic oil exhibits characteristics similar to those of parenteral emulsions, even after lyophilization and reconstitution. PMID- 26502866 TI - Effect of low-dose cyclophosphamide on endoplasmic reticulum stress and inflammatory reaction of acute renal ischemia reperfusion injury. AB - OBJECTIVE: To explore the effect of low-dose cyclophosphamide (CP) on endoplasmic reticulum stress (ERS) and inflammatory reaction of acute renal ischemia reperfusion injury (IRI), providing new ideas for clinical treatment. MATERIALS AND METHODS: Sixty healthy adult male mice were selected and divided randomly into sham operation group (n = 20), IRI group (n = 20 cases), and the experimental group (n = 20 cases). Mice in the experimental group were pretreated with low-dose CP and acute IRI model construction. Intercellular adhesion molecule-1 (ICAM-1) immunohistochemical staining was conducted after the 24h and the detection of CHOP protein by Western blot method. Postoperative 3h and 7 day survival rate, the results of ICAM-1 immunohistochemistry staining and the gray values of C/EBP homologous protein (CHOP) of mice were compared between the three groups. RESULTS: The survival rates of mice in the IRI group and the experimental group after operation were decreased significantly (p < 0.05). However, the survival rates of mice in the experimental group were higher than that in the IRI group. The differences were significant (p < 0.05). The expression of ICAM-1 was significantly reduced (p < 0.05). The difference was statistically significant. The expression of ICAM-1 was significantly reduced (p < 0.05). The gray values of mice in the IRI group and the experimental group were significantly increased. The difference was statistically significant (p < 0.05). And the gray value in the IRI group increased more than that of the experimental group. The difference was statistically significant (p < 0.05). CONCLUSIONS: The pretreatment with low dose CP for mice with acute renal IRI can reduce effectively the ERS and inflammation, which reduces kidney damage for mice and have good effect on prolonging its life. It provides a good way for the guidance of clinical research. PMID- 26502867 TI - Functional study on Boswellia phytosome as complementary intervention in asthmatic patients. AB - OBJECTIVE: The combination of inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs) is recommended for the treatment of patients with mild-to-severe persistent asthma. However, given the lack of definite and safe therapies, complementary or alternative medicines are frequently used by asthmatic patients in combination with standard treatments. PATIENTS AND METHODS: A group of asthmatic subjects have been enrolled in this multicenter study; after having verified the compliance to their current medical therapy (ICS + LABAs), the subjects have been randomized to receive Casperome(r) 500 mg/day or no additional treatment for a period of 4 weeks. They were also asked to keep track of the number of inhalations required per day and any adverse events through a daily form. RESULTS: A total of 32 subjects were enrolled in the study. Subjects receiving Casperome(r) 500 mg/day in addition to the standard ICS + LABAs treatment showed a decrease in the number of inhalations needed compared to patients who did not receive Casperome(r) therapy. The treatment was well tolerated and only mild-moderate adverse events were registered. CONCLUSIONS: The use of Casperome(r) 500 mg/day is beneficial for asthmatic patients as it helps reduce the need for inhalation therapy with ICS + LABA. PMID- 26502868 TI - Losartan improves the distribution and efficacy of doxorubicin in CT26 tumor. AB - OBJECTIVE: The effectiveness of chemotherapeutic agents is impaired by limited delivery of chemotherapeutic agents to the tumor cells. Improving drug penetration in tumor tissues is very important. We tested whether losartan, a selective antagonist against type 1 angiotensin II receptors (AT1R) with noted antifibrotic activity, can enhance the penetration and efficacy of doxorubicin. MATERIALS AND METHODS: BALB/C mice, which implanted with CT26 tumor cells, were divided into four groups: control, doxorubicin alone, losartan alone and doxorubicin + losartan combination groups. At day 0, the losartan alone and doxorubicin + losartan combination groups received losartan; and at day 8, the doxorubicin alone and doxorubicin + losartan combination groups received doxorubicin i.v. Tumor growth and intratumoral distribution of doxorubicin were evaluated. The mechanism underlying the enhanced anti-tumor effect of the combination of doxorubicin and losartan was investigated by immunohistochemical analysis. RESULTS: Treatment with losartan alone did not suppress tumor growth; In contrast, treatment with doxorubicin alone decreased tumor growth; losartan and doxorubicin were administered in combination, had a synergistic effect that the tumor growth was much more inhibited. The decreased proliferation as indicated by down-regulation of Ki67, and increased apoptosis as indicated by TUNEL and caspase-3 staining. The expression of tumor suppressor gene P53 increased in doxorubicin + losartan combination groups. CONCLUSIONS: Losartan can increase the therapeutic effectiveness of doxorubicin, yielding more great antitumor benefit. This study provided a rationale for initiating clinical trials using losartan in combination with chemotherapeutic agents to increase their therapeutic effectiveness. PMID- 26502869 TI - Ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy: a multi-centered randomized controlled trial. AB - OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) is a special complication of pregnancy characterized by skin pruritus, abnormal liver function tests and bile acids. To compare the efficacy of ursodeoxycholic acid (UDCA) and S adenosylmethionine (SAMe) monotherapy with their combined effect on intrahepatic cholestasis of pregnancy (ICP). PATIENTS AND METHODS: Singleton pregnancies with ICP in five tertiary medical centers were randomly divided into three treatment groups: oral UDCA 4*250 mg daily (Group 1, n = 41), intravenous SAMe 1000 mg daily (Group 2, n = 38), and a combination of both drugs (Group 3, n = 41) until delivery. Paired t test, analysis of covariance and non-parametric test were used. RESULTS: All therapies significantly and equally improved pruritus. The serum levels of total bile acids (TBA), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TB) in each group significantly decreased after treatment (p < 0.05). Group 1 was more effective than Group 2 in reducing TBA concentration (p < 0.05), Group 1 and Group 3 showed more effective than Group 2 in reducing AST and TB concentrations (p < 0.05), and Group 1 facilitated deliveries at term. No perinatal death or adverse drug reactions were observed. CONCLUSIONS: UDCA and SAMe are both effective and safe in the treatment of ICP. UDCA monotherapy should be used as the first line therapy for ICP because it is more efficacious, cost-effective and convenient. PMID- 26502870 TI - Mephedrone related fatalities: a review. AB - OBJECTIVE: Synthetic cathinones are an emerging class of designer drugs abused of due to their psychostimulant and hallucinogenic effects, similar to those of cocaine, methylenedioxymethamphetamine (MDMA), amphetamines and methamphetamines. Mephedrone is a cathinone analogue (4-methyl aromatic analogue of methcathinone) that was reported to be implicated in several fatalities in the media across Europe, but only a few have actually resulted in mephedrone cited as the cause of death. In this paper, we aim to systematically review analytically confirmed cases of mephedrone-related fatalities. MATERIALS AND METHODS: Relevant scientific articles were identified from Medline, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE and Google Scholar, through May 2015 using the following keywords: "Mephedrone", "fatal intoxication," "fatalities", "acute intoxication" and "death". RESULTS: In total, 10 citations met the criteria for inclusion, representing 18 fatal cases with analytically confirmed mephedrone in biological sample/s of the deceased. The death was attributed to mephedrone intoxication in 9 cases (range of post-mortem blood mephedrone concentration: 1.33-22 mg/L), whereas multiple drug toxicity, involving mephedrone was cited as cause of death in 6 cases (range of post-mortem blood mephedrone concentration: 0.04-1.3 mg/L). CONCLUSIONS: Data suggest that the abuse of mephedrone remains to be a public health issue. Mephedrone appears to have a rather narrow therapeutic window that makes its use dangerous. Dosages which supposedly fall within recreational use limits could also lead to death when combined with other drugs in certain circumstances. Forensic Toxicology laboratories must assess their testing procedures to ensure they can achieve both an appropriate screening regime and targeted quantitative analysis for the detection of mephedrone in various biological matrices. PMID- 26502871 TI - A case report of successful treatment of pyoderma gangrenosum in a patient with autoimmune hepatitis, and review of the literature. AB - BACKGROUND: Pyoderma Gangrenosum (PG) is a cutaneous condition, its diagnosis suggested by the presence of a painful cutaneous ulcer showing rapid progression. Pyoderma gangrenosum is associated with a concomitant systemic disease in 50 to 70 % of cases, including inflammatory bowel disease (IBD), rheumatoid arthritis, and lymphoproliferative disorders. Although PG has also been reported with viral hepatitis, it is rarely associated with autoimmune hepatitis. CASE PRESENTATION: A 19-year-old Caucasian female, with a prior diagnosis of autoimmune hepatitis (AIH) in remission, presented with bilateral lower limb ulcers 4 years after the diagnosis of AIH. She was diagnosed with PG and treated with high-dose prednisolone, methotrexate and cyclosporine. One year later she was well, the ulcers completely healed, and with the autoimmune hepatitis still in remission. CONCLUSION: We report a case of autoimmune hepatitis and the subsequent, rarely occurring, extra-hepatic onset of pyoderma gangrenosum, with the AIH in remission, strengthening the association between the two conditions. Since both the AIH and the PG can present serious diagnostic challenges, thus delaying vital therapy, it is important that the development of either prompts us to consider the possibility of the other developing in the future or if already present facilitate its diagnosis, such considerations making the case for a systematic follow up. PMID- 26502872 TI - A simple modified Bentall technique for surgical reconstruction of the aortic root - short and long term outcomes. AB - BACKGROUND: Since the first introduction of the Bentall technique, several modifications have been proposed to improve patient outcomes and decrease intra- and post-operative complications. We describe a simplified modification of the technique that tries to lessen the intra-operative time, improve homeostasis and miminize early and late complications. Our experience with the technique and short- and long-term patient outcomes are reported. METHODS: From August 1996 to October 2013, 110 consecutive patients underwent this modified technique. The procedure used Dacron composite graft with a mechanical valve (St. Jude Medical(r)) for aortic root replacement. To avoid intra-operative complications, no mobilization of coronary ostia was done. Additionally, the tubular aorta was kept minimally unchanged. RESULTS: Total bleeding after the operation was 450 +/- 105 mL. The mean duration of intensive care unit and hospital stay were 2 +/- 1 and 5 +/- 2 days, respectively. Sixty-six patients (60 %) were discharged from the surgical intensive care unit on the first postoperative day, 34 patients (30.9 %) were discharged on the second day and ten patients (9.1 %) needed more time to stay in the intensive care unit due to haemodynamic or respiratory problems. At 5-years follow up, survival rate was 97 %. In the three deceased patients, causes of death were mediastinitis, sepsis and myocardial infarction. No operation-related complications such as anticoagulant-related hemorrhage, valve or graft thrombosis, or coronary pseudoaneurysm were occurred during follow up. CONCLUSIONS: The proposed modification of the Bentall technique seems to minimize late intra-operative blood loss, improves homeostasis, shortens the operation time and is associated with excellent long-term outcomes in patients undergoing composite graft replacement of the aortic root. PMID- 26502873 TI - Do citation trends reflect epidemiologic patterns? Assessing MRSA, emerging and re-emerging pathogens, 1963-2014. AB - BACKGROUND: A rapid rise in PubMed citations on methicillin-resistant Staphylococcus aureus (MRSA) occurred after 2000, but the relationship of trends in citation to epidemiologic trends for infectious disease is not known. METHODS: We queried PubMed(R), for citations to the following: MRSA, HIV/AIDS, Staphylococcus aureus, severe acute respiratory syndrome, Lyme disease, avian influenza, West Nile virus, Chikungunya, Ebola virus and Middle Eastern respiratory syndrome. Incidence or mortality data were tabulated. RESULTS: We identified 560,225 citations in 1963-2014. There were two distinct qualitative citation patterns. Type I pathogens showed a decade of initial exponential growth. Type II pathogens showed a sudden spike in citations in a year or two, followed by a relative decline. MRSA most closely resembled a Type I pathogen. CONCLUSIONS: The Type I pattern pathogens had varied trends in disease incidence in the years following the exponential growth and subsequent decline in the number of citations. Their differing epidemiologic patterns did not correlate with their pattern of citations. We conclude that citation trends on MRSA cannot be used to determine past epidemiologic trends and also that the citation trend for MRSA in 1995-2011 most closely resembled that for HIV in 1981-1998. PMID- 26502874 TI - Fatty acid kinase A is an important determinant of biofilm formation in Staphylococcus aureus USA300. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA)-USA300 is notorious for its ability to cause community- and healthcare-acquired infections, which are even more difficult to treat when associated with a biofilm phenotype. We aimed to characterize the genetic determinants of biofilm formation in a USA300 skin abscess isolate (UAS391) that formed prolific biofilms. METHODS: USA300 S. aureus strains, TCH1516 and FPR3757, were found to be closely related based on whole genome mapping (ArgusTM Optical Mapping System, Opgen Inc, Gaithersburg, USA) to UAS391 (96.3-99.1 % similarity, P=0.0151), however differed markedly in biofilm formation (P=0.0001) on a dynamic assay (BioFlux 200, Fluxion Biosciences, USA). Comparison of whole genome sequences of these strains identified differences in a total of 18 genes. Corresponding Tn (bursa aurealis bearing) knockout mutants in these target genes were obtained from a publicly available mutant library of the same clonal lineage (USA300-JE2) and were characterized phenotypically for biofilm formation. Tn mutants showing significant differences in biofilm formation were utilized for transduction into a plasmid-cured erythromycin-sensitive derivative of UAS391 and for complementation experiments. All strains were tested on the dynamic assay, and 17h-biofilms were stained (SYTO9, Life Technologies) and fluorescence intensity quantified by microscopy (Zeiss, ImageJ). Gene expression levels in Tn and transduced mutants were studied by quantitative reverse transcriptase PCR (StepOnePlusTM, Applied Biosystems(r)). RESULTS: Comparison of the sequenced genomes of TCH1516, FPR3757 and UAS391 yielded a limited number of variant genes (n=18) that were hypothesized to account for the observed difference in biofilm forming capacity. Screening of Tn mutants disrupted in these target genes identified one mutant (NE229) bearing a transposon insertion in SAUSA300_1119 (fakA), which exhibited increased biofilm formation similar to UAS391 (P=0.9320). Transduction experiments confirmed that fakA::Tn corresponded to 1.9- to 4.6-fold increase in biofilm formation depending on the USA300 strain background (P<=0.0007), while complementation of the TCH1516 wild-type fakA allele in UAS391 resulted in a 4.3-fold reduction in biofilm formation (P<0.0001). CONCLUSIONS: This sequential approach, consisting of strain typing, genome comparison and functional genomics, identified fakA, a recently described fatty acid kinase in S. aureus that is essential for phospholipid synthesis and also impacts the transcription of numerous virulence factors, as a negative regulator of biofilm formation in S. aureus USA300. PMID- 26502875 TI - Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response. AB - BACKGROUND: Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. METHODS: Large scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2 (-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures. RESULTS: Expression of Cr2 in naive spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA. CONCLUSIONS: These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects. PMID- 26502876 TI - A prospective pilot study of detection of sentinel lymph nodes in gynaecological cancers using a novel near infrared fluorescence imaging system. AB - BACKGROUND: Sentinel Lymph Node (SLN) sampling may significantly reduce surgical morbidity by avoiding needless radical lymphadenectomy. In gynaecological cancers, the current practice in the UK is testing the accuracy of SLN detection using radioactive isotopes within the context of clinical trials. However, radioactive tracers pose significant logistic problems. We, therefore, conducted a pilot, observational study to assess the feasibility of a novel optical imaging device for SLN detection in gynaecological cancers using near infrared (NIR) fluorescence. METHODS: A novel, custom-made, optical imaging system was developed to enable detection of multiple fluorescence dyes and allow simultaneous bright field imaging during open surgery and laparoscopic procedures. We then evaluated the performance of the system in a prospective study of 49 women with early stage vulval, cervical and endometrial cancer who were scheduled to undergo complete lymphadenectomy. Clinically approved fluorescent contrast agents indocyanine green (ICG) and methylene blue (MB) were used. The main outcomes of the study included SLN mapping detection rates, false negative rates using the NIR fluorescence technique and safety of the procedures. We also examined the association between injection sites and differential lymphatic drainage in women with endometrial cancer by fluorescence imaging of ICG and MB. RESULTS: A total of 64 SLNs were detected during both open surgery and laparoscopy. Following dose optimisation and the learning phase, SLN detection rate approached 100 % for all cancer types with no false negatives detected. Fluorescence from ICG and MB detected para-aortic SLNs in women with endometrial cancer following uterine injection. Percutaneous SLN detection was also achieved in most women with vulval cancer. No adverse reactions associated with the use of either dyes were observed. CONCLUSIONS: This study demonstrated the successful clinical application of a novel NIR fluorescence imaging system for SLN detection across different gynaecological cancers. We showcased the first in human imaging, during the same procedure, of two fluorescence dyes in women with endometrial cancer. PMID- 26502878 TI - Multiplex PCR for detection of the Vibrio genus and five pathogenic Vibrio species with primer sets designed using comparative genomics. AB - BACKGROUND: The genus Vibrio is clinically significant and major pathogenic Vibrio species causing human Vibrio infections are V. cholerae, V. parahaemolyticus, V. vulnificus, V. alginolyticus and V. mimicus. In this study, we screened for novel genetic markers using comparative genomics and developed a Vibrio multiplex PCR for the reliable diagnosis of the Vibrio genus and the associated major pathogenic Vibrio species. METHODS: A total of 30 Vibrio genome sequences were subjected to comparative genomics, and specific genes of the Vibrio genus and five major pathogenic Vibrio species were screened. The designed primer sets from the screened genes were evaluated by single PCR using DNAs from various Vibrio spp. and other non-Vibrio bacterial strains. A sextuplet multiplex PCR using six primer sets was developed to enable detection of the Vibrio genus and five pathogenic Vibrio species. RESULTS: The designed primer sets from the screened genes yielded specific diagnostic results for target the Vibrio genus and Vibrio species. The specificity of the developed multiplex PCR was confirmed with various Vibrio and non-Vibrio strains. This Vibrio multiplex PCR was evaluated using 117 Vibrio strains isolated from the south seashore areas in Korea and Vibrio isolates were identified as Vibrio spp., V. parahaemolyticus, V. vulnificus and V. alginolyticus, demonstrating the specificity and discriminative ability of the assay towards Vibrio species. CONCLUSIONS: This novel multiplex PCR method could provide reliable and informative identification of the Vibrio genus and major pathogenic Vibrio species in the food safety industry and in early clinical treatment, thereby protecting humans against Vibrio infection. PMID- 26502879 TI - Non-participation in breast cancer screening for women with chronic diseases and multimorbidity: a population-based cohort study. AB - BACKGROUND: Chronic diseases and multimorbidity are common in western countries and associated with increased breast cancer mortality. This study aims to investigate non-participation in breast cancer screening among women with chronic diseases and multimorbidity and the role of time in this association. METHOD: This population-based cohort study used regional and national registries. Women who were invited to the first breast cancer screening round in the Central Denmark Region in 2008-09 were included (n = 149,234). Selected chronic diseases and multimorbidity were assessed up to 10 years before the screening date. Prevalence ratios (PR) were used as an association measure. RESULTS: The results indicated that women with at least one chronic condition were significantly more likely not to participate in breast cancer screening. In adjusted analysis, a significantly higher likelihood of non-participation was found for women with cancer (PR = 1.50, 95% CI: 1.40-1.60), mental illness (PR = 1.51, 95% CI: 1.42 1.60), chronic obstructive pulmonary disease (PR = 1.51, 95% CI: 1.42-1.62), neurological disorders (PR = 1.24, 95% CI: 1.12-1.37) and kidney disease (PR = 1.70, 95% CI 1.49-1.94), whereas women with chronic bowel disease (PR = 0.75, 95% CI 0.65-0.88) were more likely to participate than women without these disease. Multimorbidity was associated with increased non-participation likelihood. E.g. having 3 or more diseases was associated with 58% increased non-participation likelihood (95% CI: 27-96%). Higher non-participation was also observed for women with severe multimorbidity (PR = 1.53, 95% CI: 1.23-1.90) and mental-physical multimorbidity (PR = 1.54, 95% CI: 1.36-1.75). CONCLUSION: In conclusion, we found a strong association between non-participation in breast cancer screening for some chronic diseases and for multimorbidity. The highest propensity not to participate was observed for women with hospital contacts related to the chronic disease in the period closest to the screening date. PMID- 26502880 TI - A novel nasal powder formulation of glucagon: toxicology studies in animal models. AB - BACKGROUND: Glucagon nasal powder (GNP), a novel intranasal formulation of glucagon being developed to treat insulin-induced severe hypoglycemia, contains synthetic glucagon (10% w/w), beta-cyclodextrin, and dodecylphosphocholine. The safety of this formulation was evaluated in four studies in animal models. METHODS: The first study evaluated 28-day sub-chronic toxicology in rats treated intranasally with 1 and 2 mg of GNP/day (0.1 and 0.2 mg glucagon/rat/day). The second study evaluated 28-day sub-chronic toxicology in dogs administered 20 and 40 mg of formulation/dog/day (2 and 4 mg glucagon/dog/day) intranasally. A pulmonary insufflation study assessed acute toxicology following intra-tracheal administration of 0.5 mg of GNP (0.05 mg glucagon) to rats. Local tolerance to 30 mg of GNP (equivalent to 3 mg glucagon, the final dose for humans) was tested through direct administration into the eyes of rabbits. RESULTS: There were no test article-related adverse effects on body weight and/or food consumption, ophthalmology, electrocardiography, hematology, coagulation parameters, clinical chemistry, urinalysis, or organ weights, and no macroscopic findings at necropsy in any study. In rats, direct intra-tracheal insufflation at a dose of 0.5 mg of GNP/rat (0.05 mg glucagon/rat) did not result in adverse clinical, macroscopic, or microscopic effects. In dogs, the only adverse findings following sub-chronic use were transient (<30 s) salivation and sneezing immediately post-treatment and mild to moderate reversible histological changes to the nasal mucosa. Daily dosing over 28 days in rats resulted in mild to moderate, unilateral or bilateral erosion/ulceration of the olfactory epithelium, frequently with minimal to mild, acute to sub-acute inflammation of the lamina propria at the dorsal turbinates of the nasal cavity in 2/10 males and 3/10 females in the high-dose group (0.2 mg glucagon/day). These lesions resolved completely over 14 days. Histological examination of tissues from both sub-chronic studies in dogs and rats revealed no microscopic findings. In rabbits, clinical observations noted in the GNP-treated eye and/or surrounding areas included >=1 of the following: clear discharge, red conjunctiva, partial closure, and swelling of the peri-orbital area, which correlated with erythema and edema noted during ocular observations and grading. DISCUSSION: The studies reported here revealed no safety concerns associated with GNP in animal models. Studies published earlier have highlighted the local safety profile of intranasally administered cyclodextrins (a component of GNP). The choline group, the phosphate group, and the saturated 12-carbon aliphatic chain that are present in the dodecylphosphocholine excipient used in GNP are all present in the phospholipids and lecithins seen ubiquitously in mammalian cell membranes and are unlikely to pose safety concerns; this notion is supported by several studies conducted by the authors that revealed no safety concerns. Taken together, these results suggest that intranasal delivery of GNP holds promise as a future rescue medication for use by caregivers to treat insulin-induced hypoglycemic episodes in patients with type 1 or type 2 diabetes. CONCLUSION: This novel drug product is well tolerated in animal models. PMID- 26502877 TI - Inflammatory mediators in intra-abdominal sepsis or injury - a scoping review. AB - INTRODUCTION: Inflammatory and protein mediators (cytokine, chemokine, acute phase proteins) play an important, but still not completely understood, role in the morbidity and mortality of intra-abdominal sepsis/injury. We therefore systematically reviewed preclinical and clinical studies of mediators in intra abdominal sepsis/injury in order to evaluate their ability to: (1) function as diagnostic/prognostic biomarkers; (2) serve as therapeutic targets; and (3) illuminate the pathogenesis mechanisms of sepsis or injury-related organ dysfunction. METHODS: We searched MEDLINE, PubMed, EMBASE and the Cochrane Library. Two investigators independently reviewed all identified abstracts and selected articles for full-text review. We included original studies assessing mediators in intra-abdominal sepsis/injury. RESULTS: Among 2437 citations, we selected 182 studies in the scoping review, including 79 preclinical and 103 clinical studies. Serum procalcitonin and C-reactive protein appear to be useful to rule out infection or monitor therapy; however, the diagnostic and prognostic value of mediators for complications/outcomes of sepsis or injury remains to be established. Peritoneal mediator levels are substantially higher than systemic levels after intra-abdominal infection/trauma. Common limitations of current studies included small sample sizes and lack of uniformity in study design and outcome measures. To date, targeted therapies against mediators remain experimental. CONCLUSIONS: Whereas preclinical data suggests mediators play a critical role in intra-abdominal sepsis or injury, there is no consensus on the clinical use of mediators in diagnosing or managing intra-abdominal sepsis or injury. Measurement of peritoneal mediators should be further investigated as a more sensitive determinant of intra-abdominal inflammatory response. High-quality clinical trials are needed to better understand the role of inflammatory mediators. PMID- 26502881 TI - Predictability of epidemic malaria under non-stationary conditions with process based models combining epidemiological updates and climate variability. AB - BACKGROUND: Previous studies have demonstrated the feasibility of early-warning systems for epidemic malaria informed by climate variability. Whereas modelling approaches typically assume stationary conditions, epidemiological systems are characterized by changes in intervention measures over time, at scales typically longer than inter-epidemic periods. These trends in control efforts preclude simple application of early-warning systems validated by retrospective surveillance data; their effects are also difficult to distinguish from those of climate variability itself. METHODS: Rainfall-driven transmission models for falciparum and vivax malaria are fitted to long-term retrospective surveillance data from four districts in northwest India. Maximum-likelihood estimates (MLEs) of model parameters are obtained for each district via a recently introduced iterated filtering method for partially observed Markov processes. The resulting MLE model is then used to generate simulated yearly forecasts in two different ways, and these forecasts are compared with more recent (out-of-fit) data. In the first approach, initial conditions for generating the predictions are repeatedly updated on a yearly basis, based on the new epidemiological data and the inference method that naturally lends itself to this purpose, given its time sequential application. In the second approach, the transmission parameters themselves are also updated by refitting the model over a moving window of time. RESULTS: Application of these two approaches to examine the predictability of epidemic malaria in the different districts reveals differences in the effectiveness of intervention for the two parasites, and illustrates how the 'failure' of predictions can be informative to evaluate and quantify the effect of control efforts in the context of climate variability. The first approach performs adequately, and sometimes even better than the second one, when the climate remains the major driver of malaria dynamics, as found for Plasmodium vivax for which an effective clinical intervention is lacking. The second approach offers more skillful forecasts when the dynamics shift over time, as is the case of Plasmodium falciparum in recent years with declining incidence under improved control. CONCLUSIONS: Predictive systems for infectious diseases such as malaria, based on process-based models and climate variables, can be informative and applicable under non-stationary conditions. PMID- 26502882 TI - Is a picture worth a thousand words: an analysis of the difficulty and discrimination parameters of illustrated vs. text-alone vignettes in histology multiple choice questions. AB - BACKGROUND: Advances in cognitive load theory have led to greater understanding of how we process verbal and visual material during learning, but the evidence base with regard to the use of images within written assessments is still sparse. This study examines whether the inclusion of images within the stimulus format of multiple choice questions (MCQs) has a predictable or consistent influence on psychometric item properties, such as difficulty or discrimination. METHODS: Item analysis data from three consecutive years of histology multiple choice examinations were included in this study. All items were reviewed and categorised according to whether their stem, or stimulus format, was purely textual or included an associated image. RESULTS: A total of 195 MCQs were identified for inclusion and analysed using classical test theory; 95 used text alone and 100 included an image within the question stem. The number of students per examination ranged from 277 to 347, with a total of 60,850 student-question interactions. We initially examined whether the inclusion of an image within the item stem altered the item difficulty using Mann-Whitney U. The median item difficulty for images with purely textual stems was 0.77, while that for items incorporating an appropriate image was 0.80; this difference was not significant (0.77 vs. 0.80; p = 0.862, Mann-Whitney-U = 4818.5). Mean values showed that the Item Discrimination Index appeared unaffected by the inclusion of an image within the stem, and Item point biserial correlation also showed no difference in means between these two groups (Independent samples t-test; 2-tailed). CONCLUSION: We demonstrate that the addition of illustrations within undergraduate histology Multiple Choice Question stems has no overall influence on item difficulty, or measures of item discrimination. We conclude that the use of images in this context is statistically uncritical, and suggest that their inclusion within item stems should be based upon the principles of constructive alignment. However, further research with respect to the effect of images within item stems on cognitive processing, particularly with regard to image complexity or type, would enable the development of more informed guidelines for their use. PMID- 26502883 TI - Coronary artery size and origin imaging in children: a comparative study of MRI and trans-thoracic echocardiography. AB - BACKGROUND: The purpose of this study was to see how coronary magnetic resonance angiography (CMRA) compared to echocardiography for the detection of coronary artery origins and to compare CMRA measurements for coronary dimensions in children with published echocardiographic reference values. METHODS: Enrolled patients underwent dual cardiac phase CMRA and echocardiography under the same anesthetic. Echocardiographic measurements of the right coronary artery (RCA), left anterior descending (LAD) and left main (LM) were made. CMRA dimensions were assessed manually at the same points as the echocardiographic measurements. The number of proximal LAD branches imaged was also recorded in order to give an estimate of distal coronary tree visualization. RESULTS: Fifty patients (24 boys, mean age 4.0 years (range 18 days to 18 years)) underwent dual-phase CMRA. Coronary origins were identified in 47/50 cases for CMRA (remaining 3 were infants aged 3, 9 and 11 months). In comparison, origins were identified in 41/50 cases for echo (remaining were all older children). CMRA performed better than echocardiography in terms of distal visualization of the coronary tree (median 1 LAD branch vs. median 0; p = 0.001). Bland-Altman plots show poor agreement between echocardiography and CMRA for coronary measurements. CMRA measurements did vary according to cardiac phase (systolic mean 1.90, s.d. 0.05 mm vs. diastolic mean 1.84, s.d. 0.05 mm; p = 0.002). CONCLUSIONS: Dual-phase CMRA has an excellent (94 %) success rate for the detection of coronary origins in children. Newborn infants remain challenging and echocardiography remains the accepted imaging modality for this age group. Echocardiographic reference ranges are not applicable to CMRA measurements as agreement was poor between modalities. Future coronary reference values, using any imaging modality, should quote the phase in which it was measured. PMID- 26502884 TI - Idiopathic lung fibrosis and anti myeloperoxidase glomerulonephritis: the tree that hides the forest. AB - BACKGROUND: Although anti-neutrophil cytoplasmic antibodies [ANCA] are frequently found in patients diagnosed with idiopathic pulmonary fibrosis [IPF], current guidance does not recommend serologic testing for vasculitis. CASE PRESENTATION: A 71-year old Caucasian male, diagnosed with IPF three years earlier, presented with rapidly progressive glomerulonephritis. ANCA were found both in current and historical sera. A kidney biopsy sample was taken, which revealed a pauci-immune glomerulonephritis, but also areas of glomerular fibrosis, hence strongly suggesting unrecognized flares of an indolent vasculitis in his past. This made the diagnosis of "idiopathic" pulmonary fibrosis very unlikely. CONCLUSION: As nephrologists, we argue that testing for ANCA should be performed on a systematic basis, at least in elderly patients, even in the absence of extra-pulmonary signs of vasculitis at presentation. PMID- 26502885 TI - Improving Heat Transfer at the Bottom of Vials for Consistent Freeze Drying with Unidirectional Structured Ice. AB - The quality of lyophilized products is dependent of the ice structure formed during the freezing step. Herein, we evaluate the importance of the air gap at the bottom of lyophilization vials for consistent nucleation, ice structure, and cake appearance. The bottom of lyophilization vials was modified by attaching a rectified aluminum disc with an adhesive material. Freezing was studied for normal and converted vials, with different volumes of solution, varying initial solution temperature (from 5 degrees C to 20 degrees C) and shelf temperature (from -20 degrees C to -40 degrees C). The impact of the air gap on the overall heat transfer was interpreted with the assistance of a computational fluid dynamics model. Converted vials caused nucleation at the bottom and decreased the nucleation time up to one order of magnitude. The formation of ice crystals unidirectionally structured from bottom to top lead to a honeycomb-structured cake after lyophilization of a solution with 4% mannitol. The primary drying time was reduced by approximately 35%. Converted vials that were frozen radially instead of bottom-up showed similar improvements compared with normal vials but very poor cake quality. Overall, the curvature of the bottom of glass vials presents a considerable threat to consistency by delaying nucleation and causing radial ice growth. Rectifying the vials bottom with an adhesive material revealed to be a relatively simple alternative to overcome this inconsistency. PMID- 26502887 TI - Malaria vaccine difficult to roll out because four doses are needed, WHO says. PMID- 26502886 TI - Curcumin Affects Phase II Disposition of Resveratrol Through Inhibiting Efflux Transporters MRP2 and BCRP. AB - PURPOSE: To evaluate the impact of curcumin on the disposition of resveratrol phase II metabolites in vivo, and explain the observations by performing in vitro studies in transporter-overexpressed cells. METHODS: Pharmacokinetic studies of resveratrol with and without the co-administration of curcumin were performed in both FVB wild-type and Bcrp1 (-/-) mice. Human UGT1A9-overexpressing HeLa cells and human MRP2-overexpressing MDCK II-UGT1A1 cells were used as in vitro tools to further determine the impact of curcumin as a transporter inhibitor on resveratrol metabolites. RESULTS: We observed higher exposure of resveratrol conjugates in Bcrp1 (-/-) mice compared to wild-type mice. In wild-type mice, curcumin increased the AUC of resveratrol glucuronide by 4-fold compared to the mice treated without curcumin. The plasma levels of resveratrol and its sulfate conjugate also increased moderately. In Bcrp1 (-/-) mice, there was a further increase (6-fold increase) in AUC of resveratrol glucuronide observed when curcumin was co-administered compared to AUC values obtained in wild-type mice without curcumin treatment. In the presence of 50 nM curcumin, the clearance of resveratrol-3-O-glucuronide and resveratrol-3-O-sulfate reduced in both MRP2 overexpressing MDCKII-UGT1A1 cells and Human UGT1A9-overexpressing HeLa cells. CONCLUSIONS: These results suggest that curcumin alters the phase II distribution of resveratrol through inhibiting efflux transporters including MRP2 and BCRP. PMID- 26502888 TI - [Drug assessment: IQWiG, G-BA, and an international comparison]. AB - BACKGROUND: Since the Pharmaceutical Market Restructuring Act (Arzneimittelmarktneuordnungsgesetz-AMNOG) went into effect on 1 January 2011, new medicinal products provided under statutory health insurance have to undergo an early benefit assessment, prepared on the basis of scientific dossiers drawn up by the German Institute for Quality and Cost Effectiveness in the Health Care Sector (Institut fur Qualitat und Wirtschaftlichkeit im Gesundheitswesen-IQWiG) and adopted by the Federal Joint Committee (Gemeinsamer Bundesausschuss-G-BA). These assessments, in which the additional benefit of a product is compared with existing standard therapy and ultimately has a bearing on price negotiations with the pharmaceutical companies, are carried out on the basis of clinical trial data presented by the latter. Results so far, however, show that the IQWIG's and the G BA's assessments often vary, although both bodies have the same documentation. Such differences can also be observed on an international level. OBJECTIVES: Using selected examples, the differences in the assessments of new pharmaceuticals are presented and reasons for national and international deviations are discussed. CURRENT DATA: As yet, no systematic comparative analysis has been made of assessments of medicinal products by the respective institutions. For this reason, it was not possible to make a systematic selection of pharmaceuticals, and the cases were instead selected according to available information. CONCLUSIONS: An overview of the results shows that the diverging assessments-both national and international-are not always scientifically justifiable, but rather appear to be influenced by the-not always transparent framework parameters of the respective health system. Assessments are always shaped by certain perspectives on the data and results under scrutiny. It would undoubtedly be worthwhile to evaluate these influences to gain a better understanding of the reasons for national and international discrepancies in the assessment of additional therapeutic value of new pharmaceutical products. PMID- 26502889 TI - Hesperetin Liposomes for Cancer Therapy. AB - Hesperetin is a compound from citrus fruit that has previously been found to exert anticancer activity through a variety of mechanisms. However, the application of hesperetin to cancer therapy has been hampered by its hydrophobicity, necessitating the use of toxic solubilizing agents. Here, we have developed the first liposome-based delivery system for hesperetin. Liposomes were fabricated using the thin-layer evaporation technique and physical and pharmacological parameters were measured. The liposomes remained stable for prolonged periods of time in serum and under storage conditions, and displayed anticancer efficacy in both H441 lung cancer cells and MDA-MB-231 breast cancer cells. Furthermore, the anticancer activity was not impaired in cells expressing the multidrug resistance protein 1 (MDR-1). In conclusion, the encapsulation of hesperetin in liposomes does not interfere with therapeutic efficacy and provides a biocompatible alternative to toxic solubilizing agents, thereby enabling future clinical use of this compound for cancer therapy. PMID- 26502890 TI - New Thermoresponsive Eyedrop Formulation Containing Ibuprofen Loaded Nanostructured Lipid Carriers (NLC): Development, Characterization and Biocompatibility Studies. AB - The low bioavailability and consequently the poor therapeutic response of traditional ophthalmic formulations is caused by reduced pre-corneal residence time of the formulation in contact with the ocular surface. The use of colloidal carrier systems, namely lipid nanoparticles in combination with in situ gelling polymers, is an excellent strategy which results in the exponential increase of the bioavailability of ophthalmic drugs. In the present study, we have developed thermoresponsive eyedrops prepared with nanostructured lipid carriers (NLC) dispersions for the controlled delivery of ibuprofen. Lipid solubility studies and DSC measurements have proved that the lipids solubilise ibuprofen and present a good compatibility. NLC were prepared based on the melt-emulsification and ultrasonication technique and lipid nanoparticles with a Z-average of 120-150 nm, polydispersity index below 0.3, highly positive zeta potential and an efficacy of encapsulation of ~87% were obtained. The cytotoxicity of NLC was evaluated by the Alamar Blue reduction assay using the Y-79 human retinoblastoma cell line, and no relevant toxicity was observed after exposure to 0-100 MUg/mL NLC for up to 72 hours. The HET-CAM assay was used to assess the product eye compatibility, confirming that the developed product does not exhibit irritant potential. The in vitro release studies showed ibuprofen release over several hours. PMID- 26502891 TI - A review of research on direct-care staff data collection regarding the severity and function of challenging behavior in individuals with intellectual and developmental disabilities. AB - In working with individuals with intellectual and developmental disabilities (IDDs), it is direct care staff who are often required to collect data on individuals' behavior which is used as the basis for implementation of empirically based approaches for intervention and treatment. Due to limited resources, indirect and descriptive measures of challenging behaviors are employed to analyze the function of individuals' behaviors in place of the preferred method of multimodal assessment, which includes experimental functional analysis. To ensure the most effective services and support to individuals with IDDs, accurate and consistent data collection is critical. In this article, we highlight the importance of accurate data collection practices, conduct a comparison of data collection methods, and discuss limitations .... and barriers for staff. The article concludes with recommendations for best practices and future research. PMID- 26502892 TI - Acetylation dynamics and stoichiometry in Saccharomyces cerevisiae. PMID- 26502893 TI - Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications. AB - Neurodevelopmental disorders (NDs) encompass a spectrum of neuropsychiatric manifestations. Chromosomal regions 1q21.1, 3q29, 15q11.2, 15q13.3, 16p11.2, 16p13.1 and 22q11 harbour rare but recurrent CNVs that have been uncovered as being important risk factors for several of these disorders. These rearrangements may underlie a broad phenotypical spectrum, ranging from normal development, to learning problems, intellectual disability (ID), epilepsy and psychiatric diseases, such as autism spectrum disorders (ASDs) and schizophrenia (SZ). The highly increased risk of developing neurodevelopmental phenotypes associated with some of these CNVs makes them an unavoidable element in the clinical context in paediatrics, neurology and psychiatry. However, and although finding these risk loci has been the goal of neuropsychiatric genetics for many years, the translation of this recent knowledge into clinical practice has not been trivial. In this article, we will: (1) review the state of the art on recurrent CNVs associated with NDs, namely ASD, ID, epilepsy and SZ; (2) discuss the models used to dissect the underlying neurobiology of disease, (3) discuss how this knowledge can be used in clinical practice. PMID- 26502895 TI - Growth of Hollow Transition Metal (Fe, Co, Ni) Oxide Nanoparticles on Graphene Sheets through Kirkendall Effect as Anodes for High-Performance Lithium-Ion Batteries. AB - A general strategy based on the nanoscale Kirkendall effect has been developed to grow hollow transition metal (Fe, Co or Ni) oxide nanoparticles on graphene sheets. When applied as lithium-ion battery anodes, these hollow transition metal oxide-based composites exhibit excellent electrochemical performance, with high reversible capacities and long-term stabilities at a high current density, superior to most transition metal oxides reported to date. PMID- 26502896 TI - beta-Asarone inhibits gastric cancer cell proliferation. AB - beta-Asarone is the main volatile oil of Chinese herb Rhizoma Acori Tatarinowii. It exhibits a wide range of biological activities in many human organs. However, few studies have investigated the effect of beta-asarone on gastric cancer. The present study investigated the effect of beta-asarone on the proliferation and apoptosis of three types of differentiated human gastric cancer cell lines (SGC 7901, BGC-823 and MKN-28) in vitro as well as the related molecular mechanisms. Methyl thiazolyl tetrazolium assay, Annexin V/PI double staining, immunofluorescence test and transmission electron microscopy all confirmed that beta-asarone had an obvious dose-dependent inhibitive effect on the proliferation of human gastric cancer cells and induced apoptosis of the cell lines. Transwell invasion, wound-healing and matrix-cell adhesion experiments confirmed that beta asarone inhibited the invasion, migration and adhesion of human gastric cancer BGC-823 cells. Quantitative real-time PCR and western blotting found that beta asarone significantly activated caspase-3, caspase-8, caspase-9, Bax, Bak and suppressed Bcl-2, Bcl-xL and survivin activity. Moreover, beta-asarone increased the expression of RECK, E-cadherin and decreased the expression of MMP-2, MMP-9, MMP-14 and N-cadherin. The present study demonstrated that beta-asarone effectively inhibits the proliferation of human gastric cancer cells, induces their apoptosis and decreased the invasive, migratory and adhesive abilities. PMID- 26502897 TI - "It's natural to look for a source": A qualitative examination of alternative beliefs about HIV and AIDS in Cape Town, South Africa. AB - This article highlights how African men and women in South Africa account for the plausibility of alternative beliefs about the origins of HIV and the existence of a cure. This study draws on the notion of a "street-level epistemology of trust" knowledge generated by individuals through their everyday observations and experiences-to account for individuals' trust or mistrust of official claims versus alternative explanations about HIV and AIDS. Focus group respondents describe how past experiences, combined with observations about the power of scientific developments and perceptions of disjunctures in information, fuel their uncertainty and skepticism about official claims. HIV prevention campaigns may be strengthened by drawing on experiential aspects of HIV and AIDS to lend credibility to scientific claims, while recognizing that some doubts about the trustworthiness of scientific evidence are a form of skeptical engagement rather than of outright rejection. PMID- 26502894 TI - A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement. AB - BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824. PMID- 26502898 TI - Synthesis of Naphthyl-, Quinolin- and Anthracenyl Analogues of Clofibric Acid as PPARalpha Agonists. AB - PPARalpha is a ligand activated transcription factor belonging to the nuclear receptor subfamily, involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPARalpha activation is important in steatosis, inflammation and fibrosis in preclinical models of non alcoholic fatty liver disease identifying a new potential therapeutic area. In this work, three series of clofibric acid analogues conjugated with naphthyl, quinolin, chloroquinolin and anthracenyl scaffolds were synthesized. In an effort to obtain new compounds active as PPARalpha agonists, these molecules were evaluated for PPARalpha transactivation activity. Naphthyl and quinolin derivatives showed a good activation of PPARalpha; noteworthy, optically active naphthyl derivatives activated PPARalpha better than corresponding parent compound. PMID- 26502899 TI - Efficacy and safety of abacavir-containing combination antiretroviral therapy as first-line treatment of HIV infected children and adolescents: a systematic review and meta-analysis. AB - BACKGROUND: Abacavir is one of the recommended nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infections among children and adolescents. However, there are concerns that the antiviral efficacy of abacavir might be low when compared to other NRTIs especially among children. There are also concerns that abacavir use may lead to serious adverse events such as hypersensitivity reactions and has potential predisposition to developing cardiovascular diseases METHODS: We searched four electronic databases, four conference proceedings and two clinical trial registries in August 2014, without language restrictions. Experimental and observational studies with control groups that examined the efficacy and safety of abacavir-containing regimens in comparison with other NRTIs as first-line treatment for HIV-infected children and adolescents aged between one month and eighteen years were eligible. Two authors independently screened search results, extracted data and assessed the risk of bias of included studies using a pre-specified, standardised data extraction form and validated risk of bias tools. We also assessed the quality of evidence per outcome with the GRADE tool. RESULTS: We included two randomised controlled trials (RCTs) and two analytical cohort studies with a total of 10,595 participants. Among the RCTs we detected no difference in virologic suppression after a mean duration of 48 weeks between abacavir- and stavudine-containing regimens (2 trials; n = 326: RR 1.28; 95 % CI 0.67-2.42) with significant heterogeneity (P = 0.02; I(2) = 81 %). We also found no significant differences between the two groups for adverse events and death. After five years of follow up, virologic suppression improved with abacavir (1 trial; n = 69: RR 1.96; 95 % CI 1.11-3.44). For cohort studies, we detected that the virologic suppression activity of abacavir was less effective than stavudine in both the lopinavir/ritonavir (1 study, n = 2165: RR 0.79, 95 % CI 0.67-0.92) and efavirenz sub-groups (1 study, n = 3204: RR 0.79, 95 % CI 0.67-0.92) respectively. The quality of evidence from RCTs was moderate for virologic suppression but low for death and adverse events, while that of cohort studies was low for all three these outcomes. CONCLUSIONS: Available evidence showed little or no difference between abacavir-containing regimen and other NRTIs regarding efficacy and safety when given to children and adolescents as a first-line antiretroviral therapy. PMID- 26502900 TI - Phosphomannomutase deficiency (PMM2-CDG): ataxia and cerebellar assessment. AB - BACKGROUND: Phosphomannomutase deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. The cerebellum is nearly always affected in PMM2-CDG patients, a cerebellar atrophy progression is observed, and cerebellar dysfunction is their main daily functional limitation. Different therapeutic agents are under development, and clinical evaluation of drug candidates will require a standardized score of cerebellar dysfunction. We aim to assess the validity of the International Cooperative Ataxia Rating Scale (ICARS) in children and adolescents with genetically confirmed PMM2-CDG deficiency. We compare ICARS results with the Nijmegen Pediatric CDG Rating Scale (NPCRS), neuroimaging, intelligence quotient (IQ) and molecular data. METHODS: Our observational study included 13 PMM2-CDG patients and 21 control subjects. Ethical permissions and informed consents were obtained. Three independent child neurologists rated PMM2 CDG patients and control subjects using the ICARS. A single clinician administered the NPCRS. All patients underwent brain MRI, and the relative diameter of the midsagittal vermis was measured. Psychometric evaluations were available in six patients. The Mann-Whitney U test was used to compare ICARS between patients and controls. To evaluate inter-observer agreement in patients' ICARS ratings, intraclass correlation coefficients (ICC) were calculated. ICARS internal consistency was evaluated using Cronbach's alpha. Spearman's rank correlation coefficient test was used to correlate ICARS with NPCRS, midsagittal vermis relative diameter and IQ. RESULTS: ICARS and ICARS subscores differed between patients and controls (p < 0.001). Interobserver agreement of ICARS was "almost perfect" (ICC = 0.99), with a "good" internal reliability (Cronbach's alpha = 0.72). ICARS was significantly correlated with the total NPCRS score (rs 0.90, p < 0.001). However, there was no agreement regarding categories of severity. Regarding neuroimaging, inverse correlations between ICARS and midsagittal vermis relative diameter (rs -0.85, p = 0.003) and IQ (rs -0.94, p = 0.005) were found. Patients bearing p.E93A, p.C241S or p.R162W mutations presented a milder phenotype. CONCLUSIONS: ICARS is a reliable instrument for assessment of PMM2-CDG patients, without significant inter-rater variability. Despite our limited sample size, the results show a good correlation between functional cerebellar assessment, IQ and neuroimaging. For the first a correlation between ICARS, neuroimaging and IQ in PMM2-CDG patients has been demonstrated. PMID- 26502901 TI - The Perchlorate Reduction Genomic Island: Mechanisms and Pathways of Evolution by Horizontal Gene Transfer. AB - BACKGROUND: Perchlorate is a widely distributed anion that is toxic to humans, but serves as a valuable electron acceptor for several lineages of bacteria. The ability to utilize perchlorate is conferred by a horizontally transferred piece of DNA called the perchlorate reduction genomic island (PRI). METHODS: We compared genomes of perchlorate reducers using phylogenomics, SNP mapping, and differences in genomic architecture to interrogate the evolutionary history of perchlorate respiration. RESULTS: Here we report on the PRI of 13 genomes of perchlorate-reducing bacteria from four different classes of Phylum Proteobacteria (the Alpha-, Beta-, Gamma- and Epsilonproteobacteria). Among the different phylogenetic classes, the island varies considerably in genetic content as well as in its putative mechanism and location of integration. However, the islands of the densely sampled genera Azospira and Magnetospirillum have striking nucleotide identity despite divergent genomes, implying horizontal transfer and positive selection within narrow phylogenetic taxa. We also assess the phylogenetic origin of accessory genes in the various incarnations of the island, which can be traced to chromosomal paralogs from phylogenetically similar organisms. CONCLUSION: These observations suggest a complex phylogenetic history where the island is rarely transferred at the class level but undergoes frequent and continuous transfer within narrow phylogenetic groups. This restricted transfer is seen directly by the independent integration of near-identical islands within a genus and indirectly due to the acquisition of lineage-specific accessory genes. The genomic reversibility of perchlorate reduction may present a unique equilibrium for a metabolism that confers a competitive advantage only in the presence of an electron acceptor, which although widely distributed, is generally present at low concentrations in nature. PMID- 26502902 TI - Latent HIV-1 is activated by exosomes from cells infected with either replication competent or defective HIV-1. AB - BACKGROUND: Completion of HIV life cycle in CD4(+) T lymphocytes needs cell activation. We recently reported that treatment of resting CD4(+) T lymphocytes with exosomes produced by HIV-1 infected cells induces cell activation and susceptibility to HIV replication. Here, we present data regarding the effects of these exosomes on cells latently infected with HIV-1. RESULTS: HIV-1 latently infecting U937-derived U1 cells was activated upon challenge with exosomes purified from the supernatant of U937 cells chronically infected with HIV-1. This effect was no more detectable when exosomes from cells infected with HIV-1 strains either nef-deleted or expressing a functionally defective Nef were used, indicating that Nef is the viral determinant of exosome-induced HIV-1 activation. Treatment with either TAPI-2, i.e., a specific inhibitor of the pro-TNFalpha processing ADAM17 enzyme, or anti-TNFalpha Abs abolished HIV-1 activation. Hence, similar to what previously demonstrated for the exosome-mediated activation of uninfected CD4(+) T lymphocytes, the Nef-ADAM17-TNFalpha axis is part of the mechanism of latent HIV-1 activation. It is noteworthy that these observations have been reproduced using: (1) primary CD4(+) T lymphocytes latently infected with HIV-1; (2) exosomes from both primary CD4(+) T lymphocytes and macrophages acutely infected with HIV-1; (3) co-cultures of HIV-1 acutely infected CD4(+) T lymphocytes and autologous lymphocytes latently infected with HIV-1, and (4) exosomes from cells expressing a defective HIV-1. CONCLUSIONS: Our results strongly suggest that latent HIV-1 can be activated by TNFalpha released by cells upon ingestion of exosomes released by infected cells, and that this effect depends on the activity of exosome-associated ADAM17. These pieces of evidence shed new light on the mechanism of HIV reactivation in latent reservoirs, and might also be relevant to design new therapeutic interventions focused on HIV eradication. PMID- 26502903 TI - Interactions of Streptococcus suis serotype 2 with human meningeal cells and astrocytes. AB - BACKGROUND: Streptococcus suis serotype 2 is an important porcine pathogen and emerging zoonotic agent responsible for meningitis, of which different sequence types predominate worldwide. Though bacterial meningitis is defined as an exacerbated inflammation of the meninges, the underlying astrocytes of the glia limitans superficialis may also be implicated. However, the interactions between this pathogen and human meningeal cells or astrocytes remain unknown. Furthermore, the roles of well-described virulence factors (capsular polysaccharide, suilysin and cell wall modifications) in these interactions have yet to be studied. Consequently, the interactions between S. suis serotype 2 and human meningeal cells or astrocytes were evaluated for the first time in order to better understand their involvement during meningitis in humans. RESULTS: Streptococcus suis serotype 2 adhered to human meningeal cells and astrocytes; invasion of meningeal cells was rare however, whereas invasion of astrocytes was generally more frequent. Regardless of the interaction or cell type, differences were not observed between sequence types. Though the capsular polysaccharide modulated the adhesion to and invasion of meningeal cells and astrocytes, the suilysin and cell wall modifications only influenced astrocyte invasion. Surprising, S. suis serotype 2 induced little or no inflammatory response from both cell types, but this absence of inflammatory response was probably not due to S. suis-induced cell death. CONCLUSIONS: Though S. suis serotype 2 interacted with human meningeal cells and astrocytes, there was no correlation between sequence type and interaction. Consequently, the adhesion to and invasion of human meningeal cells and astrocytes are strain-specific characteristics. As such, the meningeal cells of the leptomeninges and the astrocytes of the glia limitans superficialis may not be directly implicated in the inflammatory response observed during meningitis in humans. PMID- 26502904 TI - Revised algorithm for heparin anticoagulation during continuous renal replacement therapy. PMID- 26502905 TI - Preferential production of G-CSF by a protein-like Lactobacillus rhamnosus GR-1 secretory factor through activating TLR2-dependent signaling events without activation of JNKs. AB - BACKGROUND: Different species and strains of probiotic bacteria confer distinct immunological responses on immune cells. Lactobacillus rhamnosus GR-1 (GR-1) is a probiotic bacterial strain found in both the intestinal and urogenital tracts, and has immunomodulatory effects on several cell types including macrophages. However, detailed immunological responses and the signaling mechanism involved in the response are largely unknown. RESULTS: We examined the production of GR-1 induced cytokines/chemokines and signaling events in macrophages. Among 84 cytokines and chemokines examined, GR-1 discretely induced granulocyte colony stimulating factor (G-CSF) mRNA at highest levels (>60-fold) without inducing other cytokines such as IL-1alpha, IL-1beta, IL-6 and TNF-alpha (<5-fold). The toll-like receptor (TLR) 2/6-agonist PAM2CSK4, TLR2/1-agonist PAM3CSK4 and TLR4 agonist lipopolysaccharide induced all of these inflammatory cytokines at high levels (>50-fold). The TLR2 ligand lipoteichoic acid activated all mitogen activated kinases, Akt and NF-kappaB; whereas, GR-1 selectively activated extracellular regulated kinases and p38, NF-kappaB and Akt, but not c-Jun N terminal kinases (JNKs) in a TLR2-dependent manner. Using specific inhibitors, we demonstrated that lack of JNKs activation by GR-1 caused inefficient production of pro-inflammatory cytokines but not G-CSF production. A secreted heat-labile protein-like molecule, 30-100 kDa in size, induced the preferential production of G-CSF. CONCLUSION: This study elucidated unique signaling events triggered by GR 1, resulting in selective production of the immunomodulatory cytokine G-CSF in macrophages. PMID- 26502907 TI - Fimbria-Encoding Gene yadC Has a Pleiotropic Effect on Several Biological Characteristics and Plays a Role in Avian Pathogenic Escherichia coli Pathogenicity. AB - The extraintestinal pathogen termed avian pathogenic Escherichia coli (APEC) is known to cause colibacillosis in chickens. The molecular basis of APEC pathogenesis is not fully elucidated yet. In this work, we deleted a component of the Yad gene cluster (yadC) in order to understand the role of Yad in the pathogenicity of the APEC strain SCI-07. In vitro, the transcription level of yadC was upregulated at 41 degrees C and downregulated at 22 degrees C. The yadC expression in vivo was more pronounced in lungs than in spleen, suggesting a role in the early steps of the infection. Chicks infected with the wild-type and mutant strains presented, respectively, 80% and 50% mortality rates. The DeltayadC strain presented a slightly decreased ability to adhere to HeLa cells with or without the d-mannose analog compared with the wild type. Real-time PCR (RT-PCR) assays showed that fimH was downregulated (P < 0.05) and csgA and ecpA were slightly upregulated in the mutant strain, showing that yadC modulates expression of other fimbriae. Bacterial internalization studies showed that the DeltayadC strain had a lower number of intracellular bacteria recovered from Hep 2 cells and HD11 cells than the wild-type strain (P < 0.05). Motility assays in soft agar demonstrated that the DeltayadC strain was less motile than the wild type (P < 0.01). Curiously, flagellum-associated genes were not dramatically downregulated in the DeltayadC strain. Taken together, the results show that the fimbrial adhesin Yad contributes to the pathogenicity and modulates different biological characteristics of the APEC strain SCI-07. PMID- 26502906 TI - Shiga Toxins Activate the NLRP3 Inflammasome Pathway To Promote Both Production of the Proinflammatory Cytokine Interleukin-1beta and Apoptotic Cell Death. AB - Shiga toxin (Stx)-mediated immune responses, including the production of the proinflammatory cytokines tumor necrosis-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), may exacerbate vascular damage and accelerate lethality. However, the immune signaling pathway activated in response to Stx is not well understood. Here, we demonstrate that enzymatically active Stx, which leads to ribotoxic stress, triggers NLRP3 inflammasome-dependent caspase-1 activation and IL-1beta secretion in differentiated macrophage-like THP-1 (D-THP-1) cells. The treatment of cells with a chemical inhibitor of glycosphingolipid biosynthesis, which suppresses the expression of the Stx receptor globotriaosylceramide and subsequent endocytosis of the toxin, substantially blocked activation of the NLRP3 inflammasome and processing of caspase-1 and IL-1beta. Processing and release of both caspase-1 and IL-1beta were significantly reduced or abolished in Stx-intoxicated D-THP-1 cells in which the expression of NLRP3 or ASC was stably knocked down. Furthermore, Stx mediated the activation of caspases involved in apoptosis in an NLRP3- or ASC-dependent manner. In Stx-intoxicated cells, the NLRP3 inflammasome triggered the activation of caspase-8/3, leading to the initiation of apoptosis, in addition to caspase-1-dependent pyroptotic cell death. Taken together, these results suggest that Stxs trigger the NLRP3 inflammasome pathway to release proinflammatory IL-1beta as well as to promote apoptotic cell death. PMID- 26502908 TI - The LasB Elastase of Pseudomonas aeruginosa Acts in Concert with Alkaline Protease AprA To Prevent Flagellin-Mediated Immune Recognition. AB - The opportunistic pathogen Pseudomonas aeruginosa is capable of establishing severe and persistent infections in various eukaryotic hosts. It encodes a wide array of virulence factors and employs several strategies to evade immune detection. In the present study, we screened the Harvard Medical School transposon mutant library of P. aeruginosa PA14 for bacterial factors that modulate interleukin-8 responses in A549 human airway epithelial cells. We found that in addition to the previously identified alkaline protease AprA, the elastase LasB is capable of degrading exogenous flagellin under calcium-replete conditions and prevents flagellin-mediated immune recognition. Our results indicate that the production of two proteases with anti-flagellin activity provides a failsafe mechanism for P. aeruginosa to ensure the maintenance of protease-dependent immune-modulating functions. PMID- 26502909 TI - Real-Time Imaging of Interactions of Neutrophils with Cryptococcus neoformans Demonstrates a Crucial Role of Complement C5a-C5aR Signaling. AB - Neutrophils have been shown to efficiently kill Cryptococcus neoformans, a causative agent of meningoencephalitis. Here, using live-cell imaging, we characterize the dynamic interactions of neutrophils with C. neoformans and the underlying mechanisms in real time. Neutrophils were directly seen to chase C. neoformans cells and then rapidly internalize them. Complement C5a-C5aR signaling guided neutrophils to migrate to the yeast cells, resulting in optimal phagocytosis and subsequent killing of the organisms. The addition of recombinant complement C5a enhanced neutrophil movement but did not induce chemotaxis, suggesting that the C5a gradient is crucial. Incubation with C. neoformans resulted in enhanced activation of Erk and p38 mitogen-activated protein (MAP) kinases (MAPKs) in neutrophils. Inhibition of the p38 MAPK pathway, but not the Erk pathway, significantly impaired neutrophil migration and its subsequent killing of C. neoformans. Deficiency of CD11b or blocking of CD11b did not affect the migration of neutrophils toward C. neoformans but almost completely abolished phagocytosis and killing of the organisms by neutrophils. C5a-C5aR signaling induced enhanced surface expression of CD11b. Interestingly, the original surface expression of CD11b was essential and sufficient for neutrophils to attach to C. neoformans but was unable to mediate phagocytosis. In contrast, the enhanced surface expression of CD11b induced by C5a-C5aR signaling was essential for neutrophil phagocytosis and subsequent killing of yeast cells. Collectively, this is the first report of the dynamic interactions of neutrophils with C. neoformans, demonstrating a crucial role of C5a-C5aR signaling in neutrophil killing of C. neoformans in real time. PMID- 26502910 TI - Skin-Specific Unsaturated Fatty Acids Boost the Staphylococcus aureus Innate Immune Response. AB - Antimicrobial fatty acids (AFAs) protect the human epidermis against invasion by pathogenic bacteria. In this study, we questioned whether human skin fatty acids (FAs) can be incorporated into the lipid moiety of lipoproteins and whether such incorporation would have an impact on innate immune stimulation in the model organism Staphylococcus aureus USA300 JE2. This organism synthesized only saturated FAs. However, when feeding USA300 with unsaturated FAs present on human skin (C16:1, C18:1, or C18:2), those were taken up, elongated stepwise by two carbon units, and finally found in the bacterial (phospho)lipid fraction. They were also observed in the lipid moiety of lipoproteins. When USA300 JE2 was fed with the unsaturated FAs, the cells and cell lysates showed an increased innate immune activation with various immune cells and peripheral blood mononuclear cells (PBMCs). Immune activation was highest with linoleic acid (C18:2). There are several pieces of evidence that the enhanced immune stimulating effect was due to the incorporation of unsaturated FAs in lipoproteins. First, the enhanced stimulation was dependent on Toll-like receptor 2 (TLR2). Second, an lgt mutant, unable to carry out lipidation of prolipoproteins, was unable to carry out immune stimulation when fed with unsaturated FAs. Third, the supplied FAs did not significantly affect growth, protein release, or expression of the model lipoprotein Lpl1. Although S. aureus is unable to synthesize unsaturated FAs, it incorporates long-chain unsaturated FAs into its lipoproteins, with the effect that the cells are better recognized by the innate immune system. This is an additional mechanism how our skin controls bacterial colonization and infection. PMID- 26502911 TI - Staphylococcus aureus Strain USA300 Perturbs Acquisition of Lysosomal Enzymes and Requires Phagosomal Acidification for Survival inside Macrophages. AB - Methicillin-resistant Staphylococcus aureus (MRSA) causes invasive, drug resistant skin and soft tissue infections. Reports that S. aureus bacteria survive inside macrophages suggest that the intramacrophage environment may be a niche for persistent infection; however, mechanisms by which the bacteria might evade macrophage phagosomal defenses are unclear. We examined the fate of the S. aureus-containing phagosome in THP-1 macrophages by evaluating bacterial intracellular survival and phagosomal acidification and maturation and by testing the impact of phagosomal conditions on bacterial viability. Multiple strains of S. aureus survived inside macrophages, and in studies using the MRSA USA300 clone, the USA300-containing phagosome acidified rapidly and acquired the late endosome and lysosome protein LAMP1. However, fewer phagosomes containing live USA300 bacteria than those containing dead bacteria associated with the lysosomal hydrolases cathepsin D and beta-glucuronidase. Inhibiting lysosomal hydrolase activity had no impact on intracellular survival of USA300 or other S. aureus strains, suggesting that S. aureus perturbs acquisition of lysosomal enzymes. We examined the impact of acidification on S. aureus intramacrophage viability and found that inhibitors of phagosomal acidification significantly impaired USA300 intracellular survival. Inhibition of macrophage phagosomal acidification resulted in a 30-fold reduction in USA300 expression of the staphylococcal virulence regulator agr but had little effect on expression of sarA, saeR, or sigB. Bacterial exposure to acidic pH in vitro increased agr expression. Together, these results suggest that S. aureus survives inside macrophages by perturbing normal phagolysosome formation and that USA300 may sense phagosomal conditions and upregulate expression of a key virulence regulator that enables its intracellular survival. PMID- 26502912 TI - Involvement of an Skp-Like Protein, PGN_0300, in the Type IX Secretion System of Porphyromonas gingivalis. AB - The oral Gram-negative anaerobic bacterium Porphyromonas gingivalis is an important pathogen involved in chronic periodontitis. Among its virulence factors, the major extracellular proteinases, Arg-gingipain and Lys-gingipain, are of interest given their abilities to degrade host proteins and process other virulence factors. Gingipains possess C-terminal domains (CTDs) and are translocated to the cell surface or into the extracellular milieu by the type IX secretion system (T9SS). Gingipains contribute to the colonial pigmentation of the bacterium on blood agar. In this study, Omp17, the PGN_0300 gene product, was found in the outer membrane fraction. A mutant lacking Omp17 did not show pigmentation on blood agar and showed reduced proteolytic activity of the gingipains. CTD-containing proteins were released from bacterial cells without cleavage of the CTDs in the omp17 mutant. Although synthesis of the anionic polysaccharide (A-LPS) was not affected in the omp17 mutant, the processing of and A-LPS modification of CTD-containing proteins was defective. PorU, a C terminal signal peptidase that cleaves the CTDs of other CTD-containing proteins, was not detected in any membrane fraction of the omp17 mutant, suggesting that the defective maturation of CTD-containing proteins by impairment of Omp17 is partly due to loss of function of PorU. In the mouse subcutaneous infection experiment, the omp17 mutant was less virulent than the wild type. These results suggested that Omp17 is involved in P. gingivalis virulence. PMID- 26502913 TI - Memory B Cells Encode Neutralizing Antibody Specific for Toxin B from the Clostridium difficile Strains VPI 10463 and NAP1/BI/027 but with Superior Neutralization of VPI 10463 Toxin B. AB - Secreted toxin B (TcdB) substantially contributes to the pathology observed during Clostridium difficile infection. To be successfully incorporated into a vaccine, TcdB-based immunogens must stimulate the production of neutralizing antibody (Ab)-encoding memory B cells (Bmem cells). Despite numerous investigations, a clear analysis of Bmem cellular responses following vaccination against TcdB is lacking. B6 mice were therefore used to test the ability of a nontoxigenic C-terminal domain (CTD) fragment of TcdB to induce Bmem cells that encode TcdB-neutralizing antibody. CTD was produced from the historical VPI 10463 strain (CTD1) and from the hypervirulent strain NAP1/BI/027 (CTD2). It was then demonstrated that CTD1 induced strong recall IgG antibody titers, and this led to the development of functional Bmem cells that could be adoptively transferred to naive recipients. Bmem cell-driven neutralizing Ab responses conferred protection against lethal challenge with TcdB1. Further experiments revealed that an experimental adjuvant (Imject) and a clinical adjuvant (Alhydrogel) were compatible with Bmem cell induction. Reactivity of human Bmem cells to CTD1 was also evident in human peripheral blood mononuclear cells (PBMCs), suggesting that CTD1 could be a good vaccine immunogen. However, CTD2 induced strong Bmem cell driven antibody titers, and the CTD2 antibody was neutralizing in vitro, but its protection against lethal challenge with TcdB2 was limited to delaying time to death. Therefore, CTD from different C. difficile strains may be a good immunogen for stimulating B cell memory that encodes in vitro neutralizing Ab but may be limited by variable protection against intoxication in vivo. PMID- 26502915 TI - An assessment of adherence to basic ecological principles by payments for ecosystem service projects. AB - Programs and projects employing payments for ecosystem service (PES) interventions achieve their objectives by linking buyers and sellers of ecosystem services. Although PES projects are popular conservation and development interventions, little is known about their adherence to basic ecological principles. We conducted a quantitative assessment of the degree to which a global set of PES projects adhered to four ecological principles that are basic scientific considerations for any project focused on ecosystem management: collection of baseline data, identification of threats to an ecosystem service, monitoring, and attention to ecosystem dynamics or the formation of an adaptive management plan. We evaluated 118 PES projects in three markets-biodiversity, carbon, and water-compiled using websites of major conservation organizations; ecology, economic, and climate-change databases; and three scholarly databases (ISI Web of Knowledge, Web of Science, and Google Scholar). To assess adherence to ecological principles, we constructed two scientific indices (one additive [ASI] and one multiplicative [MSI]) based on our four ecological criteria and analyzed index scores by relevant project characteristics (e.g., sector, buyer, seller). Carbon-sector projects had higher ASI values (P < 0.05) than water sector projects and marginally higher ASI scores (P < 0.1) than biodiversity sector projects, demonstrating their greater adherence to ecological principles. Projects financed by public-private partnerships had significantly higher ASI values than projects financed by governments (P < 0.05) and marginally higher ASI values than those funded by private entities (P < 0.1). We did not detect differences in adherence to ecological principles based on the inclusion of cobenefits, the spatial extent of a project, or the size of a project's budget. These findings suggest, at this critical phase in the rapid growth of PES projects, that fundamental ecological principles should be considered more carefully in PES project design and implementation in an effort to ensure PES project viability and sustainability. PMID- 26502917 TI - Protonation of silylenol ether via excited state proton transfer catalysis. AB - We demonstrate the photocatalytic protonation of a silylenol ether using 7-bromo 2-naphthol as an ESPT catalyst with phenol as the sacrificial proton source. Greater than 95% conversion is achieved with 1 mol% catalyst. The reaction cycle is dependent on the significantly increased acidity of the catalyst in the excited state as well as the long lifetime for the triplet excited state of 7 bromo-2-naphthol. The reaction does not occur in the absence of light (367 nm) and can readily be controlled by light intensity modulation. We also demonstrate that a 72% reaction yield can be obtained with unsubstituted naphthol as the catalyst by coupling triplet energy transfer, via a visible light absorbing (445 nm) sensitizer, into the catalytic cycle. These results open the door to an entirely new class of sensitized photocatalytic reactions that harness the excited state acidity of ESPT dyes. PMID- 26502914 TI - Parabens and Human Epidermal Growth Factor Receptor Ligand Cross-Talk in Breast Cancer Cells. AB - BACKGROUND: Xenoestrogens are synthetic compounds that mimic endogenous estrogens by binding to and activating estrogen receptors. Exposure to estrogens and to some xenoestrogens has been associated with cell proliferation and an increased risk of breast cancer. Despite evidence of estrogenicity, parabens are among the most widely used xenoestrogens in cosmetics and personal-care products and are generally considered safe. However, previous cell-based studies with parabens do not take into account the signaling cross-talk between estrogen receptor alpha (ERalpha) and the human epidermal growth factor receptor (HER) family. OBJECTIVES: We investigated the hypothesis that the potency of parabens can be increased with HER ligands, such as heregulin (HRG). METHODS: The effects of HER ligands on paraben activation of c-Myc expression and cell proliferation were determined by real-time polymerase chain reaction, Western blots, flow cytometry, and chromatin immunoprecipitation assays in ERalpha- and HER2-positive human BT 474 breast cancer cells. RESULTS: Butylparaben (BP) and HRG produced a synergistic increase in c-Myc mRNA and protein levels in BT-474 cells. Estrogen receptor antagonists blocked the synergistic increase in c-Myc protein levels. The combination of BP and HRG also stimulated proliferation of BT-474 cells compared with the effects of BP alone. HRG decreased the dose required for BP mediated stimulation of c-Myc mRNA expression and cell proliferation. HRG caused the phosphorylation of serine 167 in ERalpha. BP and HRG produced a synergistic increase in ERalpha recruitment to the c-Myc gene. CONCLUSION: Our results show that HER ligands enhanced the potency of BP to stimulate oncogene expression and breast cancer cell proliferation in vitro via ERalpha, suggesting that parabens might be active at exposure levels not previously considered toxicologically relevant from studies testing their effects in isolation. CITATION: Pan S, Yuan C, Tagmount A, Rudel RA, Ackerman JM, Yaswen P, Vulpe CD, Leitman DC. 2016. Parabens and human epidermal growth factor receptor ligand cross-talk in breast cancer cells. Environ Health Perspect 124:563-569; http://dx.doi.org/10.1289/ehp.1409200. PMID- 26502916 TI - Physicians' communication styles as correlates of elderly cancer patients' satisfaction with their doctors. AB - Physician-patient communication style is of utmost importance to patients with life-threatening diseases. This study identifies the most desired physician communication style by older cancer patients; and examines which of the studied communication styles significantly explains cancer patients' satisfaction with family physicians. A total of 200 older cancer patients, with average age of 75 years, participated in the study, yielding a response rate of 42%. Prospective respondents were randomly selected from the list of cancer patients in the central geographical district of Israel's second largest Health Maintenance Organization fund. Respondents rated their satisfaction with physicians as relatively high. All three communication styles studied were found to be associated with patient's satisfaction. Associations were found between self rated health, time since the diagnosis of cancer and satisfaction. Women were less satisfied than men with their physicians. Two variables emerged as significant predictors of satisfaction: the physician's caring communication style and patient's gender. Intervention programmes should focus on elevating physicians' awareness of the importance of their communication with cancer patients in general, and of the caring communication style in particular. PMID- 26502918 TI - CD1c(+) myeloid dendritic cells in myeloid neoplasia. AB - We determined the normal level and phenotype of CD1c(+) myeloid dendritic cells (MDCs) in blood and bone marrow and evaluated the level of CD1c(+) MDCs in 295 myeloid neoplasms. CD1c(+) MDCs were increased above the mean level of non neoplastic hospital controls in 18.0% (53/295) of myeloid malignancies, increased three standard deviations above the control mean in 14.2% (42/295) with a 10-fold or more increase compared to mean in 6.8% (20/295). Increased CD1c(+) MDCs were associated with chronic myelomonocytic leukemia (CMML) (12/24, 50%) and acute myeloid leukemia (AML) (31/140, 22%) with a strong association with AML with the inv(16) cytogenetic abnormality. The cells were not increased in chronic myelogenous leukemia (CML) and rarely increased in non-CML myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). Immunohistochemical staining of cases with increased CD1c(+) MDCs did not reveal clustering of the cells unlike that observed with myeloid neoplasms associated with increased plasmacytoid dendritic cells. Our findings indicate CD1c(+) MDC elevations are not uncommon in myeloid leukemias and are associated with CMML and AML, particularly AML with inv(16). (c) 2015 International Clinical Cytometry Society. PMID- 26502919 TI - Elevated expression of HSP90 and the antitumor effect of an HSP90 inhibitor via inactivation of the Akt/mTOR pathway in undifferentiated pleomorphic sarcoma. AB - BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a heterogeneous tumor group, and little is known about molecular target therapy for UPS. Heat shock protein 90 (HSP90) is an expressed chaperone that refolds certain denatured proteins under stress conditions. One of these proteins is Akt. The disruption of Akt signaling plays an important role in tumor progression. The present study's purpose was to analyze the HSP90 expression, Akt/mTOR pathway activation and the correlation between HSP90 expression and its pathway activation in UPS. METHODS: The status of HSP90 and the profiles of the Akt/ mTOR pathway were assessed by immunohistochemistry in 79 samples of UPS, and these data were compared with clinicopathological and histopathological findings. The expressions of indicated proteins were assessed by Western blotting in five frozen samples. After treating UPS cells with the HSP90 inhibitor, we assessed the antitumor effect of the inhibitor. RESULTS: Immunohistochemically, phosphorylated Akt (p-Akt), p-mTOR, p S6RP and p-4EBP were positive in 57.3, 51.9, 54.5 and 57.1% of the UPS samples, respectively. The expressions of those phosphorylated proteins were correlated with each other. HSP90 expression was elevated in 56.4% of the samples and was correlated with p-Akt, p-mTOR and p-S6RP. The immunohistochemical results were confirmed by Western blotting. The HSP90 inhibitor led to decreased viability and invasiveness of the cells and inactivated the AKT/mTOR pathway in vitro. CONCLUSION: Elevated expression of HSP90 is a poor-prognosis factor and is involved in the activation of the Akt/mTOR pathway in UPS. HSP90 inhibition is a potential treatment option for UPS. PMID- 26502921 TI - On the pedagogy of pharmacological communication: a study of final semester health science students. AB - BACKGROUND: There is a need to improve design in educational programmes for the health sciences in general and in pharmacology specifically. The objective of this study was to investigate and problematize pharmacological communication in educational programmes for the health sciences. METHODS: An interview study was carried out where final semester students from programmes for the medical, nursing and specialist nursing in primary health care professions were asked to discuss the pharmacological aspects of two written case descriptions of the kind they would meet in their everyday work. The study focused on the communication they envisaged taking place on the concerns the patients were voicing, in terms of two features: how communication would take place and what would be the content of the communication. A phenomenographic research approach was used. RESULTS: The results are presented as outcome spaces, sets of categories that describe the variation of ways in which the students voiced their understanding of communication in the two case descriptions and showed the qualitatively distinct ways in which the features of communication were experienced. CONCLUSIONS: The results offer a base of understanding the students' perspectives on communication that they will take with them into their professional lives. We indicate that there is room for strengthening communication skills in the field of pharmacology, integrating them into programmes of education, by more widely implementing a problem-based, a case-oriented or role-playing pedagogy where final year students work across specialisations and there is a deliberate effort to evoke and assess advanced conceptions and skills. PMID- 26502920 TI - Use of different transmission metrics to describe malaria epidemiology in the highlands of western Kenya. AB - BACKGROUND: Monitoring and evaluation of malaria programmes may require a combination of approaches to detect any effects of control. This is particularly true at lower transmission levels where detecting both infection and exposure to infection will provide additional evidence of any change. This paper describes use of three transmission metrics to explore the malaria epidemiology in the highlands of western Kenya. METHODS: A malariometric survey was conducted in June 2009 in two highland districts, Kisii and Rachuonyo South, Nyanza Province, Kenya using a cluster design. Enumeration areas were used to sample 46 clusters from which 12 compounds were randomly sampled. Individuals provided a finger-blood sample to assess malaria infection (rapid diagnostic test, PCR) and exposure (anti-Plasmodium falciparum MSP-1 antibodies) and a questionnaire was administered to record household factors and assess use of vector control interventions. RESULTS: Malaria prevalence infection rates were 3.0 % (95 % CI 2.2-4.2 %) by rapid diagnostic test (RDT) and 8.5 % (95 % CI 7.0-10.4 %) by PCR and these ranged from 0-13.1 to 0-14.8 % between clusters for RDT and PCR, respectively. Seroprevalence was 36.8 % (95 % CI 33.9-39.8) ranging from 18.6 to 65.8 %. Both RDT and PCR prevalences were highest in children aged 5-10 years but the proportion of infections that were sub-patent was highest in those between 15 and 20 years of age (78.1 %, 95 % CI 63.0-93.3 %) and those greater than 20 years (73.3 %, 95 % CI 64.5-81.9 %). Those reporting both indoor residual spraying (IRS) in their home and use of bed nets had lower exposure to malaria compared to those who reported using IRS or bed nets alone. CONCLUSIONS: In this highland site in western Kenya malaria transmission was low, but highly heterogeneous. To accurately characterize the true extent of malaria transmission, more sensitive and complementary metrics such as PCR or serology are required in addition to the standard microscopy and/or RDTs that are routinely used. This is likely to be the case in other low endemicity settings. PMID- 26502922 TI - Histone deacetylase (HDAC)-1, -2, -4 and -6 expression in human pancreatic adenocarcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients' survival. AB - BACKGROUND: Histone deacetylases (HDACs) have been associated with malignant tumor development and progression in humans. HDAC inhibitors (HDACIs) are currently being explored as anti-cancer agents in clinical trials. The present study aimed to evaluate the clinical significance of HDAC-1, -2, -4 and -6 protein expression in pancreatic adenocarcinoma. METHODS: HDAC-1, -2, -4 and -6 protein expression was assessed immunohistochemically on 70 pancreatic adenocarcinoma tissue specimens and was statistically analyzed with clinicopathological characteristics and patients' survival. RESULTS: Enhanced HDAC-1 expression was significantly associated with increased tumor proliferative capacity (p = 0.0238) and borderline with the absence of lymph node metastases (p = 0.0632). Elevated HDAC-4 expression was significantly associated with the absence of organ metastases (p = 0.0453) and borderline with the absence of lymph node metastases (p = 0.0571) and tumor proliferative capacity (p = 0.0576). Enhanced HDAC-6 expression was significantly associated with earlier histopathological stage (p = 0.0115) and borderline with smaller tumor size (p = 0.0864). Pancreatic adenocarcinoma patients with enhanced HDAC-1 and -6 expression showed significantly longer survival times compared to those with low expression (p = 0.0022 and p = 0.0113, respectively), while a borderline association concerning HDAC-2 expression was noted (p = 0.0634). CONCLUSIONS: The present study suggested that HDACs may be implicated in pancreatic malignant disease progression, being considered of clinical utility with potential use as therapeutic targets. PMID- 26502923 TI - Clinicopathological Variation of Lauren Classification in Gastric Cancer. AB - The investigation of prognostic factor for gastric cancer is still desirable because of dismal prognosis in gastric cancer. Lauren's classification is currently a useful histological classification. There are few large series evaluating the prognostic significance of Lauren's classification in gastric cancer. From January 1987 to December 2013, a total of 3071 patients received gastrectomy for gastric cancer. According Lauren's classification, 1423(46.3%) patients were intestinal type, 1000 patients (32.6%) were diffuse type, and 648 patients (21.1%) were mixed type. The clinicopathological characteristics and prognosis in Lauren's classification were analyzed in these patients. Our results showed that patients with intestinal type gastric cancer (57.7%) had a better 5 year overall survival than diffuse type (45.6%) and mixed type (43.4%, P < 0.001). The clinicopathological characteristics showed that gastric cancer patients with intestinal type were older (P < 0.001), male predominant (P < 0.001), smaller tumor size (P < 0.001), distal stomach predominant (P < 0.001), relative well differentiated (P < 0.001), less advanced Borrmann type (P < 0.001), less scirrhous type stromal reaction(P < 0.001), less infiltrating type of Ming's histology type(P < 0.001), less tumor invasion depth and less lymphovascular invasion (P < 0.001). Multivariate analysis with overall survival as an endpoint showed that age (P = 0.005), Borrmann classification (P < 0.001), pathological T category (P = 0.023), pathological N category (P < 0.001) and Lauren's classification (P = 0.003) were significant correlated in gastric cancer. Lauren's classification is an independent prognostic factor in gastric cancer patient undergoing gastrectomy. Lauren's classification can serve as a prognostic marker for gastric cancer patient receiving gastrectomy. The clinicopathological appearance and prognosis of mixed type gastric cancer is similar to diffuse type gastric cancer. PMID- 26502924 TI - Intragenic duplication in the PKHD1 gene in autosomal recessive polycystic kidney disease. AB - BACKGROUND: In the present study, we report on a couple who underwent prenatal genetic diagnosis for autosomal recessive polycystic kidney disease (ARPKD). CASE PRESENTATION: This healthy couple had previously had a healthy boy but had experienced two consecutive neonatal deaths due to respiratory distress resulting from pulmonary hypoplasia caused by oligohydramnios. The woman consulted our facility after she realized she was pregnant again. We promptly performed a carrier test for the PKHD1 gene by target exome sequencing of samples from the couple. A pathogenic mutation was identified only in the paternal allele (c.9008C>T, p.S3003F). The mutation was confirmed by Sanger sequencing of the DNA from formalin-fixed, paraffin-embedded, kidney tissue of the second neonate patient and was not found in the healthy sibling. We then performed haplotype analyses using microsatellite markers scattered throughout the PKHD1 gene. DNA from the amniocentesis was determined to belong to a carrier, and the couple decided to continue with the pregnancy, obtaining a healthy newborn. Subsequent detailed examination of the exome data suggested higher read depth at exons 45 and 46. Multiplex ligation-dependent probe amplification allowed identification of duplication of these two exons. This case suggests the potential usefulness of target exome sequencing in the prenatal diagnosis of the PKHD1 gene in ARPKD. CONCLUSIONS: This is the first report of intragenic duplication in the PKHD1 gene in ARPKD. PMID- 26502925 TI - Combination of rosuvastatin and probucol inhibits MMP-9 expression via upregulation of miR-497 in cultured HUVECs and apoE knockout mice. AB - This study deciphered the molecular mechanisms of the inhibition of MMP-9 expression using rosuvastatin in cultured human umbilical vein endothelial cells (HUVECs) and apoE knockout mice and whether the combination of rosuvastatin and probucol enhanced this effect. The role that microRNA (miR)-497 plays in the regulation of MMP-9 expression was evaluated in cultured HUVECs and apoE knockout mice using quantitative real-time reverse transcription polymerase chain reaction and Western blotting. First, TNFalpha significantly increased mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling and MMP-9 levels, and the transfection of miR-497 prevented this increase. The converse results were obtained after miR-497 suppression. Second, the administration of rosuvastatin or the combination of two drugs decreased MAPK/ERK signaling and MMP-9 levels, and the suppression of miR-497 upregulated these levels. Third, the administration of rosuvastatin or the combination of two drugs increased miR-497 expression levels in the aortas of apoE knockout mice, but the levels of serum lipids and plaque areas decreased, which improved plaque components and decreased the MAPK/ERK signaling and MMP-9 levels. Finally, the combination of the two drugs was more effective than the use of rosuvastatin alone. Rosuvastatin inhibits MMP-9 expression by upregulating miR-497 in HUVECs and apoE knockout mice, and the combination of rosuvastatin and probucol enhances this effect. PMID- 26502926 TI - Thymidylate synthase expression as a predictive biomarker of pemetrexed sensitivity in advanced non-small cell lung cancer. AB - BACKGROUND: Although it has been suggested that a high level of thymidylate synthase (TYMS) gene expression in malignant tumors is related to reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in routine clinical samples from patients treated with the drug. The purpose of this study was to quantitatively assess the impact of TYMS gene expression in tumor cells as a predictor of the efficacy of pemetrexed therapy in patients with advanced non-small cell lung cancer (NSCLC) treated at our institution. METHODS: Sixty-two NSCLC patients were included in this study: 16 patients received platins-pemetrexed as first-line NSCLC, and 46 pemetrexed in monotherapy as second- or subsequent-line treatment. Total mRNA was isolated and the expression of TYMS was analyzed by RT-qPCR. TYMS levels were calibrated against expression in normal lung tissue. RESULTS: TYMS overexpression was detected in 61 % of patients and low expression in 39 %. The response rate for patients with low TYMS expression was 0.29 compared with 0.03 in patients with overexpression (P = 0.025). A significant benefit was observed in patients with low expression both in time to progression (average TTP = 56 vs. 23 months, P = 0.001) and in overall survival (average OS = 60 vs. 25 months, P = 0.002). CONCLUSIONS: TYMS overexpression in tumor cells correlated with a reduced response to pemetrexed-containing chemotherapy and might be used as a predictive biomarker in advanced NSCLC patients. PMID- 26502927 TI - Maternal medical conditions during pregnancy and gross motor development up to age 24 months in the Upstate KIDS study. AB - AIM: We examined whether children of mothers with a medical condition diagnosed before or during pregnancy took longer to achieve gross motor milestones up to age 24 months. METHOD: We obtained information on medical conditions using self reports, birth certificates, and hospital records in 4909 mothers participating in Upstate KIDS, a population-based birth cohort. Mothers reported on their children's motor milestone achievement at 4, 8, 12, 18, and 24 months of age. RESULTS: After adjustment for covariates (including pre-pregnancy body mass index), children of mothers with gestational diabetes took longer to achieve sitting without support (hazard ratio [HR]=0.84, 95% confidence interval [CI] 0.75-0.93), walking with assistance (HR=0.88, 95% CI 0.77-0.98), and walking alone (HR=0.88, 95% CI 0.77-0.99) than children of females with no gestational diabetes. Similar findings emerged for maternal diabetes. Gestational hypertension was associated with a longer time to achieve walking with assistance. These associations did not change after adjustment for gestational age or birthweight. Severe hypertensive disorders of pregnancy were related to a longer time to achieve milestones, but not after adjustment for perinatal factors. INTERPRETATION: Children exposed to maternal diabetes, gestational or pre-gestational, may take longer to achieve motor milestones than non-exposed children, independent of maternal obesity. PMID- 26502929 TI - School Nurses' Experiences in Dealing With Bullying Situations Among Students. AB - School nurses have an important role in helping students to deal with bullying. However, most of the previously undertaken studies do not have nurses as the subjects, considering their experiences around this theme. This study used a qualitative approach through in-depth interviews with 12 school nurses (SNs). The thematic analysis was employed and supported by NVivo 10 software. Five main themes arose from the analysis: (1) understanding about bullying, (2) how they identified bullying, (3) strategies, (4) support at the workplace, and (5) SNs' role. SNs have a reasonable knowledge about this issue and are capable of helping students through dialogue. However, there is a need to be trained and have more time to be able to give proper help to the students, also using other different strategies. SNs must work more actively on this issue with schools and be supported in terms of staff numbers. PMID- 26502928 TI - Does the Size of the Effect of Adverse Events at High Ages on Daily-Life Physical Functioning Depend on the Economic Conditions Around Birth? AB - This paper considers determinants of physical functional limitations in daily life activities at high ages. Specifically, we quantify the extent to which the impact of adverse life events on this outcome is larger in case of exposure to adverse economic conditions early in life. Adverse life events include bereavement, severe illness in the family, and the onset of chronic diseases. We use a longitudinal data set of individuals born in the first decades of the 20th century. The business cycle around birth is used as an indicator of economic conditions early in life. We find that the extent to which functional limitations suffer from the onset of chronic diseases is larger if the individual was born in a recession. The long-run effect of economic conditions early in life on functional limitations at high ages runs primarily via this life event. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26502930 TI - Effect of rutin on spinal cord injury through inhibition of the expression of MIP 2 and activation of MMP-9, and downregulation of Akt phosphorylation. AB - Rutin has extensive pharmacological activities, including antibacterial and anti inflammatory activities, cooling of the blood to inhibit bleeding, reducing capillary wall fragility and anti-influenza activities. However, whether rutin can ameliorate neuropathic function in spinal cord injury (SCI) in constriction induced peripheral nerve injury remains to be elucidated. In the present study, the potential protective effects of rutin on SCI rats were investigated. Neurological function was examined using the Basso, Beattie and Bresnahan (BBB) scoring system and by measuring the water content of the spinal cord tissue in SCI rats. SCI-induced programmed cell death was measured using hematoxylin and eosin staining. In addition, the expression of macrophage inflammatory protein-2 (MIP-2) and the activation of matrix metalloproteinase-9 (MMP-9) in the SCI rats were evaluated using ELISA assay kits and zymographic analysis, respectively. The phosphorylation of protein kinase B (p-Akt) was analyzed using a western blot assay. The results demonstrated that administrating rutin began to increase BBB scores and attenuate the spinal cord water content of the SCI rats. Administrating rutin prevented SCI-induced programmed cell death. The SCI rats of in the rutin-treated group were found to exhibit lower expression levels of MIP-2 and p-Akt, reduced MMP-9 activation, compared with the SCI model rats. In conclusion, rutin was demonstrated as a potential protective agent in SCI and enhances the neurotrophic effect by inhibiting the expression of MIP-2 and activation of MMP-9, and downregulating the expression of p-Akt. PMID- 26502931 TI - Epidemiology of acute respiratory infections in children - preliminary results of a cohort in a rural north Indian community. AB - BACKGROUND: Despite acute respiratory infections being a major cause of death among children in developing countries including India, there is a lack of community-based studies that document its burden and aetiology. METHODS: A dynamic cohort of children aged 0-10 years was established in four villages in a north Indian state of Haryana from August 2012 onwards. Trained health workers conducted weekly home visits to screen children for acute respiratory infection (ARI) defined as one of the following: cough, sore throat, nasal congestion, earache/discharge, or breathing difficulty. Nurses clinically assessed these children to grade disease severity based on standard age-specific guidelines into acute upper or lower respiratory infection (AURI or ALRI) and collected nasal/throat swabs for pathogen testing. RESULTS: Our first year results show that ARI incidence in 0-10 years of age was 5.9 (5.8-6.0) per child-year with minimal gender difference, the ALRI incidence in the under-five age group was higher among boys (0.43; 0.39-0.49) as compared to girls (0.31; 0.26-0.35) per child year. Boys had 2.4 times higher ARI-related hospitalization rate as compared to girls. CONCLUSION: ARI impose a significant burden on the children of this cohort. This study platform aims to provide better evidence for prevention and control of pneumonia in developing countries. PMID- 26502932 TI - A newly discovered Bordetella species carries a transcriptionally active CRISPR Cas with a small Cas9 endonuclease. AB - BACKGROUND: Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated genes (cas) are widely distributed among bacteria. These systems provide adaptive immunity against mobile genetic elements specified by the spacer sequences stored within the CRISPR. METHODS: The CRISPR-Cas system has been identified using Basic Local Alignment Search Tool (BLAST) against other sequenced and annotated genomes and confirmed via CRISPRfinder program. Using Polymerase Chain Reactions (PCR) and Sanger DNA sequencing, we discovered CRISPRs in additional bacterial isolates of the same species of Bordetella. Transcriptional activity and processing of the CRISPR have been assessed via RT PCR. RESULTS: Here we describe a novel Type II-C CRISPR and its associated genes cas1, cas2, and cas9-in several isolates of a newly discovered Bordetella species. The CRISPR-cas locus, which is absent in all other Bordetella species, has a significantly lower GC-content than the genome-wide average, suggesting acquisition of this locus via horizontal gene transfer from a currently unknown source. The CRISPR array is transcribed and processed into mature CRISPR RNAs (crRNA), some of which have homology to prophages found in closely related species B. hinzii. CONCLUSIONS: Expression of the CRISPR-Cas system and processing of crRNAs with perfect homology to prophages present in closely related species, but absent in that containing this CRISPR-Cas system, suggest it provides protection against phage predation. The 3,117-bp cas9 endonuclease gene from this novel CRISPR-Cas system is 990 bp smaller than that of Streptococcus pyogenes, the 4,017-bp allele currently used for genome editing, and which may make it a useful tool in various CRISPR-Cas technologies. PMID- 26502933 TI - Partial weight support of the arm affects corticomotor selectivity of biceps brachii. AB - BACKGROUND: Weight support of the arm (WS) can be used in stroke rehabilitation to facilitate upper limb therapy, but the neurophysiological effects of this technique are not well understood. While an overall reduction in muscle activity is expected, the mechanism by which WS may alter the expression of muscle synergies has not been examined until now. We explored the neurophysiological effect of WS on the selectivity of biceps brachii (BB) activation in healthy adults. METHODS: Thirteen participants completed counterbalanced movement tasks in a repeated measures design. Three levels of WS (0, 45, and 90 % of full support) were provided to the arm using a commercial device (Saebo Mobile Arm Support). At each level of WS, participants maintained a flexed shoulder posture while performing rhythmic isometric elbow flexion (BB agonist) or forearm pronation (BB antagonist). Single-pulse transcranial magnetic stimulation of primary motor cortex was used to elicit motor-evoked potentials (MEPs) in BB 100 300 ms before muscle contraction. Baseline muscle activity and MEP amplitude were the primary dependent measures. Effects of movement TASK and SUPPORT LEVEL were statistically analyzed using linear mixed effects models. RESULTS: As expected, with increased support tonic activity was reduced across all muscles. This effect was greatest in the anti-gravity muscle anterior deltoid, and evident in biceps brachii and pronator teres as well. For BB MEP amplitude, TASK and SUPPORT LEVEL, interacted such that for elbow flexion, MEP amplitudes were smaller with incrementally greater WS whereas, for forearm pronation MEP amplitudes were smaller only at high WS. CONCLUSIONS: Weight support of the arm influences corticomotor selectivity of biceps brachii. WS may impact coordination independently of a global reduction in muscle activity. The amount of supportive force applied to the arm influences the neuromechanical control profile for the limb. These findings may inform the application of WS in upper limb stroke rehabilitation. PMID- 26502934 TI - Ultrafast Photoluminescence from the Core and the Shell in CdSe/CdS Dot-in-Rod Heterostructures. AB - With an ultrafast time-resolved photoluminescence system utilizing a Kerr gate, the time-resolved photoluminescence of core and shell constituents within CdSe/CdS dot-in-rod heterostructures is studied as a function of heterostructure size. Measurements performed at low excitation fluence generating, on average, less than one exciton per nanorod, reveal photoluminescence from direct recombination of carriers in the CdS heterostructure rod with lifetime generally increasing from 0.4 ps to 1.3 ps as the rod length increases. Decay of the CdS rod photoluminescence is accompanied by an increase in emission from the CdSe core on comparable time scales, also trending towards larger values as the rod length increases. The observed kinetics can be explained without invoking a non radiative trapping mechanism. We also present alloying as a mechanism for enhancing electron confinement and reducing fluorescence lifetime at nanosecond time scales. PMID- 26502935 TI - Highly divergent ancient gene families in metagenomic samples are compatible with additional divisions of life. AB - BACKGROUND: Microbial genetic diversity is often investigated via the comparison of relatively similar 16S molecules through multiple alignments between reference sequences and novel environmental samples using phylogenetic trees, direct BLAST matches, or phylotypes counts. However, are we missing novel lineages in the microbial dark universe by relying on standard phylogenetic and BLAST methods? If so, how can we probe that universe using alternative approaches? We performed a novel type of multi-marker analysis of genetic diversity exploiting the topology of inclusive sequence similarity networks. RESULTS: Our protocol identified 86 ancient gene families, well distributed and rarely transferred across the 3 domains of life, and retrieved their environmental homologs among 10 million predicted ORFs from human gut samples and other metagenomic projects. Numerous highly divergent environmental homologs were observed in gut samples, although the most divergent genes were over-represented in non-gut environments. In our networks, most divergent environmental genes grouped exclusively with uncultured relatives, in maximal cliques. Sequences within these groups were under strong purifying selection and presented a range of genetic variation comparable to that of a prokaryotic domain. CONCLUSIONS: Many genes families included environmental homologs that were highly divergent from cultured homologs: in 79 gene families (including 18 ribosomal proteins), Bacteria and Archaea were less divergent than some groups of environmental sequences were to any cultured or viral homologs. Moreover, some groups of environmental homologs branched very deeply in phylogenetic trees of life, when they were not too divergent to be aligned. These results underline how limited our understanding of the most diverse elements of the microbial world remains, and encourage a deeper exploration of natural communities and their genetic resources, hinting at the possibility that still unknown yet major divisions of life have yet to be discovered. PMID- 26502936 TI - Fronto-cerebellar dysfunction and dysconnectivity underlying cognition in friedreich ataxia: The IMAGE-FRDA study. AB - Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder defined by pathology within the cerebellum and spinal tracts. Although FRDA is most readily linked to motor and sensory dysfunctions, reported impairments in working memory and executive functions indicate that abnormalities may also extend to associations regions of the cerebral cortex and/or cerebello-cerebral interactions. To test this hypothesis, 29 individuals with genetically confirmed FRDA and 34 healthy controls performed a verbal n-back working memory task while undergoing functional magnetic resonance imaging. No significant group differences were evident in task performance. However, individuals with FRDA had deficits in brain activations both in the lateral cerebellar hemispheres, principally encompassing lobule VI, and the prefrontal cortex, including regions of the anterior insular and rostrolateral prefrontal cortices. Functional connectivity between these brain regions was also impaired, supporting a putative link between primary cerebellar dysfunction and subsequent cerebral abnormalities. Disease severity and genetic markers of disease liability were correlated specifically with cerebellar dysfunction, while correlations between behavioural performance and both cerebral activations and cerebello-cerebral connectivity were observed in controls, but not in the FRDA cohort. Taken together, these findings support a diaschisis model of brain dysfunction, whereby primary disease effects in the cerebellum result in functional changes in downstream fronto-cerebellar networks. These fronto-cerebellar disturbances provide a putative biological basis for the nonmotor symptoms observed in FRDA, and reflect the consequence of localized cerebellar pathology to distributed brain function underlying higher-order cognition. PMID- 26502938 TI - Neuroregenerative Effect of Oxandrolone: A Case Report. AB - BACKGROUND: Anabolic steroids have the clinical effect of increasing protein synthesis in muscle and other tissues. The brain and spinal cord neurons have gonadal steroid receptors and various studies have shown at structural and molecular levels that androgenic steroids have a significant trophic effect on the brain and spinal cord. CASE REPORT: We evaluated the effect of Oxandrolone (an FDA-approved anabolic steroid) at the dose of 20 mg/day for 3 months added to concomitant exercise strength training 3 times a week in a patient affected by a demyelinating disease, Charcot-Marie-Toot 1 (CMT1). After the treatment, an increase in muscular strength and walking capacity was observed. Muscle biopsy revealed a significant increase of type grouping of muscle fibers, an expression of regeneration and reinnervation processes. CONCLUSIONS: Data ensuing from this single case-report suggest that anabolic androgenic steroids have a potential neuroregenerative effect, with an inherent improvement in neuromuscular efficiency through an increased myelin synthesis at peripheral nervous system site. PMID- 26502939 TI - Rivaroxaban in secondary cardiogenic stroke prevention: two-year single-centre experience based on follow-up of 209 patients. AB - BACKGROUND: The main goal of treatment in patients with atrial fibrillation is to counteract the effects of embolisation, considering the relatively high risk of cerebral embolic events. AIM: An assessment of the efficacy and safety of rivaroxaban in secondary stroke prevention in patients with non-valvular atrial fibrillation (NVAF). METHODS: The study concerned 209 NVAF patients (male/female: 117/92; mean age 65.3 years [41-85]), who used rivaroxaban as secondary prevention of cardiogenic stroke. The patients were followed up for 24 months: the control visits were performed 12 and 24 months after the onset of the inclusion. The following aspects were analysed: the occurrence of recurrent stroke and/or transient ischaemic attack (TIA) during rivaroxaban treatment, bleeding episodes with their placement and severity assessment, drug tolerance, and evaluation of the patient's medical records including laboratory tests (e.g. creatinine clearance) and concomitant therapy. All patients underwent physical examination as well as neurological assessment. RESULTS: The mean CHA2DS2-VASc in the study group was 4.16, and the mean HAS-BLED value was 3.31. During the follow up 13 deaths were noted (6.22%), ischaemic stroke was diagnosed in five (2.39%) subjects, and TIA in three (1.43%) patients. Bleeding complications were reported in 25 (11.96%) patients, two of which were classified as major bleedings (0.95%): an intracranial bleeding (1) and a bleeding from the genital tract (1). CONCLUSIONS: For patients with NVAF and cerebrovascular events, the use of rivaroxaban in a real-world clinical setting results in a highly efficacious treatment profile and acceptable safety. PMID- 26502940 TI - Outcomes of biodegradable polymer sirolimus-eluting PROLIM stent in patients with coronary artery disease. Results of 12-month follow-up of prospective registry. AB - BACKGROUND: Data from clinical trials suggested that biodegradable-polymer-based drug-eluting stents (DES) might improve long-term clinical outcomes. PROLIM (Balton, Warsaw, Poland) DES is based on a stainless steel platform with a closed cell design releasing sirolimus from biodegradable copolymer (lactic and glycolic acid) in eight weeks. AIM: In the present study the safety and the efficacy of a PROLIM stent was assessed in patients with de novo coronary lesions in 12-month clinical follow-up. METHODS: It was a single-centre, observational, prospective registry to assess the safety and efficacy of a PROLIM stent implantation in all consecutive patients with de novo coronary artery lesions treated with percutaneous coronary intervention (PCI). The primary study endpoint was a composite safety (cardiac death, non-fatal myocardial infarction), and the second study endpoint was the efficacy of PROLIM implantation-clinically driven target vessel revascularisation (TVR) assessed at 12-month follow-up. RESULTS: One hundred patients were enrolled into the study and 118 PROLIM stents were implanted. Thirty-two (32%) patients had diabetes, 46 (46%) patients were prior PCI, and 17 (17%) patients had coronary artery bypass grafting. 67% of stented lesions were complex ones (B2/C) and 17% were bifurcations. During the 12-month follow-up primary study endpoints occurred in five (5%) patients. Two (2%) cardiac deaths were reported and three (3%) TVRs were performed, of which one was related to in-PROLIM stent restenosis. CONCLUSIONS: PCI with biodegradable polymer PROLIM DES seems to be safe and effective in 12-month follow-up. A larger trial is warranted to assess clinical outcomes post PROLIM stent implantation. PMID- 26502941 TI - Back to sinus rhythm from atrial flutter or fibrillation: dabigatran is safe without transoesophageal control. AB - BACKGROUND AND AIM: To assess the safety of dabigatran in converting persistent atrial fibrillation (PAF) and atrial flutter (AFL) to sinus rhythm (SR) without transoesophageal echocardiography (TEE) evaluation. METHODS: Consecutive patients with PAF or AFL were included between 2012 and 2015. Dabigatran was used for three weeks before and six months after cardioversion. Left atrium area (LAA) and left atrium volume (LAV) were assessed in all patients. Follow-up visits for major cardiac events occurred at 1, 3, 6, and 12 months. RESULTS: The study included 82 patients (56 male, mean age 63.1 +/- 10.4 years), of which 45 had PAF and 37 AFL. In patients with PAF, mean LAA was 30.3 +/- 5.3 cm2 and LAV 114.4 +/- 31.5 mL; in those with AFL mean LAA was 26.5 +/- 4.2 cm2 and LAV 97 +/- 24.9 mL at baseline. Forty-nine patients underwent uncomplicated electric cardioversion (38 with PAF and 11 with AFL), 11 patients were pharmacologically converted to SR (7 with PAF and 4 with AFL), and 22 patients with AFL underwent successful radiofrequency ablation. The mean CHA2DS2-VASc score was 2.96 +/- 1.39 (score > 3, 58.6%). No major cardiac events occurred during the follow-up period of 19.4 +/- 9.5 months. CONCLUSIONS: Safe cardioversion using dabigatran was achieved in this small group of patients without the need for TEE. PMID- 26502943 TI - Parameters associated with one-year mortality and in-hospital adverse events in patients after emergency pacemaker implantation. AB - BACKGROUND: Permanent cardiac pacing is the treatment of choice for severe and symptomatic bradycardia. Patients undergoing emergency pacemaker implantation are stabilised earlier by the insertion of a temporary emergency pacing lead, and they experience more comorbidities than with planned admissions. AIM: To identify the parameters associated with one-year mortality and in-hospital adverse events after emergency permanent pacemaker implantation. METHODS: This retrospective study analyses data from 131 consecutive emergency pacemaker implantations performed within a single centre. RESULTS: Cox regression analysis revealed the independent predictors of death to be: use of a temporary transvenous pacing lead (TTPL) (HR = 2.82, 95% CI 1.21-6.58, p = 0.02), age >= 78 years (OR = 3.01, 95% CI 1.22-7.42, p = 0.02), longer baseline QRS duration (HR = 1.02, 95% CI 1.00 1.03, p = 0.03), and history of myocardial infarction (MI) (HR = 2.43, 95% CI 1.04-5.68, p = 0.04). Twenty-six patients experienced in-hospital adverse events, such as: death (n = 6), cardiac arrest (n = 3), surgical complications (lead dislocation: n = 4, haematoma: n = 4, microperforation: n = 2), pneumonia or respiratory tract disease (n = 7), wound infection treated with antibiotics (n = 1), and subsequent MI following pacemaker implantation (n = 2). Multivariate logistic regression analysis showed that independent parameters associated with in-hospital adverse events were history of MI (OR = 5.01, 95% CI 1.88-13.3, p = 0.001) and stroke (OR = 3.51, 95% CI 1.16-10.55, p = 0.03). CONCLUSIONS: Our results suggest that the most serious risk factors of one-year mortality related to the use of TTPL are: age >= 78 years, longer baseline QRS duration, and history of MI. The independent parameters associated with in-hospital adverse events were the presence of a history of MI and stroke. PMID- 26502942 TI - Potassium channel changes of peripheral blood T-lymphocytes from Kazakh hypertensive patients in Northwest China and the inhibition effect towards potassium channels by telmisartan. AB - BACKGROUND AND AIM: Increasing evidence indicates that chronic inflammation is a direct or indirect manifestation of hypertension. Potassium channels are thought to be critical for lymphocyte activation, which suggests that hypertension may be an inflammatory disease initiated at the ion channel level. METHODS: This study investigated changes in interleukin (IL)-6, IL-17, and transforming growth factor beta (TGF-b1) expression in the blood of Kazakh hypertensive patients in Northwest China using ELISA technology. Whole-cell patch clamp technology was used to evaluate current changes associated with Kv1.3 and KCa3.1 in peripheral blood T lymphocytes of hypertensive patients, and to investigate current changes induced by telmisartan. We also investigated the effects of telmisartan on expression of Kv1.3 and KCa3.1 at mRNA and protein levels in peripheral blood T lymphocytes using real-time polymerase chain reaction and Western blot analysis. RESULTS: Expression of IL-6, IL-17 and TGF-b1 in the blood of Kazakh hypertensive patients in Northwest China was significantly higher than in healthy controls (p < 0.05). The current mediated by Kv1.3 and KCa3.1 and the corresponding expression at mRNA and protein levels in T lymphocytes were also higher in these hypertensive patients than in controls (p < 0.05). Telmisartan intervention for 24 h and 48 h inhibited the current and expression of Kv1.3 and KCa3.1 at mRNA and protein levels (p < 0.05). CONCLUSIONS: These results indicated that the increase in functional Kv1.3 and KCa3.1 channels expressed in T lymphocytes of Kazakh patients with hypertension was blocked by telmisartan, resulting in a reduced inflammatory response. These results provide theoretical support for the treatment of hypertension at the cellular ion channel level. PMID- 26502944 TI - [Gender and quality of life and coping over one year after myocardial infarction: do men really have the upper hand?]. AB - BACKGROUND: Multiple reports have confirmed that quality of life (QoL) in women after myocardial infarction (MI) is worse compared to men of the same age but some variation depending on QoL dimension was also reported. A less studied issue is coping after MI. AIM: The present study examined whether gender affected the level and dynamics of QoL and coping over 1 year after MI. METHODS: This questionnaire-based study included 3 stages, at the beginning and the end of a rehabilitation programme (n = 222, 163 [73%] men) and 1 year later (n = 140, 98 [70%] men). The MacNew questionnaire was used for evaluating cardiac patient specific QoL in 3 dimensions: physical, emotional and social. Coping was examined using a modified COPE scale that allows assessment of seven coping strategies. RESULTS: Compared to women, men had higher levels of emotional and physical QoL at the first and second stage of the study. At the third stage, men and women did not differ in any QoL aspect. Significant gender-time interactions were found for physical QoL (F(2.137) = 8.66; p = 0.001, eta2 = 0.07) and for 2 of 7 coping strategies: sense of humour (F(2.137) = 4.10; p = 0.02, eta2 = 0.06) and turning to religion (F(2.137) = 3.55; p = 0.03, eta2 = 0.05). CONCLUSIONS: Men demonstrated higher levels of physical and emotional QoL during inpatient rehabilitation but no gender-related differences in any QoL dimension were seen at 1 year. The dynamics of physical QoL changes was related to gender, with improvement seen in women and deterioration seen in men. There were also gender related differences in the dynamics and levels of certain coping strategies. The observed changes in QoL and coping suggest that some of the beneficial effects of rehabilitation could not be maintained over 1 year. These unfavourable changes are more frequent in men. PMID- 26502945 TI - Raised red cell distribution width as a prognostic marker in aortic valve replacement surgery. AB - BACKGROUND AND AIM: Several studies have reported that elevated red cell distribution width (RDW) is associated with poor outcomes in patients with coronary artery disease, chronic heart failure and aortic stenosis following transcatheter aortic valve replacement. Their prognostic utility in patients undergoing aortic valve replacement (AVR) surgery is unknown. METHODS: We prospectively evaluated the prognostic value of RDW in a group of 191 consecutive patients with severe symptomatic aortic stenosis undergoing AVR. The pre-defined primary endpoint at the 30-day follow-up was composed of: all cause mortality, perioperative myocardial infarction, perioperative renal failure, prolonged mechanical ventilation, stroke, heart failure, successfully resuscitated cardiac arrest, the occurrence of multiple-organ failure, and the need for additional surgery for any reason. The secondary endpoint was total mortality. RESULTS: The composite endpoint occurred in 54 patients. In univariate analysis RDW (p < 0.0001), haemoglobin level (p = 0.005), haematocrit (p = 0.01), red blood cell count (RBC; p = 0.002), glomerular filtration rate (p = 0.003), New York Heart Association classification (p = 0.02), atrial fibrillation (p = 0.0044), and pulmonary blood pressure (p = 0.004) were associated with the occurrence of the composite endpoint. RDW (p = 0.0005), haemoglobin level (p = 0.004), haematocrit (p = 0.004), RBC (p = 0.0009) and mean corpuscular volume (p = 0.01) were associated with an increased risk of death. In multivariate analysis, RDW (OR 3.274; 95% CI 1.285-8.344; p = 0.0003) and RBC (OR 0.373; 95% CI 0.176-0.787; p = 0.0097) remained independent predictors of the composite endpoint. Receiver operating characteristic analysis determined a cut-off value of RDW for the prediction of the occurrence of the combined endpoint at 14.1%. CONCLUSIONS: Elevated RDW is associated with a worse outcome following AVR, independent of RBC. PMID- 26502946 TI - spargel, the PGC-1alpha homologue, in models of Parkinson disease in Drosophila melanogaster. AB - BACKGROUND: Parkinson disease (PD) is a progressive neurodegenerative disorder presenting with symptoms of resting tremor, bradykinesia, rigidity, postural instability and additional severe cognitive impairment over time. These symptoms arise from a decrease of available dopamine in the striatum of the brain resulting from the breakdown and death of dopaminergic (DA) neurons. A process implicated in the destruction of these neurons is mitochondrial breakdown and impairment. Upkeep and repair of mitochondria involves a number of complex and key components including Pink1, Parkin, and the PGC family of genes. PGC-1alpha has been characterized as a regulator of mitochondria biogenesis, insulin receptor signalling and energy metabolism, mutation of this gene has been linked to early onset forms of PD. The mammalian PGC family consists of three partially redundant genes making the study of full or partial loss of function difficult. The sole Drosophila melanogaster homologue of this gene family, spargel (srl), has been shown to function in similar pathways of mitochondrial upkeep and biogenesis. RESULTS: Directed expression of srl-RNAi in the D. melanogaster eye causes abnormal ommatidia and bristle formation while eye specific expression of srl-EY does not produce the minor rough eye phenotype associated with high temperature GMR-Gal4 expression. Ddc-Gal4 mediated tissue specific expression of srl transgene constructs in D. melanogaster DA neurons causes altered lifespan and climbing ability. Expression of a srl-RNAi causes an increase in mean lifespan but a decrease in overall loco-motor ability while induced expression of srl-EY causes a severe decrease in mean lifespan and a decrease in loco-motor ability. CONCLUSIONS: The reduced lifespan and climbing ability associated with a tissue specific expression of srl in DA neurons provides a new model of PD in D. melanogaster which may be used to identify novel therapeutic approaches to human disease treatment and prevention. PMID- 26502947 TI - The risk of fall and fracture with the initiation of a prostate-selective alpha antagonist: a population based cohort study. AB - STUDY QUESTION: Do men starting treatment with prostate-specific alpha antagonists have increased risk of fall and fracture? METHODS: Administrative datasets from the province of Ontario, Canada, that contain patient level data were used to generate a cohort of 147,084 men aged >= 66 years who filled their first outpatient prescription for prostate-specific alpha antagonists tamsulosin, alfuzosin, or silodosin between June 2003 and December 2013 (exposed men) plus an equal sized cohort matched 1:1 (using a propensity score model) who did not initiate alpha antagonist therapy. The primary outcome was a hospital emergency room visit or inpatient admission for a fall or fracture in the 90 days after exposure. STUDY ANSWER AND LIMITATIONS: The men exposed to prostate-specific alpha antagonist had significantly increased risks of falling (odds ratio 1.14 (95% CI 1.07 to 1.21), absolute risk increase 0.17% (0.08 to 0.25%)) and of sustaining a fracture (odds ratio 1.16 (1.04 to 1.29), absolute risk increase 0.06% (0.02 to 0.11%)) compared with the unexposed cohort. This increased risk was not observed in the period before alpha antagonist use. Secondary outcomes of hypotension and head trauma were also significantly increased in the exposed cohort (odds ratios 1.80 (1.59 to 2.03) and 1.15 (1.04 to 1.27) respectively). The two cohorts were similar across 98 different covariates including demographics, comorbid conditions, medication use, healthcare use, and prior medical investigation. Potential unmeasured confounders, such as physical deconditioning, mobility impairment, and situational risk factors, may exist. The data used to identify the primary outcomes had limited sensitivity, so the absolute risks of the outcomes are probably underestimates. The study only included men >= 66 years old, and 84% of exposed men were prescribed tamsulosin, so results may not be generalizable to younger men, and there may not be statistical power to show small differences in outcomes between the drugs. WHAT THIS STUDY ADDS: Prostate-specific alpha antagonists are associated with a small but significant increased risk of fall, fracture, and head trauma, probably as a result of induced hypotension. FUNDING, COMPETING INTERESTS, DATA SHARING: This project was conducted at the Institute for Clinical Evaluative Sciences (ICES) Western Site through the Kidney, Dialysis, and Transplantation (KDT) research program. BW has received a research grant from Astellas, and L-AF does consultancy for Amgen. PMID- 26502948 TI - Novel Anticancer Drugs from Nature. PMID- 26502949 TI - Flavonoids, Breast Cancer Chemopreventive and/or Chemotherapeutic Agents. AB - Flavonoids are secondary metabolites abundantly present in commonly consumed fruits and vegetables. They possess diverse properties such as anti-inflammatory, anti-oxidant and anti-cancer. Epidemiologic studies suggest that an enrich flavonoids diet is linked to a decreased risk of breast cancer. These protective properties are due to the alteration of numerous signalling pathways involved in cancer-related phenomena such as inflammation and proliferation. Human clinical trials examining the effect of supplementation of some flavonoids on disease prevention have been conducted. There is no natural flavonoid that has been approved for the treatment of breast cancer. However, natural flavonoids served as lead compounds in the synthesis of cancer chemopreventive and/or therapeutic agents. PMID- 26502950 TI - The Role of Hesperidin in Cell Signal Transduction Pathway for the Prevention or Treatment of Cancer. AB - During past two decades, plant-derived bioactive compounds have been reported as novel therapeutic agents for prevention and/or mitigation of different human diseases such as cancer, inflammation, cardiovascular and neurodegenerative diseases. Hesperidin is known as one of the most common and bioactive constituents of Citrus (C) species which possesses multiple health-promotion effects. A plethora of scientific literature reported that hesperidin possesses in-vitro and in-vivo anticancer activities. In addition, there are numerous scientific evidences regarding the molecular mechanisms of anticancer activities of hesperidin and its aglycone, hesperetin. However, in this case, the number of comprehensive reviews on molecular mechanisms underlying the anticancer effects of hesperidin is sparse. Therefore, in this work we present a critical review of the available literature regarding the molecular mechanisms of the anticancer effects of hesperidin and its aglycone, hesperetin. PMID- 26502951 TI - The ichneumon fly and the equilibration of British natural economies in the eighteenth century. AB - The parasitic ichneumon fly, discovered by European natural philosophers in the seventeenth century, remained largely unstudied until it captured the attention of Enlightenment-era natural historians. Although this sudden surge of interest has been explained as an effort to understand the natural 'evil' of parasitism, the heyday of ichneumon studies was actually inspired by the political and agricultural context of late eighteenth-century Britain. British naturalists were captivated by this insect for reasons both philosophical and practical. In the providentially self-equilibrating qualities of 'natural' ichneumon economies, they saw solutions to political problems of famine, dearth, national wealth, governance and excess population, in addition to finding reassurance that Enlightened confidence in nature's inherent stability and fruitfulness was not unfounded. PMID- 26502952 TI - Tuning Band Alignment Using Interface Dipoles at the Pt/Anatase TiO2 Interface. AB - The Schottky barrier heights at the Pt/TiO2 (001) junctions are modulated over 0.8 eV by inserting <1 nm of LaAlO3. The large electric field in the LaAlO3 is stabilized by preserving the continuity of in-plane lattice symmetry at the oxide interface. These results greatly expand the application of dipole engineering to versatile polycrystalline metal/binary oxide functional interfaces. PMID- 26502953 TI - The Effects of Rhodiola rosea L. Extract on Anxiety, Stress, Cognition and Other Mood Symptoms. AB - This trial evaluated the impact of a Rhodiola rosea L. extract on self-reported anxiety, stress, cognition, and other mood symptoms. Eighty mildly anxious participants were randomized into two different groups of either Rhodiola rosea L (2 * 200 mg dose Vitano(r), 1 tablet taken before breakfast and 1tablet before lunch) or a control condition (no treatment). Self-report measures and cognitive tests were completed at four testing sessions over a period of 14 days. Relative to the controls, the experimental group demonstrated a significant reduction in self-reported, anxiety, stress, anger, confusion and depression at 14 days and a significant improvements in total mood. No relevant differences in cognitive performance between the groups were observed. Rhodiola rosea L (Vitano(r)) presented a favourable safety tolerability profile. Although this was a non placebo controlled trial, it is unlikely that the findings were the result of placebo effects as changes appeared gradual and were specific to certain psychological measures. However, we cannot determine a causal relationship; further investigations are recommended to support the effects of Rhodiola rosea L. extract on stress related symptoms. PMID- 26502954 TI - Costs and utilization of treatment in patients with hemophilia. AB - BACKGROUND: Although hemophilia has a potentially high economic impact, there are no published estimates of healthcare costs for this disease in Portugal. The aim of this study was to evaluate costs of treatment and hospital utilization among patients with hemophilia A and B, with and without inhibitors, over a 3-year period in a Portuguese Comprehensive Care Hemophilia Centre. This is the first study on the financial impact of healthcare costs in patients with hemophilia in Portugal. METHODS: This retrospective, observational study identified patients diagnosed with hemophilia A and B using medical and pharmacy electronic medical records and data from Centro Hospitalar Sao Joao, between January 2011 and December 2013. Patients with inhibitors were all high responders (>5 Bethesda Units [BU]). Severity was classified as mild, moderate or severe based on clotting factor levels. Two main outcomes were measured: (1) cost associated with hospital pharmacy claims (clotting factor) and (2) number of hospital visits/hospitalization. RESULTS: A cohort of 103 patients were identified: 72 (69.9 %) with hemophilia A and 31 (30.1 %) with hemophilia B. Among these, five individuals were classified as patients with inhibitors (four with hemophilia A and one with hemophilia B). From the cohort of hemophilia A patients, 36 individuals (35.0 %) were identified as having severe disease; 20 (19.4 %) moderate; and 16 (15.5 %) mild. In the cohort of hemophilia B patients, 14 (13.6 %) were identified as having severe disease; 14 (13.6 %) moderate; and three (2.9 %) mild. The total mean aggregate cost per year (including clotting factor and hospital utilization) for patients with severe hemophilia B was ?112,469, compared with ?793 for mild hemophilia A. Clotting factor concentrate amounted for 90 % of total cost in severe cases and hospital utilization was also higher in these cases. CONCLUSIONS: Hemophilia treatment is expensive, particularly for patients with severe disease and especially if they develop inhibitors to replacement clotting factors. In our study, severe hemophilia is associated with greater annual total costs in both types of hemophilia (A = ?77,587 and B = ? 112,469). Patients with inhibitors have costs 3.3 times higher than patients without inhibitors. Age was not associated with significantly greater total costs (clotting factor and hospital visits/hospitalizations). PMID- 26502955 TI - Exploring access to care among older people in the last phase of life using the behavioural model of health services use: a qualitative study from the perspective of the next of kin of older persons who had died in a nursing home. AB - BACKGROUND: There is little investigation into what care older people access during the last phase of their life and what factors enable access to care in this group. Illuminating this from the perspective of the next of kin may provide valuable insights into how the health and social care system operates with reference to providing care for this vulnerable group. The behavioural model of health services use has a wide field of application but has not been tested conceptually regarding access to care from the perspective of the next of kin. The aim of this study was to explore the care accessed by older people during the last phase of their life from the perspective of the next of kin and to conceptually test the behavioural model of health services use. METHODS: The data collection took place in 2011 by means of qualitative interviews with 14 next of kin of older people who had died in a nursing home. The interviews were analysed using directed content analysis. The behavioural model of health services use was used in deriving the initial coding scheme, including the categories: utilization of health services, consumer satisfaction and characteristics of the population at risk. RESULTS: Utilization of health services in the last phase of life was described in five subcategories named after the type of care accessed i.e. admission to a nursing home, primary healthcare, hospital care, dental care and informal care. The needs were illuminated in the subcategories: general deterioration, medical conditions and acute illness and deterioration when death approaches. Factors that enabled access to care were described in three subcategories: the organisation of care, next of kin and the older person. These factors could also constitute barriers to accessing care. Next of kin's satisfaction with care was illuminated in the subcategories: satisfaction, dissatisfaction and factors influencing satisfaction. One new category was constructed inductively: the situation of the next of kin. CONCLUSIONS: A bed in a nursing home was often accessed during what the next of kin regarded as the last phase of life. The needs among older people in the last phase of life can be regarded as complex and worsening over time. Most enabling factors lied within the organisation of care but the next of kin enabled access to care and contributed significantly to care quality. More research is needed regarding ageism and stigmatic attitudes among professionals and informal caregivers acting as a barrier to accessing care for older people in the last phase of their life. The behavioural model of health services use was extended with a new category showing that the situation of the next of kin must be taken into consideration when investigating access to care from their perspective. It may also be appropriate to include informal care as part of the concept of access when investigating access to care among older people in the last phase of their life. The results may not be transferable to older people who have not gained access to a bed in a nursing home or to countries where the healthcare system differs largely from the Swedish. PMID- 26502956 TI - Current opinion on the role of testosterone in the development of prostate cancer: a dynamic model. AB - BACKGROUND: Since the landmark study conducted by Huggins and Hodges in 1941, a failure to distinguish between the role of testosterone in prostate cancer development and progression has led to the prevailing opinion that high levels of testosterone increase the risk of prostate cancer. To date, this claim remains unproven. PRESENTATION OF THE HYPOTHESIS: We present a novel dynamic mode of the relationship between testosterone and prostate cancer by hypothesizing that the magnitude of age-related declines in testosterone, rather than a static level of testosterone measured at a single point, may trigger and promote the development of prostate cancer. TESTING THE HYPOTHESIS: Although not easily testable currently, prospective cohort studies with population-representative samples and repeated measurements of testosterone or retrospective cohorts with stored blood samples from different ages are warranted in future to test the hypothesis. IMPLICATIONS OF THE HYPOTHESIS: Our dynamic model can satisfactorily explain the observed age patterns of prostate cancer incidence, the apparent conflicts in epidemiological findings on testosterone and risk of prostate cancer, racial disparities in prostate cancer incidence, risk factors associated with prostate cancer, and the role of testosterone in prostate cancer progression. Our dynamic model may also have implications for testosterone replacement therapy. PMID- 26502957 TI - Stress responses in Streptococcus species and their effects on the host. AB - Streptococci cause a variety of diseases, such as dental caries, pharyngitis, meningitis, pneumonia, bacteremia, endocarditis, erysipelas, and necrotizing fasciitis. The natural niche of this genus of bacteria ranges from the mouth and nasopharynx to the skin, indicating that the bacteria will inevitably be subjected to environmental changes during invasion into the host, where it is exposed to the host immune system. Thus, the Streptococcus-host interaction determines whether bacteria are cleared by the host's defenses or whether they survive after invasion to cause serious diseases. If this interaction was to be deciphered, it could aid in the development of novel preventive and therapeutic agents. Streptococcus species possess many virulent factors, such as peroxidases and heat-shock proteins (HSPs), which play key roles in protecting the bacteria from hostile host environments. This review will discuss insights into the mechanism(s) by which streptococci adapt to host environments. Additionally, we will address how streptococcal infections trigger host stress responses; however, the mechanism by which bacterial components modulate host stress responses remains largely unknown. PMID- 26502958 TI - Spirosoma pulveris sp. nov., a bacterium isolated from a dust sample collected at Chungnam province, South Korea. AB - Strain JSH 5-14(T), a Gram-negative, non-motile, and curved rod-shaped bacterium, was isolated from a dust sample collected at Nonsan, Chungnam province, South Korea, and was characterized to determine its taxonomic position. Phylogenetic analysis based on the 16S rRNA gene sequence of strain JSH 5-14(T) revealed that it belongs to the genus Spirosoma, family Cytophagaceae, class Cytophagia. The highest degree of sequence similarities of strain JSH 5-14(T) were found with Spirosoma liguale DSM 74(T) (97.8%) and Spirosoma endophyticum EX 36(T) (96.2%). The predominant fatty acids were summed feature 3 (composed of C16:1 omega7c/C16:1 omega6c) and C16:1 omega5c. The major polar lipid was phosphatidylethanolamine, and the predominant respiratory quinone was MK-7. Based on the phylogenetic, chemotaxonomic, and phenotypic data, we propose the strain JSH 5-14(T) (=KCTC 42550(T) =JCM 30688(T) =KEMB 9004-165(T)) should be classified as a type strain of a novel species, for which the name Spirosoma pulveris sp. nov., is proposed. PMID- 26502959 TI - Flavobacterium jejuensis sp. nov., isolated from marine brown alga Ecklonia cava. AB - A bacterial strain, designated EC11(T) was isolated from brown alga Ecklonia cava collected from Jeju Island, Korea. EC11(T) was identified as a Gram-negative, rod shaped and yellow-pigmented bacterial strain. The strain EC11(T) grew over a temperature range of 10 degrees C to 30 degrees C (optimally at 25 degrees C), and a pH range of 6.0-10.5 (optimally at pH 7.5). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain EC11(T) belongs to the genus Flavobacterium. Strain EC11(T) shared close similarity with Flavobacterium jumunjinense HME7102(T) (96.4%), Flavobacterium dongtanense LW30(T) (95.8%), Flavobacterium haoranii LQY-7(T) (95.3%), and Flavobacterium urocaniciphilum (95.1%). The major fatty acids (> 5%) were iso-C17:0 3-OH (22.4%), iso-C15:0 3-OH (19.0%), C15:0 (12.4%), summed feature 3 (comprising C16:1 omega7c/ C16:1 omega6c; 9.78%), iso-C15:1 G (9.6%), and iso-C16:0 3-OH (9.0%). The DNA G+C content was 28.1 mol% and the strain contained MK-6 as the predominant menaquinone. The major polar lipids were phosphatidylethanolamine, two unknown aminolipids and three unknown polar lipids. Based on phenotypic, chemotaxonomic and phylogenetic analysis, strain EC11T represents a novel species of the Flavobacterium genus, for which the name Flavobacterium jejuensis sp. nov. is proposed. The type strain of F. jejuensis is EC11(T) (=KCTC 42149(T) = JCM 30735(T)). PMID- 26502960 TI - Niabella ginsenosidivorans sp. nov., isolated from compost. AB - A Gram-reaction negative, strictly aerobic, non-motile, orange colored, and rod shaped bacterium (designated BS26(T)) isolated from compost, was characterized by a polyphasic approach to clarify its taxonomic position. Strain BS26(T) was observed to grow optimally at 25-30 degrees C and at pH 7.0 on R2A and nutrient media. Strain BS26(T) showed beta-glucosidase activity that was responsible for its ability to transform ginsenoside Rb1 (one of the active components of ginseng) to ginsenoside compound-K (C-K). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain BS26(T) belongs to the genus Niabella of family Chitinophagaceae and was most closely related to Niabella soli DSM 19437(T) (94.5% similarity), N. yanshanensis CCBAU 05354(T) (94.3%), and N. aurantiaca DSM 17617(T) (93.8%). The G+C content of genomic DNA was 47.3 mol%. Chemotaxonomic data [predominant isoprenoid quinone-MK-7, major fatty acids-iso C15:0, iso-C15:1 G, iso-C17:0 3-OH, and summed feature 3 (comprising C16:1 omega7c and/or C16:1 omega6c)] supported the affiliation of strain BS26(T) to the genus Niabella. However, strain BS26(T) could be differentiated genotypically and phenotypically from the recognized species of the genus Niabella. The novel isolate therefore represents a novel species, for which the name Niabella ginsenosidivorans sp. nov. is proposed, with the type strain BS26(T) (=KACC 16620(T) =JCM 18199(T)). PMID- 26502961 TI - Enhanced method for microbial community DNA extraction and purification from agricultural yellow loess soil. AB - In this study, novel DNA extraction and purification methods were developed to obtain high-quantity and reliable quality DNA from the microbial community of agricultural yellow loess soil samples. The efficiencies of five different soil DNAextraction protocols were evaluated on the basis of DNA yield, quality and DNA shearing. Our suggested extraction method, which used CTAB, EDTA and cell membrane lytic enzymes in the extraction followed by DNA precipitation using isopropanol, yielded a maximum DNA content of 42.28 +/- 5.59 ug/g soil. In addition, among the five different purification protocols, the acid-treated polyvinyl polypyrrolidone (PVPP) spin column purification method yielded high quality DNA and recovered 91% of DNA from the crude DNA. Spectrophotometry revealed that the ultraviolet A 260/A 230 and A 260/A 280 absorbance ratios of the purified DNA were 1.82 +/- 0.03 and 1.94 +/- 0.05, respectively. PCR-based 16S rRNA amplification showed clear bands at ~1.5 kb with acid-treated PVPP purified DNA templates. In conclusion, our suggested extraction and purification protocols can be used to recover high concentration, high purity, and high molecular-weight DNA from clay and silica-rich agricultural soil samples. PMID- 26502962 TI - The crystal structure of the D-alanine-D-alanine ligase from Acinetobacter baumannii suggests a flexible conformational change in the central domain before nucleotide binding. AB - Acinetobacter baumannii, which is emerging as a multidrug-resistant nosocomial pathogen, causes a number of diseases, including pneumonia, bacteremia, meningitis, and skin infections. With ATP hydrolysis, the D-alanine-D-alanine ligase (DDL) catalyzes the synthesis of D-alanyl-D-alanine, which is an essential component of bacterial peptidoglycan. In this study, we determined the crystal structure of DDL from A. baumannii (AbDDL) at a resolution of 2.2 A. The asymmetric unit contained six protomers of AbDDL. Five protomers had a closed conformation in the central domain, while one protomer had an open conformation in the central domain. The central domain with an open conformation did not interact with crystallographic symmetry-related protomers and the conformational change of the central domain was not due to crystal packing. The central domain of AbDDL can have an ensemble of the open and closed conformations before the binding of substrate ATP. The conformational change of the central domain is important for the catalytic activity and the detail information will be useful for the development of inhibitors against AbDDL and putative antibacterial agents against A. baumannii. The AbDDL structure was compared with that of other DDLs that were in complex with potent inhibitors and the catalytic activity of AbDDL was confirmed using enzyme kinetics assays. PMID- 26502964 TI - Antiviral effects of Lactobacillus ruminis SPM0211 and Bifidobacterium longum SPM1205 and SPM1206 on rotavirus-infected Caco-2 cells and a neonatal mouse model. AB - Rotavirus is worldwide cause of severe gastroenteritis including severe diarrhea and fatal dehydration in infants and young children. There is an available vaccination program for preventing rotavirus infection, but it has limits and restrictions. Probiotics therapy could be an alternative method of antiviral prevention and modulation against rotavirus infection. In this study, we screened the antiviral activity of probiotic bacteria such as 3 Lactobacillus spp. and 14 Bifidobacterium spp. isolated from young Korean. Three of the bacteria, Lactobacillus ruminis SPM0211, Bifidobacterium longum SPM1205, and SPM1206, inhibited human strain Wa rotavirus infection in Caco-2 cells. Furthermore, these bacterial strains inhibited rotavirus replication in a rotavirus-infected neonatal mouse model. To clarify the mechanism of inhibition, we investigated gene expression of Interferon (IFN)-signaling components and IFN-inducible antiviral effectors. All 3 probiotics increased IFN-alpha and IFN-beta levels compared with the control. Gene expression of IFNsignaling components and IFN inducible antiviral effectors also increased. Overall, these results indicate that L. ruminis SPM0211, B. longum SPM1205 and 1206 efficiently inhibit rotavirus replication in vitro and in vivo. Especially, the antiviral effect of Lactobacillus ruminis SPM0211 is worthy of notice. This is the first report of L. ruminis with antiviral activity. Anti-rotaviral effects of the 3 probiotics are likely due to their modulation of the immune response through promoting type I IFNs, which are key regulators in IFN signaling pathway. PMID- 26502963 TI - The Mycobacterium tuberculosis relBE toxin:antitoxin genes are stress-responsive modules that regulate growth through translation inhibition. AB - Toxin-antitoxin (TA) genes are ubiquitous among bacteria and are associated with persistence and dormancy. Following exposure to unfavorable environmental stimuli, several species (Escherichia coli, Staphylococcus aureus, Myxococcus xanthus) employ toxin proteins such as RelE and MazF to downregulate growth or initiate cell death. Mycobacterium tuberculosis possesses three Rel TA modules (Rel Mtb ): RelBE Mtb , RelFG Mtb and RelJK Mtb (Rv1246c-Rv1247c, Rv2865-Rv2866, and Rv3357-Rv3358, respectively), which inhibit mycobacterial growth when the toxin gene (relE, relG, relK) is expressed independently of the antitoxin gene (relB, relF, relJ). In the present study, we examined the in vivo mechanism of the RelE Mtb toxin protein, the impact of RelE Mtb on M. tuberculosis physiology and the environmental conditions that regulate all three rel Mtb modules. RelE Mtb negatively impacts growth and the structural integrity of the mycobacterial envelope, generating cells with aberrant forms that are prone to extensive aggregation. At a time coincident with growth defects, RelE Mtb mediates mRNA degradation in vivo resulting in significant changes to the proteome. We establish that rel Mtb modules are stress responsive, as all three operons are transcriptionally activated following mycobacterial exposure to oxidative stress or nitrogen-limiting growth environments. Here we present evidence that the rel Mtb toxin:antitoxin family is stress-responsive and, through the degradation of mRNA, the RelE Mtb toxin influences the growth, proteome and morphology of mycobacterial cells. PMID- 26502965 TI - Membranoproliferative glomerulonephritis with predominant IgG2 and IgG3 deposition in a patient with IgG4-related disease. AB - BACKGROUND: IgG4-related disease is a novel disease entity characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. Typical renal pathology is tubulointerstitial nephritis with storiform fibrosis, although the co-existence of various glomerular lesions has been described. Here, we present the first report of a case of IgG4-related kidney disease and membranoproliferative glomerulonephritis showing the discrepancy in IgG subclasses between the kidney interstitium and glomeruli. CASE PRESENTATION: A 70 year-old Japanese woman was diagnosed with membranoproliferative glomerulonephritis and focal tubulointerstitial nephritis with IgG4-positive plasma cells. Immunofluorescence studies revealed predominant deposition of IgG3 and IgG2, but not IgG4 in the glomeruli. We administered oral prednisolone at 30 mg/day, and the abnormalities in urine and blood tests gradually resolved. CONCLUSION: In this case, different patterns of IgG subclasses detected in the glomeruli and interstitial plasma cells suggest overlapping immunologic abnormalities. The favorable clinical course in our patient suggests that steroid therapy is promising in cases of IgG4-related kidney disease accompanied by glomerulonephritis. PMID- 26502966 TI - Comparison between the effects of progesterone versus corticosteroid local injections in mild and moderate carpal tunnel syndrome: a randomized clinical trial. AB - BACKGROUND: The objective of this study was to compare the short-term effects of progesterone and corticosteroid local injections in the treatment of female patients with carpal tunnel syndrome. METHODS: A randomized clinical trial was used for this study, 60 hands with mild and moderate Carpal Tunnel Syndrome categorized in two groups were used for this study. Patients were treated with a single local injection of triamcinolone acetonide in one group and single local injection of 17-alpha hydroxy progesterone in the other group. Variables such as pain (based on Visual Analogue Scale), symptom severity and functional status (based on Bostone/Levine symptom severity and functional status scale) and nerve conduction study were evaluated before and 10 weeks after the treatments. RESULTS: Ten weeks after treatment, pain severity and median nerve sensory and motor latencies decreased while patients' functional status increased meaningfully in both groups. However, there were no meaningful differences between two groups regarding mentioned variables. Pain severity was milder and duration of post-injection pain was shorter in the corticosteroid group. The rates of patient satisfaction were also meaningfully higher in the corticosteroid group. CONCLUSIONS: Both treatments were effective in the short-term management of mild and moderate disease, clinically and electrophysiologically. There were no significant differences in therapeutic effects between two groups. TRIAL REGISTRATION: Current controlled trials IRCT2013101313442N4. PMID- 26502967 TI - I am woman - Saving bodies and minds. PMID- 26502968 TI - World stroke day proclamation: updated. PMID- 26502969 TI - Review and prioritization of stroke research recommendations to address the mission of the World Stroke Organization: a call to action from the WSO Research Committee. PMID- 26502972 TI - Injury of the lower portion of the ascending reticular activating system in a patient with intraventricular hemorrhage. PMID- 26502971 TI - Effect of magnesium treatment and glucose levels on delayed cerebral ischemia in patients with subarachnoid hemorrhage: a substudy of the Magnesium in Aneurysmal Subarachnoid Haemorrhage trial (MASH-II). AB - BACKGROUND: Magnesium treatment did not improve outcome in patients with aneurysmal subarachnoid haemorrhage in the Magnesium in Aneurysmal Subarachnoid Haemorrhage II trial. We hypothesized that high glucose levels may have offset a potential beneficial effect to prevent delayed cerebral ischemia. We investigated if magnesium treatment led to less delayed cerebral ischemia and if glucose levels interacted with magnesium treatment in the Magnesium in Aneurysmal Subarachnoid Haemorrhage II trial. AIM: To investigate the effect of magnesium treatment on occurrence of delayed cerebral ischemia and the interaction between glucose levels and magnesium treatment in subarachnoid hemorrhage patients. METHODS: The Magnesium in Aneurysmal Subarachnoid Haemorrhage was a phase III randomized placebo-controlled trial assessing the effect of magnesium sulphate on clinical outcome in aneurysmal subarachnoid hemorrhage patients. For the current study, we included only the patients admitted to the University Medical Centre Utrecht. We calculated hazard ratios for occurrence of delayed cerebral ischemia in patients treated with magnesium vs. placebo for the entire study population, and separately in the subgroups of patients with high and low mean fasting and mean daily glucose levels until onset of delayed cerebral ischemia. We used the cross-product of magnesium and glucose in the regression analysis to evaluate whether an interaction between magnesium and glucose existed. RESULTS: We included 616 patients: 307 received magnesium and 309 placebo; 156 patients had delayed cerebral ischemia. Hazard ratio for magnesium on occurrence of delayed cerebral ischemia was 1.0 (95% confidence interval: 0.7-1.4). Results were similar in patients with low or high fasting or daily glucose levels. We found no interactions between magnesium treatment and high fasting (P = 0.54) and daily glucose (P = 0.60). CONCLUSIONS: Magnesium treatment did not reduce the risk of delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage, nor was there an interaction with glucose levels. It is therefore unlikely that glucose levels explain the failure of magnesium to prevent delayed cerebral ischemia and poor outcome after aneurysmal subarachnoid hemorrhage. PMID- 26502970 TI - One-year case fatality rate following stroke in the Mashhad Stroke Incidence Study: a population-based study of stroke in Iran. AB - BACKGROUND: In developing countries, there are few comprehensive studies of mortality following stroke. AIMS AND/OR HYPOTHESIS: We aimed to determine the one year case fatality rate following stroke and to identify factors associated with death in a population-based stroke incidence study in Iran. METHODS: Six hundred eighty-four patients who had suffered a stroke between November 21, 2006, and November 20, 2007, and were recruited to the Mashhad Stroke Incidence Study were followed up at one-year. Most patients were seen in an outpatient visit. When patients had died, a verbal autopsy was conducted by telephone with the next of kin. RESULTS: A total of 226 (34.3%) patients died during the first year following stroke. The cumulative one-year case fatality rate was 30.6% following ischemic stroke and 53.0% following hemorrhagic stroke (55.8% after intracerebral hemorrhage and 35.7% after subarachnoid hemorrhage). The majority of these deaths occurred in the first 28 days after stroke (17.7% with ischemic and 43.0% with hemorrhagic stroke). Factors associated with greater mortality at one-year (excluding those who died during the first week) were hemorrhagic stroke [hazard ratio (HR) 3.99; 95% confidence interval 1.90-8.37], age (HR 1.05; 95% confidence interval 1.03-1.08), previous transient ischemic attack (HR 2.45; 95% confidence interval 1.00-5.99), and National Institutes of Health Stroke Scale on admission (HR 1.14; 95% confidence interval 1.10-1.17). CONCLUSION: Despite the younger age of stroke occurrence in Iran, the one-year case fatality rate following stroke is similar to that reported in developed countries. PMID- 26502973 TI - Top 10 research priorities relating to stroke nursing. PMID- 26502974 TI - Embolic stroke of unknown source (ESUS) in young patients. PMID- 26502975 TI - Management of in-hospital stroke. PMID- 26502976 TI - Rivaroxaban for the treatment of cerebral venous thrombosis. PMID- 26502977 TI - Analysis of in vivo turnover of tau in a mouse model of tauopathy. AB - BACKGROUND: Intracellular accumulation of tau as neurofibrillary tangles (NFTs) is the hallmark of Alzheimer's disease (AD) as well as in other tauopathies. Tau is present not only in the cytoplasm but also in the extracellular space such as cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Although clearance is one critical parameter leading to such intracellular/extracellular tau accumulation, in vivo turnover of tau has not been well characterized. The current study has attempted to precisely determine in vivo turnover rates of tau utilizing tet-off regulatable mice. In particular, we assessed intracellular tau and extracellular tau, soluble tau, insoluble tau and phosphorylated tau at certain sites utilizing a combination of in vivo microdialysis, biochemical analysis and specific ELISAs recognizing each species. To examine the effect of a tauopathy-associated mutation on tau clearance, half-lives of various tau species were compared between the mice with a FTDP-17 mutation that induces beta-sheet formation, DeltaK280 mutation (pro-aggregant mice) and control mice with additional beta-sheet breaking mutations (anti-aggregant mice). RESULTS: Here we report that tau is metabolized at much slower turnover rates in vivo than in cell culture. We found that insoluble tau in pro-aggregant mice had a significantly slower half-life (t1/2 = ~34.2 days) than soluble tau (t1/2 = ~9.7 days). In contrast, soluble tau phosphorylated in the proline rich region was cleared faster than total soluble tau. When comparing pro-aggregant mice to anti-agregant mice, turnover rates of soluble tau species were not significantly different. CONCLUSIONS: The current study provides a comprehensive description of in vivo turnover of various tau species present in mice that express human tau. The turnover rate of soluble tau was not significantly altered between pro-aggregant mice and anti-aggregant mice. This suggests that altered conformation by DeltaK280 does not have a major impact on clearance pathways for soluble tau. In contrast, different tau species displayed different half-lives. Turnover was significantly delayed for insoluble tau whereas it was accelerated for soluble tau phosphorylated in the proline rich region. These differences in susceptibilities to clearance suggest that aggregation and phosphorylation influences tau clearance which may be important in tau pathogenesis. PMID- 26502979 TI - Cost and sensitivity of restricted active-space calculations of metal L-edge X ray absorption spectra. AB - The restricted active-space (RAS) approach can accurately simulate metal L-edge X ray absorption spectra of first-row transition metal complexes without the use of any fitting parameters. These characteristics provide a unique capability to identify unknown chemical species and to analyze their electronic structure. To find the best balance between cost and accuracy, the sensitivity of the simulated spectra with respect to the method variables has been tested for two models, [FeCl6 ](3-) and [Fe(CN)6 ](3-) . For these systems, the reference calculations give deviations, when compared with experiment, of <=1 eV in peak positions, <=30% for the relative intensity of major peaks, and <=50% for minor peaks. When compared with these deviations, the simulated spectra are sensitive to the number of final states, the inclusion of dynamical correlation, and the ionization potential electron affinity shift, in addition to the selection of the active space. The spectra are less sensitive to the quality of the basis set and even a double-zeta basis gives reasonable results. The inclusion of dynamical correlation through second-order perturbation theory can be done efficiently using the state-specific formalism without correlating the core orbitals. Although these observations are not directly transferable to other systems, they can, together with a cost analysis, aid in the design of RAS models and help to extend the use of this powerful approach to a wider range of transition metal systems. PMID- 26502978 TI - Validity of self-reported height and weight for estimating prevalence of overweight among Estonian adolescents: the Health Behaviour in School-aged Children study. AB - BACKGROUND: Low to moderate agreement between self-reported and directly measured anthropometry is shown in studies for adults and children. However, this issue needs further evaluation during puberty, a period marked by several transitions. We examined the correspondence of BMI status based on self-reported versus measured anthropometric data among Estonian adolescents with a specific focus on gender and age differences. METHODS: Self-reported height and weight were determined in a national representative sample of Estonian schoolchildren collected within the framework of the HBSC (health behaviour of school-aged children) survey. Self-reported and directly measured height and weight were collected from 3379 students (1071 aged 11, 1133 aged 13 and 1175 aged 15 years). The standardized HBSC questionnaire was used for collecting self-reported data; direct anthropometric measures were taken after the HBSC questionnaires were completed. The accuracy of the self-reported values by age and gender groups were determined by comparing mean differences, Bland-Altman plots with limits of agreement, Kappa statistics, and by estimation of the sensitivity and positive predictive value for detecting overweight. RESULTS: Mean self-reported weight, height and body mass index (BMI) values were significantly lower than corresponding values obtained using direct measurements. Mean differences between self-reported and directly measured weight, height and BMI were largest among 11 year-olds and smallest among students aged 15 years. Underestimation of overweight prevalence (includes obese) showed a graded trend which decreased in older age groups; the difference was greater among girls than boys in all age groups. The mean underestimation of overweight prevalence based on self-reported anthropometry was 3.6 percentage points. The positive predictive value was 72.3 % for boys and 63.4 % for girls. CONCLUSION: A distinct age-related pattern in underestimation of weight, height and prevalence of overweight was found; the bias decreased with increasing age. The mean underestimation of overweight prevalence based on self-reports was small, 3.6 %. Self-reported height and weight remain the method of choice in large surveys for practical and logistical reasons. PMID- 26502980 TI - Measurement Uncertainty of Microscopic Laser Triangulation on Technical Surfaces. AB - Laser triangulation is widely used to measure three-dimensional structure of surfaces. The technique is suitable for macroscopic and microscopic surface measurements. In this paper, the measurement uncertainty of laser triangulation is investigated on technical surfaces for microscopic measurement applications. Properties of technical surfaces are, for example, reflectivity, surface roughness, and the presence of scratches and pores. These properties are more influential in the microscopic laser triangulation than in the macroscopic one. In the Introduction section of this paper, the measurement uncertainty of laser triangulation is experimentally investigated for 13 different specimens. The measurements were carried out with and without a laser speckle reducer. In the Materials and Methods section of this paper, the surfaces of the 13 specimens are characterized in order to be able to find correlations between the surface properties and the measurement uncertainty. The last section of this paper describes simulations of the measurement uncertainty, which allow for the calculation of the measurement uncertainty with only one source of uncertainty present. The considerations in this paper allow for the assessment of the measurement uncertainty of laser triangulation on any technical surface when some surface properties, such as roughness, are known. PMID- 26502982 TI - Intense PSMA-expression using (68)Ga-PSMA PET/CT in a paravertebral schwannoma mimicking prostate cancer metastasis. PMID- 26502983 TI - Paget bone disease demonstrated on (68)Ga-PSMA ligand PET/CT. PMID- 26502984 TI - Controlling Molecular Growth between Fractals and Crystals on Surfaces. AB - Recent studies demonstrate that simple functional molecules, which usually form two-dimensional (2D) crystal structures when adsorbed on solid substrates, are also able to self-assemble into ordered openwork fractal aggregates. To direct and control the growth of such fractal supramolecules, it is necessary to explore the conditions under which both fractal and crystalline patterns develop and coexist. In this contribution, we study the coexistence of Sierpinski triangle (ST) fractals and 2D molecular crystals that were formed by 4,4"-dihydroxy 1,1':3',1"-terphenyl molecules on Au(111) in ultrahigh vacuum. Growth competition between the STs and 2D crystals was realized by tuning substrate and molecular surface coverage and changing the functional groups of the molecular building block. Density functional theory calculations and Monte Carlo simulations are used to characterize the process. Both experimental and theoretical results demonstrate the possibility of steering the surface self-assembly to generate fractal and nonfractal structures made up of the same molecular building block. PMID- 26502985 TI - A Framework for Prioritizing Research Investments in Precision Medicine. AB - INTRODUCTION: The adoption of precision medicine (PM) has been limited in practice to date, and yet its promise has attracted research investments. Developing foundational economic approaches for directing proper use of PM and stimulating growth in this area from multiple perspectives is thus quite timely. METHODS: Building on our previously developed expected value of individualized care (EVIC) framework, we conceptualize new decision-relevant metrics to better understand and forecast the expected value of PM. Several aspects of behavior at the patient, physician, and payer levels are considered that can inform the rate and manner in which PM innovations diffuse throughout the relevant population. We illustrate this framework and the methods using a retrospective evaluation of the use of OncotypeDx genomic test among breast cancer patients. RESULTS: The enriched metrics can help inform many facets of PM decision making, such as evaluating alternative reimbursement levels for PM tests, implementation and education programs for physicians and patients, and decisions around research investments by manufacturers and public entities. We replicated prior published results on evaluation of OncotypeDx among breast cancer patients but also illustrated that those results are based on assumptions that are often not met in practice. Instead, we show how incorporating more practical aspects of behavior around PM could lead to drastically different estimates of value. CONCLUSION: We believe that the framework and the methods presented can provide decision makers with more decision-relevant tools to explore the value of PM. There is a growing recognition that data on adoption is important to decision makers. More research is needed to develop prediction models for potential diffusion of PM technologies. PMID- 26502986 TI - Opening the "black box" of nodD3, nodD4 and nodD5 genes of Rhizobium tropici strain CIAT 899. AB - BACKGROUND: Transcription of nodulation genes in rhizobial species is orchestrated by the regulatory nodD gene. Rhizobium tropici strain CIAT 899 is an intriguing species in possessing features such as broad host range, high tolerance of abiotic stresses and, especially, by carrying the highest known number of nodD genes--five--and the greatest diversity of Nod factors (lipochitooligosaccharides, LCOs). Here we shed light on the roles of the multiple nodD genes of CIAT 899 by reporting, for the first time, results obtained with nodD3, nodD4 and nodD5 mutants. METHODS: The three nodD mutants were built by insertion of Omega interposon. Nod factors were purified and identified by LC-MS/MS analyses. In addition, nodD1 and nodC relative gene expressions were measured by quantitative RT-PCR in the wt and derivative mutant strains. Phenotypic traits such as exopolysaccharide (EPS), lipopolysaccharide (LPS), swimming and swarming motilities, biofilm formation and indole acetid acid (IAA) production were also perfomed. All these experiments were carried out in presence of both inducers of CIAT 899, apigenin and salt. Finally, nodulation assays were evaluated in up to six different legumes, including common bean (Phaseolus vulgaris L.). RESULTS: Phenotypic and symbiotic properties, Nod factors and gene expression of nodD3, nodD4 and nodD5 mutants were compared with those of the wild-type (WT) CIAT 899, both in the presence and in the absence of the nod-gene-inducing molecule apigenin and of saline stress. No differences between the mutants and the WT were observed in exopolysaccharide (EPS) and lipopolysaccharide (LPS) profiles, motility, indole acetic acid (IAA) synthesis or biofilm production, either in the presence, or in the absence of inducers. Nodulation studies demonstrated the most complex regulatory system described so far, requiring from one (Leucaena leucocephala, Lotus burtii) to four (Lotus japonicus) nodD genes. Up to 38 different structures of Nod factors were detected, being higher under salt stress, except for the nodD5 mutant; in addition, a high number of structures was synthesized by the nodD4 mutant in the absence of any inducer. Probable activator (nodD3 and nodD5) or repressor roles (nodD4), possibly via nodD1 and/or nodD2, were attributed to the three nodD genes. Expression of nodC, nodD1 and each nodD studied by RT-qPCR confirmed that nodD3 is an activator of nodD1, both in the presence of apigenin and salt stress. In contrast, nodD4 might be an inducer with apigenin and a repressor under saline stress, whereas nodD5 was an inducer under both conditions. CONCLUSIONS: We report for R. tropici CIAT 899 the most complex model of regulation of nodulation genes described so far. Five nodD genes performed different roles depending on the host plant and the inducing environment. Nodulation required from one to four nodD genes, depending on the host legume. nodD3 and nodD5 were identified as activators of the nodD1 gene, whereas, for the first time, it was shown that a regulatory nodD gene-nodD4-might act as repressor or inducer, depending on the inducing environment, giving support to the hypothesis that nodD roles go beyond nodulation, in terms of responses to abiotic stresses. PMID- 26502987 TI - School-based brief psycho-educational intervention to raise adolescent cancer awareness and address barriers to medical help-seeking about cancer: a cluster randomised controlled trial. AB - OBJECTIVES: Raising cancer awareness and addressing barriers to help-seeking may improve early diagnosis. The aim was to assess whether a psycho-educational intervention increased adolescents' cancer awareness and addressed help-seeking barriers. METHODS: This was a cluster randomised controlled trial involving 2173 adolescents in 20 schools. The intervention was a 50-min presentation delivered by a member of Teenage Cancer Trust's (UK charity) education team. Schools were stratified by deprivation and roll size and randomly allocated to intervention/control conditions within these strata. Outcome measures were the number of cancer warning signs and cancer risk factors recognised, help-seeking barriers endorsed and cancer communication. Communication self-efficacy and intervention fidelity were also assessed. RESULTS: Regression models showed significant differences in the number of cancer warning signs and risk factors recognised between intervention and control groups. In intervention schools, the greatest increases in recognition of cancer warning signs at 6-month follow-up were for unexplained weight loss (from 44.2% to 62.0%) and change in the appearance of a mole (from 46.3% to 70.7%), up by 17.8% and 24.4%, respectively. Greatest increases in recognition of cancer risk factors were for getting sunburnt more than once as a child (from 41.0% to 57.6%) and being overweight (from 42.7% to 55.5%), up by 16.6% and 12.8%, respectively. Regression models showed that adolescents in intervention schools were 2.7 times more likely to discuss cancer at 2-week follow-up compared with the control group. No differences in endorsement of barriers to help-seeking were observed. CONCLUSIONS: School-based brief psycho-educational interventions are easy to deliver, require little resource and improve cancer awareness. (c) 2015 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd. PMID- 26502989 TI - Kidney cancer: TKIs associated with stroke risk. PMID- 26502988 TI - Efficient self-assembly and protective efficacy of infectious bursal disease virus-like particles by a recombinant baculovirus co-expressing precursor polyprotein and VP4. AB - BACKGROUND: Virus-like particle (VLP) technology is considered one of the most promising approaches in animal vaccines, due to the intrinsic immunogenic properties as well as high safety profile of VLPs. In this study, we developed a VLP vaccine against infectious bursal disease virus (IBDV), which causes morbidity and mortality in chickens, by expressing a baculovirus in insect cells. METHODS: To improve the self-proteolytic processing of precursor polyprotein (PP), we constructed a recombinant baculovirus transfer vector that co-expresses PP and the VP4 protease gene of IBDV. RESULTS: Expression and VLP assembly of recombinant proteins and antigenicity of the VLP were examined by Western blotting, ELISA, and transmission electron microscopy. In animal experiments, vaccination with the recombinant VLP induced strong and uniform humoral immunity and provided complete protection against challenge with very virulent (vv) IBDV in SPF chickens (n = 12). As determined by the bursa of Fabricius (BF)/body weight (B/BW) ratio, the protection against post-challenge bursal atrophy was significantly higher (P < 0.001) in VLP-vaccinated birds than in non-vaccinated controls. CONCLUSIONS: Since the protective efficacy of the VLP vaccine was comparable to that of a commercially available inactivated vaccine, the recombinant VLP merits further investigation as an alternative means of protection against vvIBD. PMID- 26502990 TI - Science and society: The influence of charities in the field of men's health. PMID- 26502993 TI - Heralded high-efficiency quantum repeater with atomic ensembles assisted by faithful single-photon transmission. AB - Quantum repeater is one of the important building blocks for long distance quantum communication network. The previous quantum repeaters based on atomic ensembles and linear optical elements can only be performed with a maximal success probability of 1/2 during the entanglement creation and entanglement swapping procedures. Meanwhile, the polarization noise during the entanglement distribution process is harmful to the entangled channel created. Here we introduce a general interface between a polarized photon and an atomic ensemble trapped in a single-sided optical cavity, and with which we propose a high efficiency quantum repeater protocol in which the robust entanglement distribution is accomplished by the stable spatial-temporal entanglement and it can in principle create the deterministic entanglement between neighboring atomic ensembles in a heralded way as a result of cavity quantum electrodynamics. Meanwhile, the simplified parity-check gate makes the entanglement swapping be completed with unity efficiency, other than 1/2 with linear optics. We detail the performance of our protocol with current experimental parameters and show its robustness to the imperfections, i.e., detuning and coupling variation, involved in the reflection process. These good features make it a useful building block in long distance quantum communication. PMID- 26502992 TI - Sequence analysis, expression profiles and function of thioredoxin 2 and thioredoxin reductase 1 in resistance to nucleopolyhedrovirus in Helicoverpa armigera. AB - The thioredoxin system, including NADPH, thioredoxin (Trx), and thioredoxin reductase (TrxR), plays significant roles in maintaining intracellular redox homeostasis and protecting organisms against oxidative damage. In this study, the characteristics and functions of H. armigera HaTrx2 and HaTrxR1 were identified. Sequence analysis showed that HaTrx2 and HaTrxR1 were both highly conserved and shared high sequence identity with other insect counterparts. The mRNA of HaTrx2 was expressed the highest in 5th instar 96 h and was mainly detected in heads and epidermis. The expression of HaTrxR1 was highly concentrated in 5th instar 72 h and 96 h, and higher in malpighian tube, midgut and hemocyte than other examined tissues. HaTrx2 and HaTrxR1 were markedly induced by various types of stress. HaTrx2- or HaTrxR1-knockdown increased ROS production in hemocytes and also increased the lipid damage in NPV infected H. armigera larvae. Furthermore, interference with expression of HaTrx2 or HaTrxR1 transcripts in H. armigera larvae resulted in increased sensitivity to NPV infection and shortened LT50 values. Our findings indicated that HaTrx2 and HaTrxR1 contribute to the susceptibility of H. armigera to NPV and also provided the theoretical basis for the in-depth study of insect thioredoxin system. PMID- 26502991 TI - Advances in understanding and treating premature ejaculation. AB - Over the past several years, many advances have been made in our understanding of the epidemiology, pathophysiology, and management of premature ejaculation. Newly developed definitions of premature ejaculation are now available, and our perception of the classification, prevalence, aetiological factors, and treatment options for premature ejaculation have evolved. Despite ongoing research, there remains much to be learned about all aspects of this common sexual disorder, in particular effective clinical diagnosis and treatment options. PMID- 26502995 TI - Chrysin inhibits human airway smooth muscle cells proliferation through the extracellular signal-regulated kinase 1/2 signaling pathway. AB - Asthma is a chronic airway inflammatory disease characterized by an increased mass of airway smooth muscle (ASM). Chrysin (5,7-dihydroxyflavone), a natural flavonoid, has been shown to exert multiple biological activities, including anti inflammatory, anti-proliferative and anti-oxidant effects, as well as the potency to ameliorate asthma in animal models. The objective of the present study was to identify the underlying mechanism of the therapeutic effects of chrysin. The impact of chrysin on basal and platelet-derived growth factor (PDGF)-induced proliferation and apoptosis of human airway smooth muscle cells (HASMCs) was investigated. Furthermore, the activation of the extracellular signal-regulated protein kinase (ERK) signaling pathway was evaluated in HASMCs. The results revealed that chrysin significantly inhibited basal as well as PDGF-induced HASMC proliferation, most likely through the suppression of ERK1/2 phosphorylation. However, chrysin did not significantly reduce PDGF-induced apoptosis of HASMCs. The present study indicated that chrysin may be a promising medication for controlling airway remodeling and clinical manifestations of asthma. PMID- 26502994 TI - Acid-induced off-response of PKD2L1 channel in Xenopus oocytes and its regulation by Ca(2.). AB - Polycystic kidney disease (PKD) protein 2 Like 1 (PKD2L1), also called transient receptor potential polycystin-3 (TRPP3), regulates Ca(2+)-dependent hedgehog signalling in primary cilia, intestinal development and sour tasting but with an unclear mechanism. PKD2L1 is a Ca(2+)-permeable cation channel that is activated by extracellular Ca(2+) (on-response) in Xenopus oocytes. PKD2L1 co-expressed with PKD protein 1 Like 3 (PKD1L3) exhibits extracellular acid-induced activation (off-response, i.e., activation following acid removal) but whether PKD1L3 participates in acid sensing remains unclear. Here we used the two-microelectrode voltage-clamp, site directed mutagenesis, Western blotting, reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence, and showed that PKD2L1 expressed in oocytes exhibits sustained off-response currents in the absence of PKD1L3. PKD1L3 co-expression augmented the PKD2L1 plasma membrane localization but did not alter the observed properties of the off-response. PKD2L1 off response was inhibited by an increase in intracellular Ca(2+). We also identified two intra-membrane residues aspartic acid 349 (D349) and glutamic acid 356 (E356) in the third transmembrane domain that are critical for PKD2L1 channel function. Our study suggests that PKD2L1 may itself sense acids and defines off-response properties in the absence of PKD1L3. PMID- 26502997 TI - Self-focused and other-focused resiliency: Plausible mechanisms linking early family adversity to health problems in college women. AB - OBJECTIVES: This study examined whether self-focused and other-focused resiliency help explain how early family adversity relates to perceived stress, subjective health, and health behaviors in college women. PARTICIPANTS: Female students (N = 795) participated between October 2009 and May 2010. METHODS: Participants completed self-report measures of early family adversity, self-focused (self esteem, personal growth initiative) and other-focused (perceived social support, gratitude) resiliency, stress, subjective health, and health behaviors. RESULTS: Using structural equation modeling, self-focused resiliency associated with less stress, better subjective health, more sleep, less smoking, and less weekend alcohol consumption. Other-focused resiliency associated with more exercise, greater stress, and more weekend alcohol consumption. Early family adversity was indirectly related to all health outcomes, except smoking, via self-focused and other-focused resiliency. CONCLUSIONS: Self-focused and other-focused resiliency represent plausible mechanisms through which early family adversity relates to stress and health in college women. This highlights areas for future research in disease prevention and management. PMID- 26502996 TI - Croconaine rotaxane for acid activated photothermal heating and ratiometric photoacoustic imaging of acidic pH. AB - Absorption of 808 nm laser light by liposomes containing a pH sensitive, near infrared croconaine rotaxane dye increases dramatically in weak acid. A stealth liposome composition permits acid activated, photothermal heating and also acts as an effective nanoparticle probe for ratiometric photoacoustic imaging of acidic pH in deep sample locations, including a living mouse. PMID- 26502998 TI - Association between GRIN2A promoter polymorphism and recovery from concussion. AB - OBJECTIVE: To determine genetic variability within the N-methyl-D-aspartate receptor 2A sub-unit (GRIN2A) gene promoter and its association with concussion recovery time. The hypothesis tested was that there would be a difference in allele and/or genotype distribution between two groups of athletes with normal and prolonged recovery. METHODS: DNA was extracted from saliva collected from a total of 87 athletes with a physician-diagnosed concussion. The (GT) variable number tandem repeats (VNTR) within the promoter region of GRIN2A was genotyped. The long (L) allele was an allele with >=25 repeats and the short (S) allele was an allele with <25 repeats in the GT tract. Participants' recovery time was followed prospectively and was categorized as normal (<=60 days) or prolonged (>60 days). RESULTS: LL carriers were 6-times more likely to recover longer than 60 days following the concussive event (p = 0.0433) when compared to SS carriers. Additionally, L allele carriers were found more frequently in the prolonged recovery group (p = 0.048). CONCLUSION: Determining genetic influence on concussion recovery will aid in future development of genetic counselling. The clinical relevance of genotyping athletes could improve management of athletes who experience concussion injuries. PMID- 26502999 TI - Four-hour delayed memory recall for stories: Theoretical and clinical implications of measuring accelerated long-term forgetting. AB - It has been noted that clinical neuropsychological assessment is "blind" to certain abnormalities of consolidation that occur beyond standard 30-min delay intervals. For example, normal forgetting at 30-min delays has been followed by enhanced forgetting at longer delays in temporal-lobe epilepsy, termed accelerated long-term forgetting (ALF). To evaluate whether ALF could be identified in the neuropsychological assessment of a small sample of examinees with head injuries or other neurological diagnoses (n = 42), a 4-hr delayed recall condition was added to the Logical Memory subtest of the Wechsler Memory Scale-Third Edition. A small percentage of examinees (5/42 or 11%), despite exhibiting unimpaired story recall immediately and after 30-min delays, showed increased forgetting when compared with the average retention of stories (M = 0.83, SD = 0.17) after a 4-hr delay. Three of these 5 examinees also had impaired scores on 20-min delayed recall of the California Verbal Learning Test-Second Edition (CVLT-II) and would have been identified as having memory impairment without an extended, 4-hr delayed recall. In fact, the highest correlation among memory indexes was between 4-hr delayed recall of stories and delayed recall of the CVLT-II word list (r = .59, p < .0001), suggesting different consolidation rates for relational and nonrelational material. PMID- 26503000 TI - Hyperamylinemia as a risk factor for accelerated cognitive decline in diabetes. AB - Type II diabetes increases the risk for cognitive decline via multiple traits. Amylin is a pancreatic hormone that has amyloidogenic and cytotoxic properties similar to the amyloid-beta peptide. The amylin hormone is overexpressed in individuals with pre-diabetic insulin resistance or obesity leading to amylin oligomerization and deposition in pancreatic islets. Amylin oligomerization was implicated in the apoptosis of the insulin-producing beta-cells. Recent studies showed that brain tissue from diabetic patients with cerebrovascular dementia or Alzheimer's disease contains significant deposits of oligomerized amylin. It has also been reported that the brain amylin deposition reduced exploratory drive, recognition memory and vestibulomotor function in a rat model that overexpresses human amylin in the pancreas. These novel findings are reviewed here and the hypothesis that type II diabetes is linked with cognitive decline by amylin accumulation in the brain is proposed. Deciphering the impact of hyperamylinemia on the brain is critical for both etiology and treatment of dementia. PMID- 26503001 TI - The venae comitantes clipping test for the evaluation of the venous drainage of the radial forearm free flap. AB - Risks of failure of the radial forearm free flap (FRFF) are mainly related to venous congestion. Two different venous drainage system have been described for the FRFF, but the choice of the best one is still controversial. The superficial systems have a larger diameter and a thicker wall veins which makes them easier to anastomose. The deep system provides most part of the venous outflow if the caliber of the venae comitantes (VCs) is adequate. We propose an intra-operative method to evaluate the FRFF venous drainage: the VCs clipping test. The test has been used in the choice of the vein to anastomose in 12 consecutive patients with oral cavity post oncological defects reconstructed with the FRFF. The cephalic vein was included in the flap; the VCs were individually clipped with small liga clips and divided with the radial artery still patent. The flap was kept with arterial inflow and superficial venous outflow till the recipient site was ready. If there were no signs of venous stasis, the VCs were kept clipped and the cephalic vein anastomosis was made. If clinical signs of venous stasis were revealed, the largest of the VCs was anastomosed to a vein of adequate caliber in the neck. No signs of flap venous congestion were observed in the postoperative period. No flap necrosis occurred. In this small series of patients the venae comitantes clipping test showed to be an easy, reliable and reproducible method to assess intra-operatively which vein to anastomose. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:647-650, 2016. PMID- 26503003 TI - Less indoor cleaning is associated with poor health and unhappiness in adults: Japanese General Social Survey, 2010. AB - Indoor environment is important to human health and well-being. The aim of the present study was to investigate the relationships among indoor cleaning, rubbish disposal and human health and well-being in a national and population-based setting. Data was retrieved from the Japanese General Social Survey, 2010. Information on demographics, lifestyle factors, frequency of indoor cleaning and rubbish disposal and self-reported health and well-being in Japanese adults was obtained by household interview. Analysis included chi-square test, logistic and multi-nominal regression modelling. Of 5003 Japanese adults (aged 20-89) included in the study cohort, 11.4 % (n = 566) never cleaned their living place, 39.1 % had occasional cleaning and 49.6 % had frequent cleaning. Moreover, 17.5 % (n = 869) never disposed rubbish, 24.9 % had occasional rubbish disposal and 57.6 % had frequent rubbish disposal. 15.0 % of Japanese adults claimed poor self-rated health, and 5.9 % reported unhappiness. Compared to people who frequently cleaned the living place, others tended to report poor self-rated health condition (relative risk ratios (RRR) 1.52, 95 % confidence intervals (CI) 1.24-1.85, P < 0.001) and unhappiness (RRR 1.47, 95 % CI 1.10-1.95, P < 0.001). The combined effects of never cleaning and never rubbish disposal significantly impacted on poor self-rated health (RRR 2.61, 95 % CI 1.40-4.88, P = 0.003) and unhappiness (RRR 2.72, 95 % CI 1.72-4.30, P < 0.001). Only half of the Japanese population frequently cleaned their living place and disposed rubbish. Less or never cleaning and rubbish disposal were associated with poor self-rated health, subjective happiness and potentially other health conditions. Public education on maintaining clean indoor environments to optimise psychological well-being in addition to the known physical health would be suggested. PMID- 26503002 TI - PCBs attenuation and abundance of Dehalococcoides spp., bphC, CheA, and flic genes in typical polychlorinated biphenyl-polluted soil under floody and dry soil conditions. AB - This study investigates PCBs attenuation and the abundance of active polychlorinated-degrading Dehalococcoides spp. biphenyl dioxygenase (bphC), chemotaxis (CheA), and flagellum (flic) genes in floody and dry soil conditions polluted with polychlorinated biphenyls. The results revealed that total PCBs, high chlorinated PCBs (>4 cl), and less chlorinated PCBs (<4 cl) decreased with the passage of time in floody and dry soil conditions. The reduction of total PCBs (13.87%) and less chlorinated PCBs (15.39%) was more in dry soil than floody soil, while high chlorinated PCBs showed more reduction in floody soil (8.06%) than dry soil. Dehaloccoides spp., bphC, CheA, and flic genes indicated temporal dynamics in abundance in floody and dry soil conditions. The highest abundance was 1.6 * 10(9), 3.7 * 10(4), and 3.6 * 10(2) copies in floody and 1.6 * 10(4) copies in dry soil for Dehalococcoides spp., bphC, CheA, and flic, respectively. Multivariate statistics (RDA) revealed that Dehaloccoides spp. were positively influenced by the higher chlorinated PCBs and soil physical properties, CheA gene with floody soil, flic gene with total PCBs and less chlorinated PCBs, and bphC gene was affected with moisture contents and less chlorinated PCBs. This study provides new insight in the attenuation of PCBs and the abundance of active Dehalococcoides spp. and genes in PCBs polluted soil under floody and dry soil conditions. PMID- 26503004 TI - Genotoxic effects of chromium oxide nanoparticles and microparticles in Wistar rats after 28 days of repeated oral exposure. AB - The nanotechnology industry has advanced rapidly in the last 10 years giving rise to the growth of the nanoparticles (NPs) with great potential in various arenas. However, the same properties that make NPs interesting raise concerns because their toxicity has not been explored. The in vivo toxicology of chromium oxide (Cr2O3)-NPs is not known till date. Therefore, this study investigated the 28-day repeated toxicity after 30, 300 and 1000 mg/kg body weight (bw)/day oral treatment with Cr2O3-NPs and Cr2O3 microparticles (MPs) in Wistar rats. The mean size of Cr2O3-NPs and Cr2O3-MPs was 34.89 +/- 2.65 nm and 3.76 +/- 3.41 MUm, respectively. Genotoxicity was assessed using comet, micronucleus and chromosomal aberration (CA) assays. The results revealed a significant increase in DNA damage in peripheral blood leucocytes and liver, micronuclei and CA in bone marrow after exposure of 300 and 1000 mg/kg doses of Cr2O3-NPs and Cr2O3-MPs only at 1000 mg/kg bw/day. Cr biodistribution was observed in all the tissues in a dose dependent manner. The maximum amount of Cr was found in the kidneys and least in the brain of the treated rats. More of the Cr was excreted in the faeces than in the urine. Furthermore, nanotreated rats displayed much higher absorption and tissue accumulation. These findings provide initial data of the probable genotoxicity and biodistribution of NPs and MPs of Cr2O3 generated through repeated oral treatment. PMID- 26503005 TI - Aerobic debromination of BDE-209 by Rhodococcus sp. coupled with zerovalent iron/activated carbon. AB - In this study, an aerobic strain identified as Rhodococcus sp. was isolated from the sediment of a typical electronic waste disassemble site, Taizhou, China. This strain could use BDE-209 as the sole carbon and energy source and degrade 65.1% of BDE-209 (initial concentration being 50 mg/L) within 144 h. To explore the BDE 209 degradation properties of this strain with the co-existed electronic donor, zerovalent iron/activated carbon (ZVI/AC) was introduced to build a microbial chemical coupling system, which was found to promote the degradation of BDE-209 slightly (74.7% in 144 h). Moreover, the debromination products in both of the batch experiments were determined with GC/MS, which showed that lower brominated PBDE congeners were produced almost in order of the number of bromine ions, ranged from nona- to di-BDEs. In addition, the possible debromination pathways of BDE-209 for each system were proposed respectively, which confirmed the microbial activity of BDE-209 debromination. Since some of the lower-brominated BDE congeners are much toxic than BDE-209, these microbial activities might bring potential hazards to the environment with BDE-209 contamination. It is the first time to investigate the transformation of BDE-209 with microbial-chemical coupling system, which is universal in the nature, thus suggesting that the ecological safety of environment exposed to PBDEs should be focused in the future. PMID- 26503006 TI - Modeling the dynamics of DDT in a remote tropical floodplain: indications of post ban use? AB - Significant knowledge gaps exist regarding the fate and transport of persistent organic pollutants like dichlorodiphenyltrichloroethane (DDT) in tropical environments. In Brazil, indoor residual spraying with DDT to combat malaria and leishmaniasis began in the 1950s and was banned in 1998. Nonetheless, high concentrations of DDT and its metabolites were recently detected in human breast milk in the community of Lake Puruzinho in the Brazilian Amazon. In this work, we couple analysis of soils and sediments from 2005 to 2014 at Puruzinho with a novel dynamic floodplain model to investigate the movement and distribution of DDT and its transformation products (dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD)) and implications for human exposure. The model results are in good agreement with the accumulation pattern observed in the measurements, in which DDT, DDE, and DDD (collectively, DDX) accumulate primarily in upland soils and sediments. However, a significant increase was observed in DDX concentrations in soil samples from 2005 to 2014, coupled with a decrease of DDT/DDE ratios, which do not agree with model results assuming a post-ban regime. These observations strongly suggest recent use. We used the model to investigate possible re-emissions after the ban through two scenarios: one assuming DDT use for IRS and the other assuming use against termites and leishmaniasis. Median DDX concentrations and p,p'-DDT/p,p'-DDE ratios from both of these scenarios agreed with measurements in soils, suggesting that the soil parameterization in our model was appropriate. Measured DDX concentrations in sediments were between the two re-emission scenarios. Therefore, both soil and sediment comparisons suggest re-emissions indeed occurred between 2005 and 2014, but additional measurements would be needed to better understand the actual re-emission patterns. Monte Carlo analysis revealed model predictions for sediments were very sensitive to highly uncertain parameters associated with DDT degradation and partitioning. With this model as a tool for understanding inter-media cycling, additional research to refine these parameters would improve our understanding of DDX fate and transport in tropical sediments. PMID- 26503007 TI - Risk assessment of heavy metals from combustion of pelletized municipal sewage sludge. AB - Fly ash and slag are important by-products obtained from combustion of municipal sewage sludge (MSS) after pelletization. The quantitative environmental impact assessment of heavy metals in fly ash and slag, compared to MSS, were performed in accordance with bioavailability and eco-toxicity, geo-accumulation index (GAI), risk assessment code (RAC), and potential ecological risk index (PERI). The results demonstrated that not only direct but also long-term bioavailability and eco-toxicity of heavy metals in fly ash and slag decreased except direct bioavailability and eco-toxicity of Pb in fly ash. The GAI demonstrated that combustion significantly weakened (P < 0.05) the pollution levels of heavy metals. PERI indicated that all risks attributed to heavy metals were significantly lowered (P < 0.05) from 777.07 (very high risk) in MSS to 288.72 (moderate risk) and 64.55 (low risk) in fly ash and slag, respectively. In terms of the RAC, seven heavy metals had low even no risk to the environments after combustion besides As in slag. The environmental risk of heavy metals in fly ash and slag was decreased compared with MSS. However, the results of PERI showed that fly ash had a moderate risk. PMID- 26503008 TI - Seasonal, interannual, and long-term variabilities in biomass burning activity over South Asia. AB - The seasonal, interannual, and long-term variations in biomass burning activity and related emissions are not well studied over South Asia. In this regard, active fire location retrievals from the Moderate Resolution Imaging Spectroradiometer (MODIS), the retrievals of aerosol optical depth (AOD) from MODIS Terra, and tropospheric column NO2 from Ozone Monitoring Instrument (OMI) are used to understand the effects of biomass burning on the tropospheric pollution loadings over South Asia during 2003-2013. Biomass burning emission estimates from Global Fire Emission Database (GFED) and Global Fire Assimilation System (GFAS) are also used to quantify uncertainties and regional discrepancies in the emissions of carbon monoxide (CO), nitrogen oxide (NOx), and black carbon (BC) due to biomass burning in South Asia. In the Asian continent, the frequency of fire activity is highest over Southeast Asia, followed by South Asia and East Asia. The biomass burning activity in South Asia shows a distinct seasonal cycle that peaks during February-May with some differences among four (north, central, northeast, and south) regions in India. The annual biomass burning activity in north, central, and south regions shows an increasing tendency, particularly after 2008, while a decrease is seen in northeast region during 2003-2013. The increase in fire counts over the north and central regions contributes 24 % of the net enhancement in fire counts over South Asia. MODIS AOD and OMI tropospheric column NO2 retrievals are classified into high and low fire activity periods and show that biomass burning leads to significant enhancement in tropospheric pollution loading over both the cropland and forest regions. The enhancement is much higher (110-176 %) over the forest region compared to the cropland (34-62 %) region. Further efforts are required to understand the implications of biomass burning on the regional air quality and climate of South Asia. PMID- 26503009 TI - Ionic liquid-modified silica-coated magnetic nanoparticles: promising adsorbents for ultra-fast extraction of paraquat from aqueous solution. AB - In the present study, ionic liquid-modified silica-coated magnetic nanoparticles (Fe3O4@SiO2@IL) were synthesized and applied as adsorbents for extraction and determination of paraquat (PQ) followed by high-performance liquid chromatography. For assurance of the extraction efficiency, the obtained results were compared with those obtained by bared magnetic nanoparticles (MNPs). Experimental design and response surface methodology were used for optimization of different parameters which affect extraction efficiency of paraquat using both adsorbents. Under the optimized conditions, extraction recoveries in the range of 20-25 and 35-40 % with satisfactory repeatability values (RSDs%, n = 4) less than 5.0 % were obtained for bared MNPs and Fe3O4@SiO2@IL, respectively. The limits of detection were 0.1 and 0.25 MUg/L using Fe3O4@SiO2@IL and bared MNPs, respectively. The linearity was obtained in the range of 0.25 to 25 MUg/L and 0.5 to 25 MUg/L for Fe3O4@SiO2@IL and bared MNPs, respectively, with the coefficients of determination better than 0.9950. Finally, Fe3O4@SiO2@IL was chosen as superior adsorbent due to more dispersion ability, higher extraction recovery, lower detection limit, as well as better linearity and repeatability. Calculated errors (%) were in the range of 3 to 10 % depicting acceptable accuracy for the analysis of PQ by the proposed method. Finally, the method was successfully applied for extraction and determination of PQ in some water and countryside soil samples. PMID- 26503010 TI - Incidence and 1-Year Outcomes of Perioperative Atrial Arrhythmia in Elderly Adults After Hip Fracture Surgery. AB - OBJECTIVES: To determine the incidence and 1-year outcomes of an elderly population with perioperative atrial arrhythmia (PAA) within 7 days of hip fracture surgery. DESIGN: Retrospective cohort study. SETTING: The Rochester Epidemiology Project (REP). PARTICIPANTS: Elderly adults consecutive undergoing hip fracture repair from 1988 to 2002 in Olmsted County, Minnesota (N = 1,088, mean age 84.0 +/- 7.4, 80.2% female). MEASUREMENTS: Baseline clinical variables were analyzed in relation to survival using Cox proportional hazards methods for comparison. RESULTS: Sixty-one participants (5.6%) developed PAA within the first 7 days. During 1 year of follow-up, 239 (22%) participants died. PAA was associated with greater mortality (45% vs 21%; hazard ratio (HR) = 2.8, 95% confidence interval (CI) = 1.9-4.2). Other mortality risk factors were male sex (HR = 2.0, 95% CI = 1.5-2.6), congestive heart failure (HR = 2.1, 95% CI = 1.7 2.8), chronic renal insufficiency (HR = 2.0, 95% CI = 1.5-2.8), dementia (HR = 2.9, 95% CI = 2.2-3.7), and American Society of Anesthesiologists risk Class III, IV, or V (HR = 3.3, 95% CI = 1.9-5.9). CONCLUSION: Elderly adults undergoing hip fracture surgery who develop PAA within 7 days have significantly higher 1-year mortality than those who do not. Further studies are indicated to determine whether prevention of PAA will reduce mortality in this population. PMID- 26503011 TI - Public health impact of strain specific immunity to Borrelia burgdorferi. AB - BACKGROUND: Lyme disease, caused by Borrelia burgdorferi, is the most common tick borne infection in the United States. Although humans can be infected by at least 16 different strains of B. burgdorferi, the overwhelming majority of infections are due to only four strains. It was recently demonstrated that patients who are treated for early Lyme disease develop immunity to the specific strain of B. burgdorferi that caused their infection. The aim of this study is to estimate the reduction in cases of Lyme disease in the United States that may occur as a result of type specific immunity. METHODS: The analysis was performed based on three analytical models that assessed the effects of type specific immunity. Observational data on the frequency with which different B. burgdorferi strains cause human infection in culture-confirmed patients with an initial episode of erythema migrans diagnosed between 1991 and 2005 in the Northeastern United States were used in the analyses. RESULTS: Assuming a reinfection rate of 3 % and a total incidence of Lyme disease per year of 300,000, the estimated number of averted cases of Lyme disease per year ranges from 319 to 2378 depending on the duration of type specific immunity and the model used. CONCLUSION: Given the assumptions of the analyses, this analysis suggests that type specific immunity is likely to have public health significance in the United States. PMID- 26503012 TI - How revascularization on the beating heart with cardiopulmonary bypass compares to off-pump? A meta-analysis of observational studies. AB - Off-pump coronary artery bypass surgery has been a controversial area of debate and the outcome profile of the technique has been thoroughly investigated. Scepticism regarding the reported outcomes and the conduct of the randomized trials comparing this technique with conventional on-pump coronary artery bypass surgery has been widely voiced, and the technique of off-pump surgery remains as an infrequently adopted approach to myocardial revascularization worldwide. Criticisms of the technique are related to lower rates of complete revascularization and its unknown long-term consequences, the significant detrimental effects on mortality and major adverse events when emergency conversion is required, and the significant lack of long-term survival and morbidity data. The hybrid technique of myocardial revascularization on the beating heart with the use of cardiopulmonary bypass may theoretically provide the beneficial effects of off-pump surgery in terms of myocardial protection and organ protection, while providing the safety and stability of on-pump surgery to allow complete revascularization. Large randomized comparison to support evidence based choices is currently lacking. In this article, we have meta-analysed the outcomes of on-pump beating heart surgery in comparison with off-pump surgery focusing on major adverse cardiovascular and cerebrovascular adverse events (MACCE) including mortality, stroke and myocardial infarction and the degree of revascularization and number of bypass grafts performed. It was demonstrated that the beating heart on-pump technique allows a significantly higher number of bypass grafts to be performed, resulting in significantly higher degree of revascularization. We have also demonstrated a slightly higher rate of 30-day mortality and MACCE with the technique although not at a statistically significant level. These results should be considered alongside the population risk profile, where a significantly higher risk cohort had undergone the beating heart on-pump technique. Long-term survival and morbidity figures are required to assess the impact of these findings in the coronary surgery patient population. PMID- 26503013 TI - Endovascular repair of pseudoaneurysms after open surgery for aortic coarctation. AB - OBJECTIVES: To analyse early and long-term results of thoracic endovascular aortic repair (TEVAR) in patients with pseudoaneurysms after open aortic coarctation (CoA) repair. METHODS: A total of 11 patients of 418 patients who had been treated with TEVAR during the period from January 1998 to April 2015 (8 males; median age 53 years) were retrospectively analysed. Dacron patch aortoplasty was primarily performed in 9 patients and subclavian flap aortoplasty in 2 patients. Seven of the 11 patients had asymptomatic pseudoaneurysms (median diameter 56 mm, range 20-65 mm) diagnosed by routine screening. Symptomatic patients presented with haemoptysis, lower limb ischaemia, haemodynamic collapse and back pain and underwent emergency repair (4/11). Adjunctive procedures at the proximal landing zone were required in 7/11 patients. The median number of implanted endoprostheses per patient was 1 (range: 1-5). The median follow-up was 60 months (range 6-161 months). RESULTS: Technical success was achieved in 91% (10/11; 1 secondary elective open conversion). The 30-day mortality was 0%. The stroke rate was 18% (2 non-disabling strokes). In 2 patients (20%), stent-graft displacement during deployment was observed. The reintervention rate was 33% (Type Ib endoleak, left arm claudication, partial coverage of the left common carotid artery). Clinical success during follow-up was achieved in 10/11 patients. In 9/10 patients, aneurysm sac shrinkage was observed. The Type II endoleak rate was 10% (1/10; intercostal artery). The overall mortality rate was 9% (1 patient died of amyotrophic lateral sclerosis). CONCLUSIONS: Endovascular treatment of post-coarctation pseudoaneurysms is feasible in elective and emergency cases, yielding durable results in the long term. Due to anatomical specifics, implantation may be challenging and requires careful procedural planning. On-site cardiothoracic surgery backup is essential in case open conversion is required. PMID- 26503014 TI - Aroused with heart: Modulation of heartbeat evoked potential by arousal induction and its oscillatory correlates. AB - Recent studies showed that the visceral information is constantly processed by the brain, thereby potentially influencing cognition. One index of such process is the heartbeat evoked potential (HEP), an ERP component related to the cortical processing of the heartbeat. The HEP is sensitive to a number of factors such as motivation, attention, pain, which are associated with higher levels of arousal. However, the role of arousal and its associated brain oscillations on the HEP has not been characterized, yet it could underlie the previous findings. Here we analysed the effects of high- (HA) and low-arousal (LA) induction on the HEP. Further, we investigated the brain oscillations and their role in the HEP in response to HA and LA inductions. As compared to LA, HA was associated with a higher HEP and lower alpha oscillations. Interestingly, individual differences in the HEP modulation by arousal induction were correlated with alpha oscillations. In particular, participants with higher alpha power during the arousal inductions showed a larger HEP in response to HA compared to LA. In summary, we demonstrated that arousal induction affects the cortical processing of heartbeats; and that the alpha oscillations may modulate this effect. PMID- 26503016 TI - Prognostic implications of RB1 tumour suppressor gene alterations in the clinical outcome of human osteosarcoma: a meta-analysis. AB - Primary osteosarcoma is the most frequent malignant bone cancer in children and teenagers. Genetic alterations at the retinoblastoma 1 (RB1) gene has been implicated in the development and progression of human osteosarcoma. Here, we performed a meta-analysis to examine the impact of RB1 mutations on the survival of osteosarcoma patients, the risk of metastasis and the histological response of osteosarcoma to chemotherapy. A systemic review of the Medline, Embase, Scopus and Cochrane Library yielded 12 eligible studies with 491 patients for this study. Forest plots resulting from our meta-analyses illustrate that loss of RB1 function results in a 1.62-fold increase in the mortality rate for osteosarcoma patients (RR = 1.62, 95% CI: 1.23-2.13; Z = 3.44, P = 0.0006), a significant increase in osteosarcoma metastasis (OR = 3.95, 95% CI: 1.86-8.38; Z = 3.57; P = 0.0004), and a significant reduction in the histological response of osteosarcoma to chemotherapy (OR = 0.35; 95% CI: 0.13-0.94; Z = -2.08; P = 0.038). Additionally, the nearly symmetrical funnel plot (Egger's test, t = 1.15, P = 0.288) indicates absence of publication bias regarding the meta-analysis that examined the correlation of RB1 alterations with the survival rate for osteosarcoma patients. Our findings suggest that RB1 alterations may serve as a prognostic marker for the management of osteosarcoma patients. PMID- 26503015 TI - Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients. AB - OBJECTIVE: To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). METHODS: 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. RESULTS: Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. CONCLUSIONS: Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients. PMID- 26503018 TI - The impact of peroxydisulphate and peroxymonosulphate on disintegration and settleability of activated sludge. AB - Chemical treatment processes have mostly been considered as an efficient way for biosolid minimization. The improvement of sludge dewatering was more a welcome side-effect of these sequential processes. In this study, heat-activated sodium peroxydisulphate (PDS) and potassium peroxymonosulphate (MPS) were applied in order to disintegrate waste activated sludge (WAS). PDS and MPS treatment of WAS results in the polymer transfer of organic matter from the solid phase to the liquid phase. Our research work was done for chemical disintegration of WAS by PDS and MPS in doses of 0.2%, 0.4%, 0.6%, 0.8% and 1% (169.5, 339.0, 508.5, 678.0 and 847.5 mg [Formula: see text]) activated at temperatures of 60 degrees C and 90 degrees C for 30 min. The application of these methods causes the soluble chemical oxygen demand value to increase in the supernatant. In addition, there was a positive influence on the sludge volume index which decreased for the highest doses of PDS of over 63% and 77% and MPS of over 78% and 82% through heat activation at temperatures of 60 degrees C and 90 degrees C, respectively. Furthermore, MPS was more successful in the floc particle destruction, therefore it caused a higher sludge settlement acceleration (sedimentation/compaction speed) than PDS. The experimental results demonstrated that the application of heat-activated PDS and MPS may become a novel effective way of processing sewage sludge. PMID- 26503017 TI - DNA microarray revealed and RNAi plants confirmed key genes conferring low Cd accumulation in barley grains. AB - BACKGROUND: Understanding the mechanism of low Cd accumulation in crops is crucial for sustainable safe food production in Cd-contaminated soils. RESULTS: Confocal microscopy, atomic absorption spectrometry, gas exchange and chlorophyll fluorescence analyses revealed a distinct difference in Cd accumulation and tolerance between the two contrasting barley genotypes: W6nk2 (a low-grain-Cd accumulating and Cd-sensitive genotype) and Zhenong8 (a high-grain-Cd accumulating and tolerant genotype). A DNA microarray analysis detected large scale changes of gene expression in response to Cd stress with a substantial difference between the two genotypes. Cd stress led to higher expression of genes involved in transport, carbohydrate metabolism and signal transduction in the low grain-Cd-accumulating genotype. Novel transporter genes such as zinc transporter genes were identified as being associated with low Cd accumulation. Quantitative RT-PCR confirmed our microarray data. Furthermore, suppression of the zinc transporter genes HvZIP3 and HvZIP8 by RNAi silencing showed increased Cd accumulation and reduced Zn and Mn concentrations in barley grains. Thus, HvZIP3 and HvZIP8 could be candidate genes related to low-grain-Cd-accumulation. CONCLUSION: Novel transporter genes such as HvZIP3 and HvZIP8 were identified as being associated with low-grain-Cd-accumulation. In addition to advancing academic knowledge, our findings may also result in potential economic benefits for molecular breeding of low Cd accumulating barley and other crops. PMID- 26503019 TI - Expression of ADAM12 is regulated by E2F1 in small cell lung cancer. AB - Our previous study reported that ADAM12 was highly expressed in small cell lung cancer (SCLC) and could be an effective marker for diagnosis and prognosis. Yet, the reason for the high expression of ADAM12 in SCLC requires further elucidation. Transcription factor E2F1 has been receiving increasing attention due to the complexity and diversity of its function in cancer. In the present study, the expression of ADAM12 was significantly decreased following silencing of E2F1 expression by siRNA, thus indicating that E2F1 may regulate the expression of ADAM12 at the level of transcription. Chromatin immunoprecipitation to-sequence analysis identified three binding sites for E2F1 in the locus for ADAM12. They were Chr10: 128010444-128011026, located in the intron of ADAM12, named seq0; Chr10: 128076927-128078127, located in the promoter of ADAM12, named seq1; and Chr10: 128086195-128086876, located in the upstream 20 kb from the transcription start site of ADAM12, named: seq2. Dual-luciferase reporter experiments revealed that seq1 not seq0 and seq2 was able to promote the expression of luciferase. Notably, co-transfection of E2F1 significantly increased the activity of seq1 not seq0 and seq2, but quantitative polymerase chain reaction results showed that seq0, seq1 and seq2 could recruit E2F1, indicating that the influence of E2F1 in regulating the expression of ADAM12 was complex. Sequence analysis clarified that seq1 was a part of the ADAM12 promoter, yet the functions of seq0 and seq2 were unknown. Fusion fragments containing seq0 seq1 or seq2-seq1 were analyzed in luciferase constructs. Compared with seq1 alone, the activities of these fusion fragments were non-significantly reduced. The activities of fusion fragments were significantly decreased following co transfection with E2F1. Thus, the present findings support the conclusion that the E2F1 transcription factor regulates the expression of ADAM12 by binding differential cis-acting elements. PMID- 26503020 TI - Dementia Knowledge Assessment Scale: Development and Preliminary Psychometric Properties. AB - OBJECTIVES: To develop a reliable and valid dementia knowledge scale to address limitations of existing measures, support knowledge evaluation in diverse populations, and inform educational intervention development. DESIGN: A five stage, systematic scale development process was employed to construct and assess the psychometric properties of the Dementia Knowledge Assessment Scale (DKAS). SETTING: Data for the study were generated in an online environment and during clinical dementia care placements from Australian (n = 1,321) and international respondents (n = 446). PARTICIPANTS: Volunteers from a dementia-related massive open online course (n = 1,651), medical students on clinical placement in a residential aged care facility (n = 40), and members of the Australian health workforce (n = 76). MEASUREMENTS: Psychometric properties of the DKAS were established using a literature review to assess the veracity of scale items, respondent feedback during pilot testing, a Delphi study with dementia experts, construction and review by an expert panel, evaluation of item difficulty, item total and interitem correlations. Principal components analysis (PCA) was also performed along with measures of test-retest reliability, internal consistency, construct validity, and concurrent validity. RESULTS: The pilot DKAS was reduced from 40 to 27 items during analysis. PCA identified four distinct and interpretable factors. The revised DKAS displays high levels of test-retest reliability; internal consistency; and preliminary construct, concurrent, and factorial validity. CONCLUSION: The 27-item DKAS is reliable and shows preliminary validity for the assessment of knowledge deficiencies and change in those who provide care and treatment for people with dementia. PMID- 26503021 TI - Cognitive consequences of early versus late antiepileptic drug withdrawal after pediatric epilepsy surgery, the TimeToStop (TTS) trial: study protocol for a randomized controlled trial. AB - BACKGROUND: The goals of intentional curative pediatric epilepsy surgery are to achieve seizure-freedom and antiepileptic drug (AED) freedom. Retrospective cohort studies have indicated that early postoperative AED withdrawal unmasks incomplete surgical success and AED dependency sooner, but not at the cost of long-term seizure outcome. Moreover, AED withdrawal seemed to improve cognitive outcome. A randomized trial is needed to confirm these findings. We hypothesized that early AED withdrawal in children is not only safe, but also beneficial with respect to cognitive functioning. DESIGN: This is a multi-center pragmatic randomized clinical trial to investigate whether early AED withdrawal improves cognitive function, in terms of attention, executive function and intelligence, quality of life and behavior, and to confirm safety in terms of eventual seizure freedom, seizure recurrences and "seizure and AED freedom." Patients will be randomly allocated in parallel groups (1:1) to either early or late AED withdrawal. Randomization will be concealed and stratified for preoperative IQ and medical center. In the early withdrawal arm reduction of AEDs will start 4 months after surgery, while in the late withdrawal arm reduction starts 12 months after surgery, with intended complete cessation of drugs after 12 and 20 months respectively. Cognitive outcome measurements will be performed preoperatively, and at 1 and 2 years following surgery, and consist of assessment of attention and executive functioning using the EpiTrack Junior test and intelligence expressed as IQ (Wechsler Intelligence Scales). Seizure outcomes will be assessed at 24 months after surgery, and at 20 months following start of AED reduction. We aim to randomize 180 patients who underwent anticipated curative epilepsy surgery below 16 years of age, were able to perform the EpiTrack Junior test preoperatively, and have no predictors of poor postoperative seizure prognosis (multifocal magnetic resonance imaging (MRI) abnormalities, incomplete resection of the lesion, epileptic postoperative electroencephalogram (EEG) abnormalities, or more than three AEDs at the time of surgery). DISCUSSION: Growing experience with epilepsy surgery has changed the view towards postoperative medication policy. In a European collaboration, we designed a multi-center pragmatic randomized clinical trial comparing early with late AED withdrawal to investigate benefits and safety of early AED withdrawal. The TTS trial is supported by the Dutch Epilepsy Fund (NL 08-10) ISRCTN88423240/ 08/05/2013. PMID- 26503022 TI - Processed meats are carcinogenic, says new review of evidence. PMID- 26503023 TI - Reduction in Estimated Glomerular Filtration Rate (eGFR) Results in an Increased Risk of Spontaneous Hemorrhagic Transformation in Patients with Large-artery Atherosclerosis Stroke. AB - The association between chronic kidney disease and spontaneous hemorrhagic transformation (HT) in patients with acute ischemic stroke is seldom reported. We performed this study to identify whether reduced estimated glomerular filtration rate (eGFR) is associated with spontaneous HT in acute ischemic stroke patients, and examine whether the association depends on stroke etiology. Patients diagnosed with acute ischemic stroke whose serum creatinine levels at admission were available were consecutively and prospectively enrolled in the Chengdu Stroke Registry Database. All were analyzed on admission by cranial computed tomography (CT) scanning, followed by regular magnetic resonance imaging (MRI) 2 3 days later and afterwards CT scan if neurological symptoms deteriorated. HT was defined based on the MRI or later CT, and eGFR was calculated using the Modification of Diet in Renal Disease equation. Univariate analysis and multivariable logistic regression were performed to determine whether reduced eGFR, defined as < 60 ml/min/1.73m2, was associated with spontaneous HT. The association was also assessed in subgroups of patients classified according to the criteria of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Of the 1,645 patients enrolled, 123 (7.5%) developed spontaneous HT and 215 (13.1%) had reduced eGFR. Reduced eGFR was significantly associated with increased risk of spontaneous HT in all ischemic stroke patients (OR 1.821, 95% CI 1.081 to 3.06, P=0.024), and in the subgroup of large artery atherosclerosis, not in the cardio embolism stroke group (OR 1.588, 95% CI 0.642 to 3.782, P=0.327). Reduced eGFR did not increase the risk of symptomatic hemorrhagic transformation (OR 0.937, 95%CI 0.247 to 3.577, P=0.924). In conclusion, reduced eGFR was significantly associated with increased risk of spontaneous HT in all ischemic stroke patients, and in large artery atherosclerosis, not in cardio-embolism stroke. Reduced eGFR did not increase the risk of symptomatic HT. PMID- 26503024 TI - Cyclooxygenase-2 and Prostaglandin E2 are Associated with Middle Cerebral Artery Occlusion and Hemorrhage in Patients with Moyamoya Disease. AB - Some inflammatory proteins, such as cyclooxygenase (COX)-2 and prostaglandin (PG) E2 are hypothesized to be implicated in the development of moyamoya disease (MMD). However, the functional roles of COX-2/PGE2 in the pathogenesis of MMD remain elusive. In this study, tiny pieces of middle cerebral artery (MCA) and superficial temporal artery (STA) were surgically harvested from 18 adult MMD patients and 5 surgical control patients. The expression levels of COX-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1) in the vascular walls were immunohistochemically detected. With additional 10 healthy controls, the plasma levels of PGE2 were also measured by enzyme-linked immunosorbent assay (ELISA). Obvious intimal thickening was observed in both STA and MCA of MMD patients, but not in the controls. However, the MCA had a thicker intima than the STA (P < 0.01). Although plasma concentrations of PGE2 had no differences among the MMD patients, surgical controls and healthy controls, MCA of most MMD patients (15/18, 83.3%) were stained positively for COX-2 and all patients for mPGES-1. Staining of both COX-2 and mPGES-1 was more abundant in the MCA of hemorrhagic patients than those in their ischemic counterparts (P = 0.001 and 0.029, respectively). The expression levels of COX-2 were positively correlated with those of mPGES-1 (r = 0.647, P = 0.004). Positive COX-2 and mPGES-1 expressions were detected neither in the MCA samples from the surgical controls nor in all STA specimens. Our findings indicate that COX-2/PGE2 may be associated with the MCA occlusion and the hemorrhagic stroke in patients with MMD. PMID- 26503025 TI - Identification of Inflammatory, Metabolic, and Cell Survival Pathways Contributing to Cerebral Small Vessel Disease by Postmortem Gene Expression Microarray. AB - Cerebral small-vessel disease (SVD) is characterized by periventricular white matter (WM) changes and general brain atrophy. SVD is prevalent in elderly individuals and is frequently associated with the development of vascular dementia (VaD). Studies of the molecular basis of SVD are sparse. We have to gain further insight into the pathogenic mechanisms of SVD. Therefore, we compared gene expression patterns in the brains of SVD and control patients, in order to identify cellular pathways changed in diseased brains. We compared the expression of mRNA transcripts in postmortem, macroscopically normal-appearing human brain tissues isolated from frontal, temporal and occipital cortical and subcortical regions in 5 SVD and 5 non-SVD control patients. Significant expression changes were determined by fold change F>1.2 in either direction, and p<0.05. We identified 228 genes differentially expressed in cortex (89 up-, 139 down regulated) and 555 genes in WM (223 up-, 332 down-regulated) in SVD patients. Pathway analyses revealed that upregulated genes were associated with inflammation and apoptosis in WM, suggesting active cell death. Downregulated genes were associated with coagulation and fatty and amino acids metabolisms. In the cortex, down-regulated genes were principally associated with neuronal functions. Our data revealed widespread changes in the transcriptome profiles in the cortex and WM of human SVD brains, with a predominance of changes in WM. We provide for the first time a comprehensive view of the molecular alterations in human SVD brains that seem to contribute to the neuropathogenesis of SVD. PMID- 26503026 TI - Assessment of Vascular Geometry for Bilateral Carotid Artery Ligation to Induce Early Basilar Terminus Aneurysmal Remodeling in Rats. AB - Bilateral common carotid artery (CCA) ligation in rabbits is a model for basilar terminus (BT) aneurysm formation. We asked if this model could be replicated in rats. Fourteen female Sprague Dawley rats underwent bilateral CCA ligation (n=8) or sham surgery (n=6). After 7 days, 5 ligated and 3 sham rats were euthanized for histological evaluation of BT aneurysm formation, while the remaining rats were imaged with magnetic resonance angiography, euthanized, and subjected to corrosion casting of the Circle of Willis (CoW). 3D micro computed tomography images of CoW casts were used for flow simulations at the rat BT, and electron micrographs of the casts were analyzed for aneurysmal and morphological changes. Results from these analyses were compared to rabbit model data (n=10 ligated and n=6 sham). Bilateral CCA ligation did not produce aneurysmal damage at the rat BT. While the surgical manipulation increased rat basilar artery flow, fluid dynamics simulations showed that the initial hemodynamic stress at the rat BT was significantly less than in rabbits. Rats also exhibited fewer morphological and pathological changes (minor changes only occurred in the posterior CoW) than rabbits, which had drastic changes throughout the CoW. A comparison of CoW anatomies demonstrated a greater number of branching arteries at the BT, larger CoW arteries in relation to basilar artery, and a steeper BT bifurcation angle in the rat. These differences could account for the lower hemodynamic stress at the BT and in the cerebrovasculature of the rat. In conclusion, bilateral CCA ligation in rats does not recapitulate the rabbit model of early flow-induced BT aneurysm. We suspect that the different CoW morphology of the rat lessens hemodynamic insults, thereby diminishing flow-induced aneurysmal remodeling. PMID- 26503027 TI - PAX4 Defines an Expandable beta-Cell Subpopulation in the Adult Pancreatic Islet. AB - PAX4 is a key regulator of pancreatic islet development whilst in adult acute overexpression protects beta-cells against stress-induced apoptosis and stimulates proliferation. Nonetheless, sustained PAX4 expression promotes beta cell dedifferentiation and hyperglycemia, mimicking beta-cell failure in diabetic patients. Herein, we study mechanisms that allow stringent PAX4 regulation endowing favorable beta-cell adaptation in response to changing environment without loss of identity. To this end, PAX4 expression was monitored using a mouse bearing the enhanced green fluorescent protein (GFP) and cre recombinase construct under the control of the islet specific pax4 promoter. GFP was detected in 30% of islet cells predominantly composed of PAX4-enriched beta-cells that responded to glucose-induced insulin secretion. Lineage tracing demonstrated that all islet cells were derived from PAX4(+) progenitor cells but that GFP expression was confined to a subpopulation at birth which declined with age correlating with reduced replication. However, this GFP(+) subpopulation expanded during pregnancy, a state of active beta-cell replication. Accordingly, enhanced proliferation was exclusively detected in GFP(+) cells consistent with cell cycle genes being stimulated in PAX4-overexpressing islets. Under stress conditions, GFP(+) cells were more resistant to apoptosis than their GFP(-) counterparts. Our data suggest PAX4 defines an expandable beta-cell sub population within adult islets. PMID- 26503028 TI - Oximetry-supported self-management for chronic obstructive pulmonary disease: mixed method feasibility pilot project. AB - BACKGROUND: Pulse oximetry could potentially contribute to self-monitoring. NHS Lothian's 'Light Touch' service provided COPD patients with a self-management plan based on symptoms and oximetry. The service was overseen (though not actively monitored) by respiratory-trained community teams who were contactable by a telephone helpline. We aimed to assess the feasibility, perceived utility and impact of the 'Light Touch' service. METHODS: A before-and-after assessment of St George's Respiratory Questionnaire (SGRQ), Hospital Anxiety and Depression Scale (HADS) and use of healthcare resources during the 6-month feasibility study compared to the previous corresponding 6-months. Paired semi-structured interviews with patients at baseline and 6-months, interviews with managers and a focus group of professionals explored perceptions of the service and self management. Transcripts were coded, and analysed thematically. RESULTS: We recruited 51 participants (mean age 69.7 years (SD 8.4); 21 (46%) male). 46 participants completed quantitative follow up (2 died, 2 were unwell, 1 refused). SGRQ: 21 (46%) participants improved by 4 or more (the minimum important difference); 12 (26%) deteriorated by 4 or more. HADS: more participants had normal scores for anxiety (65%) and depression (80%) at 6-months than at baseline (51 and 64%). More emergency therapy was prescribed during the study period compared to the previous year. Only 18 participants (39%) contacted the Light Touch Helpline during the 6-month study. Twenty patients provided a total of 36 interviews, 8 clinicians contributed to a focus group and 6 managers were interviewed. Patients considered that the oximetry readings heightened awareness of their condition and gave them confidence to make self-management decisions. Healthcare professionals valued oximetry as a tool for teaching people self management skills, but were concerned that patients rarely contacted the teams for help or advice during the study. CONCLUSIONS: 'Light Touch' shows promise as a low-cost strategy for empowering patients' self-management skills and reducing reliance on clinical supervision. PMID- 26503029 TI - Associations of chronic conditions, APOE4 allele, stress factors, and health behaviors with self-rated health. AB - BACKGROUND: Self-rated health (SRH) has been widely used to measure the overall health status of older adults. Research has shown that SRH is determined by a large array of factors, such as chronic disease conditions, genetic markers (e.g., Apolipoprotein E, APOE, NM_000041), stress factors, and health behaviors. However, few studies have incorporated these factors simultaneously in the analytic framework of SRH. The aim of this study is to examine the associations of these four sets of factors with SRH. METHODS: Using a dataset from a population-based, random-cluster survey of 1,005 elderly respondents aged 54-91 conducted in Taiwan in 2000, we use logistic regressions to examine associations of chronic health conditions, the APOE4 allele stress factors, and health behaviors with SRH. The four disease conditions include diabetes, heart diseases, gastric ulcers, and chronic obstructive pulmonary disease. Stress factors are measured by traumatic events (having an earthquake-damaged house) and chronic life stress (financial difficulty). Health behaviors include smoking, drinking alcohol, vegetable and fruit intake, daily milk intake, and physical exercise. RESULTS: Diabetes, heart diseases, gastric ulcers, and chronic obstructive pulmonary disease are found to be associated with 2.63 (95 % CI: 1.75-3.95), 1.72 (95 % CI: 1.15-2.58), 1.94 (95 % CI: 1.35-2.80), and 2.54 (95 % CI: 1.66-3.92) odds ratios of poor SRH. The APOE4 allele is found to be significantly associated with poor SRH with odd ratio of 1.58 (95 % CI: 1.02-2.41). Financial difficulty is associated with increased likelihood of poor SRH, with odds ratios of 1.76 (95 % CI: 1.22-2.54) Doing exercise more than 5 times per week are associated with reduced likelihood of poor SRH by 44 % (odds ratio is 0.56, 95 % CI: 0.39-1.82). The interaction term between gender and gastric ulcer showed that the impact of gastric ulcer on SRH is more pronounced in women than in men, with an odds ratio of 2.63 (95 % CI: 1.24-5.58). CONCLUSIONS: Chronic conditions and the APOE4 allele are significantly associated with increased likelihood of reporting poor health, and the associations appear differently among women and men. To better understand the mechanism of how people self-assess their overall health, chronic conditions and genetic components should be considered together with conventional factors such as life stress and health behaviors. PMID- 26503031 TI - Extension of oil biosynthesis during the mid-phase of seed development enhances oil content in Arabidopsis seeds. AB - Regulation of oil biosynthesis in plant seeds has been extensively studied, and biotechnological approaches have been designed to increase seed oil content. Oil and protein synthesis is negatively correlated in seeds, but the mechanisms controlling interactions between these two pathways are unknown. Here, we identify the molecular mechanism controlling oil and protein content in seeds. We utilized transgenic Arabidopsis thaliana plants overexpressing WRINKLED1 (WRI1), a master transcription factor regulating seed oil biosynthesis, and knockout mutants of major seed storage proteins. Oil and protein biosynthesis in wild-type plants was sequentially activated during early and late seed development, respectively. The negative correlation between oil and protein contents in seeds arises from competition between the pathways. Extension of WRI1 expression during mid-phase of seed development significantly enhanced seed oil content. This study demonstrates that temporal activation of genes involved in oil or storage protein biosynthesis determines the oil/protein ratio in Arabidopsis seeds. These results provide novel insights into potential breeding strategies to generate crops with high oil contents in seeds. PMID- 26503030 TI - Benzofuroxan derivatives N-Br and N-I induce intrinsic apoptosis in melanoma cells by regulating AKT/BIM signaling and display anti metastatic activity in vivo. AB - BACKGROUND: Malignant melanoma is an aggressive type of skin cancer, and despite recent advances in treatment, the survival rate of the metastatic form remains low. Nifuroxazide analogues are drugs based on the substitution of the nitrofuran group by benzofuroxan, in view of the pharmacophore similarity of the nitro group, improving bioavailability, with higher intrinsic activity and less toxicity. Benzofuroxan activity involves the intracellular production of free radical species. In the present work, we evaluated the antitumor effects of different benzofuroxan derivatives in a murine melanoma model. METHODS: B16F10 Nex2 melanoma cells were used to investigate the antitumor effects of Benzofuroxan derivatives in vitro and in a syngeneic melanoma model in C57Bl/6 mice. Cytotoxicity, morphological changes and reactive oxygen species (ROS) were assessed by a diphenyltetrasolium reagent, optical and fluorescence microscopy, respectively. Annexin-V binding and mitochondrial integrity were analyzed by flow cytometry. Western blotting and colorimetry identified cell signaling proteins. RESULTS: Benzofuroxan N-Br and N-I derivatives were active against murine and human tumor cell lines, exerting significant protection against metastatic melanoma in a syngeneic model. N-Br and N-I induce apoptosis in melanoma cells, evidenced by specific morphological changes, DNA condensation and degradation, and phosphatidylserine translocation in the plasma membrane. The intrinsic mitochondrial pathway in B16F10-Nex2 cells is suggested owing to reduced outer membrane potential in mitochondria, followed by caspase -9, -3 activation and cleavage of PARP. The cytotoxicity of N-Br and N-I in B16F10-Nex2 cells is mediated by the generation of ROS, inhibited by pre-incubation of the cells with N-acetylcysteine (NAC). The induction of ROS by N-Br and N-I resulted in the inhibition of AKT activation, an important molecule related to tumor cell survival, followed by upregulation of BIM. CONCLUSION: We conclude that N-Br and N-I are promising agents aiming at cancer treatment. They may be useful in melanoma therapy as inducers of intrinsic apoptosis and by exerting significant antitumor activity against metastatic melanoma, as presently shown in syngeneic mice. PMID- 26503032 TI - Anomalous polarization dependence of Raman scattering and crystallographic orientation of black phosphorus. AB - We investigated polarization dependence of the Raman modes in black phosphorus (BP) using five different excitation wavelengths. The crystallographic orientation was determined by comparing polarized optical microscopy with high resolution transmission electron microscopy analysis. In polarized Raman spectroscopy, the B2g mode shows the same polarization dependence regardless of the excitation wavelength or the sample thickness. On the other hand, the Ag(1) and Ag(2) modes show a peculiar polarization behavior that depends on the excitation wavelength and the sample thickness. The thickness dependence can be explained by considering the anisotropic interference effect due to the birefringence and dichroism of the BP crystal, but the wavelength dependence cannot be explained. We propose a simple and fail-proof procedure to determine the orientation of a BP crystal by combining polarized Raman scattering with polarized optical microscopy. PMID- 26503034 TI - The Role of Stage at Diagnosis in Colorectal Cancer Black-White Survival Disparities: A Counterfactual Causal Inference Approach. AB - BACKGROUND: To date, a counterfactual framework has not been used to study determinants of social inequalities in cancer. Considering the case of colorectal cancer, for which racial/ethnic differences in stage at diagnosis and survival are well documented, we quantify the extent to which black versus white survival disparities would be reduced had disparities in stage at diagnosis been eliminated in a large patient population. METHODS: We obtained data on colorectal cancer patients (diagnosed between 1992 and 2005 and followed until 2010) from US SEER (Surveillance, Epidemiology, and End Results) cancer registries. We employed a counterfactual approach to estimate the mean survival time up to the 60th month since diagnosis for black colorectal cancer patients had black-white disparities in stage at diagnosis been eliminated. RESULTS: Black patients survive approximately 4.0 [confidence interval (CI), 4.6-3.2] months less than white patients within five years since diagnosis. Had disparities in stage at diagnosis been eliminated, survival disparities decrease to 2.6 (CI, 3.4-1.7) months, an approximately 35% reduction. For patients diagnosed after the age of 65 years, disparities would be halved, while reduction of approximately 30% is estimated for younger patients. Survival disparities would be reduced by approximately 44% for women and approximately 26% for men. CONCLUSIONS: Employing a counterfactual approach and allowing for heterogeneities in black-white disparities across patients' characteristics, we give robust evidence that elimination of disparities in stage at diagnosis contributes to a substantial reduction in survival disparities in colorectal cancer. IMPACT: We provide the first evidence in the SEER population that elimination of inequities in stage at diagnosis might lead to larger reductions in survival disparities among elderly and women. PMID- 26503033 TI - Impaired prefrontal synaptic gain in people with psychosis and their relatives during the mismatch negativity. AB - The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task--for 24 patients with psychosis, 25 of their first-degree unaffected relatives, and 35 controls--and DCM was used to estimate the excitability (modeled as self-inhibition) of (source-specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context-dependent (condition-specific) and context-independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis. PMID- 26503035 TI - Secondhand Tobacco Smoke Exposure and Lung Adenocarcinoma In Situ/Minimally Invasive Adenocarcinoma (AIS/MIA). AB - The aim of this study was to estimate the effect of exposure to secondhand tobacco smoke on the incidence of lung adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA). Data from seven case-control studies participating in the International Lung Cancer Consortium (ILCCO) were pooled, resulting in 625 cases of AIS/MIA and 7,403 controls, of whom 170 cases and 3,035 controls were never smokers. Unconditional logistic regression was used to estimate adjusted ORs (ORadj) and 95% confidence intervals (CI), controlling for age, sex, race, smoking status (ever/never), and pack-years of smoking. Study center was included in the models as a random-effects intercept term. Ever versus never exposure to secondhand tobacco smoke was positively associated with AIS/MIA incidence in all subjects (ORadj = 1.48; 95% CI, 1.14-1.93) and in never smokers (ORadj = 1.45; 95% CI, 1.00-2.12). There was, however, appreciable heterogeneity of ORadj across studies (P = 0.01), and the pooled estimates were largely influenced by one large study (40% of all cases and 30% of all controls). These findings provide weak evidence for an effect of secondhand tobacco smoke exposure on AIS/MIA incidence. Further studies are needed to assess the impact of secondhand tobacco smoke exposure using the newly recommended classification of subtypes of lung adenocarcinoma. PMID- 26503036 TI - A geometric network model of intrinsic grey-matter connectivity of the human brain. AB - Network science provides a general framework for analysing the large-scale brain networks that naturally arise from modern neuroimaging studies, and a key goal in theoretical neuroscience is to understand the extent to which these neural architectures influence the dynamical processes they sustain. To date, brain network modelling has largely been conducted at the macroscale level (i.e. white matter tracts), despite growing evidence of the role that local grey matter architecture plays in a variety of brain disorders. Here, we present a new model of intrinsic grey matter connectivity of the human connectome. Importantly, the new model incorporates detailed information on cortical geometry to construct 'shortcuts' through the thickness of the cortex, thus enabling spatially distant brain regions, as measured along the cortical surface, to communicate. Our study indicates that structures based on human brain surface information differ significantly, both in terms of their topological network characteristics and activity propagation properties, when compared against a variety of alternative geometries and generative algorithms. In particular, this might help explain histological patterns of grey matter connectivity, highlighting that observed connection distances may have arisen to maximise information processing ability, and that such gains are consistent with (and enhanced by) the presence of short cut connections. PMID- 26503037 TI - Cross-Polarization Electron-Nuclear Double Resonance Spectroscopy. AB - Magnetic nuclei in the proximity of a paramagnetic center can be polarized through electron-nuclear cross-polarization and detected in electron-nuclear double resonance (ENDOR) spectroscopy. This principle is demonstrated in a single crystal model sample as well as on a protein, the beta2 subunit of E.coli ribonucleotide reductase (RNR), which contains an essential tyrosyl radical. ENDOR is a fundamental technique to detect magnetic nuclei coupled to paramagnetic centers. It is widely employed in biological and materials sciences. Despite its utility, its sensitivity in real samples is about one to two orders of magnitude lower than conventional electron paramagnetic resonance, thus restricting its application potential. Herein, we report the performance of a recently introduced concept to polarize nuclear spins and detect their ENDOR spectrum, which is based on electron-nuclear cross polarization (eNCP). A single crystal study permits us to disentangle eNCP conditions and CP-ENDOR intensities, providing the experimental foundation in agreement with the theoretical prediction. The CP-ENDOR performance on a real protein sample is best demonstrated with the spectra of the essential tyrosyl radical in the beta2 subunit of E.coli RNR. PMID- 26503038 TI - Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. AB - DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions that trigger non proteolytic ubiquitylation of adjacent chromatin areas to generate binding sites for DNA repair factors. This depends on the sequential actions of the E3 ubiquitin ligases RNF8 and RNF168 (refs 1-6), and UBC13 (also known as UBE2N), an E2 ubiquitin-conjugating enzyme that specifically generates K63-linked ubiquitin chains. Whereas RNF168 is known to catalyse ubiquitylation of H2A-type histones, leading to the recruitment of repair factors such as 53BP1 (refs 8-10), the critical substrates of RNF8 and K63-linked ubiquitylation remain elusive. Here we elucidate how RNF8 and UBC13 promote recruitment of RNF168 and downstream factors to DSB sites in human cells. We establish that UBC13-dependent K63-linked ubiquitylation at DSB sites is predominantly mediated by RNF8 but not RNF168, and that H1-type linker histones, but not core histones, represent major chromatin associated targets of this modification. The RNF168 module (UDM1) recognizing RNF8-generated ubiquitylations is a high-affinity reader of K63-ubiquitylated H1, mechanistically explaining the essential roles of RNF8 and UBC13 in recruiting RNF168 to DSBs. Consistently, reduced expression or chromatin association of linker histones impair accumulation of K63-linked ubiquitin conjugates and repair factors at DSB-flanking chromatin. These results identify histone H1 as a key target of RNF8-UBC13 in DSB signalling and expand the concept of the histone code by showing that posttranslational modifications of linker histones can serve as important marks for recognition by factors involved in genome stability maintenance, and possibly beyond. PMID- 26503039 TI - An aqueous, polymer-based redox-flow battery using non-corrosive, safe, and low cost materials. AB - For renewable energy sources such as solar, wind, and hydroelectric to be effectively used in the grid of the future, flexible and scalable energy-storage solutions are necessary to mitigate output fluctuations. Redox-flow batteries (RFBs) were first built in the 1940s and are considered a promising large-scale energy-storage technology. A limited number of redox-active materials--mainly metal salts, corrosive halogens, and low-molar-mass organic compounds--have been investigated as active materials, and only a few membrane materials, such as Nafion, have been considered for RFBs. However, for systems that are intended for both domestic and large-scale use, safety and cost must be taken into account as well as energy density and capacity, particularly regarding long-term access to metal resources, which places limits on the lithium-ion-based and vanadium-based RFB development. Here we describe an affordable, safe, and scalable battery system, which uses organic polymers as the charge-storage material in combination with inexpensive dialysis membranes, which separate the anode and the cathode by the retention of the non-metallic, active (macro-molecular) species, and an aqueous sodium chloride solution as the electrolyte. This water- and polymer based RFB has an energy density of 10 watt hours per litre, current densities of up to 100 milliamperes per square centimetre, and stable long-term cycling capability. The polymer-based RFB we present uses an environmentally benign sodium chloride solution and cheap, commercially available filter membranes instead of highly corrosive acid electrolytes and expensive membrane materials. PMID- 26503040 TI - Ion channels enable electrical communication in bacterial communities. AB - The study of bacterial ion channels has provided fundamental insights into the structural basis of neuronal signalling; however, the native role of ion channels in bacteria has remained elusive. Here we show that ion channels conduct long range electrical signals within bacterial biofilm communities through spatially propagating waves of potassium. These waves result from a positive feedback loop, in which a metabolic trigger induces release of intracellular potassium, which in turn depolarizes neighbouring cells. Propagating through the biofilm, this wave of depolarization coordinates metabolic states among cells in the interior and periphery of the biofilm. Deletion of the potassium channel abolishes this response. As predicted by a mathematical model, we further show that spatial propagation can be hindered by specific genetic perturbations to potassium channel gating. Together, these results demonstrate a function for ion channels in bacterial biofilms, and provide a prokaryotic paradigm for active, long-range electrical signalling in cellular communities. PMID- 26503041 TI - Loophole-free Bell inequality violation using electron spins separated by 1.3 kilometres. AB - More than 50 years ago, John Bell proved that no theory of nature that obeys locality and realism can reproduce all the predictions of quantum theory: in any local-realist theory, the correlations between outcomes of measurements on distant particles satisfy an inequality that can be violated if the particles are entangled. Numerous Bell inequality tests have been reported; however, all experiments reported so far required additional assumptions to obtain a contradiction with local realism, resulting in 'loopholes'. Here we report a Bell experiment that is free of any such additional assumption and thus directly tests the principles underlying Bell's inequality. We use an event-ready scheme that enables the generation of robust entanglement between distant electron spins (estimated state fidelity of 0.92 +/- 0.03). Efficient spin read-out avoids the fair-sampling assumption (detection loophole), while the use of fast random-basis selection and spin read-out combined with a spatial separation of 1.3 kilometres ensure the required locality conditions. We performed 245 trials that tested the CHSH-Bell inequality S <= 2 and found S = 2.42 +/- 0.20 (where S quantifies the correlation between measurement outcomes). A null-hypothesis test yields a probability of at most P = 0.039 that a local-realist model for space-like separated sites could produce data with a violation at least as large as we observe, even when allowing for memory in the devices. Our data hence imply statistically significant rejection of the local-realist null hypothesis. This conclusion may be further consolidated in future experiments; for instance, reaching a value of P = 0.001 would require approximately 700 trials for an observed S = 2.4. With improvements, our experiment could be used for testing less-conventional theories, and for implementing device-independent quantum secure communication and randomness certification. PMID- 26503044 TI - Economics: Higher costs of climate change. PMID- 26503042 TI - CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. AB - Selective neuronal loss is a hallmark of neurodegenerative diseases, which, counterintuitively, are often caused by mutations in widely expressed genes. Charcot-Marie-Tooth (CMT) diseases are the most common hereditary peripheral neuropathies, for which there are no effective therapies. A subtype of these diseases--CMT type 2D (CMT2D)--is caused by dominant mutations in GARS, encoding the ubiquitously expressed enzyme glycyl-transfer RNA (tRNA) synthetase (GlyRS). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons, leading to deficits in distal motor function. How mutations in GlyRS (GlyRS(CMT2D)) are linked to motor neuron vulnerability has remained elusive. Here we report that GlyRS(CMT2D) acquires a neomorphic binding activity that directly antagonizes an essential signalling pathway for motor neuron survival. We find that CMT2D mutations alter the conformation of GlyRS, enabling GlyRS(CMT2D) to bind the neuropilin 1 (Nrp1) receptor. This aberrant interaction competitively interferes with the binding of the cognate ligand vascular endothelial growth factor (VEGF) to Nrp1. Genetic reduction of Nrp1 in mice worsens CMT2D symptoms, whereas enhanced expression of VEGF improves motor function. These findings link the selective pathology of CMT2D to the neomorphic binding activity of GlyRS(CMT2D) that antagonizes the VEGF-Nrp1 interaction, and indicate that the VEGF-Nrp1 signalling axis is an actionable target for treating CMT2D. PMID- 26503043 TI - Foreign DNA capture during CRISPR-Cas adaptive immunity. AB - Bacteria and archaea generate adaptive immunity against phages and plasmids by integrating foreign DNA of specific 30-40-base-pair lengths into clustered regularly interspaced short palindromic repeat (CRISPR) loci as spacer segments. The universally conserved Cas1-Cas2 integrase complex catalyses spacer acquisition using a direct nucleophilic integration mechanism similar to retroviral integrases and transposases. How the Cas1-Cas2 complex selects foreign DNA substrates for integration remains unknown. Here we present X-ray crystal structures of the Escherichia coli Cas1-Cas2 complex bound to cognate 33 nucleotide protospacer DNA substrates. The protein complex creates a curved binding surface spanning the length of the DNA and splays the ends of the protospacer to allow each terminal nucleophilic 3'-OH to enter a channel leading into the Cas1 active sites. Phosphodiester backbone interactions between the protospacer and the proteins explain the sequence-nonspecific substrate selection observed in vivo. Our results uncover the structural basis for foreign DNA capture and the mechanism by which Cas1-Cas2 functions as a molecular ruler to dictate the sequence architecture of CRISPR loci. PMID- 26503045 TI - In situ structures of the segmented genome and RNA polymerase complex inside a dsRNA virus. AB - Viruses in the Reoviridae, like the triple-shelled human rotavirus and the single shelled insect cytoplasmic polyhedrosis virus (CPV), all package a genome of segmented double-stranded RNAs (dsRNAs) inside the viral capsid and carry out endogenous messenger RNA synthesis through a transcriptional enzyme complex (TEC). By direct electron-counting cryoelectron microscopy and asymmetric reconstruction, we have determined the organization of the dsRNA genome inside quiescent CPV (q-CPV) and the in situ atomic structures of TEC within CPV in both quiescent and transcribing (t-CPV) states. We show that the ten segmented dsRNAs in CPV are organized with ten TECs in a specific, non-symmetric manner, with each dsRNA segment attached directly to a TEC. The TEC consists of two extensively interacting subunits: an RNA-dependent RNA polymerase (RdRP) and an NTPase VP4. We find that the bracelet domain of RdRP undergoes marked conformational change when q-CPV is converted to t-CPV, leading to formation of the RNA template entry channel and access to the polymerase active site. An amino-terminal helix from each of two subunits of the capsid shell protein (CSP) interacts with VP4 and RdRP. These findings establish the link between sensing of environmental cues by the external proteins and activation of endogenous RNA transcription by the TEC inside the virus. PMID- 26503047 TI - Deep-time evolution of regeneration and preaxial polarity in tetrapod limb development. AB - Among extant tetrapods, salamanders are unique in showing a reversed preaxial polarity in patterning of the skeletal elements of the limbs, and in displaying the highest capacity for regeneration, including full limb and tail regeneration. These features are particularly striking as tetrapod limb development has otherwise been shown to be a highly conserved process. It remains elusive whether the capacity to regenerate limbs in salamanders is mechanistically and evolutionarily linked to the aberrant pattern of limb development; both are features classically regarded as unique to urodeles. New molecular data suggest that salamander-specific orphan genes play a central role in limb regeneration and may also be involved in the preaxial patterning during limb development. Here we show that preaxial polarity in limb development was present in various groups of temnospondyl amphibians of the Carboniferous and Permian periods, including the dissorophoids Apateon and Micromelerpeton, as well as the stereospondylomorph Sclerocephalus. Limb regeneration has also been reported in Micromelerpeton, demonstrating that both features were already present together in antecedents of modern salamanders 290 million years ago. Furthermore, data from lepospondyl 'microsaurs' on the amniote stem indicate that these taxa may have shown some capacity for limb regeneration and were capable of tail regeneration, including re-patterning of the caudal vertebral column that is otherwise only seen in salamander tail regeneration. The data from fossils suggest that salamander-like regeneration is an ancient feature of tetrapods that was subsequently lost at least once in the lineage leading to amniotes. Salamanders are the only modern tetrapods that retained regenerative capacities as well as preaxial polarity in limb development. PMID- 26503046 TI - Crystal structure of the RNA-dependent RNA polymerase from influenza C virus. AB - Negative-sense RNA viruses, such as influenza, encode large, multidomain RNA dependent RNA polymerases that can both transcribe and replicate the viral RNA genome. In influenza virus, the polymerase (FluPol) is composed of three polypeptides: PB1, PB2 and PA/P3. PB1 houses the polymerase active site, whereas PB2 and PA/P3 contain, respectively, cap-binding and endonuclease domains required for transcription initiation by cap-snatching. Replication occurs through de novo initiation and involves a complementary RNA intermediate. Currently available structures of the influenza A and B virus polymerases include promoter RNA (the 5' and 3' termini of viral genome segments), showing FluPol in transcription pre-initiation states. Here we report the structure of apo-FluPol from an influenza C virus, solved by X-ray crystallography to 3.9 A, revealing a new 'closed' conformation. The apo-FluPol forms a compact particle with PB1 at its centre, capped on one face by PB2 and clamped between the two globular domains of P3. Notably, this structure is radically different from those of promoter-bound FluPols. The endonuclease domain of P3 and the domains within the carboxy-terminal two-thirds of PB2 are completely rearranged. The cap-binding site is occluded by PB2, resulting in a conformation that is incompatible with transcription initiation. Thus, our structure captures FluPol in a closed, transcription pre-activation state. This reveals the conformation of newly made apo-FluPol in an infected cell, but may also apply to FluPol in the context of a non-transcribing ribonucleoprotein complex. Comparison of the apo-FluPol structure with those of promoter-bound FluPols allows us to propose a mechanism for FluPol activation. Our study demonstrates the remarkable flexibility of influenza virus RNA polymerase, and aids our understanding of the mechanisms controlling transcription and genome replication. PMID- 26503048 TI - Rhodium-catalysed syn-carboamination of alkenes via a transient directing group. AB - Alkenes are the most ubiquitous prochiral functional groups--those that can be converted from achiral to chiral in a single step--that are accessible to synthetic chemists. For this reason, difunctionalization reactions of alkenes (whereby two functional groups are added to the same double bond) are particularly important, as they can be used to produce highly complex molecular architectures. Stereoselective oxidation reactions, including dihydroxylation, aminohydroxylation and halogenation, are well established methods for functionalizing alkenes. However, the intermolecular incorporation of both carbon and nitrogen-based functionalities stereoselectively across an alkene has not been reported. Here we describe the rhodium-catalysed carboamination of alkenes at the same (syn) face of a double bond, initiated by a carbon-hydrogen activation event that uses enoxyphthalimides as the source of both the carbon and the nitrogen functionalities. The reaction methodology allows for the intermolecular, stereospecific formation of one carbon-carbon and one carbon nitrogen bond across an alkene, which is, to our knowledge, unprecedented. The reaction design involves the in situ generation of a bidentate directing group and the use of a new cyclopentadienyl ligand to control the reactivity of rhodium. The results provide a new way of synthesizing functionalized alkenes, and should lead to the convergent and stereoselective assembly of amine containing acyclic molecules. PMID- 26503049 TI - Corrigendum: Whole-genome characterization of chemoresistant ovarian cancer. PMID- 26503050 TI - Thalamic control of sensory selection in divided attention. AB - How the brain selects appropriate sensory inputs and suppresses distractors is unknown. Given the well-established role of the prefrontal cortex (PFC) in executive function, its interactions with sensory cortical areas during attention have been hypothesized to control sensory selection. To test this idea and, more generally, dissect the circuits underlying sensory selection, we developed a cross-modal divided-attention task in mice that allowed genetic access to this cognitive process. By optogenetically perturbing PFC function in a temporally precise window, the ability of mice to select appropriately between conflicting visual and auditory stimuli was diminished. Equivalent sensory thalamocortical manipulations showed that behaviour was causally dependent on PFC interactions with the sensory thalamus, not sensory cortex. Consistent with this notion, we found neurons of the visual thalamic reticular nucleus (visTRN) to exhibit PFC dependent changes in firing rate predictive of the modality selected. visTRN activity was causal to performance as confirmed by bidirectional optogenetic manipulations of this subnetwork. Using a combination of electrophysiology and intracellular chloride photometry, we demonstrated that visTRN dynamically controls visual thalamic gain through feedforward inhibition. Our experiments introduce a new subcortical model of sensory selection, in which the PFC biases thalamic reticular subnetworks to control thalamic sensory gain, selecting appropriate inputs for further processing. PMID- 26503051 TI - Global non-linear effect of temperature on economic production. AB - Growing evidence demonstrates that climatic conditions can have a profound impact on the functioning of modern human societies, but effects on economic activity appear inconsistent. Fundamental productive elements of modern economies, such as workers and crops, exhibit highly non-linear responses to local temperature even in wealthy countries. In contrast, aggregate macroeconomic productivity of entire wealthy countries is reported not to respond to temperature, while poor countries respond only linearly. Resolving this conflict between micro and macro observations is critical to understanding the role of wealth in coupled human natural systems and to anticipating the global impact of climate change. Here we unify these seemingly contradictory results by accounting for non-linearity at the macro scale. We show that overall economic productivity is non-linear in temperature for all countries, with productivity peaking at an annual average temperature of 13 degrees C and declining strongly at higher temperatures. The relationship is globally generalizable, unchanged since 1960, and apparent for agricultural and non-agricultural activity in both rich and poor countries. These results provide the first evidence that economic activity in all regions is coupled to the global climate and establish a new empirical foundation for modelling economic loss in response to climate change, with important implications. If future adaptation mimics past adaptation, unmitigated warming is expected to reshape the global economy by reducing average global incomes roughly 23% by 2100 and widening global income inequality, relative to scenarios without climate change. In contrast to prior estimates, expected global losses are approximately linear in global mean temperature, with median losses many times larger than leading models indicate. PMID- 26503052 TI - Cancer: The enemy of my enemy is my friend. PMID- 26503053 TI - Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer. AB - The gut epithelium has remarkable self-renewal capacity that under homeostatic conditions is driven by Wnt signalling in Lgr5(+) intestinal stem cells (ISCs). However, the mechanisms underlying ISC regeneration after injury remain poorly understood. The Hippo signalling pathway mediates tissue growth and is important for regeneration. Here we demonstrate in mice that Yap, a downstream transcriptional effector of Hippo, is critical for recovery of intestinal epithelium after exposure to ionizing radiation. Yap transiently reprograms Lgr5(+) ISCs by suppressing Wnt signalling and excessive Paneth cell differentiation, while promoting cell survival and inducing a regenerative program that includes Egf pathway activation. Accordingly, growth of Yap deficient organoids is rescued by the Egfr ligand epiregulin, and we find that non-cell-autonomous production of stromal epiregulin may compensate for Yap loss in vivo. Consistent with key roles for regenerative signalling in tumorigenesis, we further demonstrate that Yap inactivation abolishes adenomas in the Apc(Min) mouse model of colon cancer, and that Yap-driven expansion of Apc(-/-) organoids requires the Egfr module of the Yap regenerative program. Finally, we show that in vivo Yap is required for progression of early Apc mutant tumour-initiating cells, suppresses their differentiation into Paneth cells, and induces a regenerative program and Egfr signalling. Our studies reveal that upon tissue injury, Yap reprograms Lgr5(+) ISCs by inhibiting the Wnt homeostatic program, while inducing a regenerative program that includes activation of Egfr signalling. Moreover, our findings reveal a key role for the Yap regenerative pathway in driving cancer initiation. PMID- 26503054 TI - Quantum physics: Death by experiment for local realism. PMID- 26503056 TI - Fungal pathogen uses sex pheromone receptor for chemotropic sensing of host plant signals. AB - For more than a century, fungal pathogens and symbionts have been known to orient hyphal growth towards chemical stimuli from the host plant. However, the nature of the plant signals as well as the mechanisms underlying the chemotropic response have remained elusive. Here we show that directed growth of the soil inhabiting plant pathogen Fusarium oxysporum towards the roots of the host tomato (Solanum lycopersicum) is triggered by the catalytic activity of secreted class III peroxidases, a family of haem-containing enzymes present in all land plants. The chemotropic response requires conserved elements of the fungal cell integrity mitogen-activated protein kinase (MAPK) cascade and the seven-pass transmembrane protein Ste2, a functional homologue of the Saccharomyces cerevisiae sex pheromone alpha receptor. We further show that directed hyphal growth of F. oxysporum towards nutrient sources such as sugars and amino acids is governed by a functionally distinct MAPK cascade. These results reveal a potentially conserved chemotropic mechanism in root-colonizing fungi, and suggest a new function for the fungal pheromone-sensing machinery in locating plant hosts in a complex environment such as the soil. PMID- 26503055 TI - Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. AB - Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy. PMID- 26503057 TI - Methane storage in flexible metal-organic frameworks with intrinsic thermal management. AB - As a cleaner, cheaper, and more globally evenly distributed fuel, natural gas has considerable environmental, economic, and political advantages over petroleum as a source of energy for the transportation sector. Despite these benefits, its low volumetric energy density at ambient temperature and pressure presents substantial challenges, particularly for light-duty vehicles with little space available for on-board fuel storage. Adsorbed natural gas systems have the potential to store high densities of methane (CH4, the principal component of natural gas) within a porous material at ambient temperature and moderate pressures. Although activated carbons, zeolites, and metal-organic frameworks have been investigated extensively for CH4 storage, there are practical challenges involved in designing systems with high capacities and in managing the thermal fluctuations associated with adsorbing and desorbing gas from the adsorbent. Here, we use a reversible phase transition in a metal-organic framework to maximize the deliverable capacity of CH4 while also providing internal heat management during adsorption and desorption. In particular, the flexible compounds Fe(bdp) and Co(bdp) (bdp(2-) = 1,4-benzenedipyrazolate) are shown to undergo a structural phase transition in response to specific CH4 pressures, resulting in adsorption and desorption isotherms that feature a sharp 'step'. Such behaviour enables greater storage capacities than have been achieved for classical adsorbents, while also reducing the amount of heat released during adsorption and the impact of cooling during desorption. The pressure and energy associated with the phase transition can be tuned either chemically or by application of mechanical pressure. PMID- 26503058 TI - Microbiology: Electrical signalling goes bacterial. PMID- 26503059 TI - IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel. AB - Metastatic tumour recurrence due to failed treatments remains a major challenge of breast cancer clinical management. Here we report that interleukin-1 receptor associated kinase 1 (IRAK1) is overexpressed in a subset of breast cancers, in particular triple-negative breast cancer (TNBC), where it acts to drive aggressive growth, metastasis and acquired resistance to paclitaxel treatment. We show that IRAK1 overexpression confers TNBC growth advantage through NF-kappaB related cytokine secretion and metastatic TNBC cells exhibit gain of IRAK1 dependency, resulting in high susceptibility to genetic and pharmacologic inhibition of IRAK1. Importantly, paclitaxel treatment induces strong IRAK1 phosphorylation, an increase in inflammatory cytokine expression, enrichment of cancer stem cells and acquired resistance to paclitaxel treatment. Pharmacologic inhibition of IRAK1 is able to reverse paclitaxel resistance by triggering massive apoptosis at least in part through inhibiting p38-MCL1 pro-survival pathway. Our study thus demonstrates IRAK1 as a promising therapeutic target for TNBC metastasis and paclitaxel resistance. PMID- 26503060 TI - Effect of Intermittent Hypoxia and Rimonabant on Glucose Metabolism in Rats: Involvement of Expression of GLUT4 in Skeletal Muscle. AB - BACKGROUND: Obstructive sleep apnea (OSA) and its main feature, chronic intermit tent hypoxia (IH) during sleep, is closely associated with insulin resistance (IR) and diabetes. Rimonabant can regulate glucose metabolism and improve IR. The present study aimed to assess the effect of IH and rimonabant on glucose metabolism and insulin sensitivity, and to explore the possible mechanisms. MATERIAL AND METHODS: Thirty-two rats were randomly assigned into 4 groups: Control group, subjected to intermittent air only; IH group, subjected to IH only; IH+NS group, subjected to IH and treated with normal saline; and IH+Rim group, subjected to IH and treated with 10 mg/kg/day of rimonabant. All rats were killed after 28 days of exposure. Then, the blood and skeletal muscle were collected. We measured fasting blood glucose levels, fasting blood insulin levels, and the expression of glucose transporter 4 (GLUT4) in both mRNA and protein levels in skeletal muscle. RESULTS: IH can slow weight gain, increase serum insulin level, and reduce insulin sensitivity in rats. The expressions of GLUT4 mRNA, total GLUT4, and plasma membrane protein of GLUT4 (PM GLUT4) in skeletal muscle were decreased. Rimonabant treatment was demonstrated to improve weight gain and insulin sensitivity of the rats induced by IH. Rimonabant significantly upregulated the expression of GLUT4 mRNA, PM GLUT4, and total GLUT4 in skeletal muscle. CONCLUSIONS: The present study demonstrates that IH can cause IR and reduced expression of GLUT4 in both mRNA and protein levels in skeletal muscle of rats. Rimonabant treatment can improve IH - induced IR, and the upregulation of GLUT4 expression may be involved in this process. PMID- 26503061 TI - Modulation of Multidrug Resistance Protein 2 Efflux in the Cisplatin Resistance Human Ovarian Carcinoma Cells A2780/RCIS by Sesquiterpene Coumarins. AB - Recent in vitro studies showed that sesquiterpene coumarins (SCs) can be used as chemosensitizers. In this study, 14 SCs were isolated and purified from roots of four Ferula species and their structures were elucidated by spectroscopic methods. The purified SCs were evaluated for multidrug resistance (MDR) reversal properties in A2780/RCIS cells (cisplatin-resistant derivatives of the human ovarian carcinoma cell line A2780P). Among the tested compounds, mogoltacin, mogoltadone, farnesiferol A, farnesiferol B, farnesiferol C, lehmferin, conferdione, and samarcandin showed significant MDR reversing effects. The combination of nontoxic concentrations of SCs (20 MUM) with cisplatin enhanced cisplatin cytotoxicity on A2780/RCIS cells significantly. Flow cytometric efflux assay confirmed that the intracellular accumulation of 5-carboxyfluorescein diacetate (5-CFDA) was significantly increased in A2780/RCIS cells when treated with SCs. Our findings revealed that conferdione and samarcandin possessed the highest inhibitory effects on multidrug resistance-associated protein 2 pump efflux, and therefore, these compounds could be considered as lead scaffolds for further structure modifications. PMID- 26503062 TI - Sultones and Sultines via a Julia-Kocienski Reaction of Epoxides. AB - The development of the homologous Julia-Kocienski reaction has led to the discovery of two new reaction modes of epoxides with sulfones. These pathways allow rapid and direct access to a range of gamma-sultones and gamma-sultines. PMID- 26503063 TI - Design, Preparation, and Characterization of Zn and Cu Metallopeptides Based On Tetradentate Aminopyridine Ligands Showing Enhanced DNA Cleavage Activity. AB - The conjugation of redox-active complexes that can function as chemical nucleases to cationic tetrapeptides is pursued in this work in order to explore the expected synergistic effect between these two elements in DNA oxidative cleavage. Coordination complexes of biologically relevant first row metal ions, such as Zn(II) or Cu(II), containing the tetradentate ligands 1,4-dimethyl-7-(2 pyridylmethyl)-1,4,7-triazacyclononane ((Me2)PyTACN) and (2S,2S')-1,1'-bis(pyrid 2-ylmethyl)-2,2'-bipyrrolidine ((S,S')-BPBP) have been linked to a cationic LKKL tetrapeptide sequence. Solid-phase synthesis of the peptide-tetradentate ligand conjugates has been developed, and the preparation and characterization of the corresponding metallotetrapeptides is described. The DNA cleavage activity of Cu and Zn metallopeptides has been evaluated and compared to their metal binding conjugates as well as to the parent complexes and ligands. Very interestingly, the oxidative Cu metallopeptides 1Cu and 2Cu show an enhanced activity compared to the parent complexes, [Cu(PyTACN)](2+) and [Cu(BPBP)](2+), respectively. Under optimized conditions, 1Cu displays an apparent pseudo first-order rate constant (kobs) of ~0.16 min(-1) with a supercoiled DNA half-life time (t1/2) of ~4.3 min. On the other hand, kobs for 2Cu has been found to be ~0.11 min(-1) with t1/2 ~ 6.4 min. Hence, these results point out that the DNA cleavage activities promoted by the metallopeptides 1Cu and 2Cu render ~4-fold and ~23 rate accelerations in comparison with their parent Cu complexes. Additional binding assays and mechanistic studies demonstrate that the enhanced cleavage activities are explained by the presence of the cationic LKKL tetrapeptide sequence, which induces an improved binding affinity to the DNA, thus bringing the metal ion, which is responsible for cleavage, in close proximity. PMID- 26503064 TI - First objective association between elevated carbohydrate-deficient transferrin concentrations and alcohol-related traffic accidents. AB - BACKGROUND: Carbohydrate-deficient transferrin (CDT) is a well-recognized highly specific marker of chronic alcohol abuse. The association of CDT with alcohol related traffic accidents was evaluated to objectively validate the use of this marker for certifying the physical fitness for driving license regranting after its confiscation for drunk driving. METHODS: The study was carried out on 468 injured drivers (InjDr), who underwent mandatory blood alcohol concentration (BAC) and drug analysis in biological fluids. The InjDr group was divided into 2 subgroups on the basis of BAC legal limit adopted in Italy (BAC <= 0.5 g/l: InjDr1 ; BAC >0.5 g/l: InjDr2 ). The control group (CntDr) included 236 subjects holding safety-sensitive job positions and undergoing mandatory toxicological analyses. The determination of BAC in blood and CDT in serum were performed using validated analytical methods based on head-space gas chromatography and high performance liquid chromatography, respectively. RESULTS: The evaluation of CDT distribution in the 3 groups (CntDr, InjDr1 , InjDr2 ) showed that CDT distribution in the InjDr1 group was similar to that observed in the CntDr group (p = 0.159) and different from that observed in the InjDr2 group (p < 0.001). Partitioning the CDT data of each group into "CDT positives" and "CDT negatives" on the basis of the cut off (1.90%), it was possible to calculate the odds of the 3 groups and then the odds ratios. The odds ratio of InjDr1 versus CntDr was 4.56 (p = 0.158), whereas the odds ratio of InjDr2 versus CntDr was 132 (p < 0.001). Furthermore, a dose-response effect was found only when comparing InjDr2 with CntDr. CONCLUSIONS: The data of the present study strongly support the use of the CDT test to evaluate the risk of a subject to be involved in a road accident while driving under the influence of alcohol. PMID- 26503065 TI - Ethanol produces corticotropin-releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala. AB - BACKGROUND: Ethanol (EtOH) modulation of central amygdala (CeA) neurocircuitry plays a key role in the development of alcoholism via activation of the corticotropin-releasing factor (CRF) receptor (CRFR) system. Previous work has predominantly focused on EtOH * CRF interactions on the CeA GABA circuitry; however, our laboratory recently showed that CRF enhances CeA glutamatergic transmission. Therefore, this study sought to determine whether EtOH modulates CeA glutamate transmission via activation of CRF signaling. METHODS: The effects of EtOH on spontaneous excitatory postsynaptic currents (sEPSCs) and basal resting membrane potentials were examined via standard electrophysiology methods in adult male C57BL/6J mice. Local ablation of CeA CRF neurons (CRF(CeAhDTR) ) was achieved by targeting the human diphtheria toxin receptor (hDTR) to CeA CRF neurons with an adeno-associated virus. Ablation was quantified post hoc with confocal microscopy. Genetic targeting of the diphtheria toxin active subunit to CRF neurons (CRF(DTA) mice) ablated CRF neurons throughout the central nervous system, as assessed by quantitative reverse transcriptase polymerase chain reaction quantification of CRF mRNA. RESULTS: Acute bath application of EtOH significantly increased sEPSC frequency in a concentration-dependent manner in CeA neurons, and this effect was blocked by pretreatment of co-applied CRFR1 and CRFR2 antagonists. In experiments utilizing a CRF-tomato reporter mouse, EtOH did not significantly alter the basal membrane potential of CeA CRF neurons. The ability of EtOH to enhance CeA sEPSC frequency was not altered in CRF(CeAhDTR) mice despite a ~78% reduction in CeA CRF cell counts. The ability of EtOH to enhance CeA sEPSC frequency was also not altered in the CRF(DTA) mice despite a 3 fold reduction in CRF mRNA levels. CONCLUSIONS: These findings demonstrate that EtOH enhances spontaneous glutamatergic transmission in the CeA via a CRFR dependent mechanism. Surprisingly, our data suggest that this action may not require endogenous CRF. PMID- 26503066 TI - Phosphatidylethanol is superior to carbohydrate-deficient transferrin and gamma glutamyltransferase as an alcohol marker and is a reliable estimate of alcohol consumption level. AB - BACKGROUND: In clinical practice as well as research situations, it is of great importance to get reliable information about a patient's alcohol consumption. The aim of the study was to investigate the correlation of alcohol biomarkers (phosphatidylethanol [PEth], carbohydrate-deficient transferrin [CDT], gamma glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase) to retrospective as well as diary-based alcohol self-reports and to examine whether it is possible to correlate a biomarker result to a more precise level of alcohol consumption. METHODS: One hundred and sixty alcohol-dependent patients were included in a randomized, placebo-controlled clinical trial of pharmacotherapy for alcohol dependence, of which 115 (76 men and 39 women) completed the study. Retrospective alcohol consumption data were collected at baseline, and alcohol diaries were used during the study. Blood samples for determination of alcohol biomarkers were collected on 5 occasions during the study. RESULTS: PEth and CDT showed a better correlation with alcohol consumption documented in the diary (PEth rs = 0.56 and CDT rs = 0.35) than with retrospective consumption data (PEth rs = 0.23 and CDT rs = 0.22). An even higher correlation (rs = 0.63) was seen between the 2 alcohol biomarkers PEth and CDT. At all consumption levels, PEth had the highest sensitivity of all biomarkers studied. CONCLUSIONS: PEth was the biomarker with the best correlation to self-reported alcohol consumption. PEth was superior to CDT owing to its substantially higher sensitivity but also due to its closer correlation to self-report. PEth values can be translated into an approximate level of alcohol consumption and PEth appears to be a more reliable measure of alcohol consumption than self-reports. PMID- 26503067 TI - Resistance to temptation: the interaction of external and internal control on alcohol use during residential treatment for alcohol use disorder. AB - BACKGROUND: There is evidence that drinking during residential treatment is related to various factors, such as patients' general control beliefs and self efficacy, as well as to external control of alcohol use by program's staff and situations where there is temptation to drink. As alcohol use during treatment has been shown to be associated with the resumption of alcohol use after discharge from residential treatment, we aimed to investigate how these variables are related to alcohol use during abstinence-oriented residential treatment programs for alcohol use disorders (AUD). METHODS: In total, 509 patients who entered 1 of 2 residential abstinence-oriented treatment programs for AUD were included in the study. After detoxification, patients completed a standardized diagnostic procedure including interviews and questionnaires. Drinking was assessed by patients' self-report of at least 1 standard drink or by positive breathalyzer testing. The 2 residential programs were categorized as high or low control according to the average number of tests per patient. RESULTS: Regression analysis revealed a significant interaction effect between internal and external control suggesting that patients with high internal locus of control and high frequency of control by staff demonstrated the least alcohol use during treatment (16.7%) while patients with low internal locus of control in programs with low external control were more likely to use alcohol during treatment (45.9%). No effects were found for self-efficacy and temptation. CONCLUSIONS: As alcohol use during treatment is most likely associated with poor treatment outcomes, external control may improve treatment outcomes and particularly support patients with low internal locus of control, who show the highest risk for alcohol use during treatment. High external control may complement high internal control to improve alcohol use prevention while in treatment. PMID- 26503068 TI - Level of response to alcohol as a factor for targeted prevention in college students. AB - BACKGROUND: Heavy alcohol consumption and alcohol problems among college students are widespread and associated with negative outcomes for individuals and communities. Although current methods for prevention and intervention programming have some demonstrated efficacy, heavy drinking remains a problem. A previous pilot study and a recent large-scale evaluation (Schuckit et al., , ) found that a tailored prevention program based on a risk factor for heavy drinking, low level of response (low LR) to alcohol, was more effective at reducing heavy drinking than a state-of-the-art (SOTA) standard prevention program for individuals with the low LR risk factor. METHODS: This study enrolled 231 first semester college freshmen with either high or low LR into the same level of response-based (LRB) or SOTA online prevention programs as in the previous reports (consisting of 4 weeks of video modules), as well as a group of matched controls not receiving alcohol prevention, and compared changes in alcohol use between these groups across a 6-month period. RESULTS: Individuals in alcohol prevention programs had a greater reduction in maximum drinks per occasion and alcohol use disorder symptoms than controls. There was limited evidence for interactions between LR and prevention group in predicting change in alcohol use behaviors; only among participants with strict adherence to the program was there an interaction between LR and program in predicting maximum drinks per occasion. However, overall, low LR individuals showed greater decreases in drinking behaviors, especially risky behaviors (e.g., maximum drinks, frequency of heavy drinking) than high LR individuals. CONCLUSIONS: These results indicate that prevention programs, including brief and relatively inexpensive web-based programs, may be effective for persons at highest risk for heavier drinking, such as those with a low LR. Tailored programs may provide incremental benefits under some conditions. Long-term follow-ups and further investigations of tailored prevention programs based on other risk factors are needed. PMID- 26503069 TI - A metacognitive strategy for reducing disruptive behavior in children with fetal alcohol spectrum disorders: GoFAR pilot. AB - BACKGROUND: Fetal alcohol spectrum disorders (FASD) are often characterized by disruptive behavior problems and there are few effective interventions available. GoFAR is a novel, 3-part intervention designed to improve self-regulation and adaptive living skills of children with FASD by improving metacognitive control of emotions and arousal. METHODS: The intervention has 3 components: (i) GoFAR: a "serious game" designed to teach a metacognitive control strategy in a computer game environment; (ii) parent training on child behavioral regulation; and (iii) Behavior Analog Therapy (BAT) sessions, a practical application of the metacognitive learning methodology by parent and child in the context of learning adaptive skills. The learning strategy (FAR) teaches the child to Focus and make a plan, Act out the plan, and Reflect back on the plan. Thirty families were randomized to 3 groups: (i) GoFAR (n = 10); (ii) FACELAND (n = 10); or (iii) CONTROL (n = 10). The 2 intervention groups, GoFAR and FACELAND, used computer games to instruct children. Both groups also received 5 sessions of parent training followed by 5 sessions of joint parent/child therapy (BAT). Assessment of disruptive behavior, including frequency of temper tantrums, frustration tolerance, impulsivity, destructiveness, aggression, and maintaining attention were carried out before enrollment at Mid-Treatment, when game play and parent training were completed, and finally, after completing the BAT sessions. RESULTS: Parental report of disruptive behavior overall was significantly reduced in the GoFAR group after the first components, game play and parent training, and after the BAT sessions in the FACELAND group with no changes in the CONTROL group over time. CONCLUSIONS: The GoFAR((r)) game was well received by children and effective in teaching the required skills. Mastering the FAR metacognitive strategy was associated with a reduction in disruptive behaviors in children with FASD suggesting that effective interventions can improve outcomes for this high risk group. PMID- 26503072 TI - The development of hand preference and dichotic language lateralization in males and females with congenital adrenal hyperplasia. AB - People with congenital adrenal hyperplasia (CAH) are exposed to elevated levels of androgens in utero due to overproduction by the adrenal cortex. In order to test whether high levels of prenatal androgens influence the development of handedness preferences and left-hemisphere language representation, we studied 39 patients with CAH (28 females, 11 males) and 25 unaffected sibling controls (17 females, 8 males). Hand preference for 15 unimanual activities was evaluated via questionnaire and pantomime, and a consonant-vowel dichotic listening test was administered. Contemporary theories disagree as to whether high testosterone is said to increase or decrease the probability of developing a typical right-hand preference. Results showed no significant differences on the handedness inventory. Relative to controls, however, patients with CAH showed a significantly larger right-ear advantage on the dichotic syllables task, indicating stronger left-hemisphere lateralization of language. These results support an emerging body of evidence suggesting that high testosterone may bias lateralized development toward the population norm, but run counter to the Geschwind-Behan-Galaburda model which associates high prenatal testosterone with a greater prevalence of left-handedness. PMID- 26503070 TI - Validation of a brief screening tool for alcohol-related neuropsychological impairments. AB - BACKGROUND: Alcohol-related neuropsychological impairments mainly affect episodic memory, working memory, and visuospatial abilities, as well as executive and motor functioning. These impairments can prevent alcoholic patients (ALs) early in abstinence from benefiting fully from treatment and reduce their ability to remain abstinent. A neuropsychological assessment seems essential for making the relevant clinical decisions. However, very few alcohol treatment departments have the financial and human resources needed to conduct an extensive neuropsychological examination of each AL. The goal of this study was therefore to assess the validity and the psychometric properties of the Brief Evaluation of Alcohol-Related Neuropsychological Impairments (BEARNI), a new screening tool especially designed to assess alcohol-related neuropsychological impairments. METHODS: A total of 254 healthy controls (HCs) completed the BEARNI, and 58 of them also performed an extensive neuropsychological battery. Seventy-three ALs underwent both the BEARNI and the neuropsychological battery. This extensive neuropsychological battery of proven classification accuracy served as the reference (i.e., gold standard) for determining the ALs' cognitive status. RESULTS: An exploratory factor analysis validated the BEARNI's underlying structure, highlighting 5 factors that reflected visuospatial abilities, executive functions, ataxia, verbal episodic memory, and verbal working memory. The standardization of each BEARNI subtest and the 2 total scores revealed that this test has sufficient diagnostic accuracy for the detection of ALs with cognitive and motor impairments. CONCLUSIONS: This study indicates that the BEARNI is a useful screening tool in clinical settings for detecting ALs' motor and cognitive impairments. PMID- 26503073 TI - Design of Enzyme-Encapsulated Protein Containers by In Vivo Crystal Engineering. AB - Crystalline protein assemblies of polyhedra crystal (PhC) can be utilized as solid enzyme containers for long-term storage of enzymes with retention of their enzymatic activity. The enzymes can be released from the crystals at the optimum pH for the enzymatic activity by dissolution of the crystals using in vivo crystal engineering. PMID- 26503075 TI - Comparison of coronary risk scoring systems to predict the severity of coronary artery disease using the SYNTAX score. AB - BACKGROUND: Reliable risk scoring systems that can predict the severity of coronary artery disease (CAD) are necessary to implement effective management strategies in high-risk patients. Atherosclerotic vascular disease and with cardiovascular morbidity and mortality risk are patients who would benefit most from a change in patients at high risk factors. Framingham Risk Score, the Prospective Cardiovascular Munster (PROCAM) score and Systematic Coronary Risk Evaluation (SCORE) risk scores are used for this purpose. The severity of the CAD as detected by coronary angiography can be estimated using the SYNTAX score. In this study, it is aimed to assess the relation between SYNTAX score and the Framingham, PROCAM and SCORE scores in the context of their utility for the determination of the severity of the CAD. METHODS: A total of 205 patients with documented CAD who underwent coronary angiography due to a diagnosis of stable angina pectoris were included in this study. Coronary risk scores were determined for each patient. The relation between the SYNTAX score and the results of coronary risk scoring systems were analyzed. RESULTS: A positive relationship between the SYNTAX score, which reflects the severity of the CAD and coronary risk scores was found. However, Framingham and SCORE were superior, i.e., had more predictive value, regarding their ability to predict the SYNTAX score (p = 0.029, 0.033 and 0.002, respectively). CONCLUSIONS: Examination of the distribution of SYNTAX score across low, intermediate and high-risk groups showed a significantly higher predictive value of SCORE for high-risk patients (p = 0.005). PMID- 26503076 TI - A marked decrease in heart rate variability in Marfan syndrome patients with confirmed FBN1 mutations. AB - BACKGROUND: The studies on heart rate variability (HRV), a key predictor of all cause mortality, in Marfan syndrome (MS), up to now have not been reported, especially in patients with FBN1 mutations. METHODS: Among 18 MS patients with the phenotype of MS meeting inclusion criteria 15 have had a FBN1 gene mutation. Short electrocardiography records were taken in the supine position and during orthostatic tests. The control group consisted of 30 apparently healthy nonathletes matched by age and gender. RESULTS: Heart rates in MS patients with the FBN1 mutation were increased in both the supine position and orthostatic test (p < 0.001). Most of the time-domain (standard deviation, pNN50) and frequency domain (total power, very low, low, and high frequency) parameters of HRV were significantly reduced in the MS patients (p < 0.001). CONCLUSIONS: A marked decrease in HRV, documented in the study, may be an important clinical feature in MS patients with confirmed FBN1 gene mutations. PMID- 26503074 TI - Beneficial effects of exercise on age-related mitochondrial dysfunction and oxidative stress in skeletal muscle. AB - Mitochondria are negatively affected by ageing leading to their inability to adapt to higher levels of oxidative stress and this ultimately contributes to the systemic loss of muscle mass and function termed sarcopenia. Since mitochondria are central mediators of muscle health, they have become highly sought-after targets of physiological and pharmacological interventions. Exercise is the only known strategy to combat sarcopenia and this is largely mediated through improvements in mitochondrial plasticity. More recently a critical role for mitochondrial turnover in preserving muscle has been postulated. Specifically, cellular pathways responsible for the regulation of mitochondrial turnover including biogenesis, dynamics and autophagy may become dysregulated during ageing resulting in the reduced clearance and accumulation of damaged organelles within the cell. When mitochondrial quality is compromised and homeostasis is not re-established, myonuclear cell death is activated and muscle atrophy ensues. In contrast, acute and chronic exercise attenuates these deficits, restoring mitochondrial turnover and promoting a healthier mitochondrial pool that leads to the preservation of muscle. Additionally, the magnitude of these exercise-induced mitochondrial adaptations is currently debated with several studies reporting a lower adaptability of old muscle relative to young, but the processes responsible for this diminished training response are unclear. Based on these observations, understanding the molecular details of how advancing age and exercise influence mitochondria in older muscle will provide invaluable insight into the development of exercise protocols that will maximize beneficial adaptations in the elderly. This information will also be imperative for future research exploring pharmacological targets of mitochondrial plasticity. PMID- 26503077 TI - A randomized comparison of 5 versus 12 hours per day of cardiac contractility modulation treatment for heart failure patients: A preliminary report. AB - BACKGROUND: Cardiac contractility modulation (CCM) signals are non-excitatory electrical signals delivered during the absolute refractory period intended to improve contraction and cardiac function. Clinical trials have shown that CCM treatment significantly improves exercise tolerance and quality of life in symptomatic heart failure patients. Studies with CCM therapy typically include CCM delivery for 3, 5 or 7 h per day, although other configurations are also commonly used. Each has been associated with improved outcomes in heart failure, but it is not clear whether different application durations are associated with the various degrees of benefit. The purpose of the current pilot evaluation study was to evaluate the quality of life, exercise tolerance, and cardiac function, over a 6-month period when CCM was delivered for 5 h/day vs. 12 h/day. Increasing the daily CCM therapy duration is safe and as good as the standard CCM periods of application per day. METHODS: This single center pilot evaluation study involved 19 medically refractory symptomatic patients with heart failure and reduced left ventricular function who underwent implantation of an OptimizerTM system (Impulse Dynamics, Orangeburg, NY, USA). Patients were randomized into one of two treatment groups; 5 h/day CCM treatment or 12 h/day CCM treatment. Subjects and evaluating physicians were blinded to the study group. Subjects returned to the hospital after 12 and 24 weeks. Efficacy evaluations included changes from baseline to 24 weeks in Minnesota Living With Heart Failure Questionnaire score (MLWHFQ), maximal oxygen consumption in the cardio-pulmonary stress test (peak VO2), New York Heart Association classification (NYHA), 6-min walk distance (6MWD), and ejection fraction (EF). RESULTS: At the end of 24 weeks, clinical improvement was observed in the entire cohort in all efficacy measures (mean change from baseline of -17.1 in MLWHFQ, -0.86 in NYHA, and improvement trend of 1.48 mL O2/kg/min in peak VO2, 31.3 m in 6MWD, and 2.25% in EF). There were no significant differences, either clinically or statistically, between the groups receiving CCM for 5 h/day vs. 12 h/day. Three subjects were voluntarily withdrawn before completing the study. One subject died from pneumonia after 125 days, and 6 serious adverse events were reported, none of which was classified as related to either the device or the procedure. CONCLUSIONS: Together with previously reported experience with CCM, delivery of CCM therapy is equally safe and appears similarly effective over the range of shorter (5 h) to longer (12 h) daily periods of application. Given the small sample size, further studies are warranted. PMID- 26503078 TI - Predictive value of admission red cell distribution width-platelet ratio for no reflow phenomenon in acute ST segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - BACKGROUND: The red cell distribution width-platelet ratio (RPR), a novel inflammatory marker is currently used to predict inflammation in chronic diseases. It may be associated with adverse outcomes among artery disease but its prognostic value in ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) has not been fully investigated. There is no data regarding the association between RPR and in hospital major adverse cardiovascular events (MACEs). This study evaluated the relations between pre-procedural RPR and the in-hospital and long-term outcomes in STEMI patients undergoing primary PCI. METHODS: This study included 580 STEMI patients (77% men, mean age: 59 +/- 12 years). The patients were divided into two groups according to thrombolysis in myocardial infarction (TIMI) flow grades after primary PCI. No-reflow was defined as a post-PCI TIMI flow grade of 0, 1 or 2 (group 1). Angiographic success was defined as TIMI flow grade 3 (group 2). RESULTS: Whole blood cell count, neutrophil and lymphocyte percentages, red cell distribution width, platecrit, neutrophil-lymphocyte ratio (NLR) and RPR values were higher among patients with no-reflow. On multivariate analysis, pain to balloon time, multivessel disease, TIMI thrombus grade, tirofiban, aspirin, previous coronary artery disease, NLR, platecrit and RPR remained independent predictors of no-reflow after primary PCI. Patients in no-reflow group tended to be higher percent in-hospital MACE, including nonfatal myocardial infarction and cardiovascular mortality compared to the reflow patients. CONCLUSIONS: Admission NLR, platecrit and RPR are independent correlates of no-reflow and in-hospital MACEs among patients with STEMI undergoing primary PCI. PMID- 26503079 TI - Single spot albumin to creatinine ratio: A simple marker of long-term prognosis in non-ST segment elevation acute coronary syndromes. AB - BACKGROUND: Microalbuminuria is a known risk factor for cardiovascular morbidity and mortality suggesting that it should be a marker of endothelial dysfunction. Albumin to creatinine ratio (ACR) is an available and rapid test for microalbuminuria determination, with a high correlation with the 24-h urine collection method. There is no prospective study that evaluates the prognostic value of ACR in patients with non ST-segment elevation acute coronary syndromes (NSTE-ACS). The purpose of our study was to detect the long-term prognostic value of ACR in patients with NSTE-ACS. METHODS: Albumin to creatinine ratio was estimated in 700 patients with NSTE-ACS at admission. Median follow-up time was 18 months. The best cutoff point of ACR for death or acute myocardial infarction was 20 mg/g. Twenty-two percent of patients had elevated ACR. RESULTS: By multivariable Cox regression analysis, ACR was an independent predictor of the clinical endpoint: odds ratio 5.8 (95% confidence interval [CI] 2-16), log-rank 2 p < 0.0001 in a model including age > 65 years, female gender, diabetes mellitus, creatinine clearance, glucose levels at admission, elevated cardiac markers (troponin T/CK-MB) and ST segment depression. The addition of ACR significantly improved GRACE score C-statistics from 0.69 (95% CI 0.59-0.83) to 0.77 (95% CI 0.65-0.88), SE 0.04, 2 p = 0.03, with a good calibration with both models. CONCLUSIONS: Albumin to creatinine ratio is an independent and accessible predictor of long-term adverse outcomes in NSTE-ACS, providing additional value for risk stratification. PMID- 26503080 TI - Paravalvular leak after transcatheter aortic valve implantation (TAVI): Short term results. Data from Polish national POL-TAVI registry. AB - BACKGROUND: The authors analyzed data from Polish national POL-TAVI registry in terms of paravalvular leak (PVL) occurrence after transcatheter aortic valve implantation (TAVI) and its impact on clinical outcomes. METHODS: A total of 331 patients with severe aortic stenosis underwent TAVI (Edwards Sapien, n = 141; CoreValve, n = 190). The grade of PVL and survival rate were assessed at6-month follow-up. RESULTS: One hundred and eighty-one (54.7%) patients developed mild PVL, and 22 (6.6%) - moderate PVL after TAVI. No severe PVLs were observed. Occurrence of moderate PVL was device dependent and more frequent in the CoreValve group (p = 0.02). Larger CoreValve device used correlated with the grade of PVL (Spearman: r = 0.19; p = 0.01), but for Edwards Sapien devices this correlation was inverted (Spearman: r = -0.62; p = 0.01). Six-month mortality rate was not significant between patients with no or mild PVL compared to those with moderate PVL (p = 0.12). CONCLUSIONS: The PVL occurrence remains a frequent problem after TAVI and is device de-pendent, more common with Edwards 23 mm valve and 31 mm CoreValve prosthesis. PMID- 26503081 TI - History of diabetes mellitus is associated with elevated cardiac troponin I levels in patients with chest pain but no coronary heart disease. AB - BACKGROUND: The factors and the mechanism contributing to an increase in cardiac troponin I (cTnI) in patients with chest pain, at least one cardiovascular risk factor, and no evidence of coronary heart disease remains elusive. METHODS: Excluding patients with acute coronary syndrome and chronic myocardial isch-emia, we selected 362 consecutive patients with normal coronary angiography or computed tomography coronary angiography results or lesions causing < 50% stenosis in any of the coronary arteries from January 2012 to June 2015. Using a cut-off value of 0.01 ng/mL, patients with cTnI levels >= 0.01 ng/mL (164 patients) were compared with those with cTnI levels < 0.01 ng/mL. Logistic regression analysis was used to evaluate associations between elevated cTnI and patient characteristics. RESULTS: Other than history of diabetes mellitus (DM) (18.90% vs. 8.08%, p = 0.002), the characteristics of the patients with and without elevated cTnI levels were similar. History of DM predicted elevation of cTnI level (OR 3.34, 95% CI 1.55-7.20, p = 0.002) in logistic regression analysis. CONCLUSIONS: In total, 45.30% of patients with chest pain had elevated cTnI levels with a mean level of 0.07 +/- 0.10 ng/mL. History of DM rather than blood glucose level itself was associated with elevated cTnI levels, whereas female gender was protective against increases in cTnI levels. PMID- 26503082 TI - The impact of emergency department observation units on United States emergency department admission rates. AB - OBJECTIVE: Prior studies suggesting that the presence of emergency department (ED) observation units decrease overall ED hospital admissions have been either single-center studies or based on model simulations. The objective of this preliminary national study is to determine if the presence of ED observation units is associated with hospitals having lower ED admission rates. METHODS: We conducted a retrospective cross-sectional analysis using the 2010 National Hospital Ambulatory Care Survey and estimated ED risk-standardized hospital admission rates (RSHAR) for each center. The following were excluded from the study: ages <18 years, leaving prior to completion of ED visit, died in the ED, transferred to another facility, and missing disposition. Hospitals with less than 30 ED visits or unknown observation unit status were also excluded. We used linear regression analysis to determine the association between ED RSHAR and presence of observation units. RESULTS: There were 24,232 ED visits in 315 hospitals in the United States. Of these, 82 (20.6%) hospitals had an ED observation unit. The average ED risk-standardized hospital admission rates for hospitals with observation units and without hospital observation units were 13.7% (95% confidence interval [CI]: 11.3-16.0) and 16.0% (95% CI: 14.1-17.7), respectively. The difference of 2.3% was not statistically significant. CONCLUSIONS: In this preliminary study, we did not find an association between the presence of observation units and ED hospital admission rates. Further studies with larger sample sizes should be performed to further evaluate the impact of ED observation units on ED hospital admission rates. PMID- 26503083 TI - Emergency department observation units: Less than we bargained for? PMID- 26503084 TI - The authors reply "Changes in patient satisfaction related to hospital renovation: The experience with a new clinical building". PMID- 26503085 TI - In reference to "Changes in patient satisfaction related to hospital renovation: The experience with a new clinical building". PMID- 26503086 TI - A selective chromofluorogenic chemodosimeter for fluoride ions based on distyrylbenzenes derivatives containing dual Si-O groups. AB - A new chemodosimeter for fluoride ions based on F(-) triggered dual Si-O bond cleavage of distyrylbenzenes derivatives was developed for the first time. Upon the addition of F(-) ions, the chemodosimeter (7) displayed apparent color changes from colorless to faint yellow, with a dramatic red-shift in the emission wavelength (~100 nm), and higher selectivity for fluoride over other common anions. With the aid of fluorescence measurements, the limit of detection could be as low as 89.8 nm. Using a 'dipstick' approach, chemodosimeter (7) might serve as a prototype device for fluorescent detecting F(-) without the need for any additional equipment. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26503087 TI - Use of Natalizumab in Patients with Multiple Sclerosis: 2015 Update. PMID- 26503088 TI - A two-photon fluorescent probe for lysosomal zinc ions. AB - The selective detection of zinc ions in lysosomes over that in cytosol is achieved with a fluorescent probe, which enabled the fluorescence imaging of endogenous zinc ions in lysosomes of NIH 3T3 cells as well as mouse hippocampal tissues by two-photon microscopy under excitation at 900 nm. PMID- 26503089 TI - The iScore predicts total healthcare costs early after hospitalization for an acute ischemic stroke. AB - BACKGROUND: The ischemic Stroke risk score is a validated prognostic score which can be used by clinicians to estimate patient outcomes after the occurrence of an acute ischemic stroke. AIM: In this study, we examined the association between the ischemic Stroke risk score and patients' 30-day, one-year, and two-year healthcare costs from the perspective of a third party healthcare payer. METHODS: Patients who had an acute ischemic stroke were identified from the Registry of Canadian Stroke Network. The 30-day ischemic Stroke risk score prognostic score was determined for each patient. Direct healthcare costs at each time point were determined using administrative databases in the province of Ontario. Unadjusted mean and the impact of a 10-point increase ischemic Stroke risk score and a patient's risk of death or disability on total cost were determined. RESULTS: There were 12,686 patients eligible for the study. Total unadjusted mean costs were greatest among patients at high risk. When adjusting for patient characteristics, a 10-point increase in the ischemic Stroke risk score was associated with 8%, 7%, and 4% increase in total costs at 30 days, one-year, and two-years. The same increase was found to impact patients at low, medium, and high risk differently. When adjusting for patient characteristics, patients in the high-risk group had the highest total costs at 30 days, while patients at medium risk had the highest costs at both one and two-years. CONCLUSIONS: The ischemic Stroke risk score can be useful as a predictor of healthcare utilization and costs early after hospitalization for an acute ischemic stroke. PMID- 26503090 TI - Port wine stain treated with a combination of pulsed dye laser and topical rapamycin ointment. AB - BACKGROUND AND OBJECTIVE: A port wine stain (PWS) is a type of capillary vascular malformation composed of malformed, dilated blood vessels within the papillary and reticular dermis. Currently, pulsed dye laser (PDL) is considered the therapeutic gold standard, although greater than 90% of lesions may be refractory to treatment. Studies have shown that a delay in treatment results in a higher proportion of patients who develop hypertrophy and nodularity within lesions that become more resistant to therapy. Therapeutic resistance is multifactorial, but is believed to be largely due to revascularization after laser treatment. Oral sirolimus and topical imiquimod have shown promise as adjunctive therapies to minimize post-laser revascularization, but both have significant side effects. We wish to demonstrate the utility of adjunct topical sirolimus to reduce revascularization after PDL treatment. STUDY DESIGN/PATIENTS AND METHODS: This is a single patient case report of a 56-year-old male patient with an extensive PWS. After seeing initial improvement with PDL alone, he began to experience thickening and nodularity of his PWS necessitating surgical debulking. Since this procedure, topical sirolimus 0.5% ointment has been added to his treatment regimen as an adjunct to PDL. The patient is being treated with PDL (Vbeam Perfecta, Candela/Syneron, Wayland, MA) every 4-6 weeks at varied settings with the following laser parameters: fluence 9-11 J/cm(2), pulse duration 0.45-1.5 ms, focal spot size 7 mm, cooling 30/20. Sirolimus 0.5% ointment is applied to the area twice daily. RESULTS: The patient showed significant improvement in color and texture of his PWS. Compared to the initial therapy of PDL alone, topical sirolimus ointment in conjunction with PDL demonstrated greater improvement and maintenance of therapeutic results with fewer overall laser treatments. CONCLUSION: Topical sirolimus 0.5% ointment is a safe and effective adjunct to PDL in the treatment of PWS. PMID- 26503091 TI - Significant More Research Required: No Further Progress Without Sound Medical Data and Valid Denominators for In-Flight Medical Emergencies. PMID- 26503092 TI - Training in Travel Medicine and General Practitioners: A Long-Haul Journey! PMID- 26503093 TI - Melioidosis in Travelers: Review of the Literature. AB - BACKGROUND: Melioidosis is a bacterial infection endemic essentially in Southeast Asia and northern Australia. In temperate areas, the infection is extremely rare and is almost always imported by travelers or immigrants. The infection may affect almost any organ in the body, with various degrees of severity. METHODS: We reviewed the literature on melioidosis in travelers. For this purpose we searched PubMed and Google for relevant articles up to July 2015. RESULTS: We have identified 72 cases of melioidosis in travelers published in the literature. Melioidosis in travelers was acquired mostly in Thailand (46% of cases). The mean duration of stay in the endemic area was 36 days (range 7-330 days). Symptoms usually started at 23 days (range 1-360 days) after leaving the endemic area. The clinical presentation was varied, sepsis being the most common (34%) followed by pneumonia (29%) and abscess formation (25%). Melioidosis in travelers was less often associated with predisposing risk factors (37.5%), diabetes mellitus being the most common (21%), and had lower mortality (17%) than had the infection in autochthonous cases in Southeast Asia. CONCLUSIONS: Melioidosis in travelers has its own characteristics, which distinguish it from other autochthonous diseases in indigenous populations. The possibility of melioidosis should be considered not only in patients originating from endemic areas, but also in patients returning from travel in those regions. PMID- 26503094 TI - Imported Flood-Related Leptospirosis From Palau: Awareness of Risk Factors Leads to Early Treatment. AB - We describe two Japanese travelers with leptospirosis who visited Palau. Both travelers swam in Ngardmau Falls, which was flooded for two days after typhoon Phanfone. The diagnoses were confirmed by microscopic agglutination test or polymerase chain reaction. This is the first report of leptospirosis in travelers who returned from Palau. It should be noted that choosing the appropriate test to biologically confirm leptospirosis was highly time-dependent. Awareness of the risk factors for leptospirosis, mainly that of the exposure to contaminated fresh water after a flooding, would lead to an early and appropriate treatment before the confirmed diagnosis. PMID- 26503095 TI - The Final Frontier-What Should the Travel Medicine Practitioner Know About Space Flight Participation? PMID- 26503096 TI - Total Recall? Testing Immediate Recall Does Not Measure Effectiveness of Pre Travel Visits. PMID- 26503097 TI - Response to Letter. PMID- 26503098 TI - Intranasal Fentanyl Intoxication Leading to Diffuse Alveolar Hemorrhage. AB - CONTEXT: Increasing rates of opioid abuse, particularly fentanyl, may lead to more presentations of unusual effects of opioid toxicity. Diffuse alveolar hemorrhage is a rare complication of fentanyl overdose. CASE DETAILS: A 45-year old male presented in hypoxic respiratory failure secondary to diffuse alveolar hemorrhage requiring intubation. Comprehensive drug screening detected fentanyl without exposure to cocaine. Further history upon the patient's recovery revealed exposure to snorted fentanyl powder immediately prior to presentation. DISCUSSION: Diffuse alveolar hemorrhage is a potential, though rare, presentation of opioid intoxication. CONCLUSIONS: Recognition of less common complications of opioid abuse such as diffuse alveolar hemorrhage is important in proper management of overdoses. PMID- 26503100 TI - Erratum to: Investigating determinants of catastrophic health spending among poorly insured elderly households in urban Nigeria. PMID- 26503099 TI - A study of sertraline in dialysis (ASSertID): a protocol for a pilot randomised controlled trial of drug treatment for depression in patients undergoing haemodialysis. AB - BACKGROUND: The prevalence of depression in people receiving haemodialysis is high with estimates varying between 20 and 40 %. There is little research on the effectiveness of antidepressants in dialysis patients with the few clinical trials suffering significant methodological issues. We plan to carry out a study to evaluate the feasibility of conducting a randomised controlled trial in patients on haemodialysis who have diagnosed Major Depressive Disorder. METHODS/DESIGN: The study has two phases, a screening phase and the randomised controlled trial. Patients will be screened initially with the Beck Depression Inventory to estimate the number of patients who score 16 or above. These patients will be invited to an interview with a psychiatrist who will invite those with a diagnosis of Major Depressive Disorder to take part in the trial. Consenting patients will be randomised to either Sertraline or placebo. Patients will be followed-up for 6 months. Demographic and clinical data will be collected at screening interview, baseline interview and 2 weeks, and every month (up to 6 months) after baseline. The primary outcome is to evaluate the feasibility of conducting a randomised, double blind, placebo pilot trial in haemodialysis patients with depression. Secondary outcomes include estimation of the variability in the outcome measures for the treatment and placebo arms, which will allow for a future adequately powered definitive trial. Analysis will primarily be descriptive, including the number of patients eligible for the trial, drug exposure of Sertraline in haemodialysis patients and the patient experience of participating in this trial. DISCUSSION: There is an urgent need for this research in the dialysis population because of the dearth of good quality and adequately powered studies. Research with renal patients is particularly difficult as they often have complex medical needs. This research will therefore not only assess the outcome of anti-depressants in haemodialysis patients with depression but also the process of running a randomised controlled trial in this population. Hence, the outputs of this feasibility study will be used to inform the design and methodology of a definitive study, adequately powered to determine the efficacy of anti-depressants in patient on haemodialysis with depression. TRIAL REGISTRATION: ISRCTN registry ISRCTN06146268 and EudraCT reference: 2012-000547-27. PMID- 26503101 TI - Review: Sustainability of crossbreeding in developing countries; definitely not like crossing a meadow.... AB - Crossbreeding, considering either terminal or rotational crossing, synthetic breed creation or breed replacement, is often promoted as an efficient strategy to increase farmers' income through the improvement of productivity of local livestock in developing countries. Sustainability of crossbreeding is however frequently challenged by constraints such as poor adaptation to the local environment or lack of logistic support. In this review, we investigate factors that may influence the long-term success or the failure of crossbreeding programs, based on the scientific literature and country reports submitted for The Second Report on the State of the World's Animal Genetic Resources for Food and Agriculture. Crossbreeding activities vary widely across species and countries. Its sustainability is dependent on different prerequisites such as continual access to adequate breeding stock (especially after the end of externally funded crossbreeding projects), the opportunity of improved livestock to express their genetic potential (e.g. through providing proper inputs) and integration within a reliable market chain. As formal crossbreeding programs are often associated with adoption of other technologies, they can be a catalyst for innovation and development for smallholders. Given the increasing global demand for animal products, as well as the potential environmental consequences of climate change, there is a need for practical research to improve the implementation of long-term crossbreeding programs in developing countries. PMID- 26503102 TI - Practice pearl: the effect of canagliflozin on HbA1c and blood pressure in patients with type 2 diabetes mellitus. AB - Review of: Wilding JPH, Blonde L, Leiter LA, et al. Efficacy and safety of canagliflozin by baseline HbA1c and known duration of type 2 diabetes mellitus. J Diabetes Complications. 2015;29(3):438-444; and Weir MR, Januszewicz A, Gilbert RE, et al. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertension. 2014;16(12):875-882. Two authors did secondary analyses on the original research data for canagliflozin. Wilding et al. found that the degree of the lowering of the HbA1c in patients was greater in patients with a higher baseline HbA1c. Weir et al. found that the blood pressure lowering seen with canagliflozin was greater if the baseline blood pressures were higher. This shows that canagliflozin will have increased effects in more complicated patients. PMID- 26503104 TI - On the Shoulders of Giants. PMID- 26503105 TI - Controlled Doping of Vacancy-Containing Few-Layer MoS2 via Highly Stable Thiol Based Molecular Chemisorption. AB - MoS2 is considered a promising two-dimensional active channel material for future nanoelectronics. However, the development of a facile, reliable, and controllable doping methodology is still critical for extending the applicability of MoS2. Here, we report surface charge transfer doping via thiol-based binding chemistry for modulating the electrical properties of vacancy-containing MoS2 (v-MoS2). Although vacancies present in 2D materials are generally regarded as undesirable components, we show that the electrical properties of MoS2 can be systematically engineered by exploiting the tight binding between the thiol group and sulfur vacancies and by choosing different functional groups. For example, we demonstrate that NH2-containing thiol molecules with lone electron pairs can serve as an n-dopant and achieve a substantial increase of electron density (Deltan = 3.7 * 10(12) cm(-2)). On the other hand, fluorine-rich molecules can provide a p-doping effect (Deltan = -7.0 * 10(11) cm(-2)) due to its high electronegativity. Moreover, the n- and p-doping effects were systematically evaluated by photoluminescence (PL), X-ray photoelectron spectroscopy (XPS), and electrical measurement results. The excellent binding stability of thiol molecules and recovery properties by thermal annealing will enable broader applicability of ultrathin MoS2 to various devices. PMID- 26503103 TI - The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review. AB - BACKGROUND: Knee osteoarthritis (OA) is one of the leading causes of disability within the adult population. Current treatment options for OA of the knee include intra-articular (IA) hyaluronic acid (HA), a molecule found intrinsically within the knee joint that provides viscoelastic properties to the synovial fluid. A variety of mechanisms in which HA is thought to combat knee OA are reported in the current basic literature. METHODS: We conducted a comprehensive literature search to identify currently available primary non-clinical basic science articles focussing on the mechanism of action of IA-HA treatment. Included articles were assessed and categorized based on the mechanism of action described within them. The key findings and conclusions from each included article were obtained and analyzed in aggregate with studies of the same categorical assignment. RESULTS: Chondroprotection was the most frequent mechanism reported within the included articles, followed by proteoglycan and glycosaminoglycan synthesis, anti-inflammatory, mechanical, subchondral, and analgesic actions. HA cluster of differentiation 44 (CD44) receptor binding was the most frequently reported biological cause of the mechanisms presented. High molecular weight HA was seen to be superior to lower molecular weight HA products. HA derived through a biological fermentation process is also described as having favorable safety outcomes over avian-derived HA products. CONCLUSIONS: The non-clinical basic science literature provides evidence for numerous mechanisms in which HA acts on joint structures and function. These actions provide support for the purported clinical benefit of IA-HA in OA of the knee. Future research should not only focus on the pain relief provided by IA-HA treatment, but the disease modification properties that this treatment modality possesses as well. PMID- 26503106 TI - Optimization and evaluation of Flexicult(r) Vet for detection, identification and antimicrobial susceptibility testing of bacterial uropathogens in small animal veterinary practice. AB - BACKGROUND: Urinary tract infection (UTI) is a common reason for antimicrobial prescription in dogs and cats. The objective of this study was to optimize and evaluate a culture-based point-of-care test for detection, identification and antimicrobial susceptibility testing of bacterial uro-pathogens in veterinary practice. METHODS: Seventy-two urine samples from dogs and cats with suspected UTI presenting to seven veterinary facilities were used by clinical staff and an investigator to estimate sensitivity and specificity of Flexicult Vet A compared to laboratory reference standards for culture and susceptibility testing. Subsequently, the test was modified by inclusion of an oxacillin-containing compartment for detection of methicillin-resistant staphylococci. The performance of the modified product (Flexicult Vet B) for susceptibility testing was evaluated in vitro using a collection of 110 clinical isolates. RESULTS: Bacteriuria was reported by the laboratory in 25 (35 %) samples from the field study. The sensitivity and specificity of Flexicult Vet A for detection of bacteriuria were 83 and 100 %, respectively. Bacterial species were correctly identified in 53 and 100 % of the positive samples by clinical staff and the investigator, respectively. The susceptibility results were interpreted correctly by clinical staff for 70 % of the 94 drug-strain combinations. Higher percentages of correct interpretation were observed when the results were interpreted by the investigator in both the field (76 %) and the in vitro study (94 %). The most frequent errors were false resistance to beta-lactams (ampicillin, amoxicillin clavulanate and cephalotin) in Escherichia coli for Flexicult Vet A, and false amoxicillin-clavulanate resistance in E. coli and false ampicillin susceptibility in Staphylococcus pseudintermedius for Flexicult Vet B. The latter error can be prevented by categorizing staphylococcal strains growing in the oxacillin compartment as resistant to all beta-lactams. CONCLUSIONS: Despite the shortcomings regarding species identification by clinical staff and beta-lactam susceptibility testing of E. coli, Flexicult Vet B (commercial name Flexicult((r)) Vet) is a time- and cost-effective point-of-care test to guide antimicrobial choice and facilitate implementation of antimicrobial use guidelines for treatment of UTIs in small animals, provided that clinical staff is adequately trained to interpret the results and that clinics meet minimum standards to operate in-house culture. PMID- 26503107 TI - The need for thorough phase II studies in medicines development for Alzheimer's disease. AB - An important factor in the universal failure in phase III trials in mild to moderate Alzheimer's disease in the past decade is the lack of phase II clinical data prior to entering phase III, with common reliance on biomarker results alone. Conduction of two learn-confirm cycles according to the Sheiner model would allow go/no-go decision making to include reliable clinical efficacy data prior to conducting phase III and would likely bring the rate of late stage failure more into line with that of other neurological indications. In studies in earlier disease stages, combined phase IIB/III adaptive approaches merit consideration in view of the long timelines of each study, though advantages and disadvantages of this approach versus the classical development pathway still need careful assessment. PMID- 26503108 TI - Development and Validation of the Pride in Eating Pathology Scale (PEP-S). AB - : There is a growing body of theoretical and clinical literature highlighting the role of pride in maintaining eating disordered behaviours. Despite its clinical importance, there are no measures to assess feelings of pride associated with eating psychopathology. This study describes the development and validation of the Pride in Eating Pathology Scale (PEP-S), a self-report questionnaire that examines feelings of pride towards eating disordered symptoms (e.g., pride in food restriction, thinness and weight loss). Participants were 390 females, recruited from university and community populations, whose mean age was 26.99 years. Respondents rated pride in eating pathology on a 7-point Likert-scale. Principal Component Analysis indicated that the 60-item scale comprised a four component structure: (1) pride in weight loss, food control and thinness, (2) pride in healthy weight and healthy eating, (3) pride in outperforming others and social recognition and (4) pride in capturing other people's attention due to extreme thinness. These four components explained a total of 65.31% of the variance. The PEP-S demonstrated very good internal reliability (alpha ranging from 0.88 to 0.98) and very good test-retest reliability over a 3-week time-span (r ranging from 0.81 to 0.93). The PEP-S also showed excellent convergent and discriminant validity. Furthermore, the scale discriminated between women with high and low levels of eating psychopathology. The PEP-S is a psychometrically robust measure of pride in eating pathology. It has the potential to advance theoretical understanding and may also be clinically useful. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: The PEP-S is a valid, reliable, quick and easy to administer self-report questionnaire that measures pride related to eating pathology. The PEP-S assesses four clinically relevant dimensions: (1) pride in weight loss, food control and thinness, (2) pride in healthy weight and healthy eating, (3) pride in outperforming others and social recognition and (4) pride in capturing other people's attention due to extreme thinness. The PEP-S has very good internal and test-retest reliability, and very good convergent and discriminant validity. The PEP-S distinguishes between women with higher and lower levels of eating psychopathology. The PEP-S makes an important contribution to understanding pride in eating psychopathology, which is essential from both clinical and theoretical perspectives. PMID- 26503109 TI - Influence of 1 year of androgen deprivation therapy on lipid and glucose metabolism and fat accumulation in Japanese patients with prostate cancer. AB - BACKGROUND: We prospectively examined influence of androgen deprivation therapy (ADT) on lipid and glucose metabolisms in Japanese patients with prostate cancer. METHODS: Patients with prostate cancer who were hormone-naive and scheduled to receive long-term ADT were recruited between 2011 and 2013. Body weight, abdominal circumference and blood testing associated with lipid and glucose metabolism were recorded every 3 months during 1 year of ADT. Computed tomography (CT) was performed to measure areas of subcutaneous and visceral fat before and after 1 year of ADT. ADT was limited to a luteinizing hormone-releasing hormone (LHRH) agonist with or without bicalutamide. RESULTS: Of 218 patients registered, data were available from 177 patients who completed 1 year of ADT. Of these, CT was performed before and after 1 year of ADT in 88 patients. Median age was 75 years (range, 49-85 years). Median PSA before ADT was 16.7 ng ml(-1) (range, 0.3 3316). Clinical stage was B (54.2%), C (23.2%) and D (20.9%). Mean increases in body weight and abdominal circumference after 1 year of ADT were 2.9 and 3.0%, respectively. Mean increases in total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were 10.6, 14.3, 7.8 and 16.2%, respectively. Mean increases in fasting blood sugar and hemoglobin A1c (HbA1c) were 3.9 and 2.7%, respectively. Lipid alterations were noted in patients without comorbidities, whereas changes in HbA1c were noted in patients with diabetes mellitus at baseline. These lipid and glucose alterations were prominent in the early ADT period. Both visceral and subcutaneous fat, as measured by CT, increased by >20%. The increase in subcutaneous fat was significantly greater than that in visceral fat (P=0.028). CONCLUSIONS: One year of ADT significantly changed lipid and glucose metabolism in Japanese patients with prostate cancer. Patient characteristics or comorbidities at baseline may be associated with ADT induced metabolic changes. PMID- 26503110 TI - Clinical prospects of long noncoding RNAs as novel biomarkers and therapeutic targets in prostate cancer. AB - BACKGROUND: The lack of sensitive and specific biomarkers for prostate cancer (PCa) has led to over-diagnosis and overtreatment with uncertain benefit. Therefore, biomarkers for early diagnosis that can distinguish aggressive from indolent tumors and that can detect metastatic or recurrent disease are needed. Long noncoding RNAs (lncRNAs) are non-protein-coding RNA species. lncRNAs are dysregulated in many diseases including PCa and are emerging as major players in cancer development. lncRNAs have several features that make then suitable as both biomarkers and therapeutics, and lncRNAs regulate critical cancer hallmarks in prostate epithelial cells including proliferation and survival. METHODS: The PubMed database was searched using the terms 'long noncoding RNA', 'biomarker' and 'prostate cancer'. Known lncRNAs implicated as biomarkers and potential therapeutic targets in PCa are reviewed. RESULTS: We comprehensively review several lncRNAs with potential as biomarkers for PCa. lncRNAs including PCA3, PCATs, SChLAP1, SPRY4-IT1 and TRPM2-AS are upregulated in PCa and are cancer specific; they are, therefore, attractive lead candidate biomarkers for clinical application. Several lncRNA therapeutics are currently being investigated by several companies for the treatment of various cancers including PCa. Small interfering RNAs, antisense oligonucleotides, ribozymes, deoxyribozymes and aptemers are few promising technologies for future lncRNA bases therapeutics. CONCLUSION: lncRNA expression is altered in cancer. Aberrant regulation promotes tumor formation, progression and metastasis. lncRNAs can use as tumor markers for PCa and may be attractive novel therapeutic targets for the diagnosis and treatment of PCa. PMID- 26503111 TI - Aspirin and NSAID use in association with molecular subtypes of prostate cancer defined by TMPRSS2:ERG fusion status. AB - BACKGROUND: The TMPRSS2:ERG (T2E) gene fusion is the most common rearrangement in prostate cancer (PCa). It is unknown if these molecular subtypes have a different etiology. We evaluated aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) in association with T2E fusion status. METHODS: Subjects were from a population-based case-control study of PCa. T2E fusion status for prostatectomy cases (n=346) was determined by fluorescence in situ hybridization. Medication use was determined from questionnaires. Logistic regression, controlling for age, race, PCa family history and PSA screening, was used to evaluate the association of T2E fusion status according to medication use. RESULTS: T2E fusion was present in 171 (49%) cases, with younger cases more likely to be fusion positive (P<0.01). Current aspirin use was associated with a 37% risk reduction of T2E positive tumors (adjusted odds ratio (OR) 0.63, 95% confidence interval 0.43 0.93). Aspirin use was not associated with T2E negative PCa (adjusted OR 0.99, 0.69-1.42). There were no associations between PCa fusion status and use of nonaspirin NSAIDs or acetaminophen. CONCLUSIONS: Aspirin was associated with a significant reduction in the relative risk of T2E fusion positive, but not T2E negative, PCa. As inflammation and androgen pathways are implicated in prostate carcinogenesis, additional studies of anti-inflammatory medications in relation to these PCa subtypes are warranted. PMID- 26503113 TI - Internet-Based Approaches to Building Stakeholder Networks for Conservation and Natural Resource Management. AB - Social network analysis (SNA) is based on a conceptual network representation of social interactions and is an invaluable tool for conservation professionals to increase collaboration, improve information flow, and increase efficiency. We present two approaches to constructing internet-based social networks, and use an existing traditional (survey-based) case study to illustrate in a familiar context the deviations in methods and results. Internet-based approaches to SNA offer a means to overcome institutional hurdles to conducting survey-based SNA, provide unique insight into an institution's web presences, allow for easy snowballing (iterative process that incorporates new nodes in the network), and afford monitoring of social networks through time. The internet-based approaches differ in link definition: hyperlink is based on links on a website that redirect to a different website and relatedness links are based on a Google's "relatedness" operator that identifies pages "similar" to a URL. All networks were initiated with the same start nodes [members of a conservation alliance for the Calumet region around Chicago (n = 130)], but the resulting networks vary drastically from one another. Interpretation of the resulting networks is highly contingent upon how the links were defined. PMID- 26503112 TI - Poly-L-ornithine promotes preferred differentiation of neural stem/progenitor cells via ERK signalling pathway. AB - Neural stem/progenitor cells (NSPCs) replacement therapies are the most attractive strategies to restore an injured brain. Key challenges of such therapies are enriching NSPCs and directing them differentiation into specific neural cell types. Here, three biomaterial substrates Poly-L-ornithine (PO), Poly L-lysine (PLL) and fibronectin (FN) were investigated for their effects on proliferation and differentiation of rat NSPCs, and the underlying mechanisms were also explored. The results showed PO significantly increased NSPCs proliferation and induced preferred differentiation, compared with PLL and FN. Checking protein markers of several neural cell subtypes, it is showed PO significantly induced NSPCs expressing Doublecortin (DCX) and Olig2, one for neuroblasts and young neurons and the other for young oligodendrocytes. It is suggested the ERK signaling pathway was involving in this process because an ERK antagonist U0126 could inhibit PO's effects mentioned above, as well as an ERK pathway agonist Ceramide C6 could enhance them. Given that both neurons and oligodendrocytes are the most vulnerable cells in many neurological diseases, PO induced preferred differentiation into neurons and oligodendrocytes is a potential paradigm for NSPCs-based therapies. PMID- 26503114 TI - Suppression of Shear Banding and Transition to Necking and Homogeneous Flow in Nanoglass Nanopillars. AB - In order to improve the properties of metallic glasses (MG) a new type of MG structure, composed of nanoscale grains, referred to as nanoglass (NG), has been recently proposed. Here, we use large-scale molecular dynamics (MD) simulations of tensile loading to investigate the deformation and failure mechanisms of Cu64Zr36 NG nanopillars with large, experimentally accessible, 50 nm diameter. Our results reveal NG ductility and failure by necking below the average glassy grain size of 20 nm, in contrast to brittle failure by shear band propagation in MG nanopillars. Moreover, the results predict substantially larger ductility in NG nanopillars compared with previous predictions of MD simulations of bulk NG models with columnar grains. The results, in excellent agreement with experimental data, highlight the substantial enhancement of plasticity induced in experimentally relevant MG samples by the use of nanoglass architectures and point out to exciting novel applications of these materials. PMID- 26503116 TI - Reconstruction of two-dimensional molecular structure with laser-induced electron diffraction from laser-aligned polyatomic molecules. AB - Imaging the transient process of molecules has been a basic way to investigate photochemical reactions and dynamics. Based on laser-induced electron diffraction and partial one-dimensional molecular alignment, here we provide two effective methods for reconstructing two-dimensional structure of polyatomic molecules. We demonstrate that electron diffraction images in both scattering angles and broadband energy can be utilized to retrieve complementary structure information, including positions of light atoms. With picometre spatial resolution and the inherent femtosecond temporal resolution of lasers, laser-induced electron diffraction method offers significant opportunities for probing atomic motion in a large molecule in a typical pump-probe measurement. PMID- 26503117 TI - Lung ultrasonography for the diagnosis of 11 patients with acute respiratory distress syndrome due to bird flu H7N9 infection. AB - BACKGROUND: A novel reassortant avian-origin influenza A (H7N9) virus was found to infect three Chinese residents, the first H7N9 infection in humans in Asia. Chest computed tomography (CT) for acute respiratory distress syndrome (ARDS) diagnosis is not only expensive but also exposes patients to radiation and might cause patients to be at risk of infection during transportation; in addition, chest radiography cannot be used to monitor the lung repeatedly in real time. Therefore, the routine use of bedside lung ultrasonography for critically ill patients with ARDS is especially valuable. OBJECTIVES: The aim of this study was to evaluate the application of ultrasound for lung examination in patients with ARDS. METHODS: Eleven patients infected with H7N9 avian influenza who developed ARDS were diagnosed by lung ultrasonography. RESULTS: Six patients who had severe ARDS showed a diffuse comet tail sign or a consolidation score >= 7 and a lung ultrasound score >= 20 points. A diffuse comet tail sign or a consolidation score <= 6 and a lung ultrasound score < 25 were observed in four patients. One patient showed a diffuse comet tail sign or consolidation area in four lung areas, with an ultrasound score of 14. Among all 11 patients studied, 6 patients had thoracic puncture and drainage of pleural effusion and 2 patients had pneumothorax puncture drainage. CONCLUSIONS: Lung ultrasound could be useful for monitoring ARDS caused by the influenza virus A H7N9 strain in clinical applications. PMID- 26503118 TI - PBK/TOPK mediates promyelocyte proliferation via Nrf2-regulated cell cycle progression and apoptosis. AB - Acute myeloid leukemia (AML) is a disorder involving hematopoietic stem cells, characterized by blockage of hematopoietic cell differentiation and an increase in clonal neoplastic proliferation. AML is associated with poor patient outcome. PBK/TOPK is a protein kinase derived from PDZ-binding kinase (PBK)/T-lymphokine activated killer (T-LAK) cell-originated protein kinase (TOPK). Previous studies have shown that PBK/TOPK is expressed in hematologic tumors. In the present study, we aimed to investigate the role of PBK/TOPK in promyelocyte proliferation and to clarify the molecular mechanism. PBK/TOPK knockdown (KD) significantly decreased cell proliferation and viability in the NB4 and HL-60 promyelocytes. PBK/TOPK KD resulted in G2/M cell cycle arrest that attributed to a decrease in cdc2 and cyclin B expression. In addition, PBK/TOPK KD caused apoptosis, as evidenced by activation of the mitochondrial apoptotic pathway and an increase in TUNEL-positive cells. PBK/TOPK KD induced mitochondrial dysfunction and ROS generation, and inhibition of mitochondrial dysfunction and ROS production suppressed PBK/TOPK KD-induced cell cycle arrest and apoptosis. Moreover, PBK/TOPK KD decreased Nrf2 expression and ARE-binding activity. Overexpression of Nrf2 inhibited the PBK/TOPK KD-induced decrease in cdc2 and cyclin B expression and cell cycle arrest, and blocked ROS production and apoptosis. Based on literature and our results, it was demonstrated that Nrf2 may be a crucial regulator that mediates PBK/TOPK-exerted promotion of cell proliferation. PBK/TOPK stabilizes Nrf2, strictly regulates the ROS level, promotes cell cycle progression and inhibits apoptosis, contributing to the proliferation of promyelocytes. Our results provide new insights into the molecular mechanism of PBK/TOPK-mediated promyelocyte proliferation and shed light on the pathogenesis of AML. PMID- 26503115 TI - Polymorphisms in early neurodevelopmental genes affect natural variation in alcohol sensitivity in adult drosophila. AB - BACKGROUND: Alcohol abuse and alcoholism are significant public health problems, but the genetic basis for individual variation in alcohol sensitivity remains poorly understood. Drosophila melanogaster presents a powerful model system for dissecting the genetic underpinnings that determine individual variation in alcohol-related phenotypes. We performed genome wide association analyses for alcohol sensitivity using the sequenced, inbred lines of the D. melanogaster Genetic Reference Panel (DGRP) together with extreme QTL mapping in an advanced intercross population derived from sensitive and resistant DGRP lines. RESULTS: The DGRP harbors substantial genetic variation for alcohol sensitivity and tolerance. We identified 247 candidate genes affecting alcohol sensitivity in the DGRP or the DGRP-derived advanced intercross population, some of which met a Bonferroni-corrected significance threshold, while others occurred among the top candidate genes associated with variation in alcohol sensitivity in multiple analyses. Among these were candidate genes associated with development and function of the nervous system, including several genes in the Dopamine decarboxylase (Ddc) cluster involved in catecholamine synthesis. We found that 58 of these genes formed a genetic interaction network. We verified candidate genes using mutational analysis, targeted gene disruption through RNAi knock-down and transcriptional profiling. Two-thirds of the candidate genes have been implicated in previous Drosophila, mouse and human studies of alcohol-related phenotypes. CONCLUSIONS: Individual variation in alcohol sensitivity in Drosophila is highly polygenic and in part determined by variation in evolutionarily conserved signaling pathways that are associated with catecholamine neurotransmitter biosynthesis and early development of the nervous system. PMID- 26503120 TI - Health attitudes and suicidal ideation among university students. AB - OBJECTIVE: The purpose of this study was to examine whether positive health attitudes are associated with suicidal ideation among university students after accounting for other health risk factors linked to suicidal ideation. PARTICIPANTS: Participants were 690 undergraduates from a large midwestern university during fall semester 2011. METHODS: Participants reported demographics and health characteristics. Regression models compared individuals who reported suicidal ideation and those who did not. RESULTS: In unadjusted models, suicidal ideation was significantly negatively associated with positive health attitudes, and positively associated with depression, drug use problems, sleep problems, and being overweight. In adjusted models, more positive health attitudes continued to be significantly negatively associated with suicidal ideation. CONCLUSIONS: This study suggests a link between positive health attitudes and lower probability of suicidal ideation. Additional research is needed to assess enhancing general health attitudes as a suicide prevention effort. PMID- 26503121 TI - Ultrasound tagged near infrared spectroscopy does not detect hyperventilation induced reduction in cerebral blood flow. AB - INTRODUCTION: Continuous non-invasive monitoring of cerebral blood flow (CBF) may be important during anaesthesia and several options are available. We evaluated the CerOx monitor that employs ultrasound tagged near infrared spectroscopy to estimate changes in a CBF index (CFI). METHODS: Seven healthy males (age 21-26 years) hyperventilated and were administered phenylephrine to increase mean arterial pressure by 20-30 mmHg. Frontal lobe tissue oxygenation (ScO2) and CFI were obtained using the CerOx and mean blood flow velocity in the middle cerebral artery (MCAv mean) was determined by transcranial Doppler. Blood flow in the internal and external carotid artery (ICAf and ECAf) was determined using duplex ultrasonography and forehead skin blood flow (SkBF) and oxygenation (S skin O2) by laser Doppler and white light spectroscopy. RESULTS: During hyperventilation MCAv mean and ICAf decreased by 44% (median; interquartile range 40-49; p = 0.016) and 46% (40-53; p = 0.03), respectively. Conversely, CFI increased by 9% (2-31; p = 0.016), while no significant change was observed in ScO2. SkBF increased by 19% (9-53; p = 0.016) and S skin O2 by 6% (1-7; p = 0.047), although ECAf was unchanged. Administration of phenylephrine was not associated with any changes in MCAv mean, ICAf, ECAf, ScO2, SkBF, S skin O2, or CFI. CONCLUSION: The CerOx was able to detect a stable CBF during administration of phenylephrine. However, during hyperventilation MCAv mean and ICAf decreased while CFI increased, likely due to an increase in superficial tissue oxygenation. Thus, CFI does not provide an unbiased evaluation of changes in CBF. PMID- 26503122 TI - Association Between Sleep Problems and Symptoms of Attention Deficit Hyperactivity Disorder in Adolescence: Results From a Large Population-Based Study. AB - Sleep problems and symptoms of ADHD are common in adolescence, but detailed epidemiological assessment of their association is lacking. Using data from a recent population-based study, 9,846 adolescents aged 16 to 19 provided detailed information on sleep and symptoms of ADHD. Results confirmed a large overlap between self-reported symptoms of ADHD and all sleep variables studied. Symptoms of ADHD were linked to shorter sleep duration, longer sleep latency, and nocturnal wake time, as well as larger sleep deficiency. ADHD symptoms also increased the odds of insomnia and delayed sleep phase syndrome. The associations were only partially explained by confounders (mainly depression). The findings suggest that sleep problems should be included as a treatment target in efforts to reduce symptoms of ADHD in adolescence. PMID- 26503123 TI - The influence of processed meat consumption on chronic obstructive pulmonary disease. AB - Although cigarette smoking is the predominant risk factor for chronic obstructive pulmonary disease (COPD), many smokers do not develop COPD. Relatively little attention has been paid to other modifiable factors, such as diet, and how they might affect COPD risk. Recent studies have suggested that processed meat intake may adversely affect lung function and increase risk of developing COPD. However, the role of processed meat in the pathogenesis of COPD is largely unknown and mechanistic studies are lacking. We discuss several areas of future research that would advance our understanding regarding the role of processed meat and, more generally of diet, in the onset and in the clinical evolution of COPD. PMID- 26503125 TI - Eco-friendly synthesis of metal dichalcogenides nanosheets and their environmental remediation potential driven by visible light. AB - Exfoliated transition metal dichalcogenides (TMDs) such as WS2 and MoS2 have shown exciting potential for energy storage, catalysis and optoelectronics. So far, solution based methods for scalable production of few-layer TMDs usually involve the use of organic solvents or dangerous chemicals. Here, we report an eco-friendly method for facile synthesis of few-layer WS2 and MoS2 nanosheets using dilute aqueous solution of household detergent. Short time sonication of varying amount of bulk samples in soapy water was used to scale up the production of nanosheets. Thermal stability, optical absorption and Raman spectra of as synthesized WS2 and MoS2 nanosheets are in close agreement with those from other synthesis techniques. Efficient photocatalytic activity of TMDs nanosheets was demonstrated by decomposing Brilliant Green dye in aqueous solution under visible light irradiation. Our study shows the great potential of TMDs nanosheets for environmental remediation by degrading toxic industrial chemicals in wastewater using sunlight. PMID- 26503126 TI - HER2-positivity rates in breast cancer: no variation over time when clinicopathological features and testing are stable. AB - HER2 status is essential for breast cancer subtyping and for systemic treatment decisions as patients with HER2-positive tumours can benefit from anti-HER2 targeted therapies. However, few data are available on the current HER2-positive breast cancers rate and its evolution across years. Using data from the Cote d'Or breast cancer registry, we identified, between 1998 and 2011, 3220 women with invasive breast cancer diagnosed in the same laboratory which carries out regular internal quality controls and participates in multiannual international quality control programmes. Throughout the studied period of time, despite an increase of annual breast cancer cases, HER2 positivity rate remained stable (13.1%; P = 0.495), as did the proportion of tumours with positive hormone receptor status (P = 0.467) and the proportion of SBR grade II/III tumours (P = 0.747). Other characteristics, less strongly associated with HER2-positive status, showed either no annual variation (nodal and metastatic status, tumour size) or an annual positive trend (mean age, lobular carcinomas) or an annual negative trend (ductal carcinomas). These data reveal that in a population with stable clinical and pathological characteristics, and with the use of standardised assays, HER2 positivity rate remains stable over time. These results also emphasise that current HER2 positivity rate is lower than initially reported. PMID- 26503124 TI - Use of Renally Inappropriate Medications in Older Veterans: A National Study. AB - OBJECTIVES: To determine how many ambulatory older adults with chronic kidney disease receive medications that are contraindicated or dosed excessively given their level of renal function. DESIGN: Cross-sectional retrospective study. SETTING: U.S. Department of Veterans Affairs (VA) clinics. PARTICIPANTS: Individuals aged 65 and older with a creatinine clearance (CrCl) of 15 to 49 mL/min (N = 83,850; mean age 80; 96% male). MEASUREMENTS: Forty medications that require dose adjustment or are contraindicated in people with impaired renal function were examined. Medication use and CrCl (calculated using the Cockroft Gault equation) were assessed using VA pharmacy, laboratory, and other data sources as of October 2007. RESULTS: Thirteen percent of older veterans with a CrCl of 30 to 49 mL/min and 32% of those with a CrCl of 15 to 29 mL/min received one or more drugs that were contraindicated or prescribed at an excessive dose given the individual's level of renal function. The strongest risk factor for renally inappropriate prescribing was number of medications used; the risk of receiving renally inappropriate medications was 5.5 times as high (95% confidence interval = 5.1-5.9) in older adults taking 10 or more medications as in those taking one to three medications. Ranitidine, allopurinol, and metformin together accounted for 76% of renally misprescribed medications in individuals with a CrCl of 30 to 49 mL/min. Glyburide, ranitidine, gemfibrozil, carvedilol, and allopurinol accounted for 47% of renally misprescribed drugs for individuals with a CrCl of 15 to 29 mL/min. CONCLUSION: Inappropriate prescribing of renally cleared medications is common in ambulatory older veterans, with only a few medications accounting for most of these prescribing problems. PMID- 26503128 TI - Does selective logging change ground-dwelling beetle assemblages in a subtropical broad-leafed forest of China? AB - Selective logging with natural regeneration is advocated as a near-to-nature strategy and has been implemented in many forested systems during the last decades. However, the efficiency of such practices for the maintenance of forest species are poorly understood. We compared the species richness, abundance and composition of ground-dwelling beetles between selectively logged and unlogged forests to evaluate the possible effects of selective logging in a subtropical broad-leafed forest in southeastern China. Using pitfall traps, beetles were sampled in two naturally regenerating stands after clearcuts (ca. 50 years old, stem-exclusion stage: selectively logged 20 years ago) and two mature stands (> 80 years old, understory re-initiation stage: selectively logged 50 years ago) during 2009 and 2010. Overall, selective logging had no significant effects on total beetle richness and abundance, but saproxylic species group and some abundant forest species significantly decreased in abundance in selectively logged plots compared with unlogged plots in mature stands. Beetle assemblages showed significant differences between selectively logged and unlogged plots in mature stands. Some environmental characteristics associated with selective logging (e.g., logging strategy, stand age, and cover of shrub and moss layers) were the most important variables explaining beetle assemblage structure. Our results conclude that selective logging has no significant impacts on overall richness and abundance of ground-dwelling beetles. However, the negative effects of selective logging on saproxylic species group and some unlogged forest specialists highlight the need for large intact forested areas for sustaining the existence of forest specialist beetles. PMID- 26503129 TI - Translating Evidence Into Practice via Social Media: A Mixed-Methods Study. AB - BACKGROUND: Approximately 80% of research evidence relevant to clinical practice never reaches the clinicians delivering patient care. A key barrier for the translation of evidence into practice is the limited time and skills clinicians have to find and appraise emerging evidence. Social media may provide a bridge between health researchers and health service providers. OBJECTIVE: The aim of this study was to determine the efficacy of social media as an educational medium to effectively translate emerging research evidence into clinical practice. METHODS: The study used a mixed-methods approach. Evidence-based practice points were delivered via social media platforms. The primary outcomes of attitude, knowledge, and behavior change were assessed using a preintervention/postintervention evaluation, with qualitative data gathered to contextualize the findings. RESULTS: Data were obtained from 317 clinicians from multiple health disciplines, predominantly from the United Kingdom, Australia, the United States, India, and Malaysia. The participants reported an overall improvement in attitudes toward social media for professional development (P<.001). The knowledge evaluation demonstrated a significant increase in knowledge after the training (P<.001). The majority of respondents (136/194, 70.1%) indicated that the education they had received via social media had changed the way they practice, or intended to practice. Similarly, a large proportion of respondents (135/193, 69.9%) indicated that the education they had received via social media had increased their use of research evidence within their clinical practice. CONCLUSIONS: Social media may be an effective educational medium for improving knowledge of health professionals, fostering their use of research evidence, and changing their clinical behaviors by translating new research evidence into clinical practice. PMID- 26503130 TI - Skill-based changes in motor performance from attentional focus manipulations: a kinematic analysis. AB - In the present paper, expert and novice law enforcement officers performed a handgun shooting task under varied attention-demanding conditions; outcome (i.e. accuracy, consistency) and movement kinematics were measured (i.e. within and between-trial variability (BTV) of forearm and upper arm absolute angle). Using a dual-task paradigm, we directed participants' attention towards either a skill relevant aspect of movement execution or to a skill-irrelevant distractor and compared their data to a single-task control condition. The results showed that experts' BTV in their upper arm increased during dual-tasks relative to control, but performance was similar across all three conditions. In contrast, novices' performance was poorer during both dual-tasks relative to control, but limited changes in movement kinematics were observed. This data suggests that attention demanding situations trigger experts' ability to adapt their movement pattern to maintain end-point control. The data for novices are less clear. Implications for future research are discussed. Practitioner Summary: Expert and novice law enforcement officials completed a shooting task under baseline and attention demanding situations. Experts outperformed novices under all conditions, but exhibited increased variability in their upper arm position while shooting during attention-demanding compared to baseline conditions. Novices' movement data remained variable throughout all conditions. The data suggest that experts are able to maintain shooting performance during an attention-demanding situation by adopting a functional movement strategy. PMID- 26503131 TI - Cost-effectiveness evaluation of quadrivalent influenza vaccines for seasonal influenza prevention: a dynamic modeling study of Canada and the United Kingdom. AB - BACKGROUND: The adoption of quadrivalent influenza vaccine (QIV) to replace trivalent influenza vaccine (TIV) in immunization programs is growing worldwide, thus helping to address the problem of influenza B lineage mismatch. However, the price per dose of QIV is higher than that of TIV. In such circumstances, cost effectiveness analyses provide important and relevant information to inform national health recommendations and implementation decisions. This analysis assessed potential vaccine impacts and cost-effectiveness of a country-wide switch from TIV to QIV, in Canada and the UK, from a third-party payer perspective. METHODS: An age-stratified, dynamic four-strain transmission model which incorporates strain interaction, transmission-rate seasonality and age specific mixing in the population was used. Model input data were obtained from published literature and online databases. In Canada, we evaluated a switch from TIV to QIV in the entire population. For the UK, we considered two strategies: Children aged 2-17 years who receive the live-attenuated influenza vaccine (LAIV) switch to the quadrivalent formulation (QLAIV), while individuals aged > 18 years switch from TIV to QIV. Two different vaccination uptake scenarios in children (UK1 and UK2, which differ in the vaccine uptake level) were considered. Health and cost outcomes for both vaccination strategies, and the cost-effectiveness of switching from TIV/LAIV to QIV/QLAIV, were estimated from the payer perspective. For Canada and the UK, cost and outcomes were discounted using 5 % and 3.5 % per year, respectively. RESULTS: Overall, in an average influenza season, our model predicts that a nationwide switch from TIV to QIV would prevent 4.6 % influenza cases, 4.9 % general practitioner (GP) visits, 5.7 % each of emergency room (ER) visits and hospitalizations, and 6.8 % deaths in Canada. In the UK (UK1/UK2), implementing QIV would prevent 1.4 %/1.8 % of influenza cases, 1.6 %/2.0 % each of GP and ER visits, 1.5 %/1.9 % of hospitalizations and 4.3 %/4.9 % of deaths. Discounted incremental cost-utility ratios of $7,961 and L7,989/L7,234 per quality-adjusted life-year (QALY) gained are estimated for Canada and the UK (UK1/UK2), both of which are well within their respective cost-effectiveness threshold values. CONCLUSIONS: Switching from TIV to QIV is expected to be a cost effective strategy to further reduce the burden of influenza in both countries. PMID- 26503132 TI - Long non-coding RNA growth arrest-specific transcript 5 is involved in ovarian cancer cell apoptosis through the mitochondria-mediated apoptosis pathway. AB - The present study investigated the underlying role of growth arrest-specific transcript 5 (GAS5) in epithelial ovarian cancer (EOC), which is the main cause of death in women with malignant tumor of the genital system. In vivo GAS5 expression in 60 EOC specimens was evaluated by quantitative reverse transcription (qRT)-PCR, which was used to study the differences of GAS5 expression between EOC tissues and normal ovarian epithelium. In vitro GAS5 overexpression was applied to discover the biological functions in EOC cell lines. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide and colony formation assays were employed to investigate the effect on proliferation. The function of apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and JC-1 probe staining, and migration and invasion were detected by Transwell assay. The data show that no significant differences of GAS5 expression were observed between normal ovarian epithelium and benign epithelial lesions; however, GAS5 expression was lower in EOC tissues compared with normal ovarian epithelial tissues (6.44-fold), which was closely related to lymph node metastasis (P=0.025) and tumor node metastasis stage (P=0.035). Moreover, exogenous GAS5-inhibited proliferation promoted apoptosis and decreased migration and invasion in ovarian cancer cells. Finally, through mitochondrial potential and western blot analyses, GAS5 could disrupt mitochondrial membrane potential and promote BAX, BAK, cleaved-caspase 3 and cleaved-caspase 9 expression. Taken together, the findings of the present study revealed that GAS5 is downregulated in EOC specimens, and GAS5 inhibits EOC cell proliferation, migration and invasion, and promotes cell apoptosis. GAS5 can serve as a novel therapeutic target in patients with EOC. PMID- 26503134 TI - Enantioselective Phase-Transfer-Catalyzed Synthesis of Chiral N-Substituted 3,3 Dinitroazetidines by Aza-Michael Reaction. AB - An efficient and highly enantioselective phase-transfer-catalyzed aza-Michael reaction of 3,3-dinitroazetidine, as N-centered nucleophile, to alpha,beta unsaturated ketones has been achieved using a quinidine-based phase-transfer catalyst (0.5-1 mol %), providing chiral N-substituted 3,3-dinitroazetidines in good yields (up to 99%) and excellent enantioselectivities (90-95% ee). This is the first example of the use of azetidines as N-centered nucleophiles in catalytic enantioselective aza-Michael reactions. PMID- 26503136 TI - Effects of Nanoscale Spatial Arrangement of Arginine-Glycine-Aspartate Peptides on Dedifferentiation of Chondrocytes. AB - Cell dedifferentiation is of much importance in many cases such as the classic problem of dedifferentiation of chondrocytes during in vitro culture in cartilage tissue engineering. While cell differentiation has been much investigated, studies of cell dedifferentiation are limited, and the nanocues of cell dedifferentiation have little been reported. Herein, we prepared nanopatterns and micro/nanopatterns of cell-adhesive arginine-glycine-aspartate (RGD) peptides on nonfouling poly(ethylene glycol) (PEG) hydrogels to examine the effects of RGD nanospacing on adhesion and dedifferentiation of chondrocytes. The relatively larger RGD nanospacing above 70 nm was found to enhance the maintainence of the chondrocyte phenotype in two-dimensional culture, albeit not beneficial for adhesion of chondrocytes. A unique micro/nanopattern was employed to decouple cell spreading, cell shape, and cell-cell contact from RGD nanospacing. Under given spreading size and shape of single cells, the large RGD nanospacing was still in favor of preserving the normal phenotype of chondrocytes. Hence, the nanoscale spatial arrangement of cell-adhesive ligands affords a new independent regulator of cell dedifferentiation, which should be taken into consideration in biomaterial design for regenerative medicine. PMID- 26503133 TI - Prenatal and Early Postnatal Exposure to Cigarette Smoke Decreases BDNF/TrkB Signaling and Increases Abnormal Behaviors Later in Life. AB - BACKGROUND: Cigarette smoke exposure during prenatal and early postnatal periods increases the incidence of a variety of abnormal behaviors later in life. The purpose of this study was to identify the possible critical period of susceptibility to cigarette smoke exposure and evaluate the possibe effects of cigarette smoke during early life on brain-derived neurotrophic factor/neurotrophic tyrosine kinase receptor B signaling in the brain. METHODS: Three different age of imprinting control region mice were exposed to cigarette smoke or filtered air for 10 consecutive days beginning on either gestational day 7 by maternal exposure, or postnatal days 2 or 21 by direct inhalation. A series of behavioral profiles and neurotrophins in brain were measured 24 hours after mice received acute restraint stress for 1 hour on postnatal day 59. RESULTS: Cigarette smoke exposure in gestational day 7 and postnatal day 2 produced depression-like behaviors as evidenced by significantly increased immobility in both tail suspension and forced-swim test. Increased entry latencies, but not ambulation in the open field test, were also observed in the gestational day 7 and postnatal day 2 cigarette smoke exposure groups. Genetic analysis showed that gestational day 7 cigarette smoke exposure significantly altered mRNA level of brain-derived neurotrophic factor/tyrosine kinase receptor B in the hippocampus. However, behavioral profiles and brain-derived neurotrophic factor/tyrosine kinase receptor B signaling were not significantly changed in PND21 cigarette smoke exposure group compared with FA group. CONCLUSIONS: These results suggest that a critical period of susceptibility to cigarette smoke exposure exists in the prenatal and early postnatal period, which results a downregulation in brain derived neurotrophic factor/tyrosine kinase receptor B signaling in the hippocampus and enhances depression-like behaviors later in life. PMID- 26503135 TI - The strigolactone biosynthesis gene DWARF27 is co-opted in rhizobium symbiosis. AB - BACKGROUND: Strigolactones are a class of plant hormones whose biosynthesis is activated in response to phosphate starvation. This involves several enzymes, including the carotenoid cleavage dioxygenases 7 (CCD7) and CCD8 and the carotenoid isomerase DWARF27 (D27). D27 expression is known to be responsive to phosphate starvation. In Medicago truncatula and rice (Oryza sativa) this transcriptional response requires the GRAS-type proteins NSP1 and NSP2; both proteins are essential for rhizobium induced root nodule formation in legumes. In line with this, we questioned whether MtNSP1-MtNSP2 dependent MtD27 regulation is co-opted in rhizobium symbiosis. RESULTS: We provide evidence that MtD27 is involved in strigolactone biosynthesis in M. truncatula roots upon phosphate stress. Spatiotemporal expression studies revealed that this gene is also highly expressed in nodule primordia and subsequently becomes restricted to the meristem and distal infection zone of a mature nodules. A similar expression pattern was found for MtCCD7 and MtCCD8. Rhizobium lipo-chitooligosaccharide (LCO) application experiments revealed that of these genes MtD27 is most responsive in an MtNSP1 and MtNSP2 dependent manner. Symbiotic expression of MtD27 requires components of the symbiosis signaling pathway; including MtDMI1, MtDMI2, MtDMI3/MtCCaMK and in part MtERN1. This in contrast to MtD27 expression upon phosphate starvation, which only requires MtNSP1 and MtNSP2. CONCLUSION: Our data show that the phosphate-starvation responsive strigolactone biosynthesis gene MtD27 is also rapidly induced by rhizobium LCO signals in an MtNSP1 and MtNSP2 dependent manner. Additionally, we show that MtD27 is co-expressed with MtCCD7 and MtCCD8 in nodule primordia and in the infection zone of mature nodules. PMID- 26503138 TI - The native ant, Tapinoma melanocephalum, improves the survival of an invasive mealybug, Phenacoccus solenopsis, by defending it from parasitoids. AB - Mutualistic ants can protect their partners from natural enemies in nature. Aenasius bambawalei is an important parasitoid of the the invasive mealybug Phenacoccus solenopsis. We hypothesized that mutualism between native ants and mealybugs would favor survival of mealybugs. To test this, we examined effects of tending by the native mutualistic ant Tapinoma melanocephalum on growth of P. solenopsis colonies on Chinese hibiscus, Hibiscus rosa-sinensis, in a field setting. Ant workers with access to honeydew of mealybugs lived much longer than those provisioned only with water in the laboratory, and number of ant workers foraging increased significantly with growth of mealybug colonies in the field. In later observations, there were significant differences in densities of mealybugs between ant-tended and -excluded treatments. Survival rate of mealybugs experiencing parasitoid attack was significantly higher on ant-tended plants than on ant-excluded plants. When the parasitoid was excluded, there was no difference in survival rate of mealybugs between ant-tended and -excluded plants. In most cases, ants directly attacked the parasitoid, causing the parasitoid to take evasive action. We conclude that native ants such as T. melanocephalum have the potential to facilitate invasion and spread of P. solenopsis in China by providing them with protection from parasitoids. PMID- 26503137 TI - Cost-Effectiveness of Nutrition Intervention in Long-Term Care. AB - OBJECTIVES: To determine the cost-effectiveness of two nutrition interventions on food, beverage, and supplement intake and body weight. DESIGN: Randomized, controlled trial. SETTING: Five skilled nursing home facilities. PARTICIPANTS: Long-stay residents with orders for nutrition supplementation (N = 154). INTERVENTION: Participants were randomized into a usual care control group, an oral liquid nutrition supplement (ONS) intervention group, or a snack intervention group. Research staff provided ONS, according to orders or a variety of snack foods and beverages twice per day between meals, 5 days per week for 24 weeks and assistance to promote consumption. MEASUREMENTS: Research staff independently weighed residents at baseline and monthly during the 24-week intervention. Resident food, beverage and supplement intake and the amount of staff time spent providing assistance were assessed for 2 days at baseline and 2 days per month during the intervention using standardized observation and weighed intake procedures. RESULTS: The ONS intervention group took in an average of 265 calories more per day and the snack intervention group an average of 303 calories more per day than the control group. Staff time required to provide each intervention averaged 11 and 14 minutes per person per offer for ONS and snacks, respectively, and 3 minutes for usual care. Both interventions were cost effective in increasing caloric intake, but neither intervention had a significant effect on body weight, despite positive trends. CONCLUSION: Oral liquid nutrition supplements and snack offers were efficacious in promoting caloric intake when coupled with assistance to promote consumption and a variety of options, but neither intervention resulted in significant weight gain. PMID- 26503140 TI - Imaging Tumor Metastases with Molecular Probes. AB - Tumor metastasis is an important prognostic factor regarding long-term survival rate of cancer patients. At present, no imaging modality or technique is ideal for diagnosis of metastases. Molecular imaging has provided a fantastic tool for tumor metastases imaging. Based on the current medical imaging tools such as magnetic resonance imaging (MRI), optical, single-photon emission computed tomography (SPECT), and positron emission tomography (PET), various techniques and functional molecular probes for molecular imaging of tumor metastases have been developed. In this review, we will summarize the current status of nanoprobe based molecular imaging metastases in cancer. PMID- 26503139 TI - Fostering emotional, social, physical and educational wellbeing in rural India: the methods of a multi-arm randomized controlled trial of Girls First. AB - BACKGROUND: There are 600 million girls in low and middle income countries (LMICs), many of whom are at great risk for poor health and education. There is thus great need for programs that can effectively improve wellbeing for these girls. Although many interventions have been developed to address these issues, most focus on health and education without integrating attention to social and emotional factors. This omission is unfortunate, as nascent evidence indicates that these factors are closely related to health and education. This paper describes the methods of a 4-arm randomized controlled trial among 3,560 adolescent girls in rural Bihar, India that tested whether adding an intervention targeting social-emotional issues (based on a "resilience framework") to an adolescent health intervention would improve emotional, social, physical, and educational wellbeing to a greater extent than its components and a control group. Study arms were: (1) Girls First, a combination of the Girls First Resilience Curriculum (RC) and the Girls First Health Curriculum (HC); (2) Girls First Resilience Curriculum (RC) alone; (3) Girls First Health Curriculum (HC) alone; and (4) a school-as-usual control group (SC). METHODS: Seventy-six schools were randomized (19 per condition) and 74 local women with a tenth grade education were trained and monitored to facilitate the program. Quantitative data were collected from 3,560 girls over 4 assessment points with very low rates of participant attrition. Qualitative assessments were conducted with a subset of 99 girls and 27 facilitators. RESULTS AND CONCLUSIONS: In this article, we discuss guiding principles that facilitated trial implementation, including integrating diverse local and non-local sources of knowledge, focusing on flexibility of planning and implementation, prioritizing systematic measurement selection, and striking a balance between scientific rigor and real-world feasibility. TRIAL REGISTRATION: Clinicaltrials.gov NCT02429661 . Registered 24 April 2015. PMID- 26503141 TI - Medical devices regulatory aspects: a special focus on polymeric material based devices. AB - Medical devices form a broad range of appliances from a basic nanoparticle coating or surgical gloves to a complicated laser therapy device. These devices are designed to support patients, surgeons and healthcare personnel in meeting patients' healthcare needs. Regulatory authorities of each country regulate the process of approval, manufacturing and sales of these medical devices so as to ensure safety and quality to patients or users. Recent recalls of medical devices has increased importance of safety, awareness and regulation of the devices. Singapore and India have strong presence and national priorities in medical devices development and use. Herein we capture the rationale of each of these national regulatory bodies and compare them with the medical devices regulatory practices of USA and European nations. Apart from the comparison of various regulatory aspects, this review will specifically throw light on the polymer material based medical devices and their safety. PMID- 26503142 TI - Strategies of overcoming the physiological barriers for tumor-targeted nano-sized drug delivery systems. AB - Nano drug delivery systems (NDDSs) have been widely used in tumor-targeted therapy since they can effectively reduce the side effects of traditional antitumor drugs and improve the anti-tumor effect. We divided the in vivo process of tumor-targeted NDDSs into seven steps: blood circulation, tumor accumulation, tumor tissue penetration, target cells internalization, lysosome escape, drug release and drug response. In each step, NDDSs will encounter different types of barriers preventing their effective delivery or response. The researchers have been making efforts to find different strategies of overcoming the corresponding barriers for NDDSs. Hence, we here reviewed the recent progress of NDDSs in breaking the physiological barriers for more effective in vivo anti-tumor effect, in order to shed a new perspective on the development of tumor-targeted NDDSs. PMID- 26503143 TI - Synthetic and Biological Vesicular Nano-Carriers Designed for Gene Delivery. AB - Synthetic and biological vesicular carriers have been recognized as attractive and intelligent systems for delivery of a verity of bioactive molecules. The importance of such delivery systems can be mostly due to their physicochemical properties, i.e. a lipid bilayer surrounding an aqueous core which allows encapsulation and protection of active hydrophilic molecules such as nucleic acids. Synthetic vesicles such as liposomes have been studied as gene delivery systems for decades. However, due to their fast clearance, toxicity and immunogenicity which impose restrictions on clinical applications, some other natural lipid vesicles such as exosomes have been considered as alternatives. Attractive features of nature's own 'nano-vesicles' such as exosomes, virosomes, bacterial ghosts and erythrocyte ghosts include efficient cellular entry, physicochemical properties and evading immune responses. Nevertheless, there are advantages and disadvantages with both synthetic and biological vesicular systems. Here, we provide an overview into different vesicle-based gene delivery systems and discuss how various modifications in their structure and formulations could improve the transfection efficiency and decrease the toxicity. PMID- 26503144 TI - Ceramic Nanoparticles: Fabrication Methods and Applications in Drug Delivery. AB - Ceramic nanoparticles are primarily made up of oxides, carbides, phosphates and carbonates of metals and metalloids such as calcium, titanium, silicon, etc. They have a wide range of applications due to a number of favourable properties, such as high heat resistance and chemical inertness. Out of all the areas of ceramic nanoparticles applications, biomedical field is the most explored one. In the biomedical field, ceramic nanoparticles are considered to be excellent carriers for drugs, genes, proteins, imaging agents etc. To be able to act as a good and successful drug delivery agent, various characteristics of nanoparticles need to be controlled, such as size range, surface properties, porosity, surface area to volume ratio, etc. In achieving these properties on the favourable side, the method of preparation and a good control over process variables play a key role. Choosing a suitable method to prepare nanoparticles, along with loading of significant amount of drug(s) leads to development of effective drug delivery systems which are being explored to a great extent. Ceramic nanoparticles have been successfully used as drug delivery systems against a number of diseases, such as bacterial infections, glaucoma, etc., and most widely, against cancer. This review gives a detailed account of commonly used methods for synthesising nanoparticles of various ceramic materials, along with an overview of their recent research status in the field of drug delivery. PMID- 26503145 TI - Design of multifunctional nanocarriers for delivery of anti-cancer therapy. AB - Chemotherapy is the major and most widely used therapeutic strategy for the treatment of a wide variety of cancers. The non-specific/non-targeted drug delivery in chemotherapy leads to undesired side effects in normal and healthy tissues, and insufficient dosages to kill cancerous cells. Now-a-days, smart and intelligent multifunctional targeted nanomedicines based on various nanocarriers (dendrimers, carbon nanotubes, graphene, nanoparticles, quantum dots, self emuslifying lipidic systems and carbon nanohorns etc) are being investigated promisingly in cancer treatment. In this article, we review the role of smart and intellegent multifucntional nanocarriers in delivery of chemotherapeutic agents with the aim to develop promising treatment strategy to combat with one of the killer of man kind i.e. cancer. PMID- 26503146 TI - Polyethyleneimine-Based Nanocarriers for Gene Delivery. AB - There is a tremendous progress in the design and synthesis of nano-scaled, non viral carriers in the previous two decades. The nanodelivery systems can significantly improve biopharmaceutical features, pharmacokinetic properties and therapeutic efficacy of entrapped drugs. Branched polyethylenimine (PEI) is a cationic polymer that contains primary, secondary and tertiary amino groups. Such type of water-soluble polymer having high density of amines is one of the most promising cationic vectors for gene delivery. Hence, constructing nanocarriers that contain PEI have attracted much research effort in gene therapy because of the synergy effects of PEI molecules for their efficient transfection and the multi-functionality of nanoparticles in delivery. In this review, we focus on the recent development on the design and synthesis of four types of PEI-based nanocarriers: 1) PEI-based polymeric micelles systems; 2) PEI-based polymeric nanoparticle system; 3) PEI/silica nanoparticle systems; and 4) PEI/metal nanoparticle systems. Their in vitro gene transfaction and in vivo gene therapy will be also discussed. Results from these studies have demonstrated that PEI based nanocarriers are promising delivery systems because of their efficient gene transfection, negligible toxicity, capability to co-deliver nucleic acids and chemotherapy drugs, ease of modification with the targeting molecules, and good responsiveness to external stimulus. PMID- 26503147 TI - Nanotechnology approaches for pain therapy through transdermal drug delivery. AB - The paper focuses on the advances in the field of pain treatment by transdermal delivery of specific drugs. Starting from a short description of the skin barrier, the pharmacodynamics and pharmacokinetics including absorption, distribution, action mechanism, metabolism and toxicity, aspects related to the use of pain therapy drugs are further discussed. Most recent results on topical anesthetic agents as well as the methods proved to overcome the skin barrier and to provide efficient delivery of the drug are also discussed. The present review is proposing to summarize the recent literature on the pharmacotherapeutic principles of local anesthetics and non-steroidal anti-inflammatory drugs, generally used to alleviate pain but also the drugs as nanoformulations with potential applications in transdermal delivery. A special attention is given to efficient formulations meant for transdermal penetration enhancement of anesthetics where the drug is encapsulated into macrocyclic molecules (cyclodextrins, cyclodextrin derivatives), liposomes or polymer nanoparticles and hydrogels. PMID- 26503148 TI - Antitumoral-Lipid-Based Nanoparticles: a Platform for Future Application in Osteosarcoma therapy. AB - Osteosarcoma is the most frequent primary bone tumor in the pediatric age group. Its aggressive local growth pattern and its high propensity to metastasize, mainly to the lungs, give the disease an unfavorable prognosis that has situated this disease as one of the leading causes of pediatric cancer death. Current protocols for osteosarcoma treatment are based on neo-adjuvant (pre-operatory) chemotherapy followed by surgical resection of the tumor and a new phase of adjuvant chemotherapy. Despite the progress that these protocols have made in improving the outcome of the disease, the limited access of drugs to bone tumor and metastases, their indiscriminate distribution in the organism, the high required doses that cause intolerable toxicity and the development of multidrug resistance, still represent a major challenge. Nanotechnology has emerged as a new strategy to successfully address these problems by the development of nanoscaled drug carriers that present the ability to target the drug to the tumor cells, achieving high drug concentrations in the tumor area, while decreasing its presence in healthy tissues and therefore its potential systemic toxicity. This review summarizes the different lipid nanocarriers developed to deliver first and second-line anti-osteosarcoma drugs as well as emerging agents in the treatment of this disease. Moreover, it also discusses the potential of these nanocarriers for the treatment of osteosarcoma. PMID- 26503149 TI - Production of nanosuspensions as a tool to improve drug bioavailability: focus on topical delivery. AB - Over the past two decades nanosizing technology has become one of the most successful formulation approaches for improving the bioavailability of poorly soluble drugs, which show a low oral absorption due to low dissolution velocity. Nanocrystals are nanoparticles of pure drug, without any matrix material, with an average diameter below 1 um (typically in the range of 200-500 nm), which can be prepared in both water and non-water media as colloidal nanosuspensions stabilized using surfactants or polymers. The reduction of the drug particle diameter below 1 um increases the dissolution velocity by increasing the particle surface and decreasing the diffusion layer thickness. Nanosuspension production processes involve two different approaches such as bottom-up (drug nanocrystal precipitation) and top-down (drug particle disintegration) technologies or a combination of two. Within these main approaches, a variety of possible techniques to achieve particle size reduction have been proposed by different research groups from both industry and academia. Even though nanosuspensions formulations have been especially studied for oral and parenteral administration, nanocrystals have showed a great potential also for topical delivery through alternative routes such as dermal, pulmonary and ocular route. The purpose of this review is to describe the main technologies used to produce nanosuspensions as well as to explore the most significant results and progresses obtained by application of drug nanocrystal formulations through topical routes. PMID- 26503150 TI - Micro-/nano-electroporation for active gene delivery. AB - Gene delivery, a process of introducing foreign functional nucleic acids into target cells, has proven to be a very promising tool for inducing specific gene expression in host cells. Many different technologies have been developed for efficient gene delivery. Among them, electroporation has been adopted in gene delivery for decades, and it is currently widely used for transfection of different types of cells. Despite of the success achieved by bulk electroporation (BEP) for gene delivery in vitro and in vivo, it has significant drawbacks such as unstable transfection efficacy and low cell viability. In recent years, there is an emerging interest in understanding how individual cell accepts and responds to exogenous gene materials using single cell based micro-/nano-electroporation (MEP/NEP) technologies. In this review, the authors provide an overview of the recent development of MEP/NEP and their advantages in gene delivery. Additionally, the future perspectives of gene delivery with the application of electroporation are discussed. PMID- 26503151 TI - Diagnostic and Therapeutic Nanoparticles in Cardiovascular Diseases. AB - Cardiovascular diseases are the major cause of non-communicable illness in both developing and developed nations, representing 30% of global deaths. New therapeutic approaches are desperately needed. Nanomedicine represents one such approach, and involves using molecular entities on the scale of 10-150 nanometers, for purposes of diagnosing, treating, and preventing disease. This review provides a basic overview of nanotechnology, then reviews specific applications of nanotechnology to cardiovascular diseases. Most research has focused on diagnosing and treating atherosclerosis using nanoparticles (NPs). However, researchers are beginning to study NPs for use in acute coronary syndromes, revascularization procedures, and heart failure. Antimicrobial NPs directed at biofilms likely have applicability to identifying and treating endocarditis. Despite the large disease burden of cardiovascular diseases, there are fewer researchers and less funding being applied to this research. Additional investment in NP therapies would pay great dividends once these therapies come of age. PMID- 26503152 TI - Modern drug delivery systems for targeting the posterior segment of the eye. AB - Some of the most dangerous diseases of the eye are related to the posterior segment. Diseases such as age-related macular degeneration, cytomegalovirus retinitis, diabetic retinopathy, posterior uveitis and retinitis pigmentosa are difficult to treat using classical methods because of the many internal barriers of the eye which affect the drug efficiency. In this review, we will summarize the main research directions in the field of medicamentous treatment of posterior eye disorders belonging to the controlled drug delivery concept. The review is starting with the most important knowledge regarding anatomy and pathology of the posterior segment of the eye and is continuing with the current treatment methods of the eye posterior segment illnesses and drawbacks of these methods, the drugs administration pathways to the posterior segment of the eye. The last three sections present the state of the art regarding the latest discoveries including the commercial products in the modern drug delivery systems; the main classes of materials treated in the present review are implants, hydrogels and nano- microparticulate systems. PMID- 26503153 TI - Functionalized magnetic nanoparticles for biomedical applications. AB - Functionalized magnetic nanoparticles followed two main directions in the field of biomedical applications: one direction is as image enhancing agents for magnetic resonance imaging (MRI) and the other is as drugdelivery devices for various biologically-active substances. A third field which just emerges in nanomedicine is the field of the so-called theranostic devices which combines in the same delivery vehicle both the therapeutic agent and the contrast substance. The advantages of using nanoparticles instead of larger carriers for delivery of both drug and image contrast enhancing agents will be highlighted throughout this review article. Despite the ever increasing number of articles reporting both in vitro and in vivo studies carried out on functionalized magnetic nanoparticles and envisaging their potential biomedical applications, only few formulations reached the phase of clinical trials and even fewer became marketed products. The perspectives in the field are open, since new drugs require new delivery devices and possibly new means of functionalization. At the same time, the field of nanomedicine also provides the opportunity to better exploit drugs that are already in clinical use by improving their bioavailability through appropriate nanoformulations. PMID- 26503155 TI - TiC2: a new two-dimensional sheet beyond MXenes. AB - MXenes are attracting attention due to their rich chemistry and intriguing properties. Here a new type of metal-carbon-based sheet composed of transition metal centers and C2 dimers rather than individual C atom is designed. Taking the Ti system as a test case, density functional theory calculations combined with a thermodynamic analysis uncover the thermal and dynamic stability of the sheet, as well as a metallic band structure, anisotropic Young's modulus and Poisson's ratio, a high heat capacity, and a large Debye stiffness. Moreover, the TiC2 sheet has an excellent Li storage capacity with a small migration barrier, a lower mass density compared with standard MXenes, and better chemical stability as compared to the MXene Ti2C sheet. When Ti is replaced with other transition metal centers, diverse new MC2 sheets containing C=C dimers can be formed, the properties of which merit further investigation. PMID- 26503154 TI - The cost of illness attributable to diabetic foot and cost-effectiveness of secondary prevention in Peru. AB - BACKGROUND: Diabetes mellitus is a public health challenge worldwide, and roughly 25% of patients with diabetes in developing countries will develop at least one foot ulcer during their lifetime. The gravest outcome of an ulcerated foot is amputation, leading to premature death and larger economic costs. METHODS: This study aimed to estimate the economic costs of diabetic foot in high-risk patients in Peru in 2012 and to model the cost-effectiveness of a year-long preventive strategy for foot ulceration including: sub-optimal care (baseline), standard care as recommended by the International Diabetes Federation, and standard care plus daily self-monitoring of foot temperature. A decision tree model using a population prevalence-based approach was used to calculate the costs and the incremental cost-effectiveness ratio (ICER). Outcome measures were deaths and major amputations, uncertainty was tested with a one-way sensitivity analysis. RESULTS: The direct costs for prevention and management with sub-optimal care for high-risk diabetics is around US$74.5 million dollars in a single year, which decreases to US$71.8 million for standard care and increases to US$96.8 million for standard care plus temperature monitoring. The implementation of a standard care strategy would avert 791 deaths and is cost-saving in comparison to sub optimal care. For standard care plus temperature monitoring compared to sub optimal care the ICER rises to US$16,124 per death averted and averts 1,385 deaths. CONCLUSION: Diabetic foot complications are highly costly and largely preventable in Peru. The implementation of a standard care strategy would lead to net savings and avert deaths over a one-year period. More intensive prevention strategies such as incorporating temperature monitoring may also be cost effective. PMID- 26503156 TI - Expression of retinoic acid-binding proteins and retinoic acid receptors in sebaceous cell carcinoma of the eyelids. AB - BACKGROUND: Sebaceous cell carcinoma of the eyelid is a malignant tumor. However, the pathoetiology of sebaceous cell carcinoma is not clear. Retinoic acid (RA) signaling is essential for skin epidermal differentiation including the eyelids. In this study, we investigate the expression of beta-catenin, RA-binding proteins and RA receptors in sebaceous cell carcinoma of the eyelid and try to estimate their influence on its pathoetiology. METHODS: Retrospective, noncomparative, consecutive interventional case series. Sixteen cases of eyelid sebaceous gland carcinoma who received tumor excision at our hospital between 2001 and 2011 were included. Immunohistochemical staining for beta-catenin, cellular retinoic acid binding protein 1 (CRABP1), cellular retinoic acid binding protein 2 (CRABP2), fatty acid-binding protein 5 (FABP5), retinoic acid receptors (RAR-alpha, -beta, gamma), and retinoid X receptors (RXR-alpha, -beta, -gamma) was performed on tissue samples obtained from tumor excision. RESULTS: Of the 16 sebaceous cell carcinoma cases reviewed, six were male and 10 female. The mean follow-up period was 6.7 +/- 3.66 years (range, 0.3-13 years). Of these 16 cases, the expression of beta-catenin was significantly increased in sebaceous cell carcinoma cases. CRABP1 was similarly expressed in the sebaceous cell carcinoma and control groups. CRABP2 and FABP5 were expressed in hair follicles of lid skin in both groups, whereas the CRABP2 and FABP5 were aberrantly expressed in the tumor cells of the sebaceous glands. Notably, the expression of retinoic acid receptor (RAR beta) and retinoid X receptors (RXR-beta, -gamma) was significantly upregulated in sebaceous cell carcinoma of the eyelids. CONCLUSIONS: Our findings indicate that retinoic acid signaling is related to the pathogenesis of sebaceous cell carcinoma of the eyelids. PMID- 26503157 TI - Inhibition of motor neuron death in vitro and in vivo by a p75 neurotrophin receptor intracellular domain fragment. AB - The p75 neurotrophin receptor (p75(NTR); also known as NGFR) can mediate neuronal apoptosis in disease or following trauma, and facilitate survival through interactions with Trk receptors. Here we tested the ability of a p75(NTR)-derived trophic cell-permeable peptide, c29, to inhibit p75(NTR)-mediated motor neuron death. Acute c29 application to axotomized motor neuron axons decreased cell death, and systemic c29 treatment of SOD1(G93A) mice, a common model of amyotrophic lateral sclerosis, resulted in increased spinal motor neuron survival mid-disease as well as delayed disease onset. Coincident with this, c29 treatment of these mice reduced the production of p75(NTR) cleavage products. Although c29 treatment inhibited mature- and pro-nerve-growth-factor-induced death of cultured motor neurons, and these ligands induced the cleavage of p75(NTR) in motor-neuron like NSC-34 cells, there was no direct effect of c29 on p75(NTR) cleavage. Rather, c29 promoted motor neuron survival in vitro by enhancing the activation of TrkB-dependent signaling pathways, provided that low levels of brain-derived neurotrophic factor (BDNF) were present, an effect that was replicated in vivo in SOD1(G93A) mice. We conclude that the c29 peptide facilitates BDNF-dependent survival of motor neurons in vitro and in vivo. PMID- 26503158 TI - Luman is involved in osteoclastogenesis through the regulation of DC-STAMP expression, stability and localization. AB - Luman (also known as CREB3) is a type-II transmembrane transcription factor belonging to the OASIS family that localizes to the endoplasmic reticulum (ER) membrane under normal conditions. In response to ER stress, OASIS-family members are subjected to regulated intramembrane proteolysis (RIP), following which the cleaved N-terminal fragments translocate to the nucleus. In this study, we show that treatment of bone marrow macrophages (BMMs) with cytokines - macrophage colony-stimulating factor (M-CSF) and RANKL (also known as TNFSF11) - causes a time-dependent increase in Luman expression, and that Luman undergoes RIP and becomes activated during osteoclast differentiation. Small hairpin (sh)RNA mediated knockdown of Luman in BMMs prevented the formation of multinucleated osteoclasts, concomitant with the suppression of DC-STAMP, a protein that is essential for cell-cell fusion in osteoclastogenesis. The N-terminus of Luman facilitates promoter activity of DC-STAMP, resulting in upregulation of DC-STAMP expression. Furthermore, Luman interacts with DC-STAMP, and controls its stability and localization. These results suggest that Luman regulates the multinucleation of osteoclasts by promoting cell fusion of mononuclear osteoclasts through DC-STAMP induction and intracellular distribution during osteoclastogenesis. PMID- 26503159 TI - Measured outcomes of chronic care programs for older adults: a systematic review. AB - BACKGROUND: Wagner's Chronic Care Model (CCM), as well as the expanded version (ECCM) developed by Barr and colleagues, have been widely adopted as frameworks for prevention and management of chronic disease. Given the high prevalence of chronic illness in older persons, these frameworks can play a valuable role in reorienting the health care system to better serve the needs of seniors. We aimed to identify and assess the measured goals of E/CCM interventions in older populations. In particular, our objective was to determine the extent to which published E/CCM initiatives were evaluated based on population, community, system and individual-level outcomes (including clinical, functional and quality of life measures). METHODS: We conducted a systematic search of the Science Citation Index Web of Knowledge search tool to gather articles published between January 2003 and July 2014. We included published CCM interventions that cited at least one of the fundamental papers that introduced and described the CCM and ECCM. Studies retained for review reported evaluations of senior-focused E/CCM initiatives in community-based settings, with the topic of "older adults" OR senior* OR elder* OR geriatric OR aged. The resulting 619 published articles were independently reviewed for inclusion by two researchers. We excluded the following: systematic reviews, meta-analyses, descriptions of proposed programs, and studies whose populations did not focus on seniors. RESULTS: We identified 14 articles that met inclusion criteria. Studies used a wide range of measures, with little consensus between studies. All of the included studies used the original CCM. While a range of system-level and individual patient outcomes have been used to evaluate CCM interventions, no studies employed measures of population or community health outcomes. CONCLUSIONS: Future efforts to test E/CCM interventions with seniors would be aided by more consistent outcome measures, greater attention to outcomes for the caregivers of older persons with chronic illness, and a greater focus on population and community impacts. PMID- 26503160 TI - Engineered selective plant male sterility through pollen-specific expression of the EcoRI restriction endonuclease. AB - Unintended gene flow from transgenic plants via pollen, seed and vegetative propagation is a regulatory concern because of potential admixture in food and crop systems, as well as hybridization and introgression to wild and weedy relatives. Bioconfinement of transgenic pollen would help address some of these concerns and enable transgenic plant production for several crops where gene flow is an issue. Here, we demonstrate the expression of the restriction endonuclease EcoRI under the control of the tomato pollen-specific LAT52 promoter is an effective method for generating selective male sterility in Nicotiana tabacum (tobacco). Of nine transgenic events recovered, four events had very high bioconfinement with tightly controlled EcoRI expression in pollen and negligible to-no expression other plant tissues. Transgenic plants had normal morphology wherein vegetative growth and reproductivity were similar to nontransgenic controls. In glasshouse experiments, transgenic lines were hand-crossed to both male-sterile and emasculated nontransgenic tobacco varieties. Progeny analysis of 16 000-40 000 seeds per transgenic line demonstrated five lines approached (>99.7%) or attained 100% bioconfinement for one or more generations. Bioconfinement was again demonstrated at or near 100% under field conditions where four transgenic lines were grown in close proximity to male-sterile tobacco, and 900-2100 seeds per male-sterile line were analysed for transgenes. Based upon these results, we conclude EcoRI-driven selective male sterility holds practical potential as a safe and reliable transgene bioconfinement strategy. Given the mechanism of male sterility, this method could be applicable to any plant species. PMID- 26503162 TI - Sequential structural transitions with distinct dielectric responses in a layered perovskite organic-inorganic hybrid material: [C4H9N]2[PbBr4]. AB - A novel organic-inorganic hybrid layered perovskite-type compound of the general formula A2BX4, bis(IBA)tetrabromolead(II) (1, IBA = isobutyl-ammonium cation), has been successfully synthesized and grown as flake-like crystals, and undergoes two reversible solid-state phase transitions at 315 K and 250 K, and has been systematically characterized using differential scanning calorimetry measurements, variable-temperature structural analyses, variable-temperature powder X-ray diffraction measurements and dielectric measurements. 1 exhibits a remarkable temperature-dependent dielectric behavior, which could be switched between high and low dielectric states above room temperature, and a broad peak exists below room temperature. The most striking dielectric property is the remarkable anisotropy along the various crystallographic axes. All of these demonstrate its potential application as a high temperature switchable molecular dielectric and low temperature phase transition material. PMID- 26503163 TI - Immunomodulatory effect of ghrelin in the intestinal mucosa. AB - The gastrointestinal tract is the largest endocrine organ in the body and it produces a wide array of hormones and neuropeptides. Ghrelin, a 28-amino acid hormone produced mainly by the X/A-like endocrine cells in the gastric mucosa, has widespread tissue distribution and diverse physiological functions such as hormonal, orexigenic, metabolic, cardiovascular, neurological and immunological activities. Recent research has implicated ghrelin in gastrointestinal pathological conditions and immune system regulation, but its contribution is controversial. Although ghrelin levels are elevated in clinical active inflammatory bowel diseases, confirmation of its exact role using experimental models remains unclear. This review discusses the conflicting effects of ghrelin on intestinal inflammation, through the different possible immune and intracellular mechanisms and highlights new findings. PMID- 26503161 TI - Altered memory-related functional connectivity of the anterior and posterior hippocampus in older adults at increased genetic risk for Alzheimer's disease. AB - The hippocampal complex is affected early in Alzheimer's disease (AD). Increasingly, altered functional connectivity of the hippocampus is recognized as an important feature of preclinical AD. Carriers of the APOEE4 allele are at an increased risk for AD, which could lead to altered hippocampal connectivity even in healthy older adults. To test this hypothesis, we used a paired-associates memory task to examine differences in task-dependent functional connectivity of the anterior and posterior hippocampus in nondemented APOEE4 carriers (n = 34, 18F) and noncarriers (n = 46, 31F). We examined anterior and posterior portions of the hippocampus separately to test the theory that APOEE4-mediated differences would be more pronounced in the anterior region, which is affected earlier in the AD course. This study is the first to use a psychophysiological interaction approach to query the context-dependent connectivity of subregions of the hippocampus during a memory task in adults at increased genetic risk for AD. During encoding, APOEE4 carriers had lower functional connectivity change compared to baseline between the anterior hippocampus and right precuneus, anterior insula and cingulate cortex. During retrieval, bilateral supramarginal gyrus and right precuneus showed lower functional connectivity change with anterior hippocampus in carriers. Also during retrieval, carriers showed lower connectivity change in the posterior hippocampus with auditory cortex. In each case, APOEE4 carriers showed strong negative connectivity changes compared to noncarriers where positive connectivity change was measured. These differences may represent prodromal functional changes mediated in part by APOEE4 and are consistent with the anterior-to-posterior theory of AD progression in the hippocampus. PMID- 26503164 TI - Psyllium is not fermented in the human gut. PMID- 26503165 TI - Response to letter Dr. McRorie. PMID- 26503166 TI - Erratum. PMID- 26503167 TI - Simultaneous demultiplexing and steering of multiple orbital angular momentum modes. AB - We present a simple scheme to perform simultaneous demultiplexing and steering of multiple orbital angular momentum (OAM) modes using a single complex phase mask. By designing the phase mask, the propagation directions of demultiplexed beams can be arbitrarily steered. System experiments using orthogonal frequency division multiplexing 32-ary quadrature amplitude modulation (OFDM-32QAM) signals over two OAM modes are carried out by using a two-mode complex phase mask. Moreover, demultiplexing of sixteen OAM modes and arbitrary demultiplexed beam steering are also demonstrated in the experiment. PMID- 26503168 TI - Australian employer usage of the practice of offering reduced working hours to workers close to retirement: Extent and determinants. AB - AIM: This study aimed to determine factors associated with the implementation by employers of the practice of offering reduced working hours for workers nearing retirement. METHODS: Data came from a survey of 2000 employers of more than 50 employees each (30% response rate). RESULTS: A minority (33%) of employers offered reduced working hours to older workers nearing retirement. Factors associated with offering reduced working hours were: expecting workforce ageing to cause a loss of staff to retirement; being a large employer; being a public/not-for-profit sector employer; not experiencing difficulties recruiting labourers; having a larger proportion of workers aged over 50; experiencing national competition for labour; not experiencing difficulties recruiting machinery operators/drivers; not expecting workforce ageing to increase workplace injuries; and experiencing difficulties with the quality of candidates. CONCLUSION: A minority of employers were found to offer reduced working hours to those nearing retirement. Factors associated with their propensity to do so included industry sector, size of employer, concerns about labour supply and the effects of workforce ageing. PMID- 26503169 TI - Numb is required to prevent p53-dependent senescence following skeletal muscle injury. AB - Regeneration relies on coordinated action of multiple cell types to reconstitute the damaged tissue. Here we inactivate the endocytic adaptor protein Numb in skeletal muscle stem cells prior to chronic or severe muscle injury in mice. We observe two types of senescence in regenerating muscle; a transient senescence in non-myogenic cells of control and Numb mutant mice that partly depends on INK4a/ARF activity, and a persistent senescence in myogenic cells lacking Numb. The senescence levels of Numb-deficient muscle is reduced to wild type levels by an anti-oxidant treatment or p53 ablation, resulting in functional rescue of the regenerative potential in Numb mutants. Ex vivo experiments suggest that Numb deficient senescent cells recruit macrophages to sustain inflammation and drive fibrosis, two hallmarks of the impaired muscle regeneration in Numb mutants. These findings provide insights into previously reported developmental and oncogenic senescence that are also differentially regulated by p53. PMID- 26503171 TI - New tricks from an old dog: Another synaptotoxic fragment from APP. AB - In a surprising twist, a hitherto unrecognized cleavage of the amyloid precursor protein (APP) by eta-secretase, followed by alpha- or beta-secretase cleavage releases a novel APP proteolytic fragment, Aeta, which causes synaptic injury. PMID- 26503170 TI - Biosynthesis of the mycotoxin tenuazonic acid by a fungal NRPS-PKS hybrid enzyme. AB - Tenuazonic acid (TeA) is a well-known mycotoxin produced by various plant pathogenic fungi. However, its biosynthetic gene has been unknown to date. Here we identify the TeA biosynthetic gene from Magnaporthe oryzae by finding two TeA inducing conditions of a low-producing strain. We demonstrate that TeA is synthesized from isoleucine and acetoacetyl-coenzyme A by TeA synthetase 1 (TAS1). TAS1 is a unique non-ribosomal peptide synthetase and polyketide synthase (NRPS-PKS) hybrid enzyme that begins with an NRPS module. In contrast to other NRPS/PKS hybrid enzymes, the PKS portion of TAS1 has only a ketosynthase (KS) domain and this domain is indispensable for TAS1 activity. Phylogenetic analysis classifies this KS domain as an independent clade close to type I PKS KS domain. We demonstrate that the TAS1 KS domain conducts the final cyclization step for TeA release. These results indicate that TAS1 is a unique type of NRPS-PKS hybrid enzyme. PMID- 26503172 TI - Choline kinase-alpha protein and phosphatidylcholine but not phosphocholine are required for breast cancer cell survival. AB - High levels of total choline and phosphocholine (PC) are consistently observed in aggressive cancers. Choline kinase (Chk) catalyzes choline phosphorylation to produce PC in phosphatidylcholine (PtdCho) biosynthesis. PtdCho is the most abundant phospholipid in eukaryotic cell membranes and plays a dual role as the structural component of membranes and as a substrate to produce lipid second messengers such as phosphatidic acid and diacylglycerol. Chk-alpha, but not Chk beta, is overexpressed in various cancers, and is closely associated with tumor progression and invasiveness. We have previously shown that downregulation of mRNA using small interfering RNA (siRNA) against Chk-alpha (siRNA-Chk) or Chk short hairpin RNA, and the resultant decrease of Chk-alpha protein levels, significantly reduced proliferation in breast cancer cells and tumors. A novel potent and selective small-molecule Chk-alpha inhibitor, V-11-0711, that inhibits the catalytic activity of Chk has recently been developed. Here, we used triple negative MDA-MB-231 and SUM149 breast cancer cells to further investigate the role of Chk-alpha in cancer, by examining Chk-alpha protein levels, cell viability/proliferation, choline phospholipid and lipid metabolism, lipid droplet formation, and apoptosis, following treatment with V-11-0711. Under the conditions used in this study, treatment with V-11-0711 significantly decreased PC levels but did not reduce cell viability as long as Chk-alpha protein and PtdCho levels were not reduced, suggesting that Chk-alpha protein and PtdCho, but not PC, may be crucial for breast cancer cell survival. These data also support the approach of antitumor strategies that destabilize Chk-alpha protein or downregulate PtdCho in breast cancer treatment. PMID- 26503173 TI - Measurement of Local Sodium Ion Levels near Micelle Surfaces with Fluorescent Photoinduced-Electron-Transfer Sensors. AB - The Na(+) concentration near membranes controls our nerve signals aside from several other crucial bioprocesses. Fluorescent photoinduced electron transfer (PET) sensor molecules target Na(+) ions in nanospaces near micellar membranes with excellent selectivity against H(+). The Na(+) concentration near anionic micelles was found to be higher than that in bulk water by factors of up to 160. Sensor molecules that are not held tightly to the micelle surface only detected a Na(+) amplification factor of 8. These results were strengthened by the employment of control compounds whose PET processes are permanently "on" or "off". PMID- 26503174 TI - A Zn Metal-Organic Framework with High Stability and Sorption Selectivity for CO2. AB - A three-dimensional porous Zn metal-organic framework (UPC-12) with high thermal and chemical stability was isolated in high yield and purity from a hydrothermal reaction. UPC-12 exhibits high selectivity for CO2 due to the formation of hydrogen bonds between CO2 molecules and the -COOH groups exposed inside the channels and the effective pi-pi interactions between CO2 molecules and the pillared bipyridine moieties of the MOF. The adsorption-desorption process was studied, for the first time, by both (13)C CP-TOSS NMR spectroscopy and in situ DRIFTS. PMID- 26503175 TI - Caregiver insightfulness and young children's violence exposure: testing a relational model of risk and resilience. AB - This study employed a relational post-traumatic stress frame to explore the co contribution of young children's exposure to violence and caregiver insightfulness on child behavioral outcomes in a high-risk, non-referred sample of caregivers and preschoolers (n = 64; mean age 3.83 years, SD = .77). Caregiver insightfulness did not have a main effect on child outcomes but did moderate the relation between violence exposure and child behavior across all observed outcomes. Violence-exposed children with non-insightful caregivers demonstrated higher caregiver-rated internalizing and externalizing behaviors and observer rated negative affect than all other groups. Among children not exposed to violence, insightfulness was not related to children's behavior problems or negative affect, suggesting violence-specific processes. Though cross-sectional, results suggest that the effects of violence and caregiver insightfulness on child outcomes are contingent on one another and that caregiver insightfulness may play a protective role in contexts of violence. PMID- 26503176 TI - Preparing the Field for Feasibility Testing of a Parenting Intervention for War Affected Mothers in Northern Uganda. AB - In this article, we discuss the successful implementation of an adapted evidence based parenting intervention for families affected by two decades of war in Northern Uganda. The adaptation and adoption of such interventions to support mental health and family functioning is widely endorsed by prevention scientists and considered a priority in global mental health. The preparation and early adoption phases of engaging with a highly vulnerable community affected by war trauma are documented in this paper along with a discussion of the steps taken to adapt a parenting intervention for cultural and contextual fit. This study is a component of an overall program of research aimed at reducing the long-term negative effects of war on parenting practices and childhood outcomes, which have considerable implications for preventing mental, neurological, and substance-use disorders. The processes described here cover a 4-year period culminating in the implementation of the nine-session Enhancing Family Connection intervention piloted with a group of 14 mothers. The lessons in cultural adaptation have been valuable and the feasibility results promising for further testing the intervention. PMID- 26503177 TI - 3D Study of the Morphology and Dynamics of Zeolite Nucleation. AB - The principle aspects and constraints of the dynamics and kinetics of zeolite nucleation in hydrogel systems are analyzed on the basis of a model Na-rich aluminosilicate system. A detailed time-series EMT-type zeolite crystallization study in the model hydrogel system was performed to elucidate the topological and temporal aspects of zeolite nucleation. A comprehensive set of analytical tools and methods was employed to analyze the gel evolution and complement the primary methods of transmission electron microscopy (TEM) and nuclear magnetic resonance (NMR) spectroscopy. TEM tomography reveals that the initial gel particles exhibit a core-shell structure. Zeolite nucleation is topologically limited to this shell structure and the kinetics of nucleation is controlled by the shell integrity. The induction period extends to the moment when the shell is consumed and the bulk solution can react with the core of the gel particles. These new findings, in particular the importance of the gel particle shell in zeolite nucleation, can be used to control the growth process and properties of zeolites formed in hydrogels. PMID- 26503178 TI - Fine structure of the dorsal lingual epithelium in Tarentola annularis and Crocodylus niloticus. AB - The present study examined the morphological features, histological and histochemical aspect of the tongue of two reptilian species, Tarentola annularis (family: Gekkonidae) and Crocodylus niloticus (family: Crocodylidea), with different habitats, feeding patterns and behaviours, by light and scanning electron microscope. It was observed, that the bifurcation of the tongue was more visible in Tarentola annularis. Conical and filamentous papillae were observed on the lingual body of Tarentola annularis, while in Crocodylus niloticus both mechanical filiform and gustatory papillae appeared. The lingual mucosa in Tarentola annularis is covered by stratified squamous epithelium and keratinised but in Crocodylus niloticus it is highly folded and more heavily keratinised in the folded region and have a localised thickenings structure resembling taste buds. Mucous glands appeared in Tarentola annularis and compound tubular glands in Crocodylus niloticus. At scanning electron microscopy, abundant microridges and microvilli in both species were exhibited on papillae surface facilitated feeding habits. Histochemically, the tongue of two species is strongly positive for carbohydrate stain but with variable degree with others stains. In conclusion, there is a marked correlation between the structure of the tongue of the present reptilian species, habitats and feeding mechanism of the two species. PMID- 26503179 TI - Comparison of the craniometric parameters of wild and farm American mink (Mustela vison). AB - Skulls of 65 American minks from the West Pomeranian Province were examined (farm: n = 33, male: n = 16, female: n = 17; wild: n = 32, male: n = 20, female: n = 12). Craniometric parameters in the number of 24 were determined and measured on each skull. Results were averaged and compared, maintaining the division into sex groups. Males were found to have statistically significant differences between wild and farm animals in 20 parameters; measurements showing no statistically significant differences were: nasal length, postorbital constriction, brain case height and greatest height of the mandibular body. Females were found to have statistically significant differences between wild and farm animals in 6 parameters: condylobasal length, tooth row length, greatest length of the mandible, brain case basis length, postorbital length and palatal length. The percentage conversion of measurements into the greatest length of the skull showed differences in its proportions. Among male skulls, the parameters for which the ratio of differences was more than 2% were palatal length, zygomatic breadth and brain case height. For female skulls, no craniometric parameters showed differences in the skull proportions being greater than 2%. The occurrence of measurable changes in the craniometric parameters between domestic and farm mink populations may indicate that the domestication process is still ongoing and allows distinguishing the population affiliation of an individual specimen. PMID- 26503180 TI - Comparative anatomy of pectoral girdle and pectoral fin in Russian sturgeon and American paddlefish. AB - Acipenseriformes occupy an important place in the evolutionary history. Skeleton of their pectoral fins has elements related to teleosts, but also to tetrapods. This article summarises and compares anatomical structure of the pectoral girdle and pectoral fin of Russian sturgeon (Acipenser gueldenstaedtii) and American paddlefish (Polyodon spathula). These species possess pectoral fins with some distinctive features in their structure. The pectoral girdles are composed of both cartilaginous and ossified elements. Unlike sturgeons, American paddlefish does not have an interclavicle and suprascapular cartilage. Moreover, its cleithrum doesn't form medially directed lamina. The quantity of the proximal radials in the investigated fish species are not the same. The dorsal and ventral muscles, which act on the pectoral fin of Russian sturgeon and American paddlefish, are not equally developed. In our opinion, this is caused by the differences in the mode of life, motility of fins, as well as by stabilisation of body during swimming. PMID- 26503181 TI - Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone. AB - KEY POINTS: KCNE4 alters the biophysical properties and cellular localization of voltage-gated potassium channel Kv7.4. KCNE4 is expressed in a variety of arteries and, in mesenteric arteries, co-localizes with Kv7.4, which is important in the control of vascular contractility. Knockdown of KCNE4 leads to reduced Kv7.4 membrane abundance, a depolarized membrane potential and an augmented response to vasoconstrictors. KCNE4 is a key regulator of the function and expression of Kv7.4 in vascular smooth muscle. ABSTRACT: The KCNE ancillary subunits (KCNE1-5) significantly alter the expression and function of voltage gated potassium channels; however, their role in the vasculature has yet to be determined. The present study aimed to investigate the expression and function of the KCNE4 subunit in rat mesenteric arteries and to determine whether it has a functional impact on the regulation of arterial tone by Kv7 channels. In HEK cells expressing Kv7.4, co-expression of KCNE4 increased the membrane expression of Kv7.4 and significantly altered Kv7.4 current properties. Quantitative PCR analysis of different rat arteries found that the KCNE4 isoform predominated and proximity ligation experiments showed that KCNE4 co-localized with Kv7.4 in mesenteric artery myocytes. Morpholino-induced knockdown of KCNE4 depolarized mesenteric artery smooth muscle cells and resulted in their increased sensitivity to methoxamine being attenuated (mean +/- SEM EC50 decreased from 5.7 +/- 0.63 MUm to 1.6 +/- 0.23 MUm), which coincided with impaired effects of Kv7 modulators. When KCNE4 expression was reduced, less Kv7.4 expression was found in the membrane of the mesenteric artery myocytes. These data show that KCNE4 is consistently expressed in a variety of arteries, and knockdown of the expression product leads to reduced Kv7.4 membrane abundance, a depolarized membrane potential and an augmented response to vasoconstrictors. The present study is the first to demonstrate an integral role of KCNE4 in regulating the function and expression of Kv7.4 in vascular smooth muscle. PMID- 26503186 TI - Luminescence investigation of novel MgPbAl10O17:Tb3+ green-emitting phosphor for solid-state lighting. AB - In this work, we studied the luminescence properties of Tb(3+)-doped MgPbAl10O17 green phosphor. To understand the excitation mechanism and corresponding emission of the prepared phosphor, its structural, morphological and photoluminescence properties were investigated. In general, for green emission, Tb(3) is used as an activator and the obtained excitation and emission spectra indicated that this phosphor can be effectively excited by a wavelength of 380 nm, and exhibits bright green emission centered at 545 nm corresponding to the f -> f transition of trivalent terbium ions. The chromaticity coordinates were (C(x) = 0.263, C(y) = 0.723). The impact of Tb(3+) concentration on the relative emission intensity was investigated, and the best doping concentration was found to be 2 mol%. This study suggests that Tb(3+)-doped MgPbAl10O17 phosphor is a strong candidate for a green component in phosphor-converted white light-emitting diodes. PMID- 26503188 TI - Tumor cell specific and lysosome-targeted delivery of nitric oxide for enhanced photodynamic therapy triggered by 808 nm near-infrared light. AB - A novel cancer cell lysosome-targetable multifunctional NO-delivery nanoplatform (Lyso-Ru-NO@FA@C-TiO2) (1) was developed. It selectively targets folate-receptor overexpressed cancer cells and specifically locates within the lysosome organelle to which NO and reactive oxygen species are simultaneously released upon 808 nm NIR light irradiation. The dual-targeted nanoplatform (1) demonstrated the highest anticancer efficacy compared with nontargeted counterparts under NIR light sensitization. PMID- 26503187 TI - Diabetes and Risk of Surgical Site Infection: A Systematic Review and Meta analysis. AB - OBJECTIVE To determine the independent association between diabetes and surgical site infection (SSI) across multiple surgical procedures. DESIGN Systematic review and meta-analysis. METHODS Studies indexed in PubMed published between December 1985 and through July 2015 were identified through the search terms "risk factors" or "glucose" and "surgical site infection." A total of 3,631 abstracts were identified through the initial search terms. Full texts were reviewed for 522 articles. Of these, 94 articles met the criteria for inclusion. Standardized data collection forms were used to extract study-specific estimates for diabetes, blood glucose levels, and body mass index (BMI). A random-effects meta-analysis was used to generate pooled estimates, and meta-regression was used to evaluate specific hypothesized sources of heterogeneity. RESULTS The primary outcome was SSI, as defined by the Centers for Disease Control and Prevention surveillance criteria. The overall effect size for the association between diabetes and SSI was odds ratio (OR)=1.53 (95% predictive interval [PI], 1.11 2.12; I2, 57.2%). SSI class, study design, or patient BMI did not significantly impact study results in a meta-regression model. The association was higher for cardiac surgery 2.03 (95% PI, 1.13-4.05) compared with surgeries of other types (P=.001). CONCLUSIONS These results support the consideration of diabetes as an independent risk factor for SSIs for multiple surgical procedure types. Continued efforts are needed to improve surgical outcomes for diabetic patients. Infect. Control Hosp. Epidemiol. 2015;37(1):88-99. PMID- 26503190 TI - Beyond bedpans: Celebrating nursing and midwifery. PMID- 26503191 TI - Breastfeeding and HIV infection. PMID- 26503189 TI - Optical scatter patterns facilitate rapid differentiation of Enterobacteriaceae on CHROMagarTM Orientation medium. AB - Enterobacteriaceae family comprised pathogens and commensals and has a significant impact on food safety and public health. Enterobacteriaceae is often enumerated and presumptively identified on chromogenic media, such as CHROMagar(TM) Orientation medium based on colony profile; however, classification is highly arbitrary, and some could not be differentiated due to similar chromogen production. Here, we investigated the ability of the laser optical sensor, BARDOT (bacterial rapid detection using optical scattering technology) for rapid screening and differentiation of colonies of the major bacterial genera from Enterobacteriaceae on CHROMagar(TM) Orientation. A total of 36 strains representing 12 genera and 15 species were used to generate colony scatter image library that comprised 1683 scatter images. This library was used to differentiate mixed cultures of Enterobacteriaceae family - Klebsiella pneumoniae, Enterobacter spp., Citrobacter freundii and Serratia marcescens (KECS group); Proteus mirabilis, Morganella morganii and Providencia rettgeri (PMP group); and non-Enterobacteriaceae family: Pseudomonas aeruginosa, Acinetobacter spp. and Staphylococcus aureus (PAS group) - and data show high accuracy (83 100%) for intra-group classification of colonies in 10-22 h or even before visible production of chromogens. BARDOT successfully differentiated the major genera, including the ones that do not produce visually distinguishable chromogens on CHROMagar(TM) Orientation, providing a label-free, real-time on plate colony screening tool for Enterobacteriaceae. PMID- 26503193 TI - Is Nano a Bubble? PMID- 26503195 TI - Probing the Effect of Molecular Nonuniformity in Directed Self-Assembly of Diblock Copolymers in Nanoconfined Space. AB - Various complex self-assembled morphologies of lamellar- and cylinder-forming block copolymers comprising poly(dimethylsiloxane)-b-polylactide (PDMS-b-PLA) confined in cylindrical channels were generated. Combining top-down lithography with bottom-up block copolymer self-assembly grants access to morphologies that are otherwise inaccessible with the bulk materials. Channel diameter (D) was systematically varied with four diblock copolymers having different compositions and bulk domain spacing (L0), corresponding to a range of frustration ratios (D/L0 from 2 to 4). Excessive packing frustration imposed by the channels leads to contorted domains. The resulting morphologies depend strongly on both D/L0 and copolymer composition. Under several circumstances, mixtures of complex morphologies were observed, which hypothetically arise from the severe sensitivity to D/L0 combined with the inherent compositional/molar mass dispersities associated with the nonuniform synthetic materials and silicon templates. Stochastic calculations offer compelling support for the hypothesis, and tractable pathways toward solving this apparent conundrum are proposed. The materials hold great promise for next-generation nanofabrication to address several emerging technologies, offering significantly enhanced versatility to basic diblock copolymers as templates for fabricating complex nanoscale objects. PMID- 26503192 TI - Early life nutritional programming of health and disease in The Gambia. AB - Exposures during the early life (periconceptional, prenatal and early postnatal) period are increasingly recognized as playing an important role in the aetiology of chronic non-communicable diseases (NCD), including coronary heart disease, stroke, hypertension, Type 2 diabetes and osteoporosis. The 'Developmental Origins of Health and Disease' (DOHaD) hypothesis states that these disorders originate through unbalanced nutrition early in life and risk is highest when there is a 'mismatch' between the early- and later-life environments. Thus, the DOHaD hypothesis would predict highest risk in countries where an excess of infants are born with low birth weight and where there is a rapid transition to nutritional adequacy or excess in adulthood. Here, I will review data from work conducted in rural Gambia, West Africa. Using demographic data dating back to the 1940s, the follow-up of randomized controlled trials of nutritional supplementation in pregnancy and the 'experiment of nature' that seasonality in this region provides, we have investigated the DOHaD hypothesis in a population with high rates of maternal and infant under-nutrition, a high burden from infectious disease, and an emerging risk of NCDs. PMID- 26503197 TI - Patchwork. PMID- 26503198 TI - Policy Statement on Site-Neutral Payments in Oncology. PMID- 26503196 TI - Intermittent High-Dose Intravenous Interferon Alfa-2b for Adjuvant Treatment of Stage III Melanoma: Final Analysis of a Randomized Phase III Dermatologic Cooperative Oncology Group Trial. AB - PURPOSE: To evaluate the efficacy, safety, tolerability, and quality of life (QoL) in patients receiving intravenous, intermittent high-dose interferon alfa 2b (IFN-alpha-2b [iHDI]) compared with standard high-dose IFN-alpha-2b (HDI). PATIENT AND METHODS: Patients with stage III resected lymph node or in-transit metastasis from cutaneous malignant melanoma were randomly assigned to receive either a standard HDI regimen or three courses of IFN-alpha-2b 20 MIU/m(2) administered intravenously 5 days a week for 4 weeks then repeated every 4 months. Distant metastasis-free survival was the primary end point for efficacy analysis. In addition, relapse-free survival, overall survival, safety as determined by Common Terminology Criteria for Adverse Events criteria, and QoL were secondary end points. RESULTS: Of 649 patients enrolled, 22 patients were excluded from the intent-to-treat analysis. The remaining 627 patients were well balanced between the arms according to sex, age, and stage. After a median follow up of 55 months, a multivariable Cox model revealed no significant differences for distant metastasis-free survival (hazard ratio [HR], 1.21; P = .12) or overall survival (HR, 1.01; P = .85). In contrast, the difference for relapse free survival was significant (HR, 1.27; P = .03), favoring standard HDI. Early termination of treatment because of adverse events or QoL occurred significantly more often with HDI than with iHDI (26.0% v 14.8%; P < .001). CONCLUSION: Although the safety and QoL profiles for the intermittent regimen were favorable, no significant difference was observed for survival while the HR for relapse with iHDI was increased. Therefore, an iHDI regimen, as tested here, cannot be recommended as adjuvant treatment for high-risk melanoma. PMID- 26503199 TI - Clinical Utility of Metrics Based on Tumor Measurements in Phase II Trials to Predict Overall Survival Outcomes in Phase III Trials by Using Resampling Methods. AB - PURPOSE: Phase II clinical trials inform go/no-go decisions for proceeding to phase III trials, and appropriate end points in phase II trials are critical for facilitating this decision. Phase II solid tumor trials have traditionally used end points such as tumor response defined by Response Evaluation Criteria for Solid Tumors (RECIST). We previously reported that absolute and relative changes in tumor measurements demonstrated potential, but not convincing, improvement over RECIST to predict overall survival (OS). We have evaluated the metrics by using additional measures of clinical utility and data from phase III trials. METHODS: Resampling methods were used to assess the clinical utility of metrics to predict phase III outcomes from simulated phase II trials. In all, 2,000 phase II trials were simulated from four actual phase III trials (two positive for OS and two negative for OS). Cox models for three metrics landmarked at 12 weeks and adjusted for baseline tumor burden were fit for each phase II trial: absolute changes, relative changes, and RECIST. Clinical utility was assessed by positive predictive value and negative predictive value, that is, the probability of a positive or negative phase II trial predicting an effective or ineffective phase III conclusion, by prediction error, and by concordance index (c-index). RESULTS: Absolute and relative change metrics had higher positive predictive value and negative predictive value than RECIST in five of six treatment comparisons and lower prediction error curves in all six. However, differences were negligible. No statistically significant difference in c-index across metrics was found. CONCLUSION: The absolute and relative change metrics are not meaningfully better than RECIST in predicting OS. PMID- 26503200 TI - Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. AB - PURPOSE: Patients with metastatic rhabdomyosarcoma (RMS), except those younger than 10 years with embryonal RMS, have an estimated long-term event-free survival (EFS) of less than 20%. The main goal of this study was to improve outcome of patients with metastatic RMS by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer. PATIENTS AND METHODS: Patients with metastatic RMS received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 to 6, 20 to 25, and 47 to 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 to 19 and 26 to 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 to 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites). RESULTS: One hundred nine eligible patients were enrolled, with a median follow-up of surviving patients of 3.8 years (3-year EFS for all patients, 38% [95% CI, 29% to 48%]; survival, 56% [95% CI, 46% to 66%]). Patients with one or no Oberlin risk factor (age > 10 years or < 1 year, unfavorable primary site of disease, >= three metastatic sites, and bone or bone marrow involvement) had a 3-year EFS of 69% (95% CI, 52% to 82%); high-risk patients with two or more risk factors had a 3-year EFS of 20% (95% CI, 11% to 30%). Toxicity was similar to that on prior RMS studies. CONCLUSION: Patients with metastatic RMS with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with an historical cohort from pooled European and US studies; those with two or more risk factors have a dismal prognosis, and new approaches are needed for this very-high-risk group. PMID- 26503202 TI - Platinum Antitumor Complexes: 50 Years Since Barnett Rosenberg's Discovery. PMID- 26503201 TI - Ablative Radiotherapy Doses Lead to a Substantial Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective Dose Response Analysis. AB - PURPOSE: Standard therapies for localized inoperable intrahepatic cholangiocarcinoma (IHCC) are ineffective. Advances in radiotherapy (RT) techniques and image guidance have enabled ablative doses to be delivered to large liver tumors. This study evaluated the effects of RT dose escalation in the treatment of IHCC. PATIENTS AND METHODS: Seventy-nine consecutive patients with inoperable IHCC were identified and treated with definitive RT from 2002 to 2014. At diagnosis, the median tumor size was 7.9 cm (range, 2.2 to 17 cm). Seventy patients (89%) received systemic chemotherapy before RT. RT doses were 35 to 100 Gy (median, 58.05 Gy) in three to 30 fractions for a median biologic equivalent dose (BED) of 80.5 Gy (range, 43.75 to 180 Gy). RESULTS: Median follow-up time for patients alive at time of analysis was 33 months (range, 11 to 93 months). Median overall survival (OS) time after diagnosis was 30 months; 3-year OS rate was 44%. Radiation dose was the single most important prognostic factor; higher doses correlated with an improved local control (LC) rate and OS. The 3-year OS rate for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses (P = .017); 3-year LC rate was significantly higher (78%) after a BED greater than 80.5 Gy than after lower doses (45%, P = .04). BED as a continuous variable significantly affected LC (P = .009) and OS (P = .004). There were no significant treatment-related toxicities. CONCLUSION: Delivery of higher doses of RT improves LC and OS in inoperable IHCC. A BED greater than 80.5 Gy seems to be an ablative dose of RT for large IHCCs, with long-term survival rates that compare favorably with resection. PMID- 26503205 TI - Targeting Programmed Cell Death 1 in Ovarian Cancer. PMID- 26503203 TI - Body Mass Index Is Prognostic in Metastatic Colorectal Cancer: Pooled Analysis of Patients From First-Line Clinical Trials in the ARCAD Database. AB - PURPOSE: In recent retrospective analyses of early-stage colorectal cancer (CRC), low and high body mass index (BMI) scores were associated with worsened outcomes. Whether BMI is a prognostic or predictive factor in metastatic CRC (mCRC) is unclear. PATIENTS AND METHODS: Individual data from 21,149 patients enrolled onto 25 first-line mCRC trials during 1997 to 2012 were pooled. We assessed both prognostic and predictive effects of BMI on overall survival and progression-free survival, and we accounted for patient and tumor characteristics and therapy type (targeted v nontargeted). RESULTS: BMI was prognostic for overall survival (P < .001) and progression-free survival (P < .001), with an L-shaped pattern. That is, risk of progression and/or death was greatest for low BMI; risk decreased as BMI increased to approximately 28 kg/m(2), and then it plateaued. Relative to obese patients, patients with a BMI of 18.5 kg/m(2) had a 27% increased risk of having a PFS event (95% CI, 20% to 34%) and a 50% increased risk of death (95% CI, 43% to 56%). Low BMI was associated with poorer survival for men than women (interaction P < .001). BMI was not predictive of treatment effect. CONCLUSION: Low BMI is associated with an increased risk of progression and death among the patients enrolled on the mCRC trials, with no increased risk for elevated BMI, in contrast to the adjuvant setting. Possible explanations include negative effects related to cancer cachexia in patients with low BMI, increased drug delivery or selection bias in patients with high BMI, and potential for an interaction between BMI and molecular signaling pathways. PMID- 26503206 TI - Limited-Stage Small-Cell Lung Cancer: An Age Limit for Combined Modality Therapy? PMID- 26503204 TI - Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2. AB - PURPOSE: To explore the genetic landscape of tumors from patients enrolled on the BOLERO-2 trial to identify potential correlations between genetic alterations and efficacy of everolimus treatment. The BOLERO-2 trial has previously demonstrated that the addition of everolimus to exemestane prolonged progression-free survival by more than twofold in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. PATIENTS AND METHODS: Next-generation sequencing was used to analyze genetic status of cancer-related genes in 302 archival tumor specimens from patients representative of the BOLERO-2 study population. Correlations between the most common somatic alterations and degree of chromosomal instability, and treatment effect of everolimus were investigated. RESULTS: Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components. However, quantitative differences in everolimus benefit were observed between patient subgroups defined by the exon-specific mutations in PIK3CA (exon 20 v 9) or by different degrees of chromosomal instability in the tumor tissues. CONCLUSION: The data from this exploratory analysis suggest that the efficacy of everolimus was largely independent of the most commonly altered genes or pathways in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The potential impact of chromosomal instabilities and low-frequency genetic alterations on everolimus efficacy warrants further investigation. PMID- 26503207 TI - One and Done: A Week of Radiotherapy for Glioblastoma. PMID- 26503208 TI - Patients Who Receive Androgen Deprivation Therapy Risk Adverse Cognitive Changes. PMID- 26503209 TI - Knockdown of miR-221 promotes the cisplatin-inducing apoptosis by targeting the BIM-Bax/Bak axis in breast cancer. AB - Accumulating evidence shows that microRNAs (miRNAs) have a critical role in the initiation and progression of types of human cancer, including breast cancer. Recent research indicated that miRNAs are also related with the chemotherapy on cancers. In this study, the expression of miR-221 in breast cancer (BC) patients' serum and cancer tissues was found to be significantly up-regulated. The results of in vitro MTT assay indicated that although the anti-miR-221 oligonucleotide alone did not influence the viability of BC cell lines markedly, it significantly promoted the cytotoxicity of cisplatin (DDP) to BC cells. Mechanistic studies demonstrated that the gene of BIM (Bcl-2 interacting mediator of cell death), a pro-apoptotic Bcl-2 family protein, was up-regulated by the knockdown of miR-221. We found that the synergetic effect of anti-miR-221 on increasing the sensitivity of MDA-MB-231 was BIM dependant. Furthermore, results of immunoprecipitation showed the up-regulated BIM directly combined with the Bax and Bak, leading to mitochondrial dysfunction. Our results suggest the anti-miR-221 could promote the cisplatin-inducing apoptosis by targeting the Bim-Bax/Bak axis in breast cancer. PMID- 26503210 TI - Interleukin 10 gene -1082A/G polymorphism is associated with osteosarcoma risk and poor outcomes in the Chinese population. AB - Interleukin-10 (IL-10) is a multifunctional cytokine that participates in the development and progression of various malignant tumors. However, data regarding the role of IL-10 polymorphisms in osteosarcoma development are not available. A case-control study was conducted in 260 patients with osteosarcoma and 260 healthy controls to investigate the possible association between IL-10 polymorphisms and the risk of osteosarcoma. Our results indicate the IL-10 1082A/G (rs1800896) polymorphism is significantly associated with an increased risk of osteosarcoma in all genetic models (AG vs. AA, odds ratio (OR) = 1.56; 95 % confidence interval (CI) = 1.28-2.32, P = 0.017; GG vs. AA, OR = 1.62, 95 % CI 1.24-2.61, P = 0.013; AG + GG vs. CC, OR = 1.76, 95 % CI = 1.31-3.01, P = 0.019). However, the genotype and allele frequencies of IL-10 -819C/T (rs1800871) and 592A/C (rs1800872) polymorphisms in osteosarcoma patients did not significantly differ from controls. Further analyses revealed that the IL-10 -1082A/G (rs1800896) genotypes were associated with advanced tumor stages and metastasis in osteosarcoma patients. Additionally, a statistically significant association between the IL-10 -1082A/G (rs1800896) genotype and poor survival in osteosarcoma patients was observed. Our results demonstrate that the IL-10 -1082A/G (rs1800896) genotype is associated with an increased susceptibility and worse outcome for osteosarcoma patients in the Chinese Han population. PMID- 26503211 TI - Increased expression of interleukin-8 is an independent indicator of poor prognosis in clear-cell renal cell carcinoma. AB - On the basis of aberrant interleukin-8 (IL-8) expression, a crucial angiogenesis factor and potential therapeutic target, in clear-cell renal cell carcinoma (ccRCC), this study aims to assess the prognostic significance of IL-8 in ccRCC. This retrospective study enrolled 271 patients who underwent nephrectomy for ccRCC in a single institution. The associations of IL-8 expression with clinical and pathological features were assessed using chi-squared tests. The impact on cancer-specific survival (CSS) and relapse-free survival (RFS) was analyzed using univariable and multivariable Cox regression models. The area under the receiver operating characteristic (ROC) curve (AUC) was used as an index of prognostic performance. Intratumoral IL-8 was found to be significantly elevated in ccRCC tissues compared with peritumor tissue and be predominately localized in the cytoplasm. Moreover, high IL-8 expression was positively correlated with Fuhrman grade (P < 0.001). Multivariate Cox regression analysis identified IL-8 as an independent adverse prognostic factor of CSS (P < 0.001) and RFS (P < 0.001), which could be incorporated into the traditional TNM staging system to improve the prognostic value for CSS and RFS in ccRCC patients. The predictive accuracy of traditional TNM stage model was significantly improved when IL-8 expression was added. Increased expression of IL-8 is a potential independent adverse prognostic biomarker for CSS and RFS in patients with ccRCC after nephrectomy. PMID- 26503212 TI - FAM98A is a novel substrate of PRMT1 required for tumor cell migration, invasion, and colony formation. AB - Protein arginine methylation, which is mediated by a family of protein arginine methyltransferases (PRMTs), is associated with numerous fundamental cellular processes. Accumulating studies have revealed that the expression of multiple PRMTs promotes cancer progression. In this study, we examined the role of PRMT1 in ovarian cancer cells. PRMT1 is expressed in multiple ovarian cancer cells, and the depletion of its expression suppressed colony formation, in vivo proliferation, migration, and invasion. To gain insight into PRMT1-mediated cancer progression, we searched for novel substrates of PRMT1. We found that FAM98A, whose physiological function is unknown, was arginine-methylated by PRMT1. FAM98A is expressed in numerous ovarian cancer cell lines and is important for the malignant characteristics of ovarian cancer cells. Our results indicate the possible role of the PRMT1-FAM98A pathway in cancer progression. PMID- 26503213 TI - The c.*229C > T gene polymorphism in 3'UTR region of the topoisomerase IIbeta binding protein 1 gene and LOH in BRCA1/2 regions and their effect on the risk and progression of human laryngeal carcinoma. AB - Topoisomerase IIbeta binding protein 1 (TopBP1), a multiple-BRCT-domain, protein plays crucial roles in chromosome replication, DNA damage repair, apoptosis, and cell cycle checkpoint signalling. The aim of this study was to identify five SNPs at loci potentially located in the 3'UTR region of the TopBP1 gene (rs185903567, rs116645643, rs115160714, rs116195487, rs112843513), their relationship with the risk of squamous cell laryngeal cancer (SCLC), tumor invasiveness, and prognosis. Genotyping was performed in 323 genetically unrelated individuals with SCLC and 418 randomly selected healthy volunteers. Allele-specific TopBP1 mRNA and protein expressions were determined by using real-time PCR and Western blotting techniques, respectively. LOH in BRCA1/BRCA2 was determined by using microsatellite markers. Compared to homozygous common allele carriers, heterozygosity for the T variant was associated with increased risk of SCLC (adjusted odds ratio [OR] = 9.83, 95 % confidence interval [CI]: 3.12-22.16, p dominant < 0.0001). The presence of risk allele at rs115160714 TopBP1 determined a higher incidence of nodal metastases (OR = 7.98, 95 % CI: 3.94-16.00, p = 0.001) and higher tumor grade (OR = 6.48, 95 % CI: 0.86-48.01, p = 0.03). The heterozygotes displayed diffuse tumor growth with no distinct borderline (OR = 3.10, 95 % Cl: 0.92-10.62, p = 0.049) and higher depth of invasion (OR = 2.66, 95 % Cl: 0.78-9.03, p = 0.04). Relationships were also identified between TopBP1 mRNA/protein expression and overall survival (p < 0.0001). The incidence of LOH in BRCA1/BRCA2 was significantly related to higher tumor grade and TFG (p < 0.05). The results of this study suggest that rs115160714 TopBP1 may be a genetic marker of etiology and progression in laryngeal cancer. PMID- 26503214 TI - GALNT7, a target of miR-494, participates in the oncogenesis of nasopharyngeal carcinoma. AB - GalNAc-transferase-7 (GALNT7) is essential for the regulation of cell proliferation and has been implicated in tumorigenesis. However, the role of GALNT7 in the development and progression of nasopharyngeal carcinoma (NPC) remains unclear. Our previous study showed that GALNT7 was a putative target of miR-494, which was confirmed by luciferase reporter assay. In the present study, we demonstrated that in vitro knockdown of GALNT7 significantly inhibited the proliferation, colony formation, migration, and invasion of NPC-derived cells. In vivo tumorigenicity assay showed that miR-494 and GALNT7-small interfering RNA (siRNA) reduced tumor growth in nude mice. Taken together, our results provided new evidence for an oncogenic role of GALNT7 in NPC. PMID- 26503215 TI - CXCL5 is a potential diagnostic and prognostic marker for bladder cancer patients. AB - Chemokine C-X-C motif ligand 5 (CXCL5) is critical for bladder cancer growth and progression. Our previous study demonstrated that increase of CXCL5 in bladder cancer cell lines had an effect on tumor growth and progression. This study aims to investigate the expression of CXCL5 in tissue and urine of bladder cancer patients, in relation to clinicopathologic parameters, and as a predictive value in diagnosing and evaluating bladder cancer. Urothelial bladder cancer tissues from 255 patients were profiled for CXCL5 alterations by immunohistochemistry. Urine samples collected from patients with bladder cancer and urinary tract infections as well as healthy volunteers were analyzed by ELISA. High expression of CXCL5 in bladder cancer tissue was correlated with TNM stage (P = 0.012), cancer grade (P = 0.001), and lymph node metastasis (P = 0.007). CXCL5 alterations were associated with overall survival (P = 0.007), progression free survival (P = 0.004), and recurrence free survival in muscle invasive bladder cancers (P = 0.026). CXCL5 expression in the urine of bladder cancer patients was significantly different from urinary tract infection patients (P = 0.001) and healthy volunteers. However, urine leukocytes may predict CXCL5 levels (beta = 0.56, P < 0.001, R (2) = 0.314). CXCL5 expression in urine was also related to bladder cancer TNM stage (P = 0.039), lymph node metastasis (P = 0.023), tumor size (P = 0.007), and tumor grade (P = 0.005). The sensitivity and specificity for CXCL5/creatinine in predicting bladder cancer were 80.4 and 61.3 %, respectively. These results suggest increased CXCL5 expression in cancer tissue predicts poor survival in bladder cancer patients. CXCL5 expression in urine is useful in a minimally invasive modality for bladder cancer diagnosis. However, urine leukocytes are significant predictors of CXCL5 levels and may affect its result in bladder cancer diagnosis. PMID- 26503216 TI - Interleukin-15-transferred cytokine-induced killer cells elevated anti-tumor activity in a gastric tumor-bearing nude mice model. AB - Gastric cancer is the second leading cause of cancer-related mortality worldwide. Adoptive cell therapy (ACT) for gastric cancer is a novel therapy modality. However, the therapeutic effectiveness in vivo is still limited. The objective of this study was to assess the value of interleukin-15 (IL-15)-transferred cytokine induced killer (CIK) cells in ACT for gastric cancer. IL-15-IRES-TK retroviral vector was constructed and transferred into the CIK cells. A gastric tumor bearing nude mice model was constructed by subcutaneously injecting gastric cancer cells, BGC-823. Gastric tumor-bearing nude mice were randomly divided into three groups (five mice each group) and injected with physiological saline, CIK cells, and IL-15-IRES-TK-transfected CIK cells for 2 weeks, respectively. IL-15 IRES-TK-transferred CIK cells were prepared successfully and flow cytometry (FCM) analysis indicated that the transfection rate reached 85.7% after 5 days culture. In vivo experiment, we found that CIK cells retarded tumor growth by reducing tumor volume and tumor weight, as well as increasing tumor inhibition rate. Furthermore, IL-15-IRES-TK-transferred CIK cells showed a much stronger inhibition on tumor growth than CIK cells alone. Tumor morphology observation and growth indexes also showed that IL-15-transfected CIK cells had stronger cytotoxicity to tumor tissue than CIK cells. IL-15-IRES-TK transfection could elevate the effects of CIK cells to gastric carcinoma. The engineered CIK cells carrying IL-15-IRES-TK may be used in the ACT for gastric carcinoma, but prudent clinical trial is still indispensable. PMID- 26503217 TI - Allergic rhinitis, rhinoconjunctivitis and hayfever symptoms among children are associated with frequency of truck traffic near residences: a cross sectional study. AB - BACKGROUND: Allergic rhinitis (AR) is an increasing and common condition affecting many people globally, especially children. The aim of the study was to investigate the association between the frequency of truck traffic and allergic rhinitis symptoms, rhinoconjunctivitis and hayfever among 13 to 14 year old school children in Ekurhuleni Metropolitan Municipality, Gauteng Province, South Africa. METHODS: In a cross-sectional study design, 3764 children from 16 randomly selected high schools were eligible to participate, 3468 completed the International Study of Asthma and Allergies in Childhood (ISAAC) Phase I questionnaire of which 3424 were suitable for analysis; the overall response rate was 92%. Data were analysed using multilevel logistic regression analysis. RESULTS: The prevalence of self-reported rhinitis ever, current rhinitis rhinoconjunctivitis and hayfever was 52, 40, 21 and 37% respectively. Rhinitis ever, current rhinitis and current rhinoconjunctivitis were significantly associated with the frequency of trucks passing near residences almost all day on weekdays, (OR 1.46 95% CI: 1.16 - 1.84), (OR 1.60 95% CI: 1.24-2.02) and (OR 1.42 95% CI: 1.09-1.84) respectively. No association was observed between truck traffic and hay fever in the multiple analyses. CONCLUSION: The study shows a high prevalence of allergic rhinitis symptoms amongst children. The results support the hypothesis that traffic related pollution plays a role in the prevalence of allergic rhinitis symptoms in children residing in the area. PMID- 26503218 TI - Nurses and midwives professional support increases with improved attitudes - design and effects of a longitudinal randomized controlled process-oriented intervention. AB - BACKGROUND: Becoming parents for the first time is challenging. Mothers need both social and professional support to handle these challenges. Professionals' attitudes affect quality of care and support. So to improve professional support, an intervention consisting of a process-oriented training was performed. Due to the positive results of the intervention there is a need to illuminate the methodological approach further. The overall aim was therefore to describe a methodological approach to improve and evaluate health care professionals' attitudes toward breastfeeding and parental support in order to improve quality of care in childbearing. METHODS: This study was a longitudinal randomized control intervention study, in which groups of mothers received care in childbearing from midwives and child health nurses. These health professionals had gone through a process-oriented training, or not. In order to improve attitudes of health professionals the training was based on evidence, practical skills and reflective processes (both private and professional experiences) in relation to breastfeeding and parental support. Included in the longitudinal study were health professionals from five intervention municipalities n = 36 and health professionals from five control municipalities n = 45. All mothers who fulfilled the inclusion criteria were consecutively identified from the hospital register and asked to participate in the study. Mothers who accepted to participate were included in the interventions group (n = 206) or control groups (n = 162, n = 172 respectively) based on which municipality they belonged to. RESULTS: The results of the process-oriented training improved the professionals' attitudes toward breastfeeding and parental support. These improved attitudes in health professionals increased intervention-group mother's satisfaction with professional and social support. Intervention-group mother's relation to and feelings for their baby as well as breastfeeding was also improved. CONCLUSION: These results stress the importance of professionals' attitude in quality of care during childbearing, as well as pointing to the possibility to improve professionals' attitudes with a process-oriented training. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), trial registration: ACTRN12611000354987 . PMID- 26503219 TI - Diagnosis in chronic obstructive pulmonary disease-"Too little, too late?". PMID- 26503220 TI - Patients' perception about risks and benefits of antithrombotic treatment for the prevention of venous thromboembolism (VTE) after orthopedic surgery: a qualitative study. AB - BACKGROUND: The 9th edition of the American College of Chest Physicians' Antithrombotic Therapy and Prevention of Thrombosis guidelines emphasize the importance of considering the risk-benefit ratio of "patient-important" outcomes. However, little is known about patients' perception and understanding regarding the different outcomes of antithrombotic treatment after orthopedic surgery, and the factors that influence their decision to use these treatments. Using a series of semi-structured interviews, we explored patients' understanding and perception concerning the benefits and risks of antithrombotic treatment for the prevention of venous thromboembolism (VTE) after joint replacement surgery. METHODS: A series of semi-structured interviews were conducted with patients who had undergone knee or hip replacement surgery at a tertiary care hospital (Brigham and Women's Hospital, Boston, MA) in 2014. Discussions were recorded and transcribed. Two investigators independently coded and analyzed the data to identify important themes and concepts using the constant comparative method. RESULTS: Of 64 patients who were invited, 12 patients (19 %) completed the interviews. The majority of patients (92 %) were aware of the benefits of antithrombotic therapy for reducing the risk of blood clots, while less than half of them had a clear understanding of deep vein thrombosis and pulmonary embolism. While all patients were aware of risk of minor bleeding, only 6 patients (50 %) considered the risk of major bleeding as a possible side effect of antithrombotic treatment. Overall, patients perceived bleeding as a less important outcome than a thrombotic event. The lack of awareness about the risk of major bleeding, the assumption that a short-term exposure would not meaningfully affect bleeding risk, and the assumption that bleeding is a controllable event influenced their perception. Most patients (83 %) stated that their decision to use antithrombotic medications was mainly based on the trust in their physician's expertise. CONCLUSIONS: Patients perceived thrombotic events as more important outcomes than bleeding events. Patients' understanding of thrombotic and bleeding events varies and may play a key role in their preferences. The majority of patients stated that trust in their physician's expertise had a large influence on their decision to use antithrombotic medications. PMID- 26503221 TI - Application of diffusion tensor imaging for the diagnosis of segmental level of dysfunction in cervical spondylotic myelopathy. AB - STUDY DESIGN: A retrospective study. OBJECTIVES: Diffusion tensor imaging (DTI) reflects pathological change in the spinal cord more sensitively than conventional magnetic resonance imaging (MRI). Electrophysiological examination enables quantitative assessment of spinal cord function. Few studies have addressed the correlation between intraoperative spinal cord-evoked potentials (SCEPs) and DTI. The purpose of this study was to examine whether DTI is an objective index for the diagnosis of the segmental level of dysfunction in cervical spondylotic myelopathy (CSM). SETTING: Yamaguchi University Graduate School of Medicine, Japan. METHODS: Using 3.0-Tesla MRI, DTI values for the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured at the disc level C2/C3 through C6/C7 in 11 normal subjects and 10 subjects with CSM. Subjects with CSM were divided into two groups based on the extent of compression according to conventional MRI: single level (n=3) and multilevel (n=7). Intraoperative SCEPs were measured in subjects with CSM. For each group, the ADC and FA values were compared with SCEPs with respect to the segmental levels of dysfunction. RESULTS: For all three subjects with single-level compression and six of seven with multilevel compression, the maximal ADC value was observed at the segmental level of dysfunction as per the SCEP. Minimum FA values were observed at those sites in two of three patients with single-level compression and in only two of seven with multi-level compression. CONCLUSION: Our results suggest that ADC might serve as a supplementary diagnostic indicator of the segmental levels of dysfunction in CSM. PMID- 26503222 TI - Initial experience with the treatment of neurogenic detrusor overactivity with a new beta-3 agonist (mirabegron) in patients with spinal cord injury. AB - STUDY DESIGN: It is a retrospective chart analysis. OBJECTIVES: In patients with neurogenic lower urinary tract dysfunction (NLUTD) due to spinal cord injury (SCI), neurogenic detrusor overactivity (NDO) can cause both deterioration of the upper urinary tract and urinary incontinence. Antimuscarinic treatment is frequently discontinued due to side effects or lack of efficacy, whereas injection of onabotulinumtoxin into the detrusor is a minimally invasive procedure with risks of urinary retention, infection and haematuria. Mirabegron, a new beta-3 agonist, is a potential new agent for treatment of NDO. Aim of the study was to evaluate the efficacy of mirabegron in SCI patients with NLUTD. SETTING: Swiss Paraplegic Center, Nottwil, Switzerland. METHODS: A retrospective chart analysis of SCI patient treated with mirabegron. RESULTS: Fifteen patients with NDO were treated with mirabegron for a period of at least 6 weeks. Significant reduction of the frequency of bladder evacuation per 24 h (8.1 vs 6.4, P=0.003), and of incontinence episodes per 24 h (2.9 vs 1.3, P=0.027) was observed. Furthermore, we observed improvements in bladder capacity (from 365 to 419 ml), compliance (from 28 to 45 ml cm(-1) H(2)0) and detrusor pressure during storage phase (45.8 vs 30 cm H(2)0). At follow-up, 9/15 patients were satisfied with the therapy, 4/15 reported side effects (3 * aggravation of urinary incontinence, 1 * constipation). CONCLUSIONS: Mirabegron may evolve as an alternative in the treatment of NDO. We observed improvements in urodynamic and clinical parameters. Due to the limited number of patients and the retrospective nature of the study, prospective, placebo-controlled studies are necessary. PMID- 26503223 TI - Heterotopic ossification of the shoulder joint following spinal cord injury: an analysis of 21 cases after single-dose radiation therapy. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVES: Heterotopic ossification (HO) affecting the hips is a common complaint of patients suffering traumatic spinal cord injury. However, the incidence of HO of the shoulder is considerably rare. In this context, we report on our results of 13 patients with a total of 21 cases of shoulder HO and single-dose radiation therapy. SETTING: Department of Spinal Cord Injury and Department of General and Trauma Surgery, BG-University Hospital Bergmannsheil Bochum, Ruhr-University Bochum, Germany. METHODS: The study group consists of 12 male and 1 female patient with a mean age of 55.5 years (range from 24 to 81 years; s.d.=14.5). Primary outcome measures were defined as the number of HO relapses and the number of side or adverse effects in relation to the radiation therapy. RESULTS: At the time of latest follow-up during hospitalization, the mean shoulder flexion was 92.1 degrees while mean abduction was 94.5 degrees . The average external rotation was 26.4 degrees . No HO recurrence occurred and none of the patients suffered any adverse effects related to radiation therapy. CONCLUSIONS: In conclusion, single-dose radiation therapy in the treatment of shoulder HO due to spinal cord injury is an effective and reliable method, although the risk of secondary side effects related to the radiation therapy remain unknown. PMID- 26503224 TI - Comparative analysis of molecular mechanism of spinal cord injury with time based on bioinformatics data. AB - OBJECTIVES: This study was designed to explore the molecular mechanisms of spinal cord injury (SCI) with time. METHODS: The gene expression profile (GSE45006) including four non-injured spinal cord samples as sham-control group and 20 thoracic transected spinal cords samples as experimental group at different times was downloaded from Gene Expression Omnibus database. The time-course changes of the SCI-related differentially expressed genes (DEGs) were identified. In addition, time-series expression profile clusters of DEGs were obtained, followed by gene ontology (GO) and pathway enrichment analysis of the DEGs. Moreover, the transcriptional regulatory network was constructed. RESULTS: There were 1420, 492, 743, 568 and 533 DEGs respectively at d1, d3, w1, w2 and w8 compared with that of sham group. Importantly, 101 overlapped regulated DEGs were identified at five time points and 370 collaboratively regulated genes were identified in cluster 6. Significant functions of overlapped regulated DEGs were obtained including response to wounding and developmental process. In addition, the DEGs, such as CD14 molecule (CD14) and chemokine (C-C motif) ligand 2 (CCL2), were enriched mostly in the pathways related to tuberculosis, phagosome and NF-kappa B signaling pathway. From the transcriptional regulatory network, we identified some transription factors (TFs), including member of E26 transformation-specific (ETS) oncogene family (ELK1) and zinc finger and BTB domain containing 7A (Zbtb7a). CONCLUSION: The DEGs related to immune response during SCI may provide underlying targets for treatment of SCI. Moreover, the TFs ZBTB7A and ELK1 and their target gene (dual specificity phosphatase 18 (DUSP18)) might be therapeutic targets for the treatment of SCI. PMID- 26503225 TI - Quantitative micro-elastography: imaging of tissue elasticity using compression optical coherence elastography. AB - Probing the mechanical properties of tissue on the microscale could aid in the identification of diseased tissues that are inadequately detected using palpation or current clinical imaging modalities, with potential to guide medical procedures such as the excision of breast tumours. Compression optical coherence elastography (OCE) maps tissue strain with microscale spatial resolution and can delineate microstructural features within breast tissues. However, without a measure of the locally applied stress, strain provides only a qualitative indication of mechanical properties. To overcome this limitation, we present quantitative micro-elastography, which combines compression OCE with a compliant stress sensor to image tissue elasticity. The sensor consists of a layer of translucent silicone with well-characterized stress-strain behaviour. The measured strain in the sensor is used to estimate the two-dimensional stress distribution applied to the sample surface. Elasticity is determined by dividing the stress by the strain in the sample. We show that quantification of elasticity can improve the ability of compression OCE to distinguish between tissues, thereby extending the potential for inter-sample comparison and longitudinal studies of tissue elasticity. We validate the technique using tissue-mimicking phantoms and demonstrate the ability to map elasticity of freshly excised malignant and benign human breast tissues. PMID- 26503226 TI - Transcription factor CREB3L1 mediates cAMP and glucocorticoid regulation of arginine vasopressin gene transcription in the rat hypothalamus. AB - BACKGROUND: Arginine vasopressin (AVP), a neuropeptide hormone that functions in the regulation of water homeostasis by controlling water re-absorption at kidneys, is synthesised in supraoptic nucleus and paraventricular nucleus of the hypothalamus. An increase in plasma osmolality stimulates secretion of AVP to blood circulation and induces AVP synthesis in these nuclei. Although studies on mechanism of AVP transcriptional regulation in hypothalamus proposed that cAMP and glucocorticoids positively and negatively regulate Avp expression, respectively, the molecular mechanisms have remained elusive. Recently, we identified CREB3L1 (cAMP-responsive element binding protein 3 like 1) as a putative transcription factor of Avp transcription in the rat hypothalamus. However the mechanism of how CREB3L1 is regulated in response of hyperosmotic stress in the neurons of hypothalamus has never been reported. This study aims to investigate effect of previously reported regulators (cAMP and glucocorticoid) of Avp transcription on transcription factor CREB3L1 in order to establish a molecular explanation for cAMP and glucocorticoids effect on AVP expression. RESULTS: The effect of cAMP and glucocorticoid treatment on Creb3l1 was investigated in both AtT20 cells and hypothalamic organotypic cultures. The expression of Creb3l1 was increased in both mRNA and protein level by treatment with forskolin, which raises intracellular cAMP levels. Activation of cAMP by forskolin also increased Avp promoter activity in AtT20 cells and this effect was blunted by shRNA mediated silencing of Creb3l1. The forskolin induced increase in Creb3l1 expression was diminished by combined treatment with dexamethasone, and, in vivo, intraperitoneal dexamethasone injection blunted the increase in Creb3l1 and Avp expression induced by hyperosmotic stress. CONCLUSION: Here we shows that cAMP and glucocorticoid positively and negatively regulate Creb3l1 expression in the rat hypothalamus, respectively, and regulation of cAMP on AVP expression is mediated through CREB3L1. This data provides the connection between CREB3L1, a newly identified transcription factor of AVP expression, with the previously proposed mechanism of Avp transcription which extends our understanding in transcription regulation of Avp in the hypothalamus. PMID- 26503227 TI - Genome survey and high-density genetic map construction provide genomic and genetic resources for the Pacific White Shrimp Litopenaeus vannamei. AB - The Pacific white shrimp Litopenaeus vannamei is the dominant crustacean species in global seafood mariculture. Understanding the genome and genetic architecture is useful for deciphering complex traits and accelerating the breeding program in shrimp. In this study, a genome survey was conducted and a high-density linkage map was constructed using a next-generation sequencing approach. The genome survey was used to identify preliminary genome characteristics and to generate a rough reference for linkage map construction. De novo SNP discovery resulted in 25,140 polymorphic markers. A total of 6,359 high-quality markers were selected for linkage map construction based on marker coverage among individuals and read depths. For the linkage map, a total of 6,146 markers spanning 4,271.43 cM were mapped to 44 sex-averaged linkage groups, with an average marker distance of 0.7 cM. An integration analysis linked 5,885 genome scaffolds and 1,504 BAC clones to the linkage map. Based on the high-density linkage map, several QTLs for body weight and body length were detected. This high-density genetic linkage map reveals basic genomic architecture and will be useful for comparative genomics research, genome assembly and genetic improvement of L. vannamei and other penaeid shrimp species. PMID- 26503228 TI - Microbial responses to southward and northward Cambisol soil transplant. AB - Soil transplant serves as a proxy to simulate climate changes. Recently, we have shown that southward transplant of black soil and northward transplant of red soil altered soil microbial communities and biogeochemical variables. However, fundamental differences in soil types have prevented direct comparison between southward and northward transplants. To tackle it, herein we report an analysis of microbial communities of Cambisol soil in an agriculture field after 4 years of adaptation to southward and northward soil transplants over large transects. Analysis of bare fallow soils revealed concurrent increase in microbial functional diversity and coarse-scale taxonomic diversity at both transplanted sites, as detected by GeoChip 3.0 and DGGE, respectively. Furthermore, a correlation between microbial functional diversity and taxonomic diversity was detected, which was masked in maize cropped soils. Mean annual temperature, soil moisture, and nitrate (NO3 --N) showed strong correlations with microbial communities. In addition, abundances of ammonium-oxidizing genes (amoA) and denitrification genes were correlated with nitrification capacity and NO3 --N contents, suggesting that microbial responses to soil transplant could alter microbe-mediated biogeochemical cycle at the ecosystem level. PMID- 26503229 TI - Dry pleurisy complicating solitary pulmonary nodules caused by Mycobacterium avium: a case report. AB - INTRODUCTION: Mycobacterium avium complex (MAC) lung disease presenting as a solitary pulmonary nodule (MAC-SPN) is often asymptomatic, is more common in middle to old age, and mimics lung cancer or tuberculoma. We report herein a case of MAC-SPN in an immunocompetent young adult patient, presenting with persistent chest pain and a subacutely progressive nodule with high intense (18)F fluorodeoxyglucose uptake. Histological examination of resected specimens revealed pleurisy, which is a rare finding of MAC-SPN. CASE PRESENTATION: A 36 year-old Japanese male presented with chest pain and a subacutely progressive pulmonary nodule. Positron emission tomography-computed tomography showed high intense (18)F-fluorodeoxyglucose uptake in the nodule. Owing to his continuous chest pain and subacutely progressive nodules, wedge resection was performed using video-assisted thoracoscopic surgery. Histological examination revealed an epithelioid granuloma and pleurisy, and the lung tissue culture was positive for mycobacteria identified as M. avium. CONCLUSION: This is the first report of MAC SPN occurring with persistent chest pain, suggesting that MAC should be considered in the differential diagnosis of a solitary pulmonary nodule, even for patients who experience persistent chest pain. As in the present case, surgical resection with video-assisted thoracoscopic surgery is a reasonable approach to the diagnosis and treatment of MAC-SPN with possible malignancy, especially as MAC can be diagnosed using resected lung tissue culture with histological confirmation. PMID- 26503231 TI - Study of the tendinous vascularization for the compound radial forearm flap plus flexor carpi radialis tendon. AB - PURPOSE: The aim of this study was to explore the tendinous vascularization of flexor carpi radialis (FCR) and investigate the anatomical basis for harvesting the compound radial forearm flap (free or pedicled) with the vascularized tendon for the reconstruction of cutaneotendinous defects. METHODS: The area of the radial forearm flap was studied in seventeen forearms of fresh cadavers injected with red latex. A lozenge-shaped flap about 9 cm long and 4 cm wide was raised along the axis of the radial artery. Dissection of the flap was carried out subfascially. We searched perforators going into the flap and the nutritive branches for the tendon sheath of FCR were dissected up to their origin from the radial artery. Their distance from the scaphoid tubercle was recorded. RESULTS: We found nutritive branches for all the length of the tendon. The mean number of perforators going into the tendon sheath was 9.5 (range 8-12). Constant sizeable branches larger than 0.2 mm were identified from the scaphoid tubercle to the myotendinous junction; their distance from the scaphoid tubercle ranged between 0.5 and 12.5 cm. We found an average 0.8 perforators/cm of tendon (range 0.7-1). The donor sites were always closed primarily. CONCLUSIONS: Nutrient branches of the radial artery for the tendon of FCR were constantly found. Our anatomical findings confirm the possibility of raising a compound radial forearm flap including a sure vascularized tendon of FCR. Its clinical application provides a quick and straightforward single-stage option for the reconstruction of complex cutaneotendinous defects. PMID- 26503230 TI - Molecular architecture of the Ub-PCNA/Pol eta complex bound to DNA. AB - Translesion synthesis (TLS) is the mechanism by which DNA polymerases replicate through unrepaired DNA lesions. TLS is activated by monoubiquitination of the homotrimeric proliferating cell nuclear antigen (PCNA) at lysine-164, followed by the switch from replicative to specialized polymerases at DNA damage sites. Pol eta belongs to the Y-Family of specialized polymerases that can efficiently bypass UV-induced lesions. Like other members of the Y-Family polymerases, its recruitment to the damaged sites is mediated by the interaction with monoubiquitinated PCNA (Ub-PCNA) via its ubiquitin-binding domain and non canonical PCNA-interacting motif in the C-terminal region. The structural determinants underlying the direct recognition of Ub-PCNA by Pol eta, or Y-Family polymerases in general, remain largely unknown. Here we report a structure of the Ub-PCNA/Pol eta complex bound to DNA determined by single-particle electron microscopy (EM). The overall obtained structure resembles that of the editing PCNA/PolB complex. Analysis of the map revealed the conformation of ubiquitin that binds the C-terminal domain of Pol eta. Our present study suggests that the Ub-PCNA/Pol eta interaction requires the formation of a structured binding interface, which is dictated by the inherent flexibility of Ub-PCNA. PMID- 26503232 TI - Genome-wide analysis of chemically induced mutations in mouse in phenotype-driven screens. AB - BACKGROUND: N-ethyl-N-nitrosourea (ENU) mutagen has become the method of choice for inducing random mutations for forward genetics applications. However, distinguishing induced mutations from sequencing errors or sporadic mutations is difficult, which has hampered surveys of potential biases in the methodology in the past. Addressing this issue, we created a large cohort of mice with biological replicates enabling the confident calling of induced mutations, which in turn allowed us to conduct a comprehensive analysis of potential biases in mutation properties and genomic location. RESULTS: In the exome sequencing data we observe the known preference of ENU to cause A:T=>G:C transitions in longer genes. Mutations were frequently clustered and inherited in blocks hampering attempts to pinpoint individual causative mutations by genome analysis only. Furthermore, ENU mutations were biased towards areas in the genome that are accessible in testis, potentially limiting the scope of forward genetic approaches to only 1-10% of the genome. CONCLUSION: ENU provides a powerful tool for exploring the genome-phenome relationship, however forward genetic applications that require the mutation to be passed on through the germ line may be limited to explore only genes that are accessible in testis. PMID- 26503233 TI - Antiproliferation effect of evodiamine in human colon cancer cells is associated with IGF-1/HIF-1alpha downregulation. AB - Colon cancer is one of the most common malignancies. Although the current treatment regimes for colon cancer have been well-developed in the past decades, the prognosis remains still undesirable. It is still urgent to explore new treatment strategies for colon cancer. Natural products is one of the most useful sources for anticancer agents, although some of them have serious side-effects. Evodiamine (Evo) is an quinolone alkaloid from the traditional herb medicine Evodia rutaecarpa. In the present study, we investigated the anticancer effect of Evo in human colon cancer cells. We found that Evo exhibits prominent antiproliferation and apoptosis inducing effects in LoVo cells. Evo leads to apparent downregulation of HIF-1alpha either in vitro or in vivo; exogenous expression of HIF-1alpha can attenuate the antiproliferation effect of Evo in LoVo cells, while HIF-1alpha knockdown potentiates this effect greatly. Further analysis indicated that Evo can also inhibit the phosphorylation of Akt1/2/3 and decrease greatly the expression of IGF-1. Thus, our findings strongly suggested that the anticancer effect of Evo in human colon cancer may be partly mediated by downregulating HIF-1alpha expression, which is initiated by inactivating PI3K/Akt signaling transduction though decreasing the expression of IGF-1 in colon cancer cells. Therefore, Evo may be used alone or in combination as a potential anticancer agent for colon cancer treatment. PMID- 26503235 TI - Population pharmacokinetic modelling and simulation of 5-fluorouracil incorporating a circadian rhythm in rats. AB - 1. The aim of this study was to develop a population pharmacokinetic (PK) model for 5-fluorouracil (5-FU) and perform simulations to identify the circadian rhythm of the PK of 5-FU and the degree of circadian effects on the 5-FU plasma concentrations. 2. 5-FU plasma concentrations in rats following administration of 5-FU at varying time points throughout the day were obtained and used to develop the population PK model incorporating a circadian rhythm. The Cosinor method was used to describe the circadian variation of 5-FU clearance. 3. Our population PK model could successfully characterize the 5-FU disposition and provide reliable PK parameter estimates. The mesor, amplitude and acrophase of Cosinor model were estimated as 1.93 L/h/kg, 0.10 L/h/kg and 2.02 h, respectively. The peak clearance levels were estimated at ~2 Hours After Light Onset (HALO) and the trough levels at ~14 HALO. The plasma concentration-time profile of 5-FU after continuous infusion of 5-FU in rats successfully simulated the circadian variation of steady-state plasma concentrations. 4. The population PK model with individual 5-FU plasma concentrations, dose levels and sampling time points could be valuable for estimating area under the curve (AUC) levels and determining individual 5-FU dose management. PMID- 26503237 TI - Spin echo transverse relaxation and atrophy in multiple sclerosis deep gray matter: A two-year longitudinal study. AB - BACKGROUND: Deep gray matter (DGM) is affected in relapsing-remitting multiple sclerosis (RRMS) and may be studied using short-term longitudinal MRI. OBJECTIVE: To investigate two-year changes in spin-echo transverse relaxation rate (R2) and atrophy in DGM, and its relationship with disease severity in RRMS patients. METHODS: Twenty six RRMS patients and 26 matched controls were imaged at 4.7 T. Multiecho spin-echo R2 maps and atrophy measurements were obtained in DGM at baseline and two-year follow-up. Differences between MRI measures and correlations to disease severity were examined. RESULTS: After two years, mean R2 values in the globus pallidus and pulvinar increased by ~4% (p<0.001) in patients and <1.7% in controls. Two-year changes in R2 showed significant correlation to disease severity in the globus pallidus, pulvinar, substantia nigra, and thalamus. Multiple regression of the two-year R2 difference using these four DGM structures as variables, yielded high correlation with disease severity (r=0.83, p<0.001). Two-year changes in volume and R2 showed significant correlation only for the globus pallidus in multiple sclerosis (MS) (p<0.05). CONCLUSIONS: Two year difference R2 measurements in DGM correlate to disease severity in MS. R2 mapping and atrophy measurements over two years can be used to identify changes in DGM in MS. PMID- 26503236 TI - Defining the value of CD56, CK19, Galectin 3 and HBME-1 in diagnosis of follicular cell derived lesions of thyroid with systematic review of literature. AB - BACKGROUND: Nodular follicular lesions of thyroid gland comprise benign and malignant neoplasms, as well as some forms of hyperplasia. "Follicular" refers to origin of cells and in the same time to growth pattern - building follicles. Nodular follicular thyroid lesions have in common many morphological features, therefore attempts were made to define additional criteria for distinction between follicular adenoma, follicular carcinoma and follicular variant of papillary carcinoma. Increasing number of immunohistochemical markers is in the continual process of evaluation. METHODS: Tissue microarrays incorporating, total 201 cases, out of which 122 malignant and 79 benign follicular lesions, including neoplastic and non-neoplastic, were constructed and immunostained with antibodies to CD56, CK19, Galectin-3, HBME-1. Tissue cores were exclusively being acquired from tumour/lesion on interface with normal thyroid tissue. A systematic review of literature was done for period from the year 2001 to present time. RESULTS: All analysed markers may make a difference between benign lesions/tumours from differentiated thyroid carcinomas (p = <0.01, for all markers). Expression of all markers is significantly higher in papillary carcinoma than in follicular adenoma (p < 0.01). Statistically significant difference in expression of Galectin-3 and CD56 between follicular carcinoma and follicular adenoma was registered (p = 0.043; p = 0.028, respectively). The only marker which expression showed statistically significant difference between adenoma and carcinoma of Hurthle cells was Galectin 3 (p = 0.041). CK19 and HBME-1 were significantly expressed more in papillary carcinoma as compared to follicular carcinoma. CONCLUSION: Galectin 3 is most sensitive marker for malignancy, while loss of expression of CD56 is very specific for malignancy. Expected co-expression for combination of markers in diagnosis of follicular lesions decreases sensitivity and increases specificity for malignancy. PMID- 26503238 TI - Are drinking motives associated with sexual "hookups" among college student drinkers? AB - OBJECTIVE: This study examined associations between drinking motivation, alcohol use, and sexual hookups among college students. PARTICIPANTS: Participants (n = 755 Midwest college student drinkers; 61% female) ranged in age from 18 to 24. METHODS: Participants completed online measures of alcohol involvement (use and motives) and sexual activity. RESULTS: Alcohol use was positively linked to sexual hookups. Social and enhancement motives were positively and indirectly associated with sexual hookups via alcohol use. Drinking to cope had a direct association with sexual hookups. Social drinking was more strongly associated with hookups in men than in women, but both groups exhibited a positive association. CONCLUSIONS: This study is the first to highlight the relationships between distinct drinking motives and sexual risk behavior. The results indicate that specific motives may increase risk of sexual hookups both indirectly via alcohol use, as well as directly, at least among those that drink to cope with negative mood. PMID- 26503240 TI - Adherence to the novel oral anticoagulants: an unmet need. PMID- 26503239 TI - In vivo activity of vancomycin combined with colistin against multidrug-resistant strains of Acinetobacter baumannii in a Galleria mellonella model. AB - BACKGROUND: With increasing antibiotic resistance, the selection of effective treatment of A. baumannii infections is particularly challenging. METHODS: This study assessed the activities of the combination of vancomycin and colistin combination in vitro and in vivo using a Galleria mellonella model against four colistin-susceptible or colistin-resistant A. baumannii strains. RESULTS: In checkerboard assays, synergy was observed between vancomycin and colistin for all four strains tested (0.156 <= Fractional inhibitory concentration indices [FICI] <= 0.281). In time-kill assays, the combination showed continued bactericidal activity and synergy after 24 h for colistin-susceptible strains. For colistin resistant strains, the combination resulted in bactericidal activity within 8 h, but sustained bacterial re-growth was then observed. Treatment of G. mellonella larvae infected with lethal doses of A. baumannii (except 19606R) resulted in significantly increased survival rates when vancomycin was given with colistin compared to colistin treatment alone (p < 0.05). CONCLUSIONS: These findings suggest that regimens containing vancomycin may be useful for infections due to multidrug-resistant Acinetobacter baumannii. PMID- 26503241 TI - Sleep Environments of Children in an Urban U.S. Setting Exposed to Interpersonal Violence. AB - This study investigated how violence influences children's sleep environments. Sixty-five children ages 8-16 years and a parent or guardian were recruited from agencies serving families experiencing violence. At baseline (5 weeks post violent event), 6 months, and 12 months postbaseline, study staff collected sleep behavior information and conducted systematic, qualitative assessments of sleep environments. Child sleep problems were generally frequent and persistent. However, 9 children reported improved sleep after the violent event, mainly because perpetrators were no longer present. Sleeping environments were dynamic via changes in location and modifications to improve safety and sleep. Incongruence between children's and parents' perceptions of environmental characteristics influencing sleep was common. Families' motivation to improve children's sleep represents a foundation to build upon when working with families victimized by violence. PMID- 26503242 TI - Assessment of oxidative stress biomarkers - neuroprostanes and dihomo isoprostanes - in the urine of elite triathletes after two weeks of moderate altitude training. AB - This randomized and controlled trial investigated whether the increase in elite training at different altitudes altered the oxidative stress biomarkers of the nervous system. This is the first study to investigate four F4-neuroprostanes (F4 NeuroPs) and four F2-dihomo-isoprostanes (F2-dihomo-IsoPs) quantified in 24-h urine. The quantification was carried out by ultra high pressure liquid chromatography-triple quadrupole-tandem mass spectrometry (UHPLC-QqQ-MS/MS). Sixteen elite triathletes agreed to participate in the project. They were randomized in two groups, a group submitted to altitude training (AT, n = 8) and a group submitted to sea level training (SLT) (n = 8), with a control group (Cg) of non-athletes (n = 8). After the experimental period, the AT group triathletes gave significant data: 17-epi-17-F2t-dihomo-IsoP (from 5.2 +/- 1.4 MUg/mL 24 h( 1) to 6.6 +/- 0.6 MUg/mL 24 h(-1)), ent-7(RS)-7-F2t-dihomo-IsoP (from 6.6 +/- 1.7 MUg/mL 24 h(-1) to 8.6 +/- 0.9 MUg/mL 24 h(-1)), and ent-7-epi-7-F2t-dihomo-IsoP (from 8.4 +/- 2.2 MUg/mL 24 h(-1) to 11.3 +/- 1.8 MUg/mL 24 h(-1)) increased, while, of the neuronal degeneration-related compounds, only 10-epi-10-F4t-NeuroP (8.4 +/- 1.7 MUg/mL 24 h(-1)) and 10-F4t-NeuroP (5.2 +/- 2.9 MUg/mL 24 h(-1)) were detected in this group. For the Cg and SLT groups, no significant changes had occurred at the end of the two-week experimental period. Therefore, and as the main conclusion, the training at moderate altitude increased the F4-NeuroPs- and F2-dihomo-isoPs-related oxidative damage of the central nervous system compared to similar training at sea level. PMID- 26503243 TI - Midlife and Late-Life Smoking and Risk of Dementia in the Community: The Hisayama Study. AB - OBJECTIVES: To clarify the association between midlife and late-life smoking and risk of dementia. DESIGN: Prospective cohort study. SETTING: The Hisayama Study, Japan. PARTICIPANTS: Japanese community-dwellers without dementia aged 65 to 84 (mean age 72) followed for 17 years (1988-2005) (N = 754), 619 of whom had participated in a health examination conducted in 1973-74 (mean age, 57) and were included in the midlife analysis. MEASUREMENTS: The risk estimates of smoking status on the development of dementia were computed using a Cox proportional hazards model. RESULTS: During follow-up, 252 subjects developed all-cause dementia; 143 had Alzheimer's disease (AD), and 76 had vascular dementia (VaD). In late life, the multivariable-adjusted risk of all-cause dementia was significantly greater in current smokers than in never smokers; similar associations were seen for all-cause dementia, AD, and VaD in midlife current smokers. Meanwhile, no significant association was observed between past smoking and risk of any type of dementia in late or midlife. Multivariable analysis showed that smokers in midlife and late life had significantly greater risks than lifelong nonsmokers of all-cause dementia (adjusted hazard ratio (aHR) = 2.28, 95% confidence interval (CI) = 1.49-3.49), AD (aHR = 1.98, 95% CI = 1.09-3.61), and VaD (aHR = 2.88, 95% CI = 1.34-6.20). Such associations were not observed for midlife smokers who quit smoking in late life. CONCLUSION: Persistent smoking from mid- to late life is a significant risk factor for dementia and its subtypes in the general Japanese population. PMID- 26503244 TI - sRNATarBase 3.0: an updated database for sRNA-target interactions in bacteria. AB - Bacterial sRNAs are a class of small regulatory RNAs of about 40-500 nt in length; they play multiple biological roles through binding to their target mRNAs or proteins. Therefore, elucidating sRNA targets is very important. However, only targets of a few sRNAs have been described. To facilitate sRNA functional studies such as developing sRNA target prediction models, we updated the sRNATarBase database, which was initially developed in 2010. The new version (recently moved to http://ccb1.bmi.ac.cn/srnatarbase/) contains 771 sRNA-target entries manually collected from 213 papers, and 23 290 and 11 750 predicted targets from sRNATarget and sTarPicker, respectively. Among the 771 entries, 475 and 17 were involved in validated sRNA-mRNA and sRNA-protein interactions, respectively, while 279 had no reported interactions. We also presented detailed information for 316 binding regions of sRNA-target mRNA interactions and related mutation experiments, as well as new features, including NCBI sequence viewer, sRNA regulatory network, target prediction-based GO and pathway annotations, and error report system. The new version provides a comprehensive annotation of validated sRNA-target interactions, and will be a useful resource for bacterial sRNA studies. PMID- 26503245 TI - Tim/Timeless, a member of the replication fork protection complex, operates with the Warsaw breakage syndrome DNA helicase DDX11 in the same fork recovery pathway. AB - We present evidence that Tim establishes a physical and functional interaction with DDX11, a super-family 2 iron-sulfur cluster DNA helicase genetically linked to the chromosomal instability disorder Warsaw breakage syndrome. Tim stimulates DDX11 unwinding activity on forked DNA substrates up to 10-fold and on bimolecular anti-parallel G-quadruplex DNA structures and three-stranded D-loop approximately 4-5-fold. Electrophoretic mobility shift assays revealed that Tim enhances DDX11 binding to DNA, suggesting that the observed stimulation derives from an improved ability of DDX11 to interact with the nucleic acid substrate. Surface plasmon resonance measurements indicate that DDX11 directly interacts with Tim. DNA fiber track assays with HeLa cells exposed to hydroxyurea demonstrated that Tim or DDX11 depletion significantly reduced replication fork progression compared to control cells; whereas no additive effect was observed by co-depletion of both proteins. Moreover, Tim and DDX11 are epistatic in promoting efficient resumption of stalled DNA replication forks in hydroxyurea-treated cells. This is consistent with the finding that association of the two endogenous proteins in the cell extract chromatin fraction is considerably increased following hydroxyurea exposure. Overall, our studies provide evidence that Tim and DDX11 physically and functionally interact and act in concert to preserve replication fork progression in perturbed conditions. PMID- 26503247 TI - Mechanism of activation of methyltransferases involved in translation by the Trm112 'hub' protein. PMID- 26503248 TI - dbMAE: the database of autosomal monoallelic expression. AB - Recently, data on 'random' autosomal monoallelic expression has become available for the entire genome in multiple human and mouse tissues and cell types, creating a need for better access and dissemination. The database of autosomal monoallelic expression (dbMAE; https://mae.hms.harvard.edu) incorporates data from multiple recent reports of genome-wide analyses. These include transcriptome wide analyses of allelic imbalance in clonal cell populations based on sequence polymorphisms, as well as indirect identification, based on a specific chromatin signature present in MAE gene bodies. Currently, dbMAE contains transcriptome wide chromatin identification calls for 8 human and 21 mouse tissues, and describes over 16 000 murine and ~ 700 human cases of directly measured biased expression, compiled from allele-specific RNA-seq and genotyping array data. All data are manually curated. To ensure cross-publication uniformity, we performed re-analysis of transcriptome-wide RNA-seq data using the same pipeline. Data are accessed through an interface that allows for basic and advanced searches; all source references, including raw data, are clearly described and hyperlinked. This ensures the utility of the resource as an initial screening tool for those interested in investigating the role of monoallelic expression in their specific genes and tissues of interest. PMID- 26503246 TI - DNA deletion as a mechanism for developmentally programmed centromere loss. AB - A hallmark of active centromeres is the presence of the histone H3 variant CenH3 in the centromeric chromatin, which ensures faithful genome distribution at each cell division. A functional centromere can be inactivated, but the molecular mechanisms underlying the process of centromere inactivation remain largely unknown. Here, we describe the loss of CenH3 protein as part of a developmental program leading to the formation of the somatic nucleus in the eukaryote Paramecium. We identify two proteins whose depletion prevents developmental loss of CenH3: the domesticated transposase Pgm involved in the formation of DNA double strand cleavages and the Polycomb-like lysine methyltransferase Ezl1 necessary for trimethylation of histone H3 on lysine 9 and lysine 27. Taken together, our data support a model in which developmentally programmed centromere loss is caused by the elimination of DNA sequences associated with CenH3. PMID- 26503249 TI - BDB: biopanning data bank. AB - The BDB database (http://immunet.cn/bdb) is an update of the MimoDB database, which was previously described in the 2012 Nucleic Acids Research Database issue. The rebranded name BDB is short for Biopanning Data Bank, which aims to be a portal for biopanning results of the combinatorial peptide library. Last updated in July 2015, BDB contains 2904 sets of biopanning data collected from 1322 peer reviewed papers. It contains 25,786 peptide sequences, 1704 targets, 492 known templates, 447 peptide libraries and 310 crystal structures of target-template or target-peptide complexes. All data stored in BDB were revisited, and information on peptide affinity, measurement method and procedures was added for 2298 peptides from 411 sets of biopanning data from 246 published papers. In addition, a more professional and user-friendly web interface was implemented, a more detailed help system was designed, and a new on-the-fly data visualization tool and a series of tools for data analysis were integrated. With these new data and tools made available, we expect that the BDB database would become a major resource for scholars using phage display, with improved utility for biopanning and related scientific communities. PMID- 26503251 TI - Assembly and dynamics of the U4/U6 di-snRNP by single-molecule FRET. AB - In large ribonucleoprotein machines, such as ribosomes and spliceosomes, RNA functions as an assembly scaffold as well as a critical catalytic component. Protein binding to the RNA scaffold can induce structural changes, which in turn modulate subsequent binding of other components. The spliceosomal U4/U6 di-snRNP contains extensively base paired U4 and U6 snRNAs, Snu13, Prp31, Prp3 and Prp4, seven Sm and seven LSm proteins. We have studied successive binding of all protein components to the snRNA duplex during di-snRNP assembly by electrophoretic mobility shift assay and accompanying conformational changes in the U4/U6 RNA 3-way junction by single-molecule FRET. Stems I and II of the duplex were found to co-axially stack in free RNA and function as a rigid scaffold during the entire assembly, but the U4 snRNA 5' stem-loop adopts alternative orientations each stabilized by Prp31 and Prp3/4 binding accounting for altered Prp3/4 binding affinities in presence of Prp31. PMID- 26503250 TI - Discovery and characterization of Alu repeat sequences via precise local read assembly. AB - Alu insertions have contributed to >11% of the human genome and ~30-35 Alu subfamilies remain actively mobile, yet the characterization of polymorphic Alu insertions from short-read data remains a challenge. We build on existing computational methods to combine Alu detection and de novo assembly of WGS data as a means to reconstruct the full sequence of insertion events from Illumina paired end reads. Comparison with published calls obtained using PacBio long reads indicates a false discovery rate below 5%, at the cost of reduced sensitivity due to the colocation of reference and non-reference repeats. We generate a highly accurate call set of 1614 completely assembled Alu variants from 53 samples from the Human Genome Diversity Project (HGDP) panel. We utilize the reconstructed alternative insertion haplotypes to genotype 1010 fully assembled insertions, obtaining >99% agreement with genotypes obtained by PCR. In our assembled sequences, we find evidence of premature insertion mechanisms and observe 5' truncation in 16% of AluYa5 and AluYb8 insertions. The sites of truncation coincide with stem-loop structures and SRP9/14 binding sites in the Alu RNA, implicating L1 ORF2p pausing in the generation of 5' truncations. Additionally, we identified variable AluJ and AluS elements that likely arose due to non-retrotransposition mechanisms. PMID- 26503253 TI - rVarBase: an updated database for regulatory features of human variants. AB - We present here the rVarBase database (http://rv.psych.ac.cn), an updated version of the rSNPBase database, to provide reliable and detailed regulatory annotations for known and novel human variants. This update expands the database to include additional types of human variants, such as copy number variations (CNVs) and novel variants, and include additional types of regulatory features. Now rVarBase annotates variants in three dimensions: chromatin states of the surrounding regions, overlapped regulatory elements and variants' potential target genes. Two new types of regulatory elements (lncRNAs and miRNA target sites) have been introduced to provide additional annotation. Detailed information about variants' overlapping transcription factor binding sites (TFBSs) (often less than 15 bp) within experimentally supported TF-binding regions (~ 150 bp) is provided, along with the binding motifs of matched TF families. Additional types of extended variants and variant-associated phenotypes were also added. In addition to the enrichment in data content, an element-centric search module was added, and the web interface was refined. In summary, rVarBase hosts more types of human variants and includes more types of up-to-date regulatory information to facilitate in-depth functional research and to provide practical clues for experimental design. PMID- 26503252 TI - Recombinational repair of radiation-induced double-strand breaks occurs in the absence of extensive resection. AB - Recombinational repair provides accurate chromosomal restitution after double strand break (DSB) induction. While all DSB recombination repair models include 5'-3' resection, there are no studies that directly assess the resection needed for repair between sister chromatids in G-2 arrested cells of random, radiation induced 'dirty' DSBs. Using our Pulse Field Gel Electrophoresis-shift approach, we determined resection at IR-DSBs in WT and mutants lacking exonuclease1 or Sgs1 helicase. Lack of either reduced resection length by half, without decreased DSB repair or survival. In the exo1Delta sgs1Delta double mutant, resection was barely detectable, yet it only took an additional hour to achieve a level of repair comparable to WT and there was only a 2-fold dose-modifying effect on survival. Results with a Dnl4 deletion strain showed that remaining repair was not due to endjoining. Thus, similar to what has been shown for a single, clean HO-induced DSB, a severe reduction in resection tract length has only a modest effect on repair of multiple, dirty DSBs in G2-arrested cells. Significantly, this study provides the first opportunity to directly relate resection length at DSBs to the capability for global recombination repair between sister chromatids. PMID- 26503254 TI - Digital development: a database of cell lineage differentiation in C. elegans with lineage phenotypes, cell-specific gene functions and a multiscale model. AB - Developmental systems biology is poised to exploit large-scale data from two approaches: genomics and live imaging. The combination of the two offers the opportunity to map gene functions and gene networks in vivo at single-cell resolution using cell tracking and quantification of cellular phenotypes. Here we present Digital Development (http://www.digital-development.org), a database of cell lineage differentiation with curated phenotypes, cell-specific gene functions and a multiscale model. The database stores data from recent systematic studies of cell lineage differentiation in the C. elegans embryo containing ~ 200 conserved genes, 1400 perturbed cell lineages and 600,000 digitized single cells. Users can conveniently browse, search and download four categories of phenotypic and functional information from an intuitive web interface. This information includes lineage differentiation phenotypes, cell-specific gene functions, differentiation landscapes and fate choices, and a multiscale model of lineage differentiation. Digital Development provides a comprehensive, curated, multidimensional database for developmental biology. The scale, resolution and richness of biological information presented here facilitate exploration of gene specific and systems-level mechanisms of lineage differentiation in Metazoans. PMID- 26503255 TI - A gene network engineering platform for lactic acid bacteria. AB - Recent developments in synthetic biology have positioned lactic acid bacteria (LAB) as a major class of cellular chassis for applications. To achieve the full potential of LAB, one fundamental prerequisite is the capacity for rapid engineering of complex gene networks, such as natural biosynthetic pathways and multicomponent synthetic circuits, into which cellular functions are encoded. Here, we present a synthetic biology platform for rapid construction and optimization of large-scale gene networks in LAB. The platform involves a copy controlled shuttle for hosting target networks and two associated strategies that enable efficient genetic editing and phenotypic validation. By using a nisin biosynthesis pathway and its variants as examples, we demonstrated multiplex, continuous editing of small DNA parts, such as ribosome-binding sites, as well as efficient manipulation of large building blocks such as genes and operons. To showcase the platform, we applied it to expand the phenotypic diversity of the nisin pathway by quickly generating a library of 63 pathway variants. We further demonstrated its utility by altering the regulatory topology of the nisin pathway for constitutive bacteriocin biosynthesis. This work demonstrates the feasibility of rapid and advanced engineering of gene networks in LAB, fostering their applications in biomedicine and other areas. PMID- 26503257 TI - Fourier-transform spectroscopy using an Er-doped fiber femtosecond laser by sweeping the pulse repetition rate. AB - Femtosecond lasers allow for simultaneous detection of multiple absorption lines of a specimen over a broad spectral range of infrared or visible light with a single spectroscopic measurement. Here, we present an 8-THz bandwidth, 0.5-GHz resolution scheme of Fourier-transform spectroscopy using an Er-doped fiber femtosecond laser. A resolving power of 1.6 * 10(4) about a 1560-nm center wavelength is achieved by sweeping the pulse repetition rate of the light source on a fiber Mach-Zehnder interferometer configured to capture interferograms with a 0.02-fs temporal sampling accuracy through a well-stabilized 60-m unbalance arm length. A dual-servo mechanism is realized by combining a mechanical linear stage with an electro-optic modulator (EOM) within the fiber laser cavity, enabling stable sweeping control of the pulse repetition rate over a 1.0-MHz scan range with 0.4-Hz steps with reference to the Rb clock. Experimental results demonstrate that the P-branch lines of the H(13)CN reference cell can be observed with a signal-to-noise ratio reaching 350 for the most intense line. PMID- 26503258 TI - The evolution of bat nucleic acid-sensing Toll-like receptors. AB - We characterized the nucleic acid-sensing Toll-like receptors (TLR) of a New World bat species, the common vampire bat (Desmodus rotundus), and through a comparative molecular evolutionary approach searched for general adaptation patterns among the nucleic acid-sensing TLRs of eight different bats species belonging to three families (Pteropodidae, Vespertilionidae and Phyllostomidae). We found that the bat TLRs are evolving slowly and mostly under purifying selection and that the divergence pattern of such receptors is overall congruent with the species tree, consistent with the evolution of many other mammalian nuclear genes. However, the chiropteran TLRs exhibited unique mutations fixed in ligand-binding sites, some of which involved nonconservative amino acid changes and/or targets of positive selection. Such changes could potentially modify protein function and ligand-binding properties, as some changes were predicted to alter nucleic acid binding motifs in TLR 9. Moreover, evidence for episodic diversifying selection acting specifically upon the bat lineage and sublineages was detected. Thus, the long-term adaptation of chiropterans to a wide variety of environments and ecological niches with different pathogen profiles is likely to have shaped the evolution of the bat TLRs in an order-specific manner. The observed evolutionary patterns provide evidence for potential functional differences between bat and other mammalian TLRs in terms of resistance to specific pathogens or recognition of nucleic acids in general. PMID- 26503260 TI - Cholecystectomy and Liver Disease in Short Bowel Syndrome. AB - BACKGROUND: Recently, an association has been proposed between cholecystectomy and various liver diseases. Our aim was to determine whether cholecystectomy in short bowel patients influences the risk of liver disease. METHODS: We reviewed 422 adults: 182 underwent cholecystectomy prior to short bowel, 102 after developing short bowel, and 138 patients still had the gallbladder in place. RESULTS: Compared to pre and post short bowel, gallbladder patients were significantly less likely to have obesity (18 % and 21 % vs 9 %), central line infections (59 % and 69 % vs 46 %), intestine <60 cm (30 % and 39 % vs 26 %), and require parenteral nutrition >1 year (72 % and 77 % vs 64 %). The incidence of fatty liver was similar (31, 26, and 25 %). Fibrosis/cirrhosis was less common in the gallbladder group (26 % and 36 % vs 16 %). Frequency of end-stage liver disease was similar (15, 22, and 11 %). On multivariate analysis, cholecystectomy, parenteral nutrition >1 year, line infection, and intestine <60 cm were predictors of fibrosis/cirrhosis. Parenteral nutrition >1 year, line infection, and intestine <60 cm were predictors of end-stage liver disease. CONCLUSIONS: Cholecystectomy does not appear to increase the incidence of liver disease in short bowel patients overall. Fibrosis/cirrhosis occurs significantly less frequently in patients with an intact gallbladder. PMID- 26503259 TI - Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer. AB - INTRODUCTION: Oxaliplatin is part of pancreatic cancer therapy in the FOLFIRINOX or GEMOX/XELOX regimen. DNA damage repair is one of the factors responsible for oxaliplatin resistance that eventually develops in this cancer. Triptolide/Minnelide has been shown to be effective against pancreatic cancer in preclinical trials. In this study, we evaluated the efficacy of combination of triptolide and oxaliplatin against pancreatic cancer. METHODS: Highly aggressive pancreatic cancer cells (MIA PaCa-2 and PANC-1) were treated with oxaliplatin (0 10 MUM), low-dose triptolide (50 nM), or a combination of both for 24-48 h. Cell viability, apoptosis, and DNA damage were evaluated by appropriate methods. Nucleotide excision repair pathway components were quantitated using qPCR and Western blot. Combination of low doses of Minnelide and oxaliplatin was tested in an orthotopic murine model of pancreatic cancer. RESULTS: Proliferation of pancreatic cancer cells was markedly inhibited by combination treatment. Triptolide potentiated apoptotic cell death induced by oxaliplatin and sensitized cancer cells towards oxaliplatin-induced DNA damage by suppressing the oxaliplatin-induced DNA damage repair pathway. Combination of low doses of Minnelide and oxaliplatin inhibited tumor progression by inducing significant apoptotic cell death in these tumors. CONCLUSIONS: Combination of low doses of Minnelide and oxaliplatin has immense potential to emerge as a novel therapeutic strategy against pancreatic cancer. PMID- 26503261 TI - Inter-Observer Variability in the Interpretation of Endoscopic Mucosal Resection Specimens of Esophageal Adenocarcinoma: Interpretation of ER specimens. AB - INTRODUCTION: Endoscopic resection (ER) has revolutionized the staging and therapy of superficial esophageal adenocarcinoma. Pathologic evaluation allows an assessment of the risk of lymph node metastases based on tumor characteristics. The aim of this study was to assess the inter-observer variability in pathologic assessment of ER specimens of esophageal adenocarcinoma. METHODS: We performed a retrospective study on ER specimens of superficial esophageal adenocarcinoma from four US institutions. Original endoscopic resection slides were re-reviewed by two blinded, experienced (study) gastrointestinal pathologists for the depth of tumor invasion, tumor grade, and the presence of lymphovascular invasion (LVI). Discordance was considered present only when both study pathologists disagreed with the original report. RESULTS: There were 25 ER specimens reviewed for this study, and discordance occurred in 12 of the 25 specimens (48%) for the depth of tumor invasion. In most cases (83%), the discordance was related to overstaging a true T1a lesion. We found that only 38% of true T1a lesions were correctly staged for depth of invasion. Less commonly discordance was secondary to understaging a true T1b lesion. There was concordance between the two study pathologists in 22/25 cases (88%) on the depth of invasion. Discordance was present for tumor grade in 8/18 cases (44%) and for LVI in 4/16 cases (25%). Concordance between the study pathologists was 80% for tumor grade and 88% for LVI. CONCLUSIONS: There was an alarmingly high rate of discordance (48%) between the study pathologists and the original pathology assessment for the depth of tumor invasion in ER specimens. This was particularly common for lesions called T1b on the original pathology report. Since critical decisions are made regarding esophageal preservation or esophagectomy on the basis of the pathologic interpretations of ER specimens, it behooves surgeons to understand the inter observer variability. Review of ER specimens by an experienced GI pathologist is recommended to ensure that patients receive the appropriate treatment for superficial esophageal adenocarcinoma. PMID- 26503262 TI - Trends in Receipt and Timing of Multimodality Therapy in Early-Stage Pancreatic Cancer. AB - INTRODUCTION: Pancreatic cancer is considered a systemic disease at presentation. Therefore, multimodality therapy with surgical resection and chemotherapy is the standard of care for locoregional disease. We described treatment patterns and time trends with regard to age and treatment center in the receipt of multimodality therapy. METHODS: We used the National Cancer Data Base to identify patients >=18 years old with stage I and II pancreatic adenocarcinoma. Treatment was defined as no treatment, resection only, chemotherapy only, or multimodality therapy, which consisted of both chemotherapy (neoadjuvant or adjuvant) and resection. Trends in the receipt and type of treatment were compared. RESULTS: Of 39,441 patients, 22.8% of patients received no treatment, 18.5% received chemotherapy only, 23.0% underwent surgical resection alone, and 35.8% of patients received multimodality therapy. Receipt of multimodality therapy increased from 31.3% in 2004 to 37.9% in 2011 (p < 0.0001). Patients >55 years were less likely to receive multimodality therapy (56-64 years: OR 0.83, 95% CI 0.78-0.89; 65-75: OR 0.60, 95% CI 0.55-0.65; >=76: OR 0.17, 95% CI 0.16-0.19 compared to patients 18-55). Compared to community hospitals, patients treated at an NCI-designated center were more likely to receive multimodality therapy (OR 1.62, 95% CI 1.46-1.81) and, if they received multimodality therapy, delivery of chemotherapy in the neoadjuvant compared to adjuvant setting (OR 2.82, 95% CI 2.00-3.98). CONCLUSION: Despite increased use of multimodality therapy, it remains underutilized in all patients and especially in older patients. Receipt of multimodality therapy and neoadjuvant therapy is highly dependent on treatment at NCI-designated cancer centers. PMID- 26503264 TI - Reduced Hemispheric Asymmetry of Brain Anatomical Networks Is Linked to Schizophrenia: A Connectome Study. AB - Despite convergent evidence indicating a variety of regional abnormalities of hemispheric asymmetry in schizophrenia, patterns of wider neural network asymmetry remain to be determined. In this study, we investigated alterations in hemispheric white matter topology in schizophrenia and their association with clinical manifestations of the illness. Weighted hemispheric brain anatomical networks were constructed for each of 116 right-handed patients with schizophrenia and 66 matched healthy participants. Graph theoretical approaches were then employed to estimate the hemispheric topological properties. We found that although small-world properties were preserved in the hemispheric network, a significant hemispheric-independent deficit of global integration was found in schizophrenia. Furthermore, a significant group-by-hemisphere interaction was revealed in the characteristic path length and global efficiency, attributing to significantly reduced hemispheric asymmetry of global integration in patients compared with healthy controls. Specifically, we found reduced asymmetric nodal efficiency in several frontal regions and the hippocampus. Finally, the abnormal hemispheric asymmetry of brain anatomical network topology was associated with clinical features (duration of illness and psychotic psychopathology) in patients. Our findings provide new insights into lateralized nature of hemispheric dysconnectivity and highlight the potential for using brain network measures of hemispheric asymmetry as neural biomarkers for schizophrenia and its clinical features. PMID- 26503263 TI - Optogenetic Mapping of Intracortical Circuits Originating from Semilunar Cells in the Piriform Cortex. AB - Despite its comparatively simple trilaminar architecture, the primary olfactory (piriform) cortex of mammals is capable of performing sophisticated sensory processing, an ability that is thought to depend critically on its extensive associational (intracortical) excitatory circuits. Here, we used a novel transgenic mouse model and optogenetics to measure the connectivity of associational circuits that originate in semilunar (SL) cells in layer 2a of the anterior piriform cortex (aPC). We generated a mouse line (48L) in which channelrhodopsin-2 (ChR) could be selectively expressed in a subset of SL cells. Light-evoked excitatory postsynaptic currents (EPSCs) could be evoked in superficial pyramidal cells (17.4% of n = 86 neurons) and deep pyramidal cells (33.3%, n = 9) in the aPC, but never in ChR- SL cells (0%, n = 34). Thus, SL cells monosynaptically excite pyramidal cells, but not other SL cells. Light evoked EPSCs were also selectively elicited in 3 classes of GABAergic interneurons in layer 3 of the aPC. Our results show that SL cells are specialized for providing feedforward excitation of specific classes of neurons in the aPC, confirming that SL cells comprise a functionally distinctive input layer. PMID- 26503266 TI - Learning-Induced Metaplasticity? Associative Training for Early Odor Preference Learning Down-Regulates Synapse-Specific NMDA Receptors via mGluR and Calcineurin Activation. AB - Rat pups readily form a 24-h associative odor preference after a single trial of odor paired with intermittent stroking. Recent evidence shows that this training trial, which normally increases AMPA receptor responses in the anterior piriform cortex both 3 and 24 h following training, induces a down-regulation of NMDA receptors 3 h later followed by NMDA receptor up-regulation at 24 h. When retrained with the same odor at 3 h, rat pups unlearn the original odor preference. Unlearning can be prevented by blocking NMDA receptors during retraining. Here, the mechanisms that initiate NMDA receptor down-regulation are assessed. Blocking mGluR receptors or calcineurin during training prevents down regulation of NMDA receptors 3 h following training. Blocking NMDA receptors during training does not affect NMDA receptor down-regulation. Thus, down regulation can be engaged separately from associative learning. When unlearning occurs, AMPA and NMDA receptor levels at 24 h are reset to control levels. Calcineurin blockade during retraining prevents unlearning consistent with the role of NMDA receptor down-regulation. The relationship of these events to the metaplasticity and plasticity mechanisms of long-term depression and depotentiation is discussed. We suggest a possible functional role of NMDA receptor down-regulation in offline stabilization of learned odor representations. PMID- 26503265 TI - Cortical Layer Inversion and Deregulation of Reelin Signaling in the Absence of SOCS6 and SOCS7. AB - Mutations of the reelin gene cause severe defects in cerebral cortex development and profound intellectual impairment. While many aspects of the reelin signaling pathway have been identified, the molecular and ultimate cellular consequences of reelin signaling remain unknown. Specifically, it is unclear if termination of reelin signaling is as important for normal cortical neuron migration as activation of reelin signaling. Using mice that are single or double deficient, we discovered that combined loss of the suppressors of cytokine signaling, SOCS6 and SOCS7, recapitulated the cortical layer inversion seen in mice lacking reelin and led to a dramatic increase in the reelin signaling molecule disabled (DAB1) in the cortex. The SRC homology domains of SOCS6 and SOCS7 bound DAB1 ex vivo. Mutation of DAB1 greatly diminished binding and protected from degradation by SOCS6. Phosphorylated DAB1 was elevated in cortical neurons in the absence of SOCS6 and SOCS7. Thus, constitutive activation of reelin signaling was observed to be equally detrimental as lack of activation. We hypothesize that, by terminating reelin signaling, SOCS6 and SOCS7 may allow new cycles of reelin signaling to occur and that these may be essential for cortical neuron migration. PMID- 26503267 TI - Electrophysiological Responses in the Ventral Temporal Cortex During Reading of Numerals and Calculation. AB - Recent evidence suggests that specific neuronal populations in the ventral temporal cortex show larger electrophysiological responses to visual numerals compared with morphologically similar stimuli. This study investigates how these responses change from simple reading of numerals to the active use of numerals in an arithmetic context. We recorded high-frequency broadband (HFB) signals, a reliable measure for local neuronal population activity, while 10 epilepsy patients implanted with subdural electrodes performed separate numeral reading and calculation tasks. We found that calculation increased activity in the posterior inferior temporal gyrus (ITG) with a factor of approximately 1.5 over the first 500 ms of calculation, whereas no such increase was noted for reading numerals without calculation or reading and judging memory statements. In a second experiment conducted in 2 of the same subjects, we show that HFB responses increase in a systematic manner when the single numerals were presented successively in a calculation context: The HFB response in the ITG, to the second and third numerals (i.e., b and c in a + b = c), was approximately 1.5 times larger than the responses to the first numeral (a). These results provide electrophysiological evidence for modulation of local neuronal population responses to visual stimuli based on increasing task demands. PMID- 26503268 TI - Neuropeptide S Receptor Gene Variation Differentially Modulates Fronto-Limbic Effective Connectivity in Childhood and Adolescence. AB - The neuropeptide S (NPS) system contributes to the pathogenesis of anxiety. The more active T allele of the functional rs324981 variant in the neuropeptide S receptor gene (NPSR1) is associated with panic disorder (PD) and distorted cortico-limbic activity during emotion processing in healthy adults and PD patients. This study investigated the influence of NPSR1 genotype on fronto limbic effective connectivity within the developing brain. Sixty healthy subjects (8-21 years) were examined using an emotional go-nogo task and fMRI. Fronto limbic connectivity was determined using Dynamic Causal Modeling. In A allele carriers, connectivity between the right middle frontal gyrus (MFG) and the right amygdala was higher in older (>=14 years) than that in younger (<14 years) probands, whereas TT homozygotes >=14 years showed a reduction of fronto-limbic connectivity between the MFG and both the amygdala and the insula. Fronto-limbic connectivity varied between NPSR1 genotypes in the developing brain suggesting a risk-increasing effect of the NPSR1T allele for anxiety-related traits via impaired top-down control of limbic structures emerging during adolescence. Provided robust replication in longitudinal studies, these findings may constitute valuable biomarkers for early targeted prevention of anxiety disorders. PMID- 26503269 TI - Multidrug resistant tuberculosis: prevalence and risk factors in districts of metema and west armachiho, Northwest Ethiopia. AB - BACKGROUND: Multi drug resistant tuberculosis (MDR-TB) is an emerging challenge for TB control programs globally. According to World health organization, 2012 report Ethiopia stands 15(th) out of the 27 high priority countries in the world and 3(rd) in Africa. Updated knowledge of the magnitude of MDR-TB is so substantial to allocate resources, and to address prevention and control measures. Therefore, the aim of this study was to assess the prevalence of MDR-TB and associated risk factors in West Armachiho and Metema districts of North Gondar. METHODS: A cross-sectional study was conducted in West Armachiho and Metema districts between February 01 and June 25, 2014. A total of 124 consecutive smear positive pulmonary tuberculosis patients were included in the study. Socio-demographic and possible risk factor data were collected using a semi-structured questionnaire. Drug susceptibility testing was first performed for rifampicin using GeneXpert MTB/RIF. For those rifampicin resistant strains, drug susceptibility testing was performed for both isoniazid and rifampicin to identify MDR-TB using the proportional method on LJ media. Data were analyzed using statistical Package SPSS version 20; binary logistic regression was used to assess the association. P-values < 0.05 were considered as statistically significant. RESULTS: Of 124 smear-positive pulmonary TB patients, 117 (94.4 %) were susceptible to Rifampicin, while 7 (5.7 %) were confirmed to be resistant to Rifampicin and Isoniazid. The overall prevalence of MDR-TB was 5.7 % (2.3 % among new cases and 13.9 % among previously treated cases). History of previous treatment (OR = 7, P = 0.025) was significantly associated risk factor for MDR TB. CONCLUSION: The overall prevalence of MDR-TB was 5.7 % among cases at five health centers and a history of previous treatment was found to be a risk factor for being infected by an MDR-TB strain. Therefore, maximizing early case detection and treatment, strengthening TB infection control activities and proper implementation of DOTS are recommended to reduce the burden of MDR-TB. PMID- 26503270 TI - Expanding Range of Amblyomma americanum and Simultaneous Changes in the Epidemiology of Spotted Fever Group Rickettsiosis in the United States. AB - Spotted fever group (SFG) Rickettsia species are etiologic agents of a wide range of human infections from asymptomatic or mild infections to severe, life threatening disease. In the United States, recent passive surveillance for SFG rickettsiosis shows an increased incidence and decreased severity of reported cases. The reasons for this are not well understood; however, we hypothesize that less pathogenic rickettsiae are causing more human infections, while the incidence of disease caused by more pathogenic rickettsiae, particularly Rickettsia rickettsii, is relatively stable. During the same period, the range of Amblyomma americanum has expanded. Amblyomma americanum is frequently infected with "Candidatus Rickettsia amblyommii", a SFG Rickettsia of unknown pathogenicity. We tested our hypothesis by modeling incidence rates from 1993 to 2013, hospitalization rates from 1981 to 2013, and case fatality rates from 1981 to 2013 regressed against the presence of A. americanum, the decade of onset of symptoms, and the county of residence. Our results support the hypothesis, and we show that the expanding range of A. americanum is associated with changes in epidemiology reported through passive surveillance. We believe epidemiological and acarological data collected on individual cases from enhanced surveillance may further elucidate the reasons for the changing epidemiology of SFG rickettsiosis. PMID- 26503271 TI - Factors Influencing the Serological Response in Hepatic Echinococcus granulosus Infection. AB - Knowledge of variables influencing serology is crucial to evaluate serology results for the diagnosis and clinical management of cystic echinococcosis (CE). We analyzed retrospectively a cohort of patients with hepatic CE followed in our clinic in 2000-2012 to evaluate the influence of several variables on the results of commercial enzyme-linked immunosorbent assay (ELISA) and indirect hemagglutination (IHA) tests. Sera from 171 patients with >= 1 hepatic CE cyst, and 90 patients with nonparasitic cysts were analyzed. CE cysts were staged according to the WHO-IWGE classification and grouped by activity. A significant difference in ELISA optical density (OD) values and percentage of positivity was found among CE activity groups and with controls (P < 0.001). The serological response was also influenced by age (P < 0.001) and cyst number (P = 0.003). OD values and cyst size were positively correlated in active cysts (P = 0.001). IHA test showed comparable results. When we analyzed the results of 151 patients followed over time, we found that serology results were significantly influenced by cyst activity, size, number, and treatment <= 12 months before serum collection. In conclusion, serological responses as assessed by commercial tests depend on CE cyst activity, size and number, and time from treatment. Clinical studies and clinicians in their practice should take this into account. PMID- 26503272 TI - More Progress in Eliminating Transmission of Onchocerca volvulus and Wuchereria bancrofti in the Americas: A Portent of Global Eradication. PMID- 26503273 TI - Antileishmanial Activity of Compounds Derived from the Medicines for Malaria Venture Open Access Box Against Intracellular Leishmania major Amastigotes. AB - Leishmaniasis is a complex tropical disease caused by kinetoplastid parasitic protozoa of the genus Leishmania and is transmitted by the sand fly insect vector. Cutaneous leishmaniasis (CL) is the most common form of this disease, and CL infections often result in serious skin lesions and scars. CL remains a public health problem in many endemic countries worldwide because of the absence of effective, safe, and cost-effective drugs for treatment. One of the strategies we chose to use to find novel chemical entities worthy of further development as antileishmanials involved screening synthetic and natural products libraries. In our study, we developed a Leishmania major intracellular amastigote assay that uses the activity of luciferase as a measure of parasite proliferation and used this assay to screen a collection of 400 compounds obtained from Medicines for Malaria Venture (MMV) for their antileishmanial activity. Our results showed that 14 compounds identified by MMV as antimalarial drugs have antileishmanial activity and can potentially be optimized for CL drug development. PMID- 26503274 TI - Development and Characterization of Monoclonal Antibodies Directed Against the Nucleoprotein of Heartland Virus. AB - Heartland virus (HRTV), a phlebovirus first isolated from two Missouri farmers in 2009, has been proposed to be transmitted to humans by the bite of infected Amblyomma americanum ticks. It is closely related to severe fever with thrombocytopenia syndrome virus (SFTSV) from China, another previously unrecognized phlebovirus that has subsequently been associated with hundreds of cases of severe disease in humans. To expand diagnostic capacity to detect HRTV infections, 20 hybridoma clones secreting anti-HRTV murine monoclonal antibodies (MAbs) were developed using splenocytes from HRTV-inoculated AG129 alpha/beta and gamma interferon receptor-deficient mice. Nine of these MAbs were characterized herein for inclusion in future HRTV diagnostic assay development. All of the MAbs developed were found to be non-neutralizing and reactive to linear epitopes on HRTV nucleocapsid protein. MAb 2AF11 was found to be cross-reactive with SFTSV. PMID- 26503275 TI - One Hundred Years After Its Discovery in Guatemala by Rodolfo Robles, Onchocerca volvulus Transmission Has Been Eliminated from the Central Endemic Zone. AB - We report the elimination of Onchocerca volvulus transmission from the Central Endemic Zone (CEZ) of onchocerciasis in Guatemala, the largest focus of this disease in the Americas and the first to be discovered in this hemisphere by Rodolfo Robles Valverde in 1915. Mass drug administration (MDA) with ivermectin was launched in 1988, with semiannual MDA coverage reaching at least 85% of the eligible population in > 95% of treatment rounds during the 12-year period, 2000 2011. Serial parasitological testing to monitor MDA impact in sentinel villages showed a decrease in microfilaria skin prevalence from 70% to 0%, and polymerase chain reaction (PCR)-based entomological assessments of the principal vector Simulium ochraceum s.l. showed transmission interruption by 2007. These assessments, together with a 2010 serological survey in children 9-69 months of age that showed Ov16 IgG4 antibody prevalence to be < 0.1%, meeting World Health Organization (WHO) guidelines for stopping MDA, and treatment was halted after 2011. After 3 years an entomological assessment showed no evidence of vector infection or recrudescence of transmission. In 2015, 100 years after the discovery of its presence, the Ministry of Health of Guatemala declared onchocerciasis transmission as having been eliminated from the CEZ. PMID- 26503276 TI - Dengue Knowledge and Preventive Practices in Iquitos, Peru. AB - As part of a cluster-randomized trial to evaluate insecticide-treated curtains for dengue prevention in Iquitos, Peru, we surveyed 1,333 study participants to examine knowledge and reported practices associated with dengue and its prevention. Entomological data from 1,133 of these households were linked to the survey. Most participants knew that dengue was transmitted by mosquito bite (85.6%), but only few (18.6%) knew that dengue vectors bite during daytime. Most commonly recognized dengue symptoms were fever (86.6%), headache (76.4%), and muscle/joint pain (67.9%). Most commonly reported correct practices for mosquito control were cleaning homes (61.6%), using insecticide sprays (23%), and avoiding having standing water at home (12.3%). Higher education was associated with higher knowledge about dengue, including transmission and vector control. Higher socioeconomic status was associated with increased reported use of preventive practices requiring money expenditure. We were less likely to find Aedes aegypti eggs, larvae, or pupae in households that had < 5-year-old children at home. Although dengue has been transmitted in Iquitos since the 1990s and the Regional Health Authority routinely fumigates households, treats domestic water containers with larvicide, and issues health education messages through mass media, knowledge of dengue transmission and household practices for prevention could be improved. PMID- 26503277 TI - Incidence of Pneumococcal Pneumonia Among Adults in Rural Thailand, 2006-2011: Implications for Pneumococcal Vaccine Considerations. AB - The incidence of pneumococcal pneumonia among adults is a key driver for the cost effectiveness of pneumococcal conjugate vaccine used among children. We sought to obtain more accurate incidence estimates among adults by including results of pneumococcal urine antigen testing (UAT) from population-based pneumonia surveillance in two Thai provinces. Active surveillance from 2006 to 2011 identified acute lower respiratory infection (ALRI)-related hospital admissions. Adult cases of pneumococcal pneumonia were defined as hospitalized ALRI patients aged >= 18 years with isolation of Streptococcus pneumoniae from blood or with positive UAT. Among 39,525 adult ALRI patients, we identified 481 pneumococcal pneumonia cases (105 by blood culture, 376 by UAT only). Estimated incidence of pneumococcal pneumonia hospitalizations was 30.5 cases per 100,000 persons per year (2.2 and 28.3 cases per 100,000 persons per year by blood culture and UAT, respectively). Incidence varied between 22.7 in 2007 and 43.5 in 2010, and increased with age to over 150 per 100,000 persons per year among persons aged >= 70 years. Viral coinfections including influenza A/B, respiratory syncytial virus (RSV), and adenovirus occurred in 11% (44/409) of pneumococcal pneumonia cases tested. Use of UAT to identify cases of pneumococcal pneumonia among adults in rural Thailand substantially increases estimates of pneumococcal pneumonia burden, thereby informing cost-effectiveness analyses and vaccine policy decisions. PMID- 26503278 TI - Modeling Combinations of Pre-erythrocytic Plasmodium falciparum Malaria Vaccines. AB - Despite substantial progress in the control of Plasmodium falciparum infection due to the widespread deployment of insecticide-treated bed nets and artemisinin combination therapies, malaria remains a prolific killer, with over half a million deaths estimated to have occurred in 2013 alone. Recent evidence of the development of resistance to treatments in both parasites and their mosquito vectors has underscored the need for a vaccine. Here, we use a mathematical model of the within-host dynamics of P. falciparum infection, fit to data from controlled human malaria infection clinical trials, to predict the efficacy of co administering the two most promising subunit vaccines, RTS,S/AS01 and ChAd63-MVA ME-TRAP. We conclude that currently available technologies could be combined to induce very high levels of sterile efficacy, even in immune-naive individuals. PMID- 26503279 TI - Post-Mass Drug Administration Transmission Assessment Survey for Elimination of Lymphatic Filariasis in La Cienaga, Dominican Republic. AB - The Dominican Republic is one of four remaining countries in the Americas with lymphatic filariasis (LF). Annual mass drug administration (MDA) with albendazole and diethylcarbamazine was conducted in La Cienaga, an impoverished urban barrio in Santo Domingo, from 2004 to 2006. Eight years after the last MDA, a transmission assessment survey (TAS) was conducted in November-December 2014 to determine if LF transmission remains absent. Of 815 first and second grade primary school students (mean age: 6.51 years; range 5-9) tested by immunochromatographic test (ICT), zero (0.0%) were positive. This is below the TAS critical cutoff of nine, indicating that the area "passed" TAS and that transmission remains interrupted in La Cienaga. Importantly, this also provides evidence that three rounds of effective (> 65% coverage) MDA, likely aided by environmental improvements and periodic school-based albendazole monotherapy MDA, achieved interruption of LF transmission from a relatively low-transmission setting. PMID- 26503280 TI - Population-Based Multicentric Survey of Hepatitis B Infection and Risk Factors in the North, South, and Southeast Regions of Brazil, 10-20 Years After the Beginning of Vaccination. AB - A population-based hepatitis survey was carried out to estimate the prevalence of hepatitis B virus (HBV) infection and its predictive factors for the state capitals from the north, south, and southeast regions of Brazil. A multistage cluster sampling was used to select, successively, census tracts, blocks, households, and residents in the age group 10-69 years in each state capital. The prevalence of hepatitis B surface antigen (HBsAg) was lower than 1% in the north, southeast, and south regions. Socioeconomic condition was associated with HBV infection in north and south regions. Variables related to the blood route transmission were associated with HBV infection only in the south whereas those related to sexual behavior were associated with HBV infection in the north and south regions. Drug use was associated in all regions, but the type of drug differed. The findings presented herein highlight the diversity of the potential transmission routes for hepatitis B transmission in Brazil. In one hand, it reinforces the importance of national control strategies of large impact already in course (immunization of infants, adolescents, and adults up to 49 years of age and blood supply screening). On the other hand, it shows that there is still room for further control measures targeted to different groups within each region. PMID- 26503281 TI - Pooled Amplicon Deep Sequencing of Candidate Plasmodium falciparum Transmission Blocking Vaccine Antigens. AB - Polymorphisms within Plasmodium falciparum vaccine candidate antigens have the potential to compromise vaccine efficacy. Understanding the allele frequencies of polymorphisms in critical binding regions of antigens can help in the designing of strain-transcendent vaccines. Here, we adopt a pooled deep-sequencing approach, originally designed to study P. falciparum drug resistance mutations, to study the diversity of two leading transmission-blocking vaccine candidates, Pfs25 and Pfs48/45. We sequenced 329 P. falciparum field isolates from six different geographic regions. Pfs25 showed little diversity, with only one known polymorphism identified in the region associated with binding of transmission blocking antibodies among our isolates. However, we identified four new mutations among eight non-synonymous mutations within the presumed antibody-binding region of Pfs48/45. Pooled deep sequencing provides a scalable and cost-effective approach for the targeted study of allele frequencies of P. falciparum candidate vaccine antigens. PMID- 26503283 TI - Effect of Latitude and Seasonal Variation on Scrub Typhus, South Korea, 2001 2013. AB - In South Korea, scrub typhus is one of the most common rickettsial diseases. The number of scrub typhus patients has increased in South Korea, a total of 69,210 cases were reported from 2001 to 2013. The seasonality and relation of scrub typhus cases to latitude were analyzed in this article using data obtained from the National Notifiable Diseases Surveillance System website of the Korea Centers for Disease Control and Prevention. The incidence of scrub typhus tended to increase in the later months of the year, especially in October-December. In general, lower latitudes were associated with a later peak incidence. Our results suggest for the first time that the monthly observed incidence tended to increase in the later months of the year as the latitude decreased, and on a yearly basis in Korea. PMID- 26503282 TI - Hypoglycemia and Risk Factors for Death in 13 Years of Pediatric Admissions in Mozambique. AB - Hypoglycemia is a life-threatening complication of several diseases in childhood. We describe the prevalence and incidence of hypoglycemia among admitted Mozambican children, establishing its associated risk factors. We retrospectively reviewed clinical data of 13 years collected through an ongoing systematic morbidity surveillance in Manhica District Hospital in rural Mozambique. Logistic regression was used to identify risk factors for hypoglycemia and death. Minimum community-based incidence rates (MCBIRs) for hypoglycemia were calculated using data from the demographic surveillance system. Of 49,089 children < 15 years hospitalized in Manhica District Hospital, 45,573 (92.8%) had a glycemia assessment on admission. A total of 1,478 children (3.2%) presented hypoglycemia (< 3 mmol/L), of which about two-thirds (972) were with levels < 2.5 mmol/L. Independent risk factors for hypoglycemia on admission and death among hypoglycemic children included prostration, unconsciousness, edema, malnutrition, and bacteremia. Hypoglycemic children were significantly more likely to die (odds ratio [OR] = 7.11; P < 0.001), with an associated case fatality rate (CFR) of 19.3% (245/1,267). Overall MCBIR of hypoglycemia was 1.57 episodes/1,000 child years at risk (CYAR), significantly decreasing throughout the study period. Newborns showed the highest incidences (9.47 episodes/1,000 CYAR, P < 0.001). Hypoglycemia remains a hazardous condition for African children. Symptoms and signs associated to hypoglycemia should trigger the verification of glycemia and the implementation of life-saving corrective measures. PMID- 26503284 TI - Colony contact contributes to the diversity of gut bacteria in bumblebees (Bombus terrestris). AB - Social bees, like honeybees and bumblebees, have a close contact with nest mates of different developmental stages and generations. This could enhance bacterial transfer between nest mates and offers opportunities for direct transfer of symbionts from one generation to the next, resulting in a stable host specific gut microbiota. Gut symbionts of honeybees and bumblebees have been suggested to contribute in digestion and protection against parasites and pathogens. Here we studied the impact of contact with the bumblebee colony on the colonization potential of the bacterial families (i.e., Neisseriaceae, Orbaceae, Lactobacillaceae and Bifidobacteriaceae) occurring in the gut of adult bumblebees (Bombus terrestris). Bacterial profiles of the gut microbiota of B. terrestris were determined based on the hypervariable V4 region of the 16S rRNA using paired end Illumina sequencing. In our experiments, we created different groups in which we gradually reduced the contact with nest mates and hive material. We made 3 observations: (i) reducing the contact between the colony and the bumblebee during adult life resulted in a significant drop in the relative abundance of Lactobacillus bombicola and Lactobacillus bombi; (ii) Bifidobacteriaceae required contact with nest mates to colonize the gut of B. terrestris and a significant lower bacterial diversity was observed in bumblebees that were completely excluded from colony contact during the adult life; (iii) Snodgrassella and Gilliamella were able to colonize the gut of the adult bumblebee without any direct contact with nest mates in the adult life stage. These results indicate the impact of the colony life on the diversity of the characteristic bumblebee gut bacteria. PMID- 26503285 TI - Communicating consequences with costs: a commentary on Corso et al's cost of injury. PMID- 26503286 TI - Surgical cytoreduction of the primary tumor reduces metastatic progression in a mouse model of prostate cancer. AB - Metastatic prostate cancer (mPCa) is one of the most prevalent cancers in men worldwide. The main cause of death in these patients is androgen-resistant metastatic disease. Surgery of the primary tumor has been avoided in these patients as there is no strong evidence that supports a beneficial effect. From the biological point of view, it appears rational to hypothesize that the primary tumor may contribute to the establishment and growth of metastases. Considering this, we propose that cytoreductive surgery (CS) in advanced metastatic stage slows the progression of metastatic disease. To test this, we used a mouse model of resectable orthotopic prostate cancer (PCa) and performed CS. After surgery, metastases were smaller and less numerous in the treated mice; an effect that was observable until the end of the experiment. These results suggest that CS alone delays the progression of metastatic disease and that although this effect may be temporary, it may translate to prolonged survival, especially when used with adjuvant therapy. PMID- 26503288 TI - EphrinB2 sharpens lateral motor column division in the developing spinal cord. AB - BACKGROUND: During sensori-motor circuit development, the somas of motoneurons (MN) are distributed in a topographic manner in the ventral horn of the neural tube. Indeed, their position within the lateral motor columns (LMC) correlates with axonal trajectories and identity of target limb muscles. The mechanisms by which this topographic distribution is established remains poorly understood. To address this issue, we assessed the role of ephrinB2 in MN topographic organization in the developing mouse spinal cord. RESULTS: First, we used a reporter mouse line to establish the spatio-temporal expression pattern of EfnB2 in the developing LMC. We show that early in LMC development, ephrinB2 is differentially expressed in MN of the lateral versus medial LMC, suggesting a possible role in MN sorting and/or migration. We demonstrate that while MN specific excision of EfnB2 did not perturb specification or migration of MN, conditional loss of ephrinB2 led to the blurring of the LMC divisional boundary and to errors in the selection of LMC axon trajectory in the limb. CONCLUSIONS: Altogether, our study uncovered a novel cell autonomous role for ephrinB2 in LMC MN thus emphasizing the prevalent role of this ephrin member in maintaining cell population boundaries. PMID- 26503287 TI - Genome-wide survey and expression analysis of the OSCA gene family in rice. AB - BACKGROUND: Reception of and response to exogenous and endogenous osmotic changes is important to sustain plant growth and development, as well as reproductive formation. Hyperosmolality-gated calcium-permeable channels (OSCA) were first characterised as an osmosensor in Arabidopsis and are involved in the perception of extracellular changes to trigger hyperosmolality-induced [Ca(2+)]i increases (OICI). To explore the potential biological functions of OSCAs in rice, we performed a bioinformatics and expression analysis of the OsOSCA gene family. RESULTS: A total of 11 OsOSCA genes were identified from the genome database of Oryza sativa L. Japonica. Based on their sequence composition and phylogenetic relationship, the OsOSCA family was classified into four clades. Gene and protein structure analysis indicated that the 11 OsOSCAs shared similar structures with their homologs in Oryza sativa L. ssp. Indica, Oryza glaberrima, and Oryza brachyantha. Multiple sequence alignment analysis revealed a conserved DUF221 domain in these members, in which the first three TMs were conserved, while the others were not. The expression profiles of OsOSCA genes were analysed at different stages of vegetative growth, reproductive development, and under osmotic-associated abiotic stresses. We found that four and six OsOSCA genes showed a clear correlation between the expression profile and osmotic changes during caryopsis development and seed imbibition, respectively. Orchestrated transcription of three OsOSCAs was strongly associated with the circadian clock. Moreover, osmotic-related abiotic stress differentially induced the expression of 10 genes. CONCLUSION: The entire OSCA family is characterised by the presence of a conserved DUF221 domain, which functions as an osmotic-sensing calcium channel. The phylogenetic tree of OSCA genes showed that two subspecies of cultivated rice, Oryza sativa L. ssp. Japonica and Oryza sativa L. ssp. Indica, are more closely related than wild rice Oryza glaberrima, while Oryza brachyantha was less closely related. OsOSCA expression is organ- and tissue-specific and regulated by different osmotic-related abiotic stresses in rice. These findings will facilitate further research in this gene family and provide potential target genes for generation of genetically modified osmotic-stress-resistant plants. PMID- 26503289 TI - Health education and factors influencing acceptance of and willingness to pay for influenza vaccination among older adults. AB - BACKGROUND: The influenza vaccine is recommended in older population. However the immunization coverage varies globally. It has been reported as low as 10-20 % in some countries. This study explored the acceptance of and willingness to pay for influenza vaccination, comparing acceptance and willingness to pay before and after health education. METHODS: The study was conducted with 2693 older people in Bangkok, Thailand. Participants were divided into an education group (n = 1402) and a control group (n = 1291). A validated questionnaire measuring acceptance of and willingness to pay for vaccination was administered during semi structured interviews before and after education. Data on factors influencing acceptance were analyzed. RESULTS: Participants' mean age was 69.5 years, 80 % were women and 82.1 % had at least one co-morbidity. Of the participants, 43.5 % had previously received vaccination more than once, although 92.8 % expressed acceptance of vaccination. Acceptance was associated with a positive attitude toward vaccination (OR 2.1, 95 % CI 1.5-2.9) and a history of receiving vaccination (OR 4.1, 95 % CI 2.8-6.1). At baseline, there were no differences between the education and control groups in terms of work status (p = 0.457), co morbidities (p = 0.07), medical status (p = 0.243), and previous vaccination (p = 0.62), except for educational background (p = 0.004). Acceptance of vaccination increased to 95.8 % (p < 0.001) after education and willingness to pay increased to 82.1 % (p < 0.001). Education significantly affected those with primary school level education and no previous vaccination history, with acceptance increasing from 83.3 to 92.6 % (p < 0.001); more than twice as high as the control group (OR 2.4, 95 % CI 1.2-4.7). Viewing an educational video increased the proportion of participants with a high level of knowledge from 29.2 to 49.2 % (p < 0.001), and increased the proportion of participants with a positive attitude from 52.4 to 70.7 % (p <0.001). No significant difference was found in any parameter between the first and second assessment in the control group. CONCLUSIONS: The strategies to increase positive attitudes may enhance the acceptance of vaccination. Health education using an educational video demonstrated a significant impact on acceptance, willingness to pay, knowledge and attitude in older people. This may lead to increased sustainability of the immunization program in older people. PMID- 26503290 TI - Small-Animal Molecular Imaging for Preclinical Cancer Research: .μPET and μ.SPECT. AB - Due to different sizes of humans and rodents, the performance of clinical imaging devices is not enough for a scientifically reliable evaluation in mice and rats; therefore dedicated small-animal systems with a much higher sensitivity and spatial resolution, compared to the ones used in humans, are required. Smallanimal imaging represents a cutting-edge research method able to approach an enormous variety of pathologies in which animal models of disease may be used to elucidate the mechanisms underlying the human condition and/or to allow a translational pharmacological (or other) evaluation of therapeutic tools. Molecular imaging, avoiding animal sacrifice, permits repetitive (i.e. longitudinal) studies on the same animal which becomes its own control. In this way also the over time evaluation of disease progression or of the treatment response is enabled. Many different rodent models have been applied to study almost all kind of human pathologies or to experiment a wide series of drugs and/or other therapeutic instruments. In particular, relevant information has been achieved in oncology by in vivo neoplastic phenotypes, obtained through procedures such as subcutaneous tumor grafts, surgical transplantation of solid tumor, orthotopic injection of tumor cells into specific organs/sites of interest, genetic modification of animals to promote tumor-genesis; in this way traditional or innovative treatments, also including gene therapy, of animals with a cancer induced by a known carcinogen may be experimented. Each model has its own disadvantage but, comparing different studies, it is possible to achieve a panoramic and therefore substantially reliable view on the specific subject. Small-animal molecular imaging has become an invaluable component of modern biomedical research that will gain probably an increasingly important role in the next few years. PMID- 26503292 TI - Polysubstituted 2-Aminopyrrole Synthesis via Gold-Catalyzed Intermolecular Nitrene Transfer from Vinyl Azide to Ynamide: Reaction Scope and Mechanistic Insights. AB - A gold-catalyzed intermolecular reaction of vinyl azides and ynamides is described. This process presents an efficient and mild approach to multisubstituted 2-aminopyrroles in good-to-excellent yields. Control experiments were carried out to distinguish the reactivity between vinyl azides and the corresponding 2H-azirines. A plausible reaction mechanism was also proposed according to previous reports and our preliminary mechanistic studies. PMID- 26503291 TI - Factors associated with depression among adolescents living with HIV in Malawi. AB - BACKGROUND: Prior research suggests that a high prevalence of depression, with a detrimental impact on treatment outcomes exists among HIV-infected youth. Data on potential risk factors of depression among HIV-infected youth in sub-Saharan Africa are scarce. This cross-sectional study aimed to identify contributory/protective factors associated with depression in Malawian adolescents 12-18 years old living with HIV. METHODS: Depression was measured by a validated Chichewa version of the Beck Depression Inventory version-II (BDI-II) and the Children's Depression Rating Scale-Revised (CDRS-R). Data on variables thought to potentially be contributory/protective were collected and included: socio-demographics, past traumatic events/stressors, behavioural factors/social support, and bio-clinical parameters. Chi-square test or two-sample t-test was used to explore associations between factors and depression. Additional testing via linear/logistic regression, adjusting for age and sex, identified candidate variables (p < 0.1). Final regression models included variables with significant main effects and interactions. RESULTS: Of the 562 participants enrolled (mean age, 14.5 years [SD 2.0]; 56.1% female), the prevalence of depression was 18.9%. In multivariate linear regression, the variables significantly associated with higher BDI-II score were female gender, fewer years of schooling, death in the family/household, failing a school term/class, having a boyfriend/girlfriend, not disclosed or not having shared one's HIV status with someone else, more severe immunosuppression, and bullied for taking medications. Bullying victimization was reported by 11.6% of respondents. We found significant interactions: older participants with lower height-for-age z-scores and dissatisfied with their physical appearance had higher BDI-II scores. In multivariate logistic regression, factors significantly associated with depression were: older age, OR 1.23 (95% CI 1.07-1.42); fewer years of schooling, OR 3.30 (95% CI 1.54-7.05); and bullied for taking medications, (OR 4.20 (95% CI 2.29-7.69). CONCLUSION: Having fewer years of schooling and being bullied for taking medications were most clearly associated with depression. Programmes to support the mental health needs of HIV-infected adolescents that address issues such as disclosure, educational support, and, most notably, bullying may improve treatment outcomes and are recommended. PMID- 26503293 TI - Strongly-coupled plasmas formed from laser-heated solids. AB - We present an analysis of ion temperatures in laser-produced plasmas formed from solids with different initial lattice structures. We show that the equilibrium ion temperature is limited by a mismatch between the initial crystallographic configuration and the close-packed configuration of a strongly-coupled plasma, similar to experiments in ultracold neutral plasmas. We propose experiments to demonstrate and exploit this crystallographic heating in order to produce a strongly coupled plasma with a coupling parameter of several hundred. PMID- 26503294 TI - Development and Application of a Multielectron-Accepting Organic Oxidant for the Catalytic Transition-Metal-Free Oxidative Homocoupling of Grignard Reagents in Air. AB - Heptafluorotolyl-substituted perfluorocyclopentene acts as a four-electron oxidant for the homocoupling of Grignard reagents. It can also be used for catalytic homocoupling with a low catalyst loading (up to 2 mol %) in the presence of atmospheric oxygen. The organocatalytic cycle involves the generation of an organic radical and a perfluorocyclopentadienyl anion. PMID- 26503295 TI - The renaissance of 2,4,6-tris(2-pyrimidyl)-1,3,5-triazine (TPymT) coordination chemistry. AB - In this perspective we report on recently accumulated data on the synthesis and coordination chemistry of 2,4,6-tris(2-pyrimidyl)-1,3,5-triazine (TPymT). Although a highly attractive ligand, owing to the presence of three fused terpyridine-like coordination pockets, the coordination chemistry of TPymT has something of a chequered past. This can principally be attributed to the hydrolysis of the ligand, which readily occurs under mild conditions. Thus, after first being synthesised in 1959 it had only been used a handful of times to synthesise coordination compounds until we began reinvestigating its chemistry in early 2013. Despite the significant challenges associated with its use, our work over the past two years has demonstrated that coordination chemistry with TPymT is indeed possible. Herein, we describe an overview of this body of work as it stands, and discuss its potential impact in a variety of areas including porous materials, catalysis and crystal engineering. PMID- 26503297 TI - Effects of long-term treatment on brain volume in patients with obstructive sleep apnea syndrome. AB - We assessed structural brain damage in obstructive sleep apnea syndrome (OSA) patients (21 males) and the effects of long-term continuous positive airway pressure (CPAP) treatment (18.2 +/- 12.4 months; 8-44 months) on brain structures and investigated the relationship between severity of OSA and effects of treatment. Using deformation-based morphometry to measure local volume changes, we identified widespread neocortical and cerebellar atrophy in untreated patients compared to controls (59 males; Cohen's D = 0.6; FDR < 0.05). Analysis of longitudinally scanned magnetic resonance imaging (MRI) scans both before and after treatment showed increased brain volume following treatment (FDR < 0.05). Volume increase was correlated with longer treatment in the cortical areas that largely overlapped with the initial atrophy. The areas overlying the hippocampal dentate gyrus and the cerebellar dentate nucleus displayed a volume increase after treatment. Patients with very severe OSA (AHI > 64) presented with prefrontal atrophy and displayed an additional volume increase in this area following treatment. Higher impairment of working memory in patients prior to treatment correlated with prefrontal volume increase after treatment. The large overlap between the initial brain damage and the extent of recovery after treatment suggests partial recovery of nonpermanent structural damage. Volume increases in the dentate gyrus and the dentate nucleus possibly likely indicate compensatory neurogenesis in response to diminishing oxidative stress. Such changes in other brain structures may explain gliosis, dendritic volume increase, or inflammation. This study provides neuroimaging evidence that revealed the positive effects of long-term CPAP treatment in patients with OSA. PMID- 26503296 TI - The Montreal Cognitive Assessment: Creating a Crosswalk with the Mini-Mental State Examination. AB - OBJECTIVES: To establish Montreal Cognitive Assessment (MoCA) scores that correspond to well-established cut-points on the Mini-Mental State Examination (MMSE). DESIGN: Cross-sectional observational study. SETTING: General medical service of a large teaching hospital. PARTICIPANTS: Individuals aged 75 and older (N = 199; mean age 84, 63% female). MEASUREMENTS: The MoCA (range 0-30) and the MMSE (range 0-30) were administered within 2 hours of each other. The Abbreviated MoCA (A-MoCA; range 0-22) was calculated from the full MoCA. Scores from the three tests were analyzed using equipercentile equating, a statistical method for determining comparable scores on different tests of a similar construct by estimating percentile equivalents. RESULTS: MoCA scores were lower (mean 19.3 +/- 5.8) than MMSE scored (mean 24.1 +/- 6.6). Traditional MMSE cut-points of 27 for mild cognitive impairment and 23 for dementia corresponded to MoCA scores of 23 and 17, respectively. CONCLUSION: Scores on the full and abbreviated versions of the MoCA can be linked directly to the MMSE. The MoCA may be more sensitive to changes in cognitive performance at higher levels of functioning. PMID- 26503298 TI - Development of a Tool to Measure Youths' Food Allergy Management Facilitators and Barriers. AB - OBJECTIVE: This study's aims are to identify factors related to allergen avoidance and epinephrine carriage among youth with food allergy, develop a tool to measure food allergy management facilitators and barriers, and investigate its initial reliability and validity. METHODS: The Food Allergy Management Perceptions Questionnaire (FAMPQ) was developed based on focus groups with 19 adolescents and young adults with food allergy. Additional youth with food allergy (N = 92; ages: 13-21 years) completed food allergy clinical history and management questionnaires and the FAMPQ. RESULTS: Internal reliability estimates for the FAMPQ Facilitators and Barriers subscales were acceptable to good. Youth who were adherent to allergen avoidance and epinephrine carriage had higher Facilitator scores. Poor adherence was more likely among youth with higher Barrier scores. CONCLUSIONS: Initial FAMPQ reliability and validity is promising. Additional research is needed to develop FAMPQ clinical guidelines. PMID- 26503300 TI - Green synthesis of bacterial mediated anti-proliferative gold nanoparticles: inducing mitotic arrest (G2/M phase) and apoptosis (intrinsic pathway). AB - The physiochemical and biological properties of microbial derived gold nanoparticles have potential applications in various biomedical domains as well as in cancer therapy. We have fabricated anti-proliferative bacterial mediated gold nanoparticles (b-Au NPs) using a culture supernatant of Streptomyces clavuligerus and later characterized them by UV-visible, TEM, DLS, XRD and FT-IR spectroscopic techniques. The capping agent responsible for the nanoparticle formation was characterized based on SDS-PAGE and MALDI-TOF-MS analyses. They were tested for anticancer activity in A549, HeLa and DU145 cell lines. The biocompatibility and non-toxic nature of the nanoparticles were tested on normal human lung cell line (MRC-5). The b-Au NPs induced the cell cycle arrest in G2/M phase and also inhibited the microtubule assembly in DU145 cells. Mechanistic studies, such as ROS, MMP, Cyt-c, GSH, caspases 9, 8 and 3 activation and the Annexin V-FITC staining, along with the above parameters tested provided sufficient evidence that the b-Au NPs induced apoptosis through the intrinsic pathway. The results supported the use of b-Au NPs for future therapeutic application in cancer therapy and other biomedical applications. PMID- 26503299 TI - Quality of Life Changes and Health Care Charges Among Youth With Epilepsy. AB - OBJECTIVE: To examine differences in health care charges following a pediatric epilepsy diagnosis based on changes in health-related quality of life (HRQOL). METHODS: Billing records were obtained for 171 youth [M (SD) age = 8.9 (4.1) years] newly diagnosed with epilepsy. Differences in health care charges among HRQOL groups (stable low, declining, improving, or stable high as determined by PedsQL(TM) scores at diagnosis and 12 months after diagnosis) were examined. RESULTS: Patients with persistently low or declining HRQOL incurred higher total health care charges in the year following diagnosis (g = .49, g = .81) than patients with stable high HRQOL after controlling for epilepsy etiology, seizure occurrence, and insurance type. These relationships remained consistent after excluding health care charges for behavioral medicine or neuropsychology services (g = .49, g = .80). CONCLUSIONS: Monitoring HRQOL over time may identify youth with epilepsy at particular risk for higher health care charges. PMID- 26503301 TI - A Balancing Act: Integrating Evidence-Based Knowledge and Cultural Relevance in a Program of Prevention Parenting Research with Latino/a Immigrants. AB - Family therapists have a unique opportunity to contribute toward the reduction of widespread mental health disparities impacting diverse populations by developing applied lines of research focused on cultural adaptation. For example, although evidence-based prevention parent training (PT) interventions have been found to be efficacious with various Euro-American populations, there is a pressing need to understand which specific components of PT interventions are perceived by ethnic minority parents as having the highest impact on their parenting practices. Equally important is to examine the perceived cultural relevance of adapted PT interventions. This qualitative investigation had the primary objective of comparing and contrasting the perceived relevance of two culturally adapted versions of the efficacious parenting intervention known as Parent Management Training, the Oregon Model (PMTO). According to feasibility indicators provided by 112 Latino/a immigrant parents, as well as findings from a qualitative thematic analysis, the core parenting components across both adapted interventions were identified by the majority of research participants as relevant to their parenting practices. Participants exposed to the culturally enhanced intervention, which included culture-specific sessions, also reported high satisfaction with components exclusively focused on cultural issues that directly impact their parenting practices (e.g., immigration challenges, biculturalism). This investigation illustrates the relevant contributions that family therapy scholars can offer toward addressing mental health disparities, particularly as it refers to developing community-based prevention interventions that achieve a balance between evidence-based knowledge and cultural relevance. PMID- 26503302 TI - Adequacy of Duodenoscope Reprocessing Methods as Reported by Infectious Disease Physicians. PMID- 26503303 TI - High omega3-polyunsaturated fatty acids in fat-1 mice prevent streptozotocin induced Purkinje cell degeneration through BDNF-mediated autophagy. AB - Loss of Purkinje cells has been implicated in the development of diabetic neuropathy, and this degeneration is characterized by impairment of autophagic processes. We evaluated whether fat-1 transgenic mice, a well-established animal model that endogenously synthesizes omega3 polyunsaturated fatty acids (omega3 PUFA), are protected from Purkinje cell degeneration in streptozotocin (STZ) treated model with fat-1 mice. STZ-treated fat-1 mice did not develop hyperglycemia, motor deficits, or Purkinje cell loss. The expression of LC3 I, II, Beclin-1 and p62 were increased in the cerebellum of STZ-treated wild-type mice, and these expressions were more increased in STZ-treated fat-1 mice, but not of p62. Moreover, cerebellar Rab7, Cathepsin D, and ATP6E were increased in STZ-treated fat-1 mice. There was also increased BDNF expression in Purkinje cells without any changes in TrkB, and phosphorylation of Akt and CREB in the cerebellums of fat-1 mice. Collectively, these findings indicate that STZ-treated fat-1 mice were protected from Purkinje cell loss and exhibited increased BDNF signaling, enhancing autophagic flux activity in cerebellar Purkinje neurons. These processes may underlie Purkinje cell survival and may be potential therapeutic targets for treatment of motor deficits related to diabetic neuropathy. PMID- 26503304 TI - Corticospinal axons make direct synaptic connections with spinal motoneurons innervating forearm muscles early during postnatal development in the rat. AB - KEY POINTS: Direct connections between corticospinal (CS) axons and motoneurons (MNs) appear to be present only in higher primates, where they are essential for discrete movement of the digits. Their presence in adult rodents was once claimed but is now questioned. We report that MNs innervating forearm muscles in infant rats receive monosynaptic input from CS axons, but MNs innervating proximal muscles do not, which is a pattern similar to that in primates. Our experiments were carefully designed to show monosynaptic connections. This entailed selective electrical and optogenetic stimulation of CS axons and recording from MNs identified by retrograde labelling from innervated muscles. Morphological evidence was also obtained for rigorous identification of CS axons and MNs. These connections would be transient and would regress later during development. These results shed light on the development and evolution of direct CS-MN connections, which serve as the basis for dexterity in humans. Recent evidence suggests there is no direct connection between corticospinal (CS) axons and spinal motoneurons (MNs) in adult rodents. We previously showed that CS synapses are present throughout the spinal cord for a time, but are eliminated from the ventral horn during development in rodents. This raises the possibility that CS axons transiently make direct connections with MNs located in the ventral horn of the spinal cord. This was tested in the present study. Using cervical cord slices prepared from rats on postnatal days (P) 7-9, CS axons were stimulated and whole cell recordings were made from MNs retrogradely labelled with fluorescent cholera toxin B subunit (CTB) injected into selected groups of muscles. To selectively activate CS axons, electrical stimulation was carefully limited to the CS tract. In addition we employed optogenetic stimulation after injecting an adeno associated virus vector encoding channelrhodopsin-2 (ChR2) into the sensorimotor cortex on P0. We were then able to record monosynaptic excitatory postsynaptic currents from MNs innervating forearm muscles, but not from those innervating proximal muscles. We also showed close contacts between CTB-labelled MNs and CS axons labelled through introduction of fluorescent protein-conjugated synaptophysin or the ChR2 expression system. We confirmed that some of these contacts colocalized with postsynaptic density protein 95 in their partner dendrites. It is intriguing from both phylogenetic and ontogenetic viewpoints that direct and putatively transient CS-MN connections were found only on MNs innervating the forearm muscles in infant rats, as this is analogous to the connection pattern seen in adult primates. PMID- 26503305 TI - Spectral fitting using basis set modified by measured B0 field distribution. AB - This study sought to demonstrate and evaluate a novel spectral fitting method to improve quantification accuracy in the presence of large magnetic field distortion, especially with high fields. MRS experiments were performed using a point-resolved spectroscopy (PRESS)-type sequence at 7 T. A double-echo gradient echo (GRE) sequence was used to acquire B0 maps following MRS experiments. The basis set was modified based on the measured B0 distribution within the MRS voxel. Quantification results were obtained after fitting the measured MRS data using the modified basis set. The proposed method was validated using numerical Monte Carlo simulations, phantom measurements, and comparison of occipital lobe MRS measurements under homogeneous and inhomogeneous magnetic field conditions. In vivo results acquired from voxels placed in thalamus and prefrontal cortex regions close to the frontal sinus agreed well with published values. Instead of noise-amplifying complex division, the proposed method treats field variations as part of the signal model, thereby avoiding inherent statistical bias associated with regularization. Simulations and experiments showed that the proposed approach reliably quantified results in the presence of relatively large magnetic field distortion. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26503306 TI - Titania-Silica Materials for Enhanced Photocatalysis. AB - Mesoporous titania-organosilica nanoparticles comprised of anatase nanocrystals crosslinked with organosilica moieties have been prepared by direct co condensation of a titania precursor, tetrabuthylortotitanate (TBOT), with two organosilica precursors, 1,4-bis(triethoxysilyl) benzene (BTEB) and 1,2 bis(triethoxysilyl) ethane (BTEE), in mild conditions and in the absence of surfactant. These hybrid materials show both high surface areas (200-360 m(2) g( 1) ) and pore volumes (0.3 cm(3) g(-1) ) even after calcination, and excellent photoactivity in the degradation of rhodamine 6G and in the partial oxidation of propene under UV irradiation, especially after the calcination of the samples. During calcination, there is a change in the Ti(IV) coordination and an increase in the content of Si?O?Ti moieties in comparison with the uncalcined materials, which seems to be responsible for the enhanced photocatalytic activity of hybrid titania-silica materials as compared to both uncalcined samples and the control TiO2 . PMID- 26503307 TI - Metabolic engineering for the production of plant isoquinoline alkaloids. AB - Several plant isoquinoline alkaloids (PIAs) possess powerful pharmaceutical and biotechnological properties. Thus, PIA metabolism and its fascinating molecules, including morphine, colchicine and galanthamine, have attracted the attention of both the industry and researchers involved in plant science, biochemistry, chemical bioengineering and medicine. Currently, access and availability of high value PIAs [commercialized (e.g. galanthamine) or not (e.g. narciclasine)] is limited by low concentration in nature, lack of cultivation or geographic access, seasonal production and risk of overharvesting wild plant species. Nevertheless, most commercial PIAs are still extracted from plant sources. Efforts to improve the production of PIA have largely been impaired by the lack of knowledge on PIA metabolism. With the development and integration of next-generation sequencing technologies, high-throughput proteomics and metabolomics analyses and bioinformatics, systems biology was used to unravel metabolic pathways allowing the use of metabolic engineering and synthetic biology approaches to increase production of valuable PIAs. Metabolic engineering provides opportunity to overcome issues related to restricted availability, diversification and productivity of plant alkaloids. Engineered plant, plant cells and microbial cell cultures can act as biofactories by offering their metabolic machinery for the purpose of optimizing the conditions and increasing the productivity of a specific alkaloid. In this article, is presented an update on the production of PIA in engineered plant, plant cell cultures and heterologous micro-organisms. PMID- 26503308 TI - Specificity of Lipoprotein Chaperones for the Characteristic Lipidated Structural Motifs of their Cognate Lipoproteins. AB - Lipoprotein-binding chaperones mediate intracellular transport of lipidated proteins and determine their proper localisation and functioning. Understanding of the exact structural parameters that determine recognition and transport by different chaperones is of major interest. We have synthesised several lipid modified peptides, representative of different lipoprotein classes, and have investigated their binding to the relevant chaperones PDEdelta, UNC119a, UNC119b, and galectins-1 and -3. Our results demonstrate that PDEdelta recognises S isoprenylated C-terminal peptidic structures but not N-myristoylated peptides. In contrast, UNC119 proteins bind only mono-N-myristoylated, but do not recognise doubly lipidated and S-isoprenylated peptides at the C terminus. For galectins-1 and -3, neither binding to N-acylated, nor to C-terminally prenylated peptides could be determined. These results shed light on the specificity of the chaperone mediated cellular lipoprotein transport systems. PMID- 26503309 TI - Environmental distribution and genetic diversity of vegetative compatibility groups determine biocontrol strategies to mitigate aflatoxin contamination of maize by Aspergillus flavus. AB - Maize infected by aflatoxin-producing Aspergillus flavus may become contaminated with aflatoxins, and as a result, threaten human health, food security and farmers' income in developing countries where maize is a staple. Environmental distribution and genetic diversity of A. flavus can influence the effectiveness of atoxigenic isolates in mitigating aflatoxin contamination. However, such information has not been used to facilitate selection and deployment of atoxigenic isolates. A total of 35 isolates of A. flavus isolated from maize samples collected from three agro-ecological zones of Nigeria were used in this study. Ecophysiological characteristics, distribution and genetic diversity of the isolates were determined to identify vegetative compatibility groups (VCGs). The generated data were used to inform selection and deployment of native atoxigenic isolates to mitigate aflatoxin contamination in maize. In co inoculation with toxigenic isolates, atoxigenic isolates reduced aflatoxin contamination in grain by > 96%. A total of 25 VCGs were inferred from the collected isolates based on complementation tests involving nitrate non-utilizing (nit(-)) mutants. To determine genetic diversity and distribution of VCGs across agro-ecological zones, 832 nit(-) mutants from 52 locations in 11 administrative districts were paired with one self-complementary nitrate auxotroph tester-pair for each VCG. Atoxigenic VCGs accounted for 81.1% of the 153 positive complementations recorded. Genetic diversity of VCGs was highest in the derived savannah agro-ecological zone (H = 2.61) compared with the southern Guinea savannah (H = 1.90) and northern Guinea savannah (H = 0.94) zones. Genetic richness (H = 2.60) and evenness (E5 = 0.96) of VCGs were high across all agro ecological zones. Ten VCGs (40%) had members restricted to the original location of isolation, whereas 15 VCGs (60%) had members located between the original source of isolation and a distance > 400 km away. The present study identified widely distributed VCGs in Nigeria such as AV0222, AV3279, AV3304 and AV16127, whose atoxigenic members can be deployed for a region-wide biocontrol of toxigenic isolates to reduce aflatoxin contamination in maize. PMID- 26503310 TI - Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment. AB - Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [(18)F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence. PMID- 26503311 TI - Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels. AB - DNA methylation variation at HP1BP3 and TTC9B is modified by estrogen exposure in the rodent hippocampus and was previously shown to be prospectively predictive of postpartum depression (PPD) when modeled in antenatal blood. The objective of this study was to replicate the predictive efficacy of the previously established model in women with and without a previous psychiatric diagnosis and to understand the effects of changing hormone levels on PPD biomarker loci. Using a statistical model trained on DNA methylation data from N=51 high-risk women, we prospectively predicted PPD status in an independent N=51 women using first trimester antenatal gene expression levels of HP1BP3 and TTC9B, with an area under the receiver operator characteristic curve (AUC) of 0.81 (95% CI: 0.69 0.92, p<5 * 10(-4)). Modeling DNA methylation of these genes in N=240 women without a previous psychiatric diagnosis resulted in a cross-sectional prediction of PPD status with an AUC of 0.81 (95% CI: 0.68-0.93, p=0.01). TTC9B and HP1BP3 DNA methylation at early antenatal time points showed moderate evidence for association to the change in estradiol and allopregnanolone over the course of pregnancy, suggesting that epigenetic variation at these loci may be important for mediating hormonal sensitivity. In addition both loci showed PPD-specific trajectories with age, possibly mediated by age-associated hormonal changes. The data add to the growing body of evidence suggesting that PPD is mediated by differential gene expression and epigenetic sensitivity to pregnancy hormones and that modeling proxies of this sensitivity enable accurate prediction of PPD. PMID- 26503313 TI - [Techno-scientific revolution, sustainability of healthcare systems and stress]. PMID- 26503312 TI - Systemic inflammation and oxidative stress post-lung resection: Effect of pretreatment with N-acetylcysteine. AB - BACKGROUND AND OBJECTIVE: N-acetylcysteine has been used to treat a variety of lung diseases, where is it thought to have an antioxidant effect. In a randomized placebo-controlled double-blind study, the effect of N-acetylcysteine on systemic inflammation and oxidative damage was examined in patients undergoing lung resection, a human model of acute lung injury. METHODS: Eligible adults were randomized to receive preoperative infusion of N-acetylcysteine (240 mg/kg over 12 h) or placebo. Plasma thiols, interleukin-6, 8-isoprostane, ischaemia-modified albumin, red blood cell glutathione and exhaled breath condensate pH were measured pre- and post-operatively as markers of local and systemic inflammation and oxidative stress. RESULTS: Patients undergoing lung resection and one-lung ventilation exhibited significant postoperative inflammation and oxidative damage. Postoperative plasma thiol concentration was significantly higher in the N-acetylcysteine-treated group. However, there was no significant difference in any of the measured biomarkers of inflammation or oxidative damage, or in clinical outcomes, between N-acetylcysteine and placebo groups. CONCLUSION: Preoperative administration of N-acetylcysteine did not attenuate postoperative systemic or pulmonary inflammation or oxidative damage after lung resection. CLINICAL TRIAL REGISTRATION: NCT00655928 at ClinicalTrials.gov. PMID- 26503314 TI - [Clinical utility and psychometric properties of Prefrontal Symptoms Inventory (PSI) in acquired brain injury and degenerative dementias]. AB - INTRODUCTION: The cognitive, emotional and behavioural alterations secondary to acquired brain injury and degenerative dementias can be quantitatively and quantitatively appraised by administering self-reports that ask both patients and reliable informants about the difficulties patients have in their everyday life. SUBJECTS AND METHODS: The Prefrontal Symptoms Inventory (PSI) and the Modified Memory Failures in Everyday Life Questionnaire (MFE-30) were administered to 174 paired participants: 87 patients with brain damage or degenerative dementias and their 87 reliable informants. In addition to the psychometric goodness of the tests, the study also explored the clinical usefulness of applying these questionnaires to patients and their informants in order to obtain a rate of discrepancy in the scores as a measure of anosognosia. RESULTS: The results show how applying the PSI-20 (20 items) or the PSI (46 items), whether administered together with the MFE-30 (30 items) or not, is a very useful procedure for assessing the symptoms in individuals with acquired brain injury or degenerative dementias, since it yields a great deal of information about patients' difficulties in their daily life. CONCLUSIONS: We recommend that, in addition to the compulsory neuropsychological assessment, questionnaires or inventories of symptoms like those proposed here should be carried out, due to the fact that they offer a number of advantages from the clinical point of view, as well as being efficacious and effective in economic terms. PMID- 26503315 TI - [Taylor Complex Figure test: administration and correction according to a normalization and standardization process in Spanish population]. AB - INTRODUCTION: The Taylor Complex Figure (TCF) was created as an alternate form for the Rey-Osterrieth Complex Figure. Although both figures are widely used, to date, it has not been carried out the normalization of the TCF for Spanish population. AIM: To normalize and standardize the TCF taking into account the sociodemographic characteristics of the Spanish population. SUBJECTS AND METHODS: The present study is part of the Normacog Project. Seven hundred participants were recruited (18-90 years old), assessing the visuo-constructive ability and immediate visual memory by TCF. The effect of age, level of education and gender was analyzed on the performance of TCF and percentiles and scalar score for eight ranges of age and scalar score adjusted by the level of education. RESULTS: Results showed a significant effect of age and level of education on the performance in copy and memory of TCF, whereas gender was not significant. Age and education explained from 25.3% to 35.7% of the variance of TCF performance. The older and less educated, the worse performance shown in TCF. Percentiles, scalar score for each range of age and scalar score adjusted by the level of education were obtained. CONCLUSION: Administration instructions, scoring and the normative data of the TCF are provided taking into account the Spanish sociodemographic characteristics for adults in our country. PMID- 26503316 TI - Project ES3: attempting to quantify and measure the level of stress. AB - INTRODUCTION: The WHO has qualified stress as a 'world epidemic' due to its increasingly greater incidence on health. The work described in this paper represents an attempt to objectively quantify the level of stress. AIM: The aim of the method developed here is to measure how close or how far a subject is from a situation that can be considered 'normal' in medical and social terms. SUBJECTS AND METHODS: The literature on the pathophysiology of stress and its methods of study in experiments on both animals and humans was reviewed. Nine prospective observational studies were undertaken with different types of subjects and stressors covering the different types of stress. RESULTS: The results of the literature review made it possible to identify the different types of stress, the indicators that yield significant results, the psychometric tests and the well documented 'stressors'. This material was then used to design the general method and the details of the nine clinical trials. The preliminary results obtained in some of the studies were used to validate the indicators as well as the efficacy of the techniques used experimentally to diminish stress or to produce it. CONCLUSIONS: The early results obtained in the experimental trials show that we are on the right path towards defining and validating multivariable markers for quantifying levels of stress and also suggest that the method can be applied in a similar way to the study of mental disorders. PMID- 26503317 TI - [Variability in the clinical presentation of Pompe disease: development following enzyme replacement therapy]. AB - INTRODUCTION: Pompe disease is a generalized progressive disease caused by a deficiency of the lysosome enzyme acid alpha-glucosidase (GAA). We present three cases with different clinical symptomatology and treated with enzyme replacement therapy (ERT) with positive evolution. CASE REPORTS: Case 1: three-month old male, with weakness and rejecting meals; mild hepatomegaly, discrete macroglossia and muscular hypotony; and increased muscular enzymes. Case 2: five-month old male, with delayed motor development, severe neurosensory deafness, and respiratory disorder of difficult evolution; muscular hypotony; and mild increase in creatine kinase. Case 3: 22-year old male, with progressive dyspnea, with history of increased creatine kinase and transaminases, and hypercholesterolemia. He suffered from severe respiratory failure requiring endotraqueal intubation Muscular biopsy showed glycogen storage suggestive of Pompe disease. In the three cases, the EMG showed a characteristic pattern with pseudomyotonic discharges and the deficiency in GAA was confirmed in lymphocytes. One single mutation was observed in one case and two in the other two cases. Every patient received ERT showing a favorable evolution; with disappearance of cardiac disorders in case 1, improvement in motor development in both infants and no longer need for mechanical ventilation in case 3. CONCLUSION: Pompe disease has a wide variability in clinical expression. ERT achieves a good response, especially in infant forms of the disease. The survival of treated patients with these Pompe disease forms will allow knowing further the course of the disease. PMID- 26503318 TI - [Oxytocin in the treatment of the social deficits associated to autism spectrum disorders]. AB - INTRODUCTION: The recent involvement of oxytocin in social behavior of animals and humans has motivated the study of its effects on the social behavior of individuals with autism spectrum disorders (ASD). AIMS: To review the current state of oxytocin studies concerning its therapeutic potential in treating social deficits of the ASD population, and to establish likely future directions to be taken by the studies in this field. DEVELOPMENT: Some studies have linked oxytocin to the pathophysiology of autistic disorders. Most studies that have administered oxytocin (mainly with intranasal administration of 24 IU) to ASD subjects have shown significant improvements in their social performance with acceptable safety parameters. However, there is controversial data as the outcome measures are widely dispersed, the samples are reduced and heterogeneous, and the treatment durations are different. The limitations related to the lack of understanding of the oxytocin's action mechanisms and the symptomatic heterogeneity of ASD are hampering progress towards the establishment of oxytocin as a treatment of ASD patients. Recent studies suggest the investigation of the combination of the oxytocin treatment with social skills training, and the enhancement of endogenous secretion of oxytocin. CONCLUSION: The effects of oxytocin are promising regarding the treatment of social deficits in ASD individuals. Future studies should aim to facilitate understanding of the oxytocin's ways of action and to establish the optimal treatment regime. PMID- 26503319 TI - [Transient neurological deficit secondary to left-side stylocarotid syndrome]. PMID- 26503320 TI - [The value of ultrasounds in the detection of lingual fasciculations]. PMID- 26503321 TI - Burning mouth syndrome secondary to pregabaline in a patient with mild frontal lobes atrophy. PMID- 26503323 TI - A new questionnaire for measuring quality of life - the Stark QoL. AB - OBJECTIVE: The Stark questionnaire measures health-related quality of life (QoL) using pictures almost exclusively. It is supplemented by a minimum of words. It comprises a mental and a physical health component. METHODS: A German sample of n = 500 subjects, age and gender stratified, filled out the Stark Qol questionnaire along with various other questionnaires via internet. RESULTS: The physical component shows good reliability (Cronbach's alpha = McDonalds Omega = greatest lower bound = .93), the mental component can be improved (Cronbach's alpha = .63, McDonalds Omega = .72, greatest lower bound = .77). Confirmatory factor analysis shows a good fit (Bentlers CFI = .97). Construct validity was proven. CONCLUSION: The Stark QoL is a promising new development in measuring QoL, it is a short and easy to apply questionnaire. Additionally, it is particularly promising for international research. PMID- 26503324 TI - Recognition-induced forgetting is not due to category-based set size. AB - What are the consequences of accessing a visual long-term memory representation? Previous work has shown that accessing a long-term memory representation via retrieval improves memory for the targeted item and hurts memory for related items, a phenomenon called retrieval-induced forgetting. Recently we found a similar forgetting phenomenon with recognition of visual objects. Recognition induced forgetting occurs when practice recognizing an object during a two alternative forced-choice task, from a group of objects learned at the same time, leads to worse memory for objects from that group that were not practiced. An alternative explanation of this effect is that category-based set size is inducing forgetting, not recognition practice as claimed by some researchers. This alternative explanation is possible because during recognition practice subjects make old-new judgments in a two-alternative forced-choice task, and are thus exposed to more objects from practiced categories, potentially inducing forgetting due to set-size. Herein I pitted the category-based set size hypothesis against the recognition-induced forgetting hypothesis. To this end, I parametrically manipulated the amount of practice objects received in the recognition-induced forgetting paradigm. If forgetting is due to category-based set size, then the magnitude of forgetting of related objects will increase as the number of practice trials increases. If forgetting is recognition induced, the set size of exemplars from any given category should not be predictive of memory for practiced objects. Consistent with this latter hypothesis, additional practice systematically improved memory for practiced objects, but did not systematically affect forgetting of related objects. These results firmly establish that recognition practice induces forgetting of related memories. Future directions and important real-world applications of using recognition to access our visual memories of previously encountered objects are discussed. PMID- 26503322 TI - Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward. AB - Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate-putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices. PMID- 26503325 TI - E2-EPF UCP regulates stability and functions of missense mutant pVHL via ubiquitin mediated proteolysis. AB - BACKGROUND: Missense mutation of VHL gene is frequently detected in type 2 VHL diseases and linked to a wide range of pVHL functions and stability. Certain mutant pVHLs retain ability to regulate HIFs but lose their function by instability. In this case, regulating of degradation of mutant pVHLs, can be postulated as therapeutic method. METHOD: The stability and cellular function of missense mutant pVHLs were determine in HEK293T transient expressing cell and 786 O stable cell line. Ubiquitination assay of mutant VHL proteins was performed in vitro system. Anticancer effect of adenovirus mediated shUCP expressing was evaluated using ex vivo mouse xenograft assay. RESULTS: Three VHL missense mutants (V155A, L158Q, and Q164R) are directly ubiquitinated by E2-EPF UCP (UCP) in vitro. Mutant pVHLs are more unstable than wild type in cell. Missense mutant pVHLs interact with UCP directly in both in vitro and cellular systems. Lacking all of lysine residues of pVHL result in resistance to ubiquitination thereby increase its stability. Missense mutant pVHLs maintained the function of E3 ligase to ubiquitinate HIF-1alpha in vitro. In cells expressing mutant pVHLs, Glut-1 and VEGF were relatively upregulated compared to their levels in cells expressing wild-type. Depletion of UCP restored missense mutant pVHLs levels and inhibited cell growth. Adenovirus-mediated shUCP RNA delivery inhibited tumor growth in ex vivo mouse xenograft model. CONCLUSION: These data suggest that targeting of UCP can be one of therapeutic method in type 2 VHL disease caused by unstable but functional missense mutant pVHL. PMID- 26503326 TI - Love, faith and hope - a secondary analysis of prostate cancer survivors and their partners. AB - BACKGROUND: Men's experience of recovery from treatment for prostate cancer has been extensively researched with reports highlighting the physical side effects of treatments such as erectile dysfunction and incontinence. The psychological, emotional and spiritual burden of prostate cancer on men and their partners has received far less attention. DESIGN: In this study, a secondary thematic analysis of data from a series of separate but related qualitative studies with prostate cancer survivors and their partners was conducted to further explore themes of love, hope and faith within this population. RESULTS: This study identified unresolved needs related to the emotive concepts of love, hope and faith. The findings from this study can be employed to refine psychosocial assessments of men with prostate cancer, and provide a more comprehensive understanding of prostate cancer survivors supportive care needs. PMID- 26503327 TI - Vitamin D fortification and seasonality of birth in type 1 diabetic cases: D-tect study. AB - Fortification of margarine with vitamin D was mandatory in Denmark during 1961 1985. The aim of the study was to assess whether gestational and early infancy exposure to margarine fortification was associated with seasonality of birth in Danish type 1 diabetes (T1D) patients. The risks of T1D in Danes born during various exposure periods around margarine fortification termination in 1985 were analyzed. As expected, the T1D hazards in males unexposed to margarine fortification and born in spring were higher than in males born in autumn: relevant hazard ratios (95% confidence intervals) in various exposure groups ranged from 1.74 (1.112/2.708) to 37.43 (1.804/776.558). There were no indications of seasonality of birth in males exposed to fortification, nor in both exposed and unexposed females. The study suggests that early life exposure to low-dose vitamin D from fortified food eliminates seasonality of birth in T1D male patients. Further studies are required to investigate the identified gender differences. PMID- 26503328 TI - Factors associated with the incidence of revision total knee arthroplasty in Korea between 2007 and 2012: an analysis of the National Claim Registry. AB - BACKGROUND: The number of revision total knee arthroplasties (TKAs) in Asian countries is projected to increase with the rapid growth of primary TKA. We investigated the factors associated with the incidence of revision TKA using a nationally representative database. METHODS: Data collected by the Health Insurance Review Agency of Korea, from 260,068 TKA patients between 2007 and 2012, were used to estimate the incidence rate and cumulative incidence of revision TKA according to age, gender, and hospital TKA and prosthesis manufacturer volume. Age, hospital, and manufacturer volume were categorized into three groups. The incidence rates and cumulative incidences of revision TKA were computed by combining age and gender, and by combining hospital and prosthesis manufacturer volume. RESULTS: Incidence rates per 100,000 person-years were as follows: 1) by age: < 65 years, 447.2; 65-74 years, 363.7; >= 75 years, 270.9, 2) by gender: male, 537.8; female, 346.1; 3) by hospital volume (procedures/year): < 20, 536.9; 20-199, 432.3; >= 200, 300.1; and 4) by manufacturer volume (prostheses/year): < 1500, 772.3; 1500-3999, 453.9; >= 4000, 345.6. The revision TKA incidence rate in young males was significantly higher compared to that in elderly females. The difference in cumulative incidence, between hospitals with an annual volume of < 20 procedures and those with a volume of 20-199 procedures, was reduced for manufacturers with an annual volume of >= 4000. Similarly, the difference in cumulative incidence between manufacturers with an annual volume of <1500 prostheses and those with a volume of 1500-3999 prostheses was reduced in hospitals with an annual volume of >= 200. CONCLUSION: Revision TKA incidence varied according to age, gender, and hospital and manufacturer volume. This data could inform clinical decisions and healthcare strategies. PMID- 26503329 TI - Building a Stronger System for Tracking Nutrition-Sensitive Spending: A Methodology and Estimate of Global Spending for Nutrition-Sensitive Foreign Aid. AB - BACKGROUND: There is growing awareness that the necessary solutions for improving nutrition outcomes are multisectorial. As such, investments are increasingly directed toward "nutrition-sensitive" approaches that not only address an underlying or basic determinant of nutrition but also seek to achieve an explicit nutrition goal or outcome. Understanding how and where official development assistance (ODA) for nutrition is invested remains an important but complex challenge, as development projects components vary in their application to nutrition outcomes. Currently, no systematic method exists for tracking nutrition sensitive ODA. OBJECTIVE: To develop a methodology for classifying and tracking nutrition-sensitive ODA and to produce estimates of the amount of nutrition sensitive aid received by countries with a high burden of undernutrition. METHODS: We analyzed all financial flows reported to the Organization for Economic Co-Operation and Development's Development Assistance Committee Creditor Reporting Service in 2010 to estimate these investments. We assessed the relationships between national stunting prevalence, stunting burden, under-5 mortality, and the amount of nutrition-specific and nutrition-sensitive ODA. RESULTS: We estimate that, in 2010, a total of $379.4 million (M) US dollars (USD) was committed to nutrition-specific projects and programs of which 25 designated beneficiaries (countries and regions) accounted for nearly 85% ($320 M). A total of $1.79 billion (B) was committed to nutrition-sensitive spending, of which the top 25 countries/regions accounted for $1.4 B (82%). Nine categories of development activities accounted for 75% of nutrition-sensitive spending, led by Reproductive Health Care (30.4%), Food Aid/Food Security Programs (14.1%), Emergency Food Aid (13.2%), and Basic Health Care (5.0%). Multivariate linear regression models indicate that the amount of nutrition-sensitive (P = .001) and total nutrition ODA was significantly predicted by stunting prevalence (P = .001). The size of the total population of stunted children significantly predicted the amount of nutrition-specific ODA (P < .001). CONCLUSION: The recipient profile of nutrition-specific and nutrition-sensitive ODA is related but distinct. Nutrition indicators are associated with the level of nutrition related ODA commitments to recipient countries. A reliable estimate of nutrition spending is critical for effective planning by both donors and recipients and key for success, as the global development community recommits to a new round of goals to address the interrelated causes of undernutrition in low-income countries. PMID- 26503330 TI - Development of porcine tetraploid somatic cell nuclear transfer embryos is influenced by oocyte nuclei. AB - Cloning efficiency in mammalian systems remains low because reprogramming of donor cells is frequently incomplete. Nuclear factors in the oocyte are removed by enucleation, and this removal may adversely affect reprogramming efficiency. Here, we investigated the role of porcine oocyte nuclear factors during reprogramming. We introduced somatic cell nuclei into intact MII oocytes to establish tetraploid somatic cell nuclear transfer (SCNT) embryos containing both somatic nuclei and oocyte nuclei. We then examined the influence of the oocyte nucleus on tetraploid SCNT embryo development by assessing characteristics including pronucleus formation, cleavage rate, and blastocyst formation. Overall, tetraploid SCNT embryos have a higher developmental competence than do standard diploid SCNT embryos. Therefore, we have established an embryonic model in which a fetal fibroblast nucleus and an oocyte metaphase II plate coexist. Tetraploid SCNT represents a new research platform that is potentially useful for examining interactions between donor nuclei and oocyte nuclei. This platform should facilitate further understanding of the roles played by nuclear factors during reprogramming. PMID- 26503331 TI - Whole Exome Sequencing Identifies Frequent Somatic Mutations in Cell-Cell Adhesion Genes in Chinese Patients with Lung Squamous Cell Carcinoma. AB - Lung squamous cell carcinoma (SQCC) accounts for about 30% of all lung cancer cases. Understanding of mutational landscape for this subtype of lung cancer in Chinese patients is currently limited. We performed whole exome sequencing in samples from 100 patients with lung SQCCs to search for somatic mutations and the subsequent target capture sequencing in another 98 samples for validation. We identified 20 significantly mutated genes, including TP53, CDH10, NFE2L2 and PTEN. Pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76%, oxidative stress response in 21%, and phosphatidylinositol-3-OH kinase in 36% of the tested tumor samples. Mutations of Chromatin regulatory factor genes were identified at a lower frequency. In functional assays, we observed that knockdown of CDH10 promoted cell proliferation, soft-agar colony formation, cell migration and cell invasion, and overexpression of CDH10 inhibited cell proliferation. This mutational landscape of lung SQCC in Chinese patients improves our current understanding of lung carcinogenesis, early diagnosis and personalized therapy. PMID- 26503333 TI - Quantitative iTRAQ-based proteomic analysis of phosphoproteins and ABA-regulated phosphoproteins in maize leaves under osmotic stress. AB - Abscisic acid (ABA) regulates various developmental processes and stress responses in plants. Protein phosphorylation/dephosphorylation is a central post translational modification (PTM) in ABA signaling. However, the phosphoproteins regulated by ABA under osmotic stress remain unknown in maize. In this study, maize mutant vp5 (deficient in ABA biosynthesis) and wild-type Vp5 were used to identify leaf phosphoproteins regulated by ABA under osmotic stress. Up to 4052 phosphopeptides, corresponding to 3017 phosphoproteins, were identified by Multiplex run iTRAQ-based quantitative proteomic and LC-MS/MS methods. The 4052 phosphopeptides contained 5723 non-redundant phosphosites; 512 phosphopeptides (379 in Vp5, 133 in vp5) displayed at least a 1.5-fold change of phosphorylation level under osmotic stress, of which 40 shared common in both genotypes and were differentially regulated by ABA. Comparing the signaling pathways involved in vp5 response to osmotic stress and those that in Vp5, indicated that ABA played a vital role in regulating these pathways related to mRNA synthesis, protein synthesis and photosynthesis. Our results provide a comprehensive dataset of phosphopeptides and phosphorylation sites regulated by ABA in maize adaptation to osmotic stress. This will be helpful to elucidate the ABA-mediate mechanism of maize endurance to drought by triggering phosphorylation or dephosphorylation cascades. PMID- 26503332 TI - Retinal oxygen extraction in humans. AB - Adequate function of the retina is dependent on proper oxygen supply. In humans, the inner retina is oxygenated via the retinal circulation. We present a method to calculate total retinal oxygen extraction based on measurement of total retinal blood flow using dual-beam bidirectional Doppler optical coherence tomography and measurement of oxygen saturation by spectrophotometry. These measurements were done on 8 healthy subjects while breathing ambient room air and 100% oxygen. Total retinal blood flow was 44.3 +/- 9.0 MUl/min during baseline and decreased to 18.7 +/- 4.2 MUl/min during 100% oxygen breathing (P < 0.001) resulting in a pronounced decrease in retinal oxygen extraction from 2.33 +/- 0.51 MUl(O2)/min to 0.88 +/- 0.14 MUl(O2)/min during breathing of 100% oxygen. The method presented in this paper may have significant potential to study oxygen metabolism in hypoxic retinal diseases such as diabetic retinopathy. PMID- 26503335 TI - Security of Semi-Device-Independent Random Number Expansion Protocols. AB - Semi-device-independent random number expansion (SDI-RNE) protocols require some truly random numbers to generate fresh ones, with making no assumptions on the internal working of quantum devices except for the dimension of the Hilbert space. The generated randomness is certified by non-classical correlation in the prepare-and-measure test. Until now, the analytical relations between the amount of the generated randomness and the degree of non-classical correlation, which are crucial for evaluating the security of SDI-RNE protocols, are not clear under both the ideal condition and the practical one. In the paper, first, we give the analytical relation between the above two factors under the ideal condition. As well, we derive the analytical relation under the practical conditions, where devices' behavior is not independent and identical in each round and there exists deviation in estimating the non-classical behavior of devices. Furthermore, we choose a different randomness extractor (i.e., two-universal random function) and give the security proof. PMID- 26503334 TI - NLK functions to maintain proliferation and stemness of NSCLC and is a target of metformin. AB - OBJECTIVE: Nemo-like kinase (NLK) is an evolutionarily conserved serine/threonine kinase that regulates the activity of a wide range of signal transduction pathways. Metformin, an oral antidiabetic drug, is used for cancer prevention. However, the significance and underlying mechanism of NLK and metformin in oncogenesis has not been fully elucidated. Here, we investigate a novel role of NLK and metformin in human non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: NLK expression was analyzed in 121 NSCLCs and 92 normal lung tissue samples from benign pulmonary disease. Lentivirus vectors with NLK-shRNA were used to examine the effect of NLK on cell proliferation and tumorigenesis in vitro. Then, tumor xenograft mouse models revealed that NLK knockdown cells had a reduced ability for tumor formation compared with the control group in vivo. Multiple cell cycle regulator expression patterns induced by NLK silencing were examined by western blots in A549 cells. We also employed metformin to study its anti-cancer effects and mechanisms. Cancer stem cell property was checked by tumor sphere formation and markers including CD133, Nanog, c-Myc, and KLF4. RESULTS: Immunohistochemical (IHC) analysis revealed that NLK expression was up regulated in NSCLC cases (p < 0.001) and correlated with tumor T stage (p < 0.05). Silencing of NLK suppressed cell proliferation and tumorigenicity significantly in vitro and in vivo, which might be modulated by JUN family proteins. Furthermore, metformin selectively inhibits NLK expression and proliferation in NSCLC cells, but not immortalized noncancerous lung bronchial epithelial cells. In addition, both NLK knockdown and metformin treatment reduced the tumor sphere formation capacity and percentage of CD133+ cells. Accordingly, the expression level of stem cell markers (Nanog, c-Myc, and KLF4) were decreased significantly [corrected]. CONCLUSION: NLK is critical for cancer cell cycle progression, and tumorigenesis in NSCLC, NLK knockdown, and metformin treatment inhibit cancer cell proliferation and stemness. Metformin inhibits NLK expression and might be a potential treatment strategy for NSCLC. PMID- 26503336 TI - CMTM8 inhibits the carcinogenesis and progression of bladder cancer. AB - Bladder cancer is the most common tumor of the urinary tract. The incidence of bladder cancer has increased in the last few decades, thus novel molecular markers for early diagnosis and more efficacious treatment are urgently needed. Chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 8 (CMTM8) is downregulated in several types of cancers and is associated with tumor progression. However, CMTM8 expression has been unexplored in bladder cancer to date. Our results revealed that the expression of CMTM8 was negative in 46 of 74 (62.2%) bladder cancer samples via immunohistochemistry assay. CMTM8 downregulation was associated with advancing tumor stage and tumor grade. CMTM8 was successfully overexpressed by lentivirus in EJ and T24 cells, and the CCK-8 and Transwell assays showed that CMTM8 overexpression decreased cell proliferation, migration and invasion in vitro. In tumor xenografts upregulation of CMTM8 inhibited tumor growth and lymph node metastasis in vivo. In conclusion, overexpression of CMTM8 in bladder cancer results in reduced malignant cell growth, migration and invasion, which could make it a potential therapeutic target in the treatment of bladder cancer. PMID- 26503337 TI - Enhanced osteogenic potential of mesenchymal stem cells from cortical bone: a comparative analysis. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) hold great promise for regenerative therapies in the musculoskeletal system. Although MSCs from bone marrow (BM-MSCs) and adipose tissue (AD-MSCs) have been extensively characterized, there is still debate as to the ideal source of MSCs for tissue-engineering applications in bone repair. METHODS: MSCs were isolated from cortical bone fragments (CBF-MSCs) obtained from patients undergoing laminectomy, selected by fluorescence-activated cell sorting analysis, and tested for their potential to undergo mesodermic differentiation. CBF-MSCs were then compared with BM-MSCs and AD-MSCs for their colony-forming unit capability and osteogenic potential in both normoxia and hypoxia. After 2 and 4 weeks in inducing media, differentiation was assessed qualitatively and quantitatively by the evaluation of alkaline phosphatase (ALP) expression and mineral deposition (Von Kossa staining). Transcriptional activity of osteoblastogenesis-associated genes (Alp, RUNX2, Spp1, and Bglap) was also analyzed. RESULTS: The cortical fraction of the bone contains a subset of cells positive for MSC-associated markers and capable of tri-lineage differentiation. The hypoxic conditions were generally more effective in inducing osteogenesis for the three cell lines. However, at 2 and 4 weeks, greater calcium deposition and ALP expression were observed in both hypoxic and normoxic conditions in CBF-MSCs compared with AD- and BM-MSCs. These functional observations were further corroborated by gene expression analysis, which showed a significant upregulation of Bglap, Alp, and Spp1, with a 22.50 (+/-4.55)-, 46.56 (+/-7.4)-, 71.46 (+/ 4.16)-fold increase compared with their uninduced counterparts. CONCLUSIONS: This novel population of MSCs retains a greater biosynthetic activity in vitro, which was found increased in hypoxic conditions. The present study demonstrates that quantitative differences between MSCs retrieved from bone marrow, adipose, and the cortical portion of the bone with respect to their osteogenic potential exist and suggests the cortical bone as suitable candidate to use for orthopedic tissue engineering and regenerative medicine. PMID- 26503339 TI - Effect of taurine on intestinal recovery following intestinal ischemia reperfusion injury in a rat. AB - PURPOSE: Taurine (TAU) is a sulfur-containing amino acid that is involved in a diverse array of biological and physiological functions, including bile salt conjugation, osmoregulation, membrane stabilization, calcium modulation, anti oxidation, and immunomodulation. Several studies have established that treatment with TAU significantly protects cerebral, cardiac and testicular injury from ischemia-reperfusion (IR). The purpose of the present study was to examine the effect of TAU on intestinal recovery and enterocyte turnover after intestinal IR injury in rats. METHODS: Male Sprague-Dawley rats were divided into four experimental groups: (1) Sham rats that underwent laparotomy, (2) Sham-TAU rats that underwent laparotomy and were treated with intraperitoneal (IP) TAU (250 mg/kg); (3) IR-rats that underwent occlusion of both superior mesenteric artery and portal vein for 30 min followed by 48 h of reperfusion, and (4) IR-TAU rats that underwent IR and were treated with IP TAU (250 mg/kg) immediately before abdominal closure. Intestinal structural changes, Park's injury score, enterocyte proliferation and enterocyte apoptosis were determined 24 h following IR. The expression of Bax, Bcl-2, p-ERK and caspase-3 in the intestinal mucosa was determined using Western blot and immunohistochemistry. RESULTS: Treatment with TAU resulted in a significant decrease in Park's injury score compared to IR animals. IR-TAU rats also demonstrated a significant increase in mucosal weight in jejunum and ileum, villus height in jejunum and ileum and crypt depth in ileum compared to IR animals. IR-TAU rats also experienced significantly lower apoptotic indices in jejunum and ileum which was accompanied by a higher Bcl 2/Bax ratio compared to IR animals. CONCLUSIONS: Treatment with taurine prevents gut mucosal damage and inhibits intestinal epithelial cell apoptosis following intestinal IR in a rat. PMID- 26503340 TI - The role of the BMP signaling cascade in regulation of stem cell activity following massive small bowel resection in a rat. AB - PURPOSE: Bone morphogenetic proteins (BMPs) are a group of growth factors that are implicated in intestinal growth, morphogenesis, differentiation, and homeostasis. The role of the BMP signaling cascade in stimulation of cell proliferation after massive small bowel resection is unknown. The purpose of this study was to evaluate the role of BMP signaling during intestinal adaptation in a rat model of short bowel syndrome (SBS). METHODS: Male rats were divided into two groups: Sham rats underwent bowel transection and SBS rats underwent a 75 % bowel resection. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined 2 weeks after operation. Illumina's Digital Gene Expression analysis was used to determine the BMP signaling gene expression profiling. BMP-related genes and protein expression were determined using real time PCR, Western blotting and immunohistochemistry. RESULTS: From the total number of 20,000 probes, 8 genes related to BMP signaling were investigated. From these genes, five genes were found to be up-regulated in jejunum (BMP1-10 %, BMP2 twofold increase, BMP3-10 %, BMP2R-12 % and STAT3-28 %) and four genes to be up regulated in ileum (BMP1-16 %, BMP2-27 %, BMP3-10 %, and STAT3-20 %) in SBS vs sham animals with a relative change in gene expression level of 10 % or more. SBS rats also demonstrated a significant increase in BMP2 and STAT3 mRNA and protein levels (determined by real-time PCR and Western blot) compared to control animals. CONCLUSION: Two weeks following massive bowel resection in rats, the BMP signaling pathway is stimulated. BMP signaling may serve as an important mediator of reciprocal interactions between the epithelium and the underlying mesenchymal stroma during intestinal adaptation following massive bowel resection in a rat. PMID- 26503341 TI - Caffeine 7-N-demethylation and C-8-oxidation mediated by liver microsomal cytochrome P450 enzymes in common marmosets. AB - 1. 3-N-Demethylation of caffeine (1,3,7-trimethylxanthine) is mediated by human cytochrome P450 1A2, whereas 7-N-demethylation and C-8-hydroxylation are reportedly catalyzed by monkey P450 2C9 and rat P450 1A2, respectively. 2. Roles of marmoset P450 enzymes in caffeine oxidation were investigated using nine marmoset liver microsomes and 14 recombinantly expressed marmoset P450 enzymes. 3. Predominant caffeine 7-N-demethylation and C-8-hydroxylation activities in marmoset liver microsomes were moderately (r = 0.78, p < 0.05) and highly (r = 0.82, p < 0.01) correlated with midazolam 1'-hydroxylation activities, respectively, while the former was not strongly affected by ketoconazole or alpha naphthoflavone. 4. Caffeine C-8-hydroxylation in liver microsomes was inhibited by ketoconazole and activated by alpha-naphthoflavone, suggesting main involvements of P450 3As. 5. Recombinant marmoset P450 3As had high Vmax/Km values for C-8-hydroxylation, comparable to Km values for marmoset liver microsomes. Marmoset P450 1As efficiently mediated caffeine 3-N-demethylation and C-8-hydroxylation with apparently lower Km values than those of liver microsomes. 6. These results collectively suggest highly active marmoset P450 3A enzymes toward caffeine 8-hydorxylaiton and involvement of multiple P450 isoforms including P450 1A in caffeine 7-N- and 3-N-demethylations in marmoset livers. Marmoset P450s have slightly different properties to human or monkey P450s regarding caffeine metabolic pathways. PMID- 26503343 TI - Continuous Cognitive Tasks Improve Postural Control Compared to Discrete Cognitive Tasks. AB - Research suggests that postural control synergies are sensitive to cognitive manipulations; however, the impact of different types of cognitive tasks on postural control remains inconclusive. The authors examined the effect of discrete and continuous tasks on postural control. Sixteen healthy young adults (M age = 22.7 +/- 2.2 years) stood with feet together on a force platform while performing randomly assigned discrete and continuous cognitive tasks. Results demonstrated marked improvements in the area of 95% confidence ellipse and the standard deviation of the center of pressure in the anterior-posterior and medial lateral directions for continuous compared to discrete tasks. This reinforces the notion that continuous tasks are sufficient in providing less opportunity to consciously attend to postural control, thereby facilitating automatic postural control. PMID- 26503342 TI - Comparative transcriptomic analysis of immune responses of the migratory locust, Locusta migratoria, to challenge by the fungal insect pathogen, Metarhizium acridum. AB - BACKGROUND: The migratory locust, Locusta migratoria manilensis, is an immensely destructive agricultural pest that forms a devastating and voracious gregarious phase. The fungal insect pathogen, Metarhizium acridum, is a specialized locust pathogen that has been used as a potent mycoinsecticide for locust control. Little, however, is known about locust immune tissue, i.e. fat body and hemocyte, responses to challenge by this fungus. METHODS: RNA-seq (RNA sequencing) technology were applied to comparatively examine the different roles of locust fat body and hemocytes, the two major contributors to the insect immune response, in defense against M. acridum. According to the sequence identity to homologies of other species explored immune response genes, immune related unigenes were screened in all transcriptome wide range from locust and the differential expressed genes were identified in these two tissues, respectively. RESULTS: Analysis of differentially expressed locust genes revealed 4660 and 138 up regulated, and 1647 and 23 down-regulated transcripts in the fat body and hemocytes, respectively after inoculation with M. acridum spores. GO (Gene Ontology) enrichment analysis showed membrane biogenesis related proteins and effector proteins significantly differentially expressed in hemocytes, while the expression of energy metabolism and development related transcripts were enriched in the fat body after fungal infection. A total of 470 immune related unigenes were identified, including members of the three major insect immune pathways, i.e. Toll, Imd (immune deficiency) and JAK/STAT (janus kinase/signal transduction and activator of transcription). Of these, 58 and three were differentially expressed in the insect fat body or hemocytes after infection, respectively. Of differential expressed transcripts post challenge, 43 were found in both the fat body and hemocytes, including the LmLys4 lysozyme, representing a microbial cell wall targeting enzyme. CONCLUSIONS: These data indicate that locust fat body and hemocytes adopt different strategies in response to M. acridum infection. Fat body gene expression after M. acridum challenge appears to function mainly through activation of innate immune related genes, energy metabolism and development related genes. Hemocyte responses attempt to limit fungal infection primarily through regulation of membrane related genes and activation of cellular immune responses and release of humoral immune factors. PMID- 26503344 TI - Relative Infestation Level and Sensitivity of Grapevine Cultivars to the Leafhopper Empoasca vitis (Hemiptera: Cicadellidae). AB - The leafhopper Empoasca vitis (Gothe) (Hemiptera: Cicadellidae) feeds on veins of grapevine leaves, mainly on the phloem, causing physiological injury, color change and drying of leaf margins, yield and sugar content reduction. The relative infestation level (i.e., the probability that a plant is attacked by herbivores) of E. vitis on different grapevine cultivars and their sensitivity (i.e., the incidence of symptoms expression in response to herbivore feeding or other stimuli) to this pest were studied over four years in two vineyards located in northeastern Italy. Some cultivars (e.g., Carmenere and Sauvignon Blanc) were usually more infested than others (e.g., Cabernet Sauvignon and Pinot Gris), although some differences were observed among years and sites. The sensitivity varied among cultivars, i.e., some of them showed more symptoms than expected on the basis of infestation levels (e.g., Carmenere and Merlot), in contrast with others (e.g., Rhine Riesling and Chardonnay). Information obtained can be used within the framework of integrated pest management in vineyards. Action thresholds should differ on the basis of sensitivity. Sampling must first be carried out on the most susceptible cultivar and, if the action threshold is exceeded, it should be extended to the remaining cultivars based on their decreasing relative infestation level. PMID- 26503345 TI - Economic Benefit for Cuban Laurel Thrips Biological Control. AB - The Cuban laurel thrips, Gynaikothrips ficorum Marchal (Thysanoptera: Phlaeothripidae), is a critical insect pest of Ficus microcarpa in California urban landscapes and production nurseries. Female thrips feed and oviposit on young Ficus leaves, causing the expanding leaves to fold or curl into a discolored leaf gall. There have been attempts to establish specialist predator natural enemies of the thrips, but no success has been reported. We resampled the same areas in 2013-2014 where we had released Montandoniola confusa (= morguesi) Streito and Matocq (Hemiptera: Anthocoridae) in southern California in 1995 but had been unable to recover individuals in 1997-1998. Thrips galls were significantly reduced in all three of the locations in the recent samples compared with the earlier samples. M. confusa was present in all locations and appears to be providing successful biological control. The value of the biological control, the difference between street trees in good foliage condition and trees with poor foliage, was $58,766,166. If thrips damage reduced the foliage to very poor condition, the value of biological control was $73,402,683. Total cost for the project was $61,830. The benefit accrued for every dollar spent on the biological control of the thrips ranged from $950, if the foliage was in poor condition, to $1,187, if the foliage was in very poor condition. The value of urban forest is often underappreciated. Economic analyses that clearly demonstrate the very substantial rates of return on investment in successful biological control in urban forests provide compelling arguments for supporting future efforts. PMID- 26503346 TI - Non-O1, non-O139 Vibrio cholerae bacteremic skin and soft tissue infections. AB - BACKGROUND: Non-O1, non-O139 Vibrio cholerae can cause sporadic cases of gastroenteritis and extra-intestinal invasive infections, following exposure to contaminated seawater or freshwater or after consumption of raw seafood. Bacteremic infections with skin and soft tissue manifestations are uncommon and in most cases are associated with liver cirrhosis, haematologic malignancies, diabetes mellitus and other immunosuppressed conditions. METHODS: The medical literature was reviewed and we found 47 published cases of non-O1, non-O139 Vibrio cholerae bacteremic skin and soft tissue infections. A fatal case of bacteremia with bullous cellulitis in a 43-year-old patient with liver cirrhosis is described, which is the first reported in Greece. RESULTS: From January 1974 to May 2015, a total of 48 patients with non-O1, non-O139 Vibrio cholerae bacteremia with skin and soft tissue infections were reported. Males predominated. Liver cirrhosis, chronic liver disease and alcohol abuse were common comorbidities. The soft tissue lesions most commonly described were localised cellulitis, with or without bullous and haemorrhagic lesions (66.7%), while necrotising fasciitis was more rare (29.2%). Of the 48 patients with non O1, non-O139 V. cholerae bacteremic skin and soft tissue infections, 20 (41.7%) died despite treatment. CONCLUSION: Although rarely encountered, non-O1, non-O139 Vibrio cholerae should be included in the differential diagnosis of bacteremic skin and soft tissue infections in patients with underlying illnesses and epidemiologic risk factors. Timely and appropriate antibiotic and surgical treatments are important in the management of the infection. PMID- 26503347 TI - Efficacy and safety of low-dose SoluMatrix meloxicam in the treatment of osteoarthritis pain: a 12-week, phase 3 study. AB - OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as meloxicam are commonly used to treat osteoarthritis (OA) but are associated with potentially serious dose-related adverse events (AEs). SoluMatrix meloxicam has been developed with the goal of enabling effective treatment at low doses. This phase 3 study evaluated the efficacy and safety of low-dose SoluMatrix meloxicam capsules 5 mg and 10 mg administered once daily for 12 weeks in patients with OA related pain. RESEARCH DESIGN AND METHODS: This randomized, double-blind study enrolled patients >=40 years of age with confirmed hip or knee OA (Kellgren Lawrence grade II-III) who were chronic users of NSAIDs and/or acetaminophen for OA pain and had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale mean scores >=40 mm. Eligible patients experienced an OA pain flare (defined as a >=15 mm increase in the WOMAC pain subscale score) following discontinuation of NSAIDs/acetaminophen. Patients were randomized to receive once-daily SoluMatrix meloxicam 5 mg or 10 mg, or placebo for 12 weeks. ClinicalTrials.gov identifier: NCT01787188. MAIN OUTCOME MEASURES: The primary outcome measure was the mean change from baseline in WOMAC pain subscale score at week 12. RESULTS: Low-dose SoluMatrix meloxicam 5 mg (-36.52 [2.49]; P = 0.0005) and 10 mg (-34.41 [2.68]; P = 0.0059) once-daily treatment significantly reduced the mean (standard error) WOMAC pain subscale score from baseline at week 12 compared with placebo (-25.68 [2.64]). Patients treated with SoluMatrix meloxicam 5 mg or 10 mg reported significantly greater improvements in total WOMAC score and in WOMAC stiffness and function subscale scores at 12 weeks compared with placebo. The most common AEs in the combined low-dose SoluMatrix meloxicam group were headache, diarrhea, nausea, osteoarthritis, and urinary tract infection. CONCLUSIONS: Low-dose SoluMatrix meloxicam may have a potential role as a new therapeutic option for the management of OA-related pain. PMID- 26503348 TI - Discrepancies Between Self-Reported Usual Sleep Duration and Objective Measures of Total Sleep Time in Treatment-Seeking Overweight and Obese Individuals. AB - To examine the agreement between actigraphy-estimated and self-reported sleep duration in obese individuals, we had 63 treatment seeking overweight/obese participants complete the Pittsburgh Sleep Quality Index (PSQI) and report sleep duration for weekends and weekdays, and compared their reports to 7 days of actigraphy. Actigraph total sleep time correlated r = .20-.31 with self-report and the absolute discrepancy averaged 51-54 minutes. Only 20 of the 32 subjects (62.5%) classified as short sleepers (<7 hours/night) by actigraphy were similarly classified by self-report. Poor sleep quality was associated with greater absolute discrepancy between actigraphy and self-report. The weak correlations between self-report and actigraph should be considered in future efforts to increase sleep duration to promote weight loss in obese individuals. PMID- 26503350 TI - Mechanism of the anti-hypertensive property of the naturally occurring phenolic, malabaricone C in DOCA-salt rats. AB - In this study, we studied whether chronic oral administration of the natural antioxidant, malabaricone C (mal C) can reduce blood pressure (BP) and attenuate cardio-vascular remodeling in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The dose of mal C for its anti-hypertensive action was optimized by measuring the systolic BP (SBP). DOCA-salt rats showed very high SBP, associated with organ hypertrophy, collagen depositions, and inflammatory infiltrations in cardiac and aortic sections, reduced plasma total antioxidant status and NO level, and increased levels of TBARS, PGI2 as well as vasoconstrictors (AVP, Big ET, and ET-1). DOCA-salt also reduced smooth muscle- and endothelium-dependent vascular relaxation in rats. Mal C reversed all these changes of the DOCA-salt rats and improved their vascular reactivity. Mal C exerts anti-hypertensive property in DOCA-salt rats by reducing oxidative stress and organ hypertrophy, and improving endothelial and vascular functions. Given that mal C has appreciable natural abundance and is non-toxic to rodents, further studies would help in establishing its medicinal potential against hypertension. PMID- 26503349 TI - A p16-Ki-67-HMB45 immunohistochemistry scoring system as an ancillary diagnostic tool in the diagnosis of melanoma. AB - BACKGROUND: Melanoma is a skin cancer which treatment requires early diagnosis and large surgical removal. The histopathological diagnosis of a melanocytic tumour is sometimes difficult between a benign nevus and a malignant melanoma. We built an immunomarker-based score to differentiate nevi from melanomas. METHODS: Two independent sets of 308 (first set) and 62 (validation set) formalin-fixed and paraffin embedded tumour samples were studied using p16-Ki-67 and HMB45 MelanA dual-staining immunohistochemistry. RESULTS: In the first set of tumours, high Ki-67 index, low to null p16 immunohistochemistry and absence of HMB45 immunohistochemistry gradient were more frequent in melanomas (156 primary tumours and 78 metastases) than in nevi (74 tumours). Nevertheless, none of these single parameters was able to differentiate all primary melanomas from all nevi. We built a scoring system based on the addition of semi-quantitative scorings of Ki-67 (0: <2%; 1:2-5%; 2:6-10%, 3:11-20%; 4:>20%) and p16 (0:>50% stained cells; 1:11-50%; 2:1-10%; 3:0%) and HMB45 staining (0: gradient present; 1: doubtful/inconclusive gradient; 2: gradient absent). A p16-Ki-67-HMB45 total score from 0 to 9 permitted to classify nevi (score <4) and primary melanomas (score >=4) with a sensitivity of 97.4% and a specificity of 97.3% in the first set of tumours. Sensibility and specificity of 100 % were obtained in a second set (validation set) of 62 tumours (46 melanomas and 16 nevi). The total scoring also allowed analyzing 11 difficult or initially misdiagnosed tumours in our files. CONCLUSIONS: We propose a valuable triple p16-Ki-67-HMB45 immunohistochemistry scoring system to help pathologists in the differential diagnosis of melanomas and nevi. PMID- 26503351 TI - Newly Developed Chronic Conditions and Changes in Health-Related Quality of Life in Postmenopausal Women. AB - OBJECTIVES: To prospectively assess the effects of newly developed chronic conditions on changes in health-related quality of life (HRQoL) in postmenopausal women. DESIGN: Prospective cohort study. SETTING: Forty clinical centers in the United States. PARTICIPANTS: Women aged 50 to 79 enrolled in the Women's Health Initiative Observational Study during 1993-98 (N = 75,198). MEASUREMENTS: Onset of seven chronic conditions (hypertension, heart disease, stroke, cancer, osteoporosis, diabetes mellitus, arthritis), HRQoL based on the Medical Outcomes Study 36-item Short Form survey (SF-36), and change in HRQoL from baseline to Year 3 in scores on the Physical (PCS) and Mental (MCS) Component Summary of the SF-36. RESULTS: Each of the seven chronic conditions was statistically significantly associated with HRQoL for physical and mental health. Women with incident stroke had the greatest decline in HRQoL for physical and mental health (PCS: 10.2, 95% confidence interval (CI) = 8.3-12.1; MCS: 10.4, 95% CI = 8.8 12.1), which exceeded minimal clinically important differences (MCID). Having more new chronic conditions was associated with greater decrease in HRQoL. Declines in HRQoL in women with two or more chronic conditions exceeded MCID. Those with heart disease and stroke had the largest decline in physical health, and those with stroke and arthritis had the greatest decline in mental health. For all conditions other than stroke and diabetes mellitus, the more recently a condition was diagnosed, the greater the decrease in PCS. For stroke and cancer, a similar pattern was observed for MCS. CONCLUSION: The more conditions a woman developed, the greater reduction in HRQoL she experienced. Declines in HRQoL in women with stroke, cancer, and some combinations exceeded MCID. Findings from this study might lead to more-effective patient-centered approaches to health care for women with multiple chronic conditions. PMID- 26503352 TI - Conscientiousness increases efficiency of multicomponent behavior. AB - Many everyday situations require the flexible interruption and changing of different actions to achieve a goal. Several strategies can be applied to do so, but those requiring high levels of cognitive control seem to confer an efficiency (speed) advantage in situations requiring multi-component behavior. However, it is elusive in how far personality traits affect performance in such situations. Given that top-down control is an important aspect of personality and furthermore correlates with conscientiousness, N = 163 participants completed the NEO-FFI and performed an experimental (stop-change) paradigm assessing multicomponent behavior. Applying mathematical constraints to the behavioral data, we estimated the processing strategy of each individual. The results show that multicomponent behavior is selectively affected by conscientiousness which explained approximately 19% of the measured inter-individual behavioral variance. Conscientiousness should hence be seen as a major personality dimension modulating multicomponent behavior. Highly conscientious people showed a more effective, step-by-step processing strategy of different actions necessary to achieve a goal. In situations with simultaneous requirements, this strategy equipped them with an efficiency (speed) advantage towards individuals with lower conscientiousness. In sum, the results show that strategies and the efficiency with which people cope with situations requiring multicomponent behavior are strongly influenced by their personality. PMID- 26503353 TI - Complex patterns of cis-regulatory polymorphisms in ebony underlie standing pigmentation variation in Drosophila melanogaster. AB - Pigmentation traits in adult Drosophila melanogaster were used in this study to investigate how phenotypic variations in continuous ecological traits can be maintained in a natural population. First, pigmentation variation in the adult female was measured at seven different body positions in 20 strains from the Drosophila melanogaster Genetic Reference Panel (DGRP) originating from a natural population in North Carolina. Next, to assess the contributions of cis-regulatory polymorphisms of the genes involved in the melanin biosynthesis pathway, allele specific expression levels of four genes were quantified by amplicon sequencing using a 454 GS Junior. Among those genes, ebony was significantly associated with pigmentation intensity of the thoracic segment. Detailed sequence analysis of the gene regulatory regions of this gene indicated that many different functional cis regulatory alleles are segregating in the population and that variations outside the core enhancer element could potentially play important roles in the regulation of gene expression. In addition, a slight enrichment of distantly associated SNP pairs was observed in the ~10 kb cis-regulatory region of ebony, which suggested the presence of interacting elements scattered across the region. In contrast, sequence analysis in the core cis-regulatory region of tan indicated that SNPs within the region are significantly associated with allele-specific expression level of this gene. Collectively, the data suggest that the underlying genetic differences in the cis-regulatory regions that control intraspecific pigmentation variation can be more complex than those of interspecific pigmentation trait differences, where causal genetic changes are typically confined to modular enhancer elements. PMID- 26503354 TI - Endobronchial neurofibroma. PMID- 26503355 TI - Drug-Induced Vasculitis: New Insights and a Changing Lineup of Suspects. AB - An increasing number of therapeutic agents have been associated with a vasculitic syndrome. This usually involves small vessels, primarily capillaries, venules, and arterioles in leukocytoclastic vasculitis, small-vessel disease similar to an antineutrophil cytoplasmic antibody-related vasculitis, or mid-sized muscular arteries in a polyarteritis-like picture. Antineutrophil cytoplasmic antibodies are present in many cases of vasculitis regardless of the size of the vessel involved. Monoclonal antibodies used to treat many autoimmune disorders have become the most common agents associated with drug-induced vasculitis. Important advances in epigenetics, genetics, and neutrophil apoptosis are providing new insights into the pathogenesis of both drug-induced vasculitis and idiopathic vasculitis. Although management has not changed significantly in the past few years where withdrawal of the offending agent is the primary intervention, increasing awareness of drug-induced vasculitis can lead to earlier diagnosis and prevention of severe organ damage and fatalities. PMID- 26503357 TI - Using Computational Approaches to Improve Risk-Stratified Patient Management: Rationale and Methods. AB - BACKGROUND: Chronic diseases affect 52% of Americans and consume 86% of health care costs. A small portion of patients consume most health care resources and costs. More intensive patient management strategies, such as case management, are usually more effective at improving health outcomes, but are also more expensive. To use limited resources efficiently, risk stratification is commonly used in managing patients with chronic diseases, such as asthma, chronic obstructive pulmonary disease, diabetes, and heart disease. Patients are stratified based on predicted risk with patients at higher risk given more intensive care. The current risk-stratified patient management approach has 3 limitations resulting in many patients not receiving the most appropriate care, unnecessarily increased costs, and suboptimal health outcomes. First, using predictive models for health outcomes and costs is currently the best method for forecasting individual patient's risk. Yet, accuracy of predictive models remains poor causing many patients to be misstratified. If an existing model were used to identify candidate patients for case management, enrollment would miss more than half of those who would benefit most, but include others unlikely to benefit, wasting limited resources. Existing models have been developed under the assumption that patient characteristics primarily influence outcomes and costs, leaving physician characteristics out of the models. In reality, both characteristics have an impact. Second, existing models usually give neither an explanation why a particular patient is predicted to be at high risk nor suggestions on interventions tailored to the patient's specific case. As a result, many high risk patients miss some suitable interventions. Third, thresholds for risk strata are suboptimal and determined heuristically with no quality guarantee. OBJECTIVE: The purpose of this study is to improve risk-stratified patient management so that more patients will receive the most appropriate care. METHODS: This study will (1) combine patient, physician profile, and environmental variable features to improve prediction accuracy of individual patient health outcomes and costs; (2) develop the first algorithm to explain prediction results and suggest tailored interventions; (3) develop the first algorithm to compute optimal thresholds for risk strata; and (4) conduct simulations to estimate outcomes of risk-stratified patient management for various configurations. The proposed techniques will be demonstrated on a test case of asthma patients. RESULTS: We are currently in the process of extracting clinical and administrative data from an integrated health care system's enterprise data warehouse. We plan to complete this study in approximately 5 years. CONCLUSIONS: Methods developed in this study will help transform risk-stratified patient management for better clinical outcomes, higher patient satisfaction and quality of life, reduced health care use, and lower costs. PMID- 26503358 TI - Caveolin-1 mediates chemoresistance in cisplatin-resistant ovarian cancer cells by targeting apoptosis through the Notch-1/Akt/NF-kappaB pathway. AB - Caveolin-1 (Cav-1), a family of ubiquitously expressed oligomeric structural proteins in many mammalian cells, has been shown to be an effective regulator of tumorigenesis. Recent studies have indicated that Cav-1 can promote resistance to chemotherapy in a variety of tumors. However, the regulation of Cav-1 on chemoresistance in ovarian cancer is still unknown. In the present study, the mRNA and protein expression level was investigated by RT-PCR and western blot analysis, respectively, and the 50% inhibitory concentration (IC50) value was measured by MTT assay. The protein expression level of P-glycoprotein (P-gp), Notch-1, p-Akt and p-NF-kappaB p65 were detected using western blot analysis and the apoptotic ratio was determined using the Annexin V-FITC/PI detection kit. The results showed that the mRNA and protein expression levels of Cav-1 were significantly higher in SKOV3/DDP and A2780/DDP than in SKOV3 and A2780, respectively. Knockdown of Cav-1 significantly decreased the IC50 value in cisplatin-resistant cells. The protein expression level of P-gp in SKOV3/DDP and A2780/DDP was significant higher than SKOV3 and A2780, respectively, and had no correlation with the Cav-1 siRNA transfection. The apoptotic ratio induced by cisplatin in normal ovarian cancer cells was higher than cisplatin-resistant ovarian cancer cells, and knockdown of Cav-1 could significantly enhance cisplatin induced cell apoptosis. Furthermore, knockdown of Cav-1 was also able to significantly downregulate the protein expression level of Notch-1, p-Akt and p-NF-kappaB p65 in cisplatin-resistant ovarian cancer cells. Overexpression of Cav-1 upregulated the IC50 value, but under the effect of Notch-1 siRNA or LY294002 or PDTC, the IC50 value was markedly decreased. Our results suggested that Cav-1 can promote the chemoresistance of ovarian cancer by targeting apoptosis through the Notch-1/Akt/NF-kappaB pathway. PMID- 26503359 TI - Gram-stain-based antimicrobial selection reduces cost and overuse compared with Japanese guidelines. AB - BACKGROUND: The Gram stain has been used as an essential tool for antimicrobial stewardship in our hospital since the 1970s. The objective of this study was to clarify the difference in the targeted therapies selected based on the Gram stain and simulated empirical therapies based on the antimicrobial guidelines used in Japan. METHODS: A referral-hospital-based prospective descriptive study was undertaken between May 2013 and April 2014 in Okinawa, Japan. All enrolled patients were adults who had been admitted to the Division of Infectious Diseases through the emergency room with suspected bacterial infection at one of three sites: respiratory system, urinary tract, or skin and soft tissues. The study outcomes were the types and effectiveness of the antibiotics initially selected, and their total costs. RESULTS: Two hundred eight patients were enrolled in the study. The median age was 80 years. A significantly narrower spectrum of antibiotics was selected based on the Gram stain than was selected based on the Japanese guidelines. The treatments based on the Gram stain and on the guidelines were estimated to be equally highly effective. The total cost of antimicrobials after Gram-stain testing was less than half the cost after the guidelines were followed. CONCLUSIONS: Compared with the Japanese guidelines, the Gram stain dramatically reduced the overuse of broad-spectrum antimicrobials without affecting the effectiveness of the treatment. Drug costs were reduced by half when the Gram stain was used. The Gram stain should be included in all antimicrobial stewardship programs. PMID- 26503360 TI - Exposure to Schmallenberg virus in Irish sheep in 2013. PMID- 26503361 TI - Cerebral oxygen saturation after multiple perioperative influential factors predicts the occurrence of postoperative cognitive dysfunction. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) is a frequent complication in elderly patients undergoing major non-cardiac surgery, but its etiology is still unclear. Cerebral oxygen saturation (ScO2) represents the balance of cerebral oxygen supply and demand. The aim of present study was to evaluate the relationship between perioperative ScO2 and POCD, and to verify the hypothesis that the value of ScO2 after multiple perioperative influential factors could predict POCD in elderly patients undergoing total knee arthroplasty (TKA). METHODS: Seventy eight Patients aged more than 65 years undergoing elective TKA with intrathecal anesthesia were enrolled. Cognitive functions were assessed one day before and 6 days after surgery, and POCD were defined according to ISPOCD. Demographics were recorded. Perioperative ScO2, blood pressure (BP), blood gas analysis and other clinical data were monitored and recorded, then the decrease of ScO2, BP and PaO2 after influential factors were calculated. RESULTS: POCD occurred in 15 patients (19.2 %). BP decreased after anesthesia induction and tourniquet deflation, and PaO2 decreased after cement implantation was higher in POCD group. ScO2 of POCD group is significantly lower than non-POCD group (P < 0.05), and the absolute value and percentage decrease of ScO2 became significant between two groups after multiple influential factors. ScO2 after all influential factors (anesthesia induction, cement implantation and tourniquet deflation) had the best predictive performance for POCD (AUC = 0.742), and the optimal threshold was 66.5 %. CONCLUSIONS: Perioperative ScO2 of patients with POCD is lower than patients without POCD. ScO2 after multiple perioperative influential factors could be an effective predictor for POCD, which reveal an important role of ScO2 decrease in the development of POCD and provide possible treatment target. PMID- 26503362 TI - What are the social and individual factors that are associated with undergoing male circumcision as an HIV prevention strategy? A mixed methods study in Malawi. AB - BACKGROUND: There is compelling evidence that medical male circumcision (MMC) decreases transmission of HIV. Nevertheless, the uptake of MMC is generally very low. Understanding the characteristics of individuals who choose MMC could inform future strategies for scaling-up MMC. The main objective of this study was to explore the social and individual characteristics of men that are associated with the uptake of circumcision as an HIV prevention strategy. METHODS: A mixed methods study, comprising a cross-sectional survey and an exploratory qualitative study, was conducted in Malawi. A total number of 1644 men, of at least 18 years old, participated in this study. A multistage sampling approach was used in the survey while convenience sampling was adopted in the qualitative study. Descriptive statistics, bivariate analyses and multivariable logistic regression were performed to analyze the cross-sectional data and thematic content approach to analyze the qualitative data. RESULTS: Individuals who chose MMC were more likely to be unemployed (AOR=1.65; 95% CI: 1.30-2.11), to be married (AOR=3.16; 95% CI: 2.21-4.52) and to have had exposure to MMC promotions (AOR=1.81; 95% CI: 1.41-2.33). They were also more likely to reside in rural areas (AOR=1.85; 95% CI: 1.44-2.38), to perceive themselves as more vulnerable to HIV (AOR=1.60; 95% CI: 1.19-2.15) and to be more knowledgeable about the benefits of MMC (AOR=1.51; 95% CI: 1.16-1.97). CONCLUSIONS: The findings suggest that men who had certain social and individual characteristics (for example better knowledge of the benefits of MMC, greater perceived vulnerability to HIV, married and unemployed) were more likely to choose circumcision as a prevention strategy for HIV than those who lacked those characteristics. Strategies for increasing MMC take-up should recognize the current social/individual landscape of MMC uptake and ensure that deliberate efforts targeting marginalized categories of men are available. PMID- 26503364 TI - Silver(I)-Catalyzed Enantioselective Desymmetrization of Cyclopentenediones: Access to Highly Functionalized Bicyclic Pyrrolidines. AB - A highly enantioselective desymmetrization of prochiral cyclopentenediones via Ag(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylide has been developed successfully. The methodology performs well over a broad scope of substrates, which provides facile access to a series of highly functionalized bicyclic pyrrolidine/cyclopentane derivatives in good to high yields with excellent stereoselectivities. PMID- 26503363 TI - Transmission indices and microfilariae prevalence in human population prior to mass drug administration with ivermectin and albendazole in the Gomoa District of Ghana. AB - BACKGROUND: The Lymphatic Filariasis Elimination Programme in Ghana involves annual mass drug administration (MDA) of ivermectin and albendazole to persons living in endemic areas. This is repeated annually for 4-6 years to span across the reproductive lifespan of adult worms. In order to stimulate participation of community members in the MDA programme, this study was carried out to understand local views on transmission, management and prevention of the disease. The study also presents baseline transmission indices and microfilariae prevalence in the human population in eight endemic communities of coastal Ghana prior to the MDA. METHODS: A descriptive survey was carried out to explore perceptions on causes, treatment and prevention of lymphatic filariasis. Perceptions on community participation in disease control programmes were also assessed. After participants were selected by cluster sampling and 100 MUl of blood sampled from each individual and examined for mf microfilariae. A similar volume of blood was used to determine the presence of circulating filarial antigen. Mosquitoes were collected simultaneously at all sites by human landing catches for 4 days per month over a six-month period. All Anopheles mosquitoes were dissected and examined for the larval stages of the parasite following which molecular identification of both vector and parasite was done. RESULTS: Eight hundred and four persons were interviewed, of which 284 (32.9%; CI 31.1-34.5) acknowledged elephantiasis and hydrocoele as health related issues in the communities. Thirty three people (3.8%; CI 2.1-5.5) thought sleeping under bed net could help prevent elephantiasis. Microfilariae prevalence was 4.6% (43/941) whiles 8.7% (75/861) were positive for circulating filarial antigen. A total of 17,784 mosquitoes were collected, majority (55.8%) of which were Anopheles followed by Culex species (40%). Monthly biting rates ranged between 311 and 6116 bites/person for all the eight communities together. Annual transmission potential values for An. gambiae s.s. and An. funestus were 311.35 and 153.50 respectively. CONCLUSION: Even though the highest mf density among inhabitants was recorded in a community that had the lowest Anopheles density with Culex species constituting 95% of all mosquitoes collected, Anopheles gambiae s.s. and An. funestus remained the main vectors. PMID- 26503365 TI - Stochastic Optical Reconstruction Microscopy Imaging of Microtubule Arrays in Intact Arabidopsis thaliana Seedling Roots. AB - Super-resolution fluorescence microscopy has generated tremendous success in revealing detailed subcellular structures in animal cells. However, its application to plant cell biology remains extremely limited due to numerous technical challenges, including the generally high fluorescence background of plant cells and the presence of the cell wall. In the current study, stochastic optical reconstruction microscopy (STORM) imaging of intact Arabidopsis thaliana seedling roots with a spatial resolution of 20-40 nm was demonstrated. Using the super-resolution images, the spatial organization of cortical microtubules in different parts of a whole Arabidopsis root tip was analyzed quantitatively, and the results show the dramatic differences in the density and spatial organization of cortical microtubules in cells of different differentiation stages or types. The method developed can be applied to plant cell biological processes, including imaging of additional elements of the cytoskeleton, organelle substructure, and membrane domains. PMID- 26503367 TI - Predicting On-Road Driving Performance and Safety in Cognitively Impaired Older Adults. AB - OBJECTIVES: To evaluate the ability to predict on-road driving in cognitively impaired older drivers. DESIGN: Cross-sectional observational study. SETTING: Laboratory tests and on-road assessment. PARTICIPANTS: Drivers with cognitive impairment (Mini-Mental State Examination score < 26, N = 43, mean age 74). MEASUREMENTS: The Roadwise Review, a hazard perception test (HPT), several vision tests, and a standardized 18-km driving assessment. RESULTS: The best prediction of passing or failing the on-road test was a combination of the HPT, leg strength, visual acuity, visual search and working memory, and number of medications taken (Nagelkerke coefficient of determination = 0.40). The sensitivity of the model was 71%, and the specificity was 75%. CONCLUSION: Further research is required to determine how these tests may be used or combined with other data (e.g., medical history) to assess fitness to drive of cognitively impaired older drivers. PMID- 26503366 TI - Cost-effectiveness analysis of anidulafungin for the treatment of candidaemia and other forms of invasive candidiasis. AB - BACKGROUND: Candidaemia and other forms of invasive candidiasis (C/IC) in the intensive care unit are challenging conditions that are associated with high rates of mortality. New guidelines from the European Society for Clinical Microbiology and Infectious Diseases strongly recommend echinocandins for the first-line treatment of C/IC. Here, a cost-effectiveness model was developed from the United Kingdom perspective to examine the costs and outcomes of antifungal treatment for C/IC based on the European Society for Clinical Microbiology and Infectious Diseases guidelines. METHODS: Costs and treatment outcomes with the echinocandin anidulafungin were compared with those for caspofungin, micafungin and fluconazole. The model included non-neutropenic patients aged >=16 years with confirmed C/IC who were receiving intravenous first-line treatment. Patients were categorised as either a clinical success or failure (patients with persistent/breakthrough infection); successfully treated patients switched to oral therapy, while patients categorised as clinical failures switched to a different antifungal class. Other inputs were all-cause mortality at 6 weeks, costs of treatment-related adverse events and other medical resource utilisation costs. Resource use was derived from the published literature and from discussion with clinical experts. Drug-acquisition/administration costs were taken from standard United Kingdom costing sources. RESULTS: The model indicated that first line anidulafungin could be considered cost-effective versus fluconazole (incremental cost-effectiveness ratio L813 per life-year gained) for the treatment of C/IC. Anidulafungin was cost-saving versus caspofungin and micafungin due to lower total costs and a higher rate of survival combined with a higher probability of clinical success. DISCUSSION: European Society for Clinical Microbiology and Infectious Diseases guidelines recommend echinocandins for the first-line treatment of C/IC; our model indicated that anidulafungin marries clinical effectiveness and cost-effectiveness. CONCLUSIONS: From the United Kingdom perspective, anidulafungin was cost-effective compared with fluconazole for the treatment of C/IC and was cost-saving versus the other echinocandins. PMID- 26503368 TI - The shadows of a ghost: a survey of canine leishmaniasis in Presidente Prudente and its spatial dispersion in the western region of Sao Paulo state, an emerging focus of visceral leishmaniasis in Brazil. AB - BACKGROUND: Visceral leishmaniasis is an emerging zoonosis and its geographic distribution is restricted to tropical and temperate regions. Most of the individuals infected in Latin America are in Brazil. Despite the control measures that have been adopted, the disease is spreading throughout new regions of the country. Domestic dogs are involved in the transmission cycle and are considered to be the main epidemiologic reservoir of Leishmania infantum (syn. L. chagasi). Our aim was to determine the prevalence of canine leishmaniasis (CL) and Ehrlichiosis infection in Presidente Prudente as well as the spatial dispersion of the disease in the western region of Sao Paulo state. METHODS: Dogs underwent clinical examination and symptoms related to CL were recorded. Anti- Leishmania antibodies were detected using ELISA, rK39-immunocromatographic tests (DPP), and an indirect fluorescent antibody test (IFAT). Anti-E. canis antibodies were detected by IFAT. A follow-up was conducted in dogs that were positive in the ELISA at the baseline study. Data on the spatial distribution of L. longipalpis and CL in Sao Paulo state were obtained from Brazilian public health agencies. RESULTS: Serum samples from 4547 dogs were analyzed. The seroprevalence of CL was 11.2% by ELISA and 4.5 % by IFAT. In the follow-up, seroprevalence was 32.9% by ELISA, 15.3% by IFAT, 11.8 % by DPP test, and 66.5% for E. canis. There was a significant positive association between Leishmania and E. canis infection (P < 0.0001). In the follow-up, clinical examinations revealed symptoms compatible with CL in 33.5% of the dogs. L. longipalpis was found in 24 and CL in 15 counties of the Presidente Prudente mesoregion. The dispersion route followed the west frontier of Sao Paulo state toward Parana state. CONCLUSIONS: Low CL and high ehrlichiosis prevalence rates were found in Presidente Prudente city. This emerging focus of CL is moving through the western region of Sao Paulo state toward the border of Parana state. Integrated actions to fight the vector, parasites, infected dogs, and humans are needed to monitor the disease and implement strategies for epidemiologic control. PMID- 26503369 TI - Cyclometalated Ir(III) complexes of deprotonated N-methylbipyridinium ligands: effects of quaternised N centre position on luminescence. AB - Six new tricationic Ir(III) complexes of cyclometalating ligands derived from 1 methyl-2-(2'-pyridyl)pyridinium or 1-methyl-4-(2'-pyridyl)pyridinium are described. These complexes of the form [Ir(III)(C^N)2(N^N)](3+) (C^N = cyclometalating ligand; N^N = alpha-diimine) have been isolated and characterised as their PF6(-) and Cl(-) salts. Four of the PF6(-) salts have been studied by X ray crystallography, and structures have been obtained also for two complex salts containing MeCN and Cl(-) or two Cl(-) ligands instead of N^N. The influence of the position of the quaternised N atom in C^N and the substituents on N^N on the electronic/optical properties are compared with those of the analogous complexes where C^N derives from 1-methyl-3-(2'-pyridyl)pyridinium (B. J. Coe, et al., Dalton Trans., 2015, 44, 15420). Voltammetric studies reveal one irreversible oxidation and multiple reduction processes which are mostly reversible. The new complexes show intramolecular charge-transfer absorptions between 350 and 450 nm, and exhibit bright green luminescence, with lambdamax values in the range 508-530 nm in both aqueous and acetonitrile solutions. In order to gain insights into the factors that govern the emission properties, density functional theory (DFT) and time-dependent DFT calculations have been carried out. The results confirm that the emission arises largely from triplet excited states of the C^N ligand ((3)LC), with some triplet metal-to-ligand charge-transfer ((3)MLCT) contributions. PMID- 26503370 TI - Training community mental health staff in Guangzhou, China: evaluation of the effect of a new training model. AB - BACKGROUND: Increasing numbers of people with mental disorders receive services at primary care in China. The aims of this study are to evaluate impact of a new training course and supervision for community mental health staff to enhance their levels of mental health knowledge and to reduce their stigmatization toward people with mental illness. METHODS: A total of 77 community mental health staff from eight regions in Guangzhou in China were recruited for the study.4 regions were randomly allocated to the new training model group, and 4 to the old training model group. Levels of mental health knowledge were measured by purpose made assessment schedule and by the Mental Health Knowledge Schedule (MAKS). Stigma was evaluated by the Mental Illness: Clinicians' Attitudes Scale (MICA) and the Reported and Intended Behavior Scale (RIBS). Evaluation questionnaires were given at the beginning of course, at the end, and at 6 month and at 12 month follow-up. RESULTS: After the training period, the 6-month, and the 12-month, knowledge scores of the intervention group were higher than the control group. At 6-month and 12-month follow-up, means scores of MAKS of the intervention group increased more than the control group (both p < 0.05) when age, sex, marriage status, title and time were controlled for. At 6-month follow-up, means scores of MICA of the intervention group decreased more than that of the control group (p < 0.01). At after-training, at 6-months, and at 12-months, mean scores of RIBS of the intervention group increased more than the control (p < 0.01, p < 0.001, p < 0.001) when age, sex, marriage status, title and time were controlled for. CONCLUSIONS: Compared with the traditional training course and supervision, the new course improved community mental health staff knowledge of mental disorders, improving their attitudes toward people with mental disorder, and increasing their willingness to have contact with people with mental disorder. PMID- 26503371 TI - CytoSpectre: a tool for spectral analysis of oriented structures on cellular and subcellular levels. AB - BACKGROUND: Orientation and the degree of isotropy are important in many biological systems such as the sarcomeres of cardiomyocytes and other fibrillar structures of the cytoskeleton. Image based analysis of such structures is often limited to qualitative evaluation by human experts, hampering the throughput, repeatability and reliability of the analyses. Software tools are not readily available for this purpose and the existing methods typically rely at least partly on manual operation. RESULTS: We developed CytoSpectre, an automated tool based on spectral analysis, allowing the quantification of orientation and also size distributions of structures in microscopy images. CytoSpectre utilizes the Fourier transform to estimate the power spectrum of an image and based on the spectrum, computes parameter values describing, among others, the mean orientation, isotropy and size of target structures. The analysis can be further tuned to focus on targets of particular size at cellular or subcellular scales. The software can be operated via a graphical user interface without any programming expertise. We analyzed the performance of CytoSpectre by extensive simulations using artificial images, by benchmarking against FibrilTool and by comparisons with manual measurements performed for real images by a panel of human experts. The software was found to be tolerant against noise and blurring and superior to FibrilTool when analyzing realistic targets with degraded image quality. The analysis of real images indicated general good agreement between computational and manual results while also revealing notable expert-to-expert variation. Moreover, the experiment showed that CytoSpectre can handle images obtained of different cell types using different microscopy techniques. Finally, we studied the effect of mechanical stretching on cardiomyocytes to demonstrate the software in an actual experiment and observed changes in cellular orientation in response to stretching. CONCLUSIONS: CytoSpectre, a versatile, easy-to-use software tool for spectral analysis of microscopy images was developed. The tool is compatible with most 2D images and can be used to analyze targets at different scales. We expect the tool to be useful in diverse applications dealing with structures whose orientation and size distributions are of interest. While designed for the biological field, the software could also be useful in non biological applications. PMID- 26503372 TI - Hierarchically micro-patterned nanofibrous scaffolds with a nanosized bio-glass surface for accelerating wound healing. AB - A composite scaffold with a controlled micro-pattern, nano-sized fiber matrix and surface-modified nanobioglass component was successfully prepared for skin wound healing by combining the patterning electrospinning with pulsed laser deposition strategies, and the hierarchical micro/nano structures and nano-sized bioglass in the scaffolds could synergistically improve the efficiency and re epithelialization of wound healing. PMID- 26503374 TI - Aging-related Increase in Rho Kinase Activity in the Nigral Region Is Counteracted by Physical Exercise. AB - Abnormal activation of the RhoA/Rho kinase (ROCK) pathway plays a pivotal role in neuroinflammatory and pro-oxidative responses, axonal retraction, and apoptosis. We observed increased expression of RhoA, ROCK II, and ROCK activity in the brain of aged rats, particularly in the substantia nigra. Increased ROCK activity may enhance major mechanisms responsible for aging-related neurodegeneration, thus representing a major factor in the vulnerability of dopaminergic neurons to damage. We also observed that physical exercise decreased ROCK activation in aged rats. This suggests that decreased ROCK activation plays an important role in the neuroprotective effects of exercise observed in several previous studies. Furthermore, the present results suggest that ROCK inhibitors may constitute an effective neuroprotective strategy against aging-related risk of dopaminergic degeneration and possibly against other aging-related neurodegenerative processes. PMID- 26503375 TI - Associations of Computed Tomography-Based Trunk Muscle Size and Density With Balance and Falls in Older Adults. AB - BACKGROUND: Deficits in balance and muscle function are important risk factors for falls in older adults. Aging is associated with significant declines in muscle size and density, but associations of trunk muscle size and density with balance and falls in older adults have not been previously examined. METHODS: Trunk muscle size (cross-sectional area) and attenuation (a measure of tissue density) were measured in computed tomography scans (at the L2 lumbar level) in a cohort of older adults (mean +/- SD age of 81.9+/-6.4) residing in independent living communities. Outcome measures were postural sway measured during quiet standing and Short Physical Performance Battery (SPPB) at baseline, and falls reported by participants for up to 3 years after baseline measurements. RESULTS: Higher muscle density was associated with reduced postural sway, particularly sway velocities, in both men and women, and better Short Physical Performance Battery score in women, but was not associated with falls. Larger muscle size was associated with increased postural sway in men and women and with increased likelihood of falling in men. CONCLUSIONS: The results suggest that balance depends more on muscle quality than on the size of the muscle. The unexpected finding that larger muscle size was associated with increased postural sway and increased fall risk requires further investigation, but highlights the importance of factors besides muscle size in muscle function in older adults. PMID- 26503376 TI - Adherence to Dietary Guidelines and Successful Aging Over 10 Years. AB - BACKGROUND: We aimed to prospectively examine the relationship between overall diet quality (reflecting adherence to dietary guidelines) and successful aging in a population-based cohort of older adults. METHODS: In this population-based cohort study, we analyzed 10-year follow-up data from 1,609 adults aged 49 years and older, who were free of cancer, coronary artery disease, and stroke at the baseline and who had complete dietary data. Dietary data were collected using a semiquantitative food frequency questionnaire. Total diet scores (TDS) were allocated for intake of selected food groups and nutrients for each participant as described in the national dietary guidelines. Higher scores indicated closer adherence to dietary guidelines. Successful aging was defined as the absence of disability, depressive symptoms, cognitive impairment, respiratory symptoms, and chronic diseases (cancer, coronary artery disease, and stroke). RESULTS: At 10 year follow-up, 610 (37.9%) participants had died and 249 (15.5%) participants aged successfully. After multivariable adjustment, each 1-unit increase in TDS at baseline was associated with a 8% increased odds of successful aging 10 years later, odds ratio 1.08 (95% confidence interval 1.00-1.15). Participants in the highest (high adherence to dietary guidelines) versus lowest quartile (poor adherence to guidelines) of TDS at baseline had 58% higher odds of successful aging after 10 years, odds ratio 1.58 (95% confidence interval 1.02-2.46). CONCLUSIONS: Greater compliance with recommended national dietary guidelines (higher diet quality) was associated with an increased likelihood of successful aging, as determined through a multidomain approach. PMID- 26503378 TI - Clinical Effectiveness of Mupirocin for Preventing Staphylococcus aureus Infections in Nonsurgical Settings: A Meta-analysis. AB - A systematic literature review and meta-analysis was performed to identify effectiveness of mupirocin decolonization in prevention of Staphylococcus aureus infections, among nonsurgical settings. Of the 15 662 unique studies identified up to August 2015, 13 randomized controlled trials, 22 quasi-experimental studies, and 1 retrospective cohort study met the inclusion criteria. Studies were excluded if mupirocin was not used for decolonization, there was no control group, or the study was conducted in an outbreak setting. The crude risk ratios were pooled (cpRR) using a random-effects model. We observed substantial heterogeneity among included studies (I(2) = 80%). Mupirocin was observed to reduce the risk for S. aureus infections by 59% (cpRR, 0.41; 95% confidence interval [CI], .36-.48) and 40% (cpRR, 0.60; 95% CI, .46-.79) in both dialysis and nondialysis settings, respectively. Mupirocin decolonization was protective against S. aureus infections among both dialysis and adult intensive care patients. Future studies are needed in other settings such as long-term care and pediatrics. PMID- 26503377 TI - VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy. AB - Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu5 NAM, N,N-diethyl-5 ((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu5 NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [(3)H]inositol phosphate (IP) accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu5-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu5 occupancy in the central nervous system (CNS) with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu5 NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu5 and demonstrate an excellent CNS occupancy efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models. PMID- 26503380 TI - Strong odd-frequency correlations in fully gapped Zeeman-split superconductors. AB - It is now well established that at a superconductor/ferromagnet (S/F) interface an unconventional superconducting state arises in which the pairing is odd frequency. The hallmark signature of this superconducting state is generally understood to be an enhancement of the electronic density of states (DoS) at subgap energies close to the S/F interface. However, here we show that an odd frequency state can be present even if the DoS is fully gapped. As an example, we show that this is the case in the pioneering S/FI (where FI is a insulating ferromagnet) tunneling experiments of Meservey and Tedrow, and we derive a generalized analytical criterium to describe the effect of odd-frequency pairing on the DoS. Finally, we propose a simple experiment in which odd-frequency pairing in a Zeeman-split superconductor can be unambiguously detected via the application of an external magnetic field. PMID- 26503379 TI - Moderate Sustained Virologic Response Rates With 6-Week Combination Directly Acting Anti-Hepatitis C Virus Therapy in Patients With Advanced Liver Disease. AB - BACKGROUND: Treatment of genotype 1 hepatitis C virus (HCV) infection with combination directly acting antivirals (DAA) for 8-24 weeks is associated with high rates of sustained virologic response (SVR). We previously demonstrated that adding a third DAA to ledipasvir and sofosbuvir (LDV/SOF) can result in high SVR rates in patients without cirrhosis. In this study, we investigated whether a similar regimen would yield equivalent rates of cure in patients with advanced liver fibrosis. METHODS: Fifty patients were enrolled at the Clinical Research Center of the National Institutes of Health and associated healthcare centers. Enrollment and follow-up data from April 2014 to June 2015 are reported here. Eligible participants were aged >=18 years, had chronic HCV genotype 1 infection (serum HCV RNA >=2000 IU/mL), and stage 3-4 liver fibrosis. HCV RNA was measured using a reverse-transcription polymerase chain reaction assay. RESULTS: Of patients treated with LDV, SOF, and the NS3/4A protease inhibitor GS-9451 for 6 weeks, 76% (38 of 50; 95% confidence interval, 60%-85%) had SVR achieved 12 weeks after the end of treatment. There was no statistically significant difference in treatment efficacy between treatment-naive patients (72%, 18 of 25) and those with treatment experience (80%; 20 of 25) (P = .51). Overall, 11 patients (22%) experienced virologic relapse, and 1 (2%) was lost to follow-up at 4 weeks after treatment. No serious adverse events, discontinuations, or deaths were associated with this regimen. CONCLUSIONS: Adding a third DAA to LDV/SOF may result in a moderate SVR rate, lower than that observed in patients without cirrhosis. Significant liver fibrosis remains an impediment to achieving SVR with short duration DAA therapy. CHINESE CLINICAL TRIALS REGISTRATION: CT01805882. PMID- 26503381 TI - Correction. PMID- 26503382 TI - How GPs value guidelines applied to patients with multimorbidity: a qualitative study. AB - OBJECTIVES: To explore and describe the value general practitioner (GPs) attribute to medical guidelines when they are applied to patients with multimorbidity, and to describe which benefits GPs experience from guideline adherence in these patients. Also, we aimed to identify limitations from guideline adherence in patients with multimorbidity, as perceived by GPs, and to describe their empirical solutions to manage these obstacles. DESIGN: Focus group study with purposive sampling of participants. Focus groups were guided by an experienced moderator who used an interview guide. Interviews were transcribed verbatim. Data analysis was performed by two researchers using the constant comparison analysis technique and field notes were used in the analysis. Data collection proceeded until saturation was reached. SETTING: Primary care, eastern part of The Netherlands. PARTICIPANTS: Dutch GPs, heterogeneous in age, sex and academic involvement. RESULTS: 25 GPs participated in five focus groups. GPs valued the guidance that guidelines provide, but experienced shortcomings when they were applied to patients with multimorbidity. Taking these patients' personal circumstances into account was regarded as important, but it was impeded by a consistent focus on guideline adherence. Preventative measures were considered less appropriate in (elderly) patients with multimorbidity. Moreover, the applicability of guidelines in patients with multimorbidity was questioned. GPs' extensive practical experience with managing multimorbidity resulted in several empirical solutions, for example, using their 'common sense' to respond to the perceived shortcomings. CONCLUSIONS: GPs applying guidelines for patients with multimorbidity integrate patient-specific factors in their medical decisions, aiming for patient-centred solutions. Such integration of clinical experience and best evidence is required to practise evidence-based medicine. More flexibility in pay-for-performance systems is needed to facilitate this integration. Several improvements in guideline reporting are necessary to enhance the applicability of guidelines in patients with multimorbidity. PMID- 26503383 TI - Pilot study of a cluster randomised trial of a guided e-learning health promotion intervention for managers based on management standards for the improvement of employee well-being and reduction of sickness absence: GEM Study. AB - OBJECTIVES: To investigate the feasibility of recruitment, adherence and likely effectiveness of an e-learning intervention for managers to improve employees' well-being and reduce sickness absence. METHODS: The GEM Study (guided e-learning for managers) was a mixed methods pilot cluster randomised trial. Employees were recruited from four mental health services prior to randomising three services to the intervention and one to no-intervention control. Intervention managers received a facilitated e-learning programme on work-related stress. Main outcomes were Warwick Edinburgh Mental Wellbeing Scale (WEMWBS), 12-item GHQ and sickness absence <21 days from human resources. 35 in-depth interviews were undertaken with key informants, managers and employees, and additional observational data collected. RESULTS: 424 of 649 (65%) employees approached consented, of whom 350 provided WEMWBS at baseline and 284 at follow-up; 41 managers out of 49 were recruited from the three intervention clusters and 21 adhered to the intervention. WEMWBS scores fell from 50.4-49.0 in the control (n=59) and 51.0 49.9 in the intervention (n=225), giving an intervention effect of 0.5 (95% CI 3.2 to 4.2). 120/225 intervention employees had a manager who was adherent to the intervention. HR data on sickness absence (n=393) showed no evidence of effect. There were no effects on GHQ score or work characteristics. Online quiz knowledge scores increased across the study in adherent managers. Qualitative data provided a rich picture of the context within which the intervention took place and managers' and employees' experiences of it. CONCLUSIONS: A small benefit from the intervention on well-being was explained by the mixed methods approach, implicating a low intervention uptake by managers and suggesting that education alone may be insufficient. A full trial of the guided e-learning intervention and economic evaluation is feasible. Future research should include more active encouragement of manager motivation, reflection and behaviour change. TRIAL REGISTRATION NUMBER: ISRCTN58661009. PMID- 26503384 TI - Prevalence of vestibular dysfunction and associated factors in South Korea. AB - OBJECTIVE: To report the nationwide prevalence of dizziness and vestibular dysfunction in the Korean population and determine the associated factors. DESIGN: Cross-sectional analysis of a nationwide health survey. METHODS: We obtained data from the 2009 to 2010 Korea National Health and Nutrition Examination Surveys, which were cross-sectional surveys of the South Korean civilian, non-institutionalised population aged 40 years and older (N=3267). A field survey team performed interviews and physical examinations. Structured questionnaires were handed out and balance function tests using the modified Romberg test of standing balance on firm and compliant support surfaces were performed on participants. Failure on the modified Romberg test was regarded to indicate vestibular dysfunction. RESULTS: The prevalence of dizziness during the past year was 16.70% (95% CI 14.65% to 18.76%). The presence of vestibular dysfunction was noted in 1.84% (95% CI 1.18% to 2.51%). In addition, the prevalence of experiencing falls and positional dizziness were 1.46% (95% CI 0.87% to 2.06%) and 1.73% (95% CI 1.17% to 2.29%), respectively. Multivariable analysis revealed that dizziness was associated with increased age, female gender, hearing loss and stress. Vestibular dysfunction was associated with increased age, history of dizziness and hearing loss. CONCLUSIONS: Vertigo and dizziness are the greatest contributors to the burden of disability in the aged population. Screening for dizziness and vestibular dysfunction, and management of associated factors might be important for improving compromised quality of life due to postural imbalance caused by vestibular problems. PMID- 26503385 TI - Qualitative analysis of vendor discussions on the procurement of Computerised Physician Order Entry and Clinical Decision Support systems in hospitals. AB - OBJECTIVES: We studied vendor perspectives about potentially transferable lessons for implementing organisations and national strategies surrounding the procurement of Computerised Physician Order Entry (CPOE)/Clinical Decision Support (CDS) systems in English hospitals. SETTING: Data were collected from digitally audio-recorded discussions from a series of CPOE/CDS vendor round-table discussions held in September 2014 in the UK. PARTICIPANTS: Nine participants, representing 6 key vendors operating in the UK, attended. The discussions were transcribed verbatim and thematically analysed. RESULTS: Vendors reported a range of challenges surrounding the procurement and contracting processes of CPOE/CDS systems, including hospitals' inability to adequately assess their own needs and then select a suitable product, rushed procurement and implementation processes that resulted in difficulties in meaningfully engaging with vendors, as well as challenges relating to contracting leading to ambiguities in implementation roles. Consequently, relationships between system vendors and hospitals were often strained, the vendors attributing this to a lack of hospital management's appreciation of the complexities associated with implementation efforts. Future anticipated challenges included issues surrounding the standardisation of data to enable their aggregation across systems for effective secondary uses, and implementation of data exchange with providers outside the hospital. CONCLUSIONS: Our results indicate that there are significant issues surrounding capacity to procure and optimise CPOE/CDS systems among UK hospitals. There is an urgent need to encourage more synergistic and collaborative working between providers and vendors and for a more centralised support for National Health Service hospitals, which draws on a wider body of experience, including a formalised procurement framework with value-based product specifications. PMID- 26503386 TI - The Malaysian Breast Cancer Survivorship Cohort (MyBCC): a study protocol. AB - INTRODUCTION: Over recent decades, the burden of breast cancer has been increasing at an alarming rate in Asia. Prognostic research findings from Western countries may not readily be adapted to Asia, as the outcome of breast cancer depends on a multitude of factors ranging from genetic, clinical and histological predictors, to lifestyle and social predictors. The primary aim of this study is to determine the impact of lifestyle (eg, nutrition, physical activity), mental and sociocultural condition, on the overall survival and quality of life (QoL) among multiethnic Malaysian women following diagnosis of breast cancer. This study aims to advance the evidence on prognostic factors of breast cancer within the Asian setting. The findings may guide management of patients with breast cancer not only during active treatment but also during the survivorship period. METHODS: This hospital-based prospective cohort study will comprise patients with breast cancer (18 years and above), managed in the University Malaya Medical Centre (UMMC). We aim to recruit 1000 cancer survivors over a 6-year period. Data collection will occur at baseline (within 3 months of diagnosis), 6 months, and 1, 3 and 5 years following diagnosis. The primary outcomes are disease-free survival and overall survival, and secondary outcome is QoL. Factors measured are demographic and socioeconomic factors, lifestyle factors (eg, dietary intake, physical activity), anthropometry measurements (eg, height, weight, waist, hip circumference, body fat analysis), psychosocial aspects, and complementary and alternative medicine (CAM) usage. ETHICS AND DISSEMINATION: This protocol was approved by the UMMC Ethical Committee in January 2012. All participants are required to provide written informed consent. The findings from our cohort study will be disseminated via scientific publication as well as presentation to stakeholders including the patients, clinicians, the public and policymakers, via appropriate avenues. PMID- 26503387 TI - Long-term ambient air pollution exposure and self-reported morbidity in the Australian Longitudinal Study on Women's Health: a cross-sectional study. AB - OBJECTIVE: We sought to assess the effect of long-term exposure to ambient air pollution on the prevalence of self-reported health outcomes in Australian women. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: The geocoded residential addresses of 26,991 women across 3 age cohorts in the Australian Longitudinal Study on Women's Health between 2006 and 2011 were linked to nitrogen dioxide (NO2) exposure estimates from a land-use regression model. Annual average NO2 concentrations and residential proximity to roads were used as proxies of exposure to ambient air pollution. OUTCOME MEASURES: Self-reported disease presence for diabetes mellitus, heart disease, hypertension, stroke, asthma, chronic obstructive pulmonary disease and self-reported symptoms of allergies, breathing difficulties, chest pain and palpitations. METHODS: Disease prevalence was modelled by population-averaged Poisson regression models estimated by generalised estimating equations. Associations between symptoms and ambient air pollution were modelled by multilevel mixed logistic regression. Spatial clustering was accounted for at the postcode level. RESULTS: No associations were observed between any of the outcome and exposure variables considered at the 1% significance level after adjusting for known risk factors and confounders. CONCLUSIONS: Long-term exposure to ambient air pollution was not associated with self-reported disease prevalence in Australian women. The observed results may have been due to exposure and outcome misclassification, lack of power to detect weak associations or an actual absence of associations with self-reported outcomes at the relatively low annual average air pollution exposure levels across Australia. PMID- 26503388 TI - Impact of provision of cardiovascular disease risk estimates to healthcare professionals and patients: a systematic review. AB - OBJECTIVE: To systematically review whether the provision of information on cardiovascular disease (CVD) risk to healthcare professionals and patients impacts their decision-making, behaviour and ultimately patient health. DESIGN: A systematic review. DATA SOURCES: An electronic literature search of MEDLINE and PubMed from 01/01/2004 to 01/06/2013 with no language restriction and manual screening of reference lists of systematic reviews on similar topics and all included papers. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: (1) Primary research published in a peer-reviewed journal; (2) inclusion of participants with no history of CVD; (3) intervention strategy consisted of provision of a CVD risk model estimate to either professionals or patients; and (4) the only difference between the intervention group and control group (or the only intervention in the case of before-after studies) was the provision of a CVD risk model estimate. RESULTS: After duplicates were removed, the initial electronic search identified 9671 papers. We screened 196 papers at title and abstract level and included 17 studies. The heterogeneity of the studies limited the analysis, but together they showed that provision of risk information to patients improved the accuracy of risk perception without decreasing quality of life or increasing anxiety, but had little effect on lifestyle. Providing risk information to physicians increased prescribing of lipid-lowering and blood pressure medication, with greatest effects in those with CVD risk >20% (relative risk for change in prescribing 2.13 (1.02 to 4.63) and 2.38 (1.11 to 5.10) respectively). Overall, there was a trend towards reductions in cholesterol and blood pressure and a statistically significant reduction in modelled CVD risk (-0.39% (-0.71 to -0.07)) after, on average, 12 months. CONCLUSIONS: There seems evidence that providing CVD risk model estimates to professionals and patients improves perceived CVD risk and medical prescribing, with little evidence of harm on psychological well-being. PMID- 26503389 TI - Relationship between cardiovascular health score and year-to-year blood pressure variability in China: a prospective cohort study. AB - OBJECTIVES: On the basis of cardiovascular health factors and behaviours, the American Heart Association proposed the Cardiovascular Health Score (CHS). It has been widely used to estimate the cardiovascular health status of individuals. The aim of this study was to investigate the relationship between CHS and year-to year blood pressure variability (BPV). DESIGN: Prospective cohort study. SETTINGS: We stratified participants into two groups by gender: first group, female group; second group, male group. The relationship between CHS and year-to year blood pressure variability were analysed. PARTICIPANTS: A total of 41,613 individuals met the inclusion criteria (no history of stroke, transient ischaemic attack, myocardial infarction, malignant tumour or atrial fibrillation) and had complete blood pressure data. RESULTS: The coefficient of the variation of systolic blood pressure (SCV) was 8.33% in the total population and 8.68% and 8.22% in female and male groups, respectively (p<0.05). Multivariable linear regression analysis revealed that higher CHS was inversely associated with increasing year-to-year BPV, which persisted after adjusting for baseline systolic blood pressure and other risk factors. Each SD increase in CHS could lead to a 0.016SD decrease in SCV (p<0.05). CONCLUSIONS: In summary, CHS was inversely related to year-to-year BPV, which suggested that a healthy lifestyle may contribute to better blood pressure management. PMID- 26503390 TI - The impact of electronic prescribing systems on pharmacists' time and workflow: protocol for a time-and-motion study in English NHS hospitals. AB - INTRODUCTION: Electronic prescribing (ePrescribing) systems are rapidly being introduced into National Health Systems (NHS) hospitals in England following their widespread earlier adoption into primary care settings. Such systems require substantial changes in the way pharmacists organise their work and perform their roles. There is however as yet limited evidence on the extent to which these changes may support or compromise efficient and safe working practices by pharmacists. Identifying and quantifying these changes, and their effects, is central to informing system and work practice design, as well as informing training and implementation processes. This protocol describes a study to measure the impact of ePrescribing systems on pharmacists' time and workflow. METHODS AND ANALYSIS: A direct observational controlled pre-post implementation time-and-motion study will be conducted in six wards at one NHS Trust over two observational periods. Pharmacists will be shadowed and details of all work tasks performed will be collected and time-stamped. Task distribution, frequency and duration will be measured and changes in these measures preimplementation and postimplementation, and between control and intervention wards will be measured. Interviews with pharmacists will investigate their perceptions of the impact of the ePrescribing systems on their work and will be conducted in both periods. The extent to which pharmacists' expectations of the impact of the ePrescribing systems on their work with postimplementation reports will be qualitatively explored, as will any differences between perceptions and results from the time and-motion analysis. ETHICS AND DISSEMINATION: Institutional research ethics approval has been obtained from The University of Edinburgh. Local approval from the participating NHS Trust and informed consent from participating pharmacists have been obtained, while also complying with local governance requirements. The results of the study will be presented at conferences, published in peer-reviewed journals, and shared with members of our Patient and Public Involvement Group, to facilitate wider dissemination. PMID- 26503391 TI - Acupuncture for treating alopecia areata: a protocol of systematic review of randomised clinical trials. AB - INTRODUCTION: Acupuncture is frequently used in dermatology for treating a number of skin disorders. There is no critically appraised evidence of the potential benefits and harm of acupuncture for alopecia areata (AA). This review aims to systematically evaluate the efficacy of acupuncture for the management of AA in randomised clinical trials (RCTs). METHODS AND ANALYSIS: 13 databases will be searched from their inception. These include PubMed, AMED, EMBASE, the Cochrane Library, 6 Korean medical databases (Koreanstudies Information Service System, DBPIA, The Town Society of Science Technology, Research Information Sharing Service, KoreaMed and the Korean National Assembly Library), 3 Chinese Databases (China National Knowledge Infrastructure Database (CNKI), the Chongqing VIP Chinese Science and Technology Periodical Database (VIP) and the Wanfang Database). Only randomised clinical trials (RCTs) using any type of acupuncture for AA will be considered. The selection of the studies, data abstraction and validation will be performed independently by two researchers. Methodological quality will be assessed with Cochrane risk of bias. DISSEMINATION: The systematic review will be published in a peer-reviewed journal. The review will also be disseminated electronically and in print. Updates of the review will be conducted to inform and guide the healthcare practice and policy. TRIAL REGISTRATION NUMBER: PROSPERO 2015: CRD42015020397. PMID- 26503392 TI - Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta analysis. AB - OBJECTIVE: To compare the safety and effectiveness of long-acting beta antagonists (LABA), long-acting antimuscarinic agents (LAMA) and inhaled corticosteroids (ICS) for managing chronic obstructive pulmonary disease (COPD). SETTING: Systematic review and network meta-analysis (NMA). PARTICIPANTS: 208 randomised clinical trials (RCTs) including 134,692 adults with COPD. INTERVENTIONS: LABA, LAMA and/or ICS, alone or in combination, versus each other or placebo. PRIMARY AND SECONDARY OUTCOMES: The proportion of patients with moderate-to-severe exacerbations. The number of patients experiencing mortality, pneumonia, serious arrhythmia and cardiovascular-related mortality (CVM) were secondary outcomes. RESULTS: NMA was conducted including 20 RCTs for moderate-to severe exacerbations for 26,141 patients with an exacerbation in the past year. 32 treatments were effective versus placebo including: tiotropium, budesonide/formoterol, salmeterol, indacaterol, fluticasone/salmeterol, indacaterol/glycopyrronium, tiotropium/fluticasone/salmeterol and tiotropium/budesonide/formoterol. Tiotropium/budesonide/formoterol was most effective (99.2% probability of being the most effective according to the Surface Under the Cumulative RAnking (SUCRA) curve). NMA was conducted on mortality (88 RCTs, 97 526 patients); fluticasone/salmeterol was more effective in reducing mortality than placebo, formoterol and fluticasone alone, and was the most effective (SUCRA=71%). NMA was conducted on CVM (37 RCTs, 55,156 patients) and the following were safest: salmeterol versus each OF placebo, tiotropium and tiotropium (Soft Mist Inhaler (SMR)); fluticasone versus tiotropium (SMR); and salmeterol/fluticasone versus tiotropium and tiotropium (SMR). Triamcinolone acetonide was the most harmful (SUCRA=81%). NMA was conducted on pneumonia occurrence (54 RCTs, 61 551 patients). 24 treatments were more harmful, including 2 that increased risk of pneumonia versus placebo; fluticasone and fluticasone/salmeterol. The most harmful agent was fluticasone/salmeterol (SUCRA=89%). NMA was conducted for arrhythmia; no statistically significant differences between agents were identified. CONCLUSIONS: Many inhaled agents are available for COPD, some are safer and more effective than others. Our results can be used by patients and physicians to tailor administration of these agents. PROTOCOL REGISTRATION NUMBER: PROSPERO # CRD42013006725. PMID- 26503393 TI - The Health and Sport Engagement (HASE) Intervention and Evaluation Project: protocol for the design, outcome, process and economic evaluation of a complex community sport intervention to increase levels of physical activity. AB - INTRODUCTION: Sport is being promoted to raise population levels of physical activity for health. National sport participation policy focuses on complex community provision tailored to diverse local users. Few quality research studies exist that examine the role of community sport interventions in raising physical activity levels and no research to date has examined the costs and cost effectiveness of such provision. This study is a protocol for the design, outcome, process and economic evaluation of a complex community sport intervention to increase levels of physical activity, the Health and Sport Engagement (HASE) project part of the national Get Healthy Get Active programme led by Sport England. METHODS AND ANALYSIS: The HASE study is a collaborative partnership between local community sport deliverers and sport and public health researchers. It involves designing, delivering and evaluating community sport interventions. The aim is to engage previously inactive people in sustained sporting activity for 1*30 min a week and to examine associated health and well being outcomes. The study uses mixed methods. Outcomes (physical activity, health, well-being costs to individuals) will be measured by a series of self report questionnaires and attendance data and evaluated using interrupted time series analysis controlling for a range of sociodemographic factors. Resource use will be identified and measured using diaries, interviews and records and presented alongside effectiveness data as incremental cost-effectiveness ratios and cost-effectiveness acceptability curves. A longitudinal process evaluation (focus groups, structured observations, in-depth interview methods) will examine the efficacy of the project for achieving its aim using the principles of thematic analysis. ETHICS AND DISSEMINATION: The results of this study will be disseminated through peer-reviewed publications, academic conference presentations, Sport England and national public health organisation policy conferences, and practice-based case studies. Ethical approval was obtained through Brunel University London's research ethics committee (reference number RE33-12). PMID- 26503394 TI - Multimorbidity in elderly hospitalised patients and risk of Clostridium difficile infection: a retrospective study with the Cumulative Illness Rating Scale (CIRS). AB - OBJECTIVES: To identify the role of chronic comorbidities, considered together in a literature-validated index (Cumulative Illness Rating Scale, CIRS), and antibiotic or proton-pump inhibitor (PPI) treatments as risk factors for hospital acquired Clostridium difficile infection (CDI) in elderly multimorbid hospitalised patients. DESIGN: Retrospective cohort study. SETTING: Subacute hospital geriatric care ward in Italy. PARTICIPANTS: 505 (238 male (M), 268 female (F)) elderly (age>=65) multimorbid patients. MAIN OUTCOME MEASURES: The relationship between CDI and CIRS Comorbidity Score, number of comorbidities, antibiotic, antifungal and PPI treatments, and length of hospital stay was assessed through age-adjusted and sex-adjusted and multivariate logistic regression models. The CIRS Comorbidity Score was handled after categorisation in quartiles. RESULTS: Mean age was 80.7+/-11.3 years. 43 patients (22 M, 21 F) developed CDI. The prevalence of CDI increased among quartiles of CIRS Comorbidity Score (3.9% first quartile vs 11.1% fourth quartile, age-adjusted and sex-adjusted p=0.03). In the multivariate logistic regression analysis, patients in the highest quartile of CIRS Comorbidity Score (>=17) carried a significantly higher risk of CDI (OR 5.07, 95% CI 1.28 to 20.14, p=0.02) than patients in the lowest quartile (<9). The only other variable significantly associated with CDI was antibiotic therapy (OR 2.62, 95% CI 1.21 to 5.66, p=0.01). PPI treatment was not associated with CDI. CONCLUSIONS: Multimorbidity, measured through CIRS Comorbidity Score, is independently associated with the risk of CDI in a population of elderly patients with prolonged hospital stay. PMID- 26503396 TI - The relative importance of perceived doctor's attitude on the decision to consult for symptomatic osteoarthritis: a choice-based conjoint analysis study. AB - OBJECTIVES: Some patients spend years with painful osteoarthritis without consulting for it, including times when they are experiencing persistent severe pain and disability. Beliefs about osteoarthritis and what primary care has to offer may influence the decision to consult but their relative importance has seldom been quantified. We sought to investigate the relative importance of perceived service-related and clinical need attributes in the decision to consult a primary care physician for painful osteoarthritis. DESIGN: Partial-profile choice-based conjoint analysis study, using a self-complete questionnaire containing 10 choice tasks, each presenting two scenarios based on a combination of three out of six selected attributes. SETTING: General population. PARTICIPANTS: Adults aged 50 years and over with hip, knee or hand pain registered with four UK general practices. OUTCOME MEASURES: Relative importance of pain characteristics, level of disruption to everyday life, extent of comorbidity, assessment, management, perceived general practitioner (GP) attitude. RESULTS: 863 (74%) people responded (55% female; mean age 70 years, range: 58-93). The most important determinants of the patient's decision to consult the GP for joint pain were the extent to which pain disrupted everyday life ('most' vs 'none': relative importance 31%) and perceived GP attitude ('legitimate problem, requires treatment' vs 'part of the normal ageing process that one just has to accept': 24%). Thoroughness of assessment (14%), management options offered (13%), comorbidity (13%) and pain characteristics (5%) were less strongly associated with the decision to consult. CONCLUSIONS: Anticipating that the GP will regard joint pain as 'part of the normal ageing process that one just has to accept' is a strong disincentive to seeking help, potentially outweighing other aspects of quality of care. Alongside the recognition and management of disrupted function, an important goal of each primary care consultation for osteoarthritis should be to avoid imparting or reinforcing this perception. PMID- 26503397 TI - Classification of Healthcare-Associated Staphylococcus aureus Bacteremia: Influence of Different Definitions on Prevalence, Patient Characteristics, and Outcome. AB - We investigated whether different definitions of healthcare-associated infection influenced the prevalence, characteristics, and mortality of patients with Staphylococcus aureus bacteremia. With different definitions, the proportion of patients classified as having healthcare-associated S. aureus bacteremia varied substantially and the distribution of patient characteristics was influenced, whereas 30-day mortality remained robust. PMID- 26503395 TI - Protocol for the Care-IS Trial: a randomised controlled trial of a supportive educational intervention for carers of patients with high-grade glioma (HGG). AB - INTRODUCTION: High-grade glioma (HGG) is a rapidly progressive and debilitating disease. Primary carers experience significant levels of distress which impacts on their experience of caregiving, the quality of care received and the community in terms of the increased reliance on healthcare due to the potential development of complicated grief. This paper describes the protocol for testing the efficacy and feasibility of an intervention for primary carers of patients with HGG in order to improve preparedness to care and reduce carer distress. METHODS: Randomised controlled trial. The target population is carers of patients with HGG who are undergoing combined chemoradiotherapy. The intervention consists of 4 components: (1) initial telephone assessment of unmet needs of the carer, (2) tailoring of a personalised resource folder, (3) home visit, (4) ongoing monthly telephone contact and support for 12 months. The control arm will receive usual care. PRIMARY HYPOTHESIS: This intervention will improve preparedness for caring and reduce carer psychological distress. SECONDARY HYPOTHESIS: This intervention will reduce carer unmet needs. The longer term aim of the intervention is to reduce patient healthcare resource utilisation and, by doing so, reduce costs. Assessments will be obtained at baseline, 8 weeks post intervention, then 4, 6 and 12 months. Participants will also complete a healthcare utilisation checklist and proxy performance status which will be assessed at baseline and monthly. 240 carers will be recruited. The sample size is 180. Multilevel mixed effects regression models will be applied to test the effect of the intervention. ETHICS: Ethics approval has been gained from Curtin University and the participating sites. DISSEMINATION: Results will be reported in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registration (ACTRN)12612001147875. PMID- 26503398 TI - Comparison of simple screening criteria with the International Caries Detection and Assessment System classification in determining restorative treatment need. AB - INTRODUCTION: The Finnish Defence Forces' unique oral health-screening protocol (FDFsp) has been in use for decades. In FDFsp, restorative treatment need is determined based on the World Health Organization (WHO) criteria. The aim of this study was to compare the outcome of screening restorative treatment need with the outcome of using the International Caries Detection and Assessment System (ICDAS) classification at both individual and tooth levels. Our hypothesis was that the outcome of screening with FDFsp agrees with the outcome of using the ICDAS classification. METHODS: In this study, a trained, calibrated examiner estimated, in a visual-tactile manner the restorative treatment need of 337 young healthy adults using the FDFsp. During the screening, 74 conscripts were selected for a thorough inspection. The inclusion criteria for those selected were: having no, having one to five, or having six or more caries lesions needing restorative treatment. In the thorough inspection, the participants were inspected in a visual-tactile manner using the ICDAS classification. The association of the outcomes achieved using the two different methods was analysed at individual and tooth levels. Sensitivity, specificity, and kappa values were calculated. Wisdom teeth were excluded. RESULTS: At the individual level, the agreement between the outcomes of using FDFsp and ICDAS >=4 was excellent: sensitivity, 94.1%; specificity, 97.5%; and kappa = 0.92. When ICDAS >=3 was used, the values were 72.7%, 96.7%, and 0.66%, respectively. CONCLUSION: Screening performed by a trained examiner using specific criteria is a reliable method for detecting individuals with restorative treatment need. The outcome of screening agrees strongly with results using the ICDAS classification. PMID- 26503399 TI - Each-step activation of oxidative phosphorylation is necessary to explain muscle metabolic kinetic responses to exercise and recovery in humans. AB - KEY POINTS: The basic control mechanisms of oxidative phosphorylation (OXPHOS) and glycolysis during work transitions in human skeletal muscle are still a matter of debate. We used simulations of skeletal muscle bioenergetics to identify key system features that contribute to this debate, by comparing kinetic model outputs with experimental human data, including phosphocreatine, pH, pulmonary oxygen uptake and fluxes of ATP production by OXPHOS (vOX), anaerobic glycolysis and creatine kinase in moderate and severe intensity exercise transitions. We found that each-step activation of particular OXPHOS complexes, NADH supply and glycolysis, and strong (third-order) glycolytic inhibition by protons was required to reproduce observed phosphocreatine, pH and vOX kinetics during exercise. A slow decay of each-step activation during recovery, which was slowed further following severe exercise, was necessary to reproduce the experimental findings. Well-tested computer models offer new insight in the control of the human skeletal muscle bioenergetic system during physical exercise. ABSTRACT: To better understand muscle bioenergetic regulation, a previously-developed model of the skeletal muscle cell bioenergetic system was used to simulate the influence of: (1) each-step activation (ESA) of NADH supply (including glycolysis) and oxidative phosphorylation (OXPHOS) complexes and (2) glycolytic inhibition by protons on the kinetics of ATP synthesis from OXPHOS, anaerobic glycolysis and creatine kinase. Simulations were fitted to previously published experimental data of ATP production fluxes and metabolite concentrations during moderate and severe intensity exercise transitions in bilateral knee extension in humans. Overall, the computer simulations agreed well with experimental results. Specifically, a large (>5-fold) direct activation of all OXPHOS complexes was required to simulate measured phosphocreatine and OXPHOS responses to both moderate and severe intensity exercise. In addition, slow decay of ESA was required to fit phosphocreatine recovery kinetics, and the time constant of ESA decay was slower following severe (180 s) than moderate (90 s) exercise. Additionally, a strong inhibition of (anaerobic) glycolysis by protons (glycolytic rate inversely proportional to the cube of proton concentration) provided the best fit to the experimental pH kinetics, and may contribute to the progressive increase in oxidative ATP supply during acidifying contractions. During severe-intensity exercise, an 'additional' ATP usage (a 27% increase at 8 min, above the initial ATP supply) was necessary to explain the observed VO2 slow component. Thus, parallel activation of ATP usage and ATP supply (ESA), and a strong inhibition of ATP supply by anaerobic glycolysis, were necessary to simulate the kinetics of muscle bioenergetics observed in humans. PMID- 26503400 TI - Oligonucleotide-directed mutagenesis for precision gene editing. AB - Differences in gene sequences, many of which are single nucleotide polymorphisms, underlie some of the most important traits in plants. With humanity facing significant challenges to increase global agricultural productivity, there is an urgent need to accelerate the development of these traits in plants. oligonucleotide-directed mutagenesis (ODM), one of the many tools of Cibus' Rapid Trait Development System (RTDS(TM) ) technology, offers a rapid, precise and non transgenic breeding alternative for trait improvement in agriculture to address this urgent need. This review explores the application of ODM as a precision genome editing technology, with emphasis on using oligonucleotides to make targeted edits in plasmid, episomal and chromosomal DNA of bacterial, fungal, mammalian and plant systems. The process of employing ODM by way of RTDS technology has been improved in many ways by utilizing a fluorescence conversion system wherein a blue fluorescent protein (BFP) can be changed to a green fluorescent protein (GFP) by editing a single nucleotide of the BFP gene (CAC >TAC; H66 to Y66). For example, dependent on oligonucleotide length, applying oligonucleotide-mediated technology to target the BFP transgene in Arabidopsis thaliana protoplasts resulted in up to 0.05% precisely edited GFP loci. Here, the development of traits in commercially relevant plant varieties to improve crop performance by genome editing technologies such as ODM, and by extension RTDS, is reviewed. PMID- 26503402 TI - Hormonal contraceptive use in Ireland: trends and co-prescribing practices. AB - Hormonal contraceptives are highly prevalent. Currently, little is known about Irish hormonal contraceptive trends to date since the 1995 British media contraceptive controversy. The aim of this study was to examine recent trends in contraceptive use in Ireland and to determine the frequency of co-prescriptions with important interacting medications. Approximately 40% of the Irish population are prescribed 70% of total medicines under the Irish GMS scheme. Medicines were identified using the WHO Anatomical Therapeutic Chemical (ATC) classification system. Regression analysis was used to examine trends over time. Of all contraceptives dispensed in 2013, oral contraceptives were used the most (74%) and long acting reversible contraceptives (LARCs) the least (7.5%). Fourth generation combined oral contraceptives (COCs) predominated, although a slight significant decline was shown (P < 0.0001). Second and third generation COCs were significantly increasing and decreasing, respectively (P < 0.0001). Progestin only pills were significantly increasing (P < 0.0001 across age groups). Low rates of contraceptive co-prescribing with important interacting drugs are shown. However, 93.6% of those on enzyme-inducing anti-epileptic medications were co prescribed ineffective contraception containing <50 MUg oestrogen.Irish prescribing trends of second and third generation COCs have remained consistent since 1995. The slow decline in fourth generation COC uptake follows new evidence of an increased risk of venous thromboembolism (VTE) reported in 2011. The low, but increasing, uptake of LARCs is consistent with other countries. Co prescribing practices involving hormonal contraceptives requires continued vigilance. This study emphasizes the need to optimize co-prescribing practices involving hormonal contraceptives and anti-epileptic medications and highlights the need to address the barriers to the currently low uptake of LARC methods in Ireland. PMID- 26503401 TI - Fast macromolecular proton fraction mapping of the human liver in vivo for quantitative assessment of hepatic fibrosis. AB - The macromolecular proton fraction (MPF) is a quantitative MRI parameter determining the magnetization transfer (MT) effect in tissues, and is defined as the relative amount of immobile macromolecular protons involved in magnetization exchange with mobile water protons. MPF has the potential to provide a quantitative assessment of fibrous tissue because of the intrinsically high MPF specific for collagen. The goal of this study was to investigate the relationship between histologically determined fibrosis stage and MPF in the liver parenchyma measured using a recently developed fast single-point clinically targeted MPF mapping method. Optimal saturation parameters for single-point liver MPF measurements were determined from the analysis of liver Z spectra in vivo based on the error propagation model. Sixteen patients with chronic hepatitis C viral infection underwent 3-T MRI using an optimized liver MPF mapping protocol. Fourteen patients had prior liver biopsy with histologically staged fibrosis (METAVIR scores F0-F3) and two patients had clinically diagnosed cirrhosis (score F4 was assigned). The protocol included four breath-hold three-dimensional scans with 2 * 3 * 6-mm(3) resolution and 10 transverse sections: dynamic acquisition of MT-weighted and reference images; dynamic acquisition of three images for variable flip angle T1 mapping; dual-echo B0 map; and actual flip angle imaging B1 map. The average liver MPF was determined as the mode of the MPF histograms. MPF was significantly increased in patients with clinically significant fibrosis (scores F2-F4, n = 6) relative to patients with no or mild fibrosis (scores F0 F1, n = 10): 6.49 +/- 0.36% versus 5.94 +/- 0.26%, p < 0.01 (Mann-Whitney test). MPF and fibrosis scores were strongly positively correlated, with a Spearman's rank correlation coefficient of 0.80 (p < 0.001). This study demonstrates the feasibility of fast MPF mapping of the human liver in vivo and confirms the hypothesis that MPF is increased in hepatic fibrosis and associated with fibrosis stage. MPF may be useful as a non-invasive imaging biomarker of hepatic fibrosis. PMID- 26503403 TI - Measuring regional and district variations in the incidence of pregnancy-induced hypertension in Ghana: challenges, opportunities and implications for maternal and newborn health policy and programmes. AB - OBJECTIVES: The objectives were to assess the quality of health management information system (HMIS) data needed for assessment of local area variation in pregnancy-induced hypertension (PIH) incidence and to describe district and regional variations in PIH incidence. METHODS: A retrospective review of antenatal and delivery records of 2682 pregnant women in 10 district hospitals in the Greater Accra and Upper West regions of Ghana was conducted in 2013. Quality of HMIS data was assessed by completeness of reporting. The incidence of PIH was estimated for each district. RESULTS: Key variables for routine assessment of PIH such as blood pressure (BP) at antenatal visits, weight and height were 95-100% complete. Fundal height, gestational age and BP at delivery were not consistently reported. The incidence of PIH differed significantly between Greater Accra region (6.1%) and Upper West region (3.2%). Prevalence of obesity among pregnant women in Greater Accra region (13.9%) was significantly higher than that of women in Upper West region (2.2%). CONCLUSIONS: More attention needs to be given to understanding local area variations in PIH and possible relationships with urbanisation and lifestyle changes that promote obesity, to inform maternal and newborn health policy. This can be done with good quality routine HMIS data. PMID- 26503404 TI - Unwinding DNA and RNA with Synthetic Complexes: On the Way to Artificial Helicases. AB - Synthetic helicases can be designed on the basis of ligands that bind more strongly to single-stranded nucleic acids than to double-stranded nucleic acids. This can be achieved with ligands containing phenyl groups, which intercalate into single strands, but due to their small size not into double strands. Moreover, two phenyl rings are combined with a distance that allows bis intercalation with only single strands and not double strands. In this respect, such ligands also mimic single-strand binding (SSB) proteins. Exploration with more than 23 ligands, mostly newly synthesised, shows that the distance between the phenyl rings and between those and the linker influence the DNA unwinding efficiency, which can reach a melting point decrease of almost DeltaTm =50 degrees C at much lower concentrations than that with any other known artificial helicases. Conformational pre-organisation of the ligand plays a decisive role in optimal efficiency. Substituents at the phenyl rings have a large effect, and increase, for example, in the order of H=6 months) survival (RR 0.96, 95% CI 0.79 1.16, P = 0.65; I(2) = 16%). In addition, mechanical chest compressions were associated with worse survival to hospital admission (RR 0.94, 95% CI 0.89-1.00, P = 0.04; I(2) = 0%) and to hospital discharge (RR 0.88, 95% CI 0.78-0.99, P = 0.03; I(2) = 0%). Based on the current evidence, widespread use of mechanical devices for chest compressions in OHCA cannot be recommended. PMID- 26503430 TI - Upregulation of BTG1 enhances the radiation sensitivity of human breast cancer in vitro and in vivo. AB - X-ray-based radiotherapy is one of the most effective therapeutic strategies for breast cancer patients. However, radioresistance and side-effects continue to be the most challenging issues. B-cell translocation gene 1 (BTG1) is a member of the BTG/Tob family, which inhibits cancer growth and promotes apoptosis. We, therefore, hypothesized that BTG1 plays an important role in the radiosensitivity of breast cancer cells. In the present study, breast cancer cell lines that stably overexpressed BTG1 were used to investigate the effects of BTG1 on cell radiosensitivity in vitro. We found that overexpression of BTG1 enhanced the radiosensitivity both of p53-mutant breast cancer MDA-MB-231 cells and p53 wild type breast cancer MCF-7 cells. We also found that overexpression of BTG1 along with irradiation induced cell cycle G2/M phase arrest, promoted the formation of reactive oxygen species (ROS), increased the rate of chromosomal aberrations and increased cell apoptosis. Further investigation indicated that BTG1 overexpression along with irradiation was involved in inhibition of the PI3K/Akt signaling pathway. Importantly, the finding that BTG1 promoted ionizing radiosensitivity of breast cancer cells in vitro was confirmed in an animal model. Taken together, our data suggest that BTG1 overexpression combined with radiation therapy increases the therapeutic efficacy of breast cancer treatment via regulation of the cell cycle and apoptosis-related signaling pathways. PMID- 26503432 TI - HPMV: human protein mutation viewer - relating sequence mutations to protein sequence architecture and function changes. AB - Next-generation sequencing advances are rapidly expanding the number of human mutations to be analyzed for causative roles in genetic disorders. Our Human Protein Mutation Viewer (HPMV) is intended to explore the biomolecular mechanistic significance of non-synonymous human mutations in protein-coding genomic regions. The tool helps to assess whether protein mutations affect the occurrence of sequence-architectural features (globular domains, targeting signals, post-translational modification sites, etc.). As input, HPMV accepts protein mutations - as UniProt accessions with mutations (e.g. HGVS nomenclature), genome coordinates, or FASTA sequences. As output, HPMV provides an interactive cartoon showing the mutations in relation to elements of the sequence architecture. A large variety of protein sequence architectural features were selected for their particular relevance to mutation interpretation. Clicking a sequence feature in the cartoon expands a tree view of additional information including multiple sequence alignments of conserved domains and a simple 3D viewer mapping the mutation to known PDB structures, if available. The cartoon is also correlated with a multiple sequence alignment of similar sequences from other organisms. In cases where a mutation is likely to have a straightforward interpretation (e.g. a point mutation disrupting a well-understood targeting signal), this interpretation is suggested. The interactive cartoon can be downloaded as standalone viewer in Java jar format to be saved and viewed later with only a standard Java runtime environment. The HPMV website is: http://hpmv.bii.a-star.edu.sg/ . PMID- 26503431 TI - Intracellular Ca2+ and related proteins in patients with oral lichen planus. AB - Oral lichen planus (OLP) is suggested to be a T cell-mediated chronic inflammatory oral mucosal disease. Gene expressed in the oligodendrocyte lineage myelin basic proteins (Golli-MBP) and stromal interaction molecule 1 (STIM1) are important in the activation and function of T lymphocytes. This study aimed to analyze and compare the expression of Golli-MBP and STIM1 between OLP patients and healthy controls and to analyze the level of intracellular Ca(2+), which is involved in lymphocyte activation. The Ca(2+) fluorescent probe, Fluo-3/AM, was used to test the level of intracellular Ca(2+) in patients with OLP and healthy controls peripheral blood lymphocytes. Golli-MBP and STIM1 mRNA and protein levels were analyzed using quantitative real-time PCR and Western blot, respectively. Following lymphocyte activation, the intracellular Ca(2+) in OLP patients was markedly lower than that in the control group (P < 0.001). In OLP patients, the expression of Golli-MBP mRNA and protein was significantly upregulated compared to those of the control group (P < 0.001). Similarly, OLP patients showed markedly upregulated levels of STIM1 mRNA expression (P < 0.01) and protein compared to healthy controls. The intracellular Ca(2+) of OLP patients was markedly lower than that of healthy controls. This evidence may indicate that Ca(2+) signaling pathways in OLP patients are abnormal. The overexpression of Golli-MBP and STIM1 may play a role in the pathogenesis of OLP. PMID- 26503433 TI - ESI-LC-MS Method for Haptoglobin Fucosylation Analysis in Hepatocellular Carcinoma and Liver Cirrhosis. AB - A method for the detection of fucosylated glycans from haptoglobin in patient serum has been developed that provides enhanced sensitivity. The workflow involves isolation of the haptoglobin using an HPLC-based affinity column followed by glycan removal, extraction, and desialylation. The fucosylated glycans are then derivatized by Meladrazine, which significantly enhances the detection of the glycans in electrospray ionization. The separation of the derivatized glycans in a HILIC column shows that eight glycans from haptoglobin can be detected using less than 1 MUL of a serum sample, with excellent reproducibility and quantitation, where without derivatization the glycans could not be detected. The ratio of the fucosylated peaks to their corresponding nonfucosylated forms shows that the fucosylated glycans are upregulated in the case of hepatocellular carcinoma (HCC) samples versus cirrhosis samples, where the relatively low abundance bifucosylated tetra-antennary form can be detected and may be a particularly good marker for HCC. PMID- 26503434 TI - The potential of a multiplex high-throughput molecular assay for early detection of first and second line tuberculosis drug resistance mutations to improve infection control and reduce costs: a decision analytical modeling study. AB - BACKGROUND: Molecular resistance detection (MRD) of resistance to second-line anti-tuberculous drugs provides faster results than phenotypic tests, may shorten treatment and allow earlier separation among patients with and without second line drug resistance. METHODS: In a decision-analytical model we simulated a cohort of patients diagnosed with TB in a setting where drug resistant TB is highly prevalent and requires initial hospitalization, to explore the potential benefits of a high-throughput MRD-assay for reducing potential nosocomial transmission of highly resistant strains, and total costs for diagnosis of drug resistance, treatment and hospitalization. In the base case scenario first-line drug resistance was diagnosed with WHO-endorsed molecular tests, and second-line drug resistance with culture and phenotypic methods. Three alternative scenarios were explored, each deploying high-throughput MRD allowing either detection of second-line mutations in cultured isolates, directly on sputum, or MRD with optimized markers. RESULTS: Compared to a base case scenario, deployment of high throughput MRD reduced total costs by 17-21 %. The period during which nosocomial transmission may take place increased by 15 % compared to the base case if MRD had currently reported suboptimal sensitivity and required cultured isolates; increased by 7 % if direct sputum analysis were possible including in patients with smear-negative TB, and reduced by 24 % if the assay had improved markers, but was still performed on cultured isolates. Improved clinical sensitivity of the assay (additional markers) by more than 35 % would be needed to avoid compromising infection control. CONCLUSIONS: Further development of rapid second line resistance testing should prioritize investment in optimizing markers above investments in a platform for direct analysis of sputum. PMID- 26503435 TI - Massive Dirac Fermion Observed in Lanthanide-Doped Topological Insulator Thin Films. AB - The breaking of time reversal symmetry (TRS) in three-dimensional (3D) topological insulators (TIs), and thus the opening of a 'Dirac-mass gap' in the linearly dispersed Dirac surface state, is a prerequisite for unlocking exotic physical states. Introducing ferromagnetic long-range order by transition metal doping has been shown to break TRS. Here, we present the study of lanthanide (Ln) doped Bi2Te3, where the magnetic doping with high-moment lanthanides promises large energy gaps. Using molecular beam epitaxy, single-crystalline, rhombohedral thin films with Ln concentrations of up to ~35%, substituting on Bi sites, were achieved for Dy, Gd, and Ho doping. Angle-resolved photoemission spectroscopy shows the characteristic Dirac cone for Gd and Ho doping. In contrast, for Dy doping above a critical doping concentration, a gap opening is observed via the decreased spectral intensity at the Dirac point, indicating a topological quantum phase transition persisting up to room-temperature. PMID- 26503436 TI - Erratum to: Obesity--a risk factor for postoperative complications in general surgery? PMID- 26503438 TI - Look but ... please don't touch! PMID- 26503440 TI - Translation and Validation of the Finnish Version of the Patient-Rated Wrist Evaluation Questionnaire (PRWE) in Patients with Acute Distal Radius Fracture. AB - BACKGROUND AND AIMS: Patient-rated outcome measures have become increasingly important in clinical research. They provide research and clinical tools which can be utilized in the assessment of patient recovery and treatment efficacy. The purpose of our study was to translate and validate the original version of the PRWE form into Finnish. MATERIAL AND METHODS: We conducted the translation of the PRWE questionnaire according to standardized guidelines. Patients (N = 119) with an acute distal radius fracture were recruited, and they completed the PRWE and QuickDASH questionnaires at 2 months and 4 months after the wrist injury. RESULTS: The mean answering times were 52 days (standard deviation [SD] 9.8 days) and 116 days (standard deviation [SD] 14.8 days), respectively. Both the internal consistency (Cronbach's alpha) of 0.976 and the intraclass correlation coefficient (ICC) of 0.992 (95% CI 0.966-0.998) showed excellent reliability for the total PRWE score. The correlation coefficients between the total score, the subscales, and for improvement over time for PRWE and QuickDASH were excellent. The responsiveness was good with an effect size of 0.83 and a standard response mean of 1.22. CONCLUSION: Our study shows that the Finnish version of the PRWE is reliable, valid, and responsive for the evaluation of pain and disability after distal radius fracture. PMID- 26503441 TI - A correlativity study of plasma APL1beta28 and clusterin levels with MMSE/MoCA/CASI in aMCI patients. AB - Amnestic mild cognitive impairment (aMCI) is a sub-clinical condition characterized by memory deficits that are not severe enough to affect daily functioning. Here we investigated two potential biomarkers found in the cerebrospinal fluid of AD patients, APLP1-derived Abeta-like peptides 28 (APL1beta28) and clusterin plasma levels, in terms of their relationship to cognitive function, as reflected in the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA) and the Cognitive Assessment Screening Instrument (CASI) in aMCI patients. Forty-seven aMCI patients and thirty-five age and gender-matched healthy adult controls were recruited for this study. Using the ELISA method, we found that the mean concentrations of both APL1beta28 and clusterin were not significantly different between the control and aMCI groups. The APL1beta28 levels were positively correlated with clusterin and that both were negatively correlated with the MMSE scores of the aMCI patients. Clusterin levels were negatively correlated with the MoCA and CASI scores of the aMCI patients. Using multivariate analysis, the correlation between clusterin and MMSE/MoCA/CASI was independent of other AD risk factors including age, education, sex, body mass index and ApoE genotype. The data presented here demonstrate that plasma clusterin levels reflect cognitive function in aMCI patients. PMID- 26503442 TI - CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells are positively correlated with levels of IL-21 in active and transitional cystic echinococcosis patients. AB - BACKGROUND: In our study, we investigated whether circulating T follicular helper (Tfh) and the related cytokines are involved in human cystic echinococcosis (CE). METHODS: A total of 64 patients with CE and 30 healthy controls were enrolled in this study. Percentages of CCR7(lo)PD-1(hi) cells within CXCR5(+) CD4(+) T cells (circulating Tfh cells) were detected by flow cytometry. Levels of IL-21 and IL-4 in peripheral blood were detected by cytometric bead array. The mRNA expression of IL-21, IL-4, Bcl-6, and Blimp-1 in peripheral blood mononuclear cells (PBMCs) were measured by real-time PCR. Levels of IgG1, IgG2, IgG3, and IgG4 in the patients' sera were measured using enzyme-linked immunosorbent assay. RESULTS: Percentages of circulating Tfh cells were significantly increased in the CE1, CE2, and CE3 groups (p < 0.05). The concentrations of IL-21 and IL-4 in the serum were significantly increased in CE1, CE2, and CE3 groups (p < 0.05). IL-21 was positively correlated with circulating Tfh cells in CE3 group (r = 0.779, p < 0.05). The mRNA levels of IL-21, IL-4, and Bcl-6 were increased in CE1, CE2, and CE3 groups. Levels of IgG1 and IgG4 in patients' sera were increased in CE1, CE2, and CE3 groups. Levels of IgG2 and IgG3 were increased in CE4-5 group. Additionally, after stimulation with hydatid fluid in vitro, the levels of circulating Tfh cells, IL-21 and IL-4 in PBMCs isolated from CE patients were significantly increased (p < 0.05). CONCLUSIONS: The levels of circulating Tfh and related cytokines were significantly increased in CE patients, suggesting that they are involved in human CE. PMID- 26503444 TI - Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection. AB - Natural killer (NK) cell maturation is a tightly controlled process that endows NK cells with functional competence and the capacity to recognize target cells. Here, we found that the transcription factor (TF) Zeb2 was the most highly induced TF during NK cell maturation. Zeb2 is known to control epithelial to mesenchymal transition, but its role in immune cells is mostly undefined. Targeted deletion of Zeb2 resulted in impaired NK cell maturation, survival, and exit from the bone marrow. NK cell function was preserved, but mice lacking Zeb2 in NK cells were more susceptible to B16 melanoma lung metastases. Reciprocally, ectopic expression of Zeb2 resulted in a higher frequency of mature NK cells in all organs. Moreover, the immature phenotype of Zeb2(-/-) NK cells closely resembled that of Tbx21(-/-) NK cells. This was caused by both a dependence of Zeb2 expression on T-bet and a probable cooperation of these factors in gene regulation. Transgenic expression of Zeb2 in Tbx21(-/-) NK cells partially restored a normal maturation, establishing that timely induction of Zeb2 by T-bet is an essential event during NK cell differentiation. Finally, this novel transcriptional cascade could also operate in human as T-bet and Zeb2 are similarly regulated in mouse and human NK cells. PMID- 26503445 TI - Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection. AB - ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells. PMID- 26503447 TI - Poor survival of Methicillin-resistant Staphylococcus aureus on inanimate objects in the public spaces. AB - We investigated the prevalence of Staphylococcus aureus on shopping baskets in Osaka Prefecture, Japan. Multilocus sequence typing was performed to determine the genotypes of S. aureus isolates, and then a polymerase chain reaction method was used to detect staphylococcal enterotoxins and antibiotic resistance genes. In addition, desiccation tolerance of S. aureus isolates was evaluated in vitro. Forty-six (6.2%) S. aureus isolates were collected from 740 shopping baskets, though only one MRSA strain was identified. In multilocus sequence typing findings, ten sequence types and 24 singletons were classified, which were divided into ten clonal complexes and six singletons. The most frequent staphylococcal enterotoxin gene was seg (30.4%). Our in vitro findings demonstrated that 70% of the S. aureus isolates, including the MRSA strain, became undetectable at 12 h after desiccation at an appropriate cell density, while the others remained viable for up to 24 h. Thus, it is difficult for MRSA organisms to survive on dry surfaces found in public areas. We speculated that inanimate objects in the community are unlikely to be a potential source for transmission of MRSA and that S. aureus on such objects outside of hospital settings is not a public health threat. PMID- 26503446 TI - The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection. AB - The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during viral infection. We find that, at high concentrations, T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential. PMID- 26503448 TI - A self-stabilized coherent phonon source driven by optical forces. AB - We report a novel injection scheme that allows for "phonon lasing" in a one dimensional opto-mechanical photonic crystal, in a sideband unresolved regime and with cooperativity values as low as 10(-2). It extracts energy from a cw infrared laser source and is based on the triggering of a thermo-optical/free-carrier dispersion self-pulsing limit-cycle, which anharmonically modulates the radiation pressure force. The large amplitude of the coherent mechanical motion acts as a feedback that stabilizes and entrains the self-pulsing oscillations to simple fractions of the mechanical frequency. A manifold of frequency-entrained regions with two different mechanical modes (at 54 and 122 MHz) are observed as a result of the wide tuneability of the natural frequency of the self-pulsing. The system operates at ambient conditions of pressure and temperature in a silicon platform, which enables its exploitation in sensing, intra-chip metrology or time-keeping applications. PMID- 26503449 TI - Evolution of the highly networked deubiquitinating enzymes USP4, USP15, and USP11. AB - BACKGROUND: USP4, USP15 and USP11 are paralogous deubiquitinating enzymes as evidenced by structural organization and sequence similarity. Based on known interactions and substrates it would appear that they have partially redundant roles in pathways vital to cell proliferation, development and innate immunity, and elevated expression of all three has been reported in various human malignancies. The nature and order of duplication events that gave rise to these extant genes has not been determined, nor has their functional redundancy been established experimentally at the organismal level. METHODS: We have employed phylogenetic and syntenic reconstruction methods to determine the chronology of the duplication events that generated the three paralogs and have performed genetic crosses to evaluate redundancy in mice. RESULTS: Our analyses indicate that USP4 and USP15 arose from whole genome duplication prior to the emergence of jawed vertebrates. Despite having lower sequence identity USP11 was generated later in vertebrate evolution by small-scale duplication of the USP4-encoding region. While USP11 was subsequently lost in many vertebrate species, all available genomes retain a functional copy of either USP4 or USP15, and through genetic crosses of mice with inactivating mutations we have confirmed that viability is contingent on a functional copy of USP4 or USP15. Loss of ubiquitin exchange regulation, constitutive skipping of the seventh exon and neural specific expression patterns are derived states of USP11. Post-translational modification sites differ between USP4, USP15 and USP11 throughout evolution. CONCLUSIONS: In isolation sequence alignments can generate erroneous USP gene phylogenies. Through a combination of methodologies the gene duplication events that gave rise to USP4, USP15, and USP11 have been established. Although it operates in the same molecular pathways as the other USPs, the rapid divergence of the more recently generated USP11 enzyme precludes its functional interchangeability with USP4 and USP15. Given their multiplicity of substrates the emergence (and in some cases subsequent loss) of these USP paralogs would be expected to alter the dynamics of the networks in which they are embedded. PMID- 26503451 TI - Back to Work? Not Everyone. Examining the Longitudinal Relationships Between Informal Caregiving and Paid Work After Formal Retirement. AB - Objectives: Research on unretirement (retirees who re-enter the workforce) is burgeoning. However, no longitudinal study has examined how informal care relates to unretirement. Utilizing role theory, this study aims to explore the heterogeneity of informal care responsibilities in retirement and to examine how informal care informs re-entering the workforce in later life. Method: Data were drawn from the Health and Retirement Study of fully retired individuals aged 62 years and older in 1998 (n = 8,334) and followed to 2008. Informal care responsibilities included helping a spouse/partner with activities of daily living (ADLs) or instrumental activities of daily living (IADLs); helping parent(s) or parent-in-law(s) with ADLs or IADLs; and single or co-occurrence of care roles. Covariates included economic and social factors. Cox proportional hazard models were utilized. Results: When compared with noncaregivers, helping a spouse with ADLs or IADLs reduced the odds of returning-to-work in the subsequent wave by 78% and 55%, respectively (hazard ratio [HR]: 0.22, confidence interval [CI]: 0.06-0.87; HR: 0.45, CI: 0.21-0.97). There was no statistical difference to returning-to-work between noncaregivers and helping parents with ADLs/IADLs or multiple caregiving responsibilities. Discussion: Role theory provided a useful framework to understand the relationships of informal care and unretirement. Aspects of role strain emerged, where, spousal caregivers were less likely to come out of retirement. Spousal caregivers may face challenges to working longer, and subsequently, opportunities to bolster their retirement security are diminished. Research and policy implications are discussed. PMID- 26503452 TI - Haemophilus influenzae: a potent perinatal pathogen disproportionately isolated from Indigenous women and their neonates. AB - BACKGROUND: Nontypeable Haemophilus influenzae (NTHi) bacteraemia in pregnant women is strongly associated with pregnancy loss and preterm delivery. However, the clinical significance of isolation of NTHi from nonsterile sites is unknown. AIMS: To examine the hypothesis that isolation of NTHi from any specimen is associated with adverse perinatal outcomes and to investigate the impression that NTHi is disproportionately isolated from indigenous women and their neonates. MATERIALS AND METHODS: Cases where NTHi was isolated from maternal, fetal or neonatal specimens during the period from 1 July 1997 to 1 July 2009 were identified. Demographic and clinical data were extracted from case notes. Histopathological material was re-reviewed by a perinatal pathologist. Demographic and clinical features of the affected group were compared with the hospital obstetric population. RESULTS: NTHi was isolated from maternal, fetal or neonatal specimens in 97 pregnancies. Two women had NTHi isolated during different pregnancies. Two mothers and 10 neonates were bacteraemic. Indigenous women comprised 28% of pregnancies where NTHi was isolated, compared with 6% of the hospital obstetric population (P < 0.001). Pregnancy loss occurred in six cases (6%). Median gestation at delivery was 33 weeks. Of 96 liveborn neonates, 88 (92%) required admission to a neonatal special care unit. Four liveborn neonates died (4%). Chorioamnionitis was confirmed by histology in 31/33 (93.9%) of placentas examined. CONCLUSIONS: Isolation of NTHi occurred more commonly in indigenous women and neonates. Isolation of NTHi from any obstetric or neonatal specimen is associated with chorioamnionitis, preterm birth, pregnancy loss, early-onset neonatal sepsis and neonatal death. PMID- 26503450 TI - Optimization of lipid production with a genome-scale model of Yarrowia lipolytica. AB - BACKGROUND: Yarrowia lipolytica is a non-conventional yeast that is extensively investigated for its ability to excrete citrate or to accumulate large amounts of storage lipids, which is of great significance for single cell oil production. Both traits are thus of interest for basic research as well as for biotechnological applications but they typically occur simultaneously thus lowering the respective yields. Therefore, engineering of strains with high lipid content relies on novel concepts such as computational simulation to better understand the two competing processes and to eliminate citrate excretion. RESULTS: Using a genome-scale model (GSM) of baker's yeast as a scaffold, we reconstructed the metabolic network of Y. lipolytica and optimized it for use in flux balance analysis (FBA), with the aim to simulate growth and lipid production phases of this yeast. We validated our model and found the predictions of the growth behavior of Y. lipolytica in excellent agreement with experimental data. Based on these data, we successfully designed a fed-batch strategy to avoid citrate excretion during the lipid production phase. Further analysis of the network suggested that the oxygen demand of Y. lipolytica is reduced upon induction of lipid synthesis. According to this finding we hypothesized that a reduced aeration rate might induce lipid accumulation. This prediction was indeed confirmed experimentally. In a fermentation combining these two strategies lipid content of the biomass was increased by 80%, and lipid yield was improved more than four-fold, compared to standard conditions. CONCLUSIONS: Genome scale network reconstructions provide a powerful tool to predict the effects of genetic modifications and the metabolic response to environmental conditions. The high accuracy and the predictive value of a newly reconstructed GSM of Y. lipolytica to optimize growth conditions for lipid accumulation are demonstrated. Based on these findings, further strategies for engineering Y. lipolytica towards higher efficiency in single cell oil production are discussed. PMID- 26503453 TI - Discharge Communication in Patients Presenting to the Emergency Department With Chest Pain: Defining the Ideal Content. AB - In an emergency department (ED), discharge communication represents a crucial step in medical care. In theory, it fosters patient satisfaction and adherence to medication, reduces anxiety, and ultimately promotes better outcomes. In practice, little is known about the extent to which patients receiving discharge information understand their medical condition and are able to memorize and retrieve instructions. Even less is known about the ideal content of these instructions. Focusing on patients with chest pain, we systematically assessed physicians' and patients' informational preferences and created a memory aid to support both the provision of information (physicians) and its retrieval (patients). In an iterative process, physicians of different specialties (N = 47) first chose which of 81 items to include in an ED discharge communication for patients with acute chest pain. A condensed list of 34 items was then presented to 51 such patients to gauge patients' preferences. Patients' and physicians' ratings of importance converged in 32 of the 34 items. Finally, three experts grouped the 34 items into five categories: (1) information on diagnosis; (2) follow-up suggestions; (3) advice on self-care; (4) red flags; and (5) complete treatment, from which we generated the mnemonic acronym "InFARcT." Defining and structuring the content of discharge information seems especially important for ED physicians and patients, as stress and time constraints jeopardize effective communication in this context. Chest pain accounts for up to 10% of all patient presentations in emergency departments (EDs) (Konkelberg & Esterman, 2003). The majority of these patients will usually be discharged within hours, after exclusion of serious conditions such as myocardial infarction (Goodacre et al., 2011). A comprehensive workup of low- to intermediate-risk patients is not feasible in the ED (Reichlin et al., 2009). Yet many of these patients go on to suffer from repeated episodes of chest pain, associated with anxiety and uncertainty about diagnosis and outcome (Jones & Mountain, 2009). Effective discharge communication, empowering patients to understand and memorize medical information, should therefore be an integral part of patient care. It is a likely contributor to better outcomes (Bishop, Barlow, Hartley, & William, 1997; Kessels, 2003), higher patient satisfaction (Kessels, 2003), better adherence to medication (Cameron, 1996; Kessels, 2003), more adequate disease management, and reduced anxiety (Galloway et al., 1997; Mossman, Boudioni, & Slevin, 1999). PMID- 26503454 TI - An observational study of the effectiveness of alternative care providers in the management of obstructive sleep apnea. AB - Alternative care providers have been proposed as a substitute for physician-based management of obstructive sleep apnea. The purpose of this study was to describe the clinical course of patients with a new diagnosis of obstructive sleep apnea who were treated with continuous positive airway pressure and followed by alternative care providers at a tertiary care sleep clinic. It was hypothesized that care by alternative care providers would result in improvement of daytime sleepiness and satisfactory treatment adherence, and that a specific number of follow-up visits could be identified after which clinical outcomes no longer improved. The Epworth Sleepiness Scale score was measured for each patient at baseline and at each alternative care provider visit. Patients were discharged when they demonstrated a significant improvement in sleepiness and were adherent to therapy. The Epworth Sleepiness Scale score decreased by 3.9 points from baseline to discharge. Patients with three or more visits required more follow-up time to achieve the same clinical improvement as those with only two visits. Continuous positive airway pressure adherence was comparable to previous studies of physician-led care and improved with ongoing alternative care provider follow up. The current results suggest that clinical care by alternative care providers leads to continued improvements in sleepiness in patients with obstructive sleep apnea who are treated with continuous positive airway pressure, and that a minority of patients require longer follow-up to achieve a satisfactory clinical response to therapy. PMID- 26503455 TI - Peptide YY3-36 and glucagon-like peptide-1 in functional dyspepsia. Secretion and role in symptom generation. AB - OBJECTIVE: The role of peptide YY3-36 (PYY3-36), glucagon-like peptide-1 (GLP-1), and glucose homoeostasis in symptom development in functional dyspepsia (FD) is unclear. The aim was to investigate postprandial changes in plasma PYY3-36, GLP 1, glucose and insulin, and the relationship between PYY3-36, GLP-1, dyspeptic symptoms, and satiety measurements. MATERIALS AND METHODS: Thirty-six patients with functional dyspepsia and 18 healthy controls consumed a liquid meal at two occasions. Firstly, a fixed amount of 250 mL (300 kcal) was consumed and gastric emptying was assessed using the paracetamol method. Secondly, participants drank 75 mL (90 kcal) per five min until maximal satiety. PYY3-36, GLP-1, glucose, and insulin concentrations were assessed. Satiety measures and dyspeptic symptoms were registered using visual analogue scales. RESULTS: Gastric emptying, glucose, PYY3-36, and GLP-1 concentrations were similar in patients and controls. Patients with epigastric pain syndrome had higher postprandial insulin levels. Patients reported more satiety, nausea, and pain. Area under the curve (AUC) for GLP-1 correlated positively to nausea in patients and negatively to nausea in controls during a single meal. AUC for PYY3-36 correlated similarly to sensation of fullness in the two groups; however, the correlation was negative for the single meal and positive for the satiety test. CONCLUSIONS: In epigastric pain syndrome, postprandial insulin secretion seems to be increased. Neither GLP-1 nor PYY3-36 secretion is altered in functional dyspepsia, but postprandial GLP-1 secretion seems to correlate with nausea and PYY3-36 to the sensation of fullness, and therefore, these hormones might be involved in symptom generation. PMID- 26503456 TI - Erratum to: The association of health literacy with adherence in older adults, and its role in interventions: a systematic meta-review. PMID- 26503457 TI - Attitudes and perceptions of veterinary paraprofessionals in New Zealand to postoperative pain in dogs and cats. AB - AIM: To survey the attitudes and perceptions of veterinary paraprofessionals in New Zealand to postoperative pain in dogs and cats. METHODS: In December 2011, veterinary paraprofessionals (VP) from throughout New Zealand were invited to participate in an online survey. Eleven questions, which were divided into five sections, were used to determine demographic information, the respondents' assessment of pain after commonly performed surgeries in dogs and cats, their opinions on provision of analgesia, who had responsibility for pain monitoring and the use of any formal pain scoring system in the practice. RESULTS: Data from 165 respondents were able to be used, and 162 (98%) respondents to the survey were female. According to the respondents' estimates, fracture repair in dogs and repair of diaphragmatic hernias in cats had the highest pain score following surgery. Neutering procedures involving dogs were scored higher than for cats (p<0.01). All respondents agreed that animals benefit from perioperative analgesia. The veterinary nurse was reported to be predominantly responsible for monitoring pain in animals postoperatively by 116/165 (70.3%) respondents. Of 165 respondents, 154 (93%) considered that their knowledge of pain and assessment of pain could be enhanced. CONCLUSIONS: This survey reflects the attitudes and perceptions of a sample of VP in New Zealand to postoperative pain in dogs and cats. The results indicate that all respondents believe that surgery results in sufficient pain to warrant analgesic therapy. Routine neutering surgeries were considered to be more painful in dogs than in cats. The current survey also provides information to educators on potential areas of focus, given that 93% of respondents felt that their knowledge of pain and assessment of pain could be enhanced. PMID- 26503458 TI - Challenges in the Pharmacological Management of Nursing Home Residents with Overactive Bladder or Urinary Incontinence. AB - OBJECTIVES: To determine the proportion of nursing home (NH) residents (NHR) with overactive bladder (OAB) or urinary incontinence (UI) with potential pharmacodynamic contraindications to antimuscarinic treatment because of concomitant anticholinergic medications or acetylcholinesterase inhibitors (AChEIs) and nonpharmacological limitations to antimuscarinic treatment. DESIGN: Cross-sectional retrospective analysis. SETTING: U.S. skilled nursing facilities. PARTICIPANTS: Nursing home residents with a diagnosis of OAB or UI. MEASUREMENTS: Linked and deidentified pharmacy claims and Minimum Data Set (MDS) 3.0 records (October 1, 2010 to September 30, 2012). RESULTS: Of NHRs, 71.3% received at least one anticholinergic medication. Medications that can cause or worsen UI were used commonly. AChEIs and antimuscarinic treatment were prescribed concurrently in 24% of NHRs with OAB or UI. NHRs with OAB or UI were more likely to have concurrent moderate to severe cognitive impairment (MSCI) (70.1%) than those without (29.9%) (P < .001). NHRs with or without OAB or UI and with MSCI were more likely to be treated with an anticholinergic medication than those without MSCI (P = .001). When NHRs with MSCI, severe mobility impairment (SMI), and anticholinergic medication and AChEI use were excluded, only a small proportion of NHRs were potential candidates for antimuscarinic treatment (6.6% with OAB or UI, 6.2% with UI). CONCLUSIONS: This study advances understanding of the challenges in prescribing antimuscarinic treatment safely and appropriately in elderly NHRs with a high prevalence of drug interactions, underlying MSCI, and SMI. PMID- 26503459 TI - New management options for osteoporosis with emphasis on SERMs. AB - Albright was the first of many to show that loss of bone mass due to estrogen deficiency is an important part of the pathogenesis of postmenopausal osteoporosis. This led to the use of estrogen therapy which was shown to prevent bone loss at menopause and to reduce the risk of important fragility fractures. Selective estrogen receptor modulators (SERMs), with salutary estrogen-like skeletal effects and with protection from breast cancer, have important roles in the management of young postmenopausal women. New members of the SERM family may approach the effectiveness of estrogen in preventing bone loss and reducing fracture risk. When combined with estrogen, new SERMs prevent endometrial hyperplasia, and that combination reduces menopausal symptoms and prevents bone loss. Drugs that reduce bone turnover or stimulate bone formation by non-estrogen pathways have also been developed to treat osteoporosis. Emerging therapies, with unique mechanisms of action, may provide improved efficacy in treating women who already have osteoporosis. PMID- 26503460 TI - miR-154 targeting ZEB2 in hepatocellular carcinoma functions as a potential tumor suppressor. AB - MicroRNA-154 (miR-154) has been identified as a tumor suppressor in several types of human cancers; however, its clinical significance and function in human hepatocellular carcinoma (HCC) remain unclear. The aim of the present study was to analyze the clinical significance and cellular function of miR-154 in HCC patients. The data showed that miR-154 expression was consistently lower in HCC tissues and cell lines compared to that in matched tumor-adjacent tissues and a normal hepatic cell line, and its expression was negatively correlated with tumor differentiation (P<0.01), TNM stage (P<0.01) and lymph node metastasis (P<0.01). Restoration of miR-154 expression in HepG2 cells inhibited cell proliferation, migration and invasion, and induced apoptosis and cell arrest at the G1 phase in vitro, as well as suppressed tumor growth in a nude mouse model. Using a luciferase assay, we identified that miR-154 was able to target the 3' untranslated region (3'UTR) of ZEB2 mRNA. Then, we revealed that miR-154 was able to reduce ZEB2 expression at the levels of mRNA and protein using qRT-PCR and western blot analysis. Notably, restoration of expression of ZEB2 weakened miR 154-mediated suppression of tumor progression. In conclusion, these results indicate that miR-154 functions as a tumor suppressor in HCC by suppressing ZEB2, suggesting that miR-154 may serve as a potential target for HCC. PMID- 26503462 TI - Synthesis and sensor applications of MoS2-based nanocomposites. AB - Molybdenum disulfide (MoS2) is a typical layered transition-metal dichalcogenide material, which has aroused a great deal of interest in the past few years. Recently, more and more attention has been focused on the synthesis and applications of MoS2-based nanocomposites. In this review, we aimed to present a wider view of the synthesis of various MoS2-based nanocomposites for sensor and biosensor applications. We highlighted the potential methods like self-assembly, hydrothermal reaction, chemical vapour deposition, electrospinning, as well as microwave and laser beam treatments for the successful preparation of MoS2-based nanocomposites. On the other hand, three representative types of detection devices fabricated by the MoS2-based nanocomposites, field-effect transistor, optical, and electrochemical sensors, were introduced in detail and discussed fully. The relationships between the sensing performances and the special nanostructures within the MoS2-based nanocomposites were presented and discussed. PMID- 26503461 TI - Plasmodium berghei ANKA causes intestinal malaria associated with dysbiosis. AB - Gastrointestinal symptoms, such as abdominal pain and diarrhea, are frequently observed in patients with Plasmodium falciparum malaria. However, the correlation between malaria intestinal pathology and intestinal microbiota has not been investigated. In the present study, infection of C57BL/6 mice with P. berghei ANKA (PbA) caused intestinal pathological changes, such as detachment of epithelia in the small intestines and increased intestinal permeability, which correlated with development with experimental cerebral malaria (ECM). Notably, an apparent dysbiosis occurred, characterized by a reduction of Firmicutes and an increase in Proteobacteria. Furthermore, some genera of microbiota correlated with parasite growth and/or ECM development. By contrast, BALB/c mice are resistant to ECM and exhibit milder intestinal pathology and dysbiosis. These results indicate that the severity of cerebral and intestinal pathology coincides with the degree of alteration in microbiota. This is the first report demonstrating that malaria affects intestinal microbiota and causes dysbiosis. PMID- 26503463 TI - Early aggregation preceding the nucleation of insulin amyloid fibrils as monitored by small angle X-ray scattering. AB - The nucleation event of amyloid fibrils is one of the most crucial processes that dictate the timing and rate of the pathology of diseases; however, information regarding how protein molecules associate to produce fibril nuclei is currently limited. In order to explore this issue in more detail, we performed time resolved small angle X-ray scattering (SAXS) measurements on insulin fibrillation, in combination with additional multidirectional analyses of thioflavin T fluorescence, FTIR spectroscopy, light scattering, and light transmittance, during the fibrillation process of bovine insulin. SAXS monitoring revealed that insulin molecules associated into rod-like prefibrillar aggregates in the very early stage of the reaction. After the formation of these early aggregates, they appeared to further coalesce mutually to form larger clusters, and the SAXS profiles subsequently showed the further time evolution of conformational development towards mature amyloid fibrils. Distinct types of structural units in terms of shape in a nano-scale order, cross-beta content, and thioflavin T fluorescence intensity were observed in a manner that was dependent on the fibrillation pathways. These results suggest the presence of diverse substructures that characterize various fibrillation pathways, and eventually, manifest polymorphisms in mature amyloid fibrils. PMID- 26503464 TI - Bioengineering Human Myocardium on Native Extracellular Matrix. AB - RATIONALE: More than 25 million individuals have heart failure worldwide, with ~4000 patients currently awaiting heart transplantation in the United States. Donor organ shortage and allograft rejection remain major limitations with only ~2500 hearts transplanted each year. As a theoretical alternative to allotransplantation, patient-derived bioartificial myocardium could provide functional support and ultimately impact the treatment of heart failure. OBJECTIVE: The objective of this study is to translate previous work to human scale and clinically relevant cells for the bioengineering of functional myocardial tissue based on the combination of human cardiac matrix and human induced pluripotent stem cell-derived cardiomyocytes. METHODS AND RESULTS: To provide a clinically relevant tissue scaffold, we translated perfusion decellularization to human scale and obtained biocompatible human acellular cardiac scaffolds with preserved extracellular matrix composition, architecture, and perfusable coronary vasculature. We then repopulated this native human cardiac matrix with cardiomyocytes derived from nontransgenic human induced pluripotent stem cells and generated tissues of increasing 3-dimensional complexity. We maintained such cardiac tissue constructs in culture for 120 days to demonstrate definitive sarcomeric structure, cell and matrix deformation, contractile force, and electrical conduction. To show that functional myocardial tissue of human scale can be built on this platform, we then partially recellularized human whole-heart scaffolds with human induced pluripotent stem cell-derived cardiomyocytes. Under biomimetic culture, the seeded constructs developed force-generating human myocardial tissue and showed electrical conductivity, left ventricular pressure development, and metabolic function. CONCLUSIONS: Native cardiac extracellular matrix scaffolds maintain matrix components and structure to support the seeding and engraftment of human induced pluripotent stem cell-derived cardiomyocytes and enable the bioengineering of functional human myocardial-like tissue of multiple complexities. PMID- 26503465 TI - Specific inhibition by synthetic analogs of pyruvate reveals that the pyruvate dehydrogenase reaction is essential for metabolism and viability of glioblastoma cells. AB - The pyruvate dehydrogenase complex (PDHC) and its phosphorylation are considered essential for oncotransformation, but it is unclear whether cancer cells require PDHC to be functional or silenced. We used specific inhibition of PDHC by synthetic structural analogs of pyruvate to resolve this question. With isolated and intramitochondrial PDHC, acetyl phosphinate (AcPH, KiAcPH = 0.1 MUM) was a much more potent competitive inhibitor than the methyl ester of acetyl phosphonate (AcPMe, KiAcPMe = 40 MUM). When preincubated with the complex, AcPH also irreversibly inactivated PDHC. Pyruvate prevented, but did not reverse the inactivation. The pyruvate analogs did not significantly inhibit other 2-oxo acid dehydrogenases. Different cell lines were exposed to the inhibitors and a membrane-permeable precursor of AcPMe, dimethyl acetyl phosphonate, which did not inhibit isolated PDHC. Using an ATP-based assay, dependence of cellular viability on the concentration of the pyruvate analogs was followed. The highest toxicity of the membrane-permeable precursor suggested that the cellular action of charged AcPH and AcPMe requires monocarboxylate transporters. The relevant cell-specific transcripts extracted from Gene Expression Omnibus database indicated that cell lines with higher expression of monocarboxylate transporters and PDHC components were more sensitive to the PDHC inhibitors. Prior to a detectable antiproliferative action, AcPH significantly changed metabolic profiles of the investigated glioblastoma cell lines. We conclude that catalytic transformation of pyruvate by pyruvate dehydrogenase is essential for the metabolism and viability of glioblastoma cell lines, although metabolic heterogeneity causes different cellular sensitivities and/or abilities to cope with PDHC inhibition. PMID- 26503466 TI - A multi-stage process including transient polyploidization and EMT precedes the emergence of chemoresistent ovarian carcinoma cells with a dedifferentiated and pro-inflammatory secretory phenotype. AB - DNA-damaging drugs induce a plethora of molecular and cellular alterations in tumor cells, but their interrelationship is largely obscure. Here, we show that carboplatin treatment of human ovarian carcinoma SKOV3 cells triggers an ordered sequence of events, which precedes the emergence of mitotic chemoresistant cells. The initial phase of cell death after initiation of carboplatin treatment is followed around day 14 by the emergence of a mixed cell population consisting of cycling, cell cycle-arrested and senescent cells. At this stage, giant cells make up >80% of the cell population, p21 (CDKN1A) in strongly induced, and cell numbers remain nearly static. Subsequently, cell death decreases, p21 expression drops to a low level and cell divisions increase, including regular mitoses of giant cells and depolyploidization by multi-daughter divisions. These events are accompanied by the upregulation of stemness markers and a pro-inflammatory secretory phenotype, peaking after approximately 14 days of treatment. At the same time the cells initiate epithelial to mesenchymal transition, which over the subsequent weeks continuously increases, concomitantly with the emergence of highly proliferative, migratory, dedifferentiated, pro-inflammatory and chemoresistant cells (SKOV3-R). These cells are anchorage-independent and grow in a 3D collagen matrix, while cells on day 14 do not survive under these conditions, indicating that SKOV3-R cells were generated thereafter by the multi stage process described above. This process was essentially recapitulated with the ovarian carcinoma cell line IGROV-1. Our observations suggest that transitory cells characterized by polyploidy, features of stemness and a pro-inflammatory secretory phenotype contribute to the acquisition of chemoresistance. PMID- 26503468 TI - Impact of wall shear stress and ligand avidity on binding of anti-CD146-coated nanoparticles to murine tumor endothelium under flow. AB - The endothelial phenotype of tumor blood vessels differs from the liver and forms an important base for endothelium-specific targeting by antibody-coated nanoparticles. Although differences of shear stress and ligand avidity can modulate the nanoparticle binding to endothelium, these mechanisms are still poorly studied. This study analyzed the binding of antibody-coated nanoparticles to tumor and liver endothelium under controlled flow conditions and verified this binding in tumor models in vivo. Binding of anti-CD146-coated nanoparticles, but not of antibody was significantly reduced under increased wall shear stress and the degree of nanoparticle binding correlated with the avidity of the coating. The intravascular wall shear stress favors nanoparticle binding at the site of higher avidity of endothelial epitope which additionally promotes the selectivity to tumor endothelium. After intravenous application in vivo, pegylated self coated nanoparticles showed specific binding to tumor endothelium, whereas the nanoparticle binding to the liver endothelium was very low. This study provides a rationale that selective binding of mAb-coated nanoparticles to tumor endothelium is achieved by two factors: higher expression of endothelial epitope and higher nanoparticle shearing from liver endothelium. The combination of endothelial marker targeting and the use of shear stress-controlled nanoparticle capture can be used for selective intratumoral drug delivery. PMID- 26503467 TI - Polymorphisms involving gain or loss of CpG sites are significantly enriched in trait-associated SNPs. AB - Some single nucleotide polymorphisms (SNPs) influence the existence of CpG sites, the basis of DNA modification such as methylation and hydroxymethylation. These polymorphisms can lead to gain or loss of CpG sites and were defined as CpG site related SNPs (cgSNPs) in this study. The cgSNPs change DNA sequence and might potentially affect DNA modification such as methylation. However, the functional consequence of cgSNPs is poorly understood. We observed that a considerable proportion (23.0%) of common variants were cgSNPs in human genome. Mutations involving loss of CpG sites were associated with reduced levels of methylation (~20.2%) using The Cancer Genome Atlas (TCGA) data. Using public databases (SCAN and seeQTL) of expression quantitative trait loci (eQTLs), we found that the cgSNPs were significantly enriched in eQTLs via logistic regression and simulation test. Furthermore, we observed that cgSNPs were more likely to be trait-associated loci especially cancers using a catalog of published genome-wide association studies (GWAS) recorded by National Human Genome Research Institute (NHGRI). Our results indicated that cgSNP might be meaningful as annotation either in SNP functional prediction or in screening for trait-associated SNPs. PMID- 26503469 TI - Amphiregulin enhances intercellular adhesion molecule-1 expression and promotes tumor metastasis in human osteosarcoma. AB - Osteosarcoma is a common, high malignant, and metastatic bone cancer. Amphiregulin (AREG) has been associated with cancer cellular activities. However, the effect of AREG on metastasis activity in human osteosarcoma cells has yet to be determined. We determined that AREG increases the expression of intercellular adhesion molecule-1 (ICAM-1) through PI3K/Akt signaling pathway via its interaction with the epidermal growth factor receptor, thus resulting in the enhanced cell migration of osteosarcoma. Furthermore, AREG stimulation increased the association of NF-kappaB to ICAM-1 promoter which then up-regulated ICAM-1 expression. Finally, we observed that shRNA silencing of AREG decreased osteosarcoma metastasis in vivo. Our findings revealed a relationship between osteosarcoma metastatic potential and AREG expression and the modulating effect of AREG on ICAM-1 expression. PMID- 26503470 TI - IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry. AB - BACKGROUND: The relative contribution of isocitrate dehydrogenase mutations (mIDH) and O6-methylguanine-DNA methyltransferase promoter methylation (methMGMT) as biomarkers in glioblastoma remain poorly understood. METHODS: We investigated the association between methMGMT and mIDH with progression free survival and overall survival in a prospectively collected molecular registry of 274 glioblastoma patients. RESULTS: For glioblastoma patients who underwent Temozolomide and Radiation Therapy, OS and PFS was most favorable for those with tumors harboring both mIDH and methMGMT (median OS: 35.8 mo, median PFS: 27.5 mo); patients afflicted glioblastomas with either mIDH or methMGMT exhibited intermediate OS and PFS (mOS: 36 and 17.1 mo; mPFS: 12.2 mo and 9.9 mo, respectively); poorest OS and PFS was observed in wild type IDH1 (wtIDH1) glioblastomas that were MGMT promoter unmethylated (mOS: 15 mo, mPFS: 9.7 mo). For patients with wtIDH glioblastomas, TMZ+RT was associated with improved OS and PFS relative to patients treated with RT (OS: 15.4 mo v 9.6 mo, p < 0.001; PFS: 9.9 mo v 6.5 mo, p < 0.001). While TMZ+RT and RT treated mIDH patients exhibited improved overall survival relative to those with wtIDH, there were no differences between the TMZ+RT or RT group. These results suggest that mIDH1 conferred resistance to TMZ. Supporting this hypothesis, exogenous expression of mIDH1 in independent astrocytoma/glioblastoma lines resulted in a 3-10 fold increase in TMZ resistance after long-term passage. CONCLUSIONS: Our study demonstrates IDH mutation and MGMT promoter methylation status independently associate with favorable outcome in TMZ+RT treated glioblastoma patients. However, these biomarkers differentially impact clinical TMZ response. PMID- 26503471 TI - CD133 overexpression correlates with clinicopathological features of gastric cancer patients and its impact on survival: a systematic review and meta analysis. AB - BACKGROUND: CD133 is one of the most commonly used markers of cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical and prognostic significance of CD133 in gastric cancer remains controversial. To clarify a precise determinant of the clinical significance of CD133, we conducted a systematic review and meta analysis to elucidate the correlation of CD133 overexpression with prognosis and clinicopathological features of GC patients. METHODS: A search in the Cochrane Library, PubMed, Medline, Web of Knowledge and Chinese CNKI, CBM (up to Jun 30, 2015) was performed using the following keywords gastric cancer, CD133, AC133, prominin-1, etc. Electronic searches were supplemented by hand searching reference lists, abstracts and proceedings from meetings. Outcomes included overall survival and various clinicopathological features. Two reviewers independently screened the literature according to the inclusion and exclusion criteria, extracted the data, and assessed the methodological quality of the included studies, and then RevMan 5.2.0 software was used for meta-analysis. RESULTS: A total of 603 gastric cancer patients from 8 studies were included. The results of the meta-analyses showed that, there were significant differences of CD133 expression in the following comparisons: gastric cancer tissues vs. normal esophageal tissue (OR = 3.49, 95% CI [2.48, 490], P < 0.00001), lymph node metastasis vs. non-lymph node metastasis (OR = 2.75, 95% CI [1.99, 3.81], P < 0.00001), distant metastasis vs. non-distant metastasis (OR = 2.38, 95%CI [1.47, 3.85], P < 0.0004), clinical stages III~IV vs. clinical stages I~II (OR = 2.83, 95% CI [2.13, 3.76], P < 0.00001), as well as the accumulative 5-year overall survival rates of CD133-positive vs. CD133-negative patients (OR = 0.23, 95% CI [0.16, 0.33], P < 0.00001). CONCLUSION: Overexpression of CD133 is associated with lymph node metastasis, distant metastasis, poor TNM stage. Additionally, CD133-positive gastric cancer patients had worse prognosis. Our results indicate that CD133 may be involved in the carcinogenesis of gastric cancer. Evaluation of cytoplasmic CD133 overexpression in gastric cancer tissue sections may be useful in the future as a novel prognostic factor. Nevertheless, due to the poor quality and small sample size of included trials, more well-designed multi-center randomized controlled trials should be performed. PMID- 26503472 TI - Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis. AB - The DNA glycosylase gene MBD4 safeguards genomic stability at CpG sites and is frequently mutated at coding poly-A tracks in mismatch repair (MMR)-defective colorectal tumors (CRC). Mbd4 biallelic inactivation in mice provided conflicting results as to its role in tumorigenesis. Thus, it is unclear whether MBD4 alterations are only secondary to MMR defects without functional consequences or can contribute to the mutator phenotype. We investigated MBD4 variants in a large series of hereditary/familial and sporadic CRC cases. Whereas MBD4 frameshifts were only detected in tumors, missense variants were found in both normal and tumor DNA. In CRC with double-MBD4/MMR and single-MBD4 variants, transition mutation frequency was increased, indicating that MBD4 defects may affect the mutational landscape independently of MMR defect. Mbd4-deficient mice showed reduced survival when combined with Mlh1-/- genotype. Taken together, these data suggest that MBD4 inactivation may contribute to tumorigenesis, acting as a modifier of MMR-deficient cancer phenotype. PMID- 26503473 TI - Phase 1b study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma. AB - OBJECTIVE AND METHODS: In this phase 1b study, patients with stage 4 or unresectable stage 3 melanoma were treated with escalating doses of lenvatinib (once daily) and temozolomide (TMZ) (days 1-5) in 28-day cycles, to determine the maximum tolerated dose (MTD) of the combination. Dose Level (DL)1: lenvatinib 20 mg, TMZ 100 mg/m2; DL2: lenvatinib 24 mg, TMZ 100 mg/m2; DL3: lenvatinib 24 mg, TMZ 150 mg/m2. Adverse events (AEs) were recorded and tumor response assessed per RECIST 1.0. RESULTS: Dose-limiting toxicity occurred in 1 of 32 treated patients (DL1); MTD was not reached. The highest dose administered was lenvatinib 24 mg + TMZ 150 mg/m2. Most common treatment-related AEs included fatigue (56.3%), hypertension (53.1%), and proteinuria (46.9%). Overall objective response rate was 18.8% (6 patients), all partial response; (DL1, n = 1; DL3, n = 5). Stable disease (SD) >= 16 weeks was observed in 28.1% of patients (DL1 and DL2, n = 1 each; DL3, n = 7); 12.5% of patients had SD >= 23 weeks. Single and repeat-dose pharmacokinetics of lenvatinib were comparable across cycles and with concomitant TMZ administration. CONCLUSIONS: Lenvatinib 24 mg/day + TMZ 150 mg/m2/day (days 1 5) demonstrated modest clinical activity, an acceptable safety profile, and was administered without worsening of either lenvatinib- or TMZ-related toxicities in this patient group. PMID- 26503474 TI - Serum apolipoprotein A-I is a novel prognostic indicator for non-metastatic nasopharyngeal carcinoma. AB - BACKGROUND: We investigated the value of pretreatment serum apolipoprotein A-I (ApoA-I) in complementing TNM staging in the prognosis of non-metastatic nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: We retrospectively reviewed 1196 newly diagnosed patients with non-metastatic NPC. Disease-specific survival (DSS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) rates were compared according to serum ApoA-I level. Multivariate analysis was performed to assess the prognostic value of serum ApoA-I. RESULTS: The 5-year DSS, DMFS, and LRFS rates for patients with elevated or decreased serum ApoA-I were 81.3% versus 69.3% (P < 0.001), 83.4% versus 67.4% (P < 0.001), and 80.9% versus 67.3% (P < 0.001), respectively. ApoA-I >= 1.025 g/L was an independent prognostic factor for superior DSS, DMFS, and LRFS in multivariate analysis. After stratification by clinical stage, serum ApoA-I remained a clinically and statistically significant predictor of prognosis. CONCLUSION: Our data suggest that the level of ApoA-I at diagnosis is a novel independent prognostic marker that could complement clinical staging for risk definition in non-metastatic NPC. PMID- 26503475 TI - The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti tumorigenic effects in ovarian cancer. AB - Ovarian cancer is the 5th leading cause of cancer death among women in the United States. The mevalonate pathway is thought to be a potential oncogenic pathway in the pathogenesis of ovarian cancer. Simvastatin, a 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCR) inhibitor, is a widely used drug for inhibiting the synthesis of cholesterol and may also have anti-tumorigenic activity. Our goal was to evaluate the effects of simvastatin on ovarian cancer cell lines, primary cultures of ovarian cancer cells and in an orthotopic ovarian cancer mouse model. Simvastatin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, and caused cellular stress via reduction in the enzymatic activity of HMGCR and inhibition of the MAPK and mTOR pathways in ovarian cancer cells. Furthermore, simvastatin induced DNA damage and reduced cell adhesion and invasion. Simvastatin also exerted anti-proliferative effects on primary cell cultures of ovarian cancer. Treatment with simvastatin in an orthotopic mouse model reduced ovarian tumor growth, coincident with decreased Ki-67, HMGCR, phosphorylated-Akt and phosphorylated-p42/44 protein expression. Our findings demonstrate that simvastatin may have therapeutic benefit for ovarian cancer treatment and be worthy of further exploration in clinical trials. PMID- 26503476 TI - Buffalo (Bubalus bubalis) SCNT embryos produced from somatic cells isolated from frozen-thawed semen: effect of trichostatin A on the in vitro and in vivo developmental potential, quality and epigenetic status. AB - This study examined the effects of trichostatin A (TSA) treatment of reconstructed buffalo embryos, produced by hand-made cloning using somatic cells isolated from over a decade old frozen-thawed semen, on their in vitro and in vivo developmental competence, quality and epigenetic status. Following treatment of reconstructed embryos with TSA (0, 50 or 75 nM) for 10 h prior to culture, the cleavage (100.0 +/- 0, 94.5 +/- 2.3 and 96.1 +/- 1.2%, respectively) and blastocyst rate (50.6 +/- 2.3, 48.4 +/- 2.7 and 48.1 +/- 2.6%, respectively), total cell number (275 +/- 17.4, 289 +/- 30.1 and 317 +/- 24.2, respectively) and apoptotic index (5.6 +/- 0.7, 3.4 +/- 0.9 and 4.5 +/- 1.4, respectively) were not significantly different among the three groups. However, TSA treatment increased (P < 0.05) the global level of H4K5ac and decreased (P < 0.05) that of H3K27me3 in blastocysts whereas the global level of H3K18ac was not affected significantly. Transfer of embryos treated with 75 nM TSA (n = 10) to recipients resulted in two pregnancies (20%), one out of which was aborted in the second and the other in the third trimester whereas transfer of control embryos (n = 20) or those treated with 50 nM TSA (n = 12) did not result in any pregnancy. In conclusion, these results suggest that TSA treatment of cloned buffalo embryos produced using somatic cells isolated from frozen-thawed semen improved their epigenetic status but not the in vitro developmental potential and offspring rate. PMID- 26503477 TI - Controlled Rh-Catalyzed Mono- and Double-decarbonylation of Alkynyl alpha-Diones To Form Conjugated Ynones and Disubstituted Alkynes. AB - A Rh-catalyzed controlled decarbonylation of alkynyl alpha-diones is described. By using different ligand and solvent combinations, mono- and double decarbonylation can be selectively achieved to give conjugated ynones and disubstituted alkynes, respectively. A fundamental study on catalytic activation of unstrained C-C bonds under nonoxidative conditions is presented. PMID- 26503478 TI - The role of plant cell wall encapsulation and porosity in regulating lipolysis during the digestion of almond seeds. AB - Previous studies have provided evidence that the physical encapsulation of intracellular nutrients by cell walls of plant foods (i.e. dietary fibre) plays a predominant role in influencing macronutrient bioaccessibility (release) from plant foods during human digestion. One unexplored aspect of this is the extent to which digestive enzymes can pass through the cell-wall barrier and hydrolyse the intracellular lipid in almond seeds. The purpose of the present study was to assess the role played by cell walls in influencing the bioaccessibility and digestibility of almond lipid using a range of techniques. Digestibility experiments were performed on raw and roasted almond cells as well as isolated almond oil bodies using in vitro gastric and duodenal digestion models. Residual triacylglycerols and lipolysis products were extracted after 1 h of incubation and analysed by thin layer chromatography. The lipolysis kinetics of almond cells and oil bodies were also investigated using the pH-stat technique. Finally, the potential penetration of pancreatic lipase through the cell wall matrix was investigated using confocal microscopy. Differences in the rates and extent of lipolysis were clearly seen between almond cells and oil bodies, and these differences were observed regardless of the lipase(s) used. These results also showed that almond cell walls that are completely intact limit lipid digestibility, due to an encapsulation mechanism that hinders the diffusion of lipase into the intracellular environment and lipolysis products out of the cells. PMID- 26503479 TI - Obituary: Remembering Emeritus Professor Lester Mitscher (20 August 1931-8 May 2015). PMID- 26503480 TI - Onset of autumn shapes the timing of birth in Pyrenean chamois more than onset of spring. AB - In seasonal environments, birth dates are a central component for a species' life history, with potential long-term fitness consequences. Yet our understanding of selective pressures of environmental changes on birth dates is limited in wild mammals due to the difficulty of data collection. In a context of rapid climate change, the question of a possible mismatch between plant phenology and birth phenology also remains unanswered for most species. We assessed whether and how the timing of birth in a mountain mammal (isard, also named Pyrenean chamois, Rupicapra pyrenaica pyrenaica) tracked changes in plant growing season, accounting for maternal traits, individual heterogeneity and population density. We not only focused on spring conditions but also assessed to what extent onset of autumn can be a driver of phenological biological events and compared the magnitude of the response to the magnitude of the environmental changes. We relied on a 22-year study based on intensively monitored marked individuals of known age. Births were highly synchronized (80% of kids born within 25 days) and highly repeatable (84%; between-female variation of 9.6 days, within-female variation of 4.2 days). Individual phenotypic plasticity allows females to respond rapidly to interannual changes in plant phenology but did not prevent the existence of a mismatch: a 10-day advance in the autumn or spring plant phenology led to 3.9 and 1.3 days advance in birth dates, respectively. Our findings suggest that plant phenology may act as a cue to induce important stages of the reproductive cycle (e.g. conception and gestation length), subsequently affecting parturition dates, and stressed the importance of focusing on long-term changes during spring for which females may show much lower adaptive potential than during autumn. These results also question the extent to which individual plasticity along with high heterogeneity among individuals will allow species to cope with demographic consequences of climate changes. PMID- 26503481 TI - Inquiry-based experiments for large-scale introduction to PCR and restriction enzyme digests. AB - Polymerase chain reaction and restriction endonuclease digest are important techniques that should be included in all Biochemistry and Molecular Biology laboratory curriculums. These techniques are frequently taught at an advanced level, requiring many hours of student and faculty time. Here we present two inquiry-based experiments that are designed for introductory laboratory courses and combine both techniques. In both approaches, students must determine the identity of an unknown DNA sequence, either a gene sequence or a primer sequence, based on a combination of PCR product size and restriction digest pattern. The experimental design is flexible, and can be adapted based on available instructor preparation time and resources, and both approaches can accommodate large numbers of students. We implemented these experiments in our courses with a combined total of 584 students and have an 85% success rate. Overall, students demonstrated an increase in their understanding of the experimental topics, ability to interpret the resulting data, and proficiency in general laboratory skills. PMID- 26503483 TI - Abstracts of the IPITA-IXA-CTS 2015 Joint Congress November 15-19, 2015, Melbourne, Australia. PMID- 26503484 TI - The Chemistry of Heterasumanenes. AB - Our studies on the synthesis of heterasumanenes, where benzylic carbon atoms of the sumanene are replaced by heteroatom functionalities, are summarized. Starting from triphenylene, repetitive lithiation at a bay position followed by introduction of silylene or germylene units provided the first trisila- and trigermasumanenes with no substituents on the skeletal carbon atoms. The synthesis of a trisilasumanene bearing six butoxy groups on the skeletal carbon atoms was also accomplished by our original sila-Friedel-Crafts reaction. A heterasumanene bearing three different heteroatom functionalities was also prepared from triphenylenothiophene by a sequential lithiation method, even though protecting groups were necessary to prevent lithiation at the alpha-carbon atoms of the dibenzothiophene unit. Structural analysis and optical properties of the novel heterasumanenes are also described. PMID- 26503485 TI - Quality of antenatal and childbirth care in rural health facilities in Burkina Faso, Ghana and Tanzania: an intervention study. AB - OBJECTIVE: To assess the impact of an intervention consisting of a computer assisted clinical decision support system and performance-based incentives, aiming at improving quality of antenatal and childbirth care. METHODS: Intervention study in rural primary healthcare (PHC) facilities in Burkina Faso, Ghana and Tanzania. In each country, six intervention and six non-intervention PHC facilities, located in one intervention and one non-intervention rural districts, were selected. Quality was assessed in each facility by health facility surveys, direct observation of antenatal and childbirth care, exit interviews, and reviews of patient records and maternal and child health registers. Findings of pre- and post-intervention and of intervention and non intervention health facility quality assessments were analysed and assessed for significant (P < 0.05) quality of care differences. RESULTS: Post-intervention quality scores do not show a clear difference to pre-intervention scores and scores at non-intervention facilities. Only a few variables had a statistically significant better post-intervention quality score and when this is the case this is mostly observed in only one study-arm, being pre-/post-intervention or intervention/non-intervention. Post-intervention care shows similar deficiencies in quality of antenatal and childbirth care and in detection, prevention, and management of obstetric complications as at baseline and non-intervention study facilities. CONCLUSION: Our intervention study did not show a significant improvement in quality of care during the study period. However, the use of new technology seems acceptable and feasible in rural PHC facilities in resource constrained settings, creating the opportunity to use this technology to improve quality of care. PMID- 26503482 TI - Ageing-related changes in GABAergic inhibition in mouse auditory cortex, measured using in vitro flavoprotein autofluorescence imaging. AB - KEY POINTS: Ageing is associated with hearing loss and changes in GABAergic signalling in the auditory system. We tested whether GABAergic signalling in an isolated forebrain preparation also showed ageing-related changes. A novel approach was used, whereby population imaging was coupled to quantitative pharmacological sensitivity. Sensitivity to GABAA blockade was inversely associated with age and cortical thickness, but hearing loss did not independently contribute to the change in GABAA ergic sensitivity. Redox states in the auditory cortex of young and aged animals were similar, suggesting that the differences in GABAA ergic sensitivity are unlikely to be due to differences in slice health. To examine ageing-related changes in the earliest stages of auditory cortical processing, population auditory cortical responses to thalamic afferent stimulation were studied in brain slices obtained from young and aged CBA/CAj mice (up to 28 months of age). Cortical responses were measured using flavoprotein autofluorescence imaging, and ageing-related changes in inhibition were assessed by measuring the sensitivity of these responses to blockade of GABAA receptors using bath-applied SR95531. The maximum auditory cortical response to afferent stimulation was not different between young and aged animals under control conditions, but responses to afferent stimulation in aged animals showed a significantly lower sensitivity to GABA blockade with SR95531. Cortical thickness, but not hearing loss, improved the prediction of all imaging variables when combined with age, particularly sensitivity to GABA blockade for the maximum response. To determine if the observed differences between slices from young and aged animals were due to differences in slice health, the redox state in the auditory cortex was assessed by measuring the FAD+/NADH ratio using fluorescence imaging. We found that this ratio is highly sensitive to known redox stressors such as H2 O2 and NaCN; however, no difference was found between young and aged animals. By using a new approach to quantitatively assess pharmacological sensitivity of population-level cortical responses to afferent stimulation, these data demonstrate that auditory cortical inhibition diminishes with ageing. Furthermore, these data establish a significant relationship between cortical thickness and GABAergic sensitivity, which had not previously been observed in an animal model of ageing. PMID- 26503486 TI - Substance use disorder and risk of suicidal ideation, suicide attempt and suicide death: a meta-analysis. AB - BACKGROUND: This meta-analysis addressed the association between substance use disorder (SUD) and suicide outcomes based on current evidence. METHODS: We searched PubMed, Web of Science and Scopus until May 2015. We also searched the reference lists of included studies and Psycinfo website. We included observational (cohort, case-control, cross-sectional) studies addressing the association between SUD and suicide. Our outcomes of interest were suicide ideation, suicide attempt and suicide death. For each outcome, we calculated the odds ratio (OR) or risk ratio (RR) with 95% confidence intervals (CI) based on the random-effects model. RESULTS: We identified a total of 12 413 references and included 43 studies with 870 967 participants. There was a significant association between SUD and suicidal ideation: OR 2.04 (95% CI: 1.59, 2.50; I2 = 88.8%, 16 studies); suicide attempt OR 2.49 (95% CI: 2.00, 2.98; I2 = 94.3%, 24 studies) and suicide death OR 1.49 (95% CI: 0.97, 2.00; I2 = 82.7%, 7 studies). CONCLUSIONS: Based on current evidence, there is a strong association between SUD and suicide outcomes. However, evidence based on long-term prospective cohort studies is limited and needs further investigation. Moreover, further evidence is required to assess and compare the association between suicide outcomes and different types of illicit drugs, dose-response relationship and the way they are used. PMID- 26503488 TI - Feasibility study for assessing liver fibrosis in paediatric and adolescent patients using real-time shear wave elastography. AB - INTRODUCTION: The objective of this study was to evaluate the feasibility of shear wave elastography (SWE), as a non-invasive means of assessing liver fibrosis stage in paediatric and adolescent patients. MATERIALS AND METHODS: Consecutive paediatric and adolescent subjects scheduled for liver biopsy (LB) evaluation of known or suspected diffuse liver disease were included after informed guardian consent and subject assent in this IRB-approved single institution study. Elastograms were acquired prior to liver biopsy, from the liver under a breath-hold after normal inspiration when possible. Biopsy specimens underwent blinded pathologist review using the METAVIR scoring system. RESULTS: Twenty-four patients (M : F = 13:11) with a mean age of 17 years (range: 1-21 years) underwent liver biopsy. The distribution of fibrosis on pathological examination was: F0 = 10, F1 = 9, F2 = 1, F3 = 3, and F4 = 1. Subjects with stages F0 and F1 fibrosis had a mean SWE value of 6.93 kPa (95% CI: 6.33-7.44 kPa) and 8.33 kPa (95% CI: 6.83-10.80 kPa) respectively. The SWE value for the one subject with stage F2 fibrosis was 6.36 kPa, whereas for F3 and F4 were 8.86 (95% CI: 5.70-11.40) and 17.85 kPa respectively. The correlation between SWE values and fibrosis grade was strong (r = 0.58, P = 0.003), and the area under the ROC curve differentiatiang >=F2 fibrosis was 0.62 (95% CI: 0.26-0.98). CONCLUSION: Estimation of liver stiffness using real-time SWE is feasible using the SC6-1 ultrasound probe in paediatric and adolescent patients and strongly correlates with the stage of fibrosis. PMID- 26503489 TI - Evaluation of a 7-Methoxycoumarin-3-carboxylic Acid Ester Derivative as a Fluorescent, Cell-Cleavable, Phosphonate Protecting Group. AB - Cell-cleavable protecting groups often enhance cellular delivery of species that are charged at physiological pH. Although several phosphonate protecting groups have achieved clinical success, it remains difficult to use these prodrugs in live cells to clarify biological mechanisms. Here, we present a strategy that uses a 7-methoxycoumarin-3-carboxylic acid ester as a fluorescent protecting group. This strategy was applied to synthesis of an (E)-4-hydroxy-3-methyl-but-2 enyl diphosphate (HMBPP) analogue to assess cellular uptake and human Vgamma9Vdelta2 T cell activation. The fluorescent ester displayed low cellular toxicity (IC50 >100 MUm) and strong T cell activation (EC50 =0.018 MUm) relative to the unprotected anion (EC50 =23 MUm). The coumarin-derived analogue allowed no wash analysis of biological deprotection, which revealed rapid internalization of the prodrug. These results demonstrate that fluorescent groups can be applied both as functional drug delivery tools and useful biological probes of drug uptake. PMID- 26503490 TI - Controlled Nanopores in Thin Films of Nonstoichiometrically Supramolecularly Assembled Graft Copolymers. AB - Herein, nanometer-scale morphologies of graft-copolymer-like supramolecular thin films, composed of sulfonic acid terminated polystyrene (SPS) and poly(2 vinylpyridine) (P2VP), and their application to antireflection coatings were investigated. The intermolecular complexes of SPS and P2VP, formed through nonstoichiometric multiple hydrogen bonding between the sulfonic acid group of SPS and the nitrogen atom in pyridine unit of P2VP, occurring in film deposition allowed for the formation of spherical micelles (with SPS and P2VP as the corona and core, respectively) in the thin film. Interestingly, the domain size of the micelles was tunable from approximately 20 to 90 nm on average by controlling either the blend ratio of components or the concentration of polymer solution. Furthermore, nanoporous thin films could be easily prepared by removing the core of micelle-based nanostructures by using a simple solvent etching process, leaving sulfonic acid groups on the surface of nanopores, which can be utilized as potential functional sites. Those resultant nanoporous thin films were conveniently employed as an antireflection layer on a glass substrate, giving a maximum 97.8 % transmittance in the visible wavelength range. PMID- 26503491 TI - Therapy combinations: celebrating more milestones. PMID- 26503492 TI - Telomere length and survival in IPF patients. PMID- 26503493 TI - Sugar and artificially sweetened beverage consumption and adiposity changes: National longitudinal study. AB - BACKGROUND: In response to increasing policy action and public concern about the negative health effects of sugar-sweetened beverages (SSBs), there is increased promotion of artificially sweetened beverages (ASBs). These have been linked with obesity and diabetes in recent experimental work. This study examined associations between SSB and ASB consumption and changes in adiposity in a nationally representative sample of UK children. METHODS: We conducted a longitudinal study of 13,170 children aged 7-11 years in the UK Millennium Cohort Study, collected in 2008 and 2012. Logistic regression was used to assess socio demographic and behavioural correlates of weekly SSB and ASB consumption at 11 years. Linear regression examined associations between SSB/ASB consumption and changes in adiposity measures between 7 and 11 years. RESULTS: Boys were more likely to consume SSBs weekly (62.3% v 59.1%) than girls at age 11 years. South Asian children were more likely to consume SSBs weekly (78.8% v 58.4%) but less likely to consume ASBsweekly (51.7% v 66.3%) than White children. Daily SSB consumption was associated with increases in percentage body fat between ages 7 and 11 (+0.57%, 95% confidence intervals 0.30;0.83). Daily ASB consumption was associated with increased percentage body fat at age 11 (+1.18 kg/m(2), 0.81;1.54) and greater increases between ages 7 and 11 (+0.35 kg/m(2), 0.09;0.61). CONCLUSION: Consumption of SSBs and ASBs was associated with BMI and percentage body fat increases in UK children. Obesity prevention strategies which encourage the substitution of SSBs with ASBs may not yield the adiposity benefits originally intended and this area should be a focus for further research. PMID- 26503495 TI - Meta-analysis of the association of brain-derived neurotrophic factor Val66Met polymorphism with obsessive-compulsive disorder. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) plays an important role in neural survival and was proposed to be related to psychiatric disorders. Val66Met (also known as rs6265 or G196A), the only known functional polymorphism of the BDNF gene, has been widely studied and considered to be associated with risk of some psychiatric disorders such as bipolar disorder and schizophrenia. However, studies evaluating its association with obsessive-compulsive disorder (OCD) obtained inconsistent results. The purpose of this study was to derive a more precise estimation of the association between BDNF Val66Met polymorphism and OCD susceptibility by a meta-analysis. METHOD: We carried a structured literature search in PubMed, Embase, PsycINFO and Chinese Biomedical Database up to December 2014; and retrieved all eligible case-control studies according to the including criteria. Meta-analysis was performed for four genetic models: allelic model: Met versus Val; additive model: Met/Met versus Val/Val; recessive model: Met/Met versus Val/Val+Val/Met; and dominant model: Val/Met+Met/Met versus Val/Val. Stratified analyses were performed by ethnicity and gender where appropriate. RESULTS: A total of eight articles with nine studies including 1632 OCD cases and 2417 controls were identified. No significant association was detected in any comparison when the whole data were pooled together or stratified by ethnicity or gender in all four genetic models (p>0.05 for each comparison). CONCLUSION: Despite some limitations, our meta-analysis suggests that no significant association exists between the BDNF Val66Met polymorphism and OCD susceptibility. PMID- 26503494 TI - S-nitrosylation-dependent proteasomal degradation restrains Cdk5 activity to regulate hippocampal synaptic strength. AB - Precise regulation of synaptic strength requires coordinated activity and functions of synaptic proteins, which is controlled by a variety of post translational modification. Here we report that S-nitrosylation of p35, the activator of cyclin-dependent kinase 5 (Cdk5), by nitric oxide (NO) is important for the regulation of excitatory synaptic strength. While blockade of NO signalling results in structural and functional synaptic deficits as indicated by reduced mature dendritic spine density and surface expression of glutamate receptor subunits, phosphorylation of numerous synaptic substrates of Cdk5 and its activity are aberrantly upregulated following reduced NO production. The results show that the NO-induced reduction in Cdk5 activity is mediated by S nitrosylation of p35, resulting in its ubiquitination and degradation by the E3 ligase PJA2. Silencing p35 protein in hippocampal neurons partially rescues the NO blockade-induced synaptic deficits. These findings collectively demonstrate that p35 S-nitrosylation by NO signalling is critical for regulating hippocampal synaptic strength. PMID- 26503496 TI - Heat stroke during treatment with olanzapine, trihexyphenidyl, and trazodone in a patient with schizophrenia. AB - OBJECTIVE: Heat stroke is a medical emergency. Psychiatric patients are particularly susceptible to heat stroke. Therefore, awareness and preventive measures of heat stroke are important for both clinicians and patients. Case description A 49-year-old man with schizophrenia, who was under maintenance treatment with olanzapine 20 mg/day, trihexyphenidyl 4 mg/day, and trazodone 50 mg/day, suffered from heat stroke in a heat wave and required intensive care. He recovered with the medical treatment provided. Discussion Several factors could have contributed to the impaired thermoregulation and the occurrence of heat stroke in this case: schizophrenia, the psychotropic regimen, and lack of preventive measures. Possible differential diagnoses of heat stroke in this case include infection, neuroleptic malignant syndrome, and serotonin syndrome. CONCLUSION: Heat stroke can occur during the maintenance treatment of olanzapine, trihexyphenidyl, and trazodone for schizophrenia. Clinicians should be proactive to reduce the risk of heat stroke in psychiatric patients. PMID- 26503497 TI - The postoperative patient-reported quality of recovery in colorectal cancer patients under enhanced recovery after surgery using QoR-40. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols may reduce postoperative complications and the length of hospital stay. Studies of the effectiveness of ERAS should include not only doctor-reported outcomes, but also patient-reported outcomes, in order to better estimate their impact on recovery. However, patient-reported outcomes are not commonly reported. Thus, it needs to be assessed whether early discharge from the hospital is compatible with a better outcome from the viewpoint of the patients themselves. METHODS: The 40-item quality of recovery score (QoR-40) is a recovery-specific, and patient-rated questionnaire, which provides a good measurement of early postoperative recovery. Ninety-four colorectal cancer patients undergoing surgery under ERAS protocol management were asked to answer QoR-40 questionnaires preoperatively and on post operative day (POD) 1, 3, 6 and one month after surgery. RESULTS: The median (25th, 75th percentiles) preoperative global QoR-40 scores as an indicator of the baseline health status, was 189 (176.75, 197). On POD1 and POD3, the scores had decreased significantly to 154 (132.5, 164.25) and 177 (161.75, 190), respectively. On POD 6, the score dramatically recovered up to 183.5 (167.9, 191), which was not significantly different from the baseline level (p = 0.06). The scores at 1 month after surgery were 190 (176, 197). Younger patients, compared to older patients, and rectal cancer patients, compared to colon cancer patients, had significantly lower scores on POD1. CONCLUSION: This study clearly demonstrated that the quality of recovery based on patient-reported outcomes is in agreement with discharge around POD6 for colorectal cancer patients under ERAS. PMID- 26503498 TI - Vitamin A supplementation during pregnancy for maternal and newborn outcomes. AB - BACKGROUND: The World Health Organization recommends routine vitamin A supplementation during pregnancy or lactation in areas with endemic vitamin A deficiency (where night blindness occurs), based on the expectation that supplementation will improve maternal and newborn outcomes including mortality, morbidity and prevention of anaemia or infection. OBJECTIVES: To review the effects of supplementation of vitamin A, or one of its derivatives, during pregnancy, alone or in combination with other vitamins and micronutrients, on maternal and newborn clinical outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 March 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All randomised or quasi randomised trials, including cluster-randomised trials, evaluating the effect of vitamin A supplementation in pregnant women. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: We reviewed 106 reports of 35 trials, published between 1931 and 2015. We included 19 trials including over 310,000 women, excluded 15 trials and one is ongoing. Overall, seven trials were judged to be of low risk of bias, three were high risk of bias and for nine it was unclear. 1) Vitamin A alone versus placebo or no treatmentOverall, when trial results are pooled, vitamin A supplementation does not affect the risk of maternal mortality (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.65 to 1.20; four trials Ghana, Nepal, Bangladesh, UK, high quality evidence), perinatal mortality (RR 1.01, 95% CI 0.95 to 1.07; one study, high quality evidence), neonatal mortality, stillbirth, neonatal anaemia, preterm birth (RR 0.98, 95% CI 0.94 to 1.01, five studies, high quality evidence), or the risk of having a low birthweight baby.Vitamin A supplementation reduces the risk of maternal night blindness (RR 0.79, 95% CI 0.64 to 0.98; two trials). There is evidence that vitamin A supplements may reduce maternal clinical infection (RR 0.45, 95% CI 0.20 to 0.99, five trials; South Africa, Nepal, Indonesia, Tanzania, UK, low quality evidence) and maternal anaemia (RR 0.64, 95% CI 0.43 to 0.94; three studies, moderate quality evidence). 2) Vitamin A alone versus micronutrient supplements without vitamin AVitamin A alone compared to micronutrient supplements without vitamin A does not decrease maternal clinical infection (RR 0.99, 95% CI 0.83 to 1.18, two trials, 591 women). No other primary or secondary outcomes were reported 3) Vitamin A with other micronutrients versus micronutrient supplements without vitamin AVitamin A supplementation (with other micronutrients) does not decrease perinatal mortality (RR 0.51, 95% CI 0.10 to 2.69; one study, low quality evidence), maternal anaemia (RR 0.86, 95% CI 0.68 to 1.09; three studies, low quality evidence), maternal clinical infection (RR 0.95, 95% CI 0.80 to 1.13; I2 = 45%, two studies, low quality evidence) or preterm birth (RR 0.39, 95% CI 0.08 to 1.93; one study, low quality evidence).In HIV positive women vitamin A supplementation given with other micronutrients was associated with fewer low birthweight babies (< 2.5 kg) in the supplemented group in one study (RR 0.67, 95% CI 0.47 to 0.96; one study, 594 women). AUTHORS' CONCLUSIONS: The pooled results of three large trials in Nepal, Ghana and Bangladesh (with over 153,500 women) do not currently suggest a role for antenatal vitamin A supplementation to reduce maternal or perinatal mortality. However, the populations studied were probably different with regard to baseline vitamin A status and there were problems with follow-up of women. There is good evidence that antenatal vitamin A supplementation reduces maternal night blindness, maternal anaemia for women who live in areas where vitamin A deficiency is common or who are HIV-positive. In addition the available evidence suggests a reduction in maternal infection, but these data are not of a high quality. PMID- 26503499 TI - Are women with complications of an incomplete abortion more likely to be HIV infected than women without complications? AB - BACKGROUND: There is limited published evidence about the status of HIV among women who have had abortions or suffered from abortion complications. Understanding this connection is critical for building the evidence base and for guiding strategies to manage the sexual and reproductive health needs of women living with HIV. The purpose of this study is to determine whether women who suffered incomplete abortion complications are more likely to be HIV infected than those without complications. We hypothesized that women with incomplete abortion complications have higher rates of HIV infection than women who attended clinic for other obstetric reasons. METHODS: The analysis used a secondary dataset from a published case-control study that enrolled 1) 70 women at discharge after receiving in-patient care for complications resulting from induced abortion, and 2) 69 women (the comparison group) who visited the same hospital during the same time period for other obstetric needs. The primary outcome was seeking care for complications of incomplete abortion versus seeking care for other obstetric needs (dichotomous). The primary exposure variable was self-reported HIV status which was categorized into three groups: HIV positive, HIV negative, and HIV unknown. Unadjusted and adjusted associations between being in the abortion complications group, HIV status and other selected population characteristics were estimated using univariate and multivariate logistic regression. RESULTS: Of 139 women enrolled in this study. Seventy (50.4 %) women had abortion complications and 69 (49.6 %) did not. Of the total study population, 18 (12.9 %) were HIV positive, 50 (36.0 %) were HIV negative, and the HIV status of 71 women (51.1 %) was unknown. Compared to women who were HIV negative, women who were HIV positive had similar odds of being in the abortion complications group in both univariate and multivariate analyses (rho =0.62 and rho = 0.76). However, compared to HIV-negative women, those women who did not know their HIV status had greater odds of being in the abortion complications group (OR = 3.8, 95 % CI, 1.88, 8.20) in univariate analysis. After adjusting for potential confounding variables, the odds of being in the abortion complications group remained greater among women who did not know their HIV status compared to HIV-negative women (adjusted OR = 2.8, 95 % CI, 1.20, 6.54). CONCLUSIONS: This study points to the need for targeted interventions aimed at strengthening the delivery and coverage of HIV-testing programs for pregnant women and post abortion care. In addition, more research is needed to better understand the relationships between unsafe abortion, abortion complications and unknown HIV status. PMID- 26503500 TI - Erratum. PMID- 26503503 TI - The attitudes of general hospital doctors toward patients with comorbid mental illness. AB - OBJECTIVE: What are the attitudes of general hospital doctors toward patients with comorbid mental illness? Do certain characteristics of the health professional related to attitude valence to patients with comorbid mental illness? METHOD: An anonymous questionnaire was sent out to a cohort of doctors working in three General Hospitals in South West London. The questionnaire included vignettes to assess the respondents' attitudes toward eight patients presenting with a physical compliant with different clinical histories, including depression, schizophrenia, personality disorder, diabetes, and criminal behavior. RESULTS: A total of 52 participants completed the questionnaire; 40 females and 12 males. Across all domains, the most positive attitudes were held toward patients without a diagnosis of mental illness. The least positive attitudes were toward patients with schizophrenia, personality disorder, and those classified as "criminals," and negative attitudes relating to the unpredictability of patients was identified in these categories. There was no statistically significant difference in attitudes depending on age or level of training. However, female participants tended to endorse more positive attitudinal responses, most clearly toward patients with depression and heroin addiction. CONCLUSIONS: Negative attitudes of doctors were identified toward certain mental illness diagnoses and are likely to contribute the physical health disparity between patients with and without a comorbid mental illness. This raises the question as to how these attitudes can be changed in order to improve the parity of physical health care between patient with and without mental illness. PMID- 26503504 TI - MiR-24 functions as a tumor suppressor in nasopharyngeal carcinoma through targeting FSCN1. AB - BACKGROUND: Increasing evidence indicates that the dysregulation of miRNAs expression is involved in the tumorigenesis by acting as tumor suppressors or oncogenes. However, no study investigates the function and mechanisms of miR-24 in nasopharyngeal carcinoma (NPC). METHODS: Quantitative RT-PCR, MTT, colony formation, soft-agar, wound healing, Transwell migration and invasion assays, and xenograft tumor growth and lung metastasis models were performed to test the expression levels and functions of miR-24 in NPC. Luciferase reporter assay, quantitative RT-PCR, Western blotting, and immunohistochemistry were used to identify and verify the target of miR-24. RESULTS: The results showed that MiR-24 was obviously downregulated in NPC cell lines and tissue samples (P < 0.05). Ectopic expression of miR-24 inhibited the cell viability, proliferation, migration, and invasion in vitro (all P < 0.05), and suppressed the xenograft tumor growth and lung metastasis formation in vivo (all P < 0.05). Fascin homologue 1 (FSCN1) was verified as a direct target of miR-24, and silencing FSCN1 expression with small interfering RNA inhibited NPC cell proliferation and invasion (all P < 0.05). CONCLUSIONS: Overall, miR-24 acts as a novel tumor suppressor in the development and progression of NPC through targeting FSCN1, which providing new insight into the mechanisms of NPC carcinogenesis and suggesting the possibility of miR-24 as a therapeutic target. PMID- 26503502 TI - Multimodal description of whole brain connectivity: A comparison of resting state MEG, fMRI, and DWI. AB - Structural and functional connectivity (SC and FC) have received much attention over the last decade, as they offer unique insight into the coordination of brain functioning. They are often assessed independently with three imaging modalities: SC using diffusion-weighted imaging (DWI), FC using functional magnetic resonance imaging (fMRI), and magnetoencephalography/electroencephalography (MEG/EEG). DWI provides information about white matter organization, allowing the reconstruction of fiber bundles. fMRI uses blood-oxygenation level-dependent (BOLD) contrast to indirectly map neuronal activation. MEG and EEG are direct measures of neuronal activity, as they are sensitive to the synchronous inputs in pyramidal neurons. Seminal studies have targeted either the electrophysiological substrate of BOLD or the anatomical basis of FC. However, multimodal comparisons have been scarcely performed, and the relation between SC, fMRI-FC, and MEG-FC is still unclear. Here we present a systematic comparison of SC, resting state fMRI-FC, and MEG-FC between cortical regions, by evaluating their similarities at three different scales: global network, node, and hub distribution. We obtained strong similarities between the three modalities, especially for the following pairwise combinations: SC and fMRI-FC; SC and MEG-FC at theta, alpha, beta and gamma bands; and fMRI-FC and MEG-FC in alpha and beta. Furthermore, highest node similarity was found for regions of the default mode network and primary motor cortex, which also presented the highest hubness score. Distance was partially responsible for these similarities since it biased all three connectivity estimates, but not the unique contributor, since similarities remained after controlling for distance. PMID- 26503505 TI - The fate of systemically administrated allogeneic mesenchymal stem cells in mouse femoral fracture healing. AB - INTRODUCTION: The fate and whereabouts of the allogenic mesenchymal stem cells (MSCs) following their transplantation are not well understood. The present study investigated the fate of systemically administrated allogeneic MSCs in mouse fracture healing by using in vivo imaging and immunohistochemistry methods. METHODS: Open femoral fracture with internal fixation was established in 30 FVB mice, which were assigned to three groups receiving phosphate-buffered saline (PBS) injection, MSC systemic injection, or MSC local injection. Luc-MSCs (5 * 10(5)) isolated from the luciferase transgenic mice with FVB background were injected at 4 days after fracture. All animals were terminated at 5 weeks after fracture; examinations included bioluminescence-based in vivo imaging, micro computer tomography, mechanical testing, histology, immunohistochemistry, and double immunofluorescence staining. RESULTS: The bioluminescence signals of the Luc-MSCs at the fracture site could be detected for 12-14 days following their injection in the Luc-MSC local injection group, whereas in the Luc-MSC systemic injection group, Luc-MSCs were initially trapped in lungs for about 8-9 days and then gradually redistributed to the fracture site. Bone mineral density, bone volume/tissue volume, ultimate load, and E-modulus in the MSC injection groups were significantly higher than those in the PBS group. Double immunostaining demonstrated that the MSC local injection group had more Luc-positive cells, and there was a higher apoptotic rate at the fracture site than the MSC systemic injection group. Both Luciferase-positive MSCs and osteoblasts were present in the callus in the MSC injection groups at 5 weeks after fracture, suggesting that some of allogenic Luc-MSCs contributed to the new bone formation. Only less than 3 % of injected Luc-MSCs remained at the fracture site in the MSC injection groups at 5 weeks following the fracture, and the rest of the injected Luc-MSCs disappeared. CONCLUSIONS: Our data showed that both systemic and local injection of allogeneic MSCs promoted fracture healing through enhancing biomechanical properties, bone content, and enlarged callus sizes. Immunohistochemistry confirmed that the injected MSCs are still present in the fracture site and can differentiate into osteoblasts to participate in fracture healing even at 5 weeks following the fracture. These findings provide useful information for the use of allogenic MSCs for cell therapy applications. PMID- 26503506 TI - Spin-glass-like freezing of inner and outer surface layers in hollow gamma-Fe2O3 nanoparticles. AB - Disorder among surface spins is a dominant factor in the magnetic response of magnetic nanoparticle systems. In this work, we examine time-dependent magnetization in high-quality, monodisperse hollow maghemite nanoparticles (NPs) with a 14.8 +/- 0.5 nm outer diameter and enhanced surface-to-volume ratio. The nanoparticle ensemble exhibits spin-glass-like signatures in dc magnetic aging and memory protocols and ac magnetic susceptibility. The dynamics of the system slow near 50 K, and become frozen on experimental time scales below 20 K. Remanence curves indicate the development of magnetic irreversibility concurrent with the freezing of the spin dynamics. A strong exchange-bias effect and its training behavior point to highly frustrated surface spins that rearrange much more slowly than interior spins. Monte Carlo simulations of a hollow particle corroborate strongly disordered surface layers with complex energy landscapes that underlie both glass-like dynamics and magnetic irreversibility. Calculated hysteresis loops reveal that magnetic behavior is not identical at the inner and outer surfaces, with spins at the outer surface layer of the 15 nm hollow particles exhibiting a higher degree of frustration. Our combined experimental and simulated results shed light on the origin of spin-glass-like phenomena and the important role played by the surface spins in magnetic hollow nanostructures. PMID- 26503508 TI - Berberine-induced anticancer activities in FaDu head and neck squamous cell carcinoma cells. AB - In the present study, we investigated berberine-induced apoptosis and the signaling pathways underlying its activity in FaDu head and neck squamous cell carcinoma cells. Berberine did not affect the viability of primary human normal oral keratinocytes. In contrast, the cytotoxicity of berberine was significantly increased in FaDu cells stimulated with berberine for 24 h. Furthermore, berberine increased nuclear condensation and apoptosis rates in FaDu cells than those in untreated control cells. Berberine also induced the upregulation of apoptotic ligands, such as FasL and TNF-related apoptosis-inducing ligand, and triggered the activation of caspase-8, -7 and -3, and poly(ADP ribose) polymerase, characteristic of death receptor-dependent extrinsic apoptosis. Moreover, berberine activated the mitochondria-dependent apoptotic signaling pathway by upregulating pro-apoptotic factors, such as Bax, Bad, Apaf-1, and the active form of caspase-9, and downregulating anti-apoptotic factors, such as Bcl 2 and Bcl-xL. In addition, berberine increased the expression of the tumor suppressor p53 in FaDu cells. The pan-caspase inhibitor Z-VAD-fmk suppressed the activation of caspase-3 and prevented cytotoxicity in FaDu cells treated with berberine. Interestingly, berberine suppressed cell migration through downregulation of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, and MMP-9. Moreover, the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and p38, components of the mitogen activated protein kinase pathway that are associated with the expression of MMP and VEGF, was suppressed in FaDu cells treated with berberine for 24 h. Therefore, these data suggested that berberine exerted anticancer effects in FaDu cells through induction of apoptosis and suppression of migration. Berberine may have potential applications as a chemotherapeutic agent for the management of head and neck squamous carcinoma. PMID- 26503507 TI - Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias. AB - BACKGROUND: Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous, somewhat unpredictable diseases characterized by progressive scarring of the interstitium. Since lung function is a key determinant of survival, we reasoned that the transcriptional profile in IIP lung tissue would be associated with measures of lung function, and could enhance prognostic approaches to IIPs. RESULTS: Using gene expression profiling of 167 lung tissue specimens with IIP diagnosis and 50 control lungs, we identified genes whose expression is associated with changes in lung function (% predicted FVC and % predicted DLCO) modeled as categorical (severe vs mild disease) or continuous variables while adjusting for smoking status and IIP subtype; false discovery rate (FDR) approach was used to correct for multiple comparisons. This analysis identified 58 transcripts that are associated with mild vs severe disease (categorical analysis), including those with established role in fibrosis (ADAMTS4, ADAMTS9, AGER, HIF-1alpha, SERPINA3, SERPINE2, and SELE) as well as novel IIP candidate genes such as rhotekin 2 (RTKN2) and peptidase inhibitor 15 (PI15). Protein-protein interactome analysis of 553 genes whose expression is significantly associated with lung function when modeled as continuous variables demonstrates that more severe presentation of IIPs is characterized by an increase in cell cycle progression and apoptosis, increased hypoxia, and dampened innate immune response. Our findings were validated in an independent cohort of 131 IIPs and 40 controls at the mRNA level and for one gene (RTKN2) at the protein level by immunohistochemistry in a subset of samples. CONCLUSIONS: We identified commonalities and differences in gene expression among different subtypes of IIPs. Disease progression, as characterized by lower measures of FVC and DLCO, results in marked changes in expression of novel and established genes and pathways involved in IIPs. These genes and pathways represent strong candidates for biomarker studies and potential therapeutic targets for IIP severity. PMID- 26503509 TI - Paths to improving engagement among racial and ethnic minorities in addiction health services. AB - BACKGROUND: Members of racial and ethnic minority groups are most likely to experience limited access and poor engagement in addiction treatment. Research has been limited on the role of program capacity and delivery of comprehensive care in improving access and retention among minorities with drug abuse issues. The goal of this study was to examine the extent to which access and retention are enhanced when racial and ethnic minorities receive care from high-capacity addiction health services (AHS) programs and via coordination with mental health and receipt of HIV testing services. METHODS: This multilevel cross-sectional analysis involved data from 108 programs merged with client data from 2011 for 13,478 adults entering AHS. Multilevel negative binomial regression models were used to test interactions and indirect relationships between program capacity and days to enter treatment (wait time) and days in treatment (retention). RESULTS: Compared to low-capacity programs and non-Latino and non-African American clients, Latinos and African Americans served in high-capacity programs reported shorter wait times to admission, as hypothesized. African Americans also had longer treatment retention in high-capacity programs. Receipt of HIV testing and program coordination of mental health services played an indirect role in the relationship between program capacity and wait time. CONCLUSIONS: Program capacity and coordinated services in AHS may reduce disparities in access to care. Implications for supporting low-capacity programs to eliminate the disparity gap in access to care are discussed. PMID- 26503510 TI - Concurrence of oral and genital human papillomavirus infection in healthy men: a population-based cross-sectional study in rural China. AB - Human papillomavirus (HPV) infection, a primary cause of genital cancer, is also related to the increasing incidence of oropharyngeal cancer among young men. Relatively little is known about the concurrence of oral and genital infection among healthy individuals. Oral and genital swab exfoliated cells were collected simultaneously from 2566 men in rural China. Using general primer-mediated (SPF1/GP6+) PCR and sequencing, HPV testing results were obtained from 2228 men with both valid oral and genital specimens (beta-globin-positive). The prevalence of HPV infection was 6.7% in the oral cavity and 16.9% for the external genitalia. Among 43 men (1.9%, 43/2228) with oral-genital coinfection, 60.5% (26/43) harbored an identical HPV type at both sites. The risk of oral HPV infection was higher among men with genital infection than among uninfected men (11.4% vs. 5.7%, Adjusted OR = 2.3, 95% CI: 1.6-3.4). In addition, having multiple lifetime sexual partners was a significant risk for oral-genital HPV coinfection (Adjusted OR = 2.6, 95% CI: 1.0-7.0; 2 partners vs. 1 partner). These findings provide a basis for further understanding the natural history and transmission dynamics of oral HPV infection. PMID- 26503511 TI - Hematoma Locations Predicting Delirium Symptoms After Intracerebral Hemorrhage. AB - BACKGROUND: Delirium symptoms are associated with later worse functional outcomes and long-term cognitive impairments, but the neuroanatomical basis for delirium symptoms in patients with acute brain injury is currently uncertain. We tested the hypothesis that hematoma location is predictive of delirium symptoms in patients with intracerebral hemorrhage, a model disease where patients are typically not sedated or bacteremic. METHODS: We prospectively identified 90 patients with intracerebral hemorrhage who underwent routine twice-daily screening for delirium symptoms with a validated examination. Voxel-based lesion symptom mapping with acute computed tomography was used to identify hematoma locations associated with delirium symptoms (N = 89). RESULTS: Acute delirium symptoms were predicted by hematoma of right-hemisphere subcortical white matter (superior longitudinal fasciculus) and parahippocampal gyrus. Hematoma including these locations had an odds ratio for delirium of 13 (95 % CI 3.9-43.3, P < 0.001). Disruption of large-scale brain networks that normally support attention and conscious awareness was thus associated with acute delirium symptoms. CONCLUSIONS: Higher odds ratio for delirium was increased due to hematoma location. The location of neurological injury could be of high prognostic value for predicting delirium symptoms. PMID- 26503512 TI - Intracranial Pressure During Pressure Control and Pressure-Regulated Volume Control Ventilation in Patients with Traumatic Brain Injury: A Randomized Crossover trial. AB - INTRODUCTION: Mechanical ventilation with control of partial arterial CO2 pressures (PaCO2) is used to treat or stabilize intracranial pressure (ICP) in patients with traumatic brain injury (TBI). Pressure-regulated volume control (PRVC) is a ventilator mode where inspiratory pressures are automatically adjusted to deliver the patient a pre-set stable tidal volume (TV). This may result in a more stable PaCO2 and thus a more stable ICP compared with conventional pressure control (PC) ventilation. The aim of this study was to compare PC and PRVC ventilation in TBI patients with respect to ICP and PaCO2. METHODS: This is a randomized crossover trial including eleven patients with a moderate or severe TBI who were mechanically ventilated and had ICP monitoring. Each patient was administered alternating 2-h periods of PC and PRVC ventilation. The outcome variables were ICP and PaCO2. RESULTS: Fifty-two (26 PC, 26 PRVC) study periods were included. Mean ICP was 10.8 mmHg with PC and 10.3 mmHg with PRVC ventilation (p = 0.38). Mean PaCO2 was 36.5 mmHg (4.87 kPa) with PC and 36.1 mmHg (4.81 kPa) with PRVC (p = 0.38). There were less fluctuations in ICP (p = 0.02) and PaCO2 (p = 0.05) with PRVC ventilation. CONCLUSIONS: Mean ICP and PaCO2 were similar for PC and PRVC ventilation in TBI patients, but PRVC ventilation resulted in less fluctuation in both ICP and PaCO2. We cannot exclude that the two ventilatory modes would have impact on ICP in patients with higher ICP values; however, the similar PaCO2 observations argue against this. PMID- 26503513 TI - Delay in Diagnosis of Basilar Artery Stroke. AB - BACKGROUND: Basilar artery stroke causes substantial morbidity and mortality. Although its unusual clinical presentation potentially contributes to a delay in diagnosis, this problem has not been systematically studied. We compared intervals between symptom onset, initial presentation, and diagnosis in stroke due to basilar artery (BA) versus left middle cerebral artery (LMCA) occlusion to determine the presence of and potential reasons for diagnostic delay in BA stroke. METHODS: We retrospectively identified 21 consecutive adult patients diagnosed with BA stroke between 2009 and 2011 from our hospital's prospective stroke registry. Patients were age-, sex-, and race-matched with 21 LMCA stroke patients from the same period. All subjects had confirmed clinical and radiographic diagnosis of stroke due to occlusion or stenosis of the BA, LMCA, or left internal carotid artery. Time to diagnosis was determined independently by two investigators through medical record review. The pre-specified primary outcome was latency from emergency department (ED) arrival to stroke diagnosis. RESULTS: Median time from ED arrival to diagnosis was 8 h 24 min (IQR: 2:43 26:32) for BA and 1 h 23 min (IQR: 0:41-1:45; p < 0.001) for LMCA. Median time from symptom onset to ED arrival was 7 h 44 min (IQR 1:23-21:30) for BA and 1 h 2 min (IQR 0:36-9:41; p = 0.06) for LMCA. Four of 21 (19 %) BA patients were diagnosed within a 4-h time frame to make intravenous thrombolysis possible compared to 13 of 21 (62 %) LMCA patients (p = 0.01). CONCLUSIONS: Our results suggest that both pre-hospital and in-hospital processes cause substantial, clinically significant delays in the diagnosis of BA stroke. PMID- 26503514 TI - FAIMS and Phosphoproteomics of Fibroblast Growth Factor Signaling: Enhanced Identification of Multiply Phosphorylated Peptides. AB - We have applied liquid chromatography high-field asymmetric waveform ion mobility spectrometry tandem mass spectrometry (LC-FAIMS-MS/MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) to the investigation of site-specific phosphorylation in fibroblast growth factor (FGF) signaling. We have combined a SILAC approach with chemical inhibition by SU5402 (an FGF receptor tyrosine kinase inhibitor) and dasatinib (a Src family kinase inhibitor). The results show that incorporation of FAIMS within the workflow results in (a) an increase in the relative proportion of phosphothreonine and phosphotyrosine sites identified, (b) an increase in phosphopeptide identifications from precursors with charge states >= +3 (with an associated increase in peptide length), and (c) an increase in the identification of multiply phosphorylated peptides. Approximately 20% of the phosphorylation sites identified via the FAIMS workflow had not been reported previously, and over 80% of those were from multiply phosphorylated peptides. Moreover, FAIMS provided access to a distinct set of phosphorylation sites regulated in response to SU5402 and dasatinib. The enhanced identification of multiply phosphorylated peptides was particularly striking in the case of sites regulated by SU5402. In addition to providing a compelling example of the complementarity of FAIMS in phosphoproteomics, the results provide a valuable resource of phosphorylation sites for further investigation of FGF signaling and trafficking. PMID- 26503515 TI - Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing. AB - Phenylketonuria (PKU) is an inherited autosomal recessive disorder of phenylalanine metabolism, mainly caused by a deficiency of phenylalanine hydroxylase (PAH). The incidence of various PAH mutations differs among race and ethnicity. Here we report a spectrum of PAH mutations complied from 796 PKU patients from mainland China. The all 13 exons and adjacent intronic regions of the PAH gene were determined by next-generation sequencing. We identified 194 different mutations, of which 41 are not reported before. Several mutations reoccurred with high frequency including p.R243Q, p.EX6-96A > G, p.V399V, p.R241C, p.R111*, p.Y356*, p.R413P, and IVS4-1G > A. 76.33% of mutations were localized in exons 3, 6, 7, 11, 12. We further compared the frequency of each mutation between populations in northern and southern China, and found significant differences in 19 mutations. Furthermore, we identified 101 mutations that are not reported before in Chinese population, our study thus broadens the mutational spectrum of Chinese PKU patients. Additionally, 41 novel mutations will expand and improve PAH mutation database. Finally, our study offers proof that NGS is effective, reduces screening times and costs, and facilitates the provision of appropriate genetic counseling for PKU patients. PMID- 26503516 TI - Soil restoration with organic amendments: linking cellular functionality and ecosystem processes. AB - A hot topic in recent decades, the application of organic amendments to arid degraded soils has been shown to benefit microbially-mediated processes. However, despite the importance of soils for global sustainability, a gap has not been addressed yet in soil science: is there any connection between ecosystem community processes, cellular functionality, and microbial lifestyles (i.e. oligotrophy-copiotrophy) in restored soils? Together with classical ecosystem indicators (fatty-acids, extracellular-enzyme activities, basal respiration), state-of-the-art metaproteomics was applied to fill this gap in a model restoration experiment initiated 10-years ago by the addition of sewage-sludge and compost. Organic amendment strongly impacted ecosystem processes. Furthermore, the type of material used induced differences in the cellular functionalities through variations in the percentages of proteins involved in translation, transcription, energy production and C-fixation. We conclude that the long-term impact of organic restoration goes beyond ecosystem processes and affects cellular functionalities and phyla-lifestyles coupled with differences in microbial-community structures. PMID- 26503517 TI - Does shared decision making exist in oncologic practice? PMID- 26503519 TI - Hepatitis C in the era of direct-acting antivirals: real-world costs of untreated chronic hepatitis C; a cross-sectional study. AB - BACKGROUND: Recent advances in Hepatitis C therapeutics offer the possibility of cure but will be expensive. The cost of treatment may be partially offset by the avoidance of advanced liver disease. We performed a micro-costing study of the ambulatory healthcare utilisation of patients with Hepatitis C supplemented with inpatient diagnosis related group costs. METHODS: The staff utilisation costs associated with a Hepatitis C ambulatory visit were measured and combined with the costs of investigations to establish a mean cost per consultation. An annualised estimate of cost was produced by multiplying this by the number of consultations accessed, stratified by degree of liver impairment. Inpatient costs were established by identifying the number of inpatient episodes and multiplying by Irish diagnosis related group costs. Non-parametric bootstrapping was performed to derive mean and 95%CI values. RESULTS: Two hundred and twenty-five patients were identified. The cost of an outpatient medical review was ?136 (?3.60 SD). The cost of a Hepatitis C nursing review was ?128 (?7.30 SD). The annual mean costs of care were as follows (95%CI): Mild ?398 (?336, ?482), Moderate ?417(?335, ?503), Compensated cirrhosis ?1790 (?990, ?3164), Decompensated cirrhosis ?8302 (?3945, ?14,637), Transplantation Year 1 ?137,176 (?136,024, ?138,306), Transplantation after Year 1 ?5337 (?4942, ?5799), Hepatocellular carcinoma ?21,992 (?15,222, ?29,467), Sustained virological response ?44 (?16, ?73). CONCLUSIONS: The direct medical cost associated with Hepatitis C care in Ireland is substantial and increases exponentially with progression of liver disease. The follow-up costs of patients with a sustained virological response in this cohort were low in comparison to patients with chronic infection. PMID- 26503525 TI - Safety of Tioguanine During Pregnancy in Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: Conventional thiopurine [azathioprine and mercaptopurine] treatment during pregnancy in patients with inflammatory bowel disease [IBD] is considered to be safe; however data on the safety and teratogenicity of the non conventional thiopurine tioguanine [TG] in pregnant IBD patients are lacking. We aim to describe the safety and teratogenicity of TG treatment during pregnancy in IBD patients. METHODS: This was a retrospective, multicentre descriptive case series of female IBD patients using TG during pregnancy. Data on disease and medication history, pregnancy complications, pregnancy outcome, mode of delivery, preterm birth, birthweight, congenital abnormalities, laboratory signs of myelosuppression or hepatotoxicity, and 6-thioguaninenucleotide [6-TGN] concentrations in mother and neonate were collected. RESULTS: In all, 13 patients [77% Crohn's disease, 23% ulcerative colitis] used TG [median dose 18 g/day] during pregnancy; 19 pregnancies, including 1 twin pregnancy, were included. Spontaneous abortion occurred in three pregnancies. In 7 of the 16 ongoing pregnancies a caesarean section was performed. One neonate had a mild congenital abnormality [distal shaft hypospadias]. In the singleton pregnancies, the median birthweight was 3410 g at a median of gestational age of 39 weeks. No preterm birth [< 37 weeks] or low birthweight [< 2500 g] was observed in the singleton newborns. In the twin pregnancy an induction of labour was performed at 35 + 1 weeks of gestation because of pre-eclampsia. Both neonates had a low birthweight. CONCLUSIONS: This relatively small case series supports safe use of TG in pregnant IBD patients. Still, consideration should be given to the indication and continuation of TG during pregnancy. PMID- 26503520 TI - Determinants of outcome in patients with chronic ischemic left ventricular dysfunction undergone percutaneous coronary interventions. AB - BACKGROUND: Percutaneous coronary interventions (PCI) in patients with ischemic systolic left ventricular dysfunction (SLVD) are routinely performed although their impact on prognosis remains unclear. METHODS: We retrospectively evaluated 385 consecutive patients (76 % male, 66 +/- 9 years) with SLVD (left ventricular ejection fraction [LVEF] <=40 %) due to chronic coronary artery disease, who underwent PCI between 1999 and 2009, and explored clinical factors associated with higher risk of death or of a composite of death and hospitalization for acute decompensated heart failure (ADHF). RESULTS: The median follow-up was 28 months (inter-quartile range 14-46 months). Death and the composite outcome of death and hospitalization for ADHF occurred in 80 (21 %) and 109 (28 %) patients respectively (8.4 and 11.5 per 100 patient-years of follow-up). Insulin-dependent diabetes mellitus (IDDM), multivessel disease, LVEF < 35 %, symptoms of heart failure (HF) emerged both as independent predictors of death (adjusted hazard ratios [HR] 2.64; 1.92, 1.88 and 1.67 respectively) and composite outcome of death and hospitalization for ADHF (adjusted HR 2.22, 1.92, 1.79 and 1.94 respectively). Furthermore advanced age (HR = 1.03) emerged as independent predictors of death and having performed a stress test before PCI correlated with reduced number of deaths and ADHF hospitalizations (HR = 0.60). Of note, PCI significantly reduced the symptom of angina from 63.2 % at baseline to 16.3 % at the last follow up (p < 0.0001). CONCLUSIONS: IDDM, symptoms of HF, multivessel disease and LVEF < 35 % appear to be associated with worse outcome patients with ischemic SLVD undergoing PCI, and may be taken into account for optimal risk stratification. On the other hand, performing a stress testing before PCI seems to be associated with a more favorable outcome. PMID- 26503526 TI - Hyper sensitive protein detection by Tandem-HTRF reveals Cyclin D1 dynamics in adult mouse. AB - We present here a novel method for the semi-quantitative detection of low abundance proteins in solution that is both fast and simple. It is based on Homogenous Time Resolved Forster Resonance Energy Transfer (HTRF), between a lanthanide labeled donor antibody and a d2 or XL665 labeled acceptor antibody that are both raised against different epitopes of the same target. This novel approach we termed "Tandem-HTRF", can specifically reveal rare polypeptides from only a few microliters of cellular lysate within one hour in a 384-well plate format. Using this sensitive approach, we observed surprisingly that the core cell cycle regulator Cyclin D1 is sustained in fully developed adult organs and harbors an unexpected expression pattern affected by environmental challenge. Thus our method, Tandem-HTRF offers a promising way to investigate subtle variations in the dynamics of sparse proteins from limited biological material. PMID- 26503527 TI - Why it is important to present all the available facts about bed sharing and breastfeeding. PMID- 26503528 TI - "Homosexuality/Homophobia Is Un-African"?: Un-Mapping Transnational Discourses in the Context of Uganda's Anti-Homosexuality Bill/Act. AB - This article un-maps the recent impasse between pro- and antigay mobilization around Uganda's Anti-Homosexuality Act (AHA, 2009-2014). Drawing on scholarly and social media sources, it summarizes the increasing influence of (U.S.) transnational evangelism that has precipitated a state-religious complex of "anticipatory political homophobia" in Uganda. If transnational evangelism against same-sex sexuality in Uganda has generated a strong reaction from global LGBT human-rights advocates, this article critiques this Western homotransnationalist response by analyzing its limited terms of operation, focusing on the ways in which Uganda is hailed into the biopolitical project of a Western queer modernity. The author focuses on the copresence between homotransnationalist mobilization and "homophobic anticipatory countermobilization" as (re)organizing/suturing a global ordering project that is deeply invested in biopolitics and necropolitics. This suggests that the global flashpointing of Uganda in the context of the AHA incites further questions concerning the transnationality of "gay human rights" discourse under neoliberalism. PMID- 26503529 TI - Clinical, molecular and drug sensitivity pattern of mycobacterial isolates from extra-pulmonary tuberculosis cases in Addis Ababa, Ethiopia. AB - BACKGROUND: In conjunction with the spread of HIV infection, tuberculosis (TB) remains a major cause of illness and death worldwide. The Ethiopian national report reveals that extra pulmonary tuberculosis is on the rise and that case detection rate is exceeding that of smear positive or negative cases in many parts of the country. Different studies indicated that host and/or pathogen related factors are associated with the rise of extra pulmonary cases. However, the reason for this is not clearly known in our setting. METHODS: Specimens were taken from clinically suspected extra pulmonary patients and confirmed by cytology, histopathology and culture. Deletion typing and Spoligotyping was utilized to identify the strains. The isolates were then assigned to lineage using conformal Bayesian network (rules model) algorithm and dendrograms were drawn using UPGMA methods. In addition, drug sensitivity test was done using the indirect proportion and 24 well plate methods. RESULTS: Out of the 200 clinically suspected extra pulmonary tuberculosis patients, 106 (53 %) were between 15 and 35 years of age and 167 (83.5 %) were new while 33 (16.5 %) were retreatment cases. The culture yield was 29.5 % (59). Of these only one was M. bovis and 58 were M. tuberculosis strains with 31 different spoligotype patterns grouped into seven clusters. The largest cluster (ST53) comprised 12 (20.3 %) isolates. There was higher clustering of CAS isolates in TBLN than in any other form of extra pulmonary tuberculosis cases. Resistance to rifampicin was higher (22 %) than that for INH, STM and EMB (8.1 %, 5 % and 3 % respectively). Out of the 37 isolates tested for resistance, only 2 isolates were resistant for both STM and INH and no MDR strain was found. CONCLUSIONS: There is an ongoing active recent transmission among extra pulmonary tuberculosis in the study areas as shown by the presence of clusters. Although no MDR case was observed, there is a risk of emergence of MDR as noted from the high proportion of resistance to rifampicin. Detailed study at population level is recommended to monitor its trend. PMID- 26503532 TI - Avian influenza in Australia: a summary of 5 years of wild bird surveillance. AB - BACKGROUND: Avian influenza viruses (AIVs) are found worldwide in numerous bird species, causing significant disease in gallinaceous poultry and occasionally other species. Surveillance of wild bird reservoirs provides an opportunity to add to the understanding of the epidemiology of AIVs. METHODS: This study examined key findings from the National Avian Influenza Wild Bird Surveillance Program over a 5-year period (July 2007-June 2012), the main source of information on AIVs circulating in Australia. RESULTS: The overall proportion of birds that tested positive for influenza A via PCR was 1.9 +/- 0.1%, with evidence of widespread exposure of Australian wild birds to most low pathogenic avian influenza (LPAI) subtypes (H1-13, H16). LPAI H5 subtypes were found to be dominant and widespread during this 5-year period. CONCLUSION: Given Australia's isolation, both geographically and ecologically, it is important for Australia not to assume that the epidemiology of AIV from other geographic regions applies here. Despite all previous highly pathogenic avian influenza outbreaks in Australian poultry being attributed to H7 subtypes, widespread detection of H5 subtypes in wild birds may represent an ongoing risk to the Australian poultry industry. PMID- 26503530 TI - Association of physical activity and physical performance with tibial cartilage volume and bone area in young adults. AB - INTRODUCTION: Physical activity has been recommended to patients with knee osteoarthritis for improving their symptoms. However, it is still controversial if physical activity has effects on joint structures including cartilage volume. The aim of this study was to describe the associations between physical activity and performance measured 5 years prior and tibial cartilage volume and bone area in young adults. METHODS: Subjects broadly representative of the Australian population (n = 328, aged 31-41 years, female 47.3 %) were selected from the Childhood Determinants of Adult Health study. They underwent T1-weighted fat suppressed magnetic resonance imaging (MRI) scans of their knees. Tibial bone area and cartilage volume were measured from MRI. Physical activity (measured using long international physical activity questionnaire (IPAQ)) and performance measures (long jump, leg muscle strength, physical work capacity (PWC170)) were measured 5 years prior. RESULTS: In multivariable analyses, total physical activity (min/week) (beta: 0.30 mm(3), 95 % CI: 0.13,0.47), vigorous (beta: 0.54 mm(3), 95 % CI: 0.13,0.94), moderate (beta: 0.34 mm(3), 95 % CI: 0.01,0.67), walking (beta: 0.40 mm(3), 95 % CI: 0.07,0.72) and IPAQ category (beta: 182.9 mm(3), 95 % CI: 51.8,314.0) were positively associated with total tibial cartilage volume but not tibial bone area. PWC170, long jump and leg muscle strength were positively and significantly associated with both total tibial cartilage volume and total tibial bone area; and the associations with tibial cartilage volume decreased in magnitude but remained significant for PWC170 and long jump after further adjustment for tibial bone area. CONCLUSION: While tibial bone area is affected only by physical performance, total tibial cartilage volume can be influenced by both physical activity and performance in younger adults. The clinical significance suggests a beneficial effect for cartilage but the bone area association was restricted to performance suggesting other factors rather than physical activity may be important. PMID- 26503533 TI - Cattle movement patterns in Australia: an analysis of the NLIS database 2008 2012. AB - OBJECTIVE: To identify patterns of cattle movement that could influence disease spread in the Australian cattle population. METHODS: Records from the National Livestock Identification System database for the period January 2008 to December 2012 were accessed and analysed. Postcodes were used to allocate each individual property to one of 12 livestock production regions. National movement patterns and the characteristics of each livestock production region were quantified in terms of the number of consignments and animals moved, and seasonality of movements. RESULTS: The majority of cattle movements remained within a single livestock production region, while those that did not, usually remained within the same state or territory. Producers were the most common source of cattle, and abattoirs and other producers the most common destinations, with approximately 40% of animals moving via a saleyard. The northern regions generally moved larger consignments than the southern regions and were less connected to other regions. The eastern and south-eastern regions were very well connected by cattle movements. Seasonal patterns were seen for some regions, particularly the northern regions where weather patterns strongly influence the ability of producers to muster and transport stock. CONCLUSIONS: The movement patterns observed provide quantitative support for previous information based on surveys and expert opinion, and capture more of the variability in Australian cattle production. This information may assist with management of animal disease risks, in particular exotic diseases, and in planning surveillance programs. PMID- 26503535 TI - Adverse reactions in a population of Sydney pet rabbits vaccinated against rabbit calicivirus. AB - OBJECTIVE: To determine the general clinical presentation and incidence of adverse reactions to Cylap(r) RCD vaccinations, of a nature serious enough for veterinary attention, in a Sydney population of pet rabbits. DESIGN: A retrospective survey using hospital databases. METHODS: Nine veterinary hospitals in Sydney participated in a database search for the number of rabbits vaccinated within a 2-year period. The hospitals involved had an identified interest in rabbit medicine and included general, specialist and teaching hospitals. Details of the rabbit, vaccination event and any possible reaction were collected and analysed. RESULTS: Of 933 events recorded in 705 rabbits, 17 (1.8%) adverse reactions were observed. Of the adverse events, local injection site reactions (alopecia, abrasions and scabbing) were most common. Other reactions, including systemic signs of gastrointestinal tract stasis, lethargy and forelimb lameness, were also documented. Overall, rabbits presented for vaccination were mostly male (57.7%) and desexed (71.3%), with an average age of 28.1 months (median 19.0, range 1.4-149.8 months) and an average weight at first vaccination of 2.12 kg (median 2.08 kg, range 0.18-5.6 kg). A significant association between increasing age and decreased incidence of adverse events was demonstrated (P value, 0.038). CONCLUSIONS: The benefits of vaccination against RCV outweigh the risks of an adverse reaction occurring. Data from this study show that adverse reactions occur infrequently, are generally mild and self-resolving, and decrease in incidence with increasing age. These results are similar to previous field research on wild rabbit colonies and reports from government and industry. PMID- 26503536 TI - Coastal taipan (Oxyuranus scutellatus) envenomation of a dog. AB - CASE REPORT: An 8-year-old mixed-breed dog was envenomed by a juvenile coastal taipan (Oxyuranus scutellatus). The dog presented initially with coagulopathy and weakness, then developed neuromuscular paralysis and respiratory failure. Progressive myopathy peaked 3 days following admission. Taipan antivenom administration, mechanical ventilation therapy and supportive patient care resulted in complete recovery. Symptoms of neuropathy began to resolve 3 days following envenomation, with the dog discharged 6 days following envenomation. CONCLUSION: To the author's knowledge, this is the first reported case of coastal taipan envenomation of a dog. PMID- 26503537 TI - Alopecia in four kittens caused by abnormal maternal licking behaviour. AB - CASE REPORT: Abnormal maternal behaviour has been reported in cats, but is generally not included among the causes of alopecia in kittens. A litter of four kittens, 2 months old, was referred for evaluation of facial alopecia of differing severity. The 2-year-old queen was unaffected. Dermatological examination of the kittens did not find any infectious cause. Trichograms showed broken hair shafts with longitudinal splitting. Congenital alopecia was unlikely based on the clinical presentation. A behavioural consultation revealed abnormal grooming behaviour by the mother, who chewed and removed the hair from the kittens. The kittens were separated from the queen and alopecia resolved within a few weeks. CONCLUSION: To the authors' knowledge, this is the first report of alopecia caused by abnormal maternal licking behaviour. Abnormal maternal behaviour should be considered in cases of alopecia affecting a litter of kittens, when infectious and congenital causes have been ruled out. PMID- 26503538 TI - Retrospective analysis of causes of death in mountain pygmy-possums (Burramys parvus) at Healesville Sanctuary, Victoria, Australia. AB - BACKGROUND: Identification and characterisation of deaths is important for the veterinary management of both wild and captive animals. It is especially important as a tool for monitoring health and disease within populations of endangered species for which little information on morbidity and mortality is known. Investigations into the causes of death and other important necropsy findings were made in a captive population of the critically endangered mountain pygmy-possum (Burramys parvus). METHODS: Necropsy records from January 2000 December 2013 were reviewed for all possums that had lived and died at Healesville Sanctuary (n = 48). RESULTS: The average age of death of possums in this population was 4.7 years. The most common histological change in mountain pygmy-possums was varying degrees of chronic progressive kidney disease (n = 17). Of these cases, eight animals (47%) had histological changes suggesting the kidney disease was the likely cause of death. Other causes of death included neoplasia (n = 5), necrotising pancreatitis (n = 4), pneumonia (n = 2), reproductive disease (n = 2) and trauma (n = 2). No cause of death was able to be identified in 33.3% (n = 16) of cases. Hepatic lipidosis (n = 5), pneumonia (n = 2) and degenerative joint disease (n = 2) were the most common comorbidities found. CONCLUSION: Progressive renal disease, often with secondary metastatic mineralisation, appears to be a significant cause of mortality in captive mountain pygmy-possums and further investigation into its pathophysiology, antemortem diagnosis and treatment is warranted. PMID- 26503541 TI - Food as Risk: How Eating Habits and Food Knowledge Affect Reactivity to Pictures of Junk and Healthy Foods. AB - This study explores how people respond to images of junk versus healthy food as a function of their eating habits and food knowledge. The experiment reported here proposed and tested the idea that those with unhealthy eating habits but highly knowledgeable about healthy eating would feel more positive and also more negative toward junk food images compared to images of healthy food because they may perceive them as risky--desirable but potentially harmful. The psychophysiological data collected from participants during their exposure to pictures of junk versus healthy food supported this idea. In addition, unhealthy eaters compared to healthy eaters with the same degree of food knowledge responded more positively to all food items. The findings are critical from a health communication perspective. Because unhealthy eaters produce stronger emotional responses to images of junk food, they are more likely to process information associated with junk food with more cognitive effort and scrutiny. Thus, when targeting this group and using images of junk food, it is important to combine these images with strong message claims and relevant arguments; otherwise, if the arguments are perceived as irrelevant or weak, the motivational activation associated with junk food itself may transfer into an increased desire to consume the unhealthy product. PMID- 26503540 TI - Sustained enhancement of photosynthesis in coffee trees grown under free-air CO2 enrichment conditions: disentangling the contributions of stomatal, mesophyll, and biochemical limitations. AB - Coffee (Coffea spp.), a globally traded commodity, is a slow-growing tropical tree species that displays an improved photosynthetic performance when grown under elevated atmospheric CO2 concentrations ([CO2]). To investigate the mechanisms underlying this response, two commercial coffee cultivars (Catuai and Obata) were grown using the first free-air CO2 enrichment (FACE) facility in Latin America. Measurements were conducted in two contrasting growth seasons, which were characterized by the high (February) and low (August) sink demand. Elevated [CO2] led to increases in net photosynthetic rates (A) in parallel with decreased photorespiration rates, with no photochemical limitations to A. The stimulation of A by elevated CO2 supply was more prominent in August (56% on average) than in February (40% on average). Overall, the stomatal and mesophyll conductances, as well as the leaf nitrogen and phosphorus concentrations, were unresponsive to the treatments. Photosynthesis was strongly limited by diffusional constraints, particularly at the stomata level, and this pattern was little, if at all, affected by elevated [CO2]. Relative to February, starch pools (but not soluble sugars) increased remarkably (>500%) in August, with no detectable alteration in the maximum carboxylation capacity estimated on a chloroplast [CO2] basis. Upregulation of A by elevated [CO2] took place with no signs of photosynthetic downregulation, even during the period of low sink demand, when acclimation would be expected to be greatest. PMID- 26503542 TI - Which medications are suitable for agonist drug maintenance? AB - BACKGROUND AND AIMS: We examine the feasibility of agonist maintenance treatment for the major psychoactive drug classes: opioids, nicotine, benzodiazepines, cannabis, psychostimulants and alcohol. METHODS: Eight clinical criteria for an agonist maintenance drug were assessed for each major drug class. These related to pharmacological aspects of the drug (agonist, pharmacological stability, dose response, non-toxic) and neurocognitive sequelae (psychiatric, cognitive, craving, salience). RESULTS: Opioids and nicotine met all eight criteria for a maintenance drug. While nicotine has not been promoted widely or used for maintenance, it has the potential to fulfil that role. Cannabis met five criteria and has potential, but long-term data on cognitive impairment are required. Benzodiazepine maintenance would appear an option for the high-dose chaotic abuser, also meeting five criteria, although clinic dosing appears the safest option. Psychostimulants (three of eight criteria) and alcohol (one of eight) appear poor propositions for maintenance, in terms of both their pharmacological and their neurocognitive characteristics. CONCLUSIONS: Drug classes have properties that distinguish them in their suitability for maintenance treatment. Some classes not yet used for maintenance (notably nicotine and cannabis) have potential to fulfil such a role. Others, however, by their inherent nature, appear unsuitable for such a treatment regimen. PMID- 26503543 TI - Genome-wide evolutionary and functional analysis of the Equine Repetitive Element 1: an insertion in the myostatin promoter affects gene expression. AB - BACKGROUND: In mammals, an important source of genomic variation is insertion polymorphism of retrotransposons. These may acquire a functional role when inserted inside genes or in their proximity. The aim of this work was to carry out a genome wide analysis of ERE1 retrotransposons in the horse and to analyze insertion polymorphism in relation to evolution and function. The effect of an ERE1 insertion in the promoter of the myostatin gene, which is involved in muscle development, was also investigated. RESULTS: In the horse population, the fraction of ERE1 polymorphic loci is related to the degree of similarity to their consensus sequence. Through the analysis of ERE1 conservation in seven equid species, we established that the level of identity to their consensus is indicative of evolutionary age of insertion. The position of ERE1s relative to genes suggests that some elements have acquired a functional role. Reporter gene assays showed that the ERE1 insertion within the horse myostatin promoter affects gene expression. The frequency of this variant promoter correlates with sport aptitude and racing performance. CONCLUSIONS: Sequence conservation and insertion polymorphism of ERE1 elements are related to the time of their appearance in the horse lineage, therefore, ERE1s are a useful tool for evolutionary and population studies. Our results suggest that the ERE1 insertion at the myostatin locus has been unwittingly selected by breeders to obtain horses with specific racing abilities. Although a complex combination of environmental and genetic factors contributes to athletic performance, breeding schemes may take into account ERE1 insertion polymorphism at the myostatin promoter. PMID- 26503544 TI - Measures of body adiposity and visceral adiposity index as predictors of metabolic syndrome among Thai women with PCOS. AB - AIM: To evaluate the relationship between measures of body adiposity and visceral adiposity index (VAI) and risk of metabolic syndrome (MS) and to identify the optimal cut-off points of each measurement in Thai polycystic ovary syndrome (PCOS). METHODS: A cross-sectional study was completed physical examination, fasting plasma glucose, lipid profiles of 399 PCOS and 42 age-matched normal controls. Body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and VAI were calculated. Associations between different measures and MS were evaluated and the receiver-operating characteristic (ROC) curve was performed to determine appropriate cut-off points for identifying MS. RESULTS: Percentage of MS in PCOS was 24.6%, whereas none MS in controls. Previously recommended cut-off values for body adiposity and VAI were significantly associated with MS. ROC curve analysis of the only PCOS showed newly obtained optimal cut-off points for BMI and VAI of >=28 kg/m(2) (AUC = 0.90) and >5.6 (AUC = 0.94), respectively. Values found to be more accurate than the original ones. VAI was the best predictor, followed by BMI and WHtR. CONCLUSION: All body adiposity and VAI parameters can predict the risk of MS. Optimal values for Thai PCOS were >=28 kg/m(2) for BMI, >=0.85 for WHR, >=0.5 for WHtR and >5.6 for VAI. PMID- 26503545 TI - Identification of potential mutations and genomic alterations in the epithelial and spindle cell components of biphasic synovial sarcomas using a human exome SNP chip. AB - BACKGROUND: Synovial sarcoma (SS) is one of the most aggressive soft-tissue sarcomas and is noted for late local recurrence and metastasis. It is of uncertain histological origin and exhibits a biphasic histopathological form involving both the mesenchyme and epithelium. Thus, its diagnosis and therapy remain a huge challenge for clinicians and pathologists. This study aimed to determine whether differential morphological-associated genomic changes could aid in ascertaining the histogenesis of SS and to determine whether these sarcomas showed some specific mutated genes between epithelial and spindle cells that would promote tumor invasion and metastasis. METHODS: We conducted a comprehensive genomic analysis of mesenchymal and epithelial components in 12 formalin-fixed paraffin-embedded biphasic SS samples using the Illumina human exon microarray. Exome capture sequencing was performed to validate the single nucleotide polymorphism (SNP)-chip data, and de novo data were generated using a whole-exome chip with the Illumina exon microarray. Fisher's exact test based on PLINK analysis of the SNP-chip data. RESULTS: Here, the SNP-chip data showed that 336 SNPs had association P-values of less than 0.05 by chi-square test. We identified 23 significantly mutated genes between epithelial and spindle cell regions of SSs. Fifteen gene mutations were specific for the spindle cell component (65.2 %) and eight for the epithelial cell component (34.8 %). Most of these genes have not been previously reported in SS, and neuroguidin (NGDN), RAS protein activator like 3 (RASAL3), KLHL34 and MUM1L1 have not previously been linked to cancer; only one gene (EP300) has been reported in SS. Genomic analyses suggested that the differential SNPs in genes used for functional enrichment are mainly related to the inflammatory response pathway, adhesion, ECM-receptor interactions, TGF-beta signaling, JAK-STAT signaling, phenylalanine metabolism, the intrinsic pathway and formation of fibrin. CONCLUSIONS: This study investigated novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for SS. The identified pathways may be closely correlated with the pathogenic mechanisms underlying SS, and SS development is associated with morphological features. PMID- 26503546 TI - Wintersweet (Chimonanthus praecox) toxicity in four goats. AB - CASE HISTORY: A one-year-old female goat presented with acute onset of recumbency, seizures and vocalisation approximately 5 hours after being given access to branch trimmings from a neighbour's garden. The plant from which the pruned branches came was subsequently identified as wintersweet (Chimonanthus praecox). Three other goats kept in the same paddock displayed similar clinical signs over a period of 4 hours following the initial presentation. CLINICAL FINDINGS: All four goats were ataxic, displayed tetanic seizures and were in lateral recumbency; they had dilated pupils and were hyperaesthetic, with elevated heart and respiratory rates. After symptomatic treatment, including sedation with diazepam, one of the three goats continued to deteriorate and was subjected to euthanasia. The remaining three goats recovered over 1-14 days with nursing care and physiotherapy. DIAGNOSIS: Toxicity due to ingestion of wintersweet, which contains the alkaloid calycanthine. CLINICAL RELEVANCE: Calycanthine is a central nervous system toxin, causing convulsions. Wintersweet shrubs are present in many New Zealand gardens. Practitioners should be aware that the seeds and flowers, and possibly the leaves, of this plant are highly toxic with signs of toxicity including ataxia, hyperaesthesia and seizures. PMID- 26503548 TI - A Practice Improvement Education Program Using a Mentored Approach to Improve Nursing Facility Depression Care-Preliminary Data. AB - Depression is common in nursing facility residents. Depression data obtained using the Minimum Data Set (MDS) 3.0 offer opportunities for improving diagnostic accuracy and care quality. How best to integrate MDS 3.0 and other data into quality improvement (QI) activity is untested. The objective was to increase nursing home (NH) capability in using QI processes and to improve depression assessment and management through focused mentorship and team building. This was a 6-month intervention with five components: facilitated collection of MDS 3.0 nine-item Patient Health Questionnaire (PHQ-9) and medication data for diagnostic interpretation; education and modeling on QI approaches, team building, and nonpharmacological depression care; mentored team meetings; educational webinars; and technical assistance. PHQ-9 and medication data were collected at baseline and 6 and 9 months. Progress was measured using team participation measures, attitude and care process self-appraisal, mentor assessments, and resident depression outcomes. Five NHs established interprofessional teams that included nursing (44.1%), social work (20.6%), physicians (8.8%), and other disciplines (26.5%). Members participated in 61% of eight offered educational meetings (three onsite mentored team meetings and five webinars). Competency self-ratings improved on four depression care measures (P = .05 to <.001). Mentors observed improvement in team process and enthusiasm during team meetings. For 336 residents with PHQ-9 and medication data, depression scores did not change while medication use declined, from 37.2% of residents at baseline to 31.0% at 9 months (P < .001). This structured mentoring program improved care processes, achieved medication reductions, and was well received. Application to other NH-prevalent syndromes is possible. PMID- 26503547 TI - Single-chain antibody-fragment M6P-1 possesses a mannose 6-phosphate monosaccharide-specific binding pocket that distinguishes N-glycan phosphorylation in a branch-specific manner?. AB - The acquisition of mannose 6-phosphate (Man6P) on N-linked glycans of lysosomal enzymes is a structural requirement for their transport from the Golgi apparatus to lysosomes mediated by the mannose 6-phosphate receptors, 300 kDa cation independent mannose 6-phosphate receptor (MPR300) and 46 kDa cation-dependent mannose 6-phosphate receptor (MPR46). Here we report that the single-chain variable domain (scFv) M6P-1 is a unique antibody fragment with specificity for Man6P monosaccharide that, through an array-screening approach against a number of phosphorylated N-glycans, is shown to bind mono- and diphosphorylated Man6 and Man7 glycans that contain terminal alphaMan6P(1 -> 2)alphaMan(1 -> 3)alphaMan. In contrast to MPR300, scFv M6P-1 does not bind phosphodiesters, monophosphorylated Man8 or mono- or diphosphorylated Man9 structures. Single crystal X-ray diffraction analysis to 2.7 A resolution of Fv M6P-1 in complex with Man6P reveals that specificity and affinity is achieved via multiple hydrogen bonds to the mannose ring and two salt bridges to the phosphate moiety. In common with both MPRs, loss of binding was observed for scFv M6P-1 at pH values below the second pKa of Man6P (pKa = 6.1). The structures of Fv M6P-1 and the MPRs suggest that the change of the ionization state of Man6P is the main driving force for the loss of binding at acidic lysosomal pH (e.g. lysosome pH ~ 4.6), which provides justification for the evolution of a lysosomal enzyme transport pathway based on Man6P recognition. PMID- 26503549 TI - Differences in urinary proteins related to surgical margin status after radical prostatectomy. AB - Presented exploratory pilot study was aimed at evaluation of proteins present in urinary specimens collected from prostate cancer suffering subjects after radical prostatectomy, divided into two experimental cohorts: positive (n=15) and negative (n=15) surgical margins (PSM/NSM). The presence of PSM suggests inadequate cancer clearance and the possible need for additional treatment. Proper identification of these risk-patients is therefore of a paramount importance. Total protein profiles were firstly identified by using SDS-PAGE and compared by using partial least square discrimination analysis (PLS-DA), which revealed differences in molecular weights of 80-99 and 150-235 kDa between the experimental groups. For further identification of proteins, comparative proteomic technologies were employed. Two-dimensional gel electrophoresis with subsequent identification of protein spots by using MALDI-TOF mass fingerprinting revealed differential expression of proteins between NSM/PSM cohorts. Moreover, in PSM group, three uniquely identified proteins (cyclin-dependent kinase 6, galectin-3-binding protein and L-lactate dehydrogenase C chain) were found, which show tight connection with prostate cancer and presence of all of them was previously linked to certain aspects of prostate cancer. These proteins may be associated with the molecular mechanisms of prostate cancer development; hence, their identification may be helpful for the assessment of disease progression risk after radical prostatectomy, but also for possible early diagnosis. PMID- 26503550 TI - Abnormalities of plasma cytokines and spleen in senile APP/PS1/Tau transgenic mouse model. AB - The blood-based diagnosis has a potential to provide an alternative approach for easy diagnosis of Alzheimer's disease (AD) with less invasiveness and low-cost. However, present blood-based AD diagnosis mainly focuses on measuring the plasma Abeta level because no other biomarkers are found to possess evident transport mechanisms to pass the blood-brain barrier. In order to avoid diagnosing non demented individuals with Abeta abnormality, finding additional biomarkers to supplement plasma Abeta is essential. In this study, we introduce potential neurodegenerative biomarkers for blood-based diagnosis. We observed severe splenomegaly and structural destruction in the spleen with significantly decreased B lymphocytes in senile APPswe, PS1M146V and TauP301L transgenic mice. We also found that inflammatory cytokines associated with splenic dysfunction were altered in the plasma of these mice. These findings suggest potential involvement of the splenic dysfunction in AD and the importance of biomarker level alterations in the plasma as putative diagnostic targets for AD. PMID- 26503552 TI - Ultrathin PdTe nanowires anchoring reduced graphene oxide cathodes for efficient hydrogen evolution reaction. AB - The design and synthesis of efficient electrocatalysts for hydrogen evolution reaction under all pH conditions is extremely desirable but still remains a challenge. Here a facile method to decorate PdTe nanowires on reduced graphene oxide nanosheets (PdTe NWs/rGO) has been developed. As a robust integrated 2D hydrogen-evolving cathode catalyst, the Pd3.02Te NWs/rGO shows a low onset potential of -7 mV and maintains its catalytic activity for at least 48 h in alkaline media. It requires overpotentials (eta) of 97 and 355 mV to afford current densities of 10 and 100 mA cm(-2), respectively. The Pd3.02Te NWs/rGO also exhibits a high activity and excellent durability in acidic media. PMID- 26503551 TI - Clinico-epidemiological analysis of Post kala-azar dermal leishmaniasis (PKDL) cases in India over last two decades: a hospital based retrospective study. AB - BACKGROUND: Patients with Post kala-azar dermal leishmaniasis (PKDL) are considered a reservoir of Leishmania donovani. It is imperative to identify and treat them early for control of visceral leishmaniasis (VL), a current priority in the Indian subcontinent. We explored trends in clinico-epidemiological features of PKDL cases over last two decades, for improving management of the disease. METHODS: Clinically suspected cases were diagnosed with rK39 strip test followed by parasitological confirmation by microscopy and/or PCR/qPCR in skin tissue/slit aspirates. Patients were treated with antimonials till 2008 and subsequently with miltefosine. RESULTS: The study indicated higher incidence of PKDL cases in areas of high endemicity for VL, with 20 % cases reporting no history of VL. Approximately 26 % cases of PKDL were initially misdiagnosed at primary health centers. Duration between onset of PKDL and diagnosis was above 12 months in 80 % cases. Diagnostic sensitivity was 32-36 % with microscopy and 96 100 % with PCR/qPCR. Compliance to treatment was over 85 % with miltefosine while 15 % with antimonials. Relapse rate with miltefosine was up to 13.2 %. CONCLUSIONS: PKDL patients tend to delay reporting and are often misdiagnosed. Confirmatory diagnosis using minimally invasive skin slit aspirate samples would help overcome such issues. There was a paradigm shift in compliance with miltefosine; however, increasing relapse rate indicated the need for newer therapies with oral formulations. PMID- 26503553 TI - Annual periodicity in planktonic bacterial and archaeal community composition of eutrophic Lake Taihu. AB - Bacterioplankton plays a key role in nutrient cycling and is closely related to water eutrophication and algal bloom. We used high-throughput 16S rRNA gene sequencing to profile archaeal and bacterial community compositions in the surface water of Lake Taihu. It is one of the largest lakes in China and has suffered from recurring cyanobacterial bloom. A total of 81 water samples were collected from 9 different sites in 9 different months of 2012. We found that temporal variation of the microbial community was significantly greater than spatial variation (adonis, n = 9999, P < 1e-4). The composition of bacterial community in December was similar to that in January, and so was the archaeal community, suggesting potential annual periodicity. Unsupervised K-means clustering was used to identify the synchrony of abundance variations between different taxa. We found that the cluster consisting mostly of ACK-M1, C111 (members of acIV), Pelagibacteraceae (alfV-A) and Synechococcaceae showed relatively higher abundance in autumn. On the contrary, the cluster of Comamonadaceae and Methylophilaceae (members of lineage betI and betIV) had higher abundance in spring. The co-occurrence relationships between taxa were greatly altered during the cyanobacterial bloom according to our further network module analysis. PMID- 26503554 TI - Epidemiology of incident chlamydia and gonorrhoea infections and population attributable fractions associated with living in the inner-core of Winnipeg, Canada. AB - Population attributable fractions help to convey public health significance of differential disease risk for chlamydia and gonorrhoea. Geographical residence serves as a useful proxy for complex processes creating ill health. Using population-based data, Poisson regression models were used to examine factors associated with chlamydia and gonorrhoea incidence. Population attributable fractions due to residency in the Winnipeg Health Region's inner-core were determined for chlamydia/gonorrhoea infections among 15-59-year olds (2005-2013), stratified by age group. For both chlamydia and gonorrhoea, it was found that the 15-24-year old age group had the highest incidence rates. There was also a stronger association between residency in the inner-core and incidence for gonorrhoea, compared to chlamydia. Overall, 24% (95% CI: 12-34%) of chlamydia infections were attributable to residency in the inner-core, compared to 46% (95% CI: 35-54%) for gonorrhoea ( p < .05). Within chlamydia/gonorrhoea, no statistically significant differences in population attributable fraction were observed by age group. The conclusion was that a concentration of efforts towards inner-core residents with gonorrhoea infections may result in a relatively larger decrease in incidence. PMID- 26503555 TI - Factors associated with hepatitis B vaccination among men who have sex with men: a systematic review of published research. AB - This systematic review identified and synthesised evidence from published research regarding personal and environmental factors associated with hepatitis B virus (HBV) vaccination uptake among gay men and other men who have sex with men (MSM) in low prevalence, high-income countries. A systematic literature search identified 18 eligible papers that addressed factors potentially associated with HBV vaccination uptake among MSM, of which 16 reported research conducted in the US. Studies assessed possible associations between HBV vaccination among MSM and socio-demographic characteristics, behavioural and social-cognitive factors and indicators of health service access. Converging evidence was found for associations between HBV vaccination and younger age, gay self-identification, and not using alcohol and drugs; evidence suggests a lack of association between HBV vaccination and ethnicity. There was converging evidence for associations between HBV vaccination and social-cognitive factors, in particular knowledge, perceived vulnerability and perceived severity regarding HBV infection, and perceived barriers to HBV vaccination. Evidence further supported associations between HBV vaccination and indicators of health service access. While research regarding factors associated with HBV vaccination among MSM remains limited, the identified correlates of HBV vaccination among MSM provide important guidance for the development of health promotion interventions to effectively increase coverage of HBV vaccination among MSM. PMID- 26503556 TI - Routine HIV testing in the Emergency Department: feasible and acceptable? AB - Routine HIV testing in non-specialist settings has the potential to significantly reduce late diagnosis and delay in treatment. The objective was to determine the feasibility and acceptability of HIV testing in an Emergency Department (ED) at a busy London teaching hospital. We conducted an observational cross sectional study between March-May 2012 where patients aged between 18-65 years attending St George's ED having serological tests were offered HIV testing by ED clinical staff. Patients were given an information leaflet on HIV, including how to obtain results. Data detailing whether the test was offered (feasibility) and whether the patient consented to the test (acceptability) were documented. Information regarding reasons for not offering HIV testing and reasons why the test was declined was also recorded. During the study period, 24,171 patients aged 18-65 were seen in the ED. Data were collected from 5657 patients. The mean age was 38 years, 57% were female and 27% identified themselves as white. 48% were offered HIV testing, of which 65% accepted. Incapacity to consent to testing was cited by clinicians as the commonest reason for not offering an HIV test (76%). 'Recent HIV test' was the commonest reason for declining a test (38%). One new HIV diagnosis was made. Our experience demonstrates that routine HIV testing in the ED is feasible and acceptable. However, to make HIV testing effective and part of routine clinical care, considerable clinical leadership, staff training and additional resources are required. PMID- 26503557 TI - Kit ligand promotes the transition from primordial to primary follicles after in vitro culture of ovine ovarian tissue. AB - This study evaluated the effects of kit ligand (KL) on the morphology and development of ovine preantral follicles (fresh control) and after 7 days of in vitro culture in alpha-Minimal Essential Medium (alpha-MEM; control medium) or the presence of KL (1, 10, 50, 100 or 200 ng/ml). There was an increase in the percentage of primary follicles at the concentration of 100 ng/ml KL, compared with the fresh control, control medium (alpha-MEM) and the other KL concentrations. Follicle diameter was significantly higher than the control medium only at concentrations of 50 and 100 ng/ml KL. In conclusion, 100 ng/ml KL promoted the transition from primordial to primary follicles (follicular activation) after in vitro culture of ovine ovarian tissue. PMID- 26503558 TI - Cucurbitacins: A Systematic Review of the Phytochemistry and Anticancer Activity. AB - Cucurbitacins are highly oxidized tetracyclic triterpenoids that are widely present in traditional Chinese medicines (Cucurbitaceae family), possess strong anticancer activity, and are divided into 12 classes from A to T with over 200 derivatives. The eight most active cucurbitacin components against cancer are cucurbitacin B, D, E, I, IIa, L glucoside, Q, and R. Their mechanisms of action include antiproliferation, inhibition of migration and invasion, proapoptosis, and cell cycle arrest promotion. Cucurbitacins are also found to be the inhibitors of JAK-STAT3, Wnt, PI3K/Akt, and MAPK signaling pathways, which play important roles in the apoptosis and survival of cancer cells. Recently, new studies have discovered synergistic anticancer effects by using cucurbitacins together with clinically approved chemotherapeutic drugs, such as docetaxel and methotrexate. This paper provides a summary of recent research progress on the anticancer property of cucurbitacins and the various intracellular signaling pathways involved in the regulation of cancer cell proliferation, death, invasion, and migration. Therefore, cucurbitacins are a class of promising anticancer drugs to be used alone or be intergraded in current chemotherapies and radiotherapies to treat many types of cancers. PMID- 26503559 TI - Ursolic Acid Induces Apoptosis of Prostate Cancer Cells via the PI3K/Akt/mTOR Pathway. AB - Ursolic acid (UA), a pentacyclic triterpenoid, is known to exert antitumor activity in breast, lung, liver and colon cancers. Nonetheless, the underlying mechanism of ursolic acid in prostate cancer cells still remains unclear. In the present study, we report the chemotherapeutic effects of ursolic acid as assessed using in vitro and in vivo models. Treatment of human prostate cancer cells (LNCaP and PC-3) with UA inhibited the proliferation and induced apoptosis in both cell lines as characterized by the increased Annexin V-binding. The induction of apoptosis by UA was associated with a decrease in the levels of Bcl 2, Bcl-xl, survivin, and activated caspase-3. Treatment with UA also inhibited the expression of phosphatidylinositol-3-kinase (PI3K), phosphorylation of Akt and mTOR signaling proteins. Further, administration of UA significantly inhibited the growth of LNCaP prostate tumor xenografts in athymic nude mice, which was associated with inhibition of cell proliferation, induction of apoptosis of tumor cells and decreased expression of PI3K downstream factors, such as p-Akt and p-mTOR in tumor xenograft tissues. Our study demonstrates that UA not only inhibits cell growth but also induces apoptosis through modulation of the PI3K/Akt/mTOR pathway in human prostate cancer cells. We suggest that UA may be a new chemotherapeutic candidate against prostate cancer. PMID- 26503561 TI - Berberine Increases Doxorubicin Sensitivity by Suppressing STAT3 in Lung Cancer. AB - Berberine (BBR), an alkaloid component isolated from Chinese medicinal herb Huang Lian, has aroused broad interests for its antitumor effect in recent years. The signal transducer and activator of transcription 3 (STAT3), plays critical roles in malignant transformation and progression and was found to be constitutively activated in a variety of human cancers. In this study, we show that BBR inhibited cell proliferation, induced apoptosis, and suppressed tumor spheroid formation of lung cancer cell lines. These effects were correlated with BBR mediated suppression of both phosphorylated and total levels of STAT3 protein. Furthermore, BBR promoted STAT3 degradation by enhancing ubiquitination. Importantly, we demonstrated that BBR was able to inhibit doxorubicin (DOX) mediated STAT3 activation and sensitize lung cancer cells to the cytotoxic effect of DOX treatment. Given that BBR is widely used in clinic with low toxicity, our results are potentially important for the development of a novel combinatorial therapy with BBR and DOX in the treatment of lung cancer. PMID- 26503562 TI - Anion Photoelectron Spectroscopy and CASSCF/CASPT2/RASSI Study of Lan(-) (n = 1, 3-7). AB - We present a combined experimental and theoretical study of small lanthanum clusters. The experimental photoelectron spectra of Lan(-) (n = 1, 3-7) were obtained using negative ion photoelectron spectroscopy. Electron affinities for these clusters were found to be in a range of 0.49 eV (La) to 1.5 eV (La7). Our computational tour de force in exploring the electronic structure and its consequences for the lanthanum atom and its anion as well as for lanthanum trimer and its anion shows the multiconfigurational method and large basis set with spin orbit corrections: CASSCF/CASPT2/RASSI/ANO-RCC-L level of theory is needed to reproduce experimental accuracy. The most stable structure for La3(-) was established to be an equilateral triangle ((1)A1'). Chemical bonding analysis of the La3(-) global minimum reveals that this is the first experimentally observed species with d-AO double sigma and pi aromaticity. PMID- 26503560 TI - Effects and Mechanism of Combination of Rhein and Danshensu in the Treatment of Chronic Kidney Disease. AB - Traditional Chinese medicine (TCM) plays a systemic role in disease treatment, targeting multiple etiological factors simultaneously. Based on clinical experience, rhubarb and Salvia miltiorrhiza are commonly prescribed together for the treatment of chronic kidney disease (CKD) and have been proven to be very effective. However, the rationale of the combination remains unclear. The major active ingredients of these two herbs are rhein (RH) and danshensu (DSS), respectively. The aim of this paper is to investigate the renoprotective effects of RH and DSS in vitro and in vivo, and the underlying mechanism. A total of 5/6 nephrectomy rats and HK-2 cells were subjected to chronic renal injury. The combination of RH and DSS conferred a protective effect, as shown by a significant improvement in the renal function, blood supply, and fibrotic degree. Proinflammatory cytokines and adhesion molecules were suppressed by RH and DSS through NK-kappaB signaling. The combination also inhibited apoptosis by up regulating Bcl-2 and down-regulating Bax. Inhibiting the TGF-beta/Smad3 pathway was at least in part involved in the antifibrotic mechanism of the combination treatment of RH and DSS. This study demonstrates for the first time the renoprotective effect and the mechanism of RH and DSS combination on chronic renal injury. It could provide experimental evidence to support the rationality of the combinatorial use of TCM in clinical practices. PMID- 26503563 TI - Hepatic hemorrhage as a consequence of rapid response to combined targeted therapy in metastatic melanoma. AB - A middle-aged female with metastatic melanoma was found to have hemoperitoneum after starting systemic therapy with the BRAF and MEK inhibitors dabrafenib and trametinib. Etiology proved to be bleeding from a known hepatic metastasis. The patient was managed conservatively and eventually resumed systemic therapy with ongoing response. This case serves to illustrate the possible deleterious effects of rapid tumor response after initiation of targeted systemic therapy in patients with metastatic melanoma. PMID- 26503565 TI - Corticotropin-releasing factor type-2 receptor and corticotropin-releasing factor binding protein coexist in rat ventral tegmental area nerve terminals originated in the lateral hypothalamic area. AB - There is significant functional evidence showing that corticotropin-releasing factor type-2 receptor (CRF2R) and corticotropin-releasing factor-binding protein (CRF-BP) regulate glutamatergic synapses onto ventral tegmental area (VTA) dopaminergic neurons. It has been shown that CRF requires CRF-BP to potentiate N methyl-D-aspartate receptors in dopaminergic neurons through CRF2R, and that increases glutamate release in cocaine-treated rats through the activation of CRF2R only by agonists with high affinity to CRF-BP. Furthermore, this CRF mediated increase in VTA glutamate is responsible for stress-induced relapse to cocaine-seeking behaviour. However, there is a lack of anatomical evidence to explain the mechanisms of CRF actions in VTA. Thus, it was studied whether CRF2R and CRF-BP are expressed in VTA nerve terminals, using a synaptosomal preparation devoid of postsynaptic elements. The current results show that both proteins are co-expressed in glutamatergic and gamma-aminobutyric acid (GABA)ergic VTA synaptosomes. A main glutamatergic input to the VTA that has been associated to addictive behaviour is originated in the lateral hypothalamic area (LHA). Thus, this study was focused in the LHA-VTA input using orexin as a marker of this input. The results show that CRF2R and CRF-BP mRNA and protein are expressed in the LHA, and that both proteins are present in orexin-positive VTA synaptosomes. The results showing that CRF2R and CRF-BP are expressed in the LHA-VTA input give anatomical support to suggest that this input plays a role in stress-induced relapse to cocaine-seeking behaviour. PMID- 26503566 TI - What Is the Next Step after Endoscopic Resection of Superficial Esophageal Squamous Cell Carcinoma? PMID- 26503567 TI - Understanding Growth Patterns of Signet Ring Cell Carcinoma of the Stomach Is Necessary for Successful Endoscopic Resection. PMID- 26503568 TI - Initial Steps to Prevent Nonsteroidal Anti-Inflammatory Drug- or Aspirin-Induced Enteropathy: Long-Term Outcome Data. PMID- 26503569 TI - The Role of Barrier Dysfunction and Change of Claudin Expression in Inflammatory Bowel Disease. PMID- 26503570 TI - Assessment for Risk of Bias in Systematic Reviews and Meta-Analyses in the Field of Hepatology. AB - A systematic review (SR) provides the best and most objective analysis of the existing evidence in a particular field. SRs and derived conclusions are essential for evidence-based strategies in medicine and evidence-based guidelines in clinical practice. The popularity of SRs has also increased markedly in the field of hepatology. However, although SRs are considered to provide a higher level of evidence with greater confidence than original articles, there have been no reports on the quality of SRs and meta-analyses (MAs) in the field of hepatology. Therefore, we performed a quality assessment of 225 SRs and MAs that were recently published in the field of hepatology (January 2011 to September 2014) using A MeaSurement Tool to Assess systematic Reviews (AMSTAR). Using AMSTAR, we revealed both a shortage of assessments of the scientific quality of individual studies and a publication bias in many SRs and MAs. This review addresses the concern that SRs and MAs need to be conducted in a stricter and more objective manner to minimize bias and random errors. Thus, SRs and MAs should be supported by a multidisciplinary approach that includes clinical experts, methodologists, and statisticians. PMID- 26503571 TI - The Expanding Role of Contrast-Enhanced Endoscopic Ultrasound in Pancreatobiliary Disease. AB - Since its introduction into clinical practice in the 1980s, endoscopic ultrasound (EUS) has been described as a good imaging modality for the diagnosis of pancreatobiliary diseases. However, differential diagnosis of certain lesions based only on B-mode ultrasound images can be challenging. Clinical use of ultrasound contrast agents has expanded the utility of EUS from that of detection to characterization of pancreatobiliary lesions based on the enhancement features of contrast-enhanced EUS (CE-EUS). Current low mechanical index techniques for CE EUS using second-generation contrast agents have a number of distinct advantages over conventional diagnostic modalities in evaluating pancreatobiliary lesions, including real-time assessment of perfusion pattern, availability, and the absence of exposure to radiation. This article describes the technical aspects of CE-EUS and reviews the expanding indications in pancreatobiliary diseases and further development of this technique. PMID- 26503573 TI - Erratum: Management of Hepatocellular Carcinoma: Current Status and Future Directions. PMID- 26503572 TI - Is Whole Exome Sequencing Clinically Practical in the Management of Pediatric Crohn's Disease? AB - BACKGROUND/AIMS: The aim of this study was to identify the profile of rare variants associated with Crohn's disease (CD) using whole exome sequencing (WES) analysis of Korean children with CD and to evaluate whether genetic profiles could provide information during medical decision making. METHODS: DNA samples from 18 control individuals and 22 patients with infantile, very-early and early onset CD of severe phenotype were used for WES. Genes were filtered using panels of inflammatory bowel disease (IBD)-associated genes and genes of primary immunodeficiency (PID) and monogenic IBD. RESULTS: Eighty-one IBD-associated variants and 35 variants in PID genes were revealed by WES. The most frequently occurring variants were carried by nine (41%) and four (18.2%) CD probands and were ATG16L2 (rs11235604) and IL17REL (rs142430606), respectively. Twenty-four IBD-associated variants and 10 PID variants were predicted to be deleterious and were identified in the heterozygous state. However, their functions were unknown with the exception of a novel p.Q111X variant in XIAP (X chromosome) of a male proband. CONCLUSIONS: The presence of many rare variants of unknown significance limits the clinical applicability of WES for individual CD patients. However, WES in children may be beneficial for distinguishing CD secondary to PID. PMID- 26503575 TI - Flu vaccinations: a justified pain in the arm? PMID- 26503574 TI - Reflections on metabolic syndrome in children. PMID- 26503576 TI - Are cholesterol levels being checked and managed appropriately in UK primary care type 2 diabetes? PMID- 26503578 TI - Dr Alice MacLennan. PMID- 26503577 TI - Sources of funding for adult and paediatric CT procedures at a metropolitan tertiary hospital: How much do Medicare statistics really cover? AB - INTRODUCTION: The radiation dose to the Australian paediatric population as a result of medical imaging is of growing concern, in particular the dose from CT. Estimates of the Australian population dose have largely relied on Medicare Australia statistics, which capture only a fraction of those imaging procedures actually performed. The fraction not captured has been estimated using a value obtained for a survey of the adult population in the mid-1990s. To better quantify the fraction of procedures that are not captured by Medicare Australia, procedure frequency and funding data for adult and paediatric patients were obtained from a metropolitan tertiary teaching and research hospital. METHODS: Five calendar years of data were obtained with a financial class specified for each individual procedure. The financial classes were grouped to give the percentage of Medicare Australia billable procedures for both adult and paediatric patients. The data were also grouped to align with the Medicare Australia age cohorts. RESULTS: The percentage of CT procedures billable to Medicare Australia increased from 16% to 28% between 2008 and 2012. In 2012, the percentage billable for adult and paediatric patients was 28% and 33%, respectively; however, many adult CT procedures are performed at stand-alone clinics, which bulk bill. CONCLUSION: Using Medicare Australia statistics alone, the frequency of paediatric CT procedures performed on the Australian paediatric population will be grossly under estimated. A correction factor of 4.5 is suggested for paediatric procedures and 1.5 for adult procedures. The fraction of actual procedures performed that are captured by Medicare Australia will vary with time. PMID- 26503579 TI - Progress in Understanding the Genetic Information and Biosynthetic Pathways behind Amycolatopsis Antibiotics, with Implications for the Continued Discovery of Novel Drugs. AB - Species of Amycolatopsis, well recognized as producers of both vancomycin and rifamycin, are also known for producing other secondary metabolites, with wide usage in medicine and agriculture. The molecular genetics of natural antibiotics produced by this genus have been well studied. Since the rise of antibiotic resistance, finding new drugs to fight infection has become an urgent priority. Progress in understanding the biosynthesis of metabolites greatly helps the rational manipulation of biosynthetic pathways, and thus to achieve the goal of generating novel natural antibiotics. The efforts made in exploiting Amycolatopsis genome sequences for the discovery of novel natural products and biosynthetic pathways are summarized. PMID- 26503580 TI - Controlled Redox Chemistry at Cerium within a Tripodal Nitroxide Ligand Framework. AB - Ligand reorganization has been shown to have a profound effect on the outcome of cerium redox chemistry. Through the use of a tethered, tripodal, trianionic nitroxide ligand, [((2-tBuNOH)C6 H4 CH2 )3 N](3-) (TriNOx (3-) ), controlled redox chemistry at cerium was accomplished, and typically reactive complexes of tetravalent cerium were isolated. These included rare cationic complexes [Ce(TriNOx )thf][BAr(F) 4 ], in which Ar(F) =3,5-(CF3 )2 -C6 H3 , and [Ce(TriNOx )py][OTf]. A rare complete Ce-halide series, Ce(TriNOx )X, in which X=F(-) , Cl( ) , Br(-) , I(-) , was also synthesized. The solution chemistry of these complexes was explored through detailed solution-phase electrochemistry and (1) H NMR experiments and showed a unique shift in the ratio of species with inner- and outer-sphere anions with size of the anionic X(-) group. DFT calculations on the series of calculations corroborated the experimental findings. PMID- 26503581 TI - Effects of a high milk intake during the pre-weaning period on nutrient metabolism and growth rate in Japanese Black cattle. AB - This study aimed to determine the effects of feeding an increased volume of high fat milk during the early post-natal life on metabolite concentrations in the blood, the expression of key genes regulating intermediary metabolism in the skeletal muscles, and the rate of growth of Japanese Black cattle. All calves were fed a high-fat milk replacer (crude protein, 26%; crude fat, 25.5%; total dissolved nitrogen, 116%). Control calves (n = 4) were nursed with 500 g milk replacer until 3 months of age, whereas calves in the experimental group (n = 4) were nursed with 1800 g milk replacer until 3 months, and then the volume was gradually reduced until 5 months. Body weight was significantly higher in the experimental group than in the control group at 7 months. Plasma glucose concentrations were significantly lower in the experimental group. Expression of glucose-transporter-4 messenger RNA (mRNA) was lower, whereas that of glucose transporter 1, cluster of differentiation 36, and carnitine palmitoyltransferase 1b mRNA was significantly higher in the Longissimus thoracis of the experimental group. Nutritional status during early post-natal life appears to strongly influence the growth rate and glucose and lipid metabolism in Japanese Black cattle. PMID- 26503583 TI - Osteopetrosis and Chiari type I malformation: a rare association. AB - Osteopetrosis (OP) is hereditary X-linked, autosomal recessive (ARO), or autosomal dominant (ADO) skeletal disease. ARO has two subtypes, which are infantile malignant and intermediate type. ARO and X-linked OP have poor clinical outcome. ADO is called adult benign type because of the normal life expectancy, which has type I and type II. Here, the authors present an ADO patient with Chiari type I. Concomitant ADO with Chiari type I malformation is an extremely rare condition. Literature research yielded only one case report to date. PMID- 26503582 TI - Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker that can predict the efficacy of direct-acting anti-viral-based triple therapy for chronic hepatitis C. AB - BACKGROUND: The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+) -M2BP) is a new liver fibrosis glycobiomarker with unique fibrosis-related glyco-alteration. WFA(+) -M2BP is also a useful surrogate marker for the risk of developing hepatocellular carcinoma and for the liver functional reserve. AIM: To evaluate the diagnostic ability of WFA(+) -M2BP for liver fibrosis in the clinical setting and the clinical utility of WFA(+) -M2BP for predicting the efficacy of direct-acting anti-viral (DAA) treatment for chronic hepatitis C patients. METHODS: The study included 159 genotype 1 hepatitis C patients who received DAA-based treatment (telaprevir or simeprevir) combined with pegylated-interferon alpha plus ribavirin (108 telaprevir- and 51 simeprevir based triple treatment). The relation between baseline serum WFA(+) -M2BP and treatment efficacy was evaluated. RESULTS: The serum WFA(+) -M2BP level significantly increased with the progress of liver fibrosis. Area under the receiver operating characteristic curve analysis identified 2.17 as the cut-off index (COI) for WFA(+) -M2BP for diagnosing advanced fibrosis. The sustained virological response (SVR) rate was significantly, negatively correlated with the serum WFA(+) -M2BP level. Multiple logistic regression analysis found a low serum WFA(+) -M2BP level (<2.17 COI) to be independently associated with SVR (odds ratio, 4.35, P = 0.027). Even for prior nonresponders and patients with the interleukin-28B minor allele or histological advanced fibrosis, treatment outcome was favourable for patients with a low serum WFA(+) -M2BP level. CONCLUSION: Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker useful for predicting the efficacy of DAA-based triple therapy for chronic hepatitis C patients. PMID- 26503585 TI - Prevalence and temporal trends of physical activity counselling in primary health care in Germany from 1997-1999 to 2008-2011. AB - BACKGROUND: For patients, usually the first and most preferred contact person on health issues is still the doctor and most persons see their doctor at least once a year. Therefore, physical activity counselling strategies delivered by a physician seem to be a promising approach for physical activity improvement. The aim of this work is to show prevalence and time trends in physical activity counselling by primary health care physicians from 1997-1999 to 2008-2011 in Germany. METHODS: Data from two representative cross-sectional health interview and examination surveys of the Robert Koch Institute were used. Prevalence proportions of physicians' physical activity counselling and patients' utilisation of health promotion programmes in relation to physical activity counselling were analysed. Strengths of associations were calculated by using binary logistic regression models. Overall, 11,907 persons aged 18-64 years were included in the analyses. RESULTS: Physical activity counselling prevalence decreased from 11.1 to 9.4% in men and from 9.3 to 7.7% in women over ten years. Only persons with accumulated health risks (OR 5.33; 95% CI 1.89-15.00) and persons with diagnosed diabetes mellitus (OR 3.42; 95% CI 1.68-6.69) showed significantly higher counselling proportions in 2008-2011 compared to 1997-1999. Men were more often counselled on physical activity than women, but women showed significantly higher participation rates in physical activity promotion programmes in both surveys. In both sexes significantly higher participation rates could be observed in persons who had received some activity counselling by a physician. CONCLUSION: Although, evidence underlines the positive health effects of regular physical activity; overall, physicians counselling behaviour on physical activity decreased over time. However, it is positive to note that a trend towards a disease-specific counselling behaviour in terms of a tailored intervention could be observed. PMID- 26503584 TI - Identification of four new susceptibility loci for testicular germ cell tumour. AB - Genome-wide association studies (GWAS) have identified multiple risk loci for testicular germ cell tumour (TGCT), revealing a polygenic model of disease susceptibility strongly influenced by common variation. To identify additional single-nucleotide polymorphisms (SNPs) associated with TGCT, we conducted a multistage GWAS with a combined data set of >25,000 individuals (6,059 cases and 19,094 controls). We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P=1.5 * 10(-9)), 11q14.1 (rs7107174, GAB2, P=9.7 * 10(-11)), 16p13.13 (rs4561483, GSPT1, P=1.6 * 10(-8)) and 16q24.2 (rs55637647, ZFPM1, P=3.4 * 10( 9)). We additionally present detailed functional analysis of these loci, identifying a statistically significant relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples. These findings provide additional support for a polygenic model of TGCT risk and further insight into the biological basis of disease development. PMID- 26503586 TI - The timing and precision of action prediction in the aging brain. AB - Successful social interactions depend on the ability to anticipate other people's actions. Current conceptualizations of brain function propose that causes of sensory input are inferred through their integration with internal predictions generated in the observer's motor system during action observation. Less is known concerning how action prediction changes with age. Previously we showed that internal action representations are less specific in older compared with younger adults at behavioral and neural levels. Here, we characterize how neural activity varies while healthy older adults aged 56-71 years predict the time-course of an unfolding action as well as the relation to task performance. By using fMRI, brain activity was measured while participants observed partly occluded actions and judged the temporal coherence of the action continuation that was manipulated. We found that neural activity in frontoparietal and occipitotemporal regions increased the more an action continuation was shifted backwards in time. Action continuations that were shifted towards the future preferentially engaged early visual cortices. Increasing age was associated with neural activity that extended from posterior to anterior regions in frontal and superior temporal cortices. Lower sensitivity in action prediction resulted in activity increases in the caudate. These results imply that the neural implementation of predicting actions undergoes similar changes as the neural process of executing actions in older adults. The comparison between internal predictions and sensory input seems to become less precise with age leading to difficulties in anticipating observed actions accurately, possibly due to less specific internal action models. PMID- 26503587 TI - Respiratory frequency is strongly associated with perceived exertion during time trials of different duration. AB - In order to provide further insight into the link between respiratory frequency (fR) and the rating of perceived exertion (RPE), the present study investigated the effect of exercise duration on perceptual and physiological responses during self-paced exercise. Nine well-trained competitive male cyclists (23 +/- 3 years) performed a preliminary incremental ramp test and three randomised self-paced time trials (TTs) differing in exercise duration (10, 20 and 30 min). Both RPE and fR increased almost linearly over time, with a less-pronounced rate of increase when absolute exercise duration increased. However, when values were expressed against relative exercise duration, no between-trial differences were found in either RPE or fR. Conversely, between-trial differences were observed for minute ventilation (.VE), .VO2 and heart rate (HR), when values were expressed against relative exercise duration. Unlike the relationship between RPE and both .VE and HR, the relationship between RPE and fR was not affected by exercise duration. In conclusion, fR, but not .VE, HR or [.VO2, shows a strong relationship to RPE and a similar time course, irrespective of exercise duration. These findings indicate that fR is the best correlate of RPE during self-paced exercise, at least among the parameters and for the range of durations herein investigated. PMID- 26503588 TI - Evidence-based guideline: Management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society. PMID- 26503589 TI - Evidence-based guideline: Management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society. PMID- 26503590 TI - Mystery Case: Lafora periodic acid-Schiff inclusion bodies. PMID- 26503591 TI - Teaching NeuroImages: MRI findings in X-linked adrenoleukodystrophy. PMID- 26503592 TI - Infection, vaccination, and childhood arterial ischemic stroke. PMID- 26503594 TI - The role of structural and interpersonal violence in the lives of women: a conceptual shift in prevention of gender-based violence. PMID- 26503593 TI - Phase II trial of selective internal radiation therapy and systemic chemotherapy for liver-predominant metastases from pancreatic adenocarcinoma. AB - BACKGROUND: This prospective, open-label phase II study assessed the impact of liver-directed therapy with selective internal radiation therapy (SIRT) and systemic chemotherapy on progression-free survival (PFS) in liver-dominant metastatic pancreatic adenocarcinoma. METHODS: Patients received yttrium-90 labelled ((90)Y) resin microspheres (SIR-Spheres; Sirtex Medical Limited, Sydney, Australia) as a single procedure on day 2 of the first weekly cycle of 5 fluorouracil (5FU; 600 mg/m(2)) with the option to switch to gemcitabine (1000 mg/m(2)) after 8 weeks of 5FU. Statistical analysis was conducted using Microsoft Excel (Microsoft Corporation, Redmond, Washington, USA). The primary endpoint of the study was PFS in the liver, with a median of >= 16 weeks defined as the threshold for clinical significance. PFS and overall survival (OS) were summarised by the Kaplan-Meier method using non-parametric estimates of the survivor function. RESULTS: Fourteen eligible patients were enrolled; ten had primary tumour in situ and eight had liver-only metastases. Patients received a median (90)Y activity of 1.1 GBq and 8 weekly doses of 5FU; seven patients received a median of two doses of gemcitabine. Disease control in the liver was 93% (two confirmed partial responses [PR], one unconfirmed PR, ten stable disease). Median reduction in cancer antigen 19-9 was 72%. Median PFS was 5.2 months in the liver, which met the primary endpoint of the study, and 4.4 months at any site. PFS was prolonged in those with a resected primary compared with patients with primary in situ (median 7.8 vs. 3.4 months; p = 0.017). Median OS was 5.5 months overall and 13.6 months in patients with a resected primary. Grade 3/4 adverse events occurred in eight (57%) patients during days 0-60. There was one sudden death and another patient who died from possible treatment-related liver failure 7.0 months after SIRT. CONCLUSIONS: SIRT and chemotherapy appears to be an effective treatment for liver metastases from pancreatic cancer, likely to be of most benefit in selected patients with a resected primary tumour and liver only disease. Significant toxicity was observed and the safety of this approach in patients with metastatic pancreatic cancer will need to be confirmed in subsequent studies. Further study is warranted with SIRT and modern chemotherapies. TRIAL REGISTRATION: ACTRN12606000015549. PMID- 26503595 TI - Association between subclinical carotid atherosclerosis, hyperhomocysteinaemia and mild cognitive impairment. AB - OBJECTIVE: Evidence suggests that intima-media thickness (IMT) and plasma homocysteine (Hcy) levels are associated with one another, and both appear to be related to cognitive dysfunction. However, no connection between both factors taken together and mild cognitive impairment (MCI) has been established. This study analysed potential relationships between IMT, Hcy and MCI. METHODS: We included 105 patients with MCI and 76 controls with no history of vascular disease. All participants underwent laboratory analyses, a carotid ultrasound, and clinical and neuropsychological assessment. We used the Mantel-Haenszel test (MHT), ANCOVA and multiple linear regression models (MLRM) to examine any associations between IMT, Hcy and cognitive state. RESULTS: The MHT revealed a significant association between IMT and risk of MCI (z = 4.285, P < 0.0001). The OR for the upper quartile vs the lower quartile was 5.12 (95% CI: 2.12-12.36). MHT also showed a clear association between Hcy levels and risk of MCI (z = 3.01, P = 0.003). OR for the upper vs the lower quartile was 3.39 (95% CI: 1.41-8.12). Additionally, we found a correlation between IMT and Hcy (r = 0.162, P = 0.032). CONCLUSIONS: Our results suggest that there is a connection between IMT, Hcy levels and presence of amnestic MCI in a population with no history of clinically manifest atherosclerosis. Furthermore, there is also a connection between the IMT and Hcy levels themselves. PMID- 26503596 TI - Airline Safety Improvement Through Experience with Near-Misses: A Cautionary Tale. AB - In recent years, the U.S. commercial airline industry has achieved unprecedented levels of safety, with the statistical risk associated with U.S. commercial aviation falling to 0.003 fatalities per 100 million passengers. But decades of research on organizational learning show that success often breeds complacency and failure inspires improvement. With accidents as rare events, can the airline industry continue safety advancements? This question is complicated by the complex system in which the industry operates where chance combinations of multiple factors contribute to what are largely probabilistic (rather than deterministic) outcomes. Thus, some apparent successes are realized because of good fortune rather than good processes, and this research intends to bring attention to these events, the near-misses. The processes that create these near misses could pose a threat if multiple contributing factors combine in adverse ways without the intervention of good fortune. Yet, near-misses (if recognized as such) can, theoretically, offer a mechanism for continuing safety improvements, above and beyond learning gleaned from observable failure. We test whether or not this learning is apparent in the airline industry. Using data from 1990 to 2007, fixed effects Poisson regressions show that airlines learn from accidents (their own and others), and from one category of near-misses-those where the possible dangers are salient. Unfortunately, airlines do not improve following near-miss incidents when the focal event has no clear warnings of significant danger. Therefore, while airlines need to and can learn from certain near-misses, we conclude with recommendations for improving airline learning from all near misses. PMID- 26503597 TI - Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology. AB - Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases. PMID- 26503598 TI - CXCR2-CXCL1 axis is correlated with neutrophil infiltration and predicts a poor prognosis in hepatocellular carcinoma. AB - BACKGROUND & AIMS: Inflammation is a hallmark of cancer, yet the mechanisms that regulate immune cell infiltration into tumors remain poorly characterized. This study attempted to characterize the composition, distribution, and prognostic value of CXCR2(+) cells in hepatocellular carcinoma (HCC) and to examine the CXCR2 ligands that are responsible for local immune infiltration in different areas of HCC tumors. METHODS: Immunohistochemistry and immunofluorescene were used to identify CXCR2(+) cells in HCC tissues. Kaplan-Meier analysis and Cox regression models were applied to estimate recurrence-free survival (RFS) and overall survival (OS) for 259 HCC patients. The expression levels of CXCR2 ligands (CXCL-1, -2, -5, and -8) were measured by real-time PCR and compared with local immune cell density. The combined prognostic value of the CXCR2-CXCL1 axis was further evaluated. RESULTS: In HCC tissues, CXCR2(+) cells were mainly neutrophils that were enriched in the peri-tumoral stroma (PS) region. Kaplan Meier survival analysis showed that increased CXCR2(+) PS cells were associated with reduced RFS and OS (P = 0.015 for RFS; P = 0.002 for OS). Multivariate Cox proportional hazards analysis identified CXCR2(+) PS cell density as an independent prognostic factor for OS (hazard ratio [HR] = 1.737, 95 % confidence interval [CI] = 1.167-2.585, P = 0.006). Furthermore, we detected a positive correlation between the density of CD15(+) neutrophils and CXCL1 levels in both the peri-tumoral stroma and intra-tumoral regions. The combination of CXCR2 and CXCL1 expression levels represented a powerful predictor of a poor prognosis for patients with HCC. CONCLUSIONS: Our data showed that the CXCR2(+) cell density was an independent prognostic factor for predicting OS for HCC patients. The CXCR2-CXCL1 axis can regulate neutrophil infiltration into HCC tumor tissues and might represent a useful target for anti-HCC therapies. PMID- 26503599 TI - Age-Related Alterations in Blood Biochemical Characterization of Hepatorenal Function in the PCK Rat: A Model of Polycystic Kidney Disease. AB - PCK rats develop age-related polycystic kidney disease (PKD) and liver disease and have been used to investigate pharmacotherapies to ameliorate hepatorenal lesions for patients with PKD. The PCK rat may be useful to understand the possible susceptibility to hepatotoxicity observed in the patient with PKD having hepatic polycystic lesions. Therefore, the purpose of this study was to investigate the background blood biochemical changes that reflect the hepatorenal function of PCK rats as well as the terminal histopathology in order to determine whether this model would be suitable for extrapolating the susceptibility of hepatotoxicity in patients. The blood biochemical parameters of hepatorenal function and histopathology were investigated in PCK rats at ages 5 to 19 weeks and compared to those outcomes in the Sprague Dawley (SD) rat. There were notable blood biochemical changes possibly due to biliary dysgenesis in the PCK rat as early as 5 weeks of age. High levels of gamma-glutamyl transpeptidase, alkaline phosphatase, alanine aminotransferase, and total bile acids persisted throughout the study compared to the SD rat. Increased aspartate aminotransferase, total bilirubin, and hyperlipidemia and a decrease in albumin were also evident at 10 to 19 weeks of age possibly due to progression of cholestatic liver dysfunction secondary to age-related liver cystic progression. Increased liver weights generally correlated with the severity of biliary and hepatic histopathological changes. In male PCK rats, age-related increases in blood urea nitrogen and creatinine at 10 to 19 weeks of age were observed, and the cystic progression was more severe than that in females. These data indicate that the PCK rat showed notable blood biochemical changes reflecting alteration of the liver function compared to the SD rat. Also, there was a large individual variation in these parameters possibly due to variable progression rate of biliary dysgenesis and subsequent liver damages in PCK rats. PMID- 26503600 TI - Overall survival with and without laryngeal function preservation in 580 patients with hypopharyngeal squamous cell carcinoma. AB - The aims of the present study were to review the experience of different surgical reconstruction methods for hypopharyngeal squamous cell carcinoma (HSCC) and compared the survival of patients with and without laryngeal function (LF) preservation. The clinical characteristics of 580 patients were retrospectively obtained and analyzed. Survival curves were analyzed using the Kaplan-Meier method for survival and Cox models for hazard ratios (HRs) with 95% confidence intervals (CIs). LF was preserved in 403 cases and not preserved in 177 cases. The 3- and 5-year survival rates were 70.9 and 52.7%, respectively, in the LF preservation group and 48.4 and 30.5%, respectively, in the no LF preservation group. Compared with the patients without LF preservation, patients with LF preservation had a significantly reduced risk of overall death (HR=0.63, 95% CI: 0.50-0.80). LF preservation positively affects the prognosis of patients with HSCC. PMID- 26503602 TI - APOBEC3G Interacts with ssDNA by Two Modes: AFM Studies. AB - APOBEC3G (A3G) protein has antiviral activity against HIV and other pathogenic retroviruses. A3G has two domains: a catalytic C-terminal domain (CTD) that deaminates cytidine, and a N-terminal domain (NTD) that binds to ssDNA. Although abundant information exists about the biological activities of A3G protein, the interplay between sequence specific deaminase activity and A3G binding to ssDNA remains controversial. We used the topographic imaging and force spectroscopy modalities of Atomic Force Spectroscopy (AFM) to characterize the interaction of A3G protein with deaminase specific and nonspecific ssDNA substrates. AFM imaging demonstrated that A3G has elevated affinity for deaminase specific ssDNA than for nonspecific ssDNA. AFM force spectroscopy revealed two distinct binding modes by which A3G interacts with ssDNA. One mode requires sequence specificity, as demonstrated by stronger and more stable complexes with deaminase specific ssDNA than with nonspecific ssDNA. Overall these observations enforce prior studies suggesting that both domains of A3G contribute to the sequence specific binding of ssDNA. PMID- 26503603 TI - Mapping 3' transcript ends in the bank vole (Clethrionomys glareolus) mitochondrial genome with RNA-Seq. AB - BACKGROUND: Although posttranscriptional modification of mitochondrial (mt) transcripts plays key roles in completion of the coding information and in the expression of mtDNA-encoded genes, there is little experimental evidence on the polyadenylation status and the location of mt gene poly(A) sites for non-human mammals. RESULTS: Poly(A)-enriched RNA-Seq reads collected for two wild-caught bank voles (Clethrionomys glareolus) were mapped to the complete mitochondrial genome of that species. Transcript polyadenylation was detected as unmapped adenine residues at the ends of the mapped reads. Where the tRNA punctuation model applied, there was the expected polyadenylation, except for the nad5 transcript, whose polyadenylated 3' end is at an intergenic sequence/cytochrome b boundary. As in human, two pairs of bank vole genes, nad4l/nad4 and atp8/atp6, are expressed from bicistronic transcripts. TAA stop codons of four bank vole protein-coding genes (nad1, atp6, cox3 and nad4) are incompletely encoded in the DNA and are completed by polyadenylation. This is three genes (nad2, nad3 and cob) less than in human. The bank vole nad2 gene encodes a full stop codon (TAA in one vole and TAG in the other), which is followed by a 2 bp UTR and the gene conforms to the tRNA punctuation model. In contrast, the annotations of the reference mouse and some other rodent mt genomes in GenBank include complete TAG stop codons in both nad1 and nad2, which overlap downstream trnI and trnW, respectively. Thus the RNA-Seq data of bank voles provides a model for stop codons of mt-encoded genes in mammals comparable to humans, but at odds with some of the interpretation based purely on genomic data in mouse and other rodents. CONCLUSIONS: This work demonstrates how RNA-Seq data were useful to recover mtDNA transcriptome data in a non-model rodent and to shed more light on mammalian mtDNA transcriptome and post-transcriptional modification. Even though gene content and organisation of mtDNA are strongly conserved among mammals, annotations that neglect the transcriptome may be prone to errors in relation to the stop codons. PMID- 26503601 TI - Enhanced angiogenesis in ischemic skeletal muscle after transplantation of cell sheets from baculovirus-transduced adipose-derived stromal cells expressing VEGF165. AB - INTRODUCTION: Cell therapy using adipose-derived stromal cells (ADSC) is an intensively developing approach to promote angiogenesis and regeneration. Administration technique is crucial and among others minimal constructs - cell sheets (CS) have certain advantages. Delivery of CS allows transplantation of cells along with matrix proteins to facilitate engraftment. Cells' therapeutic potential can be also increased by expression of proangiogenic factors by viral transduction. In this work we report on therapeutic efficacy of CS from mouse ADSC transduced to express human vascular endothelial growth factor 165 a/a isoform (VEGF165), which showed potency to restore perfusion and protect tissue in a model of limb ischemia. METHODS: Mouse ADSC (mADSC) isolated from C57 male mice were expanded for CS formation (10(6)cells per CS). Constructs were transduced to express human VEGF165 by baculoviral (BV) system. CS were transplanted subcutaneously to mice with surgically induced limb ischemia and followed by laser Doppler perfusion measurements. At endpoint animals were sacrificed and skeletal muscle was evaluated for necrosis and vessel density; CS with underlying muscle was stained for apoptosis, proliferation, monocytes and blood vessels. RESULTS: Using BV system and sodium butyrate treatment we expressed human VEGF165 in mADSC (production of VEGF165 reached ~ 25-27 ng/ml/10(5) cells) and optimized conditions to ensure cells' viability after transduction. Implantation of mock-transduced CS resulted in significant improvement of limb perfusion, increased capillary density and necrosis reduction at 2 weeks post-surgery compared to untreated animals. Additional improvement of blood flow and angiogenesis was observed after transplantation of VEGF165 expressing CS indicating enhanced therapeutic potential of genetically modified constructs. Moreover, we found delivery of mADSC as CS to be superior to equivalent dose of suspended cells in terms of perfusion and angiogenesis. Histology analysis of extracted CS detected limited proliferation and approximately 10 % prevalence of apoptosis in transplanted mADSC. Significant vascularization of CS and infiltration by monocytes were found in both - BV transduced and control CS indicating graft and host interaction after transplantation. CONCLUSIONS: Delivery of ADSC by subcutaneous transplantation of CS is effective for stimulation of angiogenesis and tissue protection in limb ischemia with a potential for efficacy improvement by BV transduction to express VEGF165. PMID- 26503605 TI - Erratum to: omega-Amidase: an underappreciated, but important enzyme in L glutamine and L-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases. PMID- 26503604 TI - Multiplexed, Proteome-Wide Protein Expression Profiling: Yeast Deubiquitylating Enzyme Knockout Strains. AB - Characterizing a protein's function often requires a description of the cellular state in its absence. Multiplexing in mass spectrometry-based proteomics has now achieved the ability to globally measure protein expression levels in yeast from 10 cell states simultaneously. We applied this approach to quantify expression differences in wild type and nine deubiquitylating enzyme (DUB) knockout strains with the goal of creating "information networks" that might provide deeper, mechanistic insights into a protein's biological role. In total, more than 3700 proteins were quantified with high reproducibility across three biological replicates (30 samples in all). DUB mutants demonstrated different proteomics profiles, consistent with distinct roles for each family member. These included differences in total ubiquitin levels and specific chain linkages. Moreover, specific expression changes suggested novel functions for several DUB family members. For instance, the ubp3Delta mutant showed large expression changes for members of the cytochrome C oxidase complex, consistent with a role for Ubp3 in mitochondrial regulation. Several DUBs also showed broad expression changes for phosphate transporters as well as other components of the inorganic phosphate signaling pathway, suggesting a role for these DUBs in regulating phosphate metabolism. These data highlight the potential of multiplexed proteome-wide analyses for biological investigation and provide a framework for further study of the DUB family. Our methods are readily applicable to the entire collection of yeast deletion mutants and may help facilitate systematic analysis of yeast and other organisms. PMID- 26503606 TI - An update on transcriptional and post-translational regulation of brain voltage gated sodium channels. AB - Voltage-gated sodium channels are essential proteins in brain physiology, as they generate the sodium currents that initiate neuronal action potentials. Voltage gated sodium channels expression, localisation and function are regulated by a range of transcriptional and post-translational mechanisms. Here, we review our understanding of regulation of brain voltage-gated sodium channels, in particular SCN1A (NaV1.1), SCN2A (NaV1.2), SCN3A (NaV1.3) and SCN8A (NaV1.6), by transcription factors, by alternative splicing, and by post-translational modifications. Our focus is strongly centred on recent research lines, and newly generated knowledge. PMID- 26503607 TI - Multispectral optical metasurfaces enabled by achromatic phase transition. AB - The independent control of electromagnetic waves with different oscillating frequencies is critical in the modern electromagnetic techniques, such as wireless communications and multispectral imaging. To obtain complete control of different light waves with optical materials, the chromatic dispersion should be carefully controlled, which is however extremely difficult. In this paper, we propose a method to control the behaviors of different light waves through a metasurface which is able to generate achromatic geometric phase. Using this approach, a doughnut-shaped and a solid light spot were achieved at the same focal plane using two light sources with different wavelengths as used in the stimulation emission depletion (STED) microscope system. In order to reveal the full capacity of such method, tight focusing at multiple wavelengths is also represented, where the focal spots of different wavelengths are located at the same position. The results provided here may open a new door to the design of subminiature optical components and integrated optical system operating at multiple wavelengths. PMID- 26503608 TI - Genome-wide association study of 29 morphological traits in Aegilops tauschii. AB - Aegilops tauschii is the D-genome progenitor of hexaploid wheat (Triticum aestivum). It is considered to be an important source of genetic variation for wheat breeding, and its genome is an invaluable reference for wheat genomics. We conducted a genome-wide association study using 7,185 single nucleotide polymorphism (SNP) markers across 322 diverse accessions of Ae. tauschii that were systematically phenotyped for 29 morphological traits in order to identify marker-trait associations and candidate genes, assess genetic diversity, and classify the accessions based on phenotypic data and genotypic comparison. Using the general linear model and mixed linear model, we identified a total of 18 SNPs significantly associated with 10 morphological traits. Systematic search of the flanking sequences of trait-associated SNPs in public databases identified several genes that may be linked to variations in phenotypes. Cluster analysis using phenotypic data grouped accessions into four clusters, while accessions in the same cluster were not from the same Ae. tauschii subspecies or from the same area of origin. This work establishes a fundamental research platform for association studies in Ae. tauschii and also provides useful information for understanding the genetic mechanism of agronomic traits in wheat. PMID- 26503609 TI - Five-fraction stereotactic radiosurgery (SRS) for single inoperable high-risk non small cell lung cancer (NSCLC) brain metastases. AB - BACKGROUND: Achieving durable local control while limiting normal tissue toxicity with definitive radiation therapy in the management of high-risk brain metastases remains a radiobiological challenge. The objective of this study was to examine the local control and toxicity of a 5-fraction stereotactic radiosurgical approach for treatment of patients with inoperable single high-risk NSCLC brain metastases. METHODS: This retrospective analysis examines 20 patients who were deemed to have "high-risk" brain metastases. High-risk tumors were defined as those with a maximum diameter greater than 2 cm and/or those located within an eloquent cortex. Patients were evaluated by a neurosurgeon prior to treatment and determined to be inoperable due to tumor or patient characteristics. Patients were treated using the CyberKnife(r) SRS system in 5 fractions to a total dose of 30 Gy, 35 Gy, or 40 Gy. RESULTS: Twenty patients with a median age of 65.5 years were treated from April 2010 to August 2014 in 5 fractions to a median total dose of 35 Gy. At a median follow up of 11.3 months local tumor control was observed in 18 of 20 metastases (90 %). Both local failures were observed in patients receiving a lower dose of 30 Gy. Median pre-treatment dexamethasone dose was 10 mg/day and median post-treatment nadir dose was 0 mg/day. Salvage intracranial therapy was required in 45 % of patients. Symptomatic radionecrosis was observed in 4 of 20 patients (20 %), two of which were treated to 40 Gy and the remainder to 35 Gy. Kaplan-Meier 1-year, 2-year, and median survival were calculated to be 45 %, 20 %, and 13.2 months, respectively. CONCLUSIONS: Five-fraction SRS to a total dose of 35 Gy appears to be a safe and effective management strategy for single high-risk NSCLC brain metastases, while a total dose of 40 Gy leads to an excess risk of neurotoxicity. PMID- 26503611 TI - Geometry controlled anomalous diffusion in random fractal geometries: looking beyond the infinite cluster. AB - We investigate the ergodic properties of a random walker performing (anomalous) diffusion on a random fractal geometry. Extensive Monte Carlo simulations of the motion of tracer particles on an ensemble of realisations of percolation clusters are performed for a wide range of percolation densities. Single trajectories of the tracer motion are analysed to quantify the time averaged mean squared displacement (MSD) and to compare this with the ensemble averaged MSD of the particle motion. Other complementary physical observables associated with ergodicity are studied, as well. It turns out that the time averaged MSD of individual realisations exhibits non-vanishing fluctuations even in the limit of very long observation times as the percolation density approaches the critical value. This apparent non-ergodic behaviour concurs with the ergodic behaviour on the ensemble averaged level. We demonstrate how the non-vanishing fluctuations in single particle trajectories are analytically expressed in terms of the fractal dimension and the cluster size distribution of the random geometry, thus being of purely geometrical origin. Moreover, we reveal that the convergence scaling law to ergodicity, which is known to be inversely proportional to the observation time T for ergodic diffusion processes, follows a power-law ~T(-h) with h < 1 due to the fractal structure of the accessible space. These results provide useful measures for differentiating the subdiffusion on random fractals from an otherwise closely related process, namely, fractional Brownian motion. Implications of our results on the analysis of single particle tracking experiments are provided. PMID- 26503610 TI - Should breathing adapted radiotherapy also be applied for right-sided breast irradiation? AB - BACKGROUND: Voluntary moderate deep inspiration breath-hold (vmDIBH) is widely used for left sided breast cancer patients. The purpose of this study was to investigate the usefulness of vmDIBH in local and locoregional radiation therapy (RT) of right-sided breast cancer. MATERIALS AND METHODS: For fourteen right sided breast cancer patients, 3D-conformal (3D-CRT) RT plans (i.e., forward IMRT) were calculated on free-breathing (FB) 3D-CRT(FB) and vmDIBHCT-scans, for local- as well as locoregional breast treatment, with and without internal mammary nodes (IMN). Dose volume parameters were compared. RESULTS: For local breast treatment, no relevant reduction in mean lung dose (MLD) was found. For locoregional breast treatment without IMN, the average MLD reduced from 6.5 to 5.4 Gy (p < 0.005) for the total lung and from 11.2 to 9.7 Gy (p < 0.005) for the ipsilateral lung. For locoregional breast treatment with IMN, the average MLD reduced from 10.8 to 9.1 Gy (p < 0.005) for the total lung and from 18.7 to 16.2 Gy (p < 0.005) for the ipsilateral lung, whilea small reduction in mean heart dose of 0.4 Gy (p = 0.07) was also found. CONCLUSIONS: Breathing adapted radiation therapy in left-sided breast cancer patients is becoming widely introduced. As a result of the slight reduction in lung dose found for locoregional right-sided breast cancer treatment in this study, a slightly lower risk of pneumonitis and secondary lung cancer (in ever smoking patients) can be expected.In addition, for some patients the heart dose will also be reduced by more than 0.5 up to 2.6 Gy. We therefore suggest to also apply breath-hold for locoregional irradiation of right-sided breast cancer patients. PMID- 26503613 TI - Impurity channels of the long-lived Mossbauer effect. AB - Recent reports have suggested that the nuclear resonant absorption of a long lived Mossbauer state e.g., (93m)Nb is mediated by an entangled photon pair (biphoton) rather than by a single photon. Multipolar nuclear excitation in crystals of a single isotope with a natural abundance of 100% spreads in a region containing billions of identical nuclei. As a consequence of the delocalisation, additional decay channels via the impurities, the crystal defects, and the sample boundary, give rise to a density- and temperature-dependent decay. In this letter we report our discovery of impurity channels, the intensity of which is proportional to the square of the (93m)Nb density. PMID- 26503612 TI - Geographic variation in thermal tolerance and strategies of heat shock protein expression in the land snail Theba pisana in relation to genetic structure. AB - Land snails are exposed to conditions of high ambient temperature and low humidity, and their survival depends on a suite of morphological, behavioral, physiological, and molecular adaptations to the specific microhabitat. We tested in six populations of the land snail Theba pisana whether adaptations to different habitats affect their ability to cope with thermal stress and their strategies of heat shock protein (HSP) expression. Levels of Hsp70 and Hsp90 in the foot tissue were measured in field-collected snails and after acclimation to laboratory conditions. Snails were also exposed to various temperatures (32 up to 54 degrees C) for 2 h and HSP messenger RNA (mRNA) levels were measured in the foot tissue and survival was determined. To test whether the physiological and molecular data are related to genetic parameters, we analyzed T. pisana populations using partial sequences of nuclear and mitochondrial DNA ribosomal RNA genes. We show that populations collected from warmer habitats were more thermotolerant and had higher constitutive levels of Hsp70 isoforms in the foot tissue. Quantitative real-time polymerase chain reaction (PCR) analysis indicated that hsp70 and hsp90 mRNA levels increased significantly in response to thermal stress, although the increase in hsp70 mRNA was larger compared to hsp90 and its induction continued up to higher temperatures. Generally, warm-adapted populations had higher temperatures of maximal induction of hsp70 mRNA synthesis and higher upper thermal limits to HSP mRNA synthesis. Our study suggests that Hsp70 in the foot tissue of T. pisana snails may have important roles in determining stress resistance, while Hsp90 is more likely implicated in signal transduction processes that are activated by stress. In the phylogenetic analysis, T. pisana haplotypes were principally divided into two major clades largely corresponding to the physiological ability to withstand stress, thus pointing to genetically fixed tolerance. PMID- 26503614 TI - Children who were treated with oral immunotherapy for cows' milk allergy showed long-term desensitisation seven years later. AB - AIM: This was a follow-up of 28 schoolchildren with cows' milk allergy (CMA) who attended a randomised double-blind placebo-controlled oral immunotherapy (OIT) study. In the original study, 26 (92.9%) completed the six-month escalation phase, and 25 (89.3%) used milk daily at 12 months and 24 (85.7%) at 36 months. This study evaluated the outcome seven years later, with special attention paid to milk consumption and symptoms. METHODS: Outcome data were collected through a postal questionnaire completed three, four and five years after enrolment and by a phone questionnaire after seven years. We asked about the daily dose of milk products, any adverse reactions, any medication needed and possible discontinuation of daily milk consumption. RESULTS: Data were available at the seven-year point for 24 children and 14 (58.3%) of these continued to use milk (>=200 mL) or milk products (protein >=6400 mg) daily for seven years. However, three (21.4%) of these still reported symptoms associated with milk consumption. Of the 10 remaining children, two children used milk products daily but consumed less due to symptoms and eight (33.3%) had discontinued milk consumption. CONCLUSION: Oral immunotherapy was an effective and safe way of desensitising schoolchildren with persistent CMA. PMID- 26503615 TI - Montage of a Queering Deferred: Memory, Ownership, and Archival Silencing in the Rhetorical Biography of Langston Hughes. AB - This article explores the intersection of archival privilege and heteronormative bias in the queering of Langston Hughes. Although it has been a common belief in LGBTQ communities that Hughes was gay, the battle over how his sexuality is defined in various biographical texts involves broader issues of dominant representations of sexuality and who gets to speak for those no longer able to speak for themselves. As such, the article examines the texts Looking for Langston and The Life of Langston Hughes as well as the discourses that surrounded both. Through this case study, it is apparent that there are still numerous cultural challenges posed to historical queering and that scholars must take an inventive approach to overcome them. PMID- 26503616 TI - Recurrent skin and soft tissue infections in HIV-infected patients during a 5 year period: incidence and risk factors in a retrospective cohort study. AB - BACKGROUND: Skin and soft tissue infections (SSTIs) are common in the era of community-associated methicillin resistant Staphylococcus aureus among HIV infected patients. Recurrent infections are frequent. Risk factors for recurrence after an initial SSTI have not been well-studied. METHODS: Retrospective cohort study, single center, 2005-2009. Paper and electronic medical records were reviewed by one of several physicians. Subjects with initial SSTI were followed until the time of SSTI recurrence. Standard descriptive statistics were calculated to describe the characteristics of subjects who did and did not develop a recurrent SSTI. Kaplan-Meier methods were used to estimate the risk of recurrent SSTI. A Cox regression model was developed to identify predictors of SSTI recurrence. RESULTS: 133 SSTIs occurred in 87 individuals. 85 subjects were followed after their initial SSTI, of whom 30 (35.3 %) had a recurrent SSTI in 118.3 person-years of follow-up, for an incidence of second SSTI of 253.6 SSTIs/1000 person-years (95 % CI 166.8-385.7). The 1-year Kaplan-Meier estimated risk of a second SSTI was 29.2 % (95 % CI 20.3-41.0 %), while the 3-year risk was 47.0 % (95 % CI 34.4-61.6 %). Risk factors for recurrent SSTI in a multivariable Cox regression model were non-hepatitis liver disease (HR 3.44; 95 % CI 1.02 11.5; p = 0.05), the presence of an intravenous catheter (HR 6.50; 95 % CI 1.47 28.7; p = 0.01), and a history of intravenous drug use (IVDU) (HR 2.80; 95 % CI 1.02-7.65; p = 0.05); African-American race was associated with decreased risk of recurrent SSTI (HR 0.12; 95 % CI 0.04-0.41; p < 0.01). Some evidence was present for HIV viral load >= 1000 copies/mL as an independent risk factor for recurrent SSTI (HR 2.21; 95 % CI 0.99-4.94; p = 0.05). Hemodialysis, currently taking HAART, CD4+ count, trimethoprim-sulfamethoxazole or azithromycin use, initial SSTI type, diabetes mellitus, incision and drainage of the original SSTI, or self report of being a man who has sex with men were not associated with recurrence. CONCLUSION: Of HIV-infected patients with an SSTI, nearly 1/3 had a recurrent SSTI within 1 year. Risk factors for recurrent SSTI were non-hepatitis liver disease, intravenous catheter presence, a history of IVDU, and non-African American race. Low CD4+ count was not a significant risk factor for recurrence. PMID- 26503617 TI - Improved treatment and prognosis after acute myocardial infarction in Estonia: cross-sectional study from a high risk country. AB - BACKGROUND: The aim of the study was to explore trends in short- and long-term mortality after hospitalization for acute myocardial infarction (AMI) over the period 2001?2011 in Estonian secondary and tertiary care hospitals while adjusting for changes in baseline characteristics. METHODS: In this nationwide cross-sectional study random samples of patients hospitalized due to AMI in years 2001, 2007 and 2011 were identified and followed for 1 year. Trends in 30-day and 1-year all-cause mortality were analysed using Cox proportional hazards regression model. RESULTS: The final analysis included 423, 687 and 665 patients in years 2001, 2007 and 2011 respectively. During the study period, the prevalence of most comorbidities remained unchanged while the in-hospital and outpatient treatment improved significantly. For example, the proportion of tertiary care hospital AMI patients who underwent revascularization was almost three times higher in 2011 compared to 2001. The proportion of secondary care patients who were referred to a tertiary care centre for more advanced care increased from 5.8 to 40.1 % (p for trend <0.001). Meanwhile, the 1-year mortality rates decreased from 29.5 to 20.2 % (adjusted p = 0.004) in the tertiary and from 32.4 to 23.1 % (adjusted p = 0.006) in the secondary care. The decrease in the 30-day mortality rates was statistically significant only in the secondary care hospitals. CONCLUSIONS: The use of evidence-based treatments in Estonian AMI patients improved between 2001 and 2011. At the same time, we observed a significant reduction in the long-term mortality rates, both for patients primarily hospitalized into secondary as well as into tertiary care hospitals. PMID- 26503619 TI - Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) and proteinuria predict severity of acute kidney injury in Puumala virus infection. AB - BACKGROUND: Nephropathia epidemica (NE) is a mild form of hemorrhagic fever with renal syndrome (HFRS) that is caused by the Puumala virus. Periodic outbreaks have been described in endemic areas, with a substantial number of previously healthy individuals developing acute kidney injury (AKI). There is a considerable diversity in the clinical course of the disease, and few patients require renal replacement therapy. METHODS: We tested whether urinary neutrophil gelatinase associated lipocalin (uNGAL), urine albumin/creatinine ratio (uACR), urine protein/creatinine ratio (uPCR), urine dipstick protein, C-reactive protein, procalcitonin, leukocyte and platelet count, determined on admission to the hospital, can predict the severity of AKI. Sixty-one patients were analyzed during admission in the emergency department. RESULTS: The variables most strongly associated with peak plasma creatinine concentration were uNGAL (beta = 0.70, p <0.0001), uPCR (beta = 0.64, p = 0.001), uACR (beta = 0.61, p = 0.002), and dipstick proteinuria (beta = 0.34, p = 0.008). The highest AUC-ROC to predict stage 3 AKI according to the acute kidney injury network's (AKIN) classification was seen for uNGAL (0.81, p = 0.001). CONCLUSION: uNGAL accurately predicts the severity of AKI in NE. This could help emergency room physicians predict disease severity and allow for initial risk stratification. PMID- 26503620 TI - Assessing satisfaction with social care services among black and minority ethnic and white British carers of stroke survivors in England. AB - Overall satisfaction levels with social care are usually high but lower levels have been reported among black and minority ethnic (BME) service users in England. Reasons for this are poorly understood. This qualitative study therefore explored satisfaction with services among informal carer participants from five different ethnic groups. Fifty-seven carers (black Caribbean, black African, Asian Indian, Asian Pakistani and white British) were recruited from voluntary sector organisations and a local hospital in England, and took part in semi structured interviews using cognitive interviewing and the critical incident technique. Interviews took place from summer 2013 to spring 2014. Thematic analysis of the interviews showed that participants often struggled to identify specific 'incidents', especially satisfactory ones. When describing satisfactory services, participants talked mostly about specific individuals and relationships. Unsatisfactory experiences centred on services overall. When rating services using cognitive interviewing, explicit comparisons with expectations or experiences with other services were common. Highest satisfaction ratings tended to be justified by positive personal characteristics among practitioners, trust and relationships. Lower level ratings were mostly explained by inconsistency in services, insufficient or poor care. Lowest level ratings were rare. Overall, few differences between ethnic groups were identified, although white British participants rated services higher overall giving more top ratings. White British participants also frequently took a more overall view of services, highlighting some concerns but still giving top ratings, while South Asian carers in particular focused on negative aspects of services. Together these methods provide insight into what participants mean by satisfactory and unsatisfactory services. Cognitive interviewing was more challenging for some BME participants, possibly a reflection of the meaningfulness of the concept of service satisfaction to them. Future research should include comparisons between BME and white participants' understanding of the most positive parts of satisfaction scales and should focus on dissatisfied participants. PMID- 26503621 TI - Minodronic acid suppresses gonadotropin-releasing hormone agonist-induced bone remodeling biomarkers: a retrospective pilot study. AB - BACKGROUND: Estrogen deprivation therapy for myoma/adenomyosis decreases bone mineral density and can only be applied in the short term, as temporizing measures in the premenopausal woman. OBJECTIVE: To examine the effects of bisphosphonate minodronic acid on markers of bone turnover over a 6-month period in women receiving gonadotropin-releasing hormone agonist (GnRHa). METHODS: We retrospectively analyzed the medical records of 19 premenopausal patients with myoma/adenomyosis, who received GnRHa (leuprolide acetate, 1.88 mg/month or buserelin acetate, 900 ug/day) for 6 months from January 2014 to December 2014. Eight patients concomitantly received minodronic acid 50 mg every month during GnRHa therapy, and 11 treated with GnRHa alone. To compare these data in a case controlled study, we analyzed an age-matched group of seven (premature or natural) menopausal women treated with minodronic acid. The primary outcome was percent changes in bone turnover markers in urine at 6 months. RESULTS: In menopausal women group, minodronic acid (50 mg once-monthly) for 6 months decreased urinary deoxypyridinoline (DPD) and cross-linked N-telopeptides of type 1 collagen (NTX). Women receiving a GnRHa had a significant increase in urinary DPD and TNX at 6 months while minodronic acid during GnRHa therapy improved urinary levels of DPD and NTX to near baseline. CONCLUSION: Minodronic acid treatment appears to be promising in women with secondary bone loss receiving GnRHa treatment. PMID- 26503622 TI - Antigen-induced arthritis in rats is associated with increased growth-associated protein 43-positive intraepidermal nerve fibres remote from the joint. AB - INTRODUCTION: Pain in arthritis may be experienced in regions outside the affected joint, and hyperalgesia may even be widespread. The spread of pain is usually attributed to mechanisms in the central nervous system. We investigated whether rats with antigen-induced arthritis (AIA) exhibit peripheral changes in skin innervation remote from the inflamed joint. METHODS: After immunization, unilateral AIA in the knee joint was induced in rats. Intraepidermal nerve fibre density was determined by immunohistochemical staining for protein gene product 9.5 (PGP 9.5) and for nerve fibres expressing calcitonin gene-related peptide (CGRP), substance P (SP), transient receptor potential vanilloid 1 (TRPV1; the heat and capsaicin receptor), beta-tubulin, and growth-associated protein 43 (GAP 43; a marker of regenerating nerve fibres) in paw pad skin and back skin. Cluster of differentiation 11b (CD11b)-positive macrophages and CD3-positive T cells were quantified in skin, and macrophages were quantified in the lumbar dorsal root ganglia. In addition, pain-related behaviour was assessed. RESULTS: Intraepidermal nerve fibre density (PGP 9.5) and the numbers of fibres expressing CGRP, SP, TRPV1, or beta-tubulin did not show a significant change in the acute (3 days) or chronic phase (21 days) of AIA compared with control rats that were only immunized. However, paw skin and back skin revealed a significantly higher number of nerve fibres expressing GAP-43 at both the acute and chronic stages of AIA. The skin of arthritic rats in these regions did not contain a greater density of CD11b and CD3 immune cells than the skin of control rats. Enhanced expression of GAP-43 in nerve fibres of the skin was not related to hyperalgesia in the joint, but it accompanied persistent secondary cutaneous hyperalgesia in the skin remote from the inflamed joint. CONCLUSIONS: Although the innervation of the skin remote from the joint did not show significant abnormalities of the other nerve fibre markers, the rapid and persistent increase of GAP-43 expression is conspicuous. The data suggest that immune-mediated arthritis is associated with changes in skin innervation remote from the inflamed joint, although the skin is not inflamed, which may contribute to symptoms in nonarticular tissue remote from the affected joint. PMID- 26503623 TI - Clinical Utility of the Trail-Making Test as a Predictor of Driving Performance in Older Adults. AB - OBJECTIVES: To assess the clinical utility of the Trail-Making Tests (TMTs) as screens for impaired road-test performance. DESIGN: Secondary analyses of three data sets from previously published studies of impaired driving in older adults using comparable road test designs and outcome measures. SETTING: Two academic driving specialty clinics. PARTICIPANTS: Older drivers (N = 392; 303 with cognitive impairment, 89 controls) from Rhode Island and Missouri. MEASUREMENTS: Standard operating characteristics were evaluated for the TMT Part A (TMT-A) and Part B (TMT-B), as well as optimal upper and lower test cut-points that could be useful in defining groups of drivers with indeterminate likelihood of impaired driving who would most benefit from further screening or on-road testing. RESULTS: Discrimination remained high (>70%) when cut-points for the TMTs derived from Rhode Island data were applied to Missouri data, but calibration was poor (all P < .01). TMT-A provided the best utility for determining a range of scores (68-90 seconds) for which additional road testing would be indicated in general practice settings. A high frequency of cognitively impaired participants unable to perform the TMT-B test within the allotted time limited the utility of the test (>25%). Mere inability to complete the test in a reasonable time frame (e.g., TMT-A > 48 seconds or TMT-B > 108 seconds) may still be a useful tool in separating unsafe from safe or marginal drivers in such samples. CONCLUSION: The TMTs (particularly TMT-A) may be useful as screens for driving impairment in older drivers in general practice settings, where most people are still safe drivers, but more-precise screening measures need to be analyzed critically in a variety of clinical settings for testing cognitively impaired older drivers. PMID- 26503624 TI - A test of somatic mosaicism in the androgen receptor gene of Canada lynx (Lynx canadensis). AB - BACKGROUND: The androgen receptor, an X-linked gene, has been widely studied in human populations because it contains highly polymorphic trinucleotide repeat motifs that have been associated with a number of adverse human health and behavioral effects. A previous study on the androgen receptor gene in carnivores reported somatic mosaicism in the tissues of a number of species including Eurasian lynx (Lynx lynx). We investigated this claim in a closely related species, Canada lynx (Lynx canadensis). The presence of somatic mosaicism in lynx tissues could have implications for the future study of exonic trinucleotide repeats in landscape genomic studies, in which the accurate reporting of genotypes would be highly problematic. METHODS: To determine whether mosaicism occurs in Canada lynx, two lynx individuals were sampled for a variety of tissue types (lynx 1) and tissue locations (lynx 1 and 2), and 1,672 individuals of known sex were genotyped to further rule out mosaicism. RESULTS: We found no evidence of mosaicism in tissues from the two necropsied individuals, or any of our genotyped samples. CONCLUSIONS: Our results indicate that mosaicism does not manifest in Canada lynx. Therefore, the use of hide samples for further work involving trinucleotide repeat polymorphisms in Canada lynx is warranted. PMID- 26503626 TI - Fellowships: more not less to improve employability and patient outcomes. PMID- 26503625 TI - The HRASLS (PLA/AT) subfamily of enzymes. AB - The H-RAS-like suppressor (HRASLS) subfamily consists of five enzymes (1-5) in humans and three (1, 3, and 5) in mice and rats that share sequence homology with lecithin:retinol acyltransferase (LRAT). All HRASLS family members possess in vitro phospholipid metabolizing abilities including phospholipase A1/2 (PLA1/2) activities and O-acyltransferase activities for the remodeling of glycerophospholipid acyl chains, as well as N-acyltransferase activities for the production of N-acylphosphatidylethanolamines. The in vivo biological activities of the HRASLS enzymes have not yet been fully investigated. Research to date indicates involvement of this subfamily in a wide array of biological processes and, as a consequence, these five enzymes have undergone extensive rediscovery and renaming within different fields of research. This review briefly describes the discovery of each of the HRASLS enzymes and their role in cancer, and discusses the biochemical function of each enzyme, as well as the biological role, if known. Gaps in current understanding are highlighted and suggestions for future research directions are discussed. PMID- 26503627 TI - The Career Medical Interview: solid selector or just 'impression management'? PMID- 26503628 TI - MicroRNA-92b promotes tumor growth and activation of NF-kappaB signaling via regulation of NLK in oral squamous cell carcinoma. AB - miR-92b has been reported to be dysregulated in many types of human cancers. However, the role of miR-92b in oral squamous cell carcinoma (OSCC) is unknown. The aim of the present study was to investigate the function and mechanism of miR 92b in human OSCC. Using quantitative reverse-transcription PCR (qRT-PCR), we found that the miR-92b level in primary tumors (n=85) was significantly elevated compared with that in the adjacent normal tissues (p<0.001). A high level of miR 92b was significantly associated with a large tumor size (p=0.005), advanced tumor stage (p<0.001) and poorer prognosis (p=0.04). Functionally, miR-92b was shown to not only promote the proliferation of OSCC cells in MTT and colony formation and xenograft assays, but also to inhibit cell apoptosis in a flow cytometric assay. In western blotting and luciferase assay, NLK was identified as a direct and functional target of miR-92b. We also found that NLK was involved in miR-92b-induced cell proliferation, and its protein level was obviously downregulated in the miR-92b-overexpressing xenograft tumors. Finally, luciferase reporter assay and fluorescent immunostaining revealed that miR-92b activated the NF-kappaB signaling pathway, which may be responsible for the effects of miR-92b on cell proliferation. Taken together, our results indicate that miR-92b upregulation accelerates tumor growth and present a novel mechanism of miRNA mediated NF-kappaB activation in OSCC. PMID- 26503629 TI - Long-term rice cultivation stabilizes soil organic carbon and promotes soil microbial activity in a salt marsh derived soil chronosequence. AB - Soil organic carbon (SOC) sequestration with enhanced stable carbon storage has been widely accepted as a very important ecosystem property. Yet, the link between carbon stability and bio-activity for ecosystem functioning with OC accumulation in field soils has not been characterized. We assessed the changes in microbial activity versus carbon stability along a paddy soil chronosequence shifting from salt marsh in East China. We used mean weight diameter, normalized enzyme activity (NEA) and carbon gain from straw amendment for addressing soil aggregation, microbial biochemical activity and potential C sequestration, respectively. In addition, a response ratio was employed to infer the changes in all analyzed parameters with prolonged rice cultivation. While stable carbon pools varied with total SOC accumulation, soil respiration and both bacterial and fungal diversity were relatively constant in the rice soils. Bacterial abundance and NEA were positively but highly correlated to total SOC accumulation, indicating an enhanced bio-activity with carbon stabilization. This could be linked to an enhancement of particulate organic carbon pool due to physical protection with enhanced soil aggregation in the rice soils under long-term rice cultivation. However, the mechanism underpinning these changes should be explored in future studies in rice soils where dynamic redox conditions exist. PMID- 26503630 TI - Interplay between tetrel and triel bonds in RC6H4CN?MF3CN?BX3 complexes: A combined symmetry-adapted perturbation theory, Moller-Plesset, and quantum theory of atoms-in-molecules study. AB - Intermolecular ternary complexes composed of: (1) the centrally placed trifluoroacetonitrile or its higher analogs with central carbon exchanged by silicon or germanium (M = C, Si, Ge), (2) the benzonitrile molecule or its para derivatives on one side, and (3) the boron trifluoride of trichloride molecule (X = F, Cl) on the opposite side as well as the corresponding intermolecular tetrel- and triel-bonded binary complexes, were investigated by symmetry-adapted perturbation theory (SAPT) and the supermolecular Moller-Plesset method (MP2) at the complete basis set limit for optimized geometries. A character of interactions was studied by quantum theory of atoms-in-molecules (QTAIM). A comparison of interaction energies and QTAIM bond descriptors for dimers and trimers reveals that tetrel and triel bonds increase in their strength if present together in the trimer. For the triel-bonded complex, this growth leads to a change of the bond character from closed-shell to partly covalent for Si or Ge tetrel atoms, so the resulting bonding scheme corresponds to a preliminary stage of the SN2 reaction. Limitations of the Lewis theory of acids and bases were shown by its failure in predicting the stability order of the triel complexes. The necessity of including interaction energy terms beyond the electrostatic component for an elucidation of the nature of sigma- and pi-holes was presented by a SAPT energy decomposition and by a study of differences in monomer electrostatic potentials obtained either from isolated monomer densities, or from densities resulting from a perturbation with the effective field of another monomer. PMID- 26503632 TI - Photoswitchable anticancer activity via trans-cis isomerization of a combretastatin A-4 analog. AB - Combretastatin A-4 (CA4) is highly potent anticancer drug that acts as an inhibitor of tubulin polymerization. The core of the CA4 structure contains a cis stilbene, and it is known that the trans isomer is significantly less potent. We prepared an azobenzene analog of CA4 (Azo-CA4) that shows 13-35 fold enhancement in potency upon illumination. EC50 values in the light were in the mid nM range. Due to its ability to thermally revert to less toxic trans form, Azo-CA4 also has the ability to automatically turn its activity off with time. Azo-CA4 is less potent than CA-4 because it degrades in the presence of glutathione as evidenced by UV-Vis spectroscopy and ESI-MS. Nevertheless, Azo-CA4 represents a promising strategy for switchable potency for treatment of cancer. PMID- 26503633 TI - Sr9Mg(1.5)(PO4)7:Eu(2+): A Novel Broadband Orange-Yellow-Emitting Phosphor for Blue Light-Excited Warm White LEDs. AB - A new orange-yellow-emitting Sr9Mg(1.5)(PO4)7:Eu(2+) phosphor was prepared via high-temperature solid-state reaction. The structure and optical properties of it were studied systematically. Sr9Mg(1.5)(PO4)7:Eu(2+) can be well-excited by 460 nm blue InGaN chips and exhibit a wide emission band covering from 470 to 850 nm with two main peaks centered at 523 and 620 nm, respectively, which originate from 5d-4f dipole-allowed transitions of Eu(2+) in different crystallographic sites. The sites attribution, concentration quenching, fluorescence decay analysis, and temperature-dependent luminescence properties were investigated in detail. Furthermore, a warm white LED device was fabricated by combining a 460 nm blue InGaN chip with the optimized orange-yellow-emitting Sr9Mg(1.5)(PO4)7:Eu(2+). The color coordinate, correlated color temperature and color rendering index of the fabricated LED device were (0.393, 0.352), 3437 K, and 86.07, respectively. Sr9Mg(1.5)(PO4)7:Eu(2+) has great potential to serve as an attractive candidate in the application of blue light-excited warm white LEDs. PMID- 26503631 TI - Spectral biomarkers for chemoprevention of colonic neoplasia: a placebo controlled double-blinded trial with aspirin. AB - OBJECTIVE: A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy. DESIGN: We conducted a multicentre, prospective, randomised, double-blind placebo controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints. RESULTS: At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin's pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=-0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention. CONCLUSIONS: We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice. TRIAL NUMBER: NCT00468910. PMID- 26503634 TI - Dense Helical Electron Bunch Generation in Near-Critical Density Plasmas with Ultrarelativistic Laser Intensities. AB - The mechanism for emergence of helical electron bunch(HEB) from an ultrarelativistic circularly polarized laser pulse propagating in near-critical density(NCD) plasma is investigated. Self-consistent three-dimensional(3D) Particle-in-Cell(PIC) simulations are performed to model all aspects of the laser plasma interaction including laser pulse evolution, electron and ion motions. At a laser intensity of 10(22) W/cm(2), the accelerated electrons have a broadband spectrum ranging from 300 MeV to 1.3 GeV, with the charge of 22 nano-Coulombs(nC) within a solid-angle of 0.14 Sr. Based on the simulation results, a phase-space dynamics model is developed to explain the helical density structure and the broadband energy spectrum. PMID- 26503635 TI - Prevalence of Mycobacterium lentiflavum in cystic fibrosis patients, France. AB - BACKGROUND: Mycobacterium lentiflavum is rarely isolated in respiratory tract samples from cystic fibrosis patients. We herein describe an unusually high prevalence of M. lentiflavum in such patients. METHODS: M. lentiflavum, isolated from the respiratory tract of cystic fibrosis patients, was identified using both rpoB partial sequencing and detected directly in the sputum by using real-time PCR targeting the smpB gene. RESULTS: M. lentiflavum emerged as the third most prevalent nontuberculous mycobacterial species isolated in cystic fibrosis patients in Marseille, France. Six such patients were all male, and two of them may have fulfilled the American Thoracic Society clinical and microbiological criteria for M. lentiflavum potential lung infection. CONCLUSIONS: M. lentiflavum was the third most common mycobacteria isolated in cystic fibrosis patients, particularly in six male patients. M. lentiflavum outbreaks are emerging particularly in cystic fibrosis patients. PMID- 26503637 TI - Effect of bacterial inoculation of strains of Pseudomonas aeruginosa, Alcaligenes feacalis and Bacillus subtilis on germination, growth and heavy metal (Cd, Cr, and Ni) uptake of Brassica juncea. AB - Bacterial inoculation may influence Brassica juncea growth and heavy metal (Ni, Cr, and Cd) accumulation. Three metal tolerant bacterial isolates (BCr3, BCd33, and BNi11) recovered from mine tailings, identified as Pseudomonas aeruginosa KP717554, Alcaligenes feacalis KP717561, and Bacillus subtilis KP717559 were used. The isolates exhibited multiple plant growth beneficial characteristics including the production of indole-3-acetic acid, hydrogen cyanide, ammonia, insoluble phosphate solubilization together with the potential to protect plants against fungal pathogens. Bacterial inoculation improved seeds germination of B. juncea plant in the presence of 0.1 mM Cr, Cd, and Ni, as compared to the control treatment. Compared with control treatment, soil inoculation with bacterial isolates significantly increased the amount of soluble heavy metals in soil by 51% (Cr), 50% (Cd), and 44% (Ni) respectively. Pot experiment of B. juncea grown in soil spiked with 100 mg kg(-1) of NiCl2, 100 mg kg(-1) of CdCl2, and 150 mg kg(-1) of K2Cr2O7, revealed that inoculation with metal tolerant bacteria not only protected plants against the toxic effects of heavy metals, but also increased growth and metal accumulation of plants significantly. These findings suggest that such metal tolerant, plant growth promoting bacteria are valuable tools which could be used to develop bio-inoculants for enhancing the efficiency of phytoextraction. PMID- 26503636 TI - Deficiencies in extrusion of the second polar body due to high calcium concentrations during in vitro fertilization in inbred C3H/He mice. AB - Successful in vitro fertilization (IVF) of all inbred strains of laboratory mice has not yet been accomplished. We have previously shown that a high calcium concentration improved IVF in various inbred mice. However, we also found that in cumulus-free ova of C3H/He mice such IVF conditions significantly increased the deficiency of extrusion of the second polar body (PBII) in a dose-dependent manner (2% at 1.71 mM and 29% at 6.84 mM, P < 0.05) and that PBII extrusion was affected by high calcium levels at 2-3 h post-insemination. While developmental competence of ova without PBII extrusion to blastocysts after 96 h culture was not affected, a significant reduction in the nuclear number of the inner cell mass was observed in blastocyst fertilized under high calcium condition. We also examined how high calcium concentration during IVF affects PBII extrusion in C3H/He mice. Cumulus cells cultured under high calcium conditions showed a significantly alleviated deficient PBII extrusion. This phenomenon is likely to be specific to C3H/He ova because deficient PBII extrusion in reciprocal fertilization between C3H and BDF1 gametes was observed only in C3H/He ova. Sperm factor(s) was still involved in deficient PBII extrusion due to high calcium concentrations, as this phenomenon was not observed in ova activated by ethanol. The cytoskeletal organization of ova without PBII extrusion showed disturbed spindle rotation, incomplete formation of contractile ring and disturbed localization of actin, suggesting that high calcium levels affect the anchoring machinery of the meiotic spindle. These results indicate that in C3H/He mice high calcium levels induce abnormal fertilization, i.e. deficient PBII extrusion by affecting the cytoskeletal organization, resulting in disturbed cytokinesis during the second meiotic division. Thus, use of high calcium media for IVF should be avoided for this strain. PMID- 26503638 TI - Initial Stages of the Pyrolysis of Polyethylene. AB - An experimental study of the kinetics of the initial stages of the pyrolysis of high-density polyethylene (PE) was performed. Quantitative yields of gas-phase products (C1-C8 alkanes and alkenes) and functional groups within the remaining polyethylene melt (methyl, vinyl, vinylene, vinylidene, and branching sites) were obtained as a function of time (0-20 min) at five temperatures in the 400-440 degrees C range. Gas chromatography and NMR ((1)H and (13)C) were used to detect the gas- and condensed-phase products, respectively. Modeling of polyethylene pyrolysis was performed, with the primary purpose of determining the rate constants of several critical reaction types important at the initial pyrolysis stages. Detailed chemical mechanisms were created (short and extended mechanisms) and used with both the steady-state approximation and numerical integration of the differential kinetic equations. Rate constants of critical elementary reactions (C-C backbone scission, two kinds of H-atom transfer, radical addition to the double bond, and beta-scission of tertiary alkyl radicals) were adjusted, resulting in an agreement between the model and the experiment. The values of adjusted rate constants are in general agreement with those of cognate reactions of small molecules in the gas phase, with the exception of the rate constants of the backbone C-C scission, which is found to be approximately 1-2 orders of magnitude lower. This observation provides tentative support to the hypothesis that congested PE melt molecular environment impedes the tumbling motions of separating fragments in C-C bond scission, thus resulting in less "loose" transition state and lower rate constant values. Sensitivity of the calculations to selected uncertainties in model properties was studied. Values and estimated uncertainties of four combinations of rate constants are reported as derived from the experimental results via modeling. The dependence of the diffusion-limited rate constant for radical recombination on the changing molecular mass of polyethylene was explicitly quantified and included in the extended kinetic mechanism, which appears critical for the agreement between modeling and experiment, particularly the agreement between the experimental and the calculated activation energies for product formation rates. Calculations were performed to estimate the contribution to the overall rate of radical recombination of the "reaction diffusion" phenomenon, where recombination is driven not by the actual motion of the recombining radical sites but rather by the migration of the radical site through PE melt due to rapid hydrogen transfer; this contribution was shown to be negligible for the conditions of the current work. PMID- 26503639 TI - Lymphocyte/monocyte ratio in osteoarticular tuberculosis in children: a haematological biomarker revisited. AB - INTRODUCTION: *Work attributed to Department of Pediatric Orthopaedics, Chacha Nehru Bal Chikitsalaya, Geeta Colony, Delhi-110031(India)This study tested the hypothesis whether the lymphocyte/monocyte ratio (L/M ratio) altered significantly during treatment of paediatric osteoarticular tuberculosis (OATB) for it to be a useful monitor of the response to therapy. MATERIAL AND METHODS: Thirty immunocompetent paediatric patients with OATB treated with 6 months of uninterrupted multidrug anti-tubercular treatment with resultant clinical and radiological healing of the lesion were included. Haemoglobin, total leucocyte, monocyte and lymphocyte count, and erythrocyte sedimentation rate (ESR) were collected at 0, 2 and 6 months, and were analysed. RESULTS: The L/M ratio altered from high (11) at the start of treatment towards normalisation (9) at 2 months and (7.7) at 6 months. There was no correlation with declining ESR levels. CONCLUSIONS: The L/M ratio may have potential as an effective biomarker response. PMID- 26503640 TI - Precision chemical heating for diagnostic devices. AB - Decoupling nucleic acid amplification assays from infrastructure requirements such as grid electricity is critical for providing effective diagnosis and treatment at the point of care in low-resource settings. Here, we outline a complete strategy for the design of electricity-free precision heaters compatible with medical diagnostic applications requiring isothermal conditions, including nucleic acid amplification and lysis. Low-cost, highly energy dense components with better end-of-life disposal options than conventional batteries are proposed as an alternative to conventional heating methods to satisfy the unique needs of point of care use. PMID- 26503641 TI - A phosphodiesterase 4B-dependent interplay between tumor cells and the microenvironment regulates angiogenesis in B-cell lymphoma. AB - Angiogenesis associates with poor outcome in diffuse large B-cell lymphoma (DLBCL), but the contribution of the lymphoma cells to this process remains unclear. Addressing this knowledge gap may uncover unsuspecting proangiogenic signaling nodes and highlight alternative antiangiogenic therapies. Here, we identify the second messenger cyclic-AMP (cAMP) and the enzyme that terminates its activity, phosphodiesterase 4B (PDE4B), as regulators of B-cell lymphoma angiogenesis. We first show that cAMP, in a PDE4B-dependent manner, suppresses PI3K/AKT signals to downmodulate vascular endothelial growth factor (VEGF) secretion and vessel formation in vitro. Next, we create a novel mouse model that combines the lymphomagenic Myc transgene with germline deletion of Pde4b. We show that lymphomas developing in a Pde4b-null background display significantly lower microvessel density (MVD) in association with lower VEGF levels and PI3K/AKT activity. We recapitulate these observations by treating lymphoma-bearing mice with the FDA-approved PDE4 inhibitor, Roflumilast. Lastly, we show that primary human DLBCLs with high PDE4B expression display significantly higher MVD. Here, we defined an unsuspected signaling circuitry in which the cAMP generated in lymphoma cells downmodulates PI3K/AKT and VEGF secretion to negatively influence vessel development in the microenvironment. These data identify PDE4 as an actionable antiangiogenic target in DLBCL. PMID- 26503642 TI - Delayed diagnosis leading to accelerated-phase chronic eosinophilic leukemia due to a cytogenetically cryptic, imatinib-responsive TNIP1-PDFGRB fusion gene. PMID- 26503643 TI - The myelodysplastic syndromes flow cytometric score: a three-parameter prognostic flow cytometric scoring system. AB - The prognosis of myelodysplastic syndromes (MDS) is currently estimated by using the revised International Prognostic Scoring System (IPSS-R). Several studies have shown that further refinement of prognostication for MDS can be achieved by adding flow cytometric parameters. However, widespread implementation of flow cytometry for the prognosis of MDS is hampered by complexity of the analysis. Therefore, the aim of this study was to construct a robust and practical flow cytometric score that could be implemented as a routine procedure. To achieve this, bone marrow aspirates of 109 MDS patients were analyzed by flow cytometry. A second cohort consisting of 103 MDS patients was used to validate the MDS flow cytometric score (MFS). The parameters forming the MFS were sideward light scatter and CD117 expression of myeloid progenitor cells and CD13 expression on monocytes. Three MFS risk categories were formed. Patients with MDS and intermediate MFS scores had significantly better overall survival (OS) compared with the patients with high MFS scores. The MFS further refined prognostication within the IPSS-R low-risk category, by identifying patients with worse OS in case of high MFS. In conclusion, a practical three parameter flow cytometric prognostic score was constructed enabling further refinement of prognostication of MDS. PMID- 26503644 TI - The 18th Nitrogen Workshop: 'The nitrogen challenge - building a blueprint for food and future'. PMID- 26503645 TI - Improved synthesis and biological evaluation of Tc-99m radiolabeled AMO for miRNA imaging in tumor xenografts. AB - MicroRNAs (miRNAs) have been considered as important biomarkers for malignant tumors. In this study, we introduced an improved (99m)Tc labeling method for noninvasive visualization of overexpressed miRNAs in tumor-bearing mice. Anti miRNA-21 oligonucleotide (AMO) with partial 2'-O-methyl and phosphorothioate modification was designed and chemically synthesized. After conjugated with NHS MAG3, AMO was labeled with (99m)Tc. Optimization was made to shorten reaction time and to improve labeling efficiency. Labeling efficiency was 97%, and specific activity was 2.78 MBq/ng. During 12 h, (99m)Tc-AMO showed no significant degradation by gel electrophoresis. Its radiochemical purity was stable, between 95.8% and 99.1%. Further, (99m)Tc-AMO decreased the level of miR-21 and increased the expression of PTEN protein at cellular level, shown by qRT-PCR and Western blot. Fluorescent protein labeled AMO displayed specific distribution and good stability in tumor cells. After the administration in tumor-bearing mice, (99m)Tc AMO showed more radioactive uptake in the miR-21 over-expressed tumors than scramble control. Biodistribution results further proved the significant difference of tumor uptake between (99m)Tc-AMO and (99m)Tc-control. Therefore, this study presents an improved method with shorten time to prepare a (99m)Tc radiolabeled AMO. In addition, it supports the role of (99m)Tc-AMO for noninvasive visualization of miR-21 in malignant tumors. PMID- 26503647 TI - Cardiac Effects of Echinocandins in Endotoxemic Rats. AB - Echinocandins are known as effective and safe agents for the prophylaxis and treatment of different cohorts of patients with fungal infections. Recent studies revealed that certain pharmacokinetics of echinocandin antifungals might impact clinical efficacy and safety in special patient populations. The aim of our study was to evaluate echinocandin-induced aggravation of cardiac impairment in septic shock. Using an in vivo endotoxemic shock model in rats, we assessed hemodynamic parameters and time to hemodynamic failure (THF) after additional central-venous application of anidulafungin (2.5 mg/kg of body weight [BW]), caspofungin (0.875 mg/kg BW), micafungin (3 mg/kg BW), and control (0.9% sodium chloride). In addition, echinocandin-induced cytotoxicity was evaluated in isolated rat cardiac myocytes. THF of the animals in the caspofungin group (n = 7) was significantly reduced compared to that in the control (n = 6) (136 min versus 180 min; P = 0.0209). The anidulafungin group (n = 7) also showed a trend of reduced THF (136 min versus 180 min; log-rank test P = 0.0578). Animals in the micafungin group (n = 7) did not show significant differences in THF compared to those in the control. Control group animals and also micafungin group animals did not show altered cardiac output (CO) during our experiments. In contrast, administration of anidulafungin or caspofungin induced a decrease in CO. We also revealed a dose dependent increase of cytotoxicity in anidulafungin- and caspofungin-treated cardiac myocytes. Treatment with micafungin did not cause significantly increased cytotoxicity. Further studies are needed to explore the underlying mechanism. PMID- 26503648 TI - Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis. AB - Isavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamic in vitro model of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates of Aspergillus fumigatus. A human like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively. PMID- 26503649 TI - Bioassay for Determining Voriconazole Serum Levels in Patients Receiving Combination Therapy with Echinocandins. AB - Voriconazole levels were determined with high-performance liquid chromatography (HPLC) and a microbiological agar diffusion assay using a Candida parapsilosis isolate in 103 serum samples from an HPLC-tested external quality control program (n = 39), 21 patients receiving voriconazole monotherapy (n = 39), and 7 patients receiving combination therapy (n = 25). The results of the bioassay were correlated with the results obtained from the external quality control program samples and with the HPLC results in sera from patients on voriconazole monotherapy and on combination therapy with an echinocandin (Spearman's rank correlation coefficient [rs], > 0.93; mean +/- standard error of the mean [SEM] % difference, <12% +/- 3.8%). PMID- 26503650 TI - Cadazolid Does Not Promote Intestinal Colonization of Vancomycin-Resistant Enterococci in Mice. AB - The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side effect during treatment of Clostridium difficile-associated diarrhea (CDAD), resulting from disturbances in gut microbiota. Cadazolid (CDZ) is an investigational antibiotic with potent in vitro activity against C. difficile and against VRE and is currently in clinical development for the treatment of CDAD. We report that CDZ treatment did not lead to intestinal VRE overgrowth in mice. PMID- 26503651 TI - Novobiocin Inhibits the Antimicrobial Resistance Acquired through DNA Damage Induced Mutagenesis in Acinetobacter baumannii. AB - Acinetobacter baumannii, a worldwide emerging nosocomial pathogen, acquires antimicrobial resistances in response to DNA-damaging agents, which increase the expression of multiple error-prone DNA polymerase components. Here we show that the aminocoumarin novobiocin, which inhibits the DNA damage response in Gram positive bacteria, also inhibits the expression of error-prone DNA polymerases in this Gram-negative multidrug-resistant pathogen and, consequently, its potential acquisition of antimicrobial resistance through DNA damage-induced mutagenesis. PMID- 26503652 TI - Emergence of Mutations in the K13 Propeller Gene of Plasmodium falciparum Isolates from Dakar, Senegal, in 2013-2014. AB - The kelch 13 (K13) propeller gene is associated with artemisinin resistance. In a previous work, there were no mutations found in 138 Plasmodium falciparum isolates collected in 2012 and 2013 from patients residing in Dakar, Senegal (M. Torrentino-Madamet et al., Malar J 13:472, 2014, http://dx.doi.org/10.1186/1475 2875-13-472). However, the N554H, Q613H, and V637I mutations were identified in the propeller region of K13 in 92 (5.5%) isolates in 2013 and 2014. There were five polymorphisms identified in the Plasmodium/Apicomplexa-specific domain (K123R, N137S, N142NN/NNN, T149S, and K189T/N). PMID- 26503653 TI - In Vivo Synergy of Amphotericin B plus Posaconazole in Murine Aspergillosis. AB - Aspergillus fumigatus is the main mold causing invasive fungal infection that shows high mortality rates. Therapeutic failure and the increase in drug resistance make it necessary to explore alternative treatments for this infection. We have evaluated the efficacy of amphotericin B at 0.8 mg/kg or 0.3 mg/kg of body weight combined with 40 mg/kg of posaconazole against three A. fumigatus isolates in a murine model of disseminated infection. The combination of the polyene and the azole led to a greater increase in survival and a significantly greater reduction in tissue burden than monotherapies. PMID- 26503654 TI - Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication. AB - West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bite of mosquitoes that causes meningitis and encephalitis in humans, horses, and birds. Several studies have highlighted that flavivirus infection is highly dependent on cellular lipids for virus replication and infectious particle biogenesis. The first steps of lipid synthesis involve the carboxylation of acetyl coenzyme A (acetyl-CoA) to malonyl-CoA that is catalyzed by the acetyl-CoA carboxylase (ACC). This makes ACC a key enzyme of lipid synthesis that is currently being evaluated as a therapeutic target for different disorders, including cancers, obesity, diabetes, and viral infections. We have analyzed the effect of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) on infection by WNV. Lipidomic analysis of TOFA-treated cells confirmed that this drug reduced the cellular content of multiple lipids, including those directly implicated in the flavivirus life cycle (glycerophospholipids, sphingolipids, and cholesterol). Treatment with TOFA significantly inhibited the multiplication of WNV in a dose-dependent manner. Further analysis of the antiviral effect of this drug showed that the inhibitory effect was related to a reduction of viral replication. Furthermore, treatment with another ACC inhibitor, 3,3,14,14-tetramethylhexadecanedioic acid (MEDICA 16), also inhibited WNV infection. Interestingly, TOFA and MEDICA 16 also reduced the multiplication of Usutu virus (USUV), a WNV-related flavivirus. These results point to the ACC as a druggable cellular target suitable for antiviral development against WNV and other flaviviruses. PMID- 26503655 TI - Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors. AB - Tenofovir alafenamide fumarate (TAF) is an oral phosphonoamidate prodrug of the HIV reverse transcriptase nucleotide inhibitor tenofovir (TFV). Previous studies suggested a principal role for the lysosomal serine protease cathepsin A (CatA) in the intracellular activation of TAF. Here we further investigated the role of CatA and other human hydrolases in the metabolism of TAF. Overexpression of CatA or liver carboxylesterase 1 (Ces1) in HEK293T cells increased intracellular TAF hydrolysis 2- and 5-fold, respectively. Knockdown of CatA expression with RNA interference (RNAi) in HeLa cells reduced intracellular TAF metabolism 5-fold. Additionally, the anti-HIV activity and the rate of CatA hydrolysis showed good correlation within a large set of TFV phosphonoamidate prodrugs. The covalent hepatitis C virus (HCV) protease inhibitors (PIs) telaprevir and boceprevir potently inhibited CatA-mediated TAF activation (50% inhibitory concentration [IC50] = 0.27 and 0.16 MUM, respectively) in vitro and also reduced its anti-HIV activity in primary human CD4(+) T lymphocytes (21- and 3-fold, respectively) at pharmacologically relevant concentrations. In contrast, there was no inhibition of CatA or any significant effect on anti-HIV activity of TAF observed with cobicistat, noncovalent HIV and HCV PIs, or various prescribed inhibitors of host serine proteases. Collectively, these studies confirm that CatA plays a pivotal role in the intracellular metabolism of TAF, whereas the liver esterase Ces1 likely contributes to the hepatic activation of TAF. Moreover, this work demonstrates that a wide range of viral and host PIs, with the exception of telaprevir and boceprevir, do not interfere with the antiretroviral activity of TAF. PMID- 26503656 TI - Contribution of Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and Pretomanid in a Mouse Model of Tuberculosis. AB - New regimens based on two or more novel agents are sought to shorten or simplify treatment of tuberculosis (TB). Pretomanid (PMD) is a nitroimidazole in phase 3 trials that has significant bactericidal activity alone and in combination with bedaquiline (BDQ) and/or pyrazinamide (PZA). We previously showed that the novel combination of BDQ+PMD plus the oxazolidinone sutezolid (SZD) had sterilizing activity superior to that of the first-line regimen in a murine model of TB. The present experiments compared the activity of different oxazolidinones in combination with BDQ+PMD with or without PZA in the same model. The 3-drug regimen of BDQ+PMD plus linezolid (LZD) had sterilizing activity approaching that of BDQ+PMD+SZD and superior to that of the first-line regimen. The addition of PZA further enhanced activity. Reducing the duration of LZD to 1 month did not significantly affect the activity of the regimen. Halving the LZD dose or replacing LZD with RWJ-416457 modestly reduced activity over the first month but not after 2 months. AZD5847 and tedizolid also increased the bactericidal activity of BDQ+PMD, but they were less effective than the other oxazolidinones. These results provide optimism for safe, short-course oral regimens for drug resistant TB that may also be superior to the current first-line regimen for drug susceptible TB. PMID- 26503657 TI - Neutropenia Associated with Long-Term Ceftaroline Use. AB - Ceftaroline is a fifth-generation cephalosporin with potent antimicrobial activity against Gram-positive and Gram-negative pathogens. Neutropenia is a rare serious adverse event for the class of cephalosporins; however, we observed several cases of severe neutropenia in our outpatient infectious disease practice believed to be associated with ceftaroline use. The aim of this study was to determine the incidence of neutropenia among patients receiving ceftaroline therapy for more than 7 days. We conducted a retrospective cohort analysis of patients admitted to an 800-bed regional medical center between June 2012 and December 2014 who received ceftaroline for more than 7 days to assess the incidence of developing clinically significant neutropenia. Demographic and patient care data points as well as underlying admitting and chronic diagnoses were retrospectively collected from the medical record. Clinically significant neutropenia was defined as an absolute neutrophil count (ANC) less than 1,500 cells/mm(3). Analysis was performed to determine the incidence, severity, and outcome of neutropenia following ceftaroline administration. A total of 39 patients were included in the cohort. The median duration of therapy was 27 days. Seven patients (18%) developed neutropenia while on ceftaroline therapy. Four (10%) of the neutropenic patients had an ANC of <500 cells/mm(3). The median first neutropenic day was day 17, with the median ANC nadir of 432 cells/mm(3) on day 24. We determined that extended ceftaroline infusion is associated with the development of neutropenia. We recommend obtaining a complete blood count (CBC) with differential at the onset of therapy and weekly thereafter. Should the ANC fall below 2,500 cells/mm(3), then twice-weekly CBCs should be monitored for the duration of ceftaroline therapy, and therapy should be discontinued if the ANC falls to 1,500 cells/mm(3) or less. PMID- 26503658 TI - Gallium Potentiates the Antibacterial Effect of Gentamicin against Francisella tularensis. AB - The reasons why aminoglycosides are bactericidal have not been not fully elucidated, and evidence indicates that the cidal effects are at least partly dependent on iron. We demonstrate that availability of iron markedly affects the susceptibility of the facultative intracellular bacterium Francisella tularensis strain SCHU S4 to the aminoglycoside gentamicin. Specifically, the intracellular depots of iron were inversely correlated to gentamicin susceptibility, whereas the extracellular iron concentrations were directly correlated to the susceptibility. Further proof of the intimate link between iron availability and antibiotic susceptibility were the findings that a DeltafslA mutant, which is defective for siderophore-dependent uptake of ferric iron, showed enhanced gentamicin susceptibility and that a DeltafeoB mutant, which is defective for uptake of ferrous iron, displayed complete growth arrest in the presence of gentamicin. Based on the aforementioned findings, it was hypothesized that gallium could potentiate the effect of gentamicin, since gallium is sequestered by iron uptake systems. The ferrozine assay demonstrated that the presence of gallium inhibited >70% of the iron uptake. Addition of gentamicin and/or gallium to infected bone marrow-derived macrophages showed that both 100 MUM gallium and 10 MUg/ml of gentamicin inhibited intracellular growth of SCHU S4 and that the combined treatment acted synergistically. Moreover, treatment of F. tularensis infected mice with gentamicin and gallium showed an additive effect. Collectively, the data demonstrate that SCHU S4 is dependent on iron to minimize the effects of gentamicin and that gallium, by inhibiting the iron uptake, potentiates the bactericidal effect of gentamicin in vitro and in vivo. PMID- 26503659 TI - In Vitro Activity of Ceftaroline against Staphylococcus aureus Isolated in 2012 from Asia-Pacific Countries as Part of the AWARE Surveillance Program. AB - Ceftaroline, the active metabolite of the prodrug ceftaroline-fosamil, is an advanced-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). This investigation provides in vitro susceptibility data for ceftaroline against 1,971 S. aureus isolates collected in 2012 from seven countries (26 centers) in the Asia-Pacific region as part of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) program. Broth microdilution as recommended by the CLSI was used to determine susceptibility. In all, 62% of the isolates studied were MRSA, and the ceftaroline MIC90 for all S. aureus isolates was 2 MUg/ml (interpretive criteria: susceptible, <=1 MUg/ml). The overall ceftaroline susceptibility rate for S. aureus was 86.9%, with 100% of methicillin-sensitive S. aureus isolates and 78.8% of MRSA isolates susceptible to this agent. The highest percentages of ceftaroline-nonsusceptible MRSA isolates came from China (47.6%), all of which showed intermediate susceptibility, and Thailand (37.1%), where over half (52.8%) of isolates were resistant to ceftaroline (MIC, 4 MUg/ml). Thirty-eight ceftaroline-nonsusceptible isolates (MIC values of 2 to 4 MUg/ml) were selected for molecular characterization. Among the isolates analyzed, sequence type 5 (ST-5) was the most common sequence type encountered; however, all isolates analyzed from Thailand were ST-228. Penicillin-binding protein 2a (PBP2a) substitution patterns varied by country, but all isolates from Thailand had the Glu239Lys substitution, and 12 of these also carried an additional Glu447Lys substitution. Ceftaroline fosamil is a useful addition to the antimicrobial agents that can be used to treat S. aureus infections. However, with the capability of this species to develop resistance to new agents, it is important to recognize and monitor regional differences in trends as they emerge. PMID- 26503660 TI - A Two-Year Surveillance in Five Colombian Tertiary Care Hospitals Reveals High Frequency of Non-CG258 Clones of Carbapenem-Resistant Klebsiella pneumoniae with Distinct Clinical Characteristics. AB - The global spread of carbapenem-resistant Klebsiella pneumoniae (CR-Kp) has been largely associated with sequence type 258 (ST258) and its related variants (clonal group 258 [CG258]). Here we describe the molecular epidemiology of CR-Kp from five tertiary care hospitals in Medellin, the second largest city in Colombia. All CR-Kp-infected patients admitted from June 2012 to June 2014 were included (n = 193). Patients' clinical information was obtained from medical records. Carbapenemase KPC, VIM, IMP, NDM, and OXA-48 genes were detected by PCR. A CG258-tonB79 cluster-specific real-time PCR (targeting the multilocus sequence type [MLST] tonB79 allele), pulsed-field gel electrophoresis (PFGE), and MLST analysis were performed for typing. Remarkably, 62.2% (n = 120) of isolates were from STs unrelated to CG258 (non-CG258). KPC-3 predominated in CG258 isolates (86.3%), while KPC-2 prevailed in non-CG258 isolates (75.5%) (P < 0.001). Multidrug resistance (MDR) frequency was significantly higher in CG258 strains (91.4% versus 56.1%; P < 0.001). ST512 (a single-locus variant of ST258) is the main ST in CG258 (96.3%), and isolates in this group showed closely related pulsotype and similar resistance gene profiles, suggesting the clonal spread of this strain. In contrast, high heterogeneity of STs (34/54), including eight novel STs, was found in non-CG258 isolates. Among non-CG258 isolates, ST14 (13.3%; n = 16) and ST307 (14.2%; n = 17) were the most frequent, and they showed distinct molecular and clinical characteristics in comparison to CG258 isolates. Our results suggest that the dissemination of carbapenem resistance in Medellin is due to heterogeneous K. pneumoniae clones, likely the result of horizontal transmission of KPC in different unrelated lineages, further highlighting the challenge in CR-Kp infection control and the need for a multifocal intervention. PMID- 26503661 TI - Synthesis, Bioactivity Evaluation, and Toxicity Assessment of Novel Salicylanilide Ester Derivatives as Cercaricides against Schistosoma japonicum and Molluscicides against Oncomelania hupensis. AB - A series of novel salicylanilide ester derivatives were synthesized, characterized, and evaluated for cercaricidal potential against Schistosoma japonicum and molluscicidal potential against Oncomelania hupensis. Four derivatives exhibited remarkable cercaricidal activity superior to that of niclosamide. Among them, the most active compound, 4-chloro-2-((2-methoxy-4 nitrophenyl)carbamoyl)phenyl 4-methoxybenzoate (compound 4c), showed a marked minimum effective cercaricidal concentration as low as 0.43 MUM and significant molluscicidal activity, with a 50% lethal concentration (LC50) of 0.206 g/m(2). Particularly, compound 4c displayed 88-fold decreased fish toxicity on Danio rerio and 44-fold reduced cytotoxicity on human kidney HEK293 cells in comparison with the toxicity of niclosamide. The results indicated that 4c could serve as a promising drug candidate, with environmental safety properties, against Schistosoma japonicum at transmission stages. The preliminary molecular mechanism of target compounds in Schistosoma japonicum cercariae was also investigated. Salicylanilide ester derivatives exhibited an inhibitory effect on nitric oxide synthase (NOS) but no effect on lactate dehydrogenase (LDH) and acetylcholinesterase (AChE), and a strong and significant correlation between NOS inhibitory efficacy and cercaricidal activity was observed. In addition, 4c could downregulate the expression of NOS in a dose-dependent manner. These results suggested that NOS was probably one of the drug targets of salicylanilide esters. PMID- 26503662 TI - Within-Host Selection of Drug Resistance in a Mouse Model of Repeated Incomplete Malaria Treatment: Comparison between Atovaquone and Pyrimethamine. AB - The evolutionary selection of malaria parasites within individual hosts is an important factor in the emergence of drug resistance but is still not well understood. We have examined the selection process for drug resistance in the mouse malaria agent Plasmodium berghei and compared the dynamics of the selection for atovaquone and pyrimethamine. Resistance to these drugs has been shown to be associated with genetic lesions in the dihydrofolate reductase gene in the case of pyrimethamine and in the mitochondrial cytochrome b gene for atovaquone. A mouse malaria model for the selection of drug resistance, based on repeated incomplete treatment (RICT) with a therapeutic dose of antimalarial drugs, was established. The number of treatment cycles for the development of stable resistance to atovaquone (2.47 +/- 0.70; n = 19) was found to be significantly lower than for pyrimethamine (5.44 +/- 1.46; n = 16; P < 0.0001), even when the parental P. berghei Leiden strain was cloned prior to the resistance selection. Similar results were obtained with P. berghei Edinburgh. Mutational changes underlying the resistance were identified to be S110N in dihydrofolate reductase for pyrimethamine and Y268N, Y268C, Y268S, L271V-K272R, and G280D in cytochrome b for atovaquone. These results are consistent with the rate of mitochondrial DNA mutation being higher than that in the nucleus and suggest that mutation leading to pyrimethamine resistance is not a rare event. PMID- 26503663 TI - Development of an Intracellular Screen for New Compounds Able To Inhibit Mycobacterium tuberculosis Growth in Human Macrophages. AB - Here we describe the development and validation of an intracellular high throughput screening assay for finding new antituberculosis compounds active in human macrophages. The assay consists of a luciferase-based primary identification assay, followed by a green fluorescent protein-based secondary profiling assay. Standard tuberculosis drugs and 158 previously recognized active antimycobacterial compounds were used to evaluate assay robustness. Data show that the assay developed is a short and valuable tool for the discovery of new antimycobacterial compounds. PMID- 26503665 TI - Can pathological oligomeric proteins make good biomarkers? (Commentary on Williams et al.). PMID- 26503664 TI - Activity of Tobramycin against Cystic Fibrosis Isolates of Burkholderia cepacia Complex Grown as Biofilms. AB - Pulmonary infection with Burkholderia cepacia complex in cystic fibrosis (CF) patients is associated with more-rapid lung function decline and earlier death than in CF patients without this infection. In this study, we used confocal microscopy to visualize the effects of various concentrations of tobramycin, achievable with systemic and aerosolized drug administration, on mature B. cepacia complex biofilms, both in the presence and absence of CF sputum. After 24 h of growth, biofilm thickness was significantly reduced by exposure to 2,000 MUg/ml of tobramycin for Burkholderia cepacia, Burkholderia multivorans, and Burkholderia vietnamiensis; 200 MUg/ml of tobramycin was sufficient to reduce the thickness of Burkholderia dolosa biofilm. With a more mature 48-h biofilm, significant reductions in thickness were seen with tobramycin at concentrations of >=100 MUg/ml for all Burkholderia species. In addition, an increased ratio of dead to live cells was observed in comparison to control with tobramycin concentrations of >=200 MUg/ml for B. cepacia and B. dolosa (24 h) and >=100 MUg/ml for Burkholderia cenocepacia and B. dolosa (48 h). Although sputum significantly increased biofilm thickness, tobramycin concentrations of 1,000 MUg/ml were still able to significantly reduce biofilm thickness of all B. cepacia complex species with the exception of B. vietnamiensis. In the presence of sputum, 1,000 MUg/ml of tobramycin significantly increased the dead-to-live ratio only for B. multivorans compared to control. In summary, although killing is attenuated, high-dose tobramycin can effectively decrease the thickness of B. cepacia complex biofilms, even in the presence of sputum, suggesting a possible role as a suppressive therapy in CF. PMID- 26503666 TI - NLF20: an antimicrobial peptide with therapeutic potential against invasive Pseudomonas aeruginosa infection. AB - OBJECTIVES: Increasing resistance to antibiotics makes antimicrobial peptides interesting as novel therapeutics. Here, we report on studies of the peptide NLF20 (NLFRKLTHRLFRRNFGYTLR), corresponding to an epitope of the D helix of heparin cofactor II (HCII), a plasma protein mediating bacterial clearance. METHODS: Peptide effects were evaluated by a combination of in vitro and in vivo methods, including antibacterial, anti-inflammatory and cytotoxicity assays, fluorescence and electron microscopy, and experimental models of endotoxin shock and Pseudomonas aeruginosa sepsis. RESULTS: The results showed that NLF20 displayed potent antimicrobial effects against the Gram-negative bacteria Escherichia coli and P. aeruginosa, the Gram-positive Bacillus subtilis and Staphylococcus aureus and the fungi Candida albicans and Candida parapsilosis. Importantly, this antimicrobial effect was retained in human blood, particularly for P. aeruginosa. Fluorescence and electron microscopy studies showed that the peptide exerted membrane-breaking effects. In an animal model of P. aeruginosa sepsis, NLF20 reduced bacterial levels, resulting in improved survival. Reduced mortality was also observed in experimental animal models of endotoxin shock, which was paralleled with modulated IFN-gamma, IL-10 and coagulation responses. CONCLUSIONS: Together, these results indicate that functional epitopes of HCII may have therapeutic potential against bacterial infection. PMID- 26503667 TI - In vitro activity of ceftaroline against bacterial pathogens isolated from skin and soft tissue infections in Europe, Russia and Turkey in 2012: results from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance programme. AB - OBJECTIVES: The objective of this study was to analyse antimicrobial susceptibility testing data generated by the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) global surveillance programme for pathogens causing skin and soft tissue infections (SSTIs) in European countries in 2012. METHODS: Confirmation of pathogen identity by MALDI-TOF and antimicrobial susceptibility testing following the CLSI broth microdilution method were performed by a central laboratory. RESULTS: Using CLSI breakpoint criteria, ceftaroline was active against MSSA (n = 1116; MIC90, 0.25 mg/L; 99.8% susceptible), MRSA (n = 1467; MIC90, 1 mg/L; 92.2% susceptible) and Streptococcus pyogenes (n = 312; MIC90, 0.008 mg/L; 100% susceptible). By CLSI interpretative criteria, two S. aureus isolates (2/2583, 0.08%) were ceftaroline resistant (MIC, >=4 mg/L) and 114 isolates (114/2583, 4.4%) were ceftaroline intermediate (2 mg/L). By EUCAST interpretative criteria (MIC, >1 mg/L), 4.5% (116/2583) of S. aureus isolates were ceftaroline resistant. Most ceftaroline-non-susceptible isolates (81.0%, 94/116) were from Russia, Turkey, Italy and Hungary. Ceftaroline susceptibility was equal to or exceeded 99% for S. aureus isolates submitted by 7 of 17 countries. Against Escherichia coli (n = 349), Klebsiella pneumoniae (n = 215), Klebsiella oxytoca (n = 74) and Proteus mirabilis (n = 121), ceftaroline activity was dependent upon ESBL production. For ESBL-negative E. coli, K. pneumoniae, K. oxytoca and P. mirabilis, 87.5% (MIC90, 1 mg/L), 92.3% (MIC90, 0.5 mg/L), 93.2% (MIC90, 0.5 mg/L) and 85.1% (MIC90, 2 mg/L) of isolates were susceptible to ceftaroline, respectively. CONCLUSIONS: Ceftaroline demonstrated potent in vitro activity against a contemporary collection of bacterial pathogens from patients with SSTIs in European countries, Russia and Turkey. Surveillance programmes such as AWARE are essential to global efforts to improve antimicrobial stewardship. PMID- 26503668 TI - A review of chromatographic methods for the determination of water- and fat soluble vitamins in biological fluids. AB - Vitamins are an essential element of nutrition and thus contribute to human health. Vitamins catalyze many biochemical reactions and their lack or excess can cause health problems. Therefore, monitoring vitamin concentrations in plasma or other biological fluids may be useful in the diagnosis of various disorders as well as in the treatment process. Several chromatographic methods have been developed for the determination of these compounds in biological samples, including high-performance liquid chromatography with UV and fluorescence detection. Recently, high-performance liquid chromatography with tandem mass spectrometry methods have been widely used for the determination of vitamins in complex matrices because of their high sensitivity and selectivity. This method requires preconditioning of samples for analysis, including protein precipitation and/or various extraction techniques. The choice of method may depend on the desired cost, convenience, turnaround time, specificity, and accuracy of the information to be obtained. This article reviews the recently reported chromatographic methods used for determination of vitamins in biological fluids. Relevant papers published mostly during the last 5 years were identified by an extensive PubMed search using appropriate keywords. Particular attention was given to the preparation steps and extraction techniques. This report may be helpful in the selection of procedures that are appropriate for certain types of biological materials and analytes. PMID- 26503669 TI - New formulation of old aspirin for better delivery. AB - For better use of cyclooxygenase dependent anti-inflammatory properties and mitochondrial activities of aspirin, new hydrophobic analogues of aspirin were developed and successfully encapsulated in polymeric nanoparticles (NPs). In vivo anti-inflammatory effects of these NPs using a mouse model demonstrated unique properties of an optimized aspirin analogue to inhibit production of pro inflammatory and enrichment of anti-inflammatory cytokines. PMID- 26503671 TI - Hepatic reaction dose for parenchymal changes on Gd-EOB-DTPA-enhanced magnetic resonance images after stereotactic body radiation therapy for hepatocellular carcinoma. AB - INTRODUCTION: The present study evaluated the threshold dose for hepatic parenchymal changes on gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) images after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC). METHODS: Twenty patients with available data of follow-up MR images acquired 2-4 months after completion of SBRT were selected among the registered patients. SBRT was performed using multiple coplanar and non-coplanar beams with energies of 6 or 15 MV. All patients were treated with doses of 45 Gy administered in three fractions over 3 consecutive days. For image registration between planning computed tomography (CT) and MR images, landmark-based rigid body registration was performed using MIM software. RESULTS: Seventeen patients were included in the analysis. The median discrepancies between planning CT and MR images in the left right, anterior-posterior and superior-inferior directions were 1.38 mm, 1.24 mm and 1.72 mm, respectively. The median D50 value for the defect in the hepatobiliary phase of Gd-EOB-DTPA-enhanced MR images after SBRT was 19.8 Gy (range, 14.2-28.7 Gy), with R(2) values ranging from 0.76 to 0.99. CONCLUSIONS: The threshold dose for parenchymal changes in the hepatobiliary phase of Gd-EOB DTPA-enhanced MR images performed 2-4 months after 45 Gy of SBRT in three fractions was approximately 20 Gy. Our results provide the basis for further research on the functional loss of liver parenchyma after SBRT. PMID- 26503670 TI - Heart failure with normal ejection fraction is uncommon in acute myocardial infarction settings but associated with poor outcomes: a study of 91,360 patients admitted with index myocardial infarction between 1998 and 2010. AB - AIM: Data are scant on the incidence and prognosis of heart failure (HF) with normal ejection fraction (HFNEF, EF >49%) in an acute myocardial infarction (AMI) setting. The aim of this study was to examine incidence and predictors of HFNEF during an index acute myocardial infarction (AMI) and its subsequent associations with patient outcomes. METHODS AND RESULTS: This study analysed 91 360 patients with LVEF data from the SWEDEHEART registry on consecutive AMI patients between 1998 and 2010. Echocardiography or LV angiography was used to assess LVEF. In hospital HF diagnoses required presence of crackles, and use of i.v. diuretics or inotropic drugs during admission. Among HF patients, the proportion of HFNEF patients increased (from 18% to 31%) during the period. Incidence of HFNEF in the AMI population remained fairly unchanged (from 7.7% to 8.1%). In contrast, the proportion of HF patients with reduced EF (HFREF, EF <=49%) declined (from 47% to 26%), as did the proportion of REF patients without HF (from 20% to 16%). AMI patients with NEF without HF increased (from 25% to 50%). HFREF and HFNEF patients showed considerably higher long-term mortality compared with patients with no HF, irrespective of EF [the HFREF and HFNEF hazard ratio, compared with NEF, was 4.5 (4.4-4-6) and 3.3 (3.1-3.4), respectively, and 1.6 (1.5-1.65) for REF]. The adjusted HFNEF hazard ratio, compared with NEF, was 1.9 (1.8-2.0). Age, female gender, diabetes mellitus, hypertension, AF, and chronic kidney disease were strong predictors of HFNEF (P < 0.001). CONCLUSION: The proportion of AMI patients with HFNEF is constant over time. HFNEF patients have a considerably worse long-term prognosis compared with patients without clinical HF, irrespective of EF. PMID- 26503672 TI - Efficient Domino Hydroformylation/Benzoin Condensation: Highly Selective Synthesis of alpha-Hydroxy Ketones. AB - An improved domino hydroformylation/benzoin condensation to give alpha-hydroxy ketones has been developed. Easily available olefins are smoothly converted into the corresponding alpha-hydroxy ketones in high yields with excellent regioselectivities. Key to success is the use of a specific catalytic system consisting of a rhodium/phosphine complex and the CO2 adduct of an N-heterocyclic carbene. PMID- 26503673 TI - Bone: IGFBP1-hepatokine and target for FGF21-mediated bone loss. PMID- 26503675 TI - Dyslipidaemia: Lysosomal acid lipase deficiency-a cautious leap forward. AB - Lysosomal acid lipase deficiency can lead to liver failure and early death. A recently published placebo-controlled trial shows that enzyme-replacement therapy improves plasma levels of lipids and aminotransferases, and reduces liver fat content. However, the effect on clinical end points and an appropriate indication for treatment remain to be established. PMID- 26503674 TI - The best of both worlds - managing the cancer, saving the bone. AB - In the context of breast cancer, the importance of the skeleton in the regulation of primary tumour development and as a site for subsequent metastasis is well characterized. Our understanding of the contributions made by the host bone and bone marrow cells increasingly demonstrates the extent of the interaction between tumour cells and normal host cells. As a result, the need to develop and utilize therapies that can impede the growth and/or function of tumour cells while sparing normal host bone and bone marrow cells is immense and expanding. The need for these new treatments is, however, superimposed on the orthopaedic management of patients' quality of life, where pain control and continued locomotion are paramount. Indeed, the majority of the anticancer therapies used to date often result in direct or indirect damage to bone. Thus, although the bone microenvironment regulates tumour cell growth in bone, cells within the bone marrow niche also mediate many of the orthopaedic consequences of tumour progression as well as resistance to the antitumour effects of existing therapies. In this Review, we highlight the effects of existing cancer treatments on bone and the bone marrow microenvironment as well as the mechanisms mediating these effects and the current utility of modern orthopaedic interventions. PMID- 26503677 TI - Solving the puzzle of collective action through inter-individual differences. AB - Models of collective action infrequently account for differences across individuals beyond a limited set of strategies, ignoring variation in endowment (e.g. physical condition, wealth, knowledge, personality, support), individual costs of effort, or expected gains from cooperation. However, behavioural research indicates these inter-individual differences can have significant effects on the dynamics of collective action. The papers contributed to this theme issue evaluate how individual differences affect the propensity to cooperate, and how they can catalyse others' likelihood of cooperation (e.g. via leadership). Many of the papers emphasize the relationship between individual decisions and socio-ecological context, particularly the effect of group size. All together, the papers in this theme issue provide a more complete picture of collective action, by embracing the reality of inter-individual variation and its multiple roles in the success or failure of collective action. PMID- 26503678 TI - Communal range defence in primates as a public goods dilemma. AB - Classic socio-ecological theory holds that the occurrence of aggressive range defence is primarily driven by ecological incentives, most notably by the economic defendability of an area or the resources it contains. While this ecological cost-benefit framework has great explanatory power in solitary or pair living species, comparative work on group-living primates has always found economic defendability to be a necessary, but not sufficient condition to account for the distribution of effective range defence across the taxon. This mismatch between theory and observation has recently been ascribed to a collective action problem among group members in, what is more informatively viewed as, a public goods dilemma: mounting effective defence of a communal range against intrusions by outgroup conspecifics. We here further develop this framework, and report on analyses at three levels of biological organization: across species, across populations within a single lineage and across groups and individuals within a single population. We find that communal range defence in primates very rarely involves collective action sensu stricto and that it is best interpreted as the outcome of opportunistic and strategic individual-level decisions. Whether the public good of a defended communal range is produced by solitary, joint or collective action is thus the outcome of the interplay between the unique characteristics of each individual, local and current socio-ecological conditions, and fundamental life-history traits of the species. PMID- 26503680 TI - Individual participation in intergroup contests is mediated by numerical assessment strategies in black howler and tufted capuchin monkeys. AB - Asymmetries in resource-holding potential between opposing groups frequently determine outcomes of intergroup contests. Since both numerical superiority and high intergroup dominance rank may confer competitive advantages, group members should benefit from assessing the relative strength of rivals prior to engaging in defensive displays. However, differences in individual assessment may emerge when cost-benefit trade-offs differ among group members. We examine the influence of numerical superiority and intergroup dominance relationships on individual participation in intergroup encounters in black howler monkeys (Alouatta pigra) and tufted capuchin monkeys (Sapajus nigritus). Black howlers responded with longer vocal displays during encounters with neighbours with an equal number of resident males, while tufted capuchins increased their participation with increasing relative male group size. Within each species, males and females responded similarly to varying numerical odds, suggesting that despite pay-off asymmetries between males and females, both sexes were similarly influenced by numerical asymmetries in deciding to participate in collective group defence. Whereas the outcome of contests among tufted capuchins was determined by relative male group size, reflected in a pronounced intergroup dominance hierarchy, the absence of dominance relationships among black howler groups may have provoked prolonged vocal displays in order to assess rival groups with matching competitive abilities. PMID- 26503679 TI - 'Impact hunters' catalyse cooperative hunting in two wild chimpanzee communities. AB - Even when hunting in groups is mutually beneficial, it is unclear how communal hunts are initiated. If it is costly to be the only hunter, individuals should be reluctant to hunt unless others already are. We used 70 years of data from three communities to examine how male chimpanzees 'solve' this apparent collective action problem. The 'impact hunter' hypothesis proposes that group hunts are sometimes catalysed by certain individuals that hunt more readily than others. In two communities (Kasekela and Kanyawara), we identified a total of five males that exhibited high hunt participation rates for their age, and whose presence at an encounter with red colobus monkeys increased group hunting probability. Critically, these impact hunters were observed to hunt first more often than expected by chance. We argue that by hunting first, these males dilute prey defences and create opportunities for previously reluctant participants. This by product mutualism can explain variation in group hunting rates within and between social groups. Hunting rates declined after the death of impact hunter FG in Kasekela and after impact hunter MS stopped hunting frequently in Kanyawara. There were no impact hunters in the third, smaller community (Mitumba), where, unlike the others, hunting probability increased with the number of females present at an encounter with prey. PMID- 26503676 TI - Protein acetylation in metabolism - metabolites and cofactors. AB - Reversible acetylation was initially described as an epigenetic mechanism regulating DNA accessibility. Since then, this process has emerged as a controller of histone and nonhistone acetylation that integrates key physiological processes such as metabolism, circadian rhythm and cell cycle, along with gene regulation in various organisms. The widespread and reversible nature of acetylation also revitalized interest in the mechanisms that regulate lysine acetyltransferases (KATs) and deacetylases (KDACs) in health and disease. Changes in protein or histone acetylation are especially relevant for many common diseases including obesity, diabetes mellitus, neurodegenerative diseases and cancer, as well as for some rare diseases such as mitochondrial diseases and lipodystrophies. In this Review, we examine the role of reversible acetylation in metabolic control and how changes in levels of metabolites or cofactors, including nicotinamide adenine dinucleotide, nicotinamide, coenzyme A, acetyl coenzyme A, zinc and butyrate and/or beta-hydroxybutyrate, directly alter KAT or KDAC activity to link energy status to adaptive cellular and organismal homeostasis. PMID- 26503681 TI - Skills, division of labour and economies of scale among Amazonian hunters and South Indian honey collectors. AB - In foraging and other productive activities, individuals make choices regarding whether and with whom to cooperate, and in what capacities. The size and composition of cooperative groups can be understood as a self-organized outcome of these choices, which are made under local ecological and social constraints. This article describes a theoretical framework for explaining the size and composition of foraging groups based on three principles: (i) the sexual division of labour; (ii) the intergenerational division of labour; and (iii) economies of scale in production. We test predictions from the theory with data from two field contexts: Tsimane' game hunters of lowland Bolivia, and Jenu Kuruba honey collectors of South India. In each case, we estimate the impacts of group size and individual group members' effort on group success. We characterize differences in the skill requirements of different foraging activities and show that individuals participate more frequently in activities in which they are more efficient. We evaluate returns to scale across different resource types and observe higher returns at larger group sizes in foraging activities (such as hunting large game) that benefit from coordinated and complementary roles. These results inform us that the foraging group size and composition are guided by the motivated choice of individuals on the basis of relative efficiency, benefits of cooperation, opportunity costs and other social considerations. PMID- 26503682 TI - Multiple reputation domains and cooperative behaviour in two Latin American communities. AB - Reputations are a ubiquitous feature of human social life, and a large literature has been dedicated to explaining the relationship between prosocial reputations and cooperation in social dilemmas. However, humans form reputations in domains other than prosociality, such as economic competency that could affect cooperation. To date, no research has evaluated the relative effects of multiple reputation domains on cooperation. To bridge this gap, we analyse how prosocial and competency reputations affect cooperation in two Latin American communities (Bwa Mawego, Dominica, and Pucucanchita, Peru) across a number of social contexts (Dominica: labour contracting, labour exchange and conjugal partnership formation; Peru: agricultural and health advice network size). First, we examine the behavioural correlates of prosocial and competency reputations. Following, we analyse whether prosocial, competency, or both reputation domains explain the flow of cooperative benefits within the two communities. Our analyses suggest that (i) although some behaviours affect both reputation domains simultaneously, each reputation domain has a unique behavioural signature; and (ii) competency reputations affect cooperation across a greater number of social contexts compared to prosocial reputations. Results are contextualized with reference to the social markets in which behaviour is embedded and a call for greater theory development is stressed. PMID- 26503683 TI - Leadership solves collective action problems in small-scale societies. AB - Observation of leadership in small-scale societies offers unique insights into the evolution of human collective action and the origins of sociopolitical complexity. Using behavioural data from the Tsimane forager-horticulturalists of Bolivia and Nyangatom nomadic pastoralists of Ethiopia, we evaluate the traits of leaders and the contexts in which leadership becomes more institutional. We find that leaders tend to have more capital, in the form of age-related knowledge, body size or social connections. These attributes can reduce the costs leaders incur and increase the efficacy of leadership. Leadership becomes more institutional in domains of collective action, such as resolution of intragroup conflict, where collective action failure threatens group integrity. Together these data support the hypothesis that leadership is an important means by which collective action problems are overcome in small-scale societies. PMID- 26503684 TI - Interactions between personality and institutions in cooperative behaviour in humans. AB - Laboratory attempts to identify relationships between personality and cooperative behaviour in humans have generated inconsistent results. This may partially stem from different practices in psychology and economics laboratories, with both hypothetical players and incentives typical only in the former. Another possible cause is insufficient consideration of the contexts within which social dilemmas occur. Real social dilemmas are often governed by institutions that change the payoff structure via rewards and punishments. However, such 'strong situations' will not necessarily suppress the effects of personality. On the contrary, they may affect some personalities differentially. Extraversion and neuroticism, reflecting variation in reward and punishment sensitivity, should predict modification of cooperative behaviour following changes to the payoff structure. We investigate interactions between personality and a punishment situation via two versions of a public goods game. We find that, even in a strong situation, personality matters and, moreover, it is related to strategic shifts in cooperation. Extraversion is associated with a shift from free-riding to cooperation in the presence of punishment, agreeableness is associated with initially higher contributions regardless of game, and, contrary to our predictions, neuroticism is associated with lower contributions regardless of game. Results should lead to new hypotheses that relate variation in biological functioning to individual differences in cooperative behaviour and that consider three-way interactions among personality, institutional context and sociocultural background. PMID- 26503685 TI - When cooperation begets cooperation: the role of key individuals in galvanizing support. AB - Life abounds with examples of conspecifics actively cooperating to a common end, despite conflicts of interest being expected concerning how much each individual should contribute. Mathematical models typically find that such conflict can be resolved by partial-response strategies, leading investors to contribute relatively equitably. Using a case study approach, we show that such model expectations can be contradicted in at least four disparate contexts: (i) bi parental care; (ii) cooperative breeding; (iii) cooperative hunting; and (iv) human cooperation. We highlight that: (a) marked variation in contributions is commonplace; and (b) individuals can often respond positively rather than negatively to the contributions of others. Existing models have surprisingly limited power in explaining these phenomena. Here, we propose that, although among-individual variation in cooperative contributions will be influenced by differential costs and benefits, there is likely to be a strong genetic or epigenetic component. We then suggest that selection can maintain high investors (key individuals) when their contributions promote support by increasing the benefits and/or reducing the costs for others. Our intentions are to raise awareness in--and provide testable hypotheses of--two of the most poorly understood, yet integral, questions regarding cooperative ventures: why do individuals vary in their contributions and when does cooperation beget cooperation? PMID- 26503686 TI - The Big Man Mechanism: how prestige fosters cooperation and creates prosocial leaders. AB - Anthropological evidence from diverse societies suggests that prestige-based leadership may provide a foundation for cooperation in many contexts. Here, inspired by such ethnographic observations and building on a foundation of existing research on the evolution of prestige, we develop a set of formal models to explore when an evolved prestige psychology might drive the cultural evolution of n-person cooperation, and how such a cultural evolutionary process might create novel selection pressures for genes that make prestigious individuals more prosocial. Our results reveal (i) how prestige can foster the cultural emergence of cooperation by generating correlated behavioural phenotypes, both between leaders and followers, and among followers; (ii) why, in the wake of cultural evolution, natural selection favours genes that make prestigious leaders more prosocial, but only when groups are relatively small; and (iii), why the effectiveness of status differences in generating cooperation in large groups depends on cultural transmission (and not primarily on deference or coercion). Our theoretical framework, and the specific predictions made by these models, sketch out an interdisciplinary research programme that cross-cuts anthropology, biology, psychology and economics. Some of our predictions find support from laboratory work in behavioural economics and are consistent with several real world patterns. PMID- 26503688 TI - Genes, psychological traits and civic engagement. AB - Civic engagement is a classic example of a collective action problem: while civic participation improves life in the community as a whole, it is individually costly and thus there is an incentive to free ride on the actions of others. Yet, we observe significant inter-individual variation in the degree to which people are in fact civically engaged. Early accounts reconciling the theoretical prediction with empirical reality focused either on variation in individuals' material resources or their attitudes, but recent work has turned to genetic differences between individuals. We show an underlying genetic contribution to an index of civic engagement (0.41), as well as for the individual acts of engagement of volunteering for community or public service activities (0.33), regularly contributing to charitable causes (0.28) and voting in elections (0.27). There are closer genetic relationships between donating and the other two activities; volunteering and voting are not genetically correlated. Further, we show that most of the correlation between civic engagement and both positive emotionality and verbal IQ can be attributed to genes that affect both traits. These results enrich our understanding of the way in which genetic variation may influence the wide range of collective action problems that individuals face in modern community life. PMID- 26503687 TI - Evolving the neuroendocrine physiology of human and primate cooperation and collective action. AB - While many hormones play vital roles in facilitating or reinforcing cooperative behaviour, the neurohormones underlying competitive and cooperative behaviours are largely conserved across all mammals. This raises the question of how endocrine mechanisms have been shaped by selection to produce different levels of cooperation in different species. Multiple components of endocrine physiology- from baseline hormone concentrations, to binding proteins, to the receptor sensitivity and specificity--can evolve independently and be impacted by current socio-ecological conditions or individual status, thus potentially generating a wide range of variation within and between species. Here, we highlight several neurohormones and variation in hormone receptor genes associated with cooperation, focusing on the role of oxytocin and testosterone in contexts ranging from parenting and pair-bonding to reciprocity and territorial defence. While the studies reviewed herein describe the current state of the literature with regard to hormonal modulators of cooperation and collective action, there is still a paucity of research on hormonal mechanisms that help facilitate large scale collective action. We end by discussing several potential areas for future research. PMID- 26503689 TI - Collective action problem in heterogeneous groups. AB - I review the theoretical and experimental literature on the collective action problem in groups whose members differ in various characteristics affecting individual costs, benefits and preferences in collective actions. I focus on evolutionary models that predict how individual efforts and fitnesses, group efforts and the amount of produced collective goods depend on the group's size and heterogeneity, as well as on the benefit and cost functions and parameters. I consider collective actions that aim to overcome the challenges from nature or win competition with neighbouring groups of co-specifics. I show that the largest contributors towards production of collective goods will typically be group members with the highest stake in it or for whom the effort is least costly, or those who have the largest capability or initial endowment. Under some conditions, such group members end up with smaller net pay-offs than the rest of the group. That is, they effectively behave as altruists. With weak nonlinearity in benefit and cost functions, the group effort typically decreases with group size and increases with within-group heterogeneity. With strong nonlinearity in benefit and cost functions, these patterns are reversed. I discuss the implications of theoretical results for animal behaviour, human origins and psychology. PMID- 26503690 TI - Biodegradation of cis-1,2-Dichloroethene in Simulated Underground Thermal Energy Storage Systems. AB - Underground thermal energy storage (UTES) use has showed a sharp rise in numbers in the last decades, with aquifer thermal energy storage (ATES) and borehole thermal energy storage (BTES) most widely used. In many urban areas with contaminated aquifers, there exists a desire for sustainable heating and cooling with UTES and a need for remediation. We investigated the potential synergy between UTES and bioremediation with batch experiments to simulate the effects of changing temperature and liquid exchange that occur in ATES systems, and of only temperature change occurring in BTES systems on cis-DCE reductive dechlorination. Compared to the natural situation (NS) at a constant temperature of 10 degrees C, both UTES systems with 25/5 degrees C for warm and cold well performed significantly better in cis-DCE (cis-1,2-dichloroethene) removal. The overall removal efficiency under mimicked ATES and BTES conditions were respectively 13 and 8.6 times higher than in NS. Inoculation with Dehalococcoides revealed that their initial presence is a determining factor for the dechlorination process. Temperature was the dominating factor when Dehalococcoides abundance was sufficient. Stimulated biodegradation was shown to be most effective in the mimicked ATES warm well because of the combined effect of suitable temperature, sustaining biomass growth, and regular cis-DCE supply. PMID- 26503691 TI - Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug. AB - Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials. PMID- 26503693 TI - Sulfuricaulis limicola gen. nov., sp. nov., a sulfur oxidizer isolated from a lake. AB - A novel sulfur-oxidizing bacterium, strain HA5T, was isolated from sediment of a lake in Japan. The cells were rod-shaped (0.3-0.5 * 1.2-6.0 MUm) and Gram-stain negative. The G+C content of the genomic DNA was 63 mol%. The major components in the cellular fatty acid profile were C16 : 0 and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c). The strain oxidized thiosulfate, tetrathionate and elemental sulfur as electron donors to support autotrophic growth. Growth was observed at a temperature range of 8-37 degrees C, with optimum growth at 28-32 degrees C. The pH range for growth was pH 6.1-9.2. Optimum growth of the isolate was observed in medium without NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain belongs to the family Acidiferrobacteraceae in the class Gammaproteobacteria. The closest relative was Sulfurifustis variabilis skN76T with the highest 16S rRNA gene sequence similarity of 93 %. On the basis of phylogenetic and phenotypic properties, strain HA5T is proposed to represent a novel species of a new genus, Sulfuricaulis limicola gen. nov., sp. nov. The type strain of the type species is HA5T ( = DSM 100373T = NBRC 110752T). PMID- 26503692 TI - Transcranial alternating current stimulation affects the BOLD signal in a frequency and task-dependent manner. AB - Transcranial alternating current stimulation (tACS) has emerged as a promising tool for manipulating ongoing brain oscillations. While previous studies demonstrated frequency-specific effects of tACS on diverse cognitive functions, its effect on neural activity remains poorly understood. Here we asked how tACS modulates regional fMRI blood oxygenation level dependent (BOLD) signal as a function of frequency, current strength, and task condition. TACS was applied over the posterior cortex of healthy human subjects while the BOLD signal was measured during rest or task conditions (visual perception, passive video viewing and motor task). TACS was applied in a blockwise manner at different frequencies (10, 16, 60 and 80 Hz). The strongest tACS effects on BOLD activity were observed with stimulation at alpha (10 Hz) and beta (16 Hz) frequency bands, while effects of tACS at the gamma range were rather modest. Specifically, we found that tACS at 16 Hz induced BOLD activity increase in fronto-parietal areas. Overall, tACS effects varied as a function of frequency and task, and were predominantly seen in regions that were not activated by the task. Also, the modulated regions were poorly predicted by current density modeling studies. Taken together, our results suggest that tACS does not necessarily exert its strongest effects in regions below the electrodes and that region specificity might be achieved with tACS due to varying susceptibility of brain regions to entrain to a given frequency. PMID- 26503694 TI - Erratum To: Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma. PMID- 26503696 TI - Chemical Manufacturing and Refining Industry Legitimacy: Reflective Management, Trust, Precrisis Communication to Achieve Community Efficacy. AB - Calls for emergency right-to-know in the 1980s, and, in the 1990s, risk management planning, motivated U.S. chemical manufacturing and refining industries to operationalize a three-pronged approach to risk minimization and communication: reflective management to increase legitimacy, operational safety programs to raise trust, and community engagement designed to facilitate citizens' emergency response efficacy. To assess these management, operational, and communication initiatives, communities (often through Local Emergency Planning Committees) monitored the impact of such programs. In 2012, the fourth phase of a quasi-longitudinal study was conducted to assess the effectiveness of operational change and community outreach in one bellwether community. This study focuses on legitimacy, trust, and response efficacy to suggest that an industry can earn legitimacy credits by raising its safety and environmental impact standards, by building trust via that change, and by communicating emergency response messages to near residents to raise their response efficacy. As part of its campaign to demonstrate its concern for community safety through research, planning, and implementation of safe operations and viable emergency response systems, this industry uses a simple narrative of risk/emergency response-shelter in-place-communicated by a spokes-character: Wally Wise Guy. PMID- 26503695 TI - The effect of neuropeptide FF in the amygdala kindling model. AB - OBJECTIVE: Neuropeptide FF (NPFF) and its receptors (NPFF1 R and NPFF2 R) are differentially distributed throughout the central nervous system. NPFF reduces cortical excitability in rats when administered intracerebroventricularly (i.c.v.), and both NPFF and NPFF1 R antagonists attenuate pilocarpine-induced limbic seizures. In this study, our aim was to determine whether NPFF exerts anticonvulsant or anti-epileptogenic effects in the rat amygdala kindling model for temporal lobe seizures. METHODS: Male Wistar rats were implanted with a recording/stimulation electrode in the right amygdala and a cannula in the left lateral ventricle. In a first group of animals, the afterdischarge threshold (ADT) was determined after a single i.c.v. infusion of saline (n = 8) or NPFF (1 nmol/h for 2 h; n = 10). Subsequently, daily infusion of saline (n = 8) or NPFF (1 nmol/h for 2 h; i.c.v.; n = 9) was performed, followed by a kindling stimulus (ADT+200 MUA). Afterdischarge duration and seizure severity were evaluated after every kindling stimulus. A second group of rats (n = 7) were fully kindled, and the effect of saline or a high dose of NPFF (10 nmol/h for 2 h, i.c.v.) on ADT and the generalized seizure threshold (GST) was subsequently determined. RESULTS: In naive rats, NPFF significantly increased the ADT compared to control (435 +/- 72 MUA vs 131 +/- 23 MUA [P < 0.05]). When rats underwent daily stimulations above the ADT, NPFF did not delay or prevent kindling acquisition. Furthermore, a high dose of NPFF did not alter ADT or GST in fully kindled rats. CONCLUSIONS: I.c.v. administration of NPFF reduced excitability in the amygdala in naive, but not in fully kindled rats, and had no effect on kindling acquisition. PMID- 26503698 TI - Lapatinib enhances trastuzumab-mediated antibody-dependent cellular cytotoxicity via upregulation of HER2 in malignant mesothelioma cells. AB - EGFR/HER2 are frequently expressed in MPM tissues, however, no studies have shown the clinical benefit of using EGFR/HER2-targeting drugs in patients with malignant pleural mesothelioma (MPM). It was reported that the tyrosine kinase inhibitor (TKI) lapatinib enhanced trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) in HER2-positive breast cancer, suggesting that this combination is a promising strategy for MPM treatment. The aim of the present study was to explore the possibility of a TKI combined with trastuzumab to enhance ADCC in MPM cells. Five MPM cell lines were used to test the effects of TKIs targeting EGFR (gefitinib, afatinib and lapatinib) on cell proliferation and the expression of the HER family receptor. The combined effects of TKI with trastuzumab on ADCC were evaluated using the LDH release assay. Additionally, MPM cells were isolated from patients and evaluated for lapatinib-induced upregulation of HER family receptors and trastuzumab- or cetuximab-mediated ADCC. In MPM cell lines, HER2 expression was upregulated by lapatinib, downregulated by afatinib and unaffected by gefitinib. As expected, more trastuzumab bound to MPM cells pretreated with lapatinib than untreated cells, resulting in the enhancement of trastuzumab-mediated ADCC in MPM cells. In patient-derived MPM cells, both HER2 and EGFR were upregulated by lapatinib, resulting in the enhancement of both trastuzumab- and cetuximab-mediated ADCC. Of the three TKIs, only lapatinib enhanced trastuzumab-mediated ADCC via the upregulation of HER2 expression in MPM cells, suggesting that sequential combination of lapatinib and trastuzumab may be a promising strategy for MPM treatment. PMID- 26503697 TI - Iodine source apportionment in the Malawian diet. AB - The aim of this study was to characterise nutritional-I status in Malawi. Dietary I intakes were assessed using new datasets of crop, fish, salt and water-I concentrations, while I status was assessed for 60 women living on each of calcareous and non-calcareous soils as defined by urinary iodine concentration (UIC). Iodine concentration in staple foods was low, with median concentrations of 0.01 mg kg(-1) in maize grain, 0.008 mg kg(-1) in roots and tubers, but 0.155 mg kg(-1) in leafy vegetables. Freshwater fish is a good source of dietary-I with a median concentration of 0.51 mg kg(-1). Mean Malawian dietary-Iodine intake from food, excluding salt, was just 7.8 MUg d(-1) compared to an adult requirement of 150 MUg d(-1). Despite low dietary-I intake from food, median UICs were 203 MUg L(-1) with only 12% defined as I deficient whilst 21% exhibited excessive I intake. Iodised salt is likely to be the main source of dietary I intake in Malawi; thus, I nutrition mainly depends on the usage and concentration of I in iodised salt. Drinking water could be a significant source of I in some areas, providing up to 108 MUg d(-1) based on consumption of 2 L d(-1). PMID- 26503699 TI - Gene expression profiling analysis of CRTC1-MAML2 fusion oncogene-induced transcriptional program in human mucoepidermoid carcinoma cells. AB - BACKGROUND: Mucoepidermoid carcinoma (MEC) arises from multiple organs and accounts for the most common types of salivary gland malignancies. Currently, patients with unresectable and metastatic MEC have poor long-term clinical outcomes and no targeted therapies are available. The majority of MEC tumors contain a t(11;19) chromosomal translocation that fuses two genes, CRTC1 and MAML2, to generate the chimeric protein CRTC1-MAML2. CRTC1-MAML2 displays transforming activity in vitro and is required for human MEC cell growth and survival, partially due to its ability to constitutively activate CREB-mediated transcription. Consequently, CRTC1-MAML2 is implicated as a major etiologic molecular event and a therapeutic target for MEC. However, the molecular mechanisms underlying CRTC1-MAML2 oncogenic action in MEC have not yet been systematically analyzed. Elucidation of the CRTC1-MAML2-regulated transcriptional program and its underlying mechanisms will provide important insights into MEC pathogenesis that are essential for the development of targeted therapeutics. METHODS: Transcriptional profiling was performed on human MEC cells with the depletion of endogenous CRTC1-MAML2 fusion or its interacting partner CREB via shRNA-mediated gene knockdown. A subset of target genes was validated via real time RT-PCR assays. CRTC1-MAML2-perturbed molecular pathways in MEC were identified through pathway analyses. Finally, comparative analysis of CRTC1-MAML2 regulated and CREB-regulated transcriptional profiles was carried out to assess the contribution of CREB in mediating CRTC1-MAML2-induced transcription. RESULTS: A total of 808 differentially expressed genes were identified in human MEC cells after CRTC1-MAML2 knockdown and a subset of known and novel fusion target genes was confirmed by real-time RT-PCR. Pathway Analysis revealed that CRTC1-MAML2 regulated genes were associated with network functions that are important for cell growth, proliferation, survival, migration, and metabolism. Comparison of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles revealed common and distinct genes regulated by CRTC1-MAML2 and CREB, respectively. CONCLUSION: This study identified a specific CRTC1-MAML2-induced transcriptional program in human MEC cells and demonstrated that CRTC1-MAML2 regulates gene expression in CREB-dependent and independent manners. Our data provide the molecular basis underlying CRTC1-MAML2 oncogenic functions and lay a foundation for further functional investigation of CRTC1-MAML2-induced signaling in MEC initiation and maintenance. PMID- 26503700 TI - Twenty years and still counting: including women as participants and studying sex and gender in biomedical research. AB - BACKGROUND: This paper chronicles attempts in the United States over the past 20 years to fully represent women in clinical trials and ensure the study of sex and gender in biomedical research. We maintain that productive science with the aim of serving the public health requires examining the influence of sex and gender on health outcomes. DISCUSSION: This section provides a historical perspective on the changes in recommendations and requirements of both the National Institutes of Health - the world's largest single funder of biomedical research - and the U.S. Food and Drug Administration - the world's most influential regulator of drugs and medical devices - for the acceptable conduct of research as it relates to sex and gender. We also cite all reports by the U.S. Institute of Medicine and the U.S. Congress' General Accountability Office issued from 1990 to the present on the inclusion of sex and gender in research, and selected high-impact published studies that illustrate and document the paucity of, yet the need for, inclusion of females and consideration of sex and gender in research across an array of biomedical disciplines. The key message of this paper is that it has been 20 years since the first requirements to include women as well as men in clinical trials and analyze results by sex were mandated by a U.S. federal law, yet not nearly enough progress has been made. Recent signs of potential change in both policy and practice of scientific inquiry suggest much more progress may be within reach. However, awaiting a cultural shift to allow the study of sex and gender to be embraced is not seen as an effective strategy for change. Rather, specific instrumental recommendations are offered for how to include the study of sex and gender in research so as to increase our understanding and promotion of health for the benefit of all. PMID- 26503701 TI - Binding site residues control inhibitor selectivity in the human norepinephrine transporter but not in the human dopamine transporter. AB - The transporters for norepinephrine and dopamine (NET and DAT, respectively) constitute the molecular targets for recreational drugs and therapeutics used in the treatment of psychiatric disorders. Despite a strikingly similar amino acid sequence and predicted topology between these transporters, some inhibitors display a high degree of selectivity between NET and DAT. Here, a systematic mutational analysis of non-conserved residues within the extracellular entry pathway and the high affinity binding site in NET and DAT was performed to examine their role for selective inhibitor recognition. Changing the six diverging residues in the central binding site of NET to the complementary residues in DAT transferred a DAT-like pharmacology to NET, showing that non conserved binding site residues in NET are critical determinants for inhibitor selectivity. In contrast, changing the equivalent residues in the central site of DAT to the corresponding residues in NET had modest effects on the same inhibitors, suggesting that non-conserved binding site residues in DAT play a minor role for selective inhibitor recognition. Our data points towards distinct structural determinants governing inhibitor selectivity in NET and DAT, and provide important new insight into the molecular basis for NET/DAT selectivity of therapeutic and recreational drugs. PMID- 26503702 TI - Health economic assessment of universal immunization of toddlers against Hepatitis A Virus (HAV) in Mexico. AB - Hepatitis A virus (HAV) has shifted from high to intermediate endemicity in Mexico, which may increase the risk of clinically significant HAV infections in older children, adolescents and adults. The objective of this study was to evaluate the cost-utility of single-dose or 2-dose universal infant HAV vaccination strategy in Mexico, compared with no vaccination. A previously published dynamic model estimated the expected number of HAV cases with each strategy, and a decision model was used to estimate the costs and quality adjusted life-years (QALYs) expected with each strategy. The time horizon was 25 years (2012-2036) and the base case analysis was conducted from the perspective of the Mexican public health system. Costs and QALYs after the first year were discounted at 5% annually. Input data were taken from national databases and published sources where available. The single-dose HAV vaccination strategy had an incremental cost-utility ratio (ICUR) of Mexican peso (MXN) 2,270 per QALY gained, compared with no vaccination. The two-dose strategy had an ICUR of MXN 14,961/QALY compared with no vaccination, and an ICUR of MXN 78,280/QALY compared with the single-dose strategy. The estimated ICURs were below the threshold of 1 x Mexican gross domestic product per capita. When indirect costs were included (societal perspective), the single-dose HAV vaccination strategy would be expected to improve health outcomes and to be cost-saving. This analysis indicates that routine vaccination of toddlers against HAV would be cost effective in Mexico using either a single-dose or a 2-dose vaccination strategy. GSK study identifier: HO-12-12877. PMID- 26503704 TI - Surface protein Esp enhances pro-inflammatory cytokine expression through NF kappaB activation during enterococcal infection. AB - Enterococcal surface protein (Esp) is encoded on a pathogenicity island in Enterococcus faecalis and E. faecium and is involved in biofilm formation and binding to epithelial cells. In this study, using Esp-expressing E. faecalis MMH594 and its isogenic Esp-deficient strain, as well as purified Esp, we show that Esp is sufficient for activation of NF-kappaB and the subsequent production of pro-inflammatory cytokines IL-1beta and TNF-alpha in macrophages in vitro. In a mouse peritonitis model, we also show that mice infected with Esp-expressing E. faecalis showed comparatively higher levels of cytokines TNF-alpha, IL-1beta and IL-6 in peritoneal fluid, and IL-6 in serum. Moreover, neutrophil infiltration and tissue damage in the liver was higher in the mice infected with the Esp expressing strain compared with mice infected with the Esp-deficient mutant. These results add Esp to the growing list of enterococcal virulence factors that can modulate inflammation during infection and has implications for enterococcal pathogenesis. PMID- 26503706 TI - Sintering boron carbide ceramics without grain growth by plastic deformation as the dominant densification mechanism. AB - A new ceramic sintering approach employing plastic deformation as the dominant mechanism is proposed, at low temperature close to the onset point of grain growth and under high pressure. Based on this route, fully dense boron carbide without grain growth can be prepared at 1,675-1,700 degrees C and under pressure of (>=) 80 MPa in 5 minutes. The dense boron carbide shows excellent mechanical properties, including Vickers hardness of 37.8 GPa, flexural strength of 445.3 MPa and fracture toughness of 4.7 MPa*m(0.5). Such a process should also facilitate the cost-effective preparation of other advanced ceramics for practical applications. PMID- 26503703 TI - Inhibition of MTA1 by ERalpha contributes to protection hepatocellular carcinoma from tumor proliferation and metastasis. AB - BACKGROUND: Although expression of MTA1 inversely correlates with the nuclear localization of ERalpha, the effect and molecular mechanism of ERalpha regulation of MTA1 remain unknown. METHODS: Quantitative real-time PCR and western blot analyses were used to measure levels of MTA1. The effect on HCC cell proliferation and invasion was assessed by EdU incorporation assays and Transwell, respectively. ShRNA and dual-luciferase assays were used to investigate the regulatory relationship between MTA1 and ERalpha in cell lines. RESULTS: We found that MTA1 gene regulation by ERalpha may be influenced by nuclear corepressors. The MTA1 promoter has three functional ER-element half sites that lead to decreased MTA1 transcription and expression. ERalpha overexpression suppressed the proliferation and invasion of hepatocellular carcinoma cells (HCC). In addition, overexpression of MTA1 attenuated ERalpha mediated suppression of the proliferation and invasion of HCC cells and tumor formation in vivo. These results suggested feedback regulation between ERalpha and MTA1. In summary, our results demonstrated that ERalpha suppressed proliferation and invasion of human HCC cells through downregulation of MTA1 transcription. CONCLUSIONS: Our study is an improved description of the mechanisms of the suppressive effect of ERalpha on HCCs, adding understanding to the gender disparity of HCC progression. PMID- 26503705 TI - Medicago truncatula and Glycine max: Different Drought Tolerance and Similar Local Response of the Root Nodule Proteome. AB - Legume crops present important agronomical and environmental advantages mainly due to their capacity to reduce atmospheric N2 to ammonium via symbiotic nitrogen fixation (SNF). This process is very sensitive to abiotic stresses such as drought, but the mechanism underlying this response is not fully understood. The goal of the current work is to compare the drought response of two legumes with high economic impact and research importance, Medicago truncatula and Glycine max, by characterizing their root nodule proteomes. Our results show that, although M. truncatula exhibits lower water potential values under drought conditions compared to G. max, SNF declined analogously in the two legumes. Both of their nodule proteomes are very similar, and comparable down-regulation responses in the diverse protein functional groups were identified (mainly proteins related to the metabolism of carbon, nitrogen, and sulfur). We suggest lipoxygenases and protein turnover as newly recognized players in SNF regulation. Partial drought conditions applied to a split-root system resulted in the local down-regulation of the entire proteome of drought-stressed nodules in both legumes. The high degree of similarity between both legume proteomes suggests that the vast amount of research conducted on M. truncatula could be applied to economically important legume crops, such as soybean. PMID- 26503707 TI - Novel Monte Carlo approach quantifies data assemblage utility and reveals power of integrating molecular and clinical information for cancer prognosis. AB - Current clinical practice in cancer stratifies patients based on tumour histology to determine prognosis. Molecular profiling has been hailed as the path towards personalised care, but molecular data are still typically analysed independently of known clinical information. Conventional clinical and histopathological data, if used, are added only to improve a molecular prediction, placing a high burden upon molecular data to be informative in isolation. Here, we develop a novel Monte Carlo analysis to evaluate the usefulness of data assemblages. We applied our analysis to varying assemblages of clinical data and molecular data in an ovarian cancer dataset, evaluating their ability to discriminate one-year progression-free survival (PFS) and three-year overall survival (OS). We found that Cox proportional hazard regression models based on both data types together provided greater discriminative ability than either alone. In particular, we show that proteomics data assemblages that alone were uninformative (p = 0.245 for PFS, p = 0.526 for OS) became informative when combined with clinical information (p = 0.022 for PFS, p = 0.048 for OS). Thus, concurrent analysis of clinical and molecular data enables exploitation of prognosis-relevant information that may not be accessible from independent analysis of these data types. PMID- 26503709 TI - Flibanserin. PMID- 26503708 TI - Language processing of auditory cortex revealed by functional magnetic resonance imaging in presbycusis patients. AB - CONCLUSION: Contralateral temporal lobe activation decreases with aging, regardless of hearing status, with elderly individuals showing reduced right ear advantage. BACKGROUND: Aging and hearing loss possibly lead to presbycusis speech discrimination decline. OBJECTIVES: To evaluate presbycusis patients' auditory cortex activation under verbal stimulation. METHOD: Thirty-six patients were enrolled: 10 presbycusis patients (mean age = 64 years, range = 60-70), 10 in the healthy aged group (mean age = 66 years, range = 60-70), and 16 young healthy volunteers (mean age = 25 years, range = 23-28). These three groups underwent simultaneous 1 kHz and 90 dB single-syllable word stimuli and (blood-oxygen-level dependent functional magnetic resonance imaging) BOLD fMRI examinations. RESULTS: The main activation regions were superior temporal and middle temporal gyrus. For all aged subjects, the right region of interest (ROI) activation volume was decreased compared with the young group. With left ear stimulation, bilateral ROI activation intensity held. With right ear stimulation, the aged group's activation intensity was higher. Using monaural stimulation in the young group, contralateral temporal lobe activation volume and intensity were higher vs ipsilateral, while they were lower in the aged and presbycusis groups. On left and right ear auditory tasks, the young group showed right ear advantage, while the aged and presbycusis groups showed reduced right ear advantage. PMID- 26503710 TI - Physisorption and desorption of H2, HD and D2 on amorphous solid water ice. Effect on mixing isotopologue on statistical population of adsorption sites. AB - We study the adsorption and desorption of three isotopologues of molecular hydrogen mixed on 10 ML of porous amorphous water ice (ASW) deposited at 10 K. Thermally programmed desorption (TPD) of H2, D2 and HD adsorbed at 10 K have been performed with different mixings. Various coverages of H2, HD and D2 have been explored and a model taking into account all species adsorbed on the surface is presented in detail. The model we propose allows to extract the parameters required to fully reproduce the desorption of H2, HD and D2 for various coverages and mixtures in the sub-monolayer regime. The model is based on a statistical description of the process in a grand-canonical ensemble where adsorbed molecules are described following a Fermi-Dirac distribution. PMID- 26503711 TI - The impact of maternal factors on mortality rates among children under the age of five years in a rural Ugandan population between 2002 and 2012. AB - AIM: Accurately estimating child mortality in rural communities in Africa with poor vital registration is a challenge. We aimed to estimate mortality rates and risk factors for children under five years old in rural Uganda. METHODS: Age specific mortality rates were estimated using the synthetic cohort life-table technique for 10 118 children under the age of five years, between 2002 and 2012. Calendar year-specific hazard rates were calculated using five-year moving averages, and risk factors were explored by Cox regression. RESULTS: The mortality rate was 92 per 1000 newborn infants from birth to five years, based on a total of 256 deaths. It was 40 for boys and 23 for girls in the neonatal period and 68 for boys and 42 for girls up to the age of one year. A substantial decline in mortality from 2002 to 2012 was observed between the ages of 28 days and 11 months. Multivariate analysis demonstrated that mortality increased with decreasing child age, home delivery, human immuno-deficiency virus in the child, a birth interval of less than one year, having an unmarried mother and a maternal parity of more than four. CONCLUSION: Under-five mortality rates in rural Uganda are driven by maternal factors. PMID- 26503712 TI - Novel Self-driven Microbial Nutrient Recovery Cell with Simultaneous Wastewater Purification. AB - Conventional wastewater purification technologies consume large amounts of energy, while the abundant chemical energy and nutrient resources contained in sewage are wasted in such treatment processes. A microbial nutrient recovery cell (MNRC) has been developed to take advantage of the energy contained in wastewater, in order to simultaneously purify wastewater and recover nutrient ions. When wastewater was circulated between the anode and cathode chambers of the MNRC, the organics (COD) were removed by bacteria while ammonium and phosphate (NH4(+)-N and PO4(3-)-P) were recovered by the electrical field that was produced using in situ energy in the wastewater without additional energy input. The removal efficiencies from wastewater were >82% for COD, >96% for NH4(+)-N, and >64% for PO4(3-)-P in all the operational cycles. Simultaneously, the concentrations of NH4(+) and PO4(3-) in the recovery chamber increased to more than 1.5 and 2.2 times, respectively, compared with the initial concentrations in wastewater. The MNRC provides proof-of-concept as a sustainable, self-driven approach to efficient wastewater purification and nutrient recovery in a comprehensive bioelectrochemical system. PMID- 26503713 TI - The Role of Institutional Placement, Family Conflict, and Homosexuality in Homelessness Pathways Among Latino LGBT Youth in New York City. AB - Despite the overrepresentation of Lesbian, Gay, Bisexual, and Transgender (LGBT) youth among the homeless, the processes leading to their homelessness are understudied. This ethnographic study sought to elucidate the role of sexual orientation in the pathway to housing instability among young gay men. Fieldwork included 18 months of participant observations in public spaces and at a homeless LGBT youth organization in New York City, as well as formal semistructured interviews with 14 Latino young men and five staff. Three distinct pathways emerged. Some youth became homeless after placement in state systems of care disrupted their social support systems, while others became homeless after extreme family conflict over sexual orientation. Nonetheless, most youths became homeless as a result of long-term processes of family disintegration in which normative adolescent development and disclosure of homosexuality exacerbated preexisting conflict. These findings suggest the need to examine the accumulation of risks before disclosure exacerbates family conflict and increases their risk of homelessness. PMID- 26503714 TI - Molecular analysis of type II topoisomerases of Aeromonas hydrophila isolated from fish and levofloxacin-induced resistant isolates in vitro. AB - The mechanisms of resistance to levofloxacin for Aeromonas hydrophila isolated from diseased fish and selected in vitro were examined in this study. Levofloxacin-resistant mutants were obtained by selection of A. hydrophila in vitro. The quinolone resistance-determining regions (QRDRs) of the gyrA and parC genes were sequenced in Lev(R) strains and reverse mutation strains. All Lev(R) strains carried a point mutation at codon 83 (Ser -> Ile), and one strain (25 %) harbored a mutation at position 92 (Leu -> Met) in the GyrA-QRDR. After being transferred in a levofloxacin-free medium, one strain of the mutants was successfully reversed and the reversion was related with mutations of GyrA-QRDR at positions 81 (Gly -> Asp) and 83 (Ile -> Ser). No amino acid alteration was found in the ParC-QRDR. In addition, the minimum inhibitory concentration (MIC) of levofloxacin for the mutants was lower in the presence of reserpine, and all mutants were also resistant to some of the other quinolones. It was found that the mechanism of levofloxacin resistance of A. hydrophila selected in vitro was related to gyrA of type II topoisomerase, and an efflux mechanism was involved in the resistance as well. PMID- 26503715 TI - A qualitative exploration of how Canadian informal caregivers in medical tourism use experiential resources to cope with providing transnational care. AB - Canadians travelling abroad for privately arranged surgeries paid for out-of pocket are engaging in what has come to be known as medical tourism. They are often accompanied by friends or family members, who we call caregiver-companions. Caregiver-companions provide care in and across a variety of formal and informal settings, such as in hotels, airplanes and at home. This qualitative study examines the experiences of informal caregivers in medical tourism to learn more about the lived experiences or 'experiential resources' they draw upon to cope with providing care and avoiding caregiver burden. The care-giving literature has demonstrated that such burden can negatively impact caregivers' well-being. The unique, transnational context of care-giving in medical tourism and recent growth in popularity of this practice means that there are few supports or resources currently in place to assist informal caregivers. In this article, we report on an analysis that sought to detail how caregiver-companions draw upon their previous lived experiences to cope with providing transnational care and to minimise or avoid the onset of caregiver burden. We conducted semi-structured telephone interviews with 20 Canadians who had accompanied their friends or family members abroad for surgery between September 2013 and January 2014. Thematic analysis revealed the ways that participants had developed practical strategies to deal with the challenges they faced in medical tourism. The interviews revealed three important experiential resources drawn upon by participants: (i) previous experiences of international travel; (ii) previous experiences of informal care-giving; and (iii) dimensions of the existing relationship with the care recipient. Differences in access to and use of these experiential resources related to participants' perspectives on medical tourism and the outcomes of the trip. By identifying the experiential resources drawn upon by informal caregivers in medical tourism, we can more effectively identify supportive interventions. PMID- 26503717 TI - Of quirky channels and a fond farewell. PMID- 26503716 TI - Windows of Sensitivity to Toxic Chemicals in the Development of Cleft Palates. AB - Cleft lip and cleft palate are among the most common birth defects worldwide. There is a genetic component to the development of these malformations, as well as evidence that environmental exposures and prescription drug use may exacerbate or even produce these manifestations. Thus, it is important to understand the underlying mechanisms and when these exposures affect development of the growing fetus. The purpose of this investigation was to critically review the available literature related to orofacial cleft formation following chemical exposure and identify specific time frames for windows of sensitivity. Further, an aim was to evaluate the potential for predicting effects in humans based on animal studies. Evidence indicates that chemical causes of cleft palate development are due to dose and timing of exposure, susceptibility of the species (i.e., the genetic makeup), and mechanism of action. Several studies demonstrated that dose is a crucial factor; however, some investigators argued that even more important than dose was timing of exposure. Data show that the window of sensitivity to environmental teratogens in the development of cleft palates is quite narrow and follows closely the window of palatogenesis in the fetus of any given species. PMID- 26503719 TI - Modal affinities of endplate acetylcholine receptors caused by loop C mutations. AB - The time course of the endplate current is determined by the rate and equilibrium constants for acetylcholine receptor (AChR) activation. We measured these constants in single-channel currents from AChRs with mutations at the neurotransmitter-binding sites, in loop C. The main findings are: (a) Almost all perturbations of loop C generate heterogeneity in the channel open probability ("modes"). (b) Modes are generated by different affinities for ACh that can be either higher or lower than in the wild-type receptors. (c) The modes are stable, in so far as each receptor maintains its affinity for at least several minutes. (d) Different agonists show different degrees of modal activity. With the loop C mutation alphaP197A, there are four modes with ACh but only two with partial agonists. (e) The affinity variations arise exclusively from the alphadelta binding site. (f) Substituting four gamma-subunit residues into the delta subunit (three in loop E and one in the beta5-beta5' linker) reduces modal activity. (g) At each neurotransmitter-binding site, affinity is determined by a core of five aromatic residues. Modes are eliminated by an alanine mutation at deltaW57 but not at the other aromatics. (h) Modes are eliminated by a phenylalanine substitution at all core aromatics except alphaY93. The results suggest that, at the alphadelta agonist site, loop C and the complementary subunit surface can each adopt alternative conformations and interact with each other to influence the position of deltaW57 with respect to the aromatic core and, hence, affinity. PMID- 26503718 TI - Bimodal regulation of an Elk subfamily K+ channel by phosphatidylinositol 4,5 bisphosphate. AB - Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates Shaker K+ channels and voltage-gated Ca2+ channels in a bimodal fashion by inhibiting voltage activation while stabilizing open channels. Bimodal regulation is conserved in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, but voltage activation is enhanced while the open channel state is destabilized. The proposed sites of PIP2 regulation in these channels include the voltage-sensor domain (VSD) and conserved regions of the proximal cytoplasmic C terminus. Relatively little is known about PIP2 regulation of Ether-a-go-go (EAG) channels, a metazoan specific family of K+ channels that includes three gene subfamilies, Eag (Kv10), Erg (Kv11), and Elk (Kv12). We examined PIP2 regulation of the Elk subfamily potassium channel human Elk1 to determine whether bimodal regulation is conserved within the EAG K+ channel family. Open-state stabilization by PIP2 has been observed in human Erg1, but the proposed site of regulation in the distal C terminus is not conserved among EAG family channels. We show that PIP2 strongly inhibits voltage activation of Elk1 but also stabilizes the open state. This stabilization produces slow deactivation and a mode shift in voltage gating after activation. However, removal of PIP2 has the net effect of enhancing Elk1 activation. R347 in the linker between the VSD and pore (S4-S5 linker) and R479 near the S6 activation gate are required for PIP2 to inhibit voltage activation. The ability of PIP2 to stabilize the open state also requires these residues, suggesting an overlap in sites central to the opposing effects of PIP2 on channel gating. Open-state stabilization in Elk1 requires the N-terminal eag domain (PAS domain + Cap), and PIP2-dependent stabilization is enhanced by a conserved basic residue (K5) in the Cap. Our data shows that PIP2 can bimodally regulate voltage gating in EAG family channels, as has been proposed for Shaker and HCN channels. PIP2 regulation appears fundamentally different for Elk and KCNQ channels, suggesting that, although both channel types can regulate action potential threshold in neurons, they are not functionally redundant. PMID- 26503720 TI - Altered conductance and permeability of Cx40 mutations associated with atrial fibrillation. AB - Gap junctions ensure the rapid propagation of the action potential throughout the myocardium. Three mutant forms of connexin40 (Cx40; A96S, M163V, and G38D), the primary component of the atrial gap junction channel, are associated with atrial fibrillation and retain the ability to form functional channels. We determined the biophysical properties of these mutant gap junctions in transiently transfected HeLa and N2A cells. All three mutants showed macroscopic junctional conductances over the range of 0.5 to 40 nS, and voltage dependences comparable to those of wild-type (WT) Cx40. However, the unitary conductance of G38D channels was ~1.6-fold higher than that of WT Cx40 channels (~220 vs. ~135 pS), whereas the unitary conductances of the A96S and M163V mutants were similar to that of WT Cx40. Furthermore, the M163V and G38D channels exhibited approximately two- and approximately fivefold higher permeability to the anionic dye Lucifer yellow (LY) relative to K+ (LY/K+) compared with that of WT Cx40, whereas A96S LY transfer was similar to that of WT (G38D > M163V > A96S ~ Cx40WT). In contrast, G38D channels were almost impermeable to cationic ethidium bromide (EtBr), suggesting that G38D alters channel selectivity. Conversely, A96S and M163V channels showed enhanced EtBr permeability relative to WT Cx40, with the following permeability order: M163V > A96S > Cx40WT > G38D. Altered conductive and permeability properties of mutant channels suggest an essential role for Cx40 mediated biochemical and electrical coupling in cardiac tissues. The altered properties of the three single-base substitution mutants may play a role in mechanisms of reentry arrhythmias. PMID- 26503721 TI - A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization. AB - The epileptic encephalopathies are a group of highly heterogeneous genetic disorders. The majority of disease-causing mutations alter genes encoding voltage gated ion channels, neurotransmitter receptors, or synaptic proteins. We have identified a novel de novo pathogenic K+ channel variant in an idiopathic epileptic encephalopathy family. Here, we report the effects of this mutation on channel function and heterologous expression in cell lines. We present a case report of infantile epileptic encephalopathy in a young girl, and trio-exome sequencing to determine the genetic etiology of her disorder. The patient was heterozygous for a de novo missense variant in the coding region of the KCNB1 gene, c.1133T>C. The variant encodes a V378A mutation in the alpha subunit of the Kv2.1 voltage-gated K+ channel, which is expressed at high levels in central neurons and is an important regulator of neuronal excitability. We found that expression of the V378A variant results in voltage-activated currents that are sensitive to the selective Kv2 channel blocker guangxitoxin-1E. These voltage activated Kv2.1 V378A currents were nonselective among monovalent cations. Striking cell background-dependent differences in expression and subcellular localization of the V378A mutation were observed in heterologous cells. Further, coexpression of V378A subunits and wild-type Kv2.1 subunits reciprocally affects their respective trafficking characteristics. A recent study reported epileptic encephalopathy-linked missense variants that render Kv2.1 a tonically activated, nonselective cation channel that is not voltage activated. Our findings strengthen the correlation between mutations that result in loss of Kv2.1 ion selectivity and development of epileptic encephalopathy. However, the strong voltage sensitivity of currents from the V378A mutant indicates that the loss of voltage-sensitive gating seen in all other reported disease mutants is not required for an epileptic encephalopathy phenotype. In addition to electrophysiological differences, we suggest that defects in expression and subcellular localization of Kv2.1 V378A channels could contribute to the pathophysiology of this KCNB1 variant. PMID- 26503722 TI - Family resemblances: A common fold for some dimeric ion-coupled secondary transporters. AB - Membrane transporter proteins catalyze the passage of a broad range of solutes across cell membranes, allowing the uptake and efflux of crucial compounds. Because of the difficulty of expressing, purifying, and crystallizing integral membrane proteins, relatively few transporter structures have been elucidated to date. Although every membrane transporter has unique characteristics, structural and mechanistic similarities between evolutionarily diverse transporters have been identified. Here, we compare two recently reported structures of membrane proteins that act as antimicrobial efflux pumps, namely MtrF from Neisseria gonorrhoeae and YdaH from Alcanivorax borkumensis, both with each other and with the previously published structure of a sodium-dependent dicarboxylate transporter from Vibrio cholerae, VcINDY. MtrF and YdaH belong to the p aminobenzoyl-glutamate transporter (AbgT) family and have been reported as having architectures distinct from those of all other families of transporters. However, our comparative analysis reveals a similar structural arrangement in all three proteins, with highly conserved secondary structure elements. Despite their differences in biological function, the overall "design principle" of MtrF and YdaH appears to be almost identical to that of VcINDY, with a dimeric quaternary structure, helical hairpins, and clear boundaries between the transport and scaffold domains. This observation demonstrates once more that the same secondary transporter architecture can be exploited for multiple distinct transport modes, including cotransport and antiport. Based on our comparisons, we detected conserved motifs in the substrate-binding region and predict specific residues likely to be involved in cation or substrate binding. These findings should prove useful for the future characterization of the transport mechanisms of these families of secondary active transporters. PMID- 26503723 TI - Has the quality of reporting of randomized controlled trials in thoracic surgery improved? AB - OBJECTIVES: To evaluate the quality of reporting of randomized controlled trials (RCTs) in the thoracic surgery literature according to Consolidated Standard for Reporting of Trials (CONSORT) and to determine predictors of quality. METHODS: All RCTs published in four principal journals between 1998 and 2013 were identified in PubMed. Two independent reviewers assessed each trial using the CONSORT checklist (1996) with discrepancies resolved by a third reviewer. Mean checklist scores were compared between trials published from 1998 to 2005 and 2006 to 2013. The kappa statistic for inter-rater agreement was calculated. Stepwise multivariable linear regression was then performed to identify independent predictors of quality. RESULTS: After 2 rounds of review, 203 of the 2838 identified articles met inclusion criteria. The overall kappa coefficient was 0.95 indicating very good agreement between reviewers. The mean CONSORT score was significantly higher in 2006-13 [mean 10.8; 95% confidence interval (CI): 10.3-11.2] than in 1998-2005 (mean 9.3; 95% CI: 8.7-9.6). On multivariable analysis, there was strong evidence of an increased mean CONSORT score in studies comparing non-surgical interventions, multicentre trials, publications after 2006, studies with increased number of authors and studies funded by industries. CONCLUSIONS: Our study suggests that the quality of reporting in the thoracic surgery literature is improving with time and is predicted by factors including number of authors, multicentre trials, type of comparison, time period of publication and industry sponsorship. Ongoing efforts should be made to improve the quality of reporting in thoracic surgery. PMID- 26503724 TI - Cracking the code of arch dissection. PMID- 26503725 TI - Decellularized aortic allografts versus pulmonary autografts for aortic valve replacement in the growing sheep model: haemodynamic and morphological results at 20 months after implantation. AB - OBJECTIVES: Pulmonary autografts (PAs) represent the substitute of choice for aortic valve (AV) replacement, especially in children and young adults. Similarly, decellularized aortic valve allografts (DAVAs) have shown excellent mid-term function when implanted in the systemic circulation. The aim of this study was to compare the performance of DAVAs with that of pulmonary autografts after a Ross procedure in the growing sheep model. METHODS: AV root replacement was performed in female lambs (25 +/- 3.4 kg) using either DAVAs (n = 5) or pulmonary autografts (n = 5) as in the Ross procedure. Sheep undergoing the Ross procedure received a decellularized pulmonary allograft in place of pulmonary valve. Haemodynamics was investigated by echocardiography and magnetic resonance imaging. The roots were explanted at 20 months and examined by histology to determine the degree of repopulation and quality of the extracellular matrix, and by immunohistochemistry to characterize the repopulating cells. RESULTS: The mean valve diameter increased from 16 to 21 and from 16 to 25 mm in DAVAs and PAs, respectively. At explantation, one PA and one DAVA exhibited moderate insufficiency. Significant differences in transvalvular gradient were only found in PAs between implantation and prior to explantation. The cusps of all implants were soft, pliable and showed no major signs of degeneration. In the decellularized allografts, cell repopulation occurred at the wall and cusp level with a well-maintained, three-layered cusp structure. Ventricular cusp surface of decellularized allografts was more strongly repopulated than the arterial surface. Cusps were covered with cells positive for endothelial markers and were also repopulated by interstitial cells. CONCLUSIONS: DAVAs and PAs provide adequate haemodynamics after AV replacement in the growing sheep. While decellularized grafts are repopulated by endothelial and interstitial cells, autografts maintain in general their native cell distribution. Maintenance of valvular competence during enlargement of the valve ring is, in our opinion, representative of the capacity for physiological growth in both graft types. PMID- 26503726 TI - Spontaneous fracture and embolization of an inferior vena cava cannula: is it possible? AB - We present a case of spontaneous fracture and embolization of the distal part of a cannula into the left inferior lobar artery. The embolized fragment was captured with an angioplasty balloon and extracted through the right atrium appendage. No adverse event related to the embolization was observed and the patient was discharged with no sequelae. PMID- 26503727 TI - Postaortic left brachiocephalic vein in an adult patient with right upper lung cancer?. PMID- 26503728 TI - Late leakage from four-branch prosthetic graft after total aortic arch repair. AB - We present two cases with late graft leakage of unknown aetiology after open total aortic arch repair (TAR). Case 1: a 73-year-old woman underwent TAR for arch aneurysm with 24-mm four-branch graft. She had a previous history of pacemaker implantation for sick sinus syndrome and warfarin therapy for atrial fibrillation. Follow-up computed tomography (CT) revealed increased low-density area around the graft 4 years after surgery and blood leakage was shown in delayed-phase CT. Thoracic endovascular aortic repair (TEVAR) was performed to cover the haematic leakage, and shrinkage of the lesion was achieved 1 month after TEVAR. Case 2: a 72-year-old man with diabetes mellitus, hypertension and hyperlipidaemia was admitted to our institute for treatment of aortic arch aneurysm. TAR was successfully performed; however, leakage from the prosthetic graft was noticed by expert radiologists in follow-up delayed-phase CT scan 6 years after surgery. The leakage was resolved 1 month after TEVAR. Although the cause of late leakage was not determined, the slowly expanding haematoma proved to be treatable by additional TEVAR. PMID- 26503729 TI - Clinical impact of c-MET expression and mutational status in patients with colorectal cancer lung metastases. AB - OBJECTIVES: The c-MET tyrosine kinase is known to play a key role in tumour promotion in a variety of cancers. The prognostic significance of c-MET pathway alterations has previously been described in primary colorectal cancer (CRC). However, data on the expression and genetic mutational status of c-MET in CRC pulmonary metastases (PM) are lacking. We aimed to assess the clinical implications of alterations in the c-MET pathway in patients undergoing pulmonary metastasectomy. METHODS: From April 2009 to November 2013, all patients with complete CRC lung metastasectomy were included in this study and prospectively followed up. Tissue samples of 51 PM and 33 paired primary CRCs were stained immunohistochemically for c-MET and phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Genetic alterations of MET were detected using an exome panel on a next generation sequencing (NGS) platform. Serum hepatocyte growth factor (HGF) levels were measured in a patient subset (n = 10) before and after metastasectomy. RESULTS: c-MET expression was significantly higher at the invasive front of metastases compared with central tumour areas (P = 0.020) and was associated with nuclear pSTAT3 expression (P = 0.042). pSTAT3 but not c-MET overexpression in PM was associated with time to tumour recurrence after metastasectomy (P = 0.036). Expression levels of neither c-MET nor pSTAT3 had an impact on time to lung-specific recurrence. However, patients with c-MET or pSTAT3 overexpression in PM had a significantly worse overall survival after metastasectomy (P = 0.023 and 0.008, respectively). Mutations in the MET gene were identified in 20 patients of our cohort by NGS, which failed to be of prognostic relevance. Serum HGF did not significantly differ between patients with PM and healthy controls. CONCLUSIONS: To the best of our knowledge, this is the first structured evaluation of the c-MET axis in the context of pulmonary metastasectomy for CRC. Our results suggest that overexpression of c-MET/pSTAT3 is associated with an impaired prognosis following complete resection. Moreover, this work suggests that the value of c-MET tyrosine kinase inhibitors in the treatment of patients with CRC lung metastases should be assessed in clinical trials. PMID- 26503730 TI - Surgical intervention for bilateral coronary artery fistulas to the pulmonary artery. AB - A 60-year old female was referred to our institution for surgical intervention to treat bilateral coronary artery fistulas to the pulmonary artery (PA). Multidetector computed tomography (MDCT) imaging showed two tortuous vessels with multiple aneurysmal dilatations originating from the right coronary artery and left anterior descending artery. Furthermore, oximetry revealed an oxygen step-up of 10% between the PA and the right ventricle, consistent with an estimated left to-right shunt of 47.1%, indicating that the patient was a candidate for surgery. Under heart arrest, the main PA was longitudinally opened and a single efferent hole sized 10 mm in diameter located in the anterior sinus of the pulmonary trunk was closed. Thereafter, the two afferent vessels were individually ligated at their proximal origins. Postoperative MDCT demonstrated no evidence of abnormal vessel communication between the coronary arteries and the PA, as well as relatively dilated native coronary arteries when compared with the preoperative state. At the 6-month follow-up examination, the patient was asymptomatic and showed no complications. PMID- 26503731 TI - Intraoperative pulmonary neoplasm identification using near-infrared fluorescence imaging. AB - OBJECTIVES: Near-infrared (NIR) fluorescence imaging provides surgeons with real time visual information during surgery. The purpose of this pilot trial was to evaluate the safety and feasibility of the intraoperative detection of pulmonary neoplasms with NIR fluorescence imaging after low-dose indocyanine green (ICG) injection. METHODS: Eleven consecutive patients who were scheduled to undergo resection of pulmonary neoplasms were enrolled in this study. ICG (1 mg/kg) was administered intravenously 1 day before surgery, and the retrieved surgical specimens were examined for fluorescence signalling by using NIR fluorescence imaging system on a back table in the operating room. We analysed the fluorescence intensity, pathology, size, depth from the pleural surface and metabolic activity of the pulmonary neoplasms. RESULTS: Fluorescence signalling was detected in all specimens except in one from a patient with primary lung cancer. Two false-positive cases that presented no residual tumour with obstructive pneumonitis, after concurrent chemoradiation therapy for primary lung cancer before the operation, were identified, and their fluorescence intensity was 8.6 +/- 0.4. The mean fluorescence intensity of the eight pulmonary tumours was 3.4 +/- 1.9, and these tumours did not differ in pathology, size, depth from the pleural surface or metabolic activity. CONCLUSIONS: NIR fluorescence imaging could safely identify pulmonary neoplasms after the systemic injection of ICG. In addition, low-dose ICG is sufficient for NIR fluorescence imaging of pulmonary neoplasms. However, because the passive accumulation of ICG could not be used to discriminate tumours with inflammation, tumour-targeted fluorescence should be developed to solve this problem in the future. PMID- 26503732 TI - Self-Reported Hearing Loss Predicts 5-Year Decline in Higher-Level Functional Capacity in High-Functioning Elderly Adults: The Fujiwara-Kyo Study. AB - OBJECTIVES: To clarify the relationship between self-reported hearing loss (HL) and 5-year decline in higher-level functional capacity in high-functioning elderly adults. DESIGN: Population-based, prospective cohort study. SETTING: The Fujiwara-Kyo Study, Nara, Japan. PARTICIPANTS: Community-dwelling individuals aged 65 and older with a perfect baseline and valid follow-up instrumental activity of daily living (IADL) (n = 3,267), intellectual activity (IA) (n = 2,925), and social role (SR) (n = 2,698) scores. MEASUREMENTS: Self-reported HL was evaluated using a single question: "Do you feel you have hearing loss?" IADLs, IA, and SR were measured using the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) subscales. Geriatric syndromes (depressive symptoms, cognitive impairment, sleep disturbance, falls, urinary incontinence, visual impairment) were self-reported at baseline. Blood tests were performed to measure cardiovascular risk factors. RESULTS: During 5-year follow up, new declines developed for 213 participants in IADLs, 272 in IA, and 327 in SR. After adjustment for all covariates, including geriatric syndromes, using multiple logistic regression analysis, self-reported HL at baseline was associated with a decline in IA (odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.04-1.86) and SR (OR = 1.34, 95% CI = 1.02-1.76) but not IADLs (OR = 1.07, 95% CI = 0.76-1.48). CONCLUSION: Self-reported HL was found to be a significant predictor of decline in IA and SR. Preventive intervention against age-related HL may contribute to maintaining high-level functional capacity in independent elderly adults. PMID- 26503733 TI - The significance of regional hemoglobin oxygen saturation values and limb-to-arm ratios of near-infrared spectroscopy to detect critical limb ischemia. AB - This study examines the application of near-infrared spectroscopy to noninvasively detect critical limb ischemia using regional hemoglobin oxygen saturation in percentage values and regional hemoglobin oxygen saturation limb-to arm ratios. The regional hemoglobin oxygen saturation values and regional hemoglobin oxygen saturation limb-to-arm ratios were calculated in 61 patients with critical limb ischemia (group A). Measurements were performed in rest at four fixed spots at the most affected lower limb and at a reference spot at both upper arms. Similar measurements were performed in the left lower limb of 30 age matched control patients without peripheral arterial disease (group B). The regional hemoglobin oxygen saturation values and regional hemoglobin oxygen saturation limb-to-arm ratios were significantly different at all measured spots between the groups (all p < 0.001), except for the regional hemoglobin oxygen saturation limb-to-arm ratios of the distal vastus lateralis (p = 0.056). However, a broad overlap of individual regional hemoglobin oxygen saturation values and regional hemoglobin oxygen saturation limb-to-arm ratios was found in both groups, which resulted in poor discriminative predictive value of single measurements. Single measurements of regional hemoglobin oxygen saturation values and regional hemoglobin oxygen saturation limb-to-arm ratios at all measured spots have poor discriminative predictive value in detection of critical limb ischemia. Measurement of regional hemoglobin oxygen saturation values and regional hemoglobin oxygen saturation limb-to-arm ratios at any of the measurement spots has no added value in detecting lower limb ischemia in individuals compared with current diagnostic modalities. PMID- 26503734 TI - Knockdown of Cul4A increases chemosensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells. AB - Cullin 4A (Cul4A) promotes oncogenesis through overexpression and then ubiquitination-mediated proteolysis of tumor suppressors in various types of cancers. Transforming growth factor beta-induced (TGFBI) has been implicated as a tumor suppressor, which enhances gemcitabine chemosensitivity in lung cancer cells. The present study aimed to investigate the association of TGFBI and Cul4A and the mechanism by which Cul4A regulates TGFBI. In addition, we also evaluated the therapeutic value of Cul4A RNAi using adenoviral transfection of Cul4A RNAi in nude mouse xenograft models. We observed that knockdown of Cul4A was associated with increased sensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells. Cul4A regulated TGFBI through direct interaction and then ubiquitin-mediated protein degradation. In the nude mouse xenograft models, adenoviral transfection of Cul4A RNAi in combination with gemcitabine chemotherapy inhibited lung cancer tumor growth. As the result, combination of Cul4A RNAi with chemotherapy may provide a new approach to lung cancer treatment. PMID- 26503736 TI - Lysozyme in breast milk is a selection factor for bifidobacterial colonisation in the infant intestine. AB - The objective of this work was to study the residential characteristics of bifidobacteria, which can be classified as either human-residential bifidobacteria (HRB) or non-HRB. We investigated the growth of different strains of HRB and non-HRB in human breast milk with the aim of understanding the mechanisms involved in the unique habitation of each taxon. The growth of 37 strains of different bifidobacterial species or subspecies in breast milk was investigated by incubating each under anaerobic conditions at 37 degrees C. The tolerance of each strain to either egg white or human lysozyme was compared. Among the infant-type HRB strains, all strains of Bifidobacterium longum subsp. infantis and Bifidobacterium breve grew well in breast milk, but the growth characteristics of B. longum subsp. longum and B. bifidum were strain-dependent. In contrast, the tested strains of adult-type HRB and non-HRB generally failed to grow and died after incubation in breast milk. Most infant-type HRB strains were tolerant to high concentrations of lysozyme, while adult-type HRB strains possessed intermediate tolerance to lysozyme, and non-HRB strains were susceptible to lysozymes of egg white or human origin. These data suggest that breast milk lysozyme content plays a central role in the exclusion of non-HRB, while other factors, together with lysozyme content, are involved in the growth inhibition of adult-type strains in human milk. Our results suggest that infant type HRB strains would be suitable candidates for use as infant probiotics. PMID- 26503735 TI - Do Socioeconomic Risk Factors for Cigarette Smoking Extend to Smokeless Tobacco Use? AB - INTRODUCTION: Individuals with lower socioeconomic status (SES) are at increased risk for cigarette smoking. Less research has been conducted characterizing the relationship between SES and risk of using of other tobacco products. The present study examined SES as a risk factor for smokeless tobacco (ST) use in a US nationally representative sample, utilizing data from the 2012 National Survey on Drug Use and Health. METHODS: Odds were generated for current cigarette smoking and ST use among adults (>=18 years) based on SES markers (educational attainment, income, blue-collar employment, and unemployment) after controlling for the influence of demographics and other substance dependence. RESULTS: Odds of current cigarette smoking increased as a graded, inverse function of educational attainment as well as lower income and being unemployed. Odds of current ST use also increased as a function of lower educational attainment, although not in the linear manner seen with cigarette smoking. Odds of ST use but not cigarette smoking also increased with blue-collar employment. In contrast to patterns seen with cigarette smoking, ST use did not change in relation to income or unemployment. CONCLUSIONS: Markers of SES are significantly associated with odds of cigarette smoking and ST use, but which indicators are predictive and the shape of their relationship to use differs across the two tobacco products. PMID- 26503737 TI - Calcium phosphate supplementation increases faecal Lactobacillus spp. in a randomised trial of young adults. AB - The aim of the studies was to determine the effects of calcium carbonate and calcium phosphate supplementation on faecal Lactobacillus spp., with and without a probiotic supplement, in healthy adults. Study 1 comprised of a randomised, double-blind, crossover design; participants (n=15) received 2 capsules/d of 250 mg elemental calcium as calcium carbonate (Ca1) and calcium phosphate (Ca2) each for 2-week periods, with 2-week baseline and washout periods. Study 2 was a randomised, double-blind, crossover design; participants (n=17) received 2 capsules/d of Lactobacillus helveticus R0052 and Lactobacillus rhamnosus R0011 (probiotic) alone, the probiotic with 2 capsules/d of Ca1, and probiotic with 2 capsules/d of Ca2 each for 2-week periods with 2-week baseline and washout periods. In both studies, stools were collected during the baseline, intervention and washout periods for Lactobacillus spp. quantification and qPCR analyses. Participants completed daily questionnaires of stool frequency and compliance. In Study 1, neither calcium supplement influenced viable counts of resident Lactobacillus spp., genome equivalents of lactic acid bacteria or stool frequency. In Study 2, faecal Lactobacillus spp. counts were significantly enhanced from baseline when the probiotic was administered with Ca2 (4.83+/-0.30, 5.79+/-0.31) (P=0.02), but not with Ca1 (4.98+/-0.31) or with the probiotic alone (5.36+/-0.31, 5.55+/-0.29) (not significant). Detection of L. helveticus R0052 and L. rhamnosus R0011 was significantly increased with all treatments, but did not differ among treatments. There were no changes in weekly stool frequency. Calcium phosphate co-administration may increase gastrointestinal survival of orally-administered Lactobacillus spp. PMID- 26503738 TI - Kefir-isolated bacteria and yeasts inhibit Shigella flexneri invasion and modulate pro-inflammatory response on intestinal epithelial cells. AB - The aim of this work was to evaluate the ability of a kefir-isolated microbial mixture containing three bacterial and two yeast strains (MM) to protect intestinal epithelial cells against Shigella flexneri invasion, as well as to analyse the effect on pro-inflammatory response elicited by this pathogen. A significant decrease in S. flexneri strain 72 invasion was observed on both HT-29 and Caco-2 cells pre-incubated with MM. Pre-incubation with the individual strains Saccharomyces cerevisiae CIDCA 8112 or Lactococcus lactis subsp. lactis CIDCA 8221 also reduced the internalisation of S. flexneri into HT-29 cells although in a lesser extent than MM. Interestingly, Lactobacillus plantarum CIDCA 83114 exerted a protective effect on the invasion of Caco-2 and HT-29 cells by S. flexneri. Regarding the pro-inflammatory response on HT-29 cells, S. flexneri infection induced a significant activation of the expression of interleukin 8 (IL 8), chemokine (C-C motif) ligand 20 (CCL20) and tumour necrosis factor alpha (TNF alpha) encoding genes (P<0.05), whereas incubation of cells with MM did not induce the expression of any of the mediators assessed. Interestingly, pre incubation of HT-29 monolayer with MM produced an inhibition of S. flexneri induced IL-8, CCL20 and TNF-alpha mRNA expression. In order to gain insight on the effect of MM (or the individual strains) on this pro-inflammatory response, a series of experiments using a HT-29-NF-kappaB-hrGFP reporter system were performed. Pre-incubation of HT-29-NF-kappaB-hrGFP cells with MM significantly dampened Shigella-induced activation. Our results showed that the contribution of yeast strain Kluyveromyces marxianus CIDCA 8154 seems to be crucial in the observed effect. In conclusion, results presented in this study demonstrate that pre-treatment with a microbial mixture containing bacteria and yeasts isolated from kefir, resulted in inhibition of S. flexneri internalisation into human intestinal epithelial cells, along with the inhibition of the signalling via NF kappaB that in turn led to the attenuation of the inflammatory response. PMID- 26503739 TI - Spin-orbit ZORA and four-component Dirac-Coulomb estimation of relativistic corrections to isotropic nuclear shieldings and chemical shifts of noble gas dimers. AB - Hartree-Fock and density functional theory with the hybrid B3LYP and general gradient KT2 exchange-correlation functionals were used for nonrelativistic and relativistic nuclear magnetic shielding calculations of helium, neon, argon, krypton, and xenon dimers and free atoms. Relativistic corrections were calculated with the scalar and spin-orbit zeroth-order regular approximation Hamiltonian in combination with the large Slater-type basis set QZ4P as well as with the four-component Dirac-Coulomb Hamiltonian using Dyall's acv4z basis sets. The relativistic corrections to the nuclear magnetic shieldings and chemical shifts are combined with nonrelativistic coupled cluster singles and doubles with noniterative triple excitations [CCSD(T)] calculations using the very large polarization-consistent basis sets aug-pcSseg-4 for He, Ne and Ar, aug-pcSseg-3 for Kr, and the AQZP basis set for Xe. For the dimers also, zero-point vibrational (ZPV) corrections are obtained at the CCSD(T) level with the same basis sets were added. Best estimates of the dimer chemical shifts are generated from these nuclear magnetic shieldings and the relative importance of electron correlation, ZPV, and relativistic corrections for the shieldings and chemical shifts is analyzed. PMID- 26503740 TI - Photonic Sintering of Copper through the Controlled Reduction of Printed CuO Nanocrystals. AB - The ability to control chemical reactions using ultrafast light exposure has the potential to dramatically advance materials and their processing toward device integration. In this study, we show how intense pulsed light (IPL) can be used to trigger and modulate the chemical transformations of printed copper oxide features into metallic copper. By varying the energy of the IPL, CuO films deposited from nanocrystal inks can be reduced to metallic Cu via a Cu2O intermediate using single light flashes of 2 ms duration. Moreover, the morphological transformation from isolated Cu nanoparticles to fully sintered Cu films can also be controlled by selecting the appropriate light intensity. The control over such transformations enables for the fabrication of sintered Cu electrodes that show excellent electrical and mechanical properties, good environmental stability, and applications in a variety of flexible devices. PMID- 26503741 TI - Local distortion energy and coarse-grained elasticity of the twist-bend nematic phase. AB - The recently discovered twist-bend nematic phase of achiral bent-shaped molecules, NTB, has a doubly degenerate ground-state with a periodically modulated heliconical structure and unusual distortion elasticity, the theoretical description of which is still debated. We show that the NTB phase has the same macroscopic symmetry as another periodic mesophase, the chiral smectic A, SmA*. Based on this NTB/SmA* analogy, we develop a coarse-grained elastic model for the NTB phase. Adopting one of the existing microscopic NTB elastic models, we calculate the coarse-grained elastic constants, coherence and penetration lengths in terms of a few Frank-like nematic elastic coefficients that can be measured in macroscopic experiments. The same coarse-grained approach, applied to different local elastic models, may provide an efficient experimental test of their validity. We show that the anisotropy of the NTB coarse-grained elasticity is opposite to that of the SmA*, leading probably to different configurations of some of the defects of the "layered" NTB structure. Moreover, we argue that the intrinsic chiral frustration of the NTB phase may be resolved by penetration of the twist field into the bulk through a network of screw dislocations of the NTB pseudo-layers, resulting in a twist-bend analogue of the twist grain boundary phase TGBA. PMID- 26503742 TI - Antidiabetic and Antihyperlipidemic Properties of a Triterpenoid Compound, Dehydroeburicoic Acid, from Antrodia camphorata in Vitro and in Streptozotocin Induced Mice. AB - The aim of this study was to examine the effects of dehydroeburicoic acid (TT) on type 1 diabetes mellitus and dyslipidemia in streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice were randomly divided into six groups and given orally by gavage TT (at three dosages), metformin (Metf), fenfibrate (Feno), or vehicle for 4 weeks. STZ-induced diabetic mice showed elevations in blood glucose levels (P < 0.001). TT treatment markedly decreased blood glucose levels by 42.6-46.5%. Moreover, STZ-induced diabetic mice displayed an increase in circulating triglyceride (TG) and total cholesterol (TC) levels (P < 0.001 and P < 0.01, respectively) but a decrease in blood insulin and adiponectin levels (P < 0.01 and P < 0.05, respectively). These substances are also reversed by TT treatment, indicating TT ameliorated diabetes and dyslipidemia. Membrane skeletal muscular expression levels of glucose transporter 4 (GLUT4) and expression levels of AMPK phosphorylation (phospho-AMPK) in both liver and skeletal muscle were reduced in STZ-induced diabetic mice, which normalized upon TT treatment and correction of hyperglycemia accompanied with a decrease in mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6 Pase), which was related to the inhibition of hepatic glucose production and attenuating diabetic state. In addition, TT also showed hypolipidemic effect by increasing hepatic expression levels of peroxisome proliferator-activated receptor alpha (PPARalpha) and mRNA levels of carnitine palmitoyl transferase Ia (CPT-1a) but decreasing expression levels of fatty acid synthase (FAS), which further contributed to a decrease in circulating TG levels. TT-treated mice displayed decreased SREBP2 mRNA levels and reduced blood TC levels. These findings strongly support that TT prevents diabetic and dyslipidemic states in STZ-induced diabetic mice evidenced by regulation of GLUT4, PPARalpha, FAS, and phosphorylation of AMPK. PMID- 26503744 TI - Complementarity among plant growth promoting traits in rhizospheric bacterial communities promotes plant growth. AB - An assessment of roles of rhizospheric microbial diversity in plant growth is helpful in understanding plant-microbe interactions. Using random combinations of rhizospheric bacterial species at different richness levels, we analysed the contribution of species richness, compositions, interactions and identity on soil microbial respiration and plant biomass. We showed that bacterial inoculation in plant rhizosphere enhanced microbial respiration and plant biomass with complementary relationships among bacterial species. Plant growth was found to increase linearly with inoculation of rhizospheric bacterial communities with increasing levels of species or plant growth promoting trait diversity. However, inoculation of diverse bacterial communities having single plant growth promoting trait, i.e., nitrogen fixation could not enhance plant growth over inoculation of single bacteria. Our results indicate that bacterial diversity in rhizosphere affect ecosystem functioning through complementary relationship among plant growth promoting traits and may play significant roles in delivering microbial services to plants. PMID- 26503743 TI - Generation of integration-free induced hepatocyte-like cells from mouse fibroblasts. AB - The ability to generate integration-free induced hepatocyte-like cells (iHeps) from somatic fibroblasts has the potential to advance their clinical application. Here, we have generated integration-free, functional, and expandable iHeps from mouse somatic fibroblasts. To elicit this direct conversion, we took advantage of an oriP/EBNA1-based episomal system to deliver a set of transcription factors, Gata4, Hnf1a, and Foxa3, to the fibroblasts. The established iHeps exhibit similar morphology, marker expression, and functional properties to primary hepatocytes. Furthermore, integration-free iHeps prolong the survival of fumarylacetoacetate-hydrolase-deficient (Fah(-/-)) mice after cell transplantation. Our study provides a novel concept for generating functional and expandable iHeps using a non-viral, non-integrating, plasmid-based system that could facilitate their pharmaceutical and biomedical application. PMID- 26503745 TI - Interaction of Methanol Spray and Water-Deficit Stress on Photosynthesis and Biochemical Characteristics of Phaseolus vulgaris L. cv. Sadry. AB - This study was a factorial experiment with a completely randomized design and three replications. The four levels of methanol spraying were used. Spraying was carried out three times during the growing season at 10-day intervals beginning at 4 weeks after sowing. The spraying of solution continued until saturation of droplets on the leaves was achieved. The levels of water-deficit stress applied were nonstress, moderate water stress and severe water stress. The results showed that there was a significant difference (P <= 0.05) between the methanol and water-deficit stress treatments for chlorophyll (Chl) a and Chl b, carotenoid, total chlorophyll, net photosynthesis (PN ), intercellular CO2 (Ci ), maximal quantum yield of photosystem II photochemistry (Fv /Fm ), leaf moisture, water use efficiency and relative water content. The application of foliar methanol at all levels of water-deficit stress significantly decreased the catalase activity of the roots. Under all levels of water-deficit stress, the 30% (v/v) methanol treatment significantly decreased peroxidase activity in the roots over that for the control. The results suggest that foliar application of methanol can decrease the negative effects of water-deficit stress on Phaseolus vulgaris L. cv. Sadry. PMID- 26503747 TI - The dendritic cell high-affinity IgE receptor is overexpressed in both asthma and severe COPD. AB - BACKGROUND: The reduction of asthma exacerbations following omalizumab treatment has been related to the suppression of the high-affinity IgE receptor (FcepsilonRI) on plasmacytoid dendritic cells (DCs). However, the FcepsilonRI expression on DCs in chronic obstructive pulmonary disease (COPD) is unknown. OBJECTIVE: To compare FcepsilonRI expression on DCs in COPD with patients with allergic asthma and healthy controls, and to relate the findings to clinical parameters, blood eosinophil concentrations and serum immunoglobin E (IgE) concentrations. METHODS: Using four-colour flow cytometry, FcepsilonRI expression on blood myeloid DCs and plasmacytoid DCs was analyzed in 64 patients with COPD, 20 patients with allergic asthma, 41 asymptomatic never smokers and 21 asymptomatic current smokers. RESULTS: As compared with never smokers, current smokers displayed an increased expression of the FcepsilonRI on myeloid and plasmacytoid DCs. In patients with COPD, the expression of the FcepsilonRI on plasmacytoid DCs, but not myeloid DCs, increased from spirometric GOLD stage 2 to GOLD stage 4, and was correlated with several lung function parameters. Patients with severe COPD and patients with allergic asthma displayed a similar FcepsilonRI overexpression on plasmacytoid DCs. In all groups, there was a positive correlation between total IgE serum concentrations and the FcepsilonRI expression on plasmacytoid DCs. CONCLUSIONS AND CLINICAL RELEVANCE: Severe COPD and allergic asthma are characterized by a similar overexpression of the high affinity IgE receptor on plasmacytoid DCs. In view of the effect of anti-IgE on exacerbations in asthma, trials investigating the effect of anti-IgE on exacerbations in severe COPD appear to be warranted. PMID- 26503746 TI - Variable primary coordination environments of Cd(II) binding to three helix bundles provide a pathway for rapid metal exchange. AB - Members of the ArsR/SmtB family of transcriptional repressors, such as CadC, regulate the intracellular levels of heavy metals like Cd(II), Hg(II), and Pb(II). These metal sensing proteins bind their target metals with high specificity and affinity, however, a lack of structural information about these proteins makes defining the coordination sphere of the target metal difficult. Lingering questions as to the identity of Cd(II) coordination in CadC are addressed via protein design techniques. Two designed peptides with tetrathiolate metal binding sites were prepared and characterized, revealing fast exchange between CdS3O and CdS4 coordination spheres. Correlation of (111m)Cd PAC spectroscopy and (113)Cd NMR spectroscopy suggests that Cd(II) coordinated to CadC is in fast exchange between CdS3O and CdS4 forms, which may provide a mechanism for rapid sensing of heavy metal contaminants by this regulatory protein. PMID- 26503748 TI - Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low-density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%-65%), apolipoprotein B (48%-59%), and lipoprotein(a) (27%-50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk. PMID- 26503749 TI - Global and regional patterns in cardiovascular mortality from 1990 to 2013. AB - There is a global commitment to reduce premature cardiovascular diseases (CVDs) 25% by 2025. CVD mortality rates have declined dramatically over the past 2 decades, yet the number of life years lost to premature CVD deaths is increasing in low- and middle-income regions. Ischemic heart disease and stroke remain the leading causes of premature death in the world; however, there is wide regional variation in these patterns. Some regions, led by Central Asia, face particularly high rates of premature death from ischemic heart disease. Sub-Saharan Africa and Asia suffer disproportionately from death from stroke. The purpose of the present report is to (1) describe global trends and regional variation in premature mortality attributable to CVD, (2) review past and current approaches to the measurement of these trends, and (3) describe the limitations of existing models of epidemiological transitions for explaining the observed distribution and trends of CVD mortality. We describe extensive variation both between and within regions even while CVD remains a dominant cause of death. Policies and health interventions will need to be tailored and scaled for a broad range of local conditions to achieve global goals for the improvement of cardiovascular health. PMID- 26503750 TI - ECG response: October 27, 2015. PMID- 26503751 TI - Saphenous vein graft aneurysm causing pulmonary artery compression with exercise. PMID- 26503752 TI - Complete heart block caused by diffuse pseudotumoral cardiac involvement in granulomatosis with polyangiitis. PMID- 26503753 TI - Letter by Al-Kindi and Oliveira regarding article "cardiac sarcoidosis: epidemiology, characteristics, and outcome over 25 years in a nationwide study". PMID- 26503754 TI - Letter by Kruszelnicka et al regarding article, "evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with anti-inflammatory drugs". PMID- 26503756 TI - Correction. PMID- 26503755 TI - Reply to letter regarding article, "evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with anti-inflammatory drugs". PMID- 26503757 TI - Reversible assembly of pH responsive branched copolymer-stabilised emulsion via electrostatic forces. AB - The judicious compositional and structural design of a branched co-polymeric surfactant allows for the production of highly stable oil in water emulsion droplets with reversible electrostatic aggregation behaviour. PMID- 26503758 TI - In vivo dosimetric impact of breast tissue expanders on post-mastectomy radiotherapy. AB - INTRODUCTION: Temporary tissue expanders with metallic ports for gradual saline injection are increasingly employed to facilitate breast reconstruction after post-mastectomy radiotherapy (PMRT). Treatment beams therefore pass through a high-density rare-earth magnet. Measurements ex vivo suggest attenuation of dose to the skin and chest wall at clinical risk of relapse. The purpose of the study was to quantify the resulting dose reduction in vivo, compared with treatment planning system (TPS). METHODS: Sixteen patients receiving PMRT had in vivo dosimetry prospectively performed with ethics board approval. Port was located within the expanded chest wall using the planning CT scan. Strips of radiochromic film were laid on the skin surface underneath the bolus. To aid interpretation, ex vivo measurements were also performed, including comparison with TPS predictions. RESULTS: An average 7% reduction in dose to skin surface was measured in 15 of 16 patients. This was reproducibly located in the 'shadow' of the magnet, corresponding to each of the paths of the medial and lateral tangents. The average area was 1.07 cm(2) (range 0.39 cm(2) to 2.36 cm(2)). Ex vivo measurements confirmed attenuation of the beam in the shadow of the port. The surface area of the 'cold-spot' varied with angle of the beam relative to the metallic port. Dose attenuation in vivo differed from that predicted by the TPS. CONCLUSION: Dose is attenuated in the 'shadow' of the tissue expander port in patients receiving PMRT. This is likely to be clinically insignificant for most, but centres should undertake appropriate measurements before utilising TPS predictions. PMID- 26503759 TI - Does Gender Moderate the Relationship between Callous-Unemotional Traits and Physical Aggression? AB - The study investigates the interaction effect of callous-unemotional (CU) traits and gender on physical aggression among Nigerian adolescents. Two hundred and ninety five (295) senior secondary school students who were between 14-16 years of age participated in the study. These participants included boys (152) and girls (143). They were selected from a public senior secondary school in Anambra a South Eastern State of Nigeria and all the participants were of Igbo ethnic group. The raw data for Callous-unemotional traits and Physical Aggression were collected using Inventory of Callous-Unemotional Traits (ICU) by Frick (2004) and Aggression Scale by Orpinas and Frankowski (2001) respectively. The data were analyzed using Pearson correlation, and conditional process analysis (model number 1; Hayes, 2013). The results showed that gender correlated significantly with uncaring and physical aggression but did not correlate significantly with CU and callousness. The results further showed that gender, CU traits, uncaring and callousness subscales significantly predicted physical aggression. Gender also moderated the effect of CU traits and uncaring on physical aggression, but did not moderate the effect of callousness on physical aggression. The discussion focused on the ways of helping individuals with high level of CU traits to reduce aggression, also the limitations of the study, suggestions for further studies and the implications of the finding were highlighted. PMID- 26503760 TI - Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine. AB - A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long lasting conditioned responses to cocaine. PMID- 26503761 TI - Generation of functional human serotonergic neurons from fibroblasts. AB - The brain's serotonergic system centrally regulates several physiological processes and its dysfunction has been implicated in the pathophysiology of several neuropsychiatric disorders. While in the past our understanding of serotonergic neurotransmission has come mainly from mouse models, the development of pluripotent stem cell and induced fibroblast-to-neuron (iN) transdifferentiation technologies has revolutionized our ability to generate human neurons in vitro. Utilizing these techniques and a novel lentiviral reporter for serotonergic neurons, we identified and overexpressed key transcription factors to successfully generate human serotonergic neurons. We found that overexpressing the transcription factors NKX2.2, FEV, GATA2 and LMX1B in combination with ASCL1 and NGN2 directly and efficiently generated serotonergic neurons from human fibroblasts. Induced serotonergic neurons (iSNs) showed increased expression of specific serotonergic genes that are known to be expressed in raphe nuclei. iSNs displayed spontaneous action potentials, released serotonin in vitro and functionally responded to selective serotonin reuptake inhibitors (SSRIs). Here, we demonstrate the efficient generation of functional human serotonergic neurons from human fibroblasts as a novel tool for studying human serotonergic neurotransmission in health and disease. PMID- 26503762 TI - The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. AB - Interventions for autism are limited. The synthetic hormone oxytocin may provide a potential treatment to improve core social and behavioral difficulties in autism, but its efficacy has yet to be evaluated in young children who potentially may benefit to a greater extent. We investigated the efficacy, tolerability and safety of oxytocin treatment in young children with autism using a double-blind, randomized, placebo-controlled, crossover, clinical trial. Thirty one children with autism received 12 International Units (IU) of oxytocin and placebo nasal spray morning and night (24 IU per day) for 5 weeks, with a 4-week washout period between each treatment. Compared with placebo, oxytocin led to significant improvements on the primary outcome of caregiver-rated social responsiveness. Overall, nasal spray was well tolerated, and the most common reported adverse events were thirst, urination and constipation. This study is the first clinical trial to support the potential of oxytocin as an early intervention for young children with autism to help improve social interaction deficits. PMID- 26503765 TI - Formation of colloidal nanocrystal clusters of iron oxide by controlled ligand stripping. AB - We report a "ligand stripping" method for the creation of secondary structures of colloidal nanocrystals. Using iron oxide as an example, we demonstrate that the use of diols as "stripping agents" allows the controllable removal of the original capping ligands and induces aggregation of nanocrystals into well defined clusters. PMID- 26503764 TI - Memory impairment in aged primates is associated with region-specific network dysfunction. AB - Age-related deficits in episodic memory result, in part, from declines in the integrity of medial temporal lobe structures, such as the hippocampus, but are not thought to be due to widespread loss of principal neurons. Studies in rodents suggest, however, that inhibitory interneurons may be particularly vulnerable in advanced age. Optimal encoding and retrieval of information depend on a balance of excitatory and inhibitory transmission. It is not known whether a disruption of this balance is observed in aging non-human primates, and whether such changes affect network function and behavior. To examine this question, we combine large scale electrophysiological recordings with cell-type-specific imaging in the medial temporal lobe of cognitively assessed, aged rhesus macaques. We found that neuron excitability in the hippocampal region CA3 is negatively correlated with the density of somatostatin-expressing inhibitory interneurons in the vicinity of the recording electrodes in the stratum oriens. By contrast, no hyperexcitability or interneuron loss was observed in the perirhinal cortex of these aged, memory impaired monkeys. These data provide a link, for the first time, between selective increases in principal cell excitability and declines in a molecularly defined population of interneurons that regulate network inhibition. PMID- 26503763 TI - Genome-wide association study identifies SESTD1 as a novel risk gene for lithium responsive bipolar disorder. AB - Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 * 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD. PMID- 26503767 TI - Actin, Membrane Trafficking and the Control of Prion Induction, Propagation and Transmission in Yeast. AB - The model eukaryotic yeast Saccharomyces cerevisiae has proven a useful model system in which prion biogenesis and elimination are studied. Several yeast prions exist in budding yeast and a number of studies now suggest that these alternate protein conformations may play important roles in the cell. During the last few years cellular factors affecting prion induction, propagation and elimination have been identified. Amongst these, proteins involved in the regulation of the actin cytoskeleton and dynamic membrane processes such as endocytosis have been found to play a critical role not only in facilitating de novo prion formation but also in prion propagation. Here we briefly review prion formation and maintenance with special attention given to the cellular processes that require the functionality of the actin cytoskeleton. PMID- 26503766 TI - Regulation of Met1-linked polyubiquitin signalling by the deubiquitinase OTULIN. AB - Modification of proteins with Met1-linked 'linear' ubiquitin chains has emerged as a key regulatory signal to control inflammatory signalling via the master regulator, the transcription factor nuclear factor kappaB (NF-kappaB). While the assembly machinery, the linear ubiquitin chain assembly complex (LUBAC), and receptors for this ubiquitin chain type have been known for years, it was less clear which deubiquitinating enzymes (DUBs) hydrolyse Met1 linkages specifically. In 2013, two labs reported the previously unannotated protein FAM105B/OTULIN to be this missing Met1 linkage-specific DUB. Structural studies have revealed how OTULIN achieves its remarkable specificity, employing a mechanism of ubiquitin assisted catalysis in which a glutamate residue on the substrate complements the active site of the enzyme. The specificity of OTULIN enables it to regulate global levels of Met1-linked polyubiquitin in cells. This ability led to investigations of NF-kappaB activation from new angles, and also revealed involvement of Met1-polyubiquitin in Wnt signalling. Interestingly, OTULIN directly interacts with LUBAC, and this interaction is dynamic and can be regulated by OTULIN phosphorylation. This provides a new paradigm for how individual linkage types can be regulated by dedicated enzyme complexes mediating assembly and removal. Here we review what has been learned about OTULIN's mechanism, regulation and function, discuss the open questions in the field, and discuss how DUBs regulate the NF-kappaB response. PMID- 26503768 TI - Cellulose synthesis genes CESA6 and CSI1 are important for salt stress tolerance in Arabidopsis. AB - Two salt hypersensitive mutants she1 and she2 were identified through genetic screening. SHE1 encodes a cellulose synthase CESA6 while SHE2 encodes a cellulose synthase-interactive protein CSI1. Both of them are involved in cellulose deposition. Our results demonstrated that the sustained cellulose synthesis is important for salt stress tolerance in Arabidopsis. PMID- 26503770 TI - Ichthyotoxicity of the microalga Pseudochattonella farcimen under laboratory and field conditions in Danish waters. AB - Blooms of the marine dictyochophyte Pseudochattonella farcimen have been associated with fish kills, but attempts to verify ichthyotoxicity of this microalga under experimental conditions have not been successful. In the early spring of 2009 and 2011, P. farcimen bloomed in the inner Danish waters. The blooms occurred at a seawater temperature of ~2 degrees C and correlated with extensive kills of farmed salmonid fish (2009) and wild populations (2011). Several strains of P. farcimen were isolated from the 2009 bloom. However, exposure of rainbow trout Oncorhynchus mykiss to laboratory-grown P. farcimen cultures did not reveal any toxic effects. During the 2011 bloom, fish were exposed to bloom water under both laboratory and field conditions. While no clinical effect was observed on fish incubated in bloom water in the laboratory trial, a remarkable difference was seen in the field trial between rainbow trout kept in tanks supplied with a continuous flow of filtered versus non-filtered bloom water. Histological examination of the gill tissue revealed karyorrhexis and epithelial loosening in the affected fish. Microscopy analysis of algal cell morphology suggested that mucocysts detected on the cell surface only in freshly sampled bloom water might be associated with ichtyotoxicity. PMID- 26503771 TI - Detection and phylogenetic analysis of infectious pancreatic necrosis virus in Chile. AB - Infectious pancreatic necrosis virus (IPNV) is the etiological agent of a highly contagious disease that is endemic to salmon farming in Chile and causes great economic losses to the industry. Here we compared different diagnostic methods to detect IPNV in field samples, including 3 real-time reverse transcription PCR (qRT-PCR) assays, cell culture isolation, and indirect fluorescent antibody test (IFAT). Additionally, we performed a phylogenetic analysis to investigate the genogroups prevailing in Chile, as well as their geographic distribution and virulence. The 3 qRT-PCR assays used primers that targeted regions of the VP2 and VP1 genes of the virus and were tested in 46 samples, presenting a fair agreement within their results. All samples were positive for at least 2 of the qRT-PCR assays, 29 were positive for cell culture, and 23 for IFAT, showing less sensitivity for these latter 2 methods. For the phylogenetic analysis, portions of 1180 and 523 bp of the VP2 region of segment A were amplified by RT-PCR, sequenced and compared with sequences from reference strains and from isolates reported by previous studies carried out in Chile. Most of the sequenced isolates belonged to genogroup 5 (European origin), and 5 were classified within genogroup 1 (American origin). Chilean isolates formed clusters within each of the genogroups found, evidencing a clear differentiation from the reference strains. To our knowledge, this is the most extensive study completed for IPNV in Chile, covering isolates from sea- and freshwater salmon farms and showing a high prevalence of this virus in the country. PMID- 26503772 TI - Glugea jazanensis sp. nov. infecting Lutjanus bohar in the Red Sea: ultrastructure and phylogeny. AB - During a survey of the microsporean fauna of the two-spot red snapper Lutjanus bohar Forsskal, 1775, from the Red Sea off Jizan (Saudi Arabia), a species of Glugea Thelohan, 1891 was found that did not conform to any known species. The species is characterized by the presence of spherical xenomas (ca. 2-5 mm in diameter) in the host body cavity. Examination of the lifecycle stages and mature spores using light and transmission electron microscopy also revealed morphological characteristics typical of species of the genus Glugea. Spores were elongated-ovoid with a posterior vacuole surrounded by the polar filament coils. Mature spores were 4.5 (4.0-4.8) um long and 2.5 (2.0-2.5) um wide. The polar filament was isofilar with 28 to 30 coils, although in most cases 29 coils, organized in 3 rows. Phylogenetic study based on the partial sequence of the small subunit (SSU) rRNA gene clustered the new microsporidia within the clade grouping species of the genus Glugea. The comprehensive analysis of the parasite's ultrastructural characteristics, together with molecular data for the SSU rDNA gene, suggests that this parasite is a new species of the genus Glugea, for which the name Glugea jazanensis sp. nov. is proposed. PMID- 26503773 TI - Immunohistochemical characterization of intestinal neoplasia in zebrafish Danio rerio indicates epithelial origin. AB - Spontaneous neoplasia of the intestinal tract in sentinel and moribund zebrafish Danio rerio is common in some zebrafish facilities. We previously classified these tumors as adenocarcinoma, small-cell carcinoma, or carcinoma otherwise unspecified based on histomorphologic characteristics. Based on histological presentation, the primary differential diagnosis for the intestinal carcinomas was tumor of neuroendocrine cells (e.g. carcinoids). To further characterize the phenotype of the neoplastic cells, select tissue sections were stained with a panel of antibodies directed toward human epithelial (cytokeratin wide spectrum screening [WSS], AE1/AE3) or neuroendocrine (S100, chromogranin A) markers. We also investigated antibody specificity by Western blot analysis, using a human cell line and zebrafish tissues. Nine of the intestinal neoplasms (64%) stained for AE1/AE3; 7 (50%) also stained for WSS. None of the intestinal neoplastic cells stained for chromogranin A or S100. Endocrine cells of the pituitary gland and neurons and axons of peripheral nerves and ganglia stained for chromogranin A, whereas perineural and periaxonal cells of peripheral intestinal ganglia, and glial and ependymal cells of the brain stained for S100. Immunohistochemistry for cytokeratins confirmed the majority of intestinal neoplasms in this cohort of zebrafish as carcinomas. PMID- 26503774 TI - Oxalate nephropathy in free-living American bullfrog tadpoles. AB - In February 2014, wild American bullfrog Lithobates catesbeianus tadpoles from an artificial pond in the Kyusyu region, Japan, presented with coelomic and subcutaneous edema and erythema within the skin. A pathological examination of 57 tadpoles of American bullfrogs in the region was conducted to evaluate the disease. Crystal deposition of varying degrees was found in the kidneys of 35 tadpoles (61.4%). The crystals were transparent, pleomorphic in shape, highly birefringent in polarized light, and arranged in a radial pattern within the renal tubular lumen. Using Alizarin Red S stain and liquid chromatography, these crystals were identified as calcium oxalate. Severe coelomic and subcutaneous edema was observed in 7 of these 35 tadpoles (20.0%). Ammonia levels in coelomic fluid were extremely elevated (>1000 ug dl(-1)) in 4 tadpoles examined. These findings suggest that oxalate deposition in kidneys causes metabolic disorder with renal nephropathy. The source of the oxalate could not be determined; however, the presence of calcium oxalates in pond sediments, as revealed by liquid chromatography, suggested that the deposition was most likely due to ingestion of oxalate materials from the environment. This is the first report of oxalate nephropathy in free-living amphibians. PMID- 26503775 TI - Salamanders increase their feeding activity when infected with the pathogenic chytrid fungus Batrachochytrium dendrobatidis. AB - Immune function is a costly line of defense against parasitism. When infected with a parasite, hosts frequently lose mass due to these costs. However, some infected hosts (e.g. highly resistant individuals) can clear infections with seemingly little fitness losses, but few studies have tested how resistant hosts mitigate these costly immune defenses. We explored this topic using eastern red backed salamanders Plethodon cinereus and the fungal pathogen Batrachochytrium dendrobatidis (Bd). Bd is generally lethal for amphibians, and stereotypical symptoms of infection include loss in mass and deficits in feeding. However, individuals of P. cinereus can clear their Bd infections with seemingly few fitness costs. We conducted an experiment in which we repeatedly observed the feeding activity of Bd-infected and non-infected salamanders. We found that Bd infected salamanders generally increased their feeding activity compared to non infected salamanders. The fact that we did not observe any differences in mass change between the treatments suggests that increased feeding might help Bd infected salamanders minimize the costs of an effective immune response. PMID- 26503776 TI - Histophagous ciliate Pseudocollinia brintoni and bacterial assemblage interaction with krill Nyctiphanes simplex. I. Transmission process. AB - Histophagous ciliates of the genus Pseudocollinia cause epizootic events that kill adult female krill (Euphausiacea), but their mode of transmission is unknown. We compared 16S rRNA sequences of bacterial strains isolated from stomachs of healthy krill Nyctiphanes simplex specimens with sequences of bacterial isolates and sequences of natural bacterial communities from the hemocoel of N. simplex specimens infected with P. brintoni to determine possible transmission pathways. All P. brintoni endoparasitic life stages and the transmission tomite stage (outside the host) were associated with bacterial assemblages. 16S rRNA sequences from isolated bacterial strains showed that Photobacterium spp. and Pseudoalteromonas spp. were dominant members of the bacterial assemblages during all life phases of P. brintoni and potential pathobionts. They were apparently unaffected by the krill's immune system or the histophagous activity of P. brintoni. However, other bacterial strains were found only in certain P. brintoni life phases, indicating that as the infection progressed, microhabitat conditions and microbial interactions may have become unfavorable for some strains of bacteria. Trophic infection is the most parsimonious explanation for how P. brintoni infects krill. We estimated N. simplex vulnerability to P. brintoni infection during more than three-fourths of their life span, infecting mostly adult females. The ciliates have relatively high prevalence levels (albeit at <10% of sampled stations) and a short life cycle (estimated <7 d). Histophagous ciliate-krill interactions may occur in other krill species, particularly those that form dense swarms and attain high population densities that potentially enhance trophic transmission and allow completion of the Pseudocollinia spp. life cycle. PMID- 26503777 TI - Histophagous ciliate Pseudocollinia brintoni and bacterial assemblage interaction with krill Nyctiphanes simplex. II. Host responses. AB - Unlike decapod crustaceans of commercial interest, the krill defense system and its response to parasites and pathogens is virtually unknown. Histophagous ciliates of the genus Pseudocollinia interact with at least 7 krill species in the northeastern Pacific. Although they can cause epizootic events, the physiology of the histophagous ciliate-host interaction and krill (host) defenses remain unknown. From 1 oceanographic survey along the southwestern coast of the Baja California Peninsula near Bahia Magdalena and 2 in the Gulf of California, we investigated parasitoid-host physiological responses (fatty acid and oxidative stress indicators) of the subtropical krill Nyctiphanes simplex infected with the ciliate P. brintoni. All life stages of P. brintoni were associated with opportunistic bacterial assemblages that have not been explicitly investigated in other Pseudocollinia species (P. beringensis, P. oregonensis, and P. similis). Parasitoid ciliates exclusively infected adult females, which showed increased lipid content during gonad development. As the infection progressed, omega-3 eicosapentaenoic and docosahexaenoic fatty acids, which may act as energy sources to produce high numbers of ciliate transmission stages, were quickly depleted. Antioxidant enzymes, components of the crustacean defense system, varied throughout infection, but without inhibiting Pseudocollinia infection, i.e. higher levels of lipid oxidative damage were detected in late stages of infection. The ineffective response of the krill antioxidant defense system against histophagous ciliates and the bacteria associated with the ciliates suggests that Pseudocollinia ciliates are functionally analogous to krill predators and may have a strong influence on the population dynamics of krill. PMID- 26503778 TI - First report of Brucella ceti-associated meningoencephalitis in a long-finned pilot whale Globicephala melas. AB - Fatal Brucella ceti infection with histological lesions specific to the central nervous system has been described in only 3 species of cetaceans: striped dolphins Stenella coeruleoalba, Atlantic white-sided dolphins Lagenorhynchus acutus and short-beaked common dolphins Delphinus delphis. This paper describes the first report of a B. ceti-associated meningoencephalitis in a long-finned pilot whale Globicephala melas, showing the increasing range of species susceptibility. Brucella was recovered in larger numbers from cerebrospinal fluid than from brain tissue and is the sample of choice for isolation. PMID- 26503779 TI - Analysis of Yersinia ruckeri strains isolated from trout farms in northwest Germany. AB - Enteric redmouth disease (ERM), caused by Yersinia ruckeri, is among the most important infectious diseases in rainbow trout Oncorhynchus mykiss aquaculture in Europe. Our aim was to analyse the persistence of Y. ruckeri strains in trout farms in northwest Germany and their dissemination between farms based on a detailed molecular and phenotypical characterisation scheme. The data on identification and characterisation of Y. ruckeri strains and examining the distribution of these strains in the field could serve as a basis for preventive disease monitoring plans. During the observation period from June 2011 until June 2012, we collected 48 Y. ruckeri isolates from 12 different rainbow trout hatcheries. In total, 44 (91.7%) of the isolates were non-motile; in particular, all isolates recovered during the sampling period in winter and early spring were non-motile. In several trout farms, characteristic farm-specific Y. ruckeri isolates from particular typing groups were isolated throughout the year, while in other farms, which had a trading relationship between each other, ERM outbreaks were caused by Y. ruckeri from the same typing group. Our data indicate that in some farms, the causative Y. ruckeri strains persisted in the respective trout farm. The presence of Y. ruckeri from the same typing group in farms with a trading relationship indicates a dissemination of the infection between the farms. PMID- 26503780 TI - Acute hepatopancreatic necrosis disease (AHPND) outbreaks in Penaeus vannamei and P. monodon cultured in the Philippines. AB - Acute hepatopancreatic necrosis disease (AHPND) has recently emerged as a serious disease of cultured shrimp. It has also been described as early mortality syndrome (EMS) due to mass mortalities occurring within 20 to 30 d after stocking of ponds with postlarvae. Here, Penaeus vannamei and Penaeus monodon from shrimp farms in the Philippines were examined for the toxin-producing strain of Vibrio parahaemolyticus due to AHPND-like symptoms occurring in marketable size shrimp. In the P. vannamei, histology revealed typical AHPND pathology, such as sloughing of undifferentiated cells in the hepatopancreatic tubule epithelium. Analysis using the IQ2000 AHPND/EMS Toxin 1 PCR test generated 218 bp and 432 bp amplicons confirmative of the toxin-producing strain of V. parahaemolyticus among shrimp sampled from 8 of 9 ponds. In the P. monodon, histology revealed massive sloughing of undifferentiated cells of the hepatopancreatic tubule epithelium in the absence of basophilic bacterial cells. PCR testing generated the 2 amplicons confirmatory for AHPND among shrimp sampled from 5 of 7 ponds. This study confirms the presence of AHPND in P. vannamei and P. monodon farmed in the Philippines and suggests that the disease can also impact late-stage juvenile shrimp. PMID- 26503781 TI - The Catalytic Activity of the Ubp3 Deubiquitinating Protease Is Required for Efficient Stress Granule Assembly in Saccharomyces cerevisiae. AB - The interior of the eukaryotic cell is a highly compartmentalized space containing both membrane-bound organelles and the recently identified nonmembranous ribonucleoprotein (RNP) granules. This study examines in Saccharomyces cerevisiae the assembly of one conserved type of the latter compartment, known as the stress granule. Stress granules form in response to particular environmental cues and have been linked to a variety of human diseases, including amyotrophic lateral sclerosis. To further our understanding of these structures, a candidate genetic screen was employed to identify regulators of stress granule assembly in quiescent cells. These studies identified a ubiquitin-specific protease, Ubp3, as having an essential role in the assembly of these RNP granules. This function was not shared by other members of the Ubp protease family and required Ubp3 catalytic activity as well as its interaction with the cofactor Bre5. Interestingly, the loss of stress granules was correlated with a decrease in the long-term survival of stationary-phase cells. This phenotype is similar to that observed in mutants defective for the formation of a related RNP complex, the Processing body. Altogether, these observations raise the interesting possibility of a general role for these types of cytoplasmic RNP granules in the survival of G0-like resting cells. PMID- 26503782 TI - Genome-Wide Organization of GATA1 and TAL1 Determined at High Resolution. AB - Erythroid development and differentiation from multiprogenitor cells into red blood cells requires precise transcriptional regulation. Key erythroid transcription factors, GATA1 and TAL1, cooperate, along with other proteins, to regulate many aspects of this process. How GATA1 and TAL1 are juxtaposed along the DNA and their cognate DNA binding site across the mouse genome remains unclear. We applied high-resolution ChIP-exo (chromatin immunoprecipitation followed by 5'-to-3' exonuclease treatment and then massively parallel DNA sequencing) to GATA1 and TAL1 to study their positional organization across the mouse genome during GATA1-dependent maturation. Two complementary methods, MultiGPS and peak pairing, were used to determine high-confidence binding locations by ChIP-exo. We identified ~10,000 GATA1 and ~15,000 TAL1 locations, which were essentially confirmed by ChIP-seq (chromatin immunoprecipitation followed by massively parallel DNA sequencing). Of these, ~4,000 locations were bound by both GATA1 and TAL1. About three-quarters of them were tightly linked to a partial E-box located 7 or 8 bp upstream of a WGATAA motif. Both TAL1 and GATA1 generated distinct characteristic ChIP-exo peaks around WGATAA motifs that reflect their positional arrangement within a complex. We show that TAL1 and GATA1 form a precisely organized complex at a compound motif consisting of a TG 7 or 8 bp upstream of a WGATAA motif across thousands of genomic locations. PMID- 26503783 TI - Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity. AB - Mitochondrial oxidative and thermogenic functions in brown and beige adipose tissues modulate rates of energy expenditure. It is unclear, however, how beige or white adipose tissue contributes to brown fat thermogenic function or compensates for partial deficiencies in this tissue and protects against obesity. Here, we show that the transcription factor Yin Yang 1 (YY1) in brown adipose tissue activates the canonical thermogenic and uncoupling gene expression program. In contrast, YY1 represses a series of secreted proteins, including fibroblast growth factor 21 (FGF21), bone morphogenetic protein 8b (BMP8b), growth differentiation factor 15 (GDF15), angiopoietin-like 6 (Angptl6), neuromedin B, and nesfatin, linked to energy expenditure. Despite substantial decreases in mitochondrial thermogenic proteins in brown fat, mice lacking YY1 in this tissue are strongly protected against diet-induced obesity and exhibit increased energy expenditure and oxygen consumption in beige and white fat depots. The increased expression of secreted proteins correlates with elevation of energy expenditure and promotion of beige and white fat activation. These results indicate that YY1 in brown adipose tissue controls antagonistic gene expression programs associated with energy balance and maintenance of body weight. PMID- 26503784 TI - The Insertion in Fingers Domain in Human Telomerase Can Mediate Enzyme Processivity and Telomerase Recruitment to Telomeres in a TPP1-Dependent Manner. AB - In most human cancer cells, cellular immortalization relies on the activation and recruitment of telomerase to telomeres. The telomere-binding protein TPP1 and the TEN domain of the telomerase catalytic subunit TERT regulate telomerase recruitment. TERT contains a unique domain, called the insertion in fingers domain (IFD), located within the conserved reverse transcriptase domain. We report the role of specific hTERT IFD residues in the regulation of telomerase activity and processivity, recruitment to telomeres, and cell survival. One hTERT IFD variant, hTERT-L805A, with reduced activity and processivity showed impaired telomere association, which could be partially rescued by overexpression of TPP1 POT1. Another previously reported hTERT IFD mutant enzyme with similarly low levels of activity and processivity, hTERT-V791Y, displayed defects in telomere binding and was insensitive to TPP1-POT1 overexpression. Our results provide the first evidence that the IFD can mediate enzyme processivity and telomerase recruitment to telomeres in a TPP1-dependent manner. Moreover, unlike hTERT V791Y, hTERT-V763S, a variant with reduced activity but increased processivity, and hTERT-L805A, could both immortalize limited-life-span cells, but cells expressing these two mutant enzymes displayed growth defects, increased apoptosis, DNA damage at telomeres, and short telomeres. Our results highlight the importance of the IFD in maintaining short telomeres and in cell survival. PMID- 26503785 TI - A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGbeta Expression and Cell Differentiation. AB - Human chorionic gonadotropin (hCG) is composed of a common alpha subunit and a placenta-specific beta subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cyclic AMP (cAMP). Although the ubiquitous activating protein 2 (AP2) transcription factors TFAP2A and TFAP2C may regulate hCGbeta expression, it remains unclear how cAMP stimulates placenta specific hCGbeta gene expression and trophoblastic differentiation. Here we demonstrated that the placental transcription factor glial cells missing 1 (GCM1) binds to a highly conserved promoter region in all six hCGbeta paralogues by chromatin immunoprecipitation-on-chip (ChIP-chip) analyses. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate the hCGbeta promoter through a GCM1-binding site (GBS1), which also constitutes a previously identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between the hCGbeta promoter and GCM1 but not TFAP2C. Indeed, the hCG-cAMP-protein kinase A (PKA) signaling pathway also stimulates Ser269 and Ser275 phosphorylation of GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the fusogenic protein syncytin-1, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCGbeta expression and cell differentiation. PMID- 26503786 TI - Recruitment of beta-Arrestin into Neuronal Cilia Modulates Somatostatin Receptor Subtype 3 Ciliary Localization. AB - Primary cilia are essential sensory and signaling organelles present on nearly every mammalian cell type. Defects in primary cilia underlie a class of human diseases collectively termed ciliopathies. Primary cilia are restricted subcellular compartments, and specialized mechanisms coordinate the localization of proteins to cilia. Moreover, trafficking of proteins into and out of cilia is required for proper ciliary function, and this process is disrupted in ciliopathies. The somatostatin receptor subtype 3 (Sstr3) is selectively targeted to primary cilia on neurons in the mammalian brain and is implicated in learning and memory. Here, we show that Sstr3 localization to cilia is dynamic and decreases in response to somatostatin treatment. We further show that somatostatin treatment stimulates beta-arrestin recruitment into Sstr3-positive cilia and this recruitment can be blocked by mutations in Sstr3 that impact agonist binding or phosphorylation. Importantly, somatostatin treatment fails to decrease Sstr3 ciliary localization in neurons lacking beta-arrestin 2. Together, our results implicate beta-arrestin in the modulation of Sstr3 ciliary localization and further suggest a role for beta-arrestin in the mediation of Sstr3 ciliary signaling. PMID- 26503787 TI - High Fractional Occupancy of a Tandem Maf Recognition Element and Its Role in Long-Range beta-Globin Gene Regulation. AB - Enhancers and promoters assemble protein complexes that ultimately regulate the recruitment and activity of RNA polymerases. Previous work has shown that at least some enhancers form stable protein complexes, leading to the formation of enhanceosomes. We analyzed protein-DNA interactions in the murine beta-globin gene locus using the methyltransferase accessibility protocol for individual templates (MAPit). The data show that a tandem Maf recognition element (MARE) in locus control region (LCR) hypersensitive site 2 (HS2) reveals a remarkably high degree of occupancy during differentiation of mouse erythroleukemia cells. Most of the other transcription factor binding sites in LCR HS2 or in the adult beta globin gene promoter regions exhibit low fractional occupancy, suggesting highly dynamic protein-DNA interactions. Targeting of an artificial zinc finger DNA binding domain (ZF-DBD) to the HS2 tandem MARE caused a reduction in the association of MARE-binding proteins and transcription complexes at LCR HS2 and the adult betamajor-globin gene promoter but did not affect expression of the betaminor-globin gene. The data demonstrate that a stable MARE-associated footprint in LCR HS2 is important for the recruitment of transcription complexes to the adult betamajor-globin gene promoter during erythroid cell differentiation. PMID- 26503788 TI - Physical Connectivity Mapping by Circular Permutation of Human Telomerase RNA Reveals New Regions Critical for Activity and Processivity. AB - Telomerase is a specialized ribonucleoprotein complex that extends the 3' ends of chromosomes to counteract telomere shortening. However, increased telomerase activity is associated with ~90% of human cancers. The telomerase enzyme minimally requires an RNA (hTR) and a specialized reverse transcriptase protein (TERT) for activity in vitro. Understanding the structure-function relationships within hTR has important implications for human disease. For the first time, we have tested the physical-connectivity requirements in the 451-nucleotide hTR RNA using circular permutations, which reposition the 5' and 3' ends. Our extensive in vitro analysis identified three classes of hTR circular permutants with altered function. First, circularly permuting 3' of the template causes specific defects in repeat-addition processivity, revealing that the template recognition element found in ciliates is conserved in human telomerase RNA. Second, seven circular permutations residing within the catalytically important core and CR4/5 domains completely abolish telomerase activity, unveiling mechanistically critical portions of these domains. Third, several circular permutations between the core and CR4/5 significantly increase telomerase activity. Our extensive circular permutation results provide insights into the architecture and coordination of human telomerase RNA and highlight where the RNA could be targeted for the development of antiaging and anticancer therapeutics. PMID- 26503789 TI - Acute recreational drug and new psychoactive substance toxicity in Europe: 12 months data collection from the European Drug Emergencies Network (Euro-DEN). AB - CONTEXT: Despite the potential for recreational drugs and new psychoactive substances (NPSs) to cause significant morbidity and mortality, there is limited collection of systematic data on acute drug/NPS toxicity in Europe. OBJECTIVE: To report data on acute drug/NPS toxicity collected by a network of sentinel centres across Europe with a specialist clinical and research interest in the acute toxicity of recreational drugs and NPS to address this knowledge gap. METHODS: Sixteen sentinel centres in 10 European countries (Denmark, Estonia, France, Germany, Ireland, Norway, Poland, Spain, Switzerland and the UK) collected data on all acute drug toxicity presentations to their Emergency Rooms (ERs) for 12 months (October 2013-September 2014); information on the drug(s) involved in the presentations was on the basis of patient self-reporting. RESULTS: Data were collected on a total of 5529 presentations involving 8709 drugs (median (interquartile range [IQR]): 1 (1-2) drugs per presentation), a median of 0.3% of all ER attendances. Classical recreational drugs were most common (64.6%) followed by prescription drugs (26.5%) and NPS (5.6%). The 'top five' drugs recorded were heroin (1345 reports), cocaine (957), cannabis (904), GHB/GBL (711) and amphetamine (593). 69.5% of individuals went to hospital by ambulance (peak time between 19:00 and 02:00 at weekends); the median (IQR) age was 31 (24-39) years and 75.4% were male. Although serious clinical features were not seen in most presentations and 56.9% were medically discharged from the ER (median length of stay: 4.6 hours), a significant number (26.5%) was agitated, in 10.5% the GCS was 8 or less and 35 presented in cardiac arrest. There were 27 fatalities with opioids implicated in 13. CONCLUSION: The Euro-DEN dataset provides a unique insight into the drugs involved in and clinical pattern of toxicity/outcome of acute recreational drug toxicity presentations to hospitals around Europe. This is complimentary to other indicators of drug-related harm and helps to build a fuller picture of the public health implications of drug use in Europe. PMID- 26503790 TI - Abuse, misuse, and suicidal substance use by children on school property. AB - OBJECTIVE: The purpose of this study was to characterize the epidemiological trends associated with substances used in intentional exposures among children while on school property reported to the U.S. National Poison Data System (NPDS). MATERIALS AND METHODS: NPDS was queried for intentional (abuse, misuse, suspected suicide, and unknown intentional) exposures reported to occur on school property between calendar years 2004 and 2013. Records were restricted to children 6-18 years of age. Demographic, exposure, and clinical characteristics were assessed. RESULTS: A total of 56,882 substances were intentionally used on school property by 50,379 children, of which 39.8% were females (n = 20,070), 57.7% were males (n = 29,084), and 2.4% were unknown gender (n = 1,225). The most frequent pharmaceutical exposures reported included sedatives (n = 4,096; 8.1%), analgesics (n = 4,022; 8.0%), and cough and cold preparations (n = 3,529; 7.0%). The majority of exposures were managed on site (n = 21,464; 42.6%), followed by care at a healthcare facility (n = 20,048; 39.7%). Serious outcomes (moderate or major effects and death) accounted for nine percent of all reported exposures. Compared to reference groups, female gender, teenagers 17-18 years, and pharmaceutical substances (Prevalence Ratios = 4.6, 9.4, and 9.9, respectively) were associated with suspected suicides when compared with other intentional exposures. CONCLUSIONS: Along with other national data about behaviors in the adolescent and teenage population, additional trends in risky behavior may be gleaned by surveillance through poison centers. With over 5,000 annual reports to the poison centers about intentional exposures on school property, school personnel and parents/guardians must be vigilant about the range of pharmaceutical and non-pharmaceutical substances that are used for abuse, misuse, or suicide. PMID- 26503791 TI - Reply to Isbister and Page: Further discussion of an illuminated case of presumed brown snake (Pseudonaja spp.) envenoming. PMID- 26503792 TI - Biotransformation of Furanic and Phenolic Compounds with Hydrogen Gas Production in a Microbial Electrolysis Cell. AB - Furanic and phenolic compounds are problematic byproducts resulting from the breakdown of lignocellulosic biomass during biofuel production. The capacity of a microbial electrolysis cell (MEC) to produce hydrogen gas (H2) using a mixture of two furanic (furfural, FF; 5-hydroxymethyl furfural, HMF) and three phenolic (syringic acid, SA; vanillic acid, VA; and 4-hydroxybenzoic acid, HBA) compounds as the substrate in the bioanode was assessed. The rate and extent of biotransformation of the five compounds and efficiency of H2 production, as well as the structure of the anode microbial community, were investigated. The five compounds were completely transformed within 7-day batch runs and their biotransformation rate increased with increasing initial concentration. At an initial concentration of 1200 mg/L (8.7 mM) of the mixture of the five compounds, their biotransformation rate ranged from 0.85 to 2.34 mM/d. The anode Coulombic efficiency was 44-69%, which is comparable to that of wastewater-fed MECs. The H2 yield varied from 0.26 to 0.42 g H2-COD/g COD removed in the anode, and the bioanode volume-normalized H2 production rate was 0.07-0.1 L/L-d. The biotransformation of the five compounds took place via fermentation followed by exoelectrogenesis. The major identified fermentation products that did not transform further were catechol and phenol. Acetate was the direct substrate for exoelectrogenesis. Current and H2 production were inhibited at an initial substrate concentration of 1200 mg/L, resulting in acetate accumulation at a much higher level than that measured in other batch runs conducted with a lower initial concentration of the five compounds. The anode microbial community consisted of exoelectrogens, putative degraders of the five compounds, and syntrophic partners of exoelectrogens. The MEC H2 production demonstrated in this study is an alternative to the currently used process of reforming natural gas to supply H2 needed to upgrade bio-oils to stable hydrocarbon fuels. PMID- 26503793 TI - Miravirsen dosing in chronic hepatitis C patients results in decreased microRNA 122 levels without affecting other microRNAs in plasma. AB - BACKGROUND: MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus replication. Administration of miravirsen, an anti-miR-122 oligonucleotide, resulted in a dose dependent and prolonged decrease in HCV RNA levels in chronic hepatitis C patients. AIM: To assess the plasma level of various miRNAs in patients dosed with miravirsen. METHODS: We included 16 of 36 chronic hepatitis C patients who received five injections of either 3 mg/kg (n = 4), 5 mg/kg (n = 4), 7 mg/kg (n = 4) miravirsen or placebo (n = 4) over a 4-week period in a double blind, randomised phase 2a study. Plasma levels of 179 miRNAs were determined by qPCR and compared between patients dosed with miravirsen or placebo. RESULTS: Median plasma miR-122 level at baseline in patients receiving miravirsen was 3.9 * 10(3) compared to 1.3 * 10(4) copies/4 MUL in placebo-dosed patients (P = 0.68). At week 1, 4, 6 and 10/12, patients dosed with miravirsen had respectively a median 72-fold, 174-fold, 1109-fold and 552-fold lower expression of miR-122 than at baseline (P = 0.001, as compared to patients receiving placebo). At week 4 of dosing, miRNA-profiling demonstrated a significant lower expression of miR 210 and miR-532-5p compared to baseline (3.0 and 4.7-fold lower respectively). However, subsequent longitudinal analysis showed no significant differences in miR-210 and miR-532-5p plasma levels throughout the study period. CONCLUSIONS: We demonstrated a substantial and prolonged decrease in plasma miR-122 levels in patients dosed with miravirsen. Plasma levels of other miRNAs were not significantly affected by antagonising miR-122. PMID- 26503794 TI - Technology: Dropping in on single-cell epigenetic profiles. PMID- 26503797 TI - Functional genomics: The genetic essence of human cells. PMID- 26503796 TI - Protective alleles and modifier variants in human health and disease. AB - The combination of next-generation sequencing technologies and high-throughput genotyping platforms has revolutionized the pursuit of genetic variants that contribute towards disease. Furthermore, these technologies have provided invaluable insight into the genetic factors that prevent individuals from developing disease. Exploiting the evolutionary mechanisms that were designed by nature to help prevent disease is an attractive line of enquiry. Such efforts have the potential to generate a therapeutic target roadmap and rejuvenate the current drug-discovery pathway. By delineating the genomic factors that are protective against disease, there is potential to derive highly effective, genomically anchored medicines that assist in maintaining health. PMID- 26503798 TI - Evolution: Mix and re-match. PMID- 26503799 TI - Small-Sized Tungsten Nitride Particles Strongly Anchored on Carbon Nanotubes and their Use as Supports for Pt for Methanol Electro-oxidation. AB - The anchoring of small-sized WN (tungsten nitride) nanoparticles (NPs) with good dispersion on carbon nanotubes (CNTs) offers an effective means of obtaining promising materials for use in electrocatalysis. Herein, an effective method based on grinding treatment followed by a nitridation process is proposed to realize this goal. In the synthesis, a solution containing H4 [SiO4 (W3 O9 )4 ] (SiW12 ) and CNTs modified with polyethylenimine (PEI-CNTs) was ground to dryness. Small-sized WN NPs were anchored onto the CNTs with good dispersion after calcination under NH3 . Under hydrothermal assembly conditions (absence of grinding), WN particles of larger size and with inferior dispersion were obtained, demonstrating the important role of the grinding process. The benefit of the small-sized WN has been demonstrated by using WN/CNTs as a support for Pt to catalyze the methanol electro-oxidation reaction. The mass activity of Pt WN/CNTs-G-70 (where G denotes the grinding treatment, and 70 is the loading amount (%) of WN in the WN/CNTs) was evaluated as about 817 mA mg(-1) Pt , better that those of commercial Pt/C (340 mA mg(-1) Pt ) and Pt/CNTs (162 mA mg(-1) Pt ). The Pt-WN/CNTs-G also displayed good CO tolerance. In contrast, Pt-WN/CNTs prepared without the grinding process displayed an activity of 344 mA mg(-1) Pt , verifying the key role of grinding treatment in the preparation of WN/CNTs with good co-catalytic effect. PMID- 26503795 TI - Genetic studies in intellectual disability and related disorders. AB - Genetic factors play a major part in intellectual disability (ID), but genetic studies have been complicated for a long time by the extreme clinical and genetic heterogeneity. Recently, progress has been made using different next-generation sequencing approaches in combination with new functional readout systems. This approach has provided novel insights into the biological pathways underlying ID, improved the diagnostic process and offered new targets for therapy. In this Review, we highlight the insights obtained from recent studies on the role of genetics in ID and its impact on diagnosis, prognosis and therapy. We also discuss the future directions of genetics research for ID and related neurodevelopmental disorders. PMID- 26503800 TI - Survival probabilities with time-dependent treatment indicator: quantities and non-parametric estimators. AB - The 'landmark' and 'Simon and Makuch' non-parametric estimators of the survival function are commonly used to contrast the survival experience of time-dependent treatment groups in applications such as stem cell transplant versus chemotherapy in leukemia. However, the theoretical survival functions corresponding to the second approach were not clearly defined in the literature, and the use of the 'Simon and Makuch' estimator was criticized in the biostatistical community. Here, we review the 'landmark' approach, showing that it focuses on the average survival of patients conditional on being failure free and on the treatment status assessed at the landmark time. We argue that the 'Simon and Makuch' approach represents counterfactual survival probabilities where treatment status is forced to be fixed: the patient is thought as under chemotherapy without possibility to switch treatment or as under transplant since the beginning of the follow-up. We argue that the 'Simon and Makuch' estimator leads to valid estimates only under the Markov assumption, which is however less likely to occur in practical applications. This motivates the development of a novel approach based on time rescaling, which leads to suitable estimates of the counterfactual probabilities in a semi-Markov process. The method is also extended to deal with a fixed landmark time of interest. PMID- 26503801 TI - Ocean acidification increases the accumulation of toxic phenolic compounds across trophic levels. AB - Increasing atmospheric CO2 concentrations are causing ocean acidification (OA), altering carbonate chemistry with consequences for marine organisms. Here we show that OA increases by 46-212% the production of phenolic compounds in phytoplankton grown under the elevated CO2 concentrations projected for the end of this century, compared with the ambient CO2 level. At the same time, mitochondrial respiration rate is enhanced under elevated CO2 concentrations by 130-160% in a single species or mixed phytoplankton assemblage. When fed with phytoplankton cells grown under OA, zooplankton assemblages have significantly higher phenolic compound content, by about 28-48%. The functional consequences of the increased accumulation of toxic phenolic compounds in primary and secondary producers have the potential to have profound consequences for marine ecosystem and seafood quality, with the possibility that fishery industries could be influenced as a result of progressive ocean changes. PMID- 26503802 TI - Body Fluid Interferon-gamma Release Assay for Diagnosis of Extrapulmonary Tuberculosis in Adults: A Systematic Review and Meta-Analysis. AB - The diagnosis of extrapulmonary tuberculosis (EPTB) is difficult. In recent years, T-cell interferon-gamma release assays (IGRAs) are widely used in diagnosing tuberculosis. The aim of this meta-analysis is to evaluate the diagnostic accuracy of body fluid IGRAs in diagnosing EPTB. The PubMed, EMBASE, Web of Science, and Cochrane bibliographies were searched for English language articles. 22 studies met the inclusion criteria. The pooled sensitivity and specificity of body fluid IGRAs for diagnosing EPTB were 0.87 [95% confidence interval (CI): 0.83-0.92] and 0.85 (95% CI: 0.79-0.90), respectively. For the fluid T-SPOT.TB, the pooled sensitivity and specificity were 0.92 (95% CI: 0.88 0.95) and 0.85 (95% CI: 0.78-0.91), respectively. The diagnostic odds ratio (DOR) of the fluid T-SPOT.TB was 46.99 (95% CI: 13.69-161.28) for tuberculosis pleurisy, 26.46 (95% CI: 11.38-61.56) for tuberculosis peritonitis, and 97.86 (95% CI: 25.31-378.45) for tuberculosis meningitis. The application of T-SPOT. TB in the diagnosis of EPTB performed better in the body fluid than in the blood. The diagnostic values of the fluid T-SPOT.TB varied for different fluid categories. However, the utility of T-SPOT.TB was limited due to its suboptimal accuracy and higher cost compared with conventional tests. PMID- 26503804 TI - Enhancement of the blue photoluminescence intensity for the porous silicon with HfO2 filling into microcavities. AB - With HfO2 filled into the microcavities of the porous single-crystal silicon, the blue photoluminescence was greatly enhanced at room temperature. On one hand, HfO2 contributes to the light emission with the transitions of the defect levels for oxygen vacancy. On the other hand, the special filling-into-microcavities structure of HfO2 leads to the presence of ferroelectricity, which greatly enhances the blue emission from porous silicon. Since both HfO2 and Si are highly compatible with Si-based electronic industry, combined the low-cost and convenient process, the HfO2-filled porous Si shows a promising application prospect. PMID- 26503803 TI - Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions. AB - Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2(+)) and immunosuppressive M2 macrophages (CD163(+)) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies. PMID- 26503805 TI - Pediatric Ependymoma. AB - Over the past 150 years since Virchow's initial characterization of ependymoma, incredible efforts have been made in the classification of these tumors and in the care of pediatric patients with this disease. While the advent of modern neurosurgery and the optimization of radiation have provided significant gains, a more complex but incomplete picture of pediatric ependymomas has begun to form through a combination of international collaborations and detailed genetic and histologic characterizations. This review includes and synthesizes the clinical understanding of pediatric ependymoma and their developing molecular insight into what is truly a family of malignancies in which distinct members require different surgical approaches, radiation plans, and targeted therapies. PMID- 26503806 TI - Real-life assessment of Volumetric Modulated Arc Therapy (VMAT) toxicity in Head and Neck Squamous Cell Carcinoma (HNSCC) treatment. AB - CONCLUSION: The present study demonstrates the feasibility of VMAT in association with platin or cetuximab in HNSCC and reports VMAT-related acute and late toxicities for the first time. OBJECTIVES: New radiotherapy techniques, such as Volumetric Modulated Arc Therapy (VMAT) were developed to lower RT-related toxicity. The aim of the present study was to investigate acute and late toxicities of head and neck squamous cell carcinoma (HNSCC) patients treated using VMAT. METHODS: This study investigated retrospectively all patients with HNSCC who received VMAT in curative intent. RESULTS: From 2010-2013, 150 patients were treated. Seventy-five patients (50%) received concurrent chemotherapy with VMAT, 51 patients (34%) received VMAT alone and 24 patients (16%) received concurrent cetuximab with VMAT. Mean delivered dose to planning target volume tumor (PTV T), high risk nodes (PTV HNR), low risk nodes (PTV LNR) and prophylactic nodes (PTV PN) were: 65.2 Gy, 62.9 Gy, 55.4 Gy, and 51.5 Gy, respectively. PTV mean coverages were higher than 96.5%. Most common grade 3/4 acute infield toxicities were mucosis (n = 28, 19%), dysphagia (n = 24, 16%), and dermatitis (n = 24, 16%). With a median follow-up of 16.0 months, most common late toxicities were dysphagia (n = 30, 20%), xerostomia (n = 28, 19%), larynx stiff (n = 17, 11%), and skin fibrosis (n = 14, 9%). PMID- 26503807 TI - Reactivity in the periphery of functionalised multiple bonds of heavier group 14 elements. AB - Heavier group 14 multiple bonds have intrigued chemists since more than a century. The synthesis of stable compounds with double and triple bonds with silicon, germanium, tin and lead had considerable impact on modern ideas of chemical bonding. These developments were made possible by the use of bulky substituents that provide kinetic and thermodynamic protection. Since about a decade the compatibility of heavier multiple bonds with various functional groups has moved into focus. This review covers multiply bonded group 14 species with at least one additional reactive site. The vinylic functionalities of groups 1 and 17, resulting in nucleophilic and electrophilic disila vinyl groups, respectively, are the most prevalent and well-studied. They have been employed repeatedly for the transfer of heavier multiple bonds to yield low-valent group 14 compounds with novel structural motifs. Vinylic functionalities of groups 2 to 16 and a few sigma-bonded transition metal complexes are experimentally known, but their reactivity has been studied to a lesser extent. Donor-coordinated multiple bonds are a relatively new field of research, but the large degree of unsaturation as isomers of alkynes (as well as residual functionality in some cases) offers considerable possibility for further manipulation, e.g. for the incorporation into more extended systems. Heavier allyl halides constitute the major part of heavier multiple bonds with a functional group in allylic position and some examples of successful transformations are given. At present, remote functionalities are basically limited to para-phenylene functionalised disilenes. The reported use of the latter for further derivatisation might encourage investigations in this direction. In summary, the study of peripherally functionalised multiple bonds with heavier group 14 elements is already well beyond its infancy and may be an instrumental factor in awakening the potential of group 14 chemistry for applications in polymers and other materials. PMID- 26503809 TI - Positive impact of ABCB1 polymorphisms in overall survival and complete remission in acute myeloid leukemia: a systematic review and meta-analysis. PMID- 26503808 TI - Amino acid positions subject to multiple coevolutionary constraints can be robustly identified by their eigenvector network centrality scores. AB - As proteins evolve, amino acid positions key to protein structure or function are subject to mutational constraints. These positions can be detected by analyzing sequence families for amino acid conservation or for coevolution between pairs of positions. Coevolutionary scores are usually rank-ordered and thresholded to reveal the top pairwise scores, but they also can be treated as weighted networks. Here, we used network analyses to bypass a major complication of coevolution studies: For a given sequence alignment, alternative algorithms usually identify different, top pairwise scores. We reconciled results from five commonly-used, mathematically divergent algorithms (ELSC, McBASC, OMES, SCA, and ZNMI), using the LacI/GalR and 1,6-bisphosphate aldolase protein families as models. Calculations used unthresholded coevolution scores from which column specific properties such as sequence entropy and random noise were subtracted; "central" positions were identified by calculating various network centrality scores. When compared among algorithms, network centrality methods, particularly eigenvector centrality, showed markedly better agreement than comparisons of the top pairwise scores. Positions with large centrality scores occurred at key structural locations and/or were functionally sensitive to mutations. Further, the top central positions often differed from those with top pairwise coevolution scores: instead of a few strong scores, central positions often had multiple, moderate scores. We conclude that eigenvector centrality calculations reveal a robust evolutionary pattern of constraints-detectable by divergent algorithms- that occur at key protein locations. Finally, we discuss the fact that multiple patterns coexist in evolutionary data that, together, give rise to emergent protein functions. PMID- 26503810 TI - NAT2 gene diversity and its evolutionary trajectory in the Americas. AB - N-acetyltransferase 2 (NAT2) is responsible for metabolizing xenobiotics; NAT2 polymorphisms lead to three phenotypes: rapid, intermediate and slow acetylators. We aimed to investigate NAT2 diversity in Native Americans. NAT2 exon 2 was sequenced for 286 individuals from 21 populations (Native American and American Mestizos). Excluding the basal/rapid haplotype NAT2*4, the most frequent haplotypes are NAT2*5B (35.95%) in hunter-gatherers and NAT2*7B (20.61%) and NAT2*5B (19.08%) in agriculturalists that were related to the slow phenotype. A new haplotype was identified in two Amerindians. Data from the ~44 kb region surrounding NAT2 in 819 individuals from Africa, East-Asia, Europe and America were used in additional analyses. No significant differences in the acetylator NAT2 haplotype and phenotype distributions were found between Native American populations practicing farming and/or herding and those practicing hunting and gathering, probably because of the absence or weakness of selection pressures and presence of demographic and random processes preventing detection of any selection signal. PMID- 26503811 TI - Effect of summer daylight exposure and genetic background on growth in growth hormone-deficient children. AB - The response to growth hormone in humans is dependent on phenotypic, genetic and environmental factors. The present study in children with growth hormone deficiency (GHD) collected worldwide characterised gene-environment interactions on growth response to recombinant human growth hormone (r-hGH). Growth responses in children are linked to latitude, and we found that a correlate of latitude, summer daylight exposure (SDE), was a key environmental factor related to growth response to r-hGH. In turn growth response was determined by an interaction between both SDE and genes known to affect growth response to r-hGH. In addition, analysis of associated networks of gene expression implicated a role for circadian clock pathways and specifically the developmental transcription factor NANOG. This work provides the first observation of gene-environment interactions in children treated with r-hGH. PMID- 26503812 TI - Predictive markers in elderly patients with estrogen receptor-positive breast cancer treated with aromatase inhibitors: an array-based pharmacogenetic study. AB - So far, no reliable predictive clinicopathological markers of response to aromatase inhibitors (AIs) have been identified, and little is known regarding the role played by host genetics. To identify constitutive predictive markers, an array-based association study was performed in a cohort of 55 elderly hormone dependent breast cancer (BC) patients treated with third-generation AIs. The array used in this study interrogates variants in 225 drug metabolism and disposition genes with documented functional significance. Six variants emerged as associated with response to AIs: three located in ABCG1, UGT2A1, SLCO3A1 with a good response, two in SLCO3A1 and one in ABCC4 with a poor response. Variants in the AI target CYP19A1 resulted associated with a favourable response only as haplotype; haplotypes with increased response association were also detected for ABCG1 and SLCO3A1. These results highlight the relevance of host genetics in the response to AIs and represent a first step toward precision medicine for elderly BC patients. PMID- 26503813 TI - NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. AB - A recent study identified a variant of the NUDT15 gene (rs116855232 C>T) associated with intolerance to thiopurine in Korean patients with Crohn's disease. This study prompted us to substantiate the finding in a Taiwanese population. Four hundred and four children with acute lymphoblastic leukemia (ALL), and 100 adults with chronic immune thrombocytopenic purpura or localized lymphoma having normal bone marrow were examined. Two candidate gene approaches, pyrosequencing for NUDT15 and TaqMan assay for thiopurine methyltransferase (TPMT) genotyping (rs1142345 A>G), were performed. We showed a risk allele frequency of NUDT15 of 11.6% in children with ALL and 15.5% in adults. By contrast, the risk allele frequency of TPMT was only 1.6% in children with ALL and 0.5% in adults. The high frequency of risk variant for NUDT15, but not the very low frequency of risk variant for TPMT, was closely associated with the intolerance to mercaptopurine in children with ALL in Taiwan, contrast to that of European descent. In regard to NUDT15 polymorphism, the maximal tolerable daily doses of mercaptopurine in homozygotes, heterozygotes and wild-type groups were 9.4 mg m-2, 30.7 mg m-2 and 44.1 mg m-2, respectively. The outcomes did not differ significantly among the different genotypes. PMID- 26503815 TI - Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort. AB - The relationship between genetic variation in CYP2D6 and variable drug response represents a potentially powerful pharmacogenetic tool. However, little is known regarding this relationship in the genetically diverse South African population. The aim was therefore to evaluate the relationship between predicted and measured CYP2D6 phenotype. An XL-PCR+Sequencing approach was used to determine CYP2D6 genotype in 100 healthy volunteers and phenotype was predicted using activity scores. With dextromethorphan as the probe drug, metabolic ratios served as a surrogate measure of in vivo CYP2D6 activity. Three-hour plasma metabolic ratios of dextrorphan/dextromethorphan were measured simultaneously using semi-automated online solid phase extraction coupled with tandem mass spectrometry. Partial adaptation of the activity score system demonstrated a strong association between genotype and phenotype, as illustrated by a kappa value of 0.792, inter-rater discrepancy of 0.051 and sensitivity of 72.7%. Predicted phenotype frequencies using the modified activity score were 1.3% for poor metabolisers (PM), 7.6% for intermediate metabolisers (IM) and 87.3% for extensive metabolisers (EM). Measured phenotype frequencies were 1.3% for PM, 13.9% for IM and 84.8% for EM. Comprehensive CYP2D6 genotyping reliably predicts CYP2D6 activity in this South African cohort and can be utilised as a valuable pharmacogenetic tool. PMID- 26503816 TI - Computational discovery of transcription factors associated with drug response. AB - This study integrates gene expression, genotype and drug response data in lymphoblastoid cell lines with transcription factor (TF)-binding sites from ENCODE (Encyclopedia of Genomic Elements) in a novel methodology that elucidates regulatory contexts associated with cytotoxicity. The method, GENMi (Gene Expression iN the Middle), postulates that single-nucleotide polymorphisms within TF-binding sites putatively modulate its regulatory activity, and the resulting variation in gene expression leads to variation in drug response. Analysis of 161 TFs and 24 treatments revealed 334 significantly associated TF-treatment pairs. Investigation of 20 selected pairs yielded literature support for 13 of these associations, often from studies where perturbation of the TF expression changes drug response. Experimental validation of significant GENMi associations in taxanes and anthracyclines across two triple-negative breast cancer cell lines corroborates our findings. The method is shown to be more sensitive than an alternative, genome-wide association study-based approach that does not use gene expression. These results demonstrate the utility of GENMi in identifying TFs that influence drug response and provide a number of candidates for further testing. PMID- 26503817 TI - Gene copy number variation analysis reveals dosage-insensitive expression of CYP2E1. AB - Gene copy number variants (CNVs) of CYP2E1 have been described but not functionally characterized. Here we investigated effects of CNVs on hepatic and lymphoblastoid CYP2E1 expression. Using available single-nuleotide polymorphism microarray data and quantitative PCR, CYP2E1 gene duplication and deletion carriers were identified. CYP2E1 mRNA, protein and enzyme activity (chlorzoxazone 6-hydroxylation) phenotypes of CYP2E1 were not associated with gene copy number. Analysis of gene expression in lymphoblastoid cell lines in relation to CNV confirmed this finding in an extrahepatic tissue and for other ethnicities. Further analyses identified a linked haplotype cluster with possible influence on gene expression. In summary, our data suggest a homeostatic, gene dosage insensitive regulation of CYP2E1 expression by unknown gene dosage compensation mechanisms. This is in striking contrast to well-known structural variations of CYP2A6 and CYP2D6 that have a strong impact on expression and activity. These findings are important in the context of pharmacogenetic prediction. PMID- 26503814 TI - A genome-wide analysis of the response to inhaled beta2-agonists in chronic obstructive pulmonary disease. AB - Short-acting beta2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled beta2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 * 10(-7)) and KCNJ2 (P=1.79 * 10( 7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 * 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65. PMID- 26503818 TI - Complement 3 and metabolic syndrome induced by clozapine: a cross-sectional study and retrospective cohort analysis. AB - Metabolic syndrome (MetS) is considered to be an adverse effect of long-term treatment with atypical antipsychotics, particularly clozapine. There is strong evidence that the activation of inflammatory pathways interferes with normal metabolism and contributes to the development of MetS. C3, which is an inflammation molecule, has been reported to be associated with MetS. Because C3 is a heritable trait, we accordingly hypothesized that the gene encoding C3 (C3) would be a candidate gene for inter-individual variation in clozapine-induced MetS. We recruited 576 schizophrenia patients taking clozapine and measured the serum levels of fasting metabolic parameters. We then examined C3 mRNA and genotyped seven polymorphisms in C3. The expression quantitative trait locus (eQTL) data available for tissues were extracted by the Genotype-Tissue Expression Portal. A total of 105 patients' medical records were retrospectively reviewed to obtain the metabolic parameters during the initial 2-year clozapine treatment. The relative expression levels of C3 mRNA in patients with MetS were significantly higher than in those without MetS (P=0.02). C3 single-nucleotide polymorphism (SNP) rs2277984 was marginally associated with MetS (allelic P=0.06, odds ratio=1.36, 95% confidence interval (CI): 1.07-1.72). We found a significant association of rs2277984 with fasting triglyceride (TG) levels (P=0.004). Further, eQTL analysis revealed that rs2277984 regulates C3 expression in the liver (P=0.002). Similar results were found in the retrospective cohort analysis. The receiver operating characteristic curve showed a significant effect of the rs2277984 G allele on the percentage change of TG levels, with an area under the curve of 0.71 (95% CI: 0.60-0.81). C3 is likely to enhance TG accumulation and to confer susceptibility to clozapine-induced MetS. The C3 SNP rs2277984 may be a potential biomarker for predicting MetS risk in patients receiving clozapine treatment. PMID- 26503819 TI - Estrogen receptor-beta genetic variations and overall survival in patients with locally advanced gastric cancer. AB - Estrogen has been shown not only to reduce the incidence of colorectal cancer but also gastric cancer (GC). Polymorphisms in estrogen receptor beta gene, ESR2, correlate with colorectal cancer survival. To better understand the role of ESR2 in GC, genomic DNA extracted from 169 Japanese patients and 172 patients from Los Angeles County (LAC) was analyzed for association of overall survival (OS) with three ESR2 polymorphisms, which are of biological significance using multivariable Cox proportional hazard regression. ESR2 rs1271572 (C>A) and rs3020443 (T>G) had univariate and multivariable associations with OS in the Japanese cohort, whereas the C allele of ESR2 rs2978381 (T>C) predicted favorable OS in the Japanese cohort but worse OS in the LAC cohort. The interaction term of the ESR2 rs2978381 and cohort group reached statistical significance. Our study provides evidence that genetic variations in ESR2 gene are significantly associated with survival in patients with locally advanced GC. PMID- 26503821 TI - Latticed pentamode acoustic cloak. AB - We report in this work a practical design of pentamode acoustic cloak with microstructure. The proposed cloak is assembled by pentamode lattice made of a single-phase solid material. The function of rerouting acoustic wave round an obstacle has been demonstrated numerically. It is also revealed that shear related resonance due to weak shear resistance in practical pentamode lattices punctures broadband feature predicted based on ideal pentamode cloak. As a consequence, the latticed pentamode cloak can only conceal the obstacle in segmented frequency ranges. We have also shown that the shear resonance can be largely reduced by introducing material damping, and an improved broadband performance can be achieved. These works pave the way for experimental demonstration of pentamode acoustic cloak. PMID- 26503822 TI - Predictive validity of the body adiposity index in costa rican students. AB - OBJECTIVE: To verify the validity of the body adiposity index (BAI) in a sample of Costa Rican students. METHODS: Volunteers were 93 females (mean age = 18.6 +/- 2.4 years) and 106 males (mean age = 19.2 +/- 2.8 years). Dual-energy X-ray absorptiometry (DXA) was used as the "gold standard" to determine body fat percentage (BF%). Pearson's correlation coefficient and paired samples t-test studied the association and mean differences between BAI and DXA BF%. Concordance between BAI and DXA BF% was determined by the Lin's concordance correlation coefficient and the Bland-Altman agreement analysis. RESULTS: Significant correlations between BAI and DXA BF% were found for females (r = 0.74) and males (r = 0.53) (P < 0.001). Differences between methods were found for females (BAI = 29.3 +/- 4.1% vs. DXA = 36.5 +/- 7.9%) and males (BAI = 24.8 +/- 3.7% vs. DXA = 21.9 +/- 8.6%; P < 0.001). Concordance was poor in females and males. Bland Altman plots showed BAI underestimating and overestimating BF% in relation to the "gold standard" in females and males, respectively. CONCLUSIONS: BAI presented low agreement with BF% measured by DXA; therefore, BAI is not recommended for BF% prediction in this Central American sample studied. Am. J. Hum. Biol. 28:394-397, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26503823 TI - Optineurin mutations in patients with sporadic amyotrophic lateral sclerosis in China. AB - The purpose of this study was to assess the frequency of optineurin (OPTN) mutation in amyotrophic lateral sclerosis (ALS) patients from mainland China, as well as to characterize the relationship between OPTN mutation and clinical phenotypes. We examined the coding region of OPTN in 511 unrelated Chinese sporadic ALS (SALS) subjects and 204 healthy controls using a PCR direct sequencing strategy. Nine OPTN variants were identified, of which four were novel missense mutations: c.407C > T (p.A136V), c.1184A > G (p.K395R), c.1352T > C (p.I451T), and c.1546G > C (p.E516Q) (all heterozygous). The remaining five variants were already present in single nucleotide polymorphism databases. Patients with OPTN mutations were characterized by spinal onset, although they showed differences in disease progression. In conclusion, this study provides a genetic epidemiological characterization of OPTN mutations in Chinese patients, and our results are consistent with the proposition that such mutations are common in Asian populations. PMID- 26503820 TI - Interethnic variation of CYP2C19 alleles, 'predicted' phenotypes and 'measured' metabolic phenotypes across world populations. AB - The present study evaluates the worldwide frequency distribution of CYP2C19 alleles and CYP2C19 metabolic phenotypes ('predicted' from genotypes and 'measured' with a probe drug) among healthy volunteers from different ethnic groups and geographic regions, as well as the relationship between the 'predicted' and 'measured' CYP2C19 metabolic phenotypes. A total of 52 181 healthy volunteers were studied within 138 selected original research papers. CYP2C19*17 was 42- and 24-fold more frequent in Mediterranean-South Europeans and Middle Easterns than in East Asians (P<0.001, in both cases). Contrarily, CYP2C19*2 and CYP2C19*3 alleles were more frequent in East Asians (30.26% and 6.89%, respectively), and even a twofold higher frequency of these alleles was found in Native populations from Oceania (61.30% and 14.42%, respectively; P<0.001, in all cases), which may be a consequence of genetic drift process in the Pacific Islands. Regarding CYP2C19 metabolic phenotype, poor metabolizers (PMs) were more frequent among Asians than in Europeans, contrarily to the phenomenon reported for CYP2D6. A correlation has been found between the frequencies of CYP2C19 poor metabolism 'predicted' from CYP2C19 genotypes (gPMs) and the poor metabolic phenotype 'measured' with a probe drug (mPMs) when subjects are either classified by ethnicity (r=0.94, P<0.001) or geographic region (r=0.99, P=0.002). Nevertheless, further research is needed in African and Asian populations, which are under-represented, and additional CYP2C19 variants and the 'measured' phenotype should be studied. PMID- 26503824 TI - Topical treatment for scalp psoriasis: Comparison of patient preference, quality of life and efficacy for non-alcoholic mometasone emulsion versus calcipotriol/betamethasone gel in daily clinical practice. AB - OBJECTIVE: To evaluate patients' assessment of therapy, efficacy, quality of life and treatment adherence in patients with scalp psoriasis treated with non alcoholic mometasone emulsion or calcipotriol/betamethasone gel. METHODS: Prospective, open-label, multicentre, non-interventional study. Patients with non severe scalp psoriasis were treated with mometasone emulsion or calcipotriol/betamethasone gel. Evaluations included patient's global assessment of treatment, physician's global assessment of disease severity, quality of life (Dermatology Life Quality Index), physician's subjective evaluation of therapy, treatment adherence and adverse events. RESULTS: Ninety-five patients treated with mometasone emulsion and 88 treated with calcipotriol/betamethasone gel were included in the intention-to-treat analysis. Patients' global assessment of treatment favoured mometasone emulsion over calcipotriol/betamethasone gel (p = 0.008), with treatment rated as good/very good by 91% versus 82.5%. Patients were less likely to report irritation of fingers' skin with mometasone than with calcipotriol/betamethasone (p = 0.0015). Severity of scalp psoriasis and quality of life improved in both groups. Adherence to treatment was similar in both groups. Physicians' perception of efficacy, tolerability and compliance was better for mometasone emulsion. CONCLUSION: Non-alcoholic mometasone emulsion achieved greater acceptability to patients and physicians than calcipotriol/betamethasone gel for the treatment of scalp psoriasis. Both topical treatments were similarly effective in terms of disease severity and quality of life. PMID- 26503825 TI - GACD: Integrated Software for Genetic Analysis in Clonal F1 and Double Cross Populations. AB - Clonal species are common among plants. Clonal F1 progenies are derived from the hybridization between 2 heterozygous clones. In self- and cross-pollinated species, double crosses can be made from 4 inbred lines. A clonal F1 population can be viewed as a double cross population when the linkage phase is determined. The software package GACD (Genetic Analysis of Clonal F1 and Double cross) is freely available public software, capable of building high-density linkage maps and mapping quantitative trait loci (QTL) in clonal F1 and double cross populations. Three functionalities are integrated in GACD version 1.0: binning of redundant markers (BIN); linkage map construction (CDM); and QTL mapping (CDQ). Output of BIN can be directly used as input of CDM. After adding the phenotypic data, the output of CDM can be used as input of CDQ. Thus, GACD acts as a pipeline for genetic analysis. GACD and example datasets are freely available from www.isbreeding.net. PMID- 26503826 TI - Lower Protein Intake Mediates Association Between Lower Occlusal Force and Slower Walking Speed: From the Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians Study. AB - OBJECTIVES: To investigate the association between lower extremity motor function and occlusion in older adults and to examine the possibility of dietary intake of protein mediating the association. DESIGN: Cross-sectional, population-based study. SETTING: Urban and rural area in Japan. PARTICIPANTS: Community-dwelling septuagenarians (N = 655) and octogenarians (N = 629). MEASUREMENTS: Information was collected on occlusal force, protein intake, grip strength, walking speed, sociodemographic characteristics, and medical history. Multivariable logistic regression analysis was used to investigate the association between walking speed, occlusal force, and protein intake, and structural equation modeling analysis and mediation analysis were performed to investigate the validity of the hypothesized model and identify the indirect effect of protein intake in occlusal force and walking speed. RESULTS: The proportion of participants whose walking speed was 0.8 m/s or slower (slow walking speed) was 27.7%. Logistic regression analyses showed that slower walking speed was associated with occlusal force (odds ratio = 1.57, P = .001) after adjusting for medical history, body mass index, grip strength, and protein intake. The fit of the hypothesized model that walking speed was associated with occlusal force through protein intake was good, and the indirect effect was significant. CONCLUSION: Slower walking speed was associated with lower occlusal force. Lower protein intake mediated the association between walking speed and occlusal force. Maintaining occlusal force might prevent insufficient nutrition intake and further deterioration of motor function in older people. PMID- 26503827 TI - Monitoring Genotoxicity Potential in the Mumbuca Stream, Minas Gerais, Brazil. AB - Rivers are sites for water catchment to supply metropolitan areas but also serve as receptors for discharge of urban sewage, wastewater, and agri-industrial effluents. Bioindicators or sentinel organisms are widely used as markers of pollution in various environments. The objective of this study was to evaluate the genotoxic potential and consequent quality of the water from the Mumbuca stream, which supplies the city of Monte Carmelo, located in the Minas Triangle region, Minas Gerais, Brazil. This was achieved using two variable response bioindicators (Rhamdia quelen and Geophagus brasiliensis), the micronucleus (MN) test, and determining the presence of metals by flame atomic absorption spectrometry. Results showed that site 3 water (region of residential flow and intense industrial pottery activity) presented a greater possibility for induction of genotoxic activity, as evidenced by the increase in the MN frequency in Rhamdia quelen and Geophagus brasiliensis in comparison with the reference site water. The water of the Mumbuca stream was influenced by genotoxic agents, especially lead and chromium, assessed by the rise in MN rate. Data suggested that discharge of industrial effluents in a specific stretch of the stream interfered with biota functions. PMID- 26503828 TI - Phloretin induces apoptosis of non-small cell lung carcinoma A549 cells via JNK1/2 and p38 MAPK pathways. AB - Phloretin (Ph) existing in apples, pears and various vegetables is known to have antitumor activities in several cancer cell lines. However, little is known about its effect on human lung cancer cells. The aim of the present study was to see whether Ph could induce apoptosis of non-small cell lung cancer (NSCLC) cells, and explore the possible underlying mechanism of action. We found that Ph markedly induced cell apoptosis of NSCLC cell line A549, and inhibited the migration of A549 cells in a dose-dependent manner. The expression level of BAX, cleaved caspase-3 and -9, and degraded form of PARP was increased and Bcl-2 was decreased after Ph treatment. In addition, the phosphorylation of P38 MAPK, ERK1/2 and JNK1/2 was increased in a dose-dependent manner in parallel with Ph treatment. Inhibition of P38 MAPK and JNK1/2 by specific inhibitors significantly abolished the Ph-induced activation of the caspase-3 and -9. In vivo tumor suppression assay further indicated that Ph (20 mg/kg) displayed a more significant inhibitory effect on A549 xenografts in tumor growth. All these findings indicate that Ph is able to inhibit NSCLC A549 cell growth by inducing apoptosis through P38 MAPK and JNK1/2 pathways, and therefore may prove to be an adjuvant to the treatment of NSCLC. PMID- 26503829 TI - Protein:Ligand binding free energies: A stringent test for computational protein design. AB - A computational protein design method is extended to allow Monte Carlo simulations where two ligands are titrated into a protein binding pocket, yielding binding free energy differences. These provide a stringent test of the physical model, including the energy surface and sidechain rotamer definition. As a test, we consider tyrosyl-tRNA synthetase (TyrRS), which has been extensively redesigned experimentally. We consider its specificity for its substrate l tyrosine (l-Tyr), compared to the analogs d-Tyr, p-acetyl-, and p-azido phenylalanine (ac-Phe, az-Phe). We simulate l- and d-Tyr binding to TyrRS and six mutants, and compare the structures and binding free energies to a more rigorous "MD/GBSA" procedure: molecular dynamics with explicit solvent for structures and a Generalized Born + Surface Area model for binding free energies. Next, we consider l-Tyr, ac- and az-Phe binding to six other TyrRS variants. The titration results are sensitive to the precise rotamer definition, which involves a short energy minimization for each sidechain pair to help relax bad contacts induced by the discrete rotamer set. However, when designed mutant structures are rescored with a standard GBSA energy model, results agree well with the more rigorous MD/GBSA. As a third test, we redesign three amino acid positions in the substrate coordination sphere, with either l-Tyr or d-Tyr as the ligand. For two, we obtain good agreement with experiment, recovering the wildtype residue when l-Tyr is the ligand and a d-Tyr specific mutant when d-Tyr is the ligand. For the third, we recover His with either ligand, instead of wildtype Gln. PMID- 26503830 TI - Developing xylem-preferential expression of PdGA20ox1, a gibberellin 20-oxidase 1 from Pinus densiflora, improves woody biomass production in a hybrid poplar. AB - Woody biomass has gained popularity as an environmentally friendly, renewable and sustainable resource for liquid fuel production. Here, we demonstrate biotechnological improvement of the quantity and quality of woody biomass by employing developing xylem (DX)-preferential production of gibberellin (GA), a phytohormone that positively regulates stem growth. First, for the proof of concept experiment, we produced transgenic Arabidopsis plants expressing GA20 oxidase, a key enzyme in the production of bioactive GAs, from Pinus densiflora (PdGA20ox1) under the control of either a constitutive 35S promoter, designated 35S::PdGA20ox1, or a DX-specific promoter (originated from poplar), designated DX15::PdGA20ox1. As we hypothesized, both transgenic Arabidopsis plants (35S::PdGA20ox1 and DX15::PdGA20ox1) exhibited an accelerated stem growth that resulted in a large increase of biomass, up to 300% compared to wild-type control plants, together with increased secondary wall thickening and elongation of fibre cells. Next, we applied our concept to the production of transgenic poplar trees. Both transgenic poplar trees (35S::PdGA20ox1 and DX15::PdGA20ox1) showed dramatic increases in biomass, up to 300%, with accelerated stem growth and xylem differentiation. Cell wall monosaccharide composition analysis revealed that in both Arabidopsis and poplar, glucose and xylose contents were significantly increased. However, undesirable phenotypes of 35S::PdGA20ox1 poplar, including poor root growth and leaf development, were found. Interestingly, DX15::PdGA20ox1 poplar resulted in a reduction of undesirable phenotypes. Our results indicate that the controlled production of GAs through a tissue-specific promoter can be utilized as an efficient biotechnological tool for producing enhanced plant biomass, minimizing unwanted effects. PMID- 26503831 TI - Vaccination of chickens decreased Newcastle disease virus contamination in eggs. AB - Newcastle disease is an important health issue of poultry causing major economic losses and inhibits trade worldwide. Vaccination is used as a control measure, but it is unknown whether vaccination will prevent virus contamination of eggs. In this study, hens were sham-vaccinated or received one or two doses of inactivated LaSota vaccine, followed three weeks later by virulent Newcastle disease virus (NDV) challenge. Eggs were collected daily and shell, albumen and yolk were subjected to virus isolation, as were oral and cloacal swabs at 2 and 4 days post-challenge (dpc). A second experiment evaluated the distribution of the virus in the reproductive tract of non-vaccinates. All vaccinated chickens survived challenge, and the levels of virus shed from cloacal swabs were decreased significantly when compared to shams. In non-vaccinated hens, virus was detected in the ovary and all segments of the oviduct. Yolk, albumen and eggshell surface from eggs laid at day 4 and 5 post-infection by sham-vaccinated hens were positive for NDV, but eggs from LaSota vaccinated hens lacked virus in internal egg components (i.e. yolk and albumen) and had reduction in the number of positive eggshell surfaces. These results indicate virulent NDV can replicate in the reproductive tract of hens and contaminate internal components of eggs and eggshell surface, but vaccination was able to prevent internal egg contamination, reducing eggshell surface contamination, and reducing shedding from digestive and respiratory tracts in virulent NDV challenged hens. PMID- 26503832 TI - Comparison of FDG and FDG-labeled leukocytes PET/CT in diagnosis of infection. AB - The aim of this study is to compare FDG and FDG-labeled leukocyte (WBC) PET/CT in the diagnosis of infection using different SUV and visual thresholds for interpretation. Patients, material, method: 49 consecutive patients (27 men, 22 women, mean age: 55.7 years, range: 16-89 years) with suspected musculoskeletal infection (n = 34), vascular graft infection (n = 5), aortitis (n =1 ), endocarditis (n = 1), mass lesion which is suspicious for infection or malignity (n = 6), and fever of unknown origin (n = 2) underwent both FDG and WBC-PET/CT. Images were evaluated by both visual analysis (grade 1-3) according to uptake intensity and quantitative grading (grade 1-3) based on lesion to background SUVmax values. Final diagnosis was made by histopathological, microbiological analysis or clinical-radiological work-up. RESULTS: The diagnosis of infection was made in total 24 patients, of whom 14 were diagnosed by histopathological and the rest by clinical-radiological work-up. WBC-PET/CT imaging with the visual threshold of 1b as infection positivity (for truncal lesions uptake equivalent to liver or lumbar vertebrae uptake; for extremity lesions uptake significantly higher than neighbouring soft tissue uptake or higher than neighbouring bone marrow uptake) was found to have the highest diagnostic accuracy (AUC: 0.874, CI: 0.771-0.997, p < 0.001). The optimal SUV threshold was found to be 8.8 (p = 0.006; sensitivity: 72.7%, specificity: 82.8) and 5.3 (p < 0.001; sensitivity: 81.8%, specificity: 79.3%) for FDG and WBC-PET/CT, respectively by ROC curve analysis. CONCLUSION: WBC-PET/CT is more valuable than FDG PET/CT in the imaging of infection. Visual threshold of >1b seems to be more suitable for detection of infection. PMID- 26503833 TI - Induced Pluripotent Stem Cell-Derived Natural Killer Cells for Treatment of Ovarian Cancer. AB - Natural killer (NK) cells can provide effective immunotherapy for ovarian cancer. Here, we evaluated the ability of NK cells isolated from peripheral blood (PB) and NK cells derived from induced pluripotent stem cell (iPSC) to mediate killing of ovarian cancer cells in a mouse xenograft model. A mouse xenograft model was used to evaluate the intraperitoneal delivery of three different NK cell populations: iPSC-derived NK cells, PB-NK cells that had been activated and expanded in long-term culture, and overnight activated PB-NK cells that were isolated through CD3/CD19 depletion of PB B and T cells. Bioluminescent imaging was used to monitor tumor burden of luciferase expressing tumor lines. Tumors were allowed to establish prior to administering NK cells via intraperitoneal injection. These studies demonstrate a single dose of any of the three NK cell populations significantly reduced tumor burden. When mice were given three doses of either iPSC-NK cells or expanded PB-NK cells, the median survival improved from 73 days in mice untreated to 98 and 97 days for treated mice, respectively. From these studies, we conclude iPSC-derived NK cells mediate antiovarian cancer killing at least as well as PB-NK cells, making these cells a viable resource for immunotherapy for ovarian cancer. Due to their ability to be easily differentiated into NK cells and their long-term expansion potential, iPSCs can be used to produce large numbers of well-defined NK cells that can be banked and used to treat a large number of patients including treatment with multiple doses if necessary. PMID- 26503834 TI - Encrypted Three-dimensional Dynamic Imaging using Snapshot Time-of-flight Compressed Ultrafast Photography. AB - Compressed ultrafast photography (CUP), a computational imaging technique, is synchronized with short-pulsed laser illumination to enable dynamic three dimensional (3D) imaging. By leveraging the time-of-flight (ToF) information of pulsed light backscattered by the object, ToF-CUP can reconstruct a volumetric image from a single camera snapshot. In addition, the approach unites the encryption of depth data with the compressed acquisition of 3D data in a single snapshot measurement, thereby allowing efficient and secure data storage and transmission. We demonstrated high-speed 3D videography of moving objects at up to 75 volumes per second. The ToF-CUP camera was applied to track the 3D position of a live comet goldfish. We have also imaged a moving object obscured by a scattering medium. PMID- 26503835 TI - Direct Observation of 4-Phenoxyphenylnitrenium Ion: A Transient Absorption and Transient Resonance Raman Study. AB - Femtosecond (fs) and nanosecond (ns) transient absorption (TA) and single pulse transient resonance Raman spectroscopic investigation of the intermediates after laser photolysis of 4-phenoxyphenyl azide in acetonitrile and mixed aqueous solution is reported. fs-TA results show that the singlet 4-phenoxyphenylnitrene was produced immediately after photolysis of the azide. Then, the singlet nitrene underwent intersystem crossing (ISC) and ring expansion to generate triplet nitrene and ketenimine in acetonitrile with t = 346 ps or protonation in mixed aqueous solution with t = 37 ps, respectively, a little slower than the counterparts of the methoxy one (108 and 5.4 ps for ISC and protonation processes, respectively). The transient Raman spectrum combined density functional theory (DFT) calculation predicting the structure and vibrational frequencies suggested that phenoxyphenylnitrenium ion has a comparable quinoidal character to that of methoxy- and ethoxy-phenylnitrenium ions. All of these results indicated that the phenoxy substitution has some impact on the reactivity of phenylnitrene but a slight influence on the structure of phenylnitrenium ion. PMID- 26503837 TI - Differential Uptake Mechanisms of Fluorescent Substrates into Stem-Cell-Derived Serotonergic Neurons. AB - The actions of the neurotransmitters serotonin, dopamine, and norepinephrine are partly terminated by diffusion and in part by their uptake into neurons via the selective, high-affinity transporters for serotonin (SERT), dopamine (DAT), and norepinephrine (NET), respectively. There is also growing evidence that all three monoamines are taken up into neurons by low-affinity, high-capacity organic cation transporters (OCT) and the plasma membrane monoamine transporter (PMAT). Pharmacological characterization of these low-affinity recombinant transporter proteins in heterologous expression systems has revealed that they are not antagonized by classical inhibitors of SERT, DAT, or NET but that decynium-22 (D22) antagonizes OCT3 and PMAT, whereas corticosterone and progesterone selectively inhibit OCT3. Here, we show that SERT, PMAT, and OCT3, but not OCT1 and OCT2, are coexpressed in murine stem cell-derived serotonergic neurons. Using selective antagonists, we provide evidence that uptake of the fluorescent substrates FFN511, ASP+, and 5-HT into stem cell-derived serotonergic neurons is mediated differentially by these transporters and also involves an as yet unknown transport mechanism. PMID- 26503838 TI - Dynamic, six-axis stiffness matrix characteristics of the intact intervertebral disc and a disc replacement. AB - Thorough pre-testing is critical in assessing the likely in vivo performance of spinal devices prior to clinical use. However, there is a lack of data available concerning the dynamic testing of lumbar (porcine model) total disc replacements in all six axes under preload conditions. The aim of this study was to provide new data comparing porcine lumbar spinal specimen stiffness between the intact state and after the implantation of an unconstrained total disc replacement, in 6 degrees of freedom. The dynamic, stiffness matrix testing of six porcine lumbar isolated disc specimens was completed using triangle waves at a test frequency of 0.1 Hz. An axial preload of 500 N was applied during all testing. Specimens were tested both in the intact condition and after the implantation of the total disc replacement. Sixteen key stiffness terms were identified for the comparison of the intact and total disc replacement specimens, comprising the 6 principal stiffness terms and 10 key off-axis stiffness terms. The total disc replacement specimens were significantly different to the intact specimens in 12 of these key terms including all six principal stiffness terms. The implantation of the total disc replacement resulted in a mean reduction in the principal stiffness terms of 100%, 91%, and 98% in lateral bending, flexion-extension, and axial rotation, respectively. The novel findings of this study have demonstrated that the unconstrained, low-friction total disc replacement does not replicate the stiffness of the intact specimens. It is likely that other low-friction total disc replacements would produce similar results due to stiffness being actively minimised as part of the design of low-friction devices, without the introduction of stiffening elements or mechanisms to more accurately replicate the mechanical properties of the natural intervertebral disc. This study has demonstrated, for the first time, a method for the quantitative comparative mechanical function testing of total disc replacements and provides baseline data for the development of future devices. PMID- 26503839 TI - Biomechanical comparison of unilateral semi-rigid and dynamic stabilization on ovine vertebrae. AB - Using the unilateral pedicle screw fixation was thought to decrease the stiffness of the fixed segments. Various prospective, randomized studies were performed to determine whether unilateral pedicle screw fixation provides the necessities of bilateral fixation in one- or two-segment lumbar spinal fusion. In this study, four different unilateral pedicle screw fixation systems were evaluated to determine which one best approximated an intact spine with respect to biomechanics and kinematics. The four groups included an intact group, a unilateral facetectomy group with no fixation, a unilateral semi-rigid pedicle screw fixation group with a poly-ether-ether-ketone rod, and a unilateral dynamic pedicle screw fixation group. The bone mineral densities of all specimens were measured and specimens were matched with groups randomly. Flexion, lateral bending, and axial rotation tests were performed to compare the groups. For the flexion, lateral bending, and axial rotation tests, the best biomechanical outcomes were in the control group. The unilateral facetectomy group had the poorest performance and was not stable enough, compared with the control group. The dynamic and semi-rigid groups showed performance closer to that of the control group. The biomechanical responses of these two groups were also in good agreement, showing no significant statistical differences. Based on these test results, it is concluded that the unilateral dynamic and semi-rigid pedicle screw fixations can be used to provide stability to the vertebrae. PMID- 26503840 TI - Pullout performance comparison of pedicle screws based on cement application and design parameters. AB - Pedicle screws are the main fixation devices for certain surgeries. Pedicle screw loosening is a common problem especially for osteoporotic incidents. Cannulated screws with cement augmentation are widely used for that kind of cases. Dual lead dual cored pedicle screw has already given promising pullout values without augmentation. This study concentrates on the usage of dual lead dual core with cement augmentation as an alternative to cannulated and standard pedicle screws with cement augmentation. Five groups (dual lead dual core, normal pedicle screw and cannulated pedicle screw with augmentation, normal pedicle screw, dual lead dual cored pedicle screw) were designed for this study. Healthy bovine vertebrae and synthetic polyurethane foams (grade 20) were used as embedding test medium. Test samples were prepared in accordance with surgical guidelines and ASTM F543 standard testing protocols. Pullout tests were conducted with Instron 3300 testing frame. Load versus displacement values were recorded and maximum pullout loads were stated. The dual lead dual cored pedicle screw with poly-methyl methacrylate augmentation exhibited the highest pullout values, while dual lead dual cored pedicle screw demonstrated similar pullout strength as cannulated pedicle screw and normal pedicle screw with poly-methyl methacrylate augmentation. The dual lead dual cored pedicle screw with poly-methyl methacrylate augmentation can be used for osteoporotic and/or severe osteoporotic patients according to its promising results on animal cadaver and synthetic foams. PMID- 26503841 TI - Lessons from retrievals: Retrievals help understand the reason for revision of coated hip arthroplasties. AB - Coatings have been applied to all surfaces of hip implants with the majority performing well in the laboratory, but there are few reports of their performance in humans. The rationale for coating the metal-on-metal bearing surfaces includes a reduction in metal ion release and risk of adverse reaction to metal debris; yet there are no reports of retrieved coated metal-on-metal hip implants despite the concern that they may delaminate. The aim of this study was to better understand the performance of coated hip implants in humans through findings of three coated metal-on-metal hip resurfacings, retrieved after failure for unexplained pain. Analysis of these implants included quantification of the amount and mechanism of coating loss which was correlated with clinical, imaging and blood data. In all cases, there were large areas of complete coating loss in which the metal substrate was exposed and found to be rougher than the coated areas. The coating loss gave rise to third body abrasive wear of the coating and the exposed metal, the latter of which led to high blood levels of cobalt and chromium. Coating of the bearing surfaces of metal-on-metal hip resurfacings, therefore, do not prevent metal ion release when implanted into humans. This is an example of a need for increased retrieval analysis of newly introduced implants and expansion of laboratory testing regulations to better reflect the clinical environment. PMID- 26503842 TI - Global and segmental kinematic changes following sequential resection of posterior osteoligamentous structures in the lumbar spine: An in vitro biomechanical investigation using pure moment testing protocols. AB - Lumbar spinal surgeries may compromise the integrity of posterior osteoligamentous structures implicating mechanical stability. Circumstances necessitating a concomitant surgery to achieve restabilisation are not well understood. The main objective of this in vitro study was to quantify global and segmental (index and adjacent levels) kinematic changes in the lumbar spine following sequential resection of the posterior osteoligamentous structures using pure moment testing protocols. Six fresh frozen cadaveric kangaroo lumbar spines (T12-S1) were tested under a bending moment in flexion-extension, bilateral bending, and axial torsion in a 6-degree-of-freedom Kinematic Spine Simulator. Specimens were tested in the following order: intact state (D0), after interspinous and supraspinous ligaments transection between L4 and L5 (D1), further after a total bilateral facetectomy between L4 and L5 (D2). Segmental motions at the cephalad, damaged, and caudal levels were recorded using an infrared-based motion tracking device. Following D1, no significant change in the global range of motion was observed in any of the bending planes. Following D2, a significant increase in the global range of motion from the baseline (D0) was observed in axial torsion (median normalised change +20%). At the damaged level, D2 resulted in a significant increase in the segmental range of motion in flexion extension (+77%) and axial torsion (+492%). Additionally, a significant decrease in the segmental range of motion in axial torsion (-35%) was observed at the caudal level following D2. These results suggest that a multi-segment lumbar spine acts as a mechanism for transmitting motions, and that a compromised joint may significantly alter motion transfer to adjacent segments. We conclude that the interspinous and supraspinous ligaments play a modest role in restricting global spinal motions within physiologic limits. Following interspinous and supraspinous ligaments transection, a total bilateral facetectomy resulted in a significant increase in axial torsion motion, both at global and damaged levels, accompanied with a compensatory decrease in motion at the caudal level. PMID- 26503843 TI - The effects of DASH diet on weight loss and metabolic status in adults with non alcoholic fatty liver disease: a randomized clinical trial. AB - BACKGROUND & AIMS: This study was designed to determine the effects of the Dietary Approaches to Stop Hypertension (DASH) diet on weight loss and metabolic status in overweight patients with non-alcoholic fatty liver disease (NAFLD). METHODS: This randomized controlled clinical trial was done among 60 overweight and obese patients with NAFLD. Patients were randomly allocated to consume either the control (n = 30) or the DASH eating pattern (n = 30) for 8 weeks. Both diets were designed to be calorie-restricted. Both diets were consisted of 52-55% carbohydrates, 16-18% proteins and 30% total fats; however, the DASH diet was designed to be rich in fruits, vegetables, whole grains, and low-fat dairy products and low in saturated fats, cholesterol and refined grains. RESULTS: Adherence to the DASH eating pattern, compared to the control diet, weight (P = 0.006), BMI (P = 0.01), alanine aminotransferase (ALT) (P = 0.02), alkalin phosphatase (ALP) (P = 0.001), insulin levels (P = 0.01), homoeostasis model of assessment-estimated insulin resistance (HOMA-IR) (P = 0.01) significantly decreased and quantitative insulin sensitivity check index (QUICKI) (P = 0.004) significantly increased. Compared with the control diet, the DASH diet has resulted in significant reductions in serum triglycerides (P = 0.04) and total /HDL-cholesterol ratio (P = 0.01). Finally, decreased concentrations of serum high-sensitivity C-reactive protein (hs-CRP) (P = 0.03), malondialdehyde (MDA) (P = 0.04), increased levels of nitric oxide (NO) (P = 0.01) and glutathione (GSH) (P = 0.009) were found in the DASH group compared with the control group. CONCLUSIONS: Consumption of DASH diet for 8 weeks among patients with NAFLD had beneficial effects on weight, BMI, ALT, ALP, triglycerides, markers of insulin metabolism, inflammatory markers, GSH and MDA. PMID- 26503845 TI - MECHANISMS IN ENDOCRINOLOGY: MicroRNA in diagnostics and therapy of thyroid cancer. AB - MicroRNAs, short non-coding regulators of the gene expression, are subjects of numerous investigations assessing their potential use in the diagnostics and management of human diseases. In this review, we focus on studies that analyze the utility of microRNAs as novel diagnostic and therapeutic tools in follicular cell-derived thyroid carcinomas. This very interesting and promising field brings new insight into future strategies for personalized medicine. PMID- 26503844 TI - CETP/LPL/LIPC gene polymorphisms and susceptibility to age-related macular degeneration. AB - Three high-density lipoprotein (HDL)-related loci have been reported to be associated with age-related macular degeneration (AMD), but the results were inconsistent. In this study, the cholesteryl ester transfer protein (CETP) rs3764261 variant was significantly associated with an increased risk of AMD (odds ratio [OR] = 1.13, 95% confidence interval [CI]: 1.05-1.21, P < 0.001), and the hepatic lipase (LIPC) rs10468017 variant was associated with a significantly decreased risk of AMD (OR = 0.81, CI: 0.76-0.86, P < 0.001). Individuals carrying the lipoprotein lipase (LPL) rs12678919 polymorphism (A -> G) had no significant change in the risk of developing AMD (OR = 1.01, CI: 0.92-1.10, P = 0.17). After adjusting for the complement factor H (CFH) gene, both CETP and LPL conferred a significantly increased AMD risk (ORCETP = 1.17, CI: 1.08-1.26, P < 0.001; ORLPL = 1.11, CI: 1.01-1.22, P = 0.02). Subgroup analysis based on ethnicity revealed a significant association between the CETP variant and AMD in both Americans (OR = 1.12, CI: 1.02-1.23, P = 0.01) and Europeans (OR = 1.10, CI: 1.01-1.19, P = 0.011). This meta-analysis revealed that both CETP rs3764261 and LIPC rs10468017 polymorphisms were significantly associated with AMD risk. After adjustment for the CFH gene, CETP/LPL conferred a significantly increased susceptibility to the disease, indicating potential interactions among genes in the complement system and the lipid metabolism pathway. PMID- 26503846 TI - Genetic vasopressin 1b receptor variance in overweight and diabetes mellitus. AB - OBJECTIVE: Recently, imbalance in the vasopressin (AVP) system, measured as elevated levels of copeptin (the C-terminal part of the AVP pro-hormone) in plasma, was linked to the development of abdominal obesity and diabetes mellitus (DM). Here, we aim to investigate if the genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity and DM. DESIGN: Malmo Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991-1996. METHODS: Four tag single nucleotide polymorphisms (SNPs: rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6103) of MDC (MDC-CC) and associated with measures of obesity and DM. Significant SNPs were replicated in another 24 344 MDC individuals (MDC replication cohort). RESULTS: In MDC-CC, the major allele of rs35810727 was associated with elevated BMI (beta-coefficient +/- s.e.m.; 0.30 +/ 0.14, P=0.03) and waist (0.78 +/- 0.36, P=0.03) after age and gender adjustment. The association with BMI was replicated in the MDC replication cohort (0.21 +/- 0.07, P=0.003), whereas that with waist was not significant. In MDC-CC there was no association between the major allele of rs35810727 and DM, but in the complete MDC cohort (n=30 447) the major allele of rs35810727 was associated with DM (OR (95% CI); 1.10 (1.00-1.20), P=0.04). CONCLUSIONS: Genetic variance of AVPR1B contributes to overweight. Furthermore, our data indicate a link between AVPR1B variance and DM development. Our data point at a relationship between the disturbance of the pharmacologically modifiable AVP system and the body weight regulation. PMID- 26503847 TI - Functional Analysis of Genes Involved in the Biosynthesis of Enterocin NKR-5-3B, a Novel Circular Bacteriocin. AB - A putative biosynthetic gene cluster of the enterocin NKR-5-3B (Ent53B), a novel circular bacteriocin, was analyzed by sequencing the flanking regions around enkB, the Ent53B structural gene, using a fosmid library. A region approximately 9 kb in length was obtained, and the enkB1, enkB2, enkB3, and enkB4 genes, encoding putative biosynthetic proteins involved in the production, maturation, and secretion of Ent53B, were identified. We also determined the identity of proteins mediating self-immunity against the effects of Ent53B. Heterologous expression systems in various heterologous hosts, such as Enterococcus faecalis and Lactococcus lactis strains, were successfully established. The production and secretion of the mature Ent53B required the cooperative functions of five genes. Ent53B was produced only by those heterologous hosts that expressed protein products of the enkB, enkB1, enkB2, enkB3, and enkB4 genes. Moreover, self immunity against the antimicrobial action of Ent53B was conferred by at least two independent mechanisms. Heterologous hosts harboring the intact enkB4 gene and/or a combination of intact enkB1 and enkB3 genes were immune to the inhibitory action of Ent53B. IMPORTANCE: In addition to their potential application as food preservatives, circular bacteriocins are now considered possible alternatives to therapeutic antibiotics due to the exceptional stability conferred by their circular structure. The successful practical application of circular bacteriocins will become possible only if the molecular details of their biosynthesis are fully understood. The results of the present study offer a new perspective on the possible mechanism of circular bacteriocin biosynthesis. In addition, since some enterococcal strains are associated with pathogenicity, virulence, and drug resistance, the establishment of the first multigenus host heterologous production of Ent53B has very high practical significance, as it widens the scope of possible Ent53B applications. PMID- 26503848 TI - Gliding Direction of Mycoplasma mobile. AB - Mycoplasma mobile glides in the direction of its cell pole by a unique mechanism in which hundreds of legs, each protruding from its own gliding unit, catch, pull, and release sialylated oligosaccharides fixed on a solid surface. In this study, we found that 77% of cells glided to the left with a change in direction of 8.4 degrees +/- 17.6 degrees MUm(-1) displacement. The cell body did not roll around the cell axis, and elongated, thinner cells also glided while tracing a curved trajectory to the left. Under viscous conditions, the range of deviation of the gliding direction decreased. In the presence of 250 MUM free sialyllactose, in which the binding of the legs (i.e., the catching of sialylated oligosaccharides) was reduced, 70% and 30% of cells glided to the left and the right, respectively, with changes in direction of ~30 degrees MUm(-1). The gliding ghosts, in which a cell was permeabilized by Triton X-100 and reactivated by ATP, glided more straightly. These results can be explained by the following assumptions based on the suggested gliding machinery and mechanism: (i) the units of gliding machinery may be aligned helically around the cell, (ii) the legs extend via the process of thermal fluctuation and catch the sialylated oligosaccharides, and (iii) the legs generate a propulsion force that is tilted from the cell axis to the left in 70% and to the right in 30% of cells. IMPORTANCE: Mycoplasmas are bacteria that are generally parasitic to animals and plants. Some Mycoplasma species form a protrusion at a pole, bind to solid surfaces, and glide. Although these species appear to consistently glide in the direction of the protrusion, their exact gliding direction has not been examined. This study analyzed the gliding direction in detail under various conditions and, based on the results, suggested features of the machinery and the mechanism of gliding. PMID- 26503849 TI - Effect of LexA on Chromosomal Integration of CTXphi in Vibrio cholerae. AB - The genesis of toxigenic Vibrio cholerae involves acquisition of CTXphi, a single stranded DNA (ssDNA) filamentous phage that encodes cholera toxin (CT). The phage exploits host-encoded tyrosine recombinases (XerC and XerD) for chromosomal integration and lysogenic conversion. The replicative genome of CTXphi produces ssDNA by rolling-circle replication, which may be used either for virion production or for integration into host chromosome. Fine-tuning of different ssDNA binding protein (Ssb) levels in the host cell is crucial for cellular functioning and important for CTXphi integration. In this study, we mutated the master regulator gene of SOS induction, lexA, of V. cholerae because of its known role in controlling levels of Ssb proteins in other bacteria. CTXphi integration decreased in cells with a DeltalexA mutation and increased in cells with an SOS noninducing mutation, lexA (Ind(-)). We also observed that overexpression of host encoded Ssb (VC0397) decreased integration of CTXphi. We propose that LexA helps CTXphi integration, possibly by fine-tuning levels of host- and phage-encoded Ssbs. IMPORTANCE: Cholera toxin is the principal virulence factor responsible for the acute diarrheal disease cholera. CT is encoded in the genome of a lysogenic filamentous phage, CTXphi. Vibrio cholerae has a bipartite genome and harbors single or multiple copies of CTXphi prophage in one or both chromosomes. Two host encoded tyrosine recombinases (XerC and XerD) recognize the folded ssDNA genome of CTXphi and catalyze its integration at the dimer resolution site of either one or both chromosomes. Fine-tuning of ssDNA binding proteins in host cells is crucial for CTXphi integration. We engineered the V. cholerae genome and created several reporter strains carrying DeltalexA or lexA (Ind(-)) alleles. Using the reporter strains, the importance of LexA control of Ssb expression in the integration efficiency of CTXphi was demonstrated. PMID- 26503850 TI - The C-Terminal Zwitterionic Sequence of CotB1 Is Essential for Biosilicification of the Bacillus cereus Spore Coat. AB - Silica is deposited in and around the spore coat layer of Bacillus cereus, and enhances the spore's acid resistance. Several peptides and proteins, including diatom silaffin and silacidin peptides, are involved in eukaryotic silica biomineralization (biosilicification). Homologous sequence search revealed a silacidin-like sequence in the C-terminal region of CotB1, a spore coat protein of B. cereus. The negatively charged silacidin-like sequence is followed by a positively charged arginine-rich sequence of 14 amino acids, which is remarkably similar to the silaffins. These sequences impart a zwitterionic character to the C terminus of CotB1. Interestingly, the cotB1 gene appears to form a bicistronic operon with its paralog, cotB2, the product of which, however, lacks the C terminal zwitterionic sequence. A DeltacotB1B2 mutant strain grew as fast and formed spores at the same rate as wild-type bacteria but did not show biosilicification. Complementation analysis showed that CotB1, but neither CotB2 nor C-terminally truncated mutants of CotB1, could restore the biosilicification activity in the DeltacotB1B2 mutant, suggesting that the C-terminal zwitterionic sequence of CotB1 is essential for the process. We found that the kinetics of CotB1 expression, as well as its localization, correlated well with the time course of biosilicification and the location of the deposited silica. To our knowledge, this is the first report of a protein directly involved in prokaryotic biosilicification. IMPORTANCE: Biosilicification is the process by which organisms incorporate soluble silicate in the form of insoluble silica. Although the mechanisms underlying eukaryotic biosilicification have been intensively investigated, prokaryotic biosilicification was not studied until recently. We previously demonstrated that biosilicification occurs in Bacillus cereus and its close relatives, and that silica is deposited in and around a spore coat layer as a protective coating against acid. The present study reveals that a B. cereus spore coat protein, CotB1, which carried a C-terminal zwitterionic sequence, is essential for biosilicification. Our results provide the first insight into mechanisms required for biosilicification in prokaryotes. PMID- 26503851 TI - The Journal of Bacteriology Is 100. PMID- 26503853 TI - PRACTICAL METROLOGICAL ASPECTS OF NEUTRON PERSONAL DOSIMETRY. AB - This article addresses practical issues as being faced in the process of testing, verification and calibration of passive and active personal neutron dosemeters. Namely, a limited choice of neutron sources and geometric limitations occurring when ISO water phantom is used. The requirements of international standards for personal neutron dosemeters and the possibilities to fulfil them are discussed briefly. PMID- 26503852 TI - Sarcosine Catabolism in Pseudomonas aeruginosa Is Transcriptionally Regulated by SouR. AB - Sarcosine (N-methylglycine) is present in many environments inhabited by pseudomonads and is likely most often encountered as an intermediate in the metabolism of choline, carnitine, creatine, and glyphosate. While the enzymology of sarcosine metabolism has been relatively well studied in bacteria, the regulatory mechanisms governing catabolism have remained largely unknown. We previously determined that the sarcosine-catabolic (sox) operon of Pseudomonas aeruginosa is induced by the AraC family regulator GbdR in response to glycine betaine and dimethylglycine. However, induction of these genes was still observed in response to sarcosine in a gbdR deletion mutant, indicating that an independent sarcosine-responsive transcription factor also acted at this locus. Our goal in this study was to identify and characterize this regulator. Using a transposon-based genetic screen, we identified PA4184, or SouR (sarcosine oxidation and utilization regulator), as the sarcosine-responsive regulator of the sox operon, with tight induction specificity for sarcosine. The souR gene is required for appreciable growth on sarcosine as a carbon and nitrogen source. We also characterized the transcriptome response to sarcosine governed by SouR using microarray analyses and performed electrophoretic mobility shift assays to identify promoters directly regulated by the transcription factor. Finally, we characterized PA3630, or GfnR (glutathione-dependent formaldehyde neutralization regulator), as the regulator of the glutathione-dependent formaldehyde detoxification system in P. aeruginosa that is expressed in response to formaldehyde released during the catabolism of sarcosine. This study expands our understanding of sarcosine metabolic regulation in bacteria through the identification and characterization of the first known sarcosine-responsive transcriptional regulator. IMPORTANCE: The Pseudomonas aeruginosa genome encodes many diverse metabolic pathways, yet the specific transcription regulators controlling their expression remain mostly unknown. Here, we used a genetic screen to identify the sarcosine-specific regulator of the sarcosine oxidase operon, which we have named SouR. SouR is the first bacterial regulator shown to respond to sarcosine, and it is required for growth on sarcosine. Sarcosine is found in its free form and is also an intermediate in the catabolic pathways of glycine betaine, carnitine, creatine, and glyphosate. The similarity of SouR to the regulators of carnitine and glycine betaine catabolism suggests evolutionary diversification within this regulatory family to allow response to structurally similar but physiologically distinct ligands. PMID- 26503856 TI - SPACE DOSIMETRY MEASUREMENTS IN THE STRATOSPHERE USING DIFFERENT ACTIVE AND PASSIVE DOSIMETRY SYSTEMS. AB - Several measurements have been performed on the cosmic radiation field from the surface of the Earth up to the maximum altitudes of research aeroplanes. However, there is only limited information about that between 15 and 30 km altitudes. In order to study the radiation environment in the stratosphere, an experiment was built by students from Hungarian universities that flew on board the BEXUS (Balloon Experiments for University Students) stratospheric balloon in Northern Sweden, from the ESRANGE Space Center. The main technical goals of the experiment were to test at the first time the TRITEL 3D silicon detector telescope system in close to space conditions and to develop a balloon technology platform for advanced cosmic radiation and dosimetric measurements. The main scientific goals were to give an assessment of the cosmic radiation field at the altitude of the BEXUS balloons, to use the TRITEL system to determine dosimetric and radiation quantities during the balloon flight and to intercompare the TRITEL and Pille results to provide a correction factor for the Pille measurements. To fulfil the scientific and technological objectives, several different dosimeter systems were included in the experiment: an advanced version of the TRITEL silicon detector telescope, Geiger-Muller (GM) counters and Pille thermoluminescent dosimeters. The float altitude of the BEXUS balloon was ~28.6 km; the total flight time was ~4 h. Measurement data from the active instruments were received in real time by the ground team during the mission. There were no failures in the operation of the system; everything worked as expected. This article presents the scientific goals and results in detail. From the TRITEL measurements, the linear energy transfer spectra, the average quality factor of the cosmic radiation as well as the absorbed dose and the dose equivalent were determined. Estimations for the uncertainty in the TRITEL measurements were given. The deposited energy spectra measured with the TRITEL instrument were compared with the count rates measured with the GM counters. The experiences and results gained in the frame of the project will be used in the evaluation of TRITEL data from measurements on board the International Space Station. As an outlook a short overview is given of the planned rocket radiation experiments based on the system used in the BEXUS programme. PMID- 26503854 TI - SECOND LATIN AMERICAN INTERCOMPARISON ON INTERNAL DOSE ASSESSMENT. AB - Internal dosimetry intercomparisons are essential for the verification of applied models and the consistency of results'. To that aim, the First Regional Intercomparison was organised in 2005, and that results led to the Second Regional Intercomparison Exercise in 2013, which was organised in the frame of the RLA 9/066 and coordinated by Autoridad Regulatoria Nuclear of Argentina. Four simulated cases covering intakes of (131)I, (137)Cs and Tritium were proposed. Ninteen centres from thirteen different countries participated in this exercise. This paper analyses the participants' results in this second exercise in order to test their skills and acquired knowledge, particularly in the application of the IDEAS Guidelines. It is important to highlight the increased number of countries that participated in this exercise compared with the first one and, furthermore, the improvement in the overall performance. The impact of the International Atomic Energy Agency (IAEA) Projects since 2003 has led to a significant enhancement of internal dosimetry capabilities that strengthen the radiation protection of workers. PMID- 26503855 TI - ASSESSMENT OF THE LOCAL EXPOSURE OF SKIN ON HANDS OF NUCLEAR MEDICINE WORKERS HANDLING 18F-LABELLED RADIOPHARMACEUTICALS: PRELIMINARY CZECH STUDY. AB - The article summarises some preliminary results of the assessment of the exposure of hands of workers manipulating 18F-labelled radiopharmaceuticals based on personal monitoring at two nuclear medicine clinics in the Czech Republic. The measurements were carried out using special thermoluminescence dosemeters the readings of which could be interpreted in terms of the personal dose equivalent Hp(0.07) approximating the equivalent dose to the skin at various locations on the surface of both hands. The results have shown that out of 21 workers monitored, ~43 % (preparation and applications of radiopharmaceuticals) may reach an exposure equal to three-tenth of the annual dose limit to the skin. At the same time, it can also be concluded that in ~10 % cases of workers, the relevant dose limit may be exceeded. PMID- 26503857 TI - FADING EFFECT OF LiF:Mg,Ti AND LiF:Mg,Cu,P Ext-Rad AND WHOLE-BODY DETECTORS. AB - Thermoluminescence dosemeters are widely used in individual and environmental monitoring. The aim of this work was to compare the thermal stability of dosemeters of the Ext-Rad and whole-body card types with LiF:Mg,Ti and LiF:Mg,Cu,P detectors stored at different temperatures and periods. The dosemeters were stored at 0 degrees C, room temperature and 40 degrees C for periods that lasted 8, 30, 45, 90 and 120 d. In general, TLD-100H detectors present higher TL signal stability than TLD-100 detectors. The intensity of the signal remained constant for both materials for storage periods at 0 degrees C. At RT the same results was observed for TLD-100H. For TLD-100 detectors, a maximum variation of 22 % was registered for the longest period. At 40 degrees C the TL signal decreased with storage time for both detectors. The TL signal of TLD-100H detectors presented maximum variations of 12 % whereas for TLD-100 detectors, larger variations of 25 % were observed. PMID- 26503858 TI - Loading of Vesicles into Soft Amphiphilic Nanotubes using Osmosis. AB - The facile assembly of higher-order nanoarchitectures from simple building blocks is demonstrated by the loading of vesicles into soft amphiphilic nanotubes using osmosis. The nanotubes are constructed from rigid interdigitated bilayers which are capped with vesicles comprising phospholipid-based flexible bilayers. When a hyperosmotic gradient is applied to these vesicle-capped nanotubes, the closed system loses water and the more flexible vesicle bilayer is pulled inwards. This leads to inclusion of vesicles inside the nanotubes without affecting the tube structure, showing controlled reorganization of the self-assembled multicomponent system upon a simple osmotic stimulus. PMID- 26503859 TI - Facilitating Change: A Process of Renewal for Women Who Have Used Force in Their Intimate Heterosexual Relationships. AB - The authors highlight a community's response to women's use of force, detail aspects of intervention strategies, and introduce a conceptual model representing the women's change process. In doing so, they encourage community partnerships, continued intervention innovation, and further research. Their observations suggest an intervention philosophy and approach that women have described as one of personal "renewal." The community's experiences are notable in light of national efforts to effectively meet the needs of female survivors of intimate partner violence who have used force. PMID- 26503860 TI - Prevalence and Factors Associated With Severe Physical Intimate Partner Violence Among U.S. Black Women: A Comparison of African American and Caribbean Blacks. AB - This study explored prevalence rates and factors associated with lifetime severe physical intimate partner violence among U.S. Black women. Data from the National Survey of American Life were examined. Rates of severe physical intimate partner violence were higher among African American women compared with U.S. Caribbean Black women. Risk factors associated with reported abuse were similar to those found in earlier studies but differed by ethnic backgrounds. Demographic, resource, and situational factors were associated with severe physical intimate partner violence among U.S. Black women in general but made unique contributions by ethnic group. Implications and suggestions for future studies were discussed. PMID- 26503862 TI - Edaphobacter dinghuensis sp. nov., an acidobacterium isolated from lower subtropical forest soil. AB - An aerobic bacterium, designated DHF9T, was isolated from a soil sample collected from the lower subtropical forest of Dinghushan Biosphere Reserve, Guangdong Province, PR China. Cells were Gram-stain-negative, non-motile, short rods that multiplied by binary division. Strain DHF9T was an obligately acidophilic, mesophilic bacterium capable of growth at pH 3.5-5.5 (optimum pH 4.0) and at 10 33 degrees C (optimum 28-33 degrees C). Growth was inhibited at NaCl concentrations above 2.0 % (w/v). The major fatty acids were iso-C15 : 0, C16 : 0 and C16 : 1omega7c. The polar lipids consist of phosphatidylethanolamine, two unidentified aminolipids, two unidentified phospholipids, two unidentified polar lipids and an unidentified glycolipid. The DNA G+C content was 57.7 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain belongs to the genus Edaphobacter in subdivision 1 of the phylum Acidobacteria, with the highest 16S rRNA gene sequence similarity of 97.0 % to Edaphobacter modestus Jbg-1T. Based on phylogenetic, chemotaxonomic and physiological analyses, it is proposed that strain DHF9T represents a novel species of the genus Edaphobacter, named Edaphobacter dinghuensis sp. nov. The type strain is DHF9T ( = DSM 29920T = CGMCC 1.12997T). PMID- 26503863 TI - [The role of gastro-intestinal tract in the calcium absorption]. AB - Calcium is associated with various functions of clinical importance. Its unique distribution;low intracellular and high extracellular concentration, is crucial for the neuro-muscular function. Calcium is also indispensable for the vascular contraction and blood coagulation. Thus, circulating calcium concentration must be strictly maintained within a narrow range, for which parathyroid hormone(PTH), vitamin D, and calcitonin contribute. Food-derived protein-bound calcium must be first released in the acidic condition. Thus, gastric acid is essential for the effective calcium absorption. Intestinal calcium absorption occurs via both active transport and passive transport. For the former, such molecules as transient receptor potential vanilloid type 6(TRPV6), calbindin 9k, and Ca2+ ATPase contribute. In the adult, calcium absorption rate is approximately 30% under the ordinary condition. Lower calcium intake is associated with increased calcium absorption and decreased urinary excretion. In the Dietary Reference Intakes for Japanese, calcium requirement is determined based on factorial method. Recommended Dietary Allowance(RDA)for calcium ranges from 600-800 mg/day for adult. However, the average calcium intake is far lower than Estimated Average Requirement(EAR). Thus, an effort to increase the calcium intake, rather than considering the detailed calcium absorption rate, is most essential in Japan. PMID- 26503864 TI - [The role of the liver in vitamin D metabolism]. AB - Vitamin D3is generated in the skin, and subsequently metabolized to 25OHD3in the liver and then to 1alpha,25(OH)2D3in the kidney, and thereafter, 1alpha,25(OH)2D3exerts its biological functions by regulating gene transcription via binding to nuclear receptor, VDR in target cells. 1alpha,25(OH)2D3plays a critical role in this vitamin D endocrine system. However, it has become obvious in the recent years that plasma concentrations of 25OHD3but not 1alpha,25(OH)2D3, significantly associate with the incident risk of life style-related diseases such as osteoporosis and diabetes. Moreover, it appears that 25OHD3itself acts as a ligand for VDR. Based on the findings that liver is not only the major productive organ for 25OHD3but also the sole productive organ for DBP which serves to deliver 25OHD3to tissues and stores 25OHD3in the blood circulation, it is believed that liver plays important roles in vitamin D metabolism and vitamin D functions. The roles of the liver in vitamin D metabolism including the regulatory mechanism of the expression and activation of a 25OHD3biosynthetic enzyme, CYP2R1, remain largely unsolved. PMID- 26503865 TI - [Bone complications in chronic liver disease(hepatic osteodystrophy)]. AB - Bone complication occurs in patients with alcoholic hepatitis, chronic hepatitis C, primary biliary cirrhosis(PBC), primary sclerosing cholangitis(PSC)or post liver transplant. Prevalence of osteoporosis and fracture risk is high in these diseases. Nonalcoholic fatty liver disease(NAFLD)and non-alcoholic steatohepatitis(NASH)is increasing in prevalence. Relation of NAFLD/NASH with osteoporosis, however, is not well known, and further investigation is needed. PMID- 26503866 TI - [Bone metabolic disorder after gastrectomy]. AB - Bone metabolic disorder after gastrectomy is a silent complication, and has potential of severely disturbing quality of life. However, the awareness of this complication is not enough in clinicians. We examined the influence of gastrectomy on bone metabolism using the investigation of clinical cases and experiments with rat surgical models. We discussed the influence of the volume of resected stomach and the reconstructed route of food passage. Bone metabolic disorders were observed in 30% of patients after gastrectomy. They were milder in cases after proximal gastrectomy compared with total gastrectomy(p=0.110), and segmental/local gastrectomy compared with distal gastrectomy(p=0.080), in cases with physiological route of foods passing compared with non- physiological route(p=0.091). Similar results were observed in the experiments with rat surgical models. Both of the volume of the remnant stomach and the reconstructed food passing route are correlated with bone metabolic disorders after gastrectomy. PMID- 26503867 TI - [Bone disease in primary biliary cirrhosis]. AB - Primary biliary cirrhosis(PBC)is a chronic autoimmune cholestatic liver disease. Metabolic bone disease is recognized in a complication of chronic liver disease, particularly in PBC. Bone disease in PBC includes osteoporosis and, osteomalacia which is more frequent in advanced liver disease. It is important that PBC occurs mainly in middle-aged women who are highest risk group in primary osteoporosis. In patients with PBC, the dysfunction in enterohepatic circulation of bile acids is associated with the impaired absorption of fats and fat soluble vitamins. Vitamin D and K deficiency leads to osteoporosis resulting in increased risk of bone fracture. This article describes the characteristic and molecular mechanism in bone disease of PBC. PMID- 26503868 TI - [Inflammatory bowel disease and bone decreased bone mineral density]. AB - Metabolic bone diseases such as osteopenia and osteoporosis increase the risk of bone fracture that negatively affects quality of life of individuals. Patients with inflammatory bowel disease(IBD), including ulcerative colitis(UC)and Crohn's disease(CD), have been shown to be at increased risk of decreased bone mineral density, however frequency of metabolic bone disease in IBD and identified risk factors are varied among reports. PMID- 26503869 TI - [Hepatocellular carcinoma and vitamin K2]. AB - Despite recent progress in diagnosis and therapy, hepatocellular carcinoma(HCC)remains among the cancers with the poorest prognoses. Vitamin Ks(VKs)have been shown to suppress the growth of HCC cells. Long-term administration of VK2 has established its clinical safety, but it does not appear to exhibit marked anti-tumor effects when administered alone. For more effective use of VK2 against HCC, co-administration of VK2 with other proven anticancer agents or development of a new VK preparation with a modified side-chain should be investigated in the future. PMID- 26503870 TI - [Interferon and bone]. AB - Interferon(IFN)alpha, beta and gamma were identified, and demonstrated played a crucial role in regulating immune system. Expression of IFN alpha and beta are both promoted by viral infection, and these factors have been utilized to treat the patients with hepatitis C. Meanwhile, IFN gamma is expressed in activated T cells, such as Th1 cells, and also plays a crucial role in immune system. Beside the immune roles, IFNs were demonstrated to regulate bone homeostasis via osteoclasts, osteoblasts or both. In this review, I will discuss the roles of IFNs in bone system. PMID- 26503871 TI - [Trabecular bone changes in the spine after transarterial chemoembolization therapy for hepatocellular carcinoma]. AB - The number of computed tomography(CT)-guided interventional procedures has increased because they are less invasive and more cost-effective than open surgery. Transarterial chemoembolization(TACE)is a method in which chemotherapeutic drugs are injected into the artery that supplies the tumor. It is also well known that multidetector-CT has tremendously advanced our diagnostic capabilities broadly throughout medicine. These diagnostic benefits have combined with the widespread availability and rapidity of scanning to marked increases in CT use, for example, dynamic contrast-enhanced CT, CT perfusion imaging, and CT during angiography. However, rapidly increasing use of CT has heightened concerns about the high levels of cumulative exposure that may occur in patients undergoing recurrent imaging for chronic conditions such as chronic hepatitis or hepatocellular carcinomas. So far, bone toxicity associated with CT has received little attention. The prevalence of osteoporosis and trabecular microstructural changes using clinical MDCT-based microstructural analysis in patients after TACE with the interventional-CT system to treat hepatocellular carcinoma have been demonstrated here. PMID- 26503872 TI - [Proton pump inhibitor and bone complications]. AB - Many observational studies indicated a significant association between PPI use and increased risk of hip and vertebral fractures, but no evidence of duration effect was founded by meta-analysis. However, observational studies cannot clarify whether the observed epidemiologic association is a causal effect or a result of unmeasured/residual confounding. Furthermore, a mechanism through which PPI increase the risk of fracture has not been proven. Overall, PPI use dose not interfere with calcium absorption in most instances and, therefore, it is unlikely that PPI influence fracture risk through interfering with absorption of dietary calcium. There is no consistent effect of PPI on bone mineral density as assessed by dual energy X-ray absorptiometry testing. Thus, randomized controlled studies are required to confirm of refute these results. At this time, the author does not recommend discontinuing PPI in patients with a history of fracture or those at increased risk of fracture. However, clinicians should still endeavor to avoid using PPI in situations where benefits are minimal or clinical indication are lacking. PMID- 26503873 TI - [Clinical guidelines for bone disease in primary biliary cirrhosis]. AB - Primary biliary cirrhosis(PBC)is a chronic cholestatic liver disease and the association of osteoporosis is high. In this paper, the practical guidelines for PBC of Japan as well as those of America(AASLD)and Europe(EASL)are mentioned. Description of each guideline is essentially the same;taking sufficient calcium(1,000~1,200 mg/day)with vitamin D and weight-bearing exercise, and thereafter medication such as alendronate is recommended. PMID- 26503874 TI - [Treatment of bone disease caused by gastrectomy]. AB - Gastrectomy is undergone mainly in patients with gastric cancer. Bone diseases(osteoporosis and osteomalacia)caused by gastractomy are associated with weight loss, calcium and vitamin D inadequancy, and malnutrition. Most patients after gastrectomy have multile risk factors of bone diseases and subsequently are at a higher risk for fractures. In particular, sex hormone deficiency and aging enhance the risk for fractures. The management of bone diseases caused by gastraectomy include adequet intake of calcium, vitamin D and protein, sunlight exposure, and regular weight-bearing exercise, as well as non-smoking and avoiding excess alcohol drinking. The patients at a high risk for fractures shoud be treated with bisphosphonates. PMID- 26503875 TI - [Treatment for hepatic osteodystrophy]. AB - Chronic liver diseases, including liver cirrhosis, are caused by various pathogenesis, such as viral hepatitis, primary biliary cirrhosis, autoimmune hepatitis and steatohepatitis. There have not been enough clinical evidence about the treatment of hepatic osteodystrophy at the present time. Several reports suggested that bisphosphonates, such as alendronate, are effective for an increase in bone mineral density in patients with chronic liver disease. Vitamin D treatment might be useful for the frequent prevalence of vitamin D deficiency in the pathogenesis of hepatic oseodystrophy. The use of estrogens will be limited for the risk of liver dysfunction and hepatocellular carcinoma. PMID- 26503876 TI - [Phosphate homeostasis and oral diseases]. AB - FGF23 produced mainly by osteocytes plays a central role in phosphate homeostasis by increasing the renal phosphate excretion and suppressing the vitamin D activation. Mutations in FGF23 and its regulatory molecules such as PHEX, DMP1, and FAM20C have been shown to be responsible for hereditary hypophosphatemic diseases. Patients and animal models of these hypophosphatemic conditions often manifest dental defects, whose etiology may include hypophosphatemia and impaired vitamin D action. In addition, the mechanisms specific to each responsible gene such as accumulated ASARM peptides in PHEX deficiency and the reduced DSPP expression in DMP1 deficiency are also involved in the pathogenesis of these dental problems. PMID- 26503877 TI - Panobinostat for the treatment of relapsed or relapsed/refractory multiple myeloma: pharmacology and clinical outcomes. AB - Recently, outcomes for patients with multiple myeloma have improved dramatically due to improved and innovative therapies. However, most patients will either relapse or become refractory to current therapy. Thus, a significant unmet need remains for novel agents to treat this patient population. Panobinostat, a potent pan-deacetylase inhibitor with a unique mechanism of action targeting both epigenetic regulation of gene expression and protein metabolism, has preclinical synergy with a number of agents, including the proteasome inhibitor bortezomib. In a phase 3 trial of panobinostat with bortezomib and dexamethasone, addition of panobinostat significantly prolonged the median progression-free survival of patients with relapsed or relapsed and refractory multiple myeloma. This review focuses on clinical development of panobinostat, with particular emphasis on pharmacokinetics and adverse event management. PMID- 26503878 TI - On the Energetics of Ions in Carbon and Gold Nanotubes. AB - We investigate the insertion of halide and alkali atoms into narrow single-walled carbon nanotubes with diameters <9 A by density functional theory; both chiral and non-chiral tubes are considered. The atoms are stored in the form of ions; the concomitant charge transfer affects the band structure and makes originally semiconducting tubes conducting. The electrostatic interaction between a charge and the walls of the tube is explicitly calculated. The insertion energies and the positions of the ions are determined by a competition between electrostatic energy and Pauli repulsion. For comparison, we consider ions in gold nanotubes. Alkali ions follow the same principles in gold as in carbon tubes, but chloride is specifically adsorbed inside gold tubes. PMID- 26503879 TI - Gendered power dynamics and women's negotiation of family planning in a high HIV prevalence setting: a qualitative study of couples in western Kenya. AB - In sub-Saharan Africa, high burdens of HIV and unmet need for contraception often coexist. Research emphasises the need to engage men and couples in reproductive health, yet couples' negotiations around fertility and family planning in the context of HIV have been sparsely studied. This study examined the gendered power dynamics that frame women's and couples' negotiations of contraceptive use in western Kenya. We conducted 76 in-depth interviews with 38 couples, of whom 22 couples were concordant HIV-positive. Qualitative data were analysed using a grounded theory approach. Direct communication around contraception with men was often challenging due to perceived or expressed male resistance. A substantial minority of women avoided male reproductive decision-making authority through covert contraceptive use, with concern for severe consequences when contraceptive use was discovered. Many men assumed that family planning use signified female promiscuity and that infidelity motivated covert use. Men were more willing to use condoms to avoid HIV re-infection or on the recommendation of HIV care providers, which allowed some women leverage to insist on condom use. Our findings highlight the tension between male dominated reproductive decision making and women's agency and point to the need for gender transformative approaches seeking to challenge masculinities that negatively impact health. PMID- 26503881 TI - Fruits and Vegetables Get a Golden Halo Once Again: Is There More to the Story? PMID- 26503880 TI - Association of Fruit and Vegetable Consumption During Early Adulthood With the Prevalence of Coronary Artery Calcium After 20 Years of Follow-Up: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - BACKGROUND: The relationship between intake of fruits and vegetables (F/V) during young adulthood and coronary atherosclerosis later in life is unclear. METHODS AND RESULTS: We studied participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort of young, healthy black and white individuals at baseline (1985-1986). Intake of F/V at baseline was assessed using a semiquantitative interview administered diet history, and coronary artery calcium was measured at year 20 (2005-2006) using computed tomography. We used logistic regression to adjust for relevant variables and estimate the adjusted odds ratios and 95% confidence intervals across energy-adjusted, sex-specific tertiles of total servings of F/V per day. Among our sample (n=2506), the mean (SD) age at baseline was 25.3 (3.5) years, and 62.7% were female. After adjustment for demographics and lifestyle variables, higher intake of F/V was associated with a lower prevalence of coronary artery calcium: odds ratio (95% confidence interval) =1.00 (reference), 0.78 (0.59-1.02), and 0.74 (0.56-0.99), from the lowest to the highest tertile of F/V, P value for trend <0.001. There was attenuation of the association between F/V and coronary artery calcium after adjustment for other dietary variables, but the trend remained significant: odds ratio (95% confidence interval): 1.00 (reference), 0.84 (0.63-1.11), and 0.92 (0.67-1.26), P value for trend <0.002]. CONCLUSIONS: In this longitudinal cohort study, higher intake of F/V during young adulthood was associated with lower odds of prevalent coronary artery calcium after 20 years of follow-up. Our results reinforce the importance of establishing a high intake of F/V as part of a healthy dietary pattern early in life. PMID- 26503882 TI - Role of Reverse Divalent Cation Diffusion in Forward Osmosis Biofouling. AB - We investigated the role of reverse divalent cation diffusion in forward osmosis (FO) biofouling. FO biofouling by Pseudomonas aeruginosa was simulated using pristine and chlorine-treated thin-film composite polyamide membranes with either MgCl2 or CaCl2 draw solution. We related FO biofouling behavior-water flux decline, biofilm architecture, and biofilm composition-to reverse cation diffusion. Experimental results demonstrated that reverse calcium diffusion led to significantly more severe water flux decline in comparison with reverse magnesium permeation. Unlike magnesium, reverse calcium permeation dramatically altered the biofilm architecture and composition, where extracellular polymeric substances (EPS) formed a thicker, denser, and more stable biofilm. We propose that FO biofouling was enhanced by complexation of calcium ions to bacterial EPS. This hypothesis was confirmed by dynamic and static light scattering measurements using extracted bacterial EPS with the addition of either MgCl2 or CaCl2 solution. We observed a dramatic increase in the hydrodynamic radius of bacterial EPS with the addition of CaCl2, but no change was observed after addition of MgCl2. Static light scattering revealed that the radius of gyration of bacterial EPS with addition of CaCl2 was 20 times larger than that with the addition of MgCl2. These observations were further confirmed by transmission electron microscopy imaging, where bacterial EPS in the presence of calcium ions was globular, while that with magnesium ions was rod-shaped. PMID- 26503883 TI - Liver cancer: A model of fibrolamellar carcinoma. PMID- 26503884 TI - Therapy: Avoiding treatment failures associated with HCV resistance. PMID- 26503885 TI - Transplantation: Allocation of liver transplants-a road to consensus. AB - Rationing of livers for transplantation is a difficult problem especially when creation of national policies is needed. Italy recently convened a national consensus conference to decide who should be first in line. PMID- 26503886 TI - A novel nanobiosensor for the detection of paraoxon using chitosan-embedded organophosphorus hydrolase immobilized on Au nanoparticles. AB - Organophosphorus (OP) compounds are one of the most hazardous chemicals used as insecticides/pesticide in agricultural practices. A large variety of OP compounds are hydrolyzed by organophosphorus hydrolases (OPH; EC 3.1.8.1). Therefore, OPHs are among the most suitable candidates that could be used in designing enzyme based sensors for detecting OP compounds. In this work, a novel nanobiosensor for the detection of paraoxon was designed and fabricated. More specifically, OPH was covalently embedded onto chitosan and the enzyme-chitosan bioconjugate was then immobilized on negatively charged gold nanoparticles (AuNPs) electrostatically. The enzyme was immobilized on AuNPs without chitosan as well, to compare the two systems in terms of detection limit and enzyme stability under different pH and temperature conditions. Coumarin 1, a competitive inhibitor of the enzyme, was used as a fluorogenic probe. The emission of coumarin 1 was effectively quenched by the immobilized Au-NPs when bound to the developed nanobioconjugates. However, in the presence of paraoxon, coumarin 1 left the nanobioconjugate, leading to enhanced fluorescence intensity. Moreover, compared to the immobilized enzyme without chitosan, the chitosan-immobilized enzyme was found to possess decreased Km value by more than 50%, and increased Vmax and Kcat values by around 15% and 74%, respectively. Higher stability within a wider range of pH (2-12) and temperature (25-90 degrees C) was also achieved. The method worked in the 0 to 1050 nM concentration ranges, and had a detection limit as low as 5 * 10(-11) M. PMID- 26503887 TI - Enantioselective Synthesis of alpha-Hydroxy Amides and beta-Amino Alcohols from alpha-Keto Amides. AB - Synthesis of enantiomerically enriched alpha-hydroxy amides and beta-amino alcohols has been accomplished by enantioselective reduction of alpha-keto amides with hydrosilanes. A series of alpha-keto amides were reduced in the presence of chiral Cu(II)/(S)-DTBM-SEGPHOS catalyst to give the corresponding optically active alpha-hydroxy amides with excellent enantioselectivities by using (EtO)3SiH as a reducing agent. Furthermore, a one-pot complete reduction of both ketone and amide groups of alpha-keto amides has been achieved using the same chiral copper catalyst followed by tetra-n-butylammonium fluoride (TBAF) catalyst in presence of (EtO)3SiH to afford the corresponding chiral beta-amino alcohol derivatives. PMID- 26503888 TI - A comparison of methods for construction of fetal reference charts. AB - Reference charts for fetal measures are used for early detection of pregnancies that should be monitored closely. Construction of reference charts corresponds to estimation of quantiles of a distribution as a function of gestational age. Existing methods have been developed under various modeling assumptions, typically by fitting a polynomial regression to certain functionals of the distributions (e.g., mean, standard deviation, and quantiles). We use a large dataset to compare various existing methods for construction of reference charts. We also relax the assumptions of a parametric polynomial link between the distribution parameters and age and consider cubic splines and discretization of age in order to compare charts based on more flexible and simpler models, respectively. We compare the different methods using various tools and demonstrate the importance of considering performance measures calculated from age-stratified data. We also examine the question of sample size. We compare our charts to similar charts that have been recently published and emphasize that the source of an apparent heterogeneity should be investigated. We conclude that the choice of which method to use for construction of reference charts should take the following into account: available sample size, validity of normality assumption, and results of various performance measures. PMID- 26503890 TI - A new nanoscale metastable iron phase in carbon steels. AB - Metastable omega phase is common in body-centred cubic (bcc) metals and alloys, including high-alloying steels. Recent theoretical calculations also suggest that the omega structure may act as an intermediate phase for face-centred cubic (fcc) to-bcc transformation. Thus far, the role of the omega phase played in fcc-bcc martensitic transformation in carbon steels has not been reported. In previous investigations on martensitic carbon steels, extra electron diffraction spots were frequently observed by transmission electron microscopy (TEM), and these spots were historically ascribed to the diffraction arising from either internal twins or carbides. In this paper, an intensive TEM investigation revealed that the extra spots are in fact attributed to the metastable omega phase in particle like morphology with an overall size of several or dozens of nanometres. The strict orientation relationships between the omega phase and the ferrite matrix are in good agreement with those of the hexagonal (P6/mmm) omega phase in other bcc metals and alloys. The identification of the omega phase as well as the extra diffraction spots might provide a clue to help understand the physical mechanism of martensitic transformation in steels. PMID- 26503889 TI - Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals. AB - The antiviral activity of nucleoside reverse transcriptase inhibitors is often limited by ineffective phosphorylation. We report on a nucleoside triphosphate (NTP) prodrug approach in which the gamma-phosphate of NTPs is bioreversibly modified. A series of TriPPPro-compounds bearing two lipophilic masking units at the gamma-phosphate and d4T as a nucleoside analogue are synthesized. Successful delivery of d4TTP is demonstrated in human CD4(+) T-lymphocyte cell extracts by an enzyme-triggered mechanism with high selectivity. In antiviral assays, the compounds are potent inhibitors of HIV-1 and HIV-2 in CD4(+) T-cell (CEM) cultures. Highly lipophilic acyl residues lead to higher membrane permeability that results in intracellular delivery of phosphorylated metabolites in thymidine kinase-deficient CEM/TK(-) cells with higher antiviral activity than the parent nucleoside. PMID- 26503891 TI - Integrated Bottom-Up and Top-Down Proteomics of Patient-Derived Breast Tumor Xenografts. AB - Bottom-up proteomics relies on the use of proteases and is the method of choice for identifying thousands of protein groups in complex samples. Top-down proteomics has been shown to be robust for direct analysis of small proteins and offers a solution to the "peptide-to-protein" inference problem inherent with bottom-up approaches. Here, we describe the first large-scale integration of genomic, bottom-up and top-down proteomic data for the comparative analysis of patient-derived mouse xenograft models of basal and luminal B human breast cancer, WHIM2 and WHIM16, respectively. Using these well-characterized xenograft models established by the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium, we compared and contrasted the performance of bottom-up and top-down proteomics to detect cancer-specific aberrations at the peptide and proteoform levels and to measure differential expression of proteins and proteoforms. Bottom-up proteomic analysis of the tumor xenografts detected almost 10 times as many coding nucleotide polymorphisms and peptides resulting from novel splice junctions than top-down. For proteins in the range of 0-30 kDa, where quantitation was performed using both approaches, bottom-up proteomics quantified 3,519 protein groups from 49,185 peptides, while top-down proteomics quantified 982 proteoforms mapping to 358 proteins. Examples of both concordant and discordant quantitation were found in a ~60:40 ratio, providing a unique opportunity for top-down to fill in missing information. The two techniques showed complementary performance, with bottom-up yielding eight times more identifications of 0-30 kDa proteins in xenograft proteomes, but failing to detect differences in certain posttranslational modifications (PTMs), such as phosphorylation pattern changes of alpha-endosulfine. This work illustrates the potency of a combined bottom-up and top-down proteomics approach to deepen our knowledge of cancer biology, especially when genomic data are available. PMID- 26503893 TI - PLK1 blockade enhances therapeutic effects of radiation by inducing cell cycle arrest at the mitotic phase. AB - The cytotoxicity of ionizing radiation depends on the cell cycle phase; therefore, its pharmacological manipulation, especially the induction of cell cycle arrest at the radiosensitive mitotic-phase (M-phase), has been attempted for effective radiation therapy. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that functions in mitotic progression, and is now recognized as a potential target for radiosensitization. We herein investigated whether PLK1 blockade enhanced the cytotoxic effects of radiation by modulating cell cycle phases of cancer cells using the novel small molecule inhibitor of PLK1, TAK-960. The TAK-960 treatment exhibited radiosensitizing effects in vitro, especially when it increased the proportion of M-phase cells. TAK-960 did not sensitize cancer cells to radiation when an insufficient amount of time was provided to induce mitotic arrest. The overexpression of a PLK1 mutant, PLK1-R136G&T210D, which was confirmed to cancel the TAK-960-mediated increase in the proportion of mitotic cells, abrogated the radiosensitizing effects of TAK-960. A tumor growth delay assay also demonstrated that the radiosensitizing effects of TAK-960 depended on an increase in the proportion of M-phase cells. These results provide a rational basis for targeting PLK1 for radiosensitization when considering the therapeutic time window for M-phase arrest as the best timing for radiation treatments. PMID- 26503894 TI - Expression of Toll-Like Receptors in Chronic Histiocytic Intervillositis of the Placenta. AB - Chronic histiocytic intervillositis of the placenta (CHI) shows monocytic/histiocytic infiltration of the intervillous space. Placental malaria has a CHI-like histopathology and induces an aberrant expression of Toll-like receptors (TLR) 3, 7-9. We hypothesized that, similar to placental malaria, CHI could be associated with increased TLR expression. TLR1-10 and other inflammation associated factors were analyzed by real-time PCR and immunohistochemistry. A total of 31 formalin-fixed and paraffin-embedded placenta samples were evaluated: CHI (n = 9), and for control purposes, villitis of unknown etiology (VUE, n = 8) and placentas without inflammation (n = 14). CHI shows increased expression of monocytic TLR1, a receptor which is involved in bacterial lipopolysaccharide (LPS)-induced inflammation. This could indicate a TLR1-mediated immune mechanism in the placenta (e.g. triggered by transient, clinically inapparent maternal bacteraemia) which leads to massive monocytic/histiocytic accumulation in the intervillous space. The increased expression of TLR1 with no increased expression of TLR3 and TLR7-9 is different from that in malaria. PMID- 26503892 TI - Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin. AB - Citreoviridin, one of toxic mycotoxins derived from fungal species, can suppress lung cancer cell growth by inhibiting the activity of ectopic ATP synthase, but has limited effect on normal cells. However, the mechanism of citreoviridin triggering dynamic molecular responses in cancer cells remains unclear. Here, we performed temporal phosphoproteomics to elucidate the dynamic changes after citreoviridin treatment in cells and xenograft model. We identified a total of 829 phosphoproteins and demonstrated that citreoviridin treatment affects protein folding, cell cycle, and cytoskeleton function. Furthermore, response network constructed by mathematical modeling shows the relationship between the phosphorylated heat shock protein 90 beta and mitogen-activated protein kinase signaling pathway. This work describes that citreoviridin suppresses cancer cell growth and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling by site-specific dephosphorylation of HSP90AB1 on Serine 255 and provides perspectives in cancer therapeutic strategies. PMID- 26503895 TI - Emerging Treatments for Retinitis Pigmentosa: Genes and stem cells, as well as new electronic and medical therapies, are gaining ground. PMID- 26503896 TI - A Non-sulfided flower-like Ni-PTA Catalyst that Enhances the Hydrotreatment Efficiency of Plant Oil to Produce Green Diesel. AB - The development of a novel non-sulfided catalyst with high activity for the hydrotreatment processing of plant oils, is of high interest as a way to improve the efficient production of renewable diesel. To attempt to develop such a catalyst, we first synthesized a high activity flower-like Ni-PTA catalyst used in the hydrotreatment processes of plant oils. The obtained catalyst was characterized with SEM, EDX, HRTEM, BET, XRD, H2-TPR, XPS and TGA. A probable formation mechanism of flower-like Ni(OH)2 is proposed on the basis of a range of contrasting experiments. The results of GC showed that the conversion yield of Jatropha oil was 98.95%, and the selectivity of C11-C18 alkanes was 70.93% at 360 degrees C, 3 MPa, and 15 h(-1). The activity of this flower-like Ni-PTA catalyst was more than 15 times higher than those of the conventional Ni-PTA/Al2O3 catalysts. Additionally, the flower-like Ni-PTA catalyst exhibited good stability during the process of plant oil hydrotreatment. PMID- 26503897 TI - Radioactive seed localization in breast cancer treatment. AB - BACKGROUND: Breast cancer screening, improved imaging and neoadjuvant systemic therapy (NST) have led to increased numbers of non-palpable tumours suitable for breast-conserving surgery (BCS). Accurate tumour localization is essential to achieve a complete resection in these patients. This study evaluated the role of radioactive seed localization (RSL) in improving breast- and axilla-conserving surgery in patients with breast cancer with or without NST. METHODS: Patients who underwent RSL between 2007 and 2014 were included. Learning curves were analysed by the rates of minimally involved (in situ/invasive tumour cells on a length of 0-4 mm on ink) and positive resection margins (over 4 mm on ink) after BCS, and the median resection volume over time. RESULTS: A total of 367 patients with in situ carcinomas and 199 with non-palpable invasive breast cancer underwent RSL before primary surgery. A further 697 patients had RSL before NST, of whom 206 also underwent RSL of a histologically verified axillary lymph node metastasis. BCS was performed in 93.2 and 87.9 per cent of patients undergoing primary surgery for in situ and invasive tumours respectively, and 57.5 per cent of those in the NST group. The rate of BCS with positive resection margins was low and stable over time in the three groups (9.1, 9.7 and 11.2 per cent respectively). The median resection volume decreased significantly with time in the invasive cancer and NST groups. CONCLUSION: In the present study of more than 1200 patients and 7 years of experience, RSL was shown to facilitate breast- and axilla-conserving surgery in a diverse patient population. There was a significant reduction in resection volume while maintaining low positive resection margin rates after BCS. PMID- 26503898 TI - Ruptured dissecting PICA aneurysm with spontaneous thrombosis during pregnancy with long-term follow-up. PMID- 26503899 TI - Drug-Alcohol Interactions in Older U.S. Adults. AB - OBJECTIVES: To characterize the extent and nature of drug-alcohol interactions in older U.S. adults. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: Nationally representative population-based sample of community-dwelling older adults (N = 2,975). MEASUREMENTS: Regular drinkers were defined as respondents who consumed alcohol at least weekly. Medication use was defined as the use of a prescription or nonprescription medication or dietary supplement at least daily or weekly. Micromedex was used to determine drug interactions with alcohol and their corresponding severity. RESULTS: One thousand one hundred six (41%) of the participants consumed alcohol regularly, and 567 (20%) were at-risk for a drug alcohol interaction because they were regular drinkers and concurrently using alcohol-interacting medications. More than 90% of these interactions were of moderate or major severity. Antidepressants and analgesics were the most commonly used alcohol-interacting medications in regular drinkers. Older adult men with multiple chronic conditions had the highest prevalence of potential drug-alcohol interactions. CONCLUSION: The potential for drug-alcohol interactions in the older U.S. adult population may have important clinical implications. Efforts to better understand and prevent the use of alcohol-interacting medications by regular drinkers, particularly heavy drinkers, are warranted in this population. PMID- 26503900 TI - Resilience in eating disorders: A qualitative study. AB - The objectives of the authors in this study were two-fold: (1) to explore the role of resilience in recovery from eating disorders (EDs), and (2) to develop a model of resilience in women with EDs. Semi-structured interviews with ten women were conducted in April 2011, along with two focus groups with women who had recovered from EDs (n = 5 women each; conducted in April 2012 at the University of Deusto, Spain), one focus group with clinical experts (n = 8; conducted in April 2012 at the Foundation Against EDs of Biskay, Spain), and six narratives from primary caregivers of ED patients living in Biskay, Spain (conducted in November 2012). All data were analyzed using a grounded theory approach. All female participants acknowledged experiencing resilience in their recovery. The analysis resulted in a conceptual model of resilience composed of the following categories: deep dissatisfaction with life, turning point, acceptance, hope, determination to change, accountability for the ED, active coping, getting social support, gaining self-knowledge, getting information about EDs, increase well being, trait resilience, initiating new projects and living in the here and now. According to the model presented, resilience preceded the experience of recovery in women with EDs in this sample and could be a useful asset for future interventions. PMID- 26503904 TI - Protection provided by Rispens CVI988 vaccine against Marek's disease virus isolates of different pathotypes and early prediction of vaccine take and MD outcome. AB - We tested the level of protection provided by the Rispens CVI988 (Rispens) vaccine against challenge with a virulent Marek's disease virus (MDV) pathotype (vMDV) and a very virulent pathotype (vvMDV) and the accuracy of a range of predictive measures of Marek's disease (MD) incidence and vaccine take. Commercial layer chicks (n = 236) were vaccinated (or not) with 4000 plaque forming units (pfu) of Rispens vaccine at hatch and challenged (or not) with 500 pfu of each challenge virus five days post vaccination. The vvMDV pathotype FT158 induced higher MD incidence (65%) and mortality (33%) when compared with the vMDV pathotype MPF57 (39% and 8%, respectively). The protective index provided by the Rispens vaccine against FT158 (61%) did not differ significantly from that against MPF57 (66%). This provides additional evidence that protection provided by the Rispens vaccine is not influenced by pathotype determined in studies using vaccines of other Mardivirus species. The challenge viruses did not differ in MDV or Rispens viral load in spleen at 14 dpc (days post challenge) determined by specific quantitative polymerase chain reaction test. MDV load in peripheral blood leucocytes at 7 and 14 dpc, splenocytes at 14 dpc, feather cells at 14 and 21 dpc and isolator dust at 21 dpc were significant early indicators of subsequent MD incidence to 56 dpc. These are potentially useful as the sampling can be carried out well before the onset of MD and some measures are non invasive. The Rispens viral load in both invasive and non-invasive samples was more useful as a measure of vaccine take. PMID- 26503902 TI - Efficacy and Safety of Bevacizumab Combined with Chemotherapy for Managing Metastatic Breast Cancer: A Meta-Analysis of Randomized Controlled Trials. AB - Although the FDA revoked metastatic breast cancer (MBC) from bevacizumab (BEV) indication in 2011, BEV combined with paclitaxel has been written in the breast cancer NCCN guidelines. This systematic assessment was performed to evaluate the efficacy and safety of BEV + chemotherapy (CHE) for managing MBC. PubMed and EMBASE were searched for original articles written in English and published before July, 2015. Progression-free survival was significantly improved in the CHE + BEV arms compared to the CHE arms in overall group and in human epidermal growth factor receptor 2-negative group (HR 0.75, 95% CI: 0.68-0.84, P < 0.001; HR 0.75, 95% CI: 0.69-0.82, P < 0.001). There were no significant improvement in overall survival in the CHE + BEV arms compared to the CHE arms. Significantly more grade 3 febrile neutropenia, hypertension, proteinuria, and cardiac events were observed in the CHE + BEV arm, which are controllable and reversible. Severe bleeding occurred more in the BEV + taxane arms and in patients with brain metastases. Therefore, CHE + BEV significantly increases progression-free survival in patients with MBC, it should be considered as a treatment option for these patients under the premise of reasonable selection of target population and combined CHE drugs. PMID- 26503903 TI - Secondhand tobacco smoke exposure and susceptibility to smoking, perceived addiction, and psychobehavioral symptoms among college students. AB - OBJECTIVE: To examine the association of secondhand smoke (SHS) exposure with susceptibility to smoking, perceived addiction, and psychobehavioral effects of exposure among never- and ever-smoking college students. PARTICIPANTS: Participants were 665 college students at a large, southeastern university in the United States. METHODS: This study is a secondary analysis of online cross sectional survey data from randomly selected students in April 2013. RESULTS: Thirty-eight percent of the sample had moderate to high SHS exposure. Among never smokers, SHS exposure was associated with increased susceptibility to initiating smoking. Among ever-smokers, SHS exposure was not associated with their perceived addiction to tobacco. In the total sample, SHS exposure was associated with greater psychobehavioral symptoms of exposure. CONCLUSIONS: SHS exposure may the increase risk of smoking, especially among never-smoking college students. This study strengthens the need for prevention strategies that limit SHS exposure in college environments. PMID- 26503905 TI - Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity. AB - Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation. PMID- 26503906 TI - Keto-Enol Tautomeric Equilibrium of Acetylacetone Solution Confined in Extended Nanospaces. AB - We aim to clarify the effects of size confinement, solvent, and deuterium substitution on keto-enol tautomerization of acetylacetone (AcAc) in solutions confined in 10-100 nm spaces (i.e., extended nanospaces) using (1)H NMR spectroscopy. The keto-enol equilibrium constants of AcAc (K(EQ) = [keto]/[enol]) in various solvents confined in extended nanospaces of 200-3000 nm were examined using the area ratios of -CH3 peaks in keto to enol forms. The results showed that the keto form of AcAc in hydrogen-bonded solvents such as water and ethanol increased drastically with decreasing space sizes below about 500 nm, but the size confinement did not induce equilibrium shifts in aprotic solvents such as DMSO. The magnitudes of K(EQ) enhancement were well correlated with solvent proton donicity. It followed from the determination of thermodynamic parameters that the stabilization of intermolecular interactions between protons in water and carbonyl oxygen (C?O) in the keto form of AcAc were promoted by size confinement, and that the keto form could be energetically and structurally favored in extended nanospaces vis-a-vis the bulk space. Furthermore, the measurements of deuterium dependence of the K(EQ) values verified that the nanoconfinement-induced shifts of keto-enol tautomerization of AcAc are attributable to high proton mobility via a proton hopping mechanism of the confined water. PMID- 26503907 TI - Multifunctional Single-Phase Photocatalysts: Extended Near Infrared Photoactivity and Reliable Magnetic Recyclability. AB - A practical photocatalyst should be able to integrate together various functions including the extended solar conversion, a feasible and economic recyclability, and above the room temperature operation potential, et al., in order to fulfill the spreading application needs in nowadays. In this report, a multifunctional single-phase photocatalyst which possesses a high photoactivity extended into the near infrared region, an easy magnetic recyclability and the high temperature stability was developed by doping Co into a new layer-structured Bi7Fe3Ti3O21 material. Light absorption and photocatalytic activity of the resulted Bi7Fe(3 x)CoxTi3O21 photocatalyst were extended to the long wavelength as far as 800 nm. Its strong ferromagnetism above the room temperature enables the nanopowders fully recyclable in viscous solutions simply with a magnet bar in an experimental demonstration. Furthermore, such photoactivity and magnetic recyclability were heavily tested under high-temperature and high-viscosity conditions, which was intended to simulate the actual industrial environments. This work brings the bright light to a full availability of a new multifunctional photocatalyst, via integrating the much enhanced ferromagnetic, ferroelectric, optoelectronic properties, most importantly, into a single-phase structure. PMID- 26503908 TI - Destruction of amyloid fibrils by graphene through penetration and extraction of peptides. AB - Current therapies for Alzheimer's disease (AD) can provide a moderate symptomatic reduction or delay progression at various stages of the disease, but such treatments ultimately do not arrest the advancement of AD. As such, novel approaches for AD treatment and prevention are urgently needed. We here provide both experimental and computational evidence that pristine graphene and graphene oxide nanosheets can inhibit Abeta peptide monomer fibrillation and clear mature amyloid fibrils, thus impacting the central molecular superstructures correlated with AD pathogenesis. Our molecular dynamics simulations for the first time reveal that graphene nanosheets can penetrate and extract a large number of peptides from pre-formed amyloid fibrils; these effects seem to be related to exceptionally strong dispersion interactions between peptides and graphene that are further enhanced by strong pi-pi stacking between the aromatic residues of extracted Abeta peptides and the graphene surface. Atomic force microscopy images confirm these predictions by demonstrating that mature amyloid fibrils can be cut into pieces and cleared by graphene oxides. Thioflavin fluorescence assays further illustrate the detailed dynamic processes by which graphene induces inhibition of monomer aggregation and clearance of mature amyloid fibrils, respectively. Cell viability and ROS assays indicate that graphene oxide can indeed mitigate cytotoxicity of Abeta peptide amyloids. Our findings provide new insights into the underlying molecular mechanisms that define graphene-amyloid interaction and suggest that further research on nanotherapies for Alzheimer's and other protein aggregation-related diseases is warranted. PMID- 26503909 TI - DNA methylation patterns of protein-coding genes and long non-coding RNAs in males with schizophrenia. AB - Schizophrenia (SCZ) is one of the most complex mental illnesses affecting ~1% of the population worldwide. SCZ pathogenesis is considered to be a result of genetic as well as epigenetic alterations. Previous studies have aimed to identify the causative genes of SCZ. However, DNA methylation of long non-coding RNAs (lncRNAs) involved in SCZ has not been fully elucidated. In the present study, a comprehensive genome-wide analysis of DNA methylation was conducted using samples from two male patients with paranoid and undifferentiated SCZ, respectively. Methyl-CpG binding domain protein-enriched genome sequencing was used. In the two patients with paranoid and undifferentiated SCZ, 1,397 and 1,437 peaks were identified, respectively. Bioinformatic analysis demonstrated that peaks were enriched in protein-coding genes, which exhibited nervous system and brain functions. A number of these peaks in gene promoter regions may affect gene expression and, therefore, influence SCZ-associated pathways. Furthermore, 7 and 20 lncRNAs, respectively, in the Refseq database were hypermethylated. According to the lncRNA dataset in the NONCODE database, ~30% of intergenic peaks overlapped with novel lncRNA loci. The results of the present study demonstrated that aberrant hypermethylation of lncRNA genes may be an important epigenetic factor associated with SCZ. However, further studies using larger sample sizes are required. PMID- 26503910 TI - Post-ablation des-gamma-carboxy prothrombin level predicts prognosis in hepatitis B-related hepatocellular carcinoma. AB - BACKGROUND & AIMS: We investigated whether pre- or post-ablation serum alpha foetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) levels can predict prognosis in patients with curative radiofrequency ablation (RFA) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: We retrospectively analysed 412 patients with HBV-related single HCC treated with percutaneous RFA between January 2004 and December 2013. AFP and DCP levels were measured before (pre-ablation) and 1 month after treatment (post-ablation). We assessed predictive factors for overall and recurrence-free survival. RESULTS: On univariate analysis, Child-Pugh score, Model for End-Stage Liver Disease (MELD) score, platelet count, tumour size, Barcelona Clinic Liver Cancer (BCLC) stage, and pre- and post-ablation DCP were significant for overall survival; and age, Child-Pugh score, MELD score, platelet count, tumour size, Cancer of the Liver Italian Program (CLIP) score, BCLC stage, and pre- and post-ablation AFP and DCP were significant for recurrence-free survival. Multivariate analysis revealed significant differences in overall survival by MELD score and tumour size and in recurrence-free survival by BCLC stage. Among the tumour markers, post-ablation DCP was an independent prognostic factor for overall and recurrence-free survival [hazard ratio (HR), 3.438; 95% confidence interval (CI), 1.331-8.877; P = 0.011 and HR, 4.934; 95% CI, 2.761-8.816; P < 0.001 respectively]. Post-ablation AFP was associated with recurrence-free survival (HR, 1.995; 95% CI, 1.476-2.697; P < 0.001) but not overall survival. CONCLUSIONS: In patients with HBV-related HCC, post-ablation serum DCP is a useful biomarker for predicting survival and recurrence after curative RFA. PMID- 26503911 TI - Glass transition of aqueous solutions involving annealing-induced ice recrystallization resolves liquid-liquid transition puzzle of water. AB - Liquid-liquid transition of water is an important concept in condensed-matter physics. Recently, it was claimed to have been confirmed in aqueous solutions based on annealing-induced upshift of glass-liquid transition temperature, T(g) . Here we report a universal water-content, X(aqu) , dependence of T(g) for aqueous solutions. Solutions with X(aqu)>X(cr)(aqu)vitrify/devitrify at a constant temperature, ~T(g) , referring to freeze-concentrated phase with X(aqu)left behind ice crystallization. Those solutions with X(aqu)95% of mature mTECs, suggesting that Aire expression does not represent a particular mTEC lineage(s). We confirmed this by generating Aire/diphtheria toxin receptor-knockin mice in which long-term ablation of Aire(+) mTECs by diphtheria toxin treatment resulted in the loss of most mature mTECs beyond the proportion of those apparently expressing Aire. These results suggest that Aire expression is inherent to all mTECs but may occur at particular stage(s) and/or cellular states during their differentiation, thus accounting for the broad impact of Aire on the promiscuous gene expression of mTECs. PMID- 26503951 TI - Impact of Notch1 Deletion in Macrophages on Proinflammatory Cytokine Production and the Outcome of Experimental Autoimmune Encephalomyelitis. AB - Notch signaling is involved in regulating TLR-mediated responses in activated macrophages. In this study, we investigated the impact of Notch signaling in macrophages in an experimental autoimmune encephalomyelitis (EAE) model. To examine the impact of deficiency in Notch signaling in activated macrophages in EAE, an adoptive transfer of activated macrophages derived from Notch1(fl/fl) * Mx1cre(+/-) (Notch1 knockout [N1KO]) or CSL/Rbp-jkappa(fl/fl) * Mx1cre(+/-) (CSL/RBP-Jkappa KO) mice was performed prior to induction of EAE. Mice receiving activated N1KO macrophages showed decreased severity of EAE compared with mice receiving wild-type or CSL/RBP-Jkappa KO macrophages. In vitro restimulation of splenocytes by myelin oligodendrocyte glycoprotein 35-55 peptide from these mice revealed that cells from mice receiving N1KO macrophages produced significantly less IL-17 compared with the control mice, whereas IFN-gamma production was similar in both groups. We found that activated N1KO, but not CSL/RBP-Jkappa KO, macrophages produced less IL-6 and had lower CD80 expression compared with wild type and did not exhibit any defect in IL-12p40/70 production, whereas activated macrophages from CSL/RBP-Jkappa KO mice phenocopied gamma-secretase inhibitor treatment for reduced IL-12p40/70 production. Furthermore, the nuclear translocation of the NF-kappaB subunit c-Rel was compromised in gamma-secretase inhibitor-treated and CSL/RBP-Jkappa KO but not N1KO macrophages. These results suggest that Notch1 and CSL/RBP-Jkappa in macrophages may affect the severity of EAE differently, possibly through modulating IL-6 and CD80 expression, which is involved in the Th17 but not Th1 response. PMID- 26503952 TI - MicroRNA-26b Modulates the NF-kappaB Pathway in Alveolar Macrophages by Regulating PTEN. AB - NF-kappaB is one of the best-characterized transcription factors, providing the link between early membrane-proximal signaling events and changes in many inflammatory genes. MicroRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. In this study, we evaluated the role of miR-26b in the LPS-induced inflammatory response in bovine alveolar macrophages (bAMs). LPS stimulation of bAMs upregulated miR-26b at 1 h and downregulated it at 6 and 36 h. Overexpression of miR-26b in bAMs enhanced the LPS-induced mRNA expression of proinflammatory cytokines and chemokines, including TNF-alpha, IL-1beta, IL-8, and IL-10, but it directly inhibited that of IL-6. A similar trend was observed for the release of these cytokines and chemokines from bAMs. miR-26b directly bound the 3'-untranslated region of PTEN, leading to the reduction of PTEN protein in bAMs. miR-26b also enhanced the LPS induced NF-kappaB signaling pathway, as revealed by increased NF-kappaB transcriptional activity and phosphorylation of p65, IkappaBalpha, IkappaB kinase, and Akt. Moreover, PTEN silencing increased the LPS-induced mRNA expression of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10 and upregulated the NF kappaB pathway. Taken together, we conclude that miR-26b participates in the inflammatory response of LPS-stimulated bAMs by modulating the NF-kappaB pathway through targeting PTEN. PMID- 26503953 TI - Igs as Substrates for Transglutaminase 2: Implications for Autoantibody Production in Celiac Disease. AB - Autoantibodies specific for the enzyme transglutaminase 2 (TG2) are a hallmark of the gluten-sensitive enteropathy celiac disease. Production of the Abs is strictly dependent on exposure to dietary gluten proteins, thus raising the question how a foreign Ag (gluten) can induce an autoimmune response. It has been suggested that TG2-reactive B cells are activated by gluten-reactive T cells following receptor-mediated uptake of TG2-gluten complexes. In this study, we propose a revised model that is based on the ability of the BCR to serve as a substrate to TG2 and become cross-linked to gluten-derived peptides. We show that TG2-specific IgD molecules are preferred in the reaction and that binding of TG2 via a common epitope targeted by cells using the IgH variable gene segment (IGHV)5-51 results in more efficient cross-linking. Based on these findings we hypothesize that IgD-expressing B cells using IGHV5-51 are preferentially activated, and we suggest that this property can explain the previously reported low number of somatic mutations as well as the overrepresentation of IGHV5-51 among TG2-specific plasma cells in the celiac lesion. The model also couples gluten peptide uptake by TG2-reactive B cells directly to peptide deamidation, which is necessary for the activation of gluten-reactive T cells. It thereby provides a link between gluten deamidation, T cell activation, and the production of TG2-specific Abs. These are all key events in the development of celiac disease, and by connecting them the model may explain why the same enzyme that catalyzes gluten deamidation is also an autoantigen, something that is hardly coincidental. PMID- 26503954 TI - Tripartite Motif (TRIM) 12c, a Mouse Homolog of TRIM5, Is a Ubiquitin Ligase That Stimulates Type I IFN and NF-kappaB Pathways along with TNFR-Associated Factor 6. AB - Tripartite motif (TRIM) protein TRIM5 of the primate species restricts replication of HIV and other retroviruses. Whereas primates have a single TRIM5 gene, the corresponding locus in the mouse has expanded during evolution, now containing more than eight related genes. Owing to the complexity of the genomic organization, a mouse homolog of TRIM5 has not been fully studied thus far. In the present study, we report that Trim12c (formerly Trim12-2) encodes a TRIM5 like protein with a ubiquitin ligase activity. Similar to the primate TRIM5, TRIM12c is expressed in the cytoplasm as a punctate structure and induced upon IFN and pathogen stimulation in macrophages and dendritic cells. We show that TRIM12c interacts with TRAF6, a key protein in the pathogen recognition receptor signaling, and reciprocally enhances their ubiquitination, leading to cooperative activation of IFN and NF-kappaB pathways. This study identifies TRIM12c as a mouse TRIM5 equivalent, critical for host innate immunity. PMID- 26503955 TI - Identification of Cell Surface Straight Chain Poly-N-Acetyl-Lactosamine Bearing Protein Ligands for VH4-34-Encoded Natural IgM Antibodies. AB - B cell binding and cytotoxicity by human VH4-34-encoded Abs of the IgM isotype has been well documented. A VH4-34-IgM has recently shown a favorable early response in a phase 1 trial for treatment of B cell acute lymphoblastic leukemia. Although its B cell ligand has been identified as straight chain poly-N-acetyl lactosamine (SC-PNAL), the carrier of the sugar moiety has not been identified. Using nanoelectrospray ionization mass spectrometry, we identify the metabolic activation related protein complex of CD147-CD98 as a major carrier of poly-N acetyl-lactosamine (SC-PNAL) on human pre-B cell line Nalm-6. Previous studies have suggested CD45 as the SC-PNAL carrier for VH4-34-encoded IgG Abs. Because Nalm-6 is CD45 negative, human peripheral blood B lymphocytes and human B cell line, Reh, with high CD45 expression, were examined for SC-PNAL carrier proteins. Western blot analysis shows that the CD147-98 complex is indeed immunoprecipitated by VH4-34-encoded IgMs from human peripheral blood B lymphocytes and human B cell lines, Reh, OCI-Ly8, and Nalm-6. However, CD45 is immunoprecipitated only from peripheral B lymphocytes, but not from Reh despite the high expression of CD45. These results suggest that human B cells retain SC PNAL on the CD147-98 complex, but modulate the sugar moiety on CD45. Because the carbohydrate moiety may act as a selecting Ag for VH4-34 autoantibody repertoire, its differential expression on proteins may provide a clue to the intricate atypical regulation of the VH4-34 gene. PMID- 26503957 TI - Fair play: social norm compliance failures in behavioural variant frontotemporal dementia. AB - Adherence to social norms is compromised in a variety of neuropsychiatric conditions. Functional neuroimaging studies have investigated social norm compliance in healthy individuals, leading to the identification of a network of fronto-subcortical regions that underpins this ability. However, there is a lack of corroborative evidence from human lesion models investigating the structural anatomy of norm compliance across this fronto-subcortical network. To address this, we developed a neuroeconomic task to investigate social norm compliance in a neurodegenerative lesion model: behavioural variant frontotemporal dementia, a condition characterized by gross social dysfunction. The task assessed norm compliance across three behaviours that are well-studied in the neuroeconomics literature: fairness, prosocial and punishing behaviours. We administered our novel version of the Ultimatum Game in 22 patients with behavioural variant frontotemporal dementia and 22 age-matched controls, to assess how decision making behaviour was modulated in response to (i) fairness of monetary offers; and (ii) social context of monetary offers designed to produce either prosocial or punishing behaviours. Voxel-based morphometry was used to characterize patterns of grey matter atrophy associated with task performance. Acceptance rates between patients and controls were equivalent when only fairness was manipulated. However, patients were impaired in modulating their decisions in response to social contextual information. Patients' performance in the punishment condition was consistent with a reduced tendency to engage in punishment; this was associated with decreased grey matter volume in the anterior cingulate, orbitofrontal cortex, left dorsolateral prefrontal cortex and right inferior frontal gyrus. In the prosocial condition, patients' performance suggested a reduced expression of prosocial behaviour, associated with decreased grey matter in the anterior insula, lateral orbitofrontal cortex, anterior cingulate and dorsal striatum. Acceptance rates in the Ultimatum Game were also significantly related to impairments in the everyday expression of empathic concern. In conclusion, we demonstrate that compliance to basic social norms (fairness) can be maintained in behavioural variant frontotemporal dementia; however, more complex normative behaviours (prosociality, punishment) that require integration of social contextual information are disrupted in association with atrophy in key fronto-striatal regions. These results suggest that the integration of social contextual information to guide normative behaviour is uniquely impaired in behavioural variant frontotemporal dementia, and may explain other common features of the condition including gullibility and impaired empathy. Our findings also converge with previous functional neuroimaging investigations in healthy individuals and provide the first description of the structural anatomy of social norm compliance in a neurodegenerative lesion model. PMID- 26503956 TI - A Truncated Variant of ASCC1, a Novel Inhibitor of NF-kappaB, Is Associated with Disease Severity in Patients with Rheumatoid Arthritis. AB - Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-kappaB may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF kappaB pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-kappaB target genes (TRAIL, TNF-alpha, cIAP-1, IL8) and blocks activation of a NF-kappaB-luciferase reporter construct in five different human cell lines. Therefore, ASCC1 may contribute to avoiding a pathologic activation of this transcription factor. A truncated variant of ASCC1 (p.S78*) was found in RA patients and control individuals. Functional in vitro studies revealed that truncation abrogated the NF-kappaB inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-kappaB and the secretion of TNF-alpha in response to inflammatory stimuli. We analyzed the clinical impact of p.S78* variant in 433 patients with RA and found that heterozygous carriers of this variant needed more disease-modifying antirheumatic drugs, and more patients with this genotype needed treatment with corticoids and biologic agents. Moreover, the truncated allele-carrier group had lower rates of remission compared with the full-length variant carriers. Overall, our findings show for the first time, to our knowledge, that ASCC1 inhibits NF-kappaB activation and that a truncated and inactive variant of ASCC1 is associated with a more severe disease, which could have clinical value for assessing the progression and prognosis of RA. PMID- 26503958 TI - Virtual stenting of intracranial aneurysms: application of hemodynamic modification analysis. AB - BACKGROUND: Practical application of hemodynamic modification analysis based on computational fluid dynamics (CFD) in intracranial aneurysms is still under study. PURPOSE: To determine the clinical applicability of virtual stenting of aneurysms by comparing the simulated results with clinical outcome of real stenting. MATERIAL AND METHODS: Three-dimensional (3D) digital subtraction angiography (DSA) images were imported to a dedicated integrated prototypic CFD platform (Siemens Healthcare GmbH) which allows all necessary steps of 3D models for CFD analysis. The results of CFD simulation with virtual implantation of a stent can be visualized in the same platform for qualitative comparisons on a color-coded volume visualization window. Five small intracranial aneurysms with and without virtual stenting were analyzed and assessed on a qualitative level. Expert rating were performed for evaluating the simulated results, and comparing those to the long-term follow-up outcomes of real stenting. RESULTS: CFD simulation after virtual stenting was feasible in five differently located aneurysms and corresponded to the long-term changes of stented aneurysms by showing alteration in flow pattern. There was no significant difference (P = 0.5) between the simulated hemodynamic changes after virtual stenting and the angiographic changes after stenting in four aneurysms except one. There was good agreement regarding the assessment of the changes by two raters (kappa = 0.657). CONCLUSION: CFD analysis using patient-specific virtual stenting of the CFD platform may be used as a simple and less time-consuming test tool predicting the involution of aneurysms after stent placement by analyzing the vector visualization of the flow changes. PMID- 26503959 TI - The number of optic neuritis attacks is a potential confounder when comparing patients with NMO vs. controls by voxel-based neuroimaging analysis. AB - BACKGROUND: Voxel-based morphometric (VBM) studies in neuromyelitis optica (NMO) have shown limited reproducibility. A previous study suggests that the number of optic neuritis (ON) attacks may be a confounding factor when comparing NMO patients with controls if it is not taken into account during VBM analysis. PURPOSE: To investigate the potential confounding effect of the number of ON attacks, for both tissue volumes and perfusion by voxel-based statistical analysis. MATERIAL AND METHODS: Volumetric magnetic resonance imaging (MRI) and perfusion SPECT were obtained from 15 controls and two patient subgroups: subgroup I was composed of nine patients with one or two ON attacks; and subgroup II of six patients with three or four ON attacks. We performed non-parametric voxel-based comparison of tissue volumes and perfusion between controls versus the two patient subgroups and for the whole patient group. RESULTS: Subgroup I presented no volume reductions, contrary to subgroup II that showed unequivocal reduction. We also found hypoperfusion in different brain regions in different subgroups. The results were quite different for the whole patient group. CONCLUSION: These findings highlight the confounding effect of the number of ON attacks, providing a new methodological insight that could explain the limited reproducibility of previous VBM studies in NMO. PMID- 26503960 TI - NEDD4-mediated HSF1 degradation underlies alpha-synucleinopathy. AB - Cellular protein homeostasis is achieved by a delicate network of molecular chaperones and various proteolytic processes such as ubiquitin-proteasome system (UPS) to avoid a build-up of misfolded protein aggregates. The latter is a common denominator of neurodegeneration. Neurons are found to be particularly vulnerable to toxic stress from aggregation-prone proteins such as alpha-synuclein. Induction of heat-shock proteins (HSPs), such as through activated heat shock transcription factor 1 (HSF1) via Hsp90 inhibition, is being investigated as a therapeutic option for proteinopathic diseases. HSF1 is a master stress protective transcription factor which activates genes encoding protein chaperones (e.g. iHsp70) and anti-apoptotic proteins. However, whether and how HSF1 is dysregulated during neurodegeneration has not been studied. Here, we discover aberrant HSF1 degradation by aggregated alpha-synuclein (or alpha-synuclein induced proteotoxic stress) in transfected neuroblastoma cells. HSF1 dysregulation via alpha-synuclein was confirmed by in vivo assessment of mouse and in situ studies of human specimens with alpha-synucleinopathy. We demonstrate that elevated NEDD4 is implicated as the responsible ubiquitin E3 ligase for HSF1 degradation through UPS. Furthermore, pharmacologically induced SIRT1-mediated deacetylation can attenuate aberrant NEDD4-mediated HSF1 degradation. Indeed, we define the acetylation status of the Lys 80 residue located in the DNA-binding domain of HSF1 as a critical factor in modulating HSF1 protein stability in addition to its previously identified role in the transcriptional activity. Together with the finding that preserving HSF1 can alleviate alpha-synuclein toxicity, this study strongly suggests that aberrant HSF1 degradation is a key neurodegenerative mechanism underlying alpha-synucleinopathy. PMID- 26503961 TI - Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington's disease and spinocerebellar ataxia. AB - RNA-targeting approaches are emerging as viable therapeutics that offer an alternative method to modulate traditionally 'undrugable' targets. In the case of dominantly inherited neurodegenerative diseases, gene suppression strategies can target the underlying cause of these intractable disorders. Polyglutamine diseases are caused by CAG expansions in discrete genes, making them ideal candidates for gene suppression therapies. Here, we discuss the current state of gene suppression approaches for Huntington's disease and the spinocerebellar ataxias, including the use of antisense oligonucleotides, short-interfering RNAs, as well as viral vector-mediated delivery of short hairpin RNAs and artificial microRNAs. We focus on lessons learned from preclinical studies investigating gene suppression therapies for these disorders, particularly in rodent models of disease and in non-human primates. In animal models, recent advances in gene suppression technologies have not only prevented disease progression in a number of cases, but have also reversed existing disease, providing evidence that reducing the expression of disease-causing genes may be of benefit in symptomatic patients. Both allele- and non-allele-specific approaches to gene suppression have made great strides over the past decade, showing efficacy and safety in both small and large animal models. Advances in delivery techniques allow for broad and durable suppression of target genes, have been validated in non-human primates and in some cases, are currently being evaluated in human patients. Finally, we discuss the challenges of developing and delivering gene suppression constructs into the CNS and recent advances of potential therapeutics into the clinic. PMID- 26503963 TI - Low postoperative nonstimulated thyroglobulin as a criterion to spare radioiodine ablation. AB - This study evaluated the recurrence rate in patients with papillary thyroid carcinoma (PTC) who had low nonstimulated thyroglobulin (Tg), measured with a second-generation assay, after total thyroidectomy and who were not submitted to ablation with (131)I. The objective was to define whether low postoperative nonstimulated Tg can be used as a criterion to spare patients with PTC from therapy with (131)I. This was a prospective study including 222 patients with PTC (except for microcarcinoma restricted to the thyroid and tumor with extensive extrathyroid invasion (pT4), aggressive histology, extensive lymph node (LN) involvement, or known residual disease). After thyroidectomy, all patients had nonstimulated Tg<0.3 ng/ml, negative antithyroglobulin antibodies (TgAb) and neck ultrasonography (US) showing no anomalies. Because of this finding, the patients were not submitted to ablation with (131)I. The time of follow-up ranged from 15 to 102 months (median 62 months). Of the 222 patients, 217 (97.7%) continued to have nonstimulated Tg <0.3 ng/ml and negative US. Tg was undetectable in the last assessment in 185 of these patients and detectable in 32. Five patients (2.2%) exhibited an increase in Tg, and LN metastases were detected in 4 (structural recurrence). One patient progressed to an increase in Tg, but disease was not detected by the imaging methods (biochemical recurrence). The results obtained here suggest that patients with PTC who have low nonstimulated Tg (measured with a second-generation assay and in the absence of TgAb) and negative neck US after thyroidectomy do not require ablation with (131)I. PMID- 26503964 TI - Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial. AB - OBJECTIVES: Patients treated for head and neck carcinomas experience a significant deterioration of their quality of life during treatments because of severe side effects. Nabilone has many properties that could alleviate symptoms caused by radiotherapy and improve patients' quality of life. The aim of the present study was to compare the effects of nabilone versus placebo on the quality of life and side effects during radiotherapy for head and neck carcinomas. METHODS: Fifty-six patients were randomized to nabilone or placebo. Patients filled the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EORTC QLQ-H&N35; three independent questionnaires assessing appetite, nausea, and toxicity; and a visual analog scale for pain. These data were collected before radiotherapy, each week during radiotherapy, and 4 weeks after radiotherapy. Patients were weighed every week. RESULTS: Nabilone did not lengthen the time necessary for a 15% deterioration of quality of life (P = .4279), and it was not better than placebo for relieving symptoms like pain (P = .6048), nausea (P = .7105), loss of appetite (P = .3295), weight (P = .1454), mood (P = .3214), and sleep (P = .4438). CONCLUSION: At the dosage used, nabilone was not potent enough to improve the patients' quality of life over placebo. PMID- 26503962 TI - Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. AB - Chimeric antigen receptors (CAR) are synthetic receptors that target T cells to cell-surface antigens and augment T-cell function and persistence. Mesothelin is a cell-surface antigen implicated in tumor invasion, which is highly expressed in mesothelioma and lung, pancreas, breast, ovarian, and other cancers. Its low level expression in mesothelia, however, commands thoughtful therapeutic interventions. Encouragingly, recent clinical trials evaluating active immunization or immunoconjugates in patients with pancreatic adenocarcinoma or mesothelioma have shown responses without toxicity. Altogether, these findings and preclinical CAR therapy models using either systemic or regional T-cell delivery argue favorably for mesothelin CAR therapy in multiple solid tumors. SIGNIFICANCE: Recent success obtained with adoptive transfer of CAR T cells targeting CD19 in patients with refractory hematologic malignancies has generated much enthusiasm for T-cell engineering and raises the prospect of implementing similar strategies for solid tumors. Mesothelin is expressed in a wide range and a high percentage of solid tumors, which we review here in detail. Mesothelin CAR therapy has the potential to treat multiple solid malignancies. PMID- 26503965 TI - Comparison of 7 Published LC-MS/MS Methods for the Simultaneous Measurement of Testosterone, Androstenedione, and Dehydroepiandrosterone in Serum. AB - BACKGROUND: Recently, LC-MS/MS was stated to be the method of choice to measure sex steroids. Because information on the mutual agreement of LC-MS/MS methods is scarce, we compared 7 published LC-MS/MS methods for the simultaneous measurement of testosterone, androstenedione, and dehydroepiandrosterone (DHEA). METHODS: We used 7 published LC-MS/MS methods to analyze in duplicate 55 random samples from both men and women. We performed Passing-Bablok regression analysis and calculated Pearson correlation coefficients to assess the agreement of the methods investigated with the median concentration measured by all methods, and we calculated the intraassay CV of each method derived from duplicate results and the CVs between the methods. RESULTS: Median concentrations of testosterone were 0.22-1.36 nmol/L for women and 8.27-27.98 nmol/L for men. Androstenedione and DHEA concentrations were 0.05-5.53 and 0.58-18.04 nmol/L, respectively. Intraassay CVs were 2.9%-10%, 1.2%-8.8%, 2.7%-13%, and 4.3%-16% for testosterone in women, testosterone in men, androstenedione, and DHEA. Slopes of the regression lines calculated by Passing-Bablok regression analysis were 0.92-1.08, 0.92-1.08, 0.90-1.13, and 0.91-1.41 for all testosterone values, testosterone in women, androstenedione, and DHEA. Intermethod CVs were 14%, 8%, 30%, and 22% for testosterone in women, testosterone in men, androstenedione, and DHEA. CONCLUSIONS: In general, the LC-MS/MS methods investigated show reasonable agreement. However, some of the assays show differences in standardization, and others show high variation. PMID- 26503966 TI - Total Short-term Variability in Biomarkers of Hyperglycemia in Older Adults. PMID- 26503967 TI - In Search of the 1-Hour Rule-Out for Acute Myocardial Infarction. AB - Old habits die hard. The study by Hillinger et al. provides a framework for several observations regarding the current state of ADPs for rapid rule-out of ACS. ADPs that incorporate serial assessments of high-sensitivity cardiac troponin appear to provide a viable approach to rule out ACS with sampling over 3 h with a high NPV. The actual interval (1, 2, or 3 h) and optimal thresholds are issues still to be refined for each assay. A dual-marker strategy using copeptin does not provide incremental clinical information beyond high-sensitivity cardiac troponin, and it seems unlikely that other biomarkers will substantially improve the NPV achieved with serial high-sensitivity cardiac troponin testing alone. PMID- 26503968 TI - Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-beta-dependent activation of matrix metalloproteases. AB - Dickkopf-3 (Dkk-3) is a secreted protein whose expression is downregulated in many types of cancer. Endogenous Dkk-3 is required for formation of acini in 3D cultures of prostate epithelial cells, where it inhibits transforming growth factor (TGF)-beta/Smad signaling. Here, we examined the effects of Dkk-3 on the expression and activity of matrix metalloproteases (MMPs), which mediate the effects of TGF-beta on extracellular matrix disassembly during tissue morphogenesis and promote invasion of tumor cells. Silencing of Dkk-3 in prostate epithelial cells resulted in increased expression and enzyme activity of MMP-2 and MMP-9. Inhibition of MMP-9 partially restored normal acinar morphogenesis in Dkk-3-silenced RWPE-1 prostate epithelial cells. In PC3 prostate cancer cells, Dkk-3 inhibited TGF-beta-dependent migration and invasion. Inhibition was mediated by the Dkk-3 C-terminal cysteine-rich domain (Cys2), which also inhibited TGF-beta-induced expression of MMP9 and MMP13. In contrast, Dkk-3, but not Cys2, increased formation of normal acini in Dkk-3-silenced prostate epithelial cells. These observations highlight a role for Dkk-3 in modulating TGF beta/MMP signals in the prostate, and suggest that the Dkk-3 Cys2 domain can be used as a basis for therapies that target the tumor promoting effects of TGF-beta signaling in advanced prostate cancer. PMID- 26503969 TI - 'Welcoming the Other': psychodrama in an acute inpatient unit. AB - OBJECTIVE: In this article, the author uses the leitmotifs inherent in a critically acclaimed film and in the philosophy of Emmanuel Levinas as a backdrop for discussion around how we encounter the humanity in the Other and its particular relevance for psychiatry. She proceeds to describe the existential underpinnings of psychodrama and demonstrates how she has been directing a psychodrama group, 'Theatre of Life', which has been operating for well over a decade within a public mental health system, acute inpatient unit. Through the ensuing discussion, she illustrates how the humanistic ethic of 'welcoming the Other' is actualised in the 'here-and now' of the psychodrama group psychotherapy process. CONCLUSIONS: A thematic analysis derived from group-members' evaluation of each session illuminates their felt sense depicting the ethic in action. PMID- 26503970 TI - Downregulation of Nuclear Factor Erythroid 2-Related Factor and Associated Antioxidant Genes Contributes to Redox-Sensitive Vascular Dysfunction in Hypertension. AB - Oxidative stress is implicated in vascular dysfunction in hypertension. Although mechanisms regulating vascular pro-oxidants are emerging, there is a paucity of information on antioxidant systems, particularly nuclear factor erythroid 2 related factor (Nrf2), a master regulator of antioxidants enzymes. We evaluated the vascular regulatory role of Nrf2 in hypertension and examined molecular mechanisms, whereby Nrf2 influences redox signaling in small arteries and vascular smooth muscle cells from Wistar Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Cells were stimulated with angiotensin II in the absence/presence of Nrf2 activators (bardoxolone/L-sulforaphane). Increased vascular reactive oxygen species production (chemiluminescence and amplex red) was associated with reduced Nrf2 activity in arteries (18%) and vascular smooth muscle cells (48%) in SHRSP (P<0.05 versus WKY). Expression of antioxidant enzymes, including superoxide dismutase-1 (64%), catalase (60%), peroxiredoxin 1 (75%), and glutathione peroxidase (54%), was reduced in SHRSP. L sulforaphane reversed these effects. Angiotensin II increased nuclear accumulation of Nrf2 in vascular smooth muscle cells from WKY (197% versus vehicle), with blunted effects in SHRSP (44% versus vehicle). These responses were associated with increased antioxidant expression (superoxide dismutase-1, 32%; catalase, 42%; thioredoxin, 71%; peroxiredoxin, 1%-90%; quinone oxidoreductase, 84%; P<0.05 versus vehicle) and increased activity of superoxide dismutase-1, catalase, and thioredoxin in WKY but not in SHRSP, which exhibited increased Bach1 expression. Nrf2 activators blocked angiotensin II-induced reactive oxygen species generation. Vascular function demonstrated increased contractility (Emax WKY 113.4+/-5.6 versus SHRSP 159.0+/-8.3) and decreased endothelial-dependent relaxation (Emax WKY 88.6+/-3.1 versus SHRSP 74.6+/-3.2, P<0.05) in SHRSP, effects corrected by L-sulforaphane. Our findings suggest that Nrf2 downregulation contributes to redox-sensitive vascular dysfunction in hypertension. PMID- 26503971 TI - Hypertensive Target Organ Damage and Longitudinal Changes in Brain Structure and Function: The Second Manifestations of Arterial Disease-Magnetic Resonance Study. AB - Hypertension has been related to structural and functional brain changes. In high risk populations, hypertensive target organ damage might better represent exposure to high blood pressure than the blood pressure measurement itself. We examined the association of hypertensive target organ damage with longitudinal changes in brain structure and function within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study. Renal function, albuminuria, and left ventricular hypertrophy on electrocardiography were measured in 663 patients with manifest arterial disease (mean age, 57+/-9 years; 81% men). Automated brain segmentation was used to quantify progression of global brain atrophy (change in brain parenchymal fraction) and progression of cerebral small vessel disease on 1.5T magnetic resonance imaging, and memory and executive functioning were assessed at baseline and after on average 3.9 years of follow up. Regression analyses showed that an increasing number of signs of target organ damage was associated with more progression of global brain atrophy and more rapid decline in memory performance. Compared with no target organ damage, mean differences in change in brain parenchymal fraction (95% confidence interval) for 1 and >=2 signs of organ damage were -0.12 (-0.30; 0.06) and -0.41 (-0.77; -0.05) % intracranial volume, and mean (95% confidence interval) differences in change in memory performance (z score) were -0.15 (-0.29; -0.00) and -0.27 (-0.54; 0.01). Results were independent of blood pressure, antihypertensive treatment, and other confounders. Hypertension target organ damage was not associated with progression of cerebral small vessel disease or change in executive functioning. Routinely assessed signs of hypertensive target organ damage, and in particular impaired renal function, could be used to identify patients at the highest risk of cognitive decline. PMID- 26503973 TI - Fifty years ago: 'Emery Pneumoconiosis'. PMID- 26503974 TI - Finding 'new' occupational diseases and trends in 'old' ones. PMID- 26503975 TI - Solvent-induced encephalopathy in the Netherlands and Finland. PMID- 26503976 TI - Sentinel surveillance and occupational disease. PMID- 26503977 TI - The utility of information collected by occupational disease surveillance systems. AB - BACKGROUND: The Health and Occupation Research (THOR) network in the UK and the Republic of Ireland (ROI) is an integrated system of surveillance schemes collecting work-related ill-health (WRIH) data since 1989. In addition to providing information about disease incidence, trends in incidence and the identification of new hazards, THOR also operates an ad hoc data enquiry service enabling interested parties to request information about cases of WRIH reported to THOR. AIMS: To examine requests for information made to a network of surveillance schemes for WRIH in the UK. METHODS: Analysis via SPSS of data requests received by THOR between 2002 and 2014. RESULTS: A total of 631 requests were received by THOR between 2002 and 2014. Requests were predominantly submitted by participating THOR physicians (34%) and the main THOR funder-the UK Health & Safety Executive (HSE) (31%). The majority (67%) of requests were for information about work-related respiratory or skin disease with relatively few requests for other diagnoses, such as musculoskeletal or mental ill-health. Requests frequently related to a specific industry and/or occupation (42%) and/or a specific causal agent (58%). CONCLUSIONS: Data collected by occupational disease surveillance systems such as THOR are an extremely useful source of information, the use of which extends beyond informing government on disease incidence and trends in incidence. The data collected provide a framework that can assist a wide range of enquirers with clinical diagnoses, identification of suspected causative agents/exposures and to highlight growing risks in particular industrial and occupational sectors. PMID- 26503979 TI - Which way is up? PMID- 26503978 TI - The surveillance of occupational diseases in Italy: the MALPROF system. AB - BACKGROUND: Occupational diseases data can guide efforts to improve worker's health and safety. AIMS: To describe MALPROF, the Italian system for surveillance of work-related diseases collected by the subregional Department of Prevention. METHODS: The MALPROF system started in 1999 with contributions from Lombardy and Tuscany and spread in the following years to collect contributions from 14 out of the 20 Italian regions. MALPROF data were explored to follow-up work-related diseases and to detect emerging occupational health risks by calculating proportional reporting ratio (PRR), as in pharmacosurveillance. It classified work-related diseases according to economic sector and job activity in which the exposure occurred. Occupational physicians of the Italian National Health Service evaluate the possible causal relationship with occupational exposures and store the data in a centralized database. RESULTS: From 1999 to 2012, the MALPROF system collected about 112000 cases of workers' diseases. In 2010, more than 13000 cases of occupational diseases were reported. The most frequently reported diseases were hearing loss (n = 4378, 32%), spine disorders (n = 2394, 17%) and carpal tunnel syndrome (n = 1560, 11%). The PRR calculated for cervical disc herniation, a disease whose occupational origin has to be studied, in 1999-2010 was 2.47 [95% confidence interval (CI) 1.76-3.47] for drivers and 36.64 (95% CI 22.03-60.93) for air transport workers. CONCLUSIONS: MALPROF is a sensitive system for identifying possible associations between occupational risks and diseases, it can contribute to the development of preventive measures, to evaluate the effectiveness of preventive interventions and to stimulate research on new occupational risks and diseases. PMID- 26503980 TI - Data warehouse for detection of occupational diseases in OHS data. AB - BACKGROUND: Occupational health and safety (OHS) services collect a wide range of data during health surveillance. AIMS: To build a 'data warehouse' to make OHS data available for research and to investigate sector-specific health problems. METHODS: Medical data were extracted, transformed and loaded into the data warehouse. After validation, data on lifestyle, categorized medication use, ICD-9 CM encoded sickness absences and health complaints, collected between 2010 and 2014, were analysed with logistic regression to compare proportions between employment sectors, taking into account age, gender, body mass index (BMI) and year of examination. RESULTS: The data set comprised 585000 employees. Average age and employment seniority were 39 +/- 12 and 8 +/- 9 years, respectively. BMI was 26 +/- 5 kg/m(2). Health complaints, medication use and sickness absence significantly increased with BMI and age. The proportion of employees with health problems was highest in health care (64%), government (61%) and manufacturing (60%) and lowest in the service sector. In all sectors, 10% of workers reported locomotor health problems, apart from the service sector (8%) with similar results for medication consumption. Neuropsychological drugs were more frequently used by health care workers (8%). The transport sector contained the highest proportion of cardiological medication users (12%). Finally, 30-59% of employees reported at least one sickness absence episode. Sickness absence due to locomotor issues was highest in manufacturing (11%) and health care (10%), followed by government (9%) and construction (9%). CONCLUSIONS: Significant differences in indices of workers' health were observed between sectors. This information is now being used in the implementation of a sector-oriented health surveillance programme. PMID- 26503981 TI - Use of GIS in visualization of work-related health problems. AB - BACKGROUND: Occupational health and safety (OHS) information is often complex, diverse and unstructured and suffers from a lack of integration which usually precludes any systemic insight of the situation. AIMS: To analyse to what extent the use of geographical information systems (GISs) can help to integrate, analyse and present OHS data in a comprehensive and communicable way relevant for surveillance purposes. METHODS: We first developed a 'macro-approach' (from national to local level), mapping data related to economic activity (denominator of active workers displayed by activity sectors), as well as work-related ill health (numerators of workers suffering from work-related ill-health). The latter data are composed of compensated occupational diseases on the one hand and work related diseases investigated by specialized clinics on the other hand. Then, a 'micro-approach' was worked out, integrating at a plant level, using computer aided drawing, occupational risks data and OHS surveillance data (e.g. use of medication and sickness absence data). RESULTS: At the macro-level, microelectronics companies and workers were mapped at different scales. For the first time, we were able to compare, up to the enterprise level, complementary data showing different pictures of work-related ill-health, allowing a better understanding of OH issues in this sector. At the micro-level, new information arose from the integration of risk assessment data and medical data. CONCLUSIONS: This work illustrates to what extent GIS is a promising tool in the OHS field, and discusses related challenges (technical, ethical, biases and interpretation) and research perspectives. PMID- 26503982 TI - Verapamil-Sensitive Transport of Quinacrine and Methylene Blue via the Plasmodium falciparum Chloroquine Resistance Transporter Reduces the Parasite's Susceptibility to these Tricyclic Drugs. AB - BACKGROUND: It is becoming increasingly apparent that certain mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) alter the parasite's susceptibility to diverse compounds. Here we investigated the interaction of PfCRT with 3 tricyclic compounds that have been used to treat malaria (quinacrine [QC] and methylene blue [MB]) or to study P. falciparum (acridine orange [AO]). METHODS: We measured the antiplasmodial activities of QC, MB, and AO against chloroquine-resistant and chloroquine-sensitive P. falciparum and determined whether QC and AO affect the accumulation and activity of chloroquine in these parasites. We also assessed the ability of mutant (PfCRT(Dd2)) and wild-type (PfCRT(D10)) variants of the protein to transport QC, MB, and AO when expressed at the surface of Xenopus laevis oocytes. RESULTS: Chloroquine resistance-conferring isoforms of PfCRT reduced the susceptibility of the parasite to QC, MB, and AO. In chloroquine-resistant (but not chloroquine sensitive) parasites, AO and QC increased the parasite's accumulation of, and susceptibility to, chloroquine. All 3 compounds were shown to bind to PfCRT(Dd2), and the transport of QC and MB via this protein was saturable and inhibited by the chloroquine resistance-reverser verapamil. CONCLUSIONS: Our findings reveal that the PfCRT(Dd2)-mediated transport of tricyclic antimalarials reduces the parasite's susceptibility to these drugs. PMID- 26503983 TI - Reversion From Methicillin Susceptibility to Methicillin Resistance in Staphylococcus aureus During Treatment of Bacteremia. AB - Approximately 3% of Staphylococcus aureus strains that, according to results of conventional phenotypic methods, are highly susceptible to methicillin-like antibiotics also have polymerase chain reaction (PCR) results positive for mecA. The genetic nature of these mecA-positive methicillin-susceptible S. aureus (MSSA) strains has not been investigated. We report the first clearly defined case of reversion from methicillin susceptibility to methicillin resistance among mecA-positive MSSA within a patient during antibiotic therapy. We describe the mechanism of reversion for this strain and for a second clinical isolate that reverts at a similar frequency. The rates of reversion are of the same order of magnitude as spontaneous resistance to drugs like rifampicin. When mecA is detected by PCR in the clinical laboratory, current guidelines recommend that these strains be reported as resistant. Because combination therapy using both a beta-lactam and a second antibiotic suppressing the small revertant population may be superior to alternatives such as vancomycin, the benefits of distinguishing between mecA-positive MSSA and MRSA in clinical reports should be evaluated. PMID- 26503984 TI - Interferon-Mediated Cytokine Induction Determines Sustained Virus Control in Chronic Hepatitis C Virus Infection. AB - Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma. Interferons (IFNs) are crucial for HCV clearance and a sustained virological response (SVR), but a significant proportion of patients do not respond to IFNalpha. The underlying mechanisms of an insufficient IFN response remain largely unknown. In this study, we found that patients responding to IFNalpha with viral clearance had significantly higher serum levels of TNF-related apoptosis inducing ligand (TRAIL), compared with patients who failed to control HCV. In addition, upon direct IFNalpha exposure, peripheral blood mononuclear cells (PBMCs) from patients with SVR upregulated TRAIL, as well as IFN-gamma and the chemokines CXCL9 and CXCL10, much more strongly than cells from patients with antiviral treatment failure. As a possible mechanism of the stronger IFNalpha induced cytokine response, we identified higher levels of expression and phosphorylation of the transcription factor STAT1 in PBMCs from patients with SVR. Increased TRAIL expression additionally involved the NF-kappaB and JNK signaling pathways. Thus, SVR in chronic HCV infection is associated with a strong IFNalpha-induced cytokine response, which might allow for the early prediction of treatment efficacy in HCV infection. PMID- 26503985 TI - Pivotal role of miR-448 in the development of ROS-induced cardiomyopathy. AB - AIMS: Nicotinamide adenine dinucleotide oxidases (NOXs) are important contributors to cellular oxidative stress in the cardiovascular system. The NOX2 isoform is upregulated in numerous disorders, including dystrophic cardiomyopathy, where it drives the progression of the disease. However, mechanisms underlying NOX2 overexpression are still unknown. We investigated the role of microRNAs (miRs) in the regulation of NOX2 expression. METHODS AND RESULTS: Duchenne muscular dystrophy (DMD) was used as a model of cardiomyopathy. After screening with miRNA target prediction databases and following qRT-PCR analysis, we found drastic downregulation of miR-448-3p in hearts of mdx mice, an animal model of DMD. The downregulation correlated with overexpression of the Ncf1 gene, encoding the NOX2 regulatory subunit p47(phox). Specificity of Ncf1 targeting by miR-448-3p was validated by luciferase reporter assay. Silencing of miR-448-3p in wild-type mice had a dramatic effect on cellular and functional properties of cardiac muscle as assessed by western blotting, qRT-PCR, confocal imaging, echocardiography, and histology. Acute treatment of mice with LNA-miR 448 inhibitors led to increased Ncf1 expression, abnormally elevated reactive oxygen species (ROS) production and exacerbated Ca(2+) signalling in cardiomyocytes, reminiscent of features previously observed in dystrophic cardiac cells. In addition, chronic inhibition of miR-448-3p resulted in dilated cardiomyopathy and arrhythmia, hallmarks of dystrophic cardiomyopathy. CONCLUSIONS: Our studies suggest that downregulation of miR-448-3p leads to the increase in the expression of Ncf1 gene and p47(phox) protein, as well as to the substantial increase in NOX2-derived ROS production. Cellular oxidative stress subsequently triggers events that finally culminate in cardiac tissue damage and development of cardiomyopathy. PMID- 26503987 TI - Neuregulin-1 improves right ventricular function and attenuates experimental pulmonary arterial hypertension. AB - AIMS: Pulmonary arterial hypertension (PAH) is a serious disease that affects both the pulmonary vasculature and the right ventricle (RV). Current treatment options are insufficient. The cardiac neuregulin (NRG)-1/ErbB system is deregulated during heart failure, and treatment with recombinant human NRG-1 (rhNRG-1) has been shown to be beneficial in animal models and in patients with left ventricular (LV) dysfunction. This study aimed to evaluate the effects of rhNRG-1 in RV function and pulmonary vasculature in monocrotaline (MCT)-induced PAH and RV hypertrophy (RVH). METHODS AND RESULTS: Male wistar rats (7- to 8 weeks old, n = 78) were injected with MCT (60 mg/kg, s.c.) or saline and treated with rhNRG-1 (40 ug/kg/day) or vehicle for 1 week, starting 2 weeks after MCT administration. Another set of animals was submitted to pulmonary artery banding (PAB) or sham surgery, and followed the same protocol. MCT administration resulted in the development of PAH, pulmonary arterial and RV remodelling, and dysfunction, and increased RV markers of cardiac damage. Treatment with rhNRG-1 attenuated RVH, improved RV function, and decreased RV expression of disease markers. Moreover, rhNRG-1 decreased pulmonary vascular remodelling and attenuated MCT-induced endothelial dysfunction. The anti-remodelling effects of rhNRG-1 were confirmed in the PAB model, where rhNRG-1 treatment was able to attenuate PAB-induced RVH. CONCLUSION: rhNRG-1 treatment attenuates pulmonary arterial and RV remodelling, and dysfunction in a rat model of MCT-induced PAH and has direct anti-remodelling effects on the pressure-overloaded RV. PMID- 26503988 TI - Children with autism spectrum disorder have an exceptional explanatory drive. AB - An "explanatory drive" motivates children to explain ambiguity. Individuals with autism spectrum disorders are interested in how systems work, but it is unknown whether they have an explanatory drive. We presented children with and without autism spectrum disorder unsolvable problems in a physical and in a social context and evaluated problem-solving and explanation-seeking responses. In the physical context (but not the social context), the children with autism spectrum disorder showed a stronger explanatory drive than controls. Importantly, the number of explanatory behaviors made by children with autism spectrum disorder in the social context was independent of social and communicative impairments. Children with autism spectrum disorder did not show an exceptional explanatory drive in the social domain. These results suggest that children with autism spectrum disorder have an explanatory drive and that the explanatory drive may be domain specific. PMID- 26503986 TI - HIF-2alpha-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction. AB - AIMS: Hypoxic conditions stimulate pulmonary vasoconstriction and vascular remodelling, both pathognomonic changes in pulmonary arterial hypertension (PAH). The secreted protein thrombospondin-1 (TSP1) is involved in the maintenance of lung homeostasis. New work identified a role for TSP1 in promoting PAH. Nonetheless, it is largely unknown how hypoxia regulates TSP1 in the lung and whether this contributes to pathological events during PAH. METHODS AND RESULTS: In cell and animal experiments, we found that hypoxia induces TSP1 in lungs, pulmonary artery smooth muscle cells and endothelial cells, and pulmonary fibroblasts. Using a murine model of constitutive hypoxia, gene silencing, and luciferase reporter experiments, we found that hypoxia-mediated induction of pulmonary TSP1 is a hypoxia-inducible factor (HIF)-2alpha-dependent process. Additionally, hypoxic tsp1(-/-) pulmonary fibroblasts and pulmonary artery smooth muscle cell displayed decreased migration compared with wild-type (WT) cells. Furthermore, hypoxia-mediated induction of TSP1 destabilized endothelial cell cell interactions. This provides genetic evidence that TSP1 contributes to vascular remodelling during PAH. Expanding cell data to whole tissues, we found that, under hypoxia, pulmonary arteries (PAs) from WT mice had significantly decreased sensitivity to acetylcholine (Ach)-stimulated endothelial-dependent vasodilation. In contrast, hypoxic tsp1(-/-) PAs retained sensitivity to Ach, mediated in part by TSP1 regulation of pulmonary Kv channels. Translating these preclinical studies, we find in the lungs from individuals with end-stage PAH, both TSP1 and HIF-2alpha protein expression increased in the pulmonary vasculature compared with non-PAH controls. CONCLUSIONS: These findings demonstrate that HIF-2alpha is clearly implicated in the TSP1 pulmonary regulation and provide new insights on its contribution to PAH-driven vascular remodelling and vasoconstriction. PMID- 26503989 TI - Early deictic but not other gestures predict later vocabulary in both typical development and autism. AB - Research with typically developing children suggests a strong positive relation between early gesture use and subsequent vocabulary development. In this study, we ask whether gesture production plays a similar role for children with autism spectrum disorder. We observed 23 18-month-old typically developing children and 23 30-month-old children with autism spectrum disorder interact with their caregivers (Communication Play Protocol) and coded types of gestures children produced (deictic, give, conventional, and iconic) in two communicative contexts (commenting and requesting). One year later, we assessed children's expressive vocabulary, using Expressive Vocabulary Test. Children with autism spectrum disorder showed significant deficits in gesture production, particularly in deictic gestures (i.e. gestures that indicate objects by pointing at them or by holding them up). Importantly, deictic gestures-but not other gestures-predicted children's vocabulary 1 year later regardless of communicative context, a pattern also found in typical development. We conclude that the production of deictic gestures serves as a stepping-stone for vocabulary development. PMID- 26503991 TI - Quilting a Field Pattern Portrait Using Butcher's Methodology. AB - The nursing profession acknowledges Martha Rogers to the foundation of nursing theory as a true visionary. Butcher developed a method that ensures scientific rigor in the application of Rogerian theory, unitary field pattern portrait (UFPP), which was used to explore new phenomenon of inquiry resulting in insights into Rogerian pandimensionality. In this intervention, an American Indian tradition, quilting, became a culturally appropriate way for a nurse to facilitate healing through the application of Rogerian theory. In Rogers's theory of the science of unitary human beings, pattern unfolding becomes a way of knowing through expansion, evolving, blossoming, revealing, and openness. Rogers's theory was used to encourage healing as an American Indian mother and deeply depressed daughter created a quilting story based on Rogerian principles: resonancy, helicy, and integrality. This aesthetic field patterning modality using Butcher's UFPP captured the intervention as clients were engaged in health patterning through the American Indian tradition of quilting. Field notes with reflective journaling as recommended by Butcher assisted in the crystallization of a UFPP drawn from Rogerian nursing theory. PMID- 26503990 TI - A trial of an iPadTM intervention targeting social communication skills in children with autism. AB - This study evaluated a technology-based early intervention for social communication skills in pre-schoolers in a randomised controlled trial. Participants were 54 children aged under 6 years with a diagnosis of autism, assigned to either intervention or control conditions. The app engaged children, who played consistently, regardless of developmental level, and was rated highly by parents. There were no significant group differences in parent-report measures post-intervention, nor in a measure of parent-child play at follow-up. Therefore, this intervention did not have an observable impact on real-world social communication skills and caution is recommended about the potential usefulness of iPad(TM) apps for amelioration of difficulties in interaction. However, positive attitudes among participants, lack of harms and the potential of apps to deliver therapeutic content at low economic cost suggest this approach is worth pursuing further, perhaps targeting other skill domains. PMID- 26503992 TI - Association of Complementary and Alternative Therapies With Mental Health Outcomes in Pregnant Women Living in a Postdisaster Recovery Environment. AB - PURPOSE: The objective of this study was to determine if complementary and alternative medicine therapies are associated with mental health in postdisaster environments. DESIGN: Pregnant women (N = 402) were interviewed between 2010 and 2012 as part of a larger cross-sectional study on hurricane recovery and models of prenatal care. METHODS: Symptoms of depression (Edinburgh Postnatal Depression Screen), prenatal anxiety (Revised Prenatal Distress Questionnaire), posttraumatic stress (PCL-S), and perceived stress (PSS) were examined. Logistic regression was used to adjust for income, race, education, parity, and age. The most commonly reported therapies were prayer, music, multivitamins, massage, and aromatherapy. FINDINGS: Mental illness symptoms were common (30.7% had likely depression, 17.4% had anxiety, and 9.0% had posttraumatic stress). Massage was protective for depression (Edinburgh Postnatal Depression Index [EDSI] >8; adjusted odds ratio [aOR] = 0.6, 95% confidence interval [CI] = 0.3-0.9), while use of aromatherapy (aOR = 1.9, 95% CI = 1.1-3.2) and keeping a journal (aOR = 1.9, 95% CI = 1.1-3.2) were associated with increased odds of depression. Aromatherapy was associated with symptoms of pregnancy-related anxiety (aOR = 2.0, 95% CI = 1.1-3.8). CONCLUSIONS: Symptoms of mental illness persist after disaster, when untreated. Nurses should consider assessing for complementary and alternative medicine utilization in pregnancy as a potentially protective factor for mental health symptoms. PMID- 26503993 TI - Atypical Fibroxanthoma - Histological Diagnosis, Immunohistochemical Markers and Concepts of Therapy. AB - BACKGROUND: Atypical fibroxanthoma (AFX) is an uncommon, rapidly growing cutaneous neoplasm of uncertain histogenesis. Thus far, there are no guidelines for diagnosis and therapy of this tumor. PATIENTS AND METHODS: We included 18 patients with 21 AFX, and 2,912 patients with a total of 2,939 AFX cited in the literature between 1962 and 2014. RESULTS: In our cohort, excision with safety margin was performed in 100% of primary tumors. Local recurrences were observed in 25% of primary tumors and parotid metastases in 5%. Ten-year disease-specific survival was 100%. The literature research yielded 280 relevant publications. Over 90% of the reported cases were negative for cytokeratins, S100, desmin and human melanoma black 45 (HMB-45). Recurrent AFX was reported in 7.6% and metastasizing AFX in 2.75% cases. No significant differences in the recurrence and survival rates following wide local excision versus Mohs microsurgery were observed. Twenty-year disease-specific survival rate was 97.8%. CONCLUSION: A well-selected panel of immunohistochemical markers is necessary to establish AFX diagnosis with sufficient certainty. Adequately treated, AFX has an excellent prognosis, but long-term follow-up is recommended due to the potential for aggressive behavior. PMID- 26503994 TI - Molecular Targeted Therapies in Hepatocellular Carcinoma: Past, Present and Future. AB - Hepatocellular carcinoma (HCC) is an aggressive tumor and the sixth most common form of cancer worldwide. Surgery is the gold-standard treatment for local disease and often complemented by radiofrequency ablation or transarterial chemoembolization. In advanced disease, therapy options are limited and relapse and metastasis are common. Systemic therapy with cytotoxic drugs such as doxorubicin and cisplatin achieves low objective response rates (typically <10%) and even sorafenib, an orally administered tyrosine kinase inhibitor considered a breakthrough when introduced, prolongs median survival by little more than a year. Sorafenib blocks platelet-derived growth factor, vascular endothelial growth factor, c-KIT and rapidly accelerated fibrosarcoma signaling, and belongs to a new class of targeted drugs. It has become standard treatment for advanced stage HCC in recent years. To date, no other agent has been shown to be more effective than sorafenib in the clinical setting, which highlights the need for ongoing research to address this important clinical challenge. The current review focuses on recent advances in molecular targeted therapy for HCC. We explore the current status of evidence, identify areas of pressing experimental need, and provide an outline of promising future therapeutic options. PMID- 26503995 TI - Immunotherapies for NSCLC: Are We Cutting the Gordian Helix? AB - Chemotherapy is currently the standard-of-care for non-oncogene-driven advanced non-small cell lung cancer (NSCLC). Due to improvements in chemotherapeutic choices and supportive care, patients currently typically undergo multiple lines of chemotherapy as their disease progresses. Although treatments have improved over recent years, limited benefits are seen, especially in patients receiving later-line chemotherapy, as response rates can be low, response duration short and survival poor. Molecular-targeted therapies have provided improvement in outcomes. However, these treatments only offer a clear benefit in subsets of tumors harbouring the appropriate genomic alteration (mutation, amplification, translocation). Recent advances in immunotherapy have highlighted the potential of immuno-oncology-based treatments for NSCLC, offering the potential to provide durable responses and outcomes regardless of histology or mutation status. Blocking inhibitory pathways such as the cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) checkpoint pathways with monoclonal antibodies has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand-1(PD-L1) antibodies have shown durable responses in NSCLC, with a favourable safety profile and manageable side-effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-naive patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted-agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC. The emerging data not only offer the hope of a better cancer therapy but also provide evidence that changes our understanding on how the host immune system interacts with human cancer. It is therefore conceivable that agents blocking the CTLA-4/PD-1/PD-L1 axis will provide valuable additions to the growing armamentarium of targeted-agents. PMID- 26503996 TI - Can Imatinib Be Safely Withdrawn in Patients with Surgically Resected Metastatic GIST? AB - Patients with advanced gastrointestinal stromal tumors (GIST) are currently recommended for treatment with tyrosine kinase inhibitors (TKI) in a life-long sequence. The standard first-line treatment is imatinib mesylate (IM), which is switched to other drugs at progression or if the patient does not tolerate IM. This strategy has served many patients well as patients with advanced GIST now live for a median of approximately 5 years, compared to 18 months prior the TKI era. The prevailing hypothesis is that IM and other TKIs fail to completely eradicate metastatic GIST and that progression is inevitable if IM treatment is discontinued. Following a response to IM and surgery of metastatic lesions harbouring foci responsible for drug resistance and subsequent clinical relapse, we hypothesize that this may lead to a cure and the justification to stop IM in selected patients. We suggest that this novel strategy, a priori, warrants further investigation. We reviewed the available literature, present three clinical cases and put forward for discussion a treatment algorithm that needs confirmation within the context of a prospective clinical study. PMID- 26503997 TI - Therapeutic Potential of Thalidomide and Its Analogues in the Treatment of Cancer. AB - Thalidomide was synthesised and launched several decades ago as a drug against respiratory infections and was administered to pregnant women for relief of morning sickness. The drug was withdrawn when its teratogenic effects came to light. Thalidomide and its analogues suppressed cell proliferation and angiogenesis and controlled invasion and metastasis of tumours in pre-clinical studies. With the recognition of its immunomodulatory and anti-inflammatory, properties, thalidomide may have found a place in the treatment of many forms of cancer and autoimmune conditions. Herein the signalling pathways modulated by thalidomides via the mediation of vascular endothelial growth factor, phosphoinositide-kinase/protein kinase B and nuclear factor kappa B, and mammalian target of rapamycin, which integrates these signalling systems, are discussed. The mode of action of thalidomides and their strategic utility in therapy are evaluated in the context of potential clinical benefits. Notwithstanding the perceived benefits, the side-effects of thalidomides need to be taken into account; they do exert teratogenic effects in animal models, although being effective at lower doses, the drugs seem to show comparatively manageable and reduced toxicity. Combination therapy of thalidomides and modulators of signaling that they influence may further reduce the severity of the side-effects by delivering inhibitory effects at reduced drug dosages. Pre clinical evaluations of this kind seem warranted. PMID- 26503998 TI - Natural Products That Target Cancer Stem Cells. AB - The cancer stem cell model suggests that tumor initiation is governed by a small subset of distinct cells with stem-like character termed cancer stem cells (CSCs). CSCs possess properties of self-renewal and intrinsic survival mechanisms that contribute to resistance of tumors to most chemotherapeutic drugs. The failure to eradicate CSCs during the course of therapy is postulated to be the driving force for tumor recurrence and metastasis. Recent studies have focused on understanding the unique phenotypic properties of CSCs from various tumor types, as well as the signaling pathways that underlie self-renewal and drug resistance. Natural products (NPs) such as those derived from botanicals and food sources may modulate vital signaling pathways involved in the maintenance of CSC phenotype. The Wingless/Integrated (WNT), Hedgehog, Notch and PI3K/AKT/mTOR pathways have all been associated with quiescence and self-renewal of CSCs, as well as execution of CSC function including differentiation, multidrug resistance and metastasis. Recent studies evaluating NPs against CSC support the epidemiological evidence linking plant-based diets with reduced malignancy rates. This review covers the key aspects of NPs as modulators of CSC fate. PMID- 26503999 TI - Relationship Between Metabolic Reprogramming and Mitochondrial Activity in Cancer Cells. Understanding The Anticancer Effect of Metformin and Its Clinical Implications. AB - Metabolic reprogramming refers to the ability of cancer cells to alter their metabolism in order to support the increased energy request due to continuous growth, rapid proliferation, and other characteristics typical of neoplastic cells. This adaptation comprises of some important bioenergetic changes that, in contrary to conventional and outdated concepts, require an unchanged mitochondrial activity for their efficacy. This review highlights the characteristics of metabolic reprogramming, the role of mitochondrial activity in this particular setting, and the therapeutic possibility of targeting pathways of energy metabolism in cancer cells, with particular emphasis on metformin efficacy and its relationship with mitochondria metabolism. PMID- 26504000 TI - Brain Metastases in NSCLC - are TKIs Changing the Treatment Strategy? AB - Non-small-cell lung cancer (NSCLC) ranks as a leading cause of cancer-related death globally. Brain metastases are a frequent complication of NSCLC, with 25 40% of patients developing brain metastases during the course of the disease, often within the first 2 years after diagnosis of the primary tumor. Improvements in neurological symptoms and performance status have been reported with whole brain radiation therapy (WBRT) in combination with steroid therapy in NSCLC patients. In addition, a survival benefit has been reported for patients with a single brain metastasis treated with stereotactic radiosurgery, while the clinical outcome is improved with surgery followed by WBRT versus WBRT alone. However, due to their poor performance status, many patients with brain metastases are not eligible for surgery or radiosurgery. Furthermore, the role of systemic chemotherapy for the treatment of brain metastases is controversial due to the impenetrable nature of the blood brain barrier (BBB), with reported response rates to chemotherapy ranging from 15-30% (overall survival [OS] 6-8 months). Response rates of brain metastases to EGFR tyrosine kinase inhibitor (TKI) treatment (e.g. gefitinib, erlotinib, afatinib) in patients with NSCLC harboring EGFR mutations reach 60-80%, with a complete response rate as high as 40%. Median OS is 15-20 months, and progression-free survival in the brain reaches 6.6-11.7 months, demonstrating an improved clinical outcome. Metastatic involvement of the CNS appears to be a relatively common complication in patients with ALK-positive NSCLC and the CNS represents a dominant site of progression in ALK-positive patients treated with the ALK TKI crizotinib. In addition, CNS progression on crizotinib contributes substantially to the high levels of morbidity and mortality observed among patients with ALK-rearrangements, a finding that is consistent with low CNS penetration of the drug. Second generation ALK inhibitors (ceritinib, alectinib) are well-tolerated and demonstrate excellent intracranial activity. The various reports of dramatic and prolonged responses in brain metastases patients treated with EGFR and ALK TKIs suggest that these agents may be a valid treatment option for patients with asymptomatic brain metastases from NSCLC, especially for those with EGFR activating mutations or harboring ALK rearrangement. However, larger phase III studies are required to fully define the activity of these agents and their place in the therapeutic armamentarium of brain metastases. PMID- 26504001 TI - Primary Breast Cancer with Synchronous Metastatic Disease - Indications for Local Radiotherapy to the Breast and Chest Wall. AB - AIM: To review literature on local therapy in patients with primary metastatic breast cancer with focus on local radiotherapy (RT). PATIENTS AND METHODS: A Medline search using the key words "metastatic breast cancer", "primary resection/radiotherapy", "local therapy", "local radiotherapy" was carried out. All original studies in the English language were included in the present review. RESULTS: A total of 27 original studies including more than 33,000 patients with metastatic breast cancer were identified, including two large database analyses (n=25,757). All studies were retrospective in nature. Most studies showed a survival benefit with the addition of local therapy in a metastatic situation. The majority of studies focused on the role of surgery. Fourteen studies (52%) mentioned radiotherapy (RT) in 0.3% to 100% of patients. Six of these studies analyzed the effect of RT separately and five found an additional benefit of RT. Two studies showed best outcomes when RT and surgery were combined. CONCLUSION: Most retrospective studies showed a survival benefit for local therapy in patients with breast cancer with distant metastases. The role of RT remains unclear. Some reports showed improved outcome with the combination of surgery and RT. This approach should be considered in patients with good survival prognosis in whom local control is important. There are several prognostic factors to aid decision-making. Results of prospective randomized studies are pending. PMID- 26504002 TI - Electrochemotherapy - Evidence for Cell-type Selectivity In Vitro. AB - AIM: Electrochemotherapy (ECT) is a new cancer treatment modality that uses electroporation to potentiate chemotherapeutic agents, especially bleomycin. ECT causes both a direct toxic effect and an anti-vascular effect. The aim of the present study was to investigate a possible selective effect of ECT on the survival of fibroblasts, endothelial cells (HUVEC) and two squamous cell carcinoma cell lines (CAL-27 and SCC-4). MATERIALS AND METHODS: Cells were electroporated using two bleomycin concentrations. The survival rate was assessed 1, 2, 3 and 4 days after treatment, by two different assays. RESULTS: The survival rate of the fibroblasts was statistically significantly higher than the other cell lines at day 4. The HUVEC survival rate was statistically significantly lower than the other cell types at day 1 after electroporation alone. CONCLUSION: A selective survival effect after ECT was observed in vitro, supporting the anti-vascular effect seen in vivo. PMID- 26504003 TI - Recruitment of Cancer-Associated Fibroblasts and Blood Vessels by Orthotopic Liver Tumors Imaged in Red Fluorescent Protein (RFP) Transgenic Nude Mice. AB - BACKGROUND/AIM: The tumor microenvironment (TME) is critical for tumor growth and progression. We report here an imageable model of the TME of orthotopic liver cancer. MATERIALS AND METHODS: The transgenic red fluorescent protein (RFP) expressing nude mouse was used as the host. The RFP nude mouse expresses RFP in all organs. Non-colored Huh-7 human hepatoma cells were injected in the spleen of RFP nude mice to establish an orthotopic liver cancer model. TME formation resulting from the orthotopic liver tumor was observed using the Olympus OV100 small animal fluorescence imaging system. RESULTS: Non-colored liver cancer cells formed tumor colonies in the liver 28 days after cell transplantation to the spleen. RFP-expressing host cells and blood vessels were recruited by the liver tumors as visualized by fluorescence imaging. A desmin- and sirus-red-positive area increased around and within the liver tumor over time. CONCLUSION: These results indicate cancer-associated fibroblasts (CAFs) were recruited by the liver tumors suggesting that CAFs, along with the angiogenic tumor blood vessels, were necessary for liver-tumor growth and could serve as visible therapeutic targets. PMID- 26504004 TI - Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells. AB - Cannabinoids possess a number of characteristics that make them putative anticancer drugs, and their value as such is currently being explored in a number of clinical studies. To further understand the roles that cannabinoids may have, we performed gene expression profiling in glioma cell lines cultured with cannabidiol (CBD) and/or Delta9-tetrahydrocannabinol (THC), and pursued targets identified by this screening. Results showed that a large number of genes belonging to the heat shock protein (HSP) super-family were up-regulated following treatment, specifically with CBD. Increases were observed both at the gene and protein levels and arose as a consequence of increased generation of ROS by CBD, and correlated with an increase in a number of HSP client proteins. Furthermore, increases impeded the cytotoxic effect of CBD; an effect that was improved by co-culture with pharmacalogical inhibitors of HSPs. Similarly, culturing glioma cells with CBD and HSP inhibitors increased radiosensitivity when compared to CBD-alone. Taken together, these data indicate that the cytotoxic effects of CBD can be diminished by HSPs that indirectly rise as a result of CBD use, and that the inclusion of HSP inhibitors in CBD treatment regimens can enhance the overall effect. PMID- 26504005 TI - Up-regulation of Toll-like Receptor 9 in Osteosarcoma. AB - BACKGROUND: Increasing evidence has shown that Toll-like receptors (TLRs), key receptors in innate immunity, play a role in cancer development and progression. The present study aimed to elucidate the role of TLR expression in osteosarcoma cancer cells and patient specimens. MATERIALS AND METHODS: We investigated the expression of all of human TLRs in osteosarcoma MG-63 cells by real-time quantitative reverse transcription polymerase chain reaction. We then further explored whether the up-regulation of TLR9 expression is common in patients with osteosarcoma by examining TLR9 protein levels in 80 osteosarcoma specimens and 28 normal controls by immunohistochemistry. RESULTS: We found that among TLR family members, TLR9 was predominately expressed in osteosarcoma cells, and up regulation of TLR9 expression was found in 72 out of 80 (90%) patients with osteosarcoma but in none of 28 normal controls. Furthermore, high expression of TLR9 appeared to be associated with osteosarcoma progression. CONCLUSION: TLR9 is up-regulated in the majority of osteosarcomas, which appears to play an important role in osteosarcoma development and progression. Therefore, TLR9 may serve as a novel therapeutic target for human osteosarcoma therapy. PMID- 26504006 TI - Breast Cancer Cell Lines Exhibit Differential Sensitivities to Microtubule targeting Drugs Independent of Doubling Time. AB - BACKGROUND: Microtubule-targeting agents (MTAs) are a mainstay in breast cancer treatment, yet patient responses differ. The underlying mechanisms of these differences are unknown. While MTAs are mitotic inhibitors, recent evidence highlights that non-mitotic effects of these drugs can contribute to their anticancer effects. It is critical to identify the non-mitotic mechanisms that could contribute to differences among MTAs. However, it is not clear whether rapidly dividing cells in culture are optimal tools to address these mechanistic questions in interphase cells. MATERIALS AND METHODS: Detailed concentration response curves for five MTAs in a panel of diverse breast cancer cell lines were generated. RESULTS: Substantial differences among both drugs and cell lines, consistent with the clinical scenario, were observed. Importantly, these differences do not correlate with cell doubling time. CONCLUSION: The interphase actions of MTAs are critical to the full spectrum of their effects in cancer cells, even in cell culture models. PMID- 26504007 TI - A Theoretical Model for the Hormetic Dose-response Curve for Anticancer Agents. AB - In the present article, we quantitatively evaluated the dose-response relationship of hormetic reactions of anticancer agents in vitro. Serial dilutions of gemcitabine, cisplatin, 5-fluorouracil, vinorelbine, and paclitaxel were administered to the A549 non-small-cell lung cancer cell line. The bi-phasic sigmoidal curve with hormetic and cytotoxic effects is given by the formula y=(a b/(1+exp(c(*)log(x)-d)))/(1+exp(e(*)log(x)-f)), that was used to perform a non linear least square regression. The dose-responses of the five anticancer agents were fitted to this equation. Gemcitabine and 5-fluorouracil, which had the lowest ED50 for their hormetic reaction, had the most pronounced promotive effects out of the five anticancer agents tested. The hormetic reaction progressed exponentially with culturing time. Our theoretical model will be useful in predicting how hormetic reactions affect patients with malignant tumors. PMID- 26504008 TI - Microcystin LR Shows Cytotoxic Activity Against Pancreatic Cancer Cells Expressing the Membrane OATP1B1 and OATP1B3 Transporters. AB - Microcystin-LR (MC-LR) is a cyanobacterial cyclopeptide, known for its unique ability to cause acute liver injury. Its cellular uptake is facilitated by specific transmembrane organic anion-transporting polypeptides (OATPs) specifically OATP1B1 and 1B3. The objective of the present study was to investigate the expression of OATPs 1A2, 1B1 and 1B3 in pancreatic cancer cell lines BxPC-3 and MIA PACA-2 and assess their role in MC-LR-mediated cytotoxicity by using the novel xCELLigence system and flow cytometry. OATP1B1 and 1B3 were found to be expressed in both cell lines at both the mRNA and protein levels. The cytotoxic effects of MC-LR were proportionally related to the expression of these transporters. Moreover the cytotoxic potency of MC-LR was found superior to gemcitabine. Based on the expression of the organic anion transporting polypeptides 1B1 and 1B3 in pancreatic carcinoma tissue and cell lines and the potent cytotoxicity induced by MC-LR in vitro, we propose that this molecule could be held as structural basis for the development of novel targeted-compounds against pancreatic cancer. PMID- 26504009 TI - Expression of Estrogen Receptors in OSCC in Relation to Histopathological Grade. AB - BACKGROUND/AIM: Estrogen receptor (ER)-mediated pathways are involved in the pathogenesis of several tumors. Preliminary studies have demonstrated a significant effect of ER agonists and antagonists on oral squamous cell carcinoma (OSCC) cell lines. Recent results suggest that ER subtype-specific expression patterns might depend on the grade of differentiation of OSCC. Therefore, the aim of the present study was to evaluate the expression of ERalpha and ERbeta in OSCC and its correlation to histological tumor grade and gender. MATERIALS AND METHODS: Tumor sections of 25 patients (13 males and 12 females) retrieved from OSCC databases with two different histological gradings (well-differentiated, poorly differentiated) were evaluated. The detection of ERalpha and ERbeta expression in tumor cells and corresponding healthy mucosa adjacent to tumor was performed using immunohistochemistry. RESULTS: Well-differentiated OSCC showed no significant difference between the expression of ERbeta in tumor cells and corresponding mucosa. In poorly-differentiated OSCC the expression of ERbeta was significantly higher in tumor cells than in corresponding mucosa. In patients without regular alcohol and/or nicotine abuse, there was no significant difference of ERbeta expression in OSCC compared to corresponding healthy mucosa in contrast to patients having these risk factors. Expression of ERalpha was found in one tumor. CONCLUSION: ERbeta is the predominant ER sub-type expressed significantly higher in poorly-differentiated OSCC tumors compared to healthy mucosa adjacent to the tumor. Different expression patterns in relation to histological grade might suggest an influential role of ERbeta in tumor (de-) differentiation of OSCC. PMID- 26504010 TI - The FGFR Inhibitor NVP-BGJ398 Induces NSCLC Cell Death by Activating Caspase dependent Pathways as well as Caspase-independent Apoptosis. AB - BACKGROUND: Fibroblast growth factor receptors are expressed in diverse cell types. They play a critical role in tumor development. Their activation promotes cell-cycle progression, angiogenesis, and cell survival by induction/suppression of the expression of proteins involved. MATERIALS AND METHODS: Non-small cell lung cancer (NSCLC) cells (line H1581) were treated with NVP-BGJ398 to evaluate effects on growth by western blot, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazoliumbromide assay and cell-cycle analysis. RESULTS: NVP-BGJ398 induced cell death in H1581 cells by activating caspase-dependent mitochondrial and non-mitochondrial pathways. Caspase-independent apoptosis was also activated. Cells were found to be arrested in the G0/G1 phase. Furthermore, the expression of the tumor-suppressor gene programmed cell death 4 (PDCD4) was up-regulated with suppression of angiopoietin 2 (ANG2). This represents an additional mechanism by which NVP-BGJ389 inhibits tumor growth. CONCLUSION: Various pathways induce apoptosis in NSCLC cells by employing NVP-BGJ398. These data reflect the potential of cancer treatment utilizing small FGFR inhibitors. PMID- 26504011 TI - Oxidative Stress Activates Membrane Ion Channels in Human Biliary Epithelial Cancer Cells (Mz-Cha-1). AB - Oxidative stress is known to contribute to cell damage. In several cell types, one of the earliest effects of oxidative stress is a rapid and substantial decrease in cell volume, which in turn regulates a broad range of cell functions, including development of apoptosis. Since volume regulation is closely coupled to membrane ion permeability, activation of ion channels may play an important role in oxidative stress-related cell injury. Oxidative stress plays a major role in a variety of liver diseases and bile duct epithelia cells (BDE) represent an important site of injury. We, therefore, investigated the functional interactions of oxidative stress, cell volume and ion permeability in a BDE model. Whole-cell patch clamp studies were performed in the human Mz-Cha 1 cell line. Oxidative stress was produced by addition of H2O2 to the bath solution. Changes of intracellular Ca(2+) concentration and of crosssectional area (for calculating cell volume) were monitored by laser scanning microscopy. Exposure of Mz-Cha 1 cells to H2O2 resulted in cell shrinkage and increase of the intracellular Ca(2+) concentration. Patch-clamp studies revealed that exposure to H2O2 also resulted in the activation of ion currents with a threshold of 10(-6) M H2O2. Ion substitution studies and blocker experiments identified the currents as representing an increase in membrane K(+) and Cl-permeability. Interestingly both ion channel activation and cell shrinkage had a close relationship to the applied H2O2 concentration and were significantly inhibited by intracellular Ca(2+) chelation. These data imply that in a BDE model, oxidative stress leads to cell shrinkage through activation of Ca(2+)-dependent K(+) and Cl(-) currents. Since cell shrinkage has been associated with increased cell damage, the opening of these ion channels might contribute to the high susceptibility of biliary epithelial cancer cells to oxidative stress. PMID- 26504012 TI - Inhibition of Growth of Bladder Cancer Cells by 3-(3-Pyridinyl)-1-(4-pyridinyl)-2 propen-1-one in Combination with Other Compounds Affecting Glucose Metabolism. AB - In seven out of eight human bladder cell lines that were examined herein, growth was more dependent on the presence in the incubation medium of glucose rather than glutamine. The exception was the slowly growing RT4 cells that were more glutamine-dependent. Growth of all the cell lines was reduced by an inhibitor of 6-phosphofructo-2-kinase/2,6-bisphosphatase 3, namely 3-(3-pyridinyl)-1-(4 pyridinyl)-2-propen-1-one (3PO). Growth was also reduced by three compounds that reduce the conversion of glucose to lactate: namely 2-deoxyglucose, butyrate and dichloroacetate. Additive effects were seen when these molecules were combined with 3PO. Treatment of bladder cancer cells with phenformin resulted in growth inhibition that was frequently accompanied by increased glucose uptake and acidification of the medium that was blocked by co-incubation with 3PO. The actions of 3PO suggest that inhibitors of PFKB3 merit further investigation in the treatment of bladder cancer and they may be useful agents in combination with other drugs that inhibit cancer cell proliferation. PMID- 26504013 TI - HER2 Codon 655 (Ile/Val) Polymorphism and Breast Cancer in Austrian Women. AB - BACKGROUND: The overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer (BC) is associated with impaired prognosis. Data concerning the HER2 codon 655 polymorphism (Ile/Val) and BC risk are conflicting. MATERIALS AND METHODS: We studied the HER2 codon 655 (rs1136201) polymorphism in 80 Austrian patients with BC and 100 healthy volunteers by pyrosequencing and polymerase chain reaction. Associations between codon 655 allelic variants and clinicopathological variables (e.g. age, stage of disease, tumor type, grading, and receptor status) were studied with 2*2 tables. RESULTS: The genotypic distributions in patients with BC (AA: 63.75%, AG: 32.5%, GG: 3.75%) and controls (AA: 63%, AG: 34%, GG: 3.7%) were virtually identical (odds ratio=1.03, 95% confidence interval=0.56-1.90). A non-significant link between carrying at least one G allele and more aggressive tumor type (estrogen receptor-negative p=0.08, G3 tumor p=0.19) was observed. CONCLUSION: Genotypic variation within the codon 655 of HER2 does not alter the BC risk in Caucasian Austrian women. The association between the G allele and more aggressive tumor types requires further investigation. PMID- 26504014 TI - Core Needle Biopsy Wash Optimization: Enabling Specimen Integrity for both Cytological and Histological Evaluation. AB - BACKGROUND: The recovery of cells after washing core needle biopsies represents an under-utilized approach to extend the diagnostic capacity of these diminutive specimens. Recovery of these cells can be dedicated for molecular studies so that the biopsy itself can be used apropos for its intended purpose, diagnosis. Non enzymatic and enzymatic reagents have the potential to increase the number of cells dissociating from the tissue core, but can also negatively impact the quality of the tissue itself. MATERIALS AND METHODS: Three different means (phosphate-buffered saline, a non-enzymatic and an enzymatic solution) were used to wash core needle biopsies. The washed cells were recovered by traditional preparatory methods and evaluated for cellularity and cytomorphology. The post washed cores were processed by formalin fixation, paraffin embedding and evaluated for integrity and morphological quality. RESULTS: The enzymatic solution damaged both the cytological and tissue specimens, while the saline and non-enzymatic process allowed for the comparable recovery of cells and tissue for evaluation. CONCLUSION: Adequate numbers of cells are dissociated from the tissue core when needle biopsies are washed. The recovery and preservation of cells and tissue for morphological interpretation was optimal when solutions devoid of enzymes were used for washing. PMID- 26504015 TI - Fluorinated beta-Diketo Phosphorus Ylides Are Novel Inhibitors of the ABCB1 Efflux Pump of Cancer Cells. AB - Efflux pump inhibitors are attractive compounds that reverse multidrug resistance (MDR) in cancer cells. In the present study, 10 phosphorus ylides (P-ylides) were compared based on their MDR-reverting activity in human ATP-binding cassette sub family B member 1 (ABCB1; P-glycoprotein) gene-transfected L5178Y mouse T lymphoma cells. Among them, three P-ylides, Ph3P=C(COCF3)COPh, Ph3P=C(COC2F5)COPh and Ph3P=C(COC3F7)COPh were identified as selectively modulating the ABCB1 pump. These compounds, with low cytotoxicity against mouse T-lymphoma cells, exhibited more potency than the positive control ABCB1 inhibitor verapamil. PMID- 26504016 TI - In Vitro Efficacy of Naftifine Against Lymphoma and Multiple Myeloma. AB - BACKGROUND/AIM: Multiple myeloma is still an incurable hematological malignancy of monoclonal B-lymphocytes. While standard chemotherapy regimens have been used for years, novel agents like lenalidomide and bortezomib have become an essential part of today's therapies and significantly improve therapeutic efficacy. Nevertheless, new therapeutic strategies are still indispensable. Aberrant activation of Wnt/beta-catenin signaling promotes development of several cancers. Recently, it has been demonstrated that the Wnt pathway is activated in both lymphoma and myeloma. Thus, Wnt signaling molecules are attractive candidates for the development of new targeted-therapies. Naftifine was used in the present study since it has chemical features similar to those of other known WNT inhibitors. MATERIALS AND METHODS: The anti-tumor apoptotic effect of naftifine at doses ranging from 0.1-200 MUM was investigated on two human and one murine lymphoma, as well as in one murine and three human myeloma cell lines, and determinded by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) assay. RESULTS: Naftifine significantly reduced cell viability in all tested myeloma and lymphoma cell lines in a dose-dependent manner, while healthy cells were only slightly affected. CONCLUSION: Naftifine exhibits toxicity to hematological neoplasms in vitro. PMID- 26504017 TI - Intercellular HOCl-mediated Apoptosis Induction in Malignant Cells: Interplay Between NOX1-Dependent Superoxide Anion Generation and DUOX-related HOCl generating Peroxidase Activity. AB - Intercellular apoptosis-inducing HOCl signaling is discussed as a control step during oncogenesis. It is defined as a sophisticated interplay between transformed target cells and non-transformed or transformed effector cells. In this study, transformed target cells were seeded as clumps of high local cell density, but low total cell number. They were surrounded by large numbers of effector cells, seeded at low local density. This spatially defined experimental arrangement allowed study of the impact of siRNA-mediated knockdown of NADPH oxidase 1 (NOX1) or dual oxidase 1 (DUOX1) on intercellular HOCl signaling. Our data show that the target function of transformed cells is defined as expression of NOX1 and subsequent extracellular superoxide anion generation. The NOX domain of DUOX1 does not contribute to the target function. The peroxidase domain of DUOX1 is released from transforming growth factor beta1-treated non-transformed and transformed cells and acts in trans as HOCl-synthesizing peroxidase. These findings clarify the biochemical source of HOCl during HOCl-mediated signaling. PMID- 26504018 TI - Evaluation of 111In-labeled Anginex as Potential SPECT Tracer for Imaging of Tumor Angiogenesis. AB - Angiogenesis is a prerequisite for solid tumors to grow and metastasize, providing oxygen and nutrients to the tumor site. The protein galectin-1 has been identified to be overexpressed on tumor vasculature and represents an interesting target for anti-angiogenic therapy, as well as in molecular imaging. Therefore, the galectin-1-binding peptide Anginex was modified for radiolabeling using (111)In. In vitro, (111)In-Ax showed significantly more binding to galectin-1 positive EC-RF24 and MDA-MB-231-LITG cells than to galectin-1-negative LS174T cells and association with EC-RF24 cells was reduced in the presence of excess native Anginex. However, ex vivo biodistribution profiles showed little tumor uptake of (111)In-Ax and extensive accumulation in non-target organs. Although this study shows the ease of modification of the therapeutic peptide Anginex and favorable characteristics in vitro, in vivo assessment of the tracer revealed negligible tumor targeting. Hence, the strategy we employed lends little support for successful non-invasive imaging of tumor angiogenesis using this peptide. PMID- 26504019 TI - Site-specific Effects of DUOX1-Related Peroxidase on Intercellular Apoptosis Signaling. AB - Intercellular apoptosis-inducing HOCl signaling is known as an interplay between superoxide anions/H2O2 of transformed target cells and dual oxidase 1 (DUOX1) related peroxidase that is released from neighboring non-transformed or transformed effector cells. Effector cells are dispensable when the release of the peroxidase domain of DUOX1 from target cells is prevented through inhibition of matrix metalloproteinase (MMP) activity. Membrane-associated peroxidase is then co-localized to NADPH oxidase 1 (NOX1) and establishes HOCl signaling specifically in transformed cells, using the same biochemical pathways as classical intercellular HOCl signaling. Membrane-associated peroxidase protects against exogenous HOCl through reversal of the peroxidase reaction. In addition, membrane-associated peroxidase protects against NO/peroxynitrite signaling as it oxidates NO and decomposes peroxynitrite. The protective function of membrane associated peroxidase (in the absence of MMP) is analogous to that of catalase, whereas the destructive effect of the enzyme, i.e. the synthesis of HOCl, is independent of its localization and of MMP activity. PMID- 26504020 TI - Crizotinib Fails to Enhance the Effect of Radiation in Head and Neck Squamous Cell Carcinoma Xenografts. AB - AIM: Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head and neck squamous cell carcinomas (HNSCC) and is involved in tumor progression and associated with poor prognosis. MET can be inhibited by crizotinib, a potent ATP-competitive kinase inhibitor. We examined the effects of combining crizotinib and radiation in a pre-clinical HNSCC model. MATERIALS AND METHODS: Nine HNSCC cell lines were screened for MET expression, copy-number amplification and mutational status. The in vitro effects of crizotinib and radiation were assessed with clonogenic survival assays. MET signaling proteins were assessed with western blot and receptor tyrosine kinase array. Tumor growth delay experiments with UT-SCC-14 and UT-SCC-15 oral tongue xenografts were used to assess in vivo tumor radiosensitivity. RESULTS: All nine HNSCC cell lines showed a varying degree of MET protein and RNA expression. Increased MET copy number was not present. MET was expressed after irradiation both in vitro and in vivo. Crizotinib alone inhibited phosphorylation of MET and inhibited cell growth in vitro but did not inhibit phosphorylation of downstream signaling proteins: MAPK, AKT or c-SRC. When combined with radiation in vitro, crizotinib demonstrated radiation enhancement in only one cell line. Crizotinib did not enhance the effect of radiation in either UT-SCC-14 or UT-SCC-15 tumors grown as xenografts. CONCLUSION: MET is overexpressed in HNSCC cell lines, however, crizotinib failed to enhance the radiation response and failed to inhibit MET downstream signaling proteins in this HNSCC model. PMID- 26504021 TI - Synergistic Effect of SN-38 in Combination with Cetuximab on Angiogenesis and Cancer Cell Invasion. AB - BACKGROUND: The combination of irinotecan, a topoisomerase I inhibitor with cetuximab, an antibody against epidermal growth factor receptor, produces synergistic and beneficial effects in patients with irinotecan-refractory colorectal cancer. Our hypothesis was that synergistic effects could be due to anti-angiogenesis and anti-invasion, but not to cytotoxicity. MATERIALS AND METHODS: Cytotoxicity was assessed by viability test and flow cytometry. Anti angiogenesis, anti-invasion were studied by the endothelial cell capillary-like network formation and transmigration through an extracellular matrix. Protein kinase B (PKB, frequently cited as AKT), and extracellular signal-regulated kinases (ERK) activation was assayed by cell-based enzyme-linked immunosorbent assay (ELISA). RESULTS: Combinations of SN-38 (the active of irinotecan) and cetuximab did not induce any synergistic cytotoxicity confirmed by viability test and cell-cycle analyses. Interestingly, their combination produced synergistic anti-angiogenesis and anti-invasion activities revealed by endothelial cell capillary-like network formation and cell invasion tests. Subsequently, their combination attenuated either expression or phosphorylation of AKT and ERK1/2 using cell-based ELISA. CONCLUSION: SN-38/cetuximab combination has synergistic anti-angiogenesis and anti-invasion activities mediated by down-regulation of phosphatidylinositol-3-kinases/AKT and mitogen-activated protein kinase/ERK pathways. PMID- 26504022 TI - Identification of the Critical Site of Calponin 1 for Suppression of Ovarian Cancer Properties. AB - BACKGROUND: Although several studies have demonstrated the tumor suppressive function of CNN1 (calponin 1), no studies have performed a site-specific analysis of CNN1 on tumor cell activities. MATERIALS AND METHODS: We herein studied the site-specific effects of CNN1 in ovarian cancer cells using full-length CNN1 (fCNN1), three CNN1 repeats (3CNRs), or the first CNN1 repeat (CNR1) expression vectors. Ovarian cancer cells stably expressing each construct were analyzed for in vitro proliferation, cell motility, invasion, and soft agar assays. An in vitro model of pleural dissemination was also established. RESULTS: Cell proliferation, anchorage-independent colony formation, cell motility, and cell invasion were all suppressed in fCNN1, 3CNRs, and CNR1-stably-expressing cells. CNN1 expression in mesothelial cells suppressed cancer cell invasion into a monolayer of mesothelial cells. CONCLUSION: CNR1 showed similar suppressive effects as fCNN1. Results suggest CNR1 as a potential small synthetic peptide candidate for therapeutic strategies against ovarian cancer. PMID- 26504023 TI - Antitumor Activity of 3-Indolylmethanamines 31B and PS121912. AB - AIM: To investigate the in vivo effects of 3-indolylmethanamines 31B and PS121912 in treating ovarian cancer and leukemia, respectively. MATERIALS AND METHODS: Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and western blotting were applied to demonstrate the induction of apoptosis. Xenografted mice were investigated to show the antitumor effects of 3-indolylmethanamines. (13)C Nuclear magnetic resource (NMR) and western blotting were used to demonstrate inhibition of glucose metabolism. RESULTS: 31B inhibited ovarian cancer cell proliferation and activated caspase-3, cleaved poly (ADP-ribose) polymerase 1 (PARP1), and phosphorylated mitogen-activated protein kinases (MAPK), JUN N terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38. 31B reduced ovarian cancer xenograft tumor growth and PS121912 inhibited the growth of HL-60 derived xenografts without any sign of toxicity. Compound 31B inhibited de novo glycolysis and lipogenesis mediated by the reduction of fatty acid synthase and lactate dehydrogenase-A expression. CONCLUSION: 3-Indolylmethanamines represent a new class of antitumor agents. We have shown for the first time the in vivo anticancer effects of 3-indolylmethanamines 31B and PS121912. PMID- 26504024 TI - Plasminogen Activation System in Rectal Adenocarcinoma. AB - BACKGROUND: The purpose of the present study was to determine the extent of expression of proteins that are the elements of the plasminogen activation system, i.e. urokinase plasminogen activator (uPA), receptor of uPA (uPAR), plasminogen activating inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in the primary site of rectal adenocarcinoma, as well as in lymph node metastases, and their correlation with clinical and pathological data. MATERIALS AND METHODS: The study material consisted of archival paraffin blocks from 108 patients with confirmed oncological diagnosis, treated in 2002 and 2003 in the Lower Silesian Oncology Centre in Wroclaw. This material was used for immunohistochemical reactions with antibodies against uPA, uPAR, PAI-1 and tPA. The extent of expression was evaluated semi-quantitatively based on the immunoreactive score according to Remmele and Stegner. The obtained results were correlated with clinical and pathological data: stage of the disease (modified Dukes' classification of Astler and Coller), grade of histological malignancy, event-free survival and overall survival. RESULTS: It was found that cytoplasmic expression of uPA, uPAR, PAI-1 and tPA was higher in cells of tumor and metastases of perienteric lymph nodes in comparison to normal rectal tissues. Positive correlation was shown between expression of PAI-1 and tPA, uPA and uPAR, as well uPA and PAI-1 (r=0.70, r=0.77 and r=0.34, respectively; p<0.05 for all). Additionally, in patients with low and moderate expression of uPA and uPAR, the overall survival rate was higher in comparison to patients with high expression of the studied markers. CONCLUSION: The intensity of expression of uPA and uPAR might be a prognostic factor of survival time for patients with primary rectal adenocarcinomas. PMID- 26504025 TI - Expression of MCM-3 and MCM-7 in Primary Cutaneous T-cell Lymphomas. AB - BACKGROUND/AIM: Primary cutaneous T-cell lymphomas is a group of rare non-Hodgkin lymphomas, originally affecting the skin. Increased proliferation activity is a hallmark of diverse tumors and the proliferation rate, measured by the expression of various markers has a predictive value regarding the malignancy course. The aim of the present study was to evaluate the prognostic value and the potential correlation between the expression of proliferation markers Ki-67, MCM-3 and MCM 7, and clinicopathological data for different types of primary cutaneous T-cell lymphomas. MATERIALS AND METHODS: Immunohistochemical reactions were performed on paraffin blocks obtained from 90 patients with mycosis fungoides (MF) and 21 patients with other CTCL (oCTCL), in comparison to 19 patients with benign inflammatory dermatosis (lichen planus, eczema), serving as control. RESULTS: Statistically significant differences in the expression of Ki-67, MCM-3 and MCM-7 were observed between oCTCL vs. the control group (29% vs. 5%; 17% vs. 5%; 13% vs. 1.5%, respectively, ANOVA with Scheffe post-hoc test: p<0.01). In both, MF and oCTCL Ki-67 expression highly correlated with the expression of MCM-3 (r=0.83; p<0.001 and r=0.91; p<0.001, respectively) and MCM-7 (r=0.84; p<0.001 and r=0.87; p<0.01, respectively; Pearson correlation test). Similarly, a strong positive correlation was observed between MCM-3 and MCM-7 (r=0.81, p<0.001 and r=0.85, p<0.001). Regarding the MF group, Ki-67 and MCM-3 expression was significantly higher in advanced compared to early stages (11% vs. 3% and 15.5% vs. 5.0%, respectively, Student's t-test: p<0.05). Advanced MF had also significantly higher labeling indexes for Ki-67, MCM-3 and MCM-7 compared to benign inflammatory dermatoses (Student's t-test: p<0.01, p<0.001 and p=0.02, respectively). Considering skin involvement in MF, T1b had a significantly higher expression of Ki-67, MCM-3 and MCM-7 than T1a (p<0.001 for all comparisons) with similar observations between T2b and T2a (p=0.02; p<0.01; p=0.01, respectively, Student's t-test test). Regarding extracutaneous involvement, only MCM-3 expression in MF showed a positive relationship with both nodal and distant metastases (ANOVA with Scheffe post hoc test: p<0.01, p<0.01, respectively). Higher Ki-67 and MCM-3 expression correlated with shorter survival in MF, although the latter did not reach statistical significance (10-year survival 0.38 vs. 0.82, p=0.02, and 0.46 vs. 0.81, p=0.06, respectively; log rank test). CONCLUSION: All studied proliferation markers may had predictive values regarding the disease severity and prognosis. Further studies are required to analyze their implementation into patient stratification and treatment process such that will improve prognosis in CTCL. PMID- 26504026 TI - Combination of Genistein and Cisplatin with Two Designed Monofunctional Platinum Agents in Human Ovarian Tumour Models. AB - A great amount of research effort has been directed at platinum compounds that bind with DNA differently from cisplatin with the idea that the difference may translate into an altered spectrum of activity. Recently research has also been directed at applying combinations of platinum agents with tumour-active phytochemicals with the aim of providing a means of overcoming platinum resistance in ovarian cancer. Herein we report the synthesis of monofunctional platinum tris(3-hydroxypyridine)chloroplatinum(II) chloride (coded as LH1) and tris(imidazole)chloroplatinum(II) chloride (coded as LH2), and their activity alone and in combination with genistein and cisplatin against human ovarian A2780, cisplatin-resistant A2780(cisR) and picoplatin-resistant A2780(ZD0473R) cancer cell lines. Although both LH1 and LH2 were found to be less active than cisplatin against the tumour models, they produced synergistic outcomes in combination with genistein. Both the level of cellular accumulation of Pt and of Pt-DNA binding resulting from the combination were greater in the A2780(cisR) cell line than in the parental A2780 cell line, irrespective of the sequence of administration. Absence of association between activity of LH1 and LH2 and the level of Pt-DNA binding indicates that the cell death induced by LH1 and LH2 may not be limited to the effect of their binding with DNA. PMID- 26504027 TI - Effects of Vitamin K3 and K5 on Daunorubicin-resistant Human T Lymphoblastoid Leukemia Cells. AB - BACKGROUND/AIM: Anticancer efficacy of vitamin K derivatives on multidrug resistant cancer cells has been scarcely investigated. MATERIALS AND METHODS: The effects of vitamins K3 and K5 on proliferation of human leukemia MOLT-4 cells and on daunorubicin-resistant MOLT-4/DNR cells were estimated by a WST assay. Apoptotic cells were detected by Annexin V and propidium iodide staining, followed by flow cytometry. RESULTS: Vitamins K3 and K5 significantly inhibited proliferation of leukemic cells at 10 and 100 MUM (p<0.05), and these effects were almost equally observed in both MOLT-4 and MOLT/DNR drug-resistant cells. Vitamin K3 induced cell apoptosis at 10 and 100 MUM in both MOLT-4 and MOLT-4/DNR cells (p<0.05). Vitamin K5 also increased apoptotic cells, while rather inducing necrotic cell death. CONCLUSION: Vitamins K3 and K5 suppress MOLT-4 and MOLT 4/DNR cell-proliferation partially through induction of apoptosis, and these vitamin derivatives can overcome drug resistance due to P-glycoprotein expression. PMID- 26504028 TI - Increased Expression of MuRF1 Is Associated with Radiation-induced Laryngeal Muscle Atrophy. AB - BACKGROUND: Laryngeal muscles play an important role in breathing, sound production and trachea protection against food. Laryngeal dysfunctions during radiotherapy for head and neck cancers are common. In the present study, we aimed to investigate the early effect of radiation on the laryngeal muscles in vivo and possible mechanisms involved in this process. MATERIALS AND METHODS: Eight-week old female C57bl/ mice received neck irradiation with a single dose of 25 Gy and bilateral thyroarytenoid (TA) muscles of mice were collected at day 3, 7 and 10 post-irradiation for evaluating muscle size, myosins, myosin heavy chain (MyHC) composition and MuRF1 protein levels. RESULTS: A significant reduction in the size of muscle fibers and myosins in the TA muscles were observed at days 3, 7, 10 after radiation (p<0.05). The loss of IIB myosin was more severe than that of IIA/X myosins at day 7 post-irradiation (75% vs. 64%). MuRF1 protein level was markedly increased at day 7 and 10 after radiation (p<0.05). CONCLUSION: Radiation induced an acute muscle fiber atrophy and myosin loss in the intrinsic laryngeal muscles. MuRF1 may play an important role in the radiation-induced protein degradation in the laryngeal muscles and warrants further investigation. PMID- 26504029 TI - Investigation of Interleukin-1beta Polymorphisms in Prostate Cancer. AB - BACKGROUND: Cytokine-mediated immune and inflammatory responses are considered to play an important role in the pathogenesis of prostate cancer. The present study investigated certain interleukin-1beta (IL1beta) polymorphisms and their association with prostate cancer. MATERIALS AND METHODS: Genotyping of the IL1B 31(rs 1143627 G>A) and IL1B-511(rs 16944 A0.05, Wilcoxon test). The relative percentage difference of the averaged P(+) values between the HIPO and GrO plans evaluated together with the external beam radiation therapy plans was 0.01%, 0.37% and 0.98% for the bladder, sigmoid colon and rectum, respectively. The lowest P+ value for all the plans was 98.44% for sigmoid colon. CONCLUSION: HIPO presented comparable results in relation to manual planning with respect to dosimetric and radiobiological parameters. PMID- 26504035 TI - Incisional Recurrences After Endometrial Cancer Surgery. AB - AIM: The aim of the present study was to estimate the incisional recurrence (IR) rate after endometrial cancer (EC) staging surgery and analyze characteristics of affected patients. PATIENTS AND METHODS: We retrospectively searched for patients with EC at 2 institutions and analyzed the occurrence of IR after open, laparoscopic, or robotic surgery. Additionally, a review of the literature was performed. RESULTS: Out of 2,636 patients with EC, 1,732 (65.7%), 461 (17.5%), and 443 (16.8%) had open, laparoscopic, and robotic surgery, respectively. Only 3 patients (0.11%) had IR, all after open surgery. Additionally, 38 cases of IR were identified from the literature. Patients with non-isolated IR had worse overall survival than patients with isolated IR (p=0.04). Among this latter group, combined treatments may be associated with improved survival outcome. CONCLUSION: IR after EC surgery is rare and may occur after minimally-invasive or open operations. Combination of local and systemic treatments may provide favorable outcomes for patients with isolated IR. PMID- 26504036 TI - Laparoendoscopic Single-site Surgery (LESS) for Prophylactic Salpingo oophorectomy Improves Cosmetic Satisfaction Compared to Standard Laparoscopy. AB - AIM: Less invasive prophylactic bilateral salpingo-oophorectomy (PBSO) may diminish the general consequences of surgery for BRCA mutation carriers. The objective of the present study was to compare the psychological impact and satisfaction following minimal-invasive laparoendoscopic single-site surgery (LESS) versus that observed with the standard procedure. PATIENTS AND METHODS: This prospective longitudinal study was proposed to all consecutive patients who underwent ambulatory PBSO between January 2012 and January 2014 at our Center. The psychological impact and esthetic satisfaction were prospectively studied. Patients rated their satisfaction using the 4-grade Likert scale. Their emotional state and postoperative pain were explored respectively with validated questionnaires (IES-R, PANAS) and the Verbal Numerical Rating Scale (VNRS). Operative outcomes were also analyzed. RESULTS: Twenty patients underwent LESS PBSO and 10 patients had the standard laparoscopic (SL) PBSO. The mean satisfaction scores were significantly higher in the LESS group one month and six months after surgery. Both groups reported a reduction of intrusive thoughts and negative affects after surgery. Postoperative pain and operative outcomes were similar. CONCLUSION: A significant improvement of cosmetic satisfaction after LESS compared to SL could help patients accept PBSO. The emotional impact of PBSO is not modified by ambulatory LESS. PMID- 26504037 TI - Tumor Budding, EMT and Cancer Stem Cells in T1-2/N0 Oral Squamous Cell Carcinomas. AB - BACKGROUND: Early oral carcinomas have a high recurrence rate despite surgery with clear margins. In an attempt to classify the risk of recurrence of oral squamous cell carcinomas, we explored the significance of tumor budding, epithelial-mesenchymal transition (EMT) and certain cancer stem cell markers (CSC). MATERIALS AND METHODS: Tumor budding (single cells or clusters of <=5 cells in the tumor front, divided into high- and low-budding tumors), EMT and CSC markers were studied in 62 immunohistochemically stained slides of T1/2N0M0 oral squamous cell carcinomas. Tissues and records of follow-up were obtained from the Oslo University Hospital, Norway. Tumor budding, EMT and CSC markers were scored and analyzed. RESULTS: The only significant prognostic marker was tumor budding (p=0.043). Expression of the EMT marker E-cadherin was lost from the invasive front and tended to be a prognostic factor (p=0.17), and up-regulation of vimentin in tumor cells in the invasive front was found; this indicates that EMT had occurred. CSC markers were not associated with recurrence rate in the present study. CONCLUSION: A high budding index was related to poor prognosis in patients with oral cancer. Budding was associated with EMT-like changes. CSC factors were detected but reflected differentiation rather than stemness. Scoring of buds in patients with oral cancer may help discriminate invasive tumors prone to relapse, and thus, provide an indication for adjuvant therapy. PMID- 26504038 TI - Electrochemotherapy of a Multirecurrent Dermatofibrosarcoma Protuberans of the Orbital Margin: A Case Report. AB - Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous sarcoma with high recurrence rate. Radical surgery is the treatment of choice, although in cosmetically-sensitive areas such as the head and neck, this option is often not pursued. Electrochemotherapy (ECT) is a minimal invasive anti-tumor modality which is increasingly being used to treat skin metastases from different malignancies. A 31-year-old woman presented with subcutaneous local multirecurring DFSP located at the proximal end of the left eyebrow. ECT was offered as a palliative treatment to avoid radical disfiguring surgery. Two days following ECT, the patient was discharged in good general health. Partial tumor regression was appreciable at two months' follow-up by ultrasound and magnetic resonance imaging. At six months, residual fibrotic tissue was observed; at three years, no evidence of the tumour was detected. In our case, ECT achieved good local tumor control with excellent cosmetic results, preserving the patient's quality of life. PMID- 26504039 TI - Endoplasmic Reticulum Stress in Pancreatic Neuroendocrine Tumors is Linked to Clinicopathological Parameters and Possible Epigenetic Regulations. AB - BACKGROUND: Endoplasmic reticulum (ER) stress is a highly-conserved cellular defense mechanism in response to perturbations of ER function. The role of ER stress in pancreatic neuroendocrine tumors (pNET) still remains unclear. MATERIALS AND METHODS: We analyzed the protein expression pattern of the four key players of ER stress, (chaperone binding imunoglobluin protein (BiP), C/EBP homologous protein (CHOP), activating transcription factor 4 (ATF4) and caspase 4) as well as histone deacetylases (HDACs) by a tissue microarray (TMA) of 49 human pNET resected between 1997 and 2013 following, extensive clinicopathological characterization. RESULTS: Immunohistochemical profiling revealed a significant up-regulation of BiP, ATF4, CHOP and caspase 4 in pNET cases compared to normal controls. Correlated to clinicopathological parameters especially BiP expression could be linked to higher grading and proliferation as well as to lower survival probability. Finally, expression of ER stress markers correlated with HDAC expression in situ and pharmalogical inhibition by panobinostat significantly reduced cell viability in vitro. CONCLUSION: Up regulation of ER stress in pNET indicates the presence and engagement of ER stress signaling in this tumor entity demonstrating another possible anticancer therapy option in pNET. PMID- 26504040 TI - Low Serum Testosterone But Not Obesity Predicts High Gleason Score at Biopsy Diagnosed as Prostate Cancer in Patients with Serum PSA Lower than 20 ng/ml. AB - BACKGROUND/AIM: The impact of testosterone or obesity on the pathological grade of prostate cancer remains controversial. Therefore, in this study, we investigated the relationship of serum testosterone and body mass index (BMI) to Gleason score at biopsy. PATIENTS AND METHODS: This study included 128 Japanese patients diagnosed with prostate cancer from 2000 through 2012 whose serum testosterone level and BMI were measured before treatment. Associations between clinical parameters, including pre-treatment serum testosterone level and BMI, and Gleason score at biopsy were examined. RESULTS: The median serum testosterone and BMI were 434 ng/dl (interquartile range=362-542 ng/dl) and 23.5 kg/m(2) (interquartile range=21.7-25.4 kg/m(2)), respectively. Gleason score at biopsy was <7, 7 and >7 for 58 patients (45.3%), 52 patients (40.6%) and 18 patients (14.1%), respectively. On univariate analysis, positive finding at digital rectal examination (DRE), high prostate-specific antigen level at diagnosis and low serum testosterone level, but not BMI, were correlated with high Gleason score at biopsy. Multivariate analysis identified positive finding at DRE and low serum testosterone level as significant predictors of a high Gleason score at prostate biopsy. By combining these parameters, the predictive ability of a high Gleason score was improved. CONCLUSION: This study showed that positive finding at DRE and a low pre-treatment serum testosterone level, but not obesity, may be factors predictive of aggressive prostate cancer, indicating the diagnostic value of serum testosterone, as well as DRE findings, in risk assessment. PMID- 26504041 TI - Long-term Follow-up After Interstitial Laser Thermotherapy of Breast Cancer. AB - AIM: To review the effect of immunological changes induced by interstitial laser thermotherapy (ILT) on long-term outcome of patients with breast cancer. PATIENTS AND METHODS: Twenty-four patients with invasive breast cancer were treated with ILT followed by standard surgical excision. Immunohistological reactions on immunocompetent cells were performed on specimens obtained before and after ILT. Follow-up time was 116 (range=91-136) months. RESULTS: Significant prognostic factors were histologically-positive axillary lymph nodes and Ki67 positivity. ILT increased cytotoxic T (CD8(+)) lymphocytes within the tumor and mature dendritic cells (CD83(+)) and reduced the number of T-regulatory cells (Treg) CD25(+)/Forkhead box p3(+) (FOXP3(+)) lymphocytes in regional lymph nodes. These changes did not correlate with prognosis. The number of CD8(+) cells within the tumor, both before and after treatment, was significantly higher in patients with recurrence than in those without recurrence (p<0.01 and p<0.05, respectively). Patients with recurrent disease had a lower number of CD57(+) cells in tumor-free lymph nodes than did patients without recurrence (p<0.05). CONCLUSION: ILT did not have any long-term adverse effects. The clinical impact of the supposedly favourable immune changes after ILT should be examined in a larger patient population. PMID- 26504042 TI - Gene Expression of Col11A1 Is a Marker Not only for Pancreas Carcinoma But also for Adenocarcinoma of the Papilla of Vater, Discriminating Between Carcinoma and Chronic Pancreatitis. AB - AIM: For tumors of the periampullary region clinical differentiation between primary and tumor-associated pancreatitis might be difficult. Early diagnosis of these malignancies is essential, as they present with early invasion of surrounding tissue thus limiting therapeutic options. Using molecular markers, the preoperative diagnosis (EUS-guided needle biopsy, brush biopsy pancreatic duct) could be optimized and surgical therapy potentially adapted. Alpha1 (XI) collagen Col11A1 is essential for the extracellular matrix and normal skeletal development and has been associated with carcinogenesis. MATERIALS AND METHODS: Forty-three patients with adenocarcinoma of the pancreas, 11 with adenocarcinoma of the papilla of Vater and 23 patients with chronic pancreatitis were included in the study. For all patients mRNA expression of Col11A1 was quantified by TaqMan RT-PCR in tumor or pancreatitis specimen, as well as in the corresponding normal uninvolved tissue and correlated with diagnosis of cancer and chronic pancreatitis. RESULTS: Col11A1 mRNA expression was 5.25-fold higher in adenocarcinoma of the pancreas (p=0.006) and 8.25-fold in the papilla of Vater (p=0.002) compared to that of chronic pancreatitis specimen. CONCLUSION: Differential mRNA expression of Col11A1 may be applied to preoperatively differentiate between tumors of the periampullary region and chronic pancreatitis and this may potentially have a positive effect on patient survival. PMID- 26504043 TI - Four Synchronous Primary Malignancies of the Breast, Lung, Colon and Esophagus. AB - The literature contains few reports of patients with four more or more synchronous primary malignancies. We report the case of a 74-year-old woman who presented with synchronous primary malignant neoplasms of the breast (metaplastic carcinoma), lung (squamous cell carcinoma), esophagus (adenocarcinoma), and colon (adenocarcinoma). She was treated with multimodality therapy and demonstrated a favorable response at early follow-up. To our knowledge, this combination of synchronous primary malignancies has not been previously reported. The management of patients with multiple synchronous primary malignancies introduces a number of unique challenges which necessitate highly individualized treatment plans that may not strictly adhere to standard practices in the setting of a single malignancy. PMID- 26504044 TI - Tumor-like Chronic Pancreatitis Is Often Autoimmune Pancreatitis. AB - BACKGROUND: Distinguishing between pancreatic cancer and chronic pancreatitis (CP) is often difficult. Certain (5-6%) CP cases are autoimmune in nature, and these patients respond to corticosteroid treatment, making surgery avoidable. Our aim was to evaluate the incidence of autoimmune pancreatitis (AIP) among patients operated on for a pancreatic mass with a final histology of CP. PATIENTS AND METHODS: A total of 33 patients were operated on at the Tampere or Helsinki University Hospital for suspicion of cancer, but with final histopathological diagnosis of CP. The median age was 58 (31-81) years; 26 patients (79%) were male. There were 28 pancreaticoduodenectomes and five left pancreatic resections. Surgical specimens were re-evaluated by experienced pathologists, with representative samples chosen for immunohistochemistry Each sample was scored as positive or negative for immunoglobulin G4 (IgG4) independently by two pathologists. Honolulu consensus criteria served for AIP sub-typing. RESULTS: Out of the 33 specimens, 10 (30%) were positive for IgG4. Histopathological re evaluation of these revealed all to be type 1 AIP. CONCLUSION: The proportion of AIP, according to IgG4-positive immunohistochemistry and histological re evaluation, was much higher than expected. This suggests that by focusing on diagnosis of AIP preoperatively, certain patients might be treated with corticosteroids and possibly avoid unnecessary surgery. PMID- 26504045 TI - Translocation (1;5) in a Glomus Tumor. AB - Glomus tumor is a rare perivascular neoplasm that usually occurs in the distal extremities of young adults. Recent molecular studies have identified microRNA 143-NOTCH fusions or NOTCH1-3 rearrangements in benign and malignant glomus tumors. Herein, we describe the cytogenetic and molecular cytogenetic findings of a glomus tumor arising in the left wrist of a 45-year-old man. Physical examination showed a 1.3-cm, blue-red, tender nodule. Magnetic resonance imaging demonstrated a subcutaneous, well-circumscribed mass with low signal intensity on T1-weighted sequences and high signal intensity on T2-weighted sequences. Contrast-enhanced fat-suppressed T1-weighted sequences showed a homogeneous, strong enhancement. A marginal excision was performed and histopathological examination confirmed the diagnosis of a glomus tumor. Cytogenetic and spectral karyotypic analyses showed a novel rearrangement involving chromosome bands 1p13 and 5q32. There has been no evidence of local recurrence four months after surgery. To the best of our knowledge, this is the first case of sporadic glomus tumor with t(1;5). PMID- 26504046 TI - Extraskeletal Myxoid Chondrosarcoma Presenting as a Plantar Fibroma: Case Report and Review of the Literature. AB - BACKGROUND: Extraskeletal myxoid chondrosarcoma is a rare tumor with an indolent course, high propensity for local recurrence, metastases, and propensity for the proximal extremities of middle-aged males. CASE REPORT: We present the case of a 44-year-old man with an extraskeletal myxoid chondrosarcoma in the plantar fascia of the medial arch initially thought to be a plantar fibroma. Magnetic resonance imaging of the lesion demonstrated a lobulated subcutaneous mass plantar to the tarsal bones and inseparable from the fascia. Microscopic examination revealed a lobulated lesion composed of cords and nests of round to spindled malignant cells in a blue-gray myxoid matrix surrounded by fibrous septae. The malignant cells displayed variable positivity for S-100. CONCLUSION: Plantar extraskeletal myxoid chondrosarcoma is a rare occurrence. It should always be considered in the differential diagnosis of masses arising in the plantar fascia of the foot. PMID- 26504047 TI - Prophylactic Effect of Oral Minocycline in Combination with Topical Steroid and Skin Care Against Panitumumab-induced Acneiform Rash in Metastatic Colorectal Cancer Patients. AB - BACKGROUND: Although the anti-EGFR monoclonal antibody panitumumab is effective in treating colorectal cancer, the occurrence of severe skin disorders often discontinues therapy. Herein, we investigated by a retrospective chart review the effect of prophylactic oral minocycline in combination with skin treatment using moisturizer on the incidence of skin disorders and tumor response in metastatic colorectal cancer patients who received panitumumab. PATIENTS AND METHODS: In a total of 55 patients, 38 patients were eligible, consisting the pre-emptive group (N=25) and reactive group (N=13). Acneiform rash and other adverse events were graded according to the CTCAE v4.0. RESULTS: The occurrence of acneiform rash (grade >=2) was significantly lower in pre-emptive group than in reactive group (44.0% vs. 84.6%, p=0.04). No significant differences in the occurrence of other adverse events were observed between the two groups. Tumor response was not significantly different between the two groups (36.0% vs. 7.7%, OR, 6.75; 95% confidence interval (CI)=0.75-60.76, p=0.12). Mean time to treatment failure was 149.7 days and 110.2 days in the pre-emptive group and reactive treatment group, respectively (HR=0.58; 95% CI= 0.26-1.28, p=0.18). CONCLUSION: Prophylactic oral minocycline combined with skin care reduced panitumumab-induced acneiform rash without a significant influence on tumor response. PMID- 26504048 TI - Risk Factors for Recurrence After Curative Conversion Surgery for Unresectable Gastric Cancer. AB - AIM: To evaluate the recurrence risk after curative conversion surgery following chemotherapy for initially unresectable gastric cancer. PATIENTS AND METHODS: We retrospectively analyzed clinicopathological and postoperative recurrence-free survival (RFS) data for 34 patients who underwent curative conversion surgery. RESULTS: Recurrence was observed in 17 (50%) patients, with a median time to recurrence of 22 months (range=1-98 months). In nine (53%) patients with recurrence, the pattern was consistent with their initial metastatic disease. According to multivariate Cox regression analysis, initial clinical T4b disease (cT4b; odds ratio=6.44, 95% confidence interval=1.59-23.9; p=0.01) was the only significant independent risk factor affecting RFS. Pathological T4a or T4b disease was recorded in five-out of six (83%) patients with cT4b. CONCLUSION: Initial cT4b disease appears to predict recurrence in patients with initially unresectable gastric cancer treated with curative conversion surgery. Effective use of additional chemotherapy may be required for patients with this risk factor. PMID- 26504049 TI - Metastatic Spinal Cord Compression: A Survival Score Particularly Developed for Elderly Prostate Cancer Patients. AB - AIM: Metastatic spinal cord compression (MSCC) is an oncological emergency. Many elderly patients cannot tolerate intensive treatment and need individual approaches accounting for a patient's remaining lifetime. The goal of the present study was to develop a survival score for elderly prostate cancer patients with MSCC. PATIENTS AND METHODS: Nine characteristics were analyzed in 243 patients: age, performance status, interval from prostate cancer diagnosis until MSCC, affected vertebrae, ambulatory status, further bone lesions, visceral metastases, time developing motor deficits, fractionation schedule. RESULTS: Pre-radiotherapy ambulatory status (p<0.001), visceral metastases (p<0.001) and time developing motor deficits (p<0.001) were significant for survival on Cox regression analysis and included in the survival score. Four groups were defined: 9-12, 13-16, 17-19 and 21-23 points. Six-month survival rates were 7%, 28%, 71% and 95%, respectively (p<0.001). CONCLUSION: The present study identified four groups with different survival probabilities that require treatment strategies with different priorities ranging from symptom control to prolongation of life. PMID- 26504050 TI - Fluctuation in Plasma 5-Fluorouracil Concentration During Continuous 5 Fluorouracil Infusion for Colorectal Cancer. AB - BACKGROUND/AIM: It is generally believed that the plasma concentration of 5 fluorouracil (5-FU) is constant when 5-FU is continually administered for chemotherapy. The aim of the present study was to verify whether this is true. PATIENTS AND METHODS: Nine patients with colorectal cancer were enrolled in this study. All patients received chemotherapy; four patients received FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) and five received FOLFOX (leucovorin, 5 fluorouracil, oxaliplatin). 5-FU was administered continuously (2400 mg/m(2)) for 46 h. Serum was collected at 12 points after the start of administration. The concentration of 5-FU was evaluated using a new immunoassay method and gas chromatography-mass spectrometric (GC/MS) method. RESULTS: The concentrations of 5-FU fluctuated dramatically over time, with greater than 3-fold changes in each individual, and the pattern was not constant. CONCLUSION: Because the serum concentration of 5-FU fluctuates and displays various patterns, the dosage should not be based on body surface area. A new individualized method for determining the 5-FU dosage should be developed. PMID- 26504051 TI - Visualization of the Stomach's Arterial Networks During Esophageal Surgery Using the HyperEye Medical System. AB - AIM: The present study investigated the visualization of the arterial networks in the stomach (ANS) during gastric tube (GT) creation using indocyanine green fluorescence and the HyperEye Medical System (HEMS), and the feasibility of the HEMS-line-marking method (LMM). PATIENTS AND METHODS: We reviewed 51 consecutive patients who had undergone esophageal surgery with GT reconstruction. Patients for whom the HEMS was deployed after GT creation to confirm the anastomosed area's blood supply formed the control group (n=28). Patients for whom the HEMS was deployed before GT creation to confirm and mark the ANS border comprised the HEMS-LMM group (n=23). RESULTS: The HEMS-LMM visualized the ANS border, and the leakage rate decreased from 17.9% to 4.4% (p=0.204). CONCLUSION: The HEMS-LMM is safe and feasible for visualizing the blood supply border of the right gastroepiploic artery and the ANS before GT creation during esophageal surgery, and it might reduce leakage in esophageal surgery. PMID- 26504052 TI - Number of Lymph Node Metastases May Indicate the Regimen for Adjuvant Chemotherapy in Patients with Stage III Colorectal Cancer. AB - BACKGROUND: Adjuvant chemotherapy (ACT) may prevent recurrence in patients with stage III colorectal cancer (CRC). However, only 10% of patients benefit from ACT and no effective indicators exist to predict which patients are likely to benefit. The present study validated metastatic lymph node (MLN) number as a new indicator for ACT. PATIENTS AND METHODS: We retrospectively reviewed 173 patients with stage III CRC, who were classified by Union for International Cancer Control (UICC) stage or N category, and analyzed their overall survival (OS) and disease free survival (DFS) according to stage, number of MLNs and ACT use. RESULTS: Among 173 patients, we found 65 with only one MLN (N1a). For N1a patients treated with ACT, the 5-year OS rate was 100%; the 3-year DFS rate was 92.7% for those treated with oral ACT. CONCLUSION: The number of MLNs is a simple indicator for ACT in patients with stage III CRC. For patients with only one MLN, oral chemotherapy is a good option. PMID- 26504053 TI - Adult Pleomorphic Rhabdomyosarcoma: A Multicentre Retrospective Study. AB - BACKGROUND: Pleomorphic rhabdomyosarcoma (RMS) is a rare sub-type of RMS. Optimal treatment remains undefined. PATIENTS AND METHODS: Between 1995 and 2014, 45 patients were diagnosed and treated in three tertiary sarcoma Centers (United Kingdom, Switzerland and Germany). Treatment characteristics and outcomes were analyzed. RESULTS: The median age at diagnosis was 71.5 years (range=28.4-92.8 years). Median survival for those with localised (n=32, 71.1%) and metastatic disease (n=13, 28.9%) were 12.8 months (95% confidence interval=8.2-34.4) and 7.1 months (95% confidence interval=3.8-11.3) respectively. The relapse rate was 53.8% (four local and 10 distant relapses). In total, 14 (31.1%) patients received first line palliative chemotherapy including multi-agent paediatric chemotherapy schedules (n=3), ifosfamide-doxorubicin (n=4) and single-agent doxorubicin (n=7). Response to chemotherapy was poor (one partial remission with vincristine-actinomycin D-cyclophosphamide and six cases with stable disease). Median progression-free survival was 2.3 (range=1.2-7.3) months. CONCLUSION: Pleomorphic RMS is an aggressive neoplasm mainly affecting older patients, associated with a high relapse rate, a poor and short-lived response to standard chemotherapy and an overall poor prognosis for both localised and metastatic disease. PMID- 26504054 TI - A Tool to Estimate Survival of Elderly Patients Presenting with Metastatic Epidural Spinal Cord Compression (MESCC) from Cancer of Unknown Primary. AB - AIM: Cancers of unknown primary (CUP) account for about 10% in elderly patients with MESCC. Immediate treatment is indicated. Personalizing treatment for MESCC requires for clear understanding of the patients' survival prognosis. In this case, a tool for estimating survival would be valuable. PATIENTS AND METHODS: In 104 elderly CUP patients, nine factors were investigated: age, gender, performance score, number of affected vertebrae, ability to walk at presentation for radiotherapy, additional bone metastases, visceral metastases, time developing motor weakness, radiotherapy program. RESULTS: In multivariate analysis, the ability to walk (p=0.011) and visceral metastases (p<0.001) were associated with survival. The following scores were assigned: unable to walk=0, able to walk=1, visceral metastases=0, no visceral metastases=1. Three groups were formed (0, 1 and 2 points) with 6-month survival rates of 7%, 18% and 73% (p<0.001). CONCLUSION: This specific tool assists the physician to estimate survival and select for the most suitable radiotherapy program in elderly CUP patients with MESCC. PMID- 26504055 TI - Methylation-associated Silencing of microRNA-126 and its Host Gene EGFL7 in Malignant Pleural Mesothelioma. AB - BACKGROUND/AIM: We recently reported that miR-126 is down-regulated in malignant pleural mesothelioma (MPM) and can be combined into a 4-microRNA-classifier that can accurately diagnose MPM with high sensitivity and specificity. Herein we analyzed the epigenetic regulation of miR-126 and its host gene EGF-like domain, multiple 7 (EGFL7). MATERIALS AND METHODS: Resected formalin-fixed paraffin embedded MPM tissues from 29 patients, 14 patient-matched non-neoplastic pleura (NNP) specimens, 5 MPM diagnostic biopsies (DB), and 5 samples of pneumothorax induced benign reactive mesothelial proliferation (PTHX) were analyzed. miR-126 and EGFL7 mRNA were quantified by RT-qPCR. CpG-islands' methylation in the EGFL7 promoter was analyzed using methylation-specific PCR and in the MIR126-containing intron 7 was quantified by pyrosequencing. RESULTS: Relative to NNP, EGFL7 was under-expressed more than 4-fold in MPM (p<0.001). EGFL7 mRNA and miR-126 levels correlated in MPM (p<0.01) and NNP (p<0.001). The EGFL7 promoter region was hypermethylated in 69% of MPM and 80% of DB samples, but not in NNP and PTHX samples. EGFL7 promoter hypermethylation was associated with epithelioid histology (p<0.05) and reduced patient-survival (p<0.05). CONCLUSION: In MPM, DNA hypermethylation down-regulates miR-126 and its host gene EGFL7, therefore is a poor prognostic factor, and may represent a future therapeutic target for de methylating strategies re-establishing EGFL7 and miR-126 expression. PMID- 26504056 TI - Postoperative External Irradiation of Patients with Primary Biliary Tract Cancer: A Multicenter Retrospective Study. AB - BACKGROUND/AIM: The aim of the present study was to assess clinical outcomes of postoperative radiotherapy for biliary tract cancer patients. PATIENTS AND METHODS: Clinical results of 187 patients treated with external irradiation in 31 Japanese Institutions between 2000 and 2011 were retrospectively analyzed. The median radiation dose was 50.4 Gy in fractions of 1.8-2 Gy. RESULTS: Two-year actuarial overall survival and locoregional control (LCs) rates were 56% and 68%, respectively. In multivariate analysis, macroscopic residual tumor (R2) and irradiated doses <54 Gy were significant indicators of poor LC prognosis. For patients with complete resection (R0) or microscopic residual tumor (R1), 2-year LCs were 71% for <54 Gy and 83% for >=54 Gy; doses >=54 Gy were associated with high long-term LCs. There was no significant difference in acute adverse event rates between <54 Gy and >=54 Gy. CONCLUSION: Postoperative irradiation doses of approximately 54 Gy are safe and effective for R0 or R1 resection patients. PMID- 26504057 TI - Stereotactic Ablative Body Radiotherapy (SABR) in Pulmonary Oligometastatic/Oligorecurrent Non-small Cell Lung Cancer Patients: A New Therapeutic Approach. AB - AIM: Stage IV non-small cell lung cancer (NSCLC) is characterized by poor prognosis. Palliative chemotherapy and/or best supportive care are considered standard treatment. Nevertheless, for patients with limited distant metastases (1 5 metastases), called oligometastatic disease, better prognosis has been observed. We evaluated response rate, survival, time to progression and toxicity in oligometastatic/oligorecurrent NSCLC patients treated with stereotactic body radiotherapy (SBRT) delivered to all active sites in the lung. PATIENTS AND METHODS: Twenty-nine lung metastases in 22 patients affected by oligometastatic/oligorecurrent NSCLC were treated with SBRT to all active sites of disease. Inclusion criteria were: controlled primary tumor with complete response or stable disease after surgery/radiotherapy/combined therapy; <=4 synchronous or metachronous lung metastases at the time of treatment; no other active sites of distant metastases. RESULTS: Response to treatment was as follows: complete response in 21% of lesions, partial response in 69% of metastases, stable disease in 10%. Ninenty-one percent of patients had complete metabolic response, and 9% had a partial metabolic response. Median follow-up was 18 months. The 1-year and 2-year OS was 86% and 49%, respectively. The 1-year and 2-year PFS was 79% and 40%, respectively. Median time to progression and median OS were 18 months and 24 months, respectively. Local control was 93% at 1 year and 64% at 2 years. Overall, acute toxicity occurred in 18% (4/22) of patients; two patients experienced grade 2 pneumonitis. Grade <=2 late toxicity occurred in 50% of patients. No grade >=3 toxicities were recorded. CONCLUSION: Aggressive stereotactic radiotherapy is a feasible and well-tolerated treatment for oligometastatic/oligorrecurrent NSCLC patients with lung metastases offering longer survival. Ablative radio therapy has a potential role in the management of well-selected stage IV NSCLC patients while increasing their quality of life and survival. PMID- 26504058 TI - Induction Chemotherapy and Sequential Concomitant Chemo-radiation in Locally Advanced Head and Neck Cancers: How Induction-phase Intensity and Treatment Breaks May Impact on Clinical Outcomes. AB - AIM: The purpose of the study was to assess outcomes of locally advanced head and neck (LAHNC) treated with induction chemotherapy (ICT) and subsequent concurrent chemo-radiation. PATIENTS AND METHODS: A total of 71 LAHNC patients were treated with 2-3 cycles of docetaxel, cisplatin and 5-fluorouracil as induction chemotherapy and subsequent concurrent chemoradiation with weekly cisplatin or carboplatin. Definitive radiotherapy was delivered with intensity-modulated radiation and a simultaneous integrated boost approach up to a total dose of 70 Gy in 35 fractions to the macroscopic primary and nodal disease. RESULTS: Actuarial 2-year OS, CSS, DFS, MFS, LC were 55.3% (95%CI=39.3-68.6), 58.6% (95%CI=41.9-72), 60.5% (95%CI=47.3-71.4), 87.3% (95%CI=76.2-93.5) and 74.7% (95%CI=61.5-83.9), respectively. On multivariate analysis undergoing to 3 vs. 2 cycles of TPF (HR=22.31; 95%CI=2.68-185.66; p=0.004) and radiotherapy treatment break >4 days (HR=1.28; 95%CI=1.06-1.55; p=0.01) negatively affected cancer specific survival (CSS) with statistical significance. Achieving complete remission after ICT had a statistically significant impact on CSS (HR=0.9; 95%CI=0.01-0.54; p=0.009). Patients undergoing ICT with 3 cycles had more frequently treatment breaks compared to those submitted to 2 cycles (HR=1.36; 95%CI=1.06-1.73; p=0.01), and had statistically significant longer treatment break time (5.9+1.8 vs. 3+0.36; p=0.02). CONCLUSION: A shorter ICT phase may be a better option enhancing patients' tolerance during concurrent chemoradiation and affecting clinical outcomes. PMID- 26504059 TI - Platinum-Vinorelbine Induction Chemotherapy plus Bevacizumab With and Without Pemetrexed Switch Maintenance in Advanced NSCLC. AB - BACKGROUND: Little information is available until today regarding the effect of platinum-doublet chemotherapy with bevacizumab followed by pemetrexed as a sole maintenance treatment. Original data concerns different induction regimens plus bevacizumab with bevacizumab maintenance to progression in advanced non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Two consecutive groups of patients with advanced non-squamous NSCLC received carboplatin, vinorelbine and bevacizumab for four cycles. Group A (2010-2012) did not receive any maintenance therapy, whereas group B (2012-2013) received pemetrexed switch maintenance (500 mg/m(2)) every three weeks until disease progression. RESULTS: The median progression-free survival (PFS) was 4.4 months and 7.3 months (p<0.001) and one-year survival was 42% and 52% for Group A (n=20) and B (n=22) patients, respectively. Disease control rates were 65% and 86% (p=0.104). Deep venous thrombosis and pulmonary embolism occurred in three (15%) and seven (32%) patients in group A and B, respectively. CONCLUSION: The inferior PFS (p<0.001) without maintenance suggests that induction treatment including bevacizumab should not be planned without subsequent maintenance treatment. Whether it is better to use pemetrexed or bevacizumab, or a combination of both, as maintenance therapy is not yet established. PMID- 26504060 TI - Second-line Chemotherapy for Patients with Small Cell Lung Cancer and Interstitial Lung Disease. AB - BACKGROUND: The safety and efficacy of second-line chemotherapy for treating patients with small cell lung cancer (SCLC) and interstitial lung disease (ILD) have not been elucidated to date. PATIENTS AND METHODS: Between January 2005 and September 2013, we analyzed 23 patients with SCLC and ILD who received second line chemotherapy. Pre-existing ILD was diagnosed according to clinical features and pretreatment chest high-resolution computed tomography results. RESULTS: The overall objective response rates and disease control rates were 22% and 52%, respectively. The median respective durations of progression-free survival and overall survival were 2.1 months (95% confidence interval (CI)=2.0-3.0 months) and 7.1 months (95% CI=3.6-11.3 months), respectively. Three patients with unusual interstitial pneumonia pattern (13%) developed chemotherapy-related pneumonitis. CONCLUSION: Second-line treatment may be an effective and safe option for SCLC patients with ILD after sufficient evaluation of risks and benefits. PMID- 26504061 TI - MR Spectroscopic Profile of an Angiocentric Glioma. AB - A 2-year-old female with focal motor seizures was referred to our Center for brain MRI. Imaging revealed a non-enhancing, demarcated, cortically-based mass lesion in the right superior frontal gyrus and cingulate gyrus. Single voxel MR spectroscopy through the tumor showed markedly elevated myoinositol and/or glycine, mildly elevated choline, and moderately decreased N-acetyl aspartate. Histological assessment of the lesion following gross total resection was diagnostic of an angiocentric glioma. Herein, we present the first illustration of MR spectroscopic findings from a typical angiocentric glioma. PMID- 26504062 TI - Development and Validation of a Novel Plasma Protein Signature for Breast Cancer Diagnosis by Using Multiple Reaction Monitoring-based Mass Spectrometry. AB - AIM: We aimed to develop a plasma protein signature for breast cancer diagnosis by using multiple reaction monitoring (MRM)-based mass spectrometry. MATERIALS AND METHODS: Based on our previous studies, we selected 124 proteins for MRM. Plasma samples from 80 patients with breast cancer and 80 healthy women were used to develop a plasma proteomic signature by an MRM approach. The proteomic signature was then validated in plasma samples from 100 patients with breast cancer and 100 healthy women. RESULTS: A total of 56 proteins were optimized for MRM. In the verification cohort, 11 proteins exhibited significantly differential expression in plasma from patients with breast cancer. Three proteins (neural cell adhesion molecule L1-like protein, apolipoprotein C-1 and carbonic anhydrase 1) with highest statistical significance which gave consistent results for patients of stage I and II breast cancer were selected and a 3-protein signature was developed using binary logistic regression analysis [area under the curve (AUC)=0.851, sensitivity=80.6%]. The 3-protein signature showed similar performance in an independent validation cohort with an AUC of 0.797 and sensitivity of 77.2% for detection of stage I and II breast cancer. CONCLUSION: We developed a distinct plasma protein signature for breast cancer diagnosis based on an MRM-based approach, and the clinical value of the 3-protein signature was validated in an independent cohort. PMID- 26504063 TI - Prevalence of Vitamin D Deficiency in Patients with Bone Metastases and Multiple Myeloma. AB - BACKGROUND/AIM: Breast and prostate cancer are amongst the most prevalent malignancies globally and up to 40% of patients will develop metastatic disease, particularly to the skeleton. Multiple myeloma is the most common cancer to affect bone with up to 90% of patients developing bone lesions. Although several studies demonstrated that endocrine changes such as vitamin D deficiency promote secondary cancer growth in bone, relatively few have reported its prevalence. For this reason, the purpose of the present study was to evaluate the prevalence of hypovitaminosis D in patients with bone metastases and multiple myeloma. PATIENTS AND METHODS: Serum 25-OH-D levels of patients with metastatic bone disease were measured on admission. Statistical analyses was performed to evaluate for possible confounders of hypo-vitaminosis D. RESULTS: We found a widespread and alarming rate of vitamin D deficiency in patients with metastatic bone disease and multiple myeloma. Of note, patients with bone metastases due to breast cancer, prostate cancer and multiple myeloma rarely reached sufficient serum 25 OH-D levels. CONCLUSION: It is of utmost clinical importance to assess vitamin D levels in cancer patients, especially in those with, or at high risk of developing metastatic bone disease. PMID- 26504064 TI - Induction of Acute Myeloid Leukemia with Idarubicin, Cytarabine and Cladribine. AB - BACKGROUND: Daunorubicin and cytarabine has been the standard-of-care for induction therapy for acute myeloid leukemia (AML). Adding cladribine to daunorubicin (60 mg/m(2)) and cytarabine has increased complete remission (CR) rates and median overall survival (OS). However, the efficacy of adding cladribine to 7+3 with other anthracyclines is unknown. PATIENTS AND METHODS: We retrospectively evaluated patients with AML receiving induction with idarubicin, cytarabine and cladribine (ICC) between 1/1/2010 and 06/30/2015 at the Methodist University Hospital in Memphis, Tennessee. Institutional Review Board approval was obtained for the study. Patient, disease characteristics and outcomes were analyzed with GraphPad Prism, Microsoft Excel and SPSSv19.0 software. RESULTS: Twenty-four patients induced with ICC for AML were identified. Thirteen (54.2%) had at least one high-risk feature. Hypoplastic marrow was achieved in all by day 14; 19 (79.2%) achieved CR. Thirty-day mortality was 8.3%; 33-month OS and disease-free survival were 56% and 36%, respectively. CONCLUSION: Induction of AML with ICC was associated with a high CR rate and OS in our high-risk population. PMID- 26504065 TI - Expression of p16/Ki-67 in ASC-US/LSIL or Normal Cytology with Presence of Oncogenic HPV DNA. AB - AIM: To determine if positive dual staining of p16/Ki-67 in cytology samples from women with atypical squamous cells of undetermined significance (ASC-US), low grade squamous intraepithelial lesion (LSIL) or normal cytological reports with presence of high-risk human papillomavirus (HPV), helps in predicting the risk of developing high-grade cervical lesions during one-year of follow-up after a normal initial colposcopy. MATERIALS AND METHODS: One-hundred and sixty women with ASC-US, LSIL or otherwise normal cytology, but with the presence of high risk HPV, were referred to the colposcopy Unit of our Hospital. Cytology and HPV testing were repeated and dual staining of p16/Ki-67 performed on a new cytological specimen, and subsequently patients were colposcopically assessed and prospectively followed-up for one year, after which the colposcopy was repeated. An optional intermediate colposcopical assessment after six months was also offered. RESULTS: Out of 143/160 women with a normal initial colposcopy, 13 were ultimately lost to follow-up. Out of the remaining 130, nine developed histologically verified cervical intraepithelial neoplasia or higher grade (CIN2+) lesions during the one-year follow-up period. Two thirds of them (6/9) were initially p16/Ki-67-positive. CONCLUSION: Biomarker detection may identify women at higher risk of CIN2+, and these women may benefit from early colposcopic assessment. Women who test negatively for the biomarkers could eventually follow a less aggressive protocol. PMID- 26504066 TI - Contribution of Interleukin-4 Genotypes to Lung Cancer Risk in Taiwan. AB - AIM: Lung cancer is the leading cause of cancer-related death worldwide. Interleukin-4 (IL-4) is a typical pleiotropic T helper 2 cytokine involved in immunology during carcinogenesis. The present study aimed at evaluating the contribution of IL-4 promoter T-1099G (rs2243248), C-589T (rs2243250), C-33T (rs2070874) genetic polymorphisms to the risk of lung cancer in Taiwan. MATERIALS AND METHODS: The contributions of the promoter IL-4 polymorphic genotypes to lung cancer risk were investigated in 358 lung cancer patients and 716 age- and gender matched healthy controls. In addition, the interaction between IL-4 and individual smoking status was also evaluated. RESULTS: The percentages of CC, CT and TT for IL-4 C-589T genotypes were differentially represented as 69.0%, 26.5% and 4.5% in the lung-cancer patient group and 61.3%, 30.4% and 8.3% in the non cancer control group, respectively (p=0.0156). The TT genotype carriers were of lower risk for lung cancer (odds ratio (OR)=0.48, 95% confidence interval (CI)=0.27-0.86, p=0.0106) than the CC genotype carriers. We also analyzed the allelic frequency distributions and the results showed that the T allele of IL-4 C-589T conducted a protective effect on lung cancer susceptibility (p=0.0022). On the contrary, there was no difference in the distribution of genotypic or allelic frequencies among patients and controls for the IL-4 promoter T-1099G and C-33T. CONCLUSION: The TT genotype of IL-4 C-589T compared to the CC wild-type genotype may have a protective effect on lung cancer risk in Taiwan and may serve as an early detection and prediction marker. PMID- 26504067 TI - Long-term Survival with Ipilimumab: Experience from a National Expanded Access Program for Patients with Melanoma. AB - AIM: Evaluation of efficacy and safety of ipilimumab in patients with advanced, refractory melanoma enrolled into a national ipilimumab Expanded Access Program. PATIENTS AND METHODS: Adult patients with advanced/metastatic refractory melanoma were eligible for study inclusion. Ipilimumab was administered up to a total of four doses. RESULTS: One hundred and ninety-six patients were analyzed. Full ipilimumab induction was administered to 66.8% of patients. Median overall survival (OS) in the entire cohort was 7.5 months. Median OS for patients after four doses of ipilimumab was significantly longer than for patients with fewer doses (12.3 months vs. 2.0 months respectively; p<0.001). Median OS for patients with objective tumor response was 42.3 months. Normal baseline serum lactate dehydrogenase (LDH) and C-reactive protein (CRP) levels, and the number of affected organs correlated with improved OS. CONCLUSION: The number of affected organs and combination of baseline LDH and CRP levels could potentially serve as predictors for both treatment response and OS. PMID- 26504068 TI - Dietetic and Psychological Mindfulness Workshops for the Management of Cachectic Cancer Patients. A Randomized Study. AB - AIM: To determine if actively-treated cancer patients developing cachexia could benefit from participation to mindfulness workshops. PATIENTS AND METHODS: Subjects developing cachexia signs while treated for cancer were randomized in a trial aiming to compare an experimental group that would participate to specific workshops based on mindfulness alternating dietetic and psychological approaches, and a control group managed in accordance to usual practice. RESULTS: The recruitment was difficult (12% of the approached population). Finally 53 patients accepted to participate. Despite an unpredictable compliance of workshop participants, the final satisfaction score attained 75%. In comparison with the control group, patients randomized to the experimental group showed a significant benefit with an increase of their body weight and an improvement of their WHO status score. They also experienced an improvement of emotional function and observation faculty as well as a relief of fatigue and some digestive disorders. CONCLUSION: Selected cachectic cancer patients may benefit from this experimental approach. This approach may, however, be difficult to implement on a large scale. PMID- 26504069 TI - Ureteral Metastasis: Uncommon Manifestation in Prostate Cancer. AB - Ureteral metastasis from a primary prostate cancer is a rare event in the initial diagnosis and progression of prostate cancer. We report here the case of a 72- year-old patient who was treated for castration-resistant metastatic prostate cancer involving bone, intra-abdominal lymph nodes, bilateral adrenal glands, and a small distal ureteral lesion with left hydronephrosis considered in remission, with a luteinizing hormone-releasing hormone analog plus abiraterone acetate (AA) and prednisone after initial docetaxel plus prednisone chemotherapy. After an episode of acute left flank pain, the previous left distal intraluminal ureteral mass appeared increased in volume on computed tomographic scan and was compatible with either a metastasis from prostate cancer, transitional cell carcinoma of the ureter, or a collision tumor. After left nephroureterectomy (NU), the mass was confirmed to be of prostatic origin on histopathological examination and the only site of metastatic progression of prostate cancer. Abdominal CT-scan and the operative specimen of the NU showed no direct extension of the abdominal lymph nodes into the ureteral lesion. We speculate that this unique ureteral prostate cancer metastasis was the result of hematogenic spread of prostate cancer, although microscopic spread through the lymphatic system could not be excluded. The transient anti-tumor effect of AA plus prednisone at the level of ureteral metastasis, as far as we are aware of, has never been documented before. PMID- 26504070 TI - Surgical Management of Duodenal Gastrointestinal Stromal Tumors: A Case Report. AB - Gastrointestinal stromal tumors (GISTs) represent the most common mesenchymal tumor entity of the gastrointestinal tract. In fewer than 5% of cases, primary GISTs are located in the duodenum. Surgery represents the treatment of choice for localized tumor disease and remains challenging in GISTs located at the duodenum. The optimal surgical approach is currently discussed controversially in the literature due to the fact that extended resections in terms of pancreaticoduodenectomy may cause significant postoperative morbidity and mortality compared to limited resection. We report on a rare case of GIST located in the upper part of the duodenum treated by limited surgical resection. Avoidance of postoperative complications may lead to optimal oncological outcome in selected patients. PMID- 26504071 TI - Unresectable Middle Mediastinal Biphasic Pulmonary Blastoma. AB - We report a case of a young male who presented with an unresectable, centrally located classic biphasic pulmonary blastoma (CBPB) involving his bilateral mainstem bronchi and esophagus and a synchronous right testicular seminoma. CBPB is a rare and aggressive tumor that most commonly presents as a solitary mass in the periphery of the lung. Surgical resection is the preferred treatment for CBPB, as chemotherapy and radiation have demonstrated limited effectiveness. In the current case, four cycles of cisplatin, ifosfamide, and etoposide with concurrent radiotherapy resulted in a favorable response at three months. Currently he optimal treatment for unresectable pulmonary blastomas remains undefined. PMID- 26504072 TI - PDK1 is Expressed in Ovarian Serous Carcinoma and Correlates with Improved Survival in High-grade Tumors. AB - BACKGROUND/AIM: 3-Phosphoinositide-dependent protein kinase-1 (PDK1) mediates the cellular effects of various growth factors. Increased PDK1 expression is present in various cancers, suggesting that PDK1 may be a critical oncogene in cancer progression. However, only limited data exist on PDK1 expression in ovarian serous cancer. MATERIALS AND METHODS: We used tissue microarrays to analyze PDK1 expression in 253 primary ovarian serous carcinoma samples. RESULTS: A statistically significant negative correlation between PDK1 expression and tumor grade was found. In the high-grade group of ovarian serous carcinomas (n=189), there was a statistically significant difference in overall survival between cases with positive and negative PDK1 expression (p=0.035); positive cases showed longer overall survival. Multivariate analysis confirmed that slight PDK1 expression was an independent indicator for prolonged overall survival (HR=0.51, 95% CI=0.28-0.92, p=0.025). CONCLUSION: PDK1 appears to be a prognostic marker and a possible therapeutic target in ovarian serous carcinoma. PMID- 26504073 TI - Clinical Significance of Multinodularity in Patients with Papillary Thyroid Carcinoma. AB - Backgroud/Aim: To assess the clinical significance of nodules in multinodular thyroid if one nodule is diagnosed as papillary carcinoma (PC), we investigated 97 patients with a multinodular thyroid and histopathological diagnosis of PC. PATIENTS AND METHODS: We assessed the following variables: age and gender, fine needle aspiration diagnosis, PC nodule size and dominance, intraglandular dissemination (ID), regional lymph node (RLN) status, and distribution of diagnoses of the other nodules. RESULTS: Among 97 patients with PC, additional diagnoses were: nodular goiter (NG) in 64 patients, ID in 28, Hashimoto's thyroiditis (HT) in 26, and follicular or Hurthle cell adenoma in seven. CONCLUSION: Patients with ID, and without NG or HT more often had RLN metastases. Lower rates of RLN metastases in patients with NG and HT are probably due to smaller PC nodule sizes found during routine follow-up of these benign diseases. PMID- 26504075 TI - Errata. PMID- 26504076 TI - Retraction. PMID- 26504074 TI - Biparametric Magnetic Resonance Imaging as an Adjunct to CA125 and HE4 to Improve Characterization of Large Ovarian Masses. AB - BACKGROUND/AIM: Aim of the present study was to assess the diagnostic value of unenhanced biparametric magnetic resonance imaging (Bp-MRI) as adjunct to CA125 and human epididymis protein 4 (HE4) in the characterization of large ovarian masses. PATIENTS AND METHODS: Bp-MRI and dynamic contrast-enhanced (DCE) imaging of 53 patients with large ovarian masses were retrospectively analyzed and compared to histological diagnosis. The results of Bp-MRI and DCE were assessed by two readers in consensus for each technique individually compared to each other and then with HE4 and CA125. RESULTS: Sensitivity, specificity, negative predictive values and positive predictive values for Bp-MRI and DCE were 92.3%, 91.4%, 94.1%, 88.9% and 84.6%, 94.3%, 89.2%, 91.7%, respectively. Both Bp-MRI and DCE were significant predictors of outcome. Among biomarkers, HE4 was significant. Considering the area under receiver operating characteristic curve the model including Bp-MRI and HE4 was not significantly different from the model including DCE and HE4. CONCLUSION: Bp-MRI in addition to HE4, especially in women of pre-menopausal age, could improve the characterization of large ovarian masses. PMID- 26504077 TI - Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction. AB - Most of the steps in, and many of the factors contributing to, glucocorticoid receptor (GR)-regulated gene induction are currently unknown. A competition assay, based on a validated chemical kinetic model of steroid hormone action, is now used to identify two new factors (BRD4 and negative elongation factor (NELF) E) and to define their sites and mechanisms of action. BRD4 is a kinase involved in numerous initial steps of gene induction. Consistent with its complicated biochemistry, BRD4 is shown to alter both the maximal activity (Amax) and the steroid concentration required for half-maximal induction (EC50) of GR-mediated gene expression by acting at a minimum of three different kinetically defined steps. The action at two of these steps is dependent on BRD4 concentration, whereas the third step requires the association of BRD4 with P-TEFb. BRD4 is also found to bind to NELF-E, a component of the NELF complex. Unexpectedly, NELF-E modifies GR induction in a manner that is independent of the NELF complex. Several of the kinetically defined steps of BRD4 in this study are proposed to be related to its known biochemical actions. However, novel actions of BRD4 and of NELF-E in GR-controlled gene induction have been uncovered. The model-based competition assay is also unique in being able to order, for the first time, the sites of action of the various reaction components: GR < Cdk9 < BRD4 <= induced gene < NELF-E. This ability to order factor actions will assist efforts to reduce the side effects of steroid treatments. PMID- 26504078 TI - Dual Action of Zn2+ on the Transport Cycle of the Dopamine Transporter. AB - The dopamine transporter shapes dopaminergic neurotransmission by clearing extracellular dopamine and by replenishing vesicular stores. The dopamine transporter carries an endogenous binding site for Zn(2+), but the nature of the Zn(2+)-dependent modulation has remained elusive: both, inhibition and stimulation of DAT have been reported. Here, we exploited the high time resolution of patch-clamp recordings to examine the effects of Zn(2+) on the transport cycle of DAT: we recorded peak currents associated with substrate translocation and steady-state currents reflecting the forward transport mode of DAT. Zn(2+) depressed the peak current but enhanced the steady-state current through DAT. The parsimonious explanation is preferential binding of Zn(2+) to the outward facing conformation of DAT, which allows for an allosteric activation of DAT, in both, the forward transport mode and substrate exchange mode. We directly confirmed that Zn(2+) dissociated more rapidly from the inward- than from the outward-facing state of DAT. Finally, we formulated a kinetic model for the action of Zn(2+) on DAT that emulated all current experimental observations and accounted for all previous (in part contradictory) findings. Importantly, the model predicts that the intracellular Na(+) concentration determines whether substrate uptake by DAT is stimulated or inhibited by Zn(2+). This prediction was directly verified. The mechanistic framework provided by the current model is of relevance for the rational design of allosteric activators of DAT. These are of interest for treating de novo loss-of-function mutations of DAT associated with neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD). PMID- 26504079 TI - SAS-4 Protein in Trypanosoma brucei Controls Life Cycle Transitions by Modulating the Length of the Flagellum Attachment Zone Filament. AB - The evolutionarily conserved centriole/basal body protein SAS-4 regulates centriole duplication in metazoa and basal body duplication in flagellated and ciliated organisms. Here, we report that the SAS-4 homolog in the flagellated protozoan Trypanosoma brucei, TbSAS-4, plays an unusual role in controlling life cycle transitions by regulating the length of the flagellum attachment zone (FAZ) filament, a specialized cytoskeletal structure required for flagellum adhesion and cell morphogenesis. TbSAS-4 is concentrated at the distal tip of the FAZ filament, and depletion of TbSAS-4 in the trypomastigote form disrupts the elongation of the new FAZ filament, generating cells with a shorter FAZ associated with a longer unattached flagellum and repositioned kinetoplast and basal body, reminiscent of epimastigote-like morphology. Further, we show that TbSAS-4 associates with six additional FAZ tip proteins, and depletion of TbSAS-4 disrupts the enrichment of these FAZ tip proteins at the new FAZ tip, suggesting a role of TbSAS-4 in maintaining the integrity of this FAZ tip protein complex. Together, these results uncover a novel function of TbSAS-4 in regulating the length of the FAZ filament to control basal body positioning and life cycle transitions in T. brucei. PMID- 26504080 TI - Mutant B-Raf(V600E) Promotes Melanoma Paracellular Transmigration by Inducing Thrombin-mediated Endothelial Junction Breakdown. AB - Tumor invasiveness depends on the ability of tumor cells to breach endothelial barriers. In this study, we investigated the mechanism by which the adhesion of melanoma cells to endothelium regulates adherens junction integrity and modulates tumor transendothelial migration (TEM) by initiating thrombin generation. We found that the B-Raf(V600E) mutation in metastatic melanoma cells up-regulated tissue factor (TF) expression on cell membranes and promoted thrombin production. Co-culture of endothelial monolayers with metastatic melanoma cells mediated the opening of inter-endothelial spaces near melanoma cell contact sites in the presence of platelet-free plasma (PFP). By using small interfering RNA (siRNA), we demonstrated that B-Raf(V600E) and TF silencing attenuated the focal disassembly of adherens junction induced by tumor contact. Vascular endothelial cadherin (VE-cadherin) disassembly was dependent on phosphorylation of p120 catenin on Ser-879 and VE-cadherin on Tyr-658, Tyr-685, and Tyr-731, which can be prevented by treatment with the thrombin inhibitor, hirudin, or by silencing the thrombin receptor, protease-activated receptor-1, in endothelial cells. We also provided strong evidence that tumor-derived thrombin enhanced melanoma TEM by inducing ubiquitination-coupled VE-cadherin internalization, focal adhesion formation, and actin assembly in endothelium. Confocal microscopic analysis of tumor TEM revealed that junctions transiently opened and resealed as tumor cells accomplished TEM. In addition, in the presence of PFP, tumor cells preferentially transmigrated via paracellular routes. PFP supported melanoma transmigration under shear conditions via a B-Raf(V600E)-thrombin-dependent mechanism. We concluded that the activation of thrombin generation by cancer cells in plasma is an important process regulating melanoma extravasation by disrupting endothelial junction integrity. PMID- 26504081 TI - The High Efficiency of Photosystem I in the Green Alga Chlamydomonas reinhardtii Is Maintained after the Antenna Size Is Substantially Increased by the Association of Light-harvesting Complexes II. AB - Photosystems (PS) I and II activities depend on their light-harvesting capacity and trapping efficiency, which vary in different environmental conditions. For optimal functioning, these activities need to be balanced. This is achieved by redistribution of excitation energy between the two photosystems via the association and disassociation of light-harvesting complexes (LHC) II, in a process known as state transitions. Here we study the effect of LHCII binding to PSI on its absorption properties and trapping efficiency by comparing time resolved fluorescence kinetics of PSI-LHCI and PSI-LHCI-LHCII complexes of Chlamydomonas reinhardtii. PSI-LHCI-LHCII of C. reinhardtii is the largest PSI supercomplex isolated so far and contains seven Lhcbs, in addition to the PSI core and the nine Lhcas that compose PSI-LHCI, together binding ~ 320 chlorophylls. The average decay time for PSI-LHCI-LHCII is ~ 65 ps upon 400 nm excitation (15 ps slower than PSI-LHCI) and ~ 78 ps upon 475 nm excitation (27 ps slower). The transfer of excitation energy from LHCII to PSI-LHCI occurs in ~ 60 ps. This relatively slow transfer, as compared with that from LHCI to the PSI core, suggests loose connectivity between LHCII and PSI-LHCI. Despite the relatively slow transfer, the overall decay time of PSI-LHCI-LHCII remains fast enough to assure a 96% trapping efficiency, which is only 1.4% lower than that of PSI-LHCI, concomitant with an increase of the absorption cross section of 47%. This indicates that, at variance with PSII, the design of PSI allows for a large increase of its light-harvesting capacities. PMID- 26504082 TI - Structural Dissection of the Maltodextrin Disproportionation Cycle of the Arabidopsis Plastidial Disproportionating Enzyme 1 (DPE1). AB - The degradation of transitory starch in the chloroplast to provide fuel for the plant during the night requires a suite of enzymes that generate a series of short chain linear glucans. However, glucans of less than four glucose units are no longer substrates for these enzymes, whereas export from the plastid is only possible in the form of either maltose or glucose. In order to make use of maltotriose, which would otherwise accumulate, disproportionating enzyme 1 (DPE1; a 4-alpha-glucanotransferase) converts two molecules of maltotriose to a molecule of maltopentaose, which can now be acted on by the degradative enzymes, and one molecule of glucose that can be exported. We have determined the structure of the Arabidopsis plastidial DPE1 (AtDPE1), and, through ligand soaking experiments, we have trapped the enzyme in a variety of conformational states. AtDPE1 forms a homodimer with a deep, long, and open-ended active site canyon contained within each subunit. The canyon is divided into donor and acceptor sites with the catalytic residues at their junction; a number of loops around the active site adopt different conformations dependent on the occupancy of these sites. The "gate" is the most dynamic loop and appears to play a role in substrate capture, in particular in the binding of the acceptor molecule. Subtle changes in the configuration of the active site residues may prevent undesirable reactions or abortive hydrolysis of the covalently bound enzyme-substrate intermediate. Together, these observations allow us to delineate the complete AtDPE1 disproportionation cycle in structural terms. PMID- 26504083 TI - Hepatic Xbp1 Gene Deletion Promotes Endoplasmic Reticulum Stress-induced Liver Injury and Apoptosis. AB - Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), a highly conserved signaling cascade that functions to alleviate stress and promote cell survival. If, however, the cell is unable to adapt and restore homeostasis, then the UPR activates pathways that promote apoptotic cell death. The molecular mechanisms governing the critical transition from adaptation and survival to initiation of apoptosis remain poorly understood. We aim to determine the role of hepatic Xbp1, a key mediator of the UPR, in controlling the adaptive response to ER stress in the liver. Liver-specific Xbp1 knockout mice (Xbp1(LKO)) and Xbp1(fl/fl) control mice were subjected to varying levels and durations of pharmacologic ER stress. Xbp1(LKO) and Xbp1(fl/fl) mice showed robust and equal activation of the UPR acutely after induction of ER stress. By 24 h, Xbp1(fl/fl) controls showed complete resolution of UPR activation and no liver injury, indicating successful adaptation to the stress. Conversely, Xbp1(LKO) mice showed ongoing UPR activation associated with progressive liver injury, apoptosis, and, ultimately, fibrosis by day 7 after induction of ER stress. These data indicate that hepatic XBP1 controls the adaptive response of the UPR and is critical to restoring homeostasis in the liver in response to ER stress. PMID- 26504084 TI - Structure-based Discovery of Novel Small Molecule Wnt Signaling Inhibitors by Targeting the Cysteine-rich Domain of Frizzled. AB - Frizzled is the earliest discovered glycosylated Wnt protein receptor and is critical for the initiation of Wnt signaling. Antagonizing Frizzled is effective in inhibiting the growth of multiple tumor types. The extracellular N terminus of Frizzled contains a conserved cysteine-rich domain that directly interacts with Wnt ligands. Structure-based virtual screening and cell-based assays were used to identify five small molecules that can inhibit canonical Wnt signaling and have low IC50 values in the micromolar range. NMR experiments confirmed that these compounds specifically bind to the Wnt binding site on the Frizzled8 cysteine rich domain with submicromolar dissociation constants. Our study confirms the feasibility of targeting the Frizzled cysteine-rich domain as an effective way of regulating canonical Wnt signaling. These small molecules can be further optimized into more potent therapeutic agents for regulating abnormal Wnt signaling by targeting Frizzled. PMID- 26504085 TI - Selenoprotein S-dependent Selenoprotein K Binding to p97(VCP) Protein Is Essential for Endoplasmic Reticulum-associated Degradation. AB - Cytosolic valosin-containing protein (p97(VCP)) is translocated to the ER membrane by binding to selenoprotein S (SelS), which is an ER membrane protein, during endoplasmic reticulum-associated degradation (ERAD). Selenoprotein K (SelK) is another known p97(VCP)-binding selenoprotein, and the expression of both SelS and SelK is increased under ER stress. To understand the regulatory mechanisms of SelS, SelK, and p97(VCP) during ERAD, the interaction of the selenoproteins with p97(VCP) was investigated using N2a cells and HEK293 cells. Both SelS and SelK co-precipitated with p97(VCP). However, the association between SelS and SelK did not occur in the absence of p97(VCP). SelS had the ability to recruit p97(VCP) to the ER membrane but SelK did not. The interaction between SelK and p97(VCP) did not occur in SelS knockdown cells, whereas SelS interacted with p97(VCP) in the presence or absence of SelK. These results suggest that p97(VCP) is first translocated to the ER membrane via its interaction with SelS, and then SelK associates with the complex on the ER membrane. Therefore, the interaction between SelK and p97(VCP) is SelS-dependent, and the resulting ERAD complex (SelS-p97(VCP)-SelK) plays an important role in ERAD and ER stress. PMID- 26504086 TI - Trpm7 Protein Contributes to Intercellular Junction Formation in Mouse Urothelium. AB - Trpm7 is a divalent cation-permeable channel that has been reported to be involved in magnesium homeostasis as well as cellular adhesion and migration. We generated urothelium-specific Trpm7 knock-out (KO) mice to reveal the function of Trpm7 in vivo. A Trpm7 KO was induced by tamoxifen and was confirmed by genomic PCR and immunohistochemistry. By using patch clamp recordings in primary urothelial cells, we observed that Mg(2+)-inhibitable cation currents as well as acid-inducible currents were significantly smaller in Trpm7 KO urothelial cells than in cells from control mice. Assessment of voiding behavior indicated a significantly smaller voided volume in Trpm7 KO mice (mean voided volume 0.28 +/- 0.08 g in KO mice and 0.36 +/- 0.04 g in control mice, p < 0.05, n = 6-8). Histological analysis showed partial but substantial edema in the submucosal layer of Trpm7 KO mice, most likely due to inflammation. The expression of proinflammatory cytokines TNF-alpha and IL-1beta was significantly higher in Trpm7 KO bladders than in controls. In transmission electron microscopic analysis, immature intercellular junctions were observed in Trpm7 KO urothelium but not in control mice. These results suggest that Trpm7 is involved in the formation of intercellular junctions in mouse urothelium. Immature intercellular junctions in Trpm7 knock-out mice might lead to a disruption of barrier function resulting in inflammation and hypersensitive bladder afferent nerves that may affect voiding behavior in vivo. PMID- 26504087 TI - Reactive Oxygen Species (ROS) Mediate p300-dependent STAT1 Protein Interaction with Peroxisome Proliferator-activated Receptor (PPAR)-gamma in CD36 Protein Expression and Foam Cell Formation. AB - Previously, we have demonstrated that 15(S)-hydroxyeicosatetranoic acid (15(S) HETE) induces CD36 expression involving STAT1. Many studies have shown that peroxisome proliferator-activated receptor (PPAR)-gamma mediates CD36 expression. Therefore, we asked the question whether these transcriptional factors interact with each other in the regulation of CD36 expression by 15(S)-HETE. Here, we show that STAT1 interacts with PPARgamma in the induction of CD36 expression and foam cell formation by 15(S)-HETE. In addition, using molecular biological approaches such as EMSA, supershift EMSA, ChIP, re-ChIP, and promoter-reporter gene assays, we demonstrate that the STAT1 and PPARgamma complex binds to the STAT-binding site at -107 nucleotides in the CD36 promoter and enhances its activity. Furthermore, the interaction of STAT1 with PPARgamma depends on STAT1 acetylation, which is mediated by p300. In addition, our findings show that reactive oxygen species-dependent Syk and Pyk2 stimulation is required for p300 tyrosine phosphorylation and activation. Together, these results demonstrate that an interaction between STAT1, p300, and peroxisome proliferator-activated receptor-gamma is required for 15(S)-HETE-induced CD36 expression, oxidized low density lipoprotein uptake, and foam cell formation, critical events underlying the pathogenesis of atherosclerosis. PMID- 26504088 TI - Mechanisms of Enhancer-mediated Hormonal Control of Vitamin D Receptor Gene Expression in Target Cells. AB - The biological actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are mediated by the vitamin D receptor (VDR), whose expression in bone cells is regulated positively by 1,25(OH)2D3, retinoic acid, and parathyroid hormone through both intergenic and intronic enhancers. In this report, we used ChIP-sequencing analysis to confirm the presence of these Vdr gene enhancers in mesenchyme derived bone cells and to describe the epigenetic histone landscape that spans the Vdr locus. Using bacterial artificial chromosome-minigene stable cell lines, CRISPR/Cas9 enhancer-deleted daughter cell lines, transient transfection/mutagenesis analyses, and transgenic mice, we confirmed the functionality of these bone cell enhancers in vivo as well as in vitro. We also identified VDR-binding sites across the Vdr gene locus in kidney and intestine using ChIP-sequencing analysis, revealing that only one of the bone cell-type enhancers bound VDR in kidney tissue, and none were occupied by the VDR in the intestine, consistent with weak or absent regulation by the 1,25(OH)2D3 hormone in these tissues, respectively. However, a number of additional sites of VDR binding unique to either kidney or intestine were present further upstream of the Vdr gene, suggesting the potential for alternative regulatory loci. Importantly, virtually all of these regions retained histone signatures consistent with those of enhancers and exhibited unique DNase I hypersensitivity profiles that reflected the potential for chromatin access. These studies define mechanisms associated with hormonal regulation of the Vdr and hint at the differential nature of VDR binding activity at the Vdr gene in different primary target tissues in vivo. PMID- 26504089 TI - Forkhead Box P1 (FOXP1) Transcription Factor Regulates Hepatic Glucose Homeostasis. AB - Dysregulation of hepatic gluconeogenesis contributes to the pathogenesis of diabetes, yet the detailed molecular mechanisms remain to be fully elucidated. Here we show that FOXP1, a transcriptional repressor, plays a key role in the regulation of systemic glucose homeostasis. Hepatic expression levels of FOXP1 are decreased in diabetic mice. Modest hepatic overexpression of FOXP1 in mice inhibited the expression of gluconeogenic genes, such as peroxisome proliferators activated receptor gamma coactivator-1alpha (PGC-1alpha), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6PC), leading to a decrease in hepatic glucose production and fasting blood glucose levels in normal mice and different mouse models of diabetes, including db/db diabetic and high-fat diet induced obese mice. FOXP1 physically interacted with FOXO1 in vivo and competed with FOXO1 for binding to the insulin response element in the promoter region of gluconeogenic genes, thereby interfering expression of these genes. These results identify a previously unrecognized role for FOXP1 in the transcriptional control of hepatic glucose homeostasis. PMID- 26504090 TI - Introduction to the Special Issue: Beyond traits: integrating behaviour into plant ecology and biology. AB - The way that plants are conceptualized in the context of ecological understanding is changing. In one direction, a reductionist school is pulling plants apart into a list of measured 'traits', from which ecological function and outcomes of species interactions may be inferred. This special issue offers an alternative, and more holistic, view: that the ecological functions performed by a plant will be a consequence not only of their complement of traits but also of the ways in which their component parts are used in response to environmental and social conditions. This is the realm of behavioural ecology, a field that has greatly advanced our understanding of animal biology, ecology and evolution. Included in this special issue are 10 articles focussing not on the tried and true metaphor that plant growth is similar to animal movement, but instead on how application of principles from animal behaviour can improve our ability to understand plant biology and ecology. The goals are not to draw false parallels, nor to anthropomorphize plant biology, but instead to demonstrate how existing and robust theory based on fundamental principles can provide novel understanding for plants. Key to this approach is the recognition that behaviour and intelligence are not the same. Many organisms display complex behaviours despite a lack of cognition (as it is traditionally understood) or any hint of a nervous system. The applicability of behavioural concepts to plants is further enhanced with the realization that all organisms face the same harsh forces of natural selection in the context of finding resources, mates and coping with neighbours. As these ecological realities are often highly variable in space and time, it is not surprising that all organisms-even plants-exhibit complex behaviours to handle this variability. The articles included here address diverse topics in behavioural ecology, as applied to plants: general conceptual understanding, plant nutrient foraging, root-root interactions, and using and helping others. As a group, the articles in this special issue demonstrate how plant ecological understanding can be enhanced through incorporation of behavioural ideas and set the stage for future research in the emerging discipline of plant behavioural ecology. PMID- 26504091 TI - Commentary on: Labia Minora, Labia Majora, and Clitoral Hood Alteration: Experience-Based Recommendations. PMID- 26504092 TI - Unusual presentations and pitfalls of secondary syphilis: osteitis, pneumonia and malignancy. AB - Syphilis can show unexpected clinical characteristics rendering its diagnosis difficult. We report on two cases of secondary syphilis presenting with atypical histories of knee or cervical pain and cough. Both had bone involvement and one, pulmonary involvement, documented by MRI, CT scan and PCR. Both responded well to therapy with intravenous aqueous penicillin G followed by intramuscular benzathine penicillin G, but a pulmonary adenocarcinoma was diagnosed during follow-up in one case. PMID- 26504093 TI - Another mistaken case of appendicitis. AB - In 2010, when I was 17, I presented to hospital with progressive discomfort and pain in the right iliac fossa when eating and moving, associated with mild fever and diarrhoea. Appendicitis was suspected but immediate surgery was deferred, as the inflammatory markers did not adequately support the clinical diagnosis of appendicitis. Further tests, including MRI, were then undertaken. The MRI showed evidence of terminal ileitis and a normal appendix. Crohn's disease was considered as part of the differential diagnosis. However, a Yersinia enterocolitica infection was subsequently confirmed. The episode highlighted several learning points including preventing unnecessary surgery and the advantages of using a multidisciplinary approach involving imaging the abdomen and microbiological input. PMID- 26504094 TI - Pregnancy with a ruptured renal artery aneurysm: management concerns and endovascular management. AB - Renal artery aneurysm (RAA) affects <0.01% of the general population. Rupture of RAA is a rare catastrophe that can complicate pregnancy and is associated with high maternal and fetal mortality. Presentation is usually acute with severe flank pain, with or without haematuria, and haemodynamic instability requiring exploration and nephrectomy. A 26-year-old pregnant woman had sudden onset of gross haematuria and on evaluation was found to have a left RAA with an intrapelvic rupture and thinned out renal parenchyma. In view of the high risk of surgery, she was managed with endovascular placement of an Amplatzer type II vascular plug. Immediate and complete occlusion of blood flow was achieved and nephrectomy was avoided. Follow-up Doppler ultrasound revealed a reduced 5 cm mass in the left renal fossa with no internal flow and plug in position. She is currently on follow-up with 3-6 monthly ultrasonography not requiring any intervention. PMID- 26504095 TI - Use of enoximone in management of anaphylaxis complicated by labetalol use. AB - A 42-year-old woman with end-stage renal failure was admitted to the intensive care unit following resuscitation from a pulseless electrical activity cardiac arrest after intravenous piperacillin/tazobactam. Persistent bradycardia and hypotension, unresponsive to epinephrine and norepinephrine, were suspected to have been exacerbated by chronic labetalol therapy for resistant arterial hypertension. As an alternative, the non-adrenergic inotrope, enoximone, was started. This, combined with thrombolysis for possible pulmonary embolism, heralded significant haemodynamic improvement, allowing weaning from inotropic support. A clear CT pulmonary angiogram 2 days post-arrest and significantly raised mast cell tryptase levels confirmed anaphylaxis rather than pulmonary embolism as the precipitating cause. We believe this to be the first case report of phosphodiesterase-III inhibitor use in the management of anaphylaxis complicated by alpha/beta-blockade, and discuss the mechanism behind this effect and comparison with the more commonly reported use of glucagon. PMID- 26504097 TI - Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. PMID- 26504098 TI - Scientific misconduct or criminal offence? PMID- 26504096 TI - Comparative study of joint analysis of microarray gene expression data in survival prediction and risk assessment of breast cancer patients. AB - Microarray gene expression data sets are jointly analyzed to increase statistical power. They could either be merged together or analyzed by meta-analysis. For a given ensemble of data sets, it cannot be foreseen which of these paradigms, merging or meta-analysis, works better. In this article, three joint analysis methods, Z-score normalization, ComBat and the inverse normal method (meta analysis) were selected for survival prognosis and risk assessment of breast cancer patients. The methods were applied to eight microarray gene expression data sets, totaling 1324 patients with two clinical endpoints, overall survival and relapse-free survival. The performance derived from the joint analysis methods was evaluated using Cox regression for survival analysis and independent validation used as bias estimation. Overall, Z-score normalization had a better performance than ComBat and meta-analysis. Higher Area Under the Receiver Operating Characteristic curve and hazard ratio were also obtained when independent validation was used as bias estimation. With a lower time and memory complexity, Z-score normalization is a simple method for joint analysis of microarray gene expression data sets. The derived findings suggest further assessment of this method in future survival prediction and cancer classification applications. PMID- 26504099 TI - Hypercalcemia in metastatic breast cancer unrelated to skeletal metastasis. PMID- 26504100 TI - Addressing transgender discrimination in health. PMID- 26504101 TI - Can a new flu vaccine cure efficacy woes? PMID- 26504102 TI - Do clinicians understand the size of treatment effects? A randomized survey across 8 countries. AB - BACKGROUND: Meta-analyses of continuous outcomes typically provide enough information for decision-makers to evaluate the extent to which chance can explain apparent differences between interventions. The interpretation of the magnitude of these differences - from trivial to large - can, however, be challenging. We investigated clinicians' understanding and perceptions of usefulness of 6 statistical formats for presenting continuous outcomes from meta analyses (standardized mean difference, minimal important difference units, mean difference in natural units, ratio of means, relative risk and risk difference). METHODS: We invited 610 staff and trainees in internal medicine and family medicine programs in 8 countries to participate. Paper-based, self-administered questionnaires presented summary estimates of hypothetical interventions versus placebo for chronic pain. The estimates showed either a small or a large effect for each of the 6 statistical formats for presenting continuous outcomes. Questions addressed participants' understanding of the magnitude of treatment effects and their perception of the usefulness of the presentation format. We randomly assigned participants 1 of 4 versions of the questionnaire, each with a different effect size (large or small) and presentation order for the 6 formats (1 to 6, or 6 to 1). RESULTS: Overall, 531 (87.0%) of the clinicians responded. Respondents best understood risk difference, followed by relative risk and ratio of means. Similarly, they perceived the dichotomous presentation of continuous outcomes (relative risk and risk difference) to be most useful. Presenting results as a standardized mean difference, the longest standing and most widely used approach, was poorly understood and perceived as least useful. INTERPRETATION: None of the presentation formats were well understood or perceived as extremely useful. Clinicians best understood the dichotomous presentations of continuous outcomes and perceived them to be the most useful. Further initiatives to help clinicians better grasp the magnitude of the treatment effect are needed. PMID- 26504103 TI - Cauda equina syndrome from lumbar disc herniation. PMID- 26504104 TI - Controversies in the diagnosis and management of testosterone deficiency syndrome. PMID- 26504105 TI - Differential ligand-signaling network of CCL19/CCL21-CCR7 system. AB - Chemokine (C-C motif) receptor 7 (CCR7), a class A subtype G-Protein Coupled Receptor (GPCR), is involved in the migration, activation and survival of multiple cell types including dendritic cells, T cells, eosinophils, B cells, endothelial cells and different cancer cells. Together, CCR7 signaling system has been implicated in diverse biological processes such as lymph node homeostasis, T cell activation, immune tolerance, inflammatory response and cancer metastasis. CCL19 and CCL21, the two well-characterized CCR7 ligands, have been established to be differential in their signaling through CCR7 in multiple cell types. Although the differential ligand signaling through single receptor have been suggested for many receptors including GPCRs, there exists no resource or platform to analyse them globally. Here, first of its kind, we present the cell type-specific differential signaling network of CCL19/CCL21-CCR7 system for effective visualization and differential analysis of chemokine/GPCR signaling. Database URL: http:// www. netpath. org/ pathways? path_ id= NetPath_ 46. PMID- 26504109 TI - Ischaemic stroke in patients with atrial fibrillation with chronic kidney disease undergoing peritoneal dialysis. AB - AIMS: Little is known about the ischaemic stroke risk and benefit of warfarin therapy for stroke prevention in chronic kidney disease (CKD) patients on peritoneal dialysis (PD) with concomitant atrial fibrillation (AF). Our objective was to determine the risk of ischaemic stroke in a 'real-world' cohort of PD patients with AF, and clinical benefit or harm of aspirin and warfarin. METHODS AND RESULTS: This is a single-centred observational study of Chinese patients with non-valvular AF. Hospitalizations with ischaemic stroke and intracranial haemorrhage (ICH) were recorded. Of 9810 patients from a hospital-based AF registry, 271 CKD patients on PD with AF (76.8 +/- 12.5 years, CHA2DS2-VASc: 3.69 +/- 1.83, and HAS-BLED: 2.07 +/- 0.97) were identified. Amongst these PD patients, 24.7% received warfarin; 31.7% received aspirin; and 43.5% received no antithrombotic therapy. Amongst patients with no antithrombotic therapy, annual incidence of ischaemic stroke in PD patients was comparable with those non-CKD counterparts (9.32 vs. 9.30%/year). Similar to non-CKD patients, annual incidence of ischaemic stroke increased with increasing CHA2DS2-VASc score (CHA2DS2-VASc = 0-1: 5.76 vs. 5.70%/year, P = 1.00; and CHA2DS2-VASc >= 2: 10.80 vs. 9.94%/year, P = 0.78). Amongst PD patients, warfarin therapy was associated with lower risk of ischaemic stroke compared with aspirin [Hazard ratio (HR): 0.16, 95% confidence interval (CI): 0.04-0.66, P = 0.01] and no therapy (HR: 0.19, 95% CI: 0.06-0.65, P = 0.01), but not associated with a higher risk of ICH. CONCLUSION: In CKD patients on PD with AF, who had similar ischaemic stroke risk as non-CKD counterparts, warfarin therapy is associated with reduction in risk of ischaemic stroke without a higher risk of ICH. PMID- 26504108 TI - First-line catheter ablation of paroxysmal atrial fibrillation: outcome of radiofrequency vs. cryoballoon pulmonary vein isolation. AB - AIMS: First-line ablation prior to antiarrhythmic drug (AAD) therapy is an option for symptomatic paroxysmal atrial fibrillation (PAF); however, the optimal ablation technique, radiofrequency (RF), or cryoballoon (CB) has to be determined. METHODS AND RESULTS: The FREEZE Cohort Study compares RF and CB ablation. Treatment-naive patients were documented in the FREEZEplus Registry. Periprocedural data and outcome were analysed. From 2011 to 2014, a total of 373/4184 (8.9%) patients with PAF naive to AAD were identified. Pulmonary vein isolation (PVI) was performed with RF (n = 180) or CB (n = 193). In the RF group, patients were older (65 vs. 61 years, P < 0.01) compared with the CB group. The procedure time was significantly shorter and radiation exposure higher in the CB group. Major adverse events occurred in 1.6% (CB) and 3.7% (RF) of patients (P = 0.22). AF/atrial tachycardia (AT) recurrence until discharge was 4.5% (RF) and 8.5% (CB, P = 0.2). Follow-up (FU) >=12 months was available in 99 (RF) and 107 (CB) patients. After 1.4 years of FU, freedom from AF/atrial tachycardia (AT) was 61% (RF) and 71% (CB, P = 0.11). In the RF group, more patients underwent cardioversion, and a trend for more repeat ablations was observed. Persistent phrenic nerve palsy was observed in one patient treated by CB. CONCLUSION: First line ablation for PAF is safe and effective with either RF or CB. The procedure was faster with the CB, but the radiation exposure was higher. Although there was a trend for more recurrences and complications in the RF group, a more favourable risk profile in patients undergoing CB ablation might have biased the results. CLINICALTRIALSGOV IDENTIFIER: NCT01360008. PMID- 26504110 TI - Conceptual framework for integrating 'Pregnancy Planning and Prevention' (P3). PMID- 26504112 TI - The end of shared rooms in hospitals: a cause for celebration? PMID- 26504113 TI - Changes in sedentary behaviours across the retirement transition: a systematic review. PMID- 26504114 TI - Should guidance for the use of antihypertensive medication in older people with frailty be different? PMID- 26504115 TI - Changes in sedentary behaviours across the retirement transition: a systematic review. AB - BACKGROUND: Prolonged sedentary behaviour has been associated with a number of chronic health conditions. This issue is compounded by inactivity increasing with age. OBJECTIVE: This systematic review aimed to identify evidence regarding changes in sedentary behaviours as people move into retirement. SEARCH STRATEGY AND SELECTION CRITERIA: Nine databases (Ageline, CINAHL, Cochrane, Embase, MEDLINE, ProQuest, PubMed, SportDiscus and Web of Science) were searched in May 2014. Search terms included retirement, time use and a range of sedentary behaviours, with no date limit. Articles were selected and appraised for risk of bias by two independent reviewers. Due to the variations in measures used for reporting, data synthesis of results was qualitative. RESULTS: Two studies measured total sitting time and reported declines across retirement. Several studies examined self-reported time spent in specific sedentary leisure activities and generally reported increases in duration, prevalence or frequency (television: 7/9 studies; reading: 4/6 studies). Few other sedentary behaviours were considered. CONCLUSIONS: Changes in sedentary time across retirement are currently poorly understood with varying patterns of change identified by different study methodologies (total sitting time versus specific leisure sedentary activities). Future research that simultaneously investigates changes in a comprehensive range of sedentary behaviours across retirement is required. To date, findings suggest that interventions aimed at improving the health of this population need to be targeted at specific sedentary behaviours to provide maximum benefit. PMID- 26504116 TI - Blood pressure and 10-year mortality risk in the Milan Geriatrics 75+ Cohort Study: role of functional and cognitive status. AB - BACKGROUND: Optimal blood pressure targets in older adults are controversial. OBJECTIVE: to investigate whether the relation of blood pressure with mortality in older adults varies by age, functional and cognitive status. DESIGN: longitudinal geriatric outpatient cohort. SETTING: Milan Geriatrics 75+ Cohort Study. SUBJECTS: One thousand five hundred and eighty-seven outpatients aged 75 years and over. METHODS: The relations of systolic (SBP) and diastolic blood pressure (DBP) with mortality risk were analysed using Cox proportional hazards models. Blood pressure, Mini-Mental State Examination (MMSE) and Basic Activities of Daily Living (ADL) were assessed at baseline. All analyses were adjusted for socio-demographic factors, co-morbidities and medications. RESULTS: One thousand and forty-six patients died during 10-year follow-up. The relationships of SBP and DBP with mortality risk were U-shaped; SBP of 165 mmHg and DBP of 85 mmHg were associated with the lowest mortality. Patients with SBP < 120 mmHg and patients with SBP 120-139 mmHg had 1.64-fold (95% confidence intervals, CI 1.21 2.23) and 1.32-fold (95% CI 1.10-1.60) higher mortality risk than patients with SBP 160-179 mmHg (P values 0.001 and 0.004, respectively). In patients with SBP below 180 mmHg, higher SBP was associated with lower mortality in patients with impaired ADL and MMSE but not in those with preserved ADL and/or MMSE (P for interaction 0.033). Age did not modify the correlation of SBP with mortality. CONCLUSIONS: The correlations of SBP and DBP with mortality were U-shaped. Higher SBP is related to lower mortality in subjects with impaired ADL and MMSE. ADL and MMSE may identify older subjects who benefit from higher blood pressure. PMID- 26504117 TI - Grip strength among community-dwelling older people predicts hospital admission during the following decade. AB - BACKGROUND: Lower grip strength on admission to hospital is known to be associated with longer stay, but the link between customary grip and risk of future admission is less clear. OBJECTIVE: To compare grip strength with subsequent risk of hospital admission among community-dwelling older people in a U.K. setting. DESIGN: Cohort study with linked administrative data. SETTING: Hertfordshire, U.K. SUBJECTS: A total of 2,997 community-dwelling men and women aged 59-73 years at baseline. METHODS: The Hertfordshire Cohort Study (HCS) participants completed a baseline assessment between 1998 and 2004, during which grip strength was measured. Hospital Episode Statistics and mortality data to March 2010 were linked with the HCS database. Statistical models were used to investigate the association of grip strength with subsequent elective, emergency and long-stay hospitalisation and readmission. RESULTS: There was a statistically significant negative association between grip strength and all classes of admission in women [unadjusted hazard ratio per standard deviation (SD) decrease in grip strength for: any admission/death 1.10 (95% CI: 1.06, 1.14), elective admission/death 1.09 (95% CI: 1.05, 1.13), emergency admission/death 1.21 (95% CI: 1.13, 1.31), long-stay admission/death 1.22 (95% CI: 1.13, 1.32) and unadjusted relative risk per SD decrease in grip strength for 30-day readmission/death 1.30 (95% CI: 1.19, 1.43)]. These associations remained significant after adjustment for potential confounding factors (age, height, weight for height, smoking, alcohol, social class). In men, unadjusted rates for emergency admission/death, long-stay admission/death and readmission/death were significantly associated with grip strength; associations that similarly withstood adjustment. CONCLUSION: This study provides the first evidence that grip strength among community-dwelling men and women in the U.K. is associated with risk of hospital admission over the following decade. PMID- 26504118 TI - Predictive performance of four frailty measures in an older Australian population. AB - BACKGROUND: There are several different frailty measures available for identifying the frail elderly. However, their predictive performance in an Australian population has not been examined. OBJECTIVE: To examine the predictive performance of four internationally validated frailty measures in an older Australian population. METHODS: A retrospective study in the Australian Longitudinal Study of Ageing (ALSA) with 2,087 participants. Frailty was measured at baseline using frailty phenotype (FP), simplified frailty phenotype (SFP), frailty index (FI) and prognostic frailty score (PFS). Odds ratios (OR) were calculated to measure the association between frailty and outcomes at Wave 3 including mortality, hospitalisation, nursing home admission, fall and a combination of all outcomes. Predictive performance was measured by assessing sensitivity, specificity, positive and negative predictive values (PPV and NPV) and likelihood ratio (LR). Area under the curve (AUC) of dichotomised and the multilevel or continuous model of the measures was examined. RESULTS: Prevalence of frailty varied from 2% up to 49% between the measures. Frailty was significantly associated with an increased risk of any outcome, OR (95% confidence interval) for FP: 1.9 (1.4-2.8), SFP: 3.6 (1.5-8.8), FI: 3.4 (2.7-4.3) and PFS: 2.3 (1.8-2.8). PFS had high sensitivity across all outcomes (sensitivity: 55.2-77.1%). The PPV for any outcome was highest for SFP and FI (70.8 and 69.7%, respectively). Only FI had acceptable accuracy in predicting outcomes, AUC: 0.59-0.70. CONCLUSIONS: Being identified as frail by any of the four measures was associated with an increased risk of outcomes; however, their predictive accuracy varied. PMID- 26504119 TI - Dementia priority setting partnership with the James Lind Alliance: using patient and public involvement and the evidence base to inform the research agenda. AB - BACKGROUND: The James Lind Alliance (JLA) created an approach to elicit the views of those under-represented in research priority exercises. Building on this, the JLA Dementia Priority Setting Partnership was set up as an independent and evidence-based project to identify and prioritise unanswered questions ('uncertainties') about prevention, diagnosis, treatment and care relating to dementia. METHODS: A survey was widely disseminated to stakeholders with an interest in the needs of the older population. Thematic analysis was used to identify themes from the large amount of questions collected from which research questions were developed using PICO framework (Population, Intervention, Comparator, Outcome). Each question was checked against an extensive evidence base of high-quality systematic reviews to verify whether they were true uncertainties. FINDINGS: One thousand five hundred and sixty-three questionnaires were received, from people with dementia, carers/relatives, and health and care professionals; 85 uncertainties were identified from other sources. Questions were refined and formatted iteratively into 146 unique uncertainties. An interim prioritisation process involving diverse organisations identified the top 25 ranked questions. At a final face-to-face prioritisation workshop, 18 people representing the above constituencies arrived by consensus at the top 10 priority questions. The impact of patient and public involvement on the priorities is discussed. INTERPRETATION: The long (146 questions) and top 10 lists of dementia research priorities provide a focus for researchers, funders and commissioners. They highlight a need for more research into care for people with dementia and carers, and a need for high-quality effectiveness trials in all aspects of dementia research. PMID- 26504120 TI - Eating alone and depression in older men and women by cohabitation status: The JAGES longitudinal survey. AB - BACKGROUND: Eating by oneself may be a risk factor for mental illness among older adults, but may be influenced by cohabitation status. We examined the association between eating alone and depression in the context of cohabitation status in older adults in Japan. DESIGN: A longitudinal, population-based study. SETTING: Data from the Japan Gerontological Evaluation Study. SUBJECTS: We analysed 17,612 men and 19,581 women aged >=65 without depression (Geriatric Depression Scale <5) at baseline in 2010. METHODS: Eating status was classified into two categories: eating with others and eating alone. The risk of depression onset by 2013 was estimated using Poisson regression. RESULTS: After adjusting for socioeconomic status, physical health, nutritional status, social support, social participation, frequency of meet friends, employment status and marital status, the adjusted rate ratio (ARR) for depression onset in men who ate alone compared with those who ate with others was 2.36 (95% confidence intervals [CI]: 1.18 4.71) for those living alone and 1.03 (95% CI: 0.81-1.32) for those living with others. Among women, the ARR for depression for those who ate alone compared with those who ate with others was 1.31 (95% CI: 1.00-1.72) for those living alone and 1.21 (95% CI: 1.01-1.44) for those living with others. CONCLUSIONS: Eating alone may be a risk factor for depression. Among men, the effect of eating alone on depression may be reinforced by living alone, but appears to be broadly comparable in women living alone and women living with others. PMID- 26504121 TI - Cognition and mortality in older people: the Sydney Memory and Ageing Study. AB - BACKGROUND: Both cognitive ability and cognitive decline have been shown to predict mortality in older people. As dementia, a major form of cognitive decline, has an established association with shorter survival, it is unclear the extent to which cognitive ability and cognitive decline predict mortality in the absence of dementia. OBJECTIVE: To determine whether cognitive ability and decline in cognitive ability predict mortality in older individuals without dementia. DESIGN: The Sydney Memory and Ageing Study is an observational population-based cohort study. Participants completed detailed neuropsychological assessments and medical examinations to assess for risk factors such as depression, obesity, hypertension, diabetes, hypercholesterolaemia, smoking and physical activity. Participants were regularly assessed at 2-year intervals over 8 years. SETTING: A community sample in Sydney, Australia. SUBJECTS: One thousand and thirty-seven elderly people without dementia. RESULTS: Overall, 236 (22.8%) participants died within 8 years. Both cognitive ability at baseline and decline in cognitive ability over 2 years predicted mortality. Decline in cognitive ability, but not baseline cognitive ability, was a significant predictor of mortality when depression and other medical risk factors were controlled for. These relationships also held when excluding incident cases of dementia. CONCLUSIONS: The findings indicate that decline in cognition is a robust predictor of mortality in older people without dementia at a population level. This relationship is not accounted for by co-morbid depression or other established biomedical risk factors. PMID- 26504122 TI - The changing epidemiology of oral diseases in the elderly, their growing importance for care and how they can be managed. AB - This article provides an overview of the changing epidemiology of oral diseases and the impacts for the population. Considerable improvements have occurred in oral health, and many more people are retaining teeth for longer. However, the conditions of teeth and mouth are varied, and all older people are at risk of future oral disease. With the increased prevalence of other more general health conditions, the risks of poor oral health are increasing. Poor oral health gives rise to considerable problems that impact both on an individual's well-being and qualities of life as well as increasing the risks of general health issues. To ensure that the risks of such adverse impacts are minimised, a more collaborative approach involving all care workers is required, addressing the determinants of health and ensuring that better care management arrangements for older people are developed. PMID- 26504123 TI - Laser Acupuncture for Neonatal Abstinence Syndrome: A Randomized Controlled Trial. AB - BACKGROUND: Neonatal abstinence syndrome (NAS) is usually treated with opiate derivatives and supported with nonpharmacological treatment. METHODS: This prospective, randomized, controlled, blinded, single-center study was carried out between March 2009 and November 2014. Newborn infants diagnosed with NAS after maternal opioid substitution therapy were eligible for inclusion. Infants were randomly allocated to the acupuncture group (combining laser acupuncture and pharmacological therapy of morphine and phenobarbital) or control group (pharmacological therapy alone). Laser acupuncture was performed with a LABpen MED 10 (675 nm/10 mW) at 5 ear and 4 body acupuncture points, bilaterally, and sessions were repeated every day. The primary outcome measure was duration of oral morphine therapy for NAS. Secondary outcomes included highest single Finnegan score, time to highest single Finnegan score, maximum amount of oral morphine solution (in milliliters per kilogram and milligrams per kilogram), time to maximum amount of oral morphine solution, and length of hospital stay. RESULTS: Twenty-eight newborns (14 in each group) were eligible for analysis. Duration of oral morphine therapy was significantly reduced in the acupuncture group compared with the control group (28 vs 39 days, respectively, P = .019). In addition, we observed a significantly reduced length of hospital stay in the acupuncture group compared with the control group (35 days [interquartile range 25 to 47] vs 50 days [36 to 66], P = .048). CONCLUSIONS: Adjunctive laser acupuncture significantly reduced the duration of morphine therapy in newborns with NAS. PMID- 26504124 TI - HPV Vaccination Coverage of Male Adolescents in the United States. AB - BACKGROUND: In 2011, the Advisory Committee for Immunization Practices (ACIP) recommended routine use human papillomavirus (HPV) vaccine for male adolescents. METHODS: We used the 2013 National Immunization Survey-Teen data to assess HPV vaccine uptake (>=1 dose) and series completion (>=3 doses). Multivariable logistic regression analysis and a predictive marginal model were conducted to identify independent predictors of vaccination among adolescent males aged 13 to 17 years. RESULTS: HPV vaccination coverage with >=1 dose was 34.6%, and series completion (>=3 doses) was 13.9%. Coverage was significantly higher among non Hispanic blacks and Hispanics compared with non-Hispanic white male adolescents. Multivariable logistic regression showed that characteristics independently associated with a higher likelihood of HPV vaccination (>=1 dose) included being non-Hispanic black race or Hispanic ethnicity; having mothers who were widowed, divorced, or separated; having 1 to 3 physician contacts in the past 12 months; a well-child visit at age 11 to 12 years; having 1 or 2 vaccination providers; living in urban or suburban areas; and receiving vaccinations from >1 type of facility (P < .05). Having mothers with some college or college education, having a higher family income to poverty ratio, living in the South or Midwest, and receiving vaccinations from all sexually transmitted diseases/school/teen clinics or other facilities were independently associated with a lower likelihood of HPV vaccination (P < .05). CONCLUSIONS: Following recommendations for routine HPV vaccination among male adolescents, uptake in 2013 was low in this population. Increased efforts are needed to improve vaccination coverage, especially for those who are least likely to be vaccinated. PMID- 26504125 TI - Sirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience Beyond Infancy. AB - Congenital hyperinsulinism (CHI) due to diffuse involvement of the pancreas is a challenging and severe illness in children. Its treatment is based on chronic therapy with diazoxide and/or octreotide, followed by partial pancreatectomy, which is often not resolutive. Sirolimus, a mammalian target of rapamycin inhibitor, was reported to be effective in treating CHI in infants. We report here the case of an 8-year-old boy affected by a severe form of CHI due to a biallelic heterozygous ABCC8 mutation who responded to sirolimus with a dramatic improvement in his glucose blood level regulation and quality of life, with no serious adverse events after 6 months of follow-up. To the best of our knowledge, this is the first report of a successful intervention in an older child. It provides a promising basis for further studies comparing sirolimus with other treatments, particularly in older children. PMID- 26504126 TI - Prescription Opioids in Adolescence and Future Opioid Misuse. AB - BACKGROUND AND OBJECTIVE: Legitimate opioid use is associated with an increased risk of long-term opioid use and possibly misuse in adults. The objective of this study was to estimate the risk of future opioid misuse among adolescents who have not yet graduated from high school. METHODS: Prospective, panel data come from the Monitoring the Future study. The analysis uses a nationally representative sample of 6220 individuals surveyed in school in 12th grade and then followed up through age 23. Analyses are stratified by predicted future opioid misuse as measured in 12th grade on the basis of known risk factors. The main outcome is nonmedical use of a prescription opioid at ages 19 to 23. Predictors include use of a legitimate prescription by 12th grade, as well as baseline history of drug use and baseline attitudes toward illegal drug use. RESULTS: Legitimate opioid use before high school graduation is independently associated with a 33% increase in the risk of future opioid misuse after high school. This association is concentrated among individuals who have little to no history of drug use and, as well, strong disapproval of illegal drug use at baseline. CONCLUSIONS: Use of prescribed opioids before the 12th grade is independently associated with future opioid misuse among patients with little drug experience and who disapprove of illegal drug use. Clinic-based education and prevention efforts have substantial potential to reduce future opioid misuse among these individuals, who begin opioid use with strong attitudes against illegal drug use. PMID- 26504127 TI - Growth Charts for Children With Down Syndrome in the United States. AB - BACKGROUND AND OBJECTIVES: Children with Down syndrome (DS) have lower birth weights and grow more slowly than children without DS. Advances in and increased access to medical care have improved the health and well-being of individuals with DS; however, it is unknown whether their growth has also improved. Our objective was to develop new growth charts for children with DS and compare them to older charts from the United States and more contemporary charts from the United Kingdom. METHODS: The Down Syndrome Growing Up Study (DSGS) enrolled a convenience sample of children with DS up to 20 years of age and followed them longitudinally. Growth parameters were measured by research anthropometrists. Sex specific growth charts were generated for the age ranges birth to 36 months and 2 to 20 years using the LMS method. Weight-for-length and BMI charts were also generated. Comparisons with other curves were presented graphically. RESULTS: New DSGS growth charts were developed by using 1520 measurements on 637 participants. DSGS growth charts for children <36 months of age showed marked improvements in weight compared with older US charts. DSGS charts for 2- to 20-year-olds showed that contemporary males are taller than previous charts showed. Generally, the DSGS growth charts are similar to the UK charts. CONCLUSIONS: The DSGS growth charts can be used as screening tools to assess growth and nutritional status and to provide indications of how growth of an individual child compares with peers of the same age and sex with DS. PMID- 26504128 TI - Electronic Nicotine Delivery Systems. AB - Electronic nicotine delivery systems (ENDS) are rapidly growing in popularity among youth. ENDS are handheld devices that produce an aerosolized mixture from a solution typically containing concentrated nicotine, flavoring chemicals, and propylene glycol to be inhaled by the user. ENDS are marketed under a variety of names, most commonly electronic cigarettes and e-cigarettes. In 2014, more youth reported using ENDS than any other tobacco product. ENDS pose health risks to both users and nonusers. Nicotine, the major psychoactive ingredient in ENDS solutions, is both highly addictive and toxic. In addition to nicotine, other toxicants, carcinogens, and metal particles have been detected in solutions and aerosols of ENDS. Nonusers are involuntarily exposed to the emissions of these devices with secondhand and thirdhand aerosol. The concentrated and often flavored nicotine in ENDS solutions poses a poisoning risk for young children. Reports of acute nicotine toxicity from US poison control centers have been increasing, with at least 1 child death reported from unintentional exposure to a nicotine-containing ENDS solution. With flavors, design, and marketing that appeal to youth, ENDS threaten to renormalize and glamorize nicotine and tobacco product use. There is a critical need for ENDS regulation, legislative action, and counter promotion to protect youth. ENDS have the potential to addict a new generation of youth to nicotine and reverse more than 50 years of progress in tobacco control. PMID- 26504129 TI - Severe Hyperinsulinemic Hypoglycemia in a Neonate: Response to Sirolimus Therapy. AB - Hyperinsulinemic hypoglycemia (HH) is one of the most common causes of persistent hypoglycemic episodes in neonates. Current pharmacologic treatment of neonatal HH includes diazoxide and octreotide, whereas for diffuse, unresponsive cases a subtotal pancreatectomy may be the last resort, with questionable efficacy. Here we report a case of congenital diffuse neonatal HH, first suspected when severe hypoglycemia presented with extremely high serum insulin levels immediately after birth. Functional imaging and genetic tests later confirmed the diagnosis. Failure to respond to a sequence of different treatments and to avoid extensive surgery with predictable morbidity prompted us to introduce a recently suggested alternative therapy with sirolimus, a mammalian target of rapamycin inhibitor. Glucose intake could be reduced gradually while euglycemia was maintained, and we were able to achieve exclusively enteral feeding within 6 weeks. Sirolimus was found to be effective and well tolerated, with no major adverse side effects attributable to its administration. PMID- 26504130 TI - Global Climate Change and Children's Health. AB - Rising global temperatures are causing major physical, chemical, and ecological changes in the planet. There is wide consensus among scientific organizations and climatologists that these broad effects, known as "climate change," are the result of contemporary human activity. Climate change poses threats to human health, safety, and security, and children are uniquely vulnerable to these threats. The effects of climate change on child health include: physical and psychological sequelae of weather disasters; increased heat stress; decreased air quality; altered disease patterns of some climate-sensitive infections; and food, water, and nutrient insecurity in vulnerable regions. The social foundations of children's mental and physical health are threatened by the specter of far reaching effects of unchecked climate change, including community and global instability, mass migrations, and increased conflict. Given this knowledge, failure to take prompt, substantive action would be an act of injustice to all children. A paradigm shift in production and consumption of energy is both a necessity and an opportunity for major innovation, job creation, and significant, immediate associated health benefits. Pediatricians have a uniquely valuable role to play in the societal response to this global challenge. PMID- 26504133 TI - Public Policy to Protect Children From Tobacco, Nicotine, and Tobacco Smoke. AB - Tobacco use and tobacco smoke exposure are among the most important health threats to children, adolescents, and adults. There is no safe level of tobacco smoke exposure. The developing brains of children and adolescents are particularly vulnerable to the development of tobacco and nicotine dependence. Tobacco is unique among consumer products in that it causes disease and death when used exactly as intended. Tobacco continues to be heavily promoted to children and young adults. Flavored and alternative tobacco products, including little cigars, chewing tobacco, and electronic nicotine delivery systems are gaining popularity among youth. This statement describes important evidence-based public policy actions that, when implemented, will reduce tobacco product use and tobacco smoke exposure among youth and, by doing so, improve the health of children and young adults. PMID- 26504131 TI - Physician and Nurse Nighttime Communication and Parents' Hospital Experience. AB - BACKGROUND AND OBJECTIVE: Night teams of hospital providers have become more common in the wake of resident physician duty hour changes. We sought to examine relationships between nighttime communication and parents' inpatient experience. METHODS: We conducted a prospective cohort study of parents (n = 471) of pediatric inpatients (0-17 years) from May 2013 to October 2014. Parents rated their overall experience, understanding of the medical plan, quality of nighttime doctors' and nurses' communication with them, and quality of nighttime communication between doctors and nurses. We tested the reliability of each of these 5 constructs (Cronbach's alpha for each >.8). Using logistic regression models, we examined rates and predictors of top-rated hospital experience. RESULTS: Parents completed 398 surveys (84.5% response rate). A total of 42.5% of parents reported a top overall experience construct score. On multivariable analysis, top-rated overall experience scores were associated with higher scores for communication and experience with nighttime doctors (odds ratio [OR] 1.86; 95% confidence interval [CI], 1.12-3.08), for communication and experience with nighttime nurses (OR 6.47; 95% CI, 2.88-14.54), and for nighttime doctor-nurse interaction (OR 2.66; 95% CI, 1.26-5.64) (P < .05 for each). Parents provided the highest percentage of top ratings for the individual item pertaining to whether nurses listened to their concerns (70.5% strongly agreed) and the lowest such ratings for regular communication with nighttime doctors (31.4% excellent). CONCLUSIONS: Parent communication with nighttime providers and parents' perceptions of communication and teamwork between these providers may be important drivers of parent experience. As hospitals seek to improve the patient centeredness of care, improving nighttime communication and teamwork will be valuable to explore. PMID- 26504134 TI - Global Climate Change and Children's Health. AB - Rising global temperature is causing major physical, chemical, and ecological changes across the planet. There is wide consensus among scientific organizations and climatologists that these broad effects, known as climate change, are the result of contemporary human activity. Climate change poses threats to human health, safety, and security. Children are uniquely vulnerable to these threats. The effects of climate change on child health include physical and psychological sequelae of weather disasters, increased heat stress, decreased air quality, altered disease patterns of some climate-sensitive infections, and food, water, and nutrient insecurity in vulnerable regions. Prompt implementation of mitigation and adaptation strategies will protect children against worsening of the problem and its associated health effects. This technical report reviews the nature of climate change and its associated child health effects and supports the recommendations in the accompanying policy statement on climate change and children's health. PMID- 26504135 TI - Protecting Children From Tobacco, Nicotine, and Tobacco Smoke. AB - This technical report serves to provide the evidence base for the American Academy of Pediatrics' policy statements "Clinical Practice Policy to Protect Children From Tobacco, Nicotine, and Tobacco Smoke" and "Public Policy to Protect Children From Tobacco, Nicotine, and Tobacco Smoke." Tobacco use and involuntary exposure are major preventable causes of morbidity and premature mortality in adults and children. Tobacco dependence almost always starts in childhood or adolescence. Electronic nicotine delivery systems are rapidly gaining popularity among youth, and their significant harms are being documented. In utero tobacco smoke exposure, in addition to increasing the risk of preterm birth, low birth weight, stillbirth, placental abruption, and sudden infant death, has been found to increase the risk of obesity and neurodevelopmental disorders. Actions by pediatricians can help to reduce children's risk of developing tobacco dependence and reduce children's involuntary tobacco smoke exposure. Public policy actions to protect children from tobacco are essential to reduce the toll that the tobacco epidemic takes on our children. PMID- 26504136 TI - Variation in Utilization of Computed Tomography Imaging at Tertiary Pediatric Hospitals. AB - BACKGROUND: Recent efforts have focused on reducing computed tomography (CT) imaging in children. Although published reports show variability in CT scanning for specific indications, an assessment of the effects of institutional factors (case-mix or hospital volume) on the rate of CT scanning for any indication is necessary to better understand variability across pediatric hospitals. METHODS: Data from 2009 to 2013 on inpatient, observation, and emergency department (ED) encounters were extracted from the Pediatric Health Information System. Chronological trends and institutional variability in CT scan rates were examined by using negative binomial regression models. Case-mix was adjusted by using All Patient Refined Diagnosis Related Groups and severity level. RESULTS: Thirty hospitals were included. There were 12 531 184 patient encounters and 701 644 CT scans resulting in a mean of 56 scans per 1000 encounters (range: 26-108). The most common scan types were head (60.1%) and abdomen/pelvis (19.9%). There was an inverse relationship between the CT scan rate and hospital volume (P = .002) and a direct relationship between the CT scan rates for inpatient/observation and ED encounters (P < .001). The rate of CT imaging decreased from 69.2 to 49.6 scans per 1000 encounters during the study period (P < .001). CONCLUSIONS: The overall use of CT imaging is decreasing, and significant variability remains in CT use across tertiary pediatric hospitals. Hospital volume and institutional-level practices account for a significant portion of the variability. This finding suggests an opportunity for standardization through multi-institutional quality improvement projects to reduce CT imaging. PMID- 26504137 TI - Clinical Practice Policy to Protect Children From Tobacco, Nicotine, and Tobacco Smoke. AB - Tobacco dependence starts in childhood. Tobacco exposure of children is common and causes illness and premature death in children and adults, with adverse effects starting in the womb. There is no safe level of tobacco smoke exposure. Pediatricians should screen for use of tobacco and other nicotine delivery devices and provide anticipatory guidance to prevent smoking initiation and reduce tobacco smoke exposure. Pediatricians need to be aware of the different nicotine delivery systems marketed and available.Parents and caregivers are important sources of children's tobacco smoke exposure. Because tobacco dependence is a severe addiction, to protect children's health, caregiver tobacco dependence treatment should be offered or referral for treatment should be provided (such as referral to the national smoker's quitline at 1-800-QUIT-NOW). If the source of tobacco exposure cannot be eliminated, counseling about reducing exposure to children should be provided.Health care delivery systems should facilitate the effective prevention, identification, and treatment of tobacco dependence in children and adolescents, their parents, and other caregivers. Health care facilities should protect children from tobacco smoke exposure and tobacco promotion. Tobacco dependence prevention and treatment should be part of medical education, with knowledge assessed as part of board certification examinations. PMID- 26504139 TI - IsoMIF Finder: online detection of binding site molecular interaction field similarities. AB - IsoMIF Finder is an online server for the identification of molecular interaction field (MIF) similarities. User defined binding site MIFs can be compared to datasets of pre-calculated MIFs or against a user-defined list of PDB entries. The interface can be used for the prediction of function, identification of potential cross-reactivity or polypharmacological targets and drug repurposing. Detected similarities can be viewed in a browser or within a PyMOL session. AVAILABILITY AND IMPLEMENTATION: IsoMIF Finder uses JSMOL (no java plugin required), is cross-browser and freely available at bcb.med.usherbrooke.ca/imfi. PMID- 26504138 TI - Enhanced Sucrose Loading Improves Rice Yield by Increasing Grain Size. AB - Yield in cereals is a function of grain number and size. Sucrose (Suc), the main carbohydrate product of photosynthesis in higher plants, is transported long distances from source leaves to sink organs such as seeds and roots. Here, we report that transgenic rice plants (Oryza sativa) expressing the Arabidopsis (Arabidopsis thaliana) phloem-specific Suc transporter (AtSUC2), which loads Suc into the phloem under control of the phloem protein2 promoter (pPP2), showed an increase in grain yield of up to 16% relative to wild-type plants in field trials. Compared with wild-type plants, pPP2::AtSUC2 plants had larger spikelet hulls and larger and heavier grains. Grain filling was accelerated in the transgenic plants, and more photoassimilate was transported from the leaves to the grain. In addition, microarray analyses revealed that carbohydrate, amino acid, and lipid metabolism was enhanced in the leaves and grain of pPP2::AtSUC2 plants. Thus, enhancing Suc loading represents a promising strategy to improve rice yield to feed the global population. PMID- 26504140 TI - GenoWAP: GWAS signal prioritization through integrated analysis of genomic functional annotation. AB - MOTIVATION: Genome-wide association study (GWAS) has been a great success in the past decade. However, significant challenges still remain in both identifying new risk loci and interpreting results. Bonferroni-corrected significance level is known to be conservative, leading to insufficient statistical power when the effect size is moderate at risk locus. Complex structure of linkage disequilibrium also makes it challenging to separate causal variants from nonfunctional ones in large haplotype blocks. Under such circumstances, a computational approach that may increase signal replication rate and identify potential functional sites among correlated markers is urgently needed. RESULTS: We describe GenoWAP, a GWAS signal prioritization method that integrates genomic functional annotation and GWAS test statistics. The effectiveness of GenoWAP is demonstrated through its applications to Crohn's disease and schizophrenia using the largest studies available, where highly ranked loci show substantially stronger signals in the whole dataset after prioritization based on a subset of samples. At the single nucleotide polymorphism (SNP) level, top ranked SNPs after prioritization have both higher replication rates and consistently stronger enrichment of eQTLs. Within each risk locus, GenoWAP may be able to distinguish functional sites from groups of correlated SNPs. AVAILABILITY AND IMPLEMENTATION: GenoWAP is freely available on the web at http://genocanyon.med.yale.edu/GenoWAP. PMID- 26504141 TI - MT-HESS: an efficient Bayesian approach for simultaneous association detection in OMICS datasets, with application to eQTL mapping in multiple tissues. AB - MOTIVATION: Analysing the joint association between a large set of responses and predictors is a fundamental statistical task in integrative genomics, exemplified by numerous expression Quantitative Trait Loci (eQTL) studies. Of particular interest are the so-called ': hotspots ': , important genetic variants that regulate the expression of many genes. Recently, attention has focussed on whether eQTLs are common to several tissues, cell-types or, more generally, conditions or whether they are specific to a particular condition. RESULTS: We have implemented MT-HESS, a Bayesian hierarchical model that analyses the association between a large set of predictors, e.g. SNPs, and many responses, e.g. gene expression, in multiple tissues, cells or conditions. Our Bayesian sparse regression algorithm goes beyond ': one-at-a-time ': association tests between SNPs and responses and uses a fully multivariate model search across all linear combinations of SNPs, coupled with a model of the correlation between condition/tissue-specific responses. In addition, we use a hierarchical structure to leverage shared information across different genes, thus improving the detection of hotspots. We show the increase of power resulting from our new approach in an extensive simulation study. Our analysis of two case studies highlights new hotspots that would remain undetected by standard approaches and shows how greater prediction power can be achieved when several tissues are jointly considered. AVAILABILITY AND IMPLEMENTATION: C[Formula: see text] source code and documentation including compilation instructions are available under GNU licence at http://www.mrc-bsu.cam.ac.uk/software/. PMID- 26504142 TI - Pycellerator: an arrow-based reaction-like modelling language for biological simulations. AB - MOTIVATION: We introduce Pycellerator, a Python library for reading Cellerator arrow notation from standard text files, conversion to differential equations, generating stand-alone Python solvers, and optionally running and plotting the solutions. All of the original Cellerator arrows, which represent reactions ranging from mass action, Michales-Menten-Henri (MMH) and Gene-Regulation (GRN) to Monod-Wyman-Changeaux (MWC), user defined reactions and enzymatic expansions (KMech), were previously represented with the Mathematica extended character set. These are now typed as reaction-like commands in ASCII text files that are read by Pycellerator, which includes a Python command line interface (CLI), a Python application programming interface (API) and an iPython notebook interface. RESULTS: Cellerator reaction arrows are now input in text files. The arrows are parsed by Pycellerator and translated into differential equations in Python, and Python code is automatically generated to solve the system. Time courses are produced by executing the auto-generated Python code. Users have full freedom to modify the solver and utilize the complete set of standard Python tools. The new libraries are completely independent of the old Cellerator software and do not require Mathematica. AVAILABILITY AND IMPLEMENTATION: All software is available (GPL) from the github repository at https://github.com/biomathman/pycellerator/releases. Details, including installation instructions and a glossary of acronyms and terms, are given in the Supplementary information. PMID- 26504144 TI - Graphical pan-genome analysis with compressed suffix trees and the Burrows Wheeler transform. AB - MOTIVATION: Low-cost genome sequencing gives unprecedented complete information about the genetic structure of populations, and a population graph captures the variations between many individuals of a population. Recently, Marcus et al. proposed to use a compressed de Bruijn graph for representing an entire population of genomes. They devised an O(n log g) time algorithm called splitMEM that constructs this graph directly (i.e. without using the uncompressed de Bruijn graph) based on a suffix tree, where n is the total length of the genomes and g is the length of the longest genome. Since the applicability of their algorithm is limited to rather small datasets, there is a strong need for space efficient construction algorithms. RESULTS: We present two algorithms that outperform splitMEM in theory and in practice. The first implements a novel linear-time suffix tree algorithm by means of a compressed suffix tree. The second algorithm uses the Burrows-Wheeler transform to build the compressed de Bruijn graph in [Formula: see text] time, where sigma is the size of the alphabet. To demonstrate the scalability of the algorithms, we applied it to seven human genomes. AVAILABILITY AND IMPLEMENTATION: https://www.uni ulm.de/in/theo/research/seqana/. PMID- 26504145 TI - NMRe: a web server for NMR protein structure refinement with high-quality structure validation scores. AB - Protein structure refinement is a necessary step for the study of protein function. In particular, some nuclear magnetic resonance (NMR) structures are of lower quality than X-ray crystallographic structures. Here, we present NMRe, a web-based server for NMR structure refinement. The previously developed knowledge based energy function STAP (Statistical Torsion Angle Potential) was used for NMRe refinement. With STAP, NMRe provides two refinement protocols using two types of distance restraints. If a user provides NOE (Nuclear Overhauser Effect) data, the refinement is performed with the NOE distance restraints as a conventional NMR structure refinement. Additionally, NMRe generates NOE-like distance restraints based on the inter-hydrogen distances derived from the input structure. The efficiency of NMRe refinement was validated on 20 NMR structures. Most of the quality assessment scores of the refined NMR structures were better than those of the original structures. The refinement results are provided as a three-dimensional structure view, a secondary structure scheme, and numerical and graphical structure validation scores. AVAILABILITY AND IMPLEMENTATION: NMRe is available at http://psb.kobic.re.kr/nmre/. PMID- 26504143 TI - PDID: database of molecular-level putative protein-drug interactions in the structural human proteome. AB - MOTIVATION: Many drugs interact with numerous proteins besides their intended therapeutic targets and a substantial portion of these interactions is yet to be elucidated. Protein-Drug Interaction Database (PDID) addresses incompleteness of these data by providing access to putative protein-drug interactions that cover the entire structural human proteome. RESULTS: PDID covers 9652 structures from 3746 proteins and houses 16 800 putative interactions generated from close to 1.1 million accurate, all-atom structure-based predictions for several dozens of popular drugs. The predictions were generated with three modern methods: ILbind, SMAP and eFindSite. They are accompanied by propensity scores that quantify likelihood of interactions and coordinates of the putative location of the binding drugs in the corresponding protein structures. PDID complements the current databases that focus on the curated interactions and the BioDrugScreen database that relies on docking to find putative interactions. Moreover, we also include experimentally curated interactions which are linked to their sources: DrugBank, BindingDB and Protein Data Bank. Our database can be used to facilitate studies related to polypharmacology of drugs including repurposing and explaining side effects of drugs. AVAILABILITY AND IMPLEMENTATION: PDID database is freely available at http://biomine.ece.ualberta.ca/PDID/. PMID- 26504146 TI - DARA: a web server for rapid search of structural neighbours using solution small angle X-ray scattering data. AB - MOTIVATION: Small angle X-ray scattering (SAXS) is an established method for studying biological macromolecules in solution, whereby the experimental scattering patterns relate to the quaternary and tertiary structure of the macromolecule. Here we present DARA, a web-server, that queries over 150 000 scattering profiles pre-computed from the high resolution models of macromolecules and biological assemblies in the Protein Data Bank, to rapidly find nearest neighbours of a given experimental or theoretical SAXS pattern. Identification of the best scattering equivalents provides a straightforward and automated way of structural assessment of macromolecules based on a SAXS profile. DARA results are useful e.g. for fold recognition and finding of biologically active oligomers. AVAILABILITY AND IMPLEMENTATION: http://dara.embl-hamburg.de/. PMID- 26504147 TI - Risk Prediction in Aortic Valve Replacement: Incremental Value of the Preoperative Echocardiogram. AB - BACKGROUND: Risk prediction is a critical step in patient selection for aortic valve replacement (AVR), yet existing risk scores incorporate very few echocardiographic parameters. We sought to evaluate the incremental predictive value of a complete echocardiogram to identify high-risk surgical candidates before AVR. METHODS AND RESULTS: A cohort of patients with severe aortic stenosis undergoing surgical AVR with or without coronary bypass was assembled at 2 tertiary centers. Preoperative echocardiograms were reviewed by independent observers to quantify chamber size/function and valve function. Patient databases were queried to extract clinical data. The cohort consisted of 432 patients with a mean age of 73.5 years and 38.7% females. Multivariable logistic regression revealed 3 echocardiographic predictors of in-hospital mortality or major morbidity: E/e' ratio reflective of elevated left ventricular (LV) filling pressure; myocardial performance index reflective of right ventricular (RV) dysfunction; and small LV end-diastolic cavity size. Addition of these echocardiographic parameters to the STS risk score led to an integrated discrimination improvement of 4.1% (P<0.0001). After a median follow-up of 2 years, Cox regression revealed 5 echocardiographic predictors of all-cause mortality: small LV end-diastolic cavity size; LV mass index; mitral regurgitation grade; right atrial area index; and mean aortic gradient <40 mm Hg. CONCLUSIONS: Echocardiographic measures of LV diastolic dysfunction and RV performance add incremental value to the STS risk score and should be integrated in prediction when evaluating the risk of AVR. In addition, findings of small hypertrophied LV cavities and/or low mean aortic gradients confer a higher risk of 2-year mortality. PMID- 26504148 TI - Oxylipid Profile of Low-Dose Aspirin Exposure: A Pharmacometabolomics Study. AB - BACKGROUND: While aspirin is a well-established and generally effective anti platelet agent, considerable inter-individual variation in drug response exists, for which mechanisms are not completely understood. Metabolomics allows for extensive measurement of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response. METHODS AND RESULTS: We used a mass-spectrometry-based metabolomics platform to investigate the changes in the serum oxylipid metabolome induced by an aspirin intervention (14 days, 81 mg/day) in healthy subjects (n=156). We observed a global decrease in serum oxylipids in response to aspirin (25 metabolites decreased out of 30 measured) regardless of sex. This decrease was concomitant with a significant decrease in serum linoleic acid levels (-19%, P=1.3*10(-5)), one of the main precursors for oxylipid synthesis. Interestingly, several linoleic acid-derived oxylipids were not significantly associated with arachidonic-induced ex vivo platelet aggregation, a widely accepted marker of aspirin response, but were significantly correlated with platelet reactivity in response to collagen. CONCLUSIONS: Together, these results suggest that linoleic acid-derived oxylipids may contribute to the non COX1 mediated variability in response to aspirin. Pharmacometabolomics allowed for more comprehensive interrogation of mechanisms of action of low dose aspirin and of variation in aspirin response. PMID- 26504149 TI - Long-Term Prognostic Risk in Lower Extremity Peripheral Arterial Disease as a Function of the Number of Peripheral Arterial Lesions. AB - BACKGROUND: Although patients with peripheral artery disease (PAD) are known to have an increased risk of adverse prognosis, simple techniques to further risk stratify PAD patients would be clinically useful. A plausible but unexplored factor to predict such risk would be greater disease burden, manifested as multiple lower extremity lesions. The aim of this study was to examine the association between having multiple versus isolated lower extremity PAD lesions and long-term prognosis. METHODS AND RESULTS: A prospective cohort of 756 newly diagnosed PAD patients underwent duplex ultrasound testing to determine the number of lower extremity lesions. Cox regression models examined the independent association of lesion number (>=3 and 2 versus 1) and adverse prognosis (defined as a composite end point comprising first occurrence of either lower extremity amputation, admission for heart failure, nonfatal stroke, myocardial infarction, or unstable angina or mortality), adjusting for demographic and clinical risk factors. Analyses were replicated using an advanced Cox-based model for multiple events. A total of 173 patients (23%) had >=3 lesions, 197 (26%) had 2 lesions, and 386 (51%) had 1 lesion. After a median follow-up of 3.2 years, patients with >=3 lesions had an increased risk of experiencing a first adverse event (adjusted hazard ratio 1.60, 95% CI 1.08-2.38, P=0.020) and an increased risk of having multiple events (adjusted hazard ratio 1.53, 95% CI 1.08-2.18, P=0.018). Patients with 2 lesions had a prognosis similar to those with 1 lesion. CONCLUSIONS: Among PAD patients, a greater number of lesions is associated with an increased risk of an adverse prognosis over 3 years of follow-up. Assessing the number of lower extremity lesions might serve as a simple risk-stratification tool at initial PAD diagnosis. PMID- 26504150 TI - Incidence of Venous Thromboembolism and Benefits and Risks of Thromboprophylaxis After Cardiac Surgery: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Optimal thromboprophylaxis after cardiac surgery is uncertain. This systematic review aimed to define the incidence and risk factors for deep vein thrombosis (DVT), fatal and nonfatal pulmonary embolism (PE), and assess whether venous thromboembolism (VTE) prophylaxis was effective in reducing VTE without complications after cardiac surgery. METHODS AND RESULTS: Two reviewers independently searched and assessed the quality and outcomes of randomized, controlled trials (RCTs) and observational studies on VTE after cardiac surgery in the MEDLINE, EMBASE, and Cochrane controlled trial register (1966 to December 2014). Sixty-eight studies provided data on VTE outcomes or complications related to thromboprophylaxis after cardiac surgery. The majority of the studies were observational studies (n=49), 16 studies were RCTs, and 3 were meta-analyses. VTE prophylaxis was associated with a reduced risk of PE (relative risk [RR], 0.45; 95% confidence interval [CI], 0.28-0.72; P=0.0008) or symptomatic VTE (RR, 0.44; 95% CI, 0.28-0.71; P=0.0006) compared to the control without significant heterogeneity. Median incidence (interquartile range) of symptomatic DVT, PE, and fatal PE were 3.2% (0.6-8.1), 0.6% (0.3-2.9), and 0.3% (0.08-1.7), respectively. Previous history of VTE, obesity, left or right ventricular failure, and prolonged bed rest, mechanical ventilation, or use of a central venous catheter were common risk factors for VTE. Bleeding or cardiac tamponade requiring reoperation owing to pharmacological VTE prophylaxis alone, without systemic anticoagulation, was not observed. CONCLUSIONS: Unless proven otherwise by adequately powered RCTs, initiating pharmacological VTE prophylaxis as soon as possible after cardiac surgery for patients who have no active bleeding is highly recommended. PMID- 26504152 TI - Short- and long-term benefits of lenalidomide treatment in patients with lower risk del(5q) myelodysplastic syndromes. AB - The treatment of patients with myelodysplastic syndromes (MDS) begins with assessment of karyotype and risk. Lenalidomide is approved for the treatment of patients who have transfusion-dependent anemia due to lower-risk MDS with chromosome 5q deletion (del(5q)) with or without additional cytogenetic abnormalities, and isolated del(5q) only in the European Union. Mounting evidence suggests that lenalidomide is effective not only in reducing red blood cell (RBC) transfusion burden, but also in modifying the disease natural history by suppressing the malignant clone. Data discussed here from the pivotal phase 2 (MDS-003) and phase 3 (MDS-004) studies of lenalidomide demonstrate that lenalidomide treatment was associated with both short- and long-term benefits. These clinical benefits included high rates of RBC-transfusion independence (TI) with prolonged durations of response, high rates of cytogenetic response (CyR) associated with achievement of durable RBC-TI, no significant difference in rates of progression to acute myeloid leukemia (AML), and improvements in health related quality of life (HRQOL). Achievement of RBC-TI and CyR with lenalidomide treatment was associated with extended survival and time to AML progression. Achievement of RBC-TI and hemoglobin response was additionally associated with HRQOL benefits. Recent data describing the impact of TP53 mutations and p53 expression on the prognosis of patients with del(5q) and the impact on response to lenalidomide are also discussed. The authors provide practical recommendations for the use of lenalidomide in patients with lower-risk del(5q) MDS. PMID- 26504151 TI - Breastfeeding and breast cancer risk by receptor status--a systematic review and meta-analysis. AB - BACKGROUND: Breastfeeding is inversely associated with overall risk of breast cancer. This association may differ in breast cancer subtypes defined by receptor status, as they may reflect different mechanisms of carcinogenesis. We conducted a systematic review and meta-analysis of case-control and prospective cohort studies to investigate the association between breastfeeding and breast cancer by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. DESIGN: We searched the PubMed and Scopus databases and bibliographies of pertinent articles to identify relevant articles and used random-effects models to calculate summary odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: This meta-analysis represents 27 distinct studies (8 cohort and 19 case-control), with a total of 36 881 breast cancer cases. Among parous women, the risk estimates for the association between ever (versus never) breastfeeding and the breast cancers negative for both ER and PR were similar in three cohort and three case-control studies when results were adjusted for several factors, including the number of full-term pregnancies (combined OR 0.90; 95% CI 0.82-0.99), with little heterogeneity and no indication of publication bias. In a subset of three adjusted studies that included ER, PR, and HER2 status, ever breastfeeding showed a stronger inverse association with triple-negative breast cancer (OR 0.78; 95% CI 0.66-0.91) among parous women. Overall, cohort studies showed no significant association between breastfeeding and ER+/PR+ or ER+ and/or PR+ breast cancers, although one and two studies (out of four and seven studies, respectively) showed an inverse association. CONCLUSIONS: This meta-analysis showed a protective effect of ever breastfeeding against hormone receptor-negative breast cancers, which are more common in younger women and generally have a poorer prognosis than other subtypes of breast cancer. The association between breastfeeding and receptor-positive breast cancers needs more investigation. PMID- 26504153 TI - Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer. AB - BACKGROUND: Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor positive (ER+) MBC. PATIENTS AND METHODS: Patients (N = 297) were stratified by the number of prior therapies for metastatic disease (0-1 versus 2) and by prior NSAI use (adjuvant versus metastatic), and randomized (1 : 1 : 1) to receive oral once daily 1000 mg abiraterone acetate plus 5 mg prednisone (AA) versus AA with 25 mg E (AAE) versus 25 mg E alone (E). Each treatment arm was well balanced with regard to the proportion of patients with AR-positive breast cancer. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, clinical benefit rate, duration of response, and overall response rate. RESULTS: There was no significant difference in PFS with AA versus E (3.7 versus 3.7 months; hazard ratio [HR] = 1.1; 95% confidence interval [CI] 0.82-1.60; P = 0.437) or AAE versus E (4.5 versus 3.7 months; HR = 0.96; 95% CI 0.70-1.32; P = 0.794). Increased serum progesterone concentrations were observed in both arms receiving AA, but not with E. Grade 3 or 4 treatment-emergent adverse events associated with AA, including hypokalemia and hypertension, were less common in patients in the E (2.0% and 2.9%, respectively) and AA arms (3.4% and 1.1%, respectively) than in the AAE arm (5.8% for both). CONCLUSIONS: Adding AA to E in NSAI-pretreated ER+ MBC patients did not improve PFS compared with treatment with E. An AA-induced progesterone increase may have contributed to this lack of clinical activity. CLINICALTRIALSGOV: NCT01381874. PMID- 26504154 TI - Reproduction and development in Halocaridina rubra Holthuis, 1963 (Crustacea: Atyidae) clarifies larval ecology in the Hawaiian anchialine ecosystem. AB - Larvae in aquatic habitats often develop in environments different from those they inhabit as adults. Shrimp in the Atyidae exemplify this trend, as larvae of many species require salt or brackish water for development, while adults are freshwater-adapted. An exception within the Atyidae family is the "anchialine clade," which are euryhaline as adults and endemic to habitats with subterranean fresh and marine water influences. Although the Hawaiian anchialine atyid Halocaridina rubra is a strong osmoregulator, its larvae have never been observed in nature. Moreover, larval development in anchialine species is poorly studied. Here, reproductive trends in laboratory colonies over a 5-y period are presented from seven genetic lineages and one mixed population of H. rubra; larval survivorship under varying salinities is also discussed. The presence and number of larvae differed significantly among lineages, with the mixed population being the most prolific. Statistical differences in reproduction attributable to seasonality also were identified. Larval survivorship was lowest (12% settlement rate) at a salinity approaching fresh water and significantly higher in brackish and seawater (88% and 72%, respectively). Correlated with this finding, identifiable gills capable of ion transport did not develop until metamorphosis into juveniles. Thus, early life stages of H. rubra are apparently excluded from surface waters, which are characterized by lower and fluctuating salinities. Instead, these stages are restricted to the subterranean (where there is higher and more stable salinity) portion of Hawaii's anchialine habitats due to their inability to tolerate low salinities. Taken together, these data contribute to the understudied area of larval ecology in the anchialine ecosystem. PMID- 26504155 TI - Ethogram analysis reveals new body patterning behavior of the tropical arrow squid Doryteuthis plei off the Sao Paulo Coast. AB - Squids can express several body patterns, aided by a variety of visual signals that are produced by chromatophore organs. However, for several squid species, body patterning behavior during reproductive activity is still not completely understood. For example, what are the specific patterning changes and other visual signals, how do they appear, and how long do they last? To test the hypothesis that distinct chromatic components appear at different durations on the skin of the tropical arrow squid Doryteuthis plei in the Southern Hemisphere, we identified and described its body patterning behavior. Specimen squids were obtained from off the South Brazil Bight, near the coast of the Sao Paulo shelf. Animals were maintained and monitored in circular tanks for 62 d over six observation periods, from 2011 through 2013. An ethogram was constructed showing 19 chromatic, 5 locomotor, and 12 postural components, or body patterns, associated with reproductive behavior. New chromatic components (i.e., those not yet reported in the North Atlantic D. plei species), particularly those linked to female sexual maturity, were observed. A postural component, the "J-Posture," linked to defenses and alarm, also was noted. The average time spent for "light" components was 32 s. The corresponding "dark" components had an average duration of 28 s. Females displayed the chromatic components related to calm behavior longer than males. However, males appeared to be more dedicated to disputes over resources, and used rapid, miscellaneous visual signaling. In conclusion, new basic types of body patterns are described for D. plei. The repertoire of chromatic components reported in the ethogram is, to our knowledge, the first record for D. plei of the Southern Hemisphere. PMID- 26504156 TI - Tactical decisions for changeable cuttlefish camouflage: visual cues for choosing masquerade are relevant from a greater distance than visual cues used for background matching. AB - Cuttlefish use multiple camouflage tactics to evade their predators. Two common tactics are background matching (resembling the background to hinder detection) and masquerade (resembling an uninteresting or inanimate object to impede detection or recognition). We investigated how the distance and orientation of visual stimuli affected the choice of these two camouflage tactics. In the current experiments, cuttlefish were presented with three visual cues: 2D horizontal floor, 2D vertical wall, and 3D object. Each was placed at several distances: directly beneath (in a circle whose diameter was one body length (BL); at zero BL [(0BL); i.e., directly beside, but not beneath the cuttlefish]; at 1BL; and at 2BL. Cuttlefish continued to respond to 3D visual cues from a greater distance than to a horizontal or vertical stimulus. It appears that background matching is chosen when visual cues are relevant only in the immediate benthic surroundings. However, for masquerade, objects located multiple body lengths away remained relevant for choice of camouflage. PMID- 26504157 TI - Sound production in the aquatic isopod Cymodoce japonica (Crustacea: Peracarida). AB - A vast variety of acoustic behaviors and mechanisms occur in arthropods. Sound production, in particular, in insects and decapod crustaceans has been well documented. However, except for a brief, anecdotal statement, there has been no report on the acoustic behavior of aquatic isopods. We present the first empirical evidence in aquatic Isopoda that males of Cymodoce japonica produce sound by stridulation, or the rubbing together of body parts. Sound production was associated with tail-lifting behavior, suggesting that stridulation occurs on thoracic and/or abdominal somites. Acoustic analysis revealed that syllable length was similar throughout the stridulation, at a mode of 2500-3000 Hz. With a scanning electron microscope, we identified file-like structures on the inner surface of the dorsal exoskeleton. Each file consisted of 188 +/- 11.1 ridges at about 0.5 MUm intervals; the theoretical frequency (number of ridges per syllable length) was estimated to be 2208-3646 Hz. This finding suggests that the stridulation sounds arose from these structures. Laboratory observations show that stridulation may play a role in the threatening of other males in the context of territorial and/or reproductive competitions. PMID- 26504158 TI - Functional consequences of the asymmetric architecture of the ctenophore statocyst. AB - Ctenophores, or comb jellies, are geotactic with a statocyst that controls the activity of the eight ciliary comb rows. If a ctenophore is tilted or displaced from a position of vertical balance, it rights itself by asymmetric frequencies of beating on the uppermost and lowermost comb rows, turning to swim up or down depending on its mood. I recently discovered that the statocyst of ctenophores has an asymmetric architecture related to the sagittal and tentacular planes along the oral-aboral axis. The four groups of pacemaker balancer cilia are arranged in a rectangle along the tentacular plane, and support a superellipsoidal statolith elongated in the tentacular plane. By controlled tilting of immobilized ctenophores in either body plane with video recording of activated comb rows, I found that higher beat frequencies occurred in the sagittal than in the tentacular plane at orthogonal orientations. Similar tilting experiments on isolated statocyst slices showed that statolith displacement due to gravity and the resulting deflection of the mechanoresponsive balancers are greater in the sagittal plane. Finally, tilting experiments on a mechanical model gave results similar to those of real statocysts, indicating that the geometric asymmetries of statolith design are sufficient to account for my findings. The asymmetric architecture of the ctenophore statocyst thus has functional consequences, but a possible adaptive value is not known. PMID- 26504159 TI - Flexibility of crab chemosensory sensilla enables flicking antennules to sniff. AB - The first step in smelling is capture of odorant molecules from the surrounding fluid. We used lateral flagella of olfactory antennules of crabs Callinectes sapidus to study the physical process of odor capture by antennae bearing dense tufts of hair-like chemosensory sensilla (aesthetascs). Fluid flow around and through aesthetasc arrays on dynamically scaled models of lateral flagella of C. sapidus was measured by particle image velocimetry to determine how antennules sample the surrounding water when they flick. Models enabled separate evaluation of the effects of flicking speed, aesthetasc spacing, and antennule orientation. We found that crab antennules, like those of other malacostracan crustaceans, take a discrete water sample during each flick by having a rapid downstroke, during which water flows into the aesthetasc array, and a slow recovery stroke, when water is trapped in the array and odorants have time to diffuse to aesthetascs. However, unlike antennules of crustaceans with sparse aesthetasc arrays, crabs enhance sniffing via additional mechanisms: 1) Aesthetascs are flexible and splay as a result of the hydrodynamic drag during downstrokes, then clump together during return strokes; and 2) antennules flick with aesthetascs on the upstream side of the stalk during downstrokes, but are hidden downstream during return strokes. Aiming aesthetascs into ambient flow maintains sniffing. When gaps between aesthetascs are wide, changes in antennule speed are more effective at altering flow through the array than when gaps are narrow. Nonetheless, if crabs had fixed gap widths, their ability to take discrete samples of their odorant environment would be diminished. PMID- 26504160 TI - Identification of unstimulated constitutive immunocytes, by enzyme histochemistry, in the coenenchyme of the octocoral Swiftia exserta. AB - Most animals rely on circulating hemocytes as cellular effectors of immunity. These cells traditionally have been characterized by morphology, function, and cellular contents. Morphological descriptions use granule differences and cell shapes; functional descriptions rely on phagocytic ability and oxygen transport; and cellular content descriptions include cytochemical features and key enzymes. Key enzymes used to identify phagocytes in tissues include hydrolytic enzymes, peroxidase, and--in invertebrates--phenoloxidase. Cnidaria such as Swiftia exserta lack a circulatory system, thereby complicating the identification of immune effector cells. As a first step in identifying immunocytes, this study focused on basic enzymes used during phagocytosis and encapsulation; both processes have been reported in octocorals such as S. exserta. Earlier work suggested that there are two populations of phagocytic cells: a constitutive population and an induced population following a trauma-associated challenge. To identify the constitutive immune effector cells in S. exserta in a nonactivated state, we used cryosections of unstimulated animals and the following enzymes to serve as identifying proxies due to their roles in phagocytosis and encapsulation: (1) acid phosphatase, (2) alkaline phosphatase, (3) non-specific esterase, (4) beta-glucuronidase, (5) peroxidase, and (6) phenoloxidase. Our results indicate that in unstimulated animals, two distinct cell populations could function as immunocytes. These cell types were differentiated by their enzyme reactivity and their location within the mesoglea of S. exserta, and have been described as either "oblong granular cells" or "granular amoebocytes." PMID- 26504161 TI - A new species of Protodrilus (Annelida, Protodrilidae), covering bone surfaces bright red, in whale-fall ecosystems in the northwest Pacific. AB - There are unique ecosystems in the ocean that are driven by chemosynthesis. Whale fall communities are one of these reducing habitats, and many unknowns are left to be resolved to understand their uniqueness. A new species of the genus Protodrilus was discovered on the exposed bones of sperm whale carcasses found in the waters off Cape Nomamisaki in the northwest Pacific. Protodrilus puniceus sp. nov. was the most abundant annelid to be found on the 2.5-y-old carcasses; the exposed bone surfaces appeared bright red due to the coloration of the innumerable worms covering them. Closer inspection revealed that this species was found in the small pores of both the internal and external surfaces of the bones. P. puniceus shows simple morphology; it has paired palps and pygidial lobes, but no eyespots, nuchal organs, statocysts, or ciliary rings dorso-anteriorly-an exceptional finding in this group. A ventral ciliary band was conspicuous, extending over each segment of the animal. The male of the species possessed paired, separated lateral organs on segments 6-11; salivary glands were inconspicuous. From morphological, biological, and ecological characteristics, P. puniceus showed differences from the already known Protodrilus group of shallow interstitial inhabitants. P. puniceus is thought to be a unique deposit feeder, acquiring nutrients by adhering to organic substances from whale carcasses. This is the first description of this group to be found in the organically enriched whale-fall environments of the deep sea below 200 m and from Japanese waters. Information on a nuclear, 18S ribosomal RNA gene sequence is included. PMID- 26504162 TI - Francesca Peri: Micromanaging the lives of microglia. PMID- 26504163 TI - MT1-MMP: Endosomal delivery drives breast cancer metastasis. AB - The membrane-tethered membrane type 1-matrix metalloproteinase (MT1-MMP) mediates proteolysis-based invasive tumor growth. In this issue, Marchesin et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201506002) describe a tug-of-war mechanism regulating dynein and kinesin motors to drive endosome tubulation and MT1-MMP delivery to the surface of cancer cells, identifying a crucial regulatory axis for tumor metastasis. PMID- 26504165 TI - Stable intronic sequence RNAs have possible regulatory roles in Drosophila melanogaster. AB - Stable intronic sequence RNAs (sisRNAs) have been found in Xenopus tropicalis, human cell lines, and Epstein-Barr virus; however, the biological significance of sisRNAs remains poorly understood. We identify sisRNAs in Drosophila melanogaster by deep sequencing, reverse transcription polymerase chain reaction, and Northern blotting. We characterize a sisRNA (sisR-1) from the regena (rga) locus and show that it can be processed from the precursor messenger RNA (pre-mRNA). We also document a cis-natural antisense transcript (ASTR) from the rga locus, which is highly expressed in early embryos. During embryogenesis, ASTR promotes robust rga pre-mRNA expression. Interestingly, sisR-1 represses ASTR, with consequential effects on rga pre-mRNA expression. Our results suggest a model in which sisR-1 modulates its host gene expression by repressing ASTR during embryogenesis. We propose that sisR-1 belongs to a class of sisRNAs with probable regulatory activities in Drosophila. PMID- 26504164 TI - Tissue patterning and cellular mechanics. AB - In development, cells organize into biological tissues through cell growth, migration, and differentiation. Globally, this process is dictated by a genetically encoded program in which secreted morphogens and cell-cell interactions prompt the adoption of unique cell fates. Yet, at its lowest level, development is achieved through the modification of cell-cell adhesion and actomyosin-based contractility, which set the level of tension within cells and dictate how they pack together into tissues. The regulation of tension within individual cells and across large groups of cells is a major driving force of tissue organization and the basis of all cell shape change and cell movement in development. PMID- 26504166 TI - ERO1-independent production of H2O2 within the endoplasmic reticulum fuels Prdx4 mediated oxidative protein folding. AB - The endoplasmic reticulum (ER)-localized peroxiredoxin 4 (PRDX4) supports disulfide bond formation in eukaryotic cells lacking endoplasmic reticulum oxidase 1 (ERO1). The source of peroxide that fuels PRDX4-mediated disulfide bond formation has remained a mystery, because ERO1 is believed to be a major producer of hydrogen peroxide (H2O2) in the ER lumen. We report on a simple kinetic technique to track H2O2 equilibration between cellular compartments, suggesting that the ER is relatively isolated from cytosolic or mitochondrial H2O2 pools. Furthermore, expression of an ER-adapted catalase to degrade lumenal H2O2 attenuated PRDX4-mediated disulfide bond formation in cells lacking ERO1, whereas depletion of H2O2 in the cytosol or mitochondria had no similar effect. ER catalase did not effect the slow residual disulfide bond formation in cells lacking both ERO1 and PRDX4. These observations point to exploitation of a hitherto unrecognized lumenal source of H2O2 by PRDX4 and a parallel slow H2O2 independent pathway for disulfide formation. PMID- 26504167 TI - A conserved family of proteins facilitates nascent lipid droplet budding from the ER. AB - Lipid droplets (LDs) are found in all cells and play critical roles in lipid metabolism. De novo LD biogenesis occurs in the endoplasmic reticulum (ER) but is not well understood. We imaged early stages of LD biogenesis using electron microscopy and found that nascent LDs form lens-like structures that are in the ER membrane, raising the question of how these nascent LDs bud from the ER as they grow. We found that a conserved family of proteins, fat storage-inducing transmembrane (FIT) proteins, is required for proper budding of LDs from the ER. Elimination or reduction of FIT proteins in yeast and higher eukaryotes causes LDs to remain in the ER membrane. Deletion of the single FIT protein in Caenorhabditis elegans is lethal, suggesting that LD budding is an essential process in this organism. Our findings indicated that FIT proteins are necessary to promote budding of nascent LDs from the ER. PMID- 26504168 TI - The periciliary ring in polarized epithelial cells is a hot spot for delivery of the apical protein gp135. AB - In polarized epithelial cells, newly synthesized cell surface proteins travel in carrier vesicles from the trans Golgi network to the apical or basolateral plasma membrane. Despite extensive research on polarized trafficking, the sites of protein delivery are not fully characterized. Here we use the SNAP tag system to examine the site of delivery of the apical glycoprotein gp135. We show that a cohort of gp135 is delivered to a ring surrounding the base of the primary cilium, followed by microtubule-dependent radial movement away from the cilium. Delivery to the periciliary ring was specific to newly synthesized and not recycling protein. A subset of this newly delivered protein traverses the basolateral membrane en route to the apical membrane. Crumbs3a, another apical protein, was not delivered to the periciliary region, instead making its initial apical appearance in a pattern that resembled its steady-state distribution. Our results demonstrate a surprising "hot spot" for gp135 protein delivery at the base of the primary cilium and suggest the existence of a novel microtubule-based directed movement of a subset of apical surface proteins. PMID- 26504170 TI - ARF6-JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion. AB - Invasion of cancer cells into collagen-rich extracellular matrix requires membrane-tethered membrane type 1-matrix metalloproteinase (MT1-MMP) as the key protease for collagen breakdown. Understanding how MT1-MMP is delivered to the surface of tumor cells is essential for cancer cell biology. In this study, we identify ARF6 together with c-Jun NH2-terminal kinase-interacting protein 3 and 4 (JIP3 and JIP4) effectors as critical regulators of this process. Silencing ARF6 or JIP3/JIP4 in breast tumor cells results in MT1-MMP endosome mispositioning and reduces MT1-MMP exocytosis and tumor cell invasion. JIPs are recruited by Wiskott Aldrich syndrome protein and scar homologue (WASH) on MT1-MMP endosomes on which they recruit dynein-dynactin and kinesin-1. The interaction of plasma membrane ARF6 with endosomal JIPs coordinates dynactin-dynein and kinesin-1 activity in a tug-of-war mechanism, leading to MT1-MMP endosome tubulation and exocytosis. In addition, we find that ARF6, MT1-MMP, and kinesin-1 are up-regulated in high grade triple-negative breast cancers. These data identify a critical ARF6-JIP-MT1 MMP-dynein-dynactin-kinesin-1 axis promoting an invasive phenotype of breast cancer cells. PMID- 26504169 TI - Microtubule plus end-associated CLIP-170 initiates HSV-1 retrograde transport in primary human cells. AB - Dynamic microtubules (MTs) continuously explore the intracellular environment and, through specialized plus end-tracking proteins (+TIPs), engage a variety of targets. However, the nature of cargoes that require +TIP-mediated capture for their movement on MTs remains poorly understood. Using RNA interference and dominant-negative approaches, combined with live cell imaging, we show that herpes simplex virus particles that have entered primary human cells exploit a +TIP complex comprising end-binding protein 1 (EB1), cytoplasmic linker protein 170 (CLIP-170), and dynactin-1 (DCTN1) to initiate retrograde transport. Depletion of these +TIPs completely blocked post-entry long-range transport of virus particles and suppressed infection ~5,000-fold, whereas transferrin uptake, early endosome organization, and dynein-dependent movement of lysosomes and mitochondria remained unaffected. These findings provide the first insights into the earliest stages of viral engagement of MTs through specific +TIPs, akin to receptors, with therapeutic implications, and identify herpesvirus particles as one of a very limited number of cargoes absolutely dependent on CLIP-170-mediated capture to initiate transport in primary human cells. PMID- 26504171 TI - The HIV-1 protein Vpr impairs phagosome maturation by controlling microtubule dependent trafficking. AB - Human immunodeficiency virus type 1 (HIV-1) impairs major functions of macrophages but the molecular basis for this defect remains poorly characterized. Here, we show that macrophages infected with HIV-1 were unable to respond efficiently to phagocytic triggers and to clear bacteria. The maturation of phagosomes, defined by the presence of late endocytic markers, hydrolases, and reactive oxygen species, was perturbed in HIV-1-infected macrophages. We showed that maturation arrest occurred at the level of the EHD3/MICAL-L1 endosomal sorting machinery. Unexpectedly, we found that the regulatory viral protein (Vpr) was crucial to perturb phagosome maturation. Our data reveal that Vpr interacted with EB1, p150(Glued), and dynein heavy chain and was sufficient to critically alter the microtubule plus end localization of EB1 and p150(Glued), hence altering the centripetal movement of phagosomes and their maturation. Thus, we identify Vpr as a modulator of the microtubule-dependent endocytic trafficking in HIV-1-infected macrophages, leading to strong alterations in phagolysosome biogenesis. PMID- 26504172 TI - Quality control of mitochondrial protein synthesis is required for membrane integrity and cell fitness. AB - Mitochondrial ribosomes synthesize a subset of hydrophobic proteins required for assembly of the oxidative phosphorylation complexes. This process requires temporal and spatial coordination and regulation, so quality control of mitochondrial protein synthesis is paramount to maintain proteostasis. We show how impaired turnover of de novo mitochondrial proteins leads to aberrant protein accumulation in the mitochondrial inner membrane. This creates a stress in the inner membrane that progressively dissipates the mitochondrial membrane potential, which in turn stalls mitochondrial protein synthesis and fragments the mitochondrial network. The mitochondrial m-AAA protease subunit AFG3L2 is critical to this surveillance mechanism that we propose acts as a sensor to couple the synthesis of mitochondrial proteins with organelle fitness, thus ensuring coordinated assembly of the oxidative phosphorylation complexes from two sets of ribosomes. PMID- 26504175 TI - Perkins et al (J Infect Dis 2015; 212:578-84). PMID- 26504174 TI - Coordinated niche-associated signals promote germline homeostasis in the Drosophila ovary. AB - Stem cell niches provide localized signaling molecules to promote stem cell fate and to suppress differentiation. The Drosophila melanogaster ovarian niche is established by several types of stromal cells, including terminal filament cells, cap cells, and escort cells (ECs). Here, we show that, in addition to its well known function as a niche factor expressed in cap cells, the Drosophila transforming growth factor beta molecule Decapentaplegic (Dpp) is expressed at a low level in ECs to maintain a pool of partially differentiated germline cells that may dedifferentiate to replenish germline stem cells upon their depletion under normal and stress conditions. Our study further reveals that the Dpp level in ECs is modulated by Hedgehog (Hh) ligands, which originate from both cap cells and ECs. We also demonstrate that Hh signaling exerts its function by suppressing Janus kinase/signal transducer activity, which promotes Dpp expression in ECs. Collectively, our data suggest a complex interplay of niche-associated signals that controls the development of a stem cell lineage. PMID- 26504176 TI - ApoA-I Milano stimulates lipolysis in adipose cells independently of cAMP/PKA activation. AB - ApoA-I, the main protein component of HDL, is suggested to be involved in metabolic homeostasis. We examined the effects of Milano, a naturally occurring ApoA-I variant, about which little mechanistic information is available. Remarkably, high-fat-fed mice treated with Milano displayed a rapid weight loss greater than ApoA-I WT treated mice, and a significantly reduced adipose tissue mass, without an inflammatory response. Further, lipolysis in adipose cells isolated from mice treated with either WT or Milano was increased. In primary rat adipose cells, Milano stimulated cholesterol efflux and increased glycerol release, independently of beta-adrenergic stimulation and phosphorylation of hormone sensitive lipase (Ser563) and perilipin (Ser522). Stimulation with Milano had a significantly greater effect on glycerol release compared with WT but similar effect on cholesterol efflux. Pharmacological inhibition or siRNA silencing of ABCA1 did not diminish Milano-stimulated lipolysis, although binding to the cell surface was decreased, as analyzed by fluorescence microscopy. Interestingly, methyl-beta-cyclodextrin, a well-described cholesterol acceptor, dose-dependently stimulated lipolysis. Together, these results suggest that decreased fat mass and increased lipolysis following Milano treatment in vivo is partly explained by a novel mechanism at the adipose cell level comprising stimulation of lipolysis independently of the canonical cAMP/protein kinase A signaling pathway. PMID- 26504177 TI - Predicting complications with pretreatment testing in infantile haemangioma treated with oral propranolol. AB - BACKGROUND: Since 2008, orally administered propranolol has rapidly gained acceptance as the preferred therapy for haemangiomas, and is usually initiated by ophthalmologists, dermatologists or plastic surgeons who do not routinely use propranolol for any other indication. During the initial years when experience was limited, most healthcare professionals justifiably adopted a cautious approach when initiating and monitoring treatment. A consensus recommendation from the American Society of Dermatologists suggests routine observation, monitoring and cardiology assessments prior to propranolol initiation. AIM: This study aims to analyse treatment initiation in a large tertiary children's hospital and investigate the value of pretreatment testing in predicting commonly seen adverse reactions of propranolol. METHOD: 104 eligible patients treated between January 2009 and July 2012 were included. All patients underwent pretesting either with protocol A (administration of test dose with routine observations) or protocol B (cardiology clinic assessment, including two dimensional echocardiography without test dose). RESULTS: 38.5% (40/104) of patients developed adverse reactions during treatment; however, there were no severe or life-threatening reactions. Protocol A has a sensitivity of 0 (95% CI 0 to 0.17) and specificity of 0.95 (95% CI 0.83 to 0.99). Protocol B has a sensitivity of 0.07 (95% CI 0 to 0.34) and specificity of 0.86 (95% CI 0.63 to 0.96). CONCLUSIONS: The predictive values of both protocols for the commonly observed adverse reactions are low. In this series, there is no evidence to suggest that routine pretreatment testing before propranolol initiation is of any value in otherwise healthy children. PMID- 26504178 TI - Prevalence and clinical correlates of focal choroidal excavation in eyes with age related macular degeneration, polypoidal choroidal vasculopathy and central serous chorioretinopathy. AB - PURPOSE: To describe the prevalence and clinical characteristics of focal choroidal excavation (FCE) in patients with exudative maculopathy due to age related macular degeneration with choroidal neovascularisation (AMD-CNV), polypoidal choroidal vasculopathy (PCV) and central serous chorioretinopathy (CSC). METHODS: Three hundred and forty-three patients (343 presenting eyes and 255 fellow unaffected eyes) from consecutive patients presenting with untreated AMD-CNV, PCV or CSC are prospectively recruited. Two independent retinal specialists masked to the clinical diagnosis graded the presence of FCE by examining the findings from spectral-domain optical coherence tomography (SD OCT). The frequency and clinical characteristics of FCE in each of the three clinical diagnosis groups were compared. RESULTS: The diagnosis in the presenting eye was AMD-CNV in 92 patients, PCV in 149 patients, retinal angiomatous proliferation (RAP) in 3 patients and CSC in 99 patients; 255 fellow eyes free of clinical diseases were also graded. The prevalence of FCE was 2.3% (total 14 eyes; 10 presenting eyes, 4 fellow eyes) out of 598 eyes examined. In presenting eyes, FCE was most prevalent in PCV (6.0%), followed by AMD-CNV (1.0%) and CSC (0%), p=0.02. In fellow eyes, the prevalence of FCE was 2.9%, 0% and 1.2% in patients with PCV, AMD-CNV and CSC, respectively. Eyes with FCE had a significantly longer axial length (24.93+/-1.65 mm vs 23.49+/-1.10 mm, p<0.001), but otherwise, all other characteristics were similar. CONCLUSIONS: FCE is more common in PCV than AMD-CNV and CSC. Disturbance in the choroid/retinal pigment epithelium/Bruch membrane interface affected by FCE may be linked to the pathogenesis of PCV and AMD-CNV. PMID- 26504173 TI - Synaptopodin couples epithelial contractility to alpha-actinin-4-dependent junction maturation. AB - The epithelial junction experiences mechanical force exerted by endogenous actomyosin activities and from interactions with neighboring cells. We hypothesize that tension generated at cell-cell adhesive contacts contributes to the maturation and assembly of the junctional complex. To test our hypothesis, we used a hydraulic apparatus that can apply mechanical force to intercellular junction in a confluent monolayer of cells. We found that mechanical force induces alpha-actinin-4 and actin accumulation at the cell junction in a time- and tension-dependent manner during junction development. Intercellular tension also induces alpha-actinin-4-dependent recruitment of vinculin to the cell junction. In addition, we have identified a tension-sensitive upstream regulator of alpha-actinin-4 as synaptopodin. Synaptopodin forms a complex containing alpha actinin-4 and beta-catenin and interacts with myosin II, indicating that it can physically link adhesion molecules to the cellular contractile apparatus. Synaptopodin depletion prevents junctional accumulation of alpha-actinin-4, vinculin, and actin. Knockdown of synaptopodin and alpha-actinin-4 decreases the strength of cell-cell adhesion, reduces the monolayer permeability barrier, and compromises cellular contractility. Our findings underscore the complexity of junction development and implicate a control process via tension-induced sequential incorporation of junctional components. PMID- 26504179 TI - Correlation between peripapillary retinal thickness and serum level of vascular endothelial growth factor in patients with POEMS syndrome. AB - AIMS: To determine whether there is a significant correlation between the peripapillary retinal thickness (pRT) and the serum level of vascular endothelial growth factor (VEGF) in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome. METHODS: This was a cross-sectional, observational case series. We studied 34 eyes of 17 treatment-naive patients with POEMS syndrome whose intracranial pressure was within the normal range. The spectral-domain optical coherence tomographic (SD OCT) examinations consisted of circle scans of 3.45 mm diameter around the optic disc. The pRT was automatically measured in the SD-OCT images and was used for the statistical analysis. The serum level of VEGF was measured by ELISAs, and the correlation between the pRT and the serum level of VEGF was determined. Multivariable logistic regression analyses were used to identify independent factors that were correlated with the pRT. RESULTS: There was a significant positive correlation between the serum levels of VEGF and the average pRT of the two eyes of each patient (r=0.81, p<0.0001). There was a significant correlation between the pRT of the right and left eyes with an intraclass correlation coefficient of 0.839. Multiple regression analysis showed that the serum levels of VEGF were independent contributors to the pRT (standard regression coefficient=0.59, p=0.012). CONCLUSIONS: The significant correlation between the pRT and the serum level of VEGF suggests that the higher serum level of VEGF might be associated with the development of the optic disc oedema in patients with POEMS syndrome. PMID- 26504180 TI - Biological variation in musculoskeletal injuries: current knowledge, future research and practical implications. AB - Evidence from familial and genetic association studies have reported that DNA sequence variants play an important role, together with non-genetic factors, in the aetiology of both exercise-associated and occupational-associated acute and chronic musculoskeletal soft tissue injuries. The associated variants, which have been identified to date, may contribute to the interindividual variation in the structure and, by implication, mechanical properties of the collagen fibril and surrounding matrix within musculoskeletal soft tissues, as well as their response to mechanical loading and other stimuli. Future work should focus on the establishment of multidisciplinary international consortia for the identification of biologically relevant variants involved in modulating injury risk. These consortia will improve the limitations of the published hypothesis-driven genetic association studies, since they will allow resources to be pooled in recruiting large well-characterised cohorts required for whole-genome screening. Finally, clinicians and coaches need to be aware that many direct-to-consumer companies are currently marketing genetic tests directly to athletes without it being requested by an appropriately qualified healthcare professional, and without interpretation alongside other clinical indicators or lifestyle factors. These specific genetic tests are premature and are not necessarily required to evaluate susceptibility to musculoskeletal soft tissue injury. Current practice should rather consider susceptibility through known risk factors such as a positive family history of a specific injury, a history of other tendon and/or ligament injuries and participation in activities associated with the specific musculoskeletal injuries. Potential susceptible athletes may then be individually managed to reduce their risk profile. PMID- 26504181 TI - What is the role of 3 T MRI in sports medicine? Revisiting the marriage after the honeymoon. PMID- 26504182 TI - Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. AB - Patients with autoimmune multilineage cytopenias are often refractory to standard therapies requiring chronic immunosuppression with medications with limited efficacy and high toxicity. We present data on 30 patients treated on a multicenter prospective clinical trial using sirolimus as monotherapy. All children (N = 12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response (CR), including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within 1 to 3 months of starting sirolimus. Double-negative T cells were no longer detectable in most, yet other lymphocyte populations were spared, suggesting a targeted effect of sirolimus. We also treated 12 patients with multilineage cytopenias secondary to common variable immunodeficiency (CVID), Evans syndrome (ES), or systemic lupus erythematosus (SLE), and most achieved a CR (N = 8), although the time to CR was often slower than was seen in ALPS. Six children with single-lineage autoimmune cytopenias were treated and only 2 responded. Sirolimus was well tolerated with very few side effects. All of the responding patients have remained on therapy for over 1 year (median, 2 years; range, 1 to 4.5 years). In summary, sirolimus led to CR and durable responses in a majority of children with refractory multilineage autoimmune cytopenias. The responses seen in ALPS patients were profound, suggesting that sirolimus should be considered as a first-line, steroid sparing treatment of patients needing chronic therapy. The results in other multilineage autoimmune cytopenia cohorts were encouraging, and sirolimus should be considered in children with SLE, ES, and CVID. This trial was registered at www.clinicaltrials.gov as #NCT00392951. PMID- 26504184 TI - Ferric chloride thrombosis model: unraveling the vascular effects of a highly corrosive oxidant. PMID- 26504185 TI - Doctor manipulated hospital system for four years to abuse boys, investigation finds. PMID- 26504183 TI - Primary antifungal prophylaxis during curative-intent therapy for acute myeloid leukemia. PMID- 26504186 TI - Reduction in climate pollutants could save five million lives a year, WHO report says. PMID- 26504187 TI - REBECA: a phase I study of bevacizumab and whole-brain radiation therapy for the treatment of brain metastasis from solid tumours. PMID- 26504188 TI - World Stroke Day Proclamation 2015: Call to Preserve Cognitive Vitality. PMID- 26504189 TI - Stroke and Potentially Preventable Dementias Proclamation: Updated World Stroke Day Proclamation. PMID- 26504191 TI - Correction. PMID- 26504192 TI - Correction. PMID- 26504193 TI - Correction. PMID- 26504194 TI - Embracing social media. PMID- 26504195 TI - Obese individuals experience wheezing without asthma but not asthma without wheezing: a Mendelian randomisation study of 85,437 adults from the Copenhagen General Population Study. AB - BACKGROUND: Observational studies suggest that obesity is associated with increased risk of asthma. However, it is unknown whether this could be explained by wheezing. We tested the hypothesis that high body mass index (BMI) observationally and genetically is associated with high risk of wheezing and asthma, and that the association between high BMI and asthma is explained by wheezing. METHODS: We genotyped 85,437 individuals aged 20-100 years from the Copenhagen General Population Study for FTO (rs9939609), MC4R (rs17782313), TMEM18 (rs6548238) GNPDA2 (rs10938397) and BDNF (rs10767664); 14,500 individuals experienced wheezing and 5406 had asthma. Wheezing was self-reported, and asthma was ascertained through self-report, hospital contacts with asthma, and/or receiving medication for asthma. BMI was calculated as measured weight divided by measured height squared (kg/m2). RESULTS: In observational analyses versus BMI of 18.5-22.4 kg/m2, ORs for wheezing were 1.23 (95% CI 1.00 to 1.52) for BMI <18.5 kg/m2, 1.17 (1.10 to 1.25) for 22.5-24.9 kg/m2, 1.44 (1.35 to 1.54) for 25-27.4 kg/m2, 1.86 (1.73 to 1.99) for 27.5-29.9 kg/m2, 2.48 (2.31 to 2.66) for 30-34.9 kg/m(2), 3.86 (3.48 to 4.28) for 35-39.9 kg/m2 and 6.05 (5.12 to 7.14) for BMI >=40 kg/m2. Corresponding ORs for asthma were 1.28 (0.95 to 1.74), 1.07 (0.97 to 1.17), 1.14 (1.04 to 1.25), 1.32 (1.20 to 1.46), 1.39 (1.25 to 1.54), 1.54 (1.31 to 1.81) and 1.99 (1.55 to 2.56), respectively. Compared with BMI allele score 0 4, scores 5, 6 and 7-10 were associated with 0.22, 0.51 and 0.76 kg/m2 higher BMI, respectively. Genetically determined ORs per unit higher BMI were 1.22 (1.15 to 1.31) for wheezing, 1.18 (1.10 to 1.27) for wheezing without asthma, 1.08 (0.98 to 1.19) for asthma, and 0.85 (0.73 to 0.99) for asthma without wheezing. Corresponding observational ORs were 1.09 (1.09 to 1.10), 1.09 (1.08 to 1.09), 1.03 (1.03 to 1.04) and 0.99 (0.98 to 1.00), respectively. CONCLUSIONS: High BMI was associated with high risk of wheezing without asthma, but not with high risk of asthma without wheezing. PMID- 26504196 TI - Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity. AB - Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. Although highly inhibitory murine and human monoclonal antibodies (mAbs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. Here, we determined the cryo EM structures of chikungunya virus-like particles complexed with antibody fragments (Fab) of two highly protective human mAbs, 4J21 and 5M16, that block virus fusion with host membranes. Both mAbs bind primarily to sites within the A and B domains, as well as to the B domain's beta-ribbon connector of the viral glycoprotein E2. The footprints of these antibodies on the viral surface were consistent with results from loss-of-binding studies using an alanine scanning mutagenesis-based epitope mapping approach. The Fab fragments stabilized the position of the B domain relative to the virus, particularly for the complex with 5M16. This finding is consistent with a mechanism of neutralization in which anti CHIKV mAbs that bridge the A and B domains impede movement of the B domain away from the underlying fusion loop on the E1 glycoprotein and therefore block the requisite pH-dependent fusion of viral and host membranes. PMID- 26504197 TI - Virus-mimetic nanovesicles as a versatile antigen-delivery system. AB - It is a critically important challenge to rapidly design effective vaccines to reduce the morbidity and mortality of unexpected pandemics. Inspired from the way that most enveloped viruses hijack a host cell membrane and subsequently release by a budding process that requires cell membrane scission, we genetically engineered viral antigen to harbor into cell membrane, then form uniform spherical virus-mimetic nanovesicles (VMVs) that resemble natural virus in size, shape, and specific immunogenicity with the help of surfactants. Incubation of major cell membrane vesicles with surfactants generates a large amount of nano sized uniform VMVs displaying the native conformational epitopes. With the diverse display of epitopes and viral envelope glycoproteins that can be functionally anchored onto VMVs, we demonstrate VMVs to be straightforward, robust and tunable nanobiotechnology platforms for fabricating antigen delivery systems against a wide range of enveloped viruses. PMID- 26504198 TI - Why significant variables aren't automatically good predictors. AB - Thus far, genome-wide association studies (GWAS) have been disappointing in the inability of investigators to use the results of identified, statistically significant variants in complex diseases to make predictions useful for personalized medicine. Why are significant variables not leading to good prediction of outcomes? We point out that this problem is prevalent in simple as well as complex data, in the sciences as well as the social sciences. We offer a brief explanation and some statistical insights on why higher significance cannot automatically imply stronger predictivity and illustrate through simulations and a real breast cancer example. We also demonstrate that highly predictive variables do not necessarily appear as highly significant, thus evading the researcher using significance-based methods. We point out that what makes variables good for prediction versus significance depends on different properties of the underlying distributions. If prediction is the goal, we must lay aside significance as the only selection standard. We suggest that progress in prediction requires efforts toward a new research agenda of searching for a novel criterion to retrieve highly predictive variables rather than highly significant variables. We offer an alternative approach that was not designed for significance, the partition retention method, which was very effective predicting on a long-studied breast cancer data set, by reducing the classification error rate from 30% to 8%. PMID- 26504199 TI - Uterine endoplasmic reticulum stress-unfolded protein response regulation of gestational length is caspase-3 and -7-dependent. AB - We previously identified myometrial caspase-3 (CASP3) as a potential regulator of uterine quiescence. We also determined that during pregnancy, the functional activation of uterine CASP3 is likely governed by an integrated endoplasmic reticulum stress response (ERSR) and is consequently limited by an increased unfolded protein response (UPR). The present study examined the functional relevance of uterine UPR-ERSR in maintaining myometrial quiescence and regulating the timing of parturition. In vitro analysis of the human uterine myocyte hTERT HM cell line revealed that tunicamycin (TM)-induced ERSR modified uterine myocyte contractile responsiveness. Accordingly, alteration of in vivo uterine UPR-ERSR using a pregnant mouse model significantly modified gestational length. We determined that "normal" gestational activation of the ERSR-induced CASP3 and caspase 7 (CASP7) maintains uterine quiescence through previously unidentified proteolytic targeting of the gap junction protein, alpha 1(GJA1); however, surprisingly, TM-induced uterine ERSR triggered an exaggerated UPR that eliminated uterine CASP3 and 7 tocolytic action precociously. These events allowed for a premature increase in myometrial GJA1 levels, elevated contractile responsiveness, and the onset of preterm labor. Importantly, a successful reversal of the magnified ERSR-induced preterm birth phenotype could be achieved by pretreatment with 4-phenylbutrate, a chaperone protein mimic. PMID- 26504200 TI - Novel plasticity rule can explain the development of sensorimotor intelligence. AB - Grounding autonomous behavior in the nervous system is a fundamental challenge for neuroscience. In particular, self-organized behavioral development provides more questions than answers. Are there special functional units for curiosity, motivation, and creativity? This paper argues that these features can be grounded in synaptic plasticity itself, without requiring any higher-level constructs. We propose differential extrinsic plasticity (DEP) as a new synaptic rule for self learning systems and apply it to a number of complex robotic systems as a test case. Without specifying any purpose or goal, seemingly purposeful and adaptive rhythmic behavior is developed, displaying a certain level of sensorimotor intelligence. These surprising results require no system-specific modifications of the DEP rule. They rather arise from the underlying mechanism of spontaneous symmetry breaking, which is due to the tight brain body environment coupling. The new synaptic rule is biologically plausible and would be an interesting target for neurobiological investigation. We also argue that this neuronal mechanism may have been a catalyst in natural evolution. PMID- 26504201 TI - Impacts of high-latitude volcanic eruptions on ENSO and AMOC. AB - Large volcanic eruptions can have major impacts on global climate, affecting both atmospheric and ocean circulation through changes in atmospheric chemical composition and optical properties. The residence time of volcanic aerosol from strong eruptions is roughly 2-3 y. Attention has consequently focused on their short-term impacts, whereas the long-term, ocean-mediated response has not been well studied. Most studies have focused on tropical eruptions; high-latitude eruptions have drawn less attention because their impacts are thought to be merely hemispheric rather than global. No study to date has investigated the long term effects of high-latitude eruptions. Here, we use a climate model to show that large summer high-latitude eruptions in the Northern Hemisphere cause strong hemispheric cooling, which could induce an El Nino-like anomaly, in the equatorial Pacific during the first 8-9 mo after the start of the eruption. The hemispherically asymmetric cooling shifts the Intertropical Convergence Zone southward, triggering a weakening of the trade winds over the western and central equatorial Pacific that favors the development of an El Nino-like anomaly. In the model used here, the specified high-latitude eruption also leads to a strengthening of the Atlantic Meridional Overturning Circulation (AMOC) in the first 25 y after the eruption, followed by a weakening lasting at least 35 y. The long-lived changes in the AMOC strength also alter the variability of the El Nino Southern Oscillation (ENSO). PMID- 26504202 TI - College football, elections, and false-positive results in observational research. AB - A recent, widely cited study [Healy AJ, Malhotra N, Mo CH (2010) Proc Natl Acad Sci USA 107(29):12804-12809] finds that college football games influence voting behavior. Victories within 2 weeks of an election reportedly increase the success of the incumbent party in presidential, senatorial, and gubernatorial elections in the home county of the team. We reassess the evidence and conclude that there is likely no such effect, despite the fact that Healy et al. followed the best practices in social science and used a credible research design. Multiple independent sources of evidence suggest that the original finding was spurious reflecting bad luck for researchers rather than a shortcoming of American voters. We fail to estimate the same effect when we leverage situations where multiple elections with differing incumbent parties occur in the same county and year. We also find that the purported effect of college football games is stronger in counties where people are less interested in college football, just as strong when the incumbent candidate does not run for reelection, and just as strong in other parts of the state outside the home county of the team. Lastly, we detect no effect of National Football League games on elections, despite their greater popularity. We conclude with recommendations for evaluating surprising research findings and avoiding similar false-positive results. PMID- 26504204 TI - Correction for Liu et al., Direct evidence that suspensor cells have embryogenic potential that is suppressed by the embryo proper during normal embryogenesis. PMID- 26504203 TI - Semisynthetic protein nanoreactor for single-molecule chemistry. AB - The covalent chemistry of individual reactants bound within a protein pore can be monitored by observing the ionic current flow through the pore, which acts as a nanoreactor responding to bond-making and bond-breaking events. In the present work, we incorporated an unnatural amino acid into the alpha-hemolysin (alphaHL) pore by using solid-phase peptide synthesis to make the central segment of the polypeptide chain, which forms the transmembrane beta-barrel of the assembled heptamer. The full-length alphaHL monomer was obtained by native chemical ligation of the central synthetic peptide to flanking recombinant polypeptides. alphaHL pores with one semisynthetic subunit were then used as nanoreactors for single-molecule chemistry. By introducing an amino acid with a terminal alkyne group, we were able to visualize click chemistry at the single-molecule level, which revealed a long-lived (4.5-s) reaction intermediate. Additional side chains might be introduced in a similar fashion, thereby greatly expanding the range of single-molecule covalent chemistry that can be investigated by the nanoreactor approach. PMID- 26504205 TI - Test of Martin's overkill hypothesis using radiocarbon dates on extinct megafauna. AB - Following Martin [Martin PS (1973) Science 179:969-974], we propose the hypothesis that the timing of human arrival to the New World can be assessed by examining the ecological impacts of a small population of people on extinct Pleistocene megafauna. To that end, we compiled lists of direct radiocarbon dates on paleontological specimens of extinct genera from North and South America with the expectation that the initial decline of extinct megafauna should correspond in time with the initial evidence for human colonization and that those declines should occur first in eastern Beringia, next in the contiguous United States, and last in South America. Analyses of spacings and frequency distributions of radiocarbon dates for each region support the idea that the extinction event first commenced in Beringia, roughly 13,300-15,000 BP. For the United States and South America, extinctions commenced considerably later but were closely spaced in time. For the contiguous United States, extinction began at ca. 12,900-13,200 BP, and at ca. 12,600-13,900 BP in South America. For areas south of Beringia, these estimates correspond well with the first significant evidence for human presence and are consistent with the predictions of the overkill hypothesis. PMID- 26504207 TI - Correction for Song et al., Resolving conflict in eutherian mammal phylogeny using phylogenomics and the multispecies coalescent model. PMID- 26504206 TI - Effects of pressure on the dynamics of an oligomeric protein from deep-sea hyperthermophile. AB - Inorganic pyrophosphatase (IPPase) from Thermococcus thioreducens is a large oligomeric protein derived from a hyperthermophilic microorganism that is found near hydrothermal vents deep under the sea, where the pressure is up to 100 MPa (1 kbar). It has attracted great interest in biophysical research because of its high activity under extreme conditions in the seabed. In this study, we use the quasielastic neutron scattering (QENS) technique to investigate the effects of pressure on the conformational flexibility and relaxation dynamics of IPPase over a wide temperature range. The beta-relaxation dynamics of proteins was studied in the time ranges from 2 to 25 ps, and from 100 ps to 2 ns, using two spectrometers. Our results indicate that, under a pressure of 100 MPa, close to that of the native environment deep under the sea, IPPase displays much faster relaxation dynamics than a mesophilic model protein, hen egg white lysozyme (HEWL), at all measured temperatures, opposite to what we observed previously under ambient pressure. This contradictory observation provides evidence that the protein energy landscape is distorted by high pressure, which is significantly different for hyperthermophilic (IPPase) and mesophilic (HEWL) proteins. We further derive from our observations a schematic denaturation phase diagram together with energy landscapes for the two very different proteins, which can be used as a general picture to understand the dynamical properties of thermophilic proteins under pressure. PMID- 26504208 TI - Interatomic repulsion softness directly controls the fragility of supercooled metallic melts. AB - We present an analytic scheme to connect the fragility and viscoelasticity of metallic glasses to the effective ion-ion interaction in the metal. This is achieved by an approximation of the short-range repulsive part of the interaction, combined with nonaffine lattice dynamics to obtain analytical expressions for the shear modulus, viscosity, and fragility in terms of the ion ion interaction. By fitting the theoretical model to experimental data, we are able to link the steepness of the interionic repulsion to the Thomas-Fermi screened Coulomb repulsion and to the Born-Mayer valence electron overlap repulsion for various alloys. The result is a simple closed-form expression for the fragility of the supercooled liquid metal in terms of few crucial atomic scale interaction and anharmonicity parameters. In particular, a linear relationship is found between the fragility and the energy scales of both the screened Coulomb and the electron overlap repulsions. This relationship opens up opportunities to fabricate alloys with tailored thermoelasticity and fragility by rationally tuning the chemical composition of the alloy according to general principles. The analysis presented here brings a new way of looking at the link between the outer shell electronic structure of metals and metalloids and the viscoelasticity and fragility thereof. PMID- 26504210 TI - Atlantic hurricane surge response to geoengineering. AB - Devastating floods due to Atlantic hurricanes are relatively rare events. However, the frequency of the most intense storms is likely to increase with rises in sea surface temperatures. Geoengineering by stratospheric sulfate aerosol injection cools the tropics relative to the polar regions, including the hurricane Main Development Region in the Atlantic, suggesting that geoengineering may mitigate hurricanes. We examine this hypothesis using eight earth system model simulations of climate under the Geoengineering Model Intercomparison Project (GeoMIP) G3 and G4 schemes that use stratospheric aerosols to reduce the radiative forcing under the Representative Concentration Pathway (RCP) 4.5 scenario. Global mean temperature increases are greatly ameliorated by geoengineering, and tropical temperature increases are at most half of those temperature increases in the RCP4.5. However, sulfate injection would have to double (to nearly 10 teragrams of SO2 per year) between 2020 and 2070 to balance the RCP4.5, approximately the equivalent of a 1991 Pinatubo eruption every 2 y, with consequent implications for stratospheric ozone. We project changes in storm frequencies using a temperature-dependent generalized extreme value statistical model calibrated by historical storm surges and observed temperatures since 1923. The number of storm surge events as big as the one caused by the 2005 Katrina hurricane are reduced by about 50% compared with no geoengineering, but this reduction is only marginally statistically significant. Nevertheless, when sea level rise differences in 2070 between the RCP4.5 and geoengineering are factored into coastal flood risk, we find that expected flood levels are reduced by about 40 cm for 5-y events and about halved for 50-y surges. PMID- 26504209 TI - Global nutrient transport in a world of giants. AB - The past was a world of giants, with abundant whales in the sea and large animals roaming the land. However, that world came to an end following massive late Quaternary megafauna extinctions on land and widespread population reductions in great whale populations over the past few centuries. These losses are likely to have had important consequences for broad-scale nutrient cycling, because recent literature suggests that large animals disproportionately drive nutrient movement. We estimate that the capacity of animals to move nutrients away from concentration patches has decreased to about 8% of the preextinction value on land and about 5% of historic values in oceans. For phosphorus (P), a key nutrient, upward movement in the ocean by marine mammals is about 23% of its former capacity (previously about 340 million kg of P per year). Movements by seabirds and anadromous fish provide important transfer of nutrients from the sea to land, totalling ~150 million kg of P per year globally in the past, a transfer that has declined to less than 4% of this value as a result of the decimation of seabird colonies and anadromous fish populations. We propose that in the past, marine mammals, seabirds, anadromous fish, and terrestrial animals likely formed an interlinked system recycling nutrients from the ocean depths to the continental interiors, with marine mammals moving nutrients from the deep sea to surface waters, seabirds and anadromous fish moving nutrients from the ocean to land, and large animals moving nutrients away from hotspots into the continental interior. PMID- 26504211 TI - Behavioral assessment of sensitivity to intracortical microstimulation of primate somatosensory cortex. AB - Intracortical microstimulation (ICMS) is a powerful tool to investigate the functional role of neural circuits and may provide a means to restore sensation for patients for whom peripheral stimulation is not an option. In a series of psychophysical experiments with nonhuman primates, we investigate how stimulation parameters affect behavioral sensitivity to ICMS. Specifically, we deliver ICMS to primary somatosensory cortex through chronically implanted electrode arrays across a wide range of stimulation regimes. First, we investigate how the detectability of ICMS depends on stimulation parameters, including pulse width, frequency, amplitude, and pulse train duration. Then, we characterize the degree to which ICMS pulse trains that differ in amplitude lead to discriminable percepts across the range of perceptible and safe amplitudes. We also investigate how discriminability of pulse amplitude is modulated by other stimulation parameters-namely, frequency and duration. Perceptual judgments obtained across these various conditions will inform the design of stimulation regimes for neuroscience and neuroengineering applications. PMID- 26504212 TI - Airborne measurements of organic bromine compounds in the Pacific tropical tropopause layer. AB - Very short-lived brominated substances (VSLBr) are an important source of stratospheric bromine, an effective ozone destruction catalyst. However, the accurate estimation of the organic and inorganic partitioning of bromine and the input to the stratosphere remains uncertain. Here, we report near-tropopause measurements of organic brominated substances found over the tropical Pacific during the NASA Airborne Tropical Tropopause Experiment campaigns. We combine aircraft observations and a chemistry-climate model to quantify the total bromine loading injected to the stratosphere. Surprisingly, despite differences in vertical transport between the Eastern and Western Pacific, VSLBr (organic + inorganic) contribute approximately similar amounts of bromine [~6 (4-9) parts per trillion] [corrected] to the stratospheric input at the tropical tropopause. These levels of bromine cause substantial ozone depletion in the lower stratosphere, and any increases in future abundances (e.g., as a result of aquaculture) will lead to larger depletions. PMID- 26504213 TI - No evidence that polygynous marriage is a harmful cultural practice in northern Tanzania. AB - Polygyny is cross-culturally common and a topic of considerable academic and policy interest, often deemed a harmful cultural practice serving the interests of men contrary to those of women and children. Supporting this view, large-scale studies of national African demographic surveys consistently demonstrate that poor child health outcomes are concentrated in polygynous households. Negative population-level associations between polygyny and well-being have also been reported, consistent with the hypothesis that modern transitions to socially imposed monogamy are driven by cultural group selection. We challenge the consensus view that polygyny is harmful, drawing on multilevel data from 56 ethnically diverse Tanzanian villages. We first demonstrate the vulnerability of aggregated data to confounding between ecological and individual determinants of health; while across villages polygyny is associated with poor child health and low food security, such relationships are absent or reversed within villages, particularly when children and fathers are coresident. We then provide data indicating that the costs of sharing a husband are offset by greater wealth (land and livestock) of polygynous households. These results are consistent with models of polygyny based on female choice. Finally, we show that village-level negative associations between polygyny prevalence, food security, and child health are fully accounted for by underlying differences in ecological vulnerability (rainfall) and socioeconomic marginalization (access to education). We highlight the need for improved, culturally sensitive measurement tools and appropriate scales of analysis in studies of polygyny and other purportedly harmful practices and discuss the relevance of our results to theoretical accounts of marriage and contemporary population policy. PMID- 26504215 TI - Thermodynamic and achievable efficiencies for solar-driven electrochemical reduction of carbon dioxide to transportation fuels. AB - Thermodynamic, achievable, and realistic efficiency limits of solar-driven electrochemical conversion of water and carbon dioxide to fuels are investigated as functions of light-absorber composition and configuration, and catalyst composition. The maximum thermodynamic efficiency at 1-sun illumination for adiabatic electrochemical synthesis of various solar fuels is in the range of 32 42%. Single-, double-, and triple-junction light absorbers are found to be optimal for electrochemical load ranges of 0-0.9 V, 0.9-1.95 V, and 1.95-3.5 V, respectively. Achievable solar-to-fuel (STF) efficiencies are determined using ideal double- and triple-junction light absorbers and the electrochemical load curves for CO2 reduction on silver and copper cathodes, and water oxidation kinetics over iridium oxide. The maximum achievable STF efficiencies for synthesis gas (H2 and CO) and Hythane (H2 and CH4) are 18.4% and 20.3%, respectively. Whereas the realistic STF efficiency of photoelectrochemical cells (PECs) can be as low as 0.8%, tandem PECs and photovoltaic (PV)-electrolyzers can operate at 7.2% under identical operating conditions. We show that the composition and energy content of solar fuels can also be adjusted by tuning the band-gaps of triple-junction light absorbers and/or the ratio of catalyst-to-PV area, and that the synthesis of liquid products and C2H4 have high profitability indices. PMID- 26504214 TI - Endocannabinoid signaling mediates oxytocin-driven social reward. AB - Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions. PMID- 26504216 TI - Accurate market price formation model with both supply-demand and trend-following for global food prices providing policy recommendations. AB - Recent increases in basic food prices are severely affecting vulnerable populations worldwide. Proposed causes such as shortages of grain due to adverse weather, increasing meat consumption in China and India, conversion of corn to ethanol in the United States, and investor speculation on commodity markets lead to widely differing implications for policy. A lack of clarity about which factors are responsible reinforces policy inaction. Here, for the first time to our knowledge, we construct a dynamic model that quantitatively agrees with food prices. The results show that the dominant causes of price increases are investor speculation and ethanol conversion. Models that just treat supply and demand are not consistent with the actual price dynamics. The two sharp peaks in 2007/2008 and 2010/2011 are specifically due to investor speculation, whereas an underlying upward trend is due to increasing demand from ethanol conversion. The model includes investor trend following as well as shifting between commodities, equities, and bonds to take advantage of increased expected returns. Claims that speculators cannot influence grain prices are shown to be invalid by direct analysis of price-setting practices of granaries. Both causes of price increase, speculative investment and ethanol conversion, are promoted by recent regulatory changes-deregulation of the commodity markets, and policies promoting the conversion of corn to ethanol. Rapid action is needed to reduce the impacts of the price increases on global hunger. PMID- 26504217 TI - Sea otters, kelp forests, and the extinction of Steller's sea cow. AB - The late Pleistocene extinction of so many large-bodied vertebrates has been variously attributed to two general causes: rapid climate change and the effects of humans as they spread from the Old World to previously uninhabited continents and islands. Many large-bodied vertebrates, especially large apex predators, maintain their associated ecosystems through top-down forcing processes, especially trophic cascades, and megaherbivores also exert an array of strong indirect effects on their communities. Thus, a third possibility for at least some of the Pleistocene extinctions is that they occurred through habitat changes resulting from the loss of these other keystone species. Here we explore the plausibility of this mechanism, using information on sea otters, kelp forests, and the recent extinction of Steller's sea cows from the Commander Islands. Large numbers of sea cows occurred in the Commander Islands at the time of their discovery by Europeans in 1741. Although extinction of these last remaining sea cows during early years of the Pacific maritime fur trade is widely thought to be a consequence of direct human overkill, we show that it is also a probable consequence of the loss of sea otters and the co-occurring loss of kelp, even if not a single sea cow had been killed directly by humans. This example supports the hypothesis that the directly caused extinctions of a few large vertebrates in the late Pleistocene may have resulted in the coextinction of numerous other species. PMID- 26504219 TI - Variable impact of late-Quaternary megafaunal extinction in causing ecological state shifts in North and South America. AB - Loss of megafauna, an aspect of defaunation, can precipitate many ecological changes over short time scales. We examine whether megafauna loss can also explain features of lasting ecological state shifts that occurred as the Pleistocene gave way to the Holocene. We compare ecological impacts of late Quaternary megafauna extinction in five American regions: southwestern Patagonia, the Pampas, northeastern United States, northwestern United States, and Beringia. We find that major ecological state shifts were consistent with expectations of defaunation in North American sites but not in South American ones. The differential responses highlight two factors necessary for defaunation to trigger lasting ecological state shifts discernable in the fossil record: (i) lost megafauna need to have been effective ecosystem engineers, like proboscideans; and (ii) historical contingencies must have provided the ecosystem with plant species likely to respond to megafaunal loss. These findings help in identifying modern ecosystems that are most at risk for disappearing should current pressures on the ecosystems' large animals continue and highlight the critical role of both individual species ecologies and ecosystem context in predicting the lasting impacts of defaunation currently underway. PMID- 26504218 TI - Science for a wilder Anthropocene: Synthesis and future directions for trophic rewilding research. AB - Trophic rewilding is an ecological restoration strategy that uses species introductions to restore top-down trophic interactions and associated trophic cascades to promote self-regulating biodiverse ecosystems. Given the importance of large animals in trophic cascades and their widespread losses and resulting trophic downgrading, it often focuses on restoring functional megafaunas. Trophic rewilding is increasingly being implemented for conservation, but remains controversial. Here, we provide a synthesis of its current scientific basis, highlighting trophic cascades as the key conceptual framework, discussing the main lessons learned from ongoing rewilding projects, systematically reviewing the current literature, and highlighting unintentional rewilding and spontaneous wildlife comebacks as underused sources of information. Together, these lines of evidence show that trophic cascades may be restored via species reintroductions and ecological replacements. It is clear, however, that megafauna effects may be affected by poorly understood trophic complexity effects and interactions with landscape settings, human activities, and other factors. Unfortunately, empirical research on trophic rewilding is still rare, fragmented, and geographically biased, with the literature dominated by essays and opinion pieces. We highlight the need for applied programs to include hypothesis testing and science-based monitoring, and outline priorities for future research, notably assessing the role of trophic complexity, interplay with landscape settings, land use, and climate change, as well as developing the global scope for rewilding and tools to optimize benefits and reduce human-wildlife conflicts. Finally, we recommend developing a decision framework for species selection, building on functional and phylogenetic information and with attention to the potential contribution from synthetic biology. PMID- 26504221 TI - Correction for Maksymiuk et al., E1 of alpha-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress. PMID- 26504220 TI - Nanoscale spatial organization of the HoxD gene cluster in distinct transcriptional states. AB - Chromatin condensation plays an important role in the regulation of gene expression. Recently, it was shown that the transcriptional activation of Hoxd genes during vertebrate digit development involves modifications in 3D interactions within and around the HoxD gene cluster. This reorganization follows a global transition from one set of regulatory contacts to another, between two topologically associating domains (TADs) located on either side of the HoxD locus. Here, we use 3D DNA FISH to assess the spatial organization of chromatin at and around the HoxD gene cluster and report that although the two TADs are tightly associated, they appear as spatially distinct units. We measured the relative position of genes within the cluster and found that they segregate over long distances, suggesting that a physical elongation of the HoxD cluster can occur. We analyzed this possibility by super-resolution imaging (STORM) and found that tissues with distinct transcriptional activity exhibit differing degrees of elongation. We also observed that the morphological change of the HoxD cluster in developing digits is associated with its position at the boundary between the two TADs. Such variations in the fine-scale architecture of the gene cluster suggest causal links among its spatial configuration, transcriptional activation, and the flanking chromatin context. PMID- 26504222 TI - Determining hydrodynamic forces in bursting bubbles using DNA nanotube mechanics. AB - Quantifying the mechanical forces produced by fluid flows within the ocean is critical to understanding the ocean's environmental phenomena. Such forces may have been instrumental in the origin of life by driving a primitive form of self replication through fragmentation. Among the intense sources of hydrodynamic shear encountered in the ocean are breaking waves and the bursting bubbles produced by such waves. On a microscopic scale, one expects the surface-tension driven flows produced during bubble rupture to exhibit particularly high velocity gradients due to the small size scales and masses involved. However, little work has examined the strength of shear flow rates in commonly encountered ocean conditions. By using DNA nanotubes as a novel fluid flow sensor, we investigate the elongational rates generated in bursting films within aqueous bubble foams using both laboratory buffer and ocean water. To characterize the elongational rate distribution associated with a bursting bubble, we introduce the concept of a fragmentation volume and measure its form as a function of elongational flow rate. We find that substantial volumes experience surprisingly large flow rates: during the bursting of a bubble having an air volume of 10 mm(3), elongational rates at least as large as [Formula: see text] s(-1) are generated in a fragmentation volume of [Formula: see text] [Formula: see text]. The determination of the elongational strain rate distribution is essential for assessing how effectively fluid motion within bursting bubbles at the ocean surface can shear microscopic particles and microorganisms, and could have driven the self-replication of a protobiont. PMID- 26504223 TI - Combining paleo-data and modern exclosure experiments to assess the impact of megafauna extinctions on woody vegetation. AB - Until recently in Earth history, very large herbivores (mammoths, ground sloths, diprotodons, and many others) occurred in most of the World's terrestrial ecosystems, but the majority have gone extinct as part of the late-Quaternary extinctions. How has this large-scale removal of large herbivores affected landscape structure and ecosystem functioning? In this review, we combine paleo data with information from modern exclosure experiments to assess the impact of large herbivores (and their disappearance) on woody species, landscape structure, and ecosystem functions. In modern landscapes characterized by intense herbivory, woody plants can persist by defending themselves or by association with defended species, can persist by growing in places that are physically inaccessible to herbivores, or can persist where high predator activity limits foraging by herbivores. At the landscape scale, different herbivore densities and assemblages may result in dynamic gradients in woody cover. The late-Quaternary extinctions were natural experiments in large-herbivore removal; the paleoecological record shows evidence of widespread changes in community composition and ecosystem structure and function, consistent with modern exclosure experiments. We propose a conceptual framework that describes the impact of large herbivores on woody plant abundance mediated by herbivore diversity and density, predicting that herbivore suppression of woody plants is strongest where herbivore diversity is high. We conclude that the decline of large herbivores induces major alterations in landscape structure and ecosystem functions. PMID- 26504224 TI - The impact of large terrestrial carnivores on Pleistocene ecosystems. AB - Large mammalian terrestrial herbivores, such as elephants, have dramatic effects on the ecosystems they inhabit and at high population densities their environmental impacts can be devastating. Pleistocene terrestrial ecosystems included a much greater diversity of megaherbivores (e.g., mammoths, mastodons, giant ground sloths) and thus a greater potential for widespread habitat degradation if population sizes were not limited. Nevertheless, based on modern observations, it is generally believed that populations of megaherbivores (>800 kg) are largely immune to the effects of predation and this perception has been extended into the Pleistocene. However, as shown here, the species richness of big carnivores was greater in the Pleistocene and many of them were significantly larger than their modern counterparts. Fossil evidence suggests that interspecific competition among carnivores was relatively intense and reveals that some individuals specialized in consuming megaherbivores. To estimate the potential impact of Pleistocene large carnivores, we use both historic and modern data on predator-prey body mass relationships to predict size ranges of their typical and maximum prey when hunting as individuals and in groups. These prey size ranges are then compared with estimates of juvenile and subadult proboscidean body sizes derived from extant elephant growth data. Young proboscideans at their most vulnerable age fall within the predicted prey size ranges of many of the Pleistocene carnivores. Predation on juveniles can have a greater impact on megaherbivores because of their long interbirth intervals, and consequently, we argue that Pleistocene carnivores had the capacity to, and likely did, limit megaherbivore population sizes. PMID- 26504225 TI - Exploring the influence of ancient and historic megaherbivore extirpations on the global methane budget. AB - Globally, large-bodied wild mammals are in peril. Because "megamammals" have a disproportionate influence on vegetation, trophic interactions, and ecosystem function, declining populations are of considerable conservation concern. However, this is not new; trophic downgrading occurred in the past, including the African rinderpest epizootic of the 1890s, the massive Great Plains bison kill off in the 1860s, and the terminal Pleistocene extinction of megafauna. Examining the consequences of these earlier events yields insights into contemporary ecosystem function. Here, we focus on changes in methane emissions, produced as a byproduct of enteric fermentation by herbivores. Although methane is ~ 200 times less abundant than carbon dioxide in the atmosphere, the greater efficiency of methane in trapping radiation leads to a significant role in radiative forcing of climate. Using global datasets of late Quaternary mammals, domestic livestock, and human population from the United Nations as well as literature sources, we develop a series of allometric regressions relating mammal body mass to population density and CH4 production, which allows estimation of methane production by wild and domestic herbivores for each historic or ancient time period. We find the extirpation of megaherbivores reduced global enteric emissions between 2.2-69.6 Tg CH4 y(-1) during the various time periods, representing a decrease of 0.8-34.8% of the overall inputs to tropospheric input. Our analyses suggest that large-bodied mammals have a greater influence on methane emissions than previously appreciated and, further, that changes in the source pool from herbivores can influence global biogeochemical cycles and, potentially, climate. PMID- 26504226 TI - Discovery and functional characterization of a neomorphic PTEN mutation. AB - Although a variety of genetic alterations have been found across cancer types, the identification and functional characterization of candidate driver genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles. Here, we use whole genome sequencing of a prostate cancer tumor, computational analyses, and experimental validation to identify and predict novel oncogenic activity arising from a point mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor protein. We demonstrate that this mutation (p.A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphoinositide (PI) 3-phosphatase to a phosphoinositide (PI) 5-phosphatase. Using cellular assays, we demonstrate that this gain-of-function activity shifts cellular phosphoinositide levels, hyperactivates the PI3K/Akt cell proliferation pathway, and exhibits increased cell migration beyond canonical PTEN loss-of-function mutants. These findings suggest that mutationally modified PTEN can actively contribute to well-defined hallmarks of cancer. Lastly, we demonstrate that these effects can be substantially mitigated through chemical PI3K inhibitors. These results demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy. PMID- 26504227 TI - Purkinje cell activity during classical conditioning with different conditional stimuli explains central tenet of Rescorla-Wagner model [corrected]. AB - A central tenet of Rescorla and Wagner's model of associative learning is that the reinforcement value of a paired trial diminishes as the associative strength between the presented stimuli increases. Despite its fundamental importance to behavioral sciences, the neural mechanisms underlying the model have not been fully explored. Here, we present findings that, taken together, can explain why a stronger association leads to a reduced reinforcement value, within the context of eyeblink conditioning. Specifically, we show that learned pause responses in Purkinje cells, which trigger adaptively timed conditioned eyeblinks, suppress the unconditional stimulus (US) signal in a graded manner. Furthermore, by examining how Purkinje cells respond to two distinct conditional stimuli and to a compound stimulus, we provide evidence that could potentially help explain the somewhat counterintuitive overexpectation phenomenon, which was derived from the Rescorla-Wagner model. PMID- 26504228 TI - Topography of social touching depends on emotional bonds between humans. AB - Nonhuman primates use social touch for maintenance and reinforcement of social structures, yet the role of social touch in human bonding in different reproductive, affiliative, and kinship-based relationships remains unresolved. Here we reveal quantified, relationship-specific maps of bodily regions where social touch is allowed in a large cross-cultural dataset (N = 1,368 from Finland, France, Italy, Russia, and the United Kingdom). Participants were shown front and back silhouettes of human bodies with a word denoting one member of their social network. They were asked to color, on separate trials, the bodily regions where each individual in their social network would be allowed to touch them. Across all tested cultures, the total bodily area where touching was allowed was linearly dependent (mean r(2) = 0.54) on the emotional bond with the toucher, but independent of when that person was last encountered. Close acquaintances and family members were touched for more reasons than less familiar individuals. The bodily area others are allowed to touch thus represented, in a parametric fashion, the strength of the relationship-specific emotional bond. We propose that the spatial patterns of human social touch reflect an important mechanism supporting the maintenance of social bonds. PMID- 26504229 TI - Effects of gendered behavior on testosterone in women and men. AB - Testosterone is typically understood to contribute to maleness and masculinity, although it also responds to behaviors such as competition. Competition is crucial to evolution and may increase testosterone but also is selectively discouraged for women and encouraged for men via gender norms. We conducted an experiment to test how gender norms might modulate testosterone as mediated by two possible gender->testosterone pathways. Using a novel experimental design, participants (trained actors) performed a specific type of competition (wielding power) in stereotypically masculine vs. feminine ways. We hypothesized in H1 (stereotyped behavior) that wielding power increases testosterone regardless of how it is performed, vs. H2 (stereotyped performance), that wielding power performed in masculine but not feminine ways increases testosterone. We found that wielding power increased testosterone in women compared with a control, regardless of whether it was performed in gender-stereotyped masculine or feminine ways. Results supported H1 over H2: stereotyped behavior but not performance modulated testosterone. These results also supported theory that competition modulates testosterone over masculinity. Our findings thus support a gender->testosterone pathway mediated by competitive behavior. Accordingly, cultural pushes for men to wield power and women to avoid doing so may partially explain, in addition to heritable factors, why testosterone levels tend to be higher in men than in women: A lifetime of gender socialization could contribute to "sex differences" in testosterone. Our experiment opens up new questions of gender->testosterone pathways, highlighting the potential of examining nature/nurture interactions and effects of socialization on human biology. PMID- 26504230 TI - Two contemporaneous mitogenomes from terminal Pleistocene burials in eastern Beringia. AB - Pleistocene residential sites with multiple contemporaneous human burials are extremely rare in the Americas. We report mitochondrial genomic variation in the first multiple mitochondrial genomes from a single prehistoric population: two infant burials (USR1 and USR2) from a common interment at the Upward Sun River Site in central Alaska dating to ~11,500 cal B.P. Using a targeted capture method and next-generation sequencing, we determined that the USR1 infant possessed variants that define mitochondrial lineage C1b, whereas the USR2 genome falls at the root of lineage B2, allowing us to refine younger coalescence age estimates for these two clades. C1b and B2 are rare to absent in modern populations of northern North America. Documentation of these lineages at this location in the Late Pleistocene provides evidence for the extent of mitochondrial diversity in early Beringian populations, which supports the expectations of the Beringian Standstill Model. PMID- 26504232 TI - Transcriptional read-through is not sufficient to induce an epigenetic switch in the silencing activity of Polycomb response elements. AB - In Drosophila, Polycomb (PcG) and Trithorax (TrxG) group proteins are assembled on Polycomb response elements (PREs) to maintain tissue and stage-specific patterns of gene expression. Critical to coordinating gene expression with the process of differentiation, the activity of PREs can be switched "on" and "off." When on, the PRE imposes a silenced state on the genes in the same domain that is stably inherited through multiple rounds of cell division. When the PRE is switched off, the domain is in a state permissive for gene expression that can be stably inherited. Previous studies have suggested that a burst of transcription through a PRE sequence displaces PcG proteins and provides a universal mechanism for inducing a heritable switch in PRE activity from on to off; however, the evidence favoring this model is indirect. Here, we have directly tested the transcriptional read-through mechanism. Contrary to previous suggestions, we show that transcription through the PRE is not sufficient for inducing an epigenetic switch in PRE activity. In fact, even high levels of continuous transcription through a PRE fails to dislodge the PcG proteins, nor does it remove repressive histone marks. Our results indicate that other mechanisms involving adjacent DNA regulatory elements must be implicated in heritable switch of PRE activity. PMID- 26504231 TI - OVO-like 1 regulates progenitor cell fate in human trophoblast development. AB - Epithelial barrier integrity is dependent on progenitor cells that either divide to replenish themselves or differentiate into a specialized epithelium. This paradigm exists in human placenta, where cytotrophoblast cells either propagate or undergo a unique differentiation program: fusion into an overlying syncytiotrophoblast. Syncytiotrophoblast is the primary barrier regulating the exchange of nutrients and gases between maternal and fetal blood and is the principal site for synthesizing hormones vital for human pregnancy. How trophoblast cells regulate their differentiation into a syncytium is not well understood. In this study, we show that the transcription factor OVO-like 1 (OVOL1), a homolog of Drosophila ovo, regulates the transition from progenitor to differentiated trophoblast cells. OVOL1 is expressed in human placenta and was robustly induced following stimulation of trophoblast differentiation. Disruption of OVOL1 abrogated cytotrophoblast fusion and inhibited the expression of a broad set of genes required for trophoblast cell fusion and hormonogenesis. OVOL1 was required to suppress genes that maintain cytotrophoblast cells in a progenitor state, including MYC, ID1, TP63, and ASCL2, and bound specifically to regions upstream of each of these genes. Our results reveal an important function of OVOL1 as a regulator of trophoblast progenitor cell fate during human trophoblast development. PMID- 26504233 TI - Initiating protease with modular domains interacts with beta-glucan recognition protein to trigger innate immune response in insects. AB - The autoactivation of an initiating serine protease upon binding of pattern recognition proteins to pathogen surfaces is a crucial step in eliciting insect immune responses such as the activation of Toll and prophenoloxidase pathways. However, the molecular mechanisms responsible for autoactivation of the initiating protease remains poorly understood. Here, we investigated the molecular basis for the autoactivation of hemolymph protease 14 (HP14), an initiating protease in hemolymph of Manduca sexta, upon the binding of beta-1,3 glucan by its recognition protein, betaGRP2. Biochemical analysis using HP14 zymogen (proHP14), betaGRP2, and the recombinant proteins as truncated forms showed that the amino-terminal modular low-density lipoprotein receptor class A (LA) domains within HP14 are required for proHP14 autoactivation that is stimulated by its interaction with betaGRP2. Consistent with this result, recombinant LA domains inhibit the activation of proHP14 and prophenoloxidase, likely by competing with the interaction between betaGRP2 and LA domains within proHP14. Using surface plasmon resonance, we demonstrated that immobilized LA domains directly interact with betaGRP2 in a calcium-dependent manner and that high-affinity interaction requires the C-terminal glucanase-like domain of betaGRP2. Importantly, the affinity of LA domains for betaGRP2 increases nearly 100-fold in the presence of beta-1,3-glucan. Taken together, these results present the first experimental evidence to our knowledge that LA domains of an insect modular protease and glucanase-like domains of a betaGRP mediate their interaction, and that this binding is essential for the protease autoactivation. Thus, our study provides important insight into the molecular basis underlying the initiation of protease cascade in insect immune responses. PMID- 26504234 TI - Liver X receptor beta controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue. AB - The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type 2 diabetes. Browning is the result of the induction in WAT of a newly discovered type of adipocyte, the beige cell. When mice are exposed to cold or several kinds of hormones or treatments with chemicals, specific depots of WAT undergo a browning process, characterized by highly activated mitochondria and increased heat production and energy expenditure. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulating cholesterol, triglyceride, and glucose metabolism. Following our previous finding that LXRs serve as repressors of uncoupling protein-1 (UCP1) in classic brown adipose tissue in female mice, we found that LXRs, especially LXRbeta, also repress the browning process of subcutaneous adipose tissue (SAT) in male rodents fed a normal diet. Depletion of LXRs activated thyroid-stimulating hormone (TSH) releasing hormone (TRH)-positive neurons in the paraventricular nucleus area of the hypothalamus and thus stimulated secretion of TSH from the pituitary. Consequently, production of thyroid hormones in the thyroid gland and circulating thyroid hormone level were increased. Moreover, the activity of thyroid signaling in SAT was markedly increased. Together, our findings have uncovered the basis of increased energy expenditure in male LXR knockout mice and provided support for targeting LXRs in treatment of obesity. PMID- 26504235 TI - Lion (Panthera leo) populations are declining rapidly across Africa, except in intensively managed areas. AB - We compiled all credible repeated lion surveys and present time series data for 47 lion (Panthera leo) populations. We used a Bayesian state space model to estimate growth rate-lambda for each population and summed these into three regional sets to provide conservation-relevant estimates of trends since 1990. We found a striking geographical pattern: African lion populations are declining everywhere, except in four southern countries (Botswana, Namibia, South Africa, and Zimbabwe). Population models indicate a 67% chance that lions in West and Central Africa decline by one-half, while estimating a 37% chance that lions in East Africa also decline by one-half over two decades. We recommend separate regional assessments of the lion in the World Conservation Union (IUCN) Red List of Threatened Species: already recognized as critically endangered in West Africa, our analysis supports listing as regionally endangered in Central and East Africa and least concern in southern Africa. Almost all lion populations that historically exceeded ~ 500 individuals are declining, but lion conservation is successful in southern Africa, in part because of the proliferation of reintroduced lions in small, fenced, intensively managed, and funded reserves. If management budgets for wild lands cannot keep pace with mounting levels of threat, the species may rely increasingly on these southern African areas and may no longer be a flagship species of the once vast natural ecosystems across the rest of the continent. PMID- 26504236 TI - Optimal group size in a highly social mammal. AB - Group size is an important trait of social animals, affecting how individuals allocate time and use space, and influencing both an individual's fitness and the collective, cooperative behaviors of the group as a whole. Here we tested predictions motivated by the ecological constraints model of group size, examining the effects of group size on ranging patterns and adult female glucocorticoid (stress hormone) concentrations in five social groups of wild baboons (Papio cynocephalus) over an 11-y period. Strikingly, we found evidence that intermediate-sized groups have energetically optimal space-use strategies; both large and small groups experience ranging disadvantages, in contrast to the commonly reported positive linear relationship between group size and home range area and daily travel distance, which depict a disadvantage only in large groups. Specifically, we observed a U-shaped relationship between group size and home range area, average daily distance traveled, evenness of space use within the home range, and glucocorticoid concentrations. We propose that a likely explanation for these U-shaped patterns is that large, socially dominant groups are constrained by within-group competition, whereas small, socially subordinate groups are constrained by between-group competition and predation pressures. Overall, our results provide testable hypotheses for evaluating group-size constraints in other group-living species, in which the costs of intra- and intergroup competition vary as a function of group size. PMID- 26504237 TI - Battle between influenza A virus and a newly identified antiviral activity of the PARP-containing ZAPL protein. AB - Previous studies showed that ZAPL (PARP-13.1) exerts its antiviral activity via its N-terminal zinc fingers that bind the mRNAs of some viruses, leading to mRNA degradation. Here we identify a different antiviral activity of ZAPL that is directed against influenza A virus. This ZAPL antiviral activity involves its C terminal PARP domain, which binds the viral PB2 and PA polymerase proteins, leading to their proteasomal degradation. After the PB2 and PA proteins are poly(ADP-ribosylated), they are associated with the region of ZAPL that includes both the PARP domain and the adjacent WWE domain that is known to bind poly(ADP ribose) chains. These ZAPL-associated PB2 and PA proteins are then ubiquitinated, followed by proteasomal degradation. This antiviral activity is counteracted by the viral PB1 polymerase protein, which binds close to the PARP domain and causes PB2 and PA to dissociate from ZAPL and escape degradation, explaining why ZAPL only moderately inhibits influenza A virus replication. Hence influenza A virus has partially won the battle against this newly identified ZAPL antiviral activity. Eliminating PB1 binding to ZAPL would be expected to substantially increase the inhibition of influenza A virus replication, so that the PB1 interface with ZAPL is a potential target for antiviral development. PMID- 26504239 TI - The incidence and role of negative citations in science. AB - Citations to previous literature are extensively used to measure the quality and diffusion of knowledge. However, we know little about the different ways in which a study can be cited; in particular, are papers cited to point out their merits or their flaws? We elaborated a methodology to characterize "negative" citations using bibliometric data and natural language processing. We found that negative citations concerned higher-quality papers, were focused on a study's findings rather than theories or methods, and originated from scholars who were closer to the authors of the focal paper in terms of discipline and social distance, but not geographically. Receiving a negative citation was also associated with a slightly faster decline in citations to the paper in the long run. PMID- 26504238 TI - Cortical entrainment to music and its modulation by expertise. AB - Recent studies establish that cortical oscillations track naturalistic speech in a remarkably faithful way. Here, we test whether such neural activity, particularly low-frequency (<8 Hz; delta-theta) oscillations, similarly entrain to music and whether experience modifies such a cortical phenomenon. Music of varying tempi was used to test entrainment at different rates. In three magnetoencephalography experiments, we recorded from nonmusicians, as well as musicians with varying years of experience. Recordings from nonmusicians demonstrate cortical entrainment that tracks musical stimuli over a typical range of tempi, but not at tempi below 1 note per second. Importantly, the observed entrainment correlates with performance on a concurrent pitch-related behavioral task. In contrast, the data from musicians show that entrainment is enhanced by years of musical training, at all presented tempi. This suggests a bidirectional relationship between behavior and cortical entrainment, a phenomenon that has not previously been reported. Additional analyses focus on responses in the beta range (~15-30 Hz)-often linked to delta activity in the context of temporal predictions. Our findings provide evidence that the role of beta in temporal predictions scales to the complex hierarchical rhythms in natural music and enhances processing of musical content. This study builds on important findings on brainstem plasticity and represents a compelling demonstration that cortical neural entrainment is tightly coupled to both musical training and task performance, further supporting a role for cortical oscillatory activity in music perception and cognition. PMID- 26504240 TI - Anatomy of funded research in science. AB - Seeking research funding is an essential part of academic life. Funded projects are primarily collaborative in nature through internal and external partnerships, but what role does funding play in the formulation of these partnerships? Here, by examining over 43,000 scientific projects funded over the past three decades by one of the major government research agencies in the world, we characterize how the funding landscape has changed and its impacts on the underlying collaboration networks across different scales. We observed rising inequality in the distribution of funding and that its effect was most noticeable at the institutional level--the leading universities diversified their collaborations and increasingly became the knowledge brokers in the collaboration network. Furthermore, it emerged that these leading universities formed a rich club (i.e., a cohesive core through their close ties) and this reliance among them seemed to be a determining factor for their research success, with the elites in the core overattracting resources but also rewarding in terms of both research breadth and depth. Our results reveal how collaboration networks organize in response to external driving forces, which can have major ramifications on future research strategy and government policy. PMID- 26504241 TI - Importance of codon usage for the temporal regulation of viral gene expression. AB - The glycoproteins of herpesviruses and of HIV/SIV are made late in the replication cycle and are derived from transcripts that use an unusual codon usage that is quite different from that of the host cell. Here we show that the actions of natural transinducers from these two different families of persistent viruses (Rev of SIV and ORF57 of the rhesus monkey rhadinovirus) are dependent on the nature of the skewed codon usage. In fact, the transinducibility of expression of these glycoproteins by Rev and by ORF57 can be flipped simply by changing the nature of the codon usage. Even expression of a luciferase reporter could be made Rev dependent or ORF57 dependent by distinctive changes to its codon usage. Our findings point to a new general principle in which different families of persisting viruses use a poor codon usage that is skewed in a distinctive way to temporally regulate late expression of structural gene products. PMID- 26504243 TI - Ancient low-molecular-weight organic acids in permafrost fuel rapid carbon dioxide production upon thaw. AB - Northern permafrost soils store a vast reservoir of carbon, nearly twice that of the present atmosphere. Current and projected climate warming threatens widespread thaw of these frozen, organic carbon (OC)-rich soils. Upon thaw, mobilized permafrost OC in dissolved and particulate forms can enter streams and rivers, which are important processors of OC and conduits for carbon dioxide (CO2) to the atmosphere. Here, we demonstrate that ancient dissolved organic carbon (DOC) leached from 35,800 y B.P. permafrost soils is rapidly mineralized to CO2. During 200-h experiments in a novel high-temporal-resolution bioreactor, DOC concentration decreased by an average of 53%, fueling a more than sevenfold increase in dissolved inorganic carbon (DIC) concentration. Eighty-seven percent of the DOC loss to microbial uptake was derived from the low-molecular-weight (LMW) organic acids acetate and butyrate. To our knowledge, our study is the first to directly quantify high CO2 production rates from permafrost-derived LMW DOC mineralization. The observed DOC loss rates are among the highest reported for permafrost carbon and demonstrate the potential importance of LMW DOC in driving the rapid metabolism of Pleistocene-age permafrost carbon upon thaw and the outgassing of CO2 to the atmosphere by soils and nearby inland waters. PMID- 26504242 TI - RNAIII of the Staphylococcus aureus agr system activates global regulator MgrA by stabilizing mRNA. AB - RNAIII, the effector of the agr quorum-sensing system, plays a key role in virulence gene regulation in Staphylococcus aureus, but how RNAIII transcriptionally regulates its downstream genes is not completely understood. Here, we show that RNAIII stabilizes mgrA mRNA, thereby increasing the production of MgrA, a global transcriptional regulator that affects the expression of many genes. The mgrA gene is transcribed from two promoters, P1 and P2, to produce two mRNA transcripts with long 5' UTR. Two adjacent regions of the mgrA mRNA UTR transcribed from the upstream P2 promoter, but not the P1 promoter, form a stable complex with two regions of RNAIII near the 5' and 3' ends. We further demonstrate that the interaction has several biological effects. We propose that MgrA can serve as an intermediary regulator through which agr exerts its regulatory function. PMID- 26504245 TI - Correction for Lavergne et al., Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks. PMID- 26504244 TI - SoxC transcription factors are essential for the development of the inner ear. AB - Hair cells, the mechanosensory receptors of the inner ear, underlie the senses of hearing and balance. Adult mammals cannot adequately replenish lost hair cells, whose loss often results in deafness or balance disorders. To determine the molecular basis of this deficiency, we investigated the development of a murine vestibular organ, the utricle. Here we show that two members of the SoxC family of transcription factors, Sox4 and Sox11, are down-regulated after the epoch of hair cell development. Conditional ablation of SoxC genes in vivo results in stunted sensory organs of the inner ear and loss of hair cells. Enhanced expression of SoxC genes in vitro conversely restores supporting cell proliferation and the production of new hair cells in adult sensory epithelia. These results imply that SoxC genes govern hair cell production and thus advance these genes as targets for the restoration of hearing and balance. PMID- 26504247 TI - Iodine-containing disinfectants in preparation for caesarean section: impact on thyroid profile in cord blood. AB - BACKGROUND: Iodine-containing disinfectants are widely used for skin preparation before caesarean section. Current evidence suggests that maternal exposure to these disinfectants results in thyroid dysfunction in the newborns, but its extent is not known. OBJECTIVES: The purpose of this study was to explain the quality of the effect of these disinfectants on the thyroid function of newborns. METHODS: This cohort study was performed on all the healthy mothers with a term pregnancy who underwent caesarean section in the obstetrics emergency department of an educational hospital affiliated with Tehran University of Medical Sciences from December 2013 to December 2014. We divided this 12-month period into two consecutive 6 months. Povidone-iodine 10% (PVP-I) and chlorhexidine gluconate 4% (CHX) were used in the first and second 6 months, respectively, for skin preparation before caesarean section and also for umbilical cord disinfection. Cord blood thyroid stimulating hormone (TSH) and thyroxine (T4) were assayed by the ELISA method. RESULTS: We included 326 cases in this study, 153 in the PVP-I group and 173 in the CHX group. The incidence of cord blood TSH >= 10 mIU/L and T4 <= 7.3 ug/dL was significantly higher in the PVP-I than the CHX group. Cord blood TSH concentration showed a significant positive correlation with cord blood T4 concentration in the CHX group. Through selection of cases with cord blood T4 < 13 ug/dL, we found a negative correlation between cord blood TSH and T4 concentration in the PVP-I group. CONCLUSIONS: It seems that PVP-I has the potential to cause false-positive screening-test results and increase recall rates, which should be evaluated in further studies. TRIAL REGISTRATION NUMBER: Iranian Registry of Clinical Trials (IRCT) number IRCT201204289568N1. PMID- 26504248 TI - Acute neurological visual loss in young adults: causes, diagnosis and management. AB - Visual loss in the young adult can be caused by demyelinating diseases, inflammatory and autoimmune processes, infections, ischaemic events, and compressive lesions of the optic nerve. Diagnosis of the aetiologies of visual loss is reached by combining data from radiological studies, electrophysiological tests, and blood and cerebrospinal fluid analysis. Treatment is primarily aimed at decreasing the insult on the optic nerve and eventually controlling the primary disorder. The literature discusses separately the different aetiologies of visual loss. We present a review of the clinical characteristics of visual loss in the young adult, the different diagnostic measures, and the latest therapeutic strategies. The aim of this work is to summarise this entity in a practical way to guide clinicians in the diagnosis and management of this disorder. PMID- 26504246 TI - Tether mutations that restore function and suppress pleiotropic phenotypes of the C. elegans isp-1(qm150) Rieske iron-sulfur protein. AB - Mitochondria play an important role in numerous diseases as well as normative aging. Severe reduction in mitochondrial function contributes to childhood disorders such as Leigh Syndrome, whereas mild disruption can extend the lifespan of model organisms. The Caenorhabditis elegans isp-1 gene encodes the Rieske iron sulfur protein subunit of cytochrome c oxidoreductase (complex III of the electron transport chain). The partial loss of function allele, isp-1(qm150), leads to several pleiotropic phenotypes. To better understand the molecular mechanisms of ISP-1 function, we sought to identify genetic suppressors of the delayed development of isp-1(qm150) animals. Here we report a series of intragenic suppressors, all located within a highly conserved six amino acid tether region of ISP-1. These intragenic mutations suppress all of the evaluated isp-1(qm150) phenotypes, including developmental rate, pharyngeal pumping rate, brood size, body movement, activation of the mitochondrial unfolded protein response reporter, CO2 production, mitochondrial oxidative phosphorylation, and lifespan extension. Furthermore, analogous mutations show a similar effect when engineered into the budding yeast Rieske iron-sulfur protein Rip1, revealing remarkable conservation of the structure-function relationship of these residues across highly divergent species. The focus on a single subunit as causal both in generation and in suppression of diverse pleiotropic phenotypes points to a common underlying molecular mechanism, for which we propose a "spring-loaded" model. These observations provide insights into how gating and control processes influence the function of ISP-1 in mediating pleiotropic phenotypes including developmental rate, movement, sensitivity to stress, and longevity. PMID- 26504249 TI - Enzymes: principles and biotechnological applications. AB - Enzymes are biological catalysts (also known as biocatalysts) that speed up biochemical reactions in living organisms, and which can be extracted from cells and then used to catalyse a wide range of commercially important processes. This chapter covers the basic principles of enzymology, such as classification, structure, kinetics and inhibition, and also provides an overview of industrial applications. In addition, techniques for the purification of enzymes are discussed. PMID- 26504250 TI - Biological membranes. AB - Biological membranes allow life as we know it to exist. They form cells and enable separation between the inside and outside of an organism, controlling by means of their selective permeability which substances enter and leave. By allowing gradients of ions to be created across them, membranes also enable living organisms to generate energy. In addition, they control the flow of messages between cells by sending, receiving and processing information in the form of chemical and electrical signals. This essay summarizes the structure and function of membranes and the proteins within them, and describes their role in trafficking and transport, and their involvement in health and disease. Techniques for studying membranes are also discussed. PMID- 26504251 TI - Synthesis of F-18 labeled resazurin by direct electrophilic fluorination. AB - We present the synthesis and characterization of F18-labeled fluorinated derivatives of resazurin, a probe for cell viability. The compounds were prepared by direct fluorination of resazurin with diluted [F18]-F2 gas under acidic conditions. The fluorination occurs into the ortho-positions to the hydroxyl group producing various mono-, di-, and trifluorinated derivatives. The properties of the fluorinated resazurins are similar to the parent compound with the addition of fluorine leading to decreased pKa values and a bathochromic shift of the absorption maxima. The fluorinated resazurin derivatives can be used as probes for observation of cell viability in various cells, tissues and organs using a combination of positron emission tomography and direct optical imaging of Cerenkov luminescence. PMID- 26504252 TI - Biodiversity of Klebsormidium (streptophyta) from alpine biological soil crusts (alps, tyrol, Austria, and Italy). AB - Forty Klebsormidium strains isolated from soil crusts of mountain regions (Alps, 600-3,000 m elevation) were analyzed. The molecular phylogeny (internal transcribed spacer rDNA sequences) showed that these strains belong to clades B/C, D, E, and F. Seven main (K. flaccidum, K. elegans, K. crenulatum, K. dissectum, K. nitens, K. subtile, and K. fluitans) and four transitional morphotypes (K. cf. flaccidum, K. cf. nitens, K. cf. subtile, and K. cf. fluitans) were identified. Most strains belong to clade E, which includes isolates that prefer humid conditions. One representative of the xerophytic lineage (clade F) as well as few isolates characteristic of temperate conditions (clades B/C, D) were found. Most strains of clade E were isolated from low/middle elevations (<1,800 m above sea level; a.s.l.) in the pine-forest zone. Strains of clades B/C, D, and F occurred sporadically at higher elevations (1,548-2,843 m a.s.l.), mostly under xerophytic conditions of alpine meadows. Comparison of the alpine Klebsormidium assemblage with data from other biogeographic regions indicated similarity with soil crusts/biofilms from terrestrial habitats in mixed forest in Western Europe, North America, and Asia, as well as walls of buildings in Western European cities. The alpine assemblage differed substantially from crusts from granite outcrops and sand dunes in Eastern Europe (Ukraine), and fundamentally from soil crusts in South African drylands. Epitypification of the known species K. flaccidum, K. crenulatum, K. subtile, K. nitens, K. dissectum, K. fluitans, K. mucosum, and K. elegans is proposed to establish taxonomic names and type material as an aid for practical studies on these algae, as well as for unambiguous identification of alpine strains. New combination Klebsormidium subtile (Kutzing) Mikhailyuk, Glaser, Holzinger et Karsten comb. nov. is made. PMID- 26504254 TI - Policy Development: A Key Factor in Promoting PTD. PMID- 26504253 TI - Foreign-Born Status and Geographic Patterns of Tuberculosis Genotypes in Tarrant County, Texas. AB - Regardless of destination, immigrants arrive with health profiles typical of people in their previous surroundings. Thus, immigrants change the epidemiological profile of destination communities, and immigrant neighborhoods may represent islands of infectious disease. Genotyping has emerged as a useful surveillance tool to track the spread of disease at the molecular level. Yet the spatial distribution of infectious disease at the molecular level associated with migration and immigrant neighborhoods has received little attention. Using molecular genotyping to characterize M. tuberculosis isolated from tuberculosis cases, this article analyzes spatial variations of unique molecular M. tuberculosis strains by zip code in Tarrant County, Texas. The results suggest that immigrant neighborhoods have higher rates of unique isolates of tuberculosis (suggestive of remote transmission) compared to neighborhoods occupied by the native-born. Neighborhoods dominated by the native-born have higher rates of clustered isolates (suggestive of recent transmission). Therefore, in addition to being culturally distinct, immigrant neighborhoods may also be pathogenically distinct from surrounding neighborhoods. PMID- 26504255 TI - Inference with interference between units in an fMRI experiment of motor inhibition. AB - An experimental unit is an opportunity to randomly apply or withhold a treatment. There is interference between units if the application of the treatment to one unit may also affect other units. In cognitive neuroscience, a common form of experiment presents a sequence of stimuli or requests for cognitive activity at random to each experimental subject and measures biological aspects of brain activity that follow these requests. Each subject is then many experimental units, and interference between units within an experimental subject is likely, in part because the stimuli follow one another quickly and in part because human subjects learn or become experienced or primed or bored as the experiment proceeds. We use a recent fMRI experiment concerned with the inhibition of motor activity to illustrate and further develop recently proposed methodology for inference in the presence of interference. A simulation evaluates the power of competing procedures. PMID- 26504256 TI - Heterogeneous Households A within-subject test of asymmetric information between spouses in Kenya. AB - To identify which spouses respond to asymmetric information, I play two dictator games with each member of the couple. One decision is kept secret from the respondent's spouse, while another choice is public. Most people give the same amount in public and secret, while a minority behave opportunistically and give more to their spouse in public and less in secret. The types identified in the lab also behave differently at home. For those who behave opportunistically in the lab, greater knowledge about finances at home is associated with worse opportunism in the lab, suggesting that for these couples complete information at home is not due to trust but rather is an endogenous response to non-cooperative behavior. The paper highlights that allowing for heterogeneous types changes the conclusions we draw about appropriate models of the household and suggests that laboratory games can be used to identify household types useful in the interpretation of field data. PMID- 26504257 TI - Race-Ethnic Differences in the Non-marital Fertility Rates in 2006-2010. AB - Research in the 1980s pointed to the lower marriage rates of blacks as an important factor contributing to race differences in non-marital fertility. Our analyses update and extend this prior work to investigate whether cohabitation has become an important contributor to this variation. We use data from the 2006 2010 National Survey of Family Growth (NSFG) and to identify the relative contribution of population composition (i.e. percent sexually active single and percent cohabiting) versus rates (pregnancy rates, post-conception marriage rates) to race-ethnic variation in non-marital fertility rates (N=7,428). We find that the pregnancy rate among single (not cohabiting) women is the biggest contributor to race-ethnic variation in the non-marital fertility rate and that contraceptive use patterns among racial minorities explains the majority of the race-ethnic differences in pregnancy rates. PMID- 26504258 TI - Insecticide Transfer Efficiency and Lethal Load in Argentine Ants. AB - Trophallaxis between individual worker ants and the toxicant load in dead and live Argentine ants (Linepithema humile) in colonies exposed to fipronil and hydramethylnon experimental baits were examined using accelerator mass spectrometry (AMS). About 50% of the content of the crop containing trace levels of 14C-sucrose, 14C-hydramethylnon, and 14C-fipronil was shared between single donor and recipient ants. Dead workers and queens contained significantly more hydramethylnon (122.7 and 22.4 amol/MUg ant, respectively) than did live workers and queens (96.3 and 10.4 amol/MUg ant, respectively). Dead workers had significantly more fipronil (420.3 amol/MUg ant) than did live workers (208.5 amol/MUg ant), but dead and live queens had equal fipronil levels (59.5 and 54.3 amol/MUg ant, respectively). The distribution of fipronil differed within the bodies of dead and live queens; the highest amounts of fipronil were recovered in the thorax of dead queens whereas live queens had the highest levels in the head. Resurgence of polygynous ant colonies treated with hydramethylnon baits may be explained by queen survival resulting from sublethal doses due to a slowing of trophallaxis throughout the colony. Bait strategies and dose levels for controlling insect pests need to be based on the specific toxicant properties and trophic strategies for targeting the entire colony. PMID- 26504259 TI - Building an evidence-base for the training of evidence-based treatments in community settings: Use of an expert-informed approach. AB - In order to make EBTs available to a large number of children and families, developers and expert therapists have used their experience and expertise to train community-based therapists in EBTs. Understanding current training practices of treatment experts may be one method for establishing best practices for training community-based therapists prior to comprehensive empirical examinations of training practices. A qualitative study was conducted using surveys and phone interviews to identify the specific procedures used by treatment experts to train and implement an evidence-based treatment in community settings. Twenty-three doctoral-level, clinical psychologists were identified to participate because of their expertise in conducting and training Parent-Child Interaction Therapy. Semi-structured qualitative interviews were completed by phone, later transcribed verbatim, and analyzed using thematic coding. The de identified data were coded by two independent qualitative data researchers and then compared for consistency of interpretation. The themes that emerged following the final coding were used to construct a training protocol to be empirically tested. The goal of this paper is to not only understand the current state of training practices for training therapists in a particular EBT, Parent Child Interaction Therapy, but to illustrate the use of expert opinion as the best available evidence in preparation for empirical evaluation. PMID- 26504260 TI - Impaired Fasting Glucose in Nondiabetic Range: Is It a Marker of Cardiovascular Risk Factor Clustering? AB - BACKGROUND: Impaired fasting glucose (IFG) through the nondiabetic range (100-125 mg/dL) is not considered in the cardiovascular (CV) risk profile. AIM: To compare the clustering of CV risk factors (RFs) in nondiabetic subjects with normal fasting glucose (NFG) and IFG. MATERIAL AND METHODS: Cross-sectional study in 3739 nondiabetic subjects. Demographics, medical history, and CV risk factors were collected and lipid profile, fasting glucose levels (FBG), C-reactive protein (hsCRP), blood pressure (BP), anthropometric measurements, and aerobic capacity were determined. RESULTS: 559 (15%) subjects had IFG: they had a higher mean age, BMI, waist circumference, non-HDL cholesterol, BP, and hsCRP (p < 0.0001) and lower HDL (p < 0.001) and aerobic capacity (p < 0.001). They also had a higher prevalence of hypertension (34% versus 25%; p < 0.001), dyslipidemia (79% versus 74%; p < 0.001), and obesity (29% versus 16%; p < 0.001) and a higher Framingham risk score (8% versus 6%; p < 0.001). The probability of presenting 3 or more CV RFs adjusted by age and gender was significantly higher in the top quintile of fasting glucose (>=98 mg/dL; OR = 2.02; 1.62-2.51). CONCLUSIONS: IFG in the nondiabetic range is associated with increased cardiovascular RF clustering. PMID- 26504262 TI - Race, Ethnicity, and the Changing Context of Childbearing in the United States. AB - In what ways do childbearing patterns in the contemporary United States vary for white, black, and Hispanic women? Why do these differences exist? Although completed family size is currently similar for white and black women, and only modestly larger for Hispanic women, we highlight persistent differences across groups with respect to the timing of childbearing, the relationship context of childbearing, and the extent to which births are intended. We next evaluate key explanations for these differences. Guided by a "proximate determinants" approach, we focus here on patterns of sexual activity, contraceptive use, and post-conception outcomes such as abortion and changes in mothers' relationship status. We find contraceptive use to be a particularly important contributor to racial and ethnic differences in childbearing, yet reasons for varying use of contraception itself remain insufficiently understood. We end by reflecting on promising directions for further research. PMID- 26504261 TI - Ehlers-Danlos Syndrome, Hypermobility Type, Is Linked to Chromosome 8p22-8p21.1 in an Extended Belgian Family. AB - Joint hypermobility is a common, mostly benign, finding in the general population. In a subset of individuals, however, it causes a range of clinical problems, mainly affecting the musculoskeletal system. Joint hypermobility often appears as a familial trait and is shared by several heritable connective tissue disorders, including the hypermobility subtype of the Ehlers-Danlos syndrome (EDS HT) or benign joint hypermobility syndrome (BJHS). These hereditary conditions provide unique models for the study of the genetic basis of joint hypermobility. Nevertheless, these studies are largely hampered by the great variability in clinical presentation and the often vague mode of inheritance in many families. Here, we performed a genome-wide linkage scan in a unique three-generation family with an autosomal dominant EDS-HT phenotype and identified a linkage interval on chromosome 8p22-8p21.1, with a maximum two-point LOD score of 4.73. Subsequent whole exome sequencing revealed the presence of a unique missense variant in the LZTS1 gene, located within the candidate region. Subsequent analysis of 230 EDS HT/BJHS patients resulted in the identification of three additional rare variants. This is the first reported genome-wide linkage analysis in an EDS-HT family, thereby providing an opportunity to identify a new disease gene for this condition. PMID- 26504263 TI - Cultural Mechanisms in Neighborhood Effects Research in the United States. AB - This paper discusses the current state of the U.S. literature on cultural mechanisms in neighborhood effects research. We first define what we mean by neighborhood effects and by cultural mechanisms. We then review and critique two theoretical perspectives on the cultural context of disadvantaged neighborhoods that are explicitly integrated into recent neighborhood effects literature in the U.S.: "deviant subculture" and "cultural heterogeneity." We then draw on other related U.S. literatures from urban studies, cultural sociology, and culture and inequality to suggest some other conceptualizations that may be useful in advancing our understanding of the role of culture in neighborhood effects. We discuss the conceptual and methodological issues that will have to be grappled with in order to move this literature forward and conclude by offering concrete suggestions, both short-term and long-term, for a research agenda. PMID- 26504264 TI - Minimally invasive surgical techniques in the management of differentiated thyroid cancer. AB - Thyroid cancer is the fifth most common cancer in women with approximately 60,220 expected new cases in the United States in 2013, and the incidence continues to increase each year. Fortunately, the majority are well-differentiated thyroid cancers with excellent overall prognosis. Controversy persists regarding the optimal surgical management of differentiated thyroid cancer in terms of the extent of thyroid resection (thyroid lobectomy vs total thyroidectomy) and the utility of prophylactic central neck dissection (pCND) in low-risk PTC, and papillary thyroid microcarcinoma (PTMC, defined as <10 mm). Thyroid surgical approaches have progressed from the Kocher open incision to minimally invasive techniques that include endoscopic and robotic thyroidectomy. Overall, these minimally invasive techniques have been shown to be safe, and appear to be associated with improved cosmesis and decreased pain compared to open thyroidectomy. PMID- 26504265 TI - A survey of big data research. AB - Big data create values for business and research, but pose significant challenges in terms of networking, storage, management, analytics and ethics. Multidisciplinary collaborations from engineers, computer scientists, statisticians and social scientists are needed to tackle, discover and understand big data. This survey presents an overview of big data initiatives, technologies and research in industries and academia, and discusses challenges and potential solutions. PMID- 26504266 TI - The role of compensatory movements patterns in spontaneous recovery after stroke. AB - [Purpose] Post-stroke motor recovery consists of both true recovery and compensatory movements. Although compensatory movements are learned more quickly early after stroke, the role of compensatory movement patterns in functional recovery is controversial. We investigated the role of compensatory movement patterns in the long-term functional motor recovery after stroke. [Subjects and Methods] Male Wistar rats were subjected to photothrombotic infarction to induce motor and sensorimotor cortex lesions. The rats were given task-specific training. Behavior tests and analyses of compensatory movement patterns (head lift, limb withdrawal impairment, phantom grasps, and pellet chasing) during the single-pellet reaching test were performed 2, 7, 14, 21, 28, and 35 days post stroke. [Results] Successful retrieval during the single-pellet reaching test was significantly correlated with compensatory movement patterns in stroke groups. Motor cortex stroke showed significant correlation in limb withdrawal impairment and pellet chasing. But, sensorimotor cortex stroke was significant correlation in pellet chasing. [Conclusion] The data suggest that compensatory movements after stroke are correlated with spontaneous recovery. Since some compensatory movement patterns are detrimental to functional recovery, the correct timing of training and control of compensatory movement patterns might be important. PMID- 26504267 TI - Electromyography of symmetrical trunk movements and trunk position sense in chronic stroke patients. AB - [Purpose] To explore the differences in bilateral trunk muscle activation between chronic stroke patients and healthy controls, this study investigated the symmetry index and cross-correlation of trunk muscles during trunk flexion and extension movements. This study also assessed the differences in trunk reposition error between groups and the association between trunk reposition error and bilateral trunk muscle activation. [Subjects and Methods] Fifteen stroke patients and 15 age- and gender-matched healthy subjects participated. Bilateral trunk muscle activations were collected by electromyography during trunk flexion and extension. Trunk reposition errors in trunk flexion and extension directions were recorded by a Qualisys motion capture system. [Results] Compared with the healthy controls, the stroke patients presented lower symmetrical muscle activation of the bilateral internal oblique and lower cross-correlation of abdominal muscles during trunk flexion, and lower symmetry index and cross-correlation of erector spinae in trunk extension. They also showed a larger trunk extension reposition error. A smaller trunk reposition error was associated with higher cross correlation of bilateral trunk muscles during trunk movements in all subjects. [Conclusion] Trunk muscle function during symmetrical trunk movements and trunk reposition sense were impaired in the chronic stroke patients, and trunk position sense was associated with trunk muscle functions. Future studies should pay attention to symmetrical trunk movements as well as trunk extension position sense for patients with chronic stroke. PMID- 26504268 TI - Study on changes in skin extensibility during the development of joint contracture due to joint immobilization in rats. AB - [Purpose] The purpose of this study was to elucidate whether skin extensibility decreases when a contracture develops as a result of joint immobilization. [Subjects] This study was conducted on six female Wistar rats. [Methods] The rats were divided into two experimental groups. In the immobilized group, the right ankle joints were immobilized in complete plantar flexion by plaster casts for two weeks. In the control group, the left ankle joints had no intervention. On the final day, skin extensibility was determined from a length-tension curve by collecting skin from the posterior aspect of the ankle joint and using a tensile strength tester. [Results] Compared with the control group, the immobilized group showed a significant decrease in skin extensibility. [Conclusion] The results demonstrated that the extensibility of the skin itself decreases when joint contracture develops. PMID- 26504269 TI - Correlation between basic physical fitness and pulmonary function in Korean children and adolescents: a cross-sectional survey. AB - [Purpose] The purpose of the present study was to determine whether there was a correlation between basic physical fitness and pulmonary function in Korean school students, to present an alternative method for improving their pulmonary function. [Subjects and Methods] Two hundred forty healthy students aged 6-17 years performed physical fitness tests of hand-grip strength, sit and reach, Sargent jump, single leg stance, and pulmonary function tests of forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) using a Quark PFT. [Results] Muscle strength and power of boys improved in the late period of elementary school and middle school. Muscle strength of girls improved in the late period of elementary school. Analysis of factors affecting pulmonary function revealed that height, weight, BMI, and body fat significantly correlated with spirometric parameters. Right hand-grip strength, left hand-grip strength, and Sargent jump also significantly correlated with FVC and FEV1. [Conclusion] In order to improve the pulmonary function of children and adolescents, aerobic exercise and an exercise program to increase muscle strength and power is needed, and it should start in the late period of elementary school when muscle strength and power are rapidly increasing. PMID- 26504270 TI - Effects of 4 weeks preoperative exercise on knee extensor strength after anterior cruciate ligament reconstruction. AB - [Purpose] After an anterior cruciate ligament injury and subsequent reconstruction, quadriceps muscle weakness and disruption of proprioceptive function are common. The purpose of this study was to examine the effects of a 4 weeks preoperative exercise intervention on knee strength power and function post surgery. [Subjects and Methods] Eighty male patients (27.8+/-5.7 age), scheduled for reconstruction surgery, were randomly assigned to two groups, the preoperative exercise group (n=40) and a no preoperative exercise group (n=40). The preoperative exercise group participated in a 4-week preoperative and 12-week post-operative programs, while the no preoperative exercise group participated only in the 12-week postoperative exercise program. Isokinetic measured of quadriceps strength were obtained at 4 weeks before and 3 months after surgery. [Results] The knee extensor strength deficits measured at 60 degrees /s and 180 degrees /s was significantly lower in the preoperative exercise group compared with the no preoperative exercise group. At 3 months after surgery, the extensor strength deficit was 28.5+/-9.0% at 60 degrees /sec and 23.3+/-9.0% at 180 degrees /sec in the preoperative exercise group, whereas the no preoperative exercise group showed extensor strength deficits of 36.5+/-10.7% and 27.9+/-12.6% at 60 degrees /sec and 180 degrees /sec, respectively. The preoperative exercise group demonstrated significant improvement the single-leg hop distance. [Conclusion] Four week preoperative exercise may produce many positive effects post reconstruction surgery, including faster recovery of knee extensor strength and function, as measured by single-leg hop ability. PMID- 26504271 TI - Relationships between presynaptic inhibition and static postural sway in subjects with and without diabetic neuropathy. AB - [Purpose] Diabetic peripheral neuropathy can often lead to balance impairment. The spinal reflex is a mechanism that is reportedly important for balance, but it has not been investigated in diabetic peripheral neuropathy patients. Moreover, inhibitory or facilitatory behavior of the spinal reflex-known as presynaptic inhibition-is essential for controlling postural sway. The purpose of this study was to compare the differences in as presynaptic inhibition and balance in subjects with and without diabetic peripheral neuropathy to determine the influence of presynaptic inhibition on balance in diabetic peripheral neuropathy patients. [Subjects and Methods] Presynaptic inhibition and postural sway were tested in eight patients (mean age, 58+/-6 years) and eight normal subjects (mean age, 59+/-7 years). The mean percent difference in conditioned reflex amplitude relative to the unconditioned reflex amplitude was assessed to calculate as presynaptic inhibition. The single-leg balance index was measured using a computerized balance-measuring device. [Results] The diabetic peripheral neuropathy group showed lower presynaptic inhibition (47+/-30% vs. 75+/-22%) and decreased balance (0.65+/-0.24 vs. 0.38+/-0.06) as compared with the normal group. No significant correlation was found between as presynaptic inhibition and balance score (R=0.37). [Conclusion] Although the decreased as presynaptic inhibition observed in diabetic peripheral neuropathy patients may suggest central nervous system involvement, further research is necessary to explore the role of presynaptic inhibition in decreased balance in diabetic peripheral neuropathy patients. PMID- 26504272 TI - Clarification of functional differences between the hallux and lesser toes during the single leg stance: immediate effects of conditioning contraction of the toe plantar flexion muscles. AB - [Purpose] The purpose of this study was to determine the functional differences of the plantar flexion muscles of the hallux and lesser toes during the single leg stance by comparing postural sway in different conditioning contraction interventions. [Subjects] Thirty-four healthy, young males and females participated in this study. [Methods] The front-back and right-left direction components of maximal displacement and postural sway velocity during the single leg stance were measured in various conditioning contraction interventions for the plantar flexion muscles of the hallux or lessor toes. [Results] The main findings of this study were as follows: 1) the front-back direction component of maximal displacement was reduced by conditioning contraction of the plantar flexion muscles of the hallux, and 2) the front-back direction component of the postural sway velocity was reduced by conditioning contraction of the plantar flexion muscles of the lesser toes during the single leg stance. [Conclusion] The plantar flexion muscles of the lesser toes control the postural sway velocity. Furthermore, the plantar flexion muscles of the hallux appear to control the amplitude of postural sway. PMID- 26504273 TI - Correlation of knee proprioception with muscle strength and spasticity in stroke patients. AB - [Purpose] The purpose of this study was to investigate the relationship of knee proprioception with muscle strength and spasticity in stroke patients. [Subjects and Methods] The subjects were 31 stroke patients. The subjects received an explanation of the procedures and methods and provided informed consent before the experiment. A measurement board was used to determine the the proprioception deficit of the knee as a proprioception test. The proprioception test consisted of a passive and active angle reproduction test. A manual muscle test and modified Ashworth scale were used to evaluate knee muscle strength and spasticity level. The data were analyzed using an independent t-test and Spearman correlation. [Results] The results of this study revealed a significant difference between the affected side and non-affected side in the passive angle reproduction test and a significant difference in the correlation of the proprioception level with muscle strength and spasticity level. [Conclusion] This study indicates that the knee proprioception level is associated with spasticity and muscle strength in stroke patients. PMID- 26504274 TI - The effects of bodyweight-based exercise with blood flow restriction on isokinetic knee muscular function and thigh circumference in college students. AB - [Purpose] The purpose of this study was to investigate the effects of bodyweight based exercise with blood flow restriction on isokinetic muscular function and thigh circumference in college students. [Subjects and Methods] The subjects were 17 college students who were recruited and randomly assigned to bodyweight-based exercise with blood flow restriction and bodyweight-based exercise groups. Participants performed front lunges and squats at ratings of perceived exertion of 11-13 three times a week during a 6-week training period. The peak torque/ body weight (%) of the knee flexor and extensor was measured using a HUMAC NORM System (Cybex 770-NORM((r)), Cybex International, Medway, MA, USA), and the circumference of the thigh was measured. PASW Statistics was used for data analysis. [Results] There were significant differences in the peak torque/ body weight (%) of the flexors in both thighs (at 180 degrees /sec) after bodyweight based exercise with blood flow restriction. In addition, the circumference changes in both thighs were significant after bodyweight-based exercise with blood flow restriction and between the two groups. [Conclusion] This study suggests that bodyweight-based exercise with blood flow restriction may be an effective method to improve the muscle power and hypertrophy of the lower extremity in a clinical setting. PMID- 26504276 TI - Comparison of trunk and hip muscle activity during different degrees of lumbar and hip extension. AB - [Purpose] This study compared the activity of trunk and hip muscles during different degrees of lumbar and hip extension. [Subjects] The study enrolled 18 participants. [Methods] Two exercises (hip and lumbar extension) and two ranges (180 degrees and <180 degrees ) were studied. [Results] Differences in degree of extension affected the percentage maximal voluntary isometric contraction of the lumbar erector spinae and biceps femoris muscles, with significantly higher average values at >180 degrees than at 180 degrees lumbar extension. No significant differences were found in gluteus maximus activity according to exercise type or range. [Conclusion] Hip extension may be more effective and safer for lumbar rehabilitation than lumbar extension. PMID- 26504275 TI - Maximal lateral reaching distance on the affected side using the multi directional reach test in persons with stroke. AB - [Purpose] This study aimed to examine the relationship between maximal lateral reaching distance on the affected side and weight shifting using the Multi directional Reach Test in persons with stoke. [Subjects] Fifty-one chronic stroke participants were recruited from two rehabilitation hospitals. This study administered the Berg Balance Scale, Timed Up-and-Go, Trunk Impairment Scale, Modified Barthel Index and measured different maximal reaching distances. [Results] The maximal lateral reaching distance on the affected side was correlated with the BBS (r=0.571), TUG (r=-0.478), TIS (r=0.561), and MBI scores (r=0.499), the lateral reaching distance in all directions on the non-affected side (r=0.785), the maximal backward reaching distance (r=0.723), and the maximal forward reaching distance (r=0.673). The maximal reaching distance on the affected side was also affected by that on the non-affected side, in addition to the maximal backward reaching distance and MBI score. The final step model of stepwise multiple regression was explained 69.5%. [Conclusion] Maximal lateral reaching distance on the affected side as determined by the Multi-directional Reach Test is a good method of assessing functional performance in stroke patients. Data regarding maximal reaching distance on the non-affected side can be used to measure functional impairment on the affected side in clinical settings. PMID- 26504277 TI - The effects of finger extension on shoulder muscle activity. AB - [Purpose] This study aims to examine the effects of the extension of the fingers (distal upper limb) on the activity of the shoulder muscles (proximal upper limb). [Subjects and Methods] This study involved 14 healthy male adults with no musculoskeletal disorder or pain related to the shoulders and hands. The subjects in a sitting posture abducted the angle of the shoulder joints at 60 degrees and had their palms in the front direction. Electromyography (EMG) was comparatively analyzed to look at the activities of the infraspinatus (IS) and rhomboid major (RM) when the fingers were extended and relaxed. [Results] The activity of the IS was statistically significantly higher when the fingers were extended than when they were relaxed. [Conclusion] According to the result of this study, finger extension is considered to affect the muscles for connected shoulder joint stability. PMID- 26504278 TI - Changes in cervical muscle activity according to the traction force of an air inflatable neck traction device. AB - [Purpose] The purpose of this study was to analyze cervical muscle activity at different traction forces of an air-inflatable neck traction device. [Subjects] Eighteen males participated in this study. [Methods] The subjects put on an air inflatable neck traction device and the traction forces administered were 40, 80, and 120 mmHg. The electromyography (EMG) signals of the splenius capitis, and upper trapezius were measured to assess the muscle activity. [Results] The muscle activity of the splenius capitis was significantly higher at 80, and 120 mmHg compared to 40 mmHg. The muscle activity of the upper trapezius did not show significant differences among the traction forces. [Conclusion] Our research result showed that the air-inflatable home neck traction device did not meet the condition of muscle relaxation. PMID- 26504279 TI - Differences in onset time between the vastus medialis and lateralis during stair stepping in individuals with genu varum or valgum. AB - [Purpose] We investigated the difference in onset time between the vastus medialis and lateralis according to knee alignment during stair ascent and descent to examine the effects of knee alignment on the quadriceps during stair stepping. [Subjects] Fifty-two adults (20 with genu varum, 12 with genu valgum, and 20 controls) were enrolled. Subjects with > 4 cm between the medial epicondyles of the knees were placed in the genu varum group, whereas subjects with > 4 cm between the medial malleolus of the ankle were placed in the genu valgum group. [Methods] Surface electromyography was used to measure the onset times of the vastus medialis and vastus lateralis during stair ascent and descent. [Results] The vastus lateralis showed more delayed firing than the vastus medialis in the genu varum group, whereas vastus medialis firing was more delayed than vastus lateralis firing in the genu valgum group. Significant differences in onset time were detected between stair ascent and descent in the genu varum and valgum groups. [Conclusion] Genu varum and valgum affect quadriceps firing during stair stepping. Therefore, selective rehabilitation training of the quadriceps femoris should be considered to prevent pain or knee malalignment deformities. PMID- 26504280 TI - The effects of horseback riding simulator exercises on the muscle activity of the lower extremities according to changes in arm posture. AB - [Purpose] This study aimed to determine the effects of horseback riding simulator exercise on the muscle activities of the lower extremities according to changes in arm posture. [Subjects] The subjects of this study were 30 normal adult males and females. [Methods] The horseback riding simulator exercise used a horseback riding simulator device; two arm postures were used, posture 1 (holding the handle of the device) and posture 2 (crossing both arms, with both hands on the shoulders). Electromyography was used to compare the muscle activities of the rectus femoris, biceps femoris, and hip adductors in the lower extremities. [Results] Posture 2 had significantly higher muscle activity than posture 1. [Conclusion] Posture 2, which entailed crossing both arms with both hands on the shoulders, was an effective intervention for improved muscle activity in the hip adductors. PMID- 26504281 TI - The intra- and inter-rater reliabilities of the Short Form Berg Balance Scale in institutionalized elderly people. AB - [Purpose] The purpose of this study was to examine the intra- and inter-rater reliabilities of the Short Form Berg Balance Scale in institutionalized elderly people. [Subjects and Methods] A total of 30 elderly people in a nursing facility in Y city, South Korea, participated in this study. Two examiners administered the Short Form Berg Balance Scale to one subject to investigate inter-rater reliability. After a week, the same examiners administered the Short Form Berg Balance Scale once more to investigate intra-rater reliability. [Results] The intra-rater reliability was 0.83. The inter-rater reliability was 0.79. Both reliabilities were high (more than 0.7). [Conclusion] The Short Form Berg Balance Scale is a version of the Berg Balance Scale shortened by reducing the number of items, but its reliabilities were not lower than those of the Berg Balance Scale. The Short Form Berg Balance Scale can be useful clinically due to its short measurement time. PMID- 26504282 TI - Effects of spaced retrieval training with errorless learning in the rehabilitation of patients with dementia. AB - [Purpose] Among the non-pharmacological interventions for dementia, spaced retrieval training (SRT) is a good method for rehabilitating cognition. The purpose of this study was to examine effects of SRT with errorless learning (EL) in the rehabilitation of patients with dementia. [Subjects and Methods] Twenty nine participants with vascular dementia (VD) and Alzheimer's disease (AD) participated in the present study. The Korean version of the Consortium to Establish a Registry for Alzheimer's disease (CERAD-K) and Modified Barthel Index (MBI) were performed to assess the changes in the neuropsychological performance and the independent activities of daily living after SRT with EL. All tests were administered both before and after SRT with EL. Each SRT with EL intervention was performed for 30 minutes per day for 5 weeks. SPSS for Windows version 18.0 was used for statistical analysis. [Results] All items of the CERAD-K score of the VD group except for constructional praxis increased significantly after the SRT with EL intervention, but no significant differences from the AD group were found. The Korean version of the geriatric depression scale (GDS-K) of the VD group increased significantly after the SRT with EL intervention. The mean MBI scores of each group showed no significant difference after the intervention. [Conclusion] SRT with EL is an effective intervention for memory training of patients with dementia. Future research using sufficient sample sizes will be needed to obtain strong evidence for comparing not only the before and after intervention data but also between the groups. PMID- 26504283 TI - The influence of horseback riding training on the physical function and psychological problems of stroke patients. AB - [Purpose] The purpose of this study was to determine the influence of horseback riding training on the physical function and psychological problems of stroke patients. [Subjects and Methods] Thirty stroke patients were divided evenly into an experimental group and a control group. Both groups carried out neurodevelopmental treatment. The experimental group additionally performed mechanical horseback riding training for 30 minutes a day, 5 days a week, for 6 weeks. Physical function was evaluated using the Berg Balance Scale (BBS) and the Timed Up and Go Test (TUGT). Psychological problems were assessed using the Beck Depression Inventory (BDI). In order to compare differences within groups between before and after the experiment, the paired t test was conducted. In order to compare differences between groups before and after the experiment, the independent t test was conducted. [Results] In the experimental group, the BBS, TUGT, and BDI showed significant improvements after the intervention. The experimental group's BBS, TUGT, and BDI post-intervention changes were significantly better than those observed in the control group. [Conclusion] According to our results, horseback riding training has a positive effect on the physical function and psychological problems of stroke patients. PMID- 26504284 TI - Effect of complete decongestive therapy and a home program for patients with post mastectomy lymphedema. AB - [Purpose] Post mastectomy lymphedema is common among breast cancer survivors. It leads to physical discomfort and functional impairment. Rehabilitation forms the mainstay of treatment and is multidisciplinary. [Subjects and Methods] Sixty post mastectomy patients were allocated randomly and assigned to either a conventional treatment group (n=30) or a complete decongestive therapy (CDT) group (n=30). The conventional treatment group received manual lymphatic drainage, wore a low elastic compression garment, received glenohumeral mobilization, and performed deep breathing exercises, and the complete decongestive therapy group received CDT from a trained physiotherapist and a daily home program along with the conventional treatment, 5 days a week for 6 weeks. [Results] Arm circumference measurements were taken at five levels: the wrist, mid forearm, elbow, mid-upper arm, and axilla. The upper extremity function was evaluated using the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, and pain was assessed using the visual analogue scale. Measurements were taken at baseline, and at 4th and 6th weeks after the start of intervention. Within and between group comparisons showed significant improvements in the CDT group. [Conclusion] Complete decongestive therapy and a home program assists breast cancer related lymphedema survivors in regaining their lost functions. It also helps to improve their independence in daily activities, reduce their need for caregivers, and thereby improving their quality of life. Therefore, the results of this study showed that the CDT with a home program is an effective treatment for reducing post mastectomy lymphedema. PMID- 26504285 TI - The effects of prone bridge exercise on the Oswestry disability index and proprioception of patients with chronic low back pain. AB - [Purpose] The purpose of this study was to investigate the effect of bridge exercises on the Oswestry disability index (ODI) scores and proprioception among patients with chronic low back pain (CLBP). [Subjects and Methods] A total of 38 patients participated in this study. After eight weeks of bridge exercise, the joint position angle of the body trunk was measured and the ODI was used in survey form to investigate the intensity of the patients' low back pain. [Results] After eight weeks of exercise, the ODI showed significant differences in all three groups. Subjects' joint position sense of the trunk in both lumbar flexion and extension was also significantly different after completing the exercise program; this was true for all three groups. [Conclusion] Performing the prone bridge exercise for eight weeks improved proprioceptive function and reduced pain and impediment of activity, showing it a more effective exercise than other bridge exercises. PMID- 26504286 TI - Effects of exercise intensity on hypertension prevalence in Korean men with high sodium intake. AB - [Purpose] The purpose of present study was to investigate the effects of exercise intensity on hypertension prevalence in Korean men with high sodium intake. [Subjects and Methods] This study was based on the data collected from 2007 to 2013 in the Korean National Health and Nutritional Examination Survey. A total of 8853 male adults were included in the analysis. The odds ratios for hypertension according to exercise groups were assessed by using logistic regression of each sodium intake group. [Results] Among the 8853 subjects, 6243 had an eating habit of 4000 mg or more sodium consumption per day, and 2619 had less than 4000 mg. Among the 2619 subjects with less than 4000 mg sodium consumption, 16.7% subjects were diagnosed as having hypertension. In the subjects with 4000 mg or more sodium consumption, compared to the no-exercise group, the moderate-exercise group showed a lower likelihood of developing hypertension, with an odds ratio of 0.63 (95% confidence interval, 0.47-0.85) after adjusting for age. In multivariate models 1 and 2, odds ratios for the likelihood of developing hypertension in the moderate-exercise group decreased to 0.63 (0.43-0.91) and 0.66 (0.45-0.96), respectively. [Conclusion] Moderate exercise is significantly associated with a lower likelihood of developing hypertension in cases of high sodium intake. PMID- 26504287 TI - Effect of combination of transcranial direct current stimulation and feedback training on visuospatial neglect in patients with subacute stroke: a pilot randomized controlled trial. AB - [Purpose] To investigate the effects of a combination of transcranial direct current stimulation (tDCS) and feedback training (FT) on subacute stroke patients with unilateral visuospatial neglect. [Subjects] The subjects were randomly assigned to a tDCS + FT group (n=6) and a FT group (n=6). [Methods] Patients in the tDCS + FT group received tDCS for 20 minutes and then received FT for 30 minutes a day, 5 days a week for 3 weeks. The control group received FT for 30 minutes a day, 5 days a week for 3 weeks. [Results] After the intervention, both groups showed significant improvements in the Motor-Free Visual Perception Test (MVPT), line bisection test (LBT), and modified Barthel index (MBI) over the baseline results. The comparison of the two groups after the intervention revealed that the rDCS + FT group showed more significant improvements in MVPT, LBT, and MBI. [Conclusion] The results of this study suggest that tDCS combined with FT has a positive effect on unilateral visuospatial neglect in patients with subacute stroke. PMID- 26504288 TI - Effects of complex manual therapy on PTSD, pain, function, and balance of male torture survivors with chronic low back pain. AB - [Purpose] This study aimed to identify the impact of physiotherapy using complex manual therapy as a part of an integrated treatment for sequelae in the musculoskeletal system of torture survivors. [Subjects] This study reviewed 30 male torture survivors presenting with chronic low back pain. They were randomly selected and divided into two groups: an experimental group and a control group. [Methods] For the experimental group, complex manual therapy was performed twice a week for 8 weeks to improve the physical sequelae of patients. Improvement was measured using the PDS-K for Post-traumatic Stress Disorder (PTSD), the Visual Analog Scale (VAS) for pain examination, the Korean Oswestry Disability Index (KODI) for back function assessment, and the Balance System SD as a dynamic balance test. The total period of the intervention for both groups was 8 weeks. [Results] For the experimental group, PDS-K, VAS, KODI, and the dynamic balance test all showed significant improvements after the intervention, which they did not for the control group. In the comparison of the groups, PDS-K, VAS, KODI, and the dynamic balance test all showed significant differences. [Conclusion] Complex manual therapy for torture survivors with chronic low back pain contributes to functional recovery by reducing back pain. The treatment can be considered to have positive effects on sequelae in the musculoskeletal system of torture survivors as they age. PMID- 26504289 TI - Effects of neuromuscular electrical stimulation on masticatory muscles in elderly stroke patients. AB - [Purpose] This study aimed to examine the effects of neuromuscular electrical stimulation on masticatory muscle activation in elderly stroke patients. [Subjects and Methods] The subjects included 20 elderly patients diagnosed with stroke and 10 healthy elderly individuals. The neuromuscular electrical stimulation group received stimulation on the masseter muscle in the affected side for 30 min each day, 3 times per week for 8 weeks. In all the subjects, surface electromyography was used to measure activity of the masseter and temporal muscles in both sides under resting and clenching conditions. [Results] In the neuromuscular electrical stimulation group, after the intervention, an increase in the activity of all of the masticatory muscles was observed during clenching, with a significant increase in the activity of the masseter muscle in the affected side. Significant differences between the groups were not observed after the interventions. [Conclusion] The results of this study suggest that application of neuromuscular electrical stimulation effectively improves muscle activity in elderly stroke patients during clenching, and that this technique can be applied particularly for the improvement of the clenching activity of the masseter muscle in the affected side. PMID- 26504290 TI - Effects of two different intensities of transcutaneous electrical nerve stimulation on pain thresholds of contralateral muscles in healthy subjects. AB - [Purpose] This study aimed to investigate the differential effects of high intensity and low-intensity transcutaneous electrical nerve stimulation on the contralateral side on the pain threshold in healthy subjects. [Subjects and Methods] Twenty-five healthy adults, volunteers received two intensity levels (motor-level, 1.5 times the muscle motor threshold; sensory-level, sensory threshold of the common peroneal nerve), for 30 s on separate days. Pressure pain threshold was recorded on the contralateral tibialis anterior and deltoid muscle before, during, and after stimulation. [Results] Motor-level stimulation significantly increased the pressure pain threshold at both muscle sites, while effects of sensory-level stimulation on pressure pain thresholds were significant only at the deltoid site. The percent change in pressure pain thresholds at both sites was significantly higher during motor-level stimulation. [Conclusion] Motor level stimulation, applied unilaterally to one leg, produced immediate contralateral diffuse and segmental analgesic effects. This may be of therapeutic benefit in patients for whom transcutaneous electrical nerve stimulation cannot be directly used at the painful site. PMID- 26504291 TI - Excitability of spinal motor neurons during motor imagery of thenar muscle activity under maximal voluntary contractions of 50% and 100. AB - [Purpose] We often perform physical therapy using motor imagery of muscle contraction to improve motor function for healthy subjects and central nerve disorders. This study aimed to determine the differences in the excitability of spinal motor neurons during motor imagery of a muscle contraction at different contraction strengths. [Subjects] We recorded the F-wave in 15 healthy subjects. [Methods] In resting trial, the muscle was relaxed during F-wave recording. For motor imagery trial, subjects were instructed to imagine maximal voluntary contractions of 50% and 100% while holding the sensor of a pinch meter, and F waves were recorded for each contraction. The F-wave was recorded immediately after motor imagery. [Results] Persistence and F/M amplitude ratio during motor imagery under maximal voluntary contractions of 50% and 100% were significantly higher than that at rest. In addition, the relative values of persistence, F/M amplitude ratio, and latency were similar during motor imagery under the two muscle contraction strengths. [Conclusion] Motor imagery under maximal voluntary contractions of 50% and 100% can increase the excitability of spinal motor neurons. Differences in the imagined muscle contraction strengths are not involved in changes in the excitability of spinal motor neurons. PMID- 26504292 TI - The effect of thoracic region self-mobilization on chest expansion and pulmonary function. AB - [Purpose] The aim of this study was to determine the effects of thoracic region self-mobilization on chest expansion and pulmonary function in healthy adults. [Subjects] Nineteen healthy adults were randomly allocated to either an intervention group (n = 8) or a control group (n = 11). [Methods] Subjects in the intervention group performed self-mobilization of the thoracic region 3 times per week for 6 weeks (18 sessions). The outcome measures included chest expansion when breathing, pulmonary function, and predicted pulmonary function. [Results] There was a significant difference in chest expansion between the intervention group and the control group. However, there was no significant difference in pulmonary function between the intervention group and the control group. [Conclusion] Thoracic region self-mobilization may be beneficial for increasing chest expansion in healthy adults. PMID- 26504293 TI - Changes of general fitness and muscle properties following police cadet training. AB - [Purpose] This study was performed to examine the relationship between physical performance and muscle properties during police cadet training. The study's hypothesis was that improved physical performance brought about by training, would in turn cause a reduction in muscle flexibility. [Subjects and Methods] Fifty-nine police cadets were included in this study. Standard fitness tests and quantitative assessments of muscular biomechanical properties were conducted before, during and after the 20-week cadet training. [Results] General fitness had improved at the end of the police cadet training. There was no significant decrease in muscle flexibility as measured by the Sit-and-Reach test. However, muscle compliance of the non-dominant leg measured by the relaxation coefficient had decreased at the end of the police cadet training. [Conclusion] The increased sit-and-reach distance could be due in part to strengthening of the abdominal muscles. On the other hand, the biomechanical test, which was specific to muscle extensibility, showed a reduction in the relaxation coefficient of the non dominant leg. Our data suggests that changes in muscle compliance as a result of lower extremity training should be considered. This data may be useful in the design of a training protocol that prevents the potential injuries caused by reduced muscle flexibility. PMID- 26504294 TI - The effects of cognitive exercise therapy on chronic stroke patients' upper limb functions, activities of daily living and quality of life. AB - This study aimed to examine the effects of task-oriented exercise therapy and cognitive exercise therapy on the recovery of hand function and the quality of life in chronic stroke patients. [Subjects and Methods] A total of 16 patients with chronic stroke were selected and divided into two groups. Group I (n = 8) received task-oriented exercise therapy and Group II (n = 8) received cognitive exercise therapy. This study was conducted for eight weeks. Upper limb function was assessed using the Fugl-Meyer assessment (FMA) and manual function test (MFT); activities of daily living were assessed using the motor activity log (MAL); and the quality of life was assessed using the stroke impact scale (SIS). The pre- and post-intervention results of these tests were analyzed. [Results] There were significant differences in all areas of upper limb function, activities of daily living, and quality of life between the two groups. There were significant differences between the two groups in the post-intervention upper limb function and quality of life. [Conclusion] Application of cognitive exercise therapy was found to effect functional recovery in stroke patients. Future research should focus on application of cognitive exercise therapy in diverse populations, and assess its clinical utilization. PMID- 26504295 TI - The effects of Juchumseogi and Juchumseo Jireugi motions of taekwondo on muscle activation of paraspinal muscles. AB - [Purpose] The purpose of this study is to examine the effects of Juchumseogi and Juchumseo Jireugi motions on muscle activation of the paraspinal muscles. [Subjects] The subjects of this study were 20 healthy male students who listened to an explanation of the study methods and the purpose of the experiment, and agreed to participate in the study. [Methods] Muscle activation measurements of the paraspinal muscles at C3, T7, and L3 were taken while standing still and while performing Juchumseogi and Juchumseo Jireugi movements. The Juchumseogi and Juchumseo Jireugi motions were performed 3 times, and its mean value was used for analysis. [Results] The right and left muscle activation of paraspinal muscles induced by Juchumseogi and Juchumseo Jireugi motions in C3 and T7 were significantly higher than those induced by just standing. Muscle activation of paraspinal muscles induced by Juchumseo Jireugi motions in C3, T7, and L3 were significantly higher than those induced by Juchumseogi alone. The right and left muscle activation of paraspinal muscles induced by Juchumseo Jireugi motion in C3, T7, and L3 were significantly higher than those induced by standing and Juchumseogi alone. [Conclusion] This study demonstrated that Juchumseogi and Juchumseo Jireugi motions of Taekwondo could increase muscle activation of paraspinal muscles, and Juchumseo Jireugi motions were more effective for enhancing muscle activation of paraspinal muscles. PMID- 26504296 TI - Scoliosis screening results of primary school students (11-15 years old group) in the west side of Istanbul. AB - [Purpose] The present study aimed to find out the scoliosis prevalence 11-15 years old children and to create awareness about scoliosis. [Subjects and Methods] All of the children were assessed using the Adams Forward Bendings Test and a scoliometer. Sagittal plane changes such as kyphosis, lordosis, hypokyphosis, hypolordosis and anterior head tilt were screened. Children with trunk rotation angles (ATR) of 4 degrees or more were suspected of having scoliosis, and were evaluated for a second time for gibbosity height, arm-trunk distance, and ATR. [Results] A total of 2,207 children were screened and the evaluation revealed there were 11 girls (0.49%) with a Cobb angle of 10 degrees and more. The maximum Cobb angle was 43 degrees (right thoracic-left lumbar) and the maximum ATR was 12 degrees . Two children had kyphosis and lordosis, and one had hypokyphosis and was diagnosed as having idiopathic scoliosis. [Conclusion] Families should regularly check their children, even if they are not diagnosed as having scoliosis in school screenings. It is our opinion that our study increased the awareness of the families about scoliosis by screening, brochures and posters. In the future, if school screenings were performed as a routine procedure and scoliotic students were followed over the long term, the actual effectiveness of screening would be able to be detected. PMID- 26504297 TI - Prevalence of and risk factors for low back pain among dentists. AB - [Purpose] The purpose of this study was to determine the prevalence, symptoms of, and risk factors for low back pain among dentists as well as to discover the possible correlation of these factors with working posture and how to reduce their prevalence. [Subjects and Methods] The study was conducted among 60 dentists (28 male and 32 female) with a mean age of 25.7 years. Dentists were evaluated with the self-administered Nordic musculoskeletal evaluation chart, postural discomfort chart, and a self-prepared questionnaire. [Results] The data showed a 70% incidence of back pain among dentists, with low back pain predominating in 47.6% of cases. Most of the subjects (90.5%) had a mild-to moderate level of severity, and only 9.5% had a severe level of low back pain. The majority of the dentists (57%) treated 1-3 patients per day. Only a few dentists (17%) exercised during their rest period even though 57% of them reported taking a break during their working hours. Although 63% of the dentists were aware of the advantages of assistive tools, only 40% of them used any kind of assistive devices. [Conclusion] Dental professionals demonstrate a high prevalence of low back pain. PMID- 26504298 TI - Effects of sitting time associated with media consumption on physical activity patterns and daily energy expenditure of Saudi school students. AB - [Purpose] This study was performed to assess the effect of daily sitting time during media consumption on physical fitness, total energy expenditure (TEE), and body composition indices of Saudi school children. [Subjects and Methods] A total of 180 healthy Saudi school students (8-18 years) were included in this study. Sitting time, total energy expenditure, and levels of physical activity were evaluated with pre-validated internet based questionnaires. Body composition indices were evaluated using anthropometric analysis. [Results] Out of the studied participants, only 22.2% of students were physically inactive. Children with moderate and active physical scores demonstrated less sedentary behavior (TV viewing and computer usage), lower body composition values (BMI, WC, WHtR), and higher TEE than sedentary or mild activity level participants. Boys showed higher fitness scores and less sedentary behavior than girls. Media sitting time among the studied subjects correlated negatively with physical scores and positively with body composition. [Conclusion] The data presented here suggests that poor physical fitness, lower TEE, and longer sitting times differentially influence normal body composition indices among school children which may lead to overweight or obese individuals. Thus, decreasing sitting time during media consumption and enhancing physical activity may play a pivotal role in preventing obesity in young children. PMID- 26504299 TI - Development of an algorithm to predict comfort of wheelchair fit based on clinical measures. AB - [Purpose] The purpose of this study was to develop an algorithm to predict the comfort of a subject seated in a wheelchair, based on common clinical measurements and without depending on verbal communication. [Subjects] Twenty healthy males (mean age: 21.5 +/- 2 years; height: 171 +/- 4.3 cm; weight: 56 +/- 12.3 kg) participated in this study. [Methods] Each experimental session lasted for 60 min. The clinical measurements were obtained under 4 conditions (good posture, with and without a cushion; bad posture, with and without a cushion). Multiple regression analysis was performed to determine the relationship between a visual analogue scale and exercise physiology parameters (respiratory and metabolism), autonomic nervous parameters (heart rate, blood pressure, and salivary amylase level), and 3D-coordinate posture parameters (good or bad posture). [Results] For the equation (algorithm) to predict the visual analogue scale score, the adjusted multiple correlation coefficient was 0.72, the residual standard deviation was 1.2, and the prediction error was 12%. [Conclusion] The algorithm developed in this study could predict the comfort of healthy male seated in a wheelchair with 72% accuracy. PMID- 26504300 TI - Effect of neck and trunk rotation speeds on cerebral cortex activity and standing postural stability: a functional near-infrared spectroscopy study. AB - [Purpose] The aim of the present study was to determine whether different neck and trunk rotation speeds influence standing postural stability or frontal and temporal cortical activity during rotation in healthy young adults. [Subjects and Methods] Twelve healthy volunteers participated in this study. A custom turn table operated by one of the experimenters was placed on a platform to assess postural perturbation. Subjects were asked to stand barefoot on the turn-table in an upright position with their feet together, and measurements were obtained during high- and low-speed rotations. Postural stability was tested using a force platform and a head sensor. Cerebral cortex activity was measured using functional near-infrared spectroscopy. Brain activity, center of pressure, and head perturbation were measured simultaneously for each subject. [Results] Significant differences were found in the center of pressure and the head angular velocity between high- and low-speed rotations. However, compared to baseline, oxygenated hemoglobin levels were not significantly different during high- or low speed rotations. [Conclusion] Automatic postural responses to neck and trunk rotation while standing did not significantly activate the cerebral cortex. Therefore, the response to stimuli from the feet may be controlled by the spinal reflex rather than the cerebral cortex. PMID- 26504301 TI - Effect of stretch on improvement of muscular contractures in rats. AB - [Purpose] The purpose of this study was to investigate how a stretching torque affects muscular contractures. [Subjects] The subjects of this study were 48 male Wistar rats. [Methods] Subjects were divided into 4 groups as follows: Group 1 was the control; Group 2 had muscles in continuous fixation; Group 3 had muscles stretched in the direction of dorsiflexion by a spring balancer set at a torque of 0.3N for a period of 30 minutes after continuous fixation; and Group 4 had muscles stretched in the direction of dorsiflexion by a spring balancer set at a torque of 3.0N for a period of 30 minutes after continuous fixation. Joint fixation periods were for 2 and 4-weeks. Ankle joint range of motion and soleus flexibility were analyzed. [Results] For the 2-week joint fixation, soleus flexibility in Group 4 showed an increase compared with that of Group 3. For both fixation periods, range of motion in Group 4 showed an increase compared with that of Group 3. [Conclusion] For both fixation periods, stretching improved joint range of motion. In the 2-week joint fixation, soleus flexibility improved. However, soleus flexibility did not improve in the 4-week joint fixation. PMID- 26504302 TI - Effects of acceleration training 24 weeks after anterior cruciate ligament reconstruction on proprioceptive and dynamic balancing functions. AB - [Purpose] The present study aimed to investigate whether the effects of rehabilitation exercise performed after anterior cruciate ligament reconstruction on proprioceptive sensory and dynamic balancing functions differ between males and females. [Subjects and Methods] Eighteen subjects aged between 20-30 years enrolled in this study. The ages did not significantly differ between the males and females. The rehabilitation exercise program was performed three times per week for 12 weeks (3 months), and was initiated immediately after anterior cruciate ligament reconstruction. Thereafter, the patients visited the hospital once per week to perform rehabilitation exercise during weeks 12-24 (3-6 months), and education on self-exercise and assessments were conducted during the visits. Self-exercise was performed two times per week according to the determined program. [Results] The extension active joint position sense, extension passive joint position sense, and flexion passive joint position sense of the affected and unaffected knees did not show any interaction effects between the measurement periods or between the groups. In the case of the affected knee, the results of two-way repeated-measures analysis of variance showed no significant difference between the measurement periods or between the groups; moreover, no, interaction effects were observed between the measurement periods or between the groups. In the case of the unaffected knee, although no significant difference was observed between the measurement periods, significant differences were observed between the groups. [Conclusion] In conclusion, this study revealed that most knee rehabilitation exercise training programs can be applied to both genders during the recovery period after ACL reconstruction, except for the knee rotational feedback/feedforward function exercise that may exhibit different effects based on the gender. PMID- 26504303 TI - Investigation of psychometric properties of the Falls Efficacy Scale using Rasch analysis in patients with hemiplegic stroke. AB - [Purpose] The purpose of this study was to investigate the psychometric properties of the Falls Efficacy Scale using Rasch analysis in patients with hemiplegic stroke. [Subjects] Fifty-five community-dwelling hemiplegic stroke patients were selected as participants. [Methods] Data were analyzed using the Winsteps program (version 3.62) with the Rasch model to confirm the unidimensionality through item fit, reliability, and appropriateness of the rating scale. [Results] There were no misfit persons or items. Furthermore, infit and outfit statistics appeared adjacent. The person separation value was 3.07, and the reliability coefficient was 0.90. The reliability of all items was at an acceptable level for patients with hemiplegic stroke. [Conclusion] This was the first study to investigate the psychometric properties of the Falls Efficacy Scale using Rasch analysis. The results of this study suggest that the 6-point Falls Efficacy Scale is an appropriate tool for measuring the self-perceived fear of falling in patients with hemiplegic stroke. PMID- 26504304 TI - Plantar pressures in individuals with normal and pronated feet according to static squat depths. AB - [Purpose] The purpose of the present study was to investigate differences in plantar pressure between individuals with normal and pronated feet according to 3 static squat depths. [Subjects and Methods] Study subjects were 10 young adults with normal and pronated feet. Plantar pressures were measured in the standing position and static squat positions at 45 degrees (semi-squat) and 90 degrees (half-squat) knee flexion using the F-Mat. Subjects' plantar pressures were analyzed by dividing the foot into 4 areas: forefoot medial, forefoot lateral, midfoot, and heel. [Results] In the half-squat position, the pronated foot group showed a higher foot pressure in the forefoot medial than was seen in the normal group, whereas the normal group exhibited a higher foot pressure in the heel than was seen in the pronated foot group. [Conclusion] An increase in squat depth led to the transfer of plantar pressure to the heel in normal feet and to the forefoot medial in pronated feet. PMID- 26504305 TI - The effects of a progressive resistance training program on walking ability in patients after stroke: a pilot study. AB - [Purpose] The purpose of this study was to evaluate the effects of a progressive resistance training (PRT) program on the walking ability of chronic stroke patients with hemiparesis following chronic stroke. [Subjects and Methods] The participants of this study were fifteen hemiplegic patients. The main outcomes measured for this study were the peak torque of the knee extensor; the gait ability as measured by electric gait analysis of walking speed, walking cycle, affected side stance phase, affected side stride length, symmetry index of stance phase, and symmetry index of stride length; and 10-m walking speed; and the Berg balance scale test. [Results] Walking speed and affected side stride length significantly increased after the PRT program, and 10-m walking time significantly decreased after RPT in stroke patients. [Conclusion] These results suggest that the progressive resistance training program may, in part, improve the stride of the affected side leg of stroke patients after stroke and also positively impact walking speed. PMID- 26504306 TI - Electrophysiological characteristics according to activity level of myofascial trigger points. AB - [Purpose] This study compared the differences in electrophysiological characteristics of normal muscles versus muscles with latent or active myofascial trigger points, and identified the neuromuscular physiological characteristics of muscles with active myofascial trigger points, thereby providing a quantitative evaluation of myofascial pain syndrome and clinical foundational data for its diagnosis. [Subjects] Ninety adults in their 20s participated in this study. Subjects were equally divided into three groups: the active myofascial trigger point group, the latent myofascial trigger point group, and the control group. [Methods] Maximum voluntary isometric contraction (MVIC), endurance, median frequency (MDF), and muscle fatigue index were measured in all subjects. [Results] No significant differences in MVIC or endurance were revealed among the three groups. However, the active trigger point group had significantly different MDF and muscle fatigue index compared with the control group. [Conclusion] Given that muscles with active myofascial trigger points had an increased MDF and suffered muscle fatigue more easily, increased recruitment of motor unit action potential of type II fibers was evident. Therefore, electrophysiological analysis of these myofascial trigger points can be applied to evaluate the effect of physical therapy and provide a quantitative diagnosis of myofascial pain syndrome. PMID- 26504307 TI - Changes in stress hormone levels with the application of vibrations before resistance exercises at different intensities. AB - [Purpose] The purpose of the present study was to determine whether vibrations should be applied before resistance exercises by examining changes in stress hormone levels with vibrations applied before different exercise intensities. [Subjects] Eighteen male subjects in their 20s were included, and were randomly divided into one-repetition maximum (1RM) 50% group (50% RMG, n = 6), 1RM 70% group (70%RMG, n = 6), and 1RM 90% group (90% RMG, n = 6). [Methods] Three sets of Smith squats were performed at 1RM 50%, 70%, and 90% according to resistance intensities, and vibrations were applied for 1 min at a fixed frequency of 30 Hz before each set. Epinephrine, norepinephrine, and dopamine stress hormone levels were analyzed. [Results] Epinephrine levels were significantly higher immediately after exercise than at rest in the 50%RMG; however, no significant changes were noted in the 70%RMG and 90%RMG. Norepinephrine levels were significantly higher immediately after exercise than at rest in all three groups. However, no significant changes in dopamine levels were noted in the three groups. [Conclusion] The application of vibrations at a frequency of 30 Hz before 70%RM and 90%RM resistance exercises suppressed increases in the stress hormone epinephrine levels immediately after exercise. PMID- 26504309 TI - Analysis of muscle activations in lower extremities muscles at various angles of ankle flexion using wedges during static squat exercise. AB - [Purpose] This study aimed to investigate changes in activation of the rectus femoris, biceps femoris, tibialis anterior, and gastrocnemius muscles during one legged squats performed at various angles of ankle flexion. With the use of wedges, the muscles were activated at different angles of ankle flexion angles to establish the appropriate posture necessary for muscle strengthening and rehabilitation. [Subjects and Methods] Healthy adults aged 20-40 years were recruited from Good Morning Hospital in Ulsan City. Of the 22 participants, two dropped out during the tests, leaving a final sample of 20 participants. The wedges were 100 mm wide and 200 mm long and had inclinations of 10 degrees , 30 degrees , and 50 degrees . EMG Analyzer software was used to measure muscle activation. [Results] A significant difference in the activation of the rectus femoris muscle at various angles of ankle flexion was seen. The gastrocnemius muscle exhibited significant differences in activation among the 0 degrees -30 degrees , 0 degrees -50 degrees , and 10 degrees -50 degrees inclinations. [Conclusion] Wedge-assisted muscle activation under different ankle flexion angles can be introduced as an effective exercise option under clinical conditions. PMID- 26504308 TI - Acute cardiovascular responses while playing virtual games simulated by Nintendo Wii((r)). AB - [Purpose] This investigation evaluated the acute cardiovascular responses that occur while playing virtual games (aerobic and balance) emulated by Nintendo Wii((r)). [Subjects] Nineteen healthy male volunteers were recruited. [Methods] The ergospirometric variables of maximum oxygen consumption, metabolic equivalents, and heart rate were obtained during the aerobic (Obstacle Course, Hula Hoop, and Free Run) and balance (Soccer Heading, Penguin Slide, and Table Tilt) games of Wii Fit Plus((r)) software. To access and analyze the ergospirometric information, a VO2000 analyzer was used. Normalized data (using maximum oxygen consumption and heart rate) were analyzed using repeated measures analysis of variance and Scheffe's test. [Results] Significant differences were found among the balance and aerobic games in all variables analyzed. In addition, the Wii exercises performed were considered to be of light (balance games) and moderate (aerobic games) intensity in accordance with American College Sports Medicine exercise stratification. [Conclusion] Physical activity in a virtual environment emulated by Nintendo Wii((r)) can change acute cardiovascular responses, primarily when Wii aerobic games are performed. These results support the use of the Nintendo Wii((r)) in physical activity programs. PMID- 26504310 TI - The effect of non-elastic taping on balance and gait function in patients with stroke. AB - [Purpose] This study investigated the influence of exercise on balance ability and gait function in stroke patients after applying non-elastic tape, which can stabilize muscles and joints, to the lower extremities of the affected side. [Subjects and Methods] The subjects were 30 patients diagnosed with stroke. They were divided into an experimental group (n = 15) and a control group (n = 15). The experimental group performed mat and treadmill exercises three times a week for six weeks with non-elastic tape applied to the lower extremities of the affected side. The control group performed the same exercises but without taping. [Results] The intervention significantly improved Berg balance scale scores and timed up and go (TUG) test scores as well as reduced stance duration and stride duration in the experimental group. In the control group, statistically significant improvements were observed in TUG test scores. [Conclusion] Although some differences did not reach the level of statistical significance, the application of non-elastic tape stabilized the joints of the lower extremities, thereby increasing balance and reducing stance duration and one step duration, which resulted in a reduction of overall gait duration. PMID- 26504311 TI - Effects of the slow speed-targeting squat exercise on the vastus medialis oblique/vastus lateralis muscle ratio. AB - [Purpose] This study investigated the effects of the slow speed-targeting squat exercise on the vastus medialis oblique/vastus lateralis ratio. [Subjects] Ten asymptomatic men were recruited. [Methods] The EMG activities of the vastus medialis oblique and vastus lateralis muscles were recorded using surface electrodes. The subject performed the squat exercise under 3 different conditions. [Results] The vastus medialis oblique/vastus lateralis ratio in condition 2 (1.5 +/- 0.7) was significantly higher than that in conditions 1 and 3 (1.0 +/- 0.5, 1.1 +/- 0.8, respectively) [Conclusion] Therefore, an effectively slow movement speed is recommended for selective strengthening of vastus medialis oblique using a slow speed-targeting device that provides biofeedback. PMID- 26504312 TI - Cardiovascular effects of Zumba((r)) performed in a virtual environment using XBOX Kinect. AB - [Purpose] This study evaluated the acute cardiovascular responses during a session of Zumba((r)) Fitness in a virtual reality environment. [Subjects] Eighteen healthy volunteers were recruited. [Methods] The following cardiovascular variables: heart rate, systolic blood pressure, diastolic blood pressure, and double product were assessed before and after the practice of virtual Zumba((r)), which was performed as a continuous sequence of five choreographed movements lasting for 22 min. The game Zumba Fitness Core((r)), with the Kinect-based virtual reality system for the XBOX 360, was used to create the virtual environment. Comparisons were made among mean delta values (delta=post-Zumba((r)) minus pre-Zumba((r)) values) for systolic and diastolic blood pressure, heart rate, and double product using Student's t-test for paired samples. [Results] After a single session, a significant increase was noted in all the analyzed parameters (Systolic blood pressure=18%; Diastolic blood pressure=13%; Heart rate=67%; and Double product=97%). [Conclusion] The results support the feasibility of the use of Zumba Fitness Core((r)) with the Kinect based virtual reality system for the XBOX 360 in physical activity programs and further favor its indication for this purpose. PMID- 26504313 TI - Effect of purposeful action observation on upper extremity function in stroke patients. AB - [Purpose] The purpose of this study was to identify the effect of purposeful action observation on upper extremity function in patients with stroke. [Subjects and Methods] Twelve subjects were randomly to either the experimental group or control group. The experimental group underwent occupational therapy and a purposeful action observation program. The control group underwent occupational therapy and placebo treatment in which the subjects performed a purposeful action observation program without actually observing the purposeful actions. The Wolf Motor Function Test was used to measure upper extremity function before and after the intervention in both groups. [Results] Both the experimental and control groups demonstrated improved upper extremity function after the intervention, but there was no significant difference between groups. Compared with before the intervention, the experimental group showed significantly improved upper extremity function after the intervention. [Conclusion] Based on these results, a purposeful action observation program can improve upper extremity function in patients with stroke. In future research, more subjects should be included for evaluation of different treatments. PMID- 26504314 TI - Effects of underwater treadmill walking training on the peak torque of the knee in hemiplegic patients. AB - [Purpose] This study investigated the effects of underwater treadmill walking training on the peak torque of the knee in hemiplegic patients. [Subjects and Methods] Thirty-two subjects, who were randomly allocated to an experimental group (n=16) and a control group (n=16), performed underwater treadmill walking training and overground treadmill walking training, respectively, for 30 minutes/session, 3 sessions/week, for 6 weeks. An isokinetic dynamometer was used to assess the peak torque. [Results] The subjects in the experimental group showed an increase in the peak knee extension torque compared to the control group. [Conclusion] The results suggested that underwater treadmill walking training has a greater effect on peak knee extension torque at velocities of 60 degrees /sec and 120 degrees /sec than overground treadmill walking training. PMID- 26504315 TI - The effects of cognitive rehabilitation on Alzheimer's dementia patients' cognitive assessment reference diagnosis system performance based on level of cognitive functioning. AB - [Purpose] The purpose of this study is to apply cognitive rehabilitation according to Alzheimer's disease (AD) patients' level of cognitive functioning to compare changes in Cognitive Assessment Reference Diagnosis System performance and present standards for effective intervention. [Subjects] Subjects were 30 inpatients diagnosed with AD. Subjects were grouped by Clinical Dementia Rating (CDR) class (CDR-0.5, CDR-1, or CDR-2, n = 10 per group), which is based on level of cognitive functioning, and cognitive rehabilitation was applied for 50 minutes per day, five days per week, for four weeks. [Methods] After cognitive rehabilitation intervention, CARDS tests were conducted to evaluate memory. [Results] Bonferroni tests comparing the three groups revealed that the CDR-0.5 and CDR-1 groups showed significant increases in Delayed 10 word-list, Delayed 10 object-list, Recognition 10 object, and Recent memory performance compared to the CDR-2 group. In addition, the CDR-0.5 group showed significant decreases in Recognition 10 word performance compared to the CDR-1 group. [Conclusion] Cognitive rehabilitation, CDR-0.5 or CDR-1 subjects showed significantly greater memory improvements than CDR-2 subjects. Moreover, was not effective for CDR-2 subjects. PMID- 26504316 TI - The acute effect of neuromuscular activation in resistance exercise on human skeletal muscle with the interpolated twitch technique. AB - [Purpose] The purpose of this study was to perform a quantitative assessment of neuromechanical adaptation in skeletal muscles and to propose the scientific underpinnings of the acute effects induced by resistance exercise. [Subjects] The subjects in this study were 11 healthy adult men in their 20s who had no orthopedic history at the time of the study. To examine any signs of resistance exercise-induced changes in the ankle plantar flexor, the subjects were directed to perform a standing barbell calf raise routine. [Methods] Subjects were to carry a load equal to their weights and to perform five sets of ten repetitions. The maximal voluntary isometric contraction torque, resting twitch torque, muscle inhibition, root mean square of muscular activation, contraction time, and half relaxation time were analyzed by synchronizing a dynamometer, an electrical stimulator, and an electromyography system. [Results] The maximal voluntary isometric contraction torque appeared to decline, but the change was not statistically significant. The decline of resting twitch torque, on the other hand, was found to be statistically significant. Muscle inhibition and root mean square of muscular activation were both reduced, but both changes were not statistically significant. Lastly, contraction time and half relaxation time both statistically decreased significantly after resistance exercise. [Conclusion] These results indicate that the acute effects of resistance exercise have a greater impact on the peripheral mechanical system itself, rather than on neurological factors, in terms of the generation of muscle force. PMID- 26504317 TI - The role of visual feedback in respiratory muscle activation and pulmonary function. AB - [Purpose] It is well known that visual feedback is an important factor contributing to balance and postural control. Nevertheless, there has been little discussion about the effects of visual feedback on pulmonary function. This study was conducted to investigate the role of visual feedback on respiratory muscle activation and pulmonary function. [Subjects and Methods] The subjects were 37 healthy adults who consented to participate in this study. The study measured the muscular activation of the trunk and pulmonary function according to the absence or presence of visual feedback. [Results] The results revealed significant changes in muscular activation and pulmonary function with the use of visual feedback. [Conclusion] These findings suggest that visual feedback may play a role in increasing respiratory muscle activity and pulmonary function. PMID- 26504318 TI - The influence of an ankle foot orthosis on the percentage of weight loading during standing tasks in stroke patients. AB - [Purpose] The aim of this study was to investigate the effects of an ankle foot orthosis on weight-bearing abilities of stroke patients by comparing weight loading during performance of tasks in various standing positions on the affected side. [Subjects and Methods] This study was performed with 16 stroke patients. To measure the weight loading value and percentage of weight loading in affected lower extremities, 5 standing tasks were performed with and without an ankle foot orthosis in random order. [Results] In the rising from a chair, maintaining a standing position, and forward weight shifting tasks, the affected lower extremities showed a significantly higher percentage of weight loading with an ankle foot orthosis. In the tasks requiring weight shifting to one leg, weight shifting to the lateral side showed the best weight-bearing ability with or without an ankle foot orthosis, followed by the forward and backward weight shifting, respectively. There were statistically significant correlations in all 5 tasks with or without an ankle foot orthosis. [Conclusion] An ankle foot orthosis improves the weight-bearing ability, especially when shifting weight forward, resulting in increased weight-bearing ability in activities of daily living tasks such as quiet standing and rising from a chair. The 5 tasks in this study would be a fine assessment tool under clinical conditions to investigate the postural stability of the affected side with or without application of an ankle foot orthosis. PMID- 26504319 TI - Effects of Nordic walking and walking on spatiotemporal gait parameters and ground reaction force. AB - [Purpose] The purpose of this study was to investigate the effects of Nordic walking and walking on spatiotemporal gait parameters and ground reaction force. [Subjects] The subjects of this study were 30 young adult males, who were divided into a Nordic walking group of 15 subjects and a walking group of 15 subjects. [Methods] To analyze the spatiotemporal parameters and ground reaction force during walking in the two groups, the six-camera Vicon MX motion analysis system was used. The subjects were asked to walk 12 meters using the more comfortable walking method for them between Nordic walking and walking. After they walked 12 meters more than 10 times, their most natural walking patterns were chosen three times and analyzed. To determine the pole for Nordic walking, each subject's height was multiplied by 0.68. We then measured the spatiotemporal gait parameters and ground reaction force. [Results] Compared with the walking group, the Nordic walking group showed an increase in cadence, stride length, and step length, and a decrease in stride time, step time, and vertical ground reaction force. [Conclusion] The results of this study indicate that Nordic walking increases the stride and can be considered as helping patients with diseases affecting their gait. This demonstrates that Nordic walking is more effective in improving functional capabilities by promoting effective energy use and reducing the lower limb load, because the weight of the upper and lower limbs is dispersed during Nordic walking. PMID- 26504320 TI - Passive and active exercises are similarly effective in elderly nursing home residents. AB - [Purpose] The aim of this study was to compare the efficacy of passive motion exercise and active motion exercise on functional fitness in elderly nursing home residents. [Subjects and Methods] Twenty-three (female 22 and male 1) nursing home residents (84.8+/-4.3 yr) volunteered for this study. They were divided into a passive motion exercise group (n=12) and an active motion exercise group (n=11) and performed 30-min sessions of training twice a week for 12 weeks. Functional fitness (Arm Curl, Chair Stand, Up & Go, Sit & Reach, Back Scratch, functional Reach, and 12-min Walk tests) was evaluated before and after the intervention. [Results] No significant baseline difference was noted between the groups in measured variables. Following the 12 week intervention, no significant interaction (group * time) was noted in functional fitness variables between the groups, except for the functional reach scores (active motion exercise 40%, passive motion exercise 9%). Significant improvement over time was noted in passive motion exercise group in Arm Curl (19%), Chair Stand (15%), Up & Go (6%), and 12-min Walk (12%) scores; and in the active motion exercise group in Arm Curl (14%), Chair Stand (19%), Up & Go (11%), functional Reach (40%) and 12-min Walk (13%) scores. The adherence rates in the passive and active motion exercise groups were 95.8% and 93.1% respectively. [Conclusion] Passive motion exercise and active motion exercise were found to be similarly effective for improving the functional fitness of elderly nursing home residents. PMID- 26504321 TI - Predictive factors for the outcome of multidisciplinary treatments in chronic low back pain at the first multidisciplinary pain center of Japan. AB - [Purpose] Multidisciplinary treatments are recommended for treatment of chronic low back pain. The aim of this study was to show the associations among multidisciplinary treatment outcomes, pretreatment psychological factors, self reported pain levels, and history of pain in chronic low back pain patients. [Subjects and Methods] A total of 221 chronic low back pain patients were chosen for the study. The pretreatment scores for the 10-cm Visual Analogue Scale, Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale, Short-Form McGill Pain Questionnaire, Pain Disability Assessment Scale, pain drawings, and history of pain were collected. The patients were divided into two treatment outcome groups a year later: a good outcome group and a poor outcome group. [Results] One-hundred eighteen patients were allocated to the good outcome group. The scores for the Visual Analogue Scale, Pain Disability Assessment Scale, and affective subscale of the Short-Form McGill Pain Questionnaire and number of nonorganic pain drawings in the good outcome group were significantly lower than those in the poor outcome group. Duration of pain in the good outcome group was significantly shorter than in the poor outcome group. [Conclusion] These findings help better predict the efficacy of multidisciplinary treatments in chronic low back pain patients. PMID- 26504322 TI - Postural education and behavior among students in a city in southern Brazil: student postural education and behavior. AB - [Purpose] The aim of the present study was to assess the knowledge of the spine and posture among adolescent female students and to determine if they had access to postural education in or outside school. [Subjects and Methods] This was an epidemiological survey of a representative sample of 495 female students aged 14 to 18 years attending a regular secondary school in Sao Leopoldo, RS, Brazil. Data were collected through a questionnaire. [Results] The results showed that 16.8% of teens did not know what a spine was, 8.3% had no knowledge of posture, and 61% reported receiving no posture education. Posture awareness was associated only with posture while using a computer, while having postural education class was not associated with any postural behavior. [Conclusion] The results showed that, although most students are familiar with the spine and posture, a sizable group is not, and over half had no postural education. These findings suggest that inclusion of postural education programs in schools should be encouraged in order to promote health and prevent diseases related to the spine. PMID- 26504323 TI - The effects of ankle joint taping on gait and balance ability of healthy adults. AB - [Purpose] This study examined the effects of the application of elastic taping over the ankle joints of healthy subjects on their gait, balance ability, and muscle strength. [Subjects] Fifty healthy subjects with no orthopedic history of the ankle joint were selected and elastic taping was applied to their ankle joints. [Methods] Before and after application of the elastic taping, gait and balance ability of the subjects were evaluated. [Results] After the taping application, gait velocity significantly increased and there were significant differences in all variables of balance ability. [Conclusion] Application of elastic taping aimed at improving stability of the ankle joint had a positive effect on gait speed and balance ability. PMID- 26504324 TI - Effects of combined exercise on physical fitness and neurotransmitters in children with ADHD: a pilot randomized controlled study. AB - [Purpose] The purpose of the present study was to determine the effect of a jump rope and ball combined exercise program on the physical fitness the neurotransmitter (epinephrine, serotonin) levels of children with attention deficit hyperactivity disorder. [Subjects and Methods] The subjects were 12 boys attending elementary school, whose grade levels ranged from 1-4. The block randomization method was used to distribute the participants between the combined exercise group (n = 6) and control group (n = 6). The program consisted of a 60 min exercise (10-min warm-up, 40-min main exercise, and 10-min cool down) performed three times a week, for a total of 12 weeks. [Results] The exercise group showed a significant improvement in cardiorespiratory endurance, muscle strength, muscle endurance and flexibility after 12 weeks. A significant increase in the epinephrine level was observed in the exercise group. [Conclusion] The 12 week combined exercise program in the current study (jump rope and ball exercises) had a positive effect on overall fitness level, and neurotransmission in children with attention-deficit hyperactivity disorder. PMID- 26504325 TI - The effects of computer-assisted cognitive rehabilitation on Alzheimer's dementia patients memories. AB - [Purpose] The purpose of the present study was to conduct Computer-Assisted Cognitive Rehabilitation (COMCOG) to examine the effects of COMCOG on Alzheimer's dementia patients' memories. [Subjects] Thirty-five patients diagnosed with Alzheimer's dementia received COMCOG for 30 minutes per day, five days per week for four weeks. [Methods] Before and after the COMCOG intervention, subjects' cognitive functions were evaluated using the Cognitive Assessment Reference Diagnosis System (CARDS) and Mini-Mental State Examination-Korea (MMSE-K) test. [Results] According to the results of the evaluation, among the CARDS scores of the subjects who received COMCOG, the scores of the delayed 10-word list, delayed 10-object list, recognition 10-object, and recent memory significantly increased while the scores of recognition 10-word significantly decreased after intervention compared to before intervention. In addition, among the MMSE-K items, the orientation, registration, and recall showed significant increases. [Conclusion] Based on these results, delay in the progress of memory deterioration can be expected when COMCOG is conducted for Alzheimer's dementia patients who show declines in cognitive functions. PMID- 26504326 TI - Effects of sensorimotor foot training on the symmetry of weight distribution on the lower extremities of patients in the chronic phase after stroke. AB - [Purpose] To assess the effects of sensorimotor foot stimulation on the symmetry of weight distribution on the feet of patients in the chronic post-stroke phase. [Subjects and Methods] This study was a prospective, single blind, randomized controlled trial. In the study we examined patients with chronic stroke (post stroke duration > 1 year). They were randomly allocated to the study group (n=8) or to the control group (n=12). Both groups completed a standard six-week rehabilitation programme. In the study group, the standard rehabilitation programme was supplemented with sensorimotor foot stimulation training. Each patient underwent two assessments of symmetry of weight distribution on the lower extremities with and without visual control, on a treadmill, with stabilometry measurements, and under static conditions. [Results] Only the study group demonstrated a significant increase in the weight placed on the leg directly affected by stroke, and a reduction in asymmetry of weight-bearing on the lower extremities. [Conclusion] Sensorimotor stimulation of the feet enhanced of weight bearing on the foot on the side of the body directly affected by stroke, and a decreased asymmetry of weight distribution on the lower extremities of patients in the chronic post-stroke phase. PMID- 26504327 TI - Relationship between physical activity and function in elderly patients discharged after surgical treatment for gastrointestinal cancer. AB - [Purpose] The purpose of the present study was to observe changes in physical activity (PA) from before surgery to after discharge among elderly patients with gastrointestinal cancer and to examine the relationships between PA, function, and physique after discharge in these patients. [Subjects and Methods] The study participants were 18 elderly patients who underwent surgical treatment for gastrointestinal cancer [10 males and 8 females, aged 71.4 +/- 4.2 years (mean +/ SD)]. We evaluated patients' PA, function, and physique before surgery and after discharge. Calorie consumption as calculated using the International Physical Activity Questionnaire (IPAQ) short version was measured for PA. Isometric knee extension force (IKEF), the timed up and go test (TUGT), and the 6-minute walk distance (6MWD) were measured for function. The body mass index (BMI) was calculated for physique. [Results] Significant declines in PA and BMI were observed after discharge among the study participants. In addition, a significant correlation between PA and IKEF was observed in the discharge phase. [Conclusion] These results suggest that PA after discharge is significantly less than that before surgery and related to the functioning of the lower extremities in the same period in elderly patients who undergo surgical treatment for gastrointestinal cancer. PMID- 26504328 TI - Effects of treadmill training with the eyes closed on gait and balance ability of chronic stroke patients. AB - [Purpose] The purpose of this study was to compare the effect of treadmill walking with the eyes closed and open on the gait and balance abilities of chronic stroke patients. [Subjects and Methods] Thirty patients with chronic stroke participated in this study. The treadmill gait training for each group lasted 40 minutes, and sessions were held 3 times a week for 4 weeks. Gait ability was measured using a Biodex Gait Trainer Treadmill System. Balance ability was measured using a Biodex Balance System. [Results] After the treadmill training' the treadmill training with eyes closed (TEC) group showed significant improvements in walking distance' step length' coefficient of variation' and limit of stability (overall' lateral affected' forward lateral unaffected) compared to the treadmill training with eyes open (TEO) group. [Conclusion] The walking and balance abilities of the TEC participants showed more improvement after the treadmill walking sessions than those of the TEO participants. Therefore' treadmill walking with visual deprivation may be useful for the rehabilitation of patients with chronic stroke. PMID- 26504329 TI - Maximum force and the center of pressure trajectory length according to foot angles during stair walking. AB - [Purpose] Walking with the feet turned inward or outward often causes issues for the people with these walking patterns. The purpose of this study was to examine the influence of in-toeing and out-toeing on maximum force and the center of pressure (COP) trajectory length during stair walking. [Subjects and Methods] The subjects were 30 female university students without orthopedic diseases of the foot. The foot angle was divided into three types: in-toeing, normal, and out toeing. A plantar pressure measurement instrument was used, and the maximum force was obtained by dividing the foot into six regions covering the anterior medial lateral, middle medial-lateral, and posterior medial-lateral regions. The COP trajectory length was statistically calculated by measuring the medial-lateral, anterior-posterior, and total travel distances. [Results] During stair climbing, the maximum force was significantly different in the anterior lateral region. During stair descending, the maximum force was significantly different in the anterior lateral, middle medial, middle lateral, posterior medial, and posterior lateral regions. The COP trajectory length showed a statistically significant difference in the medio-lateral travel distance. [Conclusion] Walking with abnormal foot angles causes deformed foot structures and can result in musculoskeletal disabilities in the long term. Therefore, therapeutic intervention is required to maintain normal foot angles. PMID- 26504330 TI - Effect of changes in postural alignment on foot pressure and walking ability of stroke patients. AB - [Purpose] The aims of this study were to determine (1) the significance of walking and foot pressure in stroke patients, and (2) the association between changes in postural alignment of stroke patients. [Subjects and Methods] Foot pressure and walking ability based on postural alignment were measured in 50 stroke patients. Trunk imbalance, trunk rotation, pelvic tilt, kyphosis, lordosis were measured using DIERS formetric4D (DIERS International GmbH, Schlangenbad, Germany), which anlalyzes 3-dimensional spinal structure in order to measure postural alignment. To determine foot pressure, the support rate of weight and, average foot pressure were measured using DIERS pedoscan (DIERS International GmbH, Schlangenbad, Germany) apparatus as a pressure platform. [Results] DIERS formetric 4D, DIERS pedoscan, and a 10 m walking test were utilized to measure foot pressure and walking ability relative to changes in postural alignment in participating stroke patients. [Conclusion] This study confirmed the significance of foot pressure and walking ability as related postural alignment, indicating that postural alignment education and a recovery therapy program for functional improvement of stroke patients should be provided together. PMID- 26504331 TI - Randomized controlled comparative study on effect of training to improve lower limb motor paralysis in convalescent patients with post-stroke hemiplegia. AB - [Purpose] The motor paralysis-improving effect on the hemiplegic lower limb was compared among mirror therapy, integrated volitional-control electrical stimulation, therapeutic electrical stimulation, repetitive facilitative exercises, and the standard training method in post-stroke hemiplegia patients. [Subjects and Methods] Eighty one stroke patients admitted to a convalescent rehabilitation ward were randomly allocated to the above 5 treatment groups. Each patient performed functional training of the paralytic lower limb for 20 minutes a day for 4 weeks, and changes in the lower limb function were investigated using the Stroke Impairment Assessment Set. [Results] The hip and knee joint functions did not significantly improve in the standard training control group, but significant improvements were observed after 4 weeks in the other intervention groups. Significant improvement was noted in the ankle joint function in all groups. [Conclusion] Although the results were influenced by spontaneous recovery and the standard training in the control group, the hip and knee joints were more markedly improved by the interventions in the other 4 groups of patients with moderate paralysis, compared to the control group. PMID- 26504332 TI - Chronic widespread musculoskeletal pain in patients with obstructive sleep apnea syndrome and the relationship between sleep disorder and pain level, quality of life, and disability. AB - [Purpose] The aim of this study was to ascertain the prevalence of chronic widespread musculoskeletal pain in patients with obstructive sleep apnea syndrome and to assess the relationship between sleep disorder and pain, quality of life, and disability. [Subjects and Methods] Seventy-four patients were included in the study and classified as having mild, moderate, or severe obstructive sleep apnea. Chronic widespread pain, quality of life, and disability were evaluated. [Results] Forty-one patients (55.4%) had chronic widespread pain. Female patients had a higher incidence of chronic pain, and female patients with chronic pain had higher body mass indexes, pain levels, and disability scores than did male patients. Physical component scores of female patients with chronic pain were lower than those of male patients. No correlation was observed between the degree of sleep disorder and severity of pain, pain duration, disability, or quality of life in obstructive sleep apnea patients with pain. [Conclusion] This study showed a 55.4% prevalence of chronic widespread pain in patients with obstructive sleep apnea and a greater risk of chronic pain in female than in male patients. Female patients with obstructive sleep apnea and chronic pain have higher pain and disability levels and a lower quality of life. PMID- 26504333 TI - Correlations among trunk impairment, functional performance, and muscle activity during forward reaching tasks in patients with chronic stroke. AB - [Purpose] This study aimed to investigate the relationships among trunk impairment, functional performance, and muscle activity during forward reaching tasks in patients with chronic stroke. [Subjects and Methods] Twenty-three chronic stroke patients participated in this study. Trunk impairment and functional performance were evaluated using the Trunk Impairment Scale, Berg Balance Scale, Timed Up and Go Test, and 10-Meter Walk Test. All subjects were asked to perform 3 different forward reaching tasks (affected side reaching, forward reaching, and less-affected side reaching), and measurements were taken during these 3 tasks by using surface electromyography. Correlation analyses were performed to assess the relationships among trunk impairment, functional performance, and muscle activity during the forward reaching tasks. [Results] Spearman's correlation analysis revealed a strong, significant correlation between the Trunk Impairment Scale and functional performance, that was associated with balance and gait ability. During the 3 different forward reaching tasks, muscle activities of the less-affected lower extremity were significantly correlated with functional performance. [Conclusion] This study revealed the correlations among trunk impairment, functional performance, and muscle activity during forward reaching tasks in patients with chronic stroke and emphasized the importance of trunk rehabilitation. PMID- 26504334 TI - Biomechanical comparison of frontal plane knee joint moment arms during normal and Tai Chi walking. AB - [Purpose] Medial knee osteoarthritis, a degenerative joint disease, affects adults. The external knee adduction moment, a surrogate knee-loading measure, has clinical implications for knee osteoarthritis patients. Tai Chi is a promising intervention for pain alleviation in knee osteoarthritis; however, the characteristics of external knee adduction moment during Tai Chi have not been established. [Subjects and Methods] During normal and Tai Chi walking, a gait analysis was performed to compare the external knee adduction moment moment-arm characteristics and paired t-tests to compare moment-arm magnitudes. [Results] A significant difference was observed in the average lateral direction of moment arm magnitude during Tai Chi walking (-0.0239 +/- 0.011 m) compared to that during normal walking (-0.0057 +/- 0.004 m). No significant difference was found between conditions in average medial direction of moment-arm magnitude (normal walking: 0.0143 +/- 0.010 m; Tai Chi walking: 0.0098 +/- 0.014 m). [Conclusion] Tai Chi walking produced a larger peak lateral moment-arm value than normal walking during the stance phase, whereas Tai Chi walking and normal walking peak medial moment-arm values were similar, suggesting that medial knee joint loading may be avoided during Tai Chi walking. PMID- 26504335 TI - Relationships between problematic behaviors and motor abilities of children with cerebral palsy. AB - [Purpose] This study aimed to examine whether motor abilities of children with cerebral palsy are related to their problematic behaviors. [Subjects] The subjects were children with mental retardation who were undergoing physical therapy. [Methods] Twenty-one examiners, 13 physical therapists, and 8 occupational therapists treated and examined the subjects by using the Japanese version of the Aberrant Behavior Checklist. The Japanese version of the Aberrant Behavior Checklist scores were compared between the Gross Motor Function Classification System I to III (12 subjects) and Gross Motor Function Classification System IV and V groups (17 subjects). [Results] Lethargy and stereotypy scores significantly differed between the groups, proving that patients with Gross Motor Function Classification System levels IV and V have more severe problematic behaviors. [Conclusion] In this study, only five types of problematic behaviors, namely irritability, lethargy, stereotypy, hyperactivity, and inappropriate speech, were examined. Despite this limitation, the study clarifies that problematic behaviors of children with cerebral palsy, except lethargy and stereotypy, have little relationship with their motor abilities. PMID- 26504336 TI - Relationship of visfatin level to pancreatic endocrine hormone level, HOMA-IR index, and HOMA beta-cell index in overweight women who performed hydraulic resistance exercise. AB - [Purpose] This study aimed to examine the correlation of visfatin level to pancreatic endocrine hormone level, homeostasis model assessment of insulin resistance (HOMA-IR) index, and HOMA beta-cell index in hydraulic resistance exercise. Furthermore, it investigated the relationship between visfatin level and other variables affected by exercise in overweight women. [Subjects and Methods] The exercise group trained for 12 weeks, 70 minutes/day, 5 days/week. Visfatin level, pancreatic endocrine hormone level, HOMA-IR index, and HOMA beta cell index were measured before and after the intervention. Based on the blood insulin and glucose concentrations, HOMA-IR index, the indicator of insulin resistance, and HOMA beta-cell index, the indicator of insulin secretion level, were assessed. [Results] Interaction effects on visfatin level, insulin level, HOMA-IR index, and HOMA beta-cell index were observed. Interaction effects on glucagon and glucose levels were not observed between the intervention groups. The correlations of visfatin level to insulin, glucagon, and glucose levels, and HOMA-IR and HOMA beta-cell indexes were not significant for any of the subjects. [Conclusion] Therefore, the 12-week resistance exercise affected body composition, visfatin level, insulin level, HOMA-IR index, and HOMA beta-cell index. Finally, visfatin was not related to insulin, glucagon, and glucose levels, and HOMA-IR and HOMA beta-cell indexes. PMID- 26504337 TI - The effects of ankle joint muscle strengthening and proprioceptive exercise programs accompanied by functional electrical stimulation on stroke patients' balance. AB - [Purpose] The purpose of the present study was to examine the effects of ankle joint muscle strengthening and proprioceptive exercises accompanied by functional electrical stimulation on stroke patients' balance ability. [Methods] For six weeks beginning in April 2015, 22 stroke patients receiving physical therapy at K Hospital located in Gyeonggi-do were divided into a functional electrical stimulation (FES), ankle proprioceptive exercise and ankle joint muscle strengthening exercise group (FPS group) of 11 patients and an FES and stretching exercise group (FS group) of 11 patients. The stimulation and exercises were conducted for 30 min per day, five days per week for six weeks. Balance ability was measured using a BioRescue and the Berg balance scale, functional reach test, and the timed up-and-go test were also used as clinical evaluation indices. Repeated measures ANOVA was conducted to examine differences between before the exercises and at three and six weeks after beginning the exercises within each group, and the amounts of change between the two groups were compared. [Results] In the comparison within each group, both groups showed significant differences between before and after the experiment in all the tests and comparison between the groups showed that greater improvement was seen in all values in the FPS group. [Conclusion] In the present study, implementing FES and stretching exercises plus ankle joint muscle strengthening and proprioceptive exercises was more effective at improving stroke patients balance ability than implementing only FES and stretching exercises. PMID- 26504338 TI - Walking ability after stroke in patients from Argentina: predictive values of two tests in subjects with subacute hemiplegia. AB - [Purpose] This study aimed to determine the predictive values of the trunk control test (TCT) and functional ambulation category (FAC) for independent walking up to 6 months post stroke. [Subjects] Twenty-seven subjects with hemiplegia secondary to a unilateral hemisphere stroke were included. [Methods] The protocol was started at 45 days post stroke, with the TCT and FAC as walking predictors. At 90, 120, and 180 days post stroke, the subjects' independent walking ability was assessed by using the Wald test. [Results] The TCT was identified as an independent predictor of ambulation at 90, 120, and 180 days. Subjects who scored >= 49 in the initial test had 93.8% probability of achieving independent gait at 6 months. The FAC proved that 100% of the subjects who scored 2 at 45 days post stroke walked independently at 90 days, 100% of the subjects who scored 1 walked independently at 120 days, and only 33.3% of the subjects who scored 0 walked independently at 180 days. [Conclusion] The TCT and FAC can predict independent walking at 45 days post stroke. In subjects with FAC 0, the TCT should be used to predict patients who will be able to walk independently. PMID- 26504339 TI - Alterations of spinal range of motion while sitting in hemiplegic patients with or without gait available. AB - [Purpose] The purpose of this study was to determine alterations of spinal range of motion while sitting, in hemiplegic patients with or without gait available. [Subjects] There was a gait group (GG) of 6 subjects, and a non-gait group (NGG) of 6 subjects, both with hemiplegia after a stroke. [Methods] The subjects in both groups were given an intervention focusing on ankle dorsi-flexion of the affected foot only once for 30 minutes. The Spinal Mouse was used to gain data of the spinal range of motion before and after the intervention and 30 minutes later for follow-up test. [Results] Only in the gait group, lumbar spinal range of motion showed a significant difference when using flexion extension. Sacral hip and inclination were both increased gradually when upright flexion and flexion extension were used. [Conclusion] Facilitating foot for ankle dorsi-flexion is effective on spinal range of motion especially sacrohip, lumbar spine and inclination only for the subjects in the gait group. The results suggested that ankle dorsi-flexion exercise influences spinal range of motion in a sitting position. PMID- 26504340 TI - The effects of patient-centered task-oriented training on balance activities of daily living and self-efficacy following stroke. AB - [Purpose] This study aimed to determine whether a task-oriented training program improved balance, activities of daily living (ADL) performance, and self-efficacy in stroke patients. Twenty patients with stroke were recruited from a hospital in Cheongju, Korea. [Subjects] Ten of the subjects were assigned to an experimental group that participated in the task-oriented training program, and the other 10 were assigned to a control group that received traditional rehabilitation therapy. [Methods] In the two groups, balance was measured with the Berg Balance Scale (BBS), ADL performance with the Modified Barthel Index (MBI), and self efficacy with the Self-Efficacy Scale (SES), before and after 4 weeks of training. [Results] Comparative analysis of the experimental group's pretest and post-test results showed statistically significant differences in the BBS, MBI, and SES scores. There were also significant between-group differences in the BBS, MBI, and SES scores. [Conclusion] The results suggest that a task-oriented training program can be an effective intervention to improve balance ability, ADL performance, and self-efficacy in stroke patients. PMID- 26504341 TI - Effect of a suspension seat support chair on the trunk flexion angle and gluteal pressure during computer work. AB - [Purpose] We assessed the effects of a suspension seat support chair on the trunk flexion angle and gluteal pressure during computer work. [Subjects] Ten males were recruited. [Methods] The suspension seat support was developed to prevent abnormal gluteal pressure and a slumped sitting posture during computer work. The gluteal pressure was measured with a TekScan system and the trunk flexion angle was measured with a video camera, to compare the differences between a general chair and the suspension seat support. [Results] The gluteal peak pressures were decreased significantly in the suspension seat support versus the general chair. The trunk flexion angle was also decreased significantly in the suspension seat support compared with the general chair. [Conclusions] This study suggests that the suspension seat support chair contributes to preventing abnormal gluteal pressure and a slumped sitting posture. PMID- 26504342 TI - Knowledge among nephrologists about the importance of exercise in the intradialytic period. AB - [Purpose] To assess knowledge among nephrologists at hemodialysis services about routine intradialytic therapeutic exercise, in the city of Recife. [Subjects and Methods] A cross-sectional study, consisting of 49 nephrologists working in public and/or private hemodialysis services, who responded to a semi-structured questionnaire about their academic background, medical residency, and knowledge about exercise during the intradialytic period. [Results] About 56.3% practiced for more than 10 years as nephrologists, 69.4% did not receive information about intradialytic physical exercise while in residency, 81.6% considered intradialytic exercise to be important, and 53.0% did not prescribe exercise during hemodialysis. About 61.2% consider the level of physical activity among their patients to be poor. Nephrologists graduating within 2 years were 10 times more likely to prescribe exercise, compared to those with more than 2 years since graduation. [Conclusion] Our study found that the nephrologists interviewed do not usually prescribe intradialytic therapeutic exercise, despite understanding its importance as part of the treatment process. It is necessary to update doctors about the importance of exercise for patients during the intradialytic period, as well as to incorporate this knowledge at the undergraduate level. PMID- 26504343 TI - Effects of push-up exercise on shoulder stabilizer muscle activation according to the grip thickness of the push-up bar. AB - [Purpose] This study investigated the effects of bar thickness on shoulder stabilizer muscle activation during push-up exercise. [Subjects] Twenty-six healthy male adults in their twenties. [Methods] The study had four experimental conditions (grip thicknesses of 0%, 50%, 75%, and 100% of the subjects' hand size). Measurements were conducted from the start to the end of push-up for deltoid anterior fiber, deltoid posterior fiber, infraspinatus, serratus anterior, and pectoralis major muscle activation. [Results] The deltoid anterior fiber muscle activity was 4,852.6 +/- 975.2 in the 0%, 5,787.3 +/- 1,514.1 in the 50%, 5,635.3 +/- 1,220.1 in the 75%, and 5,032.9 +/- 841.0 in the 100% condition. The infraspinatus muscle activity was 1,877.2 +/- 451.3 in the 0%, 2,310.9 +/- 765.4 in the 50%, 2,353.6 +/- 761.9 in the 75%, and 2,016.8 +/- 347.7 in the 100% condition. The pectoralis major muscle activity was 1,675.8 +/- 355.1 in the 0%, 2,365.5 +/- 1,287.3 in the 50%, 2,125.3 +/- 382.5 in the 75%, and 1,878.8 +/- 419.7 in the 100% condition, showing significant differences respectively. [Conclusion] The use of push-up bars with different thicknesses customized to personal characteristics, rather than the conventional standard, could be more effective for training and rehabilitation. PMID- 26504344 TI - Virtual reality for cognitive rehabilitation after brain injury: a systematic review. AB - [Purpose] The purpose of this review was to investigate various types of VR programs and their use in cognitive evaluations and interventions for patients with brain injury. [Subjects and Methods] PubMed, Cochrane, and OTseeker electronic databases were searched with the search terms. At of 350 titles and abstracts were retrieved, and 17 articles were selected for this review. Selected articles were assessed on the level of evidence using the Physiotherapy Evidence Database (PEDro) scale. [Results] Articles assessing the impact of cognitive impairments in memory were most commonly found, and VR interventions elicited positive effects in patients with brain injury. [Conclusion] VR can be considered a new tool for cognitive rehabilitation after brain injury. VR interventions also have a number of advantages, e.g. cost-effectiveness, compared to other interventions. PMID- 26504345 TI - Patterns in the collaboration of practitioners and researchers in the use of electrical stimulation to treat stroke patients: a literature review. AB - [Purpose] The purpose of this study was to investigate the degree of collaboration between practitioners and researchers through research papers related to the implementation of electrical stimulation (ES) for stroke patients. [Methods] A systematic review of the literature was conducted to collect data from ES studies published before January 7, 2015. Five databases were searched for search terms related to stroke and ES. Inclusion criteria were original papers that reported on ES of the upper or lower limbs following stroke, after the exclusion of case reports, brain stimulation studies, and papers written in any languages other than English or Japanese. The outcome was the prevalence of research papers that included a practitioner as an author, that included a practitioner as an author or in the acknowledgements, and in which the practitioner was the first author. [Results] Based on the selection criteria, 165 papers were included in the final analysis. The prevalence of papers in which a practitioner was included as an author was 39%. The prevalence of papers in which a practitioner was included as an author or in the acknowledgements was 50%. A practitioner was the first author of 34% of the papers. [Conclusion] Collaboration on research papers related to ES for stroke patients is limited. PMID- 26504346 TI - The application of sonography in shoulder pain evaluation and injection treatment after stroke: a systematic review. AB - [Purpose] This review article is designed to expose the application of sonography in shoulder pain after stroke. [Methods] A range of databases was searched to identify articles that address sonography examination, with or without ultrasound guided corticosteroid injection for hemiplegic shoulder pain (HSP). The electronic databases of PubMed, CENTRAL, CINAHL, Cochrane Library, Medline were searched. [Results] According to the articles identified in our databases research, sonographic technique has potential to provide objective measurements in patients with HSP. The main sonography finding of HSP included subacromial subdeltoid (SASD) bursal effusion, tendinosis of the supraspinatus and subscapularis tendon, long head of biceps tendon sheath effusion, and shoulder subluxation. Our analysis also revealed significantly decreased pain score (VAS) and increased passive external rotation degree in the steroid injection group than control group. [Conclusion] The sonography examination is useful for HSP assessment and ultrasound guided technique is recommended for HSP injection treatment. PMID- 26504347 TI - Exercise training for non-operative and post-operative patient with cervical radiculopathy: a literature review. AB - [Purpose] Cervical radiculopathy is a clinical condition associated with pain, numbness and/or muscle weaknesses of the upper extremities due to a compression or irritation of the cervical nerve roots. It is usually managed conservatively but surgical intervention is sometimes required for those who fail to respond adequately. This study performed a literature review to determine the effects of exercise on non-operative and post-operative cervical radiculopathy patients. [Methods] The PubMed, MEDLINE, CINAHL and Scopus databases were searched to identify relevant articles published from January 1997 to May 2014, which explicitly stated that an exercise program was employed as an intervention for cervical radiculopathy. The therapeutic effectiveness and outcomes were then classified based on the International Classification of Functioning, Disability and Health (ICF) model. [Results] Eleven studies were identified and included in the final analysis. In these studies, the main forms of exercise training were specific strengthening and general stretching exercises. Levels of evidence were graded as either I or II for all studies according to the Oxford Centre for Evidence-based Medicine. The PEDro Scale score of these studies ranged from 5 to 8. [Conclusion] A review of eleven high-level evidence and high-quality studies revealed that, based on the ICF model, exercise training is beneficial for improving the body function as well as activity participation of cervical radiculopathy patients. PMID- 26504348 TI - Correlation between waist and mid-thigh circumference and cardiovascular fitness in Korean college students: a case study. AB - [Purpose] We investigated whether waist and mid-thigh circumference correlated with cardiovascular fitness (VO2max) in a selected sample of Korean college students. [Subjects and Methods] The subjects were 41 college students (25 males, 16 females; age, > 19 years) who visited the sports medicine laboratory at the Korea National University of Transportation in Chungju-si, Republic of Korea, to undergo measurements of body composition, cardiovascular fitness, and waist and mid-thigh circumference. [Results] VO2max did not correlate with waist circumference or mid-thigh circumference in males, whereas VO2max was negatively correlated with mid-thigh circumference, but not waist circumference, in females. [Conclusion] Mid-thigh circumference was not associated with cardiovascular fitness or waist in male college students. However, it was associated with cardiovascular fitness in female college students. Well-designed studies are needed to investigate this further. PMID- 26504349 TI - Whole-body vibration training improves the walking ability of a moderately impaired child with cerebral palsy: a case study. AB - [Purpose] Strength training is recommended for children with cerebral palsy. However, it is difficult for moderately impaired children with cerebral palsy, who require crutches for ambulation, to participate in this type of training. The purpose of this study was to investigate whether whole-body vibration training is an effective method of strengthening in a moderately impaired child with cerebral palsy. [Subject and Methods] This report describes an 8-year-old Japanese boy with cerebral palsy, who was ambulatory with crutches. The subject participated in physical therapy twice a week for 5 weeks. Whole-body vibration training was selected to complement the standing practice. The patient's crutch-walking ability, gross motor function, and spasticity were evaluated. [Results] The number of steps and walking duration were reduced in a 5-m walk test with crutches and gross motor function was improved. Further, the spasticity was reduced. [Conclusion] Whole-body vibration training is an effective physical therapy intervention in moderately impaired children with cerebral palsy, who are unable to walk without crutches. PMID- 26504350 TI - Impact of post-manipulation corrective core exercises on the spinal deformation and lumbar strength in golfers: a case study. AB - [Purpose] This study examined spinal shape in professional golfers with chronic back pain, and analyzed the effects of a 4-week regimen of semi-weekly manipulation and corrective core exercises on spinal shape. [Subjects] Two golfers with chronic back pain. [Methods] The pelvis and spinal vertebrae were corrected using the Thompson "drop" technique. Angle and force were adjusted to place the pelvis, lumbar spine, and thoracic vertebrae in neutral position. The technique was applied twice weekly after muscle massage in the back and pelvic areas. The golfers performed corrective, warmup stretching exercises, followed by squats on an unstable surface using the Togu ball. They then used a gym ball for repetitions of hip rotation, upper trunk extension, sit-ups, and pelvic anterior posterior, pelvic left-right, and trunk flexion-extension exercises. The session ended with cycling as a cool-down exercise. Each session lasted 60 minutes. [Results] The difference in height was measured on the left and right sides of the pelvic bone. The pelvic tilt changed significantly in both participants after the 4-week program. [Conclusion] In golfers, core muscles are critical and are closely related to spinal deformation. Core strengthening and spinal correction play a pivotal role in the correction of spinal deformation. PMID- 26504351 TI - Neurophysiological Indicators of Residual Cognitive Capacity in the Minimally Conscious State. AB - BACKGROUND: The diagnostic usefulness of electrophysiological methods in assessing disorders of consciousness (DoC) remains to be established on an individual patient level, and there is need to determine what constitutes robust experimental paradigm to elicit electrophysiological indices of covert cognitive capacity. OBJECTIVES: Two tasks encompassing active and passive conditions were explored in an event-related potentials (ERP) study. The task robustness was studied in healthy controls, and their utility to detect covert signs of command following on an individual patient level was investigated in patients in a minimally conscious state (MCS). METHODS: Twenty healthy controls and 20 MCS patients participated. The active tasks included (1) listening for a change of pitch in the subject's own name (SON) and (2) counting SON, both contrasted to passive conditions. Midline ERPs are reported. RESULTS: A larger P3 response was detected in the counting task compared to active listening to pitch change in the healthy controls. On an individual level, the counting task revealed a higher rate of responders among both healthy subjects and MCS patients. CONCLUSION: ERP paradigms involving actively counting SON represent a robust paradigm in probing for volitional cognition in minimally conscious patients and add important diagnostic information in some patients. PMID- 26504352 TI - The Mismatch Negativity: An Indicator of Perception of Regularities in Music. AB - This paper reviews music research using Mismatch Negativity (MMN). MMN is a deviation-specific component of auditory event-related potential (EPR), which detects a deviation between a sound and an internal representation (e.g., memory trace). Recent studies have expanded the notion and the paradigms of MMN to higher-order music processing such as those involving short melodies, harmony chord, and music syntax. In this vein, we firstly reviewed the evolution of MMN from sound to music and then mainly compared the differences of MMN features between musicians and nonmusicians, followed by the discussion of the potential roles of the training effect and the natural exposure in MMN. Since MMN can serve as an index of neural plasticity, it thus can be widely used in clinical and other applied areas, such as detecting music preference in newborns or assessing wholeness of central auditory system of hearing illness. Finally, we pointed out some open questions and further directions. Current music perception research using MMN has mainly focused on relatively low hierarchical structure of music perception. To fully understand the neural substrates underlying processing of regularities in music, it is important and beneficial to combine MMN with other experimental paradigms such as early right-anterior negativity (ERAN). PMID- 26504353 TI - Inferior Frontal Gyrus Activation Underlies the Perception of Emotions, While Precuneus Activation Underlies the Feeling of Emotions during Music Listening. AB - While music triggers many physiological and psychological reactions, the underlying neural basis of perceived and experienced emotions during music listening remains poorly understood. Therefore, using functional magnetic resonance imaging (fMRI), I conducted a comparative study of the different brain areas involved in perceiving and feeling emotions during music listening. I measured fMRI signals while participants assessed the emotional expression of music (perceived emotion) and their emotional responses to music (felt emotion). I found that cortical areas including the prefrontal, auditory, cingulate, and posterior parietal cortices were consistently activated by the perceived and felt emotional tasks. Moreover, activity in the inferior frontal gyrus increased more during the perceived emotion task than during a passive listening task. In addition, the precuneus showed greater activity during the felt emotion task than during a passive listening task. The findings reveal that the bilateral inferior frontal gyri and the precuneus are important areas for the perception of the emotional content of music as well as for the emotional response evoked in the listener. Furthermore, I propose that the precuneus, a brain region associated with self-representation, might be involved in assessing emotional responses. PMID- 26504354 TI - Interaction of Musicianship and Aging: A Comparison of Cortical Auditory Evoked Potentials. AB - OBJECTIVE: The goal of this study was to begin to explore whether the beneficial auditory neural effects of early music training persist throughout life and influence age-related changes in neurophysiological processing of sound. DESIGN: Cortical auditory evoked potentials (CAEPs) elicited by harmonic tone complexes were examined, including P1-N1-P2, mismatch negativity (MMN), and P3a. STUDY SAMPLE: Data from older adult musicians (n = 8) and nonmusicians (n = 8) (ages 55 70 years) were compared to previous data from young adult musicians (n = 40) and nonmusicians (n = 20) (ages 18-33 years). RESULTS: P1-N1-P2 amplitudes and latencies did not differ between older adult musicians and nonmusicians; however, MMN and P3a latencies for harmonic tone deviances were earlier for older musicians than older nonmusicians. Comparisons of P1-N1-P2, MMN, and P3a components between older and young adult musicians and nonmusicians suggest that P1 and P2 latencies are significantly affected by age, but not musicianship, while MMN and P3a appear to be more sensitive to effects of musicianship than aging. CONCLUSIONS: Findings support beneficial influences of musicianship on central auditory function and suggest a positive interaction between aging and musicianship on the auditory neural system. PMID- 26504355 TI - Modulation of Voltage-Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor-1 and Receptor-2 in Small DRG Neurons of Rats. AB - Tumor necrosis factor- (TNF-) alpha is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain. Its effects are mediated by two receptors, TNF receptor-1 (TNFR-1) and TNF receptor-2 (TNFR-2). These receptors play a crucial role in the sensitization of voltage-gated sodium channels (VGSCs), a key mechanism in the pathogenesis of chronic pain. Using the whole-cell patch-clamp technique, we examined the influence of TNFR-1 and TNFR-2 on VGSCs and TTX-resistant NaV1.8 channels in isolated rat dorsal root ganglion neurons by using selective TNFR agonists. The TNFR-1 agonist R32W (10 pg/mL) caused an increase in the VGSC current (I(Na(V))) by 27.2 +/- 5.1%, while the TNFR-2 agonist D145 (10 pg/mL) increased the current by 44.9 +/- 2.6%. This effect was dose dependent. Treating isolated NaV1.8 with R32W (100 pg/mL) resulted in an increase in I(NaV(1.8)) by 18.9 +/- 1.6%, while treatment with D145 (100 pg/mL) increased the current by 14.5 +/- 3.7%. Based on the current voltage relationship, 10 pg of R32W or D145 led to an increase in I(Na(V)) in a bell-shaped, voltage-dependent manner with a maximum effect at -30 mV. The effects of TNFR activation on VGSCs promote excitation in primary afferent neurons and this might explain the sensitization mechanisms associated with neuropathic and inflammatory pain. PMID- 26504356 TI - Polymorphisms of Tumor Necrosis Factor Alpha in Moroccan Patients with Gastric Pathology: New Single-Nucleotide Polymorphisms in TNF-alpha(-193) (G/A). AB - Polymorphisms in tumor necrosis factor alpha (TNF-alpha) gene are emerging as key determinants of gastric diseases. The TNF-alpha(-308) (G/A) and TNF-alpha(-238) (G/A) single-nucleotide polymorphisms SNPs are the most extensively studied. However, all these studies are conducted in Caucasian and Asian populations. Thus, for the first time in Africa, we sought to investigate whether polymorphisms in TNF-alpha gene were associated with the development of gastric pathology in Morocco. Two SNPs located in the promoter region (positions -308 and -238) in TNF-alpha gene were genotyped in 244 individuals (170 patients and 74 healthy controls). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression analysis. The TNF-alpha(-238) (G/A) genotype was significantly associated with a high risk of gastritis and gastric cancer (GC) (P = 0.001 and P = 0.002, resp.). Furthermore, a new polymorphism located in the promoter region at position -193 in TNF-alpha gene was identified. The distribution of this SNP was markedly different in patients suffering from ulcers. The association between TNF-alpha(-193) (G/A) genotype and high risk of ulcer was significant (P = 0.03). These results suggest that the TNF-alpha(-193) (G/A) allele has a protective function against gastric cancer by developing ulcer. PMID- 26504357 TI - Lung Epithelial TRPA1 Transduces the Extracellular ROS into Transcriptional Regulation of Lung Inflammation Induced by Cigarette Smoke: The Role of Influxed Ca2+. AB - The mechanism underlying the inflammatory role of TRPA1 in lung epithelial cells (LECs) remains unclear. Here, we show that cigarette smoke extract (CSE) sequentially induced several events in LECs. The Ca(2+) influx was prevented by decreasing extracellular reactive oxygen species (ROS) with the scavenger N acetyl-cysteine, removing extracellular Ca(2+) with the chelator EGTA, or treating with the TRPA1 antagonist HC030031. NADPH oxidase activation was abolished by its inhibitor apocynin, EGTA, or HC030031. The increased intracellular ROS was halted by apocynin, N-acetyl-cysteine, or HC030031. The activation of the MAPKs/NF-kappaB signaling was suppressed by EGTA, N-acetyl cysteine, or HC030031. IL-8 induction was inhibited by HC030031 or TRPA1 siRNA. Additionally, chronic cigarette smoke (CS) exposure in wild-type mice induced TRPA1 expression in LECs and lung tissues. In CS-exposure trpa1 (-/-) mice, the increased BALF level of ROS was similar to that of CS-exposure wild-type mice; yet lung inflammation was lessened. Thus, in LECs, CSE may initially increase extracellular ROS, which activate TRPA1 leading to an increase in Ca(2+) influx. The increased intracellular Ca(2+) contributes to activation of NADPH oxidase, resulting in increased intracellular ROS, which activate the MAPKs/NF-kappaB signaling leading to IL-8 induction. This mechanism may possibly be at work in mice chronically exposed to CS. PMID- 26504358 TI - Increased NHC Cells in the Peritoneal Cavity of Plasmacytoma Susceptible BALB/c Mouse. AB - BALB/c strain mice are unique in that they develop murine plasmacytoma (MPC) as a consequence of the inflammation induced by pristane oil injection in the peritoneal cavity. In this work the Treg, Th17, B1, B2, and NHC lymphocyte populations from the peritoneal environment of BALB/c, the susceptible strain, and C57BL/6 mice, which do not develop MPC after oil treatment, were studied. Both oil-treated strains showed decreased levels of Th17 lymphocytes, no significant variation in Treg lymphocytes, and a drastic decrease of all B lymphocyte populations. However, only oil-induced BALB/c showed increased levels of natural helper cells (NHC) which could be important in the myeloma induction. PMID- 26504359 TI - Cancer Cachexia and MicroRNAs. AB - Cancer cachexia is a paraneoplastic syndrome compromising quality of life and survival, mainly characterized by involuntary weight loss, fatigue, and systemic inflammation. The syndrome is described as a result of tumor-host interactions characterized by an inflammatory response by the host to the presence of the tumor. Indeed, systemic inflammation is considered a pivotal feature in cachexia progression and maintenance. Cytokines are intimately related to chronic systemic inflammation and the mechanisms underlying the release of these factors are not totally elucidated, the etiology of cachexia being still not fully understood. Therefore, the understanding of cachexia-related mechanisms, as well as the establishment of markers for the syndrome, is very relevant. MicroRNAs (miRNAs) are a class of noncoding RNAs interfering with gene regulation. Different miRNA expression profiles are associated with different diseases and inflammatory processes. miRNAs modulate adipose and skeletal muscle tissue metabolism in cancer cachexia and also tumor and tissue derived inflammation. Therefore, we propose a possible role for miRNAs in the modulation of the host inflammatory response during cachexia. Moreover, the establishment of a robust body of evidence in regard to miRNAs and the mechanisms underlying cachexia is mandatory, and shall contribute to the improvement of its diagnosis and treatment. PMID- 26504360 TI - Increased Risk of Cancer in relation to Gout: A Review of Three Prospective Cohort Studies with 50,358 Subjects. AB - Gout is a common inflammatory disease characterized by acute arthritis and hyperuricemia. A number of epidemiological studies have suggested the critical role of gout in carcinogenesis. The aim of this study was to estimate the association between gout and cancer risk by meta-analysis of all relevant studies published to date. A comprehensive literature search in PubMed and Embase databases from their inception up to July 1, 2014, was performed to identify eligible studies. The strength for relationship between gout and the risk of different cancers was evaluated by calculating pooled relative risks (RRs) with 95% confidence intervals (95% CIs). All analyses were carried out by STATA 12.0 software. Gout patients were at an increased risk of cancer, particularly urological cancers, digestive system cancers, and lung cancer. No such significant association between gout and the risk of breast or brain cancers was observed. Sensitivity analysis did not materially alter the pooled results. Gout is a risk factor of cancer, particularly that of urological cancers, digestive system cancers, and lung cancer. The pooled data further support the hypothesis of a link between gout and carcinogenesis. PMID- 26504361 TI - Serum Uric Acid Increases Risk of Cancer Incidence and Mortality: A Systematic Review and Meta-Analysis. AB - SUA is a potent antioxidant and thus may play a protective role against cancer. Many epidemiological studies have investigated this hypothesis but provided inconsistent and inconclusive findings. We aimed to precisely elucidate the association between SUA levels and cancer by pooling all available publications. Totally, 5 independent studies with 456,053 subjects and 12 with 632,472 subjects were identified after a comprehensive literature screening from PubMed, Embase, and Web of Science. The pooled RRs showed that individuals with high SUA levels were at an increased risk of total cancer incidence (RR = 1.03, 95% CI 1.01-1.05, P = 0.007). Positive association between high SUA levels and total cancer incidence was observed in males but not females (for men: RR = 1.05, 95% CI 1.02 1.08, P = 0.002; for women, RR = 1.01, 95% CI 0.98-1.04, P = 0.512). Besides, high SUA levels were associated with an elevated risk of total cancer mortality (RR = 1.17, 95% CI 1.04-1.32, P = 0.010), particularly in females (RR = 1.25, 95% CI 1.07-1.45, P = 0.004). The study suggests that high SUA levels increase the risk of total cancer incidence and mortality. The data do not support the hypothesis of a protective role of SUA in cancer. PMID- 26504362 TI - Contribution of Neuroinflammation to the Pathogenesis of Cancer Cachexia. AB - Inflammation characterizes the course of acute and chronic diseases and is largely responsible for the metabolic and behavioral changes occurring during the clinical journey of patients. Robust data indicate that, during cancer, functional modifications within brain areas regulating energy homeostasis contribute to the onset of anorexia, reduced food intake, and increased catabolism of muscle mass and adipose tissue. In particular, functional changes are associated with increased hypothalamic concentration of proinflammatory cytokines, which suggests that neuroinflammation may represent the adaptive response of the brain to peripheral challenges, including tumor growth. Within this conceptual framework, the vagus nerve appears to be involved in conveying alert signals to the hypothalamus, whereas hypothalamic serotonin appears to contribute to triggering catabolic signals. PMID- 26504363 TI - A Survey of Attitudes towards the Clinical Application of Systemic Inflammation Based Prognostic Scores in Cancer. AB - INTRODUCTION: The systemic inflammatory response (SIR) plays a key role in determining nutritional status and survival of patients with cancer. A number of objective scoring systems have been shown to have prognostic value; however, their application in routine clinical practice is not clear. The aim of the present survey was to examine the range of opinions internationally on the routine use of these scoring systems. METHODS: An online survey was distributed to a target group consisting of individuals worldwide who have reported an interest in systemic inflammation in patients with cancer. RESULTS: Of those invited by the survey (n = 238), 65% routinely measured the SIR, mainly for research and prognostication purposes and clinically for allocation of adjuvant therapy or palliative chemotherapy. 40% reported that they currently used the Glasgow Prognostic Score/modified Glasgow Prognostic Score (GPS/mGPS) and 81% reported that a measure of systemic inflammation should be incorporated into clinical guidelines, such as the definition of cachexia. CONCLUSIONS: The majority of respondents routinely measured the SIR in patients with cancer, mainly using the GPS/mGPS for research and prognostication purposes. The majority reported that a measure of the SIR should be adopted into clinical guidelines. PMID- 26504364 TI - 25-OH Vitamin D and Interleukin-8: Emerging Biomarkers in Cutaneous Melanoma Development and Progression. AB - BACKGROUND: There are several circulatory biomarkers that are involved in forecasting the clinical outcome of cutaneous melanoma. Serum/plasma vitamin D status is one of the markers intensively studied in this type of cutaneous cancer. The combination of validated serum biomarkers (like LDH) with new biomarkers such as IL-8, angiogenic factor, and vitamin D is still at the dawn of research. Hence, we are aiming to establish the predictive power of inflammatory biomarkers, such as IL-8, and metabolic ones, such as vitamin D. These candidate biomarkers are intended to aid classical biomarkers, such as LDH, in the prognosis of cutaneous melanoma. METHODS: Serum vitamin D and IL-8 were quantified in melanoma patients and in matching healthy controls. RESULTS: Median serum vitamin D concentrations were significantly lower (p = 0.003) in melanoma patients as compared to healthy control subjects, while around 65% of the investigated patients have proven a severe circulatory deficiency of this vitamin. IL-8 was found increased (p = 0.001) in melanoma patients as compared to controls. CONCLUSION: Upregulation of proangiogenic factors associated with vitamin D deficiency can prove to be potent future biomarkers candidates, enhancing the predictive power of classical LDH. PMID- 26504365 TI - Morphology and ultrastructure of Interfilum and Klebsormidium (Klebsormidiales, Streptophyta) with special reference to cell division and thallus formation. AB - Representatives of the closely related genera, Interfilum and Klebsormidium, are characterized by unicells, dyads or packets in Interfilum and contrasting uniseriate filaments in Klebsormidium. According to the literature, these distinct thallus forms originate by different types of cell division, sporulation (cytogony) versus vegetative cell division (cytotomy), but investigations of their morphology and ultrastructure show a high degree of similarity. Cell walls of both genera are characterized by triangular spaces between cell walls of neighbouring cells and the parental wall or central space among the walls of a cell packet, exfoliations and projections of the parental wall and cap-like and H like fragments of the cell wall. In both genera, each cell has its individual cell wall and it also has part of the common parental wall or its remnants. Therefore, vegetative cells of Interfilum and Klebsormidium probably divide by the same type of cell division (sporulation-like). Various strains representing different species of the two genera are characterized by differences in cell wall ultrastructure, particularly the level of preservation, rupture or gelatinization of the parental wall surrounding the daughter cells. The differing morphologies of representatives of various lineages result from features of the parental wall during cell separation and detachment. Cell division in three planes (usual in Interfilum and a rare event in Klebsormidium) takes place in spherical or short cylindrical cells, with the chloroplast positioned perpendicularly or obliquely to the filament (dyad) axis. The morphological differences are mainly a consequence of differing fates of the parental wall after cell division and detachment. The development of different morphologies within the two genera mostly depends on characters such as the shape of cells, texture of cell walls, mechanical interactions between cells and the influence of environmental conditions. PMID- 26504366 TI - Community level workers: awareness generation for improving children's health. AB - BACKGROUND: Routine immunisation and Vitamin A supplementation are two of many services offered by Government of India to reduce child mortality and morbidity. The three groups of community level workers (CLWs) i.e. Auxiliary Nurse Midwives from health department, Anganwadi Workers from women and child development department and Accredited Social Health Activists (ASHAs) are responsible for raising awareness and demand for these services. OBJECTIVES: The paper assesses the knowledge and participation of CLWs in generating awareness about the two services namely immunisation and Vitamin A supplementation among eligible mothers; and mother's knowledge on these two services. METHODS: The study was conducted in 16 villages of two administrative blocks of Udaipur district in Rajasthan. Multistage purposive sampling was used for study area selection. Data collection was done using mixed methods-1) observations of 16 Maternal and Child Health and Nutrition days; 2) questionnaire based survey of 46 CLWs; and 3) questionnaire based survey of 321 programme beneficiaries i.e. infant's mothers. RESULTS: Limited knowledge of CLWs and their participation in awareness generation activities for the two services was noticed, which was also reflected in the poor knowledge among mothers on the two services. CONCLUSION: The study results may partially explain the poor child immunization in Rajasthan. Initiatives to increase CLWs' knowledge of child immunization and Vitamin A supplementation; and increasing their participation in awareness generation activities need serious consideration by the healthcare system to improve immunization coverage. PMID- 26504368 TI - Demographic, Economic, Household, and Health Profile of Grandparents Responsible for Grandchildren. AB - The objective of this brief report was to outline the demographic, economic, household, and health profile of "grandparents responsible for grandchildren" (GRfGs) in the United States (US). Public Use Microdata Sample (PUMS) from the 2009-2011 American Community Survey (ACS) 3-year file was used to investigate characteristics of GRfGs by race-ethnic groups and the geographical distribution over the US mainland (contiguous states). The 9,177 actual units in the microdata are estimated to represent about 306,122 GRfGs. Population profiles are presented in tables for GRfGs of any age and the characteristics for those aged 65 and over are discussed. Amongst GRfGs aged 65 and over (n=33,168): 27% have ambulatory difficulty; 33% own their home free and clear; 77% have resided in their current residence for more than four years; 41% care for grandchild(ren) with the parent being absent; 61% are married; 36% have a college education; 77% are not in the labor force; and the majority (55%) are Non-Latino-Whites. Qualitative comparisons from descriptive statistics suggest race-ethnic minority GRfGs may be more economically and socially vulnerable than Non-Latino-Whites. Research on GRfGs and efforts on understanding how best to assist them should continue. PMID- 26504367 TI - Evolution, structure, and synthesis of vertebrate egg-coat proteins. AB - All vertebrate eggs are surrounded by an extracellular coat that supports growth of oocytes, protects oocytes, eggs, and early embryos, and participates in the process of fertilization. In mammals (platypus to human beings) the coat is called a zona pellucida (ZP) and in non-mammals (molluscs to birds), a vitelline envelope (VE). The ZP and VE are composed of just a few proteins that are related to one another and possess a common motif, called the zona pellucida domain (ZPD). The ZPD arose more than ~600 million years ago, consists of ~260 amino acids, and has 8 conserved Cys residues that participate in 4 intramolecular disulfides. It is likely that egg-coat proteins are derived from a common ancestral gene. This gene duplicated several times during evolution and gave rise to 3-4 genes in fish, 5 genes in amphibians, 6 genes in birds, and 3-4 genes in mammals. Some highly divergent sequences, N- and C-terminal to the ZPD, have been identified in egg-coat proteins and some of these sequences may be under positive Darwinian selection that drives evolution of the proteins. These and other aspects of egg-coat proteins, including their structure and synthesis, are addressed in this review. PMID- 26504369 TI - Factor Validity of a Proactive and Reactive Aggression Rating Scale. AB - Aggressive behaviors can be classified into proactive and reactive functions, though there is disagreement about whether these are distinct constructs. Data suggest that proactive and reactive aggression have different etiologies, correlates, and response to treatment. Several rating scales are available to characterize aggressive behavior as proactive or reactive; one commonly used scale was originally developed for teacher ratings, referred to here as the Antisocial Behavior Scale (ABS). However, no data are available on the psychometric properties of the ABS for parent ratings. This study examined the factor structure and convergent/divergent validity of the parent-rated ABS among 168 children aged 6-12 years with attention-deficit hyperactivity disorder, a disruptive behavior disorder, and severe aggression enrolled in a randomized clinical trial. Multidimensional item response theory was used to confirm the original factor structure. The proactive and reactive factors were distinct but moderately correlated; the algorithm items exhibited acceptable fit on the original factors. The non-algorithm items caused theoretical problems and model misfit. Convergent and divergent validity of the scale was explored between the ABS and other parent-report measures. Proactive and reactive aggression showed differential correlates consistent with expectations for externalizing symptoms. The subscales were correlated weakly or not at all with most non-externalizing symptoms, with some exceptions. Thus, the original factor structure was supported and we found preliminary evidence for the validity of the scale, though the results suggest that the constructs measured by the ABS may not be totally distinct from general behavior problems in this clinical sample. PMID- 26504370 TI - Big Data in Health Care: An Urgent Mandate to CHANGE Nursing EHRs! PMID- 26504371 TI - Mixed Brownian alignment and Neel rotations in superparamagnetic iron oxide nanoparticle suspensions driven by an ac field. AB - Superparamagnetic iron oxide nanoparticles with highly nonlinear magnetic behavior are attractive for biomedical applications like magnetic particle imaging and magnetic fluid hyperthermia. Such particles display interesting magnetic properties in alternating magnetic fields and here we document experiments that show differences between the magnetization dynamics of certain particles in frozen and melted states. This effect goes beyond the small temperature difference (DeltaT ~ 20 degrees C) and we show the dynamics to be a mixture of Brownian alignment of the particles and Neel rotation of their moments occurring in liquid particle suspensions. These phenomena can be modeled in a stochastic differential equation approach by postulating log-normal distributions and partial Brownian alignment of an effective anisotropy axis. We emphasize that precise particle-specific characterization through experiments and nonlinear simulations is necessary to predict dynamics in solution and optimize their behavior for emerging biomedical applications including magnetic particle imaging. PMID- 26504372 TI - Implementation of a vision-screening program in rural northeastern United States. AB - BACKGROUND: Rural populations comprise almost 20% of the US population and face unique barriers in receiving health care. We describe the implementation of a medical student-run free vision-screening clinic as a strategy to overcome barriers in accessing eye care in New Hampshire and Vermont. METHODS: Medical students were trained by an ophthalmologist to administer screening eye examinations. Patients from New Hampshire and Vermont were enrolled through a free community clinic. Screening included a questionnaire, distance and near visual acuity, extraocular movements, confrontational visual fields, and Amsler grid. Patients who met predetermined screening criteria were referred to an ophthalmologist or optometrist for further evaluation. Data including patient demographics, appointment attendance, level of education, and diagnoses were recorded and analyzed. RESULTS: Of 103 patients (mean age of 45.5+/-12.3 years, 63% female), 74/103 (72%) were referred for further evaluation, and 66/74 (89%) attended their referral appointments. Abnormal ophthalmologic examination findings were observed in 58/66 (88%) patients who attended their referral appointment. Uncorrected refractive error was the most common primary diagnosis in 38% of referred patients. Other diagnoses included glaucoma suspect (21%), retinal diseases (8%), amblyopia (8%), cataract (6%), others (6%), and normal examination (12%). Of the 8/74 (11%) referred patients who did not attend their appointments, reasons included patient cancellation of appointment, work conflicts, or forgetfulness. Patients traveled a mean distance of 16.6 miles (range: 0-50 miles) to attend screening examinations. Mean time for patients' last effort to seek eye care was 7.1 years (range: 1-54 years). CONCLUSION: This study underscores the high prevalence of unmet eye care needs in a rural population. Furthermore, it demonstrates that using community health centers as a patient base for screening can yield a high referral attendance rate for this at risk population and facilitate entrance into the eye care system in a rural setting. PMID- 26504374 TI - Design, synthesis, and antitumor evaluation of histone deacetylase inhibitors with L-phenylglycine scaffold. AB - In our previous research, a novel series of histone deacetylase (HDAC) inhibitors with L-phenylglycine scaffold were designed and synthesized, among which amides D3 and D7 and ureido D18 were far superior to the positive control (suberoylanilide hydroxamic acid [SAHA]) in HDAC inhibition, but were only comparable to SAHA in antiproliferation on tumor cell lines. Herein, further structural derivation of lead compounds D3, D7, and D18 was carried out to improve their cellular activities. Most of our newly synthesized compounds exhibited more potent HDAC inhibitory activities than the positive control SAHA, and several derivatives were even better than their parent compounds. However, compared with SAHA and our lead compounds, only secondary amine series compounds exhibited improved antiproliferative activities, likely due to their appropriate topological polar surface area values and cell permeabilities. In a human histiocytic lymphoma (U937) xenograft model, the most potent secondary amine 9d exhibited similar in vivo antitumor activity to that of SAHA. PMID- 26504375 TI - Patient-reported outcomes in type 2 diabetes mellitus: patients' and primary care physicians' perspectives in the Spanish health care system. AB - OBJECTIVE: Understanding patients' and physicians' perceptions of type 2 diabetes mellitus (T2DM) management and treatment has important implications for diabetes care, allowing the identification of clinical practice issues that could be improved, leading to patients' better understanding of the illness and, consequently, healthier self-management behaviors. The objective of this study was to identify differences between physicians' and T2DM patients' perceptions related to health status, patient-reported outcomes assessments, and T2DM management and treatment, in routine clinical practice in Spain. METHODS: This was an observational, cross-sectional study including 1,012 T2DM patients and 974 physicians from 47 and 52 Spanish provinces, respectively. An electronic structured self-administered questionnaire containing 17 questions was designed aiming to address both physicians' and patient's perceptions on overall T2DM health status and patient-reported outcomes. RESULTS: T2DM patients perceived a worse health status (40% reported having a "good" and 38% a "neither good nor bad" health status) compared with physicians' perceptions (77% thought patients had a "good" health status). Most patients answered being "satisfied" or "neither satisfied nor unsatisfied" with the given information, while physicians considered that patients were "satisfied" or "very satisfied" with the information for self-monitoring blood glucose and treatment administration. Fifty seven percent of patients reported that medical recommendations were "important", while 58% of physicians considered it as "very important". Fifty-three percent of patients perceived that their current T2DM treatment suited their preferences "quite a lot", and this was lower than the proportion of physicians (69%) that believed this for their patients. Additionally, a lower percentage of patients (53%) than physicians (79%) believed that their treatment improved their health related quality of life "quite a lot". All differences between patients and physicians were statistically significant (P<0.001). CONCLUSION: Patients and physicians demonstrate different views concerning all questions related to T2DM health status and diabetes management and treatment (information, recommendations, satisfaction, and preferences). PMID- 26504373 TI - Neuroprotective potential of ferulic acid in the rotenone model of Parkinson's disease. AB - Parkinson's disease (PD) is a chronic, progressive, and the second most common form of neurodegenerative disorders. In order to explore novel agents for the treatment of PD, in the current study, we have evaluated the neuroprotective efficacy of ferulic acid (FA) using rotenone (ROT)-induced rat model of PD. ROT was administered 2.5 mg/kg body weight to male Wistar rats for 4 weeks to induce the PD. Since PD is progressive and chronic in nature, the paradigm for evaluating FA was based on chronic administration for 4 weeks at the dose of 50 mg/kg, 30 minutes prior to ROT administration. ROT administration caused significant reduction in endogenous antioxidants such as superoxide dismutase, catalase, and glutathione. ROT challenge-induced lipid peroxidation evidenced by increased malondialdehyde following perturbation of antioxidant defense. Apart from oxidative stress, ROT also activated proinflammatory cytokines and enhanced inflammatory mediators such as cyclooxygenase-2 and inducible nitric oxide synthase. The immunofluorescence analysis revealed a significant increase in the number of activated microglia and astrocytes accompanied by a significant loss of dopamine (DA) neurons in the substantia nigra pars compacta area upon ROT injection. However, treatment with FA rescued DA neurons in substantia nigra pars compacta area and nerve terminals in the striatum from the ROT insult. FA treatment also restored antioxidant enzymes, prevented depletion of glutathione, and inhibited lipid peroxidation. Following treatment with FA, the inflammatory mediators such as cyclooxygenase-2 and inducible nitric oxide synthase and proinflammatory cytokines were also reduced. Further, the results were supported by a remarkable reduction of Iba-1 and GFAP hyperactivity clearly suggests attenuation of microglial and astrocytic activation. Results of our study suggest that FA has promising neuroprotective effect against degenerative changes in PD, and the protective effects are mediated through its antioxidant and anti inflammatory properties. PMID- 26504376 TI - Social representation of hearing aids: cross-cultural study in India, Iran, Portugal, and the United Kingdom. AB - BACKGROUND: The current study was aimed at understanding the social representation of hearing aids in India, Iran, Portugal, and the United Kingdom. We also compared these results to explore the cross-cultural differences and similarities among these countries. METHODS: The study involved a cross-sectional design, and the data were collected from four different countries using the snowball sampling method. Data were analyzed using a content analysis to identify the most-similar categories of responses reported, a co-occurrences analysis to see which of these categories are reported commonly, and a chi-square analysis to study if there was any association between positive, neutral, and negative connotations among participants in different countries. RESULTS: The current study revealed four different social representations of hearing aids from India, Iran, Portugal, and the United Kingdom, and also a global index. CONCLUSION: The study results provide very useful insights into how hearing aids are represented in the society. These findings may have important implications for public education and also for manufacturers from the viewpoint of designing and marketing hearing aids in different countries. PMID- 26504377 TI - Wheezing, a significant clinical phenotype of COPD: experience from the Taiwan Obstructive Lung Disease Study. AB - BACKGROUND: COPD is an important public health challenge with significant heterogeneity of clinical presentation and disease progression. Clinicians have been trying to find phenotypes that may be linked to distinct prognoses and different therapeutic choices. Not all patients with COPD present with wheezing, a possible clinical phenotype that can help differentiate patient subgroups. METHODS: The Taiwan Obstructive Lung Disease study was a retrospective, multicenter research study to investigate the treatment patterns of COPD after the implementation of the Global Initiative for Chronic Obstructive Lung Disease 2011 guidelines. Between November 2012 and August 2013, medical records were retrieved from patients with COPD aged >=40 years; patients diagnosed with asthma were excluded. Demographic data, lung function, symptom scores, and acute exacerbation were recorded and analyzed, and the differences between patients with and without wheezing were evaluated. RESULTS: Of the 1,096 patients with COPD, 424 (38.7%) had the wheezing phenotype. The wheezing group had significantly higher COPD Assessment Test scores (12.4+/-7.8 versus 10.5+/-6.7, P<0.001), higher modified Medical Research Council grade (2.0+/-1.0 versus 1.7+/ 0.9, P<0.001), and more acute exacerbations within the past year (0.9+/-1.3 versus 0.4+/-0.9, P<0.001) than the nonwheezing group. The postbronchodilator forced expiratory volume in 1 second was lower in wheezing patients (1.2+/-0.5 L versus 1.5+/-0.6 L, P<0.001). Even in patients with maintenance treatment fitting the Global Initiative for Chronic Obstructive Lung Disease 2011 guidelines, the wheezing group still had worse symptom scores and more exacerbations. CONCLUSION: Wheezing is an important phenotype in patients with COPD. Patients with COPD having the wheezing phenotype are associated with worse symptoms, more exacerbations, and worse lung function. PMID- 26504378 TI - A longitudinal, retrospective cohort study on the impact of roflumilast on exacerbations and economic burden among chronic obstructive pulmonary disease patients in the real world. AB - BACKGROUND: Roflumilast is approved in the United States to reduce the risk of COPD exacerbations in patients with severe COPD. Exacerbation rates, health care resource utilization (HCRU), and costs were compared between roflumilast patients and those receiving other COPD maintenance drugs. METHODS: LifeLinkTM Health Plan Claims Database was used to identify patients diagnosed with COPD who initiated roflumilast (roflumilast group) or >=3 other COPD maintenance drugs (non roflumilast group) from May 1, 2011 to December 31, 2012. Patients must have been enrolled for 12 months before (baseline) and 3 months after (postindex) the initiation date, >=40 years old, not systemic corticosteroid dependent, and without asthma diagnosis at baseline. Difference-in-difference models compared change from baseline in exacerbations, HCRU (office, emergency visits, and hospitalizations), and total costs between groups, adjusting for baseline differences. RESULTS: A total of 14,211 patients (roflumilast, n=710; non roflumilast, n=13,501) were included. During follow-up, the rate of overall exacerbations per patient per month decreased by 11.1% in the roflumilast group and increased by 15.9% in the non-roflumilast group (P<0.001). After controlling for baseline differences, roflumilast-treated patients experienced a greater reduction in exacerbations (0.0160 fewer exacerbations per month, P=0.01), numerically greater reductions in hospital admissions (0.003 fewer per month, P=0.57), office visits (0.46 fewer per month, P=0.26), and total costs from baseline compared with non-roflumilast patients ($116 less per month, P=0.62). CONCLUSION: In a real-world setting, patients initiating roflumilast experienced reductions in exacerbations versus patients treated with other COPD medications. PMID- 26504379 TI - Endoscopic bronchial valve treatment: patient selection and special considerations. AB - As well as lung volume reduction surgery, different minimally invasive endoscopic techniques are available to achieve lung volume reduction in patients with severe emphysema and significant hyperinflation. Lung function parameters and comorbidities of the patient, as well as the extent and distribution of the emphysema are factors to be considered when choosing the patient and the intervention. Endoscopic bronchial valve placement with complete occlusion of one lobe in patients with heterogeneous emphysema is the preferred technique because of its reversibility. The presence of high interlobar collateral ventilation will hinder successful treatment; therefore, endoscopic coil placement, polymeric lung volume reduction, or bronchoscopic thermal vapor ablation as well as lung volume reduction surgery can be used for treating patients with incomplete fissures. The effect of endoscopic lung volume reduction in patients with a homogeneous distribution of emphysema is still unclear and this subgroup should be treated only in clinical trials. Precise patient selection is necessary for interventions and to improve the outcome and reduce the risk and possible complications. Therefore, the patients should be discussed in a multidisciplinary approach prior to determining the most appropriate treatment for lung volume reduction. PMID- 26504380 TI - The effect of dietary antioxidant on the COPD risk: the community-based KoGES (Ansan-Anseong) cohort. AB - BACKGROUND: Dietary antioxidants have been suggested to have protective role against chronic obstructive pulmonary disease (COPD), but few prospective studies examined this relationship. The prospective study was conducted to evaluate the effect of dietary antioxidants on COPD risk and lung function in the Korean population. METHODS: The data were collected from the community-based Korean Genome Epidemiology Study (KoGES) cohort. To diagnose COPD, forced expiratory volume (FEV1) and forced vital capacity (FVC) were measured by spirometry. The dietary intake of antioxidant vitamins was estimated from validated Food Frequency Questionnaire. For the analysis, 325 COPD patients and 6,781 at risk subjects were selected from the cohort of 10,038 subjects. Multiple logistic regression models were used to examine the odds ratio (OR) after adjusting for age, sex, marital status, income, history of asthma, history of tuberculosis, and smoking. RESULTS: The risk of COPD was positively associated with aging, low education, low household income, lower body mass index, and cigarette smoking. The risk of COPD decreased with increase in the dietary vitamin C (ORQ1 vs Q5=0.66, P trend=0.03) and vitamin E (ORQ1 vs Q5=0.56, P trend=0.05) intake, predominantly, in men (P trend=0.01 and 0.05 for vitamins C and E, respectively). In addition, the lung function was significantly improved with increase in vitamins C (FEV1, P=0.04; FVC, P=0.03) and E (FEV1, P=0.03; FVC, P=0.04) intake. No statistically significant interactions were observed between smoking and vitamin C or E intake in relation to COPD risk among men. CONCLUSION: Our results suggest the independent beneficial effect of antioxidants, particularly vitamins C and E, on COPD risk and lung function in men. PMID- 26504381 TI - Sodium-22-radiolabeled silica nanoparticles as new radiotracer for biomedical applications: in vivo positron emission tomography imaging, biodistribution, and biocompatibility. AB - Despite their advantageous chemical properties for nuclear imaging, radioactive sodium-22 ((22)Na) tracers have been excluded for biomedical applications because of their extremely long lifetime. In the current study, we proposed, for the first time, the use of (22)Na radiotracers for pre-clinical applications by efficiently loading with silica nanoparticles (SiNPs) and thus offering a new life for this radiotracer. Crown-ether-conjugated SiNPs (300 nm; -0.18+/-0.1 mV) were successfully loaded with (22)Na with a loading efficacy of 98.1%+/-1.4%. Noninvasive positron emission tomography imaging revealed a transient accumulation of (22)Na-loaded SiNPs in the liver and to a lower extent in the spleen, kidneys, and lung. However, the signal gradually decreased in a time dependent manner to become not detectable starting from 2 weeks postinjection. These observations were confirmed ex vivo by quantifying (22)Na radioactivity using gamma-counter and silicon content using inductively coupled plasma-mass spectrometry in the blood and the different organs of interest. Quantification of Si content in the urine and feces revealed that SiNPs accumulated in the organs were cleared from the body within a period of 2 weeks and completely in 1 month. Biocompatibility evaluations performed during the 1-month follow-up study to assess the possibility of synthesized nanocarriers to induce oxidative stress or DNA damage confirmed their safety for pre-clinical applications. (22)Na-loaded nanocarriers can thus provide an innovative diagnostic agent allowing ultra sensitive positron emission tomography imaging. On the other hand, with its long lifetime, onsite generators or cyclotrons will not be required as (22)Na can be easily stored in the nuclear medicine department and be used on-demand. PMID- 26504382 TI - In vivo biocompatibility of new nano-calcium-deficient hydroxyapatite/poly-amino acid complex biomaterials. AB - OBJECTIVE: To evaluate the compatibility of novel nano-calcium-deficient hydroxyapatite/poly-amino acid (n-CDHA/PAA) complex biomaterials with muscle and bone tissue in an in vivo model. METHODS: Thirty-two New Zealand white rabbits were used in this study. Biomaterials were surgically implanted into each rabbit in the back erector spinae and in tibia with induced defect. Polyethylene was implanted into rabbits in the control group and n-CDHA/PAA into those of the experimental group. Animals were examined at four different points in time: 2 weeks, 4 weeks, 12 weeks, and 24 weeks after surgery. They were euthanized after embolization. Back erector spinae muscles with the surgical implants were examined after hematoxylin and eosin (HE) staining at these points in time. Tibia bones with the surgical implants were examined by X-ray and scanning electron microscopy (SEM) at these points in time to evaluate the interface of the bone with the implanted biomaterials. Bone tissues were sectioned and subjected to HE, Masson, and toluidine blue staining. RESULTS: HE staining of back erector spinae muscles at 4 weeks, 12 weeks, and 24 weeks after implantation of either n CDHA/PAA or polyethylene showed disappearance of inflammation and normal arrangement in the peripheral tissue of implant biomaterials; no abnormal staining was observed. At 2 weeks after implantation, X-ray imaging of bone tissue samples in both experimental and control groups showed that the peripheral tissues of the implanted biomaterials were continuous and lacked bone osteolysis, absorption, necrosis, or osteomyelitis. The connection between implanted biomaterials and bone tissue was tight. The results of HE, Masson, toluidine blue staining and SEM confirmed that the implanted biomaterials were closely connected to the bone defect and that no rejection had taken place. The n-CDHA/PAA biomaterials induced differentiation of a large number of chondrocytes. New bone trabecula began to form at 4 weeks after implanting n-CDHA/PAA biomaterials, and lamellar bone gradually formed at 12 weeks and 24 weeks after implantation. Routine blood and kidney function tests showed no significant changes at 2 weeks and 24 weeks after implantation of both biomaterials. CONCLUSION: n-CDHA/PAA composites showed good compatibility in in vivo model. In this study, n-CDHA/PAA were found to be safe, nontoxic, and biologically active in bone repair. PMID- 26504383 TI - Combination of glycosphingosomes and liposomal doxorubicin shows increased activity against dimethyl-alpha-benzanthracene-induced fibrosarcoma in mice. AB - The present study aimed to assess the antitumor effect of glycosphingolipid incorporated liposomes (glycosphingosomes) in combination with liposomal doxorubicin (Lip-Dox) in a mouse model of fibrosarcoma. Glycosphingosomes were prepared by incorporating glycosphingolipids isolated from Sphingomonas paucimobilis into the liposomes of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, cholesterol, and cardiolipin. Tumors were induced by administering dimethyl-alpha benzanthracene, and tumor-bearing mice were treated with various formulations of Dox, including free Dox, Lip-Dox, or glycosphingosomes + Lip-Dox. Mice were observed for 90 days to monitor their survival and tumor size. Free Dox, but not Lip-Dox or a combination of glycosphingosomes and Lip-Dox, caused the substantial depletion of leukocytes and significantly increased the levels of lactate dehydrogenase and creatinine kinase in mice. Tumor-bearing mice treated with a combination of glycosphingosomes and Lip-Dox showed restricted tumor growth and increased survival when compared to those treated with free Dox or Lip-Dox. The results of the present study suggest that a combination of glycosphingosomes and Lip-Dox may prove to be very effective in the treatment of tumors. PMID- 26504384 TI - Oral administration of encapsulated bovine lactoferrin protein nanocapsules against intracellular parasite Toxoplasma gondii. AB - Toxoplasma gondii is a deadly intracellular parasite known to reside in every nucleated cell and known to cause severe complications in immunocompromised host. Standard drugs are cost effective and cause side effects, therefore, there is a necessity for a new drug molecule with immunomodulatory potential. Lactoferrin (Lf) is a natural milk protein, which has shown antimicrobial properties in its nanoformulation using alginate chitosan calcium phosphate bovine lactoferrin nanocapsules (AEC-CCo-CP-bLf-NCs). The present study was aimed to analyze and compare the effect of bovine Lf (bLf) in its native as well as nanoformulation (AEC-CCo-CP-bLf-NC) against coccidian parasite T. gondii. In vitro analysis has shown a significant increase in nitric oxide production and low parasitemia in in vitro cell culture model. In vivo BALB/c mice model have been used to develop human toxoplasmosis model. After treatment with NCs it has substantially increased the bioavailability of the protein and showed comparatively increased levels of reactive oxygen species, nitric oxide production, and Th1 cytokine which helped in parasite clearance. The mechanism of action of NCs has been clarified by immunoreactivity analysis, which showed accumulation of Lf in macrophages of various visceral organs, which is the site of parasite multiplication. Effect of NCs has significantly decreased (P<0.05) the parasite load in various organs and helped survival of mice till day 25 postinfection. Fe metabolism inside the mice has been found to be maintained even after administration of mono form of Lf, this indicates novelty of Lf protein. From the present study we concluded that nanoformulation did not reduce the therapeutic potential of Lf protein; however, nanoformulation has enhanced the stability of the protein and shown anti-toxoplasmal activity. Our study presents for the first time nanoformulation of Lf protein against Toxoplasma, which has advantages over the standard drug therapy without any side effects. PMID- 26504386 TI - Preparation, characterization, in vivo pharmacokinetics, and biodistribution of polymeric micellar dimethoxycurcumin for tumor targeting. AB - Dimethoxycurcumin (DMC) is an analog of curcumin with superior efficacy in various disease models. Currently, drug delivery system research on DMC is very limited, and it has become a huge challenge to realize further developments and clinical applications. In the present study, a kind of amphiphilic block copolymer, N-t-butoxycarbonyl-phenylalanine terminated monomethoxyl poly (ethylene glycol)-b-poly (epsilon-caprolactone), or mPEG-PCL-Phe(Boc), was prepared from monomethoxyl poly (ethylene glycol)-b-poly (epsilon-caprolactone) (mPEG-PCL) with its hydroxyl terminal chemically converted into N-t butoxycarbonyl-phenylalanine (Boc-Phe). This copolymer was determined to have a fairly low critical micelle concentration (2.56*10(-3) mg/mL) and passive targeting potential to tumor tissue, and thus was applied to develop a polymeric micellar formulation of DMC for the first time. The DMC-loaded micelles prepared by thin-film hydration method had typical shell-core structure, with an average particle size of 17.9+/-0.4 nm and a polydispersity index of 0.045+/-0.011. The drug loading capacity and entrapment efficiency were 9.94%+/-0.15% and 97.22%+/ 0.18%, respectively, indicating a high-affinity interaction between DMC and the copolymer. At a concentration of 2 mg/mL, the reconstituted micelle solution could be maintained for at least 10 days at room temperature, and displayed a low initial burst release followed by a sustained release in vitro. Pharmacokinetic study in rats revealed that in vivo drug exposure of DMC was significantly increased and prolonged by intravenously administering DMC-loaded micelles when compared with the same dose of free DMC dissolved in dimethyl sulfoxide. Furthermore, in vivo distribution results from tumor-bearing nude mice demonstrated that this micellar formulation significantly changed the biodistribution profile of DMC and increased drug accumulation in tumors. Therefore, the polymeric micellar formulation of DMC, based on the amphiphilic block copolymer, mPEG-PCL-Phe(Boc), could provide a desirable method for delivering DMC, especially for applications in cancer therapy. PMID- 26504387 TI - Efficacy and safety of generic escitalopram (Lexacure((r))) in patients with major depressive disorder: a 6-week multicenter, randomized, rater-blinded, escitalopram-comparative, non-inferiority study. AB - OBJECTIVES: The primary aim of this non-inferiority study was to investigate the clinical effectiveness and safety of generic escitalopram (Lexacure((r))) versus branded escitalopram (Lexapro((r))) for patients with major depressive disorder (MDD). METHODS: The present study included 158 patients, who were randomized (1:1) to receive a flexible dose of generic escitalopram (n=78) or branded escitalopram (n=80) over a 6-week single-blind treatment period. The clinical benefits in the two groups were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS), the 17-item Hamilton Depression Rating Scale (HDRS), the Clinical Global Impressions-Severity scale (CGI-S), and the Clinical Global Impressions-Improvement scale (CGI-I) at baseline, week 1, week 2, week 4, and week 6. The frequency of adverse events (AEs) was also assessed to determine safety at each follow-up visit. RESULTS: During the 6-week study period, 30 patients (38.5%) from the generic escitalopram group and 28 patients (30.0%) from the branded escitalopram group dropped out of the study (P=0.727). The MADRS, HDRS, CGI-S, and CGI-I scores significantly decreased in both groups, and there were no significant differences between the groups. At week 6, 28 patients (57.1%) in the generic escitalopram group and 35 patients (67.3%) in the branded escitalopram group had responded to treatment (as indicated by a >=50% decrease from the baseline MADRS score; P=0.126), and the remission rates (MADRS score: <=10) were 42.9% (n=21) in generic escitalopram group and 53.8% (n=28) in the branded escitalopram group (P=0.135). The most frequently reported AEs were nausea (17.9%), sleepiness/somnolence (7.7%), weight gain (3.8%), and dry mouth (2.6%) in the generic escitalopram group and nausea (20.0%), sleepiness/somnolence (3.8%), weight gain (2.5%), and dry mouth (2.5%) in the branded escitalopram group. CONCLUSION: The present non-inferiority study demonstrated that generic escitalopram is a safe and an effective initial treatment for patients with MDD and may also be considered as an additional therapeutic option for this population. PMID- 26504385 TI - Nanotechnology in dentistry: prevention, diagnosis, and therapy. AB - Nanotechnology has rapidly expanded into all areas of science; it offers significant alternative ways to solve scientific and medical questions and problems. In dentistry, nanotechnology has been exploited in the development of restorative materials with some significant success. This review discusses nanointerfaces that could compromise the longevity of dental restorations, and how nanotechnolgy has been employed to modify them for providing long-term successful restorations. It also focuses on some challenging areas in dentistry, eg, oral biofilm and cancers, and how nanotechnology overcomes these challenges. The recent advances in nanodentistry and innovations in oral health-related diagnostic, preventive, and therapeutic methods required to maintain and obtain perfect oral health, have been discussed. The recent advances in nanotechnology could hold promise in bringing a paradigm shift in dental field. Although there are numerous complex therapies being developed to treat many diseases, their clinical use requires careful consideration of the expense of synthesis and implementation. PMID- 26504388 TI - Electroconvulsive therapy treatment in patients with somatic symptom and related disorders. AB - OBJECTIVE: Medically unexplained somatic complaints are highly prevalent, and lead to significant impairment and disability. The number of effective treatment modalities for somatic symptom and related disorders (SSDs) or somatoform disorders (SDs) remains limited. To date, there is no formal indication for electroconvulsive therapy (ECT) in SSD or SD. We report on the largest case series to date regarding the effectiveness of ECT in patients with SSD and SD. METHODS: A retrospective chart review of all patients treated with an index course of ECT at the Neuropsychiatric Program at the University of British Columbia Hospital from 2000 to 2010 was conducted. The primary outcomes consisted of changes in pseudoneurologic symptoms, pain symptoms, cardiopulmonary symptoms, and gastrointestinal symptoms. Complaints were examined pre- and post-ECT. RESULTS: Twenty-eight participants were included in this study. Twenty-one participants received right unilateral ECT. Six received bifrontal ECT. One received bitemporal ECT. Eighteen of 21 participants reported improvement in pseudoneurologic symptoms; eleven of 14 participants reported improvement in pain symptoms; one participant reported improvement in cardiopulmonary symptoms; and one of two participants reported improvement in gastrointestinal symptoms. This paper discusses the putative mechanism of action of ECT in the treatment of SD/SSD. CONCLUSION: This retrospective study suggests that ECT could be included as part of the existing treatment for refractory SSD and SD, particularly in refractory cases with comorbid mood disorders. PMID- 26504389 TI - Variation of the default mode network with altered alertness levels induced by propofol. AB - BACKGROUND: The default mode network (DMN) is closely associated with the maintenance of alertness and cognitive functions. This study aimed to observe the changes in DMN induced by increasing doses of propofol and progressively deepening sedation. METHODS: Twelve healthy subjects were selected; they received target-controlled infusion of propofol (1.0 and 3.0 MUg/mL of plasma) and underwent functional magnetic resonance imaging before sedation and when they achieved light and deep sedation states. The average degree, average shortest path length, global efficiency, local efficiency, and clustering coefficient of DMN were assessed to study the overall and internal changes of DMN with gradual changes in alertness level, as well as the relationship between thalamus and DMN. Meanwhile, basic vital signs and respiratory inhibition were recorded. RESULTS: DMN parameters were gradually inhibited with decreasing level of alertness, the differences were significant between light sedation and awake states (all P<0.01), but not between deep and light sedation states. However, the shortest path lengths of the posterior cingulate cortex, medial prefrontal cortex, and lateral parietal cortexes in the DMN were significantly increased under deep sedation. CONCLUSION: Overall, DMN is propofol-sensitive. A small dose of propofol can significantly inhibit the DMN, affecting the level of alertness. The posterior cingulate cortex, medial prefrontal cortex, and lateral parietal cortexes in the DMN are less sensitive to propofol, and could be significantly inhibited by a higher concentration of propofol, further reducing the level of alertness. PMID- 26504390 TI - Clinical correlates of complicated grief among individuals with acute coronary syndromes. AB - OBJECTIVE: The study aimed at exploring bereavement and complicated grief (CG) symptoms among subjects without a history of coronary heart disease (CHD) at the time of a first acute coronary syndrome (ACS) and to evaluate the relationship of CG symptoms and ACS. METHOD: Overall, 149 subjects with ACS (namely, acute myocardial infarct with or without ST-segment elevation or unstable angina), with no previous history of CHD, admitted to three cardiac intensive care units were included and evaluated by the Structured Clinical Interview for Complicated Grief (SCI-CG), Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and the 36-item Short-Form Health Survey (MOS-SF-36). RESULTS: Of the total sample of 149 subjects with ACS, 118 (79.2%) met criteria for DSM-5 persistent complex bereavement disorder. Among these, subjects who lost a partner, child, or sibling were older (P=0.008), less likely to be working (P=0.032), and more likely to be suffering from hypertension (P=0.021), returned higher scores on the SCI-CG (P=0.001) and developed the index ACS more frequently between 12 and 48 months after the death than those who lost a parent or another relative (P<=0.0001). The occurrence of ACS 12-48 months (P=0.019) after the loss was positively correlated with SCI-CG scores. An inverse relationship with SCI-CG scores was observed for patients who experienced ACS more than 48 months after the loss (P=0.005). The SCI-CG scores significantly predicted lower scores on the "general health" domain of MOS-SF-36 (P=0.030), as well as lower scores on "emotional well-being" domain (P=0.010). CONCLUSION: A great proportion of subjects with ACS report the loss of a loved one. Among these, the loss of a close relative and the severity of CG symptoms are associated with poorer health status. Our data corroborate previous data indicating a strong relationship between CG symptoms and severe cardiac problems. PMID- 26504391 TI - Effectiveness of cognitive behavioral therapy integrated with systematic desensitization, cognitive behavioral therapy combined with eye movement desensitization and reprocessing therapy, and cognitive behavioral therapy combined with virtual reality exposure therapy methods in the treatment of flight anxiety: a randomized trial. AB - The purpose of the research was to compare the effectiveness of the following treatment methods for fear of flying: cognitive behavioral therapy (CBT) integrated with systematic desensitization, CBT combined with eye movement desensitization and reprocessing therapy, and CBT combined with virtual reality exposure therapy. Overall, our findings have proven the efficacy of all interventions in reducing fear of flying in a pre- to post-treatment comparison. All groups showed a decrease in flight anxiety, suggesting the efficiency of all three treatments in reducing self-report measures of fear of flying. In particular, our results indicated significant improvements for the treated patients using all the treatment programs, as shown not only by test scores but also by participation in the post-treatment flight. Nevertheless, outcome measures maintained a significant effect at a 1-year follow-up. In conclusion, combining CBT with both the application of eye movement desensitization and reprocessing treatment and the virtual stimuli used to expose patients with aerophobia seemed as efficient as traditional cognitive behavioral treatments integrated with systematic desensitization. PMID- 26504392 TI - Cognitive reserve and Abeta1-42 in mild cognitive impairment (Argentina Alzheimer's Disease Neuroimaging Initiative). AB - BACKGROUND: The purpose of this study was to investigate the relationship between cognitive reserve and concentration of Abeta1-42 in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment, those with Alzheimer's disease, and in control subjects. METHODS: Thirty-three participants from the Argentina Alzheimer's Disease Neuroimaging Initiative database completed a cognitive battery, the Cognitive Reserve Questionnaire (CRQ), and an Argentinian accentuation reading test (TAP-BA) as a measure of premorbid intelligence, and underwent lumbar puncture for CSF biomarker quantification. RESULTS: The CRQ significantly correlated with TAP-BA, education, and Abeta1-42. When considering Abeta1-42 levels, significant differences were found in CRQ scores; higher levels of CSF Abeta1-42 were associated with higher CRQ scores. CONCLUSION: Reduced Abeta1-42 in CSF is considered as evidence of amyloid deposition in the brain. Previous results suggest that individuals with higher education, higher occupational attainment, and participation in leisure activities (cognitive reserve) have a reduced risk of developing Alzheimer's disease. Our results support the notion that enhanced neural activity has a protective role in mild cognitive impairment, as evidenced by higher CSF Abeta1-42 levels in individuals with more cognitive reserve. PMID- 26504393 TI - Predictors of trauma in bank employee robbery victims. AB - In the literature, there are many studies that have investigated the psychological reactions resulting from traumatic events of varying degrees, such as wars, natural disasters, and acts of violence. Few, however, are the searches performed on employees who are victims of robbery. We carried out a research to assess the psychological reactions of 644 bank employees who had been victims of robbery, especially with regard to the possible development of post-traumatic stress disorder (PTSD). The aim of this study was to evaluate the variables pre-, peri-, and postrobbery trauma in relation to the development of psychopathological symptoms. The exploration of the reactions after the robbery was carried out on 644 employees of a banking institution, present throughout the national territory, through a survey, consisting of a general description of the event, the Impact of Event Scale Revised-6 scale, and the General Health Questionnaire-12, during the days after the robbery. The analysis showed that the development of pretrauma variables is not significant and that peritrauma variables are partially significant. In particular, being directly involved in the robbery, the thought of being hurt, and the feeling of intense fear are associated with posttraumatic symptoms. Finally, among the posttrauma variables, anxiety and depression played a major role. Surprisingly, a lower level of self confidence seems to be related negatively to the PTSD symptomatology. PMID- 26504394 TI - A case of hypertrophic olivary degeneration after resection of cavernomas of the brain stem and review of the literature. AB - Hypertrophic olivary degeneration is a transsynaptic form of degeneration, which is also a result of primary or secondary lesion and can damage the dento-rubro olivary pathway. The dento-rubro-olivary pathway was first described by Guillain and Mollaret and is referred to as "the triangle of Guillain and Mollaret". Multiple factors can destroy the dento-rubro-olivary pathway, such as surgical operation, hemorrhage, tumor, trauma, inflammation, demyelination, degeneration, and radiation damage. All of the above factors can result in delayed hypertrophic olivary degeneration. Articles related to this disease cover etiology, clinical presentation, pathology changes, etc. However, to our knowledge, there has been no literature reporting the use of diffusion tensor imaging and diffusion tensor tractography to improve the diagnosis of hypertrophic olivary degeneration following resection of cavernomas in the brain stem. Herein, we report a case who was diagnosed with hypertrophic olivary degeneration following resection of cavernomas of the brain stem, verify the significance of diffusion tensor imaging and diffusion tensor tractography, and review previous literature. The development of imageology promotes and improves hypertrophic olivary degeneration diagnosis and differential diagnosis. PMID- 26504395 TI - Cigarette smoke is a risk factor for severity and treatment outcome in patients with culture-positive tuberculosis. AB - OBJECTIVE: Smoking has been associated with tuberculosis (TB); however, the effects of smoking on the effectiveness of TB treatment remain unclear. MATERIALS AND METHODS: Data were retrieved from case notes and interviews of subjects registered in the TB-reporting system from 2010 to 2012. Study cases were defined as subjects with TB-positive sputum cultures, whereas the controls were defined as subjects with non-TB-related pulmonary diseases. Statistical analyses included logistic regression and multivariate Cox proportional hazard regression models. RESULTS: A total of 245 cases with cultures positive for TB and 114 controls with non-TB-related pulmonary diseases and negative sputum cultures were recruited. Current smokers had the highest failure rate (33%) for TB treatment, and they had the most severe pulmonary lesions based on chest X-ray grading. Current smokers had a 1.36-fold (95% confidence interval 1.03-2.36, P<0.05) higher odds ratio for cultures positive for TB compared with nonsmokers. In subjects with TB-positive cultures, current smoking was associated with an increase in treatment days required for cultures to convert from positive to negative (hazard ratio 1.12, 95% confidence interval 1.03-1.39; P<0.05). CONCLUSION: Longer periods of treatment may be required for TB patients who are current smokers. PMID- 26504396 TI - Comparison of efficacy of the intermittent pneumatic compression with a high- and low-pressure application in reducing the lower limbs phlebolymphedema. AB - INTRODUCTION: The primary lymphedema and chronic venous insufficiency present an important medical problem, and effective physical therapeutic methods to treat this problem are still at the search phase. The aim of this study was to compare the efficacy of intermittent pneumatic compression (IPC) of a high- or low pressure level in the treatment of primary phlebolymphedema of the lower limbs. METHODS: The study included 81 patients with chronic venous insufficiency and primary lymphedema of the lower limbs. Group A consisted of 28 patients who underwent a monthly antiedematous therapy including a manual lymphatic drainage, multilayer bandaging, and IPC with the output pressure of 120 mmHg. Group B consisted of 27 patients who underwent the same basic treatment as group A and IPC with the output pressure of 60 mmHg. Group C (control) consisted of 26 patients who underwent only a basic treatment - without IPC. RESULTS: After completion of the study, it was found that the greatest reduction of edema occurred in patients who underwent treatment with a pressure of 120 mmHg. The comparison of percentage reduction of edema showed a statistically significant advantage of the group A over groups B and C, both for the changes in the right (P=0.01) and the left limb (P=0.01). Results in patients undergoing intermittent compression of the lower pressure (60 mmHg) were similar to those obtained in the control group. CONCLUSION: The IPC with the pressure of 120 mmHg inside the chambers effectively helps to reduce a phlebolymphedema. Furthermore, it appears that the treatments with a pressure of 60 mmHg are ineffective and their application becomes useless only in the antiedematous therapy. PMID- 26504397 TI - Prognostic nutritional index before adjuvant chemotherapy predicts chemotherapy compliance and survival among patients with non-small-cell lung cancer. AB - BACKGROUND: Adjuvant chemotherapy after the complete resection of non-small-cell lung cancer (NSCLC) is now the standard of care. To improve survival, it is important to identify risk factors for the continuation of adjuvant chemotherapy. In this study, we analyzed chemotherapy compliance and magnitude of the prognostic impact of the prognostic nutritional index (PNI) before adjuvant chemotherapy. METHODS: We conducted a retrospective review of data from 106 patients who had received adjuvant chemotherapy. The adjuvant chemotherapy consisted of an oral tegafur agent (OT) or platinum-based chemotherapy (PB). The correlations between the PNI values and recurrence-free survival (RFS) were then evaluated. RESULTS: In the PB group, the percentage of patients who completed the four planned cycles of chemotherapy was not correlated with the PNI. In the OT group, however, a significant difference was observed in the percentage of patients who completed the planned chemotherapy according to the PNI before adjuvant chemotherapy. The RFS of patients with a PNI <50 before adjuvant chemotherapy was significantly poorer than that of the patients with a PNI >=50. A multivariate analysis showed that nodal metastasis and PNI before chemotherapy were independent predictors of the RFS. However, PNI before surgery was not a predictor of the RFS. In the subgroup analysis, PNI before chemotherapy was independent predictor of the RFS in the OT group (P=0.019), but not in the PB group (P=0.095). CONCLUSION: The PNI before adjuvant chemotherapy influenced the treatment compliance with the planned chemotherapy in the OT group, but not the PB group. In addition, a low PNI before adjuvant chemotherapy was associated with a poor RFS in a multivariate analysis, especially in the OT group. PMID- 26504398 TI - Pharmacologic rationale underlying the therapeutic effects of tiotropium/olodaterol in COPD. AB - Bronchodilators are the most important drugs used for the treatment of chronic obstructive pulmonary disease (COPD). In particular, these therapeutic agents are mostly long-acting compounds utilized via inhalation, and include LAMA (long acting muscarinic receptor antagonists) and LABA (long-acting beta2-adrenoceptor agonists). Because LAMA and LABA induce bronchodilation by distinct mechanisms of action, LABA/LAMA combinations provide a reciprocal potentiation of the pharmacological effects caused by each component. Hence, many COPD patients who do not achieve a satisfactory control of their symptoms using a single, either LAMA or LABA bronchodilator, can experience relevant benefits with the use of LAMA/LABA fixed combinations. Many different LAMA/LABA combinations have been recently developed and evaluated in randomized clinical trials. In this context, our review focuses on the pharmacological mechanisms underpinning the bronchodilation elicited by the LAMA tiotropium bromide and the LABA olodaterol. We also discuss the results of the most important clinical studies carried out in COPD patients to assess the efficacy and safety of tiotropium/olodaterol combinations. PMID- 26504399 TI - Upregulated matrix metalloproteinase-2 and downregulated tissue factor pathway inhibitor-2 are risk factors for lymph node metastasis and perineural invasion in pancreatic carcinoma. AB - BACKGROUND: Dysregulated expression of matrix metalloproteinase (MMP)-2 and tissue factor pathway inhibitor (TFPI)-2 is closely associated with tumorigenesis and tumor progression. The aim of this work was to determine the predictive values of MMP-2 and TFPI-2 in identifying lymph node metastasis (LNM) and perineural invasion (PNI) in pancreatic carcinoma. METHODS: Formalin-fixed and paraffin-embedded tissue samples containing pancreatic carcinoma tissues and their corresponding para-carcinoma tissues were obtained from 122 patients with pancreatic carcinoma. The expression levels of MMP-2 and TFPI-2 were evaluated by immunohistochemistry. The roles of MMP-2 and TFPI-2 in predicting LNM and PNI in pancreatic carcinoma were analyzed. RESULTS: The level of MMP-2 expression was markedly increased in pancreatic carcinoma tissues (76.9%) compared with para carcinoma tissues (29.2%; P<0.05). In contrast, there was obviously decreased TFPI-2 expression level in pancreatic carcinoma tissues (29.2%) compared with para-carcinoma tissues (77.7%; P<0.001). Additionally, MMP-2 expression was significantly positively correlated with LNM (r=0.468, P<0.01) and PNI (r=0.637, P<0.01). In contrast, TFPI-2 expression was strongly negatively correlated with LNM (r=-0.396, P<0.001) and PNI (r=-0.460, P<0.001). Logistic regression analysis showed that high MMP-2 expression and low TFPI-2 expression acted as independent predictors for LNM and PNI in pancreatic carcinoma. CONCLUSION: Taken together, our findings suggest that upregulated MMP-2 and downregulated TFPI-2 serve as useful predictors for a high risk of LNM and PNI. Obtaining information on the expression of MMP-2 and TFPI-2 before surgery may predict the occurrence of LNM and PNI, thereby permitting reasonable and effective surgical treatment for patients with pancreatic carcinoma. PMID- 26504400 TI - CXCL12 genetic variants as prognostic markers in nasopharyngeal carcinoma. AB - The chemokine receptor 4/chemokine ligand 12 (CXCR4/CXCL12) axis plays an important role in tumorigenesis, metastasis, and recurrence of tumors. Its single nucleotide polymorphisms (SNPs) are associated with patient survival in several types of cancer. However, the prognostic value of SNPs in nasopharyngeal carcinoma (NPC) has not been fully investigated. This retrospective study assessed the relationships between CXCR4 rs2228014 and CXCL12 rs1801157 polymorphisms and patient outcome in 222 patients newly diagnosed with NPC. The analysis found no significant correlation between the presence of both SNPs and clinicopathological factors. However, univariate analysis showed that N classification, clinical stage, and the CXCL12 rs1801157 polymorphism were significantly associated with distant metastasis-free survival (P=0.018, 0.028, and 0.013, respectively) and progression-free survival (P=0.007, 0.046, and 0.021, respectively). After adjusting clinicopathological factors, multivariate analysis identified CXCL12 rs1801157 as an independent prognostic factor for distant metastasis-free survival and progression-free survival (hazard ratio: 3.332; 95% confidence interval: 1.597-6.949; P=0.001 and hazard ratio: 2.665 95% confidence interval: 1.387-5.119; P=0.003, respectively). Our results suggest that CXCL12 rs1801157 AA genotype might serve as a potential prognostic factor in patients with NPC. PMID- 26504402 TI - Bias within economic evaluations - the impact of considering the future entry of lower-cost generics on currently estimated incremental cost-effectiveness ratios of a new drug. AB - BACKGROUND: Most economic evaluation models compare a new patented drug (NPRx) to a generic comparator. Drug costs within these models are usually limited to the retail cost of both drugs at the time of model conception. However, the retail cost of the NPRx is expected to drop once generic versions of this molecule are introduced following the expiration of the NPRx's patent. The objective of this study was to examine the impact on the incremental cost-effectiveness ratio (ICER) of the future introduction of lower-cost generic versions of the NPRx within the model's time horizon. METHODS: We examined the impact of this parameter with the use of two approaches: 1) a mathematical proof identifying its impact on the NPRx's ICER; and 2) applying this parameter to a previously published economic model comparing a NPRx to a generic comparator and identifying what would have been the NPRx's ICER had this model considered this parameter. RESULTS: As expected, both the mathematical proof and the application to the previously published economic model showed that considering the future introduction of lower-cost generic versions of the NPRx within the model's time horizon lowers the NPRx's ICER. The timing of the future entry of lower-cost generic molecules, their relative price compared to that of the patented version, and the discount rate applied to future costs all influenced the results. CONCLUSION: An ICER estimated within economic evaluations comparing NPRx to generic comparators which ignore the future introduction of lower-cost generic versions of the NPRx within the model's time horizon will tend to be overestimated. Inclusion of this parameter should be considered within future economic evaluations. PMID- 26504401 TI - Profile of anti-IL-5 mAb mepolizumab in the treatment of severe refractory asthma and hypereosinophilic diseases. AB - Asthma is a complex disorder frequently associated with a poor symptom control, concomitant morbidity, mortality, and significant health care costs due to lack of compliance or inadequate therapeutic options. Interleukin-5 (IL-5) plays a key role in the pathogenesis of eosinophilic disorders, and in the latest years has become a definite target for treatment. Besides asthma, other hypereosinophilic disorders include the hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, sinonasal polyposis, COPD with eosinophilic airway inflammation, allergic rhinitis, atopic dermatitis, eosinophilic esophagitis. The introduction of mepolizumab, a fully humanized monoclonal antibody that binds to IL-5, may represent a useful therapeutic option to control exacerbations and improve asthma-related quality of life in a subgroup of patients with persistent airway eosinophilia and moderate to severe asthma. Several studies carried out in recent years allow, at present, a careful patient selection for appropriate individualized treatment in severe asthma. Further research is anyway needed in order to better understand the pathogenetic mechanisms of asthma and to find new biomarkers. The high costs of biological agents as compared with standard drugs may be largely offset by increased clinical efficacy and good safety profile in selected patients. PMID- 26504403 TI - Cost-effectiveness analysis of pregabalin for treatment of chronic low back pain in patients with accompanying lower limb pain (neuropathic component) in Japan. AB - OBJECTIVE: To assess the cost-effectiveness of pregabalin for the treatment of chronic low back pain with accompanying neuropathic pain (CLBP-NeP) from the health care payer and societal perspectives. METHODS: The cost-effectiveness of pregabalin versus usual care for treatment of CLBP-NeP was evaluated over a 12 month time horizon using the incremental cost-effectiveness ratio (ICER). Quality adjusted life years (QALYs), derived from the five-dimension, five-level EuroQol (EQ-5D-5L) questionnaire, was the measure of effectiveness. Medical costs and productivity losses were both calculated. Expected costs and outcomes were estimated via cohort simulation using a state-transition model, which mimics pain state transitions among mild, moderate, and severe pain. Distributions of pain severity were obtained from an 8-week noninterventional study. Health care resource consumption for estimation of direct medical costs for pain severity levels was derived from a physician survey. The ICER per additional QALY gained was calculated and sensitivity analyses were performed to evaluate the robustness of the assumptions across a range of values. RESULTS: Direct medical costs and hospitalization costs were both lower in the pregabalin arm compared with usual care. The estimated ICERs in the base case scenarios were approximately Y2,025,000 and Y1,435,000 per QALY gained with pregabalin from the payer and societal perspectives, respectively; the latter included indirect costs related to lost productivity. Sensitivity analyses using alternate values for postsurgical pain scores (0 and 5), initial pain severity levels (either all moderate or all severe), and the actual EQ-5D-5L scores from the noninterventional study showed robustness of results, with ICERs that were similar to the base case. Development of a cost-effectiveness acceptability curve showed high probability (>=75%) of pregabalin being cost-effective. CONCLUSION: Using data and assumptions from routine clinical practice, pregabalin is cost effective for the treatment of CLBP-NeP in Japan. PMID- 26504404 TI - Chronic peritoneal dialysis in children. AB - The incidence of end-stage renal disease in children is increasing. Peritoneal dialysis (PD) is the modality of choice in many European countries and is increasingly applied worldwide. PD enables children of all ages to be successfully treated while awaiting the ultimate goal of renal transplantation. The advantages of PD over other forms of renal replacement therapy are numerous, in particular the potential for the child to lead a relatively normal life. Indications for commencing PD, the rationale, preparation of family, technical aspects, and management of complications are discussed. PMID- 26504405 TI - Changes in saccharin preference behavior as a primary outcome to evaluate pain and analgesia in acetic acid-induced visceral pain in mice. AB - Reflex-based procedures are important measures in preclinical pain studies that evaluate stimulated behaviors. These procedures, however, are insufficient to capture the complexity of the pain experience, which is often associated with the depression of several innate behaviors. While recent studies have made efforts to evidence the suppression of some positively motivated behaviors in certain pain models, they are still far from being routinely used as readouts for analgesic screening. Here, we characterized and compared the effect of the analgesic ibuprofen (Ibu) and the stimulant, caffeine, in assays of acute pain-stimulated and pain-depressed behavior. Intraperitoneal injection of acetic acid (AA) served as a noxious stimulus to stimulate a writhing response or depress saccharin preference and locomotor activity (LMA) in mice. AA injection caused the maximum number of writhes between 5 and 20 minutes after administration, and writhing almost disappeared 1 hour later. AA-treated mice showed signs of depression-like behaviors after writhing resolution, as evidenced by reduced locomotion and saccharin preference for at least 4 and 6 hours, respectively. Depression-like behaviors resolved within 24 hours after AA administration. A dose of Ibu (40 mg/kg) - inactive to reduce AA-induced abdominal writhing - administered before or after AA injection significantly reverted pain-induced saccharin preference deficit. The same dose of Ibu also significantly reverted the AA-depressed LMA, but only when it was administered after AA injection. Caffeine restored locomotion - but not saccharin preference - in AA-treated mice, thus suggesting that the reduction in saccharin preference - but not in locomotion - was specifically sensitive to analgesics. In conclusion, AA-induced acute pain attenuated saccharin preference and LMA beyond the resolution of writhing behavior, and the changes in the expression of hedonic behavior, such as sweet taste preference, can be used as a more sensitive and translational model to evaluate analgesics. PMID- 26504406 TI - Perspectives on the clinical significance of functional pain syndromes in children. AB - Functional pain syndromes (FPS) characterize a subset of individuals who experience pain and related symptoms and disability without clear structural or disease etiology. In the pediatric population, FPS hold high clinical importance due to significant prevalence rates and potential to persist into adulthood. Although extensive research has been executed to disambiguate FPS, the syndromes that fall within its spectrum remain conceptually complex and sometimes ill defined. This paper provides an overview of available research on the classification and multifaceted etiology of FPS in youth and their effects on interpersonal, psychological, and familial function. Vital aspects of a successful multidisciplinary approach to treating this population are described; however, it is evident that future research requires more longitudinal studies. PMID- 26504407 TI - Efficacy of needle-placement technique in radiofrequency ablation for treatment of lumbar facet arthropathy. AB - BACKGROUND: Many studies have assessed the efficacy of radiofrequency ablation to denervate the facet joint as an interventional means of treating axial low-back pain. In these studies, varying procedural techniques were utilized to ablate the nerves that innervate the facet joints. To date, no comparison studies have been performed to suggest superiority of one technique or even compare the prevalence of side effects and complications. MATERIALS AND METHODS: A retrospective chart review was performed on patients who underwent a lumbar facet denervation procedure. Each patient's chart was analyzed for treatment technique (early versus advanced Australian), preprocedural visual numeric scale (VNS) score, postprocedural VNS score, duration of pain relief, and complications. RESULTS: Pre- and postprocedural VNS scores and change in VNS score between the two groups showed no significant differences. Patient-reported benefit and duration of relief was greater in the advanced Australian technique group (P=0.012 and 0.022, respectively). The advanced Australian technique group demonstrated a significantly greater median duration of relief (4 months versus 1.5 months, P=0.022). Male sex and no pain-medication use at baseline were associated with decreased postablation VNS scores, while increasing age and higher preablation VNS scores were associated with increased postablation VNS scores. Despite increasing age being associated with increased postablation VNS scores, age and the advanced Australian technique were found to confer greater patient self reported treatment benefit. CONCLUSION: The advanced Australian technique provides a significant benefit over the early Australian technique for the treatment of lumbar facet pain, both in magnitude and duration of pain relief. PMID- 26504408 TI - Identifying patients at high risk of breast cancer recurrence: strategies to improve patient outcomes. AB - Identifying patients at high risk of breast cancer recurrence has important implications not only for enabling the ability to provide accurate information to patients but also the potential to improve patient outcomes. Patients at high recurrence risk can be offered appropriate treatment to improve the overall survival. However, the major challenge is identifying patients with early-stage breast cancer at lower risk who may be spared potentially toxic therapy. The successful integration of molecular assays into clinical practice may address the problem of overtreatment and improve overall patient outcomes. PMID- 26504409 TI - A clinical evaluation to determine the safety, pharmacokinetics, and pharmacodynamics of an inositol-stabilized arginine silicate dietary supplement in healthy adult males. AB - PURPOSE: The purpose of this study was to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of an oral inositol-stabilized arginine silicate dietary supplement. SUBJECTS AND METHODS: Ten healthy males, 26.7+/-5.4 years, took three 500 mg arginine silicate capsules (active product) for 14 days. The subjects attended test visits on Days 1 and 14. Fasting blood and saliva collections were performed predose and at 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours postdose for plasma arginine, serum silicon, and salivary nitric oxide (NO) + nitrite. RESULTS: Day 1 PK parameters (adjusted for body weight) for arginine were peak serum concentration (C Max) 30.06+/-7.80 MUg/mL, time it takes to reach peak serum concentration (t Max) 1.13+/-0.52 hours, and time required to reach half its original concentration (t 1/2) 15.93+/-9.55 hours and for silicon were C Max 2.99+/-0.63 MUg/mL, t Max 2.44+/-2.05 hours, and t 1/2 34.56+/-16.56 hours. After Day 1 dose, arginine levels increased at 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, and 5 hours (P<0.01) and silicon levels increased at 1 hour and 1.5 hours (P<0.05). After Day 14 dose, arginine levels increased at 0.5 hours, 1 hour, and 1.5 hours (P<0.05) and silicon levels increased at 1 hour, 1.5 hours, 2 hours, and 3 hours (P<0.01). After 14 days of use, baseline arginine trended toward being higher than baseline Day 1 (P=0.0645), and 4-hour postdose plasma arginine was significantly higher (P=0.0488) at Day 14 than Day 1. Although not a significant difference, NO, as measured as salivary nitrate, increased in four subjects and stayed the same in six subjects at 0.5 hours after the first dose (P=0.125). After 14 days of use, baseline NO levels increased in six subjects and stayed the same in four subjects; this shift was significant (P=0.031). CONCLUSION: The arginine silicate dietary supplement increases blood levels of arginine after a single dose within 30 minutes and blood levels of silicon for up to 1.5 hours. Blood levels of arginine, silicon, and NO (salivary nitrite) were elevated consistently after 14 days of use. The observed increase in baseline salivary nitrite is supporting information that there was some improvement in NO production. Further study on the effect of this supplement on NO production and the resulting physiological effect is warranted. Within the specific protocol of this study, the product was found to be safe. PMID- 26504410 TI - Panobinostat for the treatment of multiple myeloma: the evidence to date. AB - Multiple myeloma is a malignancy involving plasma cell proliferation within the bone marrow. Survival of patients diagnosed with myeloma has significantly improved in the last decade, following the approval of novel agents. Despite great strides achieved in the management of multiple myeloma, it is still considered an incurable disease as the majority of patients relapse after initiation of therapy. Additionally, the duration of response generally decreases with an increasing number of therapy lines. The need to overcome resistance to therapy dictates research into more potent agents and those with novel mechanisms of action. A therapeutic option for relapsed/refractory myeloma includes histone deacetylase inhibition. Various histone deacetylase inhibitors, including the newly approved panobinostat, are currently under evaluation in this setting. Panobinostat for multiple myeloma is used in combination with other potent therapeutic agents, such as proteasome inhibitors and steroids. Ongoing research evaluating other panobinostat-containing regimens will provide additional insight into its place in myeloma management. PMID- 26504411 TI - A rare cause of acute abdomen in adults: Parasitic infection-related acute appendicitis. AB - Ascaris lumbricoides is a common parasitic disease all over the world, especially in less developed countries. Acute appendicitis related to parasitic infection is a rare condition. Parasitic infections should be kept in mind in patients who are admitted to the emergency department with acute abdomen, especially in endemic areas. PMID- 26504412 TI - Effects of preoperative nutritional support on colonic anastomotic healing in malnourished rats. AB - OBJECTIVE: It has been proven that malnutrition increases postoperative morbidity and mortality, and it may also negatively affect wound healing in the gastrointestinal tract. In the literature, there is only one study evaluating the effects of preoperative nutritional support on colonic anastomotic healing under malnourished conditions. In order to improve the data on this topic, an experimental study was planned to evaluate the effects of preoperative nutritional support on colonic anastomotic healing in malnourished rats. MATERIAL AND METHODS: The study included 18 male Wistar albino rats divided into 3 groups. The control (C) group was fed ad libitum for 21 days. The malnutrition (M) group and preoperative nutrition (P) group were given 50% of the daily food consumed by the rats in Group C for 21 days to induce malnutrition. At the end of 21 days, Group P was fed ad libitum for 7 days (preoperative nutritional support). Colonic transection and end-to-end anastomosis was performed at 21 days in Group C and Group M and at 28 days in Group P. The rats were sacrificed at postoperative 4 days, anastomotic bursting pressure was measured, and samples were taken to analyze tissue hydroxyproline levels. RESULTS: Anastomotic bursting pressure was significantly higher in Group C than in Group M and Group P (p<0.05), and it was significantly higher in Group P than in Group M (p<0.05). Tissue hydroxyproline levels in Group P were found to be significantly higher than those in Group M and Group C (p<0.05). CONCLUSION: One week of preoperative nutritional support increases collagen synthesis in the colon and positively affects anastomotic healing under malnourished conditions. PMID- 26504413 TI - Immune profile of asplenic patients following single or double vaccine administration: A longitudinal cross-sectional study. AB - OBJECTIVE: Splenectomy poses a lifelong threat for the development of uncontrolled sepsis despite vaccination. As it is impractical to measure the levels of each antibody against 23 most frequent bacterial serotypes, different surrogate markers of immune response should be identified. MATERIAL AND METHODS: Forty-eight patients with benign disorders were vaccinated with Pneumo-23 and Act HIB before or at the day of surgery. The immunological response and opsonization capacity of the patients after splenectomy was analyzed through the quantitative measurement of IgG, IgM, C3, and C4 titers; flow-cytometric analysis of (CD3+) T lymphocytes and (CD19+) B-lymphocytes; and isolation of CD27+ B cells by immunomagnetic positive selection. Blood samples were drawn at the sixth month and 5 and 7 years after surgery. RESULTS: The mean follow-up period was 98.4 months. All the patients in this series had normal IgG, C3, C4 levels and a normal distribution of CD19+ B-cells and CD8+ T-cells in three follow-up periods. Moreover, C3 levels markedly improved to 133.5+/-37.3 mg/dL at 5 years and remained stable thereafter. CD19+ B-lymphocyte values have progressively improved to the normal range in 98% patients at 7 years. Further, low levels of CD27+ B cell population (memory cells) was observed in only 12.5% patients at the last follow-up. Adequate seroconversion of IgG, IgM with normal C3, C4, and CD19+ B cell levels were accomplished in almost all patients. Early postoperative death and late overwhelming infections did not occur. CONCLUSION: Our results are indicative of the resumption of the immune function following Pneumo-23 and Act HIB administrations, instigated by the probable activation of B cells and adequate production of C3, C4, IgG, and IgM antibodies in remote lymphoid tissues. PMID- 26504414 TI - The impact of weight gain during adjuvant chemotherapy on survival in breast cancer. AB - OBJECTIVE: Weight gain can be detected during adjuvant chemotherapy in breast cancer patients, leading to administration of lower drug doses than planned and a decrease in long-term survival. In this study, the effect of weight gain on survival in breast cancer patients was investigated. MATERIAL AND METHODS: Breast cancer patients treated with adjuvant chemotherapy between May 2002 and May 2003 were prospectively included in the study. Patients treated with neoadjuvant chemotherapy or with chemotherapy for metastatic disease were excluded from the study. Data regarding patients' demographic, clinical and pathologic characteristics and chemotherapy protocols were recorded. Patients were grouped as those with weight gain less than or more than 3 kg, and those with a body mass index of less than or more than 30. The impact of weight gain on patients' disease-free and overall survival was investigated. Log-rank test and Cox regression analyses were utilized for survival analyses. P<0.05 value was accepted as statistically significant. RESULTS: Eighty-eight consecutive female patients with a median age of 46 (29-71) were included in the study. Patients received anthracycline based chemotherapy protocols. Weight gain was detected in 79 patients (89.8%), with more than 3 kg weight gain detected in 38 patients (43.2%). In a median follow-up time of 98 months (62-120), distant metastases were detected in 21 patients (23.9%), and 11 patients (12.5%) died. Mean disease free survival of patients with a weight gain less than and more than 3 kg during chemotherapy was 89.1+/-3.9 and 84.7+/-4.2 months (p=0.007), whereas mean overall survival was 95.6+/-2.2 and 92.5+/-2.1 months (p=0.01), respectively. Mean disease-free survival of patients with a body mass index less than and more than 30 was 87.3+/-2.3 and 85.1+/-3.6 months (p=0.4), whereas mean overall survival was 94.2+/-2.3 and 92.1+/-1.1 months (p=0.35), respectively. CONCLUSION: Weight gain during adjuvant chemotherapy has a negative effect on both disease-free and overall survival in patients with breast cancer. PMID- 26504415 TI - Does endoscopic retrograde cholangiopancreatography have a negative effect on laparoscopic cholecystectomy? AB - OBJECTIVE: We have observed that patients who had undergone endoscopic retrograde cholangiopancreatography (ERCP) had some difficulties with laparoscopic cholecystectomy procedures. Through a retrospective study, we planned to compare the surgical procedures between patients who had undergone ERCP and those who had not in order to clarify this. MATERIAL AND METHODS: The results of 122 patients who had undergone ERCP because of choledocholithiasis before undergoing laparoscopic cholecystectomy procedures between 2008 and 2011 were compared to the values of 2140 patients operated because of cholelithiasis only within the same period. RESULTS: Among the patients who underwent surgical procedures following ERCP, 80 (65%) were female and 42 (35%) were male. The average age of the patients was 51.9 years (range: 20-83 years). The operation period after the procedure was 30.14 days (range: 1-93 days). Although the hospitalization period was 4.67 days (range: 1-22 days), the postoperative hospitalization period was 2.68 days (range: 1-15 days). Regarding the difficulty of operation, adhesion in 58 (47.5%) patients, bleeding in two (1.6%) patients, and conversion to open procedure in 12 (9.8) patients were observed. In two (1.6%) patients, bleeding and biliary fistula were the reasons for re-operation. CONCLUSION: Laparoscopic cholecystectomy is more complicated in patients who underwent ERCP. PMID- 26504416 TI - Endoscopic stent placement in the management of malignant colonic obstruction: Experiences from two centers. AB - OBJECTIVE: Intestinal obstruction due to colorectal tumors requires immediate surgical decompression. Endoscopic stent placement for acute malignant colonic obstruction is gaining widespread acceptance as an alternative to emergency surgery. Our aim in this study was to evaluate the success and complication rates of endoscopic stenting for malignant colonic obstruction. MATERIAL AND METHODS: Patients with acute malignant colonic obstruction who underwent endoscopic stenting between 2011-2014 were retrospectively reviewed. Data included demographic features, localization of obstruction, endoscopic stenting indications, rate of technical and clinical success, complications, morbidity and mortality. RESULTS: Endoscopic stent was successfully placed in 77 out of 82 procedures (93.9%). A colostomy was placed in five cases in which endoscopic stent could not be inserted. There were complications in seven patients with technically successful stents (9.0%). These included three stent migrations, one perforation, and rectal hemorrhage in three patients. There were no stent-related deaths. CONCLUSION: The mortality rate of emergency surgery for malignant bowel obstruction is relatively high. The use of colonic stents can avoid surgery in patients who are not suitable for emergency surgery and may allow adequate time for preoperative preparation, counseling and staging for those who are suitable for further intervention. We believe that self-expandable metallic stent placement is a safe, effective, and minimal invasive alternative treatment method for malignant colonic obstruction. PMID- 26504417 TI - Cytoreductive surgery (SRC) and hyperthermic intraperitoneal chemotherapy (HIPEC) for treatment of peritoneal carcinomatosis: Our initial experience and technical details. AB - OBJECTIVE: The aim of this study is to present our initial experience in peritoneal carcinomatosis treatment and the technical details of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the light of current literature. MATERIAL AND METHODS: Data of 27 consecutive patients who were treated with CRS and HIPEC for peritoneal carcinomatosis in Medical Park Samsun Hospital, between November 2012 and September 2014 were retrospectively reviewed. Treatment indication and management were evaluated at the multidisciplinary oncology council. All patients underwent CRS and HIPEC with the aim of complete cytoreduction. Patients with unresectable disease and/or palliative surgery were excluded from analysis. Perioperative complications were classified according to Clavien-Dindo classification, and HIPEC-related side effects were identified using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) criteria. Demographic, clinical and histopathological data of the patients were analyzed. RESULTS: The mean age was 54 (32-72). Nineteen patients were female. The origin of peritoneal carcinomatosis was colorectal cancer in 12 patients, ovarian cancer in 12 patients, gastric cancer in 2 patients and pseudomyxoma peritonei in 1 patient. The mean Peritoneal Carcinomatosis Index was 12 (3-32), with a mean operative time of 420 (300-660) minutes. Perioperative morbidity, HIPEC-related toxicity and perioperative mortality were observed in eight (30%), one (3.7%) and four patients (14.8%), respectively. During a mean follow up of 13 (1-22) months, overall and disease-free survival rates were 95.8% and 82.6%, respectively. Two patients with colorectal cancer (after 9 and 12 months) and one patient with ovarian cancer (after 11 months) had intra-abdominal recurrence. One patient with ovarian cancer had liver metastases 13 months after surgery, and underwent resection of segments 6-7. The remaining patients are being followed-up without any recurrence. CONCLUSION: Cytoreductive surgery and HIPEC have favorable results in the treatment of patients with peritoneal carcinomatosis. Compatible with the literature, surgical outcomes of the presented series are encouraging for this treatment modality that have been recently popularized in our country. Careful perioperative evaluation, proper patient selection and multidisciplinary approach are essential for success in curative treatment of peritoneal carcinomatosis. PMID- 26504418 TI - What has changed in the clinical presentation of breast carcinoma in 15 years? AB - OBJECTIVE: The aim of this study is to investigate if there was a change in time in terms of age at diagnosis, menopausal status, pathologic tumor size, lymphatic metastasis and pathologic stage in patients with surgical treatment for breast carcinoma. MATERIAL AND METHODS: The clinical and pathological characteristics of 1223 patients with breast carcinoma who underwent surgical treatment between January 1994 and December 1998, and of 1346 patients who underwent surgical treatment with the same diagnosis between January 2004 and December 2008 were retrospectively reviewed. RESULTS: The median age at diagnosis was 48 (20-78) years during the first period, and 50 (20-91) years during the second period. While 27% of patients were 40 years of age or younger in the first period, this ratio decreased to 20% during the second period (p=0.0001). The rate of premenopausal patients was 54% in the first period and 46% in the second period (p=0.0001). The median tumor size at diagnosis was 3 cm at the first period, and 2.5 cm at the second period. The number of patients with tumor size <=2 cm increased in time from 391 (32%) to 531 (39%) (p=0.0001). Among young patients (aged <=40 years), the number of patients with tumor size 2 cm or smaller were 81 (24.5%) and 92 (33.8%) at the first and second periods, respectively (p=0.001). Lymphatic metastases rate of patients aged <=40 years was higher than patients aged >40 years, in both study periods (p=0.0001). The number of patients staged as pN1 at the first period increased from 356 (50.8%) to 441 (56.3%) at the second interval, while those staged as pN3 decreased from 251 (35.8%) to 175 (22.3%) (p=0.0001). CONCLUSION: It may be concluded that recently, breast cancer is diagnosed at older ages, the rate of young and premenopausal patients and size on diagnosis has decreased, and breast-conserving surgery is used more often. PMID- 26504419 TI - Diagnostic value of terminal ileum biopsies in patients with abnormal terminal ileum mucosal appearance. AB - OBJECTIVE: To investigate the necessity of obtaining routine ileal biopsy during colonoscopy in the patients with abnormal terminal ileum mucosal appearance if the inflammatory bowel disease is not considered. MATERIAL AND METHODS: A retrospective analysis was performed for 57 patients who were referred to a private hospital for colonoscopy between January 2008 and February 2009, in whom terminal ileum intubation was achieved and an abnormal appearance was observed. RESULTS: There were 33 men and 24 women; the mean age was 44.12+/-11.42 years. In 22 patients, the abnormality was ulcers and/or erosions. In 10 patients, there were mucosal nodularity and in 24, the finding was erythema. The time to reach to ileum from cecum was 28.78+/-24.30 s. The mean length of the examined ileum was 12.93+/-6.05 cm. There was no difference between groups according to distance covered in the ileum for diagnostic yield, but going further than 2 cm was important. CONCLUSION: There should be no need to obtain routine biopsy in patients with abnormal terminal ileum mucosa appearance, when inflammatory bowel disease is not considered. In these patients, histopathology also reveals non specific ileitis. Furthermore, in these patients, the macroscopic pathological diagnosis overlaps the histopathology, and it has a low diagnostic yield and lower clinical significance. PMID- 26504420 TI - Current options in umbilical hernia repair in adult patients. AB - Umbilical hernia is a rather common surgical problem. Elective repair after diagnosis is advised. Suture repairs have high recurrence rates; therefore, mesh reinforcement is recommended. Mesh can be placed through either an open or laparoscopic approach with good clinical results. Standard polypropylene mesh is suitable for the open onlay technique; however, composite meshes are required for laparoscopic repairs. Large seromas and surgical site infection are rather common complications that may result in recurrence. Obesity, ascites, and excessive weight gain following repair are obviously potential risk factors. Moreover, smoking may create a risk for recurrence. PMID- 26504421 TI - Leiomyosarcoma of the retrohepatic vena cava: Report of a case treated with resection and reconstruction with polytetrafluoroethylene vascular graft. AB - Leiomyosarcoma of the vena cava is a rare malignant tumor. A 61-year-old woman was admitted with right upper quadrant abdominal pain. Computed tomography revealed a retrohepatic vena cava tumor originating 2 cm below the confluence of the hepaic veins and ending 2 cm above the renal veins. The tumor was resected with 1 cm clear surgical margins, without requiring liver resection. Polytetrafluoroethylene vascular graft was used for reconstruction of the vena cava. Now 32 months postoperatively, there has been no recurrence or metastasis. Radical resection with negative surgical margins is the best curative therapy for leiomyosarcoma. Polytetrafluoroethylene vascular graft can be used in extensive tumors located at the vena cava. PMID- 26504422 TI - Lithium-associated primary hyperparathyroidism complicated by nephrogenic diabetes insipidus. AB - Lithium-associated hyperparathyroidism is the leading cause of hypercalcemia in lithium-treated patients. Lithium may lead to exacerbation of pre-existing primary hyperparathyroidism or cause an increased set-point of calcium for parathyroid hormone suppression, leading to parathyroid hyperplasia. Lithium may cause renal tubular concentration defects directly by the development of nephrogenic diabetes insipidus or indirectly by the effects of hypercalcemia. In this study, we present a female patient on long-term lithium treatment who was evaluated for hypercalcemia. Preoperative imaging studies indicated parathyroid adenoma and multinodular goiter. Parathyroidectomy and thyroidectomy were planned. During the postoperative course, prolonged intubation was necessary because of agitation and delirium. During this period, polyuria, severe dehydration, and hypernatremia developed, which responded to controlled hypotonic fluid infusions and was unresponsive to parenteral desmopressin. A diagnosis of nephrogenic diabetes insipidus was apparent. A parathyroid adenoma and multifocal papillary thyroid cancer were detected on histopathological examination. It was thought that nephrogenic diabetes insipidus was masked by hypercalcemia preoperatively. A patient on lithium treatment should be carefully followed up during or after surgery to prevent life-threatening complications of previously unrecognized nephrogenic diabetes insipidus, and the possibility of renal concentrating defects on long-term lithium use should be sought, particularly in patients with impaired consciousness. PMID- 26504423 TI - Giant perianal condyloma acuminatum: Reconstruction with bilateral gluteal fasciocutaneous V-Y advancement flap. AB - Condyloma acuminatum caused by human papilloma virus is the most common sexually transmitted infection in the anogenital region. On the other hand, giant condyloma acuminatum that is also known as Buschke-Lowenstein tumor is a rare disease. Its primary treatment is surgical excision. The purpose of this report is to present a case that reached immense dimensions in the perianal region, and to emphasize the importance of wide surgical excision. A 17-year-old woman presented with a giant mass in the perianal region for 2 years, which progressively increased in size. Local examination revealed a large vegetative lesion in the perianal area. Wide surgical excision of the involved skin and lesion was undertaken. The wound was reconstructed by bilateral gluteal fasciocutaneous V-Y advancement flap. Response to various treatments is often poor, with a high recurrence rate. In conclusion, surgical treatment with wide excision and plastic reconstruction is an effective therapy for giant anal condylomas. PMID- 26504424 TI - Acute abdomen due to Meckel's enterolith: Case report and review of the literature. AB - Meckel's diverticulum is a rare condition with an incidence of 1-3% in general population. It is usually asymptomatic and is incidentally detected during laparotomy/laparoscopy. Enterolith formation within Meckel's diverticulum is even rarer. Herein, we present the diagnosis and management of a 50-year old patient with Meckel's diverticulum enterolith and discuss this rare condition based on the literature. PMID- 26504425 TI - Primary gastric tuberculosis mimicking gastric cancer. AB - A 42-year-old female patient with no previous known diseases who had complaints of postprandial epigastric pain and weight loss and who could not be diagnosed by endoscopic biopsy, although gastric cancer was suspected radiologically and endoscopically, was diagnosed with primary gastric tuberculosis by laparotomy and frozen section. Following anti-tuberculosis treatment, a complete clinical, radiological, and endoscopic response was achieved. PMID- 26504426 TI - Non-recurrent nerve from the vagus anterio-medially located in the carotid sheath. AB - Non-recurrent inferior laryngeal nerve (ILN) arising from the vagus nerve is a rare anatomic variation. The vagus descends vertically in the cervical neurovascular bundle, between and posterior to common carotid artery (CCA) and internal jugular vein (IJV). The vagus has also some anatomic variations. We present a case of two coincident anatomic variations both ILN and the vagus nerve. A patient with multinodular goiter was surgically treated with total thyroidectomy. Both two ILNs were identified, fully exposed and preserved along their cervical courses. We found that the right non-recurrent ILN directly arises from cervical vagal trunk, and enters the larynx at usual point after a short transverse course parallel to the inferior thyroid artery. The vagus nerve, easily exposed after dissection of the right lobe of the thyroid gland, is located medially to the CCA. We discovered the association of non-recurrent ILN and medially located vagus nerve in the same patient. Non-recurrent nerve and medially located vagus nerve in the cervical neurovascular bundle are two different variations. The coincidence of right non-recurrent ILN arising from cervical part of the vagus medial to the CCA in the same patient is a very interesting feature. The safety of thyroid operations is dependent on proper identification, dissection and full exposition of ILN. The safe procedure requires complete knowledge on the anatomy of neural structures including all their anatomic variations. PMID- 26504427 TI - Development of risk-based nanomaterial groups for occupational exposure control. AB - Given the almost limitless variety of nanomaterials, it will be virtually impossible to assess the possible occupational health hazard of each nanomaterial individually. The development of science-based hazard and risk categories for nanomaterials is needed for decision-making about exposure control practices in the workplace. A possible strategy would be to select representative (benchmark) materials from various mode of action (MOA) classes, evaluate the hazard and develop risk estimates, and then apply a systematic comparison of new nanomaterials with the benchmark materials in the same MOA class. Poorly soluble particles are used here as an example to illustrate quantitative risk assessment methods for possible benchmark particles and occupational exposure control groups, given mode of action and relative toxicity. Linking such benchmark particles to specific exposure control bands would facilitate the translation of health hazard and quantitative risk information to the development of effective exposure control practices in the workplace. A key challenge is obtaining sufficient dose-response data, based on standard testing, to systematically evaluate the nanomaterials' physical-chemical factors influencing their biological activity. Categorization processes involve both science-based analyses and default assumptions in the absence of substance-specific information. Utilizing data and information from related materials may facilitate initial determinations of exposure control systems for nanomaterials. PMID- 26504428 TI - Untapped Resources: Biotechnological Potential of Peptides and Secondary Metabolites in Archaea. AB - Archaea are an understudied domain of life often found in "extreme" environments in terms of temperature, salinity, and a range of other factors. Archaeal proteins, such as a wide range of enzymes, have adapted to function under these extreme conditions, providing biotechnology with interesting activities to exploit. In addition to producing structural and enzymatic proteins, archaea also produce a range of small peptide molecules (such as archaeocins) and other novel secondary metabolites such as those putatively involved in cell communication (acyl homoserine lactones), which can be exploited for biotechnological purposes. Due to the wide array of metabolites produced there is a great deal of biotechnological potential from antimicrobials such as diketopiperazines and archaeocins, as well as roles in the cosmetics and food industry. In this review we will discuss the diversity of small molecules, both peptide and nonpeptide, produced by archaea and their potential biotechnological applications. PMID- 26504429 TI - Phosphodiesterase 6D, cGMP-specific rod delta. AB - Network Map States Transitions Functions Protein Classes Sequence Interactions Pathways Domains & Motifs Protein Structure Orthologs Sequence Interactions Pathways Domains & Motifs Protein Structure Orthologs Blast Data. PMID- 26504430 TI - Phosphodiesterase 6C, cGMP-specific cone alpha'. AB - Network Map States Transitions Functions Protein Classes Sequence Interactions Pathways Domains & Motifs Protein Structure Orthologs Sequence Interactions Pathways Domains & Motifs Protein Structure Orthologs Blast Data. PMID- 26504431 TI - Let Me Heal: An Instant Classic. PMID- 26504432 TI - A Heartfelt Letter to My Father's Doctor. PMID- 26504433 TI - Risk of Bleeding in End-Stage Liver Disease Patients Undergoing Cardiac Catheterization. AB - Patients with end-stage liver disease frequently have baseline coagulopathies. The international normalized ratio is in common use for the estimation of bleeding tendency in such patients, especially those undergoing an invasive procedure like cardiac catheterization. The practice of international normalized ratio measurement-followed by pharmacologic (for example, vitamin K or fresh frozen plasma) or nonpharmacologic intervention-is still debatable. The results of multiple randomized trials have shown the superiority of the radial approach over femoral access in reducing catheterization bleeding. This reduction in bleeding in turn decreases the risk and cost of blood-product transfusion. However, there is little evidence regarding the use of the radial approach in the end-stage liver disease patient population specifically. In this review, we summarize the studies that have dealt with cardiac catheterization in patients who have end-stage liver disease. We also discuss the role of the current measurements that are used to reduce the risk of bleeding in these same patients. PMID- 26504434 TI - Present-Day Hospital Readmissions after Left Ventricular Assist Device Implantation: A Large Single-Center Study. AB - Left ventricular assist device (LVAD) therapy improves survival, hemodynamic status, and end-organ perfusion in patients with refractory advanced heart failure. Hospital readmission is an important measure of the intensity of LVAD support care. We analyzed readmissions of 148 patients (mean age, 53.6 +/- 12.7 yr; 83% male) who received a HeartMate II LVAD from April 2008 through June 2012. The patients had severe heart failure; 60.1% were in Interagency Registry for Mechanically Assisted Circulatory Support class 1 or 2. All patients were observed for at least 12 months, and readmissions were classified as planned or unplanned. Descriptive and multivariate regression analyses were used to identify predictors of unplanned readmission. Twenty-seven patients (18.2%) had no readmissions or 69 planned readmissions, and 121 patients (81.8%) had 460 unplanned readmissions. The LVAD-related readmissions were for bleeding, thrombosis, and anticoagulation (n=103; 49.1%), pump-related infections (n=60; 28.6%), and neurologic events (n=28; 13.3%). The readmission rate was 2.1 per patient-year. Unplanned readmissions were for comorbidities and underlying cardiac disease (54.3%) or LVAD-related causes (45.7%). In the unplanned readmission rate, there was no significant difference between bridge-to transplantation and destination-therapy patients. Unplanned readmissions were associated with diabetes mellitus (odds ratio [OR]=3.3; P=0.04) and with shorter mileage from residence to hospital (OR=0.998; P=0.046). Unplanned admissions for LVAD-related sequelae and ongoing comorbidities were common. Diabetes mellitus and shorter distance from residence to hospital were significant predictors of readmission. We project that improved management of comorbidities and of anticoagulation therapy will reduce unplanned readmissions of LVAD patients in the future. PMID- 26504435 TI - Efficacy of Oral Anticoagulation in Stroke Prevention among Sinus-Rhythm Patients Who Lack Left Atrial Mechanical Contraction after Cryoablation. AB - The customary recommendation is that oral anticoagulation be withdrawn a few months after cryoablation for atrial fibrillation, independently of left atrial mechanical contraction in patients in sinus rhythm. Recently, a 5-fold increase in stroke has been described in sinus-rhythm patients who lack atrial mechanical contraction. One aim of this study was to evaluate the efficacy of oral anticoagulation in preventing postoperative stroke in such patients. This prospective study divided 154 sinus-rhythm patients into 2 groups, depending on the presence (108 patients) or absence (46 patients) of left atrial mechanical contraction at 6 months after surgery, and monitored them annually for 5 years. Those without left atrial contraction were maintained on acenocumarol. The primary endpoint was the occurrence of ischemic stroke. The median follow-up period was 29 +/- 16 months; 4 patients (2.5%), all belonging to the group with preserved atrial contraction, had ischemic stroke; the group of patients without left atrial contraction had no episodes of stroke during follow-up. Logistic binary regression analyses showed no evidence of factors independently predictive of stroke. Among anticoagulated patients in sinus rhythm without left atrial contraction, we found the incidence of stroke to be zero. In a small, nonrandomized group such as this, we cannot discount the element of chance, yet we suggest that maintaining anticoagulation might lower the incidence of stroke in this population. PMID- 26504436 TI - Coronary Interventions before Liver Transplantation Might Not Avert Postoperative Cardiovascular Events. AB - Percutaneous coronary intervention and coronary artery bypass grafting may be performed before orthotopic liver transplantation (OLT) to try to improve the condition of patients who have severe ischemic heart disease. However, data supporting improved outcomes are lacking. We reviewed the medical records of 2,010 patients who underwent OLT at our hospital from 2000 through 2010. The 51 patients who underwent coronary artery angiography within 6 months of transplantation were included in this study: 28 had mild coronary artery disease, 10 had moderate disease, and 13 had severe disease. We compared all-cause and cardiac-cause mortality rates. We found a significant difference in cardiac deaths between the groups (P <0.001), but none in all-cause death (P=0.624). Of the 10 patients who had moderate coronary artery disease, one underwent pre transplant coronary artery bypass grafting. Of 13 patients with severe disease, 3 underwent percutaneous coronary intervention, and 6 underwent coronary artery bypass grafting. Overall, 50% of patients who underwent either intervention died of cardiac-related causes, whereas no patient died of a cardiac-related cause after undergoing neither intervention (P <0.0001). We conclude that, despite coronary intervention, mortality rates remain high in OLT patients who have severe coronary artery disease. PMID- 26504437 TI - Combined Retrograde/Antegrade Approach to Transcatheter Closure of an Aortic Paravalvular Leak. AB - New interventional techniques have made transcatheter closure of aortic paravalvular leaks a viable therapeutic option to treat the sequelae of these defects, including congestive heart failure and hemolysis. We report the transcatheter closure of an aortic paravalvular leak via a combined retrograde/antegrade approach. This was necessary because of difficulty in crossing the defect with a sheath from the retrograde approach. This technique might be useful in application to other difficult structural heart interventions. To our knowledge, this is the first report of a treated paravalvular leak around a Mitroflow((r)) Aortic Pericardial Heart Valve. PMID- 26504438 TI - Evaluation of Previously Cannulated Radial Arteries as Patent Coronary Artery Bypass Conduits. AB - In coronary artery bypass grafting, good-quality conduits are needed to maximize the potential for long-term patency. Revascularization has traditionally been achieved with use of the saphenous vein and the internal thoracic arteries. In recent years, total arterial revascularization with use of the radial arteries has been promoted. Meanwhile, use of the transradial approach for coronary angiography has also increased. The long-term effects of previous cannulation in radial artery bypass grafts are not known. Therefore, we used multidetector computed tomographic angiography to investigate radial-artery graft patency in a small series of patients who had undergone transradial angiography. We found a high patency rate, and we discuss those findings here. PMID- 26504439 TI - Conservative Management of Cardiac Hemangioma for 11 Years. AB - Cardiac hemangiomas are benign tumors with an unpredictable natural history. Surgical resection is the treatment of choice; however, conservative management can be an alternative in some patients. We report a case of a left-sided cardiac hemangioma that we managed conservatively for 11 years without obvious major complications in the patient, an adult woman. PMID- 26504440 TI - Cobrahead Deformity in the Right Atrial Disc of a New-Generation Occlutech Figulla Flex II Atrial Septal Defect Occluder Device. AB - Cobrahead deformity is a known (but uncommon) phenomenon associated with the left atrial disc of the Amplatzer or Occlutech Figulla septal occluder device during percutaneous transcatheter atrial septal defect closure. It has also been postulated that the right atrial disc of the Amplatzer septal occluder device might upon occasion exhibit the cobrahead malformation. To date, only one case report concerning the cobrahead deformity in the right atrial disc of an Amplatzer septal occluder has been published, if we discount a report published as a letter to the manufacturer. Here we present the first report (known to us) of a cobrahead deformity in the right atrial disc of an Occlutech Figulla Flex II atrial septal defect occluder device during transcatheter closure of a complex atrial septal defect. PMID- 26504441 TI - Down Syndrome with Complete Atrioventricular Septal Defect, Hypertrophic Cardiomyopathy, and Pulmonary Vein Stenosis. AB - The prevalence of congenital heart disease in infants with Down syndrome is 40%, compared with 0.3% in children who have normal chromosomes. Atrioventricular and ventricular septal defects are often associated with chromosomal aberrations, such as in trisomy 21, whereas hypertrophic cardiomyopathy is chiefly thought to be secondary to specific gene mutations. We found only one reported case of congenital hypertrophic cardiomyopathy and atrioventricular septal defect in an infant with Down syndrome. Here, we report atrioventricular septal defect, hypertrophic cardiomyopathy, and pulmonary vein stenosis in a neonate with Down syndrome-an apparently unique combination. In addition, we discuss the relevant medical literature. PMID- 26504442 TI - Unruptured Sinus of Valsalva Aneurysm with Right Ventricular Outflow Tract Obstruction and Supracristal Ventricular Septal Defect: A Rare Case. AB - Unruptured right sinus of Valsalva aneurysm that causes severe obstruction of the right ventricular outflow tract is extremely rare. We describe the case of a 47 year-old woman who presented with exertional dyspnea. Upon investigation, we discovered an unruptured right sinus of Valsalva aneurysm with associated right ventricular outflow tract obstruction and a supracristal ventricular septal defect. To our knowledge, only 2 such cases have previously been reported in the medical literature. Although treatment of unruptured sinus of Valsalva aneurysm remains debatable, surgery should be considered for extremely large aneurysms or for progressive enlargement of the aneurysm on serial evaluation. Surgery was undertaken in our patient because there was clear evidence of right ventricular outflow tract obstruction, right-sided heart dilation, and associated exertional dyspnea. PMID- 26504443 TI - Massive Pulmonary Artery Aneurysm Causing Left Main Coronary Artery Compression in the Absence of Pulmonary Hypertension. AB - We report the case of a 62-year-old woman who presented with classic symptoms of stable angina. Cardiac images and catheterization results revealed absent pulmonary valve syndrome and compression of the left main coronary artery by a massively dilated pulmonary artery aneurysm. The patient's anginal symptoms were relieved after pulmonary arterioplasty. Others have described proximal left main coronary artery compression in the presence of a dilated and hypertensive pulmonary artery. To our knowledge, this is the first case in which a pulmonary artery aneurysm caused left main coronary insufficiency in the absence of pulmonary hypertension-a clinically important complication of congenital pulmonary valve-related pulmonary arteriopathy. PMID- 26504444 TI - Aspergillus Mediastinitis after Orthotopic Heart Transplantation: A Case Report. AB - A 55-year-old woman was admitted for orthotopic heart transplantation. Her medical history was notable for multiple cardiovascular problems, including ischemic cardiomyopathy that necessitated circulatory support with a left ventricular assist device. Five weeks after undergoing orthotopic heart transplantation, she developed Aspergillus calidoustus mediastinitis, for which she underwent a prolonged course of antifungal treatment that comprised (in sequence) posaconazole for 11 days, voriconazole for 10 days, and amphotericin B for 42 days. During this period, she also underwent repeated mediastinal drainage and sternal debridement, followed by sternal wiring and coverage with bilateral pectoralis advancement flaps. Four months postoperatively, she was discharged from the hospital with a successfully controlled infection and a healed sternum. To our knowledge, only 3 previous cases of Aspergillus mediastinitis after orthotopic heart transplantation have been reported in the literature, none of which was Aspergillus calidoustus. PMID- 26504445 TI - Extracorporeal Membrane Oxygenation as a Bridge to Surgery for Infective Endocarditis Complicated by Aorto-Atrial Fistula and Cardiopulmonary Collapse. AB - The timing of surgery for active infective endocarditis is challenging when patients exhibit mechanical dysfunction and hemodynamic compromise. Extracorporeal membrane oxygenation has been described in treating sepsis but not, insofar as we know, in treating the acute mechanical sequelae that arise from infective endocarditis. We report perhaps the first case that shows the usefulness of extracorporeal membrane oxygenation as a bridge to definitive treatment in a 35-year-old man who had infective endocarditis followed by aorto atrial fistula and cardiopulmonary collapse. PMID- 26504446 TI - Prompt Recognition of Left Ventricular Free-Wall Rupture Aided by the Use of Contrast Echocardiography. AB - In the modern period of reperfusion, left ventricular free-wall rupture occurs in less than 1% of myocardial infarctions. Typically, acute left ventricular free wall rupture leads to sudden death from immediate cardiac tamponade. We present the case of a 59-year-old woman who sustained a posterior-wall myocardial infarction and subsequent cardiac arrest with pulseless electrical activity. A bedside transthoracic echocardiogram showed pericardial effusion with cardiac tamponade. Emergency pericardiocentesis yielded 500 mL of blood, and spontaneous circulation returned. Contrast-enhanced echocardiograms revealed inferolateral akinesis and a new, small myocardial slit with systolic extrusion of contrast medium, consistent with left ventricular free-wall rupture. During immediate open heart surgery, a small hole in an area of necrotic tissue was discovered and repaired. This case highlights the usefulness of bedside contrast-enhanced echocardiography in confirming acute left ventricular free-wall rupture and enabling rapid surgical treatment. PMID- 26504447 TI - Spontaneous Coronary Artery Dissection with Cardiac Tamponade. AB - Spontaneous coronary artery dissection is a rare cause of acute coronary syndrome. Clinical presentation ranges from chest pain alone to ST-segment elevation myocardial infarction, ventricular fibrillation, and sudden death. The treatment of patients with spontaneous coronary artery dissection is challenging because the disease pathophysiology is unclear, optimal treatment is unknown, and short- and long-term prognostic data are minimal. We report the case of a 70-year old woman who presented with an acute ST-segment-elevation myocardial infarction secondary to a spontaneous dissection of the left anterior descending coronary artery. She was treated conservatively. Cardiac tamponade developed 16 hours after presentation. Repeat coronary angiography revealed extension of the dissection. Medical therapy was continued after the hemopericardium was aspirated. The patient remained asymptomatic 3 years after hospital discharge. To our knowledge, this is the first reported case of spontaneous coronary artery dissection in association with cardiac tamponade that was treated conservatively and had a successful outcome. PMID- 26504448 TI - Successful Prasugrel Therapy for Recurrent Left Main Stent Thrombosis in a Clopidogrel Hyporesponder. AB - Stent thrombosis is a life-threatening sequela of drug-eluting stent implantation. Dual antiplatelet therapy with aspirin and thienopyridine is typically used to prevent this catastrophic event. In terms of stent thrombosis, the major concern is the variable response of patients to clopidogrel, and this has raised interest in new antiplatelet agents. We present the case of a 64-year old woman whom we successfully treated with prasugrel after she had repeated episodes of stent thrombosis caused by a poor response to clopidogrel. This case highlights the potential role of new antiplatelet agents for patients who are undergoing drug-eluting stent implantation. PMID- 26504449 TI - Very Late Stent Thrombosis 11 Years after Implantation of a Drug-Eluting Stent. AB - Very late stent thrombosis is an infrequent yet potentially fatal complication associated with drug-eluting stents. We report the case of an 88-year-old man who sustained an ST-segment-elevation myocardial infarction 11 years after initial sirolimus-eluting stent implantation. Optical coherence tomograms of the lesion showed that the focal incomplete endothelialization of the stent struts was the likely cause; neointimal formation, neoatherosclerosis, and late stent malapposition might also have contributed. To our knowledge, this is the longest reported intervening period between stent insertion and the development of an acute coronary event secondary to very late stent thrombosis. The associated prognostic and therapeutic implications are considerable, because they illuminate the uncertainties surrounding the optimal duration of antiplatelet therapy in patients who have drug-eluting stents. Clinicians face challenges in treating these patients, particularly when competing medical demands necessitate the discontinuation of antiplatelet therapy. In addition to the patient's case, we discuss factors that can contribute to very late stent thrombosis. PMID- 26504450 TI - A Reminder of Methylene Blue's Effectiveness in Treating Vasoplegic Syndrome after On-Pump Cardiac Surgery. AB - The inflammatory response induced by cardiopulmonary bypass decreases vascular tone, which in turn can lead to vasoplegic syndrome. Indeed the hypotension consequent to on-pump cardiac surgery often necessitates vasopressor and intravenous fluid support. Methylene blue counteracts vasoplegic syndrome by inhibiting the formation of nitric oxide. We report the use of methylene blue in a 75-year-old man who developed vasoplegic syndrome after cardiac surgery. After the administration of methylene blue, his hypotension improved to the extent that he could be weaned from vasopressors. The use of methylene blue should be considered in patients who develop hypotension refractory to standard treatment after cardiac surgery. PMID- 26504451 TI - Acute Respiratory Failure Induced by Magnesium Replacement in a 62-Year-Old Woman with Myasthenia Gravis. AB - Magnesium is known to act at the neuromuscular junction by inhibiting the presynaptic release of acetylcholine and desensitizing the postsynaptic membrane. Because of these effects, magnesium has been postulated to potentiate neuromuscular weakness. We describe the case of a 62-year-old woman with myasthenia gravis and a metastatic thymoma who was admitted to our intensive care unit for management of a myasthenic crisis. The patient's neuromuscular weakness worsened in association with standard intravenous magnesium replacement, and the exacerbated respiratory failure necessitated intubation, mechanical ventilation, and an extended stay in the intensive care unit. The effect of magnesium replacement on myasthenia gravis patients has not been well documented, and we present this case to increase awareness and stimulate research. In addition, we discuss the relevant medical literature. PMID- 26504452 TI - Platypnea-Orthodeoxia Syndrome: Diagnostic Challenge and the Importance of Heightened Clinical Suspicion. AB - Platypnea-orthodeoxia syndrome is an uncommon condition of positional dyspnea and hypoxemia; symptoms occur when the patient is upright and resolve with recumbency. Causes can be broadly categorized into 4 groups: intracardiac shunting, pulmonary shunting, ventilation-perfusion mismatch, or a combination of these. Platypnea-orthodeoxia syndrome should be suspected when normal arterial oxygen saturations are recorded while an individual is supine, followed by abrupt declines in those saturations when upright. Further investigations with use of imaging and cardiac catheterization aid in the evaluation. When platypnea orthodeoxia syndrome is due to intracardiac shunting without pulmonary hypertension, intracardiac shunt closure can be curative. In this article, we report a case of platypnea-orthodeoxia syndrome in an 83-year-old woman who was successfully treated by means of percutaneous transcatheter closure of an atrial septal defect. PMID- 26504453 TI - Atrial Fibrillation in a 35-Year-Old Man with Wolff-Parkinson-White Syndrome. PMID- 26504454 TI - Pulmonary Artery Sling Causing Tracheal Stenosis in a Neonate. PMID- 26504455 TI - Repair of Bland-White-Garland Syndrome via a Modified Technique. PMID- 26504456 TI - Learning verb syntax via listening: New evidence from 22-month-olds. AB - Children recruit verb syntax to guide verb interpretation. We asked whether 22 month-olds spontaneously encode information about a particular novel verb's syntactic properties through listening to sentences, retain this information in long-term memory over a filled delay, and retrieve it to guide interpretation upon hearing the same novel verb again. Children watched dialogues in which interlocutors discussed unseen events using a novel verb in transitive (e.g., "Anna blicked the baby") or intransitive sentences ("Anna blicked"). Children later heard the verb in isolation ("Find blicking!") while viewing a two participant causal action and a one-participant action event. Children who had heard transitive dialogues looked longer at the two-participant event than did those who heard intransitive dialogues. This effect disappeared if children heard a different novel verb at test ("Find kradding!"). These findings implicate a role for distributional learning in early verb learning: Syntactic-combinatorial information about otherwise unknown words may pervade the toddler's lexicon, guiding later word interpretation. PMID- 26504457 TI - Absorption and Emission Spectra of a Flexible Dye in Solution: a Computational Time-Dependent Approach. AB - The spectroscopic properties of the organic chromophore 4-naphthoyloxy-1-methoxy 2,2,6,6-tetramethylpiperidine (NfO-TEMPO-Me) in toluene solution are explored through an integrated computational strategy combining a classical dynamic sampling with a quantum mechanical description within the framework of the time dependent density functional theory (TDDFT) approach. The atomistic simulations are based on an accurately parametrized force field, specifically designed to represent the conformational behavior of the molecule in its ground and bright excited states, whereas TDDFT calculations are performed through a selected combination of hybrid functionals and basis sets to obtain optical spectra closely matching the experimental findings. Solvent effects, crucial to obtain good accuracy, are taken into account through explicit molecules and polarizable continuum descriptions. Although, in the case of toluene, specific solvation is not fundamental, the detailed conformational sampling in solution has confirmed the importance of a dynamic description of the molecular geometry for a reliable description of the photophysical properties of the dye. The agreement between theoretical and experimental data is established and a robust protocol for the prediction of the optical behaviour of flexible fluorophores in solution is set. PMID- 26504458 TI - Vertical Electronic Excitations in Solution with the EOM-CCSD Method Combined with a Polarizable Explicit/Implicit Solvent Model. AB - The accurate calculation of electronic transition energies and properties of isolated chromophores is not sufficient to provide a realistic simulation of their excited states in solution. In fact, the solvent influences the solute geometry, electronic structure, and response to external fields. Therefore, a proper description of the solvent effect is fundamental. This can be achieved by combining polarizable explicit and implicit representations of the solvent. The former provides a realistic description of solvent molecules around the solute, while the latter introduces the electrostatic effect of the bulk solution and reduces the need of too large a number of explicit solvent molecules. This strategy is particularly appealing when an accurate method such as equation of motion coupled cluster singles and doubles (EOM-CCSD) is employed for the treatment of the chromophore. In this contribution, we present the coupling of EOM-CCSD with a fluctuating charges (FQ) model and polarizable continuum model (PCM) of solvation for vertical excitations in a state-specific framework. The theory, implementation, and prototypical applications of the method are presented. Numerical tests on small solute-water clusters show very good agreement between full EOM-CCSD and EOM-CCSD-FQ calculations, with and without PCM, with differences <= 0.1 eV. Additionally, approximated schemes that further reduce the computational cost of the method are introduced and showed to perform well compared to the full method (errors <= 0.1 eV). PMID- 26504459 TI - A SPECIAL MEETING REVIEW EDITION: Advances in the Treatment of Hepatitis C Virus Infection From EASL 2015: The 50th Annual Meeting of the European Association for the Study of the Liver * April 22-26, 2015 * Vienna, AustriaSpecial Reporting on:* Daclatasvir, Sofosbuvir, and Ribavirin Combination for HCV Patients With Advanced Cirrhosis or Posttransplant Recurrence: Phase 3 ALLY-1 Study* Efficacy and Safety of Grazoprevir and Elbasvir in Hepatitis C Genotype 1-Infected Patients With Child-Pugh Class B Cirrhosis (C-SALT Part A)* Ledipasvir/Sofosbuvir With Ribavirin Is Safe and Efficacious in Decompensated and Post Liver Transplantation Patients With HCV Infection: Preliminary Results of the Prospective SOLAR 2 Trial* Retreatment of Patients Who Failed 8 or 12 Weeks of Ledipasvir/Sofosbuvir-Based Regimens With Ledipasvir/Sofosbuvir for 24 Weeks* Sofosbuvir + Peginterferon/Ribavirin for 12 Weeks Vs Sofosbuvir + Ribavirin for 16 or 24 Weeks in Genotype 3 HCV Infected Patients and Treatment-Experienced Cirrhotic Patients With Genotype 2 HCV: The BOSON Study* Safety and Efficacy of the Combination Daclatasvir-Sofosbuvir in HCV Genotype 1-Mono-Infected Patients From the French Observational Cohort ANRS CO22 HEPATHER* C-SWIFT: Grazoprevir/Elbasvir + Sofosbuvir in Cirrhotic and Noncirrhotic, Treatment-Naive Patients With Hepatitis C Virus Genotype 1 Infection for Durations of 4, 6 or 8 Weeks and Genotype 3 Infection for Durations of 8 or 12 WeeksPLUS Meeting Abstract Summaries With Expert Commentary by: Steven L. Flamm, MD Chief, Liver Transplantation ProgramProfessor of Medicine and SurgeryNorthwestern University Feinberg School of MedicineChicago, Illinois. PMID- 26504460 TI - An Efficient Robust Eye Localization by Learning the Convolution Distribution Using Eye Template. AB - Eye localization is a fundamental process in many facial analyses. In practical use, it is often challenged by illumination, head pose, facial expression, occlusion, and other factors. It remains great difficulty to achieve high accuracy with short prediction time and low training cost at the same time. This paper presents a novel eye localization approach which explores only one-layer convolution map by eye template using a BP network. Results showed that the proposed method is robust to handle many difficult situations. In experiments, accuracy of 98% and 96%, respectively, on the BioID and LFPW test sets could be achieved in 10 fps prediction rate with only 15-minute training cost. In comparison with other robust models, the proposed method could obtain similar best results with greatly reduced training time and high prediction speed. PMID- 26504461 TI - Budd-Chiari Syndrome in China: A Systematic Analysis of Epidemiological Features Based on the Chinese Literature Survey. AB - Background. Thousands of Budd-Chiari syndrome (BCS) studies have been published in China, and yet no one has explored its incidence or prevalence in the whole country. Methods. Three most commonly used Chinese language electronic databases were searched, and epidemiological data were extracted from the selected articles. Results. By the end of 2013, 20191 BCS cases were reported in China. The mean age of BCS patients was 36.29 +/- 1.28 years, and ratio of male to female was 150/100. About 80% BCS patients were distributed in Henan, Shandong, Beijing, Jiangsu, and Anhui, and all of them except for Beijing were located in the downstream areas of Yellow River and the whole Huai River basin. The incidence and prevalence of BCS in China with and without the top 5 high prevalence areas were estimated to be 0.88/million per year and 7.69/million and 0.28/million per year and 2.21/million, respectively. Conclusions. Most BCS patients in China are distributed in the downstream areas of Yellow River and the whole Huai River basin. The incidence and prevalence are comparable to those of Western countries without taking into account the top 5 high-prevalence areas. PMID- 26504462 TI - A Retrospective Analysis of the Relationship between Ethnicity, Body Mass Index, and the Diagnosis of Gestational Diabetes in Women Attending an Australian Antenatal Clinic. AB - Purpose. To estimate the prevalence of gestational diabetes mellitus (GDM) in a multiethnic population, assess the association between country of birth (COB) and GDM, and assess whether the association varies by body mass index (BMI). Methods. A retrospective study of 5260 pregnant women attending Sunshine Hospital, Australia, between 1st July 2012 and 30th June 2013. We fitted logistic regression models to assess the association between COB and GDM. An interaction between BMI and COB was assessed by likelihood ratio test. Results. In the 4610 included in our analysis, most common were women born in Australia or New Zealand (ANZ, 1932, 41.9%) and in Southeast Asia (922, 20%). GDM was diagnosed in 606 (13.2%) women. After adjusting for confounders, women from East Asia were most likely to develop GDM (37, 24.0%) and 5-fold more likely than women from ANZ (OR = 4.77, 95% CI: 3.12, 7.31, p < 0.001). Women from other Asian countries had a 3 fold increased risk of GDM compared to women from ANZ. There was no evidence of an interaction by BMI (p = 0.24). Conclusions. Women born in Asia have higher risk of GDM compared to women born in ANZ. These data provide support for including COB in GDM management policies. PMID- 26504463 TI - Effect of Nd:YAG Low Level Laser Therapy on Human Gingival Fibroblasts. AB - Aim. To evaluate the effect of Low Level Laser Therapy (LLLT) on human gingival fibroblasts in terms of proliferation and growth factors' secretion (EGF, bFGF, and VEGF). Materials and Methods. Primary cultures of keratinized mucosa fibroblasts were irradiated by a Nd:YAG laser 1064 nm with the following energy densities: 2.6 J/cm(2), 5.3 J/cm(2), 7.9 J/cm(2), and 15.8 J/cm(2). Controls were not irradiated. Cultures were examined for cell proliferation and growth factors' secretion after 24, 48, and 72 hours. All experimental procedures were performed in duplicate. Data were analyzed by Student's t-test (p < 0.05). Results. All laser-irradiation doses applied promoted a higher cell proliferation at 48 hours in a dose-response relationship compared to controls. This difference reached statistical significance for the cultures receiving 15.8 J/cm(2) (p = 0.03). Regarding EGF, all laser irradiation doses applied promoted a higher secretion at 48 hours in a reverse dose-response pattern compared to controls. This difference reached statistical significance for the cultures receiving 2.6 J/cm(2) (p = 0.04). EGF levels at the other time points, bFGF, and VEGF showed a random variation between the groups. Conclusion. Within the limits of this study, LLLT (Nd:YAG) may induce gingival fibroblasts' proliferation and upregulate the secretion of EGF. Further studies are needed to confirm these results. PMID- 26504464 TI - Asymptomatic Bacteriuria Caused by Chromobacterium violaceum in an Immunocompetent Adult. AB - Because of increasing antimicrobial resistance, the treatment of the asymptomatic bacteriuria is not considered except in specific circumstances like during pregnancy or before invasive urologic procedures. We are reporting a first case of asymptomatic bacteriuria caused by Chromobacterium violaceum in a 16-year-old male. With the reporting of the C. violaceum which is notorious for its high propensity for hematogenous dissemination causing fatal sepsis (with reported mortality rate up to 65-80%) if prompt proper treatment is not given, as causative agent of asymptomatic bacteriuria, it is recommended to treat the asymptomatic bacteriuria caused by this organism. PMID- 26504465 TI - Hemophagocytic Lymphohistiocytosis Complicating Dengue and Plasmodium vivax Coinfection. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder. Dysfunction of cytotoxic T and natural killer (NK) cells causes uncontrolled activity of lymphocytes and histiocytes which leads to HLH. Infections, malignancies, and autoimmune disorders are associated with development of HLH. Dengue and Plasmodium vivax are rare causes of HLH. We report the first ever case of a young man who developed fatal HLH that complicated Dengue Hemorrhagic Fever (DHF) and Plasmodium vivax infection. PMID- 26504466 TI - Monoclonal antibody desensitization in a patient with a generalized urticarial reaction following denosumab administration. AB - Denosumab is a human monoclonal antibody indicated for the treatment of osteoporosis in postmenopausal women with a high risk of fractures. To our knowledge, no cases of desensitization to this drug have been described in the literature. We report the first case of generalized urticarial reaction and facial angioedema after therapy with denosumab. A subcutaneous desensitization protocol was successfully completed in this patient. Rapid desensitization is a promising method for the delivery of denosumab after a hypersensitivity reaction, and should be considered in osteoporosis treatment when no acceptable therapeutic alternatives are available. PMID- 26504467 TI - Tropomyosin, the major tropical oyster Crassostrea belcheri allergen and effect of cooking on its allergenicity. AB - BACKGROUND: Many types of shellfish including oysters are sometime cooked before ingestion and it has been demonstrated that cooking may affect the allergenicity of food. Therefore, the aim of our present study is to identify major and minor allergens of tropical oyster (Crassostrea belcheri) and to investigate the effect of different cooking processing on the allergenicity of this oyster. METHODS: Raw, boiled, fried and roasted extracts of oyster were prepared. Protein profiles were analysed using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Major and minor allergens and allergenicity patterns of all extracts were then determined by immunoblotting with sera from patients with positive skin prick tests (SPT) to the raw oyster extract. Mass-spectrometry was used to identify the major allergenic proteins of this oyster. RESULTS: SDS-PAGE of the raw extract showed 15 protein bands (20-180 kDa). In contrast, smaller numbers of protein bands were demonstrated in the boiled extract, those ranging between 40 42 and 55-150 kDa were denatured, whereas the protein profiles were altered to a similar degree by frying or roasting. The 37 kDa proteins had the highest frequency of IgE-binding (95 %), thus identified as the major allergen of this tropical oyster. Other minor IgE-binding proteins were observed at various molecular weights. Immunoblot of raw extract yielded 11 IgE-binding proteins. The cooked extracts showed only a single IgE-binding protein at 37 kDa. Mass spectrometry analysis of the 37 kDa major allergen identified this spot as tropomyosin. CONCLUSIONS: Cooked extracts produce lower IgE-binding than raw extract, which suggest that thermal treatment can be used as a tool in attempting to reduce oyster allergenicity by reducing the number of IgE-reactive bands. The degree of allergenicity of this oyster was demonstrated in the order raw > boiled > fried ~ roasted. A heat-resistent 37 kDa protein, corresponding to tropomyosin, was identified as the major allergen of this tropical oyster. PMID- 26504468 TI - Association Between TT Virus Infection and Cirrhosis in Liver Transplant Patients. AB - BACKGROUND: Cirrhosis is one of the most severe liver complications, with multiple etiologies. The torque teno virus (TTV), also known as transfusion transmitted virus, which has a high incidence in the world population, is one of the possible increasing risk factors in patients with idiopathic fulminant hepatitis and cryptogenic cirrhosis. OBJECTIVES: The aim of this study was to evaluate solitary and co-infection with TTV, in patients with cryptogenic and determined cause of cirrhosis. PATIENTS AND METHODS: In this cross-sectional study, 200 liver transplant patients were consecutively recruited between years 2007 and 2011. Patients were classified, based on recognition of the etiology of cirrhosis to determined (n = 81) and cryptogenic (n = 119) patient groups. The existence of TTV infection was analyzed, using a semi-nested polymerase chain reaction method. The presence of hepatitis B virus (HBV) infective markers, including HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), hepatitis B core antibody (HBcAb), and hepatitis B e antibody (HBeAb), was evaluated using qualitative polymerase chain reaction and enzyme linked immunosorbent assay protocols, respectively. RESULTS: The TTV infection was found in 37 of 200 (18.5%) and 53 of 200 (26.5%) plasma and tissue samples of studied liver transplanted patients, respectively. The TTV genomic DNA was found in 32 (26.9%) and 28 (23.5%) of 119 liver tissue and plasma samples of transplanted patients with cryptogenic cirrhosis, respectively. The genomic DNA of TTV was also diagnosed in 21 (25.9%) and nine (11.1%) of the 81 liver tissue and plasma samples of patients with determined cirrhosis, respectively. Significant associations were found between TTV infection with HBV molecular and immunologic infective markers, in liver transplanted patients, with determined and cryptogenic cirrhosis. CONCLUSIONS: The diagnosis of the high frequency of solitary TTV and co-infection with HBV, in both liver transplanted patients with cryptogenic and determined cirrhosis, emphasized on the importance of TTV infection in the development of cirrhosis, especially in the cases of cryptogenic ones, prompting for further studies the confirm this agent in the etiology of determined cirrhosis. PMID- 26504469 TI - Hyponatremia as the Initial Presentation of Cryptococcal Meningitis After Liver Transplantation. AB - INTRODUCTION: Meningoencephalitis is the most common clinical manifestation of cryptococcal infection, as the organism has a propensity to invade the CNS. Patients often present with elevated intracranial pressure, focal motor deficits, altered mentation and internal hydrocephalus. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported as a notable cause of euvolemic hyponatremia in immunocompromised patients. CASE PRESENTATION: A 67 year-old male with liver transplantation due to hepatitis C (HCV) related liver cirrhosis developed severe hyponatremia four months after liver transplantation, which was discovered during routine clinic visit. Patient was referred to the emergency department, treated and discharged with normal serum sodium level. Few days later, he presented with dizziness, confusion, ataxia, abnormal muscle movements and leg pain. Laboratory investigations were consistent with SIADH and revealed a sodium level of 115 mmol/L. Brain MRI showed a leptomeningeal enhancement in the superior cerebellar sulci suspicious for infection. Lumbar puncture was performed and consistent with Cryptococcus neoformans infection; therefore, cryptococcal meningitis was diagnosed. Amphotericin B was started for the patient for six weeks followed by fluconazole for one year. His level of consciousness improved significantly, and his serum sodium level slowly returned to its normal baseline over three weeks after starting amphotericin B. CONCLUSIONS: Symptomatic hyponatremia secondary to SIADH remains a rare complication of cryptococcal meningitis. PMID- 26504470 TI - Efficacy and Tolerability of Peginterferon alpha-2a and Peginterferon alpha-2b in Iranian Patients With Chronic Hepatitis C. AB - BACKGROUND: Nearly 0.5% of Iranians are infected with HCV. Peginterferon-alpha-2a and Peginterferon-alpha-2b are the two available types of interferon for the treatment of hepatitis C. Comparing the results of these two treatments is still a challenge. OBJECTIVES: The aim of this study was to compare the results of Peginterferon-alpha-2a and Peginterferon-alpha-2b in Iranian patients with chronic hepatitis C. PATIENTS AND METHODS: 289 patients with chronic hepatitis C attending Tehran Hepatitis Center (THC) and Hepatitis Clinic of Tehran Blood Transfusion Organization (TBTO) from January 2008 to April 2013 and treated with combination of Peginterferon-alpha-2a or Peginterferon-alpha-2b plus Ribavirin were enrolled in this retrospective cross-sectional study. Treatment response and side effects were compared. RESULTS: Among all naive patients, 82.0% achieved SVR, 5.4% were resistant to therapy and 11.0% withdrew the treatment. Relapse was seen in 12.2% of naive patients who finished the course of treatment. RVR and EVR were seen in 67.7% and 90.6% of naive patients, respectively. Patients divided into two groups. Group A consists of 247 patients treated with Peginterferon alpha-2a and group B 42 patients treated with Peginterferon-alpha-2b. No significant difference in treatment response was observed between naive patients of the two groups. The rates of arthralgia/myalgia, alopecia, pruritus, insomnia, dyspnea and anorexia were higher in group A and the rates of dermal problems, coryza and bleeding were higher in group B. In a subgroup analysis, the two kinds of Peginterferon-alpha-2a available in Iran were compared. Rapid and early viral responses and relapse rates were lower in the one made in Iran and the long-term responses were not different. The rates of arthralgia/myalgia, fever, alopecia, pruritus, insomnia, dyspnea, anorexia, cough, headache and abdominal pain were higher and the rates of irritability and coryza were lower in the one made in Iran. CONCLUSIONS: There was no significant difference in the efficacy of Peginterferon-alpha-2a and Peginterferon-alpha-2b in Iranian patients. Physicians might choose the treatment regimen for every individual concerning the differences in side effects of Peginterferons. PMID- 26504471 TI - Detection of Hepatitis B Virus Covalently Closed Circular DNA in the Plasma of Iranian HBeAg-Negative Patients With Chronic Hepatitis B. AB - BACKGROUND: Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a marker of HBV replication in the liver of patients infected with HBV. OBJECTIVES: This study aimed to investigate the association between the presence of cccDNA in the plasma samples of Iranian treatment-naive patients with chronic hepatitis B infection and HBV viral load and HBsAg levels. PATIENTS AND METHODS: From April 2012 to May 2015, 106 treatment-naive patients with chronic hepatitis B infection were enrolled in this cross-sectional study. The HBsAg titer was measured by the Roche HBsAg II assay on the Cobas e411 system, and HBV DNA quantitation was performed using the COBAS TaqMan 48 kit. Real-time polymerase chain reaction was performed for the detection of HBV cccDNA. RESULTS: The mean (SD) age of the patients was 41.1 +/- 12.4 years (range, 20 - 62 years). From a total of 106 study participants, 67 (63.2%) were males. The HBV cccDNA was detected in plasma specimens in 19 (17.9%) out of the total 106 patients, and a significant relationship was found between the presence of cccDNA in plasma sample of males (23.9%) and females (7.7%) (P = 0.039). Also, a significant correlation was found between the presence of cccDNA in plasma sample of the patients and HBV viral load level (P < 0.0001) and HBsAg titer (P = 0.0043). CONCLUSIONS: This study showed that cccDNA can be detected in the plasma specimen of 17.9% of Iranian treatment-naive patients with chronic hepatitis B infection. Therefore, designing prospective studies focusing on the detection of cccDNA in these patients would provide more information. PMID- 26504472 TI - Antioxidant and Anti-Inflammatory Activity Determination of One Hundred Kinds of Pure Chemical Compounds Using Offline and Online Screening HPLC Assay. AB - This study investigated the antioxidant activity of one hundred kinds of pure chemical compounds found within a number of natural substances and oriental medicinal herbs (OMH). Three different methods were used to evaluate the antioxidant activity of DPPH radical-scavenging activity, ABTS radical-scavenging activity, and online screening HPLC-ABTS assays. The results indicated that 17 compounds exhibited better inhibitory activity against ABTS radical than DPPH radical. The IC50 rate of a more practical substance is determined, and the ABTS assay IC50 values of gallic acid hydrate, (+)-catechin hydrate, caffeic acid, rutin hydrate, hyperoside, quercetin, and kaempferol compounds were 1.03 +/- 0.25, 3.12 +/- 0.51, 1.59 +/- 0.06, 4.68 +/- 1.24, 3.54 +/- 0.39, 1.89 +/- 0.33, and 3.70 +/- 0.15 MUg/mL, respectively. The ABTS assay is more sensitive to identifying the antioxidant activity since it has faster reaction kinetics and a heightened response to antioxidants. In addition, there was a very small margin of error between the results of the offline-ABTS assay and those of the online screening HPLC-ABTS assay. We also evaluated the effects of 17 compounds on the NO secretion in LPS-stimulated RAW 264.7 cells and also investigated the cytotoxicity of 17 compounds using a cell counting kit (CCK) in order to determine the optimal concentration that would provide an effective anti inflammatory action with minimum toxicity. These results will be compiled into a database, and this method can be a powerful preselection tool for compounds intended to be studied for their potential bioactivity and antioxidant activity related to their radical-scavenging capacity. PMID- 26504473 TI - Toxicopathological Evaluation of Hydroethanol Extract of Dianthus basuticus in Wistar Rats. AB - Background. Dianthus basuticus is a commonly used medicinal plant in Basotho traditional medicine for the treatment of diabetes, but there is no report on its safety or toxicity. Therefore, we evaluated the toxicity profile of the hydroethanol whole plant extract of Dianthus basuticus in Wistar rats. Methods. Acute toxicity test was performed with single oral administration of 100-3200 mg/kg body weight of D. basuticus extract to rats and the animals were observed for 14 days for signs of toxicity. The subacute toxicity experiment was conducted by oral administration of graded doses (200, 400, and 800 mg/kg) of D. basuticus extract daily for 28 days. Behavioural changes as well as haematological, biochemical, and histological parameters were then evaluated. Results. There was no observable sign of toxicity in the acute toxicity test. There were significant decreases (P < 0.05) in the feed and water intake as well as total cholesterol and triglycerides of the D. basuticus extract-treated rats in subacute toxicity study. There were no treatment related differences in the haematological, biochemical, and histopathological evaluations. Conclusions. Administration of hydroethanol extract of D. basuticus may be safe at the dosages tested in this study but its continuous usage can cause anorexia. PMID- 26504474 TI - Blackcurrant Suppresses Metabolic Syndrome Induced by High-Fructose Diet in Rats. AB - Increased fructose ingestion has been linked to obesity, hyperglycemia, dyslipidemia, and hypertension associated with metabolic syndrome. Blackcurrant (Ribes nigrum; BC) is a horticultural crop in Europe. To induce metabolic syndrome, Sprague-Dawley rats were fed 60% high-fructose diet. Treatment with BC (100 or 300 mg/kg/day for 8 weeks) significantly suppressed increased liver weight, epididymal fat weight, C-reactive protein (CRP), total bilirubin, leptin, and insulin in rats with induced metabolic syndrome. BC markedly prevented increased adipocyte size and hepatic triglyceride accumulation in rats with induced metabolic syndrome. BC suppressed oral glucose tolerance and protein expression of insulin receptor substrate-1 (IRS-1) and phosphorylated AMP activated protein kinase (p-AMPK) in muscle. BC significantly suppressed plasma total cholesterol, triglyceride, and LDL content. BC suppressed endothelial dysfunction by inducing downregulation of endothelin-1 and adhesion molecules in the aorta. Vascular relaxation of thoracic aortic rings by sodium nitroprusside and acetylcholine was improved by BC. The present study provides evidence of the potential protective effect of BC against metabolic syndrome by demonstrating improvements in dyslipidemia, hypertension, insulin resistance, and obesity in vivo. PMID- 26504476 TI - Erchen Decoction Prevents High-Fat Diet Induced Metabolic Disorders in C57BL/6 Mice. AB - Erchen decoction (ECD) is a traditional Chinese medicine prescription, which is used in the treatment of obesity, hyperlipidemia, fatty liver, diabetes, hypertension, and other diseases caused by retention of phlegm dampness. In this study we investigated the potential mechanism of ECD, using metabolism-disabled mice induced by high-fat diet. Body weight and abdominal circumference were detected. OGTT was measured by means of collecting blood samples from the tail vein. Blood lipid levels and insulin were measured using biochemical assay kit. Real-time PCR was used to measure the CDKAL1 gene expression and western blot was used to measure the protein expression. Through the research, it was found that ECD showed markedly lower body weight and abdominal circumference than those in the HFD group. Consistently, we observed that ECD significantly improved glucose tolerance, promoted the secretion of insulin and decreased the level of TG, TC level. Meanwhile, we observed significantly increased CDKAL1 mRNA and protein level in the ECD group. Therefore, we speculate that the potential molecular mechanism of ECD is to promote the CDKAL1 expression, ameliorate islet cell function, and raise insulin levels to regulate the metabolic disorder. PMID- 26504475 TI - The Effects of Bikram Yoga on Health: Critical Review and Clinical Trial Recommendations. AB - Bikram yoga is a style of hatha yoga involving a standarized series of asanas performed to an instructional dialogue in a heated environment (40.6 degrees C, 40% humidity). Several studies evaluating the effect of Bikram yoga on health related outcomes have been published over the past decade. However, to date, there are no comprehensive reviews of this research and there remains a lack of large-scale, robustly-designed randomised controlled trials (RCT) of Bikram yoga training. The purpose of this review is to contextualise and summarise trials that have evaluated the effects of Bikram yoga on health and to provide recommendations for future research. According to published literature, Bikram yoga has been shown to improve lower body strength, lower and upper body range of motion, and balance in healthy adults. Non-RCTs report that Bikram yoga may, in some populations, improve glucose tolerance, bone mineral density, blood lipid profile, arterial stiffness, mindfulness, and perceived stress. There is vast potential for further, improved research into the effects of Bikram yoga, particularly in unhealthy populations, to better understand intervention-related adaptations and their influence on the progression of chronic disease. Future research should adhere to CONSORT guidelines for better design and reporting to improve research quality in this field. PMID- 26504477 TI - Using the Theory of Planned Behaviour to Explain Use of Traditional Chinese Medicine among Hong Kong Chinese in Britain. AB - The UK Chinese are known for their underutilisation of western healthcare services. Reasons for this underutilisation are complex. The Theory of Planned Behaviour (TPB) is a widely used model of social cognition, which in the present study is being applied to traditional Chinese medicine (TCM) utilisation and satisfaction with TCM services. Two hundred and seventy-two UK Chinese aged between 15 and 91 years (M = 46.55; SD = 18.53) enrolled in the study. TCM utilisation was associated with gender, age, cultural attachment, and subjective norms. TCM users were more likely to be female and older and have a strong attachment to Chinese culture, and be influenced by the views of important others. Findings highlight the potential of the TPB in exploring TCM utilisation, whilst also throwing light on other factors influential in the use of TCM and satisfaction with TCM service provision among Chinese in the UK. PMID- 26504478 TI - From Body to Mind and Spirit: Qigong Exercise for Bereaved Persons with Chronic Fatigue Syndrome-Like Illness. AB - Bereavement may bring negative impacts on the mind, body, and spiritual well being of grieving persons. Some bereaved persons with chronic fatigue syndrome- (CFS-) illness experience a dual burden of distress. This study investigated the effects of bereavement on CFS-like illness by comparing bereaved and nonbereaved participants. It also adopted a random group design to investigate the effectiveness of Qigong on improving the well-being of bereaved participants. The Qigong intervention comprised 10 group sessions delivered twice a week for 5 weeks and home-practice for at least three times a week lasting 15-30 minutes each. The participants' fatigue, anxiety, and depression, quality of life (QoL), and spiritual well-being were measured at baseline and 3 months after treatment. The bereaved participants experienced significantly greater mental fatigue (16.09 versus 14.44, p = 0.017) and lower physical QoL (34.02 versus 37.17, p = 0.011) than their nonbereaved counterparts. After 3 months, the mental fatigue (-8 versus -4, p = 0.010) and physical fatigue (-10 versus -5, p = 0.007) experienced by intervention group had declined significantly, and improvements on their spirituality (14 versus -2, p = 0.013) and psychological QoL (8.91 versus 0.69, p = 0.002) scores exceeded those of the control group. PMID- 26504479 TI - Effects of Soothing Liver and Invigorating Spleen Recipes on the IKKbeta-NF kappaB Signaling Pathway in Kupffer Cells of Nonalcoholic Steatohepatitis Rats. AB - This study investigates the effect of soothing liver and invigorating spleen recipes on steatohepatitis examining the IKKbeta-NF-kappaB signaling pathway in KCs of NASH rats. SD male rats were randomly divided into 8 groups, and the NASH model was induced by a high-fat diet (HFD). After 26 weeks, liver tissue was examined in H&E stained sections and liver function was monitored biochemically. KCs were isolated by Seglen's method, with some modifications. The mRNA and protein expression of the IKKbeta-NF-kappaB signaling pathway components was examined by quantitative PCR and Western blotting. The results show that the high fat diet induced NASH in the rats, and the soothing liver recipe and invigorating spleen recipe decreased the levels of TNF-alpha, IL-1, and IL-6 in KCs, as well as inhibiting the mRNA and protein expression of the IKKbeta-NF-kappaB signaling pathway components. In conclusion, the experiment indicated the importance of the IKKbeta-NF-kappaB signaling pathway in KCs for the anti-inflammatory effects of the soothing liver and invigorating spleen recipes. PMID- 26504480 TI - Muscle Activation of Vastus Medialis Oblique and Vastus Lateralis in Sling-Based Exercises in Patients with Patellofemoral Pain Syndrome: A Cross-Over Study. AB - Objectives. To examine what changes are caused in the activity of the vastus medialis oblique (VMO) and vastus lateralis (VL) at the time of sling-based exercises in patients with patellofemoral pain syndrome (PFPS) and compare the muscular activations in patients with PFPS among the sling-based exercises. Methods. This was a cross-over study. Sling-based open and closed kinetic knee extension and hip adduction exercises were designed for PFPS, and electromyography was applied to record maximal voluntary contraction during the exercises. The VMO and VL activations and VMO : VL ratios for the three exercises were analyzed and compared. Results. Thirty male (age = 21.19 +/- 0.68 y) and 30 female (age = 21.12 +/- 0.74 y) patients with PFPS were recruited. VMO activations during the sling-based open and closed kinetic knee extension exercises were significantly higher (P = 0.04 and P = 0.001) than those during hip adduction exercises and VMO : VL ratio for the sling-based closed kinetic knee extension and hip adduction exercises approximated to 1. Conclusions. The sling-based closed kinetic knee extension exercise produced the highest VMO activation. It also had an appropriate VMO : VL ratio similar to sling-based hip adduction exercise and had beneficial effects on PFPS. PMID- 26504481 TI - Efficacy of Compound Kushen Injection in Relieving Cancer-Related Pain: A Systematic Review and Meta-Analysis. AB - Despite widespread popular use of complementary and alternative medicine (CAM) therapies, a rigorous evidence based on the efficacy of compound kushen injection (CKI) for cancer-related pain is lacking. In this study, we evaluated the efficacy and safety of compound kushen injection and provided information for current or future research and clinical application. Sixteen trials were identified with a total of 1564 patients. The total pain relief rate of CKI plus chemotherapy is better than chemotherapy except for colorectal cancer. The treatment groups achieved a reduction in the incidences of leukopenia and gastrointestinal, hepatic, and renal functional lesion. However, there is paucity of multi-institutional RCTs evaluating compound kushen injection for cancer pain with adequate power, duration, and sham control. The quantity and quality of RCTs are lower so that we still have to boost the research level through scientific design and normative report. PMID- 26504483 TI - Altered Impedance of Ear Acupuncture Point MT2 in Breast Cancer Patients: A Preliminary Observation. AB - Skin impedance at acupuncture points (APs) has been used as a diagnostic aid for more than 50 years. In this study, we have a diagnostic tool (JXT-2008) to measure the skin impedance of ear APs of 30 breast cancer patients and the corresponding skin impedance of ear APs of 30 healthy humans, and then we compared these changes in ear AP impedance in breast cancer patients and healthy individuals. PMID- 26504482 TI - Innovative Thoughts on Treating Diabetes from the Perspective of Traditional Chinese Medicine. AB - The rapidly increasing incidence of diabetes mellitus (DM) is becoming a major public health issue. As one of the important parts in complementary and alternative therapies, traditional Chinese medicine (TCM) is promising in treating DM. In this review, we summarize new thoughts on treating DM that aim to improve the clinical efficacy of TCM from the perspectives of principle, methods, formula, herbs, and doses. Our approach is as follows: principle: we use a combination of symptoms, syndromes, and diseases as a new mode for treating diabetes; methods: emphasizing heat-clearing in the early and middle stage of T2DM and invigorating blood circulation throughout the whole process of T2DM are two innovative methods to treat T2DM; formulas and herbs: choosing formulas and herbs based on the combination of TCM theory and current medicine. We will emphasize four strategies to help doctors choose formulas and herbs, including treatment based on syndrome differentiation, choosing herbs of bitter and sour flavors to counteract sweet flavor, choosing formulas and herbs aimed at main symptoms, and using modern pharmacological achievements in clinical practice; dose: reasonable drug dose plays an important role in the treatment of DM and a close relationship exists between dose and clinical efficacy. PMID- 26504484 TI - Deepure Tea Improves High Fat Diet-Induced Insulin Resistance and Nonalcoholic Fatty Liver Disease. AB - This study was to explore the protective effects of Deepure tea against insulin resistance and hepatic steatosis and elucidate the potential underlying molecular mechanisms. C57BL/6 mice were fed with a high fat diet (HFD) for 8 weeks to induce the metabolic syndrome. In the Deepure tea group, HFD mice were administrated with Deepure tea at 160 mg/kg/day by gavage for 14 days. The mice in HFD group received water in the same way over the same period. The age-matched C57BL/6 mice fed with standard chow were used as normal control. Compared to the mice in HFD group, mice that received Deepure tea showed significantly reduced plasma insulin and improved insulin sensitivity. Deepure tea increased the expression of insulin receptor substrate 2 (IRS-2), which plays an important role in hepatic insulin signaling pathway. Deepure tea also led to a decrease in hepatic fatty acid synthesis and lipid accumulation, which were mediated by the downregulation of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthesis (FAS), and acetyl-CoA carboxylase (ACC) proteins that are involved in liver lipogenesis. These results suggest that Deepure tea may be effective for protecting against insulin resistance and hepatic steatosis via modulating IRS-2 and downstream signaling SREBP-1c, FAS, and ACC. PMID- 26504485 TI - Subjective stress, objective heart rate variability-based stress, and recovery on workdays among overweight and psychologically distressed individuals: a cross sectional study. AB - BACKGROUND: The present study aimed to investigate how subjective self-reported stress is associated with objective heart rate variability (HRV)-based stress and recovery on workdays. Another aim was to investigate how physical activity (PA), body composition, and age are associated with subjective stress, objective stress, and recovery. METHODS: Working-age participants (n = 221; 185 women, 36 men) in this cross-sectional study were overweight (body mass index, 25.3-40.1 kg/m(2)) and psychologically distressed (>=3/12 points on the General Health Questionnaire). Objective stress and recovery were based on HRV recordings over 1 3 workdays. Subjective stress was assessed by the Perceived Stress Scale. PA level was determined by questionnaire, and body fat percentage was assessed by bioelectrical impedance analysis. RESULTS: Subjective stress was directly associated with objective stress (P = 0.047) and inversely with objective recovery (P = 0.046). These associations persisted after adjustments for sex, age, PA, and body fat percentage. Higher PA was associated with lower subjective stress (P = 0.037). Older age was associated with higher objective stress (P < 0.001). After further adjustment for alcohol consumption and regular medication, older age was associated with lower subjective stress (P = 0.043). CONCLUSIONS: The present results suggest that subjective self-reported stress is associated with objective physiological stress, but they are also apparently affected by different factors. However, some of the found associations among these overweight and psychologically distressed participants with low inter-individual variation in PA are rather weak and the clinical value of the present findings should be studied further among participants with greater heterogeneity of stress, PA and body composition. However, these findings suggest that objective stress assessment provides an additional aspect to stress evaluation. Furthermore, the results provide valuable information for developing stress assessment methods. PMID- 26504486 TI - Identifying New Candidate Genes and Chemicals Related to Prostate Cancer Using a Hybrid Network and Shortest Path Approach. AB - Prostate cancer is a type of cancer that occurs in the male prostate, a gland in the male reproductive system. Because prostate cancer cells may spread to other parts of the body and can influence human reproduction, understanding the mechanisms underlying this disease is critical for designing effective treatments. The identification of as many genes and chemicals related to prostate cancer as possible will enhance our understanding of this disease. In this study, we proposed a computational method to identify new candidate genes and chemicals based on currently known genes and chemicals related to prostate cancer by applying a shortest path approach in a hybrid network. The hybrid network was constructed according to information concerning chemical-chemical interactions, chemical-protein interactions, and protein-protein interactions. Many of the obtained genes and chemicals are associated with prostate cancer. PMID- 26504487 TI - Cell Pluripotency Levels Associated with Imprinted Genes in Human. AB - Pluripotent stem cells are exhibited similarly in the morphology, gene expression, growth properties, and epigenetic modification with embryonic stem cells (ESCs). However, it is still controversial that the pluripotency of induced pluripotent stem cell (iPSC) is much inferior to ESC, and the differentiation capacity of iPSC and ESC can also be separated by transcriptome and epigenetics. miRNAs, which act in posttranscriptional regulation of gene expression and are involved in many basic cellular processes, may reveal the answer. In this paper, we focused on identifying the hidden relationship between miRNAs and imprinted genes in cell pluripotency. Total miRNA expression patterns in iPSC and ES cells were comprehensively analysed and linked with human imprinted genes, which show a global picture of their potential function in pluripotent level. A new CPA4-KLF14 region which locates in chromosomal homologous segments (CHSs) within mammals and include both imprinted genes and significantly expressed miRNAs was first identified. Molecular network analysis showed genes interacted with imprinted genes closely and enriched in modules such as cancer, cell death and survival, and tumor morphology. This imprinted region may provide a new look for those who are interested in cell pluripotency of hiPSCs and hESCs. PMID- 26504488 TI - G2LC: Resources Autoscaling for Real Time Bioinformatics Applications in IaaS. AB - Cloud computing has started to change the way how bioinformatics research is being carried out. Researchers who have taken advantage of this technology can process larger amounts of data and speed up scientific discovery. The variability in data volume results in variable computing requirements. Therefore, bioinformatics researchers are pursuing more reliable and efficient methods for conducting sequencing analyses. This paper proposes an automated resource provisioning method, G2LC, for bioinformatics applications in IaaS. It enables application to output the results in a real time manner. Its main purpose is to guarantee applications performance, while improving resource utilization. Real sequence searching data of BLAST is used to evaluate the effectiveness of G2LC. Experimental results show that G2LC guarantees the application performance, while resource is saved up to 20.14%. PMID- 26504489 TI - Global Dynamics of a Virus Dynamical Model with Cell-to-Cell Transmission and Cure Rate. AB - The cure effect of a virus model with both cell-to-cell transmission and cell-to virus transmission is studied. By the method of next generation matrix, the basic reproduction number is obtained. The locally asymptotic stability of the virus free equilibrium and the endemic equilibrium is considered by investigating the characteristic equation of the model. The globally asymptotic stability of the virus-free equilibrium is proved by constructing suitable Lyapunov function, and the sufficient condition for the globally asymptotic stability of the endemic equilibrium is obtained by constructing suitable Lyapunov function and using LaSalle invariance principal. PMID- 26504491 TI - A polynomial time algorithm for computing the area under a GDT curve. AB - BACKGROUND: Progress in the field of protein three-dimensional structure prediction depends on the development of new and improved algorithms for measuring the quality of protein models. Perhaps the best descriptor of the quality of a protein model is the GDT function that maps each distance cutoff theta to the number of atoms in the protein model that can be fit under the distance theta from the corresponding atoms in the experimentally determined structure. It has long been known that the area under the graph of this function (GDT_A) can serve as a reliable, single numerical measure of the model quality. Unfortunately, while the well-known GDT_TS metric provides a crude approximation of GDT_A, no algorithm currently exists that is capable of computing accurate estimates of GDT_A. METHODS: We prove that GDT_A is well defined and that it can be approximated by the Riemann sums, using available methods for computing accurate (near-optimal) GDT function values. RESULTS: In contrast to the GDT_TS metric, GDT_A is neither insensitive to large nor oversensitive to small changes in model's coordinates. Moreover, the problem of computing GDT_A is tractable. More specifically, GDT_A can be computed in cubic asymptotic time in the size of the protein model. CONCLUSIONS: This paper presents the first algorithm capable of computing the near-optimal estimates of the area under the GDT function for a protein model. We believe that the techniques implemented in our algorithm will pave ways for the development of more practical and reliable procedures for estimating 3D model quality. PMID- 26504490 TI - Multivariate Radiological-Based Models for the Prediction of Future Knee Pain: Data from the OAI. AB - In this work, the potential of X-ray based multivariate prognostic models to predict the onset of chronic knee pain is presented. Using X-rays quantitative image assessments of joint-space-width (JSW) and paired semiquantitative central X-ray scores from the Osteoarthritis Initiative (OAI), a case-control study is presented. The pain assessments of the right knee at the baseline and the 60 month visits were used to screen for case/control subjects. Scores were analyzed at the time of pain incidence (T-0), the year prior incidence (T-1), and two years before pain incidence (T-2). Multivariate models were created by a cross validated elastic-net regularized generalized linear models feature selection tool. Univariate differences between cases and controls were reported by AUC, C statistics, and ODDs ratios. Univariate analysis indicated that the medial osteophytes were significantly more prevalent in cases than controls: C-stat 0.62, 0.62, and 0.61, at T-0, T-1, and T-2, respectively. The multivariate JSW models significantly predicted pain: AUC = 0.695, 0.623, and 0.620, at T-0, T-1, and T-2, respectively. Semiquantitative multivariate models predicted paint with C-stat = 0.671, 0.648, and 0.645 at T-0, T-1, and T-2, respectively. Multivariate models derived from plain X-ray radiography assessments may be used to predict subjects that are at risk of developing knee pain. PMID- 26504493 TI - National Library of Medicine report for EAHIL. PMID- 26504492 TI - Inconclusive role of human papillomavirus infection in breast cancer. AB - BACKGROUND: Epidemiological studies have examined the association between human papillomavirus (HPV) and breast cancer, but the findings are inconclusive. This study aimed to detect the prevalence of HPV in breast cancer tissue in patients from northeastern China and define the association between HPV and breast cancer using meta-analysis. METHODS: Polymerase chain reaction (PCR) was used to test cutaneous or mucosal HPV DNA sequence in 77 breast cancer samples and 77 corresponding adjacent normal tissues. The prevalence of HPV in breast cancer was estimated by pooling data from 38 studies. A meta-analysis of 16 case-control studies was conducted to investigate the association between HPV and breast cancer. RESULTS: We did not find HPV DNA sequence in any of the 154 tissue specimens we tested. However, our meta-analysis revealed a HPV prevalence of 30.30 % (95 % confidence interval [CI] = 22.30-38.40 %) among breast cancer cases; most of these involved high-risk HPV types (35.50 %, 95 % CI = 25.00-46.10 %). HPV prevalence in breast cancer varied by geographic region, publication period, and PCR detection method. An increased risk of breast cancer was observed in association with exposure to HPV (odds ratio [OR] = 3.24, 95 % CI = 1.59 6.57), which was influenced by geographic region, HPV DNA source, PCR primer used, and publication period. CONCLUSIONS: HPV, especially high-risk HPV types, may be associated with an increased risk of breast cancer, and this association varies dramatically among geographic regions. PMID- 26504494 TI - Sensory modulation disorders in childhood epilepsy. AB - BACKGROUND: Altered sensory sensitivity is generally linked to seizure susceptibility in childhood epilepsy but may also be associated to the highly prevalent problems in behavioral adaptation. This association is further suggested by the frequent overlap of childhood epilepsy with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), conditions in which altered behavioral responses to sensory stimuli have been firmly established. A continuum of sensory processing defects due to imbalanced neuronal inhibition and excitation across these disorders has been hypothesizedthat may lead to common symptoms of inadequate modulation of behavioral responses to sensory stimuli. Here, we investigated the prevalence of sensory modulation disorders among children with epilepsy and their relation with symptomatology of neurodevelopmental disorders. METHODS: We used the Sensory Profile questionnaire to assess behavioral responses to sensory stimuli and categorize sensory modulation disorders in children with active epilepsy (aged 4-17 years). We related these outcomes to epilepsy characteristics and tested their association with comorbid symptoms of ASD (Social Responsiveness Scale) and ADHD (Strengths and Difficulties Questionnaire). RESULTS: Sensory modulation disorders were reported in 49 % of the 158 children. Children with epilepsy reported increased behavioral responses associated with sensory "sensitivity," "sensory avoidance," and "poor registration" but not "sensory seeking." Comorbidity of ASD and ADHD was associated with more severe sensory modulation problems, although 27 % of typically developing children with epilepsy also reported a sensory modulation disorder. CONCLUSIONS: Sensory modulation disorders are an under-recognized problem in children with epilepsy. The extent of the modulation difficulties indicates a substantial burden on daily functioning and may explain an important part of the behavioral distress associated with childhood epilepsy. PMID- 26504495 TI - Semiparametric Contrasts of Cumulative Pre-Treatment Mortality in the Presence of Dependent Censoring. AB - In clinical settings, the necessity of treatment is often measured in terms of the patient's prognosis in the absence of treatment. Along these lines, it is often of interest to compare subgroups of patients (e.g., based on underlying diagnosis) with respect to pre-treatment survival. Such comparisons may be complicated by at least two important issues. First, mortality contrasts by subgroup may differ over follow-up time, as opposed to being constant, and may follow a form that is difficult to model parametrically. Moreover, in settings where the proportional hazards assumption fails, investigators tend to be more interested in cumulative (as opposed to instantaneous) effects on mortality. Second, pre-treatment death is censored by the receipt of treatment and in settings where treatment assignment depends on time-dependent factors that also affect mortality, such censoring is likely to be informative. We propose semiparametric methods for contrasting subgroup-specific cumulative mortality in the presence of dependent censoring. The proposed estimators are based on the cumulative hazard function, with pre-treatment mortality assumed to follow a stratified Cox model. No functional form is assumed for the nature of the non proportionality. Asymptotic properties of the proposed estimators are derived, and simulation studies show that the proposed methods are applicable to practical sample sizes. The methods are then applied to contrast pre-transplant mortality for acute versus chronic End-Stage Liver Disease patients. PMID- 26504496 TI - The Net Reclassification Index (NRI): a Misleading Measure of Prediction Improvement Even with Independent Test Data Sets. AB - The Net Reclassification Index (NRI) is a very popular measure for evaluating the improvement in prediction performance gained by adding a marker to a set of baseline predictors. However, the statistical properties of this novel measure have not been explored in depth. We demonstrate the alarming result that the NRI statistic calculated on a large test dataset using risk models derived from a training set is likely to be positive even when the new marker has no predictive information. A related theoretical example is provided in which an incorrect risk function that includes an uninformative marker is proven to erroneously yield a positive NRI. Some insight into this phenomenon is provided. Since large values for the NRI statistic may simply be due to use of poorly fitting risk models, we suggest caution in using the NRI as the basis for marker evaluation. Other measures of prediction performance improvement, such as measures derived from the ROC curve, the net benefit function and the Brier score, cannot be large due to poorly fitting risk functions. PMID- 26504497 TI - A gene expression signature identifying transient DNMT1 depletion as a causal factor of cancer-germline gene activation in melanoma. AB - BACKGROUND: Many human tumors show aberrant activation of a group of germline specific genes, termed cancer-germline (CG) genes, several of which appear to exert oncogenic functions. Although activation of CG genes in tumors has been linked to promoter DNA demethylation, the mechanisms underlying this epigenetic alteration remain unclear. Two main processes have been proposed: awaking of a gametogenic program directing demethylation of target DNA sequences via specific regulators, or general deficiency of DNA methylation activities resulting from mis-targeting or down-regulation of the DNMT1 methyltransferase. RESULTS: By the analysis of transcriptomic data, we searched to identify gene expression changes associated with CG gene activation in melanoma cells. We found no evidence linking CG gene activation with differential expression of gametogenic regulators. Instead, CG gene activation correlated with decreased expression of a set of mitosis/division-related genes (ICCG genes). Interestingly, a similar gene expression signature was previously associated with depletion of DNMT1. Consistently, analysis of a large set of melanoma tissues revealed that DNMT1 expression levels were often lower in samples showing activation of multiple CG genes. Moreover, by using immortalized melanocytes and fibroblasts carrying an inducible anti-DNMT1 small hairpin RNA (shRNA), we demonstrate that transient depletion of DNMT1 can lead to long-term activation of CG genes and repression of ICCG genes at the same time. For one of the ICCG genes (CDCA7L), we found that its down-regulation in melanoma cells was associated with deposition of repressive chromatin marks, including H3K27me3. CONCLUSIONS: Together, our observations point towards transient DNMT1 depletion as a causal factor of CG gene activation in vivo in melanoma. PMID- 26504498 TI - Five Facets of Mindfulness and Psychological Health: Evaluating a Psychological Model of the Mechanisms of Mindfulness. AB - There has been an increasing focus on determining the psychological mechanisms underlying the broad effects of mindfulness on psychological health. Mindfulness has been posited to be related to the construct of reperceiving or decentering, defined as a shift in perspective associated with decreased attachment to one's thoughts and emotions. Decentering is proposed to be a meta-mechanism that mobilizes four psychological mechanisms (cognitive flexibility, values clarification, self-regulation, and exposure), which in turn are associated with positive health outcomes. Despite preliminary support for this model, extant studies testing this model have not examined distinct facets of mindfulness. The present study used a multidimensional measure of mindfulness to examine whether this model could account for the associations between ive facets of mindfulness and psychological symptoms (depressive symptoms, stress, anxiety symptoms, alcohol-related problems) in a sample of college students (N = 944). Our findings partially support this model. We found significant double-mediated associations in the expected directions for all outcomes (stress, anxiety symptoms, and depressive symptoms) except alcohol-related problems, and for each of the facets of mindfulness except observing. However, decentering and the specific mechanisms did not fully mediate the associations among mindfulness facets and psychological health outcomes. Experimental and ecological momentary assessment designs are needed to understand the psychological processes that account for the beneficial effects of mindfulness. PMID- 26504499 TI - Transition Networks in a Cohort of Patients with Congestive Heart Failure: A Novel Application of Informatics Methods to Inform Care Coordination. AB - BACKGROUND: Unnecessary hospital readmissions are one source of escalating costs that may be reduced through improved care coordination, but how best to design and evaluate coordination programs is poorly understood. Measuring patient flow between service visits could support decisions for coordinating care, particularly for conditions such as congestive heart failure (CHF) which have high morbidity, costs, and hospital readmission rates. OBJECTIVES: To determine the feasibility of using network analysis to explore patterns of service delivery for patients with CHF in the context of readmissions. METHODS: A retrospective cohort study used de-identified records for patients >=18 years with an ICD-9 diagnosis code 428.0-428.9, and service visits between July 2011 and June 2012. Patients were stratified by admission outcome. Traditional and novel network analysis techniques were applied to characterize care patterns. RESULTS: Patients transitioned between services in different order and frequency depending on admission status. Patient-to-service CoUsage networks were diffuse suggesting unstructured flow of patients with no obvious coordination hubs. In service-to service Transition networks a specialty heart failure service was on the care path to the most other services for never admitted patients, evidence of how specialist care may prevent hospital admissions for some patients. For patients admitted once, transitions expanded for a clinic-based internal medicine service which clinical experts identified as a Patient Centered Medical Home implemented in the first month for which we obtained data. CONCLUSIONS: We detected valid patterns consistent with a targeted care initiative, which experts could understand and explain, suggesting the method has utility for understanding coordination. The analysis revealed strong but complex patterns that could not be demonstrated using traditional linear methods alone. Network analysis supports measurement of real world health care service delivery, shows how transitions vary between services based on outcome, and with further development has potential to inform coordination strategies. PMID- 26504500 TI - Retinal venous pressure: the role of endothelin. AB - The retinal venous pressure (RVP) can be measured non-invasively. While RVP is equal to or slightly above intraocular pressure (IOP) in healthy people, it is often markedly increased in patients with eye or systemic diseases. Beside a mechanical obstruction, the main cause of such an elevation is a local dysregulation of a retinal vein, particularly a constriction induced by endothelin-1 (ET-1). A local increase of ET-1 can result from a high plasma level, as ET-1 can diffuse from the fenestrated capillaries of the choroid into the optic nerve head (ONH), bypassing the blood retinal barrier. A local increase can also result from increased local production either by a sick neighboring artery or retinal tissue. Generally, the main factors increasing ET-1 are inflammations and hypoxia, either locally or in a remote organ. RVP is known to be increased in patients with glaucoma, retinal vein occlusion (RVO), diabetic retinopathy, high mountain disease, and primary vascular dysregulation (PVD). PVD is the major vascular component of Flammer syndrome (FS). An increase of RVP decreases perfusion pressure, which heightens the risk for hypoxia. An increase of RVP also elevates transmural pressure, which in turn heightens the risk for retinal edema. In patients with RVO, a high level of RVP may not only be a consequence but also a potential cause of the occlusion; therefore, it risks causing a vicious circle. Narrow retinal arteries and particularly dilated retinal veins are known risk indicators for future cardiovascular events. As the major cause for such a retinal venous dilatation is an increased RVP, RVP may likely turn out to be an even stronger predictor. PMID- 26504501 TI - Global Gene Expression Profiling in Omental Adipose Tissue of Morbidly Obese Diabetic African Americans. AB - BACKGROUND: Adipose tissues play important role in the pathophysiology of obesity related diseases including type 2 diabetes (T2D). To describe gene expression patterns and functional pathways in obesity-related T2D, we performed global transcript profiling of omental adipose tissue (OAT) in morbidly obese individuals with or without T2D. METHODS: Twenty morbidly obese (mean BMI: about 54 kg/m2) subjects were studied, including 14 morbidly obese individuals with T2D (cases) and 6 morbidly obese individuals without T2D (reference group). Gene expression profiling was performed using the Affymetrix U133 Plus 2.0 human genome expression array. Analysis of covariance was performed to identify differentially expressed genes (DEGs). Bioinformatics tools including PANTHER and Ingenuity Pathway Analysis (IPA) were applied to the DEGs to determine biological functions, networks and canonical pathways that were overrepresented in these individuals. RESULTS: At an absolute fold-change threshold of 2 and false discovery rate (FDR) < 0.05, 68 DEGs were identified in cases compared to the reference group. Myosin X (MYO10) and transforming growth factor beta regulator 1 (TBRG1) were upregulated. MYO10 encodes for an actin-based motor protein that has been associated with T2D. Telomere extension by telomerase (HNRNPA1, TNKS2), D myo-inositol (1, 4, 5)-trisphosphate biosynthesis (PIP5K1A, PIP4K2A), and regulation of actin-based motility by Rho (ARPC3) were the most significant canonical pathways and overlay with T2D signaling pathway. Upstream regulator analysis predicted 5 miRNAs (miR-320b, miR-381-3p, miR-3679-3p, miR-494-3p, and miR-141-3p,) as regulators of the expression changes identified. CONCLUSION: This study identified a number of transcripts and miRNAs in OAT as candidate novel players in the pathophysiology of T2D in African Americans. PMID- 26504502 TI - Qualitative Evaluation of a Role Play Bullying Simulation. AB - Bullying against nurses is becoming a pervasive problem. In this article, a role play simulation designed for undergraduate nursing students is described. In addition, the evaluation findings from a subsample of students who participated in a role play simulation addressing bullying behaviors are reported. Focus group sessions were completed with a subset of eight students who participated in the intervention. Sessions were audiorecorded, transcribed verbatim, and analyzed using Colaizzi's procedural steps for qualitative analysis. Themes derived from the data were "The Experience of Being Bullied", "Implementation of the Program", "Desired Outcome of the Program", and "Context of Bullying in the Nursing Profession". Role play simulation was an effective and active learning strategy to diffuse education on bullying in nursing practice. Bullying in nursing was identified as a problem worthy of incorporation into the undergraduate nursing curriculum. To further enhance the learning experience with role play simulation, adequate briefing instructions, opportunity to opt out of the role play, and comprehensive debriefing are essential. PMID- 26504503 TI - Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2015 MauiDerm Meeting. PMID- 26504505 TI - Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of pancreatic cysts by combined cytopathology and cystic content analysis. AB - Recent advances in imaging technology have resulted in an increase in incidental discoveries of pancreatic cystic lesions. Pancreatic cysts comprise a wide variety of lesions and include non-neoplastic cysts and neoplastic cysts. Because some pancreatic cysts have more of a malignant potential than others, it is absolutely essential that an accurate diagnosis is rendered so that effective care can be given to each patient. In many centers, endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) has emerged as the modality of choice that enables one to distinguish between mucinous and non-mucinous lesion, diagnose malignancy and collect cyst fluid for further diagnostic studies, such as pancreatic enzyme levels, molecular analysis and other tumor biomarkers. The current review will focus on EUS-guided FNA and the cytological diagnosis for pancreatic cysts. PMID- 26504504 TI - Oxidative Stress State Is Associated with Left Ventricular Mechanics Changes, Measured by Speckle Tracking in Essential Hypertensive Patients. AB - The oxidative stress state is characterized by an increase in oxygen reactive species that overwhelms the antioxidant defense; we do not know if these pathological changes are correlated with alterations in left ventricular mechanics. The aim was correlating the oxidative stress state with the left ventricular global longitudinal strain (GLS) and the left ventricular end diastolic pressure (LVEDP). Twenty-five patients with essential hypertension and 25 controls paired by age and gender were studied. All of the participants were subjected to echocardiography and biochemical determination of oxidative stress markers. The hypertensive patients, compared with control subjects, had significantly (p < 0.05) higher levels of oxidized proteins (5.03 +/- 1.05 versus 4.06 +/- 0.63 nmol/mg), lower levels of extracellular superoxide dismutase (EC SOD) activity (0.045 +/- 0.02 versus 0.082 +/- 0.02 U/mg), higher LVEDP (16.2 +/- 4.5 versus 11.3 +/- 1.6 mm Hg), and lower GLS (-12% versus -16%). Both groups had preserved ejection fraction and the results showed a positive correlation of oxidized proteins with GLS (r = 0.386, p = 0.006) and LVEDP (r = 0.389, p = 0.005); we also found a negative correlation of EC-SOD activity with GLS (r = 0.404, p = 0.004) and LVEDP (r = -0.347, p = 0.014). PMID- 26504506 TI - Imaging of common bile duct by linear endoscopic ultrasound. AB - Imaging of common bile duct (CBD) can be done by many techniques. Endoscopic retrograde cholangiopancreaticography is considered the gold standard for imaging of CBD. A standard technique of imaging of CBD by endoscopic ultrasound (EUS) has not been specifically described. The available descriptions mention different stations of imaging from the stomach and duodenum. The CBD lies closest to duodenum and choice of imaging may be restricted to duodenum for many operators. Generally most operators prefer multi station imaging during EUS and the choice of selecting the initial station varies from operator to operator. Detailed evaluation of CBD is frequently the main focus of imaging during EUS and in such situations multi station imaging with a high-resolution ultrasound scanner may provide useful information. Examination of the CBD is one of the primary indications for doing an EUS and it can be done from five stations: (1) the fundus of stomach; (2) body of stomach; (3) duodenal bulb; (4) descending duodenum; and (5) antrum. Following down the upper 1/3(rd) of CBD can do imaging of entire CBD from the liver window and following up the lower 1/3(rd) of CBD can do imaging of entire CBD from the pancreatic window. This article aims at simplifying the techniques of imaging of CBD by linear EUS. PMID- 26504507 TI - Reality named endoscopic ultrasound biliary drainage. AB - Endoscopic ultrasound (EUS) is used for diagnosis and evaluation of many diseases of the gastrointestinal (GI) tract. In the past, it was used to guide a cholangiography, but nowadays it emerges as a powerful therapeutic tool in biliary drainage. The aims of this review are: outline the rationale for endoscopic ultrasound-guided biliary drainage (EGBD); detail the procedural technique; evaluate the clinical outcomes and limitations of the method; and provide recommendations for the practicing clinician. In cases of failed endoscopic retrograde cholangiopancreatography (ERCP), patients are usually referred for either percutaneous transhepatic biliary drainage (PTBD) or surgical bypass. Both these procedures have high rates of undesirable complications. EGBD is an attractive alternative to PTBD or surgery when ERCP fails. EGBD can be performed at two locations: transhepatic or extrahepatic, and the stent can be inserted in an antegrade or retrograde fashion. The drainage route can be transluminal, duodenal or transpapillary, which, again, can be antegrade or retrograde [rendezvous (EUS-RV)]. Complications of all techniques combined include pneumoperitoneum, bleeding, bile leak/peritonitis and cholangitis. We recommend EGBD when bile duct access is not possible because of failed cannulation, altered upper GI tract anatomy, gastric outlet obstruction, a distorted ampulla or a periampullary diverticulum, as a minimally invasive alternative to surgery or radiology. PMID- 26504508 TI - Transgastric endoscopic gastrojejunostomy using holing followed by interrupted suture technique in a porcine model. AB - AIM: To demonstrate the feasibility and reproducibility of a pure natural orifice transluminal endoscopic surgery (NOTES) gastrojejunostomy using holing followed by interrupted suture technique using a single endoloop matched with a pair of clips in a non-survival porcine model. METHODS: NOTES gastrojejunostomy was performed on three female domestic pigs as follows: Gastrostomy, selection and retrieval of a free-floating loop of the small bowel into the stomach pouch, hold and exposure of the loop in the gastric cavity using a submucosal inflation technique, execution of a gastro-jejunal mucosal-seromuscular layer approximation using holing followed by interrupted suture technique with endoloop/clips, and full-thickness incision of the loop with a Dual knife. RESULTS: Pure NOTES side to-side gastrojejunostomy was successfully performed in all three animals. No leakage was identified via methylene blue evaluation following surgery. CONCLUSION: This novel technique for preforming a gastrointestinal anastomosis exclusively by NOTES is technically feasible and reproducible in an animal model but warrants further improvement. PMID- 26504509 TI - Unsedation colonoscopy can be not that painful: Evaluation of the effect of "Lamaze method of colonoscopy". AB - AIM: To evaluate the pain relieving effect of intervention with "Lamaze method of colonoscopy" in the process of colonoscopy. METHODS: Five hundred and eighty-five patients underwent colonoscopy were randomly divided into three groups, Lamaze group, anesthetic group and control group. Two hundred and twenty-four patients of Lamaze group, the "Lamaze method of colonoscopy" were practiced in the process of colonoscopy. The Lamaze method of colonoscopy is modified from the Lamaze method of childbirth, which helped patients to relieve pain through effective breathing control. One hundred and seventy-eight patients in anesthetic group accepted sedation colonoscopy. For 183 patients in control group, colonoscopy was performed without any intervention. The satisfactory of colon cleaning, intestinal lesions, intubation time, success ratio, pain grading and complications were recorded. All data were statistically analyzed. RESULTS: There were no significant differences at base line of the three groups (P > 0.05). Anesthetic group shows advantage in intubation time than the other two groups (P < 0.05). Lamaze group shows no advantage in intubation time than that in control group (P > 0.05). The anesthetic group showed an apparent advantage in relieving pain (P < 0.01). Therefore, the "Lamaze method of colonoscopy" performed in colonoscopy could relieve pain effectively comparing with control group (P < 0.05). The patients in anesthetic group had the highest incidence of complications (P < 0.05). CONCLUSION: The performance of the "Lamaze method of colonoscopy" in the process of colonoscopy could relieve patients' pain, minimize the incidence of complications, and is worthy promotion in clinical practice. PMID- 26504510 TI - Internal Transcribed Spacer 1 (ITS1) based sequence typing reveals phylogenetically distinct Ascaris population. AB - Taxonomic differentiation among morphologically identical Ascaris species is a debatable scientific issue in the context of Ascariasis epidemiology. To explain the disease epidemiology and also the taxonomic position of different Ascaris species, genome information of infecting strains from endemic areas throughout the world is certainly crucial. Ascaris population from human has been genetically characterized based on the widely used genetic marker, internal transcribed spacer1 (ITS1). Along with previously reported and prevalent genotype G1, 8 new sequence variants of ITS1 have been identified. Genotype G1 was significantly present among female patients aged between 10 to 15 years. Intragenic linkage disequilibrium (LD) analysis at target locus within our study population has identified an incomplete LD value with potential recombination events. A separate cluster of Indian isolates with high bootstrap value indicate their distinct phylogenetic position in comparison to the global Ascaris population. Genetic shuffling through recombination could be a possible reason for high population diversity and frequent emergence of new sequence variants, identified in present and other previous studies. This study explores the genetic organization of Indian Ascaris population for the first time which certainly includes some fundamental information on the molecular epidemiology of Ascariasis. PMID- 26504511 TI - A constraint-based modelling approach to metabolic dysfunction in Parkinson's disease. AB - One of the hallmarks of sporadic Parkinson's disease is degeneration of dopaminergic neurons in the pars compacta of the substantia nigra. The aetiopathogenesis of this degeneration is still not fully understood, with dysfunction of many biochemical pathways in different subsystems suggested to be involved. Recent advances in constraint-based modelling approaches hold great potential to systematically examine the relative contribution of dysfunction in disparate pathways to dopaminergic neuronal degeneration, but few studies have employed these methods in Parkinson's disease research. Therefore, this review outlines a framework for future constraint-based modelling of dopaminergic neuronal metabolism to decipher the multi-factorial mechanisms underlying the neuronal pathology of Parkinson's disease. PMID- 26504512 TI - Structure-Activity Relationship Studies of Cyclopropenimines as Enantioselective Bronsted Base Catalysts. AB - We recently demonstrated that chiral cyclopropenimines are viable Bronsted base catalysts in enantioselective Michael and Mannich reactions. Herein, we describe a series of structure-activity relationship studies that provide an enhanced understanding of the effectiveness of certain cyclopropenimines as enantioselective Bronsted base catalysts. These studies underscore the crucial importance of dicyclohexylamino substituents in mediating both reaction rate and enantioselectivity. In addition, an unusual catalyst CH...O interaction, which provides both ground state and transition state organization, is discussed. Cyclopropenimine stability studies have led to the identification of new catalysts with greatly improved stability. Finally, additional demonstrations of substrate scope and current limitations are provided herein. PMID- 26504513 TI - Direct Interfacial Y731 Oxidation in alpha2 by a Photobeta2 Subunit of E. coli Class Ia Ribonucleotide Reductase. AB - Proton-coupled electron transfer (PCET) is a fundamental mechanism important in a wide range of biological processes including the universal reaction catalysed by ribonucleotide reductases (RNRs) in making de novo, the building blocks required for DNA replication and repair. These enzymes catalyse the conversion of nucleoside diphosphates (NDPs) to deoxynucleoside diphosphates (dNDPs). In the class Ia RNRs, NDP reduction involves a tyrosyl radical mediated oxidation occurring over 35 A across the interface of the two required subunits (beta2 and alpha2) involving multiple PCET steps and the conserved tyrosine triad [Y356(beta2)-Y731(alpha2)-Y730(alpha2)]. We report the synthesis of an active photochemical RNR (photoRNR) complex in which a Re(I)-tricarbonyl phenanthroline ([Re]) photooxidant is attached site-specifically to the Cys in the Y356C-(beta2) subunit and an ionizable, 2,3,5-trifluorotyrosine (2,3,5-F3Y) is incorporated in place of Y731 in alpha2. This intersubunit PCET pathway is investigated by ns laser spectroscopy on [Re356]-beta2:2,3,5-F3Y731-alpha2 in the presence of substrate, CDP, and effector, ATP. This experiment has allowed analysis of the photoinjection of a radical into alpha2 from beta2 in the absence of the interfacial Y356 residue. The system is competent for light-dependent substrate turnover. Time-resolved emission experiments reveal an intimate dependence of the rate of radical injection on the protonation state at position Y731(alpha2), which in turn highlights the importance of a well-coordinated proton exit channel involving the key residues, Y356 and Y731, at the subunit interface. PMID- 26504514 TI - Pax3-induced expansion enables the genetic correction of dystrophic satellite cells. AB - BACKGROUND: Satellite cells (SCs) are indispensable for muscle regeneration and repair; however, due to low frequency in primary muscle and loss of engraftment potential after ex vivo expansion, their use in cell therapy is currently unfeasible. To date, an alternative to this limitation has been the transplantation of SC-derived myogenic progenitor cells (MPCs), although these do not hold the same attractive properties of stem cells, such as self-renewal and long-term regenerative potential. METHODS: We develop a method to expand wild type and dystrophic fresh isolated satellite cells using transient expression of Pax3. This approach can be combined with genetic correction of dystrophic satellite cells and utilized to promote muscle regeneration when transplanted into dystrophic mice. RESULTS: Here, we show that SCs from wild-type and dystrophic mice can be expanded in culture through transient expression of Pax3, and these expanded activated SCs can regenerate the muscle. We test this approach in a gene therapy model by correcting dystrophic SCs from a mouse lacking dystrophin using a Sleeping Beauty transposon carrying the human MUDYSTROPHIN gene. Transplantation of these expanded corrected cells into immune-deficient, dystrophin-deficient mice generated large numbers of dystrophin-expressing myofibers and improved contractile strength. Importantly, in vitro expanded SCs engrafted the SC compartment and could regenerate muscle after secondary injury. CONCLUSION: These results demonstrate that Pax3 is able to promote the ex vivo expansion of SCs while maintaining their stem cell regenerative properties. PMID- 26504515 TI - Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation. AB - Molecular hydrogen (H2) is clinically administered; however, in some hospitals, H2 is given to patients without consideration of its safe use. In the present study, we prepared convenient and safe devices for the drinking of super saturated H2 water, for intravenous drip infusion of H2-rich saline, and for the inhalation of H2 gas. In order to provide useful information for researchers using these devices, the changes in H2 concentration were studied. Our experimental results should contribute to the advance of non-clinical and clinical research in H2 medicine. PMID- 26504516 TI - Design of chiral urea-quaternary ammonium salt hybrid catalysts for asymmetric reactions of glycine Schiff bases. AB - Bifunctional chiral urea-containing quaternary ammonium salts can be straightforwardly synthesised in good yield and with high structural diversity via a scalable and operationally simple highly telescoped sequence starting from trans-1,2-cyclohexanediamine. These novel hybrid catalysts were systematically investigated for their potential to control glycine Schiff bases in asymmetric addition reactions. It was found that Michael addition reactions and the herein presented aldol-initiated cascade reaction can be carried out to provide enantiomeric ratios up to 95 : 5 and good yields under mild conditions at room temperature. PMID- 26504517 TI - A large and diverse collection of bovine genome sequences from the Canadian Cattle Genome Project. AB - BACKGROUND: The Canadian Cattle Genome Project is a large-scale international project that aims to develop genomics-based tools to enhance the efficiency and sustainability of beef and dairy production. Obtaining DNA sequence information is an important part of achieving this goal as it facilitates efforts to associate specific DNA differences with phenotypic variation. These associations can be used to guide breeding decisions and provide valuable insight into the molecular basis of traits. FINDINGS: We describe a dataset of 379 whole-genome sequences, taken primarily from key historic Bos taurus animals, along with the analyses that were performed to assess data quality. The sequenced animals represent ten populations relevant to beef or dairy production. Animal information (name, breed, population), sequence data metrics (mapping rate, depth, concordance), and sequence repository identifiers (NCBI BioProject and BioSample IDs) are provided to enable others to access and exploit this sequence information. CONCLUSIONS: The large number of whole-genome sequences generated as a result of this project will contribute to ongoing work aiming to catalogue the variation that exists in cattle as well as efforts to improve traits through genotype-guided selection. Studies of gene function, population structure, and sequence evolution are also likely to benefit from the availability of this resource. PMID- 26504518 TI - Multidrug resistant Enterobacteriaceae and extended spectrum beta-lactamase producing Escherichia coli: a cross-sectional study in National Kidney Center, Nepal. AB - BACKGROUND: Emergence of antibacterial resistance and production of Extended spectrum beta-lactamases (ESBLs) are responsible for the frequently observed empirical therapy failures. Most countries have experienced rapid dissemination of ESBLs producing Enterobacteriaceae isolates, particularly E. coli and Klebsiella pneumoniae. ESBLs are clinically significant and when detected, indicate the need for the use of appropriate antibacterial agents. But antibacterial choice is often complicated by multi-resistance. METHODS: This study was carried from June to November 2014 to study the multidrug resistant (MDR) Enterobacteriaceae and ESBL producing E. coli among urine isolates in hospital setting. Isolates from urine samples were primarily screened for possible ESBL production followed by phenotypic confirmation. Antibiotic susceptibility testing (AST) was done by Kirby Bauer disk diffusion method following Clinical and Laboratory Standard Institute (CLSI) guidelines. RESULTS: Out of 450 urine samples processed, 141 significant growths were obtained including 95 Enterobacteriaceae isolates with 67 E. coli. Among Enterobacteriaceae, 92 (96.84 %) were recorded as MDR and 18 (26.87 %) E. coli were confirmed as ESBLs producers. CONCLUSIONS: Using the phenotypic confirmatory test forwarded by the CLSI, relatively significant E. coli isolates tested were ESBL producers. Also high numbers of MDR organisms were isolated among Enterobacteriaceae. Isolates showed significant resistance to the commonly prescribed drugs. These findings suggest for further study in this field including the consequences of colonization with MDR and ESBL-producing bacteria both in the community and in the hospital setting. PMID- 26504520 TI - Factors associated with safe child feces disposal practices in Ethiopia: evidence from demographic and health survey. AB - BACKGROUND: According to the WHO/UNICEF Joint Monitoring Programme (JMP) for water supply and Sanitation definition, safe child feces disposal practices include: children defecation into a latrine, disposal of child stools in a latrine or burial. Inappropriate disposal of human feces including unsafe child feces disposal facilitates the transmission of pathogens. However, the factors associated with safe child feces disposal practices have not been yet well explored in Ethiopia. This study aimed to identify factors associated with safe child feces disposal practices in Ethiopia. METHODS: This study analyzed data from Ethiopian Demographic and Health Survey (EDHS) 2011. The practice of child's feces disposal was categorized into 'safe' and 'unsafe' based on the WHO/ UNICEF JMP for water supply & Sanitation definition. Binary and multivariable logistic regression models were employed to identify factors associated with safe child feces disposal practices. RESULT: The prevalence of safe child feces disposal was 33.68 % (95 % CI: 32.82-34.55). In the final multivariable logistic regression model, the practice of safe disposal of child feces was significantly associated with urban residency (AOR = 1.25, 95 % CI: 1.01-1.55) and having access to an improved latrine (AOR = 1.92, 95 % CI: 1.56-2.36). Households found in the poorer, middle, richer and richest wealth quintile had (AOR = 2.22, 95 % CI: 1.70 2.89), (AOR = 2.94, 95 % CI: 2.27-3.81), (AOR = 4.20, 95 % CI: 3.42-5.72) and (AOR = 8.06, 95 % CI: 5.91-10.99) times higher odds to practice safe child feces disposal respectively as compared households from poorest wealth quintile. Mothers/caregivers with primary, secondary and higher educational status had (AOR = 1.29, 95 % CI: 1.10-1.50), (AOR = 1. 64, 95 % CI: 1.12-2.41) and (AOR = 2.16, 95 % CI: 1.25-3.72) times higher odds to practice safe child feces disposal respectively than those mothers who had no education. Those mothers/caregivers whose child was 48-59 months old had (AOR = 2.21, 95 % CI: 1.82-2.68) times higher odds to practice safe child feces disposal as compared to mothers/caregivers who had a child with age less than 12 months old. The odds of safe child feces disposal among households who had one two and three under five years old children were (AOR = 3.11, 95 % CI: 1.87-5.19),(AOR = 2.55, 95 % CI: 1.53-4.24) and (AOR = 1.92, 95 % CI: 1.13-3.24) times higher respectively than households with four and more children of under five years old. CONCLUSION: Only one third of the mothers practiced safe child feces disposal in Ethiopia. Being an urban resident, having a higher wealth quintile, high levels of maternal education, older child age, having a lower number of under five years old children, and the presence of an improved latrine were factors associated with safe child feces disposal practices. Therefore interventions designed to improve safe child feces disposal practices should consider those factors identified. Further research is also needed to design intervention that will aim to improve safe child feces disposal. PMID- 26504519 TI - The associations between Parkinson's disease and cancer: the plot thickens. AB - Epidemiological studies support a general inverse association between the risk of cancer development and Parkinson's disease (PD). In recent years however, increasing amount of eclectic evidence points to a positive association between PD and cancers through different temporal analyses and ethnic groups. This positive association has been supported by several common genetic mutations in SNCA, PARK2, PARK8, ATM, p53, PTEN, and MC1R resulting in cellular changes such as mitochondrial dysfunction, aberrant protein aggregation, and cell cycle dysregulation. Here, we review the epidemiological and biological advances of the past decade in the association between PD and cancers to offer insight on the recent and sometimes contradictory findings. PMID- 26504521 TI - Principles and mechanisms of regeneration in the mouse model for wound-induced hair follicle neogenesis. AB - Wound induced hair follicle neogenesis (WIHN) describes a regenerative phenomenon in adult mammalian skin, wherein fully functional hair follicles regenerate de novo in the center of large excisional wounds. Originally described in rats, rabbits, sheep, and humans in 1940-60, the WIHN phenomenon was reinvestigated in mice only recently. The process of de novo hair regeneration largely duplicates the morphological and signaling features of normal embryonic hair development. Similar to hair development, WIHN critically depends on the activation of canonical WNT signaling. However, unlike hair development, WNT activation in WIHN is dependent on Fgf9 signaling generated by the immune system's gamma delta (gammadelta) T cells. The cellular bases of WIHN remain to be fully characterized, however, the available evidence leaves open the possibility for a blastema-like mechanism, wherein epidermal and/or dermal wound cells undergo epigenetic reprogramming toward a more plastic, embryonic-like state. De novo hair follicles do not regenerate from preexisting hair-fated bulge stem cells. This suggests that hair neogenesis is not driven by preexisting lineage restricted progenitors, as is the case for amputation-induced mouse digit tip regeneration, but rather may require a blastema-like mechanism. The WIHN model is characterized by several intriguing features, which await further explanation. These include: (i) minimum wound size requirement for activating neogenesis, (ii) restriction of hair neogenesis to the wound's center, (iii) imperfect patterning outcomes, both in terms of neogenic hair positioning within the wound and in terms of their orientation. Future inquires into the WIHN process, made possible by a wide array of the available skin-specific genetic tools, will undoubtedly expand our understanding of the regeneration mechanisms in adult mammals. PMID- 26504523 TI - Sea surface temperature and salinity from French research vessels, 2001-2013. AB - French Research vessels have been collecting thermo-salinometer (TSG) data since 1999 to contribute to the Global Ocean Surface Underway Data (GOSUD) programme. The instruments are regularly calibrated and continuously monitored. Water samples are taken on a daily basis by the crew and later analysed in the laboratory. We present here the delayed mode processing of the 2001-2013 dataset and an overview of the resulting quality. Salinity measurement error was a few hundredths of a unit or less on the practical salinity scale (PSS), due to careful calibration and instrument maintenance, complemented with a rigorous adjustment on water samples. In a global comparison, these data show excellent agreement with an ARGO-based salinity gridded product. The Sea Surface Salinity and Temperature from French REsearch SHips (SSST-FRESH) dataset is very valuable for the 'calibration and validation' of the new satellite observations delivered by the Soil Moisture and Ocean Salinity (SMOS) and Aquarius missions. PMID- 26504524 TI - Effects of krill oil on endothelial function and other cardiovascular risk factors in participants with type 2 diabetes, a randomized controlled trial. AB - OBJECTIVE: The purpose of this trial was to evaluate the effect of krill oil supplementation, a source of omega-3 fatty acids, on cardiovascular disease risk factors and blood glucose control among participants with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized, double-blind controlled cross-over trial was employed. Outcomes assessed were: endothelial function, blood lipids, glucose, glycated hemoglobin, serum antioxidant level, C peptide, and calculated Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores. Participants were randomized to either krill oil or olive oil supplementation for 4 weeks, underwent a 2-week washout period, and then crossed to the other supplementation for 4 weeks. All participants were then offered an additional 17 weeks of krill supplementation. Testing occurred at 3 time points: baseline, after first supplementation, and after second supplementation. Testing also occurred after an optional 17 weeks of krill oil supplementation. Difference scores were calculated for each participant in both sequences (ie, differences in outcome measures in the first and second period of the sequence). The mean and SD of the scores in the 2 sequence groups were used to test for differences between treatment effects at a significance level of p<0.05. RESULTS: A total of 47 participants were included in the initial cross-over study. Participants who received krill oil for 4 weeks had an improvement in their endothelial function and a reduction in blood C peptide levels and HOMA scores as compared with the olive oil. A total of 34 participants completed the additional 17-week supplementation period. When compared with their respective baseline measures, these participants had a statistically significant improvement in endothelial function and blood high density lipoprotein (HDL). CONCLUSIONS: Krill oil may lead to moderate improvement of cardiovascular risks, specifically endothelial dysfunction and HDL in patients with type 2 diabetes. TRIAL REGISTRATION NUMBER: Registered with ClinicalTrials.gov: NCT02091193. PMID- 26504522 TI - Test-retest resting-state fMRI in healthy elderly persons with a family history of Alzheimer's disease. AB - We present a test-retest dataset of resting-state fMRI data obtained in 80 cognitively normal elderly volunteers enrolled in the "Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease" (PREVENT-AD) Cohort. Subjects with a family history of Alzheimer's disease in first-degree relatives were recruited as part of an on-going double blind randomized clinical trial of Naproxen or placebo. Two pairs of scans were acquired ~3 months apart, allowing the assessment of both intra- and inter-session reliability, with the possible caveat of treatment effects as a source of inter-session variation. Using the NeuroImaging Analysis Kit (NIAK), we report on the standard quality of co registration and motion parameters of the data, and assess their validity based on the spatial distribution of seed-based connectivity maps as well as intra- and inter-session reliability metrics in the default-mode network. This resource, released publicly as sample UM1 of the Consortium for Reliability and Reproducibility (CoRR), will benefit future studies focusing on the preclinical period preceding the appearance of dementia in Alzheimer's disease. PMID- 26504525 TI - Secreted factors from dental pulp stem cells improve glucose intolerance in streptozotocin-induced diabetic mice by increasing pancreatic beta-cell function. AB - OBJECTIVE: Many studies have reported that stem cell transplantation promotes propagation and protection of pancreatic beta-cells in streptozotocin (STZ) induced diabetic mice without the differentiation of transplanted cells into pancreatic beta-cells, suggesting that the improvement is due to a paracrine effect of the transplanted cells. We investigated the effects of factors secreted by dental pulp stem cells from human exfoliated deciduous teeth (SHED) on beta cell function and survival. RESEARCH DESIGN AND METHODS: Conditioned medium from SHED (SHED-CM) was collected 48 h after culturing in serum-free Dulbecco's modified Eagle's medium (DMEM). The insulin levels in SHED-CM and serum-free conditioned media from human bone marrow-derived mesenchymal stem cells (BM-CM) were undetectable. STZ-induced diabetic male C57B/6J mice were injected with DMEM as a control, SHED-CM, exendin-4 (Ex-4), or BM-CM for 14 days. Mouse pancreatic beta-cell line MIN6 cells were incubated with different concentrations of STZ with SHED-CM, DMEM, Ex-4, or BM-CM for 6 h. RESULTS: Administration of 1 mL of SHED-CM twice a day improved glucose intolerance in STZ-induced diabetic mice and the effect continued for 20 days after the end of treatment. SHED-CM treatment increased pancreatic insulin content and beta-cell mass through proliferation and an intraperitoneal glucose tolerance test revealed enhanced insulin secretion. Incubation of MIN6 cells (a mouse pancreatic beta-cell line) with SHED-CM enhanced insulin secretion in a glucose concentration-dependent manner and reduced STZ-induced cell death, indicating that the amelioration of hyperglycemia was caused by the direct effects of SHED-CM on beta-cell function and survival. These effects were more pronounced than with the use of Ex-4, a conventional incretin-based drug, and BM-CM, which is a medium derived from other stem cells. CONCLUSIONS: These findings suggest that SHED-CM provides direct protection and encourages the propagation of beta-cells, and has potential as a novel strategy for treatment of diabetes. PMID- 26504526 TI - Predictors of the antibody response to influenza vaccination in older adults with type 2 diabetes. AB - OBJECTIVE: Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic inflammatory diseases of the elderly. Its development is related to the alteration of the immune system with aging characterized by immunosenescence and inflamm-aging. In turn, T2DM also alters the immune response. As a consequence, older people with T2DM are more susceptible to influenza and to its complications as compared with healthy controls. Vaccination against influenza has shown poor efficacy in the older population and even less efficacy in patients with diabetes. We studied here the antibody response to vaccination in healthy and diabetic elderly participants. RESEARCH DESIGN AND METHODS: In 2 groups of elderly participants (healthy N=119 and T2DM N=102), we measured the immunogenicity of influenza vaccine by hemagglutination inhibition assays. We assessed several blood and functional parameters as potential predictors of the vaccine efficacy. RESULTS: We found no difference between antibody responses in diabetic elderly compared with healthy elderly. Among the biological and functional determinants, the cytomegalovirus (CMV) serostatus played a more prominent role in determining the magnitude of response. We concluded that in addition to age and diabetic status, immunological history such as CMV status should be taken into account. None of the other biological or functional parameters studied could be reliably linked to the vaccine antibody response in older adults who are not frail including those with well-controlled diabetes. CONCLUSIONS: Our data strongly suggest that influenza vaccine should be administered to elderly patients with T2DM; however, the immune determinants of the antibody response to influenza vaccination should be further investigated. PMID- 26504528 TI - A rapid dehydration leaf assay reveals stomatal response differences in grapevine genotypes. AB - A simple and reliable way of phenotyping plant responses to dehydration was developed. Fully-developed leaves were detached and placed in a closed plastic box containing a salt solution to control the atmospheric water potential in the container. Three hours of dehydration (weight loss of the leaf) was optimal for measuring changes in stomatal response to dehydration. Application of the plant hormone abscisic acid (ABA) prior to leaf detachment decreased the amount of water loss, indicating that the assay was able to detect differences based on a stomatal response to dehydration. Five different Vitis genotypes (V. riparia, V. champinii, V. vinifera cv. Shiraz, V. vinifera cv. Grenache and V. vinifera cv. Cabernet Sauvignon) with known differences in drought tolerance were screened for their dehydration response and the results obtained corresponded to previous reports of stomatal responses in the vineyard. Significant differences in stomatal density along with differences in the amount and rate of water lost indicate differences in dehydration sensitivity among the genotypes screened. Differences in stomatal response to ABA were also detected. Shiraz had the lowest stomatal density and the highest ABA sensitivity among the genotypes screened, yet Shiraz lost the most amount of water, indicating that it was the least sensitive to dehydration. Despite having the highest stomatal density and intermediate stomatal sensitivity to ABA, V. riparia lost the smallest amount of water, indicating that it was the most sensitive to dehydration. The assay presented here represents a simple and reliable phenotyping method for plant responses to leaf dehydration. PMID- 26504527 TI - Molecular genetics and genomics of the Rosoideae: state of the art and future perspectives. AB - The Rosoideae is a subfamily of the Rosaceae that contains a number of species of economic importance, including the soft fruit species strawberry (Fragaria *ananassa), red (Rubus idaeus) and black (Rubus occidentalis) raspberries, blackberries (Rubus spp.) and one of the most economically important cut flower genera, the roses (Rosa spp.). Molecular genetics and genomics resources for the Rosoideae have developed rapidly over the past two decades, beginning with the development and application of a number of molecular marker types including restriction fragment length polymorphisms, amplified fragment length polymorphisms and microsatellites, and culminating in the recent publication of the genome sequence of the woodland strawberry, Fragaria vesca, and the development of high throughput single nucleotide polymorphism (SNP)-genotyping resources for Fragaria, Rosa and Rubus. These tools have been used to identify genes and other functional elements that control traits of economic importance, to study the evolution of plant genome structure within the subfamily, and are beginning to facilitate genomic-assisted breeding through the development and deployment of markers linked to traits such as aspects of fruit quality, disease resistance and the timing of flowering. In this review, we report on the developments that have been made over the last 20 years in the field of molecular genetics and structural genomics within the Rosoideae, comment on how the knowledge gained will improve the efficiency of cultivar development and discuss how these advances will enhance our understanding of the biological processes determining agronomically important traits in all Rosoideae species. PMID- 26504529 TI - Inaugural Editorial. PMID- 26504530 TI - Dynamic changes in proteins during apple (Malus x domestica) fruit ripening and storage. AB - A proteomic study, using two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight, was conducted in apple fruit (cv. 'Golden Delicious') starting at 10 days prior to harvest through 50 days in storage. Total protein was extracted using a phenol/sodium dodecyl sulfate protocol. More than 400 protein spots were detected in each gel and 55 differentially expressed proteins (p<0.05) were subjected to matrix-assisted laser desorption/ionization time-of-flight/time-of-flight analysis. Fifty-three of these proteins were finally identified using an apple expressed sequence tag database downloaded from Genome Database for Rosaceae and placed into six categories. The categories and the percentage of proteins placed in each category were stress response and defense (49.0%), energy and metabolism (34.0%), fruit ripening and senescence (5.6%), signal transduction (3.8%), cell structure (3.8%) and protein synthesis (3.8%). Proteins involved in several multiple metabolic pathways, including glycolysis, pentose-phosphate pathway, anti-oxidative systems, photosynthesis and cell wall synthesis, were downregulated, especially during the climacteric burst in respiration and during the senescent stages of fruit development. Proteins classified as allergens or involved in cell wall degradation were upregulated during the ripening process. Some protein spots exhibited a mixed pattern (increasing to maximal abundance followed by a decrease), such as 1-aminocyclopropane-1-carboxylate oxidase, L ascorbate peroxidase and abscisic acid response proteins. The identification of differentially expressed proteins associated with physiological processes identified in the current study provides a baseline of information for understanding the metabolic processes and regulatory mechanisms that occur in climacteric apple fruit during ripening and senescence. PMID- 26504531 TI - Sequential light programs shape kale (Brassica napus) sprout appearance and alter metabolic and nutrient content. AB - Different light wavelengths have specific effects on plant growth and development. Narrow-bandwidth light-emitting diode (LED) lighting may be used to directionally manipulate size, color and metabolites in high-value fruits and vegetables. In this report, Red Russian kale (Brassica napus) seedlings were grown under specific light conditions and analyzed for photomorphogenic responses, pigment accumulation and nutraceutical content. The results showed that this genotype responds predictably to darkness, blue and red light, with suppression of hypocotyl elongation, development of pigments and changes in specific metabolites. However, these seedlings were relatively hypersensitive to far-red light, leading to uncharacteristically short hypocotyls and high pigment accumulation, even after growth under very low fluence rates (<1 MUmol m(-2) s( 1)). General antioxidant levels and aliphatic glucosinolates are elevated by far red light treatments. Sequential treatments of darkness, blue light, red light and far-red light were applied throughout sprout development to alter final product quality. These results indicate that sequential treatment with narrow bandwidth light may be used to affect key economically important traits in high value crops. PMID- 26504532 TI - Identification of SSRs and differentially expressed genes in two cultivars of celery (Apium graveolens L.) by deep transcriptome sequencing. AB - Celery (Apium graveolens L.) is one of the most important and widely grown vegetables in the Apiaceae family. Due to the lack of comprehensive genomic resources, research on celery has mainly utilized physiological and biochemical approaches, rather than molecular biology, to study this crop. Transcriptome sequencing has become an efficient and economic technology for obtaining information on gene expression that can greatly facilitate molecular and genomic studies of species for which a sequenced genome is not available. In the present study, 15 893 516 and 19 818 161 high-quality sequences were obtained by RNA-seq from two celery varieties 'Ventura' and 'Jinnan Shiqin', respectively. The obtained reads were assembled into 39 584 and 41 740 unigenes with mean lengths of 683 bp and 690 bp, respectively. A total of 1939 simple sequence repeat (SSR) markers were identified in 'Ventura' and 2004 SSRs in 'Jinnan Shiqin'. Di nucleotide repeats were the most common repeat motif, accounting for 55.49% and 54.84% in 'Ventura' and 'Jinnan Shiqin', respectively. A comparison of expressed genes between the two libraries, identified 338 differentially expressed genes (DEGs). Three hundred and three of the DEGs were annotated based on a sequence similarity search utilizing eight public databases. Additionally, the expression profile of eight annotated DEGs was characterized in response to abiotic stresses. The collective data generated in the present research represent a valuable resource for further genetic and molecular studies in celery. PMID- 26504534 TI - Genetic and phenological variation of tocochromanol (vitamin E) content in wild (Daucus carota L. var. carota) and domesticated carrot (D. carota L. var. sativa). AB - Carrot roots (Daucus carota L. var. sativa) produce tocochromanol compounds, collectively known as vitamin E. However, little is known about their types and amounts. Here we determined the range and variation in types and amounts of tocochromanols in a variety of cultivated carrot accessions throughout carrot postharvest storage and reproductive stages and in wild-type roots (Daucus carota L. var. carota). Of eight possible tocochromanol compounds, we detected and quantified alpha-, and the combined peak for beta- and gamma- forms of tocopherols and tocotrienols. Significant variation in amounts of tocochromanol compounds was observed across accessions and over time. Large increases in alpha tocopherol were noted during both reproductive growth and the postharvest stages. The variation of tocochromanols in carrot root tissue provides useful information for future research seeking to understand the role of these compounds in carrot root tissue or to breed varieties with increased levels of these compounds. PMID- 26504533 TI - Transcriptional dynamics of the developing sweet cherry (Prunus avium L.) fruit: sequencing, annotation and expression profiling of exocarp-associated genes. AB - The exocarp, or skin, of fleshy fruit is a specialized tissue that protects the fruit, attracts seed dispersing fruit eaters, and has large economical relevance for fruit quality. Development of the exocarp involves regulated activities of many genes. This research analyzed global gene expression in the exocarp of developing sweet cherry (Prunus avium L., 'Regina'), a fruit crop species with little public genomic resources. A catalog of transcript models (contigs) representing expressed genes was constructed from de novo assembled short complementary DNA (cDNA) sequences generated from developing fruit between flowering and maturity at 14 time points. Expression levels in each sample were estimated for 34 695 contigs from numbers of reads mapping to each contig. Contigs were annotated functionally based on BLAST, gene ontology and InterProScan analyses. Coregulated genes were detected using partitional clustering of expression patterns. The results are discussed with emphasis on genes putatively involved in cuticle deposition, cell wall metabolism and sugar transport. The high temporal resolution of the expression patterns presented here reveals finely tuned developmental specialization of individual members of gene families. Moreover, the de novo assembled sweet cherry fruit transcriptome with 7760 full-length protein coding sequences and over 20 000 other, annotated cDNA sequences together with their developmental expression patterns is expected to accelerate molecular research on this important tree fruit crop. PMID- 26504536 TI - Effects of location within the tree canopy on carbohydrates, organic acids, amino acids and phenolic compounds in the fruit peel and flesh from three apple (Malus * domestica) cultivars. AB - Fruits from three cultivars of apple (Malus * domestica Borkh.)-'McIntosh', 'Gala' and 'Mutsu'-were harvested from the exterior and interior of the tree canopy. Peel and flesh tissues were sampled separately to determine how the position of the fruit on the tree might affect the levels of the primary and secondary metabolites in the fruit. Fruit from the outer-canopy had a higher fresh weight and a higher soluble solids content compared with inner-canopy fruit. Both the flesh and peel of the outer-canopy fruit had higher concentrations of soluble sugars and sugar alcohols, but lower starch concentrations than the inner-canopy fruit. Canopy position did not significantly affect malic acid concentrations, except in the peel of 'McIntosh' and the flesh of 'Mutsu'. Although levels of ascorbic and succinic acids were higher in the peel of the outer-canopy fruit, the responses of other organic acids to canopy position depended on tissue type and cultivar. Except for histidine, lysine, threonine and glycine, most amino acids accumulated at higher concentrations in the inner-canopy fruit. By contrast, levels of phenolic compounds from both the peel and flesh were significantly higher in the outer-canopy fruit. The significant effects of location within the canopy on both primary metabolites and secondary metabolites demonstrate the importance of light exposure on apple fruit quality. PMID- 26504535 TI - Genome and transcriptome analysis of the grapevine (Vitis vinifera L.) WRKY gene family. AB - The plant WRKY gene family represents an ancient and complex class of zinc-finger transcription factors (TFs) that are involved in the regulation of various physiological processes, such as development and senescence, and in plant response to many biotic and abiotic stresses. Despite the growing number of studies on the genomic organisation of WRKY gene family in different species, little information is available about this family in grapevine (Vitis vinifera L.). In the present study, a total number of 59 putative grapevine WRKY transcription factors (VvWRKYs) were identified based on the analysis of various genomic and proteomic grapevine databases. According to their structural and phylogentic features, the identified grapevine WRKY transcription factors were classified into three main groups. In order to shed light into their regulatory roles in growth and development as well as in response to biotic and abiotic stress in grapevine, the VvWRKYs expression profiles were examined in publicly available microarray data. Bioinformatics analysis of these data revealed distinct temporal and spatial expression patterns of VvWRKYs in various tissues, organs and developmental stages, as well as in response to biotic and abiotic stresses. To also extend our analysis to situations not covered by the arrays and to validate our results, the expression profiles of selected VvWRKYs in response to drought stress, Erysiphe necator (powdery mildew) infection, and hormone treatments (salicilic acid and ethylene), were investigated by quantitative real time reverse transcription PCR (qRT-PCR). The present study provides a foundation for further comparative genomics and functional studies of this important class of transcriptional regulators in grapevine. PMID- 26504537 TI - Growth and physiological responses of creeping bentgrass (Agrostis stolonifera) to elevated carbon dioxide concentrations. AB - The atmospheric carbon dioxide level has increased and is predicted to continue increasing, which may affect various aspects of plant growth. The objective of this study was to investigate the effects of doubling the carbon dioxide level on the growth and physiological activities of a widely utilized cool-season turfgrass species, creeping bentgrass (Agrostis stolonifera L. 'Penncross'). 'Penncross' plants were established in fritted clay medium and maintained under well-irrigated and well-fertilized conditions in growth chambers. The plants were exposed to either ambient carbon dioxide concentrations (400+/-10 umol L(-1)) or elevated carbon dioxide concentrations (800+/-10 umol L(-1)) for 12 weeks. Plants grown under elevated carbon dioxide displayed a significantly faster growth rate of their lateral stems (stolons) and increased shoot and root dry weight but a reduced specific leaf area compared to those plants at ambient carbon dioxide levels. Fast stolon growth is a highly desirable trait for turfgrass establishment and recovery from physical damage. The root length and surface area were also increased due to the elevated CO2, which may facilitate water uptake and serve critical drought-avoidance roles when irrigation water is limited. Elevated carbon dioxide caused an increase in the leaf net photosynthetic rate but a reduction in the stomatal conductance and transpiration rate, contributing to improved water use efficiency in creeping bentgrass. Efficient water use is especially important for turfgrass plant survival when irrigation water is limited. Our results suggested that cool-season turfgrass species may greatly benefit from increasingly elevated carbon dioxide concentrations via growth promotion and increasing water use efficiency. PMID- 26504538 TI - Breeding better cultivars, faster: applications of new technologies for the rapid deployment of superior horticultural tree crops. AB - Woody perennial plants, including trees that produce fruits and nuts of horticultural value, typically have long breeding cycles, and development and introduction of improved cultivars by plant breeders may require many breeding cycles and dozens of years. However, recent advances in biotechnologies and genomics have the potential to accelerate cultivar development greatly in all crops. This mini-review summarizes approaches to reduce the number and the duration of breeding cycles for horticultural tree crops, and outlines the challenges that remain to implement these into efficient breeding pipelines. PMID- 26504539 TI - Genome triplication drove the diversification of Brassica plants. AB - The genus Brassica belongs to the plant family Brassicaceae, which includes many important crop species that are used as oilseed, condiments, or vegetables throughout the world. Brassica plants comprise many diverse species, and each species contains rich morphotypes showing extreme traits. Brassica species experienced an extra whole genome triplication (WGT) event compared with the model plant Arabidopsis thaliana. Whole genome sequencing of the Brassica species Brassica rapa, Brassica oleracea and others demonstrated that WGT plays an important role in the speciation and morphotype diversification of Brassica plants. Comparative genomic analysis based on the genome sequences of B. rapa and A. thaliana clearly identified the WGT event and further demonstrated that the translocated Proto-Calepine Karyotype (tPCK, n=7) was the diploid ancestor of the three subgenomes in B. rapa. Following WGT, subsequent extensive genome fractionation, block reshuffling and chromosome reduction accompanied by paleocentromere descent from the three tPCK subgenomes during the rediploidization process produced stable diploid species. Genomic rearrangement of the diploid species and their hybridization then contributed to Brassica speciation. The subgenome dominance effect and biased gene retention, such as the over-retention of auxin-related genes after WGT, promoted functional gene evolution and thus propelled the expansion of rich morphotypes in the Brassica species. In conclusion, the WGT event initiated subsequent genomic and gene-level evolution, which further drove Brassica speciation and created rich morphotypes in each species. PMID- 26504540 TI - An optimized procedure for plant recovery from somatic embryos significantly facilitates the genetic improvement of Vitis. AB - Plant regeneration from grapevine (Vitis spp.) via somatic embryogenesis typically is poor. Recovery of plants from Vitis rotundifolia Michx. (muscadine grape) is particularly problematic due to extremely low efficiency, including extended culture durations required for embryo-plant conversion. Poor plant recovery is an obstacle to the selection of improved genetically modified lines. Somatic embryos (SEs) of V. rotundifolia cultivar Delicious (Del-HS) and Vitis vinifera L cultivar Thompson Seedless (TS) were used to identify culture media and conditions that promoted embryo differentiation and plant conversion; this resulted in a two-step culture system. In comparative culture experiments, C2D medium containing 6% sucrose was the most effective, among four distinct formulae tested, for inducing precocious SE germination and cell differentiation. This medium, further supplemented with 4 uM 6-benzylaminopurine (C2D4B), was subsequently determined to enhance post-germinative growth of SE. MS medium supplemented with 0.5 uM 1-naphthaleneacetic acid (MSN) was then utilized to stimulate root and shoot growth of germinated SE. An average of 35% and 80% 'Del HS' and 'TS' SE, respectively, developed into plants. All plants developed robust root and shoot systems and exhibited excellent survival following transfer to soil. Over 150 plants of 'Del-HS' were regenerated and established within 2.5 months, which is a dramatic reduction from the 6- to 12-month time period previously required. Similarly, 88 'TS' plant lines were obtained within the same time period. Subsequently, seven out of eight Vitis cultivars exhibited significantly increased plant conversion percentages, demonstrating broad application of the two-step culture system to produce the large numbers of independent plant lines needed for selection of desired traits. PMID- 26504541 TI - Fundamental aspects of postharvest heat treatments. AB - Heat treatments have been investigated for use in many aspects of postharvest storage. They have been developed for insect control, prevention of fungal development and prevention of postharvest storage disorders including chilling injury. The treatment times and temperature range vary widely, from days at 35 degrees C to 39 degrees C in hot air, to up to 63 degrees C for less than a minute in hot water. Much of the research has been performed to develop solutions to a particular problem, and less investigation has been conducted on the responses of the commodity to the treatment. However, since the turn of the century, a number of groups have been active in examining the molecular responses and changes that occur in commodities during and after the heat treatment. This review examines the changes at the level of transcriptome, proteome and metabolome that occur in response to the different heat treatments. PMID- 26504542 TI - Maintenance of water uptake and reduced water loss contribute to water stress tolerance of Spiraea alba Du Roi and Spiraea tomentosa L. AB - Two primarily eastern US native shrubs, Spiraea alba Du Roi and Spiraea tomentosa L., are typically found growing in wet areas, often with standing water. Both species have potential for use in the landscape, but little is known of their environmental requirements, including their adaptation to water stress. Two geographic accessions of each species were evaluated for their response to water stress under greenhouse conditions. Above-ground biomass, water relations and gas exchange were measured in well-watered and water stress treatments. In both species, water stress resulted in reduced growth, transpiration and pre-dawn water potential. However, both species also exhibited the ability to osmotically adjust to lower soil water content, resulting in maintained midday leaf turgor potential in all accessions. Net CO2 assimilation was reduced only in one accession of S. alba, primarily due to large reductions in stomatal conductance. S. tomentosa lost a larger proportion of leaves than S. alba in response to water stress. The primary water stress tolerance strategies of S. alba and S. tomentosa appear to be the maintenance of water uptake and reduced water loss. PMID- 26504543 TI - Understanding development and ripening of fruit crops in an 'omics' era. AB - Next generation sequencing has revolutionized plant biology. Not only has our understanding of plant metabolism advanced using model systems and modern chromatography, but application of 'omics'-based technology has been widely extended to non-model systems as costs have plummeted and efficiency increased. As a result, important fundamental questions relating to important horticultural crops are being answered, and novel approaches with application to industry are in progress. Here we review recent research advances on development and ripening of fruit crops, how next generation sequencing approaches are driving this advance and the emerging future landscape. PMID- 26504544 TI - Varietal identification of tea (Camellia sinensis) using nanofluidic array of single nucleotide polymorphism (SNP) markers. AB - Apart from water, tea is the world's most widely consumed beverage. Tea is produced in more than 50 countries with an annual production of approximately 4.7 million tons. The market segment for specialty tea has been expanding rapidly owing to increased demand, resulting in higher revenues and profits for tea growers and the industry. Accurate varietal identification is critically important to ensure traceability and authentication of premium tea products, which in turn contribute to on-farm conservation of tea genetic diversity. Using a set of single nucleotide polymorphism (SNP) markers developed from the expressed sequence tag (EST) database of Camilla senensis, we genotyped deoxyribonucleic acid (DNA) samples extracted from a diverse group of tea varieties, including both fresh and processed commercial loose-leaf teas. The validation led to the designation of 60 SNPs that unambiguously identified all 40 tested tea varieties with high statistical rigor (p<0.0001). Varietal authenticity and genetic relationships among the analyzed cultivars were further characterized by ordination and Bayesian clustering analysis. These SNP markers, in combination with a high-throughput genotyping protocol, effectively established and verified specific DNA fingerprints for all tested tea varieties. This method provides a powerful tool for variety authentication and quality control for the tea industry. It is also highly useful for the management of tea genetic resources and breeding, where accurate and efficient genotype identification is essential. PMID- 26504545 TI - Dynamic changes in the date palm fruit proteome during development and ripening. AB - Date palm (Phoenix dactylifera) is an economically important fruit tree in the Middle East and North Africa and is characterized by large cultivar diversity, making it a good model for studies on fruit development and other important traits. Here in gel comparative proteomics combined with tandem mass spectrometry were used to study date fruit development and ripening. Total proteins were extracted using a phenol-based protocol. A total of 189 protein spots were differentially regulated (p<=0.05). The identified proteins were classified into 14 functional categories. The categories with the most proteins were 'disease and defense' (16.5%) and 'metabolism' (15.4%). Twenty-nine proteins have not previously been identified in other fleshy fruits and 64 showed contrasting expression patterns in other fruits. Abundance of most proteins with a role in abiotic stress responses increased during ripening with the exception of heat shock proteins. Proteins with a role in anthocyanin biosynthesis, glycolysis, tricarboxylic acid cycle and cell wall degradation were upregulated particularly from the onset of ripening and during ripening. In contrast, expression of pentose phosphate- and photosynthesis-related proteins decreased during fruit maturation. Although date palm is considered a climacteric species, the analysis revealed downregulation of two enzymes involved in ethylene biosynthesis, suggesting an ethylene-independent ripening of 'Barhi' fruits. In summary, this proteomics study provides insights into physiological processes during date fruit development and ripening at the systems level and offers a reference proteome for the study of regulatory mechanisms that can inform molecular and biotechnological approaches to further improvements of horticultural traits including fruit quality and yield. PMID- 26504546 TI - Construction and validation of a gene co-expression network in grapevine (Vitis vinifera. L.). AB - Gene co-expression analysis has been widely used for predicting gene functions because genes within modules of a co-expression network may be involved in similar biological processes and exhibit similar biological functions. To detect gene relationships in the grapevine genome, we constructed a grapevine gene co expression network (GGCN) by compiling a total of 374 publically available grapevine microarray datasets. The GGCN consisted of 557 modules containing a total of 3834 nodes with 13 479 edges. The functions of the subnetwork modules were inferred by Gene ontology (GO) enrichment analysis. In 127 of the 557 modules containing two or more GO terms, 38 modules exhibited the most significantly enriched GO terms, including 'protein catabolism process', 'photosynthesis', 'cell biosynthesis process', 'biosynthesis of plant cell wall', 'stress response' and other important biological processes. The 'response to heat' GO term was highly represented in module 17, which is composed of many heat shock proteins. To further determine the potential functions of genes in module 17, we performed a Pearson correlation coefficient test, analyzed orthologous relationships with Arabidopsis genes and established gene expression correlations with real-time quantitative reverse transcriptase PCR (qRT-PCR). Our results indicated that many genes in module 17 were upregulated during the heat shock and recovery processes and downregulated in response to low temperature. Furthermore, two putative genes, Vit_07s0185g00040 and Vit_02s0025g04060, were highly expressed in response to heat shock and recovery. This study provides insight into GGCN gene modules and offers important references for gene functions and the discovery of new genes at the module level. PMID- 26504547 TI - Elucidating the molecular responses of apple rootstock resistant to ARD pathogens: challenges and opportunities for development of genomics-assisted breeding tools. AB - Apple replant disease (ARD) is a major limitation to the establishment of economically viable orchards on replant sites due to the buildup and long-term survival of pathogen inoculum. Several soilborne necrotrophic fungi and oomycetes are primarily responsible for ARD, and symptoms range from serious inhibition of growth to the death of young trees. Chemical fumigation has been the primary method used for control of ARD, and manipulating soil microbial ecology to reduce pathogen density and aggressiveness is being investigated. To date, innate resistance of apple rootstocks as a means to control this disease has not been carefully explored, partly due to the complex etiology and the difficulty in phenotyping the disease resistance. Molecular defense responses of plant roots to soilborne necrotrophic pathogens are largely elusive, although considerable progress has been achieved using foliar disease systems. Plant defense responses to necrotrophic pathogens consist of several interacting modules and operate as a network. Upon pathogen detection by plants, cellular signals such as the oscillation of Ca(2+) concentration, reactive oxygen species (ROS) burst and protein kinase activity, lead to plant hormone biosynthesis and signaling. Jasmonic acid (JA) and ethylene (ET) are known to be fundamental to the induction and regulation of defense mechanisms toward invading necrotrophic pathogens. Complicated hormone crosstalk modulates the fine-tuning of transcriptional reprogramming and metabolic redirection, resulting in production of antimicrobial metabolites, enzyme inhibitors and cell wall refortification to restrict further pathogenesis. Transcriptome profiling of apple roots in response to inoculation with Pythium ultimum demonstrated that there is a high degree of conservation regarding the molecular framework of defense responses compared with those observed with foliar tissues. It is conceivable that the timing and intensity of genotype-specific defense responses may lead to different outcomes between rootstocks in response to invasion by necrotrophic pathogens. Elucidation of host defense mechanisms is critical in developing molecular tools for genomics assisted breeding of resistant apple rootstocks. Due to their perennial nature, use of resistant rootstocks as a component for disease management might offer a durable and cost-effective benefit to tree performance than the standard practice of soil fumigation for control of ARD. PMID- 26504548 TI - Genomic variants of genes associated with three horticultural traits in apple revealed by genome re-sequencing. AB - The apple (Malus * domestica Borkh.) cultivar 'Su Shuai' exhibits greater disease resistance, shorter internodes and lighter fruit flavor compared with its parents 'Golden Delicious' and 'Indo'. To obtain a comprehensive overview of the sequence variation in these three horticultural traits, the genomes of 'Su Shuai' and 'Indo' were resequenced using next-generation sequencing and compared to the genome of 'Golden Delicious'. A wide range of genetic variations were detected, including 2 454 406 and 18 749 349 single nucleotide polymorphism (SNP) and 59 547 and 50 143 structural variants (SVs) in the 'Indo' and 'Su Shuai' genomes, respectively. Among the SVs in 'Su Shuai', 17 genes related to disease resistance, 10 genes related to Gibberellin (GA) and 19 genes associated with fruit flavor were identified. The expression patterns of eight of the SV genes were examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results of this study illustrate the genomic variation in these cultivars and provide evidence for a genetic basis for the horticultural traits of disease resistance, short internodes and lighter flavor exhibited in these cultivars. These results provide a genetic basis for the phenotypic characteristics of 'Su Shuai' and, as such, these SVs could serve as gene specific molecular markers in maker-assisted breeding of apples. PMID- 26504549 TI - Genetic and environmental control of fruit maturation, dry matter and firmness in apple (Malus * domestica Borkh.). AB - For any given genotype, the environment in which an apple is grown can influence the properties of the fruit considerably. While there has been extensive research on the mechanism of the genetic control of fruit quality traits, less effort has been made to investigate the way that these genetic mechanisms interact with the environment. To address this issue, we employed a large 'Royal Gala' * 'Braeburn' population of 572 seedlings replicated over sites in three climatically diverse apple-growing regions in New Zealand. Phenotyping for traits including fruit maturation timing, firmness and dry matter content was performed at each of these three sites for a single growing season (2011), and at two sites (Motueka and Hawke's Bay) for two seasons (2009 and 2010). The phenotype data collected over 2 years at two sites enabled the detection of 190 quantitative trait loci (QTL) that controlled these traits regardless of year or growing location, as well as some chromosomal loci that influenced the traits in a single given environment or year. For those loci that were environmentally stable over three sites, there was an interdependency of fruit maturation date, dry matter content and storage potential within this population, with two regions on Linkage Groups (LGs) 10 and 16 strongly contributing. If these loci were used in a marker-assisted selection programme to select for progeny bearing firmer fruit, this would have the unintentional consequence of selecting, high dry matter content, later maturing apples. In addition, a further 113 new QTLs with a smaller effect were identified, some of which were exhibited only in a single growing environment, demonstrating the underlying complexity of control of traits determining fruit quality, in addition to the need for being aware of environmental effects when developing new apple varieties. PMID- 26504551 TI - Transcriptome of Erysiphe necator-infected Vitis pseudoreticulata leaves provides insight into grapevine resistance to powdery mildew. AB - Powdery mildew (PM), which is caused by the pathogen Erysiphe necator (Schw.) Burr., is the single most damaging disease of cultivated grapes (Vitis vinifera) worldwide. However, little is known about the transcriptional response of grapes to infection with PM. RNA-seq analysis was used for deep sequencing of the leaf transcriptome to study PM resistance in Chinese wild grapes (V. pseudoreticulata Baihe 35-1) to better understand the interaction between host and pathogen. Greater than 100 million (M) 90-nt cDNA reads were sequenced from a cDNA library derived from PM-infected leaves. Among the sequences obtained, 6541 genes were differentially expressed (DEG) and were annotated with Gene Ontology terms and by pathway enrichment. The significant categories that were identified included the following: defense, salicylic acid (SA) and jasmonic acid (JA) responses; systemic acquired resistance (SAR); hypersensitive response; plant-pathogen interaction; flavonoid biosynthesis; and plant hormone signal transduction. Various putative secretory proteins were identified, indicating potential defense responses to PM infection. In all, 318 putative R-genes and 183 putative secreted proteins were identified, including the defense-related R-genes BAK1, MRH1 and MLO3 and the defense-related secreted proteins GLP and PR5. The expression patterns of 16 genes were further illuminated by RT-qPCR. The present study identified several candidate genes and pathways that may contribute to PM resistance in grapes and illustrated that RNA-seq is a powerful tool for studying gene expression. The RT-qPCR results reveal that effective resistance responses of grapes to PM include enhancement of JA and SAR responses and accumulation of phytoalexins. PMID- 26504552 TI - Transcriptional regulation of ethylene and jasmonate mediated defense response in apple (Malus domestica) root during Pythium ultimum infection. AB - Apple replant disease (ARD) is a significant economic restraint to the successful re-establishment of new apple orchards on sites previously planted to the same crop. Pythium ultimum, an oomycete, is a significant component of the ARD pathogen complex. Although ethylene (ET)- and jasmonic acid (JA)-mediated defense responses are intensively studied in the foliar pathosystem, the transferability of this knowledge to the interaction between a perennial root system and soilborne pathogens is unknown. The aim of this study was to test the hypothesis that the ET/JA-mediated defense response is conserved in roots of tree crops in response to infection by P. ultimum. Apple genes with the annotated function of ET/JA biosynthesis, MdERF (ethylene response factor) for signaling transduction and a gene encoding a pathogenesis-related (PR) protein (beta-chitinase, the target of ERF) were identified from the apple genome sequences. The transcriptional profiles of these genes during P. ultimum infection and after exogenous ET and/or JA treatment were characterized using qRT-PCR. Several genes showed a 10- to 60-fold upregulation in apple root tissue 24-48 h post inoculation (hpi). Exogenous ET and JA treatment exhibited either a positive or negative influence on expression of ET or JA biosynthesis genes, depending upon gene isoforms and the tissue types, while the expression of MdERF and the PR protein encoding gene was upregulated by both ET and JA treatment. Our data are consistent with the hypothesis that ET/JA-mediated defense pathways are functional in the root system of perennial tree species defending soilborne pathogens. PMID- 26504553 TI - Commonalities and differences between Brassica and Arabidopsis self incompatibility. AB - In higher plants, the self-incompatibility mechanism is important for inhibition of self-fertilization and facilitation of out-crossing. In Brassicaceae, the self incompatibility response is mediated by allele-specific interaction of the stigma localized S-locus receptor kinase (SRK) with the pollen coat-localized ligand (SCR/SP11). All self-incompatible Brassicaceae plants analyzed have been found to have the SRK and SCR/SP11 genes in the S-locus region. Although Arabidopsis thaliana is self-compatible, transformation with functional SRK-SCR genes from self-incompatible Arabidopsis species confers the self-incompatibility phenotype to A. thaliana. The allele-specific interaction between SRK and SCR activates the downstream signaling cascade of self-incompatibility. Yeast two-hybrid analysis with a kinase domain of SRK as bait and genetic analysis suggested several candidate components of self-incompatibility signaling in Brassica. Recently, A. thaliana genes orthologous to the identified genes for Brassica self incompatibility signaling were evaluated by using a self-incompatible transgenic A. thaliana plant and these orthologous genes were found not to be involved in self-incompatibility signaling in the transgenic A. thaliana. In this review, we describe common and different aspects of S-locus genomic regions and self incompatibility signaling between Brassica and Arabidopsis. PMID- 26504550 TI - Temporal and spatial control of gene expression in horticultural crops. AB - Biotechnology provides plant breeders an additional tool to improve various traits desired by growers and consumers of horticultural crops. It also provides genetic solutions to major problems affecting horticultural crops and can be a means for rapid improvement of a cultivar. With the availability of a number of horticultural genome sequences, it has become relatively easier to utilize these resources to identify DNA sequences for both basic and applied research. Promoters play a key role in plant gene expression and the regulation of gene expression. In recent years, rapid progress has been made on the isolation and evaluation of plant-derived promoters and their use in horticultural crops, as more and more species become amenable to genetic transformation. Our understanding of the tools and techniques of horticultural plant biotechnology has now evolved from a discovery phase to an implementation phase. The availability of a large number of promoters derived from horticultural plants opens up the field for utilization of native sequences and improving crops using precision breeding. In this review, we look at the temporal and spatial control of gene expression in horticultural crops and the usage of a variety of promoters either isolated from horticultural crops or used in horticultural crop improvement. PMID- 26504554 TI - Functional analysis of tomato calmodulin gene family during fruit development and ripening. AB - Calmodulin is a ubiquitous calcium sensor to recognize the different developmental and/or stimulus-triggered calcium changes and regulate plant growth and development. However, the function of calmodulin remains elusive for fleshy fruit development. We performed expression studies of a family of six calmodulin genes (SlCaMs) in tomato fruit. All calmodulins showed a double peak expression pattern. The first flat peak appeared at 10-30 days after anthesis, but their expression rapidly declined at mature green and breaker. Then a sharp and even higher peak came at turning/pink stages. Among six calmodulins, SlCaM1 had the highest expression during fruit enlargement, whereas SlCaM2 was the major calmodulin during fruit ripening. However, SlCaMs showed different patterns in three ripening mutants rin, Nor and Nr. In particular, at the stages corresponding to mature green and breaker, the expression levels of SlCaMs in those mutants were significantly higher than wild-type. Furthermore, SlCaMs, especially SlCaM2 were upregulated by ethylene. Transiently overexpressing SlCaM2 in mature green fruit delayed ripening, while reducing SlCaM2 expression accelerated ripening. Our results suggest that SlCaMs play double roles to regulate fruit ripening. Prior to the ethylene burst, the ethylene-independent repression of SlCaMs might be critical for fruit to initiate the ripening process. After the ethylene burst, SlCaMs could participate in the ethylene coordinated rapid ripening. PMID- 26504556 TI - Controlling plant architecture by manipulation of gibberellic acid signalling in petunia. AB - Since stem elongation is a gibberellic acid (GA) response, GA inhibitors are commonly used to control plant height in the production of potted ornamentals and bedding plants. In this study, we investigated interfering with GA signaling by using molecular techniques as an alternative approach. We isolated three putative GID1 genes (PhGID1A, PhGID1B and PhGID1C) encoding GA receptors from petunia. Virus-induced gene silencing (VIGS) of these genes results in stunted growth, dark-green leaves and late-flowering. We also isolated the gai mutant gene (gai 1) from Arabidopsis. We have generated transgenic petunia plants in which the gai mutant protein is over-expressed under the control of a dexamethasone-inducible promoter. This system permits induction of the dominant Arabidopsis gai mutant gene at a desired stage of plant development in petunia plants by the application of dexamethasone (Dex). The induction of gai in Dex-treated T1 petunia seedlings caused dramatic growth retardation with short internodes. PMID- 26504555 TI - A molecular framework for seasonal growth-dormancy regulation in perennial plants. AB - The timing of the onset and release of dormancy impacts the survival, productivity and spatial distribution of temperate horticultural and forestry perennials and is mediated by at least three main regulatory programs involving signal perception and processing by phytochromes (PHYs) and PHY-interacting transcription factors (PIFs). PIF4 functions as a key regulator of plant growth in response to both external and internal signals. In poplar, the expression of PIF4 and PIF3-LIKE1 is upregulated in response to short days, while PHYA and PHYB are not regulated at the transcriptional level. Integration of light and environmental signals is achieved by gating the expression and transcriptional activity of PIF4. During this annual cycle, auxin promotes the degradation of Aux/IAA transcriptional repressors through the SKP-Cullin-F-boxTIR1 complex, relieving the repression of auxin-responsive genes by allowing auxin response factors (ARFs) to activate the transcription of auxin-responsive genes involved in growth responses. Analyses of transcriptome changes during dormancy transitions have identified MADS-box transcription factors associated with endodormancy induction. Previous studies show that poplar dormancy-associated MADS-box (DAM) genes PtMADS7 and PtMADS21 are differentially regulated during the growth-dormancy cycle. Endodormancy may be regulated by internal factors, which are specifically localized in buds. PtMADS7/PtMADS21 may function as an internal regulator in poplar. The control of flowering time shares certain regulatory hierarchies with control of the dormancy/growth cycle. However, the particularities of different stages of the dormancy/growth cycle warrant comprehensive approaches to identify the causative genes for the entire cycle. A growing body of knowledge also indicates epigenetic regulation plays a role in these processes in perennial horticultural and forestry plants. The increased knowledge contributes to better understanding of the dormancy process and consequently to precise manipulation of dormancy-related horticultural traits, such as flowering time. PMID- 26504557 TI - BcRISP1, isolated from non-heading Chinese cabbage, decreases the seed set of transgenic Arabidopsis. AB - Mitochondria are the energy sources of plant cells and are involved in regulating cell development. Ubiquinol-cytochrome c reductase iron-sulfur protein, which is necessary for mitochondrial respiration, is a subunit of mitochondrial electron transport chain multimeric enzyme complexes. To better understand the biological function of the ubiquinol-cytochrome c reductase iron-sulfur protein, the full length cDNA of BcRISP1 was cloned; it was found to contain 810 base pairs and encode 269 amino acids. Unusually, high expression of the BcRISP1 gene in the archesporial cell stages was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of cytoplasmic male sterile lines and maintainer lines. The seed set was affected by the overexpression of BcRISP1, and shorter siliques with lower seed sets were observed in 35S::BcRISP1 Arabidopsis plants. These characteristics may have resulted from the reduced formation of pollen and impaired pollen tube growth. qRT-PCR results revealed that in 35S::BcRISP1 plants, the expression levels of the mitochondrial respiratory chain-related genes, COX10 and RIP1, were enhanced, whereas the expression levels of QCR7 and SDH2-1 were reduced. This result implies that overexpression of BcRISP1 in transgenic Arabidopsis plants may disrupt the mitochondrial electron transport chain by affecting the expression of mitochondrial respiratory chain-related genes and therefore, reducing the seed set. PMID- 26504558 TI - The inheritance of resistance to bacterial leaf spot of lettuce caused by Xanthomonas campestris pv. vitians in three lettuce cultivars. AB - Lettuce yields can be reduced by the disease bacterial leaf spot (BLS) caused by the pathogen Xanthomonas campestris pv. vitians (Xcv) and host resistance is the most feasible method to reduce disease losses. The cultivars La Brillante, Pavane and Little Gem express an incompatible host-pathogen interaction as a hypersensitive response (HR) to California strains of Xcv resulting in resistance. Little was known about the inheritance of resistance; however, resistance to other lettuce pathogens is often determined by resistance gene candidates (RGCs) encoding nucleotide-binding leucine-rich repeat (NB-LRR) proteins. Therefore, we determined the inheritance of BLS resistance in the cultivars La Brillante, Little Gem and Pavane and mapped it relative to RGCs. The reaction to Xcv was analyzed in nine F1, F2 and recombinant inbred line populations of lettuce from HR*compatible or HR*HR crosses. The HR in La Brillante, Pavane and Little Gem is conditioned by single dominant genes, which are either allelic or closely linked genes. The resistance gene in La Brillante was designated Xanthomonas resistance 1 (Xar1) and mapped to lettuce linkage group 2. Xar1 is present in a genomic region that contains numerous NB-LRR encoding RGCs and functional pathogen resistance loci in the RGC2 family. The Xar1 gene confers a high level of BLS resistance in the greenhouse and field that can be introgressed into commercial lettuce cultivars to reduce BLS losses using molecular markers. PMID- 26504559 TI - Developing single nucleotide polymorphism (SNP) markers from transcriptome sequences for identification of longan (Dimocarpus longan) germplasm. AB - Longan (Dimocarpus longan Lour.) is an important tropical fruit tree crop. Accurate varietal identification is essential for germplasm management and breeding. Using longan transcriptome sequences from public databases, we developed single nucleotide polymorphism (SNP) markers; validated 60 SNPs in 50 longan germplasm accessions, including cultivated varieties and wild germplasm; and designated 25 SNP markers that unambiguously identified all tested longan varieties with high statistical rigor (P<0.0001). Multiple trees from the same clone were verified and off-type trees were identified. Diversity analysis revealed genetic relationships among analyzed accessions. Cultivated varieties differed significantly from wild populations (F st=0.300; P<0.001), demonstrating untapped genetic diversity for germplasm conservation and utilization. Within cultivated varieties, apparent differences between varieties from China and those from Thailand and Hawaii indicated geographic patterns of genetic differentiation. These SNP markers provide a powerful tool to manage longan genetic resources and breeding, with accurate and efficient genotype identification. PMID- 26504560 TI - State of the science and challenges of breeding landscape plants with ecological function. AB - Exotic plants dominate esthetically-managed landscapes, which cover 30-40 million hectares in the United States alone. Recent ecological studies have found that landscaping with exotic plant species can reduce biodiversity on multiple trophic levels. To support biodiversity in urbanized areas, the increased use of native landscaping plants has been advocated by conservation groups and US federal and state agencies. A major challenge to scaling up the use of native species in landscaping is providing ornamental plants that are both ecologically functional and economically viable. Depending on ecological and economic constraints, accelerated breeding approaches could be applied to ornamental trait development in native plants. This review examines the impact of landscaping choices on biodiversity, the current status of breeding and selection of native ornamental plants, and the interdisciplinary research needed to scale up landscaping plants that can support native biodiversity. PMID- 26504561 TI - An acorn squash (Cucurbita pepo ssp. ovifera) fruit and seed transcriptome as a resource for the study of fruit traits in Cucurbita. AB - Acorn squash (Cucurbita pepo) is an iconic fall vegetable in the United States, known for its unique fruit shape and also prized for its culinary properties. Little is known about the metabolism that underlies the development of fruit quality attributes such as color, sweetness, texture and nutritional qualities in acorn squash, or any other winter squash grown worldwide. To provide insight into winter squash fruit and seed development and add to the genomic resources in the Cucurbita genus, RNA sequencing was used to generate an acorn squash fruit and seed transcriptome from the cultivar Sweet REBA at critical points throughout fruit development. 141 838 600 high-quality paired-end Illumina reads were assembled into 55 949 unigenes. 85% of unigenes with predicted open reading frames had homology with previously identified genes and over 62% could be functionally annotated. Comparison with the watermelon and cucumber genomes provided confirmation that the unigenes are full-length and comprehensive, covering an average of 90% of the coding sequence of their homologs and 72% of the cucumber and watermelon exomes. Key candidate genes associated with carotenoid and carbohydrate metabolism were identified toward a resource for winter squash fruit quality trait dissection. This transcriptome represents a major advance in C. pepo genomics, providing significant new sequence information and revealing the repertoire of genes expressed throughout winter squash fruit and seed development. Future studies on the genetic basis of fruit quality and future breeding efforts will be enhanced by tools and insights developed from this resource. PMID- 26504562 TI - Two quantitative trait loci, Dw1 and Dw2, are primarily responsible for rootstock induced dwarfing in apple. AB - The apple dwarfing rootstock 'Malling9' ('M9') has been used worldwide both to reduce scion vigour and as a genetic source for breeding new rootstocks. Progeny of 'M9' segregate for rootstock-induced dwarfing of the scion, indicating that this trait is controlled by one or more genetic factors. A quantitative trait locus (QTL) analysis of a rootstock population derived from the cross between 'M9' * 'Robusta5' (non-dwarfing) and grafted with 'Braeburn' scions identified a major QTL (Dw1) on linkage group (LG) 5, which exhibits a significant influence on dwarfing of the scion. A smaller-effect QTL affecting dwarfing (Dw2) was identified on LG11, and four minor-effect QTLs were found on LG6, LG9, LG10 and LG12. Phenotypic analysis indicates that the combination of Dw1 and Dw2 has the strongest influence on rootstock-induced dwarfing, and that Dw1 has a stronger effect than Dw2. Genetic markers linked to Dw1 and Dw2 were screened over 41 rootstock accessions that confer a range of effects on scion growth. The majority of the dwarfing and semi-dwarfing rootstock accessions screened carried marker alleles linked to Dw1 and Dw2. This suggests that most apple dwarfing rootstocks have been derived from the same genetic source. PMID- 26504563 TI - Assessing temporal flux of plant hormones in stored processing potatoes using high definition accurate mass spectrometry. AB - Plant hormones are important molecules which at low concentration can regulate various physiological processes. Mass spectrometry has become a powerful technique for the quantification of multiple classes of plant hormones because of its high sensitivity and selectivity. We developed a new ultrahigh pressure liquid chromatography-full-scan high-definition accurate mass spectrometry method, for simultaneous determination of abscisic acid and four metabolites phaseic acid, dihydrophaseic acid, 7'-hydroxy-abscisic acid and abscisic acid glucose ester, cytokinins zeatin, zeatin riboside, gibberellins (GA1, GA3, GA4 and GA7) and indole-3-acetyl-L-aspartic acid. We measured the amount of plant hormones in the flesh and skin of two processing potato cvs. Sylvana and Russet Burbank stored for up to 30 weeks at 6 degrees C under ambient air conditions. Herein, we report for the first time that abscisic acid glucose ester seems to accumulate in the skin of potato tubers throughout storage time. The method achieved a lowest limit of detection of 0.22 ng g(-1) of dry weight and a limit of quantification of 0.74 ng g(-1) dry weight (zeatin riboside), and was able to recover, detect and quantify a total of 12 plant hormones spiked on flesh and skin of potato tubers. In addition, the mass accuracy for all compounds (<5 ppm) was evaluated. PMID- 26504564 TI - A dual positional specific lipoxygenase functions in the generation of flavor compounds during climacteric ripening of apple. AB - Lipoxygenase (LOX) is an important contributor to the formation of aroma-active C6 aldehydes in apple (Malus * domestica) fruit upon tissue disruption but little is known about its role in autonomously produced aroma volatiles from intact tissue. We explored the expression of 22 putative LOX genes in apple throughout ripening, but only six LOXs were expressed in a ripening-dependent manner. Recombinant LOX1:Md:1a, LOX1:Md:1c, LOX2:Md:2a and LOX2:Md:2b proteins showed 13/9-LOX, 9-LOX, 13/9-LOX and 13-LOX activity with linoleic acid, respectively. While products of LOX1:Md:1c and LOX2:Md:2b were S-configured, LOX1:Md:1a and LOX2:Md:2a formed 13(R)-hydroperoxides as major products. Site-directed mutagenesis of Gly567 to an alanine converted the dual positional specific LOX1:Md:1a to an enzyme with a high specificity for 9(S)-hydroperoxide formation. The high expression level of the corresponding MdLOX1a gene in stored apple fruit, the genetic association with a quantitative trait locus for fruit ester and the remarkable agreement in regio- and stereoselectivity of the LOX1:Md:1a reaction with the overall LOX activity found in mature apple fruits, suggest a major physiological function of LOX1:Md:1a during climacteric ripening of apples. While LOX1:Md:1c, LOX2:Md:2a and LOX2:Md:2b may contribute to aldehyde production in immature fruit upon cell disruption our results furnish additional evidence that LOX1:Md:1a probably regulates the availability of precursors for ester production in intact fruit tissue. PMID- 26504565 TI - Mapping QTL associated with Verticillium dahliae resistance in the cultivated strawberry (Fragaria * ananassa). AB - A biparental cross of octoploid strawberry segregating for resistance to Verticillium dahliae, the causative agent of Verticillium wilt, was screened under field conditions for three seasons. Average wilt scores were significantly associated with multiple QTL, which were mostly significant across all years. Markers significantly associated with the traits were used to screen material with known wilt resistance and susceptibility phenotypes. A clear and statistically significant relationship was observed between resistant, tolerant and susceptible material and the total number of markers present in the different resistance classes. In field situations resistance QTL appear to behave in an additive manner. These markers are abundant in the cultivated strawberry germplasm indicating that, despite the large number of markers, clear genetic gain is possible through marker-assisted breeding. PMID- 26504566 TI - Relationship between gene expression and the accumulation of catechin during spring and autumn in tea plants (Camellia sinensis L.). AB - The tea plant (Camellia sinensis L.) is an important commercial crop with remarkably high catechin concentrations. Tea is popular worldwide given the plant's health benefits. Catechins are the main astringent substance in tea and are synthesized mainly via the phenylpropanoid pathway. In this study, eight cultivars of tea plants harvested both in spring and autumn were used to investigate differences in catechin concentrations by using high-performance liquid chromatography. The expression levels of genes associated with catechin biosynthesis were investigated using reverse transcription-quantitative polymerase chain reaction. The results indicated that the total catechin (TC) concentrations were significantly higher in tea plants harvested in autumn than in those harvested in spring, based on higher concentrations of epigallocatechin (EGC) in autumn tea (P<0.01). The expression of the genes phenylalanine ammonia lyase (PAL), flavanone 3-hydroxylase (F3H), flavonoid 3',5'-hydroxylase (F3'5'H), dihydroflavonol 4-reductase (DFR), and anthocyanidin synthase (ANS) is closely related to the TC content of tea plants in both spring and autumn. Positive correlations between PAL, cinnamate 4-hydroxylase (C4H), F3H, and DFR expression and EGC accumulation in autumn tea were identified, with correlation coefficients of 0.710, 0.763, 0.884, and 0.707, respectively. A negative correlation between ANS expression level and EGC concentrations in tea plants harvested in spring was noted (r=-0.732). Additionally, negative correlations between F3H and ANS expression levels and the catechin content were identified in spring tea, whereas the correlations were positive in autumn tea. Significant differences in the F3H and ANS expression levels between spring and autumn tea indicate that F3H and ANS are potentially key genes affecting catechin accumulation in tea plants. PMID- 26504568 TI - Overexpression of an ABA biosynthesis gene using a stress-inducible promoter enhances drought resistance in petunia. AB - The response of plants to drought stress includes reduced transpiration as stomates close in response to increased abscisic acid (ABA) concentrations. Constitutive overexpression of 9-cis-epoxycarotenoid dioxygenase (NCED), a key enzyme in ABA biosynthesis, increases drought resistance, but causes negative pleiotropic effects on plant growth and development. We overexpressed the tomato NCED (LeNCED1) in petunia plants under the control of a stress-inducible promoter, rd29A. Under water stress, the transgenic plants had increased transcripts of NCED mRNA, elevated leaf ABA concentrations, increased concentrations of proline, and a significant increase in drought resistance. The transgenic plants also displayed the expected decreases in stomatal conductance, transpiration, and photosynthesis. After 14 days without water, the control plants were dead, but the transgenic plants, though wilted, recovered fully when re-watered. Well-watered transgenic plants grew like non-transformed control plants and there was no effect of the transgene on seed dormancy. PMID- 26504567 TI - Water limitation and rootstock genotype interact to alter grape berry metabolism through transcriptome reprogramming. AB - Grapevine is a perennial crop often cultivated by grafting a scion cultivar on a suitable rootstock. Rootstocks influence scions, particularly with regard to water uptake and vigor. Therefore, one of the possibilities to adapt viticulture to the extended drought stress periods is to select rootstocks conferring increased tolerance to drought. However, the molecular mechanisms associated with the ability of rootstock/scion combination to influence grape berry metabolism under drought stress are still poorly understood. The transcriptomic changes induced by drought stress in grape berries (cv. Pinot noir) from vines grafted on either 110R (drought-tolerant) or 125AA (drought-sensitive) rootstock were compared. The experiments were conducted in the vineyard for two years and two grape berry developmental stages (50% and 100% veraison). The genome-wide microarray approach showed that water stress strongly impacts gene expression in the berries, through ontology categories that cover cell wall metabolism, primary and secondary metabolism, signaling, stress, and hormones, and that some of these effects strongly depend on the rootstock genotype. Indeed, under drought stress, berries from vines grafted on 110R displayed a different transcriptional response compared to 125AA-concerning genes related to jasmonate (JA), phenylpropanoid metabolism, and pathogenesis-related proteins. The data also suggest a link between JA and secondary metabolism in water-stressed berries. Overall, genes related to secondary metabolism and JA are more induced and/or less repressed by drought stress in the berries grafted on the drought-sensitive rootstock 125AA. These rootstock-dependent gene expression changes are relevant for berry composition and sensory properties. PMID- 26504569 TI - High-density mapping suggests cytoplasmic male sterility with two restorer genes in almond * peach progenies. AB - Peach (Prunus persica) and almond (Prunus dulcis) are two sexually compatible species that produce fertile offspring. Almond, a highly polymorphic species, is a potential source of new genes for peach that has a strongly eroded gene pool. Here we describe the genetics of a male sterile phenotype that segregated in two almond ('Texas') * peach ('Earlygold') progenies: an F2 (T*E) and a backcross one (T1E) to the 'Earlygold' parent. High-density maps were developed using a 9k peach SNP chip and 135 simple-sequence repeats. Three highly syntenic and collinear maps were obtained: one for the F2 (T*E) and two for the backcross, T1E (for the hybrid) and E (for 'Earlygold'). A major reduction of recombination was observed in the interspecific maps (T*E and T1E) compared to the intraspecific parent (E). The E map also had extensive monomorphic genomic regions suggesting the presence of large DNA fragments identical by descent. Our data for the male sterility character were consistent with the existence of cytoplasmic male sterility, where individuals having the almond cytoplasm required the almond allele in at least one of two independent restorer genes, Rf1 and Rf2, to be fertile. The restorer genes were located in a 3.4 Mbp fragment of linkage group 2 (Rf1) and 1.4 Mbp of linkage group 6 (Rf2). Both fragments contained several genes coding for pentatricopeptide proteins, demonstrated to be responsible for restoring fertility in other species. The implications of these results for using almond as a source of novel variability in peach are discussed. PMID- 26504570 TI - Genome-editing technologies and their potential application in horticultural crop breeding. AB - Plant breeding, one of the oldest agricultural activities, parallels human civilization. Many crops have been domesticated to satisfy human's food and aesthetical needs, including numerous specialty horticultural crops such as fruits, vegetables, ornamental flowers, shrubs, and trees. Crop varieties originated through selection during early human civilization. Other technologies, such as various forms of hybridization, mutation, and transgenics, have also been invented and applied to crop breeding over the past centuries. The progress made in these breeding technologies, especially the modern biotechnology-based breeding technologies, has had a great impact on crop breeding as well as on our lives. Here, we first review the developmental process and applications of these technologies in horticultural crop breeding. Then, we mainly describe the principles of the latest genome-editing technologies and discuss their potential applications in the genetic improvement of horticultural crops. The advantages and challenges of genome-editing technologies in horticultural crop breeding are also discussed. PMID- 26504571 TI - Current understanding of grapevine defense mechanisms against the biotrophic fungus (Erysiphe necator), the causal agent of powdery mildew disease. AB - The most economically important disease of cultivated grapevines worldwide is powdery mildew (PM) caused by the ascomycete fungus Erysiphe necator. The majority of grapevine cultivars used for wine, table grape, and dried fruit production are derived from the Eurasian grape species Vitis vinifera because of its superior aroma and flavor characteristics. However, this species has little genetic resistance against E. necator meaning that grape production is highly dependent on the frequent use of fungicides. The integration of effective genetic resistance into cultivated grapevines would lead to significant financial and environmental benefits and represents a major challenge for viticultural industries and researchers worldwide. This review will outline the strategies being used to increase our understanding of the molecular basis of V. vinifera susceptibility to this fungal pathogen. It will summarize our current knowledge of different resistance loci/genes that have evolved in wild grapevine species to restrict PM infection and assess the potential application of these defense genes in the generation of PM-resistant grapevine germplasm. Finally, it addresses future research priorities which will be important in the rapid identification, evaluation, and deployment of new PM resistance genes which are capable of conferring effective and durable resistance in the vineyard. PMID- 26504572 TI - Amplicon-based metagenomics identified candidate organisms in soils that caused yield decline in strawberry. AB - A phenomenon of yield decline due to weak plant growth in strawberry was recently observed in non-chemo-fumigated soils, which was not associated with the soil fungal pathogen Verticillium dahliae, the main target of fumigation. Amplicon based metagenomics was used to profile soil microbiota in order to identify microbial organisms that may have caused the yield decline. A total of 36 soil samples were obtained in 2013 and 2014 from four sites for metagenomic studies; two of the four sites had a yield-decline problem, the other two did not. More than 2000 fungal or bacterial operational taxonomy units (OTUs) were found in these samples. Relative abundance of individual OTUs was statistically compared for differences between samples from sites with or without yield decline. A total of 721 individual comparisons were statistically significant - involving 366 unique bacterial and 44 unique fungal OTUs. Based on further selection criteria, we focused on 34 bacterial and 17 fungal OTUs and found that yield decline resulted probably from one or more of the following four factors: (1) low abundance of Bacillus and Pseudomonas populations, which are well known for their ability of supressing pathogen development and/or promoting plant growth; (2) lack of the nematophagous fungus (Paecilomyces species); (3) a high level of two non-specific fungal root rot pathogens; and (4) wet soil conditions. This study demonstrated the usefulness of an amplicon-based metagenomics approach to profile soil microbiota and to detect differential abundance in microbes. PMID- 26504573 TI - Construction of citrus gene coexpression networks from microarray data using random matrix theory. AB - After the sequencing of citrus genomes, gene function annotation is becoming a new challenge. Gene coexpression analysis can be employed for function annotation using publicly available microarray data sets. In this study, 230 sweet orange (Citrus sinensis) microarrays were used to construct seven coexpression networks, including one condition-independent and six condition-dependent (Citrus canker, Huanglongbing, leaves, flavedo, albedo, and flesh) networks. In total, these networks contain 37 633 edges among 6256 nodes (genes), which accounts for 52.11% measurable genes of the citrus microarray. Then, these networks were partitioned into functional modules using the Markov Cluster Algorithm. Significantly enriched Gene Ontology biological process terms and KEGG pathway terms were detected for 343 and 60 modules, respectively. Finally, independent verification of these networks was performed using another expression data of 371 genes. This study provides new targets for further functional analyses in citrus. PMID- 26504574 TI - Morphological characteristics, anatomical structure, and gene expression: novel insights into gibberellin biosynthesis and perception during carrot growth and development. AB - Gibberellins (GAs) are considered potentially important regulators of cell elongation and expansion in plants. Carrot undergoes significant alteration in organ size during its growth and development. However, the molecular mechanisms underlying gibberellin accumulation and perception during carrot growth and development remain unclear. In this study, five stages of carrot growth and development were investigated using morphological and anatomical structural techniques. Gibberellin levels in leaf, petiole, and taproot tissues were also investigated for all five stages. Gibberellin levels in the roots initially increased and then decreased, but these levels were lower than those in the petioles and leaves. Genes involved in gibberellin biosynthesis and signaling were identified from the carrotDB, and their expression was analyzed. All of the genes were evidently responsive to carrot growth and development, and some of them showed tissue-specific expression. The results suggested that gibberellin level may play a vital role in carrot elongation and expansion. The relative transcription levels of gibberellin pathway-related genes may be the main cause of the different bioactive GAs levels, thus exerting influences on gibberellin perception and signals. Carrot growth and development may be regulated by modification of the genes involved in gibberellin biosynthesis, catabolism, and perception. PMID- 26504575 TI - Diversity in global gene expression and morphology across a watercress (Nasturtium officinale R. Br.) germplasm collection: first steps to breeding. AB - Watercress (Nasturtium officinale R. Br.) is a nutrient intense, leafy crop that is consumed raw or in soups across the globe, but for which, currently no genomic resources or breeding programme exists. Promising morphological, biochemical and functional genomic variation was identified for the first time in a newly established watercress germplasm collection, consisting of 48 watercress accessions sourced from contrasting global locations. Stem length, stem diameter and anti-oxidant (AO) potential varied across the accessions. This variation was used to identify three extreme contrasting accessions for further analysis. Variation in global gene expression was investigated using an Affymetrix Arabidopsis ATH1 microarray gene chip, using the commercial control (C), an accession selected for dwarf phenotype with a high AO potential (dwarfAO, called 'Boldrewood') and one with high AO potential alone. A set of transcripts significantly differentially expressed between these three accessions, were identified, including transcripts involved in the regulation of growth and development and those involved in secondary metabolism. In particular, when differential gene expression was compared between C and dwarfAO, the dwarfAO was characterised by increased expression of genes encoding glucosinolates, which are known precursors of phenethyl isothiocyanate, linked to the anti-carcinogenic effects well-documented in watercress. This study provides the first analysis of natural variation across the watercress genome and has identified important underpinning information for future breeding for enhanced anti-carcinogenic properties and morphology traits in this nutrient-intense crop. PMID- 26504576 TI - Subfunctionalization of cation/proton antiporter 1 genes in grapevine in response to salt stress in different organs. AB - Cation/proton antiporter 1 (CPA1) proteins function as regulators of monovalent ions, pH homeostasis, and other developmental processes in plants. Better understanding of the expression and regulation of CPA1 in plant responses to salinity would help the development of scientific practices in crops worldwide. In this report, we characterized all seven CPA1 family genes in grapevine (Vitis vinifera) in response to short-term osmotic and NaCl stresses. We found that two of the seven genes have subfunctionalized to be differentially expressed in response to NaCl stress in the early stage in different organs, whereas the other five members seem to play little or no role in this response. Specifically, VIT_19s0090g01480 may control Na(+) compartmentalization in grapevine roots; and VIT_05s0020g01960 may influence Na(+) transfer in stems. Based on the dynamics of ion concentrations, electrolyte leakage rates, and CPA1 gene expression in root, stem, and leaf tissues under osmotic and NaCl stresses, we suggest how grapevine responds physiologically and molecularly to the osmotic and ion toxicity of NaCl stress in the short term. This work lays a foundation for future research on the CPA1 gene family regarding its evolutionary history and biological functions for modulating salt responses in grapevine. PMID- 26504577 TI - Transcriptomic analysis reveals numerous diverse protein kinases and transcription factors involved in desiccation tolerance in the resurrection plant Myrothamnus flabellifolia. AB - The woody resurrection plant Myrothamnus flabellifolia has remarkable tolerance to desiccation. Pyro-sequencing technology permitted us to analyze the transcriptome of M. flabellifolia during both dehydration and rehydration. We identified a total of 8287 and 8542 differentially transcribed genes during dehydration and rehydration treatments respectively. Approximately 295 transcription factors (TFs) and 484 protein kinases (PKs) were up- or down regulated in response to desiccation stress. Among these, the transcript levels of 53 TFs and 91 PKs increased rapidly and peaked early during dehydration. These regulators transduce signal cascades of molecular pathways, including the up regulation of ABA-dependent and independent drought stress pathways and the activation of protective mechanisms for coping with oxidative damage. Antioxidant systems are up-regulated, and the photosynthetic system is modified to reduce ROS generation. Secondary metabolism may participate in the desiccation tolerance of M. flabellifolia as indicated by increases in transcript abundance of genes involved in isopentenyl diphosphate biosynthesis. Up-regulation of genes encoding late embryogenesis abundant proteins and sucrose phosphate synthase is also associated with increased tolerance to desiccation. During rehydration, the transcriptome is also enriched in transcripts of genes encoding TFs and PKs, as well as genes involved in photosynthesis, and protein synthesis. The data reported here contribute comprehensive insights into the molecular mechanisms of desiccation tolerance in M. flabellifolia. PMID- 26504578 TI - Carotenoid metabolism and regulation in horticultural crops. AB - Carotenoids are a diverse group of pigments widely distributed in nature. The vivid yellow, orange, and red colors of many horticultural crops are attributed to the overaccumulation of carotenoids, which contribute to a critical agronomic trait for flowers and an important quality trait for fruits and vegetables. Not only do carotenoids give horticultural crops their visual appeal, they also enhance nutritional value and health benefits for humans. As a result, carotenoid research in horticultural crops has grown exponentially over the last decade. These investigations have advanced our fundamental understanding of carotenoid metabolism and regulation in plants. In this review, we provide an overview of carotenoid biosynthesis, degradation, and accumulation in horticultural crops and highlight recent achievements in our understanding of carotenoid metabolic regulation in vegetables, fruits, and flowers. PMID- 26504579 TI - Comparative transcriptomics of Central Asian Vitis vinifera accessions reveals distinct defense strategies against powdery mildew. AB - Grape powdery mildew (PM), caused by the biotrophic ascomycete Erysiphe necator, is a devastating fungal disease that affects most Vitis vinifera cultivars. We have previously identified a panel of V. vinifera accessions from Central Asia with partial resistance to PM that possess a Ren1-like local haplotype. In this study, we show that in addition to the typical Ren1-associated late post penetration resistance, these accessions display a range of different levels of disease development suggesting that alternative alleles or additional genes contribute to determining the outcome of the interaction with the pathogen. To identify potential Ren1-dependent transcriptional responses and functions associated with the different levels of resistance, we sequenced and analyzed the transcriptomes of these Central Asian accessions at two time points of PM infection. Transcriptomes were compared to identify constitutive differences and PM-inducible responses that may underlie their disease resistant phenotype. Responses to E. necator in all resistant accessions were characterized by an early up-regulation of 13 genes, most encoding putative defense functions, and a late down-regulation of 32 genes, enriched in transcriptional regulators and protein kinases. Potential Ren1-dependent responses included a hotspot of co regulated genes on chromosome 18. We also identified 81 genes whose expression levels and dynamics correlated with the phenotypic differences between the most resistant accessions 'Karadzhandahal', DVIT3351.27, and O34-16 and the other genotypes. This study provides a first exploration of the functions associated with varying levels of partial resistance to PM in V. vinifera accessions that can be exploited as sources of genetic resistance in grape breeding programs. PMID- 26504580 TI - Ethylene resistance in flowering ornamental plants - improvements and future perspectives. AB - Various strategies of plant breeding have been attempted in order to improve the ethylene resistance of flowering ornamental plants. These approaches span from conventional techniques such as simple cross-pollination to new breeding techniques which modify the plants genetically such as precise genome-editing. The main strategies target the ethylene pathway directly; others focus on changing the ethylene pathway indirectly via pathways that are known to be antagonistic to the ethylene pathway, e.g. increasing cytokinin levels. Many of the known elements of the ethylene pathway have been addressed experimentally with the aim of modulating the overall response of the plant to ethylene. Elements of the ethylene pathway that appear particularly promising in this respect include ethylene receptors as ETR1, and transcription factors such as EIN3. Both direct and indirect approaches seem to be successful, nevertheless, although genetic transformation using recombinant DNA has the ability to save much time in the breeding process, they are not readily used by breeders yet. This is primarily due to legislative issues, economic issues, difficulties of implementing this technology in some ornamental plants, as well as how these techniques are publically perceived, particularly in Europe. Recently, newer and more precise genome-editing techniques have become available and they are already being implemented in some crops. New breeding techniques may help change the current situation and pave the way toward a legal and public acceptance if products of these technologies are indistinguishable from plants obtained by conventional techniques. PMID- 26504581 TI - Rapid screening for citrus canker resistance employing pathogen-associated molecular pattern-triggered immunity responses. AB - Citrus canker, caused by the bacterial pathogen Xanthomonas citri ssp. citri (Xcc), has been attributed to millions of dollars in loss or damage to commercial citrus crops in subtropical production areas of the world. Since identification of resistant plants is one of the most effective methods of disease management, the ability to screen for resistant seedlings plays a key role in the production of a long-term solution to canker. Here, an inverse correlation between reactive oxygen species (ROS) production by the plant and the ability of Xcc to grow and form lesions on infected plants is reported. Based on this information, a novel screening method that can rapidly identify citrus seedlings that are less susceptible to early infection by Xcc was devised by measuring ROS accumulation triggered by a 22-amino acid sequence of the conserved N-terminal part of flagellin (flg22) from X. citri ssp. citri (Xcc-flg22). In addition to limiting disease symptoms, ROS production was also correlated with the expression of basal defense-related genes such as the pattern recognition receptors LRR8 and FLS2, the leucine-rich repeat receptor-like protein RLP12, and the defense-related gene PR1, indicating an important role for pathogen-associated molecular pattern triggered immunity (PTI) in determining resistance to citrus canker. Moreover, the differential expression patterns observed amongst the citrus seedlings demonstrated the existence of genetic variations in the PTI response among citrus species/varieties. PMID- 26504582 TI - Redox proteomics of tomato in response to Pseudomonas syringae infection. AB - Unlike mammals with adaptive immunity, plants rely on their innate immunity based on pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) for pathogen defense. Reactive oxygen species, known to play crucial roles in PTI and ETI, can perturb cellular redox homeostasis and lead to changes of redox sensitive proteins through modification of cysteine sulfhydryl groups. Although redox regulation of protein functions has emerged as an important mechanism in several biological processes, little is known about redox proteins and how they function in PTI and ETI. In this study, cysTMT proteomics technology was used to identify similarities and differences of protein redox modifications in tomato resistant (PtoR) and susceptible (prf3) genotypes in response to Pseudomonas syringae pv tomato (Pst) infection. In addition, the results of the redox changes were compared and corrected with the protein level changes. A total of 90 potential redox-regulated proteins were identified with functions in carbohydrate and energy metabolism, biosynthesis of cysteine, sucrose and brassinosteroid, cell wall biogenesis, polysaccharide/starch biosynthesis, cuticle development, lipid metabolism, proteolysis, tricarboxylic acid cycle, protein targeting to vacuole, and oxidation-reduction. This inventory of previously unknown protein redox switches in tomato pathogen defense lays a foundation for future research toward understanding the biological significance of protein redox modifications in plant defense responses. PMID- 26504583 TI - Metabolic changes upon flower bud break in Japanese apricot are enhanced by exogenous GA4. AB - Gibberellin (GA4) has a significant effect on promoting dormancy release in flower buds of Japanese apricot (Prunus mume Sieb. et Zucc). The transcriptomic and proteomic changes that occur after GA4 treatment have been reported previously; however, the metabolic changes brought about by GA4 remain unknown. The present study was undertaken to assess changes in metabolites in response to GA4 treatment, as determined using gas chromatography-mass spectrometry and principal component analysis. Fifty-five metabolites that exhibited more than two fold differences in abundance (P < 0.05) between samples collected over time after a given treatment or between samples exposed to different treatments were studied further. These metabolites were categorized into six main groups: amino acids and their isoforms (10), amino acid derivatives (7), sugars and polyols (14), organic acids (12), fatty acids (4), and others (8). All of these groups are involved in various metabolic pathways, in particular galactose metabolism, glyoxylate and dicarboxylate metabolism, and starch and sucrose metabolism. These results suggested that energy metabolism is important at the metabolic level in dormancy release following GA4 treatment. We also found that more than 10-fold differences in abundance were observed for many metabolites, including sucrose, proline, linoleic acid, and linolenic acid, which might play important roles during the dormancy process. The current research extends our understanding of the mechanisms involved in budburst and dormancy release in response to GA4 and provides a theoretical basis for applying GA4 to release dormancy. PMID- 26504584 TI - Variations in zonal fruit starch concentrations of apples - a developmental phenomenon or an indication of ripening? AB - Patterns of starch hydrolysis in stem, equatorial, and calyx zones of 'Honeycrisp' and 'Empire' apples (Malus sylvestris (L.) Mill var. domestica (Borkh.) Mansf.) during maturation and ripening, and in 'Gala' apples in response to propylene or 1-methylcyclopropene (1-MCP) treatments after harvest, were studied. Differences in zonal starch concentrations were found for 'Empire' and 'Gala' fruits, but not for 'Honeycrisp'. During maturation and ripening of 'Empire', the concentration of starch was highest in the calyx end and lowest in the stem region. Differences in rates of starch hydrolysis among zones were not detected. 'Honeycrisp' and 'Empire' had the highest concentration of sorbitol in the calyx region, whereas it was highest in the stem-end region in 'Gala'. The distribution differences of glucose, fructose, and sucrose were similar in all three cultivars; higher fructose and glucose concentrations in the stem region, and higher sucrose concentrations in the calyx end of the fruit. Postharvest treatment of 'Gala' with propylene did not affect the internal ethylene concentration of the fruit but 1-MCP markedly inhibited it. Starch concentrations were highest in the calyx end but gradients of starch among zones were not changed by postharvest treatment. The rate of hydrolysis was slowed by 1 MCP treatment, but was unaffected by propylene. Postharvest treatments influenced sorbitol, glucose, and fructose concentrations. Patterns of starch concentration among the zones did not confirm differences in ripening, but reflected its uneven distribution throughout the fruit during development. Therefore, measured differences in zonal starch are most likely related to starch accumulation during fruit development, rather than differences in rates of starch degradation during ripening. PMID- 26504585 TI - Catheter detachment. PMID- 26504587 TI - A specific objective supplemental factor in evaluating acute mountain sickness: DeltaHR in combination with SaO2. AB - BACKGROUND: So far, there have been no measurements confirmed useful in diagnosing acute mountain sickness (AMS). The aim of this study was to determine the role of heart rate (HR) difference (DeltaHR) and oxygen saturation ( SaO2) as objective risk factors in aiding the diagnosis of AMS. METHODS: A total of 1,019 participants were assigned to either the acute exposure group (AEG): from 500 m to 3,700 m by flight within 2.5 h (n = 752); or the pre-acclimatization group (PAG): ascended to 4,400 m from 3,650 m within three hours by car after adapting 33 days at 3,650 m (n = 267). The questionnaires or measurements of resting SaO2 (oxygen saturation) and HR were completed between 18 and 24 h before departure and after arrival. RESULTS: Incidence of AMS was 61.3 % (461) in AEG, with 46.1 % (347) mild cases and 15.2 % (114) severe cases. In PAG, the incidence was 38.9 % (104), with 30.7 % (82) mild cases and 8.2 % (22) severe cases. The AMS subjects showed a significant increase in HR and a decrease in SaO2 levels compared with the non-AMS subjects in both groups. DeltaHR and post-exposure SaO2 were significantly correlated with the Lake Louise Score (LLS) in both groups. Stepwise logistic regression analysis revealed the DeltaHR >25 and SaO2 < 88 % in AEG as well as DeltaHR >15 and SaO2 < 86 % in PAG to be independent risk factors of AMS. Combining these two measurements could specifically indicate participants with AMS, which showed a positive predictive value of 89 % and specificity of 97 % in AEG as well as 85 % and 98 % in PAG. CONCLUSION: DeltaHR or SaO2, as objective measurements, correlate with AMS. Combination of these two measurements may be useful as an additional specific and objective factor to further confirm the diagnosis of AMS. PMID- 26504586 TI - Primary prevention of posttraumatic stress disorder: drugs and implications. AB - Because posttraumatic stress disorder (PTSD) is a highly debilitating condition, prevention is an important research topic. This article reviews possible prevention approaches that involve the administration of drugs before the traumatic event takes place. The considered approaches include drugs that address the sympathetic nervous system, drugs that interfere with the hypothalamic pituitary-adrenal (HPA) axis, narcotics and other psychoactive drugs, as well as modulators of protein synthesis. Furthermore, some thoughts on potential ethical implications of the use of drugs for the primary prevention of PTDS are presented. While there are many barriers to overcome in this field of study, this paper concludes with a call for additional research, as there are currently no approaches that are well-suited for regular use. PMID- 26504588 TI - Preparation and investigation of hydrolyzed polyacrylonitrile as a preliminary biomedical hydrogel. AB - BACKGROUND: Hydrolyzed polyacrylonitrile (HPAN) has attracted much attention as a hydrogel for a broad range of biomedical applications. Therefore, in this study, we prepared HPAN derivatives with controllable compositions by the radical polymerization of acrylonitrile (AN), methacrylic acid (MAA) and N isopropylacrylamide (NIPAM) monomers. RESULTS: The prepared poly(AN-co-MAA-co NIPAM) copolymers had different ratios of AN, MAA, and NIPAM and molecular weights ranging from 2000 to 50,000. The copolymers were prepared as films to examine their properties. The prepared copolymer films showed different solubilities, contact angles, and swelling ratios. The properties of the copolymer films were affected by the hydrophobic PAN segments and the hydrophilic PMAA or PNIPAM segments. CONCLUSION: Thus, we conclude that introducing PMAA and PNIPAM segments with different ratios and lengths into PAN segments could represent a method of controlling the hydrogel properties of copolymers. PMID- 26504589 TI - Encapsulation of pancreatic islet with HMGB1 fragment for attenuating inflammation. AB - BACKGROUND: Pancreatic islet encapsulation is one way to address the disadvantages of islet transplantation. Not only does encapsulation involve bidirectional diffusion of nutrients, oxygen, and glucose, but also it protects the graft from the recipient's immune reaction. The high mobility group box 1 (HMGB1), one of higher expression proteins in islet, can be secreted from transplanted islets and induce the inflammation. Therefore, the regulation of HMGB1-mediated inflammation is very important for successful islet transplantation. In this study, we used the HMGB1 A box, an antagonist of HMGB1 receptor in the immune cells, in the encapsulation of isolated islets as a new strategy. RESULT: For co-encapsulation of HMGB1 A box protein with islets, we evaluated the distribution of alginate bead diameter. The average diameter of empty alginate bead was similar to that of alginate bead with islets. When different concentrations of HMGB1 A box protein was co-encapsulated with islets, it did not affect the viability and insulin secretion function of the islets. When the alginate beads with islets plus HMGB1 A box protein were cultured with macrophage, the amount of TNF-alpha secreted from the macrophages was significantly attenuated when compared to cultivation of unencapsulated islets or encapsulated islets. When the alginate beads with islets plus HMGB1 A box protein were intraperitoneally xenotransplanted into the diabetic mice, the survival rate of the islets was strongly improved with 2-fold. CONCLUSION: Collectively, these results suggested that the encapsulation of HMGB1 A box protein might offer a protective effect in islet transplantation. PMID- 26504590 TI - Small-Gauge Pars Plana Vitrectomy for the Management of Symptomatic Posterior Vitreous Detachment after Phacoemulsification and Multifocal Intraocular Lens Implantation: A Pilot Study from the Pan-American Collaborative Retina Study Group. AB - Purpose. To determine the efficacy of 23-gauge pars plana vitrectomy (PPV) for symptomatic posterior vitreous detachment (PVD) on visual acuity (VA) and quality after multifocal intraocular lenses (IOLs). Methods. In this prospective case series, patients who developed symptomatic PVD and were not satisfied with visual quality due to floaters and halos after multifocal IOL implantation underwent PPV. Examinations included LogMAR uncorrected visual acuity (UCVA), intraocular pressure, biomicroscopy, and indirect ophthalmoscopy at baseline and 1, 7, 30, and 180 days postoperatively. Ultrasonography and aberrometry were performed. The Visual Functioning Questionnaire 25 (VFQ-25) was administered preoperatively and at 30 days postoperatively. Both the postoperative UCVA and questionnaire results were compared to preoperative findings using the Wilcoxon test. Results. Sixteen eyes of 8 patients were included. VA significantly improved from 0.17 to 0.09 postoperatively (P = 0.017). All patients reported improvement of halos, glare, and floaters. VFQ-25 scores significantly improved in general vision (P = 0.023), near activities (P = 0.043), distance activities (P = 0.041), mental health (P = 0.011), role difficulties (P = 0.042), and driving (P = 0.016). Conclusion. PPV may increase UCVA and quality of vision in patients with bilateral multifocal IOLs and symptomatic PVD. Larger studies are advised. PMID- 26504591 TI - Responses of Multipotent Retinal Stem Cells to IL-1beta, IL-18, or IL-17. AB - Purpose. To investigate how multipotent retinal stem cells (RSCs) isolated from mice respond to the proinflammatory signaling molecules, IL-1beta, IL-18, and IL 17A. Materials and Methods. RSCs were cultured in a specific culture medium and were treated with these cytokines. Cell viability was detected by MTT assay; ultrastructure was evaluated by transmission electron microscopy; expression of IL-17rc and proapoptotic proteins was detected by immunocytochemistry and expression of Il-6 and Il-17a was detected by quantitative RT-PCR. As a comparison, primary mouse retinal pigment epithelium (RPE) cells were also treated with IL-1beta, IL-18, or IL-17A and analyzed for the expression of Il-6 and Il-17rc. Results. Treatment with IL-1beta, IL-18, or IL-17A decreased RSC viability in a dose-dependent fashion and led to damage in cellular ultrastructure including pyroptotic and/or necroptotic cells. IL-1beta and IL-18 could induce proapoptotic protein expression. All treatments induced significantly higher expression of Il-6 and Il-17rc in both cells. However, neither IL-1beta nor IL-18 could induce Il-17a expression in RSCs. Conclusions. IL-1beta, IL-18, and IL-17A induce retinal cell death via pyroptosis/necroptosis and apoptosis. They also provoke proinflammatory responses in RSCs. Though IL 1beta and IL-18 could not induce Il-17a expression in RSCs, they both increase Il 17rc expression, which may mediate the effect of Il-17a. PMID- 26504592 TI - Human Serum Eye Drops in Eye Alterations: An Insight and a Critical Analysis. AB - Human serum contains a physiological plethora of bioactive elements naturally released by activated platelets which might have a significant effect on the regeneration of corneal layers by stimulating the cell growth. This mechanism supported the use of human serum eye drops in some ocular diseases associated with dystrophic changes and alterations of the tear film, such as persistent corneal epithelial defects and dry eye syndrome. We focused our effort on potential benefits and limitations of the use of human serum eye drops when conventional therapies failed. We reviewed the recent literature by reporting published studies from 2010 to 2014. Despite the limited evaluated study populations, most of the clinical studies have confirmed that serum eye drop therapy is effective in corneal healing by reducing ocular symptom, particularly during the short-term follow-up. In addition, three recent published studies have shown the efficacy of the serum eye drop therapy in comparison to traditional ones in intractable patients. Besides, reported ongoing clinical studies confirmed the open debate regarding the use of biologic tools for cornea regeneration. Results from these studies might open novel challenges and perspectives in the therapy of such refractory patients. PMID- 26504593 TI - Acute-Onset Vitreous Hemorrhage of Unknown Origin before Vitrectomy: Causes and Prognosis. AB - Purpose. To analyze causes and prognosis of acute-onset preoperatively unknown origin vitreous hemorrhage (VH). Methods. This study included patients who underwent vitrectomy for acute-onset preoperatively unknown origin VH. The underlying causes of VH, which were identified after vitrectomy, were analyzed. And overall visual prognosis of unknown origin VH was analyzed. Risk scoring system was developed to predict visual prognosis after vitrectomy. Results. 169 eyes were included. Among these, retinal vein occlusion (RVO), retinal break, and age-related macular degeneration (AMD) were identified in 74 (43.8%), 50 (29.6%), and 21 (12.4%) patients, respectively. After vitrectomy, logMAR BCVA significantly improved from 1.93 +/- 0.59 to 0.47 +/- 0.71. However, postoperative BCVA in AMD eyes were significantly poorer than others. Poor visual prognosis after vitrectomy was associated with old age, poor preoperative vision in both eyes, and drusen in the fellow eye. Conclusions. RVO, retinal break, and AMD are the most common causes of acute-onset preoperatively unknown origin VH and the most common causes of VH change with age. The visual prognosis of unknown origin VH is relatively good, except among AMD patients. Older patients with poor preoperative BCVA in both eyes and patients with AMD in the fellow eye are at a higher risk of poor visual prognosis following vitrectomy. PMID- 26504594 TI - Lutein Leads to a Decrease of Factor D Secretion by Cultured Mature Human Adipocytes. AB - Purpose. Complement plays an important role in the pathogenesis of age related macular degeneration (AMD) and trials are currently being conducted to investigate the effect of complement inhibition on AMD progression. We previously found that the plasma level of factor D (FD), which is the rate limiting enzyme of the complement alternative pathway, was significantly decreased following lutein supplementation. FD is synthesized by adipose tissue, which is also the main storage site of lutein. In view of these findings we tested the hypothesis whether lutein could affect FD synthesis by adipocytes. Methods. A cell line of mature human adipocytes was incubated with 50 MUg/mL lutein for 24 and 48 h, whereafter FD mRNA and protein expression were measured. Results. Lutein significantly inhibited adipocyte FD mRNA expression and FD protein release into adipocyte culture supernatants. Conclusions. Our earlier observations showing that a daily lutein supplement in individuals with early signs of AMD lowered the level of circulating FD might be caused by blocking adipocyte FD production. PMID- 26504595 TI - Wavefront-Guided Photorefractive Keratectomy with the Use of a New Hartmann-Shack Aberrometer in Patients with Myopia and Compound Myopic Astigmatism. AB - Purpose. To assess refractive and visual outcomes and patient satisfaction of wavefront-guided photorefractive keratectomy (PRK) in eyes with myopia and compound myopic astigmatism, with the ablation profile derived from a new Hartmann-Shack aberrometer. Methods. In this retrospective study, 662 eyes that underwent wavefront-guided PRK with a treatment profile derived from a new generation Hartmann-Shack aberrometer (iDesign aberrometer, Abbott Medical Optics, Inc., Santa Ana, CA) were analyzed. The preoperative manifest sphere ranged from -0.25 to -10.75 D, and preoperative manifest cylinder was between 0.00 and -5.25 D. Refractive and visual outcomes, vector analysis of the change in refractive cylinder, and patient satisfaction were evaluated. Results. At 3 months, 91.1% of eyes had manifest spherical equivalent within 0.50 D. The percentage of eyes achieving uncorrected distance visual acuity 20/20 or better was 89.4% monocularly and 96.5% binocularly. The mean correction ratio of refractive cylinder was 1.02 +/- 0.43, and the mean error of angle was 0.00 +/- 14.86 degrees at 3 months postoperatively. Self-reported scores for optical side effects, such as starburst, glare, halo, ghosting, and double vision, were low. Conclusion. The use of a new Hartmann-Shack aberrometer for wavefront-guided photorefractive keratectomy resulted in high predictability, efficacy, and patient satisfaction. PMID- 26504596 TI - Choroidal Thickness in Eyes with Unilateral Ocular Ischemic Syndrome. AB - Aim. To analyze the subfoveal choroid thickness and choroidal volume in unilateral ocular ischemic syndrome (OIS). Methods. A retrospective review was conducted for all patients with unilateral OIS from October 2010 through June 2014. The subfoveal choroidal thickness (SFChT) and choroidal volume of both eyes were compared. Results. 19 unilateral OIS patients were included in this study. The mean SFChT of OIS eyes was significantly lower than that of fellow eyes (OIS eyes: 208.89 +/- 82.62 MUm and fellow eyes: 265.31 +/- 82.77 MUm, P < 0.001). The choroidal volume of OIS eyes was significantly smaller than that of fellow eyes (OIS eyes: 0.16 +/- 0.05 mm(3) and fellow eyes: 0.21 +/- 0.05 mm(3), P < 0.001). Conclusion. The choroidal thickness and volume of OIS eyes were smaller than those of unaffected fellow eyes. Decreased choroidal circulation caused by carotid artery stenosis might affect the discordance of choroidal thickness and choroidal volume. PMID- 26504597 TI - Determination of a New Parameter, Elevated Epiretinal Membrane, by En Face OCT as a Prognostic Factor for Pars Plana Vitrectomy and Safer Epiretinal Membrane Peeling. AB - Purpose. To evaluate the significance of the area of epiretinal membrane (EM) that is not in contact with the retinal structure as a preoperative parameter for safer grasping of the EM and a prognostic factor for visual improvement/outcome. Methods. This prospective observational study included 73 consecutive patients (80 eyes) who underwent pars plana vitrectomy (PPV) and EM peeling. Corrected distance visual acuity (CDVA) and central foveal thickness (CFT) were evaluated preoperatively and at 12 months postoperatively. The number of initial peeling grasps was recorded in the operation protocol. The elevated EM portion was identified by en face optical coherence tomography (OCT) and processed digitally to calculate its area. Results. Surgery was found to significantly improve CDVA and decrease CFT. CDVA improvement correlated with elevated EM, preoperative CFT, and the number of grasping attempts. Conclusion. The detection of elevated EM via en face OCT could assist safer grasping of the EM and indicate the potential for visual outcome improvement after PPV and EM peeling. PMID- 26504598 TI - Clinical Outcome of Hypertensive Uveitis. AB - Purpose. To review the clinical outcome of patients with hypertensive uveitis. Methods. Retrospective review of uveitis patients with elevated intraocular pressure (IOP) > 25 mmHg and >1-year follow-up. Data are uveitis type, etiology, viral (VU) and nonviral uveitis (NVU), IOP, and medical and/or surgical treatment. Results. In 61 patients, IOP values are first 32.9 mmHg (SD: 9.0), highest 36.6 mmHg (SD: 9.9), 3 months after the first episode 19.54 mmHg (SD: 9.16), and end of follow-up 15.5 mmHg (SD: 6.24). Patients with VU (n = 25) were older (50.6 y/35.7 y, p = 0.014) and had more unilateral disease (100%/72.22% p = 0.004) than those with NVU (n = 36). Thirty patients (49.2%) had an elevated IOP before topical corticosteroid treatment. Patients with viral uveitis might have higher first elevated IOP (36.0/27.5 mmHg, p = 0,008) and maximal IOP (40.28/34.06 mmHg, p = 0.0148) but this was not significant when limited to the measurements before the use of topical corticosteroids (p = 0.260 and 0.160). Glaucoma occurred in 15 patients (24.59%) and was suspected in 11 (18.03%) without difference in viral and nonviral groups (p = 0.774). Conclusion. Patients with VU were older and had more unilateral hypertensive uveitis. Glaucoma frequently complicates hypertensive uveitis. Half of the patients had an elevated IOP before topical corticosteroid treatment. PMID- 26504599 TI - Does the Primary Care Experience Influence the Cancer Diagnostic Process? AB - Objective. To analyze the impact of patients' experience of care at their usual source of primary care on their choice of point of entry into cancer investigation process, time to diagnosis, and presence of metastatic cancer at time of diagnosis. Method. A questionnaire was administered to 438 patients with cancer (breast, lung, and colorectal) between 2011 and 2013 in four oncology clinics of Quebec (Canada). Multiple regression analyses (logistic and Cox models) were conducted. Results. Among patients with symptoms leading to investigation of cancer (n = 307), 47% used their usual source of primary care as the point of entry for investigation. Greater comprehensiveness of care was associated with the decision to use this source as point of entry (OR = 1.25; CI 90% = 1.06-1.46), as well as with shorter times between first symptoms and investigation (HR = 1.11; p = 0.05), while greater accessibility was associated with shorter times between investigation and diagnosis (HR = 1.13; p < 0.01). Conclusion. Experience of care at the usual source of primary care has a slight influence on the choice of point of entry for cancer investigation and on time to diagnosis. This influence appears to be more related to patients' perceptions of the accessibility and comprehensiveness of their usual source of primary care. PMID- 26504600 TI - Elevated Circulating Levels of Inflammatory Markers in Patients with Acute Coronary Syndrome. AB - Objective. We evaluated inflammatory cytokines and chemokine in peripheral blood mononuclear cells (PBMCs) in patients with either acute coronary syndrome (ACS) or stable coronary artery disease (CAD). Methods. We enrolled 20 ACS patients and 50 stable CAD patients without previous history of ACS who underwent cardiac catheterization. Patients with an estimated glomerular filtration rate of <=30 mL/min/1.73 m(2) and C-reactive protein of >=1.0 mg/dL were excluded. Blood samples were collected from the patients just before catheterization, and PBMCs were isolated from the whole blood. The levels of inflammatory cytokines and chemokine were measured by using real-time quantitative polymerase chain reaction and immunoassays. Results. The expression of tumor necrosis factor alpha (TNF alpha), interleukin- (IL-) 6, IL-10, IL-23A, IL-27, and IL-37 was significantly higher in the ACS group than in the CAD group (P < 0.05). In contrast, the expression of IL-33 was significantly lower in the ACS group than in the CAD group (P < 0.05). The ACS patients had higher plasma levels of TNF-alpha, IL-6, and IL-10 in the ACS group than in the CAD group. Conclusion. Circulating levels of pro-/anti-inflammatory cytokines, including IL-23A, IL-27, IL-33, and IL-37, may be associated with the pathogenesis of atherosclerosis in ACS patients. PMID- 26504601 TI - Perspectives of Cosmesis following Breast Conservation for Multifocal and Multicentric Breast Cancers. AB - Background. Contemporary data suggest that breast conservation treatment (BCT) for multifocal and multicentric breast cancer (MFMCBC) may be appropriate with noninferior local control rates. However, there is a paucity of data to evaluate patient's satisfaction with cosmetic outcomes after BCT for MFMCBC. This study was performed to bridge this information gap. Methods. All patients treated at the authors' healthcare facility were included in the study. Patients with MFMCBC who were assessed to be eligible for BCT underwent tumour resection using standard surgical techniques with direct parenchymal closure through a single incision. After at least three years of follow-up, they were invited to participate in a survey regarding their cosmetic outcomes. Results. Of a total of 160 patients, 40 had MFMCBC, of whom 34 (85%) underwent successful BCT. Five-year cancer-specific survival and disease-free survival were 95.7%. Twenty of the 34 patients responded to the survey. No patient rated her cosmetic outcome as "poor." Analysis indicated low agreement between patients' self-assessment and clinician-directed evaluation of aesthetic results. Conclusion. BCT for MFMCBC is feasible with acceptable survival and cosmetic outcomes. However, there appears to be a disparity between patient and clinician-directed evaluation of cosmetic results which warrant further research. PMID- 26504603 TI - Pulmonary Tuberculosis and Lepromatous Leprosy Coinfection. AB - Simultaneous occurrence of leprosy and pulmonary tuberculosis is reported infrequently in the modern era. We report a case of pulmonary tuberculosis diagnosed in patient being treated with glucocorticoids for complications of leprosy (type II reaction). Physicians should recognize that the leprosy patients treated with glucocorticoid may develop tuberculosis. PMID- 26504602 TI - Spinal Cord Hemisection Facilitates Aromatic L-Amino Acid Decarboxylase Cells to Produce Serotonin in the Subchronic but Not the Chronic Phase. AB - Neuromodulators, such as serotonin (5-hydroxytryptamine, 5-HT) and noradrenalin, play an essential role in regulating the motor and sensory functions in the spinal cord. We have previously shown that in the rat spinal cord the activity of aromatic L-amino acid decarboxylase (AADC) cells to produce 5-HT from its precursor (5-hydroxytryptophan, 5-HTP) is dramatically increased following complete spinal cord transection. In this study, we investigated whether a partial loss of 5-HT innervation could similarly increase AADC activity. Adult rats with spinal cord hemisected at thoracic level (T11/T12) were used with a postoperation interval at 5 days or 60 days. Using immunohistochemistry, first, we observed a significant reduction in the density of 5-HT-immunoreactive fibers in the spinal cord below the lesion on the injured side for both groups. Second, we found that the AADC cells were similarly expressed on both injured and uninjured sides in both groups. Third, increased production of 5-HT in AADC cells following 5-HTP was seen in 5-day but not in 60-day postinjury group. These results suggest that plastic changes of the 5-HT system might happen primarily in the subchronic phase and for longer period its function could be compensated by plastic changes of other intrinsic and/or supraspinal modulation systems. PMID- 26504604 TI - Damage Control Surgery for Hepatocellular Cancer Rupture in an Elderly Patient: Survival and Quality of Life. AB - Spontaneous rupture of hepatocellular carcinoma (HCC) is a rare emergency condition with high mortality rate. Successful management depends on patients' hemodynamic condition upon presentation and comorbidities, correct diagnosis, HCC status, liver function, and future liver remnant, as well as available sources. There is still a debate in the literature concerning the best approach in this devastating complication. Nevertheless, the primary goal should be a definitive bleeding arrest. In most cases, patients with spontaneous rupture of HCC present with hemodynamic instability, due to hemoperitoneum, necessitating an emergency treatment modality. In such cases, transcatheter arterial embolization (TAE) should be the treatment of choice. Emergency liver resection is an option when TAE fails or in cases with preserved liver function and limited tumors. Otherwise, damage control strategies, as in liver trauma, are a reasonable alternative. We report a case of an elderly patient with hemoperitoneum and hypovolemic shock from spontaneous rupture of undiagnosed HCC, who was treated successfully by emergency surgery and damage control approach. PMID- 26504605 TI - Combination Trimodality Therapy Using Vismodegib for Basal Cell Carcinoma of the Face. AB - Background. For large basal cell carcinomas (BCCs) of the head and neck, definitive surgery often requires extensive resection and reconstruction that may result in prolonged recovery and limited cosmesis. Vismodegib, a small-molecule inhibitor of the hedgehog pathway, is approved for advanced and metastatic BCCs. We present a case of advanced BCC treated with combination of vismodegib, radiotherapy, and local excision resulting in excellent response and cosmesis. Case Presentation. A 64-year-old gentleman presented with a 5-year history of a 7 cm enlarging right cheek mass, with extensive vascularization, central ulceration, and skin, soft tissue, and buccal mucosa involvement. Biopsy revealed BCC, nodular type. Up-front surgical option involved a large resection and reconstruction. After multidisciplinary discussion, we recommended and he opted for combined modality of vismodegib, radiotherapy, and local excision. The patient tolerated vismodegib well and his right cheek lesion decreased significantly in size. He was then treated with radiotherapy followed by local excision that revealed only focal residual BCC. Currently, he is without evidence of disease and has excellent cosmesis. Conclusions. We report a case of locally advanced BCC treated with trimodality therapy with vismodegib, radiotherapy, and local excision, resulting in excellent outcome and facial cosmesis, without requiring extensive resection or reconstructive surgery. PMID- 26504606 TI - A Huge Capital Drop with Compression of Femoral Vessels Associated with Hip Osteoarthritis. AB - A capital drop is a type of osteophyte at the inferomedial portion of the femoral head commonly observed in hip osteoarthritis (OA), secondary to developmental dysplasia. Capital drop itself is typically asymptomatic; however, symptoms can appear secondary to impinge against the acetabulum or to irritation of the surrounding tissues, such as nerves, vessels, and tendons. We present here a case of unilateral leg edema in a patient with hip OA, caused by a huge bone mass occurring at the inferomedial portion of the femoral head that compressed the femoral vessels. We diagnosed this bone mass as a capital drop secondary to hip OA after confirming that the mass occurred at least after the age of 63 years based on a previous X-ray. We performed early resection and total hip arthroplasty since the patient's hip pain was due to both advanced hip OA and compression of the femoral vessels; moreover, we aimed to prevent venous thrombosis secondary to vascular compression considering the advanced age and the potent risk of thrombosis in the patient. A large capital drop should be considered as a cause of vascular compression in cases of unilateral leg edema in OA patients. PMID- 26504607 TI - Hepatic Tuberculosis Mimicking Biliary Cystadenoma: A Radiological Dilemma. AB - Primary involvement of liver in tuberculosis is a rare entity. It is difficult to diagnose in absence of previous history of tuberculosis or concurrent pulmonary involvement. It is usually misdiagnosed as neoplastic liver lesion, which misdirects the treatment protocol and delays proper treatment. Here we are presenting a case of 36-year-old male patient with vague right upper quadrant abdominal pain. All the laboratory values were within normal limits. Radiological investigations were in favor of biliary cystadenoma but final diagnosis was primary focal involvement of liver in tuberculosis which was histopathologically proven to be tuberculous granulomas on biopsy of the resected mass. PMID- 26504608 TI - Gastrotracheal Fistula as a Result of Transhiatal Esophagectomy for Esophageal Cancer: An Unusual Complication. AB - Gastrotracheal fistula following open transhiatal esophagectomy (Orringer's technique) for esophageal cancer is an unusual but lethal complication. Surgical intervention with resection of the fistula tract and primary interrupted suturing of gastric and tracheal orifices using a muscle flap interposition has proved to be a successful method. We report the case of a 73-year-old male with an adenocarcinoma of the distal part of the esophagus, who underwent open transhiatal esophagectomy (Orringer's technique) with gastric tube reconstruction and cervical anastomosis. The patient did not receive induction chemoradiotherapy before the esophagectomy. Two attempts of surgical repair of fistula failed and the patient died. Being aware of warning signs such as dyspnea and respiratory distress accompanied by bilious content in the tracheal tube is helpful in the early detection and treatment of this type of fistula. PMID- 26504609 TI - Risk Factors Associated with Unsafe Injection Practices at the First Injection Episode among Intravenous Drug Users in France: Results from PrimInject, an Internet Survey. AB - Background. New drug use patterns may increase the risk of human immunodeficiency virus and hepatitis infections. In France, new injection patterns among youths with diverse social backgrounds have emerged, which may explain the persistently high rates of hepatitis C virus infection. This study explores factors associated with injection risk behaviours at first injection among users who began injecting in the post-2000 era. Methods. A cross-sectional study was conducted on the Internet from October 2010 to March 2011, through an online questionnaire. Multivariate logistic regression identified the independent correlates of needle sharing and equipment (cooker/cotton filter) sharing. Results. Among the 262 respondents (mean age 25 years), 65% were male. Both risk behaviours were positively associated with initiation before 18 years of age (aOR 3.7 CI 95% 1.3 10.6 and aOR 3.0 CI 95% 1.3-7.0) and being injected by another person (aOR 3.1 CI 95% 1.0-9.9 and aOR 3.0 CI 95% 1.3-7.1). Initiation at a party was an independent correlate of equipment sharing (aOR 2.6 95% CI 1.0-6.8). CONCLUSIONS: Results suggest a need for innovative harm reduction programmes targeting a variety of settings and populations, including youths and diverse party scenes. Education of current injectors to protect both themselves and those they might initiate into injection is critically important. PMID- 26504610 TI - Restless Legs Syndrome and Leg Motor Restlessness in Parkinson's Disease. AB - Sleep disturbances are important nonmotor symptoms in Parkinson's disease (PD) that are associated with a negative impact on quality of life. Restless legs syndrome (RLS), which is characterized by an urge to move the legs accompanied by abnormal leg sensations, can coexist with PD, although the pathophysiology of these disorders appears to be different. RLS and PD both respond favorably to dopaminergic treatment, and several investigators have reported a significant relationship between RLS and PD. Sensory symptoms, pain, motor restlessness, akathisia, and the wearing-off phenomenon observed in PD should be differentiated from RLS. RLS in PD may be confounded by chronic dopaminergic treatment; thus, more studies are needed to investigate RLS in drug-naive patients with PD. Recently, leg motor restlessness (LMR), which is characterized by an urge to move the legs that does not fulfill the diagnostic criteria for RLS, has been reported to be observed more frequently in de novo patients with PD than in age-matched healthy controls, suggesting that LMR may be a part of sensorimotor symptoms intrinsic to PD. In this paper, we provide an overview of RLS, LMR, and PD and of the relationships among these disorders. PMID- 26504611 TI - Balance Dysfunction in Parkinson's Disease: The Role of Posturography in Developing a Rehabilitation Program. AB - Balance dysfunction (BD) in Parkinson's disease (PD) is a disabling symptom, difficult to treat and predisposing to falls. The dopaminergic drugs or deep brain stimulation does not always provide significant improvements of BD and rehabilitative approaches have also failed to restore this condition. In this study, we investigated the suitability of quantitative posturographic indicators to early identify patients that could develop disabling BD. Parkinsonian patients not complaining of a subjective BD and controls were tested using a posturographic platform (PP) with open eyes (OE) and performing a simple cognitive task [counting (OEC)]. We found that patients show higher values of total standard deviation (SD) of body sway and along the medio-lateral (ML) axis during OE condition. Furthermore, total and ML SD of body sway during OE condition and total SD of body sway with OEC were higher than controls also in a subgroup of patients with normal Berg Balance Scale. We conclude that BD in Parkinsonian patients can be discovered before its appearance using a PP and that these data may allow developing specific rehabilitative treatment to prevent or delay their onset. PMID- 26504612 TI - A Polysomnographic Study of Parkinson's Disease Sleep Architecture. AB - Sleep disturbance is a common nonmotor phenomenon in Parkinson's disease (PD) affecting patient's quality of life. In this study, we examined the association between clinical characteristics with sleep disorders and sleep architecture patterns in a PD cohort. Patients underwent a standardized polysomnography study (PSG) in their "on medication" state. We observed that male gender and disease duration were independently associated with obstructive sleep apnea (OSA). Only lower levodopa equivalent dose (LED) was associated with periodic limb movement disorders (PLMD). REM sleep behavior disorder (RBD) was more common among older patients, with higher MDS-UPDRS III scores, and LED. None of the investigated variables were associated with the awakenings/arousals (A/A). Sleep efficiency was predicted by amantadine usage and age, while sleep stage 1 was predicted by dopamine agonists and Hoehn & Yahr severity. The use of MAO-B inhibitors and MDS UPDRS part III were predictors of sleep stages 2 and 3. Age was the only predictor of REM sleep stage and gender for total sleep time. We conclude that sleep disorders and architecture are poorly predictable by clinical PD characteristics and other disease related factors must also be contributing to these sleep disturbances. PMID- 26504613 TI - Detection of Gelatin Adulteration in Traditional Chinese Medicine: Analysis of Deer-Horn Glue by Rapid-Resolution Liquid Chromatography-Triple Quadrupole Mass Spectrometry. AB - Simultaneous identification of donkey-hide gelatin and bovine-hide gelatin in deer-horn glue was established by rapid-resolution liquid chromatography-triple quadrupole mass spectrometry. Water containing 1% NH4HCO3 was used for sample dissolution and trypsin was used for hydrolysis of the gelatins. After separation by a SB-C18 reversed-phase analytical column, collagen marker peptides were detected by mass spectrometry in positive electrospray ionization mode with multiple reaction monitoring. The method was specific, precise and reliable, and suitable for detection of adulterants derived from donkey-hide gelatin and bovine hide gelatin in deer-horn glue. PMID- 26504614 TI - Protective Effects of Intralipid and Caffeic Acid Phenethyl Ester on Nephrotoxicity Caused by Dichlorvos in Rats. AB - The protective effects of Caffeic Acid Phenethyl Ester (CAPE) and intralipid (IL) on nephrotoxicity caused by acute Dichlorvos (D) toxicity were investigated in this study. Forty-eight Wistar Albino rats were divided into 7 groups as follows: Control, D, CAPE, intralipid, D + CAPE, D + IL, and D + CAPE + IL. When compared to D group, the oxidative stress index (OSI) values were significantly lower in Control, CAPE, and D + IL + CAPE groups. When compared to D + IL + CAPE group, the TOS and OSI values were significantly higher in D group (P < 0.05). When mitotic cell counts were assessed in the renal tissues, it was found that mitotic cell count was significantly higher in the D group while it was lower in the D + CAPE, D + IL, and D + IL + CAPE groups when compared to the control group (P < 0.05). Also, immune reactivity showed increased apoptosis in D group and low profile of apoptosis in the D + CAPE group when compared to the Control group. The apoptosis level was significantly lower in D + IL + CAPE compared to D group (P < 0.05) in the kidneys. As a result, we concluded that Dichlorvos can be used either alone or in combination with CAPE and IL as supportive therapy or as facilitator for the therapeutic effect of the routine treatment in the patients presenting with pesticide poisoning. PMID- 26504615 TI - A Virtual Instrument System for Determining Sugar Degree of Honey. AB - This study established a LabVIEW-based virtual instrument system to measure optical activity through the communication of conventional optical instrument with computer via RS232 port. This system realized the functions for automatic acquisition, real-time display, data processing, results playback, and so forth. Therefore, it improved accuracy of the measurement results by avoiding the artificial operation, cumbersome data processing, and the artificial error in optical activity measurement. The system was applied to the analysis of the batch inspection on the sugar degree of honey. The results obtained were satisfying. Moreover, it showed advantages such as friendly man-machine dialogue, simple operation, and easily expanded functions. PMID- 26504616 TI - Analysis of Reaction between alpha-Lipoic Acid and 2-Chloro-1-methylquinolinium Tetrafluoroborate Used as a Precolumn Derivatization Technique in Chromatographic Determination of alpha-Lipoic Acid. AB - The present study offers results of analysis concerning the course of reaction between reduced alpha-lipoic acid (LA) and 2-chloro-1-methylquinolinium tetrafluoroborate (CMQT). In water environments, the reaction between CMQT and hydrophilic thiols proceeds very rapidly and the resultant products are stable. For the described analysis, optimum reaction conditions, such as concentration of the reducing agent, environment pH, and concentration of the reagent were carefully selected. The spectrophotometric assay was carried out measuring absorbance at lambda = 348 nm (i.e., the spectral band of the obtained reaction product). Furthermore, the calibration curve of lipoic acid was registered. It was concluded that the Lambert-Beer law was observed within the range 1-10 MUmol L(-1). Later, the reaction between LA and CMQT was used as precolumn derivatization in a chromatographic determination of the lipoic acid in the range 2.5-50 MUmol L(-1). Practical applicability of the designed methods was evaluated by determining lipoic acid in Revitanerv pharmaceutical preparation which contains 300 mg LA in a single capsule. The error of the determination did not exceed 0.5% in relation to the declared value. PMID- 26504617 TI - Categorical and Dimensional Definitions and Evaluations of Symptoms of ADHD: History of the SNAP and the SWAN Rating Scales. AB - An earlier version of this article was originally submitted for publication in early 2000 to introduce a new dimensional of concept of Attention Deficit Hyperactivity Disorder (ADHD) provided by the Strengths and Weaknesses of ADHD symptoms and Normal-behavior (SWAN) rating scale. The SWAN was developed to correct some obvious deficiencies of the Swanson, Nolan and Pelham (SNAP) rating scale that was based on the categorical concept of ADHD. The first submission was not accepted for publication, so a draft of the article was posted on a website (www.ADHD.net). The SWAN scale was published as a table in a review article (Swanson et al, 2001) to make it available to those interested in this dimensional approach to assessment of ADHD. Despite its relative inaccessibility, the SWAN has been used in several genetic studies of ADHD (e.g., Hay, Bennett, Levy, Sergeant, & Swanson, 2005; Cornish et al, 2005) and has been translated into several languages for European studies of ADHD (e.g., Lubke et al, 2006; Polderman et al, 2010) and into Spanish for studies in the United States (e.g., Lakes, Swanson, & Riggs, 2011; Kudo et al., this issue). Recently, invitations to include the SWAN in the PhenX Toolkit (www.phenx.org) for genomic studies (Hamilton et al, 2011) and to describe thedimensional approach of the SWAN for discussion of diagnostic (Swanson, Wigal, & Lakes, 2009) and ethical (Swanson, Wigal, Lakes, &Volkow, 2011) issues has convinced us that the unpublished article is still relevant after more than a decade, so it is presented here with some minor updates. We use examples (a) to document some consequences (e.g., over identification of extreme cases) of using statistical cutoffs based on the assumption for a distribution of SNAP ratings that is highly skewed and (b) to show how the SWAN corrects the skewness of the SNAP by rewording the items on the scale and using a wider range of rating alternatives, which corrects the tendency to over-identify extreme cases. PMID- 26504619 TI - Time-shared optical tweezers with a microlens array for dynamic microbead arrays. AB - Dynamic arrays of microbeads and cells offer great flexibility and potential as platforms for sensing and manipulation applications in various scientific fields, especially biology and medicine. Here, we present a simple method for assembling and manipulating dense dynamic arrays based on time-shared scanning optical tweezers with a microlens array. Three typical examples, including the dynamic and simultaneous bonding of microbeads in real-time, are demonstrated. The optical design and the hardware setup for our approach are also described. PMID- 26504618 TI - Bone health in HIV-infected children, adolescents and young adults: a systematic review. AB - BACKGROUND: Children and adolescents, who either acquire HIV infection perinatally, from contaminated blood products or via sexual transmission early in life, have the greatest cumulative exposure to the negative direct and indirect effects of HIV infection and ART on bone, which may lead to increased lifetime risk for osteoporosis and fracture. We conducted a systematic review to evaluate the literature on bone health in children and adolescents with HIV. METHODS: We performed a comprehensive search of the Medline, Scopus, and Cochrane Library databases (up to April 1, 2014) for studies that reported on bone imaging or bone fractures in HIV-infected children, adolescents, or young adults. RESULTS: A total of 32 publications met our inclusion criteria. Seventeen studies were cross sectional and 15 were longitudinal. The majority of studies were conducted in high-income countries, three in middle-income countries and none in low-income countries. Overall, the studies we reviewed indicate that measures of bone mass are reduced, with increased prevalence of low BMD in children and adolescents with HIV. However, the studies are highly variable with respect to comparison sources, measurement methods, adjustment techniques for body size or growth retardation, and highlighted risk factors, including aspects related to medication exposures as well as the effects of HIV infection per se. CONCLUSION: HIV infection appears to be associated with decreased bone accrual throughout childhood and adolescence. Initial studies indicate that sub-optimal bone accrual may be persistent and result in reduced peak bone mass, an important determinant of future risk of osteoporosis and fracture. Important areas for future research include evaluation of bone mass, bone quality and fracture risk across the life course among those with early-life infection with HIV, particularly in resource limited settings where the majority of children with HIV live. PMID- 26504620 TI - Method to quantify accuracy of position feedback signals of a three-dimensional two-photon laser-scanning microscope. AB - Two-photon laser-scanning microscopy enables to record neuronal network activity in three-dimensional space while maintaining single-cellular resolution. One of the proposed approaches combines galvanometric x-y scanning with piezo-driven objective movements and employs hardware feedback signals for position monitoring. However, readily applicable methods to quantify the accuracy of those feedback signals are currently lacking. Here we provide techniques based on contact-free laser reflection and laser triangulation for the quantification of positioning accuracy of each spatial axis. We found that the lateral feedback signals are sufficiently accurate (defined as <2.5 um) for a wide range of scan trajectories and frequencies. We further show that axial positioning accuracy does not only depend on objective acceleration and mass but also its geometry. We conclude that the introduced methods allow a reliable quantification of position feedback signals in a cost-efficient, easy-to-install manner and should be applicable for a wide range of two-photon laser scanning microscopes. PMID- 26504621 TI - Second harmonic generation microscopy investigation of the crystalline ultrastructure of three barley starch lines affected by hydration. AB - Second harmonic generation (SHG) microscopy is employed to study changes in crystalline organization due to altered gene expression and hydration in barley starch granules. SHG intensity and susceptibility ratio values (R'SHG ) are obtained using reduced Stokes-Mueller polarimetric microscopy. The maximum R'SHG values occur at moderate moisture indicating the narrowest orientation distribution of nonlinear dipoles from the cylindrical axis of glucan helices. The maximum SHG intensity occurs at the highest moisture and amylopectin content. These results support the hypothesis that SHG is caused by ordered hydrogen and hydroxyl bond networks which increase with hydration of starch granules. PMID- 26504622 TI - Human retinal imaging using visible-light optical coherence tomography guided by scanning laser ophthalmoscopy. AB - We achieved human retinal imaging using visible-light optical coherence tomography (vis-OCT) guided by an integrated scanning laser ophthalmoscopy (SLO). We adapted a spectral domain OCT configuration and used a supercontinuum laser as the illumating source. The center wavelength was 564 nm and the bandwidth was 115 nm, which provided a 0.97 um axial resolution measured in air. We characterized the sensitivity to be 86 dB with 226 uW incidence power on the pupil. We also integrated an SLO that shared the same optical path of the vis-OCT sample arm for alignment purposes. We demonstrated the retinal imaging from both systems centered at the fovea and optic nerve head with 20 degrees * 20 degrees and 10 degrees * 10 degrees field of view. We observed similar anatomical structures in vis-OCT and NIR-OCT. The contrast appeared different from vis-OCT to NIR-OCT, including slightly weaker signal from intra-retinal layers, and increased visibility and contrast of anatomical layers in the outer retina. PMID- 26504623 TI - In vivo multiplexed molecular imaging of esophageal cancer via spectral endoscopy of topically applied SERS nanoparticles. AB - The biological investigation and detection of esophageal cancers could be facilitated with an endoscopic technology to screen for the molecular changes that precede and accompany the onset of cancer. Surface-enhanced Raman scattering (SERS) nanoparticles (NPs) have the potential to improve cancer detection and investigation through the sensitive and multiplexed detection of cell-surface biomarkers. Here, we demonstrate that the topical application and endoscopic imaging of a multiplexed cocktail of receptor-targeted SERS NPs enables the rapid detection of tumors in an orthotopic rat model of esophageal cancer. Antibody conjugated SERS NPs were topically applied on the lumenal surface of the rat esophagus to target EGFR and HER2, and a miniature spectral endoscope featuring rotational scanning and axial pull-back was employed to comprehensively image the NPs bound on the lumen of the esophagus. Ratiometric analyses of specific vs. nonspecific binding enabled the visualization of tumor locations and the quantification of biomarker expression in agreement with immunohistochemistry and flow cytometry validation data. PMID- 26504624 TI - Handheld imaging photonic crystal biosensor for multiplexed, label-free protein detection. AB - We present a handheld biosensor system for the label-free and specific multiplexed detection of several biomarkers employing a spectrometer-free imaging measurement system. A photonic crystal surface functionalized with multiple specific ligands forms the optical transducer. The photonic crystal slab is fabricated on a glass substrate by replicating a periodic grating master stamp with a period of 370 nm into a photoresist via nanoimprint lithography and deposition of a 70-nm titanium dioxide layer. Capture molecules are coupled covalently and drop-wise to the photonic crystal surface. With a simple camera and imaging optics the surface-normal transmission is detected. In the transmission spectrum guided-mode resonances are observed that shift due to protein binding. This shift is observed as an intensity change in the green color channel of the camera. Non-functionalized image sections are used for continuous elimination of background drift. In a first experiment we demonstrate the specific and time-resolved detection of 90.0 nm CD40 ligand antibody, 90.0 nM EGF antibody, and 500 nM streptavidin in parallel on one sensor chip. In a second experiment, aptamers with two different spacer lengths are used as receptor. The binding kinetics with association and dissociation of 250 nM thrombin and regeneration of the sensor surface with acidic tris-HCl-buffer (pH 5.0) is presented for two measurement cycles. PMID- 26504625 TI - High-speed multifocal array scanning using refractive window tilting. AB - Confocal microscopy has several advantages over wide-field microscopy, such as out-of-focus light suppression, 3D sectioning, and compatibility with specialized detectors. While wide-field microscopy is a faster approach, multiplexed confocal schemes can be used to make confocal microscopy more suitable for high-throughput applications, such as high-content screening (HCS) commonly used in drug discovery. An increasingly powerful modality in HCS is fluorescence lifetime imaging microscopy (FLIM), which can be used to measure protein-protein interactions through Forster resonant energy transfer (FRET). FLIM-FRET for HCS combines the requirements of high throughput, high resolution and specialized time-resolving detectors, making it difficult to implement using wide-field and spinning disk confocal approaches. We developed a novel foci array scan method that can achieve uniform multiplex confocal acquisition using stationary lenslet arrays for high resolution and high throughput FLIM. Unlike traditional mirror galvanometers, which work in Fourier space between scan lenses, this scan method uses optical flats to steer a 2-dimension foci array through refraction. After integrating this scanning scheme in a multiplexing confocal FLIM system, we demonstrate it offers clear benefits over traditional mirror galvanometer scanners in scan linearity, uniformity, cost and complexity. PMID- 26504626 TI - In vivo cell characteristic extraction and identification by photoacoustic flow cytography. AB - We present a photoacoustic flow cytography with fast cross-sectional (B-scan) imaging to precisely identify specific cells in vivo. The B-scan imaging speed of the system is up to 200 frame/s with a lateral resolution of 1.5 MUm, which allows to dynamically image the flowing cells within the microvascular. The shape, size and photoacoustic intensity of the target cells are extracted from streaming images and integrated into a standard pattern to distinguish cell types. Circulating red blood cells and melanoma cells in blood vessels are simultaneously identified on melanoma-bearing mouse model. The results demonstrate that in vivo photoacoustic flow cytography can provide cells characteristics analysis and cell type's visual identification, which will be applied for noninvasively monitoring circulating tumor cells (CTCs) and analyzing hematologic diseases. PMID- 26504627 TI - Bubble wrap for optical trapping and cell culturing. AB - In this paper, we demonstrate that the bubbles of bubble wrap make ideal trapping chambers for integration with low-cost optical manipulation. The interior of the bubbles is sterile and gas permeable, allowing for the bubbles to be used to store and culture cells, while the flat side of the bubble wrap is of sufficient optical quality to allow for optical trapping inside the bubbles. Through the use of a 100 W bulb to cure hanging droplets of PDMS, a low-cost optical trapping system was constructed. Effector T cells were cultured in bubble wrap for 8 days and then trapped with the PDMS droplet based optical manipulation. These techniques further demonstrate the opportunities for biophysical analysis afforded through repurposing common materials in resource-limited settings. PMID- 26504628 TI - Review of fluorescence guided surgery visualization and overlay techniques. AB - In fluorescence guided surgery, data visualization represents a critical step between signal capture and display needed for clinical decisions informed by that signal. The diversity of methods for displaying surgical images are reviewed, and a particular focus is placed on electronically detected and visualized signals, as required for near-infrared or low concentration tracers. Factors driving the choices such as human perception, the need for rapid decision making in a surgical environment, and biases induced by display choices are outlined. Five practical suggestions are outlined for optimal display orientation, color map, transparency/alpha function, dynamic range compression, and color perception check. PMID- 26504629 TI - Red emissive AIE nanodots with high two-photon absorption efficiency at 1040 nm for deep-tissue in vivo imaging. AB - Deep-tissue penetration is highly required in in vivo optical bioimaging. We synthesized a type of red emissive fluorophore BT with aggregation-induced emission (AIE) property. BT molecules were then encapsulated with amphiphilic polymers to form nanodots, and a large two-photon absorption (2PA) cross-section of 2.9 * 10(6) GM at 1040 nm was observed from each BT nanodot, which was much larger than those at the wavelengths of 770 to 860 nm. In addition, 1040 nm light was found to have better penetration and focusing capability than 800 nm light in biological tissue, according to the Monte Carlo simulation. The toxicity and tissue distribution of BT nanodots were studied, and they were found to have good biocompatibility. BT nanodots were then utilized for in vivo imaging of mouse ear and brain, and an imaging depth of 700 MUm was obtained with the femtosecond (fs) excitation of 1040 nm. The red emissive AIE nanodots with high 2PA efficiency at 1040 nm would be useful for deep-tissue functional bioimaging in the future. PMID- 26504631 TI - Correlating optical coherence elastography based strain measurements with collagen content of the human ovarian tissue. AB - In this manuscript, the initial feasibility of a catheter based phase stabilized swept source optical coherence tomography (OCT) system was studied for characterization of the strain inside different human ovarian tissue groups. The ovarian tissue samples were periodically compressed with 500 Hz square wave signal along the axial direction between the surface of an unfocused transducer and a glass cover slide. The displacement and corresponding strain were calculated during loading from different locations for each tissue sample. A total of 27 ex vivo ovaries from 16 patients were investigated. Statistically significant difference (p < 0.001) was observed between the average displacement and strain of the normal and malignant tissue groups. A sensitivity of 93.2% and a specificity of 83% were achieved using 25 microstrain (MUepsilon) as the threshold. The collagen content of the tissues was quantified from the Sirius Red stained histological sections. The average collagen area fraction (CAF) obtained from the tissue groups were found to have a strong negative correlation (R = 0.75, p < 0.0001) with the amount of strain inside the tissue. This indicates much softer and degenerated tissue structure for the malignant ovaries as compared to the dense, collagen rich structure of the normal ovarian tissue. The initial results indicate that the swept source OCT system can be useful for estimating the elasticity of the human ovarian tissue. PMID- 26504632 TI - Stability and instability for low refractive-index-contrast particle trapping in a dual-beam optical trap. AB - A dual-beam optical trap is used to trap and manipulate dielectric particles. When the refractive index of these particles is comparable to that of the surrounding medium, equilibrium trapping locations within the system shift from stable to unstable depending on fiber separation and particle size. This is due to to the relationship between gradient and scattering forces. We experimentally and computationally study the transitions between stable and unstable trapping of poly(methyl methacrylate) beads for a range of parameters relevant to experimental setups involving giant unilamellar vesicles. We present stability maps for various fiber separations and particle sizes, and find that careful attention to particle size and configuration is necessary to obtain reproducible quantitative results for soft matter stretching experiments. PMID- 26504630 TI - Precancerous esophageal epithelia are associated with significantly increased scattering coefficients. AB - The progression of epithelial precancers into cancer is accompanied by changes of tissue and cellular structures in the epithelium. Correlations between the structural changes and scattering coefficients of esophageal epithelia were investigated using quantitative phase images and the scattering-phase theorem. An ex vivo study of 14 patients demonstrated that the average scattering coefficient of precancerous epithelia was 37.8% higher than that of normal epithelia from the same patient. The scattering coefficients were highly correlated with morphological features including the cell density and the nuclear-to-cytoplasmic ratio. A high interpatient variability in scattering coefficients was observed and suggests identifying precancerous lesions based on the relative change in scattering coefficients. PMID- 26504633 TI - Anti-confocal versus confocal assessment of the middle ear simulated by Monte Carlo methods. AB - The ability to monitor the inflammatory state of the middle ear mucosa would provide clinical utility. To enable spectral measurements on the mucosa whilst rejecting background signal from the eardrum an anti-confocal system is investigated. In contrast to the central pinhole in a confocal system the anti confocal system uses a central stop to reject light from the in-focus plane, the eardrum, with all other light detected. Monte Carlo simulations of this system show an increase in detected signal and improved signal-to-background ratio compared to a conventional confocal set-up used to image the middle ear mucosa. System parameters are varied in the simulation and their influence on the level of background rejection are presented. PMID- 26504634 TI - Image restoration for three-dimensional fluorescence microscopy using an orthonormal basis for efficient representation of depth-variant point-spread functions. AB - A depth-variant (DV) image restoration algorithm for wide field fluorescence microscopy, using an orthonormal basis decomposition of DV point-spread functions (PSFs), is investigated in this study. The efficient PSF representation is based on a previously developed principal component analysis (PCA), which is computationally intensive. We present an approach developed to reduce the number of DV PSFs required for the PCA computation, thereby making the PCA-based approach computationally tractable for thick samples. Restoration results from both synthetic and experimental images show consistency and that the proposed algorithm addresses efficiently depth-induced aberration using a small number of principal components. Comparison of the PCA-based algorithm with a previously developed strata-based DV restoration algorithm demonstrates that the proposed method improves performance by 50% in terms of accuracy and simultaneously reduces the processing time by 64% using comparable computational resources. PMID- 26504636 TI - 28 MHz swept source at 1.0 MUm for ultrafast quantitative phase imaging. AB - Emerging high-throughput optical imaging modalities, in particular those providing phase information, necessitate a demanding speed regime (e.g. megahertz sweep rate) for those conventional swept sources; while an effective solution is yet to be demonstrated. We demonstrate a stable breathing laser as inertia-free swept source (BLISS) operating at a wavelength sweep rate of 28 MHz, particularly for the ultrafast interferometric imaging modality at 1.0 MUm. Leveraging a tunable dispersion compensation element inside the laser cavity, the wavelength sweep range of BLISS can be tuned from ~10 nm to ~63 nm. It exhibits a good intensity stability, which is quantified by the ratio of standard deviation to the mean of the pulse intensity, i.e. 1.6%. Its excellent wavelength repeatability, <0.05% per sweep, enables the single-shot imaging at an ultrafast line-scan rate without averaging. To showcase its potential applications, it is applied to the ultrafast (28-MHz line-scan rate) interferometric time-stretch (iTS) microscope to provide quantitative morphological information on a biological specimen at a lateral resolution of 1.2 MUm. This fiber-based inertia free swept source is demonstrated to be robust and broadband, and can be applied to other established imaging modalities, such as optical coherence tomography (OCT), of which an axial resolution better than 12 MUm can be achieved. PMID- 26504635 TI - Simultaneous FRAP, FLIM and FAIM for measurements of protein mobility and interaction in living cells. AB - We present a novel integrated multimodal fluorescence microscopy technique for simultaneous fluorescence recovery after photobleaching (FRAP), fluorescence lifetime imaging (FLIM) and fluorescence anisotropy imaging (FAIM). This approach captures a series of polarization-resolved fluorescence lifetime images during a FRAP recovery, maximizing the information available from a limited photon budget. We have applied this method to analyse the behaviour of GFP-labelled coxsackievirus and adenovirus receptor (CAR) in living human epithelial cells. Our data reveal that CAR exists in oligomeric states throughout the cell, and that these complexes occur in conjunction with high immobile fractions of the receptor at cell-cell junctions. These findings shed light on previously unknown molecular associations between CAR receptors in intact cells and demonstrate the power of combined FRAP, FLIM and FAIM microscopy as a robust method to analyse complex multi-component dynamics in living cells. PMID- 26504637 TI - Label-free characterization of white blood cells by measuring 3D refractive index maps. AB - The characterization of white blood cells (WBCs) is crucial for blood analyses and disease diagnoses. However, current standard techniques rely on cell labeling, a process which imposes significant limitations. Here we present three dimensional (3D) optical measurements and the label-free characterization of mouse WBCs using optical diffraction tomography. 3D refractive index (RI) tomograms of individual WBCs are constructed from multiple two-dimensional quantitative phase images of samples illuminated at various angles of incidence. Measurements of the 3D RI tomogram of WBCs enable the separation of heterogeneous populations of WBCs using quantitative morphological and biochemical information. Time-lapse tomographic measurements also provide the 3D trajectory of micrometer sized beads ingested by WBCs. These results demonstrate that optical diffraction tomography can be a useful and versatile tool for the study of WBCs. PMID- 26504638 TI - Methodology for diagnosing of skin cancer on images of dermatologic spots by spectral analysis. AB - In this paper a new methodology for the diagnosing of skin cancer on images of dermatologic spots using image processing is presented. Currently skin cancer is one of the most frequent diseases in humans. This methodology is based on Fourier spectral analysis by using filters such as the classic, inverse and k-law nonlinear. The sample images were obtained by a medical specialist and a new spectral technique is developed to obtain a quantitative measurement of the complex pattern found in cancerous skin spots. Finally a spectral index is calculated to obtain a range of spectral indices defined for skin cancer. Our results show a confidence level of 95.4%. PMID- 26504639 TI - Wide-field Raman imaging for bone detection in tissue. AB - Inappropriate bone growth in soft tissue can occur after trauma to a limb and can cause a disruption to the healing process. This is known as Heterotopic Ossification (HO) in which regions in the tissue start to mineralize and form microscopic bone-like structures. These structures continue to calcify and develop into large, non-functional bony masses that cause pain, limit limb movement, and expose the tissue to reoccurring infections; in the case of open wounds this can lead to amputation as a result of a failed wound. Both Magnetic Resonance Imaging (MRI) and X-ray imaging have poor sensitivity and specificity for the detection of HO, thus delaying therapy and leading to poor patient outcomes. We present a low-power, fast (1 frame per second) optical Raman imaging system with a large field of view (1 cm(2)) that can differentiate bone tissue from soft tissue without spectroscopy, this in contrast to conventional Raman microscopy systems. This capability may allow for the development of instrumentation which permits bedside diagnosis of HO. PMID- 26504640 TI - Encapsulation efficiency of CdSe/ZnS quantum dots by liposomes determined by thermal lens microscopy. AB - In this study the encapsulation of core shell carboxyl CdSe/ZnS quantum dots (QDs) by phospholipids liposome complexes is presented. It makes the quantum dots water soluble and photo-stable. Fluorescence self-quenching of the QDs inside the liposomes was observed. Therefore, the thermal lens microscopy (TLM) was found to be an useful tool for measuring the encapsulation efficiency of the QDs by the liposomes, for which an optimum value of 36% was determined. The obtained limit of detection (LOD) for determining QDs concentration by TLM was 0.13 nM. Moreover, the encapsulated QDs showed no prominent cytotoxicity toward Breast cancer cells line MDA-MB-231. This study was supported by UV-visible spectroscopy, high resolution transmission electron microscopy (HRTEM) and dynamic light scattering measurements (DLS). PMID- 26504641 TI - Development of a combined broadband near-infrared and diffusion correlation system for monitoring cerebral blood flow and oxidative metabolism in preterm infants. AB - Neonatal neuromonitoring is a major clinical focus of near-infrared spectroscopy (NIRS) and there is an increasing interest in measuring cerebral blood flow (CBF) and oxidative metabolism (CMRO2) in addition to the classic tissue oxygenation saturation (StO2). The purpose of this study was to assess the ability of broadband NIRS combined with diffusion correlation spectroscopy (DCS) to measured changes in StO2, CBF and CMRO2 in preterm infants undergoing pharmaceutical treatment of patent ductus arteriosus. CBF was measured by both DCS and contrast enhanced NIRS for comparison. No significant difference in the treatment-induced CBF decrease was found between DCS (27.9 +/- 2.2%) and NIRS (26.5 +/- 4.3%). A reduction in StO2 (70.5 +/- 2.4% to 63.7 +/- 2.9%) was measured by broadband NIRS, reflecting the increase in oxygen extraction required to maintain CMRO2. This study demonstrates the applicability of broadband NIRS combined with DCS for neuromonitoring in this patient population. PMID- 26504642 TI - Multi-channel fiber photometry for population neuronal activity recording. AB - Fiber photometry has become increasingly popular among neuroscientists as a convenient tool for the recording of genetically defined neuronal population in behaving animals. Here, we report the development of the multi-channel fiber photometry system to simultaneously monitor neural activities in several brain areas of an animal or in different animals. In this system, a galvano-mirror modulates and cyclically couples the excitation light to individual multimode optical fiber bundles. A single photodetector collects excited light and the configuration of fiber bundle assembly and the scanner determines the total channel number. We demonstrated that the system exhibited negligible crosstalk between channels and optical signals could be sampled simultaneously with a sample rate of at least 100 Hz for each channel, which is sufficient for recording calcium signals. Using this system, we successfully recorded GCaMP6 fluorescent signals from the bilateral barrel cortices of a head-restrained mouse in a dual-channel mode, and the orbitofrontal cortices of multiple freely moving mice in a triple-channel mode. The multi-channel fiber photometry system would be a valuable tool for simultaneous recordings of population activities in different brain areas of a given animal and different interacting individuals. PMID- 26504643 TI - In vivo three-dimensional characterization of the adult zebrafish brain using a 1325 nm spectral-domain optical coherence tomography system with the 27 frame/s video rate. AB - In this study, a spectral-domain optical coherence tomography (SD-OCT) system was used for noninvasive imaging of the adult zebrafish brain. Based on a 1325 nm light source and two high-speed galvo mirrors, our SD-OCT system can offer a large field of view of brain morphology with high resolution (12 MUm axial and 13 MUm lateral) at video rate (27 frame/s). In vivo imaging of both the control and injured brain was performed using adult zebrafish model. The recovered results revealed that olfactory bulb, optic commissure, telencephalon, tectum opticum, cerebellum, medulla, preglomerular complex and posterior tuberculum could be clearly identified in the cross-sectional SD-OCT images of the adult zebrafish brain. The reconstructed results also suggested that SD-OCT can be used for diagnosis and monitoring of traumatic brain injury. In particular, we found the reconstructed volumetric SD-OCT images enable a comprehensive three-dimensional characterization of the control or injured brain in the intact zebrafish. PMID- 26504645 TI - Full-field transmission-type angle-deviation optical microscope with reflectivity height transformation. AB - This full-field transmission-type three-dimensional (3D) optical microscope is constructed based on the angle deviation method (ADM) and the algorithm of reflectivity-height transformation (RHT). The surface height is proportional to the deviation angle of light passing through the object. The angle deviation and surface height can be measured based on the reflectivity closed to the critical angle using a parallelogram prism and two CCDs. PMID- 26504644 TI - Cerebral metabolic rate of oxygen (CMRO2) assessed by combined Doppler and spectroscopic OCT. AB - A method of measuring cortical oxygen metabolism in the mouse brain that uses independent quantitative measurements of three key parameters: cerebral blood flow (CBF), arteriovenous oxygen extraction (OE), and hemoglobin concentration ([HbT]) is presented. Measurements were performed using a single visible light spectral/Fourier domain OCT microscope, with Doppler and spectroscopic capabilities, through a thinned-skull cranial window in the mouse brain. Baseline metabolic measurements in mice are shown to be consistent with literature values. Oxygen consumption, as measured by this method, did not change substantially during minor changes either in the fraction of inspired oxygen (FiO2) or in the fraction of inspired carbon dioxide (FiCO2), in spite of larger variations in oxygen saturations. This set of experiments supports, but does not prove, the validity of the proposed method of measuring brain oxygen metabolism. PMID- 26504646 TI - In vivo longitudinal cellular imaging of small intestine by side-view endomicroscopy. AB - Visualization of cellular dynamics in the gastrointestinal tract of living mouse model to investigate the pathophysiology has been a long-pursuing goal. Especially, for chronic disease such as Crohn's disease, a longitudinal observation of the luminal surface of the small intestine in the single mouse is highly desirable to investigate the complex pathogenesis in sequential time points. In this work, by utilizing a micro-GRIN lens based side-view endomicroscope integrated into a video-rate confocal microscopy system, we successfully performed minimally-invasive in vivo cellular-level visualization of various fluorescent cells and microvasculature in the small intestinal villi. Also, with a transgenic mouse universally expressing photoconvertible protein, Kaede, we demonstrated repetitive cellular-level confocal endoscopic visualization of same area in the small intestinal lumen of a single mouse, which revealed the continuous homeostatic renewal of the small intestinal epithelium. PMID- 26504647 TI - Limitations of the commonly used simplified laterally uniform optical fiber probe tissue interface in Monte Carlo simulations of diffuse reflectance. AB - Light propagation models often simplify the interface between the optical fiber probe tip and tissue to a laterally uniform boundary with mismatched refractive indices. Such simplification neglects the precise optical properties of the commonly used probe tip materials, e.g. stainless steel or black epoxy. In this paper, we investigate the limitations of the laterally uniform probe-tissue interface in Monte Carlo simulations of diffuse reflectance. In comparison to a realistic probe-tissue interface that accounts for the layout and properties of the probe tip materials, the simplified laterally uniform interface is shown to introduce significant errors into the simulated diffuse reflectance. PMID- 26504648 TI - Validating a bimodal intravascular ultrasound (IVUS) and near-infrared fluorescence (NIRF) catheter for atherosclerotic plaque detection in rabbits. AB - Coronary artery disease is characterized by atherosclerotic plaque formation. Despite impressive advances in intravascular imaging modalities, in vivo molecular plaque characterization remains challenging, and different multimodality imaging systems have been proposed. We validated an engineered bimodal intravascular ultrasound imaging (IVUS) / near-infrared fluorescence (NIRF) imaging catheter in vivo using a balloon injury atherosclerosis rabbit model. Rabbit aortas and right iliac arteries were scanned in vivo after indocyanine green (ICG) injection, and compared to corresponding ex vivo fluorescence and white light images. Areas of ICG accumulation were colocalized with macroscopic atherosclerotic plaque formation. In vivo imaging was performed with the bimodal catheter integrating ICG-induced fluorescence signals into cross sectional IVUS imaging. In vivo ICG accumulation corresponded to ex vivo fluorescence signal intensity and IVUS identified plaques. PMID- 26504649 TI - Ultrafast transient absorption of eumelanin suspensions: the role of inverse Raman scattering. AB - An ultrafast investigation is carried out on synthetic eumelanin suspended either in water or in DMSO-methanol. Upon photoexcitation by visible femtosecond pulses, the transient absorption (TA) dynamics of the suspensions are probed in a broad visible spectral range, showing clear nonlinearities. The latter arise from pump probe interactions that induce the inverse Raman scattering (IRS) effect. We show how eumelanin TA dynamics are modified in proximity of the solvent Stokes and anti-Stokes scattering peaks, demonstrating that IRS affects the sign of TA but not the relaxation times. We compare the results obtained in both suspensions, unveiling the role of the surrounding environment. Eventually, the intrinsic response of synthetic eumelanin to ultrafast photoexcitation is evaluated. PMID- 26504650 TI - Modal demultiplexing properties of tapered and nanostructured optical fibers for in vivo optogenetic control of neural activity. AB - Optogenetic approaches to manipulate neural activity have revolutionized the ability of neuroscientists to uncover the functional connectivity underlying brain function. At the same time, the increasing complexity of in vivo optogenetic experiments has increased the demand for new techniques to precisely deliver light into the brain, in particular to illuminate selected portions of the neural tissue. Tapered and nanopatterned gold-coated optical fibers were recently proposed as minimally invasive multipoint light delivery devices, allowing for site-selective optogenetic stimulation in the mammalian brain [Pisanello , Neuron82, 1245 (2014)]. Here we demonstrate that the working principle behind these devices is based on the mode-selective photonic properties of the fiber taper. Using analytical and ray tracing models we model the finite conductance of the metal coating, and show that single or multiple optical windows located at specific taper sections can outcouple only specific subsets of guided modes injected into the fiber. PMID- 26504651 TI - Improved two-photon imaging of living neurons in brain tissue through temporal gating. AB - We optimize two-photon imaging of living neurons in brain tissue by temporally gating an incident laser to reduce the photon flux while optimizing the maximum fluorescence signal from the acquired images. Temporal gating produces a bunch of ~10 femtosecond pulses and the fluorescence signal is improved by increasing the bunch-pulse energy. Gating is achieved using an acousto-optic modulator with a variable gating frequency determined as integral multiples of the imaging sampling frequency. We hypothesize that reducing the photon flux minimizes the photo-damage to the cells. Our results, however, show that despite producing a high fluorescence signal, cell viability is compromised when the gating and sampling frequencies are equal (or effectively one bunch-pulse per pixel). We found an optimum gating frequency range that maintains the viability of the cells while preserving a pre-set fluorescence signal of the acquired two-photon images. The neurons are imaged while under whole-cell patch, and the cell viability is monitored as a change in the membrane's input resistance. PMID- 26504652 TI - Application of full field optical studies for pulsatile flow in a carotid artery phantom. AB - A preliminary comparative measurement between particle imaging velocimetry (PIV) and laser speckle contrast analysis (LASCA) to study pulsatile flow using ventricular assist device in a patient-specific carotid artery phantom is reported. These full-field optical techniques have both been used to study flow and extract complementary parameters. We use the high spatial resolution of PIV to generate a full velocity map of the flow field and the high temporal resolution of LASCA to extract the detailed frequency spectrum of the fluid pulses. Using this combination of techniques a complete study of complex pulsatile flow in an intricate flow network can be studied. PMID- 26504653 TI - Real-time, profile-corrected single snapshot imaging of optical properties. AB - A novel acquisition and processing method that enables real-time, single snapshot of optical properties (SSOP) and 3-dimensional (3D) profile measurements in the spatial frequency domain is described. This method makes use of a dual sinusoidal wave projection pattern permitting to extract the DC and AC components in the frequency domain to recover optical properties as well as the phase for measuring the 3D profile. In this method, the 3D profile is used to correct for the effect of sample's height and angle and directly obtain profile-corrected absorption and reduced scattering maps from a single acquired image. In this manuscript, the 3D SSOP method is described and validated on tissue-mimicking phantoms as well as in vivo, in comparison with the standard profile-corrected SFDI (3D-SFDI) method. On average, in comparison with 3D-SFDI method, the 3D-SSOP method allows to recover the profile within 1.2mm and profile-corrected optical properties within 12% for absorption and 6% for reduced scattering over a large field-of-view and in real time. PMID- 26504654 TI - Passive BCI based on drowsiness detection: an fNIRS study. AB - We use functional near-infrared spectroscopy (fNIRS) to discriminate the alert and drowsy states for a passive brain-computer interface (BCI). The passive brain signals for the drowsy state are acquired from the prefrontal and dorsolateral prefrontal cortex. The experiment is performed on 13 healthy subjects using a driving simulator, and their brain activity is recorded using a continuous-wave fNIRS system. Linear discriminant analysis (LDA) is employed for training and testing, using the data from the prefrontal, left- and right-dorsolateral prefrontal regions. For classification, eight features are tested: mean oxyhemoglobin, mean deoxyhemoglobin, skewness, kurtosis, signal slope, number of peaks, sum of peaks, and signal peak, in 0~5, 0~10, and 0~15 second time windows, respectively. The results show that the best performance for classification is achieved using mean oxyhemoglobin, the signal peak, and the sum of peaks as features. The average accuracies in the right dorsolateral prefrontal cortex (83.1, 83.4 and 84.9% in the 0~5, 0~10 and 0~15 second time windows, respectively) show that the proposed method has an effective utility for detection of drowsiness for a passive BCI. PMID- 26504655 TI - Trapping and manipulation of microparticles using laser-induced convection currents and photophoresis. AB - In this work we demonstrate optical trapping and manipulation of microparticles suspended in water due to laser-induced convection currents. Convection currents are generated due to laser light absorption in an hydrogenated amorphous silicon (a:Si-H) thin film. The particles are dragged towards the beam's center by the convection currents (Stokes drag force) allowing trapping with powers as low as 0.8 mW. However, for powers >3 mW trapped particles form a ring around the beam due to two competing forces: Stokes drag and thermo-photophoretic forces. Additionally, we show that dynamic beam shaping can be used to trap and manipulate multiple particles by photophotophoresis without the need of lithographically created resistive heaters. PMID- 26504657 TI - Photophysical characterization of sickle cell disease hemoglobin by multi-photon microscopy. AB - The photophysical properties of human sickle cell disease (SCD) Hemoglobin (Hb) is characterized by multi-photon microscopy (MPM). The intrinsic two-photon excited fluorescence (TPEF) signal associated with extracted hemoglobin was investigated and the solidified SCD variant (HbS) was found to demonstrate broad emission peaking around 510 nm when excited at 800 nm. MPM is used to dynamically induce and image HbS gelling by photolysis of deoxygenated HbS. For comparison, photolysis conditions were applied to a healthy variant of human hemoglobin (HbA) and found to remain in solution not forming fibers. The use of this signal to study the mechanism of HbS polymerization associated with the sickling of SCD erythrocytes is discussed. PMID- 26504656 TI - Optical monitoring of stress-related changes in the brain tissues and vessels associated with hemorrhagic stroke in newborn rats. AB - Stress is a major factor for a risk of cerebrovascular catastrophes. Studying of mechanisms underlying stress-related brain-injures in neonates is crucial for development of strategy to prevent of neonatal stroke. Here, using a model of sound-stress-induced intracranial hemorrhages in newborn rats and optical methods, we found that cerebral veins are more sensitive to the deleterious effect of stress than arteries and microvessels. The development of venous insufficiency with decreased blood outflow from the brain accompanied by hypoxia, reduction of complexity of venous blood flow and high production of beta-arrestin 1 are possible mechanisms responsible for a risk of neonatal hemorrhagic stroke. PMID- 26504658 TI - Rhodamine B as an optical thermometer in cells focally exposed to infrared laser light or nanosecond pulsed electric fields. AB - The temperature-dependent fluorescence property of Rhodamine B was used to measure changes in temperature at the cellular level induced by either infrared laser light exposure or high intensity, ultrashort pulsed electric fields. The thermal impact of these stimuli were demonstrated at the cellular level in time and contrasted with the change in temperature observed in the extracellular bath. The method takes advantage of the temperature sensitivity of the fluorescent dye Rhodamine B which has a quantum yield linearly dependent on temperature. The thermal effects of different temporal pulse applications of infrared laser light exposure and of nanosecond pulsed electric fields were investigated. The temperature increase due to the application of nanosecond pulsed electric fields was demonstrated at the cellular level. PMID- 26504659 TI - Performance characterization of low-cost, high-speed, portable pulsed laser diode photoacoustic tomography (PLD-PAT) system. AB - Photoacoustic tomography systems that uses Q-switched Nd:YAG/OPO pulsed lasers are expensive, bulky, and hence limits its use in clinical applications. The low pulse repetition rate of these lasers makes it unsuitable for real-time imaging when used with single-element ultrasound detector. In this work, we present a pulsed laser diode photoacoustic tomography (PLD-PAT) system that integrates a compact PLD inside a single-detector circular scanning geometry. We compared its performance against the traditional Nd:YAG/OPO based PAT system in terms of imaging depth, resolution, imaging time etc. The PLD provides near-infrared pulses at ~803 nm wavelength with pulse energy ~1.4 mJ/pulse at 7 kHz repetition rate. The PLD-PAT system is capable of providing 2D image in scan time as small as 3 sec with a signal-to-noise ratio ~30. High-speed and deep-tissue imaging is demonstrated on phantoms and biological samples. The PLD-PAT system is inexpensive, portable, allows high-speed PAT imaging, and its performance is as good as traditional expensive OPO based PAT system. Therefore, it holds promises for future translational biomedical imaging applications. PMID- 26504660 TI - Minimizing projection artifacts for accurate presentation of choroidal neovascularization in OCT micro-angiography. AB - Current optical coherence tomography (OCT) based micro-angiography is prone to a projection (or tailing) effect due to the high scattering property of blood within overlying patent vessels, creating artifacts that interfere with the interpretation of retinal angiographic results. In this work, the projection effect in OCT micro-angiography is examined and its causality is explained by strong light scattering and photon propagation within blood. A simple practical approach is then introduced to minimize these artifacts presented in the outer retinal avascular space, especially useful for examining clinical cases with choroidal neovascularization (CNV). Demonstrated through in-vivo human posterior eye imaging of healthy and CNV subjects, the proposed method is shown effective to eliminate the projection artifacts in outer retinal space of OCT micro angiography, resulting in better visualization of the pathological neovascularization when compared with the current common approaches. In addition, it is also shown that the proposed method is applicable to minimize the projection artifacts appearing in deep retinal layers. PMID- 26504661 TI - Photonic non-contact estimation of blood lactate level. AB - The ability to measure the blood lactate level in a non-invasive, non-contact manner is very appealing to the sports industry as well as the home care field. That is mainly because this substance level is an imperative parameter in the course of devolving a personal workout programs. Moreover, the blood lactate level is also a pivotal means in estimation of muscles' performance capability. In this manuscript we propose an optical non-contact approach to estimate the concentration level of this parameter. Firstly, we introduce the connection between the physiological muscle tremor and the lactate blood levels. Secondly, we suggest a photonic optical method to estimate the physiological tremor. Lastly, we present the results of tests conducted to establish proof of concept to this connection. PMID- 26504662 TI - Optical clearing based cellular-level 3D visualization of intact lymph node cortex. AB - Lymph node (LN) is an important immune organ that controls adaptive immune responses against foreign pathogens and abnormal cells. To facilitate efficient immune function, LN has highly organized 3D cellular structures, vascular and lymphatic system. Unfortunately, conventional histological analysis relying on thin-sliced tissue has limitations in 3D cellular analysis due to structural disruption and tissue loss in the processes of fixation and tissue slicing. Optical sectioning confocal microscopy has been utilized to analyze 3D structure of intact LN tissue without physical tissue slicing. However, light scattering within biological tissues limits the imaging depth only to superficial portion of LN cortex. Recently, optical clearing techniques have shown enhancement of imaging depth in various biological tissues, but their efficacy for LN are remained to be investigated. In this work, we established optical clearing procedure for LN and achieved 3D volumetric visualization of the whole cortex of LN. More than 4 times improvement in imaging depth was confirmed by using LN obtained from H2B-GFP/actin-DsRed double reporter transgenic mouse. With adoptive transfer of GFP expressing B cells and DsRed expressing T cells and fluorescent vascular labeling by anti-CD31 and anti-LYVE-1 antibody conjugates, we successfully visualized major cellular-level structures such as T-cell zone, B cell follicle and germinal center. Further, we visualized the GFP expressing metastatic melanoma cell colony, vasculature and lymphatic vessels in the LN cortex. PMID- 26504663 TI - Elucidating the temporal dynamics of optical birefringence changes in crustacean nerves. AB - Intrinsic optical properties, such as optical birefringence, may serve as a tool for minimally invasive neuroimaging methods with high spatiotemporal resolution to aid in the study of neuronal activation patterns. To facilitate imaging neuronal activity by sensing dynamic birefringence, temporal characteristics behind the signal must be better understood. We have developed a novel nerve chamber to investigate changes in birefringence at the stimulation site, and at distances ~4-28 mm from that site. Using crustacean nerves with either heterogeneous or homogeneous size distributions of axon diameters, we found that the gradual (slow) recovery of the crossed-polarized signal is not explained by the arrival times of action potentials in smaller axons. Through studying the effects of stimulating current and voltage pulses, we hypothesize that the recovery may be caused by a capacitive-like coupling between firing axons and adjacent tissue structures, and we report data consistent with this hypothesis. This study will aid in the utilization of action-potential-related changes in birefringence to study fast changes in neuronal network activity. PMID- 26504664 TI - Intraoperative measurement of bowel oxygen saturation using a multispectral imaging laparoscope. AB - Intraoperative monitoring of tissue oxygen saturation (StO2 ) has potentially important applications in procedures such as organ transplantation or colorectal surgery, where successful reperfusion affects the viability and integrity of repaired tissues. In this paper a liquid crystal tuneable filter-based multispectral imaging (MSI) laparoscope is described. Motion-induced image misalignments are reduced, using feature-based registration, before regression of the tissue reflectance spectra to calculate relative quantities of oxy- and deoxyhaemoglobin. The laparoscope was validated in vivo, during porcine abdominal surgery, by making parallel MSI and blood gas measurements of the small bowel vasculature. Ischaemic conditions were induced by local occlusion of the mesenteric arcade and monitored using the system. The MSI laparoscope was capable of measuring StO2 over a wide range (30-100%) with a temporal error of +/- 7.5%. The imager showed sensitivity to spatial changes in StO2 during dynamic local occlusions, as well as tracking the recovery of tissues post-occlusion. PMID- 26504665 TI - Endoscopic Doppler optical coherence tomography and autofluorescence imaging of peripheral pulmonary nodules and vasculature. AB - We present the first endoscopic Doppler optical coherence tomography and co registered autofluorescence imaging (DOCT-AFI) of peripheral pulmonary nodules and vascular networks in vivo using a small 0.9 mm diameter catheter. Using exemplary images from volumetric data sets collected from 31 patients during flexible bronchoscopy, we demonstrate how DOCT and AFI offer complementary information that may increase the ability to locate and characterize pulmonary nodules. AFI offers a sensitive visual presentation for the rapid identification of suspicious airway sites, while co-registered OCT provides detailed structural information to assess the airway morphology. We demonstrate the ability of AFI to visualize vascular networks in vivo and validate this finding using Doppler and structural OCT. Given the advantages of higher resolution, smaller probe size, and ability to visualize vasculature, DOCT-AFI has the potential to increase diagnostic accuracy and minimize bleeding to guide biopsy of pulmonary nodules compared to radial endobronchial ultrasound, the current standard of care. PMID- 26504666 TI - Dynamics of the near response under natural viewing conditions with an open-view sensor. AB - We have studied the temporal dynamics of the near response (accommodation, convergence and pupil constriction) in healthy subjects when accommodation was performed under natural binocular and monocular viewing conditions. A binocular open-view multi-sensor based on an invisible infrared Hartmann-Shack sensor was used for non-invasive measurements of both eyes simultaneously in real time at 25Hz. Response times for each process under different conditions were measured. The accommodative responses for binocular vision were faster than for monocular conditions. When one eye was blocked, accommodation and convergence were triggered simultaneously and synchronized, despite the fact that no retinal disparity was available. We found that upon the onset of the near target, the unblocked eye rapidly changes its line of sight to fix it on the stimulus while the blocked eye moves in the same direction, producing the equivalent to a saccade, but then converges to the (blocked) target in synchrony with accommodation. This open-view instrument could be further used for additional experiments with other tasks and conditions. PMID- 26504667 TI - Management of Neuroacanthocytosis Syndromes. AB - BACKGROUND: The two core neuroacanthocytosis (NA) syndromes, chorea acanthocytosis (ChAc) and McLeod syndrome, are progressive neurodegenerative disorders that primarily affect the basal ganglia. The characteristic phenotype comprises a variety of movement disorders including chorea, dystonia, and parkinsonism, as well as psychiatric and cognitive symptoms attributable to basal ganglia dysfunction. These disorders are symptomatically managed on a case-by case basis, with very few practitioners seeing more than a single case in their careers. METHODS: A literature search was performed on PubMed utilizing the terms neuroacanthocytosis, chorea-acanthocytosis, and McLeod syndrome, and articles were reviewed for mentions of therapies, successful or otherwise. RESULTS: There have been no blinded, controlled trials and only one retrospective case series describing ChAc. The various therapies that have been used in patients with NA syndromes are summarized. DISCUSSION: Management remains at present purely symptomatic, which is similar in principle to other more common basal ganglia neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). However, there are some specific issues particular to NA syndromes that merit attention. An integrated multidisciplinary approach is the ideal management strategy for these complex and multifaceted neurodegenerative disorders. PMID- 26504668 TI - Susceptibility of Snails to Infection with Schistosomes is influenced by Temperature and Expression of Heat Shock Proteins. AB - The freshwater snail, Biomphalaria glabrata is the obligate intermediate host for the transmission of the parasitic trematode, Schistosoma mansoni the causative agent of the chronic debilitating neglected tropical disease, schistosomiasis. We showed previously that in juvenile snails, early and significant induction of stress manifested by the expression of stress proteins, Hsp 70, Hsp 90 and reverse transcriptase (RT) of the non- LTR retrotransposon, nimbus, is a characteristic feature of juvenile susceptible NMRI but not resistant BS-90 snails. These latter, however, could be rendered susceptible after mild heat shock at 32 degrees C, revealing that resistance in the BS-90 resistant snail to schistosomes is a temperature dependent trait. Here we tested the hypothesis that maintenance of BS-90 resistant snails at the permissive temperature for several generations affects the resistance phenotype displayed at the non-permissive temperature of 25 degrees C. The progeny of BS-90 snails bred and maintained through several generations (F1 to F4) at 32 degrees C were susceptible to the schistosome infection when returned to room temperature, shedding cercariae at four weeks post-infection. Moreover, the study of expression levels of the heat shock protein (Hsp) 70 protein by ELISA and western blot analysis, showed that this protein is also differentially expressed between susceptible and resistant snails, with susceptible snails expressing more protein than their resistant counterparts after early exposure to wild-type but not to radiation-attenuated miracidia. These data suggested that in the face of global warming, the ability to sustain a reduction in schistosomiasis by using refractory snails as a strategy to block transmission of the disease might prove challenging since non lethal elevation in temperature, affects snail susceptibility to S. mansoni. PMID- 26504669 TI - Targeted activation of melanoma differentiation-associated protein 5 (MDA5) for immunotherapy of pancreatic carcinoma. AB - The RIG-I-like helicase melanoma differentiation-associated protein 5 (MDA5) is an innate immune receptor for double-stranded viral RNA (dsRNA) that, upon activation, induces a Type I interferon (IFN)-driven immune response. In the present study, we demonstrate that human und murine pancreatic cancer cells express functional MDA5 and are highly sensitive to MDA5-induced cell death. Activation of MDA5 by cytosolic delivery of the synthetic dsRNA analog poly(I:C) led to phosphorylation of the transcription factor IRF3, IFNbeta production and upregulation of MHC-I expression. MDA5 signaling also induced tumor cell apoptosis via the intrinsic pathway and sensitized tumor cells toward extrinsic, Fas-mediated apoptosis. Systemic treatment of orthotopic pancreatic cancer bearing mice with the MDA5 ligand resulted in activated CD8+ T cell tumor infiltration, an increased frequency of tumor antigen-specific CD8+ T cells and an immunogenic cytokine milieu in the tumor microenvironment. These effects were paralleled by MDA5-induced pronounced tumor cell death in situ and significantly prolonged survival in two different mouse models for pancreatic cancer, an immunotherapeutic response dependent on CD8+ T cells. Treated mice were further protected from subsequent tumor challenge. In summary, we identified MDA5 as a novel therapeutic target for overcoming apoptosis resistance and tumor-mediated immunosuppression in pancreatic cancer. MDA5 ligands link innate with adaptive immune mechanisms for effective tumor control. PMID- 26504670 TI - beta3-adrenoreceptor and tumor microenvironment: a new hub. AB - The achievement of malignant traits in several cancers is associated with tumor microenvironment reactivity. New evidence show that the stress hormone noradrenaline enhances melanoma microenvironment reactivity, mainly acting through beta3-adrenoreceptors (beta2-ARs), favoring recruitment of cancer associated fibroblasts, M2-macrophages, bone marrow-derived precursors, These events concur in sustaining a pro-inflammatory and pro-angiogenic milieu, finally boosting melanoma malignancy. PMID- 26504671 TI - Documenting Nursing and Medical Students' Stereotypes about Hispanic and American Indian Patients. AB - OBJECTIVE: Hispanic Americans and American Indians face significant health disparities compared with White Americans. Research suggests that stereotyping of minority patients by members of the medical community is an important antecedent of race and ethnicity-based health disparities. This work has primarily focused on physicians' perceptions, however, and little research has examined the stereotypes healthcare personnel associate with Hispanic and American Indian patients. The present study assesses: 1) the health-related stereotypes both nursing and medical students hold about Hispanic and American Indian patients, and 2) nursing and medical students' motivation to treat Hispanic and American Indian patients in an unbiased manner. DESIGN: Participants completed a questionnaire assessing their awareness of stereotypes that healthcare professionals associate with Hispanic and American Indian patients then completed measures of their motivation to treat Hispanics and American Indians in an unbiased manner. RESULTS: Despite being highly motivated to treat Hispanic and American Indian individuals fairly, the majority of participants reported awareness of stereotypes associating these patient groups with noncompliance, risky health behavior, and difficulty understanding and/or communicating health related information. CONCLUSION: This research provides direct evidence for negative health-related stereotypes associated with two understudied minority patient groups-Hispanics and American Indians-among both nursing and medical personnel. PMID- 26504672 TI - Attentional Control and Suppressing Negative Thought Intrusions in Pathological Worry. AB - Adaptive behavior relies on the ability to effectively and efficiently ignore irrelevant information, an important component of attentional control. The current research found that fundamental difficulties in ignoring irrelevant material are related to dispositional differences in trait propensity to worry, suggesting a core deficit in attentional control in high worriers. The degree of deficit in attentional control correlated with the degree of difficulty in suppressing negative thought intrusions in a worry assessment task. A cognitive training procedure utilizing a flanker task was used in an attempt to improve attentional control. Although the cognitive training was largely ineffective, improvements in attentional control were associated with improvements in the ability to suppress worry-related thought intrusions. Across two studies, the findings indicate that the inability to control worry-related negative thought intrusions is associated with a general deficiency in attentional control. PMID- 26504673 TI - Alcohol and Emotional Contagion: An Examination of the Spreading of Smiles in Male and Female Drinking Groups. AB - Researchers have hypothesized that men gain greater reward from alcohol than women. However, alcohol-administration studies testing participants drinking alone have offered weak support for this hypothesis. Research suggests that social processes may be implicated in gender differences in drinking patterns. We examined the impact of gender and alcohol on "emotional contagion"-a social mechanism central to bonding and cohesion. Social drinkers (360 male, 360 female) consumed alcohol, placebo, or control beverages in groups of three. Social interactions were video recorded, and both Duchenne and non-Duchenne smiling were continuously coded using the Facial Action Coding System. Results revealed that Duchenne smiling (but not non-Duchenne smiling) contagion correlated with self reported reward and typical drinking patterns. Importantly, Duchenne smiles were significantly less "infectious" among sober male versus female groups, and alcohol eliminated these gender differences in smiling contagion. Findings identify new directions for research exploring social-reward processes in the etiology of alcohol problems. PMID- 26504674 TI - Negative Social Evaluative Fears Produce Social Anxiety, Food Intake, and Body Dissatisfaction: Evidence of Similar Mechanisms through Different Pathways. AB - Social anxiety and eating disorders are highly comorbid, suggesting there are shared vulnerabilities that underlie the development of these disorders. Two proposed vulnerabilities are fear of negative evaluation and social appearance anxiety (i.e., fear of negative evaluation regarding one's appearance). In the current experimental study (N=160 women) we measured these fears: (a) through a manipulation comparing fear conditions, (b) with trait fears, and (c) state fears. Results indicated that participants in the fear of negative evaluation condition increased food consumption, whereas participants in the social appearance anxiety condition and high in trait social appearance anxiety experienced the highest amounts of body dissatisfaction. Participants in the fear of evaluation and social appearance anxiety conditions experienced elevated social anxiety. These results support the idea that negative evaluation fears are shared vulnerabilities for eating and social anxiety disorders, but that the way these variables exert their effects may lead to disorder specific behaviors. PMID- 26504675 TI - Mechanisms of Selective Attention in Generalized Anxiety Disorder. AB - A well-established literature has identified different selective attentional orienting mechanisms underlying anxiety-related attentional bias, such as engagement and disengagement of attention. These mechanisms are thought to contribute to the onset and maintenance of anxiety disorders. However, conclusions to date have relied heavily on experimental work from subclinical samples. We therefore investigated individuals with diagnosed generalized anxiety disorder (GAD), healthy volunteers, and individuals with high trait anxiety (but not meeting GAD diagnostic criteria). Across two experiments we found faster disengagement from negative (angry and fearful) faces in GAD groups, an effect opposite to that expected on the basis of the subclinical literature. Together these data challenge current assumptions that we can generalize, to those with GAD, the pattern of selective attentional orienting to threat found in subclinical groups. We suggest a decisive two-stage experiment identifying stimuli of primary salience in GAD, then using these to reexamine orienting mechanisms across groups. PMID- 26504678 TI - Characterization and transferability of microsatellite markers developed for Carpinus betulus (Betulaceae)(1). AB - PREMISE OF THE STUDY: Carpinus betulus (Betulaceae) is an octoploid, ecologically important, common tree species in European woodlands. We established 11 nuclear microsatellite loci allowing for detailed analyses of genetic diversity and structure. METHODS AND RESULTS: A microsatellite-enriched library was used to develop primers for 11 microsatellite loci that revealed high allele numbers and genetic diversity in a preliminary study. CONCLUSIONS: All of the loci developed here are informative for C. betulus. In addition, the loci are transferable to several species within the genus, and almost all loci cross-amplified in species of different genera of the Betulaceae. PMID- 26504677 TI - A strategy to recover a high-quality, complete plastid sequence from low-coverage whole-genome sequencing. AB - PREMISE OF THE STUDY: We developed a bioinformatic strategy to recover and assemble a chloroplast genome using data derived from low-coverage 454 GS FLX/Roche whole-genome sequencing. METHODS: A comparative genomics approach was applied to obtain the complete chloroplast genome from a weedy biotype of rice from Uruguay. We also applied appropriate filters to discriminate reads representing novel DNA transfer events between the chloroplast and nuclear genomes. RESULTS: From a set of 295,159 reads (96 Mb data), we assembled the chloroplast genome into two contigs. This weedy rice was classified based on 23 polymorphic regions identified by comparison with reference chloroplast genomes. We detected recent and past events of genetic material transfer between the chloroplast and nuclear genomes and estimated their occurrence frequency. DISCUSSION: We obtained a high-quality complete chloroplast genome sequence from low-coverage sequencing data. Intergenome DNA transfer appears to be more frequent than previously thought. PMID- 26504676 TI - The Promise of Neurotechnology in Clinical Translational Science. AB - Neurotechnology is broadly defined as a set of devices used to understand neural processes and applications that can potentially facilitate the brain's ability to repair itself. In the past decade, an increasingly explicit understanding of basic biological mechanisms of brain-related illnesses has produced applications that allow a direct yet noninvasive method to index and manipulate the functioning of the human nervous system. Clinical scientists are poised to apply this technology to assess, treat, and better understand complex socioemotional processes that underlie many forms of psychopathology. In this review, we describe the potential benefits and hurdles, both technical and methodological, of neurotechnology in the context of clinical dysfunction. We also offer a framework for developing and evaluating neurotechnologies that is intended to expedite progress at the nexus of clinical science and neural interface designs by providing a comprehensive vocabulary to describe the necessary features of neurotechnology in the clinic. PMID- 26504679 TI - Isolation and characterization of microsatellite loci in Rehmannia glutinosa (Scrophulariaceae), a medicinal herb. AB - PREMISE OF THE STUDY: Rehmannia glutinosa (Scrophulariaceae) is used in traditional Chinese medicine. Microsatellite primers were developed and characterized for this species to evaluate its genetic diversity and population genetic structure. METHODS AND RESULTS: Sixteen microsatellite loci were isolated from R. glutinosa using an enriched genomic library, and these markers were characterized in two wild populations of this species. The number of alleles per locus ranged from two to 20. A high genetic diversity was observed in two populations, with average observed heterozygosity of 0.812 and 0.794, and average expected heterozygosity of 0.802 and 0.814, respectively. CONCLUSIONS: Rehmannia glutinosa is an important medicinal resource. The genetic markers described in our study will be useful for future population genetic studies and molecular breeding programs on this species. PMID- 26504680 TI - Isolation of nuclear microsatellites in the African timber tree Lophira alata (Ochnaceae) and cross-amplification in L. lanceolata. AB - PREMISE OF THE STUDY: Microsatellite markers were isolated in the rainforest tree Lophira alata (Ochnaceae), an important timber tree from Central Africa, and cross-amplified on its savannah counterpart, L. lanceolata. METHODS AND RESULTS: From a microsatellite-enriched library sequenced on a 454 GS FLX platform, 13 primer combinations were identified. Amplification was optimized in two multiplex reactions. The primers amplified di- and trinucelotide repeats, with two to seven alleles per locus. Eleven primers also amplified in L. lanceolata. CONCLUSIONS: Microsatellite primers developed for the genus Lophira displayed sufficient variation to investigate hybridization between congeneric species in the rainforest-savannah transition. PMID- 26504681 TI - Development and characterization of 25 microsatellite primers for Ilex chinensis (Aquifoliaceae). AB - PREMISE OF THE STUDY: To evaluate genetic variation and structure of Ilex chinensis (Aquifoliaceae), a dioecious evergreen tree, we developed 25 microsatellite markers from its nuclear genome. METHODS AND RESULTS: Based on the biotin-streptavidin capture method, 10 polymorphic and 15 monomorphic microsatellite markers were developed. Ten polymorphic loci were characterized by 87 individuals sampled from three populations located in Zhejiang Province and Shanghai, China. The number of alleles per locus varied from two to 12. The observed and expected heterozygosities were 0.0435-0.9032 and 0.3121-0.8343, respectively. CONCLUSIONS: These microsatellite markers can be useful for further genetic studies of I. chinensis populations, and so contribute to forest restoration and management. PMID- 26504682 TI - Characterization of 12 polymorphic SSR markers in Veronica subsect. Pentasepalae (Plantaginaceae) and cross-amplification in 10 other subgenera. AB - PREMISE OF THE STUDY: Microsatellite primers were developed in the perennial herbs of the diploid-polyploid complex Veronica subsect. Pentasepalae (Plantaginaceae) to investigate the role that hybridization has played in the evolution of the group, which includes several endangered species. METHODS AND RESULTS: Twelve pairs of primers leading to polymorphic and readable markers were identified and optimized from V. jacquinii and V. orbiculata using a microsatellite-enriched library method and 454 GS-FLX technique. The set of primers amplified dinucleotide to pentanucleotide repeats, and the number of alleles per locus ranged from one to six, one to 11, and one to nine for V. orsiniana, V. javalambrensis, and V. rosea, respectively. Transferability analyses were performed in 20 species corresponding to 10 different subgenera. CONCLUSIONS: These results indicate the utility of the newly developed microsatellites across Veronica subsect. Pentasepalae, which will help in the study of gene flow patterns and genetic structure. PMID- 26504683 TI - Isolation and characterization of microsatellite markers for Jasminum sambac (Oleaceae) using Illumina shotgun sequencing. AB - PREMISE OF THE STUDY: Microsatellite markers of Jasminum sambac (Oleaceae) were isolated to investigate wild germplasm resources and provide markers for breeding. METHODS AND RESULTS: Illumina sequencing was used to isolate microsatellite markers from the transcriptome of J. sambac. A total of 1322 microsatellites were identified from 49,772 assembled unigenes. One hundred primer pairs were randomly selected to verify primer amplification efficiency. Out of these tested primer pairs, 31 were successfully amplified: 18 primer pairs yielded a single allele, seven exhibited fixed heterozygosity with two alleles, and only six displayed polymorphisms. CONCLUSIONS: This study obtained the first set of microsatellite markers for J. sambac, which will be helpful for the assessment of wild germplasm resources and the development of molecular marker assisted breeding. PMID- 26504684 TI - A new technique to prepare hard fruits and seeds for anatomical studies. AB - PREMISE OF THE STUDY: A novel preparation technique was developed to examine fruits and seeds of plants with exceptionally hard or brittle tissues that are very difficult to prepare using standard histological techniques. METHODS AND RESULTS: The method introduced here was modified from a technique employed on fossil material and has been adapted for use on fruits and seeds of extant plants. A variety of fruits and seeds have been prepared with great success, and the technique will be useful for any excessively hard fruits or seeds that are not able to be prepared using traditional embedding or sectioning methods. CONCLUSIONS: When compared to existing techniques for obtaining anatomical features of fruits and seeds, the protocol described here has the potential to create high-quality thin sections of materials that are not able to be sectioned using traditional histological techniques, which can be produced quickly and without the need for harmful chemicals. PMID- 26504685 TI - GMS Interdisciplinary Plastic and Reconstructive Surgery DGPW. PMID- 26504686 TI - Traumatic diaphragmatic ruptures: clinical presentation, diagnosis and surgical approach in adults. AB - OBJECTIVE: Traumatic diaphragmatic injuries are rare, but potentially life threatening due to herniation of abdominal organs into the pleural cavities. They can be easily overlooked on initial diagnostics and a high index of suspicion is required. The aim of this retrospective study was to analyze the clinical presentation, diagnostic methods and surgical management of patients with diaphragmatic rupture at our institution. METHODS: A retrospective study was performed to analyze our experience with patients suffering from traumatic diaphragmatic rupture. Charts were reviewed for sex, age, side-location, concomitant injuries, time-to-diagnosis, diagnostic methods, surgical approach and outcome. RESULTS: Fourteen patients (median age: 46 yrs, range 18-71, 9 male, 5 female) with diaphragmatic injuries (left side: 10, right side: 4) were treated between July 2003 and September 2011. Mechanism of injury was a penetrating trauma (14%), blunt trauma (50%) and others (36%). Associated abdominal injuries included spleen rupture (n=3), liver laceration (n=2), abdominal wall laceration (n=2) and gastric perforation (n=1). Computed tomography was the most sensitive diagnostic method. All patients underwent trans-abdominal repair of the diaphragmatic defect (direct suture: 10, prosthetic mesh insertion: 4). Associated abdominal procedures included splenectomy (n=3), liver packing (n=2), abdominal wall reconstruction (n=2) and partial gastric resection (n=1). Morbidity and hospital mortality rate were 36% and 0%, respectively. Median postoperative hospital stay was 17 days (range: 7-40 days). CONCLUSION: Morbidity and mortality of diaphragmatic ruptures are mainly determined by associated injuries or complications of diaphragmatic herniation like incarceration of viscera or lung failure. Early diagnosis helps to prevent severe complications. Spiral CT-scan is the most reliable tool for acute diagnosis of diaphragmatic rupture and associated visceral lacerations. Laparotomy is an adequate surgical approach for diaphragmatic repair, especially in cases of associated abdominal organ injury. PMID- 26504687 TI - Gynecomastia in German soldiers: etiology and pathology. AB - BACKGROUND: We found a high incidence of patients with gynecomastia in the German Ministry of Defense Guard Battalion in Berlin. For this reason, we conducted the present study to investigate etiological and pathological aspects of this condition. METHODS: Within six years, a total of 211 patients underwent surgery for gynecomastia. We compared this group of patients with a control group of healthy males without signs or symptoms of gynecomastia. The two groups were matched for median age. RESULTS: The groups showed significant differences (p<0.05) in serum testosterone, free triiodothyronine (fT3), LH (luteinizing hormone) and prolactin levels and in body mass index (BMI). In addition, there was a highly significant correlation between left-sided gynecomastia and membership in the Guard Battalion. CONCLUSIONS: We found differences in hormone blood levels between gynecomastia patients and a control group. Moreover, gynecomastia was predominantly seen on the left side in guard soldiers. A possible explanation is the mechanical impact of the carbine against the left side of the body during rifle drills. PMID- 26504688 TI - Primary cutaneous adenoid carcinoma of the scalp. AB - Primary adenoid carcinoma are rare skin tumors. We present a 75-year-old female with this primary cutaneous tumor of the scalp with additional bone involvement. Wide scalp excision with bone enclosure, latissimus-dorsi-free-flap defect overage, and subsequent radiation slowed down the disease but could not prevent further skull infiltration. PMID- 26504689 TI - Panniculus, giant hernias and surgical problems in patients with morbid obesity. AB - Prevalence of morbid obesity is rising. Along with it, the adipose associated co morbidities increase - included panniculus morbidus, the end stage of obesity of the abdominal wall. In the course of time panniculus often develop a herniation of bowel. An incarcerated hernia and acute exacerbation of a chronic inflammation of the panniculus must be treated immediately and presents a surgical challenge. The resection of such massive abdominal panniculus presents several technical problems to the surgeon. Preparation of long standing or fixed hernias may require demanding adhesiolysis. The wound created is huge and difficult to manage, and accompanied by considerable complications at the outset. We provide a comprehensive overview of a possible approach for panniculectomy and hernia repair and overlook of the existing literature. PMID- 26504690 TI - The role of Nesbit's procedure in surgical reconstruction of penile deviation. AB - OBJECTIVE: We review our results after surgical reconstruction with the Nesbit's procedure for congenital or acquired penile deviation. PATIENTS AND METHODS: Etiology of penile deviation, surgical outcome for straightening the penis, postoperative patient satisfaction and clinical findings were evaluated for 5 patients undergoing Nesbit's procedure followed by a Medline review of contemporary literature regarding alternative surgical techniques. Follow-up included clinical examination, self-photography on erection and a standardized interview with erectile dysfunction assessment using IIEF-5 questionnaire. RESULTS: Overall patient satisfaction was 100% in two patients, 2 patients were partly satisfied and 1 patient reported no satisfaction because of severe penile shortening with insufficiency for sexual intercourse postoperatively. Preoperative mean angulation of the penis was 42 degrees . Four patients had Peyronie's disease and 1 patient's curvature resulted from an untreated penile fracture during sexual intercourse. CONCLUSION: The Nesbit technique can give satisfactory results for mild and moderate penile curvature. However, each technique for the reconstruction of penile deviation has its own advantages and disadvantages. Therefore proper patient selection has a major impact on further outcome. PMID- 26504691 TI - The pediculated gastrocnemius muscle flap as a treatment for soft tissue problems of the knee - indication, placement and results. AB - With the increase of endoprosthetic knee replacements, there is also an increase of critical wounds to the knee due to a high incidence of soft tissue problems (ranging from wound healing defects to severe wound infections). The literature describes a general rate of soft tissue complications of up to 20% [1], [2], with 5% [3] involving exposed bone. These complications are an increasingly important problem for surgeons. Since sufficient coverage of bones, tendons and prosthetic material with soft tissue is a necessity, the use of a pediculated muscle flap is the only solution in some cases. The gastrocnemius muscle is very useful for this purpose. It is an elaborate procedure which is associated with a high rate of complications. However, this procedure can establish a secure coverage with soft tissue, and the function of the prosthesis and the patient's extremity can be saved. We have treated 23 patients with a gastrocnemius rotation flap after knee prosthesis or knee arthrodesis infection with consecutive soft tissue damage at our hospital from 8/2004 through 3/2011. The overall rate of healing of the knee infections with stable soft tissue status is almost 87%. The revision rate with lifting of the flap and revision of the sutures at the point of insertion as well as the point of extraction was about 35% with long-term conservative or additional surgical treatments. PMID- 26504692 TI - Wound irrigation within the surgical treatment of osteomyelitis. AB - The basic treatment of osteomyelitis remains even today the surgical debridement in combination with a wound irrigation by lavage systems. Next to a comprehensive knowledge of the surgical techniques a profound knowledge of the lavage systems, the rinsing solutions used and the philosophies of revision programs are a must. In this article the typical hardware of modern lavage systems is analysed, their advantages and disadvantages are pointed out. In addition we investigate the value of common antiseptic wound irrigation solutions for their use in osteomyelitis therapy. Finally the two basic philosophies of wound revision and irrigation in the course of osteomyelitis therapy are presented and discussed. PMID- 26504693 TI - Plastic and reconstructive uterus operations by minimally invasive surgery? A review on myomectomy. AB - BACKGROUND: Plastic and reconstructive uterus operations are performed in congenital uterine anomalies or benign uterine conditions. Congenital uterine anomalies are relatively rare diseases with various approaches for surgical treatment. Therefore, to address the question of the usefulness of a minimally invasive approach in plastic uterus operations, the most common uterine condition which requires reconstructive surgery, namely myomectomy, is discussed. METHOD: Searches were conducted in PubMed and The Cochrane Library to identify relevant literature. FINDINGS: Compared with myomectomy by laparotomy and minilaparotomy, laparoscopic myomectomy is associated with improved short-term outcomes. Laparoscopy is further associated with less adhesion formation. Pregnancy rates after myomectomy in symptomatic patients might be higher after laparoscopy than after laparotomy. Although uterine ruptures following laparoscopic myomectomy are described in the literature, it seems to be a rare event. Concerning the recurrence, there is evidence that rates are similar after laparoscopy and laparotomy. CONCLUSION: Myomectomy by laparoscopy has several advantages over abdominal myomectomy (by conventional laparotomy and minilaparotomy) and should be the standard procedure. Despite the advantages of laparoscopy, abdominal myomectomy is still a frequently performed procedure. Lack of training in advanced laparoscopic procedures hampers the wide-spread use of laparoscopic myomectomy. Due to the advantages of laparoscopic surgery, efforts should be made to implement this procedure into daily practice. To provide the best care, physicians should offer patients the opportunity of a laparoscopic treatment of myomas. PMID- 26504694 TI - Differentiated surgical treatment of rectovaginal fistulae. AB - OBJECTIVE: Rectovaginal fistulae (RVF) are a serious and debilitating problem for patients and a challenge for the treating surgeons. We present our experiences in the surgical treatment of these patients. METHODS: Study population consisted of 22 consecutive patients (range 26-70 years) with RVF treated in our department between 2003 and 2009. 13 RVF were observed after colorectal or gynaecological surgery, 3 occurred after radiotherapy, 2 due to tumour infiltration, 4 because of local inflammation (3x diverticultis, 1x ulcus simplex recti). The RVF was classified in all patients before treatment as either 'low' or 'high'. RESULTS: Local procedures (transvaginal excision, preanal repair) as initial treatment were performed in 9 patients with low fistula. In 13 cases with high fistula an abdominal approach was performed to close the fistula. A recurrence was observed in 8/22 cases (36%), which were treated by a gracilis flap (n=2), a bulbospongiosus composite (n=1), a second abdominal approach (n=4), and a re local excision (n=1). Ultimatively, in 19 cases the defect healed but in 3 patients the RVF persisted. CONCLUSIONS: Most important predictor of healing/failure is etiology followed by localization and recurrence of the RVF. Local (preanal, transvaginal) procedures are suitable for low RVF, whereas abdominal surgery is necessary in high RVF. In recurrent RVF, muscle flaps are promising procedures. PMID- 26504695 TI - Adult calcaneal osteitis: incidence, etiology, diagnostics and therapy. AB - Calcaneal osteomyelitis presents a complicated situation. The specific anatomy of the os calcis and its surrounding soft tissues plays an important role in the planning and realization of the procedures needed in order to eradicate the osteomyelitic focus. The calcaneus represents a spongious bone; a fact that supports the developement of an osteomyelitis. It is the strongest bone of the foot and is highly important for the biomechanical features of physiological walking. The surrounding soft tissues are thin and contain various important anatomical structures. These might be damaged during the treatment of the osteomyelitis. In addition the vascularization of the os calcis is delicate and may be compromized during the surgical osteomyelitis treatment. Calcaneus osteomyelitis may be classified based on the routes of infection into exogenous and endogenous forms. Additionally from the clinical point of view acute and chronic forms may be distinguished from an early and a late infection. Exogenous calcaneal osteomyelitis mostly is the result of an infection with S. aureus. The treatment is equal to the therapy in other locations and based on: Eradication of the bone infectionSanitation of the soft tissue infectionReconstruction of bone and soft tissue Especially the preservation and restoration of the soft tissue is important. Thus plastic surgical procedures play an essential role. The main object of treatment is the preservation of a biomechanical functioning foot. This may be impossible due to the local situation. Calcanectomy or even below knee amputation may be needed in those cases. PMID- 26504696 TI - Laparoscopic splenectomy of a wandering spleen with coincidental enormous splenomegaly. AB - Ectopy of the spleen also referred to as wandering spleen is a rare condition and preferentially treated by laparoscopic splenopexy. However, in complicated cases with torsion and consecutive infarction of the spleen splenectomy is required. Performing the splenectomy of a wandering spleen laparoscopically has already been reported as a save therapeutic option. However, open splenectomy is usually preferred in case of massive splenomegaly for both, wandering and regular localized spleen. In this case report we describe a laparoscopic technique as alternative for conventional splenectomy in the case of a huge wandering spleen. PMID- 26504697 TI - One stage rescue procedure after capsular contracture of breast implants with autologous fat grafts collected by water assisted liposuction ("BEAULI Method"). AB - With increasing number of patients with silicone implants for breast augmentation or reconstruction we are confronted with more and more cases of capsular contracture. Not every case is resolved by resection of the capsule and exchange of implants. Many patients rather bear the consequences of severe fibrosis than to have their implants removed. The one stage procedure of implant removal and lipofilling proved to be highly efficient with good to excellent results and high patient satisfaction. Between January 2008 and October 2012 a total of 64 patients (124 breasts) with capsular fibrosis Baker III to IV were treated with autologous fat grafts collected with the body-jet((r)) by water-assisted liposuction ("BEAULI Method"). Magnetic resonance imaging (MRI) of the breasts was performed in 5 patients preoperatively and 6 month postoperatively, a clinical examination and photo documentation of all patients was done on day 1 and after 4 weeks, 12 weeks and 6 months postoperatively. The procedure included implant removal and lipofilling of the subcutaneous and intramuscular space in a single procedure by means of the BEAULI Method. The average gross amount of grafted fat was 260 ml. The average drainage time was one day. The shape of the breast changed to a more natural and ptotic form. Negative side effects like oily cysts or infections were not observed. The time of the overall procedure including liposuction was 70+/-15 min. Reoccurring capsular contracture is one of the hazards in plastic surgery. Until now the treatment of choice after more than two failed implant changes combined with resection of the capsule is usually the final removal of implants with or without possible additional autologous tissue transfer (microvascular flaps). We could add a relatively simple and efficient procedure to resolve and improve those cases by autologous fat transfer using water-assisted liposuction and the BEAULI Method. PMID- 26504699 TI - Knee arthrodesis - ultima ratio for the treatment of the infected knee. AB - The irretrievable destruction of the knee due to trauma, tumor or infection is the indication for knee arthrodesis. The main reason for knee arthrodesis in terms of infection ist the infected total knee arthroplasty. Central problem is the definition of the term "irretrievable". It is based on the subjective opinion of the attending physician and depends on his expert knowledge of this specific entity. The preservation of a functioning extremity is the main goal. This article shows the typical indications and contraindications for knee arthrodesis following septic knee diseases. In addition it gives insight into the biomechanical and technical considerations to be kept in mind. Finally the postoperative care and outcome of different techniques are analysed. PMID- 26504698 TI - Current concepts of ocular adnexal surgery. AB - Ophthalmic Plastic and Reconstructive Surgery is a specialized area of ophthalmology that deals with the management of deformities and abnormalities of the eyelids, lacrimal system and the orbit. An ophthalmoplastic surgeon is able to identify and correct abnormalities of the ocular adnexae such as ectropion, lid retraction, conjunctival scarring with severe entropion, that can cause secondary ocular surface disorders; manage patients with watering eye, and when needed intervene with a dacryocystorhinostomy by external or endonasal approach and moreover minimize disfigurement following enucleation or evisceration and prevent further corneal damage, alleviate complains of tearing and grittiness, but also cosmetic complaints in patients with Graves' orbitopathy. Aim of this manuscript was to review current established and recently evolving surgical procedures. PMID- 26504700 TI - Laparoscopic intraperitoneal mesh fixation with fibrin sealant of a Spigelian hernia. AB - Spigelian hernia is a rare clinical entity and has a subtle clinical presentation with vague abdominal pain, which can cause an important delay in diagnosis. Given the relatively high risk of incarceration the diagnosis of Spigelian hernia is an indication for surgical repair. Laparoscopic Spigelian mesh herniorraphy has gained recognition as an effective tension-free method and is associated with lower recurrence. Appropriate fixation techniques are however required to reduce complications such as nerve irritation, hematoma, and postoperative chronic pain. In this case report we describe a novel approach in laparoscopic mesh repair of Spigelian hernia, securing a lightweight composite mesh with fibrin sealant. This fixation seems to be a reasonable, feasible alternative to the standard tissue penetrating mesh fixation. PMID- 26504701 TI - BMP-2 shows characteristic extracellular patterns in osteoarthritic cartilage: a preliminary report. AB - To determine bone morphogenetic protein (BMP)-2 protein and Aggrecan in osteoarthritic and healthy cartilage with special regard to localization and degree of cartilage damage 95 samples representing osteoarthritic cartilage and 17 samples out of normal cartilage were graded histological by Mankin Score and were studied by immunohistochemistry for the expression of BMP-2 and Aggrecan. BMP-2 protein was detected intracellular in normal and in osteoarthritic cartilage. Extracellular BMP-2 was detected exclusively in osteoarthritic cartilage and exhibits characteristic extracellular patterns: samples with BMP-2 in the extracellular matrix show BMP-2 negative coronae around BMP-2 positive cells. There is a statistically significant increase in the prevalence of extracellular BMP-2 with increasing ICRS grade/Mankin grade. Aggrecan was detected in the extracellular matrix und exhibited coronas throughout all layers. A decline of extracellular Aggrecan with increasing ICRS grade could be observed. Normal cartilage shows no intracellular Aggrecan whereas an increase in the prevalence of intracellular Aggrecan could be detected in osteoarthritic cartilage. The appearance of intracellular Aggrecan is often associated with extracellular BMP-2. The detection of BMP-2 protein in normal as well as in osteoarthritic cartilage highlights the importance of BMP-2 in tissue homeostasis and point to a putative role for maintaining tissue integrity during the development of osteoarthritis. The co-appearance of extracellular BMP-2 and intracellular Aggrecan indicates a functional relationship. The most interesting result is the characteristic distribution of extracellular BMP-2. These coronas seem to have an impact during progression of osteoarthritis and need to be further investigated. PMID- 26504702 TI - Reconstructive laparoscopic prolapse surgery to avoid mesh erosions. AB - INTRODUCTION: The objective of the study is to examine the efficacy of the purely laparoscopic reconstructive management of cystocele and rectocele with mesh, to avoid the risk of erosion by the graft material, a well known complication in vaginal mesh surgery. MATERIAL AND METHODS: We performed a prospective, single case, non-randomized study in 325 patients who received laparoscopic reconstructive management of pelvic organe prolaps with mesh. The study was conducted between January 2004 and December 2012 in a private clinic in India. The most common prolapse symptoms were reducible vaginal lump, urinary stress incontinence, constipation and flatus incontinence, sexual dysfunction and dypareunia. The degree e of the prolaps was staged according to POPQ system. The approach was purely laparoscopic and involved the use of polypropylene (Prolene) or polyurethane with activated regenerated cellulose coating (Parietex) mesh. RESULTS: The mean age was 55 (30-80) years and the most of the patients were multiparous (272/325). The patients received a plastic correction of the rectocele only (138 cases), a cystocele and rectocele (187 cases) with mesh. 132 patients had a concomitant total hysterectomy; in 2 cases a laparoscopic supracervical hysterectomy was performed and 190 patients had a laparoscopic colposuspension. The mean operation time was 82.2 (60-210) minutes. The mean follow up was 3.4 (3-5) years. Urinary retention developed in 1 case, which required a new laparoscopical intervention. Bladder injury, observed in the same case was in one session closed with absorbable suture. There were four recurrences of the rectocele, receiving a posterior vaginal colporrhaphy. Erosions of the mesh were not reported or documented. CONCLUSION: The pure laparoscopic reconstructive management of the cystocele and rectocele with mesh seems to be a safe and effective surgical procedure potentially avoiding the risk of mesh erosions. PMID- 26504703 TI - Urgent resection of bleeding congenital mesenchymal chest wall hamartoma in an infant. AB - We report a case with prenatally diagnosed large cystic-solid mesenchymal chest wall hamartoma. An attempt of conservative management was made however repeated intralesional hemorrhage led to enlargement and severe anemia which required urgent resection at the age of 8 weeks. The infant had an unimpaired development over a follow-up of 4 years. PMID- 26504704 TI - Plastic end-to-end treatment of bulbar urethral stricture. AB - For bulbar urethral strictures up to 2.5 cm in length, the one-stage urethral plastic surgery with stricture excision and direct end-to-end anastomosis remains the best procedure to guarantee a high success rate. This retrospective review shows the results of 21 patients who underwent bulbar end-to-end anastomosis from 2010-2013. In 20 cases (95.3%) good results were archived. The criteria of success were identified by pre- and postoperative radiological diagnostics and uroflowmetry. PMID- 26504705 TI - A modified false vocal fold flap for functional reconstruction after frontolateral partial laryngectomy: a comparison with conventional open resection and laser cordectomy. AB - OBJECTIVE: To describe a modified flap technique (MFT) involving the use of a false vocal fold flap for glottic reconstruction and the removal of arytenoid cartilage and to compare it with conventional frontolateral partial laryngectomy (FLPL) and laser cordectomy (LC). METHODS: Twenty-eight MFT, 13 FLPL and 12 LC patients completed a standardised questionnaire for assessing aspiration, respiration, quality of life, and subjective voice quality. We analysed vocal function in terms of roughness, breathiness and hoarseness, measured voice range profiles, and performed videoendoscopy. RESULTS: No patient reported respiratory problems. Aspiration occurred in 33.3% (MFT), 41.6% (FLPL) and 16.6% (LC). Voice quality was rated as good/satisfactory by 17 MFT patients (62%), satisfactory/sufficient by 69% of FLKT patients, and sufficient/poor by 75% of LC patients. CONCLUSIONS: The modified false vocal fold flap effectively covers defects and creates a neocord that ensures good phonatory rehabilitation and has positive effects on postoperative quality of life. PMID- 26504706 TI - Quality improvement of fingerprints of decayed corpses by local thanatopractical processing (Thanatoprint). AB - Thanatopractical processing allows morphological reconstruction of even advanced decayed bodies. By extracting fluids from the body's tissue antemortem tenseness and volume can be restored. If bodies are partly subject to thanatopractical processing in the hand region ("Thanatoprint"), fingerprints of high quality can be gathered even in cases of advanced decay. Without this treatment fingerprinting can be extremely difficult, if not impossible. Thanatopractical processing could be applied successfully in cases of partial to subtotal detachment of the epidermis as well. In an interdisciplinary study 400 fingerprints of bodies in various states of decay were examined after application of Thanatoprint. In 76.75% fingerprints were applicable for data entry into AFIS (Automated Fingerprint Identification System); another 11.00% of the fingerprints could be used for the process of non-elimination. Further advantages of the method are low invasivity while maintaining the integrity of the corpse, less time- and material requirement as well as its long-lasting effect. PMID- 26504707 TI - The short stem GHEs in total hip replacement - experience after 380 implantations. AB - INTRODUCTION: Standard straight stems have been recognized as a gold standard implant in the field of hip replacement surgery. However, lately uncemented bone preserving short stems started to gain more and more popularity. This was reflected in the increasing variety of available models. Up till now, short and mid-term results are available. PATIENTS AND METHODS: In 2002, the cementless short stemmed GHEs was introduced. 380 patients were included in our study between 2002 and 2008. Only GHEs short stems were implanted. The clinical and radiological evaluations were performed in the Orthopaedic Department, Leipzig University Hospitals, on the average of 24 months (3 to 60 months) postoperatively. RESULTS: 365 primary implantations and 15 revision implantations were carried out. Average age 60 years. Favourable clinical and radiological outcome was seen in 361/380 patients (95%). Postoperative complications were seen in 19/380 patients (5%): 8 fissures/fractures (2.1%), 5 infections (1.3%), 4 aseptic loosenings (1.1%), 2 dislocations (0.5%). CONCLUSIONS: Short stem implants, including our own experience with GHEs model, are satisfying and promising. They represent a valuable supplementation of the treatment modalities in hip replacement surgery. However, long term results are still awaited. PMID- 26504708 TI - RANK-Ligand inhibitor associated osteonecrosis of the jaw. AB - Osteonecrosis of the jaw may be caused by many different triggers. One of them is described to be the drug or medication related osteonecrosis of the jaw. Since many years bisphosphonates induced the dreaded diagnosis. Recently a drug named denosumab is reported to show similar effects on the jaw. In this case report we present a RANK-Ligand inhibitor associated osteonecrosis of the lower jaw and discuss the lights and shadows of this newly introduced drug. PMID- 26504709 TI - External transpedicular spine fixation in severe spondylodiscitis - salvage procedure. AB - Specific and non-specific infections of the spine are rare. Due to their potential for severe instabilities, deformities and the impairment of neurological structures, the treatment is often prolonged and needs an interdisciplinary management. The clinical presentation is uncharacteristic, therefore diagnosis is often delayed. There are no prospective randomized studies for therapy recommendation. The surgical concept includes eradication of the infection and the reliable stabilization of involved segments. This concept is successful in most cases of endogenous vertebral osteomyelitis. The therapy of the exogenous spine infections after macro and micro surgery is more difficult, due to the critical wound situation and the involvement of the posterior parts of the spine. In these cases, infection-associated instability of the anterior part is complicated by critical posterior wound conditions. We present three cases of severe exogenous vertebral infections, where temporary external transpedicular spine fixation was used for salvage procedure, till soft tissue conditions have permitted a definitive internal stabilization. PMID- 26504710 TI - Ultrasonographically supported removal of foreign bodies of the eye lid and parapharyngeal space in a 13-year-old boy subjected to shot injuries in early childhood. AB - BACKGROUND: B-scan ultrasonography is widely used in diagnostics of head and neck pathologies. Ultrasonography can be applied intraoperatively to identify foreign materials. CASE REPORT: This case report describes the ultrasonographic identification of foreign bodies of the eye lid and parapharyngeal space in an adolescent who was injured several years ago, obviously a victim of domestic violence. B-scan ultrasonography (small part transducer, emission frequency: 7.5 MHz) proved to be a reliable tool to locate the foreign bodies. Ultrasound imaging facilitated the decision-making of the surgical approach and thus reduced the surgical exploration time. DISCUSSION: B-scan ultrasonography is a valuable tool in oral and maxillofacial surgery. The use of B-scan ultrasonography in the head neck region requires the capacity of the surgeon to fuse the ultrasonographic picture with the topography of the head and neck. The advantages and limitations of B-scan ultrasonography in the head and neck region concerning foreign body identification are briefly discussed. PMID- 26504711 TI - Improving the quality of life of parotid surgery patients through a modified facelift incision and great auricular nerve preservation. AB - Postoperative quality of life after parotidectomy depends not only on surgical outcomes, such as the complete removal of a tumour, non-recurrence and the preservation of facial nerve function, but also on scar satisfaction and the degree of sensory dysfunction in the upper cervical area and at the ear lobe. Especially young patients and women consider the scar in the infra-auricular area and in the neck region to be distressing and even disfiguring. Resection of the great auricular nerve leads to paraesthesia and hypoesthesia, which leads to discomfort in many patients especially when using the telephone, shaving or wearing earrings. A modified approach to the parotid gland via a facelift incision and the careful exposure of the great auricular nerve can reduce the aforementioned problems considerably and improve postoperative quality of life. We present our experiences with the modified approach at our institution. PMID- 26504712 TI - Diagnosis and treatment of extraabdominal desmoid fibromatosis. AB - INTRODUCTION: The desmoid fibromatosis is a very rare connective tissue disease which is recognized as semimalignant. The aim of this work is to review the relevant literature and to analyze the management of our patient collective. MATERIAL AND METHOD: Surgery was performed on 7 patients with extraabdominal desmoid fibromatosis between August 1998 and May 2007. MRI examination as well as biopsy was carried out in all cases. All patients were operated on; the mean follow up was 4 years (1-7). Upon follow up, every patient has undergone clinical and MRI examination. RESULTS: The results show that we have achieved R0 resection in 4 cases and R1 in two cases and Rx in one case. In 4 patients, no recurrence was observed after the single surgery performed in our hospital. In 2 patients a single revision surgery was performed in each case and yielded no further recurrence. In only one case, multiple surgeries (one primary and two revision surgeries) were necessary, after which no recurrence was reported. CONCLUSION: The early diagnosis of the disease is of utmost importance to the success of the outcome. MRI examination and biopsy are mandatory. Surgery is the therapy of choice. The recurrence rate is high and is linked to the difficulty of recognition of the exact infiltrative extent of the tumour. This necessitates a close follow-up. PMID- 26504713 TI - Complementary education for healthcare personnel: a strategy to increase hospital performance. AB - INTRODUCTION: The German healthcare system is facing ongoing radical change and development. The increasing tendency to urge hospitals and medical staff to work in a profit-oriented way constitute among other factors clear present and future challenges. Physicians and surgeons in particular increasingly complain of increasing stress attributed to measures aiming at cost reduction in hospitals. The highest priority must always be patient satisfaction and the delivery of good medical and human service. Problem description: The health care market in Germany has become an increasingly complex business with uncertain and unpredictable future events. Strategic planning has to enable hospitals to quickly and flexibly adapt strategies to changes in the environment that become essential to their success. The most important task is to develop a strategy that can be applied with success in all possible future scenarios. This is known as the core strategy. DISCUSSION: The core strategy for hospitals in Germany is complementary education of the medical staff as well as top management. Accordingly, courses, workshops or even part-time graduate or postgraduate education in business and economics are recommended for the medical staff. As far as non-medical hospital executives are concerned, there is no better way than to host them in a hospital department for a period of 6-12 months. This paves the way for understanding and accepting each others' opinion which increases hospital performance. CONCLUSION: Proper and complementary education of the medical staff as well as of non-medical top executives and managers of hospitals is recommended as the core strategy. This harmonizes both professional medical and managerial efforts with a synergy effect that allows soundly facing the increasingly challenging environment of the health care sector in general and in hospitals in particular. PMID- 26504714 TI - Can we still have a clear conscience, routinely offering vaginal mesh operations in plastic and reconstructive surgery of the pelvic organ prolapse? AB - INTRODUCTION: Since many years, plastic and reconstructive surgery in pelvic organ prolapse (POP) has been performed by vaginal mesh surgery. Although warnings from the scientific societies and the FDA have been published, vaginal mesh surgery still remains a routine treatment of genital prolapse in the female. BACKGROUND: Many third-degree referral centres in operative gynaecology found a high number of severe complications after mesh repair. Compared to the minor complications known from the classical non-mesh plastic and reconstructive surgery, there is a clear difference concerning the severity of complications. Additionally, mesh vaginal surgery was implemented in gynaecological prolapse operations because of the relatively high recurrence rate in classical vaginal surgery without implants; no major studies however have revealed a lower long term recurrence rate with mesh vaginal techniques. DISCUSSION: As the recurrence rate could not be lowered evaluating the meta-analysis of the published scientific studies, the higher rate of severe complications should emphasise the fact that the risk of vaginal mesh surgery is too high for these techniques to be implemented in the surgical work of a routine gynaecological operative department. CONCLUSION: Vaginal mesh surgery can no longer be a primary plastic and reconstructive therapy of pelvic organ prolapse in a routine gynaecological operative setting and department, due to the high rate of severe complications. PMID- 26504715 TI - Centro-lateral subperiosteal vertical midface lift. AB - The use of fiberendoscopic video-assisted technique in facial rejuvenation is one of the most advances in aesthetic plastic surgery of the face. It substitutes the coronal incision without the necessity of skin resection and allows a vertical reposition of the mobile soft tissue of the midface in indicated cases. It can easily be done through a small incision of the scalp just behind the coronal incision and in the temporal area. PMID- 26504716 TI - Paraffinoma of lips and oral mucosa: Case report and brief review of the literature. AB - Interstitial application of paraffin in plastic and reconstructive surgery is obsolete due to the development of permanent and extensive foreign body granulomas at the site of application. These granulomas can cause severe physical impairment and develop their own prognostic worth. Furthermore, the disperse oil droplets are not a locally stable suspension. Therefore, the desired aesthetic aspect can get lost in the course of a potential dislocation of the suspension. In addition, the interstitial confluence of non-resorbable droplets to larger oil drops causes palpable and sometimes visible indurations of the skin, the correlate of chronic inflammation. This case report describes the efforts undertaken to release the patient at least temporarily from her paraffin granulomas and to improve her appearance. The relevant literature is briefly discussed. Furthermore, we present some immunohistochemical findings to specify the foreign body reaction associated with paraffin injections into connective tissues. PMID- 26504717 TI - Nasal meatus plasty: a contribution to plastic reconstruction of the nasal valve during midfacial degloving. AB - Midfacial degloving is a proven method for easily accessing the midface, the nasal pyramid, the maxillary and ethmoidal sinuses, the orbits, as well as the anterior skull base. Indications for this method of access mainly include tumour resections in the area of the midface, the septum, the maxillary sinus, the paranasal to the sphenoidal sinus as well as the clivus. In addition, this method of access allows for the exposure of the bony structures of the midface in the event of extensive fractures. In general, this method of access combines an incision in the oral vestibule and circular incisions in the nasal vestibule area in order to release the nasal pyramid. After removing the facial wall of the maxillary sinus, extensive exposure of the surgical site is possible. One disadvantage of this method of access is the difficult reconstruction of the nasal valve area, which often leads to cicatricial stenoses and difficulties with breathing through the nose. Furthermore, wound healing problems and osteoradionecrosis in the area of the lateral margin of the anterior nasal aperture after replantation of the facial wall of the maxillary sinus have been described, because in this area sufficient soft tissue coverage cannot be ensured when a conventional technique is used. We describe a soft tissue flap pedicled in the cranial and caudal directions in the nasal valve area which makes both the reconstruction of the nasal vestibule and sufficient soft tissue coverage of the anterior nasal aperture possible. PMID- 26504718 TI - The history of the management of sternal osteomyelitis and mediastinitis - from Hippocrates until today. AB - Even during the time of Hippocrates, Galen and their colleagues recognized mediastinal affections. However, they were not considered with the surgical treatment. First progress in the treatment options of this severe disease, still denoted as 'terra incognita', over to today's gold standard are pictured. The mediastinitis-registry which was founded by the German Society for Thoracic and Cardiovascular Surgery (DGTHG) in 2011 and the recent establishment of the study group to adopt a guideline 'diagnosis and therapy of postoperative mediastinitis/sternal osteomyelitis following cardiac surgery' are attempts to a standardization of the treatment. Substantial advancement in the treatment of postoperative mediastinitis could be achieved in the past. The mortality dropped as low as less than 10%. With these implementations more benefit for the patients' outcome can be expected. PMID- 26504719 TI - Histopathological Osteomyelitis Evaluation Score (HOES) - an innovative approach to histopathological diagnostics and scoring of osteomyelitis. AB - BACKGROUND: Treatment and diagnosis of osteomyelitis are still a challenging problem for surgeons, microbiologists and histopathologists. A direct microbiological detection of bacteria in tissues is still gold standard, but it is not always successful for example in chronic osteomyelitis and/or when an antibiotic treatment has already been started or in cases of low virulent bacteria. The goal of this study was to define diagnostic criteria of osteomyelitis, the inflammatory regression of osteomyelitis ("osteomyelitis score") under specific therapy by the correlation of histopathological and microbiological and clinical standard tests. METHODS: In this retrospective analysis patients with medical history and clinically clear signs of bacterial infection and osteomyelitis underwent surgery between 01.01.2013 and 31.12.2012. Their formal consent was given. Tissue samples were taken during surgery according to defined criteria including surgical interventions. Histopathological diagnosis was carried out by conventional techniques based on defined criteria of bacterial infection in connective tissue, peri-implant membrane and bone. These results were carried out in tables by numbers representing the histopathological criteria of acute osteomyelitis (A1 to A3) as well as the chronic criteria (C1 and C2) in a semiquantitative way (scale 0 to 3). On the other hand a notational, graduated histopathological report was performed. Preoperative clinical diagnosis, perioperative macroscopic diagnosis, histopathological and microbiological findings were correlated. RESULTS: Histopathological samples of 52 surgical interventions based on the preoperative diagnosis "osteomyelitis" (AOM, ECOM or COM) were included. 37 times preoperatively signs of a chronic osteomyelitis (COM), 10 times preoperatively acute osteomyelitis (AOM) was diagnosed. Another 5 patients were preoperatively diagnosed as acute exacerbated osteomyelitis (ECOM). The correlation of the histopathological infection including the inflammatory activity and microbiological detection of bacteria was 57%. The correlation between preoperative diagnosis and histopathological findings was 68%. CONCLUSION: The relatively small 68% correlation between clinical preoperative and histopathological diagnosis and 57% correlation between preoperative clinical diagnosis and microbiological findings indicates: Clinical findings are not sufficient for the diagnosis "osteomyelitis".Clinical findings are not sufficient for the differentiation between AOM, ECOM and COM.Histopathological analysis is the critical factor for the diagnosis ("osteomyelitis") and differential diagnosis (AOM vs. COM).Histopathological analysis represents the basis for further treatment.HOES facilitates the classification of the histopathological findings.HOES is a sufficient tool for the treating physician in order to define the further treatment. PMID- 26504720 TI - Massive gastric dilatation caused by eating binges demanding surgical intervention: a case report. AB - The clinical picture of an acute abdomen is frequently encountered in emergency medicine. In most cases abdominal pathologies underlie this condition, however, also extra-abdominal diseases may present or cause an acute abdomen. The fact that this condition is potentially life-threatening highlights the importance of instant action. Here, we report on the case of a young woman that presented with an acute abdomen in our clinic. Imaging revealed a massively distended stomach reaching the lesser pelvis. Initially, the etiology for the gastric dilatation remained unsolved. On the same day we performed an explorative laparotomy in which massive amounts of clotted, undigested food was recovered via a gastrotomy. Postoperatively, upon psychiatric consultation, an eating disorder with daily eating binges could be revealed as being the cause for the acute and dramatic gastric dilatation. The patient fully recovered from surgery and psychiatric co treatment was initiated. This unique case report demonstrates how a psychiatric condition may lead to an acute abdomen, however, it also emphasizes the importance of prompt diagnosis and adequate therapy to avoid complications and allowing for full recovery. PMID- 26504721 TI - Treatment of scaphoid waist fractures with the HCS screw. AB - The aim of the study was to evaluate the clinical results of the Headless Compression Screw (HCS, Synthes) when used for treatment of acute scaphoid waist fractures. The new screw design generates interfragmentary compression with use of a compression sleeve. Twenty-one patients were treated for acute scaphoid waist fractures type B2 with HCS screws. The average time to the final follow-up examination was 12.8 months. All 21 fractures united after a mean time of 7.2 weeks. The mean DASH score was 7.1. The average motion of the wrist in extension was 61 degrees , flexion was 46 degrees , radial abduction reached 25 degrees and the ulnar abduction was 31 degrees . The maximally achieved grip strength was 86% compared to the uninjured side. Treatment of type B2 scaphoid fractures with the Headless Compression Screw showed good functional and radiographic results. The results are similar to those identified using other screw fixation systems. PMID- 26504722 TI - Concentration of platelets and growth factors in platelet-rich plasma from Goettingen minipigs. AB - In minipigs little is known about the concentration of growth factors in plasma, despite their major role in several patho-physiological processes such as healing of fractures. This prompted us to study the concentration of platelets and selected growth factors in plasma and platelet-rich plasma (PRP) preparation of sixteen Goettingen minipigs. Platelet concentrations increased significantly in PRP in comparison to native blood plasma. Generally, significant increase in the concentration of all growth factors tested was observed in the PRP in comparison to the corresponding plasma or serum. Five of the plasma samples examined contained detectable levels of bone morphogenic protein 2 (BMP-2) whereas eleven of the plasma or serum samples contained minimal amounts of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF-bb) respectively. On the other hand variable concentrations of bone morphogenic protein 7 (BMP-7) and transforming growth factor beta1 (TGF-beta1) were measured in all plasma samples. In contrast, all PRP samples contained significantly increased amounts of growth factors. The level of BMP-2, BMP-7, TGF-beta1, VEGF and PDGF-bb increased by 17.6, 1.5, 7.1, 7.2 and 103.3 fold, in comparison to the corresponding non-enriched preparations. Moreover significant positive correlations were found between platelet count and the concentrations of BMP-2 (r=0.62, p<0.001), TGF-beta1 (r=0.85, p<0.001), VEGF (r=0.46, p<0.01) and PDGF-bb (r=0.9, p<0.001). Our results demonstrate that selected growth factors are present in the platelet-rich plasma of minipigs which might thus serve as a source of autologous growth factors. PMID- 26504723 TI - Rhinophyma in tuberous sclerosis complex: case report with brief review of literature. AB - Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease characterized by the triad epilepsy, hamartomas (angiofibroma) and reduced intellectual capacity. Phenotype can vary considerably. Almost all patients with TSC have at least one characteristic dermatologic feature. Facial angiofibroma can cause severe disfigurement. It may involve the cheeks, perioral region and nose, resulting in thick layers of nodular and pustular skin. Aesthetic surgery of the face comprises an individually adapted ablation of the affected skin regions in order to improve physical appearance. Reports on the subject of surgery for nasal angiofibroma confirm the homogenous transformation of the connective tissues by this hamartoma. Hitherto there is only one report in the literature describing the typical epithelial alterations of the nasal skin compatible with a rhinophyma and adjacent angiofibroma. Here we report the successful electrosurgical treatment of a patient with TSC and extensive sebaceous glands giving rise to a rhinophyma in close association with angiofibroma. PMID- 26504724 TI - Efficacy risks of the minimal-invasive plastic and reconstructive neovagina Vecchietti technique in Mayer-Rokitansky-Kuster-Hauser syndrome. AB - INTRODUCTION: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a congenital disorder clinically defined by primary amenorrhea and infertility, congenital aplasia of the uterus and upper vagina. The patients with MRKH-syndrome have a female karyotype (46, XX), normally functioning ovaries and regular development of secondary sexual characters. Generally, the initial clinical sign of the syndrome is the failure to begin the menstrual cycle. Even though the psychological impact of the disease may be overwhelming, its physiological disorder can be successfully treated, after the surgical intervention the patients being able to have a normal sexual function. Reproduction may also be possible with assisted techniques. OBJECTIVE: The aim of the study was to evaluate the efficacy risks of the traditional laparoscopic Vecchietti method in the plastic and reconstructive treatment of vaginal agenesis, documenting complications, as well as anatomical and functional results by means of a prospective, single center, single arm study. MATERIAL AND METHODS: Between 2003 and 2011, 53 patients with MRKH-syndrome were treated in the gynecological clinic of the Kochi's Lakshmi Hospital, Kerala, India. All the patients suffered from primary amenorrhea and the karyotype was (46, XX). The clinical suspicion was confirmed sonographically and intraoperatively, showing an absent uterus or the presence of rudimentary uterine horns, with normal ovaries. All the patients received a plastic laparoscopic neovagina construction, in order to achieve a satisfactory sexual function. We adopted a combined strategy: the patients were prepared by a psychological counselling, followed by the surgical intervention and a postoperative follow-up. The surgical procedure used in this series was a laparoscopic modified Vecchietti's technique. All the patients were dismissed with the obligation to have intercourse and/or vaginal dilation 3 times a week for 6 months. RESULTS: The patients' ages varied between 13 and 40 years, with a mean age of 25 years. The mean operation time was 42.3 minutes, with a range between 36 and 63 minutes. In 2 cases, an intraoperative bladder injury occurred. A good qualitative vaginal tissue was clinically achieved in all the patients. The mean follow up period of the patients was 4 years ranging from 1 to 5 years. The anatomic success was observed in 94% of the cases and functional success in 79%. CONCLUSION: The anatomical failures in 6% were in women not having regular intercourse or not performing vaginal dilatation postoperatively. The psychological impact of the disease in combination with the performed surgery seems responsible for the difference of 15% of the cases where the anatomical result was good, but no regular intercourse could be achieved. The minimal invasive plastic and reconstructive neovagina Vecchietti technique in MRKH syndrome has a high success rate. In case of an intraoperative urinary bladder injury, the repair can be performed laparoscopically during the same session. Qualitatively good vaginal tissue and anatomical reconstruction can easily be achieved. In one patient desiring assisted reproductive medicine, a transvaginal oocyte retrieval was achieved. PMID- 26504725 TI - Antispastic therapy with botulinum toxin type A in patients with traumatic spinal cord lesion. AB - OBJECTIVES: The purpose of this study was to determine the effect of botulinum toxin injections for the treatment of spasticity after traumatic spinal cord injury. METHODS: 9 patients were included in this prospective designed study, with a follow-up of at least 2 years. All patients suffered from a massive spasticity after traumatic spinal cord lesion. Conservative treatment options did not show satisfying results. All patients were injected a maximal dose of 2,000 units of botulinum toxin A in no more than 6 skeletal muscle groups. Clinical control examinations were performed after 2 weeks and after at least 2 years. RESULTS: 6 patients reported a good or very good result. One patient offered increasing difficulty in walking for a short time after injection. 2 patients showed no beneficial effects. One patient experienced a modest temporary general weakness for 3 days. After 2 years, 3 patients showed improved function with persistent reduction of spasticity. In the other cases, the beneficial effect lasted for an average of 9 months. CONCLUSION: Botulinum toxin A injection seems to be an effective complementary therapy option in the treatment of spasticity of paraplegic patients with complete deficit of their motor function (ASIA A and B) and a spastic distribution pattern, effecting only a limited number of muscle groups. Caution has to be recommended for incomplete paretic patients, who are able to walk. PMID- 26504726 TI - Reconstructive surgery for male stress urinary incontinence: Experiences using the ATOMS((r)) system at a single center. AB - OBJECTIVE: To propose possible success-driven solutions for problem and complication rates encountered with the ATOMS((r)) sling system, based on first hand experience; and to provide possible actual alternative scenarios for the treatment of male stress urinary incontinence (SUI). PATIENTS AND METHODS: During the defined period (between 4/2010 and 04/2014), 36 patients received ATOMS((r)) system implants at our clinic. We collected pre- and post-operative evaluation data using the International Consultation on Incontinence Questionnaire Short Form (ICIQ SF). As an expansion of the questionnaire, we added questions about post-operative perineal pain, the general satisfaction with the results of the intervention and willingness to recommend the operation to a best friend. RESULTS: Our data shows a relatively high explantation rate, but a surprisingly high patient satisfaction rate. Explantation was required mainly due to late onset infections or other symptomatic factors. Compared to other studies early onset infections were rare. CONCLUSION: A non-invasive, uncomplicated adjustable system to alleviate male stress urinary incontinence remains a challenge. Although there are various systems available for the treatment of male stress urinary incontinence, it seems that despite the advantages of the ATOMS((r)) system, an artificial sphincter system may pose more advantages based on our experience, understanding and knowledge of its well-documented long-term solutions and problems. PMID- 26504727 TI - Chondroid hamartoma of the liver. AB - A 60-year-old patient presented with a solitary mass within the right hepatic lobe. Diagnostic imaging revealed a solid tumor on the diameter of 3 cm. In absence of any extrahepatic manifestation and based on FNAC findings the lesion was classisfied a primary hepatic chondroid sarcoma. However, after right hemihepatectomy histologic assessment resulted the final diagnosis of a benign chondroid hamartoma. Our findings add another variant to the versatile phenotype of liver hamartoma. PMID- 26504728 TI - Prone position in balloon kyphoplasty leads to no secondary vertebral compression fractures in osteoporotic spine - a MRI study. AB - PURPOSE: Vertebral compression fractures are the most common fractures in the elderly. Long lasting pain and deformity is responsible for consecutive impairment with markedly reduced life quality, increased morbidity and mortality. The beneficial effects of balloon kyphoplasty are verified in many studies. Subsequent fracture risk is not finally clarified, cement related risks and deformity related risks are discussed. There is less knowledge about the risk of bone marrow edema and new fractures during balloon kyphoplasty procedure. The goal of this study is to examine, if prone position during kyphoplasty is an independent risk factor for new fractures in the osteoporotic spine. METHODS: Consecutive MRI study of 20 patients with fresh, non-traumatic thoracolumbar vertebral compression fractures and balloon kyphoplasty treatment. MRI Scans of the thoracolumbar spine were obtained after surgery, before patients have been mobilized. Specific MRI changes like new bone marrow edema, signal intensity changes in adjacent and remote segments and new fractures were assessed by specialized neuro-radiologist. RESULTS: 20 MR images were examined within 48 hours after balloon kyphoplasty procedure. 85% did not show bone marrow edema extent changes after kyphoplasty. We found minor increase of bone marrow edema within the augmented vertebral body in 3 cases. We did not find any new bone marrow edema and no new fractures in adjacent and remote segments after balloon kyphoplasty treatment. CONCLUSION: Prone position leads to no new bone marrow edema and no new fractures in the osteoporotic spine. Accordingly, prone position has no risk for adjacent level fractures in osteoporotic spines. PMID- 26504729 TI - Subperiosteal preparation using a new piezoelectric device: a histological examination. AB - INTRODUCTION: Subperiosteal preparation using a periosteal elevator leads to disturbances of local immunohistochemistry and periosteal histology due to a microtrauma. Usually soft-tissue damage can be considerably reduced by using piezoelectric technology. For this reason, the effects of a novel piezoelectric device on immunohistochemistry and periosteal histology were examined and compared to conventional preparation of the periosteum using a periosteal elevator. MATERIAL AND METHODS: Lewis rats were randomly assigned to one of five groups (n=50). Subperiosteal preparation was performed using either a piezoelectric device or a periosteal elevator. Immunohistochemical and histological analyses were performed immediately after preparation as well as three and eight days postoperatively. A statistical analysis of the histological colouring was performed offline using analysis of variance (ANOVA) on ranks (p<0.05). RESULTS: At all times, immunohistochemical and histological analysis demonstrated a significantly more homogenous tissue structure in the group of rats that underwent piezosurgery than in the group of rats that underwent treatment with a periosteal elevator. CONCLUSION: The use of a piezoelectric device for subperiosteal preparation is associated with more harmonious immunohistochemical and histological results for the periosteum than the use of a conventional periosteal elevator. As a result, piezoelectric devices can be expected to have a positive effect primarily on soft tissue, in particular of the periosteal as well as on surrounding tissues. PMID- 26504730 TI - Free temporal fascia flap to cover soft tissue defects of the foot: a case report. AB - Severe soft tissue defects as a result of lye contamination remain a huge challenge in the interdisciplinary approach of trauma surgeons and plastic surgeons. Free tissue transfer is a suitable surgical option for successful reconstruction of form and function of defects in the distal parts of the lower extremities. We report the successful two-stage reconstruction of a full thickness lye contamination at the dorsum of the foot with a free temporoparietal fascia flap covered with a split-thickness skin graft from the thigh. The described method is a suitable operative alternative to anterolateral thigh flaps or other thin fascia flaps regarding flap harvest and donor site morbidity and should be considered in the portfolio of the plastic surgeon. PMID- 26504731 TI - Sinus pilonidalis in patients of German military hospitals: a review. AB - Pilonidal sinus disease (PSD) most commonly presents in young men when hair follicles enter through damaged epithelium and cause an inflammatory reaction. This results in the formation of fistular tracts. We reviewed studies based on a shared cohort of patients who presented at German military hospitals with PSD. The effect of the morphology of the sinus, perioperative protocol, and aftercare of the surgical treatment on the recurrence of PSD were evaluated. The drainage of acute abscesses before surgery, the application of methylene blue during surgery and open wound treatment were generally found to reduce the recurrence rate. A positive family history, postoperative epilation and primary suture as the healing method were found to elevate the recurrence rate. Long-term follow up of over 15 years was found to be a vital component of patient care as only 60% of the overall recurrences recorded had taken place by year 5 postoperatively. PMID- 26504732 TI - Perioperative management of patients with severe pulmonary hypertension in major orthopedic surgery: experience-based recommendations. AB - INTRODUCTION: It is known that pulmonary hypertension is associated with worse outcome in both cardiac and non-cardiac surgery. The aims of our retrospective analysis were to evaluate the outcomes of our patients with pulmonary hypertension undergoing major orthopedic surgery and to give experience-based recommendations for the perioperative management. MATERIAL AND METHODS: From 92 patients with pulmonary hypertension undergoing different kinds of surgical procedures from 2011-2014 in a tertiary academic hospital we evaluated 16 patients with major orthopedic surgery for perioperative morbidity and mortality. RESULTS: Regarding the in-hospital morbidity and mortality, one patient died postoperatively due to pulmonary infection and right heart failure (6.25%) and 6 patients suffered significant postoperative complications (37.5%; bleeding = 1, infection = 1, wound healing deficits = 3; dysrhythmia = 1). CONCLUSION: Our data show that major orthopedic surgery is feasible with satisfactory outcome even in cases of severe pulmonary hypertension by an individualized, disease-adapted interdisciplinary treatment concept. PMID- 26504733 TI - Intracorporeal knotting of a femoral nerve catheter. AB - Peripheral nerve catheters are effective and well-established tools to provide postoperative analgesia to patients undergoing orthopedic surgery. The performance of these techniques is usually considered safe. However, placement of nerve catheters may be associated with a considerable number of side effects and major complications have repeatedly been published. In this work, we report on a patient who underwent total knee replacement with spinal anesthesia and preoperative insertion of femoral and sciatic nerve catheters for postoperative analgesia. During insertion of the femoral catheter, significant resistance was encountered upon retracting the catheter. This occurred due to knotting of the catheter. The catheter had to be removed by operative intervention which has to be considered a major complication. The postoperative course was uneventful. The principles for removal of entrapped peripheral catheters are not well established, may differ from those for neuroaxial catheters, and range from cautious manipulation up to surgical intervention. PMID- 26504734 TI - Free anterolateral thigh flaps for upper extremity soft tissue reconstruction. AB - INTRODUCTION: Limb-threatening wounds of the upper extremity pose a challenge to the micro vascular surgeon. The aim of this study is to analyze the outcome of free anterolateral thigh flaps for upper extremity soft tissue reconstruction. METHODS: A retrospective review of patients undergoing this procedure from 2005 to 2012 was performed. Case note analysis was performed to determine demographic and perioperative factors, and complications and outcomes. RESULTS: Thirty-two patients with a mean age of 53 years (9-84 yrs) underwent upper extremity reconstruction with an anterolateral thigh (ALT) flap. There were 24 (75%) males and 8 (25%) females. The etiology of the soft tissue defects was: infection (44.6%); post-tumor ablation (40%); and trauma (15.6%). The defect site was most commonly in the forearm (53.1%), followed by the elbow (12.5 %), arm (12.5%) and hand (21.9%). The mean timing of free flap transfer was 6.8 days after admission to our institution (minimum 1 days, maximum 9 days). Mean operative time of surgery was 4 h 39 min (minimum 3 h 2 min, maximum 6 h 20 min). The mean hospitalization was 24.8 days (minimum 5, maximum 85). The ALT success rate was at 92.3%. Partial flap necrosis was documented in five cases (15.6%). Complete flap loss occurred in two post-traumatic cases who both lost their limbs. DISCUSSION: This flap, in the hands of experienced surgeons, provides reliable coverage of upper extremity defects. PMID- 26504735 TI - Management strategies in hospitals: scenario planning. AB - BACKGROUND: Instead of waiting for challenges to confront hospital management, doctors and managers should act in advance to optimize and sustain value-based health. This work highlights the importance of scenario planning in hospitals, proposes an elaborated definition of the stakeholders of a hospital and defines the influence factors to which hospitals are exposed to. METHODOLOGY: Based on literature analysis as well as on personal interviews with stakeholders we propose an elaborated definition of stakeholders and designed a questionnaire that integrated the following influence factors, which have relevant impact on hospital management: political/legal, economic, social, technological and environmental forces. These influence factors are examined to develop the so called critical uncertainties. Thorough identification of uncertainties was based on a "Stakeholder Feedback". RESULTS: Two key uncertainties were identified and considered in this study: the development of workload for the medical staff the profit oriented performance of the medical staff. According to the developed scenarios, complementary education of the medical staff as well as of non-medical top executives and managers of hospitals was the recommended core strategy. Complementary scenario-specific strategic options should be considered whenever needed to optimize dealing with a specific future development of the health care environment. CONCLUSION: Strategic planning in hospitals is essential to ensure sustainable success. It considers multiple situations and integrates internal and external insights and perspectives in addition to identifying weak signals and "blind spots". This flows into a sound planning for multiple strategic options. It is a state of the art tool that allows dealing with the increasing challenges facing hospital management. PMID- 26504737 TI - Angiogenesis, cell differentiation and cell survival in tissue engineering and cancer research. AB - Recent medical advances lead to a growing demand for tissue engineering and regenerative medicine in the future. Tissue engineering and regenerative medicine aim to create substitute tissue or restore lost or impaired tissue by combining biological science with engineering techniques, whereas cancer research faces the challenge to identify and hinder aberrant and uncontrolled cell growth. These two seemingly opposing fields of research share fundamental communalities. This review focuses on the shared underlying biological processes. Exploring these mechanisms of tissue growth and homeostasis from different angles will allow for creative novel approaches for both areas of research. PMID- 26504736 TI - A new variant of scaphoid reconstruction: Treatment of scaphoid non-union with avascular bone interponate and high compression screw (Synthes((r))). AB - Scaphoid fractures as frequently overseen injuries often result in scaphoid non unions, that need to be treated to prevent carpal collapse and secondary cartilage damage. Vital bone tissue and compression of fracture and bone graft ends seem to be crucial in for ossification and final bone healing. In the present study we compare our results using a high compression screw (HCS Synthes((r))) to results in the literature using different kinds of internal fixation including compression screws of various types. We present 22 patients with scaphoid non-unions treated with a bone graft and a HCS Synthes((r)). We evaluated our post-operative results. The Manchester-Modified Disability of the Shoulder, Arm and Hand-Score (M-Dash) imposed with an average of 29.8 points (MD=29 / SD=9.46 / MIN=18 / MAX=48). None of the re-evaluated patients sorrowed for pain in rest. Five patients stated pain (ranging from 4 to 8 on numeric analogue scale) after heavy burden (e.g. boxing, weight lifting).In exploring the range of motion of the operated hand we deliver the following results: dorsal extension: average 72.73 degrees (MD=80 degrees / SD=17.23 degrees / MIN=30 degrees / MAX=85 degrees ), flexion: average 73.64 degrees (MD=80 degrees / SD=8.97 degrees / MIN=60 degrees / MAX=80 degrees ), ulnar deviation: average 39.09 degrees , (MD=40 degrees / SD=2.02 degrees / MIN=35 degrees / MAX=40 degrees ), radial deviation: average 29.09 degrees , (MD=30 degrees / SD=3.01 degrees / MIN=20 degrees / MAX=30 degrees ). Additionally a performance testing was conducted: fist clenching sign: complete without pain in 100%, pinch grip: complete in 100%, moderate pain in n=1 (8.33%), opposition digitus manus I-V complete in 100%, moderate pain n=2 (16.67%). Three patients with persisting fracture gap had a scaphoid bone fractured in the proximal third; one patient even with a very small proximal fragment. One persisting non-union was localized in the middle third (period between injury and operation = 5 years). In conclusion, our patients showed better healing rates compared to results presented in the literature. Non-unions localized in the proximal third of the scaphoid did not seem to benefit using this technique. PMID- 26504738 TI - Comment on "Why and When 'Flawed' Social Network Analyses Still Yield Valid Tests of no Contagion". AB - VanderWeele et al.'s paper is a useful contribution to the on-going scientific conversation about the detection of contagion from purely observational data. It is especially helpful as a corrective to some of the more extreme statements of Lyons (2011). Unfortunately, this paper, too, goes too far in some places, and so needs some correction itself. PMID- 26504739 TI - A novel method to analyze 5-hydroxymethylcytosine in CpG sequences using maintenance DNA methyltransferase, DNMT1. AB - Hydroxymethylcytosine has been shown to be involved in DNA demethylation and gene expression. Although methods to determine the position of hydroxymethylcytosine at single-base resolution have been reported, these methods involve some difficulties. Here, we report a simple method to analyze hydroxymethylcytosine in the CpG sequence utilizing the maintenance DNA methylation activity of DNMT1, which selectively methylates hemi-methylated but not hemi-hydroxymethylated CpG sequences. The method enables monitoring of the dynamics of the hydroxymethylation state of a specific genome site. PMID- 26504740 TI - In vivo assay to monitor flavonoid uptake across plant cell membranes. AB - Flavonoids represent one of the most important molecules of plant secondary metabolism, playing many different biochemical and physiological roles. Although their essential role in plant life and human health has been elucidated by many studies, their subcellular transport and accumulation in plant tissues remains unclear. This is due to the absence of a convenient and simple method to monitor their transport. In the present work, we suggest an assay able to follow in vivo transport of quercetin, the most abundant flavonoid in plant tissues. This uptake was monitored using 2-aminoethoxydiphenyl borate (DPBA), a fluorescent probe, in non-pigmented Vitis vinifera cell cultures. PMID- 26504741 TI - FHL1 activates myostatin signalling in skeletal muscle and promotes atrophy. AB - Myostatin is a TGFbeta family ligand that reduces muscle mass. In cancer cells, TGFbeta signalling is increased by the protein FHL1. Consequently, FHL1 may promote signalling by myostatin. We therefore tested the ability of FHL1 to regulate myostatin function. FHL1 increased the myostatin activity on a SMAD reporter and increased myostatin dependent myotube wasting. In mice, independent expression of myostatin reduced fibre diameter whereas FHL1 increased fibre diameter, both consistent with previously identified effects of these proteins. However, co-expression of FHL1 and myostatin reduced fibre diameter to a greater extent than myostatin alone. Together, these data suggest that the expression of FHL1 may exacerbate muscle wasting under the appropriate conditions. PMID- 26504742 TI - Gastric Volvulus Following Left Pneumonectomy in an Adolescent Patient. AB - Gastric volvulus is a rare post-pneumonectomy complication. Although it has been described previously, published cases are limited to an older patient population. We report the youngest case of postpneumonectomy gastric volvulus to date, occurring in an 18-year-old male with a history of inflammatory myofibroblastic pseudotumor who underwent left intrapericardial pneumonectomy, and presented 13 years later with chronic intermittent mesenteroaxial gastric volvulus. While postpneumonectomy gastric volvulus is a rare occurrence, it should remain in the differential diagnosis in postoperative thoracic surgical patients presenting with chest pain. PMID- 26504743 TI - ATM rs189037 (G > A) polymorphism and risk of lung cancer and head and neck cancer: A meta-analysis. AB - A number of different epidemiological studies have measured the association between the risk of different cancers and polymorphism at promoter region of 5' untranslated region (5'-UTR) of the Ataxia-telangiectasia mutated (ATM) gene. However the results were contentious rather than conclusive. The current study was aimed at evaluating the association between the SNP (rs189037 G>A) and the risk of head and neck cancer and lung cancer by conducting a meta-analysis. A total of 9 case-control studies were considered for this quantitative analysis. Stats Direct Statistical software (version 2.7.2) was used to evaluate the crude odds ratio (OR) with their 95% confidence interval (CI). The dominant model (GG vs. GA + AA) showed no heterogeneity and the fixed effects pooled OR was found to be significant (OR = 1.14, 95% CI = 1.05-1.25) at p = 0.003. The pooled OR for fixed effects of heterozygote and homozygote mutant allele (GA vs. AA) model was significant (OR = 1.17, 95% CI = 1.04-1.30, p = 0.006) and no heterogeneity was observed for this model. The current meta-analysis manifested that ATM rs189037 G>A genetic polymorphism may contribute increased risk of head and neck and lung cancer. Moreover, the AA mutant allele was found to be related significantly with the prognosis of lung cancer and head and neck cancer. PMID- 26504744 TI - Frequency of rs731236 (Taql), rs2228570 (Fok1) of Vitamin-D Receptor (VDR) gene in Emirati healthy population. AB - Vitamin D is getting more attention everyday due to its importance in maintaining bone and calcium homeostasis, cellular proliferation, differentiation and immune response. Vitamin D is derived from diet or elicited in the skin by the activation of 7-dehydrocholesterol, which is an inert molecule that must be activated by ultraviolet light to form pre-vitamin D3. Recent studies connected the gene encoding for vitamin D (VDR) to the genetic control of bone mass and other diseases. As VDR SNPs have been associated with several disorders and diseases, it's important to investigate the allelic and genotypic distribution among populations. The aim of this study is to determine the frequency of rs731236 (Taq1) and rs2228570 (Fok1) variants in healthy Emirati individuals and compare their genotype and allele distribution with other populations. In this study 282 (female, 187; male, 95) unrelated healthy UAE nationals were involved. Two hundreds and eight two DNA samples been collected to genotype rs731236 (Taq1) and rs2228570 (Fok1) VDR SNPs. Our results indicate that the distribution of the alleles and genotypes of rs731236 (Taq1) and rs2228570 (Fok1) vary considerably in different populations. In the Emirati population the distribution of rs731236 (Taq1) and rs2228570 (Fok1) were AA 38%, AG 42%, GG 20% and AA 27%, AG 42%, GG 31% respectively. The Emirati population genotype and allele distribution of rs731236 (Taq1) and rs2228570 (Fok1) had no difference with Caucasians from USA and France. However, there was significant difference with Asian populations. PMID- 26504745 TI - TGF-beta1 gene - 509C > T promoter polymorphism modulates TGF-beta1 levels in hepatitis E patients. AB - Elevated levels of transforming growth factor-beta1 (TGF-beta1) and its positive correlation with Foxp3 expression in hepatitis E patients have indicated involvement of TGF-beta1 in hepatitis E pathogenesis. The current study determined polymorphisms in TGF-beta1 gene, plasma TGF-beta1 levels and T effector (Teff) cell proliferation and explored their association in a case control study. Polymorphisms in three selected sites (- 509C > T, + 869T > C and + 915G > C) of TGF-beta1 gene by PCR & restriction fragment length polymorphism methods, plasma TGF-beta1 quantitation by ELISA and Teff (CD4 + CD25 -) cell proliferation by CFSE method were carried out in 277 hepatitis E patients (HE) with self-limiting infection and 233 ethnically matched healthy controls (HCs) from western India. Frequency of CT genotype of - 509C > T site was significantly higher in hepatitis E patients compared to healthy controls (p = 0.017; OR 1.53, 95% CI 1.07-2.17). Plasma TGF-beta1 levels were significantly higher in HE compared to HCs. TGF-beta1 level of patient group having CT genotype of - 509C > T site was significantly higher compared to those having CC or TT genotypes. Teff cell proliferation was negatively correlated with plasma TGF-beta1 levels in HE patients (r = - 0.568; p = 0.014). Influence of TGF-beta1 promoter (- 509C > T) polymorphism on plasma TGF-beta1 levels and inverse correlation of Teff cell proliferation with plasma TGF-beta1 levels in self-limiting hepatitis E patients suggest key role of TGF-beta1 in augmentation of reported T regulatory cell mediated pathogenesis in hepatitis E. PMID- 26504746 TI - Association between glutathione S-transferase P1 Ile (105) Val gene polymorphism and chronic obstructive pulmonary disease: A meta-analysis based on seventeen case-control studies. AB - INTRODUCTION: Previous studies have shown that glutathione S-transferase P1 (GSTP1) was associated with chronic obstructive pulmonary disease (COPD). However, the association between GSTP1 Ile (105) Val gene polymorphism and COPD remains controversial. To drive a more precise estimation, we performed a meta analysis based on published case-control studies. METHODS: An electronic search of PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated (CNKI) Database for papers on GSTP1 Ile (105) Val gene polymorphism and COPD risk was performed. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the homozygote model, heterozygote model, dominant model, recessive model and an additive mode. Statistical heterogeneity, test of publication bias and sensitivity analysis was performed. The software STATA (Version 13.0) was used data analysis. RESULTS: Overall, seventeen studies with 1892 cases and 2012 controls were included in this meta-analysis. The GSTP1 Ile (105) Val polymorphism showed pooled odds ratios for the homozygote comparison (OR = 1.501, 95%CI [0.862, 2.614]), heterozygote comparison (OR = 0.924, 95%CI [0.733, 1.165]), dominant model (OR = 1.003, 95%CI [0.756, 1.331]), recessive model (OR = 1.510, 95%CI [0.934, 2.439]), and an additive model (OR = 1.072, 95%CI [0.822, 1.398]). CONCLUSIONS: In conclusion, the current meta-analysis, based on the most updated information, showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in any genetic models. The results of subgroup analysis also showed no significant association between GSTP1 Ile (105) Val gene polymorphism and COPD risk in Asian population and Caucasian population. Further studies involving large populations and careful control with age, sex, ethnicity, and cigarette smoking are greatly needed. PMID- 26504747 TI - Absence of somatic mutations of the mTOR gene in differentiated thyroid cancer. AB - Thyroid cancer is the most common endocrine malignancy with increasing incidence. Mammalian target of rapamycin (mTOR) is an important downstream mediator of phosphatidylinositol 3-kinase (PI3K/Akt) signaling and regulates cell growth, apoptosis and metabolism. The mTOR gene is frequently mutated in human cancers. Although PI3K/Akt pathway and its component genes were extensively studied in thyroid cancer, it is not known whether mTOR gene is somatically mutated and play a role in differentiated thyroid cancer (DTC). To determine the status of mTOR mutations in 53 DTC, we extensively examined 19 selected exons of mTOR gene which were reported to be frequently mutated in other human cancers. Unlike in other human cancers, we did not find common somatic mutations in the mTOR gene in differentiated thyroid cancer, except for some synonymous single nucleotide polymorphisms. Our results suggest that mTOR mutation is very rare and may not play a significant role in DTC. PMID- 26504748 TI - Efficacy of combination treatment modalities for intermediate and advanced hepatocellular carcinoma: intra-arterial therapies, sorafenib and novel small molecules. AB - Hepatocellular carcinoma (HCC) is a growing epidemic with a high mortality rate and clear need for improved therapies. In patients with Barcelona-Clinic Liver Cancer (BCLC) B and C, treatment with transarterial chemoembolization (TACE) has been the gold standard in therapy as it delays progression; however, recurrence proves common. In the US, transarterial bead embolization (TABE) has uniformly replaced TACE. With this limited armamentarium, there is need for a shift to novel strategies combining different modalities to further improve patient outcomes. Historically, HCC drug discovery concentrated on common features of HCC including its highly vascular nature and dependence on growth factors (GFs). The multikinase inhibitor sorafenib acts on angiogenesis via modulation of vascular endothelial GF expression and was the first step toward systemic targeted therapy against HCC. Sorafenib has provided clinicians with a tool to modestly improve survival by 2-6 months or longer. Despite the progress in survival provided by TACE, TABE and sorafenib independently, rigorous combination clinical trials do not consistently show significant improvement over TACE/TABE monotherapy. Other novel small molecules targeting angiogenesis such as brivanib, linifanib and everolimus have failed or are in development. Anti-HCV treatment became more feasible with the novel direct-acting antiviral agents; with the much higher and more durable treatment responses that they provide, the risk of HCC progression may be reduced. The most effective strategies in developing combination therapies are hampered by the complexities of FDA testing along with intellectual property and economic issues. To achieve significant progress, more basic science studies are necessary to help understand which novel molecules demonstrate the greatest synergy. Individual patient genomic profiling and biomarkers may help guide therapy and improve the clinician's ability to tailor treatment and to know when it could be appropriate to combine systemic therapy with transarterial embolization. Most importantly, partnerships that facilitate testing of novel therapies in intelligently designed trials based on preclinical pharmacokinetics must be established. PMID- 26504749 TI - Methods of Liver Stem Cell Therapy in Rodents as Models of Human Liver Regeneration in Hepatic Failure. AB - Cell therapy is a promising intervention for treating liver diseases and liver failure. Different animal models of human liver cell therapy have been developed in recent years. Rats and mice are the most commonly used liver failure models. In fact, rodent models of hepatic failure have shown significant improvement in liver function after cell infusion. With the advent of stem-cell technologies, it is now possible to re-programme adult somatic cells such as skin or hair-follicle cells from individual patients to stem-like cells and differentiate them into liver cells. Such regenerative stem cells are highly promising in the personalization of cell therapy. The present review article will summarize current approaches to liver stem cell therapy with rodent models. In addition, we discuss common cell tracking techniques and how tracking data help to direct liver cell therapy research in animal models of hepatic failure. PMID- 26504750 TI - The Impact of Mesenchymal Stem Cells on Differentiation of Hematopoietic Stem Cells. AB - Bone marrow microenvironment contains cellular and acellular compartments. The cellular compartment includes hematopoietic stem cells, mesenchymal stem cells and some other stromal cell types, while the acellular compartment is composed of scaffold proteins known as the extra cellular matrix. Direct cell-cell contact as well as cytokines secreted by mesenchymal stem cells during coculture of hematopoietic stem cells and mesenchymal stem cells play a critical role in hematopoiesis, and determines the fate of hematopoietic stem cells. Several studies have demonstrated the impact of mesenchymal stem cells on self-renewal, expansion, proliferation and differentiation of hematopoietic stem cells in vitro, which have shown different and contradictory results. In this paper, we will investigate the effect of mesenchymal stem cells on differentiation of hematopoietic stem cells in vitro. PMID- 26504751 TI - Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Structure, Preparation and Application. AB - Lipid nanoparticles (LNPs) have attracted special interest during last few decades. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are two major types of Lipid-based nanoparticles. SLNs were developed to overcome the limitations of other colloidal carriers, such as emulsions, liposomes and polymeric nanoparticles because they have advantages like good release profile and targeted drug delivery with excellent physical stability. In the next generation of the lipid nanoparticle, NLCs are modified SLNs which improve the stability and capacity loading. Three structural models of NLCs have been proposed. These LNPs have potential applications in drug delivery field, research, cosmetics, clinical medicine, etc. This article focuses on features, structure and innovation of LNPs and presents a wide discussion about preparation methods, advantages, disadvantages and applications of LNPs by focusing on SLNs and NLCs. PMID- 26504752 TI - Ghrelin Decreases Angiogenesis, HIF-1alpha and VEGF Protein Levels in Chronic Hypoxia in Lung Tissue of Male Rats. AB - PURPOSE: Hypoxia is a condition of decreased availability of oxygen. When cells are exposed to a low oxygen environment, they impel the hypoxia responses to adapt to new situation. The hypoxia response leads to the activation of various cellular signaling pathways. The aim of this study was to evaluate the effect of ghrelin on angiogenesis, Hypoxia-Inducible-Factor-1alpha (HIF-1) and Vascular endothelial growth factor (VEGF) levels in normobaric hypoxia situation. METHODS: Twenty four animals were divided into 4 groups (n=6): control (C), ghrelin (Gh), hypoxia (H), and hypoxic animals that received ghrelin (H+Gh). Hypoxia (11%) was induced by an Environmental Chamber System GO2 Altitude. Animals in ghrelin groups received a subcutaneous injection of ghrelin (150 MUg/kg/day) for 14 days. RESULTS: Our results showed that hypoxia significantly (p<0.05) increased angiogenesis without any significant changes on HIF-1 and VEGF levels, whereas ghrelin significantly (p<0.05) decreased angiogenesis, expression of HIF-1 and VEGF in this condition. Ghrelin administration did not show any significant changes in normal conditions. CONCLUSION: Ghrelin had no effect on angiogenesis, expression of HIF-1 and VEGF in normal oxygen conditions but it reduced angiogenesis process in lung tissue with reducing the level of HIF and VEGF in hypoxic condition. Therefore, effect of ghrelin on angiogenesis could be related to blood oxygen level. PMID- 26504753 TI - Involvement of Glycogen Synthase Kinase-3beta and Oxidation Status in the Loss of Cardioprotection by Postconditioning in Chronic Diabetic Male Rats. AB - PURPOSE: Diabetes mellitus as a main risk-factor of ischemic heart disease may interfere with postconditioning'scardioprotective effects. This study aimed to investigate the involvement of glycogen synthase kinase-3beta (GSK-3beta) and oxidation status in chronic diabetes-induced loss of cardioprotective effect of ischemic-postconditioning (IPostC) in Wistar rats. METHODS: After 8 weeks of induction of diabetes by streptozotocin (50mg/kg), hearts of control and diabetic rats were isolated and mounted on a constant-pressure Langendorff system. All hearts were subjected to 30min regional ischemia followed by 60min reperfusion (by occluding and re-opening of left anterior descending coronary artery, respectively). IPostC was applied immediately at the onset of reperfusion. At the end of reperfusion, the infarct size of myocardium was measured via computerized planimetry. Myocardial contents of malondealdehyde and glutathione as indices of oxidative status were assayed spectrophotometrically and the total and phosphorylated forms of myocardial GSK-3beta were quantified through western blotting. RESULTS: IPostC reduced the infarct size of control hearts from 41+/ 2.9% to 28+/-1.9% (P<0.05), whereas it could not induce significant changes in infarct size of diabetic animals (35+/-1.8% vs. 39+/-3.1%). IPostC-induced reduction in malondealdehyde and elevation in glutathione contents were significant only in control not in diabetic hearts. The total forms of GSK-3beta were similar in all groups; however, the phosphorylation of GSK-3beta (at Ser9) by IPostC was greater in control hearts than diabetics (P<0.01). CONCLUSION: The failure of cardioprotection by IPostC in diabetic hearts may be attributed to the loss of phosphorylation of GSK-3beta and thereby increase in oxidative stress in diabetic states. PMID- 26504754 TI - Cytoprotective Effects of Melatonin Against Amitriptyline-Induced Toxicity in Isolated Rat Hepatocytes. AB - PURPOSE: Amitriptyline, one of the commonly used tricyclic antidepressants, caused rare but severe hepatotoxicity in patients who received it continuously. Previous findings showed that the intermediate metabolites of amitriptyline produced by CYP450 are involved in hepatic injury. Melatonin is an antiaging and antioxidant hormone synthesized from pineal gland. The aim of present study was to evaluate the protective role of melatonin in an in vitro model of isolated rat hepatocytes. METHODS: Markers such as cell viability, reactive oxygen species formation, lipid peroxidation, mitochondrial membrane potential, and hepatocytes glutathione content were evaluated every 60 minutes for 180 minutes. RESULTS: Present results indicated that administration of 1mM of melatonin effectively reduced the cell death, ROS formation and lipid peroxidation, mitochondrial membrane potential collapse, and reduced cellular glutathione content caused by amitriptyline. CONCLUSION: Our results indicated that melatonin is an effective antioxidant in preventing amitriptyline-induced hepatotoxicity. We recommend further in vivo animal and clinical trial studies on the hepatoprotective effects of melatonin in patients receiving amitriptyline. PMID- 26504755 TI - Carriage of Class 1 and 2 Integrons in Quinolone, Extended-Spectrum-beta Lactamase-Producing and Multi Drug Resistant E.coli and K.pneumoniae: High Burden of Antibiotic Resistance. AB - PURPOSE: The study aimed at assessing any association between quinolone resistance, MDR and ESBL production and their relation with the presence of integrons in Esherichia coli and Klebsiella pneumoniae. METHODS: E.coli and K.pneumoniae isolated from various clinical infections were fully identified and analyzed for being quinolone resistant. These isolates were further tested for ESBL production, multi drug resistance and carriage of integrons. RESULTS: In total, 135 isolates were confirmed as quinolone resistant. K.pneumoniae was observed as potent ESBL producer in comparison to E.coli. Ciprofloxacin resistance in both organisms was related significantly with the presence of integron class 1, co-presence of class 1 and 2 as well as to the presence of ESBL production (p< 0.001). However, nalidixic acid resistance was related significantly (p< 0.01) with only integron class 1 and to the presence of ESBL production. Class 1 and 2 integrons were found in 73.5% of MDR isolates with 13.2% of them possessing both intI1 and intI2 genes. CONCLUSION: Prevalence of quinolone resistance together with ESBL production and MDR in E.coli and K.pneumoniae has contributed to the emergence of antibacterial resistance burden. The higher integron prevalence in our isolates advocates the potentiality of these isolates as a source for dissemination of resistance determinants. PMID- 26504756 TI - Formation and Characterization of Beclomethasone Dipropionate Nanoparticles Using Rapid Expansion of Supercritical Solution. AB - PURPOSE: Particle size of Beclometasone Dipropionate (BDP) was reduced by the rapid expansion of supercritical solution (RESS) process, using CO2 as supercritical solvent. Also, the effect of RESS parameters such as extraction pressure, pre-expansion temperature, and weight fraction of co-solvent on the size and distribution of BDP particles were investigated. METHODS: The effects of extraction pressure (200-260 bar), pre-expansion temperature (70-110 degrees C) and weight fraction of menthol as a co-solvent on mean particle size (MPS) of BDP were investigated by design of experiment (DOE). Particles were characterized using Scanning Electron Microscopy (SEM) and Dynamic Light Scattering (DLS). RESULTS: The average sizes of precipitated BDP were between 64.1 and 294 nm. Analysis of variance (ANOVA) showed that extraction pressure was the most significant parameter and a higher extraction pressure caused production of smaller particles. Also, it was found that higher temperature and weight fraction of co-solvent increased the MPS. The interaction effects of extraction pressure pre-expansion temperature and pre-expansion temperature-co-solvent ratio were significant through the analysis of variance. It was observed that the MPS of precipitated particles was mostly influenced by pressure. CONCLUSION: The smallest MPS of BDP obtained from the RESS process was 65 nm that revealed a significant size reduction from its original MPS of 9 MUm. Moreover, a slight change was observed for precipitated particles of BDP into spherical form while the original particles were irregular in shape. RESS process showed as a promising method for production of BDP nanoparticles that may results in improvement of drug's physicochemical properties. PMID- 26504758 TI - Preparation, Evaluation and Optimization of Multiparticulate System of Mebendazole for Colon Targeted Drug Delivery by Using Natural Polysaccharides. AB - PURPOSE: A Multiparticulate system of Mebendazole was developed for colon targeted drug delivery by using natural polysaccharides like Chitosan and Sodium alginate beads. METHODS: Chitosan microspheres were formulated by using Emulsion crosslinking method using Glutaraldehyde as crosslinking agent. Sodium-alginate beads were formulated by using Calcium chloride as gelling agent. Optimization for Chitosan microspheres was carried out by using 2(3) full factorial design. 3(2) full factorial design was used for the optimization of Sodium-alginate beads. The formulated batches were evaluated for percentage yield, particle size measurement, flow properties, percent entrapment efficiency, Swelling studies. The formulations were subjected to Stability studies and In-vitro release study (with and without rat caecal content). Release kinetics data was subjected to different dissolution models. RESULTS: The formulated batches showed acceptable particle size range as well as excellent flow properties. Entrapment efficiency for optimized batches of Chitosan microspheres and sodium alginate beads was found to be 74.18% and 88.48% respectively. In-vitro release of drug for the optimized batches was found to be increased in presence of rat caecal content. The best-fit models were koresmeyer-peppas for Chitosan microspheres and zero order for sodium-alginate beads. CONCLUSION: Chitosan and Sodium-alginate was used successfully for the formulation of Colon targeted Multiparticulate system. PMID- 26504757 TI - Doxorubicin Changes Bax /Bcl-xL Ratio, Caspase-8 and 9 in Breast Cancer Cells. AB - PURPOSE: Doxorubicin is administrated as a single agent in first-line therapy of breast cancer to induce apoptosis in tumor cells. Bax, Bcl-xL, Caspase-8 and 9 proteins are involved in induction of apoptosis. The present study describes Bax, Bcl-xL gene expression and Caspase-8 and 9 protein levels in MCF-7 cells incubated with doxorubicin at different doses an incubation times. METHODS: The cytotoxic effects of doxorubicin were studied using MTT assay. MCF-7 cells were treated with three concentrations of doxorubicin (0.1, 0.5, 1 MUM) and incubated for 24, 48 and 72 hours then expression levels of Bax and Bcl-xL genes were elucidated by Real-time RT-PCR technique and protein levels of caspase-8 and caspase-9 proteins were measured using ELISA method. Morphological modifications of the cells were also monitored via light microscopic images. RESULTS: Doxorubicin decreased the anti-apoptotic Bcl-xL and increased pro-apoptotic Bax mRNA levels. Doxorubicin induced a significant increase in Bax /Bcl-xL ratio in all doses and incubation times (p<0.05). Highest (more than 10 fold) increase in Bax /Bcl-xL ratio was revealed after 48 h incubation of the cells with in all doses of doxorubicin. Doxorubicin also increased caspase-9 level in a time and dose-dependent manner, while caspase-8 level didn't follow time and dose dependency pattern. CONCLUSION: Our results confirm that doxorubicin induces mitochondrial-dependent apoptosis by down-regulation of Bcl-xL and up- regulation of Bax and caspase-9 expressions. PMID- 26504759 TI - Aberrant Wnt/beta-Catenin Signaling Pathway in Testis of Azoospermic Men. AB - PURPOSE: The Importance and key role of Wnt/beta-catenin signaling pathway in spermatogenesis is known. Abnormalities of this pathway in Sertoli and germ cells leads to infertility. Leydig cells play an important role in spermatogenesis and male reproduction. As of now, exact position of the Wnt/beta-catenin signaling pathway disorders in the tissue and possible involvement of Leydig cells has not been investigated. METHODS: Samples of our previous study were used for common Y chromosome microdeletions screening and common CFTR gene mutations.1 beta-catenin gene expression were evaluated and compared between testicular tissue obtained by testicular sperm extraction (TESE) in two groups of obstructive (n=10) and non obstructive (n=10) azoospermic infertile men. Location of beta-catenin accumulation was detected by immunofluorescence technic and quantitatively compared in the tissue followed by counterstaining with anti-vimentin antibody. It was used as specific marker of leydig cells to determine and confirm the cells in which this gathering was occurred. RESULTS: beta-catenin gene expression does not have a significant difference between the obstructive azoospermia (0.998) and non-obstructive azoospermia group (0.891). beta-catenin was abnormally aggregated in leydig cell of non-obstructive azoospermic men. CONCLUSION: Gathering beta catenin in cytoplasm of leydig cells can disrupt spermatogenesis and cause infertility in men. PMID- 26504761 TI - New Validated Stability-Indicating Rp-HPLC Method for Simultaneous Estimation of Atorvastatin and Ezetimibe in Human Plasma by Using PDA Detector. AB - PURPOSE: This paper describes a simple, precise and accurate RP-HPLC method for simultaneous estimation of atorvastatin and ezetimibe in plasma. METHODS: The chromatographic separation of the drugs were performed on an X-Terra C8 (4.6 x 150 mm, 3.5 mm), with phosphate buffer [pH 3.5 with Ortho Phosphoric Acid] - acetonitrile 40:60 (v/v) as mobile phase. The detection was performed at 235 nm. The flow rate was maintained at 1.2 mL/min. The run time was 8.0 min. RESULTS: The accuracy and reliability of the method was assessed by evaluation of linearity (5-25 ug/mL for both atorvastatin calcium and ezetimibe), precision (intra-day RSD 0.57 % and inter-day RSD 0.02 % for atorvastatin calcium and intra day RSD 0.56 % and inter-day RSD 0.1 % for ezetimibe), accuracy (100.08- 100.84 % for atorvastatin calcium and 100.56- 101.00 % for ezetimibe), and specificity, in accordance with ICH guidelines. The LLOQ obtained by the proposed method were 1.294 and 1.384 ug/mL for atorvastatin and ezetimibe respectively. CONCLUSION: Overall the proposed method was found to be suitable and accurate for the quantitative determination in plasma. The method was effectively separated the drug from plasma. PMID- 26504760 TI - Swim Training Improves HOMA-IR in Type 2 Diabetes Induced by High Fat Diet and Low Dose of Streptozotocin in Male Rats. AB - PURPOSE: Insulin resistance plays a key role in the onset and development of type 2 diabetes mellitus (T2DM) and its complications. In this study, we evaluated the effect of swim training on insulin resistance in diabetic rats. METHODS: Forty male Wistar rats were randomly divided into four groups (n=10): sedentary control (Con), sedentary diabetic (Dia), swim trained control (Exe) and swim trained diabetic (Dia+Exe) rats. Diabetes was induced by high fat diet (HFD) and a low dose of streptozotocin (35 mg/kg, i.p). In trained groups, one week after the induction of diabetes, animals were subjected to swimming (60 min/5 days a week) for 10 weeks. At the end of training, fasting blood sugar (FBS), oral glucose tolerance test (OGTT), fasting/basal insulin, glycosylated hemoglobin (HbA1c) levels, insulin resistance index, homeostasis model assessment method (HOMA-IR), triglycerides (TG,) total cholesterol (TCh), and high density lipoprotein (HDL) levels in blood were measured. RESULTS: Swimming significantly improved OGTT (P<0.01) and HOMA-IR (P<0.01). Swim training also significantly decreased FBS (p<0.01), fasting/basal insulin (P<0.01), HbA1C (p<0.01), TG (P<0.05), and TCh (P<0.05) levels. It also significantly increased HDL (p<0.05) level. CONCLUSION: Our findings indicate that swim training improved glycemic control and insulin sensitivity in type 2 diabetes caused by high fat diet in male rats. PMID- 26504762 TI - Efficient Inactivation of Multi-Antibiotics Resistant Nosocomial Enterococci by Purified Hiracin Bacteriocin. AB - PURPOSE: Because of the emergence of multi-antibiotic resistant bacteria, a number of infectious diseases have become a major concern to treat in health care services worldwide. This situation is worsened by the fact that very limited progress has been made in developing new and potent antibiotics in recent years. In this context antimicrobial peptides (AMPs) represent new potential therapeutic compounds with bactericidal or bacteriostatic activity against closely related bacterial strains. METHODS: In this study, a collection of enterococci (n=170) from clinical sources were investigated for their potential to inhibit multiresistant nosocomial enterococci from Iranian hospitals. RESULTS: Four isolates produced antimicrobial peptides that inhibited all the antibiotic resistant enterococci. This included three Enterococcus faecium isolates producing combinations of enterocin A, B and L50 AB. The most potent antagonism was produced by E. faecalis HO91. Purification and subsequent characterization by MALDI-TOF MS, Edman degradation and DNA-sequencing revealed that the antimicrobial compound was Hiracin. The purified Hiracin was evaluated for antibacterial activity against 12 multiresistant enterococcal isolates from clinical samples. The results demonstrated that Hiracin is highly effective towards enterococci which were resistant even to antibiotics from four distinct classes. CONCLUSION: The present research addresses Hiracin as a promising alternative to conventional antibiotics in treatment of multiresistant enterococcal infections. PMID- 26504763 TI - Furosemide Loaded Silica-Lipid Hybrid Microparticles: Formulation Development, in vitro and ex vivo Evaluation. AB - PURPOSE: The main objective of the current research work was to formulate and evaluate furosemide loaded silica lipid hybrid microparticles for improved oral delivery. A novel silica-lipid hybrid microparticulate system is used for enhancing the oral absorption of low solubility and low permeability of (BCS Class IV) drugs. Silica-lipid hybrid microparticles include the drug solubilising effect of dispersed lipids and stabilizing effect of hydrophilic silica particles to increase drug solubilisation, which leads to enhanced oral bioavailability. METHODS: The slica lipid hybrid (SLH) microparticles were composed of poorly soluble drug (furosemide), dispersion of oil phase (Soya bean oil and miglyol) in lecithin (Phospholipoid 90H), non-ionic surfactant (Polysorbate 80) and adsorbent (Aerosol 380). Saturation solubility studies were performed in different oils and surfactants with increased concentration of drug revealed increased solubility of furosemide. RESULTS: In vitro dissolution studies conducted under simulated gastric medium revealed 2-4 fold increase in dissolution efficiencies for SLH microparticles compared to that of pure drug (furosemide) and marketed formulation Lasix(r). Ex vivo studies showed enhanced lipid digestibility, which improved drug permeability. Solid-state characterization of SLH microparticles by X-ray powder diffraction and Fourier transform infrared spectroscopic analysis confirmed non-crystalline nature and more compatibility of furosemide in silica lipid hybrid microparticles. CONCLUSION: It can be concluded that the role of lipids and hydrophilic silica based carrier highlighted in enhancing solubility and permeability, and hence the oral bioavailability of poorly soluble drugs. PMID- 26504764 TI - The Relationship between Solubility and Transdermal Absorption of Tadalafil. AB - PURPOSE: The aim of this study was to find a relationship between drug solubility and its transdermal permeation and find the best vehicle composition to improve transdermal permeation of Tadalafil. METHODS: Pure or binary mixtures of commonly used solvents in pharmaceutical sciences including ethanol, glycerin, N-methyl pyrrolidone (NMP), polyethylene glycol (PEG) 400 and propylene glycol (PG) were evaluated for drug solubility and transdermal delivery through the exercised rat skin employing Franz diffusion cells. RESULTS: Tadalafil showed higher solubility in NMP compared to the other solvents. The amount of Tadalafil permeation from the pure vehicles was ranked as follow: Ethanol >glycerin >NMP>PEG 400 >PG. Furthermore, the solubility and transdermal delivery from binary mixtures of NMP and PG were higher than that obtained from pure PG, and accordingly, both increased with increasing NMP concentration in the binary solvent mixtures. The Flux values were determined as following order for Ethanol>NMP>glycerin>PG>PEG 400. CONCLUSION: Generally, increase in Tadalafil solubility resulted in a decrease in its skin penetration rate and amount. However, NMP exhibited substantial drug skin penetration rate and amount accompanying with appropriate drug solvency. In conclusion, the results of this study introduced NMP as a solvent suitable for application in the formulation of topically applied drug delivery systems. PMID- 26504765 TI - Citrus Bioflavonoids Ameliorate Hyperoxaluria Induced Renal Injury and Calcium Oxalate Crystal Deposition in Wistar Rats. AB - PURPOSE: Citrus is considered as a medically important plant from ancient times and the bioflavonoids of different variety of citrus fruits were well explored for their biological activities. The study aim was to explore the effect of citrus bioflavonoids (CB) to prevent and cure hyperoxaluria induced urolithiasis. METHODS: Twenty four Wistar rats were segregated into 4 Groups. Group 1: Control; Group 2: Urolithic (EG-0.75%); Group 3: Preventive study (EG+CB, day 1-50); Group 4: Curative study (EG+CB, day 30-50). Animals received CB orally (20mg/kg body weight) after performing a toxicity study. RESULTS: Urinary risk factors and serum renal function parameters were significantly reduced by CB administration in both preventive and curative study (p<0.001). Hematoxylin & Eosin and von Kossa staining demonstrated that renal protection was offered by CB against EG insult. Immunohistochemical analyses revealed over expression and abnormal localization of THP and NF-kappaB in urolithic rats, while it was effectively regulated by CB supplementation. CONCLUSION: CB prevented and significantly controlled lithogenic factors and CaOx deposition in rats. We propose CB as a potential therapy in management of urolithiasis. PMID- 26504766 TI - Construction and Characterization of Recombinant HEK Cell Over Expressing alpha4 Integrin. AB - PURPOSE: Integrins are heterodimeric membrane proteins, which are exposed to post translational modifications in eukaryotic cells in contrast to prokaryotic cells. These modifications provide advantages for production of proper nanobody, mono and polyclonal antibody against this surface protein and also in aptamer selection process. Since the majority of diagnostic and therapeutic antibodies, target the surface epitopes, eukaryotic membrane proteins provide an appropriate model for further investigation on therapeutic agents. METHODS: Escherichia coli strain top 10, was used as host for ITGA-4 expression vector encoding the human integrin alpha4. The plasmid was extracted and consequently, ITGA-4 vector was digested to make a linear plasmid. Human Embryonic Kidney-293 (HEK-293) cell transfected with linear plasmid and subsequently screened for stable ITGA-4 expressing Cells. Three separated clones were isolated twenty one days after transfection. Chromosomal DNA was extracted from ITGA-4-transfected cells. The presence of ITGA-4 gene in HEK-293 genome was confirmed by PCR. The expression level of ITGA-4 on HEK-293 cells was also analyzed by Flow cytometry. RESULTS: Flow cytometric analysis showed that HEK-293 cells have no expression of integrin alpha4 on their surface while 95% of transfected HEK-293 cells with ITGA4, expressed different levels of integrin alpha4 on their surfaces which correlates well with genomic DNA PCR amplification results. CONCLUSION: The results suggest that we have successfully constructed the integrin alpha4 expressing HEK293 cell, which will facilitate further research into the production of antibody, nanobody and aptamer against alpha4 integrin. PMID- 26504767 TI - The Effect of Tween 20, 60, and 80 on Dissolution Behavior of Sprionolactone in Solid Dispersions Prepared by PEG 6000. AB - PURPOSE: Solid dispersions have been efficient in improving the dissolution rate and bioavailability of hydrophobic drugs. The aim of the present study was enhancement of the dissolution profile of Spironolactone using solid dispersion. METHODS: Spironolactone solid dispersions (1:1, 1:2 and 2:1 drug: carrier weight ratio) were prepared by polyethylene glycol (PEG) 6000 as a carrier by hot melt method. The influence of several amounts of Tween 20, 60, and 80 were also studied. The dissolution profile was evaluated by USP Apparatus II. RESULTS: The results showed that solid dispersions were efficacious to enhance the dissolution rate of Spironolactone in water; and the procedure indicated that there was an increase in dissolution rate for solid dispersions containing the surfactant Tweens. The solid dispersions were evaluated using Fourier-transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC) studies; and the results showed no complex formation or change in crystal shape of drug. CONCLUSION: It is concluded that solid dispersion technique can be successfully used for improvement of dissolution of Spironolactone. PMID- 26504768 TI - Apoptosis Cell Death Effect of Scrophularia Variegata on Breast Cancer Cells via Mitochondrial Intrinsic Pathway. AB - PURPOSE: Scrophularia variegata M. Beib. (Scrophulariaceae) is an Iranian medicinal plant which is used for various inflammatory disorders in traditional medicine. In this study we evaluated the anti-cancer and cytotoxic effects of the Scrophularia variegata (S. variegata) ethanolic extract on the human breast cancer cell line. METHODS: The cytotoxicity effect of the extract on MCF-7 cells was evaluated by MTT assay. In addition, Caspase activity, DNA ladder and Cell death were evaluated by ELISA, gel electrophoresis and Annexin V-FITC/PI staining, respectively. RESULTS: The S. variegata extract showed significant effect cytotoxicity on MCF-7 human breast cancer cell line. Treatment with the extract induced apoptosis on the breast cancer cells by cell cycle arrest in G2/M phase. The results indicated that cytotoxicity activity was associated with an increase of apoptosis as demonstrated by DNA fragmentation as well as an increase of the amount of caspase 3 and caspase 9. In addition, the phytochemical assay showed that the extract had antioxidant capacity and also flavonoids, phenolic compounds and phenyl propanoids were presented in the extract. CONCLUSION: Our findings indicated that S. variegata extract induced apoptosis via mitochondrial intrinsic pathway on breast cancer by cell cycle arrest in G2/M phase and an increase of caspase 3 and caspase 9. However future studies are needed. PMID- 26504769 TI - Role of a clinical pharmacist in managing diabetic nephropathy: an approach of pharmaceutical care plan. AB - AIM: To evaluate the effect of low-protein diet on renal function in patient with diabetic nephropathy. MATERIALS AND METHODS: This is a case of a 57-year-old obese patient who is a known case of type 2 diabetes, hypertension, benign prostate hypertrophy and chronic kidney disease 4(th) stage presented with the complaints of weakness, dyspnea, arthralgia, neuropathic pains and pedal edema which are prominent symptoms of Chronic kidney disease. Our healthcare team had visited patient's home and analyzed the available reports on kidney profile, fasting sugar, post prandial sugar, HbA1c, lipid profile test and prescriptions which was found to be high. The glomerular filtration rate, serum creatinine and blood urea were 24 ml/min, 3.4 mg/dL and 90 mg/dL, fasting blood sugar, post prandial blood sugar and HbA1c were 226, 305 and 7.4 %, and total cholesterol and triglycerides were 145 & 95 respectively. Further discussion on diet, it came to know that the patient was on high carbohydrate diet. By considering the objective and subjective data, our team had done the assessment and come to a conclusion that high amount of carbohydrate diet with poor medication adherence had led to the hyperglycemia which developed diabetic nephropathy. We have recommended low protein, unsaturated fat, multivitamins, antioxidants and moderate carbohydrate diet. Two dietary assessment tools had been used in order to monitor patient's adherence to the diet i.e. dietary record book and food frequency questionnaire. RESULTS: We have carefully monitored the serum creatinine, glomerular filtration rate and blood urea for 12 months initially with an interval of 30 days for 3 months and later trimonthly up-to 12 months. Glomerular filtration rate was calculated by using the formula CKD-EPI creatinine equation. The values trend for first three months of serum creatinine and glomerular filtration rate were 2.8 mg/dL, 2.6 mg/dL,1.5 mg/dL and 24 ml/min, 26 ml/min, 51 ml/min respectively. Further, results has shown a significant improvement in the 6th, 9th and 12th month. The values of serum creatinine in the 6th, 9th and 12th month were 1.3 mg/dL, 1.1 mg/dL and 0.9 mg/dL, whereas golmerular filtration rate in the 6th, 9th and 12th month were 61 ml/min, 74 ml/min and 94 ml/min. CONCLUSION: The present study has demonstrated the protein diet restriction in-order to control the progression of renal failure. The dietary intervention on diabetic nephropathy plays a significant role in controlling the kidney failures. This is the first study, to our knowledge, to demonstrate the impact of pharmacist role in managing diabetic nephropathy by providing pharmaceutical care. Pharmaceutical care services should be encouraged in the community and hospital pharmacy which definitely plays a major impact in reaching the definite outcomes and providing higher quality of life. PMID- 26504770 TI - Characterization and Development of EST-SSRs by Deep Transcriptome Sequencing in Chinese Cabbage (Brassica rapa L. ssp. pekinensis). AB - Simple sequence repeats (SSRs) are among the most important markers for population analysis and have been widely used in plant genetic mapping and molecular breeding. Expressed sequence tag-SSR (EST-SSR) markers, located in the coding regions, are potentially more efficient for QTL mapping, gene targeting, and marker-assisted breeding. In this study, we investigated 51,694 nonredundant unigenes, assembled from clean reads from deep transcriptome sequencing with a Solexa/Illumina platform, for identification and development of EST-SSRs in Chinese cabbage. In total, 10,420 EST-SSRs with over 12 bp were identified and characterized, among which 2744 EST-SSRs are new and 2317 are known ones showing polymorphism with previously reported SSRs. A total of 7877 PCR primer pairs for 1561 EST-SSR loci were designed, and primer pairs for twenty-four EST-SSRs were selected for primer evaluation. In nineteen EST-SSR loci (79.2%), amplicons were successfully generated with high quality. Seventeen (89.5%) showed polymorphism in twenty-four cultivars of Chinese cabbage. The polymorphic alleles of each polymorphic locus were sequenced, and the results showed that most polymorphisms were due to variations of SSR repeat motifs. The EST-SSRs identified and characterized in this study have important implications for developing new tools for genetics and molecular breeding in Chinese cabbage. PMID- 26504771 TI - Response of Spatial Patterns of Denitrifying Bacteria Communities to Water Properties in the Stream Inlets at Dianchi Lake, China. AB - Streams are an important sink for anthropogenic N owing to their hydrological connections with terrestrial systems, but main factors influencing the community structure and abundance of denitrifiers in stream water remain unclear. To elucidate the potential impact of varying water properties of different streams on denitrifiers, the abundance and community of three denitrifying genes coding for nitrite (nirK, nirS) and nitrous oxide (nosZ) reductase were investigated in 11 streams inlets at the north part of Dianchi Lake. The DGGE results showed the significant pairwise differences in community structure of nirK, nirS, and nosZ genes among different streams. The results of redundancy analysis (RDA) confirmed that nitrogen and phosphorus concentrations, pH, and temperature in waters were the main environmental factors leading to a significant alteration in the community structure of denitrifiers among different streams. The denitrifying community size was assessed by quantitative PCR (qPCR) of the nirS, nirK, and nosZ genes. The abundance of nirK, nirS, and nosZ was positively associated with concentrations of total N (TN) and PO4 (3-) (p < 0.001). The difference in spatial patterns between nirK and nirS community diversity, in combination with the spatial distribution of the nirS/nirK ratio, indicated the occurrence of habitat selection for these two types of denitrifiers in the different streams. The results indicated that the varying of N species and PO4 (3-) together with pH and temperature would be the main factors shaping the community structure of denitrifiers. Meanwhile, the levels of N in water, together with PO4 (3-), tend to affect the abundance of denitrifiers. PMID- 26504772 TI - The SsDREB Transcription Factor from the Succulent Halophyte Suaeda salsa Enhances Abiotic Stress Tolerance in Transgenic Tobacco. AB - Dehydration-responsive element-binding (DREB) transcription factor (TF) plays a key role for abiotic stress tolerance in plants. In this study, a novel cDNA encoding DREB transcription factor, designated SsDREB, was isolated from succulent halophyte Suaeda salsa. This protein was classified in the A-6 group of DREB subfamily based on multiple sequence alignments and phylogenetic characterization. Yeast one-hybrid assays showed that SsDREB protein specifically binds to the DRE sequence and could activate the expression of reporter genes in yeast, suggesting that the SsDREB protein was a CBF/DREB transcription factor. Real-time RT-PCR showed that SsDREB was significantly induced under salinity and drought stress. Overexpression of SsDREB cDNA in transgenic tobacco plants exhibited an improved salt and drought stress tolerance in comparison to the nontransformed controls. The transgenic plants revealed better growth, higher chlorophyll content, and net photosynthesis rate, as well as higher level of proline and soluble sugars. The semiquantitative PCR of transgenics showed higher expression of stress-responsive genes. These data suggest that the SsDREB transcription factor is involved in the regulation of salt stress tolerance in tobacco by the activation of different downstream gene expression. PMID- 26504773 TI - New Insights into Orphan Nuclear Receptor SHP in Liver Cancer. AB - Small heterodimer partner (SHP; NR0B2) is a unique orphan nuclear receptor (NR) that contains a putative ligand-binding domain but lacks a DNA-binding domain. SHP is a transcriptional corepressor affecting diverse metabolic processes including bile acid synthesis, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology via interaction with multiple NRs and transcriptional factors (TFs). Hepatocellular carcinoma (HCC) is one of the most deadly human cancers worldwide with few therapeutic options and poor prognosis. Recently, it is becoming clear that SHP plays an antitumor role in the development of liver cancer. In this review, we summarize the most recent findings regarding the new SHP interaction partners, new structural insights into SHP's gene repressing activity, and SHP protein posttranslational modifications by bile acids. We also discuss the pleiotropic role of SHP in regulating cell proliferation, apoptosis, DNA methylation, and inflammation that are related to antitumor role of SHP in HCC. Improving our understanding of SHP's antitumor role in the development of liver cancer will provide new insights into developing novel treatments or prevention strategies. Future research will focus on developing more efficacious and specific synthetic SHP ligands for pharmaceutical applications in liver cancer and several metabolic diseases such as hypercholesterolemia, obesity, diabetes, and fatty liver disease. PMID- 26504774 TI - In Vitro Evaluation of Scaffolds for the Delivery of Mesenchymal Stem Cells to Wounds. AB - Mesenchymal stem cells (MSCs) have been shown to improve tissue regeneration in several preclinical and clinical trials. These cells have been used in combination with three-dimensional scaffolds as a promising approach in the field of regenerative medicine. We compare the behavior of human adipose-derived MSCs (AdMSCs) on four different biomaterials that are awaiting or have already received FDA approval to determine a suitable regenerative scaffold for delivering these cells to dermal wounds and increasing healing potential. AdMSCs were isolated, characterized, and seeded onto scaffolds based on chitosan, fibrin, bovine collagen, and decellularized porcine dermis. In vitro results demonstrated that the scaffolds strongly influence key parameters, such as seeding efficiency, cellular distribution, attachment, survival, metabolic activity, and paracrine release. Chick chorioallantoic membrane assays revealed that the scaffold composition similarly influences the angiogenic potential of AdMSCs in vivo. The wound healing potential of scaffolds increases by means of a synergistic relationship between AdMSCs and biomaterial resulting in the release of proangiogenic and cytokine factors, which is currently lacking when a scaffold alone is utilized. Furthermore, the methods used herein can be utilized to test other scaffold materials to increase their wound healing potential with AdMSCs. PMID- 26504775 TI - Detecting Blood Flow Response to Stimulation of the Human Eye. AB - Retinal blood supply is tightly regulated under a variety of hemodynamic considerations in order to satisfy a high metabolic need and maintain both vessel structure and function. Simulation of the human eye can induce hemodynamics alterations, and attempt to assess the vascular reactivity response has been well documented in the scientific literature. Advancements in noninvasive imaging technologies have led to the characterization of magnitude and time course in retinal blood flow response to stimuli. This allowed for a better understanding of the mechanism in which blood flow is regulated, as well as identifying functional impairments in the diseased eye. Clinically, the ability to detect retinal blood flow reactivity during stimulation of the eye offers potential for the detection, differentiation, and diagnosis of diseases. PMID- 26504776 TI - Titanium-Based Hip Stems with Drug Delivery Functionality through Additive Manufacturing. AB - Postoperative infections are a major concern in patients that receive implants. These infections generally occur in areas with poor blood flow and pathogens do not always respond to antibiotic treatment. With the latest developments in nanotechnology, the incorporation of antibiotics into prosthetic implants may soon become a standard procedure. The success will, however, depend on the ability to control the release of antibiotics at concentrations high enough to prevent the development of antibiotic-resistant strains. Through additive manufacturing, antibiotics can be incorporated into cementless femoral stems to produce prosthetic devices with antimicrobial properties. With the emerging increase in resistance to antibiotics, the incorporation of antimicrobial compounds other than antibiotics, preferably drugs with a broader spectrum of antimicrobial activity, will have to be explored. This review highlights the microorganisms associated with total hip arthroplasty (THA), discusses the advantages and disadvantages of the latest materials used in hip implants, compares different antimicrobial agents that could be incorporated, and addresses novel ideas for future research. PMID- 26504778 TI - Worksite Tobacco Prevention: A Randomized, Controlled Trial of Adoption, Dissemination Strategies, and Aggregated Health-Related Outcomes across Companies. AB - Evidence based public health requires knowledge about successful dissemination of public health measures. This study analyses (a) the changes in worksite tobacco prevention (TP) in the Canton of Zurich, Switzerland, between 2007 and 2009; (b1) the results of a multistep versus a "brochure only" dissemination strategy; (b2) the results of a monothematic versus a comprehensive dissemination strategy that aim to get companies to adopt TP measures; and (c) whether worksite TP is associated with health-related outcomes. A longitudinal design with randomized control groups was applied. Data on worksite TP and health-related outcomes were gathered by a written questionnaire (baseline n = 1627; follow-up n = 1452) and analysed using descriptive statistics, nonparametric procedures, and ordinal regression models. TP measures at worksites improved slightly between 2007 and 2009. The multistep dissemination was superior to the "brochure only" condition. No significant differences between the monothematic and the comprehensive dissemination strategies were observed. However, improvements in TP measures at worksites were associated with improvements in health-related outcomes. Although dissemination was approached at a mass scale, little change in the advocated adoption of TP measures was observed, suggesting the need for even more aggressive outreach or an acceptance that these channels do not seem to be sufficiently effective. PMID- 26504777 TI - Comparative Study of the Accuracy of Different Techniques for the Laboratory Diagnosis of Schistosomiasis Mansoni in Areas of Low Endemicity in Barra Mansa City, Rio de Janeiro State, Brazil. AB - Schistosomiasis constitutes a major public health problem, with an estimated 200 million people infected worldwide. Many areas of Brazil show low endemicity of schistosomiasis, and the current standard parasitological techniques are not sufficiently sensitive to detect the low-level helminth infections common in areas of low endemicity (ALEs). This study compared the Kato-Katz (KK); Hoffman, Pons, and Janer (HH); enzyme-linked immunosorbent assay- (ELISA-) IgG and ELISA IgM; indirect immunofluorescence technique (IFT-IgM); and qPCR techniques for schistosomiasis detection in serum and fecal samples, using the circumoval precipitin test (COPT) as reference. An epidemiological survey was conducted in a randomized sample of residents from five neighborhoods of Barra Mansa, RJ, with 610 fecal and 612 serum samples. ELISA-IgM (21.4%) showed the highest positivity and HH and KK techniques were the least sensitive (0.8%). All techniques except qPCR-serum showed high accuracy (82-95.5%), differed significantly from COPT in positivity (P < 0.05), and showed poor agreement with COPT. Medium agreement was seen with ELISA-IgG (Kappa = 0.377) and IFA (Kappa = 0.347). Parasitological techniques showed much lower positivity rates than those by other techniques. We suggest the possibility of using a combination of laboratory tools for the diagnosis of schistosomiasis in ALEs. PMID- 26504779 TI - Challenges and Opportunities for Exploring Patient-Level Data. AB - The proper exploration of patient-level data will pave the way towards personalised medicine. To better assess the state of the art in this field we identify the challenges and uncover the opportunities for the exploration of patient-level data through the review of well-known initiatives and projects focusing on the exploration of patient-level data. These cover a broad array of topics, from genomics to patient registries up to rare diseases research, among others. For each, we identified basic goals, involved partners, defined strategies and key technological and scientific outcomes, establishing the foundation for our analysis framework with four pillars: control, sustainability, technology, and science. Substantial research outcomes have been produced towards the exploration of patient-level data. The potential behind these data will be essential to realise the personalised medicine premise in upcoming years. Hence, relevant stakeholders continually push forward new developments in this domain, bringing novel opportunities that are ripe for exploration. Despite last decade's translational research advances, personalised medicine is still far from being a reality. Patients' data underlying potential goes beyond daily clinical practice. There are miscellaneous challenges and opportunities open for the exploration of these data by academia and business stakeholders. PMID- 26504780 TI - Prognostic Value of Cancer Stem Cells Markers in Triple-Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) has a significant clinical relevance of being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. Increased aggressiveness of this tumor, as well as resistance to standard drug therapies, may be associated with the presence of stem cell populations within the tumor. Several stemness markers have been described for the various histological subtypes of breast cancer, such as CD44, CD24, CD133, ALDH1, and ABCG2. The role of these markers in breast cancer is not clear yet and above all there are conflicting opinions about their real prognostic value. To investigate the role of CSCs markers in TNBC cancerogenesis and tumor progression, we selected 160 TNBCs samples on which we detected protein expression of CD44, CD24, CD133, ALDH1, and ABCG2 by immunohistochemistry. Our results highlighted a real prognostic role only for CD44 in TNBCs. All other CSCs markers do not appear to be related to the survival of TNBC patients. In conclusion, despite the fact that the presence of the cancer stem cells in the tumor provides important information on its potential aggressiveness, today their detection by immunohistochemistry is not sufficient to confirm their role in carcinogenesis, because specific markers probably are not yet identified. PMID- 26504781 TI - Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model. AB - Mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). We have previously developed a mouse model that imitates a TTN truncation mutation we found in a large pedigree with DCM. While heterozygous Ttn knock-in mice do not display signs of heart failure under sedentary conditions, they recapitulate the human phenotype when exposed to the pharmacological stressor angiotensin II or isoproterenol. In this study we investigated the effects of pressure overload by transverse aortic constriction (TAC) in heterozygous (Het) Ttn knock-in mice. Two weeks after TAC, Het mice developed marked impairment of left ventricular ejection fraction (p < 0.05), while wild-type (WT) TAC mice did not. Het mice also trended toward increased ventricular end diastolic pressure and volume compared to WT littermates. We found an increase in histologically diffuse cardiac fibrosis in Het compared to WT in TAC mice. This study shows that a pattern of DCM can be induced by TAC-mediated pressure overload in a TTN-truncated mouse model. This model enlarges our arsenal of cardiac disease models, adding a valuable tool to understand cardiac pathophysiological remodeling processes and to develop therapeutic approaches to combat heart failure. PMID- 26504782 TI - Social Cognitive Mediators of Sociodemographic Differences in Colorectal Cancer Screening Uptake. AB - BACKGROUND: This study examined if and how sociodemographic differences in colorectal cancer (CRC) screening uptake can be explained by social cognitive factors. METHODS: Face-to-face interviews were conducted with individuals aged 60 70 years (n = 1309) living in England as part of a population-based omnibus survey. RESULTS: There were differences in screening uptake by SES, marital status, ethnicity, and age but not by gender. Perceived barriers (stand. b = 0.40, p < 0.001), social norms (stand. b = 0.33, p < 0.001), and screening knowledge (stand. b = 0.17, p < 0.001) had independent associations with uptake. SES differences in uptake were mediated through knowledge, social norms, and perceived barriers. Ethnic differences were mediated through knowledge. Differences in uptake by marital status were primarily mediated through social norms and to a lesser extent through knowledge. Age differences were largely unmediated, except for a small mediated effect via social norms. CONCLUSIONS: Sociodemographic differences in CRC screening uptake were largely mediated through social cognitive factors. Impact. Our findings suggest that multifaceted interventions might be needed to reduce socioeconomic inequalities. Ethnic differences might be reduced through improved screening knowledge. Normative interventions could emphasise screening as an activity endorsed by important others outside the immediate family to appeal to a wider audience. PMID- 26504783 TI - Potential of Newborn and Adult Stem Cells for the Production of Vascular Constructs Using the Living Tissue Sheet Approach. AB - Bypass surgeries using native vessels rely on the availability of autologous veins and arteries. An alternative to those vessels could be tissue-engineered vascular constructs made by self-organized tissue sheets. This paper intends to evaluate the potential use of mesenchymal stem cells (MSCs) isolated from two different sources: (1) bone marrow-derived MSCs and (2) umbilical cord blood derived MSCs. When cultured in vitro, a proportion of those cells differentiated into smooth muscle cell- (SMC-) like cells and expressed contraction associated proteins. Moreover, these cells assembled into manipulable tissue sheets when cultured in presence of ascorbic acid. Tubular vessels were then produced by rolling those tissue sheets on a mandrel. The architecture, contractility, and mechanical resistance of reconstructed vessels were compared with tissue engineered media and adventitia produced from SMCs and dermal fibroblasts, respectively. Histology revealed a collagenous extracellular matrix and the contractile responses measured for these vessels were stronger than dermal fibroblasts derived constructs although weaker than SMCs-derived constructs. The burst pressure of bone marrow-derived vessels was higher than SMCs-derived ones. These results reinforce the versatility of the self-organization approach since they demonstrate that it is possible to recapitulate a contractile media layer from MSCs without the need of exogenous scaffolding material. PMID- 26504784 TI - Alginate/Poly(gamma-glutamic Acid) Base Biocompatible Gel for Bone Tissue Engineering. AB - A technique for synthesizing biocompatible hydrogels by cross-linking calcium form poly(gamma-glutamic acid), alginate sodium, and Pluronic F-127 was created, in which alginate can be cross-linked by Ca(2+) from Ca-gamma-PGA directly and gamma-PGA molecules introduced into the alginate matrix to provide pH sensitivity and hemostasis. Mechanical properties, swelling behavior, and blood compatibility were investigated for each hydrogel compared with alginate and for gamma-PGA hydrogel with the sodium form only. Adding F-127 improves mechanical properties efficiently and influences the temperature-sensitive swelling of the hydrogels but also has a minor effect on pH-sensitive swelling and promotes anticoagulation. MG-63 cells were used to test biocompatibility. Gelation occurred gradually through change in the elastic modulus as the release of calcium ions increased over time and caused ionic cross-linking, which promotes the elasticity of gel. In addition, the growth of MG-63 cells in the gel reflected nontoxicity. These results showed that this biocompatible scaffold has potential for application in bone materials. PMID- 26504785 TI - MicroRNAs as Important Players and Biomarkers in Oral Carcinogenesis. AB - Oral cancer, represented mainly by oral squamous cell carcinoma (OSCC), is the eighth most common type of human cancer worldwide. The number of new OSCC cases is increasing worldwide, especially in the low-income countries, and the prognosis remains poor in spite of recent advances in the diagnostic and therapeutic modalities. MicroRNAs (miRNAs), 18-25 nucleotides long noncoding RNA molecules, have recently gained significant attention as potential regulators and biomarkers for carcinogenesis. Recent data show that several miRNAs are deregulated in OSCC, and they have either a tumor suppressive or an oncogenic role in oral carcinogenesis. This review summarizes current knowledge on the role of miRNAs as tumor promotors or tumor suppressors in OSCC development and discusses their potential value as diagnostic and prognostic markers in OSCC. PMID- 26504786 TI - Beyond the Limits: Clinical Utility of Novel Cardiac Biomarkers. AB - Preoperative assessment of cardiovascular risk is essential when it comes to extensive noncardiac surgery procedures. Therefore, accurate and timely diagnosis of myocyte damage is vital. In modern medical practice it is believed that the so called "multimarker" approach is the most appropriate and most accurate, but new research points out that there are novel biomarkers which could be used independently. Studies that evaluate miRNA, H-FABP, and MR-PAMP give encouraging results. When it comes to miRNA clinical studies show high statistical significance, especially in the case of acute myocardial infarction (P = 0.001). Statistical significance of P = 0.007 was found in acute coronary syndrome, when H-FABP was measured. Biochemical marker MR-PAMP showed statistical significance of P < 0.0001 in most clinical studies. PMID- 26504787 TI - Decolorization of Distillery Spent Wash Using Biopolymer Synthesized by Pseudomonas aeruginosa Isolated from Tannery Effluent. AB - A bacterial strain was isolated from tannery effluent which can tolerate high concentrations of potassium dichromate up to 1000 ppm. The isolated microorganism was identified as Pseudomonas aeruginosa by performing biochemical tests and molecular characterization. In the presence of excess of carbohydrate source, which is a physiological stress, this strain produces Polyhydroxybutyrate (PHB). This intracellular polymer, which is synthesized, is primarily a product of carbon assimilation and is employed by microorganisms as an energy storage molecule to be metabolized when other common energy sources are limitedly available. Efforts were taken to check whether the PHB has any positive effect on spent wash decolorization. When a combination of PHB and the isolated bacterial culture was added to spent wash, a maximum color removal of 92.77% was found which was comparatively higher than the color removed when the spent wash was treated individually with the PHB and Pseudomonas aeruginosa. PHB behaved as a support material for the bacteria to bind to it and thus develops biofilm, which is one of the natural physiological growth forms of microorganisms. The bacterial growth in the biofilm and the polymer together acted in synergy, adsorbing and coagulating the pollutants in the form of color pigments. PMID- 26504788 TI - Do Italian Companies Manage Work-Related Stress Effectively? A Process Evaluation in Implementing the INAIL Methodology. AB - Studies on Intervention Process Evaluation are attracting growing attention in the literature on interventions linked to stress and the wellbeing of workers. There is evidence that some elements relating to the process and content of an intervention may have a decisive role in implementing it by facilitating or hindering the effectiveness of the results. This study aimed to provide a process evaluation on interventions to assess and manage risks related to work-related stress using a methodological path offered by INAIL. The final sample is composed of 124 companies participating to an interview on aspects relating to each phase of the INAIL methodological path put in place to implement the intervention. INAIL methodology has been defined as useful in the process of assessing and managing the risks related to work-related stress. Some factors related to the process (e.g., implementation of a preliminary phase, workers' involvement, and use of external consultants) showed a role in significant differences that emerged in the levels of risk, particularly in relation to findings from the preliminary assessment. Main findings provide information on the key aspects of process and content that are useful in implementing an intervention for assessing and managing risks related to work-related stress. PMID- 26504790 TI - Evaluation of the Effectiveness and Implementation of an Adapted Evidence-Based Mammography Intervention for African American Women. AB - Breast cancer mortality disparities continue, particularly for uninsured and minority women. A number of effective evidence-based interventions (EBIs) exist for addressing barriers to mammography screening; however, their uptake and use in community has been limited. Few cancer-specific studies have evaluated adapted EBIs in new contexts, and fewer still have considered implementation. This study sought to (1) evaluate the effectiveness of an adapted mammography EBI in improving appointment keeping in African American women and (2) describe processes of implementation in a new practice setting. We used the type 1 hybrid design to test effectiveness and implementation using a quasi-experimental design. Logistic regression and intent-to-treat analysis were used to evaluate mammography appointment attendance. The no-show rate was 44% (comparison) versus 19% (intervention). The adjusted odds of a woman in the intervention group attending her appointment were 3.88 (p < 0.001). The adjusted odds of a woman attending her appointment in the intent-to-treat analysis were 2.31 (p < 0.05). Adapted EBI effectiveness was 3.88 (adjusted OR) versus 2.10 (OR) for the original program, indicating enhanced program effect. A number of implementation barriers and facilitators were identified. Our findings support previous studies noting that sequentially measuring EBI efficacy and effectiveness, followed by implementation, may be missing important contextual information. PMID- 26504789 TI - Genomic and Histopathological Tissue Biomarkers That Predict Radiotherapy Response in Localised Prostate Cancer. AB - Localised prostate cancer, in particular, intermediate risk disease, has varied survival outcomes that cannot be predicted accurately using current clinical risk factors. External beam radiotherapy (EBRT) is one of the standard curative treatment options for localised disease and its efficacy is related to wide ranging aspects of tumour biology. Histopathological techniques including immunohistochemistry and a variety of genomic assays have been used to identify biomarkers of tumour proliferation, cell cycle checkpoints, hypoxia, DNA repair, apoptosis, and androgen synthesis, which predict response to radiotherapy. Global measures of genomic instability also show exciting capacity to predict survival outcomes following EBRT. There is also an urgent clinical need for biomarkers to predict the radiotherapy fraction sensitivity of different prostate tumours and preclinical studies point to possible candidates. Finally, the increased resolution of next generation sequencing (NGS) is likely to enable yet more precise molecular predictions of radiotherapy response and fraction sensitivity. PMID- 26504791 TI - Fungal Antagonism Assessment of Predatory Species and Producers Metabolites and Their Effectiveness on Haemonchus contortus Infective Larvae. AB - The objective of this study was to assess antagonism of nematophagous fungi and species producers metabolites and their effectiveness on Haemonchus contortus infective larvae (L3). Assay A assesses the synergistic, additive, or antagonistic effect on the production of spores of fungal isolates of the species Duddingtonia flagrans, Clonostachys rosea, Trichoderma esau, and Arthrobotrys musiformis; Assay B evaluates in vitro the effect of intercropping of these isolates grown in 2% water-agar (2% WA) on L3 of H. contortus. D. flagrans (Assay A) produced 5.3 * 10(6) spores and associated with T. esau, A. musiformis, or C. rosea reduced its production by 60.37, 45.28, and 49.05%, respectively. T. esau produced 7.9 * 10(7) conidia and associated with D. flagrans, A. musiformis, or C. rosea reduced its production by 39.24, 82.27, and 96.96%, respectively. A. musiformis produced 7.3 * 10(9) spores and associated with D. flagrans, T. esau, or C. rosea reduced its production by 99.98, 99.99, and 99.98%, respectively. C. rosea produced 7.3 * 10(8) conidia and associated with D. flagrans, T. esau, or A. musiformis reduced its production by 95.20, 96.84, and 93.56%, respectively. These results show evidence of antagonism in the production of spores between predators fungi. PMID- 26504792 TI - Cutaneous and Labyrinthine Tolerance of Bioactive Glass S53P4 in Mastoid and Epitympanic Obliteration Surgery: Prospective Clinical Study. AB - OBJECTIVE: To evaluate the cutaneous and the inner ear tolerance of bioactive glass S53P4 when used in the mastoid and epitympanic obliteration for chronic otitis surgery. MATERIAL AND METHODS: Forty-one cases have been included in this prospective study. Cutaneous tolerance was clinically evaluated 1 week, 1 month, and 3 months after surgery with a physical examination of the retroauricular and external auditory canal (EAC) skin and the presence of otalgia; the inner ear tolerance was assessed by bone-conduction hearing threshold 1 day after surgery and by the presence of vertigo or imbalance. RESULTS: All surgeries but 1 were uneventful: all patients maintained the preoperative bone-conduction hearing threshold except for one case in which the round window membrane was opened during the dissection of the cholesteatoma in the hypotympanum and this led to a dead ear. No dizziness or vertigo was reported. Three months after surgery, healing was achieved in all cases with a healthy painless skin. No cases of revision surgery for removal of the granules occurred in this study. CONCLUSION: The bioactive glass S53P4 is a well-tolerated biomaterial for primary or revision chronic otitis surgery, as shown by the local skin reaction which lasted less than 3 months and by the absence of labyrinthine complications. PMID- 26504793 TI - Working Atmosphere and Job Satisfaction of Health Care Staff in Kenya: An Exploratory Study. AB - BACKGROUND: Job satisfaction and working atmosphere are important for optimal health care delivery. The study aimed to document working atmosphere and job satisfaction of health care professionals in Kenya and to explore associations between job satisfaction, staff characteristics, and working atmosphere. METHODS: Data from the integrated quality management system (IQMS) for the health sector in Kenya were used. Job satisfaction was measured with 10 items and with additional 5 items adapted to job situation in Kenya. Working atmosphere was measured with 13 item questionnaire. A stepwise linear regression analysis was performed with overall job satisfaction and working atmosphere, aspects of job satisfaction, and individual characteristics. RESULTS: Out of 832 questionnaires handed out, 435 questionnaires were completed (response rate: 52.3%). Health care staff indicated high commitment to provide quality services and low levels regarding the adequacy and functionality of equipment at their work station. The aspect "support of the ministry of health" (beta = 0.577) showed the highest score of explained variance (32.9%) regarding overall job satisfaction. CONCLUSIONS: IQMS which also evaluates job satisfaction and working atmosphere of health care staff provides a good opportunity for strengthening the recruitment and retention of health care staff as well as improving the provision of good quality of care. PMID- 26504794 TI - Osteoprotegerin and TRAIL in Acute Onset of Atrial Fibrillation. AB - BACKGROUND: There is a growing amount of evidence that inflammatory processes are involved in the development of atrial fibrillation (AF) and its complications. We decided to investigate the behavior of osteoprotegerin (OPG) and TNF-related apoptosis inducing ligand (TRAIL) in terms of acute onset of AF. METHODS AND RESULTS: We included 60 patients with acute onset of AF, candidates for pharmacological cardioversion. The presence of cardiovascular comorbidities was connected with higher concentration of OPG and lower level of TRAIL right from the first hours of AF paroxysm. The initial TRAIL level correlated also positively with left ventricle ejection fraction and negatively with left atrium diameter. We found subsequent increase of OPG in subgroups selected on the basis of CHA2DS2-VASc scoring. Although basal concentrations of studied markers did not allow prediction of the restoration of sinus rhythm, we observed important increase of TRAIL concentration in subgroup with sinus rhythm maintenance (94.11 +/- 29.46 versus 111.39 +/- 30.23 pg/mL; p = 0.002). CONCLUSIONS: OPG and TRAIL are associated with the underlying cardiovascular damage in AF, but their balance is modulated by the fact of sinus rhythm restoration. Determining the suitability of OPG and TRAIL as predictive markers in AF requires further prospective studies. PMID- 26504795 TI - Efficacy and Safety of Ashwagandha (Withania somnifera) Root Extract in Improving Sexual Function in Women: A Pilot Study. AB - BACKGROUND: Many women experience sexual dysfunction where there are orgasm disorders and sexual difficulties. Ashwagandha (Withania somnifera) is a herb known to improve the body's physical and psychological condition. OBJECTIVE: The purpose of the study was to determine the efficacy and safety of a high concentration ashwagandha root extract (HCARE) supplementation for improving sexual function in healthy females. METHODS: In this pilot study, 50 study subjects were randomized to either (i) HCARE-treated group or (ii) placebo- (starch-) treated group. The subjects consumed either HCARE or placebo capsules of 300mg twice daily for 8 weeks. Sexual function was assessed using two psychometric scales, the Female Sexual Function Index (FSFI) Questionnaire and the Female Sexual Distress Scale (FSDS), and by the number of total and successful sexual encounters. RESULTS: The analysis indicates that treatment with HCARE leads to significantly higher improvement, relative to placebo, in the FSFI Total score (p < 0.001), FSFI domain score for "arousal" (p < 0.001), "lubrication" (p < 0.001), "orgasm" (p = 0.004), and "satisfaction" (p < 0.001), and also FSDS score (p < 0.001) and the number of successful sexual encounters (p < 0.001) at the end of the treatment. CONCLUSIONS: This study demonstrated that oral administration of HCARE may improve sexual function in healthy women. The present study is registered in the Clinical Trial Registry, Government of India, with a number CTRI/2015/07/006045. PMID- 26504796 TI - Missed Opportunities for the Diagnosis of Colorectal Cancer. AB - OBJECTIVE: To examine patient and medical characteristics which predict a missed diagnostic opportunity (MDO) for colorectal cancer (CRC). METHODS: The sample consisted of 252 patients diagnosed with Stages 1-4 CRC who were diagnosed in the prior six months, had experienced symptoms prior to diagnosis, and were not diagnosed through routine screening. Systematic review of all medical records prior to patients' diagnosis was conducted. An MDO was defined as a clinical encounter where, even in the presence of presumptive CRC symptoms, the CRC diagnostic process is not started. RESULTS: 92 patients (36.5%) experienced an MDO. Almost 80% of alternate diagnoses were other GI-GU diseases, including hemorrhoids and diverticulitis. Stomach pain, anemia, and constipation were the most common symptoms experienced by the MDO group. These symptoms, and weight loss and vomiting, were more likely to be noted in the charts of the MDO patients (P < 0.04). Independent risk factors for MDO included age (<50) [OR = 2.29 (1.14 4.60), P = 0.02] and female sex [OR = 2.19 (1.16-4.16), P = 0.03]. Each additional physician seen, more than doubled the MDO risk [OR = 2.05 (1.53-2.74), P < 0.001]. CONCLUSIONS: Females, younger patients, and those consulting more physicians were all more likely to experience an MDO. Continued increased training of physicians to enhance knowledge of who is vulnerable to CRC is needed in addition to an increased focus to adherence to screening recommendations. PMID- 26504797 TI - A Genetic Algorithm Based Support Vector Machine Model for Blood-Brain Barrier Penetration Prediction. AB - Blood-brain barrier (BBB) is a highly complex physical barrier determining what substances are allowed to enter the brain. Support vector machine (SVM) is a kernel-based machine learning method that is widely used in QSAR study. For a successful SVM model, the kernel parameters for SVM and feature subset selection are the most important factors affecting prediction accuracy. In most studies, they are treated as two independent problems, but it has been proven that they could affect each other. We designed and implemented genetic algorithm (GA) to optimize kernel parameters and feature subset selection for SVM regression and applied it to the BBB penetration prediction. The results show that our GA/SVM model is more accurate than other currently available log BB models. Therefore, to optimize both SVM parameters and feature subset simultaneously with genetic algorithm is a better approach than other methods that treat the two problems separately. Analysis of our log BB model suggests that carboxylic acid group, polar surface area (PSA)/hydrogen-bonding ability, lipophilicity, and molecular charge play important role in BBB penetration. Among those properties relevant to BBB penetration, lipophilicity could enhance the BBB penetration while all the others are negatively correlated with BBB penetration. PMID- 26504798 TI - Mycobacterium avium Subspecies paratuberculosis and Bovine Leukemia Virus Seroprevalence and Associated Risk Factors in Commercial Dairy and Beef Cattle in Northern and Northeastern China. AB - Mycobacterium avium subspecies paratuberculosis (MAP) and bovine leukemia virus (BLV) are important pathogens, commonly responsible for economical loss to cattle farms all over the world, yet their epidemiology in commercial dairy and beef cattle in China is still unknown. Thus, from September 2013 to December 2014, a large-scale seroprevalence study was conducted to determine the seroprevalence and identify herd-level risk factors associated with MAP and BLV infection. The source sample was 3674 cattle from 113 herds in northern and northeastern China. Antibodies against MAP and BLV were detected using ELISA tests. At animal-level, the seroprevalence of antibodies against MAP and BLV was 11.79% (433/3674) and 18.29% (672/3674), respectively. At herd-level, the seroprevalence of antibodies against MAP and BLV was 20.35% and 21.24% (24/113), respectively. Herd size was identified to be associated with MAP infection while herd size and presence of cattle introduced from other farms were significantly associated with BLV infection. Further research is needed to confirm these findings and improve the knowledge of the epidemiology of these two pathogens in these regions and elsewhere in China. PMID- 26504800 TI - In Vivo Osseointegration Performance of Titanium Dioxide Coating Modified Polyetheretherketone Using Arc Ion Plating for Spinal Implant Application. AB - Polyetheretherketone (PEEK), which has biomechanical performance similar to that of human cancellous bone, is used widely as a spinal implant material. However, its bioinertness and hydrophobic surface properties result in poor osseointegration. This study applies a novel modification method, arc ion plating (AIP), that produces a highly osteoblast compatible titanium dioxide (TiO2) coatings on a PEEK substrate. This PEEK with TiO2 coating (TiO2/PEEK) was implanted into the femurs of New Zealand white male rabbits to evaluate its in vivo performance by the push-out test and histological observation. Analytical results show that AIP can prepare TiO2 coatings on bullet-shaped PEEK substrates as implant materials. After prolonged implantation in rabbits, no signs of inflammation existed. Newly regenerated bone formed more prominently with the TiO2/PEEK implant by histological observation. The shear strength of the bone/implant interface increases as implantation period increases. Most importantly, bone bonding performance of the TiO2/PEEK implant was superior to that of bare PEEK. The rutile-TiO2 coatings achieved better osseointegration than the anatase-TiO2 coatings. Therefore, AIP-TiO2 can serve as a novel surface modification method on PEEK for spinal interbody fusion cages. PMID- 26504799 TI - Developments in Screening Tests and Strategies for Colorectal Cancer. AB - BACKGROUND: Worldwide, colorectal cancer (CRC) is the third most common cancer in men and second most common in women. It is the fourth most common cause of cancer mortality. In the United States, CRC is the third most common cause of cancer and second most common cause of cancer mortality. Incidence and mortality rates have steadily fallen, primarily due to widespread screening. METHODS: We conducted keyword searches on PubMed in four categories of CRC screening: stool, endoscopic, radiologic, and serum, as well as news searches in Medscape and Google News. RESULTS: Colonoscopy is the gold standard for CRC screening and the most common method in the United States. Technological improvements continue to be made, including the promising "third-eye retroscope." Fecal occult blood remains widely used, particularly outside the United States. The first at-home screen, a fecal DNA screen, has also recently been approved. Radiological methods are effective but seldom used due to cost and other factors. Serum tests are largely experimental, although at least one is moving closer to market. CONCLUSIONS: Colonoscopy is likely to remain the most popular screening modality for the immediate future, although its shortcomings will continue to spur innovation in a variety of modalities. PMID- 26504801 TI - Characteristics and Outcomes of Patients with Acute Myocardial Infarction at Non PCI Capable Hospitals in 2007 and in 2014. AB - BACKGROUND: There is little known about whether characteristics and outcomes of patients with acute myocardial infarction (AMI) have changed over the years in non-PCI capable hospitals in real-life. Our aim was to assess them between 2007 and 2014. METHODS: It was a retrospective cohort study. Characteristics and in hospital mortality (standardized in cases of different characteristics between the groups by original simple method) were assessed for all patients with non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI) at two non-PCI capable hospitals: one in 2007 (n = 104) and another in 2014 (n = 58). RESULTS: In 2014, females were older than in 2007 (80.18 +/- 7.54 versus 76.15 +/- 8.77, p = 0.011), males were younger (71.61 +/- 11.22 versus 79.20 +/- 7.63, p = 0.019), less had renal failure (RF) (19% versus 34.6%, p < 0.0001) and reinfarction (13.8% versus 35.6%, p < 0.0001), and the proportion of males (31% versus 43.3%, p = 0.001) and the proportion of NSTEMI (60.3 versus 69.2, p < 0.0001) decreased. In cases of STEMI there were no differences in patient characteristics. STEMI (18.8% versus 21.7%) and standardized mortalities by gender, RF, and reinfarction NSTEMI (19.47%, 15.34%, and 17.5%, resp., versus 17.1%) showed no differences between 2007 and 2014. CONCLUSIONS: There were some differences in patient characteristics but not in mortality for AMI at non-PCI capable hospitals between 2007 and 2014. PMID- 26504802 TI - Prognostic Value of Homotypic Cell Internalization by Nonprofessional Phagocytic Cancer Cells. AB - BACKGROUND: In this study, we investigated the prognostic role of homotypic tumor cell cannibalism in different cancer types. METHODS: The phenomenon of one cell being internalized into another, which we refer to as "cell-in-cell event," was assessed in 416 cases from five head and neck cancer cohorts, as well as one anal and one rectal cancer cohort. The samples were processed into tissue microarrays and immunohistochemically stained for E-cadherin and cleaved caspase-3 to visualize cell membranes and apoptotic cell death. RESULTS: Cell-in-cell events were found in all of the cohorts. The frequency ranged from 0.7 to 17.3 cell-in cell events per mm(2). Hardly any apoptotic cells were found within the cell-in cell structures, although apoptotic cell rates were about 1.6 to two times as high as cell-in-cell rates of the same tissue sample. High numbers of cell-in cell events showed adverse effects on patients' survival in the head and neck and in the rectal cancer cohorts. In multivariate analysis, high frequency was an adverse prognostic factor for overall survival in patients with head and neck cancer (p = 0.008). CONCLUSION: Cell-in-cell events were found to predict patient outcomes in various types of cancer better than apoptosis and proliferation and might therefore be used to guide treatment strategies. PMID- 26504803 TI - miR-125b Suppresses Proliferation and Invasion by Targeting MCL1 in Gastric Cancer. AB - Understanding the molecular mechanisms underlying gastric cancer progression contributes to the development of novel targeted therapies. In this study, we found that the expression levels of miR-125b were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Additionally, miR-125b could independently predict OS and DFS in gastric cancer. We further found that upregulation of miR-125b inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. miR 125b elicits these responses by directly targeting MCL1 (myeloid cell leukemia 1), which results in a marked reduction in MCL1 expression. Transfection of miR 125b sensitizes gastric cancer cells to 5-FU-induced apoptosis. By understanding the function and molecular mechanisms of miR-125b in gastric cancer, we may learn that miR-125b has the therapeutic potential to suppress gastric cancer progression and increase drug sensitivity to gastric cancer. PMID- 26504804 TI - Short-Term Effects of Verapamil and Diltiazem in the Treatment of No Reflow Phenomenon: A Meta-Analysis of Randomized Controlled Trials. AB - Currently, there is still a lack of an optimal treatment for no reflow phenomenon (NRP). We analyzed the efficacy and safety of using nondihydropyridine calcium channel antagonists (NDHP, verapamil/diltiazem) in patients suffering from NRP. Eight RCTs with 494 participants were eligible for analysis. The pooling analysis showed that intracoronary verapamil/diltiazem injection significantly decreased the occurrence of the coronary NRP (RR: 0.3, 95% CI: 0.16-0.57; P = 0.0002) and reduced corrected thrombolysis in myocardial infarction (TIMI) frame Count (WMD = -9.24, 95% CI -13.91-4.57; P = 0.0001) in patients with NRP. Moreover, verapamil/diltiazem treatment showed superiority in reducing wall motion index (WMI) compared to the control at day 1 (WMD = 0.11, 95% CI: 0.02-0.20; P = 0.02) (P < 0.05). There was also a significantly greater decline at occurrence of the major adverse cardiac events between verapamil/diltiazem and control groups (WMD: 0.4, 95% CI: 0.19-0.84; P = 0.02). However, using verapamil/diltiazem did not provide additional improvement of left ventricular ejection fraction post procedure (at 7 days, WMD, 0.1; 95% CI, -2.43-2.63; P = 0.94; at 30 days, WMD, 0.42; 95% CI, -2.09-2.92; P = 0.75). NDHP use is beneficial in attenuating NRP and reducing 6-month MACEs in patients with NRP. PMID- 26504805 TI - Serological Diagnosis and Follow-Up of Human Cystic Echinococcosis: A New Hope for the Future? AB - Cystic echinococcosis (CE) is an important helminthic zoonotic disease caused by the Echinococcus granulosus complex. In humans, CE is a chronic disease driven by the growth of echinococcal cysts in different organs. Prognosis of this disease depends on multiple factors, including location, number, size, and stage of the cysts, making CE a disease of complex management. CE is usually asymptomatic for years and attracts limited attention from funding organizations and health authorities. For this reason, only experts' recommendations are available but no evidence-based conclusions have been drawn for CE clinical management. One of those pitfalls refers to the lack of evidence to support the use of serological tools for the diagnosis and follow-up of CE patients. In this respect, crude antigens are used to detect specific antibodies in patients, giving rise to false positive results. The advent of molecular techniques allowing the production of recombinant proteins has provided a number of candidate antigens that could overcome the problems associated with the use of crude parasite extracts in the serological assays. In this review, we present the last advances in this field, proposing the use of serology to support cyst stage-specific diagnosis and follow up. PMID- 26504806 TI - The Prevalence of Skilled Birth Attendant Utilization and Its Correlates in North West Ethiopia. AB - The low utilization of skilled birth attendants sustained high maternal mortality. The aim of this study was to assess its magnitude and correlates in Northwest Ethiopia. A study was conducted on 373 randomly selected women who gave birth in the 12 months preceding the survey. Correlates were identified using binary logistic regression. Skilled birth attendance was 18.8%. Inability to perform cultural practices in health facilities (65.5%), expecting smooth delivery (63.4%), and far distance (62%) were the main barriers. Women with urban residence (AOR = 5.46: 95% CI [2.21-13.49]), primary (AOR = 2.10: 95% CI [0.71 6.16]) and secondary-plus (AOR = 6.12: [1.39-26.92]) educational level, four-plus ANC visits (AOR = 17.33: 95% CI [4.22-71.29]), and proximity to health centers (AOR = 5.67: 95% CI [1.47-25.67]) had higher odds of using skilled birth attendants though women with no labor complications had lower odds (AOR = 0.02: 95% CI [0.01-0.05]). Skilled birth attendance use was low. Urban residence, primary-plus level of education, frequent ANC visits, living nearby the health centers, and a problem during labor were positively correlated with skilled birth attendance utilization. Stakeholders should enhance girls' education beyond primary level and ANC services and shorten distances to health facilities. PMID- 26504807 TI - Effects of rhBMP-2 on Sandblasted and Acid Etched Titanium Implant Surfaces on Bone Regeneration and Osseointegration: Spilt-Mouth Designed Pilot Study. AB - This study was conducted to evaluate effects of rhBMP-2 applied at different concentrations to sandblasted and acid etched (SLA) implants on osseointegration and bone regeneration in a bone defect of beagle dogs as pilot study using split mouth design. Methods. For experimental groups, SLA implants were coated with different concentrations of rhBMP-2 (0.1, 0.5, and 1 mg/mL). After assessment of surface characteristics and rhBMP-2 releasing profile, the experimental groups and untreated control groups (n = 6 in each group, two animals in each group) were placed in split-mouth designed animal models with buccal open defect. At 8 weeks after implant placement, implant stability quotients (ISQ) values were recorded and vertical bone height (VBH, mm), bone-to-implant contact ratio (BIC, %), and bone volume (BV, %) in the upper 3 mm defect areas were measured. Results. The ISQ values were highest in the 1.0 group. Mean values of VBH (mm), BIC (%), and BV (%) were greater in the 0.5 mg/mL and 1.0 mg/mL groups than those in 0.1 and control groups in buccal defect areas. Conclusion. In the open defect area surrounding the SLA implant, coating with 0.5 and 1.0 mg/mL concentrations of rhBMP-2 was more effective, compared with untreated group, in promoting bone regeneration and osseointegration. PMID- 26504809 TI - Efficacy of Clonostachys rosea and Duddingtonia flagrans in Reducing the Haemonchus contortus Infective Larvae. AB - The biocontrol is proven effective in reducing in vitro and in situ free-living stages of major gastrointestinal helminths, allowing progress in reducing losses by parasitism, maximizing production, and productivity. This study aimed at evaluating the predatory activity of fungal isolates of Duddingtonia flagrans and Clonostachys rosea species and its association on infective larvae (L3) of H. contortus in microplots formed by grasses and maintained in a protected environment. All groups were added with 10 mL of an aqueous suspension with 618 H. contortus L3 approximately. Group 1 was used as control and only received the infective larvae. Groups 2 and 3 received D. flagrans chlamydospores and C. rosea conidia at doses of 5 * 10(6). Group 4 received the combination of 5 * 10(6) D. flagrans chlamydospores + 5 * 10(6) C. rosea conidia. D. flagrans and C. rosea showed nematicidal effectiveness reducing by 91.5 and 88.9%, respectively, the population of H. contortus L3. However, when used in combination efficiency decreased to 74.5% predation of H. contortus L3. These results demonstrate the need for further studies to determine the existence of additive effects, synergistic or antagonistic, between these species. PMID- 26504808 TI - The Relationship between Neighborhood Immigrant Composition, Limited English Proficiency, and Late-Stage Colorectal Cancer Diagnosis in California. AB - Despite the availability of effective early detection technologies, more than half (61%) of colorectal cancers in the United States and 55% in California are identified at an advanced stage. Data on colorectal cancer patients (N = 35,030) diagnosed from 2005 to 2007 were obtained from the California Cancer Registry. Multivariate analyses found a relationship among neighborhood concentration of recent immigrants, neighborhood rates of limited English proficiency, and late stage colorectal cancer diagnosis. Hispanics living in neighborhoods with a greater percentage of recent immigrants (compared to the lowest percentage) had greater odds (OR 1.57, 95% CI 1.22, 2.02) of late-stage diagnosis whereas Hispanics living in neighborhoods with the highest percentage of limited English proficiency (compared to the lowest percentage) had lower odds (OR .71, 95% CI .51, .99) of late-stage diagnosis. These relationships were not observed for other ethnic groups. Results highlight the complex relationship among race/ethnicity, neighborhood characteristics, and colorectal cancer stage at diagnosis. PMID- 26504810 TI - Neonatal Death and Heart Failure in Mouse with Transgenic HSP60 Expression. AB - Mitochondrial heat shock proteins, such as HSP60, are chaperones responsible for the folding, transport, and quality control of mitochondrial matrix proteins and are essential for maintaining life. Both prosurvival and proapoptotic roles have been proposed for HSP60, and HSP60 is reportedly involved in the initiation of autoimmune, metabolic, and cardiovascular diseases. The role of HSP60 in pathogenesis of these diseases remains unclear, partly because of the lack of mouse models expressing HSP60. In this study we generated HSP60 conditional transgenic mice suitable for investigating in vivo outcomes by expressing HSP60 at the targeted organ in disease models. Ubiquitous HSP60 induction in the embryonic stage caused neonatal death in mice at postnatal day 1. A high incidence of atrial septal defects was observed in HSP60-expressing mice, with increased apoptosis and myocyte degeneration that possibly contributed to massive hemorrhage and sponge-like cardiac muscles. Our results showed that neonatal heart failure through HSP60 induction likely involves developmental defects and excessive apoptosis. The conditional HSP60 mouse model is useful for studying crucial biological questions concerning HSP60. PMID- 26504811 TI - Prevalence, Risk Factors, and Genetic Traits in Metabolically Healthy and Unhealthy Obese Individuals. AB - OBJECTIVE: To assess prevalence of metabolically healthy individuals among patients with abdominal obesity (AO) and to determine phenotype and potential genetic traits associated with a benign metabolic status. METHODS: 503 AO patients without cardiovascular diseases were examined. Waist circumference (WC), BMI, blood pressure, plasma glucose and serum insulin levels, HOMA-IR, lipid profile, and adiponectin (AN) and leptin (LEP) concentrations in serum were measured. Polymorphisms A19G and Q223R of the LEP and LEP receptor gene, and G276T and T45G of the AN gene were investigated. RESULTS: 91.3% of patients were metabolically unhealthy obese (MUO), and 8.7% metabolically healthy obese (MHO). MHO patients were younger, and had lesser BMI and WC, while duration of obesity, frequency, and duration of physical training were greater than MUO patients (p < 0.05). In MHO and MUO patients distribution of the G19G, G19A, and A19A genotypes of the LEP gene and G276G, G276T, and T276T genotypes of AN gene did not differ. The T45T genotype was associated with increase of metabolic disorders' risk for patients with AO (OR = 2.331; 95% CI = 1.121 / 5.132). CONCLUSIONS: Prevalence of MHO individuals among patients with AO is low. Benign metabolic status was associated with younger age, lower waist circumference, and higher physical activity, shorter duration of obesity, and G45G adiponectin genotype carriage. PMID- 26504812 TI - Collagen/Beta-Tricalcium Phosphate Based Synthetic Bone Grafts via Dehydrothermal Processing. AB - Millions of patients worldwide remain inadequately treated for bone defects related to factors such as disease or trauma. The drawbacks of metallic implant and autograft/allograft use have steered therapeutic approaches towards tissue engineering solutions involving tissue regeneration scaffolds. This study proposes a composite scaffold with properties tailored to address the macro- and microenvironmental conditions deemed necessary for successful regeneration of bone in defect areas. The biodegradable scaffold composed of porous beta tricalcium phosphate particles and collagen type I fibers is prepared from a mixture of collagen type-I and beta-tricalcium phosphate (beta-TCP) particles via lyophilization, followed by dehydrothermal (DHT) processing. The effects of both sterilization via gamma radiation and the use of DHT processing to achieve cross linking were investigated. The impact of the chosen fabrication methods on scaffold microstructure and beta-TCP particle-collagen fiber combinations were analyzed using X-ray diffractometry (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and microcomputerized tomography (u-CT). Electron spinning resonance (ESR) analysis was used to investigate free radicals formation following sterilization. Results revealed that the highly porous (65% porosity at an average of 100 um pore size), mechanically adequate, and biocompatible scaffolds can be utilized for bone defect repairs. PMID- 26504813 TI - Histological Comparison in Rats between Carbonate Apatite Fabricated from Gypsum and Sintered Hydroxyapatite on Bone Remodeling. AB - Carbonate apatite (CO3Ap), the form of apatite found in bone, has recently attracted attention. The purpose of the present study was to histologically evaluate the tissue/cellular response toward the low-crystalline CO3Ap fabricated using a dissolution-precipitation reaction with set gypsum as a precursor. When set gypsum was immersed in a 100 degrees C 1 mol/L Na3PO4 aqueous solution for 24 h, the set gypsum transformed into CO3Ap. Both CO3Ap and sintered hydroxyapatite (s-HAp), which was used as a control, were implanted into surgically created tibial bone defects of rats for histological evaluation. Two and 4 weeks after the implantation, histological sections were created and observed using light microscopy. The CO3Ap granules revealed both direct apposition of the bone matrix by osteoblasts and osteoclastic resorption. In contrast, the s-HAp granules maintained their contour even after 4 weeks following implantation which implied that there was a lack of replacement into the bone. The s-HAp granules were sometimes encapsulated with fibrous tissue, and macrophage polykaryon was occasionally observed directly apposed to the implanted granules. From the viewpoint of bone remodeling, the CO3Ap granules mimicked the bone matrix, suggesting that CO3Ap may be an appropriate bone substitute. PMID- 26504814 TI - Magnet-Facilitated Selection of Electrogenic Bacteria from Marine Sediment. AB - Some bacteria can carry out anaerobic respiration by depositing electrons on external materials, such as electrodes, thereby creating an electrical current. Into the anode chamber of microbial fuel cells (MFCs) having abiotic air-cathodes we inoculated microorganisms cultured from a magnetic particle-enriched portion of a marine tidal sediment, reasoning that since some external electron acceptors are ferromagnetic, electrogenic bacteria should be found in their vicinity. Two MFCs, one inoculated with a mixed bacterial culture and the other with an axenic culture of a helical bacterium isolated from the magnetic particle enrichment, termed strain HJ, were operated for 65 d. Both MFCs produced power, with production from the mixed culture MFC exceeding that of strain HJ. Strain HJ was identified as a Thalassospira sp. by transmission electron microscopic analysis and 16S rRNA gene comparisons. An MFC inoculated with strain HJ and operated in open circuit produced 47% and 57% of the maximal power produced from MFCs inoculated with the known electrogen Geobacter daltonii and the magnetotactic bacterium Desulfamplus magnetomortis, respectively. Further investigation will be needed to determine whether bacterial populations associated with magnetic particles within marine sediments are enriched for electrogens. PMID- 26504815 TI - Overview of the Diagnostic Methods Used in the Field for Human African Trypanosomiasis: What Could Change in the Next Years? AB - Sleeping sickness is a parasitic infection caused by two species of trypanosomes (Trypanosoma brucei gambiense and rhodesiense), transmitted by the tsetse fly. The disease eventually affects the central nervous system, resulting in severe neurological symptoms. Without treatment, death is inevitable. During the first stage of the disease, infected patients are mildly symptomatic and early detection of infection allows safer treatment (administered on an outpatient basis) which can avoid death; routine screening of the exposed population is necessary, especially in areas of high endemicity. The current therapeutic treatment of this disease, especially in stage 2, can cause complications and requires a clinical surveillance for several days. A good stage diagnosis of the disease is the cornerstone for delivering the adequate treatment. The task faced by the medical personnel is further complicated by the lack of support from local health infrastructure, which is at best weak, but often nonexistent. Therefore it is crucial to look for new more efficient technics for the diagnosis of stage which are also best suited to use in the field, in areas not possessing high level health facilities. This review, after an overview of the disease, summarizes the current diagnosis procedures and presents the advances in the field. PMID- 26504816 TI - Endothelial Expression of Scavenger Receptor Class B, Type I Protects against Development of Atherosclerosis in Mice. AB - The role of scavenger receptor class B, type I (SR-BI) in endothelial cells (EC) was examined in several novel transgenic mouse models expressing SR-BI in endothelium of mice with normal C57Bl6/N, apoE-KO, or Scarb1-KO backgrounds. Mice were also created expressing SR-BI exclusively in endothelium and liver. Endothelial expression of the Tie2-Scarb1 transgene had no significant effect on plasma lipoprotein levels in mice on a normal chow diet but on an atherogenic diet, significantly decreased plasma cholesterol levels, increased plasma HDL cholesterol (HDL-C) levels, and protected mice against atherosclerosis. In 8 month-old apoE-KO mice fed a normal chow diet, the Tie2-Scarb1 transgene decreased aortic lesions by 24%. Mice expressing SR-BI only in EC and liver had a 1.5 +/- 0.1-fold increase in plasma cholesterol compared to mice synthesizing SR BI only in liver. This elevation was due mostly to increased HDL-C. In EC culture studies, SR-BI was found to be present in both basolateral and apical membranes but greater cellular uptake of cholesterol from HDL was found in the basolateral compartment. In summary, enhanced expression of SR-BI in EC resulted in a less atherogenic lipoprotein profile and decreased atherosclerosis, suggesting a possible role for endothelial SR-BI in the flux of cholesterol across EC. PMID- 26504817 TI - Smoke-Free Workplaces Are Associated with Protection from Second-Hand Smoke at Homes in Nigeria: Evidence for Population-Level Decisions. AB - The evidence suggests that smoke-free workplace policies may change social norms towards exposing others to second-hand smoke at home. The aim of the study was to assess whether being employed in a smoke-free workplace (SFWP) is associated with living in a smoke-free home (SFH). We used the data from the Global Adult Tobacco Survey conducted in Nigeria in 2012, in which 9,765 individuals were interviewed including 1,856 persons who worked indoors. The percentage of Nigerians employed in SFWP that reported living in a SFH was higher compared to those employed in a workplace where smoking occurred (95% versus 73%). Working in a SFWP was associated with a significantly higher likelihood of living in a SFH (OR = 5.3; p < 0.001). Urban inhabitants indicated more frequently that they lived in SFH compared to rural residents (OR = 2.0; p = 0.006). The odds of living in a SFH were significantly higher among nonsmokers and nonsmokeless tobacco users compared to smokers and smokeless tobacco users (OR = 28.8; p < 0.001; OR = 7.0; p < 0.001). These findings support the need for implementation of comprehensive smoke-free policies in Nigeria that result in substantial health benefits. PMID- 26504818 TI - Single-Fraction Radiotherapy for CD30(+) Lymphoproliferative Disorders. AB - OBJECTIVES: CD30(+) lymphoproliferative disorder is a rare variant of cutaneous T cell lymphoma. Sustained complete response following first-line treatments is rare. This retrospective review evaluates the response of refractory or recurrent lesions to palliative radiation therapy. METHODS: The records of 6 patients with 12 lesions, treated with radiation therapy, were reviewed. All patients received previous first-line treatments. Patients with clinical and pathological evidence of symptomatic CD30(+) lymphoproliferative disorder, with no history of other cutaneous T-cell lymphoma variants, and with no prior radiation therapy to the index site were included. RESULTS: The median age of patients was 50.5 years (range, 15-83 years). Median size of the treated lesions was 2.5 cm (range, 2-7 cm). Four sites were treated with a single fraction of 750-800 cGy (n = 3) and 8 sites were treated with 4000-4500 cGy in 200-250 cGy fractions (n = 3). Radiation therapy was administered with electrons and bolus. Median follow-up was 113 months (range, 16-147 months). For all sites, there was 100% complete response with acute grade 1-2 dermatitis. CONCLUSIONS: For recurrent and symptomatic radiation-naive CD30(+) lymphoproliferative disorder lesions, palliative radiation therapy shows excellent response. A single fraction of 750-800 cGy is as effective as a multifractionated course and more convenient. PMID- 26504819 TI - Vascular Damage in Resistant Hypertension: TNF-Alpha Inhibition Effects on Endothelial Cells. AB - Inflammatory cytokines have been associated with the pathophysiology of hypertension and target organ damage (TOD). Resistant hypertensive patients (RHTN) are characterized by poor blood pressure control and higher prevalence of TOD. This study evaluated the relationship between plasma levels of TNF-alpha and arterial stiffness (pulse wave velocity-PWV) in 32 RHTN and 19 normotensive subjects. Moreover, we investigated the effect of TNF-alpha inhibition on human endothelial cells (HUVECs) incubated with serum from RHTN and normotensive subjects. HUVECs containing serum obtained from normotensive (n = 8) and hypertensive (n = 8) individuals were treated with TNF-alpha inhibitor (infliximab). Cell suspensions were used for measurement of DNA fragmentation and reactive oxygen species (ROS) content. RHTN patients showed higher levels of TNF alpha compared to normotensive subjects, as well as higher PWV. Positive correlation was found between TNF-alpha levels and PWV measures in the whole group. HUVECs incubated with serum from RHTN showed increased cell apoptosis and higher ROS content compared to normotensive subjects. Infliximab attenuated the apoptosis of HUVECs incubated with serum from RHTN, but no effect in ROS production was observed. Our findings suggest that TNF-alpha might mediate, at least in part, vascular damage in resistant hypertension. PMID- 26504820 TI - Is Lipoprotein-Associated Phospholipase A2 a Link between Inflammation and Subclinical Atherosclerosis in Rheumatoid Arthritis? AB - OBJECTIVE: Lipoprotein-associated phospholipase A2 (Lp-PLA2), a marker of vascular inflammation, is associated with cardiovascular disease. This prospective study of an inception cohort aimed to investigate whether the level of Lp-PLA2 is associated with subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: Patients from northern Sweden diagnosed with early RA were consecutively recruited into an ongoing prospective study. From these, all patients <=60 years (n = 71) were included for measurements of subclinical atherosclerosis at inclusion (T0) and five years later (T5). Forty age- and sex-matched controls were included. The patients were clinically assessed, SCORE, Reynolds Risk Score, and Larsen score were calculated, and blood samples were drawn from all individuals at T0 and T5. RESULTS: There was no significant difference in the level of Lp-PLA2 between patients with RA and controls (p > 0.05). In simple linear regression models among patients with RA, Lp-PLA2 at T0 was significantly associated with intima media thickness (IMT) at T0 and T5, flow mediated dilation (FMD) at T0 and T5, ever smoking, male sex, HDL cholesterol (inversely), non-HDL-cholesterol, SCORE, Reynolds Risk Score, and Larsen score (p < 0.05). CONCLUSION. In this cohort of patients with early RA, the concentration of Lp-PLA2 was associated with both subclinical atherosclerosis and disease severity. PMID- 26504821 TI - Clinical Applications of S53P4 Bioactive Glass in Bone Healing and Osteomyelitic Treatment: A Literature Review. AB - Nowadays, S53P4 bioactive glass is indicated as a bone graft substitute in various clinical applications. This review provides an overview of the current published clinical results on indications such as craniofacial procedures, grafting of benign bone tumour defects, instrumental spondylodesis, and the treatment of osteomyelitis. Given the reported results that are based on examinations, such as clinical examinations by the surgeons, radiographs, CT, and MRI images, S53P4 bioactive glass may be beneficial in the various reported applications. Especially in craniofacial reconstructions like mastoid obliteration and orbital floor reconstructions, in grafting bone tumour defects, and in the treatment of osteomyelitis very promising results are obtained. Randomized clinical trials need to be performed in order to determine whether bioactive glass would be able to replace the current golden standard of autologous bone usage or with the use of antibiotic containing PMMA beads (in the case of osteomyelitis). PMID- 26504822 TI - Protective Effects of Cilastatin against Vancomycin-Induced Nephrotoxicity. AB - Vancomycin is a very effective antibiotic for treatment of severe infections. However, its use in clinical practice is limited by nephrotoxicity. Cilastatin is a dehydropeptidase I inhibitor that acts on the brush border membrane of the proximal tubule to prevent accumulation of imipenem and toxicity. The aim of this study was to investigate the potential protective effect of cilastatin on vancomycin-induced apoptosis and toxicity in cultured renal proximal tubular epithelial cells (RPTECs). Porcine RPTECs were cultured in the presence of vancomycin with and without cilastatin. Vancomycin induced dose-dependent apoptosis in cultured RPTECs, with DNA fragmentation, cell detachment, and a significant decrease in mitochondrial activity. Cilastatin prevented apoptotic events and diminished the antiproliferative effect and severe morphological changes induced by vancomycin. Cilastatin also improved the long-term recovery and survival of RPTECs exposed to vancomycin and partially attenuated vancomycin uptake by RPTECs. On the other hand, cilastatin had no effects on vancomycin induced necrosis or the bactericidal effect of the antibiotic. This study indicates that cilastatin protects against vancomycin-induced proximal tubule apoptosis and increases cell viability, without compromising the antimicrobial effect of vancomycin. The beneficial effect could be attributed, at least in part, to decreased accumulation of vancomycin in RPTECs. PMID- 26504823 TI - Public Concern about the Sale of High-Caffeine Drinks to Children 12 Years or Younger: An Australian Regulatory Perspective. AB - BACKGROUND: Dietary exposure to high caffeine is a health risk for children. Governments are considering measures to restrict the sale of formulated caffeinated beverages (FCB) to children. Objectives. To investigate community concern about sales of high-caffeine drinks to children among Western Australian adults and describe Australian and New Zealand regulatory processes regarding FCB. METHODS: Data from the 2009 and 2012 Department of Health's Nutrition Monitoring Survey Series of 2,832 Western Australians aged 18-64 years was pooled with descriptive and ordinal logistic regression analysis performed. Current regulatory processes for FCB are reported. RESULTS: Most (85%) participants were concerned about the sale of high-caffeine drinks to children; 77.4% were very concerned in 2012 compared to 66.5% in 2009, p < .008. Females and those living with children had higher concern (odds ratio (OR) 2.11; 95% confidence interval (CI) 1.44-3.10; OR 2.16; 95% CI 1.51-3.09, resp., p < .001). Concern increased with each year of age (OR 1.04; 95% CI 1.02, 1.05, p < .001). CONCLUSIONS: Community concern regarding sale of high-caffeine energy drinks to children is high and increasing. Being female and living with children were associated with greater concern. These findings support the Australian and New Zealand regulatory controls of FCB, including labelling, promotion, and advertising to children. PMID- 26504824 TI - Biosorption of Pb(II) Ions by Klebsiella sp. 3S1 Isolated from a Wastewater Treatment Plant: Kinetics and Mechanisms Studies. AB - Lead biosorption by Klebsiella sp. 3S1 isolated from a wastewater treatment plant was investigated through a Rotatable Central Composite Experimental Design. The optimisation study indicated the following optimal values of operating variables: 0.4 g/L of biosorbent dosage, pH 5, and 34 degrees C. According to the results of the kinetic studies, the biosorption process can be described by a two-step process, one rapid, almost instantaneous, and one slower, both contributing significantly to the overall biosorption; the model that best fits the experimental results was pseudo-second order. The equilibrium studies showed a maximum lead uptake value of 140.19 mg/g according to the Langmuir model. The mechanism study revealed that lead ions were bioaccumulated into the cytoplasm and adsorbed on the cell surface. The bacterium Klebsiella sp. 3S1 has a good potential in the bioremoval of lead in an inexpensive and effective process. PMID- 26504826 TI - SAMHD1 Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis. AB - BACKGROUND: To investigate whether one or more SAMHD1 gene mutations are associated with cerebrovascular disease in the general population using a Chinese stroke cohort. METHODS: Patients with a Chinese Han background (N = 300) diagnosed with either cerebral large-artery atherosclerosis (LAA, n = 100), cerebral small vessel disease (SVD, n = 100), or other stroke-free neurological disorders (control, n = 100) were recruited. Genomic DNA from the whole blood of each patient was isolated, and direct sequencing of the SAMHD1 gene was performed. Both wild type and mutant SAMHD1 proteins identified from the patients were expressed in E. coli and purified; then their dNTPase activities and ability to form stable tetramers were analysed in vitro. RESULTS: Three heterozygous mutations, including two missense mutations c.64C>T (P22S) and c.841G>A (p.E281K) and one splice site mutation c.696+2T>A, were identified in the LAA group with a prevalence of 3%. No mutations were found in the patients with SVD or the controls (p = 0.05). The mutant SAMHD1 proteins were functionally impaired in terms of their catalytic activity as a dNTPase and ability to assemble stable tetramers. CONCLUSIONS: Heterozygous SAMHD1 gene mutations might cause genetic predispositions that interact with other risk factors, resulting in increased vulnerability to stroke. PMID- 26504825 TI - A Comparison of the Process of Remodeling of Hydroxyapatite/Poly-D/L-Lactide and Beta-Tricalcium Phosphate in a Loading Site. AB - Currently, the most commonly used bioresorbable scaffold is made of beta tricalcium phosphate (beta-TCP); it is hoped that scaffolds made of a mixture of hydroxyapatite (HA) and poly-D/L-lactide (PDLLA) will be able to act as novel bioresorbable scaffolds. The aim of this study was to evaluate the utility of a HA/PDLLA scaffold compared to beta-TCP, at a loading site. Dogs underwent surgery to replace a section of tibial bone with a bioresorbable scaffold. After the follow-up period, the scaffold was subjected to histological analysis. The HA/PDLLA scaffold showed similar bone formation and superior cell and tissue infiltration compared to the beta-TCP scaffold, as seen after Villanueva Goldner staining. Moreover, silver staining and immunohistochemistry for Von Willebrand factor and cathepsin K demonstrated better cell infiltration in the HA/PDLLA scaffold. The fibrous tissue and cells that had infiltrated into the HA/PDLLA scaffold tested positive for collagen type I and RUNX2, respectively, indicating that the tissue and cells that had infiltrated into the HA/PDLLA scaffold had the potential to differentiate into bone. The HA/PDLLA scaffold is therefore likely to find clinical application as a new bioresorbable scaffold. PMID- 26504827 TI - Novel Model of Pulmonary Artery Banding Leading to Right Heart Failure in Rats. AB - BACKGROUND: Congenital heart diseases often involve chronic pressure overload of the right ventricle (RV) which is a major cause of RV dysfunction. Pulmonary artery (PA) banding has been used to produce animal models of RV dysfunction. We have devised a new and easier method of constricting the PA and compared it directly with the partial ligation method. METHODS: Eight-week-old male Sprague Dawley rats (240-260 g) were divided into three groups: sham operation, partial pulmonary artery ligation (PAL) procedure, and pulmonary artery half-closed clip (PAC) procedure. RV function and remodeling were determined by echocardiography and histomorphometry. RESULTS: Surgical mortality was significantly lower in the PAC group while echocardiography revealed significantly more signs of RV dysfunction. At the 8th week after surgery RV fibrosis rate was significantly higher in the PAC group. CONCLUSIONS: This procedure of pulmonary artery banding in rats is easier and more efficient than partial ligation. PMID- 26504828 TI - A Pyrosequencing Assay for the Quantitative Methylation Analysis of GALR1 in Endometrial Samples: Preliminary Results. AB - Endometrial cancer is the most common malignancy of the female genital tract while aberrant DNA methylation seems to play a critical role in endometrial carcinogenesis. Galanin's expression has been involved in many cancers. We developed a new pyrosequencing assay that quantifies DNA methylation of galanin's receptor-1 (GALR1). In this study, the preliminary results indicate that pyrosequencing methylation analysis of GALR1 promoter can be a useful ancillary marker to cytology as the histological status can successfully predict. This marker has the potential to lead towards better management of women with endometrial lesions and eventually reduce unnecessary interventions. In addition it can provide early warning for women with negative cytological result. PMID- 26504829 TI - Extracellular Calcium-Dependent Modulation of Endothelium Relaxation in Rat Mesenteric Small Artery: The Role of Potassium Signaling. AB - The nature of NO- and COX-independent endothelial hyperpolarization (EDH) is not fully understood but activation of small- and intermittent-conductance Ca(2+) activated K(+) channels (SKCa and IKCa) is important. Previous studies have suggested that the significance of IKCa depends on [Ca(2+)]out. Also it has been suggested that K(+) is important through localized [K(+)]out signaling causing activation of the Na(+),K(+)-ATPase and inward-rectifying K(+) channels (Kir). Here we tested the hypothesis that the modulating effect of [Ca(2+)]out on the EDH-like response depends on [K(+)]out. We addressed this possibility using isometric myography of rat mesenteric small arteries. When [K(+)]out was 4.2 mM, relaxation to acetylcholine (ACh) was stronger at 2.5 mM [Ca(2+)]out than at 1 mM [Ca(2+)]out. Inhibition of IKCa with TRAM34 suppressed the relaxations but did not change the relation between the relaxations at the low and high [Ca(2+)]out. This [Ca(2+)]out-dependence disappeared at 5.9 mM [K(+)]out and in the presence of ouabain or BaCl2. Our results suggest that IKCa are involved in the localized [K(+)]out signaling which acts through the Na(+),K(+)-ATPase and Kir channels and that the significance of this endothelium-dependent pathway is modulated by [Ca(2+)]out. PMID- 26504830 TI - Pigment Epithelium-Derived Factor Induces Endothelial Barrier Dysfunction via p38/MAPK Phosphorylation. AB - Endothelial barrier dysfunction, which is a serious problem that occurs in various inflammatory conditions, permits extravasation of serum components into the surrounding tissues, leading to edema formation and organ failure. Pigment epithelium-derived factor (PEDF), which is a major endogenous antagonist, has been implicated in diverse biological process, but its role in endothelial barrier dysfunction has not been defined. To assess the role of PEDF in the vasculature, we evaluated the effects of exogenous PEDF using human umbilical vein endothelial cells (HUVECs) in vitro. Our results demonstrated that exogenous PEDF activated p38/MAPK signalling pathway in a dose- and time-dependent manner and induced vascular hyperpermeability as measured by the markedly increased FITC dextran leakage and the decreased transendothelial electrical resistance (TER) across the monolayer cells, which was accompanied by microtubules (MTs) disassembly and F-actin rearrangement. However, the aforementioned alterations can be arrested by the application of low concentration of p38/MAPK inhibitor SB203580. These results reveal a novel role for PEDF as a potential vasoactive substance in inducing hyperpermeability. Furthermore, our results suggest that PEDF and p38/MAPK may serve as therapeutic targets for maintaining vascular integrity. PMID- 26504831 TI - Expression of Stem Cell Markers in Preinvasive Tubal Lesions of Ovarian Carcinoma. AB - In order to better understand the ovarian serous carcinogenic process with tubal origin, we investigated the expression of stem cell markers in premalignant tubal lesions (serous tubal intraepithelial carcinoma or STIC). We found an increased stem cell marker density in the normal fallopian tube followed by a high CD117 and a low ALDH and CD44 expression in STICs raising the question of the role of the stem cell markers in the serous carcinogenic process. PMID- 26504832 TI - Health Impacts of Increased Physical Activity from Changes in Transportation Infrastructure: Quantitative Estimates for Three Communities. AB - Recently, two quantitative tools have emerged for predicting the health impacts of projects that change population physical activity: the Health Economic Assessment Tool (HEAT) and Dynamic Modeling for Health Impact Assessment (DYNAMO HIA). HEAT has been used to support health impact assessments of transportation infrastructure projects, but DYNAMO-HIA has not been previously employed for this purpose nor have the two tools been compared. To demonstrate the use of DYNAMO HIA for supporting health impact assessments of transportation infrastructure projects, we employed the model in three communities (urban, suburban, and rural) in North Carolina. We also compared DYNAMO-HIA and HEAT predictions in the urban community. Using DYNAMO-HIA, we estimated benefit-cost ratios of 20.2 (95% C.I.: 8.7-30.6), 0.6 (0.3-0.9), and 4.7 (2.1-7.1) for the urban, suburban, and rural projects, respectively. For a 40-year time period, the HEAT predictions of deaths avoided by the urban infrastructure project were three times as high as DYNAMO HIA's predictions due to HEAT's inability to account for changing population health characteristics over time. Quantitative health impact assessment coupled with economic valuation is a powerful tool for integrating health considerations into transportation decision-making. However, to avoid overestimating benefits, such quantitative HIAs should use dynamic, rather than static, approaches. PMID- 26504833 TI - Chitosan and Its Potential Use as a Scaffold for Tissue Engineering in Regenerative Medicine. AB - Tissue engineering is an important therapeutic strategy to be used in regenerative medicine in the present and in the future. Functional biomaterials research is focused on the development and improvement of scaffolding, which can be used to repair or regenerate an organ or tissue. Scaffolds are one of the crucial factors for tissue engineering. Scaffolds consisting of natural polymers have recently been developed more quickly and have gained more popularity. These include chitosan, a copolymer derived from the alkaline deacetylation of chitin. Expectations for use of these scaffolds are increasing as the knowledge regarding their chemical and biological properties expands, and new biomedical applications are investigated. Due to their different biological properties such as being biocompatible, biodegradable, and bioactive, they have given the pattern for use in tissue engineering for repair and/or regeneration of different tissues including skin, bone, cartilage, nerves, liver, and muscle. In this review, we focus on the intrinsic properties offered by chitosan and its use in tissue engineering, considering it as a promising alternative for regenerative medicine as a bioactive polymer. PMID- 26504834 TI - Renin-Angiotensin Activation and Oxidative Stress in Early Heart Failure with Preserved Ejection Fraction. AB - Animal models have suggested a role of renin-angiotensin system (RAS) activation and subsequent cardiac oxidation in heart failure with preserved ejection fraction (HFpEF). Nevertheless, RAS blockade has failed to show efficacy in treatment of HFpEF. We evaluated the role of RAS activation and subsequent systemic oxidation in HFpEF. Oxidative stress markers were compared in 50 subjects with and without early HFpEF. Derivatives of reactive oxidative metabolites (DROMs), F2-isoprostanes (IsoPs), and ratios of oxidized to reduced glutathione (E h GSH) and cysteine (E h CyS) were measured. Angiotensin converting enzyme (ACE) levels and activity were measured. On univariate analysis, HFpEF was associated with male sex (p = 0.04), higher body mass index (BMI) (p = 0.003), less oxidized E h CyS (p = 0.001), lower DROMs (p = 0.02), and lower IsoP (p = 0.03). Higher BMI (OR: 1.3; 95% CI: 1.1-1.6) and less oxidized E h CyS (OR: 1.2; 95% CI: 1.1-1.4) maintained associations with HFpEF on multivariate analysis. Though ACE levels were higher in early HFpEF (OR: 1.09; 95% CI: 1.01-1.05), ACE activity was similar to that in controls. HFpEF is not associated with significant systemic RAS activation or oxidative stress. This may explain the failure of RAS inhibitors to alter outcomes in HFpEF. PMID- 26504835 TI - Presence of Periodontopathic Bacteria DNA in Atheromatous Plaques from Coronary and Carotid Arteries. AB - OBJECTIVES: Interest in periodontitis as a potential risk factor for atherosclerosis and its complications resulted from the fact that the global prevalence of periodontal diseases is significant and periodontitis may induce a chronic inflammatory response. Many studies have analyzed the potential impact of the Porphyromonas gingivalis, major pathogen of periodontitis, on general health. The purpose of this study was to find the presence of the Porphyromonas gingivalis DNA in the atherosclerotic plaques of coronary and carotid arteries and in the periodontal pockets in patients with chronic periodontitis, who underwent surgery because of vascular diseases. METHODS AND RESULTS: The study population consisted of 91 patients with coronary artery disease or scheduled for carotid endarterectomy. The presence of Porphyromonas gingivalis DNA in atheromatous plaques and in subgingival samples was determined by PCR. Bacterial DNA was found in 21 of 91 (23%) samples taken from vessels and in 47 of 63 (74.6%) samples from periodontal pockets. CONCLUSIONS: Porphyromonas gingivalis DNA is frequently found in atheromatous plaques of patients with periodontitis. That is why more research should be conducted to prove if this periopathogen may have an impact on endothelium of patients at risk of atherosclerosis. PMID- 26504836 TI - Space-Time Analysis to Identify Areas at Risk of Mortality from Cardiovascular Disease. AB - This study aimed at identifying areas that were at risk of mortality due to cardiovascular disease in residents aged 45 years or older of the cities of Cuiaba and Varzea Grande between 2009 and 2011. We conducted an ecological study of mortality rates related to cardiovascular disease. Mortality rates were calculated for each census tract by the Local Empirical Bayes estimator. High- and low-risk clusters were identified by retrospective space-time scans for each year using the Poisson probability model. We defined the year and month as the temporal analysis unit and the census tracts as the spatial analysis units adjusted by age and sex. The Mann-Whitney U test was used to compare the socioeconomic and environmental variables by risk classification. High-risk clusters showed higher income ratios than low-risk clusters, as did temperature range and atmospheric particulate matter. Low-risk clusters showed higher humidity than high-risk clusters. The Eastern region of Varzea Grande and the central region of Cuiaba were identified as areas at risk of mortality due to cardiovascular disease in individuals aged 45 years or older. High mortality risk was associated with socioeconomic and environmental factors. More high-risk clusters were observed at the end of the dry season. PMID- 26504837 TI - Monitoring Microcirculatory Blood Flow with a New Sublingual Tonometer in a Porcine Model of Hemorrhagic Shock. AB - Tissue capnometry may be suitable for the indirect evaluation of regional hypoperfusion. We tested the performance of a new sublingual capillary tonometer in experimental hemorrhage. Thirty-six anesthetized, ventilated mini pigs were divided into sham-operated (n = 9) and shock groups (n = 27). Hemorrhagic shock was induced by reducing mean arterial pressure (MAP) to 40 mmHg for 60 min, after which fluid resuscitation started aiming to increase MAP to 75% of the baseline value (60-180 min). Sublingual carbon-dioxide partial pressure was measured by tonometry, using a specially coiled silicone rubber tube. Mucosal red blood cell velocity (RBCV) and capillary perfusion rate (CPR) were assessed by orthogonal polarization spectral (OPS) imaging. In the 60 min shock phase a significant drop in cardiac index was accompanied by reduction in sublingual RBCV and CPR and significant increase in the sublingual mucosal-to-arterial PCO2 gap (PSLCO2 gap), which significantly improved during the 120 min resuscitation phase. There was significant correlation between PSLCO2 gap and sublingual RBCV (r = -0.65, p < 0.0001), CPR (r = -0.64, p < 0.0001), central venous oxygen saturation (r = 0.50, p < 0.0001), and central venous-to-arterial PCO2 difference (r = 0.62, p < 0.0001). This new sublingual tonometer may be an appropriate tool for the indirect evaluation of circulatory changes in shock. PMID- 26504838 TI - Resting Heart Rate and Auditory Evoked Potential. AB - The objective of this study was to evaluate the association between rest heart rate (HR) and the components of the auditory evoked-related potentials (ERPs) at rest in women. We investigated 21 healthy female university students between 18 and 24 years old. We performed complete audiological evaluation and measurement of heart rate for 10 minutes at rest (heart rate monitor Polar RS800CX) and performed ERPs analysis (discrepancy in frequency and duration). There was a moderate negative correlation of the N1 and P3a with rest HR and a strong positive correlation of the P2 and N2 components with rest HR. Larger components of the ERP are associated with higher rest HR. PMID- 26504840 TI - Hypoglycaemia, Abnormal Lipids, and Cardiovascular Disease among Chinese with Type 2 Diabetes. AB - We recruited a group of 6713 consecutive Chinese patients with T2D but normal renal and liver function who were admitted to one of 81 top tertiary care hospitals in China. Mild hypoglycaemia was defined as having symptomatic hypoglycaemia in one month before hospitalization. Severe hypoglycaemia was defined as having hypoglycaemia that needed assistance from other people in three months before hospitalization. Prior cardiovascular disease (CVD) was defined as having coronary heart disease, stroke, or peripheral arterial disease. Of 6713 patients, 80 and 304 had severe and mild hypoglycaemia episodes, respectively, and 561 had CVD. Patients with severe and mild hypoglycaemia episodes were more likely to have prior CVD (32.5% versus 16.5% versus 7.7%, P < 0.0001). Both mild and severe hypoglycaemia were associated with increased risk of CVD (adjusted odds ratios (ORs): 2.64, 95% CI: 1.85-3.76 for mild hypoglycaemia; 6.59, 95% CI: 3.79-11.45 for sever hypoglycaemia) than those patients free of hypoglycaemia. Further adjustment for lipid profile did not change these two ORs. In the same way, the ORs of lipid profile for CVD were similar before and after adjustment for hypoglycaemia. We concluded that hypoglycaemia and lipid profile were independently associated with increased risk of CVD. PMID- 26504839 TI - Microstereolithography-Based Fabrication of Anatomically Shaped Beta-Tricalcium Phosphate Scaffolds for Bone Tissue Engineering. AB - Porous ceramic scaffolds with shapes matching the bone defects may result in more efficient grafting and healing than the ones with simple geometries. Using computer-assisted microstereolithography (MSTL), we have developed a novel gelcasting indirect MSTL technology and successfully fabricated two scaffolds according to CT images of rabbit femur. Negative resin molds with outer 3D dimensions conforming to the femur and an internal structure consisting of stacked meshes with uniform interconnecting struts, 0.5 mm in diameter, were fabricated by MSTL. The second mold type was designed for cortical bone formation. A ceramic slurry of beta-tricalcium phosphate (beta-TCP) with room temperature vulcanization (RTV) silicone as binder was cast into the molds. After the RTV silicone was completely cured, the composite was sintered at 1500 degrees C for 5 h. Both gross anatomical shape and the interpenetrating internal network were preserved after sintering. Even cortical structure could be introduced into the customized scaffolds, which resulted in enhanced strength. Biocompatibility was confirmed by vital staining of rabbit bone marrow mesenchymal stromal cells cultured on the customized scaffolds for 5 days. This fabrication method could be useful for constructing bone substitutes specifically designed according to local anatomical defects. PMID- 26504841 TI - Loop Mediated Isothermal Amplification for Detection of Trypanosoma brucei gambiense in Urine and Saliva Samples in Nonhuman Primate Model. AB - Human African trypanosomiasis (HAT) is a vector-borne parasitic zoonotic disease. The disease caused by Trypanosoma brucei gambiense is the most prevalent in Africa. Early diagnosis is hampered by lack of sensitive diagnostic techniques. This study explored the potential of loop mediated isothermal amplification (LAMP) and polymerase chain reaction (PCR) in the detection of T. b. gambiense infection in a vervet monkey HAT model. Six vervet monkeys were experimentally infected with T. b. gambiense IL3253 and monitored for 180 days after infection. Parasitaemia was scored daily. Blood, cerebrospinal fluid (CSF), saliva, and urine samples were collected weekly. PCR and LAMP were performed on serum, CSF, saliva, and urine samples. The detection by LAMP was significantly higher than that of parasitological methods and PCR in all the samples. The performance of LAMP varied between the samples and was better in serum followed by saliva and then urine samples. In the saliva samples, LAMP had 100% detection between 21 and 77 dpi, whereas in urine the detection it was slightly lower, but there was over 80% detection between 28 and 91 dpi. However, LAMP could not detect trypanosomes in either saliva or urine after 140 and 126 dpi, respectively. The findings of this study emphasize the importance of LAMP in diagnosis of HAT using saliva and urine samples. PMID- 26504842 TI - Awareness of Lifestyle and Colorectal Cancer Risk: Findings from the BeWEL Study. AB - It is estimated that 47% of colorectal cancers (CRC) could be prevented by appropriate lifestyles. This study aimed to identify awareness of the causes of CRC in patients who had been diagnosed with a colorectal adenoma through the Scottish Bowel Screening Programme and subsequently enrolled in an intervention trial (using diet and physical activity education and behavioural change techniques) (BeWEL). At baseline and 12-month follow-up, participants answered an open-ended question on factors influencing CRC development. Of the 329 participants at baseline, 40 (12%) reported that they did not know any risk factors and 36 (11%) failed to identify specific factors related to diet and activity. From a potential knowledge score of 1 to 6, the mean score was 1.5 (SD 1.1, range 0 to 5) with no difference between intervention and control groups. At follow-up, the intervention group had a significantly greater knowledge score and better weight loss, diet, and physical activity measures than the control group. Awareness of relevant lifestyle factors for CRC remains low in people at increased risk of the disease. Opportunities within routine NHS screening to aid the capability (including knowledge of risk factors) of individuals to make behavioural changes to reduce CRC risk deserve exploration. PMID- 26504843 TI - Comparative Analysis of Methods to Induce Myocardial Infarction in a Closed-Chest Rabbit Model. AB - OBJECTIVE: To develop a rabbit model of closed-chest catheter-induced myocardial infarction. Background. Limitations of rodent and large animal models justify the search for clinically relevant alternatives. METHODS: Microcatheterization of the heart was performed in 47 anesthetized 3-4 kg New Zealand rabbits to test five techniques of myocardial ischemia: free coils (n = 4), interlocking coils (n = 4), thrombogenic gelatin sponge (n = 4), balloon occlusion (n = 4), and alcohol injection (n = 8). In order to limit ventricular fibrillation, an antiarrhythmic protocol was implemented, with beta-blockers/amiodarone before and xylocaine infusion during the procedure. Clinical, angiographic, and echographic data were gathered. End points included demonstration of vessel occlusion (TIMI flow grades 0 and 1 on the angiogram), impairment of left ventricular function at 2 weeks after procedure (by echocardiography), and pathologically confirmed myocardial infarction. RESULTS: The best arterial access was determined to be through the right carotid artery. The internal mammary guiding catheter 4-Fr was selected as the optimal device for selective intracoronary injection. Free coils deployed prematurely and tended to prolapse into the aorta. Interlocking coils did not deploy completely and failed to provide reliable results. Gelatin sponge was difficult to handle, adhered to the catheter, and could not be clearly visualized by fluoroscopy. Balloon occlusion yielded inconsistent results. Alcohol injection was the most efficient and reproducible method for inducing myocardial infarction (4 out of 6 animals), the extent of which could be fine-tuned by using a coaxial balloon catheter as a microcatheter (0.52 mm) to achieve a superselective injection of 0.2 mL of alcohol. This approach resulted in a 20% decrease in LVEF and infarcted myocardium was confirmed histologically. CONCLUSIONS: By following a stepwise approach, a minimally invasive, effective, and reproducible rabbit model of catheter-induced myocardial infarction has been developed which addresses the limitations of rodent experiments while avoiding the logistical and cost issues associated with large animal models. PMID- 26504844 TI - MicroRNAs-mRNAs Expression Profile and Their Potential Role in Malignant Transformation of Human Bronchial Epithelial Cells Induced by Cadmium. AB - BACKGROUND: Our study was designed to elucidate whether there were miRNA and mRNA aberrantly expression profiles and potential role in malignant transformation of 16HBE induced by Cd. METHODS: mRNA and miRNA expression profiles were determined in 35th Cd-induced 16HBE and untreated 16HBE by microarray. A series of bioinformatics analyses such as predicting targets, GO, KEGG were performed to find DEGs, coexpressing networks between miRNAs and mRNAs and its functions. RESULTS: 498 DEGs were found. 8 Cd-responsive novel miRNAs predicted previously were identified, and 5 of them were downregulated. 214 target genes were predicted for the Cd-responsive miRNAs, many of which appeared to regulate gene networks. Target gene CCM2 was showed reciprocal effect by miRNAs. According to the combination analysis, hsa-miR-27b-3p regulated most of the mRNAs, especially upregulated expression genes. The differentially expressed miRNAs are involved in the biological processes and channels, and these GO and KEGG enrichment analyses result were significantly enriched in the Cd-responsive. DISCUSSION: These results provided a tight link for the miRNA-mRNA integrated network and implied the role of novel miRNAs in malignant transformation of 16HBE induced by Cadmium. It is better to understand the novel molecular mechanism of cadmium-induced tumorigenesis. PMID- 26504845 TI - The Impact of Thrombocytopenia on Outcome in Patients with Acute Coronary Syndromes: A Single Center Retrospective Study. AB - BACKGROUND: In acute coronary syndromes (ACS), treated by combined antithrombotic therapy and percutaneous coronary interventions (PCI), thrombocytopenia may occur. Our aim was to evaluate predictors and the impact of thrombocytopenia on mortality in high-risk ACS patients. METHODS: We retrospectively evaluated high risk ACS patients. Thrombocytopenia was defined as platelet count <140.000/mL or a drop in platelet count of >50% during in-hospital stay. We compared demographic, laboratory, clinical, and mortality data between nonthrombocytopenic and thrombocytopenic ACS patients and evaluated independent predictors of thrombocytopenia. RESULTS: In 371 ACS patients, thrombocytopenia was observed in 21.3%. Thrombocytopenic patients were significantly older and, less likely treated by PCIs (72.1% versus 89.7%, p < 0.001) and combined antithrombotic therapy, with increased incidence of in-hospital complications and the use of additional treatments, but with increased mortality at 30 days (27.8% versus 10.2%, p < 0.001) and 6 months (35.4% versus 13.6%, p < 0.001) when compared to nonthrombocytopenic patients. The use of antibiotics, transfusions, insertion of intra-aortic balloon pump (IABP), and prior stroke independently predicted thrombocytopenia. CONCLUSIONS: Thrombocytopenia, observed in about 20% of high risk ACS patients, was associated significantly with in-hospital complications and mortality. Predictors of thrombocytopenia were the use of antibiotics, transfusions, insertion of IABP, and prior stroke. PMID- 26504847 TI - Two-Step Pseudomaximum Amplitude-Based Confidence Interval Estimation for Oscillometric Blood Pressure Measurements. AB - Blood pressure (BP) is an important vital sign to determine the health of an individual. Although the estimation of average arterial blood pressure using oscillometric methods is possible, there are no established methods for obtaining confidence intervals (CIs) for systolic blood pressure (SBP) and diastolic blood pressure (DBP). In this paper, we propose a two-step pseudomaximum amplitude (TSPMA) as a novel approach to obtain improved CIs of SBP and DBP using a double bootstrap approach. The weighted median (WM) filter is employed to reduce impulsive and Gaussian noises in the step of preprocessing. Application of the proposed method provides tighter CIs and smaller standard deviation of CIs than the pseudomaximum amplitude-envelope and maximum amplitude algorithms with Student's t-method. PMID- 26504846 TI - Phytochemical Compounds and Protection from Cardiovascular Diseases: A State of the Art. AB - Cardiovascular diseases represent a worldwide relevant socioeconomical problem. Cardiovascular disease prevention relies also on lifestyle changes, including dietary habits. The cardioprotective effects of several foods and dietary supplements in both animal models and in humans have been explored. It was found that beneficial effects are mainly dependent on antioxidant and anti-inflammatory properties, also involving modulation of mitochondrial function. Resveratrol is one of the most studied phytochemical compounds and it is provided with several benefits in cardiovascular diseases as well as in other pathological conditions (such as cancer). Other relevant compounds are Brassica oleracea, curcumin, and berberine, and they all exert beneficial effects in several diseases. In the attempt to provide a comprehensive reference tool for both researchers and clinicians, we summarized in the present paper the existing literature on both preclinical and clinical cardioprotective effects of each mentioned phytochemical. We structured the discussion of each compound by analyzing, first, its cellular molecular targets of action, subsequently focusing on results from applications in both ex vivo and in vivo models, finally discussing the relevance of the compound in the context of human diseases. PMID- 26504848 TI - Predictive Biomarkers to Chemoradiation in Locally Advanced Rectal Cancer. AB - There has been a high local recurrence rate in rectal cancer. Besides improvements in surgical techniques, both neoadjuvant short-course radiotherapy and long-course chemoradiation improve oncological results. Approximately 40-60% of rectal cancer patients treated with neoadjuvant chemoradiation achieve some degree of pathologic response. However, there is no effective method of predicting which patients will respond to neoadjuvant treatment. Recent studies have evaluated the potential of genetic biomarkers to predict outcome in locally advanced rectal adenocarcinoma treated with neoadjuvant chemoradiation. The articles produced by the PubMed search were reviewed for those specifically addressing a genetic profile's ability to predict response to neoadjuvant treatment in rectal cancer. Although tissue gene microarray profiling has led to promising data in cancer, to date, none of the identified signatures or molecular markers in locally advanced rectal cancer has been successfully validated as a diagnostic or prognostic tool applicable to routine clinical practice. PMID- 26504849 TI - Antimicrobial Activity Evaluation on Silver Doped Hydroxyapatite/Polydimethylsiloxane Composite Layer. AB - The goal of this study was the preparation, physicochemical characterization, and microbiological evaluation of novel hydroxyapatite doped with silver/polydimethylsiloxane (Ag:HAp-PDMS) composite layers. In the first stage, the deposition of polydimethylsiloxane (PDMS) polymer layer on commercially pure Si disks has been produced in atmospheric pressure corona discharges. Finally, the new silver doped hydroxyapatite/polydimethylsiloxane composite layer has been obtained by the thermal evaporation technique. The Ag:HAp-PDMS composite layers were characterized by various techniques, such as Scanning Electron Microscopy (SEM), Glow Discharge Optical Emission Spectroscopy (GDOES), and X-ray photoelectron spectroscopy (XPS). The antimicrobial activity of the Ag:HAp-PDMS composite layer was assessed against Candida albicans ATCC 10231 (ATCC-American Type Culture Collection) by culture based and confirmed by SEM and Confocal Laser Scanning Microscopy (CLSM) methods. This is the first study reporting the antimicrobial effect of the Ag:HAp-PDMS composite layer, which proved to be active against Candida albicans biofilm embedded cells. PMID- 26504850 TI - MicroRNAs Based Therapy of Hypertrophic Cardiomyopathy: The Road Traveled So Far. AB - Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by variable expressivity, age penetrance, and a high heterogeneity. The transcriptional profile (miRNAs, mRNAs), epigenetic modifications, and posttranslational modifications seem to be highly relevant for the onset of the disease. miRNAs, small noncoding RNAs with 22 nucleotides, have been implicated in the regulation of cardiomyocyte function, being differentially expressed in several heart diseases, including HCM. Moreover, a different miRNA expression profile in the various stages of HCM development is also observed. This review summarizes the current knowledge of the profile of miRNAs characteristic of asymptomatic to overt HCM patients, discussing alongside their potential use for diagnosis and therapy. Indeed, the stability and specificity of miRNAs make them suitable targets for use as biomarkers for diagnosis and prognosis and as therapeutical targets. PMID- 26504851 TI - The Expansion of CD25 high IL-10 high FoxP3 high B Regulatory Cells Is in Association with SLE Disease Activity. AB - B regulatory cells (Bregs) belong to a subgroup of activated B cells tasked with maintaining self-tolerance and preventing autoimmunity. While sharing similar regulatory mechanisms such as IL-10 dependency, they also defer in exhibiting their suppressive effects by expressing Fas-Ligand, TGF-beta, and PDL-1. In this study we show, for the first time, the expansion of CD25(high)FoxP3(high) Bregs in systemic lupus erythematosus (SLE) patients compared to healthy individuals (18.5 +/- 3.052% versus 11.0 +/- 1.654%, p < 0.001, resp.). This expansion was also shown to correlate with SLE disease activity (r = 0.75). In addition, CD25(high)FoxP3(high) Bregs were also IL-10(high) expressing and further expanded when stimulated with semaphorin 3A. In sum we show that CD25(high)FoxP3(high) are an additional subtype of Bregs, involved in regulating SLE disease activity. Being IL-10 expressing, we may assume that they are one of the sources of increased serum IL-10 in SLE patients. Further studies are required in order to assess the relation between high serum IL-10 and CD25(high)FoxP3(high) Breg cells. PMID- 26504852 TI - Mesenchymal Stem Cells Immunosuppressed IL-22 in Patients with Immune Thrombocytopenia via Soluble Cellular Factors. AB - Mesenchymal stem cells are immunoregulation cells. IL-22 plays an important role in the pathogenesis of immune thrombocytopenia. However, the effects of mesenchymal stem cells on IL-22 production in patients with immune thrombocytopenia remain unclear. Flow cytometry analyzed immunophenotypes of mesenchymal stem cells; differentiation of mesenchymal stem cells was observed by oil red O and Alizarin red S staining; cell proliferation suppression was measured with MTS; IL-22 levels of cell-free supernatants were determined by ELISA. Mesenchymal stem cells inhibited the proliferation of activated CD4(+)T cells; moreover, mesenchymal stem cells immunosuppressed IL-22 by soluble cellular factors but not PGE2. These results suggest that mesenchymal stem cells may be a therapeutic strategy for patients with immune thrombocytopenia. PMID- 26504853 TI - FluKB: A Knowledge-Based System for Influenza Vaccine Target Discovery and Analysis of the Immunological Properties of Influenza Viruses. AB - FluKB is a knowledge-based system focusing on data and analytical tools for influenza vaccine discovery. The main goal of FluKB is to provide access to curated influenza sequence and epitope data and enhance the analysis of influenza sequence diversity and the analysis of targets of immune responses. FluKB consists of more than 400,000 influenza protein sequences, known epitope data (357 verified T-cell epitopes, 685 HLA binders, and 16 naturally processed MHC ligands), and a collection of 28 influenza antibodies and their structurally defined B-cell epitopes. FluKB was built using a modular framework allowing the implementation of analytical workflows and includes standard search tools, such as keyword search and sequence similarity queries, as well as advanced tools for the analysis of sequence variability. The advanced analytical tools for vaccine discovery include visual mapping of T- and B-cell vaccine targets and assessment of neutralizing antibody coverage. FluKB supports the discovery of vaccine targets and the analysis of viral diversity and its implications for vaccine discovery as well as potential T-cell breadth and antibody cross neutralization involving multiple strains. FluKB is representation of a new generation of databases that integrates data, analytical tools, and analytical workflows that enable comprehensive analysis and automatic generation of analysis reports. PMID- 26504854 TI - Impaired Fas-Fas Ligand Interactions Result in Greater Recurrent Herpetic Stromal Keratitis in Mice. AB - Herpes simplex virus-1 (HSV-1) infection of the cornea leads to a potentially blinding condition termed herpetic stromal keratitis (HSK). Clinical studies have indicated that disease is primarily associated with recurrent HSK following reactivation of a latent viral infection of the trigeminal ganglia. One of the key factors that limit inflammation of the cornea is the expression of Fas ligand (FasL). We demonstrate that infection of the cornea with HSV-1 results in increased functional expression of FasL and that mice expressing mutations in Fas (lpr) and FasL (gld) display increased recurrent HSK following reactivation compared to wild-type mice. Furthermore, both gld and lpr mice took longer to clear their corneas of infectious virus and the reactivation rate for these strains was significantly greater than that seen with wild-type mice. Collectively, these findings indicate that the interaction of Fas with FasL in the cornea restricts the development of recurrent HSK. PMID- 26504856 TI - Liver Expression of Sulphotransferase 2A1 Enzyme Is Impaired in Patients with Primary Sclerosing Cholangitis: Lack of the Response to Enhanced Expression of PXR. AB - BACKGROUND/AIM: Sulphotransferase 2A1 (SULT2A1) exerts hepatoprotective effects. Transcription of SULT2A1 gene is induced by pregnane-X-receptor (PXR) and can be repressed by miR-378a-5p. We studied the PXR/SULT2A1 axis in chronic cholestatic conditions: primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). MATERIALS/METHODS: Western-blot/PCRs for SULT2A1/PXR were performed in PSC (n = 11), PBC (n = 19), and control liver tissues (n = 19). PXR and SULT2A1 mRNA was analyzed in intestinal tissues from 22 PSC patients. Genomic DNA was isolated from blood of PSC patients (n = 120) and an equal number of healthy volunteers. Liver miRNA expression was evaluated using Affymetrix-Gene-Chip miRNA4.0. RESULTS: Increased PXR protein was observed in both PSC and PBC compared to controls and was accompanied by a significant increase of SULT2A1 in PBC but not in PSC. Decreased expression of SULT2A1 mRNA was also seen in ileum of patients with PSC. Unlike PBC, miRNA analysis in PSC has shown a substantial increase in liver miR-378a-5p. CONCLUSIONS: PSC is characterized by disease-specific impairment of SULT2A1 expression following PXR activation, a phenomenon which is not noted in PBC, and may account for the impaired hepatoprotection in PSC. miRNA analysis suggests that SULT2A1 expression in PSC may be regulated by miR-378a-5p, connoting its pathogenic role. PMID- 26504855 TI - Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives. AB - We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes A (*) 01, B (*) 08; A (*) 02, B (*) 44; A (*) 03, B (*) 07; A (*) 03, B (*) 14; and A (*) 29, B (*) 44. There were 138 men (58.7%). Median followup was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto's thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH. PMID- 26504857 TI - Automated Classification of Circulating Tumor Cells and the Impact of Interobsever Variability on Classifier Training and Performance. AB - Application of personalized medicine requires integration of different data to determine each patient's unique clinical constitution. The automated analysis of medical data is a growing field where different machine learning techniques are used to minimize the time-consuming task of manual analysis. The evaluation, and often training, of automated classifiers requires manually labelled data as ground truth. In many cases such labelling is not perfect, either because of the data being ambiguous even for a trained expert or because of mistakes. Here we investigated the interobserver variability of image data comprising fluorescently stained circulating tumor cells and its effect on the performance of two automated classifiers, a random forest and a support vector machine. We found that uncertainty in annotation between observers limited the performance of the automated classifiers, especially when it was included in the test set on which classifier performance was measured. The random forest classifier turned out to be resilient to uncertainty in the training data while the support vector machine's performance is highly dependent on the amount of uncertainty in the training data. We finally introduced the consensus data set as a possible solution for evaluation of automated classifiers that minimizes the penalty of interobserver variability. PMID- 26504860 TI - Finding the Right "Balance" for the Trainee. PMID- 26504861 TI - Cylindrical Batteries in the Stomach: Should We Wait 48 Hours for Removal? PMID- 26504858 TI - Genetic Predictors of Poor Prognosis in Portuguese Patients with Juvenile Idiopathic Arthritis: Data from Reuma.pt. AB - INTRODUCTION: This study aimed to assess the genetic determinants of poor outcome in Portuguese patients with juvenile idiopathic arthritis (JIA). METHODS: Our study was conducted in Reuma.pt, the Rheumatic Diseases Portuguese Register, which includes patients with JIA. We collected prospectively patient and disease characteristics and a blood sample for DNA analysis. Poor prognosis was defined as CHAQ/HAQ >0.75 at the last visit and/or the treatment with biological therapy. A selected panel of single nucleotide polymorphisms (SNPs) associated with susceptibility was studied to verify if there was association with poor prognosis. RESULTS: Of the 812 patients with JIA registered in Reuma.pt, 267 had a blood sample and registered information used to define "poor prognosis." In univariate analysis, we found significant associations with poor prognosis for allele A of TNFA1P3/20 rs6920220, allele G of TRAF1/C5 rs3761847, and allele G of PTPN2 rs7234029. In multivariate models, the associations with TRAF1/C5 (1.96 [1.17-3.3]) remained significant at the 5% level, while TNFA1P3/20 and PTPN2 were no longer significant. Nevertheless, none of associations found was significant after the Bonferroni correction was applied. CONCLUSION: Our study does not confirm the association between a panel of selected SNP and poor prognosis in Portuguese patients with JIA. PMID- 26504859 TI - The Interplay between Zinc, Vitamin D and, IL-17 in Patients with Chronic Hepatitis C Liver Disease. AB - OBJECTIVES: To assess zinc (Zn) and vitamin D (Vit. D) status in chronic Hepatitis C virus- (HCV) infected patients and their relationship to interleukin- (IL-) 17 and disease severity and then investigate whether Zn and Vit. D3 modulate IL-17 expression in chronic HCV patients. METHODS: Seventy patients and fifty healthy subjects were investigated. Serum levels of Zn, Vit. D, and IL-17 were assessed in the patients group and subgroups. Patients lymphocytes were activated in vitro in the presence or absence of Zn or Vit. D3 and then intracellular IL-17 production was assessed using flow cytometry. RESULTS: Zn and Vit. D were significantly decreased in HCV patients. Increasing disease severity leads to more reduction in Zn level opposed by increasing IL-17 level. Zn potently reduced IL-17 production in a dose-related fashion; however it did not exert any toxic effects. Although Vit. D apparently increases IL17 expression, it is unclear whether it is due to its toxic effect on cell count or lack of definite association between Vit. D and both IL-17 and disease severity. CONCLUSIONS: This study demonstrates that Zn modulates IL-17 expression and provides a rationale for evaluating this compound as a supplementary agent in the treatment of chronic HCV. PMID- 26504862 TI - Over-the-Scope Clip for Control of a Recurrent Diverticular Bleed. PMID- 26504863 TI - The Lost Buckyballs. PMID- 26504864 TI - Intrathoracic Stomach and Partial Transverse Colon with Gastric Volvulus. PMID- 26504865 TI - A Preponderance of Polyps: Sequelae of Familial Adenomatous Polyposis. PMID- 26504866 TI - Who Turned Out the Lights? An Impressive Case of Melanosis Coli. PMID- 26504867 TI - Acute Abdomen Due to Cecal Volvulus Associated With Chilaiditi Syndrome. PMID- 26504868 TI - Acute Esophageal Necrosis Presenting With Henoch-Schonlein Purpura. AB - A 63-year-old woman with abdominal pain and melena developed a palpable, purpuric rash and acute kidney injury. Skin and kidney biopsy confirmed Henoch-Schonlein purpura. Upper endoscopy revealed diffuse, circumferential, black-appearing mucosa of the esophagus consistent with acute esophageal necrosis (AEN), also known as black esophagus. AEN is a very rare cause of gastrointestinal hemorrhage with a high mortality risk. To our knowledge, there have been no prior reports of AEN associated with Henoch-Schonlein purpura or other vasculitis. PMID- 26504869 TI - Deglutition Syncope: A Case Report and Review of the Literature. AB - Deglutition syncope (DS) is a rare, neurally-mediated syncopal syndrome arising from an aberrant vagotonic reflex during swallow-associated esophageal dilation. Its association with gastroesophageal disorders often prompts gastroenterology consultation. An 89-year-old man with recent dysphagia and otalgia was admitted after a syncopal episode occurred while eating. Esophageal imaging and endoscopy demonstrated no causative abnormalities. Maxillofacial imaging revealed chronic sinusitis and mastoiditis. Telemetry monitoring demonstrated high-grade atrioventricular block and pause associated with swallowing. His symptoms and swallow-associated arrhythmia resolved after dual chamber pacemaker implantation. DS is highly treatable once identified and multidisciplinary coordination is helpful in optimizing outcomes and avoiding superfluous testing. PMID- 26504870 TI - Lower Esophageal Thickening Due to a Laparoscopic Adjustable Gastric Band. AB - Laparoscopic adjustable gastric band (LAGB) is a surgical device to treat obesity that is widely used and generally considered to be safe. We report an adverse event related to the physiological and mechanical changes that occur after LAGB placement, namely chronic obstruction resulting in marked lower esophageal thickening. PMID- 26504871 TI - Advanced Esophageal Squamous Cell Dysplasia and Early Carcinoma Detected After Remote Esophagectomy for Adenocarcinoma. AB - We present a case of squamous dysplasia and early squamous carcinoma of the esophagus after esophagectomy for esophageal adenocarcinoma. We briefly discuss mucosectomy and ablative therapy as potential treatment options. PMID- 26504872 TI - Spontaneous Paraesophageal Hematoma. AB - Spontaneous paraesophageal hematoma (SPH) likely shares a common etiology with spontaneous intramural esophageal hematoma (IEH). Patients with IEH typically present with hematemesis or melena leading to early detection and management, but patients with SPH do not have overt gastrointestinal bleeding on presentation. Management depends on the correction of the underlying causative factor. We present the first case of a spontaneous paraesophageal hematoma in a patient with hemophilia B. Awareness of this complication of hemophilia, its clinical manifestations, and imaging findings, allows for a timely diagnosis and appropriate management. PMID- 26504873 TI - Ethanol Ablation of a Peripheral Nerve Sheath Tumor Presenting as a Small Bowel Obstruction. AB - Ethanol has historically been used as an ablative agent for a variety of lesions. One of the more common applications of this technique is celiac plexus neurolysis; however, recent reports have suggested a role for the endoscopic alcohol ablation of a variety of solid and cystic lesions. We report a novel case of endoscopic ethanol ablation of a peripheral nerve sheath tumor presenting as a small bowel obstruction. PMID- 26504874 TI - A Tailgut Cyst Diagnosed by Endoscopic Ultrasound-Guided Fine-Needle Aspiration. AB - Tailgut cysts are rare developmental cysts. Surgery has been the primary method of diagnosis and treatment of these cysts, but endoscopic ultrasound (EUS) has recently been used to establish diagnosis. Only 2 cases of tailgut cyst diagnosed by EUS-guided FNA have been reported. We present a woman in her fourth decade who presented for evaluation of perirectal mass. EUS-guided fine-needle aspiration (FNA) helped establish the diagnosis of tailgut cyst. The patient opted for observation rather than surgery. PMID- 26504875 TI - Metastatic Testicular Choriocarcinoma: A Rare Cause of Upper GI Bleeding. AB - We present a case of upper gastrointestinal bleeding in an otherwise healthy 18 year-old man who presented with melena. Endoscopy revealed an ulcerated mass in the stomach and pathology confirmed this to be a malignant, poorly differentiated choriocarcinoma. Further imaging showed a left testicular mass with evidence of pulmonary, gastric, and brain metastases, and blood tests revealed an hCG level of 32,219 U/L. He was diagnosed with advanced metastatic testicular choriocarcinoma and underwent intensive induction chemotherapy and an orchidectomy. Metastatic testicular choriocarcinoma is a rare cause of gastrointestinal bleeding. PMID- 26504876 TI - Mesenteric Panniculitis Associated With Vibrio cholerae Infection. AB - We report the first case of acute Vibrio cholerae infection with computed tomography (CT) changes consistent with mesenteric panniculitis (MP). A 78-year old Indian man returned from overseas travel with progressively severe nausea, vomiting, abdominal pain, and watery diarrhea. His stool tested positive twice for Vibrio cholerae. CT revealed prominent lymph nodes and a hazy mesentery consistent with MP. Antibiotic treatment resulted in complete resolution of MP on follow-up CT 8 months later. In the setting of Vibrio cholerae infection, the CT finding of MP appears to be the result of a immunologically mediated reactive inflammatory disorder of the mesentery. PMID- 26504877 TI - Colitis Following Initiation of Sofosbuvir and Simeprevir for Genotype 1 Hepatitis C. AB - Sofosbuvir and simeprevir are used for the treatment of chronic hepatitis C (HCV) genotype 1. Both drugs have been well-tolerated, with diarrhea noted in 6% cases with sofosbuvir, 16% with sofosbuvir plus simeprevir, and 0% with simeprevir. No prior reports exist of colitis secondary to either drug or their combination. We report a patient with no prior history of inflammatory bowel disease who developed significant bloody diarrhea within 2 weeks of sofosbuvir/simeprevir initiation. Colonoscopy and biopsy confirmed pancolitis, which responded to mesalamine and completion of sofosbuvir/simeprevir. PMID- 26504878 TI - Disseminated Tuberculosis in a Patient Taking Anti-TNF Therapy for Crohn's Disease. AB - A man in his sixth decade with Crohn's colitis and who had been taking infliximab for 18 months presented with fever and weight loss. Chest CT showed numerous nodules in both lungs, and sputum culture grew Mycobacterium tuberculosis. Colonoscopy showed circumferential ulcerations from the cecum to the descending colon, and biopsies showed extensive granulomas with central necrosis, positive for acid-fast bacteria. Brain MRI revealed a thalamic ring-enhanced mass with edema, consistent with tuberculoma. Clinicians should be aware of the appropriate screening and close monitoring of tuberculosis before and during anti-tumor necrosis factor (TNF) therapy. PMID- 26504879 TI - Two Cases of Type Va Extrahepatic Bile Duct Duplication With Distal Klatskin Tumor Surgically Treated with Whipple Procedure and Hepaticojejunostomy. AB - We describe the diagnostic and therapeutic challenges of a type Va extrahepatic bile duct duplication coexistent with distally located hilar cholangiocarcinoma (Klatskin tumor). We present 2 cases that were diagnosed preoperatively and treated with a modified surgical technique of a combined pylorus-preserving Whipple procedure and hepaticojejunostomy. PMID- 26504880 TI - Acute Pancreatitis-Induced Takotsubo Cardiomyopathy in an African American Male. AB - Takotsubo cardiomyopathy (TCM) is triggered by multiple physical and psychological stressors and frequently mimics acute coronary syndrome. Acute pancreatitis as a trigger for TCM has rarely been reported. We report a 55-year old African American man with hypertension and alcohol abuse history, who presented with epigastric and sub-sternal pain and electrocardiogram demonstrating ischemic changes. Laboratory parameters revealed elevated troponin I, amylase, lipase, and metabolic acidosis. He was diagnosed with acute pancreatitis and ACS. Coronary angiogram was unrevealing for coronary atherosclerosis and he was managed conservatively for acute pancreatitis and heart failure from TCM. PMID- 26504881 TI - Xanthogranulomatous Cholecystitis Mimicking Biliary Tract Cancer. AB - We present a 42-year-old man with a 1-month history of painless jaundice, dark urine, clay-colored stools, and a 13.5-kg weight loss. Laboratory tests revealed elevated liver enzymes and CA19-9. Imaging showed dilation of both the intra- and extrahepatic bile ducts, narrowing of the bile duct at the junction of the common bile duct and common hepatic duct, and a hypoechoic mass involving the neck of the gallbladder and the muscularis propria of the duodenum. Examination of the resected gallbladder and perihilar nodes ruled out malignancy and revealed a diffuse inflammatory infiltrate of giant histiocytes with clear, lipid-containing cytoplasm (xanthoma cells), consistent with xanthogranulomatous cholecystitis. PMID- 26504882 TI - Bilhemia: A Rare Complication of Transjugular Intraheptic Portosytemic Shunt. AB - A 56-year-old woman with cirrhosis due to chronic hepatitis C underwent emergent transjugular intrahepatic portosystemic shunt (TIPS) due to a ruptured esophageal varix during esophagogastroduodenoscopy. Following TIPS, the patient experienced a rapid rise in serum bilirubin with no evidence of biliary obstruction or hepatic injury. She was determined to have bilhemia, a rare but serious complication of TIPS. PMID- 26504883 TI - Eosinophilic Liver Infiltration. AB - Eosinophilic liver infiltration is a commonly encountered focal eosinophil related inflammation with or without necrosis, which can be seen on computed tomography (CT) in the presence of peripheral eosinophilia. Although this entity has a relatively benign course, it is related to numerable conditions for which diagnosis may be challenging and requires substantial diagnostic work-up for proper management and care of the underlying disease. We report a case of a 60 year-old man who presented with a 1-week history of right upper quadrant abdominal pain with multiple ill-defined liver hypodensities associated with significant eosinophilia. PMID- 26504884 TI - Acute Hepatocellular Drug-Induced Liver Injury From Bupropion and Doxycycline. AB - The management and diagnosis of drug-induced liver injury (DILI) is often challenging, particularly when patients are taking multiple medications. We present a 29-year-old African American man who presented with jaundice and malaise after starting bupropion and doxycycline 2 weeks prior. He was found to have acute hepatocellular drug-induced liver injury with autoimmune features, and made a complete recovery with prednisone. Although bupropion and doxycycline are both known to cause liver toxicity, a closer inspection of the signature of liver injury and a review of prior related DILI cases assigns causality more to bupropion than doxycycline. PMID- 26504885 TI - Lymphoma Remission by Interferon-Free HCV Eradication Without Chemotherapy. AB - Epidemiologic studies have suggested an association between hepatitis C virus (HCV) infection and antigendriven lymphoproliferative disorders, in particular marginal zone lymphomas. Antiviral therapy has been shown to exert an anti lymphoma effect in these indolent B-cell lymphoproliferations, with survival gains observed. However, these protocols have traditionally incorporated interferon. We describe a patient with chronic hepatitis C, immune thrombocytopenia, and splenic marginal zone lymphoma who, after eradication of HCV with sofosbuvir and ribavirin, exhibited complete remission of both hematologic conditions. With the numerous new potent drugs currently available, the future looks positive with highly efficacious interferon-free regimens for HCV therapy. PMID- 26504886 TI - Peritoneal Mesothelioma: An Unusual Cause of High-Protein Ascites. AB - We present a case illustrating the workup and diagnosis of peritoneal sarcomatous mesothelioma as an unusual etiology of intestinal obstruction and high-protein ascites in an otherwise healthy man. This rare disorder is diagnosed based on immunohistochemistry, which is necessary to differentiate it from other rare sarcomatous carcinomas. In many cases, localized disease can be treated to cure with surgery and intraperitoneal chemotherapy. Advanced disease is often treated for palliation of symptoms. PMID- 26504888 TI - Causal Control of Biological Systems with Light. PMID- 26504887 TI - Deciphering hepatocellular responses to metabolic and oncogenic stress. AB - Each cell type responds uniquely to stress and fractionally contributes to global and tissue-specific stress responses. Hepatocytes, liver macrophages (MPhi), and sinusoidal endothelial cells (SEC) play functionally important and interdependent roles in adaptive processes such as obesity and tumor growth. Although these cell types demonstrate significant phenotypic and functional heterogeneity, their distinctions enabling disease-specific responses remain understudied. We developed a strategy for the simultaneous isolation and quantification of these liver cell types based on antigenic cell surface marker expression. To demonstrate the utility and applicability of this technique, we quantified liver cell-specific responses to high-fat diet (HFD) or diethylnitrosamine (DEN), a liver-specific carcinogen, and found that while there was only a marginal increase in hepatocyte number, MPhi and SEC populations were quantitatively increased. Global gene expression profiling of hepatocytes, MPhi and SEC identified characteristic gene signatures that define each cell type in their distinct physiological or pathological states. Integration of hepatic gene signatures with available human obesity and liver cancer microarray data provides further insight into the cell-specific responses to metabolic or oncogenic stress. Our data reveal unique gene expression patterns that serve as molecular "fingerprints" for the cell-centric responses to pathologic stimuli in the distinct microenvironment of the liver. The technical advance highlighted in this study provides an essential resource for assessing hepatic cell-specific contributions to metabolic and oncogenic stress, information that could unveil previously unappreciated molecular mechanisms for the cellular crosstalk that underlies the continuum from metabolic disruption to obesity and ultimately hepatic cancer. PMID- 26504889 TI - Neighborhood Integration and Connectivity Predict Cognitive Performance and Decline. AB - OBJECTIVE: Neighborhood characteristics may be important for promoting walking, but little research has focused on older adults, especially those with cognitive impairment. We evaluated the role of neighborhood characteristics on cognitive function and decline over a 2-year period adjusting for measures of walking. METHOD: In a study of 64 older adults with and without mild Alzheimer's disease (AD), we evaluated neighborhood integration and connectivity using geographical information systems data and space syntax analysis. In multiple regression analyses, we used these characteristics to predict 2-year declines in factor analytically derived cognitive scores (attention, verbal memory, mental status) adjusting for age, sex, education, and self-reported walking. RESULTS: Neighborhood integration and connectivity predicted cognitive performance at baseline, and changes in cognitive performance over 2 years. The relationships between neighborhood characteristics and cognitive performance were not fully explained by self-reported walking. DISCUSSION: Clearer definitions of specific neighborhood characteristics associated with walkability are needed to better understand the mechanisms by which neighborhoods may impact cognitive outcomes. These results have implications for measuring neighborhood characteristics, design and maintenance of living spaces, and interventions to increase walking among older adults. We offer suggestions for future research measuring neighborhood characteristics and cognitive function. PMID- 26504890 TI - Compiled data set of exact NOE distance limits, residual dipolar couplings and scalar couplings for the protein GB3. AB - We compiled an NMR data set consisting of exact nuclear Overhauser enhancement (eNOE) distance limits, residual dipolar couplings (RDCs) and scalar (J) couplings for GB3, which forms one of the largest and most diverse data set for structural characterization of a protein to date. All data have small experimental errors, which are carefully estimated. We use the data in the research article Vogeli et al., 2015, Complementarity and congruence between exact NOEs and traditional NMR probes for spatial decoding of protein dynamics, J. Struct. Biol., 191, 3, 306-317, doi:10.1016/j.jsb.2015.07.008 [1] for cross validation in multiple-state structural ensemble calculation. We advocate this set to be an ideal test case for molecular dynamics simulations and structure calculations. PMID- 26504891 TI - Mapping the topographic epitope landscape on the urokinase plasminogen activator receptor (uPAR) by surface plasmon resonance and X-ray crystallography. AB - The urokinase-type plasminogen activator receptor (uPAR or CD87) is a glycolipid anchored membrane protein often expressed in the microenvironment of invasive solid cancers and high levels are generally associated with poor patient prognosis (Kriegbaum et al., 2011 [1]). uPAR is organized as a dynamic modular protein structure composed of three homologous Ly6/uPAR domains (LU).This internally flexible protein structure of uPAR enables an allosteric regulation of the interactions with its two principal ligands: the serine protease urokinase type plasminogen activator (uPA) and the provisional matrix protein vitronectin (Vn) (Mertens et al., 2012; Gardsvoll et al., 2011; Madsen et al., 2007 [2-4]). The data presented here relates to the non-covalent trapping of one of these biologically relevant uPAR-conformations by a novel class of monoclonal antibodies (Zhao et al., 2015 [5]) and to the general mapping of the topographic epitope landscape on uPAR. The methods required to achieve these data include: (1) recombinant expression and purification of a uPAR-hybrid protein trapped in the desired conformation [patent; WO 2013/020898 A12013]; (2) developing monoclonal antibodies with unique specificities using this protein as antigen; (3) mapping the functional epitope on uPAR for these mAbs by surface plasmon resonance with a complete library of purified single-site uPAR mutants (Zhao et al., 2015; Gardsvoll et al., 2006 [5,6]); and finally (4) solving the three dimensional structures for one of these mAbs by X-ray crystallography alone and in complex with uPAR [deposited in the PDB database as 4QTH and 4QTI, respectively]. PMID- 26504892 TI - Data for the effects of ER and Golgi stresses on the ER-Golgi SNARE Syntaxin5 expression and on the betaAPP processing in cultured hippocampal neurons. AB - This paper reports the data for the effects of organelle stresses on the ER-Golgi soluble N-ethylmaleimide-sensitive factor-attachment protein receptors (ER-Golgi SNAREs) syntaxin 5 (Syx5) in neuronal cells. Quantitative as well as qualitative data are presented here to verify the upregulation of Syntaxin 5 (Syx5) under ER and Golgi stresses in hippocampal neurons. Changes in the processing of beta amyloid precursor protein (betaAPP) under ER stress were analyzed by immunological assays. In addition, our data shows the specific increase of Syx5 expression under ER and Golgi stresses. Interpretation of our data and further extensive insights into the role of Syx5 in betaAPP processing under organelle stress can be found in "ER and Golgi stresses increase ER-Golgi SNARE Syntaxin5: Implications for organelle stress and betaAPP processing" [1]. PMID- 26504893 TI - Quantitative analysis of mouse corpus callosum from electron microscopy images. AB - This article provides morphometric analysis of 72 electron microscopy images from control (n=4) and hypomyelinated (n=2) mouse corpus callosum. Measures of axon diameter and g-ratio were tabulated across all brains from two regions of the corpus callosum and a non-linear relationship between axon diameter and g-ratio was observed. These data are related to the accompanying research article comparing multiple methods of measuring g-ratio entitled 'A revised model for estimating g-ratio from MRI' (West et al., NeuroImage, 2015). PMID- 26504894 TI - An Automatic Web Service Composition Framework Using QoS-Based Web Service Ranking Algorithm. AB - Web service has become the technology of choice for service oriented computing to meet the interoperability demands in web applications. In the Internet era, the exponential addition of web services nominates the "quality of service" as essential parameter in discriminating the web services. In this paper, a user preference based web service ranking (UPWSR) algorithm is proposed to rank web services based on user preferences and QoS aspect of the web service. When the user's request cannot be fulfilled by a single atomic service, several existing services should be composed and delivered as a composition. The proposed framework allows the user to specify the local and global constraints for composite web services which improves flexibility. UPWSR algorithm identifies best fit services for each task in the user request and, by choosing the number of candidate services for each task, reduces the time to generate the composition plans. To tackle the problem of web service composition, QoS aware automatic web service composition (QAWSC) algorithm proposed in this paper is based on the QoS aspects of the web services and user preferences. The proposed framework allows user to provide feedback about the composite service which improves the reputation of the services. PMID- 26504895 TI - MATLAB Simulation of UPQC for Power Quality Mitigation Using an Ant Colony Based Fuzzy Control Technique. AB - This paper proposes a fuzzy logic based new control scheme for the Unified Power Quality Conditioner (UPQC) for minimizing the voltage sag and total harmonic distortion in the distribution system consequently to improve the power quality. UPQC is a recent power electronic module which guarantees better power quality mitigation as it has both series-active and shunt-active power filters (APFs). The fuzzy logic controller has recently attracted a great deal of attention and possesses conceptually the quality of the simplicity by tackling complex systems with vagueness and ambiguity. In this research, the fuzzy logic controller is utilized for the generation of reference signal controlling the UPQC. To enable this, a systematic approach for creating the fuzzy membership functions is carried out by using an ant colony optimization technique for optimal fuzzy logic control. An exhaustive simulation study using the MATLAB/Simulink is carried out to investigate and demonstrate the performance of the proposed fuzzy logic controller and the simulation results are compared with the PI controller in terms of its performance in improving the power quality by minimizing the voltage sag and total harmonic distortion. PMID- 26504896 TI - Effects of 5-Amyno-4-(1,3-benzothyazol-2-yn)-1-(3-methoxyphenyl)-1,2-dihydro-3H pyrrol-3-one Intake on Digestive System in a Rat Model of Colon Cancer. AB - INTRODUCTION: Pyrrol derivate 5-amyno-4-(1,3-benzothyazol-2-yn)-1-(3 methoxyphenyl)-1,2-dihydro-3H-pyrrol-3-one (D1) has shown antiproliferative activities in vitro, so investigation of the impact of D1 intake on gut organs in rats that experienced colon cancer seems to be necessary. MATERIALS AND METHODS: D1 at the dose of 2.3 mg/kg was administered per os daily for 27 (from the 1st day of experiment) or 7 (from the 21st week of experiment) weeks to rats that experienced 1,2-dimethylhydrazine (DMH)-induced colon cancer for 20 weeks. 5 Fluorouracil (5FU) was chosen as reference drug and was administered intraperitoneally weekly for 7 weeks (from the 21st week of experiment) at the dose of 45 mg/kg. RESULTS: Antitumor activity of D1 comparable with the 5FU one against DMH-induced colon cancer in rats was observed (decrease of tumor number and tumor total area up to 46%). D1 attenuated the inflammation of colon, gastric and jejunal mucosa, and the liver, caused by DMH, unlike 5FU, aggravating the latter. In addition, D1 partially normalized mucosa morphometric parameters suggesting its functional restore. CONCLUSIONS: D1 possesses, comparable with 5 fluorouracil antitumor efficacy, less damaging effects on the tissues beyond cancerous areas and contributes to partial morphological and functional gut organs recovery. PMID- 26504897 TI - An Ensemble Learning Based Framework for Traditional Chinese Medicine Data Analysis with ICD-10 Labels. AB - OBJECTIVE: This study aims to establish a model to analyze clinical experience of TCM veteran doctors. We propose an ensemble learning based framework to analyze clinical records with ICD-10 labels information for effective diagnosis and acupoints recommendation. METHODS: We propose an ensemble learning framework for the analysis task. A set of base learners composed of decision tree (DT) and support vector machine (SVM) are trained by bootstrapping the training dataset. The base learners are sorted by accuracy and diversity through nondominated sort (NDS) algorithm and combined through a deep ensemble learning strategy. RESULTS: We evaluate the proposed method with comparison to two currently successful methods on a clinical diagnosis dataset with manually labeled ICD-10 information. ICD-10 label annotation and acupoints recommendation are evaluated for three methods. The proposed method achieves an accuracy rate of 88.2% +/- 2.8% measured by zero-one loss for the first evaluation session and 79.6% +/- 3.6% measured by Hamming loss, which are superior to the other two methods. CONCLUSION: The proposed ensemble model can effectively model the implied knowledge and experience in historic clinical data records. The computational cost of training a set of base learners is relatively low. PMID- 26504898 TI - Priority Based Congestion Control Dynamic Clustering Protocol in Mobile Wireless Sensor Networks. AB - Wireless sensor network is widely used to monitor natural phenomena because natural disaster has globally increased which causes significant loss of life, economic setback, and social development. Saving energy in a wireless sensor network (WSN) is a critical factor to be considered. The sensor nodes are deployed to sense, compute, and communicate alerts in a WSN which are used to prevent natural hazards. Generally communication consumes more energy than sensing and computing; hence cluster based protocol is preferred. Even with clustering, multiclass traffic creates congested hotspots in the cluster, thereby causing packet loss and delay. In order to conserve energy and to avoid congestion during multiclass traffic a novel Priority Based Congestion Control Dynamic Clustering (PCCDC) protocol is developed. PCCDC is designed with mobile nodes which are organized dynamically into clusters to provide complete coverage and connectivity. PCCDC computes congestion at intra- and intercluster level using linear and binary feedback method. Each mobile node within the cluster has an appropriate queue model for scheduling prioritized packet during congestion without drop or delay. Simulation results have proven that packet drop, control overhead, and end-to-end delay are much lower in PCCDC which in turn significantly increases packet delivery ratio, network lifetime, and residual energy when compared with PASCC protocol. PMID- 26504899 TI - Information Retrieval and Graph Analysis Approaches for Book Recommendation. AB - A combination of multiple information retrieval approaches is proposed for the purpose of book recommendation. In this paper, book recommendation is based on complex user's query. We used different theoretical retrieval models: probabilistic as InL2 (Divergence from Randomness model) and language model and tested their interpolated combination. Graph analysis algorithms such as PageRank have been successful in Web environments. We consider the application of this algorithm in a new retrieval approach to related document network comprised of social links. We called Directed Graph of Documents (DGD) a network constructed with documents and social information provided from each one of them. Specifically, this work tackles the problem of book recommendation in the context of INEX (Initiative for the Evaluation of XML retrieval) Social Book Search track. A series of reranking experiments demonstrate that combining retrieval models yields significant improvements in terms of standard ranked retrieval metrics. These results extend the applicability of link analysis algorithms to different environments. PMID- 26504900 TI - Long-Term Outcomes of Sacrococcygeal Germ Cell Tumors in Infancy and Childhood. AB - Purpose. The aim of this study was to evaluate long-term outcomes of sacrococcygeal germ cell tumors (SC-GCTs) over a 15-year period. Materials and Methods. A retrospective review was conducted of all pediatric patients treated for SC-GCTs at our hospital from 1998 to 2012. Results. Fifty-seven patients were treated for SC-GCTs with the most common in Altman's classification type I. Age at surgery ranged from one day to 5.6 years. Tumor resection and coccygectomy were primarily performed in about 84% of the cases. Pathology revealed mature, immature, malignant sacrococcygeal teratomas (SCTs), and endodermal sinus tumors (ESTs) in 41 (72%), 4 (77%), 6 (10.5%), and 6 (10.5%), respectively. Recurrence of discase occurred in 3 of 41 patients with mature teratomas (7.3%); 2 recurrences with mature teratomas and one recurrence with EST. Five of 6 malignant SCTs and 3 of 6 ESTs responded well to the treatment. Alpha-fetoprotein (AFP) level was elevated in both malignant teratomas and ESTs. No immediate patient death was noted in any of the 57 cases, but 4 patients with malignant tumors and distant metastasis succumbed at home within 2 years of the initial treatment. Conclusion. Benign SCTs have a significant recurrence rate of approximately 7%. Close follow-up with serial AFP level monitoring should be done for 5 years after initial tumor resection and coccygectomy. The survival rate for malignant SC-GCTs with distant metastasis was unfavorable in the present study. PMID- 26504903 TI - On Relationships Between Fixation Identification Algorithms and Fractal Box Counting Methods. AB - Fixation identification algorithms facilitate data comprehension and provide analytical convenience in eye-tracking analysis. However, current fixation algorithms for eye-tracking analysis are heavily dependent on parameter choices, leading to instabilities in results and incompleteness in reporting. This work examines the nature of human scanning patterns during complex scene viewing. We show that standard implementations of the commonly used distance-dispersion algorithm for fixation identification are functionally equivalent to greedy spatiotemporal tiling. We show that modeling the number of fixations as a function of tiling size leads to a measure of fractal dimensionality through box counting. We apply this technique to examine scale-free gaze behaviors in toddlers and adults looking at images of faces and blocks, as well as large number of adults looking at movies or static images. The distributional aspects of the number of fixations may suggest a fractal structure to gaze patterns in free scanning and imply that the incompleteness of standard algorithms may be due to the scale-free behaviors of the underlying scanning distributions. We discuss the nature of this hypothesis, its limitations, and offer directions for future work. PMID- 26504901 TI - An updated h-index measures both the primary and total scientific output of a researcher. AB - The growing interest in scientometry stems from ethical concerns related to the proper evaluation of scientific contributions of an author working in a hard science. In the absence of a consensus, institutions may use arbitrary methods for evaluating scientists for employment and promotion. There are several indices in use that attempt to establish the most appropriate and suggestive position of any scientist in the field he/she works in. A scientist's Hirsch-index (h-index) quantifies their total effective published output, but h-index summarizes the total value of their published work without regard to their contribution to each publication. Consequently, articles where the author was a primary contributor carry the same weight as articles where the author played a minor role. Thus, we propose an updated h-index named Hirsch(p,t)-index that informs about both total scientific output and output where the author played a primary role. Our measure, h(p,t) = h(p),h(t), is composed of the h-index h(t) and the h-index calculated for articles where the author was a key contributor; i.e. first/shared first or senior or corresponding author. Thus, a h(p,t) = 5,10 would mean that the author has 5 articles as first, shared first, senior or corresponding author with at least 5 citations each, and 10 total articles with at least 10 citations each. This index can be applied in biomedical disciplines and in all areas where the first and last position on an article are the most important. Although other indexes, such as r- and w-indexes, were proposed for measuring the authors output based on the position of researchers within the published articles, our simpler strategy uses the already established algorithms for h-index calculation and may be more practical to implement. PMID- 26504904 TI - Topical sulfasalazine for unresponsive oral lichen planus. AB - OBJECTIVE: The purpose of this study was to evaluate the usefulness of topical sulfasalazine in the treatment of oral lichen planus (OLP) resistant to corticosteroid therapy. METHOD AND MATERIALS: Twenty-one unresponsive OLP patients were treated with topical sulfasalazine 3 times a day for 4 weeks. Each patient's symptoms and lesion size were evaluated at the beginning of therapy, and then after 4 weeks to determine the efficacy of topical sulfasalazine. Inflammatory cytokines levels in saliva were measured by ELISA. RESULTS: Seventeen patients (81%) reported improvement of discomfort and 12 patients (57%) had lesions decrease in size over 50%. Patients who had higher levels of IL-1beta and IL-8 were more responsive to topical sulfasalazine therapy. CONCLUSION: Topical sulfasalazine should be considered when OLP does not respond to corticosteroid therapy. Furthermore, high concentrations of IL-1beta and IL-8 in the saliva are useful indicators for the application of topical sulfasalazine in OLP patients refractory to steroid treatment. PMID- 26504902 TI - Prefrontal inputs to the amygdala instruct fear extinction memory formation. AB - Persistent anxiety after a psychological trauma is a hallmark of many anxiety disorders. However, the neural circuits mediating the extinction of traumatic fear memories remain incompletely understood. We show that selective, in vivo stimulation of the ventromedial prefrontal cortex (vmPFC)-amygdala pathway facilitated extinction memory formation, but not retrieval. Conversely, silencing the vmPFC-amygdala pathway impaired extinction formation and reduced extinction induced amygdala activity. Our data demonstrate a critical instructional role for the vmPFC-amygdala circuit in the formation of extinction memories. These findings advance our understanding of the neural basis of persistent fear, with implications for posttraumatic stress disorder and other anxiety disorders. PMID- 26504905 TI - A novel technique for guided bone regeneration using platelet-rich plasma and osteogenic progenitor cells: Literature-based rationale and case report. AB - Achieving predictable guided bone regeneration in critical size defects for future endosseous dental implant therapy poses a great challenge to clinicians. A novel technique utilizing autogenous osteogenic progenitor cells, calcium sulfate activated platelet-rich plasma in addition to particulate allograft was successfully used to augment a severely deficient maxillary anterior edentulous ridge. After 6 months of healing, satisfactory radiographic and clinical bone gain was noted with significant increase in alveolar ridge width. Endosseous implants were placed and restored successfully. The techniques with underlying clinical and biologic rationales are presented and discussed in this report. PMID- 26504906 TI - Evaluation of lower facial heights as related to different anthropometric measurements in dentate and completely edentulous subjects. AB - OBJECTIVE: The aim was to compare two measurements of lower facial height (base of chin-subnasale and base of chin- tip of the nose) as related to different anthropometric measurements in dentate and completely edentulous subjects. METHOD AND MATERIALS: This cross-sectional study was conducted on 132 male subjects (group 1 [G1], 120 dentate subjects; and group 2 [G2], 12 completely edentulous subjects). Base of chin-subnasale measurement (FM1), base of chin-tip of the nose measurement (FM2), Willis' measurement (FM3), glabella-subnasale measurement (FM4), length of the index finger measurement (AM1), and tip of thumb-tip of index finger measurement (AM2) of subjects of G1 and G2 were measured by using a modified caliper while the subjects in G1 closed in centric occlusion, and the subjects of G2 were asked to close the maxillary and mandibular complete dentures in centric relation. Statistical analysis was carried out by using paired t test, Pearson's correlation (PC), and regression analysis. RESULTS: There were no significant differences between G1FM1 and G1FM3, G1FM1 and G1FM4, G1FM1 and G1AM2 (P > .05), and PCs were R = 0.74, R = -0.35, and R = -0.32 respectively. However, there were significant differences between G1FM2 and G1FM3, G1FM2 and G1FM4, G1FM2 and G1AM2 (P <= .05), and there were significant differences between G2FM2 and different measurements of G2 (P <= .05). CONCLUSION: The use of the linear equation to predict the possible base of chin-subnasale measurement through the Willis' measurement was recommended and could be used as a guide during restoration of the vertical dimension of occlusion when it has been lost. PMID- 26504907 TI - The effectiveness of computerized anesthesia in primary mandibular molar pulpotomy: A randomized controlled trial. AB - OBJECTIVE: The technique of local anesthetic administration is an important consideration in the behavior guidance of a pediatric patient. The study hypothesized that there is no difference in the pain effectiveness in the experimental subjects with the use of single tooth anesthesia and the controls with the use of conventional technique (traditional inferior alveolar nerve block [IANB]).The purpose of this study was to compare the anesthesia effectiveness of traditional IANB; IANB using a computer-controlled local anesthetic delivery system (CCLAD); and intraligamental anesthesia (ILA) using CCLAD in pulpotomy of the primary mandibular second molars. METHOD AND MATERIALS: Ninety-one healthy 5- to 9-year-old children underwent pulpotomy of the mandibular second molars. They were randomly assigned into Group A (traditional IANB), Group B (IANB using CCLAD), or Group C (ILA injection using CCLAD). The effectiveness of anesthesia was measured during different steps of pulpotomy using the sounds, eyes, and motor (SEM) scale. The postoperative complications were recorded after 24 hours. RESULTS: For all five pulpotomy steps, the anesthesia effectiveness was similar among the three anesthesia techniques. Anesthesia effectiveness was not significantly different (based on SEM scores) between the three groups during clamp application, drilling of the tooth, entering the pulp, pulp extirpation, and removal of the clamp (P = .635, P = .996, P = .630, P = .945, and P = .101, respectively). There was no significant difference in postoperative complications between the three groups. CONCLUSION: The IANB anesthesia using CCLAD and periodontal ligament anesthesia using CCLAD were as effective as traditional IANB in anesthetizing the primary mandibular molars during pulpotomy. PMID- 26504908 TI - A comparison of temperature increases produced by "premium" and "standard" diamond burs: An in-vitro study. AB - OBJECTIVE: Vital tooth preparations may cause irreversible thermal damage to the pulp. The manufacturing techniques of dental burs may decrease heat production and minimize the risk of overheating and trauma to the dental pulp. Strauss (Raanana, Israel) has introduced "premium" diamond burs, claiming superior efficiency and longevity. We sought to determine the safest preparation methods by performing a comparison of intrapulpal temperature increases caused with "standard" and "premium" burs. METHOD AND MATERIALS: Three types of diamond burs (F1R, F21R, and K2) were tested on extracted human teeth (n = 8 teeth per bur type). Premium and standard manufacturing techniques were compared for each bur type (n = 24 teeth per group; total 48 teeth). An intrapulpal thermocouple was used to measure the temperature during the procedure. Comparisons were analyzed with the t test and one-way ANOVA. P <= .05 was considered significant. RESULTS: All premium burs demonstrated lower temperature increases compared to the standard burs (P <= .001 for F21R and K2, P = .086 for F1R). The temperature increases with premium burs were similar for different bur shapes, but the temperature increases with standard burs depended on the bur shape (P < .001). CONCLUSION: Using premium diamond burs for tooth preparation may reduce the risk of pulp tissue damage, and thus reduce postoperative pulp-associated complications. PMID- 26504909 TI - Necrotizing sialometaplasia related to vomiting and silastic ring vertical gastroplasty. AB - Necrotizing sialometaplasia (NS) is a self-limiting, ulcerated, benign process, affecting minor salivary glands most commonly in the palate. The comorbidity of eating disorders with NS is rare. We present a patient with bilateral NS who suffered from frequent episodes of vomiting. Review of the literature revealed a handful of such cases. The possible role of vomiting in the pathogenesis of NS is argued. PMID- 26504910 TI - Adverse pregnancy outcomes and periodontitis: A systematic review and meta analysis exploring potential association. AB - OBJECTIVE: The correlation between periodontal status and systemic conditions, among them pregnancy, is widely described in the scientific literature. The aim of the present systematic review of the literature was to evaluate periodontal diseases as an independent risk factor for adverse pregnancy outcomes. DATA: Case control studies reporting pregnancy outcomes and periodontal status of the subjects were included. Risk of bias evaluation was performed using a tool developed by the Cochrane Bias Methods Group. After risk of bias evaluation of included studies, a meta-analysis was performed computing the Risk Ratio (RR) for each pregnancy outcome. SOURCES: Electronic databases (MedLine, Embase, Cochrane Central) were searched after preparation of an appropriate search string. STUDY SELECTION: The search resulted in 422 entries that were screened. After application of inclusion and exclusion criteria, a total of 22 studies were included in the review accounting for a total of 17,053 subjects. The computed RR for periodontitis was 1.61 for preterm birth evaluated in 16 studies (P < .001), 1.65 for low birthweight evaluated in 10 studies (P < .001), and 3.44 for preterm low birthweight evaluated in four studies. CONCLUSION: The present systematic review reported a low but existing association between periodontitis and adverse pregnancy outcomes. This assumption is the result of proper corrections of biased methodologies and of heterogeneity of studies. (. PMID- 26504911 TI - Copper ion-induced fluorescence band shift of CdTe quantum dots: a highly specific strategy for visual detection of Cu(2+) with a portable UV lamp. AB - We have developed a new colorimetric strategy that allows visual detection of Cu(2+) under the irradiation of a UV lamp with high specificity based on the phenomenon that copper ions may lead to a fluorescence band shift of CdTe quantum dots (QDs) while other concomitant ions will not. PMID- 26504912 TI - [Reply: We have focus on the field of general practice]. PMID- 26504913 TI - [Acute PCI in Roskilde]. PMID- 26504914 TI - [Reply: The National Board of Health: The documentation is solid]. PMID- 26504915 TI - [Reply: Mads Koch Hansen: It's not just about distance]. PMID- 26504916 TI - [Substandard or cheating? What about the readers?]. PMID- 26504917 TI - [Psychiatric research ought to be central to long-term plans for psychiatry]. PMID- 26504918 TI - Gordon A. Mclorie. May 2, 1945-February 2, 2015. PMID- 26504919 TI - [Let us create the best medical education]. PMID- 26504920 TI - [Medical education must be rethought]. PMID- 26504921 TI - [Better protection of research subjects]. PMID- 26504922 TI - [Open letter to the Medical Association: Take responsibility for ensuring physician coverage throughout Denmark]. PMID- 26504923 TI - [Washington DC vs. Copenhagen]. PMID- 26504924 TI - [Pro medicine or pro pharma?]. PMID- 26504925 TI - [Non registered indications are clarified]. PMID- 26504926 TI - [Medicin.dk is careful]. PMID- 26504927 TI - [Withdraw Gardasil]. PMID- 26504928 TI - [Reply: Benefits outweigh possible drawbacks]. PMID- 26504929 TI - [Physicians must not contribute to hysteria]. PMID- 26504930 TI - [Yes to more eggs!]. PMID- 26504931 TI - [Faith in the future of general practice?]. PMID- 26504932 TI - Glucose Addiction in Cancer Therapy: Advances and Drawbacks. AB - While normal differentiated cells primarily use mitochondrial respiration to generate the required energy for cellular processes, most cancer cells rely on glycolysis, even in sufficient oxygen conditions. This phenomenon is known as the "Warburg effect" or aerobic glycolysis and the metabolic reprogramming of cancer cells towards this altered energy metabolism is currently recognized as one of the "hallmarks of cancer". Aerobic glycolysis underlies the rapid growth of tumor cells, with high rates of glucose consumption and lactic acid production, leading to cellular acidosis. Metabolic reprogramming renders cancer cells dependent on specific metabolic enzymes or pathways that could be exploited in cancer therapy. The development of treatments that target tumor glucose metabolism is receiving renewed attention, with several drugs targeting metabolic pathways currently in clinical trials. The search for suitable targets, however, is limited by the high plasticity of the metabolic network that can induce compensatory routes. Deregulated glucose metabolism is a prominent feature associated with resistance to classical chemotherapy or oncogene-targeted therapies, strengthening the clinical potential of combining these therapies with glycolysis inhibitors. The aim of this review is to compare the advances of different therapeutic strategies targeting the glucose "addiction" of tumor cells, highlighting their potential as effective weapons against cancer. We further discuss recent evidence for the involvement of glucose metabolism as a compensatory response to the use of drugs that target different signaling pathways, where the combination with glycolysis inhibitors could prove extraordinarily useful. PMID- 26504933 TI - [Considerations behind the Capital Region medication reviews]. PMID- 26504934 TI - [The screening program is not outdated]. PMID- 26504935 TI - [Is the screening program for colorectal cancer outdated before it has begun?]. PMID- 26504936 TI - [Rectal cancer. More or less radiation?]. PMID- 26504937 TI - [Dear patients in the capital region]. PMID- 26504938 TI - [What is a good physician?]. PMID- 26504939 TI - [DCSD is an independent body]. PMID- 26504940 TI - [DCSD plays a central role]. PMID- 26504941 TI - Midwife Laborists Provide High-Quality Care. PMID- 26504942 TI - [Should the announcement of scientific dishonesty be revised yet again?]. PMID- 26504943 TI - Antibiotic use in Pregnancy may be Associated with Childhood Obesity. PMID- 26504944 TI - Exercise Reduces Gestational Diabetes Risk. PMID- 26504945 TI - Omega-3 Fatty Acids do not Appear to Prevent Preterm Birth. PMID- 26504946 TI - Chest X-ray quiz. PMID- 26504947 TI - A Special Section on Analytical Aspects of Nanoscience and Nanotechnology. PMID- 26504948 TI - Gold and Magnetic Nanoparticles-Based Electrochemical Biosensors for Cancer Biomarker Determination. AB - Detecting cancer at early stage is one of the most important factors associated with the increase of the survival rate of the patients. Cancer biomarkers are able to detect a specific disease early and help to provide treatments before it becomes incurable in later stages. Biomarkers can also be used to determine the recurrence of the disease and to evaluate the follow-up of the patients after a chemio- or radio-therapy and surgery treatments. Electrochemical biosensors are successfully applied for the detection of cancer biomarkers due to their high sensibility, rapid response and low cost. In recent years, the advance in nanotechnology has led to the discovery and the employment of a great number of new materials in nanoscale dimensions. Due to their particular properties, the development of nanostructured biosensors (in particular using gold and magnetic nanoparticles) with high analytical performances increases constantly. In this review recent different strategies for the development of gold and magnetic nanoparticles-based electrochemical biosensors for cancer biomarkers detection were presented. PMID- 26504949 TI - Photoelectrochemical Biosensors for Nucleic Acid Detection. AB - A biosensor for detection of nucleic acids employs, as the sensing element, an oligonucleotide, with a known sequence of bases that can be used to detect specific DNA/RNA sequences through the hybridization reaction (this kind of biosensor is also called a genosensor). Many different transducers can be used in the development of a genosensor. Recently, with the emergence of novel photoelectrochemically active species and new detection schemes, photoelectrochemistry has received increasing attention in the field of biosensors. Advances in the development and applications of photoelectrochemical genosensors are reviewed in this article. PMID- 26504950 TI - Nanotechnologies for Removal of Pharmaceuticals and Personal Care Products from Water and Wastewater. A Review. AB - The occurrence of pharmaceuticals and other hazardous substances in surface waters and drinking water and the long-term exposure may represent a potential risk for both the environment and human health. Many studies have evidenced that conventional technologies used for wastewater treatment do not completely remove pharmaceuticals and personal care products (PPCPs) residues, which can be detected in receiving waters at concentrations ranging from few ng L(-1) until more than MUg L(-1). Nanomaterials are of fundamental importance in the current research efforts to develop more efficient water treatment and remediation systems in place of conventional technologies. This review provides a comprehensive overview of the most relevant works available in literature reporting the use of nanosorbents (nanotubes and zeolites), nanofiltration (NF) and advanced oxidation processes (AOPs) for the removal of PPCPs compounds from water and wastewater. The literature review of laboratory- and pilot-scale studies have shown that nanomaterials are promising tools in environmental cleaning processes and water purification, even if more researches are necessary. PMID- 26504951 TI - Thin Film Nanocrystalline TiO2 Electrodes: Dependence of Flat Band Potential on pH and Anion Adsorption. AB - Thin nanocrystalline TiO2 films were produced on ITO conductive glass by dip coating of a sol-gel TiO2 precursor. The transparent films were characterized from the optical and structural point of view with UV-Vis, Spectroscopic Ellipsometry, Raman and X-ray photoelectron spectroscopies, the roughness of the coating by AFM. The changes in the electrochemical properties features of ITO/TiO2 electrodes were evaluated in the presence of different electrolytes (KCI, Na2SO4 and phosphate buffer) with the aim to clarify the role of the ion adsorption on the structure of the electrical double layer. Electrochemical tests (Cyclic Voltammetry, CV, and Impedance Electrochemical Spectroscopy, EIS) showed a strong influence of the electrolyte properties on the semiconductor band edge position in the electrochemical scale and on band bending. The CV profiles recorded can be explained by considering that the interface capacity is due to the charging of surface states (e.g., Ti(IV) surface sites coordinated by oxygen atoms, =Ti-OH or Ti-O-Ti). The surface charge is strongly affected also by the density and nature of adsorbed ions and by dissociation of surficial OH. Of interest the fact that for the produced nanocrystalline electrodes the flat band potential, measured from the Mott-Schottky analysis of the space charge layer capacity obtained with EIS, showed a non Nernstian behavior with the pH probably caused by a change in the surface acidity as a consequence of specific anion adsorption. The modulation of flat band potential with adsorbed ions is of interest for many applications, in particular for photocatalysis (change in the redox potential of photogenerated carriers) and for photovoltaic applications like DSSC (change in the photopotentials). PMID- 26504952 TI - Surface Modeling of Nanopatterned Polymer Films Obtained by Colloidal Templated Electropolymerization. AB - Nanostructured polypyrrole surfaces are fabricated by a one step colloidal templating approach, involving simultaneous polystyrene bead deposition with the electropolymerization of the pyrrole monomer. Using response surface modeling, the influence of several experimental parameters was studied, following as response the resulted film's thickness and the nanopattern's surface density. Polystyrene beads of 100 nm were immobilized by the electropolymerization of pyrrole and the spheres were dissolved in tetrahydrofuran at room temperature. The obtained nanostructures were analyzed by atomic force microscopy (AFM) and the results served to build the mathematical model (central composite face centered design, quadratic model) best describing the correlations between variables and responses. The obtained response surface model revealed the specific influence of each of the studied variables over the followed responses and it also allowed the controlled fabrication of nanopatterned surfaces. PMID- 26504953 TI - Polycyclodextrin and Carbon Nanotubes as Composite for Tyrosinase Immobilization and Its Superior Electrocatalytic Activity Towards Butylparaben an Endocrine Disruptor. AB - We developed a protocol for the immobilization of tyrosinase (Tyr) on the composite of polycyclodextrin polymer (CDP) and carbon nanotubes for the detection of an endocrine disruptor, i.e., butylparaben (BP). The formation of the CDP polymer was characterized by UV-Vis spectrophotometry. The conducting film of cross-linked CDP and carbon nanotubes, displays excellent matrix capabilities for Tyr immobilization. The host-guest chemical reaction ability of CD and the pi-pi stacking interaction assure the bioactivity of Tyr towards butylparaben. The developed biosensor was characterized electrochemically by electrochemical impedance spectroscopy. The enzyme-substrate kinetic parameters such as the apparent Michaelis-Menten constant (K(M)(app)) was measured under saturated substrate concentration. The determination of butylparaben was carried out by using square wave voltammetry over the concentration range of 2.1 to 35.4 MUM with a detection limit of 0.1 MUM. The fabricated biosensor was successfully applied in real-life cosmetic samples with good recovery ranging from 98.5 to 102.8%. PMID- 26504954 TI - Cholesterol Oxidase Functionalised Polyaniline/Carbon Nanotube Hybrids for an Amperometric Biosensor. AB - Functional carbon nanotubes (CNT) have attracted much attention for analytical and biomedical applications. This paper describes the fabrication of a cholesterol oxidase (ChOx) immobilised polyaniline (PANI)/CNT composite electrode for the amperometric detection of cholesterol. The prepared ChOx/PANI/CNT/Au bioelectrode bound ChOx via the available functionalties of PANI (-NH2) and CNT ( COOH). Moreover, the CNT creates a network inside the matrix that strengthens the mechanical property of the bioelectrode. The multifunctional matrix is presumed to provide a 3D-mesoporous surface, which substantially enhances enzyme activity. The linear range of the biosensor for cholesterol oleate was 30-280 MUM with a response time of 10 sec. PMID- 26504955 TI - Alkaline-Phosphatase-Based Nanostructure Assemblies for Electrochemical Detection of microRNAs. AB - Different nanoarchitectures, rich in enzyme labels, are herein investigated for signal amplification in the electrochemical detection of nucleic acids and in particular of microRNAs. Dendritic amplification, accomplished by the use of streptavidin and biotinylated alkaline phosphatase, and enzyme-decorated liposomes are used as labels to amplify the microRNA-sensing, by their association to the probe-microRNA hybrid generated onto a gold transducer. Differential pulse voltammetry and faradaic impedance spectroscopy were employed to characterize these different amplification routes. PMID- 26504956 TI - Electrochemical Impedance Studies on Single and Multi-Walled Carbon Nanotubes- Polymer Nanocomposites for Biosensors Development. AB - Advances in nanoscience have allowed scientists to incorporate new nanomaterials in biosensing platforms. Carbon nanotubes are nanomaterials that facilitate the charge transfer between the bioelement and the transducer. Electrochemical impedance spectroscopy is a useful technique for the modified surface characterization. In the present approach electrochemical impedance spectroscopy was used to characterize the electrodes modified with different types of carbon nanotubes (single and multi-wall) according to their morphology and electrochemical behavior. By using Nyquist and Bode diagrams it was possible to assign the appropriate circuit considering all possible contributors. The charge transfer resistances as well as the time constants were calculated for all five types of investigated carbon nanotubes. PMID- 26504957 TI - A Novel Electrochemical Genosensor Based on Banana and Nano-Gold Modified Electrode Using Tyrosinase Enzyme as Indicator. AB - The electrochemical behavior of the tyrosinase enzyme at the surface of two electrodes, carbon paste electrode (CPE) and nano-gold modified carbon paste electrode (NGCPE), has been studied by cyclic voltammetry. Tyrosinase showed one oxidation peak (around +0.85 V) and one reduction peak at + 0.40 V versus Ag?AgCl?KCl (3 M). To calculate the values of a and k(s), the effect of potential scan rate on the electrochemical properties of tyrosinase was investigated. Cyclic voltammetry and UV-vis absorption techniques were used for the study of interaction between DNA and tyrosinase. The cyclic voltammogram of tyrosinase was obtained in the presence of different types of DNA bases for the study of tyrosinase-DNA binding. The results showed that the hydrogen binding and electrostatic interactions were important interaction mode. Moreover, a variation in tyrosinase signals intensity regarding the interaction to ssDNA and dsDNA was observed. The selectivity of the biosensor was studied using noncomplementary oligonucleotides. Finally, banana modified carbon paste electrode was also prepared to investigate the interaction of banana's tyrosinase with DNA. The limit of detection for DNA probe was calculated 0.33 pM by using the oxidation signal of accumulated tyrosinase in NGCPE. PMID- 26504958 TI - Effect of Electrophoresis on the Efficiency of Graphite-Nano-TiO2 Modified Silica Sol-Gel Electrode. AB - Electrophoresis treatment was used to improve the function of a nano-TiO2 modified sol-gel electrode. Electrodes were prepared using TiO2 nanoparticles and fine graphite powder and then treated by electrophoresis. The developed electrode was employed for the detection of lactate dehydrogenase (LDH) by following the decrease in the immobilised lactate peak current due to its LDH-mediated enzymatic oxidation. Detection was realised using square wave voltammetry (SWV). Experiments showed that the positive and negative heads of the electrophoresis treated electrode displayed different activities, with the positive head response being remarkably improved. Parameters affecting the electrode response, such as applied potential value, electrophoresis time and percentage of TiO2, were investigated and optimised. The improved performance was dependent on TiO2 concentration as well as electrophoresis voltage and time. The prepared sensor, under optimised conditions, displayed a detection limit of 0.0073 U/MUl for LDH. PMID- 26504959 TI - A DNA Aptasensor for Electrochemical Detection of Vascular Endothelial Growth Factor. AB - Electrochemical aptasensors can detect different cancer biomarkers to provide point-of-care diagnosis that is low cost, rapid, specific and sensitive. In this work, we described the development of an electrochemical single-use aptasensor for detection and analysis of vascular endothelial growth factor (VEGF). Gold nanostructured graphite screen-printed electrodes were firstly modified with a mixed monolayer of a primary thiolated DNA aptamer and a spacer thiol, 6-mercapto 1-hexanol. VEGF protein was then incubated with the aptasensor. An enzyme amplified detection scheme, based on the coupling of a streptavidin-alkaline phosphatase conjugate and secondary biotinylated aptamer was then applied. The enzyme catalyzed the hydrolysis of the electroinactive 1 -naphthyl-phosphate to 1 -naphthol; this product is electroactive and has been detected by means of differential pulse voltammetry (DPV). The aptasensor response was found to be linearly related to the target concentration between 0 and 250 nmol L(-1); the detection limit was 30 nmol L(-1). The performance of the immunoassay in terms of reproducibility and selectivity has been also studied. PMID- 26504960 TI - Ensembles-of Gold Nanowires for the Anodic Stripping Voltammetric Determination of Inorganic Arsenic. AB - 3D-ensembles of gold nanowires electrodes (3D-NEEs) are produced by electroless gold deposition in track-etched polycarbonate (PC) membranes, followed by partial etching (plama or chemical) of the polymeric membrane. These electrodes are applied to the anodic stripping voltammetric determination of inorganic As. The controlled etching of the PC template increased the gold surface area, widening the linear range of the analytical response with respect to ensembles of gold nanodisk electrodes (2D-NEEs). 3D-NEEs prepared using a chemical etching time of 10 s allows the anodic stripping determination of As(III) with a detection limit of 0.08 MUg/L and a linear range extended up to 20 MUg/L. The speciation of inorganic As (As(III) and (As(V)) in river water is possible by difference between As(III) and total inorganic As, determined after reduction of As(V) with cysteine. The proposed method is successfully validated by comparison with lCP-MS determination. PMID- 26504961 TI - Development of Carbon-Based Nano-Composite Materials for Direct Electron Transfer Based Biosensors. AB - Nafion, an ion exchange polymer that is very resistant to chemical attack, even by strong oxidant at high temperatures, has found great increasing use as a film material; however, its use as immobilizing agent in third-generation biosensors is hindered due to the low rate of charge transfer in the pure Nafion film. In this work we showed that the use of functionalized multi-walled carbon nanotubes Nafion/MWCNTs composite film for modification of the carbon-based electrode surfaces would increase the charge transfer rate greatly; the composite has proven to efficiently immobilize two different heme proteins (catalase and cytochrome c) and to enhance the electrochemical performances of several carbon electrode materials (glassy carbon, mesoporous graphite, graphite and graphene) either used as classical electrodes or screen printed ones. The electrochemical signal of both redox proteins becomes more reversible and the electron transfer kinetic constant increases. At the same time the biological activity is maintained indicating that the immobilization procedure allows the proteins to retain a native-like structure. PMID- 26504962 TI - A Voltammetric Sensor Based on Modified Multi-Walled Carbon Nanotubes for N Acetyl-L-Cysteine Determination in the Presence of Tryptophan Using 4 Chlorocatechol as a Homogenous Electrochemical Catalyst. AB - Simultaneous determination of N-acetyl-L-cysteine (NAC) and Tryptophan (Trp) has been studied at the surface of glassy carbon electrode (GCE) modified with multi walled carbon nanotubes (MWCNTs) in the presence of 4-chlorocatechol as homogenous electrochemical catalyst in aqueous media. The electrocatalytic properties of GCE modified with MWCNTs in the presence of 4-chlorocatechol toward the electrocatalytic oxidation of NAC and Trp was studied using cyclic voltammetry (CV), double-step potential chronoamperometry and differential pulse voltammetry (DPV). The results has shown that NAC participates in Michael type addition reaction with electrogenerated quinone from electrooxidation of 4 chlorocatechol at MWCNT/GCE to form the corresponding thioquinone derivative. The reoxidation of the adduct leads to increase in the oxidative current which is proportional to the concentration of NAC. Differential pulse voltammogram peak currents of NAC and Trp increased linearly with their concentration at the ranges of 5-60 MUM and 5-50 MUM, respectively and the detection limits for NAC and Trp were sequentially 3.427 MUM and 2.494 MUM. The proposed method was successfully used for the determination of NAC in pharmaceutical samples and the obtained results were found to be reasonable. PMID- 26504963 TI - Detection of DNA Hybridization by Methylene Blue Electrochemistry at Activated Nanoelectrode Ensembles. AB - Nanoelectrode ensembles (NEEs) obtained by electroless gold deposition in track etched poly-carbonate (PC) membranes are functionalized and applied for DNA hybridization detection, using methylene blue (MB) as electroactive probe. To this aim, an amine terminated (ss)DNA probe is immobilized on the PC surface of the NEE by reaction via carbodiimide and N-hydroxysulfosuccinimide. In order to increase the number of carboxylic groups present on PC and suitable for the functionalization, the surface of NEEs is oxidized with potassium permanganate. The presence of carboxylic functionalities is verified by spectrochemical titration with thionin acetate (THA) and the effect of the activation treatment on the electrode performances is evaluated by cyclic voltammetry (CV). After activation and functionalization with the probes, the NEE-based sensor is hybridized with complementary target sequences. The effect of the functionalization of the NEEs both with the (ss)DNA probe alone and after hybridization with the target, is studied by measuring the changes in the MB reduction signal by square wave voltammetry (SWV), after incubation in a suitable MB solution, rinsing and transfer to the measurement cell. It was observed that this peak signal decreases significantly after hybridization of the probe with the complementary target. Experimental evidences suggest that the interaction between MB and the guanines of (ss)DNA and (ds)DNA is at the basis of the development of the here observed analytical signal. The proposed approach allows the easy preparation and testing of NEE-based sensors for the electrochemical DNA hybridization detection. PMID- 26504964 TI - A Special Section on Nanoparticles in Liquid Media for Material Processing, Environment and Industrial Applications. PMID- 26504965 TI - Radiation-Engineered Functional Nanoparticles in Aqueous Systems. AB - Controlled synthesis of nanoscalar and nanostructured materials enables the development of novel functional materials with fine-tuned optical, mechanical, electronic, magnetic, conductive and catalytic properties that are of use in numerous applications. These materials have also found their potential use in medicine as vehicles for drug delivery, in diagnostics or in combinations thereof. In principle, nanoparticles can be divided into two broad categories, organic and inorganic nanoparticles. For both types of nanoparticles there are numerous possible synthetic routes. Considering the large difference in nature of these materials and the elementary reactions involved in the synthetic routes, most manufacturing techniques are complex and only suitable for one type of particle. Interestingly, radiation chemistry, i.e., the use of ionizing radiation from radioisotopes and accelerators to induce nanomaterials or chemical changes in materials, has proven to be a versatile tool for controlled manufacturing of both organic and inorganic nanoparticles. The advantages of using radiation chemistry for this purpose are many, such as low energy consumption, minimal use of potentially harmful chemicals and simple production schemes. For medical applications one more advantage is that the material can be sterile as manufactured. Radiation-induced synthesis can be carried out in aqueous systems, which minimizes the use of organic solvents and the need for separation and purification of the final product. The radiation chemistry of water is well known, as are the various ways of fine-tuning the reactivity of the system towards a desired target by adding different solutes. This, in combination with the controllable and adjustable irradiation process parameters, makes the technique superior to most other chemical methods. In this review, we discuss the fundamentals of radiation chemistry and radiation-induced synthesis of nanoparticles in aqueous solutions. The impact of dose and dose rate as well as of controlled addition of various solutes on the final particle composition, size and size distribution are described in detail and discussed in terms of reaction mechanism and kinetics. PMID- 26504966 TI - The Interaction Between Like-Charged Nanoparticles Mediated by Rod-Like Ions. AB - We present a brief review of recent studies of the interaction between charged nanoparticles immersed in a solution of oppositely charged rod-like counterions. To analyze these systems, we extend and employ an approximate field theory for point charges that has been shown to be accurate from the weak to the intermediate through to the strong coupling regimes. The resulting theory compares well with simulation data. We find that in the weak coupling limit, the interactions between the plates in the rod system are only repulsive. In the intermediate coupling regime, the multivalent rod-like counterions can mediate attractive interactions between the nanoparticles through two mechanisms. Charge correlations between different counterion rods lead to attractions between the plates, as in the case for the point charge counterions. For sufficiently long rods, however, bridging contributes to the attractive interaction, where the correlation of the charges within the rods is important. In the strong coupling limit, the inter-ionic charge correlations dominate the attractive interactions at short separations between the charged nanoparticles. PMID- 26504967 TI - Nanosized and Nanostructured Particles in Pulmonary Drug Delivery. AB - Nanosized objects can be used as the drug carriers with specific functionalities which are introduced to the body via the respiratory system, i.e., by inhalation. They can be carried in as aerosol nanoparticles (NPs), nanostructured particles (NSPs) or components of nanosuspensions atomized into micrometer-sized droplets. In the first part of the paper physical factors required for the effective inhalation of nanocarriers are discussed, including the flow dynamics of NPs and NSPs in the respiratory tract. Selected problems related to designing of the required properties of inhalable drug carriers are also addressed. In the next part of the paper, the importance of direct physicochemical interactions between deposited nanoparticles and pulmonary fluids (pulmonary surfactant and bronchial mucus) is emphasized. This perspective allows for a more rational definition of the efficient strategies of the delivery of nanoparticle drug carriers via inhalation. PMID- 26504968 TI - Carbon-Nanohorn Based Nanofluids for a Direct Absorption Solar Collector for Civil Application. AB - Direct solar absorption has been often considered in the past as a possible solution for solar thermal collectors for residential and small commercial applications. A direct absorption could indeed improve the performance of solar collectors by skipping one step of the heat transfer mechanism in standard devices and having a more convenient temperature distribution inside the collector. Classical solar thermal collectors have a metal sheet as absorber, designed such that water has the minimum temperature in each transversal section, in order to collect as much solar thermal energy as possible. On the other hand, in a direct configuration, the hottest part of the system is the operating fluid and this allows to have a more efficient conversion. Nanofluids, i.e., fluids with a suspension of nanoparticles, such as carbon nanohorns, could be a good and innovative family of absorbing fluids owing to their higher absorption coefficient compared to the base fluid and stability under moderate temperature gradients. Moreover, carbon nanohorns offer the remarkable advantage of a reduced toxicity over other carbon nanoparticles. In this work, a three-dimensional model of the absorption phenomena in nanofluids within a cylindrical tube is coupled with a computational fluid dynamics (CFD) analysis of the flow and temperature field. Measured optical properties of nanofluids at different concentrations have been implemented in the model. Heat losses due to conduction, convection and radiation at the boundaries are considered as well. PMID- 26504969 TI - A Comparative Study of the Dispersion of Multi-Wall Carbon Nanotubes Made by Arc Discharge and Chemical Vapour Deposition. AB - A method has been developed to characterize the dispersion of multi-wall carbon nanotubes in water using a disc centrifuge for the detection of individual carbon nanotubes, residual aggregates, and contaminants. Carbon nanotubes produced by arc-discharge have been measured and compared with carbon nanotubes produced by chemical vapour deposition. Studies performed on both pristine (see text) arc discharge nanotubes is rather strong and that high ultra-sound intensity is required to achieve complete dispersion of carbon nanotube bundles. The logarithm of the mode of the particle size distribution of the arc-discharge carbon nanotubes was found to be a linear function of the logarithm of the total ultrasonic energy input in the dispersion process. PMID- 26504970 TI - Iron/Magnetite Nanoparticles as Magnetic Delivery Systems for Antitumor Drugs. AB - In this study we investigate on the possible use of a new kind of magnetic nanostructures as drug delivery systems for anticancer drugs. The starting particles are formed by an inner core of iron, coated by magnetite as a stabilizing, magnetic layer. These units are further coated by a poly(ethylenglycol) (PEG) layer to make them less prone to the attack by macrophages and to favour longer stays in the blood stream. The resulting particles consist of several magnetic cores encapsulated by a polymer layer around 5 nm thick. The crystal structure of the designed nanostructures, as determined by X-ray powder diffraction, is compatible with a crystalline magnetite component, whereas the magnetization hysteresis data indicate a superparamagnetic behavior. Both the initial susceptibility and the saturation magnetization are lower than for the bare magnetic cores, but still significant. Drug adsorption and release tests were performed on two anticancer drugs, namely 5-fluorouracil and doxorubicin. Both are found to adsorb on the particles, but only the latter appears to be released at a reasonable rate, which is found to be very slow for 5-fluorouracil. PMID- 26504971 TI - Modeling of the Multiscale Dispersion of Nanoparticles in a Hematite Coating. AB - Images of a hematite-based epoxy coating are obtained by scanning electron microscopy (SEM). At the scale of a few micrometers, they show aggregates of hematite nano-particles organized along thin curved channels. We first segment the images and analyze them using mathematical morphology. The heterogeneous dispersion of particles is quantified using the correlation function and the granulometry of the embedding (epoxy) phase. Second, a two-scales, 3D random microstructure model with exclusion zones is proposed to simulate the spatial distribution of particles. This simple model is parametrized by four geometrical parameters related to the exclusion zones solely. The microstructure is numerically optimized, in the space of morphological parameters, on the granulometry of the embedding epoxy phase and on the microstructure correlation function, by standard gradient-descent methods. Excellent agreement is found between the SEM images and our optimized model. Finally, the size of the representative volume element associated to the optimized microstructure model is compared with that of the SEM images. PMID- 26504972 TI - Bimetallic Wiregauze Supported Pt-Ru Nanocatalysts for Hydrogen Mitigation. AB - Passive autocatalytic recombiner (PAR) is one of the most suitable devices for mitigation of hydrogen, generated in nuclear power plant under accidental conditions. For this purpose we report development of stainless steel wire gauze supported Pt-Ru nanoparticles as catalysts. Simultaneous electroless deposition has been employed for the synthesis of the catalysts. Pt-Ru based bimetallic catalysts were characterized for their rate of coating kinetics, noble metal loading, phase purity by XRD and surface morphology by SEM, TEM and elemental analysis by SIMS. Developed catalysts were found to be active for efficient recombination of hydrogen and oxygen in air as well as in presence of various prospective poisons like CO2, CH4, CO and relative humidity. Pt-Ru based bimetallic catalyst with 0.9% loading was found to be active for CO poisoning up to 400 ppm of CO. PMID- 26504973 TI - One-Pot Polyol Synthesis of Pt/CeO2 and Au/CeO2 Nanopowders as Catalysts for CO Oxidation. AB - The facile one-pot synthesis of CeO2-based catalysts has been developed to prepare a relatively large amount of nanopowders with relevant catalytic activity towards CO oxidation. The method consists of a two-steps process carried out in ethylene glycol: in the first step, 5 nm well-crystallized pure CeO2 is prepared. In a subsequent second step, a salt of a noble metal is added to the CeO2 suspension and the deposition of the noble metal on the nanocrystalline CeO2 is induced by heating. Two catalysts were prepared: Pt/CeO2 and Au/CeO2. The as prepared catalysts, the thermally treated catalysts, as well as the pure CeO2, are characterized by XRD, TGA, XPS, FTIR, HR-TEM, STEM, particle size distribution, and N2-physisorption. In spite of the identical preparation protocol, Au and Pt behave in a completely different way: Au forms rather large particles, most of them with triangular shape, easily identifiable and dispersed in the CeO2 matrix. In contrast, Pt was not identified as isolated particles. The high resolution X-ray diffraction carried out on the Pt/CeO2 thermally treated sample (500 degrees C for 1 h) shows a significant CeO2 lattice shrinkage, which can be interpreted as an at least partial incorporation of Pt into the CeO2 crystal lattice. Moreover, only Pt2+ and Pt4+ species were identified by XPS. In literature, the incorporation of Pt into the CeO2 lattice is supported by first principle calculations and experimentally demonstrated only by combustion synthesis methods. To the best of our knowledge this is the first report where ionically dispersed Pt into the CeO2 lattice is obtained via a liquid synthesis method. The thermally treated Pt/CeO2 sample revealed good activity with 50% CO conversion at almost room temperature. PMID- 26504974 TI - Photo-Physical Behaviour of CdSe Nanocrystals/Bis(dithiocarbamate) Linker Multilayered Hybrid Systems. AB - Multilayered films composed by CdSe Nanocrystals (NCs) interlinked by ethylene 1,2-bis(dithiocarbamate) or adipate anions were prepared on ITO glass via layer by-layer alternation. The films were analyzed by UV-vis, TEM, Photoluminescence (PL) emission and Pump-Probe spectroscopy. While the PL emission of the two samples present no differences, femtosecond Pump-probe experiments reveal an higher charge generation efficiency in bis(dithiocarbamate) based films than in dicarboxylate ones. PMID- 26504975 TI - A General Technique to Investigate the Aggregation of Nanoparticles by Transmission Electron Microscopy. AB - The aggregation state of nanoparticles (NPs) must be precisely known in order to study the structure-property relationship and to evaluate the exploitability of NPs dispersion for a given application. Here we report a general technique for sample preparation to investigate with transmission electron microscopy (TEM) the state of aggregation of NPs dispersed in liquid solution. Following a simple procedure which requires few minutes, the aggregates of NPs are "frozen" in a polymeric matrix simultaneously to their deposition on a TEM grid. Our technique is of general applicability and it avoids the use of cryo-TEM, which is more expensive, more time consuming and less common than ordinary TEM. Compared to the investigation of NPs aggregation in the liquid phase with dynamic light scattering, our approach avoids the problem of shielding by large aggregates and it allows the full exploitation of TEM advantages, primarily the reliable determination of shape and size of each aggregate and the precise evaluation of the number of single NPs forming each cluster. As an example, we demonstrate the use of our technique to study two frequent topics related to aggregation: the plasmon properties of gold NPs aggregates and the stability of iron oxide NPs in physiological environment. The methodology described here will be useful to advance the knowledge about how aggregation influences the physical-chemical properties of NPs. PMID- 26504976 TI - Ceramic Ink-Jet Printing for Digital Decoration: Physical Constraints for Ink Design. AB - In the last decade, the drop-on-demand (DOD) ink-jet printing has become the leading technology for the decoration of ceramic tiles. The inks employed for such application are colloidal suspensions of oxide particles (0.3 MUm) whose stability (against agglomeration and over time) is fundamental to get successfully the tile decoration. Jettability from the DOD print heads is a key requirement along with proper colour after sintering. This means that a careful set up of inks properties (viscosity, density, surface tension) is required. The phenomena involved in the different stages of the ink-jet printing process (drop ejection from the nozzles, impact and spreading on the substrates) are described through dimensionless numbers as Reynolds, Weber, and Bond numbers, or their combinations. In literature physical constraints, obtained with a semi theoretical approach on the basis of experimental evidences on other systems, allow to define a reference region in the space of the dimensionless numbers (here called "printable fluid region," PFR) where the inks should be suitable for the application. In this paper, 26 inks currently used for ceramic tile decoration were characterized and mapped in the space of dimensionless numbers for several printing conditions. For typical nozzle diameters (20-50 gm) and drop velocities (6-8 m/s), it has been found that they fall in the region identified by 3 < Re < 30, 27 < We < 160, and 0.6 < 1/Oh < 2.5, where Re, We, and Oh, are the Reynolds, Weber and Ohnesorge numbers, respectively. Such experimental region can be taken as reference to tune the colloidal interactions in proper way, though the thresholds delimiting the PFR should be better defined. PMID- 26504977 TI - Infiltration of Metal Substrates with Nanostructured CeO2 by a Room-Temperature Wet Process. AB - A room-temperature infiltration procedure for the deposition of CeO2 nanopowders on Ni-based foams employing stable CeO2 suspensions in water has been developed. It consists of a two-steps dipping process, the first in nanopowder suspension at pH 6.5 followed by further dipping into a NH3OH solution at pH 12. The pH shift represents a key factor to improve the homogeneity and dispersion of infiltrated powder by avoiding coalescence during the drying step. Water-based suspensions have been prepared starting from a commercial nanostructured CeO2. Powder was characterized by X-ray diffraction, particle size and specific surface area measurements, transmission electron microscopy. Stability of suspensions was studied by zeta potential measurements at low concentration, while sedimentation tests were carried out on highly concentrated suspensions as a function of pH, CeO2 amount and surfactant presence. Effect of CeO2 concentration, surfactant addition, pH value, substrate composition and microstructure were taken in account. Under best conditions, very homogeneous infiltrations could be obtained without any preferential orientation or agglomerates. Thermal stability of the composites infiltrated materials was also tested. The technique seems to be very promising in advanced nanostructured decorations and coating preparation. PMID- 26504978 TI - Optical Properties of Mixed Nanofluids Containing Carbon Nanohorns and Silver Nanoparticles for Solar Energy Applications. AB - Different kinds of nanofluids show peculiar characteristics. In this work, a mixed nanofluid consisting of single-wall carbon nanohorns and silver nanoparticles aqueous suspensions is prepared and optically characterized, in the perspective to merge the favorable optical characteristics of carbon nanohorn based nanofluids to the good thermal properties of silver-nanofluids. For the samples, both the spectral extinction and the scattering albedo at discrete wavelengths have been investigated. The silver nanoparticle plasmonic peak in the visible range further improves the overall nanofluid sunlight absorption properties, opening interesting perspectives for using such mixed nanofluids as solar absorber and heat transfer media in solar thermal collectors. PMID- 26504979 TI - Charge Stabilized Silver Nanoparticles Applied as Antibacterial Agents. AB - Monodisperse silver nanoparticle sols were synthesized via chemical reduction processes in aqueous environment without using polymeric stabilizing agents or surfactants. The sols obtained using various reducing agents; inorganic cell permeabilizers and organic phenolic compounds; inter alia gallic acid (GA) and tannin (TA) were thoroughly characterized by various physicochemical methods such as TEM, SEM, AFM, DLS and micro-electrophoresis. The antibacterial activity of the sols against two E. coli strains was characterized via the determination of the Minimum Bactericidal Concentration (MBC). All sols exhibited a pronounced bactericidal effect against the standard K12 strain, especially the GA and TA sols showing MBC concentration as low as 1-5 mg L(-1). In the case of the antibiotic resistant strain the highest activity (MBC of 10 mg L(-1)) was observed for the sol synthesized using sodium hypophosphate and sodium tripolyphosphate. Additionally, interactions of silver nanoparticles with bacteria cell were studied using TEM and AFM imaging. It was shown that the silver particles attach to the bacteria surface inducing disintegration, which enables their penetration inside the bacteria. Our measurements confirmed that the surface chemistry of silver nanoparticles can play a decisive role. PMID- 26504980 TI - Permeability of Soft Particles at Electrical Fields. AB - The influence of the charge on the permeability of microgel particles is studied in the presence of electric fields. Electrophoresis experiments performed on pH ionizable pNIPAM-AA microgels show that particles behave as permeable spheres when the network is ionized. However, they keep non-permeable in the absence of charge. The ionic nature of the network thus controls the permeability of the soft particles. A salt-dependent local viscosity explains these permeability changes. This is confirmed by NMR as alternative independent technique. Strongly hydrated counterions located around fixed charges on the network are considered responsible for the local viscosity variations. PMID- 26504981 TI - Influence of Cu, TiO2 Nanoparticles and Carbon Nano-Horns on Tribological Properties of Engine Oil. AB - The addition of nanoparticles in lubricating oils recently demonstrated to reduce the coefficient of friction and to increase the load-carrying capability of lubricant in coupled surfaces. In this work, different kinds of nanoparticles were tested as additives to engine oil to improve lubrication: copper and titanium oxide nanoparticles and single walled carbon nanohorns (SWCNHs). Two nanoparticle sizes were also tested in case of copper. The tribological properties of these nanofluids were evaluated by Stribeck tests, in order to compare the effect of nanoparticles on friction coefficient and electric contact resistance in different lubrication regimes. Stribeck curves showed that the coefficient of friction was reduced, compared to raw oil, by the action of Cu nanoparticles having 130 nm diameter, leading to a mean decrease of about 17%, and by SWCNHs, with a mean decrease of about 12%. Conversely, no significant changes were detected in presence of Cu nanoparticles having 50 nm diameter or of TiO2. The suspension viscosity and stability were also tested. Wear tests were also carried out, showing a reduction of wear rate up to nearly 50% for Cu nanoparticles (150 nm diameter) and around 30% for SWCNHs. The measurements showed that nanoparticles having size comparable to the mean roughness of coupled surfaces significantly improved the tribological properties of bare oil. An explanation of nanoparticle action is proposed. PMID- 26504982 TI - Characterization and Simulation of the Heat Transfer Behaviour of Water-Based ZnO Nanofluids. AB - This paper deals with the characterization and modelling of water-based nanofluids containing zinc oxide (ZnO) nanoparticles in concentrations ranging between 1 and 10 wt%. Low concentrations were chosen to reduce fouling and excessive pressure drops. First of all, the stability was verified by means of an instrument, based on the dynamic light scattering (DLS) technique, measuring mean nanoparticle diameters and Zeta potential. Moreover, nanofluids pH was measured. Then, thermal conductivities and dynamic viscosities were measured, analysing their dependence on temperature and nanoparticle concentration. Thermal conductivity was measured by means of a hot disk apparatus in the temperature range between 10 and 70 degrees C, while viscosity was measured by a magnetic suspension rheometer in the same range of temperatures. Finally, the heat transfer capability of these fluids was studied measuring their heat transfer coefficients in a dedicated apparatus between 18 and 40 degrees C. Heat transfer coefficient was evaluated at different Reynolds number, in turbulent flow regime. Reynolds and Nusselt numbers were deduced by using previously measured thermal conductivity and viscosity values. Moreover, numerical simulations in two dimensional turbulent and steady state flow were carried out. No increase in heat transfer coefficient in the temperature range between 18 and 40 degrees C was found. Comparison between experimental and numerical simulation data, in terms of wall temperature profiles, showed a good agreement. PMID- 26504983 TI - Effect of Nanoparticle Surface Chemistry on Adsorption and Fluid Phase Partitioning in Aqueous/Toluene and Cellular Systems. AB - Copolymers of di(ethylene glycol) methyl ether methacrylate (x = MeO2MA) and oligo(ethylene glycol) methyl ether methacrylate (y = OEGMA) display lower critical solution phenomena in aqueous systems that are tunable by the copolymer ratio (x:y), ionic strength, and temperature. These properties enable tuning the hydrophobicity of macromolecular systems by variation of (x:y). For nanoparticles stabilized with these macromolecules, this provides a systematic approach to understanding the impact of surface chemistry, specifically hydrophobicity, on the equilibrium and transport properties of nanomaterials in biphasic systems. We synthesized a homologous series of gold nanoparticles capped by these copolymers, Au@(MeO2MA(x)-co-OEGMA(y)). By varying the copolymer 95:5 < (x:y) < 80:20 ratio, we studied the effect of surface hydrophobicity on the nanoparticle equilibrium adsorption isotherm and phase transfer at the aqueous-toluene interface. The increase in hydrophobicity from (x:y) = 80:20 to (x:y) = 95:5 is accompanied by an increase in the fractional coverage of the aqueous-toluene interface from f = 0.3 to f > 1, or multilayer adsorption and an increase in the characteristic adsorption timescale from tau(D) = 31 to tau(D) = 450 seconds. The equilibrium partition coefficient for the aqueous/toluene systems, K(T/W) is also a strong function of (x:y), increasing from K(T/W) (80:20) = 0.7 to K(T/W) (95:5) = 9.8. We also observed an increase in cellular uptake for increasing (x:y) suggesting that surface chemistry alone plays a significant role in intercellular transport processes. PMID- 26504984 TI - Carbon Soot-Ionic Surfactant Mixed Layers at Water/Air Interfaces. AB - An experimental study is here presented on the properties of aqueous dispersions containing carbon nanoparticles and different ionic surfactants which can modify the degree of hydrophobicity/philicity of particles favoring their transfer from the dispersion bulk to the interfacial layer. Aim of this work is to understand the particle-surfactant and particle-fluid interface interactions and their effect on those macroscopic surface properties of the mixed systems which are expected related to the stability and structure of the respective particle stabilized foams. To this purpose a systematic characterization of dispersions have been carried out, based on surface tension measurement against the surfactant concentration, using a drop Profile Analysis Tensiometer (PAT). These results have been crossed with the characterization of the bulk dispersion by Dynamic Light Scattering (DLS) and zeta-potential measurements to check the effects of surfactant on the particle aggregation and on the particle surface charge, respectively. The stability of the foams obtained with the same compositions has been also investigated and correlated to the other surface and bulk properties. PMID- 26504985 TI - Proton Conducting Ceramic Powder Synthesis by a Low Temperature Method. AB - Molten salt synthesis (MSS) is a simple method for the preparation of ceramic powders with specific morphology. The main role of the molten salts is to increase the reaction rate and lower the reaction temperature. It occurs because of much higher mobility of reactants in the liquid medium than in the solid state. In this work the molten salt synthesis was applied to produce ceramic powders of La0.995Ca0.005NbO4 and BaCe(0.9-x)Zr(x)Y0.1O3. Single-phase lanthanum niobate formed in all studied conditions of the synthesis, whereas in the case of barium cerate-zirconate MSS led to forming two crystalline phases: barium cerate and barium zirconate. The heating temperature and time as well as the salt content most strongly influenced the shape and size of particles. The influence of other parameters on the powder morphology was weaker. Despite differences in size and morphology, all groups of the La0.995Ca0.005NbO4 powder obtained with the MSS method pressed into pellets and sintered gave a dense ceramic material. On the other hand in the case of barium cerate-zirconate regardless of synthesis and sintering conditions the ceramics were porous. PMID- 26504986 TI - Role of Different Solvents on the Purification of As-Synthesized Nano-Ce(1 x)Gd(x)O(2-d) Powders. AB - Ceria and rare earth-doped ceria powders have important applications in catalysis, gas sensoring, and electronics. Even if many authors report different methods for the synthesis of nano-sized doped-ceria only few of them give information about the necessary washing processes for the powder purification. The organics adsorbed on the as-synthesized particles surface strongly affect, in fact, the properties of the powder. In this work, CeO2 and Ce(1-x)Gd(x)O(2-d) (x = 0.10, 0.20, 0.30) solid solutions were produced by polyol microwave assisted method. The amount of synthesis residues adsorbed on the as-synthesized powders was firstly evaluated. The purification ability of different solvents on the as synthesized Ce0.80Gd0.20O190 was, then, accurately studied in order to obtain a clean powder without the need of any thermal treatments. The study shows that water purification allows to reduce the amount of the residues of synthesis leading to the production of nano-particles with a mono-dispersed distribution of dimensions. PMID- 26504987 TI - Role of Fillers on Dispersion of MWCNT/Fluoroelastomeric Composites for High Performance Dielectric Energy Storage Application. AB - Halloysite nanotube (HNT) and clay are introduced into multi-walled carbon nanotube (MWCNT)/fluoroelastomer (FKM) composites to improve electrical conductivity without harming mechanical and thermal properties. Hence, it has been achieved by combining the fillers (HNT and clay) with MWCNT which restricts the agglomeration of MWCNT in the matrix and allows the uniform dispersion. With just 2 wt% HNT and Clay, electrical conductivity is increased by more than four orders of magnitude (from 10(-8) to 10(-4) S/cm). Furthermore, the percolation threshold of these nanocomposites is reduced with the addition of 2 wt% HNT and clay. MWCNTs appear to have an affinity for clay that causes them to become more exfoliated in these composites. This HNT/clay-nanotube synergy may make these composites better suited for high electrical properties along with high mechanical and thermal applications. PMID- 26504988 TI - Enhanced Performance of Organic Thin Film Transistor Devices Using Hydroxyethyl Terminated P3HT as the Active Layer. AB - Hydroxyethyl-terminated poly(3-hexylthiophene) (P3HT-OH) have been synthesized via a catalyst-transfer polycondensation using Grignard metathesis mediated by a nickel-based catalyst. This hydrophilic P3HT-OH is compared against the hydrophobic P3HT when used as an active layer on silicon dioxide (SiO2) wafer for organic thin-film-transistor (OTFT) fabrication. Hydroxyl groups at a 7.5% weight content lead to more chain regularity when polymer is bonded to SiO2 wafer surface and thus enhance the performance of OTFT Device, such as an 114.2% increase in ON/OFF ratio, an 12.4% increase in mobility, a 23.3% decrease in threshold voltage and a 30.1% decrease in surface roughness. Analysis and measurements reported in this paper have illustrated for the first time the feasibility of imparting hydrophilicity to the active layer for improving the OTFT performance. PMID- 26504989 TI - Enhanced Activity and Durability of Nanosized Pt-SnO2/IrO2/CNTs Catalyst for Methanol Electrooxidation. AB - Pt-SnO2/IrO2/CNTs anode catalyst for direct methanol fuel cell was designed and prepared with IrO2/CNTs as support for the subsequent immobilization of Pt and SnO2 at the same time. The structure of the catalysts and their catalytic performance in methanol electrooxidation were investigated and the roles of IrO2 and SnO2 in methanol electrooxidation were discussed as well. Results show that Pt-SnO2/IrO2/CNTs catalyst exhibits the best activity and durability for methanol electrooxidation when compared with Pt/CNTs, Pt/IrO2/CNTs and Pt-SnO2/CNTs. According to the results of electrochemical tests and physicochemical characterizations, the enhancements of Pt-SnO2/IrO2/CNTs were attributed to the special properties of IrO2 and SnO2, in which IrO2 mainly increases the methanol oxidation activity and SnO2 mainly improves the CO oxidation ability and durability. Therefore, Pt-SnO2/IrO2/CNTs exhibits excellent performance for methanol oxidation with higher electrocatalytic activity (I(f) of 1054 A g(Pt( 1)) and powerful anti-poisoning ability (the onset potential for CO oxidation of 0.3 V) and outstanding durability (the sustained time t in CP of 617 s), revealing a suitable anode catalyst for DMFCs. PMID- 26504990 TI - Shape Dependent Thermal Conductivity of TiO2-Deionized Water and Ethylene Glycol Dispersion. AB - This paper presents the importance of different shapes and crystal phases of TiO2 nanostructures such as TiO2 P-25 (70:30 anatase and rutile), as-prepared nanorods (pure anatase) and sodium titanate nanotubes (orthorhombic Na2Ti2O5 x H2O crystal) on the thermal conductivity of de-ionized water and ethylene glycol. It revealed that TiO2 nanorods (L x W = 81-134 nm x 8-13 nm and surface area = 79 m2 g(-1)) showed always higher thermal conductivity than porous nanotubes (L x W = 85-115 nm x 9-12 nm and surface area = 176 m2 g(-1)) and commercial TiO2 P-25 (30 55 nm surface area = 56 m2 g(-1)), which was explained by their differences in crystallinity, crystal phases, compactness, surface exposed atoms, surface area and much greater mean free path of longitudinal phonon vibrations along its lateral dimensions. The subsequent effect of sonication time from 5-10 h results into the breakdown of TiO2 nanorods cluster (42 to 28 nm) with the instantaneous increase in negative zeta potential values from -31 to -45 mV, respectively, seems to be an additional cause for enhancement in its thermal conductivity. PMID- 26504991 TI - A Molecular Dynamics of Cold Neutral Atoms Captured by Carbon Nanotube Under Electric Field and Thermal Effect as a Selective Atoms Sensor. AB - Here we analyzed several physical behaviors through computational simulation of systems consisting of a zig-zag type carbon nanotube and relaxed cold atoms (Rb, Au, Si and Ar). These atoms were chosen due to their different chemical properties. The atoms individually were relaxed on the outside of the nanotube during the simulations. Each system was found under the influence of a uniform electric field parallel to the carbon nanotube and under the thermal effect of the initial temperature at the simulations. Because of the electric field, the cold atoms orbited the carbon nanotube while increasing the initial temperature allowed the variation of the radius of the orbiting atoms. We calculated the following quantities: kinetic energy, potential energy and total energy and in situ temperature, molar entropy variation and average radius of the orbit of the atoms. Our data suggest that only the action of electric field is enough to generate the attractive potential and this system could be used as a selected atoms sensor. PMID- 26504992 TI - Synthesis and Evaluation of Self-Assembled Azido Monolayer as a Novel Dielectric Layer for Fabricating Pentacene-Based Organic Thin Film Transistors. AB - Self-assembled 3-azidopropyltriethoxysilane monolayer (SAM) is used as a dielectric layer to modify the interface between the silicon dioxide wafer and the pentacene semiconductor layer in an organic thin film transistor (OTFT), Au/pentacene/3-azidopropyltriethoxysilane/SiO2/Si. Compared to the commonly used alkyl siliane C18 dielectric, 3-azidopropyltriethoxysilane which possesses stable formal charges is far more effective in increasing the ON/OFF ratio of OTFT device with an improvement of nearly three orders of magnitude. Analysis and measurements reported in this paper have illustrated for the first time the improvement of OTFT performance by a SAM compound with stable formal charges. PMID- 26504993 TI - Photophysical Properties of Zinc Tetracarboxy Phthalocyanines Conjugated to Magnetic Nanoparticles. AB - Magnetite nanoparticles (MNPs) were synthesised by the co-precipitation method and coated with amino functional groups which allowed for amide bond formation with the carboxylic acid groups on zinc tetra- or octa-carboxyphthalocyanine (ZnTCPc or ZnOCPc respectively). The absorption spectra of ZnTCPc linked to MNPs showed a reduction in aggregation, while the photophysical parameters (Phi(T), tau(T) and Phi(Delta) of ZnTCPc or ZnOCPc increased upon linking with the MNPs. PMID- 26504994 TI - RGB Recombination Zone Tuning to Improve Optical Characteristics of White Organic Light-Emitting Diodes. AB - White organic light emitting diodes (WOLEDs) were fabricated using blue, green and red emitting layers (EMLs). The device has a structure of ITO/NPB/EML/Alq3/Liq/Al. Here, to control the white color balance, the location of the blue EML in the WOLEDs was fixed and only the thickness of blue EML was changed while both thickness and position of the green and red EMLs were adjusted. When adjusting the thickness of blue EML, the occurrence area of recombination zone was changed to influence the green luminescence. When adjusting the location and thickness of red EML, it could be found that the current density is more sensitive to the location of red EML than its thickness. Furthermore, it was discovered that light was emitted due to the Forster energy transfer even if it was apart from the recombination zone. WOLEDs with a maximum luminance of 17,740 cd/m,2 an external quantum efficiency of 2.12% at 100 cd/m,2 CIE coordinates of (0.328,0.301) and a color temperature of 6,185 K were obtained. PMID- 26504995 TI - Synthesis of Hollow Carbon Nano-Onions Using the Pulsed Plasma in Liquid. AB - We synthesized carbon nano-onions (CNOs) using a low-voltage spark discharge in a liquid and studied the effects of liquid type and pulse duration. By the pulsed electric discharge between two graphite rods of 120 mm length and 6 mm diameter submerged into a 200 ml toluene or ethanol, hollow CNOs with diameters ranging from 10 to 30 nm were produced. CNOs produced using toluene grew more carbon shells than does the sample produced using ethanol. The sample that was synthesized using pulsed plasma with pulse duration of 5 MUs showed more carbon shells (10-30) than the sample prepared by 12 MUs (2 to 10). High performance liquid chromatography (HPLC) and high resolution transmission electron microscopy analyses confirmed that the sample produced at 12 MUs pulsed plasma contains fullerene C60, while the sample prepared at 5 MUs does not. PMID- 26504996 TI - Biocompatibility Assessment of Polyethylene Glycol-Poly L-Lysine-Poly Lactic-Co Glycolic Acid Nanoparticles In Vitro and In Vivo. AB - The present study was designed to evaluate the biocompatibility of nanoparticles polyethylene glycol (PEG)-poly L-lysine (PLL)-poly lactic-co-glycolic acid copolymer (PLGA) (PEG-PLL-PLGA) before clinical application. We applied some tests to assess the safety of PEG-PLL-PLGA nanoparticles (NPs). There was low cytotoxicity of PEG-PLL-PLGA NPs in vitro as detected by MTT assay. Cell apoptosis and intracellular accumulation of PEG-PLL-PLGA were determined by FCM assay. The apoptotic rate induced by nanoparticles and the fluorescence intensity of intracellular daunorubicin (DNR) demonstrated that DNR-PEG-PLL-PLGA could be taken up by the mouse fibroblast cells (L929 cells). Hemolysis test and micronucleus (MN) assay demonstrated that the nanoparticles have no obviously blood toxicity and genotoxicity. DNR-PEG-PLL-PLGA NPs were injected into mice through tail vein to calculate the median lethal dose (LD50), the results showed that they had a wide safe scale. Blood was taken by removing the eyeball of mice to study the influence of DNR-PEG-PLL-PLGA in hepatic and renal functions. The results revealed that there was no significant difference as compared with the control group. Interestingly, the pathologic changes of heart, liver, spleen, lung and kidney were observed in nanoparticles treated mice. Thus, this study demonstrates that PEG-PLL-PLGA NPs appear to be highly biocompatible and safe nanoparticles that can be suitable for further application in the treatment of tumor. PMID- 26504997 TI - Fluorescent CdS Quantum Dots: Synthesis, Characterization, Mechanism and Interaction with Gold Nanoparticles. AB - CdS quantum dot (QD) is a typical kind of II-IV nanoparticles, which plays an important role in the common type of core-shell QDs. It is of great practical significance to synthesize the water-soluble CdS QDs used in multicolor biomarkers and prepare core-shell QDs. In our case, we came up with a novel green method to manufacture CdS QDs with high quality, different size, and adopted UV vis absorption, fluorescence, FTIR, XPS, HRTEM, SAED and STEM-EDX to discuss their growth mechanism. We successfully constructed fluorescence resonance energy transfer (FRET) system between CdS QDs and gold nanoparticles (AuNPs), then comprehensively and systematically studied the interaction between them. PMID- 26504998 TI - A Nanoscale-Localized Ion Damage Josephson Junction Using Focused Ion Beam and Ion Implanter. AB - High-T(c) Josephson junctions were fabricated by nanolithography using focused ion beam (FIB) milling and ion implantation. The junctions were formed in a YBa2Cu3O7-x, thin film in regions defined using a gold-film mask with 50-nm-wide (top) slits, engraved by FIB. The focused ion beam system parameters for dwell time and passes were set to remove gold up to a precise depth. 150 keV oxygen ions were implanted at a nominal dose of up to 5 x 10(13) ions/cm2 into YBa2Cu3O7 x microbridges through the nanoscale slits. The current-voltage curves of the ion implantation junctions exhibit resistive-shunted-junction-like behavior at 77 K. The junction had an approximately linear temperature dependence of critical current. Shapiro steps were observed under microwave irradiation. A 50-nm-wide slit and 0-20-nm-thick buffer layers were chosen in order to make Josephson junctions due to the V-shape of the FIB-milled trench. PMID- 26504999 TI - Synthesis and Characterization of Poly(N-vinylcarbazole)/Graphene Nanocomposites. AB - The present work describes the dual role of graphene as an initiator and filler for polymerization of N-vinylcarbazole and formation of poly(N vinylcarbazole)/graphene (PVK/Gr) nanocomposites. Fourier transformation infrared (FTIR) and X-ray diffraction (XRD) studies confirmed the formation of PVK as well its graphene nanocomposites. Scanning electron micrograph (SEM) and transmission electron microscopy (TEM) revealed the graphene platelets are dispersed in the matrix of spherical PVK. X-ray photoelectron spectroscopy (XPS) also revealed formation of PVK and presence of interaction between PVK and graphene. Thermograivmetric analysis (TGA) have shown that the thermal stability of PVK/graphene (0.5 wt%) is maximum improved by -76 degrees C compared to neat PVK, when 20 wt% weight loss is taken as a point of comparison. Ultraviolet (UV) and photoluminescence (PL) studies established the charge transfer from polymer chains to the graphene platelets. Dielectric measurements have shown the maximum improvement (87%) in dielectric constant (epsilon) with 1 wt% graphene loading. The variation of ac conductivity (sigma) with frequency (psi) confirmed the insulating behavior of PVK/graphene nanocomposites possessing high dielectric constant. PMID- 26505000 TI - Synthesis of Bimetallic Ni-Cr Nano-Oxides as Catalysts for Methanol Oxidation in NaOH Solution. AB - Bimetallic Ni-Cr nano-oxide catalysts were synthesized by thermal decomposition method and were investigated as the anode electrocatalysts for the oxidation of methanol. The catalysts were characterized by X-ray diffraction and transmission electron microscopy. The electroactivity of the catalysts towards methanol oxidation in a solution containing 0.25 M NaOH and 1.0 M MeOH was examined using cyclic voltammetry and chronoamperometry. The results indicate that a mixture of rhombohedral-structured NiO and Cr2O3 nanocrystals generated at the calcination temperature of 500-700 degrees C while octahedral-structured spinel NiCr2O4 formed at higher temperature. The influence of metallic molar ratio on the electrocatalytic performance of the catalysts was studied. The Ni-Cr nano-oxides prepared at comparatively low temperature displayed significantly higher catalytic activity and durability in alkaline solution toward electrooxidation of methanol compared with the pure nano NiO. The results indicate a synergy effect between NiO and Cr2O3 enhancing the electrocatalytic properties of the bimetallic Ni-Cr nano-oxide catalysts. Meanwhile, NiCr2O4 hardly increased the activity and durability of the catalyst. In addition, the Ni-Cr catalyst also exhibited excellent stability and good reproducibility. Therefore, Ni-Cr nano-oxide catalyst may be a suitable and cheap electrocatalyst for methanol oxidation in alkaline medium. PMID- 26505001 TI - TiO2 Fibers: Tunable Polymorphic Phase Transformation and Electrochemical Properties. AB - A series of one-dimensional (1 D) nanoparticle-assembled TiO2 fibers with tunable polymorphs were prepared via a novel and large scale ForceSpinning process of titanium tetraisopropoxide (TTIP)/polyvinylpyrrolidone (PVP) precursor fibers followed with a thermal treatment at various calcination temperatures. The thermal and structural transformations were characterized by thermogravimetric analysis/differential scanning calorimetry, scanning electron microscopy, and X ray diffraction. The influence of polymorphic phase of the TiO2 fibers on the electrochemical performance in neutral aqueous 1 M Na2SO4 electrolyte was investigated. The polymorphic amorphous/anatase/rutile TiO2 fibers prepared at 450 degrees C achieved a highest capacitance of 21.2 F g(-1) (6.61 mF cm(-2)) at a current density of 200 mA g(-1), for which the improved electronic conductivity and activated pseudocapacitance mechanism may be responsible. This work helps bridge the gap between nanoscience and manufacturing. It also makes polymorphism control of functional materials a potential strategy for further improving supercapacitive output of metal oxides. PMID- 26505002 TI - Synthesis of LiNbO3 Nanoparticles by Citrate Gel Method. AB - We present investigations on the preparation of nearly stoichiometric lithium niobate (LiNbO3) nanoparticles using citrate gel method. Citric acid is used as a chelating agent and ethylene glycol is added for polyestarification between the chelates. In addition to the main lithium niobate phase, the secondary phase of lithium niobate, LiNb3O8, and an unreacted phase of Nb2O5 were also observed in the resultant product. The appearance of unwanted phases is a serious problem in citrate gel method. We have observed that the synthesis parameters such as molar ratio of citric acid to metal ions (R1), pH, molar ratio of ethylene glycol to citric acid (R2) and calcination temperature strongly influence the presence of the unwanted phases and these parameters are optimized to remove these phases. Evolution of the phase was investigated by powder XRD whereas TG/DTA was done to find out the crystallization temperature. It was observed that nearly stoichiometric and pure LiNbO3 nanoparticles can be obtained with the optimized parameters, R1 = 3, pH = 8, R2 >= 2 and calcination temperature = 700 degrees C. The stoichiometry of the synthesized LiNbO3 nanoparticles was investigated using Raman spectroscopy. PMID- 26505003 TI - Characterizing the Stress Intensity Factor of Graphene Sheet with Central Crack. AB - This paper aims to characterize the stress intensity factor (SIF) of atomistic graphene sheet with central crack subjected to uniaxial loading. The equilibrium configuration of the defective graphene sheet with missing covalent bonds was generated through molecular dynamics (MD) simulation. Subsequently, the local stress distribution near the crack tip of atomistic structure was evaluated using the Hardy stress formulation as well as the non-local elasticity theory. Based on the local stress distributions, the SIF of the atomistic graphene sheet was determined through the projection process. In comparison, the graphene sheet was also treated as a continuum solid, and the stress distribution near the crack tip as well as the SIF were evaluated from the finite element method (FEM). In an attempt to understand the crack size effect, the crack length was assumed to vary from 3 lattice distance to around 80 lattice distance. Results revealed that the SIF calculated based on the nonlocal elasticity theory in conjunction with the projection process is quite sensitive to the selection of the projection point. However, for the Hardy stress distribution, when the projection position is 1 lattice distance away from the crack tip, the SIF is quite consistent and the result is compatible to that obtained from the FEM analysis. Moreover, the agreement is better as the crack size is increasing. Therefore, the SIF calculated based on the Hardy stress formulation together with the projection approach could be a physical quantity correlating the defective atomistic graphene sheet with its continuum counterpart. PMID- 26505004 TI - A Facile Way for Fabricating PEGylated Hollow Mesoporous Silica Nanoparticles and Their Drug Delivery Application. AB - PEGylated hollow mesoporous silica nanoparticles (HMSN-PEG) were successfully fabricated by only one simple step through hydrothermal treatment in Na2CO3 solution. HMSN-PEG nanoparticles were transformed from conventional PEG-modified mesoporous silica nanoparticles (MSN-PEG). The as-synthesized HMSN-PEG nanoparticles exhibited higher loading capacity of anticancer drug (Doxorubicin) and better sustained release property than MSN and MSN-PEG particles. In vitro cell viability of HMSN-PEG nanoparticles to Hep-G2 cells was evaluated. HMSN-PEG nanoparticles have little in vitro cytotoxicity up to a concentration of 500 MUg/ml. Furthermore, the DOX-loaded HMSN-PEG nanoparticles exhibited higher cytotoxicity than the DOX-loaded MSN and MSN-PEG nanoparticles against Hep-G2 cells. Therefore, the HMSN-PEG nanoparticle that generated in this PEG protecting etching strategy is a promising nanocarrier toward its potential application for cancer therapy. PMID- 26505005 TI - Preparation of Polyimide/MWCNT Nanocomposites via Solid State Shearing Pulverization (S3P) Processing. AB - Polyimide/multiwall carbon nanotube (PI/MWCNT) nanocomposite films with homogeneous MWCNTs dispersion were prepared via a solid state shearing pulverization (S3P) approach. Polyimide precursor, viz., poly(amic acid) (PAA), was synthesized from 4,4'-oxydianiline (ODA) and pyromellitic dianhydride (PMDA). Then, 3,3',4,4'-benzophenonetetracarboxylic dianhydride (BTDA) was mixed with the PAA powder and acid functionalized MWCNTs (acid-MWCNTs) by solid state shearing pulverization (S3P) approach. Finally, PI/MWCNT nanocomposite films were prepared by thermal imidization at elevated temperatures. Using such an approach not only the MWCNTs are well-dispersed but also the mechanical and thermal properties of PI are improved. The tensile strength of PI was enhanced by 74% and the elongation at break decreased to 10.35% with 5.0 wt% acid- MWCNT loading. And the glass transition temperature of PI was increased to 341 degrees C from 303 degrees C because of the strong interfacial bonding between PI and acid-MWCNTs. The solid state shearing pulverization (S3P) approach developed in this study provides a novel method to prepare various polymer composites with desired particle dispersion. PMID- 26505006 TI - Liposomes Encapsulating 10-Hydroxycamptothecin-Cyclodextrin Complexes and Their In Vitro Anti-Tumor Activities. AB - Manufacturing and characterizing hydroxycamptothecin inclusion liposomes, establishing their quality standard and testing their in vitro anti-tumor activity is of significance for potential application. The neutralization agitation method was used to prepare hydroxycamptothecin inclusion and film evaporation method was utilized to manufacture hydroxycamptothecin inclusion liposomes. The phase solubility method, differential scanning calorimetry and infrared spectroscopy were used to identify the prepared inclusion complex. The hydroxycamptothecin inclusion liposomes were characterized for particle morphology, size, in vitro release and stability. The hepatoma (HepG-2), lung cancer (A549), and gastric cancer (SGC-7901) cell lines were used as models for preliminary evaluation of anti-cancer effect from the hydroxycamptothecin inclusion liposomes, done by MTT colorimetry, cytometer experiments, and apoptosis staining. The anti-cancer evaluation was compared with commercially available hydroxycamptothecin. The results showed the hydroxycamptothecin inclusion was successfully prepared by neutralization agitation method. Phase solubility method, differential scanning calorimetry and infrared spectroscopy proved the formation of the hydroxycamptothecin inclusion. The hydroxycamptothecin inclusion liposomes were successfully prepared by film evaporation method. (2) The inclusions were found to be spherical, with average particle size of 119.7 nm, zeta potential of - 45.6 mV, average inclusion rate of 70.55%, and drug-loading was 14.60%. The inclusions were also found to have a sustained release effect, when compared to the commercially available hydroxyccamptothecine. The hydroxyccamptothecine inclusion liposomes had better stability at 4 degrees. (3) The hydroxycamptothecin inclusion liposomes also exhibited better inhibition effect for the three kinds of cancer cell lines above, when compared to the commercially available hydroxycamptothecin the anti cancer effect being at a dose-dependent manner. Neutralization agitation and thin film evaporation methods can be used to manufacture hydroxycamptothecin inclusion liposomes with better encapsulation efficiency, drug-loading content, stability, sustained-release effect and stronger anti-cancer activity. PMID- 26505007 TI - Effect of Ag Thin Films on the Photoluminescence of ZnO Films. AB - The Ag-coated ZnO films were deposited on glass substrates using magnetron sputtering technique. Atomic Force Microscopy was employed to characterize the surface and the profile roughness of Ag-coated ZnO films. X-ray diffraction and X ray photoelectron were used respectively to analyze the crystalline and chemical state of survey samples. The influence of capping Ag on the photoluminescence intensities of ZnO films has been investigated. The photoluminescence spectra were found to change as the deposited Ag varied with different deposition times and annealing temperatures. Relationships between the fabrication, characterization and performance of Ag-coated ZnO films are established. The results indicate that the diffusion of Ag into ZnO films and the upward bending of the energy band near the interface of ZnO/Ag led to the decrease of ultraviolet intensities of Ag-coated ZnO films. Due to the density of surface states on the bending of energy band, it is crucial to control the surface morphology of metal/ZnO for the enhancement of light emission. PMID- 26505008 TI - Facile Synthesis of Vanadium-Pentoxide Nanoparticles and Study on Their Electrochemical, Photocatalytic Properties. AB - Vanadium pentoxide (V2O5) nanoparticles were synthesized via an anionic, cationic and non-ionic surfactant-assisted hydrothermal method. The synthesized nanoparticles were characterized by using powder X-ray diffractometer, Scanning Electron Microscope, High Resolution Transmission Electron Microscope and UV-Vis spectroscopy. The experimental results confirm the formation of vanadium pentoxide nanoparticles. Vanadium pentoxide crystalline nanoparticles were prepared from various surfactants named Sodium Dodecyl Sulphate (SDS), Cetyl Trimethyl Ammonium Bromide (CTAB) and Triton-X, resulting the crystallite size of 61.6 nm, 27.5 nm and 46 nm respectively. From the electrochemical studies, it is found that vanadium pentoxide prepared with CTAB exhibit good cycle stability when compared with other two samples. Also the ionic-conducting behavior of the materials was investigated by using impedance analysis. In addition, the photocatalytic studies were performed and found better photocatalytic efficiency in V2O5 prepared with SDS, obtained through the degradation of MO dye under UV light irradiation. Our results show that Vanadium pentoxide can be a suitable candidate for photocatalytic application and as electrode in development of futuristic supercapacitors. Also this can be employed in various environmental eco-friendly applications. PMID- 26505009 TI - Optical and Magnetic Properties of ZnO Nanoparticles Doped with Co, Ni and Mn and Synthesized at Low Temperature. AB - Zinc oxide nanomaterials were synthesized with small amounts of magnetic ions to create dilute magnetic semiconductors (DMS), by using a low temperature sol-gel method. Conditions were controlled such that a range of amounts of Co, Ni and Mn were incorporated. The incorporation could be tracked by color changes in the powders to blue for Co, green for Ni and yellow for Mn. XRD measurements showed the ZnO has the wurtzite structure with crystallites 8-12 nm in diameter. Nanoparticles were observed by SEM and TEM and TEM showed that the lattice fringes of different nanoparticles align. Nanoparticle alignment was disrupted when high concentrations of metal dopants were incorporated. Magnetic measurements showed a change in behavior from diamagnetic to paramagnetic with increasing concentration of metal dopants. PMID- 26505010 TI - Effect of Hydroxyapatite Nanoparticles on the Growth Potential of Hepatoma Cells in Nude Mice. AB - AIM: To evaluate the activity of hydroxyapatite (HAP) nanoparticles against the proliferation of hepatoma cells. METHODS: HAP nanoparticles were prepared by homogeneous precipitation. The size distribution and morphology of these nanoparticles were determined by laser particle analysis and transmission electron microscopy, respectively. Xenograft tumor models of human hepatoma cells (Bel-7402) implanted in nude mice under the right scruff skin were established and divided into two groups: treatment and control. Once the xenograft tumor grew to a diameter of 0.8 cm, 0.2 ml HAP nanoparticle suspension was injected into the tumor every day for 2 weeks. The long and short diameters of the tumors were measured before and after HAP injection, and the inhibition rate of tumor growth was calculated. Paraffin tissue sections were prepared from xenograft tumors treated as above for 2 weeks, histologically stained for DNA and agyrophilic nucleolar organizer region (AgNORs), and immuno-histologically stained for proliferating cell nuclear antigens (PCNAs). The stained sections were examined by microscopy. Images of these sections were recorded and analyzed by image analysis system and relevant software for DNA content, AgNOR intensity, and PCNA expression in the nucleus, nucleoli, and hepatoma cells, respectively. RESULTS: The HAP nanoparticles were uniformly distributed, with a size of 44.6 nm to 86.8 nm. Upon the local injection of the tumor with the HAP nanoparticles, the average volumes of the tumors were significantly reduced compared with those of the control group, which had a tumor inhibition rate of 51.32%. The DNA content, AgNOR intensity, and PCNA expression in the hepatoma cells were all significantly reduced (P < 0.01) compared with those in the control group. CONCLUSION: HAP nanoparticles inhibit the proliferation of hepatoma cells in vivo. PMID- 26505011 TI - Construction of Novel Thermosensitive Magnetic Cationic Liposomes as a Drug and Gene Co-Delivery System. AB - This study aimed to develop a novel system for co-delivery of both drugs and genes to the same cells. We described the construction of thermosensitive magnetic cationic liposomes (TSMCLs). Liposomes were prepared by thin film hydration method, then calcein release assay and DSC were used to determine the thermosensitivity of liposomes, and gel retardation experiment was performed to monitor the formation of Lipoplex (Liposomes and pDNA complex), finally the in vitro transfection experiments were performed to evaluate the transfection efficiency of the liposomes. The results showed that TSMCLs combined the features of physical targeting under magnetic guidance and hyperthermia triggered drug release upon the application of alternating magnetic field. Thus TSMCLs could be used for the co-delivery of drugs and genes and have potential application in combined chemotherapy and gene therapy for cancer. PMID- 26505012 TI - Quantitatively Understanding Cellular Uptake of Gold Nanoparticles via Radioactivity Analysis. AB - The development of multifunctional gold nanoparticles (AuNPs) underwent an explosion in the last two decades. However, many questions regarding detailed surface chemistry and how they are affecting the behaviors of AuNPs in vivo and in vitro still need to be addressed before AuNPs can be widely adapted into clinical settings. In this work, radioactivity analysis was employed for quantitative evaluation of I-125 radiolabeled AuNPs uptakes by cancer cells. Facilitated with this new method, we have conducted initial bioevaluation of surfactant-free AuNPs produced by femtosecond laser ablation. Cellular uptake of AuNPs as a function of the RGD density on the AuNP surface, as well as a function of time, has been quantified. The radioactivity analysis may shed light on the dynamic interactions of AuNPs with cancer cells, and help achieve optimized designs of AuNPs for future clinical applications. PMID- 26505013 TI - Antibacterial Properties of ZnO/Calcium Alginate Composite and Its Application in Wastewater Treatment. AB - In this study, the antibacterial activities of ZnO with various morphologies were evaluated. A possible mechanism of antibacterial activities of dumbbell like ZnO was proposed based on the microscopic studies of the interaction between bacterial and dumbbell like ZnO, and also based on the antibacterial activity of ZnO enveloped with semi permeable membrane. Monosodium glutamate (MSG) wastewater and soy sauce wastewater were treated by M. purpureus using ZnO/calcium alginate carrier. The attached and suspended biomass in MSG wastewater reached to 228 mg/g and 74 mg/g, while, the attached and suspended biomass in soy sauce wastewater was 130 mg/g and 66 mg/g, respectively. The levels of chemical oxide demand (COD), biological oxide demand (BOD5), SO4(2-) and NH3-N in the treated MSG wastewater were distinctive lower than those detected in the raw wastewater. This ZnO/calcium alginate carrier method could be utilized as an alternative to the traditional anaerobic/aerobic methods in the application of food processing wastewater treatment. PMID- 26505014 TI - High Field Emission Current Density from Patterned Carbon Nanotube Field Emitter Arrays with Random Growth. AB - High field emission (FE) current density from carbon nanotube (CNT) arrays grown on lithographically patterned silicon substrates is reported. A typical patterned field emitter array consists of bundles of nanotubes separated by a fixed gap and spread over the entire emission area. Emission performance from such an array having randomly oriented nanotube growth within each bundle is reported for different bundle sizes and separations. One typical sample with aligned CNTs within the bundle is also examined for comparison. It is seen that the current density from an array having random nanotube growth within the bundles is appreciably higher as compared to its aligned counterpart. The influence of structure on FE current densities as revealed by Raman spectroscopy is also seen. It is also observed that current density depends on edge length and increases with the same for all samples under study. Highest current density of -100 mA cm( 2) at an applied field of 5 V/MUm is achieved from the random growth patterned sample with a bundle size of 2 MUm and spacing of 4 MUm between the bundles. PMID- 26505015 TI - Reconstruction of Acetogenesis Pathway Using Short-Read Sequencing of Clostridium aceticum Genome. AB - Clostridium aceticum is an anaerobic homoacetogen, able to reduce CO2 to multi carbon products using the reductive acetyl-CoA pathway. This unique ability to use CO2 or CO makes the microbe a potential platform for the biotech industry. However, the development of genetically engineered homoacetogen for the large scale production of commodity chemicals is hampered by the limited amount of their genetic and metabolic information. Here we exploited next-generation sequencing to reveal C. aceticum genome. The short-read sequencing produced 44,871,196 high quality reads with an average length of 248 bases. Following sequence trimming step, 30,256,976 reads were assembled into 12,563 contigs with 168-fold coverage and 1,971 bases in length using de Bruijn graph algorithm. Since the k-mer hash length in the algorithm is an important factor for the quality of output contigs, a window of k-mers (k-51 to k-201) was tested to obtain high quality contigs. In addition to the assembly metrics, the functional annotation of the contigs was investigated to select the k-mer optimum. Metabolic pathway mapping using the functional annotation identified the majority of central metabolic pathways, such as the glycolysis and TCA cycle. Further, these analyses elucidated the enzymes consisting of Wood-Ljungdahl pathway, in which CO2 is fixed into acetyl-CoA. Thus, the metabolic reconstruction based on the draft genome assembly provides a foundation for the functional genomics required to engineer C. aceticum. PMID- 26505016 TI - Preparation and Growth of N-Doped Hollow Carbon Nanospheres and Their Application as Catalyst Support in Direct Borohydride Fuel Cell. AB - N-doped hollow carbon nanospheres (HCNSs) were prepared by electric arc discharge method in N2 atmosphere. X-ray Photoelectron Spectroscopy (XPS) analysis shows that their nitrogen content reaches up to 4.9 atom%. Both the low thermal conductivity of N2 and the doping of nitrogen atom make carbon unit bend to form hollow nanosphere structure. High-resolution transmission electron microscopy (HRTEM) and X-ray diffusion (XRD) analysis prove the presence of detected defects and a poor crystallinity on the HCNSs shell. Moreover, annealing treatment of HCNSs was carried out at 1100 degrees C/10 h and 1400 degrees C/2 h to research their fracture extension. It is found that HCNSs could grow into closed-tubes even with a shell at high annealing temperature. HCNSs were applied in direct borohydride fuel cell (DBFC) to evaluate their catalytic performance. The electrochemical results show that pure HCNSs doesn't have any catalysis effect, but they can greatly promote the catalytic performance of CoO, and the largest polarization current density of which achieves 1.845 A x cm(-2) at -0.7 V (vs. Hg/HgO electrode). PMID- 26505017 TI - Tuning the Magnetic Properties of Iron Oxide Nanoparticles by a Room-Temperature Air-Atmosphere (RTAA) Co-Precipitation Method. AB - The ability of a room-temperature air-atmosphere (RTAA) co-precipitation method to tune the magnetic properties of iron oxide nanoparticles was investigated. It was demonstrated that superparamagnetic nanoparticles with different particle sizes ranging from 7 to 25 nm and magnetic properties with saturation magnetization between 2 to 75 emu g(-1) can be synthesized by simply controlling the molar ratio of ferrous to ferric ions and the concentration of ammonium solution, without heat treatment or oxygen-level control. It was revealed that the tuning of the magnetic properties was associated with the compositional control between magnetite and maghemite. Ammonium concentration was also an important factor to obtain dispersed superparamagnetic (SPM) or ferrimagnetic (FM) nanoparticles. PMID- 26505018 TI - Single-Walled Carbon Nanotubes Decorated with Polypyrrole-TiO2 Nanocomposites. AB - Nanomaterials decorated with polypyrrole were synthesized using two types of oxidants by chemical oxidative polymerization method. The interaction and influence of the addition of single-walled carbon nanotubes (SWCNTs) and titanium dioxide (TiO2) nanoparticles in polypyrrole (PPy) were studied using Fourier transform infrared spectroscopy and Raman spectroscopy. Thermal stability has been observed by using thermogravimetric analysis. Electrochemical properties were calculated by using Cyclic Voltammetry to study comparative analysis between samples. Particle size measurements and morphology were determined by Field emission transmission electron microscopy. All the nanocomposites exhibit better thermal and electrochemical properties than native polymer. The size of the polypyrrole particles were in the range of 50 nm to 60 nm. PMID- 26505019 TI - The Electrochemical Behavior of TiN/316LSS Material in Simulated Body Fluid Solution. AB - We report on the fabrication and the electrochemical behavior of TiN film on the 316L stainless steel (316LSS) material in simulated body fluid (SBF) solution for implant application. The characterization results indicate that the coated TiN is completely crystalline with (111) crystal orientation. Electrochemical results of 316LSS and TiN/316LSS material after 21 days of immersion in SBF show that the durability of the TiN/316LSS is much higher than that of 316LSS, which registers a very low corrosion current density (about tens of nA cm(-2)). The formation of hydroxyapatite on the surface of the TiN/316LSS is also confirmed by SEM, EDX, X ray and IR spectroscopy. PMID- 26505020 TI - Effects of Different Lengths of Ti Nanorods Topography on Mesenchymal Stem Cell Growth and Proliferation. AB - Total hip and knee arthroplasty have being successfully performed in world-wide in recent years. However, poor osseointegration between implant (polish surface) and host bone tissue is one of the main causes for aseptic loosening in Ti-based materials and result in failure. Fabricating nanotopography is a promising method to improve cell behaviors and promote osseointegration. Ti nanorods array of vary lengths have been produced via selective corrosion of Ti substrate using electrochemical anodization technique on titanium surface. In this study, we investigated the murine bone mesenchymal stem cell (MSC) behaviors in response to these different lengths of nanorods. The result showed that the nanorod of 100 nm length increased MSCs adhesion and proliferation. Increased elongation of cytoskeleton actin was also observed on 100 nm height, which resulted in substantially up-regulation of alkaline phosphatase (ALP) activity, suggesting greater bone-forming ability than control Ti. The Ti nanorods of 100 nm length may be a promising implant surface to improve the osseointegration. PMID- 26505021 TI - The Fate of Polyol-Made ZnO and CdS Nanoparticles in Seine River Water (Paris, France). AB - This study aims to characterize nanoparticles with different compositions and structures as well as seeing their evolutions over time in a natural environment such as Seine river water (Paris, France). Face centered cubic (fcc) and hexagonal (hcp) CdS as well as hexagonal (hcp) ZnO nanoparticles were synthesized by the Polyol method. CdS nanoparticles (i) cfc structure: are agglomerated, present 100 nm length with heterogeneous diameter and 10 m2 g(-1) specific surface area (S(g)) from Brunauer Emett and Teller (BET) measurements; (ii) hcp structure: 20 nm and S(g) = 67 m2 g(-1). ZnO hcp nanoparticles presents 50 nm length and 15 nm diameter and S(g) = 54 m2 g(-1). These results are in agreement with X-ray diffraction (XRD), and small angle X-ray scattering (SAXs). After 48 h interaction with Seine river water, cryo-TEM analysis showed that ZnO nanoparticles form spherical agglomerates with 300 nm diameter; CdS nanoparticles (fcc) are agglomerated presenting large diameters (> 500 nm); and CdS nanoparticles (hcp) are not agglomerated and present the same characteristics of the starting material. After 168h of contact with Seine river water, CdS (fcc) presents only 14% of dissolution, CdS (hcp) presents both 60% dissolution and 30% reprecipitation in a cadmium carbonate form and finally almost 90% of ZnO nanoparticles are dissolved. PMID- 26505022 TI - Preparation of Au Nanoparticles Immobilized Cross-Linked Poly(4-vinylpyridine) Nanofibers and Their Catalytic Application for the Reduction of 4-Nitrophenol. AB - Catalytic nanofibers are prepared by the immobilization of Au nanoparticles (AuNPs) onto the surface of cross-linked electrospun poly(4-vinylpyridine) (P4VP) nanofibers. The crosslinking of the P4VP nanofibers by 1,4-diiodobutane via quaternization reaction greatly enhances the stability of the nanofibers against the solvent dissolution, which can then be used as promising platform for the immobilization of catalytic metal nanoparticles. The AuNPs immobilized cross linked P4VP nanofibers have shown a good catalytic activity for the reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP). PMID- 26505023 TI - Nanoparticle Capture During Directional Solidification of Nano-Sized SiC Particle Reinforced AZ91D Composites. AB - The capture/push behavior of a particle in front of a solidification interface was analyzed theoretically and experimentally in this work. Van der Waals force, viscous force, and force due to interfacial energy played important roles in the particle capture/push process. Directional solidification experiments were conducted with nano-sized SiC particle-reinforced AZ91D composites to observe the distribution of nanoparticles in different solidification morphologies under varied cooling rates. When the composite solidified with plane manner, the nanoparticles could be captured by the solidification front and distributed uniformly in the matrix. When solidified with columnar or equiaxial manners, the nanoparticles could be captured by the solidification front but distributed uniformly only in the grain boundary as a result of the difference in interfacial energy and wettability between SiC/alpha-Mg and SiC/eutectic phase. Theoretical prediction of particle capture was in agreement with the experiment results. PMID- 26505024 TI - Morphological Control of Cells on 3-Dimensional Multi-Layer Nanotopographic Structures. AB - The extracellular matrix (ECM) environment is known to play an important role in the process of various cell regulatory mechanisms. We have investigated the ability of 3-dimensional ECM geometries to induce morphological changes in cells. Bi-layer polymeric structures with submicron scale stripe patterns were fabricated using a two-step nano-imprinting technique, and the orientation angle (theta(alpha)) of the upper layer was controlled by changing its alignment with respect to the orientation of the bottom layer. When cells were grown on the mono layer stripe structure with a single orientation, they elongated along the direction of the stripe pattern. On bi-layer polymer structures, the cell morphologies gradually changed and became rounded, with an increase of thetaalpha up to 90 degrees, but the polarities of these cells were still aligned along the orientation of the upper layer. As a result, we show that the polarity and the roundness of cells can be independently regulated by adjusting the orientation of 3-dimensional hierarchical ECM topography. PMID- 26505025 TI - A Novel Osteoblast/Osteocyte Selection Method in Primary Isolated Chick Bone Cells by Atomic Force Microscopy. AB - Selection of bone cells, particularly osteoblasts and osteocytes, for analysis of cellular processes and differentiation is a very important issue because bone remodeling is a highly complex and harmonized process, which includes molecular and cellular interactions and communications. In this study, we introduce a novel osteoblast and osteocyte selection method that uses atomic force microscopy and OB7.3, an antibody of Phex, which is a specific protein marker expressed on the surface of osteocytes. The elasticity and Phex expression levels were simultaneously detected by force spectroscopy using the OB7.3-modified atomic force microscopy probe on the bone cell surface. The elastic modulus was different between osteoblasts and osteocytes. Phex expression level was analyzed by the distribution of Phex-OB7.3 rupturing. PMID- 26505026 TI - Growth of CdS Nanorods and Deposition of Silver Nanoparticles. AB - Systematic investigations have been done to deposit silver nanoparticles on seeded CdS nanorods. The CdS nanorods were synthesized by using CdS nanocrystals as seeds being indexed to the cubic structure (zinc-blende) and tetradecylphosphonic acid as surfactants to enable preferential growth on the reactive {001} facets. Ostwald ripening process occurred during the growth of CdS nanorods. Ag/CdS heterostructures were obtained through a facile method in which oleylamine was employed as reducing agents under an elevated temperature. Exposing CdS nanorods to Ag+ ions resulted in Ag domains depositing on the tips of the nanorods or defected sites embedding in the nanorod surfaces. Ag domains formed separate nuclei and grew quickly at a high concentration of AgNO3 solution. We further focused on discussing the morphology formation mechanism and optical properties of the heterostructures and the nanorods. The as-synthesized Ag/CdS heterostructures can facilitate charge separation at the metal semiconductor interface. Herein, it opens up an application possibility of enhancing photocatalytic processes and other devices. PMID- 26505027 TI - Charge Carrier Transport Mechanism Based on Stable Low Voltage Organic Bistable Memory Device. AB - A solution processed two terminal organic bistable memory device was fabricated utilizing films of polymethyl methacrylate PMMA/ZnO/PMMA on top of ITO coated glass. Electrical characterization of the device structure showed that the two terminal device exhibited favorable switching characteristics with an ON/OFF ratio greater than 1 x 10(4) when the voltage was swept between - 2 V and +3 V. The device maintained its state after removal of the bias voltage. The device did not show degradation after a 1-h retention test at 120 degrees C. The memory functionality was consistent even after fifty cycles of operation. The charge transport switching mechanism is discussed on the basis of carrier transport mechanism and our analysis of the data shows that the charge carrier trans- port mechanism of the device during the writing process can be explained by thermionic emission (TE) and space-charge-limited-current (SCLC) mechanism models while erasing process could be explained by the FN tunneling mechanism. This demonstration provides a class of memory devices with the potential for low-cost, low-power consumption applications, such as a digital memory cell. PMID- 26505028 TI - A Nanoscale Mutation-Sensitive On/Off Switch Based Assays for the Detection of Hepatitis B Virus Lamivudine-Resistant Mutations. AB - Long-term usage of lamivudine in the treatment of chronic hepatitis B virus (HBV) infection induces the emergence of drug resistance. Sensitive and specific methods aimed at detecting the mutants are clinically useful and required. The purpose of this study was to develop methods for detecting the mutations of YMDD, rtL180M, and rtV173L by nanoscale mutation-sensitive switch consisting of high fidelity polymerase and phosphorothioate-modified allele specific primers. Four assays for these hotspot mutations have been developed with the sensitivity of 100 copies and specificity of at least three log scales for matched templates over mismatched templates. In the condition of multiplex PCR, the sensitivities of these assays are approximately 1000 copies and specificities with two log scales in discrimination of mutant alleles over wild type sequences. These newly developed assays are rapid, accurate, and cost-efficient in detection of lamivudine-related HBV mutants. PMID- 26505030 TI - Band Gap Tailoring of TiO2 Nanowires by Nitrogen Doping Under N2/Ar Plasma Environment. AB - Glancing angle deposited TiO2 nanowires (NWs) were doped with nitrogen (N) using plasma-enhanced chemical vapour deposition technique, under the treatment of N2/Ar plasma. A red shift (- 0.51 eV) in the main band transition and oxygen defect related transition (-2.1 eV) was observed for the N doped TiO2 nanowires. The interstitial nitrogen introduces mid-gap levels N (2P) above the O (2P) in the TiO2 forbidden gap. The photoluminescence measurement revealed a small red shift of -7 nm of anatase band gap from N doped TiO2 nanowires due to radiative recombination of carriers from conduction band to the N (2P) trap state. The low frequency Raman peaks at 304 cm(-1) (acoustical phonons with LA mode), 618 cm(-1) (optical phonons with LO modes) and the high frequency peak at 832 cm(-1) was observed from Ti-O-N due to the partial replacement of oxygen molecules by nitrogen into TiO2, during the doping process. PMID- 26505029 TI - Observation of Room Temperature Photoluminescence from Asymmetric CuGaO2/ZnO/ZnMgO Multiple Quantum Well Structures. AB - Asymmetric (CuGaO2/ZnO/ZnMgO) and symmetric (ZnMgO/ZnO/ZnMgO) multiple quantum well (MQW) structures were successfully fabricated using pulsed laser deposition (PLD) and their comparison were made. Efficient room temperature photoluminescent (PL) emission was observed from these MQWs and temperature dependent luminescence of asymmetric and symmetric MQWs can be explained using the existing theories. A systematic blue shift was observed in both MQWs with decrease in the confinement layer thickness which could be attributed to the quantum confinement effects. The PL emission from asymmetric and symmetric MQW structures were blue shifted compared to 150 nm thick ZnO thin film grown by PLD due to quantum confinement effects. PMID- 26505031 TI - Fabrication and Characterization of Field Effect Transistor Based on High-Aspect Ratio Sulfur-Doped ZnO Nanowires. AB - Well-crystalline sulfur (S) doped ZnO nanowires have been grown via a simple thermal evaporation process on Si substrate using high purity zinc and sulfur powders in presence of oxygen. The as-grown S:ZnO nanowires were characterized in terms of their morphological structural, compositional and optical properties using several techniques such as FESEM, TEM, XRD, EDS and PL. The morphological characterizations revealed that the as-grown nanowires had diameters in the range of 60-100 nm with lengths 5-15 MUm. The details structural properties confirmed the well-crystallinity and wurtzite hexagonal phase for the prepared nanowires. Room temperature photoluminescence (PL) spectrum showed a strong green band with a suppressed UV emission. The electrical properties of single S:ZnO nanowire was examined by fabricating single nanowire based field effect transistors (FETs). The detailed electrical transport results showed that S:ZnO nanowires possess n type semiconducting behavior and exhibited an electron mobility of -67.7 cm2 V( 1) s(-1) and a carrier concentration of 2 x 10(17) cm(-3), respectively. PMID- 26505032 TI - An On-Line Platform for the Analysis of Permethylated Oligosaccharides Using Capillary Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry. AB - Permethylation is one of the most practical modifications for mass spectrometric analysis of carbohydrates. In this study, we showed a facile platform for the on line permethylation and analysis of acidic N-glycans using capillary liquid chromatography-electrospray ionization-tandem mass spectrometry to elucidate the N-glycan structures derived from glycoprotein samples. Two capillaries, individually packed with NaOH and C18 powder, were coupled to electrospray ion trap mass spectrometer. Prior to mass spectrometry, oligosaccharides were permethylated in NaOH-packed capillary by methyl iodide, and the permethylated glycans were consequently extracted from residual reagents, such as NaOH and methyl iodide, in C18-capillary, instead of using conventional chloroform extraction. After permethylation and purification, the permethylated glycans were released from C18 capillary by acetonitrile, and sprayed into mass spectrometer. Using this on-line strategy, a picomolar range of sialylated N-glycans from bovine fetuin were analyzed by tandem mass spectrometry. PMID- 26505033 TI - Fluoride Release from Hollow Silica Microsphere-Containing Dental Restorative Acrylate Resin. AB - Hollow silica microspheres with mesoporous shells were prepared by the sacrificial template method. Hollow silica microsphere-containing acrylate resin based dental restoration materials were prepared by using hollow silica microspheres as NaF reservoirs. Fluoride release performances from naked hollow silica microspheres, acrylate resin, and hollow silica microsphere-containing acrylate resin-based dental restorative materials in an artificial saliva were investigated. The results showed that hollow silica microsphere-containing acrylate resin-based dental restorative materials had higher cumulative fluoride release quantities and sustained fluoride release rates than traditional acrylate resin-based dental restorative materials. Fluoride release could be tuned by changing the mesoporous shell thickness of hollow silica microsphere. PMID- 26505034 TI - Solvothermal Synthesis of Indium Telluride Nanowires and Its Photoelectrical Property. AB - In this paper, 1D In2Te3 nanowires were synthesizes through a simple solvothermal approach. The morphology was first studied by scanning electron microscopy (SEM) and Transmission electron microscopy (TEM). From the results, the nanowires have a diameter from 100 to 200 nm and a length of dozens of microns. X-ray Diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and Raman spectrum were used to study the composition, crystal structures, and optical property. Based on the typical nanowire sample, experiment factors were changed to synthsize other samples in order to study the influence factors. A possible growth mechanism of the nanowires was proposed based on a series of experimental results. This material has a broad light detection range covering the UV-visible-NIR region from the photoelectrical test, which makes it potential for applications in photodetectors and solar cells. PMID- 26505035 TI - The Fabrication of Carbon Nanofibers Paper Supported CoO4 Nanocomposite and Their Electrochemical Properties. AB - A hierarchical network architecture consisting of Co3O4 nanoflakes network (nanonet) coats on a carbon fiber paper. For this 3 dimension (3D) architecture, the electrode shows ideal pseudocapacitive behavior and the maximum specific capacitance of 210 F/g can be reached at the constant current density of 1 A/g in 1 M KOH electrolyte, still retaining 85% of the initial capacitance after 1000 cycles of repeating charge-discharge. The improved capacity may be attributed to the unique hierarchical network structures, which improve electron/ion transport, enhancing the kinetics of redox reactions and facilitate facile stress relaxation during cycling. PMID- 26505036 TI - Effective Hotspot Arrays Based on Non-Close-Packed Gold Nanoshells in Microporous Polystyrene Film on Acupuncture Needles. AB - To constructing effective hotspot arrays in SERS substrates, gold nanoshells (GNSs) were assembled layer by layer on acupuncture needles by covalent absorption of bifunctional chemicals; three dimensional structures of the GNSs were locked by polystyrene (PS) coating; effective hotspots were obtained by removing bifunctional chemicals on surface of the GNSs, and the spacing between GNSs was enlarged by corroding gold shell layers of the GNSs partly. The strongest SERS signal was obtained from the SERS-active substrate with two-layer GNSs. After effective hotspot arrays were constructed in the SERS-active substrate with two-layer GNSs, its enhancement factor was higher about two to three orders of magnitude than that of the monolayer of close-packed GNSs. The hotspot arrays integrated on acupuncture needles would be used to detect low concentration of biomolecules in vivo. PMID- 26505037 TI - In Situ Growth of Nanowires and Fabrication of Nanogap Electrode Pairs by Selective Chemical Deposition with the Assistance of an External Magnetic Field. AB - We have successfully had nanowires in situ grow on the tip of an electrode by selective chemical deposition with the assistance of an external magnetic field. The nanowires are a few microns in length and just a few hundred nanometers in diameter. At the same time, the lateral extent of electrode was not increased obviously. This method combined the lithography technique, self-assembly monolayer (SAM), chemical deposition and the external magnetic field to get nanowires in situ grow on the tip of an electrode. So we can control the growth direction of nanowires along the specified direction at desired locations. Finally, we have fabricated the nanogap electrode pairs by means of the properties of nanowires with grown on the tip of elelctrode in magnetic field. PMID- 26505038 TI - Polyvinyl Pyrrolidone-Assisted Solvothermal Synthesis of Fe3O4 Vesicular Nanospheres. AB - Monodispersed Fe3O4 vesicular nanospheres with a diameter of 160 nm have been fabricated solvothermally in the mixed solution of ethylene glycol (EG) and ethylenediamine (en) with the surfactant polyvinyl pyrrolidone (PVP). The microstructure and magnetic properties of the products were characterized by XRD, Raman, SEM, TEM, HRTEM, N2 adsorption-desorption and SQUID techniques. The HRTEM result shows that spherical Fe3O4 nanoparticles are structurally uniform with a distinct lattice spacing of 2.6 A, which can be assigned to the (311) crystal facet of cubic Fe3O4. Besides, the as-obtained Fe3O4 vesicular nanospheres are ferromagnetic with a saturation magnetization of 86.9 emu/g as high as its bulk counterpart, demonstrating its promising applications in advanced magnetic materials and biomedicine. PMID- 26505039 TI - Functionalized Multi-Walled Carbon Nanotube Paper for Monitoring Chemical Vapors. AB - The multi-walled carbon nanotube paper is prepared by vacuum filtration of pure nanotubes and their functionalized forms prepared by KMnO4 and H2O2 oxidation or by grafting with Poly(methyl methacrylate) (PMMA) and polypyrrole to form sensory nanotubes layer for detection of volatile organic compounds in air. The selected compounds for experimentation (acetone, diethyl ether, isopentane, methanol, tetrahydrofuran) have different polarities and volume fractions of saturated vapors. The sensing is measured by electrical resistance of the paper, which increases when exposed to vapors. A reversible reaction is observed when the paper is removed from the vapors. The functionalized nanotubes differ in their sensitivity to selected organics solvents. For example, KMnO4 oxidized paper has differentiated response to all used vapors, so the measured data may indicate clearly the type of the vapor. On the other hand, the MWCNT/PMMA composite has nearly the same response to acetone, diethyl ether and tetrahydrofuran and different response to isopentane and methanol. The investigation can lead to construction of sensory unit which could be capable of detecting and identifying different vapors in the air. PMID- 26505041 TI - 4 Ways to Support Emerging Physician Leaders. PMID- 26505040 TI - Top Organizations Share Similar Characteristics. PMID- 26505042 TI - From Micromanagement to Abdication Management. PMID- 26505044 TI - Accountability: The Winning Strategy for Healthcare Today. PMID- 26505043 TI - ACHE IN 2014 AND BEYOND. PMID- 26505045 TI - Tips for Building an Entrepreneurial Culture. PMID- 26505046 TI - Erratum to: Diminutive polyp cancers and the DISCARD strategy: Much ado about nothing or the end of the affair? PMID- 26505047 TI - Looking at Beijing's skyline. PMID- 26505049 TI - Fanfare for the Uncommon Neuro-Ophthalmologist: A Tribute to Irma Miller Lessell. PMID- 26505048 TI - BIOFILMS: Oscillations relieve the siege. PMID- 26505050 TI - Martin Lubow, MD (1931-2015). PMID- 26505051 TI - Author Response. PMID- 26505052 TI - Author Response. PMID- 26505053 TI - Imaging metals in biology: balancing sensitivity, selectivity and spatial resolution. AB - Metal biochemistry drives a diverse range of cellular processes associated with development, health and disease. Determining metal distribution, concentration and flux defines our understanding of these fundamental processes. A comprehensive analysis of biological systems requires a balance of analytical techniques that inform on metal quantity (sensitivity), chemical state (selectivity) and location (spatial resolution) with a high degree of certainty. A number of approaches are available for imaging metals from whole tissues down to subcellular organelles, as well as mapping metal turnover, protein association and redox state within these structures. Technological advances in micro- and nano-scale imaging are striving to achieve multi-dimensional and in vivo measures of metals while maintaining the native biochemical environment and physiological state. This Tutorial Review discusses state-of-the-art imaging technology as a guide to obtaining novel insight into the biology of metals, with sensitivity, selectivity and spatial resolution in focus. PMID- 26505054 TI - Tuning interionic interaction for highly selective in vivo analysis. AB - The development of highly selective methodologies to enable in vivo recording of chemical signals is of great importance for studying brain functions and brain activity mapping. However, the complexity of cerebral systems presents a great challenge in the development of chem/(bio)sensors that are capable of directly and selectively recording bioactive molecules involved in brain functions. As one of the most important and popular interactions in nature, interionic interaction constitutes the chemical essence of high specificity in natural systems, which inspires us to develop highly selective chem/(bio)sensors for in vivo analysis by precisely engineering interionic interaction in the in vivo sensing system. In this tutorial review, we focus on the recent progress in the tuning of interionic interaction to improve the selectivity of biosensors for in vivo analysis. The type and property of the interionic interaction is first introduced and several strategies to improve the selectivity of the biosensors, including enzyme-based electrochemical biosensors, aptamer-based electrochemical biosensors, and the strategies to recruit recognition molecules are reviewed. We also present an overview of the potential applications of the biosensors for in vivo analysis and thereby for physiological investigations. Finally, we present the major challenges and opportunities regarding the high selectivity of in vivo analysis based on tuning interionic interaction. We believe that this tutorial review provides critical insights for highly selective in vivo analysis and offers new concepts and strategies to understand brain chemistry. PMID- 26505055 TI - Porous polymer catalysts with hierarchical structures. AB - The emergence of porous organic polymers (POPs) has provided great opportunities for new applications in heterogeneous catalysis owing to their unprecedented intrinsic structural features such as high surface areas, extraordinary framework stabilities and chemically adjustable compositions. In this tutorial review, representative recent developments in the POPs-based catalysts with hierarchically porous structures are presented. Various strategies for the syntheses of hierarchically porous polymers including hard-templating, soft templating and template-free approaches and the design of catalytically active porous polymers including post-modification, co-polymerization and self polymerization have been discussed. In addition, their catalytic properties are compared. Finally, we emphasize the importance of the synthesis of hierarchically porous polymer based heterogeneous catalysts using sustainable routes under template-free and metal-free conditions. PMID- 26505056 TI - Advances in single chain technology. AB - The recent ability to manipulate and visualize single atoms at atomic level has given rise to modern bottom-up nanotechnology. Similar exquisite degree of control at the individual polymeric chain level for producing functional soft nanoentities is expected to become a reality in the next few years through the full development of so-called "single chain technology". Ultra-small unimolecular soft nano-objects endowed with useful, autonomous and smart functions are the expected, long-term valuable output of single chain technology. This review covers the recent advances in single chain technology for the construction of soft nano-objects via chain compaction, with an emphasis in dynamic, letter shaped and compositionally unsymmetrical single rings, complex multi-ring systems, single chain nanoparticles, tadpoles, dumbbells and hairpins, as well as the potential end-use applications of individual soft nano-objects endowed with useful functions in catalysis, sensing, drug delivery and other uses. PMID- 26505057 TI - Stimuli-responsive nanogel composites and their application in nanomedicine. AB - Nanogels are nanosized crosslinked polymer networks capable of absorbing large quantities of water. Specifically, smart nanogels are interesting because of their ability to respond to biomedically relevant changes like pH, temperature, etc. In the last few decades, hybrid nanogels or composites have been developed to overcome the ever increasing demand for new materials in this field. In this context, a hybrid refers to nanogels combined with different polymers and/or with nanoparticles such as plasmonic, magnetic, and carbonaceous nanoparticles, among others. Research activities are focused nowadays on using multifunctional hybrid nanogels in nanomedicine, not only as drug carriers but also as imaging and theranostic agents. In this review, we will describe nanogels, particularly in the form of composites or hybrids applied in nanomedicine. PMID- 26505058 TI - Emerging translational research on magnetic nanoparticles for regenerative medicine. AB - Regenerative medicine, which replaces or regenerates human cells, tissues or organs, to restore or establish normal function, is one of the fastest-evolving interdisciplinary fields in healthcare. Over 200 regenerative medicine products, including cell-based therapies, tissue-engineered biomaterials, scaffolds and implantable devices, have been used in clinical development for diseases such as diabetes and inflammatory and immune diseases. To facilitate the translation of regenerative medicine from research to clinic, nanotechnology, especially magnetic nanoparticles have attracted extensive attention due to their unique optical, electrical, and magnetic properties and specific dimensions. In this review paper, we intend to summarize current advances, challenges, and future opportunities of magnetic nanoparticles for regenerative medicine. PMID- 26505059 TI - Efficacy and adverse effects of medical marijuana for chronic noncancer pain: Systematic review of randomized controlled trials. AB - OBJECTIVE: To determine if medical marijuana provides pain relief for patients with chronic noncancer pain (CNCP) and to determine the therapeutic dose, adverse effects, and specific indications. DATA SOURCES: In April 2014, MEDLINE and EMBASE searches were conducted using the terms chronic noncancer pain, smoked marijuana or cannabinoids, placebo and pain relief, or side effects or adverse events. STUDY SELECTION: An article was selected for inclusion if it evaluated the effect of smoked or vaporized cannabinoids (nonsynthetic) for CNCP; it was designed as a controlled study involving a comparison group, either concurrently or historically; and it was published in English in a peer-review journal. Outcome data on pain, function, dose, and adverse effects were collected, if available. All articles that were only available in abstract form were excluded. Synthesis A total of 6 randomized controlled trials (N = 226 patients) were included in this review; 5 of them assessed the use of medical marijuana in neuropathic pain as an adjunct to other concomitant analgesics including opioids and anticonvulsants. The 5 trials were considered to be of high quality; however, all of them had challenges with masking. Data could not be pooled owing to heterogeneity in delta-9-tetrahydrocannabinol potency by dried weight, differing frequency and duration of treatment, and variability in assessing outcomes. All experimental sessions in the studies were of short duration (maximum of 5 days) and reported statistically significant pain relief with nonserious side effects. CONCLUSION: There is evidence for the use of low-dose medical marijuana in refractory neuropathic pain in conjunction with traditional analgesics. However, trials were limited by short duration, variability in dosing and strength of delta-9-tetrahydrocannabinol, and lack of functional outcomes. Although well tolerated in the short term, the long-term effects of psychoactive and neurocognitive effects of medical marijuana remain unknown. Generalizing the use of medical marijuana to all CNCP conditions does not appear to be supported by existing evidence. Clinicians should exercise caution when prescribing medical marijuana for patients, especially in those with nonneuropathic CNCP. PMID- 26505060 TI - Strategies for improved French-language health services: Perspectives of family physicians in northeastern Ontario. AB - OBJECTIVE: To identify strategies to improve the quality of health services for Francophone patients. DESIGN: A series of semistructured key informant interviews. SETTING: Northeastern Ontario. Participants A total of 18 physicians were interviewed. Ten physicians were interviewed in French, 7 physicians were women, and 10 physicians were located in urban communities. METHODS: Purposive and snowball sampling strategies were used to conduct a series of semistructured key informant interviews with family physicians practising in communities with a large Francophone population. Principles of grounded theory were applied, guided by a framework for patient-professional communication. Results were inductively derived following an iterative data collection-data analysis process and were analyzed using a detailed thematic approach. MAIN FINDINGS: Respondents identified several strategies for providing high-quality French-language health services. Some were unique to non-French-speaking physicians (eg, using appropriate interpreter services), some were unique to French-speaking physicians (eg, using a flexible dialect), and some strategies were common to all physicians serving French populations (eg, hiring bilingual staff or having pamphlets and posters in both French and English). CONCLUSION: Physicians interviewed for this study provided high-quality health care by attributing substantial importance to effective communication. While linguistic patient-to-physician concordance is ideal, it might not always be possible. Thus, conscious efforts to attenuate communication barriers are necessary, and several effective strategies exist. PMID- 26505061 TI - Proximity and emergency department use: Multilevel analysis using administrative data from patients with cardiovascular risk factors. AB - OBJECTIVE: To determine if geographic proximity to an emergency department (ED) is related to ED use in a metropolitan population of patients with cardiovascular risk factors. DESIGN: Population-based, retrospective cohort study. SETTING: The census metropolitan area of Montreal, Que. PARTICIPANTS: Cohort of 99 400 patients with diabetes, hypertension, or dyslipidemia in 2007 without a history of cardiovascular disease. Each patient was spatially referred to 1 of 5857 dissemination areas (DAs). MAIN OUTCOME MEASURES: Annual number of visits to an ED with respect to the distance between the centroid of a patient's DA and the closest ED, controlling for age, sex, comorbidities, and neighbourhood immigration, social, and material characteristics. Multilevel logistic and negative binomial regressions were used to determine if the proximity to the closest ED was related to ED use, frequent ED use (>= 4 visits in a year), and number of ED visits. RESULTS: A total of 25 889 (26.0%) patients in the cohort visited an ED at least once during a 1-year period, among which 4563 (4.6%) were frequent users with at least 4 visits. These frequent users were responsible for 28 249 (45.5%) of all 62 021 visits to EDs. The distance between a DA and its closest ED was significantly and negatively correlated with ED use (P < .001), even after controlling for confounding variables. Patients living in a DA close to an ED were also more likely to be frequent users, but the extent of use among them (range from 4 to 82 ED visits) was not related to the distance to the closest ED. CONCLUSION: These results suggest that patients at risk of cardiovascular disease living in a metropolitan area are more likely to seek a medical encounter at the ED if they live closer to it. PMID- 26505062 TI - Measuring head circumference: Update on infant microcephaly. AB - OBJECTIVE: To provide an evidence-based update emphasizing the importance of measuring head circumference (HC) in infants, with a focus on microcephaly. QUALITY OF EVIDENCE: PubMed and EMBASE (OvidSP) were searched. Search terms used were head circumference and infants and measurement; microcephaly and infants and measurement; idiopathic microcephaly and infants; and congenital microcephaly and infants. Most of the references for this review were published in 2000 or later. Most evidence is level II. MAIN MESSAGE: Serial measurement of HC should be incorporated into routine well-child care. Measure the distance around the back of the child's head with a nonelastic tape measure held above the eyebrows and ears, and plot the measurement on an age- and sex-appropriate growth chart. Microcephaly is HC more than 2 SD below the mean. The most common disability associated with microcephaly is intellectual delay; other common concomitant conditions include epilepsy, cerebral palsy, language delay, strabismus, ophthalmologic disorders, and cardiac, renal, urinary tract, and skeletal anomalies. An interdisciplinary approach to microcephaly is warranted. Although there are no specific interventions to enhance brain growth, dietary or surgical interventions might be helpful in some cases. Infants with microcephaly who show developmental delays might benefit from early intervention programs or developmental physical and occupational therapy. CONCLUSION: Early identification of HC concerns by family physicians can be a critical first step in identifying disorders such as microcephaly, leading to referral to pediatric specialists and, as needed, provision of family-centred early intervention services. PMID- 26505064 TI - Fluconazole exposure during pregnancy. AB - QUESTION: One of my patients has just learned that she is 8 weeks pregnant. She took a 150-mg dose of fluconazole 2 weeks ago for the treatment of vaginal candidiasis and she is worried about the effect on her child and pregnancy. Can I reassure her? ANSWER: Short-term and low-dose fluconazole exposure, such as that indicated in the treatment of vaginal candidiasis, is not expected to increase the overall risk of major congenital malformations. PMID- 26505066 TI - VEGF Signaling: Methods and Protocols. Preface. PMID- 26505065 TI - Diagnosis and management of eosinophilic esophagitis in children. AB - QUESTION: After a few years of difficulty swallowing solids and feeling like food was getting stuck, a 13-year-old boy in my practice with peanut allergy and asthma was recently diagnosed with eosinophilic esophagitis (EoE). What is EoE and how is it diagnosed and managed? ANSWER: Eosinophilic esophagitis is an immune-mediated disease resulting in inflammation of the esophagus. It is increasing in prevalence and incidence in countries like Canada, and frequently occurs in children with other allergic conditions. Unexplained feeding difficulties, vomiting, and solid-food dysphagia, especially in boys with atopy, supports the possibility of having EoE. A formal diagnosis is obtained by reviewing esophageal biopsies obtained through upper endoscopy performed while the patient is taking a proton pump inhibitor. Once EoE has been established, management should involve working collaboratively with gastroenterology and allergy specialists. Medical or dietary treatments are acceptable therapeutic approaches. PMID- 26505067 TI - My son the slippery octopus. PMID- 26505068 TI - Orthodontics at Any Age. PMID- 26505069 TI - HPV A to Z and the ... New Epidemic of Oropharyngeal Cancer. PMID- 26505070 TI - Can a Periodontal Infection in an Pregnant Woman Affect Her Newborn? PMID- 26505071 TI - What Exactly is Florida's Action for Dental Health? PMID- 26505073 TI - An overview of advanced technologies for selection of probiotics and their expediency: A review. AB - It has become easy to identify and select an appropriate microorganism with the advancement in various molecular biology and analytical techniques. The majority of the novel techniques are being implemented for the identification and characterization of microorganisms used for probiotic application. Standard microbial techniques such as biochemical testing and culture techniques routinely used for probiotic microbes screening, identification and selection. However, these standard techniques may not give complete information on the microbes that can be used for probiotic production. Furthermore, alternative molecular and analytical techniques such as 16S and 23S ribosomal DNA sequencing, RNA analysis by reverse transcriptase (RT-PCR), fluorescent in situ hybridization (FISH), quantitative analysis by real time PCR (RT-PCR or qPCR) and fluorescent activated cell sorting (FACS) are potentially used to confirm and select all types of lactic acid microorganism. All these approaches can be employed in the screening and selection of appropriate lactic acid bacteria which can be potentially used for the production of human use probiotics in large scale fermentation. This review mainly focuses on various tools and techniques used for effective screening and selection of a better candidate bacterium for probiotic applications. PMID- 26505072 TI - Conversion of a Single Polypharmacological Agent into Selective Bivalent Inhibitors of Intracellular Kinase Activity. AB - Loss-of-function studies are valuable for elucidating kinase function and the validation of new drug targets. While genetic techniques, such as RNAi and genetic knockouts, are highly specific and easy to implement, in many cases post translational perturbation of kinase activity, specifically pharmacological inhibition, is preferable. However, due to the high degree of structural similarity between kinase active sites and the large size of the kinome, identification of pharmacological agents that are sufficiently selective to probe the function of a specific kinase of interest is challenging, and there is currently no systematic method for accomplishing this goal. Here, we present a modular chemical genetic strategy that uses antibody mimetics as highly selective targeting components of bivalent kinase inhibitors. We demonstrate that it is possible to confer high kinase selectivity to a promiscuous ATP-competitive inhibitor by tethering it to an antibody mimetic fused to the self-labeling protein SNAPtag. With this approach, a potent bivalent inhibitor of the tyrosine kinase Abl was generated. Profiling in complex cell lysates, with competition based quantitative chemical proteomics, revealed that this bivalent inhibitor possesses greatly enhanced selectivity for its target, BCR-Abl, in K562 cells. Importantly, we show that both components of the bivalent inhibitor can be assembled in K562 cells to block the ability of BCR-Abl to phosphorylate a direct cellular substrate. Finally, we demonstrate the generality of using antibody mimetics as components of bivalent inhibitors by generating a reagent that is selective for the activated state of the serine/threonine kinase ERK2. PMID- 26505074 TI - Chikungunya infection in DoD healthcare beneficiaries following the 2013 introduction of the virus into the Western Hemisphere, 1 January 2014 to 28 February 2015. AB - The introduction and rapid spread of chikungunya virus (CHIKV) into the Western Hemisphere after December 2013 pose a potentially significant risk to Department of Defense (DoD) personnel, operations, and the military healthcare system. This report describes the DoD experience with CHIKV between January 2014 and February 2015 using case reports in the Defense Medical Surveillance System's (DMSS) Reportable Medical Events database and the Navy and Marine Corps Public Health Center's laboratory test results database. Case finding identified 157 confirmed cases; of these, 118 (75.2%) were either active or reserve component service members and 39 (24.8%) were other beneficiaries. Exposure locations were known for 117 (74.5%) of all cases, and of these, 113 (96.6%) reported likely exposures in the Western Hemisphere; 85 (75.2%) of those cases occurred in Puerto Rico. Although historical data on CHIKV in DoD populations are scant, introduction of CHIKV into the Western Hemisphere with ongoing transmission appears to have resulted in a significant increase in the number of cases among DoD healthcare beneficiary populations. PMID- 26505075 TI - Update: Cold weather injuries, active and reserve components, U.S. Armed Forces, July 2010-June 2015. AB - From July 2014 through June 2015, the number of active and reserve component service members treated for cold injuries (n=603) was much lower than the 719 cases diagnosed during the previous, unusually cold winter of 2013- 2014. Army personnel accounted for the majority (51%) of cold injuries. Frostbite was the most common type of cold injury in each of the services except the Marine Corps for which immersion foot was unusually common. Consistent with trends from previous cold seasons, service members who were female, younger than 20 years old, or of black, non-Hispanic race/ethnicity tended to have higher cold injury rates than their respective counterparts. Numbers of cases in the combat zone have decreased in the past 3 years, most likely the result of declining numbers of personnel exposed and the changing nature of operations. It is important that awareness, policies, and procedures continue to be emphasized to reduce the toll of cold injuries among U.S. service members. PMID- 26505076 TI - Surveillance snapshot: Influenza immunization among U.S. Armed Forces healthcare workers, August 2010-April 2015. PMID- 26505077 TI - Strong Surface Treatment Effects on Reinforcement Efficiency in Biocomposites Based on Cellulose Nanocrystals in Poly(vinyl acetate) Matrix. AB - In this work, the problem to disperse cellulose nanocrystals (CNC) in hydrophobic polymer matrices has been addressed through application of an environmentally friendly chemical modification approach inspired by clay chemistry. The objective is to compare the effects of unmodified CNC and modified CNC (modCNC) reinforcement, where degree of CNC dispersion is of interest. Hydrophobic functionalization made it possible to disperse wood-based modCNC in organic solvent and cast well-dispersed nanocomposite films of poly(vinyl acetate) (PVAc) with 1-20 wt % CNC. Composite films were studied by infrared spectroscopy (FT IR), UV-vis spectroscopy, dynamic mechanical thermal analysis (DMTA), tensile testing, and field-emission scanning electron microscopy (FE-SEM). Strongly increased mechanical properties were observed for modCNC nanocomposites. The reinforcement efficiency was much lower in unmodified CNC composites, and specific mechanisms causing the differences are discussed. PMID- 26505078 TI - Quantum Calculations of Electron Tunneling in Respiratory Complex III. AB - The most detailed and comprehensive to date study of electron transfer reactions in the respiratory complex III of aerobic cells, also known as bc1 complex, is reported. In the framework of the tunneling current theory, electron tunneling rates and atomistic tunneling pathways between different redox centers were investigated for all electron transfer reactions comprising different stages of the proton-motive Q-cycle. The calculations reveal that complex III is a smart nanomachine, which under certain conditions undergoes conformational changes gating electron transfer, or channeling electrons to specific pathways. One electron tunneling approximation was adopted in the tunneling calculations, which were performed using hybrid Broken-Symmetry (BS) unrestricted DFT/ZINDO levels of theory. The tunneling orbitals were determined using an exact biorthogonalization scheme that uniquely separates pairs of tunneling orbitals with small overlaps out of the remaining Franck-Condon orbitals with significant overlap. Electron transfer rates in different redox pairs show exponential distance dependence, in agreement with the reported experimental data; some reactions involve coupled proton transfer. Proper treatment of a concerted two-electron bifurcated tunneling reaction at the Q(o) site is given. PMID- 26505079 TI - Quality of palliative care: are things improving? PMID- 26505080 TI - Making sense of life and death from a death tree. PMID- 26505081 TI - Comparing the effectiveness of intranasal fentanyl spray with oral transmucosal fentanyl citrate in breakthrough pain. AB - BACKGROUND: Breakthrough cancer pain (BTCP) is complex and severe, affecting quality of life and increasing hospitalisation. BTCP has a rapid onset that requires fast acting medication with minimal side effects. AIM: This article compares the effectiveness of intranasal fentanyl spray (INFS) and oral transmucosal fentanyl citrate (OTFC) and their alleviation of BTCP within 10 minutes of administration. METHOD: The article considers pharmacokinetic and bioavailability studies demonstrating the efficacy of the route of administration, time-based effects of pain relief as well as patient preference. CONCLUSION: The data collected indicates that INFS is more effective than OTFC for BTCP. PMID- 26505082 TI - Nurses' knowledge and attitudes towards pain assessment for people with dementia in a nursing home setting. AB - AIM: The aim of this study was to determine nurses' knowledge and attitudes towards pain assessment for people with dementia in a nursing home setting. BACKGROUND: Pain is highly prevalent among older people, yet is often under recognised and undertreated in people with dementia. People with dementia can lose the ability to report pain and it is the role of the nurse to identify and appropriately assess pain, to provide effective treatment. This requires nurses to have sufficient knowledge and training in the assessment and management of pain in residents with dementia; however, research suggests deficits in this area. METHODS: A cross-sectional survey design was used to determine nurses' knowledge and attitudes to pain assessment in dementia. A questionnaire comprising three sections was distributed to 96 registered nurses across 17 nursing homes in a health-care trust in a UK region. RESULTS: A total of 32 responses were obtained (response rate 33%). The majority of nurses had a good knowledge in relation to the assessment and management of pain in residents with dementia. There was, however, some uncertainty among nurses over analgesic choice, the safety of opioid use in dementia, and the use of dementia-specific pain assessment tools for residents with no cognitive impairment. The main barriers to effective pain assessment for older people with dementia were workload pressures, poor staffing and lack of medical support. CONCLUSION: This study highlights the need to develop pain education programmes and clear guidance specifically designed for nurses caring for older people with dementia. It also emphasises the need for better communication and co-ordination of pain treatment for nursing home residents with dementia. PMID- 26505083 TI - Uncertainties experienced by family members when one parent is dying. AB - PURPOSE: This research examined uncertainty as a salient theme for families in which a parent was dying while receiving hospice care. METHODS: Interviews were conducted with 61 participants from 26 families in the parent study to explore the strategies used by adolescents with a parent in a hospice. Second interviews were conducted with 15 original participants after the death of their parent. Conventional content analysis was used to analyse data. RESULTS: Uncertainty was a prevalent and salient theme in the participants' stories revealing patterns about the causes, barriers, effects and strategies used to manage uncertainty. CONCLUSION: Uncertainties associated with the end of life can be problematic for some people, requiring attention by health professionals. PMID- 26505085 TI - Nurses' resilience and nurturance of the self. AB - BACKGROUND: Despite the losses experienced by nurses in their role in palliative care, they wish to continue working in this environment. This is described as resilience, which enhances coping in dealing with death and grief. AIM: To explore the nature of nurses' resilience and the way it is developed. DESIGN: A qualitative research design using grounded theory methods was employed. With theoretical sampling, 18 interviews were conducted and theoretical saturation was achieved. RESULTS: Self-nurturing was evident as the way nurses developed resilience, which included knowledge of self, coping adaptively, valuing care and accepting limitations. DISCUSSION: All participants spoke of the characteristics of resilience from the blend of individual responsibility for self and the support provided by others. However, none had educational pathways to build greater resilience. CONCLUSION: Integrating support and education to foster nurses' resilience is important to enable self-protection, as well as the provision of high quality care. PMID- 26505084 TI - Registered nurses' involvement in advance care planning: an integrative review. AB - BACKGROUND: Even though registered nurses are uniquely positioned to have end-of life conversations with their patients, there is limited engagement in such discussions between patients and health-care providers. Consequently, few patients are adequately prepared to make in-the-moment treatment decisions about goals of care. OBJECTIVES: The guiding question for this integrative review was what factors influence registered nurses' involvement in advance care planning (ACP) conversations with their patients in acute care settings? METHODS: Based on integrative review guidelines, databases from CINAHL, Medline, Ovid, and ProQuest were searched from 1990-2014, yielding nine articles. RESULTS: There were four patterns found in the literature: (1) Nurses' involvement in ACP, (2) Nurses' perceptions of their roles in ACP, (3) Barriers to ACP discussions, and (4) Facilitators of ACP discussions. DISCUSSION: Additional educational opportunities related to ACP are necessary to promote integration of ACP into daily nursing care. Further research should focus on exploring operant mechanisms shaping nurses' ACP practice in acute care settings. PMID- 26505087 TI - Research roundup. AB - Synopses of a selection of recently published research articles of relevance to palliative care. PMID- 26505088 TI - Politics and palliative care: Trinidad and Tobago. AB - Dion Smyth's review of the internet for palliative nursing. PMID- 26505089 TI - Ablation of the transcription factors E2F1-2 limits neuroinflammation and associated neurological deficits after contusive spinal cord injury. AB - Traumatic spinal cord injury (SCI) induces cell cycle activation (CCA) that contributes to secondary injury and related functional impairments such as motor deficits and hyperpathia. E2F1 and E2F2 are members of the activator sub-family of E2F transcription factors that play an important role in proliferating cells and in cell cycle-related neuronal death, but no comprehensive study have been performed in SCI to determine the relative importance of these factors. Here we examined the temporal distribution and cell-type specificity of E2F1 and E2F2 expression following mouse SCI, as well as the effects of genetic deletion of E2F1-2 on neuronal cell death, neuroinflammation and associated neurological dysfunction. SCI significantly increased E2F1 and E2F2 expression in active caspase-3(+) neurons/oligodendrocytes as well as in activated microglia/astrocytes. Injury-induced up-regulation of cell cycle-related genes and protein was significantly reduced by intrathecal injection of high specificity E2F decoy oligodeoxynucleotides against the E2F-binding site or in E2F1-2 null mice. Combined E2F1+2 siRNA treatment show greater neuroprotection in vivo than E2F1 or E2F2 single siRNA treatment. Knockout of both E2F1 and E2F2 genes (E2Fdko) significantly reduced neuronal death, neuroinflammation, and tissue damage, as well as limiting motor dysfunction and hyperpathia after SCI. Both CCA reduction and functional improvement in E2Fdko mice were greater than those in E2F2ko model. These studies demonstrate that SCI-induced activation of E2F1-2 mediates CCA, contributing to gliopathy and neuronal/tissue loss associated with motor impairments and post-traumatic hyperesthesia. Thus, E2F1-2 provide a therapeutic target for decreasing secondary tissue damage and promoting recovery of function after SCI. PMID- 26505090 TI - Environmental Stresses Increase Photosynthetic Disruption by Metal Oxide Nanomaterials in a Soil-Grown Plant. AB - Despite an increasing number of studies over the past decade examining the interactions between plants and engineered nanomaterials (ENMs), very few have investigated the influence of environmental conditions on ENM uptake and toxicity, particularly throughout the entire plant life cycle. In this study, soil-grown herbaceous annual plants (Clarkia unguiculata) were exposed to TiO2, CeO2, or Cu(OH)2 ENMs at different concentrations under distinct light and nutrient levels for 8 weeks. Biweekly fluorescence and gas exchange measurements were recorded, and tissue samples from mature plants were analyzed for metal content. During peak growth, exposure to TiO2 and CeO2 decreased photosynthetic rate and CO2 assimilation efficiency of plants grown under high light and nutrient conditions, possibly by disrupting energy transfer from photosystem II (PSII) to the Calvin cycle. Exposure Cu(OH)2 particles also disrupted photosynthesis but only in plants grown under the most stressful conditions (high light, limited nutrient) likely by preventing the oxidation of a primary PSII reaction center. TiO2 and CeO2 followed similar uptake and distribution patterns with concentrations being highest in roots followed by leaves then stems, while Cu(OH)2 was present at highest concentrations in leaves, likely as ionic Cu. ENM accumulation was highly dependent on both light and nutrient levels and a predictive regression model was developed from these data. These results show that abiotic conditions play an important role in mediating the uptake and physiological impacts of ENMs in terrestrial plants. PMID- 26505091 TI - The identification of hypoxia biomarkers from exhaled breath under normobaric conditions. AB - Pilots have reported experiencing in-flight hypoxic-like symptoms since the inception of high-altitude aviation. As a result, the need to monitor pilots, in flight, for the onset of hypoxic conditions is of great interest to the aviation community. We propose that exhaled breath is an appropriate non-invasive medium for monitoring pilot hypoxic risk through volatile organic compound (VOC) analysis. To identify changes in the exhaled breath VOCs produced during periods of reduced O2 levels, volunteers were exposed to simulated flight profiles, i.e. sea level for 5 min, O2 levels found at elevated altitudes for 5 min or placebo and 5 min at 100% O2 recovery gas, using a modified flight mask interfaced with a reduced O2 breathing device. During the course of these test events, time series breath samples from the flight mask and pre/post bag samples were collected and analyzed by gas chromatography/mass spectrometry (GC/MS). Seven compounds (pentanal, 4-butyrolactone, 2-pentanone, 2-hexanone, 2-cyclopenten-1-one, 3 methylheptane and 2-heptanone) were found to significantly change in response to hypoxic conditions. Additionally, the isoprene, 2-methyl-1,3-butadiene, was found to increase following the overall exposure profile. This study establishes an experimental means for monitoring changes in VOCs in response to hypoxic conditions, a computational workflow for compound analysis via the Metabolite Differentiation and Discovery Lab and MatLab((c)) software and identifies potential volatile organic compound biomarkers of hypoxia exposure. PMID- 26505092 TI - Revealing Brown Carbon Chromophores Produced in Reactions of Methylglyoxal with Ammonium Sulfate. AB - Atmospheric brown carbon (BrC) is an important contributor to light absorption and climate forcing by aerosols. Reactions between small water-soluble carbonyls and ammonia or amines have been identified as one of the potential pathways of BrC formation. However, detailed chemical characterization of BrC chromophores has been challenging and their formation mechanisms are still poorly understood. Understanding BrC formation is impeded by the lack of suitable methods which can unravel the variability and complexity of BrC mixtures. This study applies high performance liquid chromatography (HPLC) coupled to photodiode array (PDA) detector and high resolution mass spectrometry (HRMS) to investigate optical properties and chemical composition of individual BrC components produced through reactions of methylglyoxal (MG) and ammonium sulfate (AS), both of which are abundant in the atmospheric environment. A direct relationship between optical properties and chemical composition of 30 major BrC chromophores is established. Nearly all of these chromophores are nitrogen-containing compounds that account for >70% of the overall light absorption by the MG+AS system in the 300-500 nm range. These results suggest that reduced-nitrogen organic compounds formed in reactions between atmospheric carbonyls and ammonia/amines are important BrC chromophores. It is also demonstrated that improved separation of BrC chromophores by HPLC will significantly advance understanding of BrC chemistry. PMID- 26505093 TI - Prevalence, Supplementation, and Impact of Vitamin D Deficiency in Multiple Myeloma Patients. AB - Here, we studied 83 unselected multiple myeloma patients from December 2007 through December 2014. Lower 25(OH) D levels (<10 ng/mL) were associated with higher number of plasma cells in the bone marrow. Supplementation of vitamin D was accompanied with a significant increase in hemoglobin (11.8 to 12.3 p = .039), leukocyte (4.9 to 5.8 p = .011), and erythrocyte (3.8 to 4.0 p = .004) levels, while thrombocytes (200.5 to 175.2 p = .036) decreased. In conclusion, the present study found a high incidence of vitamin D deficiency and insufficiency in MM patients. In myeloma patients, vitamin D levels and supplementation should be more widely taken into account. PMID- 26505094 TI - Methicillin-Resistant Staphylococcus aureus in the Community in Luanda, Angola: Blurred Boundaries with the Hospital Setting. AB - Although the nosocomial prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in Angola is over 60% and one of the highest in Africa, the extent of MRSA in the community is unknown. To fill this gap, we conducted a hospital-based study in which 158 children attending the emergency ward and ambulatory services of a pediatric hospital in Luanda, the capital of Angola, were screened for S. aureus nasal colonization. Overall, 70 (44.3%) individuals were colonized with S. aureus, of which 20 (28.6%) carried MRSA, resulting in a prevalence of 12.7% (20/158) of MRSA in the population screened. Molecular characterization by pulsed field gel electrophoresis (PFGE), spa typing, multilocus sequence typing, and SCCmec typing distributed the isolates into two major MRSA clones and one dominant methicillin-susceptible S. aureus (MSSA) lineage, corresponding to the main clones circulating in hospitals in Luanda. The MRSA isolates mainly belonged to clones A (PFGE type A, spa type t105, ST5-IVa-65%) and B (PFGE B, t3869, ST88 IVa-30%), while MSSA isolates mainly belonged to clone L (PFGE type L, t861, ST508-42%). S. aureus isolates showed resistance to penicillin (96%), rifampin (87%), and trimethoprim-sulfamethoxazole (21%). In conclusion, the prevalence of MRSA among children in the community in Luanda is high and seems to originate from hospitals, warranting continuous monitoring and implementation of additional infection control measures. PMID- 26505095 TI - Considering Research Outcomes as Essential Tools for Medical Education Decision Making. AB - As medical educators face the challenge of incorporating new content, learning methods, and assessment techniques into the curriculum, the need for rigorous medical education research to guide efficient and effective instructional planning increases. When done properly, well-designed education research can provide guidance for complex education decision making. In this Commentary, the authors consider the 2015 Research in Medical Education (RIME) research and review articles in terms of the critical areas in teaching and learning that they address. The broad categories include (1) assessment (the largest collection of RIME articles, including both feedback from learners and instructors and the reliability of learner assessment), (2) the institution's impact on the learning environment, (3) what can be learned from program evaluation, and (4) emerging issues in faculty development. While the articles in this issue are broad in scope and potential impact, the RIME committee noted few studies of sufficient rigor focusing on areas of diversity and diverse learners. Although challenging to investigate, the authors encourage continuing innovation in research focused on these important areas. PMID- 26505097 TI - A Methodological Review of the Assessment of Humanism in Medical Students. AB - BACKGROUND: Humanism is a complex construct that defies simplistic measurement. How educators measure humanism shapes understanding and implications for learners. This systematic review sought to address the following questions: How do medical educators assess humanism in medical students, and how does the measurement impact the understanding of humanism in undergraduate medical education (UME)? METHOD: Using the IECARES (integrity, excellence, compassion, altruism, respect, empathy, and service) Gold Foundation framework, a search of English literature databases from 2000 to 2013 on assessment of humanism in medical students revealed more than 900 articles, of which 155 met criteria for analysis. Using descriptive statistics, articles and assessments were analyzed for construct measured, study design, assessment method, instrument type, perspective/source of assessment, student level, validity evidence, and national context. RESULTS: Of 202 assessments reported in 155 articles, 162 (80%) used surveys; 164 (81%) used student self-reports. One hundred nine articles (70%) included only one humanism construct. Empathy was the most prevalent construct present in 96 (62%); 49 (51%) of those used a single instrument. One hundred fifteen (74%) used exclusively quantitative data; only 48 (31%) used a longitudinal design. Construct underrepresentation was identified as a threat to validity in half of the assessments. Articles included 34 countries; 87 (56%) were from North America. CONCLUSIONS: Assessment of humanism in UME incorporates a limited scope of a complex construct, often relying on single quantitative measures from self-reported survey instruments. This highlights the need for multiple methods, perspectives, and longitudinal designs to strengthen the validity of humanism assessments. PMID- 26505098 TI - Validity of Cognitive Load Measures in Simulation-Based Training: A Systematic Review. AB - BACKGROUND: Cognitive load theory (CLT) provides a rich framework to inform instructional design. Despite the applicability of CLT to simulation-based medical training, findings from multimedia learning have not been consistently replicated in this context. This lack of transferability may be related to issues in measuring cognitive load (CL) during simulation. The authors conducted a review of CLT studies across simulation training contexts to assess the validity evidence for different CL measures. METHOD: PRISMA standards were followed. For 48 studies selected from a search of MEDLINE, EMBASE, PsycInfo, CINAHL, and ERIC databases, information was extracted about study aims, methods, validity evidence of measures, and findings. Studies were categorized on the basis of findings and prevalence of validity evidence collected, and statistical comparisons between measurement types and research domains were pursued. RESULTS: CL during simulation training has been measured in diverse populations including medical trainees, pilots, and university students. Most studies (71%; 34) used self report measures; others included secondary task performance, physiological indices, and observer ratings. Correlations between CL and learning varied from positive to negative. Overall validity evidence for CL measures was low (mean score 1.55/5). Studies reporting greater validity evidence were more likely to report that high CL impaired learning. CONCLUSIONS: The authors found evidence that inconsistent correlations between CL and learning may be related to issues of validity in CL measures. Further research would benefit from rigorous documentation of validity and from triangulating measures of CL. This can better inform CLT instructional design for simulation-based medical training. PMID- 26505099 TI - Readiness for Residency: A Survey to Evaluate Undergraduate Medical Education Programs. AB - BACKGROUND: Health professions programs continue to search for meaningful and efficient ways to evaluate the quality of education they provide and support ongoing program improvement. Despite flaws inherent in self-assessment, recent research suggests that aggregated self-assessments reliably rank aspects of competence attained during preclerkship MD training. Given the novelty of those observations, the purpose of this study was to test their generalizability by evaluating an MD program as a whole. METHOD: The Readiness for Residency Survey (RfR) was developed and aligned with the published Readiness for Clerkship Survey (RfC), but focused on the competencies expected to be achieved at graduation. The RfC and RfR were administered electronically four months after the start of clerkship and six months after the start of residency, respectively. Generalizability and decision studies examined the extent to which specific competencies were achieved relative to one another. RESULTS: The reliability of scores assigned by a single resident was G = 0.32. However, a reliability of G = 0.80 could be obtained by averaging over as few as nine residents. Whereas highly rated competencies in the RfC resided within the CanMEDS domains of professional, communicator, and collaborator, five additional medical expert competencies emerged as strengths when the program was evaluated after completion by residents. CONCLUSIONS: Aggregated resident self-assessments obtained using the RfR reliably differentiate aspects of competence attained over four years of undergraduate training. The RfR and RfC together can be used as evaluation tools to identify areas of strength and weakness in an undergraduate medical education program. PMID- 26505100 TI - Four-Year Educational and Patient Care Outcomes of a Team-Based Primary Care Longitudinal Clerkship. AB - BACKGROUND: Longitudinal clerkships show promise in improving undergraduate primary care education. This study examines the Education-Centered Medical Home (ECMH), a longitudinal clerkship embedding teams of students across all four years into primary care clinics to provide patient care and serve as health coaches for high-risk patients. METHOD: All students graduating in 2015 were surveyed to assess attitudes, experiences, and preferences regarding primary care education. ECMH students were compared with students receiving their primary care training in a traditional curriculum (TC) using paired measures of comparison. To assess the impact of the ECMH on patient care quality, authors performed a detailed chart review at one site. RESULTS: Seventy-six percent of eligible students participated in the study. ECMH students (n = 69) and TC students (n = 68) had similar baseline academic performance and career interests. ECMH students reported more continuity-of-care experiences, higher satisfaction with their primary care learning climate (86% versus 61% in the EMCH and TC cohorts, respectively), more confidence in their quality improvement skills, and scored higher on measures of perceived patient centeredness. Students from both groups recommended the ECMH (91% and 57%, respectively). Student involvement at one ECMH site was correlated with increased patient contacts and improved delivery of recommended preventive care. CONCLUSIONS: Incorporating students longitudinally into primary care clinics is highly rated by students. The ECMH model led to improved continuity, improved perceptions of the learning climate, and higher patient centeredness. Preliminary data suggest that students add value and improve patient outcomes during longitudinal clinical experiences. PMID- 26505101 TI - Humanism, the Hidden Curriculum, and Educational Reform: A Scoping Review and Thematic Analysis. AB - BACKGROUND: Medical educators have used the hidden curriculum concept for over three decades to make visible the effects of tacit learning, including how culture, structures, and institutions influence professional identity formation. In response to calls to see more humanistic-oriented training in medicine, the authors examined how the hidden curriculum construct has been applied in the English language medical education literature with a particular (and centering) look at its use within literature pertaining to humanism. They also explored the ends to which the hidden curriculum construct has been used in educational reform efforts (at the individual, organizational, and/or systems levels) related to nurturing and/or increasing humanism in health care. METHOD: The authors conducted a scoping review and thematic analysis that draws from the tradition of critical discourse analysis. They identified 1,887 texts in the literature search, of which 200 met inclusion criteria. RESULTS: The analysis documents a strong preoccupation with negative effects of the hidden curriculum, particularly the moral erosion of physicians and the perceived undermining of humanistic values in health care. A conflation between professionalism and humanism was noted. Proposals for reform largely target medical students and medical school faculty, with very little consideration for how organizations, institutions, and sociopolitical relations more broadly contribute to problematic behaviors. CONCLUSIONS: The authors argue that there is a need to transcend conceptualizations of the hidden curriculum as antithetical to humanism and offer suggestions for future research that explores the necessity and value of humanism and the hidden curriculum in medical education and training. PMID- 26505102 TI - Seeing Things Differently or Seeing Different Things? Exploring Raters' Associations of Noncognitive Attributes. AB - BACKGROUND: Raters represent a significant source of unexplained, and often undesired, variance in performance-based assessments. To better understand rater variance, this study investigated how various raters, observing the same performance, perceived relationships amongst different noncognitive attributes measured in performance assessments. METHOD: Medical admissions data from a Multiple Mini-Interview (MMI) used at one Canadian medical school were collected and subsequently analyzed using the Many Facet Rasch Model (MFRM) and hierarchical clustering. This particular MMI consisted of eight stations. At each station a faculty member and an upper-year medical student rated applicants on various noncognitive attributes including communication, critical thinking, effectiveness, empathy, integrity, maturity, professionalism, and resolution. RESULTS: The Rasch analyses revealed differences between faculty and student raters across the eight different MMI stations. These analyses also identified that, at times, raters were unable to distinguish between the various noncognitive attributes. Hierarchical clustering highlighted differences in how faculty and student raters observed the various noncognitive attributes. Differences in how individual raters associated the various attributes within a station were also observed. CONCLUSIONS: The MFRM and hierarchical clustering helped to explain some of the variability associated with raters in a way that other measurement models are unable to capture. These findings highlight that differences in ratings may result from raters possessing different interpretations of an observed performance. This study has implications for developing more purposeful rater selection and rater profiling in performance based assessments. PMID- 26505103 TI - Characteristics and Implications of Diagnostic Justification Scores Based on the New Patient Note Format of the USMLE Step 2 CS Exam. AB - BACKGROUND: To determine the psychometric characteristics of diagnostic justification scores based on the patient note format of the United States Medical Licensing Examination Step 2 Clinical Skills exam, which requires students to document history and physical findings, differential diagnoses, diagnostic justification, and plan for immediate workup. METHOD: End-of-third year medical students at one institution wrote notes for five standardized patient cases in May 2013 (n = 180) and 2014 (n = 177). Each case was scored using a four-point rubric to rate each of the four note components. Descriptive statistics and item analyses were computed and a generalizability study done. RESULTS: Across cases, 10% to 48% provided no diagnostic justification or had several missing or incorrect links between history and physical findings and diagnoses. The average intercase correlation for justification scores ranged from 0.06 to 0.16; internal consistency reliability of justification scores (coefficient alpha across cases) was 0.38. Overall, justification scores had the highest mean item discrimination across cases. The generalizability study showed that person-case interaction (12%) and task-case interaction (13%) had the largest variance components, indicating substantial case specificity. CONCLUSIONS: The diagnostic justification task provides unique information about student achievement and curricular gaps. Students struggled to correctly justify their diagnoses; performance was highly case specific. Diagnostic justification was the most discriminating element of the patient note and had the greatest variability in student performance across cases. The curriculum should provide a wide range of clinical cases and emphasize recognition and interpretation of clinically discriminating findings to promote the development of clinical reasoning skills. PMID- 26505104 TI - Cause and Effect: Testing a Mechanism and Method for the Cognitive Integration of Basic Science. AB - BACKGROUND: Methods of integrating basic science with clinical knowledge are still debated in medical training. One possibility is increasing the spatial and temporal proximity of clinical content to basic science. An alternative model argues that teaching must purposefully expose relationships between the domains. The authors compared different methods of integrating basic science: causal explanations linking basic science to clinical features, presenting both domains separately but in proximity, and simply presenting clinical features METHOD: First-year undergraduate health professions students were randomized to four conditions: (1) science-causal explanations (SC), (2) basic science before clinical concepts (BC), (3) clinical concepts before basic science (CB), and (4) clinical features list only (FL). Based on assigned conditions, participants were given explanations for four disorders in neurology or rheumatology followed by a memory quiz and diagnostic test consisting of 12 cases which were repeated after one week. RESULTS: Ninety-four participants completed the study. No difference was found on memory test performance, but on the diagnostic test, a condition by time interaction was found (F[3,88] = 3.05, P < .03, etap = 0.10). Although all groups had similar immediate performance, the SC group had a minimal decrease in performance on delayed testing; the CB and FL groups had the greatest decreases. CONCLUSIONS: These results suggest that creating proximity between basic science and clinical concepts may not guarantee cognitive integration. Although cause-and effect explanations may not be possible for all domains, making explicit and specific connections between domains will likely facilitate the benefits of integration for learners. PMID- 26505105 TI - Thresholds of Principle and Preference: Exploring Procedural Variation in Postgraduate Surgical Education. AB - BACKGROUND: Expert physicians develop their own ways of doing things. The influence of such practice variation in clinical learning is insufficiently understood. Our grounded theory study explored how residents make sense of, and behave in relation to, the procedural variations of faculty surgeons. METHOD: We sampled senior postgraduate surgical residents to construct a theoretical framework for how residents make sense of procedural variations. Using a constructivist grounded theory approach, we used marginal participant observation in the operating room across 56 surgical cases (146 hours), field interviews (38), and formal interviews (6) to develop a theoretical framework for residents' ways of dealing with procedural variations. Data analysis used constant comparison to iteratively refine the framework and data collection until theoretical saturation was reached. RESULTS: The core category of the constructed theory was called thresholds of principle and preference and it captured how faculty members position some procedural variations as negotiable and others not. The term thresholding was coined to describe residents' daily experiences of spotting, mapping, and negotiating their faculty members' thresholds and defending their own emerging thresholds. CONCLUSIONS: Thresholds of principle and preference play a key role in workplace-based medical education. Postgraduate medical learners are occupied on a day-to-day level with thresholding and attempting to make sense of the procedural variations of faculty. Workplace-based teaching and assessment should include an understanding of the integral role of thresholding in shaping learners' development. Future research should explore the nature and impact of thresholding in workplace-based learning beyond the surgical context. PMID- 26505106 TI - Institution and Specialty Contribute to Resident Satisfaction With Their Learning Environment and Workload. AB - BACKGROUND: This large, multi-institutional study examines the relative contribution of residency specialty and institution to resident satisfaction with their learning environment and workload. METHOD: Survey responses from 798 residents were linked to institution (N = 20) and specialty (N = 10) and to characteristics of individual residency programs (N = 126) derived from the FREIDA Online database. Hierar chical linear modeling was used to estimate relative contributions of these factors to resident satisfaction with workload and learning environment. RESULTS: Institution had greater influence than specialty on resident ratings of satisfaction with their workload and learning environment. Institution and specialty accounted for more variance in satisfaction with workload than with the learning environment. There is evidence that characteristics of a given residency program in a given institution have additional impact beyond these main effects. However, characteristics of institutions or programs, such as program selectivity, off-duty periods, or number of faculty, did not explain statistically significant amounts of variance in resident satisfaction ratings. CONCLUSIONS: This study is the first to quantify the degree to which institution and specialty contribute to differences in resident perceptions of their learning environment and workload. Although organizational and institutional cultures are presumed to influence the learning environment, estimating the size of these influences requires a multi institutional and multispecialty dataset, such as this one. These results suggest that there is empirical justification for institutional interventions to improve the learning environment. PMID- 26505107 TI - Perceptions of Leaders and Clinician Educators on the Impact of International Accreditation. AB - BACKGROUND: Graduate medical education (GME) is responding to calls for reform by adopting competency-based frameworks and, in some countries, by rapidly implementing external accreditation systems. The Accreditation Council for Graduate Medical Education International (ACGME-I) began accrediting institutions in 2009. This study aimed to describe ACGME-I-accredited institutions and explore perceptions of their leaders and clinician educators (CEs) regarding preparedness, challenges, and initial impact of accreditation. METHOD: Cross sectional surveys of all ACGME-I-accredited institutions' leaders and CEs were conducted from June 2013 to June 2014. Eligible participants were identified through institution Web sites and GME offices. Combinations of Web- and paper based surveys were employed. RESULTS: Completed surveys were received from 24 (70.6%) of 34 institutional leaders and 274 (76.3%) of 359 CEs, representing 3 countries, 8 academic medical centers, 2 affiliated teaching hospitals, and 47 residency programs. Leaders and CEs felt prepared in the domains of knowledge and implementation of the competencies. Top challenges were excessive "demands on faculty time" and "bureaucratic procedures." The majority of both groups perceived a positive impact of accreditation on all learner, faculty, institution, and patient outcomes; most perceived no impact on patient satisfaction. Overall, 79.2% of leaders and 75.8% of CEs agreed or strongly agreed that seeking ACGME-I accreditation was worthwhile. CONCLUSIONS: This study indicates that despite the challenges identified, initial perceptions of the impact of ACGME-I accreditation are positive. Findings from this study may be useful to institutions and countries considering similar GME reform, though long term outcome data are needed. PMID- 26505108 TI - From Cheerleader to Coach: The Developmental Progression of Bedside Teachers in Giving Feedback to Early Learners. AB - BACKGROUND: Medical students learn clinical skills at the bedside from teaching clinicians, who often learn to teach by teaching. Little is known about the process of becoming an effective clinical teacher. Understanding how teaching skills and approaches change with experience may help tailor faculty development for new teachers. Focusing on giving feedback to early learners, the authors asked: What is the developmental progression of clinician-teachers as they learn to give clinical skills feedback to medical students? METHOD: This qualitative study included longitudinal interviews with clinician-teachers over five years in a new clinical skills teaching program for preclinical medical students. Techniques derived from grounded theory were used for initial analyses. The current study focused on one theme identified in initial analyses: giving feedback to students. Transcript passages were organized by interview year, coded, and discussed in year clusters; thematic codes were compared and emergent codes developed. RESULTS: Themes related to giving feedback demonstrated a dyadic structure: characteristic of less experienced teachers versus characteristic of experienced teachers. Seven dominant dyadic themes emerged, including teacher as cheerleader versus coach, concern about student fragility versus understanding resilience, and focus on creating a safe environment versus challenging students within a safe environment. CONCLUSIONS: With consistent teaching, clinical teachers demonstrated progress in giving feedback to students in multiple areas, including understanding students' developmental trajectory and needs, developing tools and strategies, and adopting a dynamic, challenging, inclusive team approach. Ongoing teaching opportunities with targeted faculty development may help improve clinician-teachers' feedback skills and approaches. PMID- 26505109 TI - How Do Surgery Students Use Written Language to Say What They See? A Framework to Understand Medical Students' Written Evaluations of Their Teachers. AB - BACKGROUND: There remains debate regarding the value of the written comments that medical students are traditionally asked to provide to evaluate the teaching they receive. The purpose of this study was to examine written teaching evaluations to understand how medical students conceptualize teachers' behaviors and performance. METHOD: All written comments collected from medical students about teachers in the two surgery clerkships at the University of Alberta in 2009-2010 and 2010-2011 were collated and anonymized. A grounded theory approach was used for analysis, with iterative reading and open coding to identify recurring themes. A framework capturing variations observed in the data was generated until data saturation was achieved. Domains and subdomains were named using an in situ coding approach. RESULTS: The conceptual framework contained three main domains: "Physician as Teacher," "Physician as Person," and "Physician as Physician." Under "Physician as Teacher," students commented on specific acts of teaching and subjective perceptions of an educator's teaching values. Under the "Physician as Physician" domain, students commented on elements of their educator's physicianship, including communication and collaborative skills, medical expertise, professionalism, and role modeling. Under "Physician as Person," students commented on how both positive and negative personality traits impacted their learning. CONCLUSIONS: This framework describes how medical students perceive their teachers and how they use written language to attach meaning to the behaviors they observe. Such a framework can be used to help students provide more constructive feedback to teachers and to assist in faculty development efforts aimed at improving teaching performance. PMID- 26505110 TI - Foreword: The More Things Change, the More They Stay the Same. PMID- 26505113 TI - Elasto-Inertial Pinched Flow Fractionation for Continuous Shape-Based Particle Separation. AB - Shape is an important passive marker in label-free particle and cell separation for chemical, biomedical, and environmental applications. We demonstrate herein a continuous-flow shape-based separation of spherical and peanut-shaped rigid particles of equal volume (or equivalent spherical diameter) via elasto-inertial pinched flow fractionation (eiPFF). This microfluidic technique exploits the shape dependence of the flow-induced elasto-inertial lift (and hence the cross stream migration) in viscoelastic fluids to increase the displacement of a sheath flow-focused particle mixture for a high-purity separation. The parametric effects on this shape-based particle separation via eiPFF are systematically investigated in terms of five dimensionless numbers. It is found that the separation is strongly affected by the flow rate, fluid elasticity, and channel aspect ratio. Interestingly, the elasto-inertial deflection of the peanut particles can be either greater or smaller than that of equally volumed spherical particles. This phenomenon is speculated to correlate with the rotational effects of peanut particles. PMID- 26505114 TI - Intraislet Pancreatic Ducts Can Give Rise to Insulin-Positive Cells. AB - A key question in diabetes research is whether new beta-cells can be derived from endogenous, nonendocrine cells. The potential for pancreatic ductal cells to convert into beta-cells is a highly debated issue. To date, it remains unclear what anatomical process would result in duct-derived cells coming to exist within preexisting islets. We used a whole-mount technique to directly visualize the pancreatic ductal network in young wild-type mice, young humans, and wild-type and transgenic mice after partial pancreatectomy. Pancreatic ductal networks, originating from the main ductal tree, were found to reside deep within islets in young mice and humans but not in mature mice or humans. These networks were also not present in normal adult mice after partial pancreatectomy, but TGF-beta receptor mutant mice demonstrated formation of these intraislet duct structures after partial pancreatectomy. Genetic and viral lineage tracings were used to determine whether endocrine cells were derived from pancreatic ducts. Lineage tracing confirmed that pancreatic ductal cells can typically convert into new beta-cells in normal young developing mice as well as in adult TGF-beta signaling mutant mice after partial pancreatectomy. Here the direct visual evidence of ducts growing into islets, along with lineage tracing, not only represents strong evidence for duct cells giving rise to beta-cells in the postnatal pancreas but also importantly implicates TGF-beta signaling in this process. PMID- 26505115 TI - Importance of Adult Dmbx1 in Long-Lasting Orexigenic Effect of Agouti-Related Peptide. AB - Dmbx1 is a brain-specific homeodomain transcription factor expressed primarily during embryogenesis, and its systemic disruption (Dmbx1(-/-)) in the ICR mouse strain resulted in leanness associated with impaired long-lasting orexigenic effect of agouti-related peptide (AgRP). Because spatial and temporal expression patterns of Dmbx1 change dramatically during embryogenesis, it remains unknown when and where Dmbx1 plays a critical role in energy homeostasis. In the present study, the physiological roles of Dmbx1 were examined by its conditional disruption (Dmbx1(loxP/loxP)) in the C57BL/6 mouse strain. Although Dmbx1 disruption in fetal brain resulted in neonatal lethality, its disruption by synapsin promoter-driven Cre recombinase, which eliminated Dmbx1 expression postnatally, exempted the mice (Syn-Cre;Dmbx1(loxP/loxP) mice) from lethality. Syn-Cre;Dmbx1(loxP/loxP) mice show mild leanness and impaired long-lasting orexigenic action of AgRP, demonstrating the physiological relevance of Dmbx1 in the adult. Visualization of Dmbx1-expressing neurons in adult brain using the mice harboring tamoxifen-inducible Cre recombinase in the Dmbx1 locus (Dmbx1(CreERT2/+) mice) revealed Dmbx1 expression in small numbers of neurons in restricted regions, including the lateral parabrachial nucleus (LPB). Notably, c Fos expression in LPB was increased at 48 hours after AgRP administration in Dmbx1(loxP/loxP) mice but not in Syn-Cre;Dmbx1(loxP/loxP) mice. These c-Fos positive neurons in LPB did not coincide with neurons expressing Dmbx1 or melanocortin 4 receptor but did coincide with those expressing calcitonin gene related peptide. Accordingly, Dmbx1 in the adult LPB is required for the long lasting orexigenic effect of AgRP via the neural circuitry involving calcitonin gene-related peptide neurons. PMID- 26505116 TI - Nanoparticles Containing High Loads of Paclitaxel-Silicate Prodrugs: Formulation, Drug Release, and Anticancer Efficacy. AB - We have investigated particle size, interior structure, drug release kinetics, and anticancer efficacy of PEG-b-PLGA-based nanoparticles loaded with a series of paclitaxel (PTX)-silicate prodrugs [PTX-Si(OR)3]. Silicate derivatization enabled us to adjust the hydrophobicity and hydrolytic lability of the prodrugs by the choice of the alkyl group (R) in the silicate derivatives. The greater hydrophobicity of these prodrugs allows for the preparation of nanoparticles that are stable in aqueous dispersion even when loaded with up to ca. 75 wt % of the prodrug. The hydrolytic lability of silicates allows for facile conversion of prodrugs back to the parent drug, PTX. A suite of eight PTX-silicate prodrugs was investigated; nanoparticles were made by flash nanoprecipitation (FNP) using a confined impingement jet mixer with a dilution step (CIJ-D). The resulting nanoparticles were 80-150 nm in size with a loading level of 47-74 wt % (wt %) of a PTX-silicate, which corresponds to 36-59 effective wt % of free PTX. Cryogenic transmission electron microscopy images show that particles are typically spherical with a core-shell structure. Prodrug/drug release profiles were measured. Release tended to be slower for prodrugs having greater hydrophobicity and slower hydrolysis rate. Nanoparticles loaded with PTX-silicate prodrugs that hydrolyze most rapidly showed in vitro cytotoxicity similar to that of the parent PTX. Nanoparticles loaded with more labile silicates also tended to show greater in vivo efficacy. PMID- 26505117 TI - Summary of Notifiable Noninfectious Conditions and Disease Outbreaks: Acute Occupational Pesticide-Related Illness and Injury - United States, 2007-2010. PMID- 26505118 TI - Bromodomain and extraterminal (BET) proteins regulate biliary-driven liver regeneration. AB - BACKGROUND & AIMS: During liver regeneration, hepatocytes are derived from pre existing hepatocytes. However, if hepatocyte proliferation is compromised, biliary epithelial cells (BECs) become the source of new hepatocytes. We recently reported on a zebrafish liver regeneration model in which BECs extensively contribute to hepatocytes. Using this model, we performed a targeted chemical screen to identify important factors that regulate BEC-driven liver regeneration, the mechanisms of which remain largely unknown. METHODS: Using Tg(fabp10a:CFP NTR) zebrafish, we examined the effects of 44 selected compounds on BEC-driven liver regeneration. Liver size was assessed by fabp10a:DsRed expression; liver marker expression was analyzed by immunostaining, in situ hybridization and quantitative PCR. Proliferation and apoptosis were also examined. Moreover, we used a mouse liver injury model, choline-deficient, ethionine-supplemented (CDE) diet. RESULTS: We identified 10 compounds that affected regenerating liver size. Among them, only bromodomain and extraterminal domain (BET) inhibitors, JQ1 and iBET151, blocked both Prox1 and Hnf4a induction in BECs. BET inhibition during hepatocyte ablation blocked BEC dedifferentiation into hepatoblast-like cells (HB LCs). Intriguingly, after JQ1 washout, liver regeneration resumed, indicating temporal, but not permanent, perturbation of liver regeneration by BET inhibition. BET inhibition after hepatocyte ablation suppressed the proliferation of newly generated hepatocytes and delayed hepatocyte maturation. Importantly, Myca overexpression, in part, rescued the proliferation defect. Furthermore, oval cell numbers in mice fed CDE diet were greatly reduced upon JQ1 administration, supporting the zebrafish findings. CONCLUSIONS: BET proteins regulate BEC-driven liver regeneration at multiple steps: BEC dedifferentiation, HB-LC proliferation, the proliferation of newly generated hepatocytes, and hepatocyte maturation. PMID- 26505119 TI - Restoration of T cell function in chronic hepatitis B patients upon treatment with interferon based combination therapy. AB - BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is characterized by functional impairment of HBV-specific T cells. Understanding the mechanisms behind T cell dysfunction and restoration is important for the development of optimal treatment strategies. METHODS: In this study we have first analysed the phenotype and function of HBV-specific T cells in patients with low viral load (HBV DNA <20,000IU/ml) and spontaneous control over the virus. Subsequently, we assessed HBV-specific T cells in patients with high viral load (HBV DNA >17,182IU/ml) treated with peginterferon/adefovir combination therapy who had various treatment outcomes. RESULTS: HBV-specific T cells could be detected directly ex vivo in 7/22 patients with low viral load. These showed an early differentiated memory phenotype with reduced ability to produce IL-2 and cytotoxic molecules such as granzyme B and perforin, but with strong proliferative potential. In a cohort of 28 chronic hepatitis B patients with high viral load treated with peginterferon and adefovir, HBV-specific T cells could not be detected directly ex vivo. However, HBV-specific T cells could be selectively expanded in vitro in patients with therapy-induced HBsAg clearance (HBsAg loss n=7), but not in patients without HBsAg clearance (n=21). Further analysis of HBV-specific T cell function with peptide pools showed broad and efficient antiviral responses after therapy. CONCLUSIONS: Our results show that peginterferon based combination therapy can induce HBV-specific T cell restoration. These findings may help to develop novel therapeutic strategies to reconstitute antiviral functions and enhance viral clearance. PMID- 26505120 TI - Complete removal of the tumor-bearing portal territory decreases local tumor recurrence and improves disease-specific survival of patients with hepatocellular carcinoma. AB - BACKGROUND & AIMS: Anatomic resection (AR) of the tumor-bearing portal territory has been reported to be associated with a decreased recurrence of hepatocellular carcinoma (HCC). However, because of the heterogeneity of the study populations, its oncologic advantage remains controversial. The objective of the present study was to determine the clinical advantage of AR for primary HCC, based on the data from a large prospective cohort treated under a constant surgical policy. METHODS: In 209 Child-Pugh class A patients with primary, solitary HCC measuring ?5.0cm in diameter, which was resectable either by AR or limited resection (non AR), the overall survival (OS) and disease-free survival (DFS) were compared with patients in whom complete AR was achieved and those who eventually ended up with non-AR after adjustment for the propensity scores to select AR. Advantages of AR in disease-specific survival and local recurrence were also evaluated by competing-risks regression to clarify the true oncologic impact of AR. RESULTS: The AR group showed better DFS than the non-AR group (HR, 0.67; 95% CI, 0.45 0.99; p=0.046), while no significant difference was observed in OS (hazard ratio [HR], 0.82; 95% CI, 0.46-1.48; p=0.511). Competing-risks regression revealed that AR significantly decreases local recurrence (HR, 0.12; 95% CI, 0.05-0.30; p<0.001) and improves disease-specific survival (HR, 0.50; 95% CI, 0.28-0.90; p=0.020), while the other cause of death was highly influenced by patient age (>65years) (HR, 7.51; 95% CI, 2.16-26.04; p=0.002) and not associated with AR. CONCLUSION: Complete removal of tumor-bearing portal territory decreases the risk of local recurrence and death from HCC. PMID- 26505122 TI - Three-coordinate iron(IV) bisimido complexes with aminocarbene ligation: synthesis, structure, and reactivity. AB - High-valent iron imido species are implicated as reactive intermediates in many iron-catalyzed transformations. However, isolable complexes of this type are rare, and their reactivity is poorly understood. Herein, we report the synthesis, characterization, and reactivity studies on novel three-coordinate iron(IV) bisimido complexes with aminocarbene ligation. Using our recently reported synthetic method for [LFe(NDipp)2] (L = IMes, 1; Me2-cAAC, 2), four new iron(IV) imido complexes, [(IPr)Fe(NDipp)2] (3) and [(Me2-cAAC)Fe(NR)2] (R = Mes, 4; Ad, 5; CMe2CH2Ph, 6), were prepared from the reactions of three-coordinate iron(0) compounds with organic azides. Characterization data acquired from (1)H and (13)C NMR spectroscopy, (57)Fe Mossbauer spectroscopy, and X-ray diffraction studies suggest a low-spin singlet ground state for these iron(IV) complexes and the multiple-bond character of their Fe-N bonds. A reactivity study taking the reactions of 1 as representative revealed an intramolecular alkane dehydrogenation of 1 to produce the iron(II) complex [(IMes)Fe(NHDipp)(NHC6H3-2 Pr(i)-6-CMe?CH2)] (7), a Si-H bond activation reaction of 1 with PhSiH3 to produce the iron(II) complex [(IMes)Fe(NHDipp)(NDippSiPhH2)] (8), and a [2+2] addition reaction of 1 with PhNCNPh and p-Pr(i)C6H4NCO to form the corresponding open-shell formal iron(IV) monoimido complexes [(IMes)Fe(NDipp)(N(Dipp)C(NPh)(?NPh))] (9) and [(IMes)Fe(NDipp)(N(Dipp)C(O)N(p Pr(i)C6H4))] (10), as well as [NDipp]-group-transfer reactions with CO and Bu(t)NC. Density functional theory calculations suggested that the alkane chain dehydrogenation reaction starts with a hydrogen atom abstraction mechanism, whereas the Si-H activation reaction proceeds in a [2pi+2sigma]-addition manner. Both reactions have the pathways at the triplet potential energy surfaces being energetically preferred, and have formal iron(IV) hydride and iron(IV) silyl species as intermediates, respectively. The low-coordinate nature and low d electron count (d(4)) of iron(IV) imido complexes are thought to be the key features endowing their unique reactivity. PMID- 26505121 TI - Novel pH-sensitive multifunctional envelope-type nanodevice for siRNA-based treatments for chronic HBV infection. AB - BACKGROUND & AIMS: Antiviral agents including entecavir (ETV) suppress the replication of the hepatitis B virus (HBV) genome in human hepatocytes, but they do not reduce the abundance of viral proteins. The present study focused on effectively reducing viral protein levels. METHODS: We designed siRNAs (HBV siRNA) that target consensus sequences in HBV genomes. To prevent the emergence of escaped mutant virus, we mixed three HBV-siRNAs (HBV-siRNAmix); the mixture was encapsulated in a novel pH-sensitive multifunctional envelope-type nanodevice (MEND), a hepatocyte-specific drug delivery system. Coagulation factor 7 siRNA was used to assess delivery and knockdown efficiencies of MEND/siRNA treatments in mice. The potency of MEND/HBV-siRNAmix was evaluated in primary human hepatocytes and in chimeric mice with humanized liver persistently infected with HBV. RESULTS: Effective knockdown of targets, efficient delivery of siRNA, and liver-specific delivery were each observed with MEND. MEND/HBV-siRNA caused efficient reduction of HBsAg and HBeAg in vitro and in vivo. However, ETV treatment did not efficiently reduce HBsAg or HBeAg when compared with a single MEND/HBV-siRNAmix treatment. Furthermore, the suppressive effects of a single dose of MEND/HBV-siRNAmix persisted for 14days in vitro and in vivo. CONCLUSION: We demonstrated that MEND/HBV-siRNA controlled HBV more efficiently than did ETV. Furthermore, the effect of a single dose of MEND/HBV-siRNA persisted for a long time. These results indicated that MEND/HBV-siRNA may be a promising novel HBV treatment that is more effective than reverse transcriptase inhibitors. PMID- 26505123 TI - Stress-induced adaptation of neutrophilic granulocyte activity in K and R3 carp lines. AB - Both in mammals and fish, stress induces remarkable changes in the immune response. We focused on stress-induced changes in the activity of neutrophilic granulocytes in the R3 and K lines of common carp, which showed differential stress responses. Our study clearly demonstrates that a prolonged restraint stress differentially affects the activity of K and R3 carp neutrophils. In the K line, stress decreased the respiratory burst, while in the R3 line it reduced the release of extracellular DNA. Surprisingly, the stress-induced changes in ROS production and NET formation did not correlate with changes in gene expression of the inflammatory mediators and GR receptors. In neutrophilic granulocytes from K carp, gene expression of the stress-sensitive cortisol GR1 receptor was significantly higher than in neutrophils from R3 fish, which will make these cells more sensitive to high levels of cortisol. Moreover, upon stress, neutrophilic granulocytes of K carp up-regulated gene expression of the anti inflammatory cytokine IL-10 while this was not observed in neutrophilic granulocytes of R3 carp. Therefore, we can hypothesize that, in contrast to R3 neutrophils, the more cortisol sensitive neutrophils from K carp respond to stress with up-regulation of IL-10 and consequently reduction of ROS production. Most probably the ROS-independent NET formation in K carp is not regulated by this anti-inflammatory cytokine. These data may indicate a predominantly ROS independent formation of NETs by carp neutrophilic granulocytes. Moreover, they underline the important role of IL-10 in stress-induced immunoregulation. PMID- 26505124 TI - A combined CoMFA and CoMSIA 3D-QSAR study of benzamide type antibacterial inhibitors of the FtsZ protein in drug-resistant Staphylococcus aureus. AB - A major problem today is bacterial resistance to antibiotics and the small number of new therapeutic agents approved in recent years. The development of new antibiotics capable of acting on new targets is urgently required. The filamenting temperature-sensitive Z (FtsZ) bacterial protein is a key biomolecule for bacterial division and survival. This makes FtsZ an attractive new pharmacological target for the development of antibacterial agents. There have been several attempts to develop ligands able to inhibit FtsZ. Despite the large number of synthesized compounds that inhibit the FtsZ protein, there are no quantitative structure-activity relationships (QSAR) that allow for the rational design and synthesis of promising new molecules. We present the first 3D-QSAR study of a large and diverse set of molecules that are able to inhibit the FtsZ bacterial protein. We summarize a set of chemical changes that can be made in the steric, electrostatic, hydrophobic and donor/acceptor hydrogen-bonding properties of the pharmacophore, to generate new bioactive molecules against FtsZ. These results provide a rational guide for the design and synthesis of promising new antibacterial agents, supported by the strong statistical parameters obtained from CoMFA (r(2)(pred) = 0.974) and CoMSIA (r(2)(pred) = 0.980) analyses. PMID- 26505125 TI - Practical Suggestions for the Creation and Use of Meaningful Learning Goals in Graduate Medical Education. PMID- 26505126 TI - Bioassay of cyanoacrylate tissue adhesives used for intraperitoneal mesh fixation. AB - AIMS: This study examines the intraperitoneal behavior of two cyanoacrylate tissue adhesives: Ifabond(r) and a new, non-marketed octyl cyanoacrylate adhesive (OCA) used for the intraperitoneal fixation of a laminar expanded polytetrafluoroethylene (ePTFE) mesh. MATERIAL AND METHODS: In 36 New Zealand White rabbits, 3 * 3 cm (n = 24) or 1.5 * 3 cm (n = 12) fragments of ePTFE mesh (Preclude(r) , Gore, Flagstaff, USA) were fixed to the parietal peritoneum using OCA or Ifabond(r) . Peritoneal fluid was obtained at the time of implant and at 2 weeks postimplant for determination of the cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). At 14 or 90 days postsurgery, the animals were euthanized and the meshes excised to assess host tissue incorporation, the macrophage response, apoptosis and fixation strength (T-peel tensiometry). RESULTS: Peritoneal fluid IL-6 and TNF-alpha concentrations were similar in the OCA and Ifabond(r) groups. Both adhesives gave rise to adequate mesothelialization of the laminar ePTFE. Macrophage counts were similar for the two study groups, but a significantly increase in macrophage response was observed from 14 to 90 days for Ifabond(r) . At 90 days postimplant, apoptotic cell counts was lower for the implants fixed with OCA and a fixation strength was significantly lower for OCA. CONCLUSIONS: Despite similar cytokine levels at 2 weeks and similar host tissue incorporation observed for the meshes fixed with the two adhesives, the use of Ifabond(r) gave rise to a greater apoptosis rate, although this adhesive provided a stronger fixation bond. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 312-319, 2017. PMID- 26505127 TI - Enhanced production of polygalacturonase in solid-state fermentation: selection of the process conditions, isolation and partial characterization of the enzyme. AB - Polygalacturonase (PG) production by Penicillium chrysogenum during solid-state fermentation was accompanied by decomposition of orange peels. A leaching procedure was developed through the selection of solvent, time and intensity of stirring. A maximum PG activity was observed after 48 h peel inoculation. Further cultivation decreased the enzyme activity significantly, up to 60% of the maximum PG activity. During fermentation, a rapid acidification of the solid medium which inhibited the pectinolytic enzyme, was observed. Buffering agents with different pH values and different ionic strengths were examined to identify the most suitable medium to avoid this problem. Buffer addition counteracted acidification and enhanced active protein production, which was observed for all of the applied pH values (6.5-8.0) of the buffering agent. The most satisfactory results were obtained when using the highest pH at 8.0. The protein content and PG activity increased from 3.5 mg/g and 1.09 U/g to 7.7 mg/g and 7.11 U/g during cultivation, with uncontrolled and pH-controlled medium, respectively. Measurements at wide pH and temperature ranges indicated an optimum for PG activity at pH 5.0 and 43 degrees C; however, high thermal stability corresponded to lower temperatures, and a temperature of 37 degrees C is thus recommended. Under these conditions, the operational stability was determined to be t1/2=570 h. PMID- 26505128 TI - Microbiome impact on metabolism and function of sex, thyroid, growth and parathyroid hormones. AB - Commensal bacteria and their genes associated with host are known as microbiome. In recent years, microbial influence on host endocrine system has been under detailed investigation. The role of microbiome in the pathogenesis of insulin resistance and obesity, the function of hypothalamic-pituitary-adrenal axis and secretion of hormones regulating appetite is well described in world literature. In this article we discuss poorly reviewed issues: the microbiome role in modulation of non-peptide (sex and thyroid) and peptide (growth hormone and parathyroid hormone) functions. Understanding complex bidirectional relations between host endocrine system and bacteria is of fundamental importance to understanding microbial impact on host reproduction, risk of endocrine-related cancers, pathogenesis of non-thyroidal illness syndrome, growth failure in children and hormonal changes during chronic kidney disease. This article also highlights effects of dietary compounds on microbiome composition and bacterial enzymes activity, and thus host hormonal status. PMID- 26505129 TI - Determination of biodiversity of Coprinus comatus using genotyping and metabolic profiling tools. AB - Coprinus comatus strains (CCMs) originating from Poland were identified using ITS region sequencing. Based on the sequences obtained, the genetic relationship between the CCM strains was determined and a clear separation of all strains into two main clusters was obtained. The Coprinus strains were also genetically characterized for the first time by the AFLP technique. The analysis showed that the CCMs separated into four main clusters and a high complication of a UPGMA based dendrogram was achieved. C. comatus strains included in the analysis displayed an AFLP profile similarity level in the range from 44 to 66%. The highest similarity coefficient, 0.490, was found between CCM12 and CCM13, and the lowest (0.202) between the CCM2 and CCM5 isolates. Biolog FF MicroPlates were applied to obtain data on utilization of 95 carbon sources and mycelial growth. The analysis allowed comparison of the functional diversity of the CCM strains and revealed a broad variability within the analyzed Coprinus species based on substrate utilization profiles. Significant differences (2-48) have been shown in the substrate richness values. The Biolog experiments proved to be a good profiling technology for studying the diversity in shaggy manes due to metabolic differences and demonstrated that all the strains might be considered individually. It is evident that the strain metabolic grouping does not correlate with the grouping based on the ITS sequences and AFLP profiles, however, some similarities may be observed. PMID- 26505130 TI - Antimicrobial, antiadhesive and antibiofilm potential of lipopeptides synthesised by Bacillus subtilis, on uropathogenic bacteria. AB - The aim of this study was to investigate the antimicrobial effect of lipopeptide biosurfactants from surfactin, iturin and fengycin families, synthesised by the Bacillus subtilis I'1a strain, on uropathogenic bacteria, including the effects on planktonic growth, processes of biofilm formation and dislodging. Antimicrobial activity was tested against 32 uropathogenic strains belonging to 12 different species of Gram-negative and Gram-positive bacteria. The sensitivity of 25 tested bacterial strains to the B. subtilis I'1a filtrate was confirmed by an agar diffusion assay. None of the strains seemed to be sensitive to pure surfactin at concentrations ranging from 0.1 mg * ml(-1) to 0.4 mg ml(-1). After the treatment of uropathogens with B. subtilis lipopeptides, the metabolic activity of planktonic cells was inhibited by 88.05+/-3.96% in the case of 21 studied uropathogens, the process of biofilm formation was reduced by 88.15+/ 4.77% in the case of 24 uropathogens and mature biofilms of 18 strains were dislodged by about 81.20+/-4.72%. Ten strains of uropathogenic bacteria were selected to study the antimicrobial activity of surfactin (concentrations 0.1, 0.2 and 0.4 mg * ml(-1)). Surfactin had no influence on the metabolic activity of planktonic forms of uropathogens, however, biofilms of 5 tested strains were reduced by 64.77+/-9.05% in the presence of this biosurfactant at the concentration 0.1 mg * ml(-1). The negative effect of the compound on the biofilm formation process was observed at all concentrations used. The above-described results were fully confirmed by CLSM. It could suggest that synergistic application of biosurfactants could be efficient in uropathogen eradication. PMID- 26505131 TI - Ridge Preservation Techniques in the Anterior Esthetic Zone. AB - PURPOSE: Various techniques have been developed to limit resorption of the alveolar ridge after tooth extraction, and results from using them have been promising. The aim of this study was to evaluate the role and reliability of ridge preservation (RP) in the anterior esthetic zone, in anticipation of later implant placement. MATERIALS AND METHODS: Using the MEDLINE and PubMed databases, searches were performed using combinations of different terms. RESULTS: A total of 223 studies were identified, from which 55 articles were further examined. Of these, 11 studies were randomized clinical trials, controlled clinical trials, or prospective/retrospective studies with a minimum of 5 subjects and at least 3 months of follow-up. Only human studies of RP for single-rooted tooth or bicuspid sites were included. Selection criteria also excluded studies in which primary closure was obtained. CONCLUSION: Although a direct comparison of the 11 articles was difficult because of the different techniques, materials, and healing time, no single graft material seemed to be superior. However, all studies found less ridge contraction at grafted than nongrafted sites. Long-term data about the outcomes for implants placed in sites where RP was attempted are still needed. PMID- 26505132 TI - Comparison of Marginal and Internal Adaptation of CAD/CAM and Conventional Cement Retained Implant-Supported Single Crowns. AB - PURPOSE: To evaluate the accuracy of marginal and internal adaptation of 2 computer-aided design/computer-aided manufacturing (CAD/CAM) and 2 conventionally made cement retained implant-supported restorations. MATERIALS AND METHODS: An abutment and its corresponding fixture analog (Astra Tech) were inserted in left central incisor area of a maxillary cast. Four types of implant-supported single restorations were fabricated on the abutment (n = 10): e.max CAD (Cerec AC system), zirconia-based (Cercon system), IPS e.max Press, and metal-ceramic restorations. The internal and marginal gaps of the studied groups were measured by replica method and stereomicroscope. Data were subjected to 1-way ANOVA and Scheffe post hoc tests (alpha = 0.05). RESULTS: Mean internal gaps of Cercon (59.48 +/- 16.49 MUm) and e.max Press (75.62 +/- 26.92 MUm) groups were significantly different from e.max CAD (120.29 +/- 16.74 MUm) group, but there was no significant difference between metal-ceramic restorations (89.65 +/- 47.84 MUm) and e.max CAD. The marginal gaps of e.max CAD (32.02 +/- 10.38 MUm) and Cercon restorations (34.26 +/- 11.41 MUm) were significantly superior from metal ceramics (59.19 +/- 17.81 MUm) and e.max press (74.99 +/- 24.51 MUm). CONCLUSION: Within the limitations of this study, it can be concluded that although the marginal and internal gaps of the studied implant-supported restorations were in the clinically acceptable range, single crowns made with CAD/CAM technology provide better marginal fit. PMID- 26505134 TI - Lost in space: design of experiments and scientific exploration in a Hogarth Universe. AB - A Hogarth, or 'wicked', universe is an irregular environment generating data to support erroneous beliefs. Here, we argue that development scientists often work in such a universe. We demonstrate that exploring these multidimensional spaces using small experiments guided by scientific intuition alone, gives rise to an illusion of validity and a misplaced confidence in that scientific intuition. By contrast, design of experiments (DOE) permits the efficient mapping of such complex, multidimensional spaces. We describe simulation tools that enable research scientists to explore these spaces in relative safety. PMID- 26505133 TI - Metformin synergistically sensitizes FLT3-ITD-positive acute myeloid leukemia to sorafenib by promoting mTOR-mediated apoptosis and autophagy. AB - Mutations of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD), accounting for approximately 30% of patients with acute myeloid leukemia (AML), results in poor therapeutic efficacy and short survival. Sorafenib, an oral multikinase inhibitor, can inhibit FLT3 and improve clinical outcome of FLT3 mutated leukemia. Our current studies have shown that, the antidiabetic drug metformin also exerts anti-leukemic effect by activating p-AMPK and synergistically sensitizes FLT3 mutated AML to sorafenib. Both agents suppress cell proliferation in a dose-dependent manner and induce apoptosis via cell cycle arrest, but does not obviously modulate autophagy marker, light chain 3 (LC3). Mechanistically, in the presence of metformin, the anticancer potential of sorafenib, accompanying with increased LC3 levels, is found to be synergistically enhanced with the remarkably reduced protein expression of the mTOR/p70S6K/4EBP1 pathway, while not appreciably altering cell cycle. Overall, these results show metformin in aid of sorafenib may represent a promising and attractive strategy for the treatment of FLT3-ITD mutated AML. PMID- 26505135 TI - Mathematical model of susceptibility, resistance, and resilience in the within host dynamics between a Plasmodium parasite and the immune system. AB - We developed a coupled age-structured partial differential equation model to capture the disease dynamics during blood-stage malaria. The addition of age structure for the parasite population, with respect to previous models, allows us to better characterize the interaction between the malaria parasite and red blood cells during infection. Here we prove that the system we propose is well-posed and there exist at least two global states. We further demonstrate that the numerical simulation of the system coincides with clinically observed outcomes of primary and secondary malaria infection. The well-posedness of this system guarantees that the behavior of the model remains smooth, bounded, and continuously dependent on initial conditions; calibration with clinical data will constrain domains of parameters and variables to physiological ranges. PMID- 26505136 TI - 'They can't report abuse, they can't move out. They are at the mercy of these men': exploring connections between intimate partner violence, gender and HIV in South African clinical settings. AB - This qualitative study captured South African female health provider perspectives of intimate partner violence in female patients, gender norms and consequences for patients' health. Findings indicated female patients' health behaviours were predicated on sociocultural norms of submission to men's authority and economic dependence on their partners. Respondents described how men's preferences and health decision-making in clinics affected their patients' health. Adverse gender norms and gender inequalities affected women's opportunities to be healthy, contributing to HIV risk and undermining effective HIV management in this context. Some providers, seeking to deliver a standard of quality healthcare to their female patients, demonstrated a willingness to challenge patriarchal gender relations. Findings enhance understanding of how socially-sanctioned gender norms, intimate partner violence and HIV are synergistic, also reaffirming the need for integrated HIV-intimate partner violence responses in multi-sector national strategic plans. Health providers' intimate knowledge of the lived experiences of female patients with intimate partner violence and/or HIV deepens understanding of how adverse gender norms generate health risks for women in ways that may inform policy and clinical practice in South Africa and other high-HIV prevalence settings. PMID- 26505137 TI - Altered purinergic signaling in the tumor associated immunologic microenvironment in metastasized non-small-cell lung cancer. AB - OBJECTIVES: Purines are well-known as intracellular sources for energy but they also act as extracellular signaling molecules. In the recent years, there has been a growing interest in the therapeutic potential of purinergic signaling for cancer treatment. This is the first study to analyze lung purine levels and purinergic receptors in non-small-cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: In this prospective clinical trial we enrolled 26 patients with NSCLC and 21 patients with chronic obstructive pulmonary disease (COPD) without signs of malignancy. The purine concentrations were analyzed in bronchoalveolar lavage fluid (BALF) using fluorescent/luminescent assays. Expression of purinergic receptors and ectonucleotidases were analyzed using real time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Patients with NSCLC have significantly lower ATP and ADP concentrations in BALF than patients with COPD (p=0.006 and p=0.009). Expression of the ectonucleotidase CD39 is significantly higher in BAL cells from cancer patients compared to COPD (p=0.001) as well as in metastasized tumors compared to non-metastasized tumors (p=0.009). Receptor-analysis revealed a higher expression of P2X4 (p=0.03), P2X7 (p=0.001) and P2Y1 (p=0.003) in BAL cells of tumors with distant metastasis. CONCLUSION: Our data suggests a role for CD39 in lung cancer tumor microenvironment, influencing tumor invasiveness and metastasization. Potentially the increased degradation of ATP and ADP leads to a subversion of their anti-neoplastic effects. Furthermore P2Y1, P2X4 and P2X7 receptors are upregulated in BAL cells in metastatic disease. Our findings might facilitate the identification of new therapeutic targets for cancer immunotherapy. PMID- 26505138 TI - Holographic acoustic elements for manipulation of levitated objects. AB - Sound can levitate objects of different sizes and materials through air, water and tissue. This allows us to manipulate cells, liquids, compounds or living things without touching or contaminating them. However, acoustic levitation has required the targets to be enclosed with acoustic elements or had limited manoeuvrability. Here we optimize the phases used to drive an ultrasonic phased array and show that acoustic levitation can be employed to translate, rotate and manipulate particles using even a single-sided emitter. Furthermore, we introduce the holographic acoustic elements framework that permits the rapid generation of traps and provides a bridge between optical and acoustical trapping. Acoustic structures shaped as tweezers, twisters or bottles emerge as the optimum mechanisms for tractor beams or containerless transportation. Single-beam levitation could manipulate particles inside our body for applications in targeted drug delivery or acoustically controlled micro-machines that do not interfere with magnetic resonance imaging. PMID- 26505139 TI - Individualized real-time fMRI neurofeedback to attenuate craving in nicotine dependent smokers. AB - BACKGROUND: Cue-induced craving plays an important role in relapse, and the neural correlates of cue-induced craving have been elucidated using fMRI. This study examined the utility of real-time fMRI (rtfMRI) neurofeedback to strengthen self-regulation of craving-related neural activation and cue-reactivity in cigarette smokers. METHODS: Nicotine-dependent smokers were randomized to rtfMRI neurofeedback or to a no-feedback control group. Participants completed 3 neuroimaging visits. Within each visit, an initial run during which smoking related cues were used to provoke craving, an individualized craving-related region of interest (ROI) in the prefrontal cortex or anterior cingulate cortex was identified. In the rtfMRI group, activity from the ROI was fed back via a visual display during 3 subsequent runs while participants were instructed to reduce craving during cue exposure. The control group had an identical experience with no feedback provided. RESULTS: Forty-four nicotine-dependent smokers were recruited to participate in our study; data from the 33 participants who completed a 1-week follow-up visit were included in the analysis. Subjective craving ratings and cue-induced brain activation were lower in the rtfMRI group than in the control group. LIMITATIONS: As participants were not seeking treatment, clinical outcomes are lacking. CONCLUSION: Nicotine-dependent smokers receiving rtfMRI feedback from an individualized ROI attenuated smoking cue elicited neural activation and craving, relative to a control group. Further studies are needed in treatment-seeking smokers to determine if this intervention can translate into a clinically meaningful treatment modality. PMID- 26505140 TI - Associations between arterial stiffness, depressive symptoms and cerebral small vessel disease: cross-sectional findings from the AGES-Reykjavik Study. AB - BACKGROUND: Arterial stiffness may contribute to depression via cerebral microvascular damage, but evidence for this is scarce. We therefore investigated whether arterial stiffness is associated with depressive symptoms and whether cerebral small vessel disease contributes to this association. METHODS: This cross-sectional study included a subset of participants from the AGES-Reykjavik study second examination round, which was conducted from 2007 to 2011. Arterial stiffness (carotid-femoral pulse wave velocity [CFPWV]), depressive symptoms (15 item geriatric depression scale [GDS-15]) and cerebral small vessel disease (MRI) were determined. Manifestations of cerebral small vessel disease included higher white matter hyperintensity volume, subcortical infarcts, cerebral microbleeds, Virchow-Robin spaces and lower total brain parenchyma volume. RESULTS: We included 2058 participants (mean age 79.6 yr; 59.0% women) in our analyses. Higher CFPWV was associated with a higher GDS-15 score, after adjustment for potential confounders (beta 0.096, 95% confidence interval [CI] 0.005-0.187). Additional adjustment for white matter hyperintensity volume or subcortical infarcts attenuated the association between CFPWV and the GDS-15 score, which became nonsignificant (p > 0.05). Formal mediation tests showed that the attenuating effects of white matter hyperintensity volume and subcortical infarcts were statistically significant. Virchow-Robin spaces, cerebral microbleeds and cerebral atrophy did not explain the association between CFPWV and depressive symptoms. LIMITATIONS: Our study was limited by its cross sectional design, which precludes any conclusions about causal mediation. Depressive symptoms were assessed by a self-report questionnaire. CONCLUSION: Greater arterial stiffness is associated with more depressive symptoms; this association is partly accounted for by white matter hyperintensity volume and subcortical infarcts. This study supports the hypothesis that arterial stiffness leads to depression in part via cerebral small vessel disease. PMID- 26505141 TI - Identification of segregated regions in the functional brain connectome of autistic patients by a combination of fuzzy spectral clustering and entropy analysis. AB - BACKGROUND: Several neuroimaging studies support the model of abnormal development of brain connectivity in patients with autism-spectrum disorders (ASD). In this study, we aimed to test the hypothesis of reduced functional network segregation in autistic patients compared with controls. METHODS: Functional MRI data from children acquired under a resting-state protocol (Autism Brain Imaging Data Exchange [ABIDE]) were submitted to both fuzzy spectral clustering (FSC) with entropy analysis and graph modularity analysis. RESULTS: We included data from 814 children in our analysis. We identified 5 regions of interest comprising the motor, temporal and occipitotemporal cortices with increased entropy (p < 0.05) in the clustering structure (i.e., more segregation in the controls). Moreover, we noticed a statistically reduced modularity (p < 0.001) in the autistic patients compared with the controls. Significantly reduced eigenvector centrality values (p < 0.05) in the patients were observed in the same regions that were identified in the FSC analysis. LIMITATIONS: There is considerable heterogeneity in the fMRI acquisition protocols among the sites that contributed to the ABIDE data set (e.g., scanner type, pulse sequence, duration of scan and resting-state protocol). Moreover, the sites differed in many variables related to sample characterization (e.g., age, IQ and ASD diagnostic criteria). Therefore, we cannot rule out the possibility that additional differences in functional network organization would be found in a more homogeneous data sample of individuals with ASD. CONCLUSION: Our results suggest that the organization of the whole-brain functional network in patients with ASD is different from that observed in controls, which implies a reduced modularity of the brain functional networks involved in sensorimotor, social, affective and cognitive processing. PMID- 26505142 TI - Structural covariance of neostriatal and limbic regions in patients with obsessive-compulsive disorder. AB - BACKGROUND: Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive-compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored. METHODS: We performed a mega-analysis pooling structural MRI scans from the Obsessive-compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software. RESULTS: Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial superficial amygdala and the ventromedial prefrontal cortex. LIMITATIONS: This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres. CONCLUSION: Our results provide evidence for structural network level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain alterations in patients with psychiatric disorders. PMID- 26505143 TI - Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour. AB - BACKGROUND: The monoaminergic transmitters dopamine (DA), noradrenaline (NE) and serotonin (5-HT) modulate cerebral functions via their extensive effects in the brain. Investigating their roles has led to the creation of vesicular monoaminergic transporter-2 (VMAT2) knockout (KO) mice. While this mutation results in postnatal death, VMAT2-heterozygous (HET) mice are viable and show a complex behavioural phenotype. However, the simultaneous alteration of the 3 systems prevents investigations into their individual functions. METHODS: To assess the specific role of NE, 5-HT and DA, we genetically disrupted their neurotransmission by creating conditional VMAT2-KO mice with targeted recombination. These specific recombinations were obtained by breeding VMAT2(lox/lox) mice with DBHcre, SERTcre and DATcre mice, respectively. We conducted a complete neurochemical and behavioural characterization of VMAT2-HET animals in each system. RESULTS: Conditional VMAT2-KO mice revealed an absence of VMAT2 expression, and a specific decrease in the whole brain levels of each monoamine. Although NE- and 5-HT-depleted mice are viable into adulthood, DA depletion results in postnatal death before weaning. Interestingly, alteration of the DA transmission fully accounted for the increased amphetamine response formerly observed in the VMAT2-HET mice, whereas alteration of the 5-HT system was solely responsible for the increase in cocaine response. LIMITATIONS: We used VMAT2-HET mice that displayed a mild phenotype. Because the VMAT2-KO in DA neurons is lethal, it precluded a straightforward comparison of the full KOs in the 3 systems. CONCLUSION: Given the intermingled functions of NE, 5-HT and DA in regulating cognitive and affective functions, this model will enhance understanding of their respective roles in the pathophysiology of psychiatric disorders. PMID- 26505145 TI - Divergence times and the evolution of morphological complexity in an early land plant lineage (Marchantiopsida) with a slow molecular rate. AB - We present a complete generic-level phylogeny of the complex thalloid liverworts, a lineage that includes the model system Marchantia polymorpha. The complex thalloids are remarkable for their slow rate of molecular evolution and for being the only extant plant lineage to differentiate gas exchange tissues in the gametophyte generation. We estimated the divergence times and analyzed the evolutionary trends of morphological traits, including air chambers, rhizoids and specialized reproductive structures. A multilocus dataset was analyzed using maximum likelihood and Bayesian approaches. Relative rates were estimated using local clocks. Our phylogeny cements the early branching in complex thalloids. Marchantia is supported in one of the earliest divergent lineages. The rate of evolution in organellar loci is slower than for other liverwort lineages, except for two annual lineages. Most genera diverged in the Cretaceous. Marchantia polymorpha diversified in the Late Miocene, giving a minimum age estimate for the evolution of its sex chromosomes. The complex thalloid ancestor, excluding Blasiales, is reconstructed as a plant with a carpocephalum, with filament-less air chambers opening via compound pores, and without pegged rhizoids. Our comprehensive study of the group provides a temporal framework for the analysis of the evolution of critical traits essential for plants during land colonization. PMID- 26505144 TI - Serum lipid levels and suicidality: a meta-analysis of 65 epidemiological studies. AB - BACKGROUND: We conducted a systematic review and meta-analysis to determine the association between serum lipid levels and suicidality, as evidence from previous studies has been inconsistent. METHODS: We identified relevant studies by searching Medline, Web of Science, EMBASE, and the Cochrane Database of Systematic Reviews (1980 to Dec. 5, 2014). Studies assessing the association between serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL C), low-density lipoprotein cholesterol (LDL-C) and/or triglycerides (TG) levels and suicidality were included. We used a random-effects model to take into account heterogeneity among studies. RESULTS: We included 65 studies with a total of 510 392 participants in our analysis. Compared with the nonsuicidal patients, suicidal patients had significantly lower serum TC (weighted mean difference [WMD] -22.35, 95% confidence interval [CI] -27.95 to -16.75), LDL-C (WMD -19.56, 95% CI -26.13 to -12.99) and TG (WMD -23.40, 95% CI -32.38 to -14.42) levels, while compared with the healthy controls, suicidal patients had significantly lower TC (WMD -24.75, 95% CI -27.71 to -21.78), HDL-C (WMD -1.75, 95% CI -3.01 to -0.48) and LDL-C (WMD -3.85, 95% CI -7.45 to -0.26) levels. Furthermore, compared with the highest serum TC level category, a lower serum TC level was associated with a 112% (95% CI 40%-220%) higher risk of suicidality, including a 123% (95% CI 24%-302%) higher risk of suicide attempt and an 85% (95 CI 7%-221%) higher risk of suicide completion. The cut-off values for low and high serum TC level were in compliance with the categories reported in the original studies. LIMITATIONS: A major limitation of our study is the potential heterogeneity in most of the analyses. In addition, the suicidal behaviour was examined using different scales or methods across studies, which may further explain heterogeneity among the studies. CONCLUSION: We identified an inverse association between serum lipid levels and suicidality. More mechanistic studies are needed to further explain this association. PMID- 26505146 TI - [Long term results of patients implanted with CRT-D: Results of a monocentric study]. AB - Implantable cardiac defibrillators and resynchronization devices (CRT-D) are frequently used for heart failure patients. This is a retrospective study which included 50 patients with a CRT-D. The objective was to evaluate the prevalence of cardiac events (death, hospitalization for acute heart failure, ventricular arrhythmias). During 30-month follow-up, 4 patients (8%) died, 10 patients were hospitalized for acute decompensated heart failure (20%) and 5 patients (10%) presented an appropriate choc for a ventricular arrhythmia. In total, 19 patients presented at least one cardiac event (38%). An improvement in dyspnea was reported in 84% of patients. An improvement of left ventricular ejection fraction (LVEF) was reported in 74% of patients and 12% of them have normalized LVEF. In this study, the majority of patients implanted with a CRT-D presented an improvement of their symptoms. However, residual cardiac events were reported and remain unpredictable. PMID- 26505147 TI - Endovascular repair of delayed giant iliac pseudoaneurysm following simultaneous pancreas-kidney transplantation with preserved allografts function. AB - We present a case of endovascular repair of a giant iliac artery pseudoaneurysm following simultaneous pancreas-kidney transplantation. A 64-year-old female presented to the emergency room with right flank pain 10 months after kidney and pancreas transplantation on the right iliac axis. Investigations revealed a 9.5 cm pseudoaneurysm originating from the anastomosis between the graft renal artery and the external iliac artery. The pseudoaneurysm was successfully excluded emergently with a covered stent graft preserving the normal perfusion and function of both transplanted organs. Endovascular repair may be a good and low invasive option in selected patients with transplant renal artery pseudoaneurysm. PMID- 26505148 TI - Optimised transdermal delivery of pravastatin. AB - Wiechers' programme "Formulating for Efficacy" initiated a new strategy to optimise the oil phase of topical formulations in order to achieve optimal transdermal drug delivery. This new approach uses the "Delivery Gap Theory" on any active pharmaceutical ingredients (APIs) to test if it could enhance transdermal drug delivery. The aim of the study was to formulate six different semi-solid formulations (three creams and three emulgels) with 2% pravastatin as the API in order to investigate the "Delivery Gap Principle", by determining which formulation would deliver pravastatin best to the target-site (system circulation). The three cream- and three emulgel formulations had different polarities, i.e. a formulation with polarity equal to that of the stratum corneum (optimised), a non-polar (lipophilic)- and a polar (hydrophilic)-formulation. Franz cell diffusion studies were executed over 12h and the optimised emulgel (2.578MUg/cm(2)) had the highest median amount per area obtained. Tape stripping followed the diffusion studies and in the stratum corneum-epidermis, the hydrophilic emulgel (1.448MUg/ml) contained the highest median pravastatin concentration and the epidermis-dermis the optimised emulgel (0.849MUg/ml) depicted the highest pravastatin concentration. During this study, it was observed that when both emulgel and cream formulations were compared; the emulgels enhanced the delivery of pravastatin more than the creams. PMID- 26505149 TI - Characterization of smart auto-degradative hydrogel matrix containing alginate lyase to enhance levofloxacin delivery against bacterial biofilms. AB - The aim of the present work is the characterization of smart auto-degradable microspheres composed of calcium alginate/high methoxylated pectin containing an alginate lyase (AL) from Sphingobacterium multivorum and levofloxacin. Microspheres were prepared by ionotropic gelation containing AL in its inactive form at pH 4.0. Incubation of microspheres in Tris-HCl and PBS buffers at pH 7.40 allowed to establish the effect of ion-chelating phosphate on matrix erodability and suggested an intrinsically activation of AL by turning the pH close to neutrality. Scanning electron and optical microscopies revealed the presence of holes and surface changes in AL containing microspheres. Furthermore, texturometric parameters, DSC profiles and swelling properties were showing strong changes in microspheres properties. Encapsulation of levofloxacin into microspheres containing AL showed 70% efficiency and 35% enhancement of antimicrobial activity against Pseudomonas aeruginosa biofilm. Levofloxacin release from microspheres was not changed at acidic pH, but was modified at neutral pH in presence of AL. Advantageously, only gel matrix debris were detectable after overnight incubation, indicating an autodegradative gel process activated by the pH. Absence of matrix cytotoxicity and a reduction of the levofloxacin toxicity after encapsulation were observed in mammalian CHO-K1 cell cultures. These properties make the system a potent and versatile tool for antibiotic oral delivery targeted to intestine, enhancing the drug bioavailability to eradicate bacterial biofilm and avoiding possible intestinal obstructions. PMID- 26505150 TI - Anodal sensory nerve action potentials: From physiological understanding to potential clinical applicability. AB - INTRODUCTION: Low-intensity electrical stimuli of digital nerves may generate a double peak potential (DPp), composed of a cathodal (caAP) and an anodal (anAP) potential in orthodromic recordings. METHODS: We studied the effects on caAP and anAP of stimuli of variable intensity, duration, and frequency. We also applied a conditioning stimulus to study potential differences in recovery time. RESULTS: The anAP was obtained in 33 of 40 healthy subjects (82.5%) and 4 of 20 patients with various types of sensory neuropathies (20%). Changes in stimulus duration and intensity had reciprocal effects on the amplitude of the anAP and the caAP. There were significant differences in recovery time between caAP and anAP after a conditioning stimulus. CONCLUSION: The caAP and anAP are 2 interdependent waveforms generated by different effects of the same stimulus over axons at the verge of depolarization. Muscle Nerve 53: 897-905, 2016. PMID- 26505151 TI - Pulmonary Delivery of Proteins Using Nanocomposite Microcarriers. AB - In this study, Taguchi design was used to determine optimal parameters for the preparation of bovine serum albumin (BSA)-loaded nanoparticles (NPs) using a biodegradable polymer poly(glycerol adipate-co-omega-pentadecalactone) (PGA-co PDL). NPs were prepared, using BSA as a model protein, by the double emulsion evaporation process followed by spray-drying from leucine to form nanocomposite microparticles (NCMPs). The effect of various parameters on NP size and BSA loading were investigated and dendritic cell (DC) uptake and toxicity. NCMPs were examined for their morphology, yield, aerosolisation, in vitro release behaviour and BSA structure. NP size was mainly affected by the polymer mass used and a small particle size <=500 nm was achieved. High BSA (43.67 +/- 2.3 MUg/mg) loading was influenced by BSA concentration. The spray-drying process produced NCMPs (50% yield) with a porous corrugated surface, aerodynamic diameter 1.46 +/- 141 MUm, fine particle dose 45.0 +/- 4.7 MUg and fine particle fraction 78.57 +/- 0.1%, and a cumulative BSA release of 38.77 +/- 3.0% after 48 h. The primary and secondary structures were maintained as shown by sodium dodecyl sulphate poly (acrylamide) gel electrophoresis and circular dichroism. Effective uptake of NPs was seen in DCs with >85% cell viability at 5 mg/mL concentration after 4 h. These results indicate the optimal process parameters for the preparation of protein-loaded PGA-co-PDL NCMPs suitable for inhalation. PMID- 26505152 TI - The hypolipidemic effect and antithrombotic activity of Mucuna pruriens protein hydrolysates. AB - Hydrolysates and peptide fractions (PF) obtained from M. pruriens protein concentrates with commercial and digestive enzymatic systems were studied for their hypolipidemic and antithrombotic activities. Hydrolysates obtained with Pepsin-Pancreatin (PP) and their peptide fractions inhibited cholesterol micellar solubility with a maximum value of 1.83% in PP. Wistar rats were used to evaluate the hypolipidemic effect of hydrolysates and PF. The higher reductions of cholesterol and triglyceride levels were exhibited by PP and both peptide fractions <1 kDa obtained from PP and Alcalase(r)-Flavourzyme(r) hydrolysate (AF) at a dose of 15 mg kg(-1) of animal weight. PF > 10 kDa from both hydrolysates showed the maximum antithrombotic activity with values of 33.33% for PF > 10 kDa from AF and 31.72% for PF > 10 kDa from PP. The results suggest that M. pruriens bioactive peptides with the hypolipidemic effect and antithrombotic activity might be utilized as nutraceuticals. PMID- 26505153 TI - Advanced Use of Electronic Health Records: The Depth of Nursing Notes. PMID- 26505154 TI - Effects of Defecation Strain at Various Bed Reclining Angles on Intrarectal Pressure and Cardiovascular Responses. AB - BACKGROUND: There is no clear information about the optimal bed reclining angle for promoting efficient and safe defecation in bedfast patients. OBJECTIVE: The aim of this study was to examine the optimal bed reclining angle for facilitating increases in intrarectal pressure without causing marked cardiovascular changes in order to develop an efficient and safe defecation position for bedfast patients. METHODS: Twelve healthy men participated in this study. The subjects were required to strain for 15 seconds at the end stage of inspiration while their bed was reclined at 0 degrees (supine), 15 degrees , 30 degrees , or 60 degrees . During straining, the subjects were asked to maintain (a) an intrarectal pressure of 20 mm Hg or (b) the maximal intrarectal pressure. Intrarectal pressure, blood pressure, heart rate, and abdominal muscle activity (electromyographic activity) were recorded continuously throughout the study period. RESULTS: During straining, intrarectal pressure increased with the reclining angle, and a significant linear correlation was detected between the sine of the reclining angle of the bed and intrarectal pressure (eta = .57, p < .01). When subjects were straining with the aim of maintaining maximal intrarectal pressure, the extent of the observed changes (delta) in blood pressure and heart rate did not differ significantly across the reclining angles. When subjects were straining with the aim of maintaining an intrarectal pressure of 20 mm Hg, the delta blood pressure decreased as the reclining angle increased 0 degrees : M = 23.7, SD = 15.3 mm Hg, 95% CI [11.9, 35.4]; 15 degrees : M = 25.9, SD = 10.8 mm Hg, 95% CI [17.6, 34.2]; 30 degrees : M = 17.7, SD = 9.4 mm Hg, 95% CI [10.4, 24.9]; 60 degrees : M = 15.5, SD = 9.5 mm Hg, 95% CI [8.1, 22.8]; 15 degrees versus 30 degrees : p < .05; 15 degrees versus 60 degrees : p < .05. The amount of muscle activity observed during straining decreased as the reclining angle increased. DISCUSSION: In bedfast patients, it is suggested that higher reclining angles may enable safer and more efficient defecation, because it decreases the amount of muscle activity required to increase the intrarectal pressure and reduces the potentially deleterious effects of straining on the cardiovascular system to develop an efficient and safe defecation position for bedfast patients. PMID- 26505155 TI - Future Expectations, Attitude Toward Violence, and Bullying Perpetration During Early Adolescence: A Mediation Evaluation. AB - BACKGROUND: Hopeful future expectations have been linked to positive developmental outcomes in adolescence; however, the association between future expectations and bullying perpetration has received less attention. OBJECTIVES: We examined the relationship between future expectations and physical and relational bullying perpetration and tested a mediation model that linked future expectations with bullying through attitude toward violence. METHODS: Structural equation modeling was used to examine the relationship between future expectations and bullying perpetration (relational and physical) and to test whether these relationships were mediated by attitude toward violence in a sample of U.S. seventh-grade students (Mage = 12.86 years, N = 196, 60% female, 46% African American). RESULTS: Attitude toward violence fully mediated the relationship between future expectations and physical bullying (indirect effects = -0.08, 95% CI [-0.15, -0.01], R = .17). The relationship between future expectations and relational bullying was partially mediated by attitudes toward violence (indirect effects = -0.07, 95% CI [-0.14, -0.002], R = .20). DISCUSSION: Our findings suggest that future expectations can play a role in reducing attitude toward violence and physical and relational bullying perpetration among youth. Interventions that help support the development of future goals and aspirations could play a vital role in bullying prevention efforts. PMID- 26505156 TI - Biopsychosocial Contributors to Metabolic Syndrome: A Secondary Analysis of 2007 2010 National Health and Nutrition Examination Survey Data. AB - BACKGROUND: Metabolic syndrome (MetS) is a medical disorder that encompasses obesity, hypertension, dyslipidemia, and insulin resistance and increases the risk of type 2 diabetes, cardiovascular disease, and mortality. OBJECTIVES: A secondary data analysis was conducted using the National Health and Nutrition Examination Survey 2007-2010 data to evaluate the association of biopsychosocial factors with MetS among U.S. adults. METHODS: Complex samples logistic regression models were used to estimate a parsimonious model, including contributions of biomedical, biosocial, and psychosocial factors to MetS. RESULTS: According to the study's representative sample, more than 47 million Americans had MetS. Using the biopsychosocial model, the effects of biosocial and psychosocial variables, including education, smoking, low exercise, and depression, were independent predictors of MetS after controlling for the contributions of age, gender, and race. DISCUSSION: There is a need for large-scale, longitudinal, and interventional studies to evaluate and alter these potential risk factors, thus reducing MetS. PMID- 26505157 TI - Family Typology and Appraisal of Preschoolers' Behavior by Female Caregivers. AB - BACKGROUND: Children with vulnerable caregivers may be at risk for being labeled as having behavior problems when typical behaviors are viewed by their caregivers as problematic, and therefore, research examining the accuracy of the caregivers' perceptions of children's behaviors is needed. OBJECTIVE: The purpose of this study was to use the resiliency model of family stress, adjustment, and adaptation as the theoretical foundation to explore family factors associated with the primary female caregiver's appraisal of her child's behavior, the extent to which the primary female caregiver's appraisal of her child's behavior may be distorted, and the child's level of risk of having a behavioral problem. METHODS: A cross-sectional, correlational design was used. Data were collected from female caregivers of preschoolers (N = 117). Family factors, demographic characteristics, comfort in parenting, appraisal of behaviors, daily stress, parenting stress, depressive symptoms, social support, ratings of children's behaviors, and distortion in the ratings were measured. Associations were studied using ANOVA, ANCOVA, and chi-squared tests. RESULTS: Family typology was not associated with the female caregiver's appraisals of her child's behavior (p = .31). Distortion of the caregiver's rating of her child's behavior was not associated with family hardiness (high or low; p = .20.) but was associated with having a child with an elevated risk for behavioral problems (p < .01). Families classified as vulnerable were significantly more likely to have a child with elevated risks of having behavioral problems than families classified as secure or regenerative. DISCUSSION: Findings emphasized the association between family factors (hardiness and coherence) and young children's behaviors. Additional research is needed into how these factors affect the young child's behavior and what causes a caregiver to have a distorted view of her child's behavior. PMID- 26505158 TI - Cervical Cancer, Human Papillomavirus, and Vaccination: Knowledge, Awareness, and Practices Among Turkish Hospital Nurses. AB - BACKGROUND: In cancer prevention programs, healthcare professionals are the main resource for ensuring community participation in cervical cancer screening as well as in enhancing individuals' knowledge and practices regarding cervical cancer, human papillomavirus (HPV), and HPV vaccines. AIM: This descriptive, cross-sectional study was conducted to determine Turkish hospital nurses' knowledge, awareness, and practices in relation to cervical cancer, HPV, and HPV vaccination. METHODS: This study was conducted from February 1 to March 30, 2013. A total of 464 nurses working in a university hospital located in the central Black Sea region in northern Turkey participated. RESULTS: Among participating nurses, 13.8% of the nurses underwent cervical cancer screening and 11.6% received Pap smear tests. Reasons for not engaging in cervical cancer screening included lack of sexual activity, not considering themselves to be at risk, and shame (28.2%, 18.3%, and 16.8%, respectively). None of the nurses had received the HPV vaccine; reasons included not having sufficient knowledge about the vaccine and a belief that the vaccine was not very common (57.3% and 20.7%, respectively). Nearly half (44%) stated that they would not recommend the HPV vaccine to their patients because they did not believe they had sufficient knowledge about it (56%). DISCUSSION: Knowledge about HPV infection and HPV vaccines and willingness to be vaccinated were very low among Turkish hospital nurses. Effective education strategies are needed to improve knowledge needed to support patients to receive effective cervical cancer screening and preventive services. PMID- 26505159 TI - Clinical Nursing and Midwifery Research Priorities in Eastern and Southern African Countries: Results From a Delphi Survey. AB - BACKGROUND: Because of the profound shortage of nurse and midwifery researchers in many African countries, identification of clinical nursing and midwifery research is of highest priority for the region to improve health outcomes. OBJECTIVES: The aim of this study was to gain consensus from experts on the priorities of clinical nursing and midwifery research in southern and eastern African countries. METHOD: A Delphi survey was conducted among experts in the region. Criteria for "expert" included (a) a professional nurse, (b) a bachelor's degree or higher in nursing, (c) published research, (d) affiliated with a school of nursing with at least a master's level nursing program, and/or (e) identified by the African core collaborators as an expert in the region. A list of candidates was identified through searches of published and gray literature and then vetted by core collaborators in Kenya, Malawi, and South Africa. Core collaborators held leadership roles in a nursing school and a doctoral degree in nursing, had conducted and published nursing research, and resided in an included country. RESULTS: Two rounds of the Delphi survey were required to reach consensus. In total, 40 participants completed both rounds, and at least one participant from each country completed both rounds; 73% and 85% response rates were achieved for each round, respectively. Critical clinical research priorities were infectious disease/infection control and midwifery/maternal health topics. These included subtopics such as HIV/AIDS, tuberculosis, maternal health and mortality, infant mortality, and obstetrical emergencies. Many other topics were ranked as important including patient outcomes, noncommunicable diseases, and rural health. DISCUSSION: Areas identified as research priorities were consistent with gaps identified in current literature. As evidenced by previous research, there is a lack of clinical nursing and midwifery research in these areas as well as nurses and midwives trained to conduct research; these priorities will help direct resources to the most essential research needs. PMID- 26505160 TI - Physical Activity in Latin American Immigrant Adults Living in Seville, Spain. AB - BACKGROUND: Self-rated health status of the Latin American immigrant population in Spain varies by gender, education and doing physical exercise. Physical activity patterns have not been described. OBJECTIVE: The aims are to describe self-reported physical activity in adult Latin American immigrants living in Seville (Spain) and explore relationships of physical activity with sociodemographic and health-related variables. METHOD: A representative sample of 190 immigrants between the ages of 25 and 44 years who live in Seville responded to the Centers for Disease Control's Behavioral Risk Factor Surveillance System (Spanish-language version) from May 2010 through May 2011. RESULTS: Physical activity (PA) was practiced by 66.8% during leisure time, 49.2% had a normal weight, and 20.5% were on a diet. The practice of PA was higher in women who had a normal weight, a good state of health and a higher education. Older age was associated with exercising during free time. DISCUSSION: Population-specific strategies are needed to improve the practice of PA among Latin American immigrants in Spain. Research focused on other emerging immigrant groups is needed. PMID- 26505162 TI - Notched environmental sounds: a new hearing aid-supported tinnitus treatment evaluated in 20 patients. PMID- 26505161 TI - Diabetes Learning in Virtual Environments: Testing the Efficacy of Self Management Training and Support in Virtual Environments (Randomized Controlled Trial Protocol). AB - BACKGROUND: Ongoing self-management improves outcomes for those with Type 2 diabetes (T2D); however, there are many barriers to patients receiving assistance in this from the healthcare system and peers. Findings from our pilot study showed that a virtual diabetes community on the Internet with real-time interaction among peers with T2D-and with healthcare professionals-is feasible and has the potential to influence clinical and psychosocial outcomes. OBJECTIVE: The purpose of this article is to present the protocol for the Diabetes Learning in Virtual Environments (LIVE) trial. PROTOCOL: Diabetes LIVE is a two-group, randomized controlled trial to compare effects of a virtual environment and traditional Web site on diet and physical activity. Our secondary aims will determine the effects on metabolic outcomes; effects of level of engagement and social network formation in LIVE on behavioral outcomes; potential mediating effects of changes in self-efficacy; and diabetes knowledge, diabetes-related distress, and social support on behavior change and metabolic outcomes. We will enroll 300 subjects at two sites (Duke University/Raleigh-Durham, NC and New York University/New York, NY) who have T2D and do not have serious complications or comorbidities. Those randomly assigned to the intervention group have access to the LIVE site where they can find information, synchronous classes with diabetes educators, and peer support to enhance self-management. Those in the control group have access to the same informational and educational content in a traditional asynchronous Web format. Measures of self-management, clinical outcomes, and psychosocial outcomes are assessed at baseline and 3, 6, 12, and 18 months. DISCUSSION: Should LIVE prove effective in improved self-management of diabetes, similar interventions could be applied to other prevalent chronic diseases. Innovative programs such as LIVE have potential for improving healthcare access in an easily disseminated alternative model of care that potentially improves the reach of self-management training and support. PMID- 26505164 TI - Elevated Expression of Hepatoma Up-Regulated Protein Inhibits gamma-Irradiation Induced Apoptosis of Prostate Cancer Cells. AB - Despite progression in diagnosis and treatment, prostate cancer (PCa) still represents the main cause of cancer-related mortality and morbidity in men. Although radiation therapy offers clinical benefit over other therapeutic modalities, the success of this therapeutic modality is commonly hampered by the resistance of advanced tumors. So far, the mechanisms governing tumor resistance to radiotherapy are not discussed in detail. Here, we demonstrate for the first time that the resistance of PCa to radiation therapy is attributed to elevated expression of Hepatoma Up-Regulated Protein (HURP). In PCa cells, the induction of HURP expression suppresses gamma-irradiation-induced apoptosis. gamma irradiation-induced apoptosis of PCa cells is associated with expression of E2F1, p53, p21 proteins together with the phosphorylation of apoptosis signal regulating kinase1 (ASK1), c-jun-N-terminal kinase (JNK) and Ataxia telangiectasia mutated (ATM) and histone family member X (H2AX). Whereas, the induction of HURP expression is able to suppress gamma-irradiation-induced effects on E2F1, p53, p21, ATM, ASK1, JNK and ATM, and H2AX. Also, inhibition of gamma-irradiation-induced- cytochrome c release, cleavage of caspase-9, caspase 3, PARP, and reactive oxygen species (ROS) were noted in PCa cells induced for HURP expression. The observed radio-resistance of PCa is thought to be the consequence of HURP-mediated destabilization of p53 and ATM proteins that are essential for the modulation of gamma-irradiation-induced apoptosis. Thus, based on our findings, PCa resistance to radiation therapy results from the deregulation of ASK1/ JNK; ATM/ H2AX; ATM/p53 and checkpoint kinase 2 (Chk2)/ E2F 1 in response to the elevated expression of HURP. PMID- 26505172 TI - Double-integrating-sphere system at the National Institute of Standards and Technology in support of measurement standards for the determination of optical properties of tissue-mimicking phantoms. AB - There is a need for a common reference point that will allow for the comparison of the optical properties of tissue-mimicking phantoms. After a brief review of the methods that have been used to measure the phantoms for a contextual backdrop to our approach, this paper reports on the establishment of a standardized double integrating-sphere platform to measure absorption and reduced scattering coefficients of tissue-mimicking biomedical phantoms. The platform implements a user-friendly graphical user interface in which variations of experimental configurations and model-based analysis are implemented to compute the coefficients based on a modified inverse adding-doubling algorithm allowing a complete uncertainty evaluation. Repeatability and validation of the measurement results of solid phantoms are demonstrated for three samples of different thicknesses, d = 5.08 mm, 7.09 mm, and 9.92 mm, with an absolute error estimate of 4.0% to 5.0% for the absorption coefficient and 11% to 12% for the reduced scattering coefficient (k = 2). The results are in accordance with those provided by the manufacturer. Measurements with different polarization angles of the incident light are also presented, and the resulting optical properties were determined to be equivalent within the estimated uncertainties. PMID- 26505171 TI - Scabrous overexpression in the eye affects R3/R4 cell fate specification and inhibits notch signaling. AB - BACKGROUND: Planar cell polarity (PCP) in the Drosophila eye is generated when immature ommatidial preclusters acquire opposite chirality in the dorsal and ventral halves of the eye imaginal disc and rotate 90 degrees toward the equator. The scabrous (sca) gene is involved in R8 differentiation and in the correct spacing of ommatidial clusters in eye imaginal discs, but it was also suggested to be required during ommatidial rotation. However, no clear relationships between sca and other genes involved in the process were established. RESULTS: To explore the role of Sca in PCP establishment, we performed an RNAi-based modifier genetic screen using the rough eye phenotype of sca-overexpressing flies. We found that sca overexpression mainly affects R3/R4 cell specification as it was reported in Notch mutants. Of the 86 modifiers identified in the screen, genes encoding components of Notch signaling and proteins involved in intracellular transport were of particular interest. CONCLUSIONS: These and other results obtained with a reporter line of Notch activity indicate that sca overexpression antagonizes Notch signaling in the Drosophila eye, and are inconsistent with Sca being an ommatidial rotation specific factor. We also found that microtubule motors and other proteins involved in intracellular transport are related with Sca function. PMID- 26505163 TI - Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability. AB - AIM: We aimed to assess the analgesic efficacy, pharmacokinetics, tolerability and safety of a single dose of Delta9-THC in patients with chronic abdominal pain resulting from chronic pancreatitis (CP). METHODS: This was a randomized, single dose, double-blinded, placebo-controlled, two way crossover study in patients suffering from abdominal pain as result of CP (n = 24), post hoc subdivided into opioid and non-opioid users. Delta9-THC (8 mg) or active placebo (5 mg/10 mg diazepam) was administered orally in a double dummy design. RESULTS: No treatment effect was shown for delta VAS pain scores after Delta9-THC compared with diazepam. Delta9-THC was well absorbed with a mean tmax of 123 min. No significant differences were found between Delta9-THC vs. diazepam for alertness, mood, calmness or balance. Feeling anxious and heart rate were significantly increased after Delta9-THC compared with diazepam. The most frequently reported adverse events (AEs) after Delta9-THC administration were somnolence, dry mouth, dizziness and euphoric mood. CONCLUSIONS: A single dose of Delta9-THC was not efficacious in reducing chronic pain resulting from CP, but was well tolerated with only mild or moderate AEs. The PK results in CP patients showed delayed absorption and an increased variability compared with healthy volunteers. PMID- 26505174 TI - GATA6 is overexpressed in breast cancer and promotes breast cancer cell epithelial-mesenchymal transition by upregulating slug expression. AB - Metastasis is the leading cause of death in breast cancer (BC) patients. However, until now, the mechanisms of BC metastasis remain elusive. GATA6 is a member of the GATA transcription factor family that plays critical regulatory roles in tissue development, which has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in BC remain unclear. Here we show that GATA6 is elevated in BC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of GATA6 was associated with decreased overall survival of BC patients. Overexpression of GATA6 in BC cells increased epithelial-mesenchymal transition. In contrast, silencing GATA6 in aggressive BC cells inhibited this process. Mechanistically, we found GATA6 exerts its function through active slug transcription. Slug knockdown blocked the GATA6-driven EMT. Furthermore, slug expression in human BC is positively correlated with GATA6 expression. Our results, for the first time, portray a pivotal role of GATA6 in regulating metastatic behaviors of BC cells, suggesting GATA6 is a potential therapeutic target in metastatic BCs. PMID- 26505173 TI - Red and processed meat, nitrite, and heme iron intakes and postmenopausal breast cancer risk in the NIH-AARP Diet and Health Study. AB - Previous studies have shown inconsistent associations between red and processed meat intake and breast cancer risk. N-nitroso compounds and heme iron have been hypothesized as contributing factors. We followed 193,742 postmenopausal women in the NIH-AARP Diet and Health Study and identified 9,305 incident breast cancers (1995-2006). Dietary intake was assessed using a food frequency questionnaire at baseline. We adjusted daily intakes of meat, nitrite and heme iron for energy intake using the nutrient density method. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) by quintiles of dietary exposures for all breast cancer, by stage (in-situ, localized, regional/distant) and by estrogen/progesterone receptor (ER/PR) status using Cox proportional hazards regression. Total red meat intake was positively associated with risk of regional/distant cancer (p-trend = 0.02). The risk was 25% higher in the highest vs. lowest intake quintile (95% CI = 1.03-1.52). Higher processed red meat intake (Q5 vs. Q1) was associated with 27% higher risk of localized breast cancer (95% CI = 1.01-1.27, p-trend = 0.03) and a 19% higher risk of regional/distant cancer (95% CI = 0.98-1.44, p-trend = 0.10). In addition, higher nitrite intake from processed red meat was positively associated with localized cancer (HR for Q5 vs. Q1 = 1.23, 95% CI = 1.09-1.39, p-trend < 0.0001). Heme iron intake was positively associated with breast cancer risk overall and all cancer stages (p-trend = 0.02 0.05). No heterogeneity was observed in risk associations by hormone receptor status. Our findings suggest that high consumption of red meat and processed meat may increase risk of postmenopausal breast cancer. Added nitrite and heme iron may partly contribute to these observed associations. PMID- 26505175 TI - Diffraction scattering computed tomography: a window into the structures of complex nanomaterials. AB - Modern functional nanomaterials and devices are increasingly composed of multiple phases arranged in three dimensions over several length scales. Therefore there is a pressing demand for improved methods for structural characterization of such complex materials. An excellent emerging technique that addresses this problem is diffraction/scattering computed tomography (DSCT). DSCT combines the merits of diffraction and/or small angle scattering with computed tomography to allow imaging the interior of materials based on the diffraction or small angle scattering signals. This allows, e.g., one to distinguish the distributions of polymorphs in complex mixtures. Here we review this technique and give examples of how it can shed light on modern nanoscale materials. PMID- 26505176 TI - Valproic acid stimulates proliferation of glial precursors during cortical gliogenesis in developing rat. AB - Valproic acid (VPA) is a neurotherapeutic drug prescribed for seizures, bipolar disorder, and migraine, including women of reproductive age. VPA is a well-known teratogen that produces congenital malformations in many organs including the nervous system, as well as later neurodevelopmental disorders, including mental retardation and autism. In developing brain, few studies have examined VPA effects on glial cells, particularly astrocytes. To investigate effects on primary glial precursors, we developed new cell culture and in vivo models using frontal cerebral cortex of postnatal day (P2) rat. In vitro, VPA exposure elicited dose-dependent, biphasic effects on DNA synthesis and proliferation. In vivo VPA (300 mg/kg) exposure from P2 to P4 increased both DNA synthesis and cell proliferation, affecting primarily astrocyte precursors, as >75% of mitotic cells expressed brain lipid-binding protein. Significantly, the consequence of early VPA exposure was increased astrocytes, as both S100-beta+ cells and glial fibrillary acidic protein were increased in adolescent brain. Molecularly, VPA served as an HDAC inhibitor in vitro and in vivo as enhanced proliferation was accompanied by increased histone acetylation, whereas it elicited changes in culture in cell-cycle regulators, including cyclin D1 and E, and cyclin-dependent kinase (CDK) inhibitors, p21 and p27. Collectively, these data suggest clinically relevant VPA exposures stimulate glial precursor proliferation, though at higher doses can elicit inhibition through differential regulation of CDK inhibitors. Because changes in glial cell functions are proposed as mechanisms contributing to neuropsychiatric disorders, these observations suggest that VPA teratogenic actions may be mediated through changes in astrocyte generation during development. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 780-798, 2016. PMID- 26505177 TI - An enhanced role for palliative care in the multidisciplinary approach to high risk head and neck cancer. PMID- 26505178 TI - [Aftercare in Psychosomatic Rehabilitation]. PMID- 26505179 TI - [Effectiveness of Telephone and Face-to-Face Aftercare Conversations following Inpatient Psychosomatic Rehabilitation]. AB - AIM OF THE STUDY: The effectiveness of 2 aftercare treatments was examined with regard to patients' implementation of health-enhancing recommendations and changes in psychological distress, as well as mental and physical health. METHODS: Psychosomatic patients were randomly assigned to an intervention group (aftercare over the telephone or face-to-face) or to a control group without aftercare (n=62) at the end of their treatment. Patients in the intervention group (n=139) were offered up to 4 aftercare conversations during the 3 months after their rehabilitation. Data were collected at admission (t1), at discharge (t2) as well as 3 (t3) and 9 (t4) months after discharge. Patients were asked whether they implemented health-enhancing recommendations, recorded in the discharge report, at t3 and t4. Psychological distress (SCL-90-R) was measured at t1, t2, t3 and t4, mental and physical health (SF-12) at t2, t3 and t4. RESULTS: In the intervention group, more participants implemented the recommendations made at discharge such as sports and exercises or outpatient psychotherapy as compared to the control group. Likewise, participants of the intervention group maintained better their physical health. Aftercare over the telephone and face-to-face did not differ in their effectiveness; however, less time was required for aftercare conversations over the telephone. CONCLUSIONS: Aftercare over the telephone seems to be an economical approach to support patients in implementing healthcare recommendations made at discharge after inpatient rehabilitation. PMID- 26505180 TI - [Application of the International Classification of Functioning, Disability and Health (ICF) in Psychosomatic Rehabilitation and Addiction Rehabilitation in Germany - The Current State]. AB - OBJECTIVE: The aim of this study was to gather information on the current state of the implementation of the International Classification of Functioning, Disability and Health (ICF) in psychosomatic and addiction rehabilitation. METHODS: In the summer of 2013, rehabilitation clinics in Germany were surveyed online on their ICF utilization. The questionnaire covered scope and purpose of ICF use, application of ICF core sets and assessments as well as barriers to the use of ICF. RESULTS: Of 359 clinics invited, 104 (30%) participated in the survey. Of those surveyed, 60 (61.9%) claimed to have taken measures to implement the ICF in their clinic; only 37 (38.5%), however, reported using the ICF in their daily work. The main barriers identified were complexity of the ICF, time management issues and training deficits. CONCLUSION: Approaches to ICF use are not uniform. There is a need for training programs, and guidance from health care insurance providers could help towards uniform implementation of the ICF. PMID- 26505181 TI - [Preliminary Short-term Results of an All-day Outpatient Pulmonary Rehabilitation Program in an Acute Hospital on Patients with Mild to Very Severe COPD]. AB - INTRODUCTION: Positive effects of pulmonary rehabilitation on chronic obstructive pulmonary disease (COPD) are well known, and inpatient rehabilitation programs are the preferred modality in Germany. In this paper, we report on the recent results of a daily outpatient rehabilitation program offered at an acute hospital, the first of this kind in Germany. It is not known whether this kind of rehabilitation is an effective approach. METHODS: 32 consecutive COPD patients GOLD-stage II-IV, phenotype B-D (mean 64.5+/-21.9 years; 18 male, 14 female) completed a rehabilitation program of 19 (15-21) days conducted according to the recommendations of the National Accociation for Rehabilitation. In this prospective observational study, data (walking distance in the 6-MWD, BODE-Index, HADS-, BDI/TDI-, CAT-questionnaire) were collected at the beginning (T1) and at the end (T2) of the program and the results are presented in a pre- vs. post analysis. RESULTS: We found significant positive effects for most of the measured parameters, except for body plethysmography, diffusion capacity and blood gas. Especially the increase in the 6 min walking distance (6-MWD) was remarkable (T1: 485.78+/-158.24, T2: 527.97+/-146.75 m, p=0.0212). There were no adverse events or complications. All participants were able to complete the program properly. CONCLUSION: Most of the measured parameters in COPD patients with stage II or worse disease improved significantly during the comprehensive outpatient rehabilitation program. A limitation of this study is the small number of cases, and further conclusions can only be made after examining a larger sample. The setting of this rehabilitation program in an acute hospital seems to be meaningful in an organisational and structural sense. PMID- 26505182 TI - [Assessment of Work Engagement in Patients with Hematological Malignancies: Psychometric Properties of the German Version of the Utrecht Work Engagement Scale 9 (UWES-9)]. AB - OBJECTIVE: Our purpose was the psychometric evaluation of the German version of the Utrecht Work Engagement Scale-9 (UWES-9), a self-assessment tool measuring work-related resources consisting of 9 items. METHODS: Based on a sample of 179 patients with hematological malignancies in in-patient and rehabilitative oncological settings, we tested the dimensional structure by confirmatory and explorative factor analysis. We further evaluated reliability, item characteristics, and construct validity of the UWES-9. RESULTS: The confirmatory factor analysis showed acceptable fit for both a 1-dimensional factor structure and the original 3-factor model. Based on an explorative principal component analysis, we were able to replicate the 1-dimensional factor accounting for 67% of the total variance and showing very high internal consistency (alpha=0.94) and high factor loads (0.73-0.88). The construct validity was further supported by significant positive correlations between work engagement and meaning of work, corporate feeling, commitment to the workplace, and job satisfaction. CONCLUSION: The German version of the UWES-9 shows good psychometric qualities in measuring dedication to work in patients with hematological malignancies in in-patient and rehabilitative oncological settings. PMID- 26505183 TI - [Collaborative Goal Setting in Rehabilitation (ParZivar II): Evaluation of an Intervention in Patients with Chronic Back Pain]. AB - OBJECTIVE: The "ParZivar II" project had 2 aims: optimization of the "ParZivar I" intervention by individual coaching of physicians, and evaluation of the optimized intervention. METHODS: The intervention was evaluated in a sequential control group design in 4 rehabilitation facilities with 3 measurement points. A total of n=279 patients with chronic low back pain participated in the study. RESULTS: The optimized intervention shows the potential to statistically significantly improve proximal outcomes (e. g. goal-centric processes or patient physician interaction). Regarding distal outcomes, no statistically significant differences were found. CONCLUSION: The "ParZivar" intervention is a suitable approach to increase participative goal setting. Due to the complexity of the intervention, problems of dissemination and the potential for improvement in study design, there is a need for further research. PMID- 26505184 TI - [The Impact of 2 Interventions on Implementation Fidelity of a Standardized Back School Program in Inpatient Orthopedic Rehabilitation Facilities]. AB - STUDY OBJECTIVE: Evaluation of the effectiveness of 2 implementation interventions - train-the-trainer workshops (TTT) and written implementation guideline (GL) - in terms of implementation fidelity of a back-training school within inpatient orthopedic rehabilitation. METHODS: An implementation trial was conducted using a mixed-methods approach for outcome evaluation in 10 rehabilitation clinics randomly assigned to the interventions. Data were assessed by questionnaires and observation forms. RESULTS: Trainers in the TTT condition, as compared to trainers in the GL condition, rated both their patient-oriented back school practice (d=1.37) and achievement of manual-based educational goals (W=0.18) significantly higher. Patients in the TTT condition showed significantly higher treatment satisfaction compared to patients in the GL condition (d=0.44). There were no significant group effects regarding the observed fidelity. CONCLUSIONS: An interactive TTT showed several benefits with regard to subjective outcomes compared to a written guideline. PMID- 26505185 TI - [(Neuro)psychological Rehabilitation after Stroke: a National Survey of Structures and Practice in Inpatient and Outpatient Neurological Rehabilitation]. AB - STUDY OBJECTIVE: Structures and practice of psychological units in neurological rehabilitation centres treating post-stroke patients are described. METHODS: A nationwide survey of psychological services in neurological rehabilitation centres was conducted. RESULTS: Psychologist-patient ratios differed greatly among rehabilitation centres. Post-stroke patients showed a variety of complex problems. Psychological interventions mainly comprised diagnostic evaluation as well as individual interventions and cognitive training. CONCLUSION: The complex and manifold problems of patients in neurological rehabilitation require a comprehensive knowledge of (neuro)psychological functioning. In order to support appropriate and individual treatment decisions, practice guidelines for psychological interventions in the rehabilitation of post-stroke patients are necessary. The present survey constitutes the basis for developing such practice guidelines. PMID- 26505186 TI - [Multidrug-Resistant Organisms (MDRO) in Rehabilitation Clinics in the Rhine-Main District, Germany, 2014: Prevalence and Risk Factors]. AB - BACKGROUND: While a limited number of studies have investigated the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in medical rehabilitation institutions, almost no data on the colonization of rehabilitation patients with multiresistant gram-negative rods is available. Here we report on a large multicenter study on the prevalence of MRSA and multiresistant pathogens in rehabilitation institutions in the Rhine-Main area in 2014. MATERIALS AND METHODS: Altogether, 21 rehabilitation hospitals participated. For all patients, age, gender, previous history of hospitalizations, surgery, previous colonization with multidrug-resistant organisms, use of a medical device, current antimicrobial therapy, and the current infection status were ascertained. On voluntary basis, nare and throat swabs were taken for analysis of MRSA and rectal swabs were tested for extended spectrum betalactamase-producing gram-negative bacteria (ESBL). RESULTS: 50% of 2 440 patients had a history of hospitalization within the previous 6 months while 39% had undergone surgery during the past 30 days. Approximately a quarter of the patients had been transferred to a rehabilitation hospital directly from an acute care hospital, had been under antimicrobial therapy with the past three months, or had travelled to a foreign country within the previous year. Risk factors such as lesions of the intact skin or presence of medical devices were rarely reported (< 5%) within the exception of patients undergoing geriatric or neurologic acute care rehabilitation. 0.7% (15/2155) of the patients were colonized with MRSA, while 7.7% (110/1434) showed a positive result for ESBL. The highest prevalence rates for multiresistant organisms were encountered among patients with neurologic rehabilitation (MRSA, 1.3%, and ESBL, 10.2%) or with geriatric rehabilitation (MRSA, 9.4%, and ESBL, 22.7%). CONCLUSION: In the rehabilitation patient population, the prevalence rates of MRSA and ESBL were found to be in the range of rates encountered in the general population (reported rates for MRSA, 0.5%, and ESBL, 6.3%). The known risk factors for MRSA such as skin lesions, medical devices and previous history for MRSA were also confirmed among this patient population. Direct transfer from an acute care hospital, antimicrobial treatment during the past 3 months, and wounds proved significant risk factors for ESBL colonization. Patients of neurologic rehabilitation and geriatric patients showed the highest rates of risk factors and the highest prevalence rates of multidrug-resistant organisms. It appears to be of importance for rehabilitation hospitals to be geared to the needs of patients with multidrug-resistant organisms, and prevent the transmission of these pathogens by appropriate hygiene measures. PMID- 26505187 TI - [The User Survey on the Revision of the Classification of Therapeutic Procedures]. AB - INTRODUCTION: An extensive user survey was conducted in the context of updating the Classification of Therapeutic Procedures (KTL 2015). This paper reflects the results of the user survey and raises critical discussion points. METHODS: The user survey was sent to all rehabilitation centers contracted by the German pension insurance as well as professional associations. The user survey was available both as a paper questionnaire and as an online version. The feedback of the user survey provided an important basis for the revision of the KTL. RESULT: The survey yielded 1,868 suggestions from 360 users. Most of them related to chapters E ("occupational therapy, work therapy, other functional therapy") and C ("information, motivation, training"). The change from German diplomas to the international Bachelor's and Master's degrees, and the inclusion of diagnostic and work-related procedures were the main focus of the user feedback. CONCLUSION: For the revision of the KTL, the user survey provided valuable information. Only by the inclusion of practitioners can the KTL meet the requirements of realistic and comprehensive acquisition of data on therapeutic procedures also in future. PMID- 26505188 TI - [Not Available]. PMID- 26505189 TI - Causes of Death Data in the Global Burden of Disease Estimates for Ischemic and Hemorrhagic Stroke. AB - BACKGROUND: Stroke mortality estimates in the Global Burden of Disease (GBD) study are based on routine mortality statistics and redistribution of ill-defined codes that cannot be a cause of death, the so-called 'garbage codes' (GCs). This study describes the contribution of these codes to stroke mortality estimates. METHODS: All available mortality data were compiled and non-specific cause codes were redistributed based on literature review and statistical methods. Ill defined codes were redistributed to their specific cause of disease by age, sex, country and year. The reassignment was done based on the International Classification of Diseases and the pathology behind each code by checking multiple causes of death and literature review. RESULTS: Unspecified stroke and primary and secondary hypertension are leading contributing 'GCs' to stroke mortality estimates for hemorrhagic stroke (HS) and ischemic stroke (IS). There were marked differences in the fraction of death assigned to IS and HS for unspecified stroke and hypertension between GBD regions and between age groups. CONCLUSIONS: A large proportion of stroke fatalities are derived from the redistribution of 'unspecified stroke' and 'hypertension' with marked regional differences. Future advancements in stroke certification, data collections and statistical analyses may improve the estimation of the global stroke burden. PMID- 26505190 TI - Peptides Interfering 3A Protein Dimerization Decrease FMDV Multiplication. AB - Nonstructural protein 3A is involved in relevant functions in foot-and-mouth disease virus (FMDV) replication. FMDV 3A can form homodimers and preservation of the two hydrophobic alpha-helices (alpha1 and alpha2) that stabilize the dimer interface is essential for virus replication. In this work, small peptides mimicking residues involved in the dimer interface were used to interfere with dimerization and thus gain insight on its biological function. The dimer interface peptides alpha1, alpha2 and that spanning the two hydrophobic alpha helices, alpha12, impaired in vitro dimer formation of a peptide containing the two alpha-helices, this effect being higher with peptide alpha12. To assess the effect of dimer inhibition in cultured cells, the interfering peptides were N terminally fused to a heptaarginine (R7) sequence to favor their intracellular translocation. Thus, when fused to R7, interference peptides (100 MUM) were able to inhibit dimerization of transiently expressed 3A, the higher inhibitions being found with peptides alpha1 and alpha12. The 3A dimerization impairment exerted by the peptides correlated with significant, specific reductions in the viral yield recovered from peptide-treated FMDV infected cells. In this case, alpha2 was the only peptide producing significant reductions at concentrations lower than 100 MUM. Thus, dimer interface peptides constitute a tool to understand the structure function relationship of this viral protein and point to 3A dimerization as a potential antiviral target. PMID- 26505192 TI - Zebrafish Olfacto-Retinal Centrifugal Axon Projection and Distribution: Effects of Gonadotropin-Releasing Hormone and Dopaminergic Signaling. AB - The terminalis neurons (TNs) have been described in teleost species. In zebrafish, the TNs are located in the olfactory bulb. The TNs synthesize and release gonadotropin-releasing hormone (GnRH) as one of the major neurotransmitters. The TNs project axons to many brain areas, which include the neural retina. In the retina, the TN axons synapse with dopaminergic interplexiform cells (DA-IPCs) and retinal ganglion cells (RGCs). In this research, we examine the role of GnRH and dopaminergic signaling in TN axon projection to the retina using the transgenic zebrafish Tg(GnRH-3::GFP). While the TNs developed at 34 h postfertilization (hpf), the first TN axons were not detected in the retina until 48-50 hpf, when the first DA-IPCs were differentiated. In developing embryos, inhibition of retinal GnRH signaling pathways severely interrupted the projection of TN axons to the retina. However, inhibition of retinal dopaminergic signaling produced little effect on TN axon projection. In adult retinas, inactivation of GnRH receptors disrupted the patterns of TN axon distribution, and depletion of DA-IPCs abolished the TN axons. When DA-IPCs regenerated, the TN axons reappeared. Together, the data suggest that in developing zebrafish retinas GnRH signaling is required for TN axon projection, whereas in adult retinas activation of GnRH and dopaminergic signaling transduction is required for normal distribution of the TN axons. PMID- 26505194 TI - Minding the Gap: Narrative Descriptions about Mental States Attenuate Parochial Empathy. AB - In three experiments, we examine parochial empathy (feeling more empathy for in group than out-group members) across novel group boundaries, and test whether we can mitigate parochial empathy with brief narrative descriptions. In the absence of individuating information, participants consistently report more empathy for members of their own assigned group than a competitive out-group. However, individualized descriptions of in-group and out-group targets significantly reduce parochial empathy by interfering with encoding of targets' group membership. Finally, the descriptions that most effectively decrease parochial empathy are those that describe targets' mental states. These results support the role of individuating information in ameliorating parochial empathy, suggest a mechanism for their action, and show that descriptions emphasizing targets' mental states are particularly effective. PMID- 26505191 TI - Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma. AB - PURPOSE: To determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice. METHODS: We produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by beta-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry. RESULTS: Losartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p < 0.0001). The lower RGC loss with losartan was significantly less than the loss with spironolactone or enalapril (regression model p = 0.001; drug treatment group term p = 0.01). Both losartan and enalapril significantly lowered blood pressure (p< 0.001), but losartan was protective, while enalapril led to worse than water-treated RGC loss. RGC loss after crush injury was unaffected by losartan treatment (difference from control p = 0.9). Survival of RGC in cell culture was not prolonged by sartan treatment. Axonal transport blockade after 3 day IOP elevations was less in losartan-treated than in control glaucoma eyes (p = 0.007). Losartan inhibited effects of glaucoma, including reduction in extracellular signal-related kinase activity and modification of glaucoma-related changes in scleral thickness and creep under controlled IOP. CONCLUSIONS: The neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head. PMID- 26505193 TI - The TrxG Complex Mediates Cytokine Induced De Novo Enhancer Formation in Islets. AB - To better understand how beta-cells respond to proinflammatory cytokines we mapped the locations of histone 3 lysine 4 monomethylation (H3K4me1), a post translational histone modification enriched at active and poised cis-regulatory regions, in IFNgamma, Il-1beta, and TNFalpha treated pancreatic islets. We identified 96,721 putative cis-regulatory loci, of which 3,590 were generated de novo, 3,204 had increased H3K4me1, and 5,354 had decreased H3K4me1 in IFNgamma, Il-1beta, and TNFalpha exposed islets. Roughly 10% of the de novo and increased regions were enriched for the repressive histone modification histone 3 lysine 27 trimethylation (H3K27me3) in untreated cells, and these were frequently associated with chemokine genes. We show that IFNgamma, Il-1beta, and TNFalpha exposure overcomes this repression and induces chemokine gene activation in as little as three hours, and that this expression persists for days in absence of continued IFNgamma, Il-1beta, and TNFalpha exposure. We implicate trithorax group (TrxG) complexes as likely players in the conversion of these repressed loci to an active state. To block the activity of these complexes, we suppressed Wdr5, a core component of the TrxG complexes, and used the H3K27me3 demethylase inhibitor GSK-J4. We show that GSK-J4 is particularly effective in blunting IFNgamma, Il 1beta, and TNFalpha-induced chemokine gene expression in beta-cells; however, it induced significant islet-cell apoptosis and beta-cell dysfunction. Wdr5 suppression also reduced IFNgamma, Il-1beta, and TNFalpha induced chemokine gene expression in beta-cells without affecting islet-cell survival or beta-cell function after 48hrs, but did begin to increase islet-cell apoptosis and beta cell dysfunction after four days of treatment. Taken together these data suggest that the TrxG complex is potentially a viable target for preventing cytokine induced chemokine gene expression in beta-cells. PMID- 26505195 TI - Characterization of Fast-Scan Cyclic Voltammetric Electrodes Using Paraffin as an Effective Sealant with In Vitro and In Vivo Applications. AB - Fast-scan cyclic voltammetry (FSCV) is a powerful technique for measuring sub second changes in neurotransmitter levels. A great time-limiting factor in the use of FSCV is the production of high-quality recording electrodes; common recording electrodes consist of cylindrical carbon fiber encased in borosilicate glass. When the borosilicate is heated and pulled, the molten glass ideally forms a tight seal around the carbon fiber cylinder. It is often difficult, however, to guarantee a perfect seal between the glass and carbon. Indeed, much of the time spent creating electrodes is in an effort to find a good seal. Even though epoxy resins can be useful in this regard, they are irreversible (seals are permanent), wasteful (epoxy cannot be reused once hardener is added), hazardous (hardeners are often caustic), and require curing. Herein we characterize paraffin as an electrode sealant for FSCV microelectrodes. Paraffin boasts the advantages of near-immediate curing times, simplicity in use, long shelf-life and stable waterproof seals capable of withstanding extended cycling. Borosilicate electrode tips were left intact or broken and dipped in paraffin embedding wax. Excess wax was removed from the carbon surface with xyelenes or by repeated cycling at an extended waveform (-0.4 to 1.4V, 400 V/s, 60 Hz). Then, the waveform was switched to a standard waveform (-0.4 to 1.3V, 400 V/s, 10 Hz) and cycled until stable. Wax-sealing does not inhibit electrode sensitivity, as electrodes detected linear changes in dopamine before and after wax (then xylenes) exposure. Paraffin seals are intact after 11 days of implantation in the mouse, and still capable of measuring transient changes in in vivo dopamine. From this it is clear that paraffin wax is an effective sealant for FSCV electrodes that provides a convenient substitute to epoxy sealants. PMID- 26505196 TI - Simple Modification of the Bladder Outlet Obstruction Index for Better Prediction of Endoscopically-Proven Prostatic Obstruction: A Preliminary Study. AB - PURPOSE: The bladder outlet obstruction index (BOOI), also known as the Abrams Griffiths (AG) number, is the most widely used index for predicting BOO. However, the obstructed prostatic urethra determined by the BOOI is often inconsistent with endoscopically-proven obstruction. We assessed abdominal straining pattern as a novel parameter for improving the prediction of BOO. MATERIALS AND METHODS: We retrospectively reviewed the pressure-flow studies (PFS) and cystourethroscopy in 176 BPH/LUTS patients who were unresponsive to medical therapy. During PFS, some groups of patients tried to urinate with abdominal straining, which can increases intravesical pressure and underestimate BOOI theoretically. Accordingly, the modified BOOI was defined as (PdetQmax+DeltaPabd)-2Qmax. RESULTS: Ultimately, 130 patients were eligible for the analysis. In PFS, DeltaPabd (PabdQmax-initial Pabd) was 11.81+/-13.04 cmH2O, and it was 0-9 cmH2O in 75 (57.7%), 10-19 cmH2O in 23 (17.7%) and >=20 cmH2O in 32 (24.6%) patients. An endoscopically obstructed prostatic urethra in 92 patients was correctly determined in 47 patients (51.1%) by the original BOOI versus 72 patients (78.3%) based on the modified BOOI. Meanwhile, an "unobstructed" urethra according to the original BOOI was present in 11 patients (12.0%), whereas according to the modified BOOI, only 2 (2.1%) would be labeled as "unobstructed". In receiver operating characteristic curves, the area under the curve was 0.906 using the modified BOOI number versus 0.849 in the original BOOI (p<0.05). CONCLUSIONS: The change in abdominal pressure was correlated with endoscopically-proven obstruction. Our simple modification of the BOOI on the basis of this finding better predicted bladder outlet obstruction and, therefore, should be considered when evaluating BOO in patients with LUTS/BPH. PMID- 26505198 TI - Spatio-Temporal Dynamics of Exploited Groundfish Species Assemblages Faced to Environmental and Fishing Forcings: Insights from the Mauritanian Exclusive Economic Zone. AB - Environmental changes and human activities can have strong impacts on biodiversity and ecosystem functioning. This study investigates how, from a quantitative point of view, simultaneously both environmental and anthropogenic factors affect species composition and abundance of exploited groundfish assemblages (i.e. target and non-target species) at large spatio-temporal scales. We aim to investigate (1) the spatial and annual stability of groundfish assemblages, (2) relationships between these assemblages and structuring factors in order to better explain the dynamic of the assemblages' structure. The Mauritanian Exclusive Economic Zone (MEEZ) is of particular interest as it embeds a productive ecosystem due to upwelling, producing abundant and diverse resources which constitute an attractive socio-economic development. We applied the multi variate and multi-table STATICO method on a data set consisting of 854 hauls collected during 14-years (1997-2010) from scientific trawl surveys (species abundance), logbooks of industrial fishery (fishing effort), sea surface temperature and chlorophyll a concentration as environmental variables. Our results showed that abiotic factors drove four main persistent fish assemblages. Overall, chlorophyll a concentration and sea surface temperature mainly influenced the structure of assemblages of coastal soft bottoms and those of the offshore near rocky bottoms where upwellings held. While highest levels of fishing effort were located in the northern permanent upwelling zone, effects of this variable on species composition and abundances of assemblages were relatively low, even if not negligible in some years and areas. The temporal trajectories between environmental and fishing conditions and assemblages did not match for all the entire time series analyzed in the MEEZ, but interestingly for some specific years and areas. The quantitative approach used in this work may provide to stakeholders, scientists and fishers a useful assessment for the spatio-temporal dynamics of exploited assemblages under stable or changing conditions in fishing and environment. PMID- 26505199 TI - Graphical Aids to the Estimation and Discrimination of Uncertain Numerical Data. AB - This research investigates the performance of graphical dot arrays designed to make discrimination of relative numerosity as effortless as possible at the same time as making absolute (quantitative) numerosity estimation as effortful as possible. Comparing regular, random, and hybrid (randomized regular) configurations of dots, the results indicate that both random and hybrid configurations reduce absolute numerosity estimation precision, when compared with regular dots arrays. However, discrimination of relative numerosity is significantly more accurate for hybrid dot arrays than for random dot arrays. Similarly, human subjects report significantly lower levels of subjective confidence in judgments when using hybrid dot configurations as compared with regular configurations; and significantly higher levels of subjective confidence as compared with random configurations. These results indicate that data graphics based on the hybrid, randomized-regular configurations of dots are well-suited to applications that require decisions to be based on numerical data in which the absolute quantities are less certain than the relative values. Examples of such applications include decision-making based on the outputs of empirically-based mathematical models, such as health-related policy decisions using data from predictive epidemiological models. PMID- 26505197 TI - Structural Refinement of Proteins by Restrained Molecular Dynamics Simulations with Non-interacting Molecular Fragments. AB - The knowledge of multiple conformational states is a prerequisite to understand the function of membrane transport proteins. Unfortunately, the determination of detailed atomic structures for all these functionally important conformational states with conventional high-resolution approaches is often difficult and unsuccessful. In some cases, biophysical and biochemical approaches can provide important complementary structural information that can be exploited with the help of advanced computational methods to derive structural models of specific conformational states. In particular, functional and spectroscopic measurements in combination with site-directed mutations constitute one important source of information to obtain these mixed-resolution structural models. A very common problem with this strategy, however, is the difficulty to simultaneously integrate all the information from multiple independent experiments involving different mutations or chemical labels to derive a unique structural model consistent with the data. To resolve this issue, a novel restrained molecular dynamics structural refinement method is developed to simultaneously incorporate multiple experimentally determined constraints (e.g., engineered metal bridges or spin-labels), each treated as an individual molecular fragment with all atomic details. The internal structure of each of the molecular fragments is treated realistically, while there is no interaction between different molecular fragments to avoid unphysical steric clashes. The information from all the molecular fragments is exploited simultaneously to constrain the backbone to refine a three-dimensional model of the conformational state of the protein. The method is illustrated by refining the structure of the voltage-sensing domain (VSD) of the Kv1.2 potassium channel in the resting state and by exploring the distance histograms between spin-labels attached to T4 lysozyme. The resulting VSD structures are in good agreement with the consensus model of the resting state VSD and the spin-spin distance histograms from ESR/DEER experiments on T4 lysozyme are accurately reproduced. PMID- 26505201 TI - Effects of Yoga on Heart Rate Variability and Mood in Women: A Randomized Controlled Trial. AB - OBJECTIVE: To examine the effects of an 8-week yoga program on heart rate variability and mood in generally healthy women. DESIGN: Randomized controlled trial. PARTICIPANTS: Fifty-two healthy women were randomly assigned to a yoga group or a control group. INTERVENTIONS: Participants in the yoga group completed an 8-week yoga program, which comprised a 60-minute session twice a week. Each session consisted of breathing exercises, yoga pose practice, and supine meditation/relaxation. The control group was instructed not to engage in any yoga practice and to maintain their usual level of physical activity during the study. OUTCOME MEASURES: Participants' heart rate variability, perceived stress, depressive symptoms, and state and trait anxiety were assessed at baseline (week 0) and after the intervention (week 9). RESULTS: No measures of heart rate variability changed significantly in either the yoga or control group after intervention. State anxiety was reduced significantly in the yoga group but not in the control group. No significant changes were noted in perceived stress, depression, or trait anxiety in either group. CONCLUSIONS: An 8-week yoga program was not sufficient to improve heart rate variability. However, such a program appears to be effective in reducing state anxiety in generally healthy women. Future research should involve longer periods of yoga training, include heart rate variability measures both at rest and during yoga practice, and enroll women with higher levels of stress and trait anxiety. PMID- 26505200 TI - Robust Selection Algorithm (RSA) for Multi-Omic Biomarker Discovery; Integration with Functional Network Analysis to Identify miRNA Regulated Pathways in Multiple Cancers. AB - MicroRNAs (miRNAs) play a crucial role in the maintenance of cellular homeostasis by regulating the expression of their target genes. As such, the dysregulation of miRNA expression has been frequently linked to cancer. With rapidly accumulating molecular data linked to patient outcome, the need for identification of robust multi-omic molecular markers is critical in order to provide clinical impact. While previous bioinformatic tools have been developed to identify potential biomarkers in cancer, these methods do not allow for rapid classification of oncogenes versus tumor suppressors taking into account robust differential expression, cutoffs, p-values and non-normality of the data. Here, we propose a methodology, Robust Selection Algorithm (RSA) that addresses these important problems in big data omics analysis. The robustness of the survival analysis is ensured by identification of optimal cutoff values of omics expression, strengthened by p-value computed through intensive random resampling taking into account any non-normality in the data and integration into multi-omic functional networks. Here we have analyzed pan-cancer miRNA patient data to identify functional pathways involved in cancer progression that are associated with selected miRNA identified by RSA. Our approach demonstrates the way in which existing survival analysis techniques can be integrated with a functional network analysis framework to efficiently identify promising biomarkers and novel therapeutic candidates across diseases. PMID- 26505202 TI - Efficacy of Electrocuting Devices to Catch Tsetse Flies (Glossinidae) and Other Diptera. AB - BACKGROUND: The behaviour of insect vectors has an important bearing on the epidemiology of the diseases they transmit, and on the opportunities for vector control. Two sorts of electrocuting device have been particularly useful for studying the behaviour of tsetse flies (Glossina spp), the vectors of the trypanosomes that cause sleeping sickness in humans and nagana in livestock. Such devices consist of grids on netting (E-net) to catch tsetse in flight, or on cloth (E-cloth) to catch alighting flies. Catches are most meaningful when the devices catch as many as possible of the flies potentially available to them, and when the proportion caught is known. There have been conflicting indications for the catching efficiency, depending on whether the assessments were made by the naked eye or assisted by video recordings. METHODOLOGY/PRINCIPAL FINDINGS: Using grids of 0.5m2 in Zimbabwe, we developed catch methods of studying the efficiency of E-nets and E-cloth for tsetse, using improved transformers to supply the grids with electrical pulses of ~40kV. At energies per pulse of 35-215mJ, the efficiency was enhanced by reducing the pulse interval from 3200 to 1ms. Efficiency was low at 35mJ per pulse, but there seemed no benefit of increasing the energy beyond 70mJ. Catches at E-nets declined when the fine netting normally used became either coarser or much finer, and increased when the grid frame was moved from 2.5cm to 27.5cm from the grid. Data for muscoids and tabanids were roughly comparable to those for tsetse. CONCLUSION/SIGNIFICANCE: The catch method of studying efficiency is useful for supplementing and extending video methods. Specifications are suggested for E-nets and E-cloth that are ~95% efficient and suitable for estimating the absolute numbers of available flies. Grids that are less efficient, but more economical, are recommended for studies of relative numbers available to various baits. PMID- 26505203 TI - Multi-scale Visualization of Molecular Architecture Using Real-Time Ambient Occlusion in Sculptor. AB - The modeling of large biomolecular assemblies relies on an efficient rendering of their hierarchical architecture across a wide range of spatial level of detail. We describe a paradigm shift currently under way in computer graphics towards the use of more realistic global illumination models, and we apply the so-called ambient occlusion approach to our open-source multi-scale modeling program, Sculptor. While there are many other higher quality global illumination approaches going all the way up to full GPU-accelerated ray tracing, they do not provide size-specificity of the features they shade. Ambient occlusion is an aspect of global lighting that offers great visual benefits and powerful user customization. By estimating how other molecular shape features affect the reception of light at some surface point, it effectively simulates indirect shadowing. This effect occurs between molecular surfaces that are close to each other, or in pockets such as protein or ligand binding sites. By adding ambient occlusion, large macromolecular systems look much more natural, and the perception of characteristic surface features is strongly enhanced. In this work, we present a real-time implementation of screen space ambient occlusion that delivers realistic cues about tunable spatial scale characteristics of macromolecular architecture. Heretofore, the visualization of large biomolecular systems, comprising e.g. hundreds of thousands of atoms or Mega-Dalton size electron microscopy maps, did not take into account the length scales of interest or the spatial resolution of the data. Our approach has been uniquely customized with shading that is tuned for pockets and cavities of a user-defined size, making it useful for visualizing molecular features at multiple scales of interest. This is a feature that none of the conventional ambient occlusion approaches provide. Actual Sculptor screen shots illustrate how our implementation supports the size-dependent rendering of molecular surface features. PMID- 26505205 TI - Ab Initio Studies of Calcium Carbonate Hydration. AB - Ab initio simulations of large hydrated calcium carbonate clusters are challenging due to the existence of multiple local energy minima. Extensive conformational searches around hydrated calcium carbonate clusters (CaCO3.nH2O for n = 1-18) were performed to find low-energy hydration structures using an efficient combination of Monte Carlo searches, density-functional tight binding (DFTB+) method, and density-functional theory (DFT) at the B3LYP level, or Moller Plesset perturbation theory at the MP2 level. This multilevel optimization yields several low-energy structures for hydrated calcium carbonate. Structural and energetics analysis of the hydration of these clusters revealed a first hydration shell composed of 12 water molecules. Bond-length and charge densities were also determined for different cluster sizes. The solvation of calcium carbonate in bulk water was investigated by placing the explicitly solvated CaCO3.nH2O clusters in a polarizable continuum model (PCM). The findings of this study provide new insights into the energetics and structure of hydrated calcium carbonate and contribute to the understanding of mechanisms where calcium carbonate formation or dissolution is of relevance. PMID- 26505204 TI - Radiological impact of surface water and sediment near uranium mining sites. AB - The aim of this study is to assess the radiological impact of surface water and sediment around uranium mining sites 20 years after their closing. The areas under observations are 31 former classical underground uranium mining and exploratory sites in Bulgaria, named as objects. The extraction and processing of uranium ores in the Republic of Bulgaria were ended in 1992. To assess the radiological impact of radionuclides field expeditions were performed to sample water and bottom sediment. The migration of uranium through surface water was examined as one of the major pathways for contamination spread. The range of uranium concentration in water flowing from the mining sites was from 0.012 to 6.8 mgU l(-1) with a geometric mean of 0.192 mgU l(-1). The uranium concentrations in water downstream the mining sites were approximately 3 times higher than the background value (upstream). The concentrations of Unat, (226)Ra, (210)Pb, and (232)Th in the sediment of downstream river were higher than those upstream by 3.4, 2.6, 2, and 1.7 times, respectively. The distribution coefficient of uranium reflects its high mobility in most of the sites. In order to evaluate the impact on people as well as site prioritization for more detailed assessment and water management, screening dose assessments were done. PMID- 26505206 TI - Flux of Total Mercury and Methylmercury to the Northern Gulf of Mexico from U.S. Estuaries. AB - To better understand the source of elevated methylmercury (MeHg) concentrations in Gulf of Mexico (GOM) fish, we quantified fluxes of total Hg and MeHg from 11 rivers in the southeastern United States, including the 10 largest rivers discharging to the GOM. Filtered water and suspended particles were collected across estuarine salinity gradients in Spring and Fall 2012 to estimate fluxes from rivers to estuaries and from estuaries to coastal waters. Fluxes of total Hg and MeHg from rivers to estuaries varied as much as 100-fold among rivers. The Mississippi River accounted for 59% of the total Hg flux and 49% of the fluvial MeHg flux into GOM estuaries. While some estuaries were sources of Hg, the combined estimated fluxes of total Hg (~5200 mol y(-1)) and MeHg (~120 mol y(-1)) from the estuaries to the GOM were less than those from rivers to estuaries, suggesting an overall estuarine sink. Fluxes of total Hg from the estuaries to coastal waters of the northern GOM are approximately an order of magnitude less than from atmospheric deposition. However, fluxes from rivers are significant sources of MeHg to estuaries and coastal regions of the northern GOM. PMID- 26505207 TI - Density Functional Theory and Electrochemical Studies: Structure-Efficiency Relationship on Corrosion Inhibition. AB - The relationship between structure and corrosion inhibition of a series of 30 imidazol, benzimidazol, and pyridine derivatives has been established through the investigation of quantum descriptors calculated with PBE/6-311++G**. A quantitative structure-property relationship model was obtained by examination of these descriptors using a genetic functional approximation method based on a multiple linear regression analysis. Our results indicate that the efficiency of corrosion inhibitors is strongly associated with aromaticity, electron donor ability, and molecular volume descriptors. In order to calibrate and validate the proposed model, we performed electrochemical impedance spectroscopy (EIS) studies on imidazole, 2-methylimidazole, benzimidazole, 2-chloromethylbenzimidazole, pyridine, and 2-aminopyridine compounds. The experimental values for efficiency of corrosion inhibition are in good agreement with the estimated values obtained by our model, thus confirming that our approach represents a promising and suitable tool to predict the inhibition of corrosion attributes of nitrogen containing heterocyclic compounds. The adsorption behavior of imidazole or benzimidazole heterocyclic molecules on the Fe(110) surface was also studied to elucidate the inhibition mechanism; the aromaticity played an important role in the adsorbate-surface complex. PMID- 26505208 TI - Ab Initio Simulations and Electronic Structure of Lithium-Doped Ionic Liquids: Structure, Transport, and Electrochemical Stability. AB - Density functional theory (DFT), density functional theory molecular dynamics (DFT-MD), and classical molecular dynamics using polarizable force fields (PFF MD) are employed to evaluate the influence of Li(+) on the structure, transport, and electrochemical stability of three potential ionic liquid electrolytes: N methyl-N-butylpyrrolidinium bis(trifluoromethanesulfonyl)imide ([pyr14][TFSI]), N methyl-N-propylpyrrolidinium bis(fluorosulfonyl)imide ([pyr13][FSI]), and 1-ethyl 3-methylimidazolium boron tetrafluoride ([EMIM][BF4]). We characterize the Li(+) solvation shell through DFT computations of [Li(Anion)n]((n-1)-) clusters, DFT-MD simulations of isolated Li(+) in small ionic liquid systems, and PFF-MD simulations with high Li-doping levels in large ionic liquid systems. At low levels of Li-salt doping, highly stable solvation shells having two to three anions are seen in both [pyr14][TFSI] and [pyr13][FSI], whereas solvation shells with four anions dominate in [EMIM][BF4]. At higher levels of doping, we find the formation of complex Li-network structures that increase the frequency of four anion-coordinated solvation shells. A comparison of computational and experimental Raman spectra for a wide range of [Li(Anion)n]((n-1)-) clusters shows that our proposed structures are consistent with experiment. We then compute the ion diffusion coefficients and find measures from small-cell DFT-MD simulations to be the correct order of magnitude, but influenced by small system size and short simulation length. Correcting for these errors with complementary PFF-MD simulations, we find DFT-MD measures to be in close agreement with experiment. Finally, we compute electrochemical windows from DFT computations on isolated ions, interacting cation/anion pairs, and liquid-phase systems with Li doping. For the molecular-level computations, we generally find the difference between ionization energy and electron affinity from isolated ions and interacting cation/anion pairs to provide upper and lower bounds, respectively, to experiment. In the liquid phase, we find the difference between the lowest unoccupied and highest occupied electronic levels in pure and hybrid functionals to provide lower and upper bounds, respectively, to experiment. Li-doping in the liquid-phase systems results in electrochemical windows little changed from the neat systems. PMID- 26505209 TI - Coassemblies of the Anionic Polypeptide gamma-PGA and Cationic beta-Sheet Peptides for Drug Delivery to Mitochondria. AB - The effectiveness of a drug may be highly dependent on its delivery to its target organ and even to specific intracellular organelles. In this study we developed nanoparticles (NPs) composed of the anionic polypeptide poly-gamma-glutamic acid (gamma-PGA), and a designed amphiphilic and cationic beta-sheet peptide (PFK), which tends to form fibril bilayer assemblies. These peptide assemblies generate hydrophobic niches within the NPs, which enhance the NPs' capacity to deliver amphiphilic drugs. NPs created by coassembly of gamma-PGA and PFK, and further coated with PFK, had a positive zeta-potential and were attracted to mitochondria. When applied to the human osteosarcoma cell line Saos2, the NP encapsulated lonidamin drug proved to be 300 times more cytotoxic than the free drug. PMID- 26505210 TI - Single-Cell Quantification of Cytosine Modifications by Hyperspectral Dark-Field Imaging. AB - Epigenetic modifications on DNA, especially on cytosine, play a critical role in regulating gene expression and genome stability. It is known that the levels of different cytosine derivatives are highly dynamic and are regulated by a variety of factors that act on the chromatin. Here we report an optical methodology based on hyperspectral dark-field imaging (HSDFI) using plasmonic nanoprobes to quantify the recently identified cytosine modifications on DNA in single cells. Gold (Au) and silver (Ag) nanoparticles (NPs) functionalized with specific antibodies were used as contrast-generating agents due to their strong local surface plasmon resonance (LSPR) properties. With this powerful platform we have revealed the spatial distribution and quantity of 5-carboxylcytosine (5caC) at the different stages in cell cycle and demonstrated that 5caC was a stably inherited epigenetic mark. We have also shown that the regional density of 5caC on a single chromosome can be mapped due to the spectral sensitivity of the nanoprobes in relation to the interparticle distance. Notably, HSDFI enables an efficient removal of the scattering noises from nonspecifically aggregated nanoprobes, to improve accuracy in the quantification of different cytosine modifications in single cells. Further, by separating the LSPR fingerprints of AuNPs and AgNPs, multiplex detection of two cytosine modifications was also performed. Our results demonstrate HSDFI as a versatile platform for spatial and spectroscopic characterization of plasmonic nanoprobe-labeled nuclear targets at the single-cell level for quantitative epigenetic screening. PMID- 26505211 TI - Switching the Regioselectivity of a Cyclohexanone Monooxygenase toward (+)-trans Dihydrocarvone by Rational Protein Design. AB - The regioselectivity of the Baeyer-Villiger monooxygenase-catalyzed oxidation is governed mostly by electronic effects leading to the migration of the higher substituted residue. However, in some cases, substrate binding occurs in a way that the less substituted residue lies in an antiperiplanar orientation to the peroxy bond in the Criegee intermediate yielding in the formation of the "abnormal" lactone product. We are the first to demonstrate a complete switch in the regioselectivity of the BVMO from Arthrobacter sp. (CHMOArthro) as exemplified for (+)-trans-dihydrocarvone by redesigning the active site of the enzyme. In the designed triple mutant, the substrate binds in an inverted orientation leading to a ratio of 99:1 in favor of the normal lactone instead of exclusive formation of the abnormal lactone in case of the wild type enzyme. In order to validate our computational study, the beneficial mutations were successfully transferred to the CHMO from Acinetobacter sp. (CHMOAcineto), again yielding in a complete switch of regioselectivity. PMID- 26505212 TI - Entropy Beacon: A Hairpin-Free DNA Amplification Strategy for Efficient Detection of Nucleic Acids. AB - Here, we propose an efficient strategy for enzyme- and hairpin-free nucleic acid detection called an entropy beacon (abbreviated as Ebeacon). Different from previously reported DNA hybridization/displacement-based strategies, Ebeacon is driven forward by increases in the entropy of the system, instead of free energy released from new base-pair formation. Ebeacon shows high sensitivity, with a detection limit of 5 pM target DNA in buffer and 50 pM in cellular homogenate. Ebeacon also benefits from the hairpin-free amplification strategy and zero background, excellent thermostability from 20 degrees C to 50 degrees C, as well as good resistance to complex environments. In particular, based on the huge difference between the breathing rate of a single base pair and two adjacent base pairs, Ebeacon also shows high selectivity toward base mutations, such as substitution, insertion, and deletion and, therefore, is an efficient nucleic acid detection method, comparable to most reported enzyme-free strategies. PMID- 26505213 TI - Overcoming Akt Induced Therapeutic Resistance in Breast Cancer through siRNA and Thymoquinone Encapsulated Multilamellar Gold Niosomes. AB - Akt overexpression in cancer causes resistance to traditional chemotherapeutics. Silencing Akt through siRNA provides new therapeutic options; however, poor in vivo siRNA pharmacokinetics impede translation. We demonstrate that acidic milieu sensitive multilamellar gold niosomes (Nio-Au) permit targeted delivery of both Akt-siRNA and thymoquinone (TQ) in tamoxifen-resistant and Akt-overexpressing MCF7 breast cancer cells. Octadecylamine groups of functionalized gold nanoparticles impart cationic attribute to niosomes, stabilized through polyethylene glycol. TQ's aqueous insolubility renders its encapsulation within hydrophobic core, and negatively charged siRNA binds in hydrophilic region of cationic niosomes. These niosomes were exploited to effectively knockdown Akt, thereby sensitizing cells to TQ. Immunoblot studies revealed enhanced apoptosis by inducing p53 and inhibiting MDM2 expression, which was consistent with in vivo xenograft studies. This innovative strategy, using Nio-Au to simultaneously deliver siRNA (devoid of any chemical modification) and therapeutic drug, provides an efficacious approach for treating therapy-resistant cancers with significant translational potential. PMID- 26505214 TI - Phytochemicals in Food and Nutrition. AB - The International Symposium on Phytochemicals in Medicine and Food (ISPMF2015) was held from June 26 to 29, 2015, in Shanghai, China. It is for the first time that a Phytochemical Society of Europe conference took place in China, which provided an opportunity for 270 scientists from 48 countries to communicate their up-to-date knowledge on phytochemicals. ISPMF2015 comprised exciting and various programs with 16 sessions, including 12 plenary lectures, 20 invited talks, 55 short oral presentations, and more than 130 posters. With the help of Prof. Fergus M. Clydesdale, a special issue of Critical Reviews in Food Science and Nutrition containing 11 reviews from scientists was presented in this conference. In this special issue, bioactive flavonoids and polysaccharides for human health received significant attention. PMID- 26505216 TI - Elite-adapted wheelchair sports performance: a systematic review. AB - PURPOSE: Elite-adapted sports performance has considerably improved over the last decades and winning or losing races at Paralympic Games is often a matter of a split second. In other words, every single detail counts, which underlines the necessity of optimizing training interventions and equipment for athletes in order to achieve top-class performance. However, to date, studies which include Paralympic elite athletes are scarce. METHODS: A comprehensive literature search was performed to identify potential strategies and interventions in order to optimize elite-adapted wheelchair sports performance, whereas the focus lay on respiratory muscle training (RMT), cooling (CI) and nutritional interventions (NI) as well as on individual equipment adaptations (IEA). RESULTS: The total number of studies identified for the final analysis was six for RMT, two for CI, three for NI and seven for IEA, respectively. Results point predominantly towards performance enhancing benefits for CI and IEA, whereas NI and RMT provided inhomogenous findings. CONCLUSIONS: In comparison to the able-bodied population, research in the field of Paralympic elite sport is scarce. CI and IEA seem to have significant performance enhancing benefits, whereas NI and RMT revealed controversial findings. However, due to the limited number of elite athletes with a spinal cord injury available to participate in scientific studies, general conclusions are difficult to make at this stage and in daily practice recommendations are still given mainly on an individual basis or based on personal experiences of coaches, athletes and scientists. Implications for Rehabilitaton Based on the knowledge gained in elite sports, wheelchair equipment could be optimized also for daily use. Elite sports performance could inspire wheelchair users to achieve their personal fitness goals. PMID- 26505215 TI - Rap1 induces cytokine production in pro-inflammatory macrophages through NFkappaB signaling and is highly expressed in human atherosclerotic lesions. AB - Repressor activator protein 1 (Rap1) is essential for maintaining telomere length and structural integrity, but it also exerts other non-telomeric functions. The present study tested the hypothesis that Rap1 is released into the cytoplasm and induces production of pro-inflammatory cytokines via nuclear factor kappa B (NFkappaB) signaling in macrophages, a cell type involved in the development and progression of atherosclerotic lesions. Western blotting analysis confirmed that Rap1 was present in the cytoplasm of differentiated human monocytic leukemia cells (THP-1, a macrophage-like cell line). Co-immunoprecipitation assay revealed a direct interaction between Rap1 and I kappa B kinase (IKK). Knockdown of Rap1 suppressed lipopolysaccharide-mediated activation of NFkappaB, and phosphorylation of inhibitor of kappa B alpha (IkappaBalpha) and p65 in THP-1 macrophages. The reduction of NFkappaB activity was paralleled by a decreased production of NFkappaB-dependent pro-inflammatory cytokines and an increased expression of IkappaBalpha (native NFkappaB inhibitor) in various macrophage models with pro-inflammatory phenotype, including THP-1, mouse peritoneal macrophages and bone marrow-derived M1 macrophages. These changes were observed selectively in pro-inflammatory macrophages but not in bone marrow-derived M2 macrophages (with an anti-inflammatory phenotype), mouse lung endothelial cells, human umbilical vein endothelial cells or human aortic smooth muscle cells. Immunostaining revealed that Rap1 was localized mainly in macrophage-rich areas in human atherosclerotic plaques and that the presence of Rap1 was positively correlated with the advancement of the disease process. In pro-inflammatory macrophages, Rap1 promotes cytokine production via NFkappaB activation favoring a pro-inflammatory environment which may contribute to the development and progression of atherosclerosis. PMID- 26505217 TI - Dysthyroid Orbitopathy Presenting with Gaze-Evoked Amaurosis: Case Report and Review of the Literature. AB - BACKGROUND: Gaze-evoked amaurosis (GEA) describes visual loss associated with eccentric gaze that recovers when the eye is returned to primary position. Here we describe an unusual case of bilateral GEA as the presenting feature of dysthyroid orbitopathy. This is only the third such case to be reported in the literature and the first to feature bilateral GEA in all positions of gaze without accompanying proptosis or ophthalmoplegia. CASE PRESENTATION: A 50-year old man who had recently commenced treatment for thyrotoxicosis presented with a 3-week history of typical GEA in both eyes in all positions of gaze. He subsequently developed a bilateral compressive optic neuropathy which was only partially responsive to high dose steroid therapy. CONCLUSION: Although an uncommon presenting feature of dysthyroid orbitopathy, GEA is an ominous symptom that may precede sight-threatening optic nerve compromise. When present, early immunosuppressive and/or decompressive treatment should be considered. PMID- 26505218 TI - Novel CARM1-Interacting Protein, DZIP3, Is a Transcriptional Coactivator of Estrogen Receptor-alpha. AB - Coactivator-associated arginine methyltransferase 1 (CARM1) is known to promote estrogen receptor (ER)alpha-mediated transcription in breast cancer cells. To further characterize the regulation of ERalpha-mediated transcription by CARM1, we screened CARM1-interacting proteins by yeast two-hybrid. Here, we have identified an E3 ubiquitin ligase, DAZ (deleted in azoospermia)-interacting protein 3 (DZIP3), as a novel CARM1-binding protein. DZIP3-dependent ubiquitination of histone H2A has been associated with repression of transcription. However, ERalpha reporter gene assays demonstrated that DZIP3 enhanced ERalpha-mediated transcription and cooperated synergistically with CARM1. Interaction with CARM1 was observed with the E3 ligase RING domain of DZIP3. The methyltransferase activity of CARM1 partially contributed to the synergy with DZIP3 for transcription activation, but the E3 ubiquitin ligase activity of DZIP3 was dispensable. DZIP3 also interacted with the C-terminal activation domain 2 of glucocorticoid receptor-interacting protein 1 (GRIP1) and enhanced the interaction between GRIP1 and CARM1. Depletion of DZIP3 by small interfering RNA in MCF7 cells reduced estradiol-induced gene expression of ERalpha target genes, GREB1 and pS2, and DZIP3 was recruited to the estrogen response elements of the same ERalpha target genes. These results indicate that DZIP3 is a novel coactivator of ERalpha target gene expression. PMID- 26505220 TI - Summary of Notifiable Noninfectious Conditions and Disease Outbreaks: Childhood Blood Lead Levels - United States, 2007-2012. PMID- 26505219 TI - FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of beta-Klotho. AB - The bile acid (BA)-sensing nuclear receptor, farnesoid X receptor (FXR), regulates postprandial metabolic responses, including inhibition of BA synthesis, by inducing the intestinal hormone, fibroblast growth factor (FGF)15 (FGF19 in human). In this study, we tested a novel hypothesis that FXR not only induces intestinal FGF15 but also primes the liver for effectively responding to the signal by transcriptional induction of the obligate coreceptor for FGF15, beta Klotho (betaKL). Activation of FXR by a synthetic agonist, GW4064, in mice increased occupancy of FXR and its DNA-binding partner, retinoid X receptor alpha, at FGF15-signaling component genes, particularly betaKL, and induced expression of these genes. Interestingly, mRNA levels of Fgfr4, the FGF15 receptor, were not increased by GW4064, but protein levels increased as a result of betaKL-dependent increased protein stability. Both FGF receptor 4 and betaKL protein levels were substantially decreased in FXR-knockout (KO) mice, and FGF19 signaling, monitored by phosphorylated ERK, was blunted in FXR-KO mice, FXR-KO mouse hepatocytes, and FXR-down-regulated human hepatocytes. Overexpression of betaKL in FXR-lacking hepatocytes partially restored FGF19 signaling and inhibition by FGF19 of Cyp7a1, which encodes the rate-limiting BA biosynthetic enzyme. In mice, transient inductions of intestinal Fgf15 and hepatic betaKL were temporally correlated after GW4064 treatment, and pretreatment of hepatocytes with GW4064 before FGF19 treatment enhanced FGF19 signaling, which was abolished by transcriptional inhibition or betaKL down-regulation. This study identifies FXR as a gut-liver metabolic coordinator for FGF15/19 action that orchestrates transient induction of hepatic betaKL and intestinal Fgf15/19 in a temporally correlated manner. PMID- 26505221 TI - MicroRNA-223 Is Upregulated in Active Tuberculosis Patients and Inhibits Apoptosis of Macrophages by Targeting FOXO3. AB - BACKGROUND: Macrophage apoptosis is a host innate defense mechanism against tuberculosis (TB). AIM: In this study, we aimed to investigate the role of microRNA-223 (miR-223) in macrophage apoptosis of TB. METHODS: We analyzed apoptosis in peripheral blood macrophages of active TB patients, infected human macrophages (TDMs and MDMs) with the Mycobacterium tuberculosis (Mtb) strain H37Rv, and observed the expression of miR-223 to investigate the relationship between miR-223 and macrophage apoptosis induced by Mtb. RESULTS: The apoptosis rate of peripheral blood macrophages decreased in active TB patients compared with healthy controls, and miR-223 expression increased significantly in macrophages after H37Rv infection. Transfection of human macrophages (TDMs and MDMs) with miR-223 inhibited macrophage apoptosis. We also demonstrated that miR 223 directly suppressed forkhead box O3 (FOXO3), and FOXO3 played a critical role as a mediator of the biological effects of miR-223 in macrophage apoptosis. The overexpression of FOXO3 remarkably reversed the apoptosis inhibitory effect of miR-223. CONCLUSION: Our data provide new clues for the essential role of miR-223 in the regulation of anti-Mtb-directed immune responses, which relies on the regulation of FOXO3 expression. PMID- 26505222 TI - Nanomaterial-based approaches for the detection and speciation of mercury. AB - Mercury is toxic with widespread contamination. Highly sensitive and selective approaches for mercury analysis are desired. Although conventional techniques are accurate and sensitive in the determination of mercury, these procedures are time consuming, labor-intensive and dependent heavily on expensive instrumentation. In recent years, nanomaterial-based approaches have been proved to be effective alternatives in the detection and speciation of mercury. In this review, the development of different nanomaterial-based approaches was summarized, as well as their utilization for the detection of mercury in environmental and biological samples, such as gold nanomaterials, carbon nanomaterials, quantum dots and so on. Moreover, the speciation of mercury using nanomaterials was also reviewed. PMID- 26505223 TI - Physical activity intensity can be accurately monitored by smartphone global positioning system 'app'. AB - Monitoring physical activity is important to better individualise health and fitness benefits. This study assessed the concurrent validity of a smartphone global positioning system (GPS) 'app' and a sport-specific GPS device with a similar sampling rate, to measure physical activity components of speed and distance, compared to a higher sampling sport-specific GPS device. Thirty-eight (21 female, 17 male) participants, mean age of 24.68, s = 6.46 years, completed two 2.400 km trials around an all-weather athletics track wearing GPSports ProTM (PRO), GPSports WiSpiTM (WISPI) and an iPhoneTM with a Motion X GPSTM 'app' (MOTIONX). Statistical agreement, assessed using t-tests and Bland-Altman plots, indicated an (mean; 95% LOA) underestimation of 2% for average speed (0.126 km.h( 1); -0.389 to 0.642; p < .001), 1.7% for maximal speed (0.442 km.h(-1); -2.676 to 3.561; p = .018) and 1.9% for distance (0.045 km; -0.140 to 0.232; p < .001) by MOTIONX compared to that measured by PRO. In contrast, compared to PRO, WISPI overestimated average speed (0.232 km.h(-1); -0.376 to 0.088; p < .001) and distance (0.083 km; -0.129 to -0.038; p < .001) by 3.5% whilst underestimating maximal speed by 2.5% (0.474 km.h(-1); -1.152 to 2.099; p < .001). Despite the statistically significant difference, the MOTIONX measures intensity of physical activity, with a similar error as WISPI, to an acceptable level for population based monitoring in unimpeded open-air environments. This presents a low-cost, minimal burden opportunity to remotely monitor physical activity participation to improve the prescription of exercise as medicine. PMID- 26505224 TI - Cyclotron Production of High-Specific Activity 55Co and In Vivo Evaluation of the Stability of 55Co Metal-Chelate-Peptide Complexes. AB - This work describes the production of high-specific activity 55Co and the evaluation of the stability of 55Co-metal-chelate-peptide complexes in vivo. 55Co was produced via the 58Ni(p,alpha)55Co reaction and purified using anion exchange chromatography with an average recovery of 92% and an average specific activity of 1.96 GBq/MUmol. 55Co-DO3A and 55Co-NO2A peptide complexes were radiolabeled at 3.7 MBq/MUg and injected into HCT-116 tumor xenografted mice. Positron emission tomography (PET) and biodistribution studies were performed at 24 and 48 hours postinjection and compared to those of 55CoCl2. Both 55Co-metal-chelate complexes demonstrated good in vivo stability by reducing the radiotracers' uptake in the liver by sixfold at 24 hours with ~ 1% ID/g and at 48 hours with ~ 0.5% ID/g and reducing uptake in the heart by fourfold at 24 hours with ~ 0.7% ID/g and sevenfold at 48 hours with ~ 0.35% ID/g. These results support the use of 55Co as a promising new radiotracer for PET imaging of cancer and other diseases. PMID- 26505226 TI - Melatonin and the future of critically ill patients' outcomes. PMID- 26505225 TI - Non-pharmacological interventions to reduce ICU-related psychological distress: a systematic review. AB - INTRODUCTION: Patients frequently suffer stress in intensive care units (ICUs) and many develop serious psychological morbidity after discharge. Little is known about the nature and efficacy of interventions to reduce ICU-related distress. There is growing evidence that administering sedative drugs can be harmful. Therefore we carried out a systematic review of non-pharmacological interventions to reduce ICU-related distress. EVIDENCE ACQUISITION: A systematic search was conducted using Medline, Embase, Psychinfo, Cinahl and the Web of Science. Included studies evaluated the effect of non-pharmacological interventions to reduce ICU stress. Study populations were adults in mixed or general ICUs. Outcomes were stress or psychological distress in or after the ICU, using self report or physiological measures. No meta-analysis was possible due to heterogeneity, therefore studies were arranged according to intervention type, and outcomes examined together with risk of bias criteria. EVIDENCE SYNTHESIS: Twenty-three studies were eligible, including 15 randomized controlled trials. Non-pharmacological interventions included music therapy (11 studies), mind-body practices (5) and psychological interventions (7). 12 studies showed a beneficial effect. However only three of the 12 had a low risk of bias, and many studies in the review were under-powered to detect an effect. Only 5 studies measured a medium/long term psychological outcome such as PTSD or depression at 2-12 months. CONCLUSIONS: Evidence indicates that non-pharmacological approaches to reducing ICU distress, in particular psychological interventions, may be beneficial. The evidence base would be strengthened by the implementation of fully-powered studies using robust designs, that measure longer-term outcomes. PMID- 26505227 TI - The Usefulness of Cadaveric Fungi as an Investigation Tool. PMID- 26505228 TI - Autopsy in Islam: Considerations for Deceased Muslims and Their Families Currently and in the Future. AB - Religious beliefs and cultures have influenced treatment of dead bodies in different ways by nations throughout history, and attitudes toward the deceased individuals have changed across time and so has the role and mechanism of autopsy. Islam has been a part of Europe for a long time; therefore, we would like to emphasize the important issues for Muslims and their families regarding death, autopsy, and funeral and to describe international perspectives of Muslim autopsies. Muslims have expressed their views on autopsy publically and internationally, and there have been claims of violation of the deceased, delays in burial, and nonconsideration of their religious beliefs. In this article, we aim to increase awareness and understanding of doctors about the religious and ethical issues important to Muslims and their families, so that appropriate considerations may be made where possible with regard to respectful treatment of deceased loved ones to decrease tensions presently being faced. Forensic medicine doctors could assist by undertaking autopsy without delay, in a private room by those of the same sex, and covering parts of the body not being worked on at that time. PMID- 26505229 TI - Upper Eyelid Fractional CO2 Laser Resurfacing With Incisional Blepharoplasty. AB - PURPOSE: Laser resurfacing, performed at the same time as blepharoplasty, has most commonly been applied to the lower eyelid skin but can effectively be used on the upper eyelid to reduce rhytidosis and improve skin quality. The authors evaluate the safety and efficacy of this procedure. METHODS: Fractional CO2 laser resurfacing was performed in conjunction with incisional upper blepharoplasty. The ultrapulsed laser energy was applied to the sub-brow skin, the upper medial canthal skin, and the pretarsal skin in 30 patients. Photos were obtained preoperatively and at 3 months. RESULTS: All patients demonstrated reduction in upper eyelid rhytidosis without any serious complications. Independent rhytidosis grading (0-4) showed a mean improvement of 42%. One patient experienced wound dehiscence that satisfactorily resolved without intervention. CONCLUSIONS: Upper eyelid laser resurfacing is effective and can be safely performed at the same time as upper blepharoplasty. This approach reduces or eliminates the need for medial incisions to address medial canthal skin redundancy and rhytidosis and it directly treats upper eyelid wrinkles on residual eyelid and infra-brow skin during blepharoplasty. PMID- 26505230 TI - Safety and Effectiveness of a Small Incision Lateral Eyebrow Ptosis Repair Technique Using a Frontalis Muscle Transposition Flap. AB - PURPOSE: To evaluate the safety and effectiveness of a frontalis muscle transposition flap for treatment of lateral eyebrow ptosis. METHODS: The charts of all patients undergoing frontalis muscle transposition flap eyebrow ptosis repair from December 2013 to September 2014 were reviewed. Charts with inadequate photographs were excluded. Charts were reviewed for demographics, preoperative and postoperative photographs, surgical technique, and complications. The following parameters were assessed on preoperative and postoperative photographs: corneal diameter, central brow height, and lateral brow height. Measurements were normalized to a standard corneal diameter of 11.5 mm. Statistical analysis was performed in conjunction with the Cleveland Health Institute Biostatistics Department. RESULTS: Forty-six total patients underwent frontalis muscle transposition flap eyebrow ptosis repair and the charts of 31 patients (53 cases) were reviewed. There were 20 female and 11 male patients. Average age was 69.1 +/ 7.7 years (range: 50 - 86 years). There were 9 unilateral and 22 bilateral cases. Concomitant surgeries included upper blepharoplasty (33 cases), conjunctival-Mullerectomy blepharoptosis repair (3 cases), and intralesional tetracycline injection for festoons (3 cases). Average follow-up interval between surgery and the final postoperative photograph was 10.2 weeks (range: 6-26 weeks). Overall, lateral brow height increased postoperatively by 1.78 mm (p < 0.05). In patients that underwent frontalis muscle transposition flap alone, lateral brow height increased by 2.86 mm (p < 0.05). Scalp hypesthesia was documented in 10/31 patients, and resolved in 8/10 patients at last follow up. CONCLUSIONS: A frontalis muscle transposition flap effectively addresses lateral eyebrow ptosis repair through a small, relatively concealed incision. It produces temporary scalp hypesthesia in a significant number of patients, and long-term results remain unknown. PMID- 26505231 TI - Frontalis Muscle Asymmetry and Lateral Landmarks. AB - PURPOSE: To investigate frontalis muscle asymmetry and characterize its lateral interdigitation with the orbicularis oculi muscle. METHODS: After making a mid coronal incision and bluntly dissecting to the orbital rim, the frontalis muscle was exposed, marked, and photographed. The right and left muscle bellies were analyzed and compared in both pixels and cm ratios generated with NIH ImageJ software. A ratio of >=1.5 was considered significantly asymmetric. The lateral interdigitation of the frontalis and orbicularis oculi muscles was measured from the supraorbital notch with a metric ruler. Data were analyzed using 2-sample t tests, paired t tests, log scales, and nonparametric tests were performed for sensitivity analyses. A p value of <=0.05 was considered statistically significant. RESULTS: Fifty-eight hemifaces of 29 Caucasian cadavers were studied for muscle belly asymmetry. Thirty-six hemifaces of 18 Caucasian cadavers (9 males) were dissected for lateral landmarks and average age of these specimens was 73 years (range: 35-91 years). Significant asymmetry in muscle belly area was found in 6/29 (20%) specimens, with the right muscle belly larger in all 6 specimens. On average, the right muscle belly area was 1.23 times that of the left (p = <0.001). The average frontalis-orbicularis interdigitation occurred 3.4 cm lateral to the supraorbital notch. CONCLUSIONS: Significant frontalis muscle belly asymmetry exists in 20% of Caucasians cadavers. The right muscle belly was larger on average and in all cases of significant asymmetry. The frontalis muscle interdigitates with the orbicularis oculi on average 3.4 cm lateral to the supraorbital notch. PMID- 26505232 TI - Nylon Hang Back Sutures in the Repair of Secondary Ptosis Following Overcorrected Dysthyroid Upper Eyelid Retraction. AB - PURPOSE: Repair of blepharoptosis secondary to surgical overcorrection of thyroid related primary upper eyelid retraction (secondary ptosis) can be unpredictable. This study describes the long-term results of "hang-back" nylon sutures, for an anterior approach surgical repair of secondary ptosis. METHODS: This was a retrospective consecutive case note review of patients referred with secondary ptosis (after prior upper eyelid lowering for thyroid eye disease), under the care of a single surgeon at Moorfields Eye Hospital & subsequently at Barking Havering Redbridge University Hospitals NHS Trust (SSD). In accordance with hospital trust policy, this audit was registered and all patient data was anonymized, ethical approval was not required. Patients with secondary ptosis underwent surgery under local anesthesia through an upper eyelid skin-crease incision. The anterior portion of the levator muscle was freed from all scar tissues and its action re-established on the superior part of the upper tarsal plate, using two 6-0 nylon hang-back sutures placed centrally and medially. The margin reflex distance 1 (MRD1), skin crease height, eyelid contour, symmetry of eyelid position (difference in margin reflex distance 1 <1 mm in both eyes) and degree of lagophthalmos were assessed from clinical notes preoperative and postoperatively at 1, 3, and 12 months. RESULTS: Surgery was undertaken in 14 eyelids in 13 patients (3 males; 23%), with 9/14 (65%) eyelids having undergone attempted repair of ptosis prior to referral; in 7 of the 8 (88%) eyelids with previous failed ptosis repair, the referring surgeon had used soluble hang-back sutures. As compared with an average preoperative margin reflex distance 1 of 0.9 mm (median 1, range: -1 to 2 mm), the average margin reflex distance 1 at 3 months was 3.0 mm (median 3, range: 2.5-4 mm; p < 0.0001) and 2.8 mm at 12-month follow up (median 3, range: 2-4mm; p < 0.0001). The upper eyelid central skin crease height changed from a preoperative mean of 9.8 mm (median 9, range: 5-15 mm) to 8.7 mm at 3 months (median 8, range: 7-12 mm; p = 0.1412) and 8.9 mm at 12 month follow up (median 9, range: 7-11 mm; p = 0.2930). Only 3 patients had postoperative lagophthalmos (one patient 3 mm and two patients 1 mm) at 3 months after surgery, this resolving by the 12-month postoperative visit. Thirteen cases (93%) had a good functional, symmetrical, and aesthetic result at 12 month follow up, with a late recurrence of ptosis in 1 patient (7%). CONCLUSION: The "hang back" semi-permanent suture technique for repair of over-corrected upper eyelid lowering in thyroid eye disease appears to provide an excellent and predictable long-term result with a low incidence of late recurrence of ptosis. PMID- 26505233 TI - Metastatic Embryonal Conjunctival Rhabdomyosarcoma in a 4-Year-Old Boy. AB - The authors report the case of a 4-year-old boy who presented with unilateral ptosis and a mass lesion of palpebral conjunctiva of the left upper eyelid, that had been present for 2 weeks, and had rapidly enlarged. The lesion was salmon colored and was easily distinguished from the conjunctiva. There was no obvious orbital extension in the MRI studies. Excisional biopsy was performed through a conjunctival approach. The histopathology was consistent with embryonal rhabdomyosarcoma. Thoracoabdominal CT scans revealed nodules in both lungs, indicating stage 4 disease. The patient received chemotheraphy and intensity modulated radiation therapy. Rhabdomyosarcoma confined to the conjunctiva and distant metastasis without orbital involvement is rare. It should be included in the differential diagnosis of any atypical conjunctival mass lesions in children, and histopathology is necessary to establish proper treatment. As the case indicates, detailed systemic evaluation and careful systemic follow up of these patients are mandatory. PMID- 26505234 TI - Maxillary Ameloblastoma with Orbital Involvement: An Institutional Experience and Literature Review. AB - PURPOSE: To describe 8 patients with orbital involvement by ameloblastoma and to review the literature on this topic. METHODS: The electronic medical records and pathology databases of the Hospital of the University of Pennsylvania were searched to identify all patients with histopathologically confirmed ameloblastoma diagnosed between 1990 and 2015. PubMed database was searched for all well-documented cases of maxillary ameloblastoma and ameloblastic carcinoma ex-ameloblastoma with orbital involvement published in the English literature. The information collected on the compiled 23 patients included age, sex, clinical presentation, imaging findings, management, tumor histopathologic features, and follow up. RESULTS: Review of medical records identified 8 patients with orbital involvement by ameloblastoma. Literature search yielded 15 patients with well documented orbital involvement by ameloblastoma. Most tumors occurred in men (19 of 23, M:F = 4-5:1) with an average age of 56 years. The overall rates of recurrence, visual compromise, death, and confirmed disease-related mortality were 70% (16/23), 26% (6/23), 39% (9/23), and 22% (5/23), respectively. The initial surgical approach correlated with prognosis. The rates of recurrence, orbital exenteration, and mortality in the cohort managed with conservative surgery or partial maxillectomy were 57% (8/14), 29% (4/14), and 50% (7/14), respectively. In contrast, the patients initially managed with a radical resection had substantially lower frequencies of tumor recurrence (2/7, 29%), exenteration (1/7, 14%), and death (1/7, 14%). Malignant transformation to ameloblastic carcinoma occurred in the setting of recurrent disease in 3 patients and in 1 patient with prolonged duration of symptoms, suggestive of a long standing tumor. CONCLUSIONS: Maxillary ameloblastoma can rarely involve the orbit, leading to significant ocular morbidity and occasional mortality. Prompt radical resection of the tumor has the potential to decrease the likelihood of recurrence and visual compromise, and can improve survival. PMID- 26505235 TI - Primary Extradural Ectopic Orbital Meningioma. AB - The authors describe a rare case of a primary extradural ectopic meningioma occurring in a 9-year-old female. A review of the literature with respect to clinical presentation, radiographic findings, management, and outcome among similar cases is discussed. Common features that may assist with diagnosing this unusual tumor include absence of bone or optic nerve sheath involvement, presentation at a young age, occurrence in the medial orbit, and sinus asymmetry on radiographic imaging. Preferred method of treatment is complete surgical excision. PMID- 26505236 TI - Extreme Eyelid Lymphedema Associated With Rosacea (Morbihan Disease): Case Series, Literature Review, and Therapeutic Considerations. AB - PURPOSE: To describe severe lymphedema of the eyelids, known as Morbihan disease, a previously characterized but infrequently reported and poorly understood entity related to rosacea that features solid mid-facial and eyelid lymphedema. METHODS: Retrospective chart review, histopathologic and immunohistochemical analysis, and pertinent literature consideration. RESULTS: Five cases of Morbihan disease were identified. Histopathologic examination revealed pleomorphic perivascular and perilymphatic inflammation with profound lymphangiectasis and lymph stasis, thus suggesting elements of both rosacea and localized, chronic lymphedema. Multiple therapeutic interventions were performed including systemic anti-inflammatory therapy, surgical debulking, and corticosteroid injection. CONCLUSIONS: Extreme eyelid edema associated with characteristic skin changes and histopathologic findings represents an entity known as Morbihan disease which is rare and difficult to treat. While multiple modalities have been employed with variable results, future therapeutic considerations may include the use of targeted biologic agents. PMID- 26505237 TI - In vitro starch digestibility and in vivo glycemic response of foxtail millet and its products. AB - Foxtail millet, as a leading variety in arid and semi-arid areas of Asia and Africa, can provide broad potential benefits to human health. However, its digestion properties have not been reported. So in this study, the in vitro starch digestibilities and in vivo glycemic indices (GI) of foxtail millet and pure millet products were investigated. The results showed that starch digestibility of the foxtail millet flour is obviously lower than that of wheat flour. However, deproteinization and heating significantly increased its rapidly digestible starch and decreased its slowly digestible starch and resistant starch. The GIs of pure millet products were in the following order: millet porridge (93.6 +/- 11.3) > millet steamed bread (89.6 +/- 8.8) > No. 1 millet pancake (75.0% millet flour and 25.0% extrusion flour, 83.0 +/- 9.6) > No. 2 millet pancake (without extrusion flour, 76.2 +/- 10.7) > cooked millet (64.4 +/- 8.5). They were significantly positively correlated with the rapidly digestible starch (r = 0.959), degree of gelatinization (r = 0.967) and estimated glycemic index (r = 0.988). Both in vitro and in vivo tests suggested that boiling, steaming and extrusion enhanced the formation of digestible starch and subsequently increased the GI values. Additionally, the No. 1 millet pancake and cooked millet had a relatively gentle stimulation on beta-cell. Therefore, foxtail millet, especially the cooked millet, may serve as a potential source of nutraceutical and functional food that could delay the development of type 2 diabetes. PMID- 26505238 TI - Formation constants of copper(I) complexes with cysteine, penicillamine and glutathione: implications for copper speciation in the human eye. AB - Protonation constants for the biologically-important thioamino acids cysteine (CSH), penicillamine (PSH) and glutathione (GSH), and the formation constants of their complexes with Cu(I), have been measured at 25 degrees C and an ionic strength of 1.00 mol dm(-3) (Na)Cl using glass electrode potentiometry. The first successful characterisation of binary Cu(I)-CSH and Cu(I)-GSH species over the whole pH range was achieved in this study by the addition of a second thioamino acid, which prevented the precipitation that normally occurs. Appropriate combinations of binary and ternary (mixed ligand) titration data were used to optimise the speciation models and formation constants for the binary species. The results obtained differ significantly from literature data with respect to the detection and quantification of protonated and polynuclear complexes. The present results are thought to be more reliable because of the exceptionally wide pH and concentration ranges employed, the excellent reproducibility of the data, the close agreement between the calculated and observed formation functions, and the low standard deviations and absence of numerical correlation in the constants. The present formation constants were incorporated into a large Cu speciation model which was used to predict, for the first time, metal-ligand equilibria in the biofluids of the human eye. This simulation provided an explanation for the precipitation of metallic copper in lens and cornea, which is known to occur as a consequence of Wilson's disease. PMID- 26505239 TI - Facilitated extracellular electron transfer of Shewanella loihica PV-4 by antimony-doped tin oxide nanoparticles as active microelectrodes. AB - Dissimilatory metal reducing bacteria are capable of extracellular electron transfer (EET) to insoluble metal oxides as external electron acceptors for their anaerobic respiration, which is recognized as an important energy-conversion process in natural and engineered environments, such as in mineral cycling, bioremediation, and microbial fuel/electrolysis cells. However, the low EET efficiency remains one of the major bottlenecks for its practical application. We report firstly that the microbial current generated by Shewanella loihica PV-4 (S. loihica PV-4) could be greatly improved that is up to ca. 115 fold, by adding antimony-doped tin oxide (ATO) nanoparticles in the electrochemical reactor. The results demonstrate that the biocompatible, electrically conductive ATO nanoparticles acted as active microelectrodes could facilitate the formation of a cells/ATO composite biofilm and the reduction of the outer membrane c-type cytochromes (OM c-Cyts) that are beneficial for the electron transfer from cells to electrode. Meanwhile, a synergistic effect between the participation of OM c Cyts and the accelerated EET mediated by cell-secreted flavins may play an important role for the enhanced current generation in the presence of ATO nanoparticles. Moreover, it is worth noting that the TCA cycle in S. loihica PV-4 cells is activated by adding ATO nanoparticles, even if the potential is poised at +0.2 V, thereby also improving the EET process. The results presented here may provide a simple and effective strategy to boost the EET of S. loihica PV-4 cells, which is conducive to providing potential applications in bioelectrochemical systems. PMID- 26505240 TI - The Emerging Baby Boomer Health Care Crisis. PMID- 26505243 TI - Helping Individuals With Dementia Live More Fully Through Person-Centered Practices. AB - Dementia, including Alzheimer's disease, is a health condition saddled with social stigmas and is widely misunderstood. Person-centered care practices can positively improve the psychosocial experience of living with dementia and have become the gold standard for care because of the resulting beneficial outcomes. The purpose of the current article is to describe four person-centered principles that form the foundation for dementia care practice: (a) the idea that individuals can and do live fully with dementia; (b) quality of life depends not only on the care received but also on the value that others put on their abilities and life; (c) being meaningfully engaged and having purpose are vital to well-being; and (d) respect, dignity, and choice are not only foundational to person-centered care but for basic human rights. Although efforts have been made to mandate person-centered practices, challenges remain that can direct future research and practice efforts. [Journal of Gerontological Nursing, 41(11), 9 14.]. PMID- 26505244 TI - Evidence-Based Practice Guideline: Depression Detection in Older Adults With Dementia. AB - Depression and dementia are the two most common psychiatric syndromes in the older adult population. Depression in older adults with and without dementia often goes unrecognized and untreated. The current guideline recommends a three step procedure that can be used across health care settings to screen for the presence of depressive symptoms. Implementation of the evidence-based guideline requires administration of the Mini-Mental State Examination and either the Geriatric Depression Scale Short Form or Cornell Scale for Depression in Dementia, depending on level of cognitive functioning. The algorithm provided is designed to be used by nurses, physicians, and social workers for the purpose of depression screening in older adults with dementia. Detection of depression in individuals with dementia is hindered by a lack of a validated, brief screening tool. More research is needed on the use of such screenings among older adults with cognitive impairment. PMID- 26505245 TI - Effects of the Evidence-Based Nursing Care Algorithm of Dysphagia for Nursing Home Residents. AB - HOW TO OBTAIN CONTACT HOURS BY READING THIS ARTICLE INSTRUCTIONS 1.2 contact hours will be awarded by Villanova University College of Nursing upon successful completion of this activity. A contact hour is a unit of measurement that denotes 60 minutes of an organized learning activity. This is a learner-based activity. Villanova University College of Nursing does not require submission of your answers to the quiz. A contact hour certificate will be awarded once you register, pay the registration fee, and complete the evaluation form online at http://goo.gl/gMfXaf. To obtain contact hours you must: 1. Read the article, "Effects of the Evidence-Based Nursing Care Algorithm of Dysphagia for Nursing Home Residents" found on pages 30-39, carefully noting any tables and other illustrative materials that are included to enhance your knowledge and understanding of the content. Be sure to keep track of the amount of time (number of minutes) you spend reading the article and completing the quiz. 2. Read and answer each question on the quiz. After completing all of the questions, compare your answers to those provided within this issue. If you have incorrect answers, return to the article for further study. 3. Go to the Villanova website listed above to register for contact hour credit. You will be asked to provide your name; contact information; and a VISA, MasterCard, or Discover card number for payment of the $20.00 fee. Once you complete the online evaluation, a certificate will be automatically generated. This activity is valid for continuing education credit until October 31, 2018. CONTACT HOURS This activity is co-provided by Villanova University College of Nursing and SLACK Incorporated. Villanova University College of Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. ACTIVITY OBJECTIVES 1. Explain the development and testing of the Evidence-Based Nursing Care Algorithm of Dysphagia (ENCAD) in long-term care settings. 2. Review the outcome of implementing the ENCAD for dysphagia management in a nursing home. DISCLOSURE STATEMENT Neither the planners nor the authors have any conflicts of interest to disclose. Standardized nursing care protocols for dysphagia management have not been established in nursing home settings in Korea. The purpose of the current study was to examine the effect of the Evidence-Based Nursing Care Algorithm of Dysphagia (ENCAD) on risk of dysphagia, oral health, and dysphagia-specific quality of life among nursing home residents. The ENCAD was administered to 40 residents in one nursing home in urban South Korea for 6 months. A control-intervention, time-series design was used, under which participants served as their own controls. Oral health, risk of aspiration, and dysphagia-specific quality of life were measured at baseline, post-control, and post-intervention. Findings showed that risk of aspiration (p < 0.01) and dysphagia-related quality of life (p < 0.001) improved significantly after the ENCAD was applied, whereas oral health status did not change over time (p = 0.06). Results suggest that implementing the ENCAD contributed to a reduction in the risk of aspiration and an improvement in the quality of life in nursing home residents. PMID- 26505247 TI - Understanding Elderspeak from the Perspective of Certified Nursing Assistants. AB - Elderspeak is a form of patronizing speech that is often used with older adults. The current study attempted to learn more about the conditions under which elderspeak is used as well as the intent behind using elderspeak. The sample comprised 26 certified nursing assistants (CNAs) working with older adults in long-term care facilities. Data were collected using semistructured interviews. Findings indicated that the intended purposes of elderspeak were to (a) make residents feel more comfortable, (b) make caregivers seem friendlier, (c) help residents better comprehend verbal communication, and (d) increase the likelihood that residents would cooperate during caregiving tasks. In addition, one half of the CNAs reported that elderspeak is more appropriate with individuals with dementia; many also believed that the use of elderspeak was always inappropriate. The current findings may have implications for improving training and education programs for CNAs and other professionals working in long-term care facilities. PMID- 26505249 TI - 2015 Updated AGS Beers Criteria Offer Guide for Safer Medication Use Among Older Adults. PMID- 26505248 TI - Nutrition and Cognition in Older Adults With Heart Failure: A Systematic Review. AB - Cognitive impairment is commonly observed in older adults with heart failure; nutrition is a possible contributing factor. The purpose of the current systematic review is to examine the relationship between nutrition and cognition in older adults with heart failure. A literature review was performed through August 2015 that examined published, peer-reviewed studies from PubMed, PsycINFO, CINAHL, and Web of Science. Four articles were selected for inclusion. Findings revealed that poorer nutritional habits were associated with poorer attention, executive functioning, and memory in older adults with heart failure. Nutritional biomarkers, including anemia, hyponatremia, hypokalemia, hyperglycemia, and hypoalbuminemia, were also associated with cognitive impairment. More research is needed to explore the relationship between nutrition and cognition in this population. Descriptive studies will inform scientists as they design and test nutritional interventions to optimize cognitive function in older adults with heart failure. PMID- 26505250 TI - SCNT versus iPSCs: proteins and small molecules in reprogramming. AB - Somatic cell nuclear transplantation (SCNT) and induced pluripotent stem cell (iPSC) technologies can be employed to change cell fate by reprogramming. The discoveries of SCNT and iPSCs were awarded the Nobel Prize for Physiology and Medicine in 2012, which reaffirmed the importance of cell fate plasticity. However, the low cloning efficiency of SCNT and differences between iPSCs and embryonic stem cells (ESCs) are great barriers and may be caused by incomplete or aberrant reprogramming. Additionally, the well characterized reprogramming factors Oct4, Sox2, Klf4 and c-Myc (OSKM) are not simultaneously expressed at high levels in enucleated or early embryonic oocytes, suggesting reprogramming may be different in the above two methods. Recent studies have demonstrated that small molecules and specific proteins expressed in oocytes and in early embryonic development play important roles in reprogramming by replacing transcription factors, erasing reprogramming memory and accelerating the speed and extent of reprogramming. In this review, we summarize the current state of SCNT and iPSCs technologies and discuss the latest advances in the research of proteins and small molecules affecting SCNT and iPSCs. This is an area of research in which chemical biology and proteomics are combining to facilitate improving cellular reprogramming and production of clinical grade iPSCs. PMID- 26505251 TI - Gliolectin positively regulates Notch signalling during wing-vein specification in Drosophila. AB - Notch signalling is essential for animal development. It integrates multiple pathways controlling cell fate and specification. Here we report the genetic characterization of Gliolectin, presumably a lectin, a cytoplasmic protein, significantly enriched in Golgi bodies. Its expression overlaps with regions where Notch is activated. Loss of gliolectin function results in ectopic veins, while gain of its function causes loss of wing veins. It positively regulates Enhancer of split mbeta, a target of Notch signalling. These observations suggest that it is a positive regulator of Notch signalling during wing development in Drosophila. PMID- 26505252 TI - Down-regulation of msrb3 and destruction of normal auditory system development through hair cell apoptosis in zebrafish. AB - Hearing defects can significantly influence quality of life for those who experience them. At this time, 177 deafness genes have been cloned, including 134 non-syndromic hearing-loss genes. The methionine sulfoxide reductase B3 (Ahmed et al., 2011) gene (also called DFNB74) is one such newly discovered hearing-loss gene. Within this gene c.265 T>G and c.55 T>C mutations are associated with autosomal recessive hearing loss. However, the biological role and mechanism underlying how it contributes to deafness is unclear. Thus, to better understand this mutation, we designed splicing morpholinos for the purpose of down regulating msrb3 in zebrafish. Morphants exhibited small, tiny, fused, or misplaced otoliths and abnormal numbers of otoliths. Down-regulation of msrb3 also caused shorter, thinner, and more crowded cilia. Furthermore, L1-8 neuromasts were reduced and disordered in the lateral line system; hair cells in each neuromast underwent apoptosis. Co-injection with human MSRB3 mRNA partially rescued auditory system defects, but mutant MSRB3 mRNA could not. Thus, msrb3 is instrumental for auditory system development in zebrafish and MSRB3-related deafness may be caused by promotion of hair cell apoptosis. PMID- 26505253 TI - Generation and characterization of mice harboring a conditional CXCL12 allele. AB - The chemokine CXCL12 has important functions in immune and central nervous systems. Moreover, a global disruption of CXCL12 in mice results in perinatal lethality. To circumvent this impediment and provide a tool for analyzing CXCL12 functions in specific organ systems, we have generated a mouse line harboring a loxP-site flanked exon 2 of CXCL12. A germ line deleter, beta-actin::cre was used to remove a CXCL12 exon 2 and subsequently systemic CXCL12 exon 2 deficient embryos were generated. These mutant embryos showed a marked depletion of CXCL12 transcript. As expected from the global mutant phenotype, our mutants were also characterized by highly irregular cerebellar cytoarchitecture of the external granule layer as well as altered radial migration of midbrain dopaminergic neurons. Importantly, migration of the pontine grey nucleus (PGN) was derailed and remarkably resembled the global mutant phenotype of the CXCL12 receptor - CXCR4 in this system. Despite the fact that CXCL12 signaling can be mediated through receptors other than CXCR4, our results indicate a monogamous relationship between the CXCL12 ligand and CXCR4 receptor in controlling PGN migration. Our findings further expand on the understanding of CXCL12 function in PGN development. Moreover, phenotypic similarities between our mutants and mice harboring a global CXCL12 disruption support the validity of our line. Importantly, these results strongly suggest that our conditional CXCL12 line can be used as a powerful tool to manipulate CXCL12 signaling and function in vivo. PMID- 26505254 TI - 3D culture of ovarian follicles: a system towards their engineering? AB - Infertility in women is a health priority. Designing a robust culture protocol capable of attaining complete follicle growth is an exciting challenge, for its potential clinical applications, but also as a model to observe and closely study the sequence of molecular events that lie behind the intricate relationship existing between the oocyte and surrounding follicle cells. Here, we describe the procedures used to maintain the ovarian follicle 3D architecture employing a variety of in vitro systems and several types of matrices. Collagen and alginate are the matrices that led to better results, including proof-of-concept of full term development. Pioneer in its kind, these studies underlie the drawbacks encountered and the need for a culture system that allows more quantitative analyses and predictions, projecting the culture of the ovarian follicle into the realm of tissue engineering. PMID- 26505255 TI - A simple method of image analysis to estimate CAM vascularization by APERIO ImageScope software. AB - The chick chorioallantoic membrane (CAM) assay is a well-established method to test the angiogenic stimulation or inhibition induced by molecules and cells administered onto the CAM. The quantification of blood vessels in the CAM assay relies on a semi-manual image analysis approach which can be time consuming when considering large experimental groups. Therefore we present here a simple and fast volumetric method to inspect differences in vascularization between experimental conditions related to the stimulation and inhibition of CAM angiogenesis based on the Positive Pixel Count algorithm embedded in the APERIO ImageScope software. PMID- 26505256 TI - Analysis of AtGUS1 and AtGUS2 in Arabidopsis root apex by a highly sensitive TSA MISH method. AB - A new highly sensitive whole-mount in situ hybridization method, based on tyramide signal amplification (TSA-MISH) was developed and a combined GFP detection and TSA-MISH procedure was applied for the first time in plants, to precisely define the spatial pattern of AtGUS1 and AtGUS2 expression in the root apex. beta-glucuronidases (GUSs) belonging to the glycosyl hydrolases (GHs) 79 family, are widely distributed in plants, but their functional role has not yet been fully investigated. In the model system Arabidopsis Thaliana, three different AtGUS genes have been identified which encode proteins with putative different fates. Endogenous GUS expression has been detected in different organs and tissues, but the cyto-histological domains of gene expression remain unclear. The results here reported show co-expression of AtGUS1 and AtGUS2 in different functional zones of the root apex (the cap central zone, the root cap meristem, the staminal cell niche and the cortical cell layers of the proximal meristem), while AtGUS2 is exclusively expressed in the cap peripheral layer and in the epidermis in the elongation zone. Interestingly, both genes are not expressed in the stelar portion of the proximal meristem. A spatial (cortex vs. stele) and temporal (proximal meristem vs. transition zone) regulation of AtGUS1 and AtGUS2 expression is therefore active in the root apex. This expression pattern, although globally consistent with the involvement of GUS activity in both cell proliferation and elongation, clearly indicates that AtGUS1 and AtGUS2 could control distinct downstream process depending on the developmental context and the interaction with other players of root growth control. In the future, the newly developed approaches may well be very useful to dissect such interactions. PMID- 26505257 TI - Improving Patient-Centered Care: A Cross-Sectional Survey of Prior Use and Interest in Complementary and Integrative Health Approaches Among Hospitalized Oncology Patients. AB - OBJECTIVES: To describe cancer inpatients' prior-year use of complementary and integrative health (CIH) therapies and interest in receiving CIH therapies while in the hospital. DESIGN: Observational, cross-sectional survey of prior-year use of 12 different CIH approaches and interest in receiving any of 7 CIH services in the hospital. SETTING: Surgical oncology ward of an academic medical center. PARTICIPANTS: 166 hospitalized oncology patients, with an average age of 54 years. RESULTS: The most commonly used CIH approach was vitamins/nutritional supplements (67%), followed by use of a special diet (42%) and manual therapies (39%). More than 40% of patients expressed interest in each of the therapies if it was offered during their hospital stay, and 95% of patients were interested in at least one. More than 75% expressed interest in nutritional counseling and in massage. CIH use and interest varied somewhat by demographic and clinical characteristics. CONCLUSION: Rates of CIH use among patients with cancer were high, as were their preferences to have these services available in the inpatient setting. Hospitals have the opportunity to provide patient-centered care by developing capacity to provide inpatient CIH services. PMID- 26505258 TI - Hexahalogenated and their mixed benzene derivatives as prototypes for the understanding of halogen...halogen intramolecular interactions: New insights from combined DFT, QTAIM-, and RDG-based NCI analyses. AB - A large number of fully halogenated benzene derivatives containing the fluorine, chlorine, bromine, and iodine atoms have been experimentally synthesized both as single- and co-crystals (e.g., Desiraju et al., Chem. Eur. J. 2006, 12, 2222), yet the natures of the halogen ... halogen interactions between the vicinal halogens in these compounds within the intramolecular domain are undisclosed. Given a fundamental understanding of these interactions is incredibly important in many areas of chemical, biological, supramolecular, and material sciences, we present here our newly discovered theoretical results that delineate whilst the nature of an F...F interaction in a pair of two adjacent fluorine atoms in either of the hexafluorobenzene and 1,4-dibromotetrafluorobenzene compounds examined is almost unclear, each of the latter three hexahalogenated benzene derivatives (viz., C6 Cl6 , C6 Br6 , and C6 I6 ), and each of the seven of their fully mixed hexahalogenated benzene analogues, are found to be stabilized by means of a number of halogen...halogen interactions, each a form of long-range attraction within the intramolecular domain. The Molecular Electrostatic Surface Potential model was found to be unsurprisingly unsuitable in unraveling any of the aforesaid attractions between the halogen atoms. However, such interactions successfully enunciated by a set of noncovalent interaction descriptors of geometrical, topological, and electrostatic origins. These latter properties were extracted combining the results of the Density Functional Theory electronic structure calculations with those revealed from Atoms in Molecules, and Reduced Density Gradient charge density-based topological calculations, and are expounded in detail to formalize the conclusions. (c) 2015 Wiley Periodicals, Inc. PMID- 26505259 TI - DAMQT 2.1.0: A new version of the DAMQT package enabled with the topographical analysis of electron density and electrostatic potential in molecules. AB - DAMQT-2.1.0 is a new version of DAMQT package which includes topographical analysis of molecular electron density (MED) and molecular electrostatic potential (MESP), such as mapping of critical points (CPs), creating molecular graphs, and atomic basins. Mapping of CPs is assisted with algorithmic determination of Euler characteristic in order to provide a necessary condition for locating all possible CPs. Apart from the mapping of CPs and determination of molecular graphs, the construction of MESP-based atomic basin is a new and exclusive feature introduced in DAMQT-2.1.0. The GUI in DAMQT provides a user friendly interface to run the code and visualize the final outputs. MPI libraries have been implemented for all the tasks to develop the parallel version of the software. Almost linear scaling of computational time is achieved with the increasing number of processors while performing various aspects of topography. A brief discussion of molecular graph and atomic basin is provided in the current article highlighting their chemical importance. Appropriate example sets have been presented for demonstrating the functions and efficiency of the code. PMID- 26505263 TI - Identification of new markers of recurrence in patients with unprovoked deep vein thrombosis by gene expression profiling: the retro study. AB - OBJECTIVE: The aim of this study was to assess differences in the gene expression profile of peripheral blood cells between patients with early recurrent thrombosis vs. patients without recurrent events after withdrawal of anticoagulant therapy for a first episode of unprovoked deep vein thrombosis (uDVT), to identify novel predictors of recurrence. METHODS: In the discovery population (N = 32), a microarray RNA assay followed by RT-PCR confirmation were performed. In the validation population (N = 44) a multiple RT-PCR-based strategy was applied to assess genes differentially expressed in the discovery population. RESULTS: The sex-adjusted Linear Model for Microarray Data analysis showed 102 genes differentially expressed (P < 0.01) in the discovery population. Nineteen of them underwent further confirmation in the validation population. The gene encoding for Acyl-CoA Synthetase Family Member 2 (ACSF2) was underexpressed in recurrent DVT patients in both, the discovery (P = 0.007) and validation populations (P = 0.004). In the receiver operator characteristic (ROC) analysis, the areas under the curve of ACSF2 expression were 0.77 and 0.80, respectively. CONCLUSIONS: For the first time an association between ACSF2 expression and the risk of recurrent DVT is suggested. Should this association be confirmed in larger prospective studies, ACSF2 could become useful for the selection of patients requiring extended anticoagulant therapy. PMID- 26505265 TI - Integration of Cyanine, Merocyanine and Styryl Dye Motifs with Synthetic Bacteriochlorins. AB - Understanding the effects of substituents on spectral properties is essential for the rational design of tailored bacteriochlorins for light-harvesting and other applications. Toward this goal, three new bacteriochlorins containing previously unexplored conjugating substituents have been prepared and characterized. The conjugating substituents include two positively charged species, 2-(N-ethyl 2 quinolinium)vinyl- (B-1) and 2-(N-ethyl 4-pyridinium)vinyl- (B-2), and a neutral group, acroleinyl- (B-3); the charged species resemble cyanine (or styryl) dye motifs whereas the neutral unit resembles a merocyanine dye motif. The three bacteriochlorins are examined by static and time-resolved absorption and emission spectroscopy and density functional theoretical calculations. B-1 and B-2 have Qy absorption bathochromically shifted well into the NIR region (822 and 852 nm), farther than B-3 (793 nm) and other 3,13-disubstituted bacteriochlorins studied previously. B-1 and B-2 have broad Qy absorption and fluorescence features with large peak separation (Stokes shift), low fluorescence yields, and shortened S1 (Qy ) excited-state lifetimes (~700 ps and ~100 ps). More typical spectra and S1 lifetime (~2.3 ns) are found for B-3. The combined photophysical and molecular orbital characteristics suggest the altered spectra and enhanced nonradiative S1 decay of B-1 and B-2 derive from excited-state configurations in which electron density is shifted between the macrocycle and the substituents. PMID- 26505264 TI - Optimization of singlet oxygen production from photosensitizer-incorporated, medically relevant hydrogels. AB - Photodynamic therapy and photodynamic antimicrobial chemotherapy are widely used, but despite this, the relationships between fluence, wavelength of irradiation and singlet oxygen (1 O2 ) production are poorly understood. To establish the relationships between these factors in medically relevant materials, the effect of fluence on 1 O2 production from a tetrakis(4-N-methylpyridyl)porphyrin (TMPyP) incorporated 2-hydroxyethyl methacrylate: methyl methacrylate: methacrylic acid (HEMA: MMA:MAA) copolymer, a total energy of 50.48 J/cm2 , was applied at varying illumination power, and times. 1 O2 production was characterized using anthracene 9,10-dipropionic acid, disodium salt (ADPA) using a recently described method. Using two light sources, a white LED array and a white halogen source, the LED array was found to produce less 1 O2 than the halogen source when the same power (over 500 - 600 nm) and time conditions were applied. Importantly, it showed that the longest wavelength Q band (590 nm) is primarily responsible for 1 O2 generation, and that a linear relationship exists between increasing power and time and the production of singlet oxygen. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 320-326, 2017. PMID- 26505266 TI - Analysis of ingested foreign bodies according to age, type and location: a retrospective observational study. AB - OBJECTIVE: This study aimed to analyse the types and locations of ingested foreign bodies according to different age groups, from infants to the elderly. DESIGN: A retrospective chart review. SETTING: Tertiary referral centre. PARTICIPANTS: A total of 4682 patients who ingested foreign bodies from January 2006 through February 2014. METHODS: The frequencies of foreign bodies were investigated in each age group. The types of foreign bodies were categorised into fish bones, chicken bones, seafood, tablets, food, metal, batteries, glass, teeth, plastics and others. The anatomic locations of the objects were classified as the oral cavity, tongue base, tonsils, oropharynx, hypopharynx, oesophagus, stomach and colon. The types, locations and origins of the foreign bodies were analysed according to the age groups. RESULTS: The frequency of foreign body ingestion was high in patients up to 14 years of age, after which the risk of foreign body ingestion markedly decreased. Fish bones were the most commonly suspected foreign bodies in all of the age groups. However, non-food-type foreign bodies were more common in both the young and elderly groups. The tonsils were the most common anatomic site of foreign body impaction except in the group of patients older than 65 years. The stomach and oesophagus were also common locations of foreign bodies in the groups of patients younger than 10 years (10.5%) and older than 65 years (39.4%). CONCLUSION: The frequency of foreign body ingestion was highest in young children. However, we observed specific age based characteristics that indicate specific precautions to take to avoid foreign body ingestion. PMID- 26505267 TI - Assessing the Utility of Circular Dichroism and FTIR Spectroscopy in Monoclonal Antibody Comparability Studies. AB - Protein characterization is a necessary activity during development, technical transfers, and licensure. One important aspect of protein characterization is higher order structure assessment, which can be accomplished in a variety of ways. Circular dichroism (CD) and Fourier transform infrared (FTIR) spectroscopies provide global higher order structure and are routinely used to measure the overall structure for product characterization; however, their use as comparability tools is uncertain because of their insensitivity to local or small structure changes. We use a monoclonal antibody (mAb) to explore the usefulness of CD and FTIR compared with other indirect methods of structure characterization such as size-exclusion and ion-exchange chromatographies (SEC and IEC). A panel of degraded samples of a mAb was generated; their higher order structure evaluated using CD and FTIR and was found to be largely unchanged. However, the SEC and IEC chromatograms of certain degraded samples were found to have measurable changes. Based on these studies, we conclude that the application of CD and FTIR should be reserved for global higher order structure identification or product characterization only. The use of CD or FTIR comparability of mAbs should be carefully evaluated, as comparability can be sensitively determined using indirect methods based on chromatography. PMID- 26505268 TI - Bone Marrow Aspiration: A Randomized Controlled Trial Assessing the Quality of Bone Marrow Specimens Using Slow and Rapid Aspiration Techniques and Evaluating Pain Intensity. AB - BACKGROUND/AIMS: Bone marrow aspiration (BMA) is an essential procedure in the examination of hematological disorders, but there is limited evidence as to whether the aspiration rate affects specimen quality. We aimed to assess the specimen quality and pain intensity using slow (S-technique) or rapid (R technique) aspiration. METHODS: This was a single-center, prospective, randomized patient- and assessor-blinded study of 482 patients scheduled for BMA. Specimen quality was evaluated by grading bone marrow (BM) cellularity and counting the number of marrow particles. Pain was assessed using a visual analog scale (VAS). RESULTS: We found a significant difference between the 2 groups with regard to the quality of specimens. For cellularity, the odds ratio (OR) for having a poor quality aspirate using the S-technique versus the R-technique was 3.05 [confidence interval (CI) 1.79-5.31]. For BM particles, the quality of specimens with the S-technique proved to be poor compared with the R-technique (OR 2.52; CI 1.51-4.28). We found a statistically significant difference of 1 VAS point (p < 0.001) of the median pain intensity in favor of the S-technique. CONCLUSION: Even though the pain intensity is significantly higher with the R-technique, the median difference is relatively small. We propose that the R-technique is preferable to the S-technique due to better specimen quality. PMID- 26505269 TI - Informed consent conversations and documents: A quantitative comparison. AB - BACKGROUND: Informed consent for clinical research includes 2 components: informed consent documents (ICDs) and informed consent conversations (ICCs). Readability software has been used to help simplify the language of the ICD, but to the authors' knowledge is rarely used to assess the language used during the ICC, which may influence the quality of informed consent. The current analysis was performed to determine whether length and reading levels of transcribed ICCs are lower than their corresponding ICDs for selected clinical trials, and to assess whether investigator experience affected the use of simpler language and comprehensiveness. METHODS: The current study was a prospective study in which ICCs were audiorecorded at 6 institutions when families were offered participation in pediatric phase I oncology trials. Word count, Flesch-Kincaid Grade Level (FKGL), and Flesch Reading Ease score (FRES) of the ICCs were compared with corresponding ICDs, including the frequency with which investigators addressed 8 prespecified critical consent elements during the ICC. RESULTS: Sixty-nine unique physician/protocol pairs were identified. Overall, ICCs contained fewer words (4677 vs 6364 words; P = .0016) and had a lower FKGL (6 vs 9.7; P <= .0001) and a higher FRES (77.8 vs 56.7; P<.0001) compared with their respective ICDs, but were more likely to omit critical consent elements, such as voluntariness (55%) and dose-limiting toxicities (26%). Years of investigator experience was not correlated with reliably covering critical elements or decreased linguistic complexity. CONCLUSIONS: Clinicians use more understandable language during ICCs than the corresponding ICD, but appear to less reliably cover elements critical to fully informed consent. Efforts focused at providing communication training for clinician-investigators should be made to optimize the synergy between the ICD and the ICC. PMID- 26505270 TI - Effects of Condensed-Phase Oxidants on Secondary Organic Aerosol Formation. AB - In this study we investigate the hypothesis that oxidants present within atmospheric particles can promote the formation of highly oxidized organic aerosol (OA) via oxidation reactions in the condensed phase. Secondary organic aerosol (SOA) was generated from the ozonolysis of alpha-pinene and isoprene in an environmental chamber, with seed particles systematically varied in order to assess the effects of condensed-phase oxidant levels on SOA loading and composition. The effects of particle phase (aqueous vs dry), condensed-phase oxidant source (none vs H2O2 vs Fenton chemistry), and irradiation (none vs UV) were all examined. For experiments conducted with aqueous particles but without any added oxidants, UV irradiation resulted in a small but measurable enhancement in the oxygen-to-carbon ratio (O/C). OA formed in the presence of aqueous oxidants was substantially more oxidized, with the highest oxidant concentrations leading to OA with an O/C as high as 1.4 for alpha-pinene and 2.0 for isoprene, strongly suggesting the formation of oxalate. High aqueous oxidant levels also resulted in increased loss of carbon from the condensed phase. This OA was more oxidized than in any other ozonolysis experiment reported to date, indicating that, when present, aqueous oxidants can have a dramatic effect on SOA formation. However, oxidant concentrations within atmospheric aqueous particles remain poorly constrained, making it difficult to assess the impacts of aqueous-phase oxidation on the loadings and oxidation state of atmospheric OA. PMID- 26505271 TI - Pharmacological treatment of cardiac glycoside poisoning. AB - Cardiac glycosides are an important cause of poisoning, reflecting their widespread clinical usage and presence in natural sources. Poisoning can manifest as varying degrees of toxicity. Predominant clinical features include gastrointestinal signs, bradycardia and heart block. Death occurs from ventricular fibrillation or tachycardia. A wide range of treatments have been used, the more common including activated charcoal, atropine, beta-adrenoceptor agonists, temporary pacing, anti-digoxin Fab and magnesium, and more novel agents include fructose-1,6-diphosphate (clinical trial in progress) and anticalin. However, even in the case of those treatments that have been in use for decades, there is debate regarding their efficacy, the indications and dosage that optimizes outcomes. This contributes to variability in use across the world. Another factor influencing usage is access. Barriers to access include the requirement for transfer to a specialized centre (for example, to receive temporary pacing) or financial resources (for example, anti-digoxin Fab in resource poor countries). Recent data suggest that existing methods for calculating the dose of anti-digoxin Fab in digoxin poisoning overstate the dose required, and that its efficacy may be minimal in patients with chronic digoxin poisoning. Cheaper and effective medicines are required, in particular for the treatment of yellow oleander poisoning which is problematic in resource poor countries. PMID- 26505272 TI - Low-Dose Actinomycin-D Induces Redistribution of Wild-Type and Mutated Nucleophosmin Followed by Cell Death in Leukemic Cells. AB - Specific mutations involving C-terminal part of the nucleolar protein nucleophosmin (NPM) are associated with better outcome of acute myeloid leukemia (AML) therapy, possibly due to aberrant cytoplasmic NPM localization facilitating induction of anti-NPM immune response. Actinomycin D (actD) is known to induce nucleolar stress leading to redistribution of many nucleolar proteins, including NPM. We analyzed the distribution of both wild-type and mutated NPM (NPMmut) in human cell lines, before and after low-dose actD treatment, in living cells expressing exogenous fluorescently labeled proteins as well as using immunofluorescence staining of endogenous proteins in fixed cells. The wild-type NPM form is prevalently nucleolar in intact cells and relocalizes mainly to the nucleoplasm following actD addition. The mutated NPM form is found both in the nucleoli and in the cytoplasm of untreated cells. ActD treatment leads to a marked increase in NPMmut amount in the nucleoplasm while a mild decrease is observed in the cytoplasm. Cell death was induced by low-dose actD in all the studied leukemic cell lines with different p53 and NPM status. In cells expressing the tumor suppresor p53 (CML-T1, OCI-AML3), cell cycle arrest in G1/G0 phase was followed by p53-dependent apoptosis while in p53-null HL60 cells, transient G2/M-phase arrest was followed by cell necrosis. We conclude that although actD does not increase NPM concentration in the cytoplasm, it could improve the effect of standard chemotherapy in leukemias through more general mechanisms. PMID- 26505273 TI - Massively parallel DNA sequencing from routinely processed cytological smears. AB - BACKGROUND: Data generated by next-generation sequencing technologies have a pivotal role in precision medicine. These high-throughput techniques are preferentially performed on fresh tissue, but there is an increasing need for protocols adapted to materials derived from formalin-fixed, paraffin-embedded tissue and cytology specimens. METHODS: The aim of this work was to show that cytological material collected from archival smears processed for routine diagnoses could be used for massively parallel sequencing and array-based genomic analysis for further studies. RESULTS: As a proof of concept, data obtained from May-Grunwald Giemsa- and Diff-Quik-stained archival smears were shown to be in keeping with those obtained from matched frozen controls. CONCLUSIONS: The quality of DNA extracted from routinely processed smears is compatible with the multitargeted sequencing of a large series of genes of interest with methods such as array-based genomic analysis and whole-exome sequencing. PMID- 26505274 TI - Molecular Topology and Local Dynamics Govern the Viscosity of Imidazolium-Based Ionic Liquids. AB - A series of branched ionic liquids (ILs) based on the 1-(iso-alkyl)-3 methylimidazolium cation from 1-(1-methylethyl)-3-methylimidazolium bistriflimide to 1-(5-methylhexyl)-3-methylimidazolium bistriflimide and linear ILs based on the 1-(n-alkyl)-3-methylimidazolium cation from 1-propyl-3-methylimidazolium bistriflimide to 1-heptyl-3-methylimidazolum bistriflimide were recently synthesized and their physicochemical properties characterized. For the ILs with the same number of carbons in the alkyl chain, the branched IL was found to have the same density but higher viscosity than the linear one. In addition, the branched IL 1-(2-methylpropyl)-3-methylimidazolium bistriflimide ([2mC3C1Im][NTf2]) was found to have an abnormally high viscosity. Motivated by these experimental observations, the same ILs were studied using molecular dynamics (MD) simulations in the current work. The viscosities of each IL were calculated using the equilibrium MD method at 400 K and the nonequilibrium MD method at 298 K. The results agree with the experimental trend. The ion pair (IP) lifetime, spatial distribution function, and associated potential of mean force, cation size and shape, and interaction energy components were calculated from MD simulations. A quantitative correlation between the liquid structure and the viscosity was observed. Analysis shows that the higher viscosities in the branched ILs are due to the relatively more stable packing between the cations and anions indicated by the lower minima in the potential of mean force (PMF) surface. The abnormal viscosity of [2mC3C1Im][NTf2] was found to be the result of the specific side chain length and molecular structure. PMID- 26505275 TI - A case-control study of occupational sunlight exposure and renal cancer risk. AB - Epidemiological evidence of a relationship between vitamin D and kidney cancer risk has been inconsistent despite experimental data indicating that vitamin D and its metabolites may inhibit carcinogenesis. Previously we reported an inverse association between renal cell carcinoma (RCC) risk and occupational ultraviolet (UV) exposure among European men. In this study, we examined the association between occupational UV exposure and RCC risk among US residents and investigated whether this association varied by race and sex. Lifetime occupational data for 1,217 RCC cases and 1,235 controls in a population-based case-control study, conducted from 2002 to 2007, were assessed for occupational UV exposure. We evaluated exposure metrics in quartiles based on control exposure levels and calculated associations between RCC risk and occupational UV exposure using unconditional logistic regression adjusted for sex, race, body mass index, smoking, hypertension, center, education, family history of cancer and dietary vitamin D intake. A general pattern of decreasing RCC risk with increasing UV exposure was observed. Cases had significantly lower cumulative occupational UV exposure than controls (fourth quartile vs. first: odds ratio = 0.74 [95% confidence interval = 0.56-0.99], p-trend = 0.03). Similar results were observed for other UV exposure metrics. The association with occupational UV exposure was stronger for women than for men, but did not differ by race. Our findings suggest an inverse association between occupational UV exposure and RCC, particularly among women. Given the sex finding discrepancies in this study versus our previous study, additional research is need to clarify whether the protective effects of occupational UV exposure and RCC risk are real. PMID- 26505276 TI - Comparative Toxicity of Chlorinated Saline and Freshwater Wastewater Effluents to Marine Organisms. AB - Toilet flushing with seawater results in saline wastewater, which may contain approximately 33-50% seawater. Halogenated disinfection byproducts (DBPs), especially brominated and iodinated DBPs, have recently been found in chlorinated saline wastewater effluents. With the occurrence of brominated and iodinated DBPs, the adverse effects of chlorinated saline wastewater effluents to marine ecology have been uncertain. By evaluating the developmental effects in the marine polychaete Platynereis dumerilii directly exposed to chlorinated saline/freshwater wastewater effluents, we found surprisingly that chlorinated saline wastewater effluents were less toxic than a chlorinated freshwater wastewater effluent. This was also witnessed by the marine alga Tetraselmis marina. The toxicity of a chlorinated wastewater effluent to the marine species was dominated by its relatively low salinity compared to the salinity in seawater. The organic matter content in a chlorinated wastewater effluent might be partially responsible for the toxicity. The adverse effects of halogenated DBPs on the marine species were observed pronouncedly only in the "concentrated" chlorinated wastewater effluents. pH and ammonia content in a wastewater effluent caused no adverse effects on the marine species. The results suggest that using seawater to replace freshwater for toilet flushing might mitigate the "direct" acute detrimental effect of wastewater to the marine organisms. PMID- 26505277 TI - Topological Motifs in Cyanometallates: From Building Units to Three-Periodic Frameworks. AB - This review focuses on topological features of three-periodic (framework) p, d, and f metal cyano complexes or cyanometallates, i.e. coordination compounds, where CN(-) ligands play the main structure-forming role. In addition, molecular, one-periodic (chain), and two-periodic (layer) cyanometallates are considered as possible building blocks of the three-periodic cyanometallates. All cyanometallates are treated as systems of nodes (mononuclear, polynuclear, or transitional metal cluster complexes) joined together via CN-containing spacers. The most typical nodes and spacers as well as methods of their connection are described and systematized. Particular attention is paid to the overall structural motifs in the three-periodic cyanometallates, especially to the relations between the local coordination (coordination figure) of structural units and the entire framework topology. The chemical factors are discussed that influence the cyanometallate topological properties due to modification of nodes, spacers, or coordination figures. PMID- 26505278 TI - Measurement of Lung Phosphatidylcholines in Exhaled Breath Particles by a Convenient Collection Procedure. AB - An analytical method based on high-performance liquid chromatography coupled to quadrupole tandem mass spectrometry was developed for the quantitative determination of four phosphatidylcholines (PCs) in human exhaled breath particles. Analytes were conveniently collected on an electrostatic polymer filter and extracted with methanol prior to analysis. Chromatographic separation was performed on an ultraperformance liquid chromatographic ethylene bridged hybrid phenyl column using a mobile phase consisting of water and methanol containing 4 mM ammonium formate and 0.1% ammonia. The mass spectrometer operated in positive electrospray ionization and selected reaction monitoring mode. Detection limits for PC 16:0/16:0 (dipalmitoylphosphatidylcholine, DPPC), PC 16:0/18:1, PC 16:0/18:2, and PC 18:0/18:2 were <0.01 ng/filter. Method recoveries at concentration levels of 0.1 and 10 ng/filter were 100-110% and 101-121%, respectively. Acceptable precision with coefficients of variation <20% and accuracies of 100% +/- 20% were achieved. Identification of the individual PCs was performed on the basis of two product ions with correct ion ratios and chromatographic retention times. The highest amount in exhaled breath was found for DPPC with median concentration 1.14 ng/filter (range 0.6-21 ng/filter), and median molar ratios of DPPC/PC (16:0/18:1) of 1.98 (range 0.48-2.75). A different pattern with lower molar ratio (~0.15) was found for oral fluid. The most significant element of this study was to use a precolumn in the LC system and to collecting exhaled particles in an electret polymer filter. Due to chromatographic interference by background contamination, an isolator column (PFC kit) was installed in between eluent mixer and injector to reduce contamination. This is the first LC/MS study where the method was successfully applied to analyze PCs in human exhaled breath by using a simple and convenient collection procedure. PMID- 26505279 TI - Non-fullerene electron acceptors for use in organic solar cells. AB - The active layer in a solution processed organic photovoltaic device comprises a light absorbing electron donor semiconductor, typically a polymer, and an electron accepting fullerene acceptor. Although there has been huge effort targeted to optimize the absorbing, energetic, and transport properties of the donor material, fullerenes remain as the exclusive electron acceptor in all high performance devices. Very recently, some new non-fullerene acceptors have been demonstrated to outperform fullerenes in comparative devices. This Account describes this progress, discussing molecular design considerations and the structure-property relationships that are emerging. The motivation to replace fullerene acceptors stems from their synthetic inflexibility, leading to constraints in manipulating frontier energy levels, as well as poor absorption in the solar spectrum range, and an inherent tendency to undergo postfabrication crystallization, resulting in device instability. New acceptors have to address these limitations, providing tunable absorption with high extinction coefficients, thus contributing to device photocurrent. The ability to vary and optimize the lowest unoccupied molecular orbital (LUMO) energy level for a specific donor polymer is also an important requirement, ensuring minimal energy loss on electron transfer and as high an internal voltage as possible. Initially perylene diimide acceptors were evaluated as promising acceptor materials. These electron deficient aromatic molecules can exhibit good electron transport, facilitated by close packed herringbone crystal motifs, and their energy levels can be synthetically tuned. The principal drawback of this class of materials, their tendency to crystallize on too large a length scale for an optimal heterojunction nanostructure, has been shown to be overcome through introduction of conformation twisting through steric effects. This has been primarily achieved by coupling two units together, forming dimers with a large intramolecular twist, which suppresses both nucleation and crystal growth. The generic design concept of rotationally symmetrical aromatic small molecules with extended pi orbital delocalization, including polyaromatic hydrocarbons, phthalocyanines, etc., has also provided some excellent small molecule acceptors. In most cases, additional electron withdrawing functionality, such as imide or ester groups, can be incorporated to stabilize the LUMO and improve properties. New calamitic acceptors have been developed, where molecular orbital hybridization of electron rich and poor segments can be judiciously employed to precisely control energy levels. Conformation and intermolecular associations can be controlled by peripheral functionalization leading to optimization of crystallization length scales. In particular, the use of rhodanine end groups, coupled electronically through short bridged aromatic chains, has been a successful strategy, with promising device efficiencies attributed to high lying LUMO energy levels and subsequently large open circuit voltages. PMID- 26505280 TI - Hierarchical Structure Formation of Nanoparticulate Spray-Dried Composite Aggregates. AB - The design of hierarchically structured nano- and microparticles of different sizes, porosities, surface areas, compositions, and internal structures from nanoparticle building blocks is important for new or enhanced application properties of high-quality products in a variety of industries. Spray-drying processes are well-suited for the design of hierarchical structures of multicomponent products. This structure design using various nanoparticles as building blocks is one of the most important challenges for the future to create products with optimized or completely new properties. Furthermore, the transfer of designed nanomaterials to large-scale products with favorable handling and processing can be achieved. The resultant aggregate structure depends on the utilized nanoparticle building blocks as well as on a large number of process and formulation parameters. In this study, structure formation and segregation phenomena during the spray drying process were investigated to enable the synthesis of tailor-made nanostructures with defined properties. Moreover, a theoretical model of this segregation and structure formation in nanosuspensions is presented using a discrete element method simulation. PMID- 26505281 TI - The Whole Is Other Than the Sum of the Parts. PMID- 26505282 TI - Understanding the Statics and Dynamics of the Subaxial Cervical Segments, Following C1-C2 Fusion. PMID- 26505283 TI - Neurocysticercosis-related mortality in Brazil, 2000-2011: Epidemiology of a neglected neurologic cause of death. AB - Neurocysticercosis (NCC) is an important cause of severe neurological disease mainly in low- and middle-income countries, but data on NCC mortality from endemic areas are scarce. Here we analysed the epidemiological patterns of NCC related mortality in Brazil. We included all deaths recorded in Brazil between 2000 and 2011, in which NCC was mentioned on death certificates, either as underlying or as associated cause of death. NCC was identified in 1829/12,491,280 deaths (0.015%), 1130 (61.8%) as underlying cause, and 699 (38.2%) as associated cause. Overall age-adjusted mortality rate for the period was 0.97 deaths/1,000,000 inhabitants (95% confidence interval [CI]: 0.83-1.12). The highest NCC-related mortality rates were found in males, elderly, white race/colour and residents in endemic states/regions. Age-adjusted mortality rates at national level decreased significantly over time (annual percent change [APC]: -4.7; 95% CI: -6.0 to -3.3), with a decrease in the Southeast, South and Central West regions, and a non-significant increasing trend in the North and Northeast regions. We identified spatial and spatiotemporal high-risk mortality clusters located mainly in NCC-endemic areas. Conditions related to the nervous system were the most commonly associated causes of death when NCC was mentioned as an underlying cause, and HIV/AIDS was the main underlying cause when NCC was an associated cause. NCC is a neglected and preventable cause of severe neurologic disease and death with high public health impact in Brazil. There is a clear need to strengthen nationwide epidemiological surveillance and control for the taeniasis/cysticercosis complex. PMID- 26505284 TI - Performance assessment of MCM-48 ceramic composite membrane by separation of AlCl3 from aqueous solution. AB - Three dimensional ordered mesoporous MCM-48 membrane was fabricated on a circular shaped ceramic support by in-situ hydrothermal method. The synthesized MCM-48 powder and MCM-48 ceramic composite membrane were characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA) and field emission scanning electron microscopy (FESEM). The porosity and pore size of the composite membrane are reduced considerably by the deposition of MCM-48 on the support. The formation of MCM-48 is verified by the XRD analysis. Three stepwise mechanisms for surfactant removal are observed by TGA analysis. FESEM images clearly signify the deposition of MCM-48 on the ceramic support. The pure water flux of the support and MCM-48 composite membrane is found to be 3.63*10-6 and 4.18*10 8m3/m2skPa, respectively. The above prepared MCM-48 ceramic composite membrane is employed for the removal of AlCl3 from aqueous solution and the highest rejection of 81% is obtained at an applied pressure of 276kPa with salt concentration of 250ppm. PMID- 26505285 TI - Studies on the interaction of heparin with lysozyme by multi-spectroscopic techniques and atomic force microscopy. AB - The interaction between heparin (Hep) and lysozyme (Lyso) in vitro was studied by fluorescence, UV-vis, circular dichroism (CD), resonance Rayleigh scattering (RRS) spectroscopy and atomic force microscopy (AFM) under normal physiological conditions. UV-vis spectra of Lyso showed the absorbance was significantly increased with the addition of Hep. Fluorescence studies revealed that the emission quenching of Lyso with Hep was initiated by static quenching mechanism. CD spectral studies showed that Hep induced conformational changes in the secondary structure of Lyso. RRS spectra of Lyso showed the intensity of scattering was significantly increased with the addition of Hep and the enhanced RRS intensities were proportional to the concentration of Hep in a certain range. Thus, a new RRS method using Lyso as a probe could be used for the determination of Hep. The detection limit for Hep was 3.9 ng mL(-1). In addition, the shape of the complex was characterized by AFM. The possible reaction mechanism and the reasons for the enhancement of RRS intensity had been discussed through experimental results. PMID- 26505286 TI - Binding analysis of carbon nanoparticles to human immunoglobulin G: Elucidation of the cytotoxicity of CNPs and perturbation of immunoglobulin conformations. AB - The chemical compositions, sizes and fluorescent properties of synthesized carbon nanoparticles (CNPs) were characterized. Escherichia coli (E. coli) cells were used as a model to study the cytotoxicity of CNPs, and the results of the cellular uptake of CNPs yielded excellent results: the CNPs demonstrated good biocompatibility and were non-toxic to the growth of the E. coli cells. Moreover, to assess the potential toxicity of CNPs to human health, the binding behavior of CNPs with human immunoglobulin G (HIgG) was examined by fluorescence quenching spectroscopy, synchronous fluorescence spectroscopy and circular dichroism spectroscopy under physiological conditions. The fluorescence quenching constants and parameters for the interaction at different temperatures had been calculated according to Scatchard. The thermodynamic parameters, such as enthalpy change (DeltaH), entropy change (DeltaS) and free energy change (DeltaG), were calculated, and the results indicated strong static quenching and showed that van der Waals forces, hydrogen bonds and hydrophobic interactions were the predominant intermolecular forces stabilizing the CNP-HIgG complex. Synchronous fluorescence and circular dichroism spectra provided information regarding the conformational alteration of HIgG in the presence of CNPs. These findings help to characterize the interactions between CNPs and HIgG, which may clarify the potential risks and undesirable health effects of CNPs, as well as the related cellular trafficking and systemic translocation. PMID- 26505287 TI - Biased perception about gene technology: How perceived naturalness and affect distort benefit perception. AB - In two experiments, the participants showed biased responses when asked to evaluate the benefits of gene technology. They evaluated the importance of additional yields in corn fields due to a newly introduced variety, which would increase a farmer's revenues. In one condition, the newly introduced variety was described as a product of traditional breeding; in the other, it was identified as genetically modified (GM). The two experiments' findings showed that the same benefits were perceived as less important for a farmer when these were the result of GM crops compared with traditionally bred crops. Mediation analyses suggest that perceived naturalness and the affect associated with the technology per se influence the interpretation of the new information. The lack of perceived naturalness of gene technology seems to be the reason for the participants' perceived lower benefits of a new corn variety in the gene technology condition compared with the perceptions of the participants assigned to the traditional breeding condition. The strategy to increase the acceptance of gene technology by introducing plant varieties that better address consumer and producer needs may not work because people discount its associated benefits. PMID- 26505288 TI - Pre-exposure to food temptation reduces subsequent consumption: A test of the procedure with a South-African sample. AB - It has been suggested that the consumption of unhealthy Westernized diet in a context of poverty and resultant food insecurity may have contributed to South Africa's status of the third fattest country in the World. Considering that a number of South-Africans are reported to have experienced, or are still experiencing food insecurity, procedures which have been shown to reduce the consumption of unhealthy food in higher income countries may be ineffective in South-Africa. We thus tested the robustness of the so called pre-exposure procedure in South-Africa. We also tested the moderating role of childhood poverty in the pre-exposure procedure. With the pre-exposure procedure, a respondent is exposed to a tempting unhealthy food (e.g. candy) in a context that is designed such that eating the food interferes with a task goal. The typical result is that this procedure spills over and reduces consumption of similar tempting food later on. An experimental study conducted in a South-African laboratory showed that the pre-exposure effect is robust even with a sample, where food insecurity prevails. Childhood poverty did not moderate the effect. This study proves that behavioral procedures aimed at reducing the consumption of unhealthy food would be valuable in less rich non-Western countries. Further testing of the robustness of the pre-exposure effect is however recommended in other poorer food insecure countries. PMID- 26505289 TI - A qualitative study of the role of food in family relationships: An insight into the families of Brazilian obese adolescents using photo elicitation. AB - Obesity in adolescence is a major public health issue in Brazil. The relation between food and family plays an important role in both prevention and treatment, although its precise effect has not been clearly established. The purpose of this study is to investigate the meanings of food for Brazilian obese adolescents and their parents. Semi-structured interviews were conducted with 19 individuals from two medical centers in Fortaleza-CE, Brazil: seven adolescents with obesity (six girls and one boy aged between 12 and 18 years) and their parents (seven mothers, four fathers and one grandmother). The researchers used photo elicitation for the interview; that is, one photograph taken by each adolescent was used to evoke the statements we analyze here, according to Interpretative Phenomenological Analysis. The results were categorized into two principal superordinate themes. The first described the role of food in the parent-child relationship and the second, the organization of the family group. Results show that food reinforces the adolescents' dependence on their parents and the conflicts related to parental control of their food and what they can eat. The interrelations between food and family dynamics must be considered in developing therapeutic strategies for Brazilian obese adolescents and their families. These strategies must include siblings as well as grandparents. PMID- 26505292 TI - Correction to "Enantioselective Ruthenium-Catalyzed 1,3-Dipolar Cycloadditions between C-Carboalkoxy Ketonitrones and Methacrolein: Solvent Effect on Reaction Selectivity and Its Rationale". PMID- 26505290 TI - Depressive Symptoms in Children with Chronic Kidney Disease. AB - OBJECTIVE: To assess depression in children with chronic kidney disease and to determine associations with patient characteristics, intellectual and educational levels, and health-related quality of life (HRQoL). STUDY DESIGN: Subjects aged 6 17 years from the Chronic Kidney Disease in Children cohort study completed the Children's Depression Inventory (CDI), Wechsler Abbreviated Scales of Intelligence, Wechsler Individual Achievement Test-II-Abbreviated, and the Pediatric Inventory of Quality of Life Core Scales 4.0. Regression analyses determined associations of CDI score and depression status with subject characteristics, intellectual and educational levels, and HRQoL. A joint linear mixed model and Weibull model were used to determine the effects of CDI score on longitudinal changes in glomerular filtration rate and time to renal replacement therapy. RESULTS: A total of 344 subjects completed the CDI. Eighteen (5%) had elevated depressive symptoms, and another 7 (2%) were being treated for depression. In adjusted analyses, maternal education beyond high school was associated with 5% lower CDI scores (estimate, 0.95; 95% CI, 0.92-0.99). Depression status was associated with lower IQ (99 vs 88; P = .053), lower achievement (95 vs 77.5; P < .05), and lower HRQoL by parent and child reports (effect estimates, -15.48; 95% CI, -28.71 to -2.24 and -18.39; 95% CI, -27.81 to 8.96, respectively). CDI score was not related to change in glomerular filtration rate. CONCLUSION: Children with depression had lower psychoeducational skills and worse HRQoL. Identifying and treating depression should be evaluated as a means of improving the academic performance and HRQoL of children with chronic kidney disease. PMID- 26505291 TI - Mental Health Screening Outcomes in a Pediatric Specialty Care Setting. AB - OBJECTIVE: To evaluate whether a psychosocial screening program that included free and flexible access to mental health (MH) consultation resulted in increased rate of consultations. STUDY DESIGN: This is a post hoc review of a clinical screening program in a pediatric food allergy clinic in New York City. Screening was limited to 2 days per week, providing an opportunity to compare screened and nonscreened cohorts. Previous results from more than 1000 other families were analyzed to create the 1-page screening questionnaire. Participants were children with allergies and their parents who sought care at the clinic between March and September 2013. Parents were screened for distress and quality of life burden related to their child's allergy, and children were screened for anxiety, bullying, and quality of life. The predefined primary outcome was the percentage of families who received the free MH consultation after screening vs no-screening days in the allergy clinic. RESULTS: The 3143 encounters during the study period included 1171 on screening days and 1972 on no-screening days. Most (86%) eligible families completed the screen. Almost one-half (44%) met the initial screening thresholds. A total of 71 families (6.1% of screening days encounters) were referred to a MH consultation after a secondary review, but only 11 (1% of screening days encounters) scheduled a MH appointment. Eighteen families from the no-screening days came to a MH evaluation (1% of no-screening days encounters). CONCLUSION: Screening did not lead to enhanced MH follow-up. Resources may be better used on ensuring the availability of MH care rather than on screening in pediatric specialty clinics. PMID- 26505293 TI - Endosomal Toll-Like Receptor Status in Patients with Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) predisposes to both diabetes and cardiovascular disease, and inflammation is pivotal in MetS. The Toll-like receptors (TLRs), TLR2 and TLR4, are implicated in both diabetes and atherosclerosis, are increased in MetS, and contribute to the inflammatory burden. Recent studies also suggest an evolving role of endosomal TLRs in diabetic complications. However, there is a paucity of data with regard to the expression of endosomal TLRs such as TLR3, 7-9 in MetS. AIM: Thus, in this short report, we examine expression of monocytes TLR3 and TLR9 in our cohort of subjects with nascent MetS compared to matched controls. SUBJECTS AND METHODS: Monocytes were isolated from subjects with MetS (n = 45) and matched controls (n = 37), respectively, and TLR3 and TLR9 expression was assessed by intracellular flow cytometry and correlated with nuclear factor (NF)-kappaB expression. RESULTS: We demonstrate increased endosomal TLR9 expression in MetS compared to controls that correlate with increased nuclear NF-kappaB expression in the monocytes of these subjects, with no change in TLR3 protein. CONCLUSION: Future studies are required to confirm these findings and determine the role of TLR9 in the increased cardiovascular risk in MetS. PMID- 26505294 TI - Three new anti-HBV active constituents from the traditional Chinese herb of Yin Chen (Artemisia scoparia). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yin-Chen is a famous traditional Chinese medicine (TCM) in China for the treatment of acute and chronic hepatitis. Two species, namely Artemisia scoparia and Artemisia capillaris, are documented in Chinese Pharmacopoeia as the authentic resources for Yin-Chen. Previous investigation has proved that chlorogenic acid analogs and phenolic acids are two main types of the anti-HBV active constituents of A. capillaris. However, there is no investigation concerned with the anti-HBV components of A. scoparia. AIM OF THE STUDY: The aim of the present study is to recognize the new anti-HBV constituents of A. scoparia by detailed LCMS analyses. MATERIALS AND METHODS: LCMS and bioassay-guided fractionation on the active part of A. scoparia led to the isolation of three new compounds. Their structures were determined by detailed spectroscopic analyses. Anti-HBV assay involving inhibition on HBsAg and HBeAg secretions and HBV DNA replication were performed in virto on HepG 2.2.15 cell line. RESULTS: The 90% ethanol extract of A. scoparia was revealed with anti-HBV activity for the first time, which was further separated into several fractions by column chromatography. Fr. D-4 was revealed with the highest anti-HBV activity, from which three new compounds including one unusual 4-pyridone glucoside (1) and two polyacetylene glucosides (2-3) were isolated under the guidance of LCMS analyses. Compounds 1-3 exhibited activity against the secretions of HBsAg and HBeAg, and HBV DNA replication. In particular, compounds 2 and 3 inhibited HBV DNA replication with IC50 values of 0.07 +/- 0.04 and 0.012 +/- 0.05 mM, with SI values of 23.6 and 17.1, respectively. Based on the MS/MS experiment, the fragmentation pathways of 1 in both positive and negative modes, and 2 and 3 in negative mode were proposed. The ion pairs of 388-208 (positive) and 432-206 (negative) for 1, 503-341 (negative) for 2, and 503-203 (negative) for 3, could be recognized as their respective diagnostic ions. CONCLUSIONS: The first time investigation on the anti-HBV constituents of A. scoparia yielded three new active compounds, which will provide valuable information for understanding the ethnopharmacological usage of Yin-Chen, as well as the chemical difference with A. capillaris. PMID- 26505295 TI - Antidiabetic properties of lyophilized extract of acorn (Quercus brantii Lindl.) on experimentally STZ-induced diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acorn obtained from the Quercus brantii Lindl. (QB) tree has been used in Turkish folk medicine. Some studies have reported as an antioxidant, antimicrobial, anti-inflammatory, gastroprotective, antitumoural of QB properties previously. however, its effect on the management of type diabetic 2 and oxidative stress complications is still unexplored. The aims of our study were the evaluation of the protective effect and antioxidant role of acorn lyophilized seed plant extract against STZ-induced diabetic complications as oxidative stress, hepatotoxicity and nephropathy, lipidemia and serum biomarkers of diabetes (SBD). MATERIALS AND METHODS: In-vivo studies were performed on STZ-induced diabetic rats Experiment was designed as I [Normal Control (NC)], II [Diabetes mellitus (DM)], III [DM+Acarbose (20mg/kg b.w) (DM+AC 20)], IV [DM+QB (100mg/kg b.w) (DM+QB-100)], V [DM+QB (250 mg/kg b.w) (DM+QB 250)] and VI [DM+QB (500 mg/kg b.w) (DM+QB-500)] groups. RESULTS: This study showed that the biochemical analysis showed a considerable increase in the HRDB, DB, LP, MDA and fluctuated ADSC in the II group as compared to that of control group whereas, AC and the plant lyophilized seed plant extract supplementations diet restored the STZ-induced diabetic complications towards the control. alpha glycosidase activity in DM group showed statistically significant increase with respect to control group in small intestine. Moreover, in accordance with the effects of seed extract; in diabetic rat groups to whom acorn seed extract and acarbose were given, the levels of almost all the concerned parameters were reached to the ones measured at control group. As a result, it was concluded that acorn seed extract had certain healing effects on many complications caused by diabetes. PMID- 26505296 TI - A joint compressed-sensing and super-resolution approach for very high-resolution diffusion imaging. AB - Diffusion MRI (dMRI) can provide invaluable information about the structure of different tissue types in the brain. Standard dMRI acquisitions facilitate a proper analysis (e.g. tracing) of medium-to-large white matter bundles. However, smaller fiber bundles connecting very small cortical or sub-cortical regions cannot be traced accurately in images with large voxel sizes. Yet, the ability to trace such fiber bundles is critical for several applications such as deep brain stimulation and neurosurgery. In this work, we propose a novel acquisition and reconstruction scheme for obtaining high spatial resolution dMRI images using multiple low resolution (LR) images, which is effective in reducing acquisition time while improving the signal-to-noise ratio (SNR). The proposed method called compressed-sensing super resolution reconstruction (CS-SRR), uses multiple overlapping thick-slice dMRI volumes that are under-sampled in q-space to reconstruct diffusion signal with complex orientations. The proposed method combines the twin concepts of compressed sensing and super-resolution to model the diffusion signal (at a given b-value) in a basis of spherical ridgelets with total-variation (TV) regularization to account for signal correlation in neighboring voxels. A computationally efficient algorithm based on the alternating direction method of multipliers (ADMM) is introduced for solving the CS-SRR problem. The performance of the proposed method is quantitatively evaluated on several in-vivo human data sets including a true SRR scenario. Our experimental results demonstrate that the proposed method can be used for reconstructing sub-millimeter super resolution dMRI data with very good data fidelity in clinically feasible acquisition time. PMID- 26505298 TI - Brain-robot interface driven plasticity: Distributed modulation of corticospinal excitability. AB - Brain-robot interfaces (BRI) are studied as novel interventions to facilitate functional restoration in patients with severe and persistent motor deficits following stroke. They bridge the impaired connection in the sensorimotor loop by providing brain-state dependent proprioceptive feedback with orthotic devices attached to the hand or arm of the patients. The underlying neurophysiology of this BRI neuromodulation is still largely unknown. We investigated changes of corticospinal excitability with transcranial magnetic stimulation in thirteen right-handed healthy subjects who performed 40min of kinesthetic motor imagery receiving proprioceptive feedback with a robotic orthosis attached to the left hand contingent to event-related desynchronization of the right sensorimotor cortex in the beta-band (16-22Hz). Neural correlates of this BRI intervention were probed by acquiring the stimulus-response curve (SRC) of both motor evoked potential (MEP) peak-to-peak amplitudes and areas under the curve. In addition, a motor mapping was obtained. The specificity of the effects was studied by comparing two neighboring hand muscles, one BRI-trained and one control muscle. Robust changes of MEP amplitude but not MEP area occurred following the BRI intervention, but only in the BRI-trained muscle. The steep part of the SRC showed an MEP increase, while the plateau of the SRC showed an MEP decrease. MEP mapping revealed a distributed pattern with a decrease of excitability in the hand area of the primary motor cortex, which controlled the BRI, but an increase of excitability in the surrounding somatosensory and premotor cortex. In conclusion, the BRI intervention induced a complex pattern of modulated corticospinal excitability, which may boost subsequent motor learning during physiotherapy. PMID- 26505299 TI - Premises of plasticity - And the loneliness of the medial temporal lobe. AB - In this perspective paper, we examine possible premises of plasticity in the neural substrates underlying cognitive change. We take the special role of the medial temporal lobe as an anchoring point, but also investigate characteristics throughout the cortex. Specifically, we examine the dimensions of evolutionary expansion, heritability, variability of morphometric change, and inter-individual variance in myelination with respect to the plastic potential of different brain regions. We argue that areas showing less evolutionary expansion, lower heritability, greater variability of cortical thickness change through the lifespan, and greater inter-individual differences in intracortical myelin content have a great extent of plasticity. While different regions of the brain show these features to varying extent, analyses converge on the medial temporal lobe including the hippocampi as the target of all these premises. We discuss implications for effects of training on brain structures, and conditions under which plasticity may be evoked. PMID- 26505297 TI - Application of neurite orientation dispersion and density imaging (NODDI) to a tau pathology model of Alzheimer's disease. AB - Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease. PMID- 26505300 TI - Bilingualism at the core of the brain. Structural differences between bilinguals and monolinguals revealed by subcortical shape analysis. AB - Naturally acquiring a language shapes the human brain through a long-lasting learning and practice process. This is supported by previous studies showing that managing more than one language from early childhood has an impact on brain structure and function. However, to what extent bilingual individuals present neuroanatomical peculiarities at the subcortical level with respect to monolinguals is yet not well understood, despite the key role of subcortical gray matter for a number of language functions, including monitoring of speech production and language control - two processes especially solicited by bilinguals. Here we addressed this issue by performing a subcortical surface based analysis in a sample of monolinguals and simultaneous bilinguals (N=88) that only differed in their language experience from birth. This analysis allowed us to study with great anatomical precision the potential differences in morphology of key subcortical structures, namely, the caudate, accumbens, putamen, globus pallidus and thalamus. Vertexwise analyses revealed significantly expanded subcortical structures for bilinguals compared to monolinguals, localized in bilateral putamen and thalamus, as well as in the left globus pallidus and right caudate nucleus. A topographical interpretation of our results suggests that a more complex phonological system in bilinguals may lead to a greater development of a subcortical brain network involved in monitoring articulatory processes. PMID- 26505301 TI - Carbon-wire loop based artifact correction outperforms post-processing EEG/fMRI corrections--A validation of a real-time simultaneous EEG/fMRI correction method. AB - Simultaneous EEG-fMRI combines two powerful neuroimaging techniques, but the EEG signal suffers from severe artifacts in the MRI environment that are difficult to remove. These are the MR scanning artifact and the blood-pulsation artifact- strategies to remove them are a topic of ongoing research. Additionally large, unsystematic artifacts are produced across the full frequency spectrum by the magnet's helium pump (and ventilator) systems which are notoriously hard to remove. As a consequence, experimenters routinely deactivate the helium pump during simultaneous EEG-fMRI acquisitions which potentially risks damaging the MRI system and necessitates more frequent and expensive helium refills. We present a novel correction method addressing both helium pump and ballisto cardiac (BCG) artifacts, consisting of carbon-wire loops (CWL) as additional sensors to accurately track unpredictable artifacts related to subtle movements in the scanner, and an EEGLAB plugin to perform artifact correction. We compare signal-to-noise metrics of EEG data, corrected with CWL and three conventional correction methods, for helium pump off and on measurements. Because the CWL setup records signals in real-time, it fits requirements of applications where immediate correction is necessary, such as neuro-feedback applications or stimulation time-locked to specific sleep oscillations. The comparison metrics in this paper relate to: (1) the EEG signal itself, (2) the "eyes open vs. eyes closed" effect, and (3) an assessment of how the artifact corrections impacts the ability to perform meaningful correlations between EEG alpha power and the BOLD signal. Results show that the CWL correction corrects for He pump artifact and also produces EEG data more comparable to EEG obtained outside the magnet than conventional post-processing methods. PMID- 26505302 TI - Encodings of implied motion for animate and inanimate object categories in the two visual pathways. AB - Previous research has proposed two separate pathways for visual processing: the dorsal pathway for "where" information vs. the ventral pathway for "what" information. Interestingly, the middle temporal cortex (MT) in the dorsal pathway is involved in representing implied motion from still pictures, suggesting an interaction between motion and object related processing. However, the relationship between how the brain encodes implied motion and how the brain encodes object/scene categories is unclear. To address this question, fMRI was used to measure activity along the two pathways corresponding to different animate and inanimate categories of still pictures with different levels of implied motion speed. In the visual areas of both pathways, activity induced by pictures of humans and animals was hardly modulated by the implied motion speed. By contrast, activity in these areas correlated with the implied motion speed for pictures of inanimate objects and scenes. The interaction between implied motion speed and stimuli category was significant, suggesting different encoding mechanisms of implied motion for animate-inanimate distinction. Further multivariate pattern analysis of activity in the dorsal pathway revealed significant effects of stimulus category that are comparable to the ventral pathway. Moreover, still pictures of inanimate objects/scenes with higher implied motion speed evoked activation patterns that were difficult to differentiate from those evoked by pictures of humans and animals, indicating a functional role of implied motion in the representation of object categories. These results provide novel evidence to support integrated encoding of motion and object categories, suggesting a rethink of the relationship between the two visual pathways. PMID- 26505304 TI - The European saber-toothed cat (Homotherium latidens) found in the "Spear Horizon" at Schoningen (Germany). AB - The 300,000 year old Lower Paleolithic site Schoningen 13 II-4 became world famous with the discovery of the oldest well-preserved and complete wooden spears. Through ongoing excavations, new archaeological discoveries of scientific importance are still being made from the same archaeological layer where the spears were found. In this context, remains of a rare carnivore species, the European saber-toothed cat (Homotherium latidens), were recovered. Here we present five teeth and one humerus fragment that are unambiguously from two individual saber-toothed cats. The humerus is a unique specimen; it shows evidence of hominin impacts and use as a percussor. The Homotherium remains from Schoningen are the best documented finds of this species in an archaeological setting and they are amongst the youngest specimens of Homotherium in Europe. The presence of this species as a carnivore competitor would certainly have impacted the lives of late Middle Pleistocene hominins. The discovery illustrates the possible day-to-day challenges that the Schoningen hominins would have faced and suggests that the wooden spears were not necessarily only used for hunting, but possibly also as a weapon for self-defense. PMID- 26505303 TI - Brain basis of communicative actions in language. AB - Although language is a key tool for communication in social interaction, most studies in the neuroscience of language have focused on language structures such as words and sentences. Here, the neural correlates of speech acts, that is, the actions performed by using language, were investigated with functional magnetic resonance imaging (fMRI). Participants were shown videos, in which the same critical utterances were used in different communicative contexts, to Name objects, or to Request them from communication partners. Understanding of critical utterances as Requests was accompanied by activation in bilateral premotor, left inferior frontal and temporo-parietal cortical areas known to support action-related and social interactive knowledge. Naming, however, activated the left angular gyrus implicated in linking information about word forms and related reference objects mentioned in critical utterances. These findings show that understanding of utterances as different communicative actions is reflected in distinct brain activation patterns, and thus suggest different neural substrates for different speech act types. PMID- 26505305 TI - Treatment of murine lupus with PD-LIg. AB - The binding of programmed death 1 (PD-1) to its ligands PD-L1 and PD-L2 on antigen-presenting cells has been proven to turn off autoreactive T cells and induce peripheral tolerance. In this study, fusion proteins linking the extracellular domains of murine PD-1, PD-L1 and PD-L2 to the Fc portion of a mouse immunoglobulin G2a monoclonal antibody were generated and characterized. Onset of proteinuria was delayed with mice treated with PD-LIg fusion proteins, while serum concentrations of anti-dsDNA and anti-histone antibodies were reduced by the treatment of PD-LIg without decreasing total IgG with significantly improved survival. Importantly, PD-L1Ig treatment was the most efficacious in delaying the onset of proteinuria, blocking auto-antibody production, and prolonging life time, including a delayed treatment until disease progression. These findings indicate that human PD-L1Ig fusion proteins may play an important role in conquering humans' autoimmune diseases. PMID- 26505306 TI - Klebsiella pneumoniae O antigen loss alters the outer membrane protein composition and the selective packaging of proteins into secreted outer membrane vesicles. AB - Klebsiella pneumoniae is a nosocomial pathogen which naturally secretes lipopolysaccharide (LPS) and cell envelope associated proteins into the environment through the production of outer membrane vesicles (OMVs). The loss of the LPS O antigen has been demonstrated in other bacterial species to significantly alter the composition of OMVs. Therefore, this study aimed to comprehensively analyze the impact of O antigen loss on the sub-proteomes of both the outer membrane and secreted OMVs from K. pneumoniae. As determined by LC MS/MS, OMVs were highly enriched with outer membrane proteins involved in cell wall, membrane, and envelope biogenesis as compared to the source cellular outer membrane. Deletion of wbbO, the enzyme responsible for O antigen attachment to LPS, decreased but did not eliminate this enrichment effect. Additionally, loss of O antigen resulted in OMVs with increased numbers of proteins involved in post translational modification, protein turnover, and chaperones as compared to secreted vesicles from the wild type. This alteration of OMV composition may be a compensatory mechanism to deal with envelope stress. This comprehensive analysis confirms the highly distinct protein composition of OMVs as compared to their source membrane, and provides evidence for a selective sorting mechanism that involves LPS polysaccharides. These data support the hypothesis that modifications to LPS alters both the mechanics of protein sorting and the contents of secreted OMVs and significantly impacts the protein composition of the outer membrane. PMID- 26505307 TI - MoARG1, MoARG5,6 and MoARG7 involved in arginine biosynthesis are essential for growth, conidiogenesis, sexual reproduction, and pathogenicity in Magnaporthe oryzae. AB - Arginine is one of the most versatile amino acids in eukaryote cells, which plays important roles in a multitude of processes such as protein synthesis, nitrogen metabolism, nitric oxide (NO) and urea biosynthesis. The de novo arginine biosynthesis pathway is conserved among fungal kingdom, but poorly understood in plant pathogenic fungi. Here, we characterized the functions of three synthetic enzyme-encoding genes MoARG1, MoARG5,6, and MoARG7, which involved the seventh step, second-third step and fifth step of arginine biosynthesis in Magnaporthe oryzae, respectively. Deletion of MoARG1 or MoARG5,6, resulted in arginine auxotrophic mutants, which had a strict requirement for arginine on minimal medium (MM). Both DeltaMoarg1 and DeltaMoarg5,6 severely reduced in aerial hyphal growth, pigmentation, conidiogenesis, sexual reproduction and pathogenicity. Interestingly, like Saccharomyces cerevisiae, deletion of MoARG7 caused a leaky arginine auxotrophy, and attenuated pathogenicity. Limited appressorium-mediated penetration and restricted invasive hyphae growth in host cells are responsible for the severely attenuated pathogenicity of the Arg(-) mutants. Additionally, we monitored the NO generation during conidial germination and appressorial formation in both Arg(-) mutants and wild type, and demonstrated that NO generation may not occur via arginine-dependent pathway in M. oryzae. In summary, MoARG1, MoARG5,6, and MoARG7 are required for growth, conidiogenesis, sexual reproduction, and pathogenicity in M. oryzae. PMID- 26505308 TI - Effect of retS gene on antibiotics production in Pseudomonas fluorescens FD6. AB - A hybrid sensor kinase termed RetS (regulator of exopolysaccharide and Type III secretion) controls expression of numerous genes in Pseudomonas aeruginosa. To investigate the function of RetS in P. fluorescens FD6, the retS gene was disrupted. Genetic inactivation of retS resulted in enhanced production of 2, 4 diacetylphloroglucinol, pyrrolnitrin, and pyoluteorin. The retS mutant also exhibited significant increase in phlA-lacZ, prnA-lacZ, and pltA-lacZ transcription levels, influencing expression levels of the small regulatory RNAs RsmX and RsmZ. In the gacSretS double mutant, all the phenotypic changes caused by the retS deletion were reversed to the level of gacS single mutant. Furthermore, the retS mutation drastically elevated biofilm formation and improved the colonization ability of strain FD6 on wheat rhizospheres. Based on these results, we proposed that RetS negatively controlled the production of antibiotics through the Gac/Rsm pathway in P. fluorescens FD6. PMID- 26505309 TI - Characterization of the biosynthetic gene cluster for maklamicin, a spirotetronate-class antibiotic of the endophytic Micromonospora sp. NBRC 110955. AB - Maklamicin, which is produced by the endophytic Micromonospora sp. NBRC 110955, is a spirotetronate-class antibiotic possessing anti-microbial activity against Gram-positive bacteria, and has several unique structural features different from other spirotetronates. Here we describe identification and characterization of the maklamicin biosynthetic (mak) gene cluster through draft genome sequencing, genomic library screening, and gene disruption. Sequence analysis revealed that a plausible maklamicin cluster resides in a 152 kb DNA region encoding 46 open reading frames, 24 of which can be assigned roles in the biosynthesis of polyketide backbone, spirotetronate or peripheral moieties, self-resistance and the regulation of maklamicin production. Disruption of the polyketide synthase (PKS) genes makA1 or makA4 resulted in a complete loss of maklamicin production, indicating that the type I modular PKS system is responsible for the biosynthesis of maklamicin. The mak gene cluster contained a set of biosynthetic genes for the formation of a tetronate moiety, which were found to be highly conserved in the gene clusters for spirotetronate antibiotics. Based on the estimated biosynthetic genes, we propose the biosynthetic pathway for maklamicin. Our findings provide not only insights on the biosynthetic mechanism of the unique structures in maklamicin, but also useful information to facilitate a comparative analysis of the spirotetronate biosynthetic pathways to expand the structural repertoire. PMID- 26505310 TI - Evaluation of native bacteria and manganese phosphite for alternative control of charcoal root rot of soybean. AB - Plant growth promoting rhizobacteria (PGPR) are potential agents to control plant pathogens and their combined use with biopesticides such as phosphites may constitute a novel strategy to incorporate in disease management programs. In the present study, 11 bacterial isolates were selected on the basis of their antagonistic activity against Macrophomina phaseolina in dual-culture tests, and their plant growth promoting traits. Selected isolates were characterised on the basis of auxin and siderophore production, phosphate solubilisation and rep-PCR genomic fingerprinting. Two of these isolates, identified as Pseudomonas fluorescens 9 and Bacillus subtilis 54, were further evaluated for their inhibitory capacity against M. phaseolina using in vitro (on soybean seeds) and in vivo (greenhouse assay) tests. Both bacteria were applied individually as well as in combined treatment with manganese phosphite as seed treatments. Damage severity on soybean seeds was significantly reduced, compared with the untreated control, by both bacterial strains; however, the individual application of phosphite showed to be least effective in controlling M. phaseolina. Interestingly, the phosphite treatment improved its performance under greenhouse conditions compared to the results from the in vitro assays. In the greenhouse trials, the greatest reductions in disease severity were achieved when strain P. fluorescens 9 was applied singly or when strain B. subtilis 54 was combined with manganese phosphite, achieving 82% of control in both cases. This work is the first to report the control of M. phaseolina using combined treatment with PGPR and phosphite under greenhouse conditions. PMID- 26505311 TI - Analysis of the community compositions of rhizosphere fungi in soybeans continuous cropping fields. AB - We used rhizosphere soil sampled from one field during zero year and two years of continuous cropping of high-protein soybean to analyze the taxonomic community compositions of fungi during periods of high-incidence of root rot. Our objectives were to identify the dominant pathogens in order to provide a theoretical basis for the study of pathogenesis as well as control tactics for soybean root rot induced by continuous cropping. A total of 17,801 modified internal transcribed spacer (ITS) sequences were obtained from three different soybean rhizosphere soil samples after zero year and 1 or 2 years of continuous cropping using 454 high-throughput sequencing. The dominant eumycote fungal were identified to be Ascomycota and Basidiomycota in the three soil samples. Continuous cropping of soybean affected the diversity of fungi in rhizosphere soils and increased the abundance of Thelebolus and Mortierellales significantly. Thanatephorus, Fusarium, and Alternaria were identified to be the dominant pathogenic fungal genera in rhizosphere soil from continuously cropped soybean fields. PMID- 26505312 TI - Transfer of the cloned Salmonella SPI-1 type III secretion system and characterization of its expression mechanisms in Gram negative bacteria in comparison with cloned SPI-2. AB - Cloned type III secretion systems have much potential to be used for bacterial engineering purposes involving protein secretion and substrate translocation directly into eukaryotic cells. We have previously cloned the SPI-1 and SPI-2 type III systems from the Salmonella enterica serovar Typhimurium genome using plasmid R995 which can conveniently capture large genomic segments for transfer between bacterial strains. However, though expressed and functional in Salmonella strains, cloned SPI-1 was previously observed to have a serious expression defect in other Gram negative bacteria including Escherichia coli. Here we show that cloned SPI-1 expression and secretion can be detected in the secretion preps from E. coli and Citrobacter indicating the first observation of non-Salmonella SPI-1 expression. We describe a compatible plasmid system to introduce engineered SPI-1 substrates into cloned SPI-1 strains. However, a SPI-1 translocation defect is still observed in E. coli, and we show that this is likely due to a defect in SipB expression/secretion in this species. In addition, we also examined the requirement for the hilA and ssrAB regulators in the expression of cloned SPI-1 and SPI-2, respectively. We found a strict requirement for hilA for full cloned SPI-1 expression and secretion. However, though we found that ssrAB is required for full cloned SPI-2 expression in a range of media across different bacteria, it is not required for cloned SPI-2 expression in MgM8 inducing media in S. Typhimurium. This suggests that under SPI-2 inducing conditions in S. Typhimurium, other factors can substitute for loss of ssrAB in cloned SPI-2 expression. The results provide key foundational information for the future use of these cloned systems in bacteria. PMID- 26505314 TI - Eyebrow Position Following Upper Blepharoplasty. AB - PURPOSE: To evaluate the effect of upper blepharoplasty on eyebrow height, accounting for ocular dominance, fat excision, change in MRD1, and degree of dermatochalasis. METHODS: Retrospective review of patients undergoing upper blepharoplasty between January 2013 and July 2014. Patients with a prior history of ocular trauma, disease, and surgery were excluded. Digital photographs were analyzed using NIH ImageJ software to measure pre and postoperative eyebrow height at the medial, central, and lateral positions, MRD1, and dermatochalasis. Univariable comparisons of brow height and MRD1 were performed. A multivariate analysis was used to assess for the effect of percentage change in MRD1 and dermatochalasis and of ocular dominance and fat excision in mean percentage change of eyebrow height. RESULTS: Charts of 19 patients were reviewed. Mean age was 73.2 years (SD = 8.86). There were 9 male (47.4%) and 10 female (52.6%) patients. There were 11 right eye dominant (57.9%) and 8 left eye dominant (42.1%) patients. Then 13 patients (68.4%) underwent fat removal. A univariable comparison found insufficient evidence to suggest a significant change from 0 postoperatively in brow height at all positions. A multivariable comparison found insufficient evidence to suggest MRD1, ocular dominance, or dermatochalasis were significantly associated with mean percentage change in brow height at all positions with or without fat excision. CONCLUSION: Upper blepharoplasty does not change eyebrow height at the medial, central, or lateral positions, after accounting for any impact of ocular dominance, fat excision, change in MRD1, or degree of dermatochalasis. PMID- 26505313 TI - Diallyl disulfide enhances carbon ion beams-induced apoptotic cell death in cervical cancer cells through regulating Tap73 /DeltaNp73. AB - Diallyl disulfide (DADS), extracted from crushed garlic by steam-distillation, has been reported to provide the anticancer activity in several cancer types. However, the effect of DADS on high-LET carbon beams - induced cell death remains unknown. Therefore, we used human cervical cancer cells to elucidate the molecular effects of this diallyl sulfide. Radiotherapy remains the mainstay of treatment, especially in advanced cervical cancer and there is still space to improve the radiosensitivity to reduce radiation dosage. In this study, we found that radiation effects evoked by high-LET carbon beam was marked by inhibition of cell viability, cell cycle arrest, significant rise of apoptotic cells, regulation of transcription factor, such as p73, as well as alterations of crucial mediator of the apoptosis pathway. We further demonstrated that pretreatment of 10 uM DADS in HeLa cells exposed to radiation resulted in decrease in cell viability and increased radiosensitivity. Additionally, cells pretreated with DADS obviously inhibited the radiation-induced G2/M phase arrest, but promoted radiation-induced apoptosis. Moreover, combination DADS and the radiation exacerbated the activation of apoptosis pathways through up-regulated ration of pro-apoptotic Tap73 to anti-apoptotic DeltaNp73, and its downstream proteins, such as FASLG, and APAF1. Taken together, these results suggest that DADS is a potential candidate as radio sensitive agent for cervical cancer. PMID- 26505315 TI - Diquafosol promotes corneal epithelial healing via intracellular calcium-mediated ERK activation. AB - Diquafosol is known as a purinergic P2Y2 receptor (P2Y2R) agonist that stimulates water and mucin secretion from conjunctival epithelial cells and goblet cells, leading to tear film stability in dry eye. However, its effect on corneal epithelial healing has not yet been elucidated. The aim of the present study was to evaluate the effect of diquafosol on corneal epithelial healing in vivo and on P2Y2R-related downstream signaling pathways in vitro. We administered 3% diquafosol ophthalmic solution on 3 mm-diameter epithelial defects made in rat corneas and assessed the wound closure over time. Corneal epithelial healing was significantly accelerated in diquafosol-treated eyes compared to control eyes at 12 and 24 h. During wound healing, P2Y2R staining appeared stronger in the re epithelized margin near the wound defect. To evaluate whether diquafosol stimulates epidermal growth factor receptor/extracellular-signal-regulated kinase (EGFR/ERK)-related cell proliferation and migration, simian virus 40-transfected human corneal epithelial (THCE) cells were used for in vitro experiments. Cell proliferation was accelerated by diquafosol at concentrations from 20 to 200 MUM during 48 h, but inhibited at concentrations over 2000 MUM. The intracellular calcium ([Ca(2+)]i) elevation was measured in diquafosol (100 MUM)-stimulated cells using Fluo-4/AM ([Ca(2+)]i indicator). [Ca(2+)]i elevation was observed in diquafosol-stimulated cells regardless of the presence of calcium in media, and suramin pretreatment inhibited the calcium response. The effect of diquafosol on phosphorylation of EGFR, ERK and Akt, and cell migration was determined by western blotting and in vitro cell migration assay. Diquafosol induced phosphorylation of EGFR at 2 min post-stimulation, and phosphorylation of ERK at 5 min post-stimulation. Phosphorylation of ERK was attenuated in cells pretreated with suramin or BAPTA/AM ([Ca(2+)]i chelator), and partially with AG1478 (EGFR inhibitor). Likewise, diquafosol-treated cells showed acceleration of gap closure in cell migration assay, which was inhibited by suramin, BAPTA/AM, AG1478, and U0126 (MEK inhibitor). These studies demonstrate that diquafosol is effective in promoting corneal epithelial wound healing and that this effect may result from ERK-stimulated cell proliferation and migration via P2Y2R-mediated [Ca(2+)]i elevation. PMID- 26505316 TI - Surgical options for primary hyperparathyroidism. AB - Over the last two decades, surgery for primary hyperparathyroidism has evolved to offer a panel of procedures based on improvements in imaging, new technology and, consequently, novel surgical techniques. Multiple courses of action are possible, consistent with varying degrees of complexity. From the simplest scenario of a single adenoma localized by at least two preoperative tests in the context of sporadic primary hyperparathyroidism, to revision surgery related to recurrent, persistent or multiglandular disease, the surgeon has the opportunity to adapt his strategy. However, whatever surgical approach is used, even in the absence of formal guidelines, the clinical judgment of an experienced and skilled practitioner in endocrine surgery is the real guide and key of success in complex situations. PMID- 26505317 TI - Electrocatalytic Alcohol Oxidation with TEMPO and Bicyclic Nitroxyl Derivatives: Driving Force Trumps Steric Effects. AB - Bicyclic nitroxyl derivatives, such as 2-azaadamantane N-oxyl (AZADO) and 9 azabicyclo[3.3.1]nonane N-oxyl (ABNO), have emerged as highly effective alternatives to TEMPO-based catalysts for selective oxidation reactions (TEMPO = 2,2,6,6-tetramethyl-1-piperidine N-oxyl). Their efficacy is widely attributed to their smaller steric profile; however, electrocatalysis studies described herein show that the catalytic activity of nitroxyls is more strongly affected by the nitroxyl/oxoammonium redox potential than by steric effects. The inexpensive, high-potential TEMPO derivative, 4-acetamido-TEMPO (ACT), exhibits higher electrocatalytic activity than AZADO and ABNO for the oxidation of primary and secondary alcohols. Mechanistic studies provide insights into the origin of these unexpected reactivity trends. The superior activity of ACT is especially noteworthy at high pH, where bicyclic nitroxyls are inhibited by formation of an oxoammonium hydroxide adduct. PMID- 26505318 TI - Summary of Notifiable Noninfectious Conditions and Disease Outbreaks: Surveillance for Silicosis - Michigan and New Jersey, 2003-2010. PMID- 26505319 TI - The role of epigenetics in genetic and environmental epidemiology. AB - Epidemiology is the branch of science that investigates the causes and distribution of disease in populations in order to provide preventative measures and promote human health. The fields of genetic and environmental epidemiology primarily seek to identify genetic and environmental risk factors for disease, respectively. Epigenetics is emerging as an important piece of molecular data to include in these studies because it can provide mechanistic insights into genetic and environmental risk factors for disease, identify potential intervention targets, provide biomarkers of exposure, illuminate gene-environment interactions and help localize disease-relevant genomic regions. Here, we describe the importance of including epigenetics in genetic and environmental epidemiology studies, provide a conceptual framework when considering epigenetic data in population-based studies and touch upon the many challenges that lie ahead. PMID- 26505320 TI - Govanoside A, a new steroidal saponin from rhizomes of Trillium govanianum. AB - A new spirostane steroidal saponin, govanoside A (1) along with three known compounds borassoside E (2) pennogenin (3) and diosgenin (4) were isolated from rhizomes of Trillium govanianum. Their structures were elucidated through 1D, 2D NMR spectroscopic data analysis and acid hydrolysis. Compound (2) in genus Trillium and all compounds (1-4) in T. govanianum are reported herein for the first time. Furthermore, compounds 1 &2 exhibited good to moderate activities against Aspergillus niger ATCC 16888, Aspergillus flavus ATCC 9643, Candida albicans ATCC 18804, and Candida glabrata ATCC 90030. This is a significant finding keeping in view the limited antifungal drugs for aspergillosis and candidiasis. PMID- 26505321 TI - [The EQ-5D as a measure of health outcomes]. PMID- 26505322 TI - Red mud (RM)-Induced enhancement of iron plaque formation reduces arsenic and metal accumulation in two wetland plant species. AB - Human activities have resulted in arsenic (As) and heavy metals accumulation in paddy soils in China. Phytoremediation has been suggested as an effective and low cost method to clean up contaminated soils. A combined soil-sand pot experiment was conducted to investigate the influence of red mud (RM) supply on iron plaque formation and As and heavy metal accumulation in two wetland plant species (Cyperus alternifolius Rottb., Echinodorus amazonicus Rataj), using As and heavy metals polluted paddy soil combined with three rates of RM application (0, 2%, 5%). The results showed that RM supply significantly decreased As and heavy metals accumulation in shoots of the two plants due to the decrease of As and heavy metal availability and the enhancement of the formation of iron plaque on the root surface and in the rhizosphere. Both wetland plants supplied with RM tended to have more Fe plaque, higher As and heavy metals on roots and in their rhizospheres, and were more tolerant of As and heavy metal toxicity. The results suggest that RM-induced enhancement of the formation of iron plaque on the root surface and in the rhizosphere of wetland plants may be significant for remediation of soils contaminated with As and heavy metals. PMID- 26505323 TI - Computer-based cognitive rehabilitation: the CoRe system. AB - PURPOSE: This work aims at providing a tool for supporting cognitive rehabilitation. This is a wide field, that includes a variety of diseases and related clinical pictures; for this reason the need arises to have a tool available that overcomes the difficulties entailed by what currently is the most common approach, that is, the so-called pen and paper rehabilitation. METHODS: We first organized a big number of stimuli in an ontology that represents concepts, attributes and a set of relationships among concepts. Stimuli may be words, sounds, 2D and 3D images. Then, we developed an engine that automatically generates exercises by exploiting that ontology. The design of exercises has been carried on in synergy with neuropsychologists and speech therapists. Solutions have been devised aimed at personalizing the exercises according to both patients' preferences and performance. RESULTS: Exercises addressed to rehabilitation of executive functions and aphasia-related diseases have been implemented. The system has been tested on both healthy volunteers (n = 38) and patients (n = 9), obtaining a favourable rating and suggestions for improvements. CONCLUSIONS: We created a tool able to automate the execution of cognitive rehabilitation tasks. We hope the variety and personalization of exercises will allow to increase compliance, particularly from elderly people, usually neither familiar with technology nor particularly willing to rely on it. The next step involves the creation of a telerehabilitation tool, to allow therapy sessions to be undergone from home, thus guaranteeing continuity of care and advantages in terms of time and costs for the patients and the National Healthcare System (NHS). Implications for rehabilitation Cognitive impairments can greatly impact an individual's existence, appreciably reducing his abilities and autonomy, as well as sensibly lowering his quality of life. Cognitive rehabilitation can be used to restore lost brain function or slow down degenerative diseases. Computerization of rehabilitation entails many advantages, but patients - especially elderly people - might be less prone to the use of technology and consequently reluctant towards this innovative therapeutic approach. Our software system, CoRe, supports a therapist during the administration of rehabilitation sessions: exercises can be generated dynamically, thus reducing repetitivity, and patients' performance trends automatically analysed to facilitate the assessment of their progress. Tests performed on both healthy subjects and patients provided useful information that allowed us to define an implementation strategy able to reduce patients' resistance to computerized rehabilitation as much as possible. PMID- 26505324 TI - Development and Validation of a New Molecular Diagnostic Assay for Detection of Myotonic Dystrophy Type 2. AB - BACKGROUND: Myotonic dystrophy (DM) is the most common adult form of muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia, and multiorgan involvement. Myotonic dystrophy type 2 (DM2) is caused by a [CCTG] expansion in the ZNF9/CNBP gene. The aim of this work was the validation of the new molecular diagnostic test Myotonic Dystrophy type 2 kit-FL. RESULTS: A cohort of 126 individuals was analyzed. The results show that 126/126 patients were correctly identified using the new molecular assay. In particular, 74 were DM2 positive, 39 were DM2/DM1 negative and 13 DM2 negative/DM1 positive. Approximately 9.5% (7/74) of the DM2-positive samples had a single sizeable expansion and 85% (63/74) showed multiple bands or smears. Comparative fluorescence in situ hybridization (FISH) analyses, on muscle biopsies, revealed that the sensitivity and specificity were very high (>99%). Equivalent analytical performances were obtained using different DNA extraction methods. Among affected individuals 87.5% (28/32) had electrical myotonia, 69% (22/32) proximal weakness, 41% (13/32) cataracts, and about 37.5% (12/32) cardiac conduction defects. FISH analysis and clinical data were used to support the genetic analysis. PMID- 26505325 TI - Direct observations of American eels migrating across the continental shelf to the Sargasso Sea. AB - Since inferring spawning areas from larval distributions in the Sargasso Sea a century ago, the oceanic migration of adult American eels has remained a mystery. No adult eel has ever been observed migrating in the open ocean or in the spawning area. Here, we track movements of maturing eels equipped with pop-up satellite archival tags from the Scotian Shelf (Canada) into the open ocean, with one individual migrating 2,400 km to the northern limit of the spawning site in the Sargasso Sea. The reconstructed routes suggest a migration in two phases: one over the continental shelf and along its edge in shallow waters; the second in deeper waters straight south towards the spawning area. This study is the first direct evidence of adult Anguilla migrating to the Sargasso Sea and represents an important step forward in the understanding of routes and migratory cues. PMID- 26505326 TI - Poor precompetitive sleep habits, nutrients' deficiencies, inappropriate body composition and athletic performance in elite gymnasts. AB - This study aimed to evaluate body composition, sleep, precompetitive anxiety and dietary intake on the elite female gymnasts' performance prior to an international competition. Sixty-seven rhythmic gymnasts of high performance level were evaluated in relation to sport and training practice, body composition, sleep duration, daytime sleepiness by the Epworth Sleepiness Scale (ESS), sleep quality by the Pittsburgh Sleep Quality Index (PSQI), precompetitive anxiety by the Sport Competition Anxiety Test form A (SCAT-A) and detailed dietary intake just before an international competition. Most gymnasts (67.2%) suffered from mild daytime sleepiness, 77.6% presented poor sleep quality and 19.4% presented high levels of precompetitive anxiety. The majority of gymnasts reported low energy availability (EA) and low intakes of important vitamins including folate, vitamins D, E and K; and minerals, including calcium, iron, boron and magnesium (p < .05). Gymnasts' performance was positively correlated with age (p = .001), sport practice (p = .024), number of daily training hours (p = .000), number of hours of training/week (p = .000), waist circumference (WC) (p = .008) and sleep duration (p = .005). However, it was negatively correlated with WC/hip circumference (p = .000), ESS (p = .000), PSQI (p = .042), SCAT-A (p = .002), protein g/kg (p = .028), EA (p = .002) and exercise energy expenditure (p = .000). High performance gymnasts presented poor sleep habits with consequences upon daytime sleepiness, sleep quality and low energy availability. PMID- 26505327 TI - Pycnogenol(r) and Centella asiatica to prevent asymptomatic atherosclerosis progression in clinical events. AB - BACKGROUND: The aim of this study was to evaluate the effect of the nutritional supplements Pycnogenol(r) and Centella asiatica (CA) on atherosclerosis progression in low-risk, asymptomatic subjects with carotid or femoral stenosing plaques. METHODS: The study included subjects aged 45-60 with stenosing atherosclerotic plaques (50-60%) in at least one carotid or common femoral bifurcation. Subjects were allocated into 3 groups. In Group 1 (controls), management was based on education, exercise, diet and lifestyle changes. This same management plan was used in the other two groups: Group 2 used Pycnogenol(r) (100 mg/day), while Group 3 used Pycnogenol(r) 100 mg/day plus CA (100 mg/day). The follow-up lasted 4 years. Plaque progression was assessed using the ultrasonic arterial score based on arterial wall morphology, considering plaque characteristics and the number of subjects that had cardiovascular events. Oxidative stress was also measured. RESULTS: Of the 413 individuals that were admitted, 391 individuals completed 4 years. Group distribution was comparable. The rate of progression of ultrasound arterial score was significantly lower in the two supplement groups (P<0.05) in comparison with controls suggesting a beneficial effect of Pycnogenol(r) with a significant difference in favor of the combination (P<0.05). There was a reduction in plaques progression in the supplement groups with the best effects obtained by the combination, considering maximum plaque thickness and length and echogenicity (grey scale median) (P<0.05). Plaques became generally dense (more echogenic) achieving a mixed echogenicity. The occurrence of anginal events was less than 3% in the two supplement groups (in comparison with 6.25% in controls) (P<0.05) with the best results obtained by the combination (P<0.05). The occurrence in myocardial infarctions was significantly lower for the combination (P<0.05). Minor transient ischemic attacks were also less frequent with the supplements with the best results observed with the combination (P<0.05). Events in controls - requiring hospital admission - were globally seen in 16.4% of subjects (minor events) in comparison with 8.9% of subjects using Pycnogenol(r) and only 3.3% of patients using the combination. At 4 years, oxidative stress in the supplement groups was lower than in controls (P<0.05, with no significant difference between groups 2 and 3). CONCLUSIONS: Pycnogenol(r) and the combination of Pycnogenol(r) plus CA reduce the progression of arterial plaques and the progression to clinical stages. The reduction in plaques and clinical progression was associated with a reduction in oxidative stress. The results justify a larger study to define the efficacy of the combination of Pycnogenol(r) plus CA as a prophylaxis in preclinical atherosclerosis. PMID- 26505328 TI - PET Imaging of Steroid Hormone Receptor Expression. AB - Steroid hormone receptor (SHR) expression and changes in SHR expression compared to basal levels, whether upregulated, downregulated, or mutated, form a distinguishing feature of some breast, ovarian, and prostate cancers. These receptors act to induce tumor proliferation. In the imaging context, total expression together with modulation of expression can yield predictive and prognostic information. Currently, biopsy for histologic assessment of SHR expression is routine for breast and prostate cancer; however, the technique is not well suited to the heterogeneous tumor environment and can lead to incorrect receptor expression assignment, which precludes effective treatment. The development of positron emission tomography (PET) radioligands to image receptor expression may overcome the difficulties associated with tumor heterogeneity and facilitate the assessment of metastatic disease. PMID- 26505329 TI - Readmissions in HIV-Infected Inpatients: A Large Cohort Analysis. AB - OBJECTIVE: Hospital readmissions impose considerable physical and psychological hardships on patients and represent a high, but possibly preventable, cost for insurers and hospitals alike. The objective of this study was to identify patient characteristics associated with 30-day readmission among persons living with HIV/AIDS (PLWH) using a statewide administrative database and to characterize the movement of patients between facilities. DESIGN: Retrospective cohort analysis of HIV-infected individuals in New York State using a comprehensive, all-payer database. SETTING: All hospitals in New York State. PARTICIPANTS: HIV-infected adults admitted to a medical service in 2012. PLWH identified using International Classification of Disease (ICD)-9 diagnosis codes 042 and V08. RESULTS: Of 23,544 index hospitalizations, 21.8% (5121) resulted in readmission. Multivariable predictors of readmission included insurance status, housing instability, psychoses, multiple comorbid chronic conditions, substance use, and past inpatient and emergency department visits. Over 30% of readmissions occurred at a different facility than that of the initial hospitalization. CONCLUSION: A number of patient characteristics were independently associated with hospital readmission within 30 days. Behavioral health disorders and comorbid conditions may be the strongest predictors of readmission in PLWH. Readmissions, especially those in urban areas, often result in fragmented care which may compromise the quality of care and result in harmful discontinuity of medical treatment. PMID- 26505330 TI - Impact of Youth and Adolescent Friendly Services on Retention of 10-24-Year-Olds in HIV Care and Treatment Programs in Nyanza, Kenya. PMID- 26505332 TI - Is Genotype Testing Really Cost-Effective for Primary Resistance in Brazil? PMID- 26505331 TI - Comparison of Single-Visit and Multiple-Visit Measures of Retention in Care for HIV Monitoring and Evaluation. PMID- 26505333 TI - Web Camera Use of Mothers and Fathers When Viewing Their Hospitalized Neonate. AB - BACKGROUND: Mothers and fathers of neonates hospitalized in a neonatal intensive care unit (NICU) differ in their experiences related to NICU visitation. PURPOSE: To describe the frequency and length of maternal and paternal viewing of their hospitalized neonates via a Web camera. METHODS/SEARCH STRATEGY: A total of 219 mothers and 101 fathers used the Web camera that allows 24/7 NICU viewing from September 1, 2010, to December 31, 2012, which included 40 mother and father dyads. We conducted a review of the Web camera's Web site log-on records in this nonexperimental, descriptive study. FINDINGS/RESULTS: Mothers and fathers had a significant difference in the mean number of log-ons to the Web camera system (P = .0293). Fathers virtually visited the NICU less often than mothers, but there was not a statistical difference between mothers and fathers in terms of the mean total number of minutes viewing the neonate (P = .0834) or in the maximum number of minutes of viewing in 1 session (P = .6924). Patterns of visitations over time were not measured. IMPLICATIONS FOR PRACTICE: Web camera technology could be a potential intervention to aid fathers in visiting their neonates. Both parents should be offered virtual visits using the Web camera and oriented regarding how to use the Web camera. IMPLICATIONS FOR RESEARCH: These findings are important to consider when installing Web cameras in a NICU. Future research should continue to explore Web camera use in NICUs. PMID- 26505335 TI - Polymorphisms of the bovine MC3R gene and their associations with body measurement traits and meat quality traits in Qinchuan cattle. AB - The melanocortin 3 receptor (MC3R) gene, which belongs to the rhodopsin-like family A of the G protein-coupled receptor family, plays a crucial role in feed efficiency and energy homeostasis. The aim of this study was to examine associations between bovine MC3R gene polymorphisms and body measurement traits (BMTs) and meat quality traits (MQTs). We identified three synonymous mutations (T429C, T537C, and T663C) in exon 1 of the MC3R gene in Chinese Qinchuan beef cattle (N = 271) by sequencing. D' and r(2) values revealed that these three SNPs were in strong linkage disequilibrium (LD) (r(2) > 0.33); the T429C and T537C SNPs were in complete LD (D' = 1 and r(2) = 1). Association analyses revealed that the SNPs were significantly associated with BMTs and MQTs in Qinchuan cattle. Individuals with the wild homozygotic genotypes g.TTTT and g.TT had significantly higher values of chest depth, heart girth, back fat thickness, intramuscular fat content, and loin muscle area than the mutant heterozygotic genotypes g.TCTC and g.TC. These results suggest that the MC3R gene affects MQTs in Qinchuan cattle, and that it may be a good candidate gene for marker-assisted selection. PMID- 26505336 TI - Regulation of the expression of zinc finger protein genes by microRNAs enriched within acute lymphoblastic leukemia-derived microvesicles. AB - Microvesicles (MVs) are submicrometric membrane fragments that can "engulf" cytoplasmic contents such as microRNAs (miRNAs) from their cellular origin. The study of miRNAs carried within MVs might provide insights into the roles that miRNAs play in the underlying pathophysiologic processes of acute lymphoblastic leu-kemia (ALL). We identified numerous dysregulated MV miRNAs in patients with B and T-cell ALL by using Agilent microarray analysis. Selected miRNAs obtained by microarray profiling were validated us-ing quantitative reverse transcription polymerase chain reaction. Us-ing bioinformatic tools, we found that 118 and 116 miRNAs from B- and T-ALL MVs, respectively, regulated the expression of zinc finger protein (ZFP) genes. For example, zinc finger protein 238 (ZNF238), known as a tumor suppressor, was regulated by miR-20b over-expres-sion. Conversely, ZNF267, a cancer-promoting factor, was mediated by downregulated miR-23a and miR 23b. Considering that miRNAs are generally believed to repress gene expression, antineoplastic ZNF238 was likely inhibited while the level of oncogenic ZNF267 was likely increased by miRNA dysregulation, leading to modifica-tion of the ALL microenvironment. In addition, gene ontology and sig-naling pathway analysis demonstrated that a subset of the ZFP genes targeted by altered MV miRNAs are involved in cellular biological processes including proliferation, differentiation, apoptosis, and cell cycle regulation. These findings indicated that cancer-associated MV miRNAs and their target ZFP genes might be novel pathogenic factors in ALL. However, the specific roles exerted by MV miRNAs and their target ZFP genes on the pathological mechanisms of ALL remain to be further understood. PMID- 26505337 TI - Inhibition of gap junctions relieves the hepatotoxicity of TNF-alpha. AB - The aim of this study was to observe the influence of gap junction (GJ) functional changes on the hepatotoxicity of TNF-alpha. Three different methods were employed to study functional effects of the GJ inhibition: 1) pretreatment with a GJ inhibitor; 2) inoculation of cells at high and low densities; and 3) inhibition of the expression of connexin 32 (Cx32) by small inhibitory RNA transfection. We then observed the influence of these treatments on hepatotoxicity following treatment with different concentrations of TNF-alpha for various duration. The hepatotoxicity of TNF-alpha was observed to occur in a dose and time-dependent manner; after pretreatment inhibition, the hepatotoxicity of TNF-alpha was significantly reduced (P < 0.01). The hepatotoxicity of TNF-alpha was also found to be remarkably lower in cells that had been inoculated at low density (as measured by the amount of GJ formation among cells) than in those inoculated at density (P < 0.01). In addition, following Cx32 inhibition, the hepatotoxicity of TNF-alpha was significantly decreased (P < 0.01) as well. Together, these results suggest that inhibition of GJ function or of its component Cx32 significantly decreases the hepatotoxicity of TNF-alpha, and that the expression of Cx32 plays an important role in the hepatotoxicity of TNF alpha. PMID- 26505338 TI - miR-71b regulation of insulin/IGF-1 signaling during starvation in planarians. AB - Planarians, which have a large population of stem cells called neoblasts, are molecularly tractable model systems used in the study of regeneration. However, planarians have strong resistance to hunger and have developed growth arrest strategies. For example, they can change their size and undergo growth regression during starvation periods. The results of the current study show that the microRNA, miR-71b, and the insulin/IGF-1 signaling pathway have important functions in the development of starvation-induced planarians. We demonstrate tissue-specific expression of miR-71b using in situ hybridization. By employing real-time polymerase chain reaction, we provide evidence that miR-71b is upregulated in starvation-induced planarians. Furthermore, we validate and verify the target genes of miR-71b. PMID- 26505339 TI - Relationship of EGFR DNA methylation with the severity of non-small cell lung cancer. AB - The aim of this study was to study the relationship of EGFR DNA methylation with the severity of non-small-cell lung cancer (NSCLC). We enrolled 54 patients with NSCLC between March 2013 and June 2014 from Department of Cardiothoracic Surgery in our hospital. The methylation levels in the promoter region of the EGFR gene in cancerous and pericarcinomatous tissue were tested by pyrosequencing. EGFR mRNA expression levels were detected by real-time reverse-transcription polymerase chain reaction. The SPSS software was used for data analysis. We found that EGFR gene methylation levels showed no significant differences among patients of different gender, age, or smoking status. EGFR DNA methylation levels significantly increased (P < 0.05) following NSCLC malignancy upgrading, and showed negative correlation with mRNA expression (P = 0.041). DNA methylation levels of cancerous tissues were significantly higher compared to the corresponding pericarcinomatous tissues (P < 0.05) at stages I, II, and IIIA. The methylation levels at loci 3, 6, 9 among the detected CpG islands were higher in the cancer tissues at each stage (P < 0.05). In summary, our results suggest that the DNA methylation levels of EGFR can be used as an important indicator for the stage of cancer tissue malignancy. PMID- 26505340 TI - Characterization and development of chloroplast microsatellite markers for Gossypium hirsutum, and cross-species amplification in other Gossypium species. AB - Cotton is an important economic crop worldwide; its fiber, commonly known as cotton lint, is the main natural source for the textile industry. Sixty chloroplast microsatellites were identified and characterized from the complete sequence of the Gossypium hirsutum chloroplast genome using a bioinformatic approach. Twenty chloroplast microsatellite loci were polymorphic in the 66 Gossypium germplasm accessions. A total of 85 alleles were detected, with allele numbers varying from 2-7 per locus. Polymorphism information content varied from 0.02-0.66, with a mean of 0.48. Additionally, transferability of the 20 polymorphic chloroplast microsatellite primers was evaluated in other 31 Gossypium species. Sixteen markers were successfully amplified across all species tested, while the remaining 4 markers cross-amplified in most species tested. These polymorphic chloroplast microsatellite markers may be useful tool for studies of individual identification, genetic diversity, evolution, conservation genetics, and molecular breeding in Gossypium. PMID- 26505341 TI - Repairing rabbit radial defects by combining bone marrow stroma stem cells with bone scaffold material comprising a core-cladding structure. AB - We prepared a bone scaffold material comprising a PLGA/beta-TCP core and a Type I collagen cladding, and recombined it with bone marrow stroma stem cells (BMSCs) to evaluate its potential for use in bone tissue engineering by in vivo and in vitro experiments. PLGA/beta-TCP without a cladding was used for comparison. The adherence rate of the BMSCs to the scaffold was determined by cell counting. Cell proliferation rate was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide method. The osteogenic capability was evaluated by alkaline phosphatase activity. The scaffold materials were recombined with the BMSCs and implanted into a large segmental rabbit radial defect model to evaluate defect repair. Osteogenesis was assessed in the scaffold materials by histological and double immunofluorescence labeling, etc. The adherence number, proliferation number, and alkaline phosphatase expression of the cells on the bone scaffold material with core-cladding structure were significantly higher than the corresponding values in the PLGA/beta-TCP composite scaffold material (P < 0.05). An in vivo test indicated that the bone scaffold material with core cladding structure completely degraded at the bone defect site and bone formation was completed. The rabbit large sentimental radial defect was successfully repaired. The degradation and osteogenesis rates matched well. The bone scaffold with core-cladding structure exhibited better osteogenic activity and capacity to repair a large segmental bone defect compared to the PLGA/beta-TCP composite scaffold. The bone scaffold with core-cladding structure has excellent physical properties and biocompatibility. It is an ideal scaffold material for bone tissue engineering. PMID- 26505342 TI - Interferon-alpha-2b as an adjuvant therapy prolongs survival of patients with previously resected oral muscosal melanoma. AB - Two major subtypes of melanoma include cutaneous melanoma and mucosal melanoma. The latter type is rare and usually occurs in the head and neck region. High-dose interferon-alpha-2b (IFN-alpha-2b) has proven effective in the treatment of cutaneous melanoma. Recently, a regimen of temozolomide plus cisplatin was reported more likely to improve relapse-free survival and overall survival than high-dose IFN-alpha-2b for mucosal melanoma. We conducted this study to analyze the therapeutic effect of high-dose IFN-alpha-2b for patients with oral mucosal melanoma who had received prior chemotherapy. One hundred and seventeen patients with stage III-IVa oral mucosal melanoma who had received chemotherapy were analyzed. The overall survival and relapse-free survival were compared between the patients with/without high-dose IFN-alpha-2b. The results indicate that the IFN-alpha-2b treatment group had a longer relapse-free survival rate (P = 0.0169) as compared to the control group. However, the overall survival was not significant between the two groups (P = 0.096), except in patients in stage IVa, whose overall survival increased by 20 months (P = 0.0146). The adverse reactions included a drug-induced influenza-like syndrome, gastrointestinal responses, myelosuppression, and hepatoxicity, which were predominantly of grade 1-2 and reversible. Thus, patients with resected oral mucosal melanoma, even those who have received chemotherapy, could benefit from the treatment of high-dose IFN alpha-2b. PMID- 26505343 TI - Expression of the 2-dehydro-3-deoxyphosphooc-tonate aldolase (KdsA) gene in mulberry leaves (Morus alba L.) is down-regulated under high salt and drought stress. AB - The oligosaccharide 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) is a key component of lipopolysaccharide in Gram-negative bacteria, and is also part of the pectic polysaccharide rhamnogalacturonan (RG-II) of the plant cell wall. The enzyme KDO 8-phosphate synthase (KDO8Ps), encoded by the 2-dehydro-3-deoxyphosphooctonate aldolase (KdsA) gene, catalyzes the first step in the synthesis of Kdo. In this study, the complete coding sequence of the KdsA gene from mulberry leaves was cloned and the primary structure of KDO8Ps was deduced. Alignment of the amino acid sequence of KDO8Ps from mulberry with those of five other plant species revealed a high level of evolutionary conservation. A phylogenetic tree analysis demonstrated a short genetic distance among KDO8Ps proteins of different species. Expression of the KdsA gene was higher in the second leaves than in the eighth leaves of mulberry, and was down-regulated under conditions of high salt or drought stress. Our results suggest that KdsA expression is important for the growth of new plant tissues, and is sensitive to harsh environments. PMID- 26505344 TI - Immunological characteristics of outer membrane protein omp31 of goat Brucella and its monoclonal antibody. AB - We examined the immunological characteristics of outer membrane protein omp31 of goat Brucella and its monoclonal antibody. Genomic DNA from the M5 strain of goat Brucella was amplified by polymerase chain reaction and cloned into the prokaryotic expression vector pGEX-4T-1. The expression and immunological characteristics of the fusion protein GST-omp31 were subjected to preliminary western blot detection with goat Brucella rabbit immune serum. The Brucella immunized BALB/c mouse serum was detected using purified protein. The high potency mouse splenocytes and myeloma Sp2/0 cells were fused. Positive clones were screened by enzyme-linked immunosorbent assay to establish a hybridoma cell line. Mice were inoculated intraperitoneally with hybridoma cells to prepare ascites. The mAb was purified using the n-caprylic acid-ammonium sulfate method. The characteristics of mAb were examined using western blotting and enzyme-linked immunosorbent assay. A 680-base pair band was observed after polymerase chain reaction. Enzyme digestion identification and sequencing showed that the pGEX-4T 1-omp31 prokaryotic expression vector was successfully established; a target band of approximately 57 kDa with an apparent molecular weight consistent with the size of the target fusion protein. At 25 degrees C, the expression of soluble expression increased significantly; the fusion protein GST-omp31 was detected by western blotting. Anti-omp31 protein mAb was obtained from 2 strains of Brucella. The antibody showed strong specificity and sensitivity and did not cross-react with Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Mycobacterium tuberculosis, or Bacillus pyocyaneus. The pGEX-4T-1-omp31 prokaryotic expression vector was successfully established and showed good immunogenicity. The antibody also showed strong specificity and good sensitivity. PMID- 26505345 TI - Genome-wide identification, classification, and expression analysis of sHSP genes in Chinese cabbage (Brassica rapa ssp pekinensis). AB - Small heat shock proteins (sHSPs) are essential for the plant's normal development and stress responses, especially the heat stress response. The information regarding sHSP genes in Chinese cabbage (Brassica rapa ssp pekinensis) is sparse, hence we performed a genome-wide analysis to identify sHSP genes in this species. We identified 26 non-redundant sHSP genes distributed on all chromosomes, except chromosome A7, with one additional sHSP gene identified from an expressed sequence tag library. Chinese cabbage was found to contain more sHSP genes than Arabidopsis. The 27 sHSP genes were classified into 11 subfamilies. We identified 22 groups of sHSP syntenic orthologous genes between Chinese cabbage and Arabidopsis. In addition, eight groups of paralogous genes were uncovered in Chinese cabbage. Protein structures of the 27 Chinese cabbage sHSPs were modeled using Phyre2, which revealed that all of them contain several conserved beta strands across different subfamilies. In general, gene structure was conserved within each subfamily between Chinese cabbage and Arabidopsis, except for peroxisome sHSP. Analysis of promoter motifs showed that most sHSP genes contain heat shock elements or variants. We also found that biased gene loss has occurred during the evolution of the sHSP subfamily in Chinese cabbage. Expression analysis indicated that the greatest transcript abundance of most Chinese cabbage sHSP genes was found in siliques and early cotyledon embryos. Thus, genome-wide identification and characterization of sHSP genes is a first and important step in the investigation of sHSPs in Chinese cabbage. PMID- 26505346 TI - Characterization of OsPM19L1 encoding an AWPM-19-like family protein that is dramatically induced by osmotic stress in rice. AB - The plant-specific AWPM-19-domain proteins play important roles in plant development and stress responses. In the current study, OsPM19L1 encoding Oryza sativa AWPM-19-like protein 1 was isolated from rice. Tissue-specific gene expression analysis revealed that OsPM19L1 was highly expressed in the leaf sheath of rice. Interestingly, expression of OsPM19L1 was high at the early stage of panicle development and decreased thereafter. qRT-PCR analysis indicated that OsPM19L1 was dramatically induced by 20% PEG stress (>600-fold), exogenous abscisic acid (>350-fold), salt and cold stress. Subcellular localization assay suggested that the OsPM19L1-GFP (green fluorescent protein) fusion protein was localized in the membrane system in rice cells. Moreover, under stress conditions, OsPM19L1 expression was enhanced in an ABI5-Like1 (ABL1) deficiency rice mutant, abl1, suggesting that ABL1 negatively regulates OsPM19L1 gene expression. Thus, OsPM19L1 appears to be closely associated with stress tolerance through ABA-dependent pathway in rice. PMID- 26505347 TI - AMP-activated protein kinase regulates autophagic protection against cisplatin induced tissue injury in the kidney. AB - Although the nephrotoxicity of cisplatin has been well documented as a major side effect of chemotherapy, the exact mechanism by which prosurvival and apoptotic pathways interplay to determine renal pathology remains elusive. Recent studies suggested that autophagy might serve as an adaptive mechanism to promote cell survival during acute kidney injury (AKI). We have used AKI as a disease model to investigate the mechanism regulating the cytoprotective role of autophagy in cisplatin-induced tissue damage. Pharmacological inhibitors such as chloroquine were used to manipulate autophagy during AKI, and DNA damage was evaluated by using the cellular marker gammaH2AX. Cisplatin induced extensive DNA damage during AKI. Autophagy activation served as a survival strategy to suppress cisplatin-induced DNA damage in the pathology of AKI both in vitro and in vivo. Interestingly, in the kidney, cisplatin treatment can activate AMP-activated protein kinase (AMPK), a signaling molecule that is also critical for p53 mediated inactivation of mammalian target of rapamycin (mTOR) pathways. As a result, inhibition or knockdown of AMPK can lead to repressed autophagy in cisplatin-induced AKI, resulting in more DNA damage. Activation of AMPK regulates autophagy during cisplatin-induced AKI. Given the fact that p53 can regulate autophagy by inactivating mTOR via AMPK, our results suggest that the p53 pathway may also play a critical role in the pathogenesis of cisplatin-induced renal damage. This study may further our understanding of the physiological roles of autophagy in the pathogenesis of renal injuries, and thus may have pathological implications in the clinical setting. PMID- 26505348 TI - Effect of IL-1beta, IL-8, and IL-10 polymorphisms on the development of myocardial infarction. AB - Myocardial infarction (MI) is currently a leading cause of death worldwide, and is caused by various environmental and genetic factors. We therefore conducted a case-control study to investigate the association between polymorphisms in interleukins IL-1beta, IL-8, and IL-10 and MI risk. This study recruited 260 MI patients and 285 control subjects. Genotyping of IL-1beta +3954C/T, IL-8 -251T/A, IL-10 -1082A/G, and IL-10 -819C/T were assessed using the polymerase chain reaction-restriction fragment length polymorphism method. By comparing the risk factors of MI between the case and control groups, we discovered that MI patients were more likely to have smoking and drinking habits, have a history of hypertension and diabetes, have higher triglycerides and low-density lipoprotein cholesterol levels, and a lower high-density lipoprotein cholesterol level (P < 0.05). Unconditional regression analyses showed that subjects carrying the GG genotype of the IL-10 -1082A/G polymorphism were associated with increased risk of MI, and the OR (95%CI) was 2.04 (1.15-3.65). Our study found that the IL-10 1082A/G polymorphism plays an important role in influencing the development of MI. PMID- 26505349 TI - Effects of BCL2 transfection on the cell cycle and proliferation of human GES-1 cells. AB - We investigated the effects of BCL2 transfection on the cell cycle and proliferation of GES-1 cells. A pcDNA3-BCL2 plasmid was used to transfect GES-1 cell line human gastric epithelial cells. Clones were obtained by G418 screening. BCL2-positive cells were identified by fluorescence immunohistochemistry. The pcDNA3-BCL2 vectors carrying the NeoR gene were transfected into GES-1 cells, while the empty plasmid was transfected into the same cells as controls. BCL2 positive clones were screened by neomycin 418 (G418). Flow cytometry was used to detect the cell cycle. Hematoxylin and eosin (H&E) staining revealed morphological changes, and the effects of BCL2 transfection on cell proliferation were analyzed by cell counting and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. The plasmid pcDNA3-BCL2 was identified by restriction enzyme digestion. Different degrees of BCL2 gene expression were detected in all seven clones. BCL2 was expressed mainly in the cytoplasm and the nuclear membrane. There were significantly more S-phase cells in the transfection group than in the controls. The morphology did not change after H&E staining. Cell growth was faster than in the controls after transfection for 6 days. At 24, 48, and 72 h after transfection, the A values were 4.15 +/- 0.31, 5.98 +/- 0.56, and 8.94 +/- 0.79; those of the controls were 3.01 +/- 0.20, 4.76 +/- 0.52, and 7.69 +/- 0.84; there was a significant difference between the two groups (P < 0.05). BCL2 transfection increased GES-1 cells in the S phase; the GES-1 cells were stable and BCL2 expression was high, which promoted cell proliferation. PMID- 26505350 TI - Molecular cloning and characterization of a proliferating cell nuclear antigen gene by chemically induced male sterility in wheat (Triticum aestivum L.). AB - Although a number of studies have shown that chemical hybridizing agents (CHAs) affect anther growth and regulate cell-cycle progression, little is known about the molecular and cellular mechanisms involved. Proliferating cell nuclear antigen (PCNA) is an essential factor in DNA replication, and in many other processes in eukaryotic cells. In this study, the open reading frame of TaPCNA, the PCNA in wheat (Triticum aestivum L.), was cloned by reverse transcription polymerase chain reaction (RT-PCR). Sequence analysis revealed that this gene was 792-bp long and encoded a protein with 234 amino acids. Alignment of the TaPCNA predicted sequence revealed a high degree of identity with PCNAs from other plant species. A subcellular localization assay indicated that TaPCNA was localized in the nucleus. The TaPCNA was cloned into the prokaryotic expression plasmid pET32a, and the recombinant plasmid was transformed into BL21 (DE3). TaPCNA expression was induced by 0.5 mM isopropyl-beta-D-thiogalactopyranoside and verified using sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blot assays, which indicated that the fusion protein was successfully expressed. The gene involved in the G1-to-S transition, Histone H4, was downregulated by 1376- CIMS, which is a chemically induced male sterility line. However, a semi-quantitative RT-PCR revealed that TaPCNA expression was upregulated in 1376-CIMS. Our results suggest that CHAs (SQ-1) induce DNA damage in wheat anthers. DNA damage results in either the delay or arrest of cell-cycle progression, which affects anther development. This study will help to elucidate the mechanisms of SQ-1-induced male sterility. PMID- 26505351 TI - Analysis of the drug-resistant characteristics of Klebsiella pneumoniae isolated from the respiratory tract and CTX-M ESBL genes. AB - The main aim of this study was to understand the relationship between the drug resistant characteristics of Klebsiella pneumoniae and CTX-M-type extended spectrum beta-lactamases (ESBLs), and to detect the distributions of CTX-M-type ESBLs in clinically isolated strains. CTX-M ESBL genes isolated from the clinical samples were amplified by polymerase chain reaction and identified by sequence analysis; the antibiotic susceptibility of the samples was determined using the Kirby-Bauer disc-diffusion method. One hundred and five strains among the 246 isolated strains of K. pneumoniae tested positive for ESBL production (42.68%); 92 of these produced CTX-M ESBLs. Of the 92 CTX-M ESBL strains, 81 produced CTX-M 1 ESBLs and 11 produced CTX-M-25 ESBLs. Fifty-seven of the CTX-M-1 ESBL- and six of the CTX-M-25 ESBL-producing bacteria had CTX-M ESBL genes that coexisted in the plasmid and chromosome. The Kirby-Bauer antibiotic susceptibility method revealed that CTX-M ESBL-positive strains showed a higher rate of resistance to cefazolin, cefoxitin, cefuroxime, ceftazidime, cefotaxime, aztreonam, levofloxacin, and cotrimoxazole, compared to the CTX-M ESBL-negative strains (P < 0.05). The CTX-M ESBL genes were commonly observed in the K. pneumoniae isolated from respiratory tract samples; these were significantly associated with the drug resistant characteristics of K. pneumoniae to beta-lactam antibiotics. PMID- 26505352 TI - A putative miR172-targeted CeAPETALA2-like gene is involved in floral patterning regulation of the orchid Cymbidium ensifolium. AB - APETALA2 plays critical roles in establishing meristem and organ identity during plant floral development. In this study, we obtained a CeAP2-like gene by using the mRNA differential display technique to analyze the wild type and a multitepal mutant of the orchid Cymbidium ensifolium. The full-length cDNA encoding the CeAP2-like transcription factor shows significant similarity to the cDNA of AP2 from Erycina pusilla and contains nucleotides complementary to miR172. Using a transient gene expression system of Arabidopsis protoplasts, we found that the accumulation of CeAP2-like protein and transcripts was negatively regulated by miR172, indicating this gene as a putative target of miR172. Northern blotting revealed that CeAP2-like is dominantly expressed in the sepals and petals of the wild-type flower, and shows low expression in the gynostemium. In contrast, the accumulation of CeAP2-like transcripts decreased significantly, especially in the central part of the mutant flower, corresponding to its abnormal petals and the absence of the gynostemium. Furthermore, we found an antagonistic expression pattern between CeAP2-like and AGAMOUS in the wild type, representing A- and C class genes that specify floral organ fate. However, this antagonistic distribution was modified in the multitepal mutant, and both genes showed lower expression than that in the wild type. This result suggested that the balance between CeAP2-like and AGAMOUS activity was important for the regulation of floral patterning in C. ensifolium. This study represents the first report on a class A gene and its regulatory role for floral development in the orchid C. ensifolium. PMID- 26505353 TI - Leishmania (Viannia) braziliensis in dogs in Brazil: epidemiology, co-infection, and clinical aspects. AB - Leishmaniasis is an endemic disease present in 98 countries. In Brazil, the northeast region accounts for approximately half of the cases in humans, and has experienced an increased number of positive cases in dogs. In this study, we investigated the epidemiology of canine leishmaniasis in the city of Ilheus, Bahia, using serological and molecular techniques and evaluated the possible environmental risk factors and associated clinical signs. Blood samples were collected from 560 dogs in urban and peri-urban areas in Ilheus, northeastern Brazil. Genomic DNA was extracted from the selected animals and subjected to molecular analysis using Leishmania species-specific primers and diagnosis of Trypanosoma cruzi. A total of 54.72% of dogs were positive for Leishmania braziliensis, and animals positive for both Leishmania infantum and T. cruzi were not identified. Hematologic variables were not statistically associated with cases of L. braziliensis. However, the positive animal group showed lower red blood cell and platelet counts and higher levels of urea and serum creatinine. Few dogs presented clinical signs compatible with the presence of Leishmania. Age of more than 2 years and specific hair colors were associated with positive results for L. braziliensis. The geoclimatic characteristics of the region may improve parasite survival, reproduction, and vectors. This may explain the higher rate of dogs identified as positive in this study. PMID- 26505354 TI - CCDC26 rs4295627 polymorphism (8q24.21) and glioma risk: a meta-analysis. AB - The association between the CCDC26 rs4295627 single nucleotide polymorphism (SNP) and the glioma risk has been studied previously, but these studies have yielded conflicting results. The aim of the present study is to analyze this association more vigorously, by means of a meta-analysis. A comprehensive literature search was performed in databases PubMed and EMBASE. Six articles including 12 case control studies in English with 11,368 controls and 5891 cases were eligible for the meta-analysis. We conducted subgroup analyses by the source of controls, ethnicity, and country. Our meta-analysis revealed that the rs4295627 SNP was associated with the glioma risk in a heterozygote model (TG versus TT: odds ratio = 1.35, 95% confidence interval = 1.26-1.45, P = 0.066). Moreover, our results suggested that the rs4295627 SNP was associated with a notably increased risk of glioma among Caucasians except for Swedes in 4 models (the homozygote model, recessive model, dominant model, and additive model). Nonetheless, in Sweden and China, the results showed no associations. No evidence of the publication bias was uncovered. Thus, our meta-analysis suggests that the rs4295627 SNP is associated with an increased risk of glioma. Additional studies are needed to derive more precise conclusion. PMID- 26505355 TI - Gene expression profiling of somatic and pluripotent cells reveals novel pathways involved in reprogramming. AB - We investigated gene expression in embryonic stem (ES) cells, induced pluripotent stem (iPS) cells, and fibroblasts. Microarray expression data sets obtained from the Gene Expression Omnibus were analyzed using the Partek software. Human genes from ES cells, iPS cells, and fibroblasts were ranked from low to high according to their expression levels. The gene expression mode in iPS cells was much more like the mode in ES cells, and the expression levels of fibroblast genes fluctuated more dramatically than those of iPS and ES cells. The number of genes with significantly different expression was lower in the iPS and ES cells. Several genes with the expression levels that were significantly different between ES and iPS cells were found, including LEFTY2, DLK1, and NLRP2. Four genes belonged to the low expression category in fibroblasts with the high expression category occurring in ES cells, i.e., HESRG, PROM1, NTS, and LRRN1. Analyzing the expression of these genes is helpful to elucidate the mechanisms of cell fate regulation and efficiently obtain iPS cells. PMID- 26505356 TI - Distribution and localization of abnormally expressed OPTN proteins in RGC5 retinal ganglion cells and their effects on subcellular morphology. AB - The objectives of this study were to investigate the distributions of abnormally expressed optineurin (OPTN) proteins in retinal ganglion cells (RGC5s) of transgenic rats and their effects on subcellular morphological structures. Green fluorescent protein labeled EGFP wild-type (OPTN(WT)), E50K mutant type (OPTN(E50K)), and OPTN siRNA (si-OPTN) eukaryotic expression plasmids were constructed and transfected into RGC5s. Intracellular structures were labeled with organelle specific fluorescent dyes. Construct localization and cell morphologies were visualized by confocal fluorescence microscopy. OPTN(WT) was observed to be distributed as fine punctate fluorescent particles in the cytoplasm around the nucleus, along with exhibiting nuclear expression. OPTNE50K exhibited similar distribution but with non-uniform fluorescence particle size. si-OPTN distribution was similar to that of EGFP: uniform across the cytoplasm and nucleus. Compared with the negative control group, OPTN(WT), and OPTN(E50K) and to a lesser degree pEGFP-transfected cells exhibited fracture and loss of myofilament proteins and mitochondrial swelling and cytoplasmic accumulation, along with abnormal lysosomal distribution and increased volume, and Golgi fragmentation. However, si- OPTN transfected cells exhibited no significant damage. Therefore, we demonstrated that the E50K mutation disrupts the uniformity of OPTN protein distribution upon exogenous overexpression. Furthermore, these results suggested that si-OPTN transfection, and thus potentially OPTN knockdown, did not impact subcellular morphology of RGC5 cells, whereas transfection, especially when combined with wild-type or mutant OPTN expression, led to substantial abnormalities in subcellular morphological structures. These findings lay a foundation for further research into the function of the OPTN protein. PMID- 26505357 TI - Genetic analyses, phenotypic adaptability and stability in sugarcane genotypes for commercial cultivation in Pernambuco. AB - In the present study, we assessed the agro-industrial performance of 22 sugarcane genotypes adaptable to edaphoclimatic conditions in production microregions in the State of Pernambuco, Brazil, and we recommended the commercial cultivation of select genotypes. The variables analyzed were as follows: sucrose percentage in cane juice, tonnage of saccharose per hectare (TPH), sugarcane tonnage per hectare (TCH), fiber, solid soluble contents, total recoverable sugar tonnage (ATR), and total recoverable sugar tonnage per hectare (ATR t/ha). A randomized block design with 4 repeats was used. Combined variance of the experiments, genetic parameter estimates, and environment stratification were analyzed. Phenotypic adaptability and stability were analyzed using the Annicchiarico and Wricke methods and analysis of variance. Genetic gain was estimated using the classic index and sum of ranks. Genotype selection was efficient for TPH, TCH, and ATR t/ha. Genotypes presented a great potential for improvement and a similar response pattern in Litoral Norte and Mata Sul microregions for TPH and TCH and Litoral Norte and Litoral Sul microregions for ATR t/ha. Genotypes SP78-4764, RB813804, and SP79-101 showed better productivity and phenotypic adaptability and stability, according to the Wricke and Annicchiarico methods. These genotypes can be recommended for cultivation in the sugarcane belt in the State of Pernambuco. PMID- 26505358 TI - Construction of a hepatocellular carcinoma cell line that stably expresses stathmin with a Ser25 phosphorylation site mutation. AB - We constructed hepatocellular carcinoma (HCC) cells that stably express stathmin with a Ser25 phosphorylation site mutation (stathmin S25A). We used the polymerase chain reaction for site-directed mutagenesis, constructed a stathmin S25A plasmid, and verified the results by restriction enzyme cleavage and sequencing technology. Using the liposome transfection method, stathmin wild-type and S25A HCCLM6 cells were established, which were identified by western blotting. The sequencing report of the stathmin S25A plasmid showed that stathmin serine at position 25 had mutated into alanine. Stable cells transfected with stathmin wild-type and S25A plasmids were constructed. Using western blotting, we confirmed that the expression level of stathmin pS25 in the stathmin S25A cells was reduced than that in the stathmin wild-type and HCCLM6 control cells (P < 0.05). We constructed stathmin S25A HCCLM6 cells, which offer an experimental model for further investigation of the molecular mechanism of stathmin phosphorylation in hepatocarcinogenesis. PMID- 26505359 TI - Molecular cloning and expression analysis of five GhRAXs in upland cotton (Gossypium hirsutum L.). AB - The formation of axillary meristems in leaf axils is a prerequisite for the development of lateral shoots, which largely contribute to plant architecture. Several transcription factor-encoding genes, including CUC3, RAX, LAS, LOF1, and ROX, have been cloned by screening for axillary meristem mutants in Arabidopsis thaliana. These genes will facilitate our understanding of the mechanisms underlying axillary meristem development. In this study, we report the cloning of five genes from cotton (Gossypium hirsutum L.) that are orthologous to A. thaliana REGULATORS OFAXILLARY MERISTEMS (RAX) and tomato Blind (Bl), and they are designated GhRAX1, 2, 3, 4, and 5. Sequence analyses indicated that all five genes shared conserved protein domains with RAX and Bl. Phylogenetic analyses of protein sequences revealed that GhRAX2/3/4 were close to RAX1, whereas GhRAX1 and GhRAX5 were close to RAX3. Expression patterns of these genes in different tissues were also analyzed using real-time PCR. PMID- 26505360 TI - Characterization of allele-specific expression of the X-linked gene MAO-A in trophectoderm cells of bovine embryos produced by somatic cell nuclear transfer. AB - Somatic cell nuclear transfer (SCNT) may affect epigenetic mechanisms and alter the expression of genes related to embryo development and X chromosome inactivation (XCI). We characterized allele-specific expression of the X-linked gene monoamine oxidase type A (MAO-A) in the trophectoderm (TF) of embryos produced by SCNT. Total RNA was isolated from individual biopsies (N = 25), and the allele-specific expression assessed by reverse transcription-polymerase chain reaction-restriction fragment length polymorphism. Both paternal and maternal alleles were expressed in the trophectoderm. However, a higher frequency of the mono-allelic expression of a specific allele was observed (N = 17; 68%), with the remaining samples showing the presence of mRNA from both alleles (N = 8; 32%). Considering that MAO-A is subject to XCI in bovine, our results suggest that SCNT may influence XCI because neither an imprinted (mono-allelic expression in all samples) nor a random (presence of mRNA from both alleles in all samples) pattern of XCI was observed in TF. Due to the importance of XCI in mammalian embryo development and its sensitivity to in vitro conditions, X-linked genes subject to XCI are candidates for use in the development of embryo quality molecular markers for assisted reproduction. PMID- 26505361 TI - Effect of NB-UVB on levels of MCP-1 and CCR6 mRNA in patients with psoriasis vulgaris. AB - The aim of this study is to explore the effect of narrow band ultraviolet B (NB UVB) on the chemokine receptor CCR6 mRNA levels in patients with psoriasis. Psoriasis area and severity index (PASI) values were recorded before and after the treatment with NB-UVB phototherapy of 30 psoriasis vulgaris patients. The reverse transcription-polymerase chain reaction method was used to detect the expression level of CCR6 mRNA in peripheral blood mononuclear cells, and compared with 30 healthy subjects. The PASI value of the 30 psoriasis vulgaris patients decreased significantly after 15 iterations of phototherapy treatment (P < 0.01). The expression level of CCR6 mRNA in psoriasis patients was significantly higher than in the healthy controls (P < 0.01), while the expression level of CCR6 mRNA decreased significantly after phototherapy (P < 0.01). Reduction of CCR6 level may be one of the mechanisms through which NB-UVB can treat psoriasis. PMID- 26505362 TI - Spermatogenesis and nucleolar behavior in Triatoma vandae and Triatoma williami (Hemiptera, Triatominae). AB - This study describes spermatogenesis in Triatoma vandae and the nucleolar behavior of T. vandae and Triatoma williami, with a cytotaxonomic focus. Analysis of mitotic and meiotic metaphases of T.vandae confirms the species karyotype. T. vandae presents some characteristics during meiosis that differentiate it from T. williami, including the presence of a chromocenter with two sex chromosomes individualized during early prophase, and the presence of a bi- or tripartite corpuscle inpolyploid nuclei. It was possible to observe the compaction of chromatin during prophase resulting in holocentric chromosomes. During metaphase,the autosomes presented a ring shape and the sex chromosomes were in the center of the ring. These chromosomes were separated in anaphase. Although it is common, we did not observe the phenomenon of late migration of the sex chromosomes. By means of silver ion impregnation it was possible to describe nucleologenesis in T. vandae and T. williami. In both species we observed persistence of the nucleolar material duringmeiosis. In addition to the cells in meiotic division, we also observed the presence of polyploid nuclei in the seminiferous tubule walls that nourish the cells during cell division. The nucleolar markings reflect their capacity for synthetic activity. T. vandae and T. williami presented only one nucleolar corpuscle, which reflects low synthetic activity. This study confirms the karyotype of T. vandae, describes characteristics that differentiate T. vandae and T. williami during meiosis, and describes the phenomenon of nucleolar persistence in both species. PMID- 26505363 TI - Expression patterns of Doppel in differential ovine PRNP genotypes: quantification using real-time RT-PCR. AB - Doppel is a homologue of cellular prion protein (PrP)-like protein (PrPC). Different tissue samples were collected from the central nervous system plus four regions of lymphoid system, eleven regions of digestive tract and two reproductive organs from four ARR/ARQ and four ARH/ARQ sheep, genotypes of the PrP gene. Total RNA was isolated from these samples, and Doppel mRNA was quantified by real-time RT-PCR using SYBR Green. Doppel mRNA expression was higher in the ovary, hypothalamus and brain than in other tissues, and it significantly differed between the two genotypes in brain, ileum, cecum, rectum, colon, and uterus. This study demonstrated that Doppel mRNA expression in sheep with ARR/ARQ or ARH/ARQ genotypes was very different. These findings could be helpful in future studies of the relationship between PrP and Doppel. PMID- 26505364 TI - Cloning and sequence analysis of the coding sequence of beta-actin cDNA from the Chinese alligator and suitable internal reference primers from the beta-actin gene. AB - beta-Actin is an essential component of the cytoskeleton and is stably expressed in various tissues of animals, thus, it is commonly used as an internal reference for gene expression studies. In this study, a 1731-bp fragment of beta-actin cDNA from Alligator sinensis was obtained using the homology cloning technique. Sequence analysis showed that this fragment contained the complete coding sequence of the beta-actin gene (1128 bp), encoding 375 amino acids. The amino acid sequence of beta-actin is highly conserved and its nucleotide sequence is slightly variable. Multiple alignment analyses showed that the nucleotide sequence of the beta-actin gene from A. sinensis is very similar to sequences from birds, with 94-95% identity. Ten pairs of primers with different product sizes and different annealing temperatures were screened by PCR amplification, agarose gel electrophoresis, and DNA sequencing, and could be used as internal reference primers in gene expression studies. This study expands our knowledge of beta-actin gene phylogenetic evolution and provides a basis for quantitative gene expression studies in A. sinensis. PMID- 26505366 TI - Association analysis of IL-17A and IL-17F polymorphisms in Chinese women with cervical cancer. AB - We selected six tagged single nucleotide polymorphisms (SNPs) in the interleukin 17A (IL-17A) and IL-17F genes, and evaluated the relationship between the six common SNPs and environmental factors in cervical cancer patients. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the IL 17A (rs2275913, rs3748067, and rs3819025) and IL-17F (rs763780, rs9382084, and rs1266828) SNPs. The associations between IL-17A and IL-17F gene polymorphisms and risk of cervical cancer were estimated by conditional logistic regression. Compared with the control subjects, the cervical cancer patients had a lower age at first live birth, a habit of smoking, a family history of cancer, and a greater incidence of human papillomavirus-16 or 18 infections. The logistic regression analysis showed that the variant AA genotype of rs2275913 was associated with a significantly higher risk of cervical cancer than the wild-type GG genotype (OR = 1.99, 95%CI = 1.12-3.50). However, no evidence of the association was observed between rs3748067, rs3819025, rs763780, rs9382084, and rs1266828 polymorphisms and the risk of cervical cancer. We suggest that rs2275913 may play a role in the etiology of cervical cancer. These findings could be helpful in identifying individuals at increased risk of developing cervical cancer. PMID- 26505365 TI - Significance of detecting IgH and TCRgamma gene rearrangements in patients with hemopoietic maligancies by real-time quantitative PCR. AB - The aim of our study was to investigate the association of IgH and TCRgamma gene rearrangements in hematological malignancies with the disease and clinical application. IgH and TCRgamma gene rearrangements were determined in 69 paraffin and bone marrow specimens with SYBR Green I fluorescent dye and RQ-PCR method, including 21 paraffin-embedded tissues of the onset cases and 48 bone marrow samples, representing 15 ALL and 25 AML cases. After chemotherapy, 8 cases were NHL; the 10 cases of the negative control group were healthy people. Among the ALL cases, the IgH rearrangement occurred in 80.0%, the TCRgamma rearrangement in 46.7%, and both gene rearrangements in 46.7%. Among the AML cases, the IgH rearrangement occurred in 72.0%, the TCRgamma rearrangement in 68.0%, and both gene rearrangements in 60.0%. In the lymphoma cases, the IgH rearrangement occurred in 93.1%, the TCRgamma rearrangement in 51.7%, and both gene rearrangements in 44.8%. In the negative control group, the 10 cases were all negative. There was the phenomenon of "sequence-non-fidelity" in the hematologic malignancies; the detection rate of both genes was much higher than that of the single gene. The application of the RQ-PCR method in the detection of IgH and TCRgamma gene rearrangements in hematologic malignancies has important clinical significance in MRD monitoring. PMID- 26505367 TI - Assessment of correlation between pre-miRNA-1757 polymorphism and chicken performance traits. AB - Single nucleotide polymorphism in microRNAs (miRNA) may influence their target gene selection and regulation efficiency, leading to animal phenotypic variation. The aim of this study was to evaluate the possible effect of single nucleotide polymorphisms in the miRNA-1757 gene precursor region (pre-mir-1757) on economic related traits in chicken. Genotyping was performed using Sequenom MassArray(r) iPLEX GOLD System. Association analysis was performed using SPSS19.0. The data showed that the G/C polymorphism was significantly correlated with semi evisceration weight, evisceration weight, carcass weight, body weight at 10 weeks of age, shank length at 4 weeks of age, pectoral angle at 8 weeks of age, and body slanting length and pelvis breadth at 12 weeks of age (P < 0.05), and led to the alteration of the RNA secondary structure of pre-mir-1757. Our results provide useful information for further annotation studies of miRNA function. PMID- 26505368 TI - Association of a miR-34b binding site single nucleotide polymorphism in the 3' untranslated region of the methylenetetrahydrofolate reductase gene with susceptibility to male infertility. AB - This study aims to explore the possible associations between a genetic variation in the miR-34b binding site in the 3'-untranslated region (UTR) of the methylenetetrahydrofolate reductase (MTHFR) gene (rs55763075) with male infertility in a Chinese population. Genotype distributions of the rs55763075 single nucleotide polymorphism were investigated by polymerase chain reaction and direct sequencing in a Chinese cohort that included 464 infertile men with idiopathic azoospermia or oligospermia and 458 controls with normal fertility. Overall, no significant differences in the distributions of the genotypes of the MTHFR rs55763075 polymorphism were detected between the infertility and control groups. A statistically significant increased risk of male infertility was found for carriers of the rs55763075 AA genotype when compared with homozygous carriers of the rs55763075 GG genotype in the azoospermia subgroup (OR = 1.721; 95% CI = 1.055-2.807; P = 0.031). Furthermore, we found that rs55763075 was associated with folate and homocysteine levels in patients with idiopathic azoospermia. Our results indicated that the MTHFR 3'-UTR rs55763075 polymorphism might modify the susceptibility to male infertility with idiopathic azoospermia. PMID- 26505369 TI - Development of SNP markers and their application for genetic diversity analysis in the oil palm (Elaeis guineensis). AB - The genetic evaluation of oil palm germplasm collections is required for insight into the variability among populations. The information obtained is also useful for incorporating new genetic materials into current breeding programs. Single nucleotide polymorphisms (SNPs) have been widely used in many plant genetic studies due to the availability of large numbers of genomic sequences and expressed sequence tags. The present study examined 219 oil palms collected from two natural Angolan populations, a few hundred kilometers apart. A total of 62 SNPs were designed from oil palm genomic sequences and converted to cleaved amplified polymorphic sequence (CAPS). Of these, nine were found to be informative across the two populations. The nine informative SNPs revealed mean major allele frequency of 0.693. The average expected and observed heterozygosities were 0.398 and 0.400, respectively. The mean polymorphism information content was 0.315 (ranging between 0.223 and 0.375). None of the loci deviated from Hardy-Weinberg equilibrium and no rare alleles were detected. In cluster analysis using unweighted pair group method with arithmetic, the 219 oil palms fell into two clusters. This was further supported by the population structure analysis result (K = 2), suggesting that the samples were divided into two main genetic groups. However, the two groups did not coincide with the geographic populations. Analysis of molecular variance indicated that within population variation contributed 93% of the total genetic variation. This study showed that SNP-based CAPS markers are useful for studying the genetic diversity of oil palm and have potential application for marker-trait association studies. PMID- 26505370 TI - Comparison of dimensionality reduction methods to predict genomic breeding values for carcass traits in pigs. AB - A significant contribution of molecular genetics is the direct use of DNA information to identify genetically superior individuals. With this approach, genome-wide selection (GWS) can be used for this purpose. GWS consists of analyzing a large number of single nucleotide polymorphism markers widely distributed in the genome; however, because the number of markers is much larger than the number of genotyped individuals, and such markers are highly correlated, special statistical methods are widely required. Among these methods, independent component regression, principal component regression, partial least squares, and partial principal components stand out. Thus, the aim of this study was to propose an application of the methods of dimensionality reduction to GWS of carcass traits in an F2 (Piau x commercial line) pig population. The results show similarities between the principal and the independent component methods and provided the most accurate genomic breeding estimates for most carcass traits in pigs. PMID- 26505371 TI - Phylogenetic analysis of Elymus (Poaceae) in western China. AB - Elymus L. is often planted in temperate and subtropical regions as forage. Species in the genus have 5 allopolyploid genomes that are found in the grass tribe Triticeae. To determine the phylogenetic relationships in Elymus species from western China, we estimated phylogenetic trees using sequences from the nuclear ribosomal internal transcribed spacer and non-coding chloroplast DNA sequences from 56 accessions (871 samples) of 9 polyploid Elymus species and 42 accessions from GenBank. Tetraploid and hexaploid Elymus species from western China had independent origins, and Elymus species from the same area or neighboring geographic regions were the most closely related. Based on the phylogenetic tree topology, the St- and Y-genomes were not derived from the same donor and Y-genome likely originated from the H-genome of Hordeum species, or they shared the same origin or underwent introgression. The maternal genome of tetraploid and hexaploid Elymus species originated from species of Hordeum or Pseudoroegneria. Additionally, Elymus species in western China began diverging 17 8.5 million years ago, during a period of increased aridification as a consequence of the Messinian salinity crisis. Elymus species adapted to drought and high salinity may have developed based on the environmental conditions during this period. Elymus evolution in western China may have been affected by the uplift of the Qinghai-Tibetan Plateau (5 million years ago), when Elymus seeds were dispersed by gravity or wind into a newly heterogeneous habitat, resulting in isolation. PMID- 26505372 TI - Optimization of candidate proteins for serological screening of Chlamydia trachomatis infection. AB - The aim of this study was to optimize candidate antigen proteins for serological screening of Chlamydia trachomatis infection. C. trachomatis positive serum and swabs of genital secretions were collected from 50 patients in the Tianjin Medical University General Hospital, as well as from 30 patients negative for C. trachomatis. Samples were assessed by colloidal gold assay in a sexually transmitted disease clinic as follows: serum antibodies for eight kinds of C. trachomatis immunodominant proteins (Pgp3, CPAF, CT143, CT101, CT694, CT875, CT813, and IncA) were detected, and two traditional gold standards, immunofluorescence and C. trachomatis cell culture of genital secretions, were used for comparison in order to determine the antigen protein combinations with the highest sensitivity and specificity. Of the 50 samples that tested positive for C. trachomatis infection by colloidal gold assay, 44 tested positive by micro immunofluorescence, whereas 6 tested negative. In contrast, 14 samples tested positive by cell culture, whereas 36 tested negative. Serological results of the immunodominant protein combination of Pgp3, CT694, and CT875 shared positive coincidence rates of 97.73 and 92.86% with C. trachomatis micro immunofluorescence and cell culture, respectively. No antibodies of the three proteins were detected in the 30 C. trachomatis samples that tested negative by colloidal gold assay; these samples also tested negative in C. trachomatis genital secretion culture. Overall, the combination of the three immunodominant proteins Pgp3, CT694, and CT875 had good sensitivity and specificity for serological screening of C. trachomatis infection, and the process was simple and easy to apply. PMID- 26505373 TI - Protective effect of thymoquinone on cholestatic rats with liver injury. AB - The aim of this study was to investigate the protective effects of thymoquinone treatment on cholestatic rats with liver injury. Thirty-two Sprague-Dawley rats were divided randomly into four groups: normal control, bile duct ligation model control, low-dose thymoquinone (25 mg/kg), and high-dose thymoquinone (50 mg/kg). Thymoquinone gavage was administered continuously 3 days before bile duct ligation, and saline, at the same volume, was administered to the control group. The rats were sacrificed after 2 weeks of treatment, and the liver tissues were obtained and frozen. The contents of hydroxyproline (HP), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the homogenate of the liver tissues were determined to evaluate the changes in hepatic tissue pathology by fibrosis scoring. The HP and MDA levels were significantly lower and the SOD and GPx levels were significantly higher in the thymoquinone-treatment group than the corresponding levels in the model control group, and the differences were statistically significant (P < 0.05) and dose-dependent. The hepatic necrosis areas and hepatic fibrosis scores of the thymoquinone-treatment groups were significantly lower than those of the model group (P < 0.05). Thymoquinone increased the antioxidative capacity of liver and reduced the oxidative stress damage to the liver. Thymoquinone can be used as a liver protectant in patients with cholestasis. PMID- 26505374 TI - Lack of an association between matrix metalloproteinase polymorphisms and coronary heart disease in a Han Chinese population. AB - Coronary heart disease (CHD) has become a leading cause of human deaths worldwide. Recent studied showed that polymorphisms of the matrix metalloproteinase (MMP) genes played important roles in extracellular matrix remodeling and contribute to the pathogenesis of vascular diseases. Here, we investigated whether these MMP gene polymorphisms were associated with CHD in Han Chinese. Our case-control study was involved with 1509 unrelated individuals, including 777 CHD cases and 732 controls. We selected a total of five polymorphisms whose genotypes were determined using Sequenom iPLEX technology. Our results showed there were no significant associations between the five MMP gene polymorphisms and CHD risk at either genotype or allele levels (P > 0.05). Further subgroup analyses by sex were also unable to reveal any significant association (P > 0.05). In conclusion, no significant associations were found between the five MMP gene polymorphisms and the risk of CHD in Han Chinese. PMID- 26505375 TI - Intestinal lactic acid bacteria from Muscovy duck as potential probiotics that alter adhesion factor gene expression. AB - The purpose of this study was to assess the suitability of lactic acid bacteria (LABs) isolated from Muscovy duck as a potential probiotic. Isolates were identified by targeted polymerase chain reaction and assessed in vitro for probiotic characteristics such as autoaggregation; surface-charge; hydrophobicity; tolerance to acidic pH, bile salts and protease; and expression of genes involved in Caco-2 cell adhesion. The LAB isolates exhibited strong resistance to high bile concentration and acidic pH, produced lactic acid, and bacteriostatic (P < 0.05) were identified as bacilli compared with LAB isolates of cocci. Additionally, the LAB isolates showed high sensitivity to penicillin and tetracycline antibiotics, while they were resistant to ofloxacin, Macrodantin, and cotrimoxazole. The level of F-actin mRNA increased in the groups treated with CM3, Salmonella enterica, and CM3 + S. enterica (P < 0.0001, P < 0.05 and P < 0.05 ). The level of cell adhesion molecule (CAM) and E-cadherin (E cad) mRNA expression was significantly lower in the treatment group (P < 0.05 for both) than in the control. The F-actin, CAM, and E-cad mRNA levels were significantly lower in the S. enterica and CM3 + S. enterica groups (P < 0.01) than in the CM3 group. Among these, RNA levels were higher in the CM3 + S. enterica than S. enterica group. These results indicate that the natural duck gut microflora is an excellent source for probiotic bacteria and can facilitate the establishment of criteria to select probiotic strains for the prevention of diarrhea. PMID- 26505376 TI - Haplo-block structure of Southern African village chicken populations inferred using genome-wide SNP data. AB - This study investigated the haplo-block structure, haplotype sharing, and diversity in extensively raised chicken populations of Southern Africa. Two hundred ninety village chickens from Malawi (N = 30), South Africa (N = 132), and Zimbabwe (N = 128) were included in the study, from which 649, 2104, and 2442 haplo-blocks were observed, respectively. The majority of haplo-blocks were smaller than 25 kb in size and only five blocks were more than 2000 kb in size. The low chromosomal coverage of haplo-blocks observed across the genome suggests that multiple recombination events fragmented the ancestral haplo-blocks into smaller sizes. Haplo-block sharing was observed between populations with 2325 haplo-blocks common between Zimbabwe and Malawi and 2689 between South Africa and Zimbabwe. Haplotype sharing allows transferability of genomic tools between these extensively raised chicken populations of Southern Africa. The unique haplo blocks could have originated from isolated evolution taking place in specific agro-ecological zones. Quantitative trait loci analysis revealed that genes related to body composition were spanned by these haplo-blocks. Body composition traits are important for village chicken populations, which have to harness poor quality feed obtained from the environment to meet their maintenance and production needs. PMID- 26505377 TI - Characterization of HSP70 and its expression in tissue: correlation with physiological and immune indices in goose (Anser cygnoides) serum. AB - We cloned the goose heat shock protein 70 gene (HSP70), to determine its sequence variation and elucidate its mRNA expression. We designed primers to amplify the entire goose HSP70 sequence. We used 10 commercial Wuzong goslings in a heat stress experiment. We collected tissue samples for RNA extraction and quantitative real-time polymerase chain reaction (qRT-PCR). We analyzed the variation in expression of goose HSP70 before and after heat stress. We constructed a DNA pool from six different species, for single nucleotide polymorphism (SNP) screening. We detected 18 SNPs and selected three of these SNPs for correlation analysis with biological and immune traits in 200 Wuzong geese. We showed that T+237C was significantly correlated with the serum corticosterone level, whereas T+1122C was significantly correlated with the heterophil to lymphocyte ratio. Goose HSP70 contained no introns. The results of qRT-PCR analysis revealed significant gender differences in the expression of goose HSP70 at 40 degrees C but not at 25 degrees C; moreover, in general, expression was significantly higher at 40 degrees C than at 25 degrees C. With the exception of the leg muscle and cerebellum, HSP70 expression was significantly higher in male geese than in female geese. Our results indicate that goose HSP70 plays an important role in response to severe heat stress. PMID- 26505378 TI - Lack of association between the vitamin D receptor polymorphism rs2228570 and chronic periodontitis in a Han Chinese population. AB - The vitamin D receptor (VDR) is involved in the immune response and bone metabolism, both of which are implicated in the pathogenesis of chronic periodontitis (CP). In this study, we investigated the association between the VDR single nucleotide polymorphism rs2228570 and CP susceptibility in a Han Chinese population consisting of 440 moderate or severe CP patients and 324 controls. Genomic DNA was extracted from buccal epithelial cells and genotyped using matrix-assisted laser desorption/ionization time-of-flight-mass spectrometry. No significant difference in allelic or genotypic frequencies distributions for rs2228570 was found between CP patients and controls. In conclusion, we found no statistically significant association between rs2228570 and CP in our population. PMID- 26505379 TI - Restriction-ligation-free (RLF) cloning: a high-throughput cloning method by in vivo homologous recombination of PCR products. AB - In this study, we optimized a restriction-ligation-free (RLF) method to save time and cost of constructing multiple plasmids with the same gene insert, and examined the efficacy of RLF on high-throughput multi-plasmid cloning. This method utilizes the precise DNA repair and recombination systems within Escherichia coli, which allows to bypass the in vitro restriction and ligation enzyme reactions commonly included in routine cloning procedures. A homologous arm is linked to the 5'-end of the forward primer used to amplify both the target gene and vector. A different homologous arm is linked to the 5'-end of the reverse primer. Therefore, genes can be cloned into the vectors by homologous recombination after co-transformation of the amplified target gene and the linearized vector, which bear the same homologous arm on either end. More than twenty-four different plasmids were generated by this method, which uses two simple polymerase chain reaction steps. This method is highly efficient in cloning any gene of interest into any vector at any site without sequence constraints, as no restriction and ligation reactions are required. PMID- 26505380 TI - Analysis of ITS1 sequences and genetic relationships between populations of ridgetail white prawn, Exopalaemon carinicauda, in the East China Sea. AB - Internal transcribed spacer 1 (ITS1) sequences from wild-type Exopalaemon carinicauda (N = 124) from the East China Sea were amplified and sequenced. Sequences were polymorphic and ranged from 388 to 583 bp in length. The average content of GC in sequences was significantly higher than that of AT. Altogether, 604 mutant sites with 123 haplotypes were detected; 46.7% were polymorphic sites. The genetic diversity index of population Y was highest, and the lowest was population X. Eight microsatellite sequences were detected; the most-repeated sequences were (GA)n, (AG)n, (GT)n, (TG)n, (TC)n, and (CT)n. Analysis of molecular variance revealed that genetic differentiation among the four populations were very weak, or modest. A molecular evolutionary tree was constructed using the neighbor-joining method and MEGA 6.0, and the phyletic evolutionary relationships among several Palaemonidae species examined. The phylogenetic tree showed that individuals of the same species, as well as the species of the same genus, clustered together, consistent with morphological classifications. PMID- 26505381 TI - Gli1 expression in pancreatic ductal adenocarcinoma and its clinical significance. AB - The aim of this study was to explore the correlation between the expression levels of Gli1 and p53 in pancreatic ductal adenocarcinoma (PDAC) and its pathological significance. Immunohistochemistry (IHC) was employed to measure the expression level of Gli1 and p53 in 85 sets of paraffin-embedded PDAC and corresponding para-carcinoma tissue specimens. The relationship between these results and the respective patients' clinicopathologic parameters was analyzed. IHC staining revealed that the expression levels of Gli1 and p53 in cancer tissues were evidently higher than that of para-carcinoma tissues (P < 0.05); while Gli1 expression levels correlated with the corresponding TNM stage and tumor infiltration depth, p53 expression level correlated with the respective TNM stage (P < 0.05). Taken together, this study demonstrates increased expression of Gli1 and p53 in PDAC, and proves that Gli1 could be apotential biomarker for prognostic judgment. PMID- 26505382 TI - APOA5 -1131T/C polymorphism and coronary artery disease susceptibility in Chinese population: an updated meta-analysis and review. AB - Although many studies have investigated the association of the APOA5 -1131T/C polymorphism with coronary artery disease (CAD), definite conclusions have not been drawn. To understand the effects of the APOA5 -1131T/C polymorphism on the risk of developing CAD, we performed an updated meta-analysis in the Chinese population. Relevant studies published till April 2015 were identified from databases such as PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine. A total of 19 studies including 3983 patients and 4358 controls were involved in this meta-analysis. The crude OR with 95%CI was calculated to assess the strength of the association. With the pooled data from the studies included in this meta-analysis, we found a significant association between the APOA5 1131T/C polymorphism and CAD risk in the Chinese population (C vs T: OR = 1.34, 95%CI = 1.16-1.54; CC vs TT: OR = 1.73, 95%CI = 1.30-2.30; CC vs TT and TC: OR = 1.51, 95%CI = 1.17-1.95; CC vs TC: OR = 1.30, 95%CI = 1.03-1.65). Stratified analyses according to the geographical location and source of controls revealed significantly increased risk in South China and in population-based studies. In conclusion, our meta-analysis provides substantial evidence that the APOA5 1131T/C polymorphism might contribute to CAD development in the Chinese population. PMID- 26505383 TI - Genetic variation and genetic structure of the endangered species Sinowilsonia henryi Hemsi. (Hamamelidaceae) revealed by amplified fragment length polymorphism (AFLP) markers. AB - Comprehensive research of genetic variation is crucial in designing conservation strategies for endangered and threatened species. Sinowilsonia henryi Hemsi. is a tertiary relic with a limited geographical distribution in the central and western areas of China. It is endangered because of climate change and habitat fragmentation over the last thousands of years. In this study, amplified fragment length polymorphism markers were utilized to estimate genetic diversity and genetic structure in and among S. henryi. In this study, Nei's genetic diversity and Shannon's information index were found to be 0.192 and 0.325 respectively, indicating a moderate-to-high genetic diversity in species. According to analysis of molecular variation results, 32% of the genetic variation was shown to be partitioned among populations, demonstrating a relatively high genetic divergence; this was supported by principal coordinate analysis and unweighted pair-group method with arithmetic average analysis. Moreover, the Mantel test showed that there was no significant correlation between genetic and geographical distances. The above results can be explained by the effects of habitat fragmentation, history traits, and gene drift. Based on the results, several implications were indicated and suggestions proposed for preservation strategies for this species. PMID- 26505384 TI - Determination of patellar ligament and anterior cruciate ligament geometry using MRI. AB - Ligament geometry is crucial to surgical treatment success in anterior cruciate ligament (ACL) injury. This study aimed to optimize the MRI technique to elucidate the geometry of the patellar ligament (PL) and ACL in vivo. A 1.5-T superconducting MRI system with a special surface coil and fast spin echo was used to acquire high-resolution T1-weighted images (H-T1WI) of the ACL. The sagittal plane angle was 10 degrees to 15 degrees towards the inner side of the vertical line of the tangent line axis of the femoral intercondylar fossa. The H T1WI images of the PL were centered at the lower margin of the patella and the center of the tibial tuberosity. The lengths of the PL and ACL were measured using a Radworks 5.1 workstation. ACL and PL lengths were compared between left and right knees and between genders, and left PL length measurements obtained separately by three doctors underwent correlation analysis. The quality of the images satisfied the clinical measurement requirements. The duration of sagittal image acquisition was 2 min and 25 s. The average PL length was 42.20 +/- 4.21 and 40.15 +/- 4.00 mm, and the average ACL length was 36.98 +/- 4.12 and 35.80 +/ 4.67 mm, in male and female subjects, respectively. The intraclass correlation coefficients of the PL lengths obtained by the three specialists were greater than 0.997. This MRI technique provides highly stable and repeatable in vivo data of PL and ACL geometry relevant to ACL reconstruction surgery with PL grafts. PMID- 26505385 TI - Relationship between SPOP mutation and breast cancer in Chinese population. AB - SPOP protein has been found to have ubiquitin ligase activity. Mutations in SPOP gene have been recently reported in some cancers such as prostate, gastric, colorectal cancer. We investigated SPOP DNA mutation in tumor tissues collected from 70 Chinese female breast cancer patients in Southwestern China by DNA sequencing. The results did not show mutation in our tissue samples, indicating that a mutation in the SPOP gene may not be associated with breast cancer, particularly in Chinese women. This DNA mutation analysis or DNA genotyping may provide useful and important information for genetic counseling and personalized medical treatment for different types of cancers. PMID- 26505386 TI - Effects of high intensity exhaustive exercise on SOD, MDA, and NO levels in rats with knee osteoarthritis. AB - The aim of this study was to investigate the impact of high intensity exhaustive exercise on nitric oxide (NO), malondialdehyde (MDA), and superoxide dismutase (SOD) expression in rats with knee osteoarthritis. Sprague Dawley rats were randomly divided into control (N = 5) and model (N = 35) groups; the model group was further divided into quiet (N = 5), low- (N = 15) and high- (N = 15) intensity exhaustive exercise groups. The low- and high-intensity groups were randomly divided into pre-exercise (N = 5), immediate post-exercise (N = 5), and 24-h post-exercise (N = 5) groups according to different time points for detection. NO, MDA, and SOD levels were compared between each group. The SOD levels in the quiet, low-, and high-intensity exhaustive exercise groups were lower than that in the control group, whereas the NO and MDA levels were higher in the former groups than in the controls (P < 0.05). The SOD level in the 24-h post-low intensity exhaustive exercise group was higher than that in the 24-h post-high intensity exhaustive exercise group, whereas the NO and MDA levels were lower in the 24-h post-low intensity than in the post-high intensity exercise group (P < 0.05). Overall, the results demonstrated that with the increase of exercise intensity, the SOD activity in the rats with knee osteoarthritis decreased gradually, whereas the MDA and NO levels gradually increased. Thus, the greater the exercise intensity, the more serious the impact on knee osteoarthritis. PMID- 26505387 TI - Role of salubrinal in protecting cardiomyocytes from doxorubicin-induced apoptosis. AB - We determined whether salubrinal can protect cardio-myocytes from doxorubicin induced apoptosis and explored the related mechanisms to provide experimental evidence for exploring novel drug candidates to decrease cardiac toxicity. Neonatal rat cardiomyocytes were isolated, cultured in vitro, and pretreated with salubrinal (10, 20, or 40 MUM) to observe their response to doxorubicin-induced cell apoptosis. Lactate dehydrogenase assay, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining, and flow cytometry were used to assess the extent of cardiomyocyte apoptosis. Fluorescent probes conjugated with 2',7'-dichlorofluorescein diacetate and a chemiluminescence assay were used to detect the pro-duction of reactive oxygen species. Western blotting was employed to quantify expression levels of cleaved caspase-3, cytosolic cytochrome c, and B-cell lymphoma-extra large (Bcl-xL). The mechanisms of salubrinal-related functions were also explored. Salubrinal effectively inhibited doxorubicin-induced reactive oxygen species production and nicotinamide adenine dinucleotide phosphate oxidase activation, decreased the levels of cleaved caspase-3 and cytosol cytochrome c, and increased Bcl-xL expression, thereby protecting cardiomyocytes from doxorubicin-induced apoptosis. Furthermore, salubrinal was found to protect cardiomyocytes by decreasing the dephosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha). Salubrinal can protect cardiomyocytes from doxorubicin-induced apoptosis through its effects on eIF2alpha. It possibly ameliorates cardiac toxicity and can be used in clinical practice. PMID- 26505388 TI - Resveratrol could reverse the expression of SIRT1 and MMP-1 in vitro. AB - Intervertebral disc degeneration is the main cause of lumbago disease, in which the extracellular matrix structure and moisture in the nucleus pulposus is lost continuously. In this study, we aimed to detect differential expression of silence mating type information regulation 2 homolog 1 (SIRT1) and matrix metalloproteinase-1 (MMP-1) in human intervertebral disc nucleus pulposus cells and to explore the effects of SIRT1 and MMP-1 on the development of the intervertebral disc degeneration. Intervertebral disc nucleus pulposus specimens from 41 patients who underwent lumbar protrusion resection at HuiZhou Municipal Central Hospital, during the period from October 2011 to December 2013, were studied in comparison with 23 control cases from patients who underwent fractured lumbar resection. In degenerated human intervertebral disc nucleus pulposus cells, the expression of SIRT1 is decreased and MMP-1 is increased compared with that of the control cells. Resveratrol could reverse these effects, thereby increasing the expression of SIRT1 (0.87 +/- 0.07 vs 0.54 +/- 0.04), Coll2alpha1 (0.90 +/- 0.08 vs 0.38 +/- 0.01), and aggrecan (0.69 +/- 0.07 vs 0.42 +/- 0.05) and decreasing the expression of MMP-1 (0.61 +/- 0.03 vs 0.93 +/- 0.08). These results suggest that resveratrol could possibly reverse the process of intervertebral disc degeneration and thus could be applied as a potential drug for the disease. PMID- 26505389 TI - Determination of the potential of induced pluripotent stem cells to differentiate into mouse nucleus pulposus cells in vitro. AB - We determined the potential for induced pluripotent stem (iPS) cells to differentiate into nucleus pulposus (NP)-like cells in mice. iPS cells were generated from tail-tip fibroblasts. We used a pellet culture model with the aim of determining the applicability of iPS cell-based therapy to intervertebral disc degeneration (IVD). The cell pellet was cultured in an NP cell basal medium comprising Dulbecco's modified Eagle's medium supplemented with transforming growth factor beta 1, dexamethasone, ascorbate-2-phosphate, and 1% ITS-Premix. The pellet was evaluated by quantitative reverse transcription polymerase chain reaction, immunohistochemical staining, and biochemical composition. The differentiation of iPS cells into NP cells was demonstrated by the protein and mRNA expression levels of proteoglycan, collagen II, aggrecan, and CD24. Furthermore, increased hydroxyproline content and dimethylmethylene blue staining demonstrated that the collagen II and glycosaminoglycan content in the NP cells increased with time. We have shown that cultured mouse iPS cells can be induced to differentiate into NP cells. Such proof-of-concept opens up the possibility of producing patient-specific NP cells in a relatively simple and straightforward manner with high efficiency. We are confident that such cells could be immediately useful for the study of IVD disease. PMID- 26505390 TI - Cloning and expression of the sucrose transporter gene PsSUT1 from tree peony leaf. AB - This study reports the cloning of a sucrose transporter gene, PsSUT1, from the leaf of tree peony (Paeonia suffruticosa Lind. cv 'Huhong'). Expression patterns were examined in different organs and at different developmental stages. The full length cDNA of PsSUT1 consisted of a 2001-bp sequence containing a 1557-bp open reading frame, encoding 519 amino acids with a conserved domain typical of the glycoside-pentoside-hexuronide superfamily. The amino acid sequence of PsSUT1 in tree peony shared high homology with that of other plants. At different developmental stages, PsSUT1 was expressed in roots, stems, leaves, and petals. Its expression level in stems was 10.9-fold higher than in petals at the flowering stage. Expression of PsSUT1 at the flowering stage was highest during flower development. The significant differences in PsSUT1 expression observed among developmental stages and organs were closely related to changes in sucrose content during flower opening. These results form the basis for further research on the molecular mechanisms of carbohydrate metabolism and transport during flower development in tree peony. PMID- 26505391 TI - Gene annotation and functional analysis of a newly sequenced Synechococcus strain. AB - Synechococcus sp PCC 7336 represents a newly sequenced strain, and its genome is obviously different from that of other Synechococcus strains. In this analysis, local alignment and annotation databases were constructed and combined with various bioinformatic tools to carry out gene annotation and functional analysis of this strain. From this analysis, we identified 5096 protein-coding genes and 47 RNA genes. Of these, 116 genes that were classified into 9 categories were associated with photosynthesis, and type V polymerase proteins that were identified are unique for this strain. An additional 107 genes were closely related to signal transduction pathways, which primarily comprised parts of two component regulatory systems. Gene ontogeny analysis showed that 2377 genes were annotated with a total number of 9791 functional categories, and specifically that 41 genes distributed in 4 protein complexes were involved in oxidative phosphorylation. Clusters of orthologous groups classification showed that there were 1463 homologous proteins associated with 17 specific metabolic pathways, and that most of the proteins participated in primary metabolic processes such as binding and catalysis. The phylogenetic tree based on 16S rRNA sequences indicated that Synechococcus PCC 7336 is highly likely to represent a new branch. PMID- 26505392 TI - Effect of Bcl-2-siRNA on proliferation and apoptosis of pediatric acute B lymphoblastic leukemia (A-BLL) cells. AB - This study analyzed the effect of small interfering RNA specific for the Bcl-2 gene (siRNA Bcl-2) on the proliferation and chemotherapeutic sensitivity of pediatric A-BLL cells. Marrow samples were obtained from sixty newly-diagnosed A BLL pediatric patients. The Bcl-2 mRNA expression in these samples was quantified by real time polymerase chain reaction. The Bcl-2 mRNA re-expression was analyzed by RNA interference using Bcl-2-siRNA. Cellular proliferation was detected using the MTT (Thiazolyl Blue Tetrazolium Bromide) assay. The cell apoptosis was quantified by flow cytometry. The Bcl-2 mRNA expression was significantly higher in the drug-resistance group than in the chemotherapy sensitivity group prior to chemotherapy (P < 0.05). In addition, the Bcl-2 mRNA expression in the chemotherapy sensitivity group was significantly higher before chemotherapy than that after chemotherapy (P < 0.05). The Bcl-2 mRNA expression significantly decreased in the leukemic cells of the Bcl-2-siRNA transfection group. We observed statistically significant differences in the relative mRNA expression levels among the Bcl-2-siRNA transfection, blank control, liposome empty transfection, and unrelated sequence oligonucleotide groups (P < 0.05). The rate of apoptosis in pediatric A-BLL leukemic cells was observed to increase significantly after transfection with Bcl-2-siRNA compared to the control, liposome empty transfection, and unrelated sequence oligonucleotide groups (P < 0.05). Therefore, we concluded that Bcl-2-siRNA can successfully inhibit the multiplicative capacity of A-BLL leukemic cells and promote apoptosis. PMID- 26505393 TI - Mining topological structures of protein-protein interaction networks for human brain-specific genes. AB - Compared to other placental mammals, humans have unique thinking and cognitive abilities because of their developed cerebral cortex composed of billions of neurons and synaptic connections. As the primary effectors of the mechanisms of life, proteins and their interactions form the basis of cellular and molecular functions in the living body. In this paper, we developed a pipeline for mining topological structures, identifying functional modules, and analyzing their functions from publically available datasets. A human brain-specific protein protein interaction network with 1482 nodes and 3105 edges was built using a MapReduce based shortest path algorithm. Within this, 7 functional cliques were identified using a network clustering method, 98 hub proteins were obtained by the calculation of betweenness and connectivity, and 5 closest relationship to clique connector proteins were recognized by the combination scores of topological distance and gene ontology similarity. Furthermore, we discovered functional modules interacting with TP53 protein, which involves several fragmented research study conclusions and might be an important clue for further in vivo or in silico experiments to confirm these associations. PMID- 26505394 TI - Prognostic significance of head and neck squamous cell carcinoma repair gene polymorphism. AB - The aims of this study were to analyze the polymorphisms XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, XPC Lys939Gln, ERCC1 Asn118Asn, and RAD51 -98G>C and to verify their influence on radiotherapy response and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). Peripheral blood DNA was extracted from 311 patients and analyzed by PCR-RFLP. Our results showed that in irradiated oral and oropharyngeal patients, the 939Gln allele increased 6-fold local disease relapse risk (OR = 6.04; CI = 1.47-24.88) and over 2-fold the earliness of relapse (HR = 2.63; CI = 1.04-6.70). As for the XRCC3 polymorphism, multivariate analysis showed that the 241Met allele increases over 33-fold local relapse risk (OR = 33.64; CI = 3.23-350.85), over 12-fold earliness of relapse (HR = 12.55; CI = 2.47-63.73) and over 3-fold earliness of death (HR = 3.04; CI = 1.08-8.61). For polymorphism RAD51 -98, multivariate analysis showed that allele C increases over 3-fold the risk of relapse (OR = 3.13; CI = 1.12-8.78) and over 2-fold the earliness of relapse (HR = 2.84; CI = 1.25-6.47). For polymorphism XRCC1 Arg399Gln, multivariate analysis showed that the 399Gln allele increased the risk of local disease relapse for irradiated oral and oropharyngeal patients (OR = 3.35; CI = 1.10-10.13) by over 3-fold. Based on these results, we suggest that these polymorphisms may be useful markers of prognosis in HNSCC. PMID- 26505395 TI - Molecular cloning, characterization and expression analysis of WAG-1 in the pistillody line of common wheat. AB - Wheat WAG-1 is a C-class MADS-box gene, which is orthologous to AGAMOUS in Arabidopsis. In this study, we report the cloning, characterization, and expression patterns of WAG-1 in the pistillody mutant HTS-1 and its sib-line CSTP. The cDNA of WAG-1 was found to be 765 bp in length, which was equal to the length of its open reading frame, encoding 254 amino acids. The location of WAG-1 revealed that it has three homologous genes from the short arm of chromosome 1A, 1B, and 1D. Their genomic sequences were determined to be 5864, 6454, and 6447 bp long, respectively, and possessed seven exons and six introns. Young spikes from HTS-1 contained higher levels of WAG-1 transcript than did those from CSTP, and the transcript levels in the young spikes (7-10 mm in length) of HTS-1 increased 3.3-fold relative to those of the CSTP line. The transcript level in the pistil and pistil-like stamens of HTS-1 was over 2-fold higher than that in the stamens of CSTP, and expression in the pistil-like stamens of HTS-1 was slightly higher than that in its pistils. These data provide a basis for future research into the function of WAG-1, and offer further insight into the molecular mechanism of the pistillody mutation in common wheat. PMID- 26505396 TI - Protective effects of folic acid against central nervous system neurotoxicity induced by lead exposure in rat pups. AB - Recent studies found folic acid is associated with lower blood lead (Pb) levels, and folate deficient children are more susceptible to the negative cognitive effects of Pb. This study evaluated the protective effects of folate supplementation against Pb exposure in rat pups and the mechanisms of protection. A total of 72 rats were used. Thirty were administered Pb only; 30, Pb and folic acid at the same time; and 12, only physiological saline. Protective effects of folic acid were examined at 14, 21, and 28 days after treatment. Lower blood Pb levels were found in all of the samples collected from the rats treated with folic acid. Downregulation of Bc1-2 expression and upregulation of Bax expression were observed in the neurons of folic acid-treated rats. Significantly more hematoxylin and eosin stained neurons were found in the folic acid treatment group. Nuclear enrichment and neuron apoptosis were observed by electron microscopy in the Pb-treated group. In conclusion, this study demonstrated that folic acid supplementation might offer efficient protective effects against Pb poisoning in rat pups, which was associated with less neuron damage and lower blood levels of Pb. PMID- 26505397 TI - Genetic variations in the UTR of genes related to molting in Eriocheir sinensis. AB - Crab grows by periodic molting, which is controlled by molt-inhibiting hormone (MIH) and ecdysteroids. Untranslated regions (UTRs) play crucial roles in the posttranscriptional regulation of gene expression. In this study, using crab collected from Changjiang (Yangtze), Huanghe (Yellow), Liaohe, and Yalujiang rivers, 33 haplotypes of the 3?-UTR of ecdysteroid-regulated protein (ERP) gene were identified, of which 14 haplotypes were observed in more than one individual. One hundred and forty clones of haplotype h2 (41.5%) were observed in samples from all the 4 rivers. Three haplotypes were observed to be insertions. For the whole crab sample, we found a positive Tajima's D value and a negative Fu's Fs test (Tajima's D value = 0.98726; Fu's Fs test = -27.382), although the P values were not significant (P > 0.10). The network profile of these 33 haplotypes presented a single core pattern with h2 as the core. In this study, we found that the UTR of ERP gene had a considerably high genetic polymorphism among crab from regions south to north of China. Furthermore, we observed a relatively high genetic divergence among different haplotypes, which would suggest a high diversity of the crab gene pool. PMID- 26505398 TI - Genetic divergence of physiological-quality traits of seeds in a population of peppers. AB - Brazil has a great diversity of Capsicum peppers that can be used in breeding programs. The objective of this study was to evaluate genetic variation in traits related to the physiological quality of seeds of Capsicum annuum L. in a segregating F2 population and its parents. A total of 250 seeds produced by selfing in the F1 generation resulting from crosses between UFPB 77.3 and UFPB 76 were used, with 100 seeds of both parents used as additional controls, totaling 252 genotypes. The seeds were germinated in gerboxes containing substrate blotting paper moistened with distilled water. Germination and the following vigor tests were evaluated: first count, germination velocity index, and root and shoot lengths. Data were subjected to analysis of variance, and means were compared by Scott and Knott's method at 1% probability. Tocher's clustering based on Mahalanobis distance and canonical variable analysis with graphic dispersion of genotypes were performed, and genetic parameters were estimated. All variables were found to be significant by the F test (P <= 0.01) and showed high heritability and a CVg/CVe ratio higher than 1.0, indicating genetic differences among genotypes. Parents (genotypes 1 and 2) formed distinct groups in all clustering methods. Genotypes 3, 104, 153, and 232 were found to be the most divergent according to Tocher's clustering method, and this was mainly due to early germination, which was observed on day 14, and would therefore be selected. Understanding the phenotypic variability among these 252 genotypes will serve as a basis for continuing the breeding program within this family. PMID- 26505399 TI - Association of interleukin gene polymorphisms with the risk of coronary artery disease. AB - We conducted a case-control study to investigate the genetic variants Interleukin 1beta(IL-1beta) +3953 C/T (rs1143634), IL-6 -174G/C (rs1800795), IL-8 -251T/A (rs4073), and IL-10 -1082A/G (rs1800896) and -819C/T (rs1800871) in the development of coronary artery disease (CAD). A total of 410 individuals with CAD were enrolled between January 2012 and December 2014. Genotyping of the five gene polymorphisms was performed using the polymerase chain reaction combined with restriction fragment length polymorphism methodology. By multivariate logistic regression analysis, we found that the frequencies of the CC genotype and the C allele of IL-6 -174G/C were significantly correlated with a higher risk of CAD; the adjusted ORs (95%CIs) were 2.37 (1.37-4.14) and 1.49 (1.19-1.86), respectively. In addition, the AG and GG genotypes and the G allele of IL-10 1082A/G were also significantly associated with a higher risk of CAD, and the ORs (95%CIs) were 1.42 (1.04-1.95), 2.16 (1.42-3.30), and 1.56 (1.27-1.93), respectively. However, IL-1beta+3953 C/T, IL-8 -251T/A, and IL-10 -819C/T did not significantly correlate with CAD risk. Our study suggests that the IL-6 -174G/C (rs1800795) and IL-10 -1082A/G (rs1800896) polymorphisms might be involved in the pathogenesis of CAD, and likely contribute to the genetic susceptibility for CAD. PMID- 26505400 TI - Genetic polymorphisms in very important pharmacogenomic (VIP) variants in the Tibetan population. AB - Genetic polymorphisms of very important pharmacogenomic (VIP) variants are important for personalized medicine. However, these have not been extensively studied in the Tibetan population. In this study, 82 VIP variants were detected in the Tibetan and Han (HAN) populations from northwestern China. Subsequently, we compared the differences between the Tibetan population and ten populations, including the HAN, Japanese in Tokyo (JPT), Mexican ancestry in Los Angeles (MEX), Toscans in Italy (TSI), African ancestry in Southwest USA (ASW), Luhya in California Webuye, Kenya (LWK), Gujarati Indians in Houston, Texas (GIH), Maasai in Kinyawa, Kenya (MKK), Yoruba in Ibadan, Nigeria (YRI), and Utah residents with Northern and Western European ancestry from the CEPH collection (CEU). Using the chi(2) test, we identified differences in the frequency distribution of 4, 4, 7, 10, 11, 11, 13, 15, 19, and 20 loci in the Tibetan population, compared to the HAN, JPT, MEX, TSI, ASW, LWK, GIH, MKK, YRI, and CEU populations, respectively [P < 0.05/(82*10)]. rs2115819, rs9934438, and rs689466, located in the ALOX5 (arachidonate 5-lipoxygenase), VKORC1 (vitamin K epoxide reductase complex, subunit 1) and PTGS2 (prostaglandin-endoperoxide synthase 2) genes, respectively, in the Tibetan population were different from those in most of the populations. Our results complement the information provided by the database of pharmacogenomics on Tibetan people, and provide an avenue for personalized treatment in the Tibetan population. PMID- 26505401 TI - Alleviation of streptozotocin-induced diabetes in nude mice by stem cells derived from human first trimester umbilical cord. AB - Cells isolated from human first trimester umbilical cord perivascular layer (hFTM PV) tissues display the pluripotent characteristics of stem cells. In this study, we examined whether hFTM-PV cells can differentiate into islet-like clusters (ILCs) in vitro, and whether transplantation of the hFTM-PV cells with and without differentiation in vitro can alleviate diabetes in nude mice. The hFTM-PV cells were differentiated into ILCs in vitro through a simple stepwise culture protocol. To examine the in vivo effects of the cells, the hFTM-PV cells with and without differentiation in vitro were transplanted into the abdominal cavity of nude mice with streptozotocin (STZ)-induced diabetes. Blood glucose levels, body weight, and the survival probability of the diabetic nude mice were then statistically analyzed. The hFTM-PV cells were successfully induced into ILCs that could release insulin in response to elevated concentrations of glucose in vitro. In transplantation experiments, we observed that mice transplanted with the undifferentiated hFTM-PV cells, embryonic body-like cell aggregations, or ILCs all demonstrated normalized hyperglycemia and showed improved survival rate compared with those without cell transplantation. The hFTM-PV cells have the ability to differentiate into ILCs in vitro and transplantations of undifferentiated and differentiated cells can alleviate STZ-induced diabetes in nude mice. This may offer a potential cell source for stem cell-based therapy for treating diabetes in the future. PMID- 26505402 TI - Cuticular signature in the development of Polistes versicolor. AB - Wasps belong to societies that are highly complex and diverse, especially considering social organization and parental care. They use chemicals in their daily communication, and act incisively in recognition of mates and non-nest mates, and can even identify individuals of different castes. In this study, cuticle composition was examined during the development of Polistes versicolor from the egg stage to adulthood, with the aim to assess changes in the chemical signature of the species, using gas chromatography. Linear alkanes and branched alkanes were identified that were important to distinguish the various developmental stages of P. versicolor. The variation in the linear alkanes and branched alkanes was quantitative, since most of them are present in all stages, with the exception of some linear alkanes that uniquely characterized the egg stage. At the egg stage, differences were predominant for linear alkanes C8, C24, C27, and C29. For the larval instars, there was a predominance of linear alkanes C8, C22 and C24 to C30. In the pre-pupae, pupae and adult stages, C8, C22, C24, and C26 to C30 showed a higher abundance during later developmental stages. The addition to branched alkanes increased their abundance from the egg (13.52%) to adult (22.96%) stages. PMID- 26505403 TI - Protein expression and characterization of SEP3 from Arabidopsis thaliana. AB - SEPALLATA (SEP) MADS-box genes play crucial roles in the regulation of floral growth and development. They are required for the specification of sepals, petals, stamens, and carpels as well as for floral determinacy. SEPs perform their functions through the formation of homo- or hetero-polymers, which are the molecular basis of floral quartets. In vitro assays indicated that SEP3 forms a tetramer after binding to DNA, but it is unclear whether DNA binding induces the tetramer, because SEP3 is often reported to form a dimer. Here, we analyzed the oligomeric status of SEP3 domains in the absence of the DNA-binding MADS-box domain. The truncated SEP3 was constructed as a fusion protein and expressed in prokaryotic cells. The purified protein fragment displayed as a tetramer in the size exclusion chromatographic column, and a glutaraldehyde cross-linking assay demonstrated that the protein contained a dimer unit. Yeast two-hybrid tests further verified that the fragments form homologous polymers in vivo, and that the K domain is involved in tetramer formation. Current results imply that the SEP3 protein regulates the formation of flower meristems using the tetramer as a unit, and that the DNA-binding MADS-box is dispensable for polymer formation. The C-terminal region does not contribute to homo-tetramer formation, but it may be reserved to glue other proteins. PMID- 26505404 TI - Comparative analysis of phylogenetic relationships, morphologies, and pathogenicities among Curvularia lunata isolates from maize in China. AB - To understand the effects of disease-resistant maize varieties and new cropping systems on the population of Curvularia lunata, 52 isolates of C. lunata were collected in China from 2011 to 2013. The isolates were analyzed in terms of phylogenetic relationships, morphology, and pathogenicity. Phylogenetic analysis showed that the 52 isolates clustered into 2 distinct clusters with further subdivisions, suggesting the emergence of new genetic divergence within C. lunata. Results of morphology and pathogenicity analyses demonstrated that there were significant differences among these isolates: 27 isolates were classified as fast growing, 5 as slow growing, and 20 as moderate growing. Three isolates had white-colored colonies, 13 had yellowish green-colored colonies, and the remaining isolates had dark green-colored colonies. Furthermore, conidiation rates were assessed: 30 isolates were characterized as having low conidiation rates, 15 as having medium conidiation rates, and the remaining 7 isolates as having high conidiation rates. Eleven of the isolates appeared to be strongly pathogenic against maize, 15 isolates proved to be weakly pathogenic against maize, and the remaining isolates were regarded to be moderately pathogenic. Interestingly, correlation analysis demonstrated a negative correlation between the growth rate and the pathogenicity of the isolates, while a positive correlation was observed between the conidiation rate and the pathogenicity. No correlation was observed between the colony color and the pathogenicity of the isolates. PMID- 26505405 TI - Molecular characterization and expression patterns of insulin-like growth factor binding protein genes in postnatal Nanjiang brown goats. AB - Insulin-like growth factor-binding proteins (IGFBPs) play a key role in modulating insulin-like growth factors (IGFs), and are considered candidate genes for growth traits in livestock. In this study, we identified the complete coding sequences of IGFBP-1 to -6 in the Nanjiang brown goat, and assessed gene tissue expression patterns by quantitative polymerase chain reaction. Expression of mRNA for the six gene targets was detectable in liver, heart, and longissimus dorsi (LD) muscle. Expression levels of IGFBP-1, -2 and -5 mRNA were higher in liver than in heart and LD muscle (P < 0.01), while IGFBP-6 expression was highest in LD muscle, and IGFBP-3 and -4 were predominantly expressed in LD muscle and liver. Higher IGFBP-2, -3, -4, and -6 mRNA levels were observed in LD, compared to triceps brachii muscle (P < 0.01). Additionally, the target genes had different temporal expression profiles during postnatal development. Histological assessment of muscle sections revealed a constant increase in muscle fiber diameter with aging. These results suggest that IGFBPs may be important for liver and skeletal muscle development, and may contribute to the biological function of these tissues in goats. PMID- 26505406 TI - Differentiated evolutionary relationships among chordates from comparative alignments of multiple sequences of MyoD and MyoG myogenic regulatory factors. AB - MyoD and MyoG are transcription factors that have essential roles in myogenic lineage determination and muscle differentiation. The purpose of this study was to compare multiple amino acid sequences of myogenic regulatory proteins to infer evolutionary relationships among chordates. Protein sequences from Mus musculus (P10085 and P12979), human Homo sapiens (P15172 and P15173), bovine Bos taurus (Q7YS82 and Q7YS81), wild pig Sus scrofa (P49811 and P49812), quail Coturnix coturnix (P21572 and P34060), chicken Gallus gallus (P16075 and P17920), rat Rattus norvegicus (Q02346 and P20428), domestic water buffalo Bubalus bubalis (D2SP11 and A7L034), and sheep Ovis aries (Q90477 and D3YKV7) were searched from a non-redundant protein sequence database UniProtKB/Swiss-Prot, and subsequently analyzed using the Mega6.0 software. MyoD evolutionary analyses revealed the presence of three main clusters with all mammals branched in one cluster, members of the order Rodentia (mouse and rat) in a second branch linked to the first, and birds of the order Galliformes (chicken and quail) remaining isolated in a third. MyoG evolutionary analyses aligned sequences in two main clusters, all mammalian specimens grouped in different sub-branches, and birds clustered in a second branch. These analyses suggest that the evolution of MyoD and MyoG was driven by different pathways. PMID- 26505407 TI - Association between a functional genetic polymorphism (rs2230199) and age-related macular degeneration risk: a meta-analysis. AB - The association between the rs2230199 C>G single nucleotide polymorphism (SNP) in complement component 3 and age-related macular degeneration (AMD) risk has been examined extensively but the results are not consistent among studies. The aim of this study was to perform a meta-analysis of all available studies on this SNP in relation to AMD. The comprehensive databases of PubMed, Medline, Web of Knowledge, CNKI, and Google Scholar were searched for case-control studies investigating the association between the rs2230199 polymorphism and AMD susceptibility. ORs with 95%CIs were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were also performed. A total of 15 published studies including 5593 cases and 5181 controls were used in this meta-analysis. Overall, the rs2230299 SNP was significantly associated with the risk of AMD in the overall population under the additive model (OR = 1.571, 95%CI = 1.414-1.745, P = 0.000), dominant model (OR = 1.681, 95%CI = 1.521-1.858, P = 0.000), and allelic model (OR = 1.597, 95%CI = 1.470-1.734, P = 0.000). In the subgroup analysis by ethnicity, the same results were found in Caucasian populations, while no significant correlations were found in Asian populations for all comparison models. In conclusion, our meta-analysis provides evidence that the rs2230199 polymorphism contributes to the development of AMD. Further large-scale multicenter epidemiological studies are warranted to confirm this finding. PMID- 26505408 TI - Association between the ERCC2 rs13181 polymorphism and the risk of glioma: a meta analysis. AB - Several studies have focused on the association between the ERCC2 rs13181 polymorphism and glioma risk, but the results were inconclusive. We aimed to conduct a meta-analysis to investigate the role of ERCC2 rs13181 on the risk of glioma. We searched and collated the relevant studies in both Chinese and English through the PubMed, Web of Science, Cochrane Library, and EMBASE databases published through June 1, 2014. A total of 11 studies for ERCC2 rs13181 were selected; these included 3456 glioma cases and 4957 controls. Using fixed-effects model analysis, we found that no significant difference could be identified between the ERCC2 rs13181 polymorphism and the risk of glioma. Subgroup analysis showed that the ERCC2 rs13181 GT and TT genotypes were significantly associated with an increased risk of glioma in the Chinese population [odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.17-1.85; and OR = 1.50, 95%CI = 1.02-2.22, respectively], but no significant increased risk of glioma was detected with these genotypes in the Caucasian populations. No publication bias was identified in this meta-analysis. Our meta-analysis strongly suggested that ERCC2 rs13181 was associated with a higher susceptibility to glioma in the Chinese population. PMID- 26505409 TI - Genetic parameters for milk production traits and breeding goals for Gir dairy cattle in Brazil. AB - To implement an animal breeding program, it is important to define the production circumstances of the animals of interest to determine which traits of economic interest will be selected for the breeding goal. The present study defined breeding goals and proposed selection indices for milk production and quality traits of Gir dairy cattle. First, a bioeconomic model was developed to calculate economic values. The genetic and phenotypic parameters were estimated based on records from 22,468 first-lactation Gir dairy cows and their crosses for which calving occurred between 1970 and 2011. Statistical analyses were carried out for the animal model, with multitrait analyses using the restricted maximum likelihood method. Two situations were created in the present study to define the breeding goals: 1) including only milk yield in the breeding goal (HGL1) and 2) including fat and protein in addition to the milk yield (HGL2). The heritability estimates for milk, protein, and fat production were 0.33 +/- 0.02, 0.26 +/- 0.02, and 0.24 +/- 0.02, respectively. All phenotypic and genetic correlations were highly positive. The economic values for milk, fat, and protein were US$0.18, US$0.27, and US$7.04, respectively. The expected economic responses for HGL2 and for HGL1 were US$126.30 and US$79.82, respectively. These results indicate that milk component traits should be included in a selection index to rank animals evaluated in the National Gir Dairy Breeding Program developed in Brazil. PMID- 26505410 TI - 1H-MRS before and after resuscitation following selective cerebral ultra-profound hypothermic blood flow occlusion in monkeys. AB - We investigated the effect of selective cerebral ultra-profound hypothermic blood flow occlusion on brain tissue and cell metabolism to ascertain the efficacy and safety of selective deep hypothermic technologies using proton magnetic resonance spectroscopy ((1)H-MRS). The bilateral carotid artery was blocked at room temperature for 10 min. Other neck vessels were then blocked through cold perfusion of the internal carotid artery and reflux of the ipsilateral jugular vein. Thus, selective cerebral extracorporeal circulation was established. Brain temperature was reduced to 15.1 degrees +/- 0.9 degrees C. After 60 min, cerebral blood flow recovered naturally. Routine magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and (1)H-MRS examination of the bilateral frontal cortex and basal ganglia were performed prior to surgery and 4, 24, 72 h, 21 days after recovery. The formants and areas under the curve (AUC) of N-acetyl aspartate (NAA), choline (Cho), creatine/phosphocreatine (Cr/Cr2) were analyzed using 1H-MRS. The pre- and postoperative AUC of NAA and Cho at different time points were compared. Conventional MRI and DWI showed no abnormal signal changes in the brain parenchyma or right basal ganglia before and after surgery (P > 0.05). There was no significant difference in the ratio between NAA/(Cr+Cr2) and Cho/(Cr+Cr2) before and after surgery in the bilateral basal ganglia and frontoparietal regions of the cortex (P > 0.05). Quantitative (1)H-MRS showed that selective deep cerebral hypothermia significantly improved the brain's tolerance to ischemia and hypoxia. Our results could provide a better understanding of the efficacy and safety of selective deep hypothermia and blood flow occlusion. PMID- 26505411 TI - Methylation analysis of CXCR1 in mammary gland tissue of cows with mastitis induced by Staphylococcus aureus. AB - Mastitis is the most important disease in the global dairy industry, and causes large economic losses. Staphylococcus aureus is one of most common pathogens that cause bovine mastitis. CXCR1 has been implicated as a prospective genetic marker for mastitis resistance in dairy cows; CXCR1 expression significantly increases when cows have mastitis. To investigate the mechanisms involved in its increased expression, bisulfite sequencing polymerase chain reaction (PCR) was used to detect the methylation status of CXCR1 CpG island, and quantitative fluorescence PCR was used to detect CXCR1 expression in bovine mammary tissue induced with S. aureus in three Chinese Holstein cows. No CpG island was found for bovine CXCR1 in the upstream 2-kb region, whereas one CpG island that contained 13 CpG sites was found in exon 1 of CXCR1. All of the CpG sites were under hypermethylation from 90 to 100% in the mammary tissues. When the mammary gland mRNA expression of CXCR1 was 12.10-fold higher in infected cow quarters than in uninfected quarters, the methylation levels of the CpG site at position 519 were significantly lower in the infected quarters than in the uninfected quarters. Pearson correlation analysis showed that the methylation level at position 519 was significantly negatively correlated with the CXCR1 mRNA expression level (P < 0.05). These results indicate that the methylation of the CpG site at position 519 may regulate CXCR1 expression in cows with mastitis induced by S. aureus, but further studies are needed to elucidate the mechanisms involved. PMID- 26505412 TI - Genomic selection for slaughter age in pigs using the Cox frailty model. AB - The aim of this study was to compare genomic selection methodologies using a linear mixed model and the Cox survival model. We used data from an F2 population of pigs, in which the response variable was the time in days from birth to the culling of the animal and the covariates were 238 markers [237 single nucleotide polymorphism (SNP) plus the halothane gene]. The data were corrected for fixed effects, and the accuracy of the method was determined based on the correlation of the ranks of predicted genomic breeding values (GBVs) in both models with the corrected phenotypic values. The analysis was repeated with a subset of SNP markers with largest absolute effects. The results were in agreement with the GBV prediction and the estimation of marker effects for both models for uncensored data and for normality. However, when considering censored data, the Cox model with a normal random effect (S1) was more appropriate. Since there was no agreement between the linear mixed model and the imputed data (L2) for the prediction of genomic values and the estimation of marker effects, the model S1 was considered superior as it took into account the latent variable and the censored data. Marker selection increased correlations between the ranks of predicted GBVs by the linear and Cox frailty models and the corrected phenotypic values, and 120 markers were required to increase the predictive ability for the characteristic analyzed. PMID- 26505413 TI - Classification of colon cancer based on the expression of randomly selected genes. AB - In order to ascertain the relationship between gene expression and colon cancer localization, a classification method based on random gene selection and a self organizing map network is proposed. Different numbers of genes were selected randomly from 54,675 genes of 53 colon cancer patients in stage union for international cancer control II. These patients were then divided into two sets: a training set of 36 and a validation set of 17 patients. In this study, we randomly selected 1000, 100, 50, 30, 10, 5, and 3 genes, 1000 times, respectively. The minimum misclassification ratio of each gene group was 3/17 to 4/17, and the percentage of gene groups that were less than 0.25 was approximately 1-7%. Moreover, the misclassification ratio of most gene groups (about 82-89%) was lower than 0.4. Through the analysis of these low misclassification ratio gene groups, we found that there were few common genes between them. This revealed that colon cancer localization is not associated with a single gene group but with many gene groups. Furthermore, K-fold cross validation was used to test the reliability of the possible informative genes, and the results indicated that using gene expression to classify colon tumor localization was not feasible. PMID- 26505414 TI - Gene expression profiles in the pituitary glands of Sichuan White geese during prelaying and laying periods. AB - To better understand the molecular mechanism(s) underlying egg-laying in Sichuan white geese, the profiles of genes in the pituitary gland were investigated during the prelaying and laying periods. Total RNA was extracted from the pituitary glands of geese during prelaying or laying periods and cDNA was generated. After sequencing and annotation, 54 upregulated and 84 downregulated genes were obtained from gene libraries. These genes were related primarily to biosynthetic processes, cellular nitrogen metabolic processes, transport, cell differentiation, cellular protein modification processes, signal transduction, and small molecule metabolic processes. Eleven genes were selected for further analyses using quantitative real-time PCR, and the results were generally consistent with the profiling results. Among these genes, levels of gonadotropin releasing hormone, gonadotropin-inhibitory hormone, vasoactive intestinal peptide and its receptor, follistatin, estrogen receptor beta, and the progesterone receptor were differentially overexpressed during the prelaying period compared with the laying period. These results provide a solid foundation for elucidating the molecular mechanism of egg-laying performance in Sichuan white geese. PMID- 26505415 TI - Variations in WNT3 gene are associated with incidence of non-syndromic cleft lip with or without cleft palate in a northeast Chinese population. AB - Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect. Several WNT genes are involved in craniofacial embryogenesis, and therefore may play an important role in the etiology of NSCL/P. Two SNPs (rs3809857 and rs9890413) in the WNT3 gene were subjected to case-control and case-parent analysis by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 236 unrelated patients with NSCL/P, including 128 elementary families (185 mothers and 154 fathers), and 400 control individuals from northeast China. The rs3809857 SNP, under the assumption of a dominant model, was found to induce a 2-fold lower risk of NSCL/P ORGG vs GT + TT = 0.605, 95%CI = 0.436-0.839, P = 0.003). Moreover, the family-based association test revealed an under-transmission for the minor allele T. On the other hand, we observed a significant association in the case-control and case-parent analysis of the SNP rs9890413. In addition, the P values for the haplotype of rs3809857 rs9890413 were observed to be statistically significant (P = 0.004). In conclusion, our study confirmed the association between the WNT3 variant and NSCL/P in the population tested. PMID- 26505416 TI - Chromosomal evolution in the pallescens group (Hemiptera, Triatominae). AB - Rhodnius colombiensis, in conjunction with R. pallescens and R. ecuadoriensis, forms the monophyletic pallescens group. Cytogenetic analyses of these closely related species would further our understanding of the taxonomy and evolution of this group. In this study, R. colombiensis was cytogenetically analyzed, and the results were compared with cytogenetic data from other species of the pallescens group, particularly their chromosomal evolution. We found that this triatomine has heteropycnotic blocks in five autosomal bivalents at both metaphase I and II. The derivation of R. colombiensis from R. pallescens led to significant loss of heteropycnotic and heterochromatic regions (approximately 50%). R. ecuadoriensis is the most differentiated of the group because it has lost all heterochromatin and heteropyknotic blocks in the autosomes. Based on the heteropyknotic and heterochromatic pattern of R. colombiensis and the chromosomal evolution analysis of the pallescens group, we suggest that the karyotype of R. colombiensis and R. ecuadoriensis lost its heteropycnotic and heterochromatic blocks during speciation. Furthermore, this loss could be related to adaptation to different environments. PMID- 26505417 TI - Evaluation of soybean lines and environmental stratification using the AMMI, GGE biplot, and factor analysis methods. AB - In the final phases of new soybean cultivar development, lines are cultivated in several locations across multiple seasons with the intention of identifying and selecting superior genotypes for quantitative traits. In this context, this study aimed to study the genotype-by-environment interaction for the trait grain yield (kg/ha), and to evaluate the adaptability and stability of early-cycle soybean genotypes using the additive main effects and multiplicative interaction (AMMI) analysis, genotype main effects and genotype x environment interaction (GGE) biplot, and factor analysis methods. Additionally, the efficiency of these methods was compared. The experiments were carried out in five cities in the State of Mato Grosso: Alto Taquari, Lucas do Rio Verde, Sinop, Querencia, and Rondonopolis, in the 2011/2012 and 2012/2013 seasons. Twenty-seven early-cycle soybean genotypes were evaluated, consisting of 22 lines developed by Universidade Federal de Uberlandia (UFU) soybean breeding program, and five controls: UFUS Carajas, MSOY 6101, MSOY 7211, UFUS Guarani, and Riqueza. Significant and complex genotype-by-environment interactions were observed. The AMMI model presented greater efficiency by retaining most of the variation in the first two main components (61.46%), followed by the GGE biplot model (57.90%), and factor analysis (54.12%). Environmental clustering among the methodologies was similar, and was composed of one environmental group from one location but from different seasons. Genotype G5 presented an elevated grain yield, and high adaptability and stability as determined by the AMMI, factor analysis, and GGE biplot methodologies. PMID- 26505418 TI - Evaluation of grain yield in sorghum hybrids under water stress. AB - Sorghum grain yield can be significantly affected by climatic changes, especially drought and high temperature. The purpose of this study was to evaluate hybrids of grain sorghum grown under normal irrigation conditions or water stress in order to select those likely to be more tolerant of drought. Forty-nine hybrids were grown in a randomized block design experiment, with three replications. The plots consisted of four rows of 5 m length. Grain yield, weight of 1000 grains, harvest index, days to flowering, and plant height were measured. All of these characteristics were affected by water stress; however, grain yield showed the largest relative reduction. Comparison of the various genotypes showed that some hybrids had an acceptable grain yield under water stress, and maintained a high average yield compared to growth without stress. Several hybrids gave better grain yield than commercial check cultivars: 1170090, 1170092, 1170064, 1167026, 1167064, 1170093, 1167008, 1167029, 0009061, 1167092, 1105647, and 1170019 stood out for their acceptable plant height, earliness, and higher productivity. PMID- 26505419 TI - Characterization of ESTs from black locust for gene discovery and marker development. AB - Black locust (Robinia pseudoacacia L.) is an ecologically and economically important species. However, it has relatively underdeveloped genomic resources, and this limits gene discovery and marker-assisted selective breeding. In the present study, we obtained large-scale transcriptome data using a next-generation sequencing platform to compensate for the lack of black locust genomic information. Increasing the amount of transcriptome data for black locust will provide a valuable resource for multi-gene phylogenetic analyses and will facilitate research on the mechanisms whereby conserved genes and functions are maintained in the face of species divergence. We sequenced the black locust transcriptome from a cDNA library of multiple tissues and individuals on an Illumina platform, and this produced 108,229,352 clean sequence reads. The high quality overlapping expressed sequence tags (ESTs) were assembled into 36,533 unigenes, and 4781 simple sequence repeats were characterized. A large collection of high-quality ESTs was obtained, de novo assembled, and characterized. Our results markedly expand the previous transcript catalogues of black locust and can gradually be applied to black locust breeding programs. Furthermore, our data will facilitate future research on the comparative genomics of black locust and related species. PMID- 26505420 TI - Induction and identification of Stylosanthes guianensis tetraploids. AB - Stylosanthes guianensis is an elite and important forage legume species, which is extensively cultivated in tropical areas. Polyploid breeding via exposure to colchicine is a conventional and practical method to improve varieties of S. guianensis. Terminal buds of S. guianensis Reyan No.5 seedlings were treated with different concentrations of colchicine (0.00, 0.05, 0.10, 0.15, 0.20, and 0.25%) for 24, 48, and 72 h. Morphological and cytological variants were observed at a frequency of <96% among transplanted seedlings. The cytogenetic analysis of young leaf cells was conducted on all variants to identify their ploidy levels. The most efficient procedure for tetraploid production was the treatment of seedling apical buds with 20% colchicine for 48 h, with the tetraploid induction rate being 10%. This is a relatively simple and reliable method for the production of tetraploidy in S. guianensis. PMID- 26505421 TI - Cloning, identification, and bioinformatics analysis of a putative aquaporin TsAQP from Trichinella spiralis. AB - Vaccination as a preventative strategy against Trichinella spiralis infection is an ongoing effort, although no ideal vaccine candidates have been identified until now. Identification of more effective antigens that have a role in essential life stages of the parasite and that may be effective vaccine candidates is therefore of importance. In the present study, we identified a novel aquaporin gene (TsAQP) from T. spiralis, and the potential antigenicity of TsAQP was evaluated by epitope prediction. A total of 11 post-translational modification sites were predicted in the protein and fell into 4 categories: N glycosylation; casein kinase II phosphorylation; protein kinase C phosphorylation; and N-myristoylation sites. TsAQP is a membrane intrinsic protein with high hydrophobicity; the main hydrophobic domains comprised up to 38.5% of the protein and were distributed at amino acid positions 21-43, 54-71, 83-91, 107-121, 163-174, 187-200, and 242-261. The protein consisted mainly of helices (39.58%) and loops (50%). The advanced structure of TsAQP was predicted using homology modeling, which showed that the protein was formed from 6 membrane spanning domains connected by 5 loops. Based on these analyses, 6 potential B cell epitopes and 4 potential T-cell epitopes were further predicted. These results suggest that TsAQP could be a promising antigen candidate for vaccination against T. spiralis. PMID- 26505422 TI - Cloning and functional analysis of the chitinase gene promoter in peanut. AB - Chitinase is an important pathogenesis-related protein in plants, and it can accumulate when induced by salicylic acid (SA) or other elicitors. Here, we found that chitinase mRNA levels were 4.5-times greater when peanut seedlings were sprayed with 1.5 mM SA, as compared to water. The upstream promoter sequence of the chitinase gene was cloned by TAIL-PCR and the potential cis-regulatory elements in this promoter were predicted by the cis-element databases PLACE and plantCARE. Elements in the promoter related to SA induction and disease resistance response included AS-1, GT1-motif, GRWAAW, TGTCA, W-box, and WB-box. The full-length promoter (P) and a series of 5'-deleted promoters (P1-P5) were cloned and then substituted for the 35S promoter of pCAMBIA1301-xylA, which carries the xylose isomerase gene as the selectable marker and GUS as the reporter gene. Six plant expression vectors (pCAMBIA1301-xylA-P-pCAMBIA1301-xylA P5) were obtained. The six expression vectors were then transferred into onion epidermal cells and peanut plants by Agrobacterium-mediated transformation. Both the full-length and deleted promoters resulted in GUS staining of the onion epidermis cells when induced by SA. In onion epidermis cells, GUS enzyme activity was greater after SA induction. In transgenic peanut plants, GUS mRNA levels were greater after SA induction. Consideration of the cis-regulatory elements predicted by PLACE and plantCARE suggested that AS-1, GRWAAW, and W-box are positive regulatory elements in P2 and P3 and that GT1-motif and TGTCA are negative regulatory elements between P and P2. PMID- 26505423 TI - MC1R, KIT, IGF2, and NR6A1 as markers for genetic differentiation in Thai native, wild boars, and Duroc and Chinese Meishan pigs. AB - Mutations in melanocortin 1 receptor (MC1R) gene and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) gene have been shown to affect coat color patterns in pigs. Additional functional marker genes, such as insulin like growth factor-2 (IGF2) and orphan nuclear receptor, germ cell nuclear factor (NR6A1), have been described for variations in factors such as fat deposition, litter size, and vertebra number in pigs. In this study, we investigated 129 pigs representing 4 breeds: Thai indigenous, classified into black (similar to Raad or Ka done pig) and black and white (similar to the Hailum and Kwai pig) coat color types; wild boar; Duroc; and Chinese Meishan. Mutations of MC1R, KIT, IGF2, and NR6A1 were detected using polymerase chain reaction-restriction fragment length polymorphism. The genotypes variation in MC1R and KIT genes could be used to differentiate four groups of coat color: solid black, black and white, red, and wild type. For IGF2, the GG genotype was present in wild boar only; for NR6A1 the TT genotype was found only in Duroc pigs. We identified novel 14-bp deletions in KIT that were associated with black and white coat color in Thai indigenous pigs. Insights into variations in genes presented in this study will be useful in future developmental breeding programs for the Thai native pig. PMID- 26505424 TI - Construction of a cDNA library and preliminary analysis of expressed sequence tags in Piper hainanense. AB - Black pepper is a perennial climbing vine. It is widely cultivated because its berries can be utilized not only as a spice in food but also for medicinal use. This study aimed to construct a standardized, high-quality cDNA library to facilitated identification of new Piper hainanense transcripts. For this, 262 unigenes were used to generate raw reads. The average length of these 262 unigenes was 774.8 bp. Of these, 94 genes (35.9%) were newly identified, according to the NCBI protein database. Thus, identification of new genes may broaden the molecular knowledge of P. hainanense on the basis of Clusters of Orthologous Groups and Gene Ontology categories. In addition, certain basic genes linked to physiological processes, which can contribute to disease resistance and thereby to the breeding of black pepper. A total of 26 unigenes were found to be SSR markers. Dinucleotide SSR was the main repeat motif, accounting for 61.54%, followed by trinucleotide SSR (23.07%). Eight primer pairs successfully amplified DNA fragments and detected significant amounts of polymorphism among twenty-one piper germplasm. These results present a novel sequence information of P. hainanense, which can serve as the foundation for further genetic research on this species. PMID- 26505425 TI - A SNP in the 3'-UTR of HSF1 in dairy cattle affects binding of target bta-miR 484. AB - The heat shock transcription factor 1 gene (HSF1) plays a key role in the heat stress response. We previously found a single nucleotide polymorphism (SNP) in the 3'-untranslated region (g.4693G>T) of HSF1 that was related to thermo tolerance in Chinese Holstein cattle through association analysis. However, it is not known whether other SNPs also affect thermo tolerance.In this study a novel SNP, g.1451G>T, was identified by DNA sequencing and genotyped using creating restriction site-polymerase chain reaction methodology. The g.1451G>T polymorphic site met Hardy-Weinberg equilibrium (P > 0.05). Association analysis demonstrated that this SNP had no effect on thermo tolerance traits in Holstein cattle. Findings of the study compared to the analysis of g.4693 G>T further indicated that g.4693 G>T may play an important role in thermo tolerance, although the mechanism is not clear. RNA hybrid and Targetscan prediction showed that the minimum free energy hybridization of bta-miR-484 with HSF1 3'-UTR was -31.9 kcal/mol and g.4693 G>T was in the seed sequence of bovine HSF1 that binds to bta miR-484. Analysis by Luciferase assay indicated that HSF1 expression was directly targeted by bta-miR-484 in HEK 293T cells, and the Rluc/luc ratio of wildtype (GG) was lower than that of the mutant (TT) (P < 0.05). These results suggest that g.4693 G>T affects binding of HSF1 to bta-miR-484. PMID- 26505426 TI - Expression of aquaporin 1 and 4 in rats with acute hypoxic lung injury and its significance. AB - Aquaporin (AQP)-1 and AQP-4 expression in lung tissues of SD rats during high altitude hypoxic lung injury, and the relationship between AQP-1 and AQP-4 expression, and acute hypoxic lung injury was analyzed. Thirty six healthy SD rats were divided into hypoxia 1d, 2d, 3d, 5d, and 7d groups and control group (N = 6). Pathological changes in lung tissue were observed by hematoxylin and eosin staining; lung injury was scored, and ultrastructural changes in lung tissue were observed by transmission electron microscopy. Changes in moisture content in lung tissues were determined by analyzing the wet/dry weight ratio (W/D). Localization of AQP-1 and AQP-4 was determined by immunohistochemistry. AQP-1 and AQP-4 expression were detected by western blot. Lung W/D was lower in hypoxia groups than in control group, and the highest in 3d group (P < 0.05). Light microscopy revealed a thickening alveolar wall and outstretched and congestive alveolar wall in hypoxia group; electron microscopy revealed the presence of abnormal alveolar type II epithelial cells, cavitation in cytoplasm, microvillus-like protrusions, and a reduced lamellar body. AQP- 1 and AQP-4 were mainly distributed in the capillaries and lymphatic and alveolar epithelial cells and airway epithelial cells, respectively. AQP-1 protein expression was decreased (western blot) in hypoxia 1d group (the lowest in 3d group; P < 0.05); there were no significant changes about AQP- 4 expression. Therefore, AQP-1 may be involved in abnormal transport of liquid ALI and pathogenesis of lung edema. AQP-4 may not be involved in the formation of ALI lung edema. PMID- 26505427 TI - Molecular characterization, expression, polymorphism of NR5A2 and its relationship with litter size in Hu sheep. AB - NR5A2 has been implicated in processes as diverse as steroidogenesis, cellular proliferation, ovarian follicular development, ovulation, and fertility in mammals. However, data about the relationship between NR5A2 and prolificacy in mammals are lacking. In the present study, we identified and characterized NR5A2 of Hu sheep, and investigated the correlation between NR5A2 and reproductive performance. The full-length coding region was 1488 bp, and the gene was conserved in mammals. We found a positive correlation between NR5A2 mRNA levels in the ovary and the ovulation rate and litter size of Hu sheep. We detected two single nucleotide polymorphisms (T40C and T1419C) in the coding sequence of NR5A2. At the third and average parity, litter size of Hu ewes with CC genotype at T40C locus was larger than those of ewes with TT or TC genotypes; at the T1419C locus, Hu ewes with TT genotype was greater than those of ewes with CC genotype at the third parity. Our findings demonstrated that NR5A2 was associated with reproductive performance in Hu sheep, a high prolificacy breed. PMID- 26505428 TI - Comparative analysis of polygalacturonase in the fruit of strawberry cultivars. AB - The role of polygalacturonase (PG) in the development, ripening, and softening of fruit from two strawberry cultivars with different flesh firmness and softening characteristics was compared. Changes in PG activity and gene expression during development, ripening and softening were measured. The PG genes from each cultivar were cloned and analyzed, and were classified with other PG genes using phylogenetic analysis. In Toyonoka fruit, PG activity increased gradually, reaching a peak during the pink stage, and remained at this level during post harvest softening. Changes in PG gene expression were consistent with PG activity in these softer fruits. In the firmer Sweet Charlie fruits, PG activity was detected during the initial development stage, reaching a peak at the white stage, thereafter decreasing gradually with ripening and remaining at this lower level throughout softening. Changes in PG gene expression and PG activity were not consistent in these fruit. For both Toyonoka and Sweet Charlie PG genes (FaTPG and FaSCPG, respectively), the open reading frame was 1218 bp, encoding 405 amino acids. Five different nucleotide sites were observed between the two sequences, leading to two amino acid sequence mutations. FaTPG, FaSCPG, and PG genes from the Fragaria vesca genome were classified into three clades using phylogenetic analysis. The clade containing PG genes involved in fruit softening had functional similarity but there were no functional differences between FaTPG and FaSCPG. Differences in PG activity, gene sequence, and gene expression may have led to different roles of PG during ripening and softening in strawberries with different textures. PMID- 26505429 TI - Arm-Gal4 inheritance influences development and lifespan in Drosophila melanogaster. AB - The UAS-Gal4 ectopic expression system is a widely used and highly valued tool that allows specific gene expression in Drosophila melanogaster. Yeast transcription factor Gal4 can be directed using D. melanogaster transcriptional control elements, and is often assumed to have little effect on the organism. By evaluation of the consequences of maternal and paternal inheritance of a Gal4 transgene under the transcriptional regulation of armadillo control elements (arm Gal4), we demonstrated that Gal4 expression could be detrimental to development and longevity. Male progeny expressing arm-Gal4 in the presence of UAS-lacZ transgene had reduced numbers and size of ommatidia, compared to flies expressing UAS-lacZ transgene under the control of other Gal4 transgenes. Aged at 25 degrees C, the median life span of male flies with maternally inherited elav-Gal4 was 70 days, without a responding transgene or with UAS-lacZ. The median life span of maternally inherited arm-Gal4 male flies without a responding transgene was 48 days, and 40 days with the UAS-lacZ transgene. A partial rescue of this phenotype was observed with the expression of UAS-lacZ under paternal arm-Gal4 control, having an average median lifespan of 60 days. This data suggests that arm-Gal4 has detrimental effects on Drosophila development and lifespan that are directly dependent upon parental inheritance, and that the benign responder and reporter gene UAS-lacZ may influence D. melanogaster development. These findings should be taken into consideration during the design and execution of UAS-Gal4 expression experiments. PMID- 26505430 TI - Real-time PCR evaluation of cell-free DNA subjected to various storage and shipping conditions. AB - In this study, we attempted to explore the factors affecting the yield of cell free fetal DNA (cffDNA) obtained from maternal blood samples, including the use of different types of collection tubes, the interval between sample processing, and sample shipping under extreme weather conditions. Blood samples were drawn into K3EDTA tubes and cell-stabilizing tubes (Streck blood collection tube, BCT) from women pregnant with male fetuses. Real time PCR was used to amplify a beta actin gene fragment to measure the total plasma cell-free DNA concentration, while an SRY gene fragment was used to quantify the cffDNA. The samples in the K3EDTA tubes revealed a decreased quantity of SRY after 5 days of transportation, with a median of 25.9 copies/mL (P < 0.01); however, the value remained stable at 33.4 copies/mL in the BCT tubes. We observed a statistically significant increase in stability of the amount of total DNA in the blood samples stored in K3EDTA tubes (P < 0.01) and transportated under extreme outdoor temperatures (-20 degrees -0 degrees C) than that of the control values. These results indicate that it could be possible to avoid the presence of excess maternal DNA in samples shipped under extreme weather conditions for no more than 2 days, by collecting the blood samples in BCT tubes. PMID- 26505431 TI - Genetic polymorphisms in beta-defensin II gene in Amazon sheep from Brazil. AB - The northern region of Brazil produces a large number of sheep, with Para being the largest sheep breeding state in the region. In the Amazon region, livestock production is a challenge due to the high diversity of pathogens affecting humans and animals. Defensins are antimicrobial peptides acting as a first barrier against micro-organisms and present high variation in different organisms. The objective of this study was to detect polymorphisms in exon II in beta-defensin II in Amazon sheep. The gene was amplified by PCR from DNA extracted from 47 sheep blood samples from the Santa Ines breed. Products were sequenced, aligned and analyzed. Three single nucleotide polymorphism (SNP) positions were observed with transition substitutions (A<->G) at positions 1643, 1659, and 1750. The 1643 and 1750 SNPs showed a low variability and significant deviations from Hardy Weinberg equilibrium (HWE) (P < 0.05) meanwhile the SNP 1659 showed moderate absence of genetic variability and deviation from HWE (P > 0.05). Polymorphisms at 1643 and 1659 were predicted to modify amino acids in the peptide chain (isoleucine to valine and arginine to lysine, respectively) with no effects on protein function. Results from this study suggest that SNPs are important markers for beta-defensin II efficiency studies on the immune system of sheep in the Brazilian Amazon. PMID- 26505432 TI - Molecular characterization, chromosome mapping, and expression profile of porcine CDC16. AB - Cell division cycle16 (CDC16) is a core component among the eight protein subunits of the anaphase-promoting complex (APC). APC is a cyclin degradation system that governs the exit of cells from mitosis. Not much information is available for CDC16 in pig. In this study, a 2284-bp cDNA of porcine CDC16 was obtained by rapid amplification of cDNA ends (RACE). Porcine CDC16 was assigned to SSC11 q11-17, and was determined to be significantly linked with SW1452 by using somatic cell hybrid panel and radiation hybrid panel. One novel A/G SNP anchored in intron 7 of the gene was genotyped by restriction enzyme polymerase chain reaction (PCR)-restriction fragment length polymorphism-Csp6I. In five pig breeds, Shaziling, Taoyuan, Duroc, Landrace, and Yorkshire, the A allele frequency was dominant. Quantitative PCR revealed that porcine CDC16 was expressed in ten selected tissues of 25-day-old Shaziling and Yorkshire piglets, and that the mRNA expression of CDC16 in longissimus dorsi muscle of Shaziling was higher than that of Yorkshire. Expression levels of CDC16 were highest in longissimus dorsi muscle followed by that in pancreas. CDC16 protein was detected in longissimus dorsi muscle of 25-day-old Shaziling and Yorkshire piglets by immunohistochemistry with abundant protein expression index (P > 0.05). This study provides an insight into the role of porcine CDC16 in the formation of meat. PMID- 26505433 TI - Sex differential marker FD for rapid sex identification of Litsea cubeba. AB - Litsea cubeba is an important economic tree in China. Sex identification of the species is required to reduce breeding costs. Molecular biology is an ideal method to achieve this aim because of the lack of morphological differences between male and female plants, especially at the seedling stage. Sequence related amplified polymorphism was used to amplify sex-related bands. Following sequencing, the amplified fragment Dwas used to create a sequence-characterized amplified region (SCAR) marker, FD. The SCAR marker is approximately 750 bp, is female-specific, and is expected to be useful for L. cubeba breeding programs. Furthermore, the amplified fragment L had homology to sex-determining-related genes of other species. Quantitative real-time polymerase chain reaction analysis of this fragment during flower bud development identified expression differences between male and female plants. PMID- 26505434 TI - Matrilineage differentiation of the genus Tetragonisca using mitochondrial DNA markers and the polymerase chain reaction-restriction fragment length polymorphism technique. AB - The Meliponinae are important pollinators of plant species, and one of the most managed species is Tetragonisca angustula. Initially, two subspecies were identified in T. angustula: T. angustula angustula and T. angustula fiebrigi. Subsequently, T. a. fiebrigi was considered a species, based on the coloration of its mesepisternum. The objective of the present study was to obtain genetic markers that could differentiate the two species by amplifying regions of mitochondrial DNA and conducting polymerase chain reaction-restriction fragment length polymorphism analysis. Worker bees were collected in three Brazilian states: Parana (Maringa, Altonia, and Foz do Iguacu), Sao Paulo (Dracena, Sao Carlos, and Santa Cruz do Rio Pardo), and Rondonia (Ariquemes). Ten pairs of insect heterologous primers were tested and four were used (primer pair 1, ND2 and COI; primer pair 2, COI; primer pair 8, 16S and 12S; and primer pair 9, COII). For the restriction analysis, 13 enzymes were tested: EcoRI, EcoRV, HindIII, HinfI, RsaI, PstI, XbaI, HaeIII, ClaI, XhoI, BglII, PvuII, and ScaI. Markers were obtained (primer pair 8 cleaved with EcoRV and XbaI and primer pair 9 cleaved with HaeIII, RsaI, and XbaI) that enabled matrilineage identification in the nests studied, which confirmed that hybridization could occur between both Tetragonisca species. The beginning of speciation was probably recent, and secondary contact has resulted in crosses between T. angustula females and T. fiebrigi males. Because of this hybridization, it would be appropriate to consider them as two subspecies of T. angustula. PMID- 26505435 TI - Effects of MK-801 concentration on cell proliferation in rats with focal cerebral ischemia-reperfusion. AB - We explored the relationship between MK-801 concentration and neural stem cell proliferation in rats with focal cerebral ischemia-reperfusion (FCIR). A total of 60 male Sprague Dawley rats were randomized into control (six rats), sham operation (six rats), operation (12 rats), and MK-801 groups. The MK-801 group comprised 36 rats that were subjected to different doses of MK-801 (0.2, 0.4, 0.6, 0.8, 1.0, and 1.2 mg/kg). Suture occlusion was used to establish an ischemia reperfusion model of middle cerebral artery occlusion (MCAO); 30 min before establishing the FCIR model, the MK-801 group rats were intraperitoneally injected with different doses of MK-801, while the sham-operation and control groups were injected with normal saline. Seven days after model establishment, bromodeoxyuridine-positive cerebral cortex cells adjacent to the focus of infarction were labeled for immunohistochemistry. MK-801 at a concentration of 0.4 mg/kg prevented endogenous neural stem cell proliferation, and this inhibitory effect was strengthened with increasing MK-801 concentration, especially at concentrations greater than 0.8 mg/kg. MK-801 inhibits endogenous neural stem cell proliferation in rats with FCIR, and the inhibitory effect is strengthened with increasing MK-801 concentration. PMID- 26505436 TI - Single nucleotide polymorphisms of Delta6-desaturase and Elovl5 segments and their associations with common carp (Cyprinus carpio) growth traits. AB - Highly unsaturated fatty acids (HUFAs) are crucial for the nutritional health, physiology, and reproduction of vertebrates. The Delta6-desaturase and Elovl5 elongase genes produce essential enzymes in the biosynthetic pathway of HUFAs. Single nucleotide polymorphism (SNP) analysis of genes functionally related to the growth traits of the common carp (Cyprinus carpio var. Jian) can provide useful information for common carp molecular breeding. In this study, we isolated two Delta6 Fad genes and two Elovl5 genes from the common carp. Polymerase chain reaction-restriction fragment length polymorphism was performed, and the genotypes of three SNPs (Delta6Fad-a intron 10_C73T, Delta6Fad-b intron 10_A56G, and Elovl5-a intron 5_C64A) in 712 individuals (383 females and 329 males) were detected. Correlation analysis between the genotypes and weight gain revealed that intron 10_C73T of Delta6Fad-a, intron 10_A56G of Delta6Fad-b, and intron 5_ C64A of Elovl5-a were significantly associated with common carp weight gain. Weight gain increased with the enrichment of molecular SNP markers, consistent with the characteristics of quantitative traits. Our results indicate that Delta6Fad and Elovl5 elongase genes could be candidate genes for the molecular breeding of the common carp. This study provides useful information for the improvement of this species. PMID- 26505437 TI - Meiotic behavior of Brachiaria decumbens hybrids. AB - Brachiaria decumbens is a forage grass of inestimable value for livestock in Brazil due to its production of good quality forage even when planted on acid and poor soils, although it is susceptible to pasture spittlebugs. Only one cultivar, cv. Basilisk, has been used as the pollen donor in crosses with Brachiaria ruziziensis since 1988 at Embrapa Gado de Corte Research Center. Breeding within the species only became possible from 2009 when sexual accessions were successfully tetraploidized using colchicine. Three sexual genotypes were obtained and hybridization within B. decumbens was finally achieved. Here, we evaluated microspore tetrads using conventional cytology and found meiotic indexes above 78% for all three female genitors (cD24-2, cD24-27, cD24-45), but a low meiotic index (<22%) in the natural apomictic genitor D62 (cv. Basilisk) and in 49 hybrids. Analysis of the relationship between abnormal tetrad frequency and non-viable pollen grains yielded a highly significant Pearson correlation coefficient. The t-test proved significant for the progeny of cD24-45 x D62, with lower abnormalities and pollen sterility when compared to the other two progenies resulting from cD24-2 and cD24-27 crossed to D62, but these two did not differ. Apomictic hybrids such as S036 and X030 with low pollen sterility have the potential for use in cultivar development, whereas the sexual hybrids T012, X072, and X078 might be of use as female genitors in polycross blocks if they display good agronomic traits. PMID- 26505438 TI - DNA methyltransferase 3B -149C/T polymorphism and the risk of laryngeal squamous cell carcinoma: a case-control study. AB - A variety of molecular epidemiological studies have been conducted to examine the association between the DNMT3B -149C/T polymorphism and cancer susceptibility; however, there has been no study investigating the association between the DNMT3B -149C/T polymorphism and the risk of laryngeal squamous cell carcinoma (LSCC) until now. To determine the role of the DNMT3B -149C/T polymorphism in LSCC, we genotyped 113 patients with LSCC and 110 controls from a Chinese population using polymerase chain reaction-restriction fragment length polymorphism analysis. The chi-square test was used to examine differences in the distributions of genotypes studied between patients and controls. The association between the DNMT3B -149C/T polymorphism and the risk of LSCC was estimated using ORs and their 95%CIs. Genotypic frequencies in the patients with LSCC were not similar to those of the controls, with the differences being statistically significant (P = 0.001). When the DNMT3B -149 CC genotype was used as the reference group, the CT genotype was not associated with LSCC risk (adjusted OR, 2.12; 95%CI = 0.89-5.19; P = 0.07), but the TT genotype was associated with significantly increased risk for LSCC (adjusted OR = 3.27; 95%CI = 1.79-10.66; P = 0.009). Under the recessive model of inheritance, the TT genotype was associated with significantly increased risk for LSCC (adjusted OR = 1.98; 95%CI = 1.12-5.95; P = 0.012), compared with other genotypes. These results suggested that the DNMT3B -149C/T polymorphism is associated with a genetic susceptibility for developing LSCC in a Chinese population. PMID- 26505439 TI - Differential expression of COX-2 in osteoarthritis and rheumatoid arthritis. AB - In this study, we investigated the differential expression profiles of cyclooxygenase-2 (COX-2) mRNA and proteins in osteoarthritis (OA) and rheumatoid arthritis (RA) patients to elucidate the role of COX-2 expression in the pathogenesis and development of these diseases and to provide novel drug targets for treating arthritis. A total of 60 patients who received arthroscopic surgeries for treating OA (N = 30) or RA (N = 30) were examined. Fifteen normal synovial tissue samples were included as the control group. Fibroblastic synovial cells in all samples were cultured in vitro and COX-2 mRNA, protein expression levels, and COX-2 levels were detected in synovial fluids by real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay methods, respectively. The mRNA level of COX-2 was significantly elevated in synovial cells from OA and RA patients compared to that in control samples (P < 0.05). COX 2 mRNA level was significantly higher in synovial cells from OA patients than in those from RA patients (P < 0.05). Consistent results were obtained for COX-2 protein expression levels from patients' synovial samples. In synovial fluids, OA (P < 0.05), but not RA (P > 0.05), patients showed significantly higher COX-2 levels compared to the control group. Elevated synovial COX-2 expression facilitates the pathogenesis of OA and RA, and thus this index reflects the condition of these 2 diseases. PMID- 26505440 TI - Castor bean (Ricinus communis L.) as a potential environmental bioindicator. AB - Biomonitoring of air quality using living organisms is a very interesting approach to environmental impact assessment. Organisms with a vast distribution, such as plants, are widely used for these purposes. The castor bean (Ricinus communis L.) is an oleaginous plant that can potentially be used as a bioindicator plant owing to its rapid growth and large leaves, which have a wide surface area of contact with the air and the pollutants therein. This study investigated the the bioindicator potential of the castor bean by performing several tests. We observed statistically significant differences in the concentrations of chlorophyll a and b in the leaves of plants in polluted areas compared to that in the control group plants, which were located in a pollution free area. Leaves of plants in the former group had higher peroxidase activity and showed a greater buffering ability than those of plants in the control group. The pKa values obtained via buffering capacity tests, revealed the presence of aminoazobenzene (an industrial dye) in leaves of R. communis. Genotoxicity was evaluated through the comet assay technique and revealed that other than some differences in DNA fragmentation, there is no statistically significant difference in this parameter between places analyzed. Our data indicate that R. communis can be a highly useful biological indicator. Further, we hypothesized that the castor bean can be a potential candidate for phytoremediation owing its physiological buffering capacity when exposed to substantial pollution. PMID- 26505441 TI - Association between polymorphisms in the XRCC1 gene and the risk of non-small cell lung cancer. AB - Here, we have reported a case-control study investigating the association between XRCC1 codons Arg194Trp, Arg280His, and Arg399Gln and the development of NSCLC. NSCLC patients (N = 245) and healthy controls (N = 257) were randomly selected from the Huaihe Hospital between March 2012 and August 2014. DNA extracted from the patient and control blood samples were subjected to polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) to assess the genotyping of XRCC1 Arg194Trp, Arg280His, and Arg399Gln. Multivariate logistic regression analyses revealed an association between the expression of the AA genotype and A allele genotypes and a significantly increased risk of NSCLC, compared to the GG genotype [95% confidence interval (CI); Odd's ratio (OR) = 2.82 (1.141-5.86) and 1.67 (1.17-2.37), respectively]. The potential association between the A allele of XRCC1 Arg399Gln and the risk of NSCLC was more evident in smokers (95%CI; OR = 1.70; 1.11- 2.63). In conclusion, the XRCC1 Arg399Gln polymorphism was found to be associated with increased risk of NSCLC, especially in tobacco smokers. PMID- 26505442 TI - Breeding of a target genotype variety based on identified chalkiness marker-QTL associations in rice (Oryza sativa L.). AB - The aim of this study was to breed a target genotype variety based on the identified chalkiness marker-QTL (quantitative trait locus) associations in rice. First, a permanent mapping population of rice that consisted of 525 recombinant inbred lines (RILs), which were derived from Zhenshan 97/Minghui 63, was used to identify QTLs with additive effects for rice quantitative traits and percentage of grain chalkiness (PGC). Subsequently, based on the identified QTLs in rice, the molecular marker 68923-PGC was selected to screen the low chalkiness rice line. Then, using the integration of molecular marker breeding and traditional breeding, we analyzed the genotype and phenotype of inbred lines from 525 RILs; we identified one rice variety with particularly high yields, good taste, and broad adaptability. The new variety was temporarily named RIL10, which was a high quality, high yield, and broadly adaptable variety, and it is predominantly a feature that has contributed to its geographical adaptability, which would be planted from 35 degrees E to 18 degrees E in Chinain China, where 2/3 of rice production occurs. RIL10 was a marker-assisted selection breeding achievement for producing a high quality, high yield, and broadly adaptable rice variety. PMID- 26505443 TI - Serial analysis of gene expression in adenocarcinoma samples and normal colonic mucosa in a Chinese population. AB - The goal of this study was to identify the differences in gene expression between adenocarcinoma samples and colonic normal mucosa of a Chinese population. Gene expression libraries of adenocarcinoma and normal colonic mucosa were generated by serial analysis of gene expression (SAGE). Expression tags were obtained from sequencing results using the SAGE2000 software. Representative genes of tags were determined based on the SAGEmap from NCBI. Expressed genes were selected and their expression in different libraries was compared using the SPSS 17.0 software. The expression of 78 tags representing 88 types of genes showed significant differences. Compared with normal mucosa, 38 genes showed decreased expression in cancer, whereas the expression of the remaining 50 genes showed significant up-regulation. Expressed tags in SAGE libraries of normal and cancerous tissues were significantly different. Further studies examining these genes, which showed different expression levels between the 2 tissues, may be used as tumor markers and offer clues for studying the etiopathogenesis of colon cancer. PMID- 26505444 TI - Association of CRTC2 gene polymorphisms with growth and meat quality traits of Qinchuan cattle. AB - Growth and meat quality traits play important roles in the evaluation of cattle productivity and are influenced by genetic and environmental factors. CRTC2 is a recently discovered gene related to obesity that may influence fat deposition. The aim of the current study was to detect polymorphisms of bovine CRTC2 and explore their relationships to growth and meat quality in Qinchuan cattle. Three single nucleotide polymorphisms (SNPs); g.3001 C>T; g.3034 G>A; and g.3467 T>C, were identified from sequencing results of 422 Qinchuan cattle. The genotypic distributions of both g.3034 G>A and g.3467 T>C mutations were in agreement with Hardy-Weinberg equilibrium, (P < 0.05), while the T3001C mutation was not (P > 0.05), based on chi(2) test analysis. The SNPs g.3001 C>T and g.3034 G>A are missense mutations (Ser/Phe and Ser/Thr respectively). Additionally, SNPs g.3034 G>A and g.3467 T>C showed a medium polymorphism level (0.25 < PIC< 0.50), whereas g.3001 C>T showed a low polymorphism level (PIC < 0.25). These three SNPs were significantly associated with several growth and meat quality traits in the Qinchuan cattle population (P < 0.05 or P < 0.01). Collectively, these results demonstrate that CRTC2 is involved in the regulation of cattle growth and meat quality, and suggest that CRTC2 is a potential candidate gene for marker-assisted selection in future breeding development programs for Qinchuan cattle. PMID- 26505445 TI - Construction of a full-length cDNA library and preliminary analysis of expressed sequence tags from lymphocytes of half-pipe snowboarding athletes. AB - The genes of top athletes are a valuable genetic resource for the human race, and could be exploited to identify novel genes related to sports ability, as well as other functions. We analyzed the expressed sequence tags from top half-pipe snowboarding athletes using the SMART complementary DNA (cDNA) library construction method to elucidate the characteristics of the athlete genome and the differential expression of the genes it contains. Overall, we established a full-length cDNA library from the lymphocytes of half-pipe snowboarding athletes and analyzed the inserted gene fragments. We also classified those genes according to molecular function, biological characteristics, cellular composition, protein types, and signal paths. A total of 201 functional genes were noted, which were distributed in 27 pathways. TXN, MDH1, ARL1, ARPC3, ACTG1, and other genes measured in sequence may be associated with physical ability. This suggests that the SMART cDNA library constructed from the genetic material from top athletes is an effective tool for preserving genetic sports resources and providing genetic markers of physical ability for athlete selection. PMID- 26505446 TI - Molecular characterization, tissue expression profile and SNP analysis of porcine GLP2R. AB - Glucagon-like peptide-2 receptor (GLP2R), a member of the G-protein-coupled receptor family, plays an important role in intramuscular fat formation. Little is known, however, about porcine GLP2R. In the present study, GLP2R was cloned, and its expression in pig muscle characterized. By rapid amplification of cDNA ends, gene sequence was obtained from Shaziling pigs. Full-length cDNA was 1868 bp, including an open reading frame 1665 bp in length, encoding 554 amino acids, and 203 bp at the 3' end. The GLP2R homology between porcine and other species was performed using bioinformatics techniques to construct a phylogenetic tree. Porcine GLP2R was most closely related to those from Orcinus orca and Ovis aries, and most distantly related to those from Chrysemys picta, Taeniopygia guttata, and Falco peregrinus. Real-time PCR analysis showed expression of porcine GLP2R in 10 different tissues from 25-day-old Yorkshire and Shaziling piglets, with expression levels being highest in the longissimus dorsi muscle and lowest in kidney. For each pig breed, expression level in longissimus dorsi muscle was highest among ten tissues (P < 0.05). Between the two breeds, GLP2R expression levels were significant in pancreas, the crureus and longissimus dorsi muscles (P < 0.05). A single SNP of porcine GLP2R, A343G, was identified, and genotypes were determined by PCR-RFLP. This study provides an insight into the function of GLP2R in swine. PMID- 26505447 TI - Hyperproliferative action of bovine papillomavirus: genetic and histopathological aspects. AB - The bovine papillomavirus (BPV) causes papillomas that regress spontaneously, but can also progress to malignancy. This study evaluated the role of BPV in oncogenesis. Twenty-four samples from uninfected calves and the papillomas of BPV infected cattle were subjected to molecular diagnosis, as well as histopathological and immunohistochemical analyses. The comet assay (CA) was used to evaluate the clastogenic potential of BPV. The results confirmed the presence of BPV-2, 3, 5, and 9 in infected samples. Histopathological analysis revealed acanthosis, koilocytosis, hypergranulosis, hyperkeratosis, and transformed fibroblasts.E7 and L1 BPV proteins were detected in the epithelium, as well as in the connective tissues, indicating productive infection at different sites. CA results showed that BPV-2, 5, and 9 exhibit the same level of clastogenicity. These findings support the oncogenic action of BPV in establishing a favorable microenvironment for oncogenesis. PMID- 26505448 TI - Changes in cFLIP expression in the corpus luteum throughout the estrous cycle of Shibagoats. AB - Changes in the expression of the anti-apoptotic protein cFLIP (cellular FLICE inhibitory protein) were examined in the caprine corpus luteum (CL), during development and subsequent maintenance. Corpora lutea at four different stages were collected from Shiba goats, to measure the expression of cFLIP mRNA, protein and immunolocalization. Expression of short form cFLIP (cFLIPS) mRNA was highest at the early CL stage, and decreased during late and regressed stages (P < 0.05). In contrast, long form cFLIP (cFLIPL) mRNA expression was high during early, mid and late stages, and only decreased at the regressed stage (P< 0.01). Protein expression of cFLIPS was highest at the late CL stage, and decreased at the regressed stage (P < 0.01). Protein expression of cFLIPL was highest at the early and mid CL stages, and decreased by the late and regressed stages (P < 0.01). Further expression of cFLIPL was higher at the early CL stage than at the mid stage (P < 0.01). cFLIP protein expression was detectable by immunostaining in the early, mid and late CL stages, but not at the regressed CL stage. These results are consistent with the hypothesis that cFLIP acts as a survival factor in the maintenance of CL function in goats. PMID- 26505449 TI - Influence of ERCC2 gene polymorphisms on the treatment outcome of osteosarcoma. AB - We conducted a prospective study to investigate the role of ERCC2 gene polymorphisms on the outcome of cisplatin-based treatment in patients with osteosarcoma. A total of 115 patients with osteosarcoma were included in our study. Genotyping of ERCC2 Asn312Asp (rs1799793) and Lys751Gln (rs13181) was performed using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method. Of the 115 patients, 78 showed complete or partial response to chemotherapy, with a response rate of 67.85%. Our study suggested that the AA genotype of ERCC2 Asn312Asp was associated with a better response to chemotherapy, and the related adjusted OR (95%CI) was 4.85 (1.06-42.71). By Cox proportional hazards model analysis, we found that the AA genotype of ERCC2 Asn312Asp was associated with longer overall survival of patients with osteosarcoma when compared with the GG genotype, and the hazards ratio (95%CI) for the AA genotype was 0.65 (0.27-1.47). In conclusion, our study found that the ERCC2 Asn312Asp gene polymorphism likely plays an important role in influencing the chemotherapy response and overall survival of patients with osteosarcoma. PMID- 26505450 TI - Clinical characteristics of patients with non-small cell lung cancers harboring anaplastic lymphoma kinase rearrangements and primary lung adenocarcinoma harboring epidermal growth factor receptor mutations. AB - Echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4 ALK) gene rearrangements and epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) have been intensively studied. The objective of this study was to determine the clinicopathological characteristics in genotype-specific subsets of patients with NSCLC to help ensure the optimal identification of patients whose tumors harbor these two driver mutations. The incidence of ALK rearrangements was investigated in 763 NSCLC specimens by immunohistochemistry using a D5F3 antibody, and EGFR mutations were assessed by amplification refractory mutation system (ARMS) in 222 patients with lung adenocarcinoma. Of these, 73 (9.6%) were detected as being ALK-positive; this designation was associated with young age, female gender, never-smokers, lymph node metastasis, and poor tumor differentiation, but not with histology. EGFR mutations were identified in 102 (45.9%) of 222 adenocarcinoma samples, and were more frequent in females and never-smokers. No difference in age was observed. Specifically, we identified several cases of complex EGFR mutations, and concomitant EGFR mutations and ALK rearrangements. These results suggest that young women and never-smokers are at risk for ALK rearrangement. We also identified concomitant mutations of EGFR and rearrangements of ALK in this study. PMID- 26505451 TI - Association of A-20C polymorphism in the angiotensinogen gene with essential hypertension: a meta-analysis. AB - The A-20C polymorphism in the angiotensinogen (AGT) gene has been associated with increased risk of essential hypertension in several studies; however, these studies gave inconsistent results. In this study, we performed a meta-analysis to assess the association between AGT A-20C polymorphism and essential hypertension. Published literature was retrieved from PubMed. Pooled odd's ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effect models. A total of 10 case-control studies containing 3653 cases and 3457 controls were enrolled to this meta-analysis. In a combined analysis, the results showed a significant association between the AGT A-20C polymorphism and risk of essential hypertension (AA vs CC: OR = 0.62, 95%CI = 0.46-0.84; recessive model: OR = 0.66, 95%CI = 0.49-0.88). In the subgroup analysis stratified by race, significant associations were found between the AGT A-20C polymorphism and essential hypertension risk in Asians (AA vs CC: OR = 0.59, 95%CI = 0.43-0.80; recessive model: OR = 0.63, 95%CI = 0.46-0.85). In conclusion, the results of this meta analysis suggested that the AGT A-20C polymorphism was associated with risk of essential hypertension in Asians. PMID- 26505452 TI - Polymorphic variations in manganese superoxide dismutase (MnSOD) and endothelial nitric oxide synthase (eNOS) genes contribute to the development of type 2 diabetes mellitus in the Chinese Han population. AB - Impaired antioxidant defense increases the oxidative stress and contributes to the development of type 2 diabetes mellitus (T2DM). MnSOD and eNOS are important antioxidant enzymes. This aim of this study was to verify the association of MnSOD and eNOS tagSNPs with T2DM in a Chinese Han population. Four tagSNPs of MnSOD and eight tagSNPs of eNOS were detected using TaqMan technology in 1272 healthy controls and 1234 T2DM patients. All study participants were unrelated members of the Han ethnic group in China. In this study, the frequency of the rs4880 MnSOD single nucleotide polymorphisms (SNP) genotype differed significantly between T2DM patients and controls [allele: P = 0.03, genotype: P = 0.04, odd's ratio (OR) = 1.26; 95% confidence interval (CI) = 1.07-1.49]. The A-T haplotype and G-T haplotype remained significant in T2DM after Bonferroni correction (P = 1.58 x 10(-6) and 8.00 x 10(-4), respectively) with a global p value of 7.25 x 10(-8). The rs1799983 and rs891512 SNPs of eNOS differed significantly between T2DM patients and controls [rs1799983: corrected allele: P = 2.10 x 10(-3), corrected genotype: P = 6.30 x 10(-3), OR = 1.43 (95%CI = 1.18 1.73); rs891512, corrected allele: P = 3.50 x 10(-3), corrected genotype: P = 9.10 x 10(-3), OR = 1.70 (95%CI = 1.26-2.30)]. Following Bonferroni correction, none of the haplotypes of eNOS were significant in T2DM. These results indicate that common variants in MnSOD and eNOS increased the risk of T2DM in the Chinese Han population. PMID- 26505453 TI - Influence of various quantitative trait loci (QTL) mapping methods on the mapping accuracy under varying heritability levels. AB - The study of quantitative trait effects is of great significance for molecular marker-assisted breeding. The accuracy of quantitative trait loci (QTL) mapping is the key factor affecting marker-assisted breeding, and is extremely significant. The effect of different heritability rates (10, 30, 50, 70, and 90%) on the accuracy of QTL mapping of five recombinant inbred lines (RILs) were analyzed via computer simulation. RILs display additive and epistatic genetic effects. The QTLs were analyzed using four different mapping procedures: multiple QTL model (MQM), composite interval mapping (CIM), multiple interval mapping (MIMR), and inclusive composite interval mapping (ICIM). The results revealed an increase in the QTL mapping accuracy and QTL detection power, and a decrease in the QTL interval range with the increase in heritability; conversely, an irregular number of false positive QTLs were generated. CIM and MQM only screen the additive and dominant effects; MIMR and ICIM screen the additive, dominant, and epistatic effects. The highest QTL detection power obtained using MQM and CIM was only 75%, while MIMR and ICIM showed a detection power of 100%. At heritability rates of more than 50 and less than 10%, the detection powers of the MIMR and ICIM procedures were >95 and <35%, respectively. QTL mapping has no significance at heritability rates <10%. The results of this study suggest that QTL mapping has significance at a heritability rate >30% (at least >10%) for practical marker-assisted breeding. PMID- 26505454 TI - Molecular characterization of twenty polymorphic microsatellite markers in the polyploid fruit tree species Syzygium samarangense (Myrtaceae). AB - Syzygium samarangense (Blume) Merr. & Perry (wax apple) is an important commercial fruit tree in Southeast Asia. Here, microsatellite markers were developed to evaluate genetic diversity and distinguish cultivars in this species. In total, 161 microsatellite loci with sufficient flanking sequences to design primer sets were isolated from wax apple using a magnetic bead-enrichment method. Fifty-eight primer sets were designed based on the flanking sequences of each single sequence repeat (SSR) locus and were tested using 14 wax apple cultivars/lines. Twenty SSR loci were found to be polymorphic and transferable across the 14 wax apple cultivars/lines. The number of alleles and effective number of alleles detected per locus ranged from 4 to 12 and from 1.697 to 9.800, respectively. The expected heterozygosity ranged from 0.150 to 0.595 (mean = 0.414). Polymorphism information content values ranged from 0.502 to 0.866 (mean = 0.763). These new microsatellite loci will be of value for characterization of genetic diversity in wax apples and for the identification of cultivars. PMID- 26505455 TI - Cloning, molecular characterization, and expression analysis of a nucleoporin gene (rgNUP98-96) from Rehmannia glutinosa. AB - Nucleoporin 98 (NUP98) and nucleoporin 96 (NUP96) are essential components of the nuclear pore complex (NPC) in eukaryote cells. However, there is a lack of available information about complete Rehmannia glutinosa NUP98-96 (rgNUP98-96) sequences. Here, the full-length cDNA sequence of rgNUP96-98 was isolated from R. glutinosa using rapid amplification of cDNA ends (RACE) technology, based on a cloned cDNA sequence (GenBank accession No. JZ483329). The identified rgNUP98-96 was 3476 bp, and it encoded a 1041-amino acid peptide. The BLAST search analysis of rgNUP98-96 showed an intermediate degree of similarity (60-79%) to the NUP98 96 protein sequences of 34 other plants, including the dicotyledons Erythranthe guttata, Genlisea aurea, Coffea canephora, Nicotiana benthamiana, Solanum lycopersicum, and Solanum tuberosum. The phylogenetic analysis of NUP96-98 sequences indicated that R. glutinosa and E. guttata sequences shared the closest homology. The calculated molecular mass and predicted isolectric point of the complex protein were 117.6 kDa and 4.99, respectively. The secondary and three dimensional structure studies illustrated that the rgNUP96-98 protein folded into a channel motif comprised of 34 alpha-helices, nine beta-strands, and several long loops. Using quantitative real-time PCR, the spatio-temporal expression patterns of rgNUP98-96 were analyzed in R. glutinosa, and the results indicated that rgNUP98-96 was highly expressed at the early stage of R. glutinosa tuberous root expansion, which is associated with a higher expression pattern in roots. The study provides a valuable foundation for further investigation of rgNUP96-98 molecular functions in R. glutinosa. PMID- 26505456 TI - Combination of multiple gene markers to detect circulating tumor cells in the peripheral blood of patients with non-small cell lung cancer using real-time PCR. AB - Our study aims to determine the clinical significance of human telomerase reverse transcriptase (hTERT), S-phase kinase-associated protein 2 (Skp2) and thyroid transcription factor-1 (TTF-1) mRNA expressions in peripheral blood (PB) of patients with non-small cell lung cancer (NSCLC). Real-time polymerase chain reaction was used to investigate the gene expressions of hTERT, Skp2, TTF-1 as in the PB of 60 patients with NSCLC and 20 benign lung diseases. Statistical analyses were performed to examine the correlation between the expression of these mRNA markers and the clinical pathological features of NSCLC. We found that hTERT, Skp2, and TTF-1 were overexpressed in the PB of NSCLC patients, and demonstrated high specificity as well as sensitivity when used for NSCLC diagnosis. Significant correlation was observed between disease stage and the three markers (P < 0.05). This study suggests that the genes hTERT, Skp2, and TTF 1 play important roles in tumor genesis and development, and can be used as diagnosis markers in NSCLC patients. The expression of three markers in combination can significantly improve the sensitivity and accuracy of diagnosis relative to single marker diagnosis, and provides a reliable method to detect CTCs in the PB. Additionally, these markers can also be used as diagnostic markers for clinical stages of NSCLC. PMID- 26505457 TI - Circulating B7-H4 in serum predicts prognosis in patients with hepatocellular carcinoma. AB - B7-H4 is member of the B7 family that negatively regulates the immune response, which are important for fine-tuning of the tumor microenvironment. Dysregulation of B7-H4 expression has been associated with tumor progression. However, expression level of B7-H4 in hepatocellular carcinoma (HCC) tissues is still a controversial topic. In addition, whether serum B7-H4 expression of HCC patients has any clinical value is unknown. We compared serum levels of B7-H4 in patients with HCC and healthy controls by using the ELISA method. Association between serum B7-H4 expression level and clinical parameters of HCC was further investigated. Log-rank test and Kaplan-Meier method were employed to evaluate the overall survival rate of HCC patients. Univariate and multivariate analysis of prognostic factors were performed with the Cox regression model. Our results showed that HCC patients had significantly higher serum B7-H4 level as compared with healthy controls (P < 0.001). In addition, serum B7-H4 expression was correlated with HCC clinical parameters including serum AFP expression and TNM stage. HCC patients in the higher serum B7-H4 expression group had a poorer 5 year overall survival rate (P = 0.028). Moreover, serum B7-H4 expression was shown to be an independent prognostic factor for HCC (P = 0.034). The findings from this study suggest that serum B7-H4 is an independent prognostic indicator for HCC and may be a promising biomarker for early diagnosis as well as disease prognosis of HCC. PMID- 26505458 TI - A Risk Model for Surgical Site Infection in the Gastric Cancer Surgery Using Data of 790 Patients. AB - BACKGROUND: Understanding risk factors of surgical site infections (SSIs) in gastrectomy is important to provide the best treatment for the patients with gastric cancer. METHODS: This is a retrospective observational study using the medical records of 790 patients with gastrectomy from 2005 through 2009. SSIs were classified into incisional SSIs (iSSIs) and organ/space SSIs (o/sSSIs). RESULTS: iSSIs and o/sSSIs were detected in 41 (5.2%) patients and 68 (8.6%) patients, respectively. Open surgery was the only independent risk factor (p = 0.028) for iSSIs, while open surgery (p = 0.004), concurrent splenectomy (p < 0.001), operative time >=220 min (p = 0.009), preoperative body mass index >=20.8 kg/m2 (p = 0.004) and male gender (p = 0.028) were the independent risk factors for o/sSSIs. We created a risk model for o/sSSIs using these independent risk factors. The C-index model discrimination was 0.84 (p < 0.001), and the calibration of the models demonstrated a linear correlation between the predicted and observed probability. CONCLUSION: We reported the risk factors of SSIs for gastrectomy. The risk model developed in this study for o/sSSIs pertaining to gastric cancer surgery would contribute to provide guidance for the development of best practices. PMID- 26505459 TI - Stroke Prevention Worldwide--What Could Make It Work? AB - The global burden of stroke is of continual major importance for global health. The present report addresses some of the core principles that could make stroke prevention work. The prevention of stroke shares many common features with other non-communicable diseases (NCDs); stroke prevention should therefore be part of the joint actions on NCD led by the WHO and member states. Stroke prevention is an integral part of both the 2011 UN declaration on actions on NCDs and the UN Post-2015 Sustainable Developmental Goals. Stroke prevention requires an intersectoral approach, with important responsibilities on the part of governmental bodies, non-government organizations and the health sector as well as communities, industries and individuals. Although official development assistance will need to be provided for the lowest income countries, financing will need to be raised for most countries by reallocation of resources within the country. Stroke is a prototype NCD in that there is overwhelming scientific evidence that with actions taken to reduce risk factors, the risk of stroke can be substantially reduced. Prevention of stroke will also have beneficial effects on cognitive decline and dementia. As most strokes do not lead to death, stroke statistics should not only focus on mortality, but also on disability and quality of life. All preventive actions should start early in life and continue during the life cycle. Prevention of stroke is a complex medical and a political issue with many challenges. Upscaling of efforts to prevent stroke are urgently needed in all regions, and the opportunity to act is now. PMID- 26505460 TI - Enhancement of photodetection characteristics of MoS2 field effect transistors using surface treatment with copper phthalocyanine. AB - Recently, two-dimensional materials such as molybdenum disulfide (MoS2) have been extensively studied as channel materials for field effect transistors (FETs) because MoS2 has outstanding electrical properties such as a low subthreshold swing value, a high on/off ratio, and good carrier mobility. In this study, we characterized the electrical and photo-responsive properties of MoS2 FET when stacking a p-type organic copper phthalocyanine (CuPc) layer on the MoS2 surface. We observed that the threshold voltage of MoS2 FET could be controlled by stacking the CuPc layers due to a charge transfer phenomenon at the interface. Particularly, we demonstrated that CuPc/MoS2 hybrid devices exhibited high performance as a photodetector compared with the pristine MoS2 FETs, caused by more electron-hole pairs separation at the p-n interface. Furthermore, we found the optimized CuPc thickness (~2 nm) on the MoS2 surface for the best performance as a photodetector with a photoresponsivity of ~1.98 A W(-1), a detectivity of ~6.11 * 10(10) Jones, and an external quantum efficiency of ~12.57%. Our study suggests that the MoS2 vertical hybrid structure with organic material can be promising as efficient photodetecting devices and optoelectronic circuits. PMID- 26505461 TI - New honeycomb iridium(V) oxides: NaIrO3 and Sr3CaIr2O9. AB - We report the structures and physical properties of two new iridates, NaIrO3 and Sr3CaIr2O9, both of which contain continuous two-dimensional honeycomb connectivity. NaIrO3 is produced by room temperature oxidative deintercalation of sodium from Na2IrO3, and contains edge-sharing IrO6 octahedra that form a planar honeycomb lattice. Sr3CaIr2O9, produced via conventional solid-state synthesis, hosts a buckled honeycomb lattice with novel corner-sharing connectivity between IrO6 octahedra. Both of these new compounds are comprised of Ir(5+) (5d(4)) and exhibit negligible magnetic susceptibility. They are thus platforms to investigate the origin of the nonmagnetic behavior exhibited by Ir(5+) oxides, and provide the first examples of a J = 0 state on a honeycomb lattice. PMID- 26505462 TI - Synthesis, structure and properties of the manganese-doped polyoxotitanate cage [Ti18MnO30(OEt)20(MnPhen)3] (Phen = 1,10-phenanthroline). AB - The novel heterometallic polyoxotitanate cage [Ti18MnO30(OEt)20(MnPhen)3] (1), obtained by solvothermal reaction of Ti(OEt)4 with Mn(AcO)3.(H2O)2 and 1,10 phenanthroline (Phen) in EtOH, has a C3 symmetric core structure containing an interstitial tetrahedral Mn(II) ion and is surrounded by three Mn(II)(Phen) fragments. The molecular structure is retained in thin film electrodes of 1 deposited by solution drop-casting onto fluorinated tin oxide (FTO). Both solid state and solution phase electrochemical measurements show dual redox couples, consistent with the two distinct Mn coordination environments in the cage structure. Sintering of 1 in air at 600 degrees C produces a black crystalline solid which consists of Mn-doped TiO2 (mainly in the rutile phase) together with alpha-Mn2O3. Such a composite semiconductor has an optical band gap of ca. 1.80 eV, similar to that of alpha-Mn2O3. PMID- 26505463 TI - Relationship Between Nocturnal Intraocular Pressure Variations and Sleep Macrostructure. AB - PURPOSE: The purpose of this study was to characterize the relationships between nocturnal intraocular pressure (IOP) variations and sleep macrostructure in healthy subjects. METHODS: This was a cross-sectional study conducted in a center with shared expertise in chronobiology. Twelve healthy volunteers (22.3 +/- 2.3 years) underwent a 24-hour IOP measurement session. The IOP variations of one eye were continuously estimated using a contact lens sensor (CLS) measuring the changes in corneal curvature related to the IOP and not requiring nocturnal awakening for measurements. The CLS measurement characteristics (mean, maximum, minimum, and amplitude) were evaluated across sleep stages (non-rapid eye movement [NREM] sleep [N1, N2, N3], REM) and assessed using polysomnography. The CLS signal measurement changes during sleep stage changes were calculated to evaluate the effects of sleep on IOP. RESULTS: A 24-hour IOP nyctohemeral rhythm was found in all subjects. During the nocturnal period, IOP signal values were significantly lower during wake stages than during REM and NREM N1, N2, and N3 sleep stages (P <= 0.04). The IOP signal values were significantly higher during the REM stage than during the NREM stages (P <= 0.03) and progressively decreased as NREM sleep deepened (P <= 0.04). We found a positive relationship between the micro-arousal index and the nocturnal period CLS signal SD (r = 0.76; P = 0.024) and a negative relationship between sleep efficiency and the nocturnal period CLS signal SD (r = -0.69; P = 0.041). CONCLUSIONS: Sleep micro- and macrostructure and nocturnal IOP variations are closely related in young subjects without sleep disorders. Across sleep stages, IOP is highest during REM sleep and progressively decreases as NREM sleep deepens. PMID- 26505464 TI - Melanopsin-Mediated Post-Illumination Pupil Response in Early Age-Related Macular Degeneration. AB - PURPOSE: To determine whether melanopsin-expressing intrinsically photosensitive retinal ganglion cell (ipRGC) inputs to the pupil light reflex (PLR) are affected in early age-related macular degeneration (AMD). METHODS: The PLR was measured in 40 participants (20 early AMD and 20 age-matched controls) using a custom-built Maxwellian view pupillometer. Sinusoidal stimuli (0.5 Hz, 11.9 seconds duration, 35.6 degrees diameter) were presented to the study eye and the consensual pupil response was measured to lights with high melanopsin excitation (464 nm [blue]) and with low melanopsin excitation (638 nm [red]) that biased activation to the outer retina. Two melanopsin PLR metrics were quantified: the phase amplitude percentage (PAP) during the sinusoidal stimulus presentation and the post illumination pupil response (PIPR). The PLR during stimulus presentation was analyzed using latency to constriction, the transient pupil response and maximum pupil constriction metrics. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curves. RESULTS: The blue PIPR was significantly less sustained in the early AMD group (P < 0.001). The red PIPR was not significantly different between groups (P > 0.05). The PAP and blue stimulus constriction amplitude were significantly lower in the early AMD group (P < 0.05). There was no significant difference between groups in the latency or transient amplitude for both stimuli (P > 0.05). ROC analysis showed excellent diagnostic accuracy for the blue PIPR metrics (area under the curve > 0.9). CONCLUSIONS: This is the initial report that the melanopsin-controlled PIPR is dysfunctional in early AMD. The noninvasive, objective measurement of the ipRGC controlled PIPR has excellent diagnostic accuracy for early AMD. PMID- 26505465 TI - Implications of Optic Disc Tilt in the Progression of Primary Open-Angle Glaucoma. AB - PURPOSE: To evaluate the effect of optic disc tilt on the progression of glaucoma in myopic glaucomatous eyes. METHODS: The disc tilt ratio was estimated on disc photographs. Glaucomatous progression was determined either by stereoscopic optic disc/retinal nerve fiber layer photographs or serial visual field data. All participants were categorized into two groups according to tilt ratio (nontilted [<1.3] or tilted [>=1.3]). Kaplan-Meier life-table analysis was used to compare the survival experiences (time to confirmed glaucomatous progression) between groups. The hazard ratios (HRs) for the associations between potential risk factors and progression were determined by using Cox proportional hazards modeling. RESULTS: A total of 85 eyes in 85 myopic glaucoma patients (axial length > 24 mm; mean follow-up, 4.1 years) were included. Among them, 42 eyes (49.4%) demonstrated progression and 43 eyes (50.6%) were stable on follow-up. The mean disc tilt ratio was significantly smaller, and the prevalence of disc hemorrhage higher, in the progression than the stable group (P = 0.032, P = < 0.001, respectively). The cumulative probability of progression was 24.7% in the tilted group and 68.7% in the nontilted group (P = 0.005). Disc hemorrhage (HR = 3.317; P = 0.001) and the tilt ratio (HR = 0.110; P = 0.046) were predictive of progression. CONCLUSIONS: Myopic eyes with tilted disc demonstrated a smaller probability of glaucomatous progression. Optic disc tilt may be protective against glaucoma progression, or tilted myopic glaucomatous eyes may have less progressive characteristic by nature. PMID- 26505466 TI - Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study. AB - OBJECTIVES: To investigate the potential clinical, restorative, and neuroprotective effects of long-term treatment with thiamine in Parkinson disease (PD). DESIGN: Observational open-label pilot study. SETTING: Outpatient neurologic rehabilitation clinic. PATIENTS AND METHODS: Starting in June 2012, we have recruited 50 patients with PD (33 men and 17 women; mean age, 70.4 +/- 12.9 years; mean disease duration, 7.3 +/- 6.7 years). All the patients were assessed at baseline with the Unified Parkinson's Disease Rating Scale (UPDRS) and the Fatigue Severity Scale (FSS) and began treatment with 100 mg of thiamine administered intramuscularly twice a week, without any change to personal therapy. All the patients were re-evaluated after 1 month and then every 3 months during treatment. RESULTS: Thiamine treatment led to significant improvement of motor and nonmotor symptoms: mean UPDRS scores (parts I-IV) improved from 38.55 +/- 15.24 to 18.16 +/- 15.08 (p = 2.4 * 10(-14), t test for paired data) within 3 months and remained stable over time; motor UPDRS part III score improved from 22.01 +/- 8.57 to 9.92 +/- 8.66 (p = 3.1 * 10(-22)). Some patients with a milder phenotype had complete clinical recovery. FSS scores, in six patients who had fatigue, improved from 53.00 +/- 8.17 to 23.60 +/- 7.77 (p < 0.0001, t test for paired data). Follow-up duration ranged from 95 to 831 days (mean, 291.6 +/- 207.2 days). CONCLUSIONS: Administration of parenteral high-dose thiamine was effective in reversing PD motor and nonmotor symptoms. The clinical improvement was stable over time in all the patients. From our clinical evidence, we hypothesize that a dysfunction of thiamine-dependent metabolic processes could cause selective neural damage in the centers typically affected by this disease and might be a fundamental molecular event provoking neurodegeneration. Thiamine could have both restorative and neuroprotective action in PD. PMID- 26505467 TI - Nuchal translucency distributions for different chromosomal anomalies in a large unselected population cohort. AB - OBJECTIVE: To describe the distribution of the fetal nuchal translucency thickness (NT) according to type of chromosomal aberration in a large unselected population. METHODS: Data on pregnancies with an NT measurement performed at gestational age 11 + 3 - 13 + 6 weeks from 2008 to 2011 were retrieved from the Danish National Fetal Medicine Database. Information on any genetic analysis for aneuploidy performed pre- or postnatally was also obtained. The abnormal results were grouped into 14 types of chromosomal anomalies. Distributions of NT measurements were summarized by aberration and compared with the normal/no karyotype group. RESULTS: A total of 215 223 singleton pregnancies were included in the cohort; 10548 had a normal karyotype and 1286 had an aberration. Plots of the NT measurements showed that like trisomy 21, 18 and 13 and monosomy X, the distribution for the unbalanced translocations was shifted towards larger NTs. The distributions for the balanced translocations, the uncommon trisomies and the triploidies more closely resembled that of the normal/no karyotype population. CONCLUSION: Fetuses with aneuploidies have NT distributions visually different from normal fetuses, with the exception of triploidies and uncommon autosomal trisomies. The distributions differ in shape according to type of chromosomal anomaly. (c) 2015 John Wiley & Sons, Ltd. PMID- 26505468 TI - Periodontal disease classifications revisited. AB - An American Academy of Periodontology Task Force has recently published a report on the Update to the 1999 Classification of Periodontal Diseases and Conditions, which is a focused update outlining changes to be included in a comprehensive update planned for 2017. We discuss the proposed changes, and their rationales, and conclude that the periodontal classification carousel will continue to spin until it is realized that the only way forward is a profound reconsideration of what we hope to achieve with classifications. PMID- 26505469 TI - Glycemic control in inpatients with diabetes following august changeover of trainee doctors in England. AB - The first Wednesday of August is the day of changeover of trainee doctors in England. It is widely perceived that inexperience and nonfamiliarity with the new hospital systems and policies in these first few weeks lead to increased medical errors, mismanagement, and mortality. The aim of this study was to analyze the impact of the August changeover of trainee doctors on inpatient glycemic control in a single English hospital. This is currently unknown in England. Overall, 16,870 patient-day capillary glucose reading measures in 2730 inpatients with diabetes were analyzed for 4 weeks before and after the changeover period for the years 2012, 2013, and 2014. Only inpatients hospitalized for longer than 1 day were included. Contrary to expectations, inpatient glycemic control did not worsen in the first 4 weeks after changeover compared to the preceding 4 weeks before changeover in the 3-year period. This may be due to forethought and planning by the deanery foundation school and the inpatient diabetes team in this hospital. PMID- 26505470 TI - Blood transfusion in acute and chronic pediatric settings: beliefs and practices. AB - BACKGROUND: Blood has been imbued with powerful connotations through history and across cultures. Currently bestowed with scientific meaning, blood nevertheless carries symbolic resonance. This study examines these representations among practitioners and sheds light on the clinical and nonclinical factors that guide blood transfusion (BT) decision-making in Quebec, Canada. STUDY DESIGN AND METHODS: With a qualitative exploratory study design, data were collected in the pediatric intensive care unit and the hematology-oncology unit of Sainte-Justine Hospital in 2009. A total of fifteen 1-hour-long semistructured interviews were conducted with physicians. RESULTS: Physicians affirm that the symbolic connotations of blood found in the lay population do not influence their transfusion decisions. However, there are other "social" and "cultural' aspects that influence these practices. Also, BT strategies remain diverse across units. Practitioners perceive these situations as resulting from insufficient training and by the existence of an "oral tradition" and a professional culture that are resistant to change. CONCLUSION: BT practices differ within and across units. Many dimensions intervene in the decision to transfuse, from individual clinical appreciation and local unit "culture" to formal and ad hoc training. Consistent change in BT can only occur with the implementation of norms and guidelines that are endorsed by key influential figures. An extensive multicentered study is necessary to better understand how social and cultural factors affect BT practices. This knowledge will sustain an enlightened clinical practice and lead to the recognition that peer practices are also embedded in professional cultures. PMID- 26505471 TI - Active versus passive humidification for self-ventilating tracheostomy and laryngectomy patients: a systematic review of the literature. AB - OBJECTIVE: To determine whether active or passive humidification methods are more effective in preventing pulmonary complications in self-ventilating neck breather patients. DESIGN: Systematic Review adhering to PRISMA guidance (checklist sourced from www.equator-network.org/). SETTING: Review of current published relevant literature at a tertiary department of Otolaryngology and Head & Neck Surgery. PARTICIPANTS: We included all separate studies and comparison studies of active and passive humidification techniques in adult and paediatric neck breather patients. MAIN OUTCOME MEASURES: The primary outcome is the reduction in pulmonary complications. Secondary outcomes include patient compliance; carer and user satisfaction. RESULTS AND CONCLUSIONS: Seven studies were included in this review: two RCTs (133 patients), one randomised controlled cross-over trial (29 patients), three randomised prospective studies (171 patients), and one retrospective study (73 patients). Only one study was conducted on paediatric neck breathers. The overall quality of the studies was low. Five studies were at a high risk of bias. Of the remaining two studies, one study had a low risk of bias and the other had an unclear risk. Despite limited subject evidence, results show that passive methods of humidification (mainly HME) is the preferred choice of humidification in the spontaneously breathing neck breather patients group mainly due to the reduction in pulmonary complaints, and better patient compliance. PMID- 26505472 TI - Motor Control of Landing from a Jump in Simulated Hypergravity. AB - On Earth, when landing from a counter-movement jump, muscles contract before touchdown to anticipate imminent collision with the ground and place the limbs in a proper position. This study assesses how the control of landing is modified when gravity is increased above 1 g. Hypergravity was simulated in two different ways: (1) by generating centrifugal forces during turns of an aircraft (A300) and (2) by pulling the subject downwards in the laboratory with a Subject Loading System (SLS). Eight subjects were asked to perform counter-movement jumps at 1 g on Earth and at 3 hypergravity levels (1.2, 1.4 and 1.6 g) both in A300 and with SLS. External forces applied to the body, movements of the lower limb segments and muscular activity of 6 lower limb muscles were recorded. Our results show that both in A300 and with SLS, as in 1 g: (1) the anticipation phase is present; (2) during the loading phase (from touchdown until the peak of vertical ground reaction force), lower limb muscles act like a stiff spring, whereas during the second part (from the peak of vertical ground reaction force until the return to the standing position), they act like a compliant spring associated with a damper. (3) With increasing gravity, the preparatory adjustments and the loading phase are modified whereas the second part does not change drastically. (4) The modifications are similar in A300 and with SLS, however the effect of hypergravity is accentuated in A300, probably due to altered sensory inputs. This observation suggests that otolithic information plays an important role in the control of the landing from a jump. PMID- 26505473 TI - Understanding Social Contagion in Adoption Processes Using Dynamic Social Networks. AB - There are many studies in the marketing and diffusion literature of the conditions in which social contagion affects adoption processes. Yet most of these studies assume that social interactions do not change over time, even though actors in social networks exhibit different likelihoods of being influenced across the diffusion period. Rooted in physics and epidemiology theories, this study proposes a Susceptible Infectious Susceptible (SIS) model to assess the role of social contagion in adoption processes, which takes changes in social dynamics over time into account. To study the adoption over a span of ten years, the authors used detailed data sets from a community of consumers and determined the importance of social contagion, as well as how the interplay of social and non-social influences from outside the community drives adoption processes. Although social contagion matters for diffusion, it is less relevant in shaping adoption when the study also includes social dynamics among members of the community. This finding is relevant for managers and entrepreneurs who trust in word-of-mouth marketing campaigns whose effect may be overestimated if marketers fail to acknowledge variations in social interactions. PMID- 26505474 TI - Modulation of Closed-State Inactivation in Kv2.1/Kv6.4 Heterotetramers as Mechanism for 4-AP Induced Potentiation. AB - The voltage-gated K+ (Kv) channel subunits Kv2.1 and Kv2.2 are expressed in almost every tissue. The diversity of Kv2 current is increased by interacting with the electrically silent Kv (KvS) subunits Kv5-Kv6 and Kv8-Kv9, into functional heterotetrameric Kv2/KvS channels. These Kv2/KvS channels possess unique biophysical properties and display a more tissue-specific expression pattern, making them more desirable pharmacological and therapeutic targets. However, little is known about the pharmacological properties of these heterotetrameric complexes. We demonstrate that Kv5.1, Kv8.1 and Kv9.3 currents were inhibited differently by the channel blocker 4-aminopyridine (4-AP) compared to Kv2.1 homotetramers. In contrast, Kv6.4 currents were potentiated by 4-AP while displaying moderately increased affinities for the channel pore blockers quinidine and flecainide. We found that the 4-AP induced potentiation of Kv6.4 currents was caused by modulation of the Kv6.4-mediated closed-state inactivation: suppression by 4-AP of the Kv2.1/Kv6.4 closed-state inactivation recovered a population of Kv2.1/Kv6.4 channels that was inactivated at resting conditions, i.e. at a holding potential of -80 mV. This modulation also resulted in a slower initiation and faster recovery from closed-state inactivation. Using chimeric substitutions between Kv6.4 and Kv9.3 subunits, we demonstrated that the lower half of the S6 domain (S6c) plays a crucial role in the 4-AP induced potentiation. These results demonstrate that KvS subunits modify the pharmacological response of Kv2 subunits when assembled in heterotetramers and illustrate the potential of KvS subunits to provide unique pharmacological properties to the heterotetramers, as is the case for 4-AP on Kv2.1/Kv6.4 channels. PMID- 26505475 TI - Anti-Neoplastic Cytotoxicity of SN-38-Loaded PCL/Gelatin Electrospun Composite Nanofiber Scaffolds against Human Glioblastoma Cells In Vitro. AB - Electrospun poly(epsilon-caprolactone) (PCL)/gelatin (GT) scaffolds were developed to provide controlled release of 7-ethyl-10-hydroxy camptothecin (SN 38). Acetic acid was introduced to improve the miscibility of PCL and GT to produce a homogeneous nanofiber membrane mixture. The effect of SN-38 content in binary mixtures on processability, fiber morphology, water sorption, swelling, and drug release was investigated. Electrospun PCL/GT blend nonwoven fibers showed fiber surface roughness, decreased PCL crystallinity, and increased swelling with increasing drug content of 1, 2, and 4 wt %. Additionally, increasing the SN-38 concentration reduced the degradation rate of the GT. Furthermore, we hypothesize the existence of a drug content saturation point in the monoaxial fiber to explain the different drug release patterns of PG2 compared with those of PG1 and PG4. The matrix also showed good biodegradation and anti-tumor function. Our results demonstrate that SN-38-loaded PCL/GT fibers can be obtained by electrospinning. The SN-38-loaded fibers merit further evaluation as a means to potentially prevent locoregional recurrence following surgical tumor resection. PMID- 26505476 TI - Atlantic Bluefin Tuna (Thunnus thynnus) Biometrics and Condition. AB - The compiled data for this study represents the first Atlantic and Mediterranean wide effort to pool all available biometric data for Atlantic bluefin tuna (Thunnus thynnus) with the collaboration of many countries and scientific groups. Biometric relationships were based on an extensive sampling (over 140,000 fish sampled), covering most of the fishing areas for this species in the North Atlantic Ocean and Mediterranean Sea. Sensitivity analyses were carried out to evaluate the representativeness of sampling and explore the most adequate procedure to fit the weight-length relationship (WLR). The selected model for the WLRs by stock included standardized data series (common measurement types) weighted by the inverse variability. There was little difference between annual stock-specific round weight-straight fork length relationships, with an overall difference of 6% in weight. The predicted weight by month was estimated as an additional component in the exponent of the weight-length function. The analyses of monthly variations of fish condition by stock, maturity state and geographic area reflect annual cycles of spawning and feeding behavior. We update and improve upon the biometric relationships for bluefin currently used by the International Commission for the Conservation of Atlantic Tunas, by incorporating substantially larger datasets than ever previously compiled, providing complete documentation of sources and employing robust statistical fitting. WLRs and other conversion factors estimated in this study differ from the ones used in previous bluefin stock assessments. PMID- 26505477 TI - A Network Approach to Bipolar Symptomatology in Patients with Different Course Types. AB - OBJECTIVE: The longitudinal mood course is highly variable among patients with bipolar disorder(BD). One of the strongest predictors of the future disease course is the past disease course, implying that the vulnerability for developing a specific pattern of symptoms is rather consistent over time. We therefore investigated whether BD patients with different longitudinal course types have symptom correlation networks with typical characteristics. To this end we used network analysis, a rather novel approach in the field of psychiatry. METHOD: Based on two-year monthly life charts, 125 patients with complete 2 year data were categorized into three groups: i.e., a minimally impaired (n = 47), a predominantly depressed (n = 42) and a cycling course (n = 36). Associations between symptoms were defined as the groupwise Spearman's rank correlation coefficient between each pair of items of the Young Mania Rating Scale (YMRS) and the Quick Inventory of Depressive Symptomatology (QIDS). Weighted symptom networks and centrality measures were compared among the three groups. RESULTS: The weighted networks significantly differed among the three groups, with manic and depressed symptoms being most strongly interconnected in the cycling group. The symptoms with top centrality that were most interconnected also differed among the course group; central symptoms in the stable group were elevated mood and increased speech, in the depressed group loss of self-esteem and psychomotor slowness, and in the cycling group concentration loss and suicidality. CONCLUSION: Symptom networks based on the timepoints with most severe symptoms of bipolar patients with different longitudinal course types are significantly different. The clinical interpretation of this finding and its implications are discussed. PMID- 26505479 TI - Computational Methods for Exploration and Analysis of Macromolecular Structure and Dynamics. PMID- 26505478 TI - Interleukin-17A and Toll-Like Receptor 3 Ligand Poly(I:C) Synergistically Induced Neutrophil Chemoattractant Production by Bronchial Epithelial Cells. AB - Chronic inflammatory airway diseases, such as bronchial asthma and chronic obstructive pulmonary disease, are common respiratory disorders worldwide. Exacerbations of these diseases are frequent and worsen patients' respiratory condition and overall health. However, the mechanisms of exacerbation have not been fully elucidated. Recently, it was reported that interleukin (IL)-17A might play an important role in neutrophilic inflammation, which is characteristic of such exacerbations, through increased production of neutrophil chemoattractants. Therefore, we hypothesized that IL-17A was involved in the pathogenesis of acute exacerbation, due to viral infection in chronic inflammatory airway diseases. In this study, we assessed chemokine production by bronchial epithelial cells and investigated the underlying mechanisms. Comprehensive chemokine analysis showed that, compared with poly(I:C) alone, co-stimulation of BEAS-2B cells with IL-17A and poly(I:C) strongly induced production of such neutrophil chemoattractants as CXC chemokine ligand (CXCL)8, growth-related oncogene (GRO), and CXCL1. Co stimulation synergistically induced CXCL8 and CXCL1 mRNA and protein production by BEAS-2B cells and normal human bronchial epithelial cells. Poly(I:C) induced chemokine expression by BEAS-2B cells mainly via Toll-like receptor 3/TIR-domain containing adapter-inducing interferon-beta-mediated signals. The co-stimulation with IL-17A and poly(I:C) markedly activated the p38 and extracellular-signal regulated kinase 1/2 pathway, compared with poly(I:C), although there was little change in nuclear factor-kappaB translocation into the nucleus or the transcriptional activities of nuclear factor-kappaB and activator protein 1. IL 17A promoted stabilization of CXCL8 mRNA in BEAS-2B cells treated with poly(I:C). In conclusion, IL-17A appears to be involved in the pathogenesis of chronic inflammatory airway disease exacerbation, due to viral infection by promoting release of neutrophil chemoattractants from bronchial epithelial cells. PMID- 26505480 TI - Multiscale Estimation of Binding Kinetics Using Brownian Dynamics, Molecular Dynamics and Milestoning. AB - The kinetic rate constants of binding were estimated for four biochemically relevant molecular systems by a method that uses milestoning theory to combine Brownian dynamics simulations with more detailed molecular dynamics simulations. The rate constants found using this method agreed well with experimentally and theoretically obtained values. We predicted the association rate of a small charged molecule toward both a charged and an uncharged spherical receptor and verified the estimated value with Smoluchowski theory. We also calculated the kon rate constant for superoxide dismutase with its natural substrate, O2-, in a validation of a previous experiment using similar methods but with a number of important improvements. We also calculated the kon for a new system: the N terminal domain of Troponin C with its natural substrate Ca2+. The kon calculated for the latter two systems closely resemble experimentally obtained values. This novel multiscale approach is computationally cheaper and more parallelizable when compared to other methods of similar accuracy. We anticipate that this methodology will be useful for predicting kinetic rate constants and for understanding the process of binding between a small molecule and a protein receptor. PMID- 26505481 TI - Investigation of Bovine Serum Albumin (BSA) Attachment onto Self-Assembled Monolayers (SAMs) Using Combinatorial Quartz Crystal Microbalance with Dissipation (QCM-D) and Spectroscopic Ellipsometry (SE). AB - Understanding protein adsorption kinetics to surfaces is of importance for various environmental and biomedical applications. Adsorption of bovine serum albumin to various self-assembled monolayer surfaces including neutral and charged hydrophilic and hydrophobic surfaces was investigated using in-situ combinatorial quartz crystal microbalance with dissipation and spectroscopic ellipsometry. Adsorption of bovine serum albumin varied as a function of surface properties, bovine serum albumin concentration and pH value. Charged surfaces exhibited a greater quantity of bovine serum albumin adsorption, a larger bovine serum albumin layer thickness, and increased density of bovine serum albumin protein compared to neutral surfaces at neutral pH value. The quantity of adsorbed bovine serum albumin protein increased with increasing bovine serum albumin concentration. After equilibrium sorption was reached at pH 7.0, desorption of bovine serum albumin occurred when pH was lowered to 2.0, which is below the isoelectric point of bovine serum albumin. Our data provide further evidence that combinatorial quartz crystal microbalance with dissipation and spectroscopic ellipsometry is a sensitive analytical tool to evaluate attachment and detachment of adsorbed proteins in systems with environmental implications. PMID- 26505483 TI - Another look at the informed consent process: The document and the conversation. PMID- 26505482 TI - Identification of Genes Related to Growth and Lipid Deposition from Transcriptome Profiles of Pig Muscle Tissue. AB - Transcriptome profiles established using high-throughput sequencing can be effectively used for screening genome-wide differentially expressed genes (DEGs). RNA sequences (from RNA-seq) and microRNA sequences (from miRNA-seq) from the tissues of longissimus dorsi muscle of two indigenous Chinese pig breeds (Diannan Small-ear pig [DSP] and Tibetan pig [TP]) and two introduced pig breeds (Landrace [LL] and Yorkshire [YY]) were examined using HiSeq 2000 to identify and compare the differential expression of functional genes related to muscle growth and lipid deposition. We obtained 27.18 G clean data through the RNA-seq and detected that 18,208 genes were positively expressed and 14,633 of them were co-expressed in the muscle tissues of the four samples. In all, 315 DEGs were found between the Chinese pig group and the introduced pig group, 240 of which were enriched with functional annotations from the David database and significantly enriched in 27 Gene Ontology (GO) terms that were mainly associated with muscle fiber contraction, cadmium ion binding, response to organic substance and contractile fiber part. Based on functional annotation, we identified 85 DEGs related to growth traits that were mainly involved in muscle tissue development, muscle system process, regulation of cell development, and growth factor binding, and 27 DEGs related to lipid deposition that were mainly involved in lipid metabolic process and fatty acid biosynthetic process. With miRNA-seq, we obtained 23.78 M reads and 320 positively expressed miRNAs from muscle tissues, including 271 known pig miRNAs and 49 novel miRNAs. In those 271 known miRNAs, 20 were higher and 10 lower expressed in DSP-TP than in LL-YY. The target genes of the 30 miRNAs were mainly participated in MAPK, GnRH, insulin and Calcium signaling pathway and others involved cell development, growth and proliferation, etc. Combining the DEGs and the differentially expressed (DE) miRNAs, we drafted a network of 46 genes and 18 miRNAs for regulating muscle growth and a network of 15 genes and 16 miRNAs for regulating lipid deposition. We identified that CAV2, MYOZ2, FRZB, miR 29b, miR-122, miR-145-5p and miR-let-7c, etc, were key genes or miRNAs regulating muscle growth, and FASN, SCD, ADORA1, miR-4332, miR-182, miR-92b-3p, miR-let-7a and miR-let-7e, etc, were key genes or miRNAs regulating lipid deposition. The quantitative expressions of eight DEGs and seven DE miRNAs measured with real time PCR certified that the results of differential expression genes or miRNAs were reliable. Thus, 18,208 genes and 320 miRNAs were positively expressed in porcine longissimus dorsi muscle. We obtained 85 genes and 18 miRNAs related to muscle growth and 27 genes and 16 miRNAs related to lipid deposition, which provided new insights into molecular mechanism of the economical traits in pig. PMID- 26505485 TI - Streptococcus suis Meningitis: A Systematic Review and Meta-analysis. AB - BACKGROUND: Streptococcus suis is the most common cause of meningitis in pork consuming and pig rearing countries in South-East Asia. We performed a systematic review of studies on S. suis meningitis to define the clinical characteristics, predisposing factors and outcome. METHODOLOGY: Studies published between January 1, 1980 and August 1, 2015 were identified from main literature databases and reference lists. Studies were included if they were written in West-European languages and described at least 5 adult patients with S. suis meningitis in whom at least one clinical characteristic was described. FINDINGS: We identified 913 patients with S. suis meningitis included in 24 studies between 1980 and 2015. The mean age was 49 years and 581 of 711 patients were male (82%). Exposure to pigs or pork was present in 395 of 648 patients (61%) while other predisposing factors were less common. 514 of 528 patients presented with fever (97%), 429 of 451 with headache (95%), 462 of 496 with neck stiffness (93%) and 78 of 384 patients (20%) had a skin injury in the presence of pig/pork contact. The case fatality rate was 2.9% and hearing loss was a common sequel occurring in 259 of 489 patients (53%). Treatment included dexamethasone in 157 of 300 (52%) of patients and was associated with reduced hearing loss in S. suis meningitis patients included in a randomized controlled trial. CONCLUSION: S. suis meningitis has a clear association with pig and pork contact. Mortality is low, but hearing loss occurs frequently. Dexamethasone was shown to reduce hearing loss. PMID- 26505484 TI - De Novo Assembly and Genome Analyses of the Marine-Derived Scopulariopsis brevicaulis Strain LF580 Unravels Life-Style Traits and Anticancerous Scopularide Biosynthetic Gene Cluster. AB - The marine-derived Scopulariopsis brevicaulis strain LF580 produces scopularides A and B, which have anticancerous properties. We carried out genome sequencing using three next-generation DNA sequencing methods. De novo hybrid assembly yielded 621 scaffolds with a total size of 32.2 Mb and 16298 putative gene models. We identified a large non-ribosomal peptide synthetase gene (nrps1) and supporting pks2 gene in the same biosynthetic gene cluster. This cluster and the genes within the cluster are functionally active as confirmed by RNA-Seq. Characterization of carbohydrate-active enzymes and major facilitator superfamily (MFS)-type transporters lead to postulate S. brevicaulis originated from a soil fungus, which came into contact with the marine sponge Tethya aurantium. This marine sponge seems to provide shelter to this fungus and micro-environment suitable for its survival in the ocean. This study also builds the platform for further investigations of the role of life-style and secondary metabolites from S. brevicaulis. PMID- 26505487 TI - Vapor Pressure of Hexamethylene Triperoxide Diamine (HMTD) Estimated Using Secondary Electrospray Ionization Mass Spectrometry. AB - A rapid method for vapor pressure measurement was developed and used to derive the vapor pressure curve of the thermally labile peroxide-based explosive hexamethylene triperoxide diamine (HMTD) over the temperature range from 28 to 80 degrees C. This method uses a controlled flow of vapor from a solid-phase HMTD source that is presented to an ambient-pressure-ionization mass spectrometer equipped with a secondary-electrospray-ionization (SESI) source. The subpart-per trillion sensitivity of this system enables direct detection of HMTD vapor through an intact [M + H](+) ion in real time at temperatures near 20 degrees C. By calibrating this method using vapor sources of cocaine and heroin, which have known pressure-temperature (P-T) curves, the temperature dependence of HMTD vapor was determined, and a Clausius-Clapeyron plot of ln[P (Pa)] vs 1/[T (K)] yielded a straight line with the expression ln[P (Pa)] = {(-11091 +/- 356) * 1/[T (K)]} + 25 +/- 1 (error limits are the standard error of the regression analysis). From this equation, the sublimation enthalpy of HMTD was estimated to be 92 +/- 3 kJ/mol, which compares well with the theoretical estimate of 95 kJ/mol, and the vapor pressure at 20 degrees C was estimated to be ~60 parts per trillion by volume, which is within a factor of 2 of previous theoretical estimates. Thus, this method provides not only the first direct experimental determination of HMTD vapor pressure but also a rapid, near-real-time capability to quantitatively measure low-vapor-pressure compounds, which will be useful for aiding in the development of training aids for bomb-sniffing canines. PMID- 26505486 TI - Hodgkin lymphoma: MOPP chemotherapy to PD-1 blockade and beyond. AB - Hodgkin lymphoma is a rare lymphoid malignancy affecting ~9,200 new patients in the United States annually. Progress in the management of this disease over the past 50 years has been remarkable and the prognosis of this malignancy has changed from a uniformly fatal process to one in which the vast majority of patients are expected to be cured. This remarkable progress has been due to the use of combination approaches incorporating chemotherapy and radiation therapy, and now more recently antibody-drug conjugates and immune checkpoint inhibitors. The goal for the future is to develop treatment combinations that successfully treat all patients and markedly decrease the long-term side effects. PMID- 26505488 TI - Fracture Resistance of Lithium Disilicate Ceramics Bonded to Enamel or Dentin Using Different Resin Cement Types and Film Thicknesses. AB - PURPOSE: To investigate the influence of cement film thickness, cement type, and substrate (enamel or dentin) on ceramic fracture resistance. MATERIALS AND METHODS: One hundred extracted human third molars were polished to obtain 50 enamel and 50 dentin specimens. The specimens were cemented to 1-mm-thick lithium disilicate ceramic plates with different cement film thicknesses (100 and 300 MUm) using metal strips as spacers. The cements used were etch-and-rinse (RelyX Ultimate) and self-adhesive (RelyX U200) resin cements. Compressive load was applied on the ceramic plates using a universal testing machine, and fracture loads were recorded in Newtons (N). Statistical analysis was performed by multiple regression (p < 0.05). Representative specimens were evaluated by scanning electron microscopy to control the cement film thickness. RESULTS: The RelyX Ultimate group with a cement thickness of 100 MUm cemented to enamel showed the highest mean fracture load (MFL; 1591 +/- 172.59 N). The RelyX Ultimate groups MFLs were significantly higher than the corresponding RelyX U200 groups (p < 0.05), and thinner film cement demonstrated a higher MFL than thicker films (p < 0.05). Bonding to dentin resulted in lower MFL than with enamel (p < 0.001). CONCLUSIONS: Higher fracture loads were related to thinner cement film thickness and RelyX Ultimate resin cement. Bonding to dentin resulted in lower fracture loads than bonding to enamel. CLINICAL SIGNIFICANCE: Reduced resin film thickness could reduce lithium disilicate restoration fracture. Etch-and-rinse resin cements are recommended for cementing on either enamel or dentin, compared with self-adhesive resin cement, for improved fracture resistance. PMID- 26505489 TI - Two-generational effects of contaminants in Daphnia magna: Effects of offspring quality. AB - The authors set up a protocol to perform a 2-generational ring test using the existing guidelines for the Daphnia magna reproduction test. It is well known in ecology that size and quality of offspring vary across the first clutches in D. magna and that certain chemicals affect offspring quality. Therefore, the origin of the second generation is an important factor to consider. Two-generational effects across first, second, and third clutches were evaluated using 4 nonylphenol; those across first and third clutches were evaluated using tributyltin, and those across the third clutch were evaluated using piperonyl butoxide. The compound showing the greatest aggravation of toxic effects between the parental and second generations was piperonyl butoxide, followed by 4 nonylphenol, whereas intergenerational effects of tributyltin varied across experiments. The studied chemicals affected the quantity and quality of the offspring produced by exposed females of the parental generation, those effects being greater in third-clutch neonates. Therefore, when third-clutch offspring were further exposed, they turned out to be more sensitive than the parental generation. The results are in line with those obtained in multigenerational studies using mammalian tests, which showed that, in many cases, effects on the second generation can be predicted by evaluating the quality of the offspring produced. Environ Toxicol Chem 2016;35:1470-1477. (c) 2015 SETAC. PMID- 26505490 TI - Second Malignant Neoplasms in Rhabdomyosarcoma: Victims of Our Own Success or an Underlying Genetic Predisposition Syndrome? PMID- 26505491 TI - Evaluation of a Flow-Cytometric Osmotic Fragility Test for Hereditary Spherocytosis in Chinese Patients. AB - BACKGROUND: Osmotic fragility testing based on flow cytometry was recently introduced for the screening of hereditary spherocytosis (HS). This study was undertaken to evaluate the clinical diagnostic value of a flow-cytometric osmotic fragility test for HS. METHODS: Peripheral blood was collected from 237 subjects at the First Affiliated Hospital of Guangxi Medical University, including 56 HS patients, 86 thalassemia patients and 95 healthy controls. The samples were examined by flow-cytometric osmotic fragility test and the percentage of residual red blood cells was used to determine HS. Peripheral blood smears were performed to examine the red blood cell morphology. RESULTS: With clinical diagnosis of HS as the gold standard and the percentage of residual red blood cells <23.6% as the diagnostic threshold in the flow-cytometric osmotic fragility test, the sensitivity of the flow-cytometric osmotic fragility test for HS was 85.71% and the specificity was 97.24%. CONCLUSION: The flow-cytometric osmotic fragility test combined with a red blood cell morphology test by peripheral blood smear could be a simple, practical and accurate laboratory screening method for HS. PMID- 26505493 TI - Femtosecond Heterodyne Transient-Grating Studies of Nonradiative Decay of the S2 (1(1)Bu(+)) State of beta-Carotene: Contributions from Dark Intermediates and Double-Quantum Coherences. AB - Femtosecond transient-grating spectroscopy with heterodyne detection was employed to characterize the nonradiative decay pathway in beta-carotene from the S2 (1(1)Bu(+)) state to the S1 (2(1)Ag(-)) state in benzonitrile solution. The results indicate definitively that the S2 state populates an intermediate state, Sx, on an ultrafast time scale prior to nonradiative decay to the S1 state. Numerical simulations using the response function formalism and the multimode Brownian oscillator model were used to fit the absorption and dispersion components of the transient-grating signal with a common set of parameters for all of the relevant Feynman pathways, including double-quantum coherences. The requirement for inclusion of the Sx state in the nonradiative decay pathway is the observed fast rise time of the dispersion component, which is predominantly controlled by the decay of the stimulated emission signal from the optically prepared S2 state. The finding that the excited-state absorption spectrum from the Sx state is significantly red-shifted from that of S2 and S1 leads to a new assignment for the spectroscopic origin of the Sx state. Rather than assigning Sx to a discrete electronic state, such as the (1)Bu(-) state suggested in previous work, it is proposed that the Sx state corresponds to a transition-state-like structure on the S2 potential surface. In this hypothesis, the 12 fs time constant for the decay of the S2 state corresponds to a vibrational displacement of the C-C and C?C bond-length alternation coordinates of the conjugated polyene backbone from the optically prepared Franck-Condon structure to a potential energy barrier on the S2 surface that divides planar and torsionally displaced structures. The lifetime of the Sx state would be associated with a subsequent relaxation along torsional coordinates over a steep potential energy gradient toward a conical intersection with the S1 state. This hypothesis leads to the idea that twisted structures with intramolecular charge-transfer character along the S2 torsional gradient are active in excitation energy-transfer mechanisms to (bacterio)chlorophyll acceptors. PMID- 26505496 TI - Air Quality Control Activities Proceed with Resolve. PMID- 26505495 TI - Environmental field is fragmented, yet cohesive. PMID- 26505494 TI - Differential Regulation of Telomerase Reverse Transcriptase Promoter Activation and Protein Degradation by Histone Deacetylase Inhibition. AB - Telomerase reverse transcriptase (TERT) maintains telomeres and is rate limiting for replicative life span. While most somatic tissues silence TERT transcription resulting in telomere shortening, cells derived from cancer or cardiovascular diseases express TERT and activate telomerase. In the present study, we demonstrate that histone deacetylase (HDAC) inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Finally, we demonstrate that HDAC inhibition decreases TERT expression during vascular remodeling in vivo. These data illustrate a differential regulation of TERT transcription and protein stability by HDAC inhibition and suggest that TERT may constitute an important target for the anti-proliferative efficacy of HDAC inhibitors. PMID- 26505498 TI - Fly Ash Can Be Used to Control Mine Fires. PMID- 26505497 TI - Late Approval for Environmental Measures. PMID- 26505499 TI - Air Pollution Control Equipment Backlog: $103 Million. PMID- 26505500 TI - New Machine Cleans Streams for Salmon Spawning. PMID- 26505501 TI - Activated Carbon Reuse: A Tertiary Treatment Must. PMID- 26505502 TI - Coal-Fired Plants Not Doomed by Pollution Threats. PMID- 26505503 TI - Ocean Habitation Program Begins Third Phase. PMID- 26505504 TI - Behavioral Toxicology Looks at Air Pollutants. PMID- 26505505 TI - Middleton talks about..... PMID- 26505506 TI - Fair Winds Blow for Oceanographic Decade Proposal. PMID- 26505507 TI - Rationale for Air Quality Criteria. PMID- 26505508 TI - Advanced Waste Treatment Plant Running Well. PMID- 26505509 TI - Status of Environmental Quality Legislative Measures. PMID- 26505510 TI - A Management Perspective at Federal Water Pollution Control Administration. PMID- 26505511 TI - Use of Alumina-Coated Filaments in Catalytic Mufflers Testing with Single Cylinder Engine. PMID- 26505512 TI - An Integrated Monitoring System for Water Quality Management in the Ohio Valley. PMID- 26505513 TI - Biodegradation of Linear Alkylated Sulfonates. PMID- 26505514 TI - Biodehalogenation. Reductive Dehalogenation of the Biocides Ethylene Dibromide, 1,2-Dibromo-3-chloropropane, and 2,3-Dibromobutane in Soil. PMID- 26505515 TI - Surface Effects in Gas Absorption. PMID- 26505516 TI - Use of Alumina-Coated Filaments in Catalytic Mufflers Testing with Multicylinder Engine and Vehicles. PMID- 26505517 TI - Evaluation of Quartz in Airborne Dust in the 0.5- to 2-Micron Size Range. PMID- 26505518 TI - Correction to "Effects of Acute Hydrogen Fluoride and Nitrogen Dioxide Exposures on Citrus and Ornamental Plants of Central Florida". PMID- 26505519 TI - 1968-1969 Pollution Control Directory. PMID- 26505520 TI - Supramolecular Assemblies from Poly(phenylacetylene)s. PMID- 26505521 TI - Molecular Dynamics Study of Carbon Nanotubes/Polyamide Reverse Osmosis Membranes: Polymerization, Structure, and Hydration. AB - Carbon nanotubes/polyamide (PA) nanocomposite thin films have become very attractive as reverse osmosis (RO) membranes. In this work, we used molecular dynamics to simulate the influence of single walled carbon nanotubes (SWCNTs) in the polyamide molecular structure as a model case of a carbon nanotubes/polyamide nanocomposite RO membrane. It was found that the addition of SWCNTs decreases the pore size of the composite membrane and increases the Na and Cl ion rejection. Analysis of the radial distribution function of water confined in the pores of the membranes shows that SWCNT+PA nanocomposite membranes also exhibit smaller clusters of water molecules within the membrane, thus suggesting a dense membrane structure (SWCNT+PA composite membranes were 3.9% denser than bare PA). The results provide new insights into the fabrication of novel membranes reinforced with tubular structures for enhanced desalination performance. PMID- 26505522 TI - Voices of Women Facing HIV-Related Stigma in the Deep South. AB - One in 139 women will be diagnosed with HIV in their lifetime. Thirty-four years into the epidemic, stigma remains part of the trajectory of the disease process for all individuals with HIV. Stigma associated with HIV makes it difficult for women to access HIV testing and counseling, disclose HIV status to sexual partners and health care providers, seek and remain actively engaged in medical care, effectively self-manage the disease after diagnosis, and adhere to antiretroviral therapy. The current article reports the qualitative results from a study designed to test the feasibility and acceptability of a technologically delivered stigma intervention for women with HIV in the Southeastern United States. Qualitative analysis revealed women with HIV uniformly experience, anticipate, and/or internalize stigma associated with HIV. Consequently, women with HIV experience isolation and a threat to self-concept as they make decisions about disclosure, work to maintain the secrecy of their HIV status, and contemplate a future. PMID- 26505523 TI - Motivational Interviewing Approach Used by a Community Mental Health Team. AB - The current study aimed to (a) evaluate the effectiveness of motivational interviewing, as applied by a community mental health team (CMHT) based in Singapore; (b) reduce hospital admissions and length of hospital stay; and (c) improve global functioning and satisfaction of individuals with mental illness. The current study used a quasi-experimental method. A convenience sample of 120 participants was selected from the caseload of the CMHT. Participants received motivational interviewing sessions at least once every month for 1 year. Data on the number of hospital admissions, length of hospitalization, Global Assessment of Functioning, and patient satisfaction were collected at baseline and 6 and 12 months. Participants who underwent the CMHT services with motivational interviewing were more compliant to treatment, resulting in significant reduction in hospitalization and improvement in functionality. Motivational interviewing is effective in facilitating better illness management for patients in the community. Adoption of the motivational interviewing approach may potentially provide significant benefits for psychiatric support services in the community. PMID- 26505524 TI - Decreasing Psychiatric Admission Wait Time in the Emergency Department by Facilitating Psychiatric Discharges. AB - Limited capacity in a psychiatric unit contributes to long emergency department (ED) admission wait times. Regulatory and accrediting agencies urge hospitals nationally to improve patient flow for better access to care for all types of patients. The purpose of the current study was to decrease psychiatric admission wait time from 10.5 to 8 hours and increase the proportion of patients discharged by 11 a.m. from 20% to 50%. The current study compared pre- and post-intervention data. Plan-Do-Study-Act cycles aimed to improve discharge processes and timeliness through initiation of new practices. Admission wait time improved to an average of 5.1 hours (t = 3.87, p = 0.006). The proportion of discharges occurring by 11 a.m. increased to 46% (odds ratio = 3.42, p < 0.0001). Improving discharge planning processes and timeliness in a psychiatric unit significantly decreased admission wait time from the ED, improving access to psychiatric care. PMID- 26505526 TI - Low Resolution Data-Independent Acquisition in an LTQ-Orbitrap Allows for Simplified and Fully Untargeted Analysis of Histone Modifications. AB - Label-free peptide quantification in liquid chromatography-mass spectrometry (LC MS) proteomics analyses is complicated by the presence of isobaric coeluting peptides, as they generate the same extracted ion chromatogram corresponding to the sum of their intensities. Histone proteins are especially prone to this, as they are heavily modified by post-translational modifications (PTMs). Their proteolytic digestion leads to a large number of peptides sharing the same mass, while carrying PTMs on different amino acid residues. We present an application of MS data-independent acquisition (DIA) to confidently determine and quantify modified histone peptides. By introducing the use of low-resolution MS/MS DIA, we demonstrate that the signals of 111 histone peptides could easily be extracted from LC-MS runs due to the relatively low sample complexity. By exploiting an LTQ Orbitrap mass spectrometer, we parallelized MS and MS/MS scan events using the Orbitrap and the linear ion trap, respectively, decreasing the total scan time. This, in combination with large windows for MS/MS fragmentation (50 m/z) and multiple full scan events within a DIA duty cycle, led to a MS scan cycle speed of ~45 full MS per minute, improving the definition of extracted LC-MS chromatogram profiles. By using such acquisition method, we achieved highly comparable results to our optimized acquisition method for histone peptide analysis (R(2) correlation > 0.98), which combines data-dependent acquisition (DDA) and targeted MS/MS scans, the latter targeting isobaric peptides. By using DIA, we could also remine our data set and quantify 16 additional isobaric peptides commonly not targeted during DDA experiments. Finally, we demonstrated that by performing the full MS scan in the linear ion trap, we achieve highly comparable results as when adopting high-resolution MS scans (R(2) correlation 0.97). Taken together, results confirmed that histone peptide analysis can be performed using DIA and low-resolution MS with high accuracy and precision of peptide quantification. Moreover, DIA intrinsically enables data remining to later identify and quantify isobaric peptides unknown at the time of the LC-MS experiment. These methods will open up epigenetics analyses to the proteomics community who do not have routine access to the newer generation high-resolution MS/MS generating instruments. PMID- 26505525 TI - Synthesis and Preliminary PET Imaging Studies of a FAAH Radiotracer ([11C]MPPO) Based on alpha-Ketoheterocyclic Scaffold. AB - Fatty acid amide hydrolase (FAAH) is one of the principle enzymes for metabolizing endogenous cannabinoid neurotransmitters such as anandamide, and thus regulates endocannabinoid (eCB) signaling. Selective pharmacological blockade of FAAH has emerged as a potential therapy to discern the endogenous functions of anandamide-mediated eCB pathways in anxiety, pain, and addiction. Quantification of FAAH in the living brain by positron emission tomography (PET) would help our understanding of the endocannabinoid system in these conditions. While most FAAH radiotracers operate by an irreversible ("suicide") binding mechanism, a FAAH tracer with reversibility would facilitate quantitative analysis. We have identified and radiolabeled a reversible FAAH inhibitor, 7-(2 [(11)C]methoxyphenyl)-1-(5-(pyridin-2-yl)oxazol-2-yl)heptan-1-one ([(11)C]MPPO) in 13% radiochemical yield (nondecay corrected) with >99% radiochemical purity and 2 Ci/MUmol (74 GBq/MUmol) specific activity. The tracer showed moderate brain uptake (0.8 SUV) with heterogeneous brain distribution. However, blocking studies with a potent FAAH inhibitor URB597 demonstrated a low to modest specificity to the target. Measurement of lipophilicity, metabolite, and efflux pathway analysis were also performed to study the pharmacokinetic profile of [(11)C]MPPO. In all, we reported an efficient radiolabeling and preliminary evaluation of the first-in class FAAH inhibitor [(11)C]MPPO with alpha-ketoheterocyclic scaffold. PMID- 26505528 TI - Multicolor-based discrimination of 21 short tandem repeats and amelogenin using four fluorescent universal primers. AB - The aim of this study was to develop a cost-effective genotyping method using high-quality DNA for human identification. A total of 21 short tandem repeats (STRs) and amelogenin were selected, and fluorescent fragments at 22 loci were simultaneously amplified in a single-tube reaction using locus-specific primers with 24-base universal tails and four fluorescent universal primers. Several nucleotide substitutions in universal tails and fluorescent universal primers enabled the detection of specific fluorescent fragments from the 22 loci. Multiplex polymerase chain reaction (PCR) produced intense FAM-, VIC-, NED-, and PET-labeled fragments ranging from 90 to 400 bp, and these fragments were discriminated using standard capillary electrophoretic analysis. The selected 22 loci were also analyzed using two commercial kits (the AmpFLSTR Identifiler Kit and the PowerPlex ESX 17 System), and results for two loci (D19S433 and D16S539) were discordant between these kits due to mutations at the primer binding sites. All genotypes from the 100 samples were determined using 2.5 ng of DNA by our method, and the expected alleles were completely recovered. Multiplex 22-locus genotyping using four fluorescent universal primers effectively reduces the costs to less than 20% of genotyping using commercial kits, and our method would be useful to detect silent alleles from commercial kit analysis. PMID- 26505527 TI - Sulfobetaine-Vinylimidazole Block Copolymers: A Robust Quantum Dot Surface Chemistry Expanding Bioimaging's Horizons. AB - Long-term inspection of biological phenomena requires probes of elevated intra- and extracellular stability and target biospecificity. The high fluorescence and photostability of quantum dot (QD) nanoparticles contributed to foster their promise as bioimaging tools that could overcome limitations associated with traditional fluorophores. However, QDs' potential as a bioimaging platform relies upon a precise control over the surface chemistry modifications of these nano objects. Here, a zwitterion-vinylimidazole block copolymer ligand was synthesized, which regroups all anchoring groups in one compact terminal block, while the rest of the chain is endowed with antifouling and bioconjugation moieties. By further application of an oriented bioconjugation approach with whole IgG antibodies, QD nanobioconjugates were obtained that display outstanding intra- and extracellular stability as well as biorecognition capacity. Imaging the internalization and intracellular dynamics of a transmembrane cell receptor, the CB1 brain cannabinoid receptor, both in HEK293 cells and in neurons, illustrates the breadth of potential applications of these nanoprobes. PMID- 26505529 TI - Drug Interactions Between Hepatoprotective Agents Ursodeoxycholic Acid or Glycyrrhizin and Ombitasvir/Paritaprevir/Ritonavir in Healthy Japanese Subjects. AB - PURPOSE: The 2 direct-acting antiviral combination (2D) of ombitasvir and paritaprevir (coadministered with ritonavir) is being evaluated for the treatment of chronic hepatitis C virus infection in Japan. Ursodeoxycholic acid (UDCA) and glycyrrhizin (GCR) are hepatoprotective agents widely used in Japan. A drug-drug interaction (DDI) study was conducted to guide dosing recommendations for UDCA and GCR when coadministered with the 2D regimen. METHODS: DDIs between the 2D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg orally once daily) and UDCA (50 mg orally 3 times daily) or GCR (80 mg intravenously once daily) were evaluated in a 2-arm, multiple-dose study in 24 Japanese healthy subjects under fed conditions. Pharmacokinetic and safety evaluations were performed when UDCA or GCR and the 2D regimen were administered alone and during coadministration. Exposures from coadministration of the 2D regimen plus UDCA or GCR versus the 2D regimen, UDCA, or GCR alone were compared using repeated-measures analyses of natural logarithms of the maximum plasma concentration (Cmax) and area under the curve (AUC). FINDINGS: After coadministration of the 2D regimen and UDCA, steady state exposures (Cmax and AUC) of ombitasvir, paritaprevir, and ritonavir showed a <=9% change, and UDCA exposures showed a <=20% change compared with administration alone. When the 2D regimen and GCR were coadministered, steady state exposures of ombitasvir, paritaprevir, and ritonavir were not affected (<=9% change), GCR AUC increased by 49%, and GCR Cmax was unaffected (<1% change). IMPLICATIONS: No dose adjustment is needed for UDCA, GCR, or the 2D regimen when UDCA or GCR is coadministered with the 2D regimen in hepatitis C virus-infected patients under fed conditions. Clinical monitoring of patients using GCR is recommended due to an approximately 50% increase in GCR AUC when coadministered with the 2D regimen. PMID- 26505530 TI - Tensile behaviour of structurally gradient braided prostheses for anterior cruciate ligaments. AB - Anterior cruciate ligament (ACL) is a key fibrous connective tissue that maintains the stability of a knee joint and it is the most commonly injured ligament of the knee. A synthetic prosthesis in the form of a braided structure can be an attractive alternative to biological grafts provided that the mechanical properties can be tailored to mimic the natural ACL. In the present work, the polypropylene based structurally gradient braided prostheses have been designed and developed by understanding their tensile properties. Circular braiding process was employed to fabricate structurally gradient braided prostheses by systematically placing different types of braids in defined set of layers. An analytical model for predicting the tensile properties of structurally gradient braided prostheses has been presented by modifying and combining the existing models available in the literature. Specifically, the full set of stress strain behaviour of structurally gradient braided prostheses has been computed based upon braid structural characteristics, constituent strand properties and braid kinematics. A triaxial braid in the outer layer of braided prostheses was found to withstand higher tensile stresses in comparison to a biaxial braid having same structural characteristics. A comparison has been made between the theoretical and experimental results of tensile properties of structurally gradient braided prostheses. The tensile properties of structurally gradient braided prostheses predicted through analytical route matched reasonably well with the experimental results. PMID- 26505531 TI - A global initiative to refine acute inhalation studies through the use of 'evident toxicity' as an endpoint: Towards adoption of the fixed concentration procedure. AB - Acute inhalation studies are conducted in animals as part of chemical hazard identification and characterisation, including for classification and labelling purposes. Current accepted methods use death as an endpoint (OECD TG403 and TG436), whereas the fixed concentration procedure (FCP) (draft OECD TG433) uses fewer animals and replaces lethality as an endpoint with 'evident toxicity.' Evident toxicity is defined as clear signs of toxicity that predict exposure to the next highest concentration will cause severe toxicity or death in most animals. A global initiative including 20 organisations, led by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) has shared data on the clinical signs recorded during acute inhalation studies for 172 substances (primarily dusts or mists) with the aim of making evident toxicity more objective and transferable between laboratories. Pairs of studies (5 male or 5 female rats) with at least a two-fold change in concentration were analysed to determine if there are any signs at the lower dose that could have predicted severe toxicity or death at the higher concentration. The results show that signs such as body weight loss (>10% pre-dosing weight), irregular respiration, tremors and hypoactivity, seen at least once in at least one animal after the day of dosing are highly predictive (positive predictive value > 90%) of severe toxicity or death at the next highest concentration. The working group has used these data to propose changes to TG433 that incorporate a clear indication of the clinical signs that define evident toxicity. PMID- 26505532 TI - [The pain experience according to a phenomenological view on palliative care]. AB - In palliative care, people with advanced or terminal phase cancer represent a significant proportion of patients. Persuaded that the pain and suffering they experience will never disappear from their daily life, patients are exposed to successive fracture triggered by psychosocial/physical factors. Furthermore, the difficulty in palliative care is that the pain is also a subjective phenomenon. However, the only information available to indicate pain remains the quantitative assessment of the patient or the observation of his/her behaviour. Pain caused by cancer optimally exhibits the difficulty of pain assessment, where a patient may properly assess, through their somatic pain, their own experience of pain expressed according to the consequence of illness on their history and personality. OBJECTIVES: This exploratory study aims to show how the development of analogical subjective speech has an effect on the pain experience in patients with cancer. Indeed, the hypothesis is that one can reduce the sensation of pain by transforming the emotional experience via a figurative/discursive activity due to an elaboration work and clarification of the painful experience. Method-Four terminally ill patients passed the "L'Epreuve des Trois Arbres" (three-tree test) (ETA), which consisted in drawing trees and telling their story. The ETA aims to facilitate the expression of the overall experience according to a person's perspective on a specific situation. In this experiment, quantitative and qualitative data were collected. More specifically, the quantitative data was based on the assessment of somatic pain using the visual analog scale (VAS) of 1 to 10 (0 = no pain, 10 = unbearable pain) and a qualitative analysis assessed with the ETA, which focused on the meaning of pain, a subjective component that can increase the expression of somatic pain. The pain experience is assessed before and after the execution of the ETA using the VAS. RESULTS: The results show a reduction of painful sensation and its behavioural expression. This could be due to the refocusing of attention and transformation of emotional experience through a figurative and discursive activity. DISCUSSION: The ETA seems to reduce somatic pain by allowing verbalization. The emotional repression of some patients who inhibited the expression of their pain would explain the increase of painful sensation. The psychological approach associated with the theme of the tree offers an opportunity to expound upon the experience of pain in an analogical mode, situating the current painful personal experience in a specific biography. Furthermore, part of the suffering highlighted in protocols was the break that makes the announcement of illness. It generated a sense of rupture between the time before and after, sometimes until a real crisis of identity, which can take on one of the facets of depression. ETA encourages the rebuilding of a psychic continuity between before and after the disease. PMID- 26505533 TI - Increased risk of chronic fatigue syndrome in patients with migraine: A retrospective cohort study. AB - OBJECTIVE: The common concurrence of migraine and chronic fatigue syndrome (CFS) has been reported but whether migraine poses a higher risk of CFS remains unknown. In this retrospective case-control study, we examined the association between the 2 disorders by using a nationwide, population-based database in Taiwan. METHODS: The data were retrieved and analyzed from the National Health Insurance Research Database (NHIRD) of Taiwan; 6902 newly diagnosed migraine cases from 2006-2010 were identified in a subset of the NHIRD, and 27,608 migraine-free individuals were randomly selected as the comparison cohort. The multivariate Cox proportional hazards regression model was used to investigate the risk of CFS in migraineurs after adjustment for demographic characteristics and comorbidities. RESULTS: After adjustment for the covariates, the risk of CFS was 1.5-fold higher in the migraine cohort than in the comparison cohort (52.72 vs. 28.85 per 10,000 person-years). Intriguingly, the risk was most prominent in the oldest group (>= 65 years), with a 2.11-fold increased risk (95% confidence interval 1.31-3.41) of CFS. In addition, the adjusted cumulative incidence of CFS in the follow-up years was higher in the migraine group (log-rank test, P < .0001), and CFS incidence appeared to increase with the frequency of migraine diagnoses. CONCLUSION: The current study demonstrated an increased risk of CFS in migraineurs. Proposed mechanisms in previous studies such as mitochondrial dysfunction and central sensitization may underlie the shared pathophysiology of these seemingly distinct but potentially overlapping disorders. PMID- 26505534 TI - Membrane-Associated Ubiquitin Ligase SAUL1 Suppresses Temperature- and Humidity Dependent Autoimmunity in Arabidopsis. AB - Plants have evolved elaborate mechanisms to regulate pathogen defense. Imbalances in this regulation may result in autoimmune responses that are affecting plant growth and development. In Arabidopsis, SAUL1 encodes a plant U-box ubiquitin ligase and regulates senescence and cell death. Here, we show that saul1-1 plants exhibit characteristics of an autoimmune mutant. A decrease in relative humidity or temperature resulted in reduced growth and systemic lesioning of saul1-1 rosettes. These physiological changes are associated with increased expression of salicylic acid-dependent and pathogenesis-related (PR) genes. Consistently, resistance of saul1-1 plants against Pseudomonas syringae pv. maculicola ES4326, P. syringae pv. tomato DC3000, or Hyaloperonospora arabidopsidis Noco2 was enhanced. Transmission electron microscopy revealed alterations in saul1-1 chloroplast ultrastructure and cell-wall depositions. Confocal analysis on aniline blue-stained leaf sections and cellular universal micro spectrophotometry further showed that these cell-wall depositions contain callose and lignin. To analyze signaling downstream of SAUL1, we performed epistasis analyses between saul1-1 and mutants in the EDS1/PAD4/SAG101 hub. All phenotypes observed in saul1 1 plants at low temperature were dependent on EDS1 and PAD4 but not SAG101. Taken together, SAUL1 negatively regulates immunity upstream of EDS1/PAD4, likely through the degradation of an unknown activator of the pathway. PMID- 26505535 TI - A structural classification of carbohydrate epimerases: From mechanistic insights to practical applications. AB - In recent years, carbohydrate epimerases have attracted a lot of attention as efficient biocatalysts that can convert abundant sugars (e.g.d-fructose) directly into rare counterparts (e.g.d-psicose). Despite increased research activities, no review about these enzymes has been published in more than a decade, meaning that their full potential is hard to appreciate. Here, we present an overview of all known carbohydrate epimerases based on a classification in structural families, which links every substrate specificity to a well-defined reaction mechanism. The mechanism can even be predicted for enzymes that have not yet been characterized or that lack structural information. In this review, the different families are discussed in detail, both structurally and mechanistically, with special reference to recent examples in the literature. Furthermore, the value of understanding the reaction mechanism will be illustrated by making the link to possible application and engineering targets. PMID- 26505536 TI - Mitochondrial introgression via ancient hybridization, and systematics of the Australian endemic pygopodid gecko genus Delma. AB - Of the more than 1500 species of geckos found across six continents, few remain as unfamiliar as the pygopodids - Family Pygopodidae (Gray, 1845). These gekkotans are limited to Australia (44 species) and New Guinea (2 species), but have diverged extensively into the most ecologically diverse limbless radiation save Serpentes. Current phylogenetic understanding of the family has relied almost exclusively on two works, which have produced and synthesized an immense amount of morphological, geographical, and molecular data. However, current interspecific relationships within the largest genus Delma Gray 1831 are based chiefly upon data from two mitochondrial loci (16s, ND2). Here, we reevaluate the interspecific relationships within the genus Delma using two mitochondrial and four nuclear loci (RAG1, MXRA5, MOS, DYNLL1), and identify points of strong conflict between nuclear and mitochondrial genomic data. We address mito-nuclear discordance, and remedy this conflict by recognizing several points of mitochondrial introgression as the result of ancient hybridization events. Owing to the legacy value and intraspecific informativeness, we suggest the continued use of ND2 as a phylogenetic marker. Results identify strong support for species groups, but relationships among these clades, and the placement of several enigmatic taxa remain uncertain. We suggest a more careful review of Delma australis and the 'northwest Australia' clade. Accurately assessing and addressing species richness and relationships within this endemic Australian Gekkotan genus is relevant for understanding patterns of squamate speciation across the region. PMID- 26505537 TI - Seatbelt fracture in a 5-month-old infant. PMID- 26505538 TI - Cosmetic Fillers: Perspectives on the Industry. AB - The cosmetic filler industry has evolved substantially over the last 30 years. The market is characterized by multiple fillers and a competitive dynamic among major aesthetics companies. Marketing in the United States and Europe has been different owing to regulatory constraints. Differences have led to more rapid growth in the European market. The US market has evolved owing to growth of major companies with multiple product portfolios and leverage in consumer promotion and aesthetics office marketing owing to scale. The evolution of the filler market will include new materials, injection techniques, and facilitation devices, and new areas of injection. PMID- 26505539 TI - The Hyaluronic Acid Fillers: Current Understanding of the Tissue Device Interface. AB - The article is a detailed update regarding cosmetic injectable fillers, specifically focusing on hyaluronic acid fillers. Hyaluronic acid-injectable fillers are used extensively for soft tissue volumizing and contouring. Many different hyaluronic acid-injectable fillers are available on the market and differ in terms of hyaluronic acid concentration, particle size, cross-linking density, requisite needle size, duration, stiffness, hydration, presence of lidocaine, type of cross-linking technology, and cost. Hyaluronic acid is a natural component of many soft tissues, is identical across species minimizing immunogenicity has been linked to wound healing and skin regeneration, and is currently actively being studied for tissue engineering purposes. The biomechanical and biochemical effects of HA on the local microenvironment of the injected site are key to its success as a soft tissue filler. Knowledge of the tissue-device interface will help guide the facial practitioner and lead to optimal outcomes for patients. PMID- 26505540 TI - The Case for Synthetic Injectables. AB - There are several different classes of synthetic dermal fillers and volume enhancers including semipermanent and permanent products available in the United States. Based on clinical and scientific evidence, this article reviews the chemical and polymeric properties, clinical data, patient selection, indications for use, injection technique, and adverse event profiles of permanent synthetic injectables currently used in clinical practice in the United States: medical grade liquid injectable silicone and polymethyl methacrylate. Understanding the unique characteristics of these two products reinforces the advantages and disadvantages of each, including under what circumstances they should be used and why they perform the way they do. PMID- 26505541 TI - Facial Filler Complications. AB - The use of facial fillers has greatly expanded over the past several years. Along with increased use comes a rise in documented complications, ranging from poor cosmetic result to nodules, granulomas, necrosis, and blindness. Awareness of the potential types of complications and options for management, in addition to the underlying facial anatomy, are imperative to delivering the best patient care. This article defines the complications and how to treat them and provides suggestions to avoid serious adverse outcomes. PMID- 26505542 TI - Collagen Stimulators: Poly-L-Lactic Acid and Calcium Hydroxyl Apatite. AB - Over the last decade, many studies of the structural changes observed in the aging face (in bone, fat pads, facial ligaments, muscle, skin) have increased our understanding that facial rejuvenation is more complex and nuanced than simply filling lines and folds or cutting and lifting soft tissue and skin. This, in addition to the many new products introduced to the marketplace over the same period, has fueled the evolution of panfacial rejuvenation and restoration using fillers. This article discusses current techniques used with calcium hydroxylapatite and poly-l-lactic acid to safely and effectively address changes observed in the aging face. PMID- 26505543 TI - Customized Approach to Facial Enhancement. AB - Creating a refreshed, best version of an individual face requires knowledge of facial anatomy, understanding of the interactions of fillers and neurotoxins with tissue and muscle, and dedication to the primary principal of aesthetic responsibility. The forehead ages in a similar fashion to the rest of the face with loss of volume in both subcutaneous fat and bone. Different injection techniques are recommended for the forehead, midface, lip, and lower face. Although we understand the changes associated with aging from a global perspective, each individual ages at his or her own pace and in consideration to their specific anatomy. PMID- 26505544 TI - Injectable Filler Techniques for Facial Rejuvenation, Volumization, and Augmentation. AB - Multiple fillers are available: various hyaluronic acid products, calcium hydroxylapatite, and a few others that are biocompatible with good duration and a variety of mechanical properties allowing intradermal, subdermal, and supraperiosteal injection. Facial features can be reshaped with great control using these fillers. Aging changes, including facial volume loss, can be well corrected. These treatments have become a mainstay of rejuvenation in the early facial aging patient. Injection technique is critical to obtaining excellent results. Threading, fanning, cross-hatching, bleb, and pillar techniques must be mastered. Technical execution can only measure up to, but not exceed, the quality of the aesthetic analysis. PMID- 26505545 TI - Current Concepts in Filler Injection. AB - When evaluating the face in thirds, the upper face, midface, and lower face, one may assume the lateral the temple, midface, and lateral mandible as the pillars of these subdivisions. Many of our facial aesthetic procedures address these regions, including the lateral brow lift, midface lift, and lateral face lift. As the use of facial fillers has advanced, more emphasis is placed on the correction of the temples, midlateral face, and lateral jaw line. This article is dedicated to these facial aesthetic pillars. PMID- 26505546 TI - The New Paradigm in Facial Rejuvenation: Soft Tissue Fillers 2015. PMID- 26505548 TI - Association between circulating adipokines, radiographic changes, and knee cartilage volume in patients with knee osteoarthritis. AB - OBJECTIVES: To explore the associations between serum adipokine levels, radiographic osteoarthritis (ROA) severity, and articular cartilage volume in patients with knee OA. METHOD: A cross-sectional sample of 205 patients (aged 45 74 years) with knee OA were consecutively recruited to the Anhui Osteoarthritis (AHOA) study. ROA was assessed using the Kellgren-Lawrence (KL) grading system (grades 0-4). Knee cartilage volume was determined using fat-saturated T1 weighted magnetic resonance imaging (MRI). Serum levels of the adipokines leptin, adiponectin, and resistin were measured by using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum adiponectin, but not serum leptin or resitin, was significantly associated with reduced ROA severity in univariable analyses and this association remained significant after adjustment for age, sex, body mass index (BMI), and disease duration [beta = -0.012, 95% confidence interval (CI) 0.021 to -0.002]. In ROA patients, leptin was significantly and positively associated with knee cartilage volume at patellar and medial tibial sites in both unadjusted and adjusted analyses (beta = 0.006, 95% CI 0.02-0.010 for medial tibia and beta = 0.009, 95% CI 0.001-0.018 for patella sites) but adiponectin and resistin had no significant associations with cartilage volume. In non-ROA patients, leptin, adiponectin, and resistin were not significantly associated with cartilage volume at any site. CONCLUSIONS: Serum levels of leptin are independently associated with increased knee cartilage volume. In addition, serum adiponectin is significantly and negatively associated with ROA severity, suggesting a potentially protective effect. PMID- 26505547 TI - MEK inhibitor GSK1120212-mediated radiosensitization of pancreatic cancer cells involves inhibition of DNA double-strand break repair pathways. AB - PURPOSE: Over 90% of pancreatic adenocarcinoma PC express oncogenic mutant KRAS that constitutively activates the Raf-MEK-MAPK pathway conferring resistance to both radiation and chemotherapy. MEK inhibitors have shown promising anti-tumor responses in recent preclinical and clinical studies, and are currently being tested in combination with radiation in clinical trials. Here, we have evaluated the radiosensitizing potential of a novel MEK1/2 inhibitor GSK1120212 (GSK212,or trametinib) and evaluated whether MEK1/2 inhibition alters DNA repair mechanisms in multiple PC cell lines. METHODS: Radiosensitization and DNA double-strand break (DSB) repair were evaluated by clonogenic assays, comet assay, nuclear foci formation (gammaH2AX, DNA-PK, 53BP1, BRCA1, and RAD51), and by functional GFP reporter assays for homologous recombination (HR) and non-homologous end-joining (NHEJ). Expression and activation of DNA repair proteins were measured by immunoblotting. RESULTS: GSK212 blocked ERK1/2 activity and radiosensitized multiple KRAS mutant PC cell lines. Prolonged pre-treatment with GSK212 for 24-48 hours was required to observe significant radiosensitization. GSK212 treatment resulted in delayed resolution of DNA damage by comet assays and persistent gammaH2AX nuclear foci. GSK212 treatment also resulted in altered BRCA1, RAD51, DNA-PK, and 53BP1 nuclear foci appearance and resolution after radiation. Using functional reporters, GSK212 caused repression of both HR and NHEJ repair activity. Moreover, GSK212 suppressed the expression and activation of a number of DSB repair pathway intermediates including BRCA1, DNA-PK, RAD51, RRM2, and Chk 1. CONCLUSION: GSK212 confers radiosensitization to KRAS-driven PC cells by suppressing major DNA-DSB repair pathways. These data provide support for the combination of MEK1/2 inhibition and radiation in the treatment of PC. PMID- 26505549 TI - Immunodiagnostic approaches for the detection of human toxocarosis. AB - Human toxocarosis is an important zoonosis caused by larvae of Toxocara canis/cati. The objective was to evaluate the role of IgG anti-Toxocara antibody detection and the specific IgG avidity in diagnostics of human toxocarosis. Anti Toxocara IgG antibodies and IgG avidity were evaluated by excretory-secretory (ES)-enzyme-linked immunosorbent assay (ELISA). The IgG anti-Toxocara seroprevalence in people (n = 7678) from western Slovakia was 15.3% and found to be highest in the oldest age groups. The presence of low- IgG avidity in 179 suspected patients for toxocarosis was evaluated in relation to sex, age, IgG antibody levels, eosinophilia, increased total IgE, domicile, geophagia, dog/cat ownership, anamnesis. Low- IgG avidity index was found in 30.7% of the patients. The low- IgG avidity in eosinophilic group (42.1%) was significantly higher than in non-eosinophilic group (22.0%; P = 0.043). Substantially higher eosinophilia was detected in children (under 10 years old; 55.6%) than in adults (aged >= 41 years; 17.6%; P = 0.009). Significant difference between seroprevalence of total IgE in patients coming from towns (48.8%) and patients from villages (21.3%) was established (P = 0.007). Mild negative correlation (r = -0.477, P = 0.043) was observed between the amounts of eosinophils and the values of IgG avidity. The sensitivity and specificity of IgG avidity assay were 43.8% and 83.3%, respectively. Our results suggest that besides anti-Toxocara IgG, measurement of IgG avidity may be useful for the determination of acute toxocarosis. Moreover, these tests should be accompanied by other immunological markers and determinants of examined patients such as eosinophilia, increased total IgE and age. PMID- 26505550 TI - Survival Prediction in Patients Undergoing Open-Heart Mitral Valve Operation After Previous Failed MitraClip Procedures. AB - BACKGROUND: The objective of this study was to analyze the results of open heart mitral valve operations for survival prediction in patients with previously unsuccessful MitraClip procedures. METHODS: Thirty-three consecutive patients who underwent mitral valve surgery in our institution were studied. At a median of 41 days, they had previously undergone one to five futile MitraClip implantations. At the time of their operations, patients were 72.6 +/- 10.3 years old, and the calculated risk, using the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II, was a median of 26.5%. Individual outcomes were recorded, and all patients were monitored postoperatively. RESULTS: Thirty-day mortality was 9.1%, and the overall survival at 2.2 years was 60.6%. Seven cardiac-related and six noncardiac deaths occurred. Univariate survival regression models demonstrated a significant influence of the following variables on survival: EuroSCORE II (p = 0.0022), preoperative left ventricular end-diastolic dimension (p = 0.0052), left ventricular ejection fraction (p = 0.0249), coronary artery disease (p = 0.0385), and severe pulmonary hypertension (p = 0.0431). Survivors showed considerable improvements in their New York Heart Association class (p < 0.0001), left ventricular ejection fraction (p = 0.0080), grade of mitral regurgitation (p = 0.0350), and mitral valve area (p = 0.0486). Survival after mitral repair was not superior to survival after replacement. CONCLUSIONS: Indications for surgery after failed MitraClip procedures must be considered with the greatest of care. Variables predicting postoperative survival should be taken into account regarding the difficult decision as to whether to operate or not. Our data suggest that replacement of the pretreated mitral valve is probably the more reasonable concept rather than complex repairs. When the EuroSCORE II at the time of surgery exceeds 30%, conservative therapy is advisable. PMID- 26505551 TI - Developments in Dynamic Covalent Chemistries from the Reaction of Thiols with Hexahydrotriazines. AB - Dynamic covalent chemistries have garnered significant attention for their potential to revolutionize technologies in the material fields (engineering, biomedical, and sensors) and synthetic design strategies as they provide access to stimuli responsiveness and adaptive behaviors. However, only a limited number of molecular motifs have been known to display this dynamic behavior under mild conditions. Here, we identified a dynamic covalent motif-thioaminals-that is produced from the reaction of hexahydrotriazines (HTs) with thiols. Furthermore, we report on the synthesis of a new family of step-growth polymers based on this motif. The condensation efficiently proceeds to quantitative yields within a short time frame and offers versatility in functional group tolerance; thus, it can be exploited to synthesize both small molecule thioaminals as well as high molecular weight polymers from the step-growth polymerization of HTs with dithiols. Careful evaluation of substituted HTs and organic thiols supported by DFT calculations led to a chemically diverse library of polymers based on this motif. Finally, dynamic substitution reactions were employed toward the facile preparation of functional oligomers and macromolecules. This dynamic covalent motif is particularly attractive for a range of applications that include material design and drug delivery due to the economic feasibility of synthesis. PMID- 26505552 TI - Summary of Notifiable Noninfectious Conditions and Disease Outbreaks: Foodborne and Waterborne Disease Outbreaks - United States, 1971-2012. PMID- 26505553 TI - The role and potential mechanism of resveratrol in the prevention and control of epilepsy. AB - Epilepsy is one of the most common diseases affecting the nervous system, with more than 50 million patients suffering from epilepsy worldwide. Although epilepsy has been prevalent for thousands of years, it is still not possible to completely control the disease. Despite an increase in the number of available antiepileptic drugs, the incidence of epilepsy and its cure rate have not been substantially improved; thus, there is an urgent need to identify new drugs that treat, cure or protect against epilepsy. Resveratrol is a polyphenol compound with a broad range of biological activity; not only it has considerable antiepileptic effects, but it is also neuroprotective and has functions to counter epileptic depression. Resveratrol has the potential to be a new antiepileptic drug, thus further studies are needed to better investigate its potential. PMID- 26505554 TI - On the impact of epidemic severity on network immunization algorithms. AB - There has been much recent interest in the prevention and mitigation of epidemics spreading through contact networks of host populations. Here, we investigate how the severity of epidemics, measured by its infection rate, influences the efficiency of well-known vaccination strategies. In order to assess the impact of severity, we simulate the SIR model at different infection rates on various real and model immunized networks. An extensive analysis of our simulation results reveals that immunization algorithms, which efficiently reduce the nodes' average degree, are more effective in the mitigation of weak and slow epidemics, whereas vaccination strategies that fragment networks to small components, are more successful in suppressing severe epidemics. PMID- 26505555 TI - Matrix interference from Fc-Fc interactions in immunoassays for detecting human IgG4 therapeutics. AB - BACKGROUND: An assay measuring an IgG4 biotherapeutic in human serum used a drug specific monoclonal antibody (mAb) capture reagent and an antihuman IgG4 mAb as detection reagent. However, serum IgG4 binding to the capture mAb via Fc interactions was detected by the anti-IgG4 mAb, causing high background. RESULTS: Two approaches were developed to minimize background; incorporating a mild acid sample preparation step or using the Fab of the capture antibody. Either strategy improved signal:noise dramatically, increasing assay sensitivity >20-fold. Biophysical analyses of antibody domains indicated that noncovalent Fc oligomers could inhibit the background. CONCLUSION: Matrix interference from human IgG4 binding to the capture mAb was reduced with a Fab fragment of the drug-specific capture antibody or by incorporating a mild acid sample treatment into the assay. PMID- 26505556 TI - The Frequency of Methylation Abnormalities Among Estonian Patients Selected by Clinical Diagnostic Scoring Systems for Silver-Russell Syndrome and Beckwith Wiedemann Syndrome. AB - AIMS: To study the frequency of methylation abnormalities among Estonian patients selected according to published clinical diagnostic scoring systems for Silver Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). MATERIALS AND METHODS: Forty-eight patients with clinical suspicion of SRS (n = 20) or BWS (n = 28) were included in the study group, to whom methylation-specific multiplex ligation-dependant probe amplification analysis of 11p15 region was made. In addition, to patients with minimal diagnostic score for either SRS or BWS, multilocus methylation-specific single nucleotide primer extension assay was performed. RESULTS: Five (38%) SRS patients with positive clinical scoring had abnormal methylation pattern at chromosome 11p15, whereas in the BWS group, only one patient was diagnosed with imprinting control region 2 (ICR2) hypomethylation (8%). An unexpected hypomethylation of the PLAGL1 (6q24) and IGF2R (6q25) genes in the patient with the highest BWS scoring was found. CONCLUSIONS: Compared to BWS, diagnostic criteria used for selecting SRS patients gave us a similar detection rate of 11p15 imprinting disorders as seen in other studies. A more careful selection of patients with possible BWS should be considered to improve the detection of molecularly confirmed cases. Genome-wide multilocus methylation tests could be used in routine clinical practice as it increases the detection rates of imprinting disorders. PMID- 26505557 TI - Maternal factors and the emotional and behavioural functioning of adolescents with chronic health conditions. AB - PURPOSE: This study investigated the association between mothers' mental health and education and the emotional and behavioural functioning of adolescents with chronic health conditions over time. METHODS: Data were drawn from an ongoing study. Study participants (N = 363) were recruited through eight children's rehabilitation centres. Logistic regression models were estimated. RESULTS: There were significantly reduced odds that girls would display clinical signs of hyperactivity/inattention one year later compared to boys when a maternal mental health condition was present (OR = 0.10; p < 0.01). Where low maternal education was present, girls were more likely to display peer relationship problems one year later (OR = 3.72; p < 0.01). For both genders, having a mother with less than a high school education was also associated with conduct problems one year later (OR = 2.89; p < 0.01). CONCLUSIONS: Findings support a link between maternal factors and emotional and behavioural functioning in adolescents with chronic conditions. A holistic and family-centred approach to assessment and service delivery is indicated. Implications for Rehabilitation When conducting clinical assessments, service providers should consider associations between maternal education and mental health and the emotional and behavioural functioning of adolescents with chronic health conditions. A holistic and family centred approach to assessment and service delivery is indicated to ensure adolescents with chronic conditions and their families receive support for interrelated needs. PMID- 26505558 TI - Targeted delivery of gold nanoparticle contrast agents for reporting gene detection by magnetic resonance imaging. AB - Detection of protein expression by MRI requires a high payload of Gd(III) per protein binding event. Presented here is a targeted AuDNA nanoparticle capable of delivering several hundred Gd(III) chelates to the HaloTag reporter protein. Incubating this particle with HaloTag-expressing cells produced a 9.4 contrast-to noise ratio compared to non-expressing cells. PMID- 26505559 TI - Oliver Sacks 1933-2015. PMID- 26505560 TI - From phenotypic chaos to neurobiological order. PMID- 26505561 TI - Pore dilation reconsidered. PMID- 26505562 TI - Ephrin-B3 recruits PSD-95 to synapses. PMID- 26505563 TI - The cellular target of antidepressants. PMID- 26505564 TI - Rethinking canonical cortical circuits. PMID- 26505565 TI - Do glia drive synaptic and cognitive impairment in disease? AB - Synaptic dysfunction is a hallmark of many neurodegenerative and psychiatric brain disorders, yet we know little about the mechanisms that underlie synaptic vulnerability. Although neuroinflammation and reactive gliosis are prominent in virtually every CNS disease, glia are largely viewed as passive responders to neuronal damage rather than drivers of synaptic dysfunction. This perspective is changing with the growing realization that glia actively signal with neurons and influence synaptic development, transmission and plasticity through an array of secreted and contact-dependent signals. We propose that disruptions in neuron glia signaling contribute to synaptic and cognitive impairment in disease. Illuminating the mechanisms by which glia influence synapse function may lead to the development of new therapies and biomarkers for synaptic dysfunction. PMID- 26505567 TI - Clinical characteristics and systemic therapies administered to first-time patients at a tertiary psoriasis outpatient clinic. AB - BACKGROUND: The aim of this study was to describe the clinical characteristics and the systemic therapies given to a cohort of patients attending for the first time our tertiary psoriasis outpatient clinic. METHODS: Data were extracted from an electronic database where the patients, mostly eligible for systemic therapies, are consecutively recorded. Based on skin disease severity the subjects were classified into three groups: group 1, mild psoriasis (MP; Psoriasis Area Severity Index [PASI]<=5); group 2, mild-to-moderate psoriasis (MMP; 510). RESULTS: Of the 289 patients studied, 88 (30.4%) presented with MP, 91 (31.5%) with MMP, and 110 (38%) with MSP, 89 (30.8%) of whom were affected by psoriatic arthritis. Of the 289 patients, 267 (92.3%) were deemed eligible for a systemic treatment, and 228 (85.4%) of them started a systemic treatment as monotherapy. The therapies administered were as follows: cyclosporine to 65 (28.5%); methotrexate to 59 (25.8%); etanercept to 33 (44%); adalimumab to 25 (33.3%); ustekinumab to 17 (22.6%); acitretin to 29 (12.7%); golimumab to one (1.3%). CONCLUSIONS: Our data show a composite distribution of patients eligible for a systemic therapy and attending for the first time our center. The traditional drugs were more frequently administered (67.1%) as compared to biological ones (32.9%). PMID- 26505568 TI - Evidence-Based Emergency Management Of The Pediatric Airway. AB - Pediatric airway emergencies are rare, yet they are anxiety-provoking events that can occur in both pediatric and general emergency departments. Several novel concepts regarding preoxygenation during rapid sequence intubation, anticipation and prevention of intubation-related complications, the utility of premedication agents, and the selection of induction and paralytic agents have been highlighted in recent clinical trials and review articles. In this review, we analyze the data behind these concepts, highlight current pediatric literature related to these issues, and present reasonable conclusions based on the best available evidence. We begin with an analysis of the anatomic and physiologic differences commonly encountered in the pediatric patient during rapid sequence intubation, and we then review a systematic approach to the assessment of the pediatric patient in respiratory distress (ie, the pediatric assessment triangle) and conclude with a simple approach to pediatric rapid sequence intubation, starting with the preparatory phase and ending with postintubation management. We additionally highlight several alternative airway devices and discuss special situations, including rapid sequence intubation in the obese pediatric patient and in the difficult airway patient. PMID- 26505566 TI - Measuring macroscopic brain connections in vivo. AB - Decades of detailed anatomical tracer studies in non-human animals point to a rich and complex organization of long-range white matter connections in the brain. State-of-the art in vivo imaging techniques are striving to achieve a similar level of detail in humans, but multiple technical factors can limit their sensitivity and fidelity. In this review, we mostly focus on magnetic resonance imaging of the brain. We highlight some of the key challenges in analyzing and interpreting in vivo connectomics data, particularly in relation to what is known from classical neuroanatomy in laboratory animals. We further illustrate that, despite the challenges, in vivo imaging methods can be very powerful and provide information on connections that is not available by any other means. PMID- 26505569 TI - Neurological Adverse Effects of Antipsychotics in Children and Adolescents. AB - OBJECTIVE: The aim of this study was to evaluate demographic, clinical, and treatment factors that may impact on neurological adverse effects in naive and quasi-naive children and adolescents treated with antipsychotics. METHODS: This was a 1-year, multicenter, observational study of a naive and quasi-naive pediatric population receiving antipsychotic treatment. Two subanalyses were run using the subsample of subjects taking the 3 most used antipsychotics and the subsample of antipsychotic-naive subjects. Total dyskinesia score (DyskinesiaS) and total Parkinson score (ParkinsonS) were calculated from the Maryland Psychiatric Research Center Involuntary Movement Scale, total UKU-Cognition score was calculated from the UKU Side Effect Rating Scale. Risk factors for tardive dyskinesias (TDs) defined after Schooler-Kaine criteria were studied using a logistic regression. RESULTS: Two hundred sixty-five subjects (mean age, 14.4 [SD, 2.9] years) with different Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I disorders were recruited. DyskinesiaS (P < 0.001) and ParkinsonS (P < 0.001) increased at 1-year follow-up. Risperidone was associated with higher increases in DyskinesiaS compared with quetiapine (P < 0.001). Higher increases in ParkinsonS were found with risperidone (P < 0.001) and olanzapine (P = 0.02) compared with quetiapine. Total UKU-Cognition Score decreased at follow-up. Findings were also significant when analyzing antipsychotic-naive subjects. Fifteen subjects (5.8%) fulfilled Schooler-Kane criteria for TD at follow-up. Younger age, history of psychotic symptoms, and higher cumulative exposure time were associated with TD at follow-up. CONCLUSIONS: Antipsychotics increased neurological adverse effects in a naive and quasi-naive pediatric population and should be carefully monitored. Risperidone presented higher scores in symptoms of dyskinesia and parkinsonism. Quetiapine was the antipsychotic with less neurological adverse effects. Younger subjects, psychosis, and treatment factors predicted an increased risk of TD. PMID- 26505570 TI - Lack of Analgesic Effect Induced by Ropivacaine Wound Infiltration in Thyroid Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Surgical site infiltration with local anesthetic reduces analgesic requests in various types of surgeries. Because thyroid surgery may induce severe postoperative pain, we tested the hypothesis that ropivacaine surgical site infiltration would significantly decrease postoperative administration of morphine in patients undergoing thyroid surgery. METHODS: We performed a double blind, placebo-controlled superiority trial to assess the efficacy of surgical site analgesia with ropivacaine (10 mL, 75 mg) performed at the end of thyroid surgery in adult patients. The primary end point was the proportion of patients not requiring IV morphine in the postanesthesia care unit. RESULTS: One hundred sixty-three patients completed the study, 85 in the placebo group and 88 in the ropivacaine group. The proportion of patients requiring morphine administration in the postanesthesia care unit (55% vs 53%, P = 0.80), the dose of IV morphine administered (5.6 +/- 6.1 vs 5.5 +/- 6.0 mg, P = 0.90), the total dose of opioids administered (expressed as oral morphine equivalent dose: 64 +/- 27 vs 69 +/- 29 mg, P = 0.20), and the visual analog pain scale over the first 24 hours were not significantly different between groups. The incidence of adverse events (36% vs 39%, P = 0.88), morphine-related adverse events (19% vs 17%, P = 0.84), serious adverse events (0% vs 2%, P = 0.50), and the patient satisfaction scores (9 +/- 1 vs 9 +/- 1, P = 0.70) was not significantly different between the 2 groups. CONCLUSIONS: Surgical site analgesia with ropivacaine at the end of thyroid surgery is not associated with any significant analgesic benefit. PMID- 26505571 TI - Forced-Air Warming During Pediatric Surgery: A Randomized Comparison of a Compressible with a Noncompressible Warming System. AB - BACKGROUND: Perioperative hypothermia is a common problem, challenging the anesthesiologist and influencing patient outcome. Efficient and safe perioperative active warming is therefore paramount; yet, it can be particularly challenging in pediatric patients. Forced-air warming technology is the most widespread patient-warming option, with most forced-air warming systems consisting of a forced-air blower connected to a compressible, double layer plastic and/or a paper blanket with air holes on the patient side. We compared an alternative, forced-air, noncompressible, under-body patient-warming mattress (Baby/Kleinkinddecke of MoeckWarmingSystems, Moeck und Moeck GmbH; group MM) with a standard, compressible warming mattress system (Pediatric Underbody, Bair Hugger, 3M; group BH). METHODS: The study included 80 patients aged <2 years, scheduled for elective surgery. After a preoperative core temperature measurement, the patients were placed on the randomized mattress in the operation theater and 4 temperature probes were applied rectally and to the patients' skin. The warming devices were turned on as soon as possible to the level for pediatric patients as recommended by the manufacturer (MM = 40 degrees C, BH = 43 degrees C). RESULTS: There was a distinct difference of temperature slope between the 2 groups: core temperatures of patients in the group MM remained stable and mean of the core temperature of patients in the group BH increased significantly (difference: +1.48 degrees C/h; 95% confidence interval, 0.82-2.15 degrees C/h; P = 0.0001). The need for temperature downregulation occurred more often in the BH group, with 22 vs 7 incidences (RR, 3.14; 95% confidence interval, 1.52-6.52; P = 0.0006). Skin temperatures were all lower in the MM group. Perioperatively, no side effects related to a warming device were observed in any group. CONCLUSIONS: Both devices are feasible choices for active pediatric patient warming, with the compressible mattress system being better suited to increase core temperature. The use of lower pediatric forced-air temperature settings, as recommended by the manufacturer, in the noncompressible mattress group resulted in more stable core temperature conditions, with fewer forced-air temperature adjustments necessary to avoid hyperthermia. PMID- 26505572 TI - High-Fidelity Analysis of Perioperative QTc Prolongation. AB - BACKGROUND: Prolongation of the QTc interval indicates abnormal cardiac repolarization. A recent study has shown that postoperative QTc prolongation is common. However, it is unknown whether QTc prolongation is an isolated postoperative phenomenon or occurs regularly during surgery, or whether the type of anesthesia influences its incidence. METHODS: To answer this question, we conducted a prospective cohort study (n = 300), where QTc duration was continuously recorded by 12-lead Holter electrocardiogram from 30 minutes preoperatively to up to 60 minutes postoperatively. QTc prolongation was compared between adult patients with at least 1 cardiac risk factor undergoing general (n = 101) or spinal anesthesia (n = 99) for orthopedic surgery, or local anesthesia (n = 100). Primary outcome was intraoperative QTc increase (DeltaQTc, as defined by the intraoperative-to-preoperative QTc duration difference). The incidence of long QTc episodes (QTc > 500 milliseconds for at least 15 minutes) was also determined. RESULTS: Significant QTc prolongation (median; interquartile range [IQR]) occurred during general anesthesia (DeltaQTc, +33 milliseconds; IQR, +22 to 46 milliseconds) and spinal anesthesia (DeltaQTc, +22 milliseconds; IQR, +12 to 29 milliseconds), whereas no QTc prolongation was observed during local anesthesia (biopsy, n = 53: DeltaQTc, +4 milliseconds; IQR, -4 to +7 milliseconds; coronary angiography, n = 47: DeltaQTc, +6 milliseconds; IQR, -5 to +16 milliseconds). The incidence of long QTc episodes was significantly different between general anesthesia (n = 6/63, 9.5%), spinal anesthesia (n = 1/56, 1.8%), local anesthesia for biopsy (n = 0/46, 0%), and coronary angiography (n = 0/19, 0%; P = 0.045). CONCLUSIONS: These results indicate that QTc prolongation is not an isolated postoperative phenomenon and is common during surgery under general and spinal anesthesia. PMID- 26505573 TI - Comparisons of Electroencephalographically Derived Measures of Hypnosis and Antinociception in Response to Standardized Stimuli During Target-Controlled Propofol-Remifentanil Anesthesia. AB - BACKGROUND: Current electroencephalogram (EEG)-derived measures provide information on cortical activity and hypnosis but are less accurate regarding subcortical activity, which is expected to vary with the degree of antinociception. Recently, the neurophysiologically based EEG measures of cortical input (CI) and cortical state (CS) have been shown to be prospective indicators of analgesia/antinociception and hypnosis, respectively. In this study, we compared CI and an alternate measure of CS, the composite cortical state (CCS), with the Bispectral Index (BIS) and another recently developed measure of antinociception, the composite variability index (CVI). CVI is an EEG derived measure based on a weighted combination of BIS and estimated electromyographic activity. By assessing the relationship between these indices for equivalent levels of hypnosis (as quantified using the BIS) and the nociceptive-antinociceptive balance (as determined by the predicted effect-site concentration of remifentanil), we sought to evaluate whether combining hypnotic and analgesic measures could better predict movement in response to a noxious stimulus than when used alone. METHODS: Time series of BIS and CVI indices and the raw EEG from a previously published study were reanalyzed. In our current study, the data from 80 patients, each randomly allocated to a target hypnotic level (BIS 50 or BIS 70) and a target remifentanil level (Remi-0, -2, -4 or -6 ng/mL), were included in the analysis. CCS, CI, BIS, and CVI were calculated or quantified at baseline and at a number of intervals after the application of the Observer's Assessment of Alertness/Sedation scale and a subsequent tetanic stimulus. The dependency of the putative measures of antinociception CI and CVI on effect-site concentration of remifentanil was then quantified, together with their relationship to the hypnotic measures CCS and BIS. Finally, statistical clustering methods were used to evaluate the extent to which simple combinations of antinociceptive and hypnotic measures could better detect and predict response to stimulation. RESULTS: Before stimulation, both CI and CVI differentiated patients who received remifentanil from those who were randomly allocated to the Remi-0 group (CI: Cohen's d = 0.65, 95% confidence interval, 0.48-0.83; CVI: Cohen's d = 0.72, 95% confidence interval, 0.56-0.88). Strong correlations between BIS and CCS were found (at different periods: 0.55 < R2 < 0.68, P < 0.001). Application of the Observer's Assessment of Alertness/Sedation stimulus was associated with changes in CI and CCS, whereas, subsequent to the application of both stimuli, changes in all measures were seen. Pairwise combinations of CI and CCS showed higher sensitivity in detecting response to stimulation than CVI and BIS combined (sensitivity [99% confidence interval], 75.8% [52.7%-98.8%] vs 42% [15.4%-68.5%], P = 0.006), with specificity for CI and CCS approaching significance (52% [34.7%-69.3%] vs 24% [9.1%-38.9%], P = 0.0159). CONCLUSIONS: Combining electroencephalographically derived hypnotic and analgesic quantifiers may enable better prediction of patients who are likely to respond to tetanic stimulation. PMID- 26505574 TI - The Sensitivity and Specificity of Pulmonary Carbon Dioxide Elimination for Noninvasive Assessment of Fluid Responsiveness. AB - BACKGROUND: We sought to determine whether the response of pulmonary elimination of CO2 (VCO2) to a sudden increase in positive end-expiratory pressure (PEEP) could predict fluid responsiveness and serve as a noninvasive surrogate for cardiac index (CI). METHODS: Fifty-two patients undergoing cardiovascular surgery were included in this study. By using a constant-flow ventilation mode, we performed a PEEP challenge of 1-minute increase in PEEP from 5 to 10 cm H2O. At PEEP of 5 cm H2O, patients were preloaded with 500 mL IV saline solution after which a second PEEP challenge was performed. Patients in whom fluid administration increased CI by >=15% from the individual baseline value were defined as volume responders. Beat-by-beat CI was derived from arterial pulse contour analysis, and breath-by-breath VCO2 data were collected during the protocol. The sensitivity and specificity of VCO2 for detecting the fluid responders according to CI was performed by the receiver operating characteristic curves. RESULTS: Twenty-one of 52 patients were identified as fluid responders (40%). The PEEP maneuver before fluid administration decreased CI from 2.65 +/- 0.34 to 2.21 +/- 0.32 L/min/m (P = 0.0011) and VCO2 from 150 +/- 23 to 123 +/- 23 mL/min (P = 0.0036) in responders, whereas the changes in CI and VCO2 were not significant in nonresponders. The PEEP challenge after fluid administration induced no significant changes in CI and VCO2, in neither responders nor nonresponders. PEEP-induced decreases in CI and VCO2 before fluid administration were well correlated (r = 0.75, P < 0.0001) but not thereafter. The area under the receiver operating characteristic curves for a PEEP-induced decrease in DeltaCI and DeltaVCO2 was 0.99, with a 95% confidence interval from 0.96 to 0.99 for DeltaCI and from 0.97 to 0.99 for DeltaVCO2. During the PEEP challenge, a decrease in VCO2 by 11% predicted fluid responsiveness with a sensitivity of 0.90 (95% confidence interval, 0.87-0.93) and a specificity of 0.95 (95% confidence interval, 0.92-0.98). CONCLUSIONS: PEEP-induced changes in VCO2 predicted fluid responsiveness with accuracy in patients undergoing cardiac surgery. PMID- 26505575 TI - Targeting Oliguria Reversal in Goal-Directed Hemodynamic Management Does Not Reduce Renal Dysfunction in Perioperative and Critically Ill Patients: A Systematic Review and Meta-Analysis. AB - BACKGROUND: We investigated whether resuscitation protocols to achieve and maintain urine output above a predefined threshold-including oliguria reversal as a target--prevent acute renal failure (ARF). METHODS: We performed a systematic review and meta-analysis using studies found by searching MEDLINE, EMBASE, and references in relevant reviews and articles. We included all studies that compared "conventional fluid management" (CFM) with "goal-directed therapy" (GDT) using cardiac output, urine output, or oxygen delivery parameters and reported the occurrence of ARF in critically ill or surgical patients. We divided studies into groups with and without oliguria reversal as a target for hemodynamic optimization. We calculated the combined odds ratio (OR) and 95% confidence intervals (CIs) using random-effects meta-analysis. RESULTS: We based our analyses on 28 studies. In the overall analysis, GDT resulted in less ARF than CFM (OR, 0.58; 95% CI, 0.44-0.76; P < 0.001; I = 34.3%; n = 28). GDT without oliguria reversal as a target resulted in less ARF (OR, 0.45; 95% CI, 0.34-0.61; P < 0.001; I = 7.1%; n = 7) when compared with CFM with oliguria reversal as a target. The studies comparing GDT with CFM in which the reversal of oliguria was targeted in both or in neither group did not provide enough evidence to conclude a superiority of GDT (targeting oliguria reversal in both protocols: OR, 0.63; 95% CI, 0.36-1.10; P = 0.09; I = 48.6%; n = 9, and in neither protocol: OR, 0.66; 95% CI, 0.37-1.16; P = 0.14; I = 20.2%; n = 12). CONCLUSIONS: Current literature favors targeting circulatory optimization by GDT without targeting oliguria reversal to prevent ARF. Future studies are needed to investigate the hypothesis that targeting oliguria reversal does not prevent ARF in critically ill and surgical patients. PMID- 26505576 TI - Intermittent Hypoxia Causes Inflammation and Injury to Human Adult Cardiac Myocytes. AB - BACKGROUND: Intermittent hypoxia may occur in a number of clinical scenarios, including interruption of myocardial blood flow or breathing disorders such as obstructive sleep apnea. Although intermittent hypoxia has been linked to cardiovascular and cerebrovascular disease, the effect of intermittent hypoxia on the human heart is not fully understood. Therefore, in the present study, we compared the cellular responses of cultured human adult cardiac myocytes (HACMs) exposed to intermittent hypoxia and different conditions of continuous hypoxia and normoxia. METHODS: HACMs were exposed to intermittent hypoxia (0%-21% O2), constant mild hypoxia (10% O2), constant severe hypoxia (0% O2), or constant normoxia (21% O2), using a novel cell culture bioreactor with gas-permeable membranes. Cell proliferation, lactate dehydrogenase release, vascular endothelial growth factor release, and cytokine (interleukin [IL] and macrophage migration inhibitory factor) release were assessed at baseline and after 8, 24, and 72 hours of exposure. A signal transduction pathway finder array was performed to determine the changes in gene expression. RESULTS: In comparison with constant normoxia and constant mild hypoxia, intermittent hypoxia induced earlier and greater inflammatory response and extent of cell injury as evidenced by lower cell numbers and higher lactate dehydrogenase, vascular endothelial growth factor, and proinflammatory cytokine (IL-1beta, IL-6, IL-8, and macrophage migration inhibitory factor) release. Constant severe hypoxia showed more detrimental effects on HACMs at later time points. Pathway analysis demonstrated that intermittent hypoxia primarily altered gene expression in oxidative stress, Wnt, Notch, and hypoxia pathways. CONCLUSIONS: Intermittent and constant severe hypoxia, but not constant mild hypoxia or normoxia, induced inflammation and cell injury in HACMs. Cell injury occurred earliest and was greatest after intermittent hypoxia exposure. Our in vitro findings suggest that intermittent hypoxia exposure may produce rapid and substantial damage to the human heart. PMID- 26505577 TI - Postoperative Pain Management in Children of Hispanic Origin: A Descriptive Cohort Study. AB - BACKGROUND: It has been established that pain is frequently undertreated in children following outpatient surgery. Very few studies, however, have investigated this phenomenon in ethnically diverse populations. METHODS: This study included 105 families of children aged 2 to 15 years of Hispanic origin and low income undergoing outpatient tonsillectomy and adenoidectomy surgery. Participating parents completed baseline and demographic packets. Recorded postoperative pain ratings and administration of analgesics at home for 1 week were collected during home visits. RESULTS: Despite the high (70%; 99% confidence interval [CI], 57%-82%) incidence of significant pain in the first 24 hours home, 32% (95% CI, 20%-45%) of the children received 0 to 1 dose of analgesia. Overall, 21% children (99% CI, 11%-35%) received 4 or less total doses of pain medication over the entire week after surgery. Of the total analgesic doses administered to children in the week after surgery, only 44% (99% CI, 40%-47%) were in accepted ranges. CONCLUSIONS: Despite experiencing significant postoperative pain, Hispanic children assessed in this study received suboptimal analgesic therapy at home. PMID- 26505578 TI - Prophylactic Ondansetron for the Prevention of Intrathecal Fentanyl- or Sufentanil-Mediated Pruritus: A Meta-Analysis of Randomized Trials. AB - BACKGROUND: Pruritus is a common side effect of intrathecal fentanyl or sufentanil that decreases patient satisfaction and may delay hospital discharge. There are conflicting reports about the efficacy of prophylactic ondansetron in reducing the incidence of pruritus. This meta-analysis aimed to assess the effect of prophylactic ondansetron on the incidence of intrathecal fentanyl- or sufentanil-mediated pruritus and the need for rescue treatment. METHODS: A systematic search on PubMed, Medline, and the Cochrane Central Register of Controlled Trials from January 1, 1994, to January 1, 2014, was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta analyses (PRISMA) guidelines. Randomized controlled trials evaluating the efficacy of prophylactic ondansetron on pruritus associated with intrathecal fentanyl or sufentanil were included. The primary outcome was the incidence of pruritus, and the secondary outcome was patients' need for rescue therapy. Sensitivity analyses were conducted to assess the outcomes in obstetric and nonobstetric patients and in patients who received ondansetron before or after intrathecal opioid injection. Analyses used random-effect models. RESULTS: Six randomized controlled trials involving 555 patients were included. In the overall analysis, prophylactic ondansetron did not significantly decrease the incidence of pruritus, but there was a trend toward reduced rescue medication use (risk ratio [RR], 0.57; 95% confidence interval [CI], 0.35-0.91; I = 0%; P = 0.02). Exploratory subgroups, including nonobstetric surgery patients and patients who received ondansetron before spinal opioid administration, also suggest a trend toward less rescue medication use (RR, 0.47; 95% CI, 0.26-0.85; P = 0.01; and RR, 0.62; 95% CI, 0.38-1.00; P = 0.05). CONCLUSIONS: IV 8 mg prophylactic ondansetron does not decrease the incidence of fentanyl- or sufentanil-mediated pruritus but may decrease the need for pruritus rescue medication, particularly in specific subgroups. Randomized trials are needed to confirm these results. PMID- 26505579 TI - Assessment of loading conditions with cardiac ultrasound. A comprehensive review. AB - Optimization of the preloading conditions and concomitant determination of endpoints of fluid administration are the most frequent therapeutic actions in critically ill patients. Besides a clinical appraisal, reproducible data should be acquired at the bedside to estimate the adequacy of fluid resuscitation. The dynamic assessment and determination of fluid responsiveness plays a major role in this respect. Right-sided cardiac variables, such as inferior and superior caval vein diameter variation during mechanical ventilation, are easily obtained with cardiac ultrasound. Moreover, left sided variables, including aortic flow variation, with intermittent swings of intrathoracic pressure during mechanical ventilation, may be achieved non-invasively with Doppler-echocardiography. Both in terms of resuscitation, as well as correct interpretation of various two dimensional and Doppler variables, it is essential to acquire a clear understanding of the filling status of a patient. Doppler-echocardiography plays herein a pivotal role. PMID- 26505580 TI - Bone-repair properties of biodegradable hydroxyapatite nano-rod superstructures. AB - Nano-hydroxyapatite (nano-HAp) materials show an analogous chemical composition to the biogenic mineral components of calcified tissues and depending on their topography they may mimic the specific arrangement of the crystals in bone. In this work, we have evaluated the potential of four synthesized nano-HAp superstructures for the in vitro conditions of bone-repair. Experiments are underway to investigate the effects of the material microstructure, surface roughness and hydrophilicity on their osseo-integration, osteo-conduction and osteo-induction abilities. Materials were tested in the presence of both, rat primary osteoblasts and rabbit mesenchymal stem cells. The following aspects are discussed: (i) cytotoxicity and material degradation; (ii) rat osteoblast spreading, proliferation and differentiation; and (iii) rabbit mesenchymal stem cell adhesion on nano-HAp and nano-HAp/collagen type I coatings. We effectively prepared a material based on biomimetic HAp nano-rods displaying the appropriate surface topography, hydrophilicity and degradation properties to induce the in vitro desired cellular responses for bone bonding and healing. Cells seeded on the selected material readily attached, proliferated and differentiated, as confirmed by cell viability, mitochondrial metabolic activity, alkaline phosphatase (ALP) activity and cytoskeletal integrity analysis by immunofluorescence localization of alpha-smooth muscle actin (alpha-SMA) protein. These results highlight the influence of material's surface characteristics to determine their tissue regeneration potential and their future use in engineering osteogenic scaffolds for orthopedic implants. PMID- 26505583 TI - Evening (Landscape in Brilliant Colors): Nikolai Nedashkovsky. PMID- 26505584 TI - Seeking Rational Approaches to Fixing Hospital Readmissions. PMID- 26505593 TI - Time for a More Unified Approach to Pediatric Health Care Policy?: The Case of Congenital Heart Care. PMID- 26505594 TI - A PIECE OF MY MIND. A Piece of My Mind--Actually. PMID- 26505595 TI - Mortality Trends and Signs of Health Progress in the United States: Improving Understanding and Action. PMID- 26505596 TI - Anticholinergic vs Long-Acting beta-Agonist in Combination With Inhaled Corticosteroids in Black Adults With Asthma: The BELT Randomized Clinical Trial. AB - IMPORTANCE: The efficacy and safety of long-acting beta-agonists (LABAs) have been questioned. Black populations may be disproportionately affected by LABA risks. OBJECTIVE: To compare the effectiveness and safety of tiotropium vs LABAs, when used with inhaled corticosteroids (ICS) in black adults with asthma and to determine whether allelic variation at the Arg16Gly locus of the beta2-adrenergic receptor (ADRB2) geneis associated with treatment response. DESIGN, SETTING, AND PARTICIPANTS: A multisite (n = 20), open-label, parallel-group, pragmatic randomized clinical trial conducted from March 2011 through July 2013, enrolling black adults with moderate to severe asthma in the United States. INTERVENTIONS: Patients eligible for, or receiving, step 3 or step 4 combination therapy per National Heart, Lung, and Blood Institute guidelines, received ICS plus either once-daily tiotropium (n = 532) or twice-daily LABAs (n = 538,) and were followed up for up to 18 months. Patients underwent genotyping, attended study visits at baseline, 1, 6, 12, and 18 months, and completed monthly questionnaires. MAIN OUTCOMES AND MEASURES: The primary outcome was time to asthma exacerbation, defined as a worsening asthma event requiring oral or parenteral corticosteroids. Secondary outcomes included patient-reported outcomes (Asthma Quality of Life Questionnaire, Asthma Control Questionnaire [ACQ], Asthma Symptom Utility Index, and Asthma Symptom-Free Days questionnaire), spirometry (FEV1), rescue medication use, asthma deteriorations, and adverse events. RESULTS: There was no difference between LABA + ICS vs tiotropium + ICS in time to first exacerbation (mean No. of exacerbations/person-year, 0.42 vs 0.37 (rate ratio, 0.90 [95% CI, 0.73 to 1.11], log-rank P = .31). There was no difference in change in FEV1 at 12 months (0.003 L for LABA + ICS vs -0.018 L for tiotropium + ICS; between-group difference, 0.020 [95% CI, -0.021 to 0.061], P = .33) and at 18 months (-0.053 L vs -0.078 L; between-group difference, 0.025 [95% CI, -0.045 to 0.095], P = .49). There were no differences in ACQ score at 18 months (change in score from baseline, -0.68 for LABA + ICS vs -0.72 for tiotropium + ICS; between-group difference, 0.04 [95% CI, -0.18 to 0.27], P = .70). There were no differences in other patient-reported outcomes. Arg16Gly ADRB2 alleles were not associated with differences in the effects of tiotropium + ICS vs LABA + ICS (hazard ratio for time to first exacerbation, 0.84 [95% CI, 0.47 to 1.51] for Arg/Arg vs 0.85 [95% CI, 0.63 to 1.15] for Arg/Gly or Gly/Gly, P = .97). CONCLUSIONS/RELEVANCE: Among black adults with asthma treated with ICS, adding a LABA did not improve time to asthma exacerbation compared with adding tiotropium. These findings were not affected by polymorphisms at the Arg16Gly locus of ADRB2. These findings do not support the superiority of LABA + ICS compared with tiotropium + ICS for black patients with asthma. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01290874. PMID- 26505597 TI - Temporal Trends in Mortality in the United States, 1969-2013. AB - IMPORTANCE: A systematic and comprehensive evaluation of long-term trends in mortality is important for health planning and priority setting and for identifying modifiable factors that may contribute to the trends. OBJECTIVE: To examine temporal trends in deaths in the United States for all causes and for the 6 leading causes. DESIGN, SETTING, AND PARTICIPANTS: Joinpoint analysis of US national vital statistics data from 1969 through 2013. EXPOSURE: Causes of death. MAIN OUTCOMES AND MEASURES: Total and annual percent change in age-standardized death rates and years of potential life lost before age 75 years for all causes combined and for heart disease, cancer, chronic obstructive pulmonary disease (COPD), stroke, unintentional injuries, and diabetes mellitus. RESULTS: Between 1969 and 2013, the age-standardized death rate per 100,000 decreased from 1278.8 to 729.8 for all causes (42.9% reduction; 95% CI, 42.8%-43.0%), from 156.8 to 36.0 for stroke (77.0% reduction; 95% CI, 76.9%-77.2%), from 520.4 to 169.1 for heart disease (67.5% reduction; 95% CI, 67.4%-67.6%), from 65.1 to 39.2 for unintentional injuries (39.8% reduction; 95% CI, 39.3%-40.3%), from 198.6 to 163.1 for cancer (17.9% reduction; 95% CI, 17.5%-18.2%), and from 25.3 to 21.1 for diabetes (16.5% reduction; 95% CI, 15.4%-17.5%). In contrast, the rate for COPD increased from 21.0 to 42.2 (100.6% increase; 95% CI, 98.2%-103.1%). However, during the last time segment detected by joinpoint analysis, death rate for COPD in men began to decrease and the declines in rates slowed for heart disease, stroke, and diabetes. For example, the annual decline for heart disease slowed from 3.9% (95% CI, 3.5%-4.2%) during the 2000-2010 period to 1.4% (95% CI, -3.4% to 0.6%) during the 2010-2013 period (P = .02 for slope difference). Between 1969 and 2013, age-standardized years of potential life lost per 1000 decreased from 1.9 to 1.6 for diabetes (14.5% reduction; 95% CI, 12.6%-16.4%), from 21.4 to 12.7 for cancer (40.6%; 95% CI, 40.2%-41.1%), from 19.9 to 10.4 for unintentional injuries (47.5%; 95% CI, 47.0%-48.0%), from 28.8 to 9.1 for heart disease (68.3%; 95% CI, 68.1%-68.5%), and from 6.0 to 1.5 for stroke (74.8%; 95% CI, 74.4%-75.3%). For COPD, the rate for years of potential life lost did not decrease over this time interval. CONCLUSIONS AND RELEVANCE: According to death certificate data between 1969 and 2013, an overall decreasing trend in age standardized death rate was observed for all causes combined, heart disease, cancer, stroke, unintentional injuries, and diabetes, although the rate of decrease appears to have slowed for heart disease, stroke, and diabetes. The death rate for COPD increased during this period. PMID- 26505598 TI - Widespread Scaly Eruption in a Patient With Multiple Comorbidities. PMID- 26505599 TI - Hyperprolactinemia. PMID- 26505600 TI - Abuse-Deterrent Opioid Formulations. PMID- 26505601 TI - Adequacy of Outpatient Specialty Care Access in Marketplace Plans Under the Affordable Care Act. PMID- 26505602 TI - Medical Use of Cannabinoids. PMID- 26505603 TI - Medical Use of Cannabinoids. PMID- 26505604 TI - Medical Use of Cannabinoids--Reply. PMID- 26505605 TI - Promise of Precision Medicine. PMID- 26505606 TI - Promise of Precision Medicine--Reply. PMID- 26505607 TI - Clarification of Author Affiliation. PMID- 26505608 TI - Errors in the Tables. PMID- 26505610 TI - The Cleveland Museum of Health. PMID- 26505611 TI - JAMA PATIENT PAGE. Distracted Driving. PMID- 26505613 TI - Chlorine doping reduces electron-hole recombination in lead iodide perovskites: time-domain ab initio analysis. AB - Rapid development in lead halide perovskites has led to solution-processable thin film solar cells with power conversion efficiencies close to 20%. Nonradiative electron-hole recombination within perovskites has been identified as the main pathway of energy losses, competing with charge transport and limiting the efficiency. Using nonadiabatic (NA) molecular dynamics, combined with time-domain density functional theory, we show that nonradiative recombination happens faster than radiative recombination and long-range charge transfer to an acceptor material. Doping of lead iodide perovskites with chlorine atoms reduces charge recombination. On the one hand, chlorines decrease the NA coupling because they contribute little to the wave functions of the valence and conduction band edges. On the other hand, chlorines shorten coherence time because they are lighter than iodines and introduce high-frequency modes. Both factors favor longer excited state lifetimes. The simulation shows good agreement with the available experimental data and contributes to the comprehensive understanding of electronic and vibrational dynamics in perovskites. The generated insights into design of higher-efficiency solar cells range from fundamental scientific principles, such as the role of electron-vibrational coupling and quantum coherence, to practical guidelines, such as specific suggestions for chemical doping. PMID- 26505612 TI - Development of a Cell-Based Fluorescence Polarization Biosensor Using Preproinsulin to Identify Compounds That Alter Insulin Granule Dynamics. AB - Diabetes currently affects 9.3% of the U.S. population totaling $245 billion annually in U.S. direct and indirect healthcare costs. Current therapies for diabetes are limited in their ability to control blood glucose and/or enhance insulin sensitivity. Therefore, innovative and efficacious therapies for diabetes are urgently needed. Herein we describe a fluorescent insulin reporter system (preproinsulin-mCherry, PPI-mCherry) that tracks live-cell insulin dynamics and secretion in pancreatic beta-cells with utility for high-content assessment of real-time insulin dynamics. Additionally, we report a new modality for sensing insulin granule packaging in conventional high-throughput screening (HTS), using a hybrid cell-based fluorescence polarization (FP)/internal FRET biosensor using the PPI-mCherry reporter system. We observed that bafilomycin, a vacuolar H(+) ATPase inhibitor and inhibitor of insulin granule formation, significantly increased mCherry FP in INS-1 cells with PPI-mCherry. Partial least squares regression analysis demonstrated that an increase of FP by bafilomycin is significantly correlated with a decrease in granularity of PPI-mCherry signal in the cells. The increased FP by bafilomycin is due to inhibition of self-Forster resonant energy transfer (homo-FRET) caused by the increased mCherry intermolecular distance. FP substantially decreases when insulin is tightly packaged in the granules, and the homo-FRET decreases when insulin granule packaging is inhibited, resulting in increased FP. We performed pilot HTS of 1782 FDA-approved small molecules and natural products from Prestwick and Enzo chemical libraries resulting in an overall Z'-factor of 0.52 +/- 0.03, indicating the suitability of this biosensor for HTS. This novel biosensor enables live-cell assessment of protein-protein interaction/protein aggregation in live cells and is compatible with conventional FP plate readers. PMID- 26505614 TI - Application of risk score analysis to low-coverage whole genome sequencing data for the noninvasive detection of trisomy 21, trisomy 18, and trisomy 13. AB - OBJECTIVES: Clinical performance of a low coverage, low cost, massively parallel sequencing (MPS)-based assay to stratify risk of trisomy 21, 18, and 13 pregnancies was determined. METHODS: The study included 1100 samples with birth outcome or karyotype results, comprising low-risk patients (84.2%) negative for risk indications from maternal age, serum screening, ultrasound, or family history, and high-risk patients (15.8%) with at least one of the aforementioned indications. Cell free DNA (cfDNA) was extracted from maternal plasma. Library preparation incorporated 96 index barcodes to enable sequencing on a HiSeq 2000 or 2500. Risk scores were calculated using chromosomal representation, fetal fraction, and maternal age at the estimated date of delivery. A risk score greater than or equal to 1 in 100 was used to stratify samples as high risk for trisomy 21, trisomy 18, or trisomy 13. RESULTS: Sensitivity and specificity were calculated based on risk group stratification. Trisomy 21, trisomy 18, and trisomy 13 were detected with greater than 99% sensitivity and 99.9% specificity. Fetal sex classification accuracy was 99.3%. CONCLUSIONS: We conclude that simplified MPS can be used to stratify the risk of pregnancies for trisomy 21, trisomy 18, and trisomy 13 and accurately determine fetal sex. (c) 2015 John Wiley & Sons, Ltd. PMID- 26505616 TI - Evaluation of 4DryField(r) PH as Adhesion Prevention Barrier Tested in an Optimized Adhesion Model in Rats. AB - BACKGROUND: Adhesions due to pelvic/abdominal surgery are a common serious pathology possibly entailing severe complications. This study investigates the adhesion prevention capability of the novel starch-based agent 4DryField(r) PH, which together with saline solution forms a barrier gel. Herein, an optimized adhesion model (OPAM) inducing severe adhesions/agglutinations with high reproducibility was used. METHODS: In 19 Lewis rats, a 1 * 2 cm abdominal wall defect was created, the peritoneum of the neighboring cecum was abraded, and both injured areas were approximated by suture. Rats were randomized to control (n = 10) or 4DryField PH treatment (n = 9) groups. Another 8 rats had sham surgery for safety assessment of 4DryField PH. At day 7, the quantity and quality of adhesions were assessed macro-/microscopically and evaluated statistically. RESULTS: 4DryField PH treatment significantly reduced the incidence and severity of adhesions as verified by significantly improved adhesion scorings (0.4 vs. 4.5; 1.1 vs. 9). Histology revealed reconstitution of the cecum and abdominal wall including regeneration of the visceral/parietal peritoneum. In sham-operated rats, 4DryField PH did not induce adhesion formation. CONCLUSIONS: 4DryField PH gel was highly effective in preventing adhesions. Histologically, the injured cecum and abdominal wall regenerated well in the presence of 4DryField PH. Considering the severity of OPAM trauma, the potential of 4DryField PH to prevent adhesions can be rated excellent. PMID- 26505615 TI - From Data to Action: Neuroepidemiology Informs Implementation Research for Global Stroke Prevention and Treatment. AB - As a scientific field of study, neuroepidemiology encompasses more than just the descriptive study of the frequency, distribution, determinants and outcomes of neurologic diseases in populations. It also includes experimental aspects that span the full spectrum of clinical and population science research. As such, neuroepidemiology has a strong potential to inform implementation research for global stroke prevention and treatment. This review begins with an overview of the progress that has been made in descriptive and experimental neuroepidemiology over the past quarter century with emphasis on standards for evidence generation, critical appraisal of that evidence and impact on clinical and public health practice at the national, regional and global levels. Specific advances made in high-income countries as well as in low- and middle-income countries are presented. Gaps in implementation as well as evidence gaps in stroke research, stroke burden, clinical outcomes and disparities between developed and developing countries are then described. The continuing need for high quality neuroepidemiologic data in low- and middle-income countries is highlighted. Additionally, persisting disparities in stroke burden and care by sex, race, ethnicity, income and socioeconomic status are discussed. The crucial role that national stroke registries have played in neuroepidemiologic research is also addressed. Opportunities presented by new directions in comparative effectiveness and implementation research are discussed as avenues for turning neuroepidemiological insights into action to maximize health impact and to guide further biomedical research on neurological diseases. PMID- 26505617 TI - Eradication of esophageal varices by sclerotherapy combined with argon plasma coagulation: Effect of portal hemodynamics and longitudinal clinical course. AB - BACKGROUND AND AIM: To demonstrate the effect of endoscopic injection sclerotherapy (EIS) with argon plasma coagulation (APC) as a primary/secondary prophylaxis for esophageal varies (EV) on portal hemodynamics and long-term outcomes in cirrhosis. METHODS: This prospective study included 48 cirrhotic patients (64.5 +/- 11.4 years; 26 bleeders, 22 non-bleeders). Post-treatment outcomes (EIS and APC; median observation period, 12.8 months for recurrence and 21.1 months for prognosis) were evaluated with respect to the findings of hepatic venous catheterization, Doppler ultrasound, and endoscopic ultrasonography (EUS). RESULTS: All patients showed EV eradication after endoscopic treatment, and a decreased frequency of a patent left gastric vein (pre: 83.3%, post: 27.1%, P < 0.001). However, hepatic venous pressure gradient (HVPG, mmHg) remained unchanged after the treatment, pre: 16.1 +/- 3.6, post: 15.6 +/- 3.8 (P = 0.269). Cumulative variceal recurrence/rebleeding rates were 25.5%/5.6% and 62.4%/23.1% at 1 and 3 years, respectively. Post-treatment EUS finding, area of submucosal vessels in the cardia >=12 mm2 was the only significant factor for variceal recurrence (hazard ratio 9.769, 95% confidence interval 3.046-31.337; P < 0.001). Cumulative recurrence rate was significantly higher in patients with area of submucosal vessels in the cardia >=12 mm2 (58.3% at 1 year and 100% at 3 years) than in those without (11.4% at 1 year and 40.9% at 3 years, P < 0.001). Cumulative overall survival rates were 95.2% and 71.9% at 1 and 3 years, respectively, showing no significant relationship with HVPG. CONCLUSION: EIS with APC for EV is unlikely to have a significant influence on portal pressure. PMID- 26505618 TI - Evidence synthesis activities of a hospital evidence-based practice center and impact on hospital decision making. AB - BACKGROUND: Hospital evidence-based practice centers (EPCs) synthesize and disseminate evidence locally, but their impact on institutional decision making is unclear. OBJECTIVE: To assess the evidence synthesis activities and impact of a hospital EPC serving a large academic healthcare system. DESIGN, SETTING, AND PARTICIPANTS: Descriptive analysis of the EPC's database of rapid systematic reviews since EPC inception (July 2006-June 2014), and survey of report requestors from the EPC's last 4 fiscal years. MEASUREMENTS: Descriptive analyses examined requestor and report characteristics; questionnaire examined report usability, impact, and requestor satisfaction (higher scores on 5-point Likert scales reflected greater agreement). RESULTS: The EPC completed 249 evidence reviews since inception. The most common requestors were clinical departments (29%, n = 72), chief medical officers (19%, n = 47), and purchasing committees (14%, n = 35). The most common technologies reviewed were drugs (24%, n = 60), devices (19%, n = 48), and care processes (12%, n = 31). Mean report completion time was 70 days. Thirty reports (12%) informed computerized decision support interventions. More than half of reports (56%, n = 139) were completed in the last 4 fiscal years for 65 requestors. Of the 64 eligible participants, 46 responded (72%). Requestors were satisfied with the report (mean = 4.4), and agreed it was delivered promptly (mean = 4.4), answered the questions posed (mean = 4.3), and informed their final decision (mean = 4.1). CONCLUSIONS: This is the first examination of evidence synthesis activities by a hospital EPC in the United States. Our findings suggest hospital EPCs can efficiently synthesize and disseminate evidence addressing a range of clinical topics for diverse stakeholders, and can influence local decision making. PMID- 26505619 TI - Preliminary evaluation of a highly automated instrument for the selection of CD34+ cells from mobilized peripheral blood stem cell concentrates. AB - BACKGROUND: Cell selection is an important part of manufacturing cellular therapies. A new highly automated instrument, the CliniMACS Prodigy (Miltenyi Biotec), was evaluated for the selection of CD34+ cells from mobilized peripheral blood stem cell (PBSC) concentrates using monoclonal antibodies conjugated to paramagnetic particles. STUDY DESIGN AND METHODS: PBSCs were collected by apheresis from 36 healthy subjects given granulocyte-colony-stimulating factor (G CSF) or G-CSF plus plerixafor. CD34+ cells from 11 PBSC concentrates were isolated with the automated CliniMACS Prodigy and 25 with the semiautomated CliniMACS Plus Instrument. RESULTS: The proportion of CD34+ cells in the selected products obtained with the two instruments was similar: 93.6 +/- 2.6% for the automated and 95.7 +/- 3.3% for the semiautomated instrument (p > 0.05). The recovery of CD34+ cells from PBSC concentrates was less for the automated than the semiautomated instrument (51.4 +/- 8.2% vs. 65.1 +/- 15.7%; p = 0.019). The selected products from both instruments contained few and similar quantities of platelets (PLTs) and red blood cells. The depletion of CD3+ cells was less with the automated instrument (4.34 +/- 0.2 log depletion vs. 5.20 +/- 0.35 log depletion; p < 1 * 10(-6) ). Removal of PLTs from PBSC concentrates by washing was associated with better CD34+ cell recovery. We explored the reasons for lower CD34+ cell recovery by the Prodigy and found that the nonselected cells for the Prodigy contained more PLTs than those for the CliniMACS Plus. CONCLUSIONS: CD34+ cells can be effectively selected from mobilized PBSC concentrates with the CliniMAC Prodigy, but the recovery of CD34+ cells and depletion of CD3+ cells was lower than with the semiautomated CliniMACS Plus Instrument. PMID- 26505620 TI - Influenza hospitalization epidemiology from a severe acute respiratory infection surveillance system in Jordan, January 2008-February 2014. AB - BACKGROUND: Acute respiratory infections (ARIs) are a major cause of morbidity and mortality worldwide. Influenza typically contributes substantially to the burden of ARI, but only limited data are available on influenza activity and seasonality in Jordan. METHODS: Syndromic case definitions were used to identify individuals with severe acute respiratory infections (SARI) admitted to four sentinel hospitals in Jordan. Demographic and clinical data were collected. Nasopharyngeal and oropharyngeal swabs were tested for influenza using real-time reverse transcription polymerase chain reaction and typed as influenza A or B, with influenza A further subtyped. RESULTS: From January 2008-February 2014, 2891 SARI cases were tested for influenza, and 257 (9%) were positive. While 73% of all SARI cases were under 5 years of age, only 57% of influenza-positive cases were under 5 years of age. Eight (3%) influenza-positive cases died. An annual seasonal pattern of influenza activity was observed. The proportion of influenza positive cases peaked during November-January (14-42%) in the non-pandemic years. CONCLUSIONS: Influenza is associated with substantial morbidity and mortality in Jordan. The seasonal pattern of influenza aligns with known Northern Hemisphere seasonality. Further characterization of the clinical and financial burden of influenza in Jordan will be critical in supporting decisions regarding disease control activities. PMID- 26505621 TI - Mucoadhesive Buccal Tablets Based on Chitosan/Gelatin Microparticles for Delivery of Propranolol Hydrochloride. AB - Propranolol administration through buccal route offers some distinct advantages thanks to the easy access to the oral mucosa, fast onset of action, and avoidance of hepatic and intestinal degradation mechanisms. To overcome the effective removal existing in the buccal cavity, mucoadhesive delivery systems are considered a promising approach as they facilitate a close contact with the buccal mucosa. The aim of this study was to prepare mucoadhesive tablets based on chitosan/gelatin microparticles for buccal delivery of propranolol hydrochloride. Spray-dried microparticles were prepared with different chitosan-gelatin weight ratios and characterized in terms of yield and morphology. Microparticles were subsequently compressed with the drug to obtain loaded buccal tablets. In vitro water uptake, mucoadhesion, release, and permeation tests were performed to investigate tablet ability to hydrate, to adhere to the mucosa, and to deliver drug through buccal mucosa. Microparticles showed a different morphology based on the different chitosan-gelatin weight ratios. Moreover, buccal tablets based on the prepared microparticles showed different technological and functional characteristics in virtue of their composition. In particular, tablets with an excess of chitosan showed the best mucoadhesive properties, allowed the permeation of the greatest drug amount among all formulations, and could be promising for buccal administration of propranolol hydrochloride. PMID- 26505622 TI - Fixing Formalin: A Method to Recover Genomic-Scale DNA Sequence Data from Formalin-Fixed Museum Specimens Using High-Throughput Sequencing. AB - For 150 years or more, specimens were routinely collected and deposited in natural history collections without preserving fresh tissue samples for genetic analysis. In the case of most herpetological specimens (i.e. amphibians and reptiles), attempts to extract and sequence DNA from formalin-fixed, ethanol preserved specimens-particularly for use in phylogenetic analyses-has been laborious and largely ineffective due to the highly fragmented nature of the DNA. As a result, tens of thousands of specimens in herpetological collections have not been available for sequence-based phylogenetic studies. Massively parallel High-Throughput Sequencing methods and the associated bioinformatics, however, are particularly suited to recovering meaningful genetic markers from severely degraded/fragmented DNA sequences such as DNA damaged by formalin-fixation. In this study, we compared previously published DNA extraction methods on three tissue types subsampled from formalin-fixed specimens of Anolis carolinensis, followed by sequencing. Sufficient quality DNA was recovered from liver tissue, making this technique minimally destructive to museum specimens. Sequencing was only successful for the more recently collected specimen (collected ~30 ybp). We suspect this could be due either to the conditions of preservation and/or the amount of tissue used for extraction purposes. For the successfully sequenced sample, we found a high rate of base misincorporation. After rigorous trimming, we successfully mapped 27.93% of the cleaned reads to the reference genome, were able to reconstruct the complete mitochondrial genome, and recovered an accurate phylogenetic placement for our specimen. We conclude that the amount of DNA available, which can vary depending on specimen age and preservation conditions, will determine if sequencing will be successful. The technique described here will greatly improve the value of museum collections by making many formalin fixed specimens available for genetic analysis. PMID- 26505623 TI - Understanding the Influence of Race/Ethnicity, Gender, and Class on Inequalities in Academic and Non-Academic Outcomes among Eighth-Grade Students: Findings from an Intersectionality Approach. AB - Socioeconomic, racial/ethnic, and gender inequalities in academic achievement have been widely reported in the US, but how these three axes of inequality intersect to determine academic and non-academic outcomes among school-aged children is not well understood. Using data from the US Early Childhood Longitudinal Study-Kindergarten (ECLS-K; N = 10,115), we apply an intersectionality approach to examine inequalities across eighth-grade outcomes at the intersection of six racial/ethnic and gender groups (Latino girls and boys, Black girls and boys, and White girls and boys) and four classes of socioeconomic advantage/disadvantage. Results of mixture models show large inequalities in socioemotional outcomes (internalizing behavior, locus of control, and self-concept) across classes of advantage/disadvantage. Within classes of advantage/disadvantage, racial/ethnic and gender inequalities are predominantly found in the most advantaged class, where Black boys and girls, and Latina girls, underperform White boys in academic assessments, but not in socioemotional outcomes. In these latter outcomes, Black boys and girls perform better than White boys. Latino boys show small differences as compared to White boys, mainly in science assessments. The contrasting outcomes between racial/ethnic and gender minorities in self-assessment and socioemotional outcomes, as compared to standardized assessments, highlight the detrimental effect that intersecting racial/ethnic and gender discrimination have in patterning academic outcomes that predict success in adult life. Interventions to eliminate achievement gaps cannot fully succeed as long as social stratification caused by gender and racial discrimination is not addressed. PMID- 26505624 TI - Characterizing the Propagation of Uterine Electrophysiological Signals Recorded with a Multi-Sensor Abdominal Array in Term Pregnancies. AB - The objective of this study was to quantify the number of segments that have contractile activity and determine the propagation speed from uterine electrophysiological signals recorded over the abdomen. The uterine magnetomyographic (MMG) signals were recorded with a 151 channel SARA (SQUID Array for Reproductive Assessment) system from 36 pregnant women between 37 and 40 weeks of gestational age. The MMG signals were scored and segments were classified based on presence of uterine contractile burst activity. The sensor space was then split into four quadrants and in each quadrant signal strength at each sample was calculated using center-of-gravity (COG). To this end, the cross correlation analysis of the COG was performed to calculate the delay between pairwise combinations of quadrants. The relationship in propagation across the quadrants was quantified and propagation speeds were calculated from the delays. MMG recordings were successfully processed from 25 subjects and the average values of propagation speeds ranged from 1.3-9.5 cm/s, which was within the physiological range. The propagation was observed between both vertical and horizontal quadrants confirming multidirectional propagation. After the multiple pairwise test (99% CI), significant differences in speeds can be observed between certain vertical or horizontal combinations and the crossed pair combinations. The number of segments containing contractile activity in any given quadrant pair with a detectable delay was significantly higher in the lower abdominal pairwise combination as compared to all others. The quadrant-based approach using MMG signals provided us with high spatial-temporal information of the uterine contractile activity and will help us in the future to optimize abdominal electromyographic (EMG) recordings that are practical in a clinical setting. PMID- 26505625 TI - Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma. AB - BACKGROUND: The exonic single-nucleotide variant rs11762213 located in the MET oncogene has recently been identified as a prognostic marker in clear cell renal cell carcinoma (ccRCC). This finding was validated with The Cancer Genome Atlas (TCGA) cohort, and the biologic implications were explored. METHODS: The genotype status for rs11762213 was available for 272 patients. Paired tumor-normal data, genomic data, and clinical information were acquired from ccRCC TCGA data sets. Cancer-specific survival (CSS) was analyzed with the competing risk method, and Cox proportional hazards regression was used for the analysis of the time to recurrence (TTR). Multivariate competing risk models were fitted to adjust for the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. RESULTS: The variant allele of rs11762213 was detected in 10.3% of the cohort. After adjustments for the SSIGN score, the risk allele remained a significant predictor for adverse CSS (hazard ratio [HR], 3.88; 95% confidence interval [CI], 1.99-7.56; P < .0001) and for TTR (OR, 2.97; 95% CI, 1.43-6.2; P = .003). The mapping of rs11762213 to regulatory regions within the genome suggested that it might affect a DNA enhancer region. RNA and protein sequencing data for MET did not reveal differences in steady-state expression with stratification by risk allele. CONCLUSIONS: The exonic MET variant rs11762213 is an independent predictor of adverse CSS and TTR in ccRCC and should be integrated into clinical practice for prognostic stratification. Genomic analysis suggests that the single nucleotide polymorphism may affect an enhancer region located in the coding region of MET. Further biological mechanistic interrogation is currently underway. PMID- 26505626 TI - Residues 39-56 of Stem Cell Factor Protein Sequence Are Capable of Stimulating the Expansion of Cord Blood CD34+ Cells. AB - BACKGROUND: Stem cell factor (SCF) can stimulate hematopoietic stem cell (HSC) expansion; however, the specific structural region(s) of SCF protein that are critical for this function are still unknown. A novel monoclonal antibody (named 23C8) against recombinant human SCF (rhSCF) was previously found to inhibit the ability of rhSCF to enhance HSC expansion, making it possible to identify the relevant active region to HSC. METHODS: Eleven polypeptides were synthesized, which were designed to cover the full-length of rhSCF, with overlaps that are at least 3 amino acids long. ELISA was used to identify the polypeptide(s) that specifically react with the anti-SCF. The effects of the synthetic polypeptides on human HSC expansion, or on the ability of the full-length rhSCF to stimulate cell proliferation, were evaluated ex vivo. Total cell number was monitored using hemocytometer whereas CD34+ cell number was calculated based on the proportion determined via flow cytometry on day 6 of culture. RESULTS: Of all polypeptides analyzed, only one, named P0, corresponding to the SCF protein sequence at residues 39-56, was recognized by 23C8 mAb during ELISA. P0 stimulated the expansion of CD34+ cells derived from human umbilical cord blood (UCB). Addition of P0 increased the numbers of total mononucleated cells and CD34+ cells, by ~2 fold on day 6. P0 also showed partial competition against full-length rhSCF in the ex vivo cell expansion assay. CONCLUSION: Residues 39-56 of rhSCF comprise a critical functional region for its ability to enhance expansion of human UCB CD34+ cells. The peptide P0 is a potential candidate for further development as a synthetic substitute for rhSCF in laboratory and clinical applications. PMID- 26505628 TI - Correction: Genome Wide Identification of LIM Genes in Cicer arietinum and Response of Ca-2LIMs in Development, Hormone and Pathogenic Stress. PMID- 26505627 TI - Plant Invasions Associated with Change in Root-Zone Microbial Community Structure and Diversity. AB - The importance of plant-microbe associations for the invasion of plant species have not been often tested under field conditions. The research sought to determine patterns of change in microbial communities associated with the establishment of invasive plants with different taxonomic and phenetic traits. Three independent locations in Virginia, USA were selected. One site was invaded by a grass (Microstegium vimineum), another by a shrub (Rhamnus davurica), and the third by a tree (Ailanthus altissima). The native vegetation from these sites was used as reference. 16S rRNA and ITS regions were sequenced to study root-zone bacterial and fungal communities, respectively, in invaded and non-invaded samples and analyzed using Quantitative Insights Into Microbial Ecology (QIIME). Though root-zone microbial community structure initially differed across locations, plant invasion shifted communities in similar ways. Indicator species analysis revealed that Operational Taxonomic Units (OTUs) closely related to Proteobacteria, Acidobacteria, Actinobacteria, and Ascomycota increased in abundance due to plant invasions. The Hyphomonadaceae family in the Rhodobacterales order and ammonia-oxidizing Nitrospirae phylum showed greater relative abundance in the invaded root-zone soils. Hyphomicrobiaceae, another bacterial family within the phyla Proteobacteria increased as a result of plant invasion, but the effect associated most strongly with root-zones of M. vimineum and R. davurica. Functional analysis using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) showed bacteria responsible for nitrogen cycling in soil increased in relative abundance in association with plant invasion. In agreement with phylogenetic and functional analyses, greater turnover of ammonium and nitrate was associated with plant invasion. Overall, bacterial and fungal communities changed congruently across plant invaders, and support the hypothesis that nitrogen cycling bacteria and functions are important factors in plant invasions. Whether the changes in microbial communities are driven by direct plant microbial interactions or a result of plant-driven changes in soil properties remains to be determined. PMID- 26505629 TI - The brain as immunoprecipitator of serum autoantibodies against N-Methyl-D aspartate receptor subunit NR1. AB - Autoantibodies (AB) against N-methyl-D-aspartate receptor subunit NR1 (NMDAR1) are highly seroprevalent in health and disease. Symptomatic relevance may arise upon compromised blood-brain barrier (BBB). However, it remained unknown whether circulating NMDAR1 AB appear in the cerebrospinal fluid (CSF). Of n = 271 subjects with CSF-serum pairs, 26 were NMDAR1 AB seropositive, but only 1 was CSF positive. Contrariwise, tetanus AB (non-brain-binding) were present in serum and CSF of all subjects, with CSF levels higher upon BBB dysfunction. Translational mouse experiments proved the hypothesis that the brain acts as an 'immunoprecipitator'; simultaneous injection of NMDAR1 AB and the non-brain binding green fluorescent protein AB resulted in high detectability of the former in brain and the latter in CSF. PMID- 26505630 TI - Can Silica Particles Reduce Air Pollution by Facilitating the Reactions of Aliphatic Aldehyde and NO2? AB - This study investigated the heterogeneous atmospheric reactions of acetaldehyde, propanal, and butanal with NO2 onto silica (SiO2) clusters using a theoretical approach. By analyzing spectral features and adsorption parameters, the formation of hydrogen bonds and negative adsorption energies provide evidence that an efficient spontaneous uptake of aliphatic aldehydes onto SiO2 could occur. The atmospheric reaction mechanisms show that when aldehydes and NO2 react on the surface model, the H atom abstraction reaction from the aldehydic molecule by NO2 is an exclusive channel, forming nitrous acid and acyl radicals. This study included kinetics exploring the reaction of aldehydes with NO2 using a canonical variational transition state theory. The reaction rate constants are increased in the presence of SiO2 between the temperatures 217 and 298 K. This may explain how aldehydes can temporarily stay on mineral particles without chemical reactions. The results suggest that silica can depress the rate at which the studied aldehydes react with NO2 and possibly reduce air pollution generated by these atmospheric reactions. PMID- 26505631 TI - Oriented Cell Division in the C. elegans Embryo Is Coordinated by G-Protein Signaling Dependent on the Adhesion GPCR LAT-1. AB - Orientation of spindles and cell division planes during development of many species ensures that correct cell-cell contacts are established, which is vital for proper tissue formation. This is a tightly regulated process involving a complex interplay of various signals. The molecular mechanisms underlying several of these pathways are still incompletely understood. Here, we identify the signaling cascade of the C. elegans latrophilin homolog LAT-1, an essential player in the coordination of anterior-posterior spindle orientation during the fourth round of embryonic cell division. We show that the receptor mediates a G protein-signaling pathway revealing that G-protein signaling in oriented cell division is not solely GPCR-independent. Genetic analyses showed that through the interaction with a Gs protein LAT-1 elevates intracellular cyclic AMP (cAMP) levels in the C. elegans embryo. Stimulation of this G-protein cascade in lat-1 null mutant nematodes is sufficient to orient spindles and cell division planes in the embryo in the correct direction. Finally, we demonstrate that LAT-1 is activated by an intramolecular agonist to trigger this cascade. Our data support a model in which a novel, GPCR-dependent G protein-signaling cascade mediated by LAT-1 controls alignment of cell division planes in an anterior-posterior direction via a metabotropic Gs-protein/adenylyl cyclase pathway by regulating intracellular cAMP levels. PMID- 26505632 TI - ENCORE: Software for Quantitative Ensemble Comparison. AB - There is increasing evidence that protein dynamics and conformational changes can play an important role in modulating biological function. As a result, experimental and computational methods are being developed, often synergistically, to study the dynamical heterogeneity of a protein or other macromolecules in solution. Thus, methods such as molecular dynamics simulations or ensemble refinement approaches have provided conformational ensembles that can be used to understand protein function and biophysics. These developments have in turn created a need for algorithms and software that can be used to compare structural ensembles in the same way as the root-mean-square-deviation is often used to compare static structures. Although a few such approaches have been proposed, these can be difficult to implement efficiently, hindering a broader applications and further developments. Here, we present an easily accessible software toolkit, called ENCORE, which can be used to compare conformational ensembles generated either from simulations alone or synergistically with experiments. ENCORE implements three previously described methods for ensemble comparison, that each can be used to quantify the similarity between conformational ensembles by estimating the overlap between the probability distributions that underlie them. We demonstrate the kinds of insights that can be obtained by providing examples of three typical use-cases: comparing ensembles generated with different molecular force fields, assessing convergence in molecular simulations, and calculating differences and similarities in structural ensembles refined with various sources of experimental data. We also demonstrate efficient computational scaling for typical analyses, and robustness against both the size and sampling of the ensembles. ENCORE is freely available and extendable, integrates with the established MDAnalysis software package, reads ensemble data in many common formats, and can work with large trajectory files. PMID- 26505633 TI - The Use of Prescription Drugs, Recreational Drugs, and "Soft Enhancers" for Cognitive Enhancement among Swiss Secondary School Students. AB - The use of prescription or recreational drugs for cognitive enhancement (CE) is prevalent among students. However, the prevalence of CE among Swiss school students is unknown. We therefore performed a cross-sectional online survey including >= 16-year-old students from bridge-year schools (10th grade), vocational schools, and upper secondary schools (10th-12th grade) in the Canton of Zurich to investigate the prevalence of and motives for the use of prescription drugs, recreational drugs, and/or freely available soft enhancers for CE. A total of 1,139 students were included. Of these, 54.5% reported the use of prescription drugs (9.2%), recreational drugs including alcohol (6.2%), or soft enhancers (51.3%) explicitly for CE at least once in their lives. The last year and last-month prevalence for CE considering all substances was 45.5% and 39.5%, respectively. Soft enhancers were the substances that were most commonly used (ever, last-year, and last-month, respectively), including energy drinks (33.3%, 28.4%, and 24.6%), coffee (29.8%, 25.1%, and 21.9%), and tobacco (12.6%, 9.3%, and 8.3%). CE with methylphenidate was less prevalent (4.0%, 2.8%, and 2.0%). However, the use of prescription drugs, alcohol, or illegal drugs for CE was reported by 13.3% of the participants. The most common motives for use were to stay awake and improve concentration. CE was more prevalent among students who reported higher levels of stress or performance pressure and students with psychiatric disorders. In conclusion, half of the school students had used a substance at least once in their lives to improve school performance. Soft enhancers were most commonly used. Prevalence rates were similar to those reported by Swiss university students, indicating that the use of prescription or recreational drugs for CE already occurs before starting higher education. Performance pressure, stress, and psychiatric disorders may be associated with CE. PMID- 26505634 TI - Co-expression of Interleukin-15 Enhances the Protective Immune Responses Induced by Immunization with a Murine Malaria MVA-Based Vaccine Encoding the Circumsporozoite Protein. AB - Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS,S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)-based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naive controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies. PMID- 26505636 TI - Comment On: Use of Patient Registries and Administrative Datasets for the Study of Pediatric Cancer. PMID- 26505635 TI - Egg-laying sequence influences egg mercury concentrations and egg size in three bird species: Implications for contaminant monitoring programs. AB - Bird eggs are commonly used in contaminant monitoring programs and toxicological risk assessments, but intraclutch variation and sampling methodology could influence interpretability. The authors examined the influence of egg-laying sequence on egg mercury concentrations and burdens in American avocets, black necked stilts, and Forster's terns. The average decline in mercury concentrations between the first and last eggs laid was 33% for stilts, 22% for terns, and 11% for avocets, and most of this decline occurred between the first and second eggs laid (24% for stilts, 18% for terns, and 9% for avocets). Trends in egg size with egg-laying order were inconsistent among species, and overall differences in egg volume, mass, length, and width were <3%. The authors summarized the literature, and among 17 species studied, mercury concentrations generally declined by 16% between the first and second eggs laid. Despite the strong effect of egg-laying sequence, most of the variance in egg mercury concentrations still occurred among clutches (75-91%) rather than within clutches (9%-25%). Using simulations, the authors determined that accurate estimation of a population's mean egg mercury concentration using only a single random egg from a subset of nests would require sampling >60 nests to represent a large population (10% accuracy) or >=14 nests to represent a small colony that contained <100 nests (20% accuracy). Environ Toxicol Chem 2016;35:1458-1469. Published 2015 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America. PMID- 26505637 TI - Multiclass Classification of Agro-Ecological Zones for Arabica Coffee: An Improved Understanding of the Impacts of Climate Change. AB - Cultivation of Coffea arabica is highly sensitive to and has been shown to be negatively impacted by progressive climatic changes. Previous research contributed little to support forward-looking adaptation. Agro-ecological zoning is a common tool to identify homologous environments and prioritize research. We demonstrate here a pragmatic approach to describe spatial changes in agro climatic zones suitable for coffee under current and future climates. We defined agro-ecological zones suitable to produce arabica coffee by clustering geo referenced coffee occurrence locations based on bio-climatic variables. We used random forest classification of climate data layers to model the spatial distribution of these agro-ecological zones. We used these zones to identify spatially explicit impact scenarios and to choose locations for the long-term evaluation of adaptation measures as climate changes. We found that in zones currently classified as hot and dry, climate change will impact arabica more than those that are better suited to it. Research in these zones should therefore focus on expanding arabica's environmental limits. Zones that currently have climates better suited for arabica will migrate upwards by about 500m in elevation. In these zones the up-slope migration will be gradual, but will likely have negative ecosystem impacts. Additionally, we identified locations that with high probability will not change their climatic characteristics and are suitable to evaluate C. arabica germplasm in the face of climate change. These locations should be used to investigate long term adaptation strategies to production systems. PMID- 26505638 TI - Lithium Disilicate Restorations Fatigue Testing Parameters: A Systematic Review. AB - PURPOSE: To review laboratory studies that investigated fatigue resistance of lithium disilicate (LD) crowns and fixed dental prostheses (FDPs) to elucidate study designs and testing parameters. METHODS: An electronic search was performed in PubMed, Scopus, and Ovid to identify in vitro studies that investigated fatigue resistance of LD crowns and FDPs. The search included all studies published in English in peer-reviewed journals in the period from 1998 to June 2014. The search followed a specific strategy that included combination of the following keywords: lithium disilicate, e.max, empress, all-ceramic, all ceramic, glass ceramic, fatigue, cyclic loading, dynamic loading, chewing simulator, fracture resistance, thermocycling, laboratory simulation, aging, crown, FDPs, FPDs, fixed partial denture, fixed dental prosthesis, and bridge. Studies were selected if mechanical and thermal loading parameters were clearly identified. Search results with abstracts were transferred into Endnote reference system, and duplicates were deleted. The remaining studies were then reviewed at three levels (title, abstract, full text) to further refine the articles. RESULTS: The initial search retrieved 1044 eligible studies. After deduplication, 864 records were examined by titles and then abstracts; 826 were excluded, and 38 were assessed by full-text reading. In total, 19 articles met inclusion criteria and were included in this study. CONCLUSION: The studies reviewed showed a level of heterogeneity, as testing parameters were considered through different setups. The current study demonstrated that various setting of the testing parameters and having a lack of testing standardization has likely led to inconsistency in the reported results. The obvious heterogeneity in the setting of testing variables-especially the magnitude of load and number of cycles applied-made it impractical to run direct comparisons between the reviewed studies. Therefore, specific international standardization of fatigue testing of dental restorations is urgently needed to ensure the delivery of consistent, indicative, and comparable data. PMID- 26505640 TI - T cells, teeth and tissue destruction - what do T cells do in periodontal disease? AB - The microbial plaque biofilm resides adjacent to the tissue-destructive inflammatory infiltrate in periodontitis. Although not sufficient, this biofilm is necessary for this inflammatory response. Patients with periodontitis generate antibodies specific for bacteria in the biofilm - although the role of these antibodies is not clear, there is, undoubtedly, an adaptive immune response in periodontitis. T lymphocytes are central to adaptive immunity, and provide help for B cells to generate specific antibodies. T-cell receptor recognition of peptide antigen in the context of major histocompatibility complex can result in T-cell activation. The activation and differentiation of the T-cell can take many forms, and hence numerous types of T cells have been described. The role of adaptive immune responses, and the T-cell component thereof, in periodontitis remains relatively poorly defined. This review aims to broadly summarize findings about T cells and their role in periodontitis, focusing primarily on studies of human disease with a short discussion of some animal studies. PMID- 26505639 TI - Discovery of Infection Associated Metabolic Markers in Human African Trypanosomiasis. AB - Human African trypanosomiasis (HAT) remains a major neglected tropical disease in Sub-Saharan Africa. As clinical symptoms are usually non-specific, new diagnostic and prognostic markers are urgently needed to enhance the number of identified cases and optimise treatment. This is particularly important for disease caused by Trypanosoma brucei rhodesiense, where indirect immunodiagnostic approaches have to date been unsuccessful. We have conducted global metabolic profiling of plasma from T.b.rhodesiense HAT patients and endemic controls, using 1H nuclear magnetic resonance (NMR) spectroscopy and ultra-performance liquid chromatography, coupled with mass spectrometry (UPLC-MS) and identified differences in the lipid, amino acid and metabolite profiles. Altogether 16 significantly disease discriminatory metabolite markers were found using NMR, and a further 37 lipid markers via UPLC-MS. These included significantly higher levels of phenylalanine, formate, creatinine, N-acetylated glycoprotein and triglycerides in patients relative to controls. HAT patients also displayed lower concentrations of histidine, sphingomyelins, lysophosphatidylcholines, and several polyunsaturated phosphatidylcholines. While the disease metabolite profile was partially consistent with previous data published in experimental rodent infection, we also found unique lipid and amino acid profile markers highlighting subtle but important differences between the host response to trypanosome infections between animal models and natural human infections. Our results demonstrate the potential of metabolic profiling in the identification of novel diagnostic biomarkers and the elucidation of pathogenetic mechanisms in this disease. PMID- 26505641 TI - Effect of Structure on Transport Properties (Viscosity, Ionic Conductivity, and Self-Diffusion Coefficient) of Aprotic Heterocyclic Anion (AHA) Room-Temperature Ionic Liquids. 1. Variation of Anionic Species. AB - A series of room temperature ionic liquids (RTILs) based on 1-ethyl-3 methylimidazolium ([emim](+)) with different aprotic heterocyclic anions (AHAs) were synthesized and characterized as potential electrolyte candidates for lithium ion batteries. The density and transport properties of these ILs were measured over the temperature range between 283.15 and 343.15 K at ambient pressure. The temperature dependence of the transport properties (viscosity, ionic conductivity, self-diffusion coefficient, and molar conductivity) is fit well by the Vogel-Fulcher-Tamman (VFT) equation. The best-fit VFT parameters, as well as linear fits to the density, are reported. The ionicity of these ILs was quantified by the ratio of the molar conductivity obtained from the ionic conductivity and molar concentration to that calculated from the self-diffusion coefficients using the Nernst-Einstein equation. The results of this study, which is based on ILs composed of both a planar cation and planar anions, show that many of the [emim][AHA] ILs exhibit very good conductivity for their viscosities and provide insight into the design of ILs with enhanced dynamics that may be suitable for electrolyte applications. PMID- 26505643 TI - Diamagnetic Ru(2+) in Na2La2Ti2RuO10-x (0 < x < 2): A Series of Complex Oxides Prepared by Topochemical Reduction. AB - Reaction of the n = 3 Ruddlesden-Popper phase Na2La2Ti2RuO10 with a 5% H2/95% N2 atmosphere between 300 and 900 degrees C leads to the formation of phases of composition Na2La2Ti2RuO10-x (0 < x < 2) via topochemical reduction. Magnetization data collected from Na2La2Ti2RuO10-x samples in the range 0 < x < 1 show a rapid decline in susceptibility with increasing x, consistent with the conversion of S = 1, Ru(4+) centers at x = 0 to S = 0, Ru(2+) centers at x = 1. We believe this is the first report of diamagnetic Ru(2+) centers in an extended oxide phase. Further reduction of Na2La2Ti2RuO9 leads to the reduction of Ti(4+) to Ti(3+); however, Na2La2Ti2RuO10-x samples in the range 1 < x < 2 exhibit only a very weak paramagnetic response. Given the highly insulating nature of the phases, this suggests the electrons added on reduction of titanium are paired within a local Ti-Ti bonding network in a manner analogous to that observed for TinO2n-1 phases. PMID- 26505642 TI - Research Needs for Understanding the Biology of Overdiagnosis in Cancer Screening. AB - Many cancers offer an extended window of opportunity for early detection and therapeutic intervention that could lead to a reduction in cause-specific mortality. The pursuit of early detection in screening settings has resulted in decreased incidence and mortality for some cancers (e.g., colon and cervical cancers), and increased incidence with only modest or no effect on cause-specific mortality in others (e.g., breast and prostate). Whereas highly sensitive screening technologies are better at detecting a number of suspected "cancers" that are indolent and likely to remain clinically unimportant in the lifetime of a patient, defined as overdiagnosis, they often miss cancers that are aggressive and tend to present clinically between screenings, known as interval cancers. Unrecognized overdiagnosis leads to overtreatment with its attendant (often long lasting) side effects, anxiety, and substantial financial harm. Existing methods often cannot differentiate indolent lesions from aggressive ones or understand the dynamics of neoplastic progression. To correctly identify the population that would benefit the most from screening and identify the lesions that would benefit most from treatment, the evolving genomic and molecular profiles of individual cancers during the clinical course of progression or indolence must be investigated, while taking into account an individual's genetic susceptibility, clinical and environmental risk factors, and the tumor microenvironment. Practical challenges lie not only in the lack of access to tissue specimens that are appropriate for the study of natural history, but also in the absence of targeted research strategies. This commentary summarizes the recommendations from a diverse group of scientists with expertise in basic biology, translational research, clinical research, statistics, and epidemiology and public health professionals convened to discuss research directions. J. Cell. Physiol. 231: 1870-1875, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26505644 TI - Analysis of the ToxCast Chemical-Assay Space Using the Comparative Toxicogenomics Database. AB - Many studies have attempted to predict in vivo hazards based on the ToxCast in vitro assay results with the goal of using these predictions to prioritize compounds for conventional toxicity testing. Most of these conventional studies rely on in vivo end points observed using preclinical species (e.g., mice and rats). Although the preclinical animal studies provide valuable insights, there can often be significant disconnects between these studies and safety concerns in humans. One way to address these concerns, for an admittedly more limited set of compounds, is to explore relationships between the in vitro data from human cell lines and observations from human related studies. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org ) is a rich source of data linking chemicals to human diseases/adverse events and pathways. In this study we explored the relationships between ToxCast chemicals, their ToxCast in vitro test results, and their annotations of human disease/adverse event end points as captured in the CTD database. We mined these associations to identify potentially interesting, statistically significant in vitro assay and in vivo toxicity correlations. To the best of our knowledge, this is one of the first studies analyzing the relationships between the ToxCast in vitro assays results and the CTD disease/adverse event end point annotations. The in vitro profiles identified in this analysis may prove useful for prioritizing compounds for toxicity testing, suggesting mechanisms of toxicity, and forecasting potential in vivo human drug induced injury. PMID- 26505645 TI - Cicada-Wing-Inspired Self-Cleaning Antireflection Coatings on Polymer Substrates. AB - The cicada has transparent wings with remarkable self-cleaning properties and high transmittance over the whole visible spectral range, which is derived from periodic conical structures covering the wing surface. Here we report a scalable self-assembly technique for fabricating multifunctional optical coatings that mimic cicada-wing structures. Spin-coated two-dimensional non-close-packed colloidal crystals are utilized as etching masks to pattern subwavelength structured cone arrays directly on polymer substrates. The resulting gratings exhibit broadband antireflection performance and superhydrophobic properties after surface modification. The dependence of the cone shape and size on the antireflective and self-cleaning properties has also been investigated in this study. PMID- 26505646 TI - Clarithromycin Synergistically Enhances Thalidomide Cytotoxicity in Myeloma Cells. AB - Clarithromycin (CAM) is a macrolide antibiotic that is widely used in the treatment of respiratory tract infections, sexually transmitted diseases and infections caused by the Helicobacter pylori and Mycobacterium avium complex. Recent studies showed that CAM was highly effective against multiple myeloma (MM) when used in combination with immunomodulatory drugs and dexamethasone. However, the related mechanism is still unknown. As 3 immunomodulatory agents are all effective in the respective regimen, we postulated that CAM might enhance the effect of immunomodulatory drugs. We evaluated the interaction effects of CAM and thalidomide on myeloma cells. Taking into consideration that thalidomide did not affect the proliferation of myeloma cells in vitro, we cocultured myeloma cells with peripheral blood monocytes and evaluated the effects of CAM and thalidomide on the cocultured cell model. Data showed that thalidomide and CAM synergistically inhibited the proliferation of the cells. On this same model, we also found that thalidomide and CAM synergistically decreased the secretion of tumor necrosis factor-alpha and interleukin-6. This might be caused by the effect of the 2 drugs on inhibiting the activation of ERK1/2 and AKT. These data suggest that the efficacy of CAM against MM was partly due to its synergistic action with the immunomodulatory agents. PMID- 26505647 TI - Discovery of a Small Molecule that Enhances Astrocytogenesis by Activation of STAT3, SMAD1/5/8, and ERK1/2 via Induction of Cytokines in Neural Stem Cells. AB - Identification of small molecules that direct neural stem cells (NSCs) into specific cell types would be helpful to understand the molecular mechanisms involved in regulation of NSC fate, and facilitate the development of therapeutic applications. In the current study, we developed and screened small molecules that can modulate the fate of NSCs that are derived from rat fetal cortex. Among these compounds, compounds 5 and 6 successfully differentiated NSCs into astrocytes and neurons, respectively. Compound 5 induced astrocytogenesis by increasing expression of interleukin-6, bone morphogenetic protein 2 and leukemia inhibitory factor and through consequent phosphorylation of signal transducer and activator of transcription 3 and Sma- and Mad-related protein 1/5/8 in NSCs. In addition, compound 5 increased the expression of fibroblast growth factor (FGF) 2 and FGF8 which may regulate the branching and morphology of astrocytes. Taken together, our results suggest that these small molecules can serve as a useful tool to study cell fate determination in NSCs and be used as an inexpensive alternative to cytokines to study mechanisms of astrocytogenesis. PMID- 26505648 TI - Sortase A-Mediated N-Terminal Modification of Cowpea Chlorotic Mottle Virus for Highly Efficient Cargo Loading. AB - A new strategy is described for the modification of CCMV for loading of cargoes inside the viral capsid. Sortase A, an enzyme which is present in Gram-positive bacteria, was used to attach cargo to the glycine-tagged N-termini of several CCMV variants. We show that small molecules and proteins bearing a C-terminal LPETG-motif can be attached in this way. This method allows for the site specific, covalent, and orthogonal modification of CCMV capsids in a mild fashion, leading to high encapsulation efficiencies. This strategy can easily be expanded to other types of cargoes, labeled with an LPETG-tag without altering protein function. PMID- 26505649 TI - Fast, Label-Free Tracking of Single Viruses and Weakly Scattering Nanoparticles in a Nanofluidic Optical Fiber. AB - High-speed tracking of single particles is a gateway to understanding physical, chemical, and biological processes at the nanoscale. It is also a major experimental challenge, particularly for small, nanometer-scale particles. Although methods such as confocal or fluorescence microscopy offer both high spatial resolution and high signal-to-background ratios, the fluorescence emission lifetime limits the measurement speed, while photobleaching and thermal diffusion limit the duration of measurements. Here we present a tracking method based on elastic light scattering that enables long-duration measurements of nanoparticle dynamics at rates of thousands of frames per second. We contain the particles within a single-mode silica fiber having a subwavelength, nanofluidic channel and illuminate them using the fiber's strongly confined optical mode. The diffusing particles in this cylindrical geometry are continuously illuminated inside the collection focal plane. We show that the method can track unlabeled dielectric particles as small as 20 nm as well as individual cowpea chlorotic mottle virus (CCMV) virions-26 nm in size and 4.6 megadaltons in mass-at rates of over 3 kHz for durations of tens of seconds. Our setup is easily incorporated into common optical microscopes and extends their detection range to nanometer scale particles and macromolecules. The ease-of-use and performance of this technique support its potential for widespread applications in medical diagnostics and micro total analysis systems. PMID- 26505651 TI - Self-rated health and chronic conditions are associated with blood concentrations of persistent organic pollutants in the general population of Catalonia, Spain. AB - BACKGROUND: Self-rated health (SRH) is a powerful predictor of mortality, morbidity, and need for health services. SRH generally increases with educational level, and decreases with age, number of chronic conditions, and body mass index (BMI). Because human concentrations of most persistent organic pollutants (POPs) also vary by age, education, and BMI, and because of the physiological and clinical effects of POPs, we hypothesized that body concentrations of POPs are inversely associated with SRH. OBJECTIVES: To analyze the relation between serum concentrations of POPs and SRH in the general population of Catalonia, Spain, taking into account sociodemographic factors and BMI, as well as chronic health conditions and mental disorders, measured by the General Health Questionnaire-12 (GHQ-12). METHODS: POP serum concentrations were measured by gas chromatography with electron-capture detection in 919 participants of the Catalan Health Interview Survey. RESULTS: Individuals with higher concentrations of POPs had significantly poorer SRH; e.g., the median concentration of HCB in subjects with poor SRH was twice as high as in subjects with excellent SRH (366 ng/g vs. 169 ng/g, respectively; p-value<0.001). In crude models and in models adjusted for sex and BMI, the POPs-SRH association was often dose-dependent, and the likelihood of poor or regular SRH was 2 to 4-times higher in subjects with POP concentrations in the top quartile. In models adjusted for age or for chronic conditions virtually all ORs were near unity. No associations were found between POP levels and GHQ-12. CONCLUSIONS: Individuals with higher concentrations of POPs had significantly poorer SRH, an association likely due to age and chronic conditions, but not to sex, education, social class, BMI, or mental disorders. PMID- 26505650 TI - Pesticide exposure and end-stage renal disease risk among wives of pesticide applicators in the Agricultural Health Study. AB - BACKGROUND: Pesticide exposure has been found to cause renal damage and dysfunction in experimental studies, but epidemiological research on the renal effects of chronic low-level pesticide exposure is limited. We investigated the relationships between end-stage renal disease (ESRD) among wives of licensed pesticide applicators (N=31,142) in the Agricultural Health Study (AHS) and (1) personal pesticide use, (2) exposure to the husband's pesticide use, and (3) other pesticide-associated farming and household activities. METHODS: AHS participants reported pesticide exposure via self-administered questionnaires at enrollment (1993-1997). ESRD cases were identified via linkage to the United States Renal Data System. Associations between ESRD and pesticide exposures were estimated with Cox proportional hazard regression models controlling for age at enrollment. Models of associations with farming and household factors were additionally adjusted for personal use of pesticides. RESULTS: We identified 98 ESRD cases diagnosed between enrollment and 31 December 2011. Although women who ever applied pesticides (56% of cohort) were less likely than those who did not apply to develop ESRD (Hazard Ratio (HR): 0.42; 95% CI: 0.28, 0.64), among women who did apply pesticides, the rate of ESRD was significantly elevated among those who reported the highest (vs. lowest) cumulative general pesticide use (HR: 4.22; 95% CI: 1.26, 14.20). Among wives who never applied pesticides, ESRD was associated with husbands' ever use of paraquat (HR=1.99; 95% CI: 1.14, 3.47) and butylate (HR=1.71; 95% CI: 1.00, 2.95), with a positive exposure-response pattern for husband's cumulative use of these pesticides. CONCLUSIONS: ESRD may be associated with direct and/or indirect exposure to pesticides among farm women. Future studies should evaluate indirect exposure risk among other rural populations. PMID- 26505652 TI - In vitro metabolism of BDE-47, BDE-99, and alpha-, beta-, gamma-HBCD isomers by chicken liver microsomes. AB - The in vitro oxidative metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), 2,2',4,4',5-pentabromodiphenyl ether (BDE-99), and the individual alpha-, beta- and gamma-hexabromocyclododecane (HBCD) isomers catalyzed by cytochrome P450 (CYP) enzymes was studied using chicken liver microsomes (CLMs). Metabolites were identified using a liquid chromatography-tandem mass spectrometry method and authentic standards for the oxidative metabolites of BDE-47 and BDE-99. Six hydroxylated tetra-BDEs, namely 4-hydroxy-2,2',3,4'-tetrabromodiphenyl ether (4 OH-BDE-42), 3-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (3-OH-BDE-47), 5-hydroxy 2,2',4,4'-tetrabromodiphenyl ether (5-OH-BDE-47), 6-hydroxy-2,2',4,4' tetrabromodiphenyl ether (6-OH-BDE-47), 4'-hydroxy-2,2',4,5'- tetrabromodiphenyl ether (4'-OH-BDE-49), and 2'-hydroxy-2,3',4,4'-tetrabromodiphenyl ether (2'-OH BDE-66), were identified and quantified after incubation of BDE-47 with CLMs. 4' OH-BDE-49 was the major metabolite formed. Three hydroxylated penta-BDEs (5' hydroxy-2,2',4,4',5-pentabromodiphenyl ether (5'-OH-BDE-99), 6'-hydroxy 2,2',4,4',5- pentabromodiphenyl ether (6'-OH-BDE-99), and 4'-hydroxy-2,2',4,5,5' pentabromodiphenyl ether, 4'-OH-BDE-101, were formed incubating BDE-99 with CLMs. Concentrations of BDE-99 metabolites were lower than those of BDE-47. More than four mono-hydroxylated HBCD (OH-HBCD), more than four di-hydroxylated HBCD (di-OH HBCD), more than five mono-hydroxylated pentabromocyclododecenes (OH-PBCD), and more than five di-hydroxylated pentabromocyclododecenes (di-OH-PBCD) were detected when alpha-, beta-, or gamma-HBCD were individually incubated with CLMs. Response values (the ratio between the peak areas of the target compound and its internal standard) for OH-HBCD were 1-3 orders of magnitude higher than those for OH-PBCD, di-OH-HBCD, and di-OH-PBCD, suggesting that OH-HBCD might be the major metabolites of alpha-, beta- and gamma-HBCD produced by CLMs. No diastereoisomeric or enantiomeric bioisomerisation was observed incubating alpha , beta- or gamma-HBCD with CLMs. Collectively, our data suggest that (i) BDE-47 is metabolized at a faster rate than BDE-99 by CLMs, (ii) OH-HBCD are the major hydroxylated metabolites of alpha-, beta- and gamma-HBCD produced by CLMs and (iii) the diastereoisomeric or enantiomeric bioisomerisation of alpha-, beta- and gamma-HBCD is not mediated by chicken CYP enzymes. PMID- 26505654 TI - Identification of genetic polymorphisms that predict responder/non-responder profiles to the RhD antigen. AB - BACKGROUND: Regular plasma donors who produce high titre anti-D immunoglobulin (Ig) are overseen by the Australian Red Cross Blood Service RhD Program. New donors to the program are immunised with small amounts of RhD-positive RBCs, whilst donors who have developed anti-D due to previous RhD-incompatible blood transfusion or pregnancy are boosted with RhD-positive RBCs to maintain a high level of serum anti-D Ig. A significant proportion of primarily immunised individuals do not respond to RhD immunisation and are therefore unnecessarily exposed to the risks involved in RBC sensitisation. STUDY DESIGN AND METHODS: We genotyped 184 anti-D donors for ~9000 immunological and inflammatory genetic polymorphisms on an Affymetrix GeneChip, and validated the results with a High Resolution Melt analysis assay. We built and validated a predictive logistic regression model using High Responder and Non-Responder anti-D donors that incorporated highly-associated polymorphisms and gender. RESULTS: High Responder and Non-Responder profiles in anti-D donors were significantly associated with a shortlist of 13 genetic polymorphisms and sex of the donor. The derivation of a logistic regression model showed an accuracy rate of 92.6% that was subsequently validated as 60.0% with an independent set of donor samples. CONCLUSION: This study has developed a logistic regression model and a genotyping assay that can predict the responder profiles of anti-D donors and could potentially be applied to new donors and transfusion-dependent patients in a clinical setting. Additionally, target polymorphisms identified in immunological genes could help to elucidate the immunomodulatory pathways regulating the immune response to the RhD antigen, and to other RBC antigens. PMID- 26505653 TI - Dysregulated co-stimulatory molecule expression in a Sjogren's syndrome mouse model with potential implications by microRNA-146a. AB - Sjogren's syndrome (SjS) is an autoimmune condition that primarily affects salivary and lacrimal glands, causing loss of secretion. We have previously shown that microRNA-146a (miR-146a) is over-expressed in the salivary glands and peripheral blood mononuclear cells (PBMC) of SjS-prone mice (C57BL/6.NOD Aec1Aec2, B6DC) and in PBMC of SjS patients. The purpose of this research was to identify a target molecule of miR-146a and identify subpopulations of cells affected by altered miR-146a in the salivary glands of SjS-prone mice. In silico analyses identified costimulatory molecule CD80 as a potential target of miR 146a. Luciferase assay of the human CD80 3'untranslated region demonstrated miR 146a directly inhibited CD80 protein expression as indicated by reduced luciferase reporter expression and an examination of B6DC salivary glands revealed a reduction in CD80 protein. More interestingly, the specific reduction in CD80 protein was detected from the salivary gland epithelial cell population and in interstitial dendritic cells in the glands as well. The reduction in CD80 protein levels in salivary gland epithelial cells were negatively associated with elevated miR-146a expression. Therefore, this study provides the first indication that salivary gland epithelial cells may be critically involved in SjS progression by altering CD86:CD80 protein ratio in response to miR-146a upregulation. PMID- 26505655 TI - Findings of Abnormal Videofluoroscopic Swallowing Study Identified by High Resolution Manometry Parameters. AB - OBJECTIVE: To identify the parameters of high-resolution manometry (HRM) with a significant correlation to abnormal findings of videofluoroscopic swallowing study (VFSS). DESIGN: Prospective study. SETTING: Hospital rehabilitation department. PARTICIPANTS: Patients with dysphagia symptoms (N=40). INTERVENTION: Participants were evaluated once using VFSS in neutral head position and evaluated twice using HRM with 5mL of thin fluid. MAIN OUTCOME MEASURES: HRM parameters included maximal pressure, area integral, rise time, duration of the velopharynx and tongue base, maximal pressure of pre-upper esophageal sphincter (UES), low pharynx, cricopharyngeus, minimal UES pressure, UES activity time, and nadir UES duration. HRM parameters were compared with the findings of VFSS. Receiver operating characteristic analysis was performed to obtain the cutoff value, sensitivity, and specificity of HRM parameters for the prediction of findings of VFSS. RESULTS: The maximum pressure of the velopharynx showed a significantly positive prediction for most abnormal parameters of VFSS in the pharyngeal phase. Nadir UES pressure duration was significant for impaired laryngeal elevation, residue at pyriformis sinus, and combination of penetration and aspiration. The maximum pressure of the velopharynx <180.0 showed 100% sensitivity and 75% specificity for the presence of penetration and aspiration, and the cutoff point of 178.8 showed 86.7% sensitivity and 75% specificity for the presence of subglottic aspiration. CONCLUSIONS: This study identified significant HRM parameters that are highly specific for individual abnormalities of VFSS, suggesting the cutoff value, sensitivity, and specificity. Because HRM could inform the quantitative measurement of pharyngeal weakness, the cutoff value for HRM parameters could be used to predict aspiration in patients with pharyngeal weakness. PMID- 26505656 TI - Modulation of the xenobiotic transformation system and inflammatory response by ochratoxin A exposure using a co-culture system of Caco-2 and HepG2 cells. AB - Cytotoxicity of ochratoxin A (OTA) was evaluated using the MTS assay, and membrane integrity was measured using transepithelial electrical resistance (TEER). A transwell system was used to investigate the effect of OTA on the expression of the CYP450 (1A1, 2A6, 2B6, 3A4 and 3A5), NAT2, COX-2, LOX-5, and MRP2 genes in Caco-2 and HepG2 cells. TEER decreased by a mean of 63.2% after 24 h in Caco-2 differentiated cells without inducing cell detachment; revealing damage to the intestinal epithelial cell tight junction proteins and an increase in cell permeability. Gene expression analysis showed that modulation of gene expression by OTA was higher in Caco-2 cells than in HepG2 cells, and generally, the duration of exposure to OTA had a more significant effect than the OTA dose. A general OTA down-regulation effect was observed in Caco-2 cells, in contrast with the down- and up-regulation observed in HepG2 cells. In Caco-2 cells, CYP1A1 was the gene with the highest regulation, followed by CYP3A4 and CYP3A5. Conversely, in HepG2 cells, CYP2B6 was highly regulated at 3 and 12 h compared to the other cytochromes; CYP1A1 was slightly modulated during the first 12 h, but an overexpression was observed at 24 h. Our data support the involvement of the COX-2 and 5-LOX genes in liver metabolism of OTA. On the basis of the gene expression analysis, the results suggest a possible impairment in OTA secretion at the intestinal and hepatic level due to MRP2 repression. In addition, we provide evidence of the effect of OTA on NAT2 gene expression, which had not been reported before. PMID- 26505657 TI - Aerobic Oxidative Conversion of Aromatic Aldehydes to Nitriles Using a Nitroxyl/NOx Catalyst System. AB - The first transition-metal-free aerobic oxidative conversion of aldehyde catalyzed by a nitroxyl radical/NOx system is presented for the synthesis of nitrile. In the presence of a catalytic amount of 4-AcNH-TEMPO (4-acetamido 2,2,6,6-tetramethylpiperidine-N-oxyl), NaNO2, and HNO3, benzaldehydes bearing a variety of functional groups underwent condensation with NH4OAc and following aerobic oxidation to produce nitriles selectively under an O2 balloon. Aerobic oxidative conversion of a primary alcohol instead of aldehyde is also achieved by a one-pot sequential strategy. PMID- 26505658 TI - Sepsis induced denervation-like changes at the neuromuscular junction. AB - BACKGROUND: The aim of this study was to determine the functional and biochemical changes at the neuromuscular junction (NMJ) induced by sepsis. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into three groups as follows: control, denervation, and sepsis. The rats were subjected to cecal ligation and puncture (CLP) or tibias nerve transection. NMJ function and the area of end plates were assessed, and the protein level of acetylcholine receptors and axonal neuregulin-1 was evaluated on postoperative days 1, 7, and 14. RESULTS: In the control group, the amplitude of compound muscle action potential (CMAP) was 16.51 +/- 2.53 mV. In the sepsis group, the amplitude of CMAP decreased, and duration was prolonged on postoperative days 7 and 14 (P < 0.01). Meanwhile, motor conduction velocity decreased significantly (P < 0.01). CMAP was lost in the denervation group. The twitch tension magnitude gradually declined (P < 0.05) in the sepsis group, although it could not be recorded after lesion. Sepsis and denervation upregulated the expression of gamma-nicotinic acetylcholine receptor (nAChR) and alpha7-nAChR in muscle membrane, compared with those in normal NMJ (261.4 +/- 26.5 MUm(2)). The NMJ area decreased from 254.6 +/- 23.8 MUm(2) (1 d after CLP) to 275.4 +/- 22.6 MUm(2) (7 d after CLP) to 322.7 +/- 34.4 MUm(2) (14 d after CLP). The postsynaptic NMJ had more discrete fragments (3.84 +/- 0.6) compared with the control group (2.13 +/- 0.4; P < 0.01). After denervation, NMJ underwent fragmentation and the number of discrete fragments increased (5.57 +/- 1.2; P < 0.01). NMJ area increased from 254.6 +/- 23.8 MUm(2) (1 d after CLP) to 275.4 +/- 22.6 MUm(2) (7 d after CLP) to 322.7 +/- 34.4 MUm(2) (14 d after CLP). Sepsis induced neuregulin-1 to decrease from 1 d up to 2 wk compared with the control group (P < 0.05). CONCLUSIONS: Chronic sepsis has a denervation-like effect on the NMJ, which was indicated by upregulation of heterogeneous nAChRs, the increased area of end plates, and demyelination of the motoneuron axon. PMID- 26505659 TI - Outcome of microdialysis sampling on liver surface and parenchyma. AB - BACKGROUND: To investigate whether surface microdialysis (MUD) sampling in probes covered by a plastic film, as compared to noncovered and to intraparenchymatous probes, would increase the technique's sensitivity for pathophysiologic events occurring in a liver ischemia-reperfusion model. Placement of MUD probes in the parenchyma of an organ, as is conventionally done, may cause adverse effects, e.g., bleeding, possibly influencing outcome. METHODS: A transient ischemia reperfusion model of the liver was used in six anesthetized normoventilated pigs. MUD probes were placed in the parenchyma and on the liver surface. Surface probes were either left uncovered or were covered by plastic film. RESULTS: Lactate and glucose levels were significantly higher in plastic film covered probes than in uncovered surface probes throughout the ischemic period. Glycerol levels were significantly higher in plastic film covered probes than in uncovered surface probes at 30 and 45 min into ischemia. CONCLUSIONS: Covering the MUD probe increases the sensibility of the MUD-technique in monitoring an ischemic insult and reperfusion in the liver. These findings confirm that the principle of surface MUD works, possibly replacing need of intraparenchymatous placement of MUD probes. Surface MUD seemingly allows, noninvasively from an organ's surface, via the extracellular compartment, assessment of intracellular metabolic events. The finding that covered surface MUD probes allows detection of local metabolic changes earlier than do intraparenchymatous probes, merit further investigation focusing on MUD probe design. PMID- 26505660 TI - Effect of chemotherapy and heat on biomechanical properties of absorbable sutures. AB - BACKGROUND: The quality of tissue repairs depends on tissue integrity, surgical technique, and material properties of the sutures used. Currently, there is no clear consensus on which is the best suture to use during cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. The aim of this study was to evaluate the impact of heat and chemotherapy on sutures' biomechanical properties. METHODS: Six different 3.0 absorbable sutures (Biosyn, Dexon II, Maxon, Monocryl, PDS II, and Vicryl Plus) were tested. All suture strands were incubated for a 24-h period in saline, mitomycin-c, and oxaliplatin at 37 and 45 degrees C. Suture loops were then loaded to failure using a servohydraulic testing machine. Data for tensile breaking force (TBF) and elongation rate were collected for all samples. RESULTS: Under basal condition, Maxon was the strongest of all sutures with a TBF of 59.6 +/- 4.3 N (P < 0.01), and no significant difference in TBF was observed between other sutures. Heat alone had no impact on sutures' biomechanical parameters. Exposition to mitomycin-c at 45 degrees C did not significantly affect sutures' basal tensile properties, with Maxon remaining the strongest suture. When incubated in oxaliplatin at 45 degrees C, the six suture types had a similar TBF. In all experimental conditions, multifilament sutures had a significantly lower elongation rate than monofilament sutures, and no correlations were demonstrated between elongation rate and the TBF of sutures. CONCLUSIONS: This study showed that exposition to heated chemotherapy did not significantly affect absorbable sutures biomechanical properties. PMID- 26505661 TI - The outcome of trauma patients with do-not-resuscitate orders. AB - BACKGROUND: Institutional variation in outcome of patients with do-not resuscitate (DNR) orders has not been well described in the setting of trauma. The purpose of this study was to assess the impact of trauma center designation on outcome of patients with DNR orders. MATERIALS AND METHODS: A statewide trauma database (Pennsylvania Trauma Outcome Study) was used for the analysis. Characteristics of patients with DNR orders were compared between state designated level 1 and 2 trauma centers. Inhospital mortality and major complication rates were compared using hierarchical logistic regression models that included a random effect for trauma centers. We adjusted for a number of potential confounders and allowed for nonlinearity in injury severity score and age in these models. RESULTS: A total of 106,291 patients (14 level 1 and 11 level 2 trauma centers) were identified in the Pennsylvania Trauma Outcome Study database between 2007 and 2011. We included 5953 patients with DNR orders (5.6%). Although more severely injured patients with comorbid disease were made DNR in level 1 trauma centers, trauma center designation level was not a significant factor for inhospital mortality of patients with DNR orders (odds ratio, 1.33; 95% confidence interval, 0.81-2.18; P = 0.26). Level 1 trauma centers were significantly associated with a higher rate of major complications (odds ratio, 1.75; 95% confidence interval, 1.11-2.75; P = 0.016). CONCLUSIONS: Inhospital mortality of patients with DNR orders was not significantly associated with trauma designation level after adjusting for case mix. More aggressive treatment or other unknown factors may have resulted in a significantly higher complication rate at level 1 trauma centers. PMID- 26505662 TI - Cartilage morphology assessed by high resolution micro-computed tomography in non OA knees. AB - OBJECTIVE: At the microscopic level, there is no established 3D method to measure cartilage volume and thickness. An easy, precise and accurate volume and thickness measurements of human cartilage has been developed from micro-computed tomography (micro-CT) images. DESIGN: In the medial tibial plateau of twenty nine left cadaveric knees classified as normal, vertical cores (7 mm in diameter) were extracted in three locations: lateral (LAT), medial posterior (MP) and medial anterior (MA). The cores were imaged in mineral oil with micro-CT (voxel size 10.2 MUm) and were measured cartilage volume (Cart.Vol, mm(3)) and cartilage thickness (Cart.Th, mm) using a thickness plugin. Short term reproducibility and standard deviation (ST_RMSCV%, ST_RMSSD, mm) were determined. To assess accuracy, holes with diameters of 2 mm, 3 mm, and 4 mm were artificially generated and nominal and measured hole sizes were compared. RESULTS: Precision of Cart.Vol_ST_RMSCV% was 1.35%. The mean biases between nominal hole volume and measurements were -0.49 +/- 1.5 mm(3) (2 mm), -0.41 +/- 4.2 mm(3) (3 mm) and +0.34 +/- 4.4 mm(3) (4 mm). ST_RMSSD was 100 times lower than the biological variation and the highest bias to measure volume was 24 times lower. Cart.Th results statistically differed among core extraction locations: 1.75 +/- 0.28 mm (LAT), 1.84 +/- 0.40 mm (MP) and 2.32 +/- 0.41 mm (MA). CONCLUSION: With a standard laboratory micro-CT system, it was possible to measure cartilage volume and thickness with good precision and accuracy relative to the biological variation of the specimen cohort. Cartilage measurements from micro-CT probably will improve the knowledge of the relationship between cartilage and subchondral bone and may allow to better understand the OA process. PMID- 26505664 TI - An optimum prophylactic dose of prasugrel monotherapy may safely and effectively prevent the development of experimental thrombotic strokes. PMID- 26505663 TI - Osteoclasts are recruited to the subchondral bone in naturally occurring post traumatic equine carpal osteoarthritis and may contribute to cartilage degradation. AB - The role of osteoclasts in osteochondral degeneration in osteoarthritis (OA) has rarely been investigated in spontaneous disease or animal models of OA. OBJECTIVE: The objectives of the current study were to investigate osteoclast density and location in post-traumatic OA (PTOA) and control specimens from racehorses. METHOD: Cores were harvested from a site in the equine third carpal bone, that undergoes repetitive, high intensity loading. Histological and immunohistochemical (Cathepsin K and Receptor-activator of Nuclear Factor kappa beta ligand (RANKL)) stained sections were scored (global and subregional) and the osteoclast density calculated. The cartilage histological scores were compared with osteoclast density and RANKL scores. RESULTS: There was a greater density of osteoclasts in PTOA samples and they were preferentially located in the subchondral bone plate. RANKL scores positively correlated to the scores of cartilage degeneration and the osteoclast density. The relationship between hyaline articular cartilage RANKL score and osteoclast density was stronger than that of the subchondral bone RANKL score suggesting that cartilage RANKL may have a role in recruiting osteoclasts. The RANKL score in the articular calcified cartilage correlated with the number of microcracks also suggesting that osteoclasts recruited by RANKL may contribute to calcified cartilage degeneration in PTOA. CONCLUSION: Our results support the hypothesis that osteoclasts are recruited during the progression of spontaneous equine carpal PTOA by cartilage RANKL, contributing to calcified cartilage microcracks and focal subchondral bone loss. PMID- 26505665 TI - The relationship of miR-146a gene polymorphism with carotid atherosclerosis in Chinese patients with type 2 diabetes mellitus. AB - OBJECTIVE: Atherosclerosis (AS) is regarded as the major cause of disability and death in diabetic patients. However, its precise pathogenesis is not entirely clear. Recent genome-wide association studies (GWAS) have revealed AS is related to some epigenetic changes. This study aimed to investigate the possible associations of miR-146a and transcriptional coactivator p300 polymorphisms with carotid atherosclerosis in type 2 diabetes mellitus. METHOD: This case-control study included 596 type 2 diabetes mellitus patients with carotid atherosclerosis and 379 patients without carotid atherosclerosis. Genotyping of miR-146a and p300 polymorphisms was performed by allelic discrimination assay with TaqMan-MGB probes. RESULTS: The CC genotype of rs2910164 in miR-146a was found to be associated with an increased risk of carotid vulnerable plaque in the Chinese type 2 diabetes mellitus patients, but this association was not found in the type 2 diabetes mellitus patients with carotid atherosclerosis or in the plaque load group. In addition, no significant difference in transcriptional coactivator p300 genotype distribution was observed between the type 2 diabetes mellitus patients with and without carotid atherosclerosis, plaque stability or plaque load, respectively. Stratified analyses revealed that the miR-146aCC genotype was associated with an increased risk of vulnerable plaque in subjects who were older, females, those with diabetes duration of more than 10 years, and those with hypertension. The gene-gene interactions between the miR-146a rs2910164 and p300 rs20551 polymorphisms were further analysed, but no combined effects of these two genes on enhancing the risk of carotid atherosclerosis, plaque stability, or plaque load were detected. CONCLUSION: The miR-146a rs2910164 polymorphism might be associated with carotid vulnerable plaque risk in Chinese type 2 diabetes mellitus patients, particularly in older patients, females, those with diabetes duration of more than 10 years and those with hypertension. The transcriptional coactivator p300 rs20551 polymorphism may not be a risk factor for the development or progression of atherosclerosis in type 2 diabetes mellitus. PMID- 26505666 TI - Activated prothrombin complex concentrate (FEIBA(r)) for the treatment and prevention of bleeding in patients with acquired haemophilia: A sequential study. AB - Despite anti-haemorrhagic therapy with proper doses of activated prothrombin complex concentrate (aPCC, Feiba(r)), patients with acquired haemophilia A (AHA) have a considerable risk of recurrent bleeding complications. Evidence in support of the benefit-to-risk ratio of prevention strategies with the use of lower doses of aPCC following the end of the initial treatment period is scarce and inconclusive. We report our experience in the management of 18 consecutive patients with AHA admitted to two Haemophilia centres in Italy. We managed the first 11 according to current guidelines (e.g., with conventional aPCC doses until bleeding resolution). Then, we decided to prolong the treatment beyond bleeding resolution with lower doses of the same concentrate (short-term prophylaxis) in the 7 additional patients. In these patients, the treatment was continued for as long as the titre of FVIII inhibitor was found to decrease by at least 50% when compared to the baseline one. We observed six relapses of bleeding in patients in whom aPCC was confined to the treatment of the qualifying bleeding episode, and none in patients to whom lower doses were administered until the pre specified decrease in the titre of FVIII inhibitor was achieved. No patients experienced thrombotic complications during the study period. Prolonging the treatment with lower doses of aPCC beyond the initial phase in patients with AHA in whom the titre of FVIII inhibitor is still high is likely to safely prevent further bleeding complications. PMID- 26505667 TI - Temperatures of the Ocular Surface, Lid, and Periorbital Regions of Sjogren's, Evaporative, and Aqueous-Deficient Dry Eyes Relative to Normals. AB - PURPOSE: To compare the temperatures of the ocular surface, eyelid, and periorbital skin in normal eyes with Sjogren's syndrome (SS) eyes, evaporative dry eyes (EDE), and aqueous deficient dry eyes (ADDE). METHODS: 10 eyes were analyzed in each age-matched group (normal, SS, EDE, and ADDE). A noninvasive infrared thermal camera captured two-dimensional images in three regions of interest (ROI) in each of three areas: the ocular surface, the upper eyelid, and the periorbital skin within a controlled environmental chamber. Mean temperatures in each ROI were calculated from the videos. Ocular surface time-segmented cooling rates were calculated over a 5-s blink interval. RESULTS: Relative to normal eyes, dry eyes had lower initial central OSTs (SS -0.71 degrees C, EDE 0.55 degrees C, ADDE -0.95 degrees C, KW P<.0001) and lower central upper lid temperatures (SS -0.24 degrees C, ADDE -0.51 degrees C, and EDE -0.54 degrees C, KW P<.0001). ADDE eyes had the lowest initial central OST (P<.0001), while EDE eyes had the lowest central lid temperature and lower periorbital temperatures (P<.0001). Over the 5-s interblink interval, the greatest rate of temperature loss occurred following eyelid opening, but varied by group (normals -0.52, SS 0.73, EDE -0.63, and ADDE -0.75 degrees C/s). The ADDE group also had the most substantial heat loss over the 5-s interblink interval (-0.97 degrees C). CONCLUSIONS: Differences in OST may be related to thermal differences in lids and periorbita along with an altered tear film. Thermography of the ocular surface, lids, and surrounding tissues may help to differentiate between different etiologies of dry eye. PMID- 26505668 TI - Effect of Perioperative Transfusion on Survival and Morbidity for Gastric Cancer Patients with Gastrectomy. PMID- 26505669 TI - Transfusion and Gastric Cancer Resection: In Reply to Yang and colleagues. PMID- 26505670 TI - Leukocytosis in Colorectal Cancer. PMID- 26505672 TI - A perspective on stem cell modeling of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis is a complex neurodegenerative disease. Limitations in animal models have impeded progress in studying disease pathology and potential drug discovery. Here, we will review recent advances in the development of stem cell models for the study of ALS. Additionally, we will discuss the progress toward therapeutic development derived from these stem cell based assays. PMID- 26505675 TI - Kinetic analysis of gluconate phosphorylation by human gluconokinase using isothermal titration calorimetry. AB - Gluconate is a commonly encountered nutrient, which is degraded by the enzyme gluconokinase to generate 6-phosphogluconate. Here we used isothermal titration calorimetry to study the properties of this reaction. DeltaH, KM and kcat are reported along with substrate binding data. We propose that the reaction follows a ternary complex mechanism, with ATP binding first. The reaction is inhibited by gluconate, as it binds to an Enzyme-ADP complex forming a dead-end complex. The study exemplifies that ITC can be used to determine mechanisms of enzyme catalyzed reactions, for which it is currently not commonly applied. PMID- 26505676 TI - Association between genetic variants of serotonergic and glutamatergic pathways and the concentration of neurometabolites of the anterior cingulate cortex in paediatric patients with obsessive-compulsive disorder. AB - OBJECTIVES: The present study aimed to assess the relationship between variability in genes related to the pathophysiology of obsessive-compulsive disorder (OCD) and the concentration of different neurometabolites in the anterior cingulate cortex (ACC). METHODS: We concomitantly assessed neurometabolite concentrations using 3-T (1)H-MRS and 262 single nucleotide polymorphism (SNPs) in 35 genes in 41 paediatric OCD patients. RESULTS: There were significant associations, after Bonferroni correction, between the concentration of inositol, glutamate and glutamine, and total choline and five polymorphisms located in genes related to serotonin and glutamate (i.e., the vesicular monoamine transporter 1 gene, SLC18A1 [rs6586896]; the serotonin receptor 1B gene, HTR1B [rs6296 and rs6298]; and the glutamate receptor, ionotropic, AMPA1 gene, GRIA1 [rs707176 and rs2963944]). CONCLUSIONS: The association observed between these polymorphisms and the neurometabolite concentrations could indicate the presence of a biological interaction between the serotonin and the glutamate pathways that could be involved in the pathophysiology of OCD. More studies with this methodology could increase our understanding of the aetiology and pathophysiology of OCD in children. PMID- 26505677 TI - Dual Catalysis for Selective Ring-Opening Polymerization of Lactones: Evolution toward Simplicity. AB - Much work has been directed to the design of complex single-site catalysts for ring-opening polymerization (ROP) to enhance both activity and selectivity. More simply, however, cooperative effects between Lewis acids and organocatalytic nucleophiles/Lewis bases provide a powerful alternative. In this study we demonstrate that the combination of N-heterocyclic carbenes, 1,8 diazabicycloundec-7-ene (DBU) and 4-dimethylaminopyridine (DMAP) with simple Lewis acids enables the ROP of the macrolactone pentadecalactone in a rapid and efficient manner. Remarkably, regardless of the nature of the nucleophile, the order of activity was observed to be MgX2 ? YCl3 ? AlCl3 and MgI2 > MgBr2 > MgCl2 in every case. The minimal influence of the organobase on polymerization activity allows for the use of simple and inexpensive precursors. Furthermore, extension of the study to other cyclic (di)ester monomers reveals the choice of Lewis acid to lead to monomer selective ROP activity and hence control over copolymer composition by choice of Lewis acid. This approach could lead to the realization of complex polymer structures with tunable physical properties from simple catalyst combinations. PMID- 26505673 TI - Bent out of shape: alpha-Synuclein misfolding and the convergence of pathogenic pathways in Parkinson's disease. AB - Protein inclusions made up primarily of misfolded alpha-synuclein (alpha-Syn) are the hallmark of a set of disorders known as synucleinopathies, most notably Parkinson's disease (PD). It is becoming increasingly appreciated that alpha-Syn misfolding can spread to anatomically connected regions in a prion-like manner. The protein aggregates that ensue are correlated with neurodegeneration in the various yet select neuronal populations that are affected. Recent advances have begun to shed light on the spreading and toxicity mechanisms that may be occurring in PD. Several key emerging themes are arising from this work suggesting that alpha-Syn mediated neurodegeneration is due to a combination of relative alpha-Syn expression level, connectivity to affected brain regions, and intrinsic vulnerability to pathology. PMID- 26505674 TI - Molecular heterogeneity of midbrain dopaminergic neurons--Moving toward single cell resolution. AB - Since their discovery, midbrain dopamine (DA) neurons have been researched extensively, in part because of their diverse functions and involvement in various neuropsychiatric disorders. Over the last few decades, reports have emerged that midbrain DA neurons were not a homogeneous group, but that DA neurons located in distinct anatomical locations within the midbrain had distinctive properties in terms of physiology, function, and vulnerability. Accordingly, several studies focused on identifying heterogeneous gene expression across DA neuron clusters. Here we review the importance of understanding DA neuron heterogeneity at the molecular level, previous studies detailing heterogeneous gene expression in DA neurons, and finally recent work which brings together previous heterogeneous gene expression profiles in a coordinated manner, at single cell resolution. PMID- 26505678 TI - Plasma microRNA profiles: identification of miR-744 as a novel diagnostic and prognostic biomarker in pancreatic cancer. AB - BACKGROUND: This study aims to explore novel microRNAs in plasma for screening cancer and predicting clinical outcomes in pancreatic cancer (PCa) patients using a microRNA array-based approach. METHODS: We used the Toray 3D-Gene microRNA array-based approach to compare plasma levels between PCa patients and healthy volunteers. RESULTS: (1) Six oncogenic microRNAs (miR-615-5p, -744, -575, -557, 675, and -550a) with high expression in plasma were selected. (2) By quantitative RT-PCR using plasma samples from 94 PCa patients and 68 healthy volunteers, a significantly higher level of plasma miR-744 in PCa patients than in healthy volunteers was validated in small-scale analysis (P=0.0038), two independent cohort analyses, and large-scale analysis (P<0.0001, AUC 0.8307). (3) miR-744 expression was significantly higher in PCa tissues (P=0.0069) and PCa cell lines (P=0.0074) than in normal tissues and fibroblasts, respectively. Preoperative plasma level of miR-744 was significantly reduced in postoperative samples (P=0.0063). (4) A high level of plasma miR-744, which was correlated with lymph node metastasis (P=0.0407) and recurrences (P=0.0376), was an independent poor prognostic factor of PCa patients after pancreatectomy (P=0.0007, HR 21.2 (3.17 436)). Furthermore, a high level of plasma miR-744 contributed to poorer progression-free survival of non-operable PCa patients who underwent gemcitabine based chemotherapy (P=0.0533). Overexpression of miR-744 in PCa cells induced significant chemoresistance to gemcitabine in vitro. CONCLUSIONS: Plasma miR-744 might be useful biomarker for screening PCa, monitoring, and predicting poor prognosis and chemoresistance in PCa patients. PMID- 26505679 TI - Upcoming translational challenges for uveal melanoma. AB - The past few years have witnessed major advances in the understanding of the molecular landscape of uveal melanoma (UM). The discovery of a mutational background that is completely different from the one of skin melanoma has granted to UM a stand-alone status. The absence of effective therapy for metastatic disease offers now a chessboard for targeted therapy but at the same time urges preclinical science to develop accordingly, to guide the use of economical resources to the best profit of patients. This review describes the current knowledge on the biology of this disease and discusses the challenges that must be undertaken to translate this knowledge into real benefit for patients. PMID- 26505680 TI - Urinary N1, N12-diacetylspermine is a non-invasive marker for the diagnosis and prognosis of non-small-cell lung cancer. AB - BACKGROUND: Early detection of non-small-cell lung cancer (NSCLC) and accurate prognostic risk assessment could improve patient outcome. We examined the significance of urinary N(1), N(12)-diacetylspermine (DiAcSpm) in the detection and prognostic stratification of NSCLC patients. METHODS: A DiAcSpm/cutoff ratio (DASr) was established for 260 NSCLC patients, 99 benign lung disease patients, and 140 healthy volunteers, using colloidal gold aggregation methods. The DASr was compared between patients and healthy controls, and the prognostic significance of DASr was examined. RESULTS: The median urinary DASr of NSCLC patients was significantly higher than that of healthy controls (0.810 vs 0.534, P<0.001). The DASr was higher in squamous cell carcinoma (SqCC) patients than in adenocarcinoma patients (1.18 vs 0.756, respectively, P=0.039). An increased urinary DASr value was significantly associated with pathological stage, other histological invasive factors and unfavourable outcomes in patients with completely resected NSCLC. Multivariate Cox regression analysis showed that increased urinary DASr was an independent prognostic factor (hazard ratio=4.652, 95% confidence interval (CI), 2.092-10.35; P<0.001). CONCLUSIONS: Urinary DASr was significantly increased in NSCLC, especially in SqCC. Urinary DASr was an independent poor prognostic indicator in patients with completely resected NSCLC. The DASr could be a useful biomarker for detecting malignancies and predicting prognosis. PMID- 26505682 TI - The anti-tuberculosis agents under development and the challenges ahead. AB - Tuberculosis (TB) is a serious health problem causing 1.5 million deaths worldwide. After the discovery of first-line anti-TB drugs, the mortality rate declined sharply, however, the emergence of drug-resistant strains and HIV co infection have led to increased incidence of this disease. A number of new potential antitubercular drug candidates with novel modes of action have entered clinical trials in recent years. Compounds such as gatifloxacin, moxifloxacin and linezolid, the already known antibiotics are currently being evaluated for their anti-TB activity. OPC-67683 and TMC207 have been approved for the treatment of MDR-TB patients recently, while PA-824, SQ109, PNU-100480, AZD5847, LL3858, SQ609, SQ641, BTZ043, DC-159a, CPZEN-45, Q-203, DNB1, TBA-354 are in various phases of clinical and preclinical developments. This review evaluates the current status of TB drug development and future aspects. PMID- 26505681 TI - A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. AB - BACKGROUND: The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer. METHODS: We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1:1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m(-2) as a 90-min infusion, leucovorin at 200 mg m(-2) as a 2-h infusion, and a bolus injection of 5-FU 400 mg m(-2) followed by a 46-h continuous infusion of 5-FU at 2400 mg m( 2). The XELIRI regimen consisted of irinotecan at 250 mg m(-2) as a 90-min infusion with capecitabine 1000 mg m(-2) twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity. RESULTS: Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5-7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4-8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade?3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively). CONCLUSIONS: The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity. PMID- 26505683 TI - The phantom illusion. AB - It is well known that visible luminance gradients may generate contrast effects. In this work we present a new paradoxical illusion in which the luminance range of gradual transitions has been reduced to make them invisible. By adopting the phenomenological method proposed by Kanizsa, we have found that unnoticeable luminance gradients still generate contrast effects. But, most interestingly, we have found that when their width is narrowed, rather than generating contrast effects on the surrounded surfaces, they generate an assimilation effect. Both high- and low-level interpretations of this "phantom" illusion are critically evaluated. PMID- 26505684 TI - Monocular and binocular mechanisms mediating flicker adaptation. AB - Flicker adaptation reduces subsequent temporal contrast sensitivity. Recent studies show that this adaptation likely results from neural changes in the magnocellular visual pathway, but whether this adaptation occurs at a monocular or a binocular level, or both, is unclear. Here, two experiments address this question. The first experiment exploits the observation that flicker adaptation is stronger at higher than lower temporal frequencies. Observers' two eyes adapted to 3Hz flicker with an incremental pulse at 1/4 duty cycle, either in phase or out-of-phase in the two eyes. At the binocular level, the flicker rate was 6Hz in the out-of-phase condition if the two eyes' pulse trains sum. Similar sensitivity reduction was found in both phase conditions, as expected for independent monocular adapting mechanisms. The second experiment tested for interocular transfer of adaptation between eyes. Results showed that (1) flicker adaptation was strongest with adapting and test fields in only the same eye, (2) adaptation can be partially transferred interocularly with adaptation in only the opposite eye, and (3) adaptation was weakened when both eyes were adapted simultaneously at different contrasts, compared to test-eye adaptation alone. Taken together, the findings are consistent with mechanisms of flicker adaptation at both the monocular and binocular level. PMID- 26505685 TI - The role of shape complexity in the detection of closed contours. AB - The detection of contours in noise has been extensively studied, but the detection of closed contours, such as the boundaries of whole objects, has received relatively little attention. Closed contours pose substantial challenges not present in the simple (open) case, because they form the outlines of whole shapes and thus take on a range of potentially important configural properties. In this paper we consider the detection of closed contours in noise as a probabilistic decision problem. Previous work on open contours suggests that contour complexity, quantified as the negative log probability (Description Length, DL) of the contour under a suitably chosen statistical model, impairs contour detectability; more complex (statistically surprising) contours are harder to detect. In this study we extended this result to closed contours, developing a suitable probabilistic model of whole shapes that gives rise to several distinct though interrelated measures of shape complexity. We asked subjects to detect either natural shapes (Exp. 1) or experimentally manipulated shapes (Exp. 2) embedded in noise fields. We found systematic effects of global shape complexity on detection performance, demonstrating how aspects of global shape and form influence the basic process of object detection. PMID- 26505686 TI - Tissue biomarkers of drug efficacy: case studies using a MALDI-MSI workflow. AB - MALDI MS imaging (MALDI-MSI) offers a capability to not only evaluate the distribution, localization and metabolism of drugs within tissues but also allow correlative tissue measurement of the effect of the drug on biomolecules in the targeted pathway. Particularly for MALDI-MSI, lipid molecules are readily detectable within tissues. Case study examples are provided for two different drugs targeting the sphingosine-1-phosphate/ceramide nexus in tumor xenograft tissues. A workflow combining high-resolution MALDI-MSI with on-tissue confirmation of targeted compounds using a structural library and on-tissue enzymatic digestion strategy is described. Representative images of drug metabolite distribution that correlate to an increase or decrease in sphingosine 1-phosphate or ceramide species are provided. PMID- 26505687 TI - Toward Modeling the Resistance and Resilience of "Below-ground" Fungal Communities: A Mechanistic and Trait-Based Approach. AB - The role of fungi in shaping ecosystems is well evidenced and there is growing recognition of their importance among scientists and the general public. Establishing and separating the role of key local (soil chemical, biological, and physical properties) and global (climate, dispersal limitation) drivers in fungal community structure and functioning is currently a source of frustration to mycologists. The quest to determine niche processes and environmental characteristics shaping fungal community structure, known to be important for plant and animal communities, is proving difficult, resulting in the acknowledgment that niche neutral processes (climate, dispersal limitations) may dominate. The search for predictable patterns in fungal community structure may have been restricted as the "appropriate" scales at which to measure community structure and characterize the environment have not been fully determined yet, and the focus on taxonomy makes it difficult to link environmental characteristics to fungal traits. While key determinants of microbial community composition have been uncovered for some functional groups, the differential response of functional groups is largely unknown. Before we can truly understand what drives the development of microbial community structure, an understanding of the autecology of major fungal taxa and how they interact with their immediate environment (from the micro- up to kilometer scale) is urgently needed. Furthermore, key information and empirical data is missing at the microscale due to experimental difficulties in mapping this heterogeneous and opaque environment. We therefore present a framework that would help generate this much needed empirical data and information at the microscale, together with modeling approaches to link the spatial and temporal scales. The latter is important as we propose that there is much to be gained by linking our understanding of fungal community responses across scales, in order to develop species and community environment-function predictive models. PMID- 26505688 TI - The Importance of the Microbial N Cycle in Soil for Crop Plant Nutrition. AB - Nitrogen is crucial for living cells, and prior to the introduction of mineral N fertilizer, fixation of atmospheric N2 by diverse prokaryotes was the primary source of N in all ecosystems. Microorganisms drive the N cycle starting with N2 fixation to ammonia, through nitrification in which ammonia is oxidized to nitrate and denitrification where nitrate is reduced to N2 to complete the cycle, or partially reduced to generate the greenhouse gas nitrous oxide. Traditionally, agriculture has relied on rotations that exploited N fixed by symbiotic rhizobia in leguminous plants, and recycled wastes and manures that microbial activity mineralized to release ammonia or nitrate. Mineral N fertilizer provided by the Haber-Bosch process has become essential for modern agriculture to increase crop yields and replace N removed from the system at harvest. However, with the increasing global population and problems caused by unintended N wastage and pollution, more sustainable ways of managing the N cycle in soil and utilizing biological N2 fixation have become imperative. This review describes the biological N cycle and details the steps and organisms involved. The effects of various agricultural practices that exploit fixation, retard nitrification, and reduce denitrification are presented, together with strategies that minimize inorganic fertilizer applications and curtail losses. The development and implementation of new technologies together with rediscovering traditional practices are discussed to speculate how the grand challenge of feeding the world sustainably can be met. PMID- 26505689 TI - Polyhydroxyalkanoates: Much More than Biodegradable Plastics. AB - Bacterial polyhydroxyalkanoates (PHAs) are isotactic polymers that play a critical role in central metabolism, as they act as dynamic reservoirs of carbon and reducing equivalents. These polymers have a number of technical applications since they exhibit thermoplastic and elastomeric properties, making them attractive as a replacement of oil-derived materials. PHAs are accumulated under conditions of nutritional imbalance (usually an excess of carbon source with respect to a limiting nutrient, such as nitrogen or phosphorus). The cycle of PHA synthesis and degradation has been recognized as an important physiological feature when these biochemical pathways were originally described, yet its role in bacterial processes as diverse as global regulation and cell survival is just starting to be appreciated in full. In the present revision, the complex regulation of PHA synthesis and degradation at the transcriptional, translational, and metabolic levels are explored by analyzing examples in natural producer bacteria, such as Pseudomonas species, as well as in recombinant Escherichia coli strains. The ecological role of PHAs, together with the interrelations with other polymers and extracellular substances, is also discussed, along with their importance in cell survival, resistance to several types of environmental stress, and planktonic-versus-biofilm lifestyle. Finally, bioremediation and plant growth promotion are presented as examples of environmental applications in which PHA accumulation has successfully been exploited. PMID- 26505690 TI - Catabolism of Phenol and Its Derivatives in Bacteria: Genes, Their Regulation, and Use in the Biodegradation of Toxic Pollutants. AB - Phenol and its derivatives (alkylphenols, halogenated phenols, nitrophenols) are natural or man-made aromatic compounds that are ubiquitous in nature and in human polluted environments. Many of these substances are toxic and/or suspected of mutagenic, carcinogenic, and teratogenic effects. Bioremediation of the polluted soil and water using various bacteria has proved to be a promising option for the removal of these compounds. In this review, we describe a number of peripheral pathways of aerobic and anaerobic catabolism of various natural and xenobiotic phenolic compounds, which funnel these substances into a smaller number of central catabolic pathways. Finally, the metabolites are used as carbon and energy sources in the citric acid cycle. We provide here the characteristics of the enzymes that convert the phenolic compounds and their catabolites, show their genes, and describe regulatory features. The genes, which encode these enzymes, are organized on chromosomes and plasmids of the natural bacterial degraders in various patterns. The accumulated data on similarities and the differences of the genes, their varied organization, and particularly, an astonishingly broad range of intricate regulatory mechanism may be read as an exciting adventurous book on divergent evolutionary processes and horizontal gene transfer events inscribed in the bacterial genomes. In the end, the use of this wealth of bacterial biodegradation potential and the manipulation of its genetic basis for purposes of bioremediation is exemplified. It is envisioned that the integrated high throughput techniques and genome-level approaches will enable us to manipulate systems rather than separated genes, which will give birth to systems biotechnology. PMID- 26505691 TI - Urban mining: Concepts, terminology, challenges. PMID- 26505692 TI - Antitumor activity of amidino-substituted benzimidazole and benzimidazo[1,2 a]quinoline derivatives tested in 2D and 3D cell culture systems. AB - Due to a poor clinical predictive power of 2D cell cultures, standard tool for in vitro assays in drug discovery process, there is increasing interest in developing 3D in vitro cell cultures, biologically relevant assay feasible for the development of robust preclinical anti-cancer drug screening platforms. Herein, we tested amidino-substituted benzimidazoles and benzimidazo[1,2 a]quinolines as a small platform for comparison of antitumor activity in 2D and 3D cell culture systems and correlation with structure-activity relationship. 3D cell culture method was applied on a human cancer breast (SK-BR-3, MDA-MB-231, T 47D) and pancreatic cancer cells (MIA PaCa-2, PANC-1). Results obtained in 2D and 3D models were highly comparable, but in some cases we have observed significant disagreement indicating that some prominent compounds can be discarded in early phase of researching because of compounds with false positive result. To confirm which of cell culture systems is more accurate, in vivo profiling is needed. PMID- 26505695 TI - Management Of Headache In The Pediatric Emergency Department. AB - Headaches are a common complaint among children, with increasing frequency in adolescence. According to the Agency for Healthcare Research and Quality, more than 3 million Americans seek emergency care every year due to headaches, and one third of them are attributable to migraines. Headaches have a significant impact on the lives of children and adolescents, resulting in school absence, decreased extracurricular activities, and poor academic achievement. Among patients, the spectrum of pathology varies widely, continually challenging healthcare providers to recognize serious, life-threatening conditions, while judiciously evaluating and treating all patients. This issue reviews the broad differential of primary and secondary headaches in the pediatric emergency department, summarizes effective strategies for diagnosis, and evaluates the current evidence supporting safe, appropriate treatment. As emergency clinicians treat increasingly more medically complex patients, they should be aware of the best current practices to evaluate and treat headaches in the pediatric population. PMID- 26505693 TI - The Elizabeth River Story: A Case Study in Evolutionary Toxicology. AB - The Elizabeth River system is an estuary in southeastern Virginia, surrounded by the towns of Chesapeake, Norfolk, Portsmouth, and Virginia Beach. The river has played important roles in U.S. history and has been the location of various military and industrial activities. These activities have been the source of chemical contamination in this aquatic system. Important industries, until the 1990s, included wood treatment plants that used creosote, an oil-derived product that is rich in polycyclic aromatic hydrocarbons (PAH). These plants left a legacy of PAH pollution in the river, and in particular Atlantic Wood Industries is a designated Superfund site now undergoing remediation. Numerous studies examined the distribution of PAH in the river and impacts on resident fauna. This review focuses on how a small estuarine fish with a limited home range, Fundulus heteroclitus (Atlantic killifish or mummichog), has responded to this pollution. While in certain areas of the river this species has clearly been impacted, as evidenced by elevated rates of liver cancer, some subpopulations, notably the one associated with the Atlantic Wood Industries site, displayed a remarkable ability to resist the marked effects PAH have on the embryonic development of fish. This review provides evidence of how pollutants have acted as evolutionary agents, causing changes in ecosystems potentially lasting longer than the pollutants themselves. Mechanisms underlying this evolved resistance, as well as mechanisms underlying the effects of PAH on embryonic development, are also described. The review concludes with a description of ongoing and promising efforts to restore this historic American river. PMID- 26505694 TI - Gastrointestinal dopamine as an anti-incretin and its possible role in bypass surgery as therapy for type 2 diabetes with associated obesity. AB - The objective of this review was to summarize and integrate specific clinical observations from the field of gastric bypass surgery and recent findings in beta cell biology. When considered together, these data sets suggest a previously unrecognized physiological mechanism which may explain how Roux-en-Y gastric bypass (RYGB) surgery mediates the early rapid reversal of hyperglycemia, observed before weight loss, in certain type 2 diabetes mellitus (T2DM) patients. The novel mechanism is based on a recently recognized inhibitory circuit of glucose stimulated insulin secretion driven by DA stored in beta-cell vesicles and the gut. We propose that DA and glucagon-like peptide 1 (GLP-1) represent two opposing arms of a glucose stimulated insulin secretion (GSIS) regulatory system and hypothesize that dopamine represents the "anti-incretin" hypothesized to explain the beneficial effects of bariatric surgery on T2DM. These new hypotheses and the research driven by them may directly impact our understanding of: 1) the mechanisms underlying improved glucose homeostasis seen before weight loss following bariatric surgery; and 2) the regulation of glucose stimulated insulin secretion within islets. On a practical level, these studies may result in the development of novels drugs to modulate insulin secretion and/or methods to quantitatively asses in real time beta cell function and mass. PMID- 26505697 TI - The Profunda Artery Perforator Flap: Investigating the Perforasome Using Three Dimensional Computed Tomographic Angiography. AB - BACKGROUND: The profunda artery perforator flap has been emerging as an alternative method of autologous breast reconstruction. This flap uses upper posterior thigh tissue. The profunda artery perforator perforasome is investigated using three-dimensional computed tomographic angiography. METHODS: Ten cadaveric thighs were dissected centered over the profunda artery perforator. The perforator was injected with contrast medium and the flap was then subjected to computed tomographic scanning using a GE Lightspeed 16-slice scanner. The three-dimensional images were viewed, and measurements were obtained using Aquarius software, including horizontal and vertical extensions of the flap and areas of perfusion. Clinical examples are presented. RESULTS: A profunda artery perforator (occasionally two) was consistently found in the upper medial thigh region, posterior to the gracilis muscle. The area of vascularity shown by the spread of contrast extends inferiorly beyond the usual lower border of the profunda artery perforator flap, which is usually 7 cm wide. In injected cadaveric flaps, the mean horizontal dimension was 16.7 cm and the mean vertical dimension was 16.5 cm. The mean area perfused was 8812 cm. CONCLUSIONS: The profunda artery perforator flap is a vascularly sound flap, and is a good option for autologous breast reconstruction. Advantages include a reliable pedicle, no position changes required, and possibly an improved donor-site contour from a thigh lift. It is an excellent alternative to abdominally based free flaps and can also be used in conjunction with other flaps for further volume enhancement. PMID- 26505696 TI - Differential Sensitivity Between a Virtual Reality Balance Module and Clinically Used Concussion Balance Modalities. AB - OBJECTIVE: Balance assessments are part of the recommended clinical concussion evaluation, along with computerized neuropsychological testing and self-reported symptoms checklists. New technology has allowed for the creation of virtual reality (VR) balance assessments to be used in concussion care, but there is little information on the sensitivity and specificity of these evaluations. The purpose of this study is to establish the sensitivity and specificity of a VR balance module for detecting lingering balance deficits clinical concussion care. DESIGN: Retrospective case-control study. SETTING: Institutional research laboratory. PARTICIPANTS: Normal controls (n = 94) and concussed participants (n = 27). INTERVENTIONS: All participants completed a VR balance assessment paradigm. Concussed participants were diagnosed by a Certified Athletic Trainer or physician (with 48 hours postinjury) and tested in the laboratory between 7 and 10 days postinjury. Receiver operating characteristic curves were performed to establish the VR module's sensitivity and specificity for detecting lingering balance deficits. MAIN OUTCOME MEASURES: Final balance score. RESULTS: For the VR balance module, a cutoff score of 8.25 was established to maximize sensitivity at 85.7% and specificity at 87.8%. CONCLUSIONS: The VR balance module has high sensitivity and specificity for detecting subacute balance deficits after concussive injury. CLINICAL RELEVANCE: The VR balance has a high subacute sensitivity and specificity as a stand-alone balance assessment tool and may detect ongoing balance deficits not readily detectable by the Balance Error Scoring System or Sensory Organization Test. Virtual reality balance modules may be a beneficial addition to the current clinical concussion diagnostic battery. PMID- 26505698 TI - Breast Implant-Associated Infections: The Role of the National Surgical Quality Improvement Program and the Local Microbiome. AB - BACKGROUND: The most common cause of surgical readmission after breast implant surgery remains infection. Six causative organisms are principally involved: Staphylococcus epidermidis and S. aureus, Escherichia, Pseudomonas, Propionibacterium, and Corynebacterium. The authors investigated the infection patterns and antibiotic sensitivities to characterize their local microbiome and determine ideal antibiotic selection. METHODS: A retrospective review of 2285 consecutive implant-based breast procedures was performed. Included surgical procedures were immediate and delayed breast reconstruction, tissue expander exchange, and cosmetic augmentation. Patient demographics, chemotherapy and/or irradiation status, implant characteristics, explantation reason, time to infection, microbiological data, and antibiotic sensitivities were reviewed. RESULTS: Forty-seven patients (2.1 percent) required inpatient admission for antibiotics, operative explantation, or drainage by interventional radiology. The infection rate varied depending on surgical procedure, with the highest rate seen in mastectomy and immediate tissue expander reconstruction (6.1 percent). The mean time to explantation was 41 days. Only 50 percent of infections occurred within 30 days of the indexed National Surgical Quality Improvement Program operation. The most commonly isolated organisms were coagulase-negative Staphylococcus (27 percent), methicillin-sensitive S. aureus (25 percent), methicillin-resistant S. aureus (7 percent), Pseudomonas (7 percent), and Peptostreptococcus (7 percent). All Gram-positive organisms were sensitive to vancomycin, linezolid, tetracycline, and doxycycline; all Gram-negative organisms were sensitive to gentamicin and cefepime. CONCLUSIONS: Empiric antibiotics should be vancomycin (with the possible inclusion of gentamicin) based on their broad effectiveness against the authors' unique microbiome. Minor infections should be treated with tetracycline or doxycycline as a second-line agent. National Surgical Quality Improvement Program data are adequate for monitoring and comparing breast infections but certainly not comprehensive. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26505699 TI - Consensus Recommendations for Optimal Augmentation of the Asian Face with Hyaluronic Acid and Calcium Hydroxylapatite Fillers. AB - BACKGROUND: Although the use of filling agents for soft-tissue augmentation has increased worldwide, most consensus statements do not distinguish between ethnic populations. There are, however, significant differences between Caucasian and Asian faces, reflecting not only cultural disparities, but also distinctive treatment goals. Unlike aesthetic patients in the West, who usually seek to improve the signs of aging, Asian patients are younger and request a broader range of indications. METHODS: Members of the Asia-Pacific Consensus group comprising specialists from the fields of dermatology, plastic surgery, anatomy, and clinical epidemiology-convened to develop consensus recommendations for Asians based on their own experience using cohesive polydensified matrix, hyaluronic acid, and calcium hydroxylapatite fillers. RESULTS: The Asian face demonstrates differences in facial structure and cosmetic ideals. Improving the forward projection of the "T zone" (i.e., forehead, nose, cheeks, and chin) forms the basis of a safe and effective panfacial approach to the Asian face. Successful augmentation may be achieved with both (1) high- and low-viscosity cohesive polydensified matrix/hyaluronic acid and (2) calcium hydroxylapatite for most indications, although some constraints apply. CONCLUSION: The Asia-Pacific Consensus recommendations are the first developed specifically for the use of fillers in Asian populations. CLINCIAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 26505700 TI - Comparison of Allergan, Mentor, and Sientra Contoured Cohesive Gel Breast Implants: A Single Surgeon's 10-Year Experience. AB - BACKGROUND: Contoured cohesive gel breast implants have been recently approved in the United States. These implants have been available for premarket approval studies for selected surgeons. The purpose of this study was to assess a single surgeon's outcomes in three specific clinical situations-breast augmentation, secondary augmentation, and breast reconstruction-using implants of all three contoured cohesive gel implant manufacturers (Allergan, Mentor, and Sientra) over a 10-year period. METHODS: The authors performed a prospective study of contoured cohesive silicone gel breast implants. Demographic and outcomes data were recorded. Complication rates were compared among the three implant manufacturers. RESULTS: From 2001 to 2013, 695 patients were included from U.S. Food and Drug Administration clinical trials. Mean age at implantation was 42.7 years (range, 18 to 82 years), and mean time enrolled was 5.3 years (range, <1 to 10 years). One hundred sixty-four patients (24 percent) received Allergan implants, 245 (35 percent) received Mentor implants, and 286 (41 percent) received Sientra implants. Three hundred eighty-four patients (55 percent) underwent primary augmentation, 198 (29 percent) underwent secondary augmentation, and 113 (16 percent) underwent breast reconstruction. The total complication rate was the lowest for primary augmentation of the Mentor group compared with the Allergan and Sientra groups (p < 0.05). There were no significant differences in complication rates when used for secondary augmentation and reconstruction. There was no statistically significant difference between implant group reoperation, explantation, or capsular contracture rates. Overall implant rupture and rotation rates were low (0.7 percent and 1.3 percent, respectively). Patient and surgeon satisfaction was high. CONCLUSIONS: Contoured cohesive gel breast implants overall have low complication rates and high patient and surgeon satisfaction. The authors believe these implants to be safe and effective in breast augmentation and reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 26505701 TI - Risk Factors for Readmission and Adverse Outcomes in Abdominoplasty. AB - BACKGROUND: In an era of outcomes-driven medicine, being able to benchmark complication rates of various procedures is of utmost importance. The rates of readmission, reoperation, and adverse outcomes in abdominoplasty have been previously reported, although risk factors for these adverse outcomes have not been thoroughly elucidated. This study aims to identify specific independent risk factors for readmission and other adverse outcomes of abdominoplasty. METHODS: This study retrospectively reviewed the American College of Surgeons National Surgical Quality Improvement Program and identified all abdominoplasties performed in 2011 and 2012. Univariate logistic regression analysis was used to identify significant associations between preoperative risk factors and adverse outcomes. Multivariate logistic regression analysis was then used to identify independent risk factors and causes of readmission and other adverse outcomes. RESULTS: Of the 2946 abdominoplasties identified, there were 251 readmissions (8.5 percent), 146 reoperations (5.0 percent), and 574 patients (19.5 percent) who experienced a general complication. The most common adverse outcomes were wound complications in 281 patients (9.5 percent), pulmonary complications in 67 patients (2.3 percent), and thromboembolic complications in 34 patients (1.2 percent). Multivariate regression analysis demonstrated that American Society of Anesthesiologists class above 3, preoperative cardiac comorbidities, pulmonary comorbidities, wounds or wound infections, postoperative thromboembolic complications, wound complications, and having returned to the operating room on the primary admission were independent risk factors for readmission. CONCLUSIONS: This study provides the first critical analysis of risk factors for 30-day readmission in abdominoplasty. These risk factors can aid in patient selection, surgical planning, and postoperative allocation of resources for patients undergoing abdominoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 26505704 TI - Soft-Tissue Surgery for Camptodactyly Corrects Skeletal Changes. AB - BACKGROUND: This study demonstrates the potential for radiographic and clinical improvement with surgical correction of camptodactyly. Although historically these radiographic changes have been held to be permanent, the authors encourage surgical intervention for digits with severe flexion contracture or progressive radiographic changes before skeletal maturity is reached. METHODS: The authors assessed 18 consecutively operated fingers in nine skeletally immature patients in whom advanced radiographic articular changes had occurred. Mean preoperative flexion contracture was 63 degrees (range, 35 to 105 degrees). The average age of the patients was 11 years (range, 4 to 15 years) at the time of surgery. Clinical response to surgery was studied, but radiographic articular changes were followed postoperatively as a primary outcome. RESULTS: Each patient demonstrated the classic preoperative radiographic joint changes on radiographic films at the affected proximal interphalangeal or distal interphalangeal joint. All patients had substantial clinical improvement postoperatively. Two digits had extensive radiographic damage, requiring proximal interphalangeal joint arthrodesis. Fifteen of the remaining 16 digits (94 percent) had substantial improvement or full restoration of radiographic articular congruency at average follow-up of 9 months (range, 3 to 18 months). The only joint that did not remodel fully was the one that did not have complete clinical correction. CONCLUSIONS: Even in patients with severe radiographic changes from camptodactyly, surgery can effectively improve range of motion. Once radiographic articular changes become apparent, surgical correction should be undertaken not only to prevent further joint damage but also to reverse these radiographic changes before skeletal maturity is reached. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26505702 TI - Dermal Fibroblasts from the Red Duroc Pig Have an Inherently Fibrogenic Phenotype: An In Vitro Model of Fibroproliferative Scarring. AB - BACKGROUND: The pathophysiology of hypertrophic scarring is unknown in part because of the lack of a robust animal model. Although the red Duroc pig has emerged as a promising in vivo model, the cellular mechanisms underlying Duroc scarring are unknown, and the size and cost of Duroc pigs are obstacles to their use. Given the central role of the dermal fibroblast in scarring, the authors hypothesized that dermal fibroblasts from the Duroc pig exhibit intrinsic differences in key aspects of the fibroblast response to injury compared with those from the Yorkshire pig, a same-species control that heals normally. METHODS: Duroc and Yorkshire dermal fibroblasts were isolated from uninjured dorsal skin. Actin stress fibers and focal adhesions were visualized by immunocytochemistry and transmission electron microscopy. Cell migration was measured using a scratch wound-closure assay. Contractile function was assessed by collagen gel contraction. Expression of scarring-related genes was determined by quantitative real-time reverse-transcriptase polymerase chain reaction, and transforming growth factor (TGF)-beta1 protein expression was determined by Western blotting. RESULTS: Duroc dermal fibroblasts display increased adhesion complex formation, impaired migration, enhanced collagen contraction, and profibrotic gene and protein expression profiles compared with Yorkshire fibroblasts at baseline. In addition, Duroc fibroblasts overexpressed TGF-beta1 and were less responsive to exogenous TGF-beta1. CONCLUSIONS: Duroc dermal fibroblasts have inherent myofibroblastic differentiation that may account for the pathologic scarring in these animals. The authors' data further validate the Duroc model and support Duroc fibroblast cell culture as a simple, inexpensive, reproducible, and biologically tractable in vitro model for the study of fibroproliferative scarring. PMID- 26505703 TI - Fibroblast-Specific Deletion of Hypoxia Inducible Factor-1 Critically Impairs Murine Cutaneous Neovascularization and Wound Healing. AB - BACKGROUND: Diabetes and aging are known risk factors for impaired neovascularization in response to ischemic insult, resulting in chronic wounds, and poor outcomes following myocardial infarction and cerebrovascular injury. Hypoxia-inducible factor (HIF)-1alpha, has been identified as a critical regulator of the response to ischemic injury and is dysfunctional in diabetic and elderly patients. To better understand the role of this master hypoxia regulator within cutaneous tissue, the authors generated and evaluated a fibroblast specific HIF-1alpha knockout mouse model. METHODS: The authors generated floxed HIF-1 mice (HIF-1) by introducing loxP sites around exon 1 of the HIF-1 allele in C57BL/6J mice. Fibroblast-restricted HIF-1alpha knockout (FbKO) mice were generated by breeding our HIF-1 with tamoxifen-inducible Col1a2-Cre mice (Col1a2 CreER). HIF-1alpha knockout was evaluated on a DNA, RNA, and protein level. Knockout and wild-type mice were subjected to ischemic flap and wound healing models, and CD31 immunohistochemistry was performed to assess vascularity of healed wounds. RESULTS: Quantitative real-time polymerase chain reaction of FbKO skin demonstrated significantly reduced Hif1 and Vegfa expression compared with wild-type. This finding was confirmed at the protein level (p < 0.05). HIF-1alpha knockout mice showed significantly impaired revascularization of ischemic tissue and wound closure and vascularity (p < 0.05). CONCLUSIONS: Loss of HIF-1alpha from fibroblasts results in delayed wound healing, reduced wound vascularity, and significant impairment in the ischemic neovascular response. These findings provide new insight into the importance of cell-specific responses to hypoxia during cutaneous neovascularization. PMID- 26505705 TI - The Use of an Inferior Pennant Flap during Unilateral Cleft Lip Repair Improves Lip Height Symmetry. AB - BACKGROUND: To improve the rotation of Cupid's bow and achieve sufficient vertical lip height, several variations of the Millard rotation-advancement have incorporated a small laterally based triangular flap above the cutaneous roll. This study uses three-dimensional photogrammetry to evaluate the outcomes of unilateral cleft lip repairs performed with and without pennant flaps. METHODS: Three-dimensional photographs were analyzed to assess postoperative lip height asymmetry in 90 unilateral cleft lip patients (58 complete and 32 incomplete) treated between 2001 and 2012. Cleft lip repairs were performed by three pediatric cleft surgeons using different techniques. Thirty-nine of 90 procedures (43 percent) used an inferiorly placed triangular flap. All patients were photographed at least 9 months postoperatively (mean, 4.2 years). Lip height asymmetry was based on the vertical distances from the subnasale to the peaks of Cupid's bow. RESULTS: Regression analysis revealed that the use of a pennant flap was a significant predictor of postoperative lip height asymmetry (beta = 4.2 percent, p = 0.015). The surgeon performing the repair was also a significant factor in patients with complete cleft lips (beta = 3.6 percent, p = 0.005). All three surgeons achieved greater lip height symmetry when a pennant flap was performed. CONCLUSIONS: The results of unilateral cleft lip repairs are affected by both the surgeon and the surgical technique. Procedures that used a pennant flap showed better philtral height symmetry than nonpennant repairs. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 26505706 TI - Orbital Dysmorphology in Untreated Children with Crouzon and Apert Syndromes. AB - BACKGROUND: Orbital dysmorphology and midface retrusion are the hallmarks of Crouzon and Apert syndromes. The precise nature of this deficiency is not known. METHODS: Untreated Crouzon and Apert syndrome patients and age- and sex-matched controls were included. Computed tomographic scans were digitized and reconstructed. Craniometric and volumetric data relating to the orbit were collected. RESULTS: Thirty-one scans were included (control, n = 12; Crouzon; n = 9; Apert, n = 10). The mean age of the Apert group was 5.31 +/- 5 years; Crouzon, 5.77 +/- 2.7 years; and control, 6.4 +/- 3.6 years. The bony orbit length was 12 percent shorter in Apert (p = 0.004) and 17 percent shorter in the Crouzon group when compared to controls (p < 0.0001). The bony orbital volume was 21 percent smaller in the Apert children (p = 0.0006) and 23 percent smaller in Crouzon when compared to controls (p = 0.003). Globe volume was 15 percent larger in Apert (p = 0.008) and 36 percent larger in the Crouzon group when compared to controls (p < 0.0001). Orbital soft-tissue volume was 19 percent less in the Apert group (p = 0.004) and 29 percent less in the Crouzon group (p = 0.001) when compared to controls. CONCLUSIONS: A shortened bony orbit, decreased orbital and orbital soft tissue volumes, and an increased volume of the globe were found in both conditions. Despite normal volume of the overall orbital contents, the contents are altered, and the bony orbit is shorter and holds less volume. PMID- 26505707 TI - Malar Augmentation with Pedicled Buccal Fat Pad in Orthognathic Surgery: Three Dimensional Evaluation. AB - BACKGROUND: Contemporary orthognathic surgery contemplates three-dimensional facial soft-tissue harmonization as one of the basic pillars in treatment planning. In particular, prominent malar regions are regarded as a sign of beauty and youth by Western societies. The aim of this article was to perform a subjective and objective three-dimensional evaluation of the pedicled buccal fat pad technique for malar augmentation in the context of orthognathic surgery. METHODS: Six consecutive patients with underlying dentofacial anomalies and bilateral malar hypoplasia were managed with simultaneous orthognathic surgery and pedicled buccal fat pad malar augmentation. Patient morbidity and satisfaction with the procedure were evaluated with a visual analogue scale. Cone beam computed tomographic data were used to perform a volumetric analysis at 1- and 12-month follow-up by means of image superimposition. RESULTS: Subjective analysis revealed excellent patient satisfaction and minimal pain. Mean malar volume was 115,480.91 mm preoperatively, 124,586.32 mm 1 month after surgery, and 119,008.77 mm 12 months after surgery. Thus, the final mean increase 1 year after surgery was 3527.86 mm and the average amount of resorption was 5577.55 mm. The median variations in volume were 7.77 percent at 1-month follow-up and 3.52 percent at 12-month follow-up. CONCLUSIONS: In conclusion, the pedicled buccal fat pad technique is a reasonable alternative for malar augmentation in the context of orthognathic surgery. The results of this preliminary report suggest that it provides satisfactory soft-tissue augmentation; avoids the use of foreign materials; and has minimal morbidity, high patient satisfaction, and adequate stability at 12-month follow-up. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26505708 TI - Intraparotid Location of the Great Auricular Nerve: A New Anatomical Basis for Gustatory Sweating Syndrome. AB - BACKGROUND: Gustatory sweating syndrome (also known as Frey syndrome or auriculotemporal nerve syndrome) is thought to result from a lesion of the auriculotemporal nerve. A lesion of this nerve can lead to aberrant regeneration of nerve fibers to the sweat glands and blood vessels. The occurrence of signs outside the region of the auriculotemporal nerve prompted the author to search for another anatomical basis for this syndrome. METHODS: The author dissected 46 great auricular nerves from their origin to the parotid gland and in the infratemporal fossa. The author investigated the different connections of the great auricular nerve with the facial nerve and the auriculotemporal nerve. RESULTS: The great auricular nerve was found to essentially be a parotid nerve. There was a set of intraparotid nerve connections on 14 of the 46 half-heads that were dissected. The author was able to discern three types of parotid great auricular nerve connections, which he designates as either type 1, connection with the trunk of the facial nerve and its branches; type 2, connection with the auriculotemporal nerve; or type 3, connection with the auriculotemporal nerve and the facial nerve with the formation of an intraparotid nerve circle. CONCLUSIONS: Having clearly established the nerve connections of the great auricular nerve, the author believes that it is primarily this nerve that is responsible for gustatory sweating syndrome. This allows for a better understanding of the sympathetic nervous system features and the manifestation of the syndrome outside the region of the auriculotemporal nerve. PMID- 26505709 TI - Noninvasive Monitoring of Immune Rejection in Face Transplant Recipients. AB - BACKGROUND: Chronic rejection leading to allograft loss remains a significant concern after facial allotransplantation. Chronic rejection may occur without clinical signs or symptoms. The current means of monitoring is histologic analyses of allograft biopsy specimens, which is both invasive and impractical. Prior data suggest that chronic rejection is associated with changes in intima and media thickness of vessels in arms and solid organ allografts; such data have not been published for face transplant recipients. METHODS: The authors used a 48 MHz transducer to acquire images of the bilateral facial, radial, dorsalis pedis and, if applicable, sentinel flap arteries in five face transplant recipients (8 months to 4.5 years after transplantation) and five control subjects. The authors assessed the intima, media, and adventitia thickness plus lumen and the total vessel diameter and area. RESULTS: Face transplant recipients had thicker intima in all sites compared with controls, but the ratio of the intimal thickness of facial and radial arteries was similar in face transplant recipients compared with controls (1.00 versus 0.95; p = 0.742). Intraobserver correlation showed reliable reproducibility of the measurements (r = 0.935, p <= 0.001). Interobserver correlation demonstrated reproducibility of intima measurements (r = 0.422, p <= 0.001). CONCLUSION: The authors demonstrate that ultrasound biomicroscopy is feasible for postsurgical monitoring, and have developed a new benchmark parameter, the facial artery-to-radial artery intimal thickness ratio, to be used in future testing in the setting of chronic rejection. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV. PMID- 26505710 TI - Digital Photograph Security: What Plastic Surgeons Need to Know. AB - BACKGROUND: Sharing and storing digital patient photographs occur daily in plastic surgery. Two major risks associated with the practice, data theft and Health Insurance Portability and Accountability Act (HIPAA) violations, have been dramatically amplified by high-speed data connections and digital camera ubiquity. The authors review what plastic surgeons need to know to mitigate those risks and provide recommendations for implementing an ideal, HIPAA-compliant solution for plastic surgeons' digital photography needs: smartphones and cloud storage. METHODS: Through informal discussions with plastic surgeons, the authors identified the most common photograph sharing and storage methods. For each method, a literature search was performed to identify the risks of data theft and HIPAA violations. HIPAA violation risks were confirmed by the second author (P.B.R.), a compliance liaison and privacy officer. A comprehensive review of HIPAA-compliant cloud storage services was performed. When possible, informal interviews with cloud storage services representatives were conducted. RESULTS: The most common sharing and storage methods are not HIPAA compliant, and several are prone to data theft. The authors' review of cloud storage services identified six HIPAA-compliant vendors that have strong to excellent security protocols and policies. These options are reasonably priced. CONCLUSIONS: Digital photography and technological advances offer major benefits to plastic surgeons but are not without risks. A proper understanding of data security and HIPAA regulations needs to be applied to these technologies to safely capture their benefits. Cloud storage services offer efficient photograph sharing and storage with layers of security to ensure HIPAA compliance and mitigate data theft risk. PMID- 26505711 TI - So, You Want to Make Your Bucket List? Where and When to Start. PMID- 26505712 TI - Shaping a Career in Plastic Surgery: Balancing the "Three Fs". PMID- 26505714 TI - Thoracic Intercostal Nerve Blocks Reduce Opioid Consumption and Length of Stay in Patients Undergoing Implant-Based Breast Reconstruction. AB - BACKGROUND: Traditionally, narcotics have been used for analgesia after breast surgery. However, these agents have unpleasant side effects. Intercostal nerve blockade is an alternative technique to improve postoperative pain. In this study, the authors investigate outcomes in patients who receive thoracic intercostal nerve blocks for implant-based breast reconstruction. METHODS: A retrospective chart review was performed. The operative technique for breast reconstruction and administration of nerve blocks is detailed. Demographic factors, length of stay, and complications were recorded. The consumption of morphine, Valium, Zofran, and oxycodone was recorded. Data sets for patients receiving thoracic intercostal nerve blocks were compared against those that did not. RESULTS: One hundred thirty-two patients were included. For patients undergoing bilateral reconstruction with nerve blocks, there was a significant reduction in length of stay (1.87 days versus 2.32 days; p = 0.001), consumption of intravenous morphine (5.15 mg versus 12.68 mg; p = 0.041) and Valium (22.24 mg versus 31.13 mg; p = 0.026). For patients undergoing unilateral reconstruction with nerve blocks, there was a significant reduction in consumption of intravenous morphine (2.80 mg versus 8.17 mg; p = 0.007). For bilateral reconstruction with intercostal nerve block, cost savings equaled $2873.14 per patient. For unilateral reconstruction with intercostal nerve block, cost savings equaled $1532.34 per patient. CONCLUSION: The authors' data demonstrate a reduction in the consumption of pain medication, in the hospital length of stay, and in hospital costs for patients receiving intercostal nerve blocks at the time of pectoralis elevation for implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 26505715 TI - Prevention of Capsular Contracture Using Leukotriene Antagonists. AB - BACKGROUND: Capsular contracture is a common occurrence in plastic surgery, with a prevalence varying from 0.5 percent up to 30 percent. Although the standard treatment is capsulectomy, alternative treatments have been studied, such as the use of leukotriene inhibitors. These drugs have recently been evaluated in the prophylaxis of contracture. The authors aimed to assess the efficacy of montelukast (Singulair) in the prevention of capsular contracture in patients undergoing mammaplasty with textured silicone prostheses. METHODS: The authors followed 82 patients (164 breasts) for a minimum of 2 years. Of these, 37 were administered montelukast. RESULTS: The number of affected patients and the severity were higher among the 45 patients who did not use montelukast. CONCLUSION: The prophylactic use of Singulair was, in this sample, shown to be effective in helping to reduce the incidence of capsular contracture. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 26505716 TI - Abdominoplasty: Risk Factors, Complication Rates, and Safety of Combined Procedures. AB - BACKGROUND: Among aesthetic surgery procedures, abdominoplasty is associated with a higher complication rate, but previous studies are limited by small sample sizes or single-institution experience. METHODS: A cohort of patients who underwent abdominoplasty between 2008 and 2013 was identified from the CosmetAssure database. Major complications were recorded. Univariate and multivariate analysis was performed evaluating risk factors, including age, smoking, body mass index, sex, diabetes, type of surgical facility, and combined procedures. RESULTS: The authors identified 25,478 abdominoplasties from 183,914 procedures in the database. Of these, 8,975 patients had abdominoplasty alone and 16,503 underwent additional procedures. The number of complications recorded was 1,012 (4.0 percent overall rate versus 1.4 percent in other aesthetic surgery procedures). Of these, 31.5 percent were hematomas, 27.2 percent were infections and 20.2 percent were suspected or confirmed venous thromboembolism. On multivariate analysis, significant risk factors (p < 0.05) included male sex (relative risk, 1.8), age 55 years or older (1.4), body mass index greater than or equal to 30 (1.3), multiple procedures (1.5), and procedure performance in a hospital or surgical center versus office-based surgical suite (1.6). Combined procedures increased the risk of complication (abdominoplasty alone, 3.1 percent; with liposuction, 3.8 percent; breast procedure, 4.3 percent; liposuction and breast procedure, 4.6 percent; body-contouring procedure, 6.8 percent; liposuction and body-contouring procedure, 10.4 percent). CONCLUSIONS: Abdominoplasty is associated with a higher complication rate compared with other aesthetic procedures. Combined procedures can significantly increase complication rates and should be considered carefully in higher risk patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 26505717 TI - Closed Microfracture Technique for Surgical Correction of Inferior Turbinate Hypertrophy in Rhinoplasty: Safety and Technical Considerations. AB - An abundance of surgical procedures are in use for the management of inferior turbinate hypertrophy in rhinoplasty patients. An ideal treatment approach is elusive, given the variability of patient presentation regarding obstructive nasal airway, significant complications associated with techniques that cause mucosal trauma, and the high recurrence rates associated with more conservative techniques. In an effort to improve patient safety, the authors describe a conservative technique-the closed microfracture-that provides an effective functional airway improvement and minimal to no complications. The authors propose a treatment approach for enlarged inferior turbinates based on turbinate subtype. PMID- 26505718 TI - The Systemic Effect of Burn Injury and Trauma on Muscle and Bone Mass and Composition. AB - BACKGROUND: By understanding the global inflammatory effects on distant myopathies, surgeons can better guide the rehabilitative process for burn patients. The authors tested the systemic effect of burn injury on distant injured muscle and native bone using immunohistochemistry and validated a new morphometric analytic modality to reproducibly quantify muscle atrophy using computed tomographic imaging. METHODS: In vivo studies were performed on C57/BL6 mice using an Achilles tenotomy with concurrent burn injury model. Total muscle and bone (tibia and fibula) volume/density were quantified near the site of Achilles tenotomy using micro-computed tomography at 5, 7, and 9 to 12 weeks after surgery. The impact of burn injury on the inflammatory cascade [nuclear factor (NF)-kappaB, p-NF-kappaB] and the interconnected protein catabolism signaling pathway (Atrogin-1) was assessed by immunohistochemistry. RESULTS: Muscle volume and density at the site of Achilles tenotomy in burned mice were significantly diminished compared with nonburned mice at 5 weeks and 9 to 12 weeks. Similar decreases in muscle volume and density were observed when comparing tenotomy to no tenotomy. Cortical bone health remained stable in burn/tenotomy mice compared with tenotomy. Muscle atrophy was associated with up regulation of p-NF-kappaB, NF-kappaB, and Atrogin-1 assessed by immunohistochemistry. CONCLUSIONS: Burn injury significantly decreases muscle volume and density. Increased muscle atrophy using our computed tomographic morphometric analysis correlated with a significant increase in intramuscular inflammatory markers and proteolysis enzymes. This study demonstrates a unique characterization of how burn injuries may worsen local myopathy. Moreover, it provides a novel approach for quantifying muscle atrophy over an expanded period. PMID- 26505719 TI - Effectiveness of Bone Marrow Stromal Cell Sheets in Maintaining Random-Pattern Skin Flaps in an Experimental Animal Model. AB - BACKGROUND: Bone marrow stromal cells can be applied therapeutically to enhance angiogenesis; however, the use of bone marrow stromal cell suspensions reduces efficiency because of low-level attachment. The authors hypothesized that bone marrow stromal cell sheets would facilitate cell fixation, thus enhancing angiogenesis. The authors investigated flap survival area and enhancement of angiogenic factors in a rat random-pattern skin flap model after application of bone marrow stromal cell sheets. METHODS: Bone marrow stromal cell sheets (prepared from 7-week-old rat femurs) were cultured under four different hypoxic conditions. Sheets with the highest angiogenic potential, determined by an in vitro pilot study, were injected into subcutaneous layers of the rat dorsum (bone marrow stromal cell sheet group). A control group (phosphate-buffered saline only) was included. On day 2 after injection, caudally based random-pattern skin flaps (12 * 3 cm) were elevated. On day 7 after elevation, surviving skin flap areas were measured. Skin samples were harvested from each flap and gene expression levels of vascular endothelial growth factor and basic fibroblast growth factor were measured by quantitative real-time polymerase chain reaction. RESULTS: Skin flap survival area (71.6 +/- 2.3 percent versus 51.5 +/- 3.3 percent) and levels of vascular endothelial growth factor and basic fibroblast growth factor were significantly higher in the bone marrow stromal cell sheet group than in the control group (p < 0.05). CONCLUSIONS: Implantation of bone marrow stromal cell sheets increased the survival area of random-pattern skin flaps. Expression of angiogenic factors may have contributed to the increased flap survival. PMID- 26505720 TI - Noninvasive Ultrasound of the Tibial Muscle for Longitudinal Analysis of Nerve Regeneration in Rats. AB - BACKGROUND: Today's criterion standards for measuring functional recovery after nerve trauma in experimental studies are the muscle mass ratio and the isometric tetanic force; both tests are invasive and require a sacrificial procedure. The authors propose ultrasound as a noninvasive method to determine muscle atrophy, and evaluate its validity and reliability by comparing it to muscle mass ratio, isometric tetanic force, and histology. METHODS: Fifty rats sustained a 10-mm autograft sciatic nerve reconstruction. With a 2-week interval, five animals were tested with a total follow-up of 20 weeks. The functional recovery of the hind limb muscles was measured with ultrasound, muscle mass ratio, and isometric tetanic force. In addition, neuromuscular junctions were analyzed histologically. The different evaluation techniques were compared and the reliability of the ultrasound was determined. RESULTS: Four weeks after denervation, extensive muscle atrophy resulted in a decrease of muscle mass up to 30 percent. Ultrasound showed good correlations with muscle mass ratio for both tibial (r = 0.85) and gastrocnemius muscles (r = 0.89). Both intrarater reliability (r = 0.97) and interrater reliability (r = 0.88) of the ultrasound were high. The correlation with force was lower (0.62) but still statistically significant. CONCLUSIONS: Ultrasound measurement of muscle atrophy was highly correlated with the criterion standard muscle mass ratio and was also significantly correlated with isometric tetanic force. Histologic evaluation confirmed the regeneration pattern observed with ultrasound. The authors propose that ultrasound can be used as a valid alternative to muscle mass ratio to study muscle atrophy after nerve injury in a less-invasive and more animal-friendly manner. PMID- 26505721 TI - The Effect of Medicaid Expansion on Delivery of Finger and Thumb Replantation Care to Medicaid Beneficiaries and the Uninsured. AB - BACKGROUND: Despite advances in replantation, over 80 percent of finger and thumb amputation injuries in the United States result in revision amputation. Although numerous factors contribute to this, disparities in access and delivery of replantation care play a substantial role. With ongoing Medicaid expansion under the Affordable Care Act, it is prudent to understand whether expansion of coverage changes use of replantation care. METHODS: The authors used the 2001 Medicaid expansion in New York State to evaluate changes in replantation for Medicaid beneficiaries and the uninsured. Data for patients having undergone replantation between 1998 and 2006 were obtained from the New York State Inpatient Database. The authors used an interrupted time series to evaluate the effect of Medicaid expansion on the probability that Medicaid beneficiaries or uninsured patients underwent replantation. Census data were used for population adjusted case volume analysis. RESULTS: After expansion, the likelihood of Medicaid as the primary payer for replantation increased 0.0059 percent per quarter, reaching a 1.7 percent increase 5 years after expansion. With population based analysis, this indicates that Medicaid covered 12 additional replantation cases in New York State annually. After expansion, 11 fewer of the replantation cases in New York State each year were provided to patients without health care coverage. CONCLUSIONS: Medicaid expansion resulted in a modest but significant increase in replantation for Medicaid beneficiaries. In addition, fewer patients that underwent replantation remained uninsured. Considering the substantial cost and effort burden of replantation, these findings support the benefits of Medicaid expansion on delivery and payer coverage of replantation. PMID- 26505722 TI - Permanent Tooth Agenesis and Maxillary Hypoplasia in Patients with Unilateral Cleft Lip and Palate. AB - BACKGROUND: Maxillary growth in patients with clefts is highly variable. The authors' aim was to investigate whether severity of maxillary hypoplasia is associated with the presence of permanent tooth agenesis in children with complete unilateral cleft lip and palate. METHODS: Fifty children with complete unilateral cleft lip and palate were divided into two groups of 25 children. One group had tooth agenesis of the cleft maxillary lateral incisor, whereas the other did not. Panoramic radiographs, lateral cephalometric radiographs, and dental casts were available for all children in the mixed dentition phase before preparation for alveolar bone grafting. The Modified Huddart/Bodenham scoring system was used to determine dental arch relationships on dental casts. Lateral cephalometric radiographs were traced and analyzed. Differences between groups were investigated using independent samples t tests. RESULTS: Children with complete unilateral cleft lip and palate and tooth agenesis presented with more negative Modified Huddart/Bodenham scores (-12.4 +/- 5.2) than those without tooth agenesis (-5.4 +/- 3.5) (p < 0.001), representing more severe arch constriction. These children also presented cephalometrically with reduced basal maxillary length (2.2 mm shorter; p = 0.043), alveolar maxillary length (2.9 mm shorter; p = 0.009), and alveolar maxillary protrusion (2.9 degrees less; p = 0.049) compared to those without tooth agenesis. CONCLUSIONS: Individuals with complete unilateral cleft lip and palate and tooth agenesis demonstrate more deficient maxillary growth than those without tooth agenesis. This is evident in both the sagittal and vertical dimensions, and when looking at the dentoalveolar intermaxillary relationships. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 26505723 TI - Comparison of Outcomes for Normal Saline and an Antiseptic Solution for Negative Pressure Wound Therapy with Instillation. AB - BACKGROUND: Negative-pressure wound therapy with instillation is an adjunctive treatment that uses periodic instillation of a solution and negative pressure for a wide diversity of wounds. A variety of solutions have been reported, with topical antiseptics as the most frequently chosen option. The objective of this study was to compare the outcomes of normal saline versus an antiseptic solution for negative-pressure wound therapy with instillation for the adjunctive treatment of infected wounds. METHODS: This was a prospective, randomized, effectiveness study comparing 0.9% normal saline versus 0.1% polyhexanide plus 0.1% betaine for the adjunctive treatment of infected wounds that required hospital admission and operative debridement. One hundred twenty-three patients were eligible, with 100 patients randomized for the intention-to-treat analysis and 83 patients for the per-protocol analysis. The surrogate outcomes measured were number of operative visits, length of hospital stay, time to final surgical procedure, proportion of closed or covered wounds, and proportion of wounds that remained closed or covered at the 30-day follow-up. RESULTS: There were no statistically significant differences in the demographic profiles in the two cohorts except for a larger proportion of male patients (p = 0.004). There was no statistically significant difference in the surrogate outcomes with the exception of the time to final surgical procedure favoring normal saline (p = 0.038). CONCLUSION: The authors' results suggest that 0.9% normal saline may be as effective as an antiseptic (0.1% polyhexanide plus 0.1% betaine) for negative pressure wound therapy with instillation for the adjunctive inpatient management of infected wounds. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 26505724 TI - The Superior-Edge-of-the-Knee Incision Method in Lymphaticovenular Anastomosis for Lower Extremity Lymphedema. AB - BACKGROUND: Lymphatic vessel diameter and lymph flow are important for accurate anastomosis and effective lymph-to-venous flow in lymphaticovenular anastomosis. The authors developed a reliable method, the superioredge-of-the-knee incision method, for detecting and making the best use of high-flow lymphatic vessels in the distal medial thigh between the deep and superficial fascia, where movement of the knee, combined with compression between these fascial layers, theoretically results in upward propulsion of lymphatic fluid. METHODS: Intraoperative detection of large lymphatic vessels and of venous reflux and postoperative lymphedematous volume reduction were compared between 15 patients in whom lymphaticovenular anastomoses with the superior-edge-of-the-knee incision method were undergone and 15 in whom conventional lymphaticovenular anastomoses were undergone. RESULTS: Lymphaticovenular anastomosis at the thigh yielded 30 anastomoses in the superior-edge-of-the-knee incision group and 32 anastomoses in the non-superior-edge-of-the-knee incision group. Large lymphatic vessels were more frequently found in the superior-edge-of-the-knee incision group than in the non-superior-edge-of-the-knee incision group (60.0 percent versus 18.8 percent; p = 0.002). Venous reflux occurred less frequently in the superior-edge-of-the-knee incision group than in the non-superior-edge-of-the-knee incision group (10.0 percent versus 65.6 percent; p < 0.001). Reduction of the lower extremity lymphedema index was significantly greater in the superior-edge-of-the-knee incision group than in the non-superior-edge-of-the-knee incision group (24.427 +/- 12.400 versus 0.032 +/- 20.535; p < 0.001). CONCLUSION: The superior-edge-of the-knee incision method facilitates detection and use of large, high-flow lymphatic vessels in the distal medial thigh, both of which are important for optimum therapeutic effects in patients with lower extremity lymphedema. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 26505725 TI - Face Lift. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Identify the essential anatomy of the aging face and its relationship to face-lift surgery. 2. Understand the common operative approaches to the aging face and a historical perspective. 3. Understand and describe the common complications following face lifting and treatment options. SUMMARY: Surgical rejuvenation of the aging face remains one of the most commonly performed plastic surgery procedures. This article reviews the anatomy of the face and its impact on surgical correction. In addition, this review discusses the evolution of various face-lift techniques and the current surgical approach to the aging face. Finally, this article discusses potential postoperative complications after rhytidectomy and management solutions. PMID- 26505726 TI - Financial Conflicts of Interest: An Association between Funding and Findings in Plastic Surgery. AB - BACKGROUND: Despite a growing interest in examining the effects of industry funding on research in plastic surgery, no study to date has comprehensively examined the effects of financial conflicts of interest on publication outcomes. The authors investigated the association between financial conflicts of interest and reported study findings in plastic surgery research. METHODS: The authors reviewed all entries in Plastic and Reconstructive Surgery, Annals of Plastic Surgery, and Journal of Plastic, Reconstructive & Aesthetic Surgery from January 1, 2012, to December 31, 2012. All clinical and basic science articles were analyzed. The following article characteristics were extracted: self-reported financial conflicts of interest, sample size, level of evidence, study design, and prospectiveness. The findings reported in each abstract were blindly graded as not applicable, negative, or positive. RESULTS: Of the 1650 abstracts that resulted from the authors' initial search, 568 fulfilled the inclusion criteria. The majority of the included articles covered breast (20.8 percent), experimental (19.7 percent), and general reconstruction (31.69 percent). Financial conflicts of interest were disclosed in only 17.6 percent of the articles. Of the total studies that met inclusion criteria, 66.2 percent were reviewed as having positive outcomes, and 33.8 percent were reviewed as having negative or not applicable results. Studies that disclosed a financial conflict of interest were 7.12 times more likely (p < 0.0001) to present a positive outcome over a negative outcome compared with studies with no financial conflict of interest. CONCLUSION: Investigators with a financial conflict of interest are significantly more likely to publish plastic surgery studies with a positive conclusion compared with investigators with no conflicts of interest. PMID- 26505727 TI - Reply: Comparison of Postoperative Pain Control in Autologous Abdominal Free Flap versus Implant-Based Breast Reconstruction. PMID- 26505728 TI - Line-of-Nines Guide to Define Points B and C in Mastopexy and Reduction Mammaplasty. PMID- 26505730 TI - Nanoantioxidant-driven plasmon enhanced proton-coupled electron transfer. AB - Proton-coupled electron transfer (PCET) reactions involve the transfer of a proton and an electron and play an important role in a number of chemical and biological processes. Here, we describe a novel phenomenon, plasmon-enhanced PCET, which is manifested using SiO2-coated Ag nanoparticles functionalized with gallic acid (GA), a natural antioxidant molecule that can perform PCET. These GA functionalized nanoparticles show enhanced plasmonic response at near-IR wavelengths, due to particle agglomeration caused by the GA molecules. Near-IR laser irradiation induces strong local hot-spots on the SiO2-coated Ag nanoparticles, as evidenced by surface enhanced Raman scattering (SERS). This leads to plasmon energy transfer to the grafted GA molecules that lowers the GA OH bond dissociation enthalpy by at least 2 kcal mol(-1) and therefore facilitates PCET. The nanoparticle-driven plasmon-enhancement of PCET brings together the so far unrelated research domains of nanoplasmonics and electron/proton translocation with significant impact on applications based on interfacial electron/proton transfer. PMID- 26505731 TI - Assay Development for Image-Based Quantification of Intracellular Bacterial Replication and Analysis of the Innate Immune Response to Infection. AB - Severe bacterial infection can lead to inflammation, host tissue damage, and ultimately disseminated septic shock. The mammalian innate immune system responds to microbial infection through the detection of invariant pathogen-associated molecular patterns (PAMPs) by a range of pattern recognition receptors (PRRs) expressed by the host cell. A successful immune response involves tightly coordinated signaling from these receptors, leading to a robust transcriptional response producing cytokines and antimicrobial effectors. While the PRR expressing phagocytes of the host innate immune system function to contain and degrade internalized bacteria through pathways such as selective autophagy, pathogenic bacteria may subvert this process to replicate in the host cell. We describe the development of imaging assays to investigate these host-pathogen interactions through gene perturbation screens, which could lead to the identification of novel effectors of the host response to bacterial infection. We identify markers of coordinated initial signaling in macrophages challenged with ligands to PRRs of the toll-like receptor (TLR) family and compare this response to that induced by intact bacteria of the Burkholderia cenocepacia complex (Bcc), an opportunistic pathogen that causes life-threatening infections in patients with cystic fibrosis and chronic granulomatous disease. Bcc has been shown to escape the endocytic pathway, activate selective autophagy, and replicate within human macrophages. We demonstrate robust image-based quantification of multiple stages of Bcc infection of macrophages: ubiquitin tagging of cytosolic bacteria, recruitment of selective autophagy effector proteins, and intracellular bacterial replication, and we show perturbation of bacterial replication using drug treatment or siRNA-based gene knockdown. The described panel of imaging assays can be extended to other bacterial infections and pathogenic ligand combinations where high-content siRNA screening could provide significant new insight into regulation of the innate immune response to infection. PMID- 26505732 TI - Symmetry-directed control of electronic coupling for singlet fission in covalent bis-acene dimers. AB - While singlet fission (SF) has developed in recent years within material settings, much less is known about its control in covalent dimers. Such platforms are of fundamental importance and may also find practical use in next-generation dye-sensitized solar cell applications or for seeding SF at interfaces following exciton transport. Here, facile theoretical tools based on Boys localization methods are used to predict diabatic coupling for SF via determination of one electron orbital coupling matrix elements. The results expose important design rules that are rooted in point group symmetry. For Cs-symmetric dimers, pathways for SF that are mediated by virtual charge transfer excited states destructively interfere with negative impact on the magnitude of diabatic coupling for SF. When dimers have C2 symmetry, constructive interference is enabled for certain readily achievable interchromophore orientations. Three sets of dimers exploiting these ideas are explored: a bis-tetracene pair and two sets of aza-substituted tetracene dimers. Remarkable control is shown. In one aza-substituted set, symmetry has no impact on SF reaction thermodynamics but leads to a 16-fold manipulation in SF diabatic coupling. This translates to a difference of nearly 300 in kSF with the faster of the two dimers (C2) being predicted to undergo the process on a nearly ultrafast 1.5 ps time scale. PMID- 26505729 TI - Different doses of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. AB - BACKGROUND: Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in people who are thrombocytopenic due to bone marrow failure. Although considerable advances have been made in platelet transfusion therapy in the last 40 years, some areas continue to provoke debate, especially concerning the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding.This is an update of a Cochrane review first published in 2004, and updated in 2012 that addressed four separate questions: prophylactic versus therapeutic-only platelet transfusion policy; prophylactic platelet transfusion threshold; prophylactic platelet transfusion dose; and platelet transfusions compared to alternative treatments. This review has now been split into four smaller reviews; this review compares different platelet transfusion doses. OBJECTIVES: To determine whether different doses of prophylactic platelet transfusions (platelet transfusions given to prevent bleeding) affect their efficacy and safety in preventing bleeding in people with haematological disorders undergoing myelosuppressive chemotherapy with or without haematopoietic stem cell transplantation (HSCT). SEARCH METHODS: We searched for randomised controlled trials in the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 6), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 23 July 2015. SELECTION CRITERIA: Randomised controlled trials involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people with malignant haematological disorders or undergoing HSCT that compared different platelet component doses (low dose 1.1 x 10(11)/m(2) +/- 25%, standard dose 2.2 x 10(11)/m(2) +/- 25%, high dose 4.4 x 10(11)/m(2) +/- 25%). DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included seven trials (1814 participants) in this review; six were conducted during one course of treatment (chemotherapy or HSCT).Overall the methodological quality of studies was low to moderate across different outcomes according to GRADE methodology. None of the included studies were at low risk of bias in every domain, and all the included studies had some threats to validity.Five studies reported the number of participants with at least one clinically significant bleeding episode within 30 days from the start of the study. There was no difference in the number of participants with a clinically significant bleeding episode between the low-dose and standard-dose groups (four studies; 1170 participants; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.95 to 1.13; moderate-quality evidence); low-dose and high-dose groups (one study; 849 participants; RR 1.02, 95% CI 0.93 to 1.11; moderate-quality evidence); or high-dose and standard-dose groups (two studies; 951 participants; RR 1.02, 95% CI 0.93 to 1.11; moderate-quality evidence).Three studies reported the number of days with a clinically significant bleeding event per participant. There was no difference in the number of days of bleeding per participant between the low-dose and standard-dose groups (two studies; 230 participants; mean difference -0.17, 95% CI -0.51 to 0.17; low quality evidence). One study (855 participants) showed no difference in the number of days of bleeding per participant between high-dose and standard-dose groups, or between low-dose and high-dose groups (849 participants).Three studies reported the number of participants with severe or life-threatening bleeding. There was no difference in the number of participants with severe or life-threatening bleeding between a low-dose and a standard-dose platelet transfusion policy (three studies; 1059 participants; RR 1.33, 95% CI 0.91 to 1.92; low-quality evidence); low-dose and high-dose groups (one study; 849 participants; RR 1.20, 95% CI 0.82 to 1.77; low-quality evidence); or high-dose and standard-dose groups (one study; 855 participants; RR 1.11, 95% CI 0.73 to 1.68; low-quality evidence).Two studies reported the time to first bleeding episodes; we were unable to perform a meta analysis. Both studies (959 participants) individually found that the time to first bleeding episode was either the same, or longer, in the low-dose group compared to the standard-dose group. One study (855 participants) found that the time to the first bleeding episode was the same in the high-dose group compared to the standard-dose group.Three studies reported all-cause mortality within 30 days from the start of the study. There was no difference in all-cause mortality between treatment arms (low-dose versus standard-dose: three studies; 1070 participants; RR 2.04, 95% CI 0.70 to 5.93; low-quality evidence; low-dose versus high-dose: one study; 849 participants; RR 1.33, 95% CI 0.50 to 3.54; low-quality evidence; and high-dose versus standard-dose: one study; 855 participants; RR 1.71, 95% CI 0.51 to 5.81; low-quality evidence).Six studies reported the number of platelet transfusions; we were unable to perform a meta-analysis. Two studies (959 participants) out of three (1070 participants) found that a low-dose transfusion strategy led to more transfusion episodes than a standard-dose. One study (849 participants) found that a low-dose transfusion strategy led to more transfusion episodes than a high-dose strategy. One study (855 participants) out of three (1007 participants) found no difference in the number of platelet transfusions between the high-dose and standard-dose groups.One study reported on transfusion reactions. This study's authors suggested that a high-dose platelet transfusion strategy may lead to a higher rate of transfusion-related adverse events.None of the studies reported quality-of-life. AUTHORS' CONCLUSIONS: In haematology patients who are thrombocytopenic due to myelosuppressive chemotherapy or HSCT, we found no evidence to suggest that a low-dose platelet transfusion policy is associated with an increased bleeding risk compared to a standard-dose or high-dose policy, or that a high-dose platelet transfusion policy is associated with a decreased risk of bleeding when compared to a standard-dose policy.A low-dose platelet transfusion strategy leads to an increased number of transfusion episodes compared to a standard-dose strategy. A high-dose platelet transfusion strategy does not decrease the number of transfusion episodes per participant compared to a standard-dose regimen, and it may increase the number of transfusion-related adverse events.Findings from this review would suggest a change from current practice, with low-dose platelet transfusions used for people receiving in-patient treatment for their haematological disorder and high-dose platelet transfusion strategies not being used routinely. PMID- 26505734 TI - Differential Effects of Axin2 Deficiency on the Fibrogenic and Regenerative Response in Livers of Bile Duct-Ligated Mice. AB - BACKGROUND: Wnt signaling is involved in the pathogenesis of liver fibrosis. Axin2 is a negative regulator of the canonical Wnt pathway by promoting beta catenin degradation. beta-Catenin-activating and loss-of-function mutations of Axin2 are thought to be functionally relevant for liver diseases and cancer. Thus, we hypothesized that Axin2 deficiency promotes fibrogenesis. METHODS: As the functions and mechanisms of how Axin2/beta-catenin signaling participates in the progression of liver fibrosis are unclear, we investigated the progression of liver fibrosis in Axin2-deficient mice using Axin2-LacZ reporter mice (Axin2+/-, Axin2-/-, and Axin2+/+) which underwent bile duct ligation (BDL). RESULTS: Here, we show that the expression of Axin2 is downregulated during fibrogenesis in wild type mice, which is consistent with a decreased expression of the reporter gene LacZ in Axin2+/- and Axin2-/- mice. Surprisingly, no alteration in active beta catenin/Wnt signaling occurs in Axin2-deficient mice upon BDL. Despite a less pronounced liver injury, Axin2 deficiency had only minor and no significant effects on the fibrogenic response upon BDL, i.e. slightly reduced hepatic stellate cell activity and collagen mRNA expression. However, livers of Axin2-/- mice shared a stronger cell proliferation both already at baseline as well as immediately after BDL. CONCLUSION: Our results strongly suggest, contrary to expectation, that a deficiency in Axin2 is not equivalent to an increase in active beta-catenin and target genes, indicating no functional relevance of Axin2 dependent regulation of the canonical Wnt/beta-catenin pathway in the progression of cholestatic liver injury. This also suggests that the negligible effects of Axin2 deficiency during fibrogenesis may be related to an alternative pathway. PMID- 26505733 TI - Isolation and characterization of human intestinal Enterococcus avium EFEL009 converting rutin to quercetin. AB - Quercetin is a flavonol believed to have beneficial effects on human health. Rutin, found in many plants, fruits and vegetables, is metabolized by human intestinal bacteria and converted to quercetin, where it is absorbed through the intestinal epithelium. This study aimed to isolate and characterize human intestinal bacteria capable of converting rutin to quercetin. A bacterium that can metabolize rutin was isolated from human faecal samples and identified by 16S rRNA gene sequencing. The whole-cell enzymatic activities on flavonoid glycoside and the conversion profiles of the isolate were also analysed. The bacterium was identified as Enterococcus avium EFEL009 and was shown to convert rutin to isoquercetin and then to quercetin under anaerobic conditions. Microscopic analysis revealed short chains of cocci with diameters of approx. 1 MUm. beta Glucosidase was shown to be constitutively expressed in Ent. avium, while alpha rhamnosidase was expressed following induction by rutin. Both enzymes were mainly localized to the cell surface. This study is the first report on the isolation of a quercetin-producing Ent. avium FEEL009, which could be a potential industrial starter bacterium. SIGNIFICANCE AND IMPACT OF THE STUDY: Quercetin is a member of the flavonoids family reported to have better cytoprotective abilities, stronger inhibition of lipopolysaccharide-induced nitric oxide production, and better chemoprevention than rutin. This is the first report on the isolation and characterization of Enterococcus avium EFEL009 from the human intestine which is capable of converting rutin to quercetin. PMID- 26505735 TI - Somatostatin-Immunoreactive Pancreaticoduodenal Neuroendocrine Neoplasms: Twenty Three Cases Evaluated according to the WHO 2010 Classification. AB - BACKGROUND/OBJECTIVE: Neuroendocrine neoplasms of the pancreas and duodenum with predominant or exclusive immunoreactivity for somatostatin (pdSOMs) are rare, and knowledge about tumour biology, treatment, survival and prognostic factors is limited. This study aims to describe clinical, pathological and biochemical features as well as treatment and prognosis of pdSOMs. DESIGN: Twenty-three patients with pdSOM (9 duodenal, 12 pancreatic and 2 unknown primary tumours) were identified from our prospective neuroendocrine tumour database, and data according to the study aims were recorded. RESULTS: Among the 9 patients with duodenal SOM, the male/female ratio was 4/5. All males and 1 female had neurofibromatosis type 1. Seven patients had stage 1A/B and 2 had stage 2B disease. The Ki-67 index was 1-5% (median 2%). Plasma somatostatin was elevated in the patients with 2B disease. Of the 14 patients with pancreatic SOM or an unknown primary tumour, the male/female ratio was 2/12. One male had multiple endocrine neoplasia type 1. Five had stage 1A/2B and 9 had stage 4. The Ki-67 index was 1-40% (median 7%). Plasma somatostatin was elevated in 7 patients. Patients reported symptoms related to the somatostatinoma syndrome, but none fulfilled the criteria for a full syndrome. Primary tumour in the pancreas, metastatic disease at diagnosis and higher tumour grade were all associated with significantly poorer survival. CONCLUSION: None of the patients with pdSOM presented with the full somatostatinoma syndrome. Prognostic factors are localisation of the primary tumour, dissemination and tumour grade. A Ki-67 index of 5% may discriminate the course of the disease. PMID- 26505738 TI - Fabry-Perot Microcavity Modes in Single GaP/GaNP Core/Shell Nanowires. AB - Semiconductor nanowires (NWs) are attracting increasing interest as nanobuilding blocks for optoelectronics and photonics. A novel material system that is highly suitable for these applications are GaNP NWs. In this article, we show that individual GaP/GaNP core/shell nanowires (NWs) grown by molecular beam epitaxy on Si substrates can act as Fabry-Perot (FP) microcavities. This conclusion is based on results of microphotoluminescence (MU-PL) measurements performed on individual NWs, which reveal periodic undulations of the PL intensity that follow an expected pattern of FP cavity modes. The cavity is concluded to be formed along the NW axis with the end facets acting as reflecting mirrors. The formation of the FP modes is shown to be facilitated by an increasing index contrast with the surrounding media. Spectral dependence of the group refractive index is also determined for the studied NWs. The observation of the FP microcavity modes in the GaP/GaNP core/shell NWs can be considered as a first step toward achieving lasing in this quasidirect bandgap semiconductor in the NW geometry. PMID- 26505736 TI - Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP. AB - BACKGROUND AND PURPOSE: Upon stimulation, neutrophils release their nuclear contents called neutrophil extracellular traps (NETs), which contain unfolded chromatin and lysosomal enzymes. NETs have been demonstrated to play a critical role in host defence, although the role of PGE2 , a bioactive substance generated in inflammatory tissues, in the formation of NETs remains unclear. EXPERIMENTAL APPROACH: The effects of PGE2 , agonists and antagonists of its receptors, and modulators of the cAMP-PKA pathway on the formation of NETs were examined in vitro in isolated neutrophils and in vivo in a newly established mouse model. KEY RESULTS: PGE2 inhibited PMA-induced NET formation in vitro through EP2 and EP4 Galphas-coupled receptors. Incubation with a cell-permeable cAMP analogue, dibutyryl cAMP, or various inhibitors of a cAMP-degrading enzyme, PDE, also suppressed NET formation. In the assay established here, where an agarose gel was s.c. implanted in mice and NET formation was detected on the surface of the gel, the extent of the NET formed was inhibited in agarose gels containing rolipram, a PDE4 inhibitor, and butaprost, an EP2 receptor agonist. CONCLUSIONS AND IMPLICATIONS: PGE2 inhibits NET formation through the production of cAMP. These findings will contribute to the development of novel treatments for NETosis related diseases. PMID- 26505739 TI - Photochemical Mechanism of Riboflavin-Induced Degradation of Famotidine and a Suggested Pharmaceutical Strategy for Improving Photostability. AB - The present study aimed to clarify the mechanism of photodegradation of famotidine with riboflavin (FMT/RF), and to develop a photochemically stabilized formulation of FMT/RF. Photochemical properties of RF were characterized by UV VIS spectral analysis, reactive oxygen species (ROS) assay, and photostability testing. Pharmacokinetic study was conducted in rats after intravenous administration of FMT (1 mg/kg) formulation containing RF (0.01 mg/kg). The UV VIS spectral pattern of RF partly overlapped with the sunlight spectrum, and ROS generation from photoirradiated RF was remarkable; thus, RF had high photoreactive potential. In the photostability testing, after irradiation (250 W/m(2)), degradation rate for FMT in FMT/RF was ca. 11-fold higher than that in FMT alone. The addition of radical scavengers to FMT/RF led to attenuated photodegradation of FMT/RF; in particular, the addition of L-ascorbic acid (vitamin C; VC) to FMT/RF showed ca. 86% inhibition of the photodegradation of FMT/RF. The pharmacokinetic study on FMT indicated that the addition of VC (1 mg/kg) to FMT/RF had no significant impact on the pharmacokinetic behavior of FMT. These findings suggest that ROS-mediated photochemical reaction would be involved in the photodegradation pathway of FMT/RF, and the complementary use of VC might be an attractive approach to improve the photostability of FMT/RF. PMID- 26505740 TI - CH3 NH3 PbBr3 -CH3 NH3 PbI3 Perovskite-Perovskite Tandem Solar Cells with Exceeding 2.2 V Open Circuit Voltage. AB - Perovskite-perovskite tandem solar cells with open-circuit voltages of over 2.2 V are reported. These cost-effective, solution-processible perovskite hybrid tandem solar cells with high open-circuit voltages are fabricated by the simple lamination of a front planar MAPbBr3 perovskite cell and a back MAPbI3 planar perovskite solar cell. PMID- 26505737 TI - Structural and functional connectivity between the lateral posterior-pulvinar complex and primary visual cortex in the ferret. AB - The role of higher-order thalamic structures in sensory processing remains poorly understood. Here, we used the ferret (Mustela putorius furo) as a novel model species for the study of the lateral posterior (LP)-pulvinar complex and its structural and functional connectivity with area 17 [primary visual cortex (V1)]. We found reciprocal anatomical connections between the lateral part of the LP nucleus of the LP-pulvinar complex (LPl) and V1. In order to investigate the role of this feedback loop between LPl and V1 in shaping network activity, we determined the functional interactions between LPl and the supragranular, granular and infragranular layers of V1 by recording multiunit activity and local field potentials. Coherence was strongest between LPl and the supragranular V1, with the most distinct peaks in the delta and alpha frequency bands. Inter-area interaction measured by spike-phase coupling identified the delta frequency band being dominated by the infragranular V1 and multiple frequency bands that were most pronounced in the supragranular V1. This inter-area coupling was differentially modulated by full-field synthetic and naturalistic visual stimulation. We also found that visual responses in LPl were distinct from those in V1 in terms of their reliability. Together, our data support a model of multiple communication channels between LPl and the layers of V1 that are enabled by oscillations in different frequency bands. This demonstration of anatomical and functional connectivity between LPl and V1 in ferrets provides a roadmap for studying the interaction dynamics during behaviour, and a template for identifying the activity dynamics of other thalamo-cortical feedback loops. PMID- 26505741 TI - IgE antibodies in relation to prevalence and multimorbidity of eczema, asthma, and rhinitis from birth to adolescence. AB - BACKGROUND: Eczema, asthma, and rhinitis affect a large proportion of children, but their prevalence varies with age. IgE antibodies are also common in the pediatric population. However, the links between IgE, disease, and trajectories are unclear. OBJECTIVE: To better understand the links between sensitization and disease, we studied IgE sensitization ever in relation to eczema, asthma, and rhinitis, in children followed up to 16 years of age. METHODS: From the Swedish population-based birth cohort BAMSE, 2607 children were included. Parental reports from six time points between 1 and 16 years were used to identify children with eczema, asthma, and rhinitis. Blood was collected at 4, 8, and 16 years, and sensitization ever was defined as allergen-specific IgE >=0.35 kUA /l to common food and/or inhalant allergens at any time point. Odds ratios for eczema, asthma, rhinitis, and multimorbidity in relation to sensitization ever were calculated using generalized estimating equations. RESULTS: Fifty-one percent were sensitized at least once up to 16 years. Almost a quarter of ever sensitized children did not have any disease. After adjustment for potential confounders, sensitization ever was significantly associated with the following: (i) eczema throughout childhood, (ii) multimorbidity of eczema, asthma, and rhinitis from 1 to 16 years (OR for multimorbidity: 5.11, 95% CI: 3.99-6.55), (iii) asthma and rhinitis from 4 to 16 years of age. CONCLUSIONS: Specific IgE is strongly associated with eczema and allergic multimorbidity throughout childhood and with asthma and rhinitis from age 4 years. However, 23% of the children with IgE sensitization do not develop any disease in childhood. PMID- 26505742 TI - Survey of influenza and other respiratory viruses diagnostic testing in US hospitals, 2012-2013. AB - BACKGROUND: Little is known about laboratory capacity to routinely diagnose influenza and other respiratory viruses at clinical laboratories and hospitals. AIMS: We sought to assess diagnostic practices for influenza and other respiratory virus in a survey of hospitals and laboratories participating in the US Influenza Hospitalization Surveillance Network in 2012-2013. MATERIALS AND METHODS: All hospitals and their associated laboratories participating in the Influenza Hospitalization Surveillance Network (FluSurv-NET) were included in this evaluation. The network covers more than 80 counties in 15 states, CA, CO, CT, GA, MD, MN, NM, NY, OR, TN, IA, MI, OH, RI, and UT, with a catchment population of ~28 million people. We administered a standardized questionnaire to key personnel, including infection control practitioners and laboratory departments, at each hospital through telephone interviews. RESULTS: Of the 240 participating laboratories, 67% relied only on commercially available rapid influenza diagnostic tests to diagnose influenza. Few reported the availability of molecular diagnostic assays for detection of influenza (26%) and other viral pathogens (<=20%) in hospitals and commercial laboratories. CONCLUSION: Reliance on insensitive assays to detect influenza may detract from optimal clinical management of influenza infections in hospitals. PMID- 26505743 TI - Vitamin D Status among Young Children Aged 1-3 Years: A Cross-Sectional Study in Wuxi, China. AB - BACKGROUND: The increasingly recognized importance of vitamin D has been discussed and vitamin D status among young children has attracted widespread attention in recent years. However, study on vitamin D status in young children aged 1-3 y is limited in China. OBJECTIVE: To evaluate the nutritional vitamin D status of young children aged 1-3 y in Wuxi, southeastern China. METHODS: A large cohort of 5,571 young children aged 1-3 y were recruited in this study who visited the child health clinics at the Wuxi Maternity and Child Health Hospital (latitude 31.57 degrees N) during January 2014 to January 2015. Wuxi was located in southeastern China at a latitude of 31.57 degrees N. Finger-stick blood sampling was conducted in all the subjects and serum 25-Hydroxyvitamin D (25(OH)D) levels were measured to evaluate their vitamin D status. RESULTS: In this study, serum 25(OH)D levels of young children at the age of 1-3 years ranged from 20.6-132.9 nmol/L (Median: 71.5 nmol/L). 16.1% of the population had vitamin D deficiency (<50 nmol/L), while 38.8% of the subjects had a sufficient (50-74.9 nmol/L) vitamin D level. An optimal vitamin D status (>=75 nmol/L) was found in 45.1% of the young children. The prevalence of vitamin D deficiency was higher in autumn (19.5%) than in summer (12.1%). There was no significant difference in vitamin D status between genders. The binary logistic regression analysis revealed that child age was strongly associated with vitamin D deficiency (adjusted OR: 1.173; 95%CI: 1.053-1.308; P = 0.004). CONCLUSIONS: The prevalence of vitamin D deficiency was 16.1% among young children aged 1-3 y in Wuxi. Season and child age were associated with their vitamin D status. It is implied that young children should receive adequate amounts of vitamin D supplementation and spend more time outdoors to prolong the sunlight exposure when they grow older. PMID- 26505744 TI - Unraveling the Complexity of Critical Consciousness, Political Efficacy, and Political Action Among Marginalized Adolescents. AB - This research examines the complex patterns by which distinct dimensions of critical consciousness may lead marginalized adolescents toward distinct forms of political action. Structural equation modeling was applied to nationally representative data from the Civic Education Study (2,811 ninth graders; Mage = 14.6), first establishing the measurement invariance of constructs across samples of poor or working class African American and Latino/a adolescents. Perceptions of societal inequality and aspirational beliefs that society ought to be more equal differentially predicted expected voting, conventional political action, and social action-while controlling for civic achievement and with nuances between ethnic and racial groups. Contrary to hypotheses and extant scholarship, political efficacy did not mediate or moderate relations between critical reflection and disparate forms of political action. PMID- 26505745 TI - A Systematic Review and Meta-Analysis of Fecal Contamination and Inadequate Treatment of Packaged Water. AB - BACKGROUND: Packaged water products provide an increasingly important source of water for consumption. However, recent studies raise concerns over their safety. OBJECTIVES: To assess the microbial safety of packaged water, examine differences between regions, country incomes, packaged water types, and compare packaged water with other water sources. METHODS: We performed a systematic review and meta-analysis. Articles published in English, French, Portuguese, Spanish and Turkish, with no date restrictions were identified from online databases and two previous reviews. Studies published before April 2014 that assessed packaged water for the presence of Escherichia coli, thermotolerant or total coliforms were included provided they tested at least ten samples or brands. RESULTS: A total of 170 studies were included in the review. The majority of studies did not detect fecal indicator bacteria in packaged water (78/141). Compared to packaged water from upper-middle and high-income countries, packaged water from low and lower-middle-income countries was 4.6 (95% CI: 2.6-8.1) and 13.6 (95% CI: 6.9 26.7) times more likely to contain fecal indicator bacteria and total coliforms, respectively. Compared to all other packaged water types, water from small bottles was less likely to be contaminated with fecal indicator bacteria (OR = 0.32, 95%CI: 0.17-0.58) and total coliforms (OR = 0.10, 95%CI: 0.05, 0.22). Packaged water was less likely to contain fecal indicator bacteria (OR = 0.35, 95%CI: 0.20, 0.62) compared to other water sources used for consumption. CONCLUSIONS: Policymakers and regulators should recognize the potential benefits of packaged water in providing safer water for consumption at and away from home, especially for those who are otherwise unlikely to gain access to a reliable, safe water supply in the near future. To improve the quality of packaged water products they should be integrated into regulatory and monitoring frameworks. PMID- 26505746 TI - Tau positron emission tomographic imaging in aging and early Alzheimer disease. AB - OBJECTIVE: Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease-modifying therapies. METHODS: We acquired tau positron emission tomography (PET) using (18)F T807 (AV1451), and amyloid-beta PET using (11)C Pittsburgh compound B (PiB) in older clinically normal individuals, and symptomatic patients with mild cognitive impairment or mild AD dementia. RESULTS: We found abnormally high cortical (18)F T807 binding in patients with mild cognitive impairment and AD dementia compared to clinically normal controls. Consistent with the neuropathology literature, the presence of elevated neocortical (18)F T807 binding particularly in the inferior temporal gyrus was associated with clinical impairment. The association of cognitive impairment was stronger with inferior temporal (18)F T807 than with mean cortical (11)C PIB. Regional (18)F T807 was correlated with mean cortical (11)C PiB among both impaired and control subjects. INTERPRETATION: These findings suggest that (18)F T807 PET could have value as a biomarker that reflects both the progression of AD tauopathy and the emergence of clinical impairment. PMID- 26505747 TI - Lentivirus Live Cell Array for Quantitative Assessment of Gene and Pathway Activation during Myogenic Differentiation of Mesenchymal Stem Cells. AB - Stem cell differentiation involves multiple cascades of transcriptional regulation that govern the cell fate. To study the real-time dynamics of this complex process, quantitative and high throughput live cell assays are required. Herein, we developed a lentiviral library of promoters and transcription factor binding sites to quantitatively capture the gene expression dynamics over a period of several days during myogenic differentiation of human mesenchymal stem cells (MSCs) harvested from two different anatomic locations, bone marrow and hair follicle. Our results enabled us to monitor the sequential activation of signaling pathways and myogenic gene promoters at various stages of differentiation. In conjunction with chemical inhibitors, the lentiviral array (LVA) results also revealed the relative contribution of key signaling pathways that regulate the myogenic differentiation. Our study demonstrates the potential of LVA to monitor the dynamics of gene and pathway activation during MSC differentiation as well as serve as a platform for discovery of novel molecules, genes and pathways that promote or inhibit complex biological processes. PMID- 26505749 TI - Verification of Radicals Formation in Ethanol-Water Mixture Based Solution Plasma and Their Relation to the Rate of Reaction. AB - Our previous research demonstrated that using ethanol-water mixture as a liquid medium for the synthesis of gold nanoparticles by the solution plasma process (SPP) could lead to an increment of the reaction rate of ~35.2 times faster than that in pure water. This drastic change was observed when a small amount of ethanol, that is, at an ethanol mole fraction (chiethanol) of 0.089, was added in the system. After this composition, the reaction rate decreased continuously. To better understand what happens in the ethanol-water mixture-based SPP, in this study, effect of the ethanol content on the radical formation in the system was verified. We focused on detecting the magnetic resonance of electronic spins using electron spin resonance spectroscopy to determine the type and quantity of the generated radicals at each chiethanol. Results indicated that ethanol radicals were generated in the ethanol-water mixtures and exhibited maximum quantity at the xethanol of 0.089. Relationship between the ethanol radical yield and the rate of reaction, along with possible mechanism responsible for the observed phenomenon, is discussed in this paper. PMID- 26505748 TI - Handling Permutation in Sequence Comparison: Genome-Wide Enhancer Prediction in Vertebrates by a Novel Non-Linear Alignment Scoring Principle. AB - Enhancers have been described to evolve by permutation without changing function. This has posed the problem of how to predict enhancer elements that are hidden from alignment-based approaches due to the loss of co-linearity. Alignment-free algorithms have been proposed as one possible solution. However, this approach is hampered by several problems inherent to its underlying working principle. Here we present a new approach, which combines the power of alignment and alignment free techniques into one algorithm. It allows the prediction of enhancers based on the query and target sequence only, no matter whether the regulatory logic is co-linear or reshuffled. To test our novel approach, we employ it for the prediction of enhancers across the evolutionary distance of ~450Myr between human and medaka. We demonstrate its efficacy by subsequent in vivo validation resulting in 82% (9/11) of the predicted medaka regions showing reporter activity. These include five candidates with partially co-linear and four with reshuffled motif patterns. Orthology in flanking genes and conservation of the detected co-linear motifs indicates that those candidates are likely functionally equivalent enhancers. In sum, our results demonstrate that the proposed principle successfully predicts mutated as well as permuted enhancer regions at an encouragingly high rate. PMID- 26505751 TI - Correction: Computational Fact Checking from Knowledge Networks. PMID- 26505750 TI - Sevoflurane Preconditioning Reduces Intestinal Ischemia-Reperfusion Injury: Role of Protein Kinase C and Mitochondrial ATP-Sensitive Potassium Channel. AB - Ischemic preconditioning (IPC) has been considered to be a potential therapy to reduce ischemia-reperfusion injury (IRI) since the 1980s. Our previous study indicated that sevoflurane preconditioning (SPC) also reduced intestinal IRI in rats. However, whether the protective effect of SPC is similar to IPC and the mechanisms of SPC are unclear. Thus, we compared the efficacy of SPC and IPC against intestinal IRI and the role of protein kinase C (PKC) and mitochondrial ATP-sensitive potassium channel (mKATP) in SPC. A rat model of intestinal IRI was used in this study. The superior mesenteric artery (SMA) was clamped for 60 min followed by 120 min of reperfusion. Rats with IPC underwent three cycles of SMA occlusion for 5 min and reperfusion for 5 min before intestinal ischemia. Rats with SPC inhaled sevoflurane at 0.5 minimum alveolar concentration (MAC) for 30 min before the intestinal ischemic insult. Additionally, the PKC inhibitor Chelerythrine (CHE) or mKATP inhibitor 5-Hydroxydecanoic (5-HD) was injected intraperitoneally before sevoflurane inhalation. Both SPC and IPC ameliorated intestinal IRI-induced histopathological changes, decreased Chiu's scores, reduced terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL) positive cells in the epithelium, and inhibited the expression of malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-alpha). These protective effects of SPC were similar to those of IPC. Pretreatment with PKC or mKATP inhibitor abolished SPC-induced protective effects by increasing Chiu's scores, down-regulated the expression of Bcl-2 and activated caspase-3. Our results suggest that pretreatment with 0.5 MAC sevoflurane is as effective as IPC against intestinal IRI. The activation of PKC and mKATP may be involved in the protective mechanisms of SPC. PMID- 26505752 TI - CCAAT/enhancer binding protein beta regulates the expression of tumor necrosis factor-alpha in the nucleus pulposus cells. AB - Tumor necrosis factor alpha (TNF-alpha) is important in the process of intervertebral disc (IVD) degeneration because of its ability to regulate other inflammatory mediators in autocrine and paracrine fashions. The mechanism responsible for the cell type-specific regulation of TNF-alpha is not well known. CCAAT/enhancer binding protein beta (C/EBP beta) is one of the transcriptional factors that is implicated in TNF-alpha expression. However, it is not known whether cross talk occurs between C/EBP beta and the TNF-alpha pathway in IVD cells. The expression and effect of the C/EBP beta mRNA and protein in rat IVD cells was assessed using real-time reverse transcription polymerase chain reaction, immunohistochemical, and immunofluorescence analyses. We present data that show that the C/EBP beta mRNA and protein were expressed in rat and human IVDs in vivo. We also found that the expression of TNF-alpha is regulated by the transcription factor C/EBP beta in rat NP cells. The TNF-alpha promoter was suppressed completely in the presence of the ERK inhibitor PD98059 and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190, but not in the presence of the JNK inhibitor SP600125. In addition, gain and loss of function analyses showed that the expression of TNF-alpha was regulated by C/EBP beta through the MAPK pathways. These findings showed that C/EBP beta acts as a potent pro-inflammatory mediator by inducing the TNF-alpha gene at the transcription and protein levels via the ERK1/2 and p38 pathways in rat NP cells. Our findings may open a new avenue toward the understanding of the cellular and molecular mechanisms of IVD cells. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:865-875, 2016. PMID- 26505755 TI - Reply to Comment on "Use of Patient Registries and Administrative Datasets for the Study of Pediatric Cancer". PMID- 26505754 TI - Mapping the Protein Fold Universe Using the CamTube Force Field in Molecular Dynamics Simulations. AB - It has been recently shown that the coarse-graining of the structures of polypeptide chains as self-avoiding tubes can provide an effective representation of the conformational space of proteins. In order to fully exploit the opportunities offered by such a 'tube model' approach, we present here a strategy to combine it with molecular dynamics simulations. This strategy is based on the incorporation of the 'CamTube' force field into the Gromacs molecular dynamics package. By considering the case of a 60-residue polyvaline chain, we show that CamTube molecular dynamics simulations can comprehensively explore the conformational space of proteins. We obtain this result by a 20 MUs metadynamics simulation of the polyvaline chain that recapitulates the currently known protein fold universe. We further show that, if residue-specific interaction potentials are added to the CamTube force field, it is possible to fold a protein into a topology close to that of its native state. These results illustrate how the CamTube force field can be used to explore efficiently the universe of protein folds with good accuracy and very limited computational cost. PMID- 26505753 TI - Strategies for understanding and reducing the Plasmodium vivax and Plasmodium ovale hypnozoite reservoir in Papua New Guinean children: a randomised placebo controlled trial and mathematical model. AB - BACKGROUND: The undetectable hypnozoite reservoir for relapsing Plasmodium vivax and P. ovale malarias presents a major challenge for malaria control and elimination in endemic countries. This study aims to directly determine the contribution of relapses to the burden of P. vivax and P. ovale infection, illness, and transmission in Papua New Guinean children. METHODS AND FINDINGS: From 17 August 2009 to 20 May 2010, 524 children aged 5-10 y from East Sepik Province in Papua New Guinea (PNG) participated in a randomised double-blind placebo-controlled trial of blood- plus liver-stage drugs (chloroquine [CQ], 3 d; artemether-lumefantrine [AL], 3 d; and primaquine [PQ], 20 d, 10 mg/kg total dose) (261 children) or blood-stage drugs only (CQ, 3 d; AL, 3 d; and placebo [PL], 20 d) (263 children). Participants, study staff, and investigators were blinded to the treatment allocation. Twenty children were excluded during the treatment phase (PQ arm: 14, PL arm: 6), and 504 were followed actively for 9 mo. During the follow-up time, 18 children (PQ arm: 7, PL arm: 11) were lost to follow-up. Main primary and secondary outcome measures were time to first P. vivax infection (by qPCR), time to first clinical episode, force of infection, gametocyte positivity, and time to first P. ovale infection (by PCR). A basic stochastic transmission model was developed to estimate the potential effect of mass drug administration (MDA) for the prevention of recurrent P. vivax infections. Targeting hypnozoites through PQ treatment reduced the risk of having at least one qPCR-detectable P. vivax or P. ovale infection during 8 mo of follow up (P. vivax: PQ arm 0.63/y versus PL arm 2.62/y, HR = 0.18 [95% CI 0.14, 0.25], p < 0.001; P. ovale: 0.06 versus 0.14, HR = 0.31 [95% CI 0.13, 0.77], p = 0.011) and the risk of having at least one clinical P. vivax episode (HR = 0.25 [95% CI 0.11, 0.61], p = 0.002). PQ also reduced the molecular force of P. vivax blood stage infection in the first 3 mo of follow-up (PQ arm 1.90/y versus PL arm 7.75/y, incidence rate ratio [IRR] = 0.21 [95% CI 0.15, 0.28], p < 0.001). Children who received PQ were less likely to carry P. vivax gametocytes (IRR = 0.27 [95% CI 0.19, 0.38], p < 0.001). PQ had a comparable effect irrespective of the presence of P. vivax blood-stage infection at the time of treatment (p = 0.14). Modelling revealed that mass screening and treatment with highly sensitive quantitative real-time PCR, or MDA with blood-stage treatment alone, would have only a transient effect on P. vivax transmission levels, while MDA that includes liver-stage treatment is predicted to be a highly effective strategy for P. vivax elimination. The inclusion of a directly observed 20-d treatment regime maximises the efficiency of hypnozoite clearance but limits the generalisability of results to real-world MDA programmes. CONCLUSIONS: These results suggest that relapses cause approximately four of every five P. vivax infections and at least three of every five P. ovale infections in PNG children and are important in sustaining transmission. MDA campaigns combining blood- and liver-stage treatment are predicted to be a highly efficacious intervention for reducing P. vivax and P. ovale transmission. TRIAL REGISTRATION: ClinicalTrials.gov NCT02143934. PMID- 26505756 TI - Using Social Media to Detect Outdoor Air Pollution and Monitor Air Quality Index (AQI): A Geo-Targeted Spatiotemporal Analysis Framework with Sina Weibo (Chinese Twitter). AB - Outdoor air pollution is a serious problem in many developing countries today. This study focuses on monitoring the dynamic changes of air quality effectively in large cities by analyzing the spatiotemporal trends in geo-targeted social media messages with comprehensive big data filtering procedures. We introduce a new social media analytic framework to (1) investigate the relationship between air pollution topics posted in Sina Weibo (Chinese Twitter) and the daily Air Quality Index (AQI) published by China's Ministry of Environmental Protection; and (2) monitor the dynamics of air quality index by using social media messages. Correlation analysis was used to compare the connections between discussion trends in social media messages and the temporal changes in the AQI during 2012. We categorized relevant messages into three types, retweets, mobile app messages, and original individual messages finding that original individual messages had the highest correlation to the Air Quality Index. Based on this correlation analysis, individual messages were used to monitor the AQI in 2013. Our study indicates that the filtered social media messages are strongly correlated to the AQI and can be used to monitor the air quality dynamics to some extent. PMID- 26505757 TI - Retinal Thickness and the Structure/Function Relationship in the Eyes of Older Adults with Glaucoma. AB - Glaucoma is common and shows high prevalence in older adults. However, there are few studies on the structure/function relationship in older adults with glaucoma. This prospective, cross-sectional study (conducted between February and August 2014), enrolled 102 eyes of 102 subjects aged over 75 years, including 57 eyes with primary open angle glaucoma (POAG), 15 eyes with pseudoexfoliation glaucoma (PXG), and 30 healthy eyes. Multiple regression analysis was used to determine the correlation of circumpapillary retinal nerve fiber layer thickness (cpRNFLT) and macular parameters to mean deviation (MD) to and standard automated perimetry (SAP)-measured sensitivity, assessed with the 30-2 and 10-2 programs. In each 10 2 SAP test point, Spearman's rank correlation coefficient was used to compare macular retinal nerve fiber layer thickness (mRNFLT), macular ganglion cell-inner plexiform layer thickness (GCIPLT), and mRNFL+GCIPL thickness (GCCT) with sensitivity after adjusting for retinal ganglion cell (RGC) displacement. In eyes with POAG and PXG, cpRNFLT was significantly correlated with 30-2 MD and 30-2 sensitivity. Multiple regression analysis revealed that the POAG had significantly lower cpRNFLT, mRNFLT, GCIPLT, and GCCT according to the severity of disease than control eyes after adjusting for sensitivity, age, sex, and axial length. The PXG eyes had significantly lower cpRNFLT, mRNFLT, and GCCT when compared with the early to moderate POAG eyes. GCCT was significantly correlated with 10-2 sensitivity, except in one juxtafoveal point, (r = 0.338-0.778) in the POAG eyes. The periphery of the central 10 degrees area showed a good correlation between sensitivity and mRNFLT, while the central 5.8 degrees showed a good correlation between sensitivity and GCIPLT. The correlation between structure and function was significant, and objective and quantitative method with OCT assessing glaucoma that does not require patient ability could be a possible parameter to assess diagnosis and progression in older patients with glaucoma. PMID- 26505760 TI - Information on Funding Omitted from the Article by Peter et al (Arthritis Care Res, January 2015). PMID- 26505758 TI - Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery? AB - High-throughput biology has contributed a wealth of data on chemicals, including natural products (NPs). Recently, attention was drawn to certain, predominantly synthetic, compounds that are responsible for disproportionate percentages of hits but are false actives. Spurious bioassay interference led to their designation as pan-assay interference compounds (PAINS). NPs lack comparable scrutiny, which this study aims to rectify. Systematic mining of 80+ years of the phytochemistry and biology literature, using the NAPRALERT database, revealed that only 39 compounds represent the NPs most reported by occurrence, activity, and distinct activity. Over 50% are not explained by phenomena known for synthetic libraries, and all had manifold ascribed bioactivities, designating them as invalid metabolic panaceas (IMPs). Cumulative distributions of ~200,000 NPs uncovered that NP research follows power-law characteristics typical for behavioral phenomena. Projection into occurrence-bioactivity-effort space produces the hyperbolic black hole of NPs, where IMPs populate the high-effort base. PMID- 26505759 TI - Enzymatic Synthesis of Rhamnose Containing Chemicals by Reverse Hydrolysis. AB - Rhamnose containing chemicals (RCCs) are widely occurred in plants and bacteria and are known to possess important bioactivities. However, few of them were available using the enzymatic synthesis method because of the scarcity of the alpha-L-rhamnosidases with wide acceptor specificity. In this work, an alpha-L rhamnosidase from Alternaria sp. L1 was expressed in Pichia pastroris strain GS115. The recombinant enzyme was purified and used to synthesize novel RCCs through reverse hydrolysis in the presence of rhamnose as donor and mannitol, fructose or esculin as acceptors. The effects of initial substrate concentrations, reaction time, and temperature on RCC yields were investigated in detail when using mannitol as the acceptor. The mannitol derivative achieved a maximal yield of 36.1% by incubation of the enzyme with 0.4 M L-rhamnose and 0.2 M mannitol in pH 6.5 buffers at 55 degrees C for 48 h. In identical conditions except for the initial acceptor concentrations, the maximal yields of fructose and esculin derivatives reached 11.9% and 17.9% respectively. The structures of the three derivatives were identified to be alpha-L-rhamnopyranosyl-(1->6')-D mannitol, alpha-L-rhamnopyranosyl-(1->1')-beta-D-fructopyranose, and 6,7 dihydroxycoumarin alpha-L-rhamnopyranosyl-(1->6')-beta-D-glucopyranoside by ESI MS and NMR spectroscopy. The high glycosylation efficiency as well as the broad acceptor specificity of this enzyme makes it a powerful tool for the synthesis of novel rhamnosyl glycosides. PMID- 26505762 TI - Eu3Ir2In15: A Mixed-Valent and Vacancy-Filled Variant of the Sc5Co4Si10 Structure Type with Anomalous Magnetic Properties. AB - A new compound, Eu3Ir2In15, has been synthesized using indium as an active metal flux. The compound crystallizes in the tetragonal P4/mbm space group with lattice parameters a = 14.8580(4) A, b = 14.8580(4) A, and c = 4.3901(2) A. It was further characterized by SEM-EDX studies. The effective magnetic moment (MUeff) of this compound is 7.35 MUB/Eu ion with a paramagnetic Curie temperature (thetap) of -28 K, suggesting antiferromagnetic interaction. The mixed-valent nature of Eu observed in magnetic measurements was confirmed by XANES measurements. The compound undergoes demagnetization at a low magnetic field (10 Oe), which is quite unusual for Eu-based intermetallic compounds. Temperature dependent resistivity studies reveal that the compound is metallic in nature. A comparative study was made between Eu3Ir2In15 and hypothetical vacancy-variant Eu5Ir4In10, which also crystallizes in the same crystal structure. However, our computational studies along with control experiments suggest that the latter is thermodynamically less feasible compared to the former, and hence we propose that it is highly unlikely that an RE5T4X10 would exist with X as a group 13 element. PMID- 26505761 TI - Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice. AB - Invasion of the central nervous system (CNS) by African trypanosomes represents a critical step in the development of human African trypanosomiasis. In both clinical cases and experimental mouse infections it has been demonstrated that predisposition to CNS invasion is associated with a type 1 systemic inflammatory response. Using the Trypanosoma brucei brucei GVR35 experimental infection model, we demonstrate that systemic delivery of the counter-inflammatory cytokine IL-10 lowers plasma IFN-gamma and TNF-alpha concentrations, CNS parasitosis and ameliorates neuro-inflammatory pathology and clinical symptoms of disease. The results provide evidence that CNS invasion may be susceptible to immunological attenuation. PMID- 26505763 TI - Enhancement of mass spectrometry performance for proteomic analyses using high field asymmetric waveform ion mobility spectrometry (FAIMS). AB - Remarkable advances in mass spectrometry sensitivity and resolution have been accomplished over the past two decades to enhance the depth and coverage of proteome analyses. As these technological developments expanded the detection capability of mass spectrometers, they also revealed an increasing complexity of low abundance peptides, solvent clusters and sample contaminants that can confound protein identification. Separation techniques that are complementary and can be used in combination with liquid chromatography are often sought to improve mass spectrometry sensitivity for proteomics applications. In this context, high field asymmetric waveform ion mobility spectrometry (FAIMS), a form of ion mobility that exploits ion separation at low and high electric fields, has shown significant advantages by focusing and separating multiply charged peptide ions from singly charged interferences. This paper examines the analytical benefits of FAIMS in proteomics to separate co-eluting peptide isomers and to enhance peptide detection and quantitative measurements of protein digests via native peptides (label-free) or isotopically labeled peptides from metabolic labeling or chemical tagging experiments. PMID- 26505764 TI - Characterization of lemon (Citrus limon) polar extract by liquid chromatography tandem mass spectrometry in high resolution mode. AB - Eighty four metabolites (32 flavonoids, 15 amino acids, nine carboxylic acids, six coumarins, six sugars, five phenolic acids and 11 unclassified compounds) have been tentatively identified in a polar extract from lemon, without reference standards, based on their liquid chromatography-quadrupole-time-of-flight MS/MS spectra and the comparison with databases. Despite information in databases for some families of plant compounds is poor, tentative identification based on MS/MS information (mass of the precursor ion and their fragments, together with neutral mass loss) was possible with the help of known fragmentation patterns for the given families of compounds. Both positive and negative ionization modes and at least two collision energies were always applied to obtain as much information as possible from each molecular entity, thus helping for identification. As the tentatively identified metabolites are the same regardless of the organism they belong, their fragmentation patterns are useful for identification with independence of the sample nature. PMID- 26505765 TI - Absolute photoionization cross sections of furanic fuels: 2-ethylfuran, 2 acetylfuran and furfural. AB - Absolute photoionization cross sections of the molecules 2-ethylfuran, 2 acetylfuran and furfural, including partial ionization cross sections for the dissociative ionized fragments, are measured for the first time. These measurements are important because they allow fuel quantification via photoionization mass spectrometry and the development of quantitative kinetic modeling for the complex combustion of potential fuels. The experiments are carried out using synchrotron photoionization mass spectrometry with an orthogonal time-of-flight spectrometer used for mass analysis at the Advanced Light Source of Lawrence Berkeley National Laboratory. The CBS-QB3 calculations of adiabatic ionization energies and appearance energies agree well with the experimental results. Several bond dissociation energies are also derived and presented. PMID- 26505766 TI - Evaluation of ice-tea quality by DART-TOF/MS. AB - DART (Direct Analysis in Real Time) coupled with Time-of-Flight Mass Spectrometry (TOF/MS) has been used for analyses of ice-teas. The article focuses on quality and authenticity of ice-teas as one of the most important tea-based products on the market. Twenty-one samples of ice-teas (black and green) were analysed. Selected compounds of ice-teas were determined: theobromine, caffeine, total phenolic compounds, total soluble solids, total amino acid concentration, preservatives and saccharides were determined. Fingerprints of DART-TOF/MS spectra were used for comprehensive assessment of the ice-tea samples. The DART TOF/MS method was used for monitoring the following compounds: citric acid, caffeine, saccharides, artificial sweeteners (saccharin, acesulphame K), and preservatives (sorbic and benzoic acid), phosphoric acid and phenolic compounds. The measured data were subjected to a principal components analysis. The HPLC and DART-TOF/MS methods were compared in terms of determination of selected compounds (caffeine, benzoic acid, sorbic acid and saccharides) in the ice-teas. The DART TOF/MS technique seems to be a suitable method for fast screening, testing quality and authenticity of tea-based products. PMID- 26505767 TI - Rapid structural characterization of in vivo and in vitro metabolites of tinoridine using UHPLC-QTOF-MS/MS and in silico toxicological screening of its metabolites. AB - Tinoridine is a nonsteroidal anti-inflammatory drug and also has potent radical scavenger and antiperoxidative activity. However, metabolism of tinoridine has not been thoroughly investigated. To identify in vivo metabolites, the drug was administered to Sprague-Dawley rats (n = 5) at a dose of 20 mg kg(-1), and blood, urine and feces were collected at different time points up to 24 h. In vitro metabolism was delved by incubating the drug with rat liver microsomes and human liver microsomes. The metabolites were enriched by optimized sample preparation involving protein precipitation using acetonitrile, followed by solid-phase extraction. Data processes were carried out using multiple mass defects filters to eliminate false-positive ions. A total of 11 metabolites have been identified in urine samples including hydroxyl, dealkylated, acetylated and glucuronide metabolites; among them, some were also observed in plasma and feces samples. Only two major metabolites were formed using liver microsomal incubations. These metabolites were also observed in vivo. All the 11 metabolites, which are hitherto unknown and novel, were characterized by using ultrahigh-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry in combination with accurate mass measurements. Finally, in silico toxicological screening of all metabolites was evaluated, and two metabolites were proposed to show a certain degree of lung or liver toxicity. PMID- 26505768 TI - Identification of substances migrating from plastic baby bottles using a combination of low-resolution and high-resolution mass spectrometric analysers coupled to gas and liquid chromatography. AB - This work presents a strategy for elucidation of unknown migrants from plastic food contact materials (baby bottles) using a combination of analytical techniques in an untargeted approach. First, gas chromatography (GC) coupled to mass spectrometry (MS) in electron ionisation mode was used to identify migrants through spectral library matching. When no acceptable match was obtained, a second analysis by GC-(electron ionisation) high resolution mass spectrometry time of flight (TOF) was applied to obtain accurate mass fragmentation spectra and isotopic patterns. Databases were then searched to find a possible elemental composition for the unknown compounds. Finally, a GC hybrid quadrupole-TOF-MS with an atmospheric pressure chemical ionisation source was used to obtain the molecular ion or the protonated molecule. Accurate mass data also provided additional information on the fragmentation behaviour as two acquisition functions with different collision energies were available (MS(E) approach). In the low-energy function, limited fragmentation took place, whereas for the high energy function, fragmentation was enhanced. For less volatile unknowns, ultra high pressure liquid chromatography-quadrupole-TOF-MS was additionally applied. Using a home-made database containing common migrating compounds and plastic additives, tentative identification was made for several positive findings based on accurate mass of the (de)protonated molecule, product ion fragments and characteristic isotopic ions. Six illustrative examples are shown to demonstrate the modus operandi and the difficulties encountered during identification. The combination of these techniques was proven to be a powerful tool for the elucidation of unknown migrating compounds from plastic baby bottles. PMID- 26505769 TI - Identification of degradation products of indigoids by tandem mass spectrometry. AB - The study concerns identification of photodegradation products of indigotin, indirubin and isoindigo. Experimental methodology consists of degradation of standard solutions of indigoids in a solar box and analysis of samples taken at different aging time by using capillary high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometric and spectrophotometric detectors. Identification of the formed compounds was based on careful interpretation of the electrospray ionization MS/MS spectra. Apart from the well-known degradation products of indigoids: isatin, isatoic anhydride and anthranilic acid, another seven species were also identified, and their proposed structures were confirmed by high-resolution molecular masses measurements; according to the best knowledge of authors, they have not been reported so far. The obtained results formed the basis for postulating mechanism of the process. Moreover, the MRM (Multiple Reaction Monitoring) method was developed for the identification of natural dyes and their degradation products in textiles of historical value. Apart from such colorants as indigotin and flavonoids, also presence of degradation products of indigoids was confirmed. PMID- 26505770 TI - Electron ionization LC-MS with supersonic molecular beams--the new concept, benefits and applications. AB - A new type of electron ionization LC-MS with supersonic molecular beams (EI-LC-MS with SMB) is described. This system and its operational methods are based on pneumatic spray formation of the LC liquid flow in a heated spray vaporization chamber, full sample thermal vaporization and subsequent electron ionization of vibrationally cold molecules in supersonic molecular beams. The vaporized sample compounds are transferred into a supersonic nozzle via a flow restrictor capillary. Consequently, while the pneumatic spray is formed and vaporized at above atmospheric pressure the supersonic nozzle backing pressure is about 0.15 Bar for the formation of supersonic molecular beams with vibrationally cold sample molecules without cluster formation with the solvent vapor. The sample compounds are ionized in a fly-though EI ion source as vibrationally cold molecules in the SMB, resulting in 'Cold EI' (EI of vibrationally cold molecules) mass spectra that exhibit the standard EI fragments combined with enhanced molecular ions. We evaluated the EI-LC-MS with SMB system and demonstrated its effectiveness in NIST library sample identification which is complemented with the availability of enhanced molecular ions. The EI-LC-MS with SMB system is characterized by linear response of five orders of magnitude and uniform compound independent response including for non-polar compounds. This feature improves sample quantitation that can be approximated without compound specific calibration. Cold EI, like EI, is free from ion suppression and/or enhancement effects (that plague ESI and/or APCI) which facilitate faster LC separation because full separation is not essential. The absence of ion suppression effects enables the exploration of fast flow injection MS-MS as an alternative to lengthy LC-MS analysis. These features are demonstrated in a few examples, and the analysis of the main ingredients of Cannabis on a few Cannabis flower extracts is demonstrated. Finally, the advantages of EI-LC-MS with SMB are listed and discussed. PMID- 26505771 TI - Simultaneous detection of phosphatidylcholines and glycerolipids using matrix enhanced surface-assisted laser desorption/ionization-mass spectrometry with sputter-deposited platinum film. AB - Matrix-assisted laser desorption/ionisation (MALDI) imaging mass spectrometry (IMS) allows for the simultaneous detection and imaging of several molecules in brain tissue. However, the detection of glycerolipids such as diacylglycerol (DAG) and triacylglycerol (TAG) in brain tissues is hindered in MALDI-IMS because of the ion suppression effect from excessive ion yields of phosphatidylcholine (PC). In this study, we describe an approach that employs a homogeneously deposited metal nanoparticle layer (or film) for the detection of glycerolipids in rat brain tissue sections using IMS. Surface-assisted laser desorption/ionisation IMS with sputter-deposited Pt film (Pt-SALDI-IMS) for lipid analysis was performed as a solvent-free and organic matrix-free method. Pt-SALDI produced a homogenous layer of nanoparticles over the surface of the rat brain tissue section. Highly selective detection of lipids was possible by MALDI-IMS and Pt-SALDI-IMS; MALDI-IMS detected the dominant ion peak of PC in the tissue section, and there were no ion peaks representing glycerolipids such as DAG and TAG. In contrast, Pt-SALDI-IMS allowed the detection of these glycerolipids, but not PC. Therefore, using a hybrid method combining MALDI and Pt-SALDI (i.e., matrix-enhanced [ME]-Pt-SALDI-IMS), we achieved the simultaneous detection of PC, PE and DAG in rat brain tissue sections, and the sensitivity for the detection of these molecules was better than that of MALDI-IMS or Pt-SALDI alone. The present simple ME-Pt-SALDI approach for the simultaneous detection of PC and DAG using two matrices (sputter-deposited Pt film and DHB matrix) would be useful in imaging analyses of biological tissue sections. PMID- 26505773 TI - A mass spectrometric method for rapidly assaying the chiral selectivities of the copper(I) complexes of C2-symmetric ligands. AB - A gas-phase method for rapidly assaying the enantioselectivity of metal-centered catalysts is presented. It relies on gas-phase equilibrium measurements in a quadrupole ion trap mass spectrometer. A group of well-established C2-symmetric bis-oxazoline copper(I) complexes was used to identify chiral probe reagents that are capable of profiling the quality of the asymmetric environment provided by the metal complex. The chiral probes were then applied to a wide variety of copper(I) bis-di-imine complexes. Complexes based on a BINAM backbone exhibited selectivities that were comparable to the bis-oxazolines. Taking advantage of the mass selectivity capabilities of the ion trap mass spectrometer, the method was also applied to an un-purified mix of copper(I) complexes derived from a combinatorial synthesis of bis-di-imine ligands. This approach holds promise as a rapid screening tool for potential chiral catalysts. PMID- 26505772 TI - Evaluation of mass spectrometric data using principal component analysis for determination of the effects of organic lakes on protein binder identification. AB - Matrix-assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass spectrometry is commonly used for the identification of proteinaceous binders and their mixtures in artworks. The determination of protein binders is based on a comparison between the m/z values of tryptic peptides in the unknown sample and a reference one (egg, casein, animal glues etc.), but this method has greater potential to study changes due to ageing and the influence of organic/inorganic components on protein identification. However, it is necessary to then carry out statistical evaluation on the obtained data. Before now, it has been complicated to routinely convert the mass spectrometric data into a statistical programme, to extract and match the appropriate peaks. Only several 'homemade' computer programmes without user-friendly interfaces are available for these purposes. In this paper, we would like to present our completely new, publically available, non-commercial software, ms-alone and multiMS-toolbox, for principal component analyses of MALDI-TOF MS data for R software, and their application to the study of the influence of heterogeneous matrices (organic lakes) for protein identification. Using this new software, we determined the main factors that influence the protein analyses of artificially aged model mixtures of organic lakes and fish glue, prepared according to historical recipes that were used for book illumination, using MALDI-TOF peptide mass mapping. PMID- 26505774 TI - Decellularization of intact tissue enables MALDI imaging mass spectrometry analysis of the extracellular matrix. AB - Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is a powerful molecular mapping technology that offers unbiased visualization of the spatial arrangement of biomolecules in tissue. Although there has been a significant increase in the number of applications employing this technology, the extracellular matrix (ECM) has received little attention, likely because ECM proteins are mostly large, insoluble and heavily cross-linked. We have developed a new sample preparation approach to enable MALDI IMS analysis of ECM proteins in tissue. Prior to freezing and sectioning, intact tissues are decellularized by incubation in sodium dodecyl sulfate. Decellularization removes the highly abundant, soluble species that dominate a MALDI IMS spectrum while preserving the structural integrity of the ECM. In situ tryptic hydrolysis and imaging of tryptic peptides are then carried out to accommodate the large sizes of ECM proteins. This new approach allows the use of MALDI IMS for identification of spatially specific changes in ECM protein expression and modification in tissue. PMID- 26505775 TI - Mass spectrometric profiling of valepotriates possessing various acyloxy groups from Valeriana jatamansi. AB - Valepotriates, plant secondary metabolites of the family Valerianaceae, contain various acyloxy group linkages to the valepotriate nucleus and exhibit significant biological activities. Identification of valepotriates is important to uncover potential lead compounds for the development of new sedative and antitumor drugs. However, making their structure elucidation by nuclear magnetic resonance (NMR) experiments is too difficult to be realized because of the overlapped carbonyl carbon signals of acyloxy groups substituted at different positions. Thus, the mass spectrometric profiling of these compounds in positive ion mode was developed to unveil the exact linkage of acyloxy group and the core of valepotriate. In this study, electrospray ionization tandem multistage mass spectrometry (ESI-MS/MS(n)) in ion trap and collision-induced dissociation tandem MS were used to investigate the fragmentation pathways of four types of valepotriates in Valeriana jatamansi, including 5-hydroxy-5,6-dihydrovaltrate hydrin (5-hydroxy-5,6-dihydrovaltrate chlorohydrin), 5,6-dihydrovaltrate hydrin (5,6-dihydrovaltrate chlorohydrin), 5-hydroxy-5,6-dihydrovaltrate and valtrate hydrin (valtrate chlorohydrin). The high-resolution mass spectrum (HRMS) data of all the investigated valepotriates from quadrupole time-of-flight MS/MS were used as a supportive of the fragmentation rules we hypothesized from ion-trap stepwise MS(n). As a result, the loss sequence of acyloxy groups and the abundance of key product ions, in combination with the characteristic product ions corresponding to the valepotriate nucleus, could readily differentiate the four different types of valepotriates. The summarized fragmentation rules were also successfully exploited for the structural characterization of three new trace valepotriates from V. jatamansi. The results indicated that the developed analytical method could be employed as a rapid, effective technique for structural characterization of valepotriates, especially for the trace compounds that could not be identified by NMR techniques. This study may also arouse interest for further structural analysis of other valepotriate-containing type herbal medicines. PMID- 26505776 TI - Identification of phase I and II metabolites of the new designer drug alpha pyrrolidinohexiophenone (alpha-PHP) in human urine by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). AB - Pyrrolidinophenones represent one emerging class of newly encountered drugs of abuse, also known as 'new psychoactive substances', with stimulating psychoactive effects. In this work, we report on the detection of the new designer drug alpha pyrrolidinohexiophenone (alpha-PHP) and its phase I and II metabolites in a human urine sample of a drug abuser. Determination and structural elucidation of these metabolites have been achieved by liquid chromatography electrospray ionisation quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS). By tentative identification, the exact and approximate structures of 19 phase I metabolites and nine phase II glucuronides were elucidated. Major metabolic pathways revealed the reduction of the beta-keto moieties to their corresponding alcohols, didesalkylation of the pyrrolidine ring, hydroxylation and oxidation of the aliphatic side chain leading to n-hydroxy, aldehyde and carboxylate metabolites, and oxidation of the pyrrolidine ring to its lactam followed by ring cleavage and additional hydroxylation, reduction and oxidation steps and combinations thereof. The most abundant phase II metabolites were glucuronidated beta-keto-reduced alcohols. Besides the great number of metabolites detected in this sample, alpha PHP is still one of the most abundant ions together with its beta-keto-reduced alcoholic dihydro metabolite. Monitoring of these metabolites in clinical and forensic toxicology may unambiguously prove the abuse of the new designer drug alpha-PHP. PMID- 26505777 TI - Acylphosphatidylglycerol (acyl-PG) or N-acylphosphatidylethanolamine (NAPE)? PMID- 26505778 TI - Micropatch-arrayed pads for non-invasive spatial and temporal profiling of topical drugs on skin surface. AB - Micropatch-arrayed pads (MAPAs) are presented as a facile and sensitive sampling method for spatial profiling of topical agents adsorbed on the surface of skin. MAPAs are 28 * 28 mm sized pieces of polytetrafluoroethylene containing plurality of cavities filled with agarose hydrogel. They are affixed onto skin for 10 min with the purpose to collect drugs applied topically. Polar compounds are absorbed by the hydrogel micropatches. The probes are subsequently scanned by an automated nanospray desorption electrospray ionization mass spectrometry system operated in the tapping dual-polarity mode. When the liquid junction gets into contact with every micropatch, polar compounds absorbed in the hydrogel matrix are desorbed and transferred to the ion source. A 3D-printed interface prevents evaporation of hydrogel micropatches assuring good reproducibility and sensitivity. MAPAs have been applied to follow dispersion of topical drugs applied to human skin in vivo and to porcine skin ex vivo, in the form of self-adhesive patches. Spatiotemporal characteristics of the drug dispersion process have been revealed using this non invasive test. Differences between drug dispersion in vivo and ex vivo could be observed. We envision that MAPAs can be used to investigate spatiotemporal kinetics of various topical agents utilized in medical treatment. PMID- 26505780 TI - Differential Impact of Plasma Proteins on the Adhesion Efficiency of Vascular Targeted Carriers (VTCs) in Blood of Common Laboratory Animals. AB - Vascular-targeted carrier (VTC) interaction with human plasma is known to reduce targeted adhesion efficiency in vitro. However, the role of plasma proteins on the adhesion efficiency of VTCs in laboratory animals remains unknown. Here, in vitro blood flow assays are used to explore the effects of plasma from mouse, rabbit, and porcine on VTC adhesion. Porcine blood exhibited a strong negative plasma effect on VTC adhesion while no significant plasma effect was found with rabbit and mouse blood. A brush density poly(ethylene glycol) (PEG) on VTCs was effective at improving adhesion of microsized, but not nanosized, VTCs in porcine blood. Overall, the results suggest that porcine models, as opposed to mouse, can serve as better models in preclinical research for predicting the in vivo functionality of VTCs for use in humans. These considerations hold great importance for the design of various pharmaceutical products and development of reliable drug delivery systems. PMID- 26505781 TI - Primary Plasma Cell Leukemia in the Era of Novel Agents: A Multicenter Study of the Japanese Society of Myeloma. AB - We investigated the treatment and outcome of Japanese patients with primary plasma cell leukemia (pPCL) in the era of novel agents and analyzed the risk factors affecting survival. Among 3,318 patients with symptomatic multiple myeloma (MM), 38 patients were diagnosed with pPCL. The median overall survival (OS) of the pPCL patients was 2.85 years, which was significantly extended compared with that in previous reports. The proportion of patients treated with novel agents was 61%. The OS of the patients treated with novel agents was significantly extended compared with that of patients treated without novel agents according to the generalized Wilcoxon test (2.85 vs. 1.16 years, p = 0.049). This statistical finding suggests that treatment with novel agents could have prevented early death in the patients with pPCL. Age was the only statistically significant prognostic factor associated with an inferior OS (hazard ratio 4.57). Five patients received maintenance therapy with novel agents, and their OS tended to be longer than that of the other patients without maintenance (4.45 vs. 2.85 years). Unlike MM, OS for pPCL has not been improved significantly over the last decade, especially in elderly patients. Therefore, it is important to establish the treatment strategy, particularly after induction treatment. PMID- 26505782 TI - Mechanical Stimulation and IGF-1 Enhance mRNA Translation Rate in Osteoblasts Via Activation of the AKT-mTOR Pathway. AB - Insulin-like growth factor-1 (IGF-1) is anabolic for muscle by enhancing the rate of mRNA translation via activation of AKT and subsequent activation of the mammalian target of rapamycin complex 1 (mTOR), thereby increasing cellular protein production. IGF-1 is also anabolic for bone, but whether the mTOR pathway plays a role in the rate of bone matrix protein production by osteoblasts is unknown. We hypothesized that anabolic stimuli such as mechanical loading and IGF 1 stimulate protein synthesis in osteoblasts via activation of the AKT-mTOR pathway. MC3T3-E1 osteoblasts were either or not subjected for 1 h to mechanical loading by pulsating fluid flow (PFF) or treated with or without human recombinant IGF-1 (1-100 ng/ml) for 0.5-6 h, to determine phosphorylation of AKT and p70S6K (downstream of mTOR) by Western blot. After 4 days of culture with or without the mTOR inhibitor rapamycin, total protein, DNA, and gene expression were quantified. IGF-1 (100 ng/ml) reduced IGF-1 gene expression, although PFF enhanced IGF-1 expression. IGF-1 did not affect collagen-I gene expression. IGF-1 dose-dependently enhanced AKT and p70S6K phosphorylation at 2 and 6 h. PFF enhanced phosphorylation of AKT and p70S6K already within 1 h. Both IGF-1 and PFF enhanced total protein per cell by ~30%, but not in the presence of rapamycin. Our results show that IGF-1 and PFF activate mTOR, thereby stimulating the rate of mRNA translation in osteoblasts. The known anabolic effect of mechanical loading and IGF-1 on bone may thus be partly explained by mTOR-mediated enhanced protein synthesis in osteoblasts. PMID- 26505783 TI - Herbal Extract Incorporated Nanofiber Fabricated by an Electrospinning Technique and its Application to Antimicrobial Air Filtration. AB - Recently, with the increased attention to indoor air quality, antimicrobial air filtration techniques have been studied widely to inactivate hazardous airborne microorganisms effectively. In this study, we demonstrate herbal extract incorporated (HEI) nanofibers synthesized by an electrospinning technique and their application to antimicrobial air filtration. As an antimicrobial herbal material, an ethanolic extract of Sophora flavescens, which exhibits great antibacterial activity against pathogens, was mixed with the polymer solution for the electrospinning process. We measured various characteristics of the synthesized HEI nanofibers, such as fiber morphology, fiber size distribution, and thermal stability. For application of the electrospun HEI nanofibers, we made highly effective air filters with 99.99% filtration efficiency and 99.98% antimicrobial activity against Staphylococcus epidermidis. The pressure drop across the HEI nanofiber air filter was 4.75 mmH2O at a face air velocity of 1.79 cm/s. These results will facilitate the implementation of electrospun HEI nanofiber techniques to control air quality and protect against hazardous airborne microorganisms. PMID- 26505784 TI - Dopant-Enabled Supramolecular Approach for Controlled Synthesis of Nanostructured Conductive Polymer Hydrogels. AB - Conducting polymer hydrogels emerge as a novel class of polymeric materials that show great potential in many energy, environmental, and biomedical devices. We describe here for the first time a general supramolecular approach toward controlled in situ synthesis of one-dimensional nanostructured conductive hydrogels (polypyrrole (PPy) as a model system) using a rational dopant counterion, which is a disc-shaped liquid crystal molecular copper phthalocyanine 3,4',4",4'''-tetrasulfonic acid tetrasodium salt (CuPcTs). The dopant molecule CuPcTs cross-linked the PPy chains to form a three-dimensional network that gelated into a hydrogel. The PPy hydrogel could be synthesized in bulk quantities with uniform morphology of self-assembled interconnected nanofibers. The tetra functional dopant favors a supramolecular self-assembly mechanism to form one dimensional PPy nanostructures. Furthermore, the enhanced interchain charge transport of CuPcTs doped PPy resulted in greatly enhanced conductivity and pseudocapacitance compared with pristine PPy. PMID- 26505785 TI - Enhancement of regulatory T cell-like suppressive function in MT-2 by long-term and low-dose exposure to asbestos. AB - Asbestos exposure causes lung fibrosis and various malignant tumors such as lung cancer and malignant mesothelioma. The effects of asbestos on immune cells have not been thoroughly investigated, although our previous reports showed that asbestos exposure reduced anti-tumor immunity. The effects of continuous exposure of regulatory T cells (Treg) to asbestos were examined using the HTLV-1 immortalized human T cell line MT-2, which possesses a suppressive function and expresses the Treg marker protein, Foxp3. Sublines were generated by the continuous exposure to low doses of asbestos fibers for more than one year. The sublines exposed to asbestos showed enhanced suppressive Treg function via cell cell contact, and increased production of soluble factors such as IL-10 and transforming growth factor (TGF)-beta1. These results also indicated that asbestos exposure induced the reduction of anti-tumor immunity, and efforts to develop substances to reverse this reduction may be helpful in preventing the occurrence of asbestos-induced tumors. PMID- 26505786 TI - Combinatorial Effects of Curcumin with an Anti-Neoplastic Agent on Head and Neck Squamous Cell Carcinoma Through the Regulation of EGFR-ERK1/2 and Apoptotic Signaling Pathways. AB - Globally, head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and represents approximately 6% of all diagnosed cancers. The use of anti cancer drugs, such as docetaxel, doxorubicin (DOX), 5-fluorouracil (5-FU), and cisplatin (diammine dichloroplatinum(II), CDDP), is limited due to their non specificity, drug resistance, and toxicity. A combinatorial approach may improve the efficacy of these chemotherapeutic drugs and reduce their non-specific toxicities. In the present study, curcumin, an anti-cancer phytochemical, was used in combination with 5-FU, doxorubicin, and cisplatin and their combinatorial effect on the HNSCC cell line NT8e was investigated. Our results showed that the combination of 5-FU or DOX with curcumin exhibited significant growth inhibition and enhanced apoptosis in NT8e cancer cells. Treatment with 5-FU or DOX in combination with curcumin induced apoptosis by inhibiting Bcl-2 and increasing Bax, caspase-3, and poly-ADP ribose polymerase (PARP) in NT8e cells. This was further confirmed through apoptotic characteristic features in cells, such as membrane blebbing, nuclear condensation, and cell shrinkage, as observed by DAPI staining and through decreased red/green fluorescence by JC-1. These two combinations also exhibited cell cycle growth arrest at the G1/S phase, which was confirmed by downregulation of cyclins (D1, E2, B1, and A2), CDK2, and increased p21 levels. In addition, curcumin exposure along with 5-FU or DOX inhibited cell proliferation through the downregulation of EGFR-ERK1/2 signaling molecules. Overall, our data demonstrates the promising therapeutic potential and underlying mechanisms of curcumin with 5-FU/DOX combinations as a new treatment modality for head and neck cancer management. PMID- 26505787 TI - Electrically Tunable Soft-Solid Block Copolymer Structural Color. AB - One-dimensional photonic crystals based on the periodic stacking of two different dielectric layers have been widely studied, but the fabrication of mechanically flexible polymer structural color (SC) films, with electro-active color switching, remains challenging. Here, we demonstrate free-standing electric field tunable ionic liquid (IL) swollen block copolymer (BCP) films. Placement of a polymer/ionic liquid film-reservoir adjacent to a self-assembled poly(styrene block-quaternized 2-vinylpyridine) (PS-b-QP2VP) copolymer SC film allowed the development of red (R), green (G), and blue (B) full-color SC block copolymer films by swelling of the QP2VP domains by the ionic liquid associated with water molecules. The IL-polymer/BCP SC film is mechanically flexible with excellent color stability over several days at ambient conditions. The selective swelling of the QP2VP domains could be controlled by both the ratio of the IL to a polymer in the gel-like IL reservoir layer and by an applied voltage in the range of -3 to +6 V using a metal/IL reservoir/SC film/IL reservoir/metal capacitor type device. PMID- 26505788 TI - Enzyme kinetics and inhibition of histone acetyltransferase KAT8. AB - Lysine acetyltransferase 8 (KAT8) is a histone acetyltransferase (HAT) responsible for acetylating lysine 16 on histone H4 (H4K16) and plays a role in cell cycle progression as well as acetylation of the tumor suppressor protein p53. Further studies on its biological function and drug discovery initiatives will benefit from the development of small molecule inhibitors for this enzyme. As a first step towards this aim we investigated the enzyme kinetics of this bi substrate enzyme. The kinetic experiments indicate a ping-pong mechanism in which the enzyme binds Ac-CoA first, followed by binding of the histone substrate. This mechanism is supported by affinity measurements of both substrates using isothermal titration calorimetry (ITC). Using this information, the KAT8 inhibition of a focused compound collection around the non-selective HAT inhibitor anacardic acid has been investigated. Kinetic studies with anacardic acid were performed, based on which a model for the catalytic activity of KAT8 and the inhibitory action of anacardic acid (AA) was proposed. This enabled the calculation of the inhibition constant Ki of anacardic acid derivatives using an adaptation of the Cheng-Prusoff equation. The results described in this study give insight into the catalytic mechanism of KAT8 and present the first well characterized small-molecule inhibitors for this HAT. PMID- 26505789 TI - Mmu-miR-351 attenuates the survival of cardiac arterial endothelial cells through targeting STAT3 in the atherosclerotic mice. AB - The signal transducer and activator of transcription 3 (STAT3) signaling pathway was involved in regulation of endothelial cell survival/apoptosis and was regarded as a target for prevention of atherosclerosis or other cardiovascular diseases. Factors, regulating STAT3 expression and activity, have aroused a wide range of interest, such as miRNAs or transcription factors. The aim of this study is to explore the role of miR-351, a miRNA found not long before, in the regulation of STAT3 expression and endothelial cell survival in the model mice with atherosclerosis (AS). Expression of miR-351 in the serum and cardiac arterial endothelial cells of the WT mice and AS mice was detected. Real-time qPCR analysis showed that miR-351 was upregulated in the serum and endothelial cells of the AS mice, displaying an opposite expression pattern with STAT3. To explore the role and mechanism of miR-351 in the endothelial cell survival, the miR-351 mimic was transfected in to the endothelial cells. MTT and Trypan Blue assays showed miR-351 attenuated the survival of endothelial cells. Our results of the TargetScan output and the 3'UTR luciferase reporter assay indicated that STAT3 was target of miR-351. Additionally, miR-351 resisted the elevation of STAT3 protein level and promotion of endothelial cell survival caused by SD19. Finally, our in vitro angiogenesis assay revealed that miR-351 suppressed angiogenesis and resisted the promotion of angiogenesis caused by SD19. In conclusion, miR-351 was upregulated in the atherosclerotic mice. MiR-351 can attenuate the survival of endothelial cells and suppress angiogenesis through targeting STAT3 in vitro. PMID- 26505790 TI - C-Mannosylation of thrombopoietin receptor (c-Mpl) regulates thrombopoietin dependent JAK-STAT signaling. AB - The thrombopoietin receptor, also known as c-Mpl, is a member of the cytokine superfamily, which regulates the differentiation of megakaryocytes and formation of platelets by binding to its ligand, thrombopoietin (TPO), through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. The loss of-function mutations of c-Mpl cause severe thrombocytopenia due to impaired megakaryocytopoiesis, and gain-of-function mutations cause thrombocythemia. c-Mpl contains two Trp-Ser-Xaa-Trp-Ser (Xaa represents any amino acids) sequences, which are characteristic sequences of type I cytokine receptors, corresponding to C-mannosylation consensus sequences: Trp-Xaa-Xaa-Trp/Cys. C-mannosylation is a post-translational modification of tryptophan residue in which one mannose is attached to the first tryptophan residue in the consensus sequence via C-C linkage. Although c-Mpl contains some C-mannosylation sequences, whether c-Mpl is C-mannosylated or not has been uninvestigated. We identified that c-Mpl is C mannosylated not only at Trp(269) and Trp(474), which are putative C mannosylation site, but also at Trp(272), Trp(416), and Trp(477). Using C mannosylation defective mutant of c-Mpl, the C-mannosylated tryptophan residues at four sites (Trp(269), Trp(272), Trp(474), and Trp(477)) are essential for c Mpl-mediated JAK-STAT signaling. Our findings suggested that C-mannosylation of c Mpl is a possible therapeutic target for platelet disorders. PMID- 26505791 TI - Msx1 homeodomain transcription factor and TATA-binding protein interact to repress the expression of the glycoprotein hormone alpha subunit gene. AB - Studying the regulatory mechanism of the glycoprotein hormone alpha subunit (alphaGSU) gene in thyrotropes is essential for understanding the synthesis of functional thyroid-stimulating hormone (TSH). Here, we investigated the influence of a homeodomain transcription factor Msx1 (Msh homeobox 1) on alphaGSU expression in thyrotropes. The transient expression of Msx1 inhibited the activity of an alphaGSU reporter gene, as well as its endogenous mRNA level in thyrotrope-derived alphaTSH cells. Luciferase reporter assays with serial deletion constructs and a close examination of the sequences revealed that the putative Msx1 binding site (PMS) in the alphaGSU promoter is not responsible for Msx1-mediated transcriptional repression. We also identified the TATA-box binding protein (TBP) as an interacting protein in thyrotropes. Interaction of TBP with Msx1 attenuates the inhibitory effect of Msx1 on alphaGSU gene expression in a DNA binding-independent manner. Furthermore, transient transfection studies with mutant Msx1 revealed that the interaction of TBP and Msx1 is critical for Msx1 mediated transcriptional repression of the alphaGSU. These results suggest that Msx1 functions as a transcriptional repressor of alphaGSU and that its interaction with TBP is an integral part of the mechanism by which Msx1 regulates the inhibition of alphaGSU gene expression. PMID- 26505792 TI - 3-Deazaneplanocin A suppresses aggressive phenotype-related gene expression in an oral squamous cell carcinoma cell line. AB - In tumor tissues, alterations of gene expression caused by aberrant epigenetic modifications confer phenotypic diversity on malignant cells. Although 3 deazaneplanocin A (DZNep) has been shown to reactivate tumor suppressor genes in several cancer cells, it remains unclear whether DZNep attenuates the malignant phenotypes of oral squamous cell carcinoma (OSCC) cells. In this study, we investigated the effect of DZNep on the expression of genes related to aggressive phenotypes, such as epithelial-mesenchymal transition, in OSCC cells. We found that DZNep reduced the cellular levels of polycomb group proteins (EZH2, SUZ12, BMI1, and RING1A) and the associated trimethylation of Lys27 on histone H3 and monoubiquitination of Lys119 on histone H2A in the poorly differentiated OSCC cell line SAS. Immunocytochemical staining demonstrated that DZNep induced the reorganization of filamentous actin and the membrane localization of E-cadherin associated with cell-cell adhesions. We also found an inhibitory effect of DZNep on cell proliferation using a WST assay. Finally, quantitative RT-PCR analysis demonstrated that genes involved in the aggressive phenotypes (TWIST2, EGFR, ACTA2, TGFB1, WNT5B, and APLIN) were down-regulated, whereas epithelial phenotype genes (CDH1, CLDN4, IVL, and TGM1) were up-regulated in SAS cells treated with DZNep. Collectively, our findings suggest that DZNep reverses the aggressive characteristics of OSCC cells through the dynamic regulation of epithelial plasticity via the reprogramming of gene expression patterns. PMID- 26505793 TI - GLP-1 secretion is stimulated by 1,10-phenanthroline via colocalized T2R5 signal transduction in human enteroendocrine L cell. AB - Glucagon-like peptide-1 (GLP-1) hormone is known to regulate blood glucose by an insulinotropic effect and increases proliferation as and also prevents apoptosis of pancreatic beta cells. We know that GLP-1 is secreted by nutrients such as fatty acids and sweet compounds but also bitter compounds via stimulation of G protein coupled receptors (GPCRs) in the gut. Among these, bitter compounds are multiply-contained in phytochemicals or artificial materials and perceived as ligands of various bitter taste receptors. We hypothesized that GLP-1 hormone is secreted through stimulation of a single bitter taste receptor by 1,10 phenanthroline which is known agonist of taste receptor type 2 member 5 (T2R5). To prove this hypothesis, we used the representatively well-known 1,10 phenanthroline as ligand of single receptor and evaluated the existence of T2R5 by double-labeling immunofluorescence and then 1,10-phenanthroline is able to secrete GLP-1 hormone through stimulation of T2R5 in human enteroendocrine cells. Consequently, we verify that GLP-1 hormone is colocalized with T2R5 in the human duodenum and ileum tissue and is secreted by 1,10-phenanthroline via T2R5 signal transduction in differentiated human enteroendocrine L cells. PMID- 26505794 TI - Rock2 stabilizes beta-catenin to promote tumor invasion and metastasis in colorectal cancer. AB - Rho-associated coiled-coil-containing protein kinase 2 (Rock2) is an effector for the small GTPase Rho and plays an important role in tumor progression and metastasis. However, the effect of Rock2 in colorectal cancer (CRC) still remains unclear. In this study, we found that Rock2 expression was markedly increased in clinical CRC tissues compared with adjacent non-cancerous tissues. High expression of Rock2 was correlated with tumor metastasis and poor prognosis in CRC. In addition, the knockdown of Rock2 suppressed the invasion and metastasis of CRC cells both in vitro and in vivo. Furthermore, we found that the beta catenin/TCF4 pathway contributed to the effects of Rock2 in CRC cells, and Rock2 stabilized beta-catenin by preventing its ubiquitination and degradation. Taken together, this novel pathway for beta-catenin control plays a biologically relevant role in CRC metastasis. PMID- 26505795 TI - Liposomal short-chain C6 ceramide induces potent anti-osteosarcoma activity in vitro and in vivo. AB - Osteosarcoma (OS) remains one deadly disease for many affected patients. The search for novel and more efficient anti-OS agents is urgent. In the current study, we demonstrated that liposome-packed C6 ceramide exerted potent cytotoxic effect against established (U2OS and MG-63 lines) and primary human OS cells. Meanwhile, the liposomal C6 (ceramide) induced caspase-mediated apoptotic death in OS cells. Liposomal C6 was significantly more potent than conventional free C6 in inhibiting OS cells, yet it was safe to non-cancerous bone cells (primary murine osteoblasts or human MLO-Y4 osteocytic cells). At the signaling level, we showed that liposomal C6 potently inhibited Akt activation in OS cells. Further studies revealed that a low dose of liposomal C6 dramatically sensitized the in vitro anti-OS activity of two conventional chemodrugs: methotrexate (MTX) and doxorubicin. In vivo, intravenous injection of liposomal C6 inhibited Akt activation and suppressed U2OS xenograft growth in nude mice without causing apparent toxicities. Meanwhile, when given at a low-dose (5 mg/kg body weight), liposomal C6 dramatically sensitized MTX's anti-U2OS activity in vivo. Collectively, our data demonstrate that liposomal C6 exerts potent anti-tumor activity in preclinical OS models. PMID- 26505796 TI - Protective effects of SGLT2 inhibitor luseogliflozin on pancreatic beta-cells in obese type 2 diabetic db/db mice. AB - It is well known that Sodium-Glucose Co-transporter 2 (SGLT2) inhibitors, new hypoglycemic agents, improve glycemic control by increasing urine glucose excretion, but it remained unclear how they exert protective effects on pancreatic beta-cells. In this study, we examined the effects of SGLT2 inhibitor luseogliflozin on beta-cell function and mass using obese type 2 diabetic db/db mice. Ten-week-old male diabetic db/db mice were treated with luseogliflozin 0.0025% or 0.01% in chow (Luse 0.0025% or Luse 0.01%) or vehicle (control) for 4 weeks. Urinary glucose excretion was increased in Luse groups (0.0025% and 0.01%) compared to control mice 3 days after the intervention. Fasting blood glucose levels were significantly lower in mice treated with Luse compared to control mice. Fasting serum insulin concentrations were significantly higher in mice treated with Luse compared to control mice. Triglyceride levels tended to be lower in Luse groups compared to control mice. In immunohistochemical study using pancreas tissues, beta-cell mass was larger in Luse groups compared to control group which was due to the increase of beta-cell proliferation and decrease of beta-cell apoptosis. Furthermore, in gene analysis using isolated islets, insulin 1, insulin 2, MafA, PDX-1 and GLUT2 gene expression levels were significantly higher in Luse groups compared to control group. In contrast, expression levels of fibrosis-related gene such as TGFbeta, fibronectin, collagen I and collagen III were significantly lower in Luse groups. In conclusion, SGLT2 inhibitor luseogliflozin ameliorates glycemic control and thus exerts protective effects on pancreatic beta-cell mass and function. PMID- 26505797 TI - Escin activates AKT-Nrf2 signaling to protect retinal pigment epithelium cells from oxidative stress. AB - Here we explored the anti-oxidative and cytoprotective potentials of escin, a natural triterpene-saponin, against hydrogen peroxide (H2O2) in retinal pigment epithelium (RPE) cells. We showed that escin remarkably attenuated H2O2-induced death and apoptosis of established (ARPE-19) and primary murine RPE cells. Meanwhile, ROS production and lipid peroxidation by H2O2 were remarkably inhibited by escin. Escin treatment in RPE cells resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by transcription of anti-oxidant responsive element (ARE)-regulated genes, including HO-1, NQO-1 and SRXN-1. Knockdown of Nrf2 through targeted shRNAs/siRNAs alleviated escin-mediated ARE gene transcription, and almost abolished escin-mediated anti-oxidant activity and RPE cytoprotection against H2O2. Reversely, escin was more potent against H2O2 damages in Nrf2-over-expressed ARPE-19 cells. Further studies showed that escin induced Nrf2 activation in RPE cells required AKT signaling. AKT inhibitors (LY294002 and perifosine) blocked escin-induced AKT activation, and dramatically inhibited Nrf2 phosphorylation, its cytosol accumulation and nuclear translocation in RPE cells. Escin-induced RPE cytoprotection against H2O2 was also alleviated by the AKT inhibitors. Together, these results demonstrate that escin protects RPE cells from oxidative stress possibly through activating AKT Nrf2 signaling. PMID- 26505798 TI - CD36 is involved in high glucose-induced epithelial to mesenchymal transition in renal tubular epithelial cells. AB - The epithelial-to-mesenchymal transition (EMT) plays an important role in the progression of diabetic nephropathy. Our recent study showed that ROS mediated high glucose (HG)-induced EMT in renal tubular epithelial cells. CD36, a class-B scavenger receptor, has been reported to mediate the production of ROS in chronic kidney disease. In the present study, we examined the effect of inhibition of CD36 with CD36 siRNA or sulfosuccinimidyl-oleate (SSO), a CD36 antagonist, on HG induced EMT in HK-2 cells. HG induced CD36 expression in a time-dependent manner in HK-2 cells. HG was shown to induce EMT at 72 h. This was blocked by knockdown of CD36 or treatment with SSO. Meanwhile, we also found that knockdown of CD36 or treatment with SSO inhibited HG-induced ROS generation, activation of ERK1/2 and Smad2, expression of TGF-beta1 and synthesis of fibronectin. These data suggest that inhibition of CD36 prevented HG-induced EMT in HK-2 cells, highlighting CD36 as a potential therapeutic target for diabetic nephropathy. PMID- 26505799 TI - Crystal structure of mature 2S albumin from Moringa oleifera seeds. AB - 2S albumins, the seed storage proteins, are the primary sources of carbon and nitrogen and are involved in plant defense. The mature form of Moringa oleifera (M. oleifera), a chitin binding protein isoform 3-1 (mMo-CBP3-1) a thermostable antifungal, antibacterial, flocculating 2S albumin is widely used for the treatment of water and is potentially interesting for the development of both antifungal drugs and transgenic crops. The crystal structure of mMo-CBP3-1 determined at 1.7 A resolution demonstrated that it is comprised of two proteolytically processed alpha-helical chains, stabilized by four disulfide bridges that is stable, resistant to pH changes and has a melting temperature (TM) of approximately 98 degrees C. The surface arginines and the polyglutamine motif are the key structural factors for the observed flocculating, antibacterial and antifungal activities. This represents the first crystal structure of a 2S albumin and the model of the pro-protein indicates the structural changes that occur upon formation of mMo-CBP3-1 and determines the structural motif and charge distribution patterns for the diverse observed activities. PMID- 26505800 TI - CCAAT/enhancer-binding protein CEBP-2 controls fat consumption and fatty acid desaturation in Caenorhabditis elegans. AB - Mammalian CCAAT/enhancer-binding proteins (C/EBPs) are generally known as regulators in adipocyte differentiation. However, more understanding of the role of C/EBPs in lipid and glucose metabolism remains to be discovered. In this study, we verified the effect of CEBP-2, the homolog of CEBPs, on fat storage in Caenorhabditis elegans. Expressions of 85 genes that encode the major enzymes in energy metabolic pathways were then screened in cebp-2-deficient worms using a quantitative real-time polymerase chain reaction (QRT-PCR). Our data implied that loss of function of CEBP-2 displayed a low-fat phenotype in C. elegans owing to increased expression of ech-1.1 and decreased expression of fat-5. Our findings indicated that cebp-2 controls total body fat content by governing fatty acid mitochondrial beta-oxidation and desaturation in C. elegans. These data provide insights into how C/EBPs may affect lipid metabolism in mammals in addition to regulating adipocyte differentiation. PMID- 26505801 TI - Microbiome interaction with sugar plays an important role in relapse of childhood caries. AB - Childhood caries have a high relapse rate after full mouth therapy. This study aimed to elucidate the relationship between the microbiome, sugar, and the relapse of childhood caries after therapy. A total of 24 children aged 2-4 years who underwent one caries treatment session participated in this study. Supragingival plaque was collected before therapy and 1 and 7 months after therapy, then sequenced using the 16S rRNA high-throughput approach. We found 11 phyla, 140 genera, and 444 species in 72 samples. The children were divided into relapse-free (n = 13) and relapse (n = 11) groups according to whether they relapsed 7 months after therapy. The bacterial community richness, diversity, structure, and relative abundance of bacterial taxa were significantly different between the two groups 7 months after therapy. The two groups also differed in the relative abundance of bacterial taxa, both before and 1 month after therapy. Bacterial community richness and diversity were lower in the relapse-free group 1 month after therapy. Using different operational taxonomic units between the relapse-free and relapse groups 1 month after therapy, a relapse-risk assessment model was built with 75% accuracy, 0.1905 out-of-bag error, and 66.67% validation accuracy. Patients in the relapse group had higher sugar intake frequencies than those in the relapse-free group during follow-up. Interactions between the microbiome and sugar intake frequency were found through co-occurrence networks. We conclude that the microbiome is significantly different between the relapse free and relapse groups at the time of relapse. Supragingival plaque collected immediately after therapy can be used to predict the risk of relapse. Furthermore, the correlation between sugar intake frequency and microbiome is associated with the relapse. PMID- 26505802 TI - Digital Mammography Screening: Does Age Influence the Detection Rates of Low-, Intermediate-, and High-Grade Ductal Carcinoma in Situ? AB - PURPOSE: To investigate the association between age at screening and detection rates for ductal carcinoma in situ (DCIS) separately for different nuclear grades after introduction of a population-based digital mammography screening program. MATERIALS AND METHODS: The retrospective study was approved by the ethics board and did not require informed consent. In 733 905 women aged 50-69 years who participated in a screening program for the first time in 2005-2008 (baseline examinations were performed with digital mammography), DCIS detection rates were determined for 5-year age groups (detection rates per 1000 women screened) to distinguish high-, intermediate-, and low-grade DCIS. Multivariable logistic regression was used to compare detection rates between age groups by adjusting for screening units (P < .05). RESULTS: There were 989 graded DCIS diagnoses among 733 905 women (detection rate, 1.350/00): 419 diagnoses of high-grade DCIS (detection rate, 0.570/00), 388 diagnoses of intermediate-grade DCIS (detection rate, 0.530/00), and 182 diagnoses of low-grade DCIS (detection rate, 0.250/00). Detection rate for types of DCIS combined increased significantly across age groups (50-54 years, detection rate of 1.150/00 [254 of 220 985 women]; 55-59 years, detection rate of 1.230/00 [218 of 177 782 women]; 60-64 years, detection rate of 1.340/00 [201 of 150 415 women]; and 65-69 years, detection rate of 1.710/00 [316 of 184 723 women]; P < .001). Of note, the detection rate for high grade DCIS showed a significant increase with age (odds ratio, 1.18 per 5-year age group; P < .0001). The increase was lower for intermediate-grade DCIS (odds ratio, 1.11; P = .016) and not significant for low-grade DCIS (P = .10). CONCLUSION: Total DCIS detection rates increase with age, mostly because of an increase in high- and intermediate-grade DCIS, which are precursor lesions that carry a higher risk for transition to more aggressive invasive breast cancer than low-grade DCIS. PMID- 26505803 TI - Local Recurrence Significantly Increases the Risk of Metastatic Uveal Melanoma. AB - PURPOSE: To assess of the effect of local recurrence of uveal melanoma on metastasis using a multicenter international tumor registry. DESIGN: Retrospective study using an online tumor registry. PARTICIPANTS: Patients with uveal melanoma diagnosed between 2001 and 2011. METHODS: A committee was formed to create uveal melanoma patient-specific data fields. Ten subspecialty ophthalmic oncology centers from 4 continents shared data. Patient selection criteria included diagnosis of uveal melanoma and adequate records to allow tumor staging by American Joint Committee on Cancer (AJCC) criteria and follow-up for metastatic melanoma. MAIN OUTCOME MEASURES: Local tumor recurrence and metastatic uveal melanoma. RESULTS: Of 3809 total entries, 3217 patients with ciliary body and choroidal (CBC) melanoma and 160 with iris melanoma were evaluated. There was a median follow-up of 3.7 years (95% confidence interval [CI], 3.5-3.8). One hundred fifty-two patients (4.7%) with CBC melanoma experienced local recurrence, with a cumulative incidence of 11%. Kaplan-Meier point estimates for remaining free of local recurrence were 99% (95% CI, 99-99) at 1 year, 93% (95% CI, 92-94) at 5 years, and 89% (95% CI, 86-91) at 10 years. Five- and 10-year metastasis free Kaplan-Meier estimates for the recurrence-free group were 87% (95% CI, 86 89) and 82% (95% CI, 79-84), and those for the local recurrence group were 71% (95% CI, 62-78) and 62% (95% CI, 49-72). The difference between these 2 groups was statistically significant (P < 0.001). Furthermore, local tumor recurrence increased the risk of metastasis by a hazard ratio (HR) of 6.28 (95% CI, 4.4-8.9; P < 0.001). Local recurrence was detected up to 9.8 years after treatment. Extrascleral extension also was associated with local recurrence (HR, 3.2; 95% CI, 1.5-6.7; P = 0.003), but higher AJCC T-size category was not (P = 0.63). Five patients (n = 5/161 [3.1%]) with iris melanoma demonstrated local recurrence and 1 metastasized. CONCLUSIONS: International multicenter data sharing was used to evaluate the effect of local tumor recurrence on metastatic rate. In that local tumor recurrence was associated with a significantly higher risk of systemic metastasis, effective initial treatment and long-term surveillance of treated uveal melanoma patients is necessary. PMID- 26505804 TI - Rates of Reoperation and Retinal Detachment after Macular Hole Surgery. AB - PURPOSE: To evaluate rates of reoperation and retinal detachment (RD) after macular hole surgery. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Patients in the insurance claim-based MarketScan databases from 2007 through 2013 with a record of macular hole surgery. METHODS: Patients with macular hole surgery were identified. Cases of definite (the same eye was coded both times) and presumed (the eye laterality was not coded) macular hole reoperations within 2, 3, and 12 months were queried. In addition, cases of postoperative RD within 2, 3, and 12 months were captured. MAIN OUTCOME MEASURES: Rates of macular hole reoperation and postoperative RD, including subgroup analysis based on presence or absence of internal limiting membrane (ILM) peeling. RESULTS: Records of 23465 macular hole surgeries among 20 764 patients were analyzed. Among presumed reoperations, the rates of reoperation were 4.3% (4.1% after ILM peeling and 5.0% after no ILM peeling; P = 0.01) within 2 months of surgery, 5.5% (5.3% after ILM peeling and 6.2% after no ILM peeling; P = 0.03) within 3 months of surgery, and 9.5% (9.0% after ILM peeling and 11.0% after no ILM peeling; P = 0.01) within 12 months of surgery. The rates for definite reoperations were 1.3% (1.2% after ILM peeling and 1.8% after no ILM peeling; P = 0.04) at 2 months, 1.7% (1.6% after ILM peeling and 2.5% after no ILM peeling; P = 0.004) at 3 months, and 4.1% (3.3% after ILM peeling and 7.5% after no ILM peeling; P < 0.001) at 12 months. The cumulative rate of postoperative RD was 1.81+/-0.09% to 2.18+/-0.5% after 2 months, 2.27+/-0.10% to 3.18+/-0.67% after 3 months, and 3.92+/-0.16% to 5.70+/ 1.1% after 12 months. Internal limiting membrane peeling was associated negatively with postoperative RD at 2 months (2.3% vs. 1.7%; P = 0.007), 3 months (2.8% vs. 2.1%; P = 0.004), and 12 months (4.7% vs. 3.3%; P < 0.001). CONCLUSIONS: In this sample, reoperations for macular hole were performed at low rates. Internal limiting membrane peeling was associated with lower rates of reoperation and RD. PMID- 26505805 TI - In Utero and Early-Life Exposure to Ambient Air Toxics and Childhood Brain Tumors: A Population-Based Case-Control Study in California, USA. AB - BACKGROUND: Little is known about the influence of environmental factors on the etiology of childhood brain tumors. OBJECTIVES: We examined risks for brain tumors in children after prenatal and infant exposure to monitored ambient air toxics. METHODS: We ascertained all cases of medulloblastoma, central nervous system primitive neuroectodermal tumor (PNET), and astrocytoma before 6 years of age diagnosed in 1990-2007 from the California Cancer Registry and selected controls randomly from birth rolls matched by birth year. Exposures to air toxics during pregnancy/infancy for 43 PNET, 34 medulloblastoma, and 106 astrocytoma cases and 30,569 controls living within 5 mi of a monitor were determined. With factor analysis we assessed the correlational structures of 26 probable carcinogenic toxics, and estimated odds ratios by brain tumor type in logistic regression models. RESULTS: PNETs (<= 38 cases) were positively associated with interquartile range (IQR) increases in prenatal exposure to acetaldehyde [odds ratio (OR) = 2.30; 95% CI: 1.44, 3.67], 1,3-butadiene (OR = 2.23; 95% CI: 1.28, 3.88), benzene, and toluene; and with IQR increases in exposure during the first year of life to ortho-dichlorobenzene (OR = 3.27; 95% CI: 1.17, 9.14), 1,3 butadiene (OR = 3.15; 95% CI: 1.57, 6.32), and benzene. All exposures except ortho-dichlorobenzene loaded on the same factor. Medulloblastoma (<= 30 cases) was associated with prenatal exposure to polycyclic aromatic hydrocarbons (PAHs combined: OR = 1.44; 95% CI: 1.15, 1.80). Exposures to lead and some PAHs during the first year of life were positively associated with astrocytoma, but the confidence intervals included the null value (e.g., for lead, OR = 1.40; 95% CI: 0.97, 2.03). CONCLUSIONS: Our data suggest that in utero and infancy exposures to air toxics generated by industrial and road traffic sources may increase the risk of PNET and medulloblastoma, with limited support for increased risks for astrocytoma in children up to age 6. CITATION: von Ehrenstein OS, Heck JE, Park AS, Cockburn M, Escobedo L, Ritz B. 2016. In Utero and early-life exposure to ambient air toxics and childhood brain tumors: a population-based case-control study in California, USA. Environ Health Perspect 124:1093-1099; http://dx.doi.org/10.1289/ehp.1408582. PMID- 26505806 TI - Woodward-Hoffmann's Stereochemistry of Electrocyclic Reactions: From Day 1 to the JACS Receipt Date (May 5, 1964 to November 30, 1964). AB - The publication in January 1965 of the first Woodward-Hoffmann paper, The Stereochemistry of Electrocyclic Reactions, ushered into organic chemistry both an explanation of the stereochemistry and "allowedness" or "forbiddenness" of concerted reactions and an impetus for untold numbers of research projects. In the current paper, details of the collaboration between R. B. Woodward and R. Hoffmann, from when they first met to discuss the solution to the "no-mechanism problem" to the date their first paper was received in the offices of the Journal of the American Chemical Society, will be discussed and analyzed. The primary focus will be on the historically relevant extant documents from the early 1960s. These include Hoffmann's laboratory notebooks describing his research, including his extended Huckel calculations used to explain and predict the stereochemistry of electrocyclic reactions. Drafts of the Stereochemistry of Electrocyclic Reactions paper and letters and notes by Woodward, Jerome Berson, and others will further illuminate the development of this first Woodward-Hoffmann paper. PMID- 26505807 TI - What do dogs, ancient Romans, Linus Pauling, and mass spectrometry have in common? Early lung cancer and exhaled breath. PMID- 26505808 TI - Is the self a higher-order or fundamental function of the brain? The "basis model of self-specificity" and its encoding by the brain's spontaneous activity. AB - What is the self? This is a question that has long been discussed in (Western) philosophy where the self is traditionally conceived a higher-order function at the apex or pinnacle of all functions. This tradition has been transferred to recent neuroscience where the self is often considered to be a higher-order cognitive function reflected in memory and other high-level judgements. However, other lines of research demonstrate a close and intimate relationship between self-specificity and more basic functions like perceptions, emotions and reward. This paper focuses on the relationship between self-specificity and other basic functions relating to emotions, reward and perception. I propose the basis model that conceives self-specificity as a fundamental feature of the brain's spontaneous activity. This is supported by recent findings showing rest-self overlap in midline regions as well as findings demonstrating that the resting state can predict subsequent degrees of self-specificity. I conclude that such self-specificity in the brain's spontaneous activity may be central in linking the self to either internal or external stimuli. This may also provide the basis for coding the self as subject in relation to internal (i.e., self-consciousness) or external (i.e., phenomenal consciousness) mental events. PMID- 26505809 TI - An investigation and evaluation on species and characteristics of pathogenic microorganisms in Chinese local hospital settings. AB - There are currently great concerns about the level of bacterial contamination in hospitals, as well as resistance to antimicrobial agents. The species and characteristics of microbes in Chinese hospitals are closely related to healthcare safety and the prevention and control of infections. However, data on the exposure of patients to microbes in Chinese hospitals are limited. The present study investigated the genera of microorganisms in Chinese hospitals. We evaluated their characteristics, such as antibiotic susceptibility, tolerance to disinfectants, and toxicity, using silkworms (Bombyx mori) as an animal model. Twenty-six distinct bacterial strains were isolated, and their genera were determined by sequencing their 16S rDNA regions. Twenty-five strains were resistant to one or more antibiotics, and six strains were resistant to multiple antibiotics. The results of minimal inhibitory concentration testing showed that eight strains were resistant to a chlorine-containing disinfectant, and 12 strains were resistant to Povidone-iodine. Following the injection of bacterial cultures into the silkworm hemolymph, 15 strains killed all of the silkworms within 5 d. Additionally, bacterial strain 14 killed all of silkworms within 12 h with a median lethal dose of 4 * 10(4) colony-forming units/larva. This study provides useful information for healthcare safety in Chinese hospitals. PMID- 26505810 TI - Comparing Perspectives of Patients, Caregivers, and Clinicians on Heart Failure Management. AB - BACKGROUND: Although substantial effort has been devoted to reducing readmissions among heart failure (HF) patients, little is known about factors identified by patients and caregivers that may contribute to readmissions. The goal of this study was to compare the perspectives of HF patients, their caregivers, and their care team on HF management and hospital admissions. Understanding these perspectives may lead to better strategies for improving care during the post hospital transition and for reducing preventable readmissions. METHODS AND RESULTS: We performed freelisting, an anthropologic technique in which participants list items in response to a question, with hospitalized HF patients (n = 58), their caregivers (n = 32), and clinicians (n = 67). We asked about home HF management tasks, difficulties in managing HF, and perceived reasons for hospital admission. Results were analyzed with the use of Anthropac. Salience indices (measures of the most important words for defining the domain of interest) were calculated. Patients and clinicians described similar home HF management tasks, whereas caregivers described tasks related to activities of daily living. Clinicians cited socioeconomic factors as challenges to HF management, whereas patients and caregivers cited limited functional status and daily activities. When asked about reasons for hospitalization, patients and caregivers listed distressing symptoms and illness, whereas clinicians viewed patient behaviors to be primarily responsible for admission. CONCLUSIONS: These findings highlight that although some similarities exist, there are important differences among patients, caregivers, and clinicians in how they perceive the challenges of HF management and reasons for readmission. Understanding these differences may be critical to developing strategies to reduce readmissions. PMID- 26505811 TI - The Impact of Hospital and Surgeon Volume on In-Hospital Mortality of Ventricular Assist Device Recipients. AB - BACKGROUND: The use of left ventricular assist devices (LVADs) in the United States has increased since the Food and Drug Administration approved the 1st device in 1994. Despite a rapid increase in the number of LVADs implanted per year, there are substantial variations in procedure volume among hospitals and surgeons. This study evaluated the association between hospital and surgeon volumes of LVAD procedures and in-hospital mortality. METHODS AND RESULTS: We conducted a retrospective cross-sectional analysis of all patient discharges after an LVAD implantation from University HealthSystem Consortium (UHC) academic medical center members from January 2007 through June 2012. With the use of International Classification of Diseases-9th Edition, Clinical Modification, procedure code 37.66, we identified 7714 patients who received an LVAD from 581 surgeons across 88 hospitals. The primary outcome was all-cause in-hospital mortality. Annual hospital and surgeon LVAD procedure volumes were evaluated as both continuous variables and quintiles. Hierarchical binary logistic regression models were fitted to test the association of in-hospital mortality with hospital and surgeon volume, controlling for hospital and patient characteristics. Hospital volume was not associated with lower in-hospital mortality. Highest annual surgeon volume quintile was a significant predictor of lower in-hospital mortality (odds ratio 1.69; P < .001); this model had the highest predictive accuracy, with area under the receiver operating characteristic curve of 0.79. CONCLUSIONS: Surgeons' LVAD procedure volume, not annual hospital procedure volume, was associated with in-hospital mortality. PMID- 26505812 TI - Inspiratory Muscle Weakness is Associated With Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction: A Preliminary Study. AB - BACKGROUND: The relationship between inspiratory muscle weakness (IMW) and exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) remains unestablished. METHODS AND RESULTS: The present study enrolled 40 patients with HFpEF (EF >=45%). IMW was defined as maximum inspiratory pressure <70% normal predicted values. The function of the diaphragm was assessed by means of ultrasound measurement of muscle thickening of the diaphragm. IMW was prevalent in 27.5% of patients. Patients with IMW had significantly lower vital capacity relative to normal predicted values (%VC), lower knee extensor muscle strength in relation to body weight (%KEMS), poorer nutritional status as assessed by means of the Geriatric Nutritional Risk Index, and shorter 6-minute walk distance (6MWD) compared with patients without IMW (all P < .05). Impaired diaphragm muscle thickening at end-inspiration (median value < 3.9 mm) was significantly associated with a high prevalence of IMW and reduced 6MWD (all P < .05). Subgroup analysis showed that IMW was accompanied by a further decrease in 6MWD in patients with restrictive pulmonary dysfunction (%VC <80%) or lower-limb muscle weakness (median %KEMS <30%; all P < .05). CONCLUSIONS: IMW is associated with exercise intolerance in patients with HFpEF. PMID- 26505813 TI - Prevalence of Albuminuria in a General Population Cohort of Patients With Established Chronic Heart Failure. AB - BACKGROUND: Numerous studies have reported an association between albuminuria and adverse outcomes in adults with chronic heart failure (CHF). However, the prevalence of albuminuria in adults with established CHF remains unclear. METHODS AND RESULTS: This study was a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) 1999-2012. Adults aged >=18 years were included, and diagnosis of CHF was based on participant self-report. The primary outcome was the prevalence of microalbuminuria (albumin-to-creatinine ratio 30 300 mg/g) and macroalbuminuria (albumin-to-creatinine ratio >300 mg/g) in adults with CHF. The secondary outcome was the adjusted odds ratio of any albuminuria in adults with and without CHF. During the study period, 37,961 adults did not have CHF and 1,214 adults had CHF. In adults with CHF, 22.1% (95% confidence interval [CI] 19.6%-24.7%) had microalbuminuria and 10.4% (95% CI 8.1%-12.7%) macroalbuminuria. In adjusted analyses, the odds of albuminuria in adults with CHF was 1.89-fold higher (95% CI 1.59-2.26; P < .001) than in adults without CHF. CONCLUSIONS: Taken together, albuminuria is more common in adults with CHF than in those without CHF, even after adjustment for important demographic and clinical confounders. PMID- 26505815 TI - A Case of Gastric Splenosis Mimicking a Stromal Tumor. PMID- 26505814 TI - Nucleolar repression facilitates initiation and maintenance of senescence. AB - Tumor cells with defective apoptosis pathways often respond to chemotherapy by entering irreversible cell cycle arrest with features of senescence. However, rare cells can bypass entry to senescence, or re-enter cell cycle from a senescent state. Deficiency in senescence induction and maintenance may contribute to treatment resistance and early relapse after therapy. Senescence involves epigenetic silencing of cell cycle genes and reduced rRNA transcription. We found that senescence-inducing treatments such as DNA damage and RNA polymerase I inhibition stimulate the binding between the nucleolar protein NML (nucleomethylin) and SirT1. The NML complex promotes rDNA heterochromatin formation and represses rRNA transcription. Depletion of NML reduced the levels of H3K9Me3 and H3K27Me3 heterochromatin markers on rDNA and E2F1 target promoters in senescent cells, increased rRNA transcription, and increased the frequency of cell cycle re-entry. Depletion of the nucleolar transcription repressor factor TIP5 also promoted escape from senescence. Furthermore, tumor tissue staining showed that breast tumors without detectable nucleolar NML expression had poor survival. The results suggest that efficient regulation of nucleolar rDNA transcription facilitates the maintenance of irreversible cell cycle arrest in senescent cells. Deficiency in nucleolar transcription repression may accelerate tumor relapse after chemotherapy. PMID- 26505816 TI - Biomarker and Therapeutic Potential of CSF1 in Acute Liver Failure. PMID- 26505817 TI - Neutrophil Extracellular Traps Provide a Grip on the Enigmatic Pathogenesis of Acute Pancreatitis. PMID- 26505818 TI - Targeting Integrins and Safety in an Emerging Class of Targeted Oral Therapies: Are We Prepared for Rational and Precision Choices? PMID- 26505819 TI - Next Generation of Pancreatic Enzyme Replacement Therapy: Recombinant Microbial Enzymes and Finding the Perfect Lipase. PMID- 26505820 TI - Gastroparesis: Time for a Reappraisal? PMID- 26505821 TI - Are Biochemical Markers of Bone Turnover Representative of Bone Histomorphometry in 370 Postmenopausal Women? AB - CONTEXT: The levels of bone formation and resorption can be assessed at the tissue level by bone histomorphometry on transiliac bone biopsies. Systemic biochemical markers of bone turnover reflect the overall bone formation and resorption at the level of the entire skeleton but cannot discriminate the different skeletal compartments. OBJECTIVE: Our aim was to investigate the correlations between the serum biochemical markers of formation and resorption with histomorphometric parameters. DESIGN: We performed post hoc analysis of a previous clinical study. SETTING: Patients were selected from the general population. PATIENTS: A total of 371 untreated postmenopausal osteoporotic women aged 50 to 84 years with a lumbar T-score <= -2.5 SD or <= -1 SD with at least one osteoporotic fracture. INTERVENTIONS: Transiliac bone biopsies were obtained after a double tetracycline labeling, and blood samples were collected. MAIN OUTCOME MEASURES: The static and dynamic parameters of formation and bone resorption were measured by histomorphometry. Serum biochemical markers of formation (bone alkaline phosphatase [ALP]; procollagen type I N-terminal propeptide [PINP]) and resorption (C-terminal crosslinking telopeptide of collagen type 1 [sCTX]) were assessed. RESULTS: The mean values of biochemical markers were: bone ALP, 15.0 +/- 5.2 ng/mL; PINP, 56.2 +/- 21.9 MUg/mL; and sCTX, 0.58 +/- 0.26 ng/mL. Bone ALP and PINP were significantly correlated with both the static and dynamic parameters of formation (0.21 <= r' <= 0.36; 0.01 >= P >= .0001). sCTX was significantly correlated with all resorption parameters (0.18 <= r' <= 0.24; 0.02 >= P >= .0001). CONCLUSION: Bone turnover markers were significantly but modestly associated with bone turnover parameters measured in iliac cancellous bone. The iliac crest bone may not represent perfectly the whole bone turnover. PMID- 26505822 TI - Sclerostin Serum Levels and Vascular Calcification Progression in Prevalent Renal Transplant Recipients. AB - CONTEXT: Vascular calcification (VC) is prevalent and progressive in renal transplant recipients (RTRs). Recent cross-sectional data suggest that activated Wnt signaling contributes to VC. OBJECTIVE: The objective was to investigate whether circulating levels of the Wnt antagonist sclerostin associate with progression of VC. DESIGN: This was a post hoc analysis of the longitudinal observational Brussels Renal Transplant Cohort study. SETTING: The setting was a tertiary care academic hospital. PATIENTS: Coronary artery calcification and aorta calcification were measured by multislice spiral computerized tomography in 268 prevalent RTRs (age, 53 +/- 13 y; 61% male) at baseline and remeasured in 189 patients after a median follow-up of 4.4 years. Baseline serum sclerostin levels were assessed on stored blood samples. Regression analysis was performed to identify determinants of baseline VC and progression. MAIN OUTCOME MEASURE: The main outcome measure was progression of VC. RESULTS: VC was present in up to 84% of participants at baseline. Almost half of the patients showed progression of VC, according to Hokanson criteria. The cross-sectional analysis at baseline demonstrated a direct association between sclerostin levels and VC score in univariate analysis, which became inverse after adjustment for age, gender and PTH level. Remarkably, a lower sclerostin level was identified as an independent determinant of a higher baseline aorta calcification score in the final regression model. Moreover, baseline sclerostin levels showed an inverse association with VC progression, at least after adjustment for traditional risk factors. CONCLUSIONS: Serum sclerostin levels inversely associated with VC burden and progression in prevalent RTRs after adjustment for traditional risk factors. Our data corroborate previous findings in nontransplanted chronic kidney disease patients and support the notion that sclerostin may be up-regulated in the vascular wall during the VC process as part of a local counterregulatory mechanism directed to suppress VC. Additional clinical and experimental data are required for confirmation. PMID- 26505823 TI - Gastrointestinal Hormones and Weight Loss Maintenance Following Roux-en-Y Gastric Bypass. AB - CONTEXT: Factors underlying variable weight loss (WL) after Roux-en-Y gastric bypass (RYGB) are poorly understood. OBJECTIVE: Our objective was to gain insight on the role of gastrointestinal hormones on poor WL maintenance (P-WLM) following RYGB. DESIGN AND PATIENTS: First, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin responses to a standardized mixed liquid meal (SMLM) were compared between subjects with good WL (G-WL, n = 32) or P-WLM (n = 22). Second, we evaluated food intake (FI) following blockade of gut hormonal secretion in G WL (n = 23) or P-WLM (n = 19) subjects. Finally, the impact of dietary-induced WL on the hormonal response in subjects with P-WLM (n = 14) was assessed. SETTING: This study was undertaken in a tertiary hospital. MAIN OUTCOME MEASURES: In studies 1 and 3, the outcomes measures were the areas under the curve of gut hormones following a SMLM; in study 2, FI following subcutaneous injection of saline or octreotide were evaluated. RESULTS: P-WLM associated a blunted GLP-1 (P = .044) and PYY (P = .001) responses and lesser suppression of ghrelin (P = .032) following the SMLM challenge. On saline day, FI in the G-WL (393 +/- 143 kcal) group was less than in the P-WLM (519 +/- 143 Kcal; P = .014) group. Octreotide injection resulted in enlarged FI in both groups (G-WL: 579 +/- 248 kcal, P = .014; P-WLM: 798 +/- 284 Kcal, P = .036), but the difference in FI between groups remained (P < .001). In subjects with P-WLM, dietary-induced WL resulted in larger ghrelin suppression (P = .046), but no change in the GLP-1 or PYY responses. CONCLUSION: Our data show gastrointestinal hormones play a role in the control of FI following RYGB, but do not support that changes in GLP-1, PYY, or ghrelin play a major role as determinants of P-WLM after this type of surgery. PMID- 26505824 TI - Glucose-Dependent Insulinotropic Polypeptide Is Associated With Lower Low-Density Lipoprotein But Unhealthy Fat Distribution, Independent of Insulin: The ADDITION PRO Study. AB - CONTEXT: Glucose-dependent insulinotropic polypeptide (GIP) may increase lipid clearance by stimulating lipid uptake. However, given that GIP promotes release of insulin by the pancreas and insulin is anti-lipolytic, the effect may be indirect. OBJECTIVE: In this study we examined the association between GIP and lipid metabolism in individuals with low to high risk of type 2 diabetes and assessed whether the associations were modified by or mediated through insulin. DESIGN, SETTING, AND PARTICIPANTS: Analyses were based on the Danish cross sectional ADDITION-PRO study (n = 1405). Lipid metabolism was measured by fasting plasma lipids and obesity including abdominal fat distribution assessed by ultrasonography. GIP and insulin were measured during an oral glucose tolerance test (0, 30 and 120 min). Linear regression analysis was used to study the associations between GIP, plasma lipids, and obesity measures. RESULTS: A doubling in fasting GIP levels was associated with lower low-density lipoprotein in both men (mean [95% CI] -0.10 mmol/l [-0.18--0.03]) and women (-0.14 mmol/l [ 0.23--0.04]) and with higher high-density lipoprotein in women (0.06 mmol/l [ 0.02-0.10]). In men, a doubling in stimulated GIP was associated with 0.13 cm less 0.01-0.25 sc fat but with more visceral abdominal fat (0.45 cm [0.12-0.78]) and higher waist-hip ratio (0.011 [0.004-0.019]). CONCLUSIONS: Contrary to what was previously thought, GIP may be associated with improved low-density lipoprotein clearance but with an unhealthy fat distribution independent of insulin. The effect of GIP on obesity measures was substantially different between men and women. The potential effect of GIP on visceral and sc adipose tissue physiology warrants further examination. PMID- 26505825 TI - Two Healthy Diets Modulate Gut Microbial Community Improving Insulin Sensitivity in a Human Obese Population. AB - CONTEXT: Gut microbiota, which acts collectively as a fully integrated organ in the host metabolism, can be shaped by long-term dietary interventions after a specific diet. OBJECTIVE: The aim was to study the changes in microbiota after 1 year's consumption of a Mediterranean diet (Med diet) or a low-fat, high-complex carbohydrate diet (LFHCC diet) in an obese population. DESIGN: Participants were randomized to receive the Med diet (35% fat, 22% monounsaturated) and the LFHCC diet (28% fat, 12% monounsaturated). SETTING AND PARTICIPANTS: The study was conducted in 20 obese patients (men) within the Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention (CORDIOPREV) study, an ongoing prospective, randomized, opened, controlled trial in patients with coronary heart disease. MAIN OUTCOME MEASURE: We evaluated the bacterial composition and its relationship with the whole fecal and plasma metabolome. RESULTS: The LFHCC diet increased the Prevotella and decreased the Roseburia genera, whereas the Med diet decreased the Prevotella and increased the Roseburia and Oscillospira genera (P = .028, .002, and .016, respectively). The abundance of Parabacteroides distasonis (P = .025) and Faecalibacterium prausnitzii (P = .020) increased after long-term consumption of the Med diet and the LFHCC diet, respectively. The changes in the abundance of 7 of 572 metabolites found in feces, including mainly amino acid, peptide, and sphingolipid metabolism, could be linked to the changes in the gut microbiota. CONCLUSIONS: Our results suggest that long-term consumption of the Med and LFHCC diets exerts a protective effect on the development of type 2 diabetes by different specific changes in the gut microbiota, increasing the abundance of the Roseburia genus and F. prausnitzii, respectively. PMID- 26505826 TI - The Effect of Soy Intake on Metabolic Profiles of Women With Gestational Diabetes Mellitus. AB - CONTEXT: To our knowledge, no study has examined the effects of soy intake on metabolic status of women with gestational diabetes mellitus (GDM). OBJECTIVE: This study was designed to assess the effects of soy intake on metabolic status of GDM women. METHODS: A randomized clinical trial was performed among 68 women with GDM. Women were randomly assigned to receive either a control diet containing 0.8-g/kg protein (70% animal and 30% plant proteins) (n = 34) or a soy diet containing the same amount of protein with 35% animal protein, 35% soy protein, and 30% other plant proteins (n = 34) for 6 weeks. RESULTS: Compared with soy protein consumption, the control group significantly increased fasting plasma glucose (+1.4 +/- 11.6 vs -12.7 +/- 13.2 mg/dL, P < .001), serum insulin levels (+5.0 +/- 11.6 vs -0.9 +/- 10.0 MUIU/mL, P = .02), homeostasis model of assessment-insulin resistance (+1.2 +/- 2.7 vs -0.8 +/- 2.2, P = .002), and decreased quantitative insulin sensitivity check index (-0.007 +/- 0.02 vs +0.01 +/- 0.03, P = .004). Administration of the control diet resulted in a significant difference in serum triglycerides changes (+31.3 +/- 38.0 vs +8.9 +/- 46.1 mg/dL, P = .03) compared with soy protein. There were a significant decrease in total antioxidant capacity (-35.0 +/- 136.2 vs +81.8 +/- 188.8 mmol/L, P = .005) and glutathione (-41.3 +/- 145.7 vs +53.3 +/- 117.3 MUmol/L, P = .004) by the control diet intake compared with soy protein. The control diet group had a higher incidence of newborn hyperbilirubinemia (32.4% vs 8.8%, P = .01) and newborn hospitalization (20.6% vs 2.9%, P = .02) compared with soy protein. CONCLUSION: Soy protein consumption in women with GDM significantly improved the glucose homeostasis parameters, triglycerides, and biomarkers of oxidative stress, as well as reductions in the incidence of newborn hyperbilirubinemia and hospitalizations. PMID- 26505827 TI - Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond. AB - We target the gatekeeper MET146 of c-Jun N-terminal kinase 3 (JNK3) to exemplify the applicability of X...S halogen bonds in molecular design using computational, synthetic, structural and biophysical techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calculated interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their sigma-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or threonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Determining the crystal structure of the iodine derivative in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increases the flexibility of Cepsilon of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methionine is the predominant gatekeeper (39%). PMID- 26505828 TI - In situ phenotypic heterogeneity among single cells of the filamentous bacterium Candidatus Microthrix parvicella. AB - Microorganisms in biological wastewater treatment plants require adaptive strategies to deal with rapidly fluctuating environmental conditions. At the population level, the filamentous bacterium Candidatus Microthrix parvicella (Ca. M. parvicella) has been found to fine-tune its gene expression for optimized substrate assimilation. Here we investigated in situ substrate assimilation by single cells of Ca. M. parvicella using nano-scale secondary-ion mass spectrometry (nanoSIMS). NanoSIMS imaging highlighted phenotypic heterogeneity among Ca. M. parvicella cells of the same filament, whereby (13)C-oleic acid and (13)C-glycerol-3-phosphate assimilation occurred in ~21-55% of cells, despite non assimilating cells being intact and alive. In response to alternating aerobic anoxic regimes, (13)C-oleic acid assimilation occurred among subpopulations of Ca. M. parvicella cells (~3-28% of cells). Furthermore, Ca. M. parvicella cells exhibited two temperature optima for (13)C-oleic acid assimilation and associated growth rates. These results suggest that phenotypic heterogeneity among Ca. M. parvicella cells allows the population to adapt rapidly to fluctuating environmental conditions facilitating its widespread occurrence in biological wastewater treatment plants. PMID- 26505829 TI - Superinfection exclusion and the long-term survival of honey bees in Varroa infested colonies. AB - Over the past 50 years, many millions of European honey bee (Apis mellifera) colonies have died as the ectoparasitic mite, Varroa destructor, has spread around the world. Subsequent studies have indicated that the mite's association with a group of RNA viral pathogens (Deformed Wing Virus, DWV) correlates with colony death. Here, we propose a phenomenon known as superinfection exclusion that provides an explanation of how certain A. mellifera populations have survived, despite Varroa infestation and high DWV loads. Next-generation sequencing has shown that a non-lethal DWV variant 'type B' has become established in these colonies and that the lethal 'type A' DWV variant fails to persist in the bee population. We propose that this novel stable host-pathogen relationship prevents the accumulation of lethal variants, suggesting that this interaction could be exploited for the development of an effective treatment that minimises colony losses in the future. PMID- 26505831 TI - JNK pathway signaling: a novel and smarter therapeutic targets for various biological diseases. AB - JNK pathway regulates various physiological processes including inflammatory responses, cell differentiation, cell proliferation, cell death, cell survival and expression of proteins. Deregulation of JNK is linked with various diseases including neurodegenerative disease, autoimmune disease, diabetes, cancer, cardiac hypertrophy and asthma. Three distinct genes JNK1, JNK2 and JNK3 have been identified as regulator of JNK pathway. JNK1 and JNK2 have broad tissue distribution and play a potential role in insulin resistance, inflammation and cell signaling. JNK3 is predominantly found in the CNS neurons, making it an attractive target for neurodegenerative disorders. In this review, we summarize the evidence supporting JNK as a potent therapeutic target, and small molecules from various chemical classes as JNK inhibitors. PMID- 26505830 TI - Live to cheat another day: bacterial dormancy facilitates the social exploitation of beta-lactamases. AB - The breakdown of antibiotics by beta-lactamases may be cooperative, since resistant cells can detoxify their environment and facilitate the growth of susceptible neighbours. However, previous studies of this phenomenon have used artificial bacterial vectors or engineered bacteria to increase the secretion of beta-lactamases from cells. Here, we investigated whether a broad-spectrum beta lactamase gene carried by a naturally occurring plasmid (pCT) is cooperative under a range of conditions. In ordinary batch culture on solid media, there was little or no evidence that resistant bacteria could protect susceptible cells from ampicillin, although resistant colonies could locally detoxify this growth medium. However, when susceptible cells were inoculated at high densities, late appearing phenotypically susceptible bacteria grew in the vicinity of resistant colonies. We infer that persisters, cells that have survived antibiotics by undergoing a period of dormancy, founded these satellite colonies. The number of persister colonies was positively correlated with the density of resistant colonies and increased as antibiotic concentrations decreased. We argue that detoxification can be cooperative under a limited range of conditions: if the toxins are bacteriostatic rather than bacteridical; or if susceptible cells invade communities after resistant bacteria; or if dormancy allows susceptible cells to avoid bactericides. Resistance and tolerance were previously thought to be independent solutions for surviving antibiotics. Here, we show that these are interacting strategies: the presence of bacteria adopting one solution can have substantial effects on the fitness of their neighbours. PMID- 26505832 TI - Imaging of drug and metabolite distribution by MS: case studies. AB - Analysis of drug and metabolite distribution is essential for understanding of the mechanisms underlying the pharmacological or toxicological effects. MS imaging (MSI) can visualize the distribution of drugs or biological molecules in tissue sections without radiolabeling, and distinguish between the distribution of a drug and that of its metabolites in tissue sections. Therefore, it is expected to be a potent imaging technique for drug distribution studies. This article includes cases in which MSI was used to analyze drug and metabolite distribution, and discusses the impact of data obtained by MSI in drug discovery and development. PMID- 26505833 TI - Comparison of 1-stage With 2-stage Multiple-tracts Mini-percutaneous Nephrolithotomy for the Treatment of Staghorn Stones: A Matched Cohorts Analysis. AB - OBJECTIVE: To identify the better of 2 treatment strategies, single stage vs 2 stages, and to create multiple tracts in mini-percutaneous nephrolithotomy (MPCNL) for the treatment of staghorn stone. MATERIALS AND METHODS: Records of patients who underwent MPCNL with multiple tracts for the treatment of staghorn stones from 2011 to 2013 were retrospectively reviewed. Two-stage (as group 1) and 1-stage strategies (as group 2) to establish the multiple tracts were performed. A total of 145 pairs were matched for the analysis according to age, preoperative hemoglobin, preoperative urine culture, stone surface area, and stone size. RESULTS: In group 2, 45.5% of success rate of patients were achieved after a single procedure with a mean of 2.63 +/- 0.62 tracts. The remaining patients required a second procedure, necessitating the placement of multiple tracts or the reuse of the existing tracts. The final success rate was similar in both group 1 and group 2 (82.1% vs 84.2%; P = .638). There was a significant decrease in the mean number of total access tracts, infection complications, and blood transfusion rate in group 1 than in group 2. The infection and bleeding complications were similar for both groups during the subsequent treatment. CONCLUSION: The 2-stage MPCNL treatment plan for staghorn stones was more advantageous for 2 reasons: (1) Almost half of the patients who were treated using a 1-stage treatment plan required subsequent procedure to achieve a satisfactory success rate; (2) An initial treatment plan using the 2-stage approach resulted in less complication and less tracts established. PMID- 26505834 TI - Does the Renal Parenchyma Adjacent to the Tumor Contribute to Kidney Function? A Critical Analysis of Glomerular Viability in Partial Nephrectomy Specimens. AB - OBJECTIVE: To evaluate the viability of glomeruli in the peritumor parenchyma of partial nephrectomy specimens removed for renal cell carcinoma (RCC) and relate it to kidney function, to better understand the contribution of peritumor parenchyma to renal function. MATERIALS AND METHODS: A retrospective analysis of 53 partial nephrectomies containing RCC was performed. Glomeruli within 0.25-cm increments from the tumor were quantified and histologically assessed for viability. Tumor size, minimum and maximum margin size, and pre- and postoperative estimated glomerular filtration rate (eGFR) were obtained. RESULTS: Glomerular viability positively correlated with distance from tumor with mean viable glomeruli in successive 0.25-cm increments of 0-0.25 cm, 58%; 0.25-0.5 cm, 80%; 0.5-0.75 cm, 90%; and 0.75-1.0 cm, 92%. Glomerular viability near the tumor did not correlate with preoperative eGFR, whereas decreased viability further from the tumor did correlate with worse preoperative eGFR. Tumor size showed a nonstatistically significant positive trend with minimum (median 0.15 cm) and maximum margin (median 0.7 cm) sizes. Percent change of glomerular filtration rate did not correlate with margin size (P = .190). CONCLUSION: Renal parenchyma immediately adjacent to RCC contains fewer viable glomeruli compared with the parenchyma further from the tumor. Based on this information, attempts to preserve all non-neoplastic renal parenchyma via a surgical margin approaching zero may not necessarily result in clinically relevant differences in the amount of viable glomeruli remaining or the renal function preserved. PMID- 26505836 TI - Male Readjustable Sling (MRS) System for Postprostatectomy Incontinence: Experiences of 2 Centers. AB - OBJECTIVE: To evaluate the outcomes of Male Readjustable Sling (MRS) in patients with postprostatectomy incontinence at 2 unrelated centers and to determine preoperative factors relevant to the outcome. MATERIALS AND METHODS: From January 2007 to January 2014, a total of 64 men with urinary incontinence following radical prostatectomy were treated with MRS at 2 centers. Patients were evaluated based on medical history, daily pad usage, urodynamics, and cystoscopy. The clinical outcome was evaluated according to daily pad usage and questionnaires. Success was defined according to reductions in the number of pads used per day after surgery, and factors related to surgical outcome were investigated. RESULTS: The median age of the patients was 70 years (range: 53-84), and the mean follow-up duration was 46.0 +/- 19.47 months (range: 12-89). During follow-up, readjustment of the sling was required 1.9 times on average. Daily pad usage decreased significantly from 3.42 +/- 2.00 to 0.84 +/- 1.20 (P <.001), and the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form score improved (18.65 +/- 2.61 to 10.55 +/- 6.21, P <.001) without deterioration of voiding symptoms at the last follow-up. MRS was successful in 46 of 64 patients (71.9%). Of the 18 patients who experienced surgical failure, 12 patients required secondary artificial urethral sphincter implantation. The number of daily used pads (odds ratio 1.414) and a history of pelvic irradiation (odds ratio 8.400) were potential risk factors for surgical failure. CONCLUSION: According to our midterm follow-up data, MRS is an effective and a safe treatment option for radiation-naive patients with a mild degree of postprostatectomy incontinence. PMID- 26505835 TI - Urinary IP-10, MCP-1, NGAL, Cystatin-C, and KIM-1 Levels in Prenatally Diagnosed Unilateral Hydronephrosis: The Search for an Ideal Biomarker. AB - OBJECTIVE: To investigate the urinary interferon gamma-induced protein 10 (IP 10), monocyte chemotactic protein 1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), cystatin-C, and kidney injury molecule-1 (KIM-1) levels in the management of children with prenatally diagnosed unilateral hydronephrosis. MATERIALS AND METHODS: Twenty-seven children with antenatally diagnosed hydronephrosis were enrolled into the study. The controls consisted of 9 healthy children (6 boys, 3 girls; mean age: 41.77 +/- 5.30 months). Thirteen children (9 boys, 4 girls; mean age: 48.46 +/- 21.11 months) underwent pyeloplasty on follow up; the remaining 14 (13 boys, 1 girl; mean age: 36.57 +/- 14.02 months) were followed up after being diagnosed as having nonobstructive dilatation (NOD). The urinary marker levels were measured in the pyeloplasty, the NOD, and the control groups. RESULTS: The preoperative concentrations of IP-10, MCP-1, NGAL, and KIM-1 were significantly higher in the pyeloplasty group than in the control group (P = .024, P = .002, P = .032, P = .001, respectively). The urinary IP-10 and MCP-1 levels were also significantly higher in the pyeloplasty group than in the NOD group (P = .038, P = .037, respectively). There was no significant difference between the pyeloplasty group and the NOD group regarding urinary NGAL and KIM-1. In the pyeloplasty group, urinary marker levels except cystatin-C were significantly decreased in the postoperative period. CONCLUSION: A decrease in levels of IP-10, MCP-1, NGAL, and KIM-1 after pyeloplasty may be used as a predictor of surgical outcome. Additionally, IP-10 and MCP-1 were superior to NGAL and KIM-1 in predicting who required surgery. PMID- 26505837 TI - miRNAs in melanoma: a defined role in tumor progression and metastasis. AB - The crosstalk of melanoma cells with components of the microenvironment promotes malignant cell proliferation and spread to distant tissues. Although the major pathogenetic events have already been elucidated, the mechanisms that drive the metastatic behavior of tumor cells are still undefined. MicroRNAs (miRNAs) are small non-coding RNAs that control post-transcriptional gene expression through interconnected kinases upstream of functional genes involved in tumor progression. Here, we review the biological relevance of melanoma-related miRNAs and focus on their potential role in propagating signals that may cause tumor microenvironment rearrangements, as well as disablement of the immune system and melanoma cell proliferation. PMID- 26505839 TI - Rehabilitation procedures in the management of gait disorders in the elderly. AB - Gait disorders are common and very disabling in elderly people, leading to an increase of risk of falling and reductions in quality of life. So far, many clinical classifications of gait disorders in the elderly population have been proposed. Here we suggest a novel categorization of gait disorders in elderly people, which takes into account the several resources required during gait. The biomechanical constraints, movement and sensory strategies, orientation in space, control of dynamics and cognitive processing are essential to perform safely gait. Moreover, the strictly connection between gait and balance has been discussed. According to this perspective, a literature search was performed including studies investigating the rehabilitation procedures in the management of balance and gait disorders in elderly people. Training aimed at improving muscle strength and flexibility, movement strategies, sensorimotor integration and sensory reweighting processes, balance in static and dynamic conditions and cognitive strategies have been proposed as possible therapeutic approaches in elderly people affected by gait disorders. Moreover, the role of new technological devices in improving balance and gait control has been also described. A multidisciplinary and interdisciplinary approach is fundamental for the management of gait disorders in elderly people. Rehabilitation procedures should take into consideration all the potential constraints involved in gait disorders in order to select the most appropriate intervention. PMID- 26505838 TI - Site-specific conjugation of drug-like fragments to an antimiR scaffold as a strategy to target miRNAs inside RISC. AB - We synthesized a miR-122 antimiR library in which drug-like fragments were site specifically introduced to short 2'-O-methyl-RNAs. At some sites selected fragments elevated cellular antimiR activity to that of an unmodified 23mer antimiR, whereas at others the same fragments abolished activity. The potency of the antimiRs correlated with uptake into miRISC. PMID- 26505840 TI - Multiple Drug Intolerance Syndrome in an Epileptic WomanSyndrome d'intolerance medicamenteuse multiple chez une femme epileptique. AB - Multiple drug intolerance syndrome is used for patients who express adverse drug reactions to three or more drugs without a known immunological mechanism. We report a case of an epileptic woman who presented 5 different events including skin eruption, edema, cardiac arrest, and a multi-organ involvement following a non-steroidal anti-inflammatory drug, anticonvulsants, penicillin and a macrolide. PMID- 26505842 TI - Gentle Cesarean Delivery. PMID- 26505843 TI - Strategies for Surviving and Thriving as Parents in the NICU. PMID- 26505844 TI - Death and the Pregnant Woman: A True Dilemma. PMID- 26505846 TI - Retrospective Review of Nurse-Midwifery Care at a Large University Health System. AB - The purpose of the study is to characterize practice trends, outcomes, and changes over time of a full-scope midwifery service over the past 30 years from 1983 to 2013. The types of clients served and the evolution of the services provided and resulting outcomes are described as an exemplar of the changing nature of providing midwifery services in a tertiary care hospital setting. The overall data reveal that despite small increases in intervention practices, such as epidurals, inductions, and cesarean births, midwives have a commitment to providing safe, evidenced-based, woman-centered care within a collaborative practice model at a tertiary care center. The role of midwives as leaders in supporting physiologic birth in this setting and encouraging opportunities for interprofessional education and collaborative is demonstrated. PMID- 26505847 TI - Factors Related to Intimidation During Oxytocin Administration. AB - Patient's safety and quality are foremost issues in healthcare today and are often adversely influenced by communication and issues of perceived intimidation. Labor and delivery nurses are responsible for managing oxytocin infusions, but disagreements between providers and nurses related to the administration have been shown to cause tension and affect patient's care. The purpose of this study was to survey registered nurses in labor and delivery about perceived intimidation and how intimidation influenced actions and decisions. A total of 913 registered nurses who were members of the Association of Women's Health, Obstetric, and Neonatal Nurses and identified labor and delivery comprised the sample as their clinical focus. Nurses who met the inclusion criteria were invited to participate in the survey via e-mail invitation. An online survey assessing workplace intimidation by providers while managing oxytocin inductions, as well as demographic information was completed. Participants reported past issues with intimidation that influenced how they administered oxytocin. Nurses reported that past experiences with intimidation influenced their care and that they had been involved with medication errors where intimidation played a role. Organizational factors perceived supportive management, presence of an organizational code of conduct, and environment where collaboration was encouraged were associated with decreased reports of intimidation. PMID- 26505848 TI - A Systematic Review: The Utility of the Revised Version of the Score for Neonatal Acute Physiology Among Critically Ill Neonates. AB - The revised version of the Score for Neonatal Acute Physiology (SNAP-II) has been used across all birth weights and gestational ages to measure the concept of severity of illness in critically ill neonates. The SNAP-II has been operationalized in various ways across research studies. This systematic review seeks to synthesize the available research regarding the utility of this instrument, specifically on the utility of measuring severity of illness sequentially and at later time points. A systematic review was performed and identified 35 research articles that met inclusion and exclusion criteria. The majority of the studies used the SNAP-II instrument as a measure of initial severity of illness on the first day of life. Six studies utilized the SNAP-II instrument to measure severity of illness at later time points and only 2 studies utilized the instrument to prospectively measure severity of illness. Evidence to support the use of the SNAP-II at later time points and prospectively is lacking and more evidence is needed. PMID- 26505849 TI - Joseph's Story: A Case Study of Late-Onset Necrotizing Enterocolitis From Early Birth to Recovery. AB - Although necrotizing enterocolitis (NEC) is often catastrophic among premature infants, most cases occur in the first month after birth. This case study presents Joseph's story about a 24-week surviving twin who developed severe NEC at 5 months of age just days before he was to go home. The purpose of this case study report is to place Joseph and his parents' experience in the context of what is known about NEC risk factors, clinical presentation, and treatment, and then to offer recommendations to healthcare professionals to support families from NEC diagnosis to recovery. Now 5 years old, Joseph continues to manage consequences of NEC including deafness, developmental delay, multiple food allergies, and recurrent gastrointestinal challenges from short gut syndrome. Although NEC struck late and kept Joseph in the neonatal intensive care unit for 228 days, its consequences remain with this resilient child and his family. PMID- 26505850 TI - Cerebral Oxygenation and Pain of Heel Blood Sampling Using Manual and Automatic Lancets in Premature Infants. AB - Heel blood sampling is a common but painful procedure for neonates. Automatic lancets have been shown to be more effective, with reduced pain and tissue damage, than manual lancets, but the effects of lancet type on cortical activation have not yet been compared. The study aimed to compare the effects of manual and automatic lancets on cerebral oxygenation and pain of heel blood sampling in 24 premature infants with respiratory distress syndrome. Effectiveness was measured by assessing numbers of pricks and squeezes and duration of heel blood sampling. Pain responses were measured using the premature infant pain profile score, heart rate, and oxygen saturation (SpO2). Regional cerebral oxygen saturation (rScO2) was measured using near-infrared spectroscopy, and cerebral fractional tissue oxygen extraction was calculated from SpO2 and rScO. Measures of effectiveness were significantly better with automatic than with manual lancing, including fewer heel punctures (P = .009) and squeezes (P < .001) and shorter duration of heel blood sampling (P = .002). rScO2 was significantly higher (P = .013) and cerebral fractional tissue oxygen extraction after puncture significantly lower (P = .040) with automatic lancing. Premature infant pain profile scores during (P = .004) and after (P = .048) puncture were significantly lower in the automatic than in the manual lancet group. Automatic lancets for heel blood sampling in neonates with respiratory distress syndrome significantly reduced pain and enhanced cerebral oxygenation, suggesting that heel blood should be sampled routinely using an automatic lancet. PMID- 26505851 TI - Neonatal Intensive Care Nurses' Perceptions of Parental Participation in Infant Pain Management: A Comparative Focus Group Study. AB - This comparative focus group study explored nurses' experiences and perceptions regarding parental participation in infant pain management in the neonatal intensive care unit (NICU). A total of 87 nurses from 7 NICUs in Finland, Sweden, and the United States participated in focus-group interviews (n = 25). Data were analyzed using deductive and inductive thematic analysis. Nurses' experiences and perceptions varied considerably, from nurses being in control, to nurses sharing some control with parents, to nurse-parent collaboration in infant pain management. When nurses controlled pain management, parents were absent or passive. In these cases, the nurses believed this led to better pain control for infants and protected parents from emotional distress caused by infant pain. When nurses shared control with parents, they provided information and opportunities for participation. They believed parent participation was beneficial, even if it caused nurses or parents anxiety. When nurses collaborated with parents, they negotiated the optimal pain management approach for an individual infant. The collaborative approach was most evident for the nurses in the Swedish NICUs and somewhat evident in the NICUs in Finland and the United States. Further research is needed to address some nurses' perceptions and concerns and to facilitate greater consistency in the application of evidence-based best practices. PMID- 26505852 TI - My Perinatal "Bucket" List. PMID- 26505855 TI - FDG PET/CT Findings of Intracardiac Myeloid Sarcoma. AB - Myeloid sarcoma is a rare entity, and cardiac involvement is even rarer. We presented here the FDG PET/CT findings of a 66-year-old man with a 3-month history of cough and progressive dyspnea. FDG PET/CT scan demonstrated nonuniform FDG uptake in the cardiac walls and pericardium. Biopsy of the heart revealed myeloid sarcoma. In addition, bone marrow biopsy demonstrated the acute myeloid leukemia. PMID- 26505856 TI - Prognostic Implications of the SUVmax of Primary Tumors and Metastatic Lymph Node Measured by 18F-FDG PET in Patients With Uterine Cervical Cancer: A Meta analysis. AB - PURPOSE: We conducted a meta-analysis to evaluate the prognostic value of the SUVmax measured in pretreatment primary lesions and metastatic lymph nodes (LNs) on 18F-FDG PET scans in patients with uterine cervical cancer. METHODS: A systematic search of EMBASE and MEDLINE was performed using the keywords "positron emission tomography (PET)," "uterine cervical cancer," and "prognosis." Event-free survival and overall survival were evaluated as outcomes. The impact of SUVmax on survival was measured by the effect size of the hazard ratio (HR). RESULTS: Fourteen eligible studies including 1150 patients were analyzed. Patients with a high primary SUVmax showed a worse prognosis, with an HR of 2.66 (95% confidence interval [CI], 1.90-3.74; P < 0.00001) for adverse events and an HR of 2.45 (95% CI, 1.74-3.45; P < 0.00001) for death. Patients with high SUVmax in metastatic pelvic LN (PLN) showed a worse prognosis, with an HR of 2.92 (95% CI, 1.94-4.39; P < 0.00001) for adverse events and an HR of 2.66 (95% CI, 1.60 4.43; P = 0.0002) for SUVmax in PLN for death. In addition, high SUVmax in metastatic para-aortic LN was associated with a worse prognosis, with an HR of 4.41 (95% CI, 2.32-8.38; P < 0.00001) for death. CONCLUSIONS: Patients with uterine cervical cancer and a high SUVmax primary lesion, PLN, or para-aortic LN are at higher risk of adverse events or death. PMID- 26505857 TI - 99mTc-HDP SPECT With CT Myelography in a 1-Step Procedure. AB - We present the case of a 45-year-old woman with a history of multiple back surgeries to illustrate the feasibility of combining CT myelography (myeloCT) and 99mTc-HDP SPECT/CT bone scan in a 1-step procedure to realize a combined SPECT myeloCT. Myelography CT and SPECT/CT were required to assess nerve root compression and pseudarthrosis, respectively. The proposed combined acquisition protocol provides information about nervous compression as well as pseudarthrosis in a 1 examination, optimizing radiation dose and patient comfort. PMID- 26505858 TI - FDG PET/CT Findings in Multiple Splenic Amebomas (Amebic Granulomas). AB - Splenic ameboma (amebic granuloma) is rare. A 38-year-old man with a severe pneumonia due to inhalation of swimming pool water 18 months ago complained of night sweat, tiredness, and anorexia for 1 month. Abdominal ultrasound showed multiple nodules in the spleen. These nodules showed slight enhancement on enhanced CT and intense FDG uptake on PET/CT. Splenectomy was performed. Multiple splenic amebomas were confirmed by pathology. Free-living amoebae were also detected in samples of pleural effusion and blood. Splenic ameboma, although rare, should be included in the differential diagnosis with isolated focally increased FDG activity in the spleen. PMID- 26505859 TI - Endometriosis Under Estradiol Stimulation Imaged Using 18F-FDG and Its Control After Estradiol Cessation and Progesterone Hormonal Replacement. AB - Endometriosis is a frequent and benign cause of disabling abdominal pain, for which a diagnosis suspicion is clinically raised, but its confirmation necessitates a surgical exploration by laparoscopy. Foci of endometriosis proliferate under estrogen stimulation, like normal endometrium. We present a patient under estradiol stimulation for a history of endometrial cancer who underwent a PET/CT scan to assess an abdominal lesion showing a high F-FDG uptake, which normalized under progesterone hormonal replacement and cessation of estradiol. Two consecutive biopsies confirmed endometriosis. F-FDG evaluation of endometriosis under estrogen stimulation could be a promising approach to refractory endometriosis assessment. PMID- 26505860 TI - An Unusual Bone Metastasis Mimicking SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis) Syndrome on Bone Scintigraphy. AB - The costosternoclavicular region is not a common bone metastasis site, and symmetrical involvement is even rarer. Increased tracer uptake in the manubrium and sternoclavicular joints usually gives the typical "bull-horn" appearance seen in SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis). Herein, we report a case of a 47-year-old woman with a history of invasive ductal carcinoma who had undergone left radical mastectomy 3 years earlier and presented with typical increased tracer uptake in the bilateral sternocostoclavicular region resembling the so-called bull horn. The final diagnosis of metastasis from breast cancer was made histopathologically following biopsy. PMID- 26505861 TI - Marked Response to 177Lu Prostate-Specific Membrane Antigen Treatment in Patient With Metastatic Prostate Cancer. AB - We present pretreatment Ga prostate-specific membrane antigen (PSMA) PET/CT and posttreatment Lu-PSMA whole-body scintigraphy images of a 60-year-old patient with metastatic prostate cancer who is dramatically responding to Lu-PSMA treatment. PMID- 26505862 TI - 18F-FDG PET/CT Images in a Patient With Primary Chest Wall Tuberculosis Mimicking Malignant Tumor. AB - Solitary chest wall tuberculosis (TB) is rare. We report a case of primary chest wall TB in a 66-year-old woman involving the pleura and intercostal and erector spinae muscles. There was elevated FDG uptake in the right posterior chest wall. Surgery was performed, and pathology revealed inflammatory granuloma and caseous necrosis. Familiarity with 18F-FDG PET/CT images of chest wall TB could reduce possible misdiagnosis. PMID- 26505863 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF SICKLE CELL MACULOPATHY. AB - PURPOSE: To report a case of sickle cell retinopathy imaged with optical coherence tomography angiography. METHODS: Case report. RESULTS: An asymptomatic 33-year-old man with known sickle cell anemia (SS) presented for routine eye examination. Ultrawide-field fluorescein angiography confirmed areas of temporal nonperfusion without neovascularization and subtle enlargement of the foveal avascular zone in the left eye. Spectral domain optical coherence tomography showed thinning of the inner layers of the temporal macula in both eyes. Optovue split-spectrum amplitude decorrelation angiography optical coherence tomography was performed and showed reduced flow within the superficial and deep macular plexuses of each eye, most severely within the deep retinal capillary plexus. This abnormality was more extensive than could it be appreciated with conventional angiography. CONCLUSION: This report provides evidence that optical coherence tomography angiography may be more sensitive in detecting macular capillary nonperfusion than fluorescein angiography. It also provides further evidence that the ischemic vasculopathy of sickle cell retinopathy preferentially affects the deep capillary plexus. PMID- 26505864 TI - Ozone therapy for treating foot ulcers in people with diabetes. AB - BACKGROUND: It has been reported that ozone therapy might be helpful in treating foot ulcers in people with diabetes mellitus (DM). OBJECTIVES: To assess the effects of ozone therapy on the healing of foot ulcers in people with DM. SEARCH METHODS: In March 2015 we searched: The Cochrane Wounds Group Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations), Ovid EMBASE, EBSCO CINAHL, Science Citation Index, Chinese Biomedical Literature Database and The Chinese Clinical Registry. There were no restrictions based on language, date or study setting. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared ozone therapy with sham ozone therapy or any other interventions for foot ulcers in people with DM, irrespective of publication date or language. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened all retrieved citations, selected relevant citations and extracted data. Disagreements were resolved by discussion with a third reviewer. The methodological quality of included studies and the evidence level of outcomes were assessed using the Cochrane risk of bias tool and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach respectively. Data were expressed using risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with their 95% confidence interval (95% CI). Review Manager (RevMan) software was used to analyse the data. MAIN RESULTS: Three studies (212 participants) were included in this review. The overall risk of bias was high for two trials and unclear for one.One trial (101 participants) compared ozone treatment with antibiotics for foot ulcers in people with DM. The study had a follow-up period of 20 days. This study showed that ozone treatment was associated with a greater reduction in ulcer area from baseline to the end of the study than treatment with antibiotics (MD -20.54 cm(2), 95% CI -20.61 to -20.47), and a shorter duration of hospitalisation (MD -8.00 days, 95% CI -14.17 to -1.83), but did not appear to affect the number of ulcers healed over 20 days (RR 1.10, 95% CI 0.87 to 1.40). No side effects were observed in either group.The other two trials (111 participants) compared ozone treatment plus usual care with usual care for foot ulcers in people with DM. The meta-analysis results did not show evidence of a difference between groups for the outcomes of reduction of ulcer area (MD -2.11 cm(2), 95% CI -5.29 to 1.07), the number of ulcers healed (RR 1.69, 95% CI 0.90 to 3.17), adverse events (RR 2.27, 95% CI 0.48 to 10.79), or amputation rate (RR 2.73, 95%CI 0.12, 64.42). AUTHORS' CONCLUSIONS: The available evidence was three small RCTs with unclear methodology, so we are unable to draw any firm conclusions regarding the effectiveness of ozone therapy for foot ulcers in people with DM. PMID- 26505865 TI - Facile synthesis of enzyme-embedded magnetic metal-organic frameworks as a reusable mimic multi-enzyme system: mimetic peroxidase properties and colorimetric sensor. AB - This work reports a facile and easily-achieved approach for enzyme immobilization by embedding glucose oxidase (GOx) in magnetic zeolitic imidazolate framework 8 (mZIF-8) via a de novo approach. As a demonstration of the power of such materials, the resulting GOx embedded mZIF-8 (mZIF-8@GOx) was utilized as a colorimetric sensor for rapid detection of glucose. This method was constructed on the basis of metal-organic frameworks (MOFs), which possessed very fascinating peroxidase-like properties, and the cascade reaction for the visual detection of glucose was combined into one step through the mZIF-8@GOx based mimic multi enzyme system. After characterization by electron microscopy, X-ray diffraction, nitrogen sorption, fourier transform infrared spectroscopy and vibrating sample magnetometry, the as-prepared mZIF-8@GOx was confirmed with the robust core-shell structure, the monodisperse nanoparticle had an average diameter of about 200 nm and displayed superparamagnetism with a saturation magnetization value of 40.5 emu g(-1), it also exhibited a large surface area of 396.10 m(2) g(-1). As a peroxidase mimic, mZIF-8 was verified to be highly stable and of low cost, and showed a strong affinity towards H2O2. Meanwhile, the mZIF-8 embedded GOx also exhibited improved activity, stability and greatly enhanced selectivity in glucose detection. Moreover, the mZIF-8@GOx had excellent recyclability with high activity (88.7% residual activity after 12 times reuse). PMID- 26505867 TI - Assembly and stabilization of {E(cyclo-P3)2} (E = Sn, Pb) as a bridging ligand spanning two triaryloxyniobium units. AB - Complexes (THF)0-2E[P3Nb(ODipp)3]2 (E = Sn, Pb; Dipp = 2,6-(i)Pr2C6H3) were isolated (>90%) from the salt metathesis of [Na(THF)3][P3Nb(ODipp)3] with E(2+) salts. The reaction of (THF)Sn[P3Nb(ODipp)3]2 with pyridine-N-oxide was investigated as a method to deposit a new SnP6 phase. Additionally, the neutral complex P3Nb(ODipp)2(py)2 (py = pyridine) was prepared from [Na(THF)3][P3Nb(ODipp)3] in the presence of pyridine and salts of coordinating cations (Mg(II), Sn(II), Pb(II), Ge(II), Hg(II) and Ag(I)). P3Nb(ODipp)2(py)2 was found to successfully produce AsP3 upon treatment with AsCl3. The characterization of complexes (THF)0-1Sn[P3Nb(ODipp)3]2, (THF)2Pb[P3Nb(ODipp)3]2 and P3Nb(ODipp)2(py)2, including their solid state structures, is discussed. PMID- 26505869 TI - Patterns of Performance on the Modified Cued Recall Test in Spanish Adults With Down Syndrome With and Without Dementia. AB - The assessment of memory decline in people with intellectual disability (ID) is more difficult than in the general population, due to a lack of appropriate instruments and to preexisting cognitive impairment. The aim of this study was to describe performance of healthy adults with Down syndrome (healthy-DS; prospectively cohort) on a Spanish version of the modified Cued Recall Test (mCRT). We also recruited retrospectively a cohort of DS subjects with Dementia of the Alzheimer's Type (DS-DAT). Healthy-DS obtained higher scores on free recall and total score than DS-DAT. Age was the main factor associated with decreasing mCRT scores. The mCRT was useful in DS subjects with ID at the upper end of the spectrum or ID in the middle range of the spectrum, and discriminated well between DS subjects with and without DAT. PMID- 26505868 TI - "Global" visual training and extent of transfer in amblyopic macaque monkeys. AB - Perceptual learning is gaining acceptance as a potential treatment for amblyopia in adults and children beyond the critical period. Many perceptual learning paradigms result in very specific improvement that does not generalize beyond the training stimulus, closely related stimuli, or visual field location. To be of use in amblyopia, a less specific effect is needed. To address this problem, we designed a more general training paradigm intended to effect improvement in visual sensitivity across tasks and domains. We used a "global" visual stimulus, random dot motion direction discrimination with 6 training conditions, and tested for posttraining improvement on a motion detection task and 3 spatial domain tasks (contrast sensitivity, Vernier acuity, Glass pattern detection). Four amblyopic macaques practiced the motion discrimination with their amblyopic eye for at least 20,000 trials. All showed improvement, defined as a change of at least a factor of 2, on the trained task. In addition, all animals showed improvements in sensitivity on at least some of the transfer test conditions, mainly the motion detection task; transfer to the spatial domain was inconsistent but best at fine spatial scales. However, the improvement on the transfer tasks was largely not retained at long-term follow-up. Our generalized training approach is promising for amblyopia treatment, but sustaining improved performance may require additional intervention. PMID- 26505870 TI - Randomized Controlled Trial to Evaluate an Abuse Prevention Curriculum for Women and Men With Intellectual and Developmental Disabilities. AB - This study was designed (a) to assess the impact of the ESCAPE-DD curriculum on the decision-making skills of adults with intellectual and developmental disabilities (IDD) in hypothetical situations of abuse, (b) to examine the role of problem awareness, and (c) to identify factors associated with posttest decision-making performance. Fifty-eight women and men with IDD were randomly assigned to an intervention group or a wait-list control group. Participants who experienced ESCAPE-DD made significantly greater gains on measures of overall effective decision making and safe-now effective decision-making relative to participants in the control group. Problem awareness was related to decision making, but it did not improve as a result of the intervention. Implications of the findings for future curriculum-development efforts are discussed. PMID- 26505871 TI - Have Racial and Ethnic Disparities in the Quality of Health Care Relationships Changed for Children With Developmental Disabilities and ASD? AB - The aim of this study was to determine if racial and ethnic disparities in the quality of provider interaction have changed between 2006 and 2010 for children with developmental disabilities and autism spectrum disorders (ASD). Data from the 2005/2006 and 2009/2010 National Survey of Children With Special Health Care Needs were analyzed. Results show that racial and ethnic disparities in the quality of provider interactions were substantial in both 2005/2006 and 2009/2010. Black and Latino parents were significantly less likely than White parents to report that their provider spent enough time with their child and was sensitive to the family's values. Racial and ethnic disparities in health care quality were found to be unchanged over time. Research and policy implications are discussed. PMID- 26505872 TI - The Relative Risk of Divorce in Parents of Children With Developmental Disabilities: Impacts of Lifelong Parenting. AB - We prospectively examined the risk of divorce in 190 parents of children with developmental disabilities compared to 7,251 parents of children without disabilities based on a random sample drawn from the community and followed longitudinally for over 50 years. A significant interaction between the parental group status and number of children was found: In the comparison group, having a larger number of children was related to an increased risk of divorce, whereas the number of children did not increase divorce risk among parents of children with developmental disabilities. PMID- 26505873 TI - Reasoning About Trust Among Individuals With Williams Syndrome. AB - The present study examines whether individuals with Williams syndrome (WS) might indiscriminately trust in others, as is suggested by their strong tendency to approach and interact with strangers. To assess this possibility, adults with WS (N=22) and typical development (N=25) were asked to reason about the trustworthiness of people who lie to avoid getting in trouble versus to avoid hurting others' feelings. Findings indicated that participants with WS distrusted both types of liars and made little distinction between them. These results suggest that the high level of social approach behavior in individuals with WS cannot be explained in terms of indiscriminate trust. PMID- 26505874 TI - Testing Math or Testing Language? The Construct Validity of the KeyMath-Revised for Children With Intellectual Disability and Language Difficulties. AB - Although it is often assumed that mathematics ability alone predicts mathematics test performance, linguistic demands may also predict achievement. This study examined the role of language in mathematics assessment performance for children with intellectual disability (ID) at less severe levels, on the KeyMath-Revised Inventory (KM-R) with a sample of 264 children, in grades 2-5. Using confirmatory factor analysis, the hypothesis that the KM-R would demonstrate discriminant validity with measures of language abilities in a two-factor model was compared to two plausible alternative models. Results indicated that KM-R did not have discriminant validity with measures of children's language abilities and was a multidimensional test of both mathematics and language abilities for this population of test users. Implications are considered for test development, interpretation, and intervention. PMID- 26505877 TI - Unusual dynamics of concentration fluctuations in solutions of weakly attractive globular proteins. AB - The globular protein gammaB-crystallin exhibits a complex phase behavior, where liquid-liquid phase separation characterized by a critical volume fraction phic = 0.154 and a critical temperature Tc = 291.8 K coexists with dynamical arrest on all length scales at volume fractions around phi ~ 0.3-0.35, and an arrest line that extends well into the unstable region below the spinodal. However, although the static properties such as the osmotic compressibility and the static correlation length are in quantitative agreement with predictions for binary liquid mixtures, this is not the case for the dynamics of concentration fluctuations described by the dynamic structure factor S(q,t). Using a combination of dynamic light scattering and neutron spin echo measurements, we demonstrate that the competition between critical slowing down and dynamical arrest results in a much more complex wave vector dependence of S(q,t) than previously anticipated. PMID- 26505878 TI - The DNAJB1-PRKACA chimera: Candidate biomarker and therapeutic target for fibrolamellar carcinomas. PMID- 26505881 TI - Molecular Characterization and Pathogenesis of Intraductal Papillary Mucinous Neoplasms of the Pancreas. AB - Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are noninvasive neoplasms which occur in the main pancreatic duct or its major branches. IPMNs have an important meaning in the clinic and in research since they represent around 20% of all resected pancreatic neoplasms. Morphologically, branch duct, main duct and mixed-type IPMNs can be distinguished. Histologically, they can be divided into gastric, intestinal, pancreatobiliary and oncocytic type. There are different mutations in genes such as KRAS, GNAS, RNF43 and p53. The expression of miRNAs is specific to IPMNs; altogether, 14 miRNAs have been identified so far which are differently expressed in all IPMNs in contrast to normal pancreatic tissue. It has also been observed that methylation levels can be altered in IPMNs. This review summarizes the molecular characteristics of IPMNs of the pancreas and presents currently known markers. PMID- 26505880 TI - Structurally divergent lysophosphatidic acid acyltransferases with high selectivity for saturated medium chain fatty acids from Cuphea seeds. AB - Lysophosphatidic acid acyltransferase (LPAT) catalyzes acylation of the sn-2 position on lysophosphatidic acid by an acyl CoA substrate to produce the phosphatidic acid precursor of polar glycerolipids and triacylglycerols (TAGs). In the case of TAGs, this reaction is typically catalyzed by an LPAT2 from microsomal LPAT class A that has high specificity for C18 fatty acids containing Delta9 unsaturation. Because of this specificity, the occurrence of saturated fatty acids in the TAG sn-2 position is infrequent in seed oils. To identify LPATs with variant substrate specificities, deep transcriptomic mining was performed on seeds of two Cuphea species producing TAGs that are highly enriched in saturated C8 and C10 fatty acids. From these analyses, cDNAs for seven previously unreported LPATs were identified, including cDNAs from Cuphea viscosissima (CvLPAT2) and Cuphea avigera var. pulcherrima (CpuLPAT2a) encoding microsomal, seed-specific class A LPAT2s and a cDNA from C. avigera var. pulcherrima (CpuLPATB) encoding a microsomal, seed-specific LPAT from the bacterial-type class B. The activities of these enzymes were characterized in Camelina sativa by seed-specific co-expression with cDNAs for various Cuphea FatB acyl-acyl carrier protein thioesterases (FatB) that produce a variety of saturated medium-chain fatty acids. CvLPAT2 and CpuLPAT2a expression resulted in accumulation of 10:0 fatty acids in the Camelina sativa TAG sn-2 position, indicating a 10:0 CoA specificity that has not been previously described for plant LPATs. CpuLPATB expression generated TAGs with 14:0 at the sn-2 position, but not 10:0. Identification of these LPATs provides tools for understanding the structural basis of LPAT substrate specificity and for generating altered oil functionalities. PMID- 26505879 TI - Honokiol sensitizes breast cancer cells to TNF-alpha induction of apoptosis by inhibiting Nur77 expression. AB - BACKGROUND AND PURPOSE: The orphan nuclear receptor Nur77 is implicated in the survival and apoptosis of cancer cells. The purpose of this study was to determine whether and how Nur77 serves to mediate the effect of the inflammatory cytokine TNF-alpha in cancer cells and to identify and characterize new agents targeting Nur77 for cancer therapy. EXPERIMENTAL APPROACH: The effects of TNF alpha on the expression and function of Nur77 were studied using in vitro and in vivo models. Nur77 expression was evaluated in tumour tissues from breast cancer patients. The anticancer effects of honokiol and its mechanism of action were assessed by in vitro, cell-based and animal studies. KEY RESULTS: TNF-alpha rapidly and potently induced the expression of Nur77 in breast cancer cells through activation of IkappaB kinase and JNK. Knocking down Nur77 resulted in TNF alpha-dependent apoptosis, while ectopic Nur77 expression in MCF-7 cells promoted their growth in animals. Levels of Nur77 were higher in tumour tissues than the corresponding tissues surrounding the tumour in about 50% breast cancer patients studied. Our in vitro and animal studies also identified honokiol as an effective sensitizer of TNF-alpha-induced apoptosis by inhibiting TNF-alpha-induced Nur77 mRNA expression, which could be attributed to its interference of TNFR1's interaction with receptor-interacting protein 1 (RIPK1). CONCLUSIONS AND IMPLICATIONS: TNF-alpha-induced Nur77 serves as a survival factor to attenuate the death effect of TNF-alpha in cancer cells. With its proven human safety profile, honokiol represents a promising agent that warrants further clinical development. PMID- 26505882 TI - Weak Delocalization in Graphene on a Ferromagnetic Insulating Film. AB - Graphene has been predicted to develop a magnetic moment by proximity effect when placed on a ferromagnetic film, a promise that could open exciting possibilities in the fields of spintronics and magnetic data recording. In this work, the interplay between the magnetoresistance of graphene and the magnetization of an underlying ferromagnetic insulating film is studied in detail. A clear correlation between both magnitudes is observed but through a careful modeling of the magnetization and the weak localization measurements, that such correspondence can be explained by the effects of the magnetic stray fields arising from the ferromagnetic insulator is found. The results emphasize the complexity arising at the interface between magnetic and 2D materials. PMID- 26505884 TI - Supersaturation and Precipitation of Posaconazole Upon Entry in the Upper Small Intestine in Humans. AB - The purpose of this study was to explore gastrointestinal dissolution, supersaturation and precipitation of the weakly basic drug posaconazole in humans, and to assess the impact of formulation pH and type on these processes. In a cross-over study, two posaconazole suspensions (40 mg dispersed in 240 mL water at pH 1.6 and pH 7.1, respectively) were intragastrically administered; subsequently, gastric and duodenal fluids were aspirated. In parallel, blood samples were collected. Additionally, posaconazole was intragastrically administered as a solution (20 mg in 240 mL water, pH 1.6). When posaconazole was administered as an acidified suspension, supersaturated duodenal concentrations of posaconazole were observed for approximately 45 min. However, extensive intestinal precipitation was observed. Administration of the neutral suspension resulted in subsaturated concentrations with a mean duodenal AUC0-120 min and Cmax being approximately twofold lower than for the acidified suspension. The mean plasma AUC0-8 h of posaconazole was also twofold higher following administration of the acidified suspension. Similar to the acidified suspension, significant intestinal precipitation (up to 92%) was observed following intragastric administration of the posaconazole solution. This study demonstrated for the first time the gastrointestinal behavior of a weakly basic drug administered in different conditions, and its impact on systemic exposure. PMID- 26505883 TI - Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells. AB - BACKGROUND/AIMS: Histone deacetylases (HDACs) modulate lysine acetylation on histones and are frequently deregulated in cancer. HDAC inhibitors with potent anti-tumour effects have been developed and are now being tested in clinical trials. The aim of this study was to investigate the effects of valproic acid (VPA), an inhibitor of class I and class IIa HDACs, on neuroendocrine tumour (NET) cell growth. METHODS: Three NET cell lines, GOT1 (small intestinal), KRJ-I (small intestinal), and BON (pancreatic), were treated with VPA and examined with respect to cell viability, cell cycle arrest, apoptosis, and global transcriptional response. RESULTS: We found that VPA induced a dose-dependent growth inhibition of NET cells in vitro, which was mainly due to activation of extrinsic and intrinsic apoptotic pathways. VPA induced a major transcriptional response by altering the expression of 16-19% of the protein-coding genes in NET cell lines. Pathway analysis allowed the prediction of alterations in key regulatory pathways, e.g. activation of TGF-beta1, FOXO3, p53 signalling, and inhibition of MYC signalling. Analysis of GOT1 xenografts showed reduced growth and reduced Ki-67 index, as well as an increase in apoptosis and necrosis after VPA treatment. CONCLUSIONS: We found that VPA treatment has a cytotoxic effect on NET cells of intestinal and pancreatic origin. There are several mechanisms by which VPA kills NET cells, which suggests the possibility of combination therapy. We propose that epigenetic therapy with HDAC inhibitors should be evaluated further in patients with NET disease. PMID- 26505885 TI - Recent Advances in Upconversion Nanoparticles-Based Multifunctional Nanocomposites for Combined Cancer Therapy. AB - Lanthanide-doped upconversion nanoparticles (UCNPs) have the ability to generate ultraviolet or visible emissions under continuous-wave near-infrared (NIR) excitation. Utilizing this special luminescence property, UCNPs are approved as a new generation of contrast agents in optical imaging with deep tissue-penetration ability and high signal-to-noise ratio. The integration of UCNPs with other functional moieties can endow them with highly enriched functionalities for imaging-guided cancer therapy, which makes composites based on UCNPs emerge as a new class of theranostic agents in biomedicine. Here, recent progress in combined cancer therapy using functional nanocomposites based on UCNPs is reviewed. Combined therapy referring to the co-delivery of two or more therapeutic agents or a combination of different treatments is becoming more popular in clinical treatment of cancer because it generates synergistic anti-cancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance through different mechanisms of action. Here, the recent advances of combined therapy contributed by UCNPs-based nanocomposites on two main branches are reviewed: i) photodynamic therapy and ii) chemotherapy, which are the two most widely adopted therapies of UCNPs-based composites. The future prospects and challenges in this emerging field will be also discussed. PMID- 26505886 TI - Endobronchial plasmacytoma in patient with multiple myeloma. AB - Endobronchial plasmacytoma is a rare manifestation of extramedullary plasmacytoma. A 49-year-old woman with a history of multiple myeloma consulted to our pulmonary service with progressive dyspnoea and cough and abnormal chest X ray. A lesion measuring 6 * 5 cm in size existed in anterior baseline of the right lung's lower lobe in thoracic computed tomography in addition to right bronchial narrowing and atelectasis distal in lesions. Diagnostic bronchoscopy was performed previously for the obstruction and biopsy was taken from the lesion in the right middle lobe bronchus. Endobronchial biopsies showed extensive tumour infiltration with plasmocytoid cells. Immunohistochemistry was positive CD138 and Lamda. Microscopic and immunohistochemical findings supported the diagnosis of extramedullary endobronchial plasmacytoma. PMID- 26505887 TI - Divergent response profile in activated cord blood T cells from first-born child implies birth-order-associated in utero immune programming. AB - BACKGROUND: First-born children are at higher risk of developing a range of immune-mediated diseases. The underlying mechanism of 'birth-order effects' on disease risk is largely unknown, but in utero programming of the child's immune system may play a role. OBJECTIVE: We studied the association between birth order and the functional response of stimulated cord blood T cells. METHOD: Purified cord blood T cells were polyclonally activated with anti-CD3-/anti-CD28-coated beads in a subgroup of 28 children enrolled in the COPSAC2010 birth cohort. Expression levels of seven activation markers on helper and cytotoxic T cells as well as the percentage of CD4(+) CD25(+) T cells were assessed by flow cytometry. Production of IFN-gamma, TNF-alpha, IL-17, IL-4, IL-5, IL-13, and IL-10 was measured in the supernatants. RESULTS: IL-10 secretion (P = 0.007) and CD25 expression on CD4(+) helper T cells (P = 0.0003) in the activated cord blood T cells were selectively reduced in first-born children, while the percentage of circulating CD4(+) CD25(+) cord blood T cells was independent of birth order. CONCLUSION: First-born infants display a reduced anti-inflammatory profile in T cells at birth. This possible in utero 'birth-order' T-cell programming may contribute to later development of immune-mediated diseases by increasing overall immune reactivity in first-born children as compared to younger siblings. PMID- 26505888 TI - Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. AB - OBJECTIVE: Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations in DEPDC5 as a cause of familial focal epilepsy. In this study, we investigated whether mutations in the mammalian target of rapamycin (mTOR) regulators, NPRL2 and NPRL3, also contribute to cases of focal epilepsy. METHODS: We used targeted capture and next-generation sequencing to analyze 404 unrelated probands with focal epilepsy. We performed exome sequencing on two families with multiple members affected with focal epilepsy and linkage analysis on one of these. RESULTS: In our cohort of 404 unrelated focal epilepsy patients, we identified five mutations in NPRL2 and five in NPRL3. Exome sequencing analysis of two families with focal epilepsy identified NPRL2 and NPRL3 as the top candidate-causative genes. Some patients had focal epilepsy associated with brain malformations. We also identified 18 new mutations in DEPDC5. INTERPRETATION: We have identified NPRL2 and NPRL3 as two new focal epilepsy genes that also play a role in the mTOR-signaling pathway. Our findings show that mutations in GATOR1 complex genes are the most significant cause of familial focal epilepsy identified to date, including cases with brain malformations. It is possible that deregulation of cellular growth control plays a more important role in epilepsy than is currently recognized. PMID- 26505889 TI - Oxidative Damage Does Not Occur in Striped Hamsters Raising Natural and Experimentally Increased Litter Size. AB - Life-history theory assumes that animals can balance the allocation of limited energy or resources to the competing demands of growth, reproduction and somatic maintenance, while consequently maximizing their fitness. However, somatic damage caused by oxidative stress in reproductive female animals is species-specific or is tissue dependent. In the present study, several markers of oxidative stress (hydrogen peroxide, H2O2 and malonadialdehyde, MDA) and antioxidant (catalase, CAT and total antioxidant capacity, T-AOC) were examined in striped hamsters during different stages of reproduction with experimentally manipulated litter size. Energy intake, resting metabolic rate (RMR), and mRNA expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) and UCP3 in skeletal muscle were also examined. H2O2 and MDA levels did not change in BAT and liver, although they significantly decreased in skeletal muscle in the lactating hamsters compared to the non-reproductive group. However, H2O2 levels in the brain were significantly higher in lactating hamsters than non-reproductive controls. Experimentally increasing litter size did not cause oxidative stress in BAT, liver and skeletal muscle, but significantly elevated H2O2 levels in the brain. CAT activity of liver decreased, but CAT and T-AOC activity of BAT, skeletal muscle and the brain did not change in lactating hamsters compared to non-reproductive controls. Both antioxidants did not change with the experimentally increasing litter size. RMR significantly increased, but BAT UCP1 mRNA expression decreased with the experimentally increased litter size, suggesting that it was against simple positive links between metabolic rate, UCP1 expression and free radicals levels. It may suggest that the cost of reproduction has negligible effect on oxidative stress or even attenuates oxidative stress in some active tissues in an extensive range of animal species. But the increasing reproductive effort may cause oxidative stress in the brain, indicating that oxidative stress in response to reproduction is tissue dependent. These findings provide partial support for the life-history theory. PMID- 26505890 TI - Biosorption of Cadmium and Manganese Using Free Cells of Klebsiella sp. Isolated from Waste Water. AB - In the present study, we evaluated a bacterium that was isolated from waste water for its ability to take up cadmium and manganese. The strain, identified both biochemically and by its 16S rRNA gene sequence as Klebsiella, was named Yangling I2 and was found to be highly resistant to heavy metals. Surface characterization of the bacterium via SEM revealed gross morphological changes, with cells appearing as biconcave discs after metal exposure rather than their typical rod shape. The effects of pH, temperature, heavy metal concentration, agitation and biomass concentration on the uptake of Cd(II) and Mn(II) was measured using atomic absorption spectrophotometry. The results showed that the biosorption was most affected by pH and incubation temperature, being maximized at pH 5.0 and 30 degrees C, with absorption capacities of 170.4 and 114.1 mg/g for Cd(II) and Mn(II), respectively. Two models were investigated to compare the cells' capacity for the biosorption of Cd and Mn, and the Langmuir model based on fuzzy linear regression was found to be close to the observed absorption curves and yield binding constants of 0.98 and 0.86 for Cd and Mn, respectively. This strain of Klebsiella has approximately ten times the absorption capacity reported for other strains and is promising for the removal of heavy metals from waste water. PMID- 26505891 TI - Inflammatory cytokines induce specific time- and concentration-dependent MicroRNA release by chondrocytes, synoviocytes, and meniscus cells. AB - In knee osteoarthritis (OA), concentrations of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha increase in joint tissues and synovial fluid which incite a catabolic cascade and further the progression of OA. Several microRNAs (miRNA) have been associated with apoptosis (miR-16), inflammation (miR-22, miR 146a), and matrix degradation (miR-140, miR-27b) in developed OA or its symptoms. In this study, the time- and concentration-dependent nature of cellular and extracellular miRNAs in synoviocytes, meniscus cells, and chondrocytes as influenced by inflammatory cytokines was investigated. For time-dependent studies, three cell types were stimulated with 10 ng/ml IL-1beta or 50 ng/ml TNF alpha for 8, 16, and 24 h. For concentration-dependent studies, chondrocytes were stimulated with a higher level of IL-1beta (20 ng/ml) or TNF-alpha (100 ng/ml) for 8 h. Cellular and extracellular expressions of miR-22, miR-16, miR-146a, miR 27b, and miR-140 were analyzed by RT-PCR. Time-dependent cellular miRNA expressions were similar across the three cell types with miR-146a significantly up-regulated and miR-27b significantly down-regulated at all time points. However, chondrocytes exhibited a unique extracellular miRNA profile with an increased release rate of miR-27b at 24 h. Our findings support further research into the characterization of miRNAs in synovial fluid for the development of early detection strategies of OA or cartilage injury. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:779-790, 2016. PMID- 26505892 TI - Maternal Chlamydia trachomatis Infections and Preterm Births in a University Hospital in Vitoria, Brazil. AB - BACKGROUND: Preterm birth (PTB) is a major determinant of neonatal morbimortality with adverse consequences for health. The causes are multifactorial, with intrauterine infection probably explaining most of these outcomes. It is believed that infection with Chlamydia trachomatis (CT) is also involved in PTB and premature rupture of membranes. OBJECTIVES: To evaluate the prevalence of and associated factors for CT among cases of PTB attended at a University Hospital in Vitoria, Brazil. METHODS: A cross-sectional study performed among parturient who had preterm birth from June 2012 to August 2013 in Vitoria, Brazil. Participants answered a questionnaire including demographic, behavioral, and clinical data. A sample of urine was collected and screened for CT using polymerase chain reaction. Chi-square tests were used for proportion differences and Student's-t tests and variance analysis were used for testing differences between mean values. Odds ratio was used as a measure of association with a 95% confidence interval. RESULTS: The prevalence of PTB during the period of the study was 26% and the prevalence of CT among them was 13.9%. A total of 31.6% pregnant women were younger than 25 years old and women infected by CT were even younger than women not infected by CT (p = 0.022). Most of them (76.2%) were married or had a living partner, and CT infection was more frequent among the single ones (p = 0.018); 16.7% of women reported their first sexual intercourse under 14 years old. The causes of prematurity were maternal-fetal in 40.9%; rupture of the membranes in 29.7% and premature labor in 29.4%. In multivariate analysis, being married was a protective factor for infection [OR = 0.48 (95%CI:0.24-0.97)]. None of the other characteristics were associated with CT infection. CONCLUSIONS: This study shows a high prevalence of CT infection among parturient who have preterm birth. This high prevalence highlight the need for defining screening strategies focused on young pregnant women in Brazil. PMID- 26505893 TI - Quercetin Attenuates Inflammatory Responses in BV-2 Microglial Cells: Role of MAPKs on the Nrf2 Pathway and Induction of Heme Oxygenase-1. AB - A large group of flavonoids found in fruits and vegetables have been suggested to elicit health benefits due mainly to their anti-oxidative and anti-inflammatory properties. Recent studies with immune cells have demonstrated inhibition of these inflammatory responses through down-regulation of the pro-inflammatory pathway involving NF-kappaB and up-regulation of the anti-oxidative pathway involving Nrf2. In the present study, the murine BV-2 microglial cells were used to compare anti-inflammatory activity of quercetin and cyanidin, two flavonoids differing by their alpha, beta keto carbonyl group. Quercetin was 10 folds more potent than cyanidin in inhibition of lipopolysaccharide (LPS)-induced NO production as well as stimulation of Nrf2-induced heme-oxygenase-1 (HO-1) protein expression. In addition, quercetin demonstrated enhanced ability to stimulate HO 1 protein expression when cells were treated with LPS. In an attempt to unveil mechanism(s) for quercetin to enhance Nrf2/HO-1 activity under endotoxic stress, results pointed to an increase in phospho-p38MAPK expression upon addition of quercetin to LPS. In addition, pharmacological inhibitors for phospho-p38MAPK and MEK1/2 for ERK1/2 further showed that these MAPKs target different sites of the Nrf2 pathway that regulates HO-1 expression. However, inhibition of LPS-induced NO by quercetin was not fully reversed by TinPPIX, a specific inhibitor for HO-1 activity. Taken together, results suggest an important role of quercetin to regulate inflammatory responses in microglial cells and its ability to upregulate HO-1 against endotoxic stress through involvement of MAPKs. PMID- 26505894 TI - The Role of Platelets and epsilon-Aminocaproic Acid in Arthrogryposis, Renal Dysfunction, and Cholestasis (ARC) Syndrome Associated Hemorrhage. AB - Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a rare disorder associated with platelet abnormalities resembling gray platelet syndrome. Affected patients have normal platelet numbers but abnormal morphology and function. Bleeding symptomatology ranges from postprocedural to spontaneous life-threatening hemorrhage. We report a patient with ARC syndrome and compound heterozygous mutations in VPS33B (vacuolar protein sorting 33B) who presented with significant bleeding requiring numerous admissions and transfusions. She was treated with prophylactic platelet transfusions and epsilon-aminocaproic acid. This was well-tolerated and significantly decreased transfusion requirements and admissions for bleeding. Our experience provides support for consideration of prophylactic measures in these patients as well as the possibility of using prophylaxis in related disorders. PMID- 26505895 TI - Comparison of Transanal Endoscopic Microsurgery and Total Mesorectal Excision in the Treatment of T1 Rectal Cancer: A Meta-Analysis. AB - BACKGROUND: Transanal endoscopic microsurgery (TEM) for the treatment of early stage rectal cancer has attracted attention due to its advantages of reduced surgical trauma, fewer complications, low operative mortality, rapid postoperative recovery and short hospital stay. However, there are still significant controversies regarding TEM for the treatment of rectal cancer, mainly related to the prognosis associated with this method. OBJECTIVE: This study sought to compare the efficacy of transanal endoscopic microsurgery (TEM) and total mesorectal excision (TME) for the treatment of T1 rectal cancer. METHODS: We searched the Cochrane Library, PubMed, Embase and CNKI databases. Based on the Cochrane Handbook for Systematic Reviews, we screened the trials, evaluated the quality and extracted the data. RESULTS: One randomized controlled trial (RCT) and six non-randomized controlled clinical trials (CCTs) were included in the meta-analysis (a total of 860 rectal cancer patients were included; 303 patients were treated with TEM, and 557 patients were treated with TME). Analysis revealed that all seven studies reported local recurrence rates, and there was a significant difference between the TEM and TME groups [odds ratio (OR) = 4.62, 95% confidence interval (CI) (2.03, 10.53), P = 0.0003]. A total of five studies reported distant metastasis rates, and there was no significant difference between the TEM and TME groups [OR = 0.74, 95%CI (0.32, 1.72), P = 0.49]. A total of six studies reported postoperative overall survival of the patients, and there was no significant difference between the TEM and TME groups [OR = 0.87, 95%CI(0.55, 1.38), P = 0.55]. In addition, two studies reported the postoperative disease-free survival rates of patients, and there was no significant difference between the TEM and TME groups [OR = 1.12, 95%CI (0.31, 4.12), P = 0.86]. CONCLUSIONS: For patients with T1 rectal cancer, the distant metastasis, overall survival and disease-free survival rates did not differ between the TEM and TME groups, although the local recurrence rate after TEM was higher than that after TME. PMID- 26505896 TI - C-di-GMP Regulates Motile to Sessile Transition by Modulating MshA Pili Biogenesis and Near-Surface Motility Behavior in Vibrio cholerae. AB - In many bacteria, including Vibrio cholerae, cyclic dimeric guanosine monophosphate (c-di-GMP) controls the motile to biofilm life style switch. Yet, little is known about how this occurs. In this study, we report that changes in c di-GMP concentration impact the biosynthesis of the MshA pili, resulting in altered motility and biofilm phenotypes in V. cholerae. Previously, we reported that cdgJ encodes a c-di-GMP phosphodiesterase and a DeltacdgJ mutant has reduced motility and enhanced biofilm formation. Here we show that loss of the genes required for the mannose-sensitive hemagglutinin (MshA) pilus biogenesis restores motility in the DeltacdgJ mutant. Mutations of the predicted ATPase proteins mshE or pilT, responsible for polymerizing and depolymerizing MshA pili, impair near surface motility behavior and initial surface attachment dynamics. A DeltacdgJ mutant has enhanced surface attachment, while the DeltacdgJmshA mutant phenocopies the high motility and low attachment phenotypes observed in a DeltamshA strain. Elevated concentrations of c-di-GMP enhance surface MshA pilus production. MshE, but not PilT binds c-di-GMP directly, establishing a mechanism for c-di-GMP signaling input in MshA pilus production. Collectively, our results suggest that the dynamic nature of the MshA pilus established by the assembly and disassembly of pilin subunits is essential for transition from the motile to sessile lifestyle and that c-di-GMP affects MshA pilus assembly and function through direct interactions with the MshE ATPase. PMID- 26505897 TI - Upgrading a piped water supply from intermittent to continuous delivery and association with waterborne illness: a matched cohort study in urban India. AB - BACKGROUND: Intermittent delivery of piped water can lead to waterborne illness through contamination in the pipelines or during household storage, use of unsafe water sources during intermittencies, and limited water availability for hygiene. We assessed the association between continuous versus intermittent water supply and waterborne diseases, child mortality, and weight for age in Hubli-Dharwad, India. METHODS AND FINDINGS: We conducted a matched cohort study with multivariate matching to identify intermittent and continuous supply areas with comparable characteristics in Hubli-Dharwad. We followed 3,922 households in 16 neighborhoods with children <5 y old, with four longitudinal visits over 15 mo (Nov 2010-Feb 2012) to record caregiver-reported health outcomes (diarrhea, highly credible gastrointestinal illness, bloody diarrhea, typhoid fever, cholera, hepatitis, and deaths of children <2 y old) and, at the final visit, to measure weight for age for children <5 y old. We also collected caregiver reported data on negative control outcomes (cough/cold and scrapes/bruises) to assess potential bias from residual confounding or differential measurement error. Continuous supply had no significant overall association with diarrhea (prevalence ratio [PR] = 0.93, 95% confidence interval [CI]: 0.83-1.04, p = 0.19), bloody diarrhea (PR = 0.78, 95% CI: 0.60-1.01, p = 0.06), or weight-for age z-scores (Deltaz = 0.01, 95% CI: -0.07-0.09, p = 0.79) in children <5 y old. In prespecified subgroup analyses by socioeconomic status, children <5 y old in lower-income continuous supply households had 37% lower prevalence of bloody diarrhea (PR = 0.63, 95% CI: 0.46-0.87, p-value for interaction = 0.03) than lower-income intermittent supply households; in higher-income households, there was no significant association between continuous versus intermittent supply and child diarrheal illnesses. Continuous supply areas also had 42% fewer households with >=1 reported case of typhoid fever (cumulative incidence ratio [CIR] = 0.58, 95% CI: 0.41-0.78, p = 0.001) than intermittent supply areas. There was no significant association with hepatitis, cholera, or mortality of children <2 y old; however, our results were indicative of lower mortality of children <2 y old (CIR = 0.51, 95% CI: 0.22-1.07, p = 0.10) in continuous supply areas. The major limitations of our study were the potential for unmeasured confounding given the observational design and measurement bias from differential reporting of health symptoms given the nonblinded treatment. However, there was no significant difference in the prevalence of the negative control outcomes between study groups that would suggest undetected confounding or measurement bias. CONCLUSIONS: Continuous water supply had no significant overall association with diarrheal disease or ponderal growth in children <5 y old in Hubli-Dharwad; this might be due to point-of-use water contamination from continuing household storage and exposure to diarrheagenic pathogens through nonwaterborne routes. Continuous supply was associated with lower prevalence of dysentery in children in low-income households and lower typhoid fever incidence, suggesting that intermittently operated piped water systems are a significant transmission mechanism for Salmonella typhi and dysentery-causing pathogens in this urban population, despite centralized water treatment. Continuous supply was associated with reduced transmission, especially in the poorer higher-risk segments of the population. PMID- 26505898 TI - Identification of N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6 (2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies. AB - Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound 3, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies. PMID- 26505899 TI - Parsimonious Model of Vascular Patterning Links Transverse Hormone Fluxes to Lateral Root Initiation: Auxin Leads the Way, while Cytokinin Levels Out. AB - An auxin maximum is positioned along the xylem axis of the Arabidopsis root tip. The pattern depends on mutual feedback between auxin and cytokinins mediated by the PIN class of auxin efflux transporters and AHP6, an inhibitor of cytokinin signalling. This interaction has been proposed to regulate the size and the position of the hormones' respective signalling domains and specify distinct boundaries between them. To understand the dynamics of this regulatory network, we implemented a parsimonious computational model of auxin transport that considers hormonal regulation of the auxin transporters within a spatial context, explicitly taking into account cell shape and polarity and the presence of cell walls. Our analysis reveals that an informative spatial pattern in cytokinin levels generated by diffusion is a theoretically unlikely scenario. Furthermore, our model shows that such a pattern is not required for correct and robust auxin patterning. Instead, auxin-dependent modifications of cytokinin response, rather than variations in cytokinin levels, allow for the necessary feedbacks, which can amplify and stabilise the auxin maximum. Our simulations demonstrate the importance of hormonal regulation of auxin efflux for pattern robustness. While involvement of the PIN proteins in vascular patterning is well established, we predict and experimentally verify a role of AUX1 and LAX1/2 auxin influx transporters in this process. Furthermore, we show that polar localisation of PIN1 generates an auxin flux circuit that not only stabilises the accumulation of auxin within the xylem axis, but also provides a mechanism for auxin to accumulate specifically in the xylem-pole pericycle cells, an important early step in lateral root initiation. The model also revealed that pericycle cells on opposite xylem poles compete for auxin accumulation, consistent with the observation that lateral roots are not initiated opposite to each other. PMID- 26505900 TI - Developmental Reorganization of the Cognitive Network in Pediatric Epilepsy. AB - Traditional approaches to understanding cognition in children with epilepsy (CWE) involve cross-sectional or prospective examination of diverse test measures, an approach that does not inform the interrelationship between different abilities or how interrelationships evolve prospectively. Here we utilize graph theory techniques to interrogate the development of cognitive landmarks in CWE and healthy controls (HC) using the two-year percentage change across 20 tests. Additionally, we characterize the development of cognition using traditional analyses, showing that CWE perform worse at baseline, develop in parallel with HC, statically maintaining cognitive differences two years later. Graph analyses, however, showed CWE to exhibit both lower integration and segregation in development of their cognitive networks compared to HC. In conclusion, graph analyses of neuropsychological data capture a dynamic and changing complexity in the interrelationships among diverse cognitive skills, maturation of the cognitive network over time, and the nature of differences between normally developing children and CWE. PMID- 26505901 TI - A Single Amino Acid Mutation (R104P) in the E/DRY Motif of GPR40 Impairs Receptor Function. AB - Type 2 Diabetes Mellitus with insulin resistance, pancreatic beta cell dysfunction, and hepatic glucose overproduction is increasing in epidemic proportions worldwide. G protein-coupled receptor 40 (GPR40), a clinically proven anti-diabetic drug target, is mainly expressed in pancreatic beta cells and insulin-secreting cell lines. Long chain fatty acids (LCFA) increase intracellular calcium concentration and amplify glucose-stimulated insulin secretion by activating GPR40. Here we report that the arginine 104 (R104) is critical for the normal function of GPR40. Mutation of R104 to Proline (R104P) results in complete loss of the receptor function. Linoleic acid, ligand of GPR40, could not elicit calcium increase and ERK phosphorylation in cells expressing this mutant receptor. Further study indicated the R104P mutation reduces cell surface localization of GPR40 without affecting the expression of the protein. The small portion of GPR40 R104P mutant that is still located on the membrane has no physiological function, and does not internalize in response to linoleic acid stimulation. These data demonstrate that R104 in GPR40 is critically involved in the normal receptor functions. Interestingly, R104P is a registered single-nucleotide polymorphism of GPR40. The relationship of this GPR40 variant and type 2 diabetes warrants further investigation. PMID- 26505902 TI - Two Types of 2D Layered Iodoargentates Based on Trimeric [Ag3I7] Secondary Building Units and Hexameric [Ag6I12] Ternary Building Units: Syntheses, Crystal Structures, and Efficient Visible Light Responding Photocatalytic Properties. AB - With mixed transition-metal-complex, alkali-metal, or organic cations as structure-directing agents, a series of novel two-dimensional (2D) layered inorganic-organic hybrid iodoargentates, namely, Kx[TM(2,2-bipy)3]2Ag6I11 (TM = Mn (1), Fe (2), Co (3), Ni (4), Zn (5); x = 0.89-1) and [(Ni(2,2-bipy)3][H-2,2 bipy]Ag3I6 (6), have been solvothermally synthesized and structurally characterized. All the title compounds feature 2D microporous layers composed by [Ag3I7] secondary building units based on AgI4 tetrahedra. Differently, the [Ag3I7] trimers are directly interconnected via corner-sharing to form the 2D [Ag6I11](5-) layer in compounds 1-5, whereas two neighboring [Ag3I7] trimers are initially condensed into a hexameric [Ag6I12] ternary building unit as a new node, which further self-assembles, leading to the 2D [Ag6I10](4-) layer in compound 6. The UV-vis diffuse-reflectance measurements reveal that all the compounds possess proper semiconductor behaviors with tunable band gaps of 1.66 2.75 eV, which lead to highly efficient photocatalytic degradation activities over organic pollutants under visible light irradiation compared to that of N dotted P25. Interestingly, all the samples feature distinct photodegradative speeds at the same reaction conditions, and compound 1 features the highest photocatalytic activity among the title phases. The luminescence properties, band structures, and thermal stabilities were also studied. PMID- 26505903 TI - Microbiological effectiveness of household water treatment technologies under field use conditions in rural Tanzania. AB - OBJECTIVES: To assess the microbiological effectiveness of several household water treatment and safe storage (HWTS) options in situ in Tanzania, before consideration for national scale-up of HWTS. METHODS: Participating households received supplies and instructions for practicing six HWTS methods on a rotating 5-week basis. We analysed 1202 paired samples (source and treated) of drinking water from 390 households, across all technologies. Samples were analysed for thermotolerant (TTC) coliforms, an indicator of faecal contamination, to measure effectiveness of treatment in situ. RESULTS: All HWTS methods improved microbial water quality, with reductions in TTC of 99.3% for boiling, 99.4% for WaterguardTM brand sodium hypochlorite solution, 99.5% for a ceramic pot filter, 99.5% for Aquatab(r) sodium dichloroisocyanurate (NaDCC) tablets, 99.6% for P&G Purifier of WaterTM flocculent/disinfectant sachets, and 99.7% for a ceramic siphon filter. Microbiological performance was relatively high compared with other field studies and differences in microbial reductions between technologies were not statistically significant. CONCLUSIONS: Given that microbiological performance across technologies was comparable, decisions regarding scale-up should be based on other factors, including uptake in the target population and correct, consistent, and sustained use over time. PMID- 26505905 TI - The Balance-Scale Task Revisited: A Comparison of Statistical Models for Rule Based and Information-Integration Theories of Proportional Reasoning. AB - We propose and test three statistical models for the analysis of children's responses to the balance scale task, a seminal task to study proportional reasoning. We use a latent class modelling approach to formulate a rule-based latent class model (RB LCM) following from a rule-based perspective on proportional reasoning and a new statistical model, the Weighted Sum Model, following from an information-integration approach. Moreover, a hybrid LCM using item covariates is proposed, combining aspects of both a rule-based and information-integration perspective. These models are applied to two different datasets, a standard paper-and-pencil test dataset (N = 779), and a dataset collected within an online learning environment that included direct feedback, time-pressure, and a reward system (N = 808). For the paper-and-pencil dataset the RB LCM resulted in the best fit, whereas for the online dataset the hybrid LCM provided the best fit. The standard paper-and-pencil dataset yielded more evidence for distinct solution rules than the online data set in which quantitative item characteristics are more prominent in determining responses. These results shed new light on the discussion on sequential rule-based and information-integration perspectives of cognitive development. PMID- 26505904 TI - Expression of a Chimeric Antigen Receptor in Multiple Leukocyte Lineages in Transgenic Mice. AB - Genetically modified CD8+ T lymphocytes have shown significant anti-tumor effects in the adoptive immunotherapy of cancer, with recent studies highlighting a potential role for a combination of other immune subsets to enhance these results. However, limitations in present genetic modification techniques impose difficulties in our ability to fully explore the potential of various T cell subsets and assess the potential of other leukocytes armed with chimeric antigen receptors (CARs). To address this issue, we generated a transgenic mouse model using a pan-hematopoietic promoter (vav) to drive the expression of a CAR specific for a tumor antigen. Here we present a characterization of the immune cell compartment in two unique vav-CAR transgenic mice models, Founder 9 (F9) and Founder 38 (F38). We demonstrate the vav promoter is indeed capable of driving the expression of a CAR in cells from both myeloid and lymphoid lineage, however the highest level of expression was observed in T lymphocytes from F38 mice. Lymphoid organs in vav-CAR mice were smaller and had reduced cell numbers compared to the wild type (WT) controls. Furthermore, the immune composition of F9 mice differed greatly with a significant reduction in lymphocytes found in the thymus, lymph node and spleen of these mice. To gain insight into the altered immune phenotype of F9 mice, we determined the chromosomal integration site of the transgene in both mouse strains using whole genome sequencing (WGS). We demonstrated that compared to the 7 copies found in F38 mice, F9 mice harbored almost 270 copies. These novel vav-CAR models provide a ready source of CAR expressing myeloid and lymphoid cells and will aid in facilitating future experiments to delineate the role for other leukocytes for adoptive immunotherapy against cancer. PMID- 26505906 TI - Aluminum Nanowire Arrays via Directed Assembly. AB - Freestanding and vertically-oriented metal nanowire arrays have potential utility in a number of applications, but presently lack a route to fabrication. Template based techniques, such as electrodeposition into lithographically defined nanopore arrays, have produced well-ordered nanowire arrays with a maximum pitch of about 2 MUm; such nanowires, however, tend to cluster due to local attractive forces. Here, we modify this template fabrication method to produce well-ordered, vertically-oriented, freestanding Al nanowire arrays, etched from an underlying Al substrate, with highly tunable pitch. In addition, optical measurements demonstrated that the nanowires support the propagation of surface plasmon polaritons. PMID- 26505907 TI - It's Time to Take Clarithromycin Seriously in Multiple Myeloma. PMID- 26505908 TI - Copper Nanoparticle/Multiwalled Carbon Nanotube Composite Films with High Electrical Conductivity and Fatigue Resistance Fabricated via Flash Light Sintering. AB - In this work, multiwalled carbon nanotubes (MWNTs) were employed to improve the conductivity and fatigue resistance of flash light sintered copper nanoparticle (NP) ink films. The effect of CNT weight fraction on the flash light sintering and the fatigue characteristics of Cu NP/CNT composite films were investigated. The effect of carbon nanotube length was also studied with regard to enhancing the conductivity and fatigue resistance of flash light sintered Cu NP/CNT composite films. The flash light irradiation energy was optimized to obtain high conductivity Cu NP/CNT composite films. Cu NP/CNT composite films fabricated via optimized flash light irradiation had the lowest resistivity (7.86 MUOmega.cm), which was only 4.6 times higher than that of bulk Cu films (1.68 MUOmega.cm). It was also demonstrated that Cu NP/CNT composite films had better durability and environmental stability than those of Cu NPs only. PMID- 26505909 TI - Resiliency of Stable Isotope Fractionation (delta(13)C and delta(37)Cl) of Trichloroethene to Bacterial Growth Physiology and Expression of Key Enzymes. AB - Quantification of in situ (bio)degradation using compound-specific isotope analysis requires a known and constant isotope enrichment factor (epsilon). Because reported isotope enrichment factors for microbial dehalogenation of chlorinated ethenes vary considerably we studied the potential effects of metabolic adaptation to TCE respiration on isotope fractionation (delta(13)C and delta(37)Cl) using a model organism (Desulfitobacterium hafniesne Y51), which only has one reductive dehalogenase (PceA). Cells grown on TCE for the first time showed exponential growth until 10(9) cells/mL. During exponential growth, the cell-normalized amount of PceA enzyme increased steadily in the presence of TCE (up to 21 pceA transcripts per cell) but not with alternative substrates (<1 pceA transcript per cell). Cultures initially transferred or subcultivated on TCE showed very similar isotope fractionation, both for carbon (epsiloncarbon: 8.60/00 +/- 0.30/00 or -8.80/00 +/- 0.20/00) and chlorine (epsilonchlorine: 2.70/00 +/- 0.30/00) with little variation (0.70/00) for the different experimental conditions. Thus, TCE isotope fractionation by D. hafniense strain Y51 was affected by neither growth phase, pceA transcription, or translation, nor by PceA content per cell, suggesting that transport limitations did not affect isotope fractionation. Previously reported variable epsilon values for other organohalide-respiring bacteria might thus be attributed to different expression levels of their multiple reductive dehalogenases. PMID- 26505910 TI - Combinatorial Investigations of High Temperature CuNb Oxide Phases for Photoelectrochemical Water Splitting. AB - High-throughput combinatorial methods have been useful in identifying new oxide semiconductors with the potential to be applied to solar water splitting. Most of these techniques have been limited to producing and screening oxide phases formed at temperatures below approximately 550 degrees C. We report the development of a combinatorial approach to discover and optimize high temperature phases for photoelectrochemical water splitting. As a demonstration material, we chose to produce thin films of high temperature CuNb oxide phases by inkjet printing on two different substrates: fluorine-doped tin oxide and crystalline Si, which required different sample pyrolysis procedures. The selection of pyrolysis parameters, such as temperature/time programs, and the use of oxidizing, nonreactive or reducing atmospheres determines the composition of the thin film materials and their photoelectrochemical performance. XPS, XRD, and SEM analyses were used to determine the composition and oxidation states within the copper niobium oxide phases and to then guide the production of target Cu(1+)Nb(5+) oxide phases. The charge carrier dynamics of the thin films produced by the inkjet printing are compared with pure CuNbO3 microcrystalline material obtained from inorganic bulk synthesis. PMID- 26505911 TI - Effects and mechanism of arsenic trioxide in combination with rmhTRAIL in multiple myeloma. AB - The anti-tumor potential of arsenic trioxide (ATO) and recombinant mutant human TRAIL (rmhTRAIL) has been confirmed in various kinds of tumors. However, the effects and mechanism of the two drugs in combination in multiple myeloma (MM) have not been established. In this study, we evaluated the proliferation inhibition and apoptosis induction effects of ATO and rmhTRAIL as single agents and in combination on the MM cell lines RPMI8226 and U266. Then, we used high performance liquid chromatography and mass spectrometry to find differentially expressed proteins before and after drug treatment and to analyze the mechanism underlying the effect of ATO and rmhTRAIL on MM cells. Results indicated that ATO and rmhTRAIL had synergistic or additive effects on proliferation inhibition and apoptosis induction in MM cells, and the mechanism underlying the two-drug combination might involve regulation of the expression of several proteins affected by ATO and rmhTRAIL. Our study provides evidence of a potential new combination treatment strategy for MM. PMID- 26505912 TI - Revealing the Buried Metal-Organic Interface: Restructuring of the First Layer by van der Waals Forces. AB - With the use of molecular manipulation in a cryogenic scanning tunneling microscope, the structure and rearrangement of sexiphenyl molecules at the buried interface of the organic film with the Cu(110) substrate surface have been revealed. It is shown that a reconstruction of the first monolayer of flat lying molecules occurs due to the van der Waals pressure from subsequent layers. In this rearrangement, additional sexiphenyl molecules are forced into the established complete monolayer and adopt an edge-on configuration. Incorporation of second layer molecules into the first layer is also demonstrated by purposely pushing sexiphenyl molecules with the STM tip. The results indicate that even chemisorbed organic layers at interfaces can be significantly influenced by external stress from van der Waals forces of subsequent layers. PMID- 26505913 TI - Presynaptic M3 muscarinic cholinoceptors mediate inhibition of excitatory synaptic transmission in area CA1 of rat hippocampus. AB - Acetylcholine can modulate hippocampal network function through activation of both nicotinic and muscarinic acetylcholine receptors (mAChRs). All five mAChR subtypes have been identified in the hippocampus. Besides by their involvement in excitability of hippocampal cells, synaptic plasticity and memory, a large body of research has demonstrated the involvement of presynaptic mAChRs in the inhibition of glutamatergic transmission in the hippocampus. Over the years, however, pharmacological and molecular genetic studies have yielded quite contradictory results regarding the mAChR subtype(s) involved. In this study, multi-electrode array technology was used for the pharmacological elucidation of the subtype of mAChR mediating the depression of excitatory synaptic transmission at the SC-CA1 synapse. Using selective antagonists (VU0255035, MT7, tripinamide, MT3) and allosteric potentiators (VU 10010, VU 0238429) the involvement of M1, M2, M4, and M5 subtypes was ruled out thereby implying a major modulatory role for M3 receptors in the inhibition of excitatory synaptic transmission in area CA1 of rat hippocampus. PMID- 26505914 TI - Endomorphin-1 attenuates Abeta42 induced impairment of novel object and object location recognition tasks in mice. AB - A growing body of evidence suggests that the agglomeration of amyloid-beta (Abeta) may be a trigger for Alzheimer's disease (AD). Central infusion of Abeta42 can lead to memory impairment in mice. Inhibiting the aggregation of Abeta has been considered a therapeutic strategy for AD. Endomorphin-1 (EM-1), an endogenous agonist of MU-opioid receptors, has been shown to inhibit the aggregation of Abeta in vitro. In the present study, we investigated whether EM-1 could alleviate the memory-impairing effects of Abeta42 in mice using novel object recognition (NOR) and object location recognition (OLR) tasks. We showed that co-administration of EM-1 was able to ameliorate Abeta42-induced amnesia in the lateral ventricle and the hippocampus, and these effects could not be inhibited by naloxone, an antagonist of MU-opioid receptors. Infusion of EM-1 or naloxone separately into the lateral ventricle had no influence on memory in the tasks. These results suggested that EM-1 might be effective as a drug for AD preventative treatment by inhibiting Abeta aggregation directly as a molecular modifier. PMID- 26505915 TI - Impaired short-term memory for pitch in congenital amusia. AB - Congenital amusia is a neuro-developmental disorder of music perception and production. The hypothesis is that the musical deficits arise from altered pitch processing, with impairments in pitch discrimination (i.e., pitch change detection, pitch direction discrimination and identification) and short-term memory. The present review article focuses on the deficit of short-term memory for pitch. Overall, the data discussed here suggest impairments at each level of processing in short-term memory tasks; starting with the encoding of the pitch information and the creation of the adequate memory trace, the retention of the pitch traces over time as well as the recollection and comparison of the stored information with newly incoming information. These impairments have been related to altered brain responses in a distributed fronto-temporal network, associated with decreased connectivity between these structures, as well as in abnormalities in the connectivity between the two auditory cortices. In contrast, amusic participants' short-term memory abilities for verbal material are preserved. These findings show that short-term memory deficits in congenital amusia are specific to pitch, suggesting a pitch-memory system that is, at least partly, separated from verbal memory. This article is part of a Special Issue entitled SI: Auditory working memory. PMID- 26505916 TI - Amyloid beta25-35 induced ROS-burst through NADPH oxidase is sensitive to iron chelation in microglial Bv2 cells. AB - Iron chelation therapy and inhibition of glial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can both represent possible routes for Alzheimer's disease modifying therapies. The metal hypothesis is largely focused on direct binding of metals to the N-terminal hydrophilic 1-16 domain peptides of Amyloid beta (Abeta) and how they jointly give rise to reactive oxygen species (ROS) production. The cytotoxic effects of Abeta through ROS and metals are mainly studied in neuronal cells using full-length Abeta1-40/42 peptides. Here we study cellularly-derived ROS during 2-60min in response to non-metal associated mid domain Abeta25-35 in microglial Bv2 cells by fluorescence based spectroscopy. We analyze if Abeta25-35 induce ROS production through NADPH oxidase and if the production is sensitive to iron chelation. NADPH oxidase inhibitor diphenyliodonium (DPI) is used to confirm the production of ROS through NADPH oxidase. We modulate cellular iron homeostasis by applying cell permeable iron chelators desferrioxamine (DFO) and deferiprone (DFP). NADPH oxidase subunit gp91 phox level was analyzed by Western blotting. Our results show that Abeta25-35 induces strong ROS production through NADPH oxidase in Bv2 microglial cells. Intracellular iron depletion resulted in restrained Abeta25-35 induced ROS. PMID- 26505917 TI - Phoenixin-14 enhances memory and mitigates memory impairment induced by Abeta1-42 and scopolamine in mice. AB - Phoenixin (PNX) is a recently discovered neuropeptide shown to be involved in regulating the reproductive system, anxiety-related behaviors and pain though its receptor is still unknown. PNX-14, one of the endogenous active isoforms, is reported to regulate gonadotropin releasing hormone (GnRH) receptor expression and GnRH secretion. Because GnRH system is thought to be involved in the regulation of learning and memory processes, we hypothesized that PNX-14 might be mediate learning and memory. Here, we investigated the effects of PNX-14 in memory processes, using novel object recognition (NOR) and object location recognition (OLR) tasks. Our results revealed that intracerebroventricular (i.c.v.) injection of PNX-14 (25nmol) immediately after training not only facilitated memory formation, but also prolonged memory retention in both tasks. The memory-enhancing effects of PNX-14 were also seen when it was infused into the hippocampus. Moreover, these memory-improving effects of PNX-14 could be blocked by a GnRH receptor antagonist (Cetrorelix). The memory-improving effects of PNX-14 were not related to any effects on locomotor activity. Additionally, the results suggested that i.c.v. injection of PNX-14 mitigate the memory impairment induced by the amyloid-beta1-42 (Abeta1-42) peptide and scopolamine. The present results indicate that PNX-14 facilitates memory formation and prolongs memory retention through activation of the GnRH receptor, and mitigates the memory-impairing effects of Abeta1-42 and scopolamine, suggesting that PNX-14 may be effective as a drug for enhancing memory and treating Alzheimer's disease. PMID- 26505918 TI - Distinct morphological processing of recently learned compound words: An ERP study. AB - Our vocabulary is, at least in principle, infinite. We can create new words combining existing ones in meaningful ways to form new linguistic expressions. The present study investigated the morphological processing of novel compound words in overt speech production. Native speakers of Dutch learned a series of new compounds (e.g. appelgezicht, 'apple-face') that were later used as primes in a morphological priming task. In this protocol, primes were compound words morphologically related to a target's picture name (e.g. appelgezicht was used for a picture of an apple, Dutch appel). The novel primes were compared with corresponding familiar compounds sharing a free morpheme (e.g. appelmoes, 'applesauce') and with unrelated compounds. Participants were required to read aloud words and to name pictures in a long-lag design. Behavioral and event related potentials (ERPs) data were collected in two sessions, separated by 48h. Clear facilitation of picture naming latencies was obtained when pictures were paired with morphological related words. Notably, our results show that novel compounds have a stronger priming effect than familiar compounds in both sessions, which is expressed in a marked reduction in target naming latencies and a decrease in the N400 amplitude. These results suggest that participants focused more on the separate constituents when reading novel primes than in the case of existing compounds. PMID- 26505919 TI - Reduced serine racemase expression in aging rat cerebellum is associated with oxidative DNA stress and hypermethylation in the promoter. AB - Regulation of serine racemase (SR) occurs at transcriptional and translational levels; post-translational modification, cytosolic distribution as well as allosteric effect regulate SR activity. In this study, we report a new route of SR regulation, i.e. oxidative stress and hypermethylation of the srr (gene of SR) promoter correlate with its reduced transcription in aging rat cerebella. We first showed that the mRNA and protein level of srr were decreased in the homogenates of rat cerebellum at age 12 months compared with the counterparts from age 20 days. The reduction of SR protein level in aging cerebella was evidenced by decreased immunostaining observed in the cell body of granule cells or Purkinje cells. Staining for 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker for oxidative stress to DNA, was much stronger in granule cell or Purkinje cell nuclei from rat cerebella at 12 months compared with staining at 20 days. We further detected srr promoter hypermethylation at 12 months compared with that at 20 days by use of bisulfite sequencing PCR, coinciding with elevated protein levels of DNA methyltransferase 1 (DNMT1) in homogenates of aging cerebella. In vitro, we demonstrated that chronic treatment with the oxidant, menadione (VK3), reduced srr mRNA levels, which was reversed by the DNA demethylating agent 5-Aza dC-2'-deoxycytidine (5-Aza-dC) in primary cerebellar granule cell cultures. Together, the in vivo and ex vivo results suggest that oxidative DNA stress and srr promoter hypermethylation are associated with reduced srr gene transcription and corresponding reduced protein expression in aging cerebella. PMID- 26505920 TI - Possible antidepressant effects and mechanism of electroacupuncture in behaviors and hippocampal synaptic plasticity in a depression rat model. AB - Increasing evidences show that hippocampal synaptic plasticity plays a crucial role in the pathogenesis of depression. The objective of this study was to determine whether electroacupuncture (EA) in the Wistar Kyoto (WKY) rat model of depression would exert antidepressant effects and whether this effect would be associated with changes in hippocampal synaptic plasticity. Male WKY rats were randomly divided into three groups (EA, sham EA, and blank control); Wister rats were used as normal control group. Treatment with EA was performed at Baihui (GV20) and Yintang (EX-HN3) once daily for 3 weeks. Forced swimming test (FST), open field test (OFT), and Morris water maze (MWM) were evaluated after 21-day intervention. Long-term potentiation (LTP) was evoked at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. EA treatment significantly reduced immobility time in FST. MWM test showed a significant downward trend in escape latency time from the second to fifth days of experiment, and a higher frequency of crossing the missing quadrant platform in normal control and EA vs other groups. Impaired LTP was detected in Schaffer collateral-CA1 synapses in blank control and sham EA groups. In the western blot, the expression of GluN2B showed significant increase in EA vs sham EA and blank control groups. EA was able to improve depression-like behaviors and reverse the impairment of LTP, which were likely mediated by GluN2B in the hippocampus. PMID- 26505921 TI - Qualitative and Quantitative Gadoxetic Acid-enhanced MR Imaging Helps Subtype Hepatocellular Adenomas. AB - PURPOSE: To determine which clinical variables and gadoxetic acid disodium (Gd EOB-DTPA)-enhanced magnetic resonance (MR) imaging features are associated with histologically proved hepatocellular adenoma (HCA) genotypic subtypes. MATERIALS AND METHODS: In this institutional review board-approved and Health Insurance Portability and Accountability Act-compliant study, clinical information and MR images of 49 histologically proved HCAs from January 2002 to December 2013 (21 patients; mean age, 39 years; age range, 15-59 years) were retrospectively reviewed by two radiologists. Qualitative and quantitative imaging features, including the signal intensity ratio relative to liver in each phase, were studied. HCA tissues were stained with subtype-specific markers and subclassified by a pathologist. Clinical and imaging data were correlated with pathologic findings and compared by using Fisher exact or t test, with a Bonferroni correction for multiple comparisons. RESULTS: Forty-nine HCAs were subclassified into 14 inflammatory, 20 hepatocyte nuclear factor (HNF)-1alpha-mutated, one beta catenin-activated, and 14 unclassified lesions. Intralesional steatosis was exclusively seen in HNF-1alpha-mutated lesions. Marked hyperintensity on T2 weighted images was seen in 12 of 14 (86%) inflammatory lesions compared with four of 21 (19%) HNF-1alpha-mutated, seven of 14 (50%) unclassified, and zero of one (0%) beta-catenin-activated lesion. Two large lesions (one beta-catenin activated and one unclassified) transformed into hepatocellular carcinomas and were the only lesions to enhance with marked heterogeneity. In the hepatobiliary phase, all HCA subtypes were hypoenhancing compared with surrounding liver parenchyma, and they reached their nadir signal intensity by 10 minutes after the administration of contrast material before plateauing. HNF-1alpha-mutated lesions had the lowest lesion signal intensity ratio of 0.47 +/- 0.09, compared with 0.73 +/- 0.18 for inflammatory lesions (P = .0004), 0.82 for the beta-catenin activated lesion, and 0.73 +/- 0.06 for the unclassified lesion (P = .00002). CONCLUSION: In this study, all HCA subtypes were hypoenhancing at Gd-EOB-DTPA enhanced MR imaging in the hepatobiliary phase and reached their nadir signal intensity at 10 minutes. HNF-1alpha-mutated lesions could be distinguished from other subtypes by having the lowest lesion signal intensity ratio. PMID- 26505922 TI - Association of Apparent Diffusion Coefficient with Disease Recurrence in Patients with Locally Advanced Cervical Cancer Treated with Radical Chemotherapy and Radiation Therapy. AB - PURPOSE: To investigate whether volumetrically derived apparent diffusion coefficient (ADC) from pretreatment diffusion-weighted (DW) magnetic resonance (MR) imaging is associated with disease recurrence in women with locally advanced cervical cancer treated with chemotherapy and radiation therapy. MATERIALS AND METHODS: An ethics board-approved, retrospective study was conducted in 85 women with stage IB-IVA cervical cancer treated with chemo- and radiation therapy in 2009-2013. All patients underwent MR imaging for staging, including T2-weighted and DW MR imaging series, by using a 1.5- or 3.0-T imager. The mean, median, 75th, 90th, and 95th percentile ADCs (ADCmean, ADC50, ADC75, ADC90, and ADC95, respectively) of all voxels that comprised each tumor were extracted and normalized to the mean urine ADC (nADCmean, nADC50, nADC75, nADC90, and nADC95, respectively) to reduce variability. The primary outcome was disease-free survival (DFS). Uni- and multivariable Cox regression analyses were used to evaluate the association of ADC parameters and relevant clinical variables with DFS. RESULTS: Of the 85 women included, 62 were free of disease at last follow up. Median follow-up was 37 months (range, 5-68 months). Significant variables at univariable analysis included T2-weighted derived tumor diameter, para-aortic nodal involvement, advanced stage, ADC90 and ADC95, nADC75, nADC90, and nADC95. Normalized parameters were more highly associated (hazard ratio per 0.01 increase in normalized ADC, 0.91-0.94; P < .04). Because nADC75, nADC90, and nADC95 were highly correlated, only nADC95 (which had the lowest P value) was included in multivariable analysis. At multivariable analysis, absolute and normalized ADC95 remained associated with DFS (hazard ratio, 0.90-0.98; P < .05). CONCLUSION: The volumetric ADC95 may be a useful imaging metric to predict treatment failure in patients with locally advanced cervical cancer treated with chemo- and radiation therapy. PMID- 26505923 TI - Intrinsic Resting-State Functional Connectivity in the Human Spinal Cord at 3.0 T. AB - PURPOSE: To apply resting-state functional magnetic resonance (MR) imaging to map functional connectivity of the human spinal cord. MATERIALS AND METHODS: Studies were performed in nine self-declared healthy volunteers with informed consent and institutional review board approval. Resting-state functional MR imaging was performed to map functional connectivity of the human cervical spinal cord from C1 to C4 at 1 * 1 * 3-mm resolution with a 3.0-T clinical MR imaging unit. Independent component analysis (ICA) was performed to derive resting-state functional MR imaging z-score maps rendered on two-dimensional and three dimensional images. Seed-based analysis was performed for cross validation with ICA networks by using Pearson correlation. RESULTS: Reproducibility analysis of resting-state functional MR imaging maps from four repeated trials in a single participant yielded a mean z score of 6 +/- 1 (P < .0001). The centroid coordinates across the four trials deviated by 2 in-plane voxels +/- 2 mm (standard deviation) and up to one adjacent image section +/- 3 mm. ICA of group resting-state functional MR imaging data revealed prominent functional connectivity patterns within the spinal cord gray matter. There were statistically significant (z score > 3, P < .001) bilateral, unilateral, and intersegmental correlations in the ventral horns, dorsal horns, and central spinal cord gray matter. Three-dimensional surface rendering provided visualization of these components along the length of the spinal cord. Seed-based analysis showed that many ICA components exhibited strong and significant (P < .05) correlations, corroborating the ICA results. Resting-state functional MR imaging connectivity networks are qualitatively consistent with known neuroanatomic and functional structures in the spinal cord. CONCLUSION: Resting state functional MR imaging of the human cervical spinal cord with a 3.0-T clinical MR imaging unit and standard MR imaging protocols and hardware reveals prominent functional connectivity patterns within the spinal cord gray matter, consistent with known functional and anatomic layouts of the spinal cord. PMID- 26505924 TI - Conformational Dynamics of o-Fluoro-Substituted Z-Azobenzene. AB - A conformational analysis of o-fluoro Z-azobenzene reveals a slight preference for aromatic C-F/pi interaction. Density functional theory (DFT) indicates that the conformation with a C-F/pi interaction is preferred by approximately 0.3-0.5 kcal/mol. Ground-state conformations were corroborated with X-ray crystallography. (Z)-Azobenzene (Z-AB) with at least one o-fluoro per ring displays (19)F-(19)F through-space (TS) coupling. 2D J-resolved NMR was used to distinguish through-bond from TS coupling ((TS)JFF). (TS)JFF decreases as the temperature is lowered and the multiplets coalesce into broad singlets. We hypothesize that the coalescence temperature (Tc) corresponds to the barrier for phenyl rotation. The experimentally determined barrier of 8-10 kcal/mol has been qualitatively verified by DFT where transition states with a bisected geometry were identified with zero-point energies of 6-9 kcal/mol relative to ground state. These values are significantly higher that values estimated from previous theoretical studies but lie within a reasonable range for phenyl rotation in hydrocarbon systems. PMID- 26505925 TI - Redox imaging of skeletal muscle using in vivo DNP-MRI and its application to an animal model of local inflammation. AB - Disorders of skeletal muscle are often associated with inflammation and alterations in redox status. A non-invasive technique that could localize and evaluate the severity of skeletal muscle inflammation based on its redox environment would be useful for disease identification and monitoring, and for the development of treatments; however, no such technique currently exists. We describe a method for redox imaging of skeletal muscle using dynamic nuclear polarization magnetic resonance imaging (DNP-MRI), and apply this method to an animal model of local inflammation. Female C57/BL6 mice received injections of 0.5% bupivacaine into their gastrocnemius muscles. Plasma biomarkers, myeloperoxidase activity, and histological sections were assessed at 4 and 24h after bupivacaine injection to measure the inflammatory response. In vivo DNP-MRI was performed with the nitroxyl radicals carbamoyl-PROXYL (cell permeable) and carboxy-PROXYL (cell impermeable) as molecular imaging probes at 4 and 24h after bupivacaine administration. The images obtained after carbamoyl-PROXYL administration were confirmed with the results of L-band EPR spectroscopy. The plasma biomarkers, myeloperoxidase activity, and histological findings indicated that bupivacaine injection caused acute muscle damage and inflammation. DNP-MRI images of mice treated with carbamoyl-PROXYL or carboxy-PROXYL at 4 and 24h after bupivacaine injection showed similar increases in image intensity and decay rate was significantly increased at 24h. In addition, reduction rates in individual mice at 4h and 24h showed faster trends with bupivacaine injection than in their contralateral sides by image-based analysis. These findings indicate that in vivo DNP-MRI with nitroxyl radicals can non-invasively detect changes in the focal redox status of muscle resulting from locally-induced inflammation. PMID- 26505926 TI - Immunogenic properties of the surface layer precursor of Clostridium difficile and vaccination assays in animal models. AB - Clostridium difficile is an opportunistic pathogen causing gut inflammation generally associated with an intestinal dysbiosis due to antibiotics. Several virulence factors have been identified as playing a key role in gut colonization. The surface-layer proteins, comprised of two proteins, the high molecular weight SlpA (HMW-SLP) and the low molecular weight SlpA (LMW-SLP), are the most abundant proteins on the C. difficile surface. These two proteins are derived from the Cwp84-mediated cleavage of a single precursor protein SlpA. In this study, we assessed the immunogenic properties of a recombinant SlpA precursor derived from a toxigenic C. difficile strain (630) and its protective effect as a vaccine antigen co-administered with the cholera toxin as an adjuvant in both hamster and mouse models. First, we confirmed the immunogenicity of SlpA in humans. Sera from patients with C. difficile infection were analyzed by ELISA. Patients with CDI have a greater number of SlpA antibodies than healthy patients, confirming the immunogenicity of this protein during the pathogenic process. Then, rectal vaccination assays were performed in both conventional hamsters and mice. The animals' sera were sampled before and after vaccination, and were analyzed by ELISA. In addition, in the mouse model, feces were sampled after vaccination and IgA directed against SlpA were detected by ELISA. In both models, the intestinal colonization was evaluated by fecal bacterial count after challenge. Intra-rectal vaccination with SlpA and cholera toxin as an adjuvant induced a local and systemic humoral immune response in mice and hamsters potentially responsible for the weak decrease of C. difficile colonization in mice and the partial protection observed in a lethal-hamster model. PMID- 26505928 TI - BV and non-BV associated Gardnerella vaginalis establish similar synergistic interactions with other BV-associated microorganisms in dual-species biofilms. AB - Dual-species biofilm formation between Gardnerella vaginalis strains isolated from women with or without bacterial vaginosis (BV) and other 24 BV-associated microorganisms support that the key difference in virulence potential between BV negative and BV-positive G. vaginalis strains seems not to be related with biofilm maturation. PMID- 26505927 TI - Clinical significance of direct cytotoxicity and toxigenic culture in Clostridium difficile infection. AB - BACKGROUND: Clostridium difficile infection (CDI) is the leading cause of hospital-acquired diarrhoea in developed countries. Although an optimal diagnosis is crucial, laboratory diagnostics remain challenging. Currently, the reference methods are direct cytotoxicity assay and toxigenic culture; however there is controversy in the interpretation of discordant results of these tests. OBJECTIVE: The aim of our study was to determine the clinical significance of detecting C. difficile only by toxigenic culture with a negative direct cytotoxicity assay. METHODS: We conducted a prospective study in which patients aged >2 years with CDI were enrolled and monitored at least 2 months after their last episode. Samples were tested by both cytotoxicity assay and toxigenic culture. RESULTS: During the 6-month study period, we identified 169 episodes meeting CDI criteria that had been tested by both assays, out of which 115 were positive for both cytotoxicity assay and toxigenic culture, and 54 CDI episodes (31.9%) were positive only by toxigenic culture. Overall, patients median age was 71.3, 50.9% were male and the most frequent underlying disease was malignancy. The comparison of CDI episodes positive for both assays and by toxigenic culture only revealed the following, respectively: mild CDI (77.4% vs 94.4%; p = 0.008), severe CDI (21.7% vs 5.6%; p = 0.008), severe complicated (0.9% vs 0.0%; p = 1.000), pseudomembranous colitis (1.7% vs 1.9% p = 1.000), recurrence (17.4% vs 14.8%; p = 0.825), overall mortality (8.7% vs 7.4%; p = 1.000) and CDI related mortality (2.6% vs 0%; p = 0.552). CONCLUSION: CDI episodes positive by cytotoxicity assay were more severe than those positive only by toxigenic culture, however there were a significant proportion of CDI cases (31.9%) that would have been missed if only cytotoxicity had been considered as clinically significant for CDI treatment, including severe CDI cases. Our data suggest that a positive test by toxigenic culture with a negative result for cytotoxicity should not be interpreted as colonization. PMID- 26505929 TI - Tetraspan cargo adaptors usher GPI-anchored proteins into multivesicular bodies. AB - Ubiquitinated membrane proteins are sorted into intralumenal endosomal vesicles on their way for degradation in lysosomes. Here we summarize the discovery of the Cos proteins, which work to organize and segregate ubiquitinated cargo prior to its incorporation into intralumenal vesicles of the multivesicular body (MVB). Importantly, cargoes such as GPI-anchored proteins (GPI-APs) that cannot undergo ubiquitination, rely entirely on Cos proteins for sorting into intralumenal vesicles using the same pathway that depends on ESCRTs and ubiquitin ligases that typical polytopic membrane proteins do. Here we show Cos proteins provide functions as not only adaptor proteins for ubiquitin ligases, but also as cargo carriers that can physically usher a variety of other proteins into the MVB pathway. We then discuss the significance of this new sorting model and the broader implications for this cargo adaptor mechanism, whereby yeast Cos proteins, and their likely animal analogs, provide a ubiquitin sorting signal in trans to enable sorting of a membrane protein network into intralumenal vesicles. PMID- 26505930 TI - Stress and immunity: bench to bedside approaches continue. PMID- 26505931 TI - Biomarkers of asthma and allergic airway diseases. PMID- 26505932 TI - Anaphylaxis--a practice parameter update 2015. PMID- 26505933 TI - Factors associated with the course of egg allergy in children. AB - BACKGROUND: The risk factors that affect persistence of egg allergy are under investigation. OBJECTIVE: To investigate the factors associated with the course of egg allergy and anaphylaxis in children. METHODS: Children who had been diagnosed as having an IgE-mediated egg allergy and followed up until 6 years of age were enrolled. IgE-mediated egg allergy was diagnosed by a positive skin prick test result, specific IgE (sIgE) level of 0.35 kU/L or greater, and clear cut history of egg-related symptoms or positive challenge test results. RESULTS: A total of 203 (56%) of 363 egg allergic children were followed up until 6 years of age. Egg allergy resolved in 92 children (45%) at 2 years of age, 134 children (66%) at 4 years of age, and 145 children (71%) at 6 years of age. The resolution of egg allergy was associated with baseline egg sIgE level of 6.2 kU/L or less and the absence of anaphylaxis (hazard ratio, 0.32; 95% CI, 0.21-0.49; P < .001; and hazard ratio, 0.38; 95% CI, 0.21-0.69; P = .001, respectively). Baseline factors, including cut-off level of egg sIgE level greater than 6.2 kU/L, egg sIgE level, gastrointestinal symptoms after egg exposure, anaphylaxis with egg, and concomitant cow's milk allergy, were significantly associated with later resolution of egg allergy. The multivariate logistic regression determined that the natural logarithm for egg-white sIgE (odds ratio, 1.44; 95% CI, 1.09-1.91; P = .01) and the baseline gastrointestinal symptoms with egg (odds ratio, 6.86; 95% CI, 2.93-16.06; P < .001) were significantly related to a higher risk of anaphylaxis with egg. CONCLUSION: Baseline egg white sIgE levels, baseline gastrointestinal system involvement, concomitant cow's milk allergy, and anaphylaxis with egg may predict a more severe course of egg allergy with late resolution. Moreover, egg white sIgE levels and gastrointestinal symptoms after egg exposure seem to increase the risk of anaphylaxis with egg. PMID- 26505934 TI - Response to celecoxib in a patient with indolent systemic mastocytosis presenting with intractable diarrhea. PMID- 26505935 TI - Allergen of the Month--English Oak. PMID- 26505936 TI - Percutaneous Ethanolamine Sclerotherapy of a Retrobulbar Cyst in a Child with Microphthalmos and Proptosis. PMID- 26505937 TI - Lower Extremity Vascular Access in Neonates and Infants: A Single Institutional Experience. AB - PURPOSE: To demonstrate feasibility and evaluate outcomes of direct-stick saphenous and single-incision tunneled femoral noncuffed central venous catheters (CVCs) placed in a large series of neonates and infants at a single institution. MATERIALS AND METHODS: A retrospective review was performed for all neonates and infants receiving a lower extremity CVC by interventional radiology between 2007 and 2012. Technical success, mechanical and infectious complications, and catheter outcomes were recorded. RESULTS: There were 271 primary insertions performed in 243 children by interventional radiologists in the interventional radiology suite or at the bedside. CVCs were placed via the femoral vein with single-incision technique (84.9%) or the saphenous vein via a direct-stick technique (15.1%), with a technical success rate of 100%. The total number of catheter-days was 7,917 days (median, 19 d; range, 0-220 d). The number of primary catheter-days was 5,333 days (median, 15 d; range, 0-123.0 d), and salvage procedures prolonged catheter life by 2,584 days (median, 15 d; range, 1.0-101.0 d). The mechanical and adjusted infectious complication rates were 1.67 and 0.44 per 100 catheter-days. CONCLUSIONS: Image-guided placement of saphenous or tunneled femoral catheters using a single incision is a safe and feasible method for vascular access in neonates and infants. PMID- 26505938 TI - Use of Vascular Ports for Long-Term Apheresis in Children. AB - High-flow ports have been used for apheresis in adults. The purpose of this study was to demonstrate the efficacy of ports for apheresis in children and to survey satisfaction of patients and their families with their use. A retrospective review of clinical details was combined with a prospective assessment of the experience of patients and their families. Eight patients (mean age, 10.4 y; mean weight, 35 kg) had nine ports placed for long-term apheresis. All 246 treatment sessions were completed successfully. Access difficulties occurred in eight of 246 sessions (3%). Alarms occurred in 40 of 246 sessions (16%), resulting in delays in 10 of 246 sessions (4%). A survey of early experience indicated overall satisfaction with and a preference for ports for apheresis. PMID- 26505939 TI - Malpositioned Central Catheter into Pulmonary Vein. PMID- 26505940 TI - Intraprocedural Safety and Technical Success of the MVP Micro Vascular Plug for Embolization of Pulmonary Arteriovenous Malformations. AB - This case series describes early experience, intraprocedural safety, and technical success of the MVP Micro Vascular Plug (MVP; Covidien, Irvine, California) for embolization of 20 pulmonary arteriovenous malformations (PAVMs) using 23 plugs in seven patients with hereditary hemorrhagic telangiectasia. There was no device migration, and all devices were successfully detached electrolytically. Immediate cessation of flow through the feeding artery was achieved in 21 of 23 (91%) deployments. There was one minor complication. This series demonstrates the MVP to be safe and technically successful in the treatment of PAVMs. PMID- 26505941 TI - IR and Palliative Care: A Good Match. PMID- 26505942 TI - Medical Errors in IR: Where Are We? A Systematic Review. PMID- 26505943 TI - Retrograde Thoracic Duct Embolization in a Pediatric Patient with Total Cavopulmonary Connection and Plastic Bronchitis. PMID- 26505944 TI - CT-Guided Percutaneous Cryoablation of an Aggressive Osteoblastoma: A Case Report. PMID- 26505945 TI - Fluoroscopy-Guided Transgastric Hepaticoantrostomy in a Patient with Bile Leakage Associated with Biliary Obstruction after Left Hepatic Trisectionectomy. PMID- 26505946 TI - Re: "Portal Vein Recanalization-Transjugular Intrahepatic Portosystemic Shunt Using the Transsplenic Approach to Achieve Transplant Candidacy in Patients with Chronic Portal Vein Thrombosis". PMID- 26505947 TI - Patient's Satisfaction, First! PMID- 26505948 TI - Hysteroscopic Endometrial Resection Versus Laparoscopic Supracervical Hysterectomy Hysterectomy--A Flawed Conclusion. PMID- 26505949 TI - Over-the-scope stent: a novel technique for stent elongation and deployment. PMID- 26505951 TI - Proposal for a harmonized descriptive analyte nomenclature for quantitative large molecule bioanalysis. PMID- 26505950 TI - Perilla frutescens Extract Ameliorates Acetylcholinesterase and Trimethyltin Chloride-Induced Neurotoxicity. AB - One of the critical features of Alzheimer's disease is cognitive dysfunction, which is, in part, due to decreases in acetylcholine (ACh). The ethanol extract of Perilla frutescens was selected for isolating the acetylcholinesterase (AChE) inhibitor based on preliminary screening. In vivo behavioral tests were performed to examine the effects of the P. frutescens extract on trimethyltin chloride induced impairment of learning and memory in mice. A diet containing P. frutescens extract effectively reversed learning and memory impairment on the Y maze and passive avoidance tests. To isolate the active compound from the P. frutescens extract, solvent partitioning, silica gel open column chromatography, thin-layer chromatography, and high-performance liquid chromatography were used. The AChE inhibitor was identified as rosmarinic acid. PMID- 26505952 TI - Structure identification of a polysaccharide purified from Lycium barbarium fruit. AB - The water-soluble bioactive polysaccharides can contribute to the health benefits of Lycium barbarium fruit. However, the structure characteristics of these polysaccharides remain unclear yet. An important polysaccharide (LBPA) was isolated and purified from L. barbarium in this work. It was identified by chemical and spectroscopic methods as arabinogalactan with beta-d-(1->6)-galactan as backbone, which was different to any reported polysaccharides from this species before. This arabinogalactan was comprised of Araf, Galp, GlcpA and Rhap with a molar ratio of 9.2:6.6:1.0:0.9. The side chains, including alpha-l-Araf-(1 >, alpha-l-Araf-(1->5)-alpha-l-Araf-(1->, beta-l-Araf-(1->5)-alpha-l-Araf-(1-> and alpha-l-Rhap-(1->4)-beta-d-GlcpA-(1->6)-beta-d-Galp-(1->, were linked to beta d-(1->6)-galactan at O-3. The putative structure was drawn as below. The molecular weight was determined to be 470,000g/mol by gel permeation chromatography. PMID- 26505953 TI - Microwave-assisted synthesis of porous chitosan-modified montmorillonite hydroxyapatite composite scaffolds. AB - In this study, a porous chitosan-organically modified montmorillonite hydroxyapatite (CS-OM-HA) composite scaffold was developed by combining microwave irradiation and gas foaming method. Hydroxyapatite (HA) particles of size ~ 65 nm were synthesized and characterized by X-ray diffraction (XRD) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The prepared composite scaffolds were characterized using ATR-FTIR, XRD, mercury intrusion porosimeter (MIP) and scanning electron microscopy (SEM) studies. The synergistic effect of HA and OM on the mechanical and in vitro biological properties (swelling, degradation, protein adsorption and bioactivity) of the composite scaffolds were evaluated. Swelling, degradation, mechanical property, bioactivity and protein adsorption studies of CS-OM-HA composite scaffolds have shown desirable results in comparison with the pure CS and CS-OM composite scaffolds. CS-OM-HA composite scaffolds were also found to be non-cytotoxic to MG 63 osteoblast cell lines. From the study, it can be concluded that the novel CS OM-HA composite scaffold with improved mechanical and in vitro biological properties has wide potential in non-load bearing bone tissue engineering applications. PMID- 26505956 TI - Unexpected higher stabilisation of two classical antiaromatic frameworks with a ruthenium fragment compared to the osmium counterpart: origin probed by DFT calculations. AB - Density functional theory (DFT) calculations were carried out to investigate the stability and aromaticity of metallapentalocyclobutadienes. The results reveal unexpected higher stabilisation achieved with a 4d ruthenium fragment compared to the 5d [corrected] osmium counterpart. Moreover, direct 1-3 metal-carbon bonding in the metallabutadiene unit of these two complexes is negligible. PMID- 26505957 TI - Impact of OAS1 Exon 7 rs10774671 Genetic Variation on Liver Fibrosis Progression in Egyptian HCV Genotype 4 Patients. AB - The aim of this study was to assess the impact of genetic variants of oligoadenylate synthetase 1 (OAS1) single-nucleotide polymorphism (SNP) rs10774671 at the exon 7 splice acceptor site on liver fibrosis progression and hepatitis C virus (HCV) outcome in Egyptian HCV genotype 4 patients. In this study, 195 subjects were enrolled; 60 controls and 135 chronic HCV genotype 4 patients with different fibrosis grades. All subjects were genotyped for OAS1 SNP rs10774671 polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. There was an increasing trend of liver fibrosis progression as 52.9% GG, 73.6% GA, and 83.3% AA genotypes were detected in late fibrosis patients (p = 0.025). The AA genotype was higher in the late fibrosis group than in the early fibrosis group (83.3% vs. 16.7%) (p = 0.001). The A allele was significantly affecting the liver fibrosis progression rate, more than the G allele (p = 0.001). The multivariate analysis showed that the OAS1 GA and AA genotypes were independent factors associated with liver progression (p = 0.009, odds ratio [OR] 3.467, 95% confidence interval [CI] 1.273-7.584). In addition, the A allele was associated with liver fibrosis progression (p = 0.014, OR 2.525, 95% CI 1.157-4.545). The polymorphism at OAS1 exon 7 rs3741981 might be a potential genetic marker and can be useful in the assessment of liver fibrosis progression and disease outcome in HCV-infected patients. PMID- 26505958 TI - Laparoscopic orchiopexy: short-term outcomes. Experience of a single centre. AB - BACKGROUND: Increased infertility and smaller volume accompany undescended testis. Timing of orchiopexy is still a matter of debate. We evaluated the growth of non-palpable testes after laparoscopic orchiopexy according to age at surgery, intraoperative findings and type of procedure. METHODS: Forty-one boys undergoing laparoscopy for nonpalpable testes were retrospectively reviewed and divided into two groups, <=18 months and >18 months, according to their age at surgery. RESULTS: At follow-up, 14 testes in the younger group had normal size, while 3 atrophied either after single (2) or two stage procedure (1). Similarly, in older boys 11 testes grew normally, while 5 atrophied after both procedures. CONCLUSIONS: Most of the non-palpable testes grew normally after laparoscopic orchiopexy and the postoperative volume seemed independent from the surgical strategy. Both techniques led to a few cases of testicular hypotrophy. In our experience, the age at surgery did not affect the outcome in terms of testicular growth. PMID- 26505960 TI - Human Milk Fortification Increases Bnip3 Expression Associated With Intestinal Cell Death In Vitro. AB - OBJECTIVES: The aim of the present study was to determine the in vitro effect(s) of a bovine-based human breast milk fortifier (HMF) on human intestinal cells. HMF increases the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein (Bnip3) and cell death; the prostaglandin analogue misoprostol will rescue this effect. METHODS: Cultured intestinal cells were exposed to in vitro digested human breast milk (BM) +/- HMF. Intracellular oxidation, cell damage/cell death, and BNIP3 expression were measured after exposure. RESULTS: In vitro-digested BM + HMF significantly increased intracellular oxidation, cell damage, and cell death in enterocyte cell cultures compared with either saline or BM controls, an effect that was rescued by the prostaglandin analogue, misoprostol. Bnip3 transcript and Bnip3 protein levels were significantly increased in vitro after treatment with BM + HMF. We also provide evidence that transfection of enterocytes with Bnip3 increases cell death, an effect that is rescued by a nonfunctional Bnip3 splice variant. CONCLUSIONS: Our data support the hypothesis that HMF increases intestinal Bnip3 in vitro, and that the gene product triggers cell death. We suggest that misoprostol is a promising therapy, which may reduce intestinal cell death. PMID- 26505959 TI - Coordination of planar cell polarity pathways through Spiny-legs. AB - Morphogenesis and physiology of tissues and organs requires planar cell polarity (PCP) systems that orient and coordinate cells and their behaviors, but the relationship between PCP systems has been controversial. We have characterized how the Frizzled and Dachsous-Fat PCP systems are connected through the Spiny legs isoform of the Prickle-Spiny-legs locus. Two different components of the Dachsous-Fat system, Dachsous and Dachs, can each independently interact with Spiny-legs and direct its localization in vivo. Through characterization of the contributions of Prickle, Spiny-legs, Dachsous, Fat, and Dachs to PCP in the Drosophila wing, eye, and abdomen, we define where Dachs-Spiny-legs and Dachsous Spiny-legs interactions contribute to PCP, and provide a new understanding of the orientation of polarity and the basis of PCP phenotypes. Our results support the direct linkage of PCP systems through Sple in specific locales, while emphasizing that cells can be subject to and must ultimately resolve distinct, competing PCP signals. PMID- 26505961 TI - Successful Endoscopic Needle-Knife Catheter Membranotomy of a Congenital Duodenal Web. PMID- 26505962 TI - Successful Eradication of Candida Central Venous Catheter Infection With Ambisome Line Lock in Factitious Illness. PMID- 26505963 TI - Sirolimus is a Successful Treatment for Recurrent Iron Deficiency Anaemia in Blue Rubber Bleb Naevus Syndrome. PMID- 26505966 TI - Intact crowding and temporal masking in dyslexia. AB - Phonological deficits in dyslexia are well documented. However, there is an ongoing discussion about whether visual deficits limit the reading skills of people with dyslexia. Here, we investigated visual crowding and backward masking. We presented a Vernier (i.e., two vertical bars slightly offset to the left or right) and asked observers to indicate the offset direction. Vernier stimuli are visually similar to letters and are strongly affected by crowding, even in the fovea. To increase task difficulty, Verniers are often followed by a mask (i.e., backward masking). We measured Vernier offset discrimination thresholds for the basic Vernier task, under crowding, and under backward masking, in students with dyslexia (n = 19) and age and intelligence matched students (n = 27). We found no group differences in any of these conditions. Controls with fast visual processing (good backward masking performance), were faster readers. By contrast, no such correlation was found among the students with dyslexia, suggesting that backward masking does not limit their reading efficiency. These findings indicate that neither elevated crowding nor elevated backward masking pose a bottleneck to reading skills of people with dyslexia. PMID- 26505964 TI - A fluorometric microarray with ZnO substrate-enhanced fluorescence and suppressed "coffee-ring" effects for fluorescence immunoassays. AB - A glass slide was first patterned with hydrophobic hexadecyltrimethoxysilane (HDS) and then microspotted with hydrophilic ZnO nanoparticles in an aminopropyltriethoxysilane (APS) matrix. The resulting HDS-ZnO-APS microarray could present the capability of suppressing the undesirable "coffee-ring" effects through its hydrophobic pattern so as to allow the fabrication of ZnO-APS testing microspots with a highly dense and uniform distribution. The lotus-like "self cleaning" function could also be expected to effectively curb the cross contamination of multiple sample droplets. More importantly, the introduction of ZnO nanoparticles could endow the testing microspots with substrate-enhanced fluorescence leading to signal-amplification microarray fluorometry. The practical application of the developed HDS-ZnO-APS microarray was investigated by the sandwiched fluorometric immunoassays of human IgG, showing a linear detection range from 0.010 to 10.0 ng mL(-1). Such a throughput-improved fluorometric microarray could be tailored for probing multiple biomarkers in complicated media like serum or blood. PMID- 26505967 TI - Feature expectation heightens visual sensitivity during fine orientation discrimination. AB - Attending to a stimulus enhances the sensitivity of perceptual decisions. However, it remains unclear how perceptual sensitivity varies according to whether a feature is expected or unexpected. Here, observers made fine discrimination judgments about the orientation of visual gratings embedded in low spatial-frequency noise, and psychophysical reverse correlation was used to estimate decision 'kernels' that revealed how visual features influenced choices. Orthogonal cues alerted subjects to which of two spatial locations was likely to be probed (spatial attention cue) and which of two oriented gratings was likely to occur (feature expectation cue). When an expected (relative to unexpected) feature occurred, decision kernels shifted away from the category boundary, allowing observers to capitalize on more informative, "off-channel" stimulus features. By contrast, the spatial attention cue had a multiplicative influence on decision kernels, consistent with an increase in response gain. Feature expectation thus heightens sensitivity to the most informative visual features, independent of selective attention. PMID- 26505968 TI - The HIV Care Cascade Measured Over Time and by Age, Sex, and Race in a Large National Integrated Care System. AB - HIV care cascades can evaluate programmatic success over time. However, methodologies for estimating cascade stages vary, and few have evaluated differences by demographic subgroups. We examined cascade performance over time and by age, sex, and race/ethnicity in Kaiser Permanente, providing HIV care in eight US states and Washington, DC. We created cascades for HIV+ members' age >=13 for 2010-2012. We measured "linkage" (a visit/CD4 within 90 days of being diagnosed for new patients; >=1 medical visit/year if established); "retention" (>=2 medical visits >=60 days apart); filled ART (filled >=3 months of combination ART); and viral suppression (HIV RNA <200 copies/mL last measured in year). The cascades were stratified by calendar year, sex, age, and race/ethnicity. We found men had statistically (p < 0.05) higher percent linkage, filled ART, and viral suppression for 2010 and 2011 but not for 2012. Women had significantly greater retention for all years. Annually, older age was associated (p < 0.05) with retention, filled ART, and viral suppression but not linkage. Latinos had greater (p < 0.05) retention than whites or blacks in all years, with similar retention comparing blacks and whites. Filled ART and viral suppression was increased (p < 0.05) for whites compared with all racial/ethnic groups in all years. Cascade methodology requiring success at upstream stages before measuring success at later stages (i.e., "dependent" methodology) underreported performance by up to 20% compared with evaluating each stage separately ("independent"). Thus, care results improved over time, but significant differences exist by patient demographics. Specifically, retention efforts should be targeted toward younger patients and blacks; women, blacks, and Latinos require greater ART prescribing. PMID- 26505969 TI - Medication-Taking Practices of Patients on Antiretroviral HIV Therapy: Control, Power, and Intentionality. AB - Among people living with HIV (PLWH), adherence to antiretroviral therapy (ART) is crucial for health, but patients face numerous challenges achieving sustained lifetime adherence. We conducted six focus groups with 56 PLWH regarding ART adherence barriers and collected sociodemographics and ART histories. Participants were recruited through clinics and AIDS service organizations in North Carolina. Dedoose software was used to support thematic analysis. Participants were 59% male, 77% black, aged 23-67 years, and living with HIV 4-20 years. Discussions reflected the fluid, complex nature of ART adherence. Maintaining adherence required participants to indefinitely assert consistent control across multiple areas including: their HIV disease, their own bodies, health care providers, and social systems (e.g., criminal justice, hospitals, drug assistance programs). Participants described limited control over treatment options, ART's impact on their body, and inconsistent access to ART and subsequent inability to take ART as prescribed. When participants felt they had more decision-making power, intentionally choosing whether and how to take ART was not exclusively a decision about best treating HIV. Instead, through these decisions, participants tried to regain some amount of power and control in their lives. Supportive provider relationships assuaged these struggles, while perceived side-effects and multiple co-morbidities further complicated adherence. Adherence interventions need to better convey adherence as a continuous, changing process, not a fixed state. A perspective shift among care providers could also help address negative consequences of the perceived power struggles and pressures that may drive patients to exert control via intentional medication taking practices. PMID- 26505971 TI - Program and Abstracts of the 38th Annual Meeting of the American Society of Primatologists, June 18-21, 2015. PMID- 26505970 TI - Large enhancement in the heterogeneous oxidation rate of organic aerosols by hydroxyl radicals in the presence of nitric oxide. AB - In the troposphere, the heterogeneous lifetime of an organic molecule in an aerosol exposed to hydroxyl radicals (OH) is thought to be weeks, which is orders of magnitude slower than the analogous gas phase reactions (hours). Here, we report an unexpectedly large acceleration in the effective heterogeneous OH reaction rate in the presence of NO. This 10-50 fold acceleration originates from free radical chain reactions, propagated by alkoxy radicals that form inside the aerosol by the reaction of NO with peroxy radicals, which do not appear to produce chain terminating products (e.g., alkyl nitrates), unlike gas phase mechanisms. A kinetic model, constrained by experiments, suggests that in polluted regions heterogeneous oxidation plays a much more prominent role in the daily chemical evolution of organic aerosol than previously believed. PMID- 26505972 TI - CD44 and TLR4 mediate hyaluronic acid regulation of Lgr5+ stem cell proliferation, crypt fission, and intestinal growth in postnatal and adult mice. AB - Hyaluronic acid, a glycosaminoglycan in the extracellular matrix, binds to CD44 and Toll-like receptor 4 (TLR4). We previously addressed the role of hyaluronic acid in small intestinal and colonic growth in mice. We addressed the role of exogenous hyaluronic acid by giving hyaluronic acid intraperitoneally and the role of endogenous hyaluronic acid by giving PEP-1, a peptide that blocks hyaluronic acid binding to its receptors. Exogenous hyaluronic acid increased epithelial proliferation but had no effect on intestinal length. PEP-1 resulted in a shortened small intestine and colon and diminished epithelial proliferation. In the current study, we sought to determine whether the effects of hyaluronic acid on growth were mediated by signaling through CD44 or TLR4 by giving exogenous hyaluronic acid or PEP-1 twice a week from 3-8 wk of age to wild-type, CD44(-/-), and TLR4(-/-) mice. These studies demonstrated that signaling through both CD44 and TLR4 were important in mediating the effects of hyaluronic acid on growth in the small intestine and colon. Extending our studies to early postnatal life, we assessed the effects of exogenous hyaluronic acid and PEP-1 on Lgr5(+) stem cell proliferation and crypt fission. Administration of PEP-1 to Lgr5(+) reporter mice from postnatal day 7 to day 14 decreased Lgr5(+) cell proliferation and decreased crypt fission. These studies indicate that endogenous hyaluronic acid increases Lgr5(+) stem cell proliferation, crypt fission, and intestinal lengthening and that these effects are dependent on signaling through CD44 and TLR4. PMID- 26505973 TI - Despite sequence homologies to gluten, salivary proline-rich proteins do not elicit immune responses central to the pathogenesis of celiac disease. AB - Celiac disease (CD) is an inflammatory disorder triggered by ingested gluten, causing immune-mediated damage to the small-intestinal mucosa. Gluten proteins are strikingly similar in amino acid composition and sequence to proline-rich proteins (PRPs) in human saliva. On the basis of this feature and their shared destination in the gastrointestinal tract, we hypothesized that salivary PRPs may modulate gluten-mediated immune responses in CD. Parotid salivary secretions were collected from CD patients, refractory CD patients, non-CD patients with functional gastrointestinal complaints, and healthy controls. Structural similarities of PRPs with gluten were probed with anti-gliadin antibodies. Immune responses to PRPs were investigated toward CD patient-derived peripheral blood mononuclear cells and in a humanized transgenic HLA-DQ2/DQ8 mouse model for CD. Anti-gliadin antibodies weakly cross-reacted with the abundant salivary amylase but not with PRPs. Likewise, the R5 antibody, recognizing potential antigenic gluten epitopes, showed negligible reactivity to salivary proteins from all groups. Inflammatory responses in peripheral blood mononuclear cells were provoked by gliadins whereas responses to PRPs were similar to control levels, and PRPs did not compete with gliadins in immune stimulation. In vivo, PRP peptides were well tolerated and nonimmunogenic in the transgenic HLA-DQ2/DQ8 mouse model. Collectively, although structurally similar to dietary gluten, salivary PRPs were nonimmunogenic in CD patients and in a transgenic HLA-DQ2/DQ8 mouse model for CD. It is possible that salivary PRPs play a role in tolerance induction to gluten early in life. Deciphering the structural basis for the lack of immunogenicity of salivary PRPs may further our understanding of the toxicity of gluten. PMID- 26505974 TI - Apolipoprotein A-V is present in bile and its secretion increases with lipid absorption in Sprague-Dawley rats. AB - Apolipoprotein (apo) A-V is a protein synthesized only in the liver that dramatically modulates plasma triglyceride levels. Recent studies suggest a novel role for hepatic apoA-V in regulating the absorption of dietary triglycerides, but its mode of action on the gut remains unknown. The aim of this study was to test for apoA-V in bile and to determine whether its secretion is regulated by dietary lipids. After an overnight recovery, adult male Sprague-Dawley bile fistula rats indeed secreted apoA-V into bile at a constant rate under fasting conditions. An intraduodenal bolus of intralipid (n = 12) increased the biliary secretion of apoA-V but not of other apolipoproteins, such as A-I, A-IV, B, and E. The lipid-induced increase of biliary apoA-V was abolished under conditions of poor lymphatic lipid transport, suggesting that the stimulation is regulated by the magnitude of lipids associated with chylomicrons transported into lymph. We also studied the secretion of apoA-V into bile immediately following bile duct cannulation. Biliary apoA-V increased over time (~6-fold increase at hour 16, n = 8) but the secretions of other apolipoproteins remained constant. Replenishing luminal phosphatidylcholine and taurocholate (n = 9) only enhanced apoA-V secretion in bile, suggesting that the increase was not due to depletion of phospholipids or bile salts. This is the first study to demonstrate that apoA-V is secreted into bile, introducing a potential route of delivery of hepatic apoA V to the gut lumen. Our study also reveals the uniqueness of apoA-V secretion into bile that is regulated by mechanisms different from other apolipoproteins. PMID- 26505976 TI - Volume-outcome relationship in pancreatic surgery. AB - BACKGROUND: Volume-outcome relationships related to major surgery may be of limited value if observation ends at the point of discharge without taking transfers and later events into consideration. METHODS: The volume-outcome relationship in patients who underwent pancreatic surgery between 2008 and 2010 was assessed using claims data for all inpatient episodes from Germany's largest provider of statutory health insurance covering about 30 per cent of the population. Multiple logistic regression models with random effects were used to analyse the effect of hospital volume (using volume quintiles) on 1-year mortality, adjusting for age, sex, primary disease, type of surgery and co morbidities. Additional outcomes were in-hospital (including transfer to other hospitals until final discharge) and 90-day mortality. RESULTS: Of 9566 patients identified, risk-adjusted 1-year mortality was significantly higher in the three lowest-volume quintiles compared with the highest-volume quintile (odds ratio 1.73, 1.53 and 1.37 respectively). A similar, but less pronounced, effect was demonstrated for in-hospital and 90-day mortality. The effect of hospital volume on 1-year mortality was comparable to the effect of co-morbid conditions such as renal failure. CONCLUSION: Although mortality related to pancreatic surgery is influenced by many factors, this study demonstrated lower mortality at 1 year in high-volume centres in Germany. PMID- 26505975 TI - Loss of NHE8 expression impairs intestinal mucosal integrity. AB - The newest member of the Na(+)/H(+) exchanger (NHE) family, NHE8, is abundantly expressed at the apical membrane of the intestinal epithelia. We previously reported that mucin 2 expression was significantly decreased in the colon in NHE8(-/-) mice, suggesting that NHE8 is involved in intestinal mucosal protection. In this study, we further evaluated the role of NHE8 in intestinal epithelial protection after dextran sodium sulfate (DSS) challenge. Compared with wild-type mice, NHE8(-/-) mice have increased bacterial adhesion and inflammation, especially in the distal colon. NHE8(-/-) mice are also susceptible to DSS treatment. Real-time PCR detected a remarkable increase in the expression of IL-1beta, IL-6, TNF-alpha, and IL-4 in DSS-treated NHE8(-/-) mice compared with DSS-treated wild-type littermates. Immunohistochemistry showed a disorganized epithelial layer in the colon of NHE8(-/-) mice. Periodic acid Schiff staining showed a reduction in the number of mature goblet cells and the area of the goblet cell theca in NHE8(-/-) mice. Phyloxine/tartrazine staining revealed a decrease in functional Paneth cell population in the NHE8(-/-) small intestinal crypt. The expression of enteric defensins was also decreased in NHE8( /-) mice. The reduced mucin production in goblet cells and antimicrobial peptides production in Paneth cells lead to disruption of the intestinal mucosa protection. Therefore, NHE8 may be involved in the establishment of intestinal mucosal integrity by regulating the functions of goblet and Paneth cells. PMID- 26505977 TI - Arabidopsis thaliana isoprenyl diphosphate synthases produce the C25 intermediate geranylfarnesyl diphosphate. AB - Isoprenyl diphosphate synthases (IDSs) catalyze some of the most basic steps in terpene biosynthesis by producing the prenyl diphosphate precursors of each of the various terpenoid classes. Most plants investigated have distinct enzymes that produce the short-chain all-trans (E) prenyl diphosphates geranyl diphosphate (GDP, C10 ), farnesyl diphosphate (FDP, C15 ) or geranylgeranyl diphosphate (GGDP, C20 ). In the genome of Arabidopsis thaliana, 15 trans-product forming IDSs are present. Ten of these have recently been shown to produce GGDP by genetic complementation of a carotenoid pathway engineered into Escherichia coli. When verifying the product pattern of IDSs producing GGDP by a new LC-MS/MS procedure, we found that five of these IDSs produce geranylfarnesyl diphosphate (GFDP, C25 ) instead of GGDP as their major product in enzyme assays performed in vitro. Over-expression of one of the GFDP synthases in A. thaliana confirmed the production of GFDP in vivo. Enzyme assays with A. thaliana protein extracts from roots but not other organs showed formation of GFDP. Furthermore, GFDP itself was detected in root extracts. Subcellular localization studies in leaves indicated that four of the GFDP synthases were targeted to the plastoglobules of the chloroplast and one was targeted to the mitochondria. Sequence comparison and mutational studies showed that the size of the R group of the 5th amino acid residue N-terminal to the first aspartate-rich motif is responsible for C25 versus C20 product formation, with smaller R groups (Ala and Ser) resulting in GGDP (C20 ) as a product and a larger R group (Met) resulting in GFDP (C25 ). PMID- 26505978 TI - Macroscopic and Spectroscopic Assessment of the Cosorption of Fe(II) with As(III) and As(V) on Al-Oxide. AB - The cosorption of Fe(II) with As(III) and As(V) in anoxic suspensions of gamma Al2O3 at pH 7.5 was investigated with batch kinetic experiments and synchrotron EXAFS analyses. Single-sorbate results showed that Fe(II) formed secondary Fe(II) Al(III)-layered double hydroxide (LDH) phases during reaction with the Al-oxide sorbent, whereas As(III) and As(V) formed inner-sphere surface complexes. The kinetics and mechanisms of Fe(II) and As(III) sorption were identical in dual sorbate and single-sorbate experiments, indicating that the processes involved operate independently. In contrast, As(V) and Fe(II) interacted strongly during cosorption. Fe(II) enhanced the rate and extent of As(V) removal from solution, but did not affect the mechanism of As(V) adsorption. Conversely, As(V) hindered the formation of Fe(II)-Al(III)-LDH, slowing down precipitation at low As(V) concentrations and preventing it at high concentrations. This was attributed to interference of adsorbed As(V) with the Al supply needed for Fe(II)-Al(III)-LDH precipitation, possibly combined with enhanced surface complexation of Fe(II) cations promoted by anionic As(V) surface species. No evidence was found for redox reactions between Fe(II) and As(V) or As(III), or for precipitation of Fe arsenic phases. These results improve our understanding of the geochemistry of Fe(II) and arsenic in reducing environments, and demonstrate the utility of mechanistic studies on geochemically complex model systems. PMID- 26505979 TI - The Global Burden of Stroke. PMID- 26505980 TI - Methods for Estimating the Global Burden of Cerebrovascular Diseases. AB - The Global Burden of Disease (GBD) study is a long-standing effort to report consistent and comprehensive measures of disease burden for the world. In this paper, we describe the methods used to estimate the global burden of stroke for the GBD 2013 study. Pathologic subtypes of stroke are modeled separately for two mutually exclusive and exhaustive categories: (1) ischemic stroke and (2) hemorrhagic and other non-ischemic strokes. Acute and chronic strokes are estimated separately. The GBD 2013 study has incorporated large amounts of new data on stroke death rates, incidence and case fatality. Disease modeling methods have been updated to better integrate mortality and incidence data. Future efforts will focus on incorporating data on the regional variation in severity of disability. Stroke remains a new area for disease modeling. A better understanding of stroke incidence, mortality and severity, and how it varies among countries, can help guide priority setting and improve health policy related to this important condition. PMID- 26505982 TI - Stroke Prevalence, Mortality and Disability-Adjusted Life Years in Children and Youth Aged 0-19 Years: Data from the Global and Regional Burden of Stroke 2013. AB - BACKGROUND: There is increasing recognition of stroke as an important contributor to childhood morbidity and mortality. Current estimates of global childhood stroke burden and its temporal trends are sparse. Accurate and up-to-date estimates of childhood stroke burden are important for planning research and the resulting evidence-based strategies for stroke prevention and management. OBJECTIVES: To estimate the prevalence, mortality and disability-adjusted life years (DALYs) for ischemic stroke (IS), hemorrhagic stroke (HS) and all stroke types combined globally from 1990 to 2013. METHODOLOGY: Stroke prevalence, mortality and DALYs were estimated using the Global Burden of Disease 2013 methods. All available data on stroke-related incidence, prevalence, excess mortality and deaths were collected. Statistical models and country-level covariates were employed to produce comprehensive and consistent estimates of prevalence and mortality. Stroke-specific disability weights were used to estimate years lived with disability and DALYs. Means and 95% uncertainty intervals (UIs) were calculated for prevalence, mortality and DALYs. The median of the percent change and 95% UI were determined for the period from 1990 to 2013. RESULTS: In 2013, there were 97,792 (95% UI 90,564-106,016) prevalent cases of childhood IS and 67,621 (95% UI 62,899-72,214) prevalent cases of childhood HS, reflecting an increase of approximately 35% in the absolute numbers of prevalent childhood strokes since 1990. There were 33,069 (95% UI 28,627-38,998) deaths and 2,615,118 (95% UI 2,265,801-3,090,822) DALYs due to childhood stroke in 2013 globally, reflecting an approximately 200% decrease in the absolute numbers of death and DALYs in childhood stroke since 1990. Between 1990 and 2013, there were significant increases in the global prevalence rates of childhood IS, as well as significant decreases in the global death rate and DALYs rate of all strokes in those of age 0-19 years. While prevalence rates for childhood IS and HS decreased significantly in developed countries, a decline was seen only in HS, with no change in prevalence rates of IS, in developing countries. The childhood stroke DALY rates in 2013 were 13.3 (95% UI 10.6-17.1) for IS and 92.7 (95% UI 80.5-109.7) for HS per 100,000. While the prevalence of childhood IS compared to childhood HS was similar globally, the death rate and DALY rate of HS was 6- to 7 fold higher than that of IS. In 2013, the prevalence rate of both childhood IS and HS was significantly higher in developed countries than in developing countries. Conversely, both death and DALY rates for all stroke types were significantly lower in developed countries than in developing countries in 2013. Men showed a trend toward higher childhood stroke death rates (1.5 (1.3-1.8) per 100,000) than women (1.1 (0.9-1.5) per 100,000) and higher childhood stroke DALY rates (120.1 (100.8-143.4) per 100,000) than women (90.9 (74.6-122.4) per 100,000) globally in 2013. CONCLUSIONS: Globally, between 1990 and 2013, there was a significant increase in the absolute number of prevalent childhood strokes, while absolute numbers and rates of both deaths and DALYs declined significantly. The gap in childhood stroke burden between developed and developing countries is closing; however, in 2013, childhood stroke burden in terms of absolute numbers of prevalent strokes, deaths and DALYs remained much higher in developing countries. There is an urgent need to address these disparities with both global and country-level initiatives targeting prevention as well as improved access to acute and chronic stroke care. PMID- 26505981 TI - Update on the Global Burden of Ischemic and Hemorrhagic Stroke in 1990-2013: The GBD 2013 Study. AB - BACKGROUND: Global stroke epidemiology is changing rapidly. Although age standardized rates of stroke mortality have decreased worldwide in the past 2 decades, the absolute numbers of people who have a stroke every year, and live with the consequences of stroke or die from their stroke, are increasing. Regular updates on the current level of stroke burden are important for advancing our knowledge on stroke epidemiology and facilitate organization and planning of evidence-based stroke care. OBJECTIVES: This study aims to estimate incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke (IS) and hemorrhagic stroke (HS) for 188 countries from 1990 to 2013. METHODOLOGY: Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated using all available data on mortality and stroke incidence, prevalence and excess mortality. Statistical models and country-level covariate data were employed, and all rates were age standardized to a global population. All estimates were produced with 95% uncertainty intervals (UIs). RESULTS: In 2013, there were globally almost 25.7 million stroke survivors (71% with IS), 6.5 million deaths from stroke (51% died from IS), 113 million DALYs due to stroke (58% due to IS) and 10.3 million new strokes (67% IS). Over the 1990-2013 period, there was a significant increase in the absolute number of DALYs due to IS, and of deaths from IS and HS, survivors and incident events for both IS and HS. The preponderance of the burden of stroke continued to reside in developing countries, comprising 75.2% of deaths from stroke and 81.0% of stroke-related DALYs. Globally, the proportional contribution of stroke-related DALYs and deaths due to stroke compared to all diseases increased from 1990 (3.54% (95% UI 3.11-4.00) and 9.66% (95% UI 8.47-10.70), respectively) to 2013 (4.62% (95% UI 4.01-5.30) and 11.75% (95% UI 10.45-13.31), respectively), but there was a diverging trend in developed and developing countries with a significant increase in DALYs and deaths in developing countries, and no measurable change in the proportional contribution of DALYs and deaths from stroke in developed countries. CONCLUSION: Global stroke burden continues to increase globally. More efficient stroke prevention and management strategies are urgently needed to halt and eventually reverse the stroke pandemic, while universal access to organized stroke services should be a priority. (c) 2015 S. Karger AG, Basel. PMID- 26505983 TI - Stroke Prevalence, Mortality and Disability-Adjusted Life Years in Adults Aged 20 64 Years in 1990-2013: Data from the Global Burden of Disease 2013 Study. AB - BACKGROUND: Recent evidence suggests that stroke is increasing as a cause of morbidity and mortality in younger adults, where it carries particular significance for working individuals. Accurate and up-to-date estimates of stroke burden are important for planning stroke prevention and management in younger adults. OBJECTIVES: This study aims to estimate prevalence, mortality and disability-adjusted life years (DALYs) and their trends for total, ischemic stroke (IS) and hemorrhagic stroke (HS) in the world for 1990-2013 in adults aged 20-64 years. METHODOLOGY: Stroke prevalence, mortality and DALYs were estimated using the Global Burden of Disease (GBD) 2013 methods. All available data on rates of stroke incidence, excess mortality, prevalence and death were collected. Statistical models were used along with country-level covariates to estimate country-specific stroke burden. Stroke-specific disability weights were used to compute years lived with disability and DALYs. Means and 95% uncertainty intervals (UIs) were calculated for prevalence, mortality and DALYs. The median of the percent change and 95% UI were determined for the period from 1990 to 2013. RESULTS: In 2013, in younger adults aged 20-64 years, the global prevalence of HS was 3,725,085 cases (95% UI 3,548,098-3,871,018) and IS was 7,258,216 cases (95% UI 6,996,272-7,569,403). Globally, between 1990 and 2013, there were significant increases in absolute numbers and prevalence rates of both HS and IS for younger adults. There were 1,483,707 (95% UI 1,340,579-1,658,929) stroke deaths globally among younger adults but the number of deaths from HS (1,047,735 (95% UI 945,087-1,184,192)) was significantly higher than the number of deaths from IS (435,972 (95% UI 354,018-504,656)). There was a 20.1% (95% UI -23.6 to 10.3) decline in the number of total stroke deaths among younger adults in developed countries but a 36.7% (95% UI 26.3-48.5) increase in developing countries. Death rates for all strokes among younger adults declined significantly in developing countries from 47 (95% UI 42.6-51.7) in 1990 to 39 (95% UI 35.0-43.8) in 2013. Death rates for all strokes among younger adults also declined significantly in developed countries from 33.3 (95% UI 29.8-37.0) in 1990 to 23.5 (95% UI 21.1-26.9) in 2013. A significant decrease in HS death rates for younger adults was seen only in developed countries between 1990 and 2013 (19.8 (95% UI 16.9-22.6) and 13.7 (95% UI 12.1-15.9)) per 100,000). No significant change was detected in IS death rates among younger adults. The total DALYs from all strokes in those aged 20-64 years was 51,429,440 (95% UI 46,561,382-57,320,085). Globally, there was a 24.4% (95% UI 16.6-33.8) increase in total DALY numbers for this age group, with a 20% (95% UI 11.7-31.1) and 37.3% (95% UI 23.4-52.2) increase in HS and IS numbers, respectively. CONCLUSIONS: Between 1990 and 2013, there were significant increases in prevalent cases, total deaths and DALYs due to HS and IS in younger adults aged 20-64 years. Death and DALY rates declined in both developed and developing countries but a significant increase in absolute numbers of stroke deaths among younger adults was detected in developing countries. Most of the burden of stroke was in developing countries. In 2013, the greatest burden of stroke among younger adults was due to HS. While the trends in declining death and DALY rates in developing countries are encouraging, these regions still fall far behind those of developed regions of the world. A more aggressive approach toward primary prevention and increased access to adequate healthcare services for stroke is required to substantially narrow these disparities. PMID- 26505986 TI - Elderly Patients Require Higher Doses of Sugammadex for Rapid Recovery from Deep Neuromuscular Block. AB - This study compared the doses of sugammadex needed for rapid recovery from deep neuromuscular blockade (NMB) between young and elderly adults. Twenty-two young (20-40 yrs) and 22 elderly (>=70 yrs) adults were enrolled, and deep NMB of 1-2 post-tetanic counts was maintained with rocuronium intraoperatively. Predetermined doses of sugammadex were given at the end of surgery starting at 4.0 mg/kg for the first patient of each group. Doses were decreased or increased in following patients by 0.5 mg/kg, depending on the 'success' or 'failure' of rapid recovery in the preceding patient. 'Success' was defined as adequate recovery (train-of-four ratio 0.9) within 2 min. after sugammadex administration. The median (range) of ages was 29 (20-40) and 73 (70-84) yrs for the young and elderly adults, respectively. Doses of sugammadex facilitating adequate recovery from deep NMB within 2 min. in each patient population with 50% and 95% probability were defined as ED50 and ED95 , respectively. The ED50 estimated by the Dixon's method was significantly higher in the elderly compared to young adults [4.2 +/- 0.4 mg/kg versus 3.3 +/- 0.3 mg/kg, p < 0.001]. The ED50 (83% CI) estimated by isotonic regression was 4.5 (4.2-5.0) mg/kg in elderly adults and 3.3 (3.2-3.4) mg/kg in young adults. The ED95 (95% CI) estimated by isotonic regression was 5.4 (4.9-5.5) mg/kg and 4.4 (3.9-4.5) mg/kg in the elderly and young adults, respectively. In conclusion, dose adjustments of sugammadex should be considered when rapid recovery from deep NMB is needed in elderly adults. PMID- 26505988 TI - Genomewide gene-associated microsatellite markers for the model invasive ascidian, Ciona intestinalis species complex. AB - The vase tunicate, Ciona intestinalis species complex, has become a good model for ecological and evolutionary studies, especially those focusing on microevolution associated with rapidly changing environments. However, genomewide genetic markers are still lacking. Here, we characterized a large set of genomewide gene-associated microsatellite markers for C. intestinalis spA (=C. robusta). Bioinformatic analysis identified 4654 microsatellites from expressed sequence tags (ESTs), 2126 of which successfully assigned to chromosomes were selected for further analysis. Based on the distribution evenness on chromosomes, function annotation and suitability for primer design, we chose 545 candidate microsatellites for further characterization. After amplification validation and variation assessment, 218 loci were polymorphic in at least one of the two populations collected from the coast of Arenys de Mar, Spain (N = 24-48), and Cape Town, South Africa (N = 24-33). The number of alleles, observed heterozygosity and expected heterozygosity ranged from 2 to 11, 0 to 0.833 and 0.021 to 0.818, and from 2 to 10, 0 to 0.879 and 0.031 to 0.845 for the Spanish and African populations, respectively. When all microsatellites were tested for cross-species utility, only 60 loci (25.8%) could be successfully amplified and all loci were polymorphic in C. intestinalis spB. A high level of genomewide polymorphism is likely responsible for the low transferability. The large set of microsatellite markers characterized here is expected to provide a useful genomewide resource for ecological and evolutionary studies using C. intestinalis as a model. PMID- 26505987 TI - Controlled Synthesis of Organic/Inorganic van der Waals Solid for Tunable Light Matter Interactions. AB - High-quality organic and inorganic van der Waals (vdW) solids are realized using methylammonium lead halide (CH3 NH3 PbI3 ) as the organic part (organic perovskite) and 2D inorganic monolayers as counterparts. By stacking on various 2D monolayers, the vdW solids exhibit dramatically different light emissions. Futhermore, organic/h-BN vdW solid arrays are patterned for red-light emission. PMID- 26505989 TI - Asthma and dietary intake: an overview of systematic reviews. AB - Epidemiological research on the relationship between diet and asthma has increased in the last decade. Several components found in foods have been proposed to have a series of antioxidant, anti-allergic and anti-inflammatory properties, which can have a protective effect against asthma risk. Several literature reviews and critical appraisals have been published to summarize the existing evidence in this field. In the context of this EAACI Lifestyle and asthma Task Force, we summarize the evidence from existing systematic reviews on dietary intake and asthma, using the PRISMA guidelines. We therefore report the quality of eligible systematic reviews and summarize the results of those with an AMSTAR score >=32. The GRADE approach is used to assess the overall quality of the existing evidence. This overview is centred on systematic reviews of nutritional components provided in the diet only, as a way to establish what type of advice can be given in clinical practice and to the general population on dietary habits and asthma. PMID- 26505985 TI - Atlas of the Global Burden of Stroke (1990-2013): The GBD 2013 Study. AB - BACKGROUND: World mapping is an important tool to visualize stroke burden and its trends in various regions and countries. OBJECTIVES: To show geographic patterns of incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke and hemorrhagic stroke in the world for 1990-2013. METHODOLOGY: Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated following the general approach of the Global Burden of Disease (GBD) 2010 with several important improvements in methods. Data were updated for mortality (through April 2014) and stroke incidence, prevalence, case fatality and severity through 2013. Death was estimated using an ensemble modeling approach. A new software package, DisMod-MR 2.0, was used as part of a custom modeling process to estimate YLDs. All rates were age-standardized to new GBD estimates of global population. All estimates have been computed with 95% uncertainty intervals. RESULTS: Age-standardized incidence, mortality, prevalence and DALYs/YLDs declined over the period from 1990 to 2013. However, the absolute number of people affected by stroke has substantially increased across all countries in the world over the same time period, suggesting that the global stroke burden continues to increase. There were significant geographical (country and regional) differences in stroke burden in the world, with the majority of the burden borne by low- and middle-income countries. CONCLUSIONS: Global burden of stroke has continued to increase in spite of dramatic declines in age-standardized incidence, prevalence, mortality rates and disability. Population growth and aging have played an important role in the observed increase in stroke burden. PMID- 26505990 TI - Changes in the Epidemiology of Neuroendocrine Tumours. AB - BACKGROUND: The reviewing and assessment of epidemiological characteristics of neuroendocrine tumours (NETs) remains a challenge. Despite the fact that it is an uncommon family of neoplasms, several worldwide series have revealed an increasing incidence of this rare condition. However, the data are difficult to compare over time due to changes in classification. METHODS: We compared the data related to incidence, prevalence, stage of the disease at diagnosis and survival reported in several series, focusing on the differences and trying to examine some of the probable reasons that may explain the variations in the results between studies. RESULTS AND CONCLUSIONS: The incidence of NETs is increasing over time, and their incidental discovery due to improved and more frequent imaging does not seem to be enough to explain this rise. Significant differences can be found between geographic regions and races, suggesting that environmental or genetic factors may contribute to the clinical and biological behaviour of these tumours; increasing our knowledge of oncogenesis will be necessary to explain them. As with other rare diseases, creating specific databases and multidisciplinary working groups would improve the accuracy of the information gained. PMID- 26505984 TI - Sex Differences in Stroke Incidence, Prevalence, Mortality and Disability Adjusted Life Years: Results from the Global Burden of Disease Study 2013. AB - BACKGROUND: Accurate information on stroke burden in men and women are important for evidence-based healthcare planning and resource allocation. Previously, limited research suggested that the absolute number of deaths from stroke in women was greater than in men, but the incidence and mortality rates were greater in men. However, sex differences in various metrics of stroke burden on a global scale have not been a subject of comprehensive and comparable assessment for most regions of the world, nor have sex differences in stroke burden been examined for trends over time. METHODS: Stroke incidence, prevalence, mortality, disability adjusted life years (DALYs) and healthy years lost due to disability were estimated as part of the Global Burden of Disease (GBD) 2013 Study. Data inputs included all available information on stroke incidence, prevalence and death and case fatality rates. Analysis was performed separately by sex and 5-year age categories for 188 countries. Statistical models were employed to produce globally comprehensive results over time. All rates were age-standardized to a global population and 95% uncertainty intervals (UIs) were computed. FINDINGS: In 2013, global ischemic stroke (IS) and hemorrhagic stroke (HS) incidence (per 100,000) in men (IS 132.77 (95% UI 125.34-142.77); HS 64.89 (95% UI 59.82-68.85)) exceeded those of women (IS 98.85 (95% UI 92.11-106.62); HS 45.48 (95% UI 42.43 48.53)). IS incidence rates were lower in 2013 compared with 1990 rates for both sexes (1990 male IS incidence 147.40 (95% UI 137.87-157.66); 1990 female IS incidence 113.31 (95% UI 103.52-123.40)), but the only significant change in IS incidence was among women. Changes in global HS incidence were not statistically significant for males (1990 = 65.31 (95% UI 61.63-69.0), 2013 = 64.89 (95% UI 59.82-68.85)), but was significant for females (1990 = 64.892 (95% UI 59.82 68.85), 2013 = 45.48 (95% UI 42.427-48.53)). The number of DALYs related to IS rose from 1990 (male = 16.62 (95% UI 13.27-19.62), female = 17.53 (95% UI 14.08 20.33)) to 2013 (male = 25.22 (95% UI 20.57-29.13), female = 22.21 (95% UI 17.71 25.50)). The number of DALYs associated with HS also rose steadily and was higher than DALYs for IS at each time point (male 1990 = 29.91 (95% UI 25.66-34.54), male 2013 = 37.27 (95% UI 32.29-45.12); female 1990 = 26.05 (95% UI 21.70-30.90), female 2013 = 28.18 (95% UI 23.68-33.80)). INTERPRETATION: Globally, men continue to have a higher incidence of IS than women while significant sex differences in the incidence of HS were not observed. The total health loss due to stroke as measured by DALYs was similar for men and women for both stroke subtypes in 2013, with HS higher than IS. Both IS and HS DALYs show an increasing trend for both men and women since 1990, which is statistically significant only for IS among men. Ongoing monitoring of sex differences in the burden of stroke will be needed to determine if disease rates among men and women continue to diverge. Sex disparities related to stroke will have important clinical and policy implications that can guide funding and resource allocation for national, regional and global health programs. PMID- 26505991 TI - Direct Synthesis of Unilamellar MgAl-LDH Nanosheets and Stacking in Aqueous Solution. AB - Two-dimensional (2D) materials, such as graphene, inorganic oxides, and hydroxides, are one of the most extensively studied classes of materials due to their unilamellar crystallites or nanosheet structures. In this study, instead of using the universal exfoliation method of the bulky crystal precursor, 2D crystals/nanosheets of MgAl-layered double hydroxides (LDHs) were synthesized in formamide. We propose that the obtained crystals are unilamellar according to the XRD, TEM, and AFM observations. The HRTEM and fast Fourier transform images confirm that the crystal structures are the same as those of the exfoliated MgAl LDH nanosheets. The directly synthesized sheets can stack into a 3D crystal structure, which is the same as that of typical LDHs except for the disordered orientation of the a-/b- crystal axis of each sheet. This result provides not only a novel approach to the preparation of 2D crystals but also insight into the formation mechanism of LDHs. PMID- 26505993 TI - Is Whole-Exome Sequencing an Ethically Disruptive Technology? Perspectives of Pediatric Oncologists and Parents of Pediatric Patients With Solid Tumors. AB - BACKGROUND: It has been anticipated that physician and parents will be ill prepared or unprepared for the clinical introduction of genome sequencing, making it ethically disruptive. PROCEDURE: As a part of the Baylor Advancing Sequencing in Childhood Cancer Care study, we conducted semistructured interviews with 16 pediatric oncologists and 40 parents of pediatric patients with cancer prior to the return of sequencing results. We elicited expectations and attitudes concerning the impact of sequencing on clinical decision making, clinical utility, and treatment expectations from both groups. Using accepted methods of qualitative research to analyze interview transcripts, we completed a thematic analysis to provide inductive insights into their views of sequencing. RESULTS: Our major findings reveal that neither pediatric oncologists nor parents anticipate sequencing to be an ethically disruptive technology, because they expect to be prepared to integrate sequencing results into their existing approaches to learning and using new clinical information for care. Pediatric oncologists do not expect sequencing results to be more complex than other diagnostic information and plan simply to incorporate these data into their evidence-based approach to clinical practice, although they were concerned about impact on parents. For parents, there is an urgency to protect their child's health and in this context they expect genomic information to better prepare them to participate in decisions about their child's care. CONCLUSIONS: Our data do not support the concern that introducing genome sequencing into childhood cancer care will be ethically disruptive, that is, leave physicians or parents ill prepared or unprepared to make responsible decisions about patient care. PMID- 26505992 TI - Melanopsin retinal ganglion cell loss in Alzheimer disease. AB - OBJECTIVE: Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction. METHODS: We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest-activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid beta (Abeta) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls. RESULTS: We demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, Abeta accumulation was remarkably evident inside and around mRGCs. INTERPRETATION: We show variable degrees of rest-activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Abeta deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD. PMID- 26505994 TI - Limited Effect of Chronic Valproic Acid Treatment in a Mouse Model of Machado Joseph Disease. AB - Machado-Joseph disease (MJD) is an inherited neurodegenerative disease, caused by a CAG repeat expansion within the coding region of ATXN3 gene, and which currently lacks effective treatment. In this work we tested the therapeutic efficacy of chronic treatment with valproic acid (VPA) (200mg/kg), a compound with known neuroprotection activity, and previously shown to be effective in cell, fly and nematode models of MJD. We show that chronic VPA treatment in the CMVMJD135 mouse model had limited effects in the motor deficits of these mice, seen mostly at late stages in the motor swimming, beam walk, rotarod and spontaneous locomotor activity tests, and did not modify the ATXN3 inclusion load and astrogliosis in affected brain regions. However, VPA chronic treatment was able to increase GRP78 protein levels at 30 weeks of age, one of its known neuroprotective effects, confirming target engagement. In spite of limited results, the use of another dosage of VPA or of VPA in a combined therapy with molecules targeting other pathways, cannot be excluded as potential strategies for MJD therapeutics. PMID- 26505995 TI - Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma. AB - Ewing's sarcoma is a malignant pediatric bone tumor with a poor prognosis for patients with metastatic or recurrent disease. Ewing's sarcoma cells are acutely hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition and this is being evaluated in clinical trials, although the mechanism of hypersensitivity has not been directly addressed. PARP inhibitors have efficacy in tumors with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair by homologous recombination (HR). This drives dependence on PARP1/2 due to their function in DNA single-strand break (SSB) repair. PARP inhibitors are also cytotoxic through inhibiting PARP1/2 auto-PARylation, blocking PARP1/2 release from substrate DNA. Here, we show that PARP inhibitor sensitivity in Ewing's sarcoma cells is not through an apparent defect in DNA repair by HR, but through hypersensitivity to trapped PARP1-DNA complexes. This drives accumulation of DNA damage during replication, ultimately leading to apoptosis. We also show that the activity of PARP inhibitors is potentiated by temozolomide in Ewing's sarcoma cells and is associated with enhanced trapping of PARP1-DNA complexes. Furthermore, through mining of large-scale drug sensitivity datasets, we identify a subset of glioma, neuroblastoma and melanoma cell lines as hypersensitive to the combination of temozolomide and PARP inhibition, potentially identifying new avenues for therapeutic intervention. These data provide insights into the anti cancer activity of PARP inhibitors with implications for the design of treatment for Ewing's sarcoma patients with PARP inhibitors. PMID- 26505996 TI - Whole-Genome Sequencing and Comparative Genome Analysis of Bacillus subtilis Strains Isolated from Non-Salted Fermented Soybean Foods. AB - Bacillus subtilis is the main component in the fermentation of soybeans. To investigate the genetics of the soybean-fermenting B. subtilis strains and its relationship with the productivity of extracellular poly-gamma-glutamic acid (gammaPGA), we sequenced the whole genome of eight B. subtilis stains isolated from non-salted fermented soybean foods in Southeast Asia. Assembled nucleotide sequences were compared with those of a natto (fermented soybean food) starter strain B. subtilis BEST195 and the laboratory standard strain B. subtilis 168 that is incapable of gammaPGA production. Detected variants were investigated in terms of insertion sequences, biotin synthesis, production of subtilisin NAT, and regulatory genes for gammaPGA synthesis, which were related to fermentation process. Comparing genome sequences, we found that the strains that produce gammaPGA have a deletion in a protein that constitutes the flagellar basal body, and this deletion was not found in the non-producing strains. We further identified diversity in variants of the bio operon, which is responsible for the biotin auxotrophism of the natto starter strains. Phylogenetic analysis using multilocus sequencing typing revealed that the B. subtilis strains isolated from the non-salted fermented soybeans were not clustered together, while the natto fermenting strains were tightly clustered; this analysis also suggested that the strain isolated from "Tua Nao" of Thailand traces a different evolutionary process from other strains. PMID- 26505997 TI - High Latent TB Infection Rate and Associated Risk Factors in the Eastern China of Low TB Incidence. AB - OBJECTIVES: To disclose the associated risk factors for latent tuberculosis infection (LTBI) and the current situation of LTBI in the eastern China. METHODS: A cross-sectional study was undertaken to evaluate the LTBI rate and risk factors. RESULTS: A total of 5305 subjects were finally included, with the IGRA positive rate of 19.98% (1060/5305). The LTBI rates were increasing with age (ORs were in significance from 6.60 to 20.92). Male gender significantly increased the risk of LTBI by 0.52 fold (OR = 1.52). Both smoking and drinking significantly increased the risk of LTBI (OR = 1.83 and OR = 1.67, respectively). Meanwhile, overweight and close contact with tuberculosis were risk factors for LTBI (OR = 1.36 and OR = 2.38, respectively). However, higher level of education and BCG vaccination lowered the risk of LTBI (OR = 0.16 and OR = 0.39, respectively). The multivariate logistic regression showed that age, male gender, smoking, overweight and close contacting with tuberculosis were risk factors for LTBI, but BCG vaccination was a protective factor for LTBI. CONCLUSIONS: BCG vaccination exerted protective effect on tuberculosis. However, LTBI rate in the Chinese rural area was critical and subjects above 30 years, male, smoking, overweight and close contact with tuberculosis wound be the targets for LTBI screening and source of tuberculosis. PMID- 26505998 TI - Sox11 Reduces Caspase-6 Cleavage and Activity. AB - The apoptotic cascade is an orchestrated event, whose final stages are mediated by effector caspases. Regulatory binding proteins have been identified for caspases such as caspase-3, -7, -8, and -9. Many of these proteins belong to the inhibitor of apoptosis (IAP) family. By contrast, caspase-6 is not believed to be influenced by IAPs, and little is known about its regulation. We therefore performed a yeast-two-hybrid screen using a constitutively inactive form of caspase-6 for bait in order to identify novel regulators of caspase-6 activity. Sox11 was identified as a potential caspase-6 interacting protein. Sox11 was capable of dramatically reducing caspase-6 activity, as well as preventing caspase-6 self- cleavage. Several regions, including amino acids 117-214 and 362 395 within sox11 as well as a nuclear localization signal (NLS) all contributed to the reduction in caspase-6 activity. Furthermore, sox11 was also capable of decreasing other effector caspase activity but not initiator caspases -8 and -9. The ability of sox11 to reduce effector caspase activity was also reflected in its capacity to reduce cell death following toxic insult. Interestingly, other sox proteins also had the ability to reduce caspase-6 activity but to a lesser extent than sox11. PMID- 26505999 TI - Effective, Facile, and Selective Hydrolysis of the Chemical Warfare Agent VX Using Zr6-Based Metal-Organic Frameworks. AB - The nerve agent VX is among the most toxic chemicals known to mankind, and robust solutions are needed to rapidly and selectively deactivate it. Herein, we demonstrate that three Zr6-based metal-organic frameworks (MOFs), namely, UiO-67, UiO-67-NH2, and UiO-67-N(Me)2, are selective and highly active catalysts for the hydrolysis of VX. Utilizing UiO-67, UiO-67-NH2, and UiO-67-N(Me)2 in a pH 10 buffered solution of N-ethylmorpholine, selective hydrolysis of the P-S bond in VX was observed. In addition, UiO-67-N(Me)2 was found to catalyze VX hydrolysis with an initial half-life of 1.8 min. This half-life is nearly 3 orders of magnitude shorter than that of the only other MOF tested to date for hydrolysis of VX and rivals the activity of the best nonenzymatic materials. Hydrolysis utilizing Zr-based MOFs is also selective and facile in the absence of pH 10 buffer (just water) and for the destruction of the toxic byproduct EA-2192. PMID- 26506001 TI - Water supply interruptions and suspected cholera incidence: a time-series regression in the Democratic Republic of the Congo. AB - BACKGROUND: The eastern provinces of the Democratic Republic of the Congo have been identified as endemic areas for cholera transmission, and despite continuous control efforts, they continue to experience regular cholera outbreaks that occasionally spread to the rest of the country. In a region where access to improved water sources is particularly poor, the question of which improvements in water access should be prioritized to address cholera transmission remains unresolved. This study aimed at investigating the temporal association between water supply interruptions and Cholera Treatment Centre (CTC) admissions in a medium-sized town. METHODS AND FINDINGS: Time-series patterns of daily incidence of suspected cholera cases admitted to the Cholera Treatment Centre in Uvira in South Kivu Province between 2009 and 2014 were examined in relation to the daily variations in volume of water supplied by the town water treatment plant. Quasi poisson regression and distributed lag nonlinear models up to 12 d were used, adjusting for daily precipitation rates, day of the week, and seasonal variations. A total of 5,745 patients over 5 y of age with acute watery diarrhoea symptoms were admitted to the CTC over the study period of 1,946 d. Following a day without tap water supply, the suspected cholera incidence rate increased on average by 155% over the next 12 d, corresponding to a rate ratio of 2.55 (95% CI: 1.54-4.24), compared to the incidence experienced after a day with optimal production (defined as the 95th percentile-4,794 m3). Suspected cholera cases attributable to a suboptimal tap water supply reached 23.2% of total admissions (95% CI 11.4%-33.2%). Although generally reporting less admissions to the CTC, neighbourhoods with a higher consumption of tap water were more affected by water supply interruptions, with a rate ratio of 3.71 (95% CI: 1.91-7.20) and an attributable fraction of cases of 31.4% (95% CI: 17.3%-42.5%). The analysis did not suggest any association between levels of residual chlorine in the water fed to the distribution network and suspected cholera incidence. Laboratory confirmation of cholera was not available for this analysis. CONCLUSIONS: A clear association is observed between reduced availability of tap water and increased incidence of suspected cholera in the entire town of Uvira in Eastern Democratic Republic of the Congo. Even though access to piped water supplies is low in Uvira, improving the reliability of tap water supply may substantially reduce the incidence of suspected cholera, in particular in neighbourhoods having a higher access to tap water. These results argue in favour of water supply investments that focus on the delivery of a reliable and sustainable water supply, and not only on point-of-use water quality improvements, as is often seen during cholera outbreaks. PMID- 26506000 TI - Structure Analysis Uncovers a Highly Diverse but Structurally Conserved Effector Family in Phytopathogenic Fungi. AB - Phytopathogenic ascomycete fungi possess huge effector repertoires that are dominated by hundreds of sequence-unrelated small secreted proteins. The molecular function of these effectors and the evolutionary mechanisms that generate this tremendous number of singleton genes are largely unknown. To get a deeper understanding of fungal effectors, we determined by NMR spectroscopy the 3 dimensional structures of the Magnaporthe oryzae effectors AVR1-CO39 and AVR-Pia. Despite a lack of sequence similarity, both proteins have very similar 6 beta sandwich structures that are stabilized in both cases by a disulfide bridge between 2 conserved cysteins located in similar positions of the proteins. Structural similarity searches revealed that AvrPiz-t, another effector from M. oryzae, and ToxB, an effector of the wheat tan spot pathogen Pyrenophora tritici repentis have the same structures suggesting the existence of a family of sequence-unrelated but structurally conserved fungal effectors that we named MAX effectors (Magnaporthe Avrs and ToxB like). Structure-informed pattern searches strengthened this hypothesis by identifying MAX-effector candidates in a broad range of ascomycete phytopathogens. Strong expansion of the MAX-effector family was detected in M. oryzae and M. grisea where they seem to be particularly important since they account for 5-10% of the effector repertoire and 50% of the cloned avirulence effectors. Expression analysis indicated that the majority of M. oryzae MAX-effectors are expressed specifically during early infection suggesting important functions during biotrophic host colonization. We hypothesize that the scenario observed for MAX-effectors can serve as a paradigm for ascomycete effector diversity and that the enormous number of sequence unrelated ascomycete effectors may in fact belong to a restricted set of structurally conserved effector families. PMID- 26506002 TI - Structural Analysis of Streptococcus pyogenes NADH Oxidase: Conformational Dynamics Involved in Formation of the C(4a)-Peroxyflavin Intermediate. AB - In probing the oxygen reactivity of an Enterococcus faecalis NADH oxidase (Nox; O2 -> 2H2O) C42S mutant lacking the Cys42-sulfenic acid (Cys42-SOH) redox center, we provided direct evidence of a C(4a)-peroxyflavin intermediate in the oxidative half-reaction and also described a conformational or chemical change that is rate limiting for full reoxidation of the homodimer. In this work, the Nox from Streptococcus pyogenes (SpyNox) has been expressed and crystallized, and the overoxidized wild-type [Cys44-SOH -> Cys44-sulfinic acid (Cys44-SO2H)] and C44S mutant enzyme structures have been refined at 2.0 and 2.15 A, respectively. We show that azide binds to the two-electron reduced wild-type (EH2) enzyme and to the mutant enzyme in solution, but with a significantly higher affinity for the mutant protein. The spectral course of the titration with the SpyNox EH2 form clearly indicates progressive displacement of the Cys44-S(-) -> FAD charge transfer interaction. An azide soak with C44S Nox crystals led to the structure of the complex, as refined at 2.10 A. The active-site N3(-) ligand is proximal to the Ser44 and His11 side chains, and a significant shift in the Ser44 side chain also appears. This provides an attractive explanation for the azide-induced loss of charge-transfer absorbance seen with the wild-type EH2 form and also permits accommodation of a C(4a)-peroxyflavin structural model. The conformation of Ser44 and the associated helical element, and the resulting steric accommodation, appear to be linked to the conformational change described in the E. faecalis C42S Nox oxidative half-reaction. PMID- 26506003 TI - DynaFace: Discrimination between Obligatory and Non-obligatory Protein-Protein Interactions Based on the Complex's Dynamics. AB - Protein-protein interfaces have been evolutionarily-designed to enable transduction between the interacting proteins. Thus, we hypothesize that analysis of the dynamics of the complex can reveal details about the nature of the interaction, and in particular whether it is obligatory, i.e., persists throughout the entire lifetime of the proteins, or not. Indeed, normal mode analysis, using the Gaussian network model, shows that for the most part obligatory and non-obligatory complexes differ in their decomposition into dynamic domains, i.e., the mobile elements of the protein complex. The dynamic domains of obligatory complexes often mix segments from the interacting chains, and the hinges between them do not overlap with the interface between the chains. In contrast, in non-obligatory complexes the interface often hinges between dynamic domains, held together through few anchor residues on one side of the interface that interact with their counterpart grooves in the other end. In automatic analysis, 117 of 139 obligatory (84.2%) and 203 of 246 non-obligatory (82.5%) complexes are correctly classified by our method: DynaFace. We further use DynaFace to predict obligatory and non-obligatory interactions among a set of 300 putative protein complexes. DynaFace is available at: http://safir.prc.boun.edu.tr/dynaface. PMID- 26506004 TI - Mannitol Does Not Enhance Tobramycin Killing of Pseudomonas aeruginosa in a Cystic Fibrosis Model System of Biofilm Formation. AB - Cystic Fibrosis (CF) is a human genetic disease that results in the accumulation of thick, sticky mucus in the airways, which results in chronic, life-long bacterial biofilm infections that are difficult to clear with antibiotics. Pseudomonas aeruginosa lung infection is correlated with worsening lung disease and P. aeruginosa transitions to an antibiotic tolerant state during chronic infections. Tobramycin is an aminoglycoside currently used to combat lung infections in individuals with CF. While tobramycin is effective at eradicating P. aeruginosa in the airways of young patients, it is unable to completely clear the chronic P. aeruginosa infections in older patients. A recent report showed that co-addition of tobramycin and mannitol enhanced killing of P. aeruginosa grown in vitro as a biofilm on an abiotic surface. Here we employed a model system of bacterial biofilms formed on the surface of CF-derived airway cells to determine if mannitol would enhance the antibacterial activity of tobramycin against P. aeruginosa grown on a more clinically relevant surface. Using this model system, which allows the growth of robust biofilms with high-level antibiotic tolerance analogous to in vivo biofilms, we were unable to find evidence for enhanced antibacterial activity of tobramycin with the addition of mannitol, supporting the observation that this type of co-treatment failed to reduce the P. aeruginosa bacterial load in a clinical setting. PMID- 26506005 TI - Role of the Number of Microtubules in Chromosome Segregation during Cell Division. AB - Faithful segregation of genetic material during cell division requires alignment of chromosomes between two spindle poles and attachment of their kinetochores to each of the poles. Failure of these complex dynamical processes leads to chromosomal instability (CIN), a characteristic feature of several diseases including cancer. While a multitude of biological factors regulating chromosome congression and bi-orientation have been identified, it is still unclear how they are integrated so that coherent chromosome motion emerges from a large collection of random and deterministic processes. Here we address this issue by a three dimensional computational model of motor-driven chromosome congression and bi orientation during mitosis. Our model reveals that successful cell division requires control of the total number of microtubules: if this number is too small bi-orientation fails, while if it is too large not all the chromosomes are able to congress. The optimal number of microtubules predicted by our model compares well with early observations in mammalian cell spindles. Our results shed new light on the origin of several pathological conditions related to chromosomal instability. PMID- 26506006 TI - Electronic and Mechanical Properties of Graphene-Germanium Interfaces Grown by Chemical Vapor Deposition. AB - Epitaxially oriented wafer-scale graphene grown directly on semiconducting Ge substrates is of high interest for both fundamental science and electronic device applications. To date, however, this material system remains relatively unexplored structurally and electronically, particularly at the atomic scale. To further understand the nature of the interface between graphene and Ge, we utilize ultrahigh vacuum scanning tunneling microscopy (STM) and scanning tunneling spectroscopy (STS) along with Raman and X-ray photoelectron spectroscopy to probe interfacial atomic structure and chemistry. STS reveals significant differences in electronic interactions between graphene and Ge(110)/Ge(111), which is consistent with a model of stronger interaction on Ge(110) leading to epitaxial growth. Raman spectra indicate that the graphene is considerably strained after growth, with more point-to-point variation on Ge(111). Furthermore, this native strain influences the atomic structure of the interface by inducing metastable and previously unobserved Ge surface reconstructions following annealing. These nonequilibrium reconstructions cover >90% of the surface and, in turn, modify both the electronic and mechanical properties of the graphene overlayer. Finally, graphene on Ge(001) represents the extreme strain case, where graphene drives the reorganization of the Ge surface into [107] facets. From this work, it is clear that the interaction between graphene and the underlying Ge is not only dependent on the substrate crystallographic orientation, but is also tunable and strongly related to the atomic reconfiguration of the graphene-Ge interface. PMID- 26506008 TI - Design of Super-Paramagnetic Core-Shell Nanoparticles for Enhanced Performance of Inverted Polymer Solar Cells. AB - Controlling the nature and transfer of excited states in organic photovoltaic (OPV) devices is of critical concern due to the fact that exciton transport and separation can dictate the final performance of the system. One effective method to accomplish improved charge separation in organic electronic materials is to control the spin state of the photogenerated charge-carrying species. To this end, nanoparticles with unique iron oxide (Fe3O4) cores and zinc oxide (ZnO) shells were synthesized in a controlled manner. Then, the structural and magnetic properties of these core-shell nanoparticles (Fe3O4@ZnO) were tuned to ensure superior performance when they were incorporated into the active layers of OPV devices. Specifically, small loadings of the core-shell nanoparticles were blended with the previously well-characterized OPV active layer of poly(3 hexylthiophene) (P3HT) and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM). Upon addition of the core-shell nanoparticles, the performance of the OPV devices was increased up to 25% relative to P3HT-PCBM active layer devices that contained no nanoparticles; this increase was a direct result of an increase in the short circuit current densities of the devices. Furthermore, it was demonstrated that the increase in photocurrent was not due to enhanced absorption of the active layer due to the presence of the Fe3O4@ZnO core-shell nanoparticles. In fact, this increase in device performance occurred because of the presence of the superparamagnetic Fe3O4 in the core of the nanoparticles as incorporation of ZnO only nanoparticles did not alter the device performance. Importantly, however, the ZnO shell of the nanoparticles mitigated the negative optical effect of Fe3O4, which have been observed previously. This allowed the core-shell nanoparticles to outperform bare Fe3O4 nanoparticles when the single-layer nanoparticles were incorporated into the active layer of OPV devices. As such, the new materials described here present a tangible pathway toward the development of enhanced design schemes for inorganic nanoparticles such that magnetic and energy control pathways can be tailored for flexible electronic applications. PMID- 26506007 TI - DNA Barcoding of Neotropical Sand Flies (Diptera, Psychodidae, Phlebotominae): Species Identification and Discovery within Brazil. AB - DNA barcoding has been an effective tool for species identification in several animal groups. Here, we used DNA barcoding to discriminate between 47 morphologically distinct species of Brazilian sand flies. DNA barcodes correctly identified approximately 90% of the sampled taxa (42 morphologically distinct species) using clustering based on neighbor-joining distance, of which four species showed comparatively higher maximum values of divergence (range 4.23 19.04%), indicating cryptic diversity. The DNA barcodes also corroborated the resurrection of two species within the shannoni complex and provided an efficient tool to differentiate between morphologically indistinguishable females of closely related species. Taken together, our results validate the effectiveness of DNA barcoding for species identification and the discovery of cryptic diversity in sand flies from Brazil. PMID- 26506009 TI - Muscle-bone interactions: From experimental models to the clinic? A critical update. AB - Bone is a biomechanical tissue shaped by forces from muscles and gravitation. Simultaneous bone and muscle decay and dysfunction (osteosarcopenia or sarco osteoporosis) is seen in ageing, numerous clinical situations including after stroke or paralysis, in neuromuscular dystrophies, glucocorticoid excess, or in association with vitamin D, growth hormone/insulin like growth factor or sex steroid deficiency, as well as in spaceflight. Physical exercise may be beneficial in these situations, but further work is still needed to translate acceptable and effective biomechanical interventions like vibration therapy from animal models to humans. Novel antiresorptive and anabolic therapies are emerging for osteoporosis as well as drugs for sarcopenia, cancer cachexia or muscle wasting disorders, including antibodies against myostatin or activin receptor type IIA and IIB (e.g. bimagrumab). Ideally, increasing muscle mass would increase muscle strength and restore bone loss from disuse. However, the classical view that muscle is unidirectionally dominant over bone via mechanical loading is overly simplistic. Indeed, recent studies indicate a role for neuronal regulation of not only muscle but also bone metabolism, bone signaling pathways like receptor activator of nuclear factor kappa-B ligand (RANKL) implicated in muscle biology, myokines affecting bone and possible bone-to-muscle communication. Moreover, pharmacological strategies inducing isolated myocyte hypertrophy may not translate into increased muscle power because tendons, connective tissue, neurons and energy metabolism need to adapt as well. We aim here to critically review key musculoskeletal molecular pathways involved in mechanoregulation and their effect on the bone-muscle unit as a whole, as well as preclinical and emerging clinical evidence regarding the effects of sarcopenia therapies on osteoporosis and vice versa. PMID- 26506010 TI - Compound heterozygous DUOX2 gene mutations (c.2335-1G>C/c.3264_3267delCAGC) associated with congenital hypothyroidism. Characterization of complex cryptic splice sites by minigene analysis. AB - Iodide Organification defects (IOD) represent 10% of cases of congenital hypothyroidism (CH) being the main genes affected that of TPO (thyroid peroxidase) and DUOX2 (dual oxidasa 2). From a patient with clinical and biochemical criteria suggestive with CH associated with IOD, TPO and DUOX2 genes were analyzed by means of PCR-Single Strand Conformation Polymorphism analysis and sequencing. A novel heterozygous compound to the mutations c.2335-1G>C (paternal mutation, intron 17) and c.3264_3267delCAGC (maternal mutation, exon 24) was identified in the DUOX2 gene. Ex-vivo splicing assays and subsequent RT PCR and sequencing analyses were performed on mRNA isolated from the HeLa cells transfected with wild-type and mutant pSPL3 expression vectors. The wild-type and c.2335-1G>C mutant alleles result in the complete inclusion or exclusion of exon 18, or in the activation of an exonic cryptic 5' ss with the consequent deletion of 169 bp at the end of this exon. However, we observed only a band of the expected size in normal thyroid tissue by RT-PCR. Additionally, the c.2335-1G>C mutation activates an unusual cryptic donor splice site in intron 17, located at position -14 of the authentic intron 17/exon 18 junction site, with an insertion of the last 14 nucleotides of the intron 17 in mutant transcripts with complete and partial inclusion of exon 18. The theoretical consequences of splice site mutation, predicted with the bioinformatics NNSplice, Fsplice, SPL, SPLM and MaxEntScan programs were investigated and evaluated in relation with the experimental evidence. These analyses confirm that c.2335-1G>C mutant allele would result in the abolition of the authentic splice acceptor site. The results suggest the coexistence in our patient of four putative truncated proteins of 786, 805, 806 and 1105 amino acids, with conservation of peroxidase-like domain and loss of gp91(phox)/NOX2-like domain. In conclusion a novel heterozygous compound was identified being responsible of IOD. Cryptic splicing sites have been characterized in DUOX2 gene for the first time. The use of molecular biology techniques is a valuable tool for understanding the molecular pathophysiology of this type of thyroid defects. PMID- 26506011 TI - Gating-like Motions and Wall Porosity in a DNA Nanopore Scaffold Revealed by Molecular Simulations. AB - Recently developed synthetic membrane pores composed of folded DNA enrich the current range of natural and engineered protein pores and of nonbiogenic channels. Here we report all-atom molecular dynamics simulations of a DNA nanotube (DNT) pore scaffold to gain fundamental insight into its atomic structure, dynamics, and interactions with ions and water. Our multiple simulations of models of DNTs that are composed of a six-duplex bundle lead to a coherent description. The central tube lumen adopts a cylindrical shape while the mouth regions at the two DNT openings undergo gating-like motions which provide a possible molecular explanation of a lower conductance state observed in our previous experimental study on a membrane-spanning version of the DNT (ACS Nano 2015, 9, 1117-26). Similarly, the central nanotube lumen is filled with water and ions characterized by bulk diffusion coefficients while the gating regions exhibit temporal fluctuations in their aqueous volume. We furthermore observe that the porous nature of the walls allows lateral leakage of ions and water. This study will benefit rational design of DNA nanopores of enhanced stability of relevance for sensing applications, of nanodevices with tunable gating properties that mimic gated ion channels, or of nanopores featuring defined permeation behavior. PMID- 26506013 TI - Role of inflammation and its miRNA based regulation in epilepsy: Implications for therapy. AB - There is a need to develop innovative therapeutic strategies to counteract epilepsy, a common disabling neurological disorder. Despite the recent advent of additional antiepileptic drugs and respective surgery, the treatment of epilepsy remains a major challenge. The available therapies are largely based on symptoms, and these approaches do not affect the underlying disease processes and are also associated frequently with severe side effects. This is mainly because of the lack of well-defined targets in epilepsy. The discovery that inflammatory mediators significantly contribute to the onset and recurrence of seizures in experimental seizure models, as well as the presence of inflammatory molecules in human epileptogenic tissue, highlights the possibility of targeting specific inflammation related pathways to control seizures that are otherwise resistant to the available AEDs. Emerging studies suggest that miRNAs have a significant role in regulating inflammatory pathways shown to be involved in epilepsy. These miRNAs can possibly be used as novel therapeutic targets in the treatment of epilepsy as well as serve as diagnostic biomarkers of epileptogenesis. This review highlights the immunological features underlying the pathogenesis of epileptic seizures and the possible miRNA mediated approaches for drug resistant epilepsies that modulate the immune-mediated pathogenesis. PMID- 26506012 TI - A Database of microRNA Expression Patterns in Xenopus laevis. AB - MicroRNAs (miRNAs) are short, non-coding RNAs around 22 nucleotides long. They inhibit gene expression either by translational repression or by causing the degradation of the mRNAs they bind to. Many are highly conserved amongst diverse organisms and have restricted spatio-temporal expression patterns during embryonic development where they are thought to be involved in generating accuracy of developmental timing and in supporting cell fate decisions and tissue identity. We determined the expression patterns of 180 miRNAs in Xenopus laevis embryos using LNA oligonucleotides. In addition we carried out small RNA-seq on different stages of early Xenopus development, identified 44 miRNAs belonging to 29 new families and characterized the expression of 5 of these. Our analyses identified miRNA expression in many organs of the developing embryo. In particular a large number were expressed in neural tissue and in the somites. Surprisingly none of the miRNAs we have looked at show expression in the heart. Our results have been made freely available as a resource in both XenMARK and Xenbase. PMID- 26506014 TI - Data sharing in stem cell translational science: policy statement by the International Stem Cell Forum Ethics Working Party. AB - Data and sample sharing constitute a scientific and ethical imperative but need to be conducted in a responsible manner in order to protect individual interests as well as maintain public trust. In 2014, the Global Alliance for Genomics and Health (GA4GH) adopted a common Framework for Responsible Sharing of Genomic and Health-Related Data. The GA4GH Framework is applicable to data sharing in the stem cell field, however, interpretation is required so as to provide guidance for this specific context. In this paper, the International Stem Cell Forum Ethics Working Party discusses those principles that are specific to translational stem cell science, including engagement, data quality and safety, privacy, security and confidentiality, risk-benefit analysis and sustainability. PMID- 26506015 TI - Novel Agents for the Treatment of Primary Plasma-Cell Leukemia: Lights and Shadows. PMID- 26506016 TI - Live happily live in hiding (from our affect): Alexithymia Influences affect intensity and affect frequency ratings in men. AB - Alexithymia has been frequently studied in the context of negative affect frequency but rarely in the context of positive affect frequency or in the context of affect intensity. However, affect intensity and frequency, even if they are independent, are generally confounded due to an overlap in items wording (tapping both dimensions). The aim of the study was to examine the incremental validity of alexithymia for predicting both affect intensity and frequency, regarding positive and negative valence. Two hundred and fifty five students fulfilled measurements for alexithymia, affect intensity and affect frequency. Results showed that the factor "Difficulty identifying feelings" is related to higher positive and negative affect intensity, as well as to negative affect frequency. Men were also more sensitive to positive affect intensity and frequency if they scored higher on alexithymia. They experienced less often positive affect, but the intensity of their affect was more intense. Conversely, alexithymia did not influence women's affect intensity or affect frequency. Thus, alexithymia factors are associated with specific patterns of affect intensity and frequency, highlighting an overall deficit in the processing of emotions with contrasting patterns regarding gender. PMID- 26506017 TI - Association of dietary diversity score with anxiety in women. AB - Evidence suggests that diet plays an important role in the development of mental disorders, especially anxiety. Dietary diversity score is an indicator for assessing diet quality. However, its association with anxiety has not been investigated. The aim of this study was to examine the association of dietary diversity score with anxiety. A cross-sectional study was conducted among 360 women attending health centers in the south of Tehran in 2014. General information among others were collected. Weight, height and waist circumference were measured and body mass index (BMI) was calculated. Dietary intake and anxiety score were assessed using a 24-h dietary recall and Depression, Anxiety, Stress Scales (DASS) questionnaires, respectively. Dietary diversity score was computed according to the guidelines of FAO. About 35% of the participants were found to exhibit anxiety. The dietary diversity score in 12.5% of the subjects were between 1 and 3 (low dietary diversity score) but 87.5% scored between 4 and 7 (high dietary diversity score). The adjusted mean of anxiety score in subjects with high dietary diversity score was significantly lower than those with low dietary diversity score. Dietary diversity score was found to be inversely associated with anxiety. However, the causality between anxiety and dietary diversity could not be determined. PMID- 26506018 TI - SGO1C is a non-functional isoform of Shugoshin and can disrupt sister chromatid cohesion by interacting with PP2A-B56. AB - Shugoshin (SGO1) plays a pivotal role in sister chromatid cohesion during mitosis by protecting the centromeric cohesin from mitotic kinases and WAPL. Mammalian cells contain at least 6 alternatively spliced isoforms of SGO1. The relationship between the canonical SGO1A with shorter isoforms including SGO1C remains obscure. Here we show that SGO1C was unable to replace the loss of SGO1A. Instead, expression of SGO1C alone induced aberrant mitosis similar to depletion of SGO1A, promoting premature sister chromatid separation, activation of the spindle-assembly checkpoint, and mitotic arrest. In disagreement with previously published data, we found that SGO1C localized to kinetochores. However, the ability to induce aberrant mitosis did not correlate with its kinetochore localization. SGO1C mutants that abolished binding to kinetochores still triggered premature sister chromatid separation. We provide evidence that SGO1C mediated mitotic arrest involved the sequestering of PP2A-B56 pool. Accordingly, SGO1C mutants that abolished binding to PP2A localized to kinetochores but did not induce aberrant mitosis. These studies imply that the expression of SGO1C should be tightly regulated to prevent dominant-negative effects on SGO1A and genome instability. PMID- 26506019 TI - Containment control of networked autonomous underwater vehicles: A predictor based neural DSC design. AB - This paper investigates the containment control problem of networked autonomous underwater vehicles in the presence of model uncertainty and unknown ocean disturbances. A predictor-based neural dynamic surface control design method is presented to develop the distributed adaptive containment controllers, under which the trajectories of follower vehicles nearly converge to the dynamic convex hull spanned by multiple reference trajectories over a directed network. Prediction errors, rather than tracking errors, are used to update the neural adaptation laws, which are independent of the tracking error dynamics, resulting in two time-scales to govern the entire system. The stability property of the closed-loop network is established via Lyapunov analysis, and transient property is quantified in terms of L2 norms of the derivatives of neural weights, which are shown to be smaller than the classical neural dynamic surface control approach. Comparative studies are given to show the substantial improvements of the proposed new method. PMID- 26506021 TI - N-Heterocyclic Carbene-Catalyzed Formal [3 + 2] Annulation of alpha-Bromoenals with 3-Aminooxindoles: A Stereoselective Synthesis of Spirooxindole gamma Butyrolactams. AB - A stereoselective synthetic approach to spirooxindole gamma-butyrolactams is developed via N-heterocyclic carbene-catalyzed formal [3 + 2] annulation of alpha bromoenals with 3-aminooxindoles. An enantioselective variant of this methodology is also investigated resulting in good substrate tolerance and high enantioselectivities. PMID- 26506020 TI - Comparative safety and costs of stepping down asthma medications in patients with controlled asthma. AB - BACKGROUND: Limited data exist regarding outcomes after stepping down asthma medication. OBJECTIVE: We sought to compare the safety and costs of stepping down asthma controller medications with maintaining current treatment levels in patients with controlled asthma. METHODS: Patients with persistent asthma were identified from the US Medical Expenditure Panel Survey years 2000-2010. Each patient had Medical Expenditure Panel Survey data for 2 years, and measurement was divided into 5 periods of 4 to 5 months each. Eligibility for stepping down asthma controller medications included no hospitalizations or emergency department visits for asthma in periods 1 to 3 and no systemic corticosteroid and 3 or less rescue inhalers dispensed in periods 2 and 3. Steps were defined by type and dose of chronic asthma medication based on current guidelines when comparing period 4 with period 3. The primary outcome of complete asthma control in period 5 was defined as no asthma hospitalizations, emergency department visits, and dispensed systemic corticosteroids and 2 or fewer dispensed rescue inhalers. Multivariable analyses were conducted to assess safety and costs after step down compared with those who maintained the treatment level. RESULTS: Overall, 29.9% of patients meeting the inclusion criteria (n = 4235) were eligible for step down; 89.4% (95% CI, 86.4% to 92.4%) of those who stepped down had preserved asthma control compared with 83.5% (95% CI, 79.9% to 87.0%) of those who were similarly eligible for step down but maintained their treatment level. The average monthly asthma-related cost savings was $34.02/mo (95% CI, $5.42/mo to $61.24/mo) with step down compared with maintenance of the treatment level. CONCLUSION: Stepping down asthma medications in those whose symptoms were controlled led to similar clinical outcomes at reduced cost compared with those who maintained their current treatment level. PMID- 26506022 TI - Spatial and temporal distribution of Patched-related protein in the Drosophila embryo. AB - Patched-related (Ptr) encodes a protein with 12 potential transmembrane domains and a sterol-sensing domain that is closely related in predicted topology and domain organization to Patched, the canonical receptor of the Hedgehog pathway. Here we describe the production of an antibody specific for Drosophila Ptr and analyse its spatial and temporal distribution in the embryo. We find that at early developmental stages Ptr is predominantly localized at cell periphery but later on it becomes strongly and almost exclusively expressed in hemocytes. Interestingly Ptr null mutant embryos died without hatching. Our findings suggest that Ptr plays an essential function in Drosophila development, perhaps as a new receptor of embryonic hemocytes. PMID- 26506023 TI - The influence of extreme winds on coastal oceanography and its implications for coral population connectivity in the southern Arabian Gulf. AB - Using long-term oceanographic surveys and a 3-D hydrodynamic model we show that localized peak winds (known as shamals) cause fluctuation in water current speed and direction, and substantial oscillations in sea-bottom salinity and temperature in the southern Persian/Arabian Gulf. Results also demonstrate that short-term shamal winds have substantial impacts on oceanographic processes along the southern Persian/Arabian Gulf coastline, resulting in formation of large scale (52 km diameter) eddies extending from the coast of the United Arab Emirates (UAE) to areas near the off-shore islands of Iran. Such eddies likely play an important role in transporting larvae from well-developed reefs of the off-shore islands to the degraded reef systems of the southern Persian/Arabian Gulf, potentially maintaining genetic and ecological connectivity of these geographically distant populations and enabling enhanced recovery of degraded coral communities in the UAE. PMID- 26506024 TI - An assessment of PCB and PBDE contamination in two tropical dolphin species from the Southeastern Brazilian coast. AB - PCBs and PBDEs were determined in two dolphin species, Sotalia guianensis and Steno bredanensis, from an upwelling system off the Central-northern coast of Rio de Janeiro, Brazil. PCB levels varied from 0.040 to 0.75 MUg g(-1) lw in muscles and from 0.022 to 1.32 MUg g(-1)lw in liver samples from S. guianensis. In S. bredanensis, values varied from 0.085 to 11.3 MUg g(-1) lw in muscles and from 0.024 to 18.6 MUg g(-1) lw in livers. PCB-138, -153 and -180 were the major PCB congeners detected in both species, while BDE-47 was the predominant PBDE congener found in both species. Higher concentrations in S. bredanensis were possibly related to the different feeding habits for both delphinid species. These results contribute to extend the database on organic contamination in cetaceans from the southern hemisphere, understanding their distribution and environmental fate in Southeastern Brazil. PMID- 26506025 TI - Distribution and bioaccumulation of heavy metals in marine organisms in east and west Guangdong coastal regions, South China. AB - Heavy metal (Cu, Pb, Zn, Cr, Cd, As) concentrations, distribution and bioaccumulation were studied in marine organisms in Guangdong coastal regions. Heavy metal concentrations and distribution in organisms showed characteristics according to areas and species. Heavy metal concentrations in most organisms were higher in west than in east, tightly related to the local industry structure and the disequilibrium of metal discharge. Generally, high heavy metal concentrations were detected in molluscs and low concentrations were detected in fish. Bioaccumulation factor was used to assess the accumulation level of marine organisms to heavy metals, of which Cd, Cu and As were the most accumulated elements. Accumulation abilities to heavy metals varied among organism species, such as Distorsio reticulate accumulating Cu, Zn, Cd, As, Loligo beka Sasaki accumulating Pb, Cu, Cr, and Turritella bacillum Kiener accumulating Zn, Cd, As. By comparison, Johnius belengeri, Argyrosomus argentatus, Cynoglossus sinicus Wu had relatively low accumulation abilities. PMID- 26506026 TI - Underwater noise assessment in the Gulf of Trieste (Northern Adriatic Sea, Italy) using an MSFD approach. AB - In the marine environment, underwater noise is one of the most widespread input of man-made energy. Recently, the European Commission has stressed the necessity of establishing threshold levels as a target for the descriptor 11.2.1 "Continuous low frequency sounds" in the Marine Strategy Framework Directive (MSFD). In 2012, a monthly underwater noise monitoring programme was conducted in the Gulf of Trieste (Northern Adriatic Sea, Italy); the collected acoustic samples (frequency range: 10-20,000 Hz) were analysed in the 1/3 octave bands. The stations have been further clustered following the 63 and 125 Hz bands noise levels. Average SPL levels resulted similar to those previously computed for proximate areas, indicating that the Adriatic Sea sub-region experiences high noise pressure in the marine waters. In its turn this claims for a scientific and technical international cooperation, as requested by the EU programme. No seasonal variation in local noise levels has been found. PMID- 26506027 TI - Levels and spatial distribution of perfluoroalkyl substances in China Liaodong Bay basin with concentrated fluorine industry parks. AB - Eighteen different perfluoroalkyl substances (PFASs) were investigated in 35 river water samples and 34 sediment samples collected from rivers in the Liaodong Bay basin containing two fluorine industry parks. Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) were the predominant PFASs in freshwater, with median concentrations of 26.5 ng/L and 1.87 ng/L, respectively. However, perfluorobutane sulfonate (PFBS) had the highest maximum concentration (up to 124.1 ng/L, approximately two orders of magnitude higher) in water at a site which is the nearest to the industrial source of PFASs. Total PFASs in water at this site were also the highest. In contrast, PFOA and perfluorooctadecanoate (PFOcDA) were the most abundant PFASs in sediment, with median concentrations of 1.19 ng/g and 0.35 ng/g, respectively. Total PFAS concentrations in sediment from the site near to the industrial park were significantly higher than the other rivers. Mass loading of total PFASs from the rivers flowing into Liaodong Bay was estimated to be 506 kg/year. PMID- 26506028 TI - Bio-nano hybrid materials based on bacteriorhodopsin: Potential applications and future strategies. AB - This review presents an overview of recent progress in the development of bio nano hybrid materials based on the photoactive protein bacteriorhodopsin (bR). The interfacing of bR with various nanostructures including colloidal nanoparticles (such as quantum dots and Ag NPs) and nanoparticulate thin films (such as TiO2 NPs and ZnO NPs,) has developed novel functional materials. Applications of these materials are comprehensively reviewed in two parts: bioelectronics and solar energy conversion. Finally, some perspectives on possible future strategies in bR-based nanostructured devices are presented. PMID- 26506029 TI - Fungal communities as an experimental approach to Darwin's naturalization hypothesis. AB - Darwin's naturalization hypothesis suggests that the success of an invasive species will be lower when colonizing communities are formed by phylogenetically related rather than unrelated species due to increased competition. Although microbial invasions are involved in both natural and anthropogenic processes, factors affecting the success of microbial invaders are unknown. A biological invasion assay was designed using Trichoderma cf. harzianum as the invader and two types of recipient communities assembled in microcosm assays: communities phylogenetically related to the invader, and communities phylogenetically unrelated to it. Both types of communities were invaded by T. cf. harzianum, and the success of colonization was monitored by qPCR; its effect on the genetic structure of recipient fungal communities was then assessed by DGGE profiles. T. cf. harzianum established itself in both communities, reaching 1000-10,000 times higher copy numbers in the non-related communities. However, invader establishment does not affect the structure of the invaded communities. These results suggest that the composition of recipient communities and their phylogenetic relationship to the invader affect the success of colonization by T. cf. harzianum. While this approach represents a very simplified assay, these microcosms enable an experimental test of Darwin's hypothesis in order to understand the biological invasion process in microbial communities. PMID- 26506030 TI - Vaginal Bleeding in Prepubertal Girls: Etiology and Clinical Management. AB - STUDY OBJECTIVE: We aimed to investigate the etiology and clinical management of vaginal bleeding in girls aged 0-9 years and to compare our results with previous publications. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: The records of all girls younger than 10 years of age who were seen between 2001 and 2011 at Skane University Hospital Lund for vaginal bleeding were retrospectively collected. RESULTS: We identified 86 girls with vaginal bleeding. Of those, 47 (54.7%) were diagnosed with a local lesion, the etiology was hormonal in 16 (18.6%), and in 23 (26.7%) the etiology was unclear. Trauma was the most frequent cause of local lesions and hormonal withdrawal of the newborn was the most common hormonal etiology. Two girls were diagnosed with a tumor, 1 with relapse of a vaginal rhabdomyosarcoma, and the other with recurrence of an ovarian granulosa cell tumor. There were large disparities in the clinical management of vaginal bleeding. A genital examination was conducted in 70 of 86 (81.4%), and colposcopy in only 8 of 86 of the patients (9.3%). CONCLUSION: This study confirmed vaginal bleeding as a rare finding in girls younger than 10 years of age. It is usually a benign symptom, but because there might be a serious underlying condition, proper investigation and follow-up are needed. Clinical management varied in our patient cohort. This might be because of insufficient knowledge and might indicate the need for general guidelines. PMID- 26506031 TI - Use and Effectiveness of Gonadotropin-Releasing Hormone Agonists for Prophylactic Menstrual Suppression in Postmenarchal Women Who Undergo Hematopoietic Cell Transplantation. AB - STUDY OBJECTIVE: To describe the rates of use and effectiveness of gonadotropin releasing hormone (GnRH) agonists and other forms of hormonal menstrual suppression in prevention of vaginal bleeding among young women who underwent hematopoietic stem cell transplantation (HCT). DESIGN: Retrospective descriptive study. SETTING: University-based pediatric HCT practice. PARTICIPANTS: Fifty-five postmenarchal women who underwent HCT between 2004 and 2011. INTERVENTIONS: Administration of GnRH agonists or other forms of hormonal menstrual suppression. MAIN OUTCOME MEASURES: Rates of use of GnRH agonists and other forms of hormonal menstrual suppression, and rates and descriptions of vaginal bleeding. RESULTS: Forty-six of the 55 patients had experienced regular or irregular vaginal bleeding before HCT and were considered to be at risk for thrombocytopenia associated menorrhagia. Forty of the 46 (87%) received hormonal menstrual suppression. Thirty-three patients were treated with a GnRH agonist, 4 with combined hormonal contraceptive pills, 1 with a combined hormonal contraceptive patch, 1 with depot medroxyprogesterone, and 1 with oral norethindrone. Twenty nine of the 33 patients (88%) who received a GnRH agonist had complete amenorrhea during HCT and 4 of 33 (12%) experienced some degree of vaginal bleeding. CONCLUSION: GnRH agonists appear effective in prevention of vaginal bleeding complications in most postmenarchal women who underwent HCT. Some patients who might benefit do not receive a GnRH agonist and multiple barriers exist in identification and treatment of them. PMID- 26506036 TI - [Prevalence, indication and compliance with the recommendations of prescription of low molecular weight heparin in oncology]. AB - INTRODUCTION: Venous thromboembolism is a common complication in cancer and is the second cause of death below infection. Low molecular weight heparin is the gold standard in venous thromboembolism during cancer. This work aimed to evaluate the prevalence of prescription of low molecular weight heparin used at curative dose and the compliance of our practices with the recommendations. METHODS: A retrospective study was led over a 3-month period, on adult patients suffering from venous thromboembolism who had received low molecular weight heparin at curative dose. RESULTS: A 4% prevalence of prescription of low molecular weight heparin at curative doses has been reported. The results showed an incidental discovery of venous thromboembolism on routine restaging scans in 64% cases. The most found indication was the treatment of deep vein thrombosis (51% cases). According to the dosage, overall compliance of prescription is estimated at 55%. DISCUSSION: The incidental discovery rate (64%) is consistent with the literature that confirms the high incidence of asymptomatic thrombosis. The rate of non-compliant prescriptions could result from a lack of re-evaluation and adjustment of dosages. These results confirm the need to educate practitioners in diagnosing and managing venous thromboembolism. PMID- 26506032 TI - When mothering goes awry: Challenges and opportunities for utilizing evidence across rodent, nonhuman primate and human studies to better define the biological consequences of negative early caregiving. AB - This article is part of a Special Issue "Parental Care".Across mammalian species, mothers shape socio-emotional development and serve as essential external regulators of infant physiology, brain development, behavior patterns, and emotional regulation. Caregiving quality, consistency and predictability shape the infant's underlying neurobiological processes. Although the requirements for "optimal" caregiving differ across species, the negative long-term consequences of the absence of needed caregiving (e.g. neglect) or the presence of harmful/aversive caregiving (e.g. physical abuse), are translatable across species. Recognizing the significant potential of cross species comparisons in terms of defining underlying mechanisms, effective translation requires consideration of the evolutionary, ecological, and fundamental biological and developmental differences between and among species. This review provides both an overview of several success stories of cross-species translations in relation to negative caregiving and a template for future studies seeking to most effectively define the underlying biological processes and advance research dedicated to mitigating the lasting negative health consequences of child maltreatment. PMID- 26506037 TI - Reducing IRF-1 to Levels Observed in HESN Subjects Limits HIV Replication, But Not the Extent of Host Immune Activation. AB - Cells from women who are epidemiologically deemed resistant to HIV infection exhibit a 40-60% reduction in endogenous IRF-1 (interferon regulatory factor-1), an essential regulator of host antiviral immunity and the early HIV replication. This study examined the functional consequences of reducing endogenous IRF-1 on HIV-1 replication and immune response to HIV in natural HIV target cells. IRF-1 knockdown was achieved in ex vivo CD4(+) T cells and monocytes with siRNA. IRF-1 level was assessed using flow cytometry, prior to infection with HIV-Bal, HIV IIIB, or HIV-VSV-G. Transactivation of HIV long terminal repeats was assessed by p24 secretion (ELISA) and Gag expression (reverse transcription-polymerase chain reaction (RT-PCR)). The expression of IRF-1-regulated antiviral genes was quantitated with RT-PCR. A modest 20-40% reduction in endogenous IRF-1 was achieved in >87% of ex vivo-derived peripheral CD4(+) T cells and monocytes, resulted in >90% reduction in the transactivation of the HIV-1 genes (Gag, p24) and, hence, HIV replication. Curiously, these HIV-resistant women demonstrated normal immune responses, nor an increased susceptibility to other infection. Similarly, modest IRF-1 knockdown had limited impact on the magnitude of HIV-1 elicited activation of IRF-1-regulated host immunologic genes but resulted in lessened duration of these responses. These data suggest that early expression of HIV-1 genes requires a higher IRF-1 level, compared to the host antiviral genes. Together, these provide one key mechanism underlying the natural resistance against HIV infection and further suggest that modest IRF-1 reduction could effectively limit productive HIV infection yet remain sufficient to activate a robust but transient immune response. PMID- 26506038 TI - Advanced Characterization of DNA Molecules in rAAV Vector Preparations by Single stranded Virus Next-generation Sequencing. AB - Recent successful clinical trials with recombinant adeno-associated viral vectors (rAAVs) have led to a renewed interest in gene therapy. However, despite extensive developments to improve vector-manufacturing processes, undesirable DNA contaminants in rAAV preparations remain a major safety concern. Indeed, the presence of DNA fragments containing antibiotic resistance genes, wild-type AAV, and packaging cell genomes has been found in previous studies using quantitative polymerase chain reaction (qPCR) analyses. However, because qPCR only provides a partial view of the DNA molecules in rAAV preparations, we developed a method based on next-generation sequencing (NGS) to extensively characterize single stranded DNA virus preparations (SSV-Seq). In order to validate SSV-Seq, we analyzed three rAAV vector preparations produced by transient transfection of mammalian cells. Our data were consistent with qPCR results and showed a quasi random distribution of contaminants originating from the packaging cells genome. Finally, we found single-nucleotide variants (SNVs) along the vector genome but no evidence of large deletions. Altogether, SSV-Seq could provide a characterization of DNA contaminants and a map of the rAAV genome with unprecedented resolution and exhaustiveness. We expect SSV-Seq to pave the way for a new generation of quality controls, guiding process development toward rAAV preparations of higher potency and with improved safety profiles. PMID- 26506039 TI - Novel RNA Duplex Locks HIV-1 in a Latent State via Chromatin-mediated Transcriptional Silencing. AB - Transcriptional gene silencing (TGS) of mammalian genes can be induced by short interfering RNA (siRNA) targeting promoter regions. We previously reported potent TGS of HIV-1 by siRNA (PromA), which targets tandem NF-kappaB motifs within the viral 5'LTR. In this study, we screened a siRNA panel with the aim of identifying novel 5'LTR targets, to provide multiplexing potential with enhanced viral silencing and application toward developing alternate therapeutic strategies. Systematic examination identified a novel siRNA target, si143, confirmed to induce TGS as the silencing mechanism. TGS was prolonged with virus suppression >12 days, despite a limited ability to induce post- TGS. Epigenetic changes associated with silencing were suggested by partial reversal by histone deacetylase inhibitors and confirmed by chromatin immunoprecipitation analyses, which showed induction of H3K27me3 and H3K9me3, reduction in H3K9Ac, and recruitment of argonaute-1, all characteristic marks of heterochromatin and TGS. Together, these epigenetic changes mimic those associated with HIV-1 latency. Further, robust resistance to reactivation was observed in the J-Lat 9.2 cell latency model, when transduced with shPromA and/or sh143. These data support si/shRNA-mediated TGS approaches to HIV-1 and provide alternate targets to pursue a functional cure, whereby the viral reservoir is locked in latency following antiretroviral therapy cessation. PMID- 26506040 TI - Genomic affinities revealed by GISH suggests intergenomic restructuring between parental genomes of the paleopolyploid genus Zea. AB - The present work compares the molecular affinities, revealed by GISH, with the analysis of meiotic pairing in intra- and interspecific hybrids between species of Zea obtained in previous works. The joint analysis of these data provided evidence about the evolutionary relationships among the species from the paleopolyploid genus Zea (maize and teosintes). GISH and meiotic pairing of intraspecific hybrids revealed high genomic affinity between maize (Zea mays subsp. mays) and both Zea mays subsp. parviglumis and Zea mays subsp. mexicana. On the other hand, when Zea mays subsp. huehuetenanguensis DNA was probed on maize chromosomes, a lower affinity was detected, and the pattern of hybridization suggested intergenomical restructuring between the parental genomes of maize. When DNA from Zea luxurians was used as probe, homogeneous hybridization signals were observed through all maize chromosomes. Lower genomic affinity was observed when DNA from Zea diploperennis was probed on maize chromosomes, especially at knob regions. Maize chromosomes hybridized with Zea perennis DNA showed hybridization signals on four chromosome pairs: two chromosome pairs presented hybridization signal in only one chromosomal arm, whereas four chromosome pairs did not show any hybridization. These results are in agreement with previous GISH studies, which have identified the genomic source of the chromosomes involved in the meiotic configurations of Z. perennis * maize hybrids. These findings allow postulating that maize has a parental genome not shared with Z. perennis, and the existence of intergenomic restructuring between the parental genomes of maize. Moreover, the absence of hybridization signals in all maize knobs indicate that these heterochromatic regions were lost during the Z. perennis genome evolution. PMID- 26506041 TI - Evaluation of Delayed Puberty in Adolescents With Cleft Lip/Palate. AB - OBJECTIVE: To assess the frequency of delayed puberty in adolescents with cleft lip and/or cleft palate (CL/P). DESIGN: This was a cross-sectional study of 203 patients with CL/P and no associated syndromes treated at the Hospital for Rehabilitation of Craniofacial Anomalies, University of Sao Paulo, Bauru, Brazil. We evaluated boys aged 14-19 years and girls aged 13-18 years. The patients were classified according to Tanner stages of sexual development. The age of menarche was recorded. Patients were assigned to three groups according to cleft type: isolated cleft lip (CL), cleft lip and palate (CLP), and isolated cleft palate (CP). The results were expressed as frequencies and averages and compared with pubertal changes described for typically developing adolescents as reported in the literature. RESULTS: Subjects were 115 boys and 88 girls. All boys in the CL group and the CP group had already started puberty, and two boys in the CLP group (2.3%) had delayed puberty. All girls had started puberty. The average age at menarche was 12.3 years in the CL group, 12.1 years in the CLP group, and 12.5 years in the CP group. CONCLUSIONS: The frequency of delayed puberty and the average age at menarche in adolescents with CL/P and no associated genetic syndromes or anomalies were within the expected range for typically developing adolescents (i.e., those without CL/P) in the same age group. PMID- 26506042 TI - Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome: Expanding the Phenotype. AB - We present a 3-month-old girl who displayed typical clinical characteristics of blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). She was referred to our clinic with an initial diagnosis of Down syndrome. Clinical features of elevated follicle stimulating hormone and low estradiol levels in the case were diagnosed as BPES syndrome and were consistent with BPES type 2. To date, there are no cases of BPES with cleft palate and cardiomyopathy, suggesting that these novel findings can be part of this condition. PMID- 26506043 TI - Poly(L-Lactide)/Poly(epsilon-Caprolactone) and Collagen/beta-Tricalcium Phosphate Scaffolds for the Treatment of Critical-Sized Rat Alveolar Defects: A Microtomographic, Molecular-Biological, and Histological Study. AB - OBJECTIVE: To determine the efficacy of a newly developed scaffold (col/beta-TCP) in a preclinical rat model as compared with the gold standard treatment (autograft) and control scaffolds (PLLA/PCL). DESIGN: Fifty-six Sprague-Dawley rats were randomized into four experimental groups, and critical-sized alveolar defects (7 * 4 * 3 mm) were created in each animal. Group A was the blank defect group, group B received autograft, group C received col/beta-TCP scaffolds, and group D received PLLA/PCL blend scaffolds to fill the bone defects. New bone formation was assessed radiomorphometrically, histomorphometrically, and molecular-biologically at 1 and 4 months following surgery. RESULTS: Radiomorphometrically, the best new bone volume rate at 1 month (43.7%) and 4 months (45.4%) was observed in the autograft group, and the difference was significantly higher than in the other three groups (P < .005, P < .001, P < .001 for 1 month and P = .004, P < .001, P < .001 for 4 months). Even though the new bone volume rate in the col/beta-TCP group (21.5%) was higher than that of the PLLA/PCL group (18.2%), the difference was not significant (P = .08). Molecular genetic analysis revealed significantly higher BSP and ALP gene expression levels in the autograft and col/beta-TCP groups than in the blank defect group (P = .002 and P = .004). CONCLUSION: The engineered tissue scaffolds described herein have great potential as an alternative treatment option when cost, donor region morbidity, and duration of hospitalization are considered. PMID- 26506044 TI - Early Detection of Cleft Lip by Three-Dimensional Transvaginal Ultrasound in Niche Mode in a Fetus With Trisomy 18 Diagnosed by Celocentesis. AB - Transabdominal ultrasound examination carried out at 11.3 weeks' gestation suggested the diagnosis of holoprosencephaly (HPE). Transvaginal three dimensional (3D) scan performed using the niche-mode technique enabled diagnosis of HPE, hypotelorism, and cleft lip (CL). The fetus was diagnosed with trisomy 18 by means of transvaginal celocentesis at the time of pregnancy termination. Although prenatal diagnosis of orofacial cleft can be enhanced by 3D ultrasound, only a few cases have been detected early in pregnancy. Here, we report a first trimester case in which 3D ultrasound in niche mode improved the antenatal diagnosis of CL. Early fetal karyotyping can be accomplished by celocentesis in these cases. PMID- 26506045 TI - Temporal Characteristics of Nasalization: Language Specific or Not? PMID- 26506046 TI - Alveolar Bone Grafting: Donor Site Review of 100 Consecutive Cases in Cleft Lip and Palate. AB - OBJECTIVE: Review of patients who underwent secondary alveolar bone grafting for total inpatient stay, postoperative complications, and postoperative analgesic requirements. DESIGN: Retrospective analysis of medical records. SETTING: Tertiary care center as part of a regional cleft lip and palate network. PATIENTS: All patients who underwent secondary alveolar bone grafting from the iliac crest. INTERVENTIONS: Local anesthetic was infiltrated overlying the anterior iliac crest. An incision was made to conform to the future skin crease and avoid muscle dissection. The cartilaginous cap was incised and raised, and cancellous bone was then harvested. The cavity was packed with hemostatic cellulose and closed in layers. All patients received postoperative antibiotics. All patients were prescribed regular paracetamol (acetaminophen) and ibuprofen if there were no contraindications. Oral morphine was available when requested. MAIN OUTCOME MEASURES: Length of stay, postoperative analgesic requirements, and postoperative donor site and oral complications. RESULTS: From 100 consecutive patients, 92 (92%) of the patients were discharged the day after surgery; one (1%) patient required four nights of monitoring for postoperative pyrexia of unknown origin. All patients received regular paracetamol, and the majority (86%) did not require oral morphine. Complications included seroma (4%), superficial donor site abscess (1%), postoperative pyrexia of unknown origin (2%), gingival bleeding (2%), and oral infection (2%). CONCLUSION: The findings suggest that donor site pain may be well controlled with simple, regular analgesia. Children tolerated this procedure well and were safely discharged the day after surgery. Alveolar bone grafting from the iliac crest was found to have low complication rates. PMID- 26506047 TI - Antenatal Ultrasound Detection of Cleft in Western Australia from 2003 to 2012: A Follow-Up Study. AB - AIM: To investigate trends in the rate of antenatal detection of cleft lip and palate (CLP) patients referred to the CLP Unit at Princess Margaret Hospital for Children in Perth, Western Australia during the period 2003-2012 and compare data with a previously published report covering the years 1996-2003. METHODS: This is a single-center, retrospective survey of antenatal transabdominal ultrasound screenings of mothers of infants born between July 1, 2003 and June 30, 2012 that were referred to the CLP Unit at Princess Margaret Hospital. RESULTS: Detection rates of oral clefts increased significantly when compared with outcomes reported in the same population between 1996 and 2003 (P < .05). An overall detection rate of 71.7% (165/230) was achieved for clefts involving lip and palate. Detection of isolated cleft palate (1/99) and microform (0/8) remained elusive. Most detections (76.5%) were achieved at 15 to 20 weeks of gestational age, corresponding with routine anatomical screening. A further 16.8% were detected post-20 weeks of gestation. Scans were performed by specialist obstetricians, and sonography clinics reported a detection rate of 84.6% (55/65), whereas nonspecialist clinics reported a detection rate of only 67.1% (110/164). CONCLUSION: The antenatal detection rates of oral clefts involving the lip have improved to the extent that the majority of mothers are now being referred to a cleft unit in Western Australia prior to the births of their children. As a result of this improvement, antenatal counseling is now a common facet of cleft management. PMID- 26506048 TI - Analysis of loco-regional failures in head and neck cancer after radical radiation therapy. AB - OBJECTIVES: To investigate the anatomical distribution of loco-regional treatment failures (LRF) in patients with head and neck squamous cell carcinoma (HNSCC) in relation to clinical target volume (CTV) delineation. MATERIALS AND METHODS: 56 patients with LRF were retrospectively identified. Patients were previously treated with radical intensity modulated radiotherapy (IMRT) +/- chemotherapy. Target volumes include gross tumour volume (GTV), its volumetric expansion of 10mm (GTV-HD), CTV high dose (CTV-HD) delineated by anatomic expansion from GTV and CTV low dose (CTV-LD) defined to receive a prophylactic dose. LRF were evaluated by PET-CT or CT scan. We analysed the association between sites of LRF and target volumes and dosimetry, using image co-registration. Based on percentage of volume that received 95% of prescribed dose, LRF were classified as in-field, marginal or out-field. RESULTS: Median interval time from end of treatment to LRF was 186days. 65 (95.6%) LRF were classified as in-field. Considering primary target volumes, 40 (58.8%) LRF occurred inside GTV, 13 (19.1%) in GTV-HD and 7 (10.3%) in CTV-HD. The overall 1-year and 2-year post failure survival (PFS) was 45.8% and 24.2%, respectively. Post radiation LRF managed with salvage surgery had a significantly higher median PFS when compared with palliative treatments (p=0.003). CONCLUSIONS: The majority of LRF occurred within GTV/GTV-HD, suggesting it is safe to reduce the CTV to a volumetric expansion. Given the low incidence of geographical misses, future studies should be directed towards dose escalation of high-risk volumes. Potential reduction of RT-related toxicity with volumetric expansion could facilitate salvage surgery. PMID- 26506049 TI - Cell proliferation and cell death are disturbed during prenatal and postnatal brain development after uranium exposure. AB - The developing brain is more susceptible to neurotoxic compounds than adult brain. It is also well known that disturbances during brain development cause neurological disorders in adulthood. The brain is known to be a target organ of uranium (U) exposure and previous studies have noted that internal U contamination of adult rats induces behavioral disorders as well as affects neurochemistry and neurophysiological properties. In this study, we investigated whether depleted uranium (DU) exposure affects neurogenesis during prenatal and postnatal brain development. We examined the structural morphology of the brain, cell death and finally cell proliferation in animals exposed to DU during gestation and lactation compared to control animals. Our results showed that DU decreases cell death in the cortical neuroepithelium of gestational day (GD) 13 embryos exposed at 40mg/L and 120mg/L and of GD18 fetuses exposed at 120mg/L without modification of the number of apoptotic cells. Cell proliferation analysis showed an increase of BrdU labeling in the dentate neuroepithelium of fetuses from GD18 at 120mg/L. Postnatally, cell death is increased in the dentate gyrus of postnatal day (PND) 0 and PND5 exposed pups at 120mg/L and is associated with an increase of apoptotic cell number only at PND5. Finally, a decrease in dividing cells is observed in the dentate gyrus of PND21 rats developmentally exposed to 120mg/L DU, but not at PND0 and PND5. These results show that DU exposure during brain development causes opposite effects on cell proliferation and cell death processes between prenatal and postnatal development mainly at the highest dose. Although these modifications do not have a major impact in brain morphology, they could affect the next steps of neurogenesis and thus might disrupt the fine organization of the neuronal network. PMID- 26506050 TI - Genetic modulation of oxytocin sensitivity: a pharmacogenetic approach. AB - Intranasal administration of the neuropeptide oxytocin has been shown to influence a range of complex social cognitions and social behaviors, and it holds therapeutic potential for the treatment of mental disorders characterized by social functioning deficits such as autism, social phobia and borderline personality disorder. However, considerable variability exists in individual responses to oxytocin administration. Here, we undertook a study to investigate the role of genetic variation in sensitivity to exogenous oxytocin using a socioemotional task. In a randomized, double-blind, placebo-controlled experiment with a repeated-measures (crossover) design, we assessed the performance of 203 men on an emotion recognition task under oxytocin and placebo. We took a haplotype-based approach to investigate the association between oxytocin receptor gene variation and oxytocin sensitivity. We identified a six-marker haplotype block spanning the promoter region and intron 3 that was significantly associated with our measure of oxytocin sensitivity. Specifically, the TTCGGG haplotype comprising single-nucleotide polymorphisms rs237917-rs2268498-rs4564970-rs237897 rs2268495-rs53576 is associated with increased emotion recognition performance under oxytocin versus placebo, and the CCGAGA haplotype with the opposite pattern. These results on the genetic modulation of sensitivity to oxytocin document a significant source of individual differences with implications for personalized treatment approaches using oxytocin administration. PMID- 26506052 TI - BDNF-TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms. AB - Depression is a core symptom of methamphetamine (METH) withdrawal during the first several weeks of abstinence. However, the precise mechanisms underlying METH withdrawal symptoms remain unknown. Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), have a role the in pathophysiology of depression. In this study, we examined the role of BDNF-TrkB signaling in different brain regions of male mice with METH withdrawal symptoms. Repeated METH (3 mg kg(-1) per day for 5 days) administration to mice caused a long-lasting depression-like behavior including anhedonia. Western blot analysis showed that BDNF levels in the nucleus accumbens (NAc) of METH-treated mice were significantly higher than those of control mice whereas BDNF levels in other regions, including the prefrontal cortex and hippocampus, were not altered. METH induced depression-like behavior, behavioral sensitization and dendritic changes in the NAc shell were improved by subsequent subchronic administration of TrkB antagonist ANA-12 (0.5 mg kg(-1) per day for 14 days), but not TrkB agonist 7,8 dihydroxyflavone (10 mg kg(-1) per day for 14 days). In vivo microdialysis showed that METH (1 mg kg(-1))-induced dopamine release in NAc shell of METH-treated mice was attenuated after subsequent subchronic ANA-12 administration. Interestingly, a single bilateral infusion of ANA-12 into the NAc shell, but not NAc core, showed a rapid and long-lasting therapeutic effect. However, ketamine and paroxetine had no effect. These findings suggest that increased BDNF-TrkB signaling in the NAc shell has an important role in the behavioral abnormalities after withdrawal from repeated METH administration, and that TrkB antagonists are potential therapeutic drugs for withdrawal symptoms in METH abusers. PMID- 26506051 TI - Functional genomics of human brain development and implications for autism spectrum disorders. AB - Transcription of the inherited DNA sequence into copies of messenger RNA is the most fundamental process by which the genome functions to guide development. Encoded sequence information, inherited epigenetic marks and environmental influences all converge at the level of mRNA gene expression to allow for cell type-specific, tissue-specific, spatial and temporal patterns of expression. Thus, the transcriptome represents a complex interplay between inherited genomic structure, dynamic experiential demands and external signals. This property makes transcriptome studies uniquely positioned to provide insight into complex genetic epigenetic-environmental processes such as human brain development, and disorders with non-Mendelian genetic etiologies such as autism spectrum disorders. In this review, we describe recent studies exploring the unique functional genomics profile of the human brain during neurodevelopment. We then highlight two emerging areas of research with great potential to increase our understanding of functional neurogenomics-non-coding RNA expression and gene interaction networks. Finally, we review previous functional genomics studies of autism spectrum disorder in this context, and discuss how investigations at the level of functional genomics are beginning to identify convergent molecular mechanisms underlying this genetically heterogeneous disorder. PMID- 26506053 TI - Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence. AB - Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 MUM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 MUM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3'-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence. PMID- 26506055 TI - What to expect from molecular tools for non-documented pediatric infectious diseases. AB - OBJECTIVE: Evaluation of the contribution of molecular tools to the overall diagnosis of infectious diseases in children. METHODS: Results of 16S rDNA analysis (179 children; 228 specimens), combined to specific amplification of Kingella kingae (126 children; 166 osteoarticular specimens), were retrospectively analyzed for samples with inconclusive cultures. RESULT: The overall positive yield in diagnosis was 12.8% of the patients for 16S rDNA PCR, 40.5% for K. kingae PCR and 45.2% for combined use of both methods. Results were related to clinical and biological data (direct examination, certainty/uncertainty of clinical diagnosis, fever, biological markers, previous antibiotics), and to the number of samples analyzed per patient, allowing the identification of specific situations with significant contribution of PCR methods. CONCLUSION: Molecular techniques constitute valuable tools to improve the bacterial infection diagnosis in children; however, specific indications, dedicated samples, and number of analyzed samples per patient are key points to optimize their contribution. PMID- 26506056 TI - A one-pot amidation of primary nitroalkanes. AB - It has been over a half-century since Kornblum demonstrated the conversion of a primary nitroalkane to a carboxylic acid; addition of an amine results in carboxylic acid formation as well. We describe the formation of amides from terminal nitroalkanes in a two-step, one-pot reaction involving tandem halogenation/umpolung amide synthesis (UmAS). PMID- 26506054 TI - Maternal sensitivity, infant limbic structure volume and functional connectivity: a preliminary study. AB - Mechanisms underlying the profound parental effects on cognitive, emotional and social development in humans remain poorly understood. Studies with nonhuman models suggest variations in parental care affect the limbic system, influential to learning, autobiography and emotional regulation. In some research, nonoptimal care relates to decreases in neurogenesis, although other work suggests early postnatal social adversity accelerates the maturation of limbic structures associated with emotional learning. We explored whether maternal sensitivity predicts human limbic system development and functional connectivity patterns in a small sample of human infants. When infants were 6 months of age, 20 mother infant dyads attended a laboratory-based observational session and the infants underwent neuroimaging at the same age. After considering age at imaging, household income and postnatal maternal anxiety, regression analyses demonstrated significant indirect associations between maternal sensitivity and bilateral hippocampal volume at six months, with the majority of associations between sensitivity and the amygdala demonstrating similar indirect, but not significant results. Moreover, functional analyses revealed direct associations between maternal sensitivity and connectivity between the hippocampus and areas important for emotional regulation and socio-emotional functioning. Sensitivity additionally predicted indirect associations between limbic structures and regions related to autobiographical memory. Our volumetric results are consistent with research indicating accelerated limbic development in response to early social adversity, and in combination with our functional results, if replicated in a larger sample, may suggest that subtle, but important, variations in maternal care influence neuroanatomical trajectories important to future cognitive and emotional functioning. PMID- 26506057 TI - The three missing elements in the treatment of substance use disorders: Lessons from the physician health programs. AB - To make recovery, and not relapse, the expected outcome of the treatment of moderate to severe substance use disorders, 3 currently missing elements would need to be emphasized: (1) the definition of long-term recovery as the goal of all treatment and post-treatment interventions; (2) the provision of sustained post-treatment monitoring and professional and peer support, including drug testing; and (3) the insistence by others around the patients on sustained abstinence as crucial for those suffering from moderate to severe and prolonged substance use disorders. Each of these 3 elements is central to the distinctive care management system of the state physician health programs. This approach to the long-term management of substance use disorders fits with the new direction of healthcare for serious, chronic diseases-away from isolated, and expensive acute care episodes of care and toward sustained chronic disease management with long-term monitoring, support, and early re-intervention if and when needed. PMID- 26506058 TI - Effects of alpha1-blockers on urodynamic parameters of bladder outlet obstruction in patients with lower urinary tract symptoms suggestive of benign prostatic enlargement: a review. AB - alpha1-adrenergic receptors blockers (ABs) are recommended as first-line medical therapy in men with Lower Urinary Tract Symptoms suggestive of Benign Prostatic Enlargement (LUTS/BPE). Available ABs include: terazosin, doxazosin, tamsulosin, naftopidil, alfuzosin and silodosin. These agents have different profiles of selectivity for alpha1-adrenergic receptors subtypes. All these agents are efficacious in improving both storage and voiding LUTS. In recent years the efficacy of ABs in improving urodynamic parameters of bladder outlet obstruction (BOO) has been questioned. We reviewed literature evidences about the effects of available ABs on invasive urodynamic parameters of BOO in men with LUTS/BPE. The impact of ABs therapy on urodynamic parameters indicative of BOO has been evaluated for all currently approved drugs. Available data demonstrate improvements in terms of both free uroflowmetry and pressure-flow parameters. While the impact of ABs on maximum urinary flow is clinically modest, the improvement of detrusor pressure at maximum urinary flow is more robust. Only few studies exist that directly compare the urodynamic effects of a small number of ABs. According to these studies there are no differences among ABs in terms of urodynamic efficacy. Indirect comparison of ABs suggests greater effectiveness of silodosin in terms of detrusor pressure at maximum urinary flow reduction. Studies that stratified populations based upon the degree of obstruction at baseline demonstrated greater urodynamic changes in patients with baseline BOO with respect to the unobstructed patients. Globally, the quality of studies available is low and there is considerable heterogeneity among studies. PMID- 26506059 TI - The Effects of Different Warm-up Volumes on the 100-m Swimming Performance: A Randomized Crossover Study. AB - The aim of this study was to compare the effect of 3 different warm-up (WU) volumes on 100-m swimming performance. Eleven male swimmers at the national level completed 3 time trials of 100-m freestyle on separate days and after a standard WU, a short WU (SWU), or a long WU (LWU) in a randomized sequence. All of them replicated some usual sets and drills, and the WU totaled 1,200 m, the SWU totaled 600 m, and the LWU totaled 1,800 m. The swimmers were faster after the WU (59.29 seconds; confidence interval [CI] 95%, 57.98-60.61) and after the SWU (59.38 seconds; CI 95%, 57.92-60.84) compared with the LWU (60.18 seconds; CI 95%, 58.53-61.83). The second 50-m lap after the WU was performed with a higher stroke length (effect size [ES] = 0.77), stroke index (ES = 1.26), and propelling efficiency (ES = 0.78) than that after the SWU. Both WU and SWU resulted in higher pretrial values of blood lactate concentrations [La] compared with LWU (ES = 1.58 and 0.74, respectively), and the testosterone:cortisol levels were increased in WU compared with LWU (ES = 0.86). In addition, the trial after WU caused higher [La] (ES >= 0.68) and testosterone:cortisol values compared with the LWU (ES = 0.93). These results suggest that an LWU could impair 100-m freestyle performance. The swimmers showed higher efficiency during the race after a 1200-m WU, suggesting a favorable situation. It highlighted the importance of the [La] and hormonal responses to each particular WU, possibly influencing performance and biomechanical responses during a 100-m race. PMID- 26506060 TI - Affective Responses to Acute Resistance Exercise Performed at Self-Selected and Imposed Loads in Trained Women. AB - The purpose of this study was to examine the affective responses to acute resistance exercise (RE) performed at self-selected (SS) and imposed loads in recreationally trained women. Secondary purposes were to (a) examine differences in correlates of motivation for future participation in RE and (b) determine whether affective responses to RE were related to these select motivational correlates of RE participation. Twenty recreationally trained young women (mean age = 23 years) completed 3 RE sessions involving 3 sets of 10 repetitions using loads of 40% of 1 repetition maximum (1RM), 70% 1RM, and an SS load. Affective responses were assessed before, during, and after each RE session using the Feeling Scale. Self-efficacy and intention for using the imposed and SS loads for their regular RE participation during the next month were also assessed postexercise. Results revealed that although the SS and imposed load RE sessions yielded different trajectories of change in affect during exercise (p < 0.01), comparable improvements in affect emerged after RE. Additionally, the SS condition was associated with the highest ratings of self-efficacy and intention for future RE participation (p < 0.01), but affective responses to acute RE were unrelated to self-efficacy or intention. It is concluded that acute bouts of SS and imposed load RE resulted in comparable improvements in affect; recreationally trained women reported the highest self-efficacy and intention to use the load chosen in SS condition in their own resistance training; and affective responses were unrelated to motivational correlates of resistance training. PMID- 26506061 TI - Comparison of Knee Moments and Landing Patterns During a Lateral Cutting Maneuver: Shod Vs. Barefoot. AB - Noncontact anterior cruciate ligament (ACL) injuries often occur during lateral cutting maneuvers, in which extension, adduction, and external rotation create high loads on the ACL. The aim of this study was to examine knee moments and foot strike patterns during lateral cutting when shod (SD) and barefoot (BF). Fifteen NCAA Division III athletes (7 female and 8 male; age 20.2 +/- 1.5 years; mass 71.5 +/- 11.3 kg; height, 1.7 +/- 0.06 m) without lower limb pathologies were analyzed during 5 trials of 45 degrees lateral cutting maneuvers for each limb in both BF and SD conditions with the approach speed of 4.3 m.s. Kinetic and kinematic data were collected using an 8-camera motion capture system and a force plate with collection rates at 240 Hz and 2400 Hz, respectively. Paired t-tests were used to determine differences conditions. The SD condition produced a significantly (p <= 0.05) greater peak adduction moment and cutting, whereas BF caused more anterior foot strike. Lateral cutting when BF places no more stress on the ACL than when SD. Our findings suggest that lateral cutting maneuvers when BF will not increase stress on the ACL. PMID- 26506062 TI - Unipedal Postural Balance and Countermovement Jumps After a Warm-up and Plyometric Training Session: A Randomized Controlled Trial. AB - The purpose of this study was to analyze the immediate effects of a plyometric training protocol on unipedal postural balance and countermovement jumps. In addition, we analyzed the effects of a warm-up on these parameters. Thirty-two amateur male sprinters (24.9 +/- 4.1 years; 72.3 +/- 10.7 kg; 1.78 +/- 0.05 m; 22.6 +/- 3.3 kg.m) were randomly sorted into a control group (n = 16) (they did not perform any physical activity) and a plyometric training group (n = 16) (they performed a 15-minute warm-up and a high-intensity plyometric protocol consisting of 10 sets of 15 vertical jumps). Before and after the warm-up, and immediately after and 5 minutes after the plyometric protocol, all athletes indicated the perceived exertion on calf and quad regions on a scale from 0 (no exertion) to 10 (maximum exertion). They also carried out a maximum countermovement jump and a unipedal postural balance test (athletes would remain as still as possible for 15 seconds in a left leg and right leg support stance). Results showed that, in the plyometric group, length and velocity of center-of-pressure movement in right leg support stance increased compared with baseline (p = 0.001 and p = 0.004, respectively) and to the control group (p = 0.035 and p = 0.029, respectively) immediately after the plyometric protocol. In addition, the countermovement jump height decreased right after the plyometric protocol (p < 0.001). The perceived exertion on calf and quad regions increased after the plyometry (p < 0.001). Five minutes later, these parameters remained deteriorated despite a slight recovery (length: p = 0.044; velocity: p = 0.05; countermovement jump height: p < 0.001; local exertion: p < 0.001). Data also showed that countermovement jump height improved after the warm-up (p = 0.021), but unipedal postural balance remained unaltered. As a conclusion, high-intensity plyometric exercises blunt unipedal postural balance and countermovement jump performance. The deterioration lasts at least 5 minutes, which may influence future exercises in the training session. Coaches should plan the training routine according to the immediate effects of plyometry on postural balance and vertical jumps, which play a role in injury prevention and sports performance. PMID- 26506063 TI - Aerobic Development of Elite Youth Ice Hockey Players. AB - Ice hockey is a physiologically complex sport requiring aerobic and anaerobic energy metabolism. College and professional teams often test aerobic fitness; however, there is a paucity of information regarding aerobic fitness of elite youth players. Without this knowledge, training of youth athletes to meet the standards of older age groups and higher levels of hockey may be random, inefficient, and or effective. Therefore, the purpose of this study was to determine the aerobic fitness of elite youth hockey players. A retrospective database review was performed for 200 male AAA hockey players between the ages of 13 and 17 (age, 14.4 +/- 1.2 years; height, 174.3 +/- 8.5 cm; body mass, 67.2 +/- 11.5 kg; body fat, 9.8 +/- 3.5%) before the 2012-13 season. All subjects performed a graded exercise test on a cycle ergometer, whereas expired air was collected by either a Parvo Medics TrueOne 2400 or a CareFusion Oxycon Mobile metabolic cart to determine maximal oxygen consumption (V[Combining Dot Above]O2max). Body mass, absolute V[Combining Dot Above]O2max, and the power output achieved during the last completed stage increased in successive age groups from age 13 to 15 years (p <= 0.05). Ventilatory threshold (VT) expressed as a percentage of V[Combining Dot Above]O2max and the heart rate (HR) at which VT occurred decreased between the ages of 13 and 14 years (p <= 0.05), whereas the V[Combining Dot Above]O2 at which VT occurred increased from the age of 14-15 years. There were no changes in relative V[Combining Dot Above]O2max or HRmax between any successive age groups. The aerobic fitness levels of elite youth ice hockey players increased as players age and mature physically and physiologically. However, aerobic fitness increased to a lesser extent at older ages. This information has the potential to influence off-season training and maximize the aerobic fitness of elite amateur hockey players, so that these players can meet standards set by advanced elite age groups. PMID- 26506065 TI - Randomized Split-Face Study to Assess the Efficacy and Safety of AbobotulinumtoxinA Versus OnabotulinumtoxinA in the Treatment of Melomental Folds (Depressor Anguli Oris). PMID- 26506066 TI - The Natural History of Soft Tissue Hypertrophy, Bony Hypertrophy, and Nodule Formation in Patients With Untreated Head and Neck Capillary Malformations. AB - BACKGROUND: A percentage of patients with capillary malformation (CM) develop soft tissue hypertrophy, bony hypertrophy, and/or nodule formation. OBJECTIVE: To determine the incidence, age of onset, anatomic distribution of soft tissue/bony hypertrophy, and nodule formation in patients with untreated CM. METHODS: A retrospective medical records review of head and neck CM patients presenting to a tertiary referral center over a 7-year period (2004-2011) was performed. RESULTS: Of the 160 patients with CM, 96 demonstrated progression of disease to include either soft tissue/bony hypertrophy or nodule formation. Of these, 87 patients had not received previous treatment and met the inclusion criteria for analysis. On average, soft tissue hypertrophy began at 9 years of age. The V2/maxillary segment was most commonly involved with upper lip hypertrophy being the most prominent. Fourteen percent of the patients also presented with bony hypertrophy, which began at an average age of 15 years. Nodules were present in 38/87 (44%) of patients with an average age of onset of 22 years. CONCLUSION: This study demonstrates the nature progression of CM and quantifies the clinical characteristics of hypertrophy and nodule formation with untreated head and neck CM. Early and continuous treatment is recommended in hopes of preventing CM progression. PMID- 26506068 TI - The Development of Hypertrophy in Port-Wine Stains, a Common Phenomenon that Affects Treatment Recommendations. PMID- 26506067 TI - Efficacy and Tolerability of a Novel Biopsy Device for Removing Benign Epidermal Skin Lesions. AB - BACKGROUND: The shave biopsy using a razor with an open blade is the current standard of care for sampling superficial skin lesions. OBJECTIVE: To enhance safety, the authors developed a novel biopsy device with a closed blade design for removing the epidermal layer of skin and evaluated against the open razor blade for tolerability, scarring, and accuracy in histological diagnosis. MATERIALS AND METHODS: Shave biopsies were performed using the novel device or razor blade on benign epidermal skin lesions in 10 patients on comparable body parts. Digital photography, colorimetry, scar scale evaluations, and questionnaires were used to evaluate the efficacy and tolerability of the devices. RESULTS: For all patients, accurate histological diagnoses were made regardless of device type. No statistically significant differences were detected between the novel device and razor blade in terms of scar scale assessments, colorimetry, and questionnaire responses. Both patients and the participating dermatologist reported satisfaction with the safety and performance of the novel device. No injuries to the provider occurred with either instrument. CONCLUSION: The rotating sphere biopsy device is a potential alternative to the razor blade with comparable tolerability, scarring, and accuracy in histological diagnoses, offering improved safety for patients and health care providers. PMID- 26506064 TI - A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. AB - Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCbeta) as a critical mediator of this pathway and demonstrate that the PKCbeta inhibitor enzastaurin, and the clinically available anti hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCbeta and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. PMID- 26506069 TI - CLINICAL FACTORS FOR DEVELOPING SHOCK IN RADIOCONTRAST MEDIA INDUCED ANAPHYLAXIS. AB - The aim of this study was to investigate the time interval between radiocontrast media (RCM) administration and the development of anaphylactic shock, and risk factors associated with RCM-induced anaphylactic shock. We reviewed the medical records of 154 patients with RCM-induced anaphylaxis presenting to the emergency department of a tertiary care hospital between January 2005 and December 2014. Clinical features of RCM-induced anaphylaxis were analyzed, and patients were categorized into shock and non-shock groups to identify associated factors in affected patients. Of the 154 cases of RCM-induced anaphylaxis, 101 (65.9%) patients experienced shock. The median time between RCM exposure and the onset of shock was 11 min (interquartile range, 7.0-18.8). In patients with RCM-induced anaphylaxis accompanying shock, the median time from RCM to the first symptom onset was 6 min (interquartile range, 5.0-10.0). In the multivariate analysis, age, neurological manifestations, and allergy history except RCM were associated with the development of shock. RCM-induced anaphylaxis was commonly accompanied with shock, and the time interval between RCM exposure and the onset of shock was short. Physicians should pay attention to the development of potential cardiovascular collapse in anaphylaxis patients of old age and with neurologic manifestations. PMID- 26506071 TI - THE EFFECTS OF FENOLDOPAM ON RENAL FUNCTION AND METABOLISM IN AN OVINE MODEL OF SEPTIC SHOCK. AB - INTRODUCTION: The importance of renal perfusion and metabolism in septic acute kidney injury (AKI) remains unclear. Prophylactic administration of the dopaminergic agent, fenoldopam, has been suggested to reduce the occurrence of AKI, but its effects in septic shock are poorly defined. METHODS: Sepsis was induced in 15 adult female sheep by injecting autologous feces into the abdominal cavity. Two hours later, the animals were randomized to one of three groups: low dose fenoldopam (1.0 MUg/kg/min, n = 5), high-dose fenoldopam (5.0 MUg/kg/min, n = 5), or placebo (control, n = 5). A perivascular flow probe was placed around the renal artery and a catheter in the renal vein for measurement of renal blood flow index (RBFI) and oxygen consumption (VO2renI). Metabolism in the renal cortex was evaluated using microdialysis. Serum creatinine was measured 6-hourly and the sublingual microcirculation assessed using sidestream dark-field videomicroscopy. RESULTS: High-dose fenoldopam was associated with a lower RBFI at 18 h (P = 0.032) than in the control group, but VO2renI was maintained by a higher oxygen extraction (P < 0.05 vs. baseline). Sublingual microcirculatory alterations at 18 h were more severe in the high-dose than in the control and low dose groups (P = 0.021 and P = 0.032). Renal cortex lactate and pyruvate levels increased earlier in the high-dose group than in the other two groups (P < 0.001 vs. baseline). Fenoldopam did not affect creatinine clearance or urine output. CONCLUSIONS: In this model of septic shock, fenoldopam did not improve renal blood flow, worsened microcirculatory alterations, and induced metabolic changes that were indicative of increased glycolysis. PMID- 26506070 TI - FIVE-YEAR OUTCOMES AFTER LONG-TERM OXANDROLONE ADMINISTRATION IN SEVERELY BURNED CHILDREN: A RANDOMIZED CLINICAL TRIAL. AB - Administration of oxandrolone, a nonaromatizable testosterone analog, to children for 12 months following severe burn injury has been shown to improve height, increase bone mineral content (BMC), reduce cardiac work, and augment muscle strength. Surprisingly, the increase in BMC persists well beyond the period of oxandrolone administration. This study was undertaken to determine if administration of oxandrolone for 2 years yields greater effects on long-term BMC and bone mineral density (BMD). Patients between 0 and 18 years of age with >=30% of total body surface area burned were consented to an IRB-approved protocol and randomized to receive either placebo (n = 84) or 0.1 mg/kg oxandrolone orally twice daily for 24 months (n = 35). Patients were followed prospectively from the time of admission until 5 years postburn in a single-center, intent-to-treat setting. Height, weight, BMC, and BMD were recorded annually through 5 years postinjury. The long-term administration of oxandrolone for 16 +/- 1 months postburn (range, 12.1-25.2 months) significantly increased whole-body (WB) BMC (p < 0.02) and lumbar spine (LS) BMC (p < 0.05); these effects were significantly pronounced for a longer time in patients who were in growth spurt years (7-18 years). When adjusted for height, sex, and age, LS BMD was found to significantly increase with long-term oxandrolone administration (p < 0.0009). Fewer patients receiving oxandrolone exhibited LS BMD z scores below -2.0 as compared with controls, indicating a significantly reduced risk for future fracture with oxandrolone administration. Long-term oxandrolone patients had significantly greater height velocity than controls throughout the first 2-year postburn (p < 0.05). No adverse side effects were attributed to the long-term administration of oxandrolone. A comparison of the current patients receiving long-term oxandrolone to previously described patients receiving 12 months of oxandrolone revealed that long-term oxandrolone administration imparted significantly greater increases in WB-BMC, WB-BMD, and LS-BMD (p < 0.05). In conclusion, the administration of oxandrolone for up to 24 months to severely burned pediatric patients significantly improves WB BMC, LS BMC, LS BMD, and height velocity. The administration of long-term oxandrolone was more efficacious than administration for 12 months. Additionally, fewer patients in the oxandrolone cohort met the diagnostic criteria for pediatric osteoporosis, pointing to a reduced risk for future bone fracture. This study demonstrates that administering oxandrolone for up to 2 years following severe burn injury results in greater improvements in BMC, BMD, and height velocity. PMID- 26506073 TI - The role of membrane curvature for the wrapping of nanoparticles. AB - Cellular internalization of nanoparticles requires the full wrapping of the nanoparticles by the cell membrane. This wrapping process can occur spontaneously if the adhesive interactions between the nanoparticles and the membranes are sufficiently strong to compensate for the cost of membrane bending. In this article, we show that the membrane curvature prior to wrapping plays a key role for the wrapping process, besides the size and shape of the nanoparticles that have been investigated in recent years. For membrane segments that initially bulge away from nanoparticles by having a mean curvature of the same sign as the mean curvature of the particle surface, we find strongly stable partially wrapped states that can prevent full wrapping. For membrane segments that initially bulge towards the nanoparticles, in contrast, partially wrapped states can constitute a significant energetic barrier for the wrapping process. PMID- 26506074 TI - Technical Comment on "Saccadic eye movement performance as an indicator of driving ability in elderly drivers". PMID- 26506076 TI - Journal of oral rehabilitation: what's in a name? PMID- 26506078 TI - Lipid carbonyl groups terminate the hydrogen bond network of membrane-bound water. AB - We present a combined experimental sum-frequency generation (SFG) spectroscopy and ab initio molecular dynamics simulations study to clarify the structure and orientation of water at zwitterionic phosphatidylcholine (PC) lipid and amine N oxide (AO) surfactant monolayers. Simulated O-H stretch SFG spectra of water show good agreement with the experimental data. The SFG response at the PC interface exhibits positive peaks, whereas both negative and positive bands are present for the similar zwitterionic AO interface. The positive peaks at the water/PC interface are attributed to water interacting with the lipid carbonyl groups, which act as efficient hydrogen bond acceptors. This allows the water hydrogen bond network to reach, with its (up-oriented) O-H groups, into the headgroup of the lipid, a mechanism not available for water underneath the AO surfactant. This highlights the role of the lipid carbonyl group in the interfacial water structure at the membrane interface, namely, stabilizing the water hydrogen bond network. PMID- 26506079 TI - Impact of number of [(18)F]fluorodeoxyglucose-PET-positive lymph nodes on survival of patients receiving neoadjuvant chemotherapy and surgery for oesophageal cancer. AB - BACKGROUND: [(18) F]fluorodeoxyglucose (FDG)-PET has been used to evaluate the response of primary tumours to neoadjuvant therapy for oesophageal cancer. The clinical significance of the number of PET-positive nodes before and after therapy has not been investigated previously. METHODS: [(18) F]FDG-PET was performed before and 2-3 weeks after completion of neoadjuvant chemotherapy to identify the number of PET-positive nodes, and these numbers were assessed in relation to metabolic changes in the primary tumour. RESULTS: Of 302 patients in total, 90 had no PET-positive nodes, 83 had one, 59 had two and 70 patients had three or more positive nodes before therapy. After treatment, the numbers were: none in 207 patients, one in 59, two in 20 and three or more in 16 patients. The number of PET-positive nodes after treatment was influenced by both the number of PET-positive nodes before therapy and the response to preoperative therapy, and correlated with the number of metastatic lymph nodes. Overall survival was longer in patients who had no PET-positive nodes after treatment than in those who had one or more. Multivariable analysis identified the numbers of PET-positive nodes before and after chemotherapy as independent prognostic factors, together with clinical response, tumour depth and lymph node involvement. CONCLUSION: The number of PET-positive nodes after treatment correlated with survival in patients with oesophageal cancer who underwent neoadjuvant chemotherapy. PMID- 26506080 TI - Microfluidic Flow through Polyaniline Supported by Lamellar-Structured Graphene for Mass-Transfer-Enhanced Electrocatalytic Reduction of Hexavalent Chromium. AB - Owing to its high efficiency and environmental compatibility, electroreduction holds great promise for the detoxification of aqueous Cr(VI). However, the typical electroreduction system often shows poor mass transfer, which results in slow reduction kinetics and hence higher energy consumption. Here, we demonstrate a flow-through electrode of polyaniline supported on lamellar-structured graphene (LGS-PANI) for electrocatalytic reduction of Cr(VI). The reaction kinetics of the LGS-PANI flow-through electrodes are 6.4 times (at acidic condition) and 17.3 times (at neutral condition) faster than traditional immersed parallel-plate electrodes. Computational fluid dynamics simulation suggests that the flow through mode greatly enhances the mass transfer and that the nanoscale convection induced by the PANI nanodots increases the nanoscale mass transport in the interfacial region of the electrode/solution. In situ Raman spectroscopy shows that the PANI-Cr(VI) redox reactions are dominated by the leucoemeraldine/emeraldine transition at 1.5 V cell voltage, which also remarkably contributes to the fast reaction kinetics. Using single-pass flow through mode, the LGS-PANI electrode reaches an average reduction efficiency of 99.8% with residual Cr(VI) concentration of 22.3 ppb (initial [Cr(VI)] = 10 ppm, flux = 20 L h(-1) m(-2)). A long-term stability test shows that the LGS-PANI maintains stable performance over 40 days of operation and achieves >98% reduction efficiency, with average current efficiency of as high as 99.1% (initial [Cr(VI)] = 10 ppm, flux = 50 L h(-1) m(-2)). PMID- 26506081 TI - Diterpenoid phytoalexin factor, a bHLH transcription factor, plays a central role in the biosynthesis of diterpenoid phytoalexins in rice. AB - Rice (Oryza sativa) produces diterpenoid phytoalexins (DPs), momilactones and phytocassanes as major phytoalexins. Accumulation of DPs is induced in rice by blast fungus infection, copper chloride or UV light. Here, we describe a rice transcription factor named diterpenoid phytoalexin factor (DPF), which is a basic helix-loop-helix (bHLH) transcription factor. The gene encoding DPF is expressed mainly in roots and panicles, and is inducible in leaves by blast infection, copper chloride or UV. Expression of all DP biosynthetic genes and accumulation of momilactones and phytocassanes were remarkably increased and decreased in DPF over-expressing and DPF knockdown rice, respectively. These results clearly demonstrated that DPF positively regulates DP accumulation via transcriptional regulation of DP biosynthetic genes, and plays a central role in the biosynthesis of DPs in rice. Furthermore, DPF activated the promoters of COPALYL DIPHOSPHATE SYNTHASE2 (CPS2) and CYTOCHROME P450 MONOOXYGENASE 99A2 (CYP99A2), whose products are implicated in the biosynthesis of phytocassanes and momilactones, respectively. Mutations in the N-boxes in the CPS2 upstream region, to which several animal bHLH transcription factors bind, decreased CPS2 transcription, indicating that DPF positively regulates CPS2 transcription through the N-boxes. In addition, DPF partly regulates CYP99A2 through the N-box. This study demonstrates that DPF acts as a master transcription factor in DP biosynthesis. PMID- 26506082 TI - What Should Junior Doctors Know about the Drugs they Frequently Prescribe? A Delphi Study among Physicians in the Netherlands. AB - The aim of this study was to identify the information about commonly prescribed drugs that junior doctors should know in order to prescribe rationally in daily practice, defined as essential drug knowledge (EDK). A two-round Internet Delphi study was carried out involving general practitioners from one practice cluster, and registrars and consultants from two Dutch academic and eight teaching hospitals. A preliminary list of 377 potential EDK items for three commonly prescribed drugs was assessed on a dichotomous scale; an item was considered EDK if at least 80% consensus was reached. The consensus list of EDK items was discussed by the research team to identify similarities between the three drugs, with a view to forming a list of general EDK items applicable to other commonly prescribed drugs. Sixty experts considered 93 of the 377 items (25%) as EDK. These items were then used to form a list of 10 general EDK items. The list of EDK items identified by primary and secondary care doctors could be used in medical curricula and training programmes and for assessing the prescribing competence of future junior doctors. Further research is needed to evaluate the generalizability of this list for other commonly prescribed drugs. PMID- 26506083 TI - Saphenous Vein Graft Disease Is Associated with a Low Serum Erythropoietin Level. AB - OBJECTIVE: To measure the serum erythropoietin (EPO) level in patients with saphenous vein grafts (SVGs) and to compare the EPO level in those with and without SVG disease. SUBJECTS AND METHODS: The study included 85 consecutive patients with a history of coronary artery bypass graft surgery that underwent elective coronary angiography. Patients with >30% stenosis (diseased grafts) in at least one saphenous graft were included in group 1 (diseased group: n = 40), and group 2 (nondiseased group: n = 45) consisted of patients without diseased SVGs. The EPO level was measured using enzyme-linked immunosorbent assay (ELISA) using a commercially available ELISA kit; x03C7;2 test and independent samples t test were used where appropriate. Logistic regression was used for multivariate analysis. RESULTS: There were not any significant differences in age, gender, or cardiovascular risk factors between the two groups except for increased triglyceride and low high-density lipoprotein levels in group 2. The EPO level was significantly higher in the nondiseased SVG group than in the diseased SVG group (25.5 +/- 9.6 vs. 17.8 +/- 6.8 mU ml-1, p = 0.002). Multivariate logistic regression analysis showed that the serum EPO level was an independent predictor of SVG disease (OR 1.14, 95% CI 1.06-1.24, p = 0.001). CONCLUSION: In this study, SVG disease was associated with a low serum EPO level, suggesting that a low EPO level could be predictive of and contributes to the pathophysiology of SVG disease. PMID- 26506084 TI - Optimized Silicon Electrode Architecture, Interface, and Microgeometry for Next Generation Lithium-Ion Batteries. AB - Optimized performance of silicon-ionic- liquid lithium-ion batteries through the implementation of a new electrode-microgeometry. The incorporation of 1D silicon nanowires into the cyclized-polyacrylonitrile-based electrode-architecture allows for greatly improved active material utilization, higher rate capabilities, and reduced interfacial reactions. PMID- 26506086 TI - From Right to Sin: Laws on Infanticide in Antiquity. AB - This is the first of three papers investigating changes in infanticide legislation as indicators of the attitude of states towards the neonate. In ancient East Asian societies in which the bride's family had to pay an excessive dowry, selective female infanticide was the rule, despite formal interdiction by the law. In Greece and Rome children's lives had little value, and the father's rights included killing his own children. The proportion of men greatly exceeding that of women found in many cultures and epochs suggests that girls suffered infanticide more often than boys. A kind of social birth, the ritual right to survive, rested on the procedure of name giving in the Roman culture and on the start of oral feeding in the Germanic tradition. Legislative efforts to protect the newborn began with Trajan's 'alimentaria' laws in 103 CE and Constantine's laws following his conversion to Christianity in 313 CE. Malformed newborns were not regarded as human infants and were usually killed immediately after birth. Infanticide was formally outlawed in 374 CE by Emperor Valentinian. PMID- 26506085 TI - Atorvastatin Reduces Circulating Osteoprogenitor Cells and T-Cell RANKL Expression in Osteoporotic Women: Implications for the Bone-Vascular Axis. AB - AIM: Circulating osteoprogenitors and receptor activator of nuclear factor kappa B ligand (RANKL) expression in immune cells have been implicated in the pathogenesis of osteoporosis and vascular calcification. The role played by statin therapy in the bone-vascular axis is unknown. METHODS: Twenty naive postmenopausal osteoporotic hypercholesterolemic women were treated with Atorvastatin 40 mg/day for 3 months. Gene expression analysis was performed to assess modification in osteoprotegerin (OPG)/RANK/RANKL expression in isolated T cells and monocytes. A flow cytometry analysis was used to study changes in the levels of circulating osteoprogenitor cells. RESULTS: After 3 months of treatment, Atorvastatin significantly reduced total cholesterol and LDL-C, without affecting HDL-C and triglycerides. Among circulating bone and phosphocalcium homeostasis markers, we found a significant increase in OPG levels (P < 0.01) and a modest reduction in osteocalcin (OCN) (P < 0.05). We also observed a significant reduction in RANKL expression in T cells (P < 0.05). No differences were found in the expression of RANK in T cells and RANKL and RANK in monocytes. OPG expression was low in both immune cell types and was not affected by the treatment. As for circulating osteoprogenitors, we found a significant reduction of CD34(+) BAP(+) (P < 0.05) and CD34(+) OCN(+) BAP(+) (P < 0.05) cells. In vitro studies showed that Atorvastatin reduced RANKL expression in activated human T-lymphoblastoid cells (Jurkat cell line). CONCLUSIONS: Three month Atorvastatin treatment leads to a reduction in circulating osteoprogenitor cells and RANKL expression in T cells, as well as increase in OPG serum levels. These data suggest that statins could have protective effects in the bone vascular axis. PMID- 26506087 TI - MRI as a promising tool for evaluation of the stability of cosmetic emulsions. AB - OBJECTIVE: We have recently established a novel method to evaluate the emulsion stability of pharmaceutical skin cream. The key technology of the method is magnetic resonance imaging (MRI). The purpose of this study was to verify the usefulness of the method in the cosmetic industry. METHODS: Milky lotion-type emulsions were employed as test samples. We note that the test samples were prepared by taking account of commercial milky lotions. After the sample preparation, a centrifugation treatment (5000 g for up to 120 min) was implemented to accelerate their destabilization processes. The centrifuged samples were monitored by using T2 relaxation time (T2 ) maps. Furthermore, the histograms generated from the T2 maps were analysed to investigate the destabilization process in more detail. In addition, small fractions of the upper and lower phases were collected from the centrifuged samples, and microscopic observations were conducted. RESULTS: T2 maps successfully visualized the destabilization process accompanying the centrifugation protocol. From the microscopic observations, it was clarified that the main mechanism of the destabilization process was creaming. The sensitivity of the T2 map to creaming was much superior to that of visible observation; the T2 map can detect a slight creaming that is not visible to the naked eye. In addition, the T2 map also enables the detection of slight reversible creaming-dispersion changes accompanied by a repeated centrifugation-vortexing treatment. By using the parameters derived from the histogram analysis, the creaming behaviour can be evaluated more precisely and more objectively. This study prepared emulsions containing different thickener contents and then compared their creaming behaviours. As a consequence of the analysis, we could fully evaluate the effect of thickener on the emulsion stability by the evaluation method. CONCLUSION: MRI is a promising tool for evaluation of the stability of cosmetic emulsions. PMID- 26506088 TI - Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy. AB - OBJECTIVE: Spinal muscular atrophy (SMA) is a major inherited cause of infant death worldwide. It results from mutations in a single, ubiquitously expressed gene (SMN1), with loss of lower motor neurons being the primary pathological signature. Systemic defects have also been reported in SMA patients and animal models. We investigated whether defects associated with the vasculature contribute to motor neuron pathology in SMA. METHODS: Development and integrity of the capillary bed was examined in skeletal muscle and spinal cord of SMA mice, and muscle biopsies from SMA patients and controls, using quantitative morphometric approaches on immunohistochemically labeled tissue. Pimonidazole hydrochloride-based assays were used to identify functional hypoxia. RESULTS: The capillary bed in muscle and spinal cord was normal in presymptomatic SMA mice (postnatal day 1), but failed to match subsequent postnatal development in control littermates. At mid- and late-symptomatic time points, the extent of the vascular architecture observed in two distinct mouse models of SMA was ~50% of that observed in control animals. Skeletal muscle biopsies from human patients confirmed the presence of developmentally similar, significant vascular depletion in severe SMA. Hypovascularity in SMA mouse spinal cord was accompanied by significant functional hypoxia and defects in the blood-spinal cord barrier. INTERPRETATION: Our results indicate that vascular defects are a major feature of severe forms of SMA, present in both mouse models and patients, resulting in functional hypoxia of motor neurons. Thus, abnormal vascular development and resulting hypoxia may contribute to the pathogenesis of SMA. PMID- 26506089 TI - Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 6 (STAT6) with Cell-Permeable, Phosphatase-Stable Phosphopeptide Mimics Potently Inhibits Tyr641 Phosphorylation and Transcriptional Activity. AB - Signal transducer and activator of transcription 6 (STAT6) transmits signals from cytokines IL-4 and IL-13 and is activated in allergic airway disease. We are developing phosphopeptide mimetics targeting the SH2 domain of STAT6 to block recruitment to phosphotyrosine residues on IL-4 or IL-13 receptors and subsequent Tyr641 phosphorylation to inhibit the expression of genes contributing to asthma. Structure-affinity relationship studies showed that phosphopeptides based on Tyr631 from IL-4Ralpha bind with weak affinity to STAT6, whereas replacing the pY+3 residue with simple aryl and alkyl amides resulted in affinities in the mid to low nM range. A set of phosphatase-stable, cell-permeable prodrug analogues inhibited cytokine-stimulated STAT6 phosphorylation in both Beas-2B human airway cells and primary mouse T-lymphocytes at concentrations as low as 100 nM. IL-13 stimulated expression of CCL26 (eotaxin-3) was inhibited in a dose-dependent manner, demonstrating that targeting the SH2 domain blocks both phosphorylation and transcriptional activity of STAT6. PMID- 26506090 TI - Impact of Whole-Body Radiation Dose on Response and Toxicity in Patients With Neuroblastoma After Therapy With 131 I-Metaiodobenzylguanidine (MIBG). AB - BACKGROUND: (131) I-metaiodobenzylguanidine ((131) I-MIBG) is a targeted radiopharmaceutical for patients with neuroblastoma. Despite its tumor-specific uptake, the treatment with (131) I-MIBG results in whole-body radiation exposure. Our aim was to correlate whole-body radiation dose (WBD) from (131) I-MIBG with tumor response, toxicities, and other clinical factors. METHODS: This retrospective cohort analysis included 213 patients with high-risk neuroblastoma treated with (131) I-MIBG at UCSF Benioff Children's Hospital between 1996 and 2015. WBD was determined from radiation exposure rate measurements. The relationship between WBD ordered tertiles and variables were analyzed using Cochran-Mantel-Haenszel test of trend, Kruskal-Wallis test, and one-way analysis of variance. Correlation between WBD and continuous variables was analyzed using Pearson correlation and Spearman rank correlation. RESULTS: WBD correlated with (131) I-MIBG administered activity, particularly with (131) I-MIBG per kilogram (P < 0.001). Overall response rate did not differ significantly among the three tertiles of WBD. Correlation between response by relative Curie score and WBD was of borderline significance, with patients receiving a lower WBD showing greater reduction in osteomedullary metastases by Curie score (rs = 0.16, P = 0.049). There were no significant ordered trends among tertiles in any toxicity measures (grade 4 neutropenia, thrombocytopenia < 20,000/MUl, and grade > 1 hypothyroidism). CONCLUSIONS: This study showed that (131) I-MIBG activity per kilogram correlates with WBD and suggests that activity per kilogram will predict WBD in most patients. Within the range of activities prescribed, there was no correlation between WBD and either response or toxicity. Future studies should evaluate tumor dosimetry, rather than just WBD, as a tool for predicting response following therapy with (131) I-MIBG. PMID- 26506091 TI - Phase Formation Behavior in Ultrathin Iron Oxide. AB - Nanostructured iron oxides, and especially hematite, are interesting for a wide range of applications ranging from gas sensors to renewable solar hydrogen production. A promising method for deposition of low-dimensional films is atomic layer deposition (ALD). Although a potent technique, ALD of ultrathin films is critically sensitive to the substrate and temperature conditions where initial formation of islands and crystallites influences the properties of the films. In this work, deposition at the border of the ALD window forming a hybrid ALD/pulsed CVD (pCVD) deposition is utilized to obtain a deposition less sensitive to the substrate. A thorough analysis of iron oxide phases formation on two different substrates, Si(100) and SiO2, was performed. Films between 3 and 50 nm were deposited and analyzed with diffraction techniques, high-resolution Raman spectroscopy, and optical spectroscopy. Below 10 nm nominal film thickness, island formation and phase dependent particle crystallization impose constraints for deposition of phase pure iron oxides on non-lattice-matching substrates. Films between 10 and 20 nm thickness on SiO2 could effectively be recrystallized into hematite whereas for the corresponding films on Si(100), no recrystallization occurred. For films thicker than 20 nm, phase pure hematite can be formed directly with ALD/pCVD with very low influence of the substrate on either Si or SiO2. For more lattice matched substrates such as SnO2:F, Raman spectroscopy indicated formation of the hematite phase already for films with 3 nm nominal thickness and clearly for 6 nm films. Analysis of the optical properties corroborated the analysis and showed a quantum confined blue-shift of the absorption edge for the thinnest films. PMID- 26506092 TI - klf2ash317 Mutant Zebrafish Do Not Recapitulate Morpholino-Induced Vascular and Haematopoietic Phenotypes. AB - INTRODUCTION AND OBJECTIVES: The zinc-finger transcription factor Krupsilonppel like factor 2 (KLF2) transduces blood flow into molecular signals responsible for a wide range of responses within the vasculature. KLF2 maintains a healthy, quiescent endothelial phenotype. Previous studies report a range of phenotypes following morpholino antisense oligonucleotide-induced klf2a knockdown in zebrafish. Targeted genome editing is an increasingly applied method for functional assessment of candidate genes. We therefore generated a stable klf2a mutant zebrafish and characterised its cardiovascular and haematopoietic development. METHODS AND RESULTS: Using Transcription Activator-Like Effector Nucleases (TALEN) we generated a klf2a mutant (klf2ash317) with a 14bp deletion leading to a premature stop codon in exon 2. Western blotting confirmed loss of wild type Klf2a protein and the presence of a truncated protein in klf2ash317 mutants. Homozygous klf2ash317 mutants exhibit no defects in vascular patterning, survive to adulthood and are fertile, without displaying previously described morphant phenotypes such as high-output cardiac failure, reduced haematopoetic stem cell (HSC) development or impaired formation of the 5th accessory aortic arch. Homozygous klf2ash317 mutation did not reduce angiogenesis in zebrafish with homozygous mutations in von Hippel Lindau (vhl), a form of angiogenesis that is dependent on blood flow. We examined expression of three klf family members in wildtype and klf2ash317 zebrafish. We detected vascular expression of klf2b (but not klf4a or biklf/klf4b/klf17) in wildtypes but found no differences in expression that might account for the lack of phenotype in klf2ash317 mutants. klf2b morpholino knockdown did not affect heart rate or impair formation of the 5th accessory aortic arch in either wildtypes or klf2ash317 mutants. CONCLUSIONS: The klf2ash317 mutation produces a truncated Klf2a protein but, unlike morpholino induced klf2a knockdown, does not affect cardiovascular development. PMID- 26506093 TI - In Situ Localization and Rhythmic Expression of Ghrelin and ghs-r1 Ghrelin Receptor in the Brain and Gastrointestinal Tract of Goldfish (Carassius auratus). AB - Ghrelin is a gut-brain peptide hormone, which binds to the growth hormone secretagogue receptor (GHS-R) to regulate a wide variety of biological processes in fish. Despite these prominent physiological roles, no studies have reported the anatomical distribution of preproghrelin transcripts using in situ hybridization in a non-mammalian vertebrate, and its mapping within the different encephalic areas remains unknown. Similarly, no information is available on the possible 24-h variations in the expression of preproghrelin and its receptor in any vertebrate species. The first aim of this study was to investigate the anatomical distribution of ghrelin and GHS-R1a ghrelin receptor subtype in brain and gastrointestinal tract of goldfish (Carassius auratus) using immunohistochemistry and in situ hybridization. Our second aim was to characterize possible daily variations of preproghrelin and ghs-r1 mRNA expression in central and peripheral tissues using real-time reverse transcription-quantitative PCR. Results show ghrelin expression and immunoreactivity in the gastrointestinal tract, with the most abundant signal observed in the mucosal epithelium. These are in agreement with previous findings on mucosal cells as the primary synthesizing site of ghrelin in goldfish. Ghrelin receptor was observed mainly in the hypothalamus with low expression in telencephalon, pineal and cerebellum, and in the same gastrointestinal areas as ghrelin. Daily rhythms in mRNA expression were found for preproghrelin and ghs-r1 in hypothalamus and pituitary with the acrophase occurring at nighttime. Preproghrelin, but not ghs-r1a, displayed a similar daily expression rhythm in the gastrointestinal tract with an amplitude 3-fold higher than the rest of tissues. Together, these results described for the first time in fish the mapping of preproghrelin and ghrelin receptor ghs-r1a in brain and gastrointestinal tract of goldfish, and provide the first evidence for a daily regulation of both genes expression in such locations, suggesting a possible connection between the ghrelinergic and circadian systems in teleosts. PMID- 26506094 TI - Role of LRP1 and ERK and cAMP Signaling Pathways in Lactoferrin-Induced Lipolysis in Mature Rat Adipocytes. AB - Lactoferrin (LF) is a multifunctional glycoprotein present in milk. A clinical study showed that enteric-coated bovine LF tablets decrease visceral fat accumulation. Furthermore, animal studies revealed that ingested LF is partially delivered to mesenteric fat, and in vitro studies showed that LF promotes lipolysis in mature adipocytes. The aim of the present study was to determine the mechanism underlying the induction of lipolysis in mature adipocytes that is induced by LF. To address this question, we used proteomics techniques to analyze protein expression profiles. Mature adipocytes from primary cultures of rat mesenteric fat were collected at various times after exposure to LF. Proteomic analysis revealed that the expression levels of hormone-sensitive lipase (HSL), which catalyzes the rate-limiting step of lipolysis, were upregulated and that HSL was activated by protein kinase A within 15 min after the cells were treated with LF. We previously reported that LF increases the intracellular concentration of cyclic adenosine monophosphate (cAMP), suggesting that LF activates the cAMP signaling pathway. In this study, we show that the expression level and the activity of the components of the extracellular signal-regulated kinase (ERK) signaling pathway were upregulated. Moreover, LF increased the activity of the transcription factor cAMP response element binding protein (CREB), which acts downstream in the cAMP and ERK signaling pathways and regulates the expression levels of adenylyl cyclase and HSL. Moreover, silencing of the putative LF receptor low-density lipoprotein receptor-related protein 1 (LRP1) attenuated lipolysis in LF-treated adipocytes. These results suggest that LF promoted lipolysis in mature adipocytes by regulating the expression levels of proteins involved in lipolysis through controlling the activity of cAMP/ERK signaling pathways via LRP1. PMID- 26506095 TI - Susceptibility-Weighted Imaging of the Anatomic Variation of Thalamostriate Vein and Its Tributaries. AB - BACKGROUND AND PURPOSE: Thalamostriate vein (TSV) is an important tributary of the internal cerebral vein, which mainly drains the basal ganglia and deep medulla. The purpose of this study was to explore the anatomic variation and quality of TSV and its smaller tributaries using susceptibility-weighted imaging (SWI). METHODS: We acquired SWI images in 40 volunteers on a 3.0T MR system using an 8-channel high-resolution phased array coil. The frequencies of the TSV and its tributaries were evaluated. We classified TSV into types I (forming a venous angle) and II (forming a false venous angle). We classified anterior caudate vein (ACV)into types 1 (1 trunk) and 2 (2 trunks) as well as into types A (joiningTSV), B (joining anterior septal vein), and C (joining the angle of both veins). RESULTS: The TSV drains the areas of caudate nucleus, internal capsule,lentiform nucleus, external capsule, claustrum, extreme capsule and the white matter of the frontoparietal lobes,except thalamus. The frequencies of the TSV, ACV and transverse caudate vein (ACV) were 92.5%, 87.5% and 63.8%, respectively. We found TSV types I and II in 79.7%, and 20.3% with significantly different constitution ratios (P< 0.05). The most common types of ACV were type 1 (90.0%) and type A (64.3%). CONCLUSION: The complex three-dimensional (3D) venous architecture of TSV and its small tributaries manifests great variation, with significant and practical implications for neurosurgery. PMID- 26506096 TI - Bacterial Species-Specific Activity of a Fluoroquinolone against Two Closely Related Pasteurellaceae with Similar MICs: Differential In Vitro Inoculum Effects and In Vivo Efficacies. AB - We investigated the antimicrobial activity of a fluoroquinolone against two genetically close bacterial species belonging to the Pasteurellaceae family. Time kill experiments were used to measure the in vitro activity of marbofloxacin against two strains of Mannheimia haemolytica and Pasteurella multocida with similar MICs. We observed that marbofloxacin was equally potent against 105 CFU/mL inocula M. haemolytica and P. multocida. However, an inoculum effect was observed with P. multocida, meaning that marbofloxacin activity was decreased against a 108 CFU/mL inoculum, whereas no inoculum effect was observed with M. haemolytica. Marbofloxacin activity was also tested in a lung infection model with immunocompromised mice intratracheally infected with 109 CFU of each bacteria. At the same dose, the clinical and bacteriological outcomes were much better for mice infected with M. haemolytica than for those infected with P. multocida. Moreover, bacteriological eradication was obtained with a lower marbofloxacin dose for mice infected with M. haemolytica. Our results suggest that the differential in vivo marbofloxacin efficacy observed with the two bacterial species of similar MIC could be explained by a differential inoculum effect. Consequently, MICs determined on 105 CFU inocula were not predictive of the differences in antibiotic efficacies against high bacterial inocula of closely related bacterial strains. These results could stimulate further investigations on bacterial species-specific antibiotic doses in a clinical setting. PMID- 26506098 TI - Perinatal outcomes with isolated oligohydramnios at term pregnancy. AB - AIMS: To compare the outcomes of term gestations with oligohydramnios in the absence of other underlying disorders and term gestations with normal amniotic fluid. METHODS: A retrospective analysis of obstetric outcomes in 27,708 term pregnancies. We compared three groups: labor induced because of oligohydramnios, spontaneous onset of labor with normal amniotic fluid, and labor induced because of late term pregnancy with normal amniotic fluid. We excluded pregnancies with maternal or fetal diseases or disorders potentially related with amniotic fluid alterations. The main outcome measures were mode of delivery, neonatal birth weight, umbilical artery blood pH, Apgar scores and neonatal discharge status. RESULTS: Compared to spontaneous labor, induction of labor because of oligohydramnios was associated with a higher risk of cesarean delivery and small size of the fetus for gestational age (SGA). Compared to induction because of late term pregnancy there were no significant differences in neonatal, although neonates had a higher risk of being SGA. CONCLUSION: The only perinatal outcome for which the risk was higher in term pregnancies with isolated oligohydramnios was SGA. The systematic induction of labor in these pregnancies should be questioned. PMID- 26506099 TI - Controversial ultrasound findings in mid trimester pregnancy. Evidence based approach. AB - Mid trimester fetal anatomy scan is a fundamental part of routine antenatal care. Some U/S soft markers or controversial U/S signs are seen during the scan and create some confusion regarding their relation to fetal chromosomal abnormalities. Example of these signs: echogenic focus in the heart, echogenic bowel, renal pyelectasis, ventriculomegaly, polydactely, club foot, choroid plexus cyst, single umbilical artery. We are presenting an evidence based approach from the literature for management of these controversial U/S signs. PMID- 26506100 TI - On an extended interpretation of linkage disequilibrium in genetic case-control association studies. AB - We are concerned with statistical inference for 2 * C * K contingency tables in the context of genetic case-control association studies. Multivariate methods based on asymptotic Gaussianity of vectors of test statistics require information about the asymptotic correlation structure among these test statistics under the global null hypothesis. In the case of C=2, we show that for a wide variety of test statistics this asymptotic correlation structure is given by the standardized linkage disequilibrium matrix of the K loci under investigation. Three popular choices of test statistics are discussed for illustration. In the case of C=3, the standardized composite linkage disequilibrium matrix is the limiting correlation matrix of the K locus-specific Cochran-Armitage trend test statistics. PMID- 26506097 TI - Systematic Identification of Cyclic-di-GMP Binding Proteins in Vibrio cholerae Reveals a Novel Class of Cyclic-di-GMP-Binding ATPases Associated with Type II Secretion Systems. AB - Cyclic-di-GMP (c-di-GMP) is a ubiquitous bacterial signaling molecule that regulates a variety of complex processes through a diverse set of c-di-GMP receptor proteins. We have utilized a systematic approach to identify c-di-GMP receptors from the pathogen Vibrio cholerae using the Differential Radial Capillary Action of Ligand Assay (DRaCALA). The DRaCALA screen identified a majority of known c-di-GMP binding proteins in V. cholerae and revealed a novel c di-GMP binding protein, MshE (VC0405), an ATPase associated with the mannose sensitive hemagglutinin (MSHA) type IV pilus. The known c-di-GMP binding proteins identified by DRaCALA include diguanylate cyclases, phosphodiesterases, PilZ domain proteins and transcription factors VpsT and VpsR, indicating that the DRaCALA-based screen of open reading frame libraries is a feasible approach to uncover novel receptors of small molecule ligands. Since MshE lacks the canonical c-di-GMP-binding motifs, a truncation analysis was utilized to locate the c-di GMP binding activity to the N-terminal T2SSE_N domain. Alignment of MshE homologs revealed candidate conserved residues responsible for c-di-GMP binding. Site directed mutagenesis of these candidate residues revealed that the Arg9 residue is required for c-di-GMP binding. The ability of c-di-GMP binding to MshE to regulate MSHA dependent processes was evaluated. The R9A allele, in contrast to the wild type MshE, was unable to complement the DeltamshE mutant for the production of extracellular MshA to the cell surface, reduction in flagella swimming motility, attachment to surfaces and formation of biofilms. Testing homologs of MshE for binding to c-di-GMP identified the type II secretion ATPase of Pseudomonas aeruginosa (PA14_29490) as a c-di-GMP receptor, indicating that type II secretion and type IV pili are both regulated by c-di-GMP. PMID- 26506101 TI - Continuity in drinking water supply. PMID- 26506102 TI - pMD-Membrane: A Method for Ligand Binding Site Identification in Membrane-Bound Proteins. AB - Probe-based or mixed solvent molecular dynamics simulation is a useful approach for the identification and characterization of druggable sites in drug targets. However, thus far the method has been applied only to soluble proteins. A major reason for this is the potential effect of the probe molecules on membrane structure. We have developed a technique to overcome this limitation that entails modification of force field parameters to reduce a few pairwise non-bonded interactions between selected atoms of the probe molecules and bilayer lipids. We used the resulting technique, termed pMD-membrane, to identify allosteric ligand binding sites on the G12D and G13D oncogenic mutants of the K-Ras protein bound to a negatively charged lipid bilayer. In addition, we show that differences in probe occupancy can be used to quantify changes in the accessibility of druggable sites due to conformational changes induced by membrane binding or mutation. PMID- 26506103 TI - Specificity in Mesograzer-Induced Defences in Seagrasses. AB - Grazing-induced plant defences that reduce palatability to herbivores are widespread in terrestrial plants and seaweeds, but they have not yet been reported in seagrasses. We investigated the ability of two seagrass species to induce defences in response to direct grazing by three associated mesograzers. Specifically, we conducted feeding-assayed induction experiments to examine how mesograzer-specific grazing impact affects seagrass induction of defences within the context of the optimal defence theory. We found that the amphipod Gammarus insensibilis and the isopod Idotea chelipes exerted a low-intensity grazing on older blades of the seagrass Cymodocea nodosa, which reflects a weak grazing impact that may explain the lack of inducible defences. The isopod Synischia hectica exerted the strongest grazing impact on C. nodosa via high-intensity feeding on young blades with a higher fitness value. This isopod grazing induced defences in C. nodosa as indicated by a consistently lower consumption of blades previously grazed for 5, 12 and 16 days. The lower consumption was maintained when offered tissues with no plant structure (agar-reconstituted food), but showing a reduced size of the previous grazing effect. This indicates that structural traits act in combination with chemical traits to reduce seagrass palatability to the isopod. Increase in total phenolics but not in C:N ratio and total nitrogen of grazed C. nodosa suggests chemical defences rather than a modified nutritional quality as primarily induced chemical traits. We detected no induction of defences in Zostera noltei, which showed the ability to replace moderate losses of young biomass to mesograzers via compensatory growth. Our study provides the first experimental evidence of induction of defences against meso-herbivory that reduce further consumption in seagrasses. It also emphasizes the relevance of grazer identity in determining the level of grazing impact triggering resistance and compensatory responses of different seagrass species. PMID- 26506104 TI - Assessing the Capacity of Plant Species to Accumulate Particulate Matter in Beijing, China. AB - Air pollution causes serious problems in spring in northern China; therefore, studying the ability of different plants to accumulate particulate matter (PM) at the beginning of the growing season may benefit urban planners in their attempts to control air pollution. This study evaluated deposits of PM on the leaves and in the wax layer of 35 species (11 shrubs, 24 trees) in Beijing, China. Differences in the accumulation of PM were observed between species. Cephalotaxus sinensis, Euonymus japonicus, Broussonetia papyriferar, Koelreuteria paniculata and Quercus variabilis were all efficient in capturing small particles. The plants exhibiting high amounts of total PM accumulation (on leaf surfaces and/or in the wax layer), also showed comparatively high levels of PM accumulation across all particle sizes. A comparison of shrubs and trees did not reveal obvious differences in their ability to accumulate particles based on growth form; a combination of plantings with different growth forms can efficiently reduce airborne PM concentrations near the ground. To test the relationships between leaf traits and PM accumulation, leaf samples of selected species were observed using a scanning electron microscope. Growth forms with greater amounts of pubescence and increased roughness supported PM accumulation; the adaxial leaf surfaces collected more particles than the abaxial surfaces. The results of this study may inform the selection of species for urban green areas where the goal is to capture air pollutants and mitigate the adverse effects of air pollution on human health. PMID- 26506105 TI - Expression of Beclin Family Proteins Is Associated with Tumor Progression in Oral Cancer. AB - BACKGROUND: Beclin 1 and Beclin 2 are autophagy-related proteins that show similar amino acid sequences and domain structures. Beclin 1 established the first connection between autophagy and cancer. However, the role of Beclin 2 in cancer is unclear. The aims of this study were to analyze Beclin 1 and Beclin 2 expressions in oral cancer tissues and in cell lines, and to evaluate their possible roles in cancer progression. METHODS: We investigated Beclin 1 and Beclin 2 expressions by immunohistochemistry in 195 cases of oral cancer. The prognostic roles of Beclin 1 and Beclin 2 were analyzed statistically. In vitro, overexpression and knockdown of Beclin proteins were performed on an oral cancer cell line, SAS. The immunofluorescence and autophagy flux assays confirmed that Beclin proteins were involved in autophagy. The impacts of Beclin 1 and Beclin 2 on autophagy and tumor growth were evaluated by conversion of LC3-I to LC3-II and by clonogenic assays, respectively. RESULTS: Oral cancer tissues exhibited aberrant expressions of Beclin 1 and Beclin 2. The cytoplasmic Beclin 1 and Beclin 2 expressions were unrelated in oral cancer tissues. In survival analyses, high cytoplasmic Beclin 1 expression was associated with low disease specific survival, and negative nuclear Beclin 1 expression was associated with high recurrent free survival. Patients with either high or low cytoplasmic Beclin 2 expression had significantly lower overall survival and disease specific survival rates than those with moderate expression. In oral cancer cells, overexpression of either Beclin 1 or Beclin 2 led to autophagy activation and increased clonogenic survival; knockdown of Beclin 2 impaired autophagy and increased clonogenic survival. CONCLUSIONS: Our results indicated that distinct patterns of Beclin 1 and Beclin 2 were associated with aggressive clinical outcomes. Beclin 1 overexpression, as well as Beclin 2 overexpression and depletion, contributed to tumor growth. These findings suggest Beclin proteins are associated with tumorigenesis. PMID- 26506106 TI - Clinical Report on the First Prototype of a Photoacoustic Tomography System with Dual Illumination for Breast Cancer Imaging. AB - Photoacoustic tomography is a recently developed imaging modality that can provide high spatial-resolution images of hemoglobin distribution in tissues such as the breast. Because breast cancer is an angiogenesis-dependent type of malignancy, we evaluated the clinical acceptability of breast tissue images produced using our first prototype photoacoustic mammography (PAM) system in patients with known cancer. Post-excisionally, histological sections of the tumors were stained immunohistochemically (IHC) for CD31 (an endothelial marker) and carbonic anhydrase IX (CAIX) (a marker of hypoxia). Whole-slide scanning and image analyses were used to evaluate the tumor microvessel distribution pattern and to calculate the total vascular perimeter (TVP)/area for each lesion. In this clinical study, 42 lesions were primarily scanned using PAM preoperatively, three of which were reported to be benign and were excluded from statistical analysis. Images were produced for 29 out of 39 cancers (visibility rate = 74.4%) at the median depth of 26.5 (3.25-51.2) mm. Age, menopausal status, body mass index, history of neoadjuvant treatment, clinical stage and histological tumor angiogenesis markers did not seem to affect the visibility. The oxygen saturation level in all of the measured lesions was lower than in the subcutaneous counterpart vessels (Wilcoxon test, p value<0.001), as well as in the counterpart contralateral normal breast region of interest (ROI) (Wilcoxon test, p value = 0.001). Although the oxygen saturation level was not statistically significant between CAIX-positive vs. -negative cases, lesional TVP/area showed a positive correlation with the oxygen saturation level only in the group that had received therapy before PAM. In conclusion, the vascular and oxygenation data obtained by PAM have great potential for identifying functional features of breast tumors. PMID- 26506107 TI - Influence of Phosphatidylcholine and Calcium on Self-Association and Bile Salt Mixed Micellar Binding of the Natural Bile Pigment, Bilirubin Ditaurate. AB - Recently [Neubrand, M. W., et al. (2015) Biochemistry 54, 1542-1557], we determined a concentration-dependent monomer-dimer-tetramer equilibrium in aqueous bilirubin ditaurate (BDT) solutions and explored the nature of high affinity binding of BDT monomers with monomers and micelles of the common taurine conjugated bile salts (BS). We now investigate, employing complementary physicochemical methods, including fluorescence emission spectrophotometry and quasi-elastic light scattering spectroscopy, the influence of phosphatidylcholine (PC), the predominant phospholipid of bile and calcium, the major divalent biliary cation, on these self-interactions and heterointeractions. We have used short-chain, lyso and long-chain PC species as models and contrasted our results with those of parallel studies employing unconjugated bilirubin (UCB) as the fully charged dianion. Both bile pigments interacted with the zwitterionic headgroup of short-chain lecithins, forming water-soluble (BDT) and insoluble ion pair complexes (UCB), respectively. Upon micelle formation, BDT monomers apparently remained at the headgroup mantle of short-chain PCs, but the ion pairs with UCB became internalized within the micelle's hydrophobic core. BDT interacted with the headgroups of unilamellar egg yolk (EY) PC vesicles; however, with the simultaneous addition of CaCl2, a reversible aggregation took place, but not vesicle fusion. With mixed EYPC/BS micelles, BDT became bound to the hydrophilic surface (as with simple BS micelles), and in turn, both BDT and BS bound calcium, but not other divalent cations. The calcium complexation of BDT and BS was enhanced strongly with increases in micellar EYPC, suggesting calcium mediated cross-bridging of hydrophilic headgroups at the micelle's surface. Therefore, the physicochemical binding of BDT to BS in an artificial bile medium is influenced not only by BS species and concentration but also by long-chain PCs and calcium ions that exert a specific rather than a counterion effect. This work should serve as a physicochemical template for studies with other conjugated bilirubins, including bilirubin diglucuronoside (BDG), the principal bilirubin conjugate (cBR) in human bile. PMID- 26506109 TI - Electronic Transport and Possible Superconductivity at Van Hove Singularities in Carbon Nanotubes. AB - Van Hove singularities (VHSs) are a hallmark of reduced dimensionality, leading to a divergent density of states in one and two dimensions and predictions of new electronic properties when the Fermi energy is close to these divergences. In carbon nanotubes, VHSs mark the onset of new subbands. They are elusive in standard electronic transport characterization measurements because they do not typically appear as notable features and therefore their effect on the nanotube conductance is largely unexplored. Here we report conductance measurements of carbon nanotubes where VHSs are clearly revealed by interference patterns of the electronic wave functions, showing both a sharp increase of quantum capacitance, and a sharp reduction of energy level spacing, consistent with an upsurge of density of states. At VHSs, we also measure an anomalous increase of conductance below a temperature of about 30 K. We argue that this transport feature is consistent with the formation of Cooper pairs in the nanotube. PMID- 26506108 TI - Differentiation of G:C vs A:T and G:C vs G:mC Base Pairs in the Latch Zone of alpha-Hemolysin. AB - The alpha-hemolysin (alpha-HL) nanopore can detect DNA strands under an electrophoretic force via many regions of the channel. Our laboratories previously demonstrated that trapping duplex DNA in the vestibule of wild-type alpha-HL under force could distinguish the presence of an abasic site compared to a G:C base pair positioned in the latch zone at the top of the vestibule. Herein, a series of duplexes were probed in the latch zone to establish if this region can detect more subtle features of base pairs beyond the complete absence of a base. The results of these studies demonstrate that the most sensitive region of the latch can readily discriminate duplexes in which one G:C base pair is replaced by an A:T. Additional experiments determined that while neither 8-oxo 7,8-dihydroguanine nor 7-deazaguanine opposite C could be differentiated from a G:C base pair, in contrast, the epigenetic marker 5-methylcytosine, when present in both strands of the duplex, yielded new blocking currents when compared to strands with unmodified cytosine. The results are discussed with respect to experimental design for utilization of the latch zone of alpha-HL to probe specific regions of genomic samples. PMID- 26506110 TI - Stereotactic anatomical localization in complex sinus surgery: A systematic review and meta-analysis. AB - OBJECTIVE: It is recognized that stereotactic anatomical localization (SAL) is a useful tool in endoscopic sinus surgery (ESS), but it may be most beneficial for complex rather than routine sinus procedures. This review sought to determine the safety and efficacy of SAL in complex indications for ESS. DATA SOURCES: PubMed, EMBASE, Centre for Reviews and Dissemination, and the Cochrane Library were searched from inception up to April 4, 2014. REVIEW METHODS: English studies comparing ESS with and without SAL in complex cases were included. Complex surgery included revision surgery, inverted papilloma, extensive sinus disease, or biopsy of tumors that are not exophytic. Safety outcomes included total, major, minor, orbital, dural, and major hemorrhage complications. Efficacy outcomes included operation completion, revision surgery, and patient-reported outcomes. Meta-analysis generated fixed-effects Mantel-Haenszel odds ratios (OR) and confidence intervals (CI). RESULTS: A total of 2,381 studies were identified, of which nine met the inclusion criteria. Meta-analyses indicated a reduction in the likelihood of total (OR = 0.58; 95% CI, 0.37-0.92), major (OR = 0.36; 95% CI, 0.18-0.75), and orbital complications (OR = 0.38; 95% CI, 0.17-0.83). There was no demonstrated benefit of SAL at reducing revision surgery (OR = 0.64; 95% CI, 0.38-1.08), major hemorrhage (OR = 0.77; 95% CI, 0.29-2.06), or minor complications (OR = 0.85; 95% CI, 0.48-1.50). CONCLUSION: Due to the rare outcomes under investigation, the included primary studies largely lacked the power to identify a statistically meaningful effect of SAL in ESS. However, meta analyses of primary studies demonstrated a decreased likelihood of total, major, and orbital complications in complex ESS with the use of SAL. PMID- 26506111 TI - Optical Biosensors for the Detection of Pathogenic Microorganisms. AB - Pathogenic microorganisms are causative agents of various infectious diseases that are becoming increasingly serious worldwide. For the successful treatment of pathogenic infection, the rapid and accurate detection of multiple pathogenic microorganisms is of great importance in all areas related to health and safety. Among various sensor systems, optical biosensors allow easy-to-use, rapid, portable, multiplexed, and cost-effective diagnosis. Here, we review current trends and advances in pathogen-diagnostic optical biosensors. The technological and methodological approaches underlying diverse optical-sensing platforms and methods for detecting pathogenic microorganisms are reviewed, together with the strengths and drawbacks of each technique. Finally, challenges in developing efficient optical biosensor systems and future perspectives are discussed. PMID- 26506112 TI - Optimizing the Mass-Specific Activity of Bilirubin Oxidase Adlayers through Combined Electrochemical Quartz Crystal Microbalance and Dual Polarization Interferometry Analyses. AB - Two surface analysis techniques, dual polarization interferometry (DPI) and analysis by an electrochemical quartz crystal microbalance with dissipation capability (E-QCM-D), were paired to find the deposition conditions that give the highest and most stable electrocatalytic activity per adsorbed mass of enzyme. Layers were formed by adsorption from buffered solutions of bilirubin oxidase from Myrothecium verrucaria at pH 6.0 to planar surfaces, under high enzyme loading (>=1 mg mL(-1)) for contact periods of up to 2 min. Both unmodified and carboxylate-functionalized gold-coated sensors showed that a deposition solution concentration of 10-25 mg mL(-1) gave the highest activity per mass of adsorbed enzyme with an effective catalytic rate constant (k(cat)) of about 60 s(-1). The densification of adsorbed layers observed by DPI correlated with reduced bioactivity observed by parallel E-QCM-D measurements. Postadsorption changes in thickness and density observed by DPI were incorporated into Kelvin-Voigt models of the QCM-D response. The modeled response matched experimental observations when the adlayer viscosity tripled after adsorption. PMID- 26506114 TI - Dividing the Janus vasculitis? Pathophysiology of eosinophilic granulomatosis with polyangitis. AB - Eosinophilic granulomatosis with polyangitis (EGPA) is a rare small- and medium sized vessel vasculitis belonging to the group of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV). It is commonly divided into two phenotypes depending on the presence of ANCAs targeting myeloperoxidase (MPO). MPO-ANCAs are present in 31% to 38% of patients and are associated with a vasculitis phenotype of the disease, whereas patients without MPO-ANCA are at risk of cardiac involvement. Despite significant advances in understanding the overall pathogenesis of the disease, the explanation for this dichotomy is still unclear. In this review, we synthesize our knowledge of the pathogenesis of EGPA and attempt to i) distinguish EGPA from other diseases including other AAVs, asthma, allergy and hypereosinophilic-associated conditions and ii) speculate about the preponderant mechanisms, which could explain the two disease phenotypes. PMID- 26506113 TI - miRNA-182 and the regulation of the glioblastoma phenotype - toward miRNA-based precision therapeutics. AB - Glioblastoma (GBM) is an incurable cancer, with survival rates of just 14-16 months after diagnosis. (1) Functional genomics have identified numerous genetic events involved in GBM development. One of these, the deregulation of microRNAs (miRNAs), has been attracting increasing attention due to the multiple biologic processes that individual miRNAs influence. Our group has been studying the role of miR-182 in GBM progression, therapy resistance, and its potential as GBM therapeutic. Oncogenomic analyses revealed that miR-182 is the only miRNA, out of 470 miRNAs profiled by The Cancer Genome Atlas (TCGA) program, which is associated with favorable patient prognosis, neuro-developmental context, temozolomide (TMZ) susceptibility, and most significantly expressed in the least aggressive oligoneural subclass of GBM. miR-182 sensitized glioma cells to TMZ induced apoptosis, promoted glioma initiating cell (GIC) differentiation, and reduced tumor cell proliferation via knockdown of Bcl2L12, c-Met and HIF2A. (2) To deliver miR-182 to intracranial gliomas, we have characterized Spherical Nucleic Acids covalently functionalized with miR-182 sequences (182-SNAs). Upon systemic administration, 182-SNAs crossed the blood-brain/blood-tumor barrier (BBB/BTB), reduced tumor burden, and increased animal subject survival. (2-4) Thus, miR-182-based SNAs represent a tool for systemic delivery of miRNAs and a novel approach for the precision treatment of malignant brain cancers. PMID- 26506115 TI - Clinical impact of prostate specific antigen (PSA) inter-assay variability on management of prostate cancer. AB - PURPOSE: To evaluate the inter-assay variability of six commercially available prostate specific antigen (PSA) assays, its clinical impact in prostate cancer (PCa) and comparison of automated versus manual assays. PATIENTS AND METHODS: Sera from 495 patients (425 with PCa and 70 men with Benign Prostatic Hyperplasia (BPH), were measured with six different assays [three automated assays (a-PSA) and three manual ELISA based assay (m-PSA)]. Variability, agreement and bias were measured and compared among assays using Bland Altman plots and Passing and Bablok regression analysis. The possible impact of inter-assay variability on important clinical scenarios was also studied. RESULTS: All the assays were well correlated (r: 0.88-0.98); however there was significant disagreement and bias between the systems, which were more pronounced among the a-PSA assays. The Bland Altman plot showed that the variability was high between the m-PSA assays and the standard Abbott system with mean difference of 3.8-5.8ng/ml. In contrast, the a PSA had better agreement with mean difference of 0.8-2.3ng/ml. Beckman Coulter showed the best agreement to the institutional reference (slope-1.097; 95% CI: 1.06-1.14; p<0.05, and intercept-0.20; 95% CI-0.38-0.58; p<0.05, Passing Bablok). It led to significant variability in PCa risk stratification and failure to detect biochemical failure in more than 50% cases. CONCLUSIONS: The discrepancies between the assays lead to significant clinical misinterpretation with risk group migration and detection of biochemical failure post radiotherapy. There are significant discordances between automated and ELISA based assays. PMID- 26506117 TI - Comparison of the Liaison(r) Calprotectin kit with a well established point of care test (Quantum Blue - Buhlmann-Alere(r)) in terms of analytical performances and ability to detect relapses amongst a Crohn population in follow-up. AB - BACKGROUND: Although colonoscopy associated with histopathological sampling remains the gold standard in the diagnostic and follow-up of inflammatory bowel disease (IBD), calprotectin is becoming an essential biomarker in gastroenterology. The aim of this work is to compare a newly developed kit (Liaison(r) Calprotectin - Diasorin(r)) and its two distinct extraction protocols (weighing and extraction device protocol) with a well established point of care test (Quantum Blue(r) - Buhlmann-Alere(r)) in terms of analytical performances and ability to detect relapses amongst a Crohn's population in follow-up. METHODS: Stool specimens were collected over a six month period and were composed of control and Crohn's patients. Amongst the Crohn's population disease activity (active vs quiescent) was evaluated by gastroenterologists. RESULTS: A significant difference was found between all three procedures in terms of calprotectin measurements (weighing protocol=30.3MUg/g (median); stool extraction device protocol=36.9MUg/g (median); Quantum Blue(r) (median)=63; Friedman test, P value=0.05). However, a good correlation was found between both extraction methods coupled with the Liaison(r) analyzer and between the Quantum Blue(r) (weighing protocol/extraction device protocol Rs=0.844, P=0.01; Quantum Blue(r)/extraction device protocol Rs=0.708, P=0.01; Quantum Blue(r)/weighing protocol, Rs=0.808, P=0.01). Finally, optimal cut-offs (and associated negative predictive values - NPV) for detecting relapses were in accordance with above results (Quantum Blue(r) 183.5MUg/g and NPV of 100%>extraction device protocol+Liaison(r) analyzer 124.5MUg/g and NPV of 93.5%>weighing protocol+Liaison(r) analyzer 106.5MUg/g and NPV of 95%). CONCLUSIONS: Although all three methods correlated well and had relatively good NPV in terms of detecting relapses amongst a Crohn's population in follow-up, the lack of any international standard is the origin of different optimal cut-offs between the three procedures. PMID- 26506116 TI - Skin collagen pentosidine and fluorescence in diabetes were predictors of retinopathy progression and creatininemia increase already 6years after punch biopsy. AB - OBJECTIVE: Advanced glycation end products (AGEs) of collagens appear to contribute to microvascular complications in diabetes. Do high concentrations of AGEs in skin collagen predict accelerated progression of these complications after 6 years and indicate the need for tighter anti-diabetic treatment? DESIGN AND METHODS: We measured two AGE parameters in collagen extracted from skin punch biopsies: pentosidine and fluorescence at 370/440nm, as markers and predictors of microvascular complications, in 30 patients with diabetes (14 type-1, 16 type-2) without renal insufficiency, and in age- and gender-matched normoglycemic controls, followed at Hotel-Dieu in Paris. RESULTS: At the time of biopsy, marked increases in pentosidine (p=0.0014) and fluorescence (p=0.0001) expressed per collagen hydroxyproline, were found in the patients with diabetes versus the controls. A significant effect of age was found for pentosidine, but not fluorescence, measurements in the normoglycemic controls. Therefore pentosidine but not fluorescence results were corrected for age in the patients. Pentosidine and fluorescence were correlated with diabetes duration. Fluorescence was significantly dependent on retinopathy presence and score in type-1 and type-2 diabetes, whereas pentosidine was not. Fluorescence was correlated with microalbuminuria only in type-1 diabetes. Neither fluorescence nor pentosidine were correlated with creatininemia. Already six years after biopsy, retinopathy score progression and creatininemia increase were significantly correlated with initial pentosidine and fluorescence measurements. CONCLUSIONS: These AGEs are good predictors of progression of microvascular complications and appear to be pathogenic. High skin concentrations of AGEs should induce tighter anti-diabetic treatment. PMID- 26506118 TI - Cystatin-C levels in healthy children and adolescents: Influence of age, gender, body mass index and blood pressure. AB - OBJECTIVES: Cystatin-C is considered a more sensitive and specific marker of kidney function than creatinine since it can diagnose patients with earlier-stage of renal dysfunction. The aim of this study is to determine the levels of Cystatin-C in healthy children and adolescents as well as any correlations to age, gender, body-mass index (BMI) and blood pressure (BP). DESIGN AND METHODS: Cystatin-C was measured in 536 healthy Greek children and adolescents (295 males and 241 females) using a nephelometric immunoassay. Additionally, the age, body mass index and blood pressure was recorded for each subject. RESULTS: Overall, the mean serum Cystatin-C level was 0.79 +/- 0.10 mg/L. Cystatin-C was found to be statistically significantly lower in females than in males (p < 0.001) as well as in prepubertal children compared to adolescents (p < 0.001). Higher values of Cystatin-C were observed in subjects with increased BMI (p < 0.001). Neither systolic nor diastolic blood pressure was found to significantly affect Cystatin C levels. CONCLUSIONS: The levels of Cystatin-C were statistically significantly higher in males, compared to age-matched females and also positively correlated with age and BMI. PMID- 26506119 TI - "Oh the weather outside is frightful": Severe injury secondary to falls while installing residential Christmas lights. AB - INTRODUCTION: Falls are an increasingly common source of severe traumatic injury. They now account for approximately 40% of both overall trauma volumes and injury related deaths within Canada. In northern climates, the risk of all types of falls may increase during the fall/winter months when conditions become increasingly dangerous. The purpose of this study was to define the injury and patient demographics of severe trauma that occurs during falls associated with the installation of Christmas lights. PATIENTS AND METHODS: All patients who were admitted to a referral level 1 trauma center (2002-2012) with severe injuries (ISS>=12) caused during Christmas light installation were retrospectively reviewed. Standard statistical methodology was utilised (p<0.05=significant). RESULTS: A total of 40 patients were severely injured (95% male; mean age=55 years; mean ISS=25.7 (range: 12-75)) while installing Christmas lights. Injuries included: neurologic (68%), thoracic (68%), spinal (43%), extremity (40%), and multiple other sites. Fall mechanisms were: ladder (65%), roof (30%), ground (3%) and railing (3%). Interventions included intubation and critical care (20%), as well as orthopaedic and neurosurgical operative repairs (30%). The median length of hospital stay was 15.6 days (range: 2-165). The fall-related morbidity (28%) and mortality (5%) were significant with a total of 12.5% patients requiring transfer to a long-term care or rehabilitation facility. CONCLUSIONS: Falls while installing Christmas lights during the fall/winter seasons can result in severe life-altering injuries with considerable morbidity and mortality. Caution should be employed when installing lights at any height. PMID- 26506120 TI - Synthesis of Benzofuro- and Indolo[3,2-b]indoles via Palladium-Catalyzed Double N Arylation and Their Physical Properties. AB - Two kinds of ladder-type pi-conjugated compounds, benzofuro[3,2-b]indoles (BFIs) and indolo[3,2-b]indoles (IIs), were successfully synthesized using palladium catalyzed double N-arylation of anilines with the corresponding dihalobiaryls. Photophysical properties were evaluated by UV-vis and photoluminescence spectroscopies and theoretical calculations. BFI derivatives showed higher quantum yields (33-39%) than the II derivative (29%). The absorption bands of the II derivative were more red-shifted compared to BFI derivatives. PMID- 26506121 TI - Prevalence of Myocardial Bridging in Patients With Myocardial Infarction and Nonobstructed Coronary Arteries. AB - Mechanisms of acute myocardial infarction and nonobstructed coronary arteries (MINOCA) are incompletely understood. Myocardial bridging (MB) is usually considered a benign congenital variant, but serious complications have been reported. MB has also been proposed as a cause of takotsubo syndrome (TS). We aimed to examine whether MB was more frequent in patients with MINOCA or TS than in age- and gender-matched controls and to compare the MB detection rates of coronary computed tomography angiography (CTA) and invasive coronary angiography (ICA). Patients with MINOCA (n = 57) and age- and gender-matched controls (n = 58), aged 45 to 70 were enrolled. Myocarditis was excluded by cardiovascular magnetic resonance imaging. Patients with TS (n = 15) were considered as a subgroup and therefore not excluded. Patients with MINOCA underwent ICA and all study participants underwent coronary CTA. All examinations were reviewed with focus on MB. Among 57 MINOCA patients, 15 MINOCA patients with TS and 58 controls, MB was demonstrated in 28 patients (49%), 8 patients (53%), and 26 patients (45%), respectively. There were no statistically significant differences regarding the prevalence of MB or the type, location, length, or thickness of MB. There was a statistically significant difference (p <0.01) between the detection rates of coronary CTA and ICA that demonstrated MB in 54 subjects (47%) and 13 subjects (23%), respectively. In conclusion, MB was frequent with a similar prevalence in patients with MINOCA, patients with TS and controls. This suggests that there is no causal link between MB and MINOCA or TS. Furthermore, coronary CTA detects MB at a significantly higher rate than ICA. PMID- 26506122 TI - Impact of Nonalcoholic Fatty Liver Disease on Myocardial Perfusion in Nondiabetic Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction. AB - Limited data exist on the role of nonalcoholic fatty liver disease (FLD) as a potential independent risk factor in the setting of acute coronary syndromes. The aim of this study was to evaluate the impact of FLD on myocardial perfusion and inhospital major adverse cardiac events (MACE) in the setting of ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). We examined 186 consecutive nondiabetic patients (mean age 58 +/- 11 years and 76% men) who underwent primary PCI for STEMI by ultrasound within 72 hours of admission. FLD was graded according to a semiquantitative severity score as mild (score <3) or moderate to severe (score >=3). Myocardial perfusion was determined by measuring myocardial blush grade (MBG) and ST-segment resolution (STR) analysis. Patients were divided into 2 groups according to FLD score (<3 or >=3). There were no differences with regard to postprocedural Thrombolysis In Myocardial Infarction 3 flow grade between the 2 groups (89% vs 83%, p = 0.201). Patients with FLD score >=3 were more likely to have absent myocardial perfusion (MBG 0/1, 37% vs 12%, p <0.0001), absent STR (27% vs 9%, p = 0.001), and higher inhospital MACE rate (31% vs 8%, p <0.0001). By multivariate analysis, FLD >=3 score was found to be an independent predictor of absent MBG 0/1 (odds ratio [OR] 2.856, 95% confidence interval [CI] 1.214 to 6.225, p = 0.033), absent STR (OR 2.862, 95% CI 1.242 to 6.342, p = 0.031), and inhospital MACE (OR 2.454, 95% CI 1.072 to 4.872, p = 0.048). In conclusion, we found that despite similar high rates of Thrombolysis In Myocardial Infarction 3 after primary PCI, patients with FLD score >=3 are more likely to have impaired myocardial perfusion which may contribute to adverse inhospital outcome. PMID- 26506123 TI - A novel isocoumarin with anti-influenza virus activity from Strobilanthes cusia. AB - Strobilanthes A (1), a novel isocoumarin with an unusual tetrahydro-4H-pyran-4 one moiety fused isocoumarin core skeleton, together with a known compound (2) was isolated from Strobilanthes cusia. Its chemical structures were elucidated by 2D NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction analysis. The biosynthetic pathway of 1 could be supposed to be originally derived from 3-methylisocoumarin, a product of AA-MA pathway. Both of two compounds displayed anti-influenza virus activity in vitro. PMID- 26506124 TI - Sperm cryopreservation update: Cryodamage, markers, and factors affecting the sperm freezability in pigs. AB - Cryopreservation is the most efficient method for long-term preservation of mammalian sperm. However, freeze-thawing procedures may strongly impair the sperm function and survival and thus decrease the reproductive performance. In addition, the sperm resilience to withstand cryopreservation, also known as freezability, presents a high individual variability. The present work summarizes the principles of cryoinjury and the relevance of permeating and nonpermeating cryoprotective agents. Descriptions about sperm cryodamage are mainly focused on boar sperm, but reference to other mammalian species is also made when relevant. Main cryoinjuries not only regard to sperm motility and membrane integrity, but also to the degradation effect exerted by freeze-thawing on other important components for sperm fertilizing ability, such as mRNAs. After delving into the main differences between good and poor freezability boar ejaculates, those protein markers predicting the sperm ability to sustain cryopreservation are also mentioned. Moreover, factors that may influence sperm freezability, such as season, diet, breed, or ejaculate fractions are discussed, together with the effects of different additives, like seminal plasma and antioxidants. After briefly referring to the effects of long-term sperm preservation in frozen state and the reproductive performance of frozen-thawed boar sperm, this work speculates with new research horizons on the preservation of boar sperm, such as vitrification and freeze-drying. PMID- 26506126 TI - Regeneration science needs to broaden its focus to understand why some organisms can regenerate and others not. PMID- 26506125 TI - S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation. AB - S-adenosylhomocysteine (SAH) can induce endothelial dysfunction and activation, contributing to atherogenesis; however, its role in the activation of the inflammatory mediator NFkB has not been explored. Our aim was to determine the role of NFkB in SAH-induced activation of endothelial cells. Furthermore, we examined whether SAH, as a potent inhibitor of S-adenosylmethionine-dependent methyltransferases, suppresses the function of EZH2 methyltransferase to contribute to SAH-induced endothelial cell activation. We found that excess SAH increases the expression of adhesion molecules and cytokines in human coronary artery endothelial cells. Importantly, this up-regulation was suppressed in cells expressing a dominant negative form of the NFkB inhibitor, IkB. Moreover, SAH accumulation triggers the activation of both the canonical and non-canonical NFkB pathways, decreases EZH2, and reduces histone 3 lysine 27 trimethylation. EZH2 knockdown recapitulated the effects of excess SAH on endothelial activation, i.e., it induced NFkB activation and the subsequent up-regulation of adhesion molecules and cytokines. Our findings suggest that suppression of the epigenetic regulator EZH2 by excess SAH may contribute to NFkB activation and the consequent vascular inflammatory response. These studies unveil new targets of SAH regulation, demonstrating that EZH2 suppression and NFkB activation mediated by SAH accumulation may contribute to its adverse effects in the vasculature. PMID- 26506127 TI - Cell types of origin for prostate cancer. AB - Analyses of cell types of origin for prostate cancer should result in new insights into mechanisms of tumor initiation, and may lead to improved prognosis and selection of appropriate therapies. Here, we review studies using a range of methodologies to investigate the cell of origin for mouse and human prostate cancer. Notably, analyses using tissue recombination assays support basal epithelial cells as a cell of origin, whereas in vivo lineage-tracing studies in genetically-engineered mice implicate luminal cells. We describe how these results can be potentially reconciled by a conceptual distinction between cells of origin and cells of mutation, and outline how new experimental approaches can address the potential relationship between cell types of origin and disease outcome. PMID- 26506128 TI - From the Editor. PMID- 26506129 TI - The SPRINT trial. PMID- 26506131 TI - Purine metabolism in response to hypoxic conditions associated with breath-hold diving and exercise in erythrocytes and plasma from bottlenose dolphins (Tursiops truncatus). AB - In mammalian tissues under hypoxic conditions, ATP degradation results in accumulation of purine metabolites. During exercise, muscle energetic demand increases and oxygen consumption can exceed its supply. During breath-hold diving, oxygen supply is reduced and, although oxygen utilization is regulated by bradycardia (low heart rate) and peripheral vasoconstriction, tissues with low blood flow (ischemia) may become hypoxic. The goal of this study was to evaluate potential differences in the circulating levels of purine metabolism components between diving and exercise in bottlenose dolphins (Tursiops truncatus). Blood samples were taken from captive dolphins following a swimming routine (n=8) and after a 2min dive (n=8). Activity of enzymes involved in purine metabolism (hypoxanthine guanine phosphoribosyl transferase (HGPRT), inosine monophosphate deshydrogenase (IMPDH), xanthine oxidase (XO), purine nucleoside phosphorylase (PNP)), and purine metabolite (hypoxanthine (HX), xanthine (X), uric acid (UA), inosine monophosphate (IMP), inosine, nicotinamide adenine dinucleotide (NAD(+)), adenosine, adenosine monophosphate (AMP), adenosine diphosphate (ADP), ATP, guanosine diphosphate (GDP), guanosine triphosphate (GTP)) concentrations were quantified in erythrocyte and plasma samples. Enzymatic activity and purine metabolite concentrations involved in purine synthesis and degradation, were not significantly different between diving and exercise. Plasma adenosine concentration was higher after diving than exercise (p=0.03); this may be related to dive-induced ischemia. In erythrocytes, HGPRT activity was higher after diving than exercise (p=0.007), suggesting an increased capacity for purine recycling and ATP synthesis from IMP in ischemic tissues of bottlenose dolphins during diving. Purine recycling and physiological adaptations may maintain the ATP concentrations in bottlenose dolphins after diving and exercise. PMID- 26506130 TI - Does oxygen limit thermal tolerance in arthropods? A critical review of current evidence. AB - Over the last decade, numerous studies have investigated the role of oxygen in setting thermal tolerance in aquatic animals, and there has been particular focus on arthropods. Arthropods comprise one of the most species-rich taxonomic groups on Earth, and display great diversity in the modes of ventilation, circulation, blood oxygen transport, with representatives living both in water (mainly crustaceans) and on land (mainly insects). The oxygen and capacity limitation of thermal tolerance (OCLTT) hypothesis proposes that the temperature dependent performance curve of animals is shaped by the capacity for oxygen delivery in relation to oxygen demand. If correct, oxygen limitation could provide a mechanistic framework to understand and predict both current and future impacts of rapidly changing climate. In arthropods, most studies testing the OCLTT hypothesis have considered tolerance to thermal extremes. These studies likely operate from the philosophical viewpoint that if the model can predict these critical thermal limits, then it is more likely to also explain loss of performance at less extreme, non-lethal temperatures, for which much less data is available. Nevertheless, the extent to which lethal temperatures are influenced by limitations in oxygen supply remains unresolved. Here we critically evaluate the support and universal applicability for oxygen limitation being involved in lethal temperatures in crustaceans and insects. The relatively few studies investigating the OCLTT hypothesis at low temperature do not support a universal role for oxygen in setting the lower thermal limits in arthropods. With respect to upper thermal limits, the evidence supporting OCLTT is stronger for species relying on underwater gas exchange, while the support for OCLTT in air-breathers is weak. Overall, strongest support was found for increased anaerobic metabolism close to thermal maxima. In contrast, there was only mixed support for the prediction that aerobic scope decreases near critical temperatures, a key feature of the OCLTT hypothesis. In air-breathers, only severe hypoxia (<2 kPa) affected heat tolerance. The discrepancies for heat tolerance between aquatic and terrestrial organisms can to some extent be reconciled by differences in the capacity to increase oxygen transport. As air-breathing arthropods are unlikely to become oxygen limited under normoxia (especially at rest), the oxygen limitation component in OCLTT does not seem to provide sufficient information to explain lethal temperatures. Nevertheless, many animals may simultaneously face hypoxia and thermal extremes and the combination of these potential stressors is particularly relevant for aquatic organisms where hypoxia (and hyperoxia) is more prevalent. In conclusion, whether taxa show oxygen limitation at thermal extremes may be contingent on their capacity to regulate oxygen uptake, which in turn is linked to their respiratory medium (air vs. water). Fruitful directions for future research include testing multiple predictions of OCLTT in the same species. Additionally, we call for greater research efforts towards studying the role of oxygen in thermal limitation of animal performance at less extreme, sub lethal temperatures, necessitating studies over longer timescales and evaluating whether oxygen becomes limiting for animals to meet energetic demands associated with feeding, digestion and locomotion. PMID- 26506132 TI - Predicting Adsorption Affinities of Small Molecules on Carbon Nanotubes Using Molecular Dynamics Simulation. AB - Computational techniques have the potential to accelerate the design and optimization of nanomaterials for applications such as drug delivery and contaminant removal; however, the success of such techniques requires reliable models of nanomaterial surfaces as well as accurate descriptions of their interactions with relevant solutes. In the present work, we evaluate the ability of selected models of naked and hydroxylated carbon nanotubes to predict adsorption equilibrium constants for about 30 small aromatic compounds with a variety of functional groups. The equilibrium constants determined using molecular dynamics coupled with free-energy calculation techniques are directly compared to those derived from experimental measurements. The calculations are highly predictive of the relative adsorption affinities of the compounds, with excellent correlation (r >= 0.9) between calculated and measured values of the logarithm of the adsorption equilibrium constant. Moreover, the agreement in absolute terms is also reasonable, with average errors of less than one decade. We also explore possible effects of surface loading, although we demonstrate that they are negligible for the experimental conditions considered. Given the degree of reliability demonstrated, we move on to employing the in silico techniques in the design of nanomaterials, using the optimization of adsorption affinity for the herbacide atrazine as an example. Our simulations suggest that, compared to other modifications of graphenic carbon, polyvinylpyrrolidone conjugation gives the highest affinity for atrazine-substantially greater than that of graphenic carbon alone-and may be useful as a nanomaterial for delivery or sequestration of atrazine. PMID- 26506133 TI - Letter to the Editor Regarding "Ruling Out Coronary Artery Disease in Women with Atypical Chest Pain: Results of Calcium Score Combined with Coronary Computed Tomography Angiography, and Associated Radiation Exposure". PMID- 26506134 TI - Large-scale climatic anomalies affect marine predator foraging behaviour and demography. AB - Determining the links between the behavioural and population responses of wild species to environmental variations is critical for understanding the impact of climate variability on ecosystems. Using long-term data sets, we show how large scale climatic anomalies in the Southern Hemisphere affect the foraging behaviour and population dynamics of a key marine predator, the king penguin. When large scale subtropical dipole events occur simultaneously in both subtropical Southern Indian and Atlantic Oceans, they generate tropical anomalies that shift the foraging zone southward. Consequently the distances that penguins foraged from the colony and their feeding depths increased and the population size decreased. This represents an example of a robust and fast impact of large-scale climatic anomalies affecting a marine predator through changes in its at-sea behaviour and demography, despite lack of information on prey availability. Our results highlight a possible behavioural mechanism through which climate variability may affect population processes. PMID- 26506135 TI - GRK2 compromises cardiomyocyte mitochondrial function by diminishing fatty acid mediated oxygen consumption and increasing superoxide levels. AB - The G protein-coupled receptor kinase-2 (GRK2) is upregulated in the injured heart and contributes to heart failure pathogenesis. GRK2 was recently shown to associate with mitochondria but its functional impact in myocytes due to this localization is unclear. This study was undertaken to determine the effect of elevated GRK2 on mitochondrial respiration in cardiomyocytes. Sub-fractionation of purified cardiac mitochondria revealed that basally GRK2 is found in multiple compartments. Overexpression of GRK2 in mouse cardiomyocytes resulted in an increased amount of mitochondrial-based superoxide. Inhibition of GRK2 increased oxygen consumption rates and ATP production. Moreover, fatty acid oxidation was found to be significantly impaired when GRK2 was elevated and was dependent on the catalytic activity and mitochondrial localization of this kinase. Our study shows that independent of cardiac injury, GRK2 is localized in the mitochondria and its kinase activity negatively impacts the function of this organelle by increasing superoxide levels and altering substrate utilization for energy production. PMID- 26506136 TI - Virtual Reality Body Swapping: A Tool for Modifying the Allocentric Memory of the Body. AB - An increasing amount of evidence has shown that embodiment of a virtual body via visuo-tactile stimulation can lead to an altered perception of body and object size. The current study aimed to investigate whether virtual reality (VR) body swapping can be an effective tool for modifying the enduring memory of the body. The experimental sample included 21 female participants who were asked to estimate the width and circumference of different body parts before any kind of stimulation and after two types of body swapping illusions ("synchronous visuo tactile stimulation" and "asynchronous visuo-tactile stimulation"). Findings revealed that after participants embodied a virtual body with a skinny belly (independently of the type of visuo-tactile stimulation), there was an update of the stored representation of the body: participants reported a decrease in the ratio between estimated and actual body measures for most of the body parts considered. Based on the Allocentric Lock Theory, these findings provide first evidence that VR body swapping is able to induce a change in the memory of the body. This knowledge may be potentially useful for patients suffering from eating and weight disorders. PMID- 26506137 TI - Specific detection of peste des petits ruminants virus antibodies in sheep and goat sera by the luciferase immunoprecipitation system. AB - Peste des petits ruminants (PPR) is a contagious and often fatal transboundary animal disease affecting mostly sheep, goats and wild small ruminants. This disease is endemic in most of Africa, the Middle, Near East, and large parts of Asia. The causal agent is peste des petits ruminants virus (PPRV), which belongs to the genus Morbillivirus in the family Paramyxoviridae. This genus also includes measles virus (MV), canine distemper virus (CDV) and rinderpest virus (RPV). All are closely related viruses with serological cross reactivity. In this study, we have developed a Luciferase Immunoprecipitation System (LIPS) for the rapid detection of antibodies against PPRV in serum samples and for specific differentiation from antibodies against RPV. PPR and rinderpest (RP) serum samples were assayed by PPR-LIPS and two commercially available PPR cELISA tests. The PPR-LIPS showed high sensitivity and specificity for the samples tested and showed no cross reactivity with RPV unlike the commercial PPR cELISA tests which did cross react with RPV. Based on the results shown in this study, PPR-LIPS is presented as a good candidate for the specific serosurveillance of PPR. PMID- 26506138 TI - Efficacy and safety of diclofenac sodium 2% topical solution for osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled, 4 week study. AB - OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are standard therapy for osteoarthritis (OA). Topically applied NSAIDs reduce systemic exposure compared with oral NSAIDS, and European guidelines recommend their use. The NSAID diclofenac is available in a range of topical formulations. Diclofenac 1% gel and 1.5% four times daily and 2% twice daily (BID) solutions are approved to reduce pain from OA of the knee(s). The objective of this study was to investigate the efficacy and safety of diclofenac sodium 2% topical solution BID versus vehicle control solution for treating pain associated with OA of the knee. RESEARCH DESIGN AND METHODS: A phase II, 4 week, randomized, double-blind, parallel-group, two-arm, vehicle-controlled study compared pain relief with diclofenac sodium 2% topical solution versus control (vehicle only) in patients aged 40 to 85 years with radiographically confirmed primary OA of the knee. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01119898. MAIN OUTCOME MEASURES: The primary efficacy outcome was change from baseline to the final visit in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. Secondary outcomes included additional WOMAC subscales and patient global assessment of OA. Treatment-emergent adverse events (TEAEs), skin irritation, and vital signs were assessed and collected throughout the study. RESULTS: Of 260 patients randomized, 259 received >=1 dose of study drug. Significantly greater reductions in least-squares mean (standard error) WOMAC pain scores were observed for diclofenac-treated (-4.4 [0.4]) versus vehicle treated patients (-3.4 [0.4]) at the final visit (p = 0.040). The most commonly reported TEAEs were administration site conditions. The vehicle-treated group experienced slightly more TEAEs than the active treatment group (38.8% vs. 31.5%). No serious adverse events were reported. CONCLUSIONS: Administration of diclofenac sodium 2% topical solution BID resulted in significantly greater improvement in pain reduction in patients with OA of the knee versus vehicle control and was generally well tolerated. PMID- 26506139 TI - Recent advances in the development of subunit-based RSV vaccines. AB - Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections causing pneumonia and bronchiolitis in infants. RSV also causes serious illness in elderly populations, immunocompromised patients and individuals with pulmonary or cardiac problems. The significant morbidity and mortality associated with RSV infection have prompted interest in RSV vaccine development. In the 1960s, a formalin-inactivated vaccine trial failed to protect children, and indeed enhanced pathology when naturally infected later with RSV. Hence, an alternative approach to traditional killed virus vaccines, which can induce protective immunity without serious adverse events, is desired. Several strategies have been explored in attempts to produce effective vaccine candidates including gene-based and subunit vaccines. Subunit-based vaccine approaches have shown promising efficacy in animal studies and several have reached clinical trials. The current stage of development of subunit-based vaccines against RSV is reviewed in this article. PMID- 26506140 TI - Correction to Optical and Electrochemical Methods for Determining the Effective Area and Charge Density of Conducting Polymer Modified Electrodes for Neural Stimulation. PMID- 26506141 TI - Crystallization of undercooled liquid fenofibrate. AB - Formulation of hydrophobic drugs as amorphous materials is highly advantageous as this increases their solubility in water and therefore their bioavailability. However, many drugs have a high propensity to crystallize during production and storage, limiting the usefulness of amorphous drugs. We study the crystallization of undercooled liquid fenofibrate, a model hydrophobic drug. Nucleation is the rate-limiting step; once seeded with a fenofibrate crystal, the crystal rapidly grows by consuming the undercooled liquid fenofibrate. Crystal growth is limited by the incorporation of molecules into its surface. As nucleation and growth both entail incorporation of molecules into the surface, this process likely also limits the formation of nuclei and thus the crystallization of undercooled liquid fenofibrate, contributing to the good stability of undercooled liquid fenofibrate against crystallization. PMID- 26506152 TI - Normobaric hyperoxia training in elite female hockey players. AB - BACKGROUND: Supplemental oxygen use may offer recovery benefits to team sport athletes both in training and match play. A blinded independent measures study was used to investigate the effect of supplementary oxygen use during recovery from high-intensity exercise on performance. METHODS: Fifteen female international hockey players underwent a 6 week running based training program with a 2:1 work to rest ratio. The subjects were split into 3 groups; normobaric hyperoxia (HXA), normoxia (NXA) and control (CTR). In between exercise sets HXA received 100% oxygen for 1 minute whilst NXA received a placebo in the same manner. CTR received no treatment and were not supervised. Maximal aerobic speed (MAS) was measured pre and post. Distance covered was measured along with peak heart rate (HRpeak), peak blood lactate concentration ([La-]peak) and rate of perceived exertion (RPE). RESULTS: MAS improved in HXA, NXA and CTR. However, distance ran in training was not different between groups. There was a likely positive effect on HRpeak in HXA (lower in HXA). RPE and [La-]peak response was not different between groups. CONCLUSIONS: Inhaling supplementary oxygen during recovery between high-intensity intervals did not improve physiological performance of high-level team sport players. The normobaric hyperoxia treatment had no effect on maximal aerobic (distance covered), metabolic ([La-]peak), and perception (RPE) parameters. It is not recommended as an ergogenic aid to training at sea level. PMID- 26506153 TI - SPOP the mutation. AB - Prostate cancers with mutations to a protein called SPOP use an error-prone method to repair broken DNA strands. PMID- 26506155 TI - Urinary Incontinence in Women--Practice Bulletin. PMID- 26506156 TI - Epilog. PMID- 26506154 TI - Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress. AB - Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlying the structural and functional alterations within corticolimbic brain regions, including the prefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remain unknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1) expression is down regulated in the postmortem PFC of PTSD subjects. Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models. These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology. PMID- 26506157 TI - Urinary Incontinence in Women. AB - Urinary incontinence, the involuntary leakage of urine, is caused by a variety of factors and may result in a wide range of urinary symptoms that can affect women's physical, psychological, and social well-being and sometimes can impose significant lifestyle restrictions. Identifying the etiology of each woman's urinary incontinence symptoms and developing an individualized treatment plan is essential for improving her quality of life. The purpose of this joint document of the American College of Obstetricians and Gynecologists and the American Urogynecologic Society is to review information on the current understanding of urinary incontinence in women and to outline guidelines for diagnosis and management that are consistent with the best available scientific evidence. PMID- 26506158 TI - Reoperation After Robotic and Vaginal Mesh Reconstructive Surgery: A Retrospective Cohort Study. AB - OBJECTIVES: Our primary objective was to compare reoperations after robotic assisted sacrocolpopexy and transvaginal mesh for apical prolapse repair. Our secondary aim was to record perioperative complications after robotic and vaginal surgeries. METHODS: We reviewed medical records of women who underwent vaginal apical mesh support procedures or robotic sacrocolpopexy at Winthrop University Hospital between August 2009 and August 2013. We compared reoperations and perioperative complications between the 2 groups. RESULTS: There were 245 eligible cases during the 4-year study period. One hundred eighty-one women underwent robotic-assisted sacrocolpopexy and 64 women underwent transvaginal mesh. Women who underwent robotic surgery were younger and had decreased blood loss. Patients were followed up for a median of 3 months after robotic surgery and 11.5 months after transvaginal mesh. We found no difference in overall rate of reoperation between robotic and transvaginal mesh repair for apical prolapse. Specifically, there was no difference in the rate of reoperation for mesh exposure. CONCLUSIONS: Despite recent controversies, transvaginal mesh offers the benefit of an effective minimally invasive procedure with shorter operative times, and may not pose additional risk for reoperation when compared to robotic assisted sacrocolpopexy. PMID- 26506160 TI - Obliterative Surgery for the Treatment of Pelvic Organ Prolapse: A Patient Survey on Reasons for Surgery Selection and Postoperative Decision Regret and Satisfaction. AB - OBJECTIVES: To identify patient-reported reasons for selecting obliterative surgery for the purpose of predicting decision regret and satisfaction. METHODS: We created a deidentified database of patients who underwent an obliterative procedure for prolapse from 2006 to 2013. Patients were excluded if they declined study participation, were deceased, or had dementia. Participants completed a survey regarding reasons for selecting obliterative surgery and a modified version of validated questionnaires on decision regret (Decision Regret Scale Pelvic Floor Disorder) and satisfaction (Satisfaction with Decision Scale-Pelvic Floor Disorder). Parsimonious multivariate linear regression models were constructed to determine if any of the reasons given for choosing obliterative surgery were independent predictors of decision regret and satisfaction after controlling for significant sociodemographic, clinical, and surgical outcome data identified by bivariate analysis. RESULTS: Seventy-seven women completed the surveys. "To follow my doctor's recommendations" and "no longer sexually active," and/or "did not plan to be" as reasons for selecting obliterative surgery made the most difference; however, these reasons were not identified as independent predictors of decision regret or satisfaction after controlling for confounders. The regret linear regression models identified preoperative sexual activity rather than the patient-reported reason "no longer sexually active and/or did not plan to be," as the only independent predictor of more decision regret after obliterative surgery (B coefficient 1.68, P < 0.01). The satisfaction linear regression models identified reoperation for any reason as an independent predictor of lower satisfaction (beta, -0.24; P = 0.04) and the patient-reported reason for choosing obliterative surgery "not interested in pessary" as a predictor of higher satisfaction (beta, 0.30, P = 0.01). CONCLUSIONS: This study advances our knowledge about the obliterative surgical decision making process. Behavioral and educational interventions directed at improving patient and physician communications concerning the dynamics of sexual health issues in an aging population will likely decrease regret when obliterative surgery is chosen. Minimizing reoperation after obliterative surgery through increased experience, knowledge, and improved surgical skills and patient validation when pessary is declined will likely improve satisfaction when obliterative surgery is chosen. PMID- 26506159 TI - Symptom Improvement After Prolapse and Incontinence Graft Removal in a Case Series of 306 Patients. AB - OBJECTIVES: We report our experience with removal of synthetic and biologic implants used in pelvic reconstruction in a tertiary referral center from 2005 to 2012. METHODS: We performed a retrospective cohort study of all consecutive patients who underwent surgical implant removal for treatment of implant-related complications. Symptoms were determined by patient self-assessment including validated questionnaires. One hundred seventy-nine patients completed follow-up. RESULTS: Three hundred six patients underwent removal for exposure or erosion (57%), pain (46%), and urinary symptoms or incontinence (54%). Ninety patients (29%) had previous revision. Eleven percent had pelvic organ prolapse (POP) implants, 48% had sling implants, and 41% had both implants. Mean time from removal to follow-up was 2 years (median, 2 years; range, <1-7).The majority of patients experienced symptom improvement after implant removal. Seventy-eight percent of those with pain reported pain improvement, 9% reported no change, and 14% experienced worsening. Symptom improvement was reported by 79% of those who underwent removal of a POP implant alone, 79% of those who underwent removal of POP and sling implants, and 83% of those who underwent removal of a sling alone. Quality of life was significantly improved after implant removal overall (P < 0.05) for those who underwent removal of POP and slings, and slings alone, but not for those with POP removal only. CONCLUSIONS: Pain is among the most common symptoms reported in women referred to our institution for implant-related complications. In a series of 306 complex patients with a range of implants and symptoms, removal improved implant-related pain in the majority of patients. PMID- 26506161 TI - The Emotional Burden of Pelvic Organ Prolapse in Women Seeking Treatment: A Qualitative Study. AB - OBJECTIVE: We aimed to qualitatively describe the emotional burden experienced by women seeking treatment for prolapse. We hypothesized that the condition of prolapse would have an impact on women's emotional well-being. METHODS: Women with stage II or greater symptomatic prolapse participated in focus groups or individual phone interviews. A trained facilitator conducted semi-structured focus groups and interviews. These were audio-taped and transcribed. Two authors coded transcripts and identified themes using an "editing" approach. The codebook was amended until no new major themes emerged from the data. RESULTS: Forty-four women participated (25 in focus groups and 19 in phone interviews). Mean (SD) age of women was 60 (10) years and mean (SD) prolapse leading edge was 3 (2) cm. Analysis revealed the following 3 main themes: (1) emotions associated with the condition of prolapse (minimal emotions, annoyance, irritation, frustration, anger, sadness, anxiety, depression), (2) communicating emotions related to prolapse (to friends, family, healthcare providers), and (3) emotions relating to treatment (both positive and negative effects). CONCLUSIONS: Prolapse significantly impacts women's emotional health and subjective well-being. An improved understanding of women's emotional experiences of prolapse may help providers better meet patients' needs. PMID- 26506163 TI - Apical Suspension at the Time of Hysterectomy for Uterovaginal Prolapse: A Comparative Analysis of 2001 and 2011. AB - OBJECTIVES: The primary aim of this study was to compare the proportion of concomitant apical procedures in women undergoing hysterectomy for uterovaginal prolapse in 2001 and 2011. The secondary aim was to identify factors associated with receiving concomitant apical procedures in 2001 and 2011. METHODS: The Nationwide Inpatient Sample database was queried for women with a primary diagnosis of uterovaginal prolapse who underwent hysterectomy in 2001 and 2011. The study cohort was analyzed for demographics, clinical factors, and concomitant procedures. Factors potentially associated with receiving concomitant apical procedure were evaluated using univariable analysis and multivariate logistic regression. RESULTS: A total of 14,647 women were identified (5867 in 2001 and 8780 in 2011). In 2001, 26.9% women received a concomitant apical procedure, and this proportion increased to 48.2% in 2011 (odds ratio, 2.53; 95% confidence interval, 2.36-2.72; P < 0.0001). In 2001, the mean (SD) age was 53.8 (14.1) years compared with 56.8 (13.3) years in 2011. Although vaginal hysterectomy was most common in both years, a concomitant apical procedure was more likely to be performed with abdominal hysterectomy (P < 0.001). On multivariate analysis, age older than 50 years (P = 0.0001), abdominal route of hysterectomy (P < 0.0001), and undergoing hysterectomy at an academic teaching hospital (P < 0.0001) were independently associated with concomitant apical procedures in both 2001 and 2011. CONCLUSIONS: Although the proportion of concomitant apical repair was higher in 2011 compared with 2001, it is still low given the existing data demonstrating the importance of a concomitant apical procedure at the time of hysterectomy for uterovaginal prolapse. PMID- 26506162 TI - The Differential Impact of Flatal Incontinence in Women With Anal Versus Fecal Incontinence. AB - OBJECTIVE: The differential impact on quality of life (QOL) that leakage of both stool and flatus confers on women compared with stool only is unclear. Our aim was to characterize differences in symptom distress, impact on QOL, and anorectal testing among women with leakage of stool and flatus, stool only, and flatus only. METHODS: A retrospective review was conducted of women undergoing evaluation of at least monthly bowel incontinence symptoms. Subjects were divided into the following 3 groups: liquid/solid stool and flatus (anal incontinence [AI]), liquid/solid stool only (fecal incontinence [FI]), and flatal only (FL). Baseline assessment included the Modified Manchester Health Questionnaire (MMHQ) including the Fecal Incontinence Severity Index (FISI), Short Form-12 (SF-12), as well as anorectal manometry and endoanal ultrasound evaluations. RESULTS: Of 436 subjects, 381 had AI, 45 FI, and 10 FL. Significant between-group differences were noted in MMHQ (P = 0.0002) and FISI total scores (P < 0.0001) where women with AI reflected greater negative impact than women with FI. The Short Form-12 (mental and physical component summary scores) scores were similar in all 3 groups (P = 0.22, 0.08). Resting/squeeze pressures were significantly lower in AI and FI groups compared with FL (P = 0.0004), whereas rectal capacity was similar in all 3 groups. Although exploratory, MMHQ scores were similar between FI and FL groups, although FISI scores were higher in the FI group (P < 0.0001). CONCLUSIONS: Women with AI have higher symptom specific distress and greater negative impact on QOL compared with women with FI. Treatment of all bowel incontinence symptoms is important to improve symptom-specific and general QOL. PMID- 26506164 TI - Patient Preferences for Abdominal Incisions Used for Pelvic Organ Prolapse Surgery. AB - OBJECTIVES: Approaches for performing sacrocolpopexy (laparotomy, laparoscopy, and robotically assisted) differ with regard to length of surgery, postoperative pain, and cosmetic appearance of skin incisions. The aim of our study is to better understand what factors influence patient preferences for surgical approach. METHODS: A cross-sectional study was performed using a survey. Females 18 years or older presenting to gynecologic offices were asked to complete a survey that included photographs of patient incisions 6 weeks postoperatively along with a schematic representation of each incision type (laparotomy with low transverse incision, traditional laparoscopy, and robotically assisted). Patients were first asked to rank each incision based on cosmetic appearance only. They were next given varying clinical scenarios associated with each surgical approach and asked if their preference of incision changed. A sample size of 90 subjects was needed in order to detect a 30% difference in incision preference based on appearance with an alpha of 0.05 and 80% power. RESULTS: One hundred fifty patients completed the survey. Based on cosmetic appearance alone, 70% chose laparoscopic surgery, 23% chose open, and 7% chose the robotic approach (P < 0.0001). The majority of the subjects would not change their incision preference of laparoscopy based on differing scenarios of postoperative pain (62.6%), length of surgery (65.3%), and length of hospital stay (73.6%). When asked to rank factors important in decision making, complication rate (53.9%) and surgeon experience with the procedure (32.8%) were ranked as most important. CONCLUSIONS: Based on cosmetic appearance, patients prefer the laparoscopic approach for abdominal sacrocolpopexy for pelvic organ prolapse surgery. However, complication rates and surgeon experience with the procedure are important factors in the patient's decision making. PMID- 26506165 TI - Prospective Randomized Crossover Trial Comparing Continuous and Cyclic Stimulation in InterStim Therapy. AB - OBJECTIVES: The aim of this study was to assess a difference in efficacy and patient preference in cyclic versus continuous stimulation with InterStim therapy for urge incontinence or urinary frequency. METHODS: Patients with refractory urge incontinence/urinary frequency and with recent implantation of the InterStim system were randomized to continuous or cyclic InterStim stimulation after institutional review board-approved consent. They completed a 3-day voiding diary after 1 month of stimulation. They were then switched to the alternative setting for 1 month and completed another voiding diary. Subjective responses were evaluated with the Urinary Incontinence Impact Questionnaire and the Urinary Distress Inventory. Patient preference of stimulation setting was assessed. Statistical analysis was performed with paired t tests and repeated-measures analysis of variance. RESULTS: Data were available for 32 patients. Indication for InterStim: urge incontinence = 24, frequency = 8. No differences were noted in the number of urgency or urge incontinence episodes (mild, moderate, severe, or total) with cyclic or continuous stimulation. No differences were noted in the number of number of pads per day or the number of daytime or nighttime voids. The Urinary Incontinence Impact Questionnaire and Urinary Distress Inventory symptoms scores showed no significant differences between cyclic and continuous stimulation. No significant difference was noted in measured parameters based on the order of stimulation. Continuous stimulation was preferred by 17 patients, 9 preferred cyclic stimulation, and 6 had no preference. CONCLUSIONS: No significant differences were noted in voiding diaries and subjective responses between cyclic and continuous stimulation in InterStim therapy for patients with urge incontinence or frequency. PMID- 26506166 TI - Perineal Body and Genital Hiatus in the Third Trimester and Risk of Perineal Laceration. AB - OBJECTIVE: We aimed to determine whether pelvic organ prolapse quantification measurements of genital hiatus (gh) or perineal body (pb) obtained in the late third trimester are predictors of obstetric perineal laceration in nulliparous women. METHODS: Nulliparous women with singleton gestation were prospectively recruited after 35-week gestation, and gh and pb measurements were obtained. After delivery, determination of the presence and degree of perineal laceration were recorded. Correlation of gh and pb measurements with risk of perineal laceration (defined as second, third, or fourth degree) was assessed using the Wilcoxon rank sum test. RESULTS: We recruited 224 patients and 133 met inclusion criteria after delivery. The mean (SD) age was 27.2 (4.0) years and mean (SD) prepregnancy body mass index was 24.1 (4.6) kg/m. Seventy patients (52.6%) had either a second-degree (n = 64) or third-degree (n = 6) laceration. No fourth degree lacerations were recorded. We found no significant difference in the median gh (3.5 vs 3.0 cm, P = 0.34) and pb (3.5 vs 3.5 cm, P = 0.54) measurements among women with and without perineal lacerations. CONCLUSIONS: Our data suggest that antenatal measurement of gh and pb does not correlate with the risk of obstetric perineal laceration in nulliparous patients undergoing spontaneous vaginal delivery. PMID- 26506167 TI - Ureteral Compromise in Laparoscopic Versus Vaginal Uterosacral Ligament Suspension: A Retrospective Cohort. AB - OBJECTIVES: The aim of this study was to evaluate if ureteral compromise is significantly different between laparoscopic and vaginal uterosacral ligament suspension (USLS). METHODS: This is a retrospective cohort study comparing all women who underwent laparoscopic and vaginal USLSs at 2 institutions (part of a single training program with procedures performed by 11 fellowship-trained Female Pelvic Medicine and Reconstructive Surgery gynecologic surgeons) between January 2008 and June 2013. RESULTS: A total of 208 patients in the study underwent a USLS, 148 in the laparoscopic group and 60 in the vaginal group. At baseline, there were statistically significant differences between the groups in mean age (50.4 vs 55.3 years, P = 0.008), parity (2.44 vs 2.77, P = 0.040), and prior hysterectomy (3.4% vs 11.7% in the laparoscopic and vaginal groups, respectively; P = 0.042).There were no ureteral compromises in the laparoscopic group and 6 in the vaginal group (0.0% vs 10.0%, respectively; P < 0.001). In an analysis evaluating only those ureteral compromises requiring stent placement, the higher rate of ureteral compromise in the vaginal group persisted despite exclusion of those cases requiring only suture removal and replacement (0.0% vs 5.0% in the laparoscopic and vaginal groups, respectively; P = 0.023).There was a lower median blood loss in the laparoscopic group (137.5 vs 200.0 mL, respectively; P = 0.002) as well as a lower rate of readmission (0.7% vs 6.7%, respectively; P = 0.025). There were no other significant differences in postoperative complications between the 2 groups. CONCLUSIONS: We found a lower rate of ureteral compromise in the laparoscopic approach to USLS compared with the traditional vaginal approach. PMID- 26506168 TI - Comparison of Short Term Outcomes of Sacral Nerve Stimulation and Intradetrusor Injection of OnabotulinumtoxinA (Botox) in Women With Refractory Overactive Bladder. AB - OBJECTIVES: The aim of the study was to compare the short-term outcomes of sacral nerve stimulation (SNS) and intradetrusor injection of OnabotulinumtoxinA (Botox) for overactive bladder (OAB) symptoms refractory to behavioral modifications and pharmacologic therapy. METHODS: This is a retrospective cohort study evaluating the outcomes of SNS and Botox procedures that were performed for refractory OAB symptoms at a tertiary care referral center. The primary outcome was "failure" of treatment that was defined as less than 50% improvement from the baseline symptoms at 6 months. RESULTS: Sixty-five SNS and 63 Botox procedures met the inclusion criteria. Women undergoing Botox were more likely to report failure 6 months after the intervention as compared with those undergoing SNS (20 [31.8%] vs 7 [10.8%], P = 0.003; unadjusted odds ratio = 3.85, confidence interval = 1.5 9.93; adjusted odds ratio = 4.47, confidence interval = 1.69-14.4). However, there was no difference in the proportion of women who were started on antimuscarinic medications for persistent urgency urinary incontinence after both procedures (12 [18.5%] women in SNS group and 17 [27%] women in the Botox group, P = 0.249). The most common complication of the SNS procedure was wound related (8 [12.3%]), whereas the most common complication of the Botox procedure was urinary tract infection (31 [49.2%]). CONCLUSIONS: The SNS resulted in lower failure rates at 6 months when performed for refractory OAB symptoms as compared with the Botox procedure. However, further studies are needed to evaluate the long-term cost-effectiveness of both procedures. PMID- 26506169 TI - Third International Congress on Soldiers' Physical Performance: Translating State of-the-Science Soldier Research for Operational Utility. AB - The Third International Congress on Soldiers' Physical Performance (ICSPP) was held on August 18-21, 2014 in Boston, MA, where it had a record attendance of 374 registrants from 27 countries. The Congress included 8 invited keynote lectures, 12 symposia, 1 featured science session, more than 200 oral and poster free communication sessions, 8 thematic poster sessions, and a Warfighter Readiness Roundtable. Collectively, the presentations focused on a fundamental premise that soldiers are the center of warfighting capability, and the human service member is the prime resource and key enabler of all warfighting systems. The intent of the ICSPP series is to focus on the soldier-the individual service member. As we move forward with focus placed on the human dimension of soldiering, the key to our scientific success and what will prove to be transformative will be the extent to which we can operationalize and disseminate our scientific knowledge for the benefit of our soldiers on the ground. The Congress fostered important scientific exchange, and dialog centered on improving military physical performance and readiness. As countries around the globe respond to current and emerging threats to their national security, it is increasingly clear that we must ensure optimal human performance of our military personnel. By taking advantage of the science and applications of physical fitness and injury prevention research, we can leverage our increased understanding for the optimal application of physical readiness processes while minimizing the injury risk potential. We believe that the continued scientific and evidence-based dialog across international partners will prove to be transformative in identifying the most effective strategies for human performance optimization in the 21st century. Innovation, leveraging current state-of-the-science, and international partnerships were all key themes throughout the Congress. From the ICSPP scientific program, it was clear that there is abundant scientific knowledge on how to improve soldiers' sleep, activity, and nutrition and that a major challenge is for scientists and military leaders/policy makers to work together to operationalize what is known for soldier utility on the ground. PMID- 26506170 TI - Perspectives on Aerobic and Strength Influences on Military Physical Readiness: Report of an International Military Physiology Roundtable. AB - Physical fitness training of military recruits is an enduring focus of armies. This is important for safe and effective performance of general tasks that anyone may have to perform in a military setting as well as preparation for more specialized training in specific job specialties. Decades of studies on occupationally specific physical requirements have characterized the dual aerobic and strength demands of typical military tasks; however, scientifically founded strategies to prepare recruits with a good mix of these 2 physiologically opposing capabilities have not been well established. High levels of aerobic training can compromise resistance training gains and increase injury rates. Resistance training requires a greater commitment of time and resources as well as a greater understanding of the science to produce true strength gains that may be beneficial to military performance. These are critical issues for modern armies with increased demands for well-prepared soldiers and fewer injury losses. The actual physical requirements tied to metrics of success in military jobs are also under renewed examination as women are increasingly integrated into military jobs previously performed only by men. At the third International Congress on Soldiers' Physical Performance, a roundtable of 10 physiologists with military expertise presented comparative perspectives on aerobic and strength training. These topics included the physiological basis of training benefits, how to train effectively, how to measure training effectiveness, considerations for the integration of women, and the big perspective. Key discussion points centered on (a) the significance of findings from research on integrated training, (b) strategies for effective strength development, and PMID- 26506171 TI - Physical Training Strategies for Military Women's Performance Optimization in Combat-Centric Occupations. AB - The physiological differences, particularly of upper-body strength and power, between women and men, and the rigors of combat-centric occupational demands would seem to place women at a significant disadvantage, as the U.S. military opens up previously closed combat-arms military occupational specialties (MOSs) to women. This inherent disadvantage can be significantly mitigated by implementing effective and comprehensive physical training (PT) regimens for women targeting those fitness components most critical for those tasks considered most essential for solider warfighting duties (i.e., strength and power). Regrettably, the military historical and legacy overemphasis on aerobic fitness and on "field expediency" as the major criteria for implementing training have limited the extent to which the military has fully operationalized state-of-the science PT policies. This continued legacy approach could be problematic regarding fully enhancing women's abilities to perform physically demanding combat-centric occupations and could place the successful integration of women into ground combat MOSs at significant risk. Seminal studies from the literature indicate that (a) a minimum of 6 months of periodized combined resistance/endurance training preparedness is recommended for untrained women considering entering combat-arms MOS training; (b) any comprehensive PT program should incorporate and emphasize progressive load carriage training; (c) a greater emphasis on upper body on strength/power development in military women is needed; (d) heavy resistance training in the range of 3-8 repetition maximum sets should be incorporated into training programs to target type II motor units and muscle fibers (those fibers that produce the most force and have the greatest capacity to hypertrophy); (e) low-volume, high-intensity interval training should be considered as a time-efficient training method to improve aerobic fitness while protecting against lower-body musculoskeletal injuries; (f) flexible nonlinear periodized programs should be considered to best accommodate the unpredictability and operational functional needs of the military training environment; and (g) serious consideration should be given to revamping the manner in which the military conducts physical readiness training, with a departure from "field expediency" as the major criteria for determining PT policies. With an increased emphasis on the human dimension of soldiering and concerted strategic, operational, and tactical efforts to maximize individual physical readiness and performance, the science of training physiology exists to leverage and better physically prepare women as they enter more combat-centric occupations. PMID- 26506172 TI - Physiological and Medical Aspects That Put Women Soldiers at Increased Risk for Overuse Injuries. AB - Anthropometric and physiological factors place female soldiers at a disadvantage relative to male soldiers in most aspects of physical performance. Average aerobic and anaerobic fitness levels are lower in women than in men. Thus, women have a lower overall work capacity and must exert themselves more than men to achieve the same output. The lower weight and fat-free mass and the higher body fat of women are associated with lower muscle strength and endurance, placing them at a disadvantage compared with men in performing military tasks such as lifting and carrying weights, or marching with a load. Working at a higher percentage of their maximal capacity to achieve the same performance levels as men, women tire earlier. Their smaller size, skeletal anatomy, and different bone geometry also predispose women to a higher incidence of exercise-related injuries. Consequently, the attrition rate of female soldiers in combat units is higher than that of their male counterparts. This review summarizes the literature on gender-related physiological and anatomical differences that put female soldiers at an increased risk of exercise-related injuries. PMID- 26506173 TI - Overwhelming Physiological Regulation Through Personal Protection. AB - There is often a fine line between providing appropriate personal protection and compromising capability. In some situations, protection must come first. In other circumstances, capability becomes paramount. In the military, mission-specific objectives can force personal protection to be less than ideal. Indeed, levels of protection appropriate within the civilian context could jeopardise health and operational success, and for operations conducted in the heat involving load carriage and armored protection with almost total-body clothing coverage, it is the likely thermal impediment to performance that perhaps first comes to mind. Although this consideration is appropriate, it may direct attention away from the actual cause of, and therefore preventative solutions to, physiological collapse. For instance, although classical heat illness absolutely occurs at the age extremes, and it may affect all people when air temperatures are exceptionally hot, frank hyperthermia is not generally the primary cause of exhaustion when healthy clothed individuals are working in the heat. Instead, another homoeostatic process is implicated; blood pressure regulation. In addition to participating in temperature regulation, the cardiovascular system supports oxygen delivery, blood pressure regulatory, and waste removal requirements. Therefore, the elevated cardiac output accompanying work must be shared. Accordingly, the case will be developed that thermoregulatory failure is often not the primary causal mechanism for soldier collapse, although such individuals may be hyperthermic. Alternatively, moderately, but not excessively, hyperthermic soldiers working under these conditions are perhaps more likely to collapse from cardiovascular insufficiency that precipitates uncompensable hypotension. PMID- 26506174 TI - Load Carriage: An Integrated Risk Management Approach. AB - Military load carriage (LC) gives rise to substantial risks to soldier health, tactical performance, and mission success. The aim of this article was to extract and synthesize the key findings of a series of LC research reports previously published by the authors. Five reviews and 6 studies were included, with key findings extracted and synthesized in tabulated and critical narrative form. The weight of a soldier's load is a source of risk for soldier's injuries and tactical task performance. The resulting level of risk is influenced by risk modifiers (like speed of march, terrain grade, and task type and duration) and risk controls (like administrative controls and physical conditioning). In the Australian context, these risk controls were limited, with soldiers carrying heavier loads than those mandated by doctrine and policy, and LC conditioning not meeting best practice. The diversity of LC contexts, combined with the influence of risk modifiers and risk controls, means that levels of risk associated with LC are not consistent and must be assessed on a case-by-case basis. Load weight and marching routes (terrains, gradients), distances, speed, and duration are all potentially treatable sources of LC-related risk. Potential risk treatments include not only commanders directly addressing these specific sources of risk to the extent feasible, on a case-by-case basis, when planning or conducting LC tasks but also improving administration controls (i.e., doctrine and policies) and personal protection (i.e., the physical conditioning of the soldier) as part of the hierarchy of controls. Practical application would involve commanders developing and implementing dedicated LC doctrine and policies and implementing and enforcing LC conditioning programs that meets best practice. PMID- 26506175 TI - Biomechanics of Load Carriage--Historical Perspectives and Recent Insights. AB - Loads carried by the warfighter have increased substantially throughout recorded history, with the typical U.S. ground soldier carrying external loads averaging 45 kg during operations in Afghanistan. Incidence of disability in the U.S. Army has also increased sixfold since the 1980s, predominantly driven by increases in musculoskeletal injuries, with load carriage implicated as a possible mechanism. This article will provide a brief overview of the biomechanics of load carriage and will provide some recent insights into how the stress of the loads carried by military personnel can affect the musculoskeletal system. Studies into the biomechanics of load carriage have documented motion-related differences such as increased step rate, decreased stride length, and more trunk lean with increases in pack-borne loads. However, there is a paucity of literature on the relationship between load carriage and biomechanical mechanisms of overuse injury. Findings of recent studies will be presented, which add mechanistic information to increased stresses on the lower extremity. This was particularly true at the knee, where in one study, peak knee extension moment increased 115% when carrying a 55 kg load (0.87 +/- 0.16 Nm.kg-1) vs. no external load (0.40 +/- 0.13 Nm.kg-1). Efforts to model injury mechanisms require continued biomechanical measurements in humans while carrying occupationally relevant loads to be validated. Specifically, imaging technologies (e.g., bone geometry scans) should be incorporated to produce higher fidelity model of the stresses and strains experienced by the load carrier. In addition to laboratory-based biomechanics, data are needed to further explore the mechanistic relationship between load magnitude and injury; to this end, wearable sensors should continue to be exploited to accurately quantify biomechanical stresses related to load carriage in the field. PMID- 26506176 TI - Effects of Military Load Carriage on Susceptibility to Enemy Fire During Tactical Combat Movements. AB - Current military operations require soldiers to carry heavy external loads that are widely acknowledged to impair the ability to move tactically on the battlefield. However, to date, the effect of load on susceptibility to enemy fire (the probability of being hit) has not been examined. Nineteen soldiers completed a break contact simulation (five 30-m sprints commencing every 44 seconds) and a fire and movement simulation (sixteen 6-m bounds commencing every 20 seconds) in each of the 5 load conditions (ranging from 9.8 to 30.1 kg). For each simulation, the impact of load on exposure time and peak movement velocity was examined. In addition, the 6 fastest and 6 slowest soldiers (determined by exposure time in the heaviest condition) were parsed into subgroups to examine interindividual differences in response to load. Susceptibility for the 2 subgroups was modeled using exposure time for the 2 simulations and the assumed reaction time, shooting cadence, and shooting accuracy of the enemy. Susceptibility increased as a function of load for both the break contact and fire and movement simulations and became more pronounced when the participant population was parsed into fast and slow groups. When the impact of personal protection systems was isolated and analyzed, it was found that not only were the slower participants more vulnerable (as a result of not wearing the personal protection system) but also more susceptible than the faster participants who carried 11.2 kg more load. Large interindividual differences in response to external load have meaningful consequences for battlefield susceptibility, and it is therefore critical that personnel are afforded tailored training such that they maximize their proficiency in the execution of tactical combat movements. PMID- 26506177 TI - Physiological Evaluation of a Wheeled Assistive Device for Load Carriage. AB - Carrying heavy weight imposes high physiological strain on the human body, which can adversely affect physical performance. This is especially important for soldiers whose physical performance level may influence mission completion and survival. Recently, wheel-based devices (WBDs), designed to reduce the load on the soldier, have been suggested as a possible solution. Thus, the aim of this study was to evaluate the physiological effects of a proposed WBD prototype. Ten volunteers performed 3 exercise protocols on a treadmill as follows: without carrying any load, with a military backpack, and with the WBD. While using both modalities, they carried 40% of their body weight. Data acquisition included heart rate, body core temperature, oxygen consumption, and subjective comfort. Postural sway was also measured to evaluate the effect of WBD on standing balance. There were no significant differences between the physiological measures while using both modalities. Subjective comfort evaluation showed that the WBD may be more comfortable, yet it raises difficulty in maintaining balance while walking, as can be explained by the postural sway results. We suggest that the similarity in physiological strain while using the WBD was due to reduced walking efficiency in an attempt to maintain balance. It appears that the WBD may have some biomechanical advantages in reducing the subjective pain and pressure at the shoulder region, a matter that should be further examined together with other biomechanical measures. PMID- 26506178 TI - Deformations in the Shoulder Tissues During Load Carriage: A Computational Model. AB - Shoulder soft tissue deformations seem to be one of the limiting factors of load carriage among soldiers and recreational backpackers that are required to carry heavy loads. Yet, there are no loading limits related to the forces borne by the shoulders, and the backpacks designs are not consistent with providing pressure relief from this sensitive anatomical region. The aim of this study was to develop a model that will enable to study the biomechanical loads that develop in the shoulder under heavy loads and to help in optimizing load carriage systems design. A 3-dimensional, anatomically accurate finite element model of a human shoulder was constructed based on MRI scans. The model was developed to calculate the effective stresses on the skin below the shoulder strap (superficial loads) and the effective strain in the brachial plexus region (inner tissue deformation) for loads of up to 35 kg. The model successfully predicted deformations in the soft tissue surrounding the brachial plexus when compared with deformations measured from load-bearing MRI scans. The model yielded a skin pressure mapping, which showed pressure hotspots in the clavicle region. Inner tissue deformations mapping, as assessed by brachial plexus envelop strains, were found to peak at 30% effective strain at the lateral aspect below the pectoralis muscle. The newly developed model successfully predicted soft tissue deformations in the shoulder related to backpacks. This model can be used to optimize load carriage systems for better distribution of pressure over the shoulders and lower inner tissue deformations. PMID- 26506179 TI - Hormonal Responses to Active and Passive Recovery After Load Carriage. AB - Military operations often induce fatigue resulting from load carriage. Recovery promotes military readiness. This study investigated the acute effects of AR vs. PR after load carriage on maximal isometric leg extension force (MVC) and serum hormonal concentrations. Male reservists (27 +/- 3 years, 180 +/- 7 cm, 74 +/- 11 kg, V[Combining Dot Above]O2max 64 +/- 9 ml.kg-1.min-1) completed PR (n = 8) or AR (n = 8) after 50 minutes of loaded (16 kg) uphill (gradient 4.0%) treadmill marching at individual anaerobic threshold. No differences were observed between groups in relative changes in MVC during the marching loading, after AR or PR or the next morning. Significant differences in relative responses to AR and PR postmarching loading were observed in serum testosterone (T), cortisol, and sex hormone binding globulin immediately post AR and PR; however the next morning, all serum hormone concentrations had returned to normal. This study did not reveal any significant differences between the effects of AR and PR after an hour long marching protocol at approximately anaerobic threshold on MVC or serum hormones the morning after the experimental marching protocol. Thus, based on the variable measured in this study, marching performed by physically fit army reservists at an intensity at or below anaerobic threshold may not necessitate specialized recovery protocols. PMID- 26506180 TI - Optimal Physical Training During Military Basic Training Period. AB - The goal for military basic training (BT) is to create a foundation for physical fitness and military skills of soldiers. Thereafter, more advanced military training can safely take place. Large differences in the initial physical performance of conscripts or recruits have led military units to develop more safe and effective training programs. The purpose of this review article was to describe the limiting factors of optimal physical training during the BT period. This review revealed that the high volume of low-intensity physical activity combined with endurance-type military training (like combat training, prolonged physical activity, and field shooting) during BT interferes with optimal development of maximal oxygen uptake and muscle strength of the soldiers. Therefore, more progressive, periodized, and individualized training programs are needed. In conclusion, optimal training programs lead to higher training responses and lower risks for injuries and overloading. PMID- 26506181 TI - How Effective Is Initial Military-Specific Training in the Development of Physical Performance of Soldiers? AB - The impact of basic military training (BMT) on recruit physical performance is well described. However, initial employment training (IET), the period immediately after BMT, is the final preparatory step before posting to an operational unit. There is limited evidence on the influence of this training in developing the physical attributes necessary for military duty. Therefore, this investigation determined the relative contribution of BMT and IET to develop physical capability in soldiers. Fifty-one soldiers (45 men and 6 women) were assessed at 4 time points: commencement of training (week 1), midway (week 8), at the conclusion (week 12) of BMT, and upon completion of the IET (week 18/27). Weeks 1, 12, and 18/27 are reported herein. At each time point, tasks relevant to military duties, such as 1 repetition maximum (1RM) box lift, 2 * 22 kg-jerry carry, 3.2 km of 22-kg load carriage, and preexisting assessments of military fitness, such as 20-m shuttle run, 2-minute push-ups, and sit-ups, were assessed. A subsample of recruits (n = 14) was assessed for 1RM bench press, vertical jump, 30-second high-intensity cycle ergometry, and peak treadmill oxygen consumption. A significant (p <= 0.05) decrease in 3.2 km of 22-kg load carriage (week 12, 1,109 +/- 37 seconds; week 18/27, 1,161 +/- 51 seconds), 2 * 22 kg-jerry carry (week 12, 753 +/- 72 m; week 18/27, 683 +/- 78 m), and 1RM bench press (week 12, 83.3 +/- 16.0 kg; week 18/27, 73.2 +/- 16.6 kg) was observed during IET. No change (p > 0.05) between week 12 and week 18/27 was detected in 1RM box lift, vertical jump, 30-second high-intensity cycle ergometry, sit-ups, and 20-minute shuttle run. In contrast, 2-minute push-up (week 12, 46.7 +/- 2.7; week 18/27, 57.5 +/- 3.1) performance increased significantly (p <= 0.05). Soldiers who participated in up to 15 weeks of additional IET did not make further physical performance gains in strength, power, and endurance or function before posting to their units. Thus, greater focus on the development of these physical attributes seems warranted within the IET training regimen. PMID- 26506182 TI - Physical Fitness and Hormonal Profile During an 11-Week Paratroop Training Period. AB - Physical fitness and serum hormone concentrations have been shown to change during military training. The purpose was to examine these chronic changes in paratroopers (n = 52 male conscripts) during an 11-week training period, including acute changes induced by strenuous 5-day military field training. Hormonal profiles, body mass, maximal strength, muscle endurance, and 12-minute running test were assessed at several time points during paratrooper training. In the latter part of the training period, conscripts were involved in strenuous military field training (5 days). At week 7, during specialized military training period, aerobic performance decreased (3,146 +/- 163 m) but recovered back to a baseline level (3,226 +/- 190 m) at the end of the study period (p < 0.001). Standing long jump decreased at week 7 (242 +/- 13 cm) (p < 0.001) from the baseline value (248 +/- 13 cm), whereas push-up (52 +/- 11, 60 +/- 13 repetitions per minute) and sit-up (54 +/- 6, 56 +/- 7 repetitions per minute) performances increased (p < 0.001). No changes were observed in maximal strength and body composition, neither mostly in hormone concentrations, although cortisol decreased but increased back to baseline value at the end of the study period (p <= 0.05). Acute responses after the 5-day military field training included decreased maximal strength of the lower extremities and body mass, as well as changes in androgen hormone concentrations ([INCREMENT]testosterone: -46%, [INCREMENT]insulin-like growth factor-1: -28%, [INCREMENT]sex hormone-binding globulin: +25%) compared with all other measurements (p <= 0.05). The first 4 weeks of parachute military training decreased maximal aerobic capacity and neuromuscular performance of the lower body, whereas muscular endurance increased. Moreover, 5-day military field training resulted in dramatic changes in hormone concentrations. These findings highlight the importance of periodizing paratrooper training and underline the need for sufficient recovery immediately after military field training. PMID- 26506183 TI - Effects of Added Resistance Training on Physical Fitness, Body Composition, and Serum Hormone Concentrations During Eight Weeks of Special Military Training Period. AB - A high volume of military training has been shown to compromise muscle strength development. We examined effects of added low-volume resistance training during special military training (ST) period, which took place after basic training period. Male conscripts (n = 25) were assigned to standardized ST with added resistance training group (TG, n = 13) and group with standardized ST only (control) (CG, n = 12). Standardized ST with added resistance training group performed 2 resistance training sessions per week for 8 weeks: hypertrophic strength (weeks 1-3), maximal strength (weeks 4-6) and power training (weeks 7 8). Maximal strength tests, load carriage performance (3.2 km, 27 kg), and hormone concentrations were measured before and after ST (mean +/- SD). Both groups improved similarly in their load carriage performance time (TG: 1,162 +/- 116 seconds vs. 1,047 +/- 81 seconds; CG: 1,142 +/- 95 seconds vs. 1,035 +/- 81 seconds) (p < 0.001) but decreased maximal strength of the lower extremities (TG: 5,250 +/- 1,110 N vs. 4,290 +/- 720 N; CG: 5,170 +/- 1,050 N vs. 4,330 +/- 1,230 N) and back muscles (TG: 4,290 +/- 990 N vs. 3,570 +/- 48 N; CG: 3,920 +/- 72 N vs. 3,410 +/- 53 N) (p <= 0.05). Maximal strength of the upper extremities improved in CG (1,040 +/- 200 N vs. 1,140 +/- 200 N) (p <= 0.05) but not in TG. Maximal strength of the abdominal muscles improved in TG (3,260 +/- 510 N vs. 3,740 +/- 75 N) (p <= 0.05) but not in CG. Testosterone concentration increased in CG (15.2 +/- 3.6 nmol.L-1 vs. 21.6 +/- 5.0 nmol.L-1) (p < 0.01) but not in TG (18.6 +/- 4.3 nmol.L-1 vs. 19.5 +/- 9.4 nmol.L-1). In conclusion, interference with strength gains might be related to the high volume of aerobic activities and too low volume of resistance training during ST. To develop strength characteristics, careful periodization and individualization should be adopted in ST. PMID- 26506184 TI - The Effectiveness of Basic Military Training To Improve Functional Lifting Strength in New Recruits. AB - Australian Army recruits are required to meet the incumbent baseline physical employment standards (PES) during basic military training. A box lift and place (BLP) assessment is included in the PES, and it assesses the ability to perform essential muscular strength tasks. Therefore, basic military training must provide sufficient training stimulus to enable recruits to achieve the baseline BLP standard. A study was undertaken to investigate changes in the performance of 1-repetition maximum BLP in male (n = 154; age, 21.4 years) and female (n = 20; age, 23.1 years) recruits over the first 8 weeks of a 12-week basic military training course. Both male and female recruits showed modest improvements (2.2 +/ 5.9 kg and 3.0 +/- 3.1 kg, respectively; p <= 0.05) in maximal BLP performance, and there were no differences between genders. The female recruits showed greater relative improvements compared with the male recruits (14.7 +/- 7.8% vs. 6.5 +/- 2.3%). Despite the modest improvements in BLP performance, 70% of female and 100% of male recruits achieved the baseline BLP standard (25 kg) during week 8. The 30% failure rate for female recruits, however, suggests that the basic training program should be improved. A training program that yields greater gains in muscular strength would likely increase female recruit BLP pass rates. Augmented muscular strength would also likely increase the number of recruits capable of achieving higher BLP standards for more physically demanding employment categories. A training program that yields greater improvements in muscular strength may also enable lower entry standards, thereby increasing the recruit pool. PMID- 26506185 TI - Training Methods and Training Instructors' Qualification Are Related to Recruits' Fitness Development During Basic Military Training. AB - Adequate physical fitness is essential for successful military service. Military organizations worldwide therefore make continuous efforts to improve their army's physical training (PT) programs. To investigate the effect of the training methods and the qualification of PT instructors on the development of recruits' physical fitness, the present study compared the outcomes of 2 training groups. Both study groups participated in approximately 145 minutes per week of PT. The control group executed the standard army PT prepared and supervised by army PT instructors. Content of the PT in the intervention group was similar to that of the control group, but their training sessions' methods were different. Their training sessions were organized, prepared, and delivered by more and better qualified supervisors (tertiary-educated physical education teachers). After 10 weeks of training, the participants of the intervention group experienced a significantly greater physical fitness improvement than those of the control group (positive change in endurance 32 and 17%, balance 30 and 21%, and core strength 74 and 45%, respectively). In both groups, the recruits with the lowest initial fitness levels significantly increased their performance. In the intervention group, but not the control, one-third of the recruits with the highest initial fitness levels were able to further improve their general fitness performance. This study demonstrates that the training methods and quality of instruction during PT sessions are relevant for recruits' fitness development in basic military training. PMID- 26506186 TI - Examining the Relationship Between Mental, Physical, and Organizational Factors Associated With Attrition During Maritime Forces Training. AB - For infantry units of the Dutch Ministry of Defence, high attrition rates (varying from 42 to 68%) during initial training are a persisting problem. The reasons for this attrition are diverse. Having better insight into the causes of attrition is a prerequisite for implementing preventive measures. To achieve this, a monitoring assessment system was developed that integrated the effects of physical, mental, and organizational determinants on operational readiness. The aim of this study was to implement the monitoring tools and to establish the set of determinants that best predicted attrition during infantry training of new recruits. Eighty-five recruits were monitored over a 24-week infantry training course. Before the training, recruits were screened for medical, psychological, and physical wellness. During the monitoring phase, mental, physiological, and organizational indicants were obtained using an array of tools such as questionnaires, chest belt monitors (for heart rate, acceleration, and skin temperature measurements), and computerized tests (e.g., vigilance, long-term memory). Survival analyses were used to tease out the determinants of individual and grouped predictors of attrition. Nearly half the recruits (47%) failed the training. Attrition was predicted by both physiological and mental determinants. However, the organizational determinant "trainers' judgment" on the "recruits' military quality" dominated the physiological and mental determinants. It was concluded that the monitoring system was successfully implemented during infantry training, and that the survival analysis method emphasized on single effects and interactions between the different determinants. Based on the current findings, we recommend several steps to successfully implement a monitoring method in settings with high demands. PMID- 26506187 TI - The FORCE Fitness Profile--Adding a Measure of Health-Related Fitness to the Canadian Armed Forces Operational Fitness Evaluation. AB - In 2013, the Canadian Armed Forces (CAF) implemented the Fitness for Operational Requirements of Canadian Armed Forces Employment (FORCE), a field expedient fitness test designed to predict the physical requirements of completing common military tasks. Given that attaining this minimal physical fitness standard may not represent a challenge to some personnel, a fitness incentive program was requested by the chain of command to recognize and reward fitness over and above the minimal standard. At the same time, it was determined that the CAF would benefit from a measure of general health-related fitness, in addition to this measure of operational fitness. The resulting incentive program structure is based on gender and 8 age categories. The results on the 4 elements of the FORCE evaluation were converted to a point scale from which normative scores were derived, where the median score corresponds to the bronze level, and silver, gold, and platinum correspond to a score which is 1, 2, and 3 SDs above this median, respectively. A suite of rewards including merit board point toward promotions and recognition on the uniform and material rewards was developed. A separate group rewards program was also tabled, to recognize achievements in fitness at the unit level. For general fitness, oxygen capacity was derived from FORCE evaluation results and combined with a measure of abdominal circumference. Fitness categories were determined based on relative risks of mortality and morbidity for each age and gender group. Pilot testing of this entire program was performed with 624 participants to assess participants' reactions to the enhanced test, and also to verify logistical aspects of the electronic data capture, calculation, and transfer system. The newly dubbed fitness profile program was subsequently approved by the senior leadership of the CAF and is scheduled to begin a phased implementation in June 2015. PMID- 26506188 TI - Even One Is Too Much: Sole Presence of One of the Risk Factors Overweight, Lack of Exercise, and Smoking Reduces Physical Fitness of Young Soldiers. AB - Health and physical fitness are key factors for soldiers. Increased sedentary military work, significant sitting periods during commuting and leisure time, and unhealthy dietary habits have caused a considerable increase in the number of physically unfit soldiers. Even worse, the adoption of harmful lifestyle habits occurs increasingly earlier in life. The aim of this cross-sectional study was (a) to determine the physical fitness of young male soldiers and (b) to investigate the association between physical fitness and both the presence and frequency of the health risk factors overweight, smoking, and lack of exercise. A total of 4,553 volunteers aged 18-25 years performed the Basis Fitness Test consisting of the 3 disciplines agility (11 * 10 m shuttle sprint), strength (flexed-arm hang), and endurance (1,000-m run). The presence and frequency of risk factors were determined by means of anthropometric measures (body mass index, waist circumference) and questionnaire data. The portion of soldiers without risk factors decreased from 49.4% (18-year-olds) to 16.4% for 25-year olds. Persons without risk factors completed the agility test in 41.1 +/- 3.7 seconds, flexed-arm hang in 60.1 +/- 19.7 seconds, and 1,000-m run in 235 +/- 32 seconds. Physical performance in all dimensions tested (agility, strength, endurance) notably deteriorated with the sole presence of one of the risk factors overweight, smoking, and lack of exercise. Any further risk factor led to further fitness decreases (p < 0.001). Mean performances of soldiers with 3 risk factors were 46.7 +/- 4.1 seconds (11 * 10 m shuttle sprint), 27.6 +/- 6.4 seconds (flexed-arm hang), and 298 +/- 45 seconds (1,000-m run). Impacts of unhealthy lifestyles and significant losses in physical fitness are already visible in young male soldiers. Armed Forces must intensify their efforts to maintain health and performance of their soldiers. PMID- 26506189 TI - Development and Implementation of a New Physical Training Concept in the Norwegian Navy Special Operations Command. AB - A high level of physical fitness is one important factor for optimal performance in Special Operation Forces (SOF). Still, information about physical training for SOF operators is not easily accessible. This study aimed to implement and assess a new training concept in the Norwegian Navy SOF. A longitudinal study where 22 operators completed a 6-month linear periodization (LP), followed by a 6-month nonlinear periodization (NLP) program. Both protocols were block periodized, focusing on either strength or aerobic capacity. A battery of tests covering strength, endurance, power, mobility, and body composition was performed, and individual capacity analyses were established. A training week consisted of 5 to 6 sessions including 1 or 2 individualized sessions directed towards improving the weakest capacity. The LP had a clear effect on mobility (19 +/- 9%), abdominal strength (25 +/- 16%), upper body power (PowerUB; 6 +/- 9%), standing long-jump (3 +/- 6%), pull-ups (24 +/- 31%), agility (2 +/- 4%), V[Combining Dot Above]O2max (2 +/- 3%), fat percent (-5 +/- 31%), and muscle mass (1 +/- 3%). The NLP increased abdominal strength (15 +/- 17%), standing long-jump (3 +/- 4%), and anaerobic capacity (10 +/- 8%), whereas V[Combining Dot Above]O2 max (-3 +/- 4%) and PowerUB (-2 +/- 7%) decreased. Additional analyses showed clear increases among those individually instructed to improve strength. Results support the benefits of combined periodized programming and individualized training sessions among SOF operators with initially good fitness levels. Largest effects were observed in the first phase with the LP. However, subsequent NLP additionally increased anaerobic and jumping capacity, possibly due to more frequent muscular endurance and power training. Because of frequent interruptions, the LP tended to be more difficult to follow than the NLP and is suggested when continuity is possible, whereas an NLP is recommended for maintenance and when standing on national preparedness. PMID- 26506190 TI - Concept for a Predeployment Assessment of Basic Military Fitness in the German Armed Forces. AB - Military fitness is defined as a hierarchical 4-level construct in the German armed forces: (a) "Fundamental/Baseline Fitness," (b) "Basic Military Fitness," (c) "Task Fitness," and (d) "Mission Fitness." "Fundamental/Baseline Fitness" is assessed with the "Basic Fitness Test." However, this test alone is not sufficient to assess readiness for the physical demands of deployments. The first part of the article describes the development of a tool mirroring the specific physiological requirements of military operations on a joint forces level. The "Basic Military Fitness Tool" (BMFT) combines 4 crucial military demands into one single timed test run performed with field uniform (5 kg), body armor (13.4 kg), and helmet (1.6 kg): (a) maneuver under fire: 130 m run with changes in direction, velocity, and body position, (b) casualty rescue: 40 m of dragging a 50 kg load, (c) load carrying: 100 m carrying of two 18 kg loads, and (d) load lifting: lifting a 24 kg load on to a 1.25 m high rack 5 times. The second part covers the first assessment of BMFT selectivity between high- and low-performing groups. Muscle mass and strength are important factors for working with loads. Thus, female soldiers are expected to need more time to complete BMFT because of their on average lower muscle mass. Eighteen female (age = 28.5 +/- 6.6 years, lean body mass [LBM] = 45.0 +/- 4.5 kg; mean +/- SD) and 104 male soldiers (age = 30.0 +/- 8.4, LBM = 64.3 +/- 7.1) completed isometric strength testing (hand grip = 344.3 +/- 51.4 N and 547.3 +/- 79.1 N, elbow flexors = 118.9 +/- 16.9 and 235.1 +/- 42.0, knee extensors = 433.2 +/- 87.4 and 631.4 +/- 111.4) and BMFT (259.2 +/ 44.0 and 150.0 +/- 21.1 s). Except age, all variables differed significantly (p < 0.01) between groups. PMID- 26506191 TI - Executive Summary From the National Strength and Conditioning Association's Second Blue Ribbon Panel on Military Physical Readiness: Military Physical Performance Testing. AB - The National Strength and Conditioning Association's tactical strength and conditioning program sponsored the second Blue Ribbon Panel on military physical readiness: military physical performance testing, April 18-19, 2013, Norfolk, VA. This meeting brought together a total of 20 subject matter experts (SMEs) from the U.S. Air Force, Army, Marine Corps, Navy, and academia representing practitioners, operators, researchers, and policy advisors to discuss the current state of physical performance testing across the Armed Services. The SME panel initially rated 9 common military tasks (jumping over obstacles, moving with agility, carrying heavy loads, dragging heavy loads, running long distances, moving quickly over short distances, climbing over obstacles, lifting heavy objects, loading equipment) by the degree to which health-related fitness components (e.g., aerobic fitness, muscular strength, muscular endurance, flexibility, and body composition) and skill-related fitness components (e.g., muscular power, agility, balance, coordination, speed, and reaction time) were required to accomplish these tasks. A scale from 1 to 10 (10 being highest) was used. Muscular strength, power, and endurance received the highest rating scores. Panel consensus concluded that (a) selected fitness components (particularly for skill-related fitness components) are currently not being assessed by the military; (b) field-expedient options to measure both health-based and skill based fitness components are currently available; and PMID- 26506192 TI - Human Performance Optimization Metrics: Consensus Findings, Gaps, and Recommendations for Future Research. AB - Human performance optimization (HPO) is defined as "the process of applying knowledge, skills and emerging technologies to improve and preserve the capabilities of military members, and organizations to execute essential tasks." The lack of consensus for operationally relevant and standardized metrics that meet joint military requirements has been identified as the single most important gap for research and application of HPO. In 2013, the Consortium for Health and Military Performance hosted a meeting to develop a toolkit of standardized HPO metrics for use in military and civilian research, and potentially for field applications by commanders, units, and organizations. Performance was considered from a holistic perspective as being influenced by various behaviors and barriers. To accomplish the goal of developing a standardized toolkit, key metrics were identified and evaluated across a spectrum of domains that contribute to HPO: physical performance, nutritional status, psychological status, cognitive performance, environmental challenges, sleep, and pain. These domains were chosen based on relevant data with regard to performance enhancers and degraders. The specific objectives at this meeting were to (a) identify and evaluate current metrics for assessing human performance within selected domains; (b) prioritize metrics within each domain to establish a human performance assessment toolkit; and (c) identify scientific gaps and the needed research to more effectively assess human performance across domains. This article provides of a summary of 150 total HPO metrics across multiple domains that can be used as a starting point-the beginning of an HPO toolkit: physical fitness (29 metrics), nutrition (24 metrics), psychological status (36 metrics), cognitive performance (35 metrics), environment (12 metrics), sleep (9 metrics), and pain (5 metrics). These metrics can be particularly valuable as the military emphasizes a renewed interest in Human Dimension efforts, and leverages science, resources, programs, and policies to optimize the performance capacities of all Service members. PMID- 26506193 TI - International Research Consensus: Identifying Military Research Priorities and Gaps. AB - A multidisciplinary survey was administered to military performance researchers attending the Third International Conference on Soldier Physical Performance to obtain their opinions of the priority levels and importance of research topics related to soldier health and determinants of soldier physical performance. Respondents included 140 individuals from 22 different countries, of which 96% had at least a graduate degree and 79% were associated with a military organization. The top 5 highest importance/priority research topics were (a) physical demands in operational environments, (b) measuring physical performance/fitness, (c) musculoskeletal injury mitigation programs, (d) physical employment standards, and (e) physical strength-training programs. Of what individuals thought were their most important topics, 50% reported these were not currently being researched because of higher priorities, insufficient funding, or the lack of scientific expertise. A theme analysis of research-topic areas that were important and not being researched indicated that physical employment standards and physical training studies related to soldiers' health and performance are knowledge gaps. Although these experienced researchers had diverse backgrounds and were working on a wide array of research topics, there was a surprisingly clear consensus on what they thought were important topics that needed to be addressed in common between countries or militaries. PMID- 26506194 TI - Development and Implementation of Evidence-Based Physical Employment Standards: Key Challenges in the Military Context. AB - The use of evidence-based physical employment standards is critical in selecting individuals who can meet the requirements of arduous military occupations. The methods used to generate the physical assessments and standards are critical to the process and must withstand legal scrutiny. This article addresses the challenges encountered when developing, validating, and implementing physical standards and assessments. The challenges covered by the study include: (a) identification of critical job tasks and minimum requirements for performance of the tasks, (b) involvement of military personnel as subject-matter experts, PMID- 26506195 TI - Physiological Readiness and Resilience: Pillars of Military Preparedness. AB - Warfighters require a range of physical capabilities to meet the demands of the military profession, and physical training must address performance along an entire continuum, depending on individual needs and mission requirements. Strength and power capabilities are needed for optimal performance of anaerobic tasks such as heavy load carriage, sprinting under load, and maneuvering over uneven terrain. For optimal performance, soldiers must also be able to recover from mission demands and strenuous training. The demands placed on a soldier can result in a chronic stress, leading to decreased mission performance, increased injury risk, and increased susceptibility to illness. These factors are exacerbated by inappropriate training strategies such as overemphasis on endurance exercise combined with other stressors such as lack of sleep or inadequate nutrition. Chronic stress has been linked to overreaching/overtraining and to the development of comorbidities such as metabolic syndrome, insulin resistance, and hypertension and has adverse effects on memory and cognitive function. Resistance exercise is an effective method to improve warfighter physical performance and resilience to stress, thereby impacting mission readiness. Resistance exercise in particular confers many benefits to include increased strength and power, improved body composition, and protective effects on tendons, ligaments, and bone. Physically fit individuals not only benefit from improved mission performance but also are more resilient to operational stressors faced during combat. Ultimately, resilient soldiers are better able to cope with the physical and mental demands of the military profession and over the long term will perform better while maintaining health and well-being. PMID- 26506196 TI - Improving Soldier Health and Performance by Moving Army Medicine Toward a System for Health. AB - With growing limitations on military resources, including a reduction in the overall size of our military force, the Army must make the most of every soldier in its ranks. The only way to achieve the necessary improvements in human performance with upcoming constraints will be through exploring innovative ways of thinking while implementing the best policies and doctrine that will maintain each soldier's resilience throughout their military career. Moving the Army from a traditional health care system to a system for health is expected to substantially improve and maintain soldier health and performance by focusing on 3 key areas: the Performance Triad (sleep health, physical activity, and nutrition behaviors), Delivery of Health, and Healthy Environments. The implementation of this system for health will not only improve individual soldier's resiliency/capability both throughout and beyond their military careers and benefit Army Medicine as a whole, but could also serve as a successful model for the nation if changes are adopted. PMID- 26506197 TI - Military Applicability of Interval Training for Health and Performance. AB - Militaries from around the globe have predominantly used endurance training as their primary mode of aerobic physical conditioning, with historical emphasis placed on the long distance run. In contrast to this traditional exercise approach to training, interval training is characterized by brief, intermittent bouts of intense exercise, separated by periods of lower intensity exercise or rest for recovery. Although hardly a novel concept, research over the past decade has shed new light on the potency of interval training to elicit physiological adaptations in a time-efficient manner. This work has largely focused on the benefits of low-volume interval training, which involves a relatively small total amount of exercise, as compared with the traditional high-volume approach to training historically favored by militaries. Studies that have directly compared interval and moderate-intensity continuous training have shown similar improvements in cardiorespiratory fitness and the capacity for aerobic energy metabolism, despite large differences in total exercise and training time commitment. Interval training can also be applied in a calisthenics manner to improve cardiorespiratory fitness and strength, and this approach could easily be incorporated into a military conditioning environment. Although interval training can elicit physiological changes in men and women, the potential for sex-specific adaptations in the adaptive response to interval training warrants further investigation. Additional work is needed to clarify adaptations occurring over the longer term; however, interval training deserves consideration from a military applicability standpoint as a time-efficient training strategy to enhance soldier health and performance. There is value for military leaders in identifying strategies that reduce the time required for exercise, but nonetheless provide an effective training stimulus. PMID- 26506198 TI - Adaptations to Short, Frequent Sessions of Endurance and Strength Training Are Similar to Longer, Less Frequent Exercise Sessions When the Total Volume Is the Same. AB - The hypothesis that the distribution of weekly training across several short sessions, as opposed to fewer longer sessions, enhances maximal strength gain without compromising maximal oxygen uptake was evaluated. Twenty-nine subjects completed an 8-week controlled parallel-group training intervention. One group ("micro training" [MI]: n = 21) performed nine 15-minute training sessions weekly, whereas a second group ("classical training" [CL]: n = 8) completed exactly the same training on a weekly basis but as three 45-minute sessions. For each group, each session comprised exclusively strength, high-intensity cardiovascular training or muscle endurance training. Both groups increased shuttle run performance (MI: 1,373 +/- 133 m vs. 1,498 +/- 126 m, p <= 0.05; CL: 1,074 +/- 213 m vs. 1,451 +/- 202 m, p < 0.001). In contrast to CL, MI increased peak oxygen uptake (3,744 +/- 615 mL.min-1 vs. 3,963 +/- 753 mL.min-1, p <= 0.05), maximal voluntary isometric (MVC) force of the knee extensors (646 +/- 135 N vs. 659 +/- 209 N, p < 0.001), MVC of the finger flexors (408 +/- 109 N vs. 441 +/- 131 N, p <= 0.05), and number of lunges performed in 2 minutes (65 +/- 3 vs. 73 +/- 2, p < 0.001). However, there were no significant differences between MI and CL on any measured parameters before or after the training intervention. In conclusion, similar training adaptations can be obtained with short, frequent exercise sessions or longer, less frequent sessions where the total volume of weekly training performed is the same. PMID- 26506199 TI - Human Performance Optimization: Culture Change and Paradigm Shift. AB - The term "Human Performance Optimization" (HPO) emerged across the Department of Defense (DoD) around 2006 when the importance of human performance for military success on the battlefield was acknowledged. Likewise, the term Total Force Fitness (TFF) arose as a conceptual framework within DoD in response to the need for a more holistic approach to the unparalleled operational demands with multiple deployments and strains on the United States Armed Forces. Both HPO and TFF are frameworks for enhancing and sustaining the health, well-being, and performance among our warriors and their families; they are fundamental to accomplishing our nation's mission. A demands-resources model for HPO is presented within the context of TFF to assist in operationalizing actions to enhance performance. In addition, the role leaders can serve is discussed; leaders are uniquely postured in the military chain of command to directly influence a culture of fitness for a ready force, and promote the concept that service members are ultimately responsible for their fitness and performance. PMID- 26506200 TI - Physical Training, Fitness, and Injuries: Lessons Learned From Military Studies. AB - Injuries are the leading cause of medical encounters across the U.S. military services resulting in more than 2.0 million clinic visits per year. Almost 50% of military service members experience an injury each year and half of those injuries are caused by physical training (PT), exercise, or sports. To prevent a problem as large and complex as injuries in the military requires a systematic approach. Several key questions must be answered to effectively address a problem such as injuries: (1) how big is the problem? (2) what are the causes and risk factors for the problem? (3) do modifiable risk factors for the problem exist? and (4) what works to prevent the problem? The article discusses leading causes of injuries for U.S. Army populations. It then explores key risk factors for exercise and training-related injuries: (1) the amounts of training, (2) types of training activities, (3) participants level of fitness, and (4) personal health risk behaviors. The article concludes with a review of prevention strategies illustrating interventions that have been shown to be effective, and others that are not effective. The data presented suggest that PT and exercise cause injuries and that modifications of training are most likely to prevent the problem. PMID- 26506201 TI - Pain on Functional Movement Screen Tests and Injury Risk. AB - The Functional Movement Screen (FMS) is a tool intended to evaluate limitations or asymmetries of movement to detect individuals at risk for exercise- and sports related injury. The purpose was to determine the association and predictive value of specific FMS tests with injury risk in physically active men. Soldiers aged 18 57 years completed the FMS (n = 2,476). Demographic and fitness data were collected by survey. Medical record data for any, overuse, and traumatic injury 6 months after the assessment were obtained. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value were calculated along with receiver operator characteristics to determine area under the curve (AUC). Risks, risk ratios, odds ratios (ORs), and 95% confidence intervals were calculated to assess injury risks. Multivariate logistic regression identified that pain on 5 of the 7 tests was associated with greater risk for any injury (OR = 1.50-3.51): deep squat, hurdle step, in-line lunge, trunk stability push-up, and rotary stability. However, FMS registered low sensitivity, PPV, and AUC for all 7 tests for the 3 injury types (2-24% sensitivity, 16-74% PPV, and 50-58% AUC). Although the presence of pain was associated with a higher risk of injury on 5 tests, a low sensitivity, PPV, and AUC were displayed. Therefore, caution is advised when implementing the FMS as a screening tool in an Army or similarly active population as it could lead to prevention and treatment resources being directed toward individuals who are not at greater risk for injury. PMID- 26506202 TI - U.S. Army Research on Pharmacological Enhancement of Soldier Performance: Stimulants, Anabolic Hormones, and Blood Doping. AB - The level playing field of competitive sports is an irrelevant concern in asymmetrical warfare. However, there is a common theme of pressure to use performance-enhancing drugs because athletic or military opponents may be using them to advantage. This interest is fueled by personal anecdotes, misconceptions, and myths, and decisions to use or not to use pharmacological interventions may ignore available scientific data. The U.S. Army has led research in this area, with an abundance of published data extending back to World War II. Behavioral effects have been a consistent concern. A key conclusion to be drawn from this research is that although there may be specialized applications for some of these interventions, the majority of soldiers will gain the greatest performance benefits from effective physical and mental training programs combined with good principles of rest and nutrition. Furthermore, the perceived need to improve human biology with drugs may be solving the wrong problem, trying to fit the human to the demands of poorly conceived tactics, tasks, and equipments instead of capitalizing on human capabilities. PMID- 26506203 TI - Novel Cooling Strategies for Military Training and Operations. AB - The deleterious effects of environmental heat stress, combined with high metabolic loads and protective clothing and equipment of the modern Warfighter, impose severe heat strain, impair task performance, and increase risk of heat illness, thereby reducing the chance for mission success. Despite the implementation of heat-risk mitigation procedures over the past decades, task performance still suffers and exertional heat illness remains a major military problem. We review 3 novel heat mitigation strategies that may be implemented in the training or operational environment to reduce heat strain and the risk of exertional heat illness. These strategies include ingestion of ice slurry, arm immersion cooling, and microclimate cooling. Each of these strategies is suitable for use in different scenarios and the choice of cooling strategy is contingent on the requirements, circumstances, and constraints of the training and operational scenario. Ingestion of ice slurry and arm immersion cooling are practical strategies that may be implemented during training scenarios; ice slurry can be ingested before and during exercise, whereas arm immersion cooling can be administered after exercise-heat exposure. In the operational environment, existing microclimate cooling can be implemented with retrofitted vehicles and as an unmounted system, and it has the potential for use in many military occupational scenarios. This review will discuss the efficacy, limitations, and practical considerations for field implementation of each strategy. PMID- 26506204 TI - Effects of Patrol Operation on Hydration Status and Autonomic Modulation of Heart Rate of Brazilian Peacekeepers in Haiti. AB - The stress of operational missions may challenge the maintenance of body homeostasis, affecting soldiers' cardiac autonomic control, promoting dehydration, and compromising performance. Therefore, we aimed to determine the effects of peacekeeper patrol operation in Haiti on soldiers' hydration status and cardiac autonomic modulation, and to determine whether fluctuations in autonomic modulation were associated with changes in hydration status, energy expenditure (EE), and aerobic fitness (V[Combining Dot Above]O2max). A group of 20 soldiers (23.5 +/- 4.7 years; V[Combining Dot Above]O2max 52.9 +/- 4.5 ml.kg 1.min-1) completed an operational patrol mission with a mean duration of 160.6 +/ 28.6 minutes. Before (Pre) and after (Post) the operation, the soldiers' body masses (BMs) were measured and 5-minute heart rate interbeat (R-R) intervals were recorded at rest to estimate heart rate variability (low-frequency [LF] and high frequency [HF] power, and sympathovagal balance [LF/HF]). During the mission, EE was estimated using heart rate (HR) monitors. Changes from Pre to Post in BM (%BM loss) and LF/HF (DeltaLF/HF) were used to evaluate the soldiers' dehydration levels and autonomic modulation, respectively. The mean EE was 711.0 +/- 208.7 kcal. From pre to post, increases (p < 0.01) were noted in LF normalized units (n.u.) and LF/HF and decreases (p < 0.01) were noted in BM, R-R interval, and HF n.u. The variation in DeltaLF/HF correlated with EE (r = 0.49; p = 0.02), V[Combining Dot Above]O2max (r = -0.42; p = 0.05), and %BM loss (r = 0.53; p = 0.02). The results demonstrated that an operational peacekeeper patrol with an approximate duration of 160 minutes promoted both dehydration and an imbalance in the autonomic modulation of soldiers' HR. The reduction in sympathovagal balance correlated with EE, dehydration, and aerobic conditioning. PMID- 26506205 TI - Total Body Water, Electrolyte, and Thermoregulatory Responses to Ad Libitum Water Replacement Using Two Different Water Delivery Systems During a 19-km Route March. AB - Hands-free hydration systems are often advocated for improved hydration and performance in military populations. The aim was to assess whether such systems indeed result in improved hydration in exercising soldiers. Subjects were required to complete a route march while consuming water ad libitum from either a hydration bladder (BG) or traditional canteen (CG). Water intakes of 538 ml.h-1 (BG) and 533 ml.h-1 (CG) resulted in no differences for changes in body mass, serum [Na], plasma osmolality, total body water, or time required to complete the march. There were no differences between peak exercise core temperature of the BG (38.9 degrees C) and CG (38.7 degrees C) groups. There were no differences between the groups for fluid balance, thermoregulation, or performance. This is a not a surprising finding because the amount of fluid consumed ad libitum is determined by changes in serum osmolality and not the fluid delivery system as often proposed. PMID- 26506206 TI - Physiological Implications, Performance Assessment and Risk Mitigation Strategies of Women in Combat-Centric Occupations. AB - Women have historically featured in military conflicts, but were not formally integrated into the military until the 20th century; occupations were mainly restricted to clerical or support roles. An increasing number of occupations have been opened to women and the higher physical demands of combat roles present new challenges. Inherent biological differences between sexes require women to work harder when undertaking the same tasks as men. This is reflected, in part, by the greater risk of musculoskeletal injuries of women observed notably during integrated military training. Gender "neutral" occupational standards, based on the physical requirements of the role, will ensure that women are suitably selected to cope with the demands of military tasks with a minimal risk of injury and to operational effectiveness. Initiatives such as reduced running mileage and single-sex training have contributed to a reduction in lower-limb musculoskeletal injuries, but the risk of injury remains higher in women. Nevertheless, women experience substantial gains in aerobic power and strength with appropriate and targeted training, narrowing the gap in physical performance between the sexes. Evidence-based occupational standards and optimal training programs provide short term solutions for integrating women in support combat, and indeed direct combat roles. PMID- 26506208 TI - Supramolecular gels based on boronate esters and imidazolyl donors. AB - Dative boron-nitrogen bonds can be used for the controlled assembly of boronate esters and N-donor ligands. So far, most investigations have focused on crystalline assemblies. In contrast, there are very few reports about soft materials based on dative B-N bonds. Here, we describe the formation of gels by aggregation of diboronate esters and ditopic bisimidazolyl donor ligands. Analyses of low molecular weight model compounds by NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography reveal that imidazolyl ligands form particularly strong dative bonds with boronate esters. The strong interaction allows gel formation in competitive polar solvents such as THF and acetone. In less polar solvents, very low critical gel concentrations of down to 0.02 wt% are observed. By using a diboronate ester linked by an azobenzene group, it is possible to form a photoresponsive gel. PMID- 26506209 TI - Reply to: Technical Comment on "Saccadic eye movement performance as an indicator of driving ability in elderly drivers". PMID- 26506211 TI - Impact of shortened dental arches on oral health-related quality of life. AB - This study described the prevalence of adults with shortened dental arches (SDA) in Brazil, specifically assessing the differences of oral health-related quality of life [the prevalence and severity of oral impacts on daily performance (OIDP)] by dentition status. We analysed data from the 2010 National Survey of Oral Health in Brazil, including home interviews and oral examinations. The assessment of SDA used two alternative definitions: having 3-5 natural occlusal units (OUs) in posterior teeth or having 4 OUs in posterior teeth. Both definitions included having intact anterior region and no dental prosthesis. The analysis was weighted, and a complex sampling design was used. Negative binomial regression models assessed associations as adjusted for socio-demographic conditions and dental outcomes. A total of 9779 adults (35-44 years old) participated in the study. A non-negligible proportion had SDA: 9.9% and 3.8% for the first and second definition, respectively. Individuals with SDA (first definition) ranked higher in OIDP prevalence [count ratio (CR) 1.22; 1.09-1.36, 95% confidence interval (CI)] and severity (CR = 1.43; 1.19-1.72, 95% CI) than those with more natural teeth. This difference was not statistically significant when adjusted for socio-demographic and dental covariates: OIDP prevalence (CR = 1.04; 0.92 1.17, 95% CI) and severity (CR = 1.09; 0.91-1.30, 95% CI). Analogous results were obtained when the second definition of SDA was adopted. These findings suggest that a considerable contingent of adults may function well without dental prostheses, despite having several missing teeth. This conclusion challenges the traditional approach of replacing any missing tooth and instructs the allocation of more dental resources to preventive, diagnostic and restorative services. PMID- 26506212 TI - WITHDRAWN: Domestic violence screening and intervention programmes for adults with dental or facial injury. PMID- 26506213 TI - Gastrointestinal Symptoms and Altered Intestinal Permeability Induced by Combat Training Are Associated with Distinct Metabotypic Changes. AB - Physical and psychological stress have been shown to modulate multiple aspects of gastrointestinal (GI) physiology, but its molecular basis remains elusive. We therefore characterized the stress-induced metabolic phenotype (metabotype) in soldiers during high-intensity combat training and correlated the metabotype with changes in GI symptoms and permeability. In a prospective, longitudinal study, urinary metabotyping was conducted on 38 male healthy soldiers during combat training and a rest period using gas chromatography-mass spectrometry. The urinary metabotype during combat training was clearly distinct from the rest period (partial least-squares discriminant analysis (PLSDA) Q(2) = 0.581), confirming the presence of a unique stress-induced metabotype. Differential metabolites related to combat stress were further uncovered, including elevated pyroglutamate and fructose, and reduced gut microbial metabolites, namely, hippurate and m-hydroxyphenylacetate (p < 0.05). The extent of pyroglutamate upregulation exhibited a positive correlation with an increase in IBS-SSS in soldiers during combat training (r = 0.5, p < 0.05). Additionally, the rise in fructose levels was positively correlated with an increase in intestinal permeability (r = 0.6, p < 0.005). In summary, protracted and mixed psychological and physical combat-training stress yielded unique metabolic changes that corresponded with the incidence and severity of GI symptoms and alteration in intestinal permeability. Our study provided novel molecular insights into stress induced GI perturbations, which could be exploited for future biomarker research or development of therapeutic strategies. PMID- 26506214 TI - Comparison of the clinicopathologic features and prognosis of bilateral versus unilateral multifocal papillary thyroid cancer: An updated study with more than 2000 consecutive patients. AB - BACKGROUND: Bilaterality is common in papillary thyroid cancer (PTC), but its clinical and prognostic implications are still controversial, and it remains unclear whether its behavior is more aggressive than multifocality. METHODS: The clinicopathologic features of 2211 consecutive patients with PTC who underwent surgical treatment at the authors' institute between 1997 and 2011 were reviewed. Among these surgical patients, 425 (19.2%) had bilateral PTCs, and 1786 had unilateral PTCs. The patients who had unilateral PTCs were subdivided into a group with unilateral-multifocal PTCs (210 patients) and a group with solitary PTCs (1576 patients). The 10-year disease-free survival (DFS) rates were calculated to compare the prognosis between groups. B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation status was examined by direct DNA sequencing. RESULTS: Patients who had bilateral PTCs were likely to have larger tumors, higher rates of extrathyroid extension and lymph node metastasis, and more advanced tumor stage than those who had unilateral-multifocal PTCs. Multivariate analysis identified only lymph node metastasis as an independent risk factor for PTC recurrence (P < .001). The 10-year DFS rate for patients with bilateral PTCs was much lower than that for those with unilateral-multifocal and solitary PTCs (78.8% vs 85.7% and 89.3%, respectively; P = .005). It is noteworthy that patients who had bilateral PTCs with lymph node metastasis had the worst prognosis in terms of DFS. Incidence of the BRAF V600E mutation (valine to glutamic acid mutation at position 600) was higher in the bilateral PTC group than that in the unilateral and unilateral-multifocal PTC groups. CONCLUSIONS: The current results provide initial evidence that bilateral PTCs are more aggressive than unilateral-multifocal PTCs, and patients who have bilateral disease have more advanced stage and shorter DFS. The poorer outcome of patients with bilateral PTCs may be caused in part by their high incidence of lymph node metastasis. Cancer 2016;122:198-206. (c) 2015 American Cancer Society. PMID- 26506215 TI - Carbon Monoxide Photoproduction from Particles and Solutes in the Delaware Estuary under Contrasting Hydrological Conditions. AB - Full-spectrum, ultraviolet (UV), and visible broadband apparent quantum yields (AQYs) for carbon monoxide (CO) photoproduction from chromophoric dissolved organic matter (CDOM) and particulate organic matter (POM) were determined in the Delaware Estuary in two hydrologically contrasting seasons in 2012: an unusually low flow in August and a storm-driven high flow in November. Average AQYs for CDOM and POM in November were 10 and 16 times the corresponding AQYs in August. Maximum AQYs in November occurred in a midestuary particle absorption maximum zone. Although POM AQYs were generally smaller than CDOM AQYs, the ratio of the former to the latter increased substantially from the UV to the visible. In both seasons, UV solar radiation was the primary driver for CO photoproduction from CDOM whereas visible light was the principal contributor to POM-based CO photoproduction. CDOM dominated CO photoproduction in the uppermost water layer while POM prevailed at deeper depths. On a depth-integrated basis, the Delaware Estuary shifted from a CDOM-dominated system in August to a POM-dominated system in November with respect to CO photoproduction. This study reveals that flood events may enhance photochemical cycling of terrigenous organic matter and switch the primary photochemical driver from CDOM to POM. PMID- 26506217 TI - Olfactory and cochleovestibular dysfunction after head injury in the workplace: an updated series. AB - OBJECTIVES: The objective of this study was to determine the incidence of olfactory dysfunction in workers following head injury in the work place, to define its relationship to the site, severity of injury and direction of force. The demographics of head injured workers were also assessed to determine whether those with olfactory loss were more likely to have sustained a cochleovestibular injury. DESIGN: Retrospective case analysis. SETTING: Tertiary referral university hospital in Toronto, Ontario. PARTICIPANTS: A total of 3438 consecutive patients referred from the Workplace Safety and Insurance Board (WSIB) in the province of Ontario who sustained a work-related head injury were assessed between 1987 and 2014. MAIN OUTCOME MEASURES: Olfactory and cochleovestibular dysfunction assessed by history, clinical examination and subjective and objective tests. RESULTS: Olfactory dysfunction (OD) was identified in 413 of 3438 patients (12.0%) of which 321 were diagnosed with anosmia and 92 with hyposmia. In our series, injuries from a fall were the commonest cause for OD and a frontal or mid-face impact was more likely to result in OD than other regions (P = 0.0002). A loss of consciousness (LOC) of any duration correlated with OD. In those with olfactory dysfunction, an associated skull fracture occurred in 37.1% of patients and a CSF leak in 4.1%, which was significantly higher compared with those without OD(<0.0001). Patients with OD had a higher incidence of cochlear and vestibular loss (19.9% and 20.6%, respectively) compared with those without OD (14.3% and 17.1%, respectively). CONCLUSIONS: Post-traumatic olfactory dysfunction is more likely to occur in patients who experienced a moderate to severe head injury, LOC and more likely to result from a frontal or mid-face blow to the skull. Cochleovestibular dysfunction is likely to occur concurrently with olfactory dysfunction. PMID- 26506216 TI - Comparison of native and non-native ubiquitin oligomers reveals analogous structures and reactivities. AB - Ubiquitin (Ub) chains regulate a wide range of biological processes, and Ub chain connectivity is a critical determinant of the many regulatory roles that this post-translational modification plays in cells. To understand how distinct Ub chains orchestrate different biochemical events, we and other investigators have developed enzymatic and non-enzymatic methods to synthesize Ub chains of well defined length and connectivity. A number of chemical approaches have been used to generate Ub oligomers connected by non-native linkages; however, few studies have examined the extent to which non-native linkages recapitulate the structural and functional properties associated with native isopeptide bonds. Here, we compare the structure and function of Ub dimers bearing native and non-native linkages. Using small-angle X-ray scattering (SAXS) analysis, we show that scattering profiles for the two types of dimers are similar. Moreover, using an experimental structural library and atomistic simulations to fit the experimental SAXS profiles, we find that the two types of Ub dimers can be matched to analogous structures. An important application of non-native Ub oligomers is to probe the activity and selectivity of deubiquitinases. Through steady-state kinetic analyses, we demonstrate that different families of deubiquitinases hydrolyze native and non-native isopeptide linkages with comparable efficiency and selectivity. Considering the significant challenges associated with building topologically diverse native Ub chains, our results illustrate that chains harboring non-native linkages can serve as surrogate substrates for explorations of Ub function. PMID- 26506218 TI - Carbon Quantum Dots and Their Derivative 3D Porous Carbon Frameworks for Sodium Ion Batteries with Ultralong Cycle Life. AB - A new methodology for the synthesis of carbon quantum dots (CQDs) for large production is proposed. The as-obtained CQDs can be transformed into 3D porous carbon frameworks exhibiting superb sodium storage properties with ultralong cycle life and ultrahigh rate capability, comparable to state-of-the-art carbon anode materials for sodium-ion batteries. PMID- 26506219 TI - Aspirin Attenuates Angiotensin II-induced Cardiomyocyte Hypertrophy by Inhibiting the Ca(2+)/Calcineurin-NFAT Signaling Pathway. AB - INTRODUCTION: In this study, we examined whether aspirin could inhibit cardiac hypertrophy. METHODS: We utilized cultured neonatal mouse cardiomyocytes and mice for the study and subjected to cardiomyocyte immunochemistry, qRT-PCR, and immunoblotting analysis. The cardiac function was measured using M-mode echocardiography. RESULTS: Ten MUM aspirin significantly inhibited Ang II-induced increase in cardiomyocyte size, the mRNA, and protein levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and beta-myosin heavy chain (beta-MHC) (P < 0.05). Meantime, consistent with the result in vitro, the increase in HW/BW ratio, the mRNA, and protein levels of ANP, BNP, and beta-MHC could be reduced by aspirin in vivo (P < 0.05). Analysis of cardiac function revealed that mouse hearts treated with Ang II displayed thickening of the ventricular walls, left ventricular end-diastolic dimensions, and left ventricular end-systolic dimensions were significantly decreased (P < 0.05), whereas interventricular septal thickness at end-diastole, interventricular septal thickness at end-systole, posterior wall thickness in diastole, and posterior wall thickness in systole were markedly increased (P < 0.05), which could be reversed by aspirin (P < 0.05). Moreover, aspirin blunted the increase inCa(2+) and inhibited the calcineurin activity and NFAT dephosphorylation caused by Ang II (P < 0.05). CONCLUSIONS: Aspirin inhibited cardiac hypertrophy in vitro and in vivo through inhibition of the Ca(2+)/calcineurin-NFAT signaling pathway. Therefore, these findings suggested that aspirin might become a therapeutic option to reduce cardiac hypertrophy. PMID- 26506220 TI - The best of both worlds: Using patient-reported plus physician-scored measures during the evaluation of myasthenia gravis. PMID- 26506221 TI - Versixanthones A-F, Cytotoxic Xanthone-Chromanone Dimers from the Marine-Derived Fungus Aspergillus versicolor HDN1009. AB - Six unusual xanthone-chromanone dimers, versixanthones A-F (1-6), featuring different formal linkages of tetrahydroxanthone and 2,2-disubstituted chroman-4 one monomers, were isolated from a culture of the mangrove-derived fungus Aspergillus versicolor HDN1009. The absolute configurations of 1-6, representing the central and axial chirality elements or preferred helicities, were established by a combination of X-ray diffraction analysis, chemical conversions, and TDDFT-ECD calculations. The interconversion of different biaryl linkages between 1 and 4 and between 2 and 3 in DMSO by a retro-oxa-Michael mechanism provided insight into the formation of the xanthone-chromanone dimers and supported the assignments of their absolute configurations. Compounds 1-6 exhibited cytotoxicities against the seven tested cancer cell lines, with the best IC50 value of 0.7 MUM. Compound 5 showed further inhibitory activity against topoisomerase I. PMID- 26506222 TI - ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy. AB - OBJECTIVE: Distal myopathy is a heterogeneous group of muscle diseases characterized by predominant distal muscle weakness. A study was done to identify the underlying cause of autosomal recessive adolescent onset distal myopathy. METHODS: Four patients from 2 unrelated Korean families were evaluated. To isolate the genetic cause, exome sequencing was performed. In vitro and in vivo assays using myoblast cells and zebrafish models were performed to examine the ADSSL1 mutation causing myopathy pathogenesis. RESULTS: Patients had an adolescent onset distal myopathy phenotype that included distal dominant weakness, facial muscle weakness, rimmed vacuoles, and mild elevation of serum creatine kinase. Exome sequencing identified completely cosegregating compound heterozygous mutations (p.D304N and p.I350fs) in ADSSL1, which encodes a muscle specific adenylosuccinate synthase in both families. None of the controls had both mutations, and the mutation sites were located in well-conserved regions. Both the D304N and I350fs mutations in ADSSL1 led to decreased enzymatic activity. The knockdown of the Adssl1 gene significantly inhibited the proliferation of mouse myoblast cells, and the addition of human wild-type ADSSL1 reversed the reduced viability. In an adssl1 knockdown zebrafish model, muscle fibers were severely disrupted, which was evaluated by myosin expression and birefringence. In these conditions, supplementing wild-type ADSSL1 protein reversed the muscle defect. INTERPRETATION: We suggest that mutations in ADSSL1 are the novel genetic cause of the autosomal recessive adolescent onset distal myopathy. This study broadens the genetic and clinical spectrum of distal myopathy and will be useful for exact molecular diagnostics. PMID- 26506223 TI - Up-Regulation of Intestinal Phosphate Transporter NaPi-IIb (SLC34A2) by the Kinases SPAK and OSR1. AB - BACKGROUND/AIMS: SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), kinases controlled by WNK (with-no-K[Lys] kinase), are powerful regulators of cellular ion transport and blood pressure. Observations in gene-targeted mice disclosed an impact of SPAK/OSR1 on phosphate metabolism. The present study thus tested whether SPAK and/or OSR1 contributes to the regulation of the intestinal Na(+)-coupled phosphate co-transporter NaPi-IIb (SLC34A2). METHODS: cRNA encoding NaPi-IIb was injected into Xenopus laevis oocytes without or with additional injection of cRNA encoding wild-type SPAK, constitutively active (T233E)SPAK, WNK insensitive (T233A)SPAK, catalytically inactive (D212A)SPAK, wild-type OSR1, constitutively active (T185E)OSR1, WNK insensitive (T185A)OSR1 or catalytically inactive (D164A)OSR1. The phosphate (1 mM)-induced inward current (I(Pi)) was taken as measure of phosphate transport. RESULTS: I(Pi) was observed in NaPi-IIb expressing oocytes but not in water injected oocytes, and was significantly increased by co-expression of SPAK, (T233E)SPAK, OSR1, (T185E)OSR1 or SPAK+OSR1, but not by co-expression of (T233A)SPAK, (D212A)SPAK, (T185A)OSR1, or (D164A)OSR1. SPAK and OSR1 both increased the maximal transport rate of the carrier. CONCLUSIONS: SPAK and OSR1 are powerful stimulators of the intestinal Na+-coupled phosphate co-transporter NaPi-IIb. PMID- 26506224 TI - OMIP-030: Characterization of human T cell subsets via surface markers. PMID- 26506225 TI - Lymphatic Malformation in Newborns as the First Sign of Diffuse Lymphangiomatosis: Successful Treatment with Sirolimus. AB - Cystic hygroma and lymphangioma, currently defined as 'lymphatic malformations', are developmental abnormalities of the lymphoid system with potential for rapid expansion. The management of these abnormalities depends on the site and extent of the lesion. A different disease is diffuse lymphangiomatosis. It is very rare at birth and its treatment remains controversial. A lymphatic malformation (cystic hygroma) of the neck of a newborn girl as the first sign of diffuse lymphangiomatosis and treatment of the latter condition with sirolimus are presented. A newborn girl with a presumed isolated lymphatic malformation of the neck and significant respiratory involvement was diagnosed via total-body nuclear magnetic resonance imaging to be affected by diffuse lymphangiomatosis; she was treated with sirolimus. The treatment with sirolimus was found to be very effective, with complete resolution of the disease, good tolerability, and no side effects. This report suggests the need to explore the possibility of diffuse lymphangiomatosis in neonates with apparently isolated lymphatic malformations. In the presence of clinical deterioration, sirolimus treatment may achieve excellent results with no adverse events. PMID- 26506226 TI - Macroscopic and Nanoscopic Heterogeneous Structures in a Three-Component Lipid Bilayer Mixtures Determined by Atomic Force Microscopy. AB - Much of lipid raft properties can be inferred from phase behavior of multicomponent lipid membranes. We use liquid compatible atomic force microscopy (AFM) to study a three-component system composed of 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC), egg sphingomyelin (eSM), and cholesterol. Specifically, we obtain macroscopic and nanoscopic heterogeneous structures in a broad compositional space of DOPC/eSM/cholesterol (23 degrees C). In the macroscopic liquid coexisting region, we quantify area fraction of the coexisting phases and determine a set of thermodynamic tie-lines. When lipid compositions are near the critical point, we obtain fluctuation-like nanoscopic structures. We also use AFM height images to explore the hypothetical three-phase coexisting region. Finally, we use fluorescence microscopy to compare the phase behavior from our AFM measurements to that in free-floating giant unilamellar vesicles (GUVs). Our results highlight the role of lipid composition in mediating lipid domain formation and stability. PMID- 26506227 TI - Gene Expression Profiles in Rice Developing Ovules Provided Evidence for the Role of Sporophytic Tissue in Female Gametophyte Development. AB - The development of ovule in rice (Oryza sativa) is vital during its life cycle. To gain more understanding of the molecular events associated with the ovule development, we used RNA sequencing approach to perform transcriptome-profiling analysis of the leaf and ovules at four developmental stages. In total, 25,401, 23,343, 23,647 and 23,806 genes were identified from the four developmental stages of the ovule, respectively. We identified a number of differently expressed genes (DEGs) from three adjacent stage comparisons, which may play crucial roles in ovule development. The DEGs were then conducted functional annotations and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses. Genes related to cellular component biogenesis, membrane-bounded organelles and reproductive regulation were identified to be highly expressed during the ovule development. Different expression levels of auxin-related and cytokinin-related genes were also identified at various stages, providing evidence for the role of sporophytic ovule tissue in female gametophyte development from the aspect of gene expression. Generally, an overall transcriptome analysis for rice ovule development has been conducted. These results increased our knowledge of the complex molecular and cellular events that occur during the development of rice ovule and provided foundation for further studies on rice ovule development. PMID- 26506228 TI - Contrasting Effects of Long-Term Grazing and Clipping on Plant Morphological Plasticity: Evidence from a Rhizomatous Grass. AB - Understanding the mechanism of plant morphological plasticity in response to grazing and clipping of semiarid grassland can provide insight into the process of disturbance-induced decline in grassland productivity. In recent studies there has been controversy regarding two hypotheses: 1) grazing avoidance; and 2) growth limiting mechanisms of morphological plasticity in response to defoliation. However, the experimental evidence presented for the memory response to grazing and clipping of plants has been poorly reported. This paper reports on two experiments that tested these hypotheses in field and in a controlled environment, respectively. We examined the effects of long-term clipping and grazing on the functional traits and their plasticity for Leymus chinensis (Trin.) Tzvelev (the dominate species) in the typical-steppe grassland of Inner Mongolia, China. There were four main findings from these experiments. (i) The majority of phenotypic traits of L. chinensis tended to significantly miniaturize in response to long-term field clipping and grazing. (ii) The significant response of morphological plasticity with and without grazing was maintained in a hydroponic experiment designed to remove environmental variability, but there was no significant difference in L. chinensis individual size traits for the clipping comparison. (iii) Plasticity indexes of L. chinensis traits in a controlled environment were significantly lower than under field conditions indicating that plants had partial and slight memory effect to long-term grazing. (iv) The allometry of various phenotypic traits, indicated significant trade-offs between leaf and stem allocation with variations in plant size induced by defoliation, which were maintained only under grazing in the hydroponic controlled environment experiment. Taken together, our findings suggest that the morphological plasticity of L. chinensis induced by artificial clipping was different with that by livestock grazing. The miniaturization of plant size in long-term grazed grassland may reflect retained characteristics of dwarf memory for adaptation to long-term grazing by large herbivores. PMID- 26506229 TI - Network Centrality of Resting-State fMRI in Primary Angle-Closure Glaucoma Before and After Surgery. AB - PURPOSE: Using voxel-wise degree centrality (DC), as measured by resting-state fMRI, we aimed to study alterations in the brain functional networks in patients with primary angle-closure glaucoma (PACG) and to reveal the plastic trajectories of surgery. METHODS: A total of 23 preoperative PACG patients (49.48 +/- 14.37 years old) were recruited to undergo a resting-state fMRI scan, and 9 of them were rescanned 3 months after surgery. All PACG patients underwent a complete ophthalmologic examination, including intraocular pressure (IOP), retinal nerve fiber layer (RNFL) thickness, vertical cup to disc ratio (V C/D), and average cup to disc ratio (A C/D). Another 23 gender- and age-matched healthy controls (48.18 +/- 9.40 years old) underwent scanning once for comparison. The group difference in DC was calculated in each voxel, and the correlations between the DC value and each of the clinical variables were analyzed in the PACG patients. RESULTS: Preoperative PACG (pre-PACG) patients showed significantly decreased DC in the bilateral visual cortices but increased DC in the left anterior cingulate cortex (ACC) and caudate (p < 0.05, corrected) compared with the controls. Statistical analysis showed a significantly negative correlation between DC in the bilateral visual cortices and the IOP score and between DC in the anterior cingulate cortex (ACC) and both the A C/D and V C/D scores in the pre-PACG patients. Three months after surgery, these postoperative PACG (post-PACG) patients showed a significantly increased DC in both the bilateral visual cortices and the left precentral gyrus compared with the pre-PACG patients. CONCLUSIONS: Our results suggest that PACG may contribute to decreased functional centrality in the visual system and to increased degree centrality in cognition-emotional processing regions. Alterations in visual areas seem to parallel the cup to disc ratio, but not the duration of angle closure. The changes of functional centrality in PACG patients after operation may reveal the plasticity or degeneration of the visual associated brain areas. Our findings may provide further understanding of the pathophysiology of PACG. PMID- 26506230 TI - Increased Water Storage in the Qaidam Basin, the North Tibet Plateau from GRACE Gravity Data. AB - Groundwater plays a key role in maintaining the ecology and environment in the hyperarid Qaidam Basin (QB). Indirect evidence and data from sparse observation wells suggest that groundwater in the QB is increasing but there has been no regional assessment of the groundwater conditions in the entire basin because of its remoteness and the severity of the arid environment. Here we report changes in the spatial and temporal distribution of terrestrial water storage (TWS) in the northern Tibetan Plateau (NTP) using Gravity Recovery and Climate Experiment (GRACE) data. Our study confirms long-term (2003-2012) TWS increases in the NTP. Between 2003 and 2012 the TWS increased by 88.4 and 20.6 km3 in the NTP and the QB, respectively, which is 225% and 52% of the capacity of the Three Gorges Reservoir, respectively. Soil and water changes from the Global Land Data Assimilation System (GLDAS) were also used to identify groundwater storage in the TWS and to demonstrate a long-term increase in groundwater storage in the QB. We demonstrate that increases in groundwater, not lake water, are dominant in the QB, as observed by groundwater levels. Our study suggests that the TWS increase was likely caused by a regional increase in precipitation and a decrease in evaporation. Degradation of the permafrost increases the thickness of the active layers providing increased storage for infiltrated precipitation and snow and ice melt water, which may also contribute to the increased TWS. The huge increase of water storage in the NTP will have profound effects, not only on local ecology and environment, but also on global water storage and sea level changes. PMID- 26506231 TI - A Novel SLC27A4 Splice Acceptor Site Mutation in Great Danes with Ichthyosis. AB - Ichthyoses are a group of various different types of hereditary disorders affecting skin cornification. They are characterized by hyperkeratoses of different severity levels and are associated with a dry and scaling skin. Genome wide association analysis of nine affected and 13 unaffected Great Danes revealed a genome-wide significant peak on chromosome 9 at 57-58 Mb in the region of SLC27A4. Sequence analysis of genomic DNA of SLC27A4 revealed the non-synonymous SNV SLC27A4:g.8684G>A in perfect association with ichthyosis-affection in Great Danes. The mutant transcript of SLC27A4 showed an in-frame loss of 54 base pairs in exon 8 probably induced by a new splice acceptor site motif created by the mutated A- allele of the SNV. Genotyping 413 controls from 35 different breeds of dogs and seven wolves revealed that this mutation could not be found in other populations except in Great Danes. Affected dogs revealed high amounts of mutant transcript but only low levels of the wild type transcript. Targeted analyses of SLC27A4 protein from skin tissues of three affected and two unaffected Great Danes indicated a markedly reduced or not detectable wild type and truncated protein levels in affected dogs but a high expression of wild type SLC27A4 protein in unaffected controls. Our data provide evidence of a new splice acceptor site creating SNV that results in a reduction or loss of intact SLC27A4 protein and probably explains the severe skin phenotype in Great Danes. Genetic testing will allow selective breeding to prevent ichthyosis-affected puppies in the future. PMID- 26506232 TI - Proteomic discovery of MNT as a novel interacting partner of E3 ubiquitin ligase E6AP and a key mediator of myeloid differentiation. AB - Perturbed stability of regulatory proteins is a major cause of transformations leading to cancer, including several leukemia subtypes. Here, for the first time we demonstrate that E6-associated protein (E6AP), an E3 ubiquitin ligase negatively targets MAX binding protein MNT for ubiquitin-mediated proteasome degradation and impedes ATRA mediated myeloid cell differentiation. MNT is a member of the Myc/Max/Mad network of transcription factor that regulates cell proliferation, differentiation, cellular transformation and tumorigenesis. Wild type E6AP promoted proteasome dependent degradation of MNT, while catalytically inactive E6AP having cysteine replaced with alanine at amino-acid 843 position (E6APC843A) rather stabilized it. Further, these proteins physically associated with each other both in non-myeloid (HEK293T) and myeloid cells. MNT overexpression induced G0-G1 growth arrest and promoted myeloid differentiation while its knockdown mitigated even ATRA induced differentiation suggesting MNT to be crucial for myeloid differentiation. We further showed that ATRA inhibited E6AP and stabilized MNT expression by protecting it from E6AP mediated ubiquitin proteasome degradation. Notably, E6AP knockdown in HL60 cells restored MNT expression and promoted myeloid differentiation. Taken together, our data demonstrated that E6AP negatively regulates granulocytic differentiation by targeting MNT for degradation which is required for growth arrest and subsequent myeloid differentiation by various differentiation inducing agents. PMID- 26506233 TI - Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer. AB - COX5B, a peripheral subunit of the cytochrome c oxidase complex, has previously been reported to maintain the stability of this complex. However, its functions and mechanisms involved in breast cancer progression remain unclear. Here, by performing SILAC assays in breast cancer cell models and detecting COX5B expression in tissues, we found that COX5B expression was elevated in breast cancer. Down-regulation of COX5B in breast cancer cell lines can suppress cell proliferation and induced cell senescence which was accompanied by elevating production of IL-8 and other cytokines. Interestingly, conditioned medium from COX5B knockdown cells could promote breast cancer cell migration. Mechanistic studies reveal that COX5B silence induces an increase in production of ROS, depolarization of MMP and a decrease in ATP. What's more, silence of COX5B leads to metabolic disorders, such as increased glucose uptake and decreased lactate secretion. Collectively, our study shows that loss of COX5B induces mitochondrial dysfunction and subsequently leads to cell growth suppression and cell senescence. Cytokines such as IL-8 secreted by senescent cells may in turn alter the microenvironment which could enhance cell migration. These findings may provide a novel paradigm for the treatment which combined anti-cancer drugs with particular cytokine inhibitors such as IL-8 blockers. PMID- 26506235 TI - LKB1 promotes cell survival by modulating TIF-IA-mediated pre-ribosomal RNA synthesis under uridine downregulated conditions. AB - We analyzed the mechanism underlying 5-aminoimidazole-4-carboxamide riboside (AICAR) mediated apoptosis in LKB1-null non-small cell lung cancer (NSCLC) cells. Metabolic profile analysis revealed depletion of the intracellular pyrimidine pool after AICAR treatment, but uridine was the only nucleotide precursor capable of rescuing this apoptosis, suggesting the involvement of RNA metabolism. Because half of RNA transcription in cancer is for pre-ribosomal RNA (rRNA) synthesis, which is suppressed by over 90% after AICAR treatment, we evaluated the role of TIF-IA-mediated rRNA synthesis. While the depletion of TIF-IA by RNAi alone promoted apoptosis in LKB1-null cells, the overexpression of a wild-type or a S636A TIF-IA mutant, but not a S636D mutant, attenuated AICAR-induced apoptosis. In LKB1-null H157 cells, pre-rRNA synthesis was not suppressed by AICAR when wild type LKB1 was present, and cellular fractionation analysis indicated that TIF-IA quickly accumulated in the nucleus in the presence of a wild-type LKB1 but not a kinase-dead mutant. Furthermore, ectopic expression of LKB1 was capable of attenuating AICAR-induced death in AMPK-null cells. Because LKB1 promotes cell survival by modulating TIF-IA-mediated pre-rRNA synthesis, this discovery suggested that targeted depletion of uridine related metabolites may be exploited in the clinic to eliminate LKB1-null cancer cells. PMID- 26506234 TI - MEF2 transcription factors: developmental regulators and emerging cancer genes. AB - The MEF2 transcription factors have roles in muscle, cardiac, skeletal, vascular, neural, blood and immune system cell development through their effects on cell differentiation, proliferation, apoptosis, migration, shape and metabolism. Altered MEF2 activity plays a role in human diseases and has recently been implicated in the development of several cancer types. In particular, MEF2B, the most divergent and least studied protein of the MEF2 family, has a role unique from its paralogs in non-Hodgkin lymphomas. The use of genome-scale technologies has enabled comprehensive MEF2 target gene sets to be identified, contributing to our understanding of MEF2 proteins as nodes in complex regulatory networks. This review surveys the molecular interactions of MEF2 proteins and their effects on cellular and organismal phenotypes. We include a discussion of the emerging roles of MEF2 proteins as oncogenes and tumor suppressors of cancer. Throughout this article we highlight similarities and differences between the MEF2 family proteins, including a focus on functions of MEF2B. PMID- 26506236 TI - The ribosomal protein S6 in renal cell carcinoma: functional relevance and potential as biomarker. AB - Inhibitors of the mTOR pathway, such as everolimus, are promising compounds to treat patients with renal cell carcinomas (RCCs). However, the precise mechanisms of action are far from clear, and biomarkers predicting the response to mTOR inhibitors are still missing. Here, we provide evidence that in RCCs the rpS6 protein is the major mediator of anti-tumoral effects exerted by everolimus. Inhibition of mTOR signaling results in substantially decreased clonogenicity and proliferation of RCC cells, but did not significantly induce apoptosis. Everolimus effectively blocked protein biosynthesis both in vitro and in a novel ex vivo tissue slice model using fresh vital human RCC tissue. Compared to other components of the mTOR pathway, phosphorylation of rpS6 was most effectively downregulated by everolimus. Importantly, siRNA-mediated downregulation of rpS6, but not of 4ebp1 or p27, abolished the inhibitory effects of everolimus on proliferation and protein synthesis. Moreover, we analyzed the tissue expression of phosphorylated rpS6 (p-rpS6) and non-phosphorylated rpS6 in a large collection of patients with RCCs (n=598 and n=548, respectively). Expression of both proteins qualified as independent negative prognostic markers with a substantially shorter survival of patients with RCCs exhibiting high levels of rpS6 and p-rpS6. Taken together, our functional studies identified rpS6 as a main mediator of the anti-tumoral activity of Everolimus. Therefore, further (pre )clinical evaluations of rpS6 as a predictive marker for everolimus-based treatment for RCC patients are warranted. Finally, the combined detection of phosphorylated and non-phosphorylated rpS6 could represent a robust prognostic marker to identify patients with high risk RCCs. PMID- 26506237 TI - Overexpression of ATP1B1 predicts an adverse prognosis in cytogenetically normal acute myeloid leukemia. AB - ATP1B1 encodes the Na,K-ATPase beta subunit, a key regulator of the Na+ and K+ electrochemical gradients across the plasma membrane and an essential regulator of cellular activity. We used several microarray datasets to test the prognostic efficacy of ATP1B1 expression in cytogenetically normal acute myeloid leukemia (CN-AML). Within the primary cohort (n = 157), high ATP1B1 expression (ATP1B1(high)) was associated with shorter overall survival (OS) and event-free survival (EFS) (P = 0.0068, P = 0.0039, respectively). Similar results were also obtained in the European Leukemia Net (ELN) Intermediate-I genetic category (OS: P = 0.0035, EFS: P = 0.0007). Multivariable analyses confirmed ATP1B1(high) is an independent predictor of shorter OS (P = 0.042) and EFS (P = 0.035). Analysis of another CN-AML cohort confirmed that ATP1B1(high) is associated with shorter OS (P = 0.0046, n = 162). In addition, up-regulation of oncogenes/onco-microRNAs such as MYCN, CCND2, CDK6, KIT and miR-155, among others, was associated with ATP1B1(high), which may be indicative of ATP1B1's leukemogenicity. Our results may improve risk stratification and indicate new therapeutic targets for CN-AML. PMID- 26506239 TI - Emerging role of N-myc downstream-regulated gene 2 (NDRG2) in cancer. AB - N-myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor and cell stress related gene. NDRG2 is associated with tumor incidence, progression, and metastasis. NDRG2 regulates tumor-associated genes and is regulated by multiple conditions, treatments, and protein/RNA entities, including hyperthermia, trichostatin A and 5-aza-2'-deoxycytidine, which are promising potential cancer therapeutics. In this review, we discuss the expression as well as the clinical and pathological significance of NDRG2 in cancer. The pathological processes and molecular pathways regulated by NDRG2 are also summarized. Moreover, mechanisms for increasing NDRG2 expression in tumors and the potential directions of future NDRG2 research are discussed. The information reviewed here should assist in experimental design and increase the potential of NDRG2 as a therapeutic target for cancer. PMID- 26506238 TI - miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring through the regulation of DHFR, integrins, and CD47. AB - BACKGROUND: The main cause of death in medulloblastoma is recurrence associated with leptomeningeal dissemination. During this process, the role of microRNAs (miRs) in the acquisition of metastatic phenotype remains poorly understood. This study aimed to identify the miR involved in leptomeningeal dissemination and to elucidate its biological functional mechanisms. MATERIALS AND METHODS: We analyzed the miR expression profiles of 29 medulloblastomas according to the presence of cerebrospinal fluid (CSF) seeding. Differentially expressed miRs (DEmiRs) were validated in 29 medulloblastoma tissues and three medulloblastoma cell lines. The biological functions of the selected miRs were evaluated using in vitro and in vivo studies. RESULTS: A total of 12 DEmiRs were identified in medulloblastoma with seeding, including miR-192. The reduced expression of miR 192 was confirmed in the tumor seeding group and in the medulloblastoma cells. Overexpression of miR-192 inhibited cellular proliferation by binding DHFR. miR 192 decreased cellular anchoring via the repression of ITGAV, ITGB1, ITGB3, and CD47. Animals in the miR-192-treated group demonstrated a reduction of spinal seeding (P < 0.05) and a significant survival benefit (P < 0.05). CONCLUSIONS: Medulloblastoma with seeding showed specific DEmiRs compared with those without. miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring ability. PMID- 26506241 TI - Transcription factor LSF (TFCP2) inhibits melanoma growth. AB - Late SV40 factor 3 (LSF), a transcription factor, contributes to human hepatocellular carcinoma (HCC). However, decreased expression level of LSF in skin melanoma compared to that in benign melanocytic tumors and nevi in mice and humans was found in this study. Anchorage-dependent and -independent growth of melanoma cells was suppressed by LSF overexpression through an increased percentage of G1 phase cells and an increased p21CIP1 expression level in vitro and in vivo. Anchorage-dependent growth in LSF-overexpressed melanoma cells was promoted by depletion of LSF in the LSF-overexpressed cells. Integrated results of our EMSA and chromatin immunoprecipitation assays showed binding of LSF within a 150-bp upstream region of the transcription start site of p21CIP1 in melanoma cells. Taken together, our results suggest potential roles of LSF as a growth regulator through control of the transcription of p21CIP1 in melanocytes and melanoma cells as well as a biomarker for nevus. PMID- 26506240 TI - Growth-arrest-specific 7C protein inhibits tumor metastasis via the N-WASP/FAK/F actin and hnRNP U/beta-TrCP/beta-catenin pathways in lung cancer. AB - Growth-arrest-specific 7 (GAS7) belongs to a group of adaptor proteins that coordinate the actin cytoskeleton. Among human GAS7 isoforms, only GAS7C possesses a Src homology 3 domain. We report here that GAS7C acts as a migration suppressor and can serve as a prognostic biomarker in lung cancer. GAS7C overexpression reduces lung cancer migration, whereas GAS7C knockdown enhances cancer cell migration. Importantly, ectopically overexpressed GAS7C binds tightly with N-WASP thus inactivates the fibronectin/integrin/FAK pathway, which in turn leads to the suppression of F-actin dynamics. In addition, overexpression of GAS7C sequesters hnRNP U and thus decreases the level of beta-catenin protein via the beta-TrCP ubiquitin-degradation pathway. The anti-metastatic effect of GAS7C overexpression was also confirmed using lung cancer xenografts. Our clinical data indicated that 23.6% (25/106) of lung cancer patients showed low expression of GAS7C mRNA which correlated with a poorer overall survival. In addition, low GAS7C mRNA expression was detected in 60.0% of metastatic lung cancer patients, indicating an association between low GAS7C expression and cancer progression. A significant inverse correlation between mRNA expression and promoter hypermethylation was also found, which suggests that the low level of GAS7C expression was partly due to promoter hypermethylation. Our results provide novel evidence that low GAS7C correlates with poor prognosis and promotes metastasis in lung cancer. Low GAS7C increases cancer cell motility by promoting N-WASP/FAK/F actin cytoskeleton dynamics. It also enhances beta-catenin stability via hnRNP U/beta-TrCP complex formation. Therefore, GAS7C acts as a metastasis suppressor in lung cancer. PMID- 26506242 TI - Tumors with high-density tumor infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials. AB - BACKGROUND: Tumor infiltrating lymphocytes (TILs) are considered in the prognosis of breast cancer (BC) patients. Here, we investigated the prognostic/predictive effect of TILs in patients treated in the frame of four prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-trastuzumab era. METHODS: TILs density was histologically assessed as percentage of stromal area on whole routine sections of 2613 BC (1563 Luminal A/B; 477 Luminal HER2; 246 HER2-enriched; 327 triple negative [TNBC]) and were evaluated as high/low at three cut-offs (c/o; 50% [lymphocytic predominance, LP], 35% and 25%), in separate training and validation sets. RESULTS: High TILs were present in 3.5%, 6.5% and 11.5% of all tumors, using the 50%, 35% and 25% c/o, respectively. TILs status did not interact with BC subtypes or trastuzumab treatment. LPBC patient outcome was not affected by nodal status, while high TILs were favorable in TNBC with unfavorable nodal status. When adjusted for standard clinicopathological parameters and treatment, high TILs independently predicted for favorable outcome, e.g., disease-free survival with the 35% c/o in the entire cohort (HR = 0.44, 95% CI 0.28-0.69, p < 0.001) and in specific subtypes. CONCLUSIONS: High TILs tumors, especially LPBC seem worthy validating as a separate entity of favorable prognosis in breast cancer. PMID- 26506243 TI - Crosslinking of a Peritrophic Matrix Protein Protects Gut Epithelia from Bacterial Exotoxins. AB - Transglutaminase (TG) catalyzes protein-protein crosslinking, which has important and diverse roles in vertebrates and invertebrates. Here we demonstrate that Drosophila TG crosslinks drosocrystallin, a peritrophic matrix protein, to form a stable fiber structure on the gut peritrophic matrix. RNA interference (RNAi) of the TG gene was highly lethal in flies and induced apoptosis of gut epithelial cells after oral infection with Pseudomonas entomophila. Moreover, AprA, a metalloprotease secreted by P. entomophila, digested non-crosslinked drosocrystallin fibers, but not drosocrystallin fibers crosslinked by TG. In vitro experiments using recombinant drosocrystallin and monalysin proteins demonstrated that monalysin, a pore-forming exotoxin of P. entomophila, was adsorbed on the crosslinked drosocrystallin fibers in the presence of P. entomophila culture supernatant. In addition, gut-specific TG-RNAi flies had a shorter lifespan than control flies after ingesting P. entomophila, whereas the lifespan after ingesting AprA-knockout P. entomophila was at control levels. We conclude that drosocrystallin fibers crosslinked by TG, but not non-crosslinked drosocrystallin fibers, form an important physical barrier against exotoxins of invading pathogenic microbes. PMID- 26506244 TI - Using qualitative evidence in decision making for health and social interventions: an approach to assess confidence in findings from qualitative evidence syntheses (GRADE-CERQual). AB - Simon Lewin and colleagues present a methodology for increasing transparency and confidence in qualitative research synthesis. PMID- 26506245 TI - A Virtual Mixture Approach to the Study of Multistate Equilibrium: Application to Constant pH Simulation in Explicit Water. AB - Chemical and thermodynamic equilibrium of multiple states is a fundamental phenomenon in biology systems and has been the focus of many experimental and computational studies. This work presents a simulation method to directly study the equilibrium of multiple states. This method constructs a virtual mixture of multiple states (VMMS) to sample the conformational space of all chemical states simultaneously. The VMMS system consists of multiple subsystems, one for each state. The subsystem contains a solute and a solvent environment. The solute molecules in all subsystems share the same conformation but have their own solvent environments. Transition between states is implicated by the change of their molar fractions. Simulation of a VMMS system allows efficient calculation of relative free energies of all states, which in turn determine their equilibrium molar fractions. For systems with a large number of state transition sites, an implicit site approximation is introduced to minimize the cost of simulation. A direct application of the VMMS method is for constant pH simulation to study protonation equilibrium. Applying the VMMS method to a heptapeptide of 3 ionizable residues, we calculated the pKas of those residues both with all explicit states and with implicit sites and obtained consistent results. For mouse epidermal growth factor of 9 ionizable groups, our VMMS simulations with implicit sites produced pKas of all 9 ionizable groups and the results agree qualitatively with NMR measurement. This example demonstrates the VMMS method can be applied to systems of a large number of ionizable groups and the computational cost scales linearly with the number of ionizable groups. For one of the most challenging systems in constant pH calculation, SNase Delta+PHS/V66K, our VMMS simulation shows that it is the state-dependent water penetration that causes the large deviation in lysine66's pKa. PMID- 26506246 TI - Developmental Changes in Composition and Morphology of Cuticular Waxes on Leaves and Spikes of Glossy and Glaucous Wheat (Triticum aestivum L.). AB - The glossy varieties (A14 and Jing 2001) and glaucous varieties (Fanmai 5 and Shanken 99) of wheat (Triticum aestivum L.) were selected for evaluation of developmental changes in the composition and morphology of cuticular waxes on leaves and spikes. The results provide us with two different wax development patterns between leaf and spike. The general accumulation trend of the total wax load on leaf and spike surfaces is first to increase and then decrease during the development growth period, but these changes were caused by different compound classes between leaf and spike. Developmental changes of leaf waxes were mainly the result of variations in composition of alcohols and alkanes. In addition, diketones were the third important contributor to the leaf wax changes in the glaucous varieties. Alkanes and diketones were the two major compound classes that caused the developmental changes of spike waxes. For leaf waxes, beta- and OH-beta-diketones were first detected in flag leaves from 200-day-old plants, and the amounts of beta- and OH-beta-diketones were significantly higher in glaucous varieties compared with glossy varieties. In spike waxes, beta-diketone existed in all varieties, but OH-beta-diketone was detectable only in the glaucous varieties. Unexpectedly, the glaucous variety Fanmai 5 yielded large amounts of OH-beta-diketone. There was a significant shift in the chain length distribution of alkanes between early stage leaf and flag leaf. Unlike C28 alcohol being the dominant chain length in leaf waxes, the dominant alcohol chain length of spikes was C24 or C26 depending on varieties. Epicuticular wax crystals on wheat leaf and glume were comprised of platelets and tubules, and the crystal morphology changed constantly throughout plant growth, especially the abaxial leaf crystals. Moreover, our results suggested that platelets and tubules on glume surfaces could be formed rapidly within a few days. PMID- 26506247 TI - The C34 Peptide Fusion Inhibitor Binds to the Six-Helix Bundle Core Domain of HIV 1 gp41 by Displacement of the C-Terminal Helical Repeat Region. AB - The conformational transition of the core domain of HIV-1 gp41 from a prehairpin intermediate to a six-helix bundle is responsible for virus-cell fusion. Several inhibitors which target the N-heptad repeat helical coiled-coil trimer that is fully accessible in the prehairpin intermediate have been designed. One such inhibitor is the peptide C34 derived from the C-heptad repeat of gp41 that forms the exterior of the six-helix bundle. Here, using a variety of biophysical techniques, including dye tagging, size-exclusion chromatography combined with multiangle light scattering, double electron-electron resonance EPR spectroscopy, and circular dichroism, we investigate the binding of C34 to two six-helix bundle mimetics comprising N- and C-heptad repeats either without (core(SP)) or with (core(S)) a short spacer connecting the two. In the case of core(SP), C34 directly exchanges with the C-heptad repeat. For core(S), up to two molecules of C34 bind the six-helix bundle via displacement of the C-heptad repeat. These results suggest that fusion inhibitors such as C34 can target a continuum of transitioning conformational states from the prehairpin intermediate to the six helix bundle prior to the occurrence of irreversible fusion of viral and target cell membranes. PMID- 26506248 TI - Tension between Internal and External Modes of Stabilization in Carbocations Relevant to Terpene Biosynthesis: Modulating Minima Depth via C-H...pi Interactions. AB - Density functional theory calculations on a carbocation rearrangement relevant to the biosynthesis of the sesquiterpenoid trefolane A are described, with a focus on the viability of altering the curvature of the potential energy surface through C-H...pi interactions of the sort likely to be found at the active site of a terpene synthase enzyme. These interactions are able to remove a deep minimum from a pathway to product. PMID- 26506249 TI - Identification of Novel and Conserved miRNAs from Extreme Halophyte, Oryza coarctata, a Wild Relative of Rice. AB - Oryza coarctata, a halophyte and wild relative of rice, is grown normally in saline water. MicroRNAs (miRNAs) are non-coding RNAs that play pivotal roles in every domain of life including stress response. There are very few reports on the discovery of salt-responsive miRNAs from halophytes. In this study, two small RNA libraries, one each from the control and salt-treated (450 mM NaCl for 24 h) leaves of O. coarctata were sequenced, which yielded 338 known and 95 novel miRNAs. Additionally, we used publicly available transcriptomics data of O. coarctata which led to the discovery of additional 48 conserved miRNAs along with their pre-miRNA sequences through in silico analysis. In total, 36 known and 7 novel miRNAs were up-regulated whereas, 12 known and 7 novel miRNAs were down regulated under salinity stress. Further, 233 and 154 target genes were predicted for 48 known and 14 novel differentially regulated miRNAs respectively. These targets with the help of gene ontology analysis were found to be involved in several important biological processes that could be involved in salinity tolerance. Relative expression trends of majority of the miRNAs as detected by real time-PCR as well as predicted by Illumina sequencing were found to be coherent. Additionally, expression of most of the target genes was negatively correlated with their corresponding miRNAs. Thus, the present study provides an account of miRNA-target networking that is involved in salinity adaption of O. coarctata. PMID- 26506250 TI - The Cellular Distribution of RanGAP1 Is Regulated by CRM1-Mediated Nuclear Export in Mammalian Cells. AB - The Ran GTPase activating protein RanGAP1 plays an essential role in nuclear transport by stimulating RanGTP hydrolysis in the cytoplasmic compartment. In mammalian cells, unmodified RanGAP1 is predominantly cytoplasmic, whereas modification by small ubiquitin-related modifier protein (SUMO) targets RanGAP1 to the cytoplasmic filaments of nuclear pore complex (NPC). Although RanGAP1 contains nine putative nuclear export signals and a nuclear localization signal, little is known if RanGAP1 shuttles between the nuclear and cytoplasmic compartments and how its primary localization in the cytoplasm and at the NPC is regulated. Here we show that inhibition of CRM1-mediated nuclear export using RNAi-knockdown of CRM1 and inactivation of CRM1 by leptomycin B (LMB) results in nuclear accumulation of RanGAP1. LMB treatment induced a more robust redistribution of RanGAP1 from the cytoplasm to the nucleoplasm compared to CRM1 RNAi and also uniquely triggered a decrease or loss of RanGAP1 localization at the NPC, suggesting that LMB treatment is more effective in inhibiting CRM1 mediated nuclear export of RanGAP1. Our time-course analysis of LMB treatment reveals that the NPC-associated RanGAP1 is much more slowly redistributed to the nucleoplasm than the cytoplasmic RanGAP1. Furthermore, LMB-induced nuclear accumulation of RanGAP1 is positively correlated with an increase in levels of SUMO-modified RanGAP1, suggesting that SUMOylation of RanGAP1 may mainly take place in the nucleoplasm. Lastly, we demonstrate that the nuclear localization signal at the C-terminus of RanGAP1 is required for its nuclear accumulation in cells treated with LMB. Taken together, our results elucidate that RanGAP1 is actively transported between the nuclear and cytoplasmic compartments, and that the cytoplasmic and NPC localization of RanGAP1 is dependent on CRM1-mediated nuclear export. PMID- 26506251 TI - Health-Risk Behaviour in Deprived Neighbourhoods Compared with Non-Deprived Neighbourhoods: A Systematic Literature Review of Quantitative Observational Studies. AB - BACKGROUND: There has been increasing interest in neighbourhoods' influence on individuals' health-risk behaviours, such as smoking, alcohol consumption, physical activity and diet. The aim of this review was to systematically review recent studies on health-risk behaviour among adults who live in deprived neighbourhoods compared with those who live in non-deprived neighbourhoods and to summarise what kind of operationalisations of neighbourhood deprivation that were used in the studies. METHODS: PRISMA guidelines for systematic reviews were followed. Systematic searches were performed in PubMed, Embase, Web of Science and Sociological Abstracts using relevant search terms, Boolean operators, and truncation, and reference lists were scanned. Quantitative observational studies that examined health-risk behaviour in deprived neighbourhoods compared with non deprived neighbourhoods were eligible for inclusion. RESULTS: The inclusion criteria were met by 22 studies. The available literature showed a positive association between smoking and physical inactivity and living in deprived neighbourhoods compared with non-deprived neighbourhoods. In regard to low fruit and vegetable consumption and alcohol consumption, the results were ambiguous, and no clear differences were found. Numerous different operationalisations of neighbourhood deprivation were used in the studies. CONCLUSION: Substantial evidence indicates that future health interventions in deprived neighbourhoods should focus on smoking and physical inactivity. We suggest that alcohol interventions should be population based rather than based on the specific needs of deprived neighbourhoods. More research is needed on fruit and vegetable consumption. In future studies, the lack of a uniform operationalisation of neighbourhood deprivation must be addressed. PMID- 26506252 TI - Surface Modification of TiO2 Photoanodes with Fluorinated Self-Assembled Monolayers for Highly Efficient Dye-Sensitized Solar Cells. AB - Dye aggregation and electron recombination in TiO2 photoanodes are the two major phenomena lowering the energy conversion efficiency of dye-sensitized solar cells (DSCs). Herein, we introduce a novel surface modification strategy of TiO2 photoanodes by the fluorinated self-assembled monolayer (F-SAM) formation with 1H,1H,2H,2H-perfluorooctyltriethoxysilane (PFTS), blocking the vacant sites of the TiO2 surface after dye adsorption. The F-SAM helps to efficiently lower the surface tension, resulting in efficient repelling ions, e.g., I3(-), in the electrolyte to decrease the electron recombination rate, and the role of F-SAM is characterized in detail by impedance spectroscopy using a diffusion-recombination model. In addition, the dye aggregates on the TiO2 surface are relaxed by the F SAM with large conformational perturbation (i.e., helix structure) seemingly because of steric hindrance developed during the SAM formation. Such multifunctional effects suppress the electron recombination as well as the intermolecular interactions of dye aggregates without the loss of adsorbed dyes, enhancing both the photocurrent density (11.9 -> 13.5 mA cm(-2)) and open-circuit voltage (0.67 -> 0.72 V). Moreover, the combined surface modification with the F SAM and the classical coadsorbent further improves the photovoltaic performance in DSCs. PMID- 26506253 TI - Functional recovery after cervical spinal cord injury: Role of neurotrophin and glutamatergic signaling in phrenic motoneurons. AB - Cervical spinal cord injury (SCI) interrupts descending neural drive to phrenic motoneurons causing diaphragm muscle (DIAm) paralysis. Recent studies using a well-established model of SCI, unilateral spinal hemisection of the C2 segment of the cervical spinal cord (SH), provide novel information regarding the molecular and cellular mechanisms of functional recovery after SCI. Over time post-SH, gradual recovery of rhythmic ipsilateral DIAm activity occurs. Recovery of ipsilateral DIAm electromyogram (EMG) activity following SH is enhanced by increasing brain-derived neurotrophic factor (BDNF) in the region of the phrenic motoneuron pool. Delivery of exogenous BDNF either via intrathecal infusion or via mesenchymal stem cells engineered to release BDNF similarly enhance recovery. Conversely, recovery after SH is blunted by quenching endogenous BDNF with the fusion-protein TrkB-Fc in the region of the phrenic motoneuron pool or by selective inhibition of TrkB kinase activity using a chemical-genetic approach in TrkB(F616A) mice. Furthermore, the importance of BDNF signaling via TrkB receptors at phrenic motoneurons is highlighted by the blunting of recovery by siRNA-mediated downregulation of TrkB receptor expression in phrenic motoneurons and by the enhancement of recovery evident following virally-induced increases in TrkB expression specifically in phrenic motoneurons. BDNF/TrkB signaling regulates synaptic plasticity in various neuronal systems, including glutamatergic pathways. Glutamatergic neurotransmission constitutes the main inspiratory-related, excitatory drive to motoneurons, and following SH, spontaneous neuroplasticity is associated with increased expression of ionotropic N-methyl-d-aspartate (NMDA) receptors in phrenic motoneurons. Evidence for the role of BDNF/TrkB and glutamatergic signaling in recovery of DIAm activity following cervical SCI is reviewed. PMID- 26506255 TI - Effect of lower-limb joint models on subject-specific musculoskeletal models and simulations of daily motor activities. AB - Understanding the validity of using musculoskeletal models is critical, making important to assess how model parameters affect predictions. In particular, assumptions on joint models can affect predictions from simulations of movement, and the identification of image-based joints is unavoidably affected by uncertainty that can decrease the benefits of increasing model complexity. We evaluated the effect of different lower-limb joint models on muscle and joint contact forces during four motor tasks, and assessed the sensitivity to the uncertainties in the identification of anatomical four-bar-linkage joints. Three MRI-based musculoskeletal models having different knee and ankle joint models were created and used for the purpose. Model predictions were compared against a baseline model including simpler and widely-adopted joints. In addition, a probabilistic analysis was performed by perturbing four-bar-linkage joint parameters according to their uncertainty. The differences between models depended on the motor task analyzed, and there could be marked differences at peak loading (up to 2.40 BW at the knee and 1.54 BW at the ankle), although they were rather small over the motor task cycles (up to 0.59 BW at the knee and 0.31 BW at the ankle). The model including more degrees of freedom showed more discrepancies in predicted muscle activations compared to measured muscle activity. Further, including image-based four-bar-linkages was robust to simulate walking, chair rise and stair ascent, but not stair descent (peak standard deviation of 2.66 BW), suggesting that joint model complexity should be set according to the imaging dataset available and the intended application, performing sensitivity analyses. PMID- 26506254 TI - Mechanisms of impulsive choice: III. The role of reward processes. AB - Two experiments examined the relationship between reward processing and impulsive choice. In Experiment 1, rats chose between a smaller-sooner (SS) reward (1 pellet, 10 s) and a larger-later (LL) reward (1, 2, and 4 pellets, 30 s). The rats then experienced concurrent variable-interval 30-s schedules with variations in reward magnitude to evaluate reward magnitude discrimination. LL choice behavior positively correlated with reward magnitude discrimination. In Experiment 2, rats chose between an SS reward (1 pellet, 10 s) and an LL reward (2 and 4 pellets, 30 s). The rats then received either a reward intervention which consisted of concurrent fixed-ratio schedules associated with different magnitudes to improve their reward magnitude discrimination, or a control task. All rats then experienced a post-intervention impulsive choice task followed by a reward magnitude discrimination task to assess intervention efficacy. The rats that received the intervention exhibited increases in post-intervention LL choice behavior, and made more responses for larger-reward magnitudes in the reward magnitude discrimination task, suggesting that the intervention heightened sensitivities to reward magnitude. The results suggest that reward magnitude discrimination plays a key role in individual differences in impulsive choice, and could be a potential target for further intervention developments. PMID- 26506256 TI - Effects of cryopreservation on the survival rate of the seven-band grouper (Epinephelus septemfasciatus) embryos. AB - The effects of cryopreservation and the vitrification solution on the embryo hatchability of the seven-band grouper Epinephelus septemfasciatus were evaluated in this study. Six small molecule cryoprotectants (PG, MeOH, Gly, DMF, DMSO and EG) and four macromolecular cryoprotectants (glucose, fructose, sucrose and trehalose) were used to determine the embryo toxicity levels. Results showed that the embryo survival rate was higher when the PM (24% PG + 16% MeOH):Gly ratios were 3:1 and 4:1. Further experiments showed that the embryo survival rates in PMG3S (35% PMG3 + 5% sucrose) and PMG3T (35% PMG3 + 5% trehalose) were relatively higher, which are 29.24 +/- 10.81% and 27.01 +/- 3.39%, respectively. When treated with PMG3S and PMG3T by using 5-step method, embryos at somite stage and tail-bud stage shrank in the first 6 min and gradually recovered in volume to the original. This indicated the successful permeation of the vitrification solutions into cells. Then, embryos at the embryoid body formation stage, the somite stage and the tail-bud stage were cryopreserved with PMG3S and PMG3T. In total, 82 floating embryos were obtained, 14 of which developed further, with 8 embryos at the tail-bud stage developing to the heartbeat stage, 4 embryos at the body formation stage development to the somite stage, and 2 embryos at the somite stage hatched to larval fish. PMID- 26506257 TI - Characteristics of stem cells from human exfoliated deciduous teeth (SHED) from intact cryopreserved deciduous teeth. AB - The aim of this study is to compare the characteristics of stem cells derived from human exfoliated deciduous teeth (SHED) from cryopreserved intact deciduous teeth with those of fresh SHED. In total, 20 exfoliated deciduous teeth were randomly divided into a fresh group (f-SHED; n = 11) and cryopreserved group (c SHED; n = 9; stored for 1-8 months). Following thawing and separation of the pulp, the SHED cells were cultured, and the characteristics as mesenchymal stem cells were investigated using proliferation assays, cell-cycle analysis, colony forming unit-fibroblast (CFU-F) assays, and flow cytometry analyses. Furthermore, differentiation into adipogenic and osteogenic lineages was investigated in vitro as well as in vivo via transplantation in mice. We found no significant differences between the two groups in the proliferation analyses, in the expression of mesenchymal stem cell markers, or in the adipogenic and osteogenic differentiation in vitro (p < 0.05). Furthermore, the in vivo transplantation results showed no significant differences in the quantity of bone tissue that formed or in histochemistry performance (p < 0.05). In conclusion, cryopreservation of intact exfoliated deciduous teeth appears to be a useful method for preserving SHED. PMID- 26506258 TI - AT-rich repetitive DNA sequences, transcription frequency and germ layer determination. AB - Non-coding sequences of frog embryo endoderm poly (A+) nuclear RNA are AU enriched, as compared to those of ectoderm and mesoderm. Endoderm blastomeres contain much less H1 histone than is present in ectoderm and mesoderm. H1 histone preferentially binds AT-rich DNA sequences to repress their transcription. The AT enrichment of non-coding DNA sequences transcribed into poly (A+) nuclear RNA, as well as the low amount of H1 histone, may contribute to the higher transcription frequency of mRNA of endoderm, as compared to that of ectoderm and mesoderm. A greater accumulation of H1 histone in presumptive mesoderm and ectoderm may prevent transcription of endoderm specifying genes in mesoderm and ectoderm. Experimental upregulation of various transcription factors (TFs) can redirect germ layer fate. Most of these TFs bind AT-rich consensus sequences in DNA, suggesting that H1 histone and TFs active during germ layer determination are binding similar sequences. PMID- 26506259 TI - A qualitative study of adolescents with medically unexplained symptoms and their parents. Part 2: How is healthcare perceived? AB - Medically unexplained symptoms (MUS) are common among adolescents and an important cause of clinical visits. This study sought to understand the experiences with, and perceptions of, the healthcare of adolescents who have MUS and their parents. Using a qualitative approach, six focus groups and two individual interviews were conducted with a total of ten adolescents and sixteen parents. The participants were recruited in a university hospital in Switzerland. A thematic analysis was conducted in accordance with the Grounded Theory. Six main themes emerged: needing a label for the symptoms, seeking an etiology to explain the symptoms, negotiating the medical system, medication and treatments, interactions with doctors, and the inclusion of parents during consultations. Transcending these themes, however, was the need for good communication between the adolescents, their parents and the clinicians. When explaining the symptoms, clinicians should make sure to discuss the results, investigations and lack of organic origin. PMID- 26506260 TI - Our panel of experts highlight the most important research articles across the spectrum of topics relevant to the field of regenarative medicine. PMID- 26506261 TI - Molecular characterization of two kiss genes and their expression in rohu (Labeo rohita) during annual reproductive cycle. AB - Kisspeptin is an important regulator of reproduction in mammals and presumably non-mammalian species. In the Indian subcontinent, rohu (Labeo rohita) is a commercially important seasonal breeder freshwater fish species, but till date, the expression of kisspeptin gene during different phases of annual reproductive cycle has not been investigated. To address this, we cloned and characterized kiss1 and kiss2 full-length cDNA by RACE (rapid amplification of cDNA ends), and analyzed their expressions in brain-pituitary-gonad (BPG) axis by quantitative real time PCR (qRT-PCR) assay at various gonadal developmental stages of the annual reproductive cycle. Full-length rohu kiss1 and kiss2 cDNA encodes 116 and 125 amino acids respectively, and in the adult fish, they were widely expressed in brain, pituitary, gonad, liver, muscle, kidney, intestine and eye. In male, kiss1 mRNA in brain and testis showed the highest level of expression during meiosis division of the gonad. The kiss2 mRNA revealed the highest expression during recrudescence stages in the brain, spermiation stages in pituitary and post-spawning stages in testes. In females, significantly (p<0.05) a higher level of kiss1 transcript was expressed in brain and ovary, in the full grown oocyte stages, whereas during pre-vitellogenic and vitellogenic stages in pituitary. The kiss2 gene expression was almost similar at various gonadal developmental stages in the brain and ovary, but, highest expression was detected in full grown oocyte stages in the pituitary. These results together may suggest the involvement of two kiss genes in the control of seasonal gonadal development in rohu. PMID- 26506262 TI - Detection of Inorganic Arsenic in Rice Using a Field Test Kit: A Screening Method. AB - Rice is a staple food eaten by more than 50% of the world's population and is a daily dietary constituent in most South East Asian countries where 70% of the rice export comes from and where there is a high level of arsenic contamination in groundwater used for irrigation. Research shows that rice can take up and store inorganic arsenic during cultivation, and rice is considered to be one of the major routes of exposure to inorganic arsenic, a class I carcinogen for humans. Here, we report the use of a screening method based on the Gutzeit methodology to detect inorganic arsenic (iAs) in rice within 1 h. After optimization, 30 rice commodities from the United Kingdom market were tested with the field method and were compared to the reference method (high-performance liquid chromatography-inductively coupled plasma-mass spectrometry, HPLC-ICP-MS). In all but three rice samples, iAs compound can be determined. The results show no bias for iAs using the field method. Results obtained show quantification limits of about 50 MUg kg(-1), a good reproducibility for a field method of +/ 12%, and only a few false positives and negatives (<10%) could only be recorded at the 2015 European Commission (EC) guideline for baby rice of 100 MUg kg(-1), while none were recorded at the maximum level suggested by the World Health Organization (WHO) and implemented by the EC for polished and white rice of 200 MUg kg(-1). The method is reliable, fast, and inexpensive; hence, it is suggested to be used as a screening method in the field for preselection of rice which violates legislative guidelines. PMID- 26506263 TI - Impact of Association Colloids on Lipid Oxidation in Triacylglycerols and Fatty Acid Ethyl Esters. AB - The impact of association colloids on lipid oxidation in triacylglycerols and fatty acid ethyl esters was investigated. Association colloids did not affect lipid oxidation of high oleic safflower and high linoleic safflower triacylglycerols, but were prooxidative in fish triacylglycerols. Association colloids retarded aldehyde formation in stripped ethyl oleate, linoleate, and fish oil ethyl esters. Interfacial tension revealed that lipid hydroperoxides were surface active in the presence of the surfactants found in association colloids. The lipid hydroperoxides from ethyl esters were less surface active than triacylglycerol hydroperoxides. Stripping decreased iron and copper concentrations in all oils, but more so in fatty acid ethyl esters. The combination of lower hydroperoxide surface activity and low metal concentrations could explain why association colloids inhibited lipid oxidation in fatty acid ethyl esters. This research suggests that association colloids could be used as an antioxidant technology in fatty acid ethyl esters. PMID- 26506264 TI - p21(WAF1) modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia. AB - p21(WAF1) is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21(WAF1) in drug-induced cell cycle arrest and apoptosis of acute lymphoblastic leukemia (ALL) cells was investigated using p53-functional patient-derived xenografts (PDXs), in which p21(WAF1) was epigenetically silenced in T-cell ALL (T-ALL), but not in B-cell precursor (BCP)-ALL PDXs. Upon exposure to diverse cytotoxic drugs, T-ALL PDX cells exhibited markedly increased caspase-3/7 activity and phosphatidylserine (PS) externalization on the plasma membrane compared with BCP-ALL cells. Despite dramatic differences in apoptotic characteristics between T-ALL and BCP-ALL PDXs, both ALL subtypes exhibited similar cell death kinetics and were equally sensitive to p53-inducing drugs in vitro, although T-ALL PDXs were significantly more sensitive to the histone deacetylase inhibitor vorinostat. Transient siRNA suppression of p21(WAF1) in the BCP-ALL 697 cell line resulted in a moderate depletion of the cell fraction in G1 phase and marked increase in PS externalization following exposure to etoposide. Furthermore, stable lentiviral p21(WAF1) silencing in the BCP-ALL Nalm-6 cell line accelerated PS externalization and cell death following exposure to etoposide and vorinostat, supporting previous findings. Finally, the Sp1 inhibitor, terameprocol, inhibited p21(WAF1) expression in Nalm-6 cells exposed to vorinostat and also partially augmented vorinostat-induced cell death. Taken together, these findings demonstrate that p21(WAF1) regulates the early stages of drug-induced apoptosis in ALL cells and significantly modulates their sensitivity to vorinostat. PMID- 26506266 TI - Bacterial Networks in Cells and Communities. AB - Research on the bacterial regulatory networks is currently experiencing a true revival, driven by advances in methodology and by emergence of novel concepts. The biannual conference Bacterial Networks (BacNet15) held in May 2015, in Sant Feliu de Guixols, Spain, covered progress in the studies of regulatory networks that control bacterial physiology, cell biology, stress responses, metabolism, collective behavior and evolution. It demonstrated how interdisciplinary approaches that combine molecular biology and biochemistry with the latest microscopy developments, whole cell (-omics) approaches and mathematical modeling can help understand design principles relevant in microbiology. It further showed how current biotechnology and medical microbiology could profit from our knowledge of and ability to engineer regulatory networks of bacteria. PMID- 26506265 TI - Structural and functional rejuvenation of the aged brain by an approved anti asthmatic drug. AB - As human life expectancy has improved rapidly in industrialized societies, age related cognitive impairment presents an increasing challenge. Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood-brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias. PMID- 26506268 TI - Bioactivity-guided isolation of new antiproliferative compounds from Juniperus foetidissima Willd. AB - Based on a literature survey on cytotoxic medicinal plants, Juniper species were identified as interesting source of antitumor compounds. Using bioassay-guided fractionation against Caov-4 cancer cells on acetone extract of leaves and branchlets of Juniperus foetidissima led to the isolation of a new 3H-benzofuaran 2-one: 4-methyl-3-methoxy-3H-benzofuaran-2-one (1), a new sesquiterpene: 4,9(alpha)-dihydroxy-nardosin-6-en (2) and an already known labdane-type diterpene: 15-hydroxy-8(17),13(E)-labdadiene-19-carboxilic acid (3). Compounds 1 3 exhibited cytotoxic effects, with moderate cytotoxicity against the EJ-138 bladder and CAOV-4 ovary cancer cell lines. PMID- 26506269 TI - Calvin B. Ernst, MD, 1934-2015 Editor, 1991-1996. PMID- 26506270 TI - Results of the ROADSTER multicenter trial of transcarotid stenting with dynamic flow reversal. AB - OBJECTIVE: This report presents the 30-day results of the Safety and Efficacy Study for Reverse Flow Used During Carotid Artery Stenting Procedure (ROADSTER) multicenter trial and evaluates the safety and efficacy of ENROUTE Transcarotid NPS (Silk Road Medical Inc, Sunnyvale, Calif), a novel transcarotid neuroprotection system that provides direct surgical common carotid access and cerebral embolic protection via high-rate flow reversal during carotid artery stenting (CAS). METHODS: A prospective, single-arm, multicenter clinical trial was performed to evaluate the use of the ENROUTE Transcarotid NPS during CAS procedures performed in patients considered to be at high risk for complications from carotid endarterectomy. Symptomatic patients with >=50% stenosis and asymptomatic patients with >=70% stenosis were eligible to be treated with any U.S. Food and Drug Administration-approved carotid artery stent. The primary end point was the composite of all stroke, myocardial infarction (MI), and death at 30 days postprocedure as defined in the Food and Drug Administration-approved study protocol. Secondary end points included cranial nerve injury; 30-day stroke, death, stroke/death, and MI; acute device, technical, and procedural success; and access site complications. All major adverse events were adjudicated by an independent clinical events committee. RESULTS: Between November 2012 and July 2014, 208 patients were enrolled at 18 sites. Sixty-seven patients were enrolled as lead-in cases, and 141 were enrolled in the pivotal phase. In the pivotal cohort, 26% were symptomatic and 75% were asymptomatic. Acute device and technical success were 99% (140 of 141). By hierarchical analysis, the all-stroke rate in the pivotal group was 1.4% (2 of 141), stroke and death was 2.8% (4 of 141), and stroke, death and MI was 3.5% (5 of 141). One patient (0.7%) experienced postoperative hoarseness from potential Xth cranial nerve injury, which completely resolved at the 6-month follow-up visit. CONCLUSIONS: The results of the ROADSTER trial demonstrate that the use of the ENROUTE Transcarotid NPS is safe and effective at preventing stroke during CAS. The overall stroke rate of 1.4% is the lowest reported to date for any prospective, multicenter clinical trial of CAS. PMID- 26506271 TI - Invited commentary. PMID- 26506267 TI - Origins of Programmable Nucleases for Genome Engineering. AB - Genome engineering with programmable nucleases depends on cellular responses to a targeted double-strand break (DSB). The first truly targetable reagents were the zinc finger nucleases (ZFNs) showing that arbitrary DNA sequences could be addressed for cleavage by protein engineering, ushering in the breakthrough in genome manipulation. ZFNs resulted from basic research on zinc finger proteins and the FokI restriction enzyme (which revealed a bipartite structure with a separable DNA-binding domain and a non-specific cleavage domain). Studies on the mechanism of cleavage by 3-finger ZFNs established that the preferred substrates were paired binding sites, which doubled the size of the target sequence recognition from 9 to 18bp, long enough to specify a unique genomic locus in plant and mammalian cells. Soon afterwards, a ZFN-induced DSB was shown to stimulate homologous recombination in cells. Transcription activator-like effector nucleases (TALENs) that are based on bacterial TALEs fused to the FokI cleavage domain expanded this capability. The fact that ZFNs and TALENs have been used for genome modification of more than 40 different organisms and cell types attests to the success of protein engineering. The most recent technology platform for delivering a targeted DSB to cellular genomes is that of the RNA guided nucleases, which are based on the naturally occurring Type II prokaryotic CRISPR-Cas9 system. Unlike ZFNs and TALENs that use protein motifs for DNA sequence recognition, CRISPR-Cas9 depends on RNA-DNA recognition. The advantages of the CRISPR-Cas9 system-the ease of RNA design for new targets and the dependence on a single, constant Cas9 protein-have led to its wide adoption by research laboratories around the world. These technology platforms have equipped scientists with an unprecedented ability to modify cells and organisms almost at will, with wide-ranging implications across biology and medicine. However, these nucleases have also been shown to cut at off-target sites with mutagenic consequences. Therefore, issues such as efficacy, specificity and delivery are likely to drive selection of reagents for particular purposes. Human therapeutic applications of these technologies will ultimately depend on risk versus benefit analysis and informed consent. PMID- 26506272 TI - Acoustic shadowing impairs accurate characterization of stenosis in carotid ultrasound examinations. AB - OBJECTIVE: Duplex ultrasonography (DUS) has been the mainstay for diagnosing carotid artery stenosis and is often the sole diagnostic modality used prior to intervention. Highly calcified plaque, however, results in an acoustic shadow (AcS) that obscures the vessel lumen and inhibits the sonographer's ability to obtain Doppler velocity measurements. It is unknown whether DUS can accurately determine the degree of carotid stenosis in these settings. METHODS: From July 2012 to December 2013, all patients with AcS on DUS measuring >=5 mm in the longitudinal axis were cross-referenced with multidetector computed tomographic angiography (MD-CTA) images of the neck to define the study population. After standardizing the MD-CTA windows, percent stenosis was determined by cross sectional area reduction using two separate previously described methods based on North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) criteria. DUS waveform parameters in the internal carotid artery near the AcS were then compared with these MD-CTA measurements to determine the accuracy of DUS in characterizing the severity of carotid stenosis. RESULTS: During this period, 8517 DUS studies were performed at the Massachusetts General Hospital, 550 of which had AcS, for an incidence of 6.45%. There were 92 lesions with a concomitant MD-CTA; however, seven were excluded because of poor study quality, because >=6 months had elapsed between DUS and MD-CTA, or because the patient had undergone carotid reconstruction between studies. Of the 85 remaining lesions, DUS characterized 17 as severe (peak systolic velocity [PSV] >250 cm/s), 31 as moderate (PSV = 151-250 cm/s), and 37 as mild (PSV <=150 cm/s) stenoses using PSV criteria. PSV weakly correlated with CTA-NASCET (r = 0.361; P = .004) and CTA-ECST (r = 0.306; P = .004) percent stenosis. Using PSV >250 cm/s as the predictor of >70% stenosis, and a >=70% cutoff by both CTA-ECST and CTA NASCET methods as the reference measure, DUS sensitivity ranged from 22.7% to 32.5%, specificity from 89.4% to 91.1%, positive predictive value from 88.2% to 76.4%, and negative predictive value from 25% to 60.2%. A subgroup analysis of lesions identified as non-severe by DUS revealed that waveforms with lower deceleration were associated with severe stenosis on CTA. CONCLUSIONS: In the presence of AcS, DUS alone is inadequate to accurately determine the degree of carotid stenosis with sensitivity, specificity, and negative predictive values far below that needed for clinical decision-making. MD-CTA may be necessary for improved characterization of plaque in these AcS lesions. Further studies are needed to determine DUS parameters that may identify patients who should undergo further evaluation with MD-CTA to characterize the true severity of the stenosis. PMID- 26506273 TI - Saccular aneurysm and kink of the extracranial internal carotid artery secondary to fibromuscular dysplasia. PMID- 26506274 TI - Rapidly progressive calcification of the false lumen in aortic dissection. PMID- 26506275 TI - Debate: Whether branched/fenestrated endovascular aneurysm repair procedures are better than snorkels, chimneys, or periscopes in the treatment of most thoracoabdominal and juxtarenal aneurysms. AB - Vascular surgeons are an innovative group, and during the last decade, we have seen unparalleled advances in the endovascular treatment of extensive aortic pathologies. Collaborative efforts between surgeons and industry have introduced fenestrated and branched devices that are becoming more widely used, with wider regulatory approval, availability, and less need for customization. Prior to this, parallel stent approaches had been developed to fill the void where this technology was not available or for urgent cases. A separate and distinct body of evidence and expertise subsequently developed for both strategies. This debate explores where these approaches now sit in the armamentarium of vascular surgeons. PMID- 26506276 TI - Editors' commentary. PMID- 26506277 TI - The shirt off his back. PMID- 26506278 TI - Reply: To PMID 24726826. PMID- 26506279 TI - Regarding "Novel experimental model of enlarging abdominal aortic aneurysm in rabbits". PMID- 26506280 TI - Regarding "Elastase inhibitor AZD9668 treatment prevented progression of experimental abdominal aortic aneurysms". PMID- 26506281 TI - Reply. PMID- 26506282 TI - Extended-spectrum beta-lactamase (ESBL) detection directly from urine samples with the rapid isothermal amplification-based eazyplex(r) SuperBug CRE assay: Proof of concept. AB - A commercially available assay (eazyplex(r) SuperBug CRE) detecting the most common carbapenemase and ESBL types was evaluated directly on 50 urine samples. Eazyplex(r) correctly detected ESBL-encoding genes in all 30 urine samples with confirmed ESBL production (sensitivity 100%). Two specimens showed invalid and one specimen false-positive results (specificity 97.9%). PMID- 26506283 TI - Pyrazinamide resistance determined by liquid culture at low pH better correlates with genetic mutations in MDR tuberculosis isolates. AB - We detected the pyrazinamide (PZA) susceptibility of Mycobacterium tuberculosis strains in the Bactec MGIT 960 liquid medium with different pH values. Our results demonstrated that PZA resistance determined by liquid culture at pH 5.7 (94.9%) showed better correlation with genetic changes among multidrug-resistant M. tuberculosis isolates (P=0.001). PMID- 26506284 TI - The Expression of Lung Resistance Protein in Saliva: A Novel Prognostic Indicator Protein for Carcinoma of the Breast. AB - Considering that saliva is a fluid inundated with proteins, it is possible that solubilized oncogenic proteins may be present in saliva and may be useful in differentiating between healthy and diseased individuals. As a consequence, the purpose of this study was to determine if the solubilized form of LRP was present in stimulated whole saliva and could differentiate between 16 healthy women and 16 women with confirmed Stage I breast cancer. LRP levels were determined using gel electrophoresis and Western blot technology. The results showed LRP at significantly higher concentrations among breast cancer subjects as compared to healthy women. PMID- 26506285 TI - Thermal decomposition of dolomite under CO2: insights from TGA and in situ XRD analysis. AB - Thermal decomposition of dolomite in the presence of CO2 in a calcination environment is investigated by means of in situ X-ray diffraction (XRD) and thermogravimetric analysis (TGA). The in situ XRD results suggest that dolomite decomposes directly at a temperature around 700 degrees C into MgO and CaO. Immediate carbonation of nascent CaO crystals leads to the formation of calcite as an intermediate product of decomposition. Subsequently, decarbonation of this poorly crystalline calcite occurs when the reaction is thermodynamically favorable and sufficiently fast at a temperature depending on the CO2 partial pressure in the calcination atmosphere. Decarbonation of this dolomitic calcite occurs at a lower temperature than limestone decarbonation due to the relatively low crystallinity of the former. Full decomposition of dolomite leads also to a relatively low crystalline CaO, which exhibits a high reactivity as compared to limestone derived CaO. Under CO2 capture conditions in the Calcium-Looping (CaL) process, MgO grains remain inert yet favor the carbonation reactivity of dolomitic CaO especially in the solid-state diffusion controlled phase. The fundamental mechanism that drives the crystallographic transformation of dolomite in the presence of CO2 is thus responsible for its fast calcination kinetics and the high carbonation reactivity of dolomitic CaO, which makes natural dolomite a potentially advantageous alternative to limestone for CO2 capture in the CaL technology as well as SO2in situ removal in oxy-combustion fluidized bed reactors. PMID- 26506287 TI - From the Editor. PMID- 26506286 TI - Summary of Notifiable Noninfectious Conditions and Disease Outbreaks: Surveillance for Cancer Incidence and Mortality - United States, 2011. PMID- 26506288 TI - Transformation of the Urban Health Care Safety Net: The Devolution of a Public Responsibility. AB - Reduced spending in both federal and state programs and the closure of public hospitals have serious consequences for the health of urban dwellers, especially the poor and uninsured. Through a combination of economic factors, many municipalities have formed public-private partnerships and launched community initiatives to preserve some of the elements of the health care safety net. What once was a responsibility of municipal governments, the provision of health care to poor and uninsured populations, is now posing challenges for private-sector providers. This article identifies several factors that have contributed to the incremental demise of the publicly funded urban health care safety net and how local entities and the federal government are responding to the care of the poor and uninsured. PMID- 26506289 TI - Health Care Affordability: How to Make It a Reality. AB - Health care is a big business. US health care expenditures reached $2.9 trillion in 2013. Patient spending accounted for 28% of the total, which means patients spent approximately $810 billion in 2013 for insurance premiums, deductibles, copays, coinsurance, and noncovered health care services. How are patients expected to pay almost a trillion dollars in health care expenses? There is a need to find a health care financing methodology that will make health care affordable for all patients and families. An alternative method for funding health care is discussed that includes creating a government-funded annuity during the first decade of one's life. When this annuity matures later in life, many individuals will have amassed a large pot of money with which to pay for their (and their family's) health care treatment and products. PMID- 26506290 TI - Leadership Characteristics for Health Care Managers: Perspectives of Chief Executive Officers in US Hospitals. AB - A study was conducted to determine the perceptions of chief executive officers in US hospitals regarding the most important characteristics aspiring health care executives should possess. The results of this 2012 study were compared with a previous study conducted in 2007 to determine if the perceptions had changed over time. PMID- 26506291 TI - Use of Smartphones in Hospitals. AB - Mobile technology has begun to change the landscape of the medical profession, with more than two-thirds of physicians regularly using smartphones. Smartphones have allowed health care professionals and the general public to communicate more efficiently, collect data, and facilitate clinical decision making. The methodology for this study was a qualitative literature review following a systematic approach of smartphone use among physicians in hospitals. Fifty-one articles were selected for this study based on inclusion criteria. The findings were classified and described into 7 categories: use of smartphone in obstetrics, pediatrics, surgery, internal medicine, radiology, and dermatology, which were chosen based on the documented use of smartphone application in different health care practices. A last section of patient safety and issues with confidentiality is also described. This study suggests that smartphones have been playing an increasingly important role in health care. Medical professionals have become more dependent upon medical smartphone applications. However, concerns of patient safety and confidentiality will likely lead to increased oversight of mobile device use by regulatory agencies and accrediting bodies. PMID- 26506292 TI - The Concept of Advocacy in Nursing: A Critical Analysis. AB - As health care professionals practice as a team, they take on responsibilities that are specific to their roles-responsibilities that are recognized and understood by the team and management as pertaining to their professional domain and expertise. Is advocacy part of the role of the nurse? Members of the nursing profession commonly maintain that it is, but is there a consensus on this issue, both within the profession and among other stakeholders? Is there a clear understanding of the term advocacy, and is this reflected in Codes of Practice and research into practice? An examination of significant documents and reports of empirical research reveals conflicting conceptions and opinions. There is potential for a common definition, but agreements need to be reached on whether advocacy is an essential function of nursing within the management of health care, and if so, what is advocacy's importance, focus, and limits. PMID- 26506294 TI - Case in Health Care Management. PMID- 26506293 TI - Patient and Practice Characteristics: Impact on Career Satisfaction of Obstetrician-Gynecologists. AB - This study examined demographic and practice characteristics that affect the career satisfaction of obstetrician-gynecologists. Data were retrieved from the 2008 Health Tracking Physician Survey, conducted by the Center for Studying Health System Change. The survey consisted of a nationally representative sample of physicians belonging to the American Medical Association. A final sample of 290 obstetrician-gynecologists was obtained from the study. Results indicated more than 80% of obstetrician-gynecologists were either "somewhat satisfied" or "very satisfied" with their careers in medicine. Nearly 56% were older than 48 years; 59% of respondents were men and 77% were of white race. The average obstetrician-gynecologist worked 54 hours per week in medically related activities. Regression analysis showed a significant relationship between obstetrician-gynecologist career satisfaction and the following: adequate time with patients, perceived quality of care, income, work hours, and revenue from Medicaid. In addition, Hispanic patients and the presence of formal written guidelines had a positive impact on career satisfaction. It was concluded that quality care, time with patients, work hours, and income are the major predictors of obstetrician-gynecologist career satisfaction. Further research is needed to understand the relationship between patient demographics and career satisfaction. PMID- 26506295 TI - Impact of the Relocation of a Long-term Residential Care Facility on Staff. AB - This article describes the relocation of residents and staff of a long-term residential care facility into a new state-of-the-art building in a Canadian province. All staff were surveyed about their perceptions of the moving process 2 months after the move occurred using a newly created 51-item questionnaire containing both open-ended and closed questions (5-point Likert scale). The results were positive for the 3 subscales of the survey, with average scores for premove, midmove, and postmove items of 3.67, 3.94, and 3.66, respectively. There was no significant difference in the means when comparing staff position, years of employment, or assignment to 1 or more units. Staff were very positive about the move itself, the orientation provided and overall planning, and support from coworkers and management. Some concerns were raised about staffing shortages, involvement of residents, and preparedness of the units and building. In addition, it is evident that relocation is an ongoing process, with many supports required in the months after the move. This article describes a very well planned and executed relocation of a long-term residential care facility and can provide guidance and lessons learned to assist other administrators who are planning a similar endeavor. PMID- 26506296 TI - User Satisfaction With Telehealth: Study of Patients, Providers, and Coordinators. AB - The aim of this study was to examine the satisfaction with telehealth technologies of all users-patients, health care providers, and telehealth presenters. As the use of videoconferencing in health care is rapidly increasing to allow adequate and timely access to care for patients from rural areas, it is important to examine how these technologies are perceived and utilized. Three separate surveys were used to collect data: patient, provider, and telehealth coordinator. Patient surveys were collected in a paper format, while provider and coordinator surveys were done using REDCap (Research Electronic Data Capture) application. Findings indicate high satisfaction with telehealth, as well as confidence in providing care via distance. While this is encouraging for both patients and health care organizations, further studies should be done to include urban telehealth as well as other types of health care organizations utilizing videoconferencing for clinical appointments. PMID- 26506297 TI - Early Careerist Interest and Participation in Health Care Leadership Development Programs. AB - Health care organizations are increasingly embracing leadership development programs. These programs include a variety of specific activities, such as formally structured leadership development, as well as mentoring, personal development and coaching, 360-degree feedback, and job enlargement, in order to increase the leadership skills of managers and high-potential staff. However, there is a lack of information on how early careerists in health care management view these programs and the degree to which they participate. This article reports on a study undertaken to determine how early careerists working in health care organizations view leadership development programs and their participation in such programs offered by their employers. Study findings are based on a survey of 126 early careerists who are graduates of an undergraduate health services administration program. We found varying levels of interest and participation in specific leadership development activities. In addition, we found that respondents with graduate degrees and those with higher compensation were more likely to participate in selected leadership development program activities. Implications of study findings for health care organizations and early careerists in the offering of, and participation in, leadership development programs are discussed. PMID- 26506298 TI - Lower Nurse Staffing Levels Are Associated With Occurrences of Inpatient Falls at a Large Pediatric Hospital. AB - No previous research has been published regarding the relationship between nurse staffing levels and inpatient pediatric falls, and previous research in the adult population has yielded conflicting results, probably due in many instances to suboptimal study design. The objective of this study was to examine the relationship between nurse staffing levels and pediatric patient falls in a large children's hospital. A case-control study design was used to compare the nurse staffing level during the shift of patient falls to the staffing level in the same units on shifts when patient falls did not occur. Nurse staffing levels were significantly lower in units when patient falls occurred, particularly during night shift. Targeted nurse staffing interventions in high-risk units could reduce the incidence of inpatient pediatric falls. PMID- 26506299 TI - Organizational Failure in an NHS Hospital Trust: A Qualitative Study. AB - The objective was to explore the key factors associated with organizational failure in an NHS Hospital Trust. This case study adopted a qualitative design. Fifty-seven semistructured interviews and document analyses were conducted as well. Data were analyzed using a framework analysis method. A range of symptoms of organizational performance failure was identified. These relate to a financial deficit, lack of good external relationships, inability to meet core targets, a lack of clear management systems, and low staff morale. These markers had not been taken seriously by the previous senior management team. Symptoms of failure were the reflection of presence of secondary and primary causes of failure. Poor managerial leadership, poor financial control and performance management, lack of open culture, distraction by 2 large projects, and the lack of clinician engagement were perceived as internal causes of failure and the high level of policy changes within the NHS as the key external cause. The level of deprivation in the area was also thought to have had a negative impact on performance. The findings reinforce and expand on those of recent studies across the public sector. Tracking an organization's performance and early diagnosis of performance problems, focusing on performance management systems, and taking into account contextual factors are issues that should be considered. PMID- 26506300 TI - Effectiveness of Rectal Suction Biopsy in Diagnosing Hirschsprung Disease. AB - INTRODUCTION: Rectal suction biopsy (RSB) is performed on clinical and radiological suspicion of Hirschsprung disease (HD). Positive histochemical staining for acetylcholinesterase in the lamina propria mucosa and muscularis mucosa together with the absence of ganglion cells in the submucosa confirms HD. A second RSB or a full-thickness biopsy is done in case of doubt. The primary aim of the study was to evaluate the effectiveness of RSB in diagnosing HD. In addition, the results of RSB in preterm born infants were analyzed. METHODS: This retrospective study included all infants younger than 1 year who had RSB for HD suspicion from January 2004 to April 2014. All histopathological results were reviewed. Sensitivity, specificity, positive, and negative predictive values of the first RSB were calculated. RESULTS: In total, 183 patients (99 boys, mean age 11 weeks) were included. HD was diagnosed in 55 patients (30%). A second biopsy was performed in 12/55 patients (22%), which confirmed HD in 9 patients. One patient did not undergo a second biopsy, but HD was excluded based on clinical follow-up. Thus, HD was eventually excluded in 4 of the 55 patients with a positive first RSB. HD was excluded in the first biopsy in 128 patients (70%). In 19 of those (15%), a second biopsy was done, which led to the diagnosis of HD in 10 patients. Two patients with negative biopsy results were still operated on because of the high clinical suspicion for HD, and the histopathological analysis on the operative specimen confirmed HD. Thus, HD was eventually diagnosed in 12 out of 128 patients. Thus, the sensitivity of the first RSB was 81% and the specificity was 97%. The positive predictive value was 93% and the negative predictive value was 91%. A subanalysis for the 38 preterm born infants was done, with a mean conceptional age at the time of biopsy of 44 weeks (range 34-82). Sensitivity and specificity of RSB were 83 and 97%, respectively, with one false positive and one false-negative results. CONCLUSION: The overall sensitivity of the RSB was 81%, with 12 false-negative results, in which cases extra biopsies had been necessary. The specificity was 97%, with four false-positive findings. We found that RSB can also be reliably and safely performed in preterm born infants, which implies there is no reason to postpone a RSB in those infants. New methods, such as calretinin staining, must be considered to achieve better effectiveness of the RSB for diagnosing HD. PMID- 26506301 TI - Clinical Features of Congenital Cystic Lung Diseases: A Report on a Nationwide Multicenter Study in Japan. AB - AIM: The current study aimed to assess the perinatal risk of congenital cystic lung diseases (CCLD) and to establish a suitable surgical strategy in consideration of postoperative lung growth and problems during adulthood. METHODS: Among 874 CCLD patients identified in a nationwide survey, 428 patients were born between 1992 and 2012 and treated at 10 high-volume centers were retrospectively reviewed with statistical analysis. RESULTS: In the 194 patients who were prenatally diagnosed to have CCLD, 16.7% presented with fetal hydrops as observed using ultrasonography. The Apgar score (5 minutes) was lower than 5 in 5.4%. As of postnatal day 30, 14.0% of the neonatal patients required respiratory support, and 3.3% (8/243) had died because of pulmonary hypoplasia. Among those who were asymptomatic immediately after birth, 33.6% of the patients developed the respiratory infectious symptoms during their first year of life, and 22.1% did so between the age of 1 and 2 years. The postoperative percent vital capacity among the prenatally diagnosed patients was significantly higher than that among the postnatally diagnosed patients (98.3 +/- 11.9 vs. 81.7 +/- 9.7, p < 0.0222). Late complications included thoracic deformity in 30 patients and persistent lung cyst in 4 patients, whereas malignancy was not observed in the present series. CONCLUSIONS: Approximately 10 to 15% of prenatally diagnosed CCLD patients may carry a high risk of perinatal respiratory distress. Early operation before developing episodes of lung infection, seem to be associated with a better development of the reserved lung during later life. The incidence of carcinogenesis among patients with CCLD may be extremely low. PMID- 26506302 TI - Development of a Reproducible Model of Parenteral Nutrition-Associated Liver Disease in Rats. AB - PURPOSE: For patients with intestinal failure, parenteral nutrition (PN) is a life-saving therapy. Unfortunately, hepatic dysfunction will occur in 40 to 60% of children on long-term PN. While the hepatic dysfunction is likely multifactorial, one important chemical component of the disease may be aluminum contamination of the PN. Previous studies have shown a reduction in liver injury by decreasing the aluminum concentration in PN in a pig model. We sought to develop a rat model of PN-associated liver disease (PNALD) with parenteral aluminum. METHODS: Adult Sprague-Dawley rats had intravenous long-term catheters placed. The control group underwent daily injections of saline. The study rats had daily injections of either 2 or 3 mg/kg aluminum chloride (AlCl3). At the end of 4 weeks, the rats were euthanized and liver and blood samples were taken. The livers were analyzed and graded by a pathologist for histological evidence of liver degeneration and acute and chronic inflammation. The serum was analyzed for total bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). RESULTS: There was no difference in serum values of total bilirubin, alkaline phosphatase, ALT, or AST. There was no difference in acute inflammation among the groups (1 [control], 1.2 [2 mg/kg], 1.1 [3 mg/kg]). The rats treated with parenteral aluminum had significantly more Kupffer cells than the control group (0.1 [control], 3 [2 mg/kg], 2.2 [3 mg/kg], p < 0.0001 [control vs. 2 mg/kg] and 0.0032 [control vs. 3 mg/kg]). There was also more liver degeneration in the parenteral aluminum groups than the control group (1 [control], 2 [2 mg/kg], 2.5 [3 mg/kg], p = 0.0341 [control vs. 2 mg/kg] and 0.009 [control vs. 3 mg/kg]). However, there was no difference between 2 and 3 mg/kg AlCl3 for either variable. CONCLUSION: This study suggests that 4 weeks of parenteral aluminum can induce chronic inflammation and degeneration of the liver in rats. Therefore, we believe that daily injections of parenteral aluminum can produce a viable model of PNALD in rats. However, further studies are warranted, including measurement of serum aluminum levels in infants on PN. PMID- 26506303 TI - An Arresting Story about Basement Membrane Invasion. AB - In this issue of Developmental Cell, Matus et al. (2015) reveal that to invade past basement membrane, the C. elegans anchor cell must cease dividing before differentiating and expressing pro-invasion genes. This demonstration of invasion and proliferation as mutually incompatible cell states has implications for our understanding of cancer metastasis. PMID- 26506304 TI - Morpholinos: Antisense and Sensibility. AB - For over 15 years, antisense morpholino oligonucleotides (MOs) have allowed developmental biologists to make key discoveries regarding developmental mechanisms in numerous model organisms. Recently, serious concerns have been raised as to the specificity of MO effects, and it has been recommended to discontinue their usage, despite the long experience of the scientific community with the MO tool in thousands of studies. Reviewing the many advantages afforded by MOs, we conclude that adequately controlled MOs should continue to be accepted as generic loss-of-function approach, as otherwise progress in developmental biology will greatly suffer. PMID- 26506305 TI - Square Cell Packing in the Drosophila Embryo through Spatiotemporally Regulated EGF Receptor Signaling. AB - Cells display dynamic and diverse morphologies during development, but the strategies by which differentiated tissues achieve precise shapes and patterns are not well understood. Here we identify a developmental program that generates a highly ordered square cell grid in the Drosophila embryo through sequential and spatially regulated cell alignment, oriented cell division, and apicobasal cell elongation. The basic leucine zipper transcriptional regulator Cnc is necessary and sufficient to produce a square cell grid in the presence of a midline signal provided by the EGF receptor ligand Spitz. Spitz orients cell divisions through a Pins/LGN-dependent spindle-positioning mechanism and controls cell shape and alignment through a transcriptional pathway that requires the Pointed ETS domain protein. These results identify a strategy for producing ordered square cell packing configurations in epithelia and reveal a molecular mechanism by which organized tissue structure is generated through spatiotemporally regulated responses to EGF receptor activation. PMID- 26506306 TI - Invasive Cell Fate Requires G1 Cell-Cycle Arrest and Histone Deacetylase-Mediated Changes in Gene Expression. AB - Despite critical roles in development and cancer, the mechanisms that specify invasive cellular behavior are poorly understood. Through a screen of transcription factors in Caenorhabditis elegans, we identified G1 cell-cycle arrest as a precisely regulated requirement of the anchor cell (AC) invasion program. We show that the nuclear receptor nhr-67/tlx directs the AC into G1 arrest in part through regulation of the cyclin-dependent kinase inhibitor cki-1. Loss of nhr-67 resulted in non-invasive, mitotic ACs that failed to express matrix metalloproteinases or actin regulators and lack invadopodia, F-actin-rich membrane protrusions that facilitate invasion. We further show that G1 arrest is necessary for the histone deacetylase HDA-1, a key regulator of differentiation, to promote pro-invasive gene expression and invadopodia formation. Together, these results suggest that invasive cell fate requires G1 arrest and that strategies targeting both G1-arrested and actively cycling cells may be needed to halt metastatic cancer. PMID- 26506307 TI - A Temporal Window for Signal Activation Dictates the Dimensions of a Nodal Signaling Domain. AB - Morphogen signaling is critical for the growth and patterning of tissues in embryos and adults, but how morphogen signaling gradients are generated in tissues remains controversial. The morphogen Nodal was proposed to form a long range signaling gradient via a reaction-diffusion system, on the basis of differential diffusion rates of Nodal and its antagonist Lefty. Here we use a specific zebrafish Nodal biosensor combined with immunofluorescence for phosphorylated Smad2 to demonstrate that endogenous Nodal is unlikely to diffuse over a long range. Instead, short-range Nodal signaling activation in a temporal window is sufficient to determine the dimensions of the Nodal signaling domain. The size of this temporal window is set by the differentially timed production of Nodal and Lefty, which arises mainly from repression of Lefty translation by the microRNA miR-430. Thus, temporal information is transformed into spatial information to define the dimensions of the Nodal signaling domain and, consequently, to specify mesendoderm. PMID- 26506308 TI - Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton. AB - Nucleus positioning is key for intracellular organization, cell differentiation, and organ development and is affected in many diseases, including myopathies due to alteration in amphiphysin-2 (BIN1). The actin and microtubule cytoskeletons are essential for nucleus positioning, but their crosstalk in this process is sparsely characterized. Here, we report that impairment of amphiphysin/BIN1 in Caenorhabditis elegans, mammalian cells, or muscles from patients with centronuclear myopathy alters nuclear position and shape. We show that AMPH 1/BIN1 binds to nesprin and actin, as well as to the microtubule-binding protein CLIP170 in both species. Expression of the microtubule-anchoring CAP-GLY domain of CLIP170 fused to the nuclear-envelope-anchoring KASH domain of nesprin rescues nuclear positioning defects of amph-1 mutants. Amphiphysins thus play a central role in linking the nuclear envelope with the actin and microtubule cytoskeletons. We propose that BIN1 has a direct and evolutionarily conserved role in nuclear positioning, altered in myopathies. PMID- 26506309 TI - REI-1 Is a Guanine Nucleotide Exchange Factor Regulating RAB-11 Localization and Function in C. elegans Embryos. AB - The small GTPase Rab11 dynamically changes its location to regulate various cellular processes such as endocytic recycling, secretion, and cytokinesis. However, our knowledge of its upstream regulators is still limited. Here, we identify the RAB-11-interacting protein-1 (REI-1) as a unique family of guanine nucleotide exchange factors (GEFs) for RAB-11 in Caenorhabditis elegans. Although REI-1 and its human homolog SH3-binding protein 5 do not contain any known Rab GEF domains, they exhibited strong GEF activity toward Rab11 in vitro. In C. elegans, REI-1 is expressed in the germline and co-localizes with RAB-11 on the late-Golgi membranes. The loss of REI-1 specifically impaired the targeting of RAB-11 to the late-Golgi compartment and the recycling endosomes in embryos and further reduced the RAB-11 distribution to the cleavage furrow, which resulted in cytokinesis delay. These results suggest that REI-1 is a GEF specifically regulating the RAB-11 localization and functions in early embryos. PMID- 26506310 TI - Absence of Radial Spokes in Mouse Node Cilia Is Required for Rotational Movement but Confers Ultrastructural Instability as a Trade-Off. AB - Determination of left-right asymmetry in mouse embryos is established by a leftward fluid flow that is generated by clockwise rotation of node cilia. How node cilia achieve stable unidirectional rotation has remained unknown, however. Here we show that brief exposure to the microtubule-stabilizing drug paclitaxel (Taxol) induces randomly directed rotation and changes the ultrastructure of node cilia. In vivo observations and a computer simulation revealed that a regular 9+0 arrangement of doublet microtubules is essential for stable unidirectional rotation of node cilia. The 9+2 motile cilia of the airway, which manifest planar beating, are resistant to Taxol treatment. However, the airway cilia of mice lacking the radial spoke head protein Rsph4a undergo rotational movement instead of planar beating, are prone to microtubule rearrangement, and are sensitive to Taxol. Our results suggest that the absence of radial spokes allows node cilia to rotate unidirectionally but, as a trade-off, renders them ultrastructurally fragile. PMID- 26506312 TI - Advances in antitumor polysaccharides from phellinus sensu lato: Production, isolation, structure, antitumor activity, and mechanisms. AB - Edible and medicinal fungi (mushrooms) are widely applied to functional foods and nutraceutical products because of their proven nutritive and medicinal properties. Phellinus sensu lato is a well-known medicinal mushroom that has long been used in preventing ailments, including gastroenteric dysfunction, diarrhea, hemorrhage, and cancers, in oriental countries, particularly in China, Japan, and Korea. Polysaccharides represent a major class of bioactive molecules in Phellinus s. l., which have notable antitumor, immunomodulatory, and medicinal properties. Polysaccharides that were isolated from fruiting bodies, cultured mycelia, and filtrates of Phellinus s. l. have not only activated different immune responses of the host organism but have also directly suppressed tumor growth and metastasis. Studies suggest that polysaccharides from Phellinus s. l. are promising alternative anticancer agents or synergizers for existing antitumor drugs. This review summarizes the recent development of polysaccharides from Phellinus s. l., including polysaccharide production, extraction and isolation methods, chemical structure, antitumor activities, and mechanisms of action. PMID- 26506311 TI - The Chromosome Axis Mediates Feedback Control of CHK-2 to Ensure Crossover Formation in C. elegans. AB - CHK-2 kinase is a master regulator of meiosis in C. elegans. Its activity is required for homolog pairing and synapsis and for double-strand break formation, but how it drives and coordinates these pathways to ensure crossover formation remains unknown. Here we show that CHK-2 promotes pairing and synapsis by phosphorylating a family of zinc finger proteins that bind to specialized regions on each chromosome known as pairing centers, priming their recruitment of the Polo-like kinase PLK-2. This knowledge enabled the development of a phospho specific antibody as a tool to monitor CHK-2 activity. When either synapsis or crossover formation is impaired, CHK-2 activity is prolonged, and meiotic progression is delayed. We show that this common feedback circuit is mediated by interactions among a network of HORMA domain proteins within the chromosome axis and generates a graded signal. These findings reveal conserved regulatory mechanisms that ensure faithful meiotic chromosome segregation in diverse species. PMID- 26506313 TI - Menopause, symptom clusters, and the complexity of women's lives. PMID- 26506316 TI - Progress in reducing inequalities in reproductive, maternal, newborn,' and child health in Latin America and the Caribbean: an unfinished agenda. AB - OBJECTIVE: To expand the "Countdown to 2015" analyses of health inequalities beyond the 75 countries being monitored worldwide to include all countries in Latin America and the Caribbean (LAC) that have adequate data available. METHODS: Demographic and Health Surveys and Multiple Indicator Cluster Surveys were used to monitor progress in health intervention coverage and inequalities in 13 LAC countries, five of which are included in the Countdown (Bolivia, Brazil, Guatemala, Haiti, and Peru) and eight that are not (Belize, Colombia, Costa Rica, Dominican Republic, Guyana, Honduras, Nicaragua, and Suriname). The outcomes included neonatal and under-5 year mortality rates, child stunting prevalence, and the composite coverage index-a weighted average of eight indicators of coverage in reproductive, maternal, newborn, and child health. The slope index of inequality and concentration index were used to assess absolute and relative inequalities. RESULTS: The composite coverage index showed monotonic patterns over wealth quintiles, with lowest levels in the poorest quintile. Under-5 and neonatal mortality as well as stunting prevalence were highest among the poor. In most countries, intervention coverage increased, while under-5 mortality and stunting prevalence fell most rapidly among the poor, so that inequalities were reduced over time. However, Bolivia, Guatemala, Haiti, Nicaragua, and Peru still show marked inequalities. Brazil has practically eliminated inequalities in stunting. CONCLUSIONS: LAC countries presented substantial progress in terms of reducing inequalities in reproductive, maternal, newborn, and child health interventions, child mortality, and nutrition. However, the poorest 20% of the population in most countries is still lagging behind, and renewed actions are needed to improve equity. PMID- 26506314 TI - Tiotropium Respimat((r)) vs. HandiHaler((r)): real-life usage and TIOSPIR trial generalizability. AB - AIM: Two inhaler devices (Respimat(r) and HandiHaler(r)) are available for tiotropium, a long acting anticholinergic agent. We aimed to analyze drug utilization, off-label usage and generalizability of the TIOSPIR trial results for both devices. METHODS: Patients aged >=18 years exhibiting at least one documented prescription of tiotropium in the database of the Association of Statutory Health Insurance Physicians, Bavaria, Germany, were included (years 2004-2008). Annual period prevalence rates (PPRs) were calculated stratified by age, gender and inhaler devices. Off-label usage (patients lacking a chronic obstructive pulmonary disease (COPD) diagnosis) and the proportion of patients meeting the inclusion and exclusion criteria of the TIOSPIR trial were analyzed. RESULTS: Between 2004 and 2008, PPRs increased and varied between 49.2 and 74.5 per 10 000 persons for HandiHaler(r) and between 1.5 and 9.3 per 10 000 persons for Respimat(r). Small differences regarding patient characteristics existed between the two inhaler devices. Only about 30% (HandiHaler(r) 32.1%, Respimat(r) 30.0%) of the database patients receiving tiotropium could be theoretically included in the TIOSPIR trial. CONCLUSIONS: Comparing the two tiotropium devices, no clinically relevant differences regarding patient and prescribing characteristics were revealed. Results of the TIOSPIR trial were generalizable only to a minority of our study patients, underlining the need for real-life data. PMID- 26506317 TI - [Equity-oriented monitoring in the context of universal health coverage]. AB - Monitoring inequalities in health is fundamental to the equitable and progressive realization of universal health coverage (UHC). A successful approach to global inequality monitoring must be intuitive enough for widespread adoption, yet maintain technical credibility. This article discusses methodological considerations for equity-oriented monitoring of UHC, and proposes recommendations for monitoring and target setting. Inequality is multidimensional, such that the extent of inequality may vary considerably across different dimensions such as economic status, education, sex, and urban/rural residence. Hence, global monitoring should include complementary dimensions of inequality (such as economic status and urban/rural residence) as well as sex. For a given dimension of inequality, subgroups for monitoring must be formulated taking into consideration applicability of the criteria across countries and subgroup heterogeneity. For economic-related inequality, we recommend forming subgroups as quintiles, and for urban/rural inequality we recommend a binary categorization. Inequality spans populations, thus appropriate approaches to monitoring should be based on comparisons between two subgroups (gap approach) or across multiple subgroups (whole spectrum approach). When measuring inequality absolute and relative measures should be reported together, along with disaggregated data; inequality should be reported alongside the national average. We recommend targets based on proportional reductions in absolute inequality across populations. Building capacity for health inequality monitoring is timely, relevant, and important. The development of high-quality health information systems, including data collection, analysis, interpretation, and reporting practices that are linked to review and evaluation cycles across health systems, will enable effective global and national health inequality monitoring. These actions will support equity-oriented progressive realization of UHC. PMID- 26506318 TI - Determinants of tuberculosis in Brazil: from conceptual framework to practical application. AB - OBJECTIVE: To leverage a conceptual analytical model for TB determination to identify factors that influence emergence of new cases of tuberculosis (TB) and poor TB treatment outcomes in Brazil. METHODS: This was a cross-sectional study based on data from Brazil's Notifiable Disease Surveillance System database (SINAN). It included all confirmed, incident TB cases reported in Brazil in 2007 2011: a total of 432 958 TB cases, of which 318 465 cases with complete data on treatment outcomes were included. Analysis to explain the causal network that influences TB treatment outcomes was based on a theoretical model for determining TB. Adjusted analyses were used to assess the model fit. Hierarchical logistic regression was used to model the dichotomous TB outcome; hierarchical polytomous regression was used for multinomial TB outcome. RESULTS: Of the 318 465 TB cases included, 222 186 (69.8%) were classified as "cured" and 96 279 (30.2%) as "treatment failure." Among the latter, 37 604 (11.8%) abandoned treatment; 13 193 (4.1%) died due to TB; 15 440 (4.8%) died due to causes other than TB; 28 848 (9.1%) were transferred to another municipality; and 1 194 (0.4%) developed multidrug-resistant TB. The dichotomous models were more likely to show spurious associations when compared with the polytomous model. In the polytomous model, individuals assigned to Directly Observed Treatment Short-course were more likely to be cured than others. CONCLUSIONS: Theoretical models are dynamic structures that need ongoing re-evaluation according to new findings; therefore, this is not a definitive proposal for a TB determination model or analysis plan, but rather a proposal that, at present, is adequate in Brazil and has the potential to be extrapolated or adapted to other areas. PMID- 26506319 TI - Validity of the Mexican version of the combined Foot Care Confidence / Foot-Care Behavior scale for diabetes. AB - OBJECTIVE: To 1) translate / transculturally adapt the original (English language) combined Foot Care Confidence Scale / Foot-Care Behavior instrument (FCCS-FCB) to produce a Mexican-Spanish version and 2) determine its validity and reliability in a population with diabetes in Tijuana, Mexico. METHODS: The original FCCS-FCB was translated (and back-translated), the content validated (by a group of health professional experts), and the instrument applied to 304 patients 23-78 years old in diabetes support groups in Tijuana, Mexico. Internal consistency for the study constructs ("self-efficacy," and risk / preventive foot self-care behaviors) was measured using Cronbach's alpha. The constructs were validated using principal component factor analysis. RESULTS: The Cronbach's alpha values for internal consistency were 0.782 for self-efficacy and 0.505 for behaviors. Based on the analysis, two factors explained 49.1% of the total variance for self-efficacy, and six factors explained 57.7% of the total variance for behaviors. The results were consistent with those for the original (English) version of the FCCS-FCB. CONCLUSIONS: The Mexican version of the FCCS-FCB is a reliable and valid instrument recommended for use with Mexican-Spanish-speaking patients with diabetes. PMID- 26506320 TI - [Environmental conditions and prevalence of parasitic infection in Xukuru-Kariri indigenous people, Caldas, Brazil]. AB - OBJECTIVE: To describe the environmental conditions and the parasitic infection status of Xukuru-Kariri individuals living in the municipality of Caldas, state of Minas Gerais, Brazil. METHODS: A cross-sectional study was carried out in March 2009. Sociodemographic and environmental data were collected through interviews. Water and fecal samples were collected for determination of environmental contamination and parasitic infection status. RESULTS: The Xukuru Kariri population living in Caldas included 86 people divided into 22 families. Of 22 heads of household, 81.8% had low schooling (not higher than elementary education). Of 26 water samples collected for microbiological analysis, 77.0% were positive for total coliforms and 4.0% for Escherichia coli. Residents of 27.3% of households defecated in the open. Trash was scattered in the yard of 54.5% of households. Fecal samples were collected from 60 individuals, with parasitic infection in 66.6%. The following prevalence rates were recorded: Entamoeba histolytica/dispar, 6.7%; Entamoeba coli, 60.0%; Endolimax nana, 1.8%; and Giardia duodenalis, 6.6%. CONCLUSIONS: The people included in this study faced environmental characteristics that contributed to their health vulnerability. Health actions as well as the implementation of public policies to provide sanitation, with quality water and adequate collection and treatment of human and household waste, are essential to prevent environmental degradation and improve the quality of life of these individuals. PMID- 26506321 TI - [Health and nutrition of indigenous and nonindigenous children in the Peruvian Amazon]. AB - PURPOSE: Evaluate the nutritional status of indigenous and nonindigenous children under 5 in two provinces in the Peruvian Amazon. METHODS: . Descriptive cross sectional representative study of families with children under 5 in the provinces of Bagua and Condorcanqui in Peru. The study consisted of an interview with the child's or children's mother or caregiver, anthropometric assessment, capillary hemoglobin measurement, screening for intestinal parasites in children under 5, access to health services, history of acute respiratory infections and acute diarrheal diseases, socioeconomic status, and intake of inadequately iodized salt. Using generalized linear methods, the determinants of chronic malnutrition and anemia in children were identified in each study population. RESULTS: . A total of 986 families and 1 372 children were assessed. The prevalence of chronic malnutrition was higher in the indigenous population than in the nonindigenous population (56.2% versus 21.9%); likewise for anemia (51.3% versus 40.9%). The determinants of chronic malnutrition in the two populations differed. In the indigenous population, the main determinants were an age of more than 36 months (OR 2.21; CI95% 1.61-3.04) and substandard housing (OR 2.9; CI95% 1.19-7.11), while in the non-indigenous population, they were extreme poverty (OR 2.31; IC95% 1.50-3.55) and institutional birth (OR 3.1; IC95% 2.00-4.83). CONCLUSIONS: There are marked gaps between the indigenous population and the nonindigenous population in terms of living conditions, access to health services, and the nutritional status of children under 5. Particular attention should be paid to the indigenous population to improve the way state programs and services are delivered in these contexts. PMID- 26506322 TI - [The impact of non-thrombolytic management of acute ischemic stroke in older individuals: the experience of the Federal District, Brazil]. AB - OBJECTIVE: To analyze the impact of a non-specific, decentralized treatment protocol for ischemic stroke in older individuals on the quality of the care provided in the public health care system (SUS, Sistema Unico de Saude) in the Federal District. METHOD: This retrospective historical control study employed data from the SUS Hospital Information System (SIH/SUS). Two time periods were compared: before and after the adoption of a protocol based on non-specific measures (medical therapy without alteplase) and decentralized care. A set of 2 369 admissions of patients older than 60 years with ischemic stroke was analyzed for the period of 2006/2007, and 5 207 admissions for 2010/2011. The variables were frequency, length of stay, mortality, lethality of ischemic stroke, intensive care unit (ICU) admission, and hospital reimbursement for ischemic stroke admissions. Effectiveness was evaluated based on mortality and lethality rates and efficiency was evaluated based on length of stay, use of ICU, and reimbursed amounts. RESULTS: In the second time period, there was an increase of 119.8% in the number of ischemic stroke admissions (P = 0.0001), increase of 27.3% in absolute mortality, decrease of 5.0% in lethality rate (P = 0.02), and increase of 130.6% in ICU utilization rate (P = 0.0001). There was no difference between the periods regarding mean number of inpatient days and reimbursed amounts. CONCLUSIONS: The indicators used in the present study showed improved effectiveness of acute ischemic stroke treatment with the use of a non-specific, decentralized protocol. However, no impact was observed on efficiency. PMID- 26506323 TI - National nursing strategies in seven countries of the Region of the Americas: issues and impact. AB - OBJECTIVE: To identify and examine the current national nursing strategies and policy impact of workforce development regarding human resources for health in seven selected countries in the Region of the Americas: Argentina, Canada, Costa Rica, Jamaica, Mexico, Peru, and the United States. METHODS: A review of available literature was conducted to identify publicly-available documents that describe the general backdrop of nursing human resources in these seven countries. A keyword search of PubMed was supplemented by searches of websites maintained by Ministries of Health and nursing organizations. Inclusion criteria limited documents to those published in 2008-2013 that discussed or assessed situational issues and/or progress surrounding the nursing workforce. RESULTS: Nursing human resources for health is progressing. Canada, Mexico, and the United States have stronger nursing leadership in place and multisectoral policies in workforce development. Jamaica shows efforts among the Caribbean countries to promote collaborative practices in research. The three selected countries in Central and South America championed networks to revive nursing education. Yet, overall challenges limit the opportunities to impact public health. CONCLUSIONS: The national nursing strategies prioritized multisectoral collaboration, professional competencies, and standardized educational systems, with some countries underscoring the need to align policies with efforts to promote nursing leadership, and others, focusing on expanding the scope of practice to improve health care delivery. While each country wrestles with its specific context, all require proper leadership, multisectoral collaboration, and appropriate resources to educate, train, and empower nurses to be at the forefront. PMID- 26506324 TI - Systematic review of studies evaluating urinary iodine concentration as a predictor of 24-hour urinary iodine excretion for estimating population iodine intake. AB - OBJECTIVE: To examine the usefulness of "spot" urine iodine concentrations (UICs) in predicting 24-hour urine iodine excretion (UIE) for estimating average population iodine intake. METHODS: An electronic literature search was conducted for articles published through 19 May 2013 in MEDLINE (from 1950), EMBASE (from 1980), and the Cochrane Library (from 1993) using the terms "urinary excretion (timed or spot or random) and (24 h or 24 hour), iodine (iodine deficiency), iodine (intake)," and "urine (timed, spot, random, 24-hour)." Full-text articles about studies that examined > 40 healthy human subjects and measured UIE using the 24-hour urine collection method and UIC and/or UIE using one alternative method (spot (random), timed, and "overnight" (first morning urine), fasting or not fasting) were selected and reviewed. RESULTS: The review included data from 1 434 participants across the six studies that met the inclusion criteria. The main statistical methods for comparing data from the 24-hour urine collections with the values obtained from the alternative method(s) were either regression (beta) or correlation (r) coefficients and concordance analysis through Bland-Altman plots. The urine samples collected using the alternative methods were subject to greater intra-individual and inter-individual variability than the 24-hour urine collections. There was a wide range in coefficient values for the comparisons between 24-hour URE measured in 24-hour urine collection and 24-hour UIE estimated using the alternative sampling methods. No alternative sampling method (spot, timed, or "overnight") was appropriate for estimating 24-hour UIE. CONCLUSIONS: The results of this systematic review suggest current data on UICs as a means of predicting 24-hour UIE for estimating population sodium intake are inadequate and highlight the need for further methodological investigations. PMID- 26506325 TI - Disseminating cardiovascular disease risk assessment with a PAHO mobile app: a public eHealth intervention. AB - Cardiovascular diseases are the leading cause of death in the Region of the Americas, making cardiovascular risk assessment a critical component of the clinical decision-making process. This process is facilitated by the use of appropriate tools. This article presents the technical characteristics of an application (app) developed by the Pan American Health Organization/World Health Organization (PAHO/WHO) for mobile devices and computers. Called the Cardiovascular Risk Calculator, it is based on WHO risk tables and applied to the countries of the Region. The article details the epidemiological basis of the diagram for predicting cardiovascular risk and describes the app and its four modules, its main audiences, its production process, and finally, the initial results and some of the challenges. Four months after its launch, the application was being used daily by more than 12 000 users and had been downloaded in virtually all the countries of the Region. The app can be used in by physicians, nurses, and other technical personnel in their daily practice, especially at the primary care level. Since it can also be used by the general public, special attention was paid to its design and tutorial and to ensuring that the clinical estimates and recommendations were easy to understand. This type of app facilitates communication between health care providers and users, and its systematic use in the health services, especially in primary care services, should be promoted. PMID- 26506326 TI - [Not Available]. PMID- 26506327 TI - [Not Available]. PMID- 26506328 TI - Synthesis, Molecular Structure, Metabolic Stability and QSAR Studies of a Novel Series of Anticancer N-Acylbenzenesulfonamides. AB - A series of novel N-acyl-4-chloro-5-methyl-2-(R1-methylthio)benzenesulfonamides 18-47 have been synthesized by the reaction of N-[4-chloro-5-methyl-2-(R1 methylthio) benzenesulfonyl]cyanamide potassium salts with appropriate carboxylic acids. Some of them showed anticancer activity toward the human cancer cell lines MCF-7, HCT-116 and HeLa, with the growth percentages (GPs) in the range from 7% to 46%. Quantitative structure-activity relationship (QSAR) studies on the cytotoxic activity of N-acylsulfonamides toward MCF-7, HCT-116 and HeLa were performed by using topological, ring and charge descriptors based on the stepwise multiple linear regression technique (MLR). The QSAR studies revealed three predictive and statistically significant models for the investigated compounds. The results obtained with these models indicated that the anticancer activity of N-acylsulfonamides depends on topological distances, number of ring system, maximum positive charge and number of atom-centered fragments. The metabolic stability of the selected compounds had been evaluated on pooled human liver microsomes and NADPH, both R1 and R2 substituents of the N-acylsulfonamides simultaneously affected them. PMID- 26506329 TI - Olefin Metathesis Reaction in Water and in Air Improved by Supramolecular Additives. AB - A range of water-immiscible commercially available Grubbs-type precatalysts can be used in ring-closing olefin metathesis reaction in high yields. The synthetic transformation is possible in pure water under ambient conditions. Sulfocalixarenes can help to boost the reactivity of the metathesis reaction by catalyst activation, improved mass transfer, and solubility of reactants in the aqueous reaction media. Additionally, the use of supramolecular additives allows lower catalyst loadings, but still high activity in pure water under aerobic conditions. PMID- 26506330 TI - Six-Membered Aromatic Polyazides: Synthesis and Application. AB - Aromatic polyazides are widely used as starting materials in organic synthesis and photochemical studies, as well as photoresists in microelectronics and as cross-linking agents in polymer chemistry. Some aromatic polyazides possess high antitumor activity, while many others are of considerable interest as high-energy materials and precursors of high-spin nitrenes and C3N4 carbon nitride nanomaterials. The use of aromatic polyazides in click-reactions may be a new promising direction in the design of various supramolecular systems possessing interesting chemical, physical and biological properties. This review is devoted to the synthesis, properties and applications of six-membered aromatic compounds containing three and more azido groups in the ring. PMID- 26506331 TI - Iridoids and Flavonoids of Four Siberian Gentians: Chemical Profile and Gastric Stimulatory Effect. AB - Some Gentiana species have been used by the nomadic people of Siberia as bitter teas or appetizers to eliminate digestive disorders (dyspepsia, heartburn, nausea, etc.). We studied the most frequently used gentians: Gentiana algida, G. decumbens, G. macrophylla and G. triflora. The aim of the present study was to evaluate the phytochemical features and gastrostimulatnt activity of these four gentian herbs. Five iridoids, seven flavones and mangiferin were detected in gentian herbs after analysis by microcolumn-RP-HPLC-UV-ESI-MS. A componential phytochemical profile of the G. decumbens herb is presented for the first time, as well as information about distinct phytochemicals found in gentian herbs. HPLC quantification of the specific compounds of gentian herbs demonstrated the high content of iridoids (24.73-73.53 mg/g) and flavonoids (12.92-78.14 mg/g). The results of biological activity evaluation of four gentian decoctions demonstrated their good ability to stimulate acid-, enzyme- and mucin-forming functions of the stomach attributed to mostly by iridoids and flavonoids. In general, it can be claimed that the gentian decoctions can be used as effective and safe appetizers and are also a good source of biologically active agents. PMID- 26506332 TI - Enhanced Visible Light Photocatalytic Activity of Br-Doped Bismuth Oxide Formate Nanosheets. AB - A facile method was developed to enhance the visible light photocatalytic activity of bismuth oxide formate (BiOCOOH) nanosheets via Br-doping. The as prepared samples were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, the Brunauer-Emmett-Teller surface area, UV-vis diffuse reflectance spectroscopy, photoluminescence spectra, and N2 adsorption-desorption isotherms measurement. The Br- ions replaced the COOH- ions in the layers of BiOCOOH, result in a decreased layer distance. The photocatalytic activity of the as-prepared materials was evaluated by removal of NO in qir at ppb level. The results showed that the Br-doped BiOCOOH nanosheets showed enhanced visible light photocatalytic activtiy with a NO removal of 37.8%. The enhanced activity can be ascribed to the increased visible light absorption and the promoted charge separation. PMID- 26506333 TI - Greener Selective Cycloalkane Oxidations with Hydrogen Peroxide Catalyzed by Copper-5-(4-pyridyl)tetrazolate Metal-Organic Frameworks. AB - Microwave assisted synthesis of the Cu(I) compound [Cu(u4-4-ptz)]n [1, 4-ptz=5-(4 pyridyl)tetrazolate] has been performed by employing a relatively easy method and within a shorter period of time compared to its sister compounds. The syntheses of the Cu(II) compounds [Cu3(u3-4-ptz)4(u2-N3)2(DMF)2]n?(DMF)2n (2) and [Cu(u2-4 ptz)2(H2O)2]n (3) using a similar method were reported previously by us. MOFs 1-3 revealed high catalytic activity toward oxidation of cyclic alkanes (cyclopentane, -hexane and -octane) with aqueous hydrogen peroxide, under very mild conditions (at room temperature), without any added solvent or additive. The most efficient system (2/H2O2) showed, for the oxidation of cyclohexane, a turnover number (TON) of 396 (TOF of 40 h(-1)), with an overall product yield (cyclohexanol and cyclohexanone) of 40% relative to the substrate. Moreover, the heterogeneous catalytic systems 1-3 allowed an easy catalyst recovery and reuse, at least for four consecutive cycles, maintaining ca. 90% of the initial high activity and concomitant high selectivity. PMID- 26506334 TI - gamma-Alumina Nanoparticle Catalyzed Efficient Synthesis of Highly Substituted Imidazoles. AB - gamma-Alumina nano particle catalyzed multi component reaction of benzil, arylaldehyde and aryl amines afforded the highly substituted 1,2,4,5-tetraaryl imidazoles with good to excellent yield in less reaction time under the sonication as well as the conventional methods. Convenient operational simplicity, mild conditions and the reusability of catalyst were the other advantages of this developed protocol. PMID- 26506335 TI - A Self-Adaptive Steered Molecular Dynamics Method Based on Minimization of Stretching Force Reveals the Binding Affinity of Protein-Ligand Complexes. AB - Binding affinity prediction of protein-ligand complexes has attracted widespread interest. In this study, a self-adaptive steered molecular dynamics (SMD) method is proposed to reveal the binding affinity of protein-ligand complexes. The SMD method is executed through adjusting pulling direction to find an optimum trajectory of ligand dissociation, which is realized by minimizing the stretching force automatically. The SMD method is then used to simulate the dissociations of 19 common protein-ligand complexes which are derived from two homology families, and the binding free energy values are gained through experimental techniques. Results show that the proposed SMD method follows a different dissociation pathway with lower a rupture force and energy barrier when compared with the conventional SMD method, and further analysis indicates the rupture forces of the complexes in the same protein family correlate well with their binding free energy, which reveals the possibility of using the proposed SMD method to identify the active ligand. PMID- 26506336 TI - Cytotoxicity of Triterpenes from Green Walnut Husks of Juglans mandshurica Maxim in HepG-2 Cancer Cells. AB - Among the classes of identified natural products, triterpenoids, one of the largest families, have been studied extensively for their diverse structures and variety of biological activities, including antitumor effects. In the present study, a phytochemical study of the green walnut husks of Juglans mandshurica Maxim led to the isolation of a new dammarane triterpene, 12beta, 20(R), 24(R) trihydroxydammar-25-en-3-one (6), together with sixteen known compounds, chiefly from chloroform and ethyl acetate extracts. According to their structural characteristics, these compounds were divided into dammarane-type, oleanane- and ursane-type. Dammarane-type triterpenoids were isolated for the first time from the Juglans genus. As part of our continuing search for biologically active compounds from this plant, all of these compounds were also evaluated for their cytotoxic activities against the growth of human cancer cells lines HepG-2 by the MTT assay. The results were shown that 20(S)-protopanaxadiol, 2alpha,3beta,23 trihydroxyolean-12-en-28-oic acid and 2alpha,3beta,23-trihydroxyurs-12-en-28-oic acid exhibited better cytotoxicity in vitro with IC50 values of 10.32+/-1.13, 16.13+/-3.83, 15.97+/-2.47 MUM, respectively. Preliminary structure-activity relationships for these compounds were discussed. PMID- 26506337 TI - Novel 2-Thioxanthine and Dipyrimidopyridine Derivatives: Synthesis and Antimicrobial Activity. AB - Several fused imidazolopyrimidines were synthesized starting from 6-amino-1 methyl-2-thiouracil (1) followed by nitrosation, reduction and condensation with different aromatic aldehydes to give Schiff's base. The dehydrocyclization of Schiff's bases using iodine/DMF gave Compounds 5a-g. The methylation of 5a-g using a simple alkylating agent as dimethyl sulfate ((CH3)2SO4) gave either monoalkylated imidazolopyrimidine 6a-g at room temperature or dialkylated derivatives 7a-g on heating 6a-g with ((CH3)2SO4). On the other hand, treatment of 1 with different aromatic aldehydes in absolute ethanol in the presence of conc. hydrochloric acid at room temperature and/or reflux with acetic acid afforded bis-5,5-diuracylmethylene 8a-e, which cyclized on heating with a mixture of acetic acid/HCl (1:1) to give 9a-e. Compounds 9a-e can be obtained directly by refluxing of Compound 1 with a mixture of acetic acid/HCl. The synthesized new compounds were screened for antimicrobial activity, and the MIC was measured. PMID- 26506338 TI - Antimycobacterial Activities of Endolysins Derived From a Mycobacteriophage, BTCU 1. AB - The high incidence of Mycobacterium infection, notably multidrug-resistant M. tuberculosis infection, has become a significant public health concern worldwide. In this study, we isolate and analyze a mycobacteriophage, BTCU-1, and a foundational study was performed to evaluate the antimycobacterial activity of BTCU-1 and its cloned lytic endolysins. Using Mycobacterium smegmatis as host, a mycobacteriophage, BTCU-1, was isolated from soil in eastern Taiwan. The electron microscopy images revealed that BTCU-1 displayed morphology resembling the Siphoviridae family. In the genome of BTCU-1, two putative lytic genes, BTCU 1_ORF7 and BTCU-1_ORF8 (termed lysA and lysB, respectively), were identified, and further subcloned and expressed in Escherichia coli. When applied exogenously, both LysA and LysB were active against M. smegmatis tested. Scanning electron microscopy revealed that LysA and LysB caused a remarkable modification of the cell shape of M. smegmatis. Intracellular bactericidal activity assay showed that treatment of M. smegmatis-infected RAW 264.7 macrophages with LysA or LysB resulted in a significant reduction in the number of viable intracellular bacilli. These results indicate that the endolysins derived from BTCU-1 have antimycobacterial activity, and suggest that they are good candidates for therapeutic/disinfectant agents to control mycobacterial infections. PMID- 26506339 TI - Abnormal Paraplegin Expression in Swollen Neurites, tau- and alpha-Synuclein Pathology in a Case of Hereditary Spastic Paraplegia SPG7 with an Ala510Val Mutation. AB - Mutations in the SPG7 gene are the most frequent cause of autosomal recessive hereditary spastic paraplegias and spastic ataxias. Ala510Val is the most common SPG7 mutation, with a frequency of up to 1% in the general population. Here we report the clinical, genetic, and neuropathological findings in a homozygous Ala510Val SPG7 case with spastic ataxia. Neuron loss with associated gliosis was found in the inferior olivary nucleus, the dentate nucleus of the cerebellum, the substantia nigra and the basal nucleus of Meynert. Neurofilament and/or paraplegin accumulation was observed in swollen neurites in the cerebellar and cerebral cortex. This case also showed subcortical tau-pathology in an unique distribution pattern largely restricted to the brainstem. alpha-synuclein containing Lewy bodies (LBs) were observed in the brainstem and the cortex, compatible with a limbic pattern of Braak LB-Disease stage 4. Taken together, this case shows that the spectrum of pathologies in SPG7 can include neuron loss of the dentate nucleus and the inferior olivary nucleus as well as neuritic pathology. The progressive supranuclear palsy-like brainstem predominant pattern of tau pathology and alpha-synuclein containing Lewy bodies in our SPG7 cases may be either coincidental or related to SPG7 in addition to neuron loss and neuritic pathology. PMID- 26506340 TI - Intra-Genomic Internal Transcribed Spacer Region Sequence Heterogeneity and Molecular Diagnosis in Clinical Microbiology. AB - Internal transcribed spacer region (ITS) sequencing is the most extensively used technology for accurate molecular identification of fungal pathogens in clinical microbiology laboratories. Intra-genomic ITS sequence heterogeneity, which makes fungal identification based on direct sequencing of PCR products difficult, has rarely been reported in pathogenic fungi. During the process of performing ITS sequencing on 71 yeast strains isolated from various clinical specimens, direct sequencing of the PCR products showed ambiguous sequences in six of them. After cloning the PCR products into plasmids for sequencing, interpretable sequencing electropherograms could be obtained. For each of the six isolates, 10-49 clones were selected for sequencing and two to seven intra-genomic ITS copies were detected. The identities of these six isolates were confirmed to be Candida glabrata (n=2), Pichia (Candida) norvegensis (n=2), Candida tropicalis (n=1) and Saccharomyces cerevisiae (n=1). Multiple sequence alignment revealed that one to four intra-genomic ITS polymorphic sites were present in the six isolates, and all these polymorphic sites were located in the ITS1 and/or ITS2 regions. We report and describe the first evidence of intra-genomic ITS sequence heterogeneity in four different pathogenic yeasts, which occurred exclusively in the ITS1 and ITS2 spacer regions for the six isolates in this study. PMID- 26506341 TI - Cloning, Expression, and Characterization of a Thermophilic Endoglucanase, AcCel12B from Acidothermus cellulolyticus 11B. AB - The gene ABK52392 from the thermophilic bacterium Acidothermus cellulolyticus 11B was predicted to be endoglucanase and classified into glycoside hydrolase family 12. ABK52392 encodes a protein containing a catalytic domain and a carbohydrate binding module. ABK52392 was cloned and functionally expressed in Escherichia coli. After purification by Ni-NTA agarose affinity chromatography and Q Sepharose(r) Fast Flow chromatography, the properties of the recombinant protein (AcCel12B) were characterized. AcCel12B exhibited optimal activity at pH 4.5 and 75 degrees C. The half-lives of AcCel12B at 60 and 70 degrees C were about 90 and 2 h, respectively, under acidic conditions. The specific hydrolytic activities of AcCel12B at 70 degrees C and pH 4.5 for sodium carboxymethylcellulose (CMC) and regenerated amorphous cellulose (RAC) were 118.3 and 104.0 U.mg(-1), respectively. The Km and Vmax of AcCel12B for CMC were 25.47 mg.mL(-1) and 131.75 U.mg(-1), respectively. The time course of hydrolysis for RAC was investigated by measuring reducing ends in the soluble and insoluble phases. The total hydrolysis rate rapidly decreased after the early stage of incubation and the generation of insoluble reducing ends decreased earlier than that of soluble reducing ends. High thermostability of the cellulase indicates its potential commercial significance and it could be exploited for industrial application in the future. PMID- 26506342 TI - Silkworm Thorn Stem Extract Targets RSK2 and Suppresses Solar UV-Induced Cyclooxygenase-2 Expression. AB - Excessive exposure to solar UV (sUV) is associated with numerous human skin disorders, such as carcinogenesis, skin photoaging and skin inflammation. Silkworm Thorn (Cudraniatricuspidata, SW) is a plant belonging to the Moraceae family and widely present throughout Korea, China, and Japan. Most parts of the tree (including the fruit, leaf, stem, root, and bark) is consumable as a functional food or tea. In this study, we found that SW extract (SWE) inhibited the elevated expression of sUV-induced cyclooxygenase (COX)-2 levels in both HaCaT and JB6 cells. Levels of nuclear factor-kappaB and activator protein-1, two crucial transcription factors involved in COX-2 expression, were elevated by sUV treatment. Treatment with SWE abolished this activation. SWE also inhibited sUV induced histone H3 phosphorylation. However, sUV-induced phosphorylation of Akt, c-Jun N-terminal kinase and p38 kinase remained unchanged in the presence of SWE. SWE inhibited RSK2 activity, and pull-down assays using SWE-Sepharose beads revealed that SWE binds directly with RSK2 in an ATP-competitive manner. These results suggest a potential for SWE to be developed as a cosmeceutical material and functional food constituent for the promotion of skin health. PMID- 26506343 TI - The Safety and Anti-Tumor Effects of Ozonated Water in Vivo. AB - Ozonated water is easier to handle than ozone gas. However, there have been no previous reports on the biological effects of ozonated water. We conducted a study on the safety of ozonated water and its anti-tumor effects using a tumor bearing mouse model and normal controls. Local administration of ozonated water (208 mM) was not associated with any detrimental effects in normal tissues. On the other hand, local administration of ozonated water (20.8, 41.6, 104, or 208 mM) directly into the tumor tissue induced necrosis and inhibited proliferation of tumor cells. There was no significant difference in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL)-positive cells following administration of ozonated water. The size of the necrotic areas was dependent on the concentration of ozonated water. These results indicate that ozonated water does not affect normal tissue and damages only the tumor tissue by selectively inducing necrosis. There is a possibility that it exerts through the production of reaction oxygen species (ROS). In addition, the induction of necrosis rather than apoptosis is very useful in tumor immunity. Based on these results, we believe that administration of ozonated water is a safe and potentially simple adjunct or alternative to existing antineoplastic treatments. PMID- 26506344 TI - Comparative Proteomic Analysis of Gossypium thurberi in Response to Verticillium dahliae Inoculation. AB - Verticillium wilt is threatening cotton productivity globally. This disease is caused by soil-borne Verticillium dahliae which directly infects cotton roots, and exclusively colonizes and occludes xylem vessels, finally resulting in necrosis, defoliation, and most severely, plant death. For the first time, iTRAQ (isobaric tags for relative and absolute quantification) was applied to screen the differentially expressed proteins of Gossypium thurberi inoculated with V. dahliae. A total of 6533 proteins were identified from the roots of G. thurberi after inoculation with V. dahliae, and 396 showed up- and 279 down-regulated in comparison to a mock-inoculated roots. Of these identified proteins, the main functional groups were those involved in cell wall organization and reinforcement, disease-resistant chemicals of secondary metabolism, phytohormone signaling, pathogenesis-related proteins, and disease-resistant proteins. Physiological and biochemical analysis showed that peroxidase activity, which promotes the biosynthesis and accumulation of lignin, was induced early in the hypocotyl after inoculation with V. dahliae. Similarly, salicylic acid also accumulated significantly in hypocotyl of the seedlings after inoculation. These findings provide an important knowledge of the molecular events and regulatory networks occurring during G. thurberi-V. dahliae interaction, which may provide a foundation for breeding disease-resistance in cotton. PMID- 26506345 TI - Detection and Identification of Probiotic Lactobacillus plantarum Strains by Multiplex PCR Using RAPD-Derived Primers. AB - Lactobacillus plantarum 2035 and Lactobacillus plantarum ACA-DC 2640 are two lactic acid bacteria (LAB) strains that have been isolated from Feta cheese. Both display significant potential for the production of novel probiotic food products. The aim of the present study was the development of an accurate and efficient method for the molecular detection and identification of the above strains in a single reaction. A multiplex PCR assay was designed for each strain, based on specific primers derived from Random Amplified Polymorphic DNA (RAPD) Sequenced Characterized Amplified Region (SCAR) analysis. The specificity of the assay was tested with a total of 23 different LAB strains, for L. plantarum 2035 and L. plantarum ACA-DC 2640. The multiplex PCR assay was also successfully applied for the detection of the above cultures in yogurt samples prepared in our lab. The proposed methodology may be applied for monitoring the presence of these strains in food products, thus evaluating their probiotic character. Moreover, our strategy may be adapted for other novel LAB strains with probiotic potential, thus providing a powerful tool for molecular discrimination that could be invaluable to the food industry. PMID- 26506347 TI - An enhanced data visualization method for diesel engine malfunction classification using multi-sensor signals. AB - The various multi-sensor signal features from a diesel engine constitute a complex high-dimensional dataset. The non-linear dimensionality reduction method, t-distributed stochastic neighbor embedding (t-SNE), provides an effective way to implement data visualization for complex high-dimensional data. However, irrelevant features can deteriorate the performance of data visualization, and thus, should be eliminated a priori. This paper proposes a feature subset score based t-SNE (FSS-t-SNE) data visualization method to deal with the high dimensional data that are collected from multi-sensor signals. In this method, the optimal feature subset is constructed by a feature subset score criterion. Then the high-dimensional data are visualized in 2-dimension space. According to the UCI dataset test, FSS-t-SNE can effectively improve the classification accuracy. An experiment was performed with a large power marine diesel engine to validate the proposed method for diesel engine malfunction classification. Multi sensor signals were collected by a cylinder vibration sensor and a cylinder pressure sensor. Compared with other conventional data visualization methods, the proposed method shows good visualization performance and high classification accuracy in multi-malfunction classification of a diesel engine. PMID- 26506348 TI - A new approach to detect mover position in linear motors using magnetic sensors. AB - A new method to detect the mover position of a linear motor is proposed in this paper. This method employs a simple cheap Hall Effect sensor-based magnetic sensor unit to detect the mover position of the linear motor. With the movement of the linear motor, Hall Effect sensor modules electrically separated 120 degrees along with the idea of three phase balanced condition ( va + vb + vc = 0 ) are used to produce three phase signals. The amplitude of the sensor output voltage signals are adjusted to unit amplitude to minimize the amplitude errors. With the unit amplitude signals three to two phase transformation is done to reduce the three multiples of harmonic components. The final output thus obtained is converted to position data by the use of arctangent function. The measurement accuracy of the new method is analyzed by experiments and compared with the conventional two phase method. Using the same number of sensor modules as the conventional two phase method, the proposed method gives more accurate position information compared to the conventional system where sensors are separated by 90 degrees electrical angles. PMID- 26506346 TI - The Role of Autophagy in Lupus Nephritis. AB - Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by the generation of immune responses to self-antigens. Lupus nephritis is one of the most common and severe complications in SLE patients. Though the pathogenesis of lupus nephritis has been studied extensively, unresolved questions are still left and new therapeutic methods are needed for disease control. Autophagy is a conserved catabolic process through which cytoplasmic constituents can be degraded in lysosome and reused. Autophagy plays vital roles in maintaining cell homeostasis and is involved in the pathogenesis of many diseases. In particular, autophagy can affect almost all parts of the immune system and is involved in autoimmune diseases. Based on genetic analysis, cell biology, and mechanism studies of the classic and innovative therapeutic drugs, there are growing lines of evidence suggesting the relationship between autophagy and lupus nephritis. In the present review, we summarize the recent publications investigating the relationship between autophagy and lupus nephritis and provide a new perspective towards the pathogenesis of lupus nephritis. PMID- 26506349 TI - Evaluation of SHM system produced by additive manufacturing via acoustic emission and other NDT methods. AB - During the last decades, structural health monitoring (SHM) systems are used in order to detect damage in structures. We have developed a novel structural health monitoring approach, the so-called "effective structural health monitoring" (eSHM) system. The current SHM system is incorporated into a metallic structure by means of additive manufacturing (AM) and has the possibility to advance life safety and reduce direct operative costs. It operates based on a network of capillaries that are integrated into an AM structure. The internal pressure of the capillaries is continuously monitored by a pressure sensor. When a crack nucleates and reaches the capillary, the internal pressure changes signifying the existence of the flaw. The main objective of this paper is to evaluate the crack detection capacity of the eSHM system and crack location accuracy by means of various non-destructive testing (NDT) techniques. During this study, detailed acoustic emission (AE) analysis was applied in AM materials for the first time in order to investigate if phenomena like the Kaiser effect and waveform parameters used in conventional metals can offer valuable insight into the damage accumulation of the AM structure as well. Liquid penetrant inspection, eddy current and radiography were also used in order to confirm the fatigue damage and indicate the damage location on un-notched four-point bending AM metallic specimens with an integrated eSHM system. It is shown that the eSHM system in combination with NDT can provide correct information on the damage condition of additive manufactured metals. PMID- 26506350 TI - Comparison of different classification methods for analyzing electronic nose data to characterize sesame oils and blends. AB - An electronic nose (e-nose) was used to characterize sesame oils processed by three different methods (hot-pressed, cold-pressed, and refined), as well as blends of the sesame oils and soybean oil. Seven classification and prediction methods, namely PCA, LDA, PLS, KNN, SVM, LASSO and RF, were used to analyze the e nose data. The classification accuracy and MAUC were employed to evaluate the performance of these methods. The results indicated that sesame oils processed with different methods resulted in different sensor responses, with cold-pressed sesame oil producing the strongest sensor signals, followed by the hot-pressed sesame oil. The blends of pressed sesame oils with refined sesame oil were more difficult to be distinguished than the blends of pressed sesame oils and refined soybean oil. LDA, KNN, and SVM outperformed the other classification methods in distinguishing sesame oil blends. KNN, LASSO, PLS, and SVM (with linear kernel), and RF models could adequately predict the adulteration level (% of added soybean oil) in the sesame oil blends. Among the prediction models, KNN with k = 1 and 2 yielded the best prediction results. PMID- 26506352 TI - A smartphone-based automatic diagnosis system for facial nerve palsy. AB - Facial nerve palsy induces a weakness or loss of facial expression through damage of the facial nerve. A quantitative and reliable assessment system for facial nerve palsy is required for both patients and clinicians. In this study, we propose a rapid and portable smartphone-based automatic diagnosis system that discriminates facial nerve palsy from normal subjects. Facial landmarks are localized and tracked by an incremental parallel cascade of the linear regression method. An asymmetry index is computed using the displacement ratio between the left and right side of the forehead and mouth regions during three motions: resting, raising eye-brow and smiling. To classify facial nerve palsy, we used Linear Discriminant Analysis (LDA) and Support Vector Machine (SVM), and Leave one-out Cross Validation (LOOCV) with 36 subjects. The classification accuracy rate was 88.9%. PMID- 26506351 TI - Fiber-amplifier-enhanced QEPAS sensor for simultaneous trace gas detection of NH3 and H2S. AB - A selective and sensitive quartz enhanced photoacoustic spectroscopy (QEPAS) sensor, employing an erbium-doped fiber amplifier (EDFA), and a distributed feedback (DFB) laser operating at 1582 nm was demonstrated for simultaneous detection of ammonia (NH3) and hydrogen sulfide (H2S). Two interference-free absorption lines located at 6322.45 cm(-1) and 6328.88 cm(-1) for NH3 and H2S detection, respectively, were identified. The sensor was optimized in terms of current modulation depth for both of the two target gases. An electrical modulation cancellation unit was equipped to suppress the background noise caused by the stray light. An Allan-Werle variance analysis was performed to investigate the long-term performance of the fiber-amplifier-enhanced QEPAS sensor. Benefitting from the high power boosted by the EDFA, a detection sensitivity (1sigma) of 52 parts per billion by volume (ppbv) and 17 ppbv for NH3 and H2S, respectively, were achieved with a 132 s data acquisition time at atmospheric pressure and room temperature. PMID- 26506353 TI - Passive UHF RFID tag with multiple sensing capabilities. AB - This work presents the design, fabrication, and characterization of a printed radio frequency identification tag in the ultra-high frequency band with multiple sensing capabilities. This passive tag is directly screen printed on a cardboard box with the aim of monitoring the packaging conditions during the different stages of the supply chain. This tag includes a commercial force sensor and a printed opening detector. Hence, the force applied to the package can be measured as well as the opening of the box can be detected. The architecture presented is a passive single-chip RFID tag. An electronic switch has been implemented to be able to measure both sensor magnitudes in the same access without including a microcontroller or battery. Moreover, the chip used here integrates a temperature sensor and, therefore, this tag provides three different parameters in every reading. PMID- 26506354 TI - Can smartwatches replace smartphones for posture tracking? AB - This paper introduces a human posture tracking platform to identify the human postures of sitting, standing or lying down, based on a smartwatch. This work develops such a system as a proof-of-concept study to investigate a smartwatch's ability to be used in future remote health monitoring systems and applications. This work validates the smartwatches' ability to track the posture of users accurately in a laboratory setting while reducing the sampling rate to potentially improve battery life, the first steps in verifying that such a system would work in future clinical settings. The algorithm developed classifies the transitions between three posture states of sitting, standing and lying down, by identifying these transition movements, as well as other movements that might be mistaken for these transitions. The system is trained and developed on a Samsung Galaxy Gear smartwatch, and the algorithm was validated through a leave-one subject-out cross-validation of 20 subjects. The system can identify the appropriate transitions at only 10 Hz with an F-score of 0.930, indicating its ability to effectively replace smart phones, if needed. PMID- 26506356 TI - Observability analysis of DVL/PS aided INS for a maneuvering AUV. AB - Recently, ocean exploration has increased considerably through the use of autonomous underwater vehicles (AUV). A key enabling technology is the precision of the AUV navigation capability. In this paper, we focus on understanding the limitation of the AUV navigation system. That is, what are the observable error states for different maneuvering types of the AUV? Since analyzing the performance of an underwater navigation system is highly complex, to answer the above question, current approaches use simulations. This, of course, limits the conclusions to the emulated type of vehicle used and to the simulation setup. For this reason, we take a different approach and analyze the system observability for different types of vehicle dynamics by finding the set of observable and unobservable states. To that end, we apply the observability Gramian approach, previously used only for terrestrial applications. We demonstrate our analysis for an underwater inertial navigation system aided by a Doppler velocity logger or by a pressure sensor. The result is a first prediction of the performance of an AUV standing, rotating at a position and turning at a constant speed. Our conclusions of the observable and unobservable navigation error states for different dynamics are supported by extensive numerical simulation. PMID- 26506355 TI - Measurement properties of the smartphone-based B-B Score in current shoulder pathologies. AB - This study is aimed at the determination of the measurement properties of the shoulder function B-B Score measured with a smartphone. This score measures the symmetry between sides of a power-related metric for two selected movements, with 100% representing perfect symmetry. Twenty healthy participants, 20 patients with rotator cuff conditions, 23 with fractures, 22 with capsulitis, and 23 with shoulder instabilities were measured twice across a six-month interval using the B-B Score and shoulder function questionnaires. The discriminative power, responsiveness, diagnostic power, concurrent validity, minimal detectable change (MDC), minimal clinically important improvement (MCII), and patient acceptable symptom state (PASS) were evaluated. Significant differences with the control group and significant baseline-six-month differences were found for the rotator cuff condition, fracture, and capsulitis patient groups. The B-B Score was responsive and demonstrated excellent diagnostic power, except for shoulder instability. The correlations with clinical scores were generally moderate to high, but lower for instability. The MDC was 18.1%, the MCII was 25.2%, and the PASS was 77.6. No floor effect was observed. The B-B Score demonstrated excellent measurement properties in populations with rotator cuff conditions, proximal humerus fractures, and capsulitis, and can thus be used as a routine test to evaluate those patients. PMID- 26506357 TI - Harvesting entropy for random number generation for internet of things constrained devices using on-board sensors. AB - Entropy in computer security is associated with the unpredictability of a source of randomness. The random source with high entropy tends to achieve a uniform distribution of random values. Random number generators are one of the most important building blocks of cryptosystems. In constrained devices of the Internet of Things ecosystem, high entropy random number generators are hard to achieve due to hardware limitations. For the purpose of the random number generation in constrained devices, this work proposes a solution based on the least-significant bits concatenation entropy harvesting method. As a potential source of entropy, on-board integrated sensors (i.e., temperature, humidity and two different light sensors) have been analyzed. Additionally, the costs (i.e., time and memory consumption) of the presented approach have been measured. The results obtained from the proposed method with statistical fine tuning achieved a Shannon entropy of around 7.9 bits per byte of data for temperature and humidity sensors. The results showed that sensor-based random number generators are a valuable source of entropy with very small RAM and Flash memory requirements for constrained devices of the Internet of Things. PMID- 26506358 TI - Sensors for highly toxic gases: methylamine and hydrogen chloride detection at low concentrations in an ionic liquid on Pt screen printed electrodes. AB - Commercially available Pt screen printed electrodes (SPEs) have been employed as possible electrode materials for methylamine (MA) and hydrogen chloride (HCl) gas detection. The room temperature ionic liquid (RTIL) 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C2mim][NTf2]) was used as a solvent and the electrochemical behaviour of both gases was first examined using cyclic voltammetry. The reaction mechanism appears to be the same on Pt SPEs as on Pt microelectrodes. Furthermore, the analytical utility was studied to understand the behaviour of these highly toxic gases at low concentrations on SPEs, with calibration graphs obtained from 10 to 80 ppm. Three different electrochemical techniques were employed: linear sweep voltammetry (LSV), differential pulse voltammetry (DPV) and square wave voltammetry (SWV), with no significant differences in the limits of detection (LODs) between the techniques (LODs were between 1.4 to 3.6 ppm for all three techniques for both gases). The LODs achieved on Pt SPEs were lower than the current Occupational Safety and Health Administration Permissible Exposure Limit (OSHA PEL) limits of the two gases (5 ppm for HCl and 10 ppm for MA), suggesting that Pt SPEs can successfully be combined with RTILs to be used as cheap alternatives for amperometric gas sensing in applications where these toxic gases may be released. PMID- 26506359 TI - Visual tracking based on extreme learning machine and sparse representation. AB - The existing sparse representation-based visual trackers mostly suffer from both being time consuming and having poor robustness problems. To address these issues, a novel tracking method is presented via combining sparse representation and an emerging learning technique, namely extreme learning machine (ELM). Specifically, visual tracking can be divided into two consecutive processes. Firstly, ELM is utilized to find the optimal separate hyperplane between the target observations and background ones. Thus, the trained ELM classification function is able to remove most of the candidate samples related to background contents efficiently, thereby reducing the total computational cost of the following sparse representation. Secondly, to further combine ELM and sparse representation, the resultant confidence values (i.e., probabilities to be a target) of samples on the ELM classification function are used to construct a new manifold learning constraint term of the sparse representation framework, which tends to achieve robuster results. Moreover, the accelerated proximal gradient method is used for deriving the optimal solution (in matrix form) of the constrained sparse tracking model. Additionally, the matrix form solution allows the candidate samples to be calculated in parallel, thereby leading to a higher efficiency. Experiments demonstrate the effectiveness of the proposed tracker. PMID- 26506360 TI - Matrix Production, Pigment Synthesis, and Sporulation in a Marine Isolated Strain of Bacillus pumilus. AB - The ability to produce an extracellular matrix and form multicellular communities is an adaptive behavior shared by many bacteria. In Bacillus subtilis, the model system for spore-forming bacteria, matrix production is one of the possible differentiation pathways that a cell can follow when vegetative growth is no longer feasible. While in B. subtilis the genetic system controlling matrix production has been studied in detail, it is still unclear whether other spore formers utilize similar mechanisms. We report that SF214, a pigmented strain of Bacillus pumilus isolated from the marine environment, can produce an extracellular matrix relying on orthologs of many of the genes known to be important for matrix synthesis in B. subtilis. We also report a characterization of the carbohydrates forming the extracellular matrix of strain SF214. The isolation and characterization of mutants altered in matrix synthesis, pigmentation, and spore formation suggest that in strain SF214 the three processes are strictly interconnected and regulated by a common molecular mechanism. PMID- 26506361 TI - Alkaloids with Cardiovascular Effects from the Marine-Derived Fungus Penicillium expansum Y32. AB - Three new alkaloids (1, 4 and 8), together with nine known analogues (2, 3, 5-7, and 9-12), were isolated from the marine-derived fungus Penicillium expansum Y32. Their structures including the absolute configurations were elucidated by spectroscopic and Mosher's and Marfey's methods, along with quantum electronic circular dichroism (ECD) calculations. Each of the compounds was evaluated for cardiovascular effects in a live zebrafish model. All of the compounds showed a significant mitigative effect on bradycardia caused by astemizole (ASM) in the heart rate experiments. Compounds 4-6 and 8-12 exhibited potent vasculogenetic activity in vasculogenesis experiments. This is the first study to report that these types of compounds show cardiovascular effects in zebrafish. The results suggest that these compounds could be promising candidates for cardiovascular disease lead compounds. PMID- 26506362 TI - Cell Death Inducing Microbial Protein Phosphatase Inhibitors--Mechanisms of Action. AB - Okadaic acid (OA) and microcystin (MC) as well as several other microbial toxins like nodularin and calyculinA are known as tumor promoters as well as inducers of apoptotic cell death. Their intracellular targets are the major serine/threonine protein phosphatases. This review summarizes mechanisms believed to be responsible for the death induction and tumor promotion with focus on the interdependent production of reactive oxygen species (ROS) and activation of Ca(2+)/calmodulin kinase II (CaM-KII). New data are presented using inhibitors of specific ROS producing enzymes to curb nodularin/MC-induced liver cell (hepatocyte) death. They indicate that enzymes of the arachidonic acid pathway, notably phospholipase A2, 5-lipoxygenase, and cyclooxygenases, may be required for nodularin/MC-induced (and presumably OA-induced) cell death, suggesting new ways to overcome at least some aspects of OA and MC toxicity. PMID- 26506363 TI - Social Interactions Sparked by Pictorial Warnings on Cigarette Packs. AB - The Message Impact Framework suggests that social interactions may offer smokers the opportunity to process pictorial warnings on cigarette packs more deeply. We aimed to describe adult smokers' social interactions about pictorial cigarette pack warnings in two longitudinal pilot studies. In Pilot Study 1, 30 smokers used cigarette packs with one of nine pictorial warnings for two weeks. In Pilot Study 2, 46 smokers used cigarette packs with one of five pictorial warnings for four weeks. Nearly all smokers (97%/96% in Pilot Study 1/2) talked about the warnings with other people, with the most common people being friends (67%/87%) and spouses/significant others (34%/42%). Pilot Study 2 found that 26% of smokers talked about the warnings with strangers. Discussions about the health effects of smoking and quitting smoking were more frequent during the first week of exposure to pictorial warnings than in the week prior to beginning the study (both p < 0.05). Pictorial warnings sparked social interactions about the warnings, the health effects of smoking, and quitting smoking, indicating that pictorial warnings may act as a social intervention reaching beyond the individual. Future research should examine social interactions as a potential mediator of the impact of pictorial warnings on smoking behavior. PMID- 26506364 TI - The Association Between Physical Activity, Mental Status, and Social and Family Support with Five Major Non-Communicable Chronic Diseases Among Elderly People: A Cross-Sectional Study of a Rural Population in Southern China. AB - BACKGROUND: Non-communicable chronic diseases (NCDs) have become the top threat in China. This study aimed to estimate the prevalence of major NCDs among the elderly population in rural areas in southern China and explore its associated social determinants. METHODS: A multistage cluster random sampling methodology was adopted to select a total of 9245 rural elderly people from 3860 rural households in Guangdong Province. Interviews and physical examinations were performed to collect patient information. Descriptive and logistic regression analyses were conducted to explore factors associated with the presence of major NCDs. RESULTS: Over one-third (38.5%) of the study population suffered from five major NCDs. The grade of activities of daily living (ADL), mental status, and social relationship of elderly people without NCDs were better than those with NCDs. The major factors associated with the presence of NCDs among the elderly people included age (70-79 years group and 80-89 years group), education level (senior high/technical secondary school and junior college and above), mental status (concentration, enrichment and happy life and memory), relationship with neighbours, activities of daily living (ADL) (being able to climb three floors and bend over), physical activity, marital status (bereft), and living conditions (with offspring and family members). CONCLUSIONS: The study identified several social determinants associated with the presence of major NCDs. A higher level of family support and physical exercise might contribute to improved physical condition, mental status, and ADL among the elderly people in rural areas in southern China. PMID- 26506365 TI - Elimination of Mother-To-Child Transmission of HIV Infection: The Drug Resource Enhancement against AIDS and Malnutrition Model. AB - The Drug Resource Enhancement against AIDS and Malnutrition Program (DREAM) gathered professionals in the field of Elimination of HIV-Mother-To-Child Transmission (EMTCT) in Maputo in 2013 to discuss obstacles and solutions for the elimination of HIV vertical transmission in sub-Saharan Africa. During this workshop, the benefits of administrating combined antiretroviral therapy (cART) to HIV positive women from pregnancy throughout breastfeeding were reviewed. cART is capable of reducing vertical transmission to less than 5% at 24 months of age, as well as maternal mortality and infant mortality in both HIV infected and exposed populations to levels similar to those of uninfected individuals. The challenge for programs targeting eMTCT in developing countries is retention in care and treatment adherence. Both are intrinsically related to the model of care. The drop-out from eMTCT programs before cART initiation ranges from 33%-88% while retention rates at 18-24 months are less than 50%. Comprehensive strategies including peer-to-peer education, social support and laboratory monitoring can reduce refusals to less than 5% and attain retention rates approaching 90%. Several components of the model of care for reduction of HIV-1 MTCT are feasible and implementable in scale-up strategies. A review of this model of care for HIV eMTCT is provided. PMID- 26506366 TI - Associations between Bisphenol A Exposure and Reproductive Hormones among Female Workers. AB - The associations between Bisphenol-A (BPA) exposure and reproductive hormone levels among women are unclear. A cross-sectional study was conducted among female workers from BPA-exposed and unexposed factories in China. Women's blood samples were collected for assay of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17beta-Estradiol (E2), prolactin (PRL), and progesterone (PROG). Their urine samples were collected for BPA measurement. In the exposed group, time weighted average exposure to BPA for an 8-h shift (TWA8), a measure incorporating historic exposure level, was generated based on personal air sampling. Multiple linear regression analyses were used to examine linear associations between urine BPA concentration and reproductive hormones after controlling for potential confounders. A total of 106 exposed and 250 unexposed female workers were included in this study. A significant positive association between increased urine BPA concentration and higher PRL and PROG levels were observed. Similar associations were observed after the analysis was carried out separately among the exposed and unexposed workers. In addition, a positive association between urine BPA and E2 was observed among exposed workers with borderline significance, while a statistically significant inverse association between urine BPA and FSH was observed among unexposed group. The results suggest that BPA exposure may lead to alterations in female reproductive hormone levels. PMID- 26506367 TI - The Mental Health Outcomes of Drought: A Systematic Review and Causal Process Diagram. AB - Little is understood about the long term, indirect health consequences of drought (a period of abnormally dry weather). In particular, the implications of drought for mental health via pathways such as loss of livelihood, diminished social support, and rupture of place bonds have not been extensively studied, leaving a knowledge gap for practitioners and researchers alike. A systematic review of literature was performed to examine the mental health effects of drought. The systematic review results were synthesized to create a causal process diagram that illustrates the pathways linking drought effects to mental health outcomes. Eighty-two articles using a variety of methods in different contexts were gathered from the systematic review. The pathways in the causal process diagram with greatest support in the literature are those focusing on the economic and migratory effects of drought. The diagram highlights the complexity of the relationships between drought and mental health, including the multiple ways that factors can interact and lead to various outcomes. The systematic review and resulting causal process diagram can be used in both practice and theory, including prevention planning, public health programming, vulnerability and risk assessment, and research question guidance. The use of a causal process diagram provides a much needed avenue for integrating the findings of diverse research to further the understanding of the mental health implications of drought. PMID- 26506368 TI - Molecular Analysis of Bacterial Microbiota on Brazilian Currency Note Surfaces. AB - Currency notes have been implicated as a vehicle for transmitting community acquired bacterial infections. However, the overall diversity of the bacterial population residing on banknotes is still unknown in Brazil. In this study, we aimed to investigate the overall bacterial population from 150 different Brazilian Rial (R$) notes in circulation using a culture-independent Illumina massively parallel sequencing approach of the 16S rRNA genes. Samples were randomly collected from three different street markets or "feiras" in the metropolitan region of Sao Paulo. Taxonomical composition revealed the abundance of Proteobacteria phyla, followed by Firmicutes and Streptophyta, with a total of 1193 bacterial families and 3310 bacterial genera. Most of these bacterial genera are of human, animal, and environmental origins. Also, our analysis revealed the presence of some potential pathogenic bacterial genera including Salmonella, Staphylococcus, and Klebsiella. The results demonstrate that there is a tremendous diversity of bacterial contamination on currency notes, including organisms known to be opportunistic pathogens. One of the factors that may contribute to the richness of bacterial diversity in currency notes is personal hygiene. Thus, our results underscore the need to increase public awareness of the importance of personal hygiene of money handlers who also handle food. PMID- 26506369 TI - Longitudinal Antigenic Sequences and Sites from Intra-Host Evolution (LASSIE) Identifies Immune-Selected HIV Variants. AB - Within-host genetic sequencing from samples collected over time provides a dynamic view of how viruses evade host immunity. Immune-driven mutations might stimulate neutralization breadth by selecting antibodies adapted to cycles of immune escape that generate within-subject epitope diversity. Comprehensive identification of immune-escape mutations is experimentally and computationally challenging. With current technology, many more viral sequences can readily be obtained than can be tested for binding and neutralization, making down-selection necessary. Typically, this is done manually, by picking variants that represent different time-points and branches on a phylogenetic tree. Such strategies are likely to miss many relevant mutations and combinations of mutations, and to be redundant for other mutations. Longitudinal Antigenic Sequences and Sites from Intrahost Evolution (LASSIE) uses transmitted founder loss to identify virus "hot spots" under putative immune selection and chooses sequences that represent recurrent mutations in selected sites. LASSIE favors earliest sequences in which mutations arise. With well-characterized longitudinal Env sequences, we confirmed selected sites were concentrated in antibody contacts and selected sequences represented diverse antigenic phenotypes. Practical applications include rapidly identifying immune targets under selective pressure within a subject, selecting minimal sets of reagents for immunological assays that characterize evolving antibody responses, and for immunogens in polyvalent "cocktail" vaccines. PMID- 26506370 TI - Complete Genome and Phylogeny of Puumala Hantavirus Isolates Circulating in France. AB - Puumala virus (PUUV) is the agent of nephropathia epidemica (NE), a mild form of hemorrhagic fever with renal syndrome (HFRS) in Europe. NE incidence presents a high spatial variation throughout France, while the geographical distribution of the wild reservoir of PUUV, the bank vole, is rather continuous. A missing piece of the puzzle is the current distribution and the genetic variation of PUUV in France, which has been overlooked until now and remains poorly understood. During a population survey, from 2008 to 2011, bank voles were trapped in eight different forests of France located in areas known to be endemic for NE or in area from where no NE case has been reported until now. Bank voles were tested for immunoglobulin (Ig)G ELISA serology and two seropositive animals for each of three different areas (Ardennes, Jura and Orleans) were then subjected to laboratory analyses in order to sequence the whole S, M and L segments of PUUV. Phylogenetic analyses revealed that French PUUV isolates globally belong to the central European (CE) lineage although isolates from Ardennes are clearly distinct from those in Jura and Orleans, suggesting a different evolutionary history and origin of PUUV introduction in France. Sequence analyses revealed specific amino acid signatures along the N protein, including in PUUV from the Orleans region from where NE in humans has never been reported. The relevance of these mutations in term of pathophysiology is discussed. PMID- 26506371 TI - Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum. AB - The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner much time and investment with the continuous advancement of new and innovative approaches. This review details the progress and current status of the transdermal drug delivery field and describes numerous pharmaceutical developments which have been employed to overcome limitations associated with skin delivery systems. Advantages and disadvantages of the various approaches are detailed, commercially marketed products are highlighted and particular attention is paid to the emerging field of microneedle technologies. PMID- 26506372 TI - Contribution of Organic Food to the Diet in a Large Sample of French Adults (the NutriNet-Sante Cohort Study). AB - In developed countries, the demand for organic products continues to substantially increase each year. However, little information is available regarding the level of consumption of organic food and its relative share of the whole diet. Our aim was to provide, using individual consumption data, a detailed description of organic food consumption among French adults. Conventional and organic intakes were assessed using an organic food frequency questionnaire administered to 28,245 French adults participating in the NutriNet-Sante study. P values of Student t-test or Chi-square for the difference between genders were reported. Less than 12% of the respondents reported never consuming organic food in the past year. Women consumed on average 20% organic food in their whole diet per day while men consumed an average of 18%. The proportion of vegetables consumed that came from organic sources was 31% among women and 28% among men. Overall, the estimate of the contribution of organic food from products of plant origin was higher than that from products of animal origin. Our study provides a framework for the exploration of organic consumption and its correlates and can serve as a basis for future studies investigating relationships between the level of organic food consumption and health outcomes. PMID- 26506373 TI - Adherence to a Healthy Nordic Food Index Is Associated with a Lower Risk of Type 2 Diabetes--The Danish Diet, Cancer and Health Cohort Study. AB - BACKGROUND: Type-2 diabetes (T2D) prevalence is rapidly increasing worldwide. Lifestyle factors, in particular obesity, diet, and physical activity play a significant role in the etiology of the disease. Of dietary patterns, particularly the Mediterranean diet has been studied, and generally a protective association has been identified. However, other regional diets are less explored. OBJECTIVE: The aim of the present study was to investigate the association between adherence to a healthy Nordic food index and the risk of T2D. The index consists of six food items: fish, cabbage, rye bread, oatmeal, apples and pears, and root vegetables. METHODS: Data was obtained from a prospective cohort study of 57,053 Danish men and women aged 50-64 years, at baseline, of whom 7366 developed T2D (median follow-up: 15.3 years). The Cox proportional hazards model was used to assess the association between the healthy Nordic food index and risk of T2D, adjusted for potential confounders. RESULTS: Greater adherence to the healthy Nordic food index was significantly associated with lower risk of T2D after adjusting for potential confounders. An index score of 5-6 points (high adherence) was associated with a statistically significantly 25% lower T2D risk in women (HR: 0.75, 95%CI: 0.61-0.92) and 38% in men (HR: 0.62; 95%CI: 0.53-0.71) compared to those with an index score of 0 points (poor adherence). CONCLUSION: Adherence to a healthy Nordic food index was found to be inversely associated with risk of T2D, suggesting that regional diets other than the Mediterranean may also be recommended for prevention of T2D. PMID- 26506374 TI - The Impaired Function of Macrophages Induced by Strenuous Exercise Could Not Be Ameliorated by BCAA Supplementation. AB - The aim of this study was to evaluate the effect of strenuous exercise on the functions of peritoneal macrophages in rats and to test the hypothesis that branched-chain amino acid (BCAA) supplementation will be beneficial to the macrophages of rats from strenuous exercise. Forty male Wistar rats were randomly divided into five groups: (C) Control, E) Exercise, (E1) Exercise with one week to recover, (ES) Exercise + Supplementation and (ES1) Exercise + Supplementation with 1 week to recover. All rats except those of the sedentary control were subjected to four weeks of strenuous exercise. Blood hemoglobin, serum testosterone and BCAA levels were tested. Peritoneal macrophages functions were also determined at the same time. The data showed that hemoglobin, testosterone, BCAA levels, and body weight in group E decreased significantly as compared with that of group C. Meanwhile, phagocytosis capacity (decreased by 17.07%, p = 0.031), reactive oxygen species (ROS) production (decreased by 26%, p = 0.003) and MHC II mRNA (decreased by 22%, p = 0.041) of macrophages decreased in the strenuous exercise group as compared with group C. However, the chemotaxis of macrophages did not change significantly. In addition, BCAA supplementation could slightly increase the serum BCAA levels of rats from strenuous exercise (increased by 6.70%, p > 0.05). Moreover, the body weight, the blood hemoglobin, the serum testosterone and the function of peritoneal macrophages in group ES did not change significantly as compared with group E. These results suggest that long-term intensive exercise impairs the function of macrophages, which is essential for microbicidal capability. This may represent a novel mechanism of immunosuppression induced by strenuous exercise. Moreover, the impaired function of macrophage induced by strenuous exercise could not be ameliorated by BCAA supplementation in the dosing and timing used for this study. PMID- 26506375 TI - Anti-Fatigue and Antioxidant Activity of the Polysaccharides Isolated from Millettiae speciosae Champ. Leguminosae. AB - Millettiae speciosae Champ. Leguminosae (MSC), is a well-known Chinese herb traditionally used as food material and medicine for enhancing physical strength. Our preliminary study found that the aqueous extract of this herb (MSE) had an anti-fatigue effect. In this paper, we further separated MSE into total polysaccharides (MSP) and supernatant (MSS) by alcohol precipitation, and explored which fraction was active for its anti-fatigue effect. Mice were orally administered with MSP or MSS at the doses of 200, 400, and 800 mg/kg for 20 days and the anti-fatigue effect was assessed by exhaustive swimming exercise (ESE). The biochemical parameters related to fatigue after ESE and the in vitro antioxidant activity of active fraction were determined. Our results showed that MSP, instead of MSS, significantly extended the swimming time to exhaustion (p < 0.05), indicating that MSP is responsible for the anti-fatigue effect of MSE. In addition, MSP treatment increased the levels of glucose (Glu) and muscle glycogen, whereas it decreased the accumulations of blood urea nitrogen (BUN) and lactic acid (Lac). Moreover, ESE increased the levels of creatine phosphokinase (CK), lactic dehydrogenase (LDH), and malondialdehyde (MDA) but reduced superoxide dismutase (SOD) and glutathione (GSH) in plasma. In contrast, MSP inhibited all the above changes relating to fatigue. Furthermore, an in vitro antioxidant test revealed that MSP dose-dependently scavenged .OH and DPPH free radicals. Taken together, these findings strongly suggested that MSP was able to alleviate physical fatigue by increasing energy resources and decreasing accumulation of detrimental metabolites. The antioxidant activity may crucially contribute to the observed anti-fatigue effect of MSP. PMID- 26506376 TI - The Ethanol Extract from Lonicera japonica Thunb. Regresses Nonalcoholic Steatohepatitis in a Methionine- and Choline-Deficient Diet-Fed Animal Model. AB - Nonalcoholic steatohepatitis (NASH) is characterized as fat accumulation in the hepatic tissue associated with various degrees of inflammation and progressive fibrosis. The potent anti-inflammatory and ethnopharmacological properties of Lonicera japonica Thunb. (Caprifoliaceae) make it an excellent source of novel medicinal targets for the treatment of NASH. The aim of the study was to investigate the effects of L. japonica ethanol extract (LJEE) on NASH in mice. C57BL/6J mice were fed with methionine-choline-deficient diet (MCDD) for eight weeks to promote the development of NASH. After development of the model, the mice were administered LJEE once daily via oral gavage at doses of 100, 200, or 300 mg/kg for another four weeks. Simultaneous treatments with LJEE (300 mg/kg/day) resulted in pronounced improvements in liver steatosis, ballooning degeneration, and inflammation. LJEE prevented MCDD-induced plasma level increases in aspartate aminotransferase and alanine aminotransferase. LJEE significantly reduced hepatic malondialdehyde level and ameliorated hepatic inflammation and fibrosis in MCDD-fed mice, which were associated with down regulation of cytochrome P450 2E1 suppression of multiple proinflammatory and profibrotic genes. LJEE can prevent hepatic steatosis by reducing hepatic peroxisome acyl-CoA:diacylglycerol acyltransferase 2 expression, as well as by inducing proliferator-activated receptor alpha expression. In addition, the LJEE treatments caused significant reduction in the phosphorylated form of Jun N terminal kinase along with an increase in the phosphorylated level of extra cellular signal-regulated kinase 1/2. Our study demonstrated the protective role of LJEE in ameliorating nutritional steatohepatitis. PMID- 26506377 TI - Consumption of Milk Protein or Whey Protein Results in a Similar Increase in Muscle Protein Synthesis in Middle Aged Men. AB - The differential ability of various milk protein fractions to stimulate muscle protein synthesis (MPS) has been previously described, with whey protein generally considered to be superior to other fractions. However, the relative ability of a whole milk protein to stimulate MPS has not been compared to whey. Sixteen healthy middle-aged males ingested either 20 g of milk protein (n = 8) or whey protein (n = 8) while undergoing a primed constant infusion of ring (13)C6 phenylalanine. Muscle biopsies were obtained 120 min prior to consumption of the protein and 90 and 210 min afterwards. Resting myofibrillar fractional synthetic rates (FSR) were 0.019% +/- 0.009% and 0.021% +/- 0.018% h(-1) in the milk and whey groups respectively. For the first 90 min after protein ingestion the FSR increased (p < 0.001) to 0.057% +/- 0.018% and 0.052% +/- 0.024% h(-1) in the milk and whey groups respectively with no difference between groups (p = 0.810). FSR returned to baseline in both groups between 90 and 210 min after protein ingestion. Despite evidence of increased rate of digestion and leucine availability following the ingestion of whey protein, there was similar activation of MPS in middle-aged men with either 20 g of milk protein or whey protein. PMID- 26506378 TI - Protein Beverage vs. Protein Gel on Appetite Control and Subsequent Food Intake in Healthy Adults. AB - The objective of this study was to compare the effects of food form and physicochemical properties of protein snacks on appetite and subsequent food intake in healthy adults. Twelve healthy subjects received a standardized breakfast and then 2.5 h post-breakfast consumed the following snacks, in randomized order: 0 kcal water (CON) or 96 kcal whey protein snacks as beverages with a pH of either 3.0 (Bev-3.0) or 7.0 (Bev-7.0) or gels as acid (Gel-Acid) or heated (Gel-Heated). In-vitro study showed that Bev-3.0 was more resistant to digestion than Bev-7.0, while Gel-Acid and Gel-Heated had similar digestion pattern. Appetite questionnaires were completed every 20 min until an ad libitum lunch was provided. Post-snack hunger, desire to eat, and prospective food consumption were lower following the beverages and gels vs. CON (all, p < 0.05), and post-snack fullness was greater following the snacks (except for the Bev-3.0) vs. CON (all, p < 0.05). Gel-Heated treatment led to lower prospective food consumption vs. Bev-3.0; however, no other differences were detected. Although all snacks reduced energy intake vs. CON, no differences were observed among treatments. This study suggested that whey protein in either liquid or solid form improves appetite, but the physicochemical property of protein has a minimal effect. PMID- 26506379 TI - The Fifty Year Rehabilitation of the Egg. AB - The 1968 American Heart Association announced a dietary recommendation that all individuals consume less than 300 mg of dietary cholesterol per day and no more than three whole eggs per week. This recommendation has not only significantly impacted the dietary patterns of the population, but also resulted in the public limiting a highly nutritious and affordable source of high quality nutrients, including choline which was limited in the diets of most individuals. The egg industry addressed the egg issue with research documenting the minimal effect of egg intake on plasma lipoprotein levels, as well as research verifying the importance of egg nutrients in a variety of issues related to health promotion. In 2015 dietary cholesterol and egg restrictions have been dropped by most health promotion agencies worldwide and recommended to be dropped from the 2015 Dietary Guidelines for Americans. PMID- 26506380 TI - DHA in Pregnant and Lactating Women from Coastland, Lakeland, and Inland Areas of China: Results of a DHA Evaluation in Women (DEW) Study. AB - Few studies have examined docosahexaenoic acid (DHA) in pregnant and lactating women in developing countries like China, where DHA-enriched supplements are increasingly popular. We aimed to assess the DHA status among Chinese pregnant and lactating women residing areas differing in the availability of aquatic products. In total, 1211 women in mid-pregnancy (17 +/- 2 weeks), late pregnancy (39 +/- 2 weeks), or lactation (42 +/- 7 days) were enrolled from Weihai (coastland), Yueyang (lakeland), and Baotou (inland) city, with approximately 135 women in each participant group by region. DHA concentrations were measured using capillary gas chromatography, and are reported as weight percent of total fatty acids. Mean plasma DHA concentrations were higher in coastland (mid-pregnancy 3.19%, late pregnancy 2.54%, lactation 2.24%) and lakeland women (2.45%, 1.95%, 2.26%) than inland women (2.25%, 1.67%, 1.68%) (p values < 0.001). Similar differences were observed for erythrocyte DHA. We conclude that DHA concentrations of Chinese pregnant and lactating women are higher in coastland and lakeland regions than in inland areas. DHA status in the study population appears to be stronger than populations from other countries studied to date. PMID- 26506382 TI - Proteomics Analysis to Identify and Characterize the Molecular Signatures of Hepatic Steatosis in Ovariectomized Rats as a Model of Postmenopausal Status. AB - Postmenopausal women are particularly at increased risk of developing non alcoholic fatty liver disease (NAFLD). Here we aimed to determine the impact of postmenopausal-induced NAFLD (PM-NAFLD) in an ovariectomized rat model. Sixteen six-week-old Sprague-Dawley female rats were randomly divided into two groups (eight per group), for sham-operation (Sham) or bilateral ovariectomy (Ovx). Four months after surgery, indices of liver damage and liver histomorphometry were measured. Both serum aspartate aminotransferase (AST) and alanine aminotranferease (ALT) levels were significantly higher in the Ovx than Sham group. We performed quantitative LC-MS/MS-based proteomic profiling of livers from rats with PM-NAFLD to provide baseline knowledge of the PM-NAFLD proteome and to investigate proteins involved in PM-NAFLD by ingenuity pathways analysis (IPA) to provide corroborative evidence for differential regulation of molecular and cellular functions affecting metabolic processes. Of the 586 identified proteins, the levels of 59 (10.0%) and 48 (8.2%) were significantly higher and lower, respectively, in the Ovx group compared to the Sham group. In conclusion, the changes in regulation of proteins implicated in PM-NAFLD may affect other vital biological processes in the body apart from causing postmenopause-mediated liver dysfunction. Our quantitative proteomics analysis may also suggest potential biomarkers and further clinical applications for PM-NAFLD. PMID- 26506381 TI - The Spectrum of Differences between Childhood and Adulthood Celiac Disease. AB - An old saying states that ''children are not little adults" and this certainly holds true for celiac disease, as there are many peculiar aspects regarding its epidemiology, diagnosis, clinical presentations, associated diseases, and response to treatment in pediatric compared to adult populations, to such an extent that it merits a description of its own. In fact, contrary to the past when it was thought that celiac disease was a disorder predominantly affecting childhood and characterized by a malabsorption syndrome, nowadays it is well recognized that it affects also adult and elderly people with an impressive variability of clinical presentation. In general, the clinical guidelines for diagnosis recommend starting with specific serologic testing in all suspected subjects, including those suffering from extraintestinal related conditions, and performing upper endoscopy with appropriate biopsy sampling of duodenal mucosa in case of positivity. The latter may be omitted in young patients showing high titers of anti-transglutaminase antibodies. The subsequent management of a celiac patient differs substantially depending on the age at diagnosis and should be based on the important consideration that this is a lifelong condition. PMID- 26506383 TI - Supplementation of Antipsychotic Treatment with the Amino Acid Sarcosine Influences Proton Magnetic Resonance Spectroscopy Parameters in Left Frontal White Matter in Patients with Schizophrenia. AB - Dysfunction of the glutamatergic system, the main stimulating system in the brain, has a major role in pathogenesis of schizophrenia. The frontal white matter (WM) is partially composed of axons from glutamatergic pyramidal neurons and glia with glutamatergic receptors. The natural amino acid sarcosine, a component of a normal diet, inhibits the glycine type 1 transporter, increasing the glycine level. Thus, it modulates glutamatergic transmission through the glutamatergic ionotropic NMDA (N-methyl-d-aspartate) receptor, which requires glycine as a co-agonist. To evaluate the concentrations of brain metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine, and gamma aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left frontal WM, Proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy was used. Twenty-five patients randomly chosen from a group of fifty with stable schizophrenia (DSM-IV-TR) and dominant negative symptoms, who were receiving antipsychotic therapy, were administered 2 g of sarcosine daily for six months. The remaining 25 patients received placebo. Assignment was double blinded. 1H-NMR spectroscopy (1.5 T) was performed twice: before and after the intervention. NAA, Glx and mI were evaluated as Cr and Cho ratios. All patients were also assessed twice with the Positive and Negative Syndrome Scale (PANSS). Results were compared between groups and in two time points in each group. The sarcosine group demonstrated a significant decrease in WM Glx/Cr and Glx/Cho ratios compared to controls after six months of therapy. In the experimental group, the final NAA/Cr ratio significantly increased and Glx/Cr ratio significantly decreased compared to baseline values. Improvement in the PANSS scores was significant only in the sarcosine group. In patients with schizophrenia, sarcosine augmentation can reverse the negative effect of glutamatergic system overstimulation, with a simultaneous beneficial increase of NAA/Cr ratio in the WM of the left frontal lobe. Our results further support the glutamatergic hypothesis of schizophrenia. PMID- 26506385 TI - Long-Term Effect of Docosahexaenoic Acid Feeding on Lipid Composition and Brain Fatty Acid-Binding Protein Expression in Rats. AB - Arachidonic (AA) and docosahexaenoic acid (DHA) brain accretion is essential for brain development. The impact of DHA-rich maternal diets on offspring brain fatty acid composition has previously been studied up to the weanling stage; however, there has been no follow-up at later stages. Here, we examine the impact of DHA rich maternal and weaning diets on brain fatty acid composition at weaning and three weeks post-weaning. We report that DHA supplementation during lactation maintains high DHA levels in the brains of pups even when they are fed a DHA deficient diet for three weeks after weaning. We show that boosting dietary DHA levels for three weeks after weaning compensates for a maternal DHA-deficient diet during lactation. Finally, our data indicate that brain fatty acid binding protein (FABP7), a marker of neural stem cells, is down-regulated in the brains of six-week pups with a high DHA:AA ratio. We propose that elevated levels of DHA in developing brain accelerate brain maturation relative to DHA-deficient brains. PMID- 26506384 TI - Influence of Parenting Practices on Eating Behaviors of Early Adolescents during Independent Eating Occasions: Implications for Obesity Prevention. AB - Among early adolescents (10-14 years), poor diet quality along with physical inactivity can contribute to an increased risk of obesity and associated biomarkers for chronic disease. Approximately one-third of United States (USA) children in this age group are overweight or obese. Therefore, attention to factors affecting dietary intake as one of the primary contributors to obesity is important. Early adolescents consume foods and beverages during eating occasions that occur with and without parental supervision. Parents may influence eating behaviors of early adolescents during eating occasions when they are present or during independent eating occasions by engaging in practices that affect availability of foods and beverages, and through perceived normative beliefs and expectations for intake. Therefore, the purpose of this article was to describe the influence of parenting practices on eating behaviors in general and when specifically applied to independent eating occasions of early adolescents. This information may be helpful to inform parenting interventions targeting obesity prevention among early adolescents focusing on independent eating occasions. PMID- 26506386 TI - Immune-Relevant and Antioxidant Activities of Vitellogenin and Yolk Proteins in Fish. AB - Vitellogenin (Vtg), the major egg yolk precursor protein, is traditionally thought to provide protein- and lipid-rich nutrients for developing embryos and larvae. However, the roles of Vtg as well as its derived yolk proteins lipovitellin (Lv) and phosvitin (Pv) extend beyond nutritional functions. Accumulating data have demonstrated that Vtg, Lv and Pv participate in host innate immune defense with multifaceted functions. They can all act as multivalent pattern recognition receptors capable of identifying invading microbes. Vtg and Pv can also act as immune effectors capable of killing bacteria and virus. Moreover, Vtg and Lv are shown to possess phagocytosis-promoting activity as opsonins. In addition to these immune-relevant functions, Vtg and Pv are found to have antioxidant activity, which is able to protect the host from oxidant stress. These non-nutritional functions clearly deepen our understanding of the physiological roles of the molecules, and at the same time, provide a sound basis for potential application of the molecules in human health. PMID- 26506388 TI - Long-Term Efficacy and Safety of Repeated Intravescial OnabotulinumtoxinA Injections Plus Hydrodistention in the Treatment of Interstitial Cystitis/Bladder Pain Syndrome. AB - Intravesical onabotulinumtoxinA (BoNT-A) injection can relieve symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), but lacks sustainability. Repeated injections have been shown to provide a superior outcome to a single injection, but data on long-term efficacy and safety is limited. In this prospective study, we enrolled patients with refractory IC/BPS, and treated them with 100 U of BoNT-A injection plus hydrodistention followed by repeated injections every six months for up to two years or until the patient wished to discontinue. A "top-up" dose was offered after the fourth injection. Of these 104 participants, 56.7% completed four BoNT-A injections and 34% voluntarily received the fifth injection due to exacerbated IC symptoms. With a follow-up period of up to 79 months, O'Leary-Sant symptom and problem indexes (ICSI, ICPI, OSS), pain visual analogue scale (VAS) functional bladder capacity, frequency episodes, and global response assessment (GRA) all showed significant improvement (p < 0.0001). Those who received repeated injections had a better success rate during the long term follow-up period. The incidence of adverse events did not rise with the increasing number of BoNT-A injections. A higher pre-treatment ICSI and ICPI score was predictive for successful response to repeated intravesical BoNT-A injections plus hydrodistention. PMID- 26506389 TI - The Tip of the Iceberg: Clinical Implications of Genomic Sequencing Projects in Head and Neck Cancer. AB - Recent genomic sequencing studies have provided valuable insight into genetic aberrations in head and neck squamous cell carcinoma. Despite these great advances, certain hurdles exist in translating genomic findings to clinical care. Further correlation of genetic findings to clinical outcomes, additional analyses of subgroups of head and neck cancers and follow-up investigation into genetic heterogeneity are needed. While the development of targeted therapy trials is of key importance, numerous challenges exist in establishing and optimizing such programs. This review discusses potential upcoming steps for further genetic evaluation of head and neck cancers and implementation of genetic findings into precision medicine trials. PMID- 26506387 TI - Comparative Ochratoxin Toxicity: A Review of the Available Data. AB - Ochratoxins are a group of mycotoxins produced by a variety of moulds. Ochratoxin A (OTA), the most prominent member of this toxin family, was first described by van der Merwe et al. in Nature in 1965. Dietary exposure to OTA represents a serious health issue and has been associated with several human and animal diseases including poultry ochratoxicosis, porcine nephropathy, human endemic nephropathies and urinary tract tumours in humans. More than 30 years ago, OTA was shown to be carcinogenic in rodents and since then extensive research has been performed in order to investigate its mode of action, however, this is still under debate. OTA is regarded as the most toxic family member, however, other ochratoxins or their metabolites and, in particular, ochratoxin mixtures or combinations with other mycotoxins may represent serious threats to human and animal health. This review summarises and evaluates current knowledge about the differential and comparative toxicity of the ochratoxin group. PMID- 26506390 TI - Characterization of DNA Methylation in Circulating Tumor Cells. AB - Epigenetics contributes to molecular mechanisms leading to tumor cell transformation and systemic progression of cancer. However, the dynamics of epigenetic remodeling during metastasis remains unexplored. In this context, circulating tumor cells (CTCs) might enable a direct insight into epigenetic mechanisms relevant for metastasis by providing direct access to systemic cancer. CTCs can be used as prognostic markers in cancer patients and are regarded as potential metastatic precursor cells. However, despite substantial technical progress, the detection and molecular characterization of CTCs remain challenging, in particular the analysis of DNA methylation. As recent studies have started to address the epigenetic state of CTCs, we discuss here the potential of such investigations to elucidate mechanisms of metastasis and to develop tumor biomarkers. PMID- 26506392 TI - How Porin Heterogeneity and Trade-Offs Affect the Antibiotic Susceptibility of Gram-Negative Bacteria. AB - Variations in porin proteins are common in Gram-negative pathogens. Altered or absent porins reduce access of polar antibiotics across the outer membrane and can thus contribute to antibiotic resistance. Reduced permeability has a cost however, in lowering access to nutrients. This trade-off between permeability and nutritional competence is the source of considerable natural variation in porin gate-keeping. Mutational changes in this trade-off are frequently selected, so susceptibility to detergents and antibiotics is polymorphic in environmental isolates as well as pathogens. Understanding the mechanism, costs and heterogeneity of antibiotic exclusion by porins will be crucial in combating Gram negative infections. PMID- 26506391 TI - Epigenetic Heterogeneity of B-Cell Lymphoma: Chromatin Modifiers. AB - We systematically studied the expression of more than fifty histone and DNA (de)methylating enzymes in lymphoma and healthy controls. As a main result, we found that the expression levels of nearly all enzymes become markedly disturbed in lymphoma, suggesting deregulation of large parts of the epigenetic machinery. We discuss the effect of DNA promoter methylation and of transcriptional activity in the context of mutated epigenetic modifiers such as EZH2 and MLL2. As another mechanism, we studied the coupling between the energy metabolism and epigenetics via metabolites that act as cofactors of JmjC-type demethylases. Our study results suggest that Burkitt's lymphoma and diffuse large B-cell Lymphoma differ by an imbalance of repressive and poised promoters, which is governed predominantly by the activity of methyltransferases and the underrepresentation of demethylases in this regulation. The data further suggest that coupling of epigenetics with the energy metabolism can also be an important factor in lymphomagenesis in the absence of direct mutations of genes in metabolic pathways. Understanding of epigenetic deregulation in lymphoma and possibly in cancers in general must go beyond simple schemes using only a few modes of regulation. PMID- 26506393 TI - Analysis of Codon Usage Patterns in Herbaceous Peony (Paeonia lactiflora Pall.) Based on Transcriptome Data. AB - Codon usage bias, which exists in many genomes, is mainly determined by mutation and selection. To elucidate the genetic features and evolutionary history of herbaceous peony (Paeonia lactiflora), a well-known symbol of prosperity in China, we examined synonymous codon usage in 24,216 reconstructed genes from the P. lactiflora transcriptome. The mean GC content was 44.4%, indicating that the nucleotide content of P. lactiflora genes is slightly AT rich and GC poor. The P. lactiflora genome has a wide range of GC3 (GC content at the third synonymous codon position) distribution, with a significant correlation between GC12 and GC3. ENC (effective number of codons) analysis suggested that mutational bias played a major role in shaping codon usage. Parity Rule 2 (PR2) analysis revealed that GC and AU were not used proportionally. We identified 22 "optimal codons", most ending with an A or U. Our results suggested that nucleotide composition mutation bias and translational selection were the main driving factors of codon usage bias in P. lactiflora. These results lay the foundation for exploring the evolutionary mechanisms and heterologous expression of functionally-important proteins in P. lactiflora. PMID- 26506394 TI - Kinase Inhibitors that Increase the Sensitivity of Methicillin Resistant Staphylococcus aureus to beta-Lactam Antibiotics. AB - Staphylococcus aureus are Gram-positive bacteria that are the leading cause of recurrent infections in humans that include pneumonia, bacteremia, osteomyelitis, arthritis, endocarditis, and toxic shock syndrome. The emergence of methicillin resistant S. aureus strains (MRSA) has imposed a significant concern in sustained measures of treatment against these infections. Recently, MRSA strains deficient in expression of a serine/threonine kinase (Stk1 or PknB) were described to exhibit increased sensitivity to beta-lactam antibiotics. In this study, we screened a library consisting of 280 drug-like, low-molecular-weight compounds with the ability to inhibit protein kinases for those that increased the sensitivity of wild-type MRSA to beta-lactams and then evaluated their toxicity in mice. We report the identification of four kinase inhibitors, the sulfonamides ST085384, ST085404, ST085405, and ST085399 that increased sensitivity of WT MRSA to sub-lethal concentrations of beta-lactams. Furthermore, these inhibitors lacked alerting structures commonly associated with toxic effects, and toxicity was not observed with ST085384 or ST085405 in vivo in a murine model. These results suggest that kinase inhibitors may be useful in therapeutic strategies against MRSA infections. PMID- 26506395 TI - Is Wildlife Fertility Control Always Humane? AB - Investigation of fertility control techniques to reduce reproductive rates in wildlife populations has been the source of much research. Techniques targeting wildlife fertility have been diverse. Most research into fertility control methods has focused upon efficacy, with few studies rigorously assessing animal welfare beyond opportunistic anecdote. However, fertility control techniques represent several very different mechanisms of action (modalities), each with their own different animal welfare risks. We provide a review of the mechanisms of action for fertility control methods, and consider the role of manipulation of reproductive hormones ("endocrine suppression") for the long-term ability of animals to behave normally. We consider the potential welfare costs of animal manipulation techniques that are required to administer fertility treatments, including capture, restraint, surgery and drug delivery, and the requirement for repeated administration within the lifetime of an animal. We challenge the assumption that fertility control modalities generate similar and desirable animal welfare outcomes, and we argue that knowledge of reproductive physiology and behaviour should be more adeptly applied to wild animal management decisions. We encourage wildlife managers to carefully assess long-term behavioural risks, associated animal handling techniques, and the importance of positive welfare states when selecting fertility control methods as a means of population control. PMID- 26506396 TI - Jump Horse Safety: Reconciling Public Debate and Australian Thoroughbred Jump Racing Data, 2012-2014. AB - Thoroughbred jump racing sits in the spotlight of contemporary welfare and ethical debates about horse racing. In Australia, jump racing comprises hurdle and steeplechase races and has ceased in all but two states, Victoria and South Australia. This paper documents the size, geography, composition, and dynamics of Australian jump racing for the 2012, 2013, and 2014 seasons with a focus on debate about risks to horses. We found that the majority of Australian jump racing is regional, based in Victoria, and involves a small group of experienced trainers and jockeys. Australian jump horses are on average 6.4 years of age. The jump career of the majority of horses involves participating in three or less hurdle races and over one season. Almost one quarter of Australian jump horses race only once. There were ten horse fatalities in races over the study period, with an overall fatality rate of 5.1 fatalities per 1000 horses starting in a jump race (0.51%). There was significant disparity between the fatality rate for hurdles, 0.75 fatalities per 1000 starts (0.075%) and steeplechases, 14 fatalities per 1000 starts (1.4%). Safety initiatives introduced by regulators in 2010 appear to have significantly decreased risks to horses in hurdles but have had little or no effect in steeplechases. Our discussion considers these Animals 2015, 5 1073 data in light of public controversy, political debate, and industry regulation related to jump horse safety. PMID- 26506397 TI - MicroRNA Library-Based Functional Screening Identified Androgen-Sensitive miR 216a as a Player in Bicalutamide Resistance in Prostate Cancer. AB - Prostate cancer is a major hormone-dependent tumor affecting men, and is often treated by hormone therapy at the primary stages. Despite its initial efficiency, the disease eventually acquires resistance, resulting in the recurrence of castration-resistant prostate cancer. Recent studies suggest that dysregulation of microRNA (miRNA) function is one of the mechanisms underlying hormone therapy resistance. Identification of critical miRNAs involved in endocrine resistance will therefore be important for developing therapeutic targets for prostate cancer. In the present study, we performed an miRNA library screening to identify anti-androgen bicalutamide resistance-related miRNAs in prostate cancer LNCaP cells. Cells were infected with a lentiviral miRNA library and subsequently maintained in media containing either bicalutamide or vehicle for a month. Microarray analysis determined the amounts of individual miRNA precursors and identified 2 retained miRNAs after one-month bicalutamide treatment. Of these, we further characterized miR-216a, because its function in prostate cancer remains unknown. miR-216a could be induced by dihydrotestosterone in LNCaP cells and ectopic expression of miR-216a inhibited bicalutamide-mediated growth suppression of LNCaP cells. Furthermore, a microarray dataset revealed that the expression levels of miR-216a were significantly higher in clinical prostate cancer than in benign samples. These results suggest that functional screening using an miRNA expression library could be useful for identifying novel miRNAs that contribute to bicalutamide resistance in prostate cancer. PMID- 26506398 TI - In vitro induction and proteomics characterisation of a uranyl-protein interaction network in bovine serum. AB - Uranyl ions (UO2(2+)) were shown to interact with a number of foetal serum proteins, leading to the formation of a complex that could be isolated by ultracentrifugation. The molecular weight of the complex was estimated based on size-exclusion chromatography as 650 000 Da. Online ICP AES detection indicated that UO2(2+) in the complex co-eluted with minor amounts of calcium and phosphorous, but not with magnesium. A 1D gel electrophoresis of the U-complex produced more than 10 bands of similar intensity compared with only 2-3 intense bands corresponding to the main serum proteins in the control serum, indicative of the specific interaction of UO2(2+) with minor proteins. A proteomics approach allowed for the identification of 74 proteins in the complex. Analysis of the protein-protein interaction network in the UO2(2+) complex identified 32 proteins responsible for protein-protein complex formation and 34 with demonstrated ion binding function, suggesting that UO2(2+) stimulates the formation of protein functional networks rather than using a particular molecule as its target. PMID- 26506399 TI - Automated Lab-on-a-Chip Technology for Fish Embryo Toxicity Tests Performed under Continuous Microperfusion (MUFET). AB - The fish embryo toxicity (FET) biotest has gained popularity as one of the alternative approaches to acute fish toxicity tests in chemical hazard and risk assessment. Despite the importance and common acceptance of FET, it is still performed in multiwell plates and requires laborious and time-consuming manual manipulation of specimens and solutions. This work describes the design and validation of a microfluidic Lab-on-a-Chip technology for automation of the zebrafish embryo toxicity test common in aquatic ecotoxicology. The innovative device supports rapid loading and immobilization of large numbers of zebrafish embryos suspended in a continuous microfluidic perfusion as a means of toxicant delivery. Furthermore, we also present development of a customized mechatronic automation interface that includes a high-resolution USB microscope, LED cold light illumination, and miniaturized 3D printed pumping manifolds that were integrated to enable time-resolved in situ analysis of developing fish embryos. To investigate the applicability of the microfluidic FET (MUFET) in toxicity testing, copper sulfate, phenol, ethanol, caffeine, nicotine, and dimethyl sulfoxide were tested as model chemical stressors. Results obtained on a chip based system were compared with static protocols performed in microtiter plates. This work provides evidence that FET analysis performed under microperfusion opens a brand new alternative for inexpensive automation in aquatic ecotoxicology. PMID- 26506401 TI - Does the quality of life impact of tonsillitis correlate with SIGN guideline compliance? An assessment of range and normality. AB - OBJECTIVES: To assess the scores of those who are eligible to be listed for tonsillectomy through compliance with the SIGN guidelines for any trends or range. DESIGN: A prospective study of all patients (aged 16 or above) listed for elective tonsillectomy from a nurse led tonsil clinic. Patients were given a TOI 14 questionnaire to complete after they had been added to the waiting list for surgery, but before undergoing tonsillectomy. Scores were assessed using SPSS. SETTING: Outpatient clinic. PARTICIPANTS: Patients aged over 16 listed for Tonsillectomy via SIGN Guideline 117. MAIN OUTCOME MEASURE: Scores from TOI-14, completed pre-operatively. RESULTS: 155 patients were listed from the nurse led clinic from October 2012 to August 2014; 5 questionnaires were excluded for being incomplete. The score range was 55 (15-70), with a calculated mean score of 45.62 and standard deviation of 9.701. Over 95% of results were within 2 standard deviations of the mean. A calculated negative skew also confirms that most patients who have clinical indications for tonsillectomy compliant with the SIGN guidelines show a higher score on the TOI-14. CONCLUSION: This analysis indicates a trend of pre-intervention scores on the TOI-14 questionnaire for those patients who have a SIGN guideline compliant clinical indication for a tonsillectomy. We therefore propose that this suggests correlation between 'clinically strong' indication for tonsillitis and patient perceived Quality of Life impact. PMID- 26506400 TI - The impact of stage, grade, and mucinous histology on the efficacy of systemic chemotherapy in adenocarcinomas of the appendix: Analysis of the National Cancer Data Base. AB - BACKGROUND: Adenocarcinomas of the appendix represent a heterogeneous disease depending on the presence of mucinous histology, histologic grade, and stage. In the current study, the authors sought to explore the interplay of these factors with systemic chemotherapy in a large population data set. METHODS: Patients in the National Cancer Data Base (NCDB) who were diagnosed with mucinous, nonmucinous, and signet ring cell-type appendiceal neoplasms from 1985 through 2006 were selected. Multivariable Cox proportional hazards regression models were developed. RESULTS: A total of 11,871 patients met the inclusion criteria for the current study: 50.3% had mucinous neoplasms, 40.5% had nonmucinous neoplasms, and 9.2% had signet ring cell-type neoplasms. The 5-year overall survival (OS) stratified by grade was similar among patients with American Joint Committee on Cancer stage I to stage III disease but not for those with stage IV disease. The median OS for patients with stage IV mucinous and nonmucinous tumors was 6.4 years and 2.3 years, respectively, for those with well differentiated histology (P<.0001) and was 1.5 years and 0.8 years, respectively, for those with poorly differentiated histology (P<.0001). In multivariable modeling for stage I to III disease, adjuvant chemotherapy improved OS for both mucinous and nonmucinous histologies, with hazard ratios (HRs) of 0.78 (95% confidence interval [95% CI], 0.68-0.89 [P = .0002]) and 0.83 (95% CI, 0.74-0.94 [P = .002]), respectively. For patients with stage IV disease, systemic chemotherapy significantly improved OS for those with nonmucinous (HR, 0.72; 95% CI, 0.64-0.82 [P<.0001]) but not mucinous (HR, 0.95; 95% CI, 0.86-1.04 [P = .2) histologies, although this was grade-dependent. The median OS for chemotherapy versus no chemotherapy was 6.4 years versus 6.5 years (P value not significant) for patients with mucinous, well differentiated tumors and 1.6 years versus 1.0 years (P = .0007) for patients with mucinous, poorly differentiated tumors. CONCLUSIONS: Adjuvant chemotherapy demonstrated a significant OS benefit regardless of histology. However, for patients with stage IV disease, the benefit of systemic chemotherapy varied by tumor histology and grade, with patients with well-differentiated, mucinous, appendiceal adenocarcinomas deriving no survival benefit from systemic chemotherapy. Cancer 2016;122:213-221. (c) 2015 American Cancer Society. PMID- 26506402 TI - Isometric skeletal muscle force measurement in primary myopathies. AB - INTRODUCTION: In myopathy patients, it is useful to measure skeletal muscle forces. Conventional methods require voluntary muscle activation, which can be unreliable. We evaluated a device for nonvoluntary force assessment. METHODS: We tested 8 patients (unknown myopathy n = 2, inflammatory myopathy, facioscapulohumeral muscular dystrophy, mitochondrial myopathy, dysferlinopathy, multi-minicore disease, Becker-Kiener muscular dystrophy, n = 1 each). Isometric twitch torques of ankle dorsiflexors were measured after fibular nerve stimulation. RESULTS: Six patients had decreased torques vs. 8 controls (men: median Newton-meter 1.6 vs. 5.7, women: 0.2 vs. 3.9, both P < 0.0001). Values correlated with Manual Muscle Test results (r = 0.73; r(2) = 0.53; P < 0.0001). In weak dorsiflexors, torque could be measured despite lower signal-to-noise ratios. In 2 patients with hypertrophy, we measured increased torques. CONCLUSIONS: Nonvoluntary muscle force assessment can be used in patients with myopathies, and values correlate with voluntary forces determined by traditional methods. Muscle Nerve 53: 913-917, 2016. PMID- 26506404 TI - The Role of Target Binding Kinetics in Drug Discovery. AB - Traditionally structure-activity/affinity relationships (SAR) have dominated research in medicinal chemistry. However, structure-kinetics relationships (SKR) can be very informative too. In this viewpoint we explore the molecular determinants of binding kinetics and discuss challenges for future binding kinetics studies. A scheme for future kinetics-directed drug design and discovery is also proposed. PMID- 26506405 TI - Isocyanides as Influenza A Virus Subtype H5N1 Wild-Type M2 Channel Inhibitors. AB - Basic bulky amines such as amantadine are well-characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge-neutral, bulky isocyanides exhibit activities similar to--or even higher than--that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The -NH2 to -N=C group replacement within current anti-influenza drugs was found to give compounds with high activities at low-micromolar concentrations. For example, a tenfold improvement in potency was observed for 1-isocyanoadamantane (27), with an EC50 value of 0.487 MUm against amantadine-sensitive H5N1 virus as determined by both MTT and plaque-reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine-resistant virus strains. PMID- 26506406 TI - A Molecular Clue to PTSD. AB - Work on rats and humans reveals a role for reduction in the levels of the stress regulated protein kinase SGK1 in the development of post-traumatic stress disorder. Read the Research Article. PMID- 26506407 TI - Leigh syndrome: One disorder, more than 75 monogenic causes. AB - Leigh syndrome is the most common pediatric presentation of mitochondrial disease. This neurodegenerative disorder is genetically heterogeneous, and to date pathogenic mutations in >75 genes have been identified, encoded by 2 genomes (mitochondrial and nuclear). More than one-third of these disease genes have been characterized in the past 5 years alone, reflecting the significant advances made in understanding its etiological basis. We review the diverse biochemical and genetic etiology of Leigh syndrome and associated clinical, neuroradiological, and metabolic features that can provide clues for diagnosis. We discuss the emergence of genotype-phenotype correlations, insights gleaned into the molecular basis of disease, and available therapeutic options. PMID- 26506408 TI - Preparation and characterization of a biologic scaffold and hydrogel derived from colonic mucosa. AB - Gastrointestinal pathologies, injuries, and defects affect millions of individuals each year. While there are diverse treatment options for these individuals, no ideal solution exists. The repair or replacement of gastrointestinal tissue, therefore, represents a large unmet clinical need. Biomaterials derived from extracellular matrix (ECM) scaffolds have been effectively used to repair or replace numerous tissues throughout the body in both preclinical and clinical studies. Such scaffolds are prepared from decellularized tissues, and the biochemical, structural, and biologic properties vary depending upon the source tissue from which the ECM is derived. Given the potential benefit of a site-specific ECM scaffold for some applications, the objective of this study was to prepare, characterize, and determine the in vitro and in vivo cell response to ECM derived from porcine colon. Results of this study show that porcine colon can be effectively decellularized while retaining biochemical and structural constituents of the source tissue. Two forms of colonic ECM, scaffold and hydrogel, were shown to be cell friendly and facilitate the polarization of macrophages toward an M2 phenotype both in vitro and in vivo. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 291-306, 2017. PMID- 26506409 TI - Deformation of Microporous Carbon during Adsorption of Nitrogen, Argon, Carbon Dioxide, and Water Studied by in Situ Dilatometry. AB - Adsorption-induced deformation of a monolithic, synthetic carbon of clearly distinguishable micro- and mesoporosity was analyzed by in situ dilatometry with N2 (77 K), Ar (77 K), CO2 (273 K), and H2O (298 K). A characteristic nonmonotonic shape of the strain isotherm showing contraction of the sample at initial micropore adsorption followed by expansion toward completion of micropore filling was found for all adsorbates. However, the extent of contraction and expansion varied significantly with the adsorbate type. The deformation differences observed were compared with the density ratio of the adsorbates within the micropores and the respective unconfined fluids. In particular, CO2 caused the least contraction of the sample, while in parallel adsorbed CO2 molecules were predicted to be considerably compacted inside carbon micropores compared to bulk liquid CO2. On the contrary, the packing of H2O molecules within carbon micropores is less dense than in the bulk liquid and adsorption of H2O produced the most pronounced contraction. N2 and Ar, both exhibiting essentially the same densities in adsorbed and bulk liquid phase, induced very similar deformation of the sample. These findings support theoretical predictions, which correlate adsorption-induced deformation and packing of molecules adsorbed in micropores. Additionally for the first time, we demonstrated with the N2 strain isotherm the existence of two nonmonotonic stages of subsequent contraction and expansion in the regions of micropore and mesopore filling. This characteristic behavior is expected for any micro- and mesoporous material. PMID- 26506410 TI - The AHA Moment: Assessment of the Redox Stability of Ionic Liquids Based on Aromatic Heterocyclic Anions (AHAs) for Nuclear Separations and Electric Energy Storage. AB - Because of their extended conjugated bond network, aromatic compounds generally have higher redox stability than less saturated compounds. We conjectured that ionic liquids (ILs) consisting of aromatic heterocyclic anions (AHAs) may exhibit improved radiation and electrochemical stability. Such properties are important in applications of these ILs as diluents in radionuclide separations and electrolytes in the electric energy storage devices. In this study, we systematically examine the redox chemistry of the AHAs. Three classes of these anions have been studied: (i) simple 5-atom ring AHAs, such as the pyrazolide and triazolides, (ii) AHAs containing an adjacent benzene ring, and (iii) AHAs containing electron-withdrawing groups that were introduced to reduce their basicity and interaction with metal ions. It is shown that fragmentation in the reduced and oxidized states of these AHAs does not generally occur, and the two main products, respectively, are the H atom adduct and the imidyl radical. The latter species occurs either as an N sigma-radical or as an N pi-radical, depending on the length of the N-N bond, and the state that is stabilized in the solid matrix is frequently different from that having the lowest energy in the gas phase. In some instances, the formation of the sandwich pi-stack dimer radical anions has been observed. For trifluoromethylated anions, H adduct formation did not occur; instead, there was facile loss of fluoride from their fluorinated groups. The latter can be problematic in nuclear separations, but beneficial in batteries. Overall, our study suggests that AHA-based ILs are viable candidates for use as radiation-exposed diluents and electrolytes. PMID- 26506411 TI - Cardiac Mechanics in Children with Bronchopulmonary Dysplasia. AB - BACKGROUND: Disruption of pulmonary vasculogenesis occurs in bronchopulmonary dysplasia (BPD). Increased impedance to pulmonary flow secondary to abnormal vascular development may affect ventricular mechanics. OBJECTIVES: We aimed to test the hypothesis that cardiac mechanics are altered in prematurely born children with BPD. METHODS: A cohort of 47 children was studied: 22 aged 48.9 +/- 6.4 months born preterm with BPD (group I), 13 aged 46.3 +/- 8.1 months born preterm without BPD (group II), and 12 healthy children aged 53.4 +/- 12.2 months born at term (group III). Left (LV) and right ventricular (RV) strain and strain rate were assessed by speckle-tracking echocardiography. RESULTS: The global RV systolic strain rate (p = 0.022) was significantly lower, while RV systolic strain (p = 0.05) and early diastolic strain rate (p = 0.05) and LV longitudinal systolic strain rate (p = 0.06) also tended to be lower in group I than group III. Group I also tended to have lower RV systolic strain (p = 0.09) and early diastolic strain rate (p = 0.049) and LV longitudinal systolic strain rate (p = 0.08) than group II. An increasing trend from group I to III was observed for RV lateral wall and septal systolic strain and strain rate (all p < 0.05). The LV but not RV size was significantly smaller in group I compared with group III (p < 0.05). Multiple regression identified duration of invasive ventilation (beta = 0.66, p = 0.032) as an independent determinant of RV systolic strain after adjustment for perinatal risk factors. CONCLUSION: Impairment of RV myocardial deformation occurs in children with BPD, the magnitude of which is associated negatively with the duration of invasive ventilation. PMID- 26506412 TI - Deficiency of Calcium-Independent Phospholipase A2 Beta Induces Brain Iron Accumulation through Upregulation of Divalent Metal Transporter 1. AB - Mutations in PLA2G6 have been proposed to be the cause of neurodegeneration with brain iron accumulation type 2. The present study aimed to clarify the mechanism underlying brain iron accumulation during the deficiency of calcium-independent phospholipase A2 beta (iPLA2beta), which is encoded by the PLA2G6 gene. Perl's staining with diaminobenzidine enhancement was used to visualize brain iron accumulation. Western blotting was used to investigate the expression of molecules involved in iron homeostasis, including divalent metal transporter 1 (DMT1) and iron regulatory proteins (IRP1 and 2), in the brains of iPLA2beta knockout (KO) mice as well as in PLA2G6-knockdown (KD) SH-SY5Y human neuroblastoma cells. Furthermore, mitochondrial functions such as ATP production were examined. We have discovered for the first time that marked iron deposition was observed in the brains of iPLA2beta-KO mice since the early clinical stages. DMT1 and IRP2 were markedly upregulated in all examined brain regions of aged iPLA2beta-KO mice compared to age-matched wild-type control mice. Moreover, peroxidized lipids were increased in the brains of iPLA2beta-KO mice. DMT1 and IRPs were significantly upregulated in PLA2G6-KD cells compared with cells treated with negative control siRNA. Degeneration of the mitochondrial inner membrane and decrease of ATP production were observed in PLA2G6-KD cells. These results suggest that the genetic ablation of iPLA2beta increased iron uptake in the brain through the activation of IRP2 and upregulation of DMT1, which may be associated with mitochondrial dysfunction. PMID- 26506413 TI - A Single Bout of Moderate Aerobic Exercise Improves Motor Skill Acquisition. AB - Long-term exercise is associated with improved performance on a variety of cognitive tasks including attention, executive function, and long-term memory. Remarkably, recent studies have shown that even a single bout of aerobic exercise can lead to immediate improvements in declarative learning and memory, but less is known about the effect of exercise on motor learning. Here we sought to determine the effect of a single bout of moderate intensity aerobic exercise on motor skill learning. In experiment 1, we investigated the effect of moderate aerobic exercise on motor acquisition. 24 young, healthy adults performed a motor learning task either immediately after 30 minutes of moderate intensity running, after running followed by a long rest period, or after slow walking. Motor skill was assessed via a speed-accuracy tradeoff function to determine how exercise might differentially affect two distinct components of motor learning performance: movement speed and accuracy. In experiment 2, we investigated both acquisition and retention of motor skill across multiple days of training. 20 additional participants performed either a bout of running or slow walking immediately before motor learning on three consecutive days, and only motor learning (no exercise) on a fourth day. We found that moderate intensity running led to an immediate improvement in motor acquisition for both a single session and on multiple sessions across subsequent days, but had no effect on between-day retention. This effect was driven by improved movement accuracy, as opposed to speed. However, the benefit of exercise was dependent upon motor learning occurring immediately after exercise-resting for a period of one hour after exercise diminished the effect. These results demonstrate that moderate intensity exercise can prime the nervous system for the acquisition of new motor skills, and suggest that similar exercise protocols may be effective in improving the outcomes of movement rehabilitation programs. PMID- 26506414 TI - Group Music Training and Children's Prosocial Skills. AB - We investigated if group music training in childhood is associated with prosocial skills. Children in 3rd or 4th grade who attended 10 months of music lessons taught in groups were compared to a control group of children matched for socio economic status. All children were administered tests of prosocial skills near the beginning and end of the 10-month period. Compared to the control group, children in the music group had larger increases in sympathy and prosocial behavior, but this effect was limited to children who had poor prosocial skills before the lessons began. The effect was evident even when the lessons were compulsory, which minimized the role of self-selection. The results suggest that group music training facilitates the development of prosocial skills. PMID- 26506415 TI - mTOR and MEK1/2 inhibition differentially modulate tumor growth and the immune microenvironment in syngeneic models of oral cavity cancer. AB - We investigated the effects of mTOR and MEK1/2 inhibition on tumor growth and the tumor microenvironment in immunogenic and poorly immunogenic models of murine oral cancer. In vitro, rapamycin and PD901 inhibited signaling through expected downstream targets, but only PD901 reduced viability and altered function of MOC cells. Following transplantation of MOC cells into immune-competent mice, effects on both cancer and infiltrating immune cells were characterized following rapamycin and/or PD901 treatment for 21 days. In vivo, both rapamycin and PD901 inhibition reduced primary growth of established MOC tumors on treatment. Following withdrawal of PD901, rapid rebound of tumor growth limited survival, whereas durable tumor control was observed following rapamycin treatment in immunogenic MOC1 tumors despite more robust inhibition of oncogenic signaling by PD901. Characterization of the immune microenvironment revealed diminished infiltration and activation of antigen-specific CD8+ T-cells and other immune cells following PD901 but not rapamycin in immunogenic tumors. Subsequent in vitro T-cell assays validated robust inhibition of T-cell expansion and activation following MEK inhibition compared to mTOR inhibition. CD8 cell depletion abrogated rapamycin-induced primary tumor growth inhibition in MOC1 mice. These data have critical implications in the design of combination targeted and immune therapies in oral cancer. PMID- 26506416 TI - Potential role of aquaporin 3 in gastric intestinal metaplasia. AB - Gastric intestinal metaplasia (GIM) is a pre-cancerous condition and a pivotal step in the formation of gastric cancer (GC). Aquaporin 3 (AQP3) has been found to be expressed in goblet cells rather than mucus-secreting glands. To investigate the characteristics of GIM in non-cancerous tissues adjacent to GC, as well as the expression and role of AQP3 in GIM tissues, 16 patients diagnosed with gastric adenocarcinoma of intestinal type located in the lesser curve of the antrum were consecutively enrolled in this study. A new pathological technology called "gastric mucosal sausage roll" was introduced. GIM was determined according to the updated Sydney system, and AQP3 expression in goblet cells was determined by immunohistochemistry. GIM was found in all stomach specimens, and its incidence increased with progression to GC (P < 0.001). GIM prevalence displayed remarkable association with the distance to GC in the anterior gastric wall tissues (P = 0.016) and tissues toward the cardia (P = 0.014), such that GIM was more common in the areas closer to GC (P < 0.001). AQP3 was found to be expressed in 67.71% of parts with GIM, and AQP3 immunoreactivity was identified more frequently in severe GIM areas (P < 0.001). In short, the incidence and severity of GIM correlated with the distance from GC, and AQP3 was differentially expressed in goblet cells, with most AQP3-positive goblet cells presenting in severe GIM. Together, this study suggests that AQP3 may play an important role in gastric carcinogenesis from GIM. PMID- 26506417 TI - Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. AB - Low grade serous ovarian tumours are a rare and under-characterised histological subtype of epithelial ovarian tumours, with little known of the molecular drivers and facilitators of tumorigenesis beyond classic oncogenic RAS/RAF mutations. With a move towards targeted therapies due to the chemoresistant nature of this subtype, it is pertinent to more fully characterise the genetic events driving this tumour type, some of which may influence response to therapy and/or development of drug resistance. We performed genome-wide high-resolution genomic copy number analysis (Affymetrix SNP6.0) and mutation hotspot screening (KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53) to compare a large cohort of ovarian serous borderline tumours (SBTs, n = 57) with low grade serous carcinomas (LGSCs, n = 19). Whole exome sequencing was performed for 13 SBTs, nine LGSCs and one mixed low/high grade carcinoma. Copy number aberrations were detected in 61% (35/57) of SBTs, compared to 100% (19/19) of LGSCs. Oncogenic RAS/RAF/ERBB2 mutations were detected in 82.5% (47/57) of SBTs compared to 63% (12/19) of LGSCs, with NRAS mutations detected only in LGSC. Some copy number aberrations appeared to be enriched in LGSC, most significantly loss of 9p and homozygous deletions of the CDKN2A/2B locus. Exome sequencing identified BRAF, KRAS, NRAS, USP9X and EIF1AX as the most frequently mutated genes. We have identified markers of progression from borderline to LGSC and novel drivers of LGSC. USP9X and EIF1AX have both been linked to regulation of mTOR, suggesting that mTOR inhibitors may be a key companion treatment for targeted therapy trials of MEK and RAF inhibitors. PMID- 26506418 TI - Long non-coding RNA ZFAS1 interacts with CDK1 and is involved in p53-dependent cell cycle control and apoptosis in colorectal cancer. AB - We determined expression of 83 long non-coding RNAs (lncRNAs) and identified ZFAS1 to be significantly up-regulated in colorectal cancer (CRC) tissue. In cohort of 119 CRC patients we observed that 111 cases displayed at least two times higher expression of ZFAS1 in CRC compared to paired normal colorectal tissue (P < 0.0001). By use of CRC cell lines (HCT116+/+, HCT116-/- and DLD-1) we showed, that ZFAS1 silencing decreases proliferation through G1-arrest of cell cycle, and also tumorigenicity of CRC cells. We identified Cyclin-dependent kinase 1 (CDK1) as interacting partner of ZFAS1 by pull-down experiment and RNA immunoprecipitation. Further, we have predicted by bioinformatics approach ZFAS1 to sponge miR-590-3p, which was proved to target CDK1. Levels of CDK1 were not affected by ZFAS1 silencing, but cyclin B1 was decreased in both cell lines. We observed significant increase in p53 levels and PARP cleavage in CRC cell lines after ZFAS1 silencing indicating increase in apoptosis. Our data suggest that ZFAS1 may function as oncogene in CRC by two main actions: (i) via destabilization of p53 and through (ii) interaction with CDK1/cyclin B1 complex leading to cell cycle progression and inhibition of apoptosis. However, molecular mechanisms behind these interactions have to be further clarified. PMID- 26506419 TI - Active glycolytic metabolism in CD133(+) hepatocellular cancer stem cells: regulation by MIR-122. AB - Although altered metabolic pathway is an important diagnostic maker and therapeutic target in cancer, it is poorly understood in cancer stem cells (CSCs). Here we show that the CD133 (+) hepatocellular CSCs have distinct metabolic properties, characterized by more active glycolysis over oxidative phosphorylation, compared to the CD133 (-) cells. Inhibition of PDK4 and LDHA markedly suppresses CD133 (+) stemness characteristics and overcome resistance to sorafenib (current chemotherapeutic agent for hepatocellular cancer). Addition of glucose or lactate to CD133 (-) cells promotes CSC phenotypes, as evidenced by increased CD133 (+) cell population, elevated stemness gene expression and enhanced spheroid formation. Furthermore, the liver-specific miRNA, miR-122, inhibits CSC phenotypes by regulating glycolysis through targeting PDK4. Our findings suggest that enhanced glycolysis is associated with CD133 (+) stem-like characteristics and that metabolic reprogramming through miR-122 or PDK4 may represent a novel therapeutic approach for the treatment of hepatocellular cancer. PMID- 26506420 TI - Cetuximab enhanced the efficacy of chemotherapeutic agent in ABCB1/P-glycoprotein overexpressing cancer cells. AB - The overexpression of ATP-binding cassette (ABC) transporters is closely associated with the development of multidrug resistance (MDR) in certain types of cancer, which represents a formidable obstacle to the successful cancer chemotherapy. Here, we investigated that cetuximab, an EGFR monoclonal antibody, reversed the chemoresistance mediated by ABCB1, ABCG2 or ABCC1. Our results showed that cetuximab significantly enhanced the cytotoxicity of ABCB1 substrate agent in ABCB1-overexpressing MDR cells but had no effect in their parental drug sensitive cells and ABCC1, ABCG2 overexpressing cells. Furthermore, cetuximab markedly increased intracellular accumulation of doxorubicin (DOX) and rhodamine 123 (Rho 123) in ABCB1-overexpressing MDR cancer cells in a concentration dependent manner. Cetuximab stimulated the ATPase activity but did not alter the expression level of ABCB1 or block phosphorylation of AKT and ERK. Interestingly, cetuximab decreased the cell membrane fluidity which was known to decrease the function of ABCB1. Our findings advocate further clinical investigation of combination chemotherapy of cetuximab and conventional chemotherapeutic drugs in ABCB1 overexpressing cancer patients. PMID- 26506421 TI - Cardamonin reduces chemotherapy-enriched breast cancer stem-like cells in vitro and in vivo. AB - The failure of cytotoxic chemotherapy in breast cancers has been closely associated with the presence of drug resistant cancer stem cells (CSCs). Thus, screening for small molecules that selectively inhibit growth of CSCs may offer great promise for cancer control, particularly in combination with chemotherapy. In this report, we provide the first demonstration that cardamonin, a small molecule, selectively inhibits breast CSCs that have been enriched by chemotherapeutic drugs. In addition, cardamonin also sufficiently prevents the enrichment of CSCs when simultaneously used with chemotherapeutic drugs. Specifically, cardamonin effectively abolishes chemotherapeutic drug-induced up regulation of IL-6, IL-8 and MCP-1 and activation of NF-kappaB/IKBalpha and Stat3. Furthermore, in a xenograft mouse model, co-administration of cardamonin and the chemotherapeutic drug doxorubicin significantly retards tumor growth and simultaneously decreases CSC pools in vivo. Since cardamonin has been found in some herbs, this work suggests a potential new approach for the effective treatment of breast CSCs by administration of cardamonin either concurrent with or after chemotherapeutic drugs. PMID- 26506422 TI - Bcl-xL inhibition by molecular-targeting drugs sensitizes human pancreatic cancer cells to TRAIL. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various types of cancer cells without damaging normal cells. However, in terms of pancreatic cancer, not all cancer cells are sensitive to TRAIL. In this study, we examined a panel of human pancreatic cancer cell lines for TRAIL sensitivity and investigated the effects of Bcl-2 family inhibitors on their response to TRAIL. Both ABT-263 and ABT-737 inhibited the function of Bcl 2, Bcl-xL, and Bcl-w. Of the nine pancreatic cancer cell lines tested, six showed no or low sensitivity to TRAIL, which correlated with protein expression of Bcl xL. ABT-263 significantly sensitized four cell lines (AsPC-1, Panc-1, CFPAC-1, and Panc10.05) to TRAIL, with reduced cell viability and increased apoptosis. Knockdown of Bcl-xL, but not Bcl-2, by siRNA transfection increased the sensitivity of AsPC-1 and Panc-1 cells to TRAIL. ABT-263 treatment had no effect on protein expression of Bcl-2, Bcl-xL, or c-FLIPs. In Panc-1 cells, ABT-263 increased the surface expression of death receptor (DR) 5; the NF-kappaB pathway, but not endoplasmic reticulum stress, participated in the increase. In xenograft mouse models, the combination of TRAIL and ATB-737 suppressed the in vivo tumor growth of AsPC-1 and Panc-1 cells. These results indicate that Bcl-xL is responsible for TRAIL resistance in human pancreatic cancer cells, and that Bcl-2 family inhibitors could represent promising reagents to sensitize human pancreatic cancers in DR-targeting therapy. PMID- 26506424 TI - A framework for T cell assays. PMID- 26506423 TI - Bis-cyclopropane analog of disorazole C1 is a microtubule-destabilizing agent active in ABCB1-overexpressing human colon cancer cells. AB - The novel, chemically stabilized disorazole analog, (-)-CP2-disorazole C1 (1) displayed potent anti-proliferative activity against a broad-spectrum of human colorectal cancer cells. HCT15 and H630R1 cell lines expressing high basal levels of the ABCB1 protein, known to cause multi-drug resistance, were also sensitive to growth inhibition by 1 but were resistant to both vincristine and docetaxel, two commonly used microtubule inhibitors. Compound 1 exhibited strong inhibition of tubulin polymerization at a level comparable to vincristine. In addition, treatment with 1 resulted in decreased protein levels of beta-tubulin but not alpha-tubulin. An analysis of cellular proteins known to interact with microtubules showed that 1 caused decreased expression of c-Myc, APC, Rb, and additional key cellular signaling pathways in CRC cells. Treatment with compound 1 also resulted in G2/M cell cycle arrest and induction of apoptosis, but not senescence. Furthermore, endothelial spheroid sprouting assays demonstrated that 1 suppressed angiogenesis and can, therefore, potentially prevent cancer cells from spreading and metastasizing. Taken together, these findings suggest that the microtubule disruptor 1 may be a potential drug candidate for the treatment of mCRC. PMID- 26506425 TI - Epigenetic downregulation of the ISG15-conjugating enzyme UbcH8 impairs lipolysis and correlates with poor prognosis in nasopharyngeal carcinoma. AB - We identified the UBE2L6 gene, encoding the ISG15-conjugating enzyme UbcH8, as one gene significantly downregulated by promoter hypermethylation in nasopharyngeal carcinoma (NPC). Reduced expression of the UbcH8 protein correlated with poor outcome in NPC patients. Restored expression of UBE2L6 suppressed proliferation and colony formation in NPC cells, while inducing apoptosis. Of particular interest, we found that aberrant lipid turnover was controlled by UbcH8 in NPC through ISG15-conjugation of valosin-containing protein (VCP). Tumor tissue and NPC cell lines showed conspicuously strong accumulation of lipid droplets (LDs) compared to control nasopharyngeal epithelium and non-cancerous cell lines. We demonstrated that UbcH8 counteracts degradation of adipocyte triglyceride lipase (ATGL), a key enzyme in lipid catabolism. PMID- 26506426 TI - Dosage Compensation of X-Linked Muller Element F Genes but Not X-Linked Transgenes in the Australian Sheep Blowfly. AB - In most animals that have X and Y sex chromosomes, chromosome-wide mechanisms are used to balance X-linked gene expression in males and females. In the fly Drosophila melanogaster, the dosage compensation mechanism also generally extends to X-linked transgenes. Over 70 transgenic lines of the Australian sheep blowfly Lucilia cuprina have been made as part of an effort to develop male-only strains for a genetic control program of this major pest of sheep. All lines carry a constitutively expressed fluorescent protein marker gene. In all 12 X-linked lines, female larvae show brighter fluorescence than male larvae, suggesting the marker gene is not dosage compensated. This has been confirmed by quantitative RT PCR for selected lines. To determine if endogenous X-linked genes are dosage compensated, we isolated 8 genes that are orthologs of genes that are on the fourth chromosome in D. melanogaster. Recent evidence suggests that the D. melanogaster fourth chromosome, or Muller element F, is the ancestral X chromosome in Diptera that has reverted to an autosome in Drosophila species. We show by quantitative PCR of male and female DNA that 6 of the 8 linkage group F genes reside on the X chromosome in L. cuprina. The other two Muller element F genes were found to be autosomal in L. cuprina, whereas two Muller element B genes were found on the same region of the X chromosome as the L. cuprina orthologs of the D. melanogaster Ephrin and gawky genes. We find that the L. cuprina X chromosome genes are equally expressed in males and females (i.e., fully dosage compensated). Thus, unlike in Drosophila, it appears that the Lucilia dosage compensation system is specific for genes endogenous to the X chromosome and cannot be co-opted by recently arrived transgenes. PMID- 26506428 TI - Capillary Force Driven Self-Assembly of Anisotropic Hierarchical Structures Prepared by Femtosecond Laser 3D Printing and Their Applications in Crystallizing Microparticles. AB - The hierarchical structures are the derivation of various functionalities in the natural world and have inspired broad practical applications in chemical systhesis and biological manipulation. However, traditional top-down fabrication approaches suffered from low complexity. We propose a laser printing capillary assisted self-assembly (LPCS) strategy for fabricating regular periodic structures. Microscale pillars are first produced by the localized femtosecond laser polymerization and are subsequently self-assembled into periodic hierarchical architectures with the assistance of controlled capillary force. Moreover, based on anisotropic assemblies of micropillars, the LPCS method is further developed for the preparation of more complicated and advanced functional microstructures. Pillars cross section, height, and spatial arrangement can be tuned to guide capillary force, and diverse assemblies with different configurations are thus achieved. Finally, we developed a strategy for growing micro/nanoparticles in designed spatial locations through solution-evaporation self-assembly induced by morphology. Due to the high flexibility of LPCS method, the special arrangements, sizes, and distribution density of the micro/nanoparticles can be controlled readily. Our method will be employed not only to fabricate anisotropic hierarchical structures but also to design and manufacture organic/inorganic microparticles. PMID- 26506427 TI - LXR Agonism Upregulates the Macrophage ABCA1/Syntrophin Protein Complex That Can Bind ApoA-I and Stabilized ABCA1 Protein, but Complex Loss Does Not Inhibit Lipid Efflux. AB - Macrophage ABCA1 effluxes lipid and has anti-inflammatory activity. The syntrophins, which are cytoplasmic PDZ protein scaffolding factors, can bind ABCA1 and modulate its activity. However, many of the data assessing the function of the ABCA1-syntrophin interaction are based on overexpression in nonmacrophage cells. To assess endogenous complex function in macrophages, we derived immortalized macrophages from Abca1(+/+) and Abca1(-/-) mice and show their phenotype recapitulates primary macrophages. Abca1(+/+) lines express the CD11B and F4/80 macrophage markers and markedly upregulate cholesterol efflux in response to LXR nuclear hormone agonists. In contrast, immortalized Abca1(-/-) macrophages show no efflux to apoA-I. In response to LPS, Abca1(-/-) macrophages display pro-inflammatory changes, including an increased level of expression of cell surface CD14, and 11-26-fold higher levels of IL-6 and IL-12 mRNA. Given recapitulation of phenotype, we show with these lines that the ABCA1-syntrophin protein complex is upregulated by LXR agonists and can bind apoA-I. Moreover, in immortalized macrophages, combined alpha1/beta2-syntrophin loss modulated ABCA1 cell surface levels and induced pro-inflammatory gene expression. However, loss of all three syntrophin isoforms known to bind ABCA1 did not impair lipid efflux in immortalized or primary macrophages. Thus, the ABCA1-syntrophin protein complex is not essential for ABCA1 macrophage lipid efflux but does directly interact with apoA-I and can modulate the pool of cell surface ABCA1 stabilized by apoA-I. PMID- 26506429 TI - Pathway Distribution Model for Solute Transport in Stratum Corneum. AB - One of the main functions of the skin is to reduce the amount of water evaporating from the surface of a human body with outermost layer of the epidermis, stratum corneum (SC), forming a barrier, which protects underlying tissue from dehydration. Empirical data obtained for water penetration in SC are normally analysed using mathematical models, among which the homogeneous membrane (HM) model is commonly employed to describe transport kinetics in SC. However, the HM model failed to fit simultaneously the experimental data for water permeation and desorption (Anissimov YG, Roberts MS. 2009. J Pharm Sci 98:772 781), as the model does not account for a complex structure of SC and irregular distribution of corneocytes. Our previous work (Anissimov YG, Roberts MS. 2009. J Pharm Sci 98:772-781) introduced a slow binding (SB) model that is more aligned with the true biological structure of SC. This report provides an alternative/additional model to both the HM and SB models and takes into account the distribution of effective pathways across SC for water transport. PMID- 26506430 TI - Silver-Catalyzed Enantioselective Propargylation Reactions of N Sulfonylketimines. AB - The enantioselective silver-catalyzed propargylation of N-sulfonylketimines is described. This reaction proceeds in high yield and excellent enantiomeric ratio and is compatible with a wide variety of diaryl- and alkylketimines. Synthetic transformations of homopropargylic products via enyne ring-closing metathesis, Sonogashira cross-coupling, and reduction reactions proceed with high stereochemical fidelity. Both allenyl and propargyl borolane reagents can be used to obtain homopropargylic products, a distribution most consistent with a mechanism involving transmetalation of the silver catalyst with the borolane reagent. PMID- 26506432 TI - Transparency in reporting observational studies: reflections after a year. AB - The PLOS Medicine Editors take stock of changes in the reporting of observational studies following our new transparency guidelines from August 2014. PMID- 26506431 TI - TRIM21 Promotes cGAS and RIG-I Sensing of Viral Genomes during Infection by Antibody-Opsonized Virus. AB - Encapsidation is a strategy almost universally employed by viruses to protect their genomes from degradation and from innate immune sensors. We show that TRIM21, which targets antibody-opsonized virions for proteasomal destruction, circumvents this protection, enabling the rapid detection and degradation of viral genomes before their replication. TRIM21 triggers an initial wave of cytokine transcription that is antibody, rather than pathogen, driven. This early response is augmented by a second transcriptional program, determined by the nature of the infecting virus. In this second response, TRIM21-induced exposure of the viral genome promotes sensing of DNA and RNA viruses by cGAS and RIG-I. This mechanism allows early detection of an infection event and drives an inflammatory response in mice within hours of viral challenge. PMID- 26506433 TI - Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes. AB - Recent studies have highlighted the ability of HIV to escape from cytotoxic T lymphocyte (CTL) responses that concurrently target multiple viral epitopes. Yet, the viral dynamics involved in such escape are incompletely understood. Previous analyses have made several strong assumptions regarding HIV escape from CTL responses such as independent or non-concurrent escape from individual CTL responses. Using experimental data from evolution of HIV half genomes in four patients we observe concurrent viral escape from multiple CTL responses during early infection (first 100 days of infection), providing confirmation of a recent result found in a study of one HIV-infected patient. We show that current methods of estimating CTL escape rates, based on the assumption of independent escapes, are biased and perform poorly when CTL escape proceeds concurrently at multiple epitopes. We propose a new method for analyzing longitudinal sequence data to estimate the rate of CTL escape across multiple epitopes; this method involves few parameters and performs well in simulation studies. By applying our novel method to experimental data, we find that concurrent multiple escapes occur at rates between 0.03 and 0.4 day(-1), a relatively broad range that reflects uncertainty due to sparse sampling and wide ranges of parameter values. However, we show that concurrent escape at rates 0.1-0.2 day(-1) across multiple epitopes is consistent with our patient datasets. PMID- 26506434 TI - A Within-Animal Comparison of Skilled Forelimb Assessments in Rats. AB - A variety of skilled reaching tasks have been developed to evaluate forelimb function in rodent models. The single pellet skilled reaching task and pasta matrix task have provided valuable insight into recovery of forelimb function in models of neurological injury and disease. Recently, several automated measures have been developed to reduce the cost and time burden of forelimb assessment in rodents. Here, we provide a within-subject comparison of three common forelimb assessments to allow direct evaluation of sensitivity and efficiency across tasks. Rats were trained to perform the single pellet skilled reaching task, the pasta matrix task, and the isometric pull task. Once proficient on all three tasks, rats received an ischemic lesion of motor cortex and striatum to impair use of the trained limb. On the second week post-lesion, all three tasks measured a significant deficit in forelimb function. Performance was well-correlated across tasks. By the sixth week post-lesion, only the isometric pull task measured a significant deficit in forelimb function, suggesting that this task is more sensitive to chronic impairments. The number of training days required to reach asymptotic performance was longer for the isometric pull task, but the total experimenter time required to collect and analyze data was substantially lower. These findings suggest that the isometric pull task represents an efficient, sensitive measure of forelimb function to facilitate preclinical evaluation in models of neurological injury and disease. PMID- 26506435 TI - Alterations in carbohydrate metabolism in cirrhotic patients before and after liver transplant. AB - AIM: The main objective of this study is to demonstrate whether carbohydrate metabolism alterations identified in patients with advanced cirrhosis show any improvement after liver transplant. METHODS: The study included 86 patients who underwent liver transplant between March 2010 and February 2011. An oral glucose tolerance test was performed before the liver transplant, and 6 and 12 months after. Beta cell function and insulin resistance were also calculated, applying formulae that use basal plasma glycaemia and insulin, and plasma glycaemia and insulin during an oral glucose tolerance test. Risk factors for pre- and post transplant diabetes were also studied. The diagnosis of diabetes was based on an OGTT. RESULTS: The proportion of patients with diabetes before transplant, and at month 6 and 12 after transplant were 70.9%, 48.8% and 39.2%, respectively. Compared to baseline, at month 6 the odds ratio of having diabetes was 0.39 (IC 95% [0.21, 0.73]) and at month 12 it was 0.26 (IC 95% [0.14, 0.50]). The composite insulin sensitivity index values at 6 and 12 months were 1.72 units higher (IC 95% [0.84, 2.58]) and 1.58 units higher (IC 95% [0.68, 2.44)] than baseline. A statistically significant association was found between high MELD values and high body mass index, and risk of pre-transplant diabetes (p=0.001 and p=0.033, respectively). Cirrhosis aetiology did not influence the risk of diabetes. CONCLUSIONS: In this study, we were able to ascertain that alterations in carbohydrate metabolism typical of advanced cirrhosis improve after liver transplant. This improvement is mainly due to an improvement in insulin resistance. PMID- 26506436 TI - Enhanced In Vitro Biocompatibility of Chemically Modified Poly(dimethylsiloxane) Surfaces for Stable Adhesion and Long-term Investigation of Brain Cerebral Cortex Cells. AB - Studies on the mammalian brain cerebral cortex have gained increasing importance due to the relevance of the region in controlling critical higher brain functions. Interactions between the cortical cells and surface extracellular matrix (ECM) proteins play a pivotal role in promoting stable cell adhesion, growth, and function. Poly(dimethylsiloxane) (PDMS) based platforms have been increasingly used for on-chip in vitro cellular system analysis. However, the inherent hydrophobicity of the PDMS surface has been unfavorable for any long term cell system investigations due to transitory physical adsorption of ECM proteins on PDMS surfaces followed by eventual cell dislodgement due to poor anchorage and viability. To address this critical issue, we employed the (3 aminopropyl)triethoxysilane (APTES) based cross-linking strategy to stabilize ECM protein immobilization on PDMS. The efficiency of surface modification in supporting adhesion and long-term viability of neuronal and glial cells was analyzed. The chemically modified surfaces showed a relatively higher cell survival with an increased neurite length and neurite branching. These changes were understood in terms of an increase in surface hydrophilicity, protein stability, and cell-ECM protein interactions. The modification strategy could be successfully applied for stable cortical cell culture on the PDMS microchip for up to 3 weeks in vitro. PMID- 26506437 TI - Circulating Concentrations of Vitamin B6 and Kidney Cancer Prognosis: A Prospective Case-Cohort Study. AB - Prospective cohort studies have found that prediagnostic circulating vitamin B6 is inversely associated with both risk of kidney cancer and kidney cancer prognosis. We investigated whether circulating concentrations of vitamin B6 at kidney cancer diagnosis are associated with risk of death using a case-cohort study of 630 renal cell carcinoma (RCC) patients. Blood was collected at the time of diagnosis, and vitamin B6 concentrations were quantified using LC-MS/MS. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models. After adjusting for stage, age, and sex, the hazard was 3 times lower among those in the highest compared to the lowest fourth of B6 concentration (HR4vs1 0.33, 95% CI [0.18, 0.60]). This inverse association was solely driven by death from RCC (HR4vs1 0.22, 95% CI [0.11, 0.46]), and not death from other causes (HR4vs1 0.89, 95% CI [0.35, 2.28], p-interaction = 0.008). These results suggest that circulating vitamin B6 could provide additional prognostic information for kidney cancer patients beyond that afforded by tumour stage. PMID- 26506438 TI - Evaluation and Optimization of an ELISA Procedure to Quantify Antibodies Against Pneumococcal Polysaccharides Included in the 13-Valent Conjugate Vaccine. AB - The 13-valent pneumococcal conjugate vaccine (PCV-13) is recommended for HIV infected people, although its effectiveness in this population remains under evaluation. In this study, we describe the development, optimization, and analytical validation of an ELISA procedure to measure specific antibodies for the pneumococcal polysaccharide serotypes included in PCV13 vaccine, testing sera obtained from HIV-infected outpatients (n = 30) who received the vaccine. The protocol followed the last version of WHO guidelines, based on the new standard 007sp, with the modification of employing Statens Serum Institut (SSI) antigens. We supplied the assay performance validation in terms of sensitivity, reproducibility, precision and accuracy. In addition we detailed optimal antigen coating concentrations and ELISA conditions common to all 13 serotypes, suitable for laboratories performing these assays in order to standardize the method. Our procedure showed reproducibility and reliability, making it a valid alternative for evaluating the response to pneumococcal serotypes included in PCV13 vaccine. PMID- 26506440 TI - Penetrance of pathogenic mutations in haploinsufficient genes for intellectual disability and related disorders. AB - De novo loss of function (LOF) mutations in the ASXL3 gene cause Bainbridge Ropers syndrome, a severe form of intellectual disability (ID) and developmental delay, but there is evidence that they also occur in healthy individuals. This has prompted us to look for non-pathogenic LOF variants in other ID genes. Heterozygous LOF mutations in ASXL1, a paralog of ASXL3, are known to cause Bohring-Opitz syndrome (BOS), and benign LOF mutations in this gene have not been published to date. Therefore, we were surprised to find 56 ASXL1 LOF variants in the ExAC database (http://exac.broadinstitute.org), comprising exomes from 60,706 individuals who had been selected to exclude severe genetic childhood disorders. 4 of these variants have been described as disease-causing in patients with BOS, which rules out the possibility that pathogenic and clinically neutral LOF variants in this gene are functionally distinct. Apparently benign LOF variants were also detected in several other genes for ID and related disorders, including CDH15, KATNAL2, DEPDC5, ARID1B and AUTS2, both in the ExAC database and in the 6,500 exomes of the Exome Variant Server (http://evs.gs.washington.edu/EVS/). These observations argue for low penetrance of LOF mutations in ASXL1 and other genes for ID and related disorders, which could have far-reaching implications for genetic counseling and research. PMID- 26506439 TI - A Comparison of the Anorectic Effect and Safety of the Alpha2-Adrenoceptor Ligands Guanfacine and Yohimbine in Rats with Diet-Induced Obesity. AB - The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial alpha2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of alpha2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of alpha2 adrenoceptor--yohimbine and guanfacine--act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of alpha2A-adrenoceptors and partial stimulation of alpha2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of alpha1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. alpha1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity. PMID- 26506441 TI - Carnitine palmitoyltransferase I gene in Synechogobius hasta: Cloning, mRNA expression and transcriptional regulation by insulin in vitro. AB - We cloned seven complete CPT I cDNA sequences (CPT I alpha1a-1a, CPT I alpha1a 1b, CPT I alpha1a-1c, CPT I alpha1a-2, CPT I alpha2a, CPT I alpha2b1a, CPT I beta) and a partial cDNA sequence (CPT I alpha2b1b) from Synechogobius hasta. Phylogenetic analysis shows that there are four CPT I duplications in S. hasta, CPT I duplication resulting in CPT I alpha and CPT I beta, CPT I alpha duplication producing CPT I alpha1 and CPT I alpha2, CPT I alpha2 duplication generating CPT I alpha2a and CPT I alpha2b, and CPT I alpha2b duplication creating CPT I alpha2b1a and CPT I alpha2b1b. Alternative splicing of CPT Ialpha1a results in the generation of four CPT I isoforms, CPT I alpha1a-1a, CPT I alpha1a-1b, CPT I alpha1a-1c and CPT I alpha1a-2. Five CPT I transcripts (CPT I alpha1a, CPT I alpha2a, CPT I alpha2b1a, CPT I alpha2b1b and CPT I beta) mRNAs are expressed in a wide range of tissues, but their abundance of each CPT I mRNA shows the tissue-dependent expression patterns. Insulin incubation significantly reduces the mRNA expression of CPT Ialpha1a and CPT Ialpha2a, but not other transcripts in hepatocytes of S. hasta. For the first time, our study demonstrates CPT Ialpha2b duplication and CPT I alpha1a alternative splicing in fish at transcriptional level, and the CPT I mRNAs are differentially regulated by insulin in vitro, suggesting that four CPT I isoforms may play different physiological roles during insulin signaling. PMID- 26506442 TI - Application of cryopreservation to genetic analyses of a photosynthetic picoeukaryote community. AB - Cryopreservation is useful for long-term maintenance of living strains in microbial culture collections. We applied this technique to environmental specimens from two monitoring sites at Sendai Bay, Japan and compared the microbial diversity of photosynthetic picoeukaryotes in samples before and after cryopreservation. Flow cytometry (FCM) showed no considerable differences between specimens. We used 2500 cells sorted with FCM for next-generation sequencing of 18S rRNA gene amplicons and after removing low-quality sequences obtained 10,088 37,454 reads. Cluster analysis and comparative correlation analysis of observed high-level operational taxonomic units indicated similarity between specimens before and after cryopreservation. The effects of cryopreservation on cells were assessed with representative culture strains, including fragile cryptophyte cells. We confirmed the usefulness of cryopreservation for genetic studies on environmental specimens, and found that small changes in FCM cytograms after cryopreservation may affect biodiversity estimation. PMID- 26506443 TI - Inducible expression of indoleamine 2,3-dioxygenase attenuates acute rejection of tissue-engineered lung allografts in rats. AB - Lung disease remains one of the principal causes of death worldwide and the incidence of pulmonary diseases is increasing. Complexity in treatments and shortage of donors leads us to develop new ways for lung disease treatment. One promising strategy is preparing engineered lung for transplantation. In this context, employing new immunosuppression strategies which suppresses immune system locally rather than systemic improves transplant survival. This tends to reduce the difficulties in transplant rejection and the systemic impact of the use of immunosuppressive drugs which causes side effects such as serious infections and malignancies. In our study examining the immunosuppressive effects of IDO expression, we produced rat lung tissues with the help of decellularized tissue, differentiating medium and rat mesenchymal stem cells. Transduction of these cells by IDO expressing lentiviruses provided inducible and local expression of this gene. To examine immunosuppressive properties of IDO expression by these tissues, we transplanted these allografts into rats and, subsequently, evaluated cytokine expression and histopathological properties. Expression of inflammatory cytokines IFNgamma and TNFalpha were significantly downregulated in IDO expressing allograft. Moreover, acute rejection score of this experimental group was also lower comparing other two groups and mRNA levels of FOXP3, a regulatory T cell marker, upregulated in IDO expressing group. However, infiltrating lymphocyte counting did not show significant difference between groups. This study demonstrates that IDO gene transfer into engineered lung allograft tissues significantly attenuates acute allograft damage suggesting local therapy with IDO as a strategy to reduce the need for systemic immunosuppression and, thereby, its side effects. PMID- 26506444 TI - Utilities of Patients with Hypertension in Northern Vietnam. AB - OBJECTIVES: The study aims to inform potential cost-effectiveness analysis of hypertension management in Vietnam by providing utilities and predictors of utilities in patients with hypertension. METHODS: Hypertensive patients up to 80 years old visiting the hospital were invited to participate in a survey using Quality Metric's Short-form 36v2TM translated into Vietnamese. Health-state utilities were estimated by applying a previously published algorithm. RESULTS: The mean utility of the 691 patients interviewed was 0.73. Controlling for age, sex, blood pressure (BP) stage, and history of stroke, the utilities in older patients were lower than those in younger ones, and statistically significantly different between the extremes of youngest and oldest groups (p = 0.03). Utility in males was higher than in females (p = 0.002). As expected, patients with a history of stroke appeared to exhibit lower utilities than patients without such history, but the difference was not statistically significant (p = 0.73). Patients with more than three comorbidities did have lower utilities than patients without comorbidity (p = 0.01). CONCLUSIONS: Health-state utilities found among hypertensive patients in Vietnam were similar to those found in other international studies. It is suggested that lower of health-state utilities exist among those patients who were older, female or had more than three comorbidities in comparison with respective reference groups. However, further research for confirmation is required. The data from this study provide a potential reference on health-state utilities of hypertensive patients in Vietnam as an input for future cost-effectiveness analysis of interventions. Also, it may serve as a reference for other similar populations, especially in the context of similar environments in low income countries. PMID- 26506445 TI - Diazonium modification of porous graphitic carbon with catechol and amide groups for hydrophilic interaction and attenuated reversed phase liquid chromatography. AB - Porous graphitic carbon (PGC) is an increasingly popular and attractive phase for HPLC on account of its chemical and thermal stability, and its unique separation mechanism. However, native PGC is strongly hydrophobic and in some instances excessively retentive. As part of our effort to build a library of hydrophilic covalently modified PGC phases, we functionalized PGC with catechol and amide groups by means of aryl diazonium chemistry to produce two new phases. Successful grafting was confirmed by X-ray photoelectron spectroscopy (XPS). Under HILIC conditions, the Catechol-PGC showed up to 5-fold increased retention relative to unmodified PGC and selectivity that differed from four other HILIC phases. Under reversed phase conditions, the Amide-PGC reduced the retentivity of PGC by almost 90%. The chromatographic performance of Catechol-PGC and Amide-PGC is demonstrated by separations of nucleobases, nucleosides, phenols, alkaline pharmaceuticals, and performance enhancing stimulants. These compounds had retention factors (k) ranging from 0.5 to 13. PMID- 26506446 TI - A Double Heterozygous Mutation of TNNI3 Causes Hypertrophic Cardiomyopathy in a Han Chinese Family. AB - OBJECTIVES: To investigate the variations in the TNNI3 gene in a Chinese Han family affected by hypertrophic cardiomyopathy (HCM) and the potential molecular mechanism linking these mutations with disease. METHODS: Peripheral venous blood was acquired from family members, and TNNI3 mutations were identified by DNA sequencing. The pathophysiology of TNNI3 mutations was investigated using bioinformatics, subcellular localization determination and Western blotting. RESULTS: Sanger sequencing revealed that the proband possessed 2 heterozygous mutations, c.235C>T and c.470C>T, located at exons 4 and 6 of the TNNI3 gene. The proband (II-2) and her brother (II-1), who had been previously diagnosed with HCM, harbored both mutations whereas their healthy parents harbored only 1. Alignment of the TNNI3 amino acid sequence indicated that the two Pro residues were highly conserved across species. Subcellular localization showed that both wild-type (WT) and mutant TNNI3 proteins were localized at the cell nucleus. Western blot analysis of expression in human embryonic kidney 293T cells showed that the intracellular levels of the mutant proteins were significantly decreased compared to WT TNNI3 (p < 0.01). CONCLUSIONS: Our findings showed that a double heterozygous mutation in the TNNI3 gene is involved in the pathogenesis of HCM via haploinsufficiency. These results will inspire further studies to investigating the link between the TNNI3 gene and HCM. PMID- 26506447 TI - Statistical Study of the Memory Effect in Model Natural Gas Hydrate Systems. AB - A high pressure automated lag time apparatus (HP-ALTA) was used for the investigation of the controversial memory effect in methane-propane mixed gas hydrates. The instrument can apply a large number of linear cooling ramps to a small volume of sample water under an isobaric condition of up to 15 MPa and record the maximum achievable subcooling for each cooling ramp. Over a hundred nucleation events were recorded for each of the several superheating temperatures used for the dissociation of the gas hydrate in a sample. In total, four different sample cells were used, and the effect of heating time was also studied for two of the four sample cells. A difference between two stochastic nucleation probability distributions was systematically and unambiguously quantified in terms of the most probable difference in the maximum achievable subcoolings. The protocol offers by far the most statistically robust method of quantification of the magnitude of the memory effect in each sample. From the analysis of several thousands of nucleation events, the following conclusions were made: (1) Even though the nucleation phenomena were intrinsically stochastic, a clear bias was observed which supported the existence of the memory effect. In particular, a reduction in the most probable subcooling of at least 4 K was required for positive identification of the memory effect for one of the sample cells. (2) The reduction increased as the superheating temperature was lowered. (3) The magnitude of the memory effect varied substantially among the sample cells used. (4) No significant effect of the heating time was observed in the range studied. PMID- 26506448 TI - #3: Periviable birth. AB - Approximately 0.5% of all births occur before the third trimester of pregnancy, and these very early deliveries result in the majority of neonatal deaths and more than 40% of infant deaths. A recent executive summary of proceedings from a joint workshop defined periviable birth as delivery occurring from 20 0/7 weeks to 25 6/7 weeks of gestation. When delivery is anticipated near the limit of viability, families and health care teams are faced with complex and ethically challenging decisions. Multiple factors have been found to be associated with short-term and long-term outcomes of periviable births in addition to gestational age at birth. These include, but are not limited to, nonmodifiable factors (eg, fetal sex, weight, plurality), potentially modifiable antepartum and intrapartum factors (eg, location of delivery, intent to intervene by cesarean delivery or induction for delivery, administration of antenatal corticosteroids and magnesium sulfate), and postnatal management (eg, starting or withholding and continuing or withdrawing intensive care after birth). Antepartum and intrapartum management options vary depending upon the specific circumstances but may include short-term tocolytic therapy for preterm labor to allow time for administration of antenatal steroids, antibiotics to prolong latency after preterm premature rupture of membranes or for intrapartum group B streptococci prophylaxis, and delivery, including cesarean delivery, for concern regarding fetal well-being or fetal malpresentation. Whenever possible, periviable births for which maternal or neonatal intervention is planned should occur in centers that offer expertise in maternal and neonatal care and the needed infrastructure, including intensive care units, to support such services. This document describes newborn outcomes after periviable birth, provides current evidence and recommendations regarding interventions in this setting, and provides an outline for family counseling with the goal of incorporating informed patient preferences. Its intent is to provide support and guidance regarding decisions, including declining and accepting interventions and therapies, based on individual circumstances and patient values. PMID- 26506449 TI - Postotic and preotic cranial neural crest cells differently contribute to thyroid development. AB - Thyroid development and formation vary among species, but in most species the thyroid morphogenesis consists of five stages: specification, budding, descent, bilobation and folliculogenesis. The detailed mechanisms of these stages have not been fully clarified. During early development, the cranial neural crest (CNC) contributes to the thyroid gland. The removal of the postotic CNC (corresponding to rhombomeres 6, 7 and 8, also known as the cardiac neural crest) results in abnormalities of the cardiovascular system, thymus, parathyroid glands, and thyroid gland. To investigate the influence of the CNC on thyroid bilobation process, we divided the CNC into two regions, the postotic CNC and the preotic CNC (from the mesencephalon to rhombomere 5) regions and examined. We found that preotic CNC-ablated embryos had a unilateral thyroid lobe, and confirmed the presence of a single lobe or the absence of lobes in postotic CNC-ablated chick embryos. The thyroid anlage in each region-ablated embryos was of a normal size at the descent stage, but at a later stage, the thyroid in preotic CNC-ablated embryos was of a normal size, conflicting with a previous report in which the thyroid was reduced in size in the postotic CNC-ablated embryos. The postotic CNC cells differentiated into connective tissues of the thyroid in quail-to-chick chimeras. In contrast, the preotic CNC cells did not differentiate into connective tissues of the thyroid. We found that preotic CNC cells encompassed the thyroid anlage from the specification stage to the descent stage. Finally, we found that endothelin-1 and endothelin type A receptor-knockout mice and bosentan (endothelin receptor antagonist)-treated chick embryos showed bilobation anomalies that included single-lobe formation. Therefore, not only the postotic CNC, but also the preotic CNC plays an important role in thyroid morphogenesis. PMID- 26506450 TI - Are the Recent Secular Increases in Waist Circumference among Children and Adolescents Independent of Changes in BMI? AB - BACKGROUND: Several studies have shown that the waist circumference of children and adolescents has increased over the last 25 years. However, given the strong correlation between waist circumference and BMI, it is uncertain if the secular trends in waist circumference are independent of those in BMI. METHODS: We analyzed data from 6- to 19-year-olds who participated in the 1988-1994 through 2011-2012 cycles of the National Health and Nutrition Examination Survey to assess whether the trends in waist circumference were independent of changes in BMI, race-ethnicity and age. RESULTS: Mean, unadjusted levels of waist circumference increased by 3.7 cm (boys) and 6.0 cm (girls) from 1988-94 through 2011-12, while mean BMI levels increased by 1.1 kg/m2 (boys) and 1.6 kg/m2 (girls). Overall, the proportional changes in mean levels of both waist circumference and BMI were fairly similar among boys (5.3%, waist vs. 5.6%, BMI) and girls (8.7%, waist vs. 7.7%, BMI). As assessed by the area under the curve, adjustment for BMI reduced the secular increases in waist circumference by about 75% (boys) and 50% (girls) beyond that attributable to age and race-ethnicity. There was also a race-ethnicity interaction (p < 0.001). Adjustment for BMI reduced the secular trend in waist circumference among non-Hispanic (NH) black children (boys and girls) to a greater extent (about 90%) than among other children. CONCLUSIONS: Our results indicate that among children in the U.S., about 75% (boys) and 50% (girls) of the secular increases in waist circumference since 1988-94 can be accounted for by changes in BMI. The reasons for the larger independent effects among girls and among NH blacks are uncertain. PMID- 26506451 TI - Effect of environment pH on the photophysics of fisetin in solid lipid nanoparticles. AB - Photophysical modulation of fisetin has been extensively studied in bulk aqueous as well as solid lipid nanoparticles (SLN) by varying the pH of the medium. The solution pH was varied from 5 to 9 to mimic biological environments. Neutral and anionic forms of fisetin coexist in ground state in both acidic and alkaline conditions. However, in the excited state and at low pH, the anionic form of fisetin predominates over the proton transferred form, whereas in SLNs, the proton transferred form is the major emitting species. Higher pH showed enhancement in anionic emission to different extent in the two types of environments. Limited percolation of H(+) and OH(-) ions inside the SLNs that host fisetin molecules controls their photophysics. The experimental results encourage usage of fisetin as a drug depending on the ratio of the neutral and anionic as well as the proton transferred forms under various pH conditions. PMID- 26506452 TI - Quick preparation of nanoluciferase-based tracers for novel bioluminescent receptor-binding assays of protein hormones: Using erythropoietin as a model. AB - Nanoluciferase (NanoLuc) is a newly developed small luciferase reporter with the so far brightest bioluminescence. In recent studies, we developed NanoLuc as an ultrasensitive probe for novel bioluminescent receptor-binding assays of some protein/peptide hormones. In the present study, we proposed a simple method for quick preparation of the NanoLuc-based protein tracers using erythropoietin (Epo) as a model. Epo is a glycosylated cytokine that promotes erythropoiesis by binding and activating the cell membrane receptor EpoR. For quick preparation of a bioluminescent Epo tracer, an Epo-Luc fusion protein carrying a NanoLuc-6 * His tag at the C-terminus was secretorily overexpressed in transiently transfected human embryonic kidney (HEK) 293 T cells. The Epo-Luc fusion protein retained high-binding affinities with EpoR either overexpressed in HEK293T cells or endogenously expressed in mouse erythroleukemia cells, representing a novel ultrasensitive bioluminescent tracer for non-radioactive receptor-binding assays. Sufficient Epo-Luc tracer for thousands of assays could be quickly obtained within 2 days through simple transient transfection. Thus, our present work provided a simple method for quick preparation of novel NanoLuc-based bioluminescent tracers for Epo and some other protein hormones to facilitate their ligand-receptor interaction studies. PMID- 26506453 TI - Registration and management of community patients with tuberculosis in north-west China. AB - OBJECTIVES: To describe the registration, management and characteristics of patients with tuberculosis (TB) in north-west China, and investigate whether patients with TB were diagnosed and treated in a timely manner. STUDY DESIGN: Health-facility-based retrospective data were collected from district patient registers and case reports for all patients with TB registered from January 2009 to December 2011 in Xinjiang Uygur Autonomous Region, north-west China. METHODS: Patient characteristics and clinical data were collected from the national TB epidemic reporting system using standardized case reporting forms for diagnosis, treatment and outcome. Data were collected and entered by trained health staff in the regional TB clinics. RESULTS: In total, data for 20,396 patients with TB were collected; of these, 78.5% were farmers. The age peaks were 20-44 years and 60-74 years. Average health-seeking and diagnostic delays were 32 days and two days, respectively. More than half (54.7%) of the patients with smear-negative TB were diagnosed by chest x-ray. Moreover, 94.3% of patients with TB were treated successfully. From 2009 to 2011, the health-seeking delay decreased significantly (P < 0.05), and the diagnostic delay increased significantly (P < 0.05). A significant decreasing trend in smear-positive TB was observed (P < 0.05), along with an increasing trend in treatment success (P < 0.05). CONCLUSIONS: In north west China, there is a need to focus on key high-risk populations for prevention and control of TB, such as those aged 20-44 years and 60-74 years, males and farmers. Delays in diagnosis and treatment have a negative effect on cure rates and make it more difficult to control the propagation of TB. PMID- 26506454 TI - F-box proteins: Keeping the epithelial-to-mesenchymal transition (EMT) in check. AB - F-box proteins are the key recognition subunit of multimeric E3 ubiquitin ligase complexes that participate in the proteasome degradation of specific substrates. In the last years, a discrete number of F-box proteins have been shown to regulate the epithelial-to-mesenchymal transition (EMT), a process defined by a rapid change of cell phenotype, the loss of epithelial characteristics and the acquisition of a more invasive phenotype. Specific EMT transcription factors (EMT TFs), such as Snail, Slug, Twist and Zeb, control EMT induction both during development and in cancer. These EMT-TFs are short-lived proteins that are targeted to the proteasome system by specific F-box proteins, keeping them at low levels. F-box proteins also indirectly regulate the EMT process by controlling EMT inducers, such as Notch, c-Myc or mTOR. Here we summarize the role that these F-box proteins (Fbxw1, Fbxw7, Fbxl14, Fbxl5, Fbxo11 and Fbxo45) play in controlling EMT during development and cancer progression, a process dependent on post-translational modifications that govern their interaction with target proteins. PMID- 26506455 TI - The mass action equation in pharmacology. AB - The mass action equation is the building block from which all models of drug receptor interaction are built. In the simplest case, the equation predicts a sigmoidal relationship between the amount of drug-receptor complex and the logarithm of the concentration of drug. The form of this function is also the same as most dose-response relationships in pharmacology (such as enzyme inhibition and the protein binding of drugs) but the potency term in dose response relationships very often differs in meaning from the similar term in the simple mass action relationship. This is because (i) most pharmacological systems are collections of mass action reactions in series and/or in parallel and (ii) the important assumptions in the mass action reaction are violated in complex pharmacological systems. In some systems, the affinity of the receptor R for some ligand A is modified by interaction of the receptor with the allosteric ligand B and concomitantly the affinity of the receptor for ligand B is modified to the same degree. When this occurs, the observed affinity of the ligand A for the receptor will depend on both the concentration of the co-binding allosteric ligand and its nature. The relationships between drug potency in pharmacological models and the equilibrium dissociation constants defined in single mass action reactions are discussed. More detailed knowledge of efficacy has led to new models of drug action that depend on the relative probabilities of different states, and these have taken knowledge of drug-receptor interactions beyond Guldberg and Waage. PMID- 26506456 TI - Cytogenetic Alterations in Multiple Myeloma: Prognostic Significance and the Choice of Frontline Therapy. AB - Multiple myeloma tumor cells demonstrate multiple and often complex genetic lesions as evaluated by standard cytogenetic/FISH studies. Over the past decade, specific abnormalities have been associated with standard or high-risk clinical behavior and they have become strong prognostic indicators. Further, as evidenced by recent randomized clinical trials, the choice of front-line therapy (transplant vs. no transplant, inclusion of novel drugs such as bortezomib, thalidomide, and lenalidomide) may be able to overcome the adverse effect of high risk genetic lesions. PMID- 26506457 TI - Discrimination of pulp oil and kernel oil from pequi (Caryocar brasiliense) by fatty acid methyl esters fingerprinting, using GC-FID and multivariate analysis. AB - Pequi is an oleaginous fruit whose edible oil is composed mainly by saturated and monounsaturated fatty acids. The biological and nutritional properties of pequi oil are dependent on its composition, which can change according to the oil source (pulp or kernel). There is little data in the scientific literature concerning the differences between the compositions of pequi kernel and pulp oils. Therefore, in this study, different pequi genotypes were evaluated to determine the fatty acid composition of pulp and kernel oils. PCA and PLS-DA were applied to develop a model to distinguish these oils. For all evaluated genotypes, the major fatty acids of both pulp and kernel oils were oleic and palmitic acids. Despite the apparent similarity between the analyzed samples, it was possible to discriminate pulp and kernel oils by means of their fatty acid composition using chemometrics, as well as the unique pequi genotype without endocarp spines (CPAC-PQ-SE-06). PMID- 26506458 TI - Improvement of Lesion Phenotyping in Cercospora beticola-Sugar Beet Interaction by Hyperspectral Imaging. AB - Cercospora leaf spot (CLS) caused by Cercospora beticola is the most destructive leaf disease of sugar beet and may cause high losses in yield and quality. Breeding and cultivation of disease-resistant varieties is an important strategy to control this economically relevant plant disease. Reliable and robust resistance parameters are required to promote breeding progress. CLS lesions on five different sugar beet genotypes incubated under controlled conditions were analyzed for phenotypic differences related to field resistance to C. beticola. Lesions of CLS were rated by classical quantitative and qualitative methods in combination with noninvasive hyperspectral imaging. Calculating the ratio of lesion center to lesion margin, four CLS phenotypes were identified that vary in size and spatial composition. Lesions could be differentiated into subareas based on their spectral characteristics in the range of 400 to 900 nm. Sugar beet genotypes with lower disease severity typically had lesions with smaller centers compared with highly susceptible genotypes. Accordingly, the number of conidia per diseased leaf area on resistant plants was lower. The assessment of lesion phenotypes by hyperspectral imaging with regard to sporulation may be an appropriate method to identify subtle differences in disease resistance. The spectral and spatial analysis of the lesions has the potential to improve the screening process in breeding for CLS resistance. PMID- 26506459 TI - Population Genetic Structure and the Migration of Puccinia striiformis f. sp. tritici Between the Gansu and Sichuan Basin Populations of China. AB - Puccinia striiformis f. sp. tritici is the causal pathogen of interregional epidemics of wheat stripe rust in China via long-distance migration. Gansu Province serves as putative inoculum center providing oversummering inoculum, while Sichuan Basin area serves as a region providing huge amounts of overwintering inoculum. Thus, the relationship between these two regions in population exchange and migration become important in prediction of interregional epidemics. In this study, we compared the population genetic structure and race composition between Gansu and Sichuan Basin populations to infer their migration relationships. A total of 526 isolates, spanning 3 years, were genotyped using eight pairs of amplified fragment length polymorphism markers, and a subset of 98 isolates were inoculated onto 19 Chinese differentials to perform the race analysis. Twenty-three common races and 26 shared genotypes supplied molecular evidence for migration between Gansu and Sichuan Basin populations. Bayesian assignment and principal component analysis revealed that the genetic group assignment of the Sichuan Basin populations (10SB and 11SB) changed in the spring to align with the fall Gansu populations in the prior seasons (09GS and 10GS), which indicated an asymmetric migration from Gansu Province to the Sichuan Basin area. The linkage disequilibrium and the parsimony tree length permutation test revealed a strong annual recombination signal in the Gansu populations and an inconsistent signal in the Sichuan Basin populations. PMID- 26506461 TI - Correction to Selective Tracking of Lysosomal Cu(2+) Ions Using Simultaneous Target- and Location-Activated Fluorescent Nanoprobes. PMID- 26506460 TI - Chemical composition and antimicrobial activities of Perovskia artemisioides Boiss. essential oil. AB - The Perovskia artemisioides Boiss. essential oil obtained by hydrodistillation method of flowers growing wild in the north of Iran. The study led to the identification of 29 compositions by a combination of HP-5 GC-FID and GC-MS analytical techniques. The constituents were identified in P. artemisioides essential oil with 1,8-cineole (29.9%), camphor (29.5%) and alpha-pinene (7.8%) as main constituents as well as delta-3-carene (5.1%), camphene (3.3%) and beta pinene (2.7%). The oil was identified by a much larger amount of monoterpenes (87.7%) and sesquiterpenes (6.3%). The results of antimicrobial activity exhibit that the extracted essential oil has presented a high inhibiting activity against five microbial strains up to 18 mm. Also, the MIC and MBC results displayed that Staphylococcus aureus, Escherichia coli and Salmonella typhi were inhibited by P. artemisioides essential oil. Therefore, determination of essential oils in this research showed a relatively similar pattern to those published for the other species of Perovskia. PMID- 26506462 TI - Intermediate-sensor assisted push-pull strategy and its application in heterologous deoxyviolacein production in Escherichia coli. AB - Because high-throughput screening tools are typically unavailable when using the pathway-engineering approach, we developed a new strategy, named intermediate sensor-assisted push-pull strategy, which enables sequential pathway optimization by incorporating a biosensor targeting a key pathway intermediate. As proof of concept, we constructed an L-Trp biosensor and used it to optimize the deoxyviolacein biosynthetic pathway, which we divided into two modules with L-Trp being the product of the upstream and the substrate of the downstream module for deoxyviolacein synthesis. Using the biosensor and fluorescence-activated cell sorting, the activities of the two modules were sequentially and independently optimized in Escherichia coli to achieve the desired phenotypes. By this means, we increased the deoxyviolacein titer 4.4-fold (1.92 g/L), which represents the greatest deoxyviolacein production reported. This work suggests that a biosynthetic pathway can be enhanced to produce a value-added secondary metabolite(s) without available end-product screening method by using a central metabolic junction molecule biosensor(s). PMID- 26506463 TI - Imaging of neurosarcoidosis: common, uncommon, and rare. AB - Sarcoidosis is an idiopathic inflammatory disease that may affect any organ system and have protean manifestations. Neurosarcoidosis refers to involvement of the central nervous system and may occur in patients with known sarcoidosis, or be the initial manifestation of the disease. In the latter, it can be a source of considerable confusion, given the non-specific imaging appearance. The aim of this review is to describe the imaging spectrum of neurosarcoidosis, including follow-up imaging and superimposed infections, which may occur secondary to immunosuppression. An increased awareness of this great mimicker could potentially expedite diagnosis and reduce morbidity. PMID- 26506464 TI - High-temperature water-rock interactions and hydrothermal environments in the chondrite-like core of Enceladus. AB - It has been suggested that Saturn's moon Enceladus possesses a subsurface ocean. The recent discovery of silica nanoparticles derived from Enceladus shows the presence of ongoing hydrothermal reactions in the interior. Here, we report results from detailed laboratory experiments to constrain the reaction conditions. To sustain the formation of silica nanoparticles, the composition of Enceladus' core needs to be similar to that of carbonaceous chondrites. We show that the presence of hydrothermal reactions would be consistent with NH3- and CO2 rich plume compositions. We suggest that high reaction temperatures (>50 degrees C) are required to form silica nanoparticles whether Enceladus' ocean is chemically open or closed to the icy crust. Such high temperatures imply either that Enceladus formed shortly after the formation of the solar system or that the current activity was triggered by a recent heating event. Under the required conditions, hydrogen production would proceed efficiently, which could provide chemical energy for chemoautotrophic life. PMID- 26506465 TI - Excited-state intramolecular proton-transfer (ESIPT)-inspired solid state emitters. AB - Solid state emitters based on excited state intramolecular proton transfer (ESIPT) have been attracting considerable interest since the past few years in the field of optoelectronic devices because of their desirable unique photophysical properties. The photophysical properties of the solid state ESIPT fluorophores determine their possible applicability in functional materials. Less fluorescence quantum efficiencies and short fluorescence lifetime in the solid state are the shortcomings of the existing ESIPT solid state emitters. Designing of ESIPT chromophores with high fluorescence quantum efficiencies and a long fluorescence lifetime in the solid state is a challenging issue because of the unclear mechanism of the solid state emitters in the excited state. Reported design strategies, detailed photophysical properties, and their applications will help in assisting researchers to overcome existing challenges in designing novel solid state ESIPT fluorophores for promising applications. This review highlights recently developed solid state ESIPT emitters with focus on molecular design strategies and their photophysical properties, reported in the last five years. PMID- 26506466 TI - Summary of Notifiable Noninfectious Conditions and Disease Outbreaks: Introduction to the Summary of Notifiable Noninfectious Conditions and Disease Outbreaks - United States. PMID- 26506467 TI - In situ label-free static cytometry by monitoring spatiotemporal fluctuations of image gray values. AB - Spatiotemporal fluctuation of homogeneity and randomness of gray values within an image was explored and utilized as a label-free means for cell examination. This was done by utilizing a user-friendly combination of simple bright field microscope and Cytocapture dish, wherein cells are individually held, each within a picoliter optical chamber, forming an array of cells to be repeatedly measured over time and biomanipulated in situ at single-cell resolution. First, the measured gray level information entropy (GLIE) was used and, based on the fact that living cells are not in a state of thermodynamic equilibrium but rather in a metastable state, two fluctuation-sensitive measures were proposed and examined: ASDE-the spatial average of temporal standard deviation (SD) of GLIE, and AA-the average time autocorrelation of GLIE. System performance was validated on cell free solutions. This was followed by examining the performance of the measures AGLIE, ASDE, and AA to distinguish among individual live-still, dead and live cells from various cell lines, as well as between cells which were and were not induced to differentiate. Results, which were obtained on four types of cells, indicate advantages of the proposed measures which are believed to be significant additions to the microscope-based probe-free toolbox. PMID- 26506468 TI - Mechanism of two-photon excited hemoglobin fluorescence emission. AB - Hemoglobin, one of the most important proteins in the human body, is composed of "heme" groups (iron-containing rings) and "globins" (proteins). We investigate the two-photon excited fluorescence of hemoglobin and its subunit components (heme and globin). We measure the hemoglobin fluorescence lifetime by using a streak camera of ps resolution and confirm that its lifetime is in femtosecond scale. In the study of the fluorescence properties of heme and globin, the experimental results reveal that heme is the sole fluorophore of hemoglobin. Hemoglobin fluorescence can be effectively excited only via two-photon process, because heme has a centrosymmetric molecular structure and two-photon allowed transition is forbidden for single-photon process and vice versa due to the Laporte parity selection rule. PMID- 26506469 TI - Endre A. Balazs, 1920-2015, In Memoriam PMID- 26506470 TI - Geometric analysis and estimation of the growth rate gradient on gastropod shells. AB - The morphology of gastropod shells provides a record of the growth rate at the aperture of the shell, and molecular biological studies have shown that the growth rate gradient along the aperture of a gastropod shell can be closely related to gene expression at the aperture. Here, we develop a novel method for deriving microscopic growth rates from the macroscopic shapes of gastropod shells. The growth vector map of a shell provides information on the growth rate gradient as a vector field along the aperture, over the growth history. However, it is difficult to estimate the growth vector map directly from the macroscopic shape of a specimen, because the degree of freedom of the growth vector map is very high. In order to overcome this difficulty, we develop a method of estimating the growth vector map based on a growing tube model, where the latter includes fewer parameters to be estimated. In addition, we calculate an aperture map specifying the magnitude of the growth vector at each location, which can be compared with the expression levels of several genes or proteins that are important in morphogenesis. Finally, we show a concrete example of how macroscopic shell shapes evolve in a morphospace when microscopic growth rate gradient changes. PMID- 26506471 TI - A model of compensatory molecular evolution involving multiple sites in RNA molecules. AB - Consider two sites under compensatory fitness interaction, such as a Watson-Crick base pair in an RNA helix or two interacting residues in a protein. A mutation at any one of these two sites may reduce the fitness of an individual. However, fitness may be restored by the occurrence of a second mutation at the other site. Kimura modeled this process using a two-locus haploid fitness scheme with two alleles at each locus. He predicted that compensatory evolution following this model is very rare unless selection against the deleterious single mutations is weak and linkage between the interacting sites is tight. Here we investigate the question whether the rate of compensatory evolution increases if we take the context of the two directly interacting sites into account. By "context", we mean the effect of neighboring sites in an RNA helix. Interaction between the focal pair of sites under consideration and the context may lead to so-called indirect compensation. Thus, extending Kimura's classical model of compensatory evolution, we study the effects of both direct and indirect compensation on the rate of compensatory evolution. It is shown that the effects of indirect compensation are very strong. We find that recombination does not slow down the rate of compensatory evolution as predicted by the classical model. Instead, compensatory substitutions may be relatively frequent, even if linkage between the focal interacting sites is loose, selection against deleterious mutations is strong, and mutation rate is low. We compare our theoretical results with data on RNA secondary structures from vertebrate introns. PMID- 26506472 TI - Endogenous Il10 alleviates the systemic antiviral cellular immune response and T cell-mediated immunopathology in select organs of acutely LCMV-infected mice. AB - The immunoregulatory cytokine IL-10 suppresses T-cell immunity. The complementary question, whether IL-10 is also involved in limiting the collateral damage of vigorous T cell responses, has not been addressed in detail. Here, we report that the particularly strong virus-specific immune response during acute primary infection with the lymphocytic choriomeningitis virus (LCMV) in mice is significantly further increased in Il10-deficient mice, particularly regarding frequencies and cytotoxic activity of CD8(+) T cells. This increase results in exacerbating immunopathology in select organs, ranging from transient local swelling to an increased risk for mortality. Remarkably, LCMV-induced, T cell mediated hepatitis is not affected by endogenous Il10. The alleviating effect of Il10 on LCMV-induced immunopathology was found to be operative in delayed-type hypersensitivity footpad-swelling reaction and in debilitating meningitis in mice of both the C57BL/6 and BALB/c strains. These strains are prototypic counterpoles for genetically imprinted type 1-biased versus type 2-biased T cell-mediated immune responses against various infectious pathogens. However, during acute LCMV infection, neither systemic cytokine patterns nor the impact of Il10 on LCMV induced immunopathology differed conspicuously between these two strains of mice. This study documents a physiological role of Il10 in the regulation of a balanced T-cell response limiting immunopathological damage. PMID- 26506473 TI - Human lung cancer-derived immunosuppressive plasmacytoid dendritic cells release IL-1alpha in an AIM2 inflammasome-dependent manner. AB - Plasmacytoid dendritic cells (pDCs) highly populate lung tumor masses and are strictly correlated to bad prognosis, yet their role in lung cancer is controversial. To understand their role in lung cancer, we isolated pDCs from human samples of lung obtained from non-small cell lung cancer patients undergoing thoracic surgery. Tumor masses presented a higher percentage of pDCs than healthy tissues; pDCs were in the immunosuppressive phenotype, as determined by higher levels of CD33 and PD-L1. Despite higher HLA-A and HLA-D expression, cancerous pDCs did not exert cytotoxic activity against tumor cells but instead promoted their proliferation. In this scenario, cancerous pDCs were able to produce high levels of IL-1alpha. This effect was observed on the specific activation of the inflammasome absent in melanoma 2 (AIM2), which led to higher cytoplasmic calcium release responsible for calpain activation underlying IL 1alpha release. The blockade of type I interferon receptor and of AIM2 via the addition of LL-37 significantly reduced the release of IL-1alpha, which was still high after Nod-like receptor P3 inhibition via glibenclamide. More important, mitochondrial-derived reactive oxygen species sequester diminished AIM2-dependent IL-1alpha release. Our data demonstrate that lung tumor-associated pDCs are responsive to the activation of AIM2 that promotes calcium efflux and reactive oxygen species from mitochondria, leading to calpain activation and high levels of IL-1alpha, which facilitate tumor cell proliferation in the lung. PMID- 26506474 TI - Pseudo pemphigus phenotypes in mice with inactivated desmoglein 3: further insight to the complexity of pemphigus pathophysiology. PMID- 26506475 TI - Authors' reply. PMID- 26506476 TI - CD2AP, dendrin, and cathepsin L in the kidney. PMID- 26506477 TI - Information processing during NREM sleep and sleep quality in insomnia. AB - Insomnia sufferers (INS) are cortically hyperaroused during sleep, which seems to translate into altered information processing during nighttime. While information processing, as measured by event-related potentials (ERPs), during wake appears to be associated with sleep quality of the preceding night, the existence of such an association during nighttime has never been investigated. This study aims to investigate nighttime information processing among good sleepers (GS) and INS while considering concomitant sleep quality. Following a multistep clinical evaluation, INS and GS participants underwent 4 consecutive nights of PSG recordings in the sleep laboratory. Thirty nine GS (mean age 34.56+/-9.02) and twenty nine INS (mean age 43.03+/-9.12) were included in the study. ERPs (N1, P2, N350) were recorded all night on Night 4 (oddball paradigm) during NREM sleep. Regardless of sleep quality, INS presented a larger N350 amplitude during SWS (p=0.042) while GS showed a larger N350 amplitude during late-night stage 2 sleep (p=0.004). Regardless of diagnosis, those who slept objectively well showed a smaller N350 amplitude (p=0.020) while those who slept subjectively well showed a smaller P2 (p<0.001) and N350 amplitude (p=0.006). Also, those who reported an objectively bad night as good showed smaller P2 (p< 0.001) and N350 (p=0.010) amplitudes. Information processing seems to be associated with concomitant subjective and objective sleep quality for both GS and INS. However, INS show an alteration in information processing during sleep, especially for inhibition processes, regardless of their sleep quality. PMID- 26506478 TI - Comparison of First- and Second-Generation Drug-Eluting Stents in an All-Comer Population of Patients with Diabetes Mellitus (from Katowice-Zabrze Registry). AB - BACKGROUND: This study compared safety and efficacy of first- and second generation DES in an unrestricted, real-life population of diabetic patients undergoing PCI. MATERIAL AND METHODS: The study was a subanalysis of diabetic patients from the all-comer Katowice-Zabrze Registry of patients undergoing PCI with the implantation of either first- (Paclitaxel-, Sirolimus-eluting stents) or second-generation DES (Zotarolimus-, Everolimus-, Biolimus-eluting stents). Efficacy defined as major adverse cardiac and cerebrovascular events (MACCE: death, myocardial infarction, target vessel revascularization, stroke) and safety defined as stent thrombosis (ST) were evaluated at 1 year. RESULTS: From the total of 1916 patients, 717 were diabetics. Among them, 257 (36%) were treated with first-generation DES (230 [89%] Paclitaxel-eluting stents, 27 [11%] Sirolimus-eluting stents), 460 with second-generation DES (171 [37%] Zotarolimus eluting stents, 243 [53%] Everolimus-eluting stents, 46 [10%] Biolimus-eluting stents). Rate of MACCE was equal in both groups (p=0.54). Second-generation DES had a better safety profile than first-generation DES (log-rank for cumulative ST at 1 year p<0.001). First-generation DES was a risk factor for ST (HR 5.75 [1.16 28.47], p=0.03) but not for MACCE (HR 0.89 [0.6-1.32], p=0.57). CONCLUSIONS: In a real-life setting of diabetic patients undergoing PCI, second-generation DES had lower risk of ST and similar MACCE rate compared to first-generation DES. PMID- 26506479 TI - Characterization of continuous monoclonal antibody epitopes in the N-terminus of Ro60. AB - One of the major targets of the autoimmune response in the rheumatic autoimmune diseases, Systemic Lupus Erythematosus and Sjogrens Syndrome, is the protein Ro60. Ro60 is known to associate with small misfolded RNAs, and is involved in RNA quality control and in enhancing cell survival during cellular stress, e.g. after ultaviolet irradiation. In this study, six monoclonal antibodies to Ro60 were analyzed in order to identify antigenic regions and the nature of these. Preliminary analyses revealed that two of the antibodies recognized continuous epitopes, while the remaining antibodies most likely recognized conformational epitopes. The continuous epitopes of Ro60 were characterised by modified immunoassays employing resin-bound peptides and free peptides. Peptide screenings located the epitopes to the N-terminus of Ro60, and further analyses indicated that the epitopes of the monoclonal antibodies TROVE2 and SSI-HYB 358-02 were located to amino acids 8-17 and 34-49, respectively. Moreover, charged amino acids were found to be especially important for antibody reactivity, although antibody reactivity of the monoclonal antibody TROVE2 primarily was found to be epitope backbone-dependent. PMID- 26506481 TI - [XII National Forum on Health Education]. AB - In Guadalajara, on August 19, 20 and 21 was held the XII Foro Nacional de Educacion en Salud, in line with the interest that both, the Direccion General and the Direccion de Prestaciones Medicas of the IMSS, have in training and updating the human resources for the care of the beneficiaries. The Unidad de Educacion, Investigacion y Politicas de Salud organized a meeting in which the actors of these tasks, the institutional staff and authorities from various universities worked together with the IMSS. PMID- 26506480 TI - Early-late genes of the ecdysone cascade as models for transcriptional studies. AB - The DHR3 and Hr4 early-late genes of the ecdysone cascade are described as models for transcriptional studies in Drosophila cells. In a set of experiments, it became clear that these genes are a convenient and versatile system for research into the physiological conditions upon 20-hydroxyecdysone induction. DHR3 and Hr4 gene transcription is characterized by fast activation kinetics, which enables transcriptional studies without the influence of indirect effects. A limited number of activated genes (only 73 genes are induced one hour after treatment) promote the selectivity of transcriptional studies via 20-hydroxyecdysone induction. DHR3 and Hr4 gene expression is dose dependent, is completely controlled by the hormone titer and decreases within hours of 20-hydroxyecdysone withdrawal. The DHR3 and Hr4 gene promoters become functional within 20 minutes after induction, which makes them useful tools for investigation if the early activation process. Their transcription is controlled by the RNA polymerase II pausing mechanism, which is widespread in the genome of Drosophila melanogaster but is still underinvestigated. Uniform expression activation of the DHR3 and Hr4 genes in a cell population was confirmed at both the RNA and protein levels. Homogeneity of the transcription response makes DHR3/Hr4 system valuable for investigation of the protein dynamics during transcription induction. PMID- 26506482 TI - [History of the development of screening tests for cervical cancer]. AB - Cervical cancer (CC) is one of the best known malignancies. Currently, it is accepted that the etiological factor is persistent infection with high-risk human papillomavirus (HPV). Even before the identification of its etiological factors, methods such as Pap cytology and colposcopy were developed as tools for early diagnosis on CC and its precursor lesions. At the time when such tests were being developed, they were not fully accepted by the scientific community of the time; however, as time went by, the dissemination of knowledge, and more extensive application, these tests were finally included within the international guidelines. The implementation of programs with adequate coverage and quality allowed a significant reduction in the incidence and mortality of CC. However this did not occur widely, and CC is still a public health problem in developing countries. From the epidemiological and molecular viewpoint, knowledge on HPVs laid the foundations for the development of new prevention strategies based on vaccination and molecular detection of the causal agent, currently accepted as strategies for primary and secondary prevention. It is expected that the implementation of these strategies will have a greater impact on the control on CC and other malignancies associated with HPV infection. PMID- 26506483 TI - [Features of Guillain-Barre syndrome in adults: results of a university hospital]. AB - BACKGROUND: Guillain-Barre syndrome (GBS) has a cosmopolitan distribution. Its course is usually mild and tends to limit itself, but in severe cases it can cause death. The aim of this article is to describe the characteristics of a group of adults with GBS diagnosed and treated at a university hospital. METHODS: All cases of GBS that occurred between January 1, 2005 to December 31, 2009 were analyzed. The clinical records were reviewed through the implementation of a structured survey that included the following sections: patient identification, clinical data, history of infection, season of occurrence, rates of electrophysiological variants, and lethality. RESULTS: A total of 45 patients were included; the male to female ratio was 1.4: 1 and the mean age was 48.2 +/- 16.0 years. The season with the highest number of cases was the summer. History of intestinal infection was present in 40 % of patients, and respiratory infection in 24.4%. The lethality associated with GBS was 11.1 % (95 % CI, 4.4 23.9), fatal cases occurred in patients older than the survivors (65.2 +/- 15.0 versus 46.0 +/- 14.9, p = 0.01). The most common variant was acute motor axonal neuropathy (64.4 %); there were four cases of Miller Fisher syndrome. CONCLUSIONS: The most common electromyographic variant of GBS was acute motor axonal neuropathy. The highest number of cases was observed during the summer season. PMID- 26506484 TI - [Prevalence of nosocomial infections in a secondary care hospital in Mexico]. AB - BACKGROUND: Nosocomial infections are a growing problem of great social and economic impact that affects hospitals. The aim of this study was to determine the prevalence of nosocomial infections in a secondary care hospital. METHODS: A cross-sectional, observational study. Sample size was calculated for a proportion, hospitalized patients with more than 48 hours of stay were included; descriptive statistics and hypothesis testing was done using Fisher's exact test; SPSS software version 18 was used. RESULTS: A prevalence of 9.52% was found, with an average age of 46.59 years; 64.3% of patients were female, 35.7% male. The prevalence was 16.27% in Internal Medicine department and 12.5% Surgery. CONCLUSIONS: 10 out of 100 hospitalized patients develop nosocomial infection, similar to that reported in the literature. PMID- 26506485 TI - [Obesity as a risk factor for metabolic disorders in adults with urolithiasis]. AB - BACKGROUND: Yucatan ranks first in the prevalence of urinary calculi (UL), and above the national average of obesity (OB). The aim of the study was to determine whether there is an association between obesity and metabolic disorders (MD) in patients with UL. METHODS: In a case-control design, 197 patients were studied with and without UL. Weight and height were measured; urine calcium, phosphate, magnesium, uric acid, oxalates, citrates and sodium were quantified. RESULTS: 197 subjects, 62 men and 135 women were studied; 114 subjects with UL and 83 without UL. Hyperuricosuria was more frequent in obese patients without UL. Hypocitraturia was the most frequent MD in patients both with and without OB, with and without UL. There was a positive trend towards a greater number of MD as weight increased. Urinary sodium excretion in patients with OB was significant. CONCLUSIONS: Obesity is a risk factor for MD in patients with UL. Strategies must be implemented to spread awareness on the influence of obesity on UL, and how it can be modified by diet. PMID- 26506486 TI - [Rethinking the surgical approach to intestinal obstruction surgery in neonates. Experience of a third-level hospital]. AB - BACKGROUND: Choosing laparotomy incision (transverse or midline) depends on the area that needs to be exposed, the urgency of the procedure, and the surgeon's preference. In the Hospital de Pediatria of the Centro Medico Nacional Siglo XXI of the IMSS, the traditional approach is performed by midline in these patients. Our objective was to determine if the midline approach is safe for handling neonates undergoing laparotomy for intestinal obstruction. METHODS: A retrospective study included all neonates who underwent laparotomy for intestinal obstruction by midline approach in the period from January 2010 to January 2012. RESULTS: 34 patients were studied. 88.2 % were urgency procedures; surgery time was more than 120 minutes. Surgical bleeding in all patients was less than 20 milliliters. Complications were found in 44 % of patients, of which the most frequent was infection (29 %) and wound dehiscence (20 %). As for respiratory complications, 32.4 % had atelectasis and 14.7 %, pneumonia. 14.7 % had incisional hernia at one year. CONCLUSIONS: The frequency of immediate and non immediate post-surgical complications is higher than those reported in the literature with transverse approach. The frequency of post-incisional hernia at one year is similar to that reported with the latter approach. PMID- 26506487 TI - [Dietary training for school food service providers in support of the Acuerdo Nacional para la Salud Alimentaria]. AB - BACKGROUND: To address the problem of overweight and obesity in Mexico, in 2010 the Acuerdo Nacional para la Salud Alimentaria was published. At school level, food service providers were considered essential to comply with certain commitments. The goal of this intervention was to train school food service providers in school eating establishments (SEE) as to the criteria in the general guidelines for the sale and distribution of food in schools of basic education. METHODS: 13 SEE in San Luis Potosi participated. Based on an initial diagnosis, a class-workshop of 5 sessions was designed. Knowledge regarding food was evaluated at the beginning and end of the sessions. The percentage of adherence regarding general hygiene and food preparation and distribution was obtained at the beginning, one month, and two months post-intervention. RESULTS: School food service providers had little knowledge on the objectives of the Acuerdo in food groups and combination, as well as reading labels; there were significant changes in the last two after intervention. The initial percentage of overall hygiene compliance was 60 %, with an increase of almost 20 % post-training. The preparation and distribution of food did not show significant changes. CONCLUSIONS: School food service providers acquired knowledge about the guidelines that a SEE comply with, without putting them into practice, given the economic impact that it implies. PMID- 26506488 TI - [Perception of medical emergencies in a private pediatric hospital]. AB - BACKGROUND: The aim of this study was to determine if the care of child patients on admission, coincides with perception of real urgency on the part of parents with that of the doctor and not because of perceived worry in the family (perceived emergencies). METHODS: All the care given in the emergency department, from January 1st 2009 to December 31st 2010, was analyzed. A real urgency was determined by consensus on the conditions of the child. Sociodemographic of real urgency conditions were compared against those perceived. RESULTS: 8,888 consultations were given, of which 2,024 (22.7 %) met criteria for real urgency. The main causes of real urgency were infectious diseases were followed by accidents and poisoning. Of real emergencies 17 (1 %) eventually required intensive management. Factors associated with real urgency were age, non infectious disease, occurring between Monday to Friday, during the morning shift and in the winter months. CONCLUSIONS: The frequency of care for real urgency was low compared to that reported in other pediatric centers. Restructuring of pre consultation services for the implementation of optimal patient classification before going to emergency helps greatly to optimize the use of the emergency department, deriving the patients in true need sooner. PMID- 26506489 TI - [h Index and scientific output of researchers in medicine from the University of Guadalajara, Mexico]. AB - OBJECTIVE: To evaluate by the h index the scientific output of researchers from the University of Guadalajara who belong to the Sistema Nacional de Investigadores in the field of Medicine and Health Sciences. METHODS: Researchers from the University of Guadalajara were selected from the Active SNI Researchers 2013 file. The scientific output of researchers in the fields of Medicine/Health Sciences and Biology/Chemistry was evaluated using the h index estimated by the Scopus website. A sample of capital researchers and Emeritus scientists was taken to perform the same procedure and compare data. RESULTS: The total number of researchers in the University of Guadalajara who are members of the SNI was 711, of which 67.2 % were level I and in less proportion were level II and III. Only 24.2 % of them were classified in the fields of Medicine/Health Sciences and Biology/Chemistry. The average h index value of researchers level I, II and III in Medicine/Health Sciences field was 5.4, 10.5 and 14.5, respectively. Capital and Emeritus scientists had an average h index of 23.4 and 19.8, respectively. CONCLUSION: The h index measures the quantity and quality of the scientific output and it also avoids bias in the evaluation process. It should be useful for future evaluations of the SNI members and for medical doctors who sign up for the National Academy of Medicine. PMID- 26506490 TI - [Expression of TREM-1 in patients with invasive cervical cancer and precursor lesions]. AB - BACKGROUND: It has been shown that the TREM-1 glycoprotein belongs to the immunoglobulin superfamily that induces secretion of various proinflammatory cytokines. The aim of this study was to measure the expression of TREM-1 in patients with cervical cancer. METHODS: In this cross-sectional study we included four groups of patients: GI: women with low-grade squamous intraepithelial lesion (IL) (n = 15 p / g); GII: patients with high-grade squamous IL (n = 9 w / g); GIII: patients with invasive cervical cancer (n = 9 p / g) and GIV: healthy patients (n = 15 p / g). In all patients the expression of TREM-1 and the Average Fluorescence Index (AFI) in neutrophils and monocytes were measured, as well as levels of leukocytes, neutrophils and monocytes. We used Student's t test for independent samples. For these variables, we applied Mann-Whitney rank-sum, ANOVA, and Tukey tests. Chi square test was used for qualitative variables. RESULTS: The percentages of TREM-1 expression in neutrophils and monocytes, plus the AFI in neutrophils in the 4 groups was not significantly different. The AFI of TREM-1 in monocytes was significantly different when comparing group II and group III versus group IV (p < 0.02). There was also no significant difference when comparing the mean values of leukocytes, neutrophils and monocytes in the different groups. CONCLUSION: This study shows increased expression of TREM-1 in monocytes from patients with advanced cancer. PMID- 26506491 TI - [Intrarectal povidone-iodine to reduce the risk of genitourinary infections after transrectal prostate biopsy]. AB - BACKGROUND: The aim of this study is to compare two different preparations in patients undergoing transrectal prostate biopsies samples (TPBS) and assess the prevalence of genitourinary infections (GUI). METHODS: A historical cohort of patients undergoing TBPS for suspected prostate cancer. Two groups were compared: one with endorectal lubricant jelly and another with the addition of a povidone iodine lubricating jelly. Complications were evaluated at three weeks. A bivariate analysis was performed by calculating the OR (95 % CI) to determine if the additional endorectal povidone-iodine pre-TBPS reduced GUI and other complications. RESULTS: 185 patients (Group I n = 86, Group II n = 96) were evaluated. 45 and 25 % had genitourinary tract infection (OR: 0.4, CI: 0.2-0.9, p = 0.004); fever was presented in 21 and 10 % respectively (OR: 0.42, CI: 0.1-0.9, p = 0.04). CONCLUSIONS: A reduction was observed in the presence of genitourinary infections in patients who had intrarectal povidone-iodine preparation applied. PMID- 26506492 TI - [Recurrent aneurysm of sinus of Valsalva, the world's first case report]. AB - An aneurysm of the sinus of Valsalva is a rare cardiac anomaly (0.09% of cases in autopsy studies) . This article describes the case of a male patient, 58 years old with a history of smoking and surgery for the correction of sinus of Valsalva aneurysm 31 years before, with no record of approach or type of surgery. His condition began five months before his admission with atypical chest pain. Echocardiographic diagnosis of severe aortic regurgitation, finding recurrent aneurysm of sinus of Valsalva. Surgery was performed with primary closure of the defect and aortic valve replacement with mechanical prosthesis, issuing a favorable postoperative. We present a case of which there are no reports in the current literature. PMID- 26506493 TI - [Anaphylactic shock associated with ceftriaxone, case report and literature review]. AB - This study presents a case of anaphylactic shock in a senile patient, who had a biphasic event associated with the administration of a beta-lactam cephalosporin (ceftriaxone), needing stay in the intensive care unit and support with vasoactive amines, which it is rare to see in this issue, already being in itself a difficult diagnosis and often undervalued by rejecting causes of shock in a senile patient other than cardiogenic or septic. Also, a case review is made based on epidemiological issues, clinical and paraclinical diagnosis, and current treatment implications based on current international guidelines and a review of the topic. PMID- 26506494 TI - [Knowledge transfer for STI/HIV/AIDS prevention among adolescents]. AB - BACKGROUND: The transfer of knowledge is a crucial process for the functioning and continuation of training programs. The aim of this study was to determine how the transfer process works for the program JUVENIMSS and the factors that relate to the transfer of knowledge. METHODS: The study design was correlational, involving 122 health professionals. The Scale for the Measurement of Implementation Components was used. To analyze descriptive statistical data, overall index, instrument subscales, Kolmogorov-Smirnov goodness-of-fit test, and correlations were used. RESULTS: The average age of the professionals involved in the program was 37 years (standard deviation n = 10.5), with a predominance of females (84 %), and 48 % social workers. Knowledge transfer for the prevention of STI / HIV / AIDS among adolescents is correlated with administrative support, administrative personnel management, leadership, training, supervision / technical support and performance evaluation. CONCLUSIONS: Knowledge transfer showed areas of opportunity that should be considered by decision-makers to promote the implementation and continuation of preventive programs to prevent risky sexual behavior among adolescents. PMID- 26506495 TI - [Terminology in clinical bioethics]. AB - In this article some of the most relevant terms in clinical bioethics are defined. The terms were chosen based on three criteria: impact on the most important problems in clinical bioethics, difficulty in understanding, and need to clarify their meaning. For a better understanding, the terms were grouped into 5 areas: general concepts (conflict of values, deliberation, conflict of interest, conscientious objection); justice (justice, distributive justice, models of justice, triage); clinical matters (information, competency, capability, informed consent, mature minor, coercion, secrecy, privacy, confidentiality, professional secrecy); end of life (prior instructions, limitation of therapeutic efforts, professional obstinacy, futility, palliative care, palliative sedation, principle of double effect, euthanasia, assisted suicide, persistent vegetative state, minimally conscious state, locked-in syndrome, brain death), and beginning of life (assisted reproduction, genetic counseling, preimplantation genetic diagnosis). PMID- 26506496 TI - [Organs, tissues, and cells donation in Mexico]. AB - Transplants are one of the most important advances of modern medicine; in the last 50 years in our country there have been more than fifty thousand transplants, which makes it clear that this is one of the most sought-after medical practices not only in Mexico but worldwide. In life, it is possible for a person to donate a kidney, a lung or a liver segment. When brain death occurs it is possible for a person to donate kidneys, heart, liver, pancreas, intestines, lungs, blood, hematopoietic cells, bone marrow, bones, corneas, heart valves, tendons, and arteries. However, the culture of organ donation is not widespread among Mexicans, hence in our country there is not even 50 % of the number of donations recommended by WHO, which impacts the number of patients who are waiting for an organ or tissue, which causes many of them die before receiving them. PMID- 26506497 TI - [Cutaneous lupus erythematosus, a multidimensional entity]. AB - Skin lesions caused by systemic lupus erythematosus are among the most frequent manifestations of this disease. These lesions show great variability in both their clinical and histological expression, making their understanding and study difficult. Patients presenting with cutaneous lupus do not necessarily have serious systemic complications, but they do have significant morbidity from impact on quality of life given the extent of the lesions, chronic tendency, and the risk of scarring; hence the importance of establishing a fast and effective treatment. This paper addresses the different varieties of specific injuries attributed to lupus erythematosus, correlation with systemic activity, quality of life, and the treatments available. PMID- 26506498 TI - [General Strategies for Implementation of Clinical Practice Guidelines]. AB - The need to use clinical practice guidelines (CPG) arises from the health conditions and problems that public health institutions in the country face. CPG are informative documents that help improve the quality of care processes and patient safety; having among its objectives, to reduce the variability of medical practice. The Instituto Mexicano del Seguro Social designed a strategic plan for the dissemination, implementation, monitoring and control of CPG to establish an applicable model in the medical units in the three levels of care at the Instituto. This paper summarizes some of the strategies of the plan that were made with the knowledge and experience of clinicians and managers, with which they intend to promote the adoption of the key recommendations of the guidelines, to promote a sense of belonging for health personnel, and to encourage changes in organizational culture. PMID- 26506499 TI - Hormone therapy and risk of ovarian cancer in postmenopausal women: a systematic review and meta-analysis. AB - OBJECTIVE: Our objective was to perform a meta-analysis examining the risk of ovarian cancer with different types and regimens (continuous or sequential) of hormone therapy (HT). METHODS: PubMed, Cochrane, and Embase databases were searched until December 2014 using the terms: HT, estrogen therapy (ET), ovarian cancer, postmenopausal, and menopausal. HT was considered unopposed ET, estrogen progestin therapy (EPT), or ET+EPT (ET followed by EPT). RESULTS: Of 180 studies identified, 12 were included in the meta-analysis. Of the 12 studies, 9 were cohort studies including 2,350,546 women and 7,549 cases of ovarian cancer, and 3 were case-control studies including a total of 1,347 cases and 2,052 controls. ET, EPT, and ET+EPT were associated with an increased risk of ovarian cancer: pooled hazard ratio (HR)/relative risk (RR) =1.37, 95% CI: 1.19 to 1.58, P<0.001; pooled HR/RR=1.27, 95% CI: 1.18 to 1.36, P<0.001; pooled HR/RR=1.55, 95% CI: 1.05 to 2.30, P=0.027, respectively. Continuous and sequential regimens were associated with an increased risk: pooled HR/RR=1.27, 95% CI: 1.04 to 1.54, P=0.018; pooled HR/RR=1.31, 95% CI: 1.08 to 1.58, P=0.006, respectively. HT was associated with an increased risk of serous ovarian cancer (pooled HR/RR=1.46, 95% CI=1.28-1.67, P<0.001), but not clear cell, endometrioid, or mucinous ovarian cancer. CONCLUSIONS: Hormone therapy, regardless of type or regimen, is associated with an increased ovarian cancer risk. PMID- 26506500 TI - Symptom clusters among MsFLASH clinical trial participants. AB - OBJECTIVE: Our objective was to identify symptom clusters using standardized measures completed by participants in the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health clinical trial at baseline, including hot flash interference, and sleep, depressive, anxiety, and pain symptoms. METHODS: Data from all women randomized to interventions and controls from Menopausal Strategies: Finding Lasting Answers to Symptoms and Health studies 1, 2, and 3 (N = 899) were included; 797 with complete data were used in the analyses. Scores from standardized measures obtained at baseline included the following: Hot Flash Related Daily Interference Scale, Insomnia Severity Index, Pittsburgh Sleep Quality Index, Patient Health Questionnaire-9 measure of depressed mood, Generalized Anxiety Disorder, and Brief Pain Inventory PEG scores (pain intensity [P], interference with enjoyment of life [E], and interference with daily activity [G]). Latent class analysis was used to identify symptom clusters using standardized scale scores and their established cut points. RESULTS: We identified five classes using the Bayesian Information Criterion and the Akaike Information Criterion. Women in classes 1 and 2 had high hot flash interference levels relative to the others, and class 1 (10.5% of total) included severe hot flash interference, severe sleep symptoms, and moderately severe pain symptoms (hot flash, sleep, pain). In class 2 (14.1%), severe hot flash interference was paired with the severe sleep symptoms, and moderate to severe depressed and anxious mood symptoms and pain (hot flash, sleep, mood, pain). In class 3 (39.6%), women reported moderately severe sleep symptoms with moderate hot flash interference, and low severity mood and pain symptoms (hot flash, sleep). Those in class 4 (7.0%) reported moderate hot flash interference with severe levels of anxiety and depressed mood symptoms, but low levels of other symptoms (hot flash, mood). Women in class 5 (28.7%) reported the lowest levels of all the five symptoms (low severity symptoms). CONCLUSIONS: Women meeting hot flash frequency criteria for inclusion in clinical trials exhibited multiple co-occurring symptoms that clustered into identifiable groups according to symptom interference and severity. Variability of symptom profiles between the classes was evident, indicating that the classes were composed of differing symptom types and not simply differing severity levels. These symptom clusters may be useful phenotypes for differentiating treatment effects or evaluating associations with biomarkers or genes. PMID- 26506501 TI - Middle-aged female sexual dysfunction and multimorbidity: a population-based study. AB - OBJECTIVES: The aim of the study was to evaluate the association between multimorbidity and sexual dysfunction in women aged 45 to 60 years in a cross sectional population-based study in a specific Brazilian city. It was also to evaluate the main factors associated with sexual dysfunction in the group with multimorbidity. METHODS: Cross-sectional population-based study conducted with 736 women (household survey), representative of a population of 257,434 women, to obtain data on multimorbidity and sexual dysfunction, as part of a broader study on women's health. The instrument used to evaluate sexual dysfunction was the Short Personal Experiences Questionnaire. Associations were determined between multimorbidity and sexual dysfunction and sexual dysfunction and demographic, behavioral, and medical characteristics. RESULTS: 53% of the women reported multimorbidity and 49.6% of them reported sexual dysfunction. Multiple regression analysis showed no association between sexual dysfunction and multimorbidity. Sexual dysfunction in the whole sample (with and without multimorbidity) was associated with sexual activity in the last month (prevalence ratio [PR] = 0.27, 95% CI 0.22-0.33, P < 0.001), having physical activity greater than or equal to 2 times a week (PR = 0.70, 95% CI 0.58-0.84, P < 0.001), menopause rating symptoms greater than 8 (PR = 1.25, 95% CI 1.09-1.43, P = 0.002), perimenopausal or postmenopausal status (PR = 1.57, 95% CI 1.13-2.17, P = 0.007), alcohol use greater than or equal to 1 drink/week (PR = 0.81, 95% CI 0.67-0.97, P = 0.025), and anxiety (PR = 1.15, 95% CI 1.01-1.31, P = 0.039). In the group with multimorbidity, the main factors associated with sexual dysfunction were sexual activity in the last month (PR = 0.31, 95% CI 0.25-0.39, P < 0.001), anxiety (PR = 1.33, 95% CI 1.15-1.53, P < 0.001), and physical activity (PR = 0.70, 95% CI 0.56-0.87, P = 0.002). CONCLUSIONS: There was no evidence that multimorbidity was associated with sexual dysfunction in this sample of middle-aged women. The main factors associated with sexual dysfunction in women with multimorbidity in this sample were lack of sexual activity in the last month, physical inactivity, and anxiety. This highlights the importance of sexual activity, psychological health, and physical activity for a satisfactory sexual life in the case of women with multimorbidity. PMID- 26506502 TI - Asian Elm tree inner bark prevents articular cartilage deterioration in ovariectomized obese rats with monoiodoacetate-induced osteoarthritis. AB - OBJECTIVE: We investigated whether long-term consumption of Korean mistletoe or Asian Ulmi cortex would prevent or delay menopausal symptoms and progression of osteoarthritis in estrogen-deficient obese rats. METHODS: Ovariectomized (OVX) rats were provided a 45% fat diet containing either (1) 0.6% lyophilized water extract of Korean mistletoe (KME) + 1.4% dextrose (KME; n = 10), (2) 2% lyophilized water extract of Ulmi cortex (UCE; n = 10), (3) 30 MUg/kg bw 17beta estradiol + 2% dextrose (positive control; n = 10), (4) 2% dextrose (placebo; OVX control; n = 10), or (5) 2% dextrose (normal-control; n = 10) for 4 weeks. At the beginning of the 5th week, OVX rats, except in the normal-control group, were given articular injections of monoiodoacetate into the right knee and the assigned diets were provided for an additional 3 weeks. The rats in the normal control had injections of saline into the right knee. RESULTS: KME, but not UCE, partially prevented the insulin resistance and the loss of bone mineral density and lean mass. The limping scores were lower in the descending order of the OVX control > KME and 17beta-estradiol > UCE > normal-control at day 14 and 21 (P < 0.05). The scores for pain behaviors measured by weight distribution on the right leg, maximum running velocity on a treadmill and locomotive activity, were markedly decreased in the same order as limping scores. Monoiodoacetate increased the expression of matrix metalloprotinase-3 and metalloprotinase-13 in the articular cartilage and elevated the production of inflammatory markers such as tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6, but they were lower in the UCE than in the other groups (P < 0.05). Histology of the right knee revealed cartilage damage near the tidemark of the knee and proteoglycan loss was markedly less in UCE. CONCLUSIONS: UCE was an effective therapeutic agent for preventing osteoarthritis and KME prevented decreases in lean body mass, bone mineral density, and insulin sensitivity in estrogen-deficient rats. PMID- 26506503 TI - 19th International Meeting of the European Society of Gynecological Oncology (ESGO 2015). PMID- 26506505 TI - Silatranes for binding inorganic complexes to metal oxide surfaces. AB - A ruthenium complex containing silatrane functional groups has been synthesized and covalently bound to a conductive metal oxide film composed of nanoparticulate ITO (nanoITO). The silatrane-derived siloxane surface anchors were found to be stable in the examined range of pH 2 to 11 in aqueous phosphate buffer, and the ruthenium complex was found to have stable electrochemical features with repeated electrochemical cycling. The non-coordinating properties of the silatrane group to metals, which facilitates synthesis of silatrane-labeled coordination complexes, together with the facile surface-binding procedure, robustness of the surface linkages, and stability of the electrochemical properties suggest that incorporating silatrane motifs into ligands for inorganic complexes provides superior properties for attachment of catalysts to metal oxide surfaces under aqueous conditions. PMID- 26506506 TI - A Facile Strategy for Catalyst Separation and Recycling Suitable for ATRP of Hydrophilic Monomers Using a Macroligand. AB - How to simply and efficiently separate and recycle catalyst has still been a constraint for the wide application of atom transfer radical polymerization (ATRP), especially for the polymerization systems with hydrophilic monomers because the polar functional groups may coordinate with transition metal salts, resulting in abundant catalyst residual in the resultant water-soluble polymers. In order to overcome this problem, a latent-biphasic system is developed, which can be successfully used for ATRP catalyst separation and recycling in situ for various kinds of hydrophilic monomers for the first time, such as poly(ethylene glycol) monomethyl ether methacrylate (PEGMA), 2-hydroxyethyl methacrylate (HEMA), 2-(dimethylamino)ethyl methacrylate (DMAEMA), N,N-dimethyl acrylamide (DMA), and N-isopropylacrylamide (NIPAM). Herein, random copolymer of octadecyl acrylate (OA), MA-Ln (2-(bis(pyridin-2-ylmethyl)amino)ethyl acrylate), and POA ran-P(MA-Ln) is designed as the macroligand, and heptane/ethanol is selected as the biphasic solvent. Copper(II) bromide (CuBr2 ) is employed as the catalyst, PEG-bound 2-bromo-2-methylpropanoate (PEG350 -Br) as the water-soluble ATRP initiator and 2,2'-azobis(isobutyronitrile) (AIBN) as the azo-initiator to establish an ICAR (initiators for continuous activator regeneration) ATRP system. Importantly, well-defined water-soluble polymers are obtained even though the recyclable catalyst is used for sixth times. PMID- 26506507 TI - A prospective 4-year study of the objective and subjective outcomes of fifteen patients after dynamic facial reanimation surgery. PMID- 26506508 TI - Why do local corticosteroid injections work in carpal tunnel syndrome, but not in ulnar neuropathy at the elbow? PMID- 26506509 TI - CD73 regulates vascular smooth muscle cell functions and facilitates atherosclerotic plaque formation. AB - Extracellular adenosine, generated by ecto-5'-nucleotidase (CD73) via enzymatic catalyzation, has been found to facilitate atherosclerosis (AS). Thus, suppressing CD73 may attenuate AS. In this study, we evaluated the role of CD73 during AS development and further explored cellular and molecular mechanism in smooth muscle cells (SMCs). In a mouse model of carotid artery ligation, inactivation of CD73 inhibited migration and proliferation of vascular SMCs. In in vitro experiments, RNA interference of CD73 inhibited migration, proliferation, and foam cell transformation of human umbilical artery smooth muscle cells. Further, we established an atherosclerotic model using ApoE-/- mice fed with a western diet for 16 weeks. Inactivation of CD73-attenuated AS and hyperlipidemia in ApoE-/- mice. In conclusion, our data suggest that CD73 facilitates AS by promoting migration, proliferation, and foam cell transformation of vascular SMCs and elevating serum lipid levels. Thus, inhibition of CD73 may be beneficial for prevention and treatment of AS. PMID- 26506510 TI - Nonsynaptic glycine release is involved in the early KCC2 expression. AB - The cation-chloride co-transporters are important regulators of the cellular Cl( ) homeostasis. Among them the Na(+) -K(+) -2Cl(-) co-transporter (NKCC1) is responsible for intracellular chloride accumulation in most immature brain structures, whereas the K(+) -Cl(-) co-transporter (KCC2) extrudes chloride from mature neurons, ensuring chloride-mediated inhibitory effects of GABA/glycine. We have shown that both KCC2 and NKCC1 are expressed at early embryonic stages (E11.5) in the ventral spinal cord (SC). The mechanisms by which KCC2 is prematurely expressed are unknown. In this study, we found that chronically blocking glycine receptors (GlyR) by strychnine led to a loss of KCC2 expression, without affecting NKCC1 level. This effect was not dependent on the firing of Na(+) action potentials but was mimicked by a Ca(2+) -dependent PKC blocker. Blocking the vesicular release of neurotransmitters did not impinge on strychnine effect whereas blocking volume-sensitive outwardly rectifying (VSOR) chloride channels reproduced the GlyR blockade, suggesting that KCC2 is controlled by a glycine release from progenitor radial cells in immature ventral spinal networks. Finally, we showed that the strychnine treatment prevented the maturation of rhythmic spontaneous activity. Thereby, the GlyR-activation is a necessary developmental process for the expression of functional spinal motor networks. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 764-779, 2016. PMID- 26506511 TI - Spatio-Temporal Parameters of Endosomal Signaling in Cancer: Implications for New Treatment Options. AB - The endo/lysosomal system in cells provides membranous platforms to assemble specific signaling complexes and to terminate signal transduction, thus, is essential for physiological signaling. Endocytic organelles can significantly extend signaling of activated cell surface receptors, and may additionally provide distinct locations for the generation of specific signaling outputs. Failures of regulation at different levels of endocytosis, recycling, degradation as well as aberrations in specific endo/lysosomal signaling pathways, such as mTORC1, might lead to different diseases including cancer. Therefore, a better understanding of spatio-temporal compartmentalization of sub-cellular signaling might provide an opportunity to interfere with aberrant signal transduction in pathological processes by novel combinatorial therapeutic approaches. PMID- 26506512 TI - Silver/silver chloride microneedles can detect penetration through the round window membrane. AB - HYPOTHESIS: Silver-plated microneedles can be used to confirm penetration of semi permeable membranes such as the round window membrane (RWM) by detection of voltage change at the moment of perforation. BACKGROUND: The introduction of microperforations in the RWM can significantly enhance intracochlear delivery of therapeutics. However, the moment of needle penetration through the RWM cannot be reliably detected by visualization or sensation alone. We explore the ability of electrochemical detection of penetration in defining the precise instant a microneedle enters the inner ear. METHODS: 0.2 mm diameter stainless steel Minutien pins were electroplated with copper, then silver. Pins were then soaked in bleach for 24 h to complete Ag/AgCl plating. Experiments were performed using a 3 mL Franz cell diffusion system with 1%, 2%, 3%, 4%, and 5% saline solution in the donor chamber and artificial perilymph solution in the receptor chamber separated by 5-MUm pore synthetic membrane. Continuous voltage measurements were made throughout the process of membrane penetration by the microneedle (N = 6 for each saline concentration). RESULTS: Silver-plated needles were able to detect an instantaneous change in voltage when traversing the membrane from saline solution into artificial perilymph. As calculated, the magnitude of the change in voltage upon penetration increased with increasing saline concentration and was stable across trials. CONCLUSION: Ag/AgCl coated microneedles are effective in detecting the moment of penetration across semi-permeable membranes. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 307-311, 2017. PMID- 26506514 TI - Sex-specific associations between birth weight and adult primary liver cancer in a large cohort of Danish children. AB - Whether the prenatal period is critical for the development of adult primary liver cancer (PLC) is sparsely investigated. Recently, attention has been drawn to potential sex-differences in the early origins of adult disease. The association between birth weight and adult PLC, separately in men and women was investigated, using a large cohort of 217,227 children (51% boys), born from 1936 to 1980, from the Copenhagen School Health Records Register, and followed them until 2010 in national registers. Hazard ratios (95% confidence intervals) of PLC (30 years or older) were estimated by Cox regression models stratified by birth cohort. During 5.1 million person-years of follow-up, 185 men and 65 women developed PLC. Sex modified the association between birth weight and adult PLC (p values for interaction = 0.0005). Compared with a sex-specific reference group of birth weights between 3.25 and 3.75 kg, men with birth weights between 2.00 and 3.25 kg and 3.75-5.50 kg, had HRs of 1.48 (1.06-2.05) and 0.85 (0.56-1.28), respectively. Among women the corresponding HRs were 1.71 (0.90-3.29) and 3.43 (1.73-6.82). Associations were similar for hepatocellular carcinoma only, across year of birth, and after accounting for diagnoses of alcohol-related disorders, viral hepatitis and biliary cirrhosis. Prenatal exposures influenced the risk of adult PLC, and the effects at the high birth weight levels appeared to be sex specific. These findings underscore the importance of considering sex-specific mechanisms in the early origins of adult PLC. PMID- 26506515 TI - Gross anatomical study on the human myocardial bridges with special reference to the spatial relationship among coronary arteries, cardiac veins, and autonomic nerves. AB - Coronary arteries are frequently covered by cardiac muscles. This arrangement is termed a myocardial bridge. Previous studies have shown that myocardial bridges can cause myocardial ischemic diseases or cardiac arrhythmia, but the relevant pathogenic mechanisms remain unknown. We examined 60 hearts from Japanese cadavers macroscopically to clarify the spatial relationships among coronary arteries, cardiac veins and autonomic nerves. We found 86 myocardial bridges in 47 hearts from the 60 cadavers examined (78.3%). Next, we dissected out nine hearts with myocardial bridges in detail under the operating microscope. We found no additional branches of coronary arteries on the myocardial bridge surfaces. However, the cardiac veins, which usually accompany the coronary arteries, ran independently on the myocardial bridge surfaces in the same region. Cardiac autonomic nerves comprised two rami: one was associated with the coronary artery under the myocardial bridge and the other ran on the surface of the bridge. Such spatial relationships among the coronary arteries, cardiac veins and cardiac autonomic nerves at the myocardial bridges are quite similar to those in mouse embryo hearts. PMID- 26506513 TI - Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria. AB - BACE-1 is the beta-secretase responsible for the initial amyloidogenesis in Alzheimer's disease, catalyzing hydrolytic cleavage of substrate in a pH sensitive manner. The catalytic mechanism of BACE-1 requires water-mediated proton transfer from aspartyl dyad to the substrate, as well as structural flexibility in the flap region. Thus, the coupling of protonation and conformational equilibria is essential to a full in silico characterization of BACE-1. In this work, we perform constant pH replica exchange molecular dynamics simulations on both apo BACE-1 and five BACE-1-inhibitor complexes to examine the effect of pH on dynamics and inhibitor binding properties of BACE-1. In our simulations, we find that solution pH controls the conformational flexibility of apo BACE-1, whereas bound inhibitors largely limit the motions of the holo enzyme at all levels of pH. The microscopic pKa values of titratable residues in BACE-1 including its aspartyl dyad are computed and compared between apo and inhibitor bound states. Changes in protonation between the apo and holo forms suggest a thermodynamic linkage between binding of inhibitors and protons localized at the dyad. Utilizing our recently developed computational protocol applying the binding polynomial formalism to the constant pH molecular dynamics (CpHMD) framework, we are able to obtain the pH-dependent binding free energy profiles for various BACE-1-inhibitor complexes. Our results highlight the importance of correctly addressing the binding-induced protonation changes in protein-ligand systems where binding accompanies a net proton transfer. This work comprises the first application of our CpHMD-based free energy computational method to protein ligand complexes and illustrates the value of CpHMD as an all-purpose tool for obtaining pH-dependent dynamics and binding free energies of biological systems. PMID- 26506516 TI - Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer. AB - Gain-of-function of the androgen receptor (AR) and activation of PI3K/AKT/mTOR pathway have been demonstrated to correlate with progression to castration resistant prostate cancer (CRPC). However, inhibition of AR or PI3K/mTOR alone results in a reciprocal feedback activation. Therefore, we hypothesized that dual inhibition of the AR and PI3K/mTOR pathway might lead to a synergistic inhibition of cell growth and overcome drug resistance in CRPC. Here, we reported that androgen-depletion increased AR protein level and Akt phosphorylation at Ser473 and Thr308 in LNCaP cells. Moreover, we developed resistance cell lines of LNCaP to Enzalutamide (or MDV3100), an AR inhibitor (named as LNCaP 'MDV-R') and PF 04691502, a PI3K/mTOR inhibitor (named as LNCaP 'PF-R'). MTS analysis showed that LNCaP 'PF-R' was strongly resistant to Enzalutamide treatment, and on the other hand, LNCaP 'MDV-R' was 6-fold resistant to PF-04691502 treatment. Mechanistically, LNCaP 'MDV-R' cells had significantly reduced AR, loss of PSA and increase Akt activity in contrast with LNCaP 'PF-R' cells. Combined inhibition of PI3K/mTOR and AR pathways with a variety of small molecular inhibitors led to a synergistic suppression of cell proliferation and a profound increase of apoptosis and cell cycle arrest in both androgen-dependent LNCaP and independent CRPC 22Rv1 cell lines. In conclusion, this study provides preclinical proof-of-concept that the combination of a PI3K/mTOR inhibitor with an AR inhibitor results in a synergistic anti-tumor response in non-CRPC and CRPC models. PMID- 26506517 TI - The impact of RNA binding motif protein 4-regulated splicing cascade on the progression and metabolism of colorectal cancer cells. AB - Dysregulated splicing of pre-messenger (m)RNA is considered a molecular occasion of carcinogenesis. However, the underlying mechanism is complex and remains to be investigated. Herein, we report that the upregulated miR-92a reduced the RNA binding motif 4 (RBM4) protein expression, leading to the imbalanced expression of the neuronal polypyrimidine tract-binding (nPTB) protein through alternative splicing-coupled nonsense mediated decay (NMD) mechanism. Increase in nPTB protein enhances the relative level of fibroblast growth factor receptor 2 IIIc (FGFR2) and pyruvate kinase M2 (PKM2) transcripts which contribute to the progression and metabolic signature of CRC cells. Expression profiles of RBM4 and downstream alternative splicing events are consistently observed in cancerous tissues compared to adjacent normal tissues. These results constitute a mechanistic understanding of RBM4 on repressing the carcinogenesis of colorectal cells. PMID- 26506518 TI - Overexpression of WWP1 promotes tumorigenesis and predicts unfavorable prognosis in patients with hepatocellular carcinoma. AB - WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) has been speculated to play important roles in the development of several kinds of cancers. However, the role of WWP1 in hepatocellular carcinoma(HCC) is not clear. In the present study, we investigated the expression and prognostic role of WWP1 in primary hepatocellular carcinoma (HCC) using cell lines and 149 archived HCC samples. Correlation between the functions of WWP1 in HCC was also explored. We used human HCC cell lines (BEL-7402, SMMC-7721, Hep-G2, Hep-3B, SK-hep1 and Huh7) and a normal hepatocyte cell line (LO2) along with HCC samples from patients who had undergone resection for HCC previously at our hospital. A battery of methods (real-time quantitative polymerase chain reaction; western blotting; immunohistochemical analyses; cell proliferation and colony formation assays; cell migration and cell invasion assays) were employed to assess various aspects of WWP1. We found that WWP1 expression was upregulated aberrantly at mRNA and protein levels in human primary HCC tissues. Amplified expression of WWP1 was highly correlated with poor outcome. Silencing of WWP1 expression by siRNA inhibited the proliferation, colony formation, migration and invasion of HCC cells in vitro, and resulted in significant apoptosis and cycle arrest in HCC cells. Our findings suggest that WWP1 might have an oncogenic role in human primary HCC, and that it could be used as a prognostic marker as well as a potential molecular target for the treatment of HCC. PMID- 26506519 TI - Aspartate aminotransferase-lymphocyte ratio index and systemic immune inflammation index predict overall survival in HBV-related hepatocellular carcinoma patients after transcatheter arterial chemoembolization. AB - It has been suggested that lymphocytes play central roles in host antitumor immune responses and control cancer outcome. We reviewed the clinical parameters of 189 hepatocellular carcinoma (HCC) patients and investigated the prognostic significance of lymphocyte-related scores in HCC patients following transcatheter arterial chemoembolization (TACE). Survival analysis revealed that an elevated aspartate aminotransferase-lymphocyte ratio index (ALRI) > 57 and a systemic immune-inflammation index (SII) > 300 were negatively associated with overall survival in HBV-related HCC (HR = 2.181, P = 0.003 and HR = 2.453, P = 0.003; respectively). Spearman chi-square analysis showed that ALRI had a specificity of 82.4% and that SII index had a sensitivity of 71.9% for HCC overall survival. ALRI and SII had negative predictive values of 74.6% and 80%, respectively for HCC overall survival. Additionally, Barcelona Clinic Liver Cancer (BCLC) stage C patients had significantly higher ALRI and SII scores (both P < 0.0001) and poorer overall survival (HR = 3.618, P < 0.001). Additionally, HCC patients with portal vein tumor thrombosis (PVTT) had higher ALRI and SII scores (P < 0.0001 and P = 0.0059, respectively). In conclusion, as noninvasive, low cost, easily assessable and reproducible parameters, elevated ALRI and SII should be used as negative predictive factors for overall survival in HBV-related HCC in clinical practice. PMID- 26506520 TI - Prevalence of deleterious ATM germline mutations in gastric cancer patients. AB - Besides CDH1, few hereditary gastric cancer predisposition genes have been previously reported. In this study, we discovered two germline ATM mutations (p.Y1203fs and p.N1223S) in a Chinese family with a history of gastric cancer by screening 83 cancer susceptibility genes. Using a published exome sequencing dataset, we found deleterious germline mutations of ATM in 2.7% of 335 gastric cancer patients of different ethnic origins. The frequency of deleterious ATM mutations in gastric cancer patients is significantly higher than that in general population (p=0.0000435), suggesting an association of ATM mutations with gastric cancer predisposition. We also observed biallelic inactivation of ATM in tumors of two gastric cancer patients. Further evaluation of ATM mutations in hereditary gastric cancer will facilitate genetic testing and risk assessment. PMID- 26506521 TI - Suppression of FoxO6 by lipopolysaccharide in aged rat liver. AB - The beneficial role of FoxO during aging has been proposed for its promotion of resistance to oxidative stress and inhibition of pro-inflammatory mediators. On the other hand, NF-kappaB is a pro-inflammatory transcription factor which is a key mediator of inflammatory cytokine generation. However, the correlation between FoxO6 and NF-kappaB during aging has not fully been explored.The main purpose of the present study was to elucidate mechanisms underlying the protective role of FoxO6 in the maintenance of cellular homeostasis under potent pro-inflammatory conditions induced by LPS. Initial experimentation revealed that reduced FoxO6 activity during aging was caused by its phosphorylation, which suppressed its transcriptional activity in aged livers. Transfection with FoxO6 wt virus and FoxO6-siRNA in HepG2 cells revealed that FoxO6 phosphorylation by LPS leads to NF-kappaB activation via Akt and Pak1 pathways. Furthermore, Pak1 activity was increased in a phosphatidylinositol 3-kinase independent manner, and LPS-induced FoxO6 phosphorylation and FoxO6 inactivation were Pak1-dependent in nuclear fractions of cells. Further revealed Pak1 phosphorylation by LPS permitted interaction between FoxO6 and Akt.Current study suggests FoxO6 phosphorylation facilitates the nuclear translocation of NF-kappaB via Akt and Pak1 pathways induced by LPS in aged rats. PMID- 26506523 TI - Lymphoproliferative Disorders after Lung Transplantation: Clinicopathological Characterization of 16 Cases with Identification of Very-Late-Onset Forms. AB - BACKGROUND: The incidence of posttransplant lymphoproliferative disorders (PTLD) has recently declined, but late cases are increasingly reported in lung transplant recipients. OBJECTIVES: We present our experience with PTLD after lung transplantation, attempting to examine the distinguishing characteristics of early versus late cases. METHODS: We have reviewed clinical and pathological data of all cases occurring in our institution between 2001 and 2014. RESULTS: Patients, aged 15-63 years, were mostly (12/16) Epstein-Barr virus (EBV) seropositive at the time of transplantation. Eleven early cases, occurring 9.4 +/ 5.2 months after transplantation and mostly (9/11) prior to 2010, had EBV+ diffuse large B-cell lymphomas. Lungs and/or thoracic lymph nodes were often involved (n = 8). Treatments included reduction of immune suppression (n = 11), rituximab (n = 8) and chemotherapy (n = 7). Two patients are in complete remission at 26 and 216 months. Nine patients died 8.0 +/- 6.5 months after PTLD diagnosis. Of the 5 cases with late PTLD occurring 4-23 years (mean +/- SD: 10.4 +/- 7.7) after transplantation (and 3/5 after 2009), 1 had pulmonary lymphomatoid granulomatosis (only endothoracic case), 1 cutaneous large T-cell lymphoma, 2 had anaplastic large cell lymphomas, and 1 Hodgkin's disease. Two of the 5 cases were EBV-, including one followed by a second EBV+ PTLD after 8 years of complete remission. Two patients were alive and well (follow-up: 44 and 151 months), one having suffered from EBV-related cholestatic hepatitis 6 years after the PTLD. CONCLUSION: Our small experience shows a trend toward (very) late occurrence, associated with more unusual clinicopathologic features, but not with a worse prognosis. PMID- 26506522 TI - Effect of the Subcutaneous Environment on Phase-Sensitive In Situ-Forming Implant Drug Release, Degradation, and Microstructure. AB - In situ-forming implants are a promising platform used for the release of therapeutic agents. Significant changes in behavior occur when the implants are used in vivo relative to implants formed in vitro. To understand how the injection site effects implant behavior, poly(lactic-co-glycolic acid) implants were examined after injection in the subcutaneous space of a Sprague-Dawley rat model to determine how the environment altered implant erosion, degradation, swelling, microstructure, and mock drug release. Changes in implant microstructure occurred over time for implants formed in vivo, where it was observed that the porosity was lost over the course of 5 days. Implants formed in vivo had a significantly greater burst release (p < 0.05) relative to implants formed in vitro. However, during the diffusion period of release, implants formed in vitro had a significantly higher daily release (2.1%/day, p < 0.05), which correlated to changes in implant microstructure. Additionally, implants formed in vitro had a two-fold increase in the first-order degradation kinetics relative to the implants formed in vivo. These findings suggest that the changes in implant behavior occur as a result of changes in the implant microstructure induced by the external environment. PMID- 26506524 TI - Correction: Endocytosed beta2-Microglobulin Amyloid Fibrils Induce Necrosis and Apoptosis of Rabbit Synovial Fibroblasts by Disrupting Endosomal/Lysosomal Membranes: A Novel Mechanism on the Cytotoxicity of Amyloid Fibrils. PMID- 26506525 TI - Ordering Dynamics in Neuron Activity Pattern Model: An Insight to Brain Functionality. AB - We study the domain ordering kinetics in d = 2 ferromagnets which corresponds to populated neuron activities with both long-ranged interactions, V(r) ~ r-n and short-ranged interactions. We present the results from comprehensive Monte Carlo (MC) simulations for the nonconserved Ising model with n >= 2, interaction range considering near and far neighbors. Our model results could represent the long ranged neuron kinetics (n <= 4) in consistent with the same dynamical behaviour of short-ranged case (n >= 4) at far below and near criticality. We found that emergence of fast and slow kinetics of long and short ranged case could imitate the formation of connections among near and distant neurons. The calculated characteristic length scale in long-ranged interaction is found to be n independent (L(t) ~ t1/(n-2)), whereas short-ranged interaction follows L(t) ~ t1/2 law and approximately preserve universality in domain kinetics. Further, we did the comparative study of phase ordering near the critical temperature which follows different behaviours of domain ordering near and far critical temperature but follows universal scaling law. PMID- 26506527 TI - Erratum: Relationship between gene expression and the accumulation of catechin during spring and autumn in tea plants (Camellia sinensis L.). AB - [This corrects the article DOI: 10.1038/hortres.2015.11.][This corrects the article DOI: 10.1038/hortres.2015.11.]. PMID- 26506526 TI - Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study. AB - Detecting left ventricular (LV) dysfunction at an early stage is key in addressing the heart failure epidemic. In proteome profiling experiments in mice subjected either to aortic banding or sham, the circulating CXCR3 ligands monokine induced by interferon-gamma (MIG) and interferon-gamma inducible protein 10 (IP10) were 5 to 40 fold up-regulated at eight weeks. We assessed the diagnostic value of circulating NT-pro BNP and CXCR3 ligands (MIG, IP10, Interferon-inducible T-cell alpha chemo-attractant [I-TAC]) in patients with hypertension (>=140/90 mm Hg) associated with subclinical (n = 19) or symptomatic (n = 16) diastolic LV dysfunction on echocardiography and healthy controls. NT pro BNP, MIG, IP10, I-TAC all increased (p <= 0.014) across the categories of worsening left ventricular dysfunction. In patients with symptomatic disease, MIG, IP10, and I-TAC increased 210% (p = 0.015), 140% (p = 0.007) and 120% (p = 0.035) more than NT-pro BNP. The optimal discrimination limits, obtained by maximizing Youden's index were 246 pmol/L, 65 pg/mL, 93 pg/mL, and 24 pg/mL, respectively. The odds ratios associated with the four biomarkers were significant (p <= 0.010), ranging from 4.00 for IP10 to 9.69 for MIG. With adjustment for NT-pro BNP, the CXCR3 ligands retained significance (p <= 0.028). Adding optimized thresholds for the CXCR3 ligands to NT-pro BNP enhanced (p <= 0.014) the integrated discrimination improvement and the net reclassification improvement. In conclusion, congruent with the concept that inflammation plays a key role in the pathogenesis of LV dysfunction, MIG, IP10 and I-TAC add diagnostic accuracy over and beyond NT-pro BNP. PMID- 26506528 TI - Transcriptional Profile of Bacillus subtilis sigF-Mutant during Vegetative Growth. AB - Sigma factor F is the first forespore specific transcription factor in Bacillus subtilis and controls genes required for the early stages of prespore development. The role of sigF is well studied under conditions that induce sporulation. Here, the impact of sigF disruption on the transcriptome of exponentially growing cultures is studied by micro-array analysis. Under these conditions that typically don't induce sporulation, the transcriptome showed minor signs of sporulation initiation. The number of genes differentially expressed and the magnitude of expression were, as expected, quite small in comparison with sporulation conditions. The genes mildly down-regulated were mostly involved in anabolism and the genes mildly up-regulated, in particular fatty acid degradation genes, were mostly involved in catabolism. This is probably related to the arrest at sporulation stage II occurring in the sigF mutant, because continuation of growth from the formed disporic sporangia may require additional energy. The obtained knowledge is relevant for various experiments, such as industrial fermentation, prolonged experimental evolution or zero-growth studies, where sporulation is an undesirable trait that should be avoided, e.g by a sigF mutation. PMID- 26506529 TI - Invader disruption of belowground plant mutualisms reduces carbon acquisition and alters allocation patterns in a native forest herb. AB - Invasive plants impose novel selection pressures on naive mutualistic interactions between native plants and their partners. As most plants critically rely on root fungal symbionts (RFSs) for soil resources, invaders that disrupt plant-RFS mutualisms can significantly depress native plant fitness. Here, we investigate the consequences of RFS mutualism disruption on native plant fitness in a glasshouse experiment with a forest invader that produces known anti-fungal allelochemicals. Over 5 months, we regularly applied either green leaves of the allelopathic invader Alliaria petiolata, a nonsystemic fungicide to simulate A. petiolata's effects, or green leaves of nonallelopathic Hesperis matronalis (control) to pots containing the native Maianthemum racemosum and its RFSs. We repeatedly measured M. racemosum physiology and harvested plants periodically to assess carbon allocation. Alliaria petiolata and fungicide treatment effects were indistinguishable: we observed inhibition of the RFS soil hyphal network and significant reductions in M. racemosum physiology (photosynthesis, transpiration and conductance) and allocation (carbon storage, root biomass and asexual reproduction) in both treatments relative to the control. Our findings suggest a general mechanistic hypothesis for local extinction of native species in ecosystems challenged by allelopathic invaders: RFS mutualism disruption drives carbon stress, subsequent declines in native plant vigor, and, if chronic, declines in RFS-dependent species abundance. PMID- 26506530 TI - Parameter-dependent behavior of articular cartilage: 3D mechano-electrochemical computational model. AB - BACKGROUND AND OBJECTIVE: Changes in mechano-electrochemical properties of articular cartilage play an essential role in the majority of cartilage diseases. Despite of this importance, the specific effect of each parameter into tissue behavior remains still obscure. Parametric computational modeling of cartilage can provide some insights into this matter, specifically the study of mechano electrochemical properties variation and their correlation with tissue swelling, water and ion fluxes. Thus, the aim of this study is to evaluate the influence of the main mechanical and electrochemical parameters on the determination of articular cartilage behavior by a parametric analysis through a 3D finite element model. METHODS: For this purpose, a previous 3D mechano-electrochemical model, developed by the same authors, of articular cartilage behavior has been used. Young's modulus, Poisson coefficient, ion diffusivities and ion activity coefficients variations have been analyzed and quantified through monitoring tissue simulated response. RESULTS: Simulation results show how Young's modulus and Poisson coefficient control tissue behavior rather than electrochemical properties. Meanwhile, ion diffusivity and ion activity coefficients appear to be vital in controlling velocity of incoming and outgoing fluxes. CONCLUSIONS: This parametric study establishes a basic guide when defining the main properties that are essential to be included into computational modeling of articular cartilage providing a helpful tool in tissue simulations. PMID- 26506531 TI - Multi-period medical diagnosis method using a single valued neutrosophic similarity measure based on tangent function. AB - Because of the increased volume of information available to physicians from advanced medical technology, the obtained information of each symptom with respect to a disease may contain truth, falsity and indeterminacy information. Since a single-valued neutrosophic set (SVNS) consists of the three terms like the truth-membership, indeterminacy-membership and falsity-membership functions, it is very suitable for representing indeterminate and inconsistent information. Then, similarity measure plays an important role in pattern recognition and medical diagnosis. However, existing medical diagnosis methods can only handle the single period medical diagnosis problem, but cannot deal with the multi period medical diagnosis problems with neutrosophic information. Hence, the purpose of this paper was to propose similarity measures between SVNSs based on tangent function and a multi-period medical diagnosis method based on the similarity measure and the weighted aggregation of multi-period information to solve multi-period medical diagnosis problems with single-valued neutrosophic information. Then, we compared the tangent similarity measures of SVNSs with existing similarity measures of SVNSs by a numerical example about pattern recognitions to indicate the effectiveness and rationality of the proposed similarity measures. In the multi-period medical diagnosis method, we can find a proper diagnosis for a patient by the proposed similarity measure between the symptoms and the considered diseases represented by SVNSs and the weighted aggregation of multi-period information. Then, a multi-period medical diagnosis example was presented to demonstrate the application of the proposed diagnosis method and to indicate the effectiveness of the proposed diagnosis method by the comparative analysis. The diagnosis results showed that the developed multi period medical diagnosis method can help doctors make a proper diagnosis by the comprehensive information of multi-periods. PMID- 26506532 TI - A Comparative Study of Peripheral Immune Responses to Taenia solium in Individuals with Parenchymal and Subarachnoid Neurocysticercosis. AB - BACKGROUND: The ability of Taenia solium to modulate the immune system likely contributes to their longevity in the human host. We tested the hypothesis that the nature of the immune response is related to the location of parasite and clinical manifestations of infection. METHODOLOGY: Peripheral blood mononuclear cells (PBMC) were obtained from untreated patients with neurocysticercosis (NCC), categorized as having parenchymal or subarachnoid infection by the presence of cysts exclusively within the parenchyma or in subarachnoid spaces of the brain, and from uninfected (control) individuals matched by age and gender to each patient. Using multiplex detection technology, sera from NCC patients and controls and cytokine production by PBMC after T. solium antigen (TsAg) stimulation were assayed for levels of inflammatory and regulatory cytokines. PBMC were phenotyped by flow cytometry ex vivo and following in vitro stimulation with TsAg. PRINCIPAL FINDINGS: Sera from patients with parenchymal NCC demonstrated significantly higher Th1 (IFN-gamma/IL-12) and Th2 (IL-4/IL-13) cytokine responses and trends towards higher levels of IL-1beta/IL-8/IL-5 than those obtained from patients with subarachnoid NCC. Also higher in vitro antigen driven TNF-beta secretion was detected in PBMC supernatants from parenchymal than in subarachnoid NCC. In contrast, there was a significantly higher IL-10 response to TsAg stimulation in patients with subarachnoid NCC compared to parenchymal NCC. Although no differences in regulatory T cells (Tregs) frequencies were found ex vivo, there was a trend towards greater expansion of Tregs upon TsAg stimulation in subarachnoid than in parenchymal NCC when data were normalized for the corresponding controls. CONCLUSIONS/SIGNIFICANCE: T. solium infection of the subarachnoid space is associated with an enhanced regulatory immune response compared to infection in the parenchyma. The resulting anti-inflammatory milieu may represent a parasite strategy to maintain a permissive environment in the host or diminish inflammatory damage from the host immune response in the central nervous system. PMID- 26506533 TI - Predicting the Effect of Mutations on Protein-Protein Binding Interactions through Structure-Based Interface Profiles. AB - The formation of protein-protein complexes is essential for proteins to perform their physiological functions in the cell. Mutations that prevent the proper formation of the correct complexes can have serious consequences for the associated cellular processes. Since experimental determination of protein protein binding affinity remains difficult when performed on a large scale, computational methods for predicting the consequences of mutations on binding affinity are highly desirable. We show that a scoring function based on interface structure profiles collected from analogous protein-protein interactions in the PDB is a powerful predictor of protein binding affinity changes upon mutation. As a standalone feature, the differences between the interface profile score of the mutant and wild-type proteins has an accuracy equivalent to the best all-atom potentials, despite being two orders of magnitude faster once the profile has been constructed. Due to its unique sensitivity in collecting the evolutionary profiles of analogous binding interactions and the high speed of calculation, the interface profile score has additional advantages as a complementary feature to combine with physics-based potentials for improving the accuracy of composite scoring approaches. By incorporating the sequence-derived and residue-level coarse-grained potentials with the interface structure profile score, a composite model was constructed through the random forest training, which generates a Pearson correlation coefficient >0.8 between the predicted and observed binding free-energy changes upon mutation. This accuracy is comparable to, or outperforms in most cases, the current best methods, but does not require high-resolution full-atomic models of the mutant structures. The binding interface profiling approach should find useful application in human-disease mutation recognition and protein interface design studies. PMID- 26506534 TI - Comparing the Assembly and Handedness Dynamics of (H3.3-H4)2 Tetrasomes to Canonical Tetrasomes. AB - Eukaryotic nucleosomes consists of an (H3-H4)2 tetramer and two H2A-H2B dimers, around which 147 bp of DNA are wrapped in 1.7 left-handed helical turns. During chromatin assembly, the (H3-H4)2 tetramer binds first, forming a tetrasome that likely constitutes an important intermediate during ongoing transcription. We recently showed that (H3-H4)2 tetrasomes spontaneously switch between a left- and right-handed wrapped state of the DNA, a phenomenon that may serve to buffer changes in DNA torque induced by RNA polymerase in transcription. Within nucleosomes of actively transcribed genes, however, canonical H3 is progressively replaced by its variant H3.3. Consequently, one may ask if and how the DNA chirality dynamics of tetrasomes is altered by H3.3. Recent findings that H3.3 containing nucleosomes result in less stable and less condensed chromatin further underline the need to study the microscopic underpinnings of H3.3-containing tetrasomes and nucleosomes. Here we report real-time single-molecule studies of (H3.3-H4)2 tetrasome dynamics using Freely Orbiting Magnetic Tweezers and Electromagnetic Torque Tweezers. We find that the assembly of H3.3-containing tetrasomes and nucleosomes by the histone chaperone Nucleosome Assembly Protein 1 (NAP1) occurs in an identical manner to that of H3-containing tetrasomes and nucleosomes. Likewise, the flipping behavior of DNA handedness in tetrasomes is not impacted by the presence of H3.3. We also examine the effect of free NAP1, H3.3, and H4 in solution on flipping behavior and conclude that the probability for a tetrasome to occupy the left-handed state is only slightly enhanced by the presence of free protein. These data demonstrate that the incorporation of H3.3 does not alter the structural dynamics of tetrasomes, and hence that the preferred incorporation of this histone variant in transcriptionally active regions does not result from its enhanced ability to accommodate torsional stress, but rather may be linked to specific chaperone or remodeler requirements or communication with the nuclear environment. PMID- 26506535 TI - Proteomic approach to nanotoxicity. AB - In recent years a large number of engineered nanomaterials (NMs) have been developed with promising technical benefits for consumers and medical appliances. In addition to already known potentially advantageous biological properties (antibiotic, antifungal and antiviral activity) of NMs, many new medical applications of NMs are foreseen, such as drug carriers, contrast agents, radiopharmaceuticals and many others. However, there is increasing concern about potential environmental and health effects due to NMs exposure. An increasing body of evidence suggests that NMs may trigger undesirable hazardous interactions with biological systems with potential to generate harmful effects. In this review we summarized a current state of knowledge on the proteomics approaches to nanotoxicity, including protein corona formation, in vitro and in vivo effects of exposure to NMs on proteome of different classes of organisms, from bacteria and plants to mammals. The effects of NMs on the proteome of environmentally relevant organisms are also described. SIGNIFICANCE: Despite the benefit that development of nanotechnology may bring to the society, there are still major gaps of knowledge on the influence of nanomaterials on human health and the environment. Thus, it seems necessary to conduct further interdisciplinary research to fill the knowledge gaps in NM toxicity, using more holistic approaches than offered by conventional biological techniques. "OMICS" techniques will certainly help researchers in this field. In this paper we summarized the current stage of knowledge of the effects of nanoparticles on the proteome of different organisms, including those commonly used as an environmentally relevant indicator organisms. PMID- 26506536 TI - A comparative study of venomics of Naja naja from India and Sri Lanka, clinical manifestations and antivenomics of an Indian polyspecific antivenom. AB - Naja naja (Indian cobra) from Sri Lanka and India is the WHO Category 1 medically important snakes in both countries. Some antivenom produced against Indian N. naja (NNi) were less effective against Sri Lankan N. naja (NNsl). Proteomes of NNi and NNsl venoms were studied by RP-HPLC, SDS-PAGE and LC/MS/MS. Six protein families were identified in both venoms with the most abundant were the 3 finger toxins (3FTs) where cytotoxins (CTX) subtype predominated, followed by phospholipase A2, cysteine-rich venom protein, snake venom metalloproteases, venom growth factors, and protease inhibitors. Qualitative and quantitative differences in the venomics profiles were observed. Some proteins were isolated from either NNi or NNsl venom. Postsynaptic neurotoxins (NTX) were identified for the first time in NNsl venom. Thus, there are geographic intra-specific variations of venom composition of the two N. naja. The relative abundance of CTX and NTX explained well the clinical manifestations of these venoms. Antivenomics study of an Indian antivenom (Vins) showed the antibodies effectively bound all venom toxins from both snakes but more avidly to the Indian venom proteins. The lower antibody affinity towards the 'heterologous' venom was the likely cause of poor efficacy of the Indian antivenom used to treat NNsl envenoming. PMID- 26506537 TI - Epigenetic silencing of p21 by long non-coding RNA HOTAIR is involved in the cell cycle disorder induced by cigarette smoke extract. AB - Long noncoding RNAs (lncRNAs), which are epigenetic regulators, are involved in human malignancies. Little is known, however, about the molecular mechanisms for lncRNA regulation of genes induced by cigarette smoke. We recently found that, in human bronchial epithelial (HBE) cells, the lncRNA, Hox transcript antisense intergenic RNA (HOTAIR), is associated with changes in the cell cycle caused by cigarette smoke extract (CSE). In the present study, we report that increased expression of HOTAIR and enhancer of zeste homolog 2 (EZH2), and tri-methylation of Lys 27 of histone H3 (H3K27me3), affect cell cycle progression during CSE induced transformation of HBE cells. Inhibition of HOTAIR and EZH2 by siRNAs attenuated CSE-induced decreases of p21 levels. Further, ChIP assays verified that HOTAIR and EZH2 were needed to maintain the interaction of H3K27me3 with the promoter regions of p21; combined use of a HOTAIR plasmid and EZH2 siRNA supported this observation. Thus, HOTAIR epigenetic silencing of p21 via EZH2 mediated H3K27 trimethylation contributes to changes in the cell cycle induced by CSE. These observations provide further understanding of the regulation of CSE induced lung carcinogenesis and identify new therapeutic targets. PMID- 26506538 TI - Microcystin-LR promotes proliferation by activating Akt/S6K1 pathway and disordering apoptosis and cell cycle associated proteins phosphorylation in HL7702 cells. AB - Our previous studies had shown that MC-LR inhibited PP2A activity and hyperphosphorylated PP2A substrates at 24 h exposure in HL7702 cells. Although the cytoskeleton was rearranged, the cellular effects were not observed. The purpose of the present study with HL7702 cell exposed to MC-LR for 1-72 h was to further uncover the adverse effects of MC-LR comprehensively. The results showed that there were no obvious difference in apoptosis rate and cell-cycle distribution but the cell proliferation was changed since 36 h exposure while the uptake of MC-LR and its binding to PP2A/C kept unchanged since 1h exposure. PP2A activity had not manifested continued decline compare to 24h exposure and PP2A regulator alpha4 was found to release its associated PP2A/C since 1h exposure. The increasing of p-Akt-T308, p-Akt-S473, p-S6K1, p-S6, and p-4E-BP1 since 1h MC LR exposure indicated that Akt/S6K1 cascade had been activated as early as 1h MC LR treatment. And, PI3K/Akt inhibitor (LY294002) blocked MC-LR-induced Akt/S6K1 activation and proliferation. Besides, MC-LR also led to hyperphosphorylation of c-Myc, c-Jun, Bcl-2 and Bad and activation of Cdk1. Our study indicated that MC LR exposure promoted HL7702 cell proliferation and the main mechanism was the activation of Akt/S6K1 cascade. Meanwhile, hyperphosphorylation of Bcl-2, Bad, c Myc and c-Jun might also be involved. And, the inhibition of PP2A was the major reason for these molecular changes. PMID- 26506539 TI - Lipid complex effect on fatty acid profile and chemical composition of cow milk and cheese. AB - The effect of administration of lipid complex (LC) on cow milk and cheese characteristics was studied. Lipid complex was elaborated based on grapeseed oil with synthesized conjugated linoleic acid (CLA) and Atlantic mackerel oil enriched in n-3 fatty acids. The 4-wk experiment was conducted on 30 Polish Holstein Friesian cows. The experimental group cow diet was supplemented with 400 g/d of LC (containing 38% CLA, and eicosapentaenoic acid + docosahexaenoic acid in a relative amount of 36.5%) on a humic-mineral carrier. The chemical composition and fatty acid profile of milk and rennet cheese from raw fresh milk were analyzed. Lipid complex supplementation of the total mixed ration had no effect on milk yield and milk composition, except fat content, which decreased from 4.6 to 4.1%, a 10.9% decrease. Milk from cows treated with LC had greater relative amounts of unsaturated fatty acids, particularly polyunsaturated fatty acids, and lesser relative amounts of saturated fatty acids. Lipid complex addition changed milk fat fatty acid profile: C18:2 cis-9,trans-11 and trans 10,cis-12 isomer (CLA) contents increased by 278 and 233%, respectively, as did eicosapentaenoic acid (C20:5) and docosahexaenoic acid (C22:6) contents. Milk fat fatty acid profile changes were correlated with the modifications in rennet cheese fatty acid profile. Lipid complex supplementation of dairy cows produced considerable changes in the biological value of milk and cheese fat. PMID- 26506540 TI - Milk-clotting mechanism of Dregea sinensis Hemsl. protease. AB - Dregea sinensis Hemsl. is used as a milk coagulant to produce goat milk cakes in Yunnan, China. However, the composition of milk-clotting compounds and the related mechanism have not been reported. Crude protease was extracted from the stem, purified, and then separated with a Millipore ultrafiltration centrifuge tube. Cysteine protease (procerain B) was identified as the main milk-clotting protein through electrospray ionization mass spectrometry, and its molecular weight was 23.8 kDa. The protease can partially degrade alpha-casein (CN) and completely degrade beta- and kappa-CN, and kappa-CN degradation resulted in milk clotting. The molecular weight and AA sequence of the peptide fractions were determined through matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and a peptide sequencer, respectively. The enzyme cleaved kappa CN at Ala90-Gln91 and produced deputy kappa-CN and caseinomacropeptide with molecular weights of 12 and 6.9 kDa, respectively. This cleavage site differed from the majority of chymosins cleaved at Phe105-Met106. PMID- 26506541 TI - Increasing harvest maturity of whole-plant corn silage reduces methane emission of lactating dairy cows. AB - The objective of this study was to investigate the effects of increasing maturity of whole-plant corn at harvest on CH4 emissions by dairy cows consuming corn silage (CS) based diets. Whole-plant corn was harvested at a very early [25% dry matter (DM); CS25], early (28% DM; CS28), medium (32% DM; CS32), and late (40% DM; CS40) stage of maturity. In a randomized block design, 28 lactating Holstein Friesian dairy cows, of which 8 were fitted with rumen cannula, received 1 of 4 dietary treatments designated as T25, T28, T32, and T40 to reflect the DM contents at harvest. Treatments consisted of (DM basis) 75% CS, 20% concentrate, and 5% wheat straw. Feed intake, digestibility, milk production and composition, energy and N balance, and CH4 production were measured during a 5-d period in climate respiration chambers after an adaptation to the diet for 12 d. Corn silage starch content varied between 275 (CS25) and 385 (CS40) g/kg of DM. Treatments did not affect DM intake (DMI), milk yield, or milk contents. In situ ruminal fractional degradation rate of starch decreased linearly from 0.098 to 0.059/h as maturity increased from CS25 to CS40. Apparent total-tract digestibility of DM, organic matter, crude protein, neutral detergent fiber, crude fat, starch, and gross energy (GE) decreased linearly with maturity. Treatments did not affect ruminal pH, volatile fatty acids, and ammonia concentrations, and volatile fatty acids molar proportions. The concentration of C18:3n-3 in milk fat decreased linearly, and the concentration of C18:2n-6 and the n-6:n-3 ratio increased linearly with maturity. A quadratic response occurred for the total saturated fatty acid concentration and total monounsaturated fatty acid concentration in milk fat. Methane production relative to DMI (21.7, 23.0, 21.0, and 20.1g/kg) and relative to GE intake (0.063, 0.067, 0.063, and 0.060 MJ/MJ; values for T25, T28, T32, and T40, respectively) decreased linearly with maturity. Also, CH4 emission relative to fat- and protein-corrected milk tended to decrease linearly with maturity (13.0, 13.4, 13.2, and 12.1g/kg of fat- and protein-corrected milk, for T25, T28, T32, and T40, respectively). Intake of GE and metabolizable energy, and energy retained, all expressed per unit of metabolic body weight, did not differ among treatments. Nitrogen intake, N use efficiency (milk N/N intake), and N balance were not influenced by treatments. Increasing maturity of whole-plant corn at harvest may offer an effective strategy to decrease CH4 losses with feeding CS without negatively affecting cow performance. PMID- 26506543 TI - Effects of maturity and harvest season of grass-clover silage and of forage-to concentrate ratio on milk production of dairy cows. AB - This study examined the effects of maturity and season of harvest of grass-clover silages and forage:concentrate ratio (FCR) on feed intake, milk production, chewing activity, digestibility, and fecal consistency of Holstein dairy cows. Comparison included 2 cuts in spring season (early and late) and 2 cuts in summer season (early and late) combined with high FCR (80:20; HFCR) and low FCR (50:50; LFCR). The experiment included 24 lactating Holstein cows arranged as 2 repeated 4 * 4 Latin squares with four 21-d periods and included measurements of feed composition, feed intake, milk production and composition, chewing activities, digestibilities, and fecal dry matter (DM) concentration and scoring. Forages were fed as two-thirds grass-clover and one-third corn silage supplemented with either 20 or 50% concentrate. Rations were fed ad libitum as total mixed rations. Early maturity cuts were more digestible than late maturity cuts, which was also reflected in a lower concentration of neutral detergent fiber (NDF) in early maturity cuts, whereas summer cuts had a higher crude protein concentration than spring cuts. Increased maturity decreased the intake of DM and energy, increased NDF intake, and decreased the yield of energy-corrected milk (ECM). Summer cuts increased the ECM yield compared with spring cuts. Milk yield (kg and kilogram of ECM) was numerically higher for cows fed early summer cut, independent of FCR in the ration. Milk protein concentration decreased, or tended to decrease, with maturity. For LFCR, the milk fat concentration increased with maturity resulting in a decreased protein:fat ratio. At HFCR, increased maturity increased the time spent chewing per kilogram of DM. Digestibility of silages was positively correlated with the fecal DM concentration. The DM intake and ECM yield showed no significant response to FCR in the ration, but the milk composition was affected. The LFCR decreased the milk fat percentage and increased the milk protein percentage numerically followed by a higher protein:fat ratio. Total chewing time per kilogram of DM decreased and total chewing time per kilogram of NDF increased with LFCR. This study indicates that silages from summer cuts have a similar value for milk production as do spring cuts, when forage digestibility is taken into account. Moreover, it appears that supplementation of extra concentrate has no effect on ECM production when forages with a high digestibility are fed, and that the physical structural value is adequate even when feeding high digestible forages. PMID- 26506544 TI - Short communication: Sensory profile and acceptability of a cow milk cheese manufactured by adding jenny milk. AB - The addition of jenny milk during cheesemaking has been recommended as a viable alternative to egg lysozyme for controlling late blowing defects. However, little is known on the sensory properties of the cheeses made with jenny milk. In this study, the effect of the addition of jenny milk during cheesemaking on sensory properties and consumer acceptability of cheese was evaluated. A sensory profile was carried out by 10 trained panelists on 4 cow milk cheese types. Two types of cheeses were made by adding jenny milk to cow milk during cheesemaking; the cheeses were then left to ripen for 45 and 120 d. The remaining 2 cheese types were made with only cow milk and were also left to ripen for 45 and 120 d. The attributes generated by a quantitative descriptive analysis sensory panel were effective for discriminating the 4 products. Among them, added jenny milk samples aged for 45 d had the highest intensity of some appearance descriptors (structure and color uniformity), as well as the highest intensity of sweetness. The analysis of acceptability data obtained from 89 consumers showed that added jenny milk aged for 45 d was the most preferred type of cheese, whereas no significant differences were found among the other products, which had higher intensity of bitter, salty, acid milk, and so on. PMID- 26506542 TI - Mammary gland development--It's not just about estrogen. AB - The mammary gland (MG) is one of a few organs that undergoes most of its growth after birth. Much of this development occurs concurrently with specific reproductive states, such that the ultimate goal of milk synthesis and secretion is coordinated with the nutritional requirements of the neonate. Central to the reproductive-MG axis is its endocrine regulation, and pivotal to this regulation is the ovarian secretion of estrogen (E). Indeed, it is widely accepted that estrogens are essential for growth of the MG to occur, both for ductal elongation during puberty and for alveolar development during gestation. As the factors regulating MG development continually come to light from the fields of developmental biology, lactation physiology, and breast cancer research, a growing body of evidence serves as a reminder that the MG are not as exclusively dependent on estrogens as might have been thought. The objective of this review is to summarize the state of information regarding our understanding of how estrogen (E) has been implicated as the key regulator of MG development, and to highlight some of the alternative E-independent mechanisms that have been discovered. In particular, we review our findings that dietary trans-10,cis-12 conjugated linoleic acid promotes ductal elongation and that the combination of progesterone (P) and prolactin (PRL) can stimulate branching morphogenesis in the absence of E. Ultimately, these examples stand as a healthy challenge to the question of just how important estrogens are for MG development. Answers to this question, in turn, increase our understanding of MG development across all mammals and the ways in which it can affect milk production. PMID- 26506545 TI - Multi-class, multi-residue analysis of trace veterinary drugs in milk by rapid screening and quantification using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. AB - A simple and rapid multi-class multi-residue analytical method was developed for the screening and quantification of veterinary drugs in milk by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). A total of 90 veterinary drugs investigated belonged to almost 20 classes including lincomycins, macrolides, sulfonamides, quinolones, tetracyclines, beta-agonists, beta-lactams, sedatives, beta-receptor antagonists, sex hormones, glucocorticoids, nitroimidazoles, benzimidazoles, nitrofurans, and some others. A modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) procedure was developed for the sample preparation without the solid phase extraction step. The linearity, sensitivity, accuracy, repeatability, and reproducibility of the method were fully validated. The response of the detector was linear for each target compound in a wide concentration range with a correlation coefficient (R(2)) of 0.9973 to 0.9999 (among them R(2)>0.999 for 73 of 90 analytes). The range of the limit of quantification for these compounds in the milk ranged from 0.10 to 17.30MUg/kg. The repeatability and reproducibility were in the range of 2.11 to 9.62% and 2.76 to 13.9%, respectively. The average recoveries ranged from 72.62 to 122.2% with the RSD (n=6) of 1.30 to 9.61% at 3 concentration levels. For the screening method, the data of the precursor and product ions of the target analytes were simultaneously acquired under the all ions MS/MS mode in a single run. An accurate mass database for the confirmation and identification of the target compounds was established. The applicability of the screening method was verified by applying to real milk samples. The proposed analytical method allows the identification and confirmation of the target veterinary drugs at trace levels employing quick analysis time. Certain veterinary drugs were detected in some cases. PMID- 26506546 TI - Effect of feed type and method of presentation on feeding behavior, intake, and growth of dairy calves fed a high level of milk. AB - The objective of this study was to assess the effect of different feed types and method of feed presentation in the first 12 wk of life on the feeding behavior, intake, and growth of calves fed a high milk level. Forty-eight neonatal Holstein calves were individually housed and randomly assigned to 1 of 4 treatments and fed solid feed ad libitum: silage-based total mixed ration (TMR), concentrate (CON), and chopped hay and concentrate presented in 2 manners: mixed (MIX) or separate (SEP). All calves were offered 12 L/d of acidified milk replacer (1.8 kg of dry matter) until d 38 at which time step-down weaning by 1 L/d began. At d 50 calves no longer received milk, and all calves on SEP and CON treatments were offered the MIX diet until the end of the trial, whereas TMR and MIX calves did not change feeds. Feed intakes were recorded daily, and calves were weighed twice per week. Rumination time was observed on the last 3 d of alternate weeks (wk 3, 5, 7, 9, and 11) for 1h beginning at 1500 h. Time spent feeding was determined for the last 2 d of alternate weeks. In the preweaning stage (d 1-37) average daily gain was similar for all calves (1.1 kg/d). The TMR calves had lower average daily gain than calves on the other 3 treatments during both the weaning (d 38-49; 0.2 vs. 0.7 kg/d) and postweaning (d 50-84; 0.5 vs. 1.2 kg/d) stages. This result is related to the lower dry matter intake of calves fed TMR in comparison with MIX, SEP, and CON calves in the weaning (0.2 vs. 0.5 kg/d) and postweaning (1.8 vs. 2.8 kg/d) stages. Given dry matter content of the feeds (TMR=52%, other diets=89%), the as-fed intake of the calves was similar across treatments in all 3 stages. Calves offered hay in addition to concentrate showed no difference in concentrate intake in the first 7 wk of life. Interestingly, TMR calves spent more time feeding during the postweaning stage than MIX, SEP, and CON calves (308 vs. 194 min/d) and exhibited a slower feeding rate postweaning (5.9 vs. 14.4 g of dry matter per minute). It appears that during weaning, and postweaning, calves fed TMR were attempting to maximize their nutrient intake but were unable to match that of calves in other treatments because of the high moisture content of their feed, and thus were unable to achieve similar average daily gain. Additionally, growth and total intake throughout the preweaning and weaning stages were similar for calves fed chopped hay along with concentrate and those not offered hay, suggesting no detrimental effect of feeding forage. PMID- 26506547 TI - Technical note: Validation of a handheld meter for measuring beta-hydroxybutyrate concentrations in plasma and serum from dairy cows. AB - The use of handheld meters for cow-side tests for beta-hydroxybutyrate (BHB) concentrations in whole blood has become common. The aim of this study was to compare serum BHB (sBHB) and plasma BHB (pBHB) concentrations analyzed using either a "gold standard" enzymatic laboratory method (LM; Randox Laboratories Ltd., Antrim, UK; cat. no. RB1007) or a handheld meter (PX; Precision Xtra, Abbott Diabetes Care Inc., Alameda, CA). Results from 374 (187 serum and 187 plasma) samples taken from Holstein cows from 11 d before (52 samples) to 5 d after parturition (137 samples) were used for the analysis. Statistical analysis was performed using the MIXED, REG, and LOGISTIC procedures of SAS (v9.4; SAS Institute Inc., Cary, NC). A linear mixed model with repeated measures was fitted for LM and PX. Regression and correlation analyses were completed to estimate the relationship and agreement between the 2 methods. Lin's concordance correlation coefficient (CCC) and Bland-Altman plots were used to evaluate agreement between LM and PX. Cross-validation by randomly splitting the data in model-building and validation sets was performed to estimate and validate the equation that predicted the LM results using PX. Receiver operating characteristic (ROC) curves were used to estimate the sensitivity (Se) and specificity (Sp) of PX at different threshold levels. The CCC was 0.74 for pBHB and 0.68 for sBHB. The 95% confidence interval of agreement of the Bland-Altman plot encompassed 96% of the difference between LM and PX for pBHB and 95% for sBHB. The mean difference for pBHB was -0.50+/-0.25mmol, and that for sBHB was -0.63+/-0.41mmol. The highest Se and Sp for PX were achieved when the threshold for ketosis was set to 1.8mmol/L for pBHB and 2.1mmol/L for sBHB. The area under the ROC curve was 0.97 for pBHB and 0.96 for sBHB. The negative bias shown by the Bland-Altman plots suggested that PX yielded higher pBHB and sBHB concentrations than the LM. However, the excellent test characteristics and area under the ROC curve close to 1 indicated that PX at the adjusted thresholds was able to accurately classify between samples <1.2mmol/L and those >=1.2mmol/L based on the gold standard test. PMID- 26506548 TI - The cost of feeding bred dairy heifers on native warm-season grasses and harvested feedstuffs. AB - Heifer rearing is one of the largest production expenses for dairy cattle operations, which is one reason milking operations outsource heifer rearing to custom developers. The cost of harvested feedstuffs is a major expense in heifer rearing. A possible way to lower feed costs is to graze dairy heifers, but little research exists on this topic in the mid-south United States. The objectives of this research were to determine the cost of feeding bred dairy heifers grazing native warm-season grasses (NWSG), with and without legumes, and compare the cost of grazing with the cost of rearing heifers using 3 traditional rations. The 3 rations were corn silage with soybean meal, corn silage with dry distillers grain, and a wet distillers grain-based ration. Bred Holstein heifers between 15- and 20-mo-old continuously grazed switchgrass (SG), SG with red clover (SG+RC), a big bluestem and Indiangrass mixture (BBIG), and BBIG with red clover (BBIG+RC) in Tennessee during the summer months. Total grazing days were calculated for each NWSG to determine the average cost/animal per grazing day. The average daily gain (ADG) was calculated for each NWSG to develop 3 harvested feed rations that would result in the same ADG over the same number of grazing day as each NWSG treatment. The average cost/animal per grazing day was lowest for SG ($0.48/animal/grazing d) and highest for BBIG+RC ($1.10/animal/grazing d). For both BBIG and SG, legumes increased the average cost/animal per grazing day because grazing days did not increase enough to account for the additional cost of the legumes. No difference was observed in ADG for heifers grazing BBIG (0.85 kg/d) and BBIG+RC (0.94 kg/d), and no difference was observed in ADG for heifers grazing SG (0.71 kg/d) and SG+RC (0.70 kg/d). However, the ADG for heifers grazing SG and SG+RC was lower than the ADG for heifers grazing either BBIG or BBIG+RC. The average cost/animal per grazing day was lower for all NWSG treatments than the average cost/animal per day for all comparable feed rations at a low, average, and high yardage fee. Results of this study suggest that SG was the most cost-effective NWSG alternative to harvested feeds for bred dairy heifer rearing. PMID- 26506549 TI - Short communication: Microbial quality of raw milk following commercial long distance hauling. AB - Hauling is a critical part of the commercial milk supply chain, yet very few studies have aimed to understand its effect on raw milk quality. This study focused on the effect of extended-duration tanker use during hauling on raw milk quality at a commercial facility. Standard tanker use [cleaned-in-place (CIP) once per 24h] served as a control and an incremental between-load water rinse with sanitizer treatment (RS) was evaluated to mitigate any effect from extended duration hauling. During this study, 1 commercial truck with 2 trailers was monitored for 10d. The truck collected milk at a large dairy farm, transported the milk to a manufacturing facility, and then returned to the same farm for a second load. Each round-trip journey took between 10 and 12h, allowing for 2 loads per 24-h use period. Following the second delivery, the truck was cleaned by CIP treatment starting a new treatment day. Producer samples were collected from the raw milk bulk tank on the farm before loading milk into the tanker. The same milk was sampled directly out of the tanker truck before unloading at the manufacturer. Effect on individual bacteria count, thermophilic spore count, and preliminary incubation count was quantified through common industry tests. Surface sponge swabs were also used to monitor tanker sanitation and the efficacy of cleaning treatments. Results did not identify a negative effect on raw milk quality due to extended duration hauling. Whereas the addition of RS did not provide any measurable quality benefits for the microbial milk quality, swab results demonstrated that the RS treatment was able to reduce surface bacteria in the tanker, although not to the same level as the full CIP treatment. Based on this study, current CIP practices for long distance milk hauling appear to be effective in mitigating any measurable effect on raw milk quality. PMID- 26506550 TI - Angiotensin-I-converting enzyme-inhibitory peptides in commercial Wisconsin Cheddar cheeses of different ages. AB - Bioactive peptides, including angiotensin-I-converting enzyme-inhibitory (ACEI) peptides, were investigated in commercially produced Wisconsin Cheddar cheeses that ranged in age from <= 6d to more than 2 yr. The ACEI activity of cheese was determined in water-soluble extracts (WSE) that were fractionated for components with molecular weight (MW) <= 3,000 Da, and peptides identified using HPLC and tandem mass spectrometry. The number of types of bioactive peptides increased with an increase in ripening time. Six of the identified ACEI peptides, Ile-Pro Pro (IPP), Val-Pro-Pro (VPP), Glu-Lys-Asp-Glu-Arg-Phe (EKDERF), Val-Arg-Tyr-Leu (VRYL), Tyr-Pro-Phe-Pro-Gly-Pro-Ile-Pro-Asn (YPFPGPIPN), and Phe-Phe-Val-Ala-Pro (FFVAP), with known high ACEI activity (low IC50 values, the concentration needed to inhibit ACE to 50% of its original activity) were synthesized and used to quantify the amounts of these peptides in various cheese extracts. The concentrations of these 6 ACEI peptides increased up to a certain stage of ripening. The maximum contents of IPP, VPP, and EKDERF were 2.8, 7.4, and 5.3mg/100 g of cheese, respectively, and these levels were found in a 1-yr-old Cheddar cheese sample. The maximum content of VRYL (7.5mg/100 g of cheese) was found in a 2-yr-old Cheddar cheese sample, whereas the maximum content of YPFPGPIPN (6.8 mg/100 g of cheese) was found in a 6-mo-old Cheddar cheese sample. Trace amounts of FFVAP were found in these cheeses. Aged Cheddar cheese was found to be a rich source of ACEI peptides even though large differences exist between cheeses from different manufacturers. PMID- 26506551 TI - Effect of extending the interval from Presynch to initiation of Ovsynch in a Presynch-Ovsynch protocol on fertility of timed artificial insemination services in lactating dairy cows. AB - The specific objective of this study was to determine if increasing the interval between the Presynch and Ovsynch portion of the Presynch-Ovsynch protocol (Presynch: PGF2alpha-14 d-PGF2alpha and Ovsynch: GnRH-7 d-PGF2alpha-56 h-GnRH-16 20 h-timed artificial insemination) from 12 to 14 d would reduce the fertility of lactating dairy cows not detected in estrus after Presynch that receive timed artificial insemination (TAI). Cows from 4 commercial dairy farms (n=3,165) were blocked by parity (primiparous vs. multiparous) and randomly assigned to a 12 (PSOv14-12; n=1,566) or 14 d (PSOv14-14; n=1,599) interval between the second PGF2alpha (PGF) injection of Presynch (P2) and the beginning of Ovsynch. Cows detected in estrus any time between P2 and the day of the TAI were inseminated (AIED group). From a subgroup of cows (177 and 150 in PSOv14-12 and PSOv14-14, respectively), ovarian parameters and ovulation were evaluated through determination of concentrations of progesterone (P4) in blood and transrectal ultrasonography at the time of the first GnRH (GnRH1) and the PGF injection of Ovsynch. Overall, 52.8% (n=1,671) of the cows were AIED, whereas 47.2% (n=1,494) received TAI. For cows that received TAI, pregnancies per artificial insemination 39 d after artificial insemination were similar for PSOv14-12 (36.3%) and PSOv14 14 (36.0%) but were greater for primiparous (41.5%) than multiparous cows (33.6%). Pregnancy loss from 39 to 105 d after artificial insemination was similar for PSOv14-12 (4.8%) and PSOv14-14 (8.6%), for primiparous (6.4%) and multiparous cows (7.0%), but a tendency for a treatment by parity interaction was observed. Both treatments had a similar proportion of cows with a follicle >= 10 mm and similar follicle size at GnRH1; however, the ovulatory response to GnRH was greater for PSOv14-12 (62.2%) than PSOv14-14 (46.4%). A greater proportion of cows with a functional corpus luteum (75.3 vs. 65.6%) and greater concentrations of P4 (3.9 vs. 3.3 ng/mL) at GnRH1 in PSOv14-14 than PSOv14-12 may have compensated for the reduction in fertility expected due to reduced ovulatory response to GnRH1. We concluded that extending the interval from Presynch to Ovsynch from 12 to 14 reduced ovulatory response to GnRH1 but did not reduce the fertility of cows that received TAI when cows were inseminated in estrus after presynchronization. Thus, farms that combine AIED and TAI during the Presynch Ovsynch protocol may use a 14-d interval between Presynch and Ovsynch to simplify their management without reducing fertility of cows receiving TAI. PMID- 26506552 TI - Effect of heating strategies on whey protein denaturation--Revisited by liquid chromatography quadrupole time-of-flight mass spectrometry. AB - Previous standards in the area of effect of heat treatment processes on milk protein denaturation were based primarily on laboratory-scale analysis and determination of denaturation degrees by, for example, electrophoresis. In this study, whey protein denaturation was revisited by pilot-scale heating strategies and liquid chromatography quadrupole time-of-flight mass spectrometer (LC/MC Q TOF) analysis. Skim milk was heat treated by the use of 3 heating strategies, namely plate heat exchanger (PHE), tubular heat exchanger (THE), and direct steam injection (DSI), under various heating temperatures (T) and holding times. The effect of heating strategy on the degree of denaturation of beta-lactoglobulin and alpha-lactalbumin was determined using LC/MC Q-TOF of pH 4.5-soluble whey proteins. Furthermore, effect of heating strategy on the rennet-induced coagulation properties was studied by oscillatory rheometry. In addition, rennet induced coagulation of heat-treated micellar casein concentrate subjected to PHE was studied. For skim milk, the whey protein denaturation increased significantly as T and holding time increased, regardless of heating method. High denaturation degrees were obtained for T >100 degrees C using PHE and THE, whereas DSI resulted in significantly lower denaturation degrees, compared with PHE and THE. Rennet coagulation properties were impaired by increased T and holding time regardless of heating method, although DSI resulted in less impairment compared with PHE and THE. No significant difference was found between THE and PHE for effect on rennet coagulation time, whereas the curd firming rate was significantly larger for THE compared with PHE. Micellar casein concentrate possessed improved rennet coagulation properties compared with skim milk receiving equal heat treatment. PMID- 26506553 TI - Integrating spot short-term measurements of carbon emissions and backward dietary energy partition calculations to estimate intake in lactating dairy cows fed ad libitum or restricted. AB - The objective of this study was to use spot short-term measurements of CH4 (QCH4) and CO2 (QCO2) integrated with backward dietary energy partition calculations to estimate dry matter intake (DMI) in lactating dairy cows. Twelve multiparous cows averaging 173+/-37d in milk and 4 primiparous cows averaging 179+/-27d in milk were blocked by days in milk, parity, and DMI (as a percentage of body weight) and, within each block, randomly assigned to 1 of 2 treatments: ad libitum intake (AL) or restricted intake (RI=90% DMI) according to a crossover design. Each experimental period lasted 22d with 14d for treatments adaptation and 8d for data and sample collection. Diets contained (dry matter basis): 40% corn silage, 12% grass-legume haylage, and 48% concentrate. Spot short-term gas measurements were taken in 5-min sampling periods from 15 cows (1 cow refused sampling) using a portable, automated, open-circuit gas quantification system (GreenFeed, C-Lock Inc., Rapid City, SD) with intervals of 12h between the 2daily samples. Sampling points were advanced 2h from a day to the next to yield 16 gas samples per cow over 8d to account for diurnal variation in QCH4 and QCO2. The following equations were used sequentially to estimate DMI: (1) heat production (MJ/d)=(4.96 + 16.07 / respiratory quotient) * QCO2; respiratory quotient=0.95; (2) metabolizable energy intake (MJ/d)=(heat production + milk energy) +/- tissue energy balance; (3) digestible energy (DE) intake (MJ/d)=metabolizable energy + CH4 energy + urinary energy; (4) gross energy (GE) intake (MJ/d)=DE + [(DE / in vitro true dry matter digestibility) - DE]; and (5) DMI (kg/d)=GE intake estimated / diet GE concentration. Data were analyzed using the MIXED procedure of SAS (SAS Institute Inc., Cary, NC) and Fit Model procedure in JMP (alpha=0.05; SAS Institute Inc.). Cows significantly differed in DMI measured (23.8 vs. 22.4kg/d for AL and RI, respectively). Dry matter intake estimated using QCH4 and QCO2 coupled with dietary backward energy partition calculations (Equations 1 to 5 above) was highest in cows fed for AL (22.5 vs. 20.2kg/d). The resulting R(2) were 0.28 between DMI measured and DMI estimated by gaseous measurements, and 0.36 between DMI measured and DMI predicted by the National Research Council model (2001). Results showed that spot short-term measurements of QCH4 and QCO2 coupled with dietary backward estimations of energy partition underestimated DMI by 7.8%. However, the approach proposed herein was able to significantly discriminate differences in DMI between cows fed for AL or RI. PMID- 26506554 TI - The Cost Effectiveness of Psychological and Pharmacological Interventions for Social Anxiety Disorder: A Model-Based Economic Analysis. AB - BACKGROUND: Social anxiety disorder is one of the most persistent and common anxiety disorders. Individually delivered psychological therapies are the most effective treatment options for adults with social anxiety disorder, but they are associated with high intervention costs. Therefore, the objective of this study was to assess the relative cost effectiveness of a variety of psychological and pharmacological interventions for adults with social anxiety disorder. METHODS: A decision-analytic model was constructed to compare costs and quality adjusted life years (QALYs) of 28 interventions for social anxiety disorder from the perspective of the British National Health Service and personal social services. Efficacy data were derived from a systematic review and network meta-analysis. Other model input parameters were based on published literature and national sources, supplemented by expert opinion. RESULTS: Individual cognitive therapy was the most cost-effective intervention for adults with social anxiety disorder, followed by generic individual cognitive behavioural therapy (CBT), phenelzine and book-based self-help without support. Other drugs, group-based psychological interventions and other individually delivered psychological interventions were less cost-effective. Results were influenced by limited evidence suggesting superiority of psychological interventions over drugs in retaining long-term effects. The analysis did not take into account side effects of drugs. CONCLUSION: Various forms of individually delivered CBT appear to be the most cost-effective options for the treatment of adults with social anxiety disorder. Consideration of side effects of drugs would only strengthen this conclusion, as it would improve even further the cost effectiveness of individually delivered CBT relative to phenelzine, which was the next most cost-effective option, due to the serious side effects associated with phenelzine. Further research needs to determine more accurately the long-term comparative benefits and harms of psychological and pharmacological interventions for social anxiety disorder and establish their relative cost effectiveness with greater certainty. PMID- 26506555 TI - An analysis of omitting biliary tract imaging in 668 subjects admitted to an acute care surgery service with biochemical evidence of choledocholithiasis. AB - BACKGROUND: No consensus exists for the timing and utility of biliary imaging in patients with preoperative concern for choledocholithiasis. METHODS: Admissions to an acute care surgery service with evidence of choledocholithiasis undergoing same-admission cholecystectomy without preoperative or intraoperative imaging were identified. One-way analysis of variance on the log-transformed outcomes, with the Tukey-Kramer multiple comparison procedure, were used to compare means between groups. RESULTS: A total of 668 patients with elevated but downtrending liver enzymes underwent cholecystectomy without preoperative or intraoperative imaging. Thirty-eight patients (5.7%) had postoperative biliary imaging, of whom 22 (3.3%) had definite choledocholithiasis. One case of postoperative cholangitis occurred which required readmission and endoscopic retrograde cholangiopancreatography with no long-term morbidity. Presenting liver enzymes were significantly higher in the group found to have retained stones postoperatively than those without retained stones. CONCLUSIONS: Patients presenting with biochemical evidence of choledocholithiasis who downtrend preoperatively can be safely managed by cholecystectomy with omission of biliary tract imaging. PMID- 26506556 TI - For a clearer comprehension of the lymphatic system in perihilar cholangiocarcinoma. PMID- 26506557 TI - Measuring readmissions after surgery: do different methods tell the same story? AB - BACKGROUND: Readmission is widely used as a quality metric to assess hospital performance. However, different methods to calculate readmissions may produce various results, leading to differences in classification with respect to hospital performance. This study compared 2 commonly used approaches to measure surgical readmissions: the 30-day all-cause hospital-wide readmissions (HWRs) and the potentially preventable readmissions (PPRs). METHODS: We examined the correlation between hospitals' risk-adjusted HWR and PPR rates and whether there was agreement in categorizing hospital performance between these measures among 111 hospitals with inpatient surgical programs in the Veterans Health Administration. RESULTS: We found that hospitals' HWR and PPR rates were highly correlated (r = .85, P < .0001). The overall agreement between these 2 methods in categorizing hospital performance was 82% for all surgeries, 82% for colectomy, 84% for coronary bypass, and 87% for hip/knee replacement, respectively. CONCLUSIONS: Despite differences in methodologies, the HWR and the PPR measures provided relatively consistent perceptions of hospitals' performance on surgical readmissions. PMID- 26506558 TI - Combined oral contraceptive synergistically activates mineralocorticoid receptor through histone code modifications. AB - Clinical studies have shown that the use of combined oral contraceptive in pre menopausal women is associated with fluid retention. However, the molecular mechanism is still elusive. We hypothesized that combined oral contraceptive (COC) ethinyl estradiol (EE) and norgestrel (N) synergistically activates mineralocorticoid receptor (MR) through histone code modifications. Twelve-week old female Sprague-Dawley rats were treated with olive oil (control), a combination of 0.1ug EE and 1.0ug N (low COC) or 1.0ug EE and 10.0ug N (high COC) as well as 0.1 or 1.0ug EE and 1.0 or 10.0ug N daily for 6 weeks. Expression of MR target genes in kidney cortex was determined by quantitative real-time polymerase chain reaction. MR was quantified by western blot. Recruitment of MR and RNA polymerase II (Pol II) on promoters of target genes as well as histone code modifications was analyzed by chromatin immunoprecipitation assay. Treatment with COC increased renal cortical expression of MR target genes such as serum and glucocorticoid-regulated kinase 1 (Sgk-1), glucocorticoid-induced leucine zipper (Gilz), epithelial Na(+)channel (Enac) and Na(+)-K(+)-ATPase subunit alpha1 (Atp1a1). Although COC increased neither serum aldosterone nor MR expression in kidney cortex, it increased recruitment of MR and Pol II in parallel with increased H3Ac and H3K4me3 on the promoter regions of MR target genes. However, treatment with EE or N alone did not affect renal cortical expression of Sgk-1, Gilz, Enac or Atp1a1. These results indicate that COC synergistically activates MR through histone code modifications. PMID- 26506559 TI - Effect of Prolonged Radiotherapy Treatment Time on Survival Outcomes after Intensity-Modulated Radiation Therapy in Nasopharyngeal Carcinoma. AB - PURPOSE: To estimate the influence of prolonged radiation treatment time (RTT) on survival outcomes in nasopharyngeal carcinoma after continuous intensity modulated radiation therapy. METHODS AND MATERIALS: Retrospectively review 321 patients with NPC treated between October 2009 and December 2010 and all of them underwent simultaneous accelerated intensity-modulated radiation therapy. The fractionated dose was 2-2.47 Gy/F (median 2.27 Gy), and the total dose for nasopharyngeal region was 64-74 Gy/ 28-33 fractions. The association of prolonged RTT and treatment interruption with PFS, LRFS and DFFS were assessed by univariate analysis and multivariate analysis. Survival analyses were carried out using Kaplan-Meier methodology and the log-rank test was used to assess the difference. The Cox regression proportional hazard model was used for multivariate analyses and evaluating the prognostic parameters for PFS, LRFS and DFFS. RESULTS: Univariate analysis revealed no significant associations between prolonged RTT and PFS, LRFS, DFFS when dichotomized using various cut-off values (all P>0.05). In multivariate analysis, RTT (range, 36-63 days) as a continuous variable, had no influence on any survival outcome as well (P>0.05). T and N classification were independent prognostic factors for PFS, LRFS and DFFS (all P<0.05, except T classification for LRFS, P = 0.057). Age was an independent prognostic factor for PFS (hazard ratio [HR], 1.033; P = 0.008) and DFFS (HR, 1.032; P = 0.043). CONCLUSION: We conclude that no such association between survival outcomes and radiation treatment duration (range: 36-63 days) can be found in the present retrospective study, however, we have to remind that prolongation in treatment should be limited in clinical application and interruptions caused by any reason should be minimized as much as possible. PMID- 26506560 TI - Fibulin-5 is upregulated in decidualized human endometrial stromal cells and promotes primary human extravillous trophoblast outgrowth. AB - Interactions between the highly invasive trophoblasts and the maternal uterine decidual extracellular matrix (ECM) are crucial in the determination of a successful pregnancy. Fibulin-5 (FBLN5) is a member of the fibulin family that alters cell adhesive and invasive properties and is expressed in human villous cytotrophoblasts. We aimed to determine the expression and immunolocalization of FBLN5 in human first trimester decidua and examine the effect of FBLN5 in trophoblast invasion in vitro using a first trimester placental villous outgrowth assay. We demonstrated that FBLN5 mRNA expression is upregulated in response to cAMP-mediated decidualization of primary human endometrial stromal cells, although FBLN5 itself does not enhance decidualization. We reported for the first time, FBLN5 protein production in first trimester decidual cells and also co localization to HLAG-positive EVTs in first trimester decidua. Consequently, we investigated the effects of exogenous FBLN5 on placental villous outgrowth in vitro and demonstrated that FBLN5 promotes EVT migration/invasion. This is the first study to identify FBLN5 in decidualized human endometrial stromal cells, first trimester decidua and EVT and determine a functional role for FBLN5 in human EVTs, suggesting that decidual and or EVT-derived FBLN5 regulates EVT invasion and placentation in women. PMID- 26506561 TI - Antiphospholipid antibodies bind syncytiotrophoblast mitochondria and alter the proteome of extruded syncytial nuclear aggregates. AB - INTRODUCTION: Antiphospholipid antibodies (aPL) are autoantibodies that increase the risk of women developing the hypertensive disorder pre-eclampsia. aPL are internalised by the syncytiotrophoblast and increase extrusion of necrotic multinucleated syncytial nuclear aggregates (SNAs), which may trigger endothelial dysfunction in pre-eclampsia. The mechanisms by which aPL alter death processes in the syncytiotrophoblast leading to extrusion of SNAs are unknown. METHODS: First trimester human placentae (n = 10) were dissected into explants and cultured either with aPL (50 MUg/mL), isotype-matched control antibody (50 MUg/mL), or media for 24 h. Harvested SNAs underwent iTRAQ proteomic analysis. Mitochondria in syncytiotrophoblast treated with aPL labelled with FluoroNanogold were visualised using transmission electron microscopy (TEM). RESULTS: aPL altered the expression of 72 proteins in SNAs. Thirteen proteins were involved in mitochondrial function. TEM demonstrated that aPL bind to mitochondria in the syncytiotrophoblast and may cause mitochondrial swelling. DISCUSSION: aPL disrupt mitochondria increasing the extrusion of SNAs with an altered proteome from the syncytiotrophoblast. These altered SNAs may trigger endothelial dysfunction and pre-eclampsia in these pregnancies. PMID- 26506562 TI - Cognitive mechanisms of mindfulness: A test of current models. AB - Existing models of mindfulness describe the self-regulation of attention as primary, leading to enhanced decentering and ability to access and override automatic cognitive processes. This study compared 23 experienced and 21 non meditators on tests of mindfulness, attention, decentering, and ability to override automatic cognitive processes to test the cognitive mechanisms proposed to underlie mindfulness practice. Experienced meditators had significantly higher mindfulness and decentering than non-meditators. No significant difference between groups was found on measures of attention or ability to override automatic processes. These findings support the prediction that mindfulness leads to enhanced decentering, but do not support the cognitive mechanisms proposed to underlie such enhancement. Since mindfulness practice primarily involves internally directed attention, it may be the case that cognitive tests requiring externally directed attention and timed responses do not accurately assess mindfulness-induced cognitive changes. Implications for the models of mindfulness and future research are discussed. PMID- 26506563 TI - Missed Opportunities for Measles, Mumps, and Rubella (MMR) Immunization in Mesoamerica: Potential Impact on Coverage and Days at Risk. AB - BACKGROUND: Recent outbreaks of measles in the Americas have received news and popular attention, noting the importance of vaccination to population health. To estimate the potential increase in immunization coverage and reduction in days at risk if every opportunity to vaccinate a child was used, we analyzed vaccination histories of children 11-59 months of age from large household surveys in Mesoamerica. METHODS: Our study included 22,234 children aged less than 59 months in El Salvador, Guatemala, Honduras, Mexico, Nicaragua, and Panama. Child vaccination cards were used to calculate coverage of measles, mumps, and rubella (MMR) and to compute the number of days lived at risk. A child had a missed opportunity for vaccination if their card indicated a visit for vaccinations at which the child was not caught up to schedule for MMR. A Cox proportional hazards model was used to compute the hazard ratio associated with the reduction in days at risk, accounting for missed opportunities. RESULTS: El Salvador had the highest proportion of children with a vaccine card (91.2%) while Nicaragua had the lowest (76.5%). Card MMR coverage ranged from 44.6% in Mexico to 79.6% in Honduras while potential coverage accounting for missed opportunities ranged from 70.8% in Nicaragua to 96.4% in El Salvador. Younger children were less likely to have a missed opportunity. In Panama, children from households with higher expenditure were more likely to have a missed opportunity for MMR vaccination compared to the poorest (OR 1.62, 95% CI: 1.06-2.47). In Nicaragua, compared to children of mothers with no education, children of mothers with primary education and secondary education were less likely to have a missed opportunity (OR 0.46, 95% CI: 0.24-0.88 and OR 0.25, 95% CI: 0.096-0.65, respectively). Mean days at risk for MMR ranged from 158 in Panama to 483 in Mexico while potential days at risk ranged from 92 in Panama to 239 in El Salvador. CONCLUSIONS: Our study found high levels of missed opportunities for immunizing children in Mesoamerica. Our findings cause great concern, as they indicate that families are bringing their children to health facilities, but these children are not receiving all appropriate vaccinations during visits. This points to serious problems in current immunization practices and protocols in poor areas in Mesoamerica. Our study calls for programs to ensure that vaccines are available and that health professionals use every opportunity to vaccinate a child. PMID- 26506565 TI - Comparison of laparoscopic versus open resection for colorectal liver metastases. PMID- 26506564 TI - Comparison of the international consensus guidelines for predicting malignancy in intraductal papillary mucinous neoplasms. AB - BACKGROUND: This study sought to evaluate the predictors of malignancy in the 2012 international consensus guidelines for intraductal papillary mucinous neoplasms (IPMNs) and validate their diagnostic value relative to the 2006 guidelines. METHODS: Between 2002 and 2014, 177 consecutive patients who underwent curative resection of IPMN were reviewed. Based on the 2012 guidelines, high-risk stigmata (mural nodule with enhancement, main pancreatic duct [MPD] >= 10 mm, and obstructive jaundice) and worrisome features (cyst size >= 30 mm, thickened cyst wall, mural nodule without enhancement, MPD 5-9 mm, an abrupt change in MPD diameter, and lymphadenopathy) were assessed, and predictive and diagnostic values were analyzed statistically. RESULTS: Multivariate analysis identified obstructive jaundice (odds ratio [OR], 23.9; P < .0001), abrupt change in MPD diameter (OR, 3.01; P = .017) and lymphadenopathy (OR, 5.84; P = .027) as independent predictive factors, with an accuracy of 69.8, 67.4, and 66.3%, respectively. Operative intervention was indicated in 156 patients (94.0%) using the 2006 guidelines, and in 130 (78.3%) using the 2012 guidelines. The accuracy of the 2006 guidelines was 35.5% compared with 44.8% for the 2012 guidelines. The area under the curve (AUC) for the 2006 and 2012 guidelines was 0.65 and 0.67, respectively; DeltaAUC was 0.02, which was not statistically significant. When the worrisome features were combined with high-risk stigmata, the AUC increased to 0.79. CONCLUSION: Obstructive jaundice, abrupt change in MPD diameter, and lymphadenopathy were independent predictive factors in the 2012 guidelines with high accuracy. Using the new guidelines, the number of patients with IPMN managed with observation and the predictive accuracy increased. PMID- 26506566 TI - Is combined pancreatoduodenectomy for advanced gallbladder cancer justified? AB - BACKGROUND: The clinical impact of combined pancreatoduodenectomy (PD) for advanced gallbladder cancer remains unclear. METHODS: A total of 96 patients who underwent resection for stage II, III, or IV gallbladder cancer were enrolled. Patients with lower bile duct involvement, pancreatic or duodenal infiltration, or peripancreatic lymph node metastasis were considered candidates for combined PD. The operative outcomes were compared between the patients treated with PD (PD group, n = 21) and those treated without PD (non-PD group, n = 75), and between those treated with major hepatopancreatoduodenectomy (major HPD group, n = 9) and those treated with major hepatectomy (major hepatectomy group, n = 20). RESULTS: Overall morbidity in the PD group was greater than that in the non-PD group (81% vs 23%, P < .001), whereas the overall survival (OS) was comparable between the groups (5-year OS; 39.8% vs 46.7%, P = .96). There was no in-hospital mortality in the PD group. A serum albumin <3.0 g/dL (P = .004) and tumor size >= 9.0 cm (P = .029) were associated independently with a poor prognosis in the PD group. Overall morbidity in the major HPD group was greater than that in the major hepatectomy group (89% vs 40%, P = .014), whereas the OS was comparable between the groups (5-year OS; 34.6% vs 21.1%, P = .57), and the OS of major HPD group was better than that of unresectable group (n = 18, P = .017). CONCLUSION: Combined PD, including major HPD, is beneficial for selected patients of advanced gallbladder cancer; however, the indications should be carefully evaluated because of greater morbidity rates. PMID- 26506567 TI - Hospital variation in perioperative complications for laparoscopic sleeve gastrectomy in Michigan. AB - BACKGROUND: Laparoscopic sleeve gastrectomy has surpassed gastric bypass and laparoscopic adjustable gastric banding recently as the most common weight-loss procedure. Previously, substantial concerns existed regarding variation in perioperative safety with bariatric surgery. This study aimed to assess rates of perioperative complications for laparoscopic sleeve gastrectomy across hospitals and in relation to procedure volume within the Michigan Bariatric Surgery Collaborative. STUDY DESIGN: We analyzed 8,693 patients who underwent laparoscopic sleeve gastrectomy from 2013 through 2014 across 40 hospitals in the Michigan Bariatric Surgery Collaborative. Mixed-effects logistic regression was used to assess hospital variation in risk- and reliability-adjusted rates of overall and serious 30-day complications and their relationship with hospital annual volume of stapling procedures (gastric bypass and sleeve gastrectomy). RESULTS: Overall, 5.4% of patients experienced perioperative complications. Adjusted rates of overall complications varied three-fold across hospitals, ranging from 3.6% (95% confidence interval 1.9-6.8%) to 11.0% (95% confidence interval 7.7-15.5%). Serious complications occurred in just 1.2% of patients and varied minimally. In this analysis, hospital volume was not associated with overall or serious complications. The 1 hospital with significantly less overall complication rates was high-volume (>= 125 procedures/year); however, of the 4 hospitals with significantly greater complication rates, 3 were medium-volume (50 124 procedures/year), and 1 was high-volume. The remaining hospitals were not significantly different than the cohort mean. CONCLUSION: Serious complications among patients undergoing laparoscopic sleeve gastrectomy were relatively infrequent in this cohort of patients in the Michigan Bariatric Surgery Collaborative. Rates of overall complications varied widely across the hospitals enrolled in this statewide quality collaborative, although this variation was unrelated to volume standards required for accreditation as a comprehensive bariatric surgery center. PMID- 26506568 TI - A scalable low-cost cGMP process for clinical grade production of the HIV inhibitor 5P12-RANTES in Pichia pastoris. AB - In the continued absence of an effective anti-HIV vaccine, approximately 2 million new HIV infections occur every year, with over 95% of these in developing countries. Calls have been made for the development of anti-HIV drugs that can be formulated for topical use to prevent HIV transmission during sexual intercourse. Because these drugs are principally destined for use in low-resource regions, achieving production costs that are as low as possible is an absolute requirement. 5P12-RANTES, an analog of the human chemokine protein RANTES/CCL5, is a highly potent HIV entry inhibitor which acts by achieving potent blockade of the principal HIV coreceptor, CCR5. Here we describe the development and optimization of a scalable low-cost production process for 5P12-RANTES based on expression in Pichia pastoris. At pilot (150 L) scale, this cGMP compliant process yielded 30 g of clinical grade 5P12-RANTES. As well as providing sufficient material for the first stage of clinical development, this process represents an important step towards achieving production of 5P12-RANTES at a cost and scale appropriate to meet needs for topical HIV prevention worldwide. PMID- 26506569 TI - Radical Prostatectomy versus External Beam Radiotherapy for cT1-4N0M0 Prostate Cancer: Comparison of Patient Outcomes Including Mortality. AB - BACKGROUND: Although radical prostatectomy (RP) and external beam radiotherapy (EBRT) have been considered as comparable treatments for localized prostate cancer (PC), it is controversial which treatment is better. The present study aimed to compare outcomes, including mortality, of RP and EBRT for localized PC. METHODS: We retrospectively analyzed 891 patients with cT1-4N0M0 PC who underwent either RP (n = 569) or EBRT (n = 322) with curative intent at our single institution between 2005 and 2012. Of the EBRT patients, 302 (93.8%) underwent intensity-modulated radiotherapy. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). Related to these, other-cause mortality (OCM) was also calculated. Biochemical recurrence-free survival was assessed as a secondary endpoint. Cox proportional hazards model was used for multivariate analysis. RESULTS: Median follow-up durations were 53 and 45 months, and median ages were 66 and 70 years (P <0.0001), in the RP and EBRT groups, respectively. As a whole, significantly better prognoses of the RP group than the EBRT group were observed for both OS and CSS, although OCM was significantly higher in the EBRT group. There was no death from PC in men with low and intermediate D'Amico risks, except one with intermediate-risk in the EBRT group. In high-risk patients, significantly more patients died from PC in the EBRT group than the RP group. Multivariate analysis demonstrated the RP group to be an independent prognostic factor for better CSS. On the other hand, the EBRT group had a significantly longer biochemical recurrence-free survival than the RP group. CONCLUSIONS: Mortality outcomes of both RP and EBRT were generally favorable in low and intermediate risk patients. Improvement of CSS in high risk patients was seen in patients receiving RP over those receiving EBRT. PMID- 26506571 TI - Dysfunctional understanding of mental states in personality disorders: What is the evidence? PMID- 26506570 TI - A randomized open-label clinical trial of an anti-HPV biological dressing (JB01 BD) administered intravaginally to treat high-risk HPV infection. AB - Currently, there is no specific antiviral therapy for HPV infection. We conducted a randomized open-label clinical trial of JB01-BD, an anti-HPV biological dressing from Shanxi Jinbo Pharmaceutical Co., Ltd., China, for treatment of HPV infection. Seventy-seven women with cervical infection by high-risk HPV were randomly divided into a treatment group and a non-treatment group. After treatment, about 60.5% (23/38) of HPV-positive women in the treatment group became HPV-negative compared with 13.5% (5/37) of women in the non-treatment group becoming HPV-negative (P < 0.001). These data suggest that JB01-BD is an effective topical biological agent for the treatment of cervical HPV infection. PMID- 26506572 TI - Health effects of toxicants: Online knowledge support. AB - Research in toxicology generates vast quantities of data which reside on the Web and are subsequently appropriated and utilized to support further research. This data includes a broad spectrum of information about chemical, biological and radiological agents which can affect health, the nature of the effects, treatment, regulatory measures, and more. Information is structured in a variety of formats, including traditional databases, portals, prediction models, and decision making support tools. Online resources are created and housed by a variety of institutions, including libraries and government agencies. This paper focuses on three such institutions and the tools they offer to the public: the National Library of Medicine (NLM) and its Toxicology and Environmental Health Information Program, the United States Environmental Protection Agency (EPA), and the Organisation for Economic Co-operation and Development (OECD). Reference is also made to other relevant organizations. PMID- 26506573 TI - Investigation of the effects of a sulfite molecule on human neuroblastoma cells via a novel oncogene URG4/URGCP. AB - AIM: The aim of this study is to determine the anticancer effect of sulfite on SH SY5Y neuroblastoma cells in vitro conditions and elucidate underlying molecular mechanism of sulfite and explore its therapeutic activity. MAIN METHODS: In this study, cytotoxic effects of sulfite in SH-SY5Y cels were detected over time in a dose dependent manner with the IC50 doses ranging from 0.5 to 10 mM. Genotoxic effect of sulfite was shown by comet assay. IC50 doses in the SH-SY5Y cells were detected as 5 mM. Expression profiles of the target genes related to apoptosis and cell cycle control were determined by quantitative RT-PCR. Protein changes were determined by western blot analysis. KEY FINDINGS: URG4/URGCP, CCND1, CCND2, CDK4, CDK6, E2F4 and BCL-2 gene expression levels were significantly reduced and RB1, TP53, BAX, BID, CASP2, CASP3, CASP9 and DIABLO gene expressions were significantly increased in dose group cells. The mechanism of this result may be related to sulfite dependent inhibition of cell cycle at the G1 phase by down regulating URG4/URGCP or CCND1, CDK4, CDK6 gene expression and stimulating apoptosis via the intrinsic pathway. Sulfite suppressed invasion and colony formation in SH-SY5Y cell line using matrigel invasion chamber and colony formation assay, respectively. SIGNIFICANCE: It is thought that sulfite demonstrates anticarcinogenesis activity by affecting cell cycle arrest, apoptosis s, invasion, and colony formation on SH-SY5Y cells. Sulfite may be an effective agent for treatment of neuroblastoma as a single agent or in combination with other agents. PMID- 26506574 TI - Predicting Plasma Olanzapine Concentration Following a Change in Dosage: A Population Pharmacokinetic Study. AB - INTRODUCTION: Due to high inter-individual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics currently relies on clinical trial-and-error, and predicting antipsychotic plasma concentrations before changing a dose has been a challenge. METHODS: Patients with schizophrenia receiving a stable dose of olanzapine were included. 2 plasma samples were collected at 2 given time points for the measurement of plasma olanzapine concentrations. At least 7 days after a dosage change of olanzapine, a third sample was collected. The plasma concentration of the third sample was predicted in a blinded fashion using a mixed-effects model with NONMEM((r)), using the following information: the 2 baseline plasma concentrations, the interval between the last dose and blood draw, and clinical and demographic information. RESULTS: 31 subjects (mean+/-SD age=56.0+/-11.6; 19 men) were enrolled. The mean prediction (95% confidence interval) errors were 1.6 (-2.8 to 6.0) ng/mL. A highly significant correlation was observed between the observed and predicted concentrations of the third sample (r=0.91, p<0.001). DISCUSSION: Plasma olanzapine concentrations following an actual dosage change can be predicted in advance with a high degree of certainty. PMID- 26506575 TI - Here/In This Issue and There/Abstract Thinking: Not Even in Cartoons. PMID- 26506576 TI - Chinese International Students: An Emerging Mental Health Crisis. PMID- 26506577 TI - Irritability in Youth: An Update. PMID- 26506578 TI - Suicidality in Very Young Children. PMID- 26506579 TI - Randomized Clinical Trial of Family-Based Treatment and Cognitive-Behavioral Therapy for Adolescent Bulimia Nervosa. AB - OBJECTIVE: There is a paucity of randomized clinical trials (RCTs) for adolescents with bulimia nervosa (BN). Prior studies suggest cognitive-behavioral therapy adapted for adolescents (CBT-A) and family-based treatment for adolescent bulimia nervosa (FBT-BN) could be effective for this patient population. The objective of this study was to compare the relative efficacy of these 2 specific therapies, FBT-BN and CBT-A. In addition, a smaller participant group was randomized to a nonspecific treatment (supportive psychotherapy [SPT]), whose data were to be used if there were no differences between FBT-BN and CBT-A at end of treatment. METHOD: This 2-site (Chicago and Stanford) randomized controlled trial included 130 participants (aged 12-18 years) meeting DSM-IV criteria for BN or partial BN (binge eating and purging once or more per week for 6 months). Outcomes were assessed at baseline, end of treatment, and 6 and 12 months posttreatment. Treatments involved 18 outpatient sessions over 6 months. The primary outcome was defined as abstinence from binge eating and purging for 4 weeks before assessment, using the Eating Disorder Examination. RESULTS: Participants in FBT-BN achieved higher abstinence rates than in CBT-A at end of treatment (39% versus 20%; p = .040, number needed to treat [NNT] = 5) and at 6 month follow-up (44% versus 25%; p = .030, NNT = 5). Abstinence rates between these 2 groups did not differ statistically at 12-month follow-up (49% versus 32%; p = .130, NNT = 6). CONCLUSION: In this study, FBT-BN was more effective in promoting abstinence from binge eating and purging than CBT-A in adolescent BN at end of treatment and 6-month follow-up. By 12-month follow-up, there were no statistically significant differences between the 2 treatments. CLINICAL TRIAL REGISTRATION INFORMATION: Study of Treatment for Adolescents With Bulimia Nervosa; http://clinicaltrials.gov/; NCT00879151. PMID- 26506580 TI - A Pilot Randomized Controlled Trial of Cognitive-Behavioral Therapy for Adolescents With Body Dysmorphic Disorder. AB - OBJECTIVE: Body dysmorphic disorder (BDD) typically starts in adolescence, but evidence-based treatments are yet to be developed and formally evaluated in this age group. We designed an age-appropriate cognitive-behavioral therapy (CBT) protocol for adolescents with BDD and evaluated its acceptability and efficacy in a pilot randomized controlled trial. METHOD: Thirty adolescents aged 12 to 18 years (mean = 16.0, SD = 1.7) with a primary diagnosis of BDD, together with their families, were randomly assigned to 14 sessions of CBT delivered over 4 months or a control condition of equivalent duration, consisting of written psycho-education materials and weekly telephone monitoring. Blinded evaluators assessed participants at baseline, midtreatment, posttreatment, and at 2-month follow-up. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale Modified for BDD, Adolescent Version (mean baseline score = 37.13, SD = 4.98, range = 24-43). RESULTS: The CBT group showed a significantly greater improvement than the control group, both at posttreatment (time * group interaction coefficient [95% CI] = -11.26 [-17.22 to -5.31]; p = .000) and at 2 month follow-up (time * group interaction coefficient [95% CI] = -9.62 [-15.74 to -3.51]; p = .002). Six participants (40%) in the CBT group and 1 participant (6.7%) in the control condition were classified as responders at both time points (chi(2) = 4.658, p = .031). Improvements were also seen on secondary measures, including insight, depression, and quality of life at posttreatment. Both patients and their families deemed the treatment as highly acceptable. CONCLUSION: Developmentally tailored CBT is a promising intervention for young people with BDD, although there is significant room for improvement. Further clinical trials incorporating lessons learned in this pilot study and comparing CBT and pharmacological therapies, as well as their combination, are warranted. CLINICAL TRIAL REGISTRATION INFORMATION: Cognitive-Behaviour Therapy for Adolescents With Body Dysmorphic Disorder; http://www.isrctn.com/; ISRCTN67699666. PMID- 26506581 TI - Atomoxetine, Parent Training, and Their Combination in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Impairments associated with attention-deficit/hyperactivity disorder (ADHD) and noncompliance are prevalent in children with autism spectrum disorder (ASD). However, ADHD response to stimulants is well below rates in typically developing children, with frequent side effects. Group studies of treatments for noncompliance are rare in ASD. We examined individual and combined-effectiveness of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance. METHOD: In a 3-site, 10-week, double-blind, 2 * 2 trial of ATX and PT, 128 children (ages 5-14 years) with ASD and ADHD symptoms were randomized to ATX, ATX+PT, placebo+PT, or placebo. ATX was adjusted to optimal dose (capped at 1.8 mg/kg/day) over 6 weeks and maintained for 4 additional weeks. Nine PT sessions were provided. Primary outcome measures were the parent-rated DSM ADHD symptoms on the Swanson, Nolan and Pelham (SNAP) scale and Home Situations Questionnaire (HSQ). RESULTS: On the SNAP, ATX, ATX+PT and placebo+PT were each superior to placebo (effect sizes 0.57-0.98; p values of .0005, .0004, and .025, respectively). For noncompliance, ATX and ATX+PT were superior to placebo (effect sizes 0.47-0.64; p values .03 and .0028, respectively). ATX was associated with decreased appetite but was otherwise well tolerated. CONCLUSION: Both ATX and PT resulted in significant improvement on ADHD symptoms, whereas ATX (both alone and combined with PT) was associated with significant decreases on measures of noncompliance. ATX appears to have a better side effects profile than psychostimulants in the population with ASD. CLINICAL TRIAL REGISTRATION INFORMATION: Atomoxetine, Placebo and Parent Management Training in Autism; http://clinicaltrials.gov/; NCT00844753. PMID- 26506582 TI - A Randomized, Placebo-Controlled Trial of Guanfacine Extended Release in Adolescents With Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Despite the continuity of attention-deficit/hyperactivity disorder (ADHD) into adolescence, little is known regarding use of nonstimulants to treat ADHD in adolescents. This phase 3 trial evaluated the safety and efficacy of guanfacine extended release (GXR) in adolescents with ADHD. METHOD: This 13-week, multicenter, randomized, double-blind, placebo-controlled trial evaluated once daily GXR (1-7 mg per day) in adolescents with ADHD aged 13 to 17 years. The primary endpoint was the change from baseline in the ADHD Rating Scale-IV (ADHD RS-IV) total score; key secondary endpoints included scores from the Clinical Global Impressions-Severity of Illness (CGI-S), and Learning and School domain and Family domain scores from the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) at week 13. RESULTS: A total of 314 participants were randomized (GXR, n = 157; placebo, n = 157). The majority of participants received optimal doses of 3, 4, 5, or 6 mg (30 [22.9%], 26 [19.8%], 27 [20.6%], or 24 [18.3%] participants, respectively), with 46.5% of participants receiving an optimal dose above the currently approved maximum dose limit of 4 mg. Participants receiving GXR showed improvement in ADHD-RS-IV total score compared with placebo (least squares mean score change, -24.55 [GXR] versus -18.53 [placebo]; effect size, 0.52; p <.001). More participants on GXR also showed significant improvement in CGI-S scores compared with placebo (50.6% versus 36.1%; p = .010). There was no statistically significant difference between treatments at week 13 in the 2 WFIRS P domains. Most treatment-emergent adverse events were mild to moderate, with sedation-related events reported most commonly. CONCLUSION: GXR was associated with statistically significant improvements in ADHD symptoms in adolescents. GXR was well tolerated, with no new safety signals reported. CLINICAL TRIAL REGISTRATION INFORMATION: Dose-Optimization in Adolescents Aged 13-17 Diagnosed With Attention-Deficit/Hyperactivity Disorder (ADHD) Using Extended-Release Guanfacine HCl; http://ClinicalTrials.gov/; NCT01081132. PMID- 26506583 TI - Correlates and Consequences of Suicidal Cognitions and Behaviors in Children Ages 3 to 7 Years. AB - OBJECTIVE: Despite research documenting the existence of depression and other psychiatric disorders in early childhood, little is known about the nature and consequences of suicidal cognitions and behaviors (SI) in young children ages 3 to 7 years. The identification of trajectories of SI across childhood is a critical step toward preventing childhood suicide. METHOD: Participants were 306 children enrolled in a prospective longitudinal investigation of young children and their families. Children and their families completed a baseline assessment between ages 3 and 7 years, and at least 1 follow-up assessment (ages 7-12 years). Child psychopathology, suicidal thoughts, plans, and behaviors were assessed via parent and trained interviewer report before age 9, and also with self-report after age 9. Data on maternal history of psychopathology, as well as maternal and family history of suicide attempts, were also obtained through parent report. RESULTS: Controlling for a range of clinical and demographic variables, early-childhood SI (as defined as suicidal thoughts, behavior, or any expression of plans/attempts occurring before age 7) and suicidal themes in play were concurrently associated with childhood attention-deficit/hyperactivity (ADHD) and oppositional defiant/conduct disorders (ODD/CD). Early-childhood SI also predicted school-age depression and ODD/CD; however, these findings were no longer significant after controlling for the same diagnoses at the childhood baseline. Longitudinal analysis indicated that early-childhood SI was a robust predictor of school-age SI, even after accounting for psychiatric disorders at both time points. CONCLUSION: Extending current research, these findings demonstrate that early-childhood SI confers significant risk for continuation into school-age SI and is concurrently associated with ADHD and ODD/CD. Although the meaning of early-childhood SI remains unclear, results suggest that it is a clinically important phenomenon that should be carefully assessed and taken seriously as a marker of risk for ongoing suicidal ideation/behavior. These findings suggest that early screening for SI in childhood is indicated in clinical settings, particularly in children less than 7 years of age with depression and externalizing disorders. PMID- 26506584 TI - Sex-Based Dissociation of White Matter Microstructure in Children With Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Sexual dimorphism is evident in attention-deficit/hyperactivity disorder (ADHD), including subtype prevalence, adverse outcomes, and neural phenotype. Neurobiological studies of ADHD suggest that boys show more abnormalities in motor and premotor structure and function, whereas girls differ from typically developing (TD) peers in prefrontal circuitry. We applied diffusion tensor imaging (DTI) to identify ADHD-related sex-specific differences in motor/premotor and prefrontal white matter (WM) microstructure in children. METHOD: DTI estimated differences in WM microstructure among 120 children 8 to 12 years of age, 60 with ADHD (30 boys and 30 girls) and 60 controls (30 boys and 30 girls), matched on age, IQ, and handedness. Effects of diagnosis and sex on fractional anisotropy (FA) were assessed in motor/premotor and prefrontal regions. Group differences in FA and associations with response control (e.g., reaction time variability [CVRT] and commission error rate) were examined separately within sex. RESULTS: Sex-by-diagnosis interactions were observed for FA in primary motor (M1) and medial orbitofrontal (MOFC) cortex. Post hoc tests revealed that boys with ADHD showed bilateral reductions in FA within M1, compared with TD peers; in contrast, girls with ADHD showed higher FA bilaterally within MOFC. Decreased M1 FA was associated with higher CVRT in boys and higher commission error rates in girls. For MOFC, lower FA was associated with greater CVRT and commission error rates across all participants with ADHD. CONCLUSION: ADHD affects the white matter of boys and girls differently; boys appear to be more affected in regions responsible for control of basic actions, whereas girls show more abnormalities in regions responsible for higher-level, top-down control. PMID- 26506586 TI - Mindfulness, Embodied. PMID- 26506587 TI - In Reply. PMID- 26506585 TI - Atypical Learning in Autism Spectrum Disorders: A Functional Magnetic Resonance Imaging Study of Transitive Inference. AB - OBJECTIVE: To investigate the neural mechanisms underlying impairments in generalizing learning shown by adolescents with autism spectrum disorder (ASD). METHOD: A total of 21 high-functioning individuals with ASD aged 12 to 18 years, and 23 gender-, IQ-, and age-matched adolescents with typical development (TYP), completed a transitive inference (TI) task implemented using rapid event-related functional magnetic resonance imaging (fMRI). Participants were trained on overlapping pairs in a stimulus hierarchy of colored ovals where A>B>C>D>E>F and then tested on generalizing this training to new stimulus pairings (AF, BD, BE) in a "Big Game." Whole-brain univariate, region of interest, and functional connectivity analyses were used. RESULTS: During training, the TYP group exhibited increased recruitment of the prefrontal cortex (PFC), whereas the group with ASD showed greater functional connectivity between the PFC and the anterior cingulate cortex (ACC). Both groups recruited the hippocampus and caudate comparably; however, functional connectivity between these regions was positively associated with TI performance for only the group with ASD. During the Big Game, the TYP group showed greater recruitment of the PFC, parietal cortex, and the ACC. Recruitment of these regions increased with age in the group with ASD. CONCLUSION: During TI, TYP individuals recruited cognitive control-related brain regions implicated in mature problem solving/reasoning including the PFC, parietal cortex, and ACC, whereas the group with ASD showed functional connectivity of the hippocampus and the caudate that was associated with task performance. Failure to reliably engage cognitive control-related brain regions may produce less integrated flexible learning in individuals with ASD unless they are provided with task support that, in essence, provides them with cognitive control; however, this pattern may normalize with age. PMID- 26506588 TI - Clinical Correlates of Early Generalized Overgrowth in Autism Spectrum Disorder. PMID- 26506589 TI - In Reply. PMID- 26506591 TI - Analysis of culture media screening data by projection to latent pathways: The case of Pichia pastoris X-33. AB - Cell culture media formulations contain hundreds of individual components in water solutions which have complex interactions with metabolic pathways. The currently used statistical design methods are empirical and very limited to explore such a large design space. In a previous work we developed a computational method called projection to latent pathways (PLP), which was conceived to maximize covariance between envirome and fluxome data under the constraint of metabolic network elementary flux modes (EFM). More specifically, PLP identifies a minimal set of EFMs (i.e., pathways) with the highest possible correlation with envirome and fluxome measurements. In this paper we extend the concept for the analysis of culture media screening data to investigate how culture medium components up-regulate or down-regulate key metabolic pathways. A Pichia pastoris X-33 strain was cultivated in 26 shake flask experiments with variations in trace elements concentrations and basal medium dilution, based on the standard BSM+PTM1 medium. PLP identified 3 EFMs (growth, maintenance and by product formation) describing 98.8% of the variance in observed fluxes. Furthermore, PLP presented an overall predictive power comparable to that of PLS regression. Our results show iron and manganese at concentrations close to the PTM1 standard inhibit overall metabolic activity, while the main salts concentration (BSM) affected mainly energy expenditures for cellular maintenance. PMID- 26506592 TI - Epigenetic reprogramming in the mammalian germline. PMID- 26506593 TI - Prmt5 differentiates developmental vs regenerative myogenesis. PMID- 26506595 TI - Overexpression of TREM2 enhances glioma cell proliferation and invasion: a therapeutic target in human glioma. AB - Gliomas are the most common and aggressive type of primary adult brain tumors. Although TREM2 mutation is reported to be related to Nasu-Hakola disease and Alzheimer's disease, little is known about the association between TREM2 and gliomas. Here, we reported that TREM2 was significantly overexpressed in glioma tissues compared with non-tumorous brain tissues. Furthermore, TREM2 expression was closely related to pathological grade and overall survival of patients with gliomas. Down-regulation of TREM2 in two glioma cell lines, U87 and U373, resulted in a significant reduction in cell proliferation, migration and invasion and a dramatic increase in S phase arrest and apoptosis. In vivo tumorigenesis experiment also revealed that depletion of TREM2 expression inhibited U87 cell proliferation. Moreover, based on gene set enrichment analysis (GSEA) with The Cancer Genome Atlas (TCGA) dataset, we found that TREM2 was positive related to Kyoto Encyclopedia of Genes and Genomes (KEGG) apoptosis, Cromer metastasis and KEGG chemokine pathways, which was further validated by western blot in TREM2 knockdown glioma cells and indicated a possible mechanism underlying its effects on glioma. In summary, our study suggests that TREM2 may work as an oncogene and a new effective therapeutic target for glioma treatment. PMID- 26506594 TI - Prostate cancer stem cells: the role of androgen and estrogen receptors. AB - Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable.Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (alpha and/or beta) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment.In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer. Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy. PMID- 26506596 TI - A novel gammaretroviral shuttle vector insertional mutagenesis screen identifies SHARPIN as a breast cancer metastasis gene and prognostic biomarker. AB - Breast cancer (BC) is the second leading cause of malignancy among U.S. women. Metastasis results in a poor prognosis and increased mortality, but the molecular mechanisms by which metastatic tumors occur are not well understood. Identifying the genes that drive the metastatic process could provide targets for improved therapy and biomarkers to improve BC patient outcomes. Using a forward mutagenesis screen, BC cells mutagenized with a replication-incompetent gammaretroviral vector (gammaRV) were xenotransplanted into the mammary fat pad of immunodeficient mice. In this approach the vector provirus dysregulates nearby genes, providing a selective advantage to transduced cells to form metastases. Metastatic tumors were analyzed for proviral integration sites to identify nearby candidate metastasis genes. The gammaRV has a transgene cassette that allows for rescue in bacteria and rapid identification of vector integration sites. Using this approach, we identified the previously described metastasis gene WWTR1 (TAZ), and three other novel candidate metastasis genes including SHARPIN. SHARPIN was independently validated in vivo as a BC metastasis gene. Analysis of patient data showed that SHARPIN expression predicts metastasis-free survival after adjuvant therapy. Our approach has broad potential to identify genes involved in oncogenic processes for BC and other cancers. We show here it can identify both known (WWTR1) and novel (SHARPIN) BC metastasis genes. PMID- 26506598 TI - Medical education to develop physicians' expertise: essential, but not sufficient for excellent health care. PMID- 26506599 TI - Choosing wisely Canada: integrating stewardship in medical education. PMID- 26506597 TI - ApoE4-specific Misfolded Intermediate Identified by Molecular Dynamics Simulations. AB - The increased risk of developing Alzheimer's disease (AD) is associated with the APOE gene, which encodes for three variants of Apolipoprotein E, namely E2, E3, E4, differing only by two amino acids at positions 112 and 158. ApoE4 is known to be the strongest risk factor for AD onset, while ApoE3 and ApoE2 are considered to be the AD-neutral and AD-protective isoforms, respectively. It has been hypothesized that the ApoE isoforms may contribute to the development of AD by modifying the homeostasis of ApoE physiological partners and AD-related proteins in an isoform-specific fashion. Here we find that, despite the high sequence similarity among the three ApoE variants, only ApoE4 exhibits a misfolded intermediate state characterized by isoform-specific domain-domain interactions in molecular dynamics simulations. The existence of an ApoE4-specific intermediate state can contribute to the onset of AD by altering multiple cellular pathways involved in ApoE-dependent lipid transport efficiency or in AD related protein aggregation and clearance. We present what we believe to be the first structural model of an ApoE4 misfolded intermediate state, which may serve to elucidate the molecular mechanism underlying the role of ApoE4 in AD pathogenesis. The knowledge of the structure for the ApoE4 folding intermediate provides a new platform for the rational design of alternative therapeutic strategies to fight AD. PMID- 26506600 TI - In reply to Leon-Carlyle and colleagues. PMID- 26506601 TI - Self-determination theory and scaffolding applied to medical education as a continuum. PMID- 26506602 TI - Alternatives to selling a medical school name. PMID- 26506603 TI - Medical literature: don't believe everything you read. PMID- 26506604 TI - The responsibility of academic medicine for reducing football injuries. PMID- 26506605 TI - Compliments from a white coat. PMID- 26506606 TI - Stereotype detox. PMID- 26506607 TI - Artist's statement: the mighty fellow. PMID- 26506608 TI - Medicine and the Arts. A country doctor [excerpt] by Franz Kafka. Commentary. PMID- 26506610 TI - The Gold-Hope Tang, MD 2015 Humanism in Medicine Essay Contest: second place: the doctor will see you now. PMID- 26506611 TI - Erratum: Dynamic Changes in Proteins during Apple (Malus x domestica) Fruit Ripening and Storage. AB - [This corrects the article DOI: 10.1038/hortres.2014.6.]. PMID- 26506612 TI - Muscular Activity and Fatigue in Lower-Limb and Trunk Muscles during Different Sit-To-Stand Tests. AB - Sit-to-stand (STS) tests measure the ability to get up from a chair, reproducing an important component of daily living activity. As this functional task is essential for human independence, STS performance has been studied in the past decades using several methods, including electromyography. The aim of this study was to measure muscular activity and fatigue during different repetitions and speeds of STS tasks using surface electromyography in lower-limb and trunk muscles. This cross-sectional study recruited 30 healthy young adults. Average muscle activation, percentage of maximum voluntary contraction, muscle involvement in motion and fatigue were measured using surface electrodes placed on the medial gastrocnemius (MG), biceps femoris (BF), vastus medialis of the quadriceps (QM), the abdominal rectus (AR), erector spinae (ES), rectus femoris (RF), soleus (SO) and the tibialis anterior (TA). Five-repetition STS, 10 repetition STS and 30-second STS variants were performed. MG, BF, QM, ES and RF muscles showed differences in muscle activation, while QM, AR and ES muscles showed significant differences in MVC percentage. Also, significant differences in fatigue were found in QM muscle between different STS tests. There was no statistically significant fatigue in the BF, MG and SO muscles of the leg although there appeared to be a trend of increasing fatigue. These results could be useful in describing the functional movements of the STS test used in rehabilitation programs, notwithstanding that they were measured in healthy young subjects. PMID- 26506613 TI - Mental Summation of Temporal Duration within and across Senses. AB - Perceiving, memorizing, and estimating temporal durations are key cognitive functions in everyday life. In this study, a duration summation paradigm was used to examine whether summation of temporal durations introduces an underestimation or overestimation bias, and whether this bias is common to visual and auditory modalities. Two within- or across-modality stimuli were presented sequentially for variable durations. Participants were asked to reproduce the sum of the two durations (0.6-1.1 s). We found that the sum of two durations was overestimated regardless of stimulus modalities. A subsequent control experiment indicated that the overestimation bias arose from the summation process, not perceptual or memory processes. Furthermore, we observed strong positive correlations between the overestimation bias for different sensory modalities within participants. These results suggest that the sum of two durations is overestimated, and that supra-modal processes may be responsible for this overestimation bias. PMID- 26506615 TI - TransNewGuinea.org: An Online Database of New Guinea Languages. AB - The island of New Guinea has the world's highest linguistic diversity, with more than 900 languages divided into at least 23 distinct language families. This diversity includes the world's third largest language family: Trans-New Guinea. However, the region is one of the world's least well studied, and primary data is scattered across a wide range of publications and more often then not hidden in unpublished "gray" literature. The lack of primary research data on the New Guinea languages has been a major impediment to our understanding of these languages, and the history of the peoples in New Guinea. TransNewGuinea.org aims to collect data about these languages and place them online in a consistent format. This database will enable future research into the New Guinea languages with both traditional comparative linguistic methods and novel cutting-edge computational techniques. The long-term aim is to shed light into the prehistory of the peoples of New Guinea, and to understand why there is such major diversity in their languages. PMID- 26506614 TI - Associations of Circulating Gut Hormone and Adipocytokine Levels with the Spectrum of Gastroesophageal Reflux Disease. AB - OBJECTIVE: The pathogenesis of gastroesophageal reflux disease (GERD) is complex and poorly understood. We aim to investigate the association of various circulating peptide hormones with heterogenous manifestations of GERD. METHODS: One hundred and four patients that had experienced typical GERD symptoms (heartburn and/or acid regurgitation) for at least 3 episodes per week in the past 3 months were enrolled. All patients received a baseline assessment of symptom severity and frequency with the Reflux Disease Questionnaire and an upper endoscopy to classify GERD into erosive esophagitis (EE, n = 67), non-erosive esophagitis (NE, n = 37), and Barrett's esophagus (BE, n = 8). Fifty asymptomatic subjects with an endoscopically normal esophagus were recruited as the control group. Complete anthropometric measures and blood biochemistry were obtained and fasting serum levels of adipocytokines (adiponectin and leptin) and gut hormones (ghrelin and peptide YY (PYY)) were determined by enzyme-linked immunosorbent assay in all subjects. RESULTS: All circulating peptide hormone levels were not statistically different between the GERD and control groups. However, GERD patients appeared to have lower PYY levels [median (25th-75th percentile), 80.1 (49.8-108.3) vs. 99.4 (65.8-131.9) pg/ml, p = 0.057] compared with control subjects. Among the GERD patients, ghrelin levels were inversely associated with the frequency and severity of acid regurgitation. In male GERD patients, EE was associated with significantly higher PYY levels [107.0 (55.0-120.8) vs. 32.8 (28.7-84.5) pg/ml, p = 0.026] but lower adiponectin levels [6.7 (5.6-9.3) vs. 9.9 (9.6-10.6) MUg/ml, p = 0.034] than NE. Patients with BE had significantly lower adiponectin levels [6.0 (5.1-9.2) vs. 9.2 (7.1-11.2) MUg/ml, p = 0.026] than those without BE. CONCLUSIONS: Humoral derangement of circulating peptide hormones might participate in inflammation and symptom perception in patients suffering from GERD. Further studies to clarify the exact role of these hormones in the pathogenesis of GERD are warranted. PMID- 26506616 TI - The Effects of Socioeconomic and Environmental Factors on the Incidence of Dengue Fever in the Pearl River Delta, China, 2013. AB - BACKGROUND: An outbreak of dengue fever (DF) occurred in Guangdong Province, China in 2013 with the highest number of cases observed within the preceding ten years. DF cases were clustered in the Pearl River Delta economic zone (PRD) in Guangdong Province, which accounted for 99.6% of all cases in Guangdong province in 2013. The main vector in PRD was Aedes albopictus. We investigated the socioeconomic and environmental factors at the township level and explored how the independent variables jointly affect the DF epidemic in the PRD. METHODOLOGY/PRINCIPAL FINDINGS: Six factors associated with the incidence of DF were identified in this project, representing the urbanization, poverty, accessibility and vegetation, and were considered to be core contributors to the occurrence of DF from the perspective of the social economy and the environment. Analyses were performed with Generalized Additive Models (GAM) to fit parametric and non-parametric functions to the relationships between the response and predictors. We used a spline-smooth technique and plotted the predicted against the observed co-variable value. The distribution of DF cases was over-dispersed and fit the negative binomial function better. The effects of all six socioeconomic and environmental variables were found to be significant at the 0.001 level and the model explained 45.1% of the deviance by DF incidence. There was a higher risk of DF infection among people living at the prefectural boundary or in the urban areas than among those living in other areas in the PRD. The relative risk of living at the prefectural boundary was higher than that of living in the urban areas. The associations between the DF cases and population density, GDP per capita, road density, and NDVI were nonlinear. In general, higher "road density" or lower "GDP per capita" were considered to be consistent risk factors. Moreover, higher or lower values of "population density" and "NDVI" could result in an increase in DF cases. CONCLUSION: In this study, we presented an effect analysis of socioeconomic and environmental factors on DF occurrence at the smallest administrative unit (township level) for the first time in China. GAM was used to effectively detect the nonlinear impact of the predictors on the outcome. The results showed that the relative importance of different risk factors may vary across the PRD. This work improves our understanding of the differences and effects of socioeconomic and environmental factors on DF and supports effectively targeted prevention and control measures. PMID- 26506618 TI - A Comparison of Anthropometric Measures for Assessing the Association between Body Size and Risk of Chronic Low Back Pain: The HUNT Study. AB - BACKGROUND: Previous work indicates that overweight and obese individuals carry an increased risk of experiencing chronic low back pain (LBP). It is not known, however, how the association with body size depends on the choice of anthropometric measure used. OBJECTIVE: This work compares relationships with LBP for several measures of body size. Different results may indicate underlying mechanisms for the association between body size and risk of LBP. METHODS: In a cohort study, baseline information was collected in the community-based HUNT2 (1995-1997) and HUNT3 (2006-2008) surveys in Norway. Participants were 10,059 women and 8725 men aged 30-69 years without LBP, and 3883 women and 2662 men with LBP at baseline. Associations with LBP at end of follow-up were assessed by generalized linear modeling, with adjustment for potential confounders. RESULTS: Relationships between waist-hip-ratio and occurrence of LBP at end of follow-up were weak and non-significant after adjustment for age, education, work status, physical activity, smoking, lipid levels and blood pressure. Positive associations with LBP at end of follow-up were all significant for body weight, BMI, waist circumference and hip circumference after similar adjustment, both in women without and with LBP at baseline, and in men without LBP at baseline. After additional mutual adjustment for anthropometric measures, the magnitude of the association with body weight increased in women without LBP at baseline (RR: 1.130 per standard deviation, 95% CI: 0.995-1.284) and in men (RR: 1.124, 95% CI 0.976-1.294), with other measures showing weak associations only. CONCLUSION: Central adiposity is unlikely to play a major role in the etiology of LBP. Total fat mass may be one common factor underlying the associations observed. The association with body weight remaining after mutual adjustment may reflect mechanical or structural components behind the relationship between overweight or obesity and LBP. PMID- 26506617 TI - Exposing Hidden Alternative Backbone Conformations in X-ray Crystallography Using qFit. AB - Proteins must move between different conformations of their native ensemble to perform their functions. Crystal structures obtained from high-resolution X-ray diffraction data reflect this heterogeneity as a spatial and temporal conformational average. Although movement between natively populated alternative conformations can be critical for characterizing molecular mechanisms, it is challenging to identify these conformations within electron density maps. Alternative side chain conformations are generally well separated into distinct rotameric conformations, but alternative backbone conformations can overlap at several atomic positions. Our model building program qFit uses mixed integer quadratic programming (MIQP) to evaluate an extremely large number of combinations of sidechain conformers and backbone fragments to locally explain the electron density. Here, we describe two major modeling enhancements to qFit: peptide flips and alternative glycine conformations. We find that peptide flips fall into four stereotypical clusters and are enriched in glycine residues at the n+1 position. The potential for insights uncovered by new peptide flips and glycine conformations is exemplified by HIV protease, where different inhibitors are associated with peptide flips in the "flap" regions adjacent to the inhibitor binding site. Our results paint a picture of peptide flips as conformational switches, often enabled by glycine flexibility, that result in dramatic local rearrangements. Our results furthermore demonstrate the power of large-scale computational analysis to provide new insights into conformational heterogeneity. Overall, improved modeling of backbone heterogeneity with high-resolution X-ray data will connect dynamics to the structure-function relationship and help drive new design strategies for inhibitors of biomedically important systems. PMID- 26506619 TI - Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non Hodgkin Lymphoma. AB - The checkpoint kinase 2 gene (CHEK2) codes for the CHK2 protein, an important mediator of the DNA damage response pathway. The CHEK2 gene has been recognized as a multi-cancer susceptibility gene; however, its role in non-Hodgkin lymphoma (NHL) remains unclear. We performed mutation analysis of the entire CHEK2 coding sequence in 340 NHL patients using denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA). Identified hereditary variants were genotyped in 445 non-cancer controls. The influence of CHEK2 variants on disease risk was statistically evaluated. Identified CHEK2 germline variants included four truncating mutations (found in five patients and no control; P = 0.02) and nine missense variants (found in 21 patients and 12 controls; P = 0.02). Carriers of non-synonymous variants had an increased risk of NHL development [odds ratio (OR) 2.86; 95% confidence interval (CI) 1.42-5.79] and an unfavorable prognosis [hazard ratio (HR) of progression free survival (PFS) 2.1; 95% CI 1.12-4.05]. In contrast, the most frequent intronic variant c.319+43dupA (identified in 22% of patients and 31% of controls) was associated with a decreased NHL risk (OR = 0.62; 95% CI 0.45-0.86), but its positive prognostic effect was limited to NHL patients with diffuse large B-cell lymphoma (DLBCL) treated by conventional chemotherapy without rituximab (HR-PFS 0.4; 94% CI 0.17-0.74). Our results show that germ-line CHEK2 mutations affecting protein coding sequence confer a moderately-increased risk of NHL, they are associated with an unfavorable NHL prognosis, and they may represent a valuable predictive biomarker for patients with DLBCL. PMID- 26506620 TI - Ribosomal Proteins RPS11 and RPS20, Two Stress-Response Markers of Glioblastoma Stem Cells, Are Novel Predictors of Poor Prognosis in Glioblastoma Patients. AB - Glioblastoma stem cells (GSC) co-exhibiting a tumor-initiating capacity and a radio-chemoresistant phenotype, are a compelling cell model for explaining tumor recurrence. We have previously characterized patient-derived, treatment-resistant GSC clones (TRGC) that survived radiochemotherapy. Compared to glucose-dependent, treatment-sensitive GSC clones (TSGC), TRGC exhibited reduced glucose dependence that favor the fatty acid oxidation pathway as their energy source. Using comparative genome-wide transcriptome analysis, a series of defense signatures associated with TRGC survival were identified and verified by siRNA-based gene knockdown experiments that led to loss of cell integrity. In this study, we investigate the prognostic value of defense signatures in glioblastoma (GBM) patients using gene expression analysis with Probeset Analyzer (131 GBM) and The Cancer Genome Atlas (TCGA) data, and protein expression with a tissue microarray (50 GBM), yielding the first TRGC-derived prognostic biomarkers for GBM patients. Ribosomal protein S11 (RPS11), RPS20, individually and together, consistently predicted poor survival of newly diagnosed primary GBM tumors when overexpressed at the RNA or protein level [RPS11: Hazard Ratio (HR) = 11.5, p<0.001; RPS20: HR = 4.5, p = 0.03; RPS11+RPS20: HR = 17.99, p = 0.001]. The prognostic significance of RPS11 and RPS20 was further supported by whole tissue section RPS11 immunostaining (27 GBM; HR = 4.05, p = 0.01) and TCGA gene expression data (578 primary GBM; RPS11: HR = 1.19, p = 0.06; RPS20: HR = 1.25, p = 0.02; RPS11+RPS20: HR = 1.43, p = 0.01). Moreover, tumors that exhibited unmethylated O-6 methylguanine-DNA methyltransferase (MGMT) or wild-type isocitrate dehydrogenase 1 (IDH1) were associated with higher RPS11 expression levels [corr (IDH1, RPS11) = 0.64, p = 0.03); [corr (MGMT, RPS11) = 0.52, p = 0.04]. These data indicate that increased expression of RPS11 and RPS20 predicts shorter patient survival. The study also suggests that TRGC are clinically relevant cells that represent resistant tumorigenic clones from patient tumors and that their properties, at least in part, are reflected in poor-prognosis GBM. The screening of TRGC signatures may represent a novel alternative strategy for identifying new prognostic biomarkers. PMID- 26506623 TI - [Current topics of regenerative medicine in the field of otorhinolaryngology]. PMID- 26506622 TI - Dysfunctional Presynaptic M2 Receptors in the Presence of Chronically High Acetylcholine Levels: Data from the PRiMA Knockout Mouse. AB - The muscarinic M2 receptor (M2R) acts as a negative feedback regulator in central cholinergic systems. Activation of the M2 receptor limits acetylcholine (ACh) release, especially when ACh levels are increased because acetylcholinesterase (AChE) activity is acutely inhibited. Chronically high ACh levels in the extracellular space, however, were reported to down-regulate M2R to various degrees. In the present study, we used the PRiMA knockout mouse which develops severely reduced AChE activity postnatally to investigate ACh release, and we used microdialysis to investigate whether the function of M2R to reduce ACh release in vivo was impaired in adult PRiMA knockout mice. We first show that striatal and hippocampal ACh levels, while strongly increased, still respond to AChE inhibitors. Infusion or injection of oxotremorine, a muscarinic M2 agonist, reduced ACh levels in wild-type mice but did not significantly affect ACh levels in PRiMA knockout mice or in wild-type mice in which ACh levels were artificially increased by infusion of neostigmine. Scopolamine, a muscarinic antagonist, increased ACh levels in wild-type mice receiving neostigmine, but not in wild type mice or in PRiMA knockout mice. These results demonstrate that M2R are dysfunctional and do not affect ACh levels in PRiMA knockout mice, likely because of down-regulation and/or loss of receptor-effector coupling. Remarkably, this loss of function does not affect cognitive functions in PRiMA knockout mice. Our results are discussed in the context of AChE inhibitor therapy as used in dementia. PMID- 26506621 TI - Causes of Death among AIDS Patients after Introduction of Free Combination Antiretroviral Therapy (cART) in Three Chinese Provinces, 2010-2011. AB - INTRODUCTION: Although AIDS-related deaths have had significant economic and social impact following an increased disease burden internationally, few studies have evaluated the cause of AIDS-related deaths among patients with AIDS on combination anti-retroviral therapy (cART) in China. This study examines the causes of death among AIDS-patients in China and uses a methodology to increase data accuracy compared to the previous studies on AIDS-related mortality in China, that have taken the reported cause of death in the National HIV Registry at face-value. METHODS: Death certificates/medical records were examined and a cross-sectional survey was conducted in three provinces to verify the causes of death among AIDS patients who died between January 1, 2010 and June 30, 2011. Chi square analysis was conducted to examine the categorical variables by causes of death and by ART status. Univariate and multivariate logistic regression were used to evaluate factors associated with AIDS-related death versus non-AIDS related death. RESULTS: This study used a sample of 1,109 subjects. The average age at death was 44.5 years. AIDS-related deaths were significantly higher than non-AIDS and injury-related deaths. In the sample, 41.9% (465/1109) were deceased within a year of HIV diagnosis and 52.7% (584/1109) of the deceased AIDS patients were not on cART. For AIDS-related deaths (n = 798), statistically significant factors included CD4 count <200 cells/mm3 at the time of cART initiation (AOR 1.94, 95%CI 1.24-3.05), ART naive (AOR 1.69, 95%CI 1.09-2.61; p = 0.019) and age <39 years (AOR 2.96, 95%CI 1.77-4.96). CONCLUSION: For the AIDS patients that were deceased, only those who initiated cART while at a CD4 count >=200 cells/mm3 were less likely to die from AIDS-related causes compared to those who didn't initiate ART at all. PMID- 26506624 TI - [Immunotherapy for allergic rhinitis]. PMID- 26506625 TI - Retraction. PMID- 26506626 TI - [Psycho-oncology-psychological approach to cancer patients]. PMID- 26506627 TI - [Current topics of regenerative medicine in the field of otorhinolaryngology]. PMID- 26506628 TI - [Anatomy of jugular foramen and hypoglossal canal]. PMID- 26506630 TI - [Treatment of ear disease with Kampo]. PMID- 26506629 TI - [Diagnosis and surgery for dysphagia]. PMID- 26506631 TI - [Diagnosis and management of carotid artery tumor]. PMID- 26506632 TI - Medical Devices; Immunology and Microbiology Devices; Classification of Autosomal Recessive Carrier Screening Gene Mutation Detection System. Final order. AB - The Food and Drug Administration (FDA) has classified an autosomal recessive carrier screening gene mutation detection system into class II (special controls). The special controls that apply to this device are identified in this order and will be part of the codified language for the autosomal recessive carrier screening gene mutation detection system classification. The Agency has classified the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26506633 TI - Gleb N. Budzilovich, MD. PMID- 26506634 TI - PRIMARY RETROPERITONEAL EXTRA-ORGAN TUMORS (PRET) - SURGICAL TACTICS. AB - INTRODUCTION: Retroperitoneal tumors, in general, are rare tumors which histopathological characteristics and biological behavior can be considered as benign or malignant. They originate from various tissue elements located in the retroperitoneal space. They often cover Anatomical structures of varying importance - mainly retroperitoneal vessels and organs, which determines the type of surgery - radical or palliative. They are composed of adipose tissue, vascular elements, smooth and striated muscle, neural elements germline structures. There are three main types of retroperitoneal tumors: mesodermal, neurogenic and teratosarcomas. As mentioned above each can be either benign and malignant. In most cases there are no specific symptoms except general weakness, heaviness in the abdomen, loss of appetite, progressive weight loss, headache and fever. The pain is most often located in the lumbosacral area. The tumor can also cause disturbances in urination. In patients with advanced stage can be observed significantly symmetrical or asymmetrical tumor growth in the abdominal area. The most commonly used techniques for the diagnosis of the disease are X-ray, CT-scan and MRI. MATERIAL AND METHODS: Retrospective study involving 112 cases operated in the clinic for 14-years period (2000-2014) - 101 patients, 11 of them were operated on twice in a different time interval on the occasion of relapsed malignant process. RESULTS: Out of all operated cases, 42% are males (47 cases) and 58% - women (65 cases). In most cases (72% - 81 cases) tumors are malignant. All patients were treated surgically. There were followed up a total of 89 patients over a period of 3 months to 8 years (96 months) as of the studied malignant cases 3 year survival was observed in 21 patients, and one patient has survived 96 months after total extirpation of fibrosarcoma. Early postoperative mortality (till 20th postoperative day) was registered in 3 patients - 2.67% of all operated cases. DISCUSSION: About 80% of primary retroperitoneal extra-organ tumors are generally malignant. People of all ages are affected equally and no statistically significant difference in the number of men and women is detected. There are many theories about the emergence of retroperitoneal tumors, but currently none of them has not been fully proven. Treatment depends on the type of the lesion. Surgery is the main approach and it should be applied to both benign and malignant lesions. In the case of malignancy other methods than surgical are chemo- and radiotherapy but they are less effective. PMID- 26506635 TI - WILIS IRLE ARITINS, IMPORTANT FOR CEREBRAL PROTECTION IN AORTIC SURGERY - PRIMARY CT ANGIO DATA. AB - Unilateral selective cerebral perfusion (SCP) is a method for cerebral protection in aortic arch surgery. However variations of the circle of Willis (CoW) could vitiate its protective effect. The aim of our present work was to make a retrospective analysis of 30 patients, in whom CT angio was performed between January and March 2008. Variations of Willis circle, which could compromise the perfusion during unilateral SCP were found in 21 patients (70%). We also found that many patients have significant stenosis of cerebral arteries. Our present study shows the need of extensive preoperative examination and meticulous intraoperative monitoring. PMID- 26506636 TI - ONE-STAGE (PRIMARY) RECONSTRUCTIONS OF RESECTION MANDIBULAR DEFECTS BY MEANS OF AUTOGENE VASCULARISED ILIAC AND FIBULAR TRANSPLANT. AB - Mandibular resections are most often performed in cases of tumour ablations. Contemporary oral and maxillofacial surgery acknowledges primary one-stage reconstructions of defects through microvscularised transplants. They have intact circulation due to the primarily performed vascular anastomoses. For recovery of the shape and the function of the mandible most frequently used transplants are derived from the iliac crest and fibula. Goal and objectives. We share our experience in the one-stage recovery of mandibular defects simultaneously with the resection, by means of autogene vascularised iliac and fibular transplants. Material and method. 8 patients aged from 24 to 61 (female - 1, male - 7) with tumours engaging the mandible (5 - benign and 2 - malignant) were treated surgically and followed up. We carried those out using extraoral approach in 7 cases, and intraoral aproach - in 1. The resulting post resection mandibular defects in 3 of the patients were reconstructed by means of one-stage autogene bone vascularised iliac transplants. In 5 patients the defects were recovered primarily through vascularised fibular autotransplants. The surgical techniques and protocols, to assess the outcome and characterize of the methods are presented. RESULTS: We tracked down the postoperative results of the mandibular reconstructions for a period of 1 to 3 years. Support for the lips and tongue was achieved providing for satisfactory speech and feeding. Anatomical remodeling was observed. The conditions for the production of dental implants were improved. In the case, when we used intraoral approach the facial aesthetics was fully restored, as for the rest it was satisfactory. CONCLUSIONS: Vascularised autogene iliac and fibular bone transplants are extremely appropriate for reconstructions of significant and complicated mandibular and other defects in the maxillofacial area. Their survival is independent from the recipient area, and secured through the vessel anastomoses. With sound surgical technique, success rate of the method is to a large extent guaranteed. PMID- 26506637 TI - SURGICAL STRATEGY FOR PATIENTS UNDERGOING CAROTID ENDARTERECTOMY. AB - Carotid endarterectomy (CEA) is a surgical intervention that aims to reduce neurological symptoms in carotid atherosclerosis and prevent brain damage and subsequent neurological deficit. AIM: To study the major risk factors, surgical techniques, applied diagnostic methods and perioperative complications occurring in patients undergoing CEA. MATERIALS AND METHODS: 496 surgical interventions on the occasion of stenoses and/or occlusions of the carotid arteries were performed for the period 1987-2009 at the department of Vascular Surgery and Angiology of "St. Ekaterina" - University Hospital - Sofia. All patients were operated using standard access under general or local anaesthesia. During surgeries, evaluation of cerebral hemodynamics and function was performed by transcranial Doppler Ultrasound (TCD) and cerebral oximetry (CO). Carotid shunting was selectively applied in cases of deterioration of the values of CO and TCD during cross clamping of the carotid arteries. RESULTS: The highest relative share among cerebrovascular complications took stroke with 2.7% share in the group of asymptomatic patients and 1.7% - in the symptomatic group. Considering the other types of complications with the largest relative share were cardiac complications in both groups of patients - hemodynamic disorders and myocardial infarction. CONCLUSION: Low values of postoperative mortality and stroke after CEA in our study are comparable with other leading centers, proving that CEA is safe and effective surgical procedure for stroke prevention in both symptomatic and asymptomatic patients. Accurate perioperative diagnostic allows a good approach for choosing the correct surgical strategy. PMID- 26506638 TI - RECTOCELE - A LITERATURE REVIEW WITH A CASE REPORT. AB - Rectocele is defined as an herniation of the rectal wall through a defect in the posterior rectovaginal septum in direction of the vagina. A great variety of factors can cause a rectocle. Small rectoceles are asymptomatic, but the big ones are appearing with a great variety of symptoms. Diagnosis of a rectocele is based on the clinical signs, physical examination and imaging tests. There are nonsurgical and surgical methods for treament of rectocele. Here we share our experience of successful surgical treatment of a big, sacculiform, high rectocele appeared soon after a vaginal hysterectomy. PMID- 26506639 TI - HEMORRHOIDAL DISEASE - CONTEMPORARY ASPECTS OF THE PATHOGENESIS, CLINICAL COURSE, DIAGNOSIS AND TREATMENT. AB - The hemorrhoidal disease affects mainly individuals in their active age, as the reported incidence is much lower than the actual number, due to the nature of the complaints and the "subjective feeling of discomfort" when contacting a healthcare professional. Although in a large part of the cases the disease is successfully treated by non-surgical methods, the persisting symptoms greatly lower patients' quality of life, and the development of complications is related to a high morbidity rate. The defining, diagnosis and determining of the stages of the disease do not pose any difficulties to the modern medical practice, which - however - is not the case with the selection of the optimal and most efficient treatment method. There are a great number of treatment procedures, including surgical, for the treatment of the hemorrhoidal disease. Although there are certain recommended schemes and algorithms for therapeutic behavior, the selection of the method, ensuring individualized and optimal therapy, depends on the judgment of the surgeon. PMID- 26506640 TI - [Role of the Periaqueductal Gray Matter of the Midbrain in Regulation of Somatic Pain Sensitivity During Stress: Participation of Corticotropin-Releasing Factor and Glucocorticoid Hormones]. AB - Periaqueductal gray matter of the midbrain (PAGM) plays a crucial role in the regulation of pain sensitivity under stress, involving in the stress-induced analgesia. A key hormonal system of adaptation under stress is the hypothalamic pituitary-adrenocortical (HPA) axis. HPA axis's hormones, corticotropin-releasing factor (CRF) and glucocorticoids, are involved in stress-induced analgesia. Exogenous hormones of the HPA axis, similarly to the hormones produced under stress, may cause an analgesic effect. CRF-induced analgesia may be provided by glucocorticoid hormones. CRF and glucocorticoids-induced effects on somatic pain sensitivity may be mediated by PAGM. The aim of the review was to analyze the data of literature on the role of PAGM in the regulation of somatic pain sensitivity under stress and in providing of CRF and glucocorticoid-induced analgesia. PMID- 26506641 TI - [The Connectomics: Neurophysiology, Achievements and Perspectives]. AB - The review is devoted to researches in the relatively new field of neuroscience- connectomics. The theoretical and applied aspects of connectom studying are observed. The concept of connectom is defined as well as its attributes such as connectivity. The review describes the basic modern methods of the connectom investigation, existing data on the connectom structure in normal and pathological conditions, as well as prospects for the development of a new field of knowledge--connectomics. PMID- 26506642 TI - [Gaba and its Receptors in Pathogenesis of Epilepsy]. AB - This review presents summarizes data on the structural and functional organization of the GABAergic system of the brain, mechanisms of GABAergic transmission, about the characteristics of GABA-receptors and GABAergic inhibition forms. Reviewed issues of involvement of GABA inhibitory neurotransmitter and various types of GABA-receptors in epileptogenesis. The experimental and clinical data testifying to an important role of GABA and its receptors in an epileptogenesis are presented. PMID- 26506643 TI - [The role of the Basal Ganglia in Creating Receptive Fields in the Primary Auditory Cortex and Mechanisms of their Plasticity]. AB - We suggest a mechanism for creating receptive fields of neurons in the primary auditory cortex (A1) and ventral part of the medial geniculate body (MGBv) in which the "direct" pathway through the basal ganglia participates. Dopamine released in the striatum in response to appearance of a sound tone promotes the induction of LTP of the efficacy of "strong" inputs and LTD of "weak" inputs from A1 to striatonigral cells due to activation of D1 receptors on these cells. Subsequent reorganization of neuronal activity in the network A1 field--basal ganglia--MGBv--A1 field results in a disinhibition of MGBv neuron activity, contrasting amplification of neural representation of a sound tone in MGBv and A1 field, and sharpening the receptive fields. Plastic shift of neuronal receptive fields is based on modification of efficacy of synaptic transmissions between the neocortex and striatum, and between all units of thalamocortical loop. Synaptic modification could be promoted by synchronization of activity of neurons which is based on the high-frequency oscillations relying on interdependent functioning of inhibitory cells in the considered loops. PMID- 26506644 TI - [A Role of the Basal Ganglia in Processing of Complex Sounds and Auditory Attention]. AB - A hypothetical mechanism is suggested for processing of complex sounds and auditory attention in parallel neuronal loops including various auditory cortical areas connected with parts of the medial geniculate body, inferior colliculus and basal ganglia. Release of dopamine in the striatum promotes bidirectional modulation of strong and weak inputs from the neocortex to striatal neurons giving rise to direct and indirect pathways through the basal ganglia. Subsequent synergistic disinhibition of one and inhibition of other groups of thalamic neurons by the basal ganglia result in the creation of contrasted neuronal representations of properties of auditory stimuli in related cortical areas. Contrasting is strengthened due to a simultaneous disinhibition of pedunculopontine nucleus and action at muscarine receptors on neurons in the medial geniculate body. It follows from this mechanism that involuntary attention to sound tone can enhance an early component of the responses of neurons in the primary auditory cortical area (50 msec) in the absence of dopamine due to a disinhibition of thalamic neurons via the direct pathway through the basal ganglia, whereas voluntary attention to complex sounds can enhance only those components of responses of neurones in secondary auditory cortical areas which latencies exceeds latencies of dopaminergic cells (i.e. after 100 msec). Various consequences of proposed mechanism are in agreement with known experimental data. PMID- 26506645 TI - Identification and Bioinformatics Analyses of the Basic Helix-loop-helix Transcription Factors in Xenopus laevis. AB - Xenopus laevis is a long established model organism for developmental, behavioral and neurological studies. Herein, an updated genome-wide survey was conducted using the ongoing genome project of Xenopus laevis and 106 non-redundant Basic Helix-Loop-Helix (bHLH) genes were identified in the Xenopus laevis genome databases. Gene Ontology (GO) enrichment statistics showed 51 significant GO annotations of biological processes and molecular functions and 5 significant KEGG pathways and a number of Xenopus laevis bHLH genes play significant role in specific development or special physiology processes like the development processes of muscle and eye and other organs. Furthermore, each sub-group of the bHLH family has its special gene functions except for the common GO term categories. Molecular phylogenetic analyses revealed that among these identified bHLH proteins, 105 sequences could classified into 39 families with 46, 25, 10, 5, 16 and 3 members in the corresponding high-order groups A, B, C, D, E and F, respectively with an addition bHLH member categorized as an orphan. The present study provides much useful information for further researches on Xenopus laevis. PMID- 26506646 TI - Comparative Study of the Antibacterial Activity of N, N-Diethylamido Substituted p-Toluenesulfonamides to their alpha-Toluenesulfonamide Counterparts. AB - Reaction of p-toluenesulfonyl chloride with amino acids gave sulfonamides p-T1a-k which upon amidation afforded p-T2a-k. Similarly, treatment involving alpha toluenesulfonyl chloride and amino acids afforded the sulfonamides alpha-T1a-k. These two classes of sulfonamides were synthetically modified at their COOH end position to achieve N,N-diethylamido substituted p-toluenesulfonamides p-T2a-k and alpha-toluenesulfonamides alpha-T2a-k, respectively. The chemical structures of the compounds were validated with IR, Mass spectra, NMR as well as elemental analytical data. Both classes of compounds were screened against Escherichia coli and Staphylococcus aureus and their activity werecompared. It was remarkable to note that the alpha-toluene sulfonamides alpha-T2a-k were more active than their p-toluenesulfonamide counterparts p-T2a-k. Compound 1-(benzylsulfonyl)-N,N diethylpyrrolidine-2-carboxamide alpha-T2a was the most potent antibacterial compound on S. aureus with MIC value of 3.12 MUg mL(-1) while N,N-Diethyl-3 phenyl-2-(phenylmethylsulfonamide) propanamide alpha-T2j emerged as the best antibacterial motif against E. coli with MIC value of 12.5 MUg mL(-1). Hence, these compounds especially the alpha-toluenesulfonamide core structural templates are good candidates for further study for future drug discovery. PMID- 26506647 TI - Effects of Artificial Shelter and Chitosan on Growth Performance of Freshwater Prawn (Macrobrachium lanchesteri de Man, 1911). AB - Two experiments were carried out at the Department of Fisheries, Khon Kaen University, Khon Kaen, Thailand during September 2013 to February 2014 aiming to pursue both the better growth performance and survival rate of the freshwater prawns (Macrobrachium lanchesteri) where a Completely Randomized Design (CRD) with three replications was used for each experiment. For experiment 1, different percentages of grass shelter were used, i.e. 0% (Control, T1), 25% (T2), 50% (T3) and 75% (T4). For experiment 2, different percentages of commercial chitosan were used, i.e. 0% (Control, T1), 25% (T2), 50% (T3) and 75% (T4). Both experiments were carried out at the same time and each of them was lasted for 75 days. The results showed that the added grass shelter gave significantly higher Total Weight (TW) and Survival Rate (SR) than the control treatment. However, there were no significant differences found on TW and SR among the added grass shelter treatments (T2 up to T4). Chitosan gave significantly higher TW, AW and Number of Molting (NM) than the control treatment. There were no significant differences on TW, NM and AW found amongst the chitosan treatments. The results of the experiment 1 showed that the best rate of grass shelter for the culturing of the Macrobrachium lanchesteri was at a rate of 25% (T 2) and the best rate of the chitosan was at a rate of 4% (Diet 3) for the Experiment 2. PMID- 26506648 TI - Studies on the Occurrence, Identification and Control of House Dust Mites at Rural Houses of Shebin El-Kom Locality, Egypt. AB - The present study was conducted at Elkom Elakhdar village, Shebin El-Kom, Menoufia Governorate along 2012 year seasons, to calculate and identify the species composition and the occurrence frequency of the extracted dust mites collected from three building ages at rural houses, as well as to determine the toxicity limits of different concentrations of three plant essential oils against two species of the family Pyroglyphidae the main causal of allergy to humans. The obtained results revealed that there were eleven mite species belong to five families (Pyroglyphidae, Chortoglyphidae, Glycyphagidae, Acaridae and Cheyletidae). Of the total collected mites (5276) the highest dominant percentage species was the dust mites: Dermatophagoides farinae (66.1%), followed by D. pteronyssinus (23.3%), while the percentages of the rest species: Chortoglyphus arcuatus, Lepidoglyphus destructor, Glycyphagus domesticus, Gohieria fusca, Tyrophagusputrescentiae, Caloglyphus sp, Cheyletus malaccensis, Blomia sp. and Acarus siro were ranged between 0.16-2.0%. Regarding to the effect of temperature degrees on mite population, high degrees more than 25 degrees C at summer season, decreased the numbers of D. farinae and D. pteronyssinus. Toxicological tests of the three plant essential oils against adult stages of D. farinae and D. pteronyssinus showed that lemon grass oil gave the highest toxicity effect, in comparison with geranium and thyme oils, where mortality percentages were approximately around 100% at 800 ppm concentration on both species. The LC50 of lemon grass were 228.992 and 293.615 ppm against the two species, respectively. From the results of the research, it could be recommend that it is preferable to apply control operation during summer season where the mite population density is the least, moreover, the botanical oil extracts effectively controlled the parasitic dust mites, D. farinae and D. pteronyssinus and can be used in the biological control programs, as well as, it can play effective role in the integrated management programs. PMID- 26506649 TI - Sugarcane White Leaf Disease Incidences and Population Dynamic of Leafhopper Insect Vectors in Sugarcane Plantations in Northeast Thailand. AB - The work consisted of two experiments, i.e. Experiment 1 was conducted under controlled environments where sugarcane plants were used as hosts. This investigation aimed to monitor the occurrence of the Sugarcane White Leaf disease and the abundance of Leafhopper insect vectors and also the work aimed to provide useful information in understanding some aspects on epidemiology of the Sugarcane White Leaf disease. A Completely Randomized Design with three replications was used to justify growth and development of Leafhopper insects as affected by different temperatures: 20 (T1), 25 (T2), 30 (T3) and 35 degrees C (T4). Experiment 2 was carried out to determine the numbers of Leafhopper insects with the use of light traps in the sugarcane Field 1 (ratoon plants), Field 2 (newly planted), Field 3 (newly planted) and Field 4 (ratoon plants). The results of Experiment 1 showed that growth and development of Leafhopper insects were highly affected by temperatures i.e. the higher the environmental temperature the faster the growth and development of the insects to reach its full adulthood. At 20 degrees C, Leafhopper insects took 12 days to lay eggs whereas at 25 degrees C the insects took only 6 days. Male reached its adulthood approximately 9 days earlier than female when cultured at 25 degrees C and became approximately one week at 30 degrees C or higher. The results of Experiment 2 showed that the majority of Leafhopper insects were found within the months of June and July for both newly planted and ratoon crops. A small amount was found in May and August with an exceptional case of Field 4 where the highest number of Leafhopper insects was found in April followed by June and July. For Sugarcane White Leaf disease, the disease was found in all months of the year except February for Fields 2 and 3. Newly planted sugarcane plants attained much smaller percentages of disease than those of the ratoon plants. PMID- 26506650 TI - Prevalence of Iron Deficiency Anaemia Among School Children in Kenitra, Northwest of Morocco. AB - Iron deficiency anaemia is an important health problem in Morocco. This study was conducted to estimate the prevalence of anaemia among school children in Kenitra. The sample represents school children of all educational levels and age ranged between 6-15 years. The level of hemoglobin, haematocrit, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration was measured in a group of 271 school children. The seric iron was assessed and anaemia was defined when hemoglobin < 11.5 g dL(-1). A questionnaire was developed to obtain information about the daily food consumption and socio economic conditions. The prevalence of anaemia was 16.2%. The mean hemoglobin concentration was 12.53 g dL(-1) in boys and 12.52 g dL(-1) in girls. The results suggest that iron deficiency is an important determinant of anaemia in this population. There was a significant relationship between education of the mother and anaemia in children (p = 0.004) but not with the family income. It is concluded that improving the economic status of the family, women education and health education about balanced animal and plant food consumption are recommended strategies to reduce the burden of anaemia. PMID- 26506651 TI - Effect of Palm Pollen on Sperm Parameters of Infertile Man. AB - There is a rapidly growing trend in the consumption of herbal remedies in the developing countries. The aim of this study was to determine the effects of orally administered Date Palm Pollen (DPP) on the results of semen analysis in adult infertile men. Forty infertile men participated in our study. They were treated by Pollen powder 120 mg kg(-1) in gelatinous capsules every other day, for two months. Before and at the end of therapy, the semen was collected after masturbation and sperm numbers, motility and morphology were determined. Our findings revealed that consumption of DPP improved the sperm count. The treatment was significantly increased sperm motility, morphology and forward progressive motility. Date palm pollen seems to cure male infertility by improving the quality of sperm parameters. PMID- 26506652 TI - Growth Pattern for Body Weight, Height at Withers and Body Length of Kalahari Red Goats. AB - The objective of this research was to examine the growth pattern for body weight, body length and height at withers of Kalahari Red goats using non-linear models. The body size measurement data were collected from 227 Kalahari Red female goats and fit into Gompertz and Brody growth model. The results revealed that Gompertz growth model had the best goodness of fit to describe the growth of Kalahari Red goats for body weight, body length and height at withers as shown by higher coefficient of determination (97.9, 98.9 and 99.1, respectively). The correlation coefficients between A and k for body weight, body length and height at withers were negative in both models, implying that goats of larger mature size tended to have a slower growth rate in relation to their mature size. Height at withers body weight has the highest correlation coefficient (0.96). PMID- 26506653 TI - Assessing the Impact of Sexuality and HIV/AIDS Education in Africa. PMID- 26506654 TI - Managing Endometriosis in Sub-Saharan Africa: Emerging Concepts and New Techniques. PMID- 26506655 TI - Explaining the Rapid Increase in Nigeria's Sex Ratio at Birth: Factors and Implications. AB - This paper examines the rapid increase in Nigeria's sex ratio at birth from 1.03 boys born for every 1 girl born in each year from 1996-2008 to 1.06 in each year from 2009-2014, second only to Tunisia in Africa at 1.07. The average sex ratio at birth in the world in 2014 was 1.07. In most Black African nations or Black majority nations, it is 1.03 or less. Among the factors presented for this development are: historical fluctuations of sex ratio at birth; geography and ethnicity; male preference/chasing a son; Age of parents; high death rates of male infants and males in general; and wealth/socioeconomic status. Among the potential implications are: young and poor men in Nigeria may not be able to find brides and form families due to a potential shortage of females; emigration of young and poor Nigerian men to West (Africa) and elsewhere to seek brides and form families; immigration of marriage age women from West (Africa) and around the world to Nigeria to seek husbands; and low contraceptive use and high fertility rates in Nigeria. PMID- 26506656 TI - Decision-Making for Induced Abortion in the Accra Metropolis, Ghana. AB - Decision-making for induced abortion can be influenced by various circumstances including those surrounding onset of a pregnancy. There are various dimensions to induced abortion decision-making among women who had an elective induced abortion in a cosmopolitan urban setting in Ghana, which this paper examined. A cross sectional mixed method study was conducted between January and December 2011 with 401 women who had undergone an abortion procedure in the preceding 12 months. Whereas the quantitative data were analysed with descriptive statistics, thematic analysis was applied to the qualitative data. The study found that women of various profiles have different reasons for undergoing abortion. Women considered the circumstances surrounding onset of pregnancy, person responsible for the pregnancy, gestational age at decision to terminate, and social, economic and medical considerations. Pressures from partners, career progression and reproductive intentions of women reinforced these reasons. First time pregnancies were mostly aborted regardless of gestational ages and partners' consent. Policies and programmes targeted at safe abortion care are needed to guide informed decisions on induced abortions. PMID- 26506657 TI - Who Cares? Pre and Post Abortion Experiences among Young Females in Cape Coast Metropolis, Ghana. AB - Issues of abortion are critical in Ghana largely due to its consequences on sexual and reproductive health. The negative perception society attaches to it makes it difficult for young females to access services and share their experiences. This paper examines the pre and post abortion experiences of young females; a subject scarcely researched in the country. Twenty-one clients of Planned Parenthood Association of Ghana (PPAG) clinic at Cape Coast were interviewed. Guided by the biopsychosocial model, the study revealed that fear of societal stigma, shame, and rejection by partners, as well as self-imposed stigma constituted some of the pre and post abortion experiences the respondents. Other experiences reported were bleeding, severe abdominal pain and psychological pain. The Ghana Health Services (GHS) and other service providers should partner the PPAG clinic to integrate psychosocial treatment in its abortion services while intensifying behaviour change communication and community-based stigma-reduction education in the Metropolis. PMID- 26506658 TI - Maternal Near-Miss Due to Unsafe Abortion and Associated Short-Term Health and Socio-Economic Consequences in Nigeria. AB - Little is known about maternal near-miss (MNM) due to unsafe abortion in Nigeria. We used the WHO criteria to identify near-miss events and the proportion due to unsafe abortion among women of childbearing age in eight large secondary and tertiary hospitals across the six geo-political zones. We also explored the characteristics of women with these events, delays in seeking care and the short term socioeconomic and health impacts on women and their families. Between July 2011 and January 2012, 137 MNM cases were identified of which 13 or 9.5% were due to unsafe abortions. Severe bleeding, pain and fever were the most common immediate abortion complications. On average, treatment of MNM due to abortion costs six times more than induced abortion procedures. Unsafe abortion and delays in care seeking are important contributors to MNM. Programs to prevent unsafe abortion and delays in seeking postabortion care are urgently needed to reduce abortion related MNM in Nigeria. PMID- 26506659 TI - Implementation of Family Life and HIV/AIDS Education in Nigerian Schools: A Qualitative Study on Scope, Delivery and Challenges . AB - This study utilized data from Focus Group Discussions and In-depth Interviews among secondary school students and teachers to examine the scope, delivery and challenges of FLHE implementation within states and across geopolitical zones in Nigeria. Structural Functionalism, Rational Choice and Differential Association theories were adopted as theoretical framework. Results show that several patterns in classroom teaching of FLHE are identifiable across the country. The study found that FLHE is taught at the Junior Secondary and Senior Secondary levels with variations among States on the beginning levels. The main mode of FLHE delivery is classroom instruction; other modes include assembly talk and sensitization by organizations. Despite paucity of Information, Education and Communication materials and inadequate personnel requirement, different stakeholders noted that FLHE has been beneficial to students. Therefore, effective implementation of FLHE will go a long way to ensuring that young people in Nigeria are equipped with necessary information to enable them exhibit the right attitude and behaviour towards sexuality issues. PMID- 26506660 TI - Evaluation of the Implementation of Family Life and HIV Education Programme in Nigeria. AB - Family Life and HIV Education (FLHE) programme was introduced nationwide in Nigeria in 2003. Since then little is known about the patterns of its implementation across the states in the six geo-political zones in Nigeria. This study represents an attempt to fill this lacuna in the FLHE literature in Nigeria. Quantitative data was collected from the Federal Ministry of Education and the State Ministries of Education on all salient aspects of FLHE implementation. The findings from data collected in 35 states and the Abuja Federal Capital Territory show large variations in the year of adoption of the programme, level of implementation of the programme, the proportion of implementing schools that are reporting to the coordinating government ministries/agencies, the level to which schools have been supplied with relevant curriculum, and promptness of distribution of materials across the zones. All these indices did not show significant level of interdependence. In general, there were higher levels of FLHE activities in the South than the North. Several problems affect implementation of FLHE in Nigeria, most of which will require increased financial and technical support from government and other organizations. The FLHE programme has had positive effects in the states and among schools where the implementation has been effective, underscoring the need for a more effective implementation of the programmes throughout the country. PMID- 26506661 TI - Proportion and Factors Associated with late Antenatal Care Booking among Pregnant Mothers in Gondar Town, North West Ethiopia. AB - The proportion of pregnant women initiating prenatal care during first trimester pregnancy is one of the standard clinical performance measures to assess the quality of maternal health care. Aiming to assess the proportion and factors associated with late booking at antenatal care, this health-institution based cross-sectional study was conducted from April to June 2012 among 390 pregnant mothers in Gondar town. The proportion of late entry to antenatal care was 64.9% with the mean time being 4.5 +/- 1.8 months of pregnancy. Multiple logistic regression analysis showed that respondents who didn't get information on correct time of booking, perceived the right time of booking beyond 12 weeks of pregnancy, were not autonomous to use antenatal care and recognized their pregnancy by missing periods were more likely to book late. Late booking was high in the study area. Empowering women and providing information, education and communication with emphasis on timely booking is important. PMID- 26506662 TI - Strengthening Health Systems to Accelerate Achievement of Millennium Development Goals 4 and 5: A Case Study of Ketu South and Keta Municipalities in Ghana. AB - This study aims to determine means of strengthening the health system to accelerate achievement of MDGs 4 and 5 in the Volta Region of Ghana, with a particular emphasis in the Ketu South and Keta municipalities. Secondary data have been used in this study. High maternal and infant mortality is a crucial issue in Ghana. Maternal and infant mortality is high in rural area compared to urban area due to unavailability of the service facilities. A community based health planning and services programs have been established to improve access and quality of health care in Ghana. Our study suggests that health system strengthening with community health care programs improved access to quality health care and resulted in a decrease of maternal and child mortality in Ketu South and Keta Municipalities in Ghana. PMID- 26506663 TI - HIV Status Discordance: Associated Factors Among HIV Positive Pregnant Women in Lagos, Southwest Nigeria. AB - The HIV negative partner in a HIV serodiscordant relationship is at high risk of becoming HIV infected. The annual risk of HIV infection for a partner of a person with HIV is about 10%, with higher annual transmission rates of 20-25% per year reported in Rwanda and Zambia. Although there is considerable variation across countries, recent studies in southern and east Africa countries with mature epidemics reported that up to two-thirds of infected persons in stable relationship are discordant. HIV serodiscordance is thus a recognized priority for HIV prevention intervention. In Nigeria only few studies have studied the burden of serodiscordance, making planning difficult. In this study HIV serodiscordance rate and associated factors among pregnant women were assessed in a large PMTCT clinic in Lagos Nigeria over a 9 years period. Information on HIV status disclosure, partners HIV status (confirmed by HIV test results), sociodemographic characteristics and reproductive information were obtained from the women after enrollment and entered into the case file. In the study, relevant information was managed with SPSS for windows version 19.0. The variables independently associated with HIV status discordance were determined in both univariate and multivariate analysis. P values and Odd ratio with their confidence intervals were calculated. Out of the 4435 women enrolled during the study period, 3712 (83.7%) had disclosed their status to their partner. Partner's HIV status among the women with confirmed HIV status was negative in 2065 (66.8%) women, thus a discordant rate of 66.8%. HIV status disclosure rate was 83.7%; with significantly higher disclosure rate in concordant couple (83.3%) compared to 76.8% among women in serodiscordant relationship (p = 0.00; OR: 1.5; 95% CI: 1.25-1.82). Discordant HIV status in a female positive relationship was found to be associated with history of at least two termination of pregnancy (OR: 3.05; 95% CI: 2.91-3.89) and five or more total life time sexual partnership (OR: 2.3; 95% CI: 1.27-3.21). The perception that men are the index cases is not supported by evidence from this study. We recommend the tracking of both men and women as index cases in other to reduce HIV transmission within stable relationship. Social marketing aimed at reducing concurrency should focus on both male and females, if we must reduce new HIV infection within stable relationships. PMID- 26506664 TI - Is Male Involvement in ANC and PMTCT Associated with Increased Facility-Based Obstetric Delivery in Pregnant Women? AB - Ensuring that pregnant women are delivering in a health facility and are attended to by skilled birth attendants is critical to reducing maternal and infant morbidity and mortality. This study sought to determine the associations between male involvement in antenatal care (ANC) services and pregnant women delivering at health facilities and being attended to by skilled birth attendants as well as attending postnatal care. This was a retrospective cohort study using secondary analysis of program data. We reviewed health records of all pregnant women who attended antenatal services irrespective of HIV status between March and December 2012 in 10 health facilities in three provinces of Zambia. An extraction questionnaire was used to collect sociodemographic and clinical information from registers used in services for maternal neonatal child health as well as delivery. Using logistic regression, we calculated the odds ratios (OR) and 95% confidence intervals (CI) of the association between (1) male involvement and delivery at a health facility by a skilled birth attendant and (2) male involvement and women's attendance at postnatal services. We found that more women who had been accompanied by their male partner during ANC delivered at a health facility than those who had not been accompanied (88/220 = 40% vs. 543/1787 = 30.4%, respectively; OR 1.53, 95% CI: 1.15-2.04). Also, we noted that a greater proportion of the women who returned for postnatal visits had been accompanied by their partner at ANC visits, compared to those women who came to ANC without their partner (106/220 = 48.2% vs. 661/1787 = 37.0%, respectively; OR 1.58, 95% CI: 1.20-2.10). Male involvement seems to be a key factor in women's health-seeking behaviours and could have a positive impact on maternal and infant morbidity and mortality. PMID- 26506665 TI - Fertility Preferences of Women Living with HIV in the Kumasi Metropolis, Ghana. AB - This study sought to determine fertility preferences and their predictors among women living with HIV. A survey of 295 women aged 18 to 49 years living with HIV, and attending two HIV/AIDS clinics in the Kumasi metropolis, was conducted between July and August 2012. We administered questionnaires, and retrieved records of clinical status for review. We conducted multiple logistic regressions with fertility preference as the dependent variable. Fifty-eight percent of the respondents desired to have a child. The desire to have children was associated with age >= 40 years (AOR 0.25; 95% CI: 0.06-1.00), parity > 3 (AOR 0.07; 95% CL: 0.01-0.78), those that responded that their HIV status did not affect fertility preference were more likely to desire a child (AOR 4.37; 95% CI: 1.28-14.95) and those whose partner's did not desire to have children were less likely to desire to have children (AOR 0.06; 95% CI: 0.02-0.18). Most of the respondents do not discuss their fertility preferences with healthcare providers. Policy makers should protect the health of women living with HIV by putting in place counselling and support services with regular antiretroviral medications. If implemented, this has the potential to reduce mother-to-child transmission of HIV. PMID- 26506666 TI - Urinary Tract Infection In Young Healthy Women Following Heterosexual Anal Intercourse: Case Reports. AB - Urinary tract infections (UTIs) are among the most common bacterial infections in outpatient clinical settings globally. Young healthy women are at highest risk of community-acquired UTI. While uncomplicated UTI is not life-threatening, it is associated with high morbidity and treatment costs. The pathogenesis of urinary tract infection in young healthy women is complex. It is influenced by a number of host biological and behavioural factors and virulence of the uropathogen. The infecting uropathogens in community-acquired UTI originate from the fecal flora, E. coli being the most predominant, accounting for 80-90% of these UTIs. Vaginal colonization with uropathogens, a pre-requisite for bladder infection may be facilitated by sexual intercourse, which has been shown to be a strong risk factor and predictor of UTI. While majority of studies have explored the association between heterosexual vaginal intercourse and UTI in healthy young women, the possible association with heterosexual receptive anal intercourse has not received adequate attention despite evidence of high prevalence globally. This paper presents two young healthy married women who had severe UTI following heterosexual anal intercourse and discusses possible association thereof. Understanding the risk factors for UTI and identification of possible predisposing conditions in a particular individual are important in guiding therapeutic approaches and preventive strategies. Cognisant of reportedly high prevalence of various sexual practices including receptive heterosexual anal intercourse and their impact on individuals' health, details on sexual history should always be enquired into in young women presenting with genito-urinary complaints. PMID- 26506667 TI - A systematic review of lung function testing in asthmatic young children. AB - Asthma diagnosis is difficult in young children being mainly based on clinical signs and parents' history, which is sometimes difficult to obtain. Lung function testing may improve asthma diagnosis by objectively assessing its main features, airway obstruction, spontaneously reversible or after use of a bronchodilator drug, ventilation inhomogeneity during an acute bronchoconstriction and airway hyperresponsiveness. In young children that cannot cope with classical tests, it is important to use and develop simple, short lasting methods, made in spontaneous ventilation without active cooperation. Such techniques are a measurement of respiratory resistance by forced oscillations or the interrupter technique, of specific airway resistance by plethysmography and capnography. All these parameters are sensitive to the presence of an airway obstruction and to a bronchodilator or bronchoconstrictor agent, but their cutoff values in differentiating between asthmatic and healthy children as well as their specific indications in asthma management remain to be established. PMID- 26506668 TI - Paraneoplastic syndromes: the way to an early diagnosis of lung cancer. AB - Pulmonary malignancies are the leading cause of cancer mortality around the world. The late diagnosis of lung cancer, in advanced stages, is mainly due to atypical clinical presentation. Paraneoplastic syndromes have been first described in 1825, as a group of symptoms related to a malignant disease, which are not the effect of the primary neither of the metastatic tumor. The paraneoplastic syndromes have been reported in all types of lung cancer, but more frequently in small cell lung cancer, due to its origin in neuroendocrine cell precursors. The most frequent associated syndromes described in the literature are neurological and endocrine. In most patients paraneoplastic syndromes occur prior to other symptoms of malignancy. The presence or the severity of these syndromes is not correlated with the stage of cancer. Most of the paraneoplastic syndromes disappear once the primary tumor is removed and reappear in case of cancer recurrence or metastasis. This paper is a review of paraneoplastic syndromes in lung cancer. PMID- 26506669 TI - Pulmonary metastasectomy--general issues. AB - Pulmonary metastasectomy has been widely accepted by thoracic surgeons and is applied to the treatment of a variety of histologies, but the evidence that the patient may benefit from lung metastasectomy is not yet elucidated and the best way of integrating oncologic therapies (induction or adjuvant chemotherapy or radiotherapy) with surgical resection are still unknown. When there is no good clinical alternative, the resection of pulmonary metastases can give some patients long-lasting disease free intervals. Patients should be carefully selected on the basis of clinical staging with defined prognostic indicators. In order to obtain suitable results the management of these patients should be based on a multidisciplinary team decision. PMID- 26506670 TI - Endobronchial ultrasound EBUS--a new method for the diagnosis and staging of lung cancer. AB - In this paper we present a new method, endobronchial ultrasound (EBUS), which appeared recently among the tools of the pulmonologist for the diagnosis and staging of lung cancer. Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) provides the opportunity for obtaining tissue samples required for the histologic and cytologic diagnosis of lung cancer. The advantages of EBUS have to be made popular as it is a minimally invasive method, safe, simple, fast, also with a superior cost/benefit ratio compared to any previously used methods. PMID- 26506671 TI - The concordance between phenotypic and genotypic M. tuberculosis drug susceptibility tests results: observational study. AB - Multi-drug resistant tuberculosis (MDR-TB) represents a major threat for TB control at the global level. Identification of mutations responsible for drug resistance by molecular methods can be used for rapid and specific detection of drug resistance. The aim of our study was to assess the concordance between phenotypic and genotypic tests results (GenoTypeMTBDRplus kit) for isoniazid and rifampicin resistance in M. tuberculosis isolated strains. MATERIAL AND METHODS: The specific zone mutations in rpoB, katG and inhA gene for rifampicin and isoniazid were investigated with molecular methods in 198 recently isolated unique strains from patients diagnosed with pulmonary tuberculosis. These results were compared with the absolute concentration drug susceptibility test results. RESULTS: Sensitivity, specificity, predictive positive value, predictive negative value, efficiency of genotypic method, calculated by comparing with conventional method for INH and RMP were 93.85%, 100.00%, 100.00%, 63.33%, 94.44%, and 99.26%, 82.25%, 92.46%, 98.07% and 93.93%, respectively). Cohen coefficient showed Kappa values = 0.746 (good strength of agreement) for INH, and Kappa value = 0.853 (very good strength of agreement) for RMP. CONCLUSION: The obtained results are consistent with those reported from other regions of the world. The use of rapid molecular assays reduces the time for drug resistance diagnostic to just a few days, and may help the control of the ongoing TB transmission. PMID- 26506672 TI - Non-invasive ventilation for the treatment of acute respiratory failure following ovarian hyperstimulation syndrome: report of two cases and a brief review of the literature. AB - The ovarian hyperstimulation syndrome (OHSS) is a serious but rarely fatal complication of medical interventions that seek to induce fertility; it is typically encountered in women who undergo controlled ovarian hyperstimulation, but there are very rare patients who have genetic defects who present with OHSS. In recent years, its pathogenesis has been elucidated; this knowledge will decrease the frequency of this syndrome. Clinical signs may include any or all of the following: rapid weight gain, ascites, oliguria, hemoconcentration, leukocytosis, along with intravascular hypovolemia, hyponatremia, and hyperkalemia. If the patient is not diagnosed early, ascites, pleural and more rarely pericardial effusions, severe respiratory failure and ARDS, hypercoagulability with tromboembolism and multiple organ system failure can occur. Due to the increased use of therapeutic strategies for infertility (particularly those using human chorionic gonadotropin), the systemic, particularly the pulmonary, complications of this syndrome must be identified early to allow appropriate diagnosis and management. We describe two cases of women with extremely severe OHSS presenting bilateral pleural effusions, and severe respiratory failure (paO2/FiO2 < 200) treated with non-invasive ventilation (NIV). The severe form of OHSS varies between 0.5% and 5%, depending on the population studied: intensive care may be required for management of tromboembolic complications, renal failure and severe respiratory failure. The diagnosis of severe OHSS was made, largely based on bedside ultrasonography showing increased ovarian size, mild ascites and bilateral pleural effusions. Owing to severe respiratory failure the patients were admitted to Respiratory Intermediate Care. Pulmonary intensive care may involve thoracentesis, oxygen supplementation and in more severe cases assisted ventilation. There are only a few studies in English that describe severe respiratory failure treated with non invasive ventilation, but all of them have had good outcomes. PMID- 26506673 TI - Interstitial lung disease as first clinical manifestation within the antisynthetase syndrome--dermatomyositis. AB - Diffuse interstitial pneumopathies within the diseases of the connective tissue are often a diagnosis challenge, sometimes being the initial or dominant manifestation of the underlying autoimmune disease. The case of a young man shall be presented with relatively quick dyspnoea which has appeared under the conditions of an efficient physical status and without any notable pathological history. The cause of the dyspnoea is found to be a interstitial lung disease with radiological and histopathological pattern of non-specific interstitial pneumonia. The disease screening system discovers Ac anti Ro-52 which commits research in the direction of an autoimmune disease, confirmed by highlighting Ac anti PL-7 as being an antisynthetase syndrome. Subgroup of idiopathic inflammatory myopathies, the antisynthetase syndrome is a rare chronic autoimmune disease, which is characterised by the presence of antibodies directed against aminoacyl-t-RNA-synthetases (family of intracytoplasmic enzymes with a vital role in the protein synthesis). Shortly after specifying the relevant immunological status, the consistent clinical expression with dermatomyositis is also configured. The treatment is commenced with systemic corticoid and azathioprine; despite the treatment we are witnessing a slowly progressive clinical and functional deterioration. PMID- 26506674 TI - Synchronous primary lung cancer and controlateral pulmonary renal cell carcinoma metastases. AB - Synchronous malignant lesions will always entail treatment related difficulties which would ideally require discussions within a multidisciplinary committee in such a way as to reach the optimal solution for the patient. Presented herewith are two patients suffering from lung cancer and clear cell renal carcinoma contralateral metastases and the treatment alternatives that I have opted for. PMID- 26506676 TI - Motorcycle Helmets: The Economic Burden of an Incomplete Helmet Law to Medical Care in the State of Connecticut. AB - The lack of a mandatory motorcycle helmet law leads to increased injury severity and increased health care costs. This study presents a financial model to estimate how the lack of a mandatory helmet law impacts the cost of health care in the state of Connecticut. The average cost to treat a helmeted rider and a nonhelmeted rider was $3,112 and $5,746 respectively (cost adjusted for year 2014). The total hospital treatment cost in the state of Connecticut from 2003 through 2012 was $73,106,197, with $51,508,804 attributed to nonhelmeted riders and $21,597,393 attributed to helmeted riders. The total Medicaid cost to the state of Connecticut for treating nonhelmeted patients was $18,277,317. This model demonstrates that the lack of a mandatory helmet law increases overall health care costs to the state of Connecticut, and provides a framework by which hospital costs can be reduced to contribute to the economic stability of health care economics in the state. PMID- 26506675 TI - Pulmonary hypoplasia with associated cardiac and skeletal malformations. AB - Patients with mild pulmonary hypoplasia typically use to have minimal respiratory symptoms. Nonetheless, other associated anomalies such as cardiac, gastrointestinal, genitourinary, or skeletal defects may be seen. We report the case of a 17-year-old male patient with hypoplastic right lung with secondary cardiac dextroposition, an ostium secundum atrial septal defect, a hypoplastic right pulmonary artery arising from the posterior wall of the left pulmonary artery with a retrocava course, vertebral bone fusion and pollicization due to right congenital thumb absence. PMID- 26506677 TI - Factors Associated with the Transfer of Pediatric Patients with Supracondylar Humerus Fractures to a Level I Pediatric Trauma Center. AB - OBJECTIVE: To compare the characteristics of pediatric patients with supracondylar humerus fractures transferred to a level I pediatric trauma center to those who presented directly to our institution. METHODS: Retrospective chart review of patients with a supracondylar humerus fracture during a 42-month period (2008-2011) at a major level I pediatric trauma center were reviewed. Of 195 patients, 37 were transferred from outside hospitals. RESULTS: After multivariable analysis, it was determined that transferred patients were significantly more likely to present on the weekends (p = 0.003) and require operative treatment (p < 0.001) as compared to nontransferred patients. CONCLUSIONS: Injuries requiring operative treatment and presentation on a weekend were independent predictors of the transfer of pediatric patients with supracondylar humerus fractures. PMID- 26506678 TI - The Association Between Baseline Left Atrial Volume Index and All-Cause Mortality in Patients with Heart Failure: A Meta-Analysis. AB - BACKGROUND: Enlargement of the left atrium is a marker of mortality in the general population. Left atrial volume index (LAVI) has long been proposed as a measure of prognosis in patients with heart failure (HF). The aim of this meta analysis was to assess the utility of using baseline LAVI as an independent predictor of all-cause mortality in patients with HF. METHODS: A search of Medline and Embase bibliographic databases was performed to identify studies meeting the following inclusion criteria: 1) studies evaluating a cohort of patients with HF (both reduced and preserved ejection fraction); 2) studies conducting multivariate analysis or patient matching to determine the relationship between baseline LAVI measured by echocardiography and all-cause mortality; and 3) studies reporting data on the relationship between baseline LAVI (per difference in mL/m2) and all-cause mortality. Adjusted hazard ratios depicting the association between baseline LAVI and all-cause mortality were pooled using traditional random-effects meta-analysis. RESULTS: 1,188 publications were reviewed from which four studies were included in the present meta-analysis. We found each 10 mL/m2 increase in baseline LAVI was associated with a 22% increased adjusted hazard of all-cause mortality (95% confidence interval, 13% to 31%, I2 = 14%). CONCLUSION: Baseline LAVI is an important independent predictor of all-cause mortality in patients with heart failure and should be reported routinely in these patients undergoing echocardiography. PMID- 26506679 TI - Morel-Lavallee Lesion: A Case of an American Football Injury. AB - Morel-Lavallee Lesion (MLL) is a posttraumatic, closed degloving injury where the skin and superficial fascia get separated from deep fascia (fascialata) in the trochanteric region and upper thigh, hence creating a potential space. Similar lesions at other locations (e.g., abdominal wall and lumbar regions) have been described as Morel-Lavallee effusion, hematoma, or extravasation. Injury to an area with rich vascular and lymphatic supply leads to filling of this space with blood, lymph, fat, and necrotic debris. MLL usually presents as painful fluctuant swelling in the anterolateral portion o fthe upper thigh. Many of these maybe missed at initial evaluation and present weeks to months after the initial trauma. PMID- 26506680 TI - Focusing on Patient Safety: the Challenge of Securely Sharing Electronic Medical Records in Complex Care Continuums. AB - The Patient Protection and Affordable Care Act's (PPACA) regulated approach to inclusive provision of care will increase the challenge health care administrators face ensuring secure communication and secure sharing of electronic medical records between divisions and care subcontractors. This analysis includes a summary overview of the PPACA; the Health Care and Education Reconciliation Act (HCERA) of 2010; and required Essential Health Benefits (EHB). The analysis integrates an overview of how secure communication and secure sharing of electronic medical records will be essential to clinical outcomes across complex care continuums; as well as the actionable strategies health care leadership can employ to overcome associated IT security challenges. PMID- 26506681 TI - Dosing Medications in Obese Patients. PMID- 26506682 TI - Can a Quality Collaborative Build Value in Global Surgery? Results From a Single State Experience. AB - BACKGROUND: Surgery is a critical component of global health care worldwide. Little is known about global surgery participation among surgeons in Connecticut. The goal of this pilot survey project was to determine the breadth of global surgery experience in our state. STUDY DESIGN: An electronic survey was distributed to surgeons in the state of Connecticut via the Connecticut Chapter of the American College of Surgeons (CTACS) and to departments of surgery throughout the state. RESULTS: Seventy-four surgeons and surgical residents completed the online survey from 17 different hospitals. Nineteen (25.7%) of the respondents had participated in global surgery. Most participated in yearly (56.3%), short-term experiences (94.5%). Nearly half of this group reported no formal record of outcomes (52.9%), but 17/19 (89.5%) respondents reported that accurate outcomes measures are beneficial to surgical care in resource-poor areas. Eighty-nine percent reported a willingness to participate in a surgical quality and outcomes database. CONCLUSION: A substantial proportion of surgeons in Connecticut participate in global surgery. Most surgeons value qualityin surgical care, yet outcomes are not routinely measured. This discordance may be addressed through the development of a quality improvement collaborative for global surgery. PMID- 26506683 TI - How the Military is Changing Civilian Medicine. PMID- 26506684 TI - Aid in Dying. PMID- 26506685 TI - Marijuana Patient Certification: Take Two Cookies and Call Me in the Morning. PMID- 26506687 TI - Why Not Connecticut? PMID- 26506688 TI - What Is This Word "No"? PMID- 26506690 TI - Pain, peace and practitioner health. PMID- 26506691 TI - Good governance. PMID- 26506692 TI - Magdalen survivors. PMID- 26506693 TI - Substantial contribution dental hygienist-therapists could make to dental care. PMID- 26506694 TI - Physician, heal thyself. PMID- 26506695 TI - Quiz. PMID- 26506696 TI - A man for all seasons. PMID- 26506697 TI - An instrument of two parts. PMID- 26506698 TI - Tips to avoid instrument separation in endodontics. PMID- 26506699 TI - Does access to general dental treatment affect the number and complexity of patients presenting to the acute hospital service with severe dentofacial infections? AB - AIM: This is a retrospective study to review the treatment and management of patients presenting with odontogenic infections in a large urban teaching hospital over a four-year period, comparing the number and complexity of odontogenic infections presenting to an acute general hospital in two periods, as follows: Group A (January 2008 to March 2010) versus Group B (April 2010 to December 2011). The background to the study is 'An alteration in patient access to primary dental care instituted by the Department of Health in April 2010'. OBJECTIVES: a) to identify any alteration in the pattern and complexity of patients' presentation with odontogenic infections following recent changes in access to treatment via the Dental Treatment Services Scheme (DTSS) and the Dental Treatment Benefit Scheme (DTBS) in April 2010; and, b) to evaluate the management of severe odontogenic infections. METHOD: Data was collated by a combination of a comprehensive chart review and electronic patient record analysis based on the primary discharge diagnosis as recorded in the Hospital In Patient Enquiry (HIPE) system. RESULTS: Fifty patients were admitted to the National Maxillofacial Unit, St James's Hospital, under the oral and maxillofacial service over a four-year period, with an odontogenic infection as the primary diagnosis. There was an increased number of patients presenting with odontogenic infections during Group B of the study. These patients showed an increased complexity and severity of infection. Although there was an upward trend in the numbers and complexity of infections, this trending did not reach statistical significance. CONCLUSIONS: The primary cause of infection was dental caries in all patients. Dental caries is a preventable and treatable disease. Increased resources should be made available to support access to dental care, and thereby lessen the potential for the morbidity and mortality associated with serious odontogenic infections. The study at present continues as a prospective study. PMID- 26506700 TI - Fundamentals of occlusion and restorative dentistry. Part I: basic principles. AB - This article presents the basic principles of dental occlusion and an overview of this subject area, which is important for dental professionals. Clinical relevance: A sound knowledge of dental occlusion is important in order to improve dental treatment outcome and achieve a long-lasting restoration. PMID- 26506701 TI - Making a difference. PMID- 26506702 TI - [Applications of bone drilling techniques in spinal surgery]. PMID- 26506703 TI - [Influencing factors of adjacent superior segment facet joint violation after transpedicular screw instrumentation during transforanal lumbar interbody fusion]. AB - OBJECTIVE: To explore the influencing factors of pedicle screw instrumentation and provide theoretical rationales for decreasing facet joint violation rate by radiological evaluations of superior-segment facet joint violation after pedicle screw instrumentation in transforaminal lumbar interbody fusion (TLIF). METHODS: A retrospective study was conducted for 101 patients undergoing lumbar fusion after failed conservative treatment between December 2011 and December 2013. According to the Seo classification, computed tomography was used for evaluating the position of pedicle screw with superior segment facet joint. And chi2 test was used to examine the associations between superior segment facet joint violation and gender, age, construct level, fusion length and transpedicular screw side. RESULTS: A total of 202 screws were evaluated. There were grade 0 (n =154, 76.2%), grade 1 (n = 43, 21.3%) and grade 2 (n = 5, 2.5%). In all screws, facet joint violation occurred in L5 segment more frequently than in any other segment (P < 0.05), left-side facet joint violation was more common than right side one (P < 0.05). No statistical associations existed between violation rates and gender, age and fusion length. CONCLUSION: During TLIF, there is a higher incidence of facet joint violation at right side and in L5 segment compared with other lumbar segments. PMID- 26506704 TI - [Microsurgical resection of lumbar intraspinal tumors through paraspinal approach using percutaneous tubular retractor system]. AB - OBJECTIVE: To evaluate the clinical outcomes and operative techniques of microsurgical resection of lumbar intraspinal tumors through paraspinal approach by percutaneous tubular retractor system. METHODS: A retrospective study was conducted to analyze 21 patients with lumbar intraspinal tumors between November 2011 and February 2014, including Schwannoma (n = 19) and meningioma (n = 2) without lumbar instability on preoperative images. The length of tumors was 0.6 2.0 cm. Tracheal intubation anesthesia was performed prior to microsurgery using percutaneous tubular retractor system through paraspinal approach. Operative duration, blood loss volume, postoperative wound pain duration and hospital stay were analyzed. Creatine phosphokinase (CPK-MM) level was recorded at 1 day preoperatively, 1 day, 3 days and 5 days postoperatively. The scores of Japanese Orthopedic Association (JOA) and visual analog scale (VAS) were analyzed at 1 day preoperatively, 1, 3, 5 days and 6 months postoperatively to evaluate the function status of spinal cord. Computed tomography ( CT) three-dimensional reconstruction of lumbar vertebrae was performed at 1 week postoperatively. Magnetic resonance imaging ( MRI) plain scan and enhanced scan of lumbar vertebrae were conducted preoperatively, 1 week and 6 months postoperatively. RESULTS: Complete removal of tumors was achieved in all patients without the injuries of spinal cord or nerve root. Postoperative scores of JOA and VAS improved versus preoperative ones (P < 0.05). Level of CPK-MM increased 1 day postoperatively and declined to preoperative level at 5 days postoperatively. And th difference was not statistically significant (P < 0.05). Neither residual tumor nor tumor recurrence was detected by MRI plain and enhanced scans. No postoperative spinal instability was identified by CT three-dimensional reconstruction. And no spinal deformity occurred during a follow-up period of 6 28 months. CONCLUSION: Microsurgical resection of lumbar intraspinal tumors using percutaneous tubular retractor system through paraspinal approach minimizes the injuries of paraspinal muscles, facet joint, spinous process and ligaments. This technique offers the advantages of mini-invasiveness, shorter hospital stay, rapid recovery and preserved postoperative spinal stability. PMID- 26506705 TI - [Effects on single segmental lumbar stability after graded facetectomy and laminectomy: a finite element study]. AB - OBJECTIVE: To explore the effects on degenerative single segmental lumbar spinal stability after posterior graded laminectomy and facetectomy by a finite element method. METHODS: A finite element model of L3-S1 segments with a single segmental degeneration at L4-5 level was established. Different models of L4-L5 segmental instability after posterior graded laminectomy and facetectomy were established. And interior 1/3, 1/2, 2/3 of laminar and bilateral facet joints were resected. Physical loads were applied to the models and the changes of range of motion (ROM) at L4-5 level in different models were recorded during flexion, extension, lateral bending and rotation. RESULTS: As compared to preoperative model, after resecting 1/3 bilateral facet joints at L4-5 level, L4-5 segmental ROM increased 18% during flexion, 27% during extension and 45% during torsion. And the increased degree of ROM became more obvious along with a greater resection range of bilateral facet joints. No significant difference existed in L4-5 segmental ROM during lateral bending in all models. CONCLUSION: Facet joints play vital roles in lumbar segmental stability. And segmental instability may occur when 1/3 bilateral facet joints are resected. PMID- 26506706 TI - [Three-dimensional finite element modeling and biomechanical simulation for evaluating and improving postoperative internal instrumentation of neck-thoracic vertebral tumor en bloc resection]. AB - OBJECTIVE: To employ three-dimensional finite element modeling and biomechanical simulation for evaluating the stability and stress conduction of two postoperative internal fixed modeling-multilevel posterior instrumentation ( MPI) and MPI with anterior instrumentation (MPAI) with neck-thoracic vertebral tumor en bloc resection. METHODS: Mimics software and computed tomography (CT) images were used to establish the three-dimensional (3D) model of vertebrae C5-T2 and simulated the C7 en bloc vertebral resection for MPI and MPAI modeling. Then the statistics and images were transmitted into the ANSYS finite element system and 20N distribution load (simulating body weight) and applied 1 N . m torque on neutral point for simulating vertebral displacement and stress conduction and distribution of motion mode, i. e. flexion, extension, bending and rotating. RESULTS: With a better stability, the displacement of two adjacent vertebral bodies of MPI and MPAI modeling was less than that of complete vertebral modeling. No significant differences existed between each other. But as for stress shielding effect reduction, MPI was slightly better than MPAI. CONCLUSION: From biomechanical point of view, two internal instrumentations with neck thoracic tumor en bloc resection may achieve an excellent stability with no significant differences. But with better stress conduction, MPI is more advantageous in postoperative reconstruction. PMID- 26506707 TI - [Explorations of epileptic network with cortico-cortical evoked potential]. AB - OBJECTIVE: To evaluate the cortico-cortical evoked potential (CCEP) in exploring the network in epileptics. METHODS: Two patients with intractable epilepsy underwent chronic intracranial electrode placement. According to the distribution of icta onset zones and the functional brain mapping, alternating 1 Hz electrical stimuli were delivered to the target electrodes. And CCEPs were recorded by averaging electrocorticograms time-locked to stimuli from subdural electrodes. Then icta onset zones, eloquent areas identified by electrical cortical mapping and CCEP distributions were compared. RESULTS: Typical CCEP responses were observed. The data of one patient was useful for investigating the connectivity associated with various brain networks while another patient was useful for evaluating the cortical excitability. CONCLUSION: The exploration of epileptic network is achieved through cortico-cortical evoked potential by investigating the connectivity associated with various brain networks and cortical excitability. PMID- 26506708 TI - [Value of electroencephalography/functional magnetic resonance imaging localizing epileptic foci in focal epilepsy]. AB - OBJECTIVE: To explore the diagnostic value of simultaneous electroencephalography/ functional magnetic resonance imaging ( EEG-fMRI) for epileptic foci in focal epilepsy of normal brain structure. METHODS: The normal structural images of EEG-fMRI and resting state-fMRI (RS-fMRI) with 3. OT high field MR system were performed for 15 focal epileptic patients from April 2013 to July 2014. On EEG-fMRI, epileptiform discharges were regarded as nerve stimulation. And off-line analysis yielded the blood oxygen level-dependent (BOLD) responses related to epileptiform discharges. The relationship was analyzed between BOLD activation reaction and electroencephalography-clinical symptomatology position. And the electroencephalography-clinical symptomatology position was selected as a major indicator of judging the degree of concordance. RESULTS: The involved lobes were temporal (n = 7), frontal (n = 5) and frontotemporal (n = 3). On EEG-fMRI, all patients demonstrated BOLD responses related to epileptiform discharges. Compared with electroencephalography-clinical symptomatology position, 12 cases (12/15) were fully concordant and 3 cases (3/15) partially concordant. Three patients had BOLD responses in accordance with electroencephalography-clinical symptomatology position on RS-fMRI. And the detection rate of BOLD responses was higher for EEG-fMRI than that for RS-fMRI. CONCLUSION: The BOLD responses related to epileptiform discharges may help locate noninvasively the epileptogenic region of focal epilepsy and provide additional useful information for preoperative evaluations of epilepsy. PMID- 26506709 TI - [Treatment and pathological mechanism of multicentric glioma]. AB - OBJECTIVE: To explore the diagnosis and treatment of multicentric glioma and discuss its underlying pathological mechanism. METHODS: The clinical cases of multicentric glioma at our department were prospectively collected from January 2012 to December 2014. A total of 62 cases, along with the literally reported cases with relative complete data, were studied with Kaplan-Meier and COX regression to identify the prognostic factors of disease. RESULTS: The median age was 55.3 +/- 14.3 (11-78) years. The ratio of male-to-female was 1. 27. There were synchronous (n = 48) and multichronous (n = 13) multicentric gliomas. The median survival time was 8 months and 7 months if calculated from the appearance of new tumor. Kaplan-Meier analysis revealed that the survival time was correlated with age, resection of tumor, radiotherapy and chemotherapy. And COX regression analysis indicated that only resection of tumor (s) and chemotherapy were independently correlated with the prognosis of multicentric glioma. Conclusion Multicentric glioma is mainly of high-grade glioma with a very poor prognosis. Total resection and standard chemotherapy yield a better prognosis. Radiotherapy should be prudent if there are signs of intracranial hypertension. PMID- 26506710 TI - [Clinical analysis of relapsing anti-N-methyl-D-aspartate receptor encephalitis]. AB - OBJECTIVE: With the discovery of more patients with anti-N-methyl-D-aspartate (anti- NMDAR) encephalitis, frequent clinical relapses pose a new challenge to neurologists. METHODS: Retrospective reviews were conducted for 16 hospitalized patients with relapsing anti-NMDAR encephalitis at our hospital from June 2011 until November 2014. Their clinical data including symptoms, cerebrospinal fluid (CSF) profiles, neuroimaging findings and relapsing treatment were compared with those initial episodes. RESULTS: There were 11 females and 5 males with a mean onset time of 21.2 (10-34) years. For initial episodes, the mean number of major symptoms was 5. 8 and the mean modified Rankin score (mRS) 4.56. And 7 (43.8%) cases were admitted into intensive care unit (ICU). All received first-line immunotherapy and only one case second-line immunotherapy. Ovarian teratoma was detected and resected in only one case of initial episode. Among 32 relapses, 8 cases (50% ) had multiple (2-4) relapses. There was a median delay of 5.0 (0.5 18) months for relapses. Relapses were common upon pausing or reducing immunotherapy, usually monotherapy with corticosteroids. Compared with initial episodes, relapses were less severe (mean mRS 2.69, mean number of symptom 2.59) and only 2 cases were admitted into ICU during relapses. Presentation of relapses were partial symptoms of initial episode. However, two patients had new symptoms of brain stem involvement. Brain magnetic resonance imaging (MRI) of 8 cases showed abnormality initially during initial episode and disappearance at relapses while new lesions appeared in 7 patients including 3 cases with CNS demyelinating features of central nervous system ( CNS) on MRI. The positivity rate of anti NMDAR antibody was 100% in CSF and 53.1% in sera during relapses. Anti-AQP4 and NMO-Ig were positive in one case with brain stem involvement. All cases received first-line immunotherapy and 12 chronic second-line immunotherapy. Two cases of ovarian teratoma were detected on reassessment during relapse and then resected. CONCLUSION: Inadequacy of second-line and chronic immunotherapy, occult teratoma and potential demyelination may contribute to a relapse of anti-NMDAR encephalitis. And its proper management should follow the recommendations of guidelines. PMID- 26506711 TI - [Clinical features and risk factors of biloma formation after transcatheter arterial chemoembolization]. AB - OBJECTIVE: To explore the risk factors, treatment and outcomes of biloma after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). METHODS: A total of 481 patients with a diagnosis of HCC underwent TACE at our hospital from January 2011 to December 2013. Biloma was tracked by the follow ups of computed tomography or magnetic resonance imaging (CT/ MRI) . Retrospective analyses were conducted for their clinical features, treatments and prognosis. The statistically significant factors for univariate analysis were introduced into Logistic regression models for multivariate analysis to obtain the risk factors of biloma post-TACE. RESULTS: There were 43 cases of complicated biloma after TACE. And 38 patients (88.4% ) developed biloma at 0.5-3 months post TACE while another 5 (9.7%) did so at 3-5 months. The multivariate analysis showed that bile duct dilation, a history of hepatectomy prior to TACE, use of polyvinyl alcohol (PVA) particles and nonsuperselective embolization were the risk factors of biloma formation after TACE. Among 9 symptomatics, there were jaundice (n =2) and fever (n =7). The diameter of bilomas was (8.07 +/- 3.53) cm for 9 symptomatics and (2.81 +/- 1.26) cm for 35 asymptomatics. And the difference was statistically significant (P <0. 01). Nine symptomatic patients underwent percutaneous drainage with tube and biloma diminished (n = 7) and even vanished (n = 2). Only conservative treatment was offered for 35 asymptomatics. During the follow-ups, it showed no change (n = 24) , diminishing (n = 8) and disappearance (n = 2). One case died from a greatly enlarged biloma due to hepatic failure and septic shock via a rupture into abdominal cavity and choleperitonitis. CONCLUSION: The risk factors of biloma formation after TACE for HCC are bile duct dilation, a history of hepatectomy before TACE, use of PVA particles and nonsuperselective embolization. For symptomatics, drainage must be performed timely and the prognosis is fair. For asymptomatics, regular imaging follow-ups are needed. Drainage must be performed timely when the diameter of biloma increased significantly during the follow-ups. PMID- 26506712 TI - [Clinical and prognostic analysis of decompensated cirrhosis patients Escherichia coli bloodstream infections]. AB - OBJECTIVE: To investigate the clinical characteristic and drug resistance of decompensated cirrhosis patients bloodstream infections causing by Escherichia coli, and determine risk factors for mortality among patients with bloodstream infections. METHODS: The clinical data and drug susceptibility of decompensated cirrhosis patients Escherichia coli bloodstream infections from 2009 to 2012 in 302 hospital of PLA were retrospectively analyzed. Univariable and multivariable Logistic regression was used to identify independent risk factors for all-cause mortality. RESULTS: A total 211 strains of E. coli were isolated from decompensated cirrhosis inpatients, 80 strains ESBLs detecting were positive, positive rate was 37. 9%. Most of infection source were uncertain. The drug resistance of ESBLs positive strains was higher than ESBLs negative strains, but no statistical difference existed in age, sex, basic disease, infection source, peak temperature, white blood cell count, the percentage of neutrophils between ESBLs positive strains and negative strains. 154 patients were survived and 57 patients were died after treatment, with a mortality of 27. 01%. On multivariate analysis, independent risk factors for in-hospital mortality were old age [odds ratio (OR) = 2.429], abnormal pulse (OR = 2.977), liver failure (OR = 11.159), hepatic encephalopathy (OR = 2.524 ) , septic shock (OR = 8.837), acute kidney injury (OR = 3.758), gastrointestinal bleeding(OR = 4.118). Body temperature of > 39 degrees C (OR = 0.301) had protective effect to lower mortality. A Logistic probobility model was created by adding points for each independent risk factor, and had a c-statistic of 0.898. CONCLUSIONS: Due to decompensated cirrhosis patients Escherichia ecu bloodstream infection severity and had prognosis, early effective antimicrobial therapy and severe complication prevention should be taken to reduce mortality. PMID- 26506713 TI - [Diversity of Lactobacillus in vagina of vulvovaginal candidiasis]. AB - OBJECTIVE: To investigate the Lactobacillus species in the vaginas of vulvovaginal candidiasis and to assess the prevalence of each Lactobacillus species in vulvovaginal candidiasis. METHODS: 154 vaginal samples were analyzed, 92 of which were from fertile healthy women, and 62 of which were from women with vulvovaginal candidiasis; and species-specific PCR showed the prevalence of each Lactobacillus species Species-specific PCR was used to investigate the prevalence of each Lactobacillus species in healthy Chinese women and the women with vulvovaginal candidiasis. RESULTS: In women with vulvovaginal candidiasis: L. iners (6.5%), L. cripatus (79.0%), L. gasseri (37.1%), L. jensenii (74.2%), L. acidophilus (16.1%), L. brevis (19.4%), L. plantarum (1.6%), L. johnsonii (51.6%), L. fermentum (8.1%), L. salivarius (9.7%), L. reuter (1.6%), L. paracasei (8.1%), L. delbrueckii (3. 2% ) ; More than two different Lactobacillus species coexisted in 98% of women with vulvovaginal candidiasis, and no anyone species existed in 2% of them; In fertile women: L. iners (82.6%), L. cripatus (70.7%), L. gasseri (67.4%), L. jensenii (40.2%), L. acidophilus (39.1%), L. brevis (23.9%), L. plantarum (5.4%), L. rhamnosus (1.1%), L. paracasei (1.1%), L. reuter (1.1%) i, L. johnsonii (3.3%), L. fermentum (2.2%), L. salivarius (2.2%); More than two different Lactobacillus species coexisted in 97% of fertile women, and only one species existed in 3% of fertile women. CONCLUSIONS: Species of lactobacillus in women with vulvovaginal candidiasis did not significantly reduced compared with healthy women. Lactobacillus inert may be a marker of the change of vaginal microenvironment; Lactobacillus crispatus is a dominant lactobacillus in the vaginal of fertile healthy women, pregnant women and women with vulvovaginal candidiasis. PMID- 26506714 TI - [Evaluation of 99mTc-ECD SPECT/CT brain imaging with scenium analysis in patients with generalized anxiety disorder]. AB - OBJECTIVE: To assess the perfusion changes in brains of patients with varying levels of generalized anxiety disorder (GAD). METHODS: A total of 38 GAD outpatients of Department of Psychiatry at our hospital from February to August, 2014 and 10 healthy controls received a 99mTC-ECD SPECT/CT scan with scenium analysis. Differences between brain perfusion and anxiety levels were analyzed by SPSS 16. 0 with one-way ANOVA, Pearson's Chi-square, t test and Spearman's correlation. RESULTS: They were grouped according to the levels of anxiety severity, i. e. mild (n = 11) , moderate (n = 16) and severe (n = 11). They had significantly lower blood flow in right superior frontal medial gyrus, right precuneus, right putamen, bilateral paracentral lobule and bilateral supplementary motor area (t = -2.19, -2.14, -2.22, -2.34, -2.08, -3.26, -2.72, P < 0.05). Individuals had significantly greater blood flow in mild group than those of control group in right olfactory (t = 2.09 P = 0.05). Individuals of moderate group had significantly lower blood flow than those of control group in left superior frontal gyrus medial orbital, right superior frontal gyrus medial orbital and left supplementary motor area, but greater in right olfactory (t = 2.16, -2.24, -2.49, 2.17, P = 0.04, 0.04, 0.02, 0.04). Individuals had lower blood flow in severe group than those of control group in left frontal lobe, right putamen, left paracentral lobule, right paracentral lobule, left precuneus, right precuneus, left parietal lobe, left precentral, right precentral, right postcentral, left rolandic operculum, left supplementary motor area, right supplementary motor area and left central region (t = -2.32, -2.11, -3.16, -2.61, -2.39, -2.18, -2.32, -2.67, -2.14, -2.11, -2.25, -4.38, -3.54, -2.38, P = 0.03, 0.05, 0.01, 0.02, 0.03, 0.04, 0.03, 0.02, 0.05, 0.05, 0.04, 0.00, 0.00, 0.03). Statistical differences existed in right middle frontal gyms orbital part (mild: 0.96 +/- 0.07, moderate: 1.03 +/- 0.06, severe: 0.98 +/- 0.08, P = 0.04) and left paracentral (mild: 0.91 +/- 0.07, moderate: 093 +/- 004 severe: 0.87 +/- 0.07, P = 0.02). There was a tendency of negative correlation between perfusion in right middle cingulate and paracingulate gyri, left precuneus, right precuneus and left thalamus and anxiety scores by Spearman's correlation analysis (r = -0.28, -0.28, -0.27, -0.29, P = 0.09, 0.09, 0.10, 0.07). CONCLUSION: Scenium software provides quantitative measurements for diagnosis of GAD in different anxiety levels. Also larger samples are required for confirming the results in further studies. PMID- 26506715 TI - [Imaging features of humerus, radius and ulna rare malformation]. AB - OBJECTIVE: To investigate the imaging features of humerus, radius and ulna rare malformation. METHODS: A retrospective analysis of the clinical data and image of 40 cases of humerus and the radius and ulna rare developmental deformity andadmitted to hospital affiliated to 1958 - 2014 years in The Affiliated Hospital of Hangzhou Normal University and the Third Hospital of Hebei Medical University. Take the Swanson classification as the basis, the image changes of different types of malformations are classified and summarized. RESULTS: 40 cases of humerus , radius and ulna rare malformation in 19 males and 21 females, age 18 days to 51 years, mean age (11.6 +/- 11.5) years; a total of 10 kinds of deformities to Swanson classification, radius and ulna: failure of formation of parts 9 cases, for radial defect; failure of differentiation are congenital radioulnar synostosis 6 cases, Madelung' s deformity 12 cases, congenital radial head dislocation 4 cases; duplication 2 cases, for double ulna syndrome; overgrowth 2 cases, as long ulna short radial deformity; undergrowth 1 case, for the micromelia. Humerus and ulna bony involvement: failure of differentiation 1 case, for brachial radial synostosis; failure of formation of parts 1 case, for amelia. There is still one kind of deformity can not be accurately classified as patella cubiti 2 cases. CONCLUSIONS: Humerus, radius and ulna although more types of malformations and the incidence rate is not high, only a comprehensive understanding of different deformity classification and characteristics, combined with the typical imaging findings in order to arrive at a correct diagnosis to avoid misdiagnosis. PMID- 26506716 TI - [Effects and activated mechanism of adenosine triphosphate on BK channel of coronary smooth muscle cells]. AB - OBJECTIVE: To explore the effects and activation mechanism of adenosine triphosphate (ATP) on large conductance calcium-activated potassium channel ( BK channel) in coronary artery smooth muscle cells. METHODS: Coronary smooth muscle cells were isolated by enzyme digestion from Sprague-Dawley rats. And BK currents were recorded by patch clamp technique in whole cell configuration. The effects of ATP on cytosolic calcium concentrations were examined by recording the changes of fluorescence intensity ratios. RESULTS: BK current densities were (137 +/- 13) pA/pF and (179 +/- 15) pA/pF before and after a perfusion of 1 mmol/L ATP (P < 0.05). The fluorescence ratios were 2.46 +/- 0.08 and 4.04 +/- 0.21 (P < 0.05) before and after 0.5 mmol/L perfusion. After incubating with purine receptor (P2Y1) blocker MRS2179, phospholipase C (PLC) blocker U73122 and inositol triphosphate (IP3) blocker 2-APB, the fluorescence ratios were 2.7 +/- 0.06, 2.65 +/- 0.12 and 2.69 +/- 0.13 respectively. Compared with control group, all fluorescence ratios decreased after incubating with three blockers (P < 0.05). CONCLUSION: ATP may elevate intracellular calcium concentration via P2Y1-PLC-IP3 pathway consequently activating BK channel. PMID- 26506717 TI - [Simplify and trivialize the reporting of adverse events]. PMID- 26506718 TI - [Health surveillance for care safety]. PMID- 26506719 TI - [Pharmacovigilance, an implementation closer to the players in the field]. PMID- 26506720 TI - [Accompany the nurse in the optimal management of therapeutics]. PMID- 26506721 TI - [Continuing education, a tool to enhance blood safety in the hospital]. PMID- 26506722 TI - [Organize a real risk management of hospital infection]. PMID- 26506723 TI - [Addiction care and addiction surveillance, two complementary dynamics]. PMID- 26506724 TI - [Coordination of hospital surveillance]. PMID- 26506725 TI - PREFACE. Adult Dengue. PMID- 26506726 TI - DENGUE: GLOBAL THREAT. AB - Dengue is a mosquito-borne viral disease, which is currently an expanding global problem. Four closely related dengue serotypes cause the disease, which ranges from asymptomatic infection to undifferentiated fever, dengue fever (DF), and dengue hemorrhagic fever (DHF). DHF is characterized by fever, bleeding diathesis, and a tendency to develop a potentially fatal shock syndrome. Dengue infection with organ impairment mainly involves the central nervous system and the liver. Consistent hematological findings include vasculopathy, coagulopathy, and thrombocytopenia. Laboratory diagnosis includes virus isolation, serology, and detection of dengue ribonucleic acid. Successful treatment, which is mainly supportive, depends on early recognition of the disease and careful monitoring for shock. A severity-based revised dengue classification for medical interventions has been developed and validated in many countries. There is no specific dengue treatment, and prevention is currently limited to vector control measures. The world's first, large-scale dengue vaccine efficacy study demonstrated its efficacy and a reduction of dengue disease severity with a good safety profile in a study of more than 30,000 volunteers from Asia and Latin America. PMID- 26506727 TI - DENGUE PATIENTS AT PHOTHARAM HOSPITAL: A CLINICAL TRIAL SITE OF DENGUE VACCINE. AB - Between 2005 and 2013, 1,868 dengue patients, 916 male and 952 female, were admitted to Photharam Hospital, Ratchaburi, Thailand. Among these patients, there were 1,209 with dengue fever (DF), 598 with dengue hemorrhagic fever (DHF), and 61 with dengue shock syndrome (DSS) with 1 death. The disease was seen all year round with a higher incidence in the rainy season. A trend of shift in age group towards older children and adults was seen during the study period. These data show that dengue patient admissions to Photharam Hospital are common, causing a heavy burden on the health system. Only one death was seen during the period of study, indicating that early recognition and effective management of dengue patients occurred. The trend towards higher age in dengue patients during the study period is a problem of concern and needs further clarification. PMID- 26506728 TI - FOCAL DENGUE VIRUS TRANSMISSION IN KAMPHAENG PHET, THAILAND AND IMPLICATIONS FOR MANAGEMENT. AB - Dengue is the most globally prevalent vector-borne viral disease. However, our understanding of dengue virus (DENV) transmission is incomplete. Prospective longitudinal cohort and cluster studies in Kamphaeng Phet, Thailand have contributed much to our understanding of DENV transmission. These studies have demonstrated the spatiotemporal heterogeneity of DENV transmission with highly focal transmission at small scales in a rural setting. Geographic cluster studies have suggested the presence of small "hotspots" of transmission at the house level that may have a disproportionately high impact on local spread. These hotspots should be considered when planning overall vector control interventions. The combined cohort and cluster design have shown that clinically inapparent DENV infections from prospective longitudinal cohorts likely consist of a clinical spectrum of infections from asymptomatic to mildly symptomatic with and without fever. The proportion of all DENV infections that are completely asymptomatic may be substantially lower than those considered to be inapparent in cohort studies. In addition, some of these inapparent infections from cohort studies have viable DENV and may potentially contribute to virus transmission. These findings require further validation in other settings and in adults and children. A more comprehensive understanding of DENV transmission will be critical to inform prevention, prognostication and management strategies. PMID- 26506730 TI - DENGUE VIRUS VIRULENCE AND DISEASES SEVERITY. AB - The dengue virus is the causative agent of a wide spectrum of clinical manifestations, ranging from mild acute febrile illness to classical dengue fever, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). DHF and DSS are the potentially fatal forms of dengue virus infection, which has become an intractable public health problem in many countries. The pathogeneses of DHF/ DSS are not clearly understood. One hypothesis concerning virus virulence and the immune enhancement hypothesis has been debated. Although dengue disease severity has been associated with evidence of genetic differences in dengue strains, virus virulence has been difficult to measure because of the lack of in vivo and in vitro models of the disease. PMID- 26506729 TI - ASSOCIATION BETWEEN MANNOSE-BINDING LECTIN GENE POLYMORPHISMS AND SUSCEPTIBILITY TO DENGUE VIRUS INFECTION: A PRELIMINARY REPORT. AB - Mannose-binding lectin (MBL) can bind with a wide range of pathogens and can activate through lectin pathway or enhances opsonophagocytosis. MBL is encoded by the MBL2 gene and single-nucleotide polymorphisms (SNPs) in the promoter and exon have functional effects on serum levels of MBL. MBL deficiency has been shown to predispose to infectious diseases. We assess whether or not, the variant MBL alleles are associated with susceptibility to dengue infection. Patients with confirmed dengue infection who were admitted to King Chulalongkorn Memorial Hospital during a calendar year were studied. Controls were patients without dengue infection. Deoxyribonucleic acid (DNA) was extracted from 50 MUl of peripheral blood mononuclear cell (PBMC) using the DNA Blood Mini Kit. The SNPs in the promoter (-221 X/Y) and exon 1 (codon 54 A/B) of MBL2 gene were genotyped by using 2 separate cycling reactions of the TaqMan allele discrimination system. Serum levels of MBL were determined by double-antibody sandwich ELISA. Chi-square was used for statistical analysis. Serum MBL levels and genotypes were determined in 110 dengue patients (mean age 18.1 years; 62 males and 48 females) and 42 controls (mean age 25.8 years; males: females = 1:1). Our study showed that YB haplotype is associated with low serum levels of MBL. There was no association between MBL2 gene polymorphisms and susceptibility to dengue infection. The higher frequency of YB in dengue patients than in controls suggesting the likelihood of an association. Further studies are warranted. PMID- 26506731 TI - HEMOSTATIC STUDIES IN DENGUE PATIENTS. AB - The pathogenesis of hematologic changes in dengue patients is not clearly understood. Consistent hematological findings include vasculopathy, thrombocytopenia, and coagulopathy. There are evidences suggesting that dengue virus causes pathophysiological changes that involve all of the consistent hematologic findings resulting in vasculopathy, reduction in platelet number as well as platelet dysfunction, and reduction of several coagulation factors. Laboratory evidences of disseminated intravascular coagulation (DIC) are also demonstrated in all degrees of severity in dengue patients. Only in severe dengue cases is profound DIC aggravated, leading to uncontrolled bleeding and death. A study to determine the extent of the activation of endothelial cells and the hemostatic system in correlation with clinical severity and also to detect the best prognostic factor for severe dengue showed plasma von Willebrand factor antigen (VWF:Ag) to be the best indicator of progression to severe dengue. PMID- 26506732 TI - REPORTING PROGRESS ON THE USE OF THE WHO 2009 DENGUE CASE CLASSIFICATION: A REVIEW. AB - This review reports on the progress in the use of the WHO 2009 dengue case classification--dengue and severe dengue--following up on a previous review (Horstick et al, 2012). The previous review detailed Steps 1 - 5 in developing the 2009 WHO case classification. As a further step, a systematic review of published studies comparing the two classifications has been published with 12 studies and a further 10 expert opinion papers that recommend the use of the 2009 WHO dengue case classification for clinical management, epidemiology, and clinical research. Furthermore, a formal expert consensus was reached in La Habana, Cuba in 2013 with dengue experts from the Americas, sharing experiences that applied the 2009 WHO dengue case classification. The expert panel recommended to 1) update ICD10, 2) include the 2009 WHO case classification in country epidemiological reports globally, and 3) implement studies improving sensitivity/specificity of the dengue case definition. PMID- 26506733 TI - LABORATORY DIAGNOSIS OF DENGUE VIRUS INFECTIONS. AB - Dengue diagnosis was one of the topics discussed at "the adult dengue" presentations. In this paper, a review is presented focusing on the main challenges of dengue laboratory diagnosis. Accurate and efficient diagnosis of dengue is important for clinical care, surveillance support, pathogenesis studies, and vaccine research. Laboratory diagnosis is also important for case confirmation. Laboratory dengue diagnosis can be performed through virus isolation, genome and antigen detection and serological studies. For virus detection, dengue viremia is short, usually observed two or three days before onset of fever and lasts four to five days later. Therefore, samples for virus detection must be taken in the first four to five days of the disease during febrile phase. In recent years, PCR (polymerase chain reaction) has become an important tool as a quick method for diagnosis of dengue, another is detection of NS1 antigen, using commercial ELISA kit. Serological studies, for primary infection, the dominant immunoglobulin isotype is IgM, anti-IgM may appear during febrile phase (50% of cases), the other half, it appears within 2-3 days of defervescence. Once detectable, IgM levels rise quickly and appears to peak about 2 weeks after the onset of symptoms, then they decline to undetectable level over 2-3 months. Anti-IgG appears shortly afterwards with very low level. The physiological definition of a primary infection is therefore characterized by a high molar fraction of anti-dengue IgM and low molar fraction of IgG. Secondary dengue infections are characterized by a rapid increase in IgG antibodies, anti dengue IgM appears in most instances, the level are dramatically lower. PMID- 26506734 TI - DENGUE FEVER AND DENGUE HEMORRHAGIC FEVER IN ADULTS. AB - Dengue fever and dengue hemorrhagic fever are re-emerging diseases that are endemic in the Tropics. The global prevalence of dengue cases has increased in South-East Asia, Africa, the Western Pacific, and the Americas. The increasingly widespread distribution and the rising incidence of dengue virus infections are related to increased distribution of Aedes aegypti, an increasingly urban population, and increasing air travel. Several Southeast Asian countries show that the age of the reported dengue cases has increased from 5-9 years, to older children and young adults. Dengue infection in adolescents and adults has also been recognized as a potential hazard to international travelers returning from endemic areas, especially SoutheastAsia. Dengue is one disease entity with different clinical presentations; often with unpredictable clinical evolutions and outcomes. Bleeding manifestations in adult patients, including petechiae and menorrhagia were also frequently found; however, massive hematemesis may occur in adult patients because of peptic ulcer disease and may not be associated with profound shock as previously reported in children. Although shock and plasma leakage seem to be more prevalent as age decreases, the frequency of internal hemorrhage rises as age increases. Increase in liver enzymes found in both children and adults indicated liver involvement during dengue infections. Pre existing liver diseases in adults such as chronic hepatitis, alcoholic cirrhosis, and hemoglobinopathies may aggravate the liver impairment in dengue infection. Fulminant hepatitis is a rare but well described problem in adult patients with dengue infection. Currently, no specific therapeutic agent exists for dengue. The early recognition of dengue infection, bleeding tendency, and signs of circulatory collapse would reduce mortality rates in adult patients with dengue infection. PMID- 26506735 TI - LIVER COMPLICATIONS IN ADULT DENGUE AND CURRENT MANAGEMENT. AB - Adult dengue patients have a lower prevalence of bleeding tendency and greater prevalence of abnormal liver function tests than children with dengue infections. At least two-thirds of adult dengue patients have abnormal liver function tests. Our article aims to detail the clinical findings of liver complications in adult patients with dengue infection. The predictors of liver complications and the associations with failure of other organs were reviewed; for example, high-level ALT during the febrile stage has been associated with shock. In addition, this review includes the current interventions for treatment of acute liver failure in adult dengue patients including N-acetylcysteine, and artificial liver dialysis. PMID- 26506736 TI - ELECTROLYTE DISTURBANCE AND KIDNEY DYSFUNCTION IN DENGUE VIRAL INFECTION. AB - Dengue virus infection (DVI) is endemic in tropical countries in both children and adults. The classical presentation includes fever, hepatomegaly, thrombocytopenia-related bleeding disorders, and plasma leakage. Multi-organ involvement, including kidneys is found in complex cases. Asymptomatic electrolyte disturbances, abnormal urinalysis, and more severe manifestation such as acute kidney injury (AKI) usually indicate kidney involvement. Such manifestations are not rare in DVI, but are often not recognized and can cause the physician to misread the real situation of the patient. The prevalence of electrolyte disturbances or kidney involvement reported in studies varies widely by country and mainly depends on the severity of DVI and age of the patients. The prevalence of DVI-induced AKI ranges from 0.2%-10.0% in children and 2.2%-35.7% in adults. The prevalence among all age groups appears to be increasing in the last decade. Dengue shock syndrome (DSS) has been reported to be an independent risk factor for AKI development. The mechanism of DVI-induced AKI is complex and the details are to date undetermined. Urinalysis, serum electrolytes and creatinine measurements should be performed to document renal involvement in DVI patients for early detection and initiation of appropriate fluid therapy with close monitoring. Renal replacement therapy may be required in some cases. The presence of AKI dramatically increases the mortality rate among both childhood and adulthood DVI from 12%-44% to more than 60%. PMID- 26506737 TI - DENGUE WITH CENTRAL NERVOUS SYSTEM INVOLVEMENT. AB - Dengue has spread to new geographic areas affecting both children and adults, and it has become a global threat. Dengue with central nervous system involvement includes febrile seizures, encephalopathy, encephalitis, aseptic meningitis, intracranial hemorrhages, intracranial thrombosis, subdural effusions, mononeuropathies, polyneuropathies, Guillain-Barre syndrome, and transverse myelitis. These manifestations may be associated with co-infections, co morbidities, or complications of prolonged shock. It is important to consider dengue as a cause for the above neurological presentations, particularly in endemic territories for dengue disease. PMID- 26506738 TI - FLUID AND HEMODYNAMIC MANAGEMENT IN SEVERE DENGUE. AB - In the critical phase of dengue fever, the leakage of intravascular fluid into interstitial space and 3rd space can cause hemoconcentration and severe complications such as dengue shock syndrome (DSS), and it can lead to multiple organ failure, followed by death. Close monitoring, early detection and prompt management are the keys in successful treatment. In a hemodynamically unstable patient, crystalloid is the fluid of choice in initial management. However, if they are not responsive despite adequate resuscitation, a careful search for others causes is mandatory and fluids should be switched from crystalloid to colloid. If the leakage leads to restriction of the use of fluids (pulmonary edema), the addition of a vasopressor such as norepinephrine needs to be considered. After stabilizing the hemodynamics and clinical improvement, the physician has to know when to reduce and discontinue the fluid to avoid congestion and others complications. PMID- 26506739 TI - INTERIM ANALYSIS OF THE CONTRIBUTION OF HIGH-LEVEL EVIDENCE FOR DENGUE VECTOR CONTROL. AB - This interim analysis reviews the available systematic literature for dengue vector control on three levels: 1) single and combined vector control methods, with existing work on peridomestic space spraying and on Bacillus thuringiensis israelensis; further work is available soon on the use of Temephos, Copepods and larvivorous fish; 2) or for a specific purpose, like outbreak control, and 3) on a strategic level, as for example decentralization vs centralization, with a systematic review on vector control organization. Clear best practice guidelines for methodology of entomological studies are needed. There is a need to include measuring dengue transmission data. The following recommendations emerge: Although vector control can be effective, implementation remains an issue; Single interventions are probably not useful; Combinations of interventions have mixed results; Careful implementation of vector control measures may be most important; Outbreak interventions are often applied with questionable effectiveness. PMID- 26506740 TI - DENGUE VACCINES. AB - The uniqueness of the dengue viruses (DENVs) and the spectrum of disease resulting from infection have made dengue vaccine development difficult. Several vaccine candidates are currently being evaluated in clinical studies. The candidate currently at the most advanced clinical development stage, a live attenuated tetravalent vaccine based on the chimeric yellow fever-dengue virus (CYD-TDV), has progressed to Phase 3 efficacy studies. Several other live attenuated vaccines, as well as subunit, DNA, and purified inactivated vaccine candidates are at earlier stages of clinical development. Additional technological approaches, such as virus-vectored and Virus-Like Particles (VLP) based vaccines are under evaluation in preclinical studies. PMID- 26506741 TI - FATAL RHABDOMYOLYSIS IN DENGUE HEMORRHAGIC FEVER: A CASE REPORT. AB - Dengue hemorrhagic fever is caused by dengue virus infection. The classical manifestations consist of fever, thrombocytopenia, and hemoconcentration. However, its unusual complications may be fatal, such as prolong shock, massive bleeding, volume overload, and unusual manifestations, for example, severe rhabdomyolysis. Here we report a case of 17-year old Thai man who was referred to our hospital because of 7-day fever with thrombocytopenia, hemoconcentration and right pleural effusion. The serology tests confirmed to be dengue infection. He developed various complications: severe hepatitis, coagulopathy, and heavy proteinuria; encephalopathy that needed a respiratory ventilator. On day 12 of fever, he had myalgia and passed dark urine. Serum creatinine and serum creatinine phosphokinase (CPK) were found abnormally high. He was diagnosed as severe rhabdomyolysis with acute kidney injury, and immediate hemodialysis was performed. He did not respond to treatment and expired within three hours. Although the mechanism of severe rhabdomyolysis in dengue fever is not clearly known, it may theoretically be proposed such as direct muscle cell injury leading to myositis by dengue virus, myotoxic cytokines which are produced in response to viral infection, dehydration or hypophosphatemia. PMID- 26506742 TI - DENGUE INFECTION IN PREGNANCY. AB - While dengue infection is still on the increase in adults in Thailand, it also affects pregnant women, especially pregnant teenagers. This study was designed to investigate dengue infection during pregnancy. Seven cases of dengue infection in pregnant women were admitted to Ban Pong Hospital, Ratchaburi, Thailand, between 2008 and 2012. Dengue infection presented in all pregnancy trimesters. There were two severe cases: one was dengue hemorrhagic fever in the first trimester, and the second was at a critical stage of the infection during labor. There were three cases of abortion. These three cases included one complete, one incomplete, and one threatened abortion, with rising hematocrits of 22.8%, 17.1%, and 14.7%, respectively. Two out of the three teenage pregnancies experienced complete and threatened abortions, while the third abortion case was a threatened abortion pregnancy at the critical stage of infection during intrapartum. Leukopenia was identified in six out of seven women. Low baseline hematocrit and low maximum hematocrit were laboratory findings. Clinical management involved administration of intravenous fluids and antipyretics. Favorable outcomes can be obtained through early diagnosis and supportive treatment. The morbidity profile can be more serious in teenage pregnancies. Additional studies should be conducted to establish whether low baseline hematocrit, low percentages of rising hematocrit in pregnant women with dengue infection, and abortions (with a high degree of increasing hematocrit during the critical stage of the disease) are typical clinical signs. PMID- 26506743 TI - SEVERE DENGUE IN PREGNANT WOMEN. AB - Over half of the world's population lives in areas at risk of dengue infection with 70% of overall disease burden in Asia. A shifting in age group of dengue patients towards adulthood has been widely seen in Asia. This will affect an increase in incidence of dengue infection in childbearing age and pregnant women. Two cases of severe dengue in pregnant women admitted to Photharam Hospital, Ratchaburi, Thailand were described. Both of them had dengue shock syndrome with organopathy involving the central nervous system with alteration of consciousness in one. They had uneventful recoveries following intensive care. This report emphasizes the hazards of dengue infection in pregnant women, which needs special consideration. Early recognition with careful monitoring and symptomatic management are the key factors in a favorable outcome for a dengue patient. PMID- 26506744 TI - DENGUE INFECTION IN ELDERLY PATIENTS. AB - From 2005 to 2013, there were 15 dengue patients aged over 60 years old who were admitted to Photharam Hospital, Ratchaburi, Thailand. Ten were females and five were males. Nine had dengue fever (DF), and 6 had dengue hemorrhagic fever (DHF). A trending shift in age group towards adults has been seen during the past decades. No deaths were seen in these elderly patients with dengue disease, indicating early recognition and effective management of these dengue patients. The trend towards higher age in dengue patients is a problem of concern, which needs further elaboration. PMID- 26506745 TI - PRACTICAL GUIDELINE FOR MANAGEMENT OF DENGUE IN ADULTS: 2014. PMID- 26506746 TI - Midline Shift Threshold Value for Hemiparesis in Chronic Subdural Hematoma. AB - INTRODUCTION: Chronic subdural hematoma (CSDH) has a variety of clinical presentations, with numerous neurological symptoms and signs. Hemiparesis is one of the leading signs that potentially indicates CSDH. OBJECTIVE: Purpose of this study was to determine the threshold (cut-off) value of midsagittal line (MSL) shift after which hemiparesis is likely to appear. METHODS: The study evaluated 83 patients with 53 unilateral and 30 bilateral CSDHs in period of three years. Evaluated computed tomography (CT) findings in patients with CSDH were diameter of the hematoma and midsagittal line shift, measured on non-contrast CT scan in relation with occurrence of hemiparesis. Threshold values of MSL shift for both types of CSDHs were obtained as maximal (equal) sensitivity and specificity (intersection of the curves). RESULTS: MSL is a good predictor for hemiparesis occurrence (total sample, AUROC 0.75, p=0.0001). Unilateral and bilateral CSDHs had different threshold values of the MSL for hemiparesis development. Results suggested that in unilateral CSDH the threshold values of MSL could be at 10 mm (AUROC=0.65; p=0.07). For bilateral CSDH the threshold level of MSL shift was 4.5 mm (AUROC=0.77; p=0.01). CONCLUSION: Our study pointed on the phenomenon that midsagittal line shift can predict hemiparesis occurrence. Hemiparesis in patients with bilateral CSDH was more related to midsagittal line shift compared with unilateral CSDH. When value of midsagittal line shift exceed the threshold level, hemiparesis occurs with certain probability. PMID- 26506747 TI - Paranoid Schizophrenia versus Schizoaffective Disorder: Neuropsychological Aspects. AB - INTRODUCTION: Neuropsychological aspects of paranoid schizophrenia have still not been examined enough.These disorders are usually not studied separately, but are included in the studies about schizophrenic patients with positive symptoms. Despite the fact that schizophrenia represents a heterogeneous group of mental disorders, usually it is not separated from schizoaffective disorder in neuropsychological researches. OBJECTIVE: The essence of this research is to evaluate cognitive functioning of patients with paranoid schizophrenia and schizoaffective disorder by applying neuropsychological tests. METHODS: The research included 91 subjects, right handed, from 30 to 53 years old, who were classified into three groups: inpatients with paranoid schizophrenia in remission (n=31), inpatients with schizoaffective disorder in remission (n=30) and healthy subjects (n=30). RESULTS: Both groups of patients showed poorer achievements than healthy subjects in most of the applied tests. Patients with schizoaffective disorder showed global loss of intellectual efficiency, executive dysfunction and compromised visual-construction organization. Patients with paranoid schizophrenia expressed partial loss of intellectual efficiency with verbal IQ and executive functions preserved. CONCLUSION: In the remission phase, patients with paranoid schizophrenia expressed cognitive disorders in moderate degree, but when it comes to patients with schizoaffective disorder, more massive cognitive, deficits were registered. PMID- 26506748 TI - Histological Effects of Enamel Matrix Derivative on Exposed Dental Pulp. AB - INTRODUCTION: Direct pulp capping procedure is a therapeutic application of a drug on exposed tooth pulp in order to ensure the closure of the pulp chamber and to allow the healing process to take place. OBJECTIVE: The aim of this study was to examine the histological effects of Emdogain(r) on exposed tooth pulp of a Vietnamese pig (Sus scrofa verus). METHODS: The study comprised 20 teeth of a Vietnamese pig. After class V preparation on the buccal surfaces of incisors, canines and first premolars, pulp was exposed. In the experimental group, the perforations were capped with Emdogain(r) (Straumann, Basel, Switzerland), while in the control group pulp capping was performed with MTA(r) (Dentsply Tulsa Dental, Johnson City, TN, USA). All cavities were restored with glass-ionomer cement (GC Fuji VIII, GC Corporation, Tokyo, Japan). The observational period was 28 days, after which the animal was sacrificed and histological preparations were made. A light microscope was used to analyze dentin bridge formation, tissue reorganization and inflammation, and the presence of bacteria in the pulp. RESULTS: The formation of dentin bridge was observed in the experimental and control groups. Inflammation of the pulp was mild to moderate in both groups. Angiogenesis and many odontoblast-like cells, responsible for dentin bridge formation, were observed. Necrosis was not observed in any case, nor were bacteria present in the pulp. CONCLUSION: Histological analysis indicated a favorable therapeutic effect of Emdogain(r) Gel in direct pulp capping of Vietnamese pigs. Pulp reaction was similar to that of MTA(r). PMID- 26506749 TI - The Analysis of the Risk Factors in the Arterial Switch Operation for Treatment of D-Transposition of the Great Arteries in One Pediatric Cardiac Center in Serbia. AB - INTRODUCTION: The arterial "switch" operation has been the operation of choice for children born with D-transposition of the great arteries (D-TGA) for more than 30 years in countries with developed pediatric cardiac surgery program. After two decades of successful treatment of these children with the atrial "switch" corrections (Mustard or Senning operative techniques), the arterial "switch"operation (ASO) had been introduced as a routine technique in one pediatric cardiac center in Serbia. OBJECTIVE: The aim of this study was the analysis of the identified risk factors involved with the ASO in the preoperative, operative and postoperative period and their impact on the survival of the operated children. METHODS: A retrospective nonrandomized study of 52 operated patients with D-TGA by the ASO in the period between May 1, 2003 and December 31, 2011, divided into two groups. The data collection consisted of preoperative, operative and postoperative factors during the in-hospital stay and until the discharge from the hospital. Descriptive and differential statistical methods were used for analysis. RESULTS: Ten individual risk factors were identified as significant for the immediate survival of children operated with the ASO technique. CONCLUSION: The arterial "switch" surgical operative technique is a complex neonatal/young infant procedure in which the preoperative status carried a significant risk as well as the surgical technique itself. These results differ from the results published throughout the world and are a representation of an evolutionary process of one center in Serbia starting the ASO procedure. PMID- 26506750 TI - Minimally Invasive Esophagectomy for Cancer: Single Center Experience after 44 Consecutive Cases. AB - INTRODUCTION: At the Department of Minimally Invasive Upper Digestive Surgery of the Hospital for Digestive Surgery in Belgrade, hybrid minimally invasive esophagectomy (hMIE) has been a standard of care for patients with resectable esophageal cancer since 2009. As a next and final step in the change management, from January 2015 we utilized total minimally invasive esophagectomy (tMIE) as a standard of care. OBJECTIVE: The aim of the study was to report initial experiences in hMIE (laparoscopic approach) for cancer and analyze surgical technique, major morbidity and 30-day mortality. METHODS: A retrospective cohort study included 44 patients who underwent elective hMIE for esophageal cancer at the Department for Minimally Invasive Upper Digestive Surgery, Hospital for Digestive Surgery, Clinical Center of Serbia in Belgrade from April 2009 to December 2014. RESULTS: There were 16 (36%) middle thoracic esophagus tumors and 28 (64%) tumors of distal thoracic esophagus. Mean duration of the operation was 319 minutes (approximately five hours and 20 minutes). The average blood loss was 173.6 ml. A total of 12 (27%) of patients had postoperative complications and mean intensive care unit stay was 2.8 days. Mean hospital stay after surgery was 16 days. The average number of harvested lymph nodes during surgery was 31.9. The overall 30-day mortality rate within 30 days after surgery was 2%. CONCLUSION: As long as MIE is an oncological equivalent to open esophagectomy (OE), better relation between cost savings and potentially increased effectiveness will make MIE the preferred approach in high-volume esophageal centers that are experienced in minimally invasive procedures. PMID- 26506751 TI - Severe Blunt Hepatic Trauma in Polytrauma Patient - Management and Outcome. AB - INTRODUCTION: Despite the fact that treatment of liver injuries has dramatically evolved, severe liver traumas in polytraumatic patients still have a significant morbidity and mortality. OBJECTIVE: The purpose of this study was to determine the options for surgical management of severe liver trauma as well as the outcome. METHODS: In this retrospective study 70 polytraumatic patients with severe (American Association for the Surgery of Trauma [AAST] grade III-V) blunt liver injuries were operated on at the Clinic for Emergency Surgery. RESULTS: Mean age of patients was 48.26+/-16.80 years; 82.8% of patients were male. Road traffic accident was the leading cause of trauma, seen in 63 patients (90.0%). Primary repair was performed in 36 patients (51.4%), while damage control with perihepatic packing was done in 34 (48.6%). Complications related to the liver occurred in 14 patients (20.0%). Liver related mortality was 17.1%. Non-survivors had a significantly higher AAST grade (p=0.0001), higher aspartate aminotransferase level (p=0.01), lower hemoglobin level (p=0.0001), associated brain injury (p=0.0001), perioperative complications (p=0.001) and higher transfusion score (p=0.0001). The most common cause of mortality in the "early period" was uncontrolled bleeding, in the "late period" mortality was caused by sepsis and acute respiratory distress syndrome. CONCLUSION: Patients with high grade liver trauma who present with hemorrhagic shock and associated severe injury should be managed operatively. Mortality from liver trauma is high for patients with higher AAST grade of injury, associated brain injury and massive transfusion score. PMID- 26506752 TI - [Parameters of Anaerobic Physiological Profile of Elite Athletes]. AB - INTRODUCTION: Anaerobic capacity is much less evaluated in literature compared to aerobic component. Anaerobic performance of athletes can be measured using different motoric tests, lasting 20 to 30 seconds, one of them being the Wingate anaerobic test (WAnT). OBJECTIVE: The aim of this study was to determine the work performed and power generated by athletes and non-athletes during a 30-second high intensity exercise, as well as to compare explosive characteristics of subjects using a new parameter of WAnT, named explosive power, or slope of power. METHODS: All parameters of anaerobic power were investigated in 152 subjects classed into different groups depending on their physical fitness and sport specialties as follows: non-athletes (n=31), rowers (n=26), volleyball players (n=37), handball players (n=34) and judo players (n=24). The WAnT, as well as basic anthropometric measurements, was administrated to all participants. RESULTS: Values of anaerobic parameters were higher in the group of athletes compared to physically inactive subjects.The highest values of the WAnT parameters were registered in the group of volleyball players (AP=1 006 W; relative AP=11.4 W/ kg, AC=19.8 kJ), compared to athletes of other sport disciplines (volleyball, rowing and judo). The new parameter of the WAnT, explosive power, also showed highest values in volleyball players (EP=1 54 W/s; relative EP=1.74 W/s/kg). These differences were statistically significant (p<0.05). CONCLUSION: The results of laboratory tests can provide useful information on improvements in training processes. The new parameter of the WAnT could be implemented in further analyses of explosive characteristics of muscle contraction. PMID- 26506753 TI - Influenza B Viruses in the Population of Province of Vojvodina during the 2012/2013 Season: Differentiation of B/Yamagata and B/Victoria Lineages by Real time RT-PCR, Antigenic and Phylogenetic Characterization. AB - INTRODUCTION: At present, two phylogenetically distinct influenza B virus lineages, B/Yamagata and B/ Victoria, co-circulate worldwide and can cause significant morbidity and mortality. OBJECTIVE: The aim of this study was to determine the prevalences of two influenza B virus lineages in the population of Vojvodina and to identify their antigenic and phylogenetic properties. METHODS: A total of 369 and 334 nasopharyngeal, or nasal/throat swab samples, collected during the 2012/2013 and 2013/2014 seasons, respectively, were tested using specific singleplex influenza A, influenza B, influenza B/Yamagata and influenza B/Victoria real-time reverse transcription polymerase chain reaction (RT-PCR) assays. Antigenic and genetic testing were done by hemagglutination inhibition assay and hemagglutinin and neuraminidase gene sequence analysis, respectively. RESULTS: During the 2012/2013 season, influenza B viruses were present in 53.4% (101/189) of influenza positive samples.The B/Yamagata-like viruses (81.2%) significantly predominated over the B/Victoria-like viruses (18.8%). Comparing to B/Victoria-like positive patients, among B/Yamagata-like positive patients, children 5-14 years of age were significantly more represented (5.3% vs. 35.4%, respectively), as well as patients with mild form of illness (15.8% vs. 45.1%, respectively). The results of sequence analysis and antigenic testing showed that tested viruses were not closely related to B/Wisconsin/1/2010, the vaccine virus for 2012/2013. During the 2013/2014 season influenza B viruses were not detected. CONCLUSION: The results of this study confirmed the health significance of influenza B viruses and indicated that B/Yamagata-like viruses were significantly more prevalent than B/Victoria lineage viruses, during the 2012/2013 season. They also showed a sub-optimal match between the tested viruses and the vaccine virus for season 2012/2013. PMID- 26506754 TI - [Toxoplasmosis and Pregnancy: Reliability of Internet Sources of Information]. AB - INTRODUCTION: Health education of women of childbearing age has been shown to be an acceptable approach to the prevention of toxoplasmosis, the most frequent congenitally transmitted parasitic infection. OBJECTIVE: The aim of this study was to evaluate the Internet as a source of health education on toxoplasmosis in pregnancy. METHODS: A group of 100 pregnant women examined in the National Reference Laboratory for Toxoplasmosis was surveyed by a questionnaire on the source of their information on toxoplasmosis. We also analyzed information offered by websites in the Serbian and Croatian languages through the Google search engine, using "toxoplasmosis" as a keyword. The 23 top websites were evaluated for comprehensiveness and accuracy of information on the impact of toxoplasmosis on the course of pregnancy, diagnosis and prevention. RESULTS: Having knowledge on toxoplasmosis was confirmed by 64 (64.0%) examined women, 40.6% (26/64) of whom learned about toxoplasmosis through the Internet, 48.4% from physicians, and 10.9% from friends. Increase in the degree of education was found to be associated with the probability that pregnant women would be informed via the Internet (RR=3.15, 95% CI=1.27-7.82, p=0.013). Analysis of four interactive websites (allowing users to ask questions) showed that routes of infection were the most common concern, particularly the risk presented by pet cats and dogs, followed by the diagnosis of infection (who and when should be tested, and how should the results be interpreted). Of 20 sites containing educational articles, only seven were authorized and two listed sources. Evaluation confirmed that information relevant to pregnant women was significantly more accurate than comprehensive, but no site gave both comprehensive and completely accurate information. Only four sites (20%) were good sources of information for pregnant women. CONCLUSION: Internet has proved itself as an important source of information. However, despite numerous websites, only a few offer reliable information to the Serbian (or Croat) speaking community, and none present complete and accurate information relevant to pregnant women. PMID- 26506755 TI - Astasia-Abasia and Ganser Syndrome in a Preadolescent Girl: A Case Report. AB - INTRODUCTION: Astasia is the inability to maintain an upright body position without assistance in the absence of motor weakness or sensory loss. Abasia is described as the inability to walk or as uncoordinated walking, while preserving mobility of the lower limbs. Ganser syndrome is described as a dissociative disorder characterized by approximate answers, somatic conversion symptoms, clouding of consciousness, as well as visual and auditory pseudohallucinations. The aim of this study is to present a case that seemed like a combination of neurological and internal disturbances, but actually represented a psychogenic disorder. CASE OUTLINE: This paper presents the case of a 13-year-old patient with the first manifestation of the inability to walk and stand. Medical history, diagnostic instruments and differential diagnostic methods have been presented in detail. The clinical manifestation was initially interpreted as a neurological disorder. However, after the application of diagnostic procedures and a change in family circumstances, the patient was diagnosed with a psychogenic movement disorder, astasia-abasia, with progressive clinical presentation that included dissociative psychotic reactions (Ganser syndrome). Differential diagnosis as well as the elements of the therapeutic approach have been discussed. CONCLUSION: Presenting a case of psychogenic astasia-abasia in children contributes to a better understanding and differentiating between conditions with a clinical presentation of signs and symptoms dealt with by other branches of medicine. PMID- 26506756 TI - Unilateral Adie's Tonic Pupil and Viral Hepatitis - Report of Two Cases. AB - INTRODUCTION: Adie's (tonic) pupil is a neuro-ophthalmological disorder characterized by a tonically dilated pupil, which is unresponsive to light. It is caused by damage to postganglionic fibers of the parasympathetic innervation of the eye, usually by a viral.or bacterial infection. Adie's syndrome includes diminished deep tendon reflexes. OUTLINE OF CASES: We report data of a 59-year old female with unequal pupil sizes. She complained of blurred vision and headache mainly while reading. She had a 35-year history of hepatitis B and liver cirrhosis. On exam, left pupil was mydriatic and there was no response to light and at slit lamp we saw segments of the sphincter constrict. We performed 0.125% pilocarpine test and there was a remarkable reduction of size in the left pupil. The second case is a 55-year-old female who was referred to the University Eye Clinic because of a headache and mydriatic left pupil. She had diabetes mellitus type 2, as well as hepatitis A virus 20 years earlier. On exam, the left pupil was mydriatic, with no response to light. Test with diluted pilocarpine was positive. Neurological examinations revealed no abnormality in either case so we excluded Adie's syndrome. CONCLUSION: Adie's tonic pupil is benign neuro ophthalmological disorder of unknown etiology. Most patients commonly present no symptoms and anisocoria is noticed accidentally. Although the etiology is unknown, there are some conditions that cause tonic pupil. It may be a part of a syndrome in which tonic pupil is associated with absent deep tendon reflexes. PMID- 26506757 TI - The Lipomatosis of the Parapharyngeal and Retropharyngeal Space: A Case Report. AB - INTRODUCTION: Lipomas are the most common benign mesenchymal tumors, which account for almost 50% of all soft-tissue tumors. CASE OUTLINE: The case of a 75 year-old patient with a slow growing lesion of para- and retropharyngeal space was reported. The patient was suffering from progressive dysphagia, respiratory obstruction and sleep apnea. CONCLUSION: An external surgical approach is the treatment of choice. Etiology, differential diagnosis and therapy of head and neck lipomas has been discussed. PMID- 26506758 TI - Inflammatory Myofibroblastic Tumours of the Respiratory Tract: A Series of Three Cases with Varying Clinical Presentations and Treatment. AB - INTRODUCTION: Inflammatory myofibroblastic tumor in the respiratory system is a rare and controversial disease. It is macroscopically well-circumscribed, non encapsulated, firm and usually a yellowish-white mass. Histologically it is composed of the following spindled and inflammatory cells: lymphocytes, plasma cells, and histiocytes, including Touton type multinucleated giant cells. CASE OUTLINE: The series included a 49-year-old man with a tracheal inflammatory myofibroblastic tumor who complained of hoarseness; a 42-year-old man who was coughing and had a blood-stained sputum, and inflammatory myofibroblastic tumor was in the right main and intermediate bronchus; and a 32-year-old man with chest pain and inflammatory myofibroblastic tumor as a solitary peripheral nodule in the left lower lobe. In all the cases, the tumor was resected bronchoscopically and surgically. CONCLUSION: Inflammatory myofibroblastic tumor of the lung and the trachea is rare. Complete resection, when possible, should be the choice of treatment. After the complete removal, prognosis is generally excellent and recurrences are rare. PMID- 26506759 TI - Hybrid Procedure for a Descending Thoracic and Subclavian Artery Aneurysm in a Patient with Previous Abdominal Aortic Surgery: Case Report. AB - INTRODUCTION: Hybrid procedures represent staged or simultaneous endovascular and open surgical techniques in the treatment of complex pathologies of the thoracic and abdominal aorta. We are presenting a patient with previous abdominal aortic surgery in whom hybrid vascular procedure for descending aorta and left subclavian artery aneurysm was performed. CASE OUTLINE: A 63-year-old female patient was admitted for computed tomography angiography. Descending aorta aneurysm (7.6 cm) as well as aneurysm of the left subclavian artery (LSA) was noted. Eight years ago she underwent abdominal aortic aneurysm resection and aortoiliac bypass. Standard TEVAR (thoracic endovascular aortic repair) procedure couldn't be done due to small dimensions of previous "Y" graft (12x6 mm), so first we did LSA transposition and after three days hybrid procedure. After "Y" graft exposure, anastomosis between the corps of "Y" graft and tubular graft 10 mm was created and through this conduit thoracic stent-graft was placed followed by complete "Y"graft replacement. After 6 months angiography showed regular postoperative findings. CONCLUSION: Combined surgical and endovascular procedures in thoracic aorta pathology treatment could be useful solutions with favorable outcome. PMID- 26506760 TI - Anaphylaxis on Graft Reperfusion during Orthotopic Liver Transplantation: A Case Study. AB - INTRODUCTION: Hemodynamic instability is a common occurrence during liver transplantation (LT). Hypotension and hemodynamic instability during graft reperfusion are most commonly consequences of the postreperfusion syndrome (PRS). CASE OUTLINE: In this report, we present a case of severe cardiovascular collapse leading to cardiac arrest which occurred in the course of graft reperfusion during LT. Persistent hypotension, non-responsive to regular measures such as volume filling and the use of vasopressors, yielded the question of whether other mechanisms were involved in causing it. Diffuse redness of the face and body, swelling of the face, lips and tongue with tongue prolapse, accompanied with severe cardiovascular collapse indicated that it was an anaphylactic reaction. This caused a dilemma as to what instigated the reaction. The trigger may have been the pharmacological substance administered during the graft reperfusion, or the one administered immediately prior to the reperfusion.The substances in question would most likely be either the University of Wisconsin preservation solution (UW), which was administered during the reperfusion, or Hepatect, which the patient received immediately prior to reperfusion. CONCLUSION: The clinical syndrome resulting from degranulation of mast cells and basophils in anaphylaxis is very similar to the PRS in LT. Clinical features play the most important role in establishing a timely diagnosis and early treatment of anaphylaxis. Swift administration of epinephrine reduces the chances of a fatal outcome. Better information on both donor and recipient can improve the efficiency of therapy and prophylaxis for anaphylaxis. PMID- 26506761 TI - Isolated Fallopian Tube Torsion - A Challenge for the Timely Diagnosis and Treatment. AB - INTRODUCTION: Isolated torsion of the fallopian tube is a rare cause of acute lower abdominal pain and infrequent indication for surgical treatment. CASE OUTLINE: A 16-year-old girl was referred to the hospital due to the non-specific symptoms over period of a few months and pain acutization in the right infraumbilical region lasting for two days. Complete laboratory analyses were normal. Ultrasound examination revealed a round mass (23x14 mm) within the right fallopian tube with color Doppler whirlpool sign, normal ovary, and a simple ipsilateral paratubal cyst (50x40 mm). Laparoscopy showed a dilated and two times torquated right fallopian tube, as well as signs of chronic appendicitis. The tube was twisted about its longitudinal axis and it was livid, but not gangrenous. After appendectomy, fallopian tube was detorquated, cyst extracted and preservation of the tube was performed. Postoperatively, antibiotic therapy was administered based on antibiogram. On follow-up examinations within the next four months postoperative course was uneventful. CONCLUSION: Since there are no pathognomonic symptoms, clinical or laboratory findings, diagnosis of this condition is challenging. Familiarity with Doppler whirlpool sign can enable a timely diagnosis and treatment of isolated fallopian tube torsions. However, the diagnosis is rarely made before operation. Unlike in our case, surgery is often performed too late, and delay of intervention may result in failure to save the fallopian tube. PMID- 26506762 TI - Streptococcal Necrotizing Fasciitis with Toxic Shock Syndrome and Rapid Fatal Outcome. AB - INTRODUCTION: Streptococcal necrotizing fasciitis (NF) is a serious soft tissue infection with rapid progression of inflammatory process among superficial or deep fascia, systemic host response to infection leading to toxic shock syndrome (TSS), and multiple organ failure. Lethality is high. CASE OUTLINE: A 46-year-old male without co-morbidities was admitted to the Emergency Department with redness, swelling and pain on his right lower leg. He became sick two days earlier with malaise, chills and shivering. On admission he was hypotensive, anuric, with erythematous rash on his face, neck and chest, with acute renal failure and elevated creatine phosphokinase level. During the next several hours, the changes on his right lower leg rapidly spread to the whole leg, followed by skin destruction and subcutaneous bleeding, indicating NF. Aggressive antimicrobial, supportive and symptomatic therapy was initiated immediately and on the same evening surgical intervention was performed. Despite these measures, a rapid development of severe TSS, with lethal outcome, occurred in less than 40 hours after the admission. Streptococcus pyogenes (group A beta-hemolytic Streptococcus) was isolated from the throat, skin and tissue obtained during the surgery. CONCLUSION: Necrotizing fasciitis is a very serious disease with unpredictable course. For that reason doctors must devote a great deal of attention to early, i.e. timely diagnosis of this disease, whose treatment with a multidisciplinary approach is very important. PMID- 26506763 TI - Techniques of the Tympanomastoidectomy with Reconstruction of the Posterior Bone Wall of the External Auditory Canal. AB - A combined tympanoplasty method, the mobile-bridge tympanoplasty, has been applied at the Clinic for Ear, Nose and Throat Diseases in Novi Sad since 1998. Mobile-bridge tympanoplasty is performed at our Clinic by applying Feldmann's procedure utilizing a microsurgical oscillating saw. It is a combination of closed and open techniques for surgical treatment of middle ear diseases. In addition to this technique, a method for reconstruction of the posterior bone wall of the external auditory canal was introduced. This procedure is applied in cases of damage or impairment of the bony ear canal wall using mastoid cortical temporal bone graft or modeled cartilage of the concha. Maintenance of general anatomical relations in the middle ear enables good ventilation of pneumatic spaces of the middle ear and Eustachian tube permeability, thus providing good conditions for ossicular chain reconstruction. The incidence of recurrent cholesteatoma in combined mobile-bridge tympanoplasty and tympanoplasty with reconstruction of the posterior bone wall was 6% in total. The incidence values for the recurrent cholesteatoma in closed tympanoplasty and in cases of open techniques were 10%. Mobile-bridge tympanoplasty and reconstruction of the posterior bone wall of external auditory canal are methods of choice in surgical treatment of middle ear cholesteatoma that progressed to the attic space, sinus tympani and facial recess. PMID- 26506764 TI - [The Stem-Cell Application in Ischemic Heart Disease: Basic Principles, Specifics and Practical Experience from Clinical Studies]. AB - Longer life duration, different clinical presentations of coronary disease, as well as high incidence of comorbidity in patients with ischemic heart disease have led to an increase in the incidence of ischemic heart failure. Despite numerous and new treatment methods that act on different pathophysiological mechanisms that cause heart failure, and whose aim is to slowdown or stop the progression of this devastating disease, morbidity and mortality in these patients remain high. These facts have firstly led to the introduction of the experimental, and then clinical studies with the application of stem cells in patients with ischemic heart disease. Previous studies have shown that the application of stem cells is a feasible and safe method in patients with acute coronary syndrome, as well as in patients with chronic ischemic cardiomyopathy, but the efficacy of these methods in both of the abovementioned clinical syndromes has yet to be established.This review paper outlines the basic principles of treatment of ischemic heart disease with stem cells, as well as the experience and knowledge gained in previous clinical studies. PMID- 26506765 TI - Multiple Sharp Force Injuries to the Head - The Crime of Passion. AB - INTRODUCTION: The Institute of Forensic Medicine was founded by Professor Milovan Milovanovid (1884-1948) in 1923 as part of School of Medicine of the University of Belgrade, and also established the Institute's forensic collection worthy of a museum.This paper illustrates the way Professor Milovanovie made this collection into a teaching aid for student education. We present a case of crime of passion from the year 1931, from our Institute's collection. CASE OUTLINE: The victim was a 30-year-old woman with multiple stab wounds of the head, neck and arms. It was noted in the case history that the deceased woman was a maid with a wealthy merchant, as well as that she had "dubious morals" for that time, with three wooers at the same time. Injuries to the forearms and the index finger prove that the victim tried to defend herself. In the autopsy record there is a drawn figure of a kitchen knife with a rounded blade tip, which explains the absence of stab wounds to the skull, and the presence of the impression skull fractures and crushed skull bones. It was concluded that the death occurred due to exsanguination, in turn due to transection of the left carotid artery, probably caused by sharp force, while the manner of death was homicide. Some of the most prominent autopsy findings were multiple mutilating overkill sharp force injuries, localized on the head, indicated sexually motivated murder. CONCLUSION: Combining the museum specimen, diagrams with injuries, drawn figure of the kitchen knife used, and photographs taken during the autopsy and the police investigation, Professor Milovanovie was able to properly illustrate this intriguing case to students without a computer or a PowerPoint presentation. PMID- 26506766 TI - Benefits of Student-Centered Tandem Teaching in Medical English. AB - This paper addresses some of the key notions about English for special purposes with special regard to English for medical purposes. The content was determined by observations and based on authors' professional experience. The starting point of a medical English course is a thorough analysis of students' needs, which is then used in course design and definition of appropriate learning goals. The student is at the center of learning and it is necessary to establish a positive cooperation between students and teachers. As medical English course is highly context-based, the inclusion of medical teachers can offer many opportunities for a successful learning process. PMID- 26506767 TI - [Work environments and mortality attributable to smoking: a study among male citizens from 2010 to 2012 in Tianjin, China]. AB - OBJECTIVE: To analyze the mortality attributable to smoking in different work environments among male citizens in Tianjin, China, and to provide scientific evidence for banning smoking in workplaces and public places. METHODS: The data of 38 312 male deaths 18-69 years of age in Tianjin from 2010 to 2012 were collected. The risk of death due to lung cancer and cardiovascular diseases attributed to smoking in different work environments was analyzed. RESULTS: Among the male deaths 18-69 years of age in Tianjin, 22.57% were caused by smoking, and the life scan of smokers was shortened by 5 years on average. The smokers who started smoking at an early age and had high dialy cigarette consumption were at high risk of death.The risk of death due to cardiovascular and cerebrovascular diseases among workers in indoor workshop(OR=1.82,95%CI: 1.55 2.15), indoor office personnel (OR=1.59, 95%CI: 1.39-1.81) Indoor public places (OR=1 .55, 95%U: 1.19 2.01) were higher than outdoor workers (OR=1.23,95%CI: 1.12-1.35). The risk of death due to lung cancer among workers in indoor workshop (OR =3.80,95% CI: 3.03-4.76), indoor office personnel (OR =3.04,95% CI: 2.48-3.73) Indoor public places (OR =4.63,95% CI:3.08-6.96)were higher than outdoor workers (OR 2.57,95% CI:2.22-2.97). The risk of death due to lung cancer and cardiovascular diseases among indoor workers was higher than that among outdoor workers. The risk of death due to lung cancer among indoor workers in public places who started smoking when they were younger than 18 years of age was higher than those among outdoor workers and other indoor workers. CONCLUSION: Smoking is a major risk factor for mortality among male citizens in Tianjin, and also a key factor for the loss of labor productivity. Indoor workers have a higher risk of mortality than outdoor workers. In order to reduce the mortality attributable to smoking, effective actions should be taken as soon as possible to ban smoking in indoor workplaces. PMID- 26506768 TI - [Impact of work-related musculoskeletal disorders on work ability among workers]. AB - OBJECTIVE: To assess the impact of work-related musculoskeletal disorders (WRMDs) on work ability among workers. METHODS: A total of 1686 workers in various occupations, such as administration and education, were enrolled as subjects using the random cluster sampling method. The WRMDs and work ability of all subjects were evaluated using standardized Nordic questionnaires for the analysis of musculoskeletal symptoms and the Work Ability Index (WAI) scale, respectively. Comparison of work ability and its classification between the disease group and the non-disease group was performed by paired t test, RxC table chi2 test, and the Wilcoxon rank-sum test. The relationship between work duration and work ability was analyzed by the Spearman correlation test and a multi-level model. RESULTS: (1). The work ability of workers in the disease group was significantly lower than that in the non-disease group (P<0.0 1). (2) There were significant differences in work ability between workers with different work durations (<10 years, 10-20 years, and >=20 years) (F=22.124, P< 0.01). With the increase in work duration, the work ability of workers declined in both groups, and the work ability of workers in the disease group (Spearman coefficient rs=-0. 172, P<0.01) had a more significant decline than that in the non-disease group (Spearman coefficient rs=-0.104, P<0.01). WRMDs were important risk factors for the decrease in work ability among workers. (3) There were significant differences in constituent ratios and levels of work ability classification between the disease group and the non-disease group (chi2=121.097, P<0.01; Z=-10.699, P<0.01). The proportions of workers with poor and medium work ability in the disease group were significantly higher than those in the non-disease group, while the proportion of works with excellent work ability in the disease group was significantly lower than that in the non-disease group. The similar characteristics in constituent ratios and levels of work ability classification could be found between the disease group and the non- disease group in various occupations (P<0.01). CONCLUSION: WRMDs have a harmful effect on the work ability of workers, and the work ability of workers substantially declines with the increase in exposure time (work duration). PMID- 26506769 TI - [A study of divalent metal transporter 1 and ferroportin 1 in brain of rats with manganese-induced parkinsonism]. AB - OBJECTIVE: To study the changes in the expression of divalent metal transporter 1 (DMT1) and ferroportin 1 (FP1) in the substantia nigra (SN) of rats with manganese-induced parkinsonism. METHODS: Eighty Sprague-Dawley rats were randomly divided into four groups. Rats in the control group were injected intraperitoneally with saline solution. Rats in the low-dose, medium-dose, and high-dose groups were injected intraperitoneally with 5, 15, and 20 mg/kg MnC12 solution, respectively, for 16 weeks. Three behavioral tests were performed at the 16th week. The concentration of Mn2+ in the SN was determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES), and the positive expression of tyrosine hydroxylase (TH) was measured by immunohistochemical staining to determine whether rats with manganese-induced parkinsonism were successfully produced. The expression of DMT1 and FP1 in SN was measured by immunohistochemical staining and fluorescent quantitative polymerase chain reaction. RESULTS: Rats with manganese-induced parkinsonism were successfully produced using the above method. Compared with that in the control group, the concentrations of Mn2+ in the SN of rats exposed to 5, 15, and 20 mg/kg Mn2+ were significantly higher (1.72?0.33 vs 0.56 +/- 0.20 ug/g, P<0.01; 2.92+/-0.77 vs 0.56+/-0.20 ug/g, P<0.01; 5.65+/-1.60 vs 0.56+/-0.20 ug/g, P<0.01). The mean ODs of TH-positive cells in the SN of rats exposed to 5, 15, and 20 mg/kg Mn+ were significantly lower than that in the control group (0.054+/-0.008 vs 0.109+/ 0.019, P<0.01; 0.016+/-0.004 vs 0.109+/-0.019, P<0.01; 0.003+/-0.001 vs 0.109+/ 0.019, P<0.01). Compared with that in the control group, the mean optical densities (ODs) of DMT1-positive cells in the SN of rats exposed to 15, and 20 mg/kg Mn2+ were significantly higher (0.062+/-0.004 vs 0.015+/-0.007, P<0.01; 0.116+/-0.064 vs 0.015+/-0.007, P<0.01). The mean ODs of FP1-positive cells in the SN of rats exposed to 5, 15, and 20 mg/kg Mn2+ were significantly lower than that in the control group (0.092+/-0.011 vs 0.306+/-0.081, P<0.01; 0.048+/-0.008 vs 0.306+/-0.081, P<0.01; 0.008+/-0.002 vs 0.306+/-0.081, P< 0.01). Rats exposed to 15 and 20 mg/kg Mn2+ had significantly higher expression of DMT1 mRNA in the SN than those in the control group (0.052+/-0.0126 vs 0.001+/-0.0004, P<0.05; 0.124+/-0.0299 vs 0.001+/-0.0004, P<0.05). However, rats exposed to 5, 15, and 20 mg/kg Mn2 had significantly lower expression of FP1 mRNA in the SN than those in the control group (0.059+/-0.0076 vs 0.162+/-0.0463, P<0.05; 0.033+/-0.0094 vs 0.162+/-0.0463, P< 0.05; 0.002+/-0.0007 vs 0.162+/-0.0463, P<0.05). CONCLUSION: The increased expression of DMT1 and reduced expression of FP1 may be involved in the processes of Mn2+ accumulation in the SN and dopaminergic neuron loss in rats with manganese-induced parkinsonism. PMID- 26506770 TI - [Investigation of current cognition of occupational exposure to HIV in healthcare workers in Liuzhou, China]. AB - OBJECTIVE: To investigate the current cognition of occupational exposure to human immunodeficiency virus (HIV) and the personal occupational protection awareness in healthcare workers in Liuzhou, China. METHODS: A total of 270 healthcare workers were selected from 10 hospitals in Liuzhou by stratified random sampling for a cross-sectional study. And a self-administered questionnaire of occupational exposure to HIV was designed to conduct a survey. The descriptive analysis of data was carried out by Excel. And a logistic regression analysis was done to analyze the effects of different factors on healthcare workers' cognition of occupational exposure to HIV using the statistical analysis software SPSS 19.0. RESULTS: A total of 260 usable questionnaires (96.3%) were returned. Among them, 220 healthcare workers (84.6%) had received the trainings on occupational exposure to HIV; 223 healthcare wofkers (85.8%) were aware of the rules and regulations on prevention of occupational exposure to HIV and the operation procedures in their hospitals. The healthcare workers who had not received the trainings or had not known the rules and regulations and the operation procedures were mainly from primary or secondary hospitals. A total of 106 healthcare workers (40.8%) had directly contacted patients' blood or body fluids; 154 healthcare workers (59.2%) were injured by sharp instruments, and most were hollow needle stick injuries (98/154, 63.6%). A total of 168 healthcare workers (68.08%) had better cognitive awareness of occupational exposure to HIV, and 76 healthcare workers (29.2%) had moderate cognitive awareness. Some healthcare workers had poor knowledge in the common sense of AIDS/HIV and occupational exposure to HIV, the personal protection awareness of occupational exposure, or the disposal measures after occupational exposure. The univariate analysis using chi-square test showed that occupation and professional title were significantly correlated with the cognition (P<0.05). The multivariate logistic regression analysis showed that the doctors (OR3.8; P<0.05), nurses (OR3.04, P<0.05), and laboratory technicians (OR=9.51, P<0.05) had better awareness compared with the others. The healthcare workers with a primary or lower professional title had poorer awareness compared with the healthcare workers with a higher professional title (OR=0.47, P<0.05). CONCLUSION: Healthcare workers have the risk of occupational exposure to HIT. They do not have comprehensive and systematic knowledge related to occupational exposure to HIV, and they have a high demand for training. PMID- 26506771 TI - [Development of knowledge, attitude and practice questionnaire on prevention and control of occupational diseases]. AB - OBJECTIVE: To develop the knowledge, attitude and practice questionnaire on the prevention and control of occupational diseases for occupational groups, and to provide a convenient and effective tool for the survey of knowledge, attitude, and behavior on the prevention and control of occupational diseases in occupational groups and the evaluation of intervention effect. METHODS: The initial questionnaire which was evaluated by the experts was used to carry out a pre-survey in Guangzhou, China. The survey results were statistically analyzed by t test, identification index method, correlation analysis, and Cronbach's a coefficient method. And then the questionnaire was further modified, and the content of the questionnaire was determined finally. RESULTS: After modification, there were 18 items on knowledge, 16 items on attitude, and 12 items on behavior in the "Knowledge, attitude and practice questionnaire on the prevention and control of occupational diseases for enterprise managers"; there were 19 items on knowledge, 10 items on attitude, and 11 items on behavior in the "Knowledge, attitude and practice questionnaire on the prevention and control of occupational diseases for workers". CONCLUSION: The knowledge, attitude and practice questionnaire on the prevention and control of occupational diseases for occupational groups is developed successfully, and it is a convenient and effective tool for the survey of knowledge, attitude, and behavior on the prevention and control of occupational diseases in occupational groups and the evaluation of intervention effect. PMID- 26506772 TI - [Epidemiological analysis of heat stroke from 2009 to 2013 in Wuhan, China]. PMID- 26506773 TI - [Analysis of risk factors for hypertension among taxi drivers on different shifts]. AB - OBJECTIVE: To investigate the incidence and risk factors for hypertension among taxi drivers working different shifts. METHODS: Using the cluster sampling method, 415 day-shift and 304 night-shift taxi drivers in Jinan, China were selected and investigated. The influencing factors for hypertension were analyzed. RESULTS: The incidence of hypertension in all taxi drivers was 33.2%. The incidence of hypertension in night-shift drivers was significantly higher than that in day-shift drivers (37.8% vs 29.9%, P<0.05). According to multivariate analysis, the incidence of hypertension in day-shift drivers was closely related to body mass index (BMI), working years, working hours, sleep duration, rest days, diet quality, water intake, and smoking, while the incidence of hypertension in night-shift drivers was closely related to BMI, working years, working hours, part-time job, sleep duration, rest days, and drinking. CONCLUSION: BMI, working years, and working hours are the common risk factors for hypertension in day-shift and night-shift drivers. Sleep duration and rest days are the common protective factors. The risk factors for hypertension in taxi drivers vary with different shifts. PMID- 26506774 TI - [Survey of occupational health condition in a shipyard in Guangzhou, China]. AB - OBJECTIVE: To investigate the occupational health condition in a shipyard in Guangzhou, China, and to provide a basis for improving the working environment. METHODS: The monitoring data on occupational harmful factors in the workplace and the data on health examination of the workers were analyzed, and the occupational health condition in the shipyard was evaluated with the related occupational health standards. RESULTS: Except benzene, toluene, and electromagnetic radiation, the dust (2.02%), grinding wheel dust (3.85%), wood dust (2 out of 4 workers exceeded the standard), welding fume (16.85%), manganese dioxide (17.98%), dimethylbenzene (8.00%), and noise (53.20%) were all out of limits to different degrees. The health examination results of 2450 workers in the shipyard showed that the respiratory impairment of dust-exposed workers (3.19%) and the hearing impairment of noise-exposed workers (12.21%) were comparatively severe. CONCLUSION: The occupational health condition in this shipyard is not good. In order to protect the workers from health hazards, it is urgent and necessary to improve the working environment and strengthen the personal protective measures. PMID- 26506775 TI - [Analysis of the control effect of peer support for electrical workers with hypertension disease]. PMID- 26506776 TI - [The influence of dichloromethane on oxidotive stress in mouse liver]. PMID- 26506777 TI - [Effect of noise on antioxidant capacity of brain tissue in guinea pigs]. AB - OBJECTIVE: To investigate the effect of noise on the antioxidant capacity in different regions of brain tissue in guinea pigs. METHODS: Thirty male white red eye guinea pigs were equally and randomly divided into five groups: 1-, 3-, 7-, and 14-day groups after noise exposure and control group. The guinea pigs of the experimental groups were exposed to steady white noise with a sound pressure level at 100 dB for 8 h per day and for 2 consecutive days. The auditory brainstem response (ABR) of guinea pigs, as well as the glutathione (GSH) level, methane dicarboxylic aldehyde (MDA) level, and superoxide dismutase (SOD) activity in the cerebrum, cerebellum, and hippocampus, was determined prior to and 1, 3, 7, and 14 days after noise exposure. RESULTS: After noise exposure, the shifts in ABR threshold of the experimental groups were significantly higher than that of the control group (P<0.05). Compared with those in the control group, the SOD activity and GSH level both significantly decreased in the cerebrum tissue of each experimental group after noise exposure (P<0.05) and MDA content significantly increased in the 1-day group (P<0.05). As for cerebellum tissue, the SOD activity and GSH level in the 7-day group were significantly lower than those in the control group (P<0.05), but there was no difference in MDA level between each experimental group and the control group (P>0.05). In comparison with those in the control group, the GSH and MDA levels in the 1-day group after noise exposure were significantly higher, and the GSH and MDA levels in the 3-day group and the MDA level in the 7-day group after noise exposure were significantly lower (all P<0.05). CONCLUSION: Noise exposure can lead to hearing loss and affect the antioxidant capacity of brain tissue, which indicates that the improvement in antioxidant levels may alleviate noise-induced damage. PMID- 26506778 TI - [Clinical analysis of Ginkgo biloba injection combined with traditional therapy in treatment of explosive deafness]. AB - OBJECTIVE: To investigate the clinical efficacy of Ginkgo biloba injection combined with traditional therapy in the treatment of explosive deafness. METHODS: Fifty-six (98 ears) participants who were all coal miners were selected. These patients were diagnosed with explosive deafness. and admitted to the otolaryngology department of our hospital from May 2010 to October 2013. They were.equally divided into control group and treatment group according to the therapeutic method. The patients in the control group only received traditional therapy, such as hyperbaric oxygen, while the patients in the treatment group were given Ginkgo biloba injection in addition to the therapy for the control group. The improvement in hearing was recorded and compared between the two groups. RESULTS: The rate of improvement in tinnitus symptom in the treatment group was 78.0% (32/41), significantly higher than that in the control group (55.6%, 25/45) (chi2=4.857, P<0.05); compared with the treatment group (93.5%, 43/46), the control group had a significant lower overall response rate at 76.9% (40/52) (chi2=5.160, P<0.05). CONCLUSION: Compared with traditional therapy alone, combined ginkgo biloba extract injection and traditional therapy can significantly improve tinnitus symptom and overall response rate in the treatment of explosive deafness in coal miners, which suggests that the combination therapy is worthy of clinical application. PMID- 26506779 TI - [Application of arthroscopic technique in knee osteoarthritis of oil field mine workers]. PMID- 26506780 TI - [Clinical observation of using integrative medicine to treat 58 cases cement mill workers with pneumoconiosis]. PMID- 26506781 TI - [Analysis of eye ultrasonography in patients with trinitrotoluene cataract]. AB - OBJECTIVE: To evaluate the diagnostic value of ultrasonography for trinitrotoluene (TNT) cataract. METHODS: The morphology and internal echoes of 90 lenses of 45 TNT cataract patients and 120 lenses of 60 healthy adults were observed and compared using ultrasonography and slit lamp, and the hemodynamic parameters of the post-ophthalmic artery were also measured. The findings of the slit-lamp microscope were regarded as diagnostic criteria, and the sensitivity, specificity, and accordance rate of ultrasonography in the diagnosis of TNT cataract were calculated. RESULTS: The sensitivity, specificity, and accordance rate of ultrasonography in the diagnosis of TNT cataract were 93.33%, 100.00%, and 97.14%, respectively; the positive and negative predictive values were 100% and 95.23%, respectively; the positive and negative likelihood ratios were 93.33 and 0.67, especuvey. With the progression TNT cataract, utrasonography showed that the lenses demonstrated morphological changes (spindle-shaped, spherical, and discoid morphologies), and the arc echoes of the posterior capsule were thickened and enhanced. The TNT cataract patients showed significantly lower peak systolic velocity and end-diastolic velocity of the ophthalmic artery (OA) and central retinal artery (P<0.01) and a significantly higher resistance index (P<0.05) than the healthy adults. CONCLUSION: The sensitivity of ultrasonography in the diagnosis of TNT cataract is similar to that of slit lamp. Ultrasonography can demonstrate objectively the shape, range, and degree of lens opacity in an efficient manner, which is conducive to the diagnosis and staging of TNT cataract by slit lamp, and can also provide hemodynamic information of the OA, thus providing new ideas for clinical physicians in evaluating the disease and clinical efficacy as well as exploring therapies. PMID- 26506782 TI - [The successful treatment of children by paraquat poisoning].